TW200823216A

TW200823216A - Combination therapies for rheumatoid arthritis

Info

Publication number: TW200823216A
Application number: TW096132844A
Authority: TW
Inventors: Paul Steven Changelian; Samuel Hyman Zwillich
Original assignee: Pfizer Prod Inc
Priority date: 2006-09-05
Filing date: 2007-09-04
Publication date: 2008-06-01
Also published as: WO2008029237A3; JP2008069149A; AR062658A1; WO2008029237A2

Abstract

This disclosure relates to pharmaceutical combination therapies for the treatment or prevention of arthritis, such as rheumatoid arthritis, in a human comprising a Janus Kinase inhibitor or a pharmaceutically acceptable salt thereof and at least one anti-arthritic agent or a pharmaceutically acceptable salt thereof. This disclosure also relates to certain methods for treating or preventing arthritis, such as rheumatoid arthritis, in a human comprising co-administering to a human a Janus Kinase inhibitor or a pharmaceutically acceptable salt thereof and at least one anti-arthritic agent or a pharmaceutically acceptable salt thereof.

Description

200823216 九、發明說明：【發明所屬之技術領域】發明領域本揭示内容係有關於用於治療或預防人類之關節炎病 _ 5症或症狀。諸如類風濕性關節炎的藥學組合治療物，其勹括傑納斯激酶抑制劑，諸如目前揭示之吡咯并[2 3引旅一化合物，或其藥學上可接受鹽，其係為蛋白質激畴，]^ ( _，傑納斯激酶3(有時在文中稱為JAK3)之抑制劑；及至、少一種抗關節炎藥劑或其藥學上可接受鹽。本揭示内容亦 10有關於用於治療或預防此等關節炎病症或症狀之方法與此等藥學組合治療物及其藥學組成物之用途。〃發明背景 MK3為蛋白質鱗之傑簡族n雖然該族之其 :15它成s本質上由所有组織表現，但是;ΑΚ3表現性限於造^ ( 細胞。其與藉JAK3#〇IL_2、IL_4、IL_7、IL_9、化_15、及il_2i 之多鏈受體共有的r鏈非共價鍵結而傳訊之基本功用一致SCID病患人口業經確認具有嚴重減少量之认幻蛋白質或對"有r鏈有透傳缺陷，其表示免疫抑制應該起因於經由該MK3路徑而阻斷傳訊。動物研究已表示JAK3不僅在B 及τ淋巴細胞成熟中扮演重要角色，而且胤3在原構性上為維持Τ細胞機能所必需。經由本新職制而調節免疫活性之方法證明可適用於治療τ細胞增生病症，諸如移植排斥及自體免疫疾病，諸如類風濕性關節炎。 5 200823216 使用ϋ比洛并[2,3-d],咬化合物治療或預防類風濕性關節炎之先前方法揭示在美專利第7,〇9 L2Q8號中，該專利案之内容實際上在此併入本案以為參者資料。文中討論之特定t各并[2,3-d]嘧啶化合物亦揭示在美國專利第6,627,754 5號及美國專利公開案第2003/0073719號中，這兩種專利案之内容實際上在此併入本案以為參考資料。現在已發現含特定傑納斯激酶抑制劑，諸如現在揭示之吡咯并卩，3_d]嘧 %化合物之特疋藥學組合治療物能有效治療或預防人類之關即或症狀’諸如關節炎，其包括類風濕性關節炎。 10 【】發明概要 1不㈣—方面係有關於用於治療或預防人類之類風濕性關節炎的藥學έ人 ' 、'’ Ό ^療物，其包含傑納斯激酶抑制劑或其藥學上可接受_ 1別 15 上可接受鹽。 I至〉、-種抗_炎_或其藥學下式化合物特疋實化例中，該傑的斯激酶抑制劑為200823216 IX. INSTRUCTIONS: FIELD OF THE INVENTION The present disclosure relates to the treatment or prevention of arthritis or symptoms in humans. A pharmaceutical combination therapy such as rheumatoid arthritis, which includes a Janus kinase inhibitor, such as the currently disclosed pyrrole [2 3], or a pharmaceutically acceptable salt thereof, which is a protein domain ,]^ ( _, an inhibitor of Janus kinase 3 (sometimes referred to herein as JAK3); and at least one anti-arthritic agent or a pharmaceutically acceptable salt thereof. The present disclosure also relates to treatment Or a method for preventing such arthritic conditions or symptoms and the use of such pharmaceutical combination therapeutics and pharmaceutical compositions thereof. 发明 BACKGROUND OF THE INVENTION MK3 is a protein scale of the Jane family, although the family of it: 15 it becomes s essentially Expressed by all tissues, however; ΑΚ3 expression is limited to the formation of cells (the cells with r-chain non-covalent bonds shared by the multi-chain receptors of JAK3#〇IL_2, IL_4, IL_7, IL_9, _15, and il_2i The basic function of the communication is consistent with the fact that the SCID patient population has been confirmed to have a severely reduced amount of the peculiar protein or has a translocation defect in the r chain, which indicates that immunosuppression should result from blocking the communication via the MK3 pathway. Research has shown that JAK3 is not only in B It plays an important role in the maturation of τ lymphocytes, and 胤3 is necessary for maintaining the function of sputum cells in the original structure. The method of regulating immune activity via this new teaching system proves to be applicable to the treatment of tau cell proliferative disorders, such as transplant rejection and autologous Immune diseases, such as rheumatoid arthritis. 5 200823216 The previous method of treating or preventing rheumatoid arthritis using a bismuth compound [2,3-d] is disclosed in US Patent No. 7, 〇9 L2Q8 The contents of this patent application are hereby incorporated by reference in its entirety by reference in its entirety in the entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire all The contents of the two patents are hereby incorporated by reference in its entirety by reference to the entire disclosure of the entire disclosure of the disclosure of the disclosure of the entire disclosure of the disclosure of the disclosure of the disclosure of the disclosure of the disclosure of the disclosure of the disclosure of the disclosure of the disclosure of疋 Pharmaceutical combination therapy can effectively treat or prevent humans' symptoms or symptoms, such as arthritis, including rheumatoid arthritis. 10 [] Summary of Invention 1 (4) - Aspects A pharmaceutical remedy for treating or preventing rheumatoid arthritis in humans, which comprises a Janus kinase inhibitor or a pharmaceutically acceptable salt thereof. I to 〉 - an anti-inflammatory drug or a pharmaceutical compound of the following formula, wherein the Jasmin kinase inhibitor is

R3 1 或其藥學上可接受鹽；其中Η R1為下式基團 R5 R\N/(〇H2)y 6 20 200823216 其中y為0、1或2; R4係選自以下所組成之群組··氫、（CrC6)烷基、（CrC6) 烷磺醯基、（C^C：6)烯基、（CVC6)炔基，其中該烷基、烯基及炔基可選擇性經以下基團取代：氘、羥基、胺基、三氟 5甲基、(Ci-C4)烧氧基、（crc6)醯氧基、(c!-c6)烧胺基、（(CVC6) ^ 烷基)2胺基、氰基、硝基、（cvc6)烯基、（C2-C6)炔基或(CVC6) 醯胺基；或R4為(C3-C1G)環烷基，其中該環烷基可選擇性經以下基團取代：氣、經基、胺基、三氟甲基、（crc6)醯氧《基、（CrC6)醯胺基、（Q-C6)烷胺基、（(CVC6)烷基)2胺基、 10氰基、氰基(CrC6)烷基、三氟曱基(crC6)烷基、硝基、琐基(CrC6)烷基或(CrC6)醯胺基； R5為（C^-C9)雜環烧基，其中該雜環炫基必需經1至$種以下之基團取代：魏基、氰基、胺基、氣、經基、（CpCJ 烧基、（C1-C6)烧氧基、鹵素、（Ci_C6)醯基、（Ci-C6)燒胺基、 15 胺基(CVQ)烷基、（CrC6)烷氧基、-CO-NH、（CVC6)烧胺基， _CO-、（C2-C6)烯基、（C2-C6)块基、（Q-C6)烧胺基、經基(crc6) ^ 7 烧基、（Ci_C6)烧乳基(Ci_C6)烧基、（C^-Cg)酿氧基((^>^6)烧基、硝基、乳基(C「C6)烧基、鹵（c^-C6)烧基、石肖基(crc6) 烧基、三氟甲基、二氟曱基(C1-C6)烧基、（Ci-C6)酿胺基、 20 (CrC6雕胺基(Ci-C6)烧基、（Q-C6)烧氧基(crc6)^胺基、胺基(Ci_C6)酿基、胺基(Cl-C6)酿基(Ci_C6)院基、（(^-(^6)烧胺基（Ci_C6)醯基、（(Ci-C6)烧基）2胺基醯基、 r15r16n-co-〇-、R15R16N_c〇-(crc6)烧基、（cvc6)烷基 -s(0)m、R15R16NS(0)m、WMsewcvc,)烷基、 7 200823216 R15S(0)mR16N、R^SCCOmRWNCCrC^)烷基，其中m為0、1或 2，且R15及R16各獨立選自氫或(CrCJ烷基；或下式基團：R3 1 or a pharmaceutically acceptable salt thereof; wherein R 1 is a group of the formula R 5 R \ N / (〇 H 2 ) y 6 20 200823216 wherein y is 0, 1 or 2; R 4 is selected from the group consisting of Hydrogen, (CrC6)alkyl, (CrC6) alkanesulfonyl, (C^C:6)alkenyl, (CVC6)alkynyl, wherein the alkyl, alkenyl and alkynyl groups are selectively via Group substitution: hydrazine, hydroxy, amine, trifluoro 5 methyl, (Ci-C4) alkoxy, (crc6) decyloxy, (c!-c6) acryl, ((CVC6) ^ alkyl) 2Amino, cyano, nitro, (cvc6)alkenyl, (C2-C6)alkynyl or (CVC6)nonylamino; or R4 is (C3-C1G)cycloalkyl, wherein the cycloalkyl is optional Substituted by the following groups: gas, mercapto, amine, trifluoromethyl, (crc6) oxime ", (CrC6) decyl, (Q-C6) alkylamino, (CVC6) alkyl 2 Amino, 10 cyano, cyano (CrC6) alkyl, trifluoromethyl (crC6) alkyl, nitro, trimethyl (CrC6) alkyl or (CrC6) decylamino; R5 is (C^ -C9) a heterocyclic group in which the heterocyclic group has to be substituted with 1 to less than the following groups: a thiol group, a cyano group, an amine group, a gas group, a thiol group, (CpCJ alkyl group, (C1-C6) Alkoxy Halogen, (Ci_C6) fluorenyl, (Ci-C6) acrylamine, 15 amino (CVQ) alkyl, (CrC6) alkoxy, -CO-NH, (CVC6) acryl, _CO-, (C2 -C6) alkenyl group, (C2-C6) block group, (Q-C6) arunyl group, thiol (crc6)^7 alkyl group, (Ci_C6) succinyl group (Ci_C6) alkyl group, (C^-Cg Alkoxy ((^>^6) alkyl, nitro, lactyl (C "C6" alkyl, halogen (c^-C6) alkyl, schlossyl (crc6) alkyl, trifluoromethyl, Difluorodecyl (C1-C6) alkyl, (Ci-C6) an amine group, 20 (CrC6 acetamino group (Ci-C6) alkyl group, (Q-C6) alkoxy group (crc6) amine group, Amine (Ci_C6), amino (Cl-C6), (Ci_C6), ((^-(^6), amidino (Ci_C6) thiol, ((Ci-C6))) Amino fluorenyl, r15r16n-co-〇-, R15R16N_c〇-(crc6)alkyl, (cvc6)alkyl-s(0)m, R15R16NS(0)m, WMsewcvc,)alkyl, 7 200823216 R15S(0 mR16N, R^SCCOmRWNCCrC^)alkyl, wherein m is 0, 1 or 2, and R15 and R16 are each independently selected from hydrogen or (CrCJ alkyl; or a group of the formula:

其中a為0、1、2、3或4 ; 5 b、c、e、f及g各獨立為0或1 ; d為0、1、2或 3 ; X為s(0)n，其中η為0、1或2 ;氧、羰基或-C(=N-氰基)-; Y為S(0)n，其中η為0、1或2 ;或羰基；且 Ζ為羰基、C(0)0-、C(0)NR-或S(0)n，其中 η為0、1或2 ; 10 R6、R7、R8、R9、R10及R11各獨立選自以下所組成之群組··氫或可選擇性經氘、羥基、胺基、三氟甲基、（Q-C6) 醯氧基、（CrC6)醯胺基、（CrC6)烷胺基、（(CVC6)烷基)2胺基、氰基、氰基(Ci-Cd烷基、三氟甲基(CrCd烷基、硝基、硝基(CrC6)烷基或(Ci-C6)醯胺基取代之(cvc6)烷基； 15 R12為羧基、氰基、胺基、側氧基、氘、羥基、三氟甲基、（crc6)烷基、三氟甲基(crc6)烷基、（crc6)烷氧基、鹵素、（Crc6)醯基、（CrC6)烷胺基、（(CVC6)烷基)2胺基、胺基(CVC6)烷基、（CVC6)烷氧基-CO-NH、（CVC6)烷胺基 -CO-、（C2-C6)烯基、（C2-C6)炔基、羥基(CVC6)烷基、（cvc6) 20 烷氧基(CVC6)烷基、（CVC6)醯氧基(CVC6)烷基、硝基、氰 200823216 基(CrC6)烷基、鹵（crC6)烷基、硝基(CrC6)烷基、（CVC6) 醯胺基、（CVC6)醯胺基(crc6)烷基、（crc6)烷氧基(cvc6) 醯胺基、胺基(crc6)醯基、胺基(crc6)醯基(crc6)烷基、 (CVC6)烷胺基（Q-C6)醯基、（(crc6)烷基）2胺基（CVC6)醯 5 基、R15R16N-C0-0-、rMr^N-CCKCVQ)烷基、R15C(〇)NH、 r15oc(o)nh、r15nhc(o)nh、（CrC6)烷基-S(0)m、（Q-C6) 烷基-S(0)m-(crc6)炫基、R15R16NS(0)m、R15R16NS(0)m(Cl-C6) 烷基、R15S(0)mR16N、R15S(0)mR16N(CrC6)烷基，其中 m為〇、 1或2且R15及R16各獨立選自氫或烷基； 10 R2及R3各獨立選自以下所組成之群組：氫、氘、胺基、鹵素、經基、硝基、魏基、（C2_C6)浠基、（C2-C6)炔基、三氟甲基、三氟甲氧基、（CrC6)烷基、（CrC6)烷氧基、（C3_C一環烷基，其中該烷基、烷氧基或環烷基可選擇性經1至3種選自以下之基團取代：_素、羥基、羧基、胺基(CrC6)烷 15硫基、（crc6)烷胺基、（(crc6)烷基)2胺基、（c5-c9)雜芳基、 (C2-C9)雜環烷基、（C3-C9)環烷基或(C6-C1G)芳基；或RW 各獨立為（C3-C1G)環烷基、（C3-C1g)環烷氧基、（crc6)烷胺基、（(CrC6)烷基)2胺基、（C6-C1())芳胺基、（CVC6)烷硫基、 (CVCiq)芳硫基、（Ci_C6)烧亞績醯基、（CVCio)芳亞績酿基、 20 (CVC6)烧石黃醯基、（C6-Ci〇)芳石黃醯基、（Ci-C6)酿基、（crc6) 烷氧基-CO_NH-、（CrC6)烷胺基-CO-、（cvc9)雜芳基、（c2_C9) 雜環烷基或(C6-CiG)芳基，其中該雜芳基、雜環烷基及芳基可選擇性經1至3種以下基團取代：_素、（CVC6)烷基、（cvc6) 烷基-CO-NH-、（c「c6)烷氧基-CO_NH_、（crc6)烷基 9 200823216 -CO-NHKCVC^)烷基、（CrQ)烷氧基-CO-NIHCi-C^)烷基、 (CrC6)烷氧基_CO-NH-(CrC6)烷氧基、羧基、羧基(CrC6) 烷基、羧基(CrC6)烷氧基、节氧羰基(CrC6)烷氧基、（CrC6) 烷氧羰基(CrC6)烷氧基、（C6-C1())芳基、胺基、胺基(Q-C6) 5 烷基、（CrC6)烷氧羰基胺基、（C6-C1G)芳基(CVC6)烷氧羰基胺基、（CVC6)烷胺基、（(CVC6)烷基)2胺基、（crc6)烷胺基 (Crc6)烷基、（(CrC6)烷基)2胺基(CVC6)烷基、羥基、（crc6) 烷氧基、（CrC6)烷氧羰基、（CrCJ烷氧羰基(CrCO烷基、 (cvc6)烷氧基-CO-NH-、氰基、（C5-C9)雜環烷基、胺基 10 -CO-NH-、（CVC6)烷胺基-CO-NH-、（(Ci-Q)烷基）2 胺基 -CO-NH-、（C6-C1())芳胺基-CO-NH-、（C5-C9)雜芳胺基 -CO-NH-、（CrC6)烷胺基-CO-NiHCVC^)烷基、（(q-Q)烷基）2胺基-CO-NtHCVCO烷基、（C6-C1())芳胺基 -CO-NH-CCVC^)烷基、（C5-C9)雜芳胺基_CO_NH-(CVC6)燒基、（CVC6)烷磺醯基、（CVC6)烷磺醯胺基、（CVC6)烷磺醯胺基(CVC6)烷基、（C6-C1G)芳磺醯基、（C6_C1())芳磺醯胺基、 (C6-C1())芳磺醯胺基(crc6)烷基、（C5-C9)雜芳基或（c2_C9) 雜環烷基。在特定實施例中，該傑納斯激酶抑制劑為式I化合物； R1 R2Where a is 0, 1, 2, 3 or 4; 5 b, c, e, f and g are each independently 0 or 1; d is 0, 1, 2 or 3; X is s(0)n, where η Is 0, 1 or 2; oxygen, carbonyl or -C(=N-cyano)-; Y is S(0)n, where η is 0, 1 or 2; or carbonyl; and hydrazine is carbonyl, C(0 0-, C(0)NR- or S(0)n, where η is 0, 1 or 2; 10 R6, R7, R8, R9, R10 and R11 are each independently selected from the group consisting of: Hydrogen or optionally via hydrazine, hydroxy, amine, trifluoromethyl, (Q-C6) decyloxy, (CrC6) decylamino, (CrC6)alkylamino, ((CVC6)alkyl) 2 amine a cyano group, a cyano group, a cyano group (Ci-Cd alkyl group, a trifluoromethyl group (CrCd alkyl group, a nitro group, a nitro (CrC6) alkyl group or a (Ci-C6) amidino group-substituted (cvc6) alkyl group; 15 R12 is carboxy, cyano, amine, pendant oxy, hydrazine, hydroxy, trifluoromethyl, (crc6)alkyl, trifluoromethyl (crc6)alkyl, (crc6) alkoxy, halogen, ( Crc6) mercapto, (CrC6)alkylamino, ((CVC6)alkyl) 2 amine, amine (CVC6) alkyl, (CVC6) alkoxy-CO-NH, (CVC6) alkylamino-CO -, (C2-C6) alkenyl, (C2-C6) alkynyl, hydroxy (CVC6) alkyl, (cvc6) 20 alkoxy (CVC6) alkane (CVC6) anthraceneoxy (CVC6) alkyl, nitro, cyanide 200823216 (CrC6) alkyl, halo(crC6)alkyl, nitro(CrC6)alkyl, (CVC6) amidino, (CVC6) Amidino (crc6) alkyl, (crc6) alkoxy (cvc6) decylamino, amino (crc6) fluorenyl, amine (crc6) fluorenyl (crc6) alkyl, (CVC6) alkylamino ( Q-C6) fluorenyl, ((crc6)alkyl) 2 amine (CVC6) 醯5 group, R15R16N-C0-0-, rMr^N-CCKCVQ) alkyl, R15C(〇)NH, r15oc(o) Nh, r15nhc(o)nh, (CrC6)alkyl-S(0)m, (Q-C6)alkyl-S(0)m-(crc6) leuntyl, R15R16NS(0)m, R15R16NS(0) m(Cl-C6)alkyl, R15S(0)mR16N, R15S(0)mR16N(CrC6)alkyl, wherein m is deuterium, 1 or 2 and R15 and R16 are each independently selected from hydrogen or alkyl; 10 R2 and R3 is each independently selected from the group consisting of hydrogen, hydrazine, amine, halogen, thiol, nitro, thiol, (C2_C6) fluorenyl, (C2-C6) alkynyl, trifluoromethyl, tri Fluoromethoxy, (CrC6)alkyl, (CrC6)alkoxy, (C3_C-cycloalkyl, wherein the alkyl, alkoxy or cycloalkyl group may be optionally subjected to 1 to 3 groups selected from the group consisting of Substitution: _, hydroxyl, carboxyl, amine (CrC6 Alkenyl 15 thio, (rcc6)alkylamino, ((crc6)alkyl) 2 amine, (c5-c9)heteroaryl, (C2-C9)heterocycloalkyl, (C3-C9)cycloalkane Or (C6-C1G) aryl; or RW each independently (C3-C1G)cycloalkyl, (C3-C1g)cycloalkoxy, (crc6)alkylamino, ((CrC6)alkyl)2amine Base, (C6-C1()) arylamino group, (CVC6) alkylthio group, (CVCiq) arylthio group, (Ci_C6) calcined fluorenyl group, (CVCio) aryl arsenic, 20 (CVC6) Astragalus, (C6-Ci〇) aryl feldspar, (Ci-C6), (crc6) alkoxy-CO_NH-, (CrC6) alkylamino-CO-, (cvc9) heteroaryl, (c2_C9 a heterocycloalkyl or (C6-CiG)aryl group, wherein the heteroaryl group, heterocycloalkyl group and aryl group are optionally substituted with 1 to 3 groups: _, (CVC6) alkyl, ( Cvc6) alkyl-CO-NH-, (c"c6) alkoxy-CO_NH_, (crc6)alkyl 9 200823216 -CO-NHKCVC^)alkyl, (CrQ)alkoxy-CO-NIHCi-C^ Alkyl, (CrC6) alkoxy_CO-NH-(CrC6) alkoxy, carboxy, carboxy (CrC6) alkyl, carboxy (CrC6) alkoxy, oxycarbonyl (CrC6) alkoxy, ( CrC6) alkoxycarbonyl (CrC6) alkoxy, (C6-C1()) aryl, Amino, aminyl (Q-C6) 5 alkyl, (CrC6) alkoxycarbonylamino, (C6-C1G) aryl (CVC6) alkoxycarbonylamino, (CVC6) alkylamino, (CVC6) alkane Amino group, (crc6) alkylamino (Crc6) alkyl, ((CrC6)alkyl) 2 amine (CVC6) alkyl, hydroxy, (crc6) alkoxy, (CrC6) alkoxycarbonyl, (CrCJ alkoxycarbonyl (CrCO alkyl, (cvc6) alkoxy-CO-NH-, cyano, (C5-C9) heterocycloalkyl, amine 10-CO-NH-, (CVC6) alkylamino -CO-NH-, ((Ci-Q)alkyl) 2 Amino-CO-NH-, (C6-C1()) arylamino-CO-NH-, (C5-C9) Heteroarylamino- CO-NH-, (CrC6) alkylamino-CO-NiHCVC^)alkyl, ((qQ)alkyl) 2 amine-CO-NtHCVCO alkyl, (C6-C1()) arylamino-CO- NH-CCVC^)alkyl, (C5-C9)heteroarylamino_CO_NH-(CVC6) alkyl, (CVC6) alkanesulfonyl, (CVC6) alkanesulfonyl, (CVC6) alkanesulfonamide (CVC6)alkyl, (C6-C1G) arylsulfonyl, (C6_C1()) arylsulfonylamino, (C6-C1()) arylsulfonylamino (crc6) alkyl, (C5-C9 a heteroaryl group or a (c2_C9) heterocycloalkyl group. In a particular embodiment, the Janus kinase inhibitor is a compound of formula I; R1 R2

或其藥學上可接受鹽；其中 R1為下式基團 200823216Or a pharmaceutically acceptable salt thereof; wherein R1 is a group of the formula: 200823216

(4 其中y為0、1或2 ; R4係選自以下所組成之群組：氳、（CrCd烷基、（Ci-C6) 烷磺醯基、（c2-c6)烯基、（C2-C6)炔基，其中該烷基、烯基 5 及炔基可選擇性經以下基團取代：氘、羥基、胺基、三氟甲基、（C1-C4)烧氧基、（CVC6)醯氧基、（Q-C6)烧胺基、（(Ci-C6) 烧基)2胺基、氰基、頌基、（C2-C6)稀基、（C2-C6)快基或(CrC6) 醯胺基；或R4為(C3-C1G)環烷基，其中該環烷基可選擇性經以下基團取代：氘、羥基、胺基、三氟甲基、（CrC6)醯氧 10基、（CrC6)醯胺基、（CrC6)烷胺基、（(CVC6)烷基)2胺基、氰基、氰基(Crc6)烷基、三氟甲基(crC6)烷基、硝基、硝基(crc6)烷基或(c!-c6)醯胺基； R5為經1至5種選自以下之基團取代的哌啶基：羧基、氰基、胺基、氘、羥基、（CrC6)烷基、烷氧基、鹵 15 素、（cvc6)醯基、（Crc6)烷胺基、胺基（crc6)烷基、 (CrC6)烷氧基、-CO-NH、（CrC6)烷胺基-CO-、（C2-C6)烯基、（C2-C6)炔基、（Crc6)烷胺基、羥基（Cl_c6)烷基、 (cvc6)烧氧基(crc6)烧基、（CVC6)醯氧基(c「c6)烧基、硝基、氰基(CVC6)烷基、鹵（crC6)烷基、硝基(CrC6)烷基、 20三氟甲基、三氟曱基(CrC6)烷基、（Crc6)醯胺基、（CVC6) 醯胺基（CVC6)烷基、（Ci_C6)烷氧基（crc6)醯胺基、胺基 11 200823216 (CVC6)醯基、胺基(CVC6)醯基(CVC6)烧基、（Crc6)烧胺基 (Ci_C6)醢基、（(CVC6)烧基）2 胺基（Ci_C6)醢基、 R15R16N-C0-0-、RbR^N-CCKCVC^)烧基、（Q-C6)烷基 -s(0)m、R15R16NS(0)m、RMRi6NS(0)m(Cl_c6)烷基、 5 R15S(0)mR16N、RbSCOkRbNA-G)烷基，其中n^〇、1 或2，且R15及R16各獨立選自氫或(crC6)烷基；或下式基團：(4 wherein y is 0, 1 or 2; R4 is selected from the group consisting of hydrazine, (CrCd alkyl, (Ci-C6) alkanesulfonyl, (c2-c6) alkenyl, (C2- C6) alkynyl, wherein the alkyl, alkenyl 5 and alkynyl groups are optionally substituted by hydrazine, hydroxy, amino, trifluoromethyl, (C1-C4) alkoxy, (CVC6) fluorene Oxyl, (Q-C6) acrylamine, ((Ci-C6)alkyl) 2 amine, cyano, fluorenyl, (C2-C6), (C2-C6) fast or (CrC6) Amidino group; or R4 is a (C3-C1G)cycloalkyl group, wherein the cycloalkyl group is optionally substituted with a group: an anthracene, a hydroxyl group, an amine group, a trifluoromethyl group, a (CrC6) anthracene 10 group, (CrC6) amidino group, (CrC6) alkylamino group, ((CVC6) alkyl) 2 amine group, cyano group, cyano (Crc6) alkyl group, trifluoromethyl (crC6) alkyl group, nitro group, nitrate a (crc6)alkyl group or a (c!-c6)nonylamino group; R5 is a piperidinyl group substituted with 1 to 5 groups selected from the group consisting of a carboxyl group, a cyano group, an amine group, an anthracene group, a hydroxyl group, and (CrC6). Alkyl, alkoxy, halo-15, (cvc6) fluorenyl, (Crc6)alkylamino, amine (crc6) alkyl, (CrC6) alkoxy, -CO-NH, (CrC6) alkylamine base-CO-, (C2 -C6) alkenyl, (C2-C6)alkynyl, (Crc6)alkylamino, hydroxy(Cl_c6)alkyl, (cvc6)alkoxy (crc6)alkyl, (CVC6)decyloxy (c"c6 Carboxyl, nitro, cyano (CVC6) alkyl, halo(crC6)alkyl, nitro(CrC6)alkyl, 20 trifluoromethyl, trifluoromethyl (CrC6) alkyl, (Crc6) fluorene Amine, (CVC6) decylamino (CVC6) alkyl, (Ci_C6) alkoxy (crc6) decylamino, amine 11 200823216 (CVC6) fluorenyl, amine (CVC6) fluorenyl (CVC6) alkyl (Crc6) an amine group (Ci_C6) fluorenyl group, ((CVC6) alkyl group) 2 amine group (Ci_C6) fluorenyl group, R15R16N-C0-0-, RbR^N-CCKCVC^) alkyl group, (Q-C6 Alkyl-s(0)m, R15R16NS(0)m, RMRi6NS(0)m(Cl_c6)alkyl, 5 R15S(0)mR16N, RbSCOkRbNA-G)alkyl, wherein n^〇, 1 or 2, And R15 and R16 are each independently selected from hydrogen or (crC6)alkyl; or a group of the formula:

(cr9r1\ ^(Y)e 其中a為Ο、1、2、3或4 ; 10 b、c、e、f及g各獨立為〇或1 ; d為0、1、2或 3 ; X為S(0)n，其中n為〇、1或2 ;氧、羰基或_C(=N_氰基> ; Y為S(0)n ’其中η為〇、1或2;或幾基；且 ζ為幾基、c(0)0-、C(0)NR_或s(0)n，其中η為〇、域2 ; 15 R6、R7、R8、R9、R1G及R11各獨立選自以下所組成之群組·氫或可選擇性經氘、羥基、胺基、三氟甲基、（Ci-C6) 酿氧基、（CVQ)醯胺基、（Cl_C6)烧胺基、（(Cl_c6)烧基)2胺基、氰基、氰基(CVC6)烧基、三II甲基(CVC6)烧基、石肖基、硝基(Ci-C6)烷基或(CVC6)醯胺基取代之(C^CJ烷基； 12 200823216 R12為羧基、氰基、胺基、側氧基、氘、羥基、三氟甲基、（CrC6)烷基、三氟甲基(Q-Q)烷基、（CrC6)烷氧基、鹵素、（CrC6)醯基、（CrC6)烷胺基、（(crC6)烷基)2胺基、胺基(Crc6)烷基、（CVC6)烷氧基-CO-NH、（crc6)烷胺基 5 -CO-、（C2_C6)烯基、（C2-C6)炔基、羥基(CrC6)烷基、（CrC6) 烧氧基(C1-C6)烧基、（Ci_C6)驢氧基(C1-C6)院基、梢基、乳基(Ci_C6)烧基、鹵（Ci-C6)烧基、硝基(Ci-C6)烧基、（Cl-C6) 醯胺基、（CVC6)醯胺基(CrC6)烷基、（Q-C6)烷氧基(CrC6) 醯胺基、胺基(CrC6)醯基、胺基(CrC6)醯基(CrC6)烷基、 10 (CVC6)烷胺基(CVC6)醯基、（(CVC6)烷基)2胺基（c「c6)醯基、R15R16N-C0-0-、R15R16N-C〇-(CrC6)烧基、R15C(0)NH、 r15oc(o)nh、r15nhc(0)nh、（CrC6)烷基-S(0)m、（Cl-C6) 烷基-S(0)m-(Ci-C6)烧基、R15R16NS(0)m、R15R16NS(0)m(CVC6) 烧基、R15S(0)mR16N、烧基，其中 m為 0、 15 1或2且r15&r16各獨立選自氯或(CrC6)烷基； R2及R3各為氫。在特定實施例中，該傑納斯激酶抑制劑為下式I化合物 R R2(cr9r1\^(Y)e where a is Ο, 1, 2, 3 or 4; 10 b, c, e, f and g are each independently 1 or 1; d is 0, 1, 2 or 3; X is S(0)n, where n is deuterium, 1 or 2; oxygen, carbonyl or _C(=N-cyano)>; Y is S(0)n ' where η is 〇, 1 or 2; or a few And ζ is a few bases, c(0)0-, C(0)NR_ or s(0)n, where η is 〇, domain 2; 15 R6, R7, R8, R9, R1G and R11 are each independently selected From the group consisting of: hydrogen or optionally via hydrazine, hydroxy, amine, trifluoromethyl, (Ci-C6) methoxy, (CVQ) decyl, (Cl_C6) acryl, ( (Cl_c6)alkyl group, cyano group, cyano group (CVC6) alkyl group, tri-II methyl group (CVC6) alkyl group, schlossyl group, nitro (Ci-C6) alkyl group or (CVC6) decyl group substituted (C^CJ alkyl; 12 200823216 R12 is carboxyl, cyano, amine, pendant oxy, hydrazine, hydroxy, trifluoromethyl, (CrC6) alkyl, trifluoromethyl (QQ) alkyl, ( CrC6) alkoxy, halogen, (CrC6) fluorenyl, (CrC6) alkylamino, ((crC6)alkyl) 2 amine, amine (Crc6) alkyl, (CVC6) alkoxy-CO-NH , (crc6) alkylamino 5-CO-, (C2_C6) alkenyl, (C2-C6) alkynyl, hydroxy (CrC6) alkane (CrC6) alkoxy (C1-C6) alkyl, (Ci_C6) decyloxy (C1-C6), base, dairy (Ci_C6) alkyl, halogen (Ci-C6) alkyl, nitrate (Ci-C6) alkyl group, (Cl-C6) decylamino group, (CVC6) decylamino (CrC6) alkyl group, (Q-C6) alkoxy group (CrC6) decylamino group, amine group (CrC6) Sulfhydryl, amine (CrC6) fluorenyl (CrC6) alkyl, 10 (CVC6) alkylamino (CVC6) fluorenyl, ((CVC6) alkyl) 2 amine (c "c6) fluorenyl, R15R16N-C0 -0-, R15R16N-C〇-(CrC6) alkyl, R15C(0)NH, r15oc(o)nh, r15nhc(0)nh, (CrC6)alkyl-S(0)m, (Cl-C6) Alkyl-S(0)m-(Ci-C6)alkyl, R15R16NS(0)m, R15R16NS(0)m(CVC6) alkyl, R15S(0)mR16N, alkyl, wherein m is 0, 15 1 Or 2 and r15&r16 are each independently selected from chloro or (CrC6)alkyl; R2 and R3 are each hydrogen. In a particular embodiment, the Janus kinase inhibitor is a compound of formula I R R2

或其藥學上可接受鹽；其中 R1為下式基围 13 200823216 R5Or a pharmaceutically acceptable salt thereof; wherein R1 is a base of the formula 13 200823216 R5

ach2) 其中y為0 ; R為(Ci-C6)烧基； R5為經1至5種選自以下之基團取代的哌啶基：羧基、 5氰基、胺基、氘、羥基、（CrC6)烷基、（CVC6)烷氧基、鹵素、（cvc6)醯基、（CVC6)烷胺基、胺基（c「c6)烷基、 (C!-C6)烷氧基、-CO-NH、（CVC6)烷胺基-CO·、（C2-C6)烯基、（C2-C6)炔基、（Q-C6)烧胺基、經基（crc6)院基、 (CVC6)烷氧基(CVC6)烷基、（cvc6)醯氧基(cvc6)烷基、硝 10 基、氰基(CVC6)烷基、鹵（crc6)烷基、硝基(crc6)烷基、三氟甲基、三氟甲基(cvc6)烷基、（CVC6)醯胺基、（crc6) 醯胺基(CrC6)烷基、（CrC6)烷氧基（Q-C6)醯胺基、胺基 (CrD醯基、胺基(CrC6)醯基(CrC6)烧基、（c「c6)烧胺基 (crc6)醯基、（(cvc6)烷基）2胺基（CVC6)醯基、 15 R15R16N-C0-0-、R15R16N-CO-(CKC6)烧基、（CVC6)烷基 S(0)m、R15R16NS(0)m、R15R16NS(0)m(CVC6)烷基、 R15S(0)mR16N、rMSCOU^NA-Cs)烧基；或下式基團Ach2) wherein y is 0; R is (Ci-C6)alkyl; R5 is piperidinyl substituted with 1 to 5 groups selected from the group consisting of carboxy, 5 cyano, amine, hydrazine, hydroxy, ( CrC6)alkyl, (CVC6)alkoxy, halogen, (cvc6)decyl, (CVC6)alkylamino, amine (c"c6)alkyl, (C!-C6)alkoxy, -CO- NH, (CVC6) alkylamino-CO·, (C2-C6) alkenyl, (C2-C6) alkynyl, (Q-C6) acryl, rhenyl (crc6), (CVC6) alkoxy (CVC6)alkyl, (cvc6)decyloxy(cvc6)alkyl, nitrate 10, cyano(CVC6)alkyl, halo(crc6)alkyl, nitro(crc6)alkyl, trifluoromethyl , trifluoromethyl (cvc6) alkyl, (CVC6) decylamino, (crc6) decylamino (CrC6) alkyl, (CrC6) alkoxy (Q-C6) decylamino, amine (CrD醯Base, amine (CrC6) fluorenyl (CrC6) alkyl, (c "c6) acryl (crc6) fluorenyl, ((cvc6) alkyl) 2 amine (CVC6) fluorenyl, 15 R15R16N-C0- 0-, R15R16N-CO-(CKC6) alkyl, (CVC6) alkyl S(0)m, R15R16NS(0)m, R15R16NS(0)m(CVC6)alkyl, R15S(0)mR16N, rMSCOU^NA -Cs) a base; or a group of the formula

