在其最廣泛的實施例(實施例1)中，本發明係關於式(I)化合物及/或其醫藥學上可接受之鹽，如上文發明內容章節中所描述。 本發明之實施例2係關於實施例1之化合物或其醫藥學上可接受之鹽，其中Hal為氯或氟。 本發明之實施例3係關於實施例1之化合物或其醫藥學上可接受之鹽，其中Hal為氯。 本發明之實施例4係關於實施例1、2或3之化合物或其醫藥學上可接受之鹽，其中R1
為甲基。 本發明之實施例5係關於實施例1、2或3之化合物或其醫藥學上可接受之鹽，其中R1
為氫。 本發明之實施例6係關於實施例1、2、3或4之化合物或其醫藥學上可接受之鹽，其中R1
在締合之聯吡啶環之位6處為甲基。 本發明之實施例7係關於實施例1或4之化合物或其醫藥學上可接受之鹽，該醫藥學上可接受之鹽係選自4-((2-氯苯基)胺基)-6-(吡啶-2-基胺基) 菸鹼醯胺及4-((2-氯苯基)胺基)-6-((6-甲基吡啶-2-基)胺基)菸鹼醯胺。 實施例8係關於包含治療有效量的根據實施例1至7中任一者之化合物及一或多種醫藥學上可接受之載劑的醫藥組合物。 實施例9係關於包含治療有效量的根據實施例1至7中任一者之化合物或其醫藥學上可接受之鹽及一或多種治療學上之活性輔劑的組合。 實施例10係關於調節個體中之JAK活性之方法，其中該方法包含向該個體投與治療有效量的根據實施例1至7中任一者之化合物或其醫藥學上可接受之鹽。 實施例11係關於適用作藥劑的根據實施例1至7中任一者之化合物或其醫藥學上可接受之鹽。 定義 如本文所使用，術語「C1
-C6
烷基」係指具有至多6個碳原子之完全飽和分支鏈或未分支鏈烴部分。除非另外指出，否則其係指具有1至6個碳原子、1至4個碳原子或1至2個碳原子之烴部分。烷基之代表性實例包括(但不限於)甲基、乙基、正丙基、異丙基、正丁基、第二丁基、異丁基、第三丁基、正戊基、異戊基、新戊基、正己基及其類似者。 如本文所使用，術語「鹵素」或「鹵基」係指氟、氯、溴及碘；且其可尤其係指氯、氟。 如本文所使用，術語「鹽」係指本發明化合物之酸加成鹽或鹼加成鹽。「鹽」尤其包括「醫藥學上可接受之鹽」。術語「醫藥學上可接受之鹽」係指保留本發明化合物之生物學效用及特性且通常在生物學上或其他方面所需要的鹽。在許多情況下，本發明化合物能夠藉助於胺基及/或羧基或其類似基團之存在而形成酸鹽及/或鹼鹽。 醫藥學上可接受之酸加成鹽可由無機酸及有機酸形成，該等酸加成鹽例如乙酸鹽、氯鹽/鹽酸鹽、檸檬酸鹽、反丁烯二酸鹽、酒石酸鹽、甲苯磺酸鹽及三氟乙酸鹽。 可自其衍生鹽之無機酸包括(例如)鹽酸、氫溴酸、硫酸、硝酸、磷酸及其類似者。 可自其衍生鹽之有機酸包括(例如)乙酸、丙酸、乙醇酸、草酸、順丁烯二酸、丙二酸、丁二酸、反丁烯二酸、酒石酸、檸檬酸、苯甲酸、杏仁酸、甲磺酸、乙磺酸、甲苯磺酸、磺基水楊酸及其類似者。 本發明之醫藥學上可接受之鹽可藉由習知的化學方法由鹼性或酸性部分合成。一般而言，該等鹽可藉由使此等化合物之游離酸形式與化學計算量之適當鹼(諸如，Na、Ca、Mg或K之氫氧化物、碳酸鹽、碳酸氫鹽或其類似者)反應，或藉由使此等化合物之游離鹼形式與化學計算量之適當酸反應來製備。該等反應通常在水中或有機溶劑中或在兩者之混合物中進行。一般而言，在可實行時，需要使用如醚、乙酸乙酯、乙醇、異丙醇或乙腈之非水性介質。其他適合之鹽之列舉可見於例如「Remington's Pharmaceutical Sciences」，第20版，Mack Publishing Company, Easton, Pa., (1985)中；及「Handbook of Pharmaceutical Salts: Properties, Selection, and Use」，Stahl及Wermuth (Wiley-VCH, Weinheim, Germany, 2002)中。 本文中給定之任何式亦意欲表示化合物之未經標記之形式以及經同位素標記之形式。經同位素標記之化合物具有由本文所給定之式所描繪的結構，除了一或多個原子由具有選定原子質量或質量數之原子替換之外。可併入本發明化合物中之同位素之實例包括氫、碳、氮、氧、磷、氟及氯之同位素，分別諸如2
H、3
H、11
C、13
C、14
C、15
N、18
F、31
P、32
P、35
S、36
Cl、125
I。本發明包括如本文所定義之各種經同位素標記之化合物，例如其中存在放射性同位素(諸如3
H及14
C)之彼等化合物，或其中存在非放射性同位素(諸如2
H及13
C)之彼等化合物。此等經同位素標記之化合物適用於代謝研究(使用14
C)、反應動力學研究(使用例如2
H或3
H)、偵測或成像技術(諸如，包括藥物或受質組織分佈分析之正電子發射斷層攝影法(PET)或單光子放射電腦斷層攝影法(SPECT))，或適用於患者之放射性治療。特定言之，18
F或經標記之化合物可對於PET或SPECT研究而言為尤其需要的。經同位素標記之式(I)化合物一般可藉由熟習此項技術者所已知的習知技術，或藉由與隨附實例及製備中所描述之彼等方法類似的方法，使用適當的經同位素標記之試劑替代先前採用之未經標記試劑來製備。 此外，使用較重同位素(特定言之氘(亦即，2
H或D))進行取代可得到由更高代謝穩定性產生之某些治療優勢，例如活體內半衰期增加或劑量需求降低或治療指數改良。應理解，在此上下文中，氘被視為式(I)化合物之取代基。此類較重同位素(具體言之氘)之濃度可由同位素增濃因素定義。如本文所使用之術語「同位素增濃因素」意謂指定同位素之同位素豐度與天然豐度之間的比率。若本發明化合物中之取代基標示為氘，則該化合物所具有的各指定氘原子之同位素增濃因素分別為至少3500 (在各指定氘原子處52.5%氘併入)、至少4000 (60%氘併入)、至少4500 (67.5%氘併入)、至少5000 (75%氘併入)、至少5500 (82.5%氘併入)、至少6000 (90%氘併入)、至少6333.3 (95%氘併入)、至少6466.7 (97%氘併入)、至少6600 (99%氘併入)或至少6633.3 (99.5%氘併入)。 根據本發明之醫藥學上可接受之溶劑合物包括其中結晶之溶劑可經同位素取代之彼等溶劑合物，例如D2
O、d6
-丙酮、d6
-DMSO。 本發明之化合物，亦即含有能夠充當氫鍵之供體及/或受體之基團的式(I)化合物可能能夠用適合的共晶形成劑形成共晶。此等共晶可藉由已知共晶形成程序自式(I)化合物製備。此等程序包括研磨、加熱、共昇華、共熔融或在溶液中在結晶條件下使式(I)化合物與共晶形成劑接觸，及分離藉此形成之共晶。合適的共晶形成劑包括描述於WO 2004/078163中之彼等共晶形成劑。因此本發明進一步提供包含式(I)化合物之共晶。 如本文所使用，術語「醫藥學上可接受之載劑」包括如熟習此項技術者將已知的任何及所有溶劑、分散介質、包衣、界面活性劑、抗氧化劑、防腐劑(例如抗細菌劑、抗真菌劑)、等張劑、吸收延遲劑、鹽、防腐劑、藥物穩定劑、黏合劑、賦形劑、崩解劑、潤滑劑、甜味劑、調味劑、色素及其類似者及其組合(參見例如，Remington's Pharmaceutical Sciences，第18版，Mack Printing Company，1990，第1289至1329頁)。除非任何習知的載劑與活性成分不相容，否則涵蓋其在治療或醫藥組合物中之用途。 術語本發明之化合物的「治療有效量」係指將誘發個體之生物學或醫學反應的本發明之化合物的量，該等反應例如降低或抑制酶或蛋白質活性或改善症狀、緩解病狀、減緩或延緩疾病進展或預防疾病等。在一個非限制性實施例中，術語「治療有效量」係指當向個體投與時具有以下效用的本發明之化合物的量：(1)有效地至少部分緩解、抑制、預防及/或改善(i)由JAK介導的或(ii)與JAK活性相關聯的或(iii)由JAK之活性(正常或異常)表徵的病狀或病症或疾病；或(2)有效地降低或抑制JAK之活性；或(3)有效地減少或抑制JAK之表現。在另一非限制性實施例中，術語「治療有效量」係指當投與給細胞或組織或非細胞生物物質或介質時具有以下效用的本發明之化合物的量：有效地至少部分降低或抑制JAK之活性；或有效地部分或完全減少或抑制JAK之表現。 如本文所使用，術語「個體」係指動物。典型地，動物為哺乳動物。個體亦指例如靈長類動物(例如人類，男性或女性)、牛、綿羊、山羊、馬、犬、貓、兔、大鼠、小鼠、魚、鳥及其類似者。在某些實施例中，個體為靈長類動物。在其他實施例中，個體為人類。 如本文所使用，術語「抑制(inhibit/inhibition/inhibiting)」係指減少或遏止既定病狀、症狀或病症或疾病，或顯著降低生物活性或過程之基線活性。 如本文所使用，術語「治療(treat/treating/treatment)」任何疾病或病症在一個實施例中係指改善疾病或病症(亦即，減緩或停滯或減少疾病或其至少一個臨床症狀之發展)。在另一實施例中，「治療」係指緩解或改善至少一個生理參數，包括患者可能無法辯別之生理參數。在又一實施例中，「治療」係指在身體上(例如，可辯別症狀之穩定化)、生理上(例如身體參數之穩定化)或在兩方面調節疾病或病症。在又一實施例中，「治療」係指預防或延緩疾病或病症之發作或發展或進展。 如本文所使用，若個體將在生物學、醫學或生活品質上受益於治療，則該個體「需要」該治療。 如本文所使用，除非本文中另外指示或與上下文明顯矛盾，否則本發明之上下文中(尤其在申請專利範圍之上下文中)所用的術語「一(a/an)」、「該(the)」及類似術語應解釋為涵蓋單數及複數兩者。 除非本文中另外指示或與上下文明顯矛盾，否則本文中所描述之所有方法均可以任何適合的次序進行。本文中所提供之任何及所有實例或例示性語言(例如「諸如」)之使用僅意欲更好地闡明本發明，而不對以其他方式主張的本發明之範疇造成限制。 本發明之一或多種化合物的任何不對稱原子(例如，碳或其類似者)可以外消旋或對映異構性增濃之形式存在，例如(R
)組態、(S
)組態或(R , S
)組態。在某些實施例中，各不對稱原子在(R
)組態或(S
)組態中具有至少50%對映異構體過量、至少60%對映異構體過量、至少70%對映異構體過量、至少80%對映異構體過量、至少90%對映異構體過量、至少95%對映異構體過量或至少99%對映異構體過量。在具有不飽和雙鍵之原子處的取代基若可能則以順式 -
(Z
)-或反式 -
(E
)-形式存在。 因此，如本文所使用，本發明之化合物可呈以下可能的各者中之一者之形式：旋轉異構體、滯轉異構體、互變異構體、幾何(順式
或反 式
)異構體、非對映異構體、光學異構體(對映體)、外消旋體或其混合物。 任何所得異構體之混合物可基於組分之物理化學差異而分離成純的或實質上純的幾何或光學異構體、非對映異構體、外消旋體，例如藉由層析及/或分步結晶。 任何所得最終產物或中間物之外消旋體可藉由已知方法而解析成光學對映體，例如藉由分離其非對映異構體鹽(該鹽用光學活性酸或鹼獲得)及釋放光學活性酸性或鹼性化合物。特定言之，鹼性部分可因此用於將本發明之化合物解析成其光學對映體，例如藉由分步結晶用光學活性酸形成之鹽，該光學活性酸例如酒石酸、二苯甲醯基酒石酸、二乙醯基酒石酸、二-O , O '
-對甲苯甲醯基酒石酸、杏仁酸、蘋果酸或樟腦-10-磺酸。外消旋產物亦可藉由對掌性層析來解析，例如使用對掌性固定相之高壓液相層析(HPLC)。 此外，本發明之化合物(包括其鹽)亦可以其水合物之形式獲得，或包括用於其結晶之其他溶劑。本發明之化合物可固有地或經設計以與醫藥學上可接受之溶劑(包括水)形成溶劑合物；因此，本發明意欲涵蓋溶劑化及非溶劑化形式兩者。術語「溶劑合物」係指本發明之化合物(包括其醫藥學上可接受之鹽)與一或多種溶劑分子之分子複合物。此等溶劑分子為通常用於醫藥技術中已知對接受者無害的彼等溶劑分子，例如水、乙醇及其類似者。術語「水合物」係指其中溶劑分子為水之複合物。 本發明之化合物(包括其鹽、水合物及溶劑合物)可固有地或經設計以形成多晶型物。 在另一態樣中，本發明提供一種包含本發明之化合物及醫藥學上可接受之載劑的醫藥組合物。該醫藥組合物可針對諸如經口投與、非經腸投與及經直腸投與等特定投與途徑加以調配。另外，本發明之醫藥組合物可製成固體形式(包括(但不限於)膠囊、錠劑、丸劑、顆粒劑、散劑或栓劑)或液體形式(包括(但不限於)溶液、懸浮液或乳液)。可對醫藥組合物進行習知醫藥操作(諸如滅菌)及/或該等醫藥組合物可含有習知惰性稀釋劑、潤滑劑或緩衝劑以及佐劑(諸如防腐劑、穩定劑、濕潤劑、乳化劑及緩衝劑等)。 醫藥組合物通常為包含活性成分以及以下之錠劑或明膠膠囊： a)稀釋劑，例如乳糖、右旋糖、蔗糖、甘露醇、山梨醇、纖維素及/或甘胺酸； b)潤滑劑，例如二氧化矽、滑石、硬脂酸、硬脂酸之鎂鹽或鈣鹽及/或聚乙二醇；對於錠劑亦為如此 c)黏合劑，例如矽酸鎂鋁、澱粉糊、明膠、黃蓍、甲基纖維素、羧甲基纖維素鈉及/或聚乙烯吡咯啶酮；若需要 d)崩解劑，例如澱粉、瓊脂、褐藻酸或其鈉鹽，或起泡混合物；及/或 e)吸附劑、著色劑、調味劑及甜味劑。 錠劑可根據此項技術中已知之方法經薄膜包覆或經腸溶包衣包覆。 用於經口投與之適合的組合物包括有效量之本發明化合物，其呈錠劑、口含錠、水性或油性懸浮液、分散性散劑或顆粒劑、乳液、硬或軟膠囊或糖漿或酏劑之形式。