JP2008069149A - Combination therapy for rheumatoid arthritis - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a pharmaceutical combination therapy for the treatment or prevention of arthritis, such as human rheumatoid arthritis. <P>SOLUTION: The pharmaceutical combination therapy comprises co-administrating a Janus Kinase inhibitor or a pharmaceutically acceptable salt thereof and at least one anti-arthritic agent or a pharmaceutically acceptable salt thereof. The Janus Kinase inhibitor is preferably a 7H-pyrrolo[2,3-d]pyrimidine derivative and, concretely, 3-ä(3R, 4R)-4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidin-1-yl}-3-oxo-propionitrile or a pharmaceutically acceptable salt thereof is illustrated as a preferable compound. <P>COPYRIGHT: (C)2008,JPO&INPIT

Description

  The present disclosure relates to Janus kinases such as the currently disclosed pyrrolo [2,3-d] pyrimidine compounds that are inhibitors of protein kinases such as the enzyme Janus kinase 3 (sometimes referred to herein as JAK3). Drug combination therapy for the treatment or prevention of human arthritic disorders or symptoms, such as rheumatoid arthritis, comprising an inhibitor or a pharmaceutically acceptable salt thereof and at least one anti-arthritic agent or a pharmaceutically acceptable salt thereof About. The present disclosure also relates to methods for the treatment or prevention of such arthritic disorders or symptoms and the use of such drug combination therapies and pharmaceutical compositions thereof.

  JAK3 is a member of the Janus family of protein kinases. While other members of this family are expressed in essentially all tissues, JAK3 expression is restricted to hematopoietic cells. This is due to the unsharedness of JAK3 and the gamma chain common to these multi-chain receptors via receptors for IL-2, IL-4, IL-7, IL-9, IL-15, and IL-21. Consistent with its essential role in binding signaling. The SCID patient population has been confirmed to show a severe decrease in JAK3 protein levels or a genetic deficiency for the common gamma chain, suggesting that immunosuppression should result from blocking signaling through the JAK3 pathway. The Not only does JAK3 play an important role in B and T lymphocyte maturation, but animal studies have suggested that JAK3 is constitutively required to maintain T cell function. Modulation of immune activity by this novel mechanism can prove useful in the treatment of transplant rejection and autoimmune diseases such as T cell proliferative disorders such as rheumatoid arthritis.

  Previous methods of treating or preventing rheumatoid arthritis using a pyrrolo [2,3-d] pyrimidine compound are described in US Pat. No. 7,091,91, the contents of which are hereby incorporated by reference. No. 208. Some pyrrolo [2,3-d] pyrimidine compounds discussed herein are disclosed in US Pat. No. 6,627,754 and US Pat. No. 6,627,754, both of which are hereby incorporated by reference. It is also discussed in Publication 2003/0073719. Several drug combination therapies, including some Janus kinase inhibitors such as the pyrrolo [2,3-d] pyrimidine compounds disclosed at present, treat human arthritic disorders or symptoms such as arthritis including rheumatoid arthritis Or it has now been found to be effective for prevention.

  In one aspect, the disclosure provides for the treatment or prevention of human rheumatoid arthritis comprising a Janus kinase inhibitor or a pharmaceutically acceptable salt thereof and at least one anti-arthritic agent or a pharmaceutically acceptable salt thereof. Related to drug combination therapy.

  In some embodiments, the Janus kinase inhibitor has the formula

の化合物またはその薬学的に許容できる塩であり、式中、
Ｒ^１は、式

Or a pharmaceutically acceptable salt thereof, wherein:
R ¹ is the formula

の基であり、
式中、ｙは、０、１または２であり、
Ｒ^４は、水素、（Ｃ_１〜Ｃ_６）アルキル、（Ｃ_１〜Ｃ_６）アルキルスルホニル、（Ｃ_２〜Ｃ_６）アルケニル、（Ｃ_２〜Ｃ_６）アルキニルからなる群から選択され、そのアルキル、アルケニルおよびアルキニル基は、重水素、ヒドロキシ、アミノ、トリフルオロメチル、（Ｃ_１〜Ｃ_４）アルコキシ、（Ｃ_１〜Ｃ_６）アシルオキシ、（Ｃ_１〜Ｃ_６）アルキルアミノ、（（Ｃ_１〜Ｃ_６）アルキル）_２アミノ、シアノ、ニトロ、（Ｃ_２〜Ｃ_６）アルケニル、（Ｃ_２〜Ｃ_６）アルキニルまたは（Ｃ_１〜Ｃ_６）アシルアミノで置換されていてもよく、あるいはＲ^４は、（Ｃ_３〜Ｃ_１０）シクロアルキルであり、そのシクロアルキル基は、重水素、ヒドロキシ、アミノ、トリフルオロメチル、（Ｃ_１〜Ｃ_６）アシルオキシ、（Ｃ_１〜Ｃ_６）アシルアミノ、（Ｃ_１〜Ｃ_６）アルキルアミノ、（（Ｃ_１〜Ｃ_６）アルキル）_２アミノ、シアノ、シアノ（Ｃ_１〜Ｃ_６）アルキル、トリフルオロメチル（Ｃ_１〜Ｃ_６）アルキル、ニトロ、ニトロ（Ｃ_１〜Ｃ_６）アルキルまたは（Ｃ_１〜Ｃ_６）アシルアミノで置換されていてもよく、
Ｒ^５は、（Ｃ_２〜Ｃ_９）ヘテロシクロアルキルであり、そのヘテロシクロアルキル基は、１〜５個のカルボキシ、シアノ、アミノ、重水素、ヒドロキシ、（Ｃ_１〜Ｃ_６）アルキル、（Ｃ_１〜Ｃ_６）アルコキシ、ハロ、（Ｃ_１〜Ｃ_６）アシル、（Ｃ_１〜Ｃ_６）アルキルアミノ、アミノ（Ｃ_１〜Ｃ_６）アルキル、（Ｃ_１〜Ｃ_６）アルコキシ−ＣＯ−ＮＨ、（Ｃ_１〜Ｃ_６）アルキルアミノ−ＣＯ−、（Ｃ_２〜Ｃ_６）アルケニル、（Ｃ_２〜Ｃ_６）アルキニル、（Ｃ_１〜Ｃ_６）アルキルアミノ、アミノ（Ｃ_１〜Ｃ_６）アルキル、ヒドロキシ（Ｃ_１〜Ｃ_６）アルキル、（Ｃ_１〜Ｃ_６）アルコキシ（Ｃ_１〜Ｃ_６）アルキル、（Ｃ_１〜Ｃ_６）アシルオキシ（Ｃ_１〜Ｃ_６）アルキル、ニトロ、シアノ（Ｃ_１〜Ｃ_６）アルキル、ハロ（Ｃ_１〜Ｃ_６）アルキル、ニトロ（Ｃ_１〜Ｃ_６）アルキル、トリフルオロメチル、トリフルオロメチル（Ｃ_１〜Ｃ_６）アルキル、（Ｃ_１〜Ｃ_６）アシルアミノ、（Ｃ_１〜Ｃ_６）アシルアミノ（Ｃ_１〜Ｃ_６）アルキル、（Ｃ_１〜Ｃ_６）アルコキシ（Ｃ_１〜Ｃ_６）アシルアミノ、アミノ（Ｃ_１〜Ｃ_６）アシル、アミノ（Ｃ_１〜Ｃ_６）アシル（Ｃ_１〜Ｃ_６）アルキル、（Ｃ_１〜Ｃ_６）アルキルアミノ（Ｃ_１〜Ｃ_６）アシル、（（Ｃ_１〜Ｃ_６）アルキル）_２アミノ（Ｃ_１〜Ｃ_６）アシル、Ｒ^１５Ｒ^１６Ｎ−ＣＯ−Ｏ−、Ｒ^１５Ｒ^１６Ｎ−ＣＯ−（Ｃ_１〜Ｃ_６）アルキル、（Ｃ_１〜Ｃ_６）アルキル−Ｓ（Ｏ）_ｍ、Ｒ^１５Ｒ^１６ＮＳ（Ｏ）_ｍ、Ｒ^１５Ｒ^１６ＮＳ（Ｏ）_ｍ（Ｃ_１〜Ｃ_６）アルキル、Ｒ^１５Ｓ（Ｏ）_ｍＲ^１６Ｎ、Ｒ^１５Ｓ（Ｏ）_ｍＲ^１６Ｎ（Ｃ_１〜Ｃ_６）アルキルで置換されていなければならず、そのｍは、０、１または２であり、またＲ^１５およびＲ^１６は、それぞれ独立に水素または（Ｃ_１〜Ｃ_６）アルキルから選択され、あるいは式

The basis of
In which y is 0, 1 or 2;
R ⁴ is selected from the group consisting of hydrogen, (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkylsulfonyl, (C ₂ -C ₆ ) alkenyl, (C ₂ -C ₆ ) alkynyl, Alkyl, alkenyl and alkynyl groups are deuterium, hydroxy, amino, trifluoromethyl, (C ₁ -C ₄ ) alkoxy, (C ₁ -C ₆ ) acyloxy, (C ₁ -C ₆ ) alkylamino, ((C ₁ -C _{6) alkyl) 2} amino, cyano, _{nitro, (C} 2 -C ₆₎ alkenyl _may be substituted with _(C 2 -C ₆₎ alkynyl, or _(C 1 -C ₆₎ acylamino, or R ⁴ is (C ₃ -C ₁₀ ) cycloalkyl, the cycloalkyl group being deuterium, hydroxy, amino, trifluoromethyl, (C ₁ -C ₆ ) acyloxy. Xi, (C ₁ -C ₆ ) acylamino, (C ₁ -C ₆ ) alkylamino, ((C ₁ -C ₆ ) alkyl) ₂ amino, cyano, cyano (C ₁ -C ₆ ) alkyl, trifluoromethyl ( C ₁ -C ₆ ) alkyl, nitro, nitro (C ₁ -C ₆ ) alkyl or (C ₁ -C ₆ ) acylamino may be substituted,
R ⁵ is (C ₂ -C ₉ ) heterocycloalkyl, whose heterocycloalkyl group is 1-5 carboxy, cyano, amino, deuterium, hydroxy, (C ₁ -C ₆ ) alkyl, ( C ₁ -C ₆₎ alkoxy, _{halo, (C} 1 ~C _{6) acyl, (C} 1 ~C ₆₎ alkylamino, amino _(C 1 ~C _{6) alkyl, (C} 1 ~C ₆₎ alkoxy -CO- _{NH, (C} 1 _{~C 6)} alkylamino _{-CO -, (C 2 ~C 6} ) _{alkenyl, (C} 2 _{~C 6) alkynyl, (C} 1 _{~C 6)} alkylamino, amino _(C 1 -C ₆ ) alkyl, hydroxy _(C 1 -C _{6) alkyl, (C} 1 -C ₆₎ alkoxy _(C 1 -C _{6) alkyl, (C} 1 -C ₆₎ acyloxy _(C 1 -C ₆₎ alkyl, nitro, cyano _(C 1 ~ ₆₎ alkyl, halo _(C 1 -C ₆₎ alkyl, nitro _(C 1 -C ₆₎ alkyl, trifluoromethyl, trifluoromethyl _(C 1 -C _{6) alkyl, (C} 1 -C ₆₎ acylamino, ( C ₁ -C ₆₎ acylamino _(C 1 _{~C 6) alkyl, (C} 1 _{~C 6)} alkoxy _(C 1 _{~C 6)} acylamino, amino _(C 1 _{~C 6)} acyl, amino _(C 1 -C ₆ ) Acyl (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkylamino (C ₁ -C ₆ ) acyl, ((C ₁ -C ₆ ) alkyl) ₂ amino (C ₁ -C ₆ ) acyl, ^{R 15 R 16 N-CO-} O-, R 15 R 16 N-CO- (C 1 ~C 6) _{alkyl, (C} 1 _{~C 6)} alkyl _{^{-S (O) m, R 15}} R 16 NS (O _{^{) m, R 15 R 16 NS}} (O _{m (C} 1 _{~C 6)} ^alkyl, must be substituted with _{^{R 15 S (O) m R}} 16 N, R 15 S (O) m R 16 N (C 1 ~C 6) alkyl, the m Is 0, 1 or 2, and R ¹⁵ and R ¹⁶ are each independently selected from hydrogen or (C ₁ -C ₆ ) alkyl, or

の基であり、
式中、ａは、０、１、２、３または４であり、
ｂ、ｃ、ｅ、ｆおよびｇは、それぞれ独立に０または１であり、
ｄは、０、１、２、または３であり、
Ｘは、ｎが０、１もしくは２であるＳ（Ｏ）_ｎ、酸素、カルボニルまたは−Ｃ（＝Ｎ−シアノ）−であり、
Ｙは、ｎが０、１もしくは２であるＳ（Ｏ）_ｎ、またはカルボニルであり、また
Ｚは、カルボニル、Ｃ（Ｏ）Ｏ−、Ｃ（Ｏ）ＮＲ−またはｎが０、１もしくは２であるＳ（Ｏ）_ｎであり、
Ｒ^６、Ｒ^７、Ｒ^８、Ｒ^９、Ｒ^１０およびＲ^１１は、それぞれ独立に、水素、または重水素、ヒドロキシ、アミノ、トリフルオロメチル、（Ｃ_１〜Ｃ_６）アシルオキシ、（Ｃ_１〜Ｃ_６）アシルアミノ、（Ｃ_１〜Ｃ_６）アルキルアミノ、（（Ｃ_１〜Ｃ_６）アルキル）_２アミノ、シアノ、シアノ（Ｃ_１〜Ｃ_６）アルキル、トリフルオロメチル（Ｃ_１〜Ｃ_６）アルキル、ニトロ、ニトロ（Ｃ_１〜Ｃ_６）アルキルもしくは（Ｃ_１〜Ｃ_６）アシルアミノで置換されていてもよい（Ｃ_１〜Ｃ_６）アルキルからなる群から選択され、
Ｒ^１２は、カルボキシ、シアノ、アミノ、オキソ、重水素、ヒドロキシ、トリフルオロメチル、（Ｃ_１〜Ｃ_６）アルキル、トリフルオロメチル（Ｃ_１〜Ｃ_６）アルキル、（Ｃ_１〜Ｃ_６）アルコキシ、ハロ、（Ｃ_１〜Ｃ_６）アシル、（Ｃ_１〜Ｃ_６）アルキルアミノ、（（Ｃ_１〜Ｃ_６）アルキル）_２アミノ、アミノ（Ｃ_１〜Ｃ_６）アルキル、（Ｃ_１〜Ｃ_６）アルコキシ−ＣＯ−ＮＨ、（Ｃ_１〜Ｃ_６）アルキルアミノ−ＣＯ−、（Ｃ_２〜Ｃ_６）アルケニル、（Ｃ_２〜Ｃ_６）アルキニル、（Ｃ_１〜Ｃ_６）アルキルアミノ、ヒドロキシ（Ｃ_１〜Ｃ_６）アルキル、（Ｃ_１〜Ｃ_６）アルコキシ（Ｃ_１〜Ｃ_６）アルキル、（Ｃ_１〜Ｃ_６）アシルオキシ（Ｃ_１〜Ｃ_６）アルキル、ニトロ、シアノ（Ｃ_１〜Ｃ_６）アルキル、ハロ（Ｃ_１〜Ｃ_６）アルキル、ニトロ（Ｃ_１〜Ｃ_６）アルキル、トリフルオロメチル、トリフルオロメチル（Ｃ_１〜Ｃ_６）アルキル、（Ｃ_１〜Ｃ_６）アシルアミノ、（Ｃ_１〜Ｃ_６）アシルアミノ（Ｃ_１〜Ｃ_６）アルキル、（Ｃ_１〜Ｃ_６）アルコキシ（Ｃ_１〜Ｃ_６）アシルアミノ、アミノ（Ｃ_１〜Ｃ_６）アシル、アミノ（Ｃ_１〜Ｃ_６）アシル（Ｃ_１〜Ｃ_６）アルキル、（Ｃ_１〜Ｃ_６）アルキルアミノ（Ｃ_１〜Ｃ_６）アシル、（（Ｃ_１〜Ｃ_６）アルキル）_２アミノ（Ｃ_１〜Ｃ_６）アシル、Ｒ^１５Ｒ^１６Ｎ−ＣＯ−Ｏ−、Ｒ^１５Ｒ^１６Ｎ−ＣＯ−（Ｃ_１〜Ｃ_６）アルキル、Ｒ^１５Ｃ（Ｏ）ＮＨ、Ｒ^１５ＯＣ（Ｏ）ＮＨ、Ｒ^１５ＮＨＣ（Ｏ）ＮＨ、（Ｃ_１〜Ｃ_６）アルキル−Ｓ（Ｏ）_ｍ、（Ｃ_１〜Ｃ_６）アルキル−Ｓ（Ｏ）_ｍ−（Ｃ_１〜Ｃ_６）アルキル、Ｒ^１５Ｒ^１６ＮＳ（Ｏ）_ｍ、Ｒ^１５Ｒ^１６ＮＳ（Ｏ）_ｍ（Ｃ_１〜Ｃ_６）アルキル、Ｒ^１５Ｓ（Ｏ）_ｍＲ^１６Ｎ、Ｒ^１５Ｓ（Ｏ）_ｍＲ^１６Ｎ（Ｃ_１〜Ｃ_６）アルキルであり、そのｍは、０、１または２であり、またＲ^１５およびＲ^１６は、それぞれ独立に水素または（Ｃ_１〜Ｃ_６）アルキルから選択され、
Ｒ^２およびＲ^３は、それぞれ独立に水素、重水素、アミノ、ハロ、ヒドロキシ、ニトロ、カルボキシ、（Ｃ_２〜Ｃ_６）アルケニル、（Ｃ_２〜Ｃ_６）アルキニル、トリフルオロメチル、トリフルオロメトキシ、（Ｃ_１〜Ｃ_６）アルキル、（Ｃ_１〜Ｃ_６）アルコキシ、（Ｃ_３〜Ｃ_１０）シクロアルキルからなる群から選択され、そのアルキル、アルコキシまたはシクロアルキル基は、ハロ、ヒドロキシ、カルボキシ、アミノ（Ｃ_１〜Ｃ_６）アルキルチオ、（Ｃ_１〜Ｃ_６）アルキルアミノ、（（Ｃ_１〜Ｃ_６）アルキル）_２アミノ、（Ｃ_５〜Ｃ_９）ヘテロアリール、（Ｃ_２〜Ｃ_９）ヘテロシクロアルキル、（Ｃ_３〜Ｃ_９）シクロアルキルまたは（Ｃ_６〜Ｃ_１０）アリールから選択される１〜３個の基で置換されていてもよく、あるいはＲ^２およびＲ^３は、それぞれ独立に（Ｃ_３〜Ｃ_１０）シクロアルキル、（Ｃ_３〜Ｃ_１０）シクロアルコキシ、（Ｃ_１〜Ｃ_６）アルキルアミノ、（（Ｃ_１〜Ｃ_６）アルキル）_２アミノ、（Ｃ_６〜Ｃ_１０）アリールアミノ、（Ｃ_１〜Ｃ_６）アルキルチオ、（Ｃ_６〜Ｃ_１０）アリールチオ、（Ｃ_１〜Ｃ_６）アルキルスルフィニル、（Ｃ_６〜Ｃ_１０）アリールスルフィニル、（Ｃ_１〜Ｃ_６）アルキルスルホニル、（Ｃ_６〜Ｃ_１０）アリールスルホニル、（Ｃ_１〜Ｃ_６）アシル、（Ｃ_１〜Ｃ_６）アルコキシ−ＣＯ−ＮＨ−、（Ｃ_１〜Ｃ_６）アルキルアミノ−ＣＯ−、（Ｃ_５〜Ｃ_９）ヘテロアリール、（Ｃ_２〜Ｃ_９）ヘテロシクロアルキルまたは（Ｃ_６〜Ｃ_１０）アリールであり、そのヘテロアリール、ヘテロシクロアルキルおよびアリール基は、１〜３個のハロ、（Ｃ_１〜Ｃ_６）アルキル、（Ｃ_１〜Ｃ_６）アルキル−ＣＯ−ＮＨ−、（Ｃ_１〜Ｃ_６）アルコキシ−ＣＯ−ＮＨ−、（Ｃ_１〜Ｃ_６）アルキル−ＣＯ−ＮＨ−（Ｃ_１〜Ｃ_６）アルキル、（Ｃ_１〜Ｃ_６）アルコキシ−ＣＯ−ＮＨ−（Ｃ_１〜Ｃ_６）アルキル、（Ｃ_１〜Ｃ_６）アルコキシ−ＣＯ−ＮＨ−（Ｃ_１〜Ｃ_６）アルコキシ、カルボキシ、カルボキシ（Ｃ_１〜Ｃ_６）アルキル、カルボキシ（Ｃ_１〜Ｃ_６）アルコキシ、ベンジルオキシカルボニル（Ｃ_１〜Ｃ_６）アルコキシ、（Ｃ_１〜Ｃ_６）アルコキシカルボニル（Ｃ_１〜Ｃ_６）アルコキシ、（Ｃ_６〜Ｃ_１０）アリール、アミノ、アミノ（Ｃ_１〜Ｃ_６）アルキル、（Ｃ_１〜Ｃ_６）アルコキシカルボニルアミノ、（Ｃ_６〜Ｃ_１０）アリール（Ｃ_１〜Ｃ_６）アルコキシカルボニルアミノ、（Ｃ_１〜Ｃ_６）アルキルアミノ、（（Ｃ_１〜Ｃ_６）アルキル）_２アミノ、（Ｃ_１〜Ｃ_６）アルキルアミノ（Ｃ_１〜Ｃ_６）アルキル、（（Ｃ_１〜Ｃ_６）アルキル）_２アミノ（Ｃ_１〜Ｃ_６）アルキル、ヒドロキシ、（Ｃ_１〜Ｃ_６）アルコキシ、カルボキシ、カルボキシ（Ｃ_１〜Ｃ_６）アルキル、（Ｃ_１〜Ｃ_６）アルコキシカルボニル、（Ｃ_１〜Ｃ_６）アルコキシカルボニル（Ｃ_１〜Ｃ_６）アルキル、（Ｃ_１〜Ｃ_６）アルコキシ−ＣＯ−ＮＨ−、（Ｃ_１〜Ｃ_６）アルキル−ＣＯ−ＮＨ−、シアノ、（Ｃ_５〜Ｃ_９）ヘテロシクロアルキル、アミノ−ＣＯ−ＮＨ−、（Ｃ_１〜Ｃ_６）アルキルアミノ−ＣＯ−ＮＨ−、（（Ｃ_１〜Ｃ_６）アルキル）_２アミノ−ＣＯ−ＮＨ−、（Ｃ_６〜Ｃ_１０）アリールアミノ−ＣＯ−ＮＨ−、（Ｃ_５〜Ｃ_９）ヘテロアリールアミノ−ＣＯ−ＮＨ−、（Ｃ_１〜Ｃ_６）アルキルアミノ−ＣＯ−ＮＨ−（Ｃ_１〜Ｃ_６）アルキル、（（Ｃ_１〜Ｃ_６）アルキル）_２アミノ−ＣＯ−ＮＨ−（Ｃ_１〜Ｃ_６）アルキル、（Ｃ_６〜Ｃ_１０）アリールアミノ−ＣＯ−ＮＨ−（Ｃ_１〜Ｃ_６）アルキル、（Ｃ_５〜Ｃ_９）ヘテロアリールアミノ−ＣＯ−ＮＨ−（Ｃ_１〜Ｃ_６）アルキル、（Ｃ_１〜Ｃ_６）アルキルスルホニル、（Ｃ_１〜Ｃ_６）アルキルスルホニルアミノ、（Ｃ_１〜Ｃ_６）アルキルスルホニルアミノ（Ｃ_１〜Ｃ_６）アルキル、（Ｃ_６〜Ｃ_１０）アリールスルホニル、（Ｃ_６〜Ｃ_１０）アリールスルホニルアミノ、（Ｃ_６〜Ｃ_１０）アリールスルホニルアミノ（Ｃ_１〜Ｃ_６）アルキル、（Ｃ_１〜Ｃ_６）アルキルスルホニルアミノ、（Ｃ_１〜Ｃ_６）アルキルスルホニルアミノ（Ｃ_１〜Ｃ_６）アルキル、（Ｃ_５〜Ｃ_９）ヘテロアリールまたは（Ｃ_２〜Ｃ_９）ヘテロシクロアルキルで置換されていてもよい。

The basis of
Where a is 0, 1, 2, 3 or 4;
b, c, e, f and g are each independently 0 or 1,
d is 0, 1, 2, or 3;
X is S (O) _{n in} which n is 0, 1 or 2, oxygen, carbonyl or -C (= N-cyano)-
Y is S (O) _n where n is 0, 1 or 2, or carbonyl, and Z is carbonyl, C (O) O—, C (O) NR—, or n is 0, 1 or 2 S (O) _n which is
R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ and R ¹¹ are each independently hydrogen, or deuterium, hydroxy, amino, trifluoromethyl, (C ₁ -C ₆ ) acyloxy, (C _1- C _{6) acylamino, (C} 1 -C ₆₎ alkylamino, _((C 1 _{~C 6) alkyl) 2} amino, cyano, cyano _(C 1 -C ₆₎ alkyl, trifluoromethyl _(C 1 _-C 6) Selected from the group consisting of alkyl, nitro, nitro (C ₁ -C ₆ ) alkyl or (C ₁ -C ₆ ) alkyl optionally substituted with (C ₁ -C ₆ ) acylamino;
R ¹² is carboxy, cyano, amino, oxo, deuterium, hydroxy, trifluoromethyl, (C ₁ -C ₆ ) alkyl, trifluoromethyl (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkoxy , Halo, (C ₁ -C ₆ ) acyl, (C ₁ -C ₆ ) alkylamino, ((C ₁ -C ₆ ) alkyl) ₂ amino, amino (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆₎ alkoxy _{-CO-NH, (C 1 ~C} 6) alkylamino _{-CO -, (C 2 ~C 6} ) _{alkenyl, (C} 2 -C _{6) alkynyl, (C} 1 -C ₆₎ alkylamino, hydroxy (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkoxy (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) acyloxy (C ₁ -C ₆ ) alkyl, nitro, cyano (C ₁ -C C ₆ ) Alkyl, halo (C ₁ -C ₆ ) alkyl, nitro (C ₁ -C ₆ ) alkyl, trifluoromethyl, trifluoromethyl (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) acylamino, (C ₁ -C ₆₎ acylamino _(C 1 ~C _{6) alkyl, (C} 1 ~C ₆₎ alkoxy _(C 1 ~C ₆₎ acylamino, amino _(C 1 ~C ₆₎ acyl, amino _(C 1 ~C 6) Acyl (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkylamino (C ₁ -C ₆ ) acyl, ((C ₁ -C ₆ ) alkyl) ₂ amino (C ₁ -C ₆ ) acyl, R ¹⁵ R ¹⁶ N—CO—O—, R ¹⁵ R ¹⁶ N—CO— (C ₁ -C ₆ ) alkyl, R ¹⁵ C (O) NH, R ¹⁵ OC (O) NH, R ¹⁵ NHC (O) NH , _(C 1 ~C ₆₎ alkyl - _{(O) m, (C 1} ~C 6) alkyl _{-S (O) m - (C} 1 ~C 6) ^{_{alkyl, R 15 R 16 NS (O}} ) m, R 15 R 16 NS (O) m (C ₁ -C ₆ ) alkyl, R ¹⁵ S (O) _m R ¹⁶ N, R ¹⁵ S (O) _m R ¹⁶ N (C ₁ -C ₆ ) alkyl, where m is 0, 1 or 2 And R ¹⁵ and R ¹⁶ are each independently selected from hydrogen or (C ₁ -C ₆ ) alkyl;
R ² and R ³ are each independently hydrogen, deuterium, amino, halo, hydroxy, nitro, carboxy, (C ₂ -C ₆ ) alkenyl, (C ₂ -C ₆ ) alkynyl, trifluoromethyl, trifluoromethoxy , (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkoxy, (C ₃ -C ₁₀ ) cycloalkyl, wherein the alkyl, alkoxy or cycloalkyl group is halo, hydroxy, carboxy , Amino (C ₁ -C ₆ ) alkylthio, (C ₁ -C ₆ ) alkylamino, ((C ₁ -C ₆ ) alkyl) ₂ amino, (C ₅ -C ₉ ) heteroaryl, (C ₂ -C ₉ ) _{heterocycloalkyl,} optionally substituted with 1 to 3 groups selected from _(C 3 -C ₉₎ cycloalkyl or _(C 6 _{-C 10)} aryl Be good or ^{R 2} and ^{R 3,} are each independently _(C 3 _{~C 10) cycloalkyl, (C} 3 ~C _{10) cycloalkoxy, (C} 1 _{~C 6)} alkylamino, _((C 1 ~ C _{6) alkyl) 2 amino, (C} 6 _{~C 10) arylamino, (C} 1 _{~C 6) alkylthio, (C} 6 _{~C 10) arylthio, (C} 1 _{~C 6)} alkylsulfinyl, _(C 6 ~ C _{10) arylsulfinyl, (C} 1 _{~C 6) alkylsulfonyl, (C} 6 _{~C 10) arylsulfonyl, (C} 1 _{~C 6) acyl, (C} 1 _{~C 6)} alkoxy -CO-NH -, ( C ₁ -C ₆ ) alkylamino-CO—, (C ₅ -C ₉ ) heteroaryl, (C ₂ -C ₉ ) heterocycloalkyl or (C ₆ -C ₁₀ ) aryl, The heteroaryl, heterocycloalkyl and aryl groups, 1-3 _{halo, (C} 1 _{~C 6) alkyl, (C} 1 _{~C 6)} alkyl _{-CO-NH -, (C 1} ~C 6) alkoxy _{-CO-NH -, (C 1} ~C 6) alkyl _{-CO-NH- (C 1 ~C 6} ) _{alkyl, (C} 1 _{~C 6)} alkoxy _{-CO-NH- (C 1 ~C 6} ) alkyl, (C ₁ -C ₆ ) alkoxy-CO—NH— (C ₁ -C ₆ ) alkoxy, carboxy, carboxy (C ₁ -C ₆ ) alkyl, carboxy (C ₁ -C ₆ ) alkoxy, benzyloxycarbonyl (C ₁ -C _{6) alkoxy, (C} 1 ~C ₆₎ alkoxycarbonyl _(C 1 ~C _{6) alkoxy, (C} 6 ~C ₁₀₎ aryl, amino, amino _(C 1 ~C ₆₎ alkyl, (C ₁ -C _{6) alkoxycarbonylamino, (C} 6 ~C ₁₀₎ aryl _(C 1 -C _{6) alkoxycarbonylamino, (C} 1 ~C ₆₎ alkylamino, _((C 1 ~C _{6) alkyl) 2} amino , (C ₁ -C ₆ ) alkylamino (C ₁ -C ₆ ) alkyl, ((C ₁ -C ₆ ) alkyl) ₂ amino (C ₁ -C ₆ ) alkyl, hydroxy, (C ₁ -C ₆ ) alkoxy , Carboxy, carboxy (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkoxycarbonyl, (C ₁ -C ₆ ) alkoxycarbonyl (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkoxy- _{CO-NH -, (C 1} ~C 6) alkyl -CO-NH-, _{cyano, (C} 5 _{~C 9)} heterocycloalkyl, amino _{-CO-NH -, (C 1} ~C 6) Alkylamino _{-CO-NH -, ((C} 1 ~C 6) _{alkyl) 2} amino _{-CO-NH -, (C 6} ~C 10) arylamino _{-CO-NH -, (C 5} ~C 9) heteroarylamino _{-CO-NH -, (C 1} ~C 6) alkylamino _{-CO-NH- (C 1 ~C 6} ) alkyl, _((C 1 ~C _{6) alkyl) 2} amino -CO-NH- _(C 1 ~ C _{6) alkyl, (C} 6 _{~C 10)} arylamino _{-CO-NH- (C 1 ~C 6} ) _{alkyl, (C} 5 _{~C 9)} heteroarylamino _{-CO-NH- (C 1 ~C 6} ) Alkyl, (C ₁ -C ₆ ) alkylsulfonyl, (C ₁ -C ₆ ) alkylsulfonylamino, (C ₁ -C ₆ ) alkylsulfonylamino (C ₁ -C ₆ ) alkyl, (C ₆ -C ₁₀ ) aryl Sulfonyl , (C ₆ -C ₁₀ ) arylsulfonylamino, (C ₆ -C ₁₀ ) arylsulfonylamino (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkylsulfonylamino, (C ₁ -C ₆ ) alkyl It may be substituted with sulfonylamino (C ₁ -C ₆ ) alkyl, (C ₅ -C ₉ ) heteroaryl or (C ₂ -C ₉ ) heterocycloalkyl.