20 其中： m為0、1或2 ; 200823216 R15及R16各獨立選自氫或(CrC6)烷基； d為1 ; R9及R1G各獨立選自以下所組成之群組：氫或可選擇性經乳、經基、胺基、三就甲基、（Ci_C6)酿氣基、（Ci_C6)酿 5 胺基、（q-q)烷胺基、（(cvq)烷基)2胺基、氰基、氰基(cvd 烷基、三氟甲基(CrC6)烷基、硝基、硝基(CrCJ烷基或(CrC6) 醯胺基取代之(CVC6)烷基； R12為氰基、三氟曱基、（Q-C6)烷基、三氟甲基(Ci-Ce) 烷基、（CVC6)烷胺基、（(crc6)烷基)2胺基、（c2-c6)炔基、 10 氰基(CrC6)烷基、（CrC6)烷基-S(0)m，其中m為0、1或2 ;且 R2及R3各為Η。在式I化合物之特定實施例中，a為0;b為1;Χ為羰基； c為0 ; d為0 ; e為0 ; f為0，且g為0。在式I化合物之特定實施例中，a為0 ; b為1 ; X為羰基； 15 c為1 ; d為0 ; e為0 ; f為0，且g為0。在式I化合物之特定實施例中，a為0;b為1;X為羰基； c為1 ; d為0 ; e為0 ; f為0，且g為0 〇在式I化合物之特定實施例中，a為0;b為1 ;X為-C(=N= 氣基)-，c為1，d為0，e為0，f為0 ’且g為0。 20 在式I化合物之特定實施例中，a為0 ; b為0 ; c為0 ; d 為 0 ; e為 0 ; f為 0 ; g為 1 ;且Z為-C(0)-0-。在式I化合物之特定實施例中，a為0 ; b為1 ; X為S(0)n ; η為2 ; c為0 ; d為0 ; e為0 ; f為0，且g為0 〇 15 200823216 在式I化合物之特定實施例中，a為0; b為1 ; X為S(0)n ; η為2 ; c為0 ; d為2 ; e為0 ; f為1 ; g為1 ;且Z為羰基。在式I化合物之特定實施例中，a為0; b為1 ; X為S(0)n ; η為2 ; c為0 ; d為2 ; e為0 ; f為1 ;且g為0 ° 5 在式I化合物之特定實施例中，a為0 ; b為1 ; X為羰基； c為 1 ; d為 0 ; e為 1 ; Y為 S(0)n ; η為 2 ; f為 0 ;且g為 0。在式I化合物之特定實施例中，a為0; b為1 ; X為S(0)n ; η為2 ; c為1 ; d為0 ; e為0 ; f為0 ;且g為0 〇在式I化合物之特定實施例中，R12為氰基、三氟甲基、 10 (CrC6)烷基、三氟甲基(cvc6)烷基、（CVC6)烷胺基、（(cvc6) 烷基)2胺基、（c2-c6)炔基、氰基(CVC6)烷基、（crc6)烷基 -s(0)m，其中 m為0、1 或2。在式I化合物之特定實施例中，該傑納斯激酶抑制劑係選自以下所組成之群組： 15 甲基-[4-甲基-1-(丙烷-1-磺醯基)-哌啶-3-基]-(711_吡咯弁[2,3-d] ♦11 定-4-基)-胺， 4-甲基-3-[甲基-(7H-吡咯并[2,3_d]嘧啶-4-基)-胺基]-哌啶-1-羧酸甲酯； 3,3,3_三氟-l-{4-甲基-3-[甲基-(7H-吡咯并[2,3-d]嘧啶 20 -4-基)-胺基]-σ底咬-1 _基}-丙-1 -嗣， 4-甲基-3-[甲基-(7Η-吡咯并[2,3-d]嘧啶-4-基)-胺基]-哌啶-1-羧酸二甲醯胺； ({4-甲基-3-[甲基-(7H-吡咯并[2,3-d ]嘧啶-4-基）-胺基]-°底ϋ定-1 -竣基}-胺基)-乙酸乙酉旨， 16 200823216 3·{4-甲基-3-[甲基-(7H-吡咯并[2,3-d]嘧啶-4_基）-胺基]_嘴啶-1-基}_3-側氧基丙腈； 3,3,3-三氟-l-{4-甲基[甲基-(5-曱基_7H-吡咯并 [2,3-d]喷唆_4_基)胺基]定小基}_丙_卜酮； 5 1气4-甲基-3-[甲基-(7H-吡咯并[2,3-d]嘧啶-4-基）-胺基]-哌啶小基卜丁-3-炔-1，； M3-[(5-氣-7H-吡咯并[2,3-d]嘧啶-4-基）-甲基-胺基]冰甲基-旅啶」基卜丙小酮； Μ3·”-氟-7H-吼咯并[2,3-d]嘧啶-4-基）-甲基-胺 10基]冰甲基_呢啶小基卜丙+酮； N-氰基-4-甲基-3-[甲基-(7H-。比嘻并[2,3-d]嘧唆-4-基)_ 胺基]_Ν’_丙基·旅啶小叛基脒； Ν•氰基-4，Ν’，Ν’-三甲基-3-[曱基-(7Η-吡咯并[2,3-d]嘧咬-4-基)-胺基]_哌啶·丨_羧基脒； 15 曱基-[(3R，4R)-4-甲基-H丙烷_1_磺醯基）“底啶_3· 基]-(7Η-吡咯并[2,3-d]嘧啶-4_基)·胺； (3R，4R)-4-甲基-3-[甲基-(7H-吡咯并[2,3-d]嘧啶 _4_ 基)_ 胺基]-哌啶-1-羧酸甲酯； 3,3,3_三氟-1-{(3R，4R)冰甲基_3_[曱基_(7H•吡略并 20 [2,3吶嘧啶_4·基)胺基]哌啶_1_基卜丙_丨_酮； (3R，4R)-4-甲基-3-[甲基_(7H-吡咯并[2,3-d]嘧啶美）胺基]_哌啶-1-羧酸二甲醯胺； {(3R，4R)-4-甲基-3-[甲基-(7H· 口比咯并[2,3-d]嘧啶胺基]-。辰°定-1-魏基}-胺基)-乙酸乙酉旨； 17 200823216 3_d]嘧啶-4- 3-{(3R，4R)-4-甲基-3·[曱基-(7H-。比π各并[2 基)-胺基l·哌啶-1-基}-3-側氧基_丙腈； 3,3,3-三氟-l-{(3R，4R)-4-甲基_3_[甲基_(5_ T基-7H-口比 5 l-{(3R，4R)-4-甲基-3-[甲基-(7Η· t各并[2 3 d]m_ 基)"胺基]-σ辰咬_1-基}丁 ·3·快-1-嗣； l-{(3R，4R)-3-[(5-氣-7Η-吡咯并[2,3-d]嘧啶_4_基）甲某 -胺基]-4-曱基_°辰咬-1-基}-丙-1-嗣； l-{(3R，4R)-3-[(5-氟-7H-吡咯并[2,3-d]嘧啶_4_基)_ 甲某 10 •胺基]-4-甲基·°底咬-l-基}-丙; (3R，4R)-N_氰基-4-甲基-3-[甲基_(7Η“比咯并[2,3_dh密 11 定-4_基)-胺基]-Ν’-丙基-旅咬小幾基脒；及 (3R，4R)-N-氰基·4，Ν’，Ν’_三甲基-3-[甲基 _(7H_t各并 [2,3_d]嘧啶-4-基)-胺基]-哌啶小羧基脒； 15或彼等之藥學上可接受鹽。在式I化合物之特定實施例中，該傑納斯激酶抑制劑係選自以下所組成之群組；甲基-[4-甲基]·(丙烧小石黃酷基)-σ辰咬-3-基]-(7H-口比洛并[2,3-d]嘧啶_4_基)_胺基； 2〇 4·甲基各[甲基-(7H-a比洛并[2,3-d]。密咬-4-基)-胺基]-°辰咬-l-羧酸甲酯； 3,3,3-三氟_1]4-甲基-3-[甲基-(7H-吡咯并[2,3-d]嘧啶 -4-基l·胺基]旅啶_1_基}_丙小酮；甲基-3-[甲基-(7H-吡咯并[2,3-d]嘧啶-4-基)-胺基l·哌 18 200823216 啶-1-羧酸二甲醯胺； ({4-甲基 _3·[甲基 _(7Η_·并[2,3_d]対] 哌啶-1_羧基}-胺基)_乙酸乙酯；土 5 10 15 20 °辰°定小基}-3-側氧基-丙腈； 3,3,3_三氟-l-{4-甲基-3-「甲其κ田# 丞L T暴-(孓甲基-7H-吡咯并 [2,3-d]嘧啶-4-基)-胺基]-哌啶_丨_基卜丙_丨__ ; H4-甲基·3·[甲基_(7H_ t各并[2,3_d]㈣_4_基)胺基]哌啶-1-基卜丁-3-炔小酮； 1-{3-[(5-氣-7H-吡咯并[2,3_d]嘧啶_4_基甲美基H-甲基底啶_1_基卜丙]_酮； Η3-[(5·氟·7Η-切并[2,3_d]㈣冰基）_甲基·胺基]-4-甲基-η辰u定_1_基卜丙酉同；、N-氰基_4_甲基_3·[甲基_(7H_t各并[2,3_咐咬冬奸 fe基]_N’_丙基-旅咬·ι_竣基脒，·及 Ν-氰基-4，Ν，，Ν，-三甲基 _3_「甲, 土 j [甲基-(7H “比咯并[2,3-d]嘧咬_4_基)-胺基]旅π定小竣基脒，或彼等之藥學上可接受鹽。在或1化合物之特定實施例中，該傑納斯抑制劑係選自以下所組成之群組；甲基-[(3R，4R)-4-甲其！,工 w , τ暴小（丙烷小磺醯基哌啶_3_ 基]_(7Η-吼咯并[2,3-d]嘧啶_4_基)_胺； (3R，4R)_)-4·甲基 _3-[甲美 , 土 ""(7H-比口各并[2,3-d] 口密口定-4- 基)·胺基]-σ底咬-1-竣酸甲酉旨； 19 200823216 3,3,3·三氟-l_{(3R，4R)-4-甲基-3-[甲基-(7H-口比洛并 [2,3-(1]17治咬_4-基)-胺基]-12辰唆-1-基}-丙_1-酮； (3R，4R)-4-甲基-3-[曱基-(711_吡咯并[2,3-d]。密啶-4-基)- 胺基]-哌啶-1-羧酸二甲醯胺； 5 {(3R，4Rl·4-甲基 _3·[甲基 _(7H-吡咯并[2,3-d]嘧啶-4-基)- 胺基]-哌啶-1-羧基}-胺基)_乙酸乙酯； 3_{(3R，4R)_4·甲基-3-[甲基-(7H-吡咯并[2,3-d]嘧啶-4_ 基)·胺基]•哌啶-1-基}-3-側氧基-丙腈； 3,3,3-三氟-1-{(3R，4R)_4-甲基-3-[甲基_(5_ 甲基-7H-口比 10 u各并[2,3_d]嘧啶-4-基)_胺基]-哌啶-1-基}_丙小酮； 1-{(3R，4R)_4_ 甲基-3-[甲基-(7H-吡咯并[2,3-d]嘧啶-4-基)_胺基]-哌啶_1-基}-丁-3·炔小酮； l-{(3R，4R)-3-[(5j_7H-吡咯并[2,3-d]嘧啶-4-基)-甲基 -胺基]-4-甲基-哌啶小基卜丙小酮； 15 氟-7H-吡咯并[2,3-d]嘧啶-4-基)-甲基 •fee基]-4-甲基-旅σ定_1·基卜丙小_ ; (3R，4R)_N-氰基-4-曱基-3-[甲基-(7Η-吡咯并[2,3-d]嘧 °定_4_基)-胺基]-Ν’-丙基-旅啶-1-羧基脒；及 (3R，4R)-N-氰基-4，Ν’，Ν’-三甲基-3-[甲基-(7Η-吡咯并 20 [2,3_嘧啶-4-基]-胺基)哌啶-1-羧基脒；或彼等之藥學上可接受鹽。在特定實施例中，該傑納斯激酶抑制劑為式ΙΑ化合物： 20 20082321620 wherein: m is 0, 1 or 2; 200823216 R15 and R16 are each independently selected from hydrogen or (CrC6)alkyl; d is 1; R9 and R1G are each independently selected from the group consisting of: hydrogen or optionally Milk, trans, amino, trimethyl, (Ci_C6), (Ci_C6), 5 amine, (qq) alkylamino, (cvq) alkyl) 2, cyano, Cyano (cvd alkyl, trifluoromethyl (CrC6) alkyl, nitro, nitro (CrCJ alkyl or (CrC6) decylamino substituted (CVC6) alkyl; R12 is cyano, trifluoromethyl (Q-C6)alkyl, trifluoromethyl(Ci-Ce)alkyl, (CVC6)alkylamino, ((crc6)alkyl) 2 amine, (c2-c6)alkynyl, 10 cyano (CrC6)alkyl, (CrC6)alkyl-S(0)m, wherein m is 0, 1 or 2; and R2 and R3 are each Η. In a particular embodiment of the compound of Formula I, a is 0; Is a carbonyl group; c is 0; d is 0; e is 0; f is 0, and g is 0. In a particular embodiment of the compound of Formula I, a is 0; b is 1; X is a carbonyl group; 15 c is 1; d is 0; e is 0; f is 0, and g is 0. In a particular embodiment of the compound of formula I, a is 0; b is 1; X is a carbonyl; c is 1; d is 0 ; e is 0; f is 0, and g is 0 〇 In a particular embodiment of the composition, a is 0; b is 1; X is -C (=N = gas group)-, c is 1, d is 0, e is 0, f is 0' and g is 0. In a particular embodiment of the compound of formula I, a is 0; b is 0; c is 0; d is 0; e is 0; f is 0; g is 1; and Z is -C(0)-0- In a particular embodiment of the compound of formula I, a is 0; b is 1; X is S(0)n; η is 2; c is 0; d is 0; e is 0; f is 0, and g is 0 〇15 200823216 In a particular embodiment of the compound of formula I, a is 0; b is 1; X is S(0)n; η is 2; c is 0; d is 2; e is 0; f is 1; g is 1; and Z is carbonyl. In a particular embodiment of the compound of formula I, a is 0; b is 1; X is S(0)n; η is 2; c is 0; d is 2; f is 1; and g is 0 ° 5 In a particular embodiment of the compound of formula I, a is 0; b is 1; X is a carbonyl group; c is 1; d is 0; e is 1; Y is S (0) n is 2; f is 0; and g is 0. In a particular embodiment of the compound of formula I, a is 0; b is 1; X is S(0)n; η is 2; c is 1; d is 0; e is 0; f is 0; and g is 0. In a particular embodiment of the compound of formula I, R12 is cyano, trifluoromethyl, 10(CrC6)alkyl, trifluoromethyl (cvc6) )alkyl,( CVC6) alkylamino, ((cvc6)alkyl) 2 amine, (c2-c6) alkynyl, cyano (CVC6) alkyl, (crc6)alkyl-s(0)m, where m is 0, 1 or 2. In a particular embodiment of the compound of Formula I, the Janus kinase inhibitor is selected from the group consisting of: 15 methyl-[4-methyl-1-(propan-1-sulfonyl)-piperidin Arid-3-yl]-(711_pyrrole[2,3-d] ♦11-1,4-yl)-amine, 4-methyl-3-[methyl-(7H-pyrrolo[2,3_d Methyl pyrimidin-4-yl)-amino]-piperidine-1-carboxylate; 3,3,3-trifluoro-l-{4-methyl-3-[methyl-(7H-pyrrole [2,3-d]pyrimidine 20 -4-yl)-amino]-σ bottom bite-1 _yl}-propan-1 -indole, 4-methyl-3-[methyl-(7Η-pyrrole [2,3-d]pyrimidin-4-yl)-amino]-piperidine-1-carboxylic acid dimethylamine; ({4-methyl-3-[methyl-(7H-pyrrolo[2] ,3-d ]pyrimidin-4-yl)-amino]-° ϋ -1 -1 - fluorenyl}-amino)-acetic acid acetonitrile, 16 200823216 3·{4-methyl-3-[methyl -(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]]- phenidin-1-yl}_3-oxopropanenitrile; 3,3,3-trifluoro-l- {4-methyl [methyl-(5-fluorenyl-7H-pyrrolo[2,3-d] sputum _4_yl)amino] succinyl}} propyl propyl ketone; 5 1 gas 4 -methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidine-dipyridin-3-yne-1,; M3-[ (5-Gas-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-methyl-amine Alkyl-branched methyl-braziside kebpropanone; Μ3·”-fluoro-7H-indolo[2,3-d]pyrimidin-4-yl)-methyl-amine 10yl] ice methyl N-cyano-4-methyl-3-[methyl-(7H-. bis-[2,3-d]pyrimidin-4-yl)-amino group ]_Ν'_propyl·L. pyridine; Ν•cyano-4,Ν',Ν'-trimethyl-3-[mercapto-(7Η-pyrrolo[2,3-d]pyrimidine咬-4-yl)-amino]-piperidine·丨-carboxy 脒; 15 fluorenyl-[(3R,4R)-4-methyl-H propane_1_sulfonyl) "acne _3· (-)-(7Η-pyrrolo[2,3-d]pyrimidin-4-yl)amine; (3R,4R)-4-methyl-3-[methyl-(7H-pyrrolo[2,3 -d]pyrimidine _4_yl)_amino]-piperidine-1-carboxylic acid methyl ester; 3,3,3_trifluoro-1-{(3R,4R) ice methyl_3_[mercapto-( 7H•pyrolo[20,3pyrimidin-4-yl]amino]piperidine_1-ylpropanyl-indole-ketone; (3R,4R)-4-methyl-3-[methyl_ (7H-pyrrolo[2,3-d]pyrimidine) Amino]-piperidine-1-carboxylic acid dimethylamine; {(3R,4R)-4-methyl-3-[methyl-( 7H·Phenoxy[2,3-d]pyrimidinyl]-.辰°定-1-魏基}-Amino)-acetic acid ethyl acetate; 17 200823216 3_d]pyrimidine-4- 3-{(3R,4R)-4-methyl-3.[indenyl-(7H-. Ratio π each [2 base)-aminol.piperidin-1-yl}-3-oxo-propiononitrile; 3,3,3-trifluoro-l-{(3R,4R)-4- Methyl_3_[methyl_(5_T-yl-7H-port ratio 5 l-{(3R,4R)-4-methyl-3-[methyl-(7Η·t each [2 3 d]m_) Base) "Amino]-σ辰咬_1-基}丁·3·快-1-嗣; l-{(3R,4R)-3-[(5-Ga-7Η-pyrrolo[2, 3-d]pyrimidine _4_yl)methyl-amino]-4-mercapto-[Chen-1-yl}-propan-1-yl; l-{(3R,4R)-3-[( 5-fluoro-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-methyl-10-amino]-4-methyl·°bottom-l-yl}-prop; (3R,4R )-N-cyano-4-methyl-3-[methyl_(7Η"bibromo[2,3_dh dense 11--4-yl)-amino]-Ν'-propyl-buck bite small a few bases; and (3R,4R)-N-cyano-4,Ν',Ν'_trimethyl-3-[methyl-(7H_t-[2,3_d]pyrimidin-4-yl)- Amino]-piperidine small carboxy oxime; 15 or a pharmaceutically acceptable salt thereof. In a particular embodiment of the compound of Formula I, the Janus kinase inhibitor is selected from the group consisting of: methyl -[4-methyl]·(C-Small Stone Cool base) - σ辰咬-3-yl]-(7H-mouth biluo[2,3-d]pyrimidin-4-yl)-amino group; 2〇4·methyl each [methyl-(7H -a 比洛和[2,3-d].Mispin-4-yl)-amino]-°Chen-l-carboxylate; 3,3,3-trifluoro_1]4-A Benzyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yll-amino] benzylidene-1-yl}-propanone; methyl-3-[methyl -(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-aminol·piperidine 18 200823216 pyridine-1-carboxylic acid dimethyl hydrazine; ({4-methyl _3·[methyl _(7Η_·和[2,3_d]対] piperidine-1_carboxy}-amino)-ethyl acetate; soil 5 10 15 20 ° ° ° small base}-3-sideoxy-propionitrile; 3,3,3_trifluoro-l-{4-methyl-3-"甲其κ田# 丞LT storm-(孓methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl )-amino]-piperidine _ 丨 _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 1-kibbut-3-yne small ketone; 1-{3-[(5-gas-7H-pyrrolo[2,3_d]pyrimidin-4-ylmethylmethylidene H-methyl decyl-1-yl)卜-[ketone; Η3-[(5·fluoro·7Η-cut and [2,3_d](tetra)))-methyl-amino]-4-methyl-η辰u定_1_基卜丙同; N-cyano_4_methyl_3·[methyl_(7H_t each [2,3_咐 bite winter Fe-based]_N'_propyl-Broad bite·ι_竣基脒,··Ν-cyano-4,Ν,,Ν,-trimethyl_3_“A, soil j [methyl-(7H” More than [2,3-d] pyrimidine _4_yl)-amino] π 竣竣竣脒, or their pharmaceutically acceptable salts. In a particular embodiment of the compound or compound, the Janus inhibitor is selected from the group consisting of methyl-[(3R,4R)-4-methyl! , work w, τ storm small (propane sulfonylpiperidine _3_ yl)__(7Η-吼[2,3-d]pyrimidin-4-yl)-amine; (3R,4R)_)- 4·methyl_3-[甲美,土""(7H-specific mouth [2,3-d] mouth-mouth -4- base)·amine]-σ bottom bite-1-竣酉 ;; 19 200823216 3,3,3·Trifluoro-l_{(3R,4R)-4-methyl-3-[methyl-(7H- 口比洛和[2,3-(1 ]17治咬_4-基)-Amino]-12- Chen唆-1-yl}-propan-1-one; (3R,4R)-4-methyl-3-[indenyl-(711_pyrrole) And [2,3-d].Mididine-4-yl)-amino]-piperidine-1-carboxylic acid dimethylamine; 5 {(3R,4Rl·4-methyl_3·[methyl _(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidine-1-carboxy}-amino)-ethyl acetate; 3_{(3R,4R)_4·A 3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]piperidin-1-yl}-3-oxo-propanenitrile; 3,3 ,3-trifluoro-1-{(3R,4R)_4-methyl-3-[methyl-(5-methyl-7H-port ratio 10 u each [2,3_d]pyrimidin-4-yl)_ Amino]-piperidin-1-yl}-propanone; 1-{(3R,4R)_4_methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidine-4- ))-amino]-piperidin-1-yl}-but-3-enyl ketone; l-{(3R,4R)-3-[(5j_7H-pyrrolo[2,3-d]pyrimidine-4 - )-methyl-amino]-4-methyl-piperidinyl propyl ketone; 15 fluoro-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-methyl•fee] -4-Methyl-Brigade σ定_1·基卜丙小_ ; (3R,4R)_N-Cyano-4-indolyl-3-[methyl-(7Η-pyrrolo[2,3-d ] pyrimidine _4_yl)-amino]-Ν'-propyl-Brididine-1-carboxyindole; and (3R,4R)-N-cyano-4,Ν',Ν'-三甲Alkyl-3-[methyl-(7Η-pyrrolo-20[2,3-pyrimidin-4-yl]-amino)piperidine-1-carboxyindole; or a pharmaceutically acceptable salt thereof. In a particular embodiment, the Janus kinase inhibitor is a hydrazine compound: 20 200823216

其中Ar、R1、及R2如美國專利7,037,925之申請專利範圍第1 項所定義，該專利之内容實際上係概括地且明確地在此併入本案以為參考資料。該傑納斯激酶抑制劑亦可以是美國 5 專利7,〇37,925中所詳述之任何其它化合物。在特定實施例中，該傑納斯激酶抑制劑為式〗化合物Wherein, Ar, R1, and R2 are as defined in claim 1 of the U.S. Patent No. 7,037,925, the disclosure of which is hereby incorporated by reference in its entirety in its entirety in its entirety herein. The Janus kinase inhibitor may also be any of the other compounds detailed in U.S. Patent No. 7, 〇37,925. In a particular embodiment, the Janus kinase inhibitor is a compound of formula

Ar-((¾)级、 0) X ΟAr-((3⁄4) level, 0) X Ο

/、中Ar、R、X、R、R、及a如美國專利公開案第2⑽_7则4 10/, Medium Ar, R, X, R, R, and a as in US Patent Publication No. 2 (10)_7 then 4 10

號之申請專利範圍第1項所定義，該專利㈣案Μ容實際上係概括地且明確地在此併人本案以為參考㈣。該傑納抑制劑亦可以是美國專利公開案第讓心測视〒所咩述之任何其它化合物。下式化合物在特定實施例中，該傑納斯抑制劑為 15 其中 R1、A、The scope of the patent application scope is defined in item 1. The content of the patent (4) is actually summarized and explicitly referred to in this case as a reference (4). The Jena inhibitor may also be any other compound described in the U.S. Patent Publication No. PCT. Compound of the formula: In a particular embodiment, the Janus inhibitor is 15 wherein R1, A,

B、及W如美國專利公開案第 2005/0137201 號 21 200823216 之申请專利範圍第1項所定義，該專利公開案之内容實際上係概括地且明確地在此併入本案以為參考資料。該傑納斯激酶抑制劑可以是美國專利公開案第2〇〇5/〇1372〇1號中所詳述之任何其它化合物，特別為於實施例173所提及之作為 5 JAK3抑制劑的化合物。在特定實施例中，該傑納斯激酶抑制劑為如藉美國專利公開案第2005/0261253號而定義之可經i或多種基團A〇取代的式500-511之任一種化合物，該專利公開案之内容實際上係概括地且明確地在此併入本案以為參考資料。該傑 1〇納斯激峰抑制劑亦可以是美國專利公開案第2005/0261253 就中所詳述之任何其它化合物。在特定實施例中，該傑納斯激酶抑制劑為式〗化合物B, and W, as defined in U.S. Patent Publication No. 2005/0137201, filed on Jan. No. No. No. No. 2005/01. The Janus kinase inhibitor may be any of the other compounds detailed in U.S. Patent Publication No. 2,5/1,372,1, specifically the compound referred to as Example 5 173 as a 5 JAK3 inhibitor. . In a particular embodiment, the Janus kinase inhibitor is any one of formulas 500-511, as defined by U.S. Patent Publication No. 2005/0261253, which may be substituted with i or a plurality of groups A. The content of the disclosure is in fact broadly and explicitly incorporated herein by reference. The Jasper's peak inhibitor may also be any other compound detailed in U.S. Patent Publication No. 2005/0261253. In a particular embodiment, the Janus kinase inhibitor is a compound of formula

其中Rl、R2、R3、R4、及R5如美國專利公開案第2006/0183906 15就之申請專利範圍第1項所定義，該專利公開案之内容實際上係概括地且明確地在此併入本案以為參考資料。該傑納斯激崎抑制劑亦可以是美國專利公開案第2006/0183906中所詳述之任何其它化合物。在特定實施例中，該傑納斯激酶抑制劑為式I化合物： 22 200823216Wherein Rl, R2, R3, R4, and R5 are as defined in U.S. Patent Application Publication No. 2006/0183906, the disclosure of which is hereby incorporated herein in This case is considered as reference material. The Genesis inhibitor can also be any of the other compounds detailed in U.S. Patent Publication No. 2006/0183906. In a particular embodiment, the Janus kinase inhibitor is a compound of formula I: 22 200823216

其中Di、D2、D3、D4、A、及B如美國專利公開案第 2006/0106020號之申請專利範圍第1項所定義，該專利公開案之内容實際上係概括地且明確地在此併入本案以為參考 5 資料。該傑納斯激酶抑制劑亦可以是美國專利公開案第 2006/0106020號中所詳述之任何其它化合物。在特定貫施例中’该傑納斯激酶抑制劑為W〇 2005/105146之第12至17頁中所述作為JAK3激酶抑制劑之化合物，該專利案之内容實際上係概括地且明確地在此併 10 入本案以為參考資料。在特定實施例中，該傑納斯激酶抑制劑為式丨化合物Wherein Di, D2, D3, D4, A, and B are as defined in claim 1 of U.S. Patent Publication No. 2006/0106020, the disclosure of which is hereby expressly and expressly In this case, I think it refers to 5 materials. The Janus kinase inhibitor can also be any of the other compounds detailed in U.S. Patent Publication No. 2006/0106020. In certain embodiments, the Genus kinase inhibitor is a compound of the JAK3 kinase inhibitor described on pages 12 to 17 of W〇2005/105146, the content of which is generally and explicitly I am here to enter the case for reference. In a particular embodiment, the Janus kinase inhibitor is a hydrazine compound

其中ARW、及R5如美國專利公開案第應/〇214817 號之申請專利範圍第1項所定義，該專利公開案之内容實際 b上係概括地且明確地在此併入本案以為參考資料。該傑納斯激_制劑亦可以是美國專利公開案第2004膨4817號中所詳述之任何其它化合物，特別為於該專利案之實例9所述作為JAK3抑制劑的化合物。在特定實施例中，該傑納斯激崎抑制劑為式Η匕合物： 23 200823216Wherein ARW, and R5 are as defined in claim 1 of the U.S. Patent Application Serial No. 2,148, file, the disclosure of which is hereby incorporated by reference in its entirety in its entirety in its entirety in its entirety in its entirety in its entirety in its entirety The Genesis® formulation may also be any of the other compounds detailed in U.S. Patent Publication No. 2004, pp. 4,417, specifically to the compound of the JAK3 inhibitor described in Example 9 of the patent. In a particular embodiment, the Janus Aesthetic Inhibitor is a chelating compound: 23 200823216

其中Ri、R2、R3、R4、R5、八及乂如美國專利公開案第 2006/0122213號之申請專利範圍第1項所定義，該專利公開案之内容實際上係概括地且明確地在此併入本案以為參考 5 資料。該傑納斯激酶抑制劑亦可以是美國專利公開案第 2006/0122213號中所詳述之任何其它化合物，特別為該專利案之表I及II所示之化合物。在特定實施例中，該傑納斯激酶抑制劑為式〗化合物：Wherein Ri, R2, R3, R4, R5, VIII, and 乂 are as defined in claim 1 of US Patent Publication No. 2006/0122213, the contents of which are hereby expressly and expressly Incorporating this case for reference 5 information. The Janus kinase inhibitor may also be any of the other compounds detailed in U.S. Patent Publication No. 2006/0122213, specifically the compounds shown in Tables I and II of the patent. In a particular embodiment, the Janus kinase inhibitor is a compound of formula:

10 ’、中R Z、Z、及2如美國專利公開案第2Q()6/〇1837 號之申請專利範圍第1所定義，該專利上係概括地且明確地在此併入本1案、本案M為參考資料。該傑 =崎抑㈣亦可以是美國專利公開案咖讓83761 中所詳述之任何其它化合物，特示的化合物。 4 寺別為該專利案之表則在特定實施例中，該傑納斯激_# 24 15 200823216 m 其中R、R、R、X、χ2及χ3如美國專利公開案第 2005/0165G29號之中請專利範圍第丨項所定義，該專利公開案之内容實際上係概括地且明確地在此併人本案以為參考10', the middle RZ, Z, and 2 are as defined in the patent application scope 1 of the U.S. Patent Publication No. 2Q(6), the entire disclosure of which is hereby expressly This case M is a reference material. The Jay = Rugged (4) may also be any other compound, a specific compound, as detailed in U.S. Patent Publication No. 83,761. 4 Temple is a table of the patent. In a specific embodiment, the Janus is _# 24 15 200823216 m wherein R, R, R, X, χ 2 and χ 3 are as disclosed in US Patent Publication No. 2005/0165 G29 The content of the patent publication is defined in the third paragraph of the patent, and the content of the patent disclosure is in fact generally and explicitly used in this case.

Rl: K:!Rl: K:!

資料。該傑納斯激酶抑制劑亦可以是美國專利公開案第 2005/0165029號中所詳述之任何其它化合物。 ’、在特定實施例中，該傑納斯激酶抑制劑為式Ϊ化合物data. The Janus kinase inhibitor can also be any of the other compounds detailed in U.S. Patent Publication No. 2005/0165029. In a particular embodiment, the Janus kinase inhibitor is a hydrazine compound

10其中R、R、R、R、χΐ、Αχ2如美國專利公開案第 2005/圖389號之申請專利範圍第旧所定義，該專利公開案之内容實際上係概括地且明確地在此併入本案以為參考資料。該傑納斯激酶抑制劑亦可料美國專利公開案第 2005/0187389號中所詳述之任何其它化合物。 15 祕定實施例中，該傑納斯鱗抑制劑為式I化合物··10 wherein R, R, R, R, χΐ, Αχ2 are as defined in the patent application scope of U.S. Patent Publication No. 2005/ 389, the disclosure of which is expressly and expressly In this case, I think it is a reference. The Janus kinase inhibitor can also be taken from any of the other compounds detailed in U.S. Patent Publication No. 2005/0187389. 15 In the secret example, the Janus scale inhibitor is a compound of formula I.

25 200823216 /、中R R、R、R4、及γ如美國專利6邦，161之巾請專利祀圍第1項所疋義，該專利案之内容實際上係概括地且明確地在此併人本案以為參考資料。該傑納斯激酶抑制劑亦可 5 10 以是美國專利6,943，101巾所魏之任何其它化合物，特別為該專利案之表I所示之化合物。在特疋實施财，該傑納斯激齡卩制為式丨化合物：25 200823216 /, RR, R, R4, and γ, such as the United States Patent 6 State, 161 towel, please refer to the first paragraph of the patent, the content of the patent is actually a general and clear here This case is considered as reference material. The Janus kinase inhibitor may also be any other compound of U.S. Patent No. 6,943,101, specifically the compound shown in Table I of the patent. In the special implementation of the money, the Janus is aging to a compound of the formula:

J 1 R〆其中R、R、^^^^、及丫如美國專利公開案第2005/0277642號之中請專利範圍第1項所定義，該專利公開案之全文實社係池地料確地在崎人本案以為參考資料。該傑納斯激酶抑制查丨亦可以是美國專利公開案第 2005/0277642號中所詳述之任士 _ 1具匕化合物，特別為該專利案之表I所示的化合物。在特定實施例中， ^、、内斯激_抑制劑為式I化合物：J 1 R〆 wherein R, R, ^^^^, and 丫 are as defined in the first paragraph of the patent scope of US Patent Publication No. 2005/0277642, the full text of the patent disclosure is The land was considered as a reference in the case of Saki. The Janus kinase inhibitory assay can also be a compound of the formula 1-1 as detailed in U.S. Patent Publication No. 2005/0277642, specifically the compound shown in Table I of the patent. In a particular embodiment, the ^, Nes-exciting inhibitor is a compound of formula I:

其中 R1、R2、R4、R5、R6、r7 i〇 R、尺⑺及又如美國專利案號第ό，452,005號及相關美、⑵寻、国專利案號第6,313，129號、 26 15 200823216 第 6,313，130號、第 6,177,433號、第6,080,747號、第6,326,373 號、6,080,748號與美國專利公開案案號第2004/0192711號及第2005/0187233號所定義，該等專利案之内容實際上係概括地且明確地在此併入本案以為參考資料。該傑納斯激 5 酶抑制劑亦可以是美國專利案號第6,452,005號及相關美國專利案號第6,313，129號、第6,313，130號、第6，177,433號、第6,080,747號、第6,326,373號、第6,080,748號與美國專利公開案案號第2004/0192711號及2005/0187233號中所詳述之任何其它化合物。 10 在特定實施例中，該傑納斯激酶抑制劑為Jack J. Chen 專人，Deyelopment of Pyrimidine-Based Inhibitors of JanusWherein R1, R2, R4, R5, R6, r7 i〇R, ruler (7) and U.S. Patent No. 452,005 and related US, (2) Quest, National Patent No. 6,313,129, 26 15 200823216 Nos. 6,313,130, 6,177,433, 6,080,747, 6,326,373, 6,080, 748, and U.S. Patent Publication Nos. 2004/0192711 and 2005/0187233, the contents of which are actually The present invention is hereby incorporated by reference in its entirety and expressly. The Janus 5 enzyme inhibitor can also be US Patent No. 6,452,005 and related U.S. Patent Nos. 6,313,129, 6,313,130, 6,177,433, 6,080,747, 6,326,373 Any other compound as detailed in U.S. Patent Publication Nos. 2004/0192711 and 2005/0187233. In a particular embodiment, the Janus kinase inhibitor is Jack J. Chen, Deeyelopment of Pyrimidine-Based Inhibitors of Janus

Tyrosine_Kinase_3? Bioorganic & Medicinal Chemistry (2006)(doi.l016/j.bmcl.2006.08.0822)之第 1 圖所示的JAK3抑制劑中之任一種Tyrosine_Kinase_3? Any of the JAK3 inhibitors shown in Figure 1 of Bioorganic & Medicinal Chemistry (2006) (doi.l016/j.bmcl.2006.08.0822)

該資料實際上在此併入本案以為參考資料。該傑納斯激酶抑制劑亦可以是文中所詳述之任何其它化合物，特別為文中之表I及II所示之化合物。This material is actually incorporated herein into the case for reference. The Janus kinase inhibitor may also be any of the other compounds detailed herein, particularly the compounds shown in Tables I and II herein.

在特定實施例中，該抗關節炎藥劑為選自以下所組成 20之群組的NSAID(非類固醇消炎藥）或COX-2(環-氧合酶2)抑制劑：乙醯基柳酸及其它柳酸鹽，諸如三柳酸膽鹼镁、阿札丙宗（azapropazone)、卡洛芬（carpr〇fen)、塞力可西 27 200823216 (celecoxib)、雙氣芬酸鉀(diclofenac potassium)、雙氯芬酸鈉、雙氟尼酸（diflunisal)、依托道酸（etodolac)、芬布芬 (fenbufen)、芬諾普芬（fenoprofen)、氟芬那酸（flufenamic acid)、氟比洛芬(flurbiprofen)、布洛芬(ibuprofen)、σ弓卜朶美 5 辛(indomethacin)、酮洛芬(ketoprofen)、甲芬那酸(mefenamic acid)、米羅昔康（meloxicam)、萘丁美酮（nabumetone)、萘普生（naproxen)、萘普生鈉、噚丙畊（oxaprozin)、吡咯芬 (pirprofen)、舒洛芬(suprofen)、雙水楊酸酯（salsalate)、舒林酸(sulindac)、替諾昔康（tenoxicam)、嚷洛芬酸(tiaprofenic 10 acid)、及托美丁(tolmetin)。鑑於本揭示内容之優勢，熟悉本項技藝者可輕易瞭解其它合適NS ΑΠ)及/或COX_2抑制劑。在特定實施例中，該抗關節炎藥劑為選自以下所組成之群組的腎上腺促糖皮質激素（口服、非經腸及/或關節内投藥）：乙酸氫皮質酮、第三-丁基乙酸氫皮質酮、乙酸地塞米 15 松((1以&11^1^01^3061316)、第三-丁基乙酸地塞米松、氫化發尼松(prednisolone)、乙酸氫化潑尼松、第三-丁基乙酸氫化潑尼松、潑尼松、甲基氫化潑尼松、乙酸甲基氫化潑尼松 '安西諾隆(triamcinolone)縮丙酮化物、安西諾隆二縮丙 _化物、及安西諾隆六縮丙酮化物。鑑於本揭示内容之優 20 勢’熟悉本項技藝者可輕易瞭解其它合適腎上腺促糖皮質激素。在特定實施例中，該抗關節炎藥劑為選自以下所組成之群Μ的SCE(小化學成份)DMARD(疾病修飾抗風濕病藥物）：羥基氯喳、氯喳、達波松（dapsone)、舒沙拉。井 28 200823216 (sulfasalazine)、阿美蘇嗓呤（methotrexate)、雷夫米德 (leflunomide)、硫唾17票呤(azathioprine)、d-青黴胺、環孢黴素A、及金組份，諸如硫化蘋果酸金鈉、及金硫葡萄糖、及奥倫費（auranofin)。 5 在特定實施例中，該抗關節藥劑為選自以下所組成之群組的生物DMARD :依坦賽特（etanercept)、因福西麻 (infliximab)、阿達里麻（adalimumab)、阿那肯拉（anakinra)、阿巴塔塞（abatacept)、雷突西麻（rituximab)、托西朱麻 (tocilizmnab)、及色托朱麻佩果(certolizumab pegol)。鑑於本 10 揭示内容之優勢，熟悉本項技藝者可輕易瞭解其它合適 DMARD(SCE或生物性製劑）。在特定實施例中，該抗關節炎藥劑為止痛劑，諸如乙醯基苯酚。鑑於本揭示内容之優勢，熟悉本項技藝者可輕易瞭解其它合適止痛劑。 15 在特定實施例中’該抗關節炎藥劑為選自以下所組成之群組的可選擇性併用乙醯基苯酚之鸦片樣物質：嗎啡、可待因、右丙氧啡（propoxyphene)、二氫可待因酮 (hydrocodone)、美沙酮（methadone)、氫嗎啡酮 (hydromoiphone)、羥可酮(oxycodone)、芬坦尼（fentanyl)、 20 丁丙諾啡(buPrenorPhine)、及布托啡諾（butorphanol)。鑑於本揭示内容之優勢，熟悉本項技藝者可輕易瞭解其它合適的鴉片樣物質。本揭示内容另一方面係有關於治療或預防人類之類風濕性關節炎的方法，其包括對人類共投予治療上有效量之 29 200823216 劑或其藥學上可接受鹽及至少— 傑納斯激嗨抑制 =劑或其藥學上可接受鹽，其中該傑二酶種抗關節该專抗關炎_之定義如文中所述。，抑制劑及性關方面係有關於用於治療或預防牛皮_ 其藥學上可其包含傑納斯激糾制劑或 ==傑一一‘二: 10 15 20 癬性有關於治療或預防人類之牛皮 Ρ人的方法，其包括對人類共投予治反傑納斯激_卩咖或其鮮上可接受鹽及以上有效量之炎藥劑或其藥學上可接受鹽，其中該傑納斯:J抗關節該等抗關節炎藥劑之定義如文中所述。顿梅抑制劑及連二 =:::=關r於治療或預防_ 可二鹽及至少一種抗關節炎藥劑或其』之定二二=傑納斯_抑制劑及該等抗關節炎藥劑關節於治療或預防人類之會椎火的方法，其包括對人類妓於名效量之傑納斯___其#學予治療上有抗關節炎藥劑或其藥學上可接受鹽，===至少一種制劑及該等抗_炎_之定義如文中所；7销激酶抑 30 200823216 實施例之詳述可瞭解文中所揭示之該等法的另外特徵及優點。式】較佳實施例之詳細說明In a particular embodiment, the anti-arthritic agent is an NSAID (non-steroidal anti-inflammatory drug) or a COX-2 (cyclo-oxygenase 2) inhibitor selected from the group consisting of: acetylsulfate Other salicylates, such as choline magnesium laurate, azapropazone, carprofen, celecoxib, celocoxib, diclofenac potassium, diclofenac Sodium, diflunisal, etodolac, fenbufen, fenoprofen, flufenamic acid, flurbiprofen, cloth Ibuprofen, indomethacin, ketoprofen, mefenamic acid, meloxicam, nabumetone, naphthalene Naproxen, naproxen sodium, oxaprozin, pirprofen, suprofen, salsalate, sulindac, tenoxicam ( Tenoxicam), tiaprofenic 10 acid, and tolmetin. In view of the advantages of this disclosure, other suitable NS(R) and/or COX2 inhibitors will be readily apparent to those skilled in the art. In a particular embodiment, the anti-arthritic agent is an adrenal glucocorticoid (administered orally, parenterally, and/or intra-articularly) selected from the group consisting of hydrocorticosterone acetate, third-butyl Hydrocorticosterone acetate, dexamethasone 15 pine ((1 & 11^1^01^3061316), third-butyl acetate dexamethasone, hydrogenated prednisolone, prednisolone acetate, prednisolone acetate, Tertiary butyrate prednisolone, prednisone, methylprednisolone, methylprednisolone acetate triamcinolone acetonide, ansinolon di-propylation, and Anxi Noron hexaploate. In view of the advantages of the present disclosure, other suitable adrenal glucocorticoids can be readily understood by those skilled in the art. In a particular embodiment, the anti-arthritic agent is selected from the group consisting of Group of SCE (Small Chemical Ingredients) DMARD (Disease Modified Antirheumatic Drugs): Hydroxychloropurine, Chloroquinone, Dapsone, Shusha. Well 28 200823216 (sulfasalazine), Amesuxate (methotrexate), Leflunomide, sulfur saliva 17 Azathioprine, d-penicillamine, cyclosporine A, and gold components, such as sodium sulphate malate, and gold sulphur glucose, and auranofin. 5 In a particular embodiment, The anti-articular agent is a bio-DMARD selected from the group consisting of: etanercept, infliximab, adalimumab, anakinra, abatase (abatacept), rituximab, tocilizmnab, and certolizumab pegol. Given the advantages of this disclosure, those skilled in the art can easily understand other suitable DMARD (SCE or biological preparation). In a particular embodiment, the anti-arthritic agent is an analgesic agent, such as acetal phenol. Other suitable analgesics are readily apparent to those skilled in the art in view of the advantages of this disclosure. In a particular embodiment, the anti-arthritic agent is an opioid-like material that is selectively used in combination with acetol: morphine, codeine, propoxyphene, Hydrocodone (h Ydrocodone), methadone, hydromoiphone, oxycodone, fentanyl, 20 buprenorphine, and butorphanol. In view of the advantages of this disclosure, other suitable opioid materials will be readily apparent to those skilled in the art. Another aspect of the present disclosure relates to a method of treating or preventing rheumatoid arthritis in humans comprising co-administering to a human a therapeutically effective amount of 29 200823216 or a pharmaceutically acceptable salt thereof and at least - Janus A stimulating inhibition agent or a pharmaceutically acceptable salt thereof, wherein the genomic enzyme is resistant to joints as defined herein. , inhibitors and sexual aspects are related to the treatment or prevention of cowhide _ its pharmaceutically acceptable inclusion of Janus stimulating preparations or == Jie Yiyi' 2: 10 15 20 癣有有有治疗治疗治疗治疗治疗A method of psoriasis comprising administering to a human a total of an anti-Jess yin or a freshly acceptable salt thereof and an effective amount of the inflammatory agent or a pharmaceutically acceptable salt thereof, wherein the genus: J anti-articular such anti-arthritic agents are defined as described herein. Dimensional inhibitors and even two =:::============================================================================= A method of treating or preventing a vertebral fire in a human body, which comprises treating an artificial anti-arthritic agent or a pharmaceutically acceptable salt thereof on a human genus. = at least one formulation and the definition of such anti-inflammatory _ as defined herein; 7 pin kinase 30. The details and advantages of the methods disclosed herein can be understood from the detailed description of the examples. Detailed description of the preferred embodiment

雖然本揭示内容之特定實施例現在係參考製法及圖解中所述之特定較佳實施例，應該瞭解此等實施例僅作為實例且僅闡明可代表本揭示内容之原理的應用之許多合適特疋實轭例的少數。鑣於本揭示内容之優勢，熟悉本項技藝者可知各種蜒化及修飾且這些變化及修飾被認為屬於如附力申明專利範圍中進一步定義之本揭示内容的精神及範圍。除非另有定義，文中使用之所有技術及科學名詞具有如一般技術者普遍瞭解之屬於本揭示内容的相同意義。定義除非另有指定，如文中使用，該名詞“烷基，，包括具有直鍵或分支鏈分子團或其組合之飽和單價烴基。While the present invention has been described with respect to the preferred embodiments of the preferred embodiments of the present invention, it is understood A few of the actual yoke cases. </ RTI> </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; Unless otherwise defined, all technical and scientific terms used herein have the same meaning meaning Definitions Unless otherwise specified, the term "alkyl," as used herein, includes saturated monovalent hydrocarbon radicals having straight or branched chain molecular groups or combinations thereof.