意欲用於經口使用之組合物根據此項技術中已知用於醫藥組合物之製造的任何方法來製備，且此類組合物可含有一或多種選自由甜味劑、調味劑、著色劑及防腐劑組成之群的試劑，以提供醫藥學上精緻且可口之製劑。錠劑可含有活性成分與適合於製造錠劑的醫藥學上可接受之無毒賦形劑之混雜物。舉例而言，此等賦形劑為惰性稀釋劑，諸如碳酸鈣、碳酸鈉、乳糖、磷酸鈣或磷酸鈉；粒化劑及崩解劑，例如玉米澱粉或褐藻酸；黏合劑，例如澱粉、明膠或阿拉伯膠；及潤滑劑，例如硬脂酸鎂、硬脂酸或滑石。錠劑未經包覆或藉由已知技術包覆以延緩胃腸道中之崩解及吸收，且藉此提供歷經更長時間段之持續作用。舉例而言，可採用時間延緩材料，諸如單硬脂酸甘油酯或二硬脂酸甘油酯。用於經口使用之調配物可以硬明膠膠囊形式或軟明膠膠囊形式呈現，在該等硬明膠膠囊中，活性成分與惰性固體稀釋劑(例如碳酸鈣、磷酸鈣或高嶺土)混合，在該等軟明膠膠囊中，活性成分與水或油介質(例如花生油、液體石蠟或橄欖油)混合。 某些可注射組合物為水性等張溶液或懸浮液，且栓劑宜自脂肪乳液或懸浮液製備。該等組合物可經滅菌，及/或含有佐劑，諸如防腐劑、穩定劑、濕潤劑或乳化劑、溶解促進劑、用於調控滲透壓之鹽及/或緩衝劑。此外，其亦可含有其他治療學上有價值之物質。該等組合物分別根據習知混合、粒化或包覆方法製備，且含有約0.1-75%之活性成分，或含有約1-50%之活性成分。 用於經皮施用之適合的組合物包括有效量的本發明化合物與適合的載劑。適用於經皮遞送之載劑包括可吸收的藥理學上可接受之溶劑，以輔助穿過宿主之皮膚。舉例而言，經皮裝置呈繃帶形式，其包含襯底部件、含有化合物(視情況與載劑一起)之儲集層、視情況存在的經延長之時間段以受控制及預定速率遞送宿主皮膚之化合物的速率控制障壁及將裝置固定在皮膚上之構件。 用於局部施用(例如施用至皮膚及眼睛)之適合的組合物包括水溶液、懸浮液、軟膏、乳霜、凝膠或(例如)藉由噴霧劑或其類似物而遞送的可噴塗之調配物。此類局部遞送系統將尤其適合於經皮施用，例如用於治療皮膚癌，例如以防曬霜、洗劑、噴霧劑及其類似物用於預防性用途。因此，其尤其適用於此項技術中熟知之局部(包括化妝)調配物。該等調配物可含有增溶劑、穩定劑、張力增強劑、緩衝劑及防腐劑。 如本文所使用，局部施用亦可涉及吸入或鼻內施用。其可適宜地以乾燥散劑(單獨以混合物(例如與乳糖之無水摻合物)形式或混合組分顆粒(例如與磷脂))形式自乾燥散劑吸入器遞送，或以噴霧劑噴霧形式在使用或不使用適合之推進劑的情況下自加壓容器、泵、噴射器、霧化器或噴霧器遞送。 本發明進一步提供包含本發明之化合物作為活性成分之無水醫藥組合物及劑型，因為水可促進某些化合物之降解。 本發明之無水醫藥組合物及劑型可利用無水或含有較低水分之成分及較低水分或較低濕度之條件製備。可製備且儲存無水醫藥組合物，從而維持其無水性質。因此，使用已知防止暴露於水之材料封裝無水組合物以使得其可包括於適合處方集套組中。適合的封裝之實例包括(但不限於)氣密性密封箔、塑膠、單位劑量容器(例如，小瓶)、泡殼包裝及條帶包裝。 本發明進一步提供醫藥組合物及劑型，其包含降低作為活性成分之本發明化合物將分解之速率的一或多種藥劑。在本文中稱為「穩定劑」之該等藥劑包括(但不限於)諸如抗壞血酸之抗氧化劑、pH緩衝劑或鹽緩衝劑等。實驗部分
縮寫： BINAP： (2,2'-雙(二苯膦基)-1,1'-聯萘) Cs2
CO3
： 碳酸銫 DMSO： 二甲亞碸 g： 公克 h： 小時 NaHMDS： 雙(三甲基矽烷基)醯胺鈉 min： 分鐘 MS： 質譜 mL或ml： 毫升 Pd2
(dba)3
： 參(二亞苄基丙酮)二鈀(0) THF： 四氫呋喃 UPLC： 超效能液相層析法分析方法 液相層析法 ：
UPLC/MS： Waters Acquity UPLC + Waters ZQ2000 MS UV-PDA： 210 - 450 nM MS範圍： 100-1200 Da 管柱： Acquity HSS T3 2.1 × 50 mm 1.8 µ 60℃ 移動相： A：水+0.05%甲酸 B：乙腈+0.04%甲酸 中間物 3 之合成 6 - 氯 - 4 -(( 2 - 氯苯基 ) 胺基 ) 菸 鹼醯胺： 在0℃下，向1
(9.3 g，48.7 mmol)及2
(7.68 mL，73 mmol)於THF (100 mL)中之溶液中逐滴添加雙(三甲基矽烷基)醯胺鈉(NaHMDS)於THF (340.8 mL)中之1 M溶液，且在氮氣氛圍下在25℃下攪拌混合物3小時。混合物用水淬滅，用乙酸乙酯萃取，用硫酸鈉乾燥，且在減壓下濃縮。將粗產物與乙醚(200 mL)一起攪拌0.5小時且加以過濾，得到呈淡黃色固體狀之3
(12.8 g，95%純度)。MS：282.0 (M+1)+
;1
H NMR (DMSO-d6) δ= 8.52 (1 H, s), 11.00 (1 H, s), 9.74 (1 H, m), 8.59 (1 H, s), 8.09 (2 H, m), 7.70 (1 H, d), 7.59 (1 H, d), 7.52 (1 H, t), 7.43 (1 H, t), 7.40 (1 H, m), 7.17 (2 H, m), 6.72 (1 H, d), 2.26 (3 H, s)。實例 1 之合成 4 -(( 2 - 氯苯基 ) 胺基 )- 6 -( 吡啶 - 2 - 基胺基 ) 菸鹼醯胺： 在25℃下向3
(5.9 g，20.9 mmol)於二噁烷(150 mL)中之攪拌溶液中添加4
(2.95 g，31.4 mmol)、Cs2
CO3
(17 g，52.3 mmol)、Pd2
(dba)3
(1.92 g，2.09 mmol)、BINAP (1.95 g，3.14 mmol)及三乙胺(4.4 mL，31.4 mmol)。使所得溶液脫氣且在100℃下加熱16小時。混合物用水稀釋，用乙酸乙酯萃取，用鹽水洗滌，用硫酸鈉乾燥，且在真空下濃縮。藉由使用40 g Silicycle管柱(4%甲醇於二氯甲烷中)之combi flash進行純化，得到呈灰白色固體狀之實例1 (1.6 g，98%純度)。滯留時間：0.67 min；MS：340.1 (M+1)+
;1
H NMR (DMSO-d6/D2
O) δ= 8.52 (1 H, s), 8.11 (1 H, m), 7.72-7.62 (3 H, m), 7.56 (1 H, m), 7.41 (2 H, m), 7.18 (1 H, m), 6.90 (1 H, m)。實例 2 之合成 4 -(( 2 - 氯苯基 ) 胺基 )- 6 -(( 6 - 甲基吡啶 - 2 - 基 ) 胺基 ) 菸鹼醯胺： 在25℃下向3
(5.9 g，20.9 mmol)於二噁烷(150 mL)中之攪拌溶液中添加4
(3.39 g，31.4 mmol)、Cs2
CO3
(17 g，52.3 mmol)、Pd2
(dba)3
(1.92 g，2.09 mmol)、BINAP (1.95 g，3.14 mmol)及三乙胺(4.4 mL，31.4 mmol)。使所得溶液脫氣且在100℃下加熱16小時。混合物用水稀釋，用乙酸乙酯萃取，用鹽水洗滌，用硫酸鈉乾燥，且在真空下濃縮。藉由使用40 g Silicycle管柱(4%甲醇於二氯甲烷中)之combi flash進行純化，得到呈灰白色固體狀之實例2 (2.9 g，99.5%純度)。滯留時間：0.74 min；MS：354.2 (M+1)+
;1
H NMR (DMSO-d6) δ= 10.84 (1 H, s), 8.60 (1 H, s), 8.35 (1 H, m), 7.80 (1 H, m), 7.59 (2 H, m), 7.41 (1 H, m), 7.25 (1 H, m), 6.73 (1 H, s)。 生物學部分 酶JAK分析。對於酶分析，在昆蟲細胞中表現活性激酶結構域之親和純化GST融合體(GST-JAK1 (866-1154)、GST-JAK2 (808-1132)、GST-JAK3 (811-1124)及GST-TYK2 (888-1187))或自Invitrogen (Carlsbad，USA)購買。使用8點化合物之連續稀釋液在384孔微量滴定盤中進行所有分析。藉由逐步添加每孔4.5 µl之2倍肽/ATP溶液及每孔4.5 µl之2倍酶溶液開始激酶反應。用於分析之最終ATP濃度對應於針對各別酶單獨判定之KmATP。分析緩衝液：50 mM HEPES、pH 7.5、1 mM DTT、0.02% Tween20、0.02% BSA、0.6% DMSO、10 mM β-甘油磷酸鹽及10 µM原釩酸鈉。特異性地調整其他組分以用於各別激酶分析：JAK1：16 nM酶、70 µM ATP、2 µM肽基質、12 mM MgCl2
。JAK2：1.8 nM酶、20 µM ATP、2 µM肽基質、9 mM MgCl2
。JAK3：13 nM酶、18 µM ATP、2 µM肽基質、1.5 mM MgCl2
。Tyk2：3.5 nM酶、35 µM ATP、2 µM肽基質、9 mM MgCl2
。停止溶液為100 mM HEPES、pH 7.5、5% DMSO、0.1%卡立珀(Caliper)包覆試劑、10 mM EDTA及0.015% Brij35。用於JAK2及Tyk2分析之肽基質為FITC-Ahx-KKSRGDYMTMQIG-NH2，且用於JAK2及JAK3分析之肽基質為羧基螢光素-Ahx-GGEEEEYFELVKKKK。將激酶反應在30℃下培育60分鐘且藉由添加每孔16 µl停止溶液而終止。在卡立珀LC3000工作站上使用卡立珀微流遷移率改變技術分離磷酸化肽與未磷酸化肽，且根據所形成之磷酸-肽的量計算激酶活性。 經由JAK酶分析判定IC50
數據：
效用部分 本發明化合物通常適用於預防或治療其中JAK起作用之病症或疾病，例如適用於選自以下之疾病或病症：過敏性疾病、呼吸道疾病(諸如哮喘及慢性阻塞性肺病(COPD))、類風濕性關節炎、全身性幼發型特發性關節炎(SOJIA)、痛風、尋常天疱瘡、特發性血小板減少性紫瘢、全身性紅斑性狼瘡症、多發性硬化症、重症肌無力、休格連氏症候群、栓塞性血小板減少性紫瘢、慢性自體免疫蕁麻疹、過敏症(異位性皮膚炎、接觸性皮膚炎、過敏性鼻炎)、動脈粥樣硬化、1型糖尿病、2型糖尿病、發炎性腸病、潰瘍性結腸炎、克羅恩氏病、胰臟炎、絲球體腎炎、古巴士德氏症候群、橋本氏甲狀腺炎、格雷氏疾病、抗體介導之移植排斥反應(AMR)、移植物抗宿主疾病、B細胞介導之超急性及急性或慢性移植排斥反應。 較佳地，本發明化合物尤其適用於預防及/或治療影響免疫系統或由免疫系統介導之疾病或病症。 劑量 對於上述用途，所需劑量當然將視投與模式、待治療之特定病狀及所需效果而變化。一般而言，每公斤體重約0.02 mg至25 mg之日劑量獲得全身性滿意結果。在較大哺乳動物(例如，人類)中所指示之日劑量通常可介於約0.2 mg至約2 g範圍內，宜(例如)以至多一日四次之分次劑量或以延緩形式投與。用於經口投與之合適的單位劑型通常可包含約0.1 mg至500 mg之活性成分。 投與途徑 本發明之化合物可藉由任何習知途徑投與，特定之非經腸途徑(例如，以可注射溶液或懸浮液形式)、經腸(例如，經口)途徑(例如，以錠劑或膠囊形式)、局部途徑(例如，以洗劑、凝膠、軟膏或乳膏形式，或以鼻用或栓劑形式)。局部投與可(例如)投與至皮膚。局部投與之另一形式可投與至眼睛。包含與至少一種醫藥學上可接受之載劑或稀釋劑結合之本發明化合物的醫藥組合物可藉由與醫藥學上可接受之載劑或稀釋劑混合以習知的方式製備。 本發明之化合物可以游離形式或以醫藥學上可接受之鹽形式投與。此等鹽或水合物可以習知的方式製備，且通常可展現與游離化合物大約相同的活性。 根據前述內容，本發明亦提供： (1)適用作藥物或適用作藥劑之本發明化合物或其醫藥學上可接受之鹽； (2)適用作JAK調節劑，例如適用於上文闡述之特定適應症中之任一者的本發明化合物或其醫藥學上可接受之鹽； (3)例如適用於上文闡述之適應症中之任一者的醫藥組合物，其包含本發明化合物或其醫藥學上可接受之鹽以及一或多種其對應的醫藥學上可接受之稀釋劑或載劑； (4)用於治療或預防其中JAK調節起作用或涉及JAK調節之疾病或病狀的方法，例如用於治療有需要之個體的上文所闡述之特定適應症中之任一者的方法，該方法包含向個體投與有效量的本發明化合物或其醫藥學上可接受之鹽； (5)本發明化合物或其醫藥學上可接受之鹽的用途，其係用於製造用以治療或預防其中JAK調節起作用或涉及JAK調節(例如，如上文所指示)之疾病或病狀的藥劑； 6)本發明化合物或其醫藥學上可接受之鹽的用途，其係用於治療或預防其中JAK調節起作用或涉及JAK調節(例如，如上文所指示)之疾病或病狀。 組合 式(I)化合物可作為唯一的活性成分投與或與其他藥物結合(例如，作為其他藥物之佐劑)投與，該等其他藥物例如：免疫抑制劑或免疫調節劑或其他抗炎劑，例如用於治療或預防同種移植或異種移植急性或慢性排斥反應或發炎性或自體免疫病症；或化學治療劑，例如惡性細胞抗增殖劑。舉例而言，式(I)化合物可與鈣調神經磷酸酶抑制劑(例如，環孢素A或FK 506)或mTOR抑制劑(例如，雷帕黴素(rapamycin))組合使用。 