  In some embodiments, the Janus kinase inhibitor is of formula I

の化合物またはその薬学的に許容できる塩であり、式中、
Ｒ^１は、式

Or a pharmaceutically acceptable salt thereof, wherein:
R ¹ is the formula

の基であり、
式中、ｙは、０、１または２であり、
Ｒ^４は、水素、（Ｃ_１〜Ｃ_６）アルキル、（Ｃ_１〜Ｃ_６）アルキルスルホニル、（Ｃ_２〜Ｃ_６）アルケニル、（Ｃ_２〜Ｃ_６）アルキニルからなる群から選択され、そのアルキル、アルケニルおよびアルキニル基は、重水素、ヒドロキシ、アミノ、トリフルオロメチル、（Ｃ_１〜Ｃ_４）アルコキシ、（Ｃ_１〜Ｃ_６）アシルオキシ、（Ｃ_１〜Ｃ_６）アルキルアミノ、（（Ｃ_１〜Ｃ_６）アルキル）_２アミノ、シアノ、ニトロ、（Ｃ_２〜Ｃ_６）アルケニル、（Ｃ_２〜Ｃ_６）アルキニルまたは（Ｃ_１〜Ｃ_６）アシルアミノで置換されていてもよく、あるいはＲ^４は、（Ｃ_３〜Ｃ_１０）シクロアルキルであり、そのシクロアルキル基は、重水素、ヒドロキシ、アミノ、トリフルオロメチル、（Ｃ_１〜Ｃ_６）アシルオキシ、（Ｃ_１〜Ｃ_６）アシルアミノ、（Ｃ_１〜Ｃ_６）アルキルアミノ、（（Ｃ_１〜Ｃ_６）アルキル）_２アミノ、シアノ、シアノ（Ｃ_１〜Ｃ_６）アルキル、トリフルオロメチル（Ｃ_１〜Ｃ_６）アルキル、ニトロ、ニトロ（Ｃ_１〜Ｃ_６）アルキルまたは（Ｃ_１〜Ｃ_６）アシルアミノで置換されていてもよく、
Ｒ^５は、１〜５個のカルボキシ、シアノ、アミノ、重水素、ヒドロキシ、（Ｃ_１〜Ｃ_６）アルキル、（Ｃ_１〜Ｃ_６）アルコキシ、ハロ、（Ｃ_１〜Ｃ_６）アシル、（Ｃ_１〜Ｃ_６）アルキルアミノ、アミノ（Ｃ_１〜Ｃ_６）アルキル、（Ｃ_１〜Ｃ_６）アルコキシ−ＣＯ−ＮＨ、（Ｃ_１〜Ｃ_６）アルキルアミノ−ＣＯ−、（Ｃ_２〜Ｃ_６）アルケニル、（Ｃ_２〜Ｃ_６）アルキニル、（Ｃ_１〜Ｃ_６）アルキルアミノ、アミノ（Ｃ_１〜Ｃ_６）アルキル、ヒドロキシ（Ｃ_１〜Ｃ_６）アルキル、（Ｃ_１〜Ｃ_６）アルコキシ（Ｃ_１〜Ｃ_６）アルキル、（Ｃ_１〜Ｃ_６）アシルオキシ（Ｃ_１〜Ｃ_６）アルキル、ニトロ、シアノ（Ｃ_１〜Ｃ_６）アルキル、ハロ（Ｃ_１〜Ｃ_６）アルキル、ニトロ（Ｃ_１〜Ｃ_６）アルキル、トリフルオロメチル、トリフルオロメチル（Ｃ_１〜Ｃ_６）アルキル、（Ｃ_１〜Ｃ_６）アシルアミノ、（Ｃ_１〜Ｃ_６）アシルアミノ（Ｃ_１〜Ｃ_６）アルキル、（Ｃ_１〜Ｃ_６）アルコキシ（Ｃ_１〜Ｃ_６）アシルアミノ、アミノ（Ｃ_１〜Ｃ_６）アシル、アミノ（Ｃ_１〜Ｃ_６）アシル（Ｃ_１〜Ｃ_６）アルキル、（Ｃ_１〜Ｃ_６）アルキルアミノ（Ｃ_１〜Ｃ_６）アシル、（（Ｃ_１〜Ｃ_６）アルキル）_２アミノ（Ｃ_１〜Ｃ_６）アシル、Ｒ^１５Ｒ^１６Ｎ−ＣＯ−Ｏ−、Ｒ^１５Ｒ^１６Ｎ−ＣＯ−（Ｃ_１〜Ｃ_６）アルキル、（Ｃ_１〜Ｃ_６）アルキル−Ｓ（Ｏ）_ｍ、Ｒ^１５Ｒ^１６ＮＳ（Ｏ）_ｍ、Ｒ^１５Ｒ^１６ＮＳ（Ｏ）_ｍ（Ｃ_１〜Ｃ_６）アルキル、Ｒ^１５Ｓ（Ｏ）_ｍＲ^１６Ｎ、Ｒ^１５Ｓ（Ｏ）_ｍＲ^１６Ｎ（Ｃ_１〜Ｃ_６）アルキルで置換されているピペリジニルであり、そのｍは、０、１または２であり、またＲ^１５およびＲ^１６は、それぞれ独立に水素または（Ｃ_１〜Ｃ_６）アルキルから選択され、あるいは式

The basis of
In which y is 0, 1 or 2;
R ⁴ is selected from the group consisting of hydrogen, (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkylsulfonyl, (C ₂ -C ₆ ) alkenyl, (C ₂ -C ₆ ) alkynyl, Alkyl, alkenyl and alkynyl groups are deuterium, hydroxy, amino, trifluoromethyl, (C ₁ -C ₄ ) alkoxy, (C ₁ -C ₆ ) acyloxy, (C ₁ -C ₆ ) alkylamino, ((C ₁ -C _{6) alkyl) 2} amino, cyano, _{nitro, (C} 2 -C ₆₎ alkenyl _may be substituted with _(C 2 -C ₆₎ alkynyl, or _(C 1 -C ₆₎ acylamino, or R ⁴ is (C ₃ -C ₁₀ ) cycloalkyl, the cycloalkyl group being deuterium, hydroxy, amino, trifluoromethyl, (C ₁ -C ₆ ) acyloxy. Xi, (C ₁ -C ₆ ) acylamino, (C ₁ -C ₆ ) alkylamino, ((C ₁ -C ₆ ) alkyl) ₂ amino, cyano, cyano (C ₁ -C ₆ ) alkyl, trifluoromethyl ( C ₁ -C ₆ ) alkyl, nitro, nitro (C ₁ -C ₆ ) alkyl or (C ₁ -C ₆ ) acylamino may be substituted,
R ⁵ is 1-5 carboxy, cyano, amino, deuterium, hydroxy, (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkoxy, halo, (C ₁ -C ₆ ) acyl, ( C ₁ -C ₆₎ alkylamino, amino _(C 1 ~C _{6) alkyl, (C} 1 ~C ₆₎ alkoxy _{-CO-NH, (C 1 ~C} 6) alkylamino -CO _{-, (C} 2 ~C _{6) alkenyl, (C} 2 -C _{6) alkynyl, (C} 1 -C ₆₎ alkylamino, amino _(C 1 -C ₆₎ alkyl, hydroxy _(C 1 -C _{6) alkyl,} (C 1 _-C 6) alkoxy _(C 1 _{~C 6) alkyl, (C} 1 _{~C 6)} acyloxy _(C 1 _{~C 6)} alkyl, nitro, cyano _(C 1 _{~C 6)} alkyl, halo _(C 1 _{~C 6)} alkyl, nitro _(C 1 ~C ₆₎ Al Le, trifluoromethyl, trifluoromethyl _(C 1 _{~C 6) alkyl, (C} 1 _{~C 6) acylamino, (C} 1 _{~C 6)} acylamino _(C 1 _{~C 6) alkyl, (C} 1 -C ₆ ) Alkoxy (C ₁ -C ₆ ) acylamino, amino (C ₁ -C ₆ ) acyl, amino (C ₁ -C ₆ ) acyl (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkylamino (C ₁ -C ₆ ) acyl, ((C ₁ -C ₆ ) alkyl) ₂ amino (C ₁ -C ₆ ) acyl, R ¹⁵ R ¹⁶ N—CO—O—, R ¹⁵ R ¹⁶ N—CO— (C ₁ -C _{6) alkyl, (C} 1 ~C ₆₎ alkyl _{^{-S (O) m, R 15}} R 16 NS (O) m, R 15 R 16 NS (O) m (C 1 ~C 6) alkyl, R _{^{15 S (O) m R 16}} N, R 15 S (O _{^{m R 16 N (C 1 ~C}} 6) piperidinyl substituted with alkyl, that m is 0, 1 or 2, also ^{R 15} and ^{R 16} are each independently hydrogen or _(C 1 ~ C ₆ ) selected from alkyl or the formula

の基であり、
式中、ａは、０、１、２、３または４であり、
ｂ、ｃ、ｅ、ｆおよびｇは、それぞれ独立に０または１であり、
ｄは、０、１、２、または３であり、
Ｘは、ｎが０、１もしくは２であるＳ（Ｏ）_ｎ、酸素、カルボニルまたは−Ｃ（＝Ｎ−シアノ）−であり、
Ｙは、ｎが０、１もしくは２であるＳ（Ｏ）_ｎ、またはカルボニルであり、また
Ｚは、カルボニル、Ｃ（Ｏ）Ｏ−、Ｃ（Ｏ）ＮＲ−またはｎが０、１もしくは２であるＳ（Ｏ）_ｎであり、
Ｒ^６、Ｒ^７、Ｒ^８、Ｒ^９、Ｒ^１０およびＲ^１１は、それぞれ独立に、水素、または重水素、ヒドロキシ、アミノ、トリフルオロメチル、（Ｃ_１〜Ｃ_６）アシルオキシ、（Ｃ_１〜Ｃ_６）アシルアミノ、（Ｃ_１〜Ｃ_６）アルキルアミノ、（（Ｃ_１〜Ｃ_６）アルキル）_２アミノ、シアノ、シアノ（Ｃ_１〜Ｃ_６）アルキル、トリフルオロメチル（Ｃ_１〜Ｃ_６）アルキル、ニトロ、ニトロ（Ｃ_１〜Ｃ_６）アルキルもしくは（Ｃ_１〜Ｃ_６）アシルアミノで置換されていてもよい（Ｃ_１〜Ｃ_６）アルキルからなる群から選択され、
Ｒ^１２は、カルボキシ、シアノ、アミノ、オキソ、重水素、ヒドロキシ、トリフルオロメチル、（Ｃ_１〜Ｃ_６）アルキル、トリフルオロメチル（Ｃ_１〜Ｃ_６）アルキル、（Ｃ_１〜Ｃ_６）アルコキシ、ハロ、（Ｃ_１〜Ｃ_６）アシル、（Ｃ_１〜Ｃ_６）アルキルアミノ、（（Ｃ_１〜Ｃ_６）アルキル）_２アミノ、アミノ（Ｃ_１〜Ｃ_６）アルキル、（Ｃ_１〜Ｃ_６）アルコキシ−ＣＯ−ＮＨ、（Ｃ_１〜Ｃ_６）アルキルアミノ−ＣＯ−、（Ｃ_２〜Ｃ_６）アルケニル、（Ｃ_２〜Ｃ_６）アルキニル、（Ｃ_１〜Ｃ_６）アルキルアミノ、ヒドロキシ（Ｃ_１〜Ｃ_６）アルキル、（Ｃ_１〜Ｃ_６）アルコキシ（Ｃ_１〜Ｃ_６）アルキル、（Ｃ_１〜Ｃ_６）アシルオキシ（Ｃ_１〜Ｃ_６）アルキル、ニトロ、シアノ（Ｃ_１〜Ｃ_６）アルキル、ハロ（Ｃ_１〜Ｃ_６）アルキル、ニトロ（Ｃ_１〜Ｃ_６）アルキル、トリフルオロメチル、トリフルオロメチル（Ｃ_１〜Ｃ_６）アルキル、（Ｃ_１〜Ｃ_６）アシルアミノ、（Ｃ_１〜Ｃ_６）アシルアミノ（Ｃ_１〜Ｃ_６）アルキル、（Ｃ_１〜Ｃ_６）アルコキシ（Ｃ_１〜Ｃ_６）アシルアミノ、アミノ（Ｃ_１〜Ｃ_６）アシル、アミノ（Ｃ_１〜Ｃ_６）アシル（Ｃ_１〜Ｃ_６）アルキル、（Ｃ_１〜Ｃ_６）アルキルアミノ（Ｃ_１〜Ｃ_６）アシル、（（Ｃ_１〜Ｃ_６）アルキル）_２アミノ（Ｃ_１〜Ｃ_６）アシル、Ｒ^１５Ｒ^１６Ｎ−ＣＯ−Ｏ−、Ｒ^１５Ｒ^１６Ｎ−ＣＯ−（Ｃ_１〜Ｃ_６）アルキル、Ｒ^１５Ｃ（Ｏ）ＮＨ、Ｒ^１５ＯＣ（Ｏ）ＮＨ、Ｒ^１５ＮＨＣ（Ｏ）ＮＨ、（Ｃ_１〜Ｃ_６）アルキル−Ｓ（Ｏ）_ｍ、（Ｃ_１〜Ｃ_６）アルキル−Ｓ（Ｏ）_ｍ−（Ｃ_１〜Ｃ_６）アルキル、Ｒ^１５Ｒ^１６ＮＳ（Ｏ）_ｍ、Ｒ^１５Ｒ^１６ＮＳ（Ｏ）_ｍ（Ｃ_１〜Ｃ_６）アルキル、Ｒ^１５Ｓ（Ｏ）_ｍＲ^１６Ｎ、Ｒ^１５Ｓ（Ｏ）_ｍＲ^１６Ｎ（Ｃ_１〜Ｃ_６）アルキルであり、そのｍは、０、１または２であり、またＲ^１５およびＲ^１６は、それぞれ独立に水素または（Ｃ_１〜Ｃ_６）アルキルから選択され、
Ｒ^２およびＲ^３は、それぞれ水素である。

The basis of
Where a is 0, 1, 2, 3 or 4;
b, c, e, f and g are each independently 0 or 1,
d is 0, 1, 2, or 3;
X is S (O) _{n in} which n is 0, 1 or 2, oxygen, carbonyl or -C (= N-cyano)-
Y is S (O) _n where n is 0, 1 or 2, or carbonyl, and Z is carbonyl, C (O) O—, C (O) NR—, or n is 0, 1 or 2 S (O) _n which is
R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ and R ¹¹ are each independently hydrogen, or deuterium, hydroxy, amino, trifluoromethyl, (C ₁ -C ₆ ) acyloxy, (C _1- C _{6) acylamino, (C} 1 -C ₆₎ alkylamino, _((C 1 _{~C 6) alkyl) 2} amino, cyano, cyano _(C 1 -C ₆₎ alkyl, trifluoromethyl _(C 1 _-C 6) Selected from the group consisting of alkyl, nitro, nitro (C ₁ -C ₆ ) alkyl or (C ₁ -C ₆ ) alkyl optionally substituted with (C ₁ -C ₆ ) acylamino;
R ¹² is carboxy, cyano, amino, oxo, deuterium, hydroxy, trifluoromethyl, (C ₁ -C ₆ ) alkyl, trifluoromethyl (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkoxy , Halo, (C ₁ -C ₆ ) acyl, (C ₁ -C ₆ ) alkylamino, ((C ₁ -C ₆ ) alkyl) ₂ amino, amino (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆₎ alkoxy _{-CO-NH, (C 1 ~C} 6) alkylamino _{-CO -, (C 2 ~C 6} ) _{alkenyl, (C} 2 -C _{6) alkynyl, (C} 1 -C ₆₎ alkylamino, hydroxy (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkoxy (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) acyloxy (C ₁ -C ₆ ) alkyl, nitro, cyano (C ₁ -C C ₆ ) Alkyl, halo (C ₁ -C ₆ ) alkyl, nitro (C ₁ -C ₆ ) alkyl, trifluoromethyl, trifluoromethyl (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) acylamino, (C ₁ -C ₆₎ acylamino _(C 1 ~C _{6) alkyl, (C} 1 ~C ₆₎ alkoxy _(C 1 ~C ₆₎ acylamino, amino _(C 1 ~C ₆₎ acyl, amino _(C 1 ~C 6) Acyl (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkylamino (C ₁ -C ₆ ) acyl, ((C ₁ -C ₆ ) alkyl) ₂ amino (C ₁ -C ₆ ) acyl, R ¹⁵ R ¹⁶ N—CO—O—, R ¹⁵ R ¹⁶ N—CO— (C ₁ -C ₆ ) alkyl, R ¹⁵ C (O) NH, R ¹⁵ OC (O) NH, R ¹⁵ NHC (O) NH , _(C 1 ~C ₆₎ alkyl - _{(O) m, (C 1} ~C 6) alkyl _{-S (O) m - (C} 1 ~C 6) ^{_{alkyl, R 15 R 16 NS (O}} ) m, R 15 R 16 NS (O) m (C ₁ -C ₆ ) alkyl, R ¹⁵ S (O) _m R ¹⁶ N, R ¹⁵ S (O) _m R ¹⁶ N (C ₁ -C ₆ ) alkyl, where m is 0, 1 or 2 And R ¹⁵ and R ¹⁶ are each independently selected from hydrogen or (C ₁ -C ₆ ) alkyl;
R ² and R ³ are each hydrogen.

  In some embodiments, the Janus kinase inhibitor is of formula I

の化合物またはその薬学的に許容できる塩であり、式中、
Ｒ^１は、式

Or a pharmaceutically acceptable salt thereof, wherein:
R ¹ is the formula

の基であり、
式中、ｙは、０であり、
Ｒ^４は、（Ｃ_１〜Ｃ_６）アルキルであり、
Ｒ^５は、１〜５個のカルボキシ、シアノ、アミノ、重水素、ヒドロキシ、（Ｃ_１〜Ｃ_６）アルキル、（Ｃ_１〜Ｃ_６）アルコキシ、ハロ、（Ｃ_１〜Ｃ_６）アシル、（Ｃ_１〜Ｃ_６）アルキルアミノ、アミノ（Ｃ_１〜Ｃ_６）アルキル、（Ｃ_１〜Ｃ_６）アルコキシ−ＣＯ−ＮＨ、（Ｃ_１〜Ｃ_６）アルキルアミノ−ＣＯ−、（Ｃ_２〜Ｃ_６）アルケニル、（Ｃ_２〜Ｃ_６）アルキニル、（Ｃ_１〜Ｃ_６）アルキルアミノ、アミノ（Ｃ_１〜Ｃ_６）アルキル、ヒドロキシ（Ｃ_１〜Ｃ_６）アルキル、（Ｃ_１〜Ｃ_６）アルコキシ（Ｃ_１〜Ｃ_６）アルキル、（Ｃ_１〜Ｃ_６）アシルオキシ（Ｃ_１〜Ｃ_６）アルキル、ニトロ、シアノ（Ｃ_１〜Ｃ_６）アルキル、ハロ（Ｃ_１〜Ｃ_６）アルキル、ニトロ（Ｃ_１〜Ｃ_６）アルキル、トリフルオロメチル、トリフルオロメチル（Ｃ_１〜Ｃ_６）アルキル、（Ｃ_１〜Ｃ_６）アシルアミノ、（Ｃ_１〜Ｃ_６）アシルアミノ（Ｃ_１〜Ｃ_６）アルキル、（Ｃ_１〜Ｃ_６）アルコキシ（Ｃ_１〜Ｃ_６）アシルアミノ、アミノ（Ｃ_１〜Ｃ_６）アシル、アミノ（Ｃ_１〜Ｃ_６）アシル（Ｃ_１〜Ｃ_６）アルキル、（Ｃ_１〜Ｃ_６）アルキルアミノ（Ｃ_１〜Ｃ_６）アシル、（（Ｃ_１〜Ｃ_６）アルキル）_２アミノ（Ｃ_１〜Ｃ_６）アシル、Ｒ_１５Ｒ_１６Ｎ−ＣＯ−Ｏ−、Ｒ_１５Ｒ_１６Ｎ−ＣＯ−（Ｃ_１〜Ｃ_６）アルキル、（Ｃ_１〜Ｃ_６）アルキル−Ｓ（Ｏ）_ｍ、Ｒ_１５Ｒ_１６ＮＳ（Ｏ）_ｍ、Ｒ_１５Ｒ_１６ＮＳ（Ｏ）_ｍ（Ｃ_１〜Ｃ_６）アルキル、Ｒ_１５Ｓ（Ｏ）_ｍＲ_１６Ｎ、Ｒ_１５Ｓ（Ｏ）_ｍＲ_１６Ｎ（Ｃ_１〜Ｃ_６）アルキルで置換されているピペリジニル、または式

The basis of
Where y is 0,
R ⁴ is (C ₁ -C ₆ ) alkyl;
R ⁵ is 1-5 carboxy, cyano, amino, deuterium, hydroxy, (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkoxy, halo, (C ₁ -C ₆ ) acyl, ( C ₁ -C ₆₎ alkylamino, amino _(C 1 ~C _{6) alkyl, (C} 1 ~C ₆₎ alkoxy _{-CO-NH, (C 1 ~C} 6) alkylamino -CO _{-, (C} 2 ~C _{6) alkenyl, (C} 2 -C _{6) alkynyl, (C} 1 -C ₆₎ alkylamino, amino _(C 1 -C ₆₎ alkyl, hydroxy _(C 1 -C _{6) alkyl,} (C 1 _-C 6) alkoxy _(C 1 _{~C 6) alkyl, (C} 1 _{~C 6)} acyloxy _(C 1 _{~C 6)} alkyl, nitro, cyano _(C 1 _{~C 6)} alkyl, halo _(C 1 _{~C 6)} alkyl, nitro _(C 1 ~C ₆₎ Al Le, trifluoromethyl, trifluoromethyl _(C 1 _{~C 6) alkyl, (C} 1 _{~C 6) acylamino, (C} 1 _{~C 6)} acylamino _(C 1 _{~C 6) alkyl, (C} 1 -C ₆ ) Alkoxy (C ₁ -C ₆ ) acylamino, amino (C ₁ -C ₆ ) acyl, amino (C ₁ -C ₆ ) acyl (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkylamino (C ₁ -C ₆ ) acyl, ((C ₁ -C ₆ ) alkyl) ₂ amino (C ₁ -C ₆ ) acyl, R ₁₅ R ₁₆ N—CO—O—, R ₁₅ R ₁₆ N—CO— (C ₁ -C _{6) alkyl, (C} 1 ~C ₆₎ alkyl _{-S (O) m, R 15} R 16 NS (O) m, R 15 R 16 NS (O) m (C 1 ~C 6) alkyl, R _{15 S (O) m R 16} N, R 15 S (O _{m R 16 N (C 1 ~C} 6) piperidinyl substituted with alkyl or formula,

の基であり、
式中、
ｍは、０、１または２であり、
Ｒ_１５およびＲ_１６は、それぞれ独立に水素または（Ｃ_１〜Ｃ_６）アルキルから選択され、
ｄは、１であり、
Ｒ^９およびＲ^１０は、それぞれ独立に、水素、または重水素、ヒドロキシ、アミノ、トリフルオロメチル、（Ｃ_１〜Ｃ_６）アシルオキシ、（Ｃ_１〜Ｃ_６）アシルアミノ、（Ｃ_１〜Ｃ_６）アルキルアミノ、（（Ｃ_１〜Ｃ_６）アルキル）_２アミノ、シアノ、シアノ（Ｃ_１〜Ｃ_６）アルキル、トリフルオロメチル（Ｃ_１〜Ｃ_６）アルキル、ニトロ、ニトロ（Ｃ_１〜Ｃ_６）アルキルもしくは（Ｃ_１〜Ｃ_６）アシルアミノで置換されていてもよい（Ｃ_１〜Ｃ_６）アルキルからなる群から選択され、
Ｒ^１２は、シアノ、トリフルオロメチル、（Ｃ_１〜Ｃ_６）アルキル、トリフルオロメチル（Ｃ_１〜Ｃ_６）アルキル、（Ｃ_１〜Ｃ_６）アルキルアミノ、（（Ｃ_１〜Ｃ_６）アルキル）_２アミノ、（Ｃ_２〜Ｃ_６）アルキニル、シアノ（Ｃ_１〜Ｃ_６）アルキル、（Ｃ_１〜Ｃ_６）アルキル−Ｓ（Ｏ）_ｍであり、そのｍは、０、１または２であり、また
Ｒ^２およびＲ^３は、それぞれＨである。

The basis of
Where
m is 0, 1 or 2;
R ₁₅ and R ₁₆ are each independently selected from hydrogen or (C ₁ -C ₆ ) alkyl;
d is 1,
R ⁹ and R ¹⁰ are each independently hydrogen or deuterium, hydroxy, amino, trifluoromethyl, (C ₁ -C ₆ ) acyloxy, (C ₁ -C ₆ ) acylamino, (C ₁ -C ₆ ) Alkylamino, ((C ₁ -C ₆ ) alkyl) ₂ amino, cyano, cyano (C ₁ -C ₆ ) alkyl, trifluoromethyl (C ₁ -C ₆ ) alkyl, nitro, nitro (C ₁ -C ₆ ) Selected from the group consisting of alkyl or (C ₁ -C ₆ ) alkyl optionally substituted with (C ₁ -C ₆ ) acylamino;
R ¹² is cyano, trifluoromethyl, (C ₁ -C ₆ ) alkyl, trifluoromethyl (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkylamino, ((C ₁ -C ₆ ) alkyl. ) ₂ amino, (C ₂ -C ₆ ) alkynyl, cyano (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkyl-S (O) _m , where m is 0, 1 or 2 And R ² and R ³ are each H.

  In some embodiments of the compound of Formula I, a is 0, b is 1, X is carbonyl, c is 0, d is 0, e is 0, and f is 0 and g is 0.

  In some embodiments of the compound of Formula I, a is 0, b is 1, X is carbonyl, c is 0, d is 1, e is 0, and f is 0 and g is 0.

  In some embodiments of the compound of Formula I, a is 0, b is 1, X is carbonyl, c is 1, d is 0, e is 0, and f is 0 and g is 0.

  In some embodiments of the compound of formula I, a is 0, b is 1, X is —C (═N═cyano) —, c is 1, d is 0, e is 0, f is 0, and g is 0.

  In some embodiments of the compound of Formula I, a is 0, b is 0, c is 0, d is 0, e is 0, f is 0, and g is 1 and Z is —C (O) —O—.

In some embodiments of the compound of Formula I, a is 0, b is 1, X is S (O) _n , n is 2, c is 0, and d is 0 Yes, e is 0, f is 0, and g is 0.

In some embodiments of the compound of Formula I, a is 0, b is 1, X is S (O) _n , n is 2, c is 0, d is 2 Yes, e is 0, f is 1, g is 1, and Z is carbonyl.

In some embodiments of the compound of formula I, a is 0, b is 1, X is S (O) _n , n is 2, c is 0, d is 2 Yes, e is 0, f is 1, and g is 0.

In some embodiments of the compound of Formula I, a is 0, b is 1, X is carbonyl, c is 1, d is 0, e is 1, and Y is S (O) _n , n is 2, f is 0, and g is 0.

In some embodiments of the compound of Formula I, a is 0, b is 1, X is S (O) _n , n is 2, c is 1, and d is 0. Yes, e is 0, f is 0, and g is 0.

In some embodiments of the compound of Formula I, R ¹² is cyano, trifluoromethyl, (C ₁ -C ₆ ) alkyl, trifluoromethyl (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ). Alkylamino, ((C ₁ -C ₆ ) alkyl) ₂ amino, (C ₂ -C ₆ ) alkynyl, cyano (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkyl-S (O) _m And m is 0, 1 or 2.