自以下特& 學組合物及其方From the following special & composition and its side

如文中使用，該名詞“烷氧基，，包括0-烷基，其中“烷基，，如上文定義。除非另有指定，如文中使用，該名詞“鹵素，，包括氟、氣、〉臭或峨。如文中使用，該名詞“(CVC9)雜環烷基，，係指吡咯啶基、四氫呋喃基、二氫呋喃基、四氫哌喃基、哌喃基、硫辰南基、吖丙啶基、環氧乙烷基、亞曱基二氧基、色烯基、異圬唑啶基、1，3_嘮唑啶基、異噻唑啶基、丨，3_噻唑啶_3_ 基1，2』比唾啶-2-基、丨，3』比唑啶小基、哌啶基、硫嗎啉基、 31 200823216 1，2-四氫嘍讲_2_基、1，3-四氫嘍畊·3_基、四氫咳二啡As used herein, the term "alkoxy," includes 0-alkyl, wherein "alkyl," is as defined above. Unless otherwise specified, the term "halogen," includes fluorine, gas, or odor or hydrazine. As used herein, the term "(CVC9)heterocycloalkyl, refers to pyrrolidinyl, tetrahydrofuranyl, Dihydrofuranyl, tetrahydropyranyl, piperidyl, thiophenylidene, aziridine, oxiranyl, fluorenylenedioxy, chromenyl, isoxazolidinyl, 1, 3_oxazolidinyl, isothiazolidinyl, indole, 3_thiazolidine_3_yl 1,2"pyridin-2-yl, indole, 3"pyrazolidineyl, piperidinyl, thiomorpholine Base, 31 200823216 1,2-tetrahydroanthracene _2_yl, 1,3-tetrahydroindole, 3_yl, tetrahydroculceptine

㈣基、色滿基等。-般技術者可瞭解該等(C2_c9)雜環烧基環之連接係經由碳或一個Sp3混成氮雜原子。悉一节、嗎啉四氫吖呼基、口比洛基、三峻基、四峻基、咪σ坐基、噚二唑基、1，2,3-噚二唑基、1，3,5-噻二如文中使用，該名詞“(CVC9)雜芳基，，係指呋喃基、噻吩基、嘍唑基、吡唑基、異嘍唑基、噚唑基、異噚唑基、(4) Base, color and base. It will be appreciated by those skilled in the art that the linkage of the (C2_c9) heterocycloalkyl ring is a nitrogen heteroatom via carbon or a Sp3. A section, morpholine tetrahydro oxime, mouth 洛洛基, 三峻基, 四峻基, 咪σ基基, oxadiazolyl, 1,2,3-oxadiazolyl, 1,3, 5-thiadi is as used herein, the term "(CVC9)heteroaryl," refers to furanyl, thienyl, oxazolyl, pyrazolyl, isoxazolyl, oxazolyl, isoxazolyl,

基、1，2,4-嘴二吐基、咐(啶基、嘧啶基、咣畊基、嚏吨基Base, 1,2,4-mouth dithiol, anthracene (pyridyl, pyrimidinyl, hydrazine, xanthenyl)

吡啶基、噌啉基、喋啶基、嘌呤基、6,7_二氫^沁⑴吡啶基、苯并[b]噻吩基、5,6,7,8-四氫-喳啉_3_基、苯并嘮唑基、苯并噻唑基、苯并異噻唑基、苯并異噚唑基、苯并咪唑基、噻茚基、異嚷茆基、笨并呋喃基、異苯并呋喃基、異吲哚基、吲 15 α朶基、吲井基、吲唾基、異唆琳基、4琳基、酜啡基、嗜噚啉基、喳唑啉基、苯并噚畊基等。一般技術者可瞭解該等 (CrC9)雜環烷基環之連接係經由碳原子或一種sp3混成氮雜原子。當文中使用日守’（CVC1())芳基係指苯基或萘基。 20 如文中使用，該名詞“藥學組合治療物，，或“組合治療物，，通常指傑納斯抑制劑與一或多種文中所揭示之抗關節炎藥劑一起投予。換g之，該名詞“藥學組合治療物，，意指呈以下劑型之可以以藥學上可接受形式同時與一或多種文中所揭示之抗關節炎藥劑投予的傑納斯激酶抑制劑（諸如 32 200823216 式⑴化合物）：⑴相同的劑物，其表示含傑納斯激酿“列如相同錠劑或藥學組成丁3請教晦抑制劑(諸種文中所揭示之抗關節炎_、飞夕學組忠礼.·. 士及藥學上可接受載劑之藥於口服，（11)具相同投藥方式之不同劑型，例如包括適可接2含傑納斯_抑制劑（諸如式⑴化合物）及藥學上劑的第一藥學組成物、及適於口服之含一或多種 :揭不之抗關節炎藥劑與藥學上可接受載劑的第二藥二成物之套組；及⑽具有不同投藥方式之μ劑型，例 10 15 \ 20 =適於口服之含傑納斯激峰抑制劑(諸如式(ι)化合物) 藥^上可接受載劑的第—藥學組成物、及適於非經腸投卜❹種文中所揭示之抗關節炎藥劑的第二藥學組疏2套組。此外，鑑於本揭示内容之優勢，熟悉本項技 ^:知#奸不只—種文中所揭示之抗關節炎藥劑時，八钟藥劑不需要共用相同投藥方式，例如包括適於口服之 =‘納斯激晦抑制劑（諸如式⑴化合物）及藥學上可接受載 d之第一藥學組成物、適於口服之含如文中所揭示之第一抗關節炎藥劑及藥學上可接受載劑之第二藥學組成物、及 :於非經腸投藥之含文中所揭示之第二抗關節炎藥劑與藥予上可接文载劑之第三藥學組成。熟悉本項技藝者可知就藥學組合治療物，，而言，上文所謂之同時投藥意指可按相同時間表，亦即於相同時間及同一天，或按不同時間表，Pyridyl, porphyrin, acridinyl, fluorenyl, 6,7-dihydroindolyl (1) pyridyl, benzo[b]thienyl, 5,6,7,8-tetrahydro-porphyrin_3_ Benzo, benzoxazolyl, benzothiazolyl, benzisothiazolyl, benzisoxazolyl, benzimidazolyl, thioxyl, isodecyl, benzofuranyl, isobenzofuranyl , isodecyl, fluorene 15 α, 吲基, 吲基, 唆唆、, 4 linyl, morphine, porphyrinyl, oxazoline, benzopyrene. One of ordinary skill will appreciate that the linkage of the (CrC9) heterocycloalkyl ring is a nitrogen heteroatom via a carbon atom or a sp3. The use of R&D '(CVC1()) aryl refers to phenyl or naphthyl as used herein. 20 As used herein, the term "pharmaceutical combination therapy," or "combination therapy, generally refers to a Janus inhibitor administered with one or more of the anti-arthritis agents disclosed herein. The term "pharmaceutical combination therapy" means a Janus kinase inhibitor (such as the following dosage form which can be administered in a pharmaceutically acceptable form simultaneously with one or more of the anti-arthritic agents disclosed herein (such as 32 200823216 Compound of formula (1): (1) the same agent, which means that it contains Janus stimulating "column of the same lozenge or pharmaceutical composition" (inhibition of anti-arthritis as disclosed in the literature) Group loyalty.. and pharmaceutically acceptable carrier drugs are given orally, (11) different dosage forms with the same dosage form, including, for example, suitable for containing Janus-inhibitors (such as compounds of formula (1)) and pharmacy a first pharmaceutical composition of the active agent, and a kit comprising one or more of: a second drug of the anti-arthritic agent and a pharmaceutically acceptable carrier; and (10) having different administration modes μ dosage form, Example 10 15 \ 20 = a pharmaceutical composition containing a Janus peak inhibitor (such as a compound of formula (1)), an acceptable carrier, and a parenteral drug suitable for oral administration The anti-arthritic agent disclosed in the essay The pharmaceutical group is divided into two sets. In addition, in view of the advantages of the present disclosure, it is not necessary to share the same administration method when the anti-arthritic agent disclosed in the above-mentioned article is known to be familiar with the present invention, for example, including Suitable for oral administration = 'Nastimin inhibitor (such as a compound of formula (1)) and a pharmaceutically acceptable first pharmaceutical composition of d, suitable for oral administration comprising a first anti-arthritic agent and pharmacy as disclosed herein a second pharmaceutical composition comprising an acceptable carrier; and a second pharmaceutical composition comprising a second anti-arthritic agent and a drug as disclosed in the parenteral administration. It can be seen that in the case of a pharmaceutical combination treatment, the above-mentioned simultaneous administration means that the same schedule can be used, that is, at the same time and on the same day, or on different schedules.

亦Γ不同但未必顯著不同之時間表，投予含傑納斯激_P 制劑之藥學組成物及含該抗關節炎藥劑之藥學組成物 (群）。關於這點，#按不同時間表投傾含傑納斯激崎抑制 33 200823216 :!之藥學組成物及含抗關節炎藥劑之藥種不同時縣㈣可稱為“背景”或“㈣㈣(群化，此 =次投予呈特定劑型之該含傑_:抑= 5 組成物，且可以每日一次投予該含抗關節炎举劑成物(群），藉此在每日投藥中之 W之本學組之藥學組成物可(但未必)與該含組成物(群）同時投予。當然，鑑於本揭示内容之^樂予本項技藝者可輕易瞭解“藥學組合治療物，，之^人’热悉且其係為該名詞定義之一部份。八匕3適變異 10 如:中:吏用，該名詞“傑納斯激_ 中揭不之生物檢定法所測定如错文納斯激峰’亦即則、MK2、及做/中之’種或多種傑 (群)。代表性傑納斯激酶抑制劑包括文中所揭示之 15 物。杈佳之傑納斯激梅抑制劑為^伽，叫 : 魄3___4_基)_胺基]，丙腈或其藥學上可接受鹽。例乳基- 的學一療〜義㈣μ傑納斯料抑制劑及—或多 20 本揭㈣容-方面財_祕治療_ ==的藥治療物，其包含傑納斯心 :可接受:可接懷至少-種抗關節炎峨其藥學在特疋實她例中，該傑納斯激酶抑制劑為下式化合物 34 200823216 R1 D2A pharmaceutical composition comprising a Janus® _P preparation and a pharmaceutical composition (group) containing the anti-arthritic agent are also administered on different, but not significantly different, schedules. Regarding this point, ######################################################################################################### In this case, the composition is contained in a specific dosage form, and the anti-arthritic agent (group) can be administered once a day, thereby being administered daily. The pharmaceutical composition of the group of W may (but not necessarily) be administered simultaneously with the composition (group). Of course, in view of the present disclosure, the skilled artisan can readily understand "pharmaceutical combination therapy, ^人's hot and its part is part of the definition of the noun. Gossip 3 is suitable for variation 10 such as: medium: use, the term "Jenas _ _ _ _ _ _ _ _ _ Wennas's peaks are also known as MK2, and do / in the 'species or a variety of Jie (group). Representative Janus kinase inhibitors include the 15 disclosed in the article. The agent is gamma, called: 魄3___4_yl)-amino group, propionitrile or a pharmaceutically acceptable salt thereof. Example of a milk base - a treatment of ~ Yi (four) μ Genus Inhibitors and - or more than 20 (4) volume - aspects of the financial _ secret treatment _ = = drug treatment, which contains Janus heart: acceptable: can take care of at least - an anti-arthritis 峨 its pharmacy in In her case, the Janus kinase inhibitor is a compound of the formula 34 200823216 R1 D2

或其藥學上可接受鹽；其中 R1為下式基團 R5 R4、/(而 y 5 其中y為0、1或2 ; R4係選自以下所組成之群組：氫、（CrC6)烷基、（CVQ) 烷磺醯基、（C2-C6)烯基、（C2-C6)炔基，其中該烷基、烯基及炔基可選擇性經以下基團取代：氘、羥基、胺基、三氟甲基、（CrC4)烷氧基、（CrC6)醯氧基、（CrC6)烷胺基、（(CrC6) 10 烷基)2胺基、氰基、硝基、（C2-C6)烯基、（C2-C6)炔基或(CVC6) 醯胺基；或R4為(C3-C1G)環烷基，其中該環烷基可選擇性經以下基團取代：氘、羥基、胺基、三氟曱基、（CrCJ醯氧基、（Ci_C6)&&fe 基、（Ci_C6)烧胺基、（(Ci-C6)烧基)2 胺基、氣基、氰基(C「C6)烧基、三氟甲基(Q-C6)烧基、墙基、石肖 15 基(crc6)烷基或(crc6)醯胺基； R5為（C2-C9)雜環烷基，其中該雜環烷基必需經1至5種以下之基團取代··羧基、氰基、胺基、氘、羥基、（crc6) 烷基、（CrC6)烷氧基、函素、（CrC6)醯基、（CVC6)烷胺基、胺基(CrCd烷基、（CVC6)烷氧基、-CO-NH、（CVC6)烷胺基 20 -CO-、（C2-C6)烯基、（C2-C6)炔基、（CrC6)烷胺基、羥基(CrC6) 35 200823216 烷基、（CVC6)烷氧基(CVC6)烷基、（CrC6)醯氧基(CrC6)烷基、石肖基、氰基(C「C6)烧基、_(Ci-C6)烧基、琐基(C「C6) 烷基、三氟甲基、三氟甲基(crc6)烷基、（crc6)醯胺基、 (Ci_C6)醯胺基(Ci_C6)烧基、（Cl_C6)烧氧基(Ci-C6)醯胺基、 5 胺基(Crc6)醯基、胺基(CrC6)醯基(CrC6)烷基、（Crc6)烷胺基（Ci-C6)醯基、（(Ci-C6)燒基）2胺基（CVC6)醯基、 R15R16N-CO_〇-、R15R16N-CO-(CrC6)烷基、（crc6)烷基 -s(0)m、R15R16NS(0)m、R15R16NS(0)m(CrC6)烷基、 R15S(0)mR16N、R15S(0)mR16N(CrC6)烷基，其中m為〇、1或 10 2，且R15及R16各獨立選自氫或(Q-C6)烷基；或下式基團：Or a pharmaceutically acceptable salt thereof; wherein R1 is a group of the formula R5R4, /(and y5 wherein y is 0, 1 or 2; and R4 is selected from the group consisting of hydrogen, (CrC6) alkyl (CVQ) alkanesulfonyl, (C2-C6)alkenyl, (C2-C6)alkynyl, wherein the alkyl, alkenyl and alkynyl groups are optionally substituted by hydrazine, hydroxy, amine , trifluoromethyl, (CrC4) alkoxy, (CrC6) alkoxy, (CrC6) alkylamino, ((CrC6) 10 alkyl) 2 amine, cyano, nitro, (C2-C6) Alkenyl, (C2-C6)alkynyl or (CVC6)nonylamino; or R4 is (C3-C1G)cycloalkyl, wherein the cycloalkyl group is optionally substituted with: hydrazine, hydroxy, amine , trifluoromethyl, (CrCJ decyloxy, (Ci_C6) && Fe, (Ci_C6) acryl, ((Ci-C6) alkyl) 2 amine, gas, cyano (C" C6) alkyl, trifluoromethyl (Q-C6) alkyl, wall group, fluorenyl 15 (crc6) alkyl or (crc6) decylamino; R5 is (C2-C9) heterocycloalkyl, wherein The heterocycloalkyl group must be substituted with 1 to 5 or less groups of a carboxyl group, a cyano group, an amine group, a hydrazine group, a hydroxyl group, a (crc6) alkyl group, a (CrC6) alkoxy group, and a functional group. , (CrC6) fluorenyl, (CVC6) alkylamino, amine (CrCd alkyl, (CVC6) alkoxy, -CO-NH, (CVC6) alkylamino 20-CO-, (C2-C6) alkene , (C2-C6) alkynyl, (CrC6) alkylamino, hydroxy (CrC6) 35 200823216 alkyl, (CVC6) alkoxy (CVC6) alkyl, (CrC6) decyloxy (CrC6) alkyl, Succinyl, cyano (C "C6" alkyl, _ (Ci-C6) alkyl, tribasic (C "C6" alkyl, trifluoromethyl, trifluoromethyl (crc6) alkyl, (crc6) 醯Amine, (Ci_C6) decylamino (Ci_C6) alkyl, (Cl_C6) alkoxy (Ci-C6) decylamine, 5 amine (Crc6) fluorenyl, amine (CrC6) fluorenyl (CrC6) alkane (Crc6)alkylamino (Ci-C6) fluorenyl, ((Ci-C6)alkyl) 2 amine (CVC6) fluorenyl, R15R16N-CO_〇-, R15R16N-CO-(CrC6)alkyl , (crc6)alkyl-s(0)m, R15R16NS(0)m, R15R16NS(0)m(CrC6)alkyl, R15S(0)mR16N, R15S(0)mR16N(CrC6)alkyl, wherein m is 〇, 1 or 10 2 , and R 15 and R 16 are each independently selected from hydrogen or (Q-C 6 )alkyl; or a group of the formula:

其中a為0、1、2、3或4 ; b、c、e、f及g各獨立為〇或1 ; d為0、1、2或 3 ; 15 X為S(〇)n，其中η為〇、1或2 ;氧、羰基或_C(=N_氰基 Y為S(0)n ’其中η為〇、1或2;或羰基；且 Ζ為羰基、c(0)0-、C(0)NR_或S(0)n，其中_〇、13戈2 ; R6、R7、R8、R9、R1。及Rn各獨立選自以下所組成之群組：氫或可選擇性經氣、經基、胺基、三氟甲基、（C1_C6) 酿氧基、（q-C推胺基、（Cl_c6)烧胺基、（(Ci_C6)烧基)滋 36 20 200823216 基、氰基、氰基(Ci-C6)烧基、三氟甲基烧基、頌基、硝基(Crc6)烷基或(Ci-Cd醯胺基取代之(Q-C6)烷基； R12為羧基、氰基、胺基、側氧基、氘、羥基、三氟甲基、（CrC6)烷基、三氟甲基(CVC6)烷基、（crc6)烷氧基、 5 函素、（crc6)醯基、（crc6)烷胺基、（(crc6)烷基)2胺基、胺基(CrC6)烷基、（CrC6)烷氧基-CO-NH、（CrC6)烷胺基 -CO-、（C2-C6)卸基、（C2-C6)快基、^基(Ci_C6)烧基、（Ci_C6) 烷氧基(CrCs)烷基、（CrC6)醯氧基(CVC6)烷基、硝基、氰基(Ci_C6)烧基、_(Ci-C6)烧基、石肖基(Ci-C6)院基、（Ci_C6) 10 醯胺基、（crc6)醯胺基(crc6)烷基、（crc6)烷氧基(crc6) 醯胺基、胺基(crc6)醯基、胺基(crc6)醯基(cvc6)烷基、 (CrC6)烷胺基（CVC6)醯基、（(CVC6)烷基)2胺基（crc6)醯基、R15R16N-C0-0-、R15R16N-CO-(CVC6)烷基、r15c(o)nh、 R150C(0)NH、R15NHC(0)NH、（CVC6)烷基-s(o)m、（Crc6) 15 烷基 4(0)^((^-(:6)烷基、RbR^NSaVR^R^NSCCOJCrC^) 烷基、R15S(0)mR16N、R15S(0)mR16N(CrC6):^基，其中 m為 Ο、 1或2且R15及R16各獨立選自氫或(CrC6)烷基； R2及R3各獨立選自以下所組成之群組：氫、氘、胺基、鹵素、羥基、硝基、羧基、（C2-C6)烯基、（C2-C6)炔基、三 20 氟甲基、三氟甲氧基、（CrC6)烷基、（CrC6)烷氧基、（C3-C1()) 環院基’其中該烧基、烧氧基或環烧基可選擇性經1至3種選自以下之基團取代：i素、羥基、羧基、胺基(CrC6)烷硫基、（Ci_C6)烧胺基、（(Ci-C6)烧基)2胺基、（C5-C9)雜芳基、 (C2-C9)雜環烧基、（C3_C9)環烧基或(C6-Ci〇)芳基；或R2及R3 37 200823216 各獨立為（CVCio)環烧基、（CVCio)環烧氧基、（(^-(^6)燒胺基、（(CVC6)烧基)2胺基、（C6_Ci〇)芳胺基、（CVQ)院硫基、 (CVCw)芳硫基、（Ci-C6)院亞石黃醯基、（C6-C1())芳亞磺醯基、 (Ci-C6)烧石黃酿基、（C6_Ci〇)芳石黃基、（Ci-C6)酿基、 5 烷氧基-CO-NH-、（cvc6)烷胺基-CO·、（C5-C9)雜芳基、（c2_C9) 雜環烷基或(C6-C1G)芳基，其中該雜芳基、雜環烷基及芳基可選擇性經1至3種以下基團取代：A素、（Crc6)烷基、（Cl_c6) 烧基 _CO-NH_、（CVC6)烧氧基-CO-NH·、（C〗_C6)烧基 -CO_NH-(CrC6)烷基、（CVC6)烷氧基-CO-NH-(CrC6)烷基、 10 (c!-c6)烷氧基-CO-NiHCVC^)烷氧基 '羧基、羧基(Cl_c6) 烷基、羧基(CVC6)烷氧基、节氧羰基(Q-C6)烷氧基、（Cl_c6：) 烷氧羰基(crc6)烷氧基、（c6-c1G)芳基、胺基、胺基(Cl_c6) 院基、（C1-C6)烧氧幾基胺基、（C6_CiG)芳基(C1-C6)烧氧魏基胺基、（Ci_C6)烧胺基、（(Ci_C6)烧基)2胺基、（Ci_C6)烧胺基 15 (CrC6)烷基、（(CrC6)烷基)2胺基(CrC6)烷基、羥基、（CVC6) 烧氧基、（C1-C6)烧氧幾基、（C1-C6)烧氧魏基(cvc6)烧基、 (Ci-C6)烧氧基-CO-NH-、氰基、（C5_C9)雜環烧基、胺基 -CO_NH-、（CrC6)烷胺基-CO-NH-、（(CrC6)烷基）2 胺基 -CO-NH-、（C6-C1())芳胺基 _CO_NH-、（C5-C9)雜芳胺基 20 -CO-NH-、（CVC6)烷胺基-CO-NH-O^-CO烷基、（(CVQ)烷基）2 胺基-CO-NH-(Ci_C6)院基、（c6-Ci〇)芳胺基 -CO-NHJCVC^)烷基、（C5-C9)雜芳胺基-CO-NHJCVC^)烷基、（CVC6)烷磺醯基、（CVC6)烷磺醯胺基、（crC6)烷磺醯胺基(CVC6)烷基、（CVCnO芳磺醯基、（c6-C1G)芳磺醯胺基、 38 200823216 (c6-c10)芳續醯胺基(Cl_c6)烧基、（C5_c9)雜芳基或％_〇雜壤烧基。在式I化合物之特定實施例中，該傑納斯激酶抑制劑係選自以下所組成之群組： 5 甲基β[4-甲基小（丙烧小績醯基底咬-3-基]口各并[2,3-d]嘧啶_4_基)-胺； 4_甲基-3-[曱基_(7H-吡咯并[2,3-d]嘧啶_4_基)_胺基]-哌啶-1-羧酸甲酯； 3,3,3_三氟-1·{4·甲基-3-[甲基-(7H-吡咯并[2,3-d]嘧啶 10 _4_基)-胺基]•采啶小基}-丙_ι_酮； 4-甲基-3-[甲基-(7H-吡咯并[2,3-d]嘧啶-4-基)-胺基]-哌 °定-1-羧酸二曱醯胺； ({4-甲基-3-[甲基-(7H-吡咯并[2,3-d]嘧啶-4·基)-胺基]_ 〇底°疋小緩基卜胺基)-乙酸乙酉旨； 15 甲基-3-[甲基-(7H-吡咯并[2,3-d]嘧啶-4-基）-胺基]-°底啶-1-基卜3-側氧基·丙腈； 3,3,3-三氟-i-{4-甲基_3·[甲基_(5_甲基-7H-吡咯并 [2,3_d>密啶_4·基)_胺基]_σ辰啶]_基》_丙小酮； Μ4-甲基-3-[甲基-(7Η-吡咯并[2,3-d]嘧啶-4-基）-胺 2〇基]-π底 °定_1_基}-丁-3-炔-1-酮； ΜΜ(5-氣-7Η_吡咯并[2,3-d]嘧啶-4-基）-甲基-胺基]-4-甲基-旅咬-1·基卜丙; M3-[(5-氟-7H-吡咯并[2,3_d]嘧啶_4_基）-甲基-胺基]-4-曱基-旅啶_i-基卜丙小酮； 39 200823216 N-氰基-4-甲基-3-[甲基_(7H-吡咯并[2,3-d]嘧啶-4-基)-胺基]-Ν’-丙基-σ底σ定-1-叛基脉； Ν-氰基_4，Ν，，Ν’-三曱基·3_[甲基-(7Η-吡咯并[2,3-d]嘧啶-4_基> 胺基]-哌啶-1-羧基脒； 5 甲基-[(3R，4R)-4-甲基小（丙烧小石黃醯基）_呢咬各基]-(7H-吡咯并[2,3-d]嘧啶_4_基)·胺； (3R，4R)_4-甲基-3_[曱基各并[2,3-d]务定_4·基)- 胺基]-哌啶-1-羧酸甲酯； 3,3,3-三氟-l-{(3R，4R)-4-甲基-3-[曱基-(7H-吡咯并 10 [2,3-(1]嘴唆-4-基)-胺基]_°辰咬-1-基}_丙_1_酮； (3R，4R)_4-甲基-3-[甲基-(7H-吡咯并[2,3-d]。密啶_4_基)_ 胺基]-哌啶_1_羧酸二甲醯胺； {(3R，4R)-4_ 甲基-3-[甲基 _(7H-咣咯并[2,3_d]嘧。定 _4_ 基)-胺基]-旅°定-1-叛基}-胺基)-乙酸乙酯； 15 3-{(3R，4R)-4-甲基-3-[甲基-(7H-吡咯并[2,3_d]嘧啶_4_ 基)-胺基]-σ底咬-1-基}-3-側氧基-丙腈； 3,3,3_三氟-l-{(3R，4R)-4·甲基-3-[甲基_(5_ 甲基_7Η_咣咯并[2,3_d]嘧啶冬基)_胺基]』辰啶基卜丙_丨_酮； 1-{(3R，4RM-甲基-3-[甲基_(7H_,比咯并[2,3-d]嘧啶斗 2〇基)-胺基]』底17定-1 _基}-丁-3-快-1 -嗣； l-{(3R，4R)-3-[(5-氯-7H-t各并[2,3-d]嘴啶 _4_ 基)甲基 -胺基]-4-甲基_呢啶-1·基卜丙小酮； l-{(3R，4R)-3-[(5_氟_7H_„比咯并 Od]嘧啶I基)_ 甲基 -胺基]-4-甲基-呢啶小基}—丙酮； 200823216 (3R,4R)_N-氰基-4-甲基-3-[曱基_(7H-吡咯并[2,3_d]嘧 ϋ定-4-基)·胺基]-Ν’-丙基-σ底咬-1-竣基脉，及 (3R，4R)-N-氰基·4，Ν’，Ν’_三甲基-3-[甲基-(7Η-吡咯并 [2,3-d]α密咬-4_基)-胺基]-°辰σ定-1 -竣基脉， 5 或彼等之藥學上可接受鹽。在特定實施例中，該傑納斯激酶抑制劑為3-{4-甲基 -3-[甲基- (7Η·17比洛弁[2,3-d] ♦σ定-4-基)-胺基]-。底唆-1-基}-3_ 側氧基-丙腈或其藥學上可接受鹽。在特定實施例中，該傑納斯激酶抑制劑為 10 3-{(3R，4R)-4-甲基-3-[甲基-(7Η-吡咯并[2,3-d]嘧啶-4-基）- 胺基]-哌啶-1_基}-3-側氧基-丙腈或其藥學上可接受鹽。在特定實施例中，該3-{4-曱基-3-[甲基-(7H-吡咯并 [2,3-d]密咬-4-基）-胺基]-°瓜σ定-1-基}-3 -側氧基-丙骑及/或 3-{(3R，4R)-4-甲基-3-[甲基-(7Η-吡咯并[2,3-d]嘧啶-4-基）-15 胺基]-哌啶_1-基}-3-側氧基-丙腈之藥學上可接受鹽為檸檬酸鹽，諸如單檸檬酸鹽。在特定實施例中，如美國專利第 6,965,027號中所述之此等化合物具結晶狀，該專利案之内容在此併入本案以為參考資料。本揭示内容之傑納斯激酶抑制劑可以呈藥學上可接受 20 酸加成鹽形式。該等用於製備本揭示内容之前述鹼化合物的藥學上可接受酸加成鹽之酸為可形成以下非毒性酸加成鹽的酸：含藥理上可接受陰離子之鹽，諸如鹽酸鹽、氫溴酸鹽、氫碘酸鹽、硝酸鹽、硫酸鹽、硫酸氫鹽、磷酸鹽、酸式磷酸鹽、乙酸鹽、乳酸鹽、檸檬酸鹽、酸式檸檬酸鹽、 41 200823216 酒石酸鹽、酒石酸氫鹽、琥j白酸鹽、順丁稀二酸蜂、反丁稀二酸鹽、葡萄糖酸鹽、葡萄糖二酸鹽、苯甲酸：：甲炉酸鹽、乙績酸鹽、苯續酸鹽、對_甲苯續酸鹽及帕莫酸: (pamoate)[亦即1,1，亞甲基-雙你經基j萘甲酸鹽)]。、孤 5 纟揭示内容之該等傑納斯抑制劑可以呈藥^上可接受驗加成鹽。該等可作為製備酸性之式丨化合物的藥學上可接受驗鹽之試劑的化學驗為可以與此等化合物形成非毒性驗鹽之化學驗。此等非毒性驗鹽包括，但不限於：衍生自: 等藥理上可接受陽離子，諸如驗金屬陽離子(例如卸及納） H)及驗土金屬陽離子(例㈣域）之㈣、銨或水溶性胺加成鹽:諸如1^甲基還原葡萄糖胺（亦即葡甲胺(meglumine))，及藥學上可接受有機胺之低碳烷醇銨與其它鹼鹽。文中所述之某些傑納斯激酶抑制劑具酸性且可以與各種藥理上可接受陽離子形成驗鹽。此等鹽之實例包括驗金 15屬或鹼土金屬鹽且特定言之，該等納及卸鹽。這些鹽全部白由驾知技術製成。该等作為製備本揭示内容之藥學上可接又驗鹽的试劑之化學鹼為可以與揭示内容之酸性化合物形成非毒性驗鹽的化學驗。此等非毒性驗鹽包括衍生自此等藥理上可接受陽離子，諸如納、_、約及鎮等之驗鹽。 2〇可藉使用含所欲藥理上可接受陽離子之水性溶液處理對應酸性化合物’然後較佳於減壓下使所形成溶液蒸發至乾燥而輕易地製成這些鹽。或者，亦可藉將該等酸性化合物之低碳烷醇系溶液及所欲鹼金屬烷氧化物一起混合，然後以如月ί述之相同方式將所形成溶液蒸發至乾燥而製成這些 42 200823216 5 鹽。在任一種情況下，較佳使用化學計量之試劑以確保反應完成及獲得所欲最終產物之最大產率。在特定實施例中，該傑納斯激峰抑制劑為以下專利案中所詳述及/或例示之化合物： USSN 09/335030,其係以美击 w 焉國專利第6,635,762號頒予； USSN 10/640079，其位、你Μ美國專利公開案第 2004-0058922Α1 號頒予； USSN 09/335121 ； / % USSN 09/956645，其係以美上為國專利第6,610,847號頒予； 10 USSN 10/442807,其係以義為國專利第6,890,929號頒予； USSN 11/064,873，复後 /、係以美國專利公開案第 2005-0171128 號頒予； 15 USS謂細69,其係以國專鄕6,627,754號頒予； ⑽謂顯27,其細美國專利第6,956，剛虎頒予； USSN 11/211，217，其係以古乂果國專利第7,091，208號頒予； USSN 11/474,233 ; V USSN圆獅其係以美國專利第6 696 567號頒予； USSN腦廳，其細㈣專利第6，％2,993號頌予； 20 USSN 11/112307，其 &、、係从美國專利公開案第 2005-0197349 號頒予； USSN 10/154699，复& 、係、以美國專利公開案第 2003- 0073719A1 號頒予； USSN 10/869101 ，复 # 以美國專利公開案第 2004- 0229923 A1 號頒予； 43 200823216 USSN 10/310078，其係以美國專利第6,965,〇27號頒予； USSN 11/032990，其係以美國專利公開案第 2005-0159434A1 號頒予，所有專利案之内容實際上在此併入本案以為參考資料。 5 本揭示内容之該等傑納斯激酶抑制劑包括所有構形異構物（例如順式及反式異構物）及彼等之混合物。此等化合物具有輕易為熟悉本項技藝者所知之不對稱中心且因此係以不同鏡像異構型及非對映異構型存在。本揭示内容係有關於用於本揭示内容之此等化合物的所有光學異構物及 10立體異構物及彼等之混合物的用途、及所有藥學組成物與可使用或含有彼等之治療方法。關於這點，本揭示内容兼包括E及Z構形。更詳細地，藉在或不在作為共溶劑之水存在下在合適溶劑（諸如乙醇）中以二取代之酒石酸或酒石酸鹽的特定光學異構物處理式HNR4R5化合物之外消旋混合 15物而進行用以得到式1該R1取代基之化合物的鏡像異構物外消旋混合物之拆分。使用美國專利案第10/154,699號中所揭示之此等方法可獲得超過90%之所欲鏡像異構物，該專利案之内容實際上在此併入本案以為參考資料。可用於該拆分之特定拆分劑包括酒石酸及酒石酸衍生物，諸如二_對 20 -曱苯甲醯基丄-酒石酸及(S)-(+)-腺酸(本賽松(pencyphos)， (S)-(+)-2-羥基_5,5-二甲基_4_苯基_；ι，3,2-二氧基磷雜環己烷 -2-氧化物）鹽。當然，鑑於本揭示内容之優勢，熟悉本項技藝者可瞭解潛在性可用於拆分此等式HNR4R5化合物之其它合適拆分劑。 44 200823216 本揭示内容之該等傑納斯激酶抑制劑亦可以呈互變異構物存在。本揭示内容係有關於所有此等互變異構物及彼等之混合物的用途。該拆分物質與特定鏡像異構物間之交互作用可拆分 5 該外消旋混合物，藉此該拆分物質及鏡像異構物之沈澱物可得到一種所欲立體特異性物質且其中溶液内之其餘鏡像異構物可因此各別離析。因此，根據所欲特定鏡像異構物及所使用分離方法（亦即自沈澱物或溶液），可同時選擇該拆分性質之立體特異性；例如該拆分劑，諸如酒石酸衍生物 10 之“L”型可得到該R1取代基之“R”型與含該“L”型之溶液的沈澱物，反之亦然。前述拆分劑能有效得到式III化合物（如上述，呈沈澱物或溶液形式）之3R，4R鏡像異構物 ημWhere a is 0, 1, 2, 3 or 4; b, c, e, f and g are each independently 1 or 1; d is 0, 1, 2 or 3; 15 X is S(〇)n, where η Is 〇, 1 or 2; oxygen, carbonyl or _C (=N-cyano Y is S(0)n ' wherein η is 〇, 1 or 2; or carbonyl; and Ζ is carbonyl, c(0)0- , C(0)NR_ or S(0)n, wherein _〇, 13 Ge 2; R6, R7, R8, R9, R1, and Rn are each independently selected from the group consisting of: hydrogen or optional By gas, mercapto, amine, trifluoromethyl, (C1_C6), oxy, (qC, amide, (Cl_c6), amine ((Ci_C6)), 36 20 200823216, cyano, Cyano (Ci-C6) alkyl, trifluoromethylalkyl, decyl, nitro (Crc6) alkyl or (Ci-Cd decyl substituted (Q-C6) alkyl; R12 is carboxyl, cyanide Base, amine group, pendant oxy group, hydrazine, hydroxy group, trifluoromethyl group, (CrC6) alkyl group, trifluoromethyl (CVC6) alkyl group, (crc6) alkoxy group, cyclin, (crc6) fluorenyl group , (crc6) alkylamino, ((crc6)alkyl) 2 amine, amine (CrC6) alkyl, (CrC6) alkoxy-CO-NH, (CrC6) alkylamino-CO-, (C2 -C6) unloading group, (C2-C6) fast group, ^ group (Ci_C6) alkyl group, (Ci_C6) alkoxy group (Cr Cs) alkyl, (CrC6) decyloxy (CVC6) alkyl, nitro, cyano (Ci_C6) alkyl, _(Ci-C6) alkyl, schishyl (Ci-C6), (Ci_C6) 10 Amidino, (rcc6) amidino (crc6) alkyl, (crc6) alkoxy (crc6) amidino, amine (crc6) fluorenyl, amine (crc6) fluorenyl (cvc6) alkyl, (CrC6) alkylamino (CVC6) fluorenyl, ((CVC6) alkyl) 2 amine (crc6) fluorenyl, R15R16N-C0-0-, R15R16N-CO-(CVC6) alkyl, r15c(o)nh , R150C(0)NH, R15NHC(0)NH, (CVC6)alkyl-s(o)m, (Crc6) 15 alkyl 4(0)^((^-(:6)alkyl, RbR^NSaVR ^R^NSCCOJCrC^) alkyl, R15S(0)mR16N, R15S(0)mR16N(CrC6): wherein m is Ο, 1 or 2 and R15 and R16 are each independently selected from hydrogen or (CrC6)alkyl R2 and R3 are each independently selected from the group consisting of hydrogen, hydrazine, amine, halogen, hydroxy, nitro, carboxy, (C2-C6)alkenyl, (C2-C6)alkynyl, tri-20 fluoro a methyl group, a trifluoromethoxy group, a (CrC6) alkyl group, a (CrC6) alkoxy group, or a (C3-C1()) ring-based group wherein the alkyl group, an alkoxy group or a cycloalkyl group may be selectively subjected to 1 Substituted to three groups selected from the group consisting of: i, hydroxyl, carboxyl, amine (CrC 6) alkylthio, (Ci_C6) acrylamine, ((Ci-C6)alkyl) 2 amine, (C5-C9) heteroaryl, (C2-C9) heterocycloalkyl, (C3_C9) ring-burning Or (C6-Ci〇) aryl; or R2 and R3 37 200823216 each independently (CVCio) cycloalkyl, (CVCio) cycloalkoxy, ((^-(^6) acrylamine, ((CVC6 ) an amine group, 2 amine group, (C6_Ci〇) arylamine group, (CVQ) institute sulfur group, (CVCw) arylthio group, (Ci-C6) institute sulphate, (C6-C1()) sulphite Sulfhydryl, (Ci-C6) burnt stone yellow base, (C6_Ci〇) aryl stone yellow base, (Ci-C6) brewing base, 5 alkoxy-CO-NH-, (cvc6) alkylamine-CO· (C5-C9)heteroaryl, (c2_C9)heterocycloalkyl or (C6-C1G)aryl, wherein the heteroaryl, heterocycloalkyl and aryl are optionally substituted with 1 to 3 groups Substitution: A, (Crc6) alkyl, (Cl_c6) alkyl _CO-NH_, (CVC6) alkoxy-CO-NH, (C _ C6) alkyl-CO_NH-(CrC6) alkyl, ( CVC6) alkoxy-CO-NH-(CrC6)alkyl, 10(c!-c6)alkoxy-CO-NiHCVC^)alkoxy'carboxyl, carboxy(Cl_c6)alkyl, carboxy(CVC6)alkane Oxyl, oxycarbonyl (Q-C6) alkoxy, (Cl_c6:) alkoxycarbonyl (crc6) alkoxy, ( C6-c1G) aryl, amine, amine (Cl_c6), (C1-C6) alkoxyamino, (C6_CiG) aryl (C1-C6), oxy-transylamino, (Ci_C6) An amine group, ((Ci_C6) alkyl) 2 amine group, (Ci_C6) acryl group 15 (CrC6) alkyl group, ((CrC6) alkyl) 2 amine group (CrC6) alkyl group, hydroxyl group, (CVC6) Oxyl group, (C1-C6) aerobic acid group, (C1-C6) oxy-oxygen group (cvc6) alkyl group, (Ci-C6) alkoxy group-CO-NH-, cyano group, (C5_C9) heterocyclic ring Alkyl, amine-CO_NH-, (CrC6) alkylamino-CO-NH-, ((CrC6) alkyl) 2 amine-CO-NH-, (C6-C1()) arylamine _CO_NH- (C5-C9) Heteroarylamino 20-CO-NH-, (CVC6) alkylamino-CO-NH-O^-CO alkyl, ((CVQ)alkyl) 2 Amino-CO-NH- (Ci_C6), (c6-Ci〇) arylamino-CO-NHJCVC^)alkyl, (C5-C9)heteroarylamino-CO-NHJCVC^)alkyl, (CVC6) alkanesulfonyl, (CVC6) alkanesulfonylamino, (crC6) alkanesulfonylamino (CVC6) alkyl, (CVCnO arylsulfonyl, (c6-C1G) arylsulfonylamino, 38 200823216 (c6-c10) Amidino (Cl_c6) alkyl, (C5_c9) heteroaryl or % 〇 heterologous. In a particular embodiment of the compound of Formula I, the Janus kinase inhibitor is selected from the group consisting of: 5 methyl β [4-methyl small (propyl acetonide 醯 base -3- base] Mouth [2,3-d]pyrimidin-4-yl)-amine; 4-methyl-3-[indenyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amine Methyl]-piperidine-1-carboxylate; 3,3,3-trifluoro-1·{4·methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidine 10 _4_yl)-amino]•picidine small group}-propyl_ι-ketone; 4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl) -amino]-piperidin-1-carboxylic acid diamine; ({4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4yl)- Amino] 〇疋疋疋疋 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 15 Base]--endridin-1-yl-p-3-oxo-propanenitrile; 3,3,3-trifluoro-i-{4-methyl_3·[methyl-(5-methyl-7H -pyrrolo[2,3_d> pyridine _4.yl)-amino]- σ 啶 ] _ _ _ _ _ _ ke ketone; Μ 4-methyl-3-[methyl-(7Η-pyrrolo[2, 3-d]pyrimidin-4-yl)-amine 2 fluorenyl]-π ° 定 _ _ _ _ _ -3- acetyl-1-one; ΜΜ (5-gas-7Η_pyrrolo[2, 3-d]pyrimidin-4-yl)-methyl- Amino]-4-methyl-bunk bit-1·kibprop; M3-[(5-fluoro-7H-pyrrolo[2,3_d]pyrimidin-4-yl)-methyl-amino]-4 - mercapto-braziside _i-kibpropanone; 39 200823216 N-cyano-4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl )-Amino]-Ν'-propyl-σ- bottom sigma--1-rebase; Ν-cyano _4, Ν,, Ν'-trisyl, 3_[methyl-(7Η-pyrrole [2,3-d]pyrimidin-4-yl]amino]-piperidine-1-carboxyindole; 5 methyl-[(3R,4R)-4-methyl small (propyl sulphur) Biting each group]-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amine; (3R,4R)_4-methyl-3_[indenyl[2,3-d] Methylamino]-piperidine-1-carboxylic acid methyl ester; 3,3,3-trifluoro-l-{(3R,4R)-4-methyl-3-[indenyl- (7H-pyrrolo 10 [2,3-(1] oxime-4-yl)-amino]_°chen-1-yl}_propan-1-one; (3R,4R)_4-methyl -3-[methyl-(7H-pyrrolo[2,3-d]. pyridine-4-yl)-amino]-piperidine-1-carboxylic acid dimethylamine; {(3R,4R) -4_methyl-3-[methyl-(7H-indolo[2,3_d]pyrimidine. _4_yl)-amino]-branches--1-amino}-amino)-ethyl acetate; 15 3-{(3R,4R)-4-methyl-3-[methyl-( 7H-pyrrolo[2,3_d]pyrimidin-4-yl)-amino]-σ bottom -1-yl}-3-sideoxy-propionitrile; 3,3,3_trifluoro-l-{( 3R,4R)-4·methyl-3-[methyl-(5-methyl-7 Η 咣并[2,3_d]pyrimidinyl)-amino] 辰啶基卜卜丨酮酮 ketone; 1-{(3R,4RM-methyl-3-[methyl-(7H_, bis-[2,3-d]pyrimidin-2-yl)-amino]- bottom 17--1 _ group}-丁-3-快-1 -嗣; l-{(3R,4R)-3-[(5-chloro-7H-t each [2,3-d])-methyl 4-amino group ]-4-methyl-nathene-1·kibpropanone; l-{(3R,4R)-3-[(5_fluoro_7H_„比比和Od]pyrimidine I))-methyl- Amino]-4-methyl-nathene small group}-acetone; 200823216 (3R,4R)_N-cyano-4-methyl-3-[indenyl-(7H-pyrrolo[2,3_d]pyrimidine ϋ定-4-yl)-amino]-Ν'-propyl-σ bottom bite-1-竣 base pulse, and (3R,4R)-N-cyano group 4,Ν',Ν'_三甲Benzyl-3-[methyl-(7Η-pyrrolo[2,3-d]α 密-4_yl)-amino]-° 辰定 -1 -1 - 竣脉, 5 or their pharmacy An acceptable salt. In a particular embodiment, the Janus kinase inhibitor is 3- {4-methyl-3-[methyl-(7Η·17 比洛弁[2,3-d] ♦σ定-4-yl)-amino]-. 唆-1-yl}-3_ side Oxy-propionitrile or a pharmaceutically acceptable salt thereof. In a particular embodiment, the Janus kinase inhibitor is 10 3-{(3R,4R)-4-methyl-3-[methyl-(7Η Pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidine-1-yl}-3-oxo-propanenitrile or a pharmaceutically acceptable salt thereof. In a particular embodiment , the 3-{4-mercapto-3-[methyl-(7H-pyrrolo[2,3-d] dimethyl-4-yl)-amino]-[ guanidine-1-yl}- 3-terpenyloxy-propryride and/or 3-{(3R,4R)-4-methyl-3-[methyl-(7Η-pyrrolo[2,3-d]pyrimidin-4-yl)- A pharmaceutically acceptable salt of 15 amino]-piperidin-1 -yl}-3-oxo-propanenitrile is a citrate salt, such as a monocitrate salt. In a particular embodiment, such as U.S. Patent No. 6,965,027 The compounds described herein are crystalline and the contents of this patent are incorporated herein by reference. The Janus kinase inhibitors of the present disclosure may be in the form of a pharmaceutically acceptable 20 acid addition salt. a pharmaceutically acceptable acid addition salt for use in the preparation of the aforementioned base compound of the present disclosure An acid which forms the following non-toxic acid addition salt: a salt containing a pharmacologically acceptable anion such as a hydrochloride, a hydrobromide, a hydroiodide, a nitrate, a sulfate, a hydrogen sulfate, a phosphate, Acid phosphate, acetate, lactate, citrate, acid citrate, 41 200823216 tartrate, hydrogen tartrate, albinoate, cis-succinic acid, anti-succinic acid, Gluconate, Glucerate, Benzoic acid:: catecholate, ethyl citrate, benzoate, p-toluene and palmitic acid: (pamoate) [ie 1,1, ya Methyl-double you through the base j-naphthoate)]. These Janus inhibitors, which reveal the content, can be tested as acceptable salts. These chemistry, which can be used as a pharmaceutically acceptable salt-reagent for the preparation of acidic hydrazine compounds, can form a non-toxic salt chemistry with such compounds. Such non-toxic salts include, but are not limited to, derived from: pharmacologically acceptable cations such as metal cations (eg, unloaded) H) and soil metal cations (eg, domains) (IV), ammonium or water soluble Amine addition salts: such as methyl glucosamine (i.e., meglumine), and lower alkanolammonium and other base salts of pharmaceutically acceptable organic amines. Certain of the Janus kinase inhibitors described herein are acidic and can form a salt with various pharmaceutically acceptable cations. Examples of such salts include gold test 15 or alkaline earth metal salts and, in particular, such salts and unloading salts. These salts are all made by the driving technique. The chemical bases which are useful as pharmaceutically acceptable salt-reagents for the preparation of the present disclosure are those which form non-toxic salt tests with the disclosed acidic compounds. Such non-toxic salts include salts derived from such pharmacologically acceptable cations as Na, _, 约, and 镇. These salts can be readily prepared by treating the corresponding acidic compound with an aqueous solution containing the desired pharmacologically acceptable cation and then evaporating the resulting solution to dryness preferably under reduced pressure. Alternatively, these can be prepared by mixing the lower alcohol alkanol solution of the acidic compound and the desired alkali metal alkoxide, and then evaporating the formed solution to dryness in the same manner as described in the month of 2008. salt. In either case, it is preferred to use a stoichiometric amount of reagent to ensure complete reaction and to obtain the maximum yield of the desired end product. In a particular embodiment, the Janus peak inhibitor is a compound detailed and/or exemplified in the following patent: USSN 09/335030, which is issued under the name of US Patent No. 6,635,762; USSN 10/640079, in its place, US Patent Publication No. 2004-0058922Α1; USSN 09/335121; /% USSN 09/956645, which is issued under US Patent No. 6,610,847; 10 USSN 10 /442807, which is issued by the national patent No. 6,890,929; USSN 11/064,873, after the reissue/, issued in US Patent Publication No. 2005-0171128; 15 USS is referred to as 69, which is a national special鄕 6,627,754; (10) is said to be 27, its fine US patent 6,956, given by the tiger; USSN 11/211,217, which is granted by the ancient fruit country patent No. 7,091,208; USSN 11/474,233 V USSN round lion is granted by US Patent No. 6 696 567; USSN Brain Hall, its fine (4) patent No. 6, No. 2,993 ;; 20 USSN 11/112307, its &,, from US patent Publication No. 2005-0197349; USSN 10/154699, Fu & Department, US Patent Publication No. 2003 - US Patent No. 10, 869,101, issued to USSN 10/869,101, issued to US Patent Publication No. 2004-022923 A1, and issued to US Patent No. 6, 965, No. 27; USSN 11 U.S. Patent Application Publication No. 2005-0159434A1, the entire disclosure of which is hereby incorporated by reference in its entirety. 5 Such Janus kinase inhibitors of the present disclosure include all configurational isomers (e.g., cis and trans isomers) and mixtures thereof. Such compounds are readily present in the asymmetric centers known to those skilled in the art and are therefore present in different mirror image isomeric and diastereomeric forms. The disclosure is directed to the use of all optical isomers and 10 stereoisomers and mixtures thereof for such compounds of the present disclosure, and all pharmaceutical compositions and methods of treatment in which they may be used or contained . In this regard, the present disclosure also includes E and Z configurations. In more detail, the racemic mixture of the HNR4R5 compound is treated with a specific optical isomer of disubstituted tartaric acid or tartaric acid in a suitable solvent such as ethanol in the presence or absence of water as a cosolvent. Resolution of the racemic mixture of the mirror image isomers used to obtain the R1 substituent of formula 1. More than 90% of the desired smectomers can be obtained using such methods as disclosed in U.S. Patent No. 10/154,699, the disclosure of which is incorporated herein by reference. Specific resolving agents that can be used for this resolution include tartaric acid and tartaric acid derivatives such as di-p- 20-nonylbenzhydryl-tartaric acid and (S)-(+)-adenoic acid (pencyphos). (S)-(+)-2-Hydroxy-5,5-dimethyl-4-phenylene; i,3,2-dioxyphospholane-2-oxide) salt. Of course, in view of the advantages of this disclosure, those skilled in the art will be aware of other suitable resolving agents that can potentially be used to resolve the compounds of this formula HNR4R5. 44 200823216 These Genus kinase inhibitors of the present disclosure may also exist as tautomers. The disclosure is directed to the use of all such tautomers and mixtures thereof. The interaction between the resolved material and the specific mirror image isomer can resolve 5 the racemic mixture, whereby the resolved material and the precipitate of the mirror image isomer can obtain a desired stereospecific material and the solution therein The remaining mirror image isomers can therefore be separated separately. Thus, depending on the particular mirror image isomer and the separation method used (ie, from the precipitate or solution), the stereospecificity of the resolution property can be selected simultaneously; for example, the resolving agent, such as the tartaric acid derivative 10 The L" form provides a precipitate of the "R" form of the R1 substituent and a solution containing the "L" form, and vice versa. The above-mentioned resolving agent can effectively obtain the 3R, 4R mirror isomer of the compound of the formula III (as described above, in the form of a precipitate or a solution) ημ