根據前述內容，本發明進一步提供： (7)如上文所定義之方法，其包含共同投與(例如，同時或依序投與)治療有效量的：a)式I化合物或其醫藥學上可接受之鹽；及b)第二原料藥，該第二原料藥(例如)適用於上文所闡述之特定適應症中之任一者； (8)組合(例如，套組)，其包含治療有效量的式I化合物或其醫藥學上可接受之鹽及第二原料藥，該第二原料藥(例如)如上文所揭示。 當本發明之化合物與(例如)如上文所揭示之其他免疫抑制劑/免疫調節劑、抗炎劑或抗贅生劑結合投與時，共同投與之藥物或藥劑的劑量必定將視所採用之共藥物或共藥劑的類型或所使用之特定藥物或藥劑或正治療之病狀等而變化。In its broadest embodiment (Example 1), the invention relates to a compound of formula (I) and/or a pharmaceutically acceptable salt thereof, as described in the Summary of the Invention section above. Embodiment 2 of the present invention relates to the compound of Embodiment 1, or a pharmaceutically acceptable salt thereof, wherein Hal is chlorine or fluorine. Embodiment 3 of the present invention pertains to the compound of Embodiment 1, or a pharmaceutically acceptable salt thereof, wherein Hal is chlorine. Embodiment 4 of the present invention relates to the compound of Embodiment 1, 2 or 3, or a pharmaceutically acceptable salt thereof, wherein R 1 is a methyl group. Embodiment 5 of the present invention relates to the compound of Embodiment 1, 2 or 3, or a pharmaceutically acceptable salt thereof, wherein R 1 is hydrogen. Embodiment 6 of the present invention relates to the compound of Embodiment 1, 2, 3 or 4, or a pharmaceutically acceptable salt thereof, wherein R 1 is a methyl group at position 6 of the associated bipyridyl ring. Embodiment 7 of the present invention relates to the compound of Embodiment 1 or 4 or a pharmaceutically acceptable salt thereof, the pharmaceutically acceptable salt being selected from the group consisting of 4-((2-chlorophenyl)amino)- 6-(pyridin-2-ylamino) Nicotinamide and 4-((2-chlorophenyl)amino)-6-((6-methylpyridin-2-yl)amino)nicotinium amine. Embodiment 8 is directed to a pharmaceutical composition comprising a therapeutically effective amount of a compound according to any one of embodiments 1 to 7 and one or more pharmaceutically acceptable carriers. Embodiment 9 relates to a combination comprising a therapeutically effective amount of a compound according to any one of embodiments 1 to 7, or a pharmaceutically acceptable salt thereof, and one or more therapeutically active adjuvants. Embodiment 10 is a method for modulating JAK activity in an individual, wherein the method comprises administering to the individual a therapeutically effective amount of a compound according to any one of embodiments 1 to 7 or a pharmaceutically acceptable salt thereof. Embodiment 11 relates to a compound according to any one of embodiments 1 to 7 or a pharmaceutically acceptable salt thereof, which is suitable for use as a medicament. Definitions As used herein, the term "C 1 -C 6 alkyl" refers to a fully saturated branched or unbranched hydrocarbon moiety having up to 6 carbon atoms. Unless otherwise indicated, it refers to a hydrocarbon moiety having from 1 to 6 carbon atoms, from 1 to 4 carbon atoms, or from 1 to 2 carbon atoms. Representative examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, tert-butyl, n-pentyl, isuf Base, neopentyl, n-hexyl and the like. As used herein, the term "halogen" or "halo" refers to fluoro, chloro, bromo and iodo; and may especially refer to chloro and fluoro. As used herein, the term "salt" refers to an acid or base addition salt of a compound of the invention. "Salt" includes, inter alia, "pharmaceutically acceptable salts." The term "pharmaceutically acceptable salts" refers to salts which retain the biological utility and properties of the compounds of the invention and which are generally required biologically or otherwise. In many cases, the compounds of the invention are capable of forming acid and/or base salts by virtue of the presence of amine groups and/or carboxyl groups or the like. The pharmaceutically acceptable acid addition salts can be formed from inorganic acids and organic acids such as acetates, chlorides/hydrochlorides, citrates, fumarates, tartrates, toluenes. Sulfonate and trifluoroacetate. Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like. Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, Mandelic acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, sulfosalicylic acid and the like. The pharmaceutically acceptable salts of the present invention can be synthesized from basic or acidic moieties by conventional chemical methods. In general, the salts can be obtained by subjecting the free acid form of such compounds to a stoichiometric amount of a suitable base such as a hydroxide, carbonate, bicarbonate or the like of Na, Ca, Mg or K. The reaction is prepared by reacting the free base form of such compounds with a stoichiometric amount of the appropriate acid. These reactions are usually carried out in water or in an organic solvent or in a mixture of the two. In general, when practicable, it is desirable to use a non-aqueous medium such as ether, ethyl acetate, ethanol, isopropanol or acetonitrile. Examples of other suitable salts can be found, for example, in "Remington's Pharmaceutical Sciences", 20th Edition, Mack Publishing Company, Easton, Pa., (1985); and "Handbook of Pharmaceutical Salts: Properties, Selection, and Use", Stahl and Wermuth (Wiley-VCH, Weinheim, Germany, 2002). Any formula given herein is also intended to indicate the unlabeled form of the compound as well as the isotopically labeled form. An isotopically labeled compound has a structure depicted by the formula given herein except that one or more atoms are replaced by an atom having a selected atomic mass or mass number. Examples of isotopes which may be incorporated into the compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine, such as 2 H, 3 H, 11 C, 13 C, 14 C, 15 N, 18 F, respectively. , 31 P, 32 P, 35 S, 36 Cl, 125 I. The invention includes various isotopically-labeled compounds as defined herein, such as compounds in which radioisotopes such as 3 H and 14 C are present, or in which non-radioactive isotopes such as 2 H and 13 C are present Compound. These isotopically labeled compounds are suitable for metabolic studies (using 14 C), reaction kinetic studies (using, for example, 2 H or 3 H), detection or imaging techniques (such as positrons including drug or matrix distribution analysis) Emission tomography (PET) or single photon emission computed tomography (SPECT), or for radiotherapy of patients. In particular, 18 F or labeled compounds may be particularly desirable for PET or SPECT studies. Isotopically labeled compounds of formula (I) can generally be prepared by conventional techniques known to those skilled in the art, or by methods analogous to those described in the accompanying examples and preparations. Isotopically labeled reagents are prepared in place of previously unlabeled reagents. In addition, substitution with heavier isotopes (specifically ( 2 H or D)) may result in certain therapeutic advantages resulting from higher metabolic stability, such as increased in vivo half-life or reduced dose requirements or therapeutic index. Improvement. It will be understood that in this context, hydrazine is considered to be a substituent of the compound of formula (I). The concentration of such heavier isotopes (specifically) can be defined by isotopic enrichment factors. The term "isotopic enrichment factor" as used herein means the ratio between the isotope abundance of a given isotope and the natural abundance. If the substituent in the compound of the present invention is labeled as hydrazine, the isotope enrichment factor of each of the specified ruthenium atoms of the compound is at least 3,500 (incorporating 52.5% 各 at each designated ruthenium atom), at least 4000 (60%)氘Incorporated), at least 4500 (67.5% 氘 incorporation), at least 5000 (75% 氘 incorporation), at least 5500 (82.5% 氘 incorporation), at least 6000 (90% 氘 incorporation), at least 6333.3 (95%氘Incorporated), at least 6466.7 (97% 氘 incorporation), at least 6600 (99% 氘 incorporation) or at least 6633.3 (99.5% 氘 incorporation). The pharmaceutically acceptable solvates according to the invention include those in which the solvent of the crystals can be isotopically substituted, such as D 2 O, d 6 -acetone, d 6 -DMSO. The compounds of the invention, i.e., compounds of formula (I) containing a group capable of acting as a donor and/or acceptor for hydrogen bonding, may be capable of forming a eutectic with a suitable eutectic former. Such co-crystals can be prepared from compounds of formula (I) by known eutectic formation procedures. Such procedures include grinding, heating, co-subliming, co-melting or contacting a compound of formula (I) with a eutectic forming agent in solution under crystallization conditions, and isolating the eutectic formed thereby. Suitable eutectic formers include those eutectic formers described in WO 2004/078163. The invention therefore further provides a eutectic comprising a compound of formula (I). As used herein, the term "pharmaceutically acceptable carrier" includes any and all solvents, dispersion media, coatings, surfactants, antioxidants, preservatives (eg, antibodies known to those skilled in the art). Bacterial agents, antifungal agents), isotonic agents, absorption delaying agents, salts, preservatives, drug stabilizers, binders, excipients, disintegrating agents, lubricants, sweeteners, flavoring agents, pigments and the like And combinations thereof (see, for example, Remington's Pharmaceutical Sciences, 18th ed., Mack Printing Company, 1990, pages 1289 to 1329). Unless any of the conventional carriers are incompatible with the active ingredient, their use in therapeutic or pharmaceutical compositions is contemplated. The term "therapeutically effective amount" of a compound of the invention refers to the amount of a compound of the invention which will induce a biological or medical response in an individual, such as reducing or inhibiting the activity of an enzyme or protein or ameliorating symptoms, ameliorating the condition, slowing down Or delay disease progression or prevent disease. In one non-limiting embodiment, the term "therapeutically effective amount" refers to an amount of a compound of the invention that has the following utility when administered to an individual: (1) effective at least partially alleviating, inhibiting, preventing, and/or ameliorating (i) a condition or disorder or disease mediated by JAK or (ii) associated with JAK activity or (iii) characterized by JAK activity (normal or abnormal); or (2) effective reduction or inhibition of JAK Activity; or (3) effectively reducing or inhibiting the performance of JAK. In another non-limiting embodiment, the term "therapeutically effective amount" refers to an amount of a compound of the invention that has the following utility when administered to a cell or tissue or non-cellular biological material or medium: effectively at least partially reduced or Inhibiting the activity of JAK; or effectively partially or completely reducing or inhibiting the performance of JAK. As used herein, the term "individual" refers to an animal. Typically, the animal is a mammal. An individual also refers to, for example, a primate (eg, human, male or female), cow, sheep, goat, horse, dog, cat, rabbit, rat, mouse, fish, bird, and the like. In certain embodiments, the individual is a primate. In other embodiments, the individual is a human. As used herein, the term "inhibition/inhibition/inhibiting" refers to reducing or arresting a given condition, symptom or condition or disease, or significantly reducing the baseline activity of a biological activity or process. As used herein, the term "treat/treating/treatment" in any embodiment refers to amelioration of a disease or condition (ie, slowing or arresting or reducing the progression of a disease or at least one of its clinical symptoms). . In another embodiment, "treating" refers to alleviating or ameliorating at least one physiological parameter, including physiological parameters that the patient may not be able to discern. In yet another embodiment, "treating" refers to modulating a disease or condition both physically (eg, identifiable by the stabilization of symptoms), physiologically (eg, stabilization of body parameters), or both. In yet another embodiment, "treating" refers to preventing or delaying the onset or progression or progression of a disease or condition. As used herein, an individual "needs" the treatment if the individual will benefit from treatment in biology, medicine, or quality of life. As used herein, the terms "a/an" and "the" are used in the context of the present invention (especially in the context of the claims) unless the context clearly indicates otherwise. And similar terms are to be construed as covering both singular and plural. All methods described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted. The use of any and all examples or exemplary language, such as "such as" or "an" Any asymmetric atom of one or more compounds of the invention (e.g., carbon or the like) may exist in the form of racemic or enantiomeric enrichment, such as ( R ) configuration, ( S ) configuration or ( R , S ) configuration. In certain embodiments, each asymmetric atom has at least 50% enantiomeric excess, at least 60% enantiomeric excess, at least 70% enantiomeric in the ( R ) configuration or ( S ) configuration. The isomer excess, at least 80% enantiomeric excess, at least 90% enantiomeric excess, at least 95% enantiomeric excess, or at least 99% enantiomeric excess. Atom having an unsaturated double bond of the substituent groups, if possible in places cis - (Z) - or trans - (E) - forms. Thus, as used herein, the compounds of the present invention may be in the form of a respective one of the following possibilities are those of: rotamers, slow turn isomers, tautomers, geometric (cis or trans) iso A conformation, a diastereomer, an optical isomer (enantiomer), a racemate or a mixture thereof. Mixtures of any of the resulting isomers can be separated into pure or substantially pure geometric or optical isomers, diastereomers, racemates based on physicochemical differences of the components, for example by chromatography and / or step by step. Any resulting end product or intermediate racemate can be resolved into the optical enantiomer by known methods, for example by separation of its diastereomeric salt (which is obtained from an optically active acid or base) and Release of optically active acidic or basic compounds. In particular, the basic moiety can thus be used to resolve a compound of the invention into its optical enantiomer, for example a salt formed by optically active acid by fractional crystallization, such as tartaric acid, benzoic acid tartaric acid, di-acetyl tartaric acid, di - O, O '- methyl p acyl tartaric, mandelic acid, malic acid or camphor-10-sulfonic acid. Racemic products can also be resolved by palm chromatography, for example using high pressure liquid chromatography (HPLC) on the palmitic stationary phase. Further, the compounds of the present invention (including salts thereof) may also be obtained in the form of their hydrates or include other solvents for their crystallization. The compounds of the invention may be inherently or designed to form solvates with pharmaceutically acceptable solvents, including water; therefore, the invention is intended to encompass both solvated and unsolvated forms. The term "solvate" refers to a molecular complex of a compound of the invention, including a pharmaceutically acceptable salt thereof, with one or more solvent molecules. Such solvent molecules are those solvent molecules commonly used in medical technology that are known to be harmless to the recipient, such as water, ethanol, and the like. The term "hydrate" refers to a complex in which the solvent molecule is water. The compounds of the invention, including their salts, hydrates and solvates, may be inherently or designed to form polymorphs. In another aspect, the invention provides a pharmaceutical composition comprising a compound of the invention and a pharmaceutically acceptable carrier. The pharmaceutical composition can be formulated for specific administration routes such as oral administration, parenteral administration, and rectal administration. In addition, the pharmaceutical compositions of the present invention can be formulated into solid forms (including but not limited to capsules, troches, pills, granules, powders or suppositories) or in liquid form (including but not limited to solutions, suspensions or emulsions). ). The pharmaceutical compositions may be subjected to conventional pharmaceutical operations such as sterilization and/or such pharmaceutical compositions may contain conventional inert diluents, lubricants or buffers, and adjuvants such as preservatives, stabilizers, wetting agents, emulsifying agents. Agents and buffers, etc.). The pharmaceutical composition is usually a tablet or gelatin capsule containing the active ingredient and the following: a) a diluent such as lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and/or glycine; b) a lubricant For example, cerium oxide, talc, stearic acid, magnesium or calcium stearate and/or polyethylene glycol; for tablets, also c) binders such as magnesium aluminum silicate, starch paste, gelatin , scutellaria, methylcellulose, sodium carboxymethylcellulose and/or polyvinylpyrrolidone; if necessary, d) a disintegrant such as starch, agar, alginic acid or a sodium salt thereof, or a foaming mixture; / or e) adsorbents, colorants, flavoring agents and sweeteners. Tablets can be coated with a film or an enteric coating according to methods known in the art. Suitable compositions for oral administration include an effective amount of a compound of the invention in the form of a lozenge, a buccal, an aqueous or oily suspension, a dispersible powder or granule, an emulsion, a hard or soft capsule or a syrup or The form of tincture. Compositions intended for oral use are prepared according to any method known in the art for the manufacture of pharmaceutical compositions, and such compositions may contain one or more selected from the group consisting of sweeteners, flavoring agents, coloring agents. And a group of preservatives to provide a pharmaceutically elegant and palatable preparation. Tablets may contain admixtures of the active ingredient withpharmaceutically acceptable non-toxic excipients suitable for the manufacture of lozenges. For example, such excipients are inert diluents such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating agents and disintegrating agents such as corn starch or alginic acid; binders such as starch, Gelatin or gum arabic; and a lubricant such as magnesium stearate, stearic acid or talc. The tablets are uncoated or coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period of time. For example, a time delay material such as glyceryl monostearate or glyceryl distearate may be employed. The formulations for oral use can be presented in the form of hard gelatin capsules or soft gelatin capsules in which the active ingredient is mixed with an inert solid diluent such as calcium carbonate, calcium phosphate or kaolin. In soft gelatin capsules, the active ingredient is mixed with a water or oil medium such as peanut oil, liquid paraffin or olive oil. Certain injectable compositions are aqueous isotonic solutions or suspensions, and suppositories are preferably prepared from a fat emulsion or suspension. The compositions may be sterilized and/or contain adjuvants such as preservatives, stabilizers, wetting or emulsifying agents, dissolution promoters, salts for regulating osmotic pressure and/or buffers. In addition, it may also contain other therapeutically valuable substances. The compositions are prepared according to conventional mixing, granulating or coating methods and contain from about 0.1% to about 75% of the active ingredient or from about 1% to about 50% of the active ingredient. Suitable compositions for transdermal administration comprise an effective amount of a compound of the invention and a suitable carrier. Carriers suitable for transdermal delivery include absorbable, pharmacologically acceptable solvents to aid passage through the skin of the host. By way of example, the transdermal device is in the form of a bandage comprising a substrate component, a reservoir containing a compound (as appropriate with the carrier), optionally over a prolonged period of time to deliver the host skin at a controlled and predetermined rate The rate of the compound controls the barrier and the means for securing the device to the skin. Suitable compositions for topical application (e.g., to the skin and eyes) include aqueous solutions, suspensions, ointments, creams, gels or sprayable formulations delivered, for example, by sprays or the like. . Such topical delivery systems will be particularly suitable for transdermal administration, for example for the treatment of skin cancer, for example with sunscreens, lotions, sprays and the like for prophylactic use. Thus, it is particularly suitable for topical (including make-up) formulations well known in the art. These formulations may contain solubilizers, stabilizers, tonicity enhancing agents, buffers, and preservatives. Topical administration, as used herein, may also involve inhalation or intranasal administration. It may suitably be delivered as a dry powder (either alone in the form of a mixture (eg, an anhydrous blend with lactose) or as a mixed component particle (eg, with a phospholipid)) from a dry powder inhaler, or in the form of a spray spray or Delivery from a pressurized container, pump, ejector, nebulizer or nebulizer without the use of a suitable propellant. The present invention further provides anhydrous pharmaceutical compositions and dosage forms comprising the compound of the present invention as an active ingredient because water promotes degradation of certain compounds. The anhydrous pharmaceutical compositions and dosage forms of the present invention can be prepared using anhydrous or low moisture containing ingredients with lower moisture or lower humidity conditions. Anhydrous pharmaceutical compositions can be prepared and stored to maintain their anhydrous character. Thus, the anhydrous composition is encapsulated using a material known to prevent exposure to water such that it can be included in a suitable formulary kit. Examples of suitable packages include, but are not limited to, hermetic sealing foils, plastics, unit dose containers (eg, vials), blister packs, and strip packs. The invention further provides pharmaceutical compositions and dosage forms comprising one or more agents that reduce the rate at which the compound of the invention will decompose as an active ingredient. Such agents referred to herein as "stabilizers" include, but are not limited to, antioxidants such as ascorbic acid, pH buffers or salt buffers, and the like. Experimental part Abbreviation: BINAP: (2,2'-bis(diphenylphosphino)-1,1'-binaphthyl) Cs 2 CO 3 : cesium carbonate DMSO: dimethyl hydrazine g: g hr h: hour NaHMDS: double (trimethyldecyl) guanamine sodium min: minute MS: mass spectrum mL or ml: ml Pd 2 (dba) 3 : ginseng (dibenzylideneacetone) dipalladium (0) THF: tetrahydrofuran UPLC: ultra-performance liquid phase Chromatographic method Liquid chromatography : UPLC/MS: Waters Acquity UPLC + Waters ZQ2000 MS UV-PDA: 210 - 450 nM MS range: 100-1200 Da Column: Acquity HSS T3 2.1 × 50 mm 1.8 μ 60 °C mobile phase: A: water +0.05% formic acid B: acetonitrile + 0.04% formic acid Intermediate 3 Synthesis of 6 - chloro --4-- ((2 - chlorophenyl) amino) nicotinic Amides: Add bis(trimethyldecyl) decylamine (NaHMDS) dropwise to a solution of 1 (9.3 g, 48.7 mmol) and 2 (7.68 mL, 73 mmol) in THF (100 mL) at 0 °C The solution was stirred in THF (340.8 mL), and the mixture was stirred at 25 ° C for 3 hr under nitrogen atmosphere. The mixture was quenched with EtOAc (EtOAc)EtOAc. The crude product was stirred with diethyl ether (200 mL) for 0.5 h and are filtered to give a light yellow solid of 3 (12.8 g, 95% purity). MS: 282.0 (M+1) + ; 1 H NMR (DMSO-d6) δ= 8.52 (1H, s), 11.00 (1 H, s), 9.74 (1 H, m), 8.59 (1 H, s ), 8.09 (2 H, m), 7.70 (1 H, d), 7.59 (1 H, d), 7.52 (1 H, t), 7.43 (1 H, t), 7.40 (1 H, m), 7.17 (2 H, m), 6.72 (1 H, d), 2.26 (3 H, s). Example 1 Synthesis of 4 - ((2 - chlorophenyl) amino) - 6 - (pyridin - 2 - ylamino) niacinamide: Add 4 (2.95 g, 31.4 mmol), Cs 2 CO 3 (17 g, 52.3 mmol), Pd 2 to a stirred solution of 3 (5.9 g, 20.9 mmol) in dioxane (150 mL) at 25 °C (dba) 3 (1.92 g, 2.09 mmol), BINAP (1.95 g, 3.14 mmol) and triethylamine (4.4 mL, 31.4 mmol). The resulting solution was degassed and heated at 100 ° C for 16 hours. The mixture was diluted with EtOAc (EtOAc)EtOAc. Purification by combi flash using a 40 g EtOAc EtOAc (EtOAc) Retention time: 0.67 min; MS: 340.1 (M+1) + ; 1 H NMR (DMSO-d6/D 2 O) δ = 8.52 (1 H, s), 8.11 (1 H, m), 7.72-7.62 ( 3 H, m), 7.56 (1 H, m), 7.41 (2 H, m), 7.18 (1 H, m), 6.90 (1 H, m). Example 2 Synthesis of 4 - ((2 - chlorophenyl) amino) - 6 - ((6 - methyl pyridin - 2 - yl) amino) niacinamide: Add 4 (3.39 g, 31.4 mmol), Cs 2 CO 3 (17 g, 52.3 mmol), Pd 2 to a stirred solution of 3 (5.9 g, 20.9 mmol) in dioxane (150 mL) at 25 °C. (dba) 3 (1.92 g, 2.09 mmol), BINAP (1.95 g, 3.14 mmol) and triethylamine (4.4 mL, 31.4 mmol). The resulting solution was degassed and heated at 100 ° C for 16 hours. The mixture was diluted with EtOAc (EtOAc)EtOAc. Purification by combi flash using a 40 g EtOAc EtOAc (EtOAc) Retention time: 0.74 min; MS: 354.2 (M+1) + ; 1 H NMR (DMSO-d6) δ = 10.84 (1 H, s), 8.60 (1 H, s), 8.35 (1 H, m), 7.80 (1 H, m), 7.59 (2 H, m), 7.41 (1 H, m), 7.25 (1 H, m), 6.73 (1 H, s). Biological part of the enzyme JAK analysis. For enzyme analysis, affinity purified GST fusions (GST-JAK1 (866-1154), GST-JAK2 (808-1132), GST-JAK3 (811-1124) and GST-TYK2 expressing active kinase domains in insect cells (888-1187)) or purchased from Invitrogen (Carlsbad, USA). All analyses were performed in a 384 well microtiter plate using serial dilutions of 8-point compounds. The kinase reaction was initiated by stepwise addition of 4.5 μl of 2 times peptide/ATP solution per well and 4.5 μl of 2 times enzyme solution per well. The final ATP concentration for analysis corresponds to KmATP determined separately for each enzyme. Assay buffer: 50 mM HEPES, pH 7.5, 1 mM DTT, 0.02% Tween 20, 0.02% BSA, 0.6% DMSO, 10 mM β-glycerophosphate and 10 μM sodium orthovanadate. The other components were specifically adjusted for individual kinase analysis: JAK1: 16 nM enzyme, 70 μM ATP, 2 μM peptide matrix, 12 mM MgCl 2 . JAK2: 1.8 nM enzyme, 20 μM ATP, 2 μM peptide matrix, 9 mM MgCl 2 . JAK3: 13 nM enzyme, 18 μM ATP, 2 μM peptide matrix, 1.5 mM MgCl 2 . Tyk2: 3.5 nM enzyme, 35 μM ATP, 2 μM peptide matrix, 9 mM MgCl 2 . The stop solution was 100 mM HEPES, pH 7.5, 5% DMSO, 0.1% Caliper coated reagent, 10 mM EDTA and 0.015% Brij35. The peptide matrix for JAK2 and Tyk2 analysis was FITC-Ahx-KKSRGDYMTMQIG-NH2, and the peptide matrix for JAK2 and JAK3 analysis was carboxyfluorescein-Ahx-GGEEEEYFELVKKKK. The kinase reaction was incubated at 30 ° C for 60 minutes and terminated by the addition of 16 μl stop solution per well. The phosphorylated peptide and the unphosphorylated peptide were separated using a Cariper microfluid mobility shifting technique on a Carlyle LC3000 workstation, and the kinase activity was calculated based on the amount of phosphopeptide-form formed. IC 50 is determined via the JAK enzyme analysis of data: Utility Part The compounds of the present invention are generally suitable for the prevention or treatment of a condition or disease in which JAK plays a role, for example, for a disease or condition selected from the group consisting of an allergic disease, a respiratory disease (such as asthma and chronic obstructive pulmonary disease (COPD)), Rheumatoid arthritis, systemic juvenile idiopathic arthritis (SOJIA), gout, pemphigus vulgaris, idiopathic thrombocytopenic purpura, systemic lupus erythematosus, multiple sclerosis, myasthenia gravis, Hugh's syndrome, embolic thrombocytopenic purpura, chronic autoimmune urticaria, allergies (atopic dermatitis, contact dermatitis, allergic rhinitis), atherosclerosis, type 1 diabetes, 2 Type 2 diabetes, inflammatory bowel disease, ulcerative colitis, Crohn's disease, pancreatitis, spheroid nephritis, Gubus syndrome, Hashimoto's thyroiditis, Gracie's disease, antibody-mediated transplant rejection ( AMR), graft versus host disease, B cell mediated hyperacute and acute or chronic graft rejection. Preferably, the compounds of the invention are especially useful for the prevention and/or treatment of diseases or conditions that affect or are mediated by the immune system. Dosage For the above uses, the required dose will of course vary depending on the mode of administration, the particular condition being treated, and the desired effect. In general, a systemic satisfactory result is obtained at a daily dose of about 0.02 mg to 25 mg per kilogram of body weight. The daily dose indicated in a larger mammal (e.g., a human) can generally range from about 0.2 mg to about 2 g, preferably, for example, in divided doses of up to four times a day or in a delayed form. . Suitable unit dosage forms for oral administration will generally contain from about 0.1 mg to 500 mg of the active ingredient. Routes of Administration The compounds of the present invention can be administered by any conventional route, either parenterally (for example, in the form of injectable solutions or suspensions) or enterally (for example, orally) (for example, ingots). Or a topical route (for example, in the form of a lotion, gel, ointment or cream, or in the form of a nasal or suppository). Local administration can, for example, be administered to the skin. Another form of local administration can be administered to the eye. A pharmaceutical composition comprising a compound of the invention in combination with at least one pharmaceutically acceptable carrier or diluent can be prepared in a conventional manner by mixing with a pharmaceutically acceptable carrier or diluent. The compounds of the invention may be administered in free form or in the form of a pharmaceutically acceptable salt. Such salts or hydrates can be prepared in a conventional manner and generally exhibit about the same activity as the free compound. In accordance with the foregoing, the present invention also provides: (1) a compound of the present invention or a pharmaceutically acceptable salt thereof suitable for use as a medicament or a pharmaceutical agent; (2) suitable for use as a JAK modulator, for example, as specified above. A compound of the present invention, or a pharmaceutically acceptable salt thereof, in any one of the indications; (3) a pharmaceutical composition, for example, suitable for use in any of the indications set forth above, comprising a compound of the present invention or a pharmaceutically acceptable salt and one or more of its corresponding pharmaceutically acceptable diluents or carriers; (4) A method for treating or preventing a disease or condition in which JAK regulation acts or involves JAK regulation A method, for example, for treating any of the specific indications set forth above for an individual in need thereof, the method comprising administering to the individual an effective amount of a compound of the invention or a pharmaceutically acceptable salt thereof; 5) Use of a compound of the present invention or a pharmaceutically acceptable salt thereof for the manufacture of a disease or condition for the treatment or prevention of JAK regulation or involving JAK regulation (for example, as indicated above) Pharmacy; 6) Ben Use of a compound of the invention, or a pharmaceutically acceptable salt thereof, for the treatment or prevention of a disease or condition in which JAK regulation is active or involved in JAK regulation (e.g., as indicated above). The compound of formula (I) may be administered as the sole active ingredient or in combination with other drugs (for example, as adjuvants for other drugs) such as immunosuppressants or immunomodulators or other anti-inflammatory agents. For example, for the treatment or prevention of acute or chronic rejection of an allograft or xenograft or an inflammatory or autoimmune disorder; or a chemotherapeutic agent, such as a malignant cell antiproliferative. For example, a compound of formula (I) can be used in combination with a calcineurin inhibitor (eg, cyclosporin A or FK 506) or an mTOR inhibitor (eg, rapamycin). In accordance with the foregoing, the present invention further provides: (7) A method as defined above, comprising co-administering (e.g., simultaneously or sequentially) a therapeutically effective amount: a) a compound of formula I or a pharmaceutically acceptable compound thereof a salt to be accepted; and b) a second drug substance, for example, suitable for use in any of the specific indications set forth above; (8) a combination (eg, a kit) comprising a treatment An effective amount of a compound of formula I, or a pharmaceutically acceptable salt thereof, and a second drug substance, for example, as disclosed above. When a compound of the invention is administered in combination with, for example, other immunosuppressive/immunomodulatory, anti-inflammatory or anti-neoplastic agents as disclosed above, the dose of the co-administered drug or agent will necessarily be The type of the co-drug or co-agent or the particular drug or agent used or the condition being treated, etc., varies.