In some embodiments of the compound of Formula I, the Janus kinase inhibitor is
Methyl- [4-methyl-1- (propane-1-sulfonyl) -piperidin-3-yl]-(7H-pyrrolo [2,3-d] pyrimidin-4-yl) -amine;
4-methyl-3- [methyl- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -amino] -piperidine-1-carboxylic acid methyl ester;
3,3,3-trifluoro-1- {4-methyl-3- [methyl- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -amino] -piperidin-1-yl} -propane -1-one;
4-methyl-3- [methyl- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -amino] -piperidine-1-carboxylic acid dimethylamide;
({4-Methyl-3- [methyl- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -amino] -piperidine-1-carbonyl} -amino) -acetic acid ethyl ester;
3- {4-methyl-3- [methyl- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -amino] -piperidin-1-yl} -3-oxo-propionitrile;
3,3,3-trifluoro-1- {4-methyl-3- [methyl- (5-methyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl) -amino] -piperidine-1- Il} -propan-1-one;
1- {4-methyl-3- [methyl- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -amino] -piperidin-1-yl} -but-3-in-1-one;
1- {3-[(5-chloro-7H-pyrrolo [2,3-d] pyrimidin-4-yl) -methyl-amino] -4-methyl-piperidin-1-yl} -propan-1-one;
1- {3-[(5-fluoro-7H-pyrrolo [2,3-d] pyrimidin-4-yl) -methyl-amino] -4-methyl-piperidin-1-yl} -propan-1-one;
N-cyano-4-methyl-3- [methyl- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -amino] -N′-propyl-piperidine-1-carboxamidine;
N-cyano-4, N ′, N′-trimethyl-3- [methyl- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -amino] -piperidine-1-carboxamidine;
Methyl-[(3R, 4R) -4-methyl-1- (propane-1-sulfonyl) -piperidin-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] -piperidine-1-carboxylic acid methyl ester;
3,3,3-trifluoro-1-{(3R, 4R) -4-methyl-3- [methyl- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -amino] -piperidine- 1-yl} -propan-1-one;
(3R, 4R) -4-methyl-3- [methyl- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -amino] -piperidine-1-carboxylic acid dimethylamide;
{(3R, 4R) -4-methyl-3- [methyl- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -amino] -piperidine-1-carbonyl} -amino) -acetic acid ethyl ester ;
3-{(3R, 4R) -4-methyl-3- [methyl- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -amino] -piperidin-1-yl} -3-oxo- Propionitrile;
3,3,3-trifluoro-1-{(3R, 4R) -4-methyl-3- [methyl- (5-methyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl) -amino ] -Piperidin-1-yl} -propan-1-one;
1-{(3R, 4R) -4-methyl-3- [methyl- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -amino] -piperidin-1-yl} -but-3- In-1-on;
1-{(3R, 4R) -3-[(5-Chloro-7H-pyrrolo [2,3-d] pyrimidin-4-yl) -methyl-amino] -4-methyl-piperidin-1-yl}- Propan-1-one;
1-{(3R, 4R) -3-[(5-Fluoro-7H-pyrrolo [2,3-d] pyrimidin-4-yl) -methyl-amino] -4-methyl-piperidin-1-yl}- Propan-1-one;
(3R, 4R) -N-cyano-4-methyl-3- [methyl- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -amino] -N'-propyl-piperidine-1-carboxamidine And (3R, 4R) -N-cyano-4, N ′, N′-trimethyl-3- [methyl- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -amino] -piperidine-; 1-carboxamidine,
Or it is selected from the group consisting of pharmaceutically acceptable salts thereof.

In some embodiments of the compound of Formula I, the Janus kinase inhibitor is
Methyl- [4-methyl-1- (propane-1-sulfonyl) -piperidin-3-yl]-(7H-pyrrolo [2,3-d] pyrimidin-4-yl) -amine;
4-methyl-3- [methyl- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -amino] -piperidine-1-carboxylic acid methyl ester;
3,3,3-trifluoro-1- {4-methyl-3- [methyl- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -amino] -piperidin-1-yl} -propane -1-one;
4-methyl-3- [methyl- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -amino] -piperidine-1-carboxylic acid dimethylamide;
({4-Methyl-3- [methyl- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -amino] -piperidine-1-carbonyl} -amino) -acetic acid ethyl ester;
3- {4-methyl-3- [methyl- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -amino] -piperidin-1-yl} -3-oxo-propionitrile;
3,3,3-trifluoro-1- {4-methyl-3- [methyl- (5-methyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl) -amino] -piperidine-1- Il} -propan-1-one;
1- {4-methyl-3- [methyl- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -amino] -piperidin-1-yl} -but-3-in-1-one;
1- {3-[(5-chloro-7H-pyrrolo [2,3-d] pyrimidin-4-yl) -methyl-amino] -4-methyl-piperidin-1-yl} -propan-1-one;
1- {3-[(5-fluoro-7H-pyrrolo [2,3-d] pyrimidin-4-yl) -methyl-amino] -4-methyl-piperidin-1-yl} -propan-1-one;
N-cyano-4-methyl-3- [methyl- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -amino] -N′-propyl-piperidine-1-carboxamidine; and N-cyano- 4, N ′, N′-trimethyl-3- [methyl- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -amino] -piperidine-1-carboxamidine,
Or it is selected from the group consisting of pharmaceutically acceptable salts thereof.

In some embodiments of the compound of Formula I, the Janus kinase inhibitor is
Methyl-[(3R, 4R) -4-methyl-1- (propane-1-sulfonyl) -piperidin-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] -piperidine-1-carboxylic acid methyl ester;
3,3,3-trifluoro-1-{(3R, 4R) -4-methyl-3- [methyl- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -amino] -piperidine- 1-yl} -propan-1-one;
(3R, 4R) -4-methyl-3- [methyl- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -amino] -piperidine-1-carboxylic acid dimethylamide;
{(3R, 4R) -4-methyl-3- [methyl- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -amino] -piperidine-1-carbonyl} -amino) -acetic acid ethyl ester ;
3-{(3R, 4R) -4-methyl-3- [methyl- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -amino] -piperidin-1-yl} -3-oxo- Propionitrile;
3,3,3-trifluoro-1-{(3R, 4R) -4-methyl-3- [methyl- (5-methyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl) -amino ] -Piperidin-1-yl} -propan-1-one;
1-{(3R, 4R) -4-methyl-3- [methyl- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -amino] -piperidin-1-yl} -but-3- In-1-on;
1-{(3R, 4R) -3-[(5-Chloro-7H-pyrrolo [2,3-d] pyrimidin-4-yl) -methyl-amino] -4-methyl-piperidin-1-yl}- Propan-1-one;
1-{(3R, 4R) -3-[(5-Fluoro-7H-pyrrolo [2,3-d] pyrimidin-4-yl) -methyl-amino] -4-methyl-piperidin-1-yl}- Propan-1-one;
(3R, 4R) -N-cyano-4-methyl-3- [methyl- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -amino] -N'-propyl-piperidine-1-carboxamidine And (3R, 4R) -N-cyano-4, N ′, N′-trimethyl-3- [methyl- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -amino] -piperidine-; 1-carboxamidine,
Or it is selected from the group consisting of pharmaceutically acceptable salts thereof.

  In some embodiments, the Janus kinase inhibitor is of Formula IA

の化合物であり、
式中、Ａｒ、Ｒ^１、およびＲ^２は、本明細書においてその内容が一般的および具体的に参照により本明細書に組み込まれる、米国特許第７，０３７，９２５号の請求項１で定義されている通りである。ヤヌスキナーゼ阻害剤は、米国特許第７，０３７，９２５号に具体的に記載されている任意の他の化合物であってもよい。

A compound of
Wherein Ar, R ¹ , and R ² are defined in claim 1 of US Pat. No. 7,037,925, the contents of which are hereby incorporated herein by reference generally and specifically. It is as it is. The Janus kinase inhibitor may be any other compound specifically described in US Pat. No. 7,037,925.

  In some embodiments, the Janus kinase inhibitor is of formula I

の化合物であり、
式中、Ａｒ、Ｒ、Ｘ、Ｒ^１、Ｒ^２、およびａは、本明細書においてその内容が一般的および具体的に参照により本明細書に組み込まれる、米国公開２００６／０１７３０３４号の請求項１で定義されている通りである。ヤヌスキナーゼ阻害剤は、米国公開２００６／０１７３０３４号に具体的に記載されている任意の他の化合物であってもよい。

A compound of
Wherein Ar, R, X, R ¹ , R ² , and a are claims of US Publication No. 2006/0173034, the contents of which are hereby incorporated herein by reference in general and specifically. As defined in 1. The Janus kinase inhibitor may be any other compound specifically described in US Publication No. 2006/0173034.

  In some embodiments, the Janus kinase inhibitor has the formula

の化合物であり、
式中、Ｒ^１、Ａ、Ｂ、およびＷは、本明細書においてその内容が一般的および具体的に参照により本明細書に組み込まれる、米国公開２００５／０１３７２０１号の請求項１で定義されている通りである。ヤヌスキナーゼ阻害剤は、米国公開２００５／０１３７２０１号に具体的に記載されている任意の他の化合物、特に実施例１７３でＪＡＫ３阻害剤であると言及されているものであってもよい。

A compound of
Wherein R ¹ , A, B, and W are defined in claim 1 of US Publication No. 2005/0137201, the contents of which are hereby incorporated herein by reference in a general and specific manner. That's right. The Janus kinase inhibitor may be any other compound specifically described in US Publication No. 2005/0137201, particularly those mentioned in Example 173 as being a JAK3 inhibitor.

In some embodiments, the Janus kinase inhibitor has one or more as defined in US Publication No. 2005/0261253, the contents of which are hereby generally and specifically incorporated herein by reference. A compound of any one of formulas 500 to 511 substituted with the group A ⁰ of The Janus kinase inhibitor may be any other compound specifically described in US Publication No. 2005/0261253.

  In some embodiments, the Janus kinase inhibitor is of formula I

の化合物であり、
式中、Ｒ^１、Ｒ^２、Ｒ^３、Ｒ^４、およびＲ^５は、本明細書においてその内容が一般的および具体的に参照により本明細書に組み込まれる、米国公開２００６／０１８３９０６号の請求項１で定義されている通りである。ヤヌスキナーゼ阻害剤は、米国公開２００６／０１８３９０６号に具体的に記載されている任意の他の化合物であってもよい。

A compound of
Wherein R ¹ , R ² , R ³ , R ⁴ , and R ⁵ are claimed in US Publication No. 2006/0183906, the contents of which are hereby incorporated herein by reference in general and specifically. As defined in item 1. The Janus kinase inhibitor may be any other compound specifically described in US Publication No. 2006/0183906.

  In some embodiments, the Janus kinase inhibitor is of formula I

の化合物であり、
式中、Ｄ^１、Ｄ^２、Ｄ^３、Ｄ^４、Ａ、およびＢは、本明細書においてその内容が一般的および具体的に参照により本明細書に組み込まれる、米国公開２００６／０１０６０２０号の請求項１で定義されている通りである。ヤヌスキナーゼ阻害剤は、米国公開２００６／０１０６０２０号に具体的に記載されている任意の他の化合物であってもよい。

A compound of
In which D ¹ , D ² , D ³ , D ⁴ , A, and B are as described in US Publication No. 2006/0106020, the contents of which are hereby incorporated herein by reference in general and specifically. As defined in claim 1. The Janus kinase inhibitor may be any other compound specifically described in US Publication No. 2006/0106020.

  In some embodiments, the Janus kinase inhibitor is a JAK3 kinase inhibitor in WO 2005/105146, particularly pages 12-17, the contents of which are hereby incorporated herein by reference in general and specifically. It is a compound that is mentioned as being.

  In some embodiments, the Janus kinase inhibitor is of formula I

の化合物であり、
式中、Ｒ^１、Ｒ^２、Ｒ^３、Ｒ^４、およびＲ^５は、本明細書においてその内容が一般的および具体的に参照により本明細書に組み込まれる、米国公開２００４／０２１４８１７号の請求項１で定義されている通りである。ヤヌスキナーゼ阻害剤は、米国公開２００４／０２１４８１７号に具体的に記載されている任意の他の化合物、特に実施例９でＪＡＫ３阻害剤であると言及されているものであってもよい。

A compound of
Wherein R ¹ , R ² , R ³ , R ⁴ , and R ⁵ are claimed in US Publication No. 2004/0214817, the contents of which are hereby incorporated herein by reference in general and specifically. As defined in item 1. The Janus kinase inhibitor may be any other compound specifically described in US Publication No. 2004/0214817, particularly those mentioned in Example 9 as being a JAK3 inhibitor.

  In some embodiments, the Janus kinase inhibitor is of formula I

の化合物であり、
式中、Ｒ^１、Ｒ^２、Ｒ^３、Ｒ^４、Ｒ^５、Ａおよびｘは、本明細書においてその内容が一般的および具体的に参照により本明細書に組み込まれる、米国公開２００６／０１２２２１３号の請求項１で定義されている通りである。ヤヌスキナーゼ阻害剤は、米国公開２００６／０１２２２１３号に具体的に記載されている任意の他の化合物、特に表ＩおよびＩＩで示されているものであってもよい。

A compound of
Wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , A and x are U.S. Publication 2006/0122213, the contents of which are hereby incorporated herein by reference in their entirety and specifically. As defined in claim 1 of the present application. The Janus kinase inhibitor may be any other compound specifically described in US Publication No. 2006/0122213, particularly those shown in Tables I and II.

  In some embodiments, the Janus kinase inhibitor is of formula I

の化合物であり、
式中、Ｒ^１、Ｒ^２、Ｚ^１、Ｚ^２、およびＺ^３は、本明細書においてその内容が一般的および具体的に参照により本明細書に組み込まれる、米国公開２００６／０１８３７６１号の請求項１で定義されている通りである。ヤヌスキナーゼ阻害剤は、米国公開２００６／０１８３７６１号に具体的に記載されている任意の他の化合物、特に表ＩおよびＩＩで示されているものであってもよい。

A compound of
Wherein R ¹ , R ² , Z ¹ , Z ² , and Z ³ are claims of US Publication No. 2006/0183761, the contents of which are hereby incorporated herein by reference in general and specifically. As defined in item 1. The Janus kinase inhibitor may be any other compound specifically described in US Publication No. 2006/0183761, particularly those shown in Tables I and II.

  In some embodiments, the Janus kinase inhibitor is of formula I

の化合物であり、
式中、Ｒ^１、Ｒ^３、Ｒ^５、Ｘ^１、Ｘ^２およびＸ^３は、本明細書においてその内容が一般的および具体的に参照により本明細書に組み込まれる、米国公開２００５／０１６５０２９号の請求項１で定義されている通りである。ヤヌスキナーゼ阻害剤は、米国公開２００５／０１６５０２９号に具体的に記載されている任意の他の化合物であってもよい。

A compound of
Wherein R ¹ , R ³ , R ⁵ , X ¹ , X ² and X ³ are U.S. Publication No. 2005/0165029, the contents of which are hereby incorporated herein by reference in general and specifically. As defined in claim 1 of the present invention. The Janus kinase inhibitor may be any other compound specifically described in US Publication No. 2005/0165029.

  In some embodiments, the Janus kinase inhibitor is of formula I

の化合物であり、
式中、Ｒ^１、Ｒ^２、Ｒ^３、Ｒ^５、Ｘ^１、およびＸ^２は、本明細書においてその内容が一般的および具体的に参照により本明細書に組み込まれる、米国公開２００５／０１８７３８９号の請求項１で定義されている通りである。ヤヌスキナーゼ阻害剤は、米国公開２００５／０１８７３８９号に具体的に記載されている任意の他の化合物であってもよい。

A compound of
Wherein R ¹ , R ² , R ³ , R ⁵ , X ¹ , and X ² are U.S. Publication No. 2005/0187389, the contents of which are hereby incorporated herein by reference in general and specifically. As defined in claim 1 of the above. The Janus kinase inhibitor may be any other compound specifically described in US Publication No. 2005/0187389.

  In some embodiments, the Janus kinase inhibitor is of formula I

の化合物であり、
式中、Ｒ^１、Ｒ^２、Ｒ^３、Ｒ^４、およびＹは、本明細書においてその内容が一般的および具体的に参照により本明細書に組み込まれる、米国特許第６，９４３，１６１号の請求項１で定義されている通りである。ヤヌスキナーゼ阻害剤は、米国特許第６，９４３，１６１号に具体的に記載されている任意の他の化合物、特に表Ｉで示されているものであってもよい。

A compound of
Wherein R ¹ , R ² , R ³ , R ⁴ , and Y are U.S. Patent No. 6,943,161, the contents of which are hereby incorporated herein by reference in general and specifically As defined in claim 1 of the present invention. The Janus kinase inhibitor may be any other compound specifically described in US Pat. No. 6,943,161, particularly those shown in Table I.

  In some embodiments, the Janus kinase inhibitor is of formula I

の化合物であり、
式中、Ｒ^１、Ｒ^２、Ｒ^３、Ｒ^４、Ｘ、Ｘ^１、Ｘ^２、およびＹは、本明細書においてその内容が一般的および具体的に参照により本明細書に組み込まれる、米国公開２００５／０２７７６４２号の請求項１で定義されている通りである。ヤヌスキナーゼ阻害剤は、米国公開２００５／０２７７６４２号に具体的に記載されている任意の他の化合物、特に表Ｉで示されているものであってもよい。

A compound of
Wherein R ¹ , R ² , R ³ , R ⁴ , X, X ¹ , X ² , and Y are US, the contents of which are hereby incorporated herein by reference in their entirety and specifically. As defined in claim 1 of publication 2005/0277642. The Janus kinase inhibitor may be any other compound specifically described in US Publication No. 2005/0277642, particularly those shown in Table I.

  In some embodiments, the Janus kinase inhibitor is of formula I

の化合物であり、
式中、Ｒ^１、Ｒ^２、Ｒ^４、Ｒ^５、Ｒ^６、Ｒ^７、Ｒ^８、Ｒ^９、Ｒ^１０、およびＸは、本明細書においてその全ての内容が一般的および具体的に参照により本明細書に組み込まれる、米国第６，４５２，００５号および関連米国第６，３１３，１２９号；第６，３１３，１３０号；第６，１７７，４３３号；第６，０８０，７４７号；第６，３２６，３７３号；第６，０８０，７４８号ならびに米国公開２００４／０１９２７１１号および２００５／０１８７２３３号で定義されている通りである。ヤヌスキナーゼ阻害剤は、米国第６，４５２，００５号および関連米国第６，３１３，１２９号；第６，３１３，１３０号；第６，１７７，４３３号、第６，０８０，７４７号；第６，３２６，３７３号；第６，０８０，７４８号ならびに米国公開２００４／０１９２７１１号および２００５／０１８７２３３号に具体的に記載されている任意の他の化合物であってもよい。

A compound of
Wherein R ¹ , R ² , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , and X are generally and specifically referenced herein in their entirety. US 6,452,005 and related US 6,313,129; 6,313,130; 6,177,433; 6,080,747, incorporated herein by reference. As defined in US Pat. Nos. 6,326,373; 6,080,748 and US Publication Nos. 2004/0192711 and 2005/0187233. Janus kinase inhibitors are disclosed in US 6,452,005 and related US 6,313,129; 6,313,130; 6,177,433, 6,080,747; 6,326,373; 6,080,748 and any other compound specifically described in US Publication Nos. 2004/0192711 and 2005/0187233.

  In some embodiments, the Janus kinase inhibitor is Jack J. et al., Herein incorporated by reference. Chen et al., Development of Pyrimidine-Based Inhibitors of Janus Tyrosine Kinase 3, Bioorganic & Medicinal Chemistry Letters (2006), doi. 1016 / j. bmcl. Any one of the JAK3 inhibitors shown in FIG. 1 of 2006.8.0822.

ヤヌスキナーゼ阻害剤は、その中、特に表ＩおよびＩＩに具体的に記載されている任意の他の化合物であってもよい。

The Janus kinase inhibitor may be any other compound, among others specifically described in Tables I and II.

  In some embodiments, the anti-arthritic agent is other salicylic acid such as acetylsalicylic acid and choline magnesium trisalicylic acid, azapropazone, carprofen, celecoxib, diclofenac potassium, diclofenac sodium, diflunisal, etodolac, fenbufen, fenoprofen, flufenamic acid, NSAID selected from the group consisting of flurbiprofen, ibuprofen, indomethacin, ketoprofen, mefenamic acid, meloxicam, nabumetone, naproxen, naproxen sodium, oxaprozin, pyrprofen, suprofen, salsalate, sulindac, tenoxicam, thiaprofenic acid, and tolmethine Non-steroidal anti-inflammatory agent) or COX-2 (cyclooxygenase 2) inhibitor . Other suitable NSAIDs and / or COX-2 inhibitors should be readily apparent to those skilled in the art having the benefit of this disclosure.

  In some embodiments, hydrocortisone acetate, tertbutyl acetate hydrocortisone, dexamethasone acetate, tertbutyl dexamethasone acetate, prednisolone, prednisolone acetate, prednisolone tertbutyl acetate, prednisone, methylprednisolone, methylprednisolone acetate, triamcinolone acetonide, triamcinolone diacetonide And an anti-arthritic agent selected from the group consisting of triamcinolone hexaacetonide is glucocorticoid (oral, parenteral and / or intra-articular). Other suitable glucocorticoids should be readily apparent to those skilled in the art having the benefit of this disclosure.

  In some embodiments, the anti-arthritic agent is hydroxychloroquine, chloroquine, dapsone, sulfasalazine, methotrexate, leflunomide, azathioprine, d-penicillamine, cyclosporin A, and sodium gold thiomalate, aurothioglucose, and auranofin SCE (small chemical component) DMARD (disease modifying antirheumatic drug) selected from the group consisting of gold compounds.

  In some embodiments, the anti-arthritic agent is a biological DMARD selected from the group consisting of etanercept, infliximab, adalimumab, anakinra, abatacept, rituximab, tocilizumab, and sertolizumab pegol. Other suitable DMARDs (SCE or biological) should be readily apparent to those of ordinary skill in the art having the benefit of this disclosure.

  In some embodiments, the anti-arthritic agent is an analgesic such as acetaminophen. Other suitable analgesics should be readily apparent to those skilled in the art having the benefit of this disclosure.

  In some embodiments, the anti-arthritic agent may be used in combination with acetaminophen selected from the group consisting of morphine, codeine, propoxyphene, hydrocodone, methadone, hydromorphone, oxycodone, fentanyl, buprenorphine, and butorphanol. It is an opioid. Other suitable opioids should be readily apparent to those skilled in the art having the benefit of this disclosure.

  In another aspect, the present disclosure contemplates co-administering to a human a therapeutically effective amount of both a Janus kinase inhibitor or a pharmaceutically acceptable salt thereof and at least one anti-arthritic agent or a pharmaceutically acceptable salt thereof. Wherein the Janus kinase inhibitor and anti-arthritic agent are defined as described herein.

  In another aspect, the disclosure provides for treating or preventing psoriatic arthritis comprising a Janus kinase inhibitor or a pharmaceutically acceptable salt thereof and at least one anti-arthritic agent or a pharmaceutically acceptable salt thereof. With regard to drug combination therapy, Janus kinase inhibitors and anti-arthritic agents are defined as described herein.

  In another aspect, the present disclosure contemplates co-administering to a human a therapeutically effective amount of both a Janus kinase inhibitor or a pharmaceutically acceptable salt thereof and at least one anti-arthritic agent or a pharmaceutically acceptable salt thereof. Wherein the Janus kinase inhibitor and the anti-arthritic agent are defined as described herein.

  In another aspect, the disclosure provides for treating or preventing ankylosing spondylitis comprising a Janus kinase inhibitor or a pharmaceutically acceptable salt thereof and at least one anti-arthritic agent or a pharmaceutically acceptable salt thereof. And Janus kinase inhibitors and anti-arthritic agents are defined as described herein.

  In another aspect, the present disclosure contemplates co-administering to a human a therapeutically effective amount of both a Janus kinase inhibitor or a pharmaceutically acceptable salt thereof and at least one anti-arthritic agent or a pharmaceutically acceptable salt thereof. And a method for treating or preventing ankylosing spondylitis in humans, wherein Janus kinase inhibitors and anti-arthritic agents are defined as described herein.

  Additional features and advantages of the drug combinations and methods disclosed herein will become apparent from the following detailed description of several embodiments.

  While specific embodiments of the present disclosure will now be described in connection with certain preferred embodiments described in the recipes and schemes, such embodiments are merely exemplary and are merely exemplary. It should be understood that there are many possible specific embodiments that may be representative of just a few examples of the components of the present disclosure. Various changes and modifications should be apparent to those skilled in the art having the benefit of this disclosure, and are considered to be within the spirit and scope of this disclosure as further defined in the appended claims. .

  Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs.

Definitions As used herein, the term “alkyl” includes saturated monovalent hydrocarbon groups having a linear or branched moiety or combinations thereof, unless otherwise indicated.

  As used herein, the term “alkoxy” includes O-alkyl groups, where “alkyl” is defined above.

  As used herein, the term “halo” includes fluoro, chloro, bromo or iodo unless otherwise indicated.

As used herein, the term “(C ₂ -C ₉ ) heterocycloalkyl” refers to pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydropyranyl, pyranyl, thiopyranyl, aziridinyl, oxiranyl, methylenedioxyl, chromenyl, isoxax Zolidinyl, 1,3-oxazolidine-3-yl, isothiazolidinyl, 1,3-thiazolidin-3-yl, 1,2-pyrazolidine-2-yl, 1,3-pyrazolidin-1-yl, piperidinyl Thiomorpholinyl, 1,2-tetrahydrothiazin-2-yl, 1,3-tetrahydrothiazin-3-yl, tetrahydrothiadiazinyl, morpholinyl, 1,2-tetrahydrodiazin-2-yl, 1,3- Tetrahydrodiazin-1-yl, tetrahydroazepinyl, piperazi Means nil, chromanyl and the like; One skilled in the art will appreciate that the attachment of the (C ₂ -C ₉ ) heterocycloalkyl ring is through a carbon or sp ³ hybrid nitrogen heteroatom.

As used herein, the term “(C ₂ -C ₉ ) heteroaryl” refers to furyl, thienyl, thiazolyl, pyrazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyrrolyl, triazolyl, tetrazolyl, imidazolyl, 1,3,5-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,3-oxadiazolyl, 1,3,5-thiadiazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, 1, 2,4-triazinyl, 1,2,3-triazinyl, 1,3,5-triazinyl, pyrazolo [3,4-b] pyridinyl, cinnolinyl, pteridinyl, purinyl, 6,7-dihydro-5H- [1] pyridinyl , Benzo [b] thiophenyl, 5,6,7,8-teto Lahydro-quinolin-3-yl, benzoxazolyl, benzothiazolyl, benzisothiazolyl, benzisoxazolyl, benzimidazolyl, thianaphthenyl, isothianaphthenyl, benzofuranyl, isobenzofuranyl, isoindolyl, indolyl, indolizinyl, indazolyl, isoquinolyl Quinolyl, phthalazinyl, quinoxalinyl, quinazolinyl, benzooxazinyl and the like. One skilled in the art will appreciate that the attachment of the (C ₂ -C ₉ ) heterocycloalkyl ring is through a carbon atom or sp ³ hybridized nitrogen heteroatom.

As used herein, (C ₆ -C ₁₀ ) aryl means phenyl or naphthyl.

  As used herein, the term “drug combination therapy” or simply “combination therapy” generally means administering a Janus kinase inhibitor in combination with one or more of the anti-arthritic agents disclosed herein. . In other words, the term “drug combination therapy” refers to a Janus kinase inhibitor, such as a compound of formula (I), in a pharmaceutically acceptable form together with one or more anti-arthritic agents disclosed herein. (I) the same dosage form, eg, a Janus kinase inhibitor, such as the same tablet or compound of formula (I), one or more anti-arthritic agents disclosed herein, and a pharmaceutically acceptable carrier A pharmaceutical composition comprising: (ii) separate dosage forms having the same mode of administration, eg, a Janus kinase inhibitor such as a compound of formula (I) and a pharmaceutically acceptable carrier A first pharmaceutical composition suitable for oral administration and a second pharmaceutical composition suitable for oral administration comprising one or more anti-arthritic agents disclosed herein and a pharmaceutically acceptable carrier Include And (iii) separate dosage forms with different modes of administration, for example, a first pharmaceutical composition suitable for oral administration comprising a Janus kinase inhibitor such as a compound of formula (I) and a pharmaceutically acceptable carrier And a second pharmaceutical composition suitable for parenteral administration comprising one or more anti-arthritic agents disclosed herein and a pharmaceutically acceptable carrier. . Further, to those of ordinary skill in the art having the benefit of this disclosure, when administering two or more anti-arthritic agents disclosed herein, the agents need not share the same mode of administration, eg, formula ( A first pharmaceutical composition suitable for oral administration comprising a Janus kinase inhibitor such as a compound of I) and a pharmaceutically acceptable carrier, a first anti-arthritic agent disclosed herein and a pharmaceutically acceptable A second pharmaceutical composition suitable for oral administration comprising a carrier, and a third pharmaceutical composition suitable for parenteral administration comprising a second anti-arthritic agent disclosed herein and a pharmaceutically acceptable carrier It will be appreciated that the kit may comprise For those skilled in the art, in the “drug combination therapy” said co-administration means that the pharmaceutical composition comprising the Janus kinase inhibitor and the pharmaceutical composition comprising the anti-arthritic agent are on the same schedule, ie simultaneously and on the same day It will be understood that it represents administration on a schedule, ie, a different but not necessarily different schedule. In that regard, when a pharmaceutical composition comprising a Janus kinase inhibitor and a pharmaceutical composition comprising an anti-arthritic agent are administered on different schedules, such different schedules are referred to herein as “background” or “background administration”. Sometimes referred to as a calligraphy. A pharmaceutical composition comprising a Janus kinase inhibitor is not necessarily, but can be administered simultaneously with a pharmaceutical composition comprising an anti-arthritic agent during one of the daily administrations, for example, Janus kinase A pharmaceutical composition comprising an inhibitor can be administered twice daily in a dosage form, and a pharmaceutical composition comprising an anti-arthritic agent can be administered once daily. Of course, other variations suitable for “drug combination therapy” should be readily apparent to those of ordinary skill in the art having the benefit of this disclosure and are part of the meaning of this term.

  As used herein, the term “janus kinase inhibitor” refers to one or more of the Janus kinases, ie, JAK1, JAK2, and JAK3, as measured by the biological assays disclosed herein. The compound which shows an inhibitory action with respect to 1 type of these is represented. Preferred Janus kinase inhibitors include those of Formula I disclosed herein. A more preferred Janus kinase inhibitor is 3-{(3R, 4R) -4-methyl-3- [methyl- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -amino] -piperidine-1 -Yl} -3-oxo-propionitrile or a pharmaceutically acceptable salt thereof.

  Since the term “concomitant” is used in the definition of “drug combination therapy”, the term “co-administering” refers to a Janus kinase inhibitor and one or more anti-cancer agents. Represents administration of an arthritic drug “concomitant”.

  In one aspect, the disclosure provides for treating or preventing human rheumatoid arthritis comprising a Janus kinase inhibitor or a pharmaceutically acceptable salt thereof and at least one anti-arthritic agent or a pharmaceutically acceptable salt thereof. Related to drug combination therapy.