15 在特定實施例中，係藉以下步驟而進行式III化合物之拆分： a)在合適溶液内混合式III化合物之外消旋混合物及具有特定立體特異性之拆分化合物，其費時足以自該溶液大量沈澱該外消旋混合物之立體特異性異構物； 20 b)根據所欲該化合物之立體特異形式，可收集該沈澱 45 200823216 物並將其純化或收集母液並再晶化其中所含之鏡像異構物。就某些物貝而a，使用本揭示内容之拆分作用，其包括漿體至漿體之轉化，係形成漿體而非溶液。 5 15 20 進行該拆分及沈殿之溫度較佳為環境溫度，且雖然沈殿時間並未受限，但就效率而言，較佳不超過約4小時。為促進該拆分，較佳使用該外消旋混合物中之呈安定形式的鏡像異構物且在酸加成_式(諸如鹽㈣）而非在游離態驗形式中，該式Π化合物最具安定，後，因此，該外消旋化合物混合物較佳在拆分前進行轉化。因此，例如較佳在具有少量之作為共_的甲苯之乙醇中進行朗化合物之鹽酸 |的1成步驟。或者在該鹽形成步驟中可使用具有甲苯、 ^曰_氣甲;^、_氯乙烧或四氫吱喃共溶劑之甲醇、異丙醇、乙腈或四氫㈣（或彼等具或不具作為共溶劑之水 :合物）。該HC1鹽更特佳，因為該形式可得到優異純化及改良得自先前步驟之其它立體異構物。用於該拆分之較佳置換溶劑為乙酸⑽。甲苯、乙骑或庚烷亦可作為溶劑。包括ΓΓ離析溶劑為_。可祕這-方面之其它溶劑及四C:、甲基乙—基異丙基，、乙腈、二夫南’料溶劑村與彼此或水作為共溶劑。里性Z之拆分化合物包括酒石酸及其呈如所述之立體特的衍生物，諸如甲苯甲醯基及苯甲《酒石酸。 t 包括立體特異性腺酸及其衍生物。促進沈殿及再晶化，可選擇性添加晶種，但是較佳 46 200823216 為了獲得具有較少再結晶物之較高ee物質而泰加。本揭示内容亦涵蓋含本揭示内容之傑納斯激酶抑制劑 (諸如該等式I化合物）前藥的藥學組成物及此等前藥在本揭示藥學組合治療物中之用途。具有游離態胺基、酿胺基、 (norvlin)、石-丙胺酸、、胺基丁酸、瓜胺酸、高半胱胺酸、In a particular embodiment, the resolution of the compound of formula III is carried out by the following steps: a) mixing a racemic mixture of a compound of formula III with a resolution compound having a specific stereospecificity in a suitable solution, which is time consuming and sufficient The solution precipitates a large amount of the stereospecific isomer of the racemic mixture; 20 b) depending on the stereospecific form of the desired compound, the precipitate 45 200823216 can be collected and purified or collected and recrystallized. Contains mirror image isomers. For certain objects, a splitting action of the present disclosure, including slurry to slurry conversion, is used to form a slurry rather than a solution. 5 15 20 The temperature of the split and the slab is preferably ambient temperature, and although the time of the chamber is not limited, it is preferably no more than about 4 hours in terms of efficiency. To facilitate the resolution, it is preferred to use a mirror-image isomer in a stable form in the racemic mixture and in the acid addition form (such as salt (iv)) rather than in the free form, the formula is the most Stabilization, afterwards, therefore, the racemic compound mixture is preferably converted prior to resolution. Therefore, for example, a one-step step of performing hydrochloric acid of a lanthanum compound in ethanol having a small amount of toluene as a total amount is preferred. Or in the salt forming step, methanol, isopropanol, acetonitrile or tetrahydrogen (tetra) having toluene, 曰气气 ^, ^, _ chloroethane or tetrahydrofuran co-solvent may be used (or with or without Water as a cosolvent: compound). The HC1 salt is even more preferred because it provides excellent purification and improved other stereoisomers from the previous steps. A preferred displacement solvent for this resolution is acetic acid (10). Toluene, ethyl or heptane can also be used as a solvent. Including cesium separation solvent is _. Other solvents that can be secreted in this respect and four C:, methyl ethyl isopropyl, acetonitrile, bisflurane solvent solvent and each other or water as a cosolvent. The resolving compounds of the neutral Z include tartaric acid and its derivatives as described above, such as tolylmethyl and benzoic acid, tartaric acid. t includes stereospecific adeno acids and derivatives thereof. Promote sedimentation and recrystallization, selective seeding, but preferably 46 200823216 In order to obtain a higher ee substance with less recrystallized matter, Taiga. The disclosure also encompasses pharmaceutical compositions comprising prostaglandin inhibitors of the present disclosure, such as the compounds of the formula I, and the use of such prodrugs in the present pharmaceutical combination therapy. Has free amine group, amine group, (norvlin), stone-alanine, aminobutyric acid, citrulline, homocysteine,

至式I之上述取代基的化合物。 5羥基或羧基之式I化合物可轉化成前藥。前藥包括其中胺基酸殘基或2或多個（例如2、3或4個）胺基酸殘基之多肽鏈可藉肽鍵而共價結合至式I化合物之游離態胺基、羥基或綾酸基的化合物。該等胺基酸殘基包括通常可藉3個字母而命名之 20種天然產生之胺基酸且亦包括4_羥基脯胺酸、羥基賴胺 1〇酸、迪莫辛(demosine)、異迪莫辛、3_甲基組胺酸、諾夫林 47A compound of the above substituent of formula I. The 5-hydroxy or carboxy-based compound of formula I can be converted into a prodrug. Prodrugs include a polypeptide chain in which an amino acid residue or two or more (eg, 2, 3 or 4) amino acid residues can be covalently bonded to a free amine group, hydroxyl group of a compound of formula I by a peptide bond or a decanoic acid-based compound. The amino acid residues include 20 naturally occurring amino acids, which are generally named by three letters, and also include 4-hydroxyproline, hydroxylysamine, demosine, and iso Dimocine, 3-methylhistamine, Novolin 47

XXI 200823216XXI 200823216

製法ASystem A

ClCl

XX D2XX D2

XIXXIX

Cl D2Cl D2

XVI 48 200823216XVI 48 200823216

製法BSystem B

4949

XVII 200823216 圖解1XVII 200823216 Illustration 1

Cl d2Cl d2

R3 XVI RR3 XVI R

R3 3R3 3

XVXV

R3 I 50 200823216R3 I 50 200823216

圖解2Illustration 2

XXIVXXIV

XXIIIXXIII

XV 51 200823216 圖解3XV 51 200823216 Illustration 3

在製法A之反應1中，係藉使XXI與N-氣琥珀醯亞胺、 N-漠玻ίό驢亞胺或N-換號ίό酿亞胺反應而使式XXI 4-氯π比 5 咯并[2,3-d]嘧啶化合物，其中R為氫或保護基團（諸如苯石黃醯基或苄基)轉化成式XX 4-氯-5_鹵吡咯并[2,3-d]嘧啶化合物，其中Y為氣、溴或碘。在氣仿中將該反應混合物加熱至回流，其費時介於約1小時至約3小時之間、較佳約1小時。或者在製法A之反應1中，係藉於約_；1〇。〇至約10°C間之溫度 10 (較佳約〇°C)下在硫酸中使XXI與硝酸反應而使該式XXI 4- 氣。比嘻并[2,3-d]嘧啶，其中R為氩，轉化成對應之式XX 4-氯硝基吡咯并[2,3-d]嘧啶，其中γ為硝基，費時介於約5 分鐘至約15分鐘之間，較佳約1〇分鐘。藉在各種熟悉本項 52 200823216 技藝者已知之條件（諸如鈀氫解或氯化錫（IV)及鹽酸）下使 XXI進行反應而使孩式XXI化合物，其中γ為硝基，轉化成對應式XX4-氯-5_胺基各并[2,3_d]u密咬。在製法A之反應2中，係藉於約-78艽之溫度下以N_丁基 5鋰處理XX，並於約-78°C至室溫間之溫度(較佳室溫）下使如此形成之二陰離子中間產物與烧基鹵或节基齒反應而使該式XX 4-氯-5-鹵吡咯并[2,3-d]嘧啶化合物，其中R為氫，轉化成對應式XIX化合物，其中R2為（Crc6)烷基或苄基。或者’使如此形成之二陰離子與分子氧反應以形成對應式χιχ 1〇 4_氣-5-羥基吡咯并[2,3_d]嘧啶化合物，其中R2為羥基。藉於約-78°C之溫度下以N_丁基鋰處理χχ，繼而於約_78t：2 酿度下添加氣化鋅而使該式XX化合物，其中γ為溴或碘且R 為苯磺酸根，轉化成式ΧΙΧ化合物，其中R2為(C6_cy芳基或乙烯基。然後在催化量之把存在下，使如此形成之對應 15有機鋅中間產物與芳基碘或碘乙烯反應。於約50°C至約80 C間之溫度(較佳約70。〇下攪拌該反應混合物，費時介於約 1小時至約3小時之間、較佳約丨小時。在製法A之反應3中，係藉於約_78它之溫度下，在極性非貝子性溶劑，諸如四氫呋喃，存在下，以丁基裡、二 2〇異丙基胺鋰或氫化鈉處理χιχ而使該式χιχ化合物轉化成對應式XVI化合物。使如此形成之陰離子性中間產物進一步反應，其係藉·（a)當R3為烷基或苄基時，於約_78π至室溫間之溫度(較佳·78°〇下與烧基_或节基鹵進行反應；⑻當 R為院氧基時，於約-78°C至室溫間之溫度(較佳·78〇下與 53 200823216 醛或酮進行反應；及(C)於約-78°C至室溫間之溫度(較佳-78 °C)下與氯化辞進行反應，然後在催化量鈀之存在下使如此形成之對應有機鋅中間產物與芳基碘或碘乙烯反應。於約 50°C至約80°C間之溫度（較佳約70°C)下攪拌所形成反應混 5 合物，費時介於約1小時至約3小時之間、較佳約1小時。或者使如此形成之陰離子與分子氧反應以形成對應之式XVI 4-氣-6-羥基吡咯并[2,3-d]嘧啶化合物，其中R3為經基。在製法B之反應1中，係根據上文之製法a之反應3中所述的程序使式XXI 4-氯吡咯并[2,3-d]嘧啶化合物轉化成對 10 應之式XXII化合物。你很蘇上文之製法Λ的反應1及2 中所述之程序使式XXII化合物轉化成對應式XVI化合物。在圖解i之反應1中，係藉在驗，諸如氯化納或碳酸奸， 15 20 及極性非質子性溶劑，諸如二甲基甲醯胺或四氫吱喃，存In Reaction 1 of Process A, XXI is reacted with N-gas amber imine, N-glyoximine or N-exchanger to make the formula XXI 4-chloroπ ratio 5 And a [2,3-d]pyrimidine compound wherein R is hydrogen or a protecting group such as benzinyl or benzyl is converted to the formula XX 4-chloro-5-halopyrrolo[2,3-d]pyrimidine compound Where Y is gas, bromine or iodine. The reaction mixture is heated to reflux in a gas stream which is between about 1 hour and about 3 hours, preferably about 1 hour. Or in Reaction 1 of Process A, it is borrowed from about _;1〇. XXI is reacted with nitric acid in sulfuric acid at a temperature of about 10 ° C (preferably about 〇 ° C) to give the formula XXI 4-gas. Comparing 嘻[2,3-d]pyrimidine, wherein R is argon, is converted to the corresponding formula XX 4-chloronitropyrrolo[2,3-d]pyrimidine, wherein γ is a nitro group, which takes about 5 Between minutes and about 15 minutes, preferably about 1 minute. XXI is reacted under conditions known to those skilled in the art, such as palladium hydrogenolysis or tin (IV) chloride and hydrochloric acid, to convert a compound of formula XXI, wherein γ is a nitro group, into a corresponding formula. XX4-chloro-5-amino groups are each [2,3_d]u. In Reaction 2 of Process A, XX is treated with N-butyl 5 lithium at a temperature of about -78 Torr, and is carried out at a temperature between about -78 ° C and room temperature (preferably room temperature). The dianion intermediate formed is reacted with a ketone halide or a benzyl group to give a compound of the formula XX 4-chloro-5-halopyrrolo[2,3-d]pyrimidine wherein R is hydrogen to a corresponding compound of formula XIX Wherein R2 is (Crc6)alkyl or benzyl. Or reacting the thus formed dianion with molecular oxygen to form a corresponding formula χιχ 1〇 4_gas-5-hydroxypyrrolo[2,3-d]pyrimidine compound, wherein R2 is a hydroxyl group. The compound of formula XX is obtained by treating hydrazine with N-butyllithium at a temperature of about -78 ° C, and then adding zinc hydride at a concentration of about _78 t:2, wherein γ is bromine or iodine and R is benzene. The sulfonate is converted to a hydrazine compound wherein R2 is (C6_cyaryl or vinyl) and the corresponding 15 organozinc intermediate thus formed is reacted with aryl iodide or iodoethylene in the presence of a catalytic amount. The reaction mixture is stirred at a temperature of from 50 ° C to about 80 C (preferably about 70. The reaction mixture is stirred for about 1 hour to about 3 hours, preferably about 丨 hours. In Reaction 3 of Process A, Converting the χιχ compound to χ χ 它它它它它它它它它它它它它它它它它它它它它它它它它它它它它它它它它它它它它它它它它它它它它它它它它Corresponding to the compound of formula XVI. The anion intermediate thus formed is further reacted by (a) when R3 is an alkyl group or a benzyl group, at a temperature of from about -78 π to room temperature (preferably 78 ° 〇) The reaction is carried out with a calcinyl group or a benzyl halide; (8) when R is a hospitaloxy group, the temperature is between about -78 ° C and room temperature. Degree (preferably 78〇 under reaction with 53 200823216 aldehyde or ketone; and (C) reaction with chlorination at a temperature between about -78 ° C and room temperature (preferably -78 ° C), then The corresponding organozinc intermediate thus formed is reacted with aryl iodide or iodoethylene in the presence of a catalytic amount of palladium. The mixture is formed by stirring at a temperature between about 50 ° C and about 80 ° C (preferably about 70 ° C). The reaction mixture is timed between about 1 hour and about 3 hours, preferably about 1 hour, or the anion thus formed is reacted with molecular oxygen to form the corresponding formula XVI 4-gas-6-hydroxypyrrole. a [2,3-d]pyrimidine compound wherein R3 is a trans group. In Reaction 1 of Process B, the compound of formula XXI 4-chloropyrrolo[2, is prepared according to the procedure described in Reaction 3 of Process a above. Conversion of the 3-d]pyrimidine compound to the compound of formula XXII. The procedure described in Reactions 1 and 2 of the above process is used to convert the compound of formula XXII to the corresponding compound of formula XVI. In 1 , by means of tests, such as sodium chloride or carbonic acid, 15 20 and polar aprotic solvents, such as dimethylformamide or tetrahydrofuran,

在下以苯石心氯、节基氯或节基漠處理而使該式XVH 4-氯吼略并[2,3-物定化合物轉化成對應式謂化合物，立中R為苯《基«基。Wc^7Gt間之溫度(較㈣ 30C)下攪拌該反應混合物，費時介於則小時至約之間、較佳約2小時。、在圖解丄之反應2中，係a 使該™ 4·氣蝴式職作偶合™ 4-胺基翁跡d]対蝴對應式XV 4-氣蝴[2,34_^==，伽所獲得之鏡像異構物，亦即式一 54 200823216 偶合反應以產生對應式XV 4-胺基吡咯并[2,3-d]嘧啶化合物，其具有與式NHR4R5之經拆分反應物相同的立體化學性質。亦即可在不會逆轉或損失立體化學性質之情況下進行此等實施例中之偶合反應2且在可保留立體化學性質之情 5況下進行該等反應。在下述合成法之剩下步驟中可持續不The XVH 4-chloroindole is slightly treated by treatment with benzotridyl chloride, benzyl chloride or benzylidene [2,3-formal compound is converted into the corresponding formula, and R is benzene. . The reaction mixture is stirred at a temperature between Wc and 7 Gt (compared to (4) 30 C), and the time is between hours and about, preferably about 2 hours. In the reaction 2 of the diagram, the system a makes the TM 4· gas butterfly type coupling TM 4-amine based on the d] 対 butterfly corresponding XV 4- gas butterfly [2, 34_^ ==, gamma The obtained mirror image isomer, i.e., Formula No. 54 200823216, is coupled to give the corresponding XV 4-aminopyrrolo[2,3-d]pyrimidine compound having the same stereotype as the recombined reaction of the formula NHR4R5. Chemical properties. Alternatively, the coupling reaction 2 in the examples can be carried out without reversing or losing the stereochemical properties and the reaction can be carried out while retaining the stereochemical properties. Sustainable in the remaining steps of the synthesis below

會逆轉或損失立體化學性質及保留立體化學性質的功用以獲得式I化合物、於約60°C至約120°C間之溫度(較佳約8〇。〇下在醇溶劑，諸如第三-丁醇、甲醇或乙醇，或其它高沸點有機溶劑（諸如二甲基甲醯胺、三乙胺、^冬二。号烷或丨，^ 10二氣乙烷）中進行該反應。典型的反應時間介於約2小時至約48小時之間、較佳約16小時。當R5為含氮之雜環烷基時，各氮必需經保護基團，諸如苄基，保護。在不會影響該吡咯并[2,3-d]嘧啶環上之R保護基團的適於特定保護基團之條件了進行該R5保護基團之移除。在氫及觸媒，諸如碳載 15劑氫氧化鈀，存在下，在醇溶劑(諸如乙醇）中造并妨R5^罐基團（节基)之移除。如此形成之含該R5氮之雜環烷基可進一步與各種列的式Π親電子劑反應。就尿素形成二，係於二至約靴間之溫度下，在驗，諸如竣酸納或碳酸二存在下在溶劑(諸如乙腈或二甲基甲酿胺）中使式職電如異氰_、胺基甲酸毅胺^氯，與該雜院二之h反應，費時介於約24小時至約72小時之間。㈣胺及々醯胺形成而言，聽環境溫度下錢二氣甲職式11親電子劑，：基乳及尹▲乳，與該雜烧基π氮反應，費時介於約12小時 55 200823216 土、、、j 小胺，諸如ΗΓ可以藉於環境溫度下，在碳化二酸亞在溶劑㈣絲基㈣基碳化：料胺，存在下㈣番氣甲烧）中使㈣與雜燒基反應而進行ai胺形成’費時12至24小時。就烧基形成而言，^❿胺下’在溶_如甲醇）中使式職電子劑，諸如、了溫度 :醯:、腈、醋、及心_胺，與該雜 = =原劑，諸如氰細氫化鈉，存在下在溶劑(諸如甲 10 駿與該餘基反應而進行燒基形成，f時介於約^ 小時至約18小時之間。口、在日解丄之反應3中，係藉在醇溶劑（諸如甲醇或乙醇) 或混合溶劑(諸如醇/四氫咬响或醇/水）中以驗，諸如氯氧化納或氫氧化鉀，處理xv而自該式抑化合物，其中r為苯績醯基移除保護基團以得對應式I化合物。於室溫下進行該反 15應，費時介於約15分鐘至約1小時之間、較佳30分鐘。藉於約-78 C下在氨中以鈉處理χν而進行自式χν化合物，其中 R為苄基，移除該保護基團之步驟，費時介於約15分鐘至約 1小時之間。在圖解2之反應1中，係根據上文之圖解丄反應2中所述 20的程序使式XX 4-氣吡咯并[2,3-d]嘧啶化合物轉化成對應式\11\^4-胺基吨洛并[2,3-(1]嘴咬化合物。在圖解2之反應2中，係使式XXIV 4-胺基-5-鹵吼哈并 [2,3-d]嘧啶化合物，其中R為苯磺酸根且z為溴或碘，轉化成對應式XXIII化合物，其係藉：（a)當R2為芳基時，於約50 56 200823216 C至約l〇〇°c間之溫度（較佳約7〇。〇下在催化量鈀(〇)存在下’在非質子性溶劑（諸如四氫呋喃或二噚烷）中使XXIV與芳基二經基侧酸反應，費時介於約2小時至約48小時之間、較佳約12小時；（b)當R2為炔基時，於室溫下在催化量碘化 5銅⑴及把(〇)、與極性溶劑，諸如二甲基甲醯胺，存在下使 XXIV與炔類反應，費時介於約1小時至約5小時之間、較佳約3小時；及(c)當R2為乙烯基或苯乙烯基時，於約8〇〇c至約 l〇〇°C間之溫度（較佳約1〇〇。〇下在催化量鈀存在下在二甲酿胺、二嘈烷或四氫呋喃中使又幻¥與烯類或苯乙烯反應， 10費時介於約2小時至約48小時之間、較佳約48小時。在圖解2之反應3中，係根據上文之製法a反應3中所述的程序使式XXIII化合物轉化成對應式χν化合物。在圖解i之反應1中，係根據上文之圖解]_反應2中所述的程序使式XVII化合物轉化成對應式I化合物。 15 在特定實施例中，該抗關節炎藥劑為選自以下所組成之群組的NSAID(非類固醇消炎藥物或COX-2(環-氧合酶2) 抑制劑：乙醯基柳酸(例如Aspirin®)及其它柳酸鹽，諸如三柳酸膽鹼鎂（例如Trilisate®)、阿札丙宗、卡洛芬、塞力可西（例如如美國專利第5,466,823號、第5,563，165號、第 20 5,760,068號、第 5,972,986號中所述之Celebrex®);瓦德可西(valdecoxib)(例如如美國專利第5,633,272號、第6,441，014 號中所述之Bextra®);羅飛可西(rofecoxib)(例如如美國專利第 5,474,995號、第 5,691,374號、第 6,063,811 號、第 6,239，173 號中所述之Vioxx®)、雙氣芬酸卸、雙氯芬酸鈉（例如如美 57 200823216 國專利第5,601，843號、第5,698,225號中所述之Voltaren®、 Cataflam®)、雙氟尼酸（例如Dolobid®)、依托道酸（例如 Lodine®)、芬布芬、芬諾普芬(例如Nalfon®)、氟芬那酸、氟比洛芬(例如Ansaid®)、布洛芬(例如Advil®)、朶美辛 5 (例如Indocin®)、酮洛芬（例如Orudis®)、甲氯芬那酸躁 (meclofenamate)(例如 Meclomen®)、曱芬那酸（例如 Ponstel®)、米羅昔康（例如如美國專利第6,184,220號中所述之Mobic®)、萘丁美酮（例如Relafen®)、萘普生（例如 Aleve®)、萘普生納、口等丙讲(例如Daypro®)、比口各芬、舒 10 洛芬、雙水楊酸酯（例如Disalcid®、Salflex®)、舒林酸(例如Clinoril®)、替諾昔康、噻咯芬酸、及托美丁（例如 Tolectin®)。鑑於本揭示内容之優勢，熟悉本項技藝者輕易瞭解其它合適NSAID。在特定實施例中’該抗關節炎藥劑為選自以下所組成 15之群組的腎上腺促糖皮質激素（口服、非經腸及/或關節内投藥）：乙酸氫皮質酮、第三-丁基乙酸氫皮質酮、乙酸地塞米松、第三-丁基乙酸地塞米松、氫化發尼松、乙酸氫化潑尼松、第三-丁基乙酸氫化潑尼松、潑尼松、甲基氫化潑尼松、乙酸甲基氫化潑尼松、安西諾隆縮丙酮化物、安西諾隆二 20縮丙酮化物、及安西諾隆六縮丙酮化物。鑑於本揭示内容之優勢，熟悉本項技藝者可輕易瞭解其它合適腎上腺促糖皮質激素。在特定實施例中，該抗關節炎藥劑為選自以下所組成之群組的SCEDMARD(疾病修飾抗風濕病藥物”羥基氯喳 58 200823216 (例如Plaquenil®)、氯喳、達波松、舒沙拉畊（例如 Azulfidine®)、阿美蘇喋呤(例如Trexall®、Methotrex®)、雷夫米德（例如Arava®)、硫嗤σ票呤(例如Imuran®)、d-青黴胺 (例如Cuprimine®)、環孢黴素A(例如Sandimmune®)及金化 5 合物，其包括硫化蘋果酸金鈉(例如Aurolate)、金硫葡萄糖 (例如Solganal)、及奥倫費（例如Ridaura®)。在特別實施例中，該抗關節炎藥劑為選自以下所組成之群組的生物DMARD :依坦賽特(例如Enbrel®)、因福西麻 (例如Remicade®)、阿達里麻(例如Humira®)、阿那肯拉(例 10 如Kineret®)、阿巴塔塞（例如Orencia®)、雷突西麻（例如 Rituxan®)、托西朱麻(例如Actemra®)、及色托朱麻佩果。鑑於本揭示内容之優勢，熟悉本項技藝者可輕易瞭解其它合適DMARD(SCE或生物性）。在特定實施例中，當該抗關節炎藥劑為DMARD時，該 15抗關節炎藥劑較佳為阿美蘇嘌吟（有時在文中稱為 “MTX”）。在特定實施例中，該抗關節炎藥劑為止痛劑，諸如乙醯基芬酚(例如Tylenol®)。鑑於本揭示内容之優勢，熟悉本項技藝者可輕易瞭解其它合適止痛劑。 20 在特定實施例中，該抗關節炎藥劑為選自以下所組成之群組的可選擇性併用乙醯基苯酚之鴉片樣物質：嗎徘、可待因、右丙氧啡（例如Darvocet®)、二氫可待因酮（例如 Vicodin®)、美沙_ (例如D〇1〇phine⑧）、氫嗎啡_ (例如 Dilaudid®)、羥可酮(例如perc〇cet⑧）、芬坦尼、丁丙諾徘(例 59 200823216 如Submex®)、及布托啡諾(例如Stad〇1⑧）。鑑於本揭示内容之優勢，熟悉本項技藝者可輕易瞭解其它合適的鴆片樣物質。在特定實施例中，當文中所揭示之藥學組合治療物或方法中所投予之抗關節藥劑並非DMARD時，即使投予超過 5 -種藥學組成物，由於文中所揭示之藥學組成物包含被視為D MARD之傑納斯激崎抑制劑，所以熟悉本項技藝者通常將此種投藥稱為單治療法。然而，如文巾使用，該名詞“藥學組合治療物”亦包括此等“單治療物”。可以以習知方法使用一或多種藥學上可接受載劑調製 10本揭示内容之組成物。該藥學上可接受載劑可以是本項技藝中已知之任何此種載劑，其包括在，例如— Pharmaceutical Sciences, Mack Publishing Co., (A. R.The utility of reversing or losing stereochemical properties and retaining stereochemical properties to obtain a compound of formula I at a temperature between about 60 ° C and about 120 ° C (preferably about 8 Torr. Underarm in an alcohol solvent, such as a third - The reaction is carried out in butanol, methanol or ethanol, or other high-boiling organic solvents such as dimethylformamide, triethylamine, dimethylidene or hydrazine, 10 dioxane. Typical reactions The time is between about 2 hours and about 48 hours, preferably about 16 hours. When R5 is a nitrogen-containing heterocycloalkyl group, each nitrogen must be protected with a protecting group, such as a benzyl group, without affecting the The removal of the R5 protecting group is carried out under conditions suitable for the particular protecting group of the R protecting group on the pyrrolo[2,3-d]pyrimidine ring. Hydrogen and a catalyst, such as 15 hydroxy hydroxides on carbon In the presence of palladium, in the alcohol solvent (such as ethanol), the R5^ can be removed (the base group). The thus formed heterocyclic alkyl group containing the R5 nitrogen can further be combined with various columns. The electronic agent reacts. In the case of urea formation, it is at the temperature between two and about the boot, in the presence of, for example, sodium citrate or carbonic acid. In the case of a reagent such as acetonitrile or dimethylamine, a reaction such as isocyanide, amidiamine, and chlorine is reacted with the compound, which takes between about 24 hours and about 72 hours. (4) In the case of amine and guanamine formation, listening to ambient temperature, money, gas, and eleven electrons, base milk and Yin ▲ milk, react with the miscible π nitrogen, which takes about 12 hours. 55 200823216 Soil, and j small amines, such as strontium, can be used in ambient temperature, in the presence of carbonic acid diacids in the solvent (4) silk-based (tetra)-based carbonization: in the presence of amines (4) in the presence of (four) The aiamine formation by the base reaction 'takes 12 to 24 hours. In the case of the formation of a base, an electron agent such as a temperature: 醯:, a nitrile, a vinegar, and a heart amine, and the like, are used in a solvent such as methanol. For example, sodium cyanide hydride is formed in the presence of a solvent such as methyl 10 to react with the residue to form a group, and f is between about 2 hours and about 18 hours. By treating in an alcohol solvent (such as methanol or ethanol) or a mixed solvent (such as alcohol/tetrahydrobeater or alcohol/water), such as sodium oxychloride or potassium hydroxide, treating xv from the compound, Wherein r is a phenyl group-based deprotection group to give a corresponding compound of formula I. The reaction is carried out at room temperature for a period of from about 15 minutes to about 1 hour, preferably 30 minutes. A compound of the formula ,ν is carried out by treating χν with sodium in ammonia at -78 C, wherein R is a benzyl group, and the step of removing the protecting group takes between about 15 minutes and about 1 hour. In Reaction 1, the formula XX 4-pyrrolo[2,3-d]pyrimidine compound is converted to the corresponding formula \11 according to the procedure of 20 described in Scheme 2 above. \^4-Amino-Toxo[2,3-(1] mouth bite compound. In Reaction 2 of Scheme 2, the formula XXIV 4-amino-5-halo-haha [2,3-d a pyrimidine compound, wherein R is benzenesulfonate and z is bromine or iodine, converted to a corresponding compound of formula XXIII by: (a) when R2 is aryl, at about 50 56 200823216 C to about 10 ° The temperature between c (preferably about 7 〇. under the catalytic amount of palladium (〇) in the presence of a catalytic amount of palladium (〇) in an aprotic solvent (such as tetrahydrofuran or dioxane) to react XXIV with the aryl dipyridyl acid, time consuming Between about 2 hours and about 48 hours, preferably about 12 hours; (b) when R2 is an alkynyl group, iodinating 5 copper (1) and (〇) with a polar solvent at a catalytic amount at room temperature, The reaction of XXIV with an alkyne in the presence of dimethylformamide, for example, is between about 1 hour and about 5 hours, preferably about 3 hours; and (c) when R2 is a vinyl or styryl group. , at a temperature of from about 8 ° C to about 10 ° C (preferably about 1 〇〇. under the catalytic amount of palladium in the presence of dimethylamine, dioxane or tetrahydrofuran Ethylene or styrene reaction, 10 takes about 2 hours to Between about 48 hours, preferably about 48 hours. In Reaction 3 of Scheme 2, the compound of formula XXIII is converted to the corresponding compound of formula ν according to the procedure described in Scheme 3, Reaction 3 above. In one embodiment, the compound of formula XVII is converted to the corresponding compound of formula I according to the procedure described in the above Schemes - Reaction 2. In a particular embodiment, the anti-arthritic agent is a group selected from the group consisting of NSAID (non-steroidal anti-inflammatory drugs or COX-2 (cyclo-oxygenase 2) inhibitors: acetyl sulphate (eg Aspirin®) and other salicylates, such as magnesium choline (such as Trilisate®), Azaprozin, carprofen, celecoxib (for example, Celebrex® as described in U.S. Patent Nos. 5,466,823, 5,563, 165, 205, 760, 068, 5, 972, 986); valdecoxib (e.g., Bextra® as described in U.S. Patent Nos. 5,633,272, 6, 441, 014); Rofecoxib (e.g., U.S. Patent Nos. 5,474,995, 5,691,374, 6,063,811, 6,239, Vioxx®, bis, fen, and diclofen described in 173 Sodium (e.g., Voltaren®, Cataflam®), diflunisal (e.g., Dolobid®), etodoic acid (e.g., Lodine®), fenbux as described in U.S. Patent No. 5, 602, 843, No. 5, 698, 225. Fen, fennoprofen (eg Nalfon®), flufenamic acid, flurbiprofen (eg Ansaid®), ibuprofen (eg Advil®), domicin 5 (eg Indocin®), ketoprofen (eg For example, Orudis®), meclofenamate (eg, Meclomen®), acenamate (eg, Ponstel®), and miroxican (eg, Mobic® as described in US Patent No. 6,184,220), Nabumetone (eg Relafen®), naproxen (eg Aleve®), naproxen, oral, etc. (eg Daypro®), bisulphate, sö 10, and salsalate ( Examples include: Disalcid®, Salflex®, sulindac (eg Clinoril®), tenoxicam, ciclofen, and tolmetine (eg Tolectin®). In view of the advantages of this disclosure, those skilled in the art will readily appreciate other suitable NSAIDs. In a particular embodiment, the anti-arthritic agent is an adrenal glucocorticoid (administered orally, parenterally, and/or intra-articularly) selected from the group consisting of 15: hydrocorticosterone acetate, third-butyl Hydrocorticosterone acetate, dexamethasone acetate, dexamethasone tert-butyl acetate, hydrogenated prednisone, prednisone acetate, prednisolone tert-butyl acetate, prednisone, methyl hydrogenation Prednisone, methylprednisolone acetate, ansinoprozil acetonide, ansinolon 225 acetonide, and ansinolon hexaploate. In view of the advantages of this disclosure, other suitable adrenal glucocorticoids will be readily apparent to those skilled in the art. In a particular embodiment, the anti-arthritic agent is a SCEDMARD (disease modified antirheumatic drug) hydroxy chloroquinone 58 200823216 (eg Plaquenil®), chloranil, dabson, sula ploughing selected from the group consisting of (eg Azulfidine®), Amesu (eg Trexall®, Methotrex®), Lefmid (eg Arava®), thioxanium (eg Imuran®), d-penicillamine (eg Cuprimine®), Cyclosporin A (such as Sandimmune®) and goldated compounds, including sodium sulphate malate (such as Aurolate), gold sulphur glucose (such as Solganal), and Orenfe (such as Ridaura®). In one embodiment, the anti-arthritic agent is a bio-DMARD selected from the group consisting of: Entanset (eg Enbrel®), Infesima (eg Remicade®), Adaris (eg Humira®), A. Nakenla (Example 10 such as Kineret®), Abatase (eg Orencia®), Thalasso (eg Rituxan®), Tosiju (eg Actemra®), and Troxone Pepe. Advantages of the disclosure, those skilled in the art can easily understand other suitable DMARDs (SCE or Biologically. In a particular embodiment, when the anti-arthritic agent is a DMARD, the 15 anti-arthritic agent is preferably Amesu (sometimes referred to herein as "MTX"). In a particular embodiment The anti-arthritic agent analgesic agent, such as ethenylphenfenol (e.g., Tylenol®). In view of the advantages of the present disclosure, other suitable analgesics can be readily appreciated by those skilled in the art. 20 In certain embodiments, The anti-arthritic agent is an opioid-like substance that can be selectively used in combination with acetaminophen selected from the group consisting of: ruthenium, codeine, dextromethorphan (eg, Darvocet®), hydrocodone (eg, Vicodin®), Mesa (eg D〇1〇phine8), hydromorphine (eg Dilaudid®), oxycodone (eg perc〇cet8), fentanyl, buprenorphine (example 59 200823216 eg Submex ®), and butorphanol (e.g., Stad〇 18). In view of the advantages of the present disclosure, other suitable smear-like materials can be readily understood by those skilled in the art. In certain embodiments, the pharmacy disclosed herein Antibiotic administered in combination therapy or method When the joint agent is not a DMARD, even if more than five kinds of pharmaceutical compositions are administered, since the pharmaceutical composition disclosed herein contains a Janus-based inhibitor of D MARD, it is common for those skilled in the art to Administration of a drug is referred to as a monotherapy. However, as used herein, the term "pharmaceutical combination therapy" also includes such "monotherapy". The compositions of the present disclosure may be prepared in a conventional manner using one or more pharmaceutically acceptable carriers. The pharmaceutically acceptable carrier can be any such carrier known in the art and is included, for example, in Pharmaceutical Sciences, Mack Publishing Co., (A. R.