  In some embodiments, the Janus kinase inhibitor has the formula

Ｉ
の化合物またはその薬学的に許容できる塩であり、式中
Ｒ^１は、式

I
Or a pharmaceutically acceptable salt thereof, wherein R ¹ is a compound of the formula

の基であり、
式中、ｙは、０、１または２であり、
Ｒ^４は、水素、（Ｃ_１〜Ｃ_６）アルキル、（Ｃ_１〜Ｃ_６）アルキルスルホニル、（Ｃ_２〜Ｃ_６）アルケニル、（Ｃ_２〜Ｃ_６）アルキニルからなる群から選択され、そのアルキル、アルケニルおよびアルキニル基は、重水素、ヒドロキシ、アミノ、トリフルオロメチル、（Ｃ_１〜Ｃ_４）アルコキシ、（Ｃ_１〜Ｃ_６）アシルオキシ、（Ｃ_１〜Ｃ_６）アルキルアミノ、（（Ｃ_１〜Ｃ_６）アルキル）_２アミノ、シアノ、ニトロ、（Ｃ_２〜Ｃ_６）アルケニル、（Ｃ_２〜Ｃ_６）アルキニルまたは（Ｃ_１〜Ｃ_６）アシルアミノで置換されていてもよく、あるいはＲ^４は、（Ｃ_３〜Ｃ_１０）シクロアルキルであり、そのシクロアルキル基は、重水素、ヒドロキシ、アミノ、トリフルオロメチル、（Ｃ_１〜Ｃ_６）アシルオキシ、（Ｃ_１〜Ｃ_６）アシルアミノ、（Ｃ_１〜Ｃ_６）アルキルアミノ、（（Ｃ_１〜Ｃ_６）アルキル）_２アミノ、シアノ、シアノ（Ｃ_１〜Ｃ_６）アルキル、トリフルオロメチル（Ｃ_１〜Ｃ_６）アルキル、ニトロ、ニトロ（Ｃ_１〜Ｃ_６）アルキルまたは（Ｃ_１〜Ｃ_６）アシルアミノで置換されていてもよく、
Ｒ^５は、（Ｃ_２〜Ｃ_９）ヘテロシクロアルキルであり、そのヘテロシクロアルキル基は、１〜５個のカルボキシ、シアノ、アミノ、重水素、ヒドロキシ、（Ｃ_１〜Ｃ_６）アルキル、（Ｃ_１〜Ｃ_６）アルコキシ、ハロ、（Ｃ_１〜Ｃ_６）アシル、（Ｃ_１〜Ｃ_６）アルキルアミノ、アミノ（Ｃ_１〜Ｃ_６）アルキル、（Ｃ_１〜Ｃ_６）アルコキシ−ＣＯ−ＮＨ、（Ｃ_１〜Ｃ_６）アルキルアミノ−ＣＯ−、（Ｃ_２〜Ｃ_６）アルケニル、（Ｃ_２〜Ｃ_６）アルキニル、（Ｃ_１〜Ｃ_６）アルキルアミノ、アミノ（Ｃ_１〜Ｃ_６）アルキル、ヒドロキシ（Ｃ_１〜Ｃ_６）アルキル、（Ｃ_１〜Ｃ_６）アルコキシ（Ｃ_１〜Ｃ_６）アルキル、（Ｃ_１〜Ｃ_６）アシルオキシ（Ｃ_１〜Ｃ_６）アルキル、ニトロ、シアノ（Ｃ_１〜Ｃ_６）アルキル、ハロ（Ｃ_１〜Ｃ_６）アルキル、ニトロ（Ｃ_１〜Ｃ_６）アルキル、トリフルオロメチル、トリフルオロメチル（Ｃ_１〜Ｃ_６）アルキル、（Ｃ_１〜Ｃ_６）アシルアミノ、（Ｃ_１〜Ｃ_６）アシルアミノ（Ｃ_１〜Ｃ_６）アルキル、（Ｃ_１〜Ｃ_６）アルコキシ（Ｃ_１〜Ｃ_６）アシルアミノ、アミノ（Ｃ_１〜Ｃ_６）アシル、アミノ（Ｃ_１〜Ｃ_６）アシル（Ｃ_１〜Ｃ_６）アルキル、（Ｃ_１〜Ｃ_６）アルキルアミノ（Ｃ_１〜Ｃ_６）アシル、（（Ｃ_１〜Ｃ_６）アルキル）_２アミノ（Ｃ_１〜Ｃ_６）アシル、Ｒ^１５Ｒ^１６Ｎ−ＣＯ−Ｏ−、Ｒ^１５Ｒ^１６Ｎ−ＣＯ−（Ｃ_１〜Ｃ_６）アルキル、（Ｃ_１〜Ｃ_６）アルキル−Ｓ（Ｏ）_ｍ、Ｒ^１５Ｒ^１６ＮＳ（Ｏ）_ｍ、Ｒ^１５Ｒ^１６ＮＳ（Ｏ）_ｍ（Ｃ_１〜Ｃ_６）アルキル、Ｒ^１５Ｓ（Ｏ）_ｍＲ^１６Ｎ、Ｒ^１５Ｓ（Ｏ）_ｍＲ^１６Ｎ（Ｃ_１〜Ｃ_６）アルキルで置換されていなければならず、そのｍは、０、１または２であり、またＲ^１５およびＲ^１６は、それぞれ独立に水素または（Ｃ_１〜Ｃ_６）アルキルから選択され、あるいは式

The basis of
In which y is 0, 1 or 2;
R ⁴ is selected from the group consisting of hydrogen, (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkylsulfonyl, (C ₂ -C ₆ ) alkenyl, (C ₂ -C ₆ ) alkynyl, Alkyl, alkenyl and alkynyl groups are deuterium, hydroxy, amino, trifluoromethyl, (C ₁ -C ₄ ) alkoxy, (C ₁ -C ₆ ) acyloxy, (C ₁ -C ₆ ) alkylamino, ((C ₁ -C _{6) alkyl) 2} amino, cyano, _{nitro, (C} 2 -C ₆₎ alkenyl _may be substituted with _(C 2 -C ₆₎ alkynyl, or _(C 1 -C ₆₎ acylamino, or R ⁴ is (C ₃ -C ₁₀ ) cycloalkyl, the cycloalkyl group being deuterium, hydroxy, amino, trifluoromethyl, (C ₁ -C ₆ ) acyloxy. Xi, (C ₁ -C ₆ ) acylamino, (C ₁ -C ₆ ) alkylamino, ((C ₁ -C ₆ ) alkyl) ₂ amino, cyano, cyano (C ₁ -C ₆ ) alkyl, trifluoromethyl ( C ₁ -C ₆ ) alkyl, nitro, nitro (C ₁ -C ₆ ) alkyl or (C ₁ -C ₆ ) acylamino may be substituted,
R ⁵ is (C ₂ -C ₉ ) heterocycloalkyl, whose heterocycloalkyl group is 1-5 carboxy, cyano, amino, deuterium, hydroxy, (C ₁ -C ₆ ) alkyl, ( C ₁ -C ₆₎ alkoxy, _{halo, (C} 1 ~C _{6) acyl, (C} 1 ~C ₆₎ alkylamino, amino _(C 1 ~C _{6) alkyl, (C} 1 ~C ₆₎ alkoxy -CO- _{NH, (C} 1 _{~C 6)} alkylamino _{-CO -, (C 2 ~C 6} ) _{alkenyl, (C} 2 _{~C 6) alkynyl, (C} 1 _{~C 6)} alkylamino, amino _(C 1 -C ₆ ) alkyl, hydroxy _(C 1 -C _{6) alkyl, (C} 1 -C ₆₎ alkoxy _(C 1 -C _{6) alkyl, (C} 1 -C ₆₎ acyloxy _(C 1 -C ₆₎ alkyl, nitro, cyano _(C 1 ~ ₆₎ alkyl, halo _(C 1 -C ₆₎ alkyl, nitro _(C 1 -C ₆₎ alkyl, trifluoromethyl, trifluoromethyl _(C 1 -C _{6) alkyl, (C} 1 -C ₆₎ acylamino, ( C ₁ -C ₆₎ acylamino _(C 1 _{~C 6) alkyl, (C} 1 _{~C 6)} alkoxy _(C 1 _{~C 6)} acylamino, amino _(C 1 _{~C 6)} acyl, amino _(C 1 -C ₆ ) Acyl (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkylamino (C ₁ -C ₆ ) acyl, ((C ₁ -C ₆ ) alkyl) ₂ amino (C ₁ -C ₆ ) acyl, ^{R 15 R 16 N-CO-} O-, R 15 R 16 N-CO- (C 1 ~C 6) _{alkyl, (C} 1 _{~C 6)} alkyl _{^{-S (O) m, R 15}} R 16 NS (O _{^{) m, R 15 R 16 NS}} (O _{m (C} 1 _{~C 6)} ^alkyl, must be substituted with _{^{R 15 S (O) m R}} 16 N, R 15 S (O) m R 16 N (C 1 ~C 6) alkyl, the m Is 0, 1 or 2, and R ¹⁵ and R ¹⁶ are each independently selected from hydrogen or (C ₁ -C ₆ ) alkyl, or

の基であり、
式中、ａは、０、１、２、３または４であり、
ｂ、ｃ、ｅ、ｆおよびｇは、それぞれ独立に０または１であり、
ｄは、０、１、２、または３であり、
Ｘは、ｎが０、１もしくは２であるＳ（Ｏ）_ｎ、酸素、カルボニルまたは−Ｃ（＝Ｎ−シアノ）−であり、
Ｙは、ｎが０、１もしくは２であるＳ（Ｏ）_ｎ、またはカルボニルであり、また
Ｚは、カルボニル、Ｃ（Ｏ）Ｏ−、Ｃ（Ｏ）ＮＲ−またはｎが０、１もしくは２であるＳ（Ｏ）_ｎであり、
Ｒ^６、Ｒ^７、Ｒ^８、Ｒ^９、Ｒ^１０およびＲ^１１は、それぞれ独立に、水素、または重水素、ヒドロキシ、アミノ、トリフルオロメチル、（Ｃ_１〜Ｃ_６）アシルオキシ、（Ｃ_１〜Ｃ_６）アシルアミノ、（Ｃ_１〜Ｃ_６）アルキルアミノ、（（Ｃ_１〜Ｃ_６）アルキル）_２アミノ、シアノ、シアノ（Ｃ_１〜Ｃ_６）アルキル、トリフルオロメチル（Ｃ_１〜Ｃ_６）アルキル、ニトロ、ニトロ（Ｃ_１〜Ｃ_６）アルキルもしくは（Ｃ_１〜Ｃ_６）アシルアミノで置換されていてもよい（Ｃ_１〜Ｃ_６）アルキルからなる群から選択され、
Ｒ^１２は、カルボキシ、シアノ、アミノ、オキソ、重水素、ヒドロキシ、トリフルオロメチル、（Ｃ_１〜Ｃ_６）アルキル、トリフルオロメチル（Ｃ_１〜Ｃ_６）アルキル、（Ｃ_１〜Ｃ_６）アルコキシ、ハロ、（Ｃ_１〜Ｃ_６）アシル、（Ｃ_１〜Ｃ_６）アルキルアミノ、（（Ｃ_１〜Ｃ_６）アルキル）_２アミノ、アミノ（Ｃ_１〜Ｃ_６）アルキル、（Ｃ_１〜Ｃ_６）アルコキシ−ＣＯ−ＮＨ、（Ｃ_１〜Ｃ_６）アルキルアミノ−ＣＯ−、（Ｃ_２〜Ｃ_６）アルケニル、（Ｃ_２〜Ｃ_６）アルキニル、（Ｃ_１〜Ｃ_６）アルキルアミノ、ヒドロキシ（Ｃ_１〜Ｃ_６）アルキル、（Ｃ_１〜Ｃ_６）アルコキシ（Ｃ_１〜Ｃ_６）アルキル、（Ｃ_１〜Ｃ_６）アシルオキシ（Ｃ_１〜Ｃ_６）アルキル、ニトロ、シアノ（Ｃ_１〜Ｃ_６）アルキル、ハロ（Ｃ_１〜Ｃ_６）アルキル、ニトロ（Ｃ_１〜Ｃ_６）アルキル、トリフルオロメチル、トリフルオロメチル（Ｃ_１〜Ｃ_６）アルキル、（Ｃ_１〜Ｃ_６）アシルアミノ、（Ｃ_１〜Ｃ_６）アシルアミノ（Ｃ_１〜Ｃ_６）アルキル、（Ｃ_１〜Ｃ_６）アルコキシ（Ｃ_１〜Ｃ_６）アシルアミノ、アミノ（Ｃ_１〜Ｃ_６）アシル、アミノ（Ｃ_１〜Ｃ_６）アシル（Ｃ_１〜Ｃ_６）アルキル、（Ｃ_１〜Ｃ_６）アルキルアミノ（Ｃ_１〜Ｃ_６）アシル、（（Ｃ_１〜Ｃ_６）アルキル）_２アミノ（Ｃ_１〜Ｃ_６）アシル、Ｒ^１５Ｒ^１６Ｎ−ＣＯ−Ｏ−、Ｒ^１５Ｒ^１６Ｎ−ＣＯ−（Ｃ_１〜Ｃ_６）アルキル、Ｒ^１５Ｃ（Ｏ）ＮＨ、Ｒ^１５ＯＣ（Ｏ）ＮＨ、Ｒ^１５ＮＨＣ（Ｏ）ＮＨ、（Ｃ_１〜Ｃ_６）アルキル−Ｓ（Ｏ）_ｍ、（Ｃ_１〜Ｃ_６）アルキル−Ｓ（Ｏ）_ｍ−（Ｃ_１〜Ｃ_６）アルキル、Ｒ^１５Ｒ^１６ＮＳ（Ｏ）_ｍ、Ｒ^１５Ｒ^１６ＮＳ（Ｏ）_ｍ（Ｃ_１〜Ｃ_６）アルキル、Ｒ^１５Ｓ（Ｏ）_ｍＲ^１６Ｎ、Ｒ^１５Ｓ（Ｏ）_ｍＲ^１６Ｎ（Ｃ_１〜Ｃ_６）アルキルであり、そのｍは、０、１または２であり、またＲ^１５およびＲ^１６は、それぞれ独立に水素または（Ｃ_１〜Ｃ_６）アルキルから選択され、
Ｒ^２およびＲ^３は、それぞれ独立に水素、重水素、アミノ、ハロ、ヒドロキシ、ニトロ、カルボキシ、（Ｃ_２〜Ｃ_６）アルケニル、（Ｃ_２〜Ｃ_６）アルキニル、トリフルオロメチル、トリフルオロメトキシ、（Ｃ_１〜Ｃ_６）アルキル、（Ｃ_１〜Ｃ_６）アルコキシ、（Ｃ_３〜Ｃ_１０）シクロアルキルからなる群から選択され、そのアルキル、アルコキシまたはシクロアルキル基は、ハロ、ヒドロキシ、カルボキシ、アミノ（Ｃ_１〜Ｃ_６）アルキルチオ、（Ｃ_１〜Ｃ_６）アルキルアミノ、（（Ｃ_１〜Ｃ_６）アルキル）_２アミノ、（Ｃ_５〜Ｃ_９）ヘテロアリール、（Ｃ_２〜Ｃ_９）ヘテロシクロアルキル、（Ｃ_３〜Ｃ_９）シクロアルキルまたは（Ｃ_６〜Ｃ_１０）アリールから選択される１〜３個の基で置換されていてもよく、あるいはＲ^２およびＲ^３は、それぞれ独立に（Ｃ_３〜Ｃ_１０）シクロアルキル、（Ｃ_３〜Ｃ_１０）シクロアルコキシ、（Ｃ_１〜Ｃ_６）アルキルアミノ、（（Ｃ_１〜Ｃ_６）アルキル）_２アミノ、（Ｃ_６〜Ｃ_１０）アリールアミノ、（Ｃ_１〜Ｃ_６）アルキルチオ、（Ｃ_６〜Ｃ_１０）アリールチオ、（Ｃ_１〜Ｃ_６）アルキルスルフィニル、（Ｃ_６〜Ｃ_１０）アリールスルフィニル、（Ｃ_１〜Ｃ_６）アルキルスルホニル、（Ｃ_６〜Ｃ_１０）アリールスルホニル、（Ｃ_１〜Ｃ_６）アシル、（Ｃ_１〜Ｃ_６）アルコキシ−ＣＯ−ＮＨ−、（Ｃ_１〜Ｃ_６）アルキルアミノ−ＣＯ−、（Ｃ_５〜Ｃ_９）ヘテロアリール、（Ｃ_２〜Ｃ_９）ヘテロシクロアルキルまたは（Ｃ_６〜Ｃ_１０）アリールであり、そのヘテロアリール、ヘテロシクロアルキルおよびアリール基は、１〜３個のハロ、（Ｃ_１〜Ｃ_６）アルキル、（Ｃ_１〜Ｃ_６）アルキル−ＣＯ−ＮＨ−、（Ｃ_１〜Ｃ_６）アルコキシ−ＣＯ−ＮＨ−、（Ｃ_１〜Ｃ_６）アルキル−ＣＯ−ＮＨ−（Ｃ_１〜Ｃ_６）アルキル、（Ｃ_１〜Ｃ_６）アルコキシ−ＣＯ−ＮＨ−（Ｃ_１〜Ｃ_６）アルキル、（Ｃ_１〜Ｃ_６）アルコキシ−ＣＯ−ＮＨ−（Ｃ_１〜Ｃ_６）アルコキシ、カルボキシ、カルボキシ（Ｃ_１〜Ｃ_６）アルキル、カルボキシ（Ｃ_１〜Ｃ_６）アルコキシ、ベンジルオキシカルボニル（Ｃ_１〜Ｃ_６）アルコキシ、（Ｃ_１〜Ｃ_６）アルコキシカルボニル（Ｃ_１〜Ｃ_６）アルコキシ、（Ｃ_６〜Ｃ_１０）アリール、アミノ、アミノ（Ｃ_１〜Ｃ_６）アルキル、（Ｃ_１〜Ｃ_６）アルコキシカルボニルアミノ、（Ｃ_６〜Ｃ_１０）アリール（Ｃ_１〜Ｃ_６）アルコキシカルボニルアミノ、（Ｃ_１〜Ｃ_６）アルキルアミノ、（（Ｃ_１〜Ｃ_６）アルキル）_２アミノ、（Ｃ_１〜Ｃ_６）アルキルアミノ（Ｃ_１〜Ｃ_６）アルキル、（（Ｃ_１〜Ｃ_６）アルキル）_２アミノ（Ｃ_１〜Ｃ_６）アルキル、ヒドロキシ、（Ｃ_１〜Ｃ_６）アルコキシ、カルボキシ、カルボキシ（Ｃ_１〜Ｃ_６）アルキル、（Ｃ_１〜Ｃ_６）アルコキシカルボニル、（Ｃ_１〜Ｃ_６）アルコキシカルボニル（Ｃ_１〜Ｃ_６）アルキル、（Ｃ_１〜Ｃ_６）アルコキシ−ＣＯ−ＮＨ−、（Ｃ_１〜Ｃ_６）アルキル−ＣＯ−ＮＨ−、シアノ、（Ｃ_５〜Ｃ_９）ヘテロシクロアルキル、アミノ−ＣＯ−ＮＨ−、（Ｃ_１〜Ｃ_６）アルキルアミノ−ＣＯ−ＮＨ−、（（Ｃ_１〜Ｃ_６）アルキル）_２アミノ−ＣＯ−ＮＨ−、（Ｃ_６〜Ｃ_１０）アリールアミノ−ＣＯ−ＮＨ−、（Ｃ_５〜Ｃ_９）ヘテロアリールアミノ−ＣＯ−ＮＨ−、（Ｃ_１〜Ｃ_６）アルキルアミノ−ＣＯ−ＮＨ−（Ｃ_１〜Ｃ_６）アルキル、（（Ｃ_１〜Ｃ_６）アルキル）_２アミノ−ＣＯ−ＮＨ−（Ｃ_１〜Ｃ_６）アルキル、（Ｃ_６〜Ｃ_１０）アリールアミノ−ＣＯ−ＮＨ−（Ｃ_１〜Ｃ_６）アルキル、（Ｃ_５〜Ｃ_９）ヘテロアリールアミノ−ＣＯ−ＮＨ−（Ｃ_１〜Ｃ_６）アルキル、（Ｃ_１〜Ｃ_６）アルキルスルホニル、（Ｃ_１〜Ｃ_６）アルキルスルホニルアミノ、（Ｃ_１〜Ｃ_６）アルキルスルホニルアミノ（Ｃ_１〜Ｃ_６）アルキル、（Ｃ_６〜Ｃ_１０）アリールスルホニル、（Ｃ_６〜Ｃ_１０）アリールスルホニルアミノ、（Ｃ_６〜Ｃ_１０）アリールスルホニルアミノ（Ｃ_１〜Ｃ_６）アルキル、（Ｃ_１〜Ｃ_６）アルキルスルホニルアミノ、（Ｃ_１〜Ｃ_６）アルキルスルホニルアミノ（Ｃ_１〜Ｃ_６）アルキル、（Ｃ_５〜Ｃ_９）ヘテロアリールまたは（Ｃ_２〜Ｃ_９）ヘテロシクロアルキルで置換されていてもよい。

The basis of
Where a is 0, 1, 2, 3 or 4;
b, c, e, f and g are each independently 0 or 1,
d is 0, 1, 2, or 3;
X is S (O) _{n in} which n is 0, 1 or 2, oxygen, carbonyl or -C (= N-cyano)-
Y is S (O) _n where n is 0, 1 or 2, or carbonyl, and Z is carbonyl, C (O) O—, C (O) NR—, or n is 0, 1 or 2 S (O) _n which is
R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ and R ¹¹ are each independently hydrogen, or deuterium, hydroxy, amino, trifluoromethyl, (C ₁ -C ₆ ) acyloxy, (C _1- C _{6) acylamino, (C} 1 -C ₆₎ alkylamino, _((C 1 _{~C 6) alkyl) 2} amino, cyano, cyano _(C 1 -C ₆₎ alkyl, trifluoromethyl _(C 1 _-C 6) Selected from the group consisting of alkyl, nitro, nitro (C ₁ -C ₆ ) alkyl or (C ₁ -C ₆ ) alkyl optionally substituted with (C ₁ -C ₆ ) acylamino;
R ¹² is carboxy, cyano, amino, oxo, deuterium, hydroxy, trifluoromethyl, (C ₁ -C ₆ ) alkyl, trifluoromethyl (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkoxy , Halo, (C ₁ -C ₆ ) acyl, (C ₁ -C ₆ ) alkylamino, ((C ₁ -C ₆ ) alkyl) ₂ amino, amino (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆₎ alkoxy _{-CO-NH, (C 1 ~C} 6) alkylamino _{-CO -, (C 2 ~C 6} ) _{alkenyl, (C} 2 -C _{6) alkynyl, (C} 1 -C ₆₎ alkylamino, hydroxy (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkoxy (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) acyloxy (C ₁ -C ₆ ) alkyl, nitro, cyano (C ₁ -C C ₆ ) Alkyl, halo (C ₁ -C ₆ ) alkyl, nitro (C ₁ -C ₆ ) alkyl, trifluoromethyl, trifluoromethyl (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) acylamino, (C ₁ -C ₆₎ acylamino _(C 1 ~C _{6) alkyl, (C} 1 ~C ₆₎ alkoxy _(C 1 ~C ₆₎ acylamino, amino _(C 1 ~C ₆₎ acyl, amino _(C 1 ~C 6) Acyl (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkylamino (C ₁ -C ₆ ) acyl, ((C ₁ -C ₆ ) alkyl) ₂ amino (C ₁ -C ₆ ) acyl, R ¹⁵ R ¹⁶ N—CO—O—, R ¹⁵ R ¹⁶ N—CO— (C ₁ -C ₆ ) alkyl, R ¹⁵ C (O) NH, R ¹⁵ OC (O) NH, R ¹⁵ NHC (O) NH , _(C 1 ~C ₆₎ alkyl - _{(O) m, (C 1} ~C 6) alkyl _{-S (O) m - (C} 1 ~C 6) ^{_{alkyl, R 15 R 16 NS (O}} ) m, R 15 R 16 NS (O) m (C ₁ -C ₆ ) alkyl, R ¹⁵ S (O) _m R ¹⁶ N, R ¹⁵ S (O) _m R ¹⁶ N (C ₁ -C ₆ ) alkyl, where m is 0, 1 or 2 And R ¹⁵ and R ¹⁶ are each independently selected from hydrogen or (C ₁ -C ₆ ) alkyl;
R ² and R ³ are each independently hydrogen, deuterium, amino, halo, hydroxy, nitro, carboxy, (C ₂ -C ₆ ) alkenyl, (C ₂ -C ₆ ) alkynyl, trifluoromethyl, trifluoromethoxy , (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkoxy, (C ₃ -C ₁₀ ) cycloalkyl, wherein the alkyl, alkoxy or cycloalkyl group is halo, hydroxy, carboxy , Amino (C ₁ -C ₆ ) alkylthio, (C ₁ -C ₆ ) alkylamino, ((C ₁ -C ₆ ) alkyl) ₂ amino, (C ₅ -C ₉ ) heteroaryl, (C ₂ -C ₉ ) _{heterocycloalkyl,} optionally substituted with 1 to 3 groups selected from _(C 3 -C ₉₎ cycloalkyl or _(C 6 _{-C 10)} aryl Be good or ^{R 2} and ^{R 3,} are each independently _(C 3 _{~C 10) cycloalkyl, (C} 3 ~C _{10) cycloalkoxy, (C} 1 _{~C 6)} alkylamino, _((C 1 ~ C _{6) alkyl) 2 amino, (C} 6 _{~C 10) arylamino, (C} 1 _{~C 6) alkylthio, (C} 6 _{~C 10) arylthio, (C} 1 _{~C 6)} alkylsulfinyl, _(C 6 ~ C _{10) arylsulfinyl, (C} 1 _{~C 6) alkylsulfonyl, (C} 6 _{~C 10) arylsulfonyl, (C} 1 _{~C 6) acyl, (C} 1 _{~C 6)} alkoxy -CO-NH -, ( C ₁ -C ₆ ) alkylamino-CO—, (C ₅ -C ₉ ) heteroaryl, (C ₂ -C ₉ ) heterocycloalkyl or (C ₆ -C ₁₀ ) aryl, The heteroaryl, heterocycloalkyl and aryl groups, 1-3 _{halo, (C} 1 _{~C 6) alkyl, (C} 1 _{~C 6)} alkyl _{-CO-NH -, (C 1} ~C 6) alkoxy _{-CO-NH -, (C 1} ~C 6) alkyl _{-CO-NH- (C 1 ~C 6} ) _{alkyl, (C} 1 _{~C 6)} alkoxy _{-CO-NH- (C 1 ~C 6} ) alkyl, (C ₁ -C ₆ ) alkoxy-CO—NH— (C ₁ -C ₆ ) alkoxy, carboxy, carboxy (C ₁ -C ₆ ) alkyl, carboxy (C ₁ -C ₆ ) alkoxy, benzyloxycarbonyl (C ₁ -C _{6) alkoxy, (C} 1 ~C ₆₎ alkoxycarbonyl _(C 1 ~C _{6) alkoxy, (C} 6 ~C ₁₀₎ aryl, amino, amino _(C 1 ~C ₆₎ alkyl, (C ₁ -C _{6) alkoxycarbonylamino, (C} 6 ~C ₁₀₎ aryl _(C 1 -C _{6) alkoxycarbonylamino, (C} 1 ~C ₆₎ alkylamino, _((C 1 ~C _{6) alkyl) 2} amino , (C ₁ -C ₆ ) alkylamino (C ₁ -C ₆ ) alkyl, ((C ₁ -C ₆ ) alkyl) ₂ amino (C ₁ -C ₆ ) alkyl, hydroxy, (C ₁ -C ₆ ) alkoxy , Carboxy, carboxy (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkoxycarbonyl, (C ₁ -C ₆ ) alkoxycarbonyl (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkoxy- _{CO-NH -, (C 1} ~C 6) alkyl -CO-NH-, _{cyano, (C} 5 _{~C 9)} heterocycloalkyl, amino _{-CO-NH -, (C 1} ~C 6) Alkylamino _{-CO-NH -, ((C} 1 ~C 6) _{alkyl) 2} amino _{-CO-NH -, (C 6} ~C 10) arylamino _{-CO-NH -, (C 5} ~C 9) heteroarylamino _{-CO-NH -, (C 1} ~C 6) alkylamino _{-CO-NH- (C 1 ~C 6} ) alkyl, _((C 1 ~C _{6) alkyl) 2} amino -CO-NH- _(C 1 ~ C _{6) alkyl, (C} 6 _{~C 10)} arylamino _{-CO-NH- (C 1 ~C 6} ) _{alkyl, (C} 5 _{~C 9)} heteroarylamino _{-CO-NH- (C 1 ~C 6} ) Alkyl, (C ₁ -C ₆ ) alkylsulfonyl, (C ₁ -C ₆ ) alkylsulfonylamino, (C ₁ -C ₆ ) alkylsulfonylamino (C ₁ -C ₆ ) alkyl, (C ₆ -C ₁₀ ) aryl Sulfonyl , (C ₆ -C ₁₀ ) arylsulfonylamino, (C ₆ -C ₁₀ ) arylsulfonylamino (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkylsulfonylamino, (C ₁ -C ₆ ) alkyl It may be substituted with sulfonylamino (C ₁ -C ₆ ) alkyl, (C ₅ -C ₉ ) heteroaryl or (C ₂ -C ₉ ) heterocycloalkyl.

In some embodiments of the compound of Formula I, the Janus kinase inhibitor is
Methyl- [4-methyl-1- (propane-1-sulfonyl) -piperidin-3-yl]-(7H-pyrrolo [2,3-d] pyrimidin-4-yl) -amine;
4-methyl-3- [methyl- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -amino] -piperidine-1-carboxylic acid methyl ester;
3,3,3-trifluoro-1- {4-methyl-3- [methyl- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -amino] -piperidin-1-yl} -propane -1-one;
4-methyl-3- [methyl- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -amino] -piperidine-1-carboxylic acid dimethylamide;
({4-Methyl-3- [methyl- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -amino] -piperidine-1-carbonyl} -amino) -acetic acid ethyl ester;
3- {4-methyl-3- [methyl- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -amino] -piperidin-1-yl} -3-oxo-propionitrile;
3,3,3-trifluoro-1- {4-methyl-3- [methyl- (5-methyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl) -amino] -piperidine-1- Il} -propan-1-one;
1- {4-methyl-3- [methyl- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -amino] -piperidin-1-yl} -but-3-in-1-one;
1- {3-[(5-chloro-7H-pyrrolo [2,3-d] pyrimidin-4-yl) -methyl-amino] -4-methyl-piperidin-1-yl} -propan-1-one;
1- {3-[(5-fluoro-7H-pyrrolo [2,3-d] pyrimidin-4-yl) -methyl-amino] -4-methyl-piperidin-1-yl} -propan-1-one;
N-cyano-4-methyl-3- [methyl- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -amino] -N′-propyl-piperidine-1-carboxamidine;
N-cyano-4, N ′, N′-trimethyl-3- [methyl- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -amino] -piperidine-1-carboxamidine;
Methyl-[(3R, 4R) -4-methyl-1- (propane-1-sulfonyl) -piperidin-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] -piperidine-1-carboxylic acid methyl ester;
3,3,3-trifluoro-1-{(3R, 4R) -4-methyl-3- [methyl- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -amino] -piperidine- 1-yl} -propan-1-one;
(3R, 4R) -4-methyl-3- [methyl- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -amino] -piperidine-1-carboxylic acid dimethylamide;
{(3R, 4R) -4-methyl-3- [methyl- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -amino] -piperidine-1-carbonyl} -amino) -acetic acid ethyl ester ;
3-{(3R, 4R) -4-methyl-3- [methyl- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -amino] -piperidin-1-yl} -3-oxo- Propionitrile;
3,3,3-trifluoro-1-{(3R, 4R) -4-methyl-3- [methyl- (5-methyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl) -amino ] -Piperidin-1-yl} -propan-1-one;
1-{(3R, 4R) -4-methyl-3- [methyl- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -amino] -piperidin-1-yl} -but-3- In-1-on;
1-{(3R, 4R) -3-[(5-Chloro-7H-pyrrolo [2,3-d] pyrimidin-4-yl) -methyl-amino] -4-methyl-piperidin-1-yl}- Propan-1-one;
1-{(3R, 4R) -3-[(5-Fluoro-7H-pyrrolo [2,3-d] pyrimidin-4-yl) -methyl-amino] -4-methyl-piperidin-1-yl}- Propan-1-one;
(3R, 4R) -N-cyano-4-methyl-3- [methyl- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -amino] -N'-propyl-piperidine-1-carboxamidine And (3R, 4R) -N-cyano-4, N ′, N′-trimethyl-3- [methyl- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -amino] -piperidine-; 1-carboxamidine,
Or it is selected from the group consisting of pharmaceutically acceptable salts thereof.

  In some embodiments, the Janus kinase inhibitor is 3- {4-methyl-3- [methyl- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -amino] -piperidine-1- IL} -3-oxo-propionitrile or a pharmaceutically acceptable salt thereof.

  In some embodiments, the Janus kinase inhibitor is 3-{(3R, 4R) -4-methyl-3- [methyl- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -amino. ] -Piperidin-1-yl} -3-oxo-propionitrile or a pharmaceutically acceptable salt thereof.

  In some embodiments, 3- {4-methyl-3- [methyl- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -amino] -piperidin-1-yl} -3-oxo -Propionitrile and / or 3-{(3R, 4R) -4-methyl-3- [methyl- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -amino] -piperidine-1- A pharmaceutically acceptable salt of yl} -3-oxo-propionitrile is a citrate such as a monocitrate. In some embodiments, such compounds are crystals, as discussed in US Pat. No. 6,965,027, the contents of which are hereby incorporated by reference.

  The Janus kinase inhibitor of the present disclosure may be in the form of a pharmaceutically acceptable acid addition salt. The acids used to prepare the pharmaceutically acceptable acid addition salts of the aforementioned basic compounds of the present disclosure are non-toxic acid addition salts, ie, hydrochloride, hydrobromide, hydroiodide, nitrate , Sulfate, bisulfate, phosphate, acid phosphate, acetate, lactate, citrate, acid citrate, tartrate, hydrogen tartrate, succinate, maleate, fumarate , Gluconate, saccharide, benzoate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate and pamoate [ie, 1,1′-methylene-bis- It forms a salt containing a pharmacologically acceptable anion such as (2-hydroxy-3-naphthoate)] salt.

  The Janus kinase inhibitor of the present disclosure may be in the form of a pharmaceutically acceptable base addition salt. Chemical bases that can be used as reagents for preparing pharmaceutically acceptable base salts of compounds of formula I that are acidic in nature are those that form non-toxic base salts with such compounds. Such non-toxic base salts include alkali metal cations (eg potassium and sodium) and alkaline earth metal cations (eg calcium and magnesium), ammonium or soluble amine addition salts such as N-methylglucamine- (meglumine), And those derived from such pharmacologically acceptable cations such as, but not limited to, lower alkanol ammonium and other base salts of pharmaceutically acceptable organic amines.

  Some Janus kinase inhibitors referred to herein are essentially basic and are capable of forming a wide variety of different salts with various inorganic and organic acids. Such salts must be pharmaceutically acceptable for administration to animals, but the compounds of the present disclosure are first isolated from the reaction mixture as pharmaceutically unacceptable salts, and then the latter can also be treated by alkaline reagents. It is often often desirable to simply convert to the free base compound followed by conversion of the latter free base to a pharmaceutically acceptable acid addition salt. Acid addition salts of the basic compounds of the present disclosure are readily prepared by treating the basic compound with a substantially equivalent amount of the selected mineral or organic acid aqueous solvent or a suitable organic solvent such as methanol or ethanol. . The desired solid salt is readily obtained after careful evaporation of the solvent. The desired acid salt can also be precipitated from an organic solvent solution of the free base by adding the appropriate mineral or organic acid to the solution.

  Some Janus kinase inhibitors referred to herein are acidic in nature and can form base salts with various pharmacologically acceptable cations. Examples of such salts are alkali metal or alkaline earth metal salts, especially sodium and potassium salts. These salts are all prepared by conventional techniques. Chemical bases used as reagents for preparing the pharmaceutically acceptable base salts of the present disclosure are those that form non-toxic base salts with the acidic compounds of the present disclosure. Such non-toxic base salts include those derived from pharmacologically acceptable cations such as sodium, potassium, calcium and magnesium. 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 preferably to dryness under reduced pressure. it can. Alternatively, they can be prepared by mixing together a lower alkanol solution of an acidic compound and the desired alkali metal alkoxide and then evaporating the resulting solution to dryness as previously described. In either case, stoichiometric amounts of reagents are preferably used to ensure reaction integrity and maximum yield of the desired end product.

In some embodiments, the Janus kinase inhibitor is hereby incorporated herein by reference in its entirety:
USSN 09/335030 issued as US Pat. No. 6,635,762;
USSN 10/640079, published as US Publication No. 2004-0058922A1;
USSN 09/335121;
USSN 09/9566645, issued as US Pat. No. 6,610,847;
USSN 10/442807, issued as US Pat. No. 6,890,929;
USSN 11 / 064,873 published as US Publication No. 2005-0171128;
USSN 09/732669 issued as US Pat. No. 6,627,754;
USSN 10/640227, issued as US Pat. No. 6,956,041;
USSN 11 / 211,217, issued as US Pat. No. 7,091,208;
USSN 11 / 474,233;
USSN 09/891028, issued as US Pat. No. 6,696,567;
USSN 10/463724, issued as US Pat. No. 6,962,993;
USSN 11/112307, published as US Publication No. 2005-0197349;
USSN 10/154699 published as US Publication 2003-0073719A1;
USSN 10/869101 published as US Publication No. 2004-0229923 A1;
USSN 10/310078, issued as US Pat. No. 6,965,027;
USSN 11/032990, published as US Publication No. 2005-0159434A1
Or a compound specified and / or exemplified.

Janus kinase inhibitors of the present disclosure include all conformers (eg, cis and trans isomers) and mixtures thereof. Such compounds have asymmetric centers that are readily apparent to those skilled in the art and therefore exist in different enantiomeric and diastereoisomeric forms. The present disclosure relates to the use of all optical isomers and stereoisomers and mixtures thereof of such compounds used in the present disclosure, and all pharmaceutical compositions and methods of treatment that may use or contain them. In this regard, the present disclosure includes both E and Z configurations. In particular, resolution of a racemic mixture of enantiomers of a compound used to produce the R ¹ substituent of formula I can be achieved by reacting a compound of formula HNR ⁴ R ⁵ , eg, a racemic mixture of a compound of formula III As a specific optical isomer of disubstituted tartaric acid or tartrate dissolved in a suitable solvent such as ethanol with or without water. The desired enantiomer can be obtained in greater than 90% using the method disclosed in US application 10 / 154,699, the contents of which are hereby incorporated herein by reference. Specific resolving agents useful for the resolution include di-p-toluoyl-L-tartaric acid and (S)-(+)-andenoic acid (pencyphos, (S)-(+)- There are optical isomers of tartaric acid and tartaric acid derivatives such as 2-hydroxy-5,5-dimethyl-4-phenyl-1,3,2-dioxyphosphorinane-2-oxide) salt. Of course, one of ordinary skill in the art having the benefit of this disclosure will appreciate other suitable resolving agents that are potentially useful for resolving such compounds of formula HNR ⁴ R ⁵ .

  The Janus kinase inhibitor of the present disclosure may exist as a tautomer. The present disclosure relates to the use of all such tautomers and mixtures thereof.

The racemic mixture is resolved by the interaction between the enantiomer of the resolving material and the specific enantiomer, thereby obtaining one of the desired stereospecific materials from the precipitation of the resolving material and the enantiomer. Thus, the remaining enantiomers in the solution can be isolated individually. Thus, depending on the particular enantiomer desired and the separation method to be used (ie from precipitation or solution), the stereospecific nature of the resolution property can be concomitantly selected; eg tartrate derivatives etc. The “L” form of the resolving agent results in precipitation of the “R” form of the R ¹ substituent and a solution containing the “L” form, and vice versa.

  The resolving agent described above is effective to produce the 3R, 4R enantiomer of the compound of formula III (either as precipitated or in solution as described):

いくつかの実施形態では、式ＩＩＩの化合物の分割は：
ａ）溶液からラセミ混合物の立体特異性的な異性体の大量の沈殿を可能にするのに十分な時間、適切な溶液中で式ＩＩＩの化合物のラセミ混合物と定義された立体特異性を有する分割化合物とを混合するステップ；
ｂ）望まれる化合物の立体特異的形態に応じて、沈殿を捕集し、精製するステップまたは母液を捕集し、そこに含まれる鏡像異性体を再結晶させるステップ
によって行う。

In some embodiments, resolution of the compound of formula III is:
a) Resolution with the stereospecificity defined as a racemic mixture of the compound of formula III in a suitable solution for a time sufficient to allow a large amount of precipitation of the stereospecific isomer of the racemic mixture from solution. Mixing with the compound;
b) depending on the stereospecific form of the desired compound, by collecting the precipitate and purifying or collecting the mother liquor and recrystallizing the enantiomers contained therein.

  Depending on the material, a slurry is produced rather than a solution, and inter-slurry conversion is involved in the division of this disclosure. The term “solution” includes both solutions and slurries.

  The temperature at which splitting and precipitation occurs is preferably ambient temperature and the precipitation time is preferably about 4 hours or less, although not limited for efficiency. To facilitate resolution, it is desirable to use the enantiomers in a stable form of the racemic mixture, and the compound of formula II is most stable in acid addition salt forms such as hydrochloride rather than the free base form. It is preferred that the compound mixture is converted depending on the situation prior to resolution. Thus, for example, the formation of the hydrochloride salt of the compound of formula II is preferably carried out in ethanol with a small amount of toluene as co-solvent. Alternatively, methanol, isopropanol, acetonitrile, or tetrahydrofuran (or mixtures thereof with or without water as a cosolvent) with toluene, ethyl acetate, dichloromethane, dichloroethane, or tetrahydrofuran cosolvent can be used for salt formation. The HCl salt form is particularly preferred because the HCl salt form allows for excellent purification and is rich in other stereoisomers from the previous step.

  The preferred displacement solvent used in the resolution is ethyl acetate. Toluene, acetonitrile, or heptane is also useful as a solvent.

  A preferred isolation solvent is acetone. Other solvents useful in this regard include isopropanol, ethanol, methyl ethyl ketone, methyl isopropyl ketone, acetonitrile, and tetrahydrofuran. Solvents can also be used as co-solvents with each other or with water.

  Preferred resolution compounds include tartaric acid and its derivatives, such as toluoyl and benzoyl tartaric acid, having the stereospecific stereostructure as described above. Other resolution compounds include stereospecific adenoic acids and derivatives thereof.

  Addition of seed crystals is optional to facilitate precipitation and recrystallization, but is preferred to obtain higher ee material with less recrystallization.

  The present disclosure also encompasses pharmaceutical compositions containing a prodrug of a Janus kinase inhibitor of the present disclosure, such as a compound of Formula I, and the use of such prodrugs in currently disclosed drug combination therapies. Compounds of formula I having free amino, amide, hydroxy or carboxyl groups can be converted into prodrugs. Prodrugs include those amino acid residues, or a polypeptide chain of two or more (eg, 2, 3 or 4) amino acid residues via a peptide bond, the free amino, hydroxy or carboxylic acid group of a compound of formula I Includes a covalently bonded compound. Amino acid residues include the 20 naturally occurring amino acids, generally represented by three letter abbreviations, and also 4-hydroxyproline, hydroxylysine, demosin, isodesomocin, 3-methylhistidine, norvlin, β -Alanine, γ-aminobutyric acid, citrulline, homocysteine, homoserine, ornithine and methionine sulfone are also included. Prodrugs also include compounds in which the carbonate, carbamic acid, amide and alkyl ester are covalently bonded to the substituent of formula I above through the carbonyl carbon prodrug side chain.

  In reaction 1 of preparation A, a 4-chloropyrrolo [2,3-d] pyrimidine compound of formula XXI, wherein R is hydrogen or a protecting group such as benzenesulfonyl or benzyl, is prepared by reacting XXI with N-chlorosuccinimide, N-bromo Conversion to a 4-chloro-5-halopyrrolo [2,3-d] pyrimidine compound of formula XX where Y is chloro, bromo or iodo by reacting with succinimide or N-iodosuccinimide. The reaction mixture is heated to reflux in chloroform for a period of about 1 hour to about 3 hours, preferably about 1 hour. Alternatively, in Reaction 1 of Preparation A, 4-chloropyrrolo [2,3-d] pyrimidine of Formula XXI, wherein R is hydrogen, is about -10 ° C to about 10 ° C of XXI and nitric acid in sulfuric acid. By reacting at a temperature, preferably about 0 ° C., for a period of about 5 minutes to about 15 minutes, preferably about 10 minutes, the corresponding 4-chloro-5-nitropyrrolo [2, wherein Y is nitro, 3-d] Convert to pyrimidine. A compound of formula XXI where Y is nitro is reacted with XXI under various conditions well known to those skilled in the art, such as palladium hydrogenolysis or tin (IV) chloride and hydrochloric acid, wherein Y is amino Convert to the corresponding 4-chloro-5-aminopyrrolo [2,3-d] pyrimidine of formula XX.

In Reaction 2 of Preparation A, a 4-chloro-5-halopyrrolo [2,3-d] pyrimidine compound of Formula XX, wherein R is hydrogen, is treated with N-butyllithium at a temperature of about −78 ° C. And reacting the dianion intermediate so produced with an alkyl halide or benzyl halide at a temperature of about −78 ° C. to room temperature, preferably at room temperature, wherein R ² is (C ₁ -C ₆ ) alkyl or Convert to the corresponding compound of formula XIX which is benzyl. Alternatively, the dianion so produced is reacted with molecular oxygen to produce the corresponding 4-chloro-5-hydroxypyrrolo [2,3-d] pyrimidine compound of formula XIX, wherein R ² is hydroxy. . A compound of formula XX where Y is bromine or iodine and R is a benzenesulfonate is treated with N-butyllithium at a temperature of about -78 ° C followed by a temperature of about -78 ° C. Zinc chloride is added to convert to a compound of formula XIX where R ² is (C ₆ -C ₁₂ ) aryl or vinyl. The corresponding organozinc intermediate thus produced is then reacted with an aryl iodide or vinyl iodide in the presence of a catalytic amount of palladium. The reaction mixture is stirred at a temperature of about 50 ° C. to about 80 ° C., preferably about 70 ° C., for a period of about 1 hour to about 3 hours, preferably about 1 hour.

In Reaction 3 of Preparation A, treating a compound of formula XIX with N-butyllithium, lithium diisopropylamine or sodium hydride at a temperature of about −78 ° C. in the presence of a polar protic solvent such as tetrahydrofuran. To the corresponding compound of formula XVI. The anion intermediate so produced is (a) when R ³ is alkyl or benzyl and at a temperature of about −78 ° C. to room temperature, preferably −78 ° C. with an alkyl halide or benzyl halide; (b) R ³ When is an alkoxy, it is further reacted with an aldehyde or ketone at a temperature from about −78 ° C. to room temperature, preferably at −78 ° C .; and (c) zinc chloride at a temperature from about −78 ° C. to room temperature, preferably at −78 ° C. The corresponding organozinc intermediate thus produced is then reacted with an aryl iodide or vinyl iodide in the presence of a catalytic amount of palladium. The resulting reaction mixture is stirred at a temperature of about 50 ° C. to about 80 ° C., preferably about 70 ° C. for a period of about 1 hour to about 3 hours, preferably about 1 hour. Alternatively, the anion so produced is reacted with molecular oxygen to produce the corresponding 4-chloro-6-hydroxypyrrolo [2,3-d] pyrimidine compound of formula XVI, wherein R ³ is hydroxy. .

  In Reaction 1 of Preparation B, the 4-chloropyrrolo [2,3-d] pyrimidine compound of Formula XXI is converted to the corresponding compound of Formula XXII according to the procedure described above in Reaction 3 of Preparation A.

  In Reaction 2 of Preparation B, the compound of formula XXII is converted to the corresponding compound of Formula XVI according to the procedure described above in Reactions 1 and 2 of Preparation A.

  In Reaction 1 of Scheme 1, a 4-chloropyrrolo [2,3-d] pyrimidine compound of formula XVII is prepared in the presence of a base such as sodium hydride or potassium carbonate and a polar aprotic solvent such as dimethylformamide or tetrahydrofuran. Is converted to the corresponding compound of formula XVI wherein R is benzenesulfonyl or benzyl by treatment with benzenesulfonyl chloride, benzyl chloride or benzyl bromide. The reaction mixture is stirred at a temperature of about 0 ° C. to about 70 ° C., preferably about 30 ° C., for a period of about 1 hour to about 3 hours, preferably about 2 hours.

In Reaction 2 of Scheme 1, a 4-chloropyrrolo [2,3-d] pyrimidine compound of formula XVI is reacted with an amine of formula HNR ⁴ R ⁵ and XVI by coupling the corresponding 4-aminopyrrolo [2,3 of formula XV. -D] Convert to pyrimidine compound. In some embodiments, a 4-chloropyrrolo [2,3-d] pyrimidine compound of formula XVI is coupled with an enantiomer that has achieved resolution of NHR ⁴ R ⁵ , ie, a single stereoisomer of formula III. To obtain the corresponding 4-aminopyrrolo [2,3-d] pyrimidine compound of formula XV having the same stereochemistry as the resolved reactant of formula NHR ⁴ R ⁵ . That is, the coupling reaction 2 in such an embodiment proceeds without reversal or loss of stereochemistry and instead proceeds with retention of stereochemistry. This lack of stereochemistry inversion or loss and retention of stereochemistry continues for the rest of the synthesis described below to give compounds of formula I. The reaction is carried out at a temperature of about 60 ° C. to about 120 ° C. in an alcohol solvent such as tert-butanol, methanol or ethanol, or other high boiling organic solvents such as dimethylformamide, triethylamine, 1,4-dioxane or 1,2-dichloroethane. Preferably at about 80 ° C. Normal reaction times are about 2 hours to about 48 hours, preferably about 16 hours. When R ⁵ is a nitrogen containing a heterocycloalkyl group, each nitrogen must be protected by a protecting group such as benzyl. Removal of the R ⁵ protecting group is carried out under conditions appropriate for the particular protecting group being used that does not affect the R protecting group on the pyrrolo [2,3-d] pyrimidine ring. Removal of the R ⁵ protecting group in the case of benzyl is carried out in an alcohol solvent such as ethanol in the presence of hydrogen and a catalyst such as palladium hydroxide / carbon. The R ⁵ nitrogen containing the heterocycloalkyl group so produced may be further reacted with a variety of different electrophiles of formula II. In the case of urea production, an electrophile of formula II such as isocyanate, carbamic acid and carbamoyl chloride is reacted in the presence of a base such as sodium or potassium carbonate at a temperature of about 20 ° C. to about 100 ° C. for about 24 hours to about 72 hours. For a period of time, react with the R ⁵ nitrogen of the heteroalkyl group in a solvent such as acetonitrile or dimethylformamide. For the formation of amides and sulfonamides, electrophiles of formula II such as acyl chlorides and sulfonyl chlorides are reacted with a solvent such as methylene chloride in the presence of a base such as pyridine for a period of about 12 hours to about 24 hours at ambient temperature. In which it is reacted with the R ⁵ nitrogen of the heteroalkyl group. Amide formation involves reacting a carboxylic acid with a heteroalkyl group in a solvent such as methylene chloride in the presence of a carbodiimide such as 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide at ambient temperature for 12-24 hours. Can also be implemented. For alkyl formation, electrophiles of formula II such as α, β-unsaturated amides, acids, nitriles, esters, and α-haloamides are allowed to react at ambient temperature with a solvent such as methanol for a period of about 12 hours to about 18 hours. In which it is reacted with the R ⁵ nitrogen of the heteroalkyl group. Alkyl formation is carried out by reacting an aldehyde with a heteroalkyl group in a solvent such as methanol in the presence of a reducing agent such as sodium cyanoborohydride for a period of about 12 hours to about 18 hours at ambient temperature. You can also.

  In Reaction 3 of Scheme 1, removal of the protecting group from a compound of formula XV where R is benzenesulfonyl to obtain the corresponding compound of formula I can be accomplished by reacting XV with an alcohol solvent such as methanol or ethanol, or alcohol / Treatment with an alkali base such as sodium hydroxide or potassium hydroxide in a mixed solvent such as tetrahydrofuran or alcohol / water. The reaction is carried out at room temperature for a period of about 15 minutes to about 1 hour, preferably 30 minutes. Removal of the protecting group from the compound of Formula XV where R is benzyl is accomplished by treating XV with sodium in ammonia for a period of about 15 minutes to about 1 hour at a temperature of about -78 ° C.

  In Reaction 2 of Scheme 2, the 4-chloropyrrolo [2,3-d] pyrimidine compound of Formula XX is converted to the corresponding 4-aminopyrrolo [2,3-d of Formula XXIV according to the procedure described above in Reaction 2 of Scheme 1. ] Convert to pyrimidine compound.

In Reaction 2 of Scheme 2, a 4-amino-5-halopyrrolo [2,3-d] pyrimidine compound of Formula XXIV, wherein R is a benzenesulfonate salt and Z is bromine or iodine, is XXIV (a ) In the presence of a catalytic amount of palladium (0), a temperature of about 50 ° C. to about 100 ° C., preferably about 70 ° C. for a period of about 2 hours to about 48 hours, preferably about 12 hours, such as tetrahydrofuran or dioxane. In an aprotic solvent when R ² is aryl, aryl boronic acid; (b) catalytic amounts of copper (I) and palladium (0), and in the presence of a polar solvent such as dimethylformamide at room temperature in about 1 hour to about 5 hours period, preferably about 3 hours, when R ² is alkynyl, alkyne; in the presence of palladium and (c) a catalytic amount, about 80 ° C. to about 10 ° C. temperature, preferably at about 100 ° C., for a period of about 2 hours to about 48 hours, preferably about 48 hours, dimethylformamide, dioxane or tetrahydrofuran, when R ² is vinyl or styrenyl, reacts with alkene or styrene To the corresponding compound of formula XXIII.

  In Reaction 3 of Scheme 2, the compound of Formula XXIII is converted to the corresponding compound of Formula XV according to the procedure described above in Reaction 3 of Preparation A.

  In Reaction 1 of Scheme 3, the compound of Formula XVII is converted to the corresponding compound of Formula I according to the procedure described above in Reaction 2 of Scheme 1.

  In some embodiments, the anti-arthritic agent is other salicylic acid such as acetylsalicylic acid (eg, aspirin®) and choline magnesium trisalicylic acid (eg, trilysate®), azapropazone, carprofen, celecoxib (eg, Celebrex (registered trademark) described in US Pat. Nos. 5,466,823; 5,563,165; 5,760,068; 5,972,986); Vectra® described in US Pat. No. 5,633,272; 6,441,014; lefecoxib (eg, US Pat. Nos. 5,474,995; 5,691,374). No. 6,063,811; Biox (Registration) described in No. 6,239,173 Standard)), diclofenac potassium, diclofenac sodium (for example, Voltaren (registered trademark), Catafram (registered trademark) described in US Pat. Nos. 5,601,843; 5,698,225), diflunisal (for example, , Drobid®), etodolac (eg, Lodine®), fenbufen, fenoprofen (eg, Narfone®), flufenamic acid, flurbiprofen (eg, unsided ( Ansaid®), ibuprofen (eg Advil®), indomethacin (eg Indacin®), ketoprofen (eg Ordiz®), meclofenamate (eg meclomene ( Registered trademark)), mefenamic acid (for example, , Ponster®), meloxicam (eg, Movic® described in US Pat. No. 6,184,220), nabumetone (eg, loraphen®), naproxen (eg, Registered trademark)), naproxen sodium, oxaprozin (eg, Daypro®), pirprofen, suprofen, salsalate (eg, disarside®, Salflex®), sulindac ( For example, NSAID (non-steroidal anti-inflammatory agent) or COX-2 (cyclooxygenase 2) inhibition selected from the group consisting of clinolinyl (registered trademark)), tenoxicam, thiaprofenic acid, and tolmethine (eg, trectin (registered trademark)) With agent is there. Other suitable NSAIDs should be readily apparent to those skilled in the art having the benefit of this disclosure.

  In some embodiments, the anti-arthritic agent is hydrocortisone acetate, tertbutyl acetate hydrocortisone, dexamethasone acetate, tertbutyl dexamethasone acetate, prednisolone, prednisolone acetate, tertbutyl acetate prednisolone, prednisone, methylprednisolone methylprednisolone acetate, triamcinolone acetonide, A glucocorticoid (oral, parenteral and / or intra-articular) selected from the group consisting of triamcinolone diacetonide and triamcinolone hexaacetonide. Other suitable glucocorticoids should be readily apparent to those skilled in the art having the benefit of this disclosure.

  In some embodiments, the anti-arthritic agent is a hydroxychloroquine (eg, plaquinyl®), chloroquine, dapsone, sulfasalazine (eg, azalfidine®), methotrexate (eg, Trexall®). ), Methotrex (R)), leflunomide (e.g. Alava (R)), azathioprine (e.g. Imran (R)), d-penicillamine (e.g. Cuprimin (R)), cyclosporin A (E.g., Sandymun <(R)>) and gold sodium thiomalate (e.g., Aurolate), aurothioglucose (e.g., Sorganal), and auranofin (e.g., Ridaur). ) (A SCE DMARD selected from the group consisting of R)) gold compounds, including (disease-modifying antirheumatic drugs).

  In some embodiments, the anti-arthritic agent is etanercept (eg, Enbrel®), infliximab (eg, Remicade®), adalimumab (eg, Humira®), anakinra (eg, kinelet) (R)), abatacept (eg, Orencia (R)), rituximab (eg, Rituxan (R)), tocilizumab (eg, Actemra (R)), and certolizumab pegol. Is a scientific DMARD. Other suitable DMARDs (SCE or biological) should be readily apparent to those of ordinary skill in the art having the benefit of this disclosure.

  In some embodiments where the anti-arthritic agent is DMARD, the anti-arthritic agent is preferably methotrexate (sometimes referred to herein as “MTX”).

  In some embodiments, the anti-arthritic agent is an analgesic such as acetaminophen (eg, Tylenol®). Other suitable analgesics should be readily apparent to those skilled in the art having the benefit of this disclosure.

  In some embodiments, the anti-arthritic agent is morphine, codeine, propoxyphene (eg, darboset®), hydrocodone (eg, vicodin®), methadone (eg, dolphin®) , Hydromorphone (eg Dilodide®), oxycodone (eg Percoset®), fentanyl, buprenorphine (eg Subtex®) and butorphanol (eg Stador®) ) Opioids that may be used in combination with acetaminophen selected from the group consisting of: Other suitable opioids should be readily apparent to those skilled in the art having the benefit of this disclosure.

  In some embodiments where the anti-arthritic agent being administered in combination therapy or a method disclosed herein is not DMARD, such administration comprises a pharmaceutical composition comprising a Janus kinase inhibitor disclosed herein. Since the product is considered DMARD, it may also be commonly referred to as monotherapy by those skilled in the art despite administering more than one pharmaceutical composition. Nevertheless, the term “drug combination therapy” as used herein includes such “monotherapy”.

  The compositions of the present disclosure can be prepared in a conventional manner using one or more pharmaceutically acceptable carriers. Pharmaceutically acceptable carriers are described, for example, in Remington's Pharmaceutical Sciences, Mack Publishing Co. , (AR Gennaro ed. 1985), and any such carrier known in the art. Pharmaceutical compositions of the presently disclosed compounds are obtained by conventional means known in the art including, for example, mixing at least one presently disclosed compound and a pharmaceutically acceptable carrier. Can be prepared.

  The presently disclosed compounds can also be prepared for sustained delivery by methods well known to those skilled in the art. Examples of such formulations are found in US Pat. Nos. 3,119,742, 3,492,397, 3,538,214, 4,060,598, and 4,173,626. be able to.

  Accordingly, the active compounds of the present disclosure can be prepared in a form suitable for oral, buccal, intranasal, parenteral (eg, intravenous, intramuscular or subcutaneous), rectal administration, administration by inhalation or insufflation, or active The compound can be prepared for topical administration.

  For oral administration, the pharmaceutical composition comprises, for example, a binder (eg pregelatinized corn starch, polyvinylpyrrolidone or hydroxypropylmethylcellulose); a filler (eg lactose, microcrystalline cellulose or calcium phosphate); a lubricant (eg stearin Prepared by conventional means together with pharmaceutically acceptable excipients such as disintegrants (eg, potato starch or sodium starch glycolate); or wetting agents (eg, sodium lauryl sulfate); Can be in the form of a tablet or capsule. The tablets can be coated by methods well known in the art. Liquid dosage forms for oral administration can take the form of, for example, solutions, syrups or suspensions, or they can be presented as a dry product that is dissolved in water or other suitable vehicle before use. Such liquid formulations include suspending agents (eg, sorbitol syrup, methylcellulose or hardened edible fat); emulsifying agents (eg, lecithin or gum arabic); non-aqueous vehicles (eg, tonsils oil, oily esters or ethyl alcohol). And can be prepared by conventional means together with pharmaceutically acceptable additives such as preservatives (eg, methyl or propyl p-hydroxybenzoate or sorbic acid).