Gennaro edit. 1985)中所述之載劑。可藉本項技藝中已知之習知方法而製備本發明所揭示之該等化合物的藥學組成 15物，例如使至少一種本發明所揭示之化合物與藥學上可接受載劑混合。亦可根據-般技術者所熟知之方法將所揭示化合物調製成適於持續遞送的化合物。此等配方之實例可以在以下專利案中找到：美國專利第3，119,742號、第MM·號、 20 第 3,538,214號、第4,〇6〇,598號、及第4，173,626號。因此’可將本揭示内容之活性化合物調製成適於以下形式：口服、頰投藥、鼻内投藥、非經腸(例如靜脈内、肌内或皮下)投藥、直腸投藥、吸入或灌氣投藥，或可將該等活性化合物調製成適於局部投藥之形式。 200823216 就口服而言，該等藥學組成物可以呈，例如藉習知方法使用藥學上可接受賦形劑而製成之錠劑或膠囊形式，該等賦形劑包括，諸如結合劑，例如預膠化玉米殿粉、聚乙烯吡咯啶酮或羥丙基甲基纖維素；填料，例如乳糖、微晶 5 狀纖維素或磷酸鈣；潤滑劑，例如硬脂酸鎂、滑石或二氧化矽；分解劑，例如馬鈴薯澱粉或羥基乙酸鈉澱粉；或濕潤劑，例如月桂基硫酸鈉。可藉本項技藝中已為吾人所熟知之方法而將該等錠劑覆膜。適於口服之液體製劑可以呈，例如溶劑、糖漿或懸浮液形式，或其可以呈適於在使 10 用前經水或其它合適媒劑重組之乾產物形式◦可藉習知方法使用藥學上可接受添加劑製成此等液體製劑，該等添加劑包括，諸如懸浮劑，例如山梨糖醇糖漿、甲基纖維素或氫化食用脂肪；乳化劑，例如卵磷脂或金合歡膠；非水性媒劑，例如杏仁油、油性S旨或乙醇；及防腐劑，例如對-經 15 基苯甲酸甲酯或對-羥基苯甲酸丙酯或山梨酸。就頰投藥而言，該組成物可以呈以習知方式所調製之錠劑或含片形式。就鼻内投藥或吸入投藥而言，本揭示内容之活性化合物最好以溶液或懸浮液形式自泵喷霧器遞送，其係藉患者 20 而擠取或泵取，或借助於合適推進劑，例如二氯二氟甲烷、三氯氟甲烷、二氣四氟乙烷、二氧化碳或其它合適氣體，自加壓容器或霧化器提供氣溶膠喷劑。就加壓氣溶膠而言，可藉提供一可遞送計算量之閥而測定劑量單位。該加壓容器或霧化器可含有該活性化合物之溶液或懸浮液。可 61 200823216 適用於吸入器或灌氣器之膠囊及藥筒（由例如明膠製成）調製成含有本揭示内容之化合物及合適粉末基劑，諸如乳糖或;殿粉之粉末混合物。可將本揭示内容之活性化合物調製成適於藉注射，其 5包括使用習知導管插入術或輸注法，而進行非經腸投藥。適用於注射之配方可以以單位劑型，例如具有添加防腐劑之安瓶或多劑量容器提供。該等組成物可以呈下述形式：諸如在油性或水性媒劑中之懸浮液、溶液或乳液，且可含有調配劑，諸如懸浮劑、安定劑及/或分散劑。或者該活性 1〇成份可以呈適於在使用前經合適媒劑，例如無菌無熱原水，重組之粉末形式。亦可將本揭示内容之活性化合物調製成直腸組成物，諸如含有習知栓劑基劑，諸如可可脂或其它甘油醋之栓劑或保留灌腸劑。 15 20 =局私樂而5 ’可將本揭示化合物調製成軟膏或乳劑。方法Φ里九、在4等藥學組合治療物及文中所揭示之相關上有巧旦1等傑納斯激梅抑制劑及抗關節炎藥劑係以治療及/或’結本項技藝者可㈣瞭解獲得所欲藥理抑制劑°在特定實關巾，納斯激酶之投予劑量為; 〇iiu_i 母日1至42次之每單位劑量的之間^成份。該劑量可在1或多次給藥方案斯抑制劑内不等。在特定實施例(其中雜、辟上可接受鹽係經口服）中，該等活性化合 62 200823216 5 物之劑量範圍可以自1至50毫克BID(亦即每曰兩次）或自5 至20毫克QD(亦即每曰一次）、且較佳1毫克BID、2毫克 BID、3毫克BID、4毫克BID、5毫克BID、6毫克BID、7毫克BID、8毫克BID、9毫克BID、10毫克BID、11毫克BID、 12毫克BID、13毫克BID、Η毫克BID、15毫克BID、20毫克BID、25毫克BID或30毫克BID、且較佳〇·25毫克BID、0.5 毫克BID、1毫克BID、5毫克BID、10毫克BID、20毫克BID、且更佳1毫克BID、3毫克BID、5毫克BID、15毫克BID、20 毫克QD。 10 在特定實施例中，該抗關節炎藥劑(在文中有時直接稱 15 為“藥劑”)之投予劑量為1毫克至5克（亦即5 0 00毫克），例如5 毫克、10毫克、25毫克、50毫克、1〇〇毫克、250毫克、500 毫克、750毫克、1000毫克、125〇毫克、1500毫克、1750毫克、2000毫克或彼等之組合。就所提供該等抗關節炎藥劑之各劑量而言，如熟悉本項技藝者所知可每日兩次、每曰 / i 20 一次、每週一次等投予，例如指定劑量之該藥劑。阿美蘇嗓吟(“MTX”)之典型每週-次的投予劑量為5毫克、7.5毫克、1〇毫克:12.5毫克、b毫克、17.5毫克、20毫克、22.5 毫克、及25¾克。在特定實施例中，當然根據毒性或耐藥性之缺乏，典型上在一段拉权時間内，例如週復一週、月復一月等，以2.5毫克增量姆★ g力口（以滴定方式增加)MTX之劑ϊ ° 在特定實施例中，若患者月減考具有極佳反應或若連同另一種辨劑，諸如生物性藥劑，汰越 a 〜樂，則可降低（亦即以滴定法滅量）MTX之劑量。在其它督、h 1鈪例中，該MTX之劑量係以分次 63 200823216 給藥之方式投予，諸如以每週為基礎，每12小時5毫克χ3 次劑量。當然，鑑於本揭示内容之優勢，熟悉本項技藝者可輕易瞭解在組合治療物中本揭示内容之化合物及該等抗關節炎藥劑之其它合適投予劑量。 5 在文中所揭示之該等藥學組合治療物的特定實施例中，該等活性化合物之投予劑量為0.25毫克BID，且阿美蘇喋呤之投予劑量為每週一次5毫克。在文中所揭示之該等藥學組合治療物的特定實施例中，該等活性化合物之投予劑量為0.25毫克BID，且阿美蘇 10 喋呤之投予劑量為每週一次7.5毫克。在文中所揭示之該等藥學組合治療物的特定實施例中，該等活性化合物之投予劑量為0.25毫克BID，且阿美蘇喋呤之投予劑量為每週一次15毫克。在文中所揭示之該等藥學組合治療物的特定實施例 15 中，該等活性化合物之投予劑量為0.5毫克BID，且阿美蘇喋呤之投予劑量為每週一次5毫克。在文中所揭示之該等藥學組合治療物的特定實施例中，該等活性化合物之投予劑量為0.5毫克BID，且阿美蘇喋呤之投予劑量為每週一次7.5毫克。 20 在文中所揭示之該等藥學組合治療物的特定實施例中，該等活性化合物之投予劑量為0.5毫克BID，且阿美蘇嗓呤之投予劑量為每週一次15毫克。在文中所揭示之該等藥學組合治療物的特定實施例中，該等活性化合物之投予劑量為1毫克BID，且阿美蘇喋 64 200823216 呤之投予劑量為每週一次5毫克。在文中所揭示之該等藥學組合治療物的特定實施例中，該等活性化合物之投予劑量為1毫克BID，且阿美蘇喋呤之投予劑量為每週一次7.5毫克。 5 在文中所揭示之該等藥學組合治療物的特定實施例中，該等活性化合物之投予劑量為1毫克BID，且阿美蘇喋呤之投予劑量為每週一次15毫克。在文中所揭示之該等藥學組合治療物的特定實施例中，該等活性化合物之投予劑量為3毫克BID，且阿美蘇喋 10 呤之投予劑量為每週一次5毫克。在文中所揭示之該等藥學組合治療物的特定實施例中，該等活性化合物之投予劑量為3毫克BID，且阿美蘇喋呤之投予劑量為每週一次7.5毫克。在文中所揭示之該等藥學組合治療物的特定實施例 15 中，該等活性化合物之投予劑量為3毫克BID，且阿美蘇喋呤之投予劑量為每週一次15毫克。在文中所揭示之該等藥學組合治療物的特定實施例中，該等活性化合物之投予劑量為5毫克BID，且阿美蘇喋呤之投予劑量為每週一次5毫克。 20 在文中所揭示之該等藥學組合治療物的特定實施例中，該等活性化合物之投予劑量為5毫克BID，且阿美蘇喋呤之投予劑量為每週一次7.5毫克。在文中所揭示之該等藥學組合治療物的特定實施例中，該等活性化合物之投予劑量為5毫克BID，且阿美蘇喋 65 200823216 呤之投予劑量為每週一次15毫克。在文中所揭示之該等藥學組合治療物的特定實施例中，該等活性化合物之投予劑量為10毫克BID，且阿美蘇喋呤之投予劑量為每週一次5毫克。 5 在文中所揭示之該等藥學組合治療物的特定實施例中，該等活性化合物之投予劑量為10毫克BID，且阿美蘇喋呤之投予劑量為每週一次7.5毫克。在文中所揭示之該等藥學組合治療物的特定實施例中，該等活性化合物之投予劑量為10毫克BID，且阿美蘇喋 10 呤之投予劑量為每週一次15毫克。在文中所揭示之該等藥學組合治療物的特定實施例中，該等活性化合物之投予劑量為15毫克BID，且阿美蘇喋呤之投予劑量為每週一次5毫克。在文中所揭示之該等藥學組合治療物的特定實施例 15 中，該等活性化合物之投予劑量為15毫克BID，且阿美蘇喋呤之投予劑量為每週一次7.5毫克。在文中所揭示之該等藥學組合治療物的特定實施例中，該等活性化合物之投予劑量為15毫克BID，且阿美蘇喋呤之投予劑量為每週一次15毫克。 20 在文中所揭示之該等藥學組合治療物的特定實施例中，該等活性化合物之投予劑量為5毫克QD，且阿美蘇喋呤之投予劑量為每週一次5毫克。在文中所揭示之該等藥學組合治療物的特定實施例中，該等活性化合物之投予劑量為5毫克QD，且阿美蘇喋 66 200823216 呤之投予劑量為每週一次7.5毫克。在文中所揭示之該等藥學組合治療物的特定實施例中，該等活性化合物之投予劑量為5毫克QD，且阿美蘇喋呤之投予劑量為每週一次15毫克。 5 在文中所揭示之該等藥學組合治療物的特定實施例中，該等活性化合物之投予劑量為10毫克QD，且阿美蘇喋呤之投予劑量為每週一次5毫克。在文中所揭示之該等藥學組合治療物的特定實施例中，該等活性化合物之投予劑量為10毫克QD，且阿美蘇喋 10 呤之投予劑量為每週一次7.5毫克。在文中所揭示之該等藥學組合治療物的特定實施例中，該等活性化合物之投予劑量為10毫克QD，且阿美蘇喋呤之投予劑量為每週一次15毫克。在文中所揭示之該等藥學組合治療物的特定實施例 15 中，該等活性化合物之投予劑量為20毫克QD，且阿美蘇喋呤之投予劑量為每週一次5毫克。在文中所揭示之該等藥學組合治療物的特定實施例中，該等活性化合物之投予劑量為20毫克QD，且阿美蘇喋呤之投予劑量為每週一次7.5毫克。 20 在文中所揭示之該等藥學組合治療物的特定實施例中，該等活性化合物之投予劑量為20毫克QD，且阿美蘇喋呤之投予劑量為每週一次15毫克。一般成人之氣溶膠配方較佳經安排以致使氣溶劑之各計量或“喷量(puff)”含有20微克至1000微克之本揭示内容 67 200823216 化合物。氣溶劑之總每日劑量在〇·1毫克至1000毫克之範圍内。投藥可以每日數次，例如2、3、4或8次，每次可提供，例如1、2或3種劑量。可藉以下活體外檢定試驗而表示式I化合物或其藥學 5 上可接受鹽抑制傑納斯激酶3之能力及證明其用以治療由傑納斯激酶3表示特性之病症或症狀的效力。 1物學檢定法 JAK3(JH1 : GST碰催檢定法該JAK3激酶檢定法係使用藉在麩胱甘肽-塞法羅斯糖 10 (Sepaharose)上進行親和力層析法而純化之經桿狀病毒感染SF9細胞（人類JAK3之GST及催化結構域的融合蛋白質）中所表現的蛋白質。適於該反應之基質為聚-麵胺酸_酪胺酸 (PGT(4 : 1)，Sigma編目號#P〇275)，其係於37°C下以 1〇〇微克/毫升塗覆至Nunc Maxi Sorp盤上費時一次。塗覆後之次 15日上午，清洗該盤3次並添加JAK3至含100微升激酶緩衝劑 (50mM HEPES(pH7.3) > 125mM NaCl > 24mM MgCl2+〇.2uM ATP+lmM正釩酸鈉）之井内。於室溫下進行該反應，費時 30分鐘且再清洗該盤3次。藉標準ELISA檢定法使用抗^粦酸酪胺酸抗體(ICN PY20，編目號#69-l5M)所測定一特定井 20 内之填酸化酪胺酸含量。 A類1L-2依存性1細胞胚 I筛檢法侧定化合物對活體外IL_2依存性τ細胞胚增生的抑制作用。由於經由IL-2受體之傳訊需要，所以JAK-3之細胞活性抑制劑應該可抑制江^存性τ細胞胚 200823216 增生。自新鮮的人血離析適於本檢定法之細胞。使用 Accuspin System-Histopaque-1077(Sigma #A7054)分離單核細胞後，藉使用 Lympho-Kwik T(One Lambda, Inc·，Cat 5 #LK-50T)之頁選擇而離析原發性人類τ細胞。以1至2xl〇6 個/毫升之密度在培養基(RPMI+10%經熱失活之牛胎兒血清(Hyclone Cat #A-1111-L)+1%青黴素/鏈黴素(Gibco))内培養T細胞並藉添加1微克/毫升pHA(Murex Diagnostics，Cat #HA 16)而誘發增生。於37°C下在5% c〇2中經3天後，在培 10養基内清洗細胞3次’使其以1至2x1 〇6個細胞/毫升之密度再懸浮於另含1 〇〇單位/毫升之人類重組型IL_2(R&D Systems， Cat #202-IL)的培養基内。一週後，該等細胞具IL_2依存性且藉每週兩次餵等量之培養基+1〇〇單位/毫升之IL_2而維持該IL_2依存性至高3週。 15 為了測定試驗化合物抑制IL - 2依存性τ細胞增生之能力，將IL-2依存性細胞清洗3次，再懸浮於培養基内，然後接種（50,000細胞/井/(u毫升）在平底％井微量滴定盤 (Fdcon #353075)中。自試驗化合物在DMS〇中之麵m儲備洛液以IGuM開始以—式3份添加化合物之連續2倍稀釋液 2〇至井内。-小時後，添加1〇單位/毫升之U至各試驗井内。然後於37°C及5%〇)2下培育該盤，f時72小時，然後使該盤經3η·胸腺核苷（0 5微居里CuCi)/井）(nen⑸ ET-027A)脈衝，並再培育18小時。然後以％井盤採集器採集培養盤且藉在Paekard TGp c_t閃燦計數器上進行計 69 200823216 數而測定增生細胞内之也胸腺核普的併入量。藉畫出增生抑制％對試驗化合物之濃度的曲線而分析數據。自該㈣圖測定IC50值(uM)。種劑量& L^3-dl 嘧啶-4-某 V 啲無規化 5 皇主動性類風濕性關基 _3-『甲基胺基定-1-基卜3_侧氧基_兩慰劑控制性就給 3-{(3R，4R)-4-甲基-3·[甲基-(7H，各并[2 3_㈣咬冰基)嫌]如小基}各側氧基.丙猜(“該試驗化合物，，)為具口服活性之合«擇性獻3抑_，其在發炎性關節炎之嚅齒動物模式及罹患者牛皮癖之者中已證明有效。本研究係用以比車乂對罹患中度至嚴重主動性類風濕性關節炎 (“RA”)之受實驗者分別投予3種劑量之職驗化合物及安、費日寸6週並在給藥後進行6週追蹤以瞭解這兩種藥物專X實驗者之健康及機能狀態的功效、安全性及影響。記錄對阿美«呤或TNF抑制劑有不合適反應或因非可接受之毒性而中斷投藥之受實驗者、已中斷所有画細或生物性抗風濕病治療物之受實驗者、及已顯露至少9處疼 =璧痛點、6處腫脹點及全身性炎症之受實驗者。對接受 U该试驗化合物5毫克BID、15毫克BID或30毫克 (1 1 · 1 ·丨)之該等受實驗者隨機取樣。允許接受背景 NSAID可西(c〇xlb)、低劑量腎上腺促糖皮質激素及止痛劑。 70 200823216 結果對264個受實驗者隨機取樣，且全部皆接受至少一劑量之該試驗化合物。試驗化合物治療 (BID) (隨機取樣）第6週反應者百分比戒斷數 ACR 20 ACR 50 ACR 70 改良的 HAQ-DI 由於 LOE 由於 AE 任一原因安慰劑 (N=65) 29% 6% 3% 31% 12% 2% 26% 5毫克 (N=61) 70% 33% 13% 57% 2% 2% 5% 15毫克 (N=69) 81% 54% 22% 71% 1% 4% 13% 30毫克 (N=69) 77% 51% 28% 70—% 1% 7% 25% 於第6週之ACR 20為主要分析。該HAQ-DI之改良被定義為至少〇·3單位。 ^失之數據經所進行之最後一次觀測數據取代。試驗化合物群組與安慰劑比較，所有？值<0.〇5 LOE=“缺乏功效’’，AE=與研究藥物有關之副作用 (戒斷數並未經統計學比較） ____ 5 劑量依存性增加且最常報告之副作用為頭痛及噁心。在該5毫克BID之1個受實驗者及該30毫克BID劑量組之2個受實驗者身上發現劑量依存性降低之嗜中性白血球數 (<1000個/毫米3)。與安慰劑劑量組（患者之感染率為26.2%) 比較，該15及30毫克BID之受實驗者的感染率增加（各為 10 30.4%) ’但是並未發生伺機性感染，亦發現LDL及HDL膽固醇皆劑量依存性增加但LDL/HDL比率未變化，且平均血清肌酸酐可逆性增加(〇〇4至〇·〇6毫克/分升）。結論在RA之病徵及症狀的治療上，所有3種劑量之該試驗 15化合物的效力遠高於安慰劑，其效力於第1週開始發生並持績超過或等於6週。15毫克BID及更低之劑量亦具安全性且通常具良好耐藥性。 71 200823216 對類風濕悻11_節炎受實驗者投予多劑詈口服 3-{(3r，4r)-4-甲基基吡咯并「2,3-Dl嘧啶-4-篡V脸基[旅啶小基}-?_-側氧^基-丙腊及單一劑量口服阿美蔽喋呤之藥物動力學的第1期開放標簸研究 5 研究目標 •當對罹患RA之受試驗者投予該試驗化合物，3-{(3R，4R)-4-甲基_3_[甲基-(7H-吡咯并[2,3_d]嘧啶·4_基)_胺基]_σ辰啶小基卜3-側氧基-丙腈時估計ΜΤΧ對該試驗化合物之藥物動力學的影響； 10 •估計多劑量該試驗化合物(30毫克Q12小時)對ΜΤΧ之藥物動力學的影響； •評估其投予該試驗化合物（30毫克Q12小時)及ΜΤΧ之短期安全性及耐藥性。使12個年齡介於18與65歲之經診斷罹患類風濕性關節 15炎且符合所有登錄標準受實驗者(8個女性/4個男性）參加本研究。本研究為開放標籤、非隨機取樣性之固定序列的藥物對藥物交互作用研究。第〇天時確認受實驗者。在第1天早上’在禁食一夜並在第一餐前2小時使受實驗者接受彼等之 2〇每週個體化ΜΤΧ劑量；收集ΜΤΧ血液ΡΚ試樣，費時48小時 ~直到第3天。在最後之ΜΤχ血液ΡΚ試樣收集後，在第3天 —直到第6天期間使受實驗者接受30毫克該試驗化合物q12 小時。在第6天時，收集所有12小時之試驗化合物血液pk 試樣。在第7天時，使受實驗者接受彼等之與3〇毫克計量之 72 200823216 該試驗化合物共投予之每週個體化MTX劑量，繼而收集所有48小時之試驗化合物及ΜΤΧ血液ΡΚ試樣。各受試驗者參與之時間共約14天；且在監督下自第0天開始維持，直到第 9天出院為止。雖然在第9天獲得最後藥物動力學的血液試 5樣後，受實驗者才出院，但是必需在進行該受實驗者之下一次每週ΜΤΧ劑量前安排該等受實驗者返回醫院以進行追踪採訪（約第11至第13天）。使受實驗者接受如下文指定之治療法：第1天第2天第3至6天 ^7天第8及9天 MTX 個別治療單一劑量無治療試驗化合物 3〇毫克Q12小時試驗化合物 — 30毫克（僅早上劑量）加上 MTX個別單' —劑量無治療 10 若合適，在本研究之第6及7天後計算口服劑量試驗化合物之血漿濃度的多劑量藥物動力學參數。若合適，在本研究第1及7天後計算口服劑量ΜΤΧ之血漿濃度的單一劑量：藥物動力學參數。該等藥物動力學參數之定義如下：在自 Λ 1 15時間0至給藥後最後觀測時間點（最後)[AUClast]之血漿濃度時間·曲線下的區域、在自〇至給藥後12小時(AUCu)之血漿濃度時間-曲線下的區域；於穩態下之最大觀測濃度 (cmax);於穩態下達到最大觀測濃測濃度之時間。製成該等藥物動力學參數[AUC及Cmax]之點及區間估計值。就 20間隔估計值而言，可製成90%可信區間（I)。該等數據係以圖及/或表格形式呈現且敘述性摘述。 73 200823216 10 15 基質 ΡΚ參數分析等級驗化合物 MTX^ 血漿 AUC12 In A、D - AUCiast In - Cmax In A、D A、〇 Tmax 氺 R A、D A、D tl/2 R A、D A、D CL/F In A、D a^d^' 尿 Ae〇_24 In A、D A、D clr In A、D 解釋· A=使用統計學模式進行分析，D=以敘述性統計學顯示 In=自然對數變換，R==原始的（未經變換），*=若數據許可" 於下述時間將全血試樣(各5毫升，其足以提供最少2〇毫升血漿）收集在含有肝素鈉之合適標記的試管内： PK採樣方案 >究8手The carrier described in Gennaro edit. 1985). The pharmaceutical composition of the compounds disclosed herein may be prepared by conventional methods known in the art, for example, by mixing at least one of the compounds disclosed herein with a pharmaceutically acceptable carrier. The disclosed compounds can also be formulated into compounds suitable for sustained delivery according to methods well known to those skilled in the art. Examples of such formulations can be found in the following patents: U.S. Patent Nos. 3,119,742, MM, 20, 538,214, 4, 6, 598, and 4,173,626. Thus, the active compounds of the present disclosure may be formulated to be suitable for oral, buccal, intranasal, parenteral (eg, intravenous, intramuscular or subcutaneous) administration, rectal administration, inhalation or infusion, Alternatively, the active compounds may be formulated in a form suitable for topical administration. 200823216 For oral administration, such pharmaceutical compositions may be in the form of a tablet or capsule prepared by conventional methods using pharmaceutically acceptable excipients, such as, for example, a binding agent, for example, Gelatinized corn house powder, polyvinylpyrrolidone or hydroxypropyl methylcellulose; fillers such as lactose, microcrystalline cellulose 5 or calcium phosphate; lubricants such as magnesium stearate, talc or cerium oxide; a decomposing agent such as potato starch or sodium glycolate starch; or a wetting agent such as sodium lauryl sulfate. These tablets may be coated by methods known in the art to which they are well known. The liquid preparation suitable for oral administration may be in the form of, for example, a solvent, syrup or suspension, or it may be in the form of a dry product suitable for reconstitution by water or other suitable vehicle before use. Acceptable additives are formulated into such liquid preparations, such as, for example, suspending agents such as sorbitol syrup, methylcellulose or hydrogenated edible fats; emulsifiers such as lecithin or acacia; non-aqueous vehicles, For example, almond oil, oily or ethanol; and preservatives such as p-propyl 15-methylbenzoate or propyl-hydroxybenzoate or sorbic acid. For buccal administration, the composition may be in the form of a tablet or lozenge prepared in a conventional manner. For intranasal or inhalation administration, the active compounds of the present disclosure are preferably delivered as a solution or suspension from a pump nebulizer which is squeezed or pumped by the patient 20, or by means of a suitable propellant, For example, dichlorodifluoromethane, trichlorofluoromethane, dioxetane, carbon dioxide or other suitable gas, an aerosol spray is provided from a pressurized container or atomizer. In the case of a pressurized aerosol, the dosage unit can be determined by providing a valve that delivers a calculated amount. The pressurized container or nebulizer may contain a solution or suspension of the active compound. 61 200823216 Capsules and cartridges (made, for example, of gelatin) suitable for use in an inhaler or a device are formulated to contain a compound of the present disclosure and a suitable powder base such as lactose or a powder mixture of a powder. The active compounds of the present disclosure may be formulated for injection by injection, including 5 by parenteral administration using conventional catheterization or infusion methods. Formulations suitable for injection may be presented in unit dosage form, such as ampoules or multi-dose containers with added preservatives. The compositions may be in the form of a suspension, solution or emulsion, such as in an oily or aqueous vehicle, and may contain formulating agents such as suspending, stabilizing and/or dispersing agents. Alternatively, the active ingredient may be in the form of a powder suitable for constitution by a suitable vehicle, such as sterile pyrogen-free water, before use. The active compounds of the present disclosure may also be formulated into rectal compositions such as those containing conventional suppository bases such as cocoa butter or other glycerin, or retention enemas. 15 20 = bureaucratic and 5' The compounds of the present disclosure can be formulated into ointments or emulsions. Method Φ 里九九九九九九九九九七七七七七七七七七七七七七七七七七七七七七七七七七七七七七七七七七七七七七七七Understand the acquisition of the desired pharmacological inhibitor ° in the specific real towel, the dose of Naskin kinase is; 〇iiu_i mother day 1 to 42 times per unit dose between the ingredients. The dose may vary within one or more dosing regimens. In a particular embodiment wherein the heterozygous acceptable salt is administered orally, the dosage of the active compound 62 200823216 5 can range from 1 to 50 mg BID (ie twice per week) or from 5 to 20 Mg QD (ie once per week), and preferably 1 mg BID, 2 mg BID, 3 mg BID, 4 mg BID, 5 mg BID, 6 mg BID, 7 mg BID, 8 mg BID, 9 mg BID, 10 Mg BID, 11 mg BID, 12 mg BID, 13 mg BID, Η mg BID, 15 mg BID, 20 mg BID, 25 mg BID or 30 mg BID, and preferably 〇 25 mg BID, 0.5 mg BID, 1 mg BID, 5 mg BID, 10 mg BID, 20 mg BID, and better 1 mg BID, 3 mg BID, 5 mg BID, 15 mg BID, 20 mg QD. In a particular embodiment, the anti-arthritic agent (sometimes referred to herein as 15 "agent") is administered at a dose of from 1 mg to 5 g (i.e., 500 mg), for example, 5 mg, 10 mg. 25 mg, 50 mg, 1 mg, 250 mg, 500 mg, 750 mg, 1000 mg, 125 mg, 1500 mg, 1750 mg, 2000 mg or a combination thereof. For each dose of such anti-arthritic agents provided, it can be administered twice daily, once per 曰 / i 20 times, once a week, etc., as known to those skilled in the art, for example, a prescribed dose of the agent. Typical weekly doses of Amesu ("MTX") are 5 mg, 7.5 mg, 1 mg: 12.5 mg, b mg, 17.5 mg, 20 mg, 22.5 mg, and 253⁄4 g. In a particular embodiment, of course, depending on the lack of toxicity or drug resistance, typically within a period of extended weighting, such as weekly, monthly, and monthly, with a 2.5 mg increment of g g (by titration) Increasing) Agent for MTX ϊ ° In a particular embodiment, if the patient has a good monthly reduction or if it is combined with another agent, such as a biological agent, it can be reduced (ie, titrated) The amount of MTX is eliminated. In other administrations, the dose of MTX is administered in a divided dose of 63 200823216, such as 5 mg χ 3 doses per 12 hours on a weekly basis. Of course, in view of the advantages of the present disclosure, the compounds of the present disclosure and other suitable dosages of such anti-arthritic agents in combination therapies will be readily apparent to those skilled in the art. 5 In a particular embodiment of the pharmaceutical combination therapeutics disclosed herein, the active compound is administered at a dose of 0.25 mg BID and the amesulide is administered at a dose of 5 mg per week. In a particular embodiment of the pharmaceutical combination therapeutics disclosed herein, the active compound is administered at a dose of 0.25 mg BID and the Amesu 10 oxime is administered at a dose of 7.5 mg once a week. In a particular embodiment of the pharmaceutical combination therapeutics disclosed herein, the active compound is administered at a dose of 0.25 mg BID and the amesulide is administered at a dose of 15 mg once a week. In a specific example 15 of the pharmaceutical combination therapeutics disclosed herein, the active compound is administered at a dose of 0.5 mg BID and the amesulide is administered at a dose of 5 mg once a week. In a particular embodiment of the pharmaceutical combination therapeutics disclosed herein, the active compound is administered at a dose of 0.5 mg BID and the amesulide is administered at a dose of 7.5 mg once a week. In a particular embodiment of the pharmaceutical combination therapeutics disclosed herein, the active compound is administered at a dose of 0.5 mg BID and the amesulide is administered at a dose of 15 mg once a week. In a particular embodiment of the pharmaceutical combination therapeutics disclosed herein, the active compound is administered at a dose of 1 mg BID, and the dosage of Amesu 64 200823216 is 5 mg once a week. In a particular embodiment of the pharmaceutical combination therapeutics disclosed herein, the active compound is administered at a dose of 1 mg BID and the amisemidine is administered at a dose of 7.5 mg once a week. 5 In a particular embodiment of the pharmaceutical combination therapeutics disclosed herein, the active compound is administered at a dose of 1 mg BID and the amoxicillin is administered at a dose of 15 mg once a week. In a particular embodiment of the pharmaceutical combination therapeutics disclosed herein, the active compound is administered at a dose of 3 mg BID and the Amesu oxime is administered at a dose of 5 mg per week. In a particular embodiment of such pharmaceutical combination therapies disclosed herein, the active compound is administered at a dose of 3 mg BID and the amifulrone is administered at a dose of 7.5 mg once a week. In a specific embodiment 15 of the pharmaceutical combination therapeutics disclosed herein, the active compound is administered at a dose of 3 mg BID, and the administration of amesulidine is 15 mg once a week. In a particular embodiment of the pharmaceutical combination therapeutics disclosed herein, the active compound is administered at a dose of 5 mg BID and the amisemidine is administered at a dose of 5 mg once a week. In a particular embodiment of such pharmaceutical combination therapies disclosed herein, the active compound is administered at a dose of 5 mg BID and the amisemidine is administered at a dose of 7.5 mg once a week. In a particular embodiment of the pharmaceutical combination therapeutics disclosed herein, the active compound is administered at a dose of 5 mg BID, and the dosage of Amesu 65 200823216 is 15 mg once a week. In a particular embodiment of the pharmaceutical combination therapeutics disclosed herein, the active compound is administered at a dose of 10 mg BID and the amisemidine is administered at a dose of 5 mg per week. 5 In a particular embodiment of the pharmaceutical combination therapeutics disclosed herein, the active compound is administered at a dose of 10 mg BID and the amifulrone is administered at a dose of 7.5 mg once a week. In a particular embodiment of the pharmaceutical combination therapeutics disclosed herein, the active compound is administered at a dose of 10 mg BID and the amesulide 10 oxime is administered at a dose of 15 mg once a week. In a particular embodiment of such pharmaceutical combination therapies disclosed herein, the active compound is administered at a dose of 15 mg BID and the amisemidine is administered at a dose of 5 mg per week. In a specific embodiment 15 of the pharmaceutical combination therapeutics disclosed herein, the active compound is administered at a dose of 15 mg BID, and the dosage of amesulidine is 7.5 mg once a week. In a particular embodiment of such pharmaceutical combination therapies disclosed herein, the active compound is administered at a dose of 15 mg BID and the administration of amethioprine is administered at a dose of 15 mg per week. In a particular embodiment of the pharmaceutical combination therapeutics disclosed herein, the active compound is administered at a dose of 5 mg QD and the amoxicillin is administered at a dose of 5 mg once a week. In a particular embodiment of the pharmaceutical combination therapeutics disclosed herein, the active compound is administered at a dose of 5 mg QD and the Amesu sulphate 66 200823216 is administered at a dose of 7.5 mg once a week. In a particular embodiment of the pharmaceutical combination therapeutics disclosed herein, the active compound is administered at a dose of 5 mg QD and the amoxicillin is administered at a dose of 15 mg once a week. 5 In a particular embodiment of the pharmaceutical combination therapeutics disclosed herein, the active compound is administered at a dose of 10 mg QD and the amisemidine is administered at a dose of 5 mg once a week. In a particular embodiment of such pharmaceutical combination therapies disclosed herein, the active compound is administered at a dose of 10 mg QD and the administration of amesu oxime is administered at a dose of 7.5 mg per week. In a particular embodiment of such pharmaceutical combination therapies disclosed herein, the active compound is administered at a dose of 10 mg QD and the administration of aesthetide is 15 mg once a week. In a specific embodiment 15 of the pharmaceutical combination therapeutics disclosed herein, the active compound is administered at a dose of 20 mg QD, and the administration of amesudem is 5 mg once a week. In a particular embodiment of the pharmaceutical combination therapeutics disclosed herein, the active compound is administered at a dose of 20 mg QD and the amisemidine is administered at a dose of 7.5 mg once a week. In a particular embodiment of the pharmaceutical combination therapeutics disclosed herein, the active compound is administered at a dose of 20 mg QD and the amisemidine is administered at a dose of 15 mg once a week. The aerosol formulations of the general adult are preferably arranged such that each meter or "puff" of the aerosol contains from 20 micrograms to 1000 micrograms of the present disclosure 67 200823216 compound. The total daily dose of the aerosol is in the range of from 1 mg to 1000 mg. Administration can be several times a day, for example 2, 3, 4 or 8 times, each time providing, for example 1, 2 or 3 doses. The ability of a compound of formula I or a pharmaceutically acceptable salt thereof to inhibit Genus kinase 3 and demonstrate its efficacy in treating a condition or condition characterized by the properties of Janus kinase 3 can be expressed by the following in vitro assay. 1Material assay JAK3 (JH1: GST touch assay) This JAK3 kinase assay uses baculovirus infection purified by affinity chromatography on succinate-separate sugar 10 (Sepaharose) Protein expressed in SF9 cells (GST of human JAK3 and fusion protein of catalytic domain). The substrate suitable for this reaction is poly- faceamine-tyrosine (PGT (4: 1), Sigma Catalog #P 〇 275), which was applied to the Nunc Maxi Sorp plate at 1 ° μg/ml at 37 ° C. It took a while to wash the plate 3 times and added JAK 3 to 100 μm. Into the well of a kinase buffer (50 mM HEPES (pH 7.3) > 125 mM NaCl > 24 mM MgCl 2 + 2UM ATP + lmM sodium vanadate). The reaction was carried out at room temperature for 30 minutes and the plate was washed again. 3 times. The content of acidified tyrosine in a specific well 20 was determined by standard ELISA assay using anti-antimony tyrosine antibody (ICN PY20, catalog #69-l5M). Class A 1L-2 Dependence 1 Cell embryo I screening method for the inhibition of IL-2-dependent tau cell embryo proliferation in vitro. Need, so the inhibitor of cell activity of JAK-3 should inhibit the proliferation of γ cell embryo 200823216. The cells suitable for this assay were isolated from fresh human blood. Use Accuspin System-Histopaque-1077 (Sigma #A7054) After isolation of monocytes, primary human tau cells were isolated by using the page selection of Lympho-Kwik T (One Lambda, Inc., Cat 5 #LK-50T), at a density of 1 to 2 x 1 〇 6 cells/ml. Culture medium (RPMI + 10% heat-inactivated bovine fetal serum (Hyclone Cat #A-1111-L) + 1% penicillin/streptomycin (Gibco)) and add 1 μg/ml pHA (Murex) Diagnostics, Cat #HA 16) induced hyperplasia. After 3 days at 37 ° C in 5% c〇2, the cells were washed 3 times in culture 10 to make them 1 to 2 x 1 〇 6 cells / The density of the milliliters was resuspended in a medium containing 1 〇〇 unit/ml of human recombinant IL-2 (R&D Systems, Cat #202-IL). After one week, the cells were IL-2 dependent and borrowed twice a week. The same amount of medium was fed once + 1 unit/ml of IL 2 to maintain the IL 2 dependency for up to 3 weeks. 15 In order to determine the test compound inhibits IL - 2 The ability to accumulate tau cells, wash IL-2 dependent cells 3 times, resuspend in the medium, and then inoculate (50,000 cells / well / (u ml) in the flat bottom % well microtiter plate (Fdcon #353075) . From the surface of the test compound in the DMS mm reserve Lok solution started with IGuM in a 3-fold serial dilution of the compound added to the well. After the hour, add 1 unit/ml of U to each test well. The plate was then incubated at 37 ° C and 5% 〇) 2 for 72 hours, then the plate was pulsed with 3η·thymidine (0 5 microcuries CuCi)/well (nen(5) ET-027A). And cultivate for another 18 hours. The plates were then harvested with a % well disk harvester and the amount of thymic nucleus incorporated into the proliferating cells was determined by counting the number of 2008 20081616 on the Paekard TGp c_t flash counter. The data was analyzed by plotting the % inhibition of proliferation versus the concentration of the test compound. The IC50 value (uM) was determined from the (iv) plot. Dosage & L^3-dl pyrimidine-4-V 啲 randomization 5 Emperor active rheumatoid _3-"Methylamine -1-butyl 3_sideoxy _ two comfort The controllability of the agent is given to 3-{(3R,4R)-4-methyl-3.[methyl-(7H, each [2 3_(four) biting ice base)] such as small base} each side oxy. ("The test compound,") is a combination of oral activity, which has been proven to be effective in the model of inflammatory arthritis and in patients with psoriasis. The subjects who were suffering from moderate to severe active rheumatoid arthritis ("RA") were given three doses of the test compound and the ampere-hours for 6 weeks and after the administration. Weekly tracking to understand the efficacy, safety, and impact of the health and function status of the two drug-specific X testers. Recording inappropriate response to Ami's 呤 or TNF inhibitor or discontinuation of administration due to unacceptable toxicity The experimenter, the subject who has discontinued all the fine or biological anti-rheumatic treatments, and the subjects who have revealed at least 9 pain=pain points, 6 swelling points, and systemic inflammation. U The test compound 5 mg BID, 15 mg BID or 30 mg (1 1 ·1 · 丨) of the subjects were randomly sampled. Allowed to receive background NSAID kexi (c〇xlb), low dose adrenal glucocorticoid Hormone and analgesic. 70 200823216 Results 264 subjects were randomized and all received at least one dose of the test compound. Test compound treatment (BID) (random sampling) Week 6 Responder percentage abstinence ACR 20 ACR 50 ACR 70 Modified HAQ-DI due to LOE Placebo for any reason AE (N=65) 29% 6% 3% 31% 12% 2% 26% 5 mg (N=61) 70% 33% 13% 57% 2% 2% 5% 15 mg (N=69) 81% 54% 22% 71% 1% 4% 13% 30 mg (N=69) 77% 51% 28% 70-% 1% 7% 25 % ACR 20 is the primary analysis at week 6. The HAQ-DI improvement is defined as at least 〇·3 units. ^The missing data is replaced by the last observation data performed. The test compound group is compared with placebo. All values <0.〇5 LOE=“Lack of efficacy”', AE=side effects associated with study drug (without statistical comparison) ____ 5 Dose dependence increased Often report side effects were headache and nausea. A dose-dependent decrease in the number of neutrophils (<1000/mm3) was found in one of the 5 mg BID subjects and the two subjects in the 30 mg BID dose group. Compared with the placebo dose group (patient infection rate was 26.2%), the infection rate of the 15 and 30 mg BID subjects increased (10 30.4% each) 'but no opportunistic infection occurred, and LDL and LDL were found. HDL cholesterol was dose-dependently increased but the LDL/HDL ratio was unchanged, and the mean serum creatinine was reversibly increased (〇〇4 to 〇·〇6 mg/dl). Conclusions In the treatment of symptoms and symptoms of RA, all three doses of this test compound were much more potent than placebo, and their efficacy began to occur at week 1 with a duration of more than or equal to 6 weeks. The 15 mg BID and lower doses are also safe and generally well tolerated. 71 200823216 For rheumatoid sputum 11_ inflammation, the experiment was administered with multiple doses of sputum orally 3-{(3r,4r)-4-methylpyrrole and "2,3-Dl pyrimidine-4-篡V face base [ The first open-label study of the pharmacokinetics of lysine-based small-base---_---oxyxyl-propanoid and single-dose oral Ame sputum 5 Research objectives • When administered to subjects who have RA The test compound, 3-{(3R,4R)-4-methyl_3_[methyl-(7H-pyrrolo[2,3_d]pyrimidin-4-yl)-amino]- σ 啶小基 3 - the effect of oxime on the pharmacokinetics of the test compound when oxy-propionitrile; 10 • Estimation of the effect of multiple doses of the test compound (30 mg Q12 hours) on the pharmacokinetics of sputum; Test compound (30 mg Q12 hours) and short-term safety and drug resistance of sputum. Twelve age-related diagnoses of rheumatoid arthritis between the ages of 18 and 65 years of age and in compliance with all criteria for registration (8 Female/4 males) participated in the study. This study was an open-label, non-random sampling of fixed-sequence drug-to-drug interaction studies. The third day was confirmed by the experimenter. One morning morning, 'fasting for one night and allowing the subjects to receive 2 weeks of individualized sputum doses for 2 hours before the first meal; collecting sputum blood sputum samples, which took 48 hours until the 3rd day. After the final blood sputum sample collection, the subject received 30 mg of the test compound for 12 hours on day 3 - until day 6. On day 6, all 12 hours of test compound blood pk sample was collected. On the 7th day, subjects were given a weekly dose of individualized MTX administered in combination with their test compound of 3,200 mg, and then all the 48 hours of test compound and blood test were collected. The subjects participated for a total of 14 days; and under supervision, they were maintained from day 0 until discharge on the 9th day. Although the final pharmacokinetic blood test was obtained on the 9th day, The experimenter was discharged from the hospital, but it was necessary to arrange for the subjects to return to the hospital for follow-up interviews (about days 11 to 13) before performing the next weekly dose of the subject. The subjects were accepted as follows Means Treatment: Day 1 Day 2 Day 3-6 Day 7 Day 8th and 9th Day MTX Individual Treatment Single dose no treatment test compound 3 〇 mg Q12 hour test compound - 30 mg (only morning dose) plus MTX Individual Single '-Dose No Treatment 10 If appropriate, multi-dose pharmacokinetic parameters for plasma concentrations of oral dose test compounds were calculated after days 6 and 7 of the study. If appropriate, calculated after days 1 and 7 of the study Single dose of plasma concentration of oral dose ΜΤΧ: pharmacokinetic parameters. These pharmacokinetic parameters are defined as follows: the area under the plasma concentration time curve from the time of Λ 1 15 to the last observation time point (final) [AUClast], from autologous to 12 hours after administration (AUCu) plasma concentration time - the area under the curve; the maximum observed concentration at steady state (cmax); the time at which the maximum observed concentration is reached at steady state. The points and interval estimates for these pharmacokinetic parameters [AUC and Cmax] were prepared. For the 20-interval estimate, a 90% confidence interval (I) can be made. The data is presented in a graphical and/or tabular format and is a narrative summary. 73 200823216 10 15 Matrix ΡΚ parameter analysis Grade test compound MTX^ Plasma AUC12 In A, D - AUCiast In - Cmax In A, DA, 〇Tmax 氺RA, DA, D tl/2 RA, DA, D CL/F In A D a^d^' Urine Ae〇_24 In A, DA, D clr In A, D Explanation · A = statistical analysis is used, D = narrative statistics show In = natural logarithmic transformation, R = = original (untransformed), *= if data is permitted " Whole blood samples (5 ml each, sufficient to provide a minimum of 2 ml of plasma) are collected in a suitable test tube containing sodium heparin at the following times : PK sampling plan >

前) ，後卜2、3、4、8及12小時（在日^上給藥前必需取出該12小 ____ 前及小時第7天給藥— ~第7天給藥動力=====物下獲得該等藥物樣之3分鐘二獲得差’其限制條件為該試樣收集 u作為實驗方案偏讀據收集卫具(例如CRF)崎。時縣根據來源文件藥物動力學(ρκ) 藥物動力學參數之統計學分析中之患者具有至少一種 74 200823216 :不mrtr據數據之有效性，分析組可含有 u梁物動力學參數之不同患者數。就該等參數，AUC12、AUQ⑽ 及 Ae，品士、仏〜 CLrenal 5 10 15 20 所呈現之統計學分析以估計經調整幾何平均數與 / _ 〇%可信區間的比率（試驗物/參考物）。同 ^別等參數’ Tmax&ti/2而言，進行統計學分析以估計位數或經調整平均數與所呈現相_%可信區間驗,參考物）。就各分析物而言，以混合作用模 ^針為〜作用及就患者而言為隨機作用）分析 l . AUClast. cmax . CL/F ^ CLrenal 24)及未變換之參數(W。自本模式估計經調整平均差異（試驗物-參考物）與對應9〇%可信區間的估計值。就〜12 AUClast、C_、CL/F、CLrenal及 Ae24而言，取出該經调整平均差異與該差異之9〇%可信限值之指數以導出經調正成何平均數（试驗物/參考物）與該比率之如❻义可信區間的L匕率。與另一化合物其投予之各分析物為該試驗化合物且單獨投予之各分析物為該參考物。使用混合REML估算法、化合物對稱之變數-共變數結構及Satterthwaite自由對數度之SAS Pr〇c進行該混合作用模式。在各分析物内之未變換(原始)PK參數Tmax上進行非參數性分析。使用SAS，PrOC_StatXact 程序以進行這些分析。製成治療間之中位數差異（H〇dges丄ehmann)、及接近該等差異之精確90% CI的點估計數。就該等參數，AUC12、AUClast、Cmax、Tmax、t1/2、口服 75 200823216 ’月除率CL/F、尿中之排泄量（Ae24)為腎清除率（CLrenal)而 °在本研九報告中提供藉分析物而摘述數據之敘述統計學(N、平均數、中位數、cv%、標準偏差、最低值及最高值）除上述敘述統計學外，提供AuCU、Αυ^、c·、 CL/F、CLrenal及ΛΑ#之幾何平均值。提供各分析物之根據時間而變化的濃度之圖示。結論貧料組分析（包含受實驗者/不包含受實驗者）在4等藥物動力學’副作用及實驗室分析中包括接受 10研究藥物之所有12個受實驗者。統计及分析問題：使SAS軟體程式(第8·2版)以進行資料摘述及統計學分析。統计學結果ΡΚ參數之摘述：試驗化合物: 15 得自該試驗化合物之藥物動力學參數的統計學分析結果之摘述係提供在下表中。參數 auc12(毫微克小時 /毫升） cmax(毫微克/毫升） CL/F(升/小時） Ae12(毫克） CLrenal(升/小時）試驗 (T) 參考 (R) 試驗平均數 T/R 比率（％) 90%可信區間 (%) C B 1344.12 1304.20 103.06 99.00 107.29Before, after, 2, 3, 4, 8 and 12 hours (required before the administration of the day ^ before the 12 small ____ before the administration and the 7th day after the administration - ~ 7th day of administration power ==== = Obtaining the drug samples for 3 minutes and obtaining the difference 'There is a condition for the sample to be collected as a test program for the partial reading of the collection aids (eg CRF). The county according to the source document pharmacokinetics (ρκ) The patient in the statistical analysis of the pharmacokinetic parameters has at least one of 74 200823216: no mrtr according to the validity of the data, the analysis group may contain different numbers of patients with u beam kinetic parameters. For these parameters, AUC12, AUQ(10) and Ae , 士士, 仏~ CLrenal 5 10 15 20 Statistical analysis presented to estimate the ratio of the adjusted geometric mean to / _ 〇% confidence interval (test substance / reference). The same parameter and other parameters ' Tmax & For ti/2, statistical analysis was performed to estimate the number of digits or adjusted mean and the presented phase _% confidence interval test, reference). For each analyte, the effect of the mixed action is as follows: and the patient is random.) AUClast. cmax . CL/F ^ CLrenal 24) and untransformed parameters (W. From this mode) Estimate the adjusted mean difference (test substance-reference) and the estimated value of the corresponding 9〇% confidence interval. For the ~12 AUClast, C_, CL/F, CLrenal and Ae24, take the adjusted average difference and the difference The index of the 9〇% confidence limit is used to derive the average of the adjusted mean (test substance/reference) and the L匕 rate of the ratio as the confidence interval of the ratio. The analyte is the test compound and each analyte administered alone is the reference. The mixed action mode is performed using a mixed REML estimation method, a compound symmetry variable-covariate structure, and a Satterthwaite free logarithmic SAS Pr〇c. Nonparametric analysis was performed on the untransformed (original) PK parameter Tmax within each analyte. The SAS, PrOC_StatXact program was used to perform these analyses. The median difference between treatments (H〇dges丄ehmann) was made, and the Equal difference 90% CI Point estimates. For these parameters, AUC12, AUClast, Cmax, Tmax, t1/2, oral 75 200823216 'month removal rate CL/F, urine excretion (Ae24) is the renal clearance rate (CLrenal) and ° In the report of this study, the narrative statistics (N, mean, median, cv%, standard deviation, minimum value, and highest value) of the data are provided by means of the analyte. In addition to the above-mentioned narrative statistics, AuCU and Αυ are provided. Geometric mean of ^, c·, CL/F, CLrenal, and ΛΑ#. Provides a graphical representation of the concentration of each analyte as a function of time. Conclusion Analysis of the poor group (including subjects/excluding subjects) All 12 subjects receiving 10 study drugs were included in the 4th Pharmacokinetics' side effects and laboratory analysis. Statistics and Analysis Questions: The SAS software program (version 8.2) was used for data review and statistics. Statistical analysis. Statistical results ΡΚ Parameter summary: Test compound: 15 A summary of the statistical analysis of the pharmacokinetic parameters obtained from the test compound is provided in the table below. Parameter auc12 (ngm/hr) Cmax (ng/ml) CL/F ( Liters/hour) Ae12 (mg) CLrenal (liters/hour) Test (T) Reference (R) Test Average T/R Ratio (%) 90% confidence interval (%) C B 1344.12 1304.20 103.06 99.00 107.29

C C C CC C C C

B B B B 374.26 19673.5 6.25 4647.20 364.39 21989.1 6.32 4844.60 102.71 89.47 98.86 95.93 tl/2(小時） Tmax(小時）B B B B 374.26 19673.5 6.25 4647.20 364.39 21989.1 6.32 4844.60 102.71 89.47 98.86 95.93 tl/2 (hours) Tmax (hours)

CC

B 互調整 2·70 2.57 中位數 0.13 93.79 82.92 87.90 86.07 112.47 96.53 111.19 106.91 -0.02 0.28 治療標籤：Β: 〇.25 76 200823216 與僅投予穩態試驗化合物3〇毫克比較，在與單一劑量 MTX(個體化給藥）共投予後之穩態試驗化合物3〇毫克的平均曝露值未受影響。對數變換之數據的所有9〇%可信區間王。P在80至125%無作用限值之範圍内。類似地，時間參數 5 之所有90%可信區間包含零。阿美蔌喋呤ίΜΤΧ): 知自ΜΤΧ之藥物動力學參數的統計學分析結果之摘述提供在下表中參數試驗參考經調整之幾何平均數 T/R -比率（％) 90%可信區間 (%) (T) (R) 試驗參考下上 AUC24(毫微克小時 /毫升） C A 1489.14 1661.30 89.64 76.92 104.46 Cmax(毫微克/亳升） C A 408.36 468.06 87.25 76.03 100.12 CL/F(升/小時） C A 10067.0 9217.12 109.22 93.35 127.79 Ae24(毫克） C A 7.32 9.24 79.18 56.13 111.69 CLrenal(升/小時） C A 4813.95 5271.06 91.33 69.49 120.03 tl/2(小時） C A 經調整之平均數 3.00 2.64 T-R之差 0.37 0.24 0.50 Tmax(小時） C A 中位數 1.25 1.00 0.25 0.00 0.25 治療標籤：A=MTX個體化給藥；C= =試驗化合物30毫克+MTX個體化給藥。與僅投予單一劑量ΜΤΧ比較，在與穩態試驗化合物3〇毫克共投予後之單一劑量ΜΤΧ平均曝露值分別降低〜10%(就AUC24而言）及〜13%(就cmax而言）。類似地，Αε24 及CIrenal分別降低〜21%及〜9。/。，而CL/F增加〜9%且〖1/2遲緩 15 〇·37小時。Tmax似乎不受影響。該等對數變換之ρκ參數的所有90%可信區間並不完全包含在該80至125%無作用限值内且該90%自彳吕區間並不包括零。 77 200823216 本研究並未報告死亡或嚴重副作用。並於副作心提早中_研究。僅純讀驗料於== 療有關之副作用而暫時中斷本研究藥物。〃 5 使用根據治療迫切性、身體系統、較佳期限、及嚴重性之研究者評估(輕度、中度或嚴重)與起因，使用_ra 川=將治療期間及最後一天治療後之遲滯期[(無限)_ *之所有e發現或自生的副作用製絲格。治療迫切性作用之定義為〇不存在於基線或基線階段期間且在經本研究樂物開始治療後才發生之作用，及2)存在於基線，但是在經本研究藥物開始治療後，嚴重程度增加之作用。若個別受實驗者之任一種副作用顯示不只一種嚴重程度，則述表中使用最大嚴重程度；缺失之嚴重程度被分類為嚴重。臨床性實驗室試驗評估於治療期間或在最後一天治療後之遲滯期[(無限）日數]内所收集之實驗室試驗結果以瞭解見潛在臨床上重 20要I·生之異吊現象。將導致治療中斷或本研究藥物之變化的實驗室試驗記錄為副作用，於此時藉該研究者評估其與治療關係實驗性異常現象僅發生在第】天時ALT增加之一受實僅投予Μτχ) ’在本研究期間，ALT持續增加，但是在追蹤期間再消退至正常範圍。 78 200823216 生命徵象：於該組合治療物[試驗化合物（3〇毫克Q12小時)+ΜΤΧ S D ]治療期間所發生之具潛在臨床重要性之生命徵象資料的類別總結表之大多數發病率如下表所示： 5 參數標準受實驗者（研究曰）治療仰队的收縮壓自基線>=30毫米汞柱降低 XXXXXXX4(1) MTX SD 仰臥的收縮壓自基線>=30毫米汞柱降低 XXXXXXX4(7,8,9&11) Combo 仰臥的舒張壓 <50毫米汞柱 XXXXXXX5(5&6) 僅 CP BID 仰臥的舒張壓 <50毫米汞柱 XXXXXXX5(7) Combo 仰臥的舒張壓自基線>=20毫米汞柱降低 XXXXXXX4(11) Combo 仰臥的舒張壓自基線>=20毫米采柱降低 XXXXXXX6(7) Combo 仰臥的舒張壓自基線>=20毫米汞柱增加 XXXXXXX8(11) Combo 心電圖：在ECG報告中並無顯著發現物。在經該組合治療物之 ΜΤΧ及試驗化合物治療期間，就3位受實驗者而言，收縮壓及舒張壓中度降低。就這些受實驗者而言，其中一位亦經 , 1〇歷收縮壓稍降低(僅投予ΜΤΧ)或舒張壓稍降低(僅投予試驗 f 化合物）。於經該組合治療物中之MTX及試驗化合物治療期間，有一位受實驗者之仰臥收縮壓稍降低溫。更明確地，在任何治療方案中，並未受實驗者顯示大於500msec之QT 或QTcF或大於60msec之QTcB或QTcF基線的變化。一位受 15 實驗者[接受試驗化合物（30毫克Q12小時)+MTX SD]經歷大於500msec[〜500msec(第7天）]之QTcB。當在第1天接受 MTXSD時，該同一位受實驗者經歷QTcB及QTcF基線之大於30msec增加（分別為-46&-33msec)。當在第3天接受試驗化 79 200823216 合物(30毫克&12小時）時，該同一位受實驗者亦經歷qtcb 基線之30msec增加（〜37msec)。結論檢視這12位受實驗者之PK資料，顯示MTX共投藥對該 5 試驗化合物之AUC(0至12)或Cmax並無影響。然而，與僅投予單一劑量之MTX比較就MTX AUC24及Cmax而言，試驗化合物共投藥分別可減少〜10%及〜13%。與僅投予穩態試驗化合物(30毫克）比較，在具有單一劑量MTX之藥學組合治療物中試驗化合物(3 0毫克）的穩態曝露值並未受影響。與僅投 10予MTX比較，就AUC24及Cmax而言，在具有穩態試驗化合物 (30毫克）之藥學組合治療物中之MTX的單一劑量曝露值分別可減少〜10%及〜13%。僅投予穩態試驗化合物(3〇毫克)及單一劑量MTX以及以藥學組合治療投予之治療通常具很令人滿意的耐藥性。 15 以下實例係闡明本揭示内容該等化合物之製法，但是該製法並不限於本揭示内容之詳述。熔點並未經校正。NMR 資料係以每百萬之份數（5)表示且參考得自試樣溶劑（除非另有指定’其係為含氣氣仿）之氣鎖止信號。可使用不需進一步純化之市售試劑。THF係指四氫呋喃。DMF係指N，N-20二甲基甲醯胺。在使用化學電離法（銨）之Hewlett Packard 5989®或使用具有0.1%甲酸之乙腈/水的50/50混合物作為電離劑之Fisons(或Micro Mass)常壓化學電離(APCI)裝置上記錄低解析度質譜（LRMS)。室溫或環境溫度係指2〇至25 X：。下述ICso值係得自上述之JAK3(JH1:GST)酚催檢定法 200823216 (不包括實例33)且其係為多次實驗(n=4至6,其中n=l代表操作3回）之結果。實例1 曱基-(7H-吡咯并「2,3_dl嘧啶-4-某胺某卜味 5 g定-1-基丨•乙g同B Mutual adjustment 2·70 2.57 Median 0.13 93.79 82.92 87.90 86.07 112.47 96.53 111.19 106.91 -0.02 0.28 Therapeutic label: Β: 〇.25 76 200823216 Compared with the administration of a steady-state test compound of only 3 mg, in a single dose of MTX (Individualized administration) The average exposure value of the steady state test compound after 3 mg was not affected. All 9〇% confidence intervals for log transformed data. P is in the range of 80 to 125% no effect limit. Similarly, all 90% confidence intervals for time parameter 5 contain zeros. Ami蔌喋呤ίΜΤΧ): A summary of the results of the statistical analysis of the pharmacokinetic parameters of the self-producing is provided in the table below. The parameter test refers to the adjusted geometric mean T/R-ratio (%) 90% confidence interval ( %) (T) (R) Test reference under AUC24 (nanogram hours/ml) CA 1489.14 1661.30 89.64 76.92 104.46 Cmax (nanograms per liter) CA 408.36 468.06 87.25 76.03 100.12 CL/F (liters per hour) CA 10067.0 9217.12 109.22 93.35 127.79 Ae24 (mg) CA 7.32 9.24 79.18 56.13 111.69 CLrenal (liters / hour) CA 4813.95 5271.06 91.33 69.49 120.03 tl / 2 (hours) CA adjusted average 3.00 2.64 TR difference 0.37 0.24 0.50 Tmax (hours) CA median 1.25 1.00 0.25 0.00 0.25 Treatment label: A = MTX individualized administration; C = = test compound 30 mg + MTX individualized administration. The average exposure to a single dose after co-administration with a steady-state test compound of 3 mg was reduced by ~10% (in terms of AUC24) and ~13% (in terms of cmax) compared to a single dose of sputum alone. Similarly, Αε24 and CIrenal are reduced by ~21% and ~9, respectively. /. , CL / F increased by ~ 9% and 1/2 slow 15 〇 · 37 hours. Tmax seems to be unaffected. All 90% confidence intervals for the ρκ parameters of the logarithmic transformations are not fully contained within the 80 to 125% no-action limit and the 90% self-decoding interval does not include zero. 77 200823216 This study did not report death or serious side effects. And in the early work of the vice _ research. The study drug was temporarily discontinued only on the basis of the side effects of the == treatment. 〃 5 Use a researcher's assessment (mild, moderate or severe) and cause based on treatment urgency, body system, better duration, and severity, using _rachuan = lag period after treatment and last day of treatment [(Unlimited) _ * All e found or spontaneous side effects made in silk. The urgency of treatment is defined as the effect that does not occur during the baseline or baseline phase and does not occur after the start of treatment in this study, and 2) is present at baseline, but after the treatment of the study drug begins, the severity increases. effect. If any of the side effects of the individual subject shows more than one severity, the maximum severity is used in the table; the severity of the loss is classified as severe. Clinical Laboratory Trial Evaluate the results of laboratory tests collected during the treatment period or during the lag period [(unlimited) days after the last day of treatment to understand the potential clinical impact of the phenomenon. A laboratory test that would result in a discontinuation of treatment or a change in the drug of the study was recorded as a side effect, at which point the investigator assessed that the experimental abnormality associated with the treatment occurred only on the first day when one of the ALT increases was only administered. Μτχ) ' During the study period, ALT continued to increase, but subsided to the normal range during the follow-up period. 78 200823216 Signs of life: Most of the incidence rates for the summary of the clinically important signs of vital signs that occur during the treatment of this combination [test compound (3 mg mg Q12 hours) + ΜΤΧ SD] are shown in the table below. Show: 5 parameters of the standard subject (study 曰) treatment of the systolic pressure of the squad from the baseline > = 30 mm Hg decreased XXXXXXX4 (1) MTX SD supine systolic pressure from the baseline > = 30 mm Hg decreased XXXXXXX4 ( 7,8,9&11) Combo supine diastolic pressure <50 mm Hg XXXXXXX5 (5&6) CP BID supine diastolic pressure<50 mm Hg XXXXXXX5(7) Combo supine diastolic pressure from baseline&gt ;=20 mm Hg lower XXXXXXX4(11) Combo supine diastolic pressure from baseline>=20 mm colony lowered XXXXXXX6(7) Combo supine diastolic pressure from baseline>=20 mm Hg increased XXXXXXX8(11) Combo Electrocardiogram: There were no significant findings in the ECG report. During the treatment with the combination of the treatment and the test compound, the systolic blood pressure and the diastolic blood pressure were moderately reduced for the three subjects. For these subjects, one of them also had a slight decrease in systolic blood pressure (only sputum administration) or a slight decrease in diastolic blood pressure (only test compound f was administered). During the treatment of MTX and test compound in the combination treatment, one subject's supine systolic pressure was slightly lowered. More specifically, in any treatment regimen, the subject did not show QT or QTcF greater than 500 msec or a change in QTcB or QTcF baseline greater than 60 msec. One subject received 15 trials [test compound (30 mg Q12 hours) + MTX SD] experienced QTcB greater than 500 msec [~500 msec (day 7)]. When MTXSD was received on day 1, the same subject experienced an increase of more than 30 msec in the QTcB and QTcF baselines (-46 & -33 msec, respectively). The same subject experienced a 30 msec increase in the qtcb baseline (~37 msec) when tested on Day 3, 7923223216 (30 mg & 12 hours). Conclusions The PK data of the 12 subjects were examined and showed that the MTX co-administration had no effect on the AUC (0 to 12) or Cmax of the 5 test compounds. However, in the case of MTX AUC24 and Cmax compared to MTX with only a single dose, the test compound can be reduced by ~10% and ~13%, respectively. The steady state exposure of the test compound (30 mg) was not affected in the pharmaceutical combination treatment with a single dose of MTX compared to the steady-state test compound alone (30 mg). The single dose exposure of MTX in a pharmaceutical combination treatment with a steady state test compound (30 mg) was reduced by ~10% and ~13%, respectively, in terms of AUC24 and Cmax compared to 10 doses of MTX alone. Administration of a steady-state test compound (3 mg) and a single dose of MTX, as well as treatment with a pharmaceutical combination, is generally very satisfactory. The following examples illustrate the preparation of such compounds in the present disclosure, but the methods are not limited to the details of the disclosure. The melting point is not corrected. The NMR data is expressed in parts per million (5) and is referenced to the gas lock signal from the sample solvent (unless otherwise specified). Commercially available reagents that do not require further purification can be used. THF means tetrahydrofuran. DMF refers to N,N-20 dimethylformamide. Record low resolution on a Fisons (or Micro Mass) atmospheric pressure chemical ionization (APCI) device using chemical ionization (ammonium) Hewlett Packard 5989® or a 50/50 mixture with 0.1% formic acid in acetonitrile/water as the ionizer Mass spectrometry (LRMS). Room temperature or ambient temperature means 2 〇 to 25 X:. The following ICso values were obtained from the above JAK3 (JH1:GST) phenolic assay 200823216 (excluding Example 33) and were performed multiple times (n=4 to 6, where n=l represents 3 operations) result. Example 1 Mercapto-(7H-pyrrolo-[2,3-dl-pyrimidine-4-amine-a certain taste 5 g-dec-1-yl丨•乙g同

方法A 〇 -节基-4-曱基-°底咬-3-基)-甲月安添加1 ·4毫升(2.3毫莫耳）乙酸至藉Iorio, M.A.及Damia， G·，Tetrahedron，丛，5519 (1970)與Grieco等人，J0urnai of the 10 American Chemical Society, 107, 1768(1985)之方法（使用 5%甲醇作為共溶劑），這兩種資料之全文在此併入本案以為參考資料），而製成之1·苄基-4-甲基-哌啶-3-酮(2.3克，11.5 毫莫耳)在23毫升2M甲胺之四氫呋喃中之攪拌溶液内，並於室溫下在密封瓶内攪拌所形成混合物，費時16小時。添加 15三乙酿氧硼氫化鈉(4·9克，23毫莫耳）並於室溫下在密封瓶内攪拌該新混合物，費時24小時，於此時藉添加in氫氧化納（50毫升）而中止反應。然後以醚(80毫升)3次，萃取反應混合物，使該組合醚層在硫酸鈉(NajO4)上乾燥並真空濃縮至乾燥以得到1 ·7克（69%)如白色固體之標題化合物。 20 LRMS : 219.1 (Μ+1)。方組苄某-4-甲基底°定_3-基密咬-(7H-pit 口各并j^，3_dig密ϋ定_4_ 基)_胺於100°C下在密封瓶内加熱藉Davoll，j. Am. Chem 81 200823216Method A 〇-knotyl-4-mercapto--bottom-3-yl)-methanoamine added 1 ·4 ml (2.3 mmol) of acetic acid to Iorio, MA and Damia, G·, Tetrahedron, plexus , 5519 (1970) and Grieco et al, J0urnai of the 10 American Chemical Society, 107, 1768 (1985) (using 5% methanol as a co-solvent), the entire contents of which are incorporated herein by reference. And a solution of 1 benzyl-4-methyl-piperidin-3-one (2.3 g, 11.5 mmol) in 23 ml of 2M methylamine in tetrahydrofuran and at room temperature The resulting mixture was stirred in a sealed bottle and took 16 hours. Add 15 triethyl borohydride (4.9 g, 23 mmol) and stir the new mixture in a sealed bottle at room temperature for 24 hours, then add in sodium hydroxide (50 ml) ) and stop the reaction. The reaction mixture was extracted with EtOAc (3 mL). 20 LRMS : 219.1 (Μ +1). Square group benzyl -4-methyl bottom ° _3- base bite - (7H-pit mouth and j ^, 3_dig ϋ ϋ _4_ base) _ amine at 100 ° C in a sealed bottle of heating Davoll, j. Am. Chem 81 200823216

Soc·，拉，131(1960)之方法，該資料之全文在此併入本案以為參考資料，而製成之4-氣吡咯并[2,3-d]嘧啶(2.4克，15.9 毫莫耳)及得自方法A之產物（1.7克，7.95毫莫耳)在2當量二乙胺中之溶液，費時3天。冷却至室溫度並於減壓下濃縮 5 後，藉驟層分析法(二氧化矽；3%甲醇在二氯甲烷中之溶液) 而純化殘留物以得到1.3克（50%)如無色油之標題化合物。 LRMS ·· 336·1(Μ+1)。The method of Soc, La, 131 (1960), the entire contents of which is hereby incorporated by reference in its entirety by reference in its entirety, for the preparation of 4-pypyrrolo[2,3-d]pyrimidine (2.4 g, 15.9 mmol) And a solution of the product from Method A (1.7 g, 7.95 mmol) in 2 equivalents of diethylamine, which took 3 days. After cooling to room temperature and concentrating under reduced pressure 5, the residue was purified by EtOAc (EtOAc m. Title compound. LRMS ·· 336·1 (Μ+1).