  For buccal administration, the composition can take the form of tablets or lozenges prepared by conventional methods.

  For intranasal administration or administration by inhalation, the active compounds of the present disclosure are in the form of solutions or suspensions from a pump spray container that is crushed or pumped by the patient, or a suitable propellant such as dichlorodifluoromethane, Conveniently delivered as an aerosol spray presentation from a pressurized container or nebulizer using trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In the case of a pressurized aerosol, the unit dose can be determined by providing a valve to deliver a metered amount. The pressurized container or nebulizer may contain a solution or suspension of the active compound. Capsules and cartridges (eg, made from gelatin) for use in inhalers or insufflators can be prepared containing a powder mix of a compound of the present disclosure and a suitable powder base such as lactose or starch.

  The active compounds of the present disclosure can be prepared for parenteral administration by injection, including using conventional catheterization or infusion. Formulations for injection can be presented in unit dosage forms with preservatives added, for example, ampoules or multi-volume containers. The compositions can take the form of suspensions, solutions or emulsions in oily or aqueous vehicles and may contain preparations such as suspending, stabilizing and / or dispersing agents. Alternatively, the active ingredient may be in powder form, which is dissolved in a suitable vehicle such as sterile pyrogen-free water before use.

  The active compounds of the present disclosure can also be prepared in rectal compositions such as suppositories or retention enemas, eg, containing conventional suppository bases such as cocoa butter or other glycerides.

  For topical administration, the presently disclosed compounds can be prepared as ointments or creams.

  It is readily apparent to those skilled in the art that Janus kinase inhibitors and anti-arthritic agents typically achieve the desired pharmacological and / or physiological effects in the drug combination therapy and related methods disclosed herein. Is administered in a therapeutically effective amount. In some embodiments, the Janus kinase inhibitor or pharmaceutically acceptable salt thereof (sometimes referred to herein as an “active compound”) is, for example, per unit dose that can be administered 1 to 4 times per day. The active ingredient is administered at a dose of 0.1 to 1000 mg. Dosage levels may vary between one or more dosing schedules or within the same dosing schedule. In some embodiments in which the Janus kinase inhibitor or pharmaceutically acceptable salt thereof is administered orally, the dose of active compound is 1-50 mg BID (ie twice daily) or 5-20 mg QD (ie daily). Range, 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, 14 mg BID, 15 mg BID, 20 mg BID, 25 mg BID, or 30 mg BID, preferably 0.25 mg BID, preferably 0.25 mg BID 1 mg BID, 5 mg BID, 10 mg BID, 20 mg BID, more preferably 1 mg BID, 3 mg BID, 5 mg BID, 15 mg, BID, It may be a 0mgQD.

  In some embodiments, the anti-arthritic agent (sometimes referred to herein simply as a “drug”) is 1 mg to 5 g (ie, 5000 mg), such as 5 mg, 10 mg, 25 mg, 50 mg, 100 mg, 250 mg, Administer at doses of 500 mg, 750 mg, 1000 mg, 1250 mg, 1500 mg, 1750 mg, 2000 mg, or combinations thereof. For each dose given to an anti-arthritic agent, these agents can be administered in a predetermined amount, eg, twice a day, daily, weekly, etc., as will be apparent to those skilled in the art. Methotrexate (“MTX”) is usually administered in weekly doses of 5 mg, 7.5 mg, 10 mg, 12.5 mg, 15 mg, 17.5 mg, 20 mg, 22.5 mg, and 25 mg. In some embodiments, the dose of MTX is usually increased by 2.5 mg (ie, gradually increased over a period of time, eg, weekly, monthly, etc.), depending of course on toxicity or lack of tolerance. ). In some embodiments, the dose of MTX is reduced (ie, gradually reduced) if the patient responds well or is administered with another agent, such as a biological agent. In other embodiments, the dose of MTX is administered in divided doses such as 5 mg Q 12 hours x 3 doses on a weekly basis. Of course, other dosage levels suitable for the compounds of the present disclosure and anti-arthritic agents administered in combination therapy should be readily apparent to those of skill in the art having the benefit of the present disclosure.

  In some embodiments of the drug combination therapy disclosed herein, the active compound is administered at a dose of 0.25 mg BID and methotrexate is administered once a week at a dose of 5 mg.

  In some embodiments of the drug combination therapies disclosed herein, the active compound is administered at a dose of 0.25 mg BID and methotrexate is administered once a week at a dose of 7.5 mg.

  In some embodiments of the drug combination therapies disclosed herein, the active compound is administered at a dose of 0.25 mg BID and methotrexate is administered once a week at a dose of 15 mg.

  In some embodiments of the drug combination therapy disclosed herein, the active compound is administered at a dose of 0.5 mg BID and methotrexate is administered once a week at a dose of 5 mg.

  In some embodiments of the drug combination therapy disclosed herein, the active compound is administered at a dose of 0.5 mg BID and methotrexate is administered once a week at a dose of 7.5 mg.

  In some embodiments of the drug combination therapy disclosed herein, the active compound is administered at a dose of 0.5 mg BID and methotrexate is administered once a week at a dose of 15 mg.

  In some embodiments of the drug combination therapy disclosed herein, the active compound is administered at a dose of 1 mg BID and methotrexate is administered at a dose of 5 mg once a week.

  In some embodiments of the drug combination therapy disclosed herein, the active compound is administered at a dose of 1 mg BID and methotrexate is administered at a dose of 7.5 mg once weekly.

  In some embodiments of the drug combination therapies disclosed herein, the active compound is administered at a dose of 1 mg BID and methotrexate is administered at a dose of 15 mg once a week.

  In some embodiments of the drug combination therapies disclosed herein, the active compound is administered at a dose of 3 mg BID and methotrexate is administered once a week at a dose of 5 mg.

  In some embodiments of the drug combination therapies disclosed herein, the active compound is administered at a dose of 3 mg BID and methotrexate is administered at a dose of 7.5 mg once weekly.

  In some embodiments of the drug combination therapy disclosed herein, the active compound is administered at a dose of 3 mg BID and methotrexate is administered at a dose of 15 mg once a week.

  In some embodiments of the drug combination therapy disclosed herein, the active compound is administered at a dose of 5 mg BID and methotrexate is administered once a week at a dose of 5 mg.

  In some embodiments of the drug combination therapy disclosed herein, the active compound is administered at a dose of 5 mg BID and methotrexate is administered once a week at a dose of 7.5 mg.

  In some embodiments of the drug combination therapies disclosed herein, the active compound is administered at a dose of 5 mg BID and methotrexate is administered once a week at a dose of 15 mg.

  In some embodiments of the drug combination therapies disclosed herein, the active compound is administered at a dose of 10 mg BID and methotrexate is administered at a dose of 5 mg once a week.

  In some embodiments of the drug combination therapies disclosed herein, the active compound is administered at a dose of 10 mg BID and methotrexate is administered at a dose of 7.5 mg once weekly.

  In some embodiments of the drug combination therapy disclosed herein, the active compound is administered at a dose of 10 mg BID and methotrexate is administered at a dose of 15 mg once a week.

  In some embodiments of the drug combination therapies disclosed herein, the active compound is administered at a dose of 15 mg BID and methotrexate is administered once a week at a dose of 5 mg.

  In some embodiments of the drug combination therapy disclosed herein, the active compound is administered at a dose of 15 mg BID and methotrexate is administered once a week at a dose of 7.5 mg.

  In some embodiments of the drug combination therapies disclosed herein, the active compound is administered at a dose of 15 mg BID and methotrexate is administered once a week at a dose of 15 mg.

  In some embodiments of the drug combination therapies disclosed herein, the active compound is administered at a dose of 5 mg QD and methotrexate is administered at a dose of 5 mg once a week.

  In some embodiments of the drug combination therapy disclosed herein, the active compound is administered at a dose of 5 mg QD and methotrexate is administered at a dose of 7.5 mg once weekly.

  In some embodiments of the drug combination therapy disclosed herein, the active compound is administered at a dose of 5 mg QD and methotrexate is administered once a week at a dose of 15 mg.

  In some embodiments of the drug combination therapies disclosed herein, the active compound is administered at a dose of 10 mg QD and methotrexate is administered at a dose of 5 mg once a week.

  In some embodiments of the drug combination therapy disclosed herein, the active compound is administered at a dose of 10 mg QD and methotrexate is administered at a dose of 7.5 mg once weekly.

  In some embodiments of the drug combination therapy disclosed herein, the active compound is administered at a dose of 10 mg QD and methotrexate is administered at a dose of 15 mg once a week.

  In some embodiments of the drug combination therapies disclosed herein, the active compound is administered at a dose of 20 mg QD and methotrexate is administered once a week at a dose of 5 mg.

  In some embodiments of the drug combination therapies disclosed herein, the active compound is administered at a dose of 20 mg QD and methotrexate is administered once a week at a dose of 7.5 mg.

  In some embodiments of the drug combination therapy disclosed herein, the active compound is administered at a dose of 20 mg QD and methotrexate is administered at a dose of 15 mg once a week.

  Standard adult human aerosol formulations are preferably arranged so that each metered dose or “single inhalation” aerosol contains 20 μg to 1000 μg of a compound of the present disclosure. The total daily dose with an aerosol will be within the range 0.1 mg to 1000 mg. Administration may be several times daily, for example 2, 3, 4 or 8 times, giving for example, 1, 2 or 3 doses each time.

  The ability of compounds of formula I or their pharmaceutically acceptable salts to inhibit Janus kinase 3 and consequently exhibit their effectiveness in the treatment of disorders or conditions characterized by Janus kinase 3 is demonstrated in vitro. Shown in assay test.

Biological Assay JAK3 (JH1: GST) Enzyme Assay The JAK3 kinase assay is a protein expressed in baculovirus-infected SF9 cells (GST fusion protein and human JAK3 catalyst) purified on glutathione-sepharose by affinity chromatography. Domain). The substrate for the reaction is poly-glutamic acid-tyrosine (PGT (4: 1), Sigma catalog # P0275) coated on Nunc Maxi Sorp plates at 100 μg / ml overnight at 37 ° C. In the morning after coating, the plate is washed 3 times and JAK3 is added to wells containing 100 μl of kinase buffer (50 mM HEPES, pH 7.3, 125 mM NaCl, 24 mM MgCl ₂ ) +0.2 uM ATP + 1 mM Na orthovanadate). The reaction proceeds at room temperature for 30 minutes and the plate is washed three more times. The level of phosphorylated tyrosine in a given well is quantified by a standard ELISA assay utilizing an anti-phosphotyrosine antibody (ICN PY20, cat. # 69-151-1).

Inhibition of human IL-2 dependent T cell bud proliferation This screen measures the inhibitory effect of compounds on IL-2 dependent T cell bud proliferation in vitro. Since JAK-3 is required for signal transduction through the IL-2 receptor, an inhibitor of JAK-3 cell activity should inhibit IL-2-dependent T cell bud proliferation.

The cells for this assay are isolated from fresh human blood. Mononuclear cells were isolated using Accuspin System-Histopaque-1077 (Sigma # A7054), and primary human T cells were subjected to negative selection using Lympho-Kwik T (One Lambda, Inc., Cat # LK-50T). Isolate. T cells were cultured at 1-2 × 10 ⁶ / ml in medium (RPMI + 10% heat-inactivated fetal bovine serum (Hyclone Cat # A-1111-L) + 1% penicillin / streptomycin (Gibco)), 10 ug / ml Induction to proliferate by adding PHA (Murex Diagnostics, Cat #HA 16). After 3 days culture at 37 ° C. in 5% CO ₂ , the cells were washed 3 times in medium, resuspended and medium + 100 units / ml human recombinant IL-2 (R & D Systems, Cat # 202-IL) Medium to a density of 1-2 × 10 ⁶ cells / ml. After one week, the cells are IL-2 dependent and can be maintained for up to 3 weeks by giving equal volume of medium + 100 units / ml of IL-2 twice a week.

To assess the ability of test compounds to inhibit IL-2 dependent T cell proliferation, IL-2 dependent cells were washed three times, resuspended in media, then flat bottom 96 well microtiter plates (Falcon # 350,000) (50,000 cells / well / 0.1 ml). From a 10 mM stock solution of the test compound in DMSO, a serial 2-fold dilution of the compound is added to triplicate wells starting at 10 uM. After 1 hour, 10 units / ml IL-2 is added to each test well. The plates are then incubated for 72 hours at 37 ^° C., 5% CO ₂ . Plates are then pulse labeled with ³ H-thymidine (0.5 uCi / well) (NEN Cat # NET-027A) and incubated for an additional 18 hours. The culture plate is then harvested in a 96 well plate harvester and the amount of ³ H-thymidine incorporated into the proliferating cells is determined by counting with a Packard Top Count scintillation counter. Data are analyzed by plotting% growth inhibition versus concentration of test compound. IC ₅₀ values (uM) are determined from this plot.
(Example)

3-{(3R, 4R) -4-methyl-3- [methyl- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -amino] -piperidine-1 in the treatment of active rheumatoid arthritis Randomized, double-blind, placebo-controlled trial of 3 dose levels of -yl} -3-oxo-propionitrile versus placebo 3-{(3R, 4R) -4-methyl-3- [methyl- (7H- Pyrrolo [2,3-d] pyrimidin-4-yl) -amino] -piperidin-1-yl} -3-oxo-propionitrile ("test compound") is a rodent model of inflammatory arthritis and psoriasis Is an orally active, moderately selective inhibitor of JAK3 that has shown efficacy in subjects suffering from This study is designed to compare the efficacy, safety, tolerability and effect on health and functional status of the three dose levels of test compound versus placebo, and moderate to severe active rheumatoid arthritis (“RA”) ) For 6 weeks, followed by follow-up after 6 weeks of administration.

  The subject has discontinued all DMARD or biological anti-rheumatic therapy and has had at least nine pain / tender joints who have unacceptable toxicity, an inappropriate response to methotrexate or a TNF inhibitor, or have been suspended for it, They enrolled when they showed evidence of 6 swollen joints and systemic inflammation. They were randomized 1: 1: 1: 1 to placebo, test compound 5 mg BID, 15 mg BID or 30 mg BID. Background NSAIDs, coxibs, low dose glucocorticoids and analgesics were allowed.

Results 264 subjects were randomized and all received at least one dose of test compound.

有害事象は用量依存的に増加し、最も一般に報告されたのは頭痛および悪心であった。好中球数は用量依存的に減少し、≦１０００／ｍｍ^３のカウントが、５ｍｇＢＩＤにおいて１対象、３０ｍｇＢＩＤ投与グループにおいて２対象で観察された。感染速度は、プラセボ投与グループ（対象の２６．２％）と比較して１５および３０ｍｇＢＩＤ（それぞれ３０．４％）で増大したように思われたが、日和見感染は起こらなかった。ＬＤＬ／ＨＤＬ比に変化がない、ＬＤＬおよびＨＤＬコレステロールの両方の用量に依存した増加、ならびに０．０４〜０．０６ｍｇ／ｄＬの、平均血清クレアチニンの可逆的増加も観察された。

Adverse events increased in a dose-dependent manner and the most commonly reported were headache and nausea. Neutrophil counts decreased in a dose-dependent manner, and counts ≦ 1000 / mm ³ were observed in 1 subject at 5 mg BID and 2 subjects in the 30 mg BID dose group. The rate of infection appeared to increase at 15 and 30 mg BID (30.4% each) compared to the placebo group (26.2% of subjects), but no opportunistic infection occurred. A dose-dependent increase in both LDL and HDL cholesterol, with no change in the LDL / HDL ratio, and a reversible increase in mean serum creatinine from 0.04 to 0.06 mg / dL were also observed.

Conclusion All three dose levels of test compound were very effective compared to placebo in the treatment of signs and symptoms of RA starting at week 1 and maintained for 6 weeks or more. Dosage levels below 15 mg BID also seemed safe and generally well tolerated.

Oral 3-{(3R, 4R) -4-methyl-3- [methyl- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -amino] -piperidin-1-yl in subjects with rheumatoid arthritis } Phase III of pharmacokinetics of multiple doses of -3-oxo-propionitrile and single dose of oral methotrexate, open-label study purpose. 3-{(when administered to subjects with RA 3R, 4R) -4-methyl-3- [methyl- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -amino] -piperidin-1-yl} -3-oxo-propionitrile, Estimating the effect of MTX on the pharmacokinetics of the test compound;
Estimating the effect of multiple doses of the test compound (30 mg Q 12h) on the pharmacokinetics of MTX;
To assess the short-term safety and tolerability of co-administration of test compound (30 mg Q 12h) and MTX.

  Twelve subjects aged 18-65 years (female 8 / male 4) entered the study who were diagnosed with rheumatoid arthritis and included meeting all inclusion criteria.

  This was an open-label, non-randomized, fixed sequence, drug-drug interaction study. Subjects were hospitalized on day 0. On the morning of day 1, subjects were given their weekly individual MTX doses after overnight fasting and 2 hours prior to the first meal; MTX blood PK samples were collected for 48 hours until day 3. On day 3, after collecting the last MTX blood PK sample, subjects were given 30 mg of test compound Q 12h until day 6. On day 6, a complete 12 hour test compound blood PK sample was collected. On day 7, subjects were given their weekly individual MTX dose in a co-administration with a 30 mg dose of test compound, followed by collection of a complete 48-hour test compound and MTX blood PK sample. Each subject participated for a total of about 14 days; they remained in control until released on days 0-9. The subject was released after the last pharmacokinetic blood sample was obtained on day 9, but was required to return for a scheduled follow-up visit before the subject's next weekly MTX administration ( About 11-13 days).

  Subjects were assigned to the following treatments as indicated below:

After day 6 and 7 of the study, multiple dose pharmacokinetic parameters were calculated where possible with respect to plasma concentrations of orally administered test compounds. After the first and seventh days of the study, single dose pharmacokinetic parameters were calculated where possible for plasma concentrations of orally administered MTX. The pharmacokinetic parameters were defined as follows: plasma concentration from time 0 after administration to the last observed time point (last)-area under the time curve [AUC _last ], plasma concentration at time 0 to 12 hours after administration- Area under time curve (AUC ₁₂ ); maximum observed concentration at steady state (C _maximum ); time to maximum observed concentration at steady state (T _maximum ). Estimates of points and intervals of pharmacokinetic parameters [AUC and C _max ] were made. A 90% confidence interval (CI) was constructed for interval estimation. The data is shown in graph form and / or tabular form, and is shown in a descriptive summary.

全血サンプル（各５ｍＬ、最小限の２．０ｍＬ血漿を得るのに十分な量）を、ナトリウムヘパリンを含有する適切なラベル付きチューブ中に以下の時間に捕集した：

Whole blood samples (5 mL each, sufficient to obtain a minimum of 2.0 mL plasma) were collected in appropriate labeled tubes containing sodium heparin at the following times:

  All efforts were made to obtain pharmacokinetic samples with the correct nominal time for dosing. However, as long as the exact time of sample collection is recorded in the source document and data collection tool (eg CRF), it can be obtained within 10% of the nominal time from dosing (eg within 3 minutes of a 30 minute sample). Samples taken were not captured as protocol deviations.

Pharmacokinetics (PK)
Subjects included in the statistical analysis of pharmacokinetic parameters had at least one such pharmacokinetic parameter. The analysis set may include different numbers of subjects for different pharmacokinetic parameters based on the validity of the data.

For the parameters AUC ₁₂ , AUC _last , C _max , CL / F, CL _kidney and Ae ₂₄ , statistical analysis was performed to estimate the ratio of the corrected geometric means (test / baseline), indicating the associated 90% confidence interval Will be. Similarly, statistical analysis for parameters T _max and t _1/2 estimated median or modified mean difference (test-criteria), respectively, and showed an associated 90% confidence interval. For each specimen, treatment is considered a fixed effect, subject is considered a random effect, and natural-logarithmic transformation parameters (AUC ₁₂ , AUC _last , C _max , CL / F, CL _kidney and Ae ₂₄ ) using a mixed effects model. And unconverted parameters (t _1/2 ) were analyzed. A corrected mean difference (test-criteria) and corresponding 90% confidence interval estimates were estimated from this model. For AUC ₁₂ , AUC _last , C _max , CL / F, CL _kidney and Ae ₂₄ , the corrected mean difference and the 90% confidence limit for the difference are raised to the power of the corrected geometric mean ratio (test / baseline) and 90 for this ratio. An estimate of the% confidence interval was derived. Each specimen co-administered with other compounds was a test compound, and each specimen administered alone was the reference.

  A mixed effects model was performed using SAS Proc Mixed along with REML estimation, compound symmetric dispersion-covariance structure and Satterthweight degree of freedom algorithm.

Non-parametric analysis was performed on the untransformed (raw) PK parameter T _{max in} each specimen. SAS (R) / Proc-StatXact 5 (R) procedure Paired was used for these analyses. A point estimate of the median difference between treatments (Hodges-Lehmann) and an accurate 90% CI (Lehmann) around the difference were constructed.

Parameters AUC ₁₂ , AUC _last , C _maximum , T _maximum , t _1/2 , oral clearance CL / F, amount excreted in urine (Ae ₂₄ ) and renal clearance (CL _kidney ) are aggregated by specimen Descriptive statistics (N, mean, median, CV%, standard deviation, minimum and maximum) were shown in the study report. In addition to the descriptive statistics described above, geometric means were shown for AUC ₁₂ , AUC _last , C _max , CL / F, CL _kidney and Ae ₂₄ . A graphical representation of concentration over time is shown for each specimen.

Result analysis dataset (subject inclusion / exclusion):
All 12 subjects who received study medication were included in pharmacokinetic, adverse events and laboratory analyses.

Statistical and analytical results:
Data aggregation and statistical analysis were performed using SAS software program version 8.2.

Summary of statistical findings PK parameters:
Test compound:
A summary of the results from statistical analysis of the pharmacokinetic parameters of the test compounds is shown in the table below.

  Steady state test compound 30 mg mean exposure after co-administration with single dose MTX (individual administration) was unaffected compared to that of 30 mg steady state test compound administered alone. All 90% confidence intervals for log-transformed data were completely within the 80-125% invalid limit. Similarly, all 90% confidence intervals for both time parameters included zero.

Methotrexate (MTX):
A summary of the results from statistical analysis of MTX pharmacokinetic parameters is shown in the table below.

定常状態試験化合物３０ｍｇと一緒の同時投与後の１回投与ＭＴＸ平均暴露は、単独で投与した１回投与ＭＴＸのそれと比較して、ＡＵＣ_２４について〜１０％およびＣ_最大について〜１３％減少した。同様に、ＡＥ_２４およびＣｌ_腎臓は、それぞれ〜２１％および〜９％減少したが、ＣＬ／Ｆは〜９％増加し、ｔ_１／２は０．３７時間遅れた。Ｔ_最大は影響を受けないようであった。対数変換ＰＫパラメーターの全９０％信頼区間は、８０〜１２５％無効限界以内に完全に含まれておらず、９０％信頼区間にはゼロが含まれていなかった。

Single dose MTX mean exposure after co-administration with 30 mg of steady state test compound was reduced by -10% for AUC ₂₄ and -13% for C _max compared to that of single dose MTX administered alone. Similarly, AE ₂₄ and Cl _kidneys decreased ˜21% and ˜9%, respectively, while CL / F increased ˜9% and t _1/2 was delayed 0.37 hours. T _max seemed unaffected. All 90% confidence intervals for the log-transformed PK parameters were not completely included within the 80-125% invalid limit, and the 90% confidence interval did not include zero.

  No deaths or serious adverse events were reported from this study. None of the subjects discontinued the study early due to adverse events. Two (2) subjects temporarily discontinued study drug due to non-treatment related adverse events.

  All study treatment-related adverse events were considered mild in severity, with the exception of two moderate symptoms in one subject (tension headache and migraine).

  All observed or voluntarily reported adverse events occurring during treatment or within the delay time [(infinite) days after the last day of treatment] are manifestations under study treatment, body system, preferred term, and severe Tabulated using MedDRA dictionary based on degree (mild, moderate, or severe) and causal investigator assessment. The onset events under study treatment were 1) events that did not exist at baseline or during the baseline period and occurred after initiation of treatment with study drug and 2) those that occurred at baseline but did not An event that increased in severity after the treatment used was defined. If any one adverse event for a single subject was given more than one severity, the highest severity was used in the spreadsheet; the missing severity was classified as severe.

Laboratory test:
Laboratory test results collected during treatment or within a delay time [(infinite) days after the last day of treatment] were evaluated for potential clinically significant abnormalities. Laboratory tests that resulted in treatment discontinuation or study drug change were recorded as adverse events, and then the investigator assessed the relationship to treatment. Laboratory abnormalities were significant only for one subject who showed an increase in ALT on day 1 (MTX alone) that persisted during the study but recovered to the normal range during follow-up.

Signs of survival:
Most of the outbreaks listed in the categorized summary of survival signs data of potential clinical interest occurred during combination therapy [test compound (30 mg Q 12h) + MTX SD] as indicated below.

electro-cardiogram:
There were no notable findings in the ECG report. There was a gradual decrease in both systolic and diastolic blood pressure for 3 subjects during treatment with MTX and test compound in combination therapy. Of these subjects, one subject experienced a slight decrease even during systole (MTX alone) or diastolic (test compound alone). There was one subject who showed a slight increase in supine diastolic blood pressure during treatment with MTX and a test compound in combination therapy. In particular, none of the subjects showed changes from baseline in QT or QTcF greater than 500 msec, or QTcB or QTcF greater than 60 msec in either treatment plan. One subject [test compound (30 mg Q 12h) + MTX SD] experienced QTcB over 500 msec [˜500 msec (day 7)]. The same subject experienced an increase of more than 30 msec from baseline in both QTcB and QTcF while receiving MTX SD on day 1 (˜46 & ˜33 msec, respectively). The same subject also experienced an increase of more than 30 msec from baseline with both QTcBs (-37 msec) while receiving the test compound (30 mg q12 h) on day 3.

Conclusion Review of the PK data for 12 subjects revealed that there was no effect of MTX co-administration on AUC (0-12) or C _{max of} test compounds. However, co-administration of test compounds decreases MTX AUC ₂₄ by -10% and C _max by -13% compared to that of single dose MTX administered alone. Steady state exposure of test compound (30 mg) in drug combination therapy with single dose MTX was unaffected compared to steady state test compound (30 mg) administered alone. Single dose exposure of MTX in combination therapy with steady state test compound (30 mg) was reduced by -10% for AUC ₂₄ and -13% for C _max compared to MTX administered alone. Treatment of steady state test compound (30 mg) and single dose MTX administered alone and in combination therapy was generally very well tolerated.

The following examples illustrate the preparation of compounds of the present disclosure, but are not limited to the details thereof. The melting point is not corrected. The NMR data is reported in parts per million (δ) and is based on the deuterium lock signal from the sample solvent (deuterochloroform unless otherwise specified). Commercial reagents were utilized without further purification. THF means tetrahydrofuran. DMF means N, N-dimethylformamide. Low resolution mass spectra (LRMS) can be obtained from Hewlett Packard 5989® utilizing chemical ionization (ammonium) or Fisons using a 50/50 mixture of acetonitrile / water with 0.1% formic acid as the ionizing agent (or Recorded on one of the Micro Mass) atmospheric pressure chemical ionization (APCI) platforms. Room or ambient temperature means 20-25 ° C. The IC ₅₀ values reported below were obtained from the above JAK3 (JH1: GST) enzyme assay (except for Example 33) and are the result of multiple experiments (n = 4-6, where n = 1 is 3). Represents street work).

1- {4-Methyl-3- [methyl- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -amino] -piperidin-1-yl} -ethanone Method A
(1-Benzyl-4-methyl-piperidin-3-yl) -methyl-amine Both references are dissolved in 23 mL of 2M methylamine in tetrahydrofuran, both references are incorporated by reference in their entirety. A. And Damia, G .; 1-benzyl-, prepared by the method of Tetrahedron, 26, 5519 (1970) and Grieco et al., Journal of the American Chemical Society, 107, 1768 (1985), modified with 5% methanol as a co-solvent. To a stirred solution of 4-methyl-piperidin-3-one (2.3 grams, 11.5 mmol) was added acetic acid 1.4 mL (23 mmol) and the resulting mixture was stirred in a sealed tube at room temperature for 16 hours. Sodium triacetoxyborohydride (4.9 grams, 23 mmol) was added and the new mixture was stirred in a sealed tube at room temperature for 24 h, at which point the reaction was quenched after addition of 1 N sodium hydroxide (50 mL). The reaction mixture was then extracted 3 × 80 mL with ether and the combined ether layer was dried over sodium sulfate (Na ₂ SO ₄ ) and concentrated to dryness in vacuo to give 1.7 g (69%) of the title compound as a white solid Got as. LRMS: 219.1 (M + 1).

Method B
(1-Benzyl-4-methyl-piperidin-3-yl) -methyl- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -amine, which is incorporated by reference in its entirety. Am. Chem. Soc. 82, 131 (1960), the product from Method A dissolved in a solution of 4-chloropyrrolo [2,3-d] pyrimidine (2.4 grams, 15.9 mmol) and 2 equivalents of triethylamine. (1.7 grams, 7.95 mmol) was heated in a sealed tube at 100 ° C. for 3 days. After cooling to room temperature and concentrating under reduced pressure, the residue was purified by flash chromatography (silica; 3% methanol in dichloromethane) to give 1.3 grams (50%) of the title compound as a colorless oil. LRMS: 336.1 (M + 1).

Method C
Methyl- (4-methyl-piperidin-3-yl)-(7H-pyrrolo [2,3-d] pyrimidin-4-yl) -amine product from Method B dissolved in 15 mL of ethanol (0.7 grams , 2.19 mmol) was added 1.5 mL of 2N hydrochloric acid and the reaction mixture was degassed with a nitrogen purge. To the reaction mixture was then added 0.5 grams of 20% palladium hydroxide / carbon (50% water) (Aldrich) and the resulting mixture was shaken (Parr-Shaker) at room temperature under a 50 psi hydrogen atmosphere for 2 days. The celite filtered reaction mixture was concentrated to dryness in vacuo and the residue was purified by flash chromatography (silica; 5% methanol in dichloromethane) to give 0.48 grams (90%) of the title compound. LRMS: 246.1 (M + 1).

Method D
1- {4-Methyl-3- [methyl- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -amino] -piperidin-1-yl} -ethanone 10: 1 dissolved in 5 mL of dichloromethane / pyridine To a stirred solution of the product from Method C (0.03 grams, 0.114 mmol) was added acetyl chloride (0.018 grams, 0.228 mmol) and the resulting mixture was stirred at room temperature for 18 hours. The reaction mixture was then partitioned between dichloromethane and saturated sodium bicarbonate (NaHCO ₃ ). The organic layer was washed again with saturated NaHCO ₃ , dried over sodium sulfate and concentrated to dryness in vacuo. The residue was purified by preparative thin layer chromatography (PTLC) (silica; 4% methanol in dichloromethane) to give 0.005 mg (15%) of the title compound as a colorless oil. LRMS: 288.1 (M + 1). IC ₅₀ = 0.1475μM.

  The title compounds of Examples 2-26 were prepared by a method similar to that described in Example 1.

[1- (2-Amino-ethanesulfonyl) -4-methyl-piperidin-3-yl] -methyl- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -amine [1- (2- Amino-ethanesulfonyl) -4-methyl-piperidin-3-yl] -methyl-amine. LRMS: 353. IC ₅₀ = 0.103μM.

(1-ethanesulfonyl-4-methyl-piperidin-3-yl) -methyl- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -amine (1-ethanesulfonyl-4-methyl-piperidine- 3-yl) -methyl-amine. LRMS: 338. IC ₅₀ = 0.1365μM.

[1- (Butane-1-sulfonyl) -4-methyl-piperidin-3-yl] -methyl- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -amine [1- (butane-1 -Sulfonyl) -4-methyl-piperidin-3-yl] -methyl-amine. LRMS: 366. IC ₅₀ = 0.3725μM.

4-Methyl-3- [methyl- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -amino] -piperidine-1-carboxylic acid isobutyl ester 4-methyl-3-methylamino-piperidine-1 -Carboxylic acid isobutyl ester. LRMS: 346. IC ₅₀ = 0.5595μM.

N- (2- {4-Methyl-3- [methyl- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -amino] -piperidine-1-sulfonyl} -ethyl) -propionamide N- [2- (4-Methyl-3-methylamino-piperidine-1-sulfonyl) -ethyl] -propionamide. LRMS: 409. IC ₅₀ = 0.1915μM.

(2- {4-Methyl-3- [methyl- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -amino] -piperidine-1-sulfonyl} -ethyl) -carbamic acid methyl ester [2 -(4-Methyl-3-methylamino-piperidine-1-sulfonyl) -ethyl] -carbamic acid methyl ester. LRMS: 411. IC ₅₀ = 0.0415μM.

N- (2- {4-Methyl-3- [methyl- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -amino] -piperidine-1-sulfonyl} -ethyl) -isobutyramide N- [2- (4-Methyl-3-methylamino-piperidine-1-sulfonyl) -ethyl] -isobutyramide. LRMS: 423. IC ₅₀ = 0.0485μM.

(1-Methanesulfonyl-piperidin-3-yl) -methyl- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -amine (1-methanesulfonyl-piperidin-3-yl) -methyl-amine . LRMS: 310. IC ₅₀ = 0.346333333μM.

(1-ethanesulfonyl-piperidin-3-yl) -methyl- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -amine (1-ethanesulfonyl-piperidin-3-yl) -methyl-amine . LRMS: 324. IC ₅₀ = 0.6255μM.

Methyl- [1- (propane-1-sulfonyl) -piperidin-3-yl]-(7H-pyrrolo [2,3-d] pyrimidin-4-yl) -amine (1-propylsulfonyl-piperidin-3-yl) ) -Methyl-amine. LRMS: 338. IC ₅₀ = 0.4585μM.

[1- (Butane-1-sulfonyl) -piperidin-3-yl] -methyl- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -amine (1-butylsulfonyl-piperidin-3-yl) ) -Methyl-amine. LRMS: 352. IC ₅₀ = 0.4125μM.

2,2-Dimethyl-N- (2- {4-methyl-3- [methyl- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -amino] -piperidine-1-sulfonyl} -ethyl ) -Propionamide 2,2-dimethyl-N- [2- (4-methyl-3-methylamino-piperidine-1-sulfonyl) -ethyl] -propionamide. LRMS: 437. IC ₅₀ = 0.788μM.

3- {4-Methyl-3- [methyl- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino] -piperidin-1-yl} -3-oxo-propionitrile 3- (4 -Methyl-3-methylamino-piperidin-1-yl) -3-oxo-propionitrile. LRMS: 313. IC ₅₀ = 0.0034μM.

(3- {4-Methyl-3- [methyl- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -amino] -piperidin-1-yl} -3-oxo-propyl) -carbamic acid tert-Butyl ester [3- (4-Methyl-3-methylamino-piperidin-1-yl) -3-oxo-propyl] -carbamic acid tert-butyl ester. LRMS: 417. IC ₅₀ = 0.5479μM.

Methyl- [4-methyl-1- (propane-1-sulfonyl) -piperidin-3-yl]-(7H-pyrrolo [2,3-d] pyrimidin-4-yl) -amine methyl- [4-methyl- 1- (Propane-1-sulfonyl) -piperidin-3-yl] -amine. LRMS: 352. IC ₅₀ = 0.0595μM.

3-Amino-1- {4-methyl-3- [methyl- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -amino] -piperidin-1-yl} -propan-1-one 3 -Amino-1- (4-methyl-3-methylamino-piperidin-1-yl) -propan-1-one. LRMS: 317. IC ₅₀ = 1.588μM.

2-methoxy-1- {4-methyl-3- [methyl- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -amino] -piperidin-1-yl} -ethanone 2-methoxy-1 -(4-Methyl-3-methylamino-piperidin-1-yl) -ethanone. LRMS: 318. IC ₅₀ = 0.443333333μM.

2-Dimethylamino-1- {4-methyl-3- [methyl- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -amino] -piperidin-1-yl} -ethanone 2-dimethylamino -1- (4-Methyl-3-methylamino-piperidin-1-yl) -ethanone. LRMS: 331. IC ₅₀ = 2.5465 μM.

(3- {4-Methyl-3- [methyl- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -amino] -piperidin-1-yl} -3-oxo-propyl) -carbamic acid tert-Butyl ester [3- (4-Methyl-3-methylamino-piperidin-1-yl) -3-oxo-propyl] -carbamic acid tert-butyl ester. LRMS: 417. IC ₅₀ = 5.479μM.

3,3,3-trifluoro-1- {4-methyl-3- [methyl- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -amino] -piperidin-1-yl} -propane -1-one 3,3,3-trifluoro-1- (4-methyl-3-methylamino-piperidin-1-yl) -propan-1-one. LRMS: 356.3. IC ₅₀ = 0.019333333μM.

N- (2- {4-methyl-3- [methyl- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -amino] -piperidin-1-yl} -2-oxo-ethyl)- Acetamide N- [2- (4-Methyl-3-methylamino-piperidin-1-yl) -2-oxo-ethyl] -acetamide. LRMS: 345. IC ₅₀ = 7.13033333μM.

3-Ethoxy-1- {4-methyl-3- [methyl- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -amino] -piperidin-1-yl} -propan-1-one 3 -Ethoxy-1- (4-methyl-3-methylamino-piperidin-1-yl) -propan-1-one. LRMS: 346. IC ₅₀ = 0.7686μM.

4-Methyl-3- [methyl- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -amino] -piperidine-1-carboxylic acid methylamide 4-methyl-3-methylamino-piperidine-1- Carboxylic acid methylamide. LRMS: 303. IC ₅₀ = 0.2355μM.

4-Methyl-3- [methyl- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -amino] -piperidine-1-carboxylic acid diethylamide 4-methyl-3-methylamino-piperidine-1- Carboxylic acid diethylamide. LRMS: 345. IC ₅₀ = 0.205μM.

Methyl- [4-methyl-1- (2-methylamino-ethanesulfonyl) -piperidin-3-yl]-(7H-pyrrolo [2,3-d] pyrimidin-4-yl) -amine methyl- [4- Methyl-1- (2-methylamino-ethanesulfonyl) -piperidin-3-yl] -amine. LRMS: 367. IC ₅₀ = 1.124μM.

  Examples 27-31 show the resolution of compounds of formula III.

(Stable salt generation)
(1-Benzyl-4-methylpiperidin-3-yl) -methylamine bishydrochloride (1-benzyl-4-methylpiperidin-3-yl) -methylamine dissolved in 10 liters of toluene at 3 ° C. and 120 liters of ethanol To 23.4 kg of solution, 25 liters of 32% aqueous HCl was added while keeping the reaction temperature below 10 ° C. 100 liters of solvent was distilled off under partial vacuum and 215 liters of ethyl acetate was added at 30 ° C. 210 liters of solvent was distilled off under partial vacuum, 215 liters of alternative ethyl acetate was added, and an additional 210 liters of solvent were distilled off under partial vacuum. 111 liters of acetone is added at 35 ° C., the suspension is cooled to 0 ° C., then the product, (1-benzyl-4-methylpiperidin-3-yl) -methylamine bishydrochloride is filtered off and acetone is added. Washed with 55 liters. The wet cake was dissolved three times in ethanol (10 volume equivalents at reflux) and reslurried to increase the cis: trans diastereomeric ratio from 91: 9 to over 97: 3. The total amount recovered was 19.4 kg and the yield was 62%. 1H NMR (CD ₃ OD, 400 MHz): δ 7.55 (m, 5H), 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 to 3.00 (m, 3H), 2.78 (3, 3H), 2 .55 (m, 1H), 2.14 (m, 1H), 1.90 (m, 1H), 1.16 (d, J = 7.2 Hz, 3H)

(Split)
Bis [(1-benzyl-4-methylpiperidin-3-yl) -methylamine] di-p-toluyl-L-tartrate Dissolved in 16 liters of water (1-benzyl-4-methylpiperidin-3-yl) -33 liters of 2N sodium hydroxide was added to a solution of 9.5 kg of methylamine bishydrochloride. A solid was precipitated from the mixture. The slurry was diluted with 43 liters of isopropanol and 11 liters of methanol to redissolve the solid. Di-p-toluyl-L-tartaric acid (6.3 kg) was added with solid precipitation. The slurry was heated to reflux to redissolve the solid and then slowly cooled to 72 ° C. Bis [(1-benzyl-4-methylpiperidin-3-yl) -methylamine] di-p-toluyl-L-tartrate seed crystals were added (180 grams) and the cloudy solution was slowly cooled to 15 ° C. . The solid was filtered and washed with isopropanol to obtain 5.9 kg of [(1-benzyl-4-methylpiperidin-3-yl) -methylamine] di-p-toluyl-L-tartrate in 44% yield. . 1H NMR (CD ₃ OD, 400 MHz): δ 8.04 (d, J = 8.4 Hz, 2H), 7.30 (m, 7H), 5.86 (s, 1H), 4.91 (s, 3H), 3.64 (d, J = 12.8 Hz, 1H), 3.41 (d, J = 12.8 Hz, 1H), 3.09 (s, 1H), 2.90 (m, 2H) 2.40 (s, 3H), 2.22 (m, 2H), 1.92 (m, 1H), 1.57 (m, 2H), 1.03 (d, J = 7.2 Hz, 3H) )

(Fencyphos split)
To a 6.83 gram (31.3 mmol) solution in 250 ml IPA and 10 ml water, 7.57 g (31.3 mmol) (+) phenciphos was added and the mixture was heated to reflux to obtain a clear solution. 90% ee seed crystals were added at a temperature of about 65 ° C. Crystallization began within 1 hour and the mixture reached room temperature overnight. Isolation gave 6.85 g (47%) with 99% ee. The filtrate was concentrated, TBME, water and K ₂ CO ₃ were added and the layers were separated. The organic layer was dried (Na ₂ SO ₄ ) and the solvent was evaporated. The resulting oil (3.99 grams) was dissolved in 200 ml of IPA and 10 ml of water and 4.4 grams (−) phenciphos was added. The mixture was heated to reflux and allowed to cool to room temperature overnight. This gave 6 grams (41%) of salt with 99.9 +% ee. Analysis was done for free amines. The free amine was obtained by treating the salt with TBME, water and K ₂ CO ₃ .

The following schematically illustrates the methods of Examples 27-29, where Bn is defined as benzyl (—CH ₂ —C ₆ H ₅ ):

Sample processing:
The compound of formula III was filtered through a 0.2 um nylon 66 filter disk.

Procedure: (96% ethanol 4% water as solvent)
0.8711 grams of the compound of formula III in the filtrate was dissolved in 5.0 ml of 96/4 ethanol / water. 1.544 grams of di-p-toluoyl-L-tartaric acid was added and the mixture was stirred to obtain a clear solution. The solution was left at room temperature for about 4 hours. The resulting slurry was filtered on Whatman # 2 filter paper and washed with 4.0 ml of 96: 4 ethanol / water. The solid was air dried to give 0.488 grams of diastereomeric salt.

  0.488 grams of diastereomeric salt was suspended in 50 ml of water and then 50 ml of methylene chloride was added. The pH of the mixture was adjusted to about 9 using saturated sodium bicarbonate followed by 1.0N sodium hydroxide. After pH adjustment was complete, the layers were separated and the methylene chloride layer was filtered through Whatman # 2 filter paper. The solvent was then removed by evaporation under reduced pressure to give a light orange oil. The weight was not measured. This oil was evaluated by gas chromatography.

  Analytical assay: 97.3% desired enantiomer by normalized range percentage.

Procedure: (100% ethanol as solvent)
0.8714 grams of (1-benzyl-4-methyl-piperidin-3-yl) -methyl-amine was dissolved in 5.0 ml of 200 proof ethanol. 1.544 grams of di-p-toluoyl-L-tartaric acid was added and the mixture was stirred to obtain a clear solution. The solution was left at room temperature for about 4 hours. The resulting slurry was filtered on Whatman # 2 filter paper and washed with 4.0 ml of 96: 4 ethanol / water. The solid was air dried to give 0.628 grams of diastereomeric salt.

  0.628 grams of diastereomeric salt was suspended in 50 ml of water and then 50 ml of methylene chloride was added. The pH of the mixture was adjusted to about 9 using saturated sodium bicarbonate followed by 0.1N sodium hydroxide. After pH adjustment was complete, the layers were separated and the methylene chloride layer was filtered through Whatman # 2 filter paper. The solvent was then removed by evaporation under reduced pressure to give a pale yellow oil. The weight was not measured. Analytical assay was performed by oil assessment: desired enantiomer 90.5% by normalized range percentage.

3-{(3R, 4R) -4-methyl-3- [methyl- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -amino] -piperidin-1-yl} -3-oxo- Propionitrile Method A
(3R, 4R)-(1-Benzyl-4-methyl-piperidin-3-yl) -methyl- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -amine, incorporated in its entirety by reference. Davoll, J .; Am. Chem. Soc. , 82, 131 (1960), 4-chloropyrrolo [2,3-d] pyrimidine (5.37 grams, 34.9 mmol), the product from Example 28 (6 grams, 27.5 mmol) and Potassium carbonate (11.4 grams, 82.5 mmol) was mixed in water (60 ml). The slurry was heated at reflux for 90 hours. The mixture was cooled to 90 ^° C. and toluene (60 ml) was added. The biphasic mixture was filtered through filter aid and the layers were separated. The aqueous layer was extracted with toluene. The mixed toluene layer was washed with 1N NaOH, treated with activated carbon, and filtered through a filter aid. Toluene was evaporated in vacuo and the residue was crystallized from a 1: 1 mixture of isopropyl acetate and hexane to give 5 grams of an off-white solid; 54% yield. LRMS: 336.1 (M + 1).

Method B
Methyl-((3R, 4R) -4-methyl-piperidin-3-yl)-(7H-pyrrolo [2,3-d] pyrimidin-4-yl) -amine Formation from Method A dissolved in 15 mL of ethanol To the product (0.7 grams, 2.19 mmol) was added 1.5 mL of 2N hydrochloric acid and the reaction mixture was degassed with a nitrogen purge. To the reaction mixture was then added 0.5 grams of 20% palladium hydroxide / carbon (50% water) (Aldrich) and the resulting mixture was shaken (Parr-Shaker) at room temperature under a 50 psi hydrogen atmosphere for 2 days. The celite filtered reaction mixture was concentrated to dryness in vacuo and the residue was purified by flash chromatography (silica; 5% methanol in dichloromethane) to give 0.48 grams (90%) of the title compound. LRMS: 246.1 (M + 1).

Method C
3-{(3R, 4R) -4-methyl-3- [methyl- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -amino] -piperidin-1-yl} -3-oxo- To a stirred solution of the product from Method B (1.0 g) dissolved in 30 mL of propionitrile ethanol was added 0.82 g of cyano-acetic acid 2,5-dioxo-pyrrolidin-1-yl ester and the resulting mixture was Stir at room temperature for 2 hours. The reaction mixture was filtered through Celite® and concentrated in vacuo. The residue was redissolved in dichloromethane, washed with saturated, aqueous sodium bicarbonate, dried over sodium sulfate, filtered and concentrated to dryness in vacuo to give 1.1 g (86%) of the title compound as a yellow foam. Got as a body. LRMS: 313 (M + 1). IC ₅₀ = 0.0024μM.

1-{(3R, 4R) -4-methyl-3- [methyl- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -amino] -piperidin-1-yl} -ethanone 10: 1 To a stirred solution of the product from Method B (0.03 grams, 0.114 mmol) dissolved in 5 mL of dichloromethane / pyridine is added acetyl chloride (0.018 grams, 0.228 mmol) and the resulting mixture is at room temperature. Stir for 18 hours. The reaction mixture was then partitioned between dichloromethane and saturated sodium bicarbonate (NaHCO ₃ ). The organic layer was washed again with saturated NaHCO ₃ , dried over sodium sulfate and concentrated to dryness in vacuo. The residue was purified by preparative thin layer chromatography (PTLC) (silica; 4% methanol in dichloromethane) to give 0.005 g (15%) of the title compound as a colorless oil. LRMS (M + 1): 288.2. IC ₅₀ = 0.523μM.

  The title compounds of Examples 34-35 and 47 were prepared by a method similar to that described in Example 33. The title compounds of Examples 36-46 and 48-57 were prepared by a method similar to that described in Example 33.

(3R, 4R)-[1- (2-Amino-ethanesulfonyl) -4-methyl-piperidin-3-yl] -methyl- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -amine LRMS (M + 1): 353.4. IC ₅₀ = 0.0435μM.

(3R, 4R)-(1-ethanesulfonyl-4-methyl-piperidin-3-yl) -methyl- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -amine LRMS (M + 1): 338 .3. IC ₅₀ = 0.0143μM.

(3R, 4R)-[1- (Butane-1-sulfonyl) -4-methyl-piperidin-3-yl] -methyl- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -amine

(3R, 4R) -4-Methyl-3- [methyl- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -amino] -piperidine-1-carboxylic acid isobutyl ester

N- (2-{(3R, 4R) -4-methyl-3- [methyl- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -amino] -piperidine-1-sulfonyl} -ethyl ) -Propionamide

(2-{(3R, 4R) -4-methyl-3- [methyl- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -amino] -piperidine-1-sulfonyl} -ethyl)- Carbamate methyl ester

N- (2-{(3R, 4R) -4-methyl-3- [methyl- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -amino] -piperidine-1-sulfonyl} -ethyl ) -Isobutyramide

(3R, 4R)-(1-Methanesulfonyl-piperidin-3-yl) -methyl- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -amine

((3R, 4R) -1-ethanesulfonyl-piperidin-3-yl) -methyl- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -amine

(3R, 4R) -Methyl- [1- (propane-1-sulfonyl) -piperidin-3-yl]-(7H-pyrrolo [2,3-d] pyrimidin-4-yl) -amine

(3R, 4R)-[1- (Butan-1-sulfonyl) -piperidin-3-yl] -methyl- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -amine

2,2-Dimethyl-N-((3R, 4R) -2- {4-methyl-3- [methyl- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -amino] -piperidine- 1-sulfonyl} -ethyl) -propionamide

(3-{(3R, 4R) -4-methyl-3- [methyl- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -amino] -piperidin-1-yl} -3-oxo -Propyl) -carbamic acid tert-butyl ester

Methyl-[(3R, 4R) -4-methyl-1- (propane-1-sulfonyl) -piperidin-3-yl]-(7H-pyrrolo [2,3-d] pyrimidin-4-yl) -amine LRMS (M + 1): 352.3. IC ₅₀ = 0.0173μM.

3-Amino-1-{(3R, 4R) -4-methyl-3- [methyl- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -amino] -piperidin-1-yl}- Propan-1-one

2-Methoxy-1-{(3R, 4R) -4-methyl-3- [methyl- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -amino] -piperidin-1-yl}- Ethanon

2-dimethylamino-1-{(3R, 4R) -4-methyl-3- [methyl- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -amino] -piperidin-1-yl} -Ethanon

(3-{(3R, 4R) -4-methyl-3- [methyl- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -amino] -piperidin-1-yl} -3-oxo -Propyl) -carbamic acid tert-butyl ester

3,3,3-trifluoro-1-{(3R, 4R) -4-methyl-3- [methyl- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -amino] -piperidine- 1-yl} -propan-1-one

N- (2-{(3R, 4R) -4-methyl-3- [methyl- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -amino] -piperidin-1-yl} -2 -Oxo-ethyl) -acetamide

3-Ethoxy-1-{(3R, 4R) -4-methyl-3- [methyl- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -amino] -piperidin-1-yl}- Propan-1-one

(3R, 4R) -4-Methyl-3- [methyl- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -amino] -piperidine-1-carboxylic acid methylamide

(3R, 4R) -4-Methyl-3- [methyl- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -amino] -piperidine-1-carboxylic acid diethylamide

(3R, 4R) -methyl- [4-methyl-1- (2-methylamino-ethanesulfonyl) -piperidin-3-yl]-(7H-pyrrolo [2,3-d] pyrimidin-4-yl)- Amine

  References to other documents such as patents, patent applications, journals, books, etc. are made throughout the present disclosure. All such documents are hereby incorporated herein by reference in their entirety.

It is to be understood that the foregoing description is exemplary and explanatory in nature and exemplifies the general inventive concept and its preferred embodiments disclosed at the present time. Through routine experimentation, one of ordinary skill in the art having the benefit of this disclosure can identify obvious modifications and variations without departing from the spirit and scope of this disclosure. Accordingly, the present disclosure is not to be limited by the foregoing description, but rather by the following claims and their equivalents.

Claims (40)

A drug combination therapy for treating or preventing human rheumatoid arthritis comprising a Janus kinase inhibitor or a pharmaceutically acceptable salt thereof and at least one anti-arthritic agent or a pharmaceutically acceptable salt thereof. The Janus kinase inhibitor has the formula

Or a pharmaceutically acceptable salt thereof, wherein:
R ¹ is the formula

The basis of
In which y is 0, 1 or 2;
R ⁴ is selected from the group consisting of hydrogen, (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkylsulfonyl, (C ₂ -C ₆ ) alkenyl, (C ₂ -C ₆ ) alkynyl, Alkyl, alkenyl and alkynyl groups are deuterium, hydroxy, amino, trifluoromethyl, (C ₁ -C ₄ ) alkoxy, (C ₁ -C ₆ ) acyloxy, (C ₁ -C ₆ ) alkylamino, ((C ₁ -C _{6) alkyl) 2} amino, cyano, _{nitro, (C} 2 -C ₆₎ alkenyl _may be substituted with _(C 2 -C ₆₎ alkynyl, or _(C 1 -C ₆₎ acylamino, or R ⁴ is (C ₃ -C ₁₀ ) cycloalkyl, and the cycloalkyl group is deuterium, hydroxy, amino, trifluoromethyl, (C ₁ -C ₆ ) acyloxy. Xi, (C ₁ -C ₆ ) acylamino, (C ₁ -C ₆ ) alkylamino, ((C ₁ -C ₆ ) alkyl) ₂ amino, cyano, cyano (C ₁ -C ₆ ) alkyl, trifluoromethyl ( C ₁ -C ₆ ) alkyl, nitro, nitro (C ₁ -C ₆ ) alkyl or (C ₁ -C ₆ ) acylamino may be substituted,
R ⁵ is (C ₂ -C ₉ ) heterocycloalkyl, wherein the heterocycloalkyl group is 1-5 carboxy, cyano, amino, deuterium, hydroxy, (C ₁ -C ₆ ) alkyl, ( C ₁ -C ₆₎ alkoxy, _{halo, (C} 1 ~C _{6) acyl, (C} 1 ~C ₆₎ alkylamino, amino _(C 1 ~C _{6) alkyl, (C} 1 ~C ₆₎ alkoxy -CO- _{NH, (C} 1 _{~C 6)} alkylamino _{-CO -, (C 2 ~C 6} ) _{alkenyl, (C} 2 _{~C 6) alkynyl, (C} 1 _{~C 6)} alkylamino, amino _(C 1 -C ₆ ) alkyl, hydroxy _(C 1 -C _{6) alkyl, (C} 1 -C ₆₎ alkoxy _(C 1 -C _{6) alkyl, (C} 1 -C ₆₎ acyloxy _(C 1 -C ₆₎ alkyl, nitro, cyano _(C 1 ~ ₆₎ alkyl, halo _(C 1 -C ₆₎ alkyl, nitro _(C 1 -C ₆₎ alkyl, trifluoromethyl, trifluoromethyl _(C 1 -C _{6) alkyl, (C} 1 -C ₆₎ acylamino, ( C ₁ -C ₆₎ acylamino _(C 1 _{~C 6) alkyl, (C} 1 _{~C 6)} alkoxy _(C 1 _{~C 6)} acylamino, amino _(C 1 _{~C 6)} acyl, amino _(C 1 -C ₆ ) Acyl (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkylamino (C ₁ -C ₆ ) acyl, ((C ₁ -C ₆ ) alkyl) ₂ amino (C ₁ -C ₆ ) acyl, ^{R 15 R 16 N-CO-} O-, R 15 R 16 N-CO- (C 1 ~C 6) _{alkyl, (C} 1 _{~C 6)} alkyl _{^{-S (O) m, R 15}} R 16 NS (O _{^{) m, R 15 R 16 NS}} (O _{m (C} 1 _{~C 6)} ^alkyl, must be substituted with _{^{R 15 S (O) m R}} 16 N, R 15 S (O) m R 16 N (C 1 ~C 6) alkyl, wherein , M is 0, 1 or 2, and R ¹⁵ and R ¹⁶ are each independently selected from hydrogen or (C ₁ -C ₆ ) alkyl, or

The basis of
Where a is 0, 1, 2, 3 or 4;
b, c, e, f and g are each independently 0 or 1,
d is 0, 1, 2, or 3;
X is S (O) _{n in} which n is 0, 1 or 2, oxygen, carbonyl or -C (= N-cyano)-
Y is S (O) _n where n is 0, 1 or 2, or carbonyl, and Z is carbonyl, C (O) O—, C (O) NR—, or n is 0, 1 or 2 S (O) _n which is
R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ and R ¹¹ are each independently hydrogen, or deuterium, hydroxy, amino, trifluoromethyl, (C ₁ -C ₆ ) acyloxy, (C _1- C _{6) acylamino, (C} 1 -C ₆₎ alkylamino, _((C 1 _{~C 6) alkyl) 2} amino, cyano, cyano _(C 1 -C ₆₎ alkyl, trifluoromethyl _(C 1 _-C 6) Selected from the group consisting of alkyl, nitro, nitro (C ₁ -C ₆ ) alkyl or (C ₁ -C ₆ ) alkyl optionally substituted with (C ₁ -C ₆ ) acylamino;
R ¹² is carboxy, cyano, amino, oxo, deuterium, hydroxy, trifluoromethyl, (C ₁ -C ₆ ) alkyl, trifluoromethyl (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkoxy , Halo, (C ₁ -C ₆ ) acyl, (C ₁ -C ₆ ) alkylamino, ((C ₁ -C ₆ ) alkyl) ₂ amino, amino (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆₎ alkoxy _{-CO-NH, (C 1 ~C} 6) alkylamino _{-CO -, (C 2 ~C 6} ) _{alkenyl, (C} 2 -C _{6) alkynyl, (C} 1 -C ₆₎ alkylamino, hydroxy (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkoxy (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) acyloxy (C ₁ -C ₆ ) alkyl, nitro, cyano (C ₁ -C C ₆ ) Alkyl, halo (C ₁ -C ₆ ) alkyl, nitro (C ₁ -C ₆ ) alkyl, trifluoromethyl, trifluoromethyl (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) acylamino, (C ₁ -C ₆₎ acylamino _(C 1 ~C _{6) alkyl, (C} 1 ~C ₆₎ alkoxy _(C 1 ~C ₆₎ acylamino, amino _(C 1 ~C ₆₎ acyl, amino _(C 1 ~C 6) Acyl (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkylamino (C ₁ -C ₆ ) acyl, ((C ₁ -C ₆ ) alkyl) ₂ amino (C ₁ -C ₆ ) acyl, R ¹⁵ R ¹⁶ N—CO—O—, R ¹⁵ R ¹⁶ N—CO— (C ₁ -C ₆ ) alkyl, R ¹⁵ C (O) NH, R ¹⁵ OC (O) NH, R ¹⁵ NHC (O) NH , _(C 1 ~C ₆₎ alkyl - _{(O) m, (C 1} ~C 6) alkyl _{-S (O) m - (C} 1 ~C 6) ^{_{alkyl, R 15 R 16 NS (O}} ) m, R 15 R 16 NS (O) m (C ₁ -C ₆ ) alkyl, R ¹⁵ S (O) _m R ¹⁶ N, R ¹⁵ S (O) _m R ¹⁶ N (C ₁ -C ₆ ) alkyl, where m is 0, 1 or 2 And R ¹⁵ and R ¹⁶ are each independently selected from hydrogen or (C ₁ -C ₆ ) alkyl;
R ² and R ³ are each independently hydrogen, deuterium, amino, halo, hydroxy, nitro, carboxy, (C ₂ -C ₆ ) alkenyl, (C ₂ -C ₆ ) alkynyl, trifluoromethyl, trifluoromethoxy , (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkoxy, (C ₃ -C ₁₀ ) cycloalkyl, wherein the alkyl, alkoxy or cycloalkyl group is halo, hydroxy, carboxy , Amino (C ₁ -C ₆ ) alkylthio, (C ₁ -C ₆ ) alkylamino, ((C ₁ -C ₆ ) alkyl) ₂ amino, (C ₅ -C ₉ ) heteroaryl, (C ₂ -C ₉ ) _{heterocycloalkyl,} optionally substituted with 1 to 3 groups selected from _(C 3 -C ₉₎ cycloalkyl or _(C 6 _{-C 10)} aryl Be good or ^{R 2} and ^{R 3,} are each independently _(C 3 _{~C 10) cycloalkyl, (C} 3 ~C _{10) cycloalkoxy, (C} 1 _{~C 6)} alkylamino, _((C 1 ~ C _{6) alkyl) 2 amino, (C} 6 _{~C 10) arylamino, (C} 1 _{~C 6) alkylthio, (C} 6 _{~C 10) arylthio, (C} 1 _{~C 6)} alkylsulfinyl, _(C 6 ~ C _{10) arylsulfinyl, (C} 1 _{~C 6) alkylsulfonyl, (C} 6 _{~C 10) arylsulfonyl, (C} 1 _{~C 6) acyl, (C} 1 _{~C 6)} alkoxy -CO-NH -, ( C ₁ -C ₆ ) alkylamino-CO—, (C ₅ -C ₉ ) heteroaryl, (C ₂ -C ₉ ) heterocycloalkyl or (C ₆ -C ₁₀ ) aryl, The heteroaryl, heterocycloalkyl and aryl groups may be 1 to 3 halos, (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkyl-CO—NH—, (C ₁ -C ₆ ) alkoxy. _{-CO-NH -, (C 1} ~C 6) alkyl _{-CO-NH- (C 1 ~C 6} ) _{alkyl, (C} 1 _{~C 6)} alkoxy _{-CO-NH- (C 1 ~C 6} ) alkyl, (C ₁ -C ₆ ) alkoxy-CO—NH— (C ₁ -C ₆ ) alkoxy, carboxy, carboxy (C ₁ -C ₆ ) alkyl, carboxy (C ₁ -C ₆ ) alkoxy, benzyloxycarbonyl (C ₁ -C _{6) alkoxy, (C} 1 ~C ₆₎ alkoxycarbonyl _(C 1 ~C _{6) alkoxy, (C} 6 ~C ₁₀₎ aryl, amino, amino _(C 1 ~C ₆₎ alkyl, (C ₁ -C _{6) alkoxycarbonylamino, (C} 6 ~C ₁₀₎ aryl _(C 1 -C _{6) alkoxycarbonylamino, (C} 1 ~C ₆₎ alkylamino, _((C 1 ~C _{6) alkyl) 2} amino , (C ₁ -C ₆ ) alkylamino (C ₁ -C ₆ ) alkyl, ((C ₁ -C ₆ ) alkyl) ₂ amino (C ₁ -C ₆ ) alkyl, hydroxy, (C ₁ -C ₆ ) alkoxy , Carboxy, carboxy (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkoxycarbonyl, (C ₁ -C ₆ ) alkoxycarbonyl (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkoxy- _{CO-NH -, (C 1} ~C 6) alkyl -CO-NH-, _{cyano, (C} 5 _{~C 9)} heterocycloalkyl, amino _{-CO-NH -, (C 1} ~C 6) Alkylamino _{-CO-NH -, ((C} 1 ~C 6) _{alkyl) 2} amino _{-CO-NH -, (C 6} ~C 10) arylamino _{-CO-NH -, (C 5} ~C 9) heteroarylamino _{-CO-NH -, (C 1} ~C 6) alkylamino _{-CO-NH- (C 1 ~C 6} ) alkyl, _((C 1 ~C _{6) alkyl) 2} amino -CO-NH- _(C 1 ~ C _{6) alkyl, (C} 6 _{~C 10)} arylamino _{-CO-NH- (C 1 ~C 6} ) _{alkyl, (C} 5 _{~C 9)} heteroarylamino _{-CO-NH- (C 1 ~C 6} ) Alkyl, (C ₁ -C ₆ ) alkylsulfonyl, (C ₁ -C ₆ ) alkylsulfonylamino, (C ₁ -C ₆ ) alkylsulfonylamino (C ₁ -C ₆ ) alkyl, (C ₆ -C ₁₀ ) aryl Sulfonyl , (C ₆ -C ₁₀ ) arylsulfonylamino, (C ₆ -C ₁₀ ) arylsulfonylamino (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkylsulfonylamino, (C ₁ -C ₆ ) alkyl sulfonylamino _(C 1 -C _{6) alkyl,} optionally substituted with _(C 5 _{~C 9)} heteroaryl or _(C 2 _{~C 9)} heterocycloalkyl, drug combination therapy of claim 1.   Claims a is 0, b is 1, X is carbonyl, c is 0, d is 0, e is 0, f is 0, and g is 0. Item 3. Drug combination therapy according to Item 2.   Claims a is 0, b is 1, X is carbonyl, c is 0, d is 1, e is 0, f is 0, and g is 0. Item 3. Drug combination therapy according to Item 2.   Claims a is 0, b is 1, X is carbonyl, c is 1, d is 0, e is 0, f is 0, and g is 0. Item 3. Drug combination therapy according to Item 2.   a is 0, b is 1, X is -C (= N = cyano)-, c is 1, d is 0, e is 0, f is 0, The drug combination therapy according to claim 2, wherein g is 0.   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 (O) The drug combination therapy according to claim 2, which is -O-. a is 0, b is 1, X is S (O) _n , n is 2, c is 0, d is 0, e is 0, and f is 0 The drug combination therapy according to claim 2, wherein g is 0. a is 0, b is 1, X is S (O) _n , n is 2, c is 0, d is 2, e is 0, and f is 1 The combination therapy according to claim 2, wherein G is 1, and Z is carbonyl. a is 0, b is 1, X is S (O) _n , n is 2, c is 0, d is 2, e is 0, and f is 1 The drug combination therapy according to claim 2, wherein g is 0. a is 0, b is 1, X is carbonyl, c is 1, d is 0, e is 1, Y is S (O) _n , n is 2 The drug combination therapy according to claim 2, wherein f is 0 and g is 0. a is 0, b is 1, X is S (O) _n , n is 2, c is 1, d is 0, e is 0, and f is 0 The drug combination therapy according to claim 2, wherein g is 0. R ¹² is cyano, trifluoromethyl, (C ₁ -C ₆ ) alkyl, trifluoromethyl (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkylamino, ((C ₁ -C ₆ ) alkyl. ) ₂ amino, (C ₂ -C ₆ ) alkynyl, cyano (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkyl-S (O) _m , where m is 0, 1 or 2 The drug combination therapy according to claim 2, wherein The Janus kinase inhibitor is
Methyl- [4-methyl-1- (propane-1-sulfonyl) -piperidin-3-yl]-(7H-pyrrolo [2,3-d] pyrimidin-4-yl) -amine;
4-methyl-3- [methyl- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -amino] -piperidine-1-carboxylic acid methyl ester;
3,3,3-trifluoro-1- {4-methyl-3- [methyl- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -amino] -piperidin-1-yl} -propane -1-one;
4-methyl-3- [methyl- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -amino] -piperidine-1-carboxylic acid dimethylamide;
({4-Methyl-3- [methyl- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -amino] -piperidine-1-carbonyl} -amino) -acetic acid ethyl ester;
3- {4-methyl-3- [methyl- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -amino] -piperidin-1-yl} -3-oxo-propionitrile;
3,3,3-trifluoro-1- {4-methyl-3- [methyl- (5-methyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl) -amino] -piperidine-1- Il} -propan-1-one;
1- {4-methyl-3- [methyl- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -amino] -piperidin-1-yl} -but-3-in-1-one;
1- {3-[(5-chloro-7H-pyrrolo [2,3-d] pyrimidin-4-yl) -methyl-amino] -4-methyl-piperidin-1-yl} -propan-1-one;
1- {3-[(5-fluoro-7H-pyrrolo [2,3-d] pyrimidin-4-yl) -methyl-amino] -4-methyl-piperidin-1-yl} -propan-1-one;
N-cyano-4-methyl-3- [methyl- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -amino] -N′-propyl-piperidine-1-carboxamidine;
N-cyano-4, N ′, N′-trimethyl-3- [methyl- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -amino] -piperidine-1-carboxamidine;
Methyl-[(3R, 4R) -4-methyl-1- (propane-1-sulfonyl) -piperidin-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] -piperidine-1-carboxylic acid methyl ester;
3,3,3-trifluoro-1-{(3R, 4R) -4-methyl-3- [methyl- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -amino] -piperidine- 1-yl} -propan-1-one;
(3R, 4R) -4-methyl-3- [methyl- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -amino] -piperidine-1-carboxylic acid dimethylamide;
{(3R, 4R) -4-methyl-3- [methyl- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -amino] -piperidine-1-carbonyl} -amino) -acetic acid ethyl ester ;
3-{(3R, 4R) -4-methyl-3- [methyl- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -amino] -piperidin-1-yl} -3-oxo- Propionitrile;
3,3,3-trifluoro-1-{(3R, 4R) -4-methyl-3- [methyl- (5-methyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl) -amino ] -Piperidin-1-yl} -propan-1-one;
1-{(3R, 4R) -4-methyl-3- [methyl- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -amino] -piperidin-1-yl} -but-3- In-1-on;
1-{(3R, 4R) -3-[(5-Chloro-7H-pyrrolo [2,3-d] pyrimidin-4-yl) -methyl-amino] -4-methyl-piperidin-1-yl}- Propan-1-one;
1-{(3R, 4R) -3-[(5-Fluoro-7H-pyrrolo [2,3-d] pyrimidin-4-yl) -methyl-amino] -4-methyl-piperidin-1-yl}- Propan-1-one;
(3R, 4R) -N-cyano-4-methyl-3- [methyl- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -amino] -N'-propyl-piperidine-1-carboxamidine And (3R, 4R) -N-cyano-4, N ′, N′-trimethyl-3- [methyl- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -amino] -piperidine-; 1-carboxamidine,
The drug combination therapy according to claim 2, which is selected from the group consisting of or a pharmaceutically acceptable salt thereof.   The Janus kinase inhibitor is 3-{(3R, 4R) -4-methyl-3- [methyl- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -amino] -piperidine-1- The drug combination therapy according to claim 1, which is yl} -3-oxo-propionitrile or a pharmaceutically acceptable salt thereof.   The drug combination therapy according to claim 1, wherein the anti-arthritis drug is DMARD.   The DMARD is etanercept, infliximab, adalimumab, anakinra, abatacept, rituximab, tocilizumab, certolizumab pegol, hydroxychloroquine, chloroquine, dapsone, sulfasalazine, sodium gold thiomalate, aurothioglucose, auranofin, methotrexate, leflupurine d The drug combination therapy according to claim 16, selected from the group consisting of penicillamine, abatacept and cyclosporin A.   The drug combination therapy according to claim 17, wherein the DMARD is methotrexate.   The Janus kinase inhibitor is 3-{(3R, 4R) -4-methyl-3- [methyl- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -amino] -piperidin-1-yl } -3-Oxo-propionitrile or a pharmaceutically acceptable salt thereof, The drug combination therapy according to claim 1, wherein the anti-arthritic agent is methotrexate or a pharmaceutically acceptable salt thereof.   3-{(3R, 4R) -4-methyl-3- [methyl- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -amino] -piperidin-1-yl} -3-oxo- Propionitrile or a pharmaceutically acceptable salt thereof is administered in an amount of about 1 mg BID, 5 mg BID, 10 mg BID, 15 mg BID, 20 mg BID, 25 mg BID, or 30 mg BID, and methotrexate is administered weekly in an amount of 5 mg, 7.5 mg, or 15 mg. The drug combination therapy according to claim 19.   Janus kinase inhibitor or pharmaceutic thereof for preparing a medicament for treating or preventing human rheumatoid arthritis for co-administration with at least one anti-arthritic agent or a pharmaceutically acceptable salt thereof Use of chemically acceptable salts. The Janus kinase inhibitor has the formula

Or a pharmaceutically acceptable salt thereof, wherein:
R ¹ is the formula

The basis of
In which y is 0, 1 or 2;
R ⁴ is selected from the group consisting of hydrogen, (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkylsulfonyl, (C ₂ -C ₆ ) alkenyl, (C ₂ -C ₆ ) alkynyl, Alkyl, alkenyl and alkynyl groups are deuterium, hydroxy, amino, trifluoromethyl, (C ₁ -C ₄ ) alkoxy, (C ₁ -C ₆ ) acyloxy, (C ₁ -C ₆ ) alkylamino, ((C ₁ -C _{6) alkyl) 2} amino, cyano, _{nitro, (C} 2 -C ₆₎ alkenyl _may be substituted with _(C 2 -C ₆₎ alkynyl, or _(C 1 -C ₆₎ acylamino, or R ⁴ is (C ₃ -C ₁₀ ) cycloalkyl, and the cycloalkyl group is deuterium, hydroxy, amino, trifluoromethyl, (C ₁ -C ₆ ) acyloxy. Xi, (C ₁ -C ₆ ) acylamino, (C ₁ -C ₆ ) alkylamino, ((C ₁ -C ₆ ) alkyl) ₂ amino, cyano, cyano (C ₁ -C ₆ ) alkyl, trifluoromethyl ( C ₁ -C ₆ ) alkyl, nitro, nitro (C ₁ -C ₆ ) alkyl or (C ₁ -C ₆ ) acylamino may be substituted,
R ⁵ is (C ₂ -C ₉ ) heterocycloalkyl, wherein the heterocycloalkyl group is 1-5 carboxy, cyano, amino, deuterium, hydroxy, (C ₁ -C ₆ ) alkyl, ( C ₁ -C ₆₎ alkoxy, _{halo, (C} 1 ~C _{6) acyl, (C} 1 ~C ₆₎ alkylamino, amino _(C 1 ~C _{6) alkyl, (C} 1 ~C ₆₎ alkoxy -CO- _{NH, (C} 1 _{~C 6)} alkylamino _{-CO -, (C 2 ~C 6} ) _{alkenyl, (C} 2 _{~C 6) alkynyl, (C} 1 _{~C 6)} alkylamino, amino _(C 1 -C ₆ ) alkyl, hydroxy _(C 1 -C _{6) alkyl, (C} 1 -C ₆₎ alkoxy _(C 1 -C _{6) alkyl, (C} 1 -C ₆₎ acyloxy _(C 1 -C ₆₎ alkyl, nitro, cyano _(C 1 ~ ₆₎ alkyl, halo _(C 1 -C ₆₎ alkyl, nitro _(C 1 -C ₆₎ alkyl, trifluoromethyl, trifluoromethyl _(C 1 -C _{6) alkyl, (C} 1 -C ₆₎ acylamino, ( C ₁ -C ₆₎ acylamino _(C 1 _{~C 6) alkyl, (C} 1 _{~C 6)} alkoxy _(C 1 _{~C 6)} acylamino, amino _(C 1 _{~C 6)} acyl, amino _(C 1 -C ₆ ) Acyl (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkylamino (C ₁ -C ₆ ) acyl, ((C ₁ -C ₆ ) alkyl) ₂ amino (C ₁ -C ₆ ) acyl, ^{R 15 R 16 N-CO-} O-, R 15 R 16 N-CO- (C 1 ~C 6) _{alkyl, (C} 1 _{~C 6)} alkyl _{^{-S (O) m, R 15}} R 16 NS (O _{^{) m, R 15 R 16 NS}} (O _{m (C} 1 _{~C 6)} ^alkyl, must be substituted with _{^{R 15 S (O) m R}} 16 N, R 15 S (O) m R 16 N (C 1 ~C 6) alkyl, wherein , M is 0, 1 or 2, and R ¹⁵ and R ¹⁶ are each independently selected from hydrogen or (C ₁ -C ₆ ) alkyl, or

The basis of
Where a is 0, 1, 2, 3 or 4;
b, c, e, f and g are each independently 0 or 1,
d is 0, 1, 2, or 3;
X is S (O) _{n in} which n is 0, 1 or 2, oxygen, carbonyl or -C (= N-cyano)-
Y is S (O) _n where n is 0, 1 or 2, or carbonyl, and Z is carbonyl, C (O) O—, C (O) NR—, or n is 0, 1 or 2 S (O) _n which is
R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ and R ¹¹ are each independently hydrogen, or deuterium, hydroxy, amino, trifluoromethyl, (C ₁ -C ₆ ) acyloxy, (C _1- C _{6) acylamino, (C} 1 -C ₆₎ alkylamino, _((C 1 _{~C 6) alkyl) 2} amino, cyano, cyano _(C 1 -C ₆₎ alkyl, trifluoromethyl _(C 1 _-C 6) Selected from the group consisting of alkyl, nitro, nitro (C ₁ -C ₆ ) alkyl or (C ₁ -C ₆ ) alkyl optionally substituted with (C ₁ -C ₆ ) acylamino;
R ¹² is carboxy, cyano, amino, oxo, deuterium, hydroxy, trifluoromethyl, (C ₁ -C ₆ ) alkyl, trifluoromethyl (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkoxy , Halo, (C ₁ -C ₆ ) acyl, (C ₁ -C ₆ ) alkylamino, ((C ₁ -C ₆ ) alkyl) ₂ amino, amino (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆₎ alkoxy _{-CO-NH, (C 1 ~C} 6) alkylamino _{-CO -, (C 2 ~C 6} ) _{alkenyl, (C} 2 -C _{6) alkynyl, (C} 1 -C ₆₎ alkylamino, hydroxy (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkoxy (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) acyloxy (C ₁ -C ₆ ) alkyl, nitro, cyano (C ₁ -C C ₆ ) Alkyl, halo (C ₁ -C ₆ ) alkyl, nitro (C ₁ -C ₆ ) alkyl, trifluoromethyl, trifluoromethyl (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) acylamino, (C ₁ -C ₆₎ acylamino _(C 1 ~C _{6) alkyl, (C} 1 ~C ₆₎ alkoxy _(C 1 ~C ₆₎ acylamino, amino _(C 1 ~C ₆₎ acyl, amino _(C 1 ~C 6) Acyl (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkylamino (C ₁ -C ₆ ) acyl, ((C ₁ -C ₆ ) alkyl) ₂ amino (C ₁ -C ₆ ) acyl, R ¹⁵ R ¹⁶ N—CO—O—, R ¹⁵ R ¹⁶ N—CO— (C ₁ -C ₆ ) alkyl, R ¹⁵ C (O) NH, R ¹⁵ OC (O) NH, R ¹⁵ NHC (O) NH , _(C 1 ~C ₆₎ alkyl - _{(O) m, (C 1} ~C 6) alkyl _{-S (O) m - (C} 1 ~C 6) ^{_{alkyl, R 15 R 16 NS (O}} ) m, R 15 R 16 NS (O) m (C ₁ -C ₆ ) alkyl, R ¹⁵ S (O) _m R ¹⁶ N, R ¹⁵ S (O) _m R ¹⁶ N (C ₁ -C ₆ ) alkyl, where m is 0, 1 or 2 And R ¹⁵ and R ¹⁶ are each independently selected from hydrogen or (C ₁ -C ₆ ) alkyl;
R ² and R ³ are each independently hydrogen, deuterium, amino, halo, hydroxy, nitro, carboxy, (C ₂ -C ₆ ) alkenyl, (C ₂ -C ₆ ) alkynyl, trifluoromethyl, trifluoromethoxy , (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkoxy, (C ₃ -C ₁₀ ) cycloalkyl, wherein the alkyl, alkoxy or cycloalkyl group is halo, hydroxy, carboxy , Amino (C ₁ -C ₆ ) alkylthio, (C ₁ -C ₆ ) alkylamino, ((C ₁ -C ₆ ) alkyl) ₂ amino, (C ₅ -C ₉ ) heteroaryl, (C ₂ -C ₉ ) _{heterocycloalkyl,} optionally substituted with 1 to 3 groups selected from _(C 3 -C ₉₎ cycloalkyl or _(C 6 _{-C 10)} aryl Be good or ^{R 2} and ^{R 3,} are each independently _(C 3 _{~C 10) cycloalkyl, (C} 3 ~C _{10) cycloalkoxy, (C} 1 _{~C 6)} alkylamino, _((C 1 ~ C _{6) alkyl) 2 amino, (C} 6 _{~C 10) arylamino, (C} 1 _{~C 6) alkylthio, (C} 6 _{~C 10) arylthio, (C} 1 _{~C 6)} alkylsulfinyl, _(C 6 ~ C _{10) arylsulfinyl, (C} 1 _{~C 6) alkylsulfonyl, (C} 6 _{~C 10) arylsulfonyl, (C} 1 _{~C 6) acyl, (C} 1 _{~C 6)} alkoxy -CO-NH -, ( C ₁ -C ₆ ) alkylamino-CO—, (C ₅ -C ₉ ) heteroaryl, (C ₂ -C ₉ ) heterocycloalkyl or (C ₆ -C ₁₀ ) aryl, The heteroaryl, heterocycloalkyl, and aryl groups are 1 to 3 halo, (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkyl-CO—NH—, (C ₁ -C ₆ ) alkoxy. _{-CO-NH -, (C 1} ~C 6) alkyl _{-CO-NH- (C 1 ~C 6} ) _{alkyl, (C} 1 _{~C 6)} alkoxy _{-CO-NH- (C 1 ~C 6} ) alkyl, (C ₁ -C ₆ ) alkoxy-CO—NH— (C ₁ -C ₆ ) alkoxy, carboxy, carboxy (C ₁ -C ₆ ) alkyl, carboxy (C ₁ -C ₆ ) alkoxy, benzyloxycarbonyl (C ₁ -C _{6) alkoxy, (C} 1 ~C ₆₎ alkoxycarbonyl _(C 1 ~C _{6) alkoxy, (C} 6 ~C ₁₀₎ aryl, amino, amino _(C 1 ~C ₆₎ alkyl, (C ₁ -C _{6) alkoxycarbonylamino, (C} 6 ~C ₁₀₎ aryl _(C 1 -C _{6) alkoxycarbonylamino, (C} 1 ~C ₆₎ alkylamino, _((C 1 ~C _{6) alkyl) 2} amino , (C ₁ -C ₆ ) alkylamino (C ₁ -C ₆ ) alkyl, ((C ₁ -C ₆ ) alkyl) ₂ amino (C ₁ -C ₆ ) alkyl, hydroxy, (C ₁ -C ₆ ) alkoxy , Carboxy, carboxy (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkoxycarbonyl, (C ₁ -C ₆ ) alkoxycarbonyl (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkoxy- _{CO-NH -, (C 1} ~C 6) alkyl -CO-NH-, _{cyano, (C} 5 _{~C 9)} heterocycloalkyl, amino _{-CO-NH -, (C 1} ~C 6) Alkylamino _{-CO-NH -, ((C} 1 ~C 6) _{alkyl) 2} amino _{-CO-NH -, (C 6} ~C 10) arylamino _{-CO-NH -, (C 5} ~C 9) heteroarylamino _{-CO-NH -, (C 1} ~C 6) alkylamino _{-CO-NH- (C 1 ~C 6} ) alkyl, _((C 1 ~C _{6) alkyl) 2} amino -CO-NH- _(C 1 ~ C _{6) alkyl, (C} 6 _{~C 10)} arylamino _{-CO-NH- (C 1 ~C 6} ) _{alkyl, (C} 5 _{~C 9)} heteroarylamino _{-CO-NH- (C 1 ~C 6} ) Alkyl, (C ₁ -C ₆ ) alkylsulfonyl, (C ₁ -C ₆ ) alkylsulfonylamino, (C ₁ -C ₆ ) alkylsulfonylamino (C ₁ -C ₆ ) alkyl, (C ₆ -C ₁₀ ) aryl Sulfonyl , (C ₆ -C ₁₀ ) arylsulfonylamino, (C ₆ -C ₁₀ ) arylsulfonylamino (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkylsulfonylamino, (C ₁ -C ₆ ) alkyl sulfonylamino _(C 1 _{~C 6) alkyl,} optionally substituted with _(C 5 _{~C 9)} heteroaryl or _(C 2 _{~C 9)} heterocycloalkyl, use according to claim 21.   Claims a is 0, b is 1, X is carbonyl, c is 0, d is 0, e is 0, f is 0, and g is 0. Item 23. Use according to Item 22.   Claims a is 0, b is 1, X is carbonyl, c is 0, d is 1, e is 0, f is 0, and g is 0. Item 23. Use according to Item 22.   Claims a is 0, b is 1, X is carbonyl, c is 1, d is 0, e is 0, f is 0, and g is 0. Item 23. Use according to Item 22.   a is 0, b is 1, X is -C (= N = cyano)-, c is 1, d is 0, e is 0, f is 0, 23. Use according to claim 22, wherein g is 0.   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 (O) 23. Use according to claim 22, wherein -O-. a is 0, b is 1, X is S (O) _n , n is 2, c is 0, d is 0, e is 0, and f is 0 24. Use according to claim 22, wherein g is 0. a is 0, b is 1, X is S (O) _n , n is 2, c is 0, d is 2, e is 0, and f is 1 23. Use according to claim 22, wherein g is 1 and Z is carbonyl. a is 0, b is 1, X is S (O) _n , n is 2, c is 0, d is 2, e is 0, and f is 1 24. Use according to claim 22, wherein g is 0. a is 0, b is 1, X is carbonyl, c is 1, d is 0, e is 1, Y is S (O) _n , n is 2 23. Use according to claim 22, wherein f is 0 and g is 0. a is 0, b is 1, X is S (O) _n , n is 2, c is 1, d is 0, e is 0, and f is 0 24. Use according to claim 22, wherein g is 0. R ¹² is cyano, trifluoromethyl, (C ₁ -C ₆ ) alkyl, trifluoromethyl (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkylamino, ((C ₁ -C ₆ ) alkyl. ) ₂ amino, (C ₂ -C ₆ ) alkynyl, cyano (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkyl-S (O) _m , where m is 0, 1 or 2 23. Use according to claim 22, wherein The Janus kinase inhibitor is
Methyl- [4-methyl-1- (propane-1-sulfonyl) -piperidin-3-yl]-(7H-pyrrolo [2,3-d] pyrimidin-4-yl) -amine;
4-methyl-3- [methyl- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -amino] -piperidine-1-carboxylic acid methyl ester;
3,3,3-trifluoro-1- {4-methyl-3- [methyl- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -amino] -piperidin-1-yl} -propane -1-one;
4-methyl-3- [methyl- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -amino] -piperidine-1-carboxylic acid dimethylamide;
({4-Methyl-3- [methyl- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -amino] -piperidine-1-carbonyl} -amino) -acetic acid ethyl ester;
3- {4-methyl-3- [methyl- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -amino] -piperidin-1-yl} -3-oxo-propionitrile;
3,3,3-trifluoro-1- {4-methyl-3- [methyl- (5-methyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl) -amino] -piperidine-1- Il} -propan-1-one;
1- {4-methyl-3- [methyl- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -amino] -piperidin-1-yl} -but-3-in-1-one;
1- {3-[(5-chloro-7H-pyrrolo [2,3-d] pyrimidin-4-yl) -methyl-amino] -4-methyl-piperidin-1-yl} -propan-1-one;
1- {3-[(5-fluoro-7H-pyrrolo [2,3-d] pyrimidin-4-yl) -methyl-amino] -4-methyl-piperidin-1-yl} -propan-1-one;
N-cyano-4-methyl-3- [methyl- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -amino] -N′-propyl-piperidine-1-carboxamidine;
N-cyano-4, N ′, N′-trimethyl-3- [methyl- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -amino] -piperidine-1-carboxamidine;
Methyl-[(3R, 4R) -4-methyl-1- (propane-1-sulfonyl) -piperidin-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] -piperidine-1-carboxylic acid methyl ester;
3,3,3-trifluoro-1-{(3R, 4R) -4-methyl-3- [methyl- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -amino] -piperidine- 1-yl} -propan-1-one;
(3R, 4R) -4-methyl-3- [methyl- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -amino] -piperidine-1-carboxylic acid dimethylamide;
{(3R, 4R) -4-methyl-3- [methyl- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -amino] -piperidine-1-carbonyl} -amino) -acetic acid ethyl ester ;
3-{(3R, 4R) -4-methyl-3- [methyl- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -amino] -piperidin-1-yl} -3-oxo- Propionitrile;
3,3,3-trifluoro-1-{(3R, 4R) -4-methyl-3- [methyl- (5-methyl-7H-pyrrolo [2,3-d] pyrimidin-4-yl) -amino ] -Piperidin-1-yl} -propan-1-one;
1-{(3R, 4R) -4-methyl-3- [methyl- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -amino] -piperidin-1-yl} -but-3- In-1-on;
1-{(3R, 4R) -3-[(5-Chloro-7H-pyrrolo [2,3-d] pyrimidin-4-yl) -methyl-amino] -4-methyl-piperidin-1-yl}- Propan-1-one;
1-{(3R, 4R) -3-[(5-Fluoro-7H-pyrrolo [2,3-d] pyrimidin-4-yl) -methyl-amino] -4-methyl-piperidin-1-yl}- Propan-1-one;
(3R, 4R) -N-cyano-4-methyl-3- [methyl- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -amino] -N'-propyl-piperidine-1-carboxamidine And (3R, 4R) -N-cyano-4, N ′, N′-trimethyl-3- [methyl- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -amino] -piperidine-; 1-carboxamidine,
23. Use according to claim 22, selected from the group consisting of or a pharmaceutically acceptable salt thereof.   The Janus kinase inhibitor is 3-{(3R, 4R) -4-methyl-3- [methyl- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -amino] -piperidine-1- 23. The method of claim 22, which is yl} -3-oxo-propionitrile or a pharmaceutically acceptable salt thereof.   The use according to claim 21, wherein the anti-arthritic agent is DMARD.   The DMARD is etanercept, infliximab, adalimumab, anakinra, abatacept, rituximab, tocilizumab, certolizumab pegol, hydroxychloroquine, chloroquine, dapsone, sulfasalazine, sodium gold thiomalate, aurothioglucose, auranofin, methotrexate, leflupurine d 37. Use according to claim 36, selected from the group consisting of penicillamine, abatacept and cyclosporin A.   38. Use according to claim 37, wherein the DMARD is methotrexate.   The Janus kinase inhibitor is 3-{(3R, 4R) -4-methyl-3- [methyl- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -amino] -piperidin-1-yl 23. Use according to claim 21, wherein the compound is} -3-oxo-propionitrile or a pharmaceutically acceptable salt thereof and the anti-arthritic agent is methotrexate or a pharmaceutically acceptable salt thereof.   3-{(3R, 4R) -4-methyl-3- [methyl- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -amino] -piperidin-1-yl} -3-oxo- Propionitrile or a pharmaceutically acceptable salt thereof is administered in an amount of about 1 mg BID, 5 mg BID, 10 mg BID, 15 mg BID, 20 mg BID, 25 mg BID, or 30 mg BID, and methotrexate is administered weekly in an amount of 5 mg, 7.5 mg, or 15 mg. 40. The use according to claim 39.