方法C 曱基-(4-曱基-旅唆-3-基口各并「2,3-d~l·密难-4-其 10 添加丨.5毫升之2N鹽酸至得自方法b之產物（〇.7克， 2.19毫莫耳)在15毫升乙醇中之溶液内並藉氮滌洗而使反應混合物脫氣。然後添加0.5克之20%碳載氫氧化鈀(5〇% 水)(Aldrich)至該反應混合物内並於室溫在50psi氫氣壓下搖動(Parr-搖動器）所形成混合物，費時2天。將經賽力特石夕 15藻土(Celite)過濾之反應混合物真空濃縮至乾燥並藉驟層分析法（二氧化矽；5%甲醇在二氣甲烧中之溶液）而純化殘留物以得到0.48克(90%)標題化合物。LRMS : 246.1(M+1)。Method C thiol-(4-mercapto-tour 唆-3-base each and "2,3-d~l·密难-4-10 added 丨.5 ml of 2N hydrochloric acid to obtain method b The product (〇7 g, 2.19 mmol) was degassed by washing with nitrogen in a solution of 15 ml of ethanol. Then 0.5 g of 20% palladium hydroxide on carbon (5 〇% water) was added ( Aldrich) to the reaction mixture and shaking (Parr-shaker) to form a mixture at room temperature under a hydrogen pressure of 50 psi, which took 2 days. The reaction mixture filtered through Celite was concentrated in vacuo. The residue was purified by EtOAc EtOAc EtOAc (EtOAc)

方法D ii{4-甲i-3-『甲吡咯#「2,3-dl嘧啶-4-某V胺某1-喩 20 咬· 1 -基丨·乙嗣添加乙醯氣(0.018克，0.228毫莫耳）至得自方法C之產物(0·03克’ 0.114毫莫耳)在5毫升10 :丨之二氣甲烷/σ比啶混合物中的攪拌溶液内並於室溫下攪拌所形成混合物，費時 18小時。然後使該反應混合物分溶在一氯甲烷與飽和碳酸 82 200823216 氫鈉(NaHC03)之間。再以飽和NaHC03清洗有機層，在硫酸鈉上乾燥並真空濃縮至乾燥。藉製備性薄層層析法 (PTLC)(二氧化矽；4%曱醇在二氯甲烷中之溶液）而純化殘留物以得到0.005毫克（15%)如無色油之標題化合物。 5 LRMS : 288·1(Μ+1)。Κ：50=0·1475μΜ。實例2至26之標題化合物係藉似實例丨所述之方法而製成。實例2 胺基-乙石舞醯棊)-4甲基基1-甲某各# f2,3-dl 口密喷-4-摹脸 0 [1-(2_胺基-乙石黃醯基)4_甲基》^辰唆基]-甲胺。LRMS : 353。Ι(：50=〇·1〇3μΜ。實例1 (j-乙磺醯卷-4-甲基-哌啶-3-基}^曱基-(7Η·咄咯并『2j-dl嘧 p定-4-基V脸 5 乙磺醯基-4·甲基·哌啶-3-基)-甲胺。LRMS : 338。 Ι〇5〇=0·1365μΜ 〇實例4 U-(丁烧-1-石黃醮基M-甲基-呢^_3_基1_甲基各并『2,3-(11-4-某)-胺 0 [1_(丁烷小磺醯基)-4_甲基·哌啶_3·基]-甲胺。LRMS : 366。 Ι〇5〇=0.3725μΜ。實例1 生-甲基-3_『艺基-(7正呢π备并丨2^11嘧啶-4-篡\脸篡1-喩难二 1-羧酸異丁酯 83 200823216 4-甲基-3_甲胺基-哌啶-1-羧酸異丁酯。LRMS : 346。 Ι(：50=0·5595μΜ。實例6 Ν_(2·{4_甲基_3_『甲基-(7Η-吡咯#「2,3-dl嘧嘧-4-基胺某1-5 p辰咬-1 -石黃酿基丨-乙基)-丙酿基 (2_{4_甲基-3-[甲基-(7H-吡咯并[2,3_d]嘧啶-4-基）-胺基]-^^-1-磺醯基}-乙基)-胺基甲酸甲酉旨 N· [2-(4-甲基-3 -甲胺基_σ底咬-1·石黃酿基)-乙基]-丙驢胺。 LRMS : 409。Ι(：50=0·1915μΜ。 10 實例7 (2_{4_曱基-3-「甲基-(711-咐^各并「2,3-(11^密。定-4-基胺基底啶-1-磺醯基μ乙基)_胺基曱酸曱酯 [2-(4-甲基-3 -甲胺基底咬_1_石黃醢基)_乙基]-胺基甲酸甲酯。LRMS : 4U。Ι(：50=0·0415μΜ。 15 實例8 Ν-(2-{4-曱基-3-『曱基-(7Η-ρ比洛并r2,3-d~|痛唯-4-基）-胺基Ια辰唆-l-確酿基丨-乙基異丁酿胺 Ν-[2-(4-甲基-3-甲胺基-旅啶-1-磺醯基乙基]_異丁醯胺。LRMS : 423。Κ：5〇=〇·〇485μΜ。 20 實例9 (1-甲石黃醯基-ρ辰口定-3-基)·甲某 (1-甲磺醯基-哌啶-3-基）-甲胺。LRMS : 310。 Κ：50=0·346333333μΜ。實例10 84 200823216 Π _ Λ碏醯某-呱啶-3 -基）-甲_蓋_(7H-吡咯并「2,3-dl嘧啶-4-基)胺 (1-乙磺醯基-哌啶-3-基）·甲胺。LRMS : 324。 Κ：50=0·6255μΜ。 5 實例11 甲篡-Π-(丙烷-1-磺醯基哌啶_3_基1-(71!-吡咯#f2.3-dl嘧啶-4-基)-胺 (1_丙磺醯基_哌啶各基）_甲胺。LRMS : 352。 Ι(：50=0·4125μΜ 〇 10 實例12 Π〆丁烷-1-碏醯基V喩啶-3-基1-甲基-(7Η-吡咯#「2.3_dl嘧口定 (1- 丁石黃酿基·旅°定-3-基）-甲胺。LRMS : 352。 Κ：50=0·4125μΜ。 15 實例13 2,2-二甲基_Ν-(2-{4-甲基-3-「曱基-(7Η-吡咯 #「2.3_dl嘧嘧 -4-基)-胺基l-p|咬-1-石蓊酿基丨-乙基丙酿胺 2,2_二甲基-N-[2-(4-甲基-3-甲胺基-哌啶-1-磺醯基)_乙基]-丙醯胺。LRMS : 437。Κ：5〇=0·788μΜ。 20 實例14 3_{4·甲基-3-「甲某·Γ7Η-吡咯#「2·3-(ί1嘧啶-4-某）脍其1-嘬啶 -1-基丨-3-側氣某 3-(4_甲基-3-甲胺基-哌啶小基）_3_側氧基_丙腈。 LRMS ·· 313。Ι(：5〇=〇·〇〇34μΜ。 85 200823216 實例15 基-3-「甲基-(7H-吡咯并|"2,3-dl嘧啶_4_基)_胺某l-岭啶-1-基_丨-3-側氣基-丙基胺基甲酸第丁醋 [3-(4-甲基-3_甲胺基-哌啶-1-基)_3-側氧基-丙基]-胺基 5 甲酸第三，丁酯。LRMS : 417。IC50=〇.5479pM。實例16 甲基甲基小（丙烧_1_石黃醯基痕嘧-V幕啦# 「2,3-dl嘧嗦_4_基)·胺甲基_[4_甲基·1_(丙烧-1-石黃醯基）·旅咬_3_基]-胺。 10 LRMS : 352。Κ：5〇=0·0595μΜ。實例17 1ιΜΑι1_{4-甲基-3-「甲基-(7Η-吡咯并r2,3-dl嘧咭-4-基)-胺基Vp底喷-1 -某丨-丙-1 -嗣 3 -胺基小(4_甲基_3_甲胺基辰唆-1·基）_丙-1-酮。 15 LRMS : 317。Κ：50=1·588μΜ。實例18 2-甲乳幕-1-{4-曱基-3-「甲基-(7Η_口比ρ各并「2.3-dl。密唆-4-基) 胺基1-喻咬-1-基丨-乙嗣 2-甲氧基-1-(4-甲基-3-甲胺基定_1_基）_乙酮。 20 LRMS : 318。Κ：50=0·443333333μΜ。實例19 2·二甲脸篡-Μ4-甲基-3-「甲基-Γ7Η-咄咯并『13-dl嘧啶-4-基)-胺某基丨-乙嗣 2-二甲胺基-1-(4-甲基-3-甲胺基-旅。定_1_基）-乙酮。 86 200823216 LRMS : 331。Κ：50=2·5465μΜ。實例20 (3-{4-甲基-(7Η-ρ比略并『2,3-d~| 喊淀基}-3-侧氣基-丙基V胺基曱酸第三-丁酯 [3-(4-甲基-3-曱胺基·σ底咬-1-基)-3-侧氧基_丙基]-胺基甲酸第三-丁酯。LRMS : 417。Κ：5〇=5.479μΜ。實例21 3,3,3_三氟-1-{4_曱基-3-Γ甲基-(7Η-口比味并『2,3-dl痛咬-4-Method D ii {4-甲i-3-"pyrrolidone#"2,3-dl-pyrimidine-4-V-amine 1-喩20 bite · 1 -ylindole·acetamidine added acetamidine (0.018 g, 0.228 mmol) to the product from Method C (0·03 g '0.114 mmol) in a stirred solution of 5 mL of a 10: hydrazine methane/sigmaidine mixture and stirred at room temperature The mixture was allowed to stand for 18 hours. The reaction mixture was partitioned between EtOAc (EtOAc m.) The residue was purified by preparative thin-layer chromatography ( EtOAc (EtOAc): EtOAc (EtOAc) 288·1(Μ+1).Κ:50=0·1475μΜ. The title compounds of Examples 2 to 26 were prepared by the method described in Example . Example 2 Amino-Ethyl-Dipper-4 Methyl group 1-A each # f2,3-dl mouth spray 摹摹 face 0 [1-(2_amino-ethidinyl) 4_methyl"^ 唆唆]]-methylamine. LRMS: 353. Ι (:50=〇·1〇3μΜ. Example 1 (j-B醯卷-4-Methyl-piperidin-3-yl}^曱--(7Η·咄咯和『2j-dl-pyrimidine-4-yl V face 5 ethylsulfonyl-4-methyl·pipe Acridine-3-yl)-methylamine. LRMS: 338. Ι〇5〇=0·1365μΜ 〇Example 4 U-(丁烧-1-石黄醮基M-Methyl-呢^_3_基1_甲基"2,3-(11-4-)-amine 0 [1_(butane sulfonyl)-4-methyl-piperidinyl-3-yl]-methylamine. LRMS: 366. Ι 〇5〇=0.3725μΜ. Example 1 Bio-methyl-3_"Yiji-(7正?π备丨2^11-pyrimidine-4-篡\篡篡1-喩难二1-carboxylic acid isobutyl ester 83 200823216 4-methyl-3-methylamino-piperidine-1-carboxylic acid isobutyl ester. LRMS: 346. Ι (: 50 = 0.555 μμΜ. Example 6 Ν _ (2·{4_methyl_3_ 『Methyl-(7Η-pyrrole#"2,3-dl-pyrimidin-4-ylamine 1-5 pchen bite-1 - scutellaria-ethyl)-propyl aryl (2_{4_ Methyl-3-[methyl-(7H-pyrrolo[2,3_d]pyrimidin-4-yl)-amino]-^^-1-sulfonyl}-ethyl)-carbamic acid formazan N·[2-(4-Methyl-3-methylamino] σ 咬 -1 · · · · - - - - L L L L L L L : : : : : : : : : : : : : : : : : : : : : : :. 10 Example 7 (2_{4_曱基-3-"Methyl-(711-咐^ each and "2,3-(11^密密。). -4--4-ylamine phenyl pyridine-1-sulfonyl μethyl)-amino decanoate [2-(4-methyl-3-methylamine substrate _1_石黄醢基)_ethyl] - methyl carbamate. LRMS: 4U. Ι(:50=0·0415μΜ. 15 Example 8 Ν-(2-{4-曱基-3-『曱基-(7Η-ρ比洛和r2,3-d~|痛唯-4-基) -Amino Ια辰唆-l- Indeed 丨-丨-ethyl isobutyl amide Ν-[2-(4-methyl-3-methylamino-tripidine-1-sulfonylethyl)- Butylamine. LRMS: 423. Κ:5〇=〇·〇485μΜ. 20 Example 9 (1-methylglycosyl-ρ 口口定-3-yl)·甲(1-methylsulfonyl-piperidine- 3-yl)-methylamine. LRMS: 310. Κ:50=0·346333333μΜ. Example 10 84 200823216 Π _ Λ碏醯呱 - acridine-3 -yl)--a _ _ _ (7H-pyrrole "2 , 3-dl pyrimidin-4-yl)amine (1-ethylsulfonyl-piperidin-3-yl)-methylamine. LRMS: 324. Κ: 50 = 0.6255 μΜ. 5 Example 11 formazan-Π- (propane-1-sulfonylpiperidine _3_yl 1-(71!-pyrrole#f2.3-dl-pyrimidin-4-yl)-amine (1_propylsulfonyl-piperidine)-A Amine. LRMS: 352. Ι(:50=0·4125μΜ 〇10 Example 12 Π〆 Butane-1-fluorenyl V 喩 -3--3-yl 1-methyl-(7Η-pyrrole #“2.3_dl Ding (1-butyl sylvestre sylvestre) - methylamine. LRMS: 352. Κ: 50 = 0·4125 μΜ. 15 Example 13 2,2-dimethyl-Ν-(2- {4-methyl-3-"indolyl-(7Η-pyridyl) #"2.3_dl"Aminopyrimidin-4-yl)-Amino-based lp|Bite-1-stone 丨-based 乙基-ethyl propylamine 2,2-dimethyl-N-[2-(4-methyl- 3-Methylamino-piperidine-1-sulfonyl)-ethyl]-propanamide. LRMS: 437. Κ: 5 〇 = 788 Μ. 20 Example 14 3_{4·methyl-3-" A, Γ7Η-pyrrole #"2·3-(ί1-pyrimidin-4-), its 1-acridin-1-ylindole-3-side gas, a 3-(4-methyl-3-methylamino group - piperidine small group)_3_sideoxy-propanenitrile. LRMS ·· 313.Ι(:5〇=〇·〇〇34μΜ. 85 200823216 Example 15 Base-3-"Methyl-(7H-pyrrole| "2,3-dl-pyrimidine_4_yl)-amine a l-lingridin-1-yl-indole-3-side gas-propyl propyl carbamate butyl vinegar [3-(4-methyl- 3_Methylamino-piperidin-1-yl)_3-tertiaryoxy-propyl]-amino-5carboxylic acid third, butyl ester. LRMS: 417. IC50=〇.5479pM. Example 16 Methylmethyl (丙烧_1_石黄醯基痕菌-V幕啦# "2,3-dl-pyrimidine_4_yl)·Aminomethyl_[4_methyl·1_(propyl sinter-1- fluorenyl) Travel bite _3_ base]-amine. 10 LRMS: 352. Κ: 5〇=0·0595μΜ. Example 17 1ιΜΑι1_{4-methyl-3-"methyl-(7Η-pyrrolo-r2,3-dl-pyrimidin-4-yl)-amine-based Vp-bottom-1 - 丨-propyl-1 -嗣3 -Amino small (4-methyl-3-methylamino-indenyl-1)-propan-1-one. 15 LRMS : 317. Κ: 50 = 1.588 μΜ. Example 18 2-A-breast curtain - 1-{4-mercapto-3-"methyl-(7Η_mouth ratio ρ and "2.3-dl. 唆-4-yl" Amine 1 - 咬-1-基丨-乙嗣2- Methoxy-1-(4-methyl-3-methylaminodin-1-yl)-ethanone. 20 LRMS : 318. Κ: 50 = 0.443333333 μΜ. Example 19 2·Dimethyl face-篡4 -Methyl-3-"methyl-Γ7Η-咄并"13-dl-pyrimidin-4-yl)-amine 丨-丨-嗣2-dimethylamino-1-(4-methyl-3- Methylamino-Brigade. Iodine-based ethyl ketone. 86 200823216 LRMS : 331. Κ:50=2·5465μΜ. Example 20 (3-{4-methyl-(7Η-ρ ratio slightly 『2 ,3-d~| 叫方基}-3-lateral gas-propyl propylamine decanoic acid tert-butyl ester [3-(4-methyl-3-nonylamino) σ bottom bite-1- 3-)oxy-propyl]-carbamic acid tert-butyl ester. LRMS: 417. Κ: 5 〇 = 5.479 μΜ. Example 21 3,3,3_trifluoro-1-{4_ Mercapto-3-indole methyl-(7Η-mouth odor and "2,3-dl bite -4-

基胺基l-g底咬-1-基丨•丙-1-綱 3,3,3-二鼠-1-(4-甲基-3-甲胺基-°辰。定_1_基）_丙-1_酮。 LRMS : 356.3。Ι(：50=〇·〇19333333μΜ。實例22 Ν·(2:丄4;甲基-(7Η·吡咯并「2,3-dl哨咜丄早）:美1-旅咬_1-基}-2-趾氧基-己篡n醯脍 N-[2-(4_甲基-3_ f胺基-哌啶小基)_2_側氧基·乙基乙醯胺。LRMS : 345。Ι(：5〇=7·13033333μΜ。實例23 3H基甲基_(7Η_吡咯莽「2 3_dl嘧嘧冰基)二胺基1-°底唆-1-基丨·丙-1 -西同 3-乙氧基_1-(4-甲基-3-甲胺基-哌啶-i_基)_丙4_酮。 LRMS : 346。Ι(：50=〇·7686μΜ。實例24 4_甲基-3·『甲基^iLzfc咯并dell嘧啶-4-某V脍篡1-哌1 -1-羧酸甲醯胺 87 200823216 4-甲基-3-甲胺基-哌啶小羧酸甲醯胺。LRMS : 303。 Ι(：50=0·2355μΜ。實例25 4-甲基-3-「曱基-(7Η-口比洛开「2,3-dlρ密啤-4-基胺基1-口密咬 5 -1-羧酸二乙醯胺 4-甲基-3·甲胺基-哌啶-1-羧酸二乙醯胺。LRMS : 345。 Ι(：50=0·205μΜ 〇實例26 甲基-「4-甲基-1-(2-甲胺基-乙磺醯基)^底啶_3_基ΐ-(7Η-吡咯 10 #r2.3-dl 嘧啶-4-某 V 胺甲基-[4-甲基-1-(2-甲胺基-乙石黃醯基)-旅。定-3-基]-胺。 LRMS : 367。Ι(：50=1·124μΜ。實例27至31係闡明式III化合物之拆分：Amino group lg bottom bite-1-ylindole • propyl-1-class 3,3,3-di-rho-1-(4-methyl-3-methylamino-°chen. 定_1_基)_ C-1 - ketone. LRMS: 356.3. Ι(:50=〇·〇19333333μΜ. Example 22 Ν·(2:丄4; methyl-(7Η·pyrrole “2,3-dl whistle early”: US 1-Brigade bite_1-based} 2-tolyloxy-hexanyl n醯脍N-[2-(4-methyl-3_f-amino-piperidineyl)-2-oxoxyethylethylamine. LRMS: 345. (:5〇=7·13033333μΜ. Example 23 3H-methylmethyl-(7Η_pyrrole “2 3_dl-pyrimidinyl)diamine 1-° bottom 唆-1-yl丨·propyl-1 -xitong 3 -Ethoxyl-1-(4-methyl-3-methylamino-piperidine-i-yl)-propan-4-one. LRMS: 346. Ι (:50 = 〇 ·7686μΜ. Example 24 4_甲-3-3·“Methyl^iLzfc-and dell-pyrimidine-4-V脍篡1-piperone-1-1-carboxylic acid formamide 87 200823216 4-methyl-3-methylamino-piperidine carboxylic acid Formamide. LRMS: 303. Ι(:50=0·2355μΜ. Example 25 4-methyl-3-"indolyl-(7Η-口比洛开"2,3-dlρ密啤酒-4-ylamine Base 1-mouth bite 5 -1-carboxylic acid diethylamine 4-methyl-3.methylamino-piperidine-1-carboxylic acid diethylamine. LRMS: 345. Ι (: 50 = 0 205μΜ 〇Example 26 Methyl-"4-methyl-1-(2-methylamino-ethanesulfonyl)^-endidine_3_ylindole-(7Η-pyrrole 10 #r2.3-dl pyrimidine-4 - a V amine methyl-[4-methyl-1-(2-methylamine) - B stone yellow acyl) - Tour given 3-yl] - amine LRMS:.. 367.Ι (: 50 = 1 · 124μΜ Examples 27 to 31 illustrate the resolution of a compound of formula-based III:.

III 15 實例27(安定性成) L1-苄基甲基p辰咬-3-某甲胺雙鹽酸鹽於3°C下添加32%HC1在水中之溶液(25升）至23·4公斤 (1-苄基-4-甲基哌啶-3-基)-甲胺在1〇升甲苯及12〇升乙醇中之溶液内，使反應溫度維持在l〇°C以下。在部份真空下蒸 20餾100升溶劑，並於30°C下添加215升乙酸乙酯。在部份真 88 200823216 空下蒸餾210升溶劑，並再添加215升乙酸乙酯，然後在部份真空下用蒸餾210升溶劑。於35°C下添加111升丙酮，使該懸浮液冷却至〇°C，然後濾出該產物，（1-苄基-4-甲基哌咬-3-基)-甲胺雙鹽酸鹽，並經55升丙酮清洗。在乙醇(於回 5 流下丨〇體積當量）内再漿化該濕餅共3次以使順式：反式之非對映異構物比率自91 : 9提高至大於97 : 3。總回收量為 19·4公斤，62%產率。lHNMR(CD3OD，400MHz):57.55(m， 5Ή)，4.88(s，3H)，4.52(d，J=12.8Hz，1H)，4.45(d，J=12.8 Hz， 1H)，3.76(m，1H)，3.67(m，1H)，3.40-3.00(m，3H)，2.78(3, 1〇 3H)，2.55(m，1H)，2.14(m，1H)，1.90(m，1H)，1.16(d，J=7.2Hz， 3H) 〇實例28(拆分）曱基喩啶-3 -某甲胺1二-對-甲苯甲醯基-L-酒 15 添加33升之2N氫氧化鈉至9.5公斤（1-节基-4-甲基哌啶基)_甲胺雙鹽酸鹽在16升水中之溶液内。自該等混合物 /尤;殿固體’使該漿體經43升異丙酵及11升甲醇稀釋以再溶解"亥專固體。添加二-對-甲苯甲醯-L-酒石酸(6.3公斤）並沈 J又固體。將該漿體加熱至回流體以再溶解該等固體，然後 &又、却至72C。添加雙[(1-节基-4-甲基旅唆-3-基)-甲胺] —-對-甲苯甲醯基_L_酒石酸鹽晶種（18〇克），並使該混濁狀 ’谷液緩慢冷却至15°C。過濾該等固體並經異丙醇清洗以得到5.9公斤（44%產率）雙[(1-苄基-4-甲基哌啶-3-基)-甲胺]二-對-甲笨甲醯基-L-酒石酸鹽。1HNMR(CD3OD，400MHz):5 89 200823216 8.〇4(d，J=8.4Hz，2H)，7.30(m，7H)，5.86(s，1H)，4.91(S， 3H) ’ 3.64(d，J=12.8Hz，1H)，3.41(cU=12.8Hz，1H)，3.〇9(s， 1H) ’ 2 9〇(m，2H)，2.40(s，3H)，2.22(m，2H)，1.92(m，1H)， 1.57(m，2H)，l.〇3(d，2Hz，3h)。 5 fAlK本賽松拆分) 添加7.57克(+)本賽松(31·3毫莫耳）至6 83克(313毫莫耳)在250毫升ΙΡΑ及1〇毫升水中之溶液内，並將該混合物加熱至回流以獲得清澈溶液。於約65°C之溫度下添加比為 90%之晶種。在一小時内開始結晶反應並使該反應物達室 10溫’費時一夜。進行離析以得到具有比為99%之6.85克 (47%)。濃縮濾液，添加τΒΜΕ、水及K2C〇3並分離各層。在NaJO4上乾燥有機層並蒸發溶劑。使所形成油（3 99^ 溶解在200毫升ΙΡΑ及10毫升水中並添加4.4克㈠苯賽松。將該混合物加熱至回流並使其冷却至室溫，費時一夜。其可 15 得到具有比為99.9+%之6克(41%)鹽。在該游離態胺上進行分析。藉以ΤΒΜΕ、水及ICO3處理該鹽而獲得該游離態胺。下文以圖解方式闡明實例27至29之方法（其中Bn之定義為节基(-CH2-C6H5))= 200823216 Η3α、 ch3hn'、、 HCI、水、乙醇 H3C%, CH3HN'^III 15 Example 27 (stability formation) L1-benzylmethyl p-butyl-3-methylamine dihydrochloride salt solution of 32% HCl in water (25 liters) to 23.4 kg at 3 ° C (1-Benzyl-4-methylpiperidin-3-yl)-methylamine In a solution of 1 liter of toluene and 12 liters of ethanol, the reaction temperature was maintained below 10 °C. 100 liters of the solvent was distilled under a partial vacuum, and 215 liters of ethyl acetate was added at 30 °C. 210 liters of solvent was distilled under a portion of the true 88 200823216, and an additional 215 liters of ethyl acetate was added, followed by distillation of 210 liters of the solvent under partial vacuum. 111 L of acetone was added at 35 ° C, the suspension was cooled to 〇 ° C, and then the product was filtered off, (1-benzyl-4-methylpiperidin-3-yl)-methylamine dihydrochloride And washed with 55 liters of acetone. The wet cake was repulped three times in ethanol (equivalent volume equivalent under reflux) to increase the cis:trans diastereomer ratio from 91:9 to greater than 97:3. The total recovery was 19.4 kg, 62% yield. lHNMR (CD3OD, 400MHz): 57.55 (m, 5 Ή), 4.88 (s, 3H), 4.52 (d, J = 12.8 Hz, 1H), 4.45 (d, J = 12.8 Hz, 1H), 3.76 (m, 1H) ), 3.67 (m, 1H), 3.40-3.00 (m, 3H), 2.78 (3, 1 〇 3H), 2.55 (m, 1H), 2.14 (m, 1H), 1.90 (m, 1H), 1.16 ( d, J = 7.2 Hz, 3H) 〇 Example 28 (resolution) 曱-based acridine-3 - a methylamine 1 di-p-toluamyl-L-wine 15 Add 33 liters of 2N sodium hydroxide to 9.5 A solution of kilograms (1-pyrimidin-4-methylpiperidinyl)-methylamine dihydrochloride in 16 liters of water. The slurry was diluted with 43 liters of isopropanil and 11 liters of methanol to re-dissolve the solids from the mixture. Add di-p-toluamyl-L-tartaric acid (6.3 kg) and sink J and solid. The slurry was heated to a return fluid to redissolve the solids, then & again, to 72C. Adding bis[(1-pyryl-4-methyl benz-3-yl)-methylamine]--p-tolylmethyl hydrazine_L_tartrate seed crystal (18 gram) and making the turbidity 'The solution was slowly cooled to 15 °C. The solid was filtered and washed with isopropanol to give 5.9 kg (44% yield) bis[(1-benzyl-4-methylpiperidin-3-yl)-methylamine]di-p--- Mercapto-L-tartrate. 1H NMR (CD3OD, 400MHz): 5 89 200823216 8. 〇 4 (d, J = 8.4 Hz, 2H), 7.30 (m, 7H), 5.86 (s, 1H), 4.91 (S, 3H) ' 3.64 (d, J=12.8Hz, 1H), 3.41 (cU=12.8Hz, 1H), 3.〇9(s, 1H) ' 2 9〇(m, 2H), 2.40(s, 3H), 2.22(m, 2H) , 1.92 (m, 1H), 1.57 (m, 2H), l. 〇 3 (d, 2 Hz, 3h). 5 fAlK Bensaisong split) Add 7.57 grams (+) of this Sai Songsong (31.3 millimoles) to 6 83 grams (313 millimoles) in a solution of 250 ml of water and 1 ml of water, and The mixture was heated to reflux to obtain a clear solution. A seed crystal having a ratio of 90% is added at a temperature of about 65 °C. The crystallization reaction started within one hour and the reaction was allowed to reach room temperature for a night. Segregation was carried out to obtain 6.85 g (47%) having a ratio of 99%. The filtrate was concentrated, τ ΒΜΕ, water and K 2 C 〇 3 were added and the layers were separated. The organic layer was dried over NaJO4 and solvent was evaporated. The resulting oil (3 99^ was dissolved in 200 ml of hydrazine and 10 ml of water and 4.4 g of (1) benzethon was added. The mixture was heated to reflux and allowed to cool to room temperature, which took a night. 99.9+% of 6 grams (41%) of salt. Analysis was carried out on the free amine. The free amine was obtained by treating the salt with hydrazine, water and ICO3. The methods of Examples 27 to 29 are exemplified below (wherein Bn Defined as the base (-CH2-C6H5)) = 200823216 Η3α, ch3hn', HCI, water, ethanol H3C%, CH3HN'^

外消旋外消旋Racemic racemization

1) NaOH1) NaOH

2Ηα IPO, MeOH 對：甲笨甲鐵基七酒石酸鹽 η3ο〇2Ηα IPO, MeOH Pair: 甲甲甲铁基七酒石盐 η3ο〇

CH3HN ch3hnv' .N8n 外消旋 COOH hLo%^h3' f CH3HM〆 2HCI NBn 外消旋 1>游離態鹼 2) Hq^C) crp、oCH3HN ch3hnv' .N8n racemic COOH hLo%^h3' f CH3HM〆 2HCI NBn racemic 1> free base 2) Hq^C) crp, o

COOH 99%eeCOOH 99%ee

實例30 試樣處理：經由0·2微米尼龍66渡片而過濾式in化合物。 5 塞序：（96%乙醇及4%7lc作辱笮制) 使0.8711克該濾液之式ΠΙ化合物溶解在5·〇毫升之96: 4 比率的乙醇/水中。添加1.544克二-對-甲苯甲醯基丄_酒石酸並攪拌該混合物以獲得清澈溶液。於室溫下靜置該溶液，費時約4小時。在華特門(Whatman)第2號濾紙上過濾所形成 1〇漿體並經4·0毫升之％ : 4比率的乙醇/水清洗。風乾該等固體以得到0.488克非對映異構物鹽。使0.488克該非對映異構物鹽懸浮在5〇毫升水中，然後添加二氣甲烷。先後使用飽和碳酸氫鈉及1〇N氫氧化鈉將泫混合物之pH調整至約9。一旦該pH調整完成時，分離各 91 200823216 層並經由華特門第2號濾紙而過濾該二氯甲烷層。然後藉減壓蒸發而移除溶劑以得到淺橘色油。未測定重量。藉氣相層析法而評估該油。分析測定值：藉歸一化面積％而獲得97·3%所欲鏡像異 5 構物。 f例31 鱼座丄（100%乙醇作為滚变q 使0.8714克（1-节基-心甲基_旅咬各基)甲胺溶解在5.0 *升200安全乙醇中。添加1544克二_對_甲苯甲醯基_l_酒 10石酸並攪拌該混合物以獲得清澈溶液。於室溫下靜置該溶液’費時約4小時。在華特門第2號濾紙上過濾所形成漿體並經4.0¾升之96 : 4比率的乙醇/水清洗。風乾該等固體以得到0.628克非對映異構物鹽。使0.628克該非對映異構物鹽懸浮在5〇毫升水中，然後 15添加5〇耄升二氣甲烷。先後使用飽和碳酸氫鈉及0.1N氫氧化鈉將該混合物之pH調整至約9。一旦該？11調整完成，分離各層並經由華特門第2號濾紙而過濾該二氣甲烷層。藉減壓蒸發而移除溶劑以得到淺黃色油。未測定重量。進行該油之療發以提供分析測定值：藉歸一化面積％而獲得9〇.5% 2〇所欲鏡像異構物。實例32 -(7Η-吡咯莽「2,3_dl 嘧啶二4-某 V 篮基氧篡―而崎Example 30 Sample Treatment: The compound in the formula was filtered via a 0.2 micron nylon 66 pellet. 5 Plug order: (96% ethanol and 4% 7lc for abusive system) 0.8711 g of the hydrazine compound of the filtrate was dissolved in a 96:4 ratio of ethanol/water in a volume of 5·〇 ml. 1.544 g of di-p-tolylmethylhydrazine-tartaric acid was added and the mixture was stirred to obtain a clear solution. The solution was allowed to stand at room temperature and took about 4 hours. The formed slurry was filtered on Whatman's No. 2 filter paper and washed with 40.0 ml of a ratio of 4: ethanol/water. The solids were air dried to give 0.488 g of diastereomer salt. 0.488 g of this diastereomeric salt was suspended in 5 ml of water and then di-methane was added. The pH of the hydrazine mixture was adjusted to about 9 using saturated sodium bicarbonate and 1 〇N sodium hydroxide. Once the pH adjustment is complete, each layer of 91 200823216 is separated and the methylene chloride layer is filtered through a Walter No. 2 filter paper. The solvent was then removed by evaporation under reduced pressure to give a light orange oil. The weight was not measured. The oil was evaluated by gas chromatography. The measured value was analyzed: 97.3% of the desired image was obtained by normalizing the area %. f Example 31 Fish cockroaches (100% ethanol as knurling q) 0.8714 g (1-pyramyl-heart methyl _ _ each base) methylamine was dissolved in 5.0 * liter of 200 safe ethanol. Add 1544 g two pairs _toluamyl _l_ wine 10 sulphuric acid and stirring the mixture to obtain a clear solution. The solution was allowed to stand at room temperature for about 4 hours. The slurry was filtered on a Waltgate No. 2 filter paper and It was washed with 4.03⁄4 liters of 96:4 ratio of ethanol/water. The solids were air dried to give 0.628 g of diastereomer salt. 0.628 g of this diastereomer salt was suspended in 5 mL of water, then 15 Add 5 liters of di-methane. The pH of the mixture was adjusted to about 9 using saturated sodium bicarbonate and 0.1 N sodium hydroxide. Once the adjustment was completed, the layers were separated and passed through a Walter No. 2 filter paper. The digas methane layer was filtered. The solvent was removed by evaporation under reduced pressure to give a pale-yellow oil. The weight was not determined. The oil treatment was carried out to provide analytical measurements: 9 %.5% by normalized area % 2 镜像 Mirroring isomers. Example 32 - (7Η-pyrrole "2,3_dl pyrimidine 2 - a V basket oxo

方法A 92 200823216 (3R，4R):g:至基二4-甲基·哌啶_3_基)_ 甲篡彳3_di 嘧啶-4-基)-胺在水中組合 IfDavoll，J. Am. Chem. Soc.，泣，131 (1960)，其全文在此併入本案以為參考資料之方法而製成的 5 4-氣吡咯并[2,3-d]嘧啶(5.37克，319毫莫耳）、得自實例28 之產物(6克，27.5毫莫耳）、及碳酸鉀（11.4克，82.5毫莫耳）。於回流下加熱該漿體，費時90小時。使該混合物冷却至9〇 °C並添加甲苯(60毫升）。經由助濾劑而過濾該雙相混合物並分離各層。以甲苯萃取水性層。使該等組合甲苯層經川 10 Na0H清洗，經活性炭處理，並經由助濾劑而過濾。真空蒸發該曱苯並自1 : 1之乙酸異丙酯及己烷混合物晶化殘留物以得到5克近純白色固體；54%產率。LRMS : 336.1(M+1)。Method A 92 200823216 (3R, 4R): g: to bis-dimethyl-piperidinyl-3-yl)-carbazide 3_dipyrimidin-4-yl)-amine in water combination IfDavoll, J. Am. Chem Soc., Weep, 131 (1960), the entire disclosure of which is hereby incorporated by reference in its entirety by reference in its entirety by reference in its entirety in The product from Example 28 (6 g, 27.5 mmol), and potassium carbonate (11.4 g, 82.5 mmol). The slurry was heated under reflux for 90 hours. The mixture was cooled to 9 ° C and toluene (60 mL) was added. The biphasic mixture was filtered through a filter aid and the layers were separated. The aqueous layer was extracted with toluene. The combined toluene layers were washed with 10 Na0H, treated with activated carbon, and filtered through a filter aid. The toluene was evaporated in vacuo and the residue was crystallized from 1:1 mixture of isopropyl acetate and hexane to give 5 g of a crude white solid; 54% yield. LRMS: 336.1 (M + 1).

方法B 4R)-4_曱篡·喩嘧-3-基W7H-咄咯# ddl嘧啶 15 -4-基胺添加1.5毫升2N鹽酸至得自方法A之產物（0.7克，2.19 毫莫耳）溶解在15毫升乙醇中之溶液内並藉氮滌洗而使反應混合物脫氣。然後添加0.5克之20%碳載氫氧化鈀（50% 水）(Aldrich)至該反應混合物内並於室溫在5〇psi氫壓下搖 20 動(Parr_搖動器）所形成混合物，費時2天。在真空中將經賽力特;ε夕藻土過濾之反應混合物濃縮至乾燥並藉驟層分析法 (二氧化矽；5%甲醇在二氯曱烷中之溶液）而純化殘留物以得到0.48克(90%)標題化合物。LRMS : 246·1(Μ+1)。Method B 4R)-4_曱篡·喩μi-3-yl W7H-咄α# ddl pyrimidine 15 -4-ylamine Add 1.5 ml of 2N hydrochloric acid to the product from Method A (0.7 g, 2.19 mmol) The reaction mixture was degassed by dissolving in a solution of 15 ml of ethanol and washing with nitrogen. Then add 0.5 g of 20% carbon palladium hydroxide (50% water) (Aldrich) to the reaction mixture and shake the mixture (Parr_shaker) at room temperature under 5 psi hydrogen pressure for 2 hours. day. The reaction mixture filtered through Celite; Evaporation was concentrated to dryness in vacuo and the residue was purified by EtOAc (EtOAc m. Gram (90%) of the title compound. LRMS: 246·1 (Μ+1).

方法C 93 200823216 3-{(3R，4R)-4—-Jf 基-3-『甲基-(711_吡咯并『2,3-dl嘧咭-H_ 胺某1-哌啶-1_-基13-侧氡基-丙_ 添加0.82克氰基-乙酸2,5-二氧基-σ比略咬_1_基酯至得自方法B之產物（1 · 0克）>谷解在3 0宅升乙醇中之攪拌溶液内 5 並於室溫下授拌所形成混合物，費時2小時。經由賽力特石夕藻土(Celite®)而過濾該反應混合物並真空濃縮。使殘留物再溶解於二氯甲烧中，經飽和水性碳酸氫鈉清洗，在硫酸納上乾燥，過渡並真空7辰縮至乾無以付到1.1克(86%)如黃色發泡體之標題化合物。LRMS : 313(M+1)。Ι(：50=〇·〇〇24μΜ。 10 實例33 甲基-3-「甲某-(7Η-吡咯并「2·3-(ΓΙ 嘧噔 _4早胺基1 - °底定-1 -基丨-乙銅添加乙醇氯(0.018克，0.228毫莫耳）至得自方法B之產物(0.03克，0.114毫莫耳)溶解在5毫升之10 : j二氣甲烷/吡 15啶中之攪拌溶液内並於室溫下攪拌所形成混合物，費時18 小時。然後使該反應混合物分溶在二氣甲烷與飽和碳酸氫鈉(NaHC〇3)之間。再以飽和NaHC〇3清洗有機層，在硫酸鈉上乾燥並真空濃縮至乾燥。藉製備性薄層層析法 (PTLC)(二氧化矽；4%甲醇在二氯甲烷中之溶液）而純化殘 20留物以得到0·005克⑴％)如無色油之標題化合物。 LRMS(M+1) ·· 288.2。Ι(：50=0·523μΜ。藉類似實例33中所述之方法而製備實例34至35、及47 之標題化合物。藉類似實例33中所述之方法而製備實例36 至46及48至57之標題化合物。 94 200823216 實例34 (3R，4RM1_(2-脸其-λ旙醯某V4·甲基-喩啶-3-基1-甲基 -(7H-p 比17定开[*2·3-(11^ 咬-4-某胺 LRMS(M+1) : 353.4。IC50=〇.〇435pM 〇 5 實例35 (3R，4R)_(1-乙石蕾酿基-4-甲基-°底°定-3-基甲基-(7H-ff|：bg定开『2,3-d~l·密咱>4_摹)胗 LRMS(M+1) : 338.3。Κ：50=0·〇143μΜ 〇實例36 10 (3R,4RM1-(丁烷-1-碏醯某V4-曱基·呱啶-3-基1-甲基-Γ7Η· 吡咯并Odl嘧噔-4-某胺實例37 (3R，4R)-4·甲某-3-「甲篡-ΠΗ-吡啶并「2.3-dl嘧啶-4_基）-胺基1-哌啶-1_羧酸異丁酯 15 實例38 沁(2-((311,41〇-4-甲基-3_「甲基-(711-吡咯其「2.3-(11嘧啶-4-基)-胺基定-1-石蕾酿基丨-乙基)-丙酿胺實例39 (2-((3R.4R)-4-甲基-3-「甲基-(7H-吡咯#「2.3-dl嘧啶-4-基）-20 胺基1-哌啶-1-碏醯某丨-乙基)-胺基甲酸甲酯實例40 N-(2_i(3R,4R)-4·甲某-「甲基-(7H-吡啶舁 r2.3-dl嘧啶-4-基）-胺基1-呱啶-1-磺醯基丨-乙基)-異丁醯基實例41 95 200823216 (3R,4R)-n-甲石蓊醯某底啶基）_甲基-(7H_^啶并丨2.3-dl嘧啶 -4-基)-胺實例42 ((3RT4RV卜乙石蓊醯基底啶-3-基)-甲基-(7H_。比咯并「2,3-dl嘧 5 ρ定-4-基胺實例43 甲某-Π-(丙烷-1-碏醯胺哌啶-3_基1-Γ7Η-吡咯并 f2vVdl嘧啶-4-基)-胺實例44 10 (3R.4RVH彳丁烷-1-磺醯基哌啶-3-基1-甲基-Γ7Η-吡咯并「2.3-dl嘧嘧-4-基胺實例45 2.2-二甲某-N-(T3R,4R)-2-{4-甲基·3_「甲某 _Γ7Η_ 吡咯并「2.3-dl嘧啶-4_基）-胺基1-哌啶_1·磺醯基丨-乙基)-丙醯胺 15 實例46 (3-(GR.4RV4-甲基-3-『甲某-Γ7Η-吡咯并「2.3-dl嘧啶-4-基)-胺基1-哌啶·1-基丨-3-側氧基-丙基)-胺基甲酸第三-丁酯實例47 I基·『(3R，4R)-4-甲基-1-(丙烷-1-磺醯基喩啶-3-某U7H-20 吡咯#『2.3-dl嘧啶-4-基胺 LRMS(M+1) : 352.3。Ι(：5〇=0·0173μΜ。實例48 h胺基-l-U3R,4R)-4-甲某_3·「甲基-(7Η-咄咯并『2…Vdl嘧啶二4-基胺基1-°底唆-1-基丨丙-1-醜 96 200823216 t例49 21 氧基-1 - {(3R，4R)-4- 吡咯并『2·3-dl 嘧 °定-4-基)-胺基1-°底咬-1-美丄>乙酮實例50 5 胺基-1-{(3R，4R)4j基-3_「甲某_门沁咄咯并『9 vdl 。密咬-4-基)-胺基1-°瓜咬-1 二基丨-乙酮實例51 (3_jl!R，4R上全甲基-『3二^(7H_吡咯并「2 3_dl痛嘧_4_篡胺基卜旅咬ϋ}-3-佩息基_丙基)_胺某甲酸第三_丁酯 10 實例52 3,3,3·二狀：基_3 [·甲某_(7Η_吡咯其『2 3_引嘧咬-4-基)-胺基定-^1基卜丙_ι-酮實例53 N-(2-{(3R，4R)-4-甲基二3-『甲某-Γ7Η-咄略 #『2,3-dl 嘧啶-4· 15 某V胺基1-哌啶-1-基丨侧氣某·乙基)-乙醯基實例54 V乙氳基-1-{(3R,4RV4_曱基-3_「甲基-(7H-吡咯并「2,3-dl嘧请-4-基)-胺基l_p辰唆-1-基丨·丙-1-酮實例55 20 nR.4R)-4-曱基-3-「甲基-(7H-吡咯共「2,3-dl嘧啶-4-基）·胺基1_略°定-1-繞酸曱醯吃實例56 97 200823216 (3R，4R)-4-甲基_3-「甲基-Γ7Η-吡咯并『2,3_dl嘧啶-4-基）胺基1-哌啶-1-羧酸二乙醯胺實例57 (3R,4R)-甲基-Γ4-甲基-1-(2-甲胺基-乙磺醯基）-哌啶-3-5 基M7H-吡咯并Odl嘧啶-4-基)-胺本揭示内容從頭至尾已參考其它文件，諸如專利案、專利申請案、期刊、書籍等。實際上所有此等文件之全文在此併入本案以為參考貢料。應瞭解前述說明文僅為例證說明且係用以闡明本發明 10 之一般概念及其較佳實施例。例行實驗方法從頭至尾，鑑於本揭示内容之優勢，熟悉本項技藝者可瞭解只要不違背本揭示内容之精神及範圍可以有明顯的修飾及變異。因此，本揭示内容不受限於上述說明文，而係受限於以下申請專利範圍及彼等之同等物。 15 【圖式簡單說明】 (無）【主要元件符號說明】 (無） 98Method C 93 200823216 3-{(3R,4R)-4—Jf-yl-3-“methyl-(711-pyrrolo- 2,3-dl-pyrimidine-H-amine 1-piperidine-1_-yl 13- side fluorenyl-propanoid - adding 0.82 g of cyano-acetic acid 2,5-dioxy-σ ratio slightly biting _1 _ ester to the product of method B (1.0 g) > The mixture was stirred and stirred at room temperature for 5 hours. The reaction mixture was filtered through Celite® and concentrated in vacuo. Re-dissolved in methylene chloride, washed with saturated aqueous sodium bicarbonate, dried over sodium sulfate, and evaporated to dryness to dryness to dryness to afford to afford to afford the title compound as a yellow foam. LRMS : 313 (M+1).Ι(:50=〇·〇〇24μΜ. 10 Example 33 Methyl-3-"A-(7Η-pyrrolo-"2·3-(ΓΙ 噔噔 44 early amine Base 1 - ° ding -1 - hydrazine - copper plus ethanol chloride (0.018 g, 0.228 mmol) to the product from Method B (0.03 g, 0.114 mmol) dissolved in 5 ml of 10 : j The resulting mixture was stirred in a stirred solution of di-methane/pyrididine and allowed to stand at room temperature for 18 hours. The reaction mixture is then partitioned between di-methane and saturated sodium bicarbonate (NaHC EtOAc). Chromatography (PTLC) (cluster; 4% MeOH in EtOAc) EtOAc (EtOAc) 288.2. Ι (: 50 = 0. 523 μΜ. The title compounds of Examples 34 to 35, and 47 were prepared by a method similar to that described in Example 33. Examples 36 to 46 were prepared by the method described in Example 33. And the title compound of 48 to 57. 94 200823216 Example 34 (3R, 4RM1_(2-face--λ旙醯V4·methyl-acridin-3-yl 1-methyl-(7H-p is 17 fixed) [*2·3-(11^ bite-4-amine LRMS(M+1): 353.4. IC50=〇.〇435pM 〇5 Example 35 (3R,4R)_(1-Ethyl buds-4 -Methyl-[the bottom] -3-ylmethyl-(7H-ff|:bg fixed "2,3-d~l·m咱>4_摹)胗LRMS(M+1) : 338.3 Κ:50=0·〇143μΜ 〇Example 36 10 (3R,4RM1-(butane-1-碏醯V4-indolyl-acridin-3-yl 1-methyl-Γ7Η·pyrrolo-Odl噔-4-A certain amine example 37 (3R,4R)-4·甲某-3-"甲篡-ΠΗ-pyridine and "2.3-dl-pyrimidin-4-yl"-amino-1-piperidine-1_carboxylate Isobutyl butyrate 15 Example 38 沁(2-((311,41〇-4-methyl-3_"methyl-(711-pyrrole"2.3-(11-pyrimidin-4-yl)-aminolated-1 - Shilei Stuffed Ethyl-Ethyl)-Acetylamine Example 39 (2-((3R.4R)-4-Methyl-3-"methyl-(7H-pyrrole#"2.3-dl-pyrimidine-4- Methyl)-amino 1 -piperidin-1-yl-methyl-ethyl)-carbamic acid methyl ester Example 40 N-(2_i(3R,4R)-4·甲-"Methyl-(7H -pyridinium r2.3-dlpyrimidin-4-yl)-amino-1-pyridin-1-sulfonylhydrazine-ethyl)-isobutylhydrazino example 41 95 200823216 (3R,4R)-n-methyl sarcophagus醯醯 ) ) _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _比并「 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 Example) Amine Example 44 10 (3R.4RVH 彳 Butane-1-sulfonylpiperidin-3-yl 1-methyl-Γ7Η-pyrrolo and 2.3-dl-pyrimidin-4-ylamine Example 45 2.2- Dimethyl-N-(T3R,4R)-2-{4-methyl·3_"甲某_Γ7Η_pyrrolo-"2.3-dl-pyrimidin-4-yl)-amino-1-piperidine_1·sulfonate Base oxime-ethyl)-propanamide 15 Example 46 (3-(GR.4RV4-methyl-3-"methyl-Γ7Η-pyrrolo-"2.3-dl-pyrimidin-4-yl)-aminol-piperidin Pyridin-1-ylindole-3-yloxy-propyl)-carbamic acid tert-butyl ester Example 47 I-based "(3R,4R)-4-methyl-1-(propane-1-sulfonate)醯-pyridin-3-one U7H-20 pyrrole #『2.3-dl-pyrimidin-4-ylamine LRMS(M+1) : 352.3.Ι(:5〇=0·0173μΜ. Example 48h-amino-l- U3R,4R)-4-A _3·"Methyl-(7Η-咄并和『2...Vdl-pyrimidinedi-4-ylamino-1-° bottom 唆-1-yl 丨-1--1-96 96 200823216 t Example 49 21 oxy-1 - {(3R,4R)-4-pyrrolo "2·3-dl pyridin-4-yl)-aminol 1-° bottom bite -1- 丄丄 gt; B Ketone Example 50 5 Amino-1-{(3R,4R)4j-based-3_"甲某_门沁咄咯9 vdl. 密-4-yl)-aminol 1-° melon bit-1 bis-indole-ethanone example 51 (3_jl!R, 4R on all-methyl-"3二^(7H_pyrrole "2 3_dl pain 嘧_4_ 篡基卜 ϋ ϋ -3- -3- 佩 -3- -3- -3- -3- _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ A _(7Η_pyrrole 『2 3 _ 嘧咬 -4- -4-yl)-amino-but-l1 kibpropenyl-ι-ketone Example 53 N-(2-{(3R,4R)-4- Methyl di- 3 - "甲甲-Γ7Η-咄略#"2,3-dl pyrimidine-4·15 V-aminol 1-piperidin-1-ylindole side gas ·Ethyl)-ethenyl group 54 V acetyl ketone-1-{(3R,4RV4_mercapto-3_"methyl-(7H-pyrrolo- 2,3-dl-pyrazin-4-yl)-amine-l-p-Chen-1-yl丨·propan-1-one example 55 20 nR.4R)-4-mercapto-3- "methyl-(7H-pyrrole total "2,3-dl pyrimidin-4-yl)-amine 1_ slightly ° Example of -1- 绕曱醯 56 56 56 97 200823216 (3R,4R)-4-methyl_3-"methyl-Γ7Η-pyrrolo-[2,3-dl-pyrimidin-4-yl)amino-1-piperidine 1-carboxylic acid diethylamine Example 57 (3R,4R)-Methyl-indole 4-methyl-1-(2-methylamino-ethanesulfonyl)-piperidine-3-5-based M7H-pyrrole And Odl pyrimidin-4-yl)-amine The disclosure has been referred to other documents from beginning to end, such as Case, patent applications, periodicals, books and so on. In fact, the entire text of all such documents is incorporated herein by reference. It is to be understood that the foregoing description is only illustrative and is intended to illustrate the general concepts of the invention and its preferred embodiments. Routine Experimental Methods From the beginning to the end, in light of the advantages of the present disclosure, those skilled in the art will appreciate that modifications and variations can be made without departing from the spirit and scope of the disclosure. Therefore, the disclosure is not limited by the foregoing description, but is limited to the scope of the claims and their equivalents. 15 [Simple description of the diagram] (none) [Description of main component symbols] (none) 98

Claims

200823216 X. Patent Application Range: 1. 2. A pharmaceutical combination therapeutic for treating or preventing rheumatoid arthritis in humans, comprising: a Janus kinase inhibitor or a pharmaceutically acceptable salt thereof; and at least one An anti-arthritic agent or a pharmaceutically acceptable salt thereof. The pharmaceutical combination therapy of claim 1, wherein the Genesis kinase inhibitor is a compound of the formula R1 D2

Or a pharmaceutically acceptable salt thereof; wherein 10 R1 is a group of the formula: wherein y is hydrazine,

R5 (CH2)y

15 R4 is selected from the group consisting of hydrogen, (Q-C6) alkyl, (CrC6) alkanesulfonyl, (C2-C6)alkenyl, (C2-C6)alkynyl, wherein the alkane The base, alkenyl and alkynyl groups may be optionally substituted by hydrazine, hydroxy, amino, trifluoromethyl, (CrC4)alkoxy, (CrC6)decyloxy, (CVC6)alkylamino, ( (crc6)alkyl)2amino, cyano, nitro, (c2-c6)alkenyl, (C2-C6)alkynyl or (CrC6)nonylamino; or R4 is (C3-C1()) An alkyl group, wherein the cycloalkyl group is optionally substituted with a hydrazine, a hydroxy group, an amine group, a trifluoromethyl group, a (crc6) alkoxy group, a (crc6) amidino group, (crc6) 99 20 200823216 an alkane Amino, ((crc6)alkyl) 2 amine, cyano, cyano (cvcd alkyl, trifluoromethyl (crc6) alkyl, nitro, nitro (crc6) alkyl or (crc6) decylamine R5 is a (C2-C9)heterocycloalkyl group, wherein the heterocycloalkyl group has to be substituted with 1 to 5 or less groups: a carboxyl group, a cyano group, an amine group, an anthracene group, a hydroxyl group, (Ci-C6) Alkyl, (crc6)alkoxy, halogen, (cvc^)decyl, (cvc^)alkylamino, amino(CrC6)alkyl, (CrC6)alkoxy, -C O-NH, (CrC6) alkylamino-CO-, (c2-c6)alkenyl, (c2-c6)alkynyl, (cvc6)alkylamino, hydroxy(cvg)alkyl, (CVC6)alkoxy (cvg)alkyl, (crc6) 10 decyloxy (CVC6) alkyl, nitro, cyano (CVC6) alkyl, i(crc6) alkyl, nitro (crc6) alkyl, trifluoromethyl, Trifluoromethyl (crc6) alkyl, (cvc6) decylamino, (CrC6) decylamino (CrC6) alkyl, (CVC6) alkoxy (Q-C6) decylamino, amine (Q-C6 ) mercapto, amine (Q-C6) fluorenyl (cvcd alkyl, (cvq) alkylamino (cvco fluorenyl, ((crc6) 15 alkyl) 2 amine (CVC6) fluorenyl, r15r16n-co- O_, RbRMN-CCKCVC^)alkyl, (Ci-CJ alkyl-S(0)m, R15R16NS(0)m, R15R16NS(0)m(C!-C6)alkyl, R15S(0)mR16N, RbSCCOmR ^NCCVC^)alkyl, wherein m is 0, 1 or 2, and R15 and R16 are each independently selected from hydrogen or (Q-C6)alkyl; or the following formula 20: 100 200823216

Where a is 0, 1, 2, 3 or 4; b, c, e, f and g are each independently 0 or 1; 5 d is Ο, 1, 2 or 3; X is S(0)n, where η Is Ο, 1 or 2; oxygen, carbonyl or -C(=N-cyano)-; Y is S(0)n, where η is 0, 1 or 2; or carbonyl; and hydrazine is carbonyl, C(0 0-, C(0)NR- or S(0)n, wherein η is 0, 1 or 2; R6, R7, R8, R9, R10 and R11 are each independently selected from the group consisting of: hydrogen Or optionally via hydrazine, hydroxy, amino, trifluoromethyl, (crc6) decyloxy, (crc6) decylamino, (crc6)alkylamino, ((crc6)alkyl) 2 amine, cyanide a cyano(Q-C6)alkyl group, a trifluoromethyl group (Ci-Cd alkyl group, a nitro group, a nitro(CrC6) alkyl group or a (Q-C6)nonylamino group substituted (crc6)alkyl group; 15 R12 is a carboxyl group, a cyano group, an amine group, a pendant oxy group, a hydrazine group, a hydroxyl group, a trifluoromethyl group, a (CVC6) alkyl group, a trifluoromethyl group (CVC6) alkyl group, a (cvc6) alkoxy group, a hydroxyl group, (Crc6) mercapto, (CVC6) alkylamino, ((crc6) alkyl) 2 amine, amine (Q-C6) alkyl, (CVC6) alkoxy-CO-NH, (CrC6) alkylamine -C0-, (c2-c6) alkenyl, (c2-c6) alkynyl, hydroxy 20 (crc6) alkyl, (CrC6) alkoxy (CrC6 Alkyl, (CVC6) decyloxy 101 200823216 (CrD, base, cyano (crC6), dentate (CVC6), nitro (CrC6) alkyl, (CrC6) decyl, (CrC6) anthracenyl (Ci-C6) alkyl, (CVC6) alkoxy (qC^) amidino, amine (CrC6) fluorenyl, amine (CrC6) fluorenyl (CrC6) alkyl, ( CrC6) alkylamino (CrC6) 醯5 group, ((Ci-C6) alkyl) 2 amine (CVC6) fluorenyl, R15R16N-C0-0-, R15R16N-CO-(CrC6) alkyl, r15c (0 NH, R150C(0)NH, R15NHC(0)NH, (crc6)alkyl_s(o)m, (c"c6)alkyl-SCCOnHCVCe, R15R16NS(0)m, RMR^NSCOWCrC^) Alkyl, R15S(0)mR16N, R15S(0)mR16N(CrC6)alkyl, wherein mi〇 is 〇, i or 2 and Rl5 and R16 are each independently selected from hydrogen or (crc6)alkyl; R2 and R3 are each independently Selected from the group consisting of hydrogen, hydrazine, amine, halogen, hydroxy, nitro, carboxyl, (C2-C6)alkenyl, (C2-C6) fast radical, difluoromethyl, difluoromethane a (C1-C6)alkyl group, (Ci_C6) alkoxy group, (C3-C1G)cycloalkyl group, wherein the alkyl group, alkoxy group or cycloalkane group 15 is optionally selected from 1 to 3 selected from the group consisting of Group substitution: halogen Hydroxy, carboxyl, amino (Q-C6) thiol, ((VC6) alkylamino, ((CVC6) alkyl) 2 amine, (CVC9) heteroaryl, (c2_c9) heterocycloalkyl, ( C3-c9) cycloalkyl or (CVC1())aryl; or R2 and R3 are each independently (c3_ClG)cycloalkyl, (C3-C1G)cycloalkoxy, (CVC6)alkylamino, ((Crc6 Alkyl) 2 20 Amino '(C6-C1())arylamino, (Crc6)alkylthio, (c6-c1())arylthio, (Ci-C6), sulphate, (C6) -C1()) aryl sulfhydryl, (Ci-C^) pyrithionin, (c6-c1()) arylsulfonyl, (crc6) fluorenyl, (crC6) alkoxy-C0_NH·, ( C1_C6) alkylamino-CO-, (c5-c9)heteroaryl, (c2-c9)heterocycloalkyl or (CVCw)aryl, wherein the heteroaryl, heterocycloalkyl and 102 200823216 aryl Selectively substituted with 1 to 3 groups: halogen, (CrC6) alkyl hydrazine-(:6) alkyl-CO-NH-, (Ci-C6) alkoxy-CO-NH-yCrD alkyl- CO-NH-(CrC6)alkyl, (CrC6)alkoxy-CO-NIHCVC^) alkyl, (CrC6) alkoxy-CO-NH-(CrC6) alkoxy, carboxyl, carboxyl (CrC6) alkane Base, carboxyl (CrC6) alkoxy, oxycarbonyl (CrC6) alkoxy, (CrC6) alkoxy (CVC6) alkoxy group, (C6-C1()) aryl group, amine group, amine group (Ci-C6) alkyl group, (Ci_C6) leucoylamino group, (C6_Ci〇) aryl group (CrC6) Alkoxycarbonylamino, (CrC6)alkylamino, ((CrC6)alkyl) 2 amine, (CVC6) alkylamino (CVC6) alkyl, ((CrC6) alkyl) 2 amine (Q-C6 Alkyl, hydroxy, (CrC6) alkoxy, (CrC6) alkoxycarbonyl, (CrC6) alkoxycarbonyl (CVCJ alkyl, (CVC6) alkoxy_CO_NH-, cyano, (C5-C9) Cycloalkyl, amine-CO-NH-, (CVQ) alkylamino-CO-NH-, ((CVC6) alkyl) 2 amine-CO-NH-, (C6-C10) arylamino-CO -NH-, (C5-C9)heteroarylamino-CO-NH-, (CrC6)alkylamino-CO-NIHCVC^)alkyl, ((CVC6)alkyl)2 Amino-CO-NHJCi-C ^) alkyl, (C6-C10) arylamino-CO-NHJCVC^) alkyl, (C5-C9) heteroarylamino-(7)-cis-%^) alkyl, (cvc6) Institute of scutellaria, ( Cvc: 6) sulfonamide, (Cl_C6) sulfonamide (Ci_C6) alkyl, (eve-arylsulfonyl, (cvc1)) arylsulfonylamine, (C6-Ci〇) Anthraquinone (CrC6) alkyl, (CVC9) heteroaryl or (CVC9) heterocycloalkyl. 3. The pharmaceutical combination therapeutic of claim 2, wherein _〇; b is 1; X is a group; 〇 is 0; d is 0; 6 is 〇; α〇; and § is 〇. 4. The pharmaceutical combination therapeutic of claim 2, wherein a^; b is 1; X is a singular group; 0 is 〇; d is 0; 6 is 〇; f is 〇; and g is 〇. 103 200823216 5. The pharmaceutical combination therapeutic of claim 2, wherein a is 0; b is 1; X is a carbonyl group; c is Ο; d is Ο; e is Ο; f is Ο; and g is 0. 6. The pharmaceutical combination therapeutic of claim 2, wherein a is Ο; b is 1, X is -C(=N=gas group)-, c is 1, d is Ο, and e is Ο, f Ο, and 5 g is 〇0 7. The pharmaceutical combination therapeutic of claim 2, wherein a is Ο; b is Ο; c is Ο; d is Ο; e is Ο; f is Ο; g Is 1; and Z is -C(0)_0-. 8. The pharmaceutical combination therapeutic of claim 2, wherein a is 0; b is 1; X is S(0)n; η is 2; C is 0; d is 0; e is 0; 0 ; and g 10 is 0. 9. The pharmaceutical combination therapeutic of claim 2, wherein a is 0; b is 1, X is S(0)n, η is 2, c is 0, d is 2, and e is 0, f is 1, g is 1, and Z is a carbonyl group. 10. The pharmaceutical combination therapeutic of claim 2, wherein a is 10; 15 b is 1; X is S(0)n; η is 2; c is 0; d is 2; e is 0; Is 1; and g is 0. 11. The pharmaceutical combination therapeutic of claim 2, wherein a is 0; b is 1; X is a carbonyl group; c is 1; d is 0; e is 1; Y is S(0)n; Is 2; f is 0; and g is 0. 20 12. The pharmaceutical combination therapeutic of claim 2, wherein a is 0; b is 1; X is S(0)n; η is 2; c is 1; d is 0; e is 0; Is 0; and g is 0. 13. The pharmaceutical combination therapeutic of claim 2, wherein R12 is cyano, trifluoromethyl, (CVC6) alkyl, trifluoromethyl (CVQ) alkyl, (CVC6) 104 200823216 aromatine ((CrQ)alkyl) 2 amine group, (C2-C6) block group, cyano group (crC6) group, (CrC6)alkyl-S(0)m, wherein m is hydrazine, 1 or 2. 14. The pharmaceutical combination therapeutic of claim 2, wherein the Janus kinase inhibitor is selected from the group consisting of: 5 methylmethyl small (propyl-1-n-xanthine) ) - Well. Ding-3-yl]-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amine; 4·methyl-3-[methyl-(7H-portpyr[2,3- d]pyrimidin-4-yl)-amino]-piperidine-1-carboxylic acid methyl ester; 3.3.3-difluoro-1-{4-methyl-3-[methyl-(711) And [2,3-(1] shouting 1 aridin-4-yl)-amino]-piperidin-1-yl}-propanone; 4-methyl-3-[methyl-(7H-叱) [2,3-d]pyrimidin-4-yl)-amino]-π-cyanidine-1-carboxylic acid dimethylamine; ({4_methyl-3-[methyl-(7Η-pyrrole) And [2,3-pyrimidinyl]amino)-[beta]-mercapto]-amino}-acetic acid ethyl ethoxylate; 15 3-{4-methyl_3_[mercapto-[7H_ Pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidin-1-yldi 3-oxo-propanenitrile; 3.3.3-difluoro-l-{4-methyl -3-[methyl-(5_methyl-Luo[2,3_(1]^σ-decyl-4-yl)-amino]-Brigade. 定小基卜丙_ι_|同; 1-{4 -methyl-3-[methyl-(7Η-pyrrolo[2,3-d]pyrimidin-4-yl)-amine 20-base] bottom bite-1-kibbut-3-block-1-net; 1-{3-[(5-chloro-7Η·pyrrolo[2,3-d]pyrimidinyl)-methyl-amino]-4-methyl-σ σ 定 -1 · · · · -1 -ketone; 1-{3-[(5-fluoro-711-mouth ratio slightly [2,3-(1]. dimethyl-4-yl)-methyl-amino]-4-methyl-σ Benzo-1-pyridin-1-one; 105 200823216 N-Cyano-4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino ]-Ν'-propyl-piperidine-1-carboxyindole; Ν-cyano-4, hydrazine, Ν'-trimethyl-3-[methyl_(7ΐκ咯[2,3·ά] Pyrimidin-4-yl)-amino]-piperidine-1-carboxyindole; methyl-[(3R,4R)-4-methyl-1-(propanesulfonyl)-piperidine-3-yl] -(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amine; (3R,4R)-4-methyl-3-[methyl-(7H-pyrrolo[2,3-d ]pyrimidin-4-yl)-amino]-cyanopyridine-1-carboxylic acid methyl ester; 3.3.3-difluoro-1-{(3R,4R)_4-methyl-3_[methyl-(7H - mouth ratio π and [2,3-(1]% bite-4_yl)-amino]-°Chen-1_yl}-propanone; (3R,4R)-4-methyl- 3-[Methyl-(7Η·pyrrolo[2,3_d]pyrimidin-4-yl)-amino]-piperidine-1-carboxylic acid dimethylamine; {(3R,4R)-4-methyl- 3-[Methyl-(7H"Biluo[2,3_d], ate-4.yl)-amino]-brupidine-1-carboxy}amino)-ethyl acetate; 3-{(3R, 4R)-4-methyl-3-[methyl-(7H_cyclopyrazolo[2,3-d]pyrimidinyl)-amino]-sucking small base side oxy-propionitrile; 3.3. 3-trifluoro_1-{(3r,4r)_4•methyl_3_[methyl_(5_ decyl·7H_) Each [2,3_d]pyrimidin-4-yl)-amino]--biting small base acetone; methyl-3-[mercapto-(7H-mouth piroxime [2,3-d] pyrimidine bite Amino-l-piperidin-l-yl}-but-3-yn-1-one; 1 -U3R,4R)-3-[(5-chloro-7H-pyrrolo[2,3_d]pyrimidine _4_yl)_methylamino group>4.methyl-piperidin-1-yl}_propan-;!-ketone; fluoro-7H-pyrrolo[2,3-d]pyrimidine-4_ Methyl-amino]-4-methyl-piperidin-1-yl}-propanyl- ketone; 106 200823216 (3R,4R)-N-cyano-4_methyl-3-[A Base-(7H-pyrrolo[2,3-d]. Σσ定-4-yl)-amino]-Ν'-propyl-Brigade 17--1-indenyl, and (3R,4R)-N-cyano-4,Ν',Ν'_三甲-3-[Methyl-(7Η-pyrrolo[2,3-(1]. 密11定-4-yl)-amino]-Brigade 1 定-1-竣 base lung, 5 or their A pharmaceutically acceptable salt according to the invention of claim 1, wherein the Janus kinase inhibitor is 3-{(3R,4R)-4-methyl-3-[methyl- (7Η-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidin-1-yl}-3-oxo-propanenitrile or a pharmaceutically acceptable salt thereof. The pharmaceutical combination therapy of claim 1, wherein the anti-arthritic agent is a DMARD. 17. The pharmaceutical combination therapy of claim 16, wherein the DMARD is selected from the group consisting of:依坦特特,因福西麻,阿达果麻, Anakina, Abatase, Lei Txi Ma, Tosi 15 Zhu Ma, Toto Zhuma Peiguo, hydroxy gas, chloranil, Dabson , Shu salad, sodium sulphate, gold sulphur glucose, Orenfe, Amesu, Lefmide, azathioprine, d-penicillamine, and cyclosporine 18. A pharmaceutical combination therapy according to claim 17, wherein the DMARD is Amesu. 20 19. The pharmaceutical combination therapy of claim 1, wherein the Janus kinase inhibits The agent is 3-{(3R,4R)-4-methyl-3-[methyl-(7H-pyrrolo[2,3-(1]11-dimethyl-4-yl)-amino]-Brigade 11 Or a pharmaceutically acceptable salt thereof, and the anti-arthritic agent is amethizol or a pharmaceutically acceptable salt thereof. 107 200823216 20. A pharmaceutical combination therapy of 19, wherein 3-{(3R,4R)_4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino] -°Bottom-1-yl}-3-sidedoxy-cyan or its acceptable salt is administered at a dose of about 1 mg BID, 5 mg BID, 10 mg BID, 5 15 mg BID, 20 Mg BID, 25 mg BID or 30 mg BID, and a weekly dose of Amesa is 5 mg, 7.5 mg or 15 mg. 10 21. Can be combined with at least one anti-arthritic agent or its pharmacy Acceptable salt-administered Janus kinase inhibitor or a pharmaceutically acceptable salt thereof for preparation In the treatment or prophylaxis of rheumatoid arthritis in a human medicament. 22. The patent application of the scope of use of 21, wherein the Janus kinase inhibitor is a compound of the formula Si kinase inhibitor is a compound of the formula R1 P2

Or a pharmaceutically acceptable salt thereof; wherein R1 is a group of the formula

R5 (CH2)y R4 is selected from the group consisting of hydrogen, (CrC6) alkyl, 20 (cvc6) alkanesulfonyl, (c2-c6)alkenyl, (c2-c6)alkynyl, wherein The alkane 108 200823216, alkenyl and alkynyl groups may be optionally substituted by hydrazine, hydroxy, amine, difluoromethyl, (CrC4) alkoxy, (clec6) decyloxy, (crc6) alkane Amino, ((CrC6)alkyl) 2 amine, cyano, nitro, (C2-C6)alkenyl, (C2-C6)alkynyl or (Ci-C6)nonylamino; or R4 is (c3 -c1G) a cycloalkyl group, wherein the cycloalkyl group is optionally substituted with a gas, a trans-group, an amine group, a di-halomethyl group, a (Crc6) alkoxy group, a (CVC6) amidino group, crC6) Acrylamine, ((CrC6)alkyl) 2 amine, cyano, cyano (Ci_c6) alkyl, trifluoromethyl (CrC6) alkyl, nitro, nitro (Ci-Cs) alkyl Or (Ci-Cd guanamine; 10 R5 is (C2_C9) heterocycloalkyl) wherein the heterocyclic group must be substituted with 1 to 5 groups: carboxyl, cyano, amine, oxime, hydroxy, (Cl-C6) alkyl, (CrC6) alkoxy, halogen, (crc6) fluorenyl, (CVC6) acrylamine, amine (Q-C6) alkyl, (Cr C6) alkoxy, -CO-NH, (CVC6) alkylamino-CO-, (C2-C6)alkenyl, (C2-C6)alkynyl, (CVC6)alkylamino, 15 hydroxy(CrC6) (CrC6) alkoxy (crc6) alkyl, (CrC6) ethoxy (C1-C6), cumyl, cyano (C!-C6) alkyl, _(Ci_C6) alkyl, nitrate (rcc6)alkyl, trifluoromethyl, trifluoromethyl(crc6)alkyl, (CVC6)nonylamino, (CrC6)nonylamino (CVC6)alkyl, (c!-c6) alkoxy (CrC6) amidino group, amine group (q-CO fluorenyl group, amine group (Q-C6) 20 fluorenyl group (Crc6) alkyl group, (CrCd alkylamino group (CVC6) fluorenyl group, ((CrC6) alkyl group) 2 Amino (c!-c6) fluorenyl, r15r16n-co-o-, RbR^N-CCKCrC^)alkyl, (Q-C6)alkyl-S(0)m, R15R16NS(0)m, R15R16NS (0) m(CrC6)alkyl, R15S(0)mR16N, R15S(0)mR16N(CrC6)alkyl, wherein m is 0, 109 200823216 1 or 2, and R15 and R16 are each independently selected from hydrogen or (Q) -C6)alkyl; or a group of the formula:

(cr6r7l where a is 0, 1, 2, 3 or 4; 5 b, c, e, f and g are each independently 0 or 1; d is 0, 1, 2 or 3; X is S(0)n, Wherein η is 0, 1 or 2; oxygen, carbonyl or -C(=N-cyano)-; Y is S(0)n, wherein η is 0, 1 or 2; or a carbonyl group; and hydrazine is a carbonyl group, C (0) 0_, C(0)NR- or S(0)n, where η is 0, 1 or 2; 10 R6, R7, R8, R9, R10 and R11 are each independently selected from the group consisting of: Hydrogen or optionally via hydrazine, hydroxy, amine, trifluoromethyl, (CVC6) decyloxy, (CrC6) decylamino, (CrC6)alkylamino, ((CVC6)alkyl) 2 amine, Cyano, cyano (CrCJ alkyl, trifluoromethyl (Q-C6) alkyl, nitro, nitro (crc6) alkyl or (crc6) decyl substituted 15 (CrC6) alkyl; R12 is Carboxy, cyano, amine, pendant, oxime, hydroxy, trifluoromethyl, (CVC6)alkyl, trifluoromethyl(CrC6)alkyl, (CVC6) alkoxy, halogen, (Crc6)醯, (CVC6) alkylamino, ((crc6) alkyl) 2 amine, amine (CVC6) alkyl, (CVC6) alkoxy-CO-NH, 20 (CVC6) alkylamino-CO-, (c2-c6) alkenyl, (c2_c6)alkynyl, hydroxy 110 200823216 (crc6)alkyl, Crc6) alkoxy (crc6) alkyl, (crc6) decyloxy (CVC6) alkyl, schlossyl, cyano (crc6), i(cvc6) alkyl, nitro(CrC6) alkyl, (CVC6醯Amino, (CVC6) decylamino (cvc6:) alkyl, (Ci-C6) alkoxy (Ci_C6) 6S amine, amine (C1-C6), 5-amino (CrC6) 醯(CrC6)alkyl, (CVC6)alkylamino (CVC6) fluorenyl, ((c--C6)alkyl) 2 amine (CVC6) fluorenyl, R15R16N-C0-0-, RMrWN-CCKQ-C ^) alkyl, r15c(o)nh, r15oc(o)nh, r15nhc(o)nh, (Q-C6)alkyl-s(0)m, (CVC6)alkyl s(0)m·%· ^) alkyl, R15R16NS(0)m, rMrMnSCOWC^Q) 10 alkyl, R15S(〇)mR16N, RbSCCOmRbNA-C^)alkyl, wherein m is 0, 1 or 2 and R15 and R16 are each independently selected from hydrogen Or (CVC6)alkyl; R2 and R3 are each independently selected from the group consisting of hydrogen, hydrazine, amine, halogen, hydroxy, nitro, carboxy, (c2-c6)alkenyl, (c2-c6) a free radical, a trifluoromethyl, a trifluoromethoxy, an alkyl, a (crc6) alkoxy, a 15 (C3_C1G) cycloalkyl group, wherein the pendant, alkoxy or cycloalkyl group is selectively 1 through Three kinds of groups selected from the group consisting of halogen, hydroxyl, Amino group (cvc: 6) thiol group, (cvq) acryl group, ((cvc6)alkyl) 2 amine group, (CVC9) heteroaryl group, (c2-c9) heterocycloalkyl group, (c3 -c9) cycloalkyl or (C6-C1())aryl; or R2 and R3 are each independently (C3_Cl〇)cycloalkyl, (c3_Ci〇)20 cycloalkoxy, (Ci-C6)alkylamino , ((CVC6)alkyl)2amino, (c6-c10)arylamino, (CVC6)alkylthio, (c6-c1())arylthio, (CVC6)alkylsulfinyl, (CVQo Arylsulfonyl, (CVC6) alkanesulfonyl, (c6-c10) arylsulfonyl, (CrC6) fluorenyl, (CVC6) alkoxy-CO-NH-, (CVC6) alkylamine- CO·, (Q-C9)heteroaryl, (c2_c9)heterocycloalkyl or (c6-c10) 111 200823216 aryl, wherein the heteroaryl, heterocycloalkyl and aryl are optionally 1 to 3 Substituted group substitutions: i, (rcc6)alkyl, (crc6)alkyl-CO-NH-, (CrC6)alkoxy-CO-NH-, (CVC6)alkyl-CO-NlHCrC^) , (CVC6) alkoxy-0)_ is a 1-((:1-(:6) alkane 5 group, (CVC6) alkoxy-CO-NH-A-CO alkoxy group, a carboxyl group, a carboxyl group ( CVC6) alkyl, carboxyl (CrC6) alkoxy, benzyloxycarbonyl (CrC6) alkoxy '(CrC6) alkoxycarbonyl (CrC6) alkoxy group, (C6-C1()) aryl group, amine group, amine group (CVC6) alkyl group, (cvc6) alkoxycarbonylamino group, (c6_c10) aryl (Q-C6) alkoxycarbonyl group Amino, (crc6)alkylamino, ((crc6)alkyl)2, (CVC6)alkylamino (cvc6)alkyl, ((crc6)alkyl)2amino (crc6)alkyl, Hydroxy, (CrC6) alkoxy, (crc6) alkoxycarbonyl, (CVC6) alkoxycarbonyl (CrC6) alkyl, (CVC6) alkoxy-CO-NH-, cyano, (C5-C9) heterocyclic Alkyl, amine-CO-NH-, (CrC6) alkylamino _CO-NH_, ((CVC6) alkyl) 2 amine-CO-NH·, (C6-C1()) arylamine 15 - CO-NH-, (C5-C9) heteroarylamino-CO-NH-, (CrC6) alkylamino-CO-NH-(CrC6) alkyl, ((CrC6)alkyl) 2 amine-CO- NIHCVCO alkyl, (C6_C1()) arylamino-CO-NIHCVCd alkyl, (C5_C9)heteroarylamino-CO-NHJCVC^), (Ci-C6) burnt-stone, (CVQ) alkanesulfonate Amine, (CVC6) alkanesulfonylamino (C "C6" 20 alkyl, (C6-C1G) arylsulfonyl, (CVC1G) arylsulfonylamino, (c6-c10) arylsulfonylamino ( CVQ) alkyl, (C5_C9)heteroaryl or (c2-c9)heterocycloalkyl. 23. The use of claim 22, wherein a is 〇; b is 1; X is a rotam group; c is 0; d is 0; e is 0; f is 〇; and g is 〇. 24. The use of claim 22, wherein a is 〇; b is 1; X is 112 200823216 carbonyl; c is 0; d is 1; e is 0; f is 0; and g is 0. 25. For the use of claim 22, wherein a is Ο; b is 1; X is carbonyl; c is 1; d is 0; e is 0; f is 0; and g is 0. 26. For the purposes of application No. 22, where a is 0; b is 1; X is 5-C (=N=gas base), c is 1, d is 0, e is 0, and f is 0. And g is 0. 27. For the purposes of claim 22, where a is 0; b is 0; c is 0; d is 0, e is 0, f is 0, g is 1, and Z is -C(0), 0- 〇28. For the purposes of claim 22, where a is 0; b is 1; X is S(0)n; η is 2; c is 0; d is 0; e is 0; 0 ; and g is 0. 10 29. The use of claim 22, wherein a is 0; b is 1; X is S(0)n; η is 2; c is 0; d is 2; e is 0; f is 1; g is 1; and Z is a carbonyl group. 30. The use of claim 22, wherein a is 0; b is 1; X is S(0)n; η is 2; c is 0; d is 2; e is 0; f is 1; g is 0. 15 31. The use of claim 22, wherein a is 0; b is 1; X is a carbonyl group; c is 1; d is 0; e is 0; Y is S(0)n; η is 2; f is 0; and g is 0. 32. The use of claim 22, wherein a is 0; b is 1; X is S(0)n; η is 2; c is 1; d is 0; e is 0; f is 0; g is 0. 20 33. The use of claim 22, wherein R12 is cyano, trifluoromethyl, (CrC6)alkyl, trifluoromethyl(CrC6)alkyl, (CrC6)alkylamine, ((CrC6) Alkyl)2amino, (C2-C6)alkynyl, cyano(Q-C6)alkyl, (CrC6)alkyl-S(0)m, wherein m is 0, 1 or 2. 34. The use of claim 22, wherein the Janus kinase inhibitor 113 200823216 is selected from the group consisting of: thiol-[4-mercapto-1-(propane-1-sulfonate) Base)-piperidinyl-3-yl]-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amine; 4-mercapto-3-[methyl-(711-pyrrolo[2, 3-d]pyrimidin-4-yl)-amine 5 yl l piperidine-1-carboxylic acid decyl ester; 3.3.3-trifluoro-l-{4-methyl-3-[methyl-(7H- Pyrrolo[2,3-d]pyrimidin-4yl)-amino]piperidine small group}_propanone-ketone; 4-methyl_3_[methyl-(7H_叱叱[2, 3-(1]pyrimidin-4-yl)-amino]-piperidine-1-carboxylic acid diamine; 10 ({4-methyl-3-[methyl-(7Η_σ比洛和[2, 3-σ-Bitter-4-yl]-Amino)- σ σ 定 -1- -1- 叛 ] - - - - - - - 3- 3- 3- 3- 3- 3- 3- 3- 3- 3- 3- 3- 2,3-d]. dimethyl-4-yl)-amino]-piperidin-1-yl}-3-oxo-propanenitrile; 3.3.3-trifluoro-l-{4-methyl -3-[methyl-(5-fluorenyl-7H-. piroxicam 15 [2,3-(1], 1,4-yl)-amino]---------- 1-1 ketone; 1-{4-methyl-3-[indenyl-(7H-mouth piroxi[2,3-d> dimethyl-4-yl)-amino]- σ base 11 - 1 · 基}•丁-3-快-1_酬I ; 1_{3-[(5-chlorine -7Η-pyrrolo[2,3_d]pyrimidin-4-yl)-methyl-amino]-4-methyl-σ sigma-l-yl}-propan-1_ steel; 2〇1_{3_ [(5_Fluoro-711_pyrrolo[2,3_d]pyrimidin-4-yl)-methyl-amino]]4-methyl-Brigade-11--1-yl}-propan-1-Month|; N -Cyano-4-methyl-3_[indolyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-indole-propyl-brazilide small carboxyl group; -Cyano-4, Ν', Ν'-trimethyl-3. [Methyl-(7Η-pyrrolo[2,3-d] 114 200823216 % °-4-yl)-amino] chen.定_1_魏基肺; methyl-[(3R,4R)-4·methyl small (propyl smokite) _ mouth n-base H7H" than 嘻[2,3-d] bite ice (3R,4R)-4·methyl-3_[methyl_(7Η_σ ratio, each [2 3 d] feeding n 5 base)-amino group] 辰σ定-1-carboxylic acid A 3.3.3-Difluoro-l-{(3R,4R)-4-methyl-3-[methyl-(7Η-pyrrolo[2,3-d]pyrimidinyl)-amino] (3R,4R)-4-methyl-3-[methyl-(7H"pyrolo[2,3_dKn-yl)-amino]-bred bite-l-acid Diamine dicarboxylic acid; 10 {(3R,4R) ice methyl-indole methyl-(paw-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-°chen唆-1-suppressed Amino) ethyl acetate; 3-{ (3R,4R)_4-methyl-3-[methyl-(7H"pyrolo[2,3_d]pyrimidin-4-yl)-amino]-brazidin-1-ylbu 3_side oxygen -propionitrile; 3.3.3-difluoro-1-{(3炅,4 ft)-4-methyl_3-[methyl-(5-methyl-7-only 15-pyrrolo[2,3 -d]a pyridine _4·yl)-amino] 啶 __ι_基卜丙小_ ; l-{(3R,4R)-4-methyl-3-[methyl-(7H·pyrrole And [2,3_d]pyrimidin-4-yl)-amino]_σ辰喘>1-kibbut-3-yn-1-one; l-{(3R,4R)-3-[(5- Chloro-7Η·pyrrolo[2,3-d]pyrimidin-4-yl)-methyl-amino]-4-methyl-σ 唆-l-yl}-propanone; 2〇1_{( 3 ft, 41 〇-3-[(5-fluoro-711-pyrrolo[2,3-(1]pyrimidin-4-yl)-methyl-amino] ylmethyl-piperidin-1-yl} _C-indole·ketone; (3R,4R)-N-cyano-4-methyl-3_[methyl-(7Η-. Comparing with the mouth [2,3-d] mouth-biting 4-yl)-amino]-Ν'-propyl- ° Chen bite small carboxyl group; and (3R,4R)-N-cyano group_4 ,Ν',Ν,_三甲-3-[methyl-(7Η-π比洛和115 200823216 [2'3 d]疋-4_yl)amine] bottom bite_1_carboxyl lung; or A pharmaceutically acceptable salt. 35. The use of claim 22, wherein the Janus kinase inhibitor is 3-{(3R,4R)-4-methyl_3_[methyl-(7Η·pyrrolo[2,3- d] Pyrimidine 5 yl)-amino]-piperidin-1-yl}-3- oxo-propanenitrile or a pharmaceutically acceptable salt thereof. 36. The use of claim 21, wherein the anti-arthritic agent is a DMARD. 37. The use of claim 36, wherein the dmard is selected from the group consisting of: 1 依特、、、、、、、、、、、、、、、、、、、、、、、、、 Lei xixi, taxi Zhuma, color toxin 夙备备备备备备备备备备备备备备备备备备备备备备备备备备备备备备备备备备备备备备备备备备备Lefmid, sparse, d_penicillamine, and cyclosporine A. 38. The use of the scope of claim 37, wherein the DMARD is Ami π ticket. 39. The use of the scope of claim 21, wherein the Janus irritating agent is 3-{(3R, 4RM_methyl-3_[曱基_(7Η♦ each [23_d^定2〇-^ Ketoamino]-piperidine-indenyl}-]- oxo-propanenitrile or a pharmaceutically acceptable salt thereof and the anti-arthritic agent is amethrin or its medicinal wind 1 accepting salt. For example, the application of the scope of claim 39, 3_{(3r, 4rm_methyl_3·[methyl-(7H-吼D each [2,3_d] mouth bite_4_ base) The dosage of the amine aziridine diyl} 3-oxy-propionitrile or a pharmaceutically acceptable salt thereof is 116 200823216 About 1 mg BID, 5 mg BID, 10 mg BID, 15 mg BID, 20 mg BID, 25 mg BID or 30 mg BID, and the weekly dose of Amesu is 5 mg, 7.5 mg or 15 mg. V 117 200823216 VII. Designated representative figure: (1) The representative representative of the case is: () Fig. (n) The simple description of the symbol of the representative figure: 8. If there is a chemical formula in this case, please disclose the chemical formula that best shows the characteristics of the invention: