TW201134826A - Pyrrolopyrazine kinase inhibitors - Google Patents

Abstract

The present invention relates to the use of novel pyrrolopyrazine derivatives of Formula I, wherein the variables n, p, q, Q, X, X' and Y are defined as described herein, which inhibit JAK and SYK and are useful for the treatment of auto-immune and inflammatory diseases.

Description

201134826 VI. INSTRUCTIONS OF THE INVENTION: FIELD OF THE INVENTION The present invention relates to the use of novel pyrrolopyrazine derivatives which are JAK and SYK inhibitors and which selectively inhibit JAK3 and are useful for the treatment of autoimmune immunity. Diseases and inflammatory diseases. [Prior Art] Protein kinases constitute one of the largest families of human enzymes, and many different signaling processes are regulated by the addition of phosphate groups to proteins; in detail, tyrosine kinase phosphorylates tyrosine residues Part of the protein. The lysine kinase family includes members that control cell growth, migration, and differentiation. Abnormal kinase activity is involved in a variety of human diseases, including cancer, autoimmune diseases, and inflammatory diseases. Because protein kinases are a key cellular signaling regulator, they provide a means to modulate cellular function with small molecule inhibitors of kinase activity, and thus achieve superior drug design goals. In addition to treating the S#-mediated disease process, selective and potent inhibitors of kinase activity are also useful for studying cellular signaling processes and identifying other cellular targets associated with therapy. JAK (jAnus Kinases) is a family of cytoplasmic protein tyrosine kinases including JAK1, JAK2, JAK3 and TYK2. Each jAK is preferably associated with the intracytoplasmic portion of the discontinuous cytokine receptor /w/wm(10)/. 16 (1998), pp. 293-page 322). JAK is activated after ligand binding and initiates signaling by phosphorylating a cytokine receptor that lacks its intrinsic kinase activity. This phosphorylation produces a docking site for other molecules called STAT proteins (signal transducers and transcriptional activators) 154395.doc 201134826, and phosphorylated JAK binds to various STAT proteins. A STAT protein or STAT is a DNA-binding protein that is activated by phosphorylating a tyrosine residue and acts as a signaling molecule and transcription factor, and ultimately with a specific DNA sequence present in the promoter of a cytokine-responsive gene. Binding (Leonard et al, (2000), J. Allergy Clin. Immunol. 105: 877-888). JAK/STAT signaling has been implicated in a variety of aberrant immune responses, such as allergies, asthma, autoimmune diseases (such as transplantation (allogeneic allograft) rejection), rheumatoid arthritis, amyotrophic lateral sclerosis And multiple sclerosis, as well as solid malignancies and hematological malignancies (such as leukemia and lymphoma). Thus, JAK and STAT are components of multiple possible interlaced signal transduction pathways 19 (2000), pp. 5662- 5679, which indicate that it is difficult to specifically target without interfering with other signal transduction pathways. A feature in the JAK-STAT path. JAK kinases (including JAK3) are abundantly expressed in primary white disease cells in children with acute lymphoblastic leukemia, the most common form of childhood cancer, and studies have found STAT activation and regulatory cells in certain cells. Correlation of apoptotic signals (Demoulin et al., (1996), Mol. Cell. Biol. 16:4710-6; Jurlander et al., (1997), Blood. 89: 4146-52; Kaneko et al., (1997). ), Clin. Exp. Immun. 109: 185-193; and Nakamura et al. (1996), J. Biol. Chem. 271: 19483-8). It is also known to be important for lymphocyte differentiation, function and survival. JAK3 is especially useful in the function of Limba cells, macrophages and mast cells. 154395.doc 201134826 is used. Due to the importance of this JAK kinase, compounds that modulate the JAK pathway, including compounds that are selective for JAK3, can be used to treat diseases or conditions involving lymphocyte, macrophage, or mast cell function (Kudlacz et al., 2004). Am. J. Transplant 4: 51-57; Changelian (2003) Science 302: 875_878). Conditions that are expected to be applicable to treatment, such as leukemia, lymphoma, transplant rejection, such as islet transplant rejection, bone marrow transplantation (eg, graft versus host disease), may be applied to the JAK pathway or to the regulation of JAK kinase (specifically JAK3). ), autoimmune diseases (such as diabetes) and inflammation (such as asthma, allergic reactions). The conditions that can benefit from JAK3 inhibition are discussed in more detail below. However, contrary to the relatively ubiquitous performance of JAK1, JAK2 and Tyk2, JAK3 has a more limited and regulated performance. Although some JAK (JAK1, JAK2, Tyk2) are used in various cytokine receptors, JAK3 is only used in cytokines containing ye in the receptor. Therefore, JAK3 is known to be involved in the cytokine signaling of receptors of cytokines (IL-2, IL-4, IL-7, IL-9, IL-15 and IL-21) which still use common gamma bonds. Has a role. JAK1 interacts with receptors for the cytokines IL-2, IL-4, IL-7, IL-9 and IL-21, while JAK2 interacts with receptors for IL-9 and TNF-α. Certain cytokines and Receptor oligomerization occurs when receptors (eg, IL-2, IL-4, IL-7, IL-9, IL-15, and IL-21) bind, resulting in a close approach to the cytoplasmic tail of the associated JAK kinase It helps to squamousize the glutamic acid residue on the JAK kinase. This descaling leads to activation of JAK kinase. Animal studies have shown that JAK3 not only has a critical role in the maturation of B and T lymphocytes, but also requires JAK3 to maintain T cell function in composition. 154395.doc 201134826 By adjusting the immunological activity by this novel mechanism, it can be demonstrated to be useful in the treatment of tau cell proliferative disorders such as transplant rejection and autoimmune diseases.

The specific term 'JΑΚ3' has been involved in various biological processes. For example, IL-4 and IL-9-induced proliferation and survival of murine mast cells have been shown to be dependent on JAK3- and gamma chain-signaling (Suzuki et al., (2000), Blood 96: 2172-2180). JAK3 also plays a key role in IgE receptor-mediated mast cell degranulation (Malaviya et al., (1999), Biochem. Biophys. Res. Commun. 25 7:807-813) and has been shown to inhibit JAK3 kinase prevention. Type I allergic reactions, including anaphylaxis (Malaviya et al. (1999), J. Biol. Chem. 274:27028-27038). It has also been shown that inhibition of JAK3 can exert immunosuppressive effects on allograft rejection (Kirken, (2001), Transpl. Proc. 33: 3268-3270). JAK3 kinase has also been implicated in early and late stage rheumatoid arthritis (Muller-Ladner et al, (2000), J. Immunal 164:3894-3901), family amyotrophic lateral sclerosis (Trieu et al., ( 2000), Biochem Biophys. Res. Commun. 267:22-25), leukemia (Sudbeck et al., (1999), Clin. Cancer Res. 5:1569-1582), mycosis fungoides (a form of T-cell lymphoma) (Nielsen et al. (1997), Prac. Natl. Acad. Sci. USA 94:6764-6769) and abnormal cell growth (Yu et al., (1997), J. Immunol. 159: 5206-5210; Catlett- Falcone et al. (1999), Immunity 10: 105-115) related mechanisms. JAK3 inhibitors are immunosuppressants for the following therapies: organ transplantation, xenograft, lupus, multiple sclerosis, rheumatoid arthritis, psoriasis, type I diabetes and diabetic complications, cancer, asthma, ectopic 154395. Doc 201134826 Sexual dermatitis, autoimmune sputum gland disorders, ulcerative colitis, Crohn's disease, Alzheimer's disease, leukemia and other indications requiring immunosuppression. The non-hematopoietic performance of JAK3 has also been reported, but its functional importance remains to be elucidated (J. /wmizwo/. 168 (2002), p. 2475 - p. 2482). Because SCID bone marrow transplantation is effective (5/ooc? 103 (2004), p. 2009 - p. 2018), it appears that JAK3 is unlikely to have the necessary non-redundant functions in other tissues or organs. Therefore, in contrast to other targets of immunosuppressive drugs, the restricted distribution of JAK3 is attractive. Agents that act on molecular targets that are limited to the immune system can lead to optimal efficacy: toxicity ratio. Thus, targeting JAK3 theoretically provides immunosuppression where it is needed (i.e., on cells actively involved in the immune response) without any effect beyond the range of such cell populations. Although defective immune responses have been described in various STAT_/_ strains (·/· /«veihg. MeA 44 (1996), p. 304 - p. 311; Cwrr. CW/ 5ίο/· 9 (1997), p. 233 Pages - p. 239), but the widespread distribution of STATs and their lack of enzymatic activity that can be caused by small molecule inhibitors have prevented them from being selected as a key target for immunosuppression. S ΥΚ (spleen tyrosine kinase) is a non-receptor tyrosine kinase necessary for activation of sputum cells via BCR signaling. SYK is activated upon binding to phosphorylated BCR and thus induces early signaling events after BCR activation. Mice lacking SYK exhibit early blockade of sputum cell development (Cheng et al. Nature 378: 303, 1995; Turner et al. Nature 378: 298, 1995). Thus, SYK enzyme activity in cells is inhibited by autologous antibodies. Produced as 154395.doc 201134826 was proposed as a treatment for autoimmune diseases. In addition to its role in BCR signaling and B cell activation, SYK also plays a key role in FcsRI-mediated mast cell degranulation and eosinophil activation. Thus, SYK is involved in allergic conditions, including asthma (reviewed in Wong et al. Expert Opin Investig Drugs 13: 743, 2004). SYK binds to the phosphorylated gamma chain of FcsRI via its SH2 domain and is required for downstream signaling (Taylor et al. Mol. Cell. Biol. 15:4149, φ 1995). SYK-deficient mast cells show defective degranulation, arachidonic acid and cytokine secretion (Costello et al. Oncogene 13: 2595, 1996). Pharmacological agents that inhibit SYK activity in mast cells have also shown this effect (Yamamoto et al. J Pharmacol Exp Ther 306: 1174, 2003). Treatment with SYK antisense oligonucleotides can inhibit antigen-induced eosinophils and neutrophil infiltration in an animal model of asthma (Stenton et al. J Immunol 169: 1028, 2002). SYK-deficient eosinophils also showed impaired activation in response to FcsR stimulation (Lach-Trifilieffe et al. # Blood 96: 2506, 2000). Therefore, small molecule inhibitors of SYK will be suitable for the treatment of allergic-induced inflammatory diseases, including asthma. Given that many conditions are expected to benefit from treatments that modulate JAK and/or SYK pathways, it is readily apparent that new compounds that modulate JAK and/or SYK pathways and methods of using such compounds will provide substantial treatment for a variety of patients. benefit. Provided herein are novel pyrrolopyrazine derivatives for the treatment of conditions in which targeting the JAK and/or SYK pathway or inhibiting JAK or SYK kinases (especially JAK3) are therapeutically suitable for the treatment of autoimmune diseases and inflammatory diseases. The novel pyrrolopyrazine derivatives provided herein selectively inhibit JAK3 154395.doc 201134826 and are useful in the treatment of autoimmune diseases and inflammatory diseases. The compounds of the invention modulate the JAK and/or SYK pathway and are used to treat 痳白耱&

Sickly inhibits JAK3. For example, the compounds of the present invention inhibit the adaptation of JAK3 and SYK', among which preferred compounds are selective for jAK3 of jak kinase and are novel pyrrolopy pyridin derivatives for the treatment of autoimmune diseases and inflammatory diseases. Furthermore, the compounds of the present invention inhibit jAK3 and JAK2, wherein the preferred compound is selective for JAK3 of JAK kinase and is a novel novel sigma-dosin derivative for the treatment of autoimmune diseases and inflammatory diseases. Similarly, the compounds of the invention inhibit JAK3 and JAK1, with preferred compounds being selective for JAK3 of JAK kinase and suitable for the treatment of autoimmune diseases and inflammatory diseases. SUMMARY OF THE INVENTION The present application provides a compound of formula I,

g , wherein: Y is CH(R)); R1 is Η or Rla;

Rla is a lower alkyl group substituted by one or more Rla', low carbon 154395.doc •10· 201134826 alkoxy, phenyl, phenyl fluorenyl, heteroaryl, cycloalkyl, heterocycloalkyl Or a cycloalkylalkyl group;

Rla' is dentate, lower alkyl, lower carboalkyl, lower alkoxy, lower carbon hydroxy, lower carbyl, pendant oxy, hydroxy or -CN; X is C(R2) (R3), N(R2), S(=0)2 or Ο; each R2 is independently Η or R2a; each R2a is independently lower alkyl, lower haloalkyl, haloformin, lower hexane Oxy, lower hydroxyalkyl, cyano, cyano lower alkyl, hydroxy, C(=0)R2a' or S(=0)2R2a'; each Ra2' is independently hydrazine or lower alkyl; Each X' is independently a functional element, a lower alkyl group, a cyano group, a hydroxyl group, a lower haloalkyl group, a lower hydroxyalkyl group, a heteroaryl group, a spiroheterocycloalkyl group, a spirocycloalkyl group or a lower alkoxy group. a base, a lower alkylamino group or a lower dialkylamino group; or X' and R2 together form a bicyclic ring system optionally substituted by one or more V; 9 R2 is a halogen, a low carbon alkyl group, a low carbon An alkoxy group, a mercapto group, a transalkylene lower alkyl group, a lower halohaloalkyl group, a lower hydroxyalkylcyano group or a -s(o)2ch3; R3 is an anthracene, a hydroxyl group, a halogen or a lower alkyl group; or R2 And R3 together form a spiro ring system which is replaced by one or more R2'; q is 0, 1, 2, 3 or 4; η is 0 or 1; ρ is 0 or 1; Q is Η Halogen, hydroxy, cyano or Q'; 154395.doc • 11 - 201134826 Q' is a lower alkyl, lower alkoxy, lower alkynyl, lower alkoxy group substituted by one or more Qa as appropriate , cycloalkyl, cycloalkoxy, phenoxy, phenyl, cycloalkenyl, heterocycloalkyl or heteroaryl; Q, Qb or Qc;

Qb is a producer, a pendant oxy group, a hydroxyl group, -CN, -SCH3, -S(〇)2CH3 or -s(=o)ch3;

QlQ^Qe'; or two Qa together form a double loop system that replaces Lu by one or more Qb or Qc as appropriate;

Qd is -0 (Qe), -S (=0) 2 (Qe), -C (=0) N (Qe) 2, S (0) 2 (Qe), -C (=0) (Qe) , -C(=0)0(Qe), -N(Qe)2, -N(Qe)C(=0)(Qe), -N(Qe)C(=0)0(Qe) or -N (Qe)C(=0)N(Qe)2; each (^ is independently H or Qe'; each Qe' is independently a lower alkyl, phenyl, benzene substituted with one or more Qf as appropriate Methyl, lower carboxyalkyl, lower alkoxy, cycloalkyl, cycloalkyl lower alkyl, cycloalkenyl, heterocycloalkyl or heteroaryl;

Qf is Q4Qh;

Qg is halogen, hydroxy, cyano, pendant oxy or -C(=0)(Qh);

Qh is a lower alkyl group, a lower alkene group, a lower alkoxy group, an amine group, a phenyl group, a benzyl group, a cycloalkyl group, a heterocycloalkyl group or a heteroaryl group substituted by one or more Qi as the case may be. Base; and 154395.doc •12· 201134826

Qi is a halogen, a hydroxyl group, a cyano group, a lower alkyl group, a lower carbon or a lower alkoxy group; or a pharmaceutically acceptable salt thereof. This application provides a compound of formula I'.

Γ , where: Y is CE^R1); R1 is Η or Rla;

Rla is a lower alkyl, lower alkoxy, phenyl, alkoxy, heteroaryl, cycloalkyl, heterocycloalkyl or cycloalkyl group substituted by one or more Rla' as appropriate;

Rla is _, lower alkyl, lower alkyl i, lower alkoxy, lower hydroxyalkyl, lower haloalkyl, pendant oxy, hydroxy or -CN; X is C(R2) ( R3), N(R2)'s(=0)2 or Ο; each R2 is independently Η or R2a; each R2a is independently lower alkyl, lower carbitol, dentate, lower alkoxy , low carbon burnt group, cyano group, low alkyl group, hydroxyl group, C(=0)R2a• or S(=0)2R2a\ each 1^2_ independently Η or lower alkyl; 154395 .doc •13· 201134826 each x, independently dentin, lower alkyl, cyano, hydroxy, lower haloalkyl, lower hydroxyalkyl, heteroaryl, spiroheterocycloalkyl, spiro a 'lower alkoxy group, a lower alkylamino group or a lower dialkylamino group; or X. and R2 together form a bicyclic ring system optionally substituted by one or more R 2 '; R 2 ' is a peptidin , lower alkyl, lower alkoxy, hydroxy, hydroxy lower alkyl, lower carbohydrazide, lower carbon ketanyl or -S(0)2CH3; R3 is hydrazine, hydroxy, halogen or low carbon Or an alkyl group; or R 2 and R 3 together form a spiro ring system which is optionally substituted by one or more R 2 '; q is 0, 1, 2, 3 or 4; η is 0 or 1; ρ is 0 or 1; Q is hydrazine, halogen, thiol, cyano or Q'; Q' is a lower alkyl, lower alkenyl, lower alkynyl group, optionally substituted by one or more Qa Alkoxy, cycloalkyl, cycloalkoxy, phenyl, cycloalkenyl, heterocycloalkyl or heteroaryl;

QlQb or Qc;

Qb is a element, a pendant oxy group, a hydroxyl group, -CN, -SCH3, -S(〇)2CH3 or -s(=o)ch3; Q, Q4Qe_; or two Qa are formed as one or more depending on the situation. Double-ring system replaced by Qb or QC; (^ is -0((^), -S(=〇)2(Qe), _C(=0)N(Qe)2, _S(0)2(Qe) 154395. Doc •14- 201134826 , -C(=0)(Qe), -C(=〇)〇(Qe), -N(Qe)2, _N(Qe)C(=〇)(Qe), -N( Qe) C(=0)〇(Qe) or -N(Qe)C(=〇)N(Qe)2; each Qlf is H or Qe'; each Qe' is independently one or more depending on the situation Qf substituted lower alkyl, phenyl, benzyl, lower carbon lialkyl, lower alkoxy, cycloalkyl, cycloalkyl lower alkyl, cycloalkenyl, heterocycloalkyl or heteroaryl Base; • Q%Q4Qh;

Qg is halogen, hydroxy, cyano, pendant oxy or -C(=0)(Qh);

Qh is a lower alkyl, lower alkene, lower alkoxy, amine, phenyl, benzyl, cycloalkyl, heterocycloalkyl or heteroaryl substituted by one or more β as the case may be. And Q1 is dentate, hydroxy, cyano, lower alkyl, lower _alkyl or lower alkoxy; or a pharmaceutically acceptable salt thereof. This application provides a compound of formula I, ',

154395.doc •15· 201134826 Y is CH(R丨); R1 is H or Rla;

Rla is a lower alkyl, lower alkoxy, phenyl, benzyl, heteroaryl, cycloalkyl, heterocycloalkyl or cycloalkylalkyl group optionally substituted with one or more rM;

Rla' is a decano, lower alkyl, lower alkyl, lower alkoxy, lower hydroxyalkyl, lower haloalkyl, pendant oxy, hydroxy or -CN; X is C(R2) (R3), N(R2) or hydrazine; each R2 is independently hydrazine or R2a; each R2a is independently a lower alkyl group, lower carbon! i alkyl, halogen, lower alkoxy, lower hydroxyalkyl, cyano, cyano lower alkyl, hydroxy, C(=0)R2a• or S(=0)2R2a; each 1132' independently Is a hydrazine or a lower alkyl group; each Y is independently a functional element, a lower alkyl group, a cyano group, a hydroxyl group, a lower haloalkyl group, a lower hydroxyalkyl group, a heteroaryl group, a spiroheterocycloalkyl group, a spiro ring An alkyl group, a lower alkoxy group, a lower alkylamino group or a lower dialkylamino group; or X' and R2 together form a bicyclic ring system optionally substituted by one or more R 2 '; R 2 ' is a , lower alkyl, lower alkoxy, hydroxy, lower haloalkyl, lower hydroxyalkylcyano or -s(o)2ch3; R3 is hydrazine, hydroxy, halogen or lower alkyl; q is 0, 1, 2, 3 or 4; η is 0 or 1; ρ is 0 or 1; 154395.doc -16· 201134826 Q is Η, halogen, thiol, cyano or Q'; Q, as the case may be One or more Qa substituted lower alkyl, lower alkenyl, lower alkynyl, cycloalkyl, phenyl, cycloalkenyl, heterocycloalkyl or heteroaryl; Q, Qb or Qc;

Qb is dentate, pendant oxy, hydroxy, -CN, -SCH3, -S(0)2CH3 or -s(=〇)ch3; • Qe is Qd4Qe'; or two Qa-forms form one or a double loop system replaced by multiple Qb or Qc;

Qd^-0(Qe)' -S(=0)2(Qe) ' -C(=0)N(Qe)2 ' -S(0)2(Qe) , _c(=〇)(Qe), -C(=0)0(Qe), -N(Qe)2, -N(Qe)C(=0)(Qe), -N(Qe)C(=0)〇(Qe) or -N( Qe) C(=0)N(Qe)2; each (^ is independently H or Qe'; each V is independently a lower alkyl, phenyl, phenyl group substituted by one or more Qfs as appropriate a base, a lower halohaloalkyl group, a lower alkoxy group, a cycloalkyl group, a cycloalkenyl group, a heterocycloalkyl group or a heteroaryl group;

Qg is halogen, hydroxy, cyano, pendant oxy or _ C (=0) (Qh);

Qh is a low carbon alkyl group, a low carbon agglomerate group, a low carbon alkoxy group, an amine group, a phenyl group, a stupid methyl group, a cycloalkyl group, a heterocycloalkyl group or a heteroaryl group substituted by one or more Q1 as the case may be. 154395.doc • 17- 201134826 base; and Q1 is dentate, hydroxyl, cyano, lower alkyl, low carbon dentate or lower carboxy; or a pharmaceutically acceptable salt thereof. The present invention provides a method of treating an inflammatory condition or an autoimmune condition. The method comprises administering to a patient in need thereof a therapeutically effective amount of a compound according to any one of claims 1 to 40. The present application provides a pharmaceutical composition comprising a compound of formula Z in admixture with a pharmaceutically acceptable carrier, excipient or diluent. DEFINITIONS As used herein, the phrase "a system of J refers to one or more such entities, for example, a compound refers to one or more compounds or at least one compound. Therefore, "1", "one" "One or more (s)" and "at least one (a)" may be used interchangeably herein. sheet. As used herein, the broadest definition is provided for each of the bases as set forth in the Summary of the Invention or the broadest scope of application. All other embodiments provided below, which may be present in various embodiments and which are not explicitly defined, retain the broadest definitions set forth in the Summary. As used in this specification, the syllabus “includes” should be interpreted as having an open-ended meaning in either the transitional phrase or the subject of the application. That is, the terms "synonymous with the phrase "at least" and "including at least" are used in the context of a method, and the term "comprising" means that the method includes at least the steps but may also include Other steps m in the case of a compound or composition 'the term 'comprising' means 154 395. doc 201134826 but may also include other compounds or compositions including at least the features or components, characteristics or components. "Or" is used in the meaning of "include" or "any" or "and/or" unless otherwise specified. it is good. Independently, "is used herein to indicate that a certain variable is applied in either case" and has the same or a different definition of the presence or absence of the same compound, regardless of the code. In the case of a compound that appears twice in R and is defined as "independent carbon or nitrogen", both R" can be carbon, two r" can be nitrogen, or one R" can be carbon The other is nitrogen. Any variable (e.g., X, X, or Q) in the field that describes and describes more than one or more of any part or formula of a compound used or claimed by the invention 'is defined at every occurrence and all other It does not matter when it appears. Likewise, combinations of substituents and/or variables are permissible only if such compounds result in stable compounds.

The symbol "*" at the key end or "·..." drawn through the key refers to the connection point of the functional base or another chemical part with the rest of the molecule to which it belongs. Thus, for example:

MeC(=0)0R4 where R4=*-<1 or [<] MeC(=0)0~〇. The key drawn into the ring system (as opposed to being connected to a different apex) indicates that the bond can be attached to any suitable ring atom. The term "optional" or "as appropriate" as used herein means that the event or circumstance described later may or may not occur, and that the description includes the circumstances in which the event or circumstance occurs and the event or circumstance does not occur. Example 154395.doc •19· 201134826 The term “replaced as appropriate” means that a portion substituted as appropriate may incorporate hydrogen or a substituent. As used herein, the phrase "to form a bicyclic system together" means to combine to form a bicyclic ring system wherein each ring may be composed of 4 to 7 carbon atoms or 4 to 7 carbon atoms and heteroatoms, and may be saturated or unsaturated. . The term "about" is used herein to mean approximation, left and right, approximate or approximate. When the term "about" is used in conjunction with a numerical range, it is modified by extending the upper and lower boundaries of the listed numerical values. In general, the term "about" is used herein to modify the value within 2 〇 0 / 〇 deviation above and below the value. The definitions described herein may be supplemented to form chemically relevant combinations such as "heteroalkylaryl", "dentylheteroaryl", "arylalkylheterocyclyl", "alkylcarbonyl", "Alkoxyalkyl", "cycloalkylalkyl" and the like. When the term "alkyl" is used as the suffix after another term, such as in "phenylalkyl" or "hydroxyalkyl", this is intended to mean that the alkyl group as defined above is selected from one to two other Substituent substitution of the specified group. Thus, for example, "phenylalkyl" refers to an alkyl group having up to two phenyl substituents, and thus includes benzyl, stupid ethyl and biphenyl. The "alkylaminoalkyl group" is an alkyl group having 1 to 2 alkylamino substituents. "Hydroxyalkyl" includes hydroxyethyl, 2-hydroxypropyl, 1 (hydroxymethyl)-2-methylpropyl, 2 hydroxybutyl ' 2,3_butyl 2-(thiol), 3 - by propyl and the like. Thus, the term "hydroxyalkyl" as used herein, is used to define a subset of heteroalkyl groups as defined below. The term -(aryl)alkyl means an unsubstituted alkyl or aralkyl group. The term (hetero)aryl refers to an aryl or heteroaryl group. 154395.doc 201134826 Formula I, oxime and II, compounds exhibit tautomerism. The tautomeric compound may exist in the form of two or more substances which are mutually convertible. The proton transfer tautomer system is produced by the migration of a covalently bonded hydrogen atom between two atoms. Tautomers are generally in equilibrium and attempts to separate individual tautomers typically result in a mixture having chemical and physical properties consistent with the mixture of compounds. The equilibrium position depends on the chemical characteristics within the molecule. For example, in many aliphatic aldehydes and aliphatic ketones (such as acetaldehyde), the predominant form is the keto form; and in phenols, the predominant form is the enol form. Common proton transfer tautomers include ketone/enol (_C(=0)_CH_S_C(-OH)-CH-), decylamine/imine (_c(=〇)_NH to _c(_〇h) =n_) and lung (·CpNW-NH-tCGNHR^N·) tautomers. The latter two are especially common in heteroaromatic rings and heterocycles and the invention encompasses all tautomeric forms of the compounds. The technical and scientific terms used herein have the meaning commonly understood by those skilled in the art to which the invention pertains, unless otherwise defined. Various methods and materials known to those skilled in the art are referred to herein. Standard references describing the general principles of pharmacology include Goodman and Gilman, 77^ Pharmacol〇gical Basis 〇f Therapeutics (4)

Hill Companies Inc., New York (2001). The invention may be carried out using any suitable materials and/or methods known to those skilled in the art. However, preferred materials and methods are described. Unless otherwise stated, the materials, reagents and analogs mentioned in the following description and examples are available from commercial sources. The term "mercapto" as used herein denotes a radical of the formula _c(=〇)R, wherein R is nitrogen or a lower alkyl group as defined herein. As used herein, the term 154395.doc • 21 - 201134826 "Alkylcarbonyl J represents a group of the formula C(= 〇)R where R is a succinct group as defined herein. The term Cw 醯 refers to from 1 to 6 A group of carbon atoms - C(=0)R. The term "arylcarbonyl" as used herein means a group of the formula C(0)R, wherein R is aryl; the term "benzazole" as used herein R is a "aryl group" of a phenyl group. The term "alkyl" as used herein denotes a non-branched or branched chain saturated monovalent hydrocarbon residue containing from 1 to 10 carbon atoms. The term "lower alkyl" means a straight or branched hydrocarbon residue having from 1 to 6 carbon atoms. As used herein, "c"·丨G alkyl" means an alkyl group consisting of 1 to 1 carbon. Examples of alkyl groups include, but are not limited to, low carbon including methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl or pentyl, isopentyl, neopentyl, hexyl Alkyl, heptyl and octyl. When the term "alkyl" is used as the suffix after the other term, as in "phenylalkyl" or "hydroxyalkyl", this is intended to mean that the alkyl group as defined above is selected from one to two Substituent substitution of the specified group. Thus, for example, "phenylalkyl" denotes a radical R, R", wherein R• is phenyl and R" is an alkylene group as defined herein, wherein it is understood that the point of attachment of the phenylalkyl moiety is at extension On the base. Examples of aryl bases include, but are not limited to, benzyl, phenylethyl, 3-phenyl. The term "aryl base" or "aralkyl" is similarly explained except that R' is an aryl group. The term "heteroarylalkyl" is interpreted in a similar manner except for R, optionally as aryl or heteroaryl. The term "dental base" as used herein denotes a branchless or branched alkane group as defined above and which is substituted with 2, 3 or more hydrogen atoms via a ? The term "low-carbohaloalkyl" means a straight or branched hydrocarbon residue having from 1 to 6 carbon atoms and deuterium, 2, I54395.doc • 22·201134826, three or more hydrogen atoms substituted by dentate. Examples are 1-fluoromethyl, 1-oxymethyl, 1-bromomethyl, 1-iodomethyl, difluoromethyl, trifluoromethyl, trichloroindolyl, tribromomethyl, triiodomethyl , 1-fluoroethyl, 1-oxyethyl, 1-bromoethyl, 1-iodoethyl, 2-fluoroethyl, 2-chloroethyl, 2-bromoethyl, 2-iodoethyl, 2 , 2-dichloroethyl, 3-bromopropyl or 2,2,2-trifluoroethyl. The term "alkylene" as used herein, unless otherwise indicated, means a divalent saturated straight chain hydrocarbon radical having from 1 to 10 carbon atoms (eg (CH2)n), or a branched chain having from 2 to 1 carbon atoms. Saturated divalent hydrocarbon groups (e.g., _CHMe- or -CH2CH〇Pr) CH2_). Except in the case of an anthracene group, the open price of an alkyl group is not attached to the same atom. Examples of the stretching group include, but are not limited to, an anthracenylene group, an ethyl group, a propyl group, a 2-methyl group, a propyl group, a dimethyl group, an ethyl group, a butyl group, and a 2-ethylbutyl group. The term "alkoxy" as used herein, means _〇-alkyl, wherein alkyl is as defined above, such as decyloxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, Isobutoxy, tert-butoxy, pentyloxy, hexyloxy, including isomers thereof. As used herein, "lower alkoxy" means an alkoxy group having a "lower alkyl group" as defined above. As used herein, "CM oxime alkoxy" means an alkyl group having a C-io-0-alkyl group. The term "alkyl group" as used herein denotes an alkyl group as defined herein and having one to three hydrogen atoms on a different carbon atom replaced by a hydroxy group. The term "cycloalkyl" as used herein means a saturated carbocyclic ring containing from 3 to 8 carbon atoms, i.e., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl. As used herein, r CM cycloalkyl refers to a ring-based base composed of 3 to 7 carbons in the carbocyclic ring 154395.doc • 23- 201134826. The term "cycloalkenyl" means a partially unsaturated carbocyclic ring β having 5 to 7 carbon atoms and having a carbon-carbon double bond in the ring unless otherwise specified, for example, c5 (cycloalkenyl means having 5 to 6 member atoms) The cycloalkenyl group. In certain embodiments, the cycloalkenyl group has one carbon-carbon double bond in the ring. In other embodiments, the cycloalkenyl group has more than one carbon-carbon double bond in the ring. However, the cycloalkenyl group The ring is not an aromatic ring. The cycloalkenyl group may be optionally substituted with one or more substituents. Examples of cycloalkenyl groups include, but are not limited to, cyclopentenyl and cyclohexenyl. The term "dentate" or "as used herein" as used herein. "Tooth radical" means fluoro, silane, bromine or volute. The term "amine group" as used herein encompasses _NR2, wherein each R group is independently hydrazine or lower alkyl, wherein lower alkyl is as defined herein Examples of amine groups include dimethylamino, methylamino and ΝΗ^ "As used herein, the term "aryl" means monocyclic or bicyclic (also known as "biaryl") substituted or unsubstituted. Examples of substituted carbocyclic aromatic groups aryl are phenyl, naphthyl and the like. "Heteroaryl" means a monocyclic, bicyclic ("heteroaryl") or tricyclic group having from 5 to 18 ring atoms having at least one aromatic ring containing from 4 to 8 atoms per ring. Incorporating one or more ν, 〇 or 8 atoms, the remaining ring atoms are carbon, it should be understood that the point of attachment of the heteroaryl group should be on the ring. As is well known to those skilled in the art, the heteroaryl ring and all of it are The conjugate is less aromatic than the conjugate. Therefore, for the purposes of the present invention, the heteroaryl group only needs to have some degree of aromatic character. Examples of the heteroaryl moiety include 5 to 6 ring atoms and (1) hetero Atomic single-ring aromatic heterocycles, package 154395.doc •24· 201134826 including but not limited to pyridyl, pyrimidinyl, pyridyl, pyrrolyl, carbazolyl, azo-based, °-based ° 恶 ° ° sit, ° ° ° ° sit, ° plug saliva, different ° plug, three beta sitine, triazolyl, thienyl, furyl, thiadiazole and oxadiazoline, which may be through one or Multiple, preferably one or two substituents selected from the group consisting of hydroxyl, cyano, alkyl, alkoxy, thio, lower haloalkoxy, alkyl Base, self-base, halogenated group, alkyl group, alkyl group, halogen, amine group, alkyl amine group, dialkylamino group, aminoalkyl group, alkylaminoalkyl group And a dialkylaminoalkyl group, a nitro group, an alkoxycarbonyl group and an amine carbenyl group, an alkylamine oxime group, a dialkylamino group, an arylamine aryl group, a decylamino group And an arylmethylamino group. Examples of the bicyclic moiety include, but are not limited to, guanyl, oxazolyl, isoquinolinyl, benzofuranyl, benzothienyl, benzoxazole, stupid and isoxazole, Benzothiazole, pyrrolopyridinyl, pyroindole and pheno-isothiazole. The terms "heterocycloalkyl", "heterocyclyl" or "heterocycle" as used herein, unless otherwise indicated. A monovalent saturated cyclic indenyl group having the following characteristics: consisting of one or more rings, preferably one to two rings (3 to 8 atoms per ring), incorporating one or more ring carbon atoms and one or a plurality of ring heteroatoms (selected from ruthenium, osmium or s(=O)0_2), wherein the point of attachment may be via a carbon atom or a heteroatom' and it may optionally be one or more, Substituted with one or two or three substituents selected from the group consisting of hydroxyl, pendant oxy, cyano, lower alkyl, lower alkoxy, lower alkoxy, alkylthio, yl , haloalkyl, hydroxyalkyl, nitro, alkoxycarbonyl, amine, alkylamino, alkylsulfonyl, arylsulfonyl, alkylaminosulfonyl, arylaminesulfonate Stuffing group, alkylsulfonylamino group, arylsulfonylamino group, alkylamino group 154395.doc -25- 201134826 base, arylamino group, leumino group, aryl group Amino group. Examples of heterocyclic groups include, but are not limited to, azetidinyl, pyrrolidinyl, hexahydroazetyl, oxetanyl, tetrahydrofuranyl, tetraargon. Tertiary, oxazole, thazolidinyl, isoxazolidinyl, pyrrolidinyl, morphinyl, benzyl, piperidinyl, isoindolyl, dihydroisoquinolinyl, Tetrahydropyranyl, tetrahydroporphyrinyl, imidazolinyl, thiomorpholinyl, acridinyl and imidazolyl 0 "Organic rejection" includes vascularization and/or non-vascularization (eg bone marrow) Acute allograft or xenograft rejection and chronic allograft or xenograft rejection in transplantation of islet cells. The term "excipient" as used herein refers to a compound that is suitable for the preparation of a pharmaceutical composition, generally safe, non-toxic, and biologically and otherwise undesirable, and which includes veterinary use and Human extracts use the approved excipients. The compounds of the invention may be administered alone, but will generally be administered in admixture with one or more suitable pharmaceutical excipients, diluents or carriers for the desired route of administration and standard pharmaceutical practice. "Pharmaceutically acceptable" means a pharmaceutical composition suitable for the preparation of a safe, non-toxic and biologically or otherwise undesirable material, and which is acceptable for veterinary and human medical use. Pharmaceutical composition. Living and learning! The "medicalally acceptable salt" form of the knife can also be used to initially impart the pharmacokinetic properties of the sexual component that are not present in the non-salt form and "actively affect the active ingredient in the body. >, "Pharmaceutically acceptable salt" of a therapeutically active tablet is meant to be pharmaceutically acceptable. 154395.doc -26 - 201134826 Salt acceptable and having the pharmacological activity of the desired parent compound . The salts include: (1) an acid addition salt formed with an inorganic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or an acid addition salt formed with an organic acid The organic acid is such as acetic acid, propionic acid, caproic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, Tartaric acid, citric acid, stupid formic acid, 3-(4-pyridylbenzhydryl)benzoic acid, cinnamic acid, mandelic acid, phthalic acid, ethanesulfonic acid, 1,2-ethane-disulfonic acid, 2- Hydroxyethanesulfonic acid, benzenesulfonic acid, 4-benzoic acid, 2-naphthoic acid, 4-toluic acid, camphor acid, 4-methylbicyclo[2.2.2]-oct-2-ene-1 -decanoic acid, glucoheptonic acid, 3-phenylpropionic acid, trimethylacetic acid, tert-butylacetic acid, lauryl sulfate, gluconic acid, face acid, hydroxynaphthoic acid, salicylic acid, stearic acid Or muric acid and the like; or (2) a salt formed when the acid proton present in the parent compound is replaced by a metal ion (for example, an alkali metal ion, a soil metal ion or an aluminum ion); or Alkali Such as ethanolamine, diethanolamine, triethanolamine, tromethamine, N- methylglucamine and the like inspection amine) salts formed when coordinated. Preferred groups of the chemical groups defined above are those specifically exemplified in the examples. In one variation of formula I, hydrazine or II", Q is a cycloalkyl or heteroaryl group optionally substituted with a lower alkyl group. In a variation of I, Γ or II'', X is C(R2)(R3). In one variation of I, Γ or ΙΓ', R2 is lower alkyl, cyano, halogen, lower alkoxy, lower haloalkyl, heteroaryl or hydroxy. In one variation of I, Γ or II', 11 is 〇 and p is 〇. 154395.doc -27· 201134826

Where i is at i, I is at I, I is at I, I η is 1 and ρ is 〇. η is 1 and ρ is 1. η is 0 and ρ is 1. q is 0. q is 1. R1 is a variant in which Rla 〇q is 0 and R1 is a lower alkyl hydrazine or ΙΓ' in a variant of I or II in a variant of Γ or &' Or a variant of II'· in a variation of ' or ΙΓ', a variant of I' or ΙΓ', a lower alkoxy group, a cycloalkyl group, a low-magnetic occupant-#上" low anti-tooth burning Or a lower carbon-alkylcycloalkyl group in the formula I, oxime or II", wherein R is lower alkyl or cycloalkyl. R3 is Η. R3 is a lower alkyl group. R3 is a dentate. q is 0 and R1 is a low carbon yard or q is 0 and R3 is Η » q is 0 and R3 is a lower alkyl group. q is 0 and R3 is halogen. R is, in one or more variants of I, I' or II" in a variant of I, I' or II1, in a variant of I, Γ or II" Γ or a variant of II" in the middle of the ring. In a variant of I, Γ or II" in a variant of I, Γ or II" in a variant of I, Γ or II, in a variation of I, Γ or II" ...substituted lower alkyl, low magnetic, anti-grave, gas, cycloalkyl, lower haloalkyl or lower carbon-alkylcyclohexyl. In the case of I, Γ or II·', it is quite arbitrarily. In the formula I, Rla is a lower alkyl group or a lower haloalkyl group. In a change of I, Γ or II'·; 4, 丄1仏^, R is lower alkyl, lower alkane 154395.doc •28- 201134826 oxy, cycloalkyl, low carbon tooth Alkyl or low carbon dentate cycloalkyl. In a variation of dip or Π, η is 1, p is 1, and R1 is a low carbon yard, a low carbon alkoxy group, a ring base group, a low carbon tooth burn group or a low carbon halogen group. Ring-burning base. In a variation of dip or Π", η is 1, ρ is 1, and R1 is lower alkyl or cycloalkyl. In a variant of I, Γ or II", Rl is low carbon The base or ring ruthenium 'η is 1 'p is 1, and q is 〇. In a variation of I, I, or II", r1 is a low carbon or cycloalkyl group, and η is 1 , P is 1 ' and Han 3 is Η. In the dimorphism of the dip or Π", R1 is a low-carbon alkyl or a cycloalkyl group, η is 1, ρ is 1 ' and R3 is a lower alkane. In a variation of I, I' or II", with a low carbon or a ring, η is 1, ρ is 1 ' and R3 is halogen. A variation in I, Γ or ΙΓ Wherein η is 〇, 卩 is 丨, and R1 is a low-carbon alkyl group, a low-carbon alkoxy group, a ring-based group, a low-carbon dentate group or a low-carbon dentate-based cycloalkyl group. In I, Γ or II In a variation of '', 40, ? is i, and Rl is a low carbon yard or a ring-based base. In a variation of I, Γ or II", Rl is a lower alkyl or cycloalkyl group, η is 0, P is 1, and q is 〇. In a variation of I, Γ or II", Rl is low carbon Alkyl or cycloalkyl, η is 0, ρ is 1, and R3 is η. In one variation of I, hydrazine or hydrazine, R1 is lower alkyl or cycloalkane 154395.doc -29- 201134826, η is 0, ? is !, and R3 is lower alkyl. In a variation of I, I, or II", R1 is lower alkyl or cycloalkyl, η is 0, 卩 is !, and R3 is halogen. In one variation of II or 11, n is 〇, p is 〇, and R1 is lower alkyl, lower alkoxy, cycloalkyl, lower carbon or alkyl In a variation of I, Γ or II, η is 〇, ρ is 〇, and the 丨 is lower alkyl or cycloalkyl. In a variation of II or 11, Is a lower alkyl or cycloalkyl group, η is 0' p is 0, and q is 〇. In one variation of I, I or II, r1 is lower alkyl or cycloalkyl, η is 0' p is 〇, and 尺 3 is Η. In one variation of II or 11, Ri is lower alkyl or cycloalkyl, η is 0, P is 0, and ... is lower alkyl. In a variation of 11 , R 1 is lower alkyl or cycloalkyl, and η is 0 ' p is And that the prime _ I, Γ or II ". 4 a ridge of a spot where, [eta] is 1, ρ is 0, R is a lower Shu

Affiliation, low carbon alkoxy, ring, ρ I $ group, lower alkyl or lower carboxyalkyl group. In a variable of 1, 1' or ΙΓ', t t , I 匕 ^ / where η is 1, ρ is 0, and R1 is a low carbon group or a cycloalkyl group. In the formula I, Γ or II", η is 1, p is 0, R1 is a lower alkyl group or a cycloalkyl group, and q is 〇. In a variation of I, 1' or II", η is 1, p is 0, R丨 is low carbon 154395.doc 201134826 alkyl or cycloalkyl, R3 is Η. η is 1, ρ is 0, R1 is low carbon η is 1 ' ρ is 0, R1 is low carbon Q is determined by one or more Q as a case of a lower alkyl group in I, Γ or II" A variant of the alkyl or cycloalkyl group, R3 is a low carbon alkyl group. In one variation of I, Γ or II", a base or a cycloalkyl group, and R3 is a halogen.

A cycloalkyl or heteroaryl group in which a Q-substituted cycloalkyl, phenyl or heteroaryl group is substituted in a variant of I, r or II" in a variant of I, oxime or II". In a variation of I, I, or π", 乂 is post 2). In a variation of ϊ, γ, or η", r2 is a low carbon & base, an atmosphere, a lignin, Low carbon, oxygen, low carbon sulfhydryl, heteroaryl, stupid or thiol. In a variation of br or π", R2 is a low carbon yard, cyano, halogen, lower alkoxy , low carbon-alkyl, stupid or hydroxyl. In a variation of dip or Π, R2 is low-wei, cyano, dentate, low-breaking oxy, low-carbon ketone, phenyl Or a base, and ^ is Η. In a variation of I, I, or II", (10) 1-sided oxy-1,3-dihydro-iso-β-bend substituted by one or more Qa as appropriate Buxo_2_yl, cycloalkyl, imidazolyl, cycloalkoxy, lower alkoxy, phenyl, phenoxy, oxazolyl, pyridyl, thiazolylthiophene [3,2- 6] Pyridin-2-yl or triazolyl. In a variant of I, I' or II", Qa is optionally substituted by one or more Qfs - 〇Qe ' -N(Qe)2, _c (=〇)N(Qe)2, aza-bicyclo[3"〇]hex-3-yl, lower haloalkyl, lower alkyl, ring Alkyl, phenyl, morpholine 154395.doc -31 · 201134826 benzyl, lower alkoxy, cycloalkyl lower alkyl, piperazinyl, pyrazolyl, pyridinyl, indenyl, hydrazine In one variation of I, I1 or II", Qf is halogen or -C(=0)(Qh) 'where Qh is lower alkyl. In a variation of I, Γ or II" , X is C(r2)(r3) and Q is a cycloalkyl, phenyl or heteroaryl group optionally substituted with one or more Qa. In one variation of I, Γ or II", R2 is low Carboalkyl, cyano, halogen, lower alkoxy, lower carbyl, heteroaryl or hydroxy, again C(R2)(R3) and Q is optionally substituted by one or more Qa Alkyl, stupid or heteroaryl. In a variation of I, γ or π'', 11 is (), p is 〇, R2 is lower alkyl, cyano, dentate, lower alkoxy a group, a lower alkyl group, a heteroaryl group or a hydroxy group, X is C(R)(R3) and Q is optionally a cycloalkyl group, a phenyl group or a heteroaryl group substituted by 卩3. In a variation of I' or II", η is 丨, p is 〇, and R2 is low carbon.

An alkyl group, a cyano group, a self group, a low carbon alkoxy group, a low carbon i group, a heteroaryl group or a hydroxyl group X is C(R)(R) and q is a cycloalkane substituted by one or more Qa as the case may be. Base, phenyl or heteroaryl. In a variation of 卜 or Π, η is 1, p is 1, and R 2 is lower alkyl, cyano, dentate, lower alkoxy, lower carbyl, heteroaryl or The base X is C(R)(r) and q is a cycloalkyl, phenyl or heteroaryl group optionally substituted by one or more. In the variants of I, I' or II", R2 is cyano 'C(R)(R) and Q is optionally substituted by a number of Qa, 154395.doc • 32 · 201134826 or Heteroaryl In a variation of I or 11, q is deuterium, R2 is lower alkyl, cyanogen, low carbon alkoxy, low carbon functional group, heteroaryl Or a radical, C(R)(R) and q is a cycloalkyl, phenyl or heteroaryl group substituted by one or more ^ as appropriate. In a variant of /I or II, q is R, R 2 is cyano, χ is C(R )(R ) and Q is a cycloalkyl, phenyl or heteroaryl group optionally substituted with one or more Qa. In one variation of I, I or II, R1 is lower alkylalkyl lower alkoxy 2-yl' cycloalkyl, lower haloalkyl or lower haloalkylcycloalkyl, q is hydrazine, and R is A cyano group, X is c(r2)(r3) and Q is a cycloalkyl, phenyl or heteroaryl group optionally substituted with one or more Qa. In one variation of oxime, I or II", R1 is lower alkyl or cycloalkyl 'q is 0, R is cyano, and x is cycloalkyl 'benzene substituted with one or more Qa as appropriate Base or heteroaryl. In a variation of I, Γ or II", R3 is H, R1 is lower alkyl or % alkyl, q is 0, R2 is cyano, R2 is lower alkyl, cyano, halogen, lower Carboalkoxy, lower alkyl-alkyl, heteroaryl or hydroxy, hydrazine is C(R)(R) and Q is cycloalkyl, phenyl or heteroaryl optionally substituted with one or more Qa. In a variation of I, Γ or ΙΓ', 'R3 is lower alkyl, R1 is lower alkyl or cycloalkyl, (! is 0, R2 is cyano, R2 is lower alkyl, cyano , dentate, lower alkoxy, lower alkyl, heteroaryl or hydroxy, χ is C(R )(R ) and Q is a cycloalkyl group optionally substituted by one or more Qa, benzene 154395 .doc •33· 201134826 yl or heteroaryl. This application provides a method of treating an inflammatory condition or an autoimmune condition, the method comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula I. The invention provides the above method, which comprises the steps of administering a chemotherapeutic or anti-proliferative agent, an anti-inflammatory agent, an immunomodulator or an immunosuppressive agent, a god's agent, and a medicament for treating cardiovascular diseases. Another therapeutic agent for treating diabetes or an agent for treating immunodeficiency. The present application provides a method of treating rheumatoid arthritis comprising administering a therapeutically effective amount of a compound of formula I to a patient in need thereof. The present application provides a method of treating asthma, the method comprising The patient is administered a therapeutically effective amount of a compound of formula I. The present application provides a method of treating an inflammatory condition comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula I. The present application provides a method of inhibiting tau cell proliferation. A method of sexually treating a method comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula I. The present invention provides a method of inhibiting a tau cell proliferative disorder comprising administering to a patient in need thereof therapeutically effective The present invention provides a method of the above formula, wherein the proliferative disorder is cancer. The application provides a method of treating a beta cell proliferative disorder, the method comprising administering to a patient in need thereof a therapeutically effective amount Compound I. The present invention provides a method for treating an immune disorder comprising: lupus, multiple sclerosis, rheumatoid arthritis, psoriasis, type 2 diabetes, organ transplant complications, xenograft, diabetes, cancer, Asthma, 154395.doc • 34- 201134826 Atopic dermatitis, autoimmune thyroid disease, ulcerative knot Inflammation, Crohn's disease, Alzheimer's disease (A) zheimer's disease, and leukemia, the method comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula I. This application provides A method of preventing or treating all forms of organ rejection (including acute allograft or xenograft rejection and chronic allograft or xenograft rejection), vascularization or non-vascular grafting, including to patients in need thereof Administration of a compound of formula j. The present application provides a method of inhibiting JAK3 activity by administering a compound of formula Η, or !", wherein the compound is in the phoenix 3 = two in vitro biochemical assay ^(3) is a curse or Less than 5 〇 micro moules. The application provides the above method, wherein the compound is 1 mM or less than Namo in an in vitro biochemical assay of JAK3 activity. The present application provides the above method wherein the compound is in the in vitro biochemical assay of JAK3 activity, and the heart is 1 () Naim or less than 1 〇Nomo 0 - a method for inhibiting SYK activity, the method includes administration The IC5 of the compound in the in vitro biochemical assay of SYK activity in the cardiac compound/, is 50 micromolar or less than 5 micromolar. The application provides the above method, wherein the compound is biochemically assayed for % of in vitro biochemical assays of SYK activity. For Tanay Moore or less than the nemesis. The present application provides the above method wherein the compound is active in syk activity 154395.doc -35 - 201134826 In vitro biochemical assay wherein ^(7) is 1 〇Nemo or less than 1 〇Nemo. The present application provides a method of treating an inflammatory condition comprising administering a therapeutically effective amount of an anti-inflammatory compound to a compound of formula 1 in combination with a patient in need thereof. The present application provides a method of treating an immune condition comprising administering a therapeutically effective amount of an immunosuppressive compound to a compound of formula I in combination with a patient in need thereof. The application provides a pharmaceutical composition comprising a mixture of a compound of formula J, 〖, or _, and at least one pharmaceutically acceptable carrier, excipient or diluent. The application provides the above method, further comprising a chemotherapeutic or anti-proliferative agent, an anti-inflammatory agent, an immunomodulator or an immunosuppressive agent, a neurotrophic factor, an agent for treating cardiovascular diseases, an agent for treating diabetes, or treating an immunodeficiency Another therapeutic agent for the agent of the disease. The present application provides a method of preparing a compound of Formula I, hydrazine, or J". The application provides a compound as described above for the treatment of an inflammatory condition or an autoimmune condition. The present application provides a compound as described above for use in the treatment of any of the conditions mentioned above. The application provides a use of a compound of the formula 1 'ι, *Γ, which is used in the manufacture of A drug for the treatment of inflammatory conditions. The application provides a use of a compound of formula I, 1, or 1. in the manufacture of a medicament for the treatment of an autoimmune disorder. This application provides the invention as described above. 154395.doc • 36 - 201134826 Compounds Examples of typical compounds encompassed by the present invention and falling within the scope of the present invention are provided in the following table. These and subsequent preparation methods are provided to enable those skilled in the art to more clearly understand and practice the invention. The examples and methods of preparation are not to be construed as limiting the scope of the invention, but are merely illustrative and representative of the invention. In general, the nomenclature used in this application is based on version 4.0 AUTONOMTM, a Beilstein Institute computerized system for generating IUPAC system nomenclature. If there is a difference between the structure and the name assigned to the structure, the structure shown should prevail. If the stereochemistry of a portion of a structure or structure is not indicated, for example, by bold or dashed lines, then the structure or a portion of the structure is understood to encompass all stereoisomers thereof. Table I describes the compounds of formula I exemplified.

Table I. Compound structure system name ΜΡ 1-1 2-cyclopropyl _5//-° piroxi[2,3-6]σ ratio tillage-7-decanoic acid ((R)-l-fluorenyl winter Side oxy-2·° piroxime-1-yl-ethyl)-bristamine 237.0- 239.0 1-2 alarm 0 2-cyclopropyl-5//-n ratio [2,3-6] Pyridin-7-decanoic acid ((R)-l-mercapto-2-yloxy-2-σ-endyl-1-ylethyl)·Arylamine 190.0- 192.0 154395.doc -37- 201134826 1 -3 ° 2-cyclopropyl-5//-pyrrolo[2,3-δ]pyrazine-7-decanoic acid [(R)-l-(pyrrolidin-1-carbonyl)-propyl]-oxime Amine 240.9- 242.5 1-4 ° 2-cyclopropyl-5//-pyrrolo[2,3-6]» than plough-7-formic acid [(R)-2-mercapto-1-(pyrrolidinium- 1-carbonyl)-propyl]-nonylamine 171.0- 172.1 1-5 ° 2-cyclopropyl-5//-n ratio argon[2,3-6] 0 ratio ** well-7-formic acid (( R)-l-cyclopropyl-2· oxo-2-0 pirate-1-yl-ethyl)-guanamine 254.0- 256.0 1-6 矜〇2-cyclopropyl-5//- Pyrrolo[2,3-6]pyrazine-7-decanoic acid ((S)-l-methyl-2-oxo-oxyl-2-° ratio bite-1·yl-ethyl)-bristamine 1 -7 η〇Λ(0 0 2-cyclopropyl-5//-pyrrolo[2,3-6]pyrazine-7-decanoic acid [(R)-2-mercapto-1-(periole) Base)-propyl]-bristamine 183.0- 185.0 154395.doc 38- 201134826

1-8 ° 2-cyclopropyl-biha-[2,3-6]a ratio tillage-7-formic acid [(R)-2-mercapto-1-(Merlin-4)-propyl) ]--N-amine 154.0- 156.0 1-9 O- 2-cyclopropyl-5-danbiha and [2,3-6]° than tillage-7-decanoic acid [(R)-2-(3-decyloxy) -Pylo-[l-l-yl)-1-methyl-2-oxo-ethyl]-nonylamine 1-10 ° 2-cyclopropyl-5//-°Biluo[2,3 -6]0 ratio tillage-7-decanoic acid [(R)-2,2-dimercapto-1-(pyrrolidin-1-carbonyl)-propyl]-decylamine 201.0- 203.0 0 r 1-11 iVW0 2-cyclopropyl-5//-pyrrolo-p,3-6]pyrazine-7-decanoic acid [(R)-2-(3·经基·0比嘻 bit-1-yl)-1- Mercapto-2·sideoxy-ethyl]-decylamine 1-12 矜o 2-cyclopropyl-5//·°°°[2,3-6]° than phenyl-7-formic acid ( (S)-l-mercapto-2-oxo-2-bromo-1-yl-ethyl)-bristamine 154395.doc 39- 201134826 1-13 Η^Υ° Η, 2-(1- Ethyl-1//-pyrazol-4-yl)-5//-0 is more than [2,3-6]° ratio ρ well-7-decanoic acid [(R)-2,2-dimethyl -1 -(pyrrolidin-1-carbonyl) propyl]-nonylamine 1-14 ην^νΛ^ν〇νΗ η 5 2-cyclopropyl-5//-pyrrolo[2,3-6] Pyridin-7-decanoic acid [(R)-2-(3-indolyl-pyrrole-1-yl)-1-methyl-2-oxo-ethyl]-nonylamine 1-15% 2 -cyclopropyl-5// -°Bilo and [2,3-6] ° than tillage-7-decanoic acid [(R)-l-methyl-2-(3-methyl-0)-bito-1-yl)-2- Side oxy-ethyl]-nonylamine 1-16% 2-cyclopropyl-5//-pyrrolo[2,3-6]pyrazine-7-carboxylic acid [(R)-l-methyl-2 -(2-indylbibilol-1-yl)-2. sideoxy-ethyl]-decylamine 1-17 2-cyclopropyl-5//-pyrrolo[2,3-6]pyridin Plough-7-formic acid ((R)-2-azetidin-1-yl-1-yl-2-yloxy-ethyl)-decylamine

154395.doc ·40· 201134826

V 1-18 2-phenoxy-5//-° ratio is [2,3-6]. Specific tillage-7-formic acid [(R)-2-mercapto-1-(pyrrolidin-1-carbonyl)-propyl]-nonylamine 1-19 ° 2-cyclopropyl-5/ί-°Bilo And [2,3-6]° than cultivable-7-formic acid [2,2,2-trifluoro-1 -(»Bis-Butyl-1-yl)-ethyl]-bristamine 1-20 % I 〇夂~ 2-cyclopropyl-5//·° is more than 嘻[2,3-6]° than Β井-7-decanoic acid [(R)-2-(3_cyano-azetidine) Alkyl-1-yl)-1-indolyl-2-oxo-ethyl]-bristamine 1-21 i>2-cyclopropyl-5//-"bibromo[2,3-6 Pyridin-7-decanoic acid [(R)-2-(3,3-dioxo-pyhad-1-yl)-1-indolyl-2-yloxy-ethyl]-decylamine 0 7 1-22 NN 2-cyclopropyl-5//·. Bilo and [2, 3-6]. Specific tillage-7-decanoic acid [(R)-2-((S)-3-fluoro-pyrrolidin-1-yl)-1-fluorenyl-2-yloxy-ethyl]-decylamine 154395 .doc • 41 - 201134826 1-23 F % 2-cyclopropyl-5//-pyrrolo[2,3-6]pyr-7-carboxylic acid [(R)-2-((R)-3- Gas-pyridolidin-1-yl)-1-mercapto-2-oxo-ethyl]-nonylamine 1-24 fioc. 2-cyclopropyl-5//-° ratio of [2,3-6] ° to 11 well-7-carboxylic acid [(R)-l-methyl-2-(2-oxa-6-nitrogen) Hetero-spiro[3.3]hept-6-yl)-2-oxo-ethyl]-nonylamine 1-25 2-cyclopropyl-5//-pyrrolo[2,3-6]pyrazine- 7-formic acid [(R)-l-fluorenyl-2-p-oxy-2-(3-dimethylmethyl·0 to p each -1-amino)-ethyl]-S&amine 1-26 NN 2-cyclopropyl-5//-pyrrolo[2,3-acyl-pyrazine-7-carboxylic acid ((R)-l-cyclopentyl-2-yloxy-2-n ratio 鸣 bit-1 -yl-ethyl)-nonylamine 1-27 VN^ 2-(1-ethyl-1//-pyrazol-4-yl)-5//-"bibromo[2,3-6] ° ratio • Well-7-formic acid ((R)-1 -cyclopropyl-2-oxo-2-pyridyl-1-yl-ethyl)-bristamine 210-212

154395.doc • 42· 201134826 1-28 Ν Ν V 2-(1-Ethyl-1//-pyrazol-4-yl)-5i/-.咯 并 [2,3-6]° than 啩-7-decanoic acid [(R)-l-(3-cyano-3-indolyl-pyrrole-1-yl)-2,2-di Methyl-propyl]-nonylamine 228-230 1-29 2-cyclopropyl-5/f·pyrrolo[2,3-6]pyrazine-7-carboxylic acid [(R)-l-(3- Cyano-piperidin-1-yl)-2,2·dimercaptopropyl]-nonanamine 1-30 2-cyclopropyl-5//-. Bis-[2,3-6]pyrazine-7-carboxylic acid [(R)-l-((S)-3-cyano-pyrrolidine-1-carbonyl)-2,2-dimethyl-propane ]]-nonylamine 1-31 2-cyclopropyl-5//-pyrrolo[2,3-6]pyrazine-7-decanoic acid [(R)-l-((R)-3-cyano -0 than slightly biting -1 -yl) · 2,2-dimercapto-propyl]-nonylamine 1-32 2-cyclopropyl-5//-pyrrolo[2,3-6]pyrazine -7-decanoic acid [(R)-2,2-dimercapto-1-(slightly -1-pyranyl)-propyl]-bristamine 43- 154395.doc 201134826 1-33 Ϊ S' 2- The cyclopropyl-5//-° ratio is [2, 3-6]. Ratio 11 Well-7-formic acid [(R)-l-(3-indolyl-azetidinyl-1·yl)-2,2-dimercaptopropyl]-decylamine 1-34 NN > VN^ 2-(1-ethyl-1//-»Bizozol-4-yl)-5//-pyrrolo[2,3-6]pyrazine-7-decanoic acid [(R)- L-(l-Methyl-cyclopropyl)-2-oxooxy-2-°Bilidine-1 ·yl-ethyl]-decylamine 218- 220 1-35 2-cyclopropyl-5/ /-pyrrolo[2,3-6]pyrazine-7-decanoic acid [(R)-l-(4-fluoro-piperidin-1-yl)-2,2-dimethyl-propane Base]- guanamine 249- 251 1-36 N/ NN 2-(1 -ethyl-1//~° ratio ° sit-4-yl)-5//-pyrrolo[2,3-6]pyridin Plough-7-formic acid [(R)-l-(3-fluoro-3-fluoro)-branched-1-yl)-2,2·didecyl-propyl]-S&amine 1-37 -αΛ切° 2-Cyclopropyl-57/-pyrrolo[2,3-6]pyrazine-7-carboxylic acid ((R)-l-cyclohexyl-2-yloxy-2-ntt lozenite -1 ·yl-ethyl)-decylamine • 44· 154395.doc 201134826

1-38 NNV 2-(1-ethyl-lif-pyrazol-4-yl)-5i/-pyrrolo[2,3-6]pyridyl well-7-decanoic acid {(R)-l-[ 3-(4,5-dihydro-l/ί-imidazol-2-yl)-3-oxo-° ratio °bit-1-recarbo]-2,2-dimethyl-propyl}-oxime Amine 1-39 I 2-cyclopropyl-5//-. Ratio of [2,3-ό]° to 11 Well-7-formic acid [(R)-l-(3-cyano-3-indolyl-azetidin-1-carbonyl)-2,2 -Dimethyl-propyl]-nonylamine 1-40 x 2-cyclopropyl-5//-"bibromo[2,3-6]. Specific tillage-7-decanoic acid [(R)-2-(3-cyano-azetidin-1-yl)·1-cyclodecyl-2-yloxy-ethyl]-decylamine 1 -41 w 0 2-cyclopropyl-5//-° ratio 咯[2,3-6]°ΒΒ-7-decanoic acid [(R)-l-(3,3-difluoro-pyridyl)洛-l-Weiyl)-2,2-dimercapto-propyl]-nonylamine 1-42 N〆V Ί> 2-cyclopropyl-5i/-pyrrolo[2,3-6]pyridin Plough-7-decanoic acid [(R)-l-(3,4-dihydro-1 from isoquinolin-2-carbonyl)-2,2-dimethyl-propyl]-decylamine 154395.doc • 45- 201134826 1-43 2-Cyclopropyl-5//-. More than [2,3-6] pyridyl. Well-7-formic acid [(R)-l-(4-indolyl-slightly-l-one-reactive)-3-methyl-butyl]-nonylamine 1-44 ° 2-cyclopropyl-5-open -pyrrolo[2,3-6]pyrazine-7-carboxylic acid [(R)-l-(4-cyano-4-indolyl-nitrient-1-yl)-2,2-didecyl -propyl]-bristamine 1-45 ° 2-cyclopropyl-5//-pyrrolo[2,3-6]pyrazine-7-carboxylic acid [(R)-2-(4-cyano-piperidin) Bite-1 -yl)-1 -cyclodecyl-2-yloxy-ethyl]-nonylamine 1-46 Ν Ν 2-cyclopropyl than slightly [2,3-ό]σ ratio tillage-7 -formic acid [(S)-2-(4-carbyl·piperidin-1-yl)-2-oxo-l-(1-dioxymethyl-cyclopropyl)-ethyl]-decylamine 1-47 2-cyclopropyl-5//·11 piroxi[2,3-ό]0 than cultivable-7-carboxylic acid [(R)-2-(4-mercapto-piperidin-1-yl) -2-Sideoxy-1-(1-trifluoromethyl-cyclopropyl)-ethyl]-decylamine

154395.doc -46- 201134826

1-48 Λ 2·cyclopropyl-5//~n is more than 嘻[2,3-6]D than argon-7-decanoic acid [(R)-l·benzoyl-2-(4- gas Base-σ bottom bit-1-yl)-2-yloxy-ethyl]-nonylamine 1-49 :>Αν〇γ" % 2-cyclopropyl-5//-pyrrolo[2,3 -6]pyrazine-7-formic acid [(R)-l-(4-cyano-piperidin-1·yl)-3,3-didecyl-butyl]-guanamine 1-50 V 2 -(3,5-bis-trifluoromethyl-phenyl)-5//-pyrrolo[2,3-6]pyrazine-7-decanoic acid [(R)-1 -(4·气基· Slightly bite-1 - prison base) -2,2-dimercaptopropyl]-bristamine 1-51 NN Vo 2-(3-pyrrolidin-1-yl-phenyl)-5//-. More than [2,3-6]. Bis-7-carboxylic acid [(R)-1-(4-cyano-substrate-1-yl)-2,2-dimercapto-propyl]-decylamine 154395.doc 47- 201134826 1-52 ° 2-cyclopropyl-5//-° ratio is [2,3-6]. Specific tillage-7-formic acid [(R)-l-(4,4-dioxa-piperidin-1-yl)-2,2-dimethyl-propyl]-nonylamine 1-53 ν> ° 2-(1-methyl-1//-pyrazol-4-yl)-5//-pyrrolo[2,3-6]pyrazine-7-decanoic acid [(R)-l-(3- Fluoro-azetidin-1-carbonyl)-2,2-dimethyl-propyl]-nonylamine VN- 1-54 2-(1//-°bizozol-4-yl)-5 //-pyrrolo[2,3-6]pyrazine-7-decanoic acid [(R)-l-(4·cyano-piperidin-1-carbonyl)·2,2-dimercapto-propyl --Amine νΝΗ 1-55 Η, 2-(1-methyl-I//-0-pyrazol-4-yl)-5//-pyrrolo[2,3-6]pyrazole-7-曱Acid [(R)-l-(4-cyano-piperidin-1-carbonyl)-2,2·didecyl-propyl]-decylamine VN-

154395.doc 48- 201134826

1-56 2-(1-Ethyl-1//-pyrazol-4-yl)-5//-0 piroxi[2,3-6]0 ratio p well-7-formic acid [(R) -l-(4-cyano-piperidin-1-carbonyl)-2,2-dimethyl-propyl]-nonylamine 1-57 ° 2-cyclopropyl-577-pyrrolo[2,3- 6]pyrazine-7·decanoic acid [(R)-l-(4-ethylindolyl-piperazine-1-carbonyl)-2,2-dimercapto-propyl]-nonylamine 1-58 Ν ...Ν 〇2-cyclopropyl-5/ί-pyrrolo[2,3-6]pyrrole-7-carboxylic acid [(R)-2,2-diindolyl small (4-difluoromethyl- π bottom bit-1-yl)-propyl]-bristamine 〇\7^ p 1-59 ν> ° νΝ- 2-(1-methyl-17/-pyrazol-4-yl)-5/ /-pyrrolo[2,3-6]pyridyl-7-decanoic acid [(R)-l-((S)-3-cyano-pyrrolidines small carbonyl)-2,2-didecyl- Propyl]-amidoxime / 1-60 w 0 VN- 2-(dibu-l/ί-pyrazol-4-yl)-5i/-0 than haha[2,3-6]0 than brown 7-decanoic acid [(foot)-1-((1?>)-3-ylyl-<1 than Hatch-1-carbonyl)-2,2-dimethyl-propyl]-guanamine 154395.doc -49- 201134826 1-61 2-cyclopropyl-5//·°Biluo[2,3-6]° than tillage-7·decanoic acid [(R)-2-(4-cyanide) ··piperidin-1-yl)-1 -cyclopropyl-2-sidedoxy_ethyl]• decylamine 1-62 NNV 2-(1-ethyl-I//·0 ratio 0 sitting-4 -based)-5//-pyrrolo[2,3-6]pyrazine -7-decanoic acid [(R)-2-(3-cyano-azetidin-1-yl)-1-indolyl-2-yloxy-ethyl]-decylamine 1-63 Λ °N^ ΝΛ 2-(1-methyl-spin-4-yl. 比略和[2,3-6]°Α_-7-carboxylic acid [(R)-2-(4-cyano-piperidine-1 -yl)·1-cyclopropyl-2-oxo-ethyl]-bristamine 1-64 H^vC/ -0 0 2-(3,4,5-trimethoxy-phenyl)-5 //-pyrrolo[2,3-6]pyrazine-7-formic acid [(R)-1 -(4.azetyl-slightly-1-prison)-2,2-dimethyl-propyl ]--------------------------------------------------------------------------------------------------------------------------------------- -4-phenyl-peptid-1-pylon-)-2,2-dimercapto-propyl]-decylamine

154395.doc -50- 201134826

1-66 2-(2,5-Dimethoxy-phenyl)-5//-pyrrolo[2,3-6]pyrazine-7-decanoic acid [(R)-1-(4-enhanced Base-Phenyl-1-yl)-2,2-dimethyl-propyl]-nonylamine 1-67 NN > VN^ 2-(1-ethyl-17/-pyrazol-4-yl -5//-pyrrolo[2,3-6]pyrazine-7-decanoic acid [(R)-2-(4-cyano-piperidin-1-yl)-1-indenyl-2- Oxyloxy-ethyl]-nonylamine 1-68 2-cyclopropyl-5open-pyrrolo[2,3-6]pyridin-7-decanoic acid [(R)-2-(3-cyanide) --azetidin-1-yl)-1·cyclopropyl-2-oxo-ethyl]•-enamine 1-69 v> ° VN- 2-(1-mercapto-1// -pyrazol-4-yl)-5//-pyrrolo[2,3-6]pyrazine-7-decanoic acid [(R)-l-(3-cyano-azetidin-1- Carbonyl Group>3-Methyl-butyl]-nonylamine 1-70 NN\ 2-(1·methyl-1//-pyrazol-4-yl)-5//-pyrrolo[2,3- 6] Pyridin-7-formic acid [(R)-2-(3-cyano-azetidin-1-yl)-1 ·cyclopropyl-2-oxo-ethyl]-decylamine 154395.doc -51 - 201134826 1-71 l/ 2-(Buethyl-1//-pyrazol-4-yl)-5//-0 ratio [2,3-6]° than tillage-7- Formic acid [(R)-2-(4-carbyl-piperidine small)-1 _cyclopropyl-2-oxo-ethyl]-decylamine 1-72 0 2-cyclopropyl-5/ /-pyrrolo[2,3-6]pyrazine-7-carboxylic acid [(R)-l-(4-hydroxyl -4-three defeated ---. Bottom bite - 1 prison base) -2,2-di-methyl-propyl]-nonylamine 1-73 ° 2-cyclopropyl-5//-pyrrolo[ 2,3-6]pyrazine-7-formic acid [(R)-l-(4-hydroxy-4-indolyl-σ-bottom-1·yl)-2,2-dimethyl-propyl] • Indoleamine 1-74 2-(1-ethyl-1//-pyrazol-4-yl)-5//-pyrrolo[2,3-6]pyrazine-7-decanoic acid [(S) -2-(4-cyano-piperidin-1-yl)-2-oxoyl-1-(1-tris-methyl-cyclopropyl)-ethyl]-nonylamine VN-^

154395.doc 52- 201134826

1-75 2-(1-Ethyl-17/-pyrazol-4-yl)-5/f-indolo[2,3-6]pyrazine-7-carboxylic acid [(R)-2-( 4-cyano-piperidin-1-yl)-2-oxo-l-(1-trifluorodecyl-cyclopropyl)-ethyl]-bristamine VN^ 1-76 w ° VN- 2 -(1-mercapto-1//-pyrazol-4-yl)-5//-pyrrolo[2,3-6]pyrazine-7-carboxylic acid [(R)-2-(3-cyano) -azetidin-1-yl)-1-cyclohexyl-2-oxo-ethyl]-chiral amine 1-77 2-(1-indolyl-1-lelimidin-4-yl)-5i /-0Biluo[2,3-6]0 to 11 Well-7-decanoic acid [(R)-l-(4-cyano-piperidin-1 -carbonyl)-2,2-didecyl -propyl]-nonylamine 1-78 2-(1-cyclopropyl-1//-0 than 〇-4-yl)_ 5//-pyrrolo[2,3-6]pyrazine-7 ·Formic acid [(R)· 1 -(4·cyano·slightly bite · 1 · thiol)-2,2-dimercapto-propyl]-decylamine NN, 154395.doc 53- 201134826 1-79 Ο 2-[l-(2,2,2-Trifluoro-ethyl-pyrazol-4-yl]-5//-° ratio 咯[2,3-6]° 耕-7-carboxylic acid [( R)-l-(4-|L-piperidine-1-reactive)-2,2-dimercapto-propyl]-nonylamine 1-80 2-cyclopropyl-5//- ratio咯[2,3-6]. Specific tillage-7-decanoic acid [(R)-2-((S)-3-carbyl-° ratio bite-1 -yl)-1 ·cyclopropyl- 2-sided oxy-ethyl]• decylamine 1-81 NN, 2-(1-methyl-li/- Zin-4-yl)-5//-pyrrolo[2,3-6]pyr 11 well-7-decanoic acid [(R)-2-((S)-3-cyanopyrrolidin-1 (1)-cyclopropyl-2-oxo-ethyl]-decylamine 1-82 ", 2-(1-methyl-17/-pyrazol-4-yl)-5//-0 ～°[2,3-6]0 whistle·_7-decanoic acid [(R)-2-((R)-3-cyano-pyrrolidin-1-yl)-1-cyclopropyl- 2-sided oxy-ethyl]-nonylamine 1-83 2-cyclopropyl-5//-pyrrolo[2,3-6]pyridin-7-decanoic acid [(R)-2-(( R)-3-cyano-0 piroxime-1-yl)-1-cyclopropyl·2-o-oxy-ethyl]-decylamine

154395.doc 54- 201134826

1-84 2-Cyclopropyl-5//-pyrrolo[2,3-6]pyrazine-7-decanoic acid [(R)-l-cyclopropyl-2-(2-oxa-6-) Aza-spiro[3.3]hept-6-yl)-2-oxo-ethyl]-chiral amine 1-85 ΝΛ 2-(1-methyl-1//-° than salivin-4) -5//-pyrrolo[2,3-6]pyrazine-7-decanoic acid [(R)-1 -cyclopropyl-2-(2-oxa-6-aza-spiro[3.3]g -6-yl)-2-oxo-ethyl]-nonylamine 1-86 ^ Η 2-cyclopropyl-[2,3-6] 'rough -7-decanoic acid [(R)- L-cyclopropyl-2-((lS,5R,6R)-6-hydroxymethyl-3-aza-bicyclo[3.1.0]hex-3-yl)-2-yloxy-ethyl] -Acetamine 1-87 ^V〇h Ν-Ν Η 2-(1-mercapto-17/-pyrazol-4-yl)-5//-pyrrolo[2,3-6]pyr-7 -carboxylic acid [(R)_l_cyclopropyl-2-((lS,5R,6R)-6-hydroxymethyl-3-aza-bicyclo[3.1.0]hex-3-yl)-2- side Oxy-ethyl]-nonylamine 1-88 2-cyclopropyl-5//-° pyrrolo[2,3-6]»b h-7-carboxylic acid [(R)-l-cyclopropyl -2-(U-di-oxy-purine λ6-thiomorpholine·4·yl)-2-oxo-ethyl]-bristamine 154395.doc 55- 201134826 1-89 ΝΛ 2-(1- Mercapto-1//-pyrazol-4-yl)-5i/-'pyrho[2,3-punch ratio p-well-7-carboxylic acid [(R)-1 ·cyclopropyl-2-(1) , 1-di-oxy-1 λό-thiomorpholin-4-yl)-2-yloxy- Alkylamine 1-90 2-cyclohexyloxy-5//-° pyrrolo[2,3-6] pyridin-7-decanoic acid [(R)-l-(4-cyano- Piperidine-1-Rebel)·2,2·Dimercapto-propyl]·Indoleamine 1-91 〇, 0 V^/^N y 2-(3,3,3-Trifluoro-propoxy )-5i/-吼 并[2,3-6]pyrazine-7-decanoic acid [(R)-1-(4-amino-pyrylene-1-yl)-2,2-dimethyl Base·propyl]-nonylamine 1-92 〇v^ 0 N〇^n 2-cyclopentyloxy-5//--pyrho[2,3-6]pyridinium. Well-7-formic acid [(R)-l-(4-cyano-piperidin-1-carbonyl)-2,2-dimercapto-propyl]-nonylamine 1-93 〇, ° V_/^NF —|—FF 2-(2,2,2-triethoxyl p-[2,3-6]pyrazine-7-decanoic acid [(R)-1-(4-alcohol-slightly bite- 1-mono)-2,2-dimethyl-propyl]-guanamine

154395.doc -56- 201134826

1-94 0 丫° 2-Isopropoxy-pyrolo[2,3-6]pyrazine-7-carboxylic acid [(R)-l-(4-cyano-piperidin-1-carbonyl)-2 ,2-dimethyl-propyl]-nonylamine 1-95 Q"- 2-(4-gas-1-o-oxy-1,3-dihydro-isoindole-2-ylpyrrolo[ 2,3-6] 'Bit-7-decanoic acid [(R)-2-(3-cyano-azetidin-1-yl)-1-cyclopropyl-2-yloxy- Ethyl]-nonylamine 1-96 〇-ci 2-(7-gas-thieno[3,2-6]pyridin-2-yl)-5//-° ratio [2,3-6] » Ratio-well-7-decanoic acid [(R)-2-(3-aryl-azetidin-1-yl)-1-cyclopropyl-2-oxo-ethyl]-oxime Amine 1-97 wO 2-(7-β piroxime _ 1 -yl· sold benzo[3,2-6]acridine-2·kibido[2,3-6]. -formic acid [(R)-2-(3-cyano.cyclobutan-1-yl)-1.cyclopropyl-2-oxo-ethyl]-bristamine 1-98 F 2- [7-(2,2,2-trifluoro-ethoxy)-thieno[3,2-6]pyridin-2-yl]-5//-pyrrolo[2,3-6]pyrazine- 7-decanoic acid [(R)-2-(3-cyano-azetidin-1-ylcyclopropyl-2-oxo-ethyl]-bristamine 154395.doc •57- 201134826 1 -99

2-(7-decyloxy-thieno[3,2-6]pyridin-2-yl)-5//-° ratio [2,3-6]. Specificin-7-formic acid [(R)-2-(3-cyano-azetidin-1-yl)·1-cyclopropyl-2-o-oxy-ethyl]-decylamine 1- 100

2-(7-Gas-thieno[3,2-6]pyridin-2-ylpyrolo[2,3-6]» than argon-7-decanoic acid [(R)-2-(3-cyanide) -azetidin-1·yl)-1-indolyl-2-oxo-ethyl]-decylamine

1-101

2-(7-π ratio bite-1 -yl-α-sepeno[3,2·6] ° than pyridine-2-yl)-5//--pyrho[2,3-shoot ratio. Well-7-formic acid [(R)-2-(3-|l-yl-SL heterocyclobutan-1-yl)-1-methyl-2-oxo-ethyl]-nonylamine 1-102

2-[7-(2,2,2-tris-ethoxy)-»seceno[3,2-6]»pyridin-2-yl]pyrho[2,3-6]pyrr Plough-7-decanoic acid [(R)-2-(3-cyano-azetidin-1-yl)-1-indenyl-2-oxo-ethyl]-bristamine

154395.doc 58- 201134826

HH〇1-103 §乂, °°, 2-(7-decyloxy-thieno[3,2-6]pyridin-2-yl)-5//-pyrrolo[2,3-6] Pyridin-7-formic acid [(R)-2-(3-cyano-azetidinyl-1)yl-1indolyl-2·sideoxyethyl]-bristamine 1-104 2-(1,3-Dimercapto-1//-pyrazol-4-yl)-5//-pyrrolo[2,3-6]pyrazine-7-decanoic acid [(R)-2- (3-cyano-azetidin-1-yl)-1-indenyl-2-oxo-ethyl]·decyl 1-105 2-(1-ethyl-1//-pyridyl Azole-4-yl)-5//-0 piroxime-卩口-刎吼喷---capric acid [(S)-l-(4-cyano-piperidin-1-carbonyl)-3,3 ,3-tris-propyl]-nonylamine 1-106 VN^ 2-(1-ethyl-1/pyrazol-4-yl)-5//-0 is more than [2,3-6 ]° ratio 11 Well-7-decanoic acid [(R)-l-(4-cyano-piperidin-1-carbonyl)-3,3,3-tris-propyl]-decylamine 154395.doc 59 - 201134826 1-107 NN ^^NnO 2-(1-Cyclopentyl-1//-[1,2,3]triazol-4-yl)-5//-3⁄4t-[2,3-6 ]'> Specific tillage-7-decanoic acid [(R)-2-(4-cyano-piperidin-1-yl)-1-cyclopropyl-2-oxo-ethyl]-decylamine 1-108 NN 2-(1-phenyl-1/ί-[1,2,3]triazol-4-yl)-5i/-indole[2,3-6]. Specific tillage-7-decanoic acid [(R)-2-(4. cyano-piperidin-1-yl)-1-cyclopropyl-2-oxo-ethyl]-decylamine 1-109 NN Vo 2-(3-pyrrolidin-1-yl-phenyl)-5//-pyrrolo[2,3-6]pyrazine-7-decanoic acid [(R)-2-(3-yl-based- Azetidin-1-yl)-1 -mercapto-2-oxo-ethyl]-nonylamine 1-110 NN %^〇' 2-(3-decylamine decyl-phenyl )-57/-0 Biluo[2,3-6]° ratio 0 well-7-decanoic acid [(R)-2-(3-|L-azetidin-1-yl)- 1-methyl-2-oxo-ethyl]-decylamine

154395.doc 60- 201134826

I-lll ^ VN 2-(3-isopropylaminoindenyl-phenyl)-5/f-pyrrolo[2,3-6]pyrazine-7-decanoic acid [(R)-2-( 3-cyano-azetidin-1-yl)-1-methyl-2-oxo-ethyl]-guanamine ' 1-112 NX XN 〆^Hj> 2-[3-(ring Propylmercapto-aminoindenyl)-phenyl]-5//-pyrrolo[2,3-pyridin-7-carboxylic acid [(R)-2-(3-cyano-azetidine) Benzene-1-yl)-1-mercapto-2-yloxy-ethyl]•decylamine w 1-113 N^> 2-(4-cyclopenta-1 -dilutylpyrylene-2-yl )-5if-pyrrolo[2,3-ί>]pyr 11 -7-decanoic acid [(R)-2-(3-cyano-azetidin-1-yl)-1-fluorenyl -2-Sideoxy-ethyl]-nonylamine 1-114 2-cyclopropyl-5//-. Ratio of [2,3-6]° to plough-7·formic acid [(R)-2-(4-cyano-piperidin-1-yl)-2-oxo-1-phenyl-B ] • 154 395395.doc • 61 - 201134826 1-115 % 2-0 than bite-2-yl-5//·η piroxi[2,3-6]pyrazine-7-carboxylic acid [(R -l-(4-cyano-piperidin-1-carbonyl)-2,2-dimercapto-propyl]-nonylamine 1-116 2-cyclopropyl-5//-pyrrolo[2, 3-6]pyrazine-7-formic acid [(R)-2-(4-cyano-piperidin-1 -yl)-1 _cyclopropylmethyl·2- oxo-ethyl]- Amine 1-117 ◎ Os 2-[1-(4-fluoro-phenyl)-1. Bizolyl-4-yl]-57/-»birtho[2,3-6]° than cultivable-7-carboxylic acid [(R)-l-(4-cyano-piperidin-1-carbonyl)- 2,2-Dimercapto-propyl]-bristamine 1-118 Ηλ / 2-(4·di-gasmethyl-° ratio bit-2-yl) 5//·pyrrolo[2,3-6] Pyridin-7-formic acid [(R)-1-(4-carbyl-pyrylene-1-yl)-2,2-dimercapto-propyl]-decylamine 154395.doc 62- 201134826

1-119 ο 2-(1-Cyclopropylmethyl-1//-imidazol-4-ylpyrolo[2,3-6]indole-7-decanoic acid [(R) small (4-cyanide) Base-piperidin-1-carbonyl)-2,2-dimethyl-propyl]•chiral amine 1-120 2-(1-cyclopentyl-1//-imidazol-4-yl)-5// -pyrrolo[2,3-6]pyrazine-7-decanoic acid [(R)-l-(4-cyano-p-pyridin-1-carbonyl) 2,2-dimercapto-propyl]-oxime Amine 1-121 H, 2-(1-cyclopentyl-1//-imidazol-4-yl)-5//-pyrrolo[2,3-6]pyridin-7-decanoic acid [(R) -2-(4-Nitro-peptidyl-1-yl)-1_cyclopropyl-2·sideoxy-ethyl]-bristamine 1-122 'F 2-[1-(2,2,2 -trifluoro-ethyl)-1//-imidazol-4-yl]-5//-pyrrolo[2,3-6]pyrazine-7-decanoic acid [(R)-l-(4-cyanide Base-piperidone·1-monoyl-2,2·didecyl-propyl]-decylamine 154395.doc 63- 201134826 2-[3-(3,3-dimethyl-pyrrolidin-1- ))-phenyl]-5//-0 ratio 咯 Ρ, 3-6] 1-123 Ο 〇 '比耕-7-decanoic acid [(R)-2-(3-cyano-nitrogen heterocycle) Butan-1-yl)-1-mercapto-2-oxo-ethyl]-bristamine 2-cyclopropyl-5//-° ratio [2,3-6]« ratio 1- 124 % cultivable-7-formic acid [(lR,2S)-l-(4-cyano-0 hen.-1--1-yl)-2-methylbutyl]-guanamine Ν 2-(3 , 4,5-trimethoxy-phenyl)-5//-. And P, 3-6]° than tillage-7-decanoic acid 1-125 Ο 0 [(R)-2-(3-indolyl-azetidin-1-yl)-1_indolyl- 2-sided oxy-ethyl]- decylamine / ην^Υ^νΛ^νΟ^ 2-[(lS,5R)-3-(3-Aza-bicycloindole η 5 [3.1.0]hex-3 -yl)-phenyl]-5//-. Ratio 1-126 Ο Η ^3-nC^ 咯 并[2,3-6]pyrazine-7-carboxylic acid [(11)-2-(3- Cyano-azetidin-1-yl)-1 -indolyl-2-oxo-ethyl]-decylamine

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1-127 2-(4-decyloxy-acridin-2-yl)-5//-pyrrolo[2,3-6]pyrazine-7-carboxylic acid [(11)-1-(4-enhanced Base-expansion biting-1-yl)-2,2-dimercapto-propyl]-nonylamine 1-128 Q 2-(4-trifluoromethyl-phenyl)-5//-pyrene咯[2,3-6]pyrazine-7-carboxylic acid [(R)-l-(4-nitro-l-yl-1-yl)-2,2-dimercapto-propyl]-醯Amine FF 1-129 N ,) a 2-(4-cyclopropyl decyloxy group than a ketone-2-yl)-5//"pyrolo[2,3-6]咐^ well-7-formic acid [(R)-2-(4-Cyano-piperidin-1·yl)-1-cyclopropyl·2· oxirane-ethyl]•••·········· -cyclodecyloxy to chito-2-yl)_5-open-pyrrolo[2,3-6]pyrazine-7-decanoic acid [(R)-l-(4-cyano-piperidin-1- Carbonyl)-2,2-dimethyl-propyl]-nonylamine 154395.doc 65- 201134826 1-131 ^<| 2-(4-cyclopropylmethoxy-α ratio -2- base) -5//-吼 并 [2,3-^^ than arable 7-decanoic acid [(R)-2-(3-cyano-azetidin-1 base)·1·methyl- 2-sided oxyethyl]-bristamine 1-132 ° S: aF 2-[1-(2,5-difluoro-phenyl)-1//-imidazol-4-yl]-5 ft.-.咯 并 [2,3-6] ° ratio tillage-7-formic acid [(R)-2-(3-cyano-azetidin-1-yl)-1_cyclopropyl-2- side Oxy-ethyl]-bristamine 1-133 F 2-[1-(2,3,5-trifluoro-phenylimidazol-4-yl]-5//-° ratio 咯[2,3- 6]-specific tillage-7-formic acid [(R)-2-(3-cyano-azetidin-1-yl)-1-cyclopropyl-2-oxo-ethyl]-oxime Amine 1-134 Ws Ο 4 W ° VN^ 2-(1-ethyl-1 from pyrazol-4-yl)-5//-°big and [2,3-6]° ratio 11 well-7 -formic acid [(R)-l-(4,4-difluoro-piperidin-1-carbonyl)-2,2-dimethyl-propyl]-decylamine

154395.doc 66- 201134826

1-135 η〇Λ 尤c〇° 2-cyclopropyl-5//-n ratio 咯[2,3-6]pyrazine-7-decanoic acid [(R)-l-(7,8- Dihydro·5 ole [1,6]acridine-6-carbonyl)-2,2-dimercapto-propyl]-nonylamine 1-136 ° 2-cyclopropyl-5//-pyrrolo[2 ,3-6]pyrazine-7-decanoic acid [(R)-2-(3-cyano-azetidin-1-yl)-2-yloxy-1-(tetrazine-pyrene -4-yl)-ethyl]-bristamine 1-137 ° 2-cyclopropylpyrolo[2,3-6]» than plough-7-formic acid [(S)-2-(3-cyano) -azetidin-1·yl)-2-oxoyl-1-(tetrazine-pyran-4-yl)-ethyl]-bristamine 1-138 2-cyclopropyl-5// -pyrrolo[2,3-6]« than -7-carboxylic acid [(R)-l-(2,3-di-argon-吲0-to-1-yl)-2,2-dimethyl- Propyl]-nonylamine 1-139 ^°g^dF w ° VN^ 2-(1-ethyl-1//-pyrazol-4-yl)-5-lo 0biha[2,3-6 ]° ratio p well-7-formic acid [(R)-1 -cyclopropyl-2-(3,3 -diox-0-specific °-1-yl)-2-oxo-ethyl ]-decylamine 154395.doc -67- 201134826 1-140 w ° VN-/ 2-(1 -ethyl-1·ίΓ-0 vs. 0--4-yl)·5/f-pyrrolo[2, 3-6] Pyridin-7-formic acid [(R)-l-(4-hydroxy-4-methyl-piperidin-1-yl)-2,2-dimethyl-propyl]-decylamine 1-141 ° 2-cyclopropyl-5//-«比比和[2,3-6 ]n 比井-7-decanoic acid [(R)-2-(3-cyano-3-methyl-azetidin-1-yl)-1-cyclopropyl_2_sideoxy- Ethyl]-bristamine 1-142 w ° VN- 2-(1-methyl-li/-pyrazol-4-yl)-5i/-pyrrolo[2,3-6]pyrazine-7-曱Acid [(R)-2-(3-cyano-3-indolyl-azetidin-1·yl)-1-cyclopropyl-2-indolyl-ethyl]-decylamine 1- 143 w ° VN- 2-(1-methyl ratio) sit-4-yl)-5//-0 piroxime and P, 3-6]° than -7-decanoic acid [(11)-1- (3-indolyl-3-indolyl-azetidin-1-carbonyl)-2,2-dimercapto-propyl]-nonylamine 1-144 w ° VN^ 2-(1-ethyl Sodium-4-yl)-5//-pyrrolo[2,3-6]pyrazine-7-carboxylic acid [(R)-l-cyclopropyl-2-(4,4-digas-π bottom bite -1-yl)-2-oxo-ethyl]-bristamine

154395.doc ·68· 201134826

1-145 W ° 2-(4-Terbutyl-pyridin-2-yl)-5/ί-pyrrolo[2,3-&]pyrazine-7-decanoic acid [(R)-2- (4-cyano-piperidin-1-yl)-1-cyclopropyl-2-oxo-ethyl]-bristamine 2-(1-ethyl-1//-pyrazol-4-yl )-5//-° ratio D and [2,3-6]0 to whistle-7-decanoic acid 1-146 ° [(R)-l-cyclopropyl-2-(4-pyrimidin-4 -difluorodecyl-piperidin-1-yl)-2-oxo-ethyl]-nonylamine VN^ 2-(4-phenylpyridin-2-yl)-5//-° ratio 1 -147 }=\ η r ^ W ° 并[2,3-6]pyrazine-7-decanoic acid [(R)-2-(4-carbyl-σ bottom bit-1-yl)-1- Cyclopropyl-2-oxo-ethyl]-bristamine 2-(1-ethyl-1//-pyrazol-4-yl)-5//-pyrrolo[2,3-6]pyrr 11 Well-7-decanoic acid 1-148 W ° [(R)-l-cyclopropyl-2-(3-carbyl-3-methyl-azetidin-1-yl)-2- side Oxy-ethyl]-decylamine βν^Λ jC 2-cyclopropyl-5//-"bibromo[2,3-6]° ratio 1-149 ° tillage-7-decanoic acid [(lR , 2R)-l-(4-cyano-. bottom bite-1·yl)-2-mercapto-butyl]-decylamine 154395.doc -69- 201134826 1-150 w 0 VN- 2-( 1-mercapto-17/-pyrazol-4-yl)-5//-0 piroxi[2,3-6]0 to 0 well-7-decanoic acid [(R) small cyclopropyl-2 -(3,3-difluoro-azetidin-1-yl)-2-side Base-ethyl]-nonylamine 1-151 w 0 VN- 2-(1-mercapto-1//-pyrazol-4-yl)-5//-0 ratio D and [2,3-6 ]0 ratio p well-7-decanoic acid [(R)-2-(3-cyano-3-ethyl-heterocyclic dihydro)>-1-yl)-1-cyclopropyl-2- side Oxy-ethyl]-bristamine 1-152 w 0 2_(4-BtLe^-l-yl-B ratio 1^-2-yl_)-5/f-pyrrolo[2,3-6]pyrr Plough-7·formic acid [(R)-2-(3-cyano-azetidin-1-yl)-1-indenyl-2-yloxy-ethyl]-decylamine 1-153 w ° 2-(4-π ratio-yl-D ratio bit-2-yl)-5//-pyrrolo[2,3-6]pyrazine-7-carboxylic acid [(R)-2-(3-cyanide) -azetidin-1-yl)-1-methyl-2-oxo-ethyl]-nonylamine 1-154 w ° 2-(4-σ-cephen-2-yl-bite- 2-yl)-5-leopyrrolo[2,3·έ]pyrazine-7·formic acid[(R)-2-(4·氱基· slightly bite·1 _ group)-1 cyclopropyl-2- Oxo-ethyl]-decylamine

154395.doc ·70· 201134826

1-155 ° 2-(4-Methylaminoindenyl-pyridin-2-yl)-5//-»pyrho[2,3-6]. Specific tillage-7-decanoic acid [(R)-2-(3-cyano-azetidinyl rl-yl)-1 -methyl-2-oxoethyl]-decylamine 1-156 6s Cl 2-(2-Gas-thiazol-5-yl)-5//-pyrrolo[2,3-6]pyrazine-7-carboxylic acid [(R)-l-(4-alkyl·π辰Bite-1-rebase)-2,2-dimethyl-propyl]-nonylamine 1-157 NU F 2-[1-(3,5-di-phenyl)-2-indolyl-indole /f-imidazol-4-yl]-5if-pyrrolo[;2,3-6]pyrazine-7-carboxylic acid [(R)-l-(3-alcoholic-cyclohexyl-1-in-1 Base)-2,2-dimethyl-propyl]•nonylamine 1-158 Νμ rxy 2-[1-(3-f-phenyl)-2-indenyl-17/-imidazol-4-yl] -5//-n ratio 咯[2,3-6] «比耕-7-decanoic acid [(R)-l-(3-cyano-azetidin-1-carbonyl)-2, 2-dimercapto-propyl]-decylamine 154395.doc -71 - 201134826 1-159 2-(2-mercapto-1-phenyl-1//-imidazol-4-ylpyrho[2, 3-6]»比耕-7-formic acid [(R)-2-(3-cyano-azetidin-1 -yl)-1 -cyclopropyl-2-oxo-ethyl] • guanamine 1-160 \ F 2-(4-trifluoromethyl-phenylpyrolo[2,3-6]pyrazine-7-decanoic acid [(R)-2-(3-yl-yl- Gas-heterocyclic Dingyuan·1-yl)-1-cyclopropyl-2-oxo-ethyl]-nonylamine 1-161 2-[4-(4-乙毛基-略十一井-1- Base)-phenyl]-5//-»比比和[2,3- 6]"比耕-7-decanoic acid [(R)-2-(3-cyano-azetidin V Λ rl rl-yl)-1-cyclopropyl-2- oxo-ethyl ]-guanamine

154395.doc 72- 201134826

1-162 Φ 2-[4-(4-Methyl-yl)-phenyl]-5//-° ratio 咯[2,3-6]' than tillage-7-decanoic acid [(R)- 2-(3-cyano-azetidin-1-yl)-1-cyclopropyl-2-oxo-ethyl]-nonylamine 1-163 0 0 2-(4-morpholine- 4-yl-phenyl)-5//-pyrrolo[2,3-6].啼-7-decanoic acid [(R)-2-(3-cyano-azetidin-1-yl)·1-cyclopropyl-2-o-oxy-ethyl]• decylamine 1 -164,, 2-(4-Dimethylaminophenyl)-5//-pyrrolo[2,3-6]pyrazine-7-decanoic acid [(R)-2-(3-cyanide) -azetidin-1-yl)-1-cyclopropyl-2-oxo-ethyl]-nonylamine 1-165 ΝΑ 2-[2-methyl-1-(2,2, 2-Trifluoro-ethyl)-1 from imidazol-4-yl]-5//-pyrrolo[2,3-6]pyridin-7-decanoic acid [(R)-2-(3-cyano) -azetidin-1-yl)-1-cyclopropyl-2. oxo-ethyl]-S&amine FfF 154395.doc -73- 201134826 1-166

2-phenyl-5//-»pyrolo[2,3-6]pyrazine-7-carboxylic acid [(R)-2-(3·cyano-azetidin-1-yl)- General procedure for the preparation of valproate 11 to argon-based starting materials by 1-cyclopropyl-2-oxo-ethyl]-decanamine 1

Process 2

Human fork n^Y〇H — H 0 〇

154395.doc • 74- 201134826 Process 3

General Process Description In the above general scheme, Q may be hydrazine, hydrazine, hydroxy, cyano or Q' 'Q' may be a lower alkyl group or a lower aryl group substituted by one or more Qa as appropriate. a lower alkynyl group, a lower alkoxy group, a cycloalkyl group, a cycloalkoxy group, a phenyl group, a cycloalkenyl group, a heterocycloalkyl group or a heteroaryl group, Qa may be Qb or qc, and Qb may be halogen, side oxygen Base, hydroxyl, -CN, -SCH3, _S(0)2CH3 or -S(=0)CH3 'Qc may be Q^Qe' ' or two Qa - forming a double ring substituted by one or more Qb or qc For the system, Qd can be -〇(Qe), _S(=0)2(Qe), -C(=0)N(Qe)2, -S(0)2(Qe), -C(=0)( Qe), -C(=〇)〇(Qe), -N(Qe)2, -N(Qe)C(=0)(Qe), -N(Qe)C(=0)〇(Qe) or _N(Qe)C(=0)N(Qe)2, each Qe may independently be H or Qe 'each Qe' may independently be a low carbon alkyl group, phenyl substituted by one or more Qf as appropriate , benzyl, lower carboxyalkyl, lower alkoxy, cycloalkyl lower alkyl, cycloalkenyl, heterocycloalkyl or heteroaryl, Qf can be Qg or Qh, Qg can be self-priming , hydroxy, cyano, pendant oxy or _C( = 〇) (Qh), Qh may be a lower alkyl, low carbon substituted by one or more Q1 as appropriate Alkyl, 154395.doc •75· 201134826 low carbon alkoxy, amine, base, benzyl, cycloalkyl, heterocycloalkyl or heteroaryl, and Q1 can be dentate, hydroxyl, cyano , lower alkyl, lower haloalkyl or lower alkoxy β In the above general scheme, R1 may be hydrazine or Rla, and Ru may be a lower alkyl group substituted by one or more Rla', as the case may be. Lower alkoxy, strepto, benzyl, heteroaryl, cycloalkyl, heterocycloalkyl or cycloalkylalkyl, and Rla. can be halogen, low carbon alkyl, low carbon | , low carbon alkoxy, low carbon alkyl, low carbon halogen, pendant oxy, thiol or -CN. In the above general scheme, R4 and R5 together form a heterocyclic moiety as defined herein in the formula [|,:

X may be C(R2)(R3), N(R2), S(=0)2 or Ο, each R2 may independently be Η or R2a, and each R2a may independently be a lower alkyl group or a lower alkane a group, a halogen, a lower alkoxy group, a lower hydroxyalkyl group, a cyano group, a cyano lower alkyl group, a hydroxyl group, C(=0)R2a· or S(=0)2R2a, each of which may independently be Η Or lower alkyl, each X' may independently be dentate, lower alkyl, cyano, hydroxy, lower haloalkyl, lower hydroxyalkyl, heteroaryl, spiroheterocycloalkyl, spiro An alkyl group, a lower alkoxy group, a lower alkylamino group or a lower dialkylamino group, or X. together with R2 forms a bicyclic ring system optionally substituted with one or more R 2 ', and R 2 ' may be halogen , lower alkyl, lower alkoxy, hydroxy, hydroxy lower alkyl, lower 154395.doc -76- 201134826 carbamoalkyl, lower hydroxyalkylcyano or _S(〇)2CH3, R3 H, a trans group, a halogen or a lower alkyl group or R2 and R3 together form a bicyclic ring system which is optionally substituted by one or more R 2 ·, q may be 0, i, 2, 3 or 4, η may be 〇 or 1, and ρ can be 0 or 1. Procedure 1

Method A Step 1 To 2-bromo-5H-pyrrolo[2,3-b]pyrazine (5.0 g, 25.2 mmol) in 1,4-di. A portion of the suspension (100 mL) was added with a solution of 〇M NaOH (25 mL, 50.0 mmol) and 37% aqueous formaldehyde (19 mL·, 252 mmol). The dark homogeneous reaction mixture was removed overnight at room temperature. The organic matter is evaporated under reduced pressure. The aqueous layer was neutralized with 1.0 M EtOAc and EtOAc (EtOAc). The combined organics were concentrated to give 2.6 g of a light solid. After standing, a thick brown precipitate formed in the water layer. The precipitate was collected by filtration and dried. The brown solid was extracted with 10% hot MeOH /EtOAc (3 x 200 mL). The extracts were combined and evaporated to give a further yield of 3.05 g of an orange solid (2-bromo-7-hydroxymethylpyrolo[2,3-b]pyrazine-5-yl)-nonanol. (87°/〇). Step 2 To a suspension of (2-bromo-7-hydroxyindole-pyrrolo[2,3-b]pyr-5-yl)-methanol (5.65 g '21.9 mmol) in THF (150 mL) Add 2.0 Μ 154395.doc •77· 201134826

Aqueous NaOH (33 mL, 66 mm 〇 1). The homogenous reaction mixture was searched off overnight and then the organics were removed under reduced pressure. The aqueous residue was brought to pH 4 with a 1 M aqueous solution of HCl. The resulting precipitate was collected via filtration and rinsed with EtOAc to yield 3.68 <RTIgt; The filtrate was extracted with Et 〇Ac (2×), and the organics were concentrated under reduced pressure to give a crude product of 〇92 g of a yellow solid bromo-5H-pyrrolo[2,3-b]pyridin-7-yl)-methanol. The rate was 4 6 〇g (92%). Step 3 Prepare the Jones reagent by carefully adding concentrated H2S〇4 (23 mL) to Cr03 (2.67 g), followed by dilution to 〇0 with 仏0. Nes reagent; 2 〇Μ) stock solution. Slow addition of Jones reagent to a partial suspension of (2-bromo-5H-pyrrolo[2,3-b]pyrrol-7-yl)-methanol (4.6 g, 20.1 mmol) in acetone (300 mL) 9 mL, 24.0 mmol). The starting material gradually dissolves during the addition and forms a green thick precipitate. The reaction mixture was stirred for 5 min then quenched with EtOAc (EtOAc)EtOAc. Concentration of the filtrate gave 4.76 g of 2-bromo-5H-biha[2,3-b] as a yellow solid. It is used without further purification than "• Well-7-A. Here. Subsequent To this solution of solid in DMF (50 mL) was added NaH (EtOAc &lt;RTI ID=0.0&gt;&gt; The reaction mixture was stirred at room temperature for 3 Torr, then cooled to &lt;RTI ID=0.0&gt;&gt;&gt;&&&&&&&&&&&&&& The reaction mixture was warmed to EtOAc (3 mL). The combined organics were washed with H.sub.2 (3.sub.3) and brine, then dried and evaporated. The residue 154395.doc •78·201134826 was purified by Si〇2 chromatography (20% to 30% EtOAc/hexanes). 3.82 g (53° / 〇) as a yellow solid 2·bromo-5-(2- Trimethyl sulfonyl-ethoxycarbonyl)-5Η-. More than 0 each [2,3-b]nhb_-7 - 曱骏. Method B Step 1 In a dry round bottom flask, 2-Methyl-5H-[rho][2,3-b]^ (5.0 g ' 25.2 mmol) was dissolved in DMF (50%). The reaction mixture was cooled to 0 C ' and sodium hydride (6% dispersion in mineral oil, 122 g, 3 0.6 mmol) was added. The reaction mixture was allowed to warm to room rt and stirred for 5 min then cooled to 0 &lt;0&gt;C and SEM-C1 (5.4 mL, 30.4 mmol). After the addition was completed, the ice bath was removed and the reaction mixture was stirred at room temperature for 1, 5 hours. The reaction mixture was quenched with 50 mL water and EtOAc (EtOAc) The combined organic layers were washed twice with 30 mL of water and washed with &lt The residue was adsorbed onto ca. 20 g SiO 2 and chromatographed with EtOAc (EtOAc:EtOAc) Combine all the product-containing fractions and concentrate to obtain 6_61 g (80 ° / 〇) gradually solidified pale yellow oil in the form of 2-bromo-5-(2_trimethyl-stone-ethoxymethyl)_5H-0 ratio Luohe [2,3-b] ° than the well. Step 2 In a round bottom flask, 2-bromo-5-(2-trimethyldecyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyridinium (6.58 g' 20.0 mm) 〇l) was dissolved in trioxane (stabilized with pentene, 120 mL) and added with gas sulfhydryl dimercaptoacetated ammonium iodide (10.3 g, 80.2 mmol). The reaction mixture was stirred under reflux for 8 hours while allowing a steady stream of nitrogen to bubble through the reaction mixture. The dark brown solution was allowed to cool to room temperature and stirred overnight. Saturate the NaHC〇3 solution with approximately 丨〇〇 mL 154395.doc •79· 201134826 Carefully quench the reaction mixture (note: exotherm)' then extract twice with 2 mL of diethyl ether. The combined organic layers were dried over sodium sulfate, dried and concentrated. The residue was adsorbed onto ca. 20 g Si.sub.2 and chromatographed with EtOAc (EtOAc:EtOAc) All the fractions containing the product were combined and concentrated to give 5.92 g (83%) of y. ,3·b]° ratio _7-capric acid and 2-chloro-5-(2-trimethyldecyl-ethoxymethyl)-5H-indolo[2,3_b]II ¢ Well _7_ Approximately 3:1 mixture of formaldehyde. Procedure 2

In the flask, 2-bromo-5-(2-tridecyldecyloxymethyl)-511-pyrolo[2,3-b]0 was compared with the phenyl-7-oxime (3.11 g, 8.74 mmol). Dissolved in dioxane (120 mL) and H2O (30 mL) and allowed to cool at 0 °C. Amino acid (5.09 g, 52.4 mmol) and sodium sulfite (1.28 g, 11.4 mmol) and dihydrogen |f (14.3 g, 104.9 mmol) in H20 (75) were added via the addition funnel over 15 min. Solution in mL). The reaction mixture was allowed to warm to room temperature over 2 hours. The resulting yellow solid was filtered, washed with H20 and hexane and dried. The filtrate was then extracted with EtOAc and the combined organics were washed with brine and dried with &lt;RTIgt; A total of 3.71 g of 2-bromo-5-(2-trimethyldecyloxyethoxy)-5H-pyrrolo[2,3-b]° ratio of only -7-decanoic acid was obtained as a yellow solid. 154395.doc • 80 · 201134826 Procedure 3

Step 1 2-Bromo-5-(2-trimethyldecyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carbaldehyde (0.33 g, 0.93 mmol), Cyclopropyl-acid (〇.12 g, 1.39 mmol), tricyclohexylphosphine (0.026 g, 0.09 mmol), acetic acid saturated (11) (0.01 g, 0.046 mmol), and dishwashing (three g) (〇·63 g, A mixture of 2.97 mmol) in 4 mL of toluene and 0.5 mL of water was flushed with argon for 5 minutes and then heated at 100 ° C for 18 hours. The cooled mixture was filtered with EtOAc EtOAc EtOAc. The residue was purified by silica gel chromatography eluting with 10% EtOAc / hexanes to afford 0.24 g (81%) of 2- propyl propyl-5-(2-tridecyl decyl )-5H-pyridox[2,3-b]. Tillage-7-furfural. Step 2 2-Actylpropyl-5-(2-tridecyldecyl-ethoxymethyl)·5H-pyrrolo[2,3-b]pyrrol-7-furfural at 〇°C (0.24 g, 0.75 mmol) A solution of sulfonic acid (〇 44 g, 4_54 mmol) was added to a solution of 1,4-dioxane (10 mL) and water (2 mL). Then, a solution of sodium chlorite (〇9 g, 〇98 clawed melon (1)) and potassium monohydrogen phosphate (1.22 g, 9.0 mmol) in 6 mL of water was added dropwise. After the addition, the reaction mixture was allowed to warm to room rt and stirred for 2 hr then then </ br> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; The organic layer was washed with brine, dried over sodium sulfate The residue was triturated with hexane to give &lt;RTI ID=0.0&gt;&gt;&gt;&gt; More than [2,3 tons] pyridin-7-decanoic acid. Procedure 4

Step 1 2-Derivative-5-((2-(tridecyldecyl)ethoxy)methyl)_5Η_βpyrolo[2,3-b] mantle-7-furfural (1.33 g, 3.73) Methyl) and 1-ethyl-4-(4,4,5,5-tetradecyl-i,3,2-dioxaborin-2-yl sitting (995 mg, 4.48 mmol) in i,2_DmE ( Add in solution in 20 mL)

Pd(Ph3P)4 (0.22 g, 0.19 mmol) &amp; 2.0 MK2COyjc| &amp; (5.6 ml, 11.2 mmol). The reaction mixture was degassed by bubbling with N2 for 15 minutes and then heated at 100 ° C overnight. The resulting maroon reaction mixture was cooled and diluted with EtOAc (EtOAc) (EtOAc) The combined organics were dried over MgSO 4 and concentrated. Purification of the crude residue by SiO 2 chromatography (30% to 80%EtOAc/hexanes) to yield 1.12 g (81%) 5-(5-((3-(tridecyl)alkyl)ethoxy)indolyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxaldehyde. Step 2 154395.doc -82· 201134826 2-(1-Ethyl-1H-pyrazol-4-yl)-5-((2-(trimethyldecyl)ethoxy) at 0 °C曱-)-5H-pyrrolo[2,3-b]pyrrol-7-furfural (1.12 g, 3.01 mmol) in 1,4-dioxane (SO mL) and H2O (10 mL) Amine acid (1·76 g '1 8.1 mmol) was added to the solution. A solution of NaC102 (0.44 g, 3.92 mmol) and KH2P04 (4.92 g, 36.2 mmol) in H.sub.2 (30 mL) was then added over 15 min. The ice bath was removed and the yellow turbid reaction mixture was stirred at room temperature for 2.5 h. The reaction mixture was diluted with EtOAc (EtOAc) The combined organic layers were dried with EtOAc EtOAc EtOAc EtOAcjHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH 4-yl)-5-((2-(trimethylsulfanyl)ethoxy)indolyl)-5H-. The ratio is slightly [3,2-b] ° than the p-well-7-decanoic acid. Pharmaceutical Compositions and Administration The compounds of the present invention can be formulated into a wide variety of oral dosage forms and carriers. Oral administration can be in the form of lozenges, coated lozenges, dragees, hard and soft gelatin capsules, solutions, emulsions, syrups or suspensions. The compounds of the invention are effective when administered by other routes of administration, including continuous (intravenous drip), topical, parenteral, intramuscular, intravenous, subcutaneous, transdermal (which may include penetration enhancers) ), buccal, nasal, inhalation and suppository administration and other routes of administration. The preferred mode of administration is generally to use a suitable daily dosing regimen πι&apos; which can be adjusted depending on the degree of pain and the patient's response to the active ingredient. The compound of the present invention and its pharmaceutically acceptable use can be prepared by formulating a salt together with one or more excipient carriers or diluents to form a pharmaceutical composition and a unit of agent S. The pharmaceutical compositions and unit dosage forms may contain conventional ratios 154395.doc • 83- 201134826 known ingredients, with or without other active compounds or ingredients, and unit dosage forms may contain any suitable proportions commensurate with the intended daily dosage range An effective amount of the active ingredient. The pharmaceutical composition may be used in the form of a solid such as a lozenge or a filling capsule; a semi-solid; a powder; a sustained release formulation; or a liquid such as a solution, suspension, emulsion, elixir or filling capsule for oral use; or for the rectum Or in the form of a suppository for vaginal administration; or as a sterile injectable solution for parenteral use. A typical preparation contains from about 5% to about 95% active compound (W/W). The term "formulation" or "dosage form" is intended to include both solid and liquid formulations of the active compound, and those skilled in the art will appreciate that the active ingredient may be present in separate formulations depending on the target organ or tissue and the desired dosage. Pharmacokinetic parameters. Solid form preparations include powders, lozenges, pills, capsules, suppositories, and dispersible granules. The solid carrier can be one or more substances which may also act as diluents, flavoring agents, solubilizers, lubricants, suspending agents, binders, preservatives, tablet disintegrating agents or encapsulating materials. In powders, the carrier is typically a finely divided solid in admixture with the finely divided active component. In lozenges, the active component will generally be mixed in a suitable ratio with the carrier having the necessary binding strength and compressed into the desired shape and size. Suitable carriers include, but are not limited to, magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, low melting waxes , cocoa butter and similar carriers. The solid form preparation may contain, in addition to the active ingredient, a coloring agent, a flavoring agent, a stabilizer, a buffering agent, an artificial sweetener, and a natural sweetener, a dispersing agent, a thickening agent, a solubilizing agent, and the like. Liquid formulations are also suitable for oral administration, including (iv) formulations including emulsions, syrups, 154395.doc • 84· 201134826, aqueous solutions and aqueous suspensions. Such formulations include solid form preparations which are intended to be converted, shortly before use, to liquid form preparations. The emulsion may be prepared in a solution such as an aqueous solution of propylene glycol, or may contain an emulsifier such as (iv) lipid, sorbitan monooleate or gum arabic. The aqueous solution can be prepared by dissolving the active component in water and adding suitable colorants, flavoring agents, stabilizers, and bulking agents. The water (iv) float can be prepared by dispersing the finely divided active ingredient in water with a viscous material such as natural or synthetic gum, resin, methylcellulose, sodium decyl cellulose, and other well-known suspending agents. The compounds of the invention may be formulated for parenteral administration (for example by injection such as rapid injection or continuous infusion) and may be presented in ampoules with preservatives, prefilled syringes, small volume infusions or multi-dose containers. Unit dosage form. The composition may take the form of a suspension, a bath or an emulsion such as in an oily or aqueous vehicle, for example, in the form of a solution in an aqueous solution of polyethylene glycol. Examples of oily or non-aqueous vehicles, diluents, solvents or vehicles include propanol, polyethylene glycol, vegetable oils (such as olive oil), and injectable organic esters (such as ethyl oleate), and may contain formulating agents. Such as preservatives, wetting agents, emulsifying or suspending agents, stabilizers and/or dispersing agents. Alternatively, the active ingredient can be in the form of a powder which can be obtained by sterile isolation of the sterile solid or by lyophilization from the solution for reconstitution with a suitable vehicle (for example, sterile, pyrogen free water) before use. The compounds of the invention may be formulated as ointments, creams or lotions, or as a transdermal patch for topical administration to the epidermis. For example, ointments and creams may be formulated with an aqueous or oily base suitable for thickening and/or gelling agents 154395.doc -85·201134826. The lotion may be formulated with an aqueous or oily base and will generally also contain one or more emulsifying, stabilizing, dispersing, suspending, thickening or coloring agents. Formulations suitable for topical administration in the mouth include: buccal tablets containing the active agent in a flavoring base (usually sucrose and gum arabic or tragacanth); tablets which are contained in an inert matrix such as gelatin and glycerin or sucrose And an active ingredient in gum arabic; and a mouthwash comprising the active ingredient in a liquid carrier. The compounds of the invention may be formulated as a suppository for administration. The low melting point wax (such as a mixture of fatty acid glycerides or cocoa butter) may be first melted, and the active component is uniformly dispersed, for example, by stirring. The molten homogeneous mixture is then poured into a mold of suitable size to allow it to cool and solidify. The compounds of the invention may be formulated for vaginal administration. Uterine trays, tampons, creams, gels, pastes, foams or sprays containing such carriers in addition to the active ingredient are known in the art to be suitable. The compounds of the invention may be formulated for nasal administration. The solution or suspension can be applied directly to the nasal cavity by conventional means, such as by means of a dropper, pipette or spray. Formulations may be provided in single or multiple doses. In the case of a dropper or a pipette, this can be achieved by the patient administering a suitable predetermined volume of solution or suspension. In the case of a nebulizer, this can be achieved, for example, by means of a metered atomizing spray pump. The compounds of the invention may be formulated for aerosol administration, especially to the respiratory tract and include intranasal administration. The compound will generally have a small particle size of, for example, about 5 microns or less. The particle size can be obtained by means known in the art, for example by micronization. The active ingredient is suitable for propellants such as gas a carbide 154395.doc -86 - 201134826 (CFC) (eg difluorodifluorodecane, tri-fluorofluoromethane or di-tetrafluoroethane) or carbon dioxide or other suitable gas The aerosol provided in the pressurized pack suitably also contains a surfactant such as an egg fat. The dosage of the drug can be controlled by a metering valve. Alternatively, the active ingredient may be presented in the form of a dry powder, such as a powder mixture of the compound in a suitable powder base such as lactose, starch, starch derivatives (such as hydroxypropyl methylcellulose) and polyethylene ketones (pvp). . The powder carrier forms a gel in the nasal cavity. Powder Compositions • may be in unit dosage form, e.g., in a gelatin capsule or cartridge or in a blister pack, and the powder may be administered by the inhaler from such gelatin capsules or cartridges or in a blister pack. If desired, the formulations may be prepared with enteric coatings which are suitable for sustained release or controlled release administration of the active ingredient. For example, the compounds of the invention may be formulated in a transdermal or subcutaneous drug delivery device. Such delivery systems are advantageous when sustained release of the compound is necessary and when patient compliance with the treatment regimen is critical. The compounds in the transdermal delivery system are usually attached to the skin adhesion • solid support. Related compounds may also be combined with a penetration enhancer (e.g., hydrazine (1 · eleven * oxaza-cycloheptan-2-one)). The sustained release delivery system is inserted into the subcutaneous layer subcutaneously by surgery or injection. The subcutaneous implant encapsulates the compound in a lipid soluble film (e.g., polyoxyxene rubber) or a biodegradable polymer (e.g., polyacetic acid). Suitable formulations and pharmaceutical carriers, diluents and excipients are described in Remington: The Science and Practice of Pharmacy 1995, edited by E. W. Martin, Mack Publishing Company, 19th edition, Easton,

In Pennsylvania. The skilled blending scientist can modify the formulation according to the teachings of the present specification 154395.doc-87-201134826 to provide a plurality of formulations using the (iv) dosing route without the composition of the present invention being damaging or impairing its therapeutic activity. For example, 'improving the compounds of the invention to make them more soluble in water or other vehicles can be easily achieved by minor changes (salt formulation, cooling, etc.), which are well within the general skill of the art. . It is also within the general skill of the art to improve the route of administration of a particular compound and the dosage regimen to control the pharmacokinetics of the compounds of the invention to achieve maximum benefit in the patient. The term "therapeutically effective amount" as used herein means the amount required to alleviate the symptoms of an individual's disease. The dosage can be adjusted to individual needs in each particular case. Depending on factors such as the severity of the condition to be treated, the age and general health of the patient, the other drug being treated, the route and form of administration, and the other preferences and experience of the relevant medical practitioner, the dosage may be within a wide range. Variety. For oral administration, in single treatment and/or combination therapy, the dose of strontium is preferably between about 001 11^ and 1,000 mg per kilogram of body weight per day. The dose of strontium is preferably between about 1 mg and about 500 mg per kilogram of body weight per day, more preferably between mg and about 1 mg per kg of body weight per day, and optimally between every kilogram of body weight per day. Between about 10 mg. Thus, for administration to 7 ounces of individual, the dosage may range from about 7 mg to 0.7 g per day. The sputum dose can be administered in a single dose or in divided doses, usually between 1 and 5 doses per day. In general, treatment is initiated with a smaller dose that is less than the optimal dose of the compound. Thereafter, the dose is increased in small increments until the individual patient achieves optimal results. Those skilled in the art of treating the diseases described herein are not required to undue experimentation and rely on personal knowledge, experience, and the disclosure of the present application 154395.doc-88-201134826 to determine the therapeutically effective amount of the compound of the invention for use in a given disease and patient. The pharmaceutical preparation is preferably in unit dosage form. In this form, the preparation is subdivided into unit doses containing appropriate quantities of the active ingredient. The unit dosage form can be a package preparation containing discrete amounts of preparation such as a packaged lozenge, capsules and vials or ampoules. Further, the unit dosage form can be a capsule, lozenge, lozenge or lozenge itself, or it can be a suitable number of any such compositions in the form of a package. Indications and Methods of Treatment The present application provides a method of treating an inflammatory condition or an autoimmune condition, the method comprising administering to a patient in need thereof a therapeutically effective amount of a "knot." The present application provides the above method, The method further comprises administering to the other therapeutic agent selected from the group consisting of a chemotherapeutic or anti-proliferative agent, an anti-inflammatory agent, an immunomodulatory or immunosuppressive agent, a neurotrophic factor, an agent for treating cardiovascular diseases, an agent for treating diabetes, or a treatment The present invention provides a method of treating rheumatoid arthritis comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula I. The present application provides a method of treating asthma, which The method comprises administering to a patient in need thereof a therapeutically effective amount of a compound of formula I. The present application provides a method of treating an inflammatory condition, the present invention comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula I. The present invention provides a method for inhibiting a T cell proliferative disorder, the method comprising administering a therapeutically effective treatment to a patient in need thereof A compound of formula I. 154 395. doc • 89- 201134826 The present application is directed to a method of inhibiting a tau cell proliferative disorder comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula I. The method provides the above method, wherein the proliferative disorder is cancer. The present application provides a method of treating a sputum cell proliferative disorder, the method comprising administering to a patient in need thereof a therapeutically effective amount of a compound. A method of treating immune disorders including: lupus, multiple sclerosis, rheumatoid arthritis, psoriasis, tau type diabetes, organ transplant complications, xenografts, diabetes, cancer, asthma, atopic dermatitis, Autoimmune thyroid disorders, ulcerative colitis, Crohn's disease, Alzheimer's disease, and leukemia, the method comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula I. The present invention provides a method for preventing or treating all forms of organ rejection (including acute allograft or xenograft rejection and chronic allograft or xenograft rejection), administrative or non-vascular grafting. Including administration of a compound of the formula to a patient in need thereof. The application provides a method of inhibiting JAK3 activity, which comprises administering a compound of formula I, wherein the compound is in an in vitro biochemical assay of JAK3 activity (9). Micro-mole or less than 5 〇 micro-mole. The present application provides the above method, wherein the compound is 1 in an in vitro biochemical assay of JAK3 activity (: 50 is 1 〇〇Nerium or less than 1 〇〇Nemo. The present application provides the above method, wherein The compound is one of the in vitro biochemical assays for JAK3 activity (:" is 1 〇Nemo or less than 1 〇Nemo 154395.doc •90-201134826 A method of inhibiting SYK activity, the gastric method comprises a cast A compound wherein the IC5 of the compound in the SYK activity is 50 micromolar or less than 50 micromolar. The present application provides the above method, wherein the compound is in vitro biochemistry of δγκ activity. The heart of the test is! (10) Nymole or less than (10) to win the ear.

The application provides the above method, wherein (1)(9) of the compound in the in vitro biochemical assay of SYK activity is 1 〇Nemo or less than 1 〇Nemo. The present application provides a method of treating an inflammatory condition comprising administering to a patient in need thereof a therapeutically effective amount of an anti-inflammatory compound combination compound. The present application provides a method of treating an immune disorder comprising co-administering to a patient in need thereof a therapeutically effective amount of an immunosuppressive compound in combination with a compound of Formula I. [Embodiment] Examples The following examples illustrate compounds falling within the scope of the present invention. Preparation and biological evaluation. These and subsequent preparation methods are provided to enable those skilled in the art to more clearly understand and practice the invention. The examples and methods of preparation are not to be construed as limiting the scope of the invention, but merely to illustrate and represent the invention. The abbreviations commonly used in the abbreviations include: acetonitrile (Ac), azobisisobutyronitrile (AIBN), atmosphere (Atm), 9-boronbicycloindole·3·1] decane (9·ΒΒΝ or 154395. Doc •91 · 201134826 BBN), tert-butoxycarbonyl (Boc), di-tert-butyl dicarbonate or boc anhydride (B0C20), benzyl (Bn), butyl (Bu), chemical abstracts registration number ( CASRN), benzyloxycarbonyl (CBZ or Z), carbonyl diimidazole (CDI), 1,4-diazabicyclo [2.2.2] octane (DABCO), diethylaminosulfur trifluoride (DAST) ), dibenzylideneacetone (dba), 1,5-diazabicyclo[4.3.0]non-5-ene (08 &gt; 〇, 1,8-diazabicyclo. [5.4.0] 1--7-ene (081;), hydrazine, hydrazine, dicyclohexylcarbodiimide (DCC), 1,2-dioxaethane (DCE), di-methane (DCM), azobisphthalic acid Ethyl ester (DEAD), diisopropyl azodicarboxylate (DIAD), diisobutylaluminum hydride (DIBAL or DIBAL-H), diisopropylethylamine (DIPEA), N,N-didecyl Acetamide (DMA), 4-N,N-diaminoguanidine pyridine (DMAP), N,N-dimercaptocarboxamide (DMF), disulfoxide (DMSO), 1,1·-double -(diphenyl Ethyl (dppe), hydrazine, hydrazine-bis-(diphenylphosphino)ferrocene (dppf), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide Hydrochloride (EDCI), ethyl (Et), ethyl acetate (EtOAc), ethanol (EtOH), ethyl 2-ethoxy-2//-quinolin-1-indoleate (EEDQ), diethyl ether ( Et20), hexafluorophosphate acetic acid 0-(7-azabenzotriazol-1-yl)-indole, hydrazine, hydrazine Ν'-tetramethylhydrazine (HATU), acetic acid (HOAc), 1-N- Hydroxybenzotriazole (HOBt), high pressure liquid chromatography (HPLC), isopropanol (IPA), lithium hexamethylene diazoxide (LiHMDS), methanol (MeOH), melting point (mp or MP), MeS02 - (methylsulfonyl or Ms), mercapto (Me), acetonitrile (MeCN), m-chloroperbenzoic acid (MCPBA), mass spectrometry (ms or MS), mercapto tert-butyl ether (MTBE), N- Bromobutylimine (NBS), N-carboxy anhydride (NCA), N-chlorobutanediamine (NCS), N-mercaptomorpholine (NMM), N-decylpyrrolidone ( NMP), chromic acid pyridinium (PCC), dichromate pyrene (PDC), benzene 154395.doc -92- 201134826 base (Ph), propyl (Pr), isopropyl (i-pr), pound /square 吋 (psi), pyridine (pyr), room temperature (rt RT), 2-(trimethylsulfanyl) ethoxylated sulfhydryl gas (SEMC1), tert-butyldimethylmethylalkyl or t_BuMe2Si (TBDMS), triethylamine (TEA or Et3N), 2, 2, 6,6-tetradecyl "Ichenbit-1-oxyl (TEMPO), trifluoromethanesulfonate or CF3S02-(Tf), trifluoroacetic acid (TFA), 1,1·-bis-2,2 6,6-tetradecylheptane-2,6-dione (TMHD), 0-benzotriazol-1-yl-N,N,N,N,-tetramethyltetrafluoroborate (TBTU) ), thin layer chromatography (TLC), tetrahydrofuran (THF), trimethylsulfonyl or Me3Si (TMS), p-toluenesulfonic acid monohydrate (Ts〇H or pTsOH), 4-Me-C6H4S〇2· or Toluene-based (Ts), N-urethane-N-reasteric anhydride (UNCA). Conventional nomenclatures including the prefixes (n), x (), second (sec_), third (tert_), and neo (neo) have their usual meaning when used with the alkyl moiety. (J. Rigaudy and D. P. Klesney, Nomenclature in

Organic Chemistry, IUPAC 1979 Pergamon Press, Oxford.). PREPARATION EXAMPLES Example 1. 2-Cyclopropyl-5H-pyrrolo[2,3-b]pyrho-7-decanoic acid [(R)-2,2-dimethyl-1-(pyrrolidin-1- Carbonyl)-propyl]-guanamine

Step 1 154395.doc -93- 201134826 A 50 mL round bottom flask was charged with Boc-D-third-leucine (1.00 g, 4.32 mmol), HOBT (728 mg, 4.76 mmol), EDC (912 mg, 4.76 mmol) and pyrrolidine (0.57 mL, 6.89 mmol). Then DMF (18 mL) and N,N-diisopropylethylamine (1.l m 6.3 mmol) were added sequentially. The yellow reaction mixture was stirred at room temperature overnight then quenched with H20 andEtOAcEtOAc. The combined organic layers were washed twice with H.sub.2 and washed with brine and then dried over Na.sub. The residue was purified with EtOAc / EtOAc (EtOAc:EtOAc) 1-Phenoxy-1-(pyrrolidin-1-yl)butan-2-ylcarbamate. Step 2 'Methyl (r)-tert-butyl 3,3-dimethyl-1-oxo-l-(pyrrolidin-1-yl)butan-2-ylamine in a 10 mL round bottom flask The formate (0.160 g, 0.56 mmol) was dissolved in a 1.0 Μ hydrogenated hydrazine solution (3.6 ml, 3.6 mmol). The reaction mixture was stirred overnight at room temperature, then concentrated to give 14 g of (y),yield as as as as as as as as as as as as as as as as as as as as as as as as as as as as as as as as as as as as as as as as as as as as as as as as as as as as as as as as as as as as as as as as as as - Ketone hydrochloride, which was used without further purification. Step 3 A 10 mL round bottom flask was charged with 2-cyclopropyl-5-((2-(trimethyldecyl)ethoxy)methyl)-5H-pyrrole [2,3-bp ratio tillage -7-carboxylic acid (0.12 g, 0.36 mmol), (R)-2-amino-3,3-dimethyl-1-(pyrrolidinyl)-i-yl)butanone hydrochloride (137 mg, 0.53 mmol ), HOBt (61 mg, 0.40 mmol) and EDC (76 mg '0.40 mmol). Then DMF (1.6 mL) and N,N-diisopropylethylamine (0.16 ml, 0.92 mmol) were added sequentially. The mixture was stirred at room temperature 154395.doc -94 - 201134826 The pale yellow reaction mixture was taken overnight, then quenched with water and taken with diethyl ether (2 χ 5 〇 mL). The combined organic layers were washed twice with water and brine and dried over sodium sulfate. The residue was purified by chromatography with 8 g of EtOAc (EtOAc EtOAc EtOAc (EtOAc) 3 3 dimethyl-small-oxy-1-(pyrrolidinium-fluorenyl)but-2-yl)-5-((2-((trimethyldecyl)ethoxy)indolyl)-5H-° ratio洛和[2,3-b]. than cultivating -7-carbamamine. Step 4 '(R)_2_cyclopropyl_n_(33 didecyl small side oxy) in a 1 〇mL round bottom flask -1-(pyrrolidin-1-yl,)but-2-yl)-5-((2-((tridecyldecyl)ethoxy)methyl)-5H-pyrrolo[2,3- b] pyridin-7-decylamine (0.19 g '0.34 mmol) dissolved in dichloromethane (4 mL). Add 5 mL of trifluoroacetic acid, 13.7 mmol) and stir the pale yellow reaction mixture for 2 hours at room temperature 'Then was concentrated under reduced pressure. The residue was dissolved in toluene mL), concentrated and then placed under high vacuum for 30 min. The obtained foam was dissolved in dioxane (1.4 mL) and ethylenediamine (1⁄4 mL, 20.7 mmol) was added. The light yellow reaction mixture was stirred at room temperature for 2 hr then EtOAc (EtOAc) The combined organic layers were washed with water and brine then dried over sodium sulfate] The residue was purified by EtOAc EtOAc EtOAc (EtOAc) Wet-milling with EtOAc afforded 63 mg (5%) of white powdery 2-cyclopropyl-5H-pyrrolo[2,3-b]pyrazine-7-decanoic acid [(R)-2,2-di Mercapto-1-(pyrrole-1-carbonyl)-propyl]-guanamine. MS: (M+H)+=370; mp=201.0-203.0 〇154395.doc 95-201134826 Example 2· 2-(1-Ethyl-1Η-pyrazol-4-yl)-5Η-pyrrolo[2 ,3-b]pyrazine-7-formic acid [(R)-2,2-dimercapto-1-(pyrrolidin-1-carbonyl)-propyl]-decylamine

Step 1 Combine 2-bromo-5-(2-trimethyldecylethoxyethoxymethyl)-5H-0 in the flask with a ratio of 2,3-b] to argon-7-decanoic acid (125 Mg, 0.34 mmol), (R)-2-amino-3,3-dimethyl-1-pyrrolidin-1-yl-butan-1-one hydrochloride (155 mg, 0.70 mmol), EDC ( 148 mg, 0.77 mmol) and HOBt (104 mg, 0.772 mmol). DMF (4.0 mL) and i-Pr2NEt (0.19 mL, 1.07 mmol) were added sequentially. The reaction mixture was stirred at room temperature for 1 hour and then concentrated. The residue was dissolved in EtOAc and 10% EtOAc (EtOAc)EtOAc. Viscous brown oil 2_bromo·5-(2-trimethyldecyl-ethoxycarbonyl)_5Η-pyrrolo[2,3-b]pyrrolic acid [(R)-2,2-di Methyl-1-(pyrrolidinylcarbonylpropyl decylamine. Step 2 2-bromo·5·(2-trimethyldecyl-ethoxymethyl)·5η·pyrrolo[2, in a pressure tube 3-b]pyrazine-7·formic acid [(R)_2,2·didecyl_丨_(pyrrolidine_丨_carbonyl 154395.doc -96- 201134826 base)-propyl]decylamine (162 mg, 0.30 mmol) and 1-ethyl-1H-0 were dissolved in DME (3.0 mL) with benzo-4-ol acid ester (80 mg, 0.36 mmol). Add K2C〇3 in water (2.0 Μ, 0.45 mL) , 0.90 mmol) and Pd(PPh3) 4 (l 7 mg, 0.015 mmol), and the mixture was degassed with a gentle N 2 stream for 15 min. The vial was then sealed and heated at 90 ° C for 6 hours. The mixture was quenched with EtOAc (EtOAc)EtOAc. The residue gave 125 mg (75%) ofyield of 2-(1-ethyl-1H-pyrazol-4-yl)-5-(2-trimethylsulfanyl-ethoxymethyl) as a pale brown foam. -5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2,2-dimethyl-1-(pyrrolidin-1-carbonyl)-propyl]-guanamine. 3-way 2-(1-ethyl-1H-pyrazol-4-yl)-5-(2-trimethylsulfonyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyridin Adding TFA to a solution of hydrazine-7-formic acid [(R)-2,2-dimercapto-1·(pyrobitone-1-3⁄4yl)-propyl]-bristamine in CH2C12 (2.25 mL) 0.75 mL). The reaction mixture was stirred overnight and concentrated. The residue was dissolved in EtOAc EtOAc EtOAc EtOAc EtOAc The reaction mixture was concentrated, and the residue was purified mjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj _5Η_^〇[2,3-b]pyrazine-7-carboxylic acid [(R)-2,2·dimethylpyrrolidinylcarbonyl)-propyl]-guanamine. MS: (M+H)+ = 424. Example 3. 2-Cyclopropyl-5Η-»pyrolo[2,3-bp ratio tillage-7-formic acid ((R)-i_cyclopentyl_2_side 154395.doc-97- 201134826 Oxygen 2-pyrrolidin-1-yl-ethyl)-guanamine

Prepared according to the procedure described in Example 1 in which Boc-D-cyclopentylglycine was substituted for Boc-D-tris-leucine. MS: (M+H)+=382. Example 4. 2-(1-Ethyl-1H-pyrazol-4-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid ((R)-l-cyclopropyl- 2-sided oxy-2-&quot;bilobitone-1-yl-ethyl)-decylamine

Prepared according to the procedure described in Example 1 in which Boc-D-cyclopropylglycine was substituted for Boc-D-third-leucine, and 2·(1_ethyl_1H_pyrazole-4) · -5-((2-((trimethyldecyl)ethoxy)methyl)_5H-0 pyrrolo[32b] pyridin-7-carboxylic acid instead of 2-cyclopropyl-5-(2- Trimethyl sulfonyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7·decanoic acid. MS: (M+H)+=408; mp=2 10·0- 212.0. Example S. 154395.doc -98- 201134826 2-3⁄4propyl-5H-pyrrolo[2,3-b]«specific tillage-7_carboxylic acid [(R)_2_(3,3•difluoro-pyridyl)嘻.D--1-yl)-1-indol-2-yloxy-ethyl decylamine

Zero was prepared according to the procedure described in Example 1, in which Boc-D-tris-leucine was replaced with Boc-D-alanine and pyrrolidine was replaced with 3,3-difluoropyrrolidine hydrochloride. MS: (M+H)+=364. Example 6. 2-Cyclopropyl-5H-pyrrolo[2,3-b]pyrazine-7-decanoic acid [(R)-2-(3-cyano ratio π each -1-yl)-1 -methyl-2-oxo-ethylbumin

CN

Prepared according to the procedure described in Example 1, wherein Boc-D-tris-leucine was replaced with Boc-D-alanine and pyrrolidine was replaced with pyrrolidine-3-carbonitrile hydrochloride. MS: (M+H)+=353. Example 7. 2-(1-Ethyl-1H-° than sal-4-yl)·5Η-0 ratio p and [2,3-b] n well-7-formic acid 154395.doc •99· 201134826 [ (R)-2-(3-cyano-3-methylpyrrolidin-1-yl)-1-indenyl 2-sideoxy-ethyl]-decylamine

Step 1 Slowly add LiHMDS (1.0 Μ) to a solution of 3-cyanopyrrolidine-1-carboxylic acid tert-butyl ester (1·〇g, 5.1 mmol) in THF (20 mL) at -78 °C. In THF, 5.6 mL, 5.6 mmol). The reaction mixture was stirred at -78 °C for 30 min, then moth-salted (0.48 mL, 7.64 mmol). The reaction mixture was stirred at -78 °C for 30 min then warmed to EtOAc EtOAc. Diluted with EtOAc (2×), EtOAc (EtOAc) Purification of the residue by EtOAc (20% to 40%EtOAcEtOAcEtOAc) Ding-1-carboxylic acid tert-butyl ester. Step 2 A sample of 3-cyano-3-methylpyrrolidine_ι_carboxylic acid tert-butyl ester (〇 5〇 g ' 2.38 mmol) was dissolved in 1.0 M HCl/Me〇H (12 mL). The reaction mixture was stirred at room temperature overnight and then concentrated to give EtOAc EtOAc EtOAc EtOAc EtOAc Step 3 154395.doc •100· 201134826 2-(1-Ethyl-1H-pyrazol-4-yl)-5H-pyrrolo[2,3-b]pyridin-7-carboxylic acid [(R)-2 -(3-cyano-3-indolyl-pyrrolidin-1-yl; fluorenyl-2-yloxyethyl)-guanamine. Prepared according to the procedure described in Example 1, wherein 3-A Substituting pyrrolidine-3-carbonitrile hydrochloride for pyrrolidine and using 2_(1_ethyl_1H_Dbiazole-4.yl)-5-((2_((dimercaptoalkyl)) Oxy)methyl)_5Η-ι1 is substituted with [3,2-b]pyrazine-7-carboxylic acid instead of 2-cyclopropyl-5-(2-trimethyldecyl-ethoxymethyl)- 5H- 0 is 0 to 0 and [2,3-b] «Bit-7-decanoic acid. MS: (M+H)+=463; mp=228.0-230.0. Example 8. 2-Cyclopropyl-5H -pyrrolo[2,3-b]pyridin. Well-7-formic acid [(R)-2-(3-cyano-azetidin-1-yl)-1-methyl-2-oxo G-ethyl]-guanamine

Step 1 Boc-D-alanine (1.0 g, 5.29 mmol) and four succinic acid sulphate-stupid tris-s--1-yl-N,N,N',N'-tetramethyl group (1· 87 g, 5.81 mmol) was dissolved in dichloromethane. 3-Cyanoazetidine hydrochloride (0.94 g, 7.93 mmol) and N,N-diisopropylethylamine (2.3 mL, 13.2 mmol) were added, and the mixture was stirred at room temperature for 16 hr. Water and acetic acid were added to separate and separate the layers. The aqueous layer was extracted with ethyl acetate more than once. The combined organic layer was dried with sodium sulfate (yield and dried over sodium sulfate). The residue was purified by silica gel chromatography (ethyl acetate/hexane) to afford 0.91 g (68%) [(R)-2- (3-Cyanide 154395.doc -101- 201134826 Azetidine·1_yl)_丨_曱yl-2-sided oxyethyl]•T-butyl carbamic acid. Step 2: [(R)_2-(3-Cyano-azetidinylmethyl-2-ylideneoxyethyl]-amino phthalic acid tert-butyl ester (1 〇 5 g ' 3 27 Methyl acetate was dissolved in 4 mL of methylene chloride. The solution was cooled in an ice bath and 1.2 mL of trifluoroacetic acid was slowly added. After 1.5 hours, the reaction was concentrated to give the amine-propionyl-azetidine- 3-carbonitrile trifluoroacetate, which was used without further purification. Step 3 2-Cyclopropyl-5Η-»Birdo[2,3-b] 〇比耕-7-carboxylic acid [(R)-2-(3-cyano-azetidin-1-yl) )-1-fluorenyl-2-p-oxy-ethyl]-decylamine. Prepared according to the procedure described in Steps 3 to 4 of Example 1, wherein α1_((κ)·2·amino-propionyl)-azetidin-3-indene nitrile trifluoroacetate was substituted for (R)_2 Amino-3,3-dimethyl-1-(pyrrolidin-1-yl)butan-1-one hydrochloride. MS: (M+H)+=339. Example 9. 2-Cyclopropyl-5H-. Bis-[2,3-b]&quot;Binyl-7-decanoic acid [(R)-l-(3-cyano-azetidin-1-carbonyl)-2,2-dimethyl -propyl]•guanamine

2 ten /^CN

V was prepared according to the procedure described in Example 8 wherein Boc-O-alanine was replaced by B〇c-D-third leucine. MS: (M+H)+=381. 154395.doc -102- 201134826 Example ίο. 2-Cyclopropyl-5H-pyrrolo[2,3_b]pyrazine_7-carboxylic acid cyano-3-indolyl-azetidin-1-carbonyl)_2,2 -dimercaptopropyl propyl amide

Step 1 3-cyanoazetidine hydrochloride (3 64 g, 3〇7 was suspended in 77 mL of dioxane. Triethylamine (4 3 mL, 3〇7 mm〇1) was added, followed by Di-tert-butyl dicarbonate (8 〇g, 36 8 mm 〇1) was added dropwise. The reaction mixture was stirred for 16 hours, then diluted with aqueous hydrochloric acid and dioxane. The layers were separated and the aqueous layer was extracted with dioxane. The combined organic layer was washed with MgSO.sub.sub.sub.sub.sub.sub.sub.sub.sub.sub.sub. Tributyl hexadecanoate citrate. Step 2 Dissolve 3-cyanoazetidin-1_carboxylic acid tert-butyl ester (〇5 g, 2 74 mmol) in 11 mL THF and react Cool to _78 cc. Add bis((trimethyl sulphate) tyramine (3.02 mL 1 M THF solution, 3.02 mmol) slowly. After 30 min, iodine (o. The reaction mixture was stirred at -78 ° C for 30 minutes, then warmed to room temperature over a period of hr., water and ethyl acetate were added to the reaction, and the layers were separated, and 154395.doc •103·201134826 The aqueous layer was extracted twice more. The combined organic layer was washed with EtOAc EtOAc EtOAc. 3-cyano-3-methyl-cyclohexane-1 -carboxylic acid tert-butyl ester. Step 3 3-Hydroxy-3-methyl-azetidin-1-carboxylic acid tert-butyl Vinegar (ο.〗]g, 1·17 mmol) was dissolved in 12 mL of di-methane, then the reaction was stirred in an ice bath. Trifluoroacetic acid (3.6 mL) was slowly added and the solution was allowed to warm to room temperature. 3 φ hours Thereafter, the reaction mixture was evaporated to give 3-cyano-3-methyl-azetidin trifluoroacetate which was used without further purification. Step 4 2-cyclopropyl-5H-pyrrolo[2,3 -b] pyridin-7-formic acid cyano-3-methyl-azetidine_ι_carbonyl)_2,2-diindolyl-propyl]-guanamine ◎ according to the procedure described in Example 8 Prepared by 3-cyano-3 methylazide

The alkane trifluoroacetate replaces 3-cyanoazetidine hydrochloride and replaces b〇c_d_alanine with Boc-D-third-leucine. Ms: (M+H)+=395. Example 11. 2-Cyclopropyl-5H·Material [2,3 handsome ratio, well_7_carboxylic acid [(r) i (4_ aryl acridine-1·carbonyl)·2,2-dimethyl ·propyl]•guanamine

Wherein the procedure described in Example 1 was used to prepare 154395.doc-104-201134826 «Byrrolidine' and all steps to remove the N-Boc protecting group were replaced with trifluoroacetic acid instead of hydrochloric acid. MS: (M+H)+= 409; mp=249.0-251.0. Example 12· 2-(1-Ethyl-1Η-pyrazol-4-yl)-5Η-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-l-(3-cyano) -3-fluoro-pyrrolidine·ι_carbonyl)·2,2-dimercapto-propyl]-guanamine

Step 1 Add KCN (1.05 g, 16.2) to a solution of 3-tertyloxypyrrolidine-1-decanoate tert-butyl ester (2.0 g, 10.8 mmol) in THF (10 mL) at EtOAc. Methyl) and H2O (10 mL). A solution of sodium hydrogen sulfite (1.69 g, 16.2 mmol) in H.sub.2O (10 mL) was added. The turbid reaction mixture was stirred at 0 °C for 1 hour, then extracted with CHC13 (3x). The combined organic layers were dried over MgSO 4 and concentrated. The resulting pale brown oil was dissolved in CH.sub.2Cl.sub.2 (30 mL) and cooled to -78[deg.] C., then DAST (90%) (1.74 ml, 11.9 mmol). The reaction mixture was stirred at -78 °C for 10 minutes, then warmed to 〇 ° C and stirred for 1 hour. It was carefully quenched with saturated aqueous NaHCO3, then diluted with H.sub.2 and extracted with CH.sub.2CI. The combined organics were dried <RTI ID=0.0>(M </RTI> </RTI> <RTI ID=0.0> Doc -105· 201134826 。 3-Fluoric acid bicinch-1 -carboxylic acid tert-butyl ester. Step 2 To a solution of 3-cyano-3-fluoropyrrolidinel-carboxylic acid tert-butyl ester (240 mg, 1.12 mmol) in CH.sub.2Cl.sub.2 (5 mL). The light yellow reaction mixture was stirred at room temperature for 4 hr then concentrated to a yellow oil and dried under high vacuum. The above oil (23 7 mg '1.04 mmol), (R)-2-(t-butoxycarbonylamino)-3,3-dimercaptobutyric acid (200 mg '0.87 mmol) was combined in a 50 mL flask. And HOBT (146 mg, 0.95 mmol). DMF (4 mL), HATU (362 mg, 0.95 mmol) and N,N-diisopropylethylamine (0.45 mL, 2.59 mmol) were then added. The yellow reaction mixture was stirred with EtOAc EtOAc (EtOAc) The combined organics were washed with 〇 2 〇 (3 χ), then dried over MgSO 4 and concentrated. The crude residue was purified by EtOAc (20% to 50%EtOAcEtOAc) elute Biloxi-1-yl)_3,3-dimethyl-1 -t-oxybut-2-enylcarbamic acid tert-butyl ester. Step 3 To (2R)-l-(3·cyano-3-fluoroindol, each biting-1-yl)_3,3-dimethyl_1_sideoxybutan-2-ylaminocarboxylic acid TCA (2.0 mL, 26.0 mmol) was added to a solution of tributyl ester (234 mg, 0.72 mmol) in CH2C12 (5 mL). The reaction mixture was stirred at room temperature for 3 hours, then concentrated and dried under high vacuum to afford &lt;&quot;&quot;&quot;&quot&&&&&&&&&&&&&&& Pyridine-3-carbonitrile trifluoroacetate, which was used without further purification. 0 154395.doc -106 - 201134826 Step 4 2-(Buethyl-1H-pyrazol-4-yl)-5H-pyrrolo[2, 3_b] Pyridine_7_carboxylic acid [(R)-l-(3-cyano-3-fluoro-pyrrolidine-1-carbonyl)-2'2-dimethyl-propyl]-decylamine. Prepared according to the procedure described in Example 3, steps 3 to 4, wherein

1-((R)-2-Amino-3,3-dimercaptobutyl)-3-fluoropyrrolidine_3-carbonitrile trifluoroacetate instead of (R)-2-amino-3,3-di Methyl-hydrazine 11 is more than -1 -yl) butan-1-indole hydrochloride, and 2-(1-ethyl-1H-pyrazol-4-yl)-5-((2-(( Trimethyldecyl)ethoxy)indolyl)-511-«bibromo[3,2exo]1&gt;Compared with cultivable-7-formic acid instead of 2-cyclopropyl-5-(2-tridecyldecane -Ethoxymethyl)_5H_indolepyr[2,3-b]pyridin-7-carboxylic acid MS: (M+H)+=467. Example 13. 2-Cyclopropyl-5H -° ratio [[2,3-b]. Specific tillage-7-formic acid [(R)-1·((8)_3·cyano-piperidin-1-carbonyl)-2,2-didecyl-propyl ]-Indoleamine and 2-cyclopropyl-5H-n than s-[2,3-b]e than plough-7-carboxylic acid [(R)-l-((R)-3-cyano-piperidine Small carbonyl)-2,2-dimethyl-propyl]-guanamine

Prepared according to the procedure described in Example 1, wherein the piperidine-3-carbonitrile trifluoroacetate was substituted for the piroxicam, and all the steps for removing the N-Boc protecting group used trifluoroacetic acid instead of hydrochloric acid. The non-pair of 154395.doc-107·201134826 isomerized by SiO2 chromatography in step 3. R, S diastereomer, MS: (M+H)+ = 409; R, R diastereomer, MS: (M+H)+=4〇9. Example 14. 2-Cyclopropyl-5Η-0Λ 0 each [2,3-b]° ratio of spray-7-formic acid [(R)-l-((S)-3-carbyl-pyrrolidin-1 -carbonyl)-2,2-dimethyl-propyl]-decylamine

Prepared according to the procedure described in Example 1, in which (s)-pyrrolidine-3-carbonitrile difluoroacetate was substituted for each of the ratios of η and replaced with Fmoc-D-third-leucine for Boc-D. - Third - leucine. The FMOC protecting group is removed in step 2 using a trihydroxydecylaminodecane-polystyrene resin. MS: (M+H)+=395. Example 15. 2-Cyclopropyl-5H-&quot;bibromo[2,3-b]吼井-7-decanoic acid [(RW-GR)·〗·Cyanopyrrolidin-1-carbonyl) ·2,2-dimethyl-propyl]•decalamine

Prepared according to the procedure described in Example 1, wherein (R) _ 〇 _ _ _ _ _ 154 395.doc • 108 · 201134826 nitrile trifluoroacetate instead of pyrrolidine, and Fmoc-D-third-white Amine acid replaces Boc-D-third-leucine. The FMOC protecting group is removed in step 2 using a trihydroxydecylaminomethane-polystyrene resin. MS: (M+H)+=395. Example 16. 2-Cyclopropyl-5H-pyrrolo[2,3-b]pyrh-7-nonanoic acid [(R)-2-(4-cyano-piperidin-1-yl)-2- 2-oxo-1-(1-trifluorodecyl-cyclopropylpolyethyl)•decalamine and 2-cyclopropyl-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [( S)-2-(4-cyano-piperidin-1-yl)-2-oxo-l-(1-trifluoromethylcycloprop)-ethyl]-decylamine

Prepared according to the procedure described in Example 1, in which pyrrolidine was replaced by 0-inch nitrile and Boc was replaced by NB〇C-2-(l-trifluoromethylcyclopropyl)_DL_glycine. -D-Third-leucine, and all the steps of removing N_B〇 (the step of protecting the base are to use trifluoroacetic acid instead of hydrochloric acid. In step 3, the R and S are separated by chromatographic preparation of sfc. R. enantiomer, (M+H)+=46i; S enantiomer, (M+H)+=461. Example 17. 2-cyclopropyl-5H-n ratio And [2,3 aspect ratio, well.7_carboxylic acid ((called · cyclohexyl · 2_ sideoxy-2-0 piroxime-1-yl-ethyl) _ decylamine 154395.doc • 109 · 201134826

Prepared according to the procedure described in Example 1 in which Boc-D-trihexylglycine was replaced by Boc-D-cyclohexylglycine. MS: (M+H)+=396. Example 18. 2-Cyclopropyl-5H-pyrrolo[2,3-b]pyrazine-7-decanoic acid [(R)-l-(4,4-difluoro-piperidine-1_yl) )-2,2-dimethyl-propyl]-bristamine

Prepared according to the procedure described in Example 1, in which pyrrolidine was replaced with 4,4-difluoropiperidine hydrochloride. MS: (M+H)+=420. Example 19. 2-Cyclopropyl-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2,2-dimethyl-indole-difluoro | methyl-nivine. Ding-1-rebase)-propyl]-bristamine

154395.doc -110· 201134826 Prepared according to the procedure described in Example 1, wherein 4-(trifluoromethyl)piperidine hydrochloride was replaced by a ratio of n to n. MS: (M+H)+=452. Example 20. 2-Cyclopropyl-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-l-(4-cyano-piperidin-1-carbonyl)-3-methyl G-butyl]-guanamine

Prepared according to the procedure described in Example 1, wherein Boc-D-tris-leucine was replaced with B?c-D-leucine and pyrrolidine was replaced with piperidin-4-indene. All of the steps for removing the N-Boc protecting group used trifluoroacetic acid. MS: (M+H)+= 409 ° Example 21. 2-cyclopropyl-5Η-pyrrolo[2,3_b]° ～h-7·decyl-2-yloxy-2-pyrrolidine- 1-yl-ethyl)-decylamine

Prepared according to the procedure described in Example i, in which Boc-D-tris-leucine was replaced with Boc-D-alanine. MS: (M+H)+=328; mp=237.0- -Ill - 154395.doc 201134826 239.0 » Example 22. 2-Cyclopropyl-5H-pyrrolo[2,3-b]pyrazine-7-formic acid ((...-丨-Methyl-2-oxo- 2-β-bottom-1-yl-ethyl)-decylamine

Prepared according to the procedure described in Example 1, in which piperidine was substituted for the pyrrole bite and Boc-D-alanine was substituted for Boc-D-third-leucine. MS: (M+H)+=342; mp=190.0-192.0. Example 23. 2-Cyclopropyl-5H-0 piroxi[2,3-b]. Ratio p well-7-formic acid [(r)_b (. piroxime-bucarbonyl)-propyl]-guanamine

Prepared according to the procedure described in Example 1 in which Boc-D-aminobutyric acid was substituted for Boc-D-tris-leucine. MS: (M+H)+=342; mp=240.9-242.5 〇Example 24. 154395.doc .112- 201134826 2-Cyclopropyl-5H-0 Biluo[2,3-b]0 ratio p well -7-carboxylic acid [(R)-2-methyl·ι_(0-pyridyl-1 -carbonyl)-propyl]-decylamine

Prepared according to the procedure described in Example 1, in which Boc-D-tris-leucine was replaced with Boc-D-proline. MS: (M+H)+=356; mp=l71.0-172.1 » Example 25. 2-Cyclopropyl-5H-pyrrolo[2,3-b]pyridin-7-decanoic acid ((R) -l-cyclopropyl-2-indolyl-2 -D ratio 定··1·yl-ethyl)-nitramine

Prepared according to the procedure described in Example 1, in which Boc-D-tris-glycine was replaced by Boc-D-cyclopropylglycine. MS: (M+H)+=354; mp= 254.0-256.0 ° Example 26. 2-Cyclopropyl-5H-pyrrolo[2,3_b]pyrazine-7-decanoic acid [(R)-2-indole -1(piperidin-1-carbonyl)-propyl]-nonylamine 154395.doc -113- 201134826

Prepared according to the procedure described in Example 1, in which the bite was replaced by a bite, and Boc-D-tereic acid was replaced by Boc-D-alginic acid. MS: (M+H)+=370; mp=l83.0-185.0. Example 27. 2-Cyclopropyl-5H-. Bisolo[2,3-b]pyridin-7-carboxylic acid [(R)-2-indolyl 1-(morpholin-4-carbonyl)-propyl]-guanamine

Prepared according to the procedure described in Example 1, in which morphine was replaced by hydrazine and replaced with Boc-D-proline to B〇C-D-third-leucine. Ms: (Μ+Η)+= 372 ; mp=154.0-156.0 ° Example 28. 2-Cyclopropyl-5H-pyrrolo[2,3-b]pyridin-7-carboxylic acid [(R)-2- (3-methoxy.pyrrolidin-1-yl)-1-indolyl-2-oxo-ethyl]-decylamine

154395.doc • 114- 201134826 Prepared according to the procedure described in Example 1, in which pyrrolidine was replaced by 3-methoxypyrrolidinium hydrochloride, and B〇c D was replaced by Boc_D_alanine. . MS: (M+H)+=358. Example 29· 2-Cyclopropyl-5H-pyrrolo[2,3-b]pyrazine-7-decanoic acid [(R)-2-(3-hydroxy·.pyrrolidin-1-yl)-1 -methyl-2-oxo-ethyl]-decylamine

Prepared according to the procedure described in Example 1, wherein 3-hydroxypyrrolidine was substituted for pyrrolidine and Boc-D-alanine was substituted for Boc-D-third-leucine. MS: (M+H)+=344 ° Example 30. 2-Cyclopropyl-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-l-methyl-2-( 3-methyl-.pyrrolidin-1-yl)-2-oxo-ethyl]•decylamine

Prepared according to the procedure described in Example 1, wherein 3-pyridylpyrrolidinium 154395.doc •115-201134826-propyrrolidine and Boc-D-alanine were substituted for Boc-D-third-leucine. MS: (M+H)+=342. Example 31. 2_Cyclopropyl-5H-0 ratio slightly [2,3-b]0 to p-well-7-decanoic acid [(R)-1 -methyl-2-(2-methyl-pyrrole) Pyridin-1-yl)-2-oxo-ethyl]-decylamine

Prepared according to the procedure described in Example 1, wherein 2-methylpyrrolidine was substituted for pyrrolidine and Boc-D-alanine was substituted for Boc-D-third-leucine. MS: (M+H)+=342. Example 32· 2-Cyclopropyl-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [2,2,2-trifluoro-1-(pyrrole0-1-amino)-B Amine

Step 1 In a 5〇11^ round bottom flask, 3,3,3-trifluoro-0[-alanine (〇.60, 4-2 mmol) was suspended in EtOAc (10 mL). Add ethylamine (〇7〇 154395.doc • 116·201134826 11^, 5.〇111111〇1) and di-tert-butyl dicarbonate (1〇§,46111111〇1). The light yellow solution was stirred at room temperature over the weekend. The reaction mixture was diluted with about 丨〇〇 mL dichloromethane and washed with about 15 mL of aq. The aqueous layer was extracted with about 1 mL of methane. The organic layer was combined, dried over sodium sulfate EtOAcjHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH . Step 2 2-Cyclopropyl-5H-pyrrolo[2,3-b]pyrazine-7-decanoic acid [2,2,2-trifluoro-b (.bitter than 1-carbonyl)-ethyl ]_醯amine. Prepared according to the procedure described in Example 1, wherein 2-tert-butoxycarbonylamino-3,3,3-trifluoro-propionic acid was replaced

Boc-D-third-leucine. MS: (M+H)+=;382. Example 33. 2-Cyclopropyl-5H-pyrrolo[2,3-b]indole -7-carboxylic acid [(R)-2-((S)_3-fluoro-0-pyridin-1-yl) )-1-methyl-2-oxo-ethyl]-decylamine

Prepared according to the procedure described in Example 1 wherein (S)-3-fluoropyrene hydrochloride was substituted for pyrrolidine and B〇c_D_alanine was substituted for Boc-D-third-leucine. MS: (M+H)+=346. Example 34. 2-Cyclopropyl-5H-pyrrolo[2,3_b]pyrazine_7_carboxylic acid [(R)-2-((R)-3-fluoro-pyridyl 154395.doc •117- 201134826 -1-yl)-1·fluorenyl·2_sideoxy-ethyl]-decylamine

Prepared according to the procedure described in Example 1 wherein (R)_3_fluoropyrrolidine hydrochloride was substituted for the ratio of pyrrolidine and Boc-D-alanine was substituted for Boc-D-third-leucine. MS: (M+H)+=346. Example 35. 2-Cyclopropyl-5Η-»birdo[2,3_b]pyrazine_7-decanoic acid methyl-2-oxoxy-2-(3-trifluoromethylpyrrolidine·丨_ Base)_ethyl]-decylamine

Prepared according to the procedure described in Example 1, wherein 3-(trifluoromethyl)pyrrolidine hydrochloride was substituted for pyrrolidine and Boc-D-alanine was substituted for Boc-D-tris-leucine. MS: (M+H)+=396. Example 36. 2-Cyclopropyl-5H-pyrrolo[2,3-b]pyrh-7-carboxylic acid [(R)-2,2-dimethyl-1-(piperidin-1-carbonyl)- Propyl]-nonylamine 154395.doc -118· 201134826

Prepared according to the procedure described in Example 1, in which piperidine was substituted for pyrrolidine. MS: (M+H)+==384. Example 37. 2-Cyclopropyl-5H-pyrrolo[2,3-b]pyrazine_7•carboxylic acid [(R)_2_(3-cyano-azetidin-1-yl)-1- Cyclopentyl-2-sided oxy-ethyl]-decylamine

Prepared according to the procedure described in Example 12, in which Boc-D-alanine was replaced by b〇c_d_cyclopentylglycine. Ms: (m+H)+=393. Example 38. 2-1⁄4 propyl-5H-pyrrolo[2,3_b]pyridin-7-formic acid-difluoro-pyridyl

154395.doc • 119· 201134826 Prepared according to the procedure described in Example 1, in which the ratio of beloridine was replaced by 3,3-difluoropyrrolidine hydrochloride. MS: (M+H)+=406. Example 39. 2-Cyclopropyl-5H-. Ratio of [2,3-b]° to p-well-7-formic acid [(r)_i_(3,4-di-argon-1H-isoquinoline-2-carbonyl)-2,2-didecyl- Propyl]-guanamine

Prepared according to the procedure described in Example 1, in which pyrrolidine was replaced with 1,2,3,4-tetrahydroisoquinoline. MS: (M+H)+=432. Example 40. 2-Cyclopropyl-5H-0 piroxime [2,3-b]° ratio __7-carboxylic acid [(R)-i-(4-carbyl-4-mercapto-0 bottom bite - 1-reactive)-2,2-dimethyl-propyl]-bristamine

Step 1 4-Cyanopitrile-1-carboxylic acid tert-butyl ester (〇.70 g, 3.3 mmol) was dissolved in THF (14 mL). The solution was cooled to -76 ° C and bis((trimethyldecyl) guanamine lithium (1.0 154395.doc • 120-201134826 in THF, 3.7 mL, 3.7 mmol) was added dropwise over 15 min. The yellow solution was stirred at _76 〇c for 3 Torr, then iodonane (0.32 mL, 5 &gt; 1 mm 〇1) was slowly added. The reaction mixture was stirred at 768 ° for 30 minutes and then warmed to room temperature over a hydr. The reaction mixture was quenched with EtOAc EtOAc (EtOAc)EtOAc. The residue was purified by EtOAc / EtOAc (EtOAc:EtOAc). In the bottom flask, 4-cyano-4-indenyl-pyro-_ι-carboxylic acid tert-butyl ester (〇·35 g '1.56 mmol) was dissolved in 1. 〇]^ gasification hydroquinone solution (9〇 The mixture was stirred at room temperature overnight, then concentrated to give &lt;RTI ID=0.0&gt;&gt;&&&&&&&&&&&&& It is used. Step 3 2-Cyclopropyl-5H-pyrrolo[2,3-b]pyrazine-7-decanoic acid [(R)-l-(4-cyano-4-methyl-tripidine -i-yl) 2,2-dimethyl-propyl]-nonylamine. Prepared according to the procedure described in Example i, in which the pyrrole was replaced by 4·mercapto-piperidine-4-carbonitrile hydrochloride Acridine. MS: (M+H)+= 423. Example 41. 2_cyclopropyl-5H-pyrrolo[2,3-b]pyr, well-7-decanoic acid [(R)-2-(4 -cyano-piperidin-1-yl)-1_cyclopentyl_2_sideoxy-ethyl]-decylamine 154395.doc •121- 201134826

Prepared according to the procedure described in Example 1, in which piperidin-4-phthalonitrile was substituted for &quot;bibromopyridine and Boc-D-cyclopentylglycine was substituted for Boc-D-third-leucine- All steps in the removal of the N-Boc protecting group used trifluoroacetic acid instead of hydrochloric acid. MS: (M+H)+=421. Example 42. 2-Cyclopropyl-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-l-benzyl-2-(4-cyano)piperidin-1-yl -2-sided oxy-ethyl]-decylamine

Prepared according to the procedure described in Example 1, wherein pyridinium was replaced by piperidine-4 carbonitrile and B〇c_D third leucine was replaced by Boc-D-phenylalanine, and all N-Boc protecting groups were removed. The steps used all of them to replace hydrochloric acid with trifluoroacetic acid. MS: (M+H)+=443. Example 43. 2-Cyclopropyl·5Η·t each [2,3 handsome ratio _·7·carboxylic acid primal 154395.doc •122· 201134826 bite-1-carbonyl)-3,3-didecyl -butyl]-guanamine

Prepared according to the procedure described in Example 1 in which piperidine-4, carbonitrile was substituted for pyrrolidine and Boc-β-tert-butyl-D-alanine was substituted for B〇c_D_third · leucine All steps in the removal of the N-Boc protecting group used triacetic acid instead of hydrochloric acid. MS: (M+H)+=423. Example 44. 2-(3,5-Bis-Trifluoromethylphenyl)-5pyrrolo[2,3_b]pyrazine_7-decanoic acid [(R)-l-(4-cyano- Piperidin-1-yl)_2,2·dimethyl-propyl]-decylamine

Prepared according to the procedure described in Example 2, in the step 1, replacing the amine group _3,3- with an amine group of mono-dimethyl-butanyl bromide-' acetonitrile trifluoroacetate. · One base -1-. Bilo-1-yl-butan-1-indole hydrochloride and in step 2, 3,5-bis-trifluoromethyl-phenyl-acid is substituted for 1-ethyl than 〇4_facial acid 154395.doc •123· 201134826 Pinacol ester. MS: (M+H)+=581. Example 45. 2-(3-Pyrrolidin-1-yl-phenyl)-5H-pyrrolo[2 3_b]pyrazole-7carboxylic acid [(r)·1_(4·cyano-piperidin-1-carbonyl) )-2,2·dimethyl-propyl]-decylamine

Prepared according to the procedure described in Example 2, substituting in step 1 with 丨_((r)_2-amino-3,3-dimethyl-butanyl)-piperidine-4-carbonitrile trifluoroacetate ( r)_2_Amino-3,3-dimethyl-1-pyrrolidin-1-yl-butan-one keto hydrochloride and 3-(1-pyrrolidinyl)phenyl-acid in step 2 Hydrochloric acid replaces 丨_ethyl_1H_pyrazole-guanine acid pinacol ester. MS: (M+H)+=514. Example 46. 2-(1-Methyl-1H-pyrazol-4-yl)-5H-pyrrolo[2,3-b]pyrazine-7_f acid [(R)-l-(3-cyano) -azetidin-1-carbonyl)-2,2-dimercapto-propyl]-bristamine

Prepared according to the procedure described in Example 1, in which cyanopyridine was replaced by 3-cyanoazetidine 154395.doc •124·201134826 alkane hydrochloride and 2-(1-methyl-1H•pyrazole·4_ )5_((2_((trimethyl decyl) ethoxy)methyl)-5H-pyrrolo[3,2-b]pyrrolin-7-nonanoic acid instead of 2-cyclopropyl-5-( 2-二曱基石石院_ethoxymethyl)_511〇 ratio n[2,3-b]pyrazine-7-decanoic acid. All the steps of removing the NB〇c protecting group use trifluoro Acetic acid replaces hydrochloric acid. MS: (M+H)+=421. Example 47. 2·(1Η-η ratio β sits _4_ base)-5H-0 ratio slightly [2,3-b] ° ratio tillage-7 - cyano-piperidin-1-carbonyl)-2,2-dimethyl-propyl]-guanamine

Prepared according to the procedure described in Example 2, substituting (1^)_2_amino-3 in the step 1 with amino-3,3-dimercapto-butenyl)-nitrient _4-carbonitrile trifluoroacetate , 3-Dimethyl-1-pyrrolidin-1-yl-butan-1-one hydrochloride and in the step 2 is in the 1-Boc-n ratio. Instead of 1-ethyl-1H-, sit -4-monic acid pinacol ester. Than &quot; sit -4- 酉 acid acid pinacol ester. MS: (M+H)+=435. Example 48. 2-(1-Methyl-1H-pyrazol-4-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-l-(4-) -Bit bite -1 prison base)_2,2_Dimethyl-propyl]•Stew amine 154395.doc -125- 201134826

Prepared according to the procedure described in Example 2, in step 1, replaced with 1-((R)-2-amino-3,3-dimethyl-butanyl)-piperidine-4-carbonitrile trifluoroacetate (R)_2_Amino-3,3-dimethyl-1-pyrrolidine-buyl-butan-1-one hydrochloride and in step 2 is 1-mercapto-1H-. The ratio of 1-ethyl-lH-n is replaced by the bis--4-amino acid pinacol ester. Sit _ 4-face acid pinacol ester. MS: (M+H)+=449. Example 49. 2-(1-Ethyl-1H-pyrazol-4-yl)·5Η-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-l-(4-cyano) -piperidin-1-carbonyl)·2,2-dimethyl-propyl]-guanamine

Prepared according to the procedure described in Example 2, substituting ((M)-amino-3,3-dimercapto-butenyl)-piperidine-4-carbonitrile trifluoroacetate in step J (R) _2_Amino-3,3-dimethyl-1-pyrrolidinyl-butanone hydrochloride. MS: (M+H)+= 463. Example 50· 154395.doc •126- 201134826 2-( 3,4,5-trimethoxyoxyphenyl)-5H-pyrrolo[2,3-b]pyrazine-7-decanoic acid [(R)-l-(4-cyano-piperidine-1 -carbonyl)-2,2-dimercapto-propyl]-guanamine

Prepared according to the procedure described in Example 2, substituting l-((R)-2-amino-3,3-dimercapto-butenyl)-piperidine-4-carbonitrile trifluoroacetate in step 1. (R)_2-Amino-3,3-dimethyl-1-D-Bile-1-yl-butan-1-indole hydrochloride and in step 2 with 3,4,5-trimethoxy Phenyl g-p-acid replaces 1-ethyl-1H-pyrazole-4-tanoic acid pinacol ester. MS: (M+H)+=535. Example 51. 2-(2,5-Dimethoxy-phenyl)-5H-0 piroxi[2,3-b] ratio 井-7-decanoic acid [(R)_ 1-(4- Cyano-piperidin-1-carbonyl)-2,2-dimercaptopropyl]-decylamine

CN was prepared in step 1 by replacing l-((R)-2-amine-difluoroacetate with (R)-2- according to the procedure described in Example 2, benzyl-3,3-dimercapto-butenyl) _ piperidine_4_甲154395.doc •127· 201134826 Amino-3,3-dimethyl-1-. Bilo bitten-1-yl-butan-1-one hydrochloride and in step 2 replaces 1-ethyl-1H-pyrazole_4_gmin acid with 2,5-dimethoxyphenyl tanning acid Alcohol ester. MS: (M+H)+=505. Example 52. 2-Cyclopropyl-5H-pyrrolo[2'3-b]pyridin, well-7-formic acid [(R)]-(4-ethyl-branched-piperidin-1-carbonyl)-2, 2-dimethyl-propyl]-guanamine

Prepared according to the procedure described in Example 1, in which pyrrolidine was replaced by 1-ethylhydrazinepipe 7 well. MS: (M+H)+=427. Example 53. 2-(1-Methyl-1H-pyrazole-4-yl)_5Η·pyrrolo[2,3-b]. Comparison _7_formic acid

• 4-Base)-5_ Prepared according to the procedure described in Example 1 wherein (S)~ each bite_3·carbonitrile triacetate acetate was substituted for pyrrolidine and 2-(1-methyl-1H-. Biazole _4_某, &lt; 154395.doc 128· 201134826 ((2-((trimethyl decyl) ethoxy) fluorenyl) _5H-n ratio 咯[3,2_b]lItb „ well. 7 -carboxylic acid instead of 2-cyclopropyl-5-(2-trimethyldecyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-decanoic acid. All de-N-Boc The step of protecting the group uses trifluoroacetic acid instead of hydrochloric acid. MS: (M+H)+=435. Example 54. 2-(1-methyl-1H-0 ratio σ-s--4-yl)-5H-0 ratio °[2,3-b]0 ratio p well·7-formic acid [(foot)-1-((11)-3-cyano-° ratio 17 °°-1-amino)-2, 2-dimercapto-propyl]-decylamine

Prepared according to the procedure described in Example 1, wherein (R)-pyrrole bit _3. carbonitrile trifluoroacetate was substituted for pyrrolidine and 2-(1-methyl-1H-pyrazol-4-yl)- 5-((2-((Trimethyl sulphate))ethoxy) fluorenyl)-5H-° piroxi[3,2-b] »Compound _ 7-carboxylic acid instead of 2-cyclopropyl-5 -(2-tridecylidenealkyl-ethoxymethyl)_5H_pyrrolo[2,3-b]pyrazine-7-carboxylic acid. All steps for removing the N-Boc protecting group use trifluoroacetic acid instead of hydrochloric acid. MS: (M+H)+=435. Example 55. 2_Cyclopropyl-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(4-cyano) -piperidin-1-yl)-1-cyclopropyl-2-oxo-ethyl]• decylamine 154395.doc -129- 201134826

Prepared according to the procedure described in Example 1, in which pyrrolidine was replaced by 0 曱 曱 曱 且 且 且 且 且 且 且 且 且 且 且 且 。 。 。 。 。 。 在 在 在 在 在 在 在 在The 2,2,2·trifluoroethanol was used to remove the N_B〇c protecting group. MS: (M+H)+=393. Spring Example 56. 2-(1-mercapto-1H-.biazole- 4-yl)-5H-nb abbreviated [2,3-b]. Specific cultivative-7-decanoic acid [(R)-2-(4-cyano-substitudin-1-yl)-1-cyclopropyl_ 2-sided oxy-ethyl]-decylamine

Prepared according to the procedure described in Example 1, wherein pyridinium was replaced by piperidine-4-carbonitrile, and B〇c_D_third·leucine was replaced by Boc-D·cyclopropylglycine, and 2- (1-methyl-1H-pyrazol-4-yl)-5-((2-((trimethylsulfonyl)ethoxy)methyl)-5H-° ratio)[3,2 -b]° Instead of cultivating -7-decanoic acid instead of 2-cyclopropyl-5-(2-trimethylglycine-ethoxymethyl)-5H-. The ratio is slightly [2,3-b]. The n-b〇c protecting group was removed using 2,2,2-trifluoroethanol in a microwave reactor. MS: (M+H)+=433. 154395.doc •130- 201134826 Example 57. 2-(1-Ethyl-1H-pyridinyl)-5H-pyrrolo[2,3_b]pyrimidin-7-carboxylic acid [(R)-2-(3-cyano-azetidine) Alkan-1_yl)_1_methyl·2_sideoxy-ethyl]-decylamine

Prepare 'wherein 3-cyanoazetidine hydrochloride in place of pyrrolidine' with B〇C_D_alanine instead of Boc-D-third-leucine, and 2-(()乙ethyl-1H-° ratio 0 -4-yl)-5-((2-((trimethylglycine)ethoxy)methyl)-5Η-βpyrho[3,2-b]pyridyl Plowing -7-carboxylic acid instead of 2-cyclopropyl-5-(2-trimethyldecyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-formic acid. The step of removing the N-Boc protecting group uses trifluoroacetic acid instead of hydrochloric acid. MS: (M+H)+=393. Example 58. 2-(1-Ethyl-1H-pyrazole-4-yl)_5H•pyrrole And [厶弘...pyridin_7_carboxylic acid [(R)-2-(4-cyano-piperidinyl]-yl)-丨_methyl·2_sideoxy-ethyl]-decylamine

154395.doc • 131 - 201134826 Prepared according to the procedure described in Example 1 with the replacement of pyrrolidine with piperidine 4-carbonitrile and Boc-D-third-leucine with Boc-D-alanine, And 2_(1-ethyl-11^ ratio. Sit-4-yl)-5-((2-((trimethylglucenyl)ethoxy)methyl)-5H-pyrrolo[3,2 -b]pyrazine-7-decanoic acid instead of 2-cyclopropyl_5_(2·trimethylsulfanyl-ethoxymethyl)-5H-. Ratio 11 and [2,3-b]0 The p-well-7-decanoic acid. All the steps of removing the N-Boc protecting group used trifluoroacetic acid instead of hydrochloric acid. MS: (M+H)+=421. Example 59. 2-Cyclopropyl-5H-pyrrole And [2,3-b]pyrazine-7-carboxylic acid ((R)-2-azetidin-1-yl-1-methyl-2-oxo-ethyl)-nitramine

Prepared according to the procedure described in Example 1, which was replaced with azetidine hydrochloride. It is more specific than bromide and replaces b〇c-D-third-leucine with Boc-D-alanine. All steps in the removal of the N-Boc protecting group used trifluoroacetic acid instead of hydrochloric acid. MS: (M+H)+=314. Example 60. 2-Cyclopropyl-5H-0 to 11 and [2,3-b]° than well-7-decanoic acid [(R)-1-indolyl-2-(2-oxo-6) -aza-spiro[3.3]hept-6-yl)-2-oxo-ethyl]-decylamine 154395.doc •132- 201134826

Prepared according to the procedure described in the real m, in which 2_gas _6___ snail [3.3] heptane (a) sigh ~. C heart m. / rape 2 〇〇 8, 4512) instead of pyrrole bite and Boc-D • Alanine replaces Boc_D_third leucine. Removal of the n_b〇c protecting group was achieved using 2,2,2-tri Iethanol in a microwave reactor. Ms: (M+H)+=356. Example 61. 2-(1-Ethyl-m-pyrazole-4-yl)_5Η·pyrrolo[2,3_b]pyrazine·7-carboxylic acid [(R)-l-(l-fluorenyl-cyclopropane Base)-2-yloxy_2_. Than a little bite

Step 1 Add pcc (5 51 g, 25 5 at room temperature) to a solution of (1-mercaptocyclopropyl)methanol (2.0 g, 23 2 mm 〇1) in CH 2 Cl 2 (1 mL) The dark brown reaction mixture was allowed to stand overnight. The reaction mixture was filtered through a pad of Celite, and washed with CH2C12W. The filtrate was concentrated at ambient temperature. The crude brown oily residue was passed through 2 &quot; Rinse with CH2Cl2. 154395.doc • 133- 201134826 Concentrate the filtrate at ambient temperature to obtain 2.4 g of light yellow-green oil in the form of 1-mercapto-cyclopropanone-a-path, which is used without further purification. Add (S)-2-amino-2-phenylethanol (2.74 g, 20.0 mmol) and MgS〇4 (3 g) ^ to a solution of cyclopropanecarboxaldehyde (1.85 g, 22.0 mmol) in CHC13 (30 mL) The turbid reaction mixture was stirred at room temperature for 3 hours 'then filtered' washed with CHCl3 (1 mL), cooled to &lt;RTI ID=0.0&gt;&&&&&&&&&&&&&&& The orange reaction mixture was stirred at ° C for 1 h then warmed to rt overnight. The mixture was quenched with &lt;RTI ID=0.0&gt; It was neutralized with a 1% aqueous solution of Na〇H and extracted with CH.sub.2.sub.2, and the combined organics were dried over <RTIgt; </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; After 1 minute, at this time, the oxime alkyl group was removed. It was extracted with CHKh (2 χ), dried over MgS04 and concentrated. The residue was purified by si 〇 2 chromatography (ίο% to 30% Et0Ac/hexane). 1.0 g (22%) of a single diastereomer (R) 2 -((s) 2 -hydroxy-1-phenylethylamino)-2-(1-indolylcyclopropyl)acetonitrile as a colorless oil. Step 3 Dissolve (R)-2-((S)-2-carbyl-1-phenylethylamino)_2_(1曱-cyclopropyl)acetonitrile (1.0 g '4.3 mmol) in 6 M HCl aqueous solution (1 〇, 6 〇〇 mm 〇 1) and heated at 10 (TC for 2 hrs. The reaction mixture was cooled to room temperature and slowly adjusted to pH = 8 using 4 M NaOH. The resulting white precipitate was collected via the transition and Drying under high vacuum gave 〇34 g of product. The filtrate was evaporated to a white solid, which was then triturated with a small portion of cold water, filtered and dried, then </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; The yield was [ο g (92%) (R) -2 - ((S) -2- hydroxy-1-phenylethyl) -2 (1-methylcyclopropyl) acetic acid. Step 4 Suspension of (R)-2-((S)-2.hydroxy-1-phenylethylamino)·2_(ι-methylcyclopropyl)acetic acid (1.0 g, 4.0 mmol) in Me〇H (50 mL). 1.0 HCl in MeOH (4.0 mL, 4.0 min 〇l) was added and all solids were dissolved to give a colorless solution. Add 10°/. Pd/C (l〇〇 mg) and stir overnight under h2 balloon. The reaction mixture was filtered with EtOAc (EtOAc)EtOAc. The filtrate was concentrated to a viscous white solid (1.0 g). Wet-milling with Et20 gave 700 mg of (R)-2-amino-2-(1-methylcyclopropyl)acetic acid hydrochloride as a white solid. Step 5 Add to a suspension of (R)-2-amino-2-(1-indolylcyclopropyl)acetic acid hydrochloride (664 mg, 4.0 mmol) in 1,4-dioxane (8 mL) Ίο μ NaOH in water (4.0 mL, 4.0 mmol). All solids were dissolved to give a colorless solution. Add ditributyl dicarbonate (875 mg '4.0 mmol) and stir vigorously overnight at room temperature. The reaction mixture was diluted with Ηβ, neutralized with 1. 〇 μ HC1 and extracted with CH 2 C 12 (3×). The combined organics were dried over MgS 4 and concentrated to a viscous colourless oil. It was wet-milled with petroleum ether for several hours to obtain ruthenium (42 g) (46%) of two portions of (R)tributoxycarbonylamino-(1-methyl-cyclopropyl)-acetic acid as a white solid. Step 6 2_(1·Ethyl-1H-pyrazole·4-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [() 1 (1-methyl-cyclopropyl) _2_Sideoxy_2-π piroxime_ι_yl-ethyl]-bristamine. Prepared according to the procedure described in Example 1, wherein (R)·T-butoxy 154395.doc -135- 201134826 carbonylamino-(1-methyl-cyclopropyl)-acetic acid was substituted for Boc-D- Tri-leucine and 2-(1-ethyl-1Η-π ratio -4-yl)-5-((2-((trimethyl fluorenyl)ethoxy)methyl)-5H-pyrrole And [3,2-b]pyrazine-7-carboxylic acid instead of 2-cyclopropyl-5-(2-tridecylfluorenyl-ethoxymethyl)_5Η·pyrrolo[2,3-b]pyridin Plough-7-decanoic acid MS: (M+H)+=422. Example 62. 2-Cyclopropyl-5H-pyrrolo[2,3-b]&quot;Bist -7-carboxylic acid [(R) -l-(4-Hydroxy-4-phenyl-piperidine-1-carbonyl)-2,2-dimercapto-propyl]-guanamine

Step 1 A round bottom flask was charged with Boc-D-third-leucine (0.30 g, 1.3 mmol), 4-hydroxy-4-phenylpiperidine (345 mg, 1.95 mmol), HOBT (218 mg ' 1.43 mmol) and EDC (274 mg, 1.43 mmol). Then DMF (6 mL) and N,N-diisopropylethylamine (0.34 m, 1.95 mmol) were added sequentially. The pale yellow reaction mixture was stirred at rt EtOAc then EtOAc (EtOAc) The organic layers were combined, washed twice with water and brine brine then dried over sodium sulfate. The residue was purified by flash chromatography eluting EtOAc (EtOAc) 201134826 Tetylene butyl)-2,2-dimethyl-propyl]-aminocarbamate. Step 2 In a 5 mL microwave vial was charged [(r)_ ι·(4-pyridyl-4-phenyl-piperidine-i-carbonyl)-2,2-dimethyl-propyl]-amino group T-butyl citrate (0.20 g, 0.51 mmol) and 2,2,2-trifluoroethanol (2.6 mL). The vial was flushed with argon, then sealed and heated at 150 ° C under microwave irradiation for 4 hours. Concentration of the reaction mixture 'obtained 0.19 g of (r) 2 -amino-1-(4-hydroxy-4-phenyl-piperidin-1-yl)-3,3-didecyl-butyl-1 - Ketone, which was used without further purification. Step 3: In a round bottom flask was charged 2-cyclopropyl-5-((2-((tridecyl)alkyl)ethoxy)indolyl)-5H- Pyrrolo[2,3-b]pyrazine-7-decanoic acid (0.12 g, 0.36 mmol), (R)-2-amino-1-(4-hydroxy-4-phenylpiperidin-1-yl -3,3-Dimercaptobutan-1-one (191 mg, 0.49 mmol), HOBT (61 mg, 0.40 mmol) and EDC (76 mg, 0.40 mmol), followed by sequential addition of DMF (1.6 mL) And N,N-diisopropylethylamine (〇·ΐ2 ml, 0.68 mmol). The pale yellow reaction mixture was stirred at room temperature over the weekend, then quenched with water and extracted with diethyl ether (2×). , and washed twice with water and once with brine, then dried over sodium sulfate, filtered and concentrated.

The residue was purified with EtOAc EtOAc EtOAc (EtOAc:EtOAc) _5H-. More than [2,3-b]. Specific cultivar-7-formic acid [(R)-l-(4-hydroxy-4.phenyl-piperidine-indolyl)-2,2-dimercapto-propyl]-guanamine. Step 4 154395.doc -137- 201134826 In a round bottom flask, 2-cyclopropyl-5-(2-tridecyldecyl-ethoxycarbonyl)-5H-.比 并 [2,3_b]II than cultivating hydroxy _4_phenyl _ 0 bottom -1-amino)-2,2-dimethyl-propyl]-decylamine (0.21 g, 〇. 33 mmol) was dissolved in acetonitrile (4.2 mL). 18-crown-6 (89 mg, 0.33 mmol) and fluorinated planer (507 mg, 3.34 mmol) were added. The reaction mixture was stirred overnight at 85 ° C and then stirred at room temperature for 24 hours. Adding Shiqi gum (about 1 g) to the reaction mixture, and concentrating the suspension and chromatography by 12 g si〇2 with 0 -100% EtOAc / heptane to 〇 〇 〇% Me 〇 H / EtOAc / Wet-milled with di-methane/hexane to obtain 45 mg (26%) of a yellow powder of 2-cyclopropyl-5H-pyrrolo[2,3-b]pyrazine-7-decanoic acid [(R)-l -(4-Hydroxy-4-phenyl-piperidin-1-carbonyl)-2,2-dimercapto-propyl]-decylamine. MS: (M+H)+=476. Example 63

2-Cyclopropyl-5H-pyrrolo[2,3_b]pyrazine-7-carboxylic acid methyl-2-oxo-2-pyrrolidin-1·yl·ethyl)-decylamine. Prepared according to the procedure described in the Examples, in which Boc-L-third-leucine was replaced with Boc-L-alanine. Removal of the protecting group was achieved using 2,2,2-trifluoroethanol in a microwave reactor. MS: (M+H)+=328. Example 64. 2-Cyclopropyl-5H-pyrrolo[2,3-b]pyrazine-7·carboxylic acid ((yq methyl_2_J oxygen 154395.doc •138- 201134826 base_2-piperidine-1 -yl-ethyl)-bristamine

Prepared according to the procedure described in Example 1 wherein piperidine was substituted for pyrrole and Bod-alanine was substituted for Boc-D_third leucine. Huan (M+H)+=342. Example 65. 2-Cyclopropyl-5H4 oxo[2,3_b] hydrazine _7·carboxylic acid [(R)_2_(3-carbyl-azetidin-1-ylcyclopropyl side oxygen Base-ethyl]-decylamine

Prepared according to the procedure described in Example 1, in which 3 - cyanoazetidine hydrochloride was substituted for bilol and B - c_D-cyclopropylglycine was substituted for Boc-D-third-leucine . Removal of the N-Boc protecting group was achieved using 2,2,2-trifluoroethanol in a microwave reactor. MS: (M+H)+=365. Example 66. 2-(i-Methyl-1H-pyrazole-4-yl)-5H-pyrrolo[2,3-b]pyrazine-7-decanoic acid [(R)-2-(3-cyanide) -azetidine-buyl)-1_cyclopropyl-2-sidedoxy-ethyl 154395.doc -139· 201134826 base]•guanamine

Prepared according to the procedure described in Example 1 , in which 3 - cyanoazetidine hydrochloride was substituted for β than Harbin's, and B 〇 cD-cyclopropyl glycine was substituted for Boc-D-third-leucine And 2-(1-indenyl·1Η-» than 嗤-4-yl)-5-((2-((trimethyldecyl)ethoxy) fluorenyl)-511-°°° And [3,2-b]»Compounds to 2-cyclopropyl-5-(2-trimethylsulfonyl-ethoxymethyl)-5H-pyrrolo[2,3- b] Pyridine-7-formic acid. Removal of N-Boc protecting group using 2,2,2-trifluoroethanol in a microwave reactor. MS: (M+H)+=405. Example 67. 2-( 1-mercapto-1H-pyrazol-4-yl)·5Η-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-l-(3-cyano-azetidine · 1-carbonyl)-3-mercapto-butyl]-guanamine

Prepared according to the procedure described in Example 1_, with 3-cyanoazetidine 154395.doc • 140-201134826 burning hydrochloric acid instead. Bilobidine 'replaces b〇cD-third-leucine' with Boc-D-leucine and 2-(1-methyl-1H-pyrazol-4-yl)-5-((2- ((三f基基石基基)ethoxy)methylbiha and -7-carboxylic acid instead of 2-cyclopropyl-5-(2-trimethyldecyl-ethoxymethyl)_5Η•pyrrole And [23_b]. Peptide-7-formic acid. All steps to remove the N-Boc protecting group use trifluoroacetic acid instead of hydrochloric acid. MS: (M+H)+=421. Example 68. 2_(Bu ethyl 0 ratio 0 sit-4-yl)-5H-»Biloze[2,3-b]. Ratio p well-7-formic acid [(R)-2-(4-cyano-b. -1-cyclopropyl_2-sideoxy-ethyl]•••

Prepared according to the procedure described in Example 1, which replaced piperidin-4-pyronitrile with pyrrolidine and B〇CD-cyclopropylglycine for B〇c_D_third-leucine, and 2 -(1-ethyl-1H-pyrazol-4-yl)-5-((2-((tridecylfluorenyl)ethoxy)indolyl)-5H-&quot;比比和[3,2 -bp ratio tiller 7-formic acid instead of 2_cyclopropyl·5-(2-dimethyl Shih Hyun &gt; keto-ethoxymethyl)-5^1-.Bilobut[2,3- 13] Debbie "» Well-7-formic acid. All steps to remove the N-Boc protecting group use trifluoroacetic acid instead of hydrochloric acid. MS: (M+H) + = 447. Example 69. 2-Cyclopropyl- 5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid hydroxy_4_曱154395.doc -141 - 201134826 gi-piperidine-1-carbonyl)-2,2-dimethyl-propyl] - guanamine

Prepared according to the procedure described in Example 1 wherein the 4-methyl base was used. Alcohol substitutes ° ° ° each bite. MS: (M+H)+=414. Example 70. 2·Cyclopropyl-5H-0 piroxi[2,3-b]0 than tillage_7_carboxylic acid [(R)-1_(4-hydroxy-4-trifluoromethyl-piperidine- 1-carbonyl)-2,2-dimercapto-propyl]-guanamine

Step 1 4-Phenyloxypiperidine_1-carboxylic acid benzyl ester (1 〇 g' 4.3 mmol) was dissolved in THF (10 mL) in a three-neck round bottom flask. The reaction mixture was cooled to 0 ° C and tridecyl (trifluoromethyl) decane (0.78 mL, 5.3 mmol). Then, TBAF (in THF, 〇·〇 μ solution, 0.05 mL, 0.05 mmol) was added, thereby raising the internal temperature to 3 Torr. Hey. The reaction mixture was stirred overnight at room temperature. Additional TBAF (1.0 Μ solution in THF, 4.3 mL·' 4.3 mmol) was added and the reaction mixture was stirred at room temperature for 45 h. The reaction mixture was quenched with EtOAc EtOAc (EtOAc). The residue was triturated with toluene to give &lt;RTI ID=0.0&gt;&gt;&gt; Step 2 In a round bottom flask, 4-hydroxy-4-trifluoromethyl-piperidinic acid benzyl acetate (0.82 g, 2.7 mmol) was dissolved in Et0H (5 mL). Add 1 〇 0 / 〇 / / carbon (DeSussa type, 82 mg) and vacuum the flask, rinse with argon, draw into two and rinse with air. The reaction mixture was allowed to stand under a hydrogen atmosphere (balloon) at room temperature, followed by a transition through Shixia, and rinsed with Me〇H. The filtrate was concentrated to give 4-trifluoromethyl-piperidin-4-ol as a pale yellow solid of 44 g (97%). Step 3 Cyclopropyl-5Η-pyrrolo[2,3-b]pyrazine_7_carboxylic acid [(8) small hydroxy-4_trifluoromethyl-piperidine-1·carbonyl)-2,2-dimethyl -propyl]•guanamine. Prepared according to the procedure described in Example 1, which was replaced with 4-trifluoromethyl-piperidine. Biloxime MS: (Μ+Η)+=468. Example 71. 2 (1-ethyl-1Η-indole than sal-4-(yl))-5Η·° than each [2,3-b] ratio "well-7-decanoic acid [(R)-2-( 4·Cyano-Nanyl 丨 丨 基 ) _2 _2 _2 -1 -1 -1 -1 -1 -1 -1 -1 及 及 及 及 及 及 及 及 及 及 及 及 及 及 及 及 及 及 及 及 及 及 及More than saliva_4_base)_5 only. Biluo[2,3-b]pyrrole_7_carboxylic acid [(8)_2_(4-cyano-p-pyridinyl)_2 sideoxy + U-trifluoroanthracene Base-cyclopropyl)-ethyl]-decylamine 154395.doc • 143· 201134826

Prepared according to the procedure described in Example 1 where it was replaced with piperidine_4_曱. Bilobidine' is replaced by N-Boc-2-(l-trifluoromethylcyclopropyl)_dl-glycine

Boc-D-second-leucine, and 2-(1-ethyl-1 Η-β than sal-4_yl)_5_((2·((dimethyl decyl)ethoxy)) Methyl)·5η·»比比和[3,2_b]〇Compared to _7_carboxylic acid instead of 2-cyclopropyl-5-(2-trimethyl-stone-ethoxymethyl)_5H_〇 And [2, 3 handsome than spray -7-decanoic acid. All steps of removing the N_B〇c protecting group are replaced with tridulonic acid instead of hydrochloric acid. In step 3, R and S are separated by chromatography on palm-form preparative SFC. Enantiomer. R enantiomer, (m+h)+=5i5; S enantiomer, (M+H)+= 515. Example 72.

2-(1-methyl-1H-. ratio. sit on it, ςτυ 4_ base)_5Η·°bi-[2,3-b]pyridinium[(R)-2-(3-carbyl-aza Cyclobutane p-cyclobutanyl)-1-cyclohexyl-2-oxo-yl]-decylamine

154395.doc -144- 201134826

Alkyne hydrochloride replaces pyrrolidine, and Boc_D-cyclohexylglycine replaces b〇c_d-third-leucine with 2·(1_methyl-1H-pyrazole_4_yl)·5_(2 ((Trimethyl sulphate) ethoxy)methyl)-5 Η-° ratio slightly [3,2-b]. Substituting well-7-decanoic acid instead of 2_cyclopropyl-5-(2-triterpene) Base alkyl-ethoxymethyl)_5H_pyrrolo[2,3_b]pyrazine-7-carboxylic acid. All steps to remove the n-Boc protecting group use trifluoroacetic acid instead of hydrochloric acid. MS: (M+H ) += 447. Example 73. 2-(1_Mercapto-1H.imidazol-4-yl)-5H-pyrrolo[2,3-b]pyrazine-7·decanoic acid [(R)-1-( 4-cyano-anthracene bite-1-yl)_2,2-dimethyl-propyl]•nitramine

Step 1 1-Methyl-4-tributylstannyl-1H-methane was prepared according to WO 2007/062288. Step 2 In a pressure tube, 2-bromo-5-(2-tridecyldecyl-ethoxycarbonyl)- 511-pyrrolo[2,3-]pyrazine-7-carboxylic acid [(11) 1-(4-cyano-piperidin-1-carbonyl)_ 2,2-dimethylpropyl]•decalamine (125 mg, 0.22 mmol) and 1-indolyl-4-tributyltinyl- 1H-B m sitting (97 mg, 0.26 mmol) was dissolved in DMF (2 154395.doc -145 - 201134826 mL). Pd(PPh3)4 (12.5 mg, 0.01 mmol) and Cul (8 mg, 0.04 mmol) were added. The tube was sealed and heated at 80 &lt;0&gt;C for 1.5 h. The reaction mixture was cooled to rt. The organic extract was washed with a saturated aqueous solution of LiCl and brine, dried and concentrated with EtOAc. The residue was purified by EtOAc EtOAc (EtOAcEtOAcEtOAc (2-trimethyldecyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-l-(4-cyano-piperidine-1 -carbonyl)-2,2-dimercapto-propyl]-decylamine. Step 3 2-(1-Methyl-1H-imidazol-4-yl)-5H-pyrrolo[2,3-b]pyrazine-7-decanoic acid [(R)-l-(4-carbyl· It is a bite of _ι_subunit) 2,2-dimethyl-propyl]-guanamine. Prepared according to the procedure described in Example 4, Step 4, wherein 2-(1-methyl-1H-methane.yt-4-yl)-5-(2-tridecyldecyl-ethoxymethyl) ·5Η·pyrrolo[2,3-b]pyrazine·7_carboxylic acid [(R)-i_(4-cyano-piperidine·:μcarbonyl)_2,2-didecyl-propyl]-醯Amines for (R)-2-cyclopropyl·indole-(3,3-dimercapto-1·trioxy-1-((pyrrolidin-1-yl)butan-2-yl)-5- ((2-((Trimethyldecyl)ethoxy)indolyl)-5-pyrrolo[2,3-b]pyrazine-7-carboxamide. MS: (Μ+Η)+=449 Example 74. 2-(1_Ethyl-1Η- «I ratio. Sodium-4-yl)-5Η- 0 ratio"[2,3-b] ° ratio tillage_7_decanoic acid {(R) )-l-[3-(4,5-Dihydro-1H-imidazol-2-yl)-3-fluoropyrrolidine-1-carbonyl]_ 2,2-dimercapto-propyl bromoamine 154395 .doc • 146- 201134826

2-(1-Ethyl-1H-pyrazol-4-yl)-5H-pyrrolo[2,3-b]pyrazine-7-decanoic acid {(R)-l-[3-(4, 5-Dihydro-1H-imidazole-2.yl)-3-fluoro-pyrrolidine-1-carbonyl]-2,2-dimethyl-propyl}.decylamine. Separation was carried out as another product of Step 4 of Example 16. MS: (M+H)+=510. Example 75. 2-Phenoxy-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-methyl-1-(pyrrolidin-1-carbonyl)-propyl] - guanamine

Step 1 2-Bromo-5-(2-trimethyl; ^ &amp; yl-ethoxymethylpyrolo[2,3-b] at 150 ° C in a sealed tube under nitrogen. Plowing -7-furfural (3.29 g, 9.23 mmol), benzene (1.04 g, 11.08 mmol), K3P〇4 (3,92 g, 18.46 mmol), [2'-(di-tert-butyl-phosphorus) Alkyl)-biphenyl-2-yl]-dimethyl-amine (0.157 g, 0.46 mmol), Pd(OAc) 2 (〇.l〇3 g, 〇·46 mmol) and degassing benzene (50 Mixture of mL) was stirred overnight. The reaction mixture was stirred 154395.doc • 147-201134826 and cooled to room temperature and partitioned between ethyl acetate and water. The aqueous layer was extracted with ethyl acetate and the combined organic layer was passed through MgS04 Drying, filtration and concentration. The residue was purified by EtOAc EtOAc EtOAc (EtOAc)矽alkyl_ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-formaldehyde. Step 2 Carefully add concentrated to Cr03 (2.67 g)!^8〇4 (2 3 mL), followed by dilution with Ηβ to 1 〇mL to prepare a stock solution of Jones reagent (2.67 M). At 0 ° C to 2-phenoxy-5-(2-trimethyldecyl-ethoxy hydrazine Jones reagent (5 mL, 13 4 mmol) was added dropwise to a solution of 5H-pyrrolo[2,3_b]pyr, well-7-formaldehyde (2 35 g, 6 37 mm 〇1) in acetone (75 mL) The reaction mixture was stirred at room temperature for 2 hr then EtOAc EtOAc (EtOAc)EtOAc. The residue was dried <RTI ID=0.0></RTI> to <RTI ID=0.0></RTI> <RTIgt; </RTI> <RTIgt; (2-trimethyl sulphate-ethoxymethyl)-5H-° ratio slightly [2,3-b] ° cultivable-7-carboxylic acid. Step 3 to 2-phenoxy-5-(2 · Trimethyl sulfonyl ethoxymethyl) _5H_ fluorenyl [2,3-b] 0 to 11 well-7-carboxylic acid (〇.1〇g, 0.26 mmol), 4-dimethylamine Addition of a solution of pyridine (0.048 g' 0.39 mmol) and (3-dimethylamino-propyl)-ethyl-carbodiimide (0.075 g, 0.39 mmol) in CH2C12 (2 mL) (R)-2-Amino-3-methyl-1-pyrrolidinyl-indole-butan-1-one (0.066 g '0.39 mmol) in CH2C12 (0.5 mL). The reaction mixture was stirred at room temperature 154395.doc • 148-201134826 overnight. Then was quenched with water and extracted with ethyl acetate (3×). The organic layer was washed with water and a saturated aqueous solution of NaCl and dried over MgSO 4 , filtered and concentrated. The residue was purified by EtOAc EtOAc EtOAc (EtOAc) Pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-methyl-1-(pyrrolidinium)-propyl]-propylamine. Step 4 • To the 2-step phenoxy-5-(2-trimethyldecyl-ethoxyindenyl)-5H of step 3, the ratio of [2,3-1&gt;]° -Trifluoroacetic acid added to a solution of formic acid [(foot)-2-methyl-1-(11-bite-l-l-yl)-propyl]-nonylamine in dichloromethane (0.5 mL) (0.7 mL). The reaction mixture was stirred at room temperature overnight then concentrated. The residue was mixed with THF (1 mL), water (0.5 mL) and Et.sub.3N (0.5 mL) and then concentrated. The residue was partitioned between acetic acid and water and the aqueous layer was extracted with ethyl acetate. The combined organic layers were dried over MgSO 4 and concentrated. The residue was purified by EtOAc EtOAc (EtOAc: EtOAc (EtOAc) -b]0 than ρ well-7-formic acid [(R)-2-methyl-1-(indoloquinol-1)-propyl]-guanamine. MS: 408 (M+H)+. Example 76. 2-(1-cyclopropyl-1H-0 is 0--4-yl)-5H-° than 嘻[2,3-b]0 to p-well_7_carboxylic acid [(R)- l -(4.Cyano-sodium decyl-1-indenyl)-2,2-dimercapto-propyl]-nonylamine 154395.doc -149- 201134826

Step 1 Combine 4-iodo-1H-pyrazole (1.00 g, 5.16 mmol), cyclopropyl tanning acid (886 mg, 10.3 mmol) and sodium carbonate (1.09 g, 10.3 mm 〇1) in a flask and suspend the mixture. In 1,2-diethane (20 mL). Adding acetic acid steel (11) (936 mg ' 5.16 mmol) and 2,2-dipyridine (805 mg ' 5.16 mmol) of 1,2-digas (40 mL) and heating to 50 ° C suspension Liquid 'and the resulting mixture was heated overnight at 70 °C. The mixture was then cooled and filtered and the solid was washed with EtOAc. The combined filtrates were concentrated and the residue was crystallised from EtOAc EtOAc The organic layer was washed with saturated NaH4C1' sat. NaHC.sub.3 and saturated NaCI and dried over EtOAc. The solution was concentrated and the residue was purified by EtOAc EtOAc EtOAc EtOAc EtOAc Step 2 1-Cyclopropyl-4-oxazole (405 mg, 1.73 mmol) was dissolved in THF (8.0 mL) and the solution was cooled to EtOAc. Isopropylmagnesium chloride (2.0 Μ ' in THF, 1.04 mL, 2.08 mmol) was added dropwise and the mixture was stirred at 〇 ° C for 45 min, after which was added 2·isopropoxy-4,4,5,5-tetra Methyl·1,3,2-oxo-deodorization (0.53 mL, 2.60 mmol) and 154395.doc-150-201134826 mixture was warmed to room temperature over 1 hour. The mixture was quenched with 50% aq. The organic extract was washed with saturated NaCl, and the solution was concentrated and concentrated with EtOAc. The residue was purified by Si 〇 2 chromatography (20% - 5% EtOAc / EtOAc) to yield 405 mg (83%) of colorless viscous oil. Alcohol ester. Step 3

2-(1-cyclopropyl-1Η-° ratio 0 sit-4 -yl)-5H-0 ratio slightly [2,3-b]n ratio p well-7-formic acid [(R)-l-( 4-N-based-Broadcasting-based base-2,2-«-mercapto-propyl]-bristamine. Prepared according to the procedure described in Example 2, in step 1, replaced with 1-((R)-2-amino-3,3-dimethyl-butanyl)-piperidine-4-indolonitrile tri-gas acetate (R)-2-amino-3,3-dimethyl-1·pyrrolidinyl-bupropion-butanone hydrochloride and in step 2 is cyclopropyl-1H-pyrazole-4- _ Acid pinacol ester replaces ethyl ethyl 1-H-pyrazole-4- face acid pinacol ester. MS: (M+H)+=475.

Example 77. 2-[l-(2,2,2-Trifluoro-ethyl)-lH-pyrazol-4-yl]-5H-pyrrolo[2,3-b]«^ than tillage_7· Formic acid [(R)-1_(4_Cyanide base bite)_2,2_monomethyl]propyl]_

Step 1 154395.doc 201134826 In the microwave small flight, make 4-fill-1 Η-. Suspension (1.00 g, 5.16 mmol) and cesium carbonate (6.72 g, 20.6 mmol) in DMF (8.0 mL) and addition of 1,1,1-di-IL-2-Moth Ethylene (2.06 mL, 20.6 mmol) » » At 90. The mixture was heated under microwave for 60 minutes, then the mixture was filtered and washed with EtOAc. The filtrate was concentrated and then dissolved in EtOAc and 50% saturated aqueous NH4CI. The organic layer was washed with saturated LiCl and saturated NaCl then dried over MgSO 4 . The solution was concentrated and the residue was purified by EtOAc EtOAc EtOAc EtOAc EtOAc Defeat ethyl)-1 Η-°Λ β sit. Step 2 1-(2,2,2-Difluoroethyl)·1Η_pyrazole_4_mepin acid pinacol ester. Prepared according to the procedure described in Example 2, Step 2, in which 4-iodo-1_(2,2,2·trifluoroethyl)·1Η·°Λ° was substituted for cyclopropyl-4-iodo-1Η- Pyrazole. Step 3 2_[1-(2,2,2_Trifluoro-ethyl)·1Η·°Bizozol-4-yl]-5Η-pyrrolo[2,3_b] Pyridin-7-decanoic acid [(R Small (4. cyano-0-pyridinium small carbonyl dimethyl propyl) decylamine. Prepared according to the procedure described in Example 2, in the step of ((R)-2-amino-3,3 -Dimethyl·butanyl)·Pyridinium I曱nitrile trifluoroacetate instead of (R)-2·Amino·3,3_Dimethyl stomach... 定]•基·丁]•嗣HCl Salt and replace the 1-ethyl·1Η-pyrazole·4·§ acid pinacol ester with M2,2,2j dimethyl primal ester in step 2. ms: (M+H)+=517 Example 78. 2-(1-ethyl-m-pyridyl.sodium_4_yl)_5Η·pyrrolo[2,3_b]carboxylic acid 154395.doc •152· 201134826 [(R)-1-(4,4 -difluoro-piperidin-1-carbonyl)-2,2-dimethylpropyl]-decylamine

Prepared according to the procedure described in Example 1, wherein pyridinium was replaced with 4,4-difluoropiperidine hydrochloride and 2-(1-ethyl-1H-pyrazole-4)-5-(( 2-((tridecyldecylalkyl)ethoxy)methyl)-5H-pyrrolo[3,2-b]pyridin-7-carboxylic acid instead of 2·cyclopropyl-5-(2-tridecyldecane -Ethoxymethyl)_5H_pyrrolo[2,3 ton] pyridin-7-formic acid MS: (M+H)+=474. Example 79. 2-Cyclopropyl-5H-&quot; Mouth [2,3-b]» than spray_7_carboxylic acid [(R)-l-(7,8-dihydro-5Η-Π,6]acridine_6·carbonyl)_2,2_2 Mercaptopropyl] guanamine

Prepared according to the procedure described in Example 1, wherein _tMS: (M+H) + = 433 was replaced with 5,6,7,8-tetrazin- 4 bite hydrochloride. Example 80. 2_玉衣丙-5 Η·π比洛其"9 1 u ί . n 开U,3-b]pyrazine_7_carboxylic acid [(R)_2-(3-cyano- Nitrogen 154395.doc •153· 201134826 Heterocyclic butyl-1-yl)-2-oxooxy_1_(tetrahydro-n-propan-4-yl)-ethyl]-bristamine and 2-cyclopropyl -5H-pyrrolo[2,3_b] oxime ratio 1^-7-carboxylic acid [(S)-2-(3-cyano-azetidin-1-yl)-2-oxoyl_1_( Tetrahydrodean-4(yl)-ethyl]-decylamine

Prepared according to the procedure described in Example 1 in which the azetidine-4-carbonitrile hydrochloride was replaced with 0-bend-4-indene nitrile and NB〇c-4'-tetrahydropentanylglycine The acid replaces Boc-D-third-leucine. All steps for removing the N-Boc protecting group used trifluoroacetic acid instead of hydrochloric acid. Separation of the R and S enantiomers r enantiomers by preparative SFC chromatography in step 3, (M+H)+=409; S enantiomer, (m+h ) += 4〇9. Example 81. 2.······· )-2,2-dimethyl-propyl]-decylamine

154395.doc -154- 201134826 Prepared according to the procedure described in Example 1, in which pyrrolidine was replaced by porphyrin. MS: (M+H)+=418. Example 82. 2-(1-Ethyl-1H-pyrazol-4-yl)-5H-pyrrolo[2,3_b]pyrazine_7_carboxylic acid [(R)-l-cyclopropyl-2-( 3,3-difluoro-la-rrolidine-丨-yl)_2_sideoxy-ethyl]-decylamine

Prepared according to the procedure described in Example 1, in which pyrrolidine was replaced by 3,3-difluoropyrrolidine hydrochloride and b〇cD-third-leucine was replaced by Boc-D-cyclopropylglycine. And 2-(1-ethyl-1H-pyrazol-4-yl)-5-((2-((trimethyldecyl)ethoxy)methyl)-[3,2-b] °Compared to argon-7-formic acid instead of 2-cyclopropyl-5-(2-trimethyldecyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid. : (M+H)+=444. Example 83. 2-(1-Ethyl-1H-pyrazol-4-yl)-5Η·pyrrolo[2,3-b]pyrazine-7-carboxylic acid [( R)-l-(4-Hydroxy-4-methyl-piperidin-1-carbonyl)-2,2-dimethyl-propyl]-bristamine 154395.doc •155- 201134826

Prepared according to the procedure described in Example 1, in which pyridin was replaced by 4-methyl-piperidin-4-ol and 2-(1-ethyl-1H-pyrazol-4-yl)-5-(( 2-((Trimethyldecyl)ethoxy)methyl)-5H-indolepyrrolo[3,2-b]° instead of tillage_7_carboxylic acid instead of 2-cyclopropyl-5-(2- Trimethyldecyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid MS: (M+H)+=468. Example 84. 2-cyclopropyl -5H-pyrrolo[2,3-b]pyrh-7-nonanoic acid [(R)-2-((s)_3-cyano-pyrrolidin-1-yl)-1-cyclopropyl-2 - side oxy-ethyl]-guanamine

Prepared according to the procedure described in Example 1, wherein (S)-pyrrolidine-3·carbonitrile was substituted for pyrrolidine and Boc-D-cyclopropylglycine was substituted for B〇c_D_third_leucine The removal of the N-Boc protecting group from step 2 was achieved using 2,2,2-trifluoroethanol in a microwave reactor. The removal of the SEM protecting group in step 4 was achieved using CsF in refluxing acetonitrile. MS: (M+H)+=379. Example 85. 154395.doc 156- 201134826 [(R)-2-((S)-3-cyano.. than bite small base) small cyclopropyl_2_sideoxy]]-guanamine

2-0-曱基-1Η·η ratio. Sodium-4-yl)_5H_D ratio slightly [2,3 b]oxime than phage-7 was prepared according to the procedure described in Example 1, in which (s)-pyrrolidine-3, indoleonitrile was substituted for pyrrolidine. Substituting Boc-D-cyclopropylglycine for B〇c_D_third, leucine, and 2-(1-methyl-1H-pyrazol-4-yl)-5-((2- ((Trimethyldecyl)ethoxy)methyl)-5H-pyrrolo[3,2-b]pyrazine_7_carboxylic acid instead of 2_cyclopropyl-5-(2-trimethyldecyl) · Ethoxymethyl) _5h-indolepyr[2,3-b] ton -7-carboxylic acid. Use 2,2,2-trifluoroethanol in a microwave reactor to achieve the removal of N in step 2. -Boc protecting group. The removal of the SEM protecting group in step 4 was achieved using CsF in refluxing acetonitrile. MS: (M+H) + = 419. Example 86. 2-cyclopropyl-5H-pyrrolo[2, 3-b]pyrazine-7-decanoic acid [(R)-2-((R)-3-cyano-pyrrolidin-1-yl)-1-cyclopropyl-2-oxo-ethyl ]-guanamine

154395.doc • 157- 201134826 Prepared according to the procedure described in Example 1, in which pyrrolidine was replaced by (R) pyrrolidine-3-carbonitrile and Boc-D was replaced by Boc-D-cyclopropylglycine. - Third · leucine. The removal of the N-Boc protecting group in Step 2 was achieved using 2,2,2-trifluoroethanol in a microwave reactor. The removal of the SEM protecting group in step 4 was achieved using CsF in refluxing acetonitrile. MS: (M+H)+=379. Example 87. 2-(1-Methyl-1H-pyrazol-4-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-((R)- 3-cyanopyrrolidin-1-yl)-cyclopropyl·2_sideoxy-ethyl]-decylamine

Prepared according to the procedure described in Example 1, wherein (R)-pyrrolidine_3-carbonitrile was substituted for pyrrolidine and Boc-D-cyclopropylglycine was substituted for B〇c_D_third_leucine, And 2-(didecyl-1H-pyrazole·4·yl)·5-((2-((trimethyldecyl)ethoxy) fluorenyl)-5Η-0 嘻[3,2- b]n than the well _7_carboxylic acid instead of 2_cyclopropyl-5-(2-tridecylfluorenyl-ethoxyindolyl)_5H_pyrrolo[2,3_b]pyrazine-7-carboxylic acid. Deprotection of the N-Boc protecting group in step 2 was achieved using 2,2,2-trifluoroethanol in a microwave reactor. The removal of the SEM protecting group in step 4 was carried out using CsF in refluxing acetonitrile. MS: ( M+H)+=419. Example 88· 154395.doc •158· 201134826 2-Cyclopropyl-5H-pyrrolo[2,3-b]pyrazine-7-decanoic acid [(R)-l·环Propyl-2-(2-oxa-6-aza-spiro[3.3]hept-6-yl)-2-oxo-ethyl]-decylamine

Prepared according to the procedure described in Example 1, in which 2-oxa-6-aza-spiro[3.3]heptanoic acid was substituted for beclozine and Boc-D-cyclopropylglycine was substituted for Boc-D. - Third - leucine. The removal of the N-Boc protecting group in Step 2 was achieved using 2,2,2-trifluoroethanol in a microwave reactor. The SEM-protected substrate in step 4 was achieved using CsF in refluxing acetonitrile. MS: (M+H)+=382. Example 89. 2-(1-Methyl-111-° ratio '&gt;Spin-4-yl)-511-0 to 17 and [2,3-1)]&gt;1 to '1 well-7- Formic acid [(R)-l-cyclopropyl-2-(2-oxa-6-aza-spiro[3.3]hept-6-yl)-2-oxo-ethyl]-decylamine

Prepared according to the procedure described in Example 1, in which pyrrolidine was replaced by 2-oxa-6-aza-spiro[3.3]heptane oxalic acid, and I54395.doc was replaced by Boc-D-cyclopropylglycine. · 201134826

Boc-D-third-leucine- and 2-(1-methyl-1Η-η than sal-4-yl)-5-((2-((三曱基石夕•)) ethoxylate Methyl)-5H-.Compared with &quot;Ethylene[3,2-b]»pyryl-7-decanoic acid instead of 2-cyclopropyl-5-(2-trimethyl-stone)曱5)_5H_0 piroxime [2,3-b] ° than phenyl-7-formic acid. The removal of N-Boc protecting group in step 2 was achieved using 2,2,2-trifluoroiethanol in a microwave reactor. The removal of §em in step 4 is achieved by using CsF in refluxing acetonitrile. MS: (M+H)+ = 422. Example 90. 2-cyclopropyl-5H-pyrrolo[2,3 -b]pyrh-7-carboxylic acid [(r)-^cyclopropyl_2_((18,5 ft, 6 ft)-6-hydroxymethyl-3-aza-bicyclo[3.1.〇] _ 3_yl)_2_sideoxy-ethyl]-bristamine

Prepared according to the procedure described in Example 1, wherein (1α,5α,6α)_3_azabis%[3·1·〇]hex-6-yl sterol was substituted for pyrrolidine ' and b〇c_d_ ring Propylglycine replaces Boc-D-third-leucine. Removal of the N_Boc protecting group in step 2 was achieved using 2,2,2-trifluoro*ethanol in a microwave reactor. The removal of the SEM protecting group in step 4 was achieved using CsF in refluxing acetonitrile. MS: (M+H)+=396. Example 91. 2-(1-Methyl-1H.pyrazol-4-yl)_511_pyrrolo[2,3_b]pyrazine_7_carboxylic acid [(R)-l-cyclopropyl-2_((1S) ,5R,6R)_6_hydroxymethyl_3•azabicyclo[3"〇] 154395.doc 201134826 hex-3-yl)-2-yloxyethyl]-guanamine

OH

According to the procedure described in Example 1, the preparation of the preparation, wherein (1α, 5α, 6α)_3_azabicyclo[3丄0]hexanyl methanol is substituted for pyrrolidine to b〇c_d•cyclopropylglycan Amine acid replaces B〇C_D-third-leucine' and is 2(1 methyl-ih "ratio. sit_4_yl)-5_((2·((didecyl)alkyl)ethoxy)曱基)5H "(4) and pyridin-7-decanoic acid instead of 2_cyclopropyl·5_(2_trimethylsulfonylalkylethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine -7-decanoic acid. The removal of the n-boc protecting group in step 2 was achieved using 2,2,2-trifluoroethanol in a microwave reactor. The removal of the SEM protecting group in step 4 was achieved using CsF in refluxing acetonitrile. MS: (M+H)+=436. Example 92. 2-Cyclopropyl-5H-pyrrolo[2,3-b]pyrazine-7-decanoic acid [(R)-l-cyclopropyl.2 · (1,1-di-oxy-thio- methionine _4_yl)_2-sideoxy-ethyl]-decylamine

154395.doc -161- 201134826 Prepared according to the procedure described in Example 1 in which thiopheneline 丨, 丨_dioxide was substituted for pyrrolidine and BocT-cyclopropylglycine was substituted for boc_d_third- Amino acid. The removal of the N-Boc protecting group in Step 2 was achieved using 2,2,2-trifluoroethanol in a microwave reactor. The de-SEM protected system in Step 4 was achieved using CsF in refluxing acetonitrile. MS: (M+H)+=418. Example 93. 2-(1-Mercapto-1H-0 ratio 坐-4-yl)-5H-0 〇[2,3-b] 〇比井-7_carboxylic acid [(R)- L-cyclopropyl-2-(1,1-di-oxy-thio- methionine-4-yl)-2-oxo-ethyl]-decylamine

Prepared according to the procedure described in Example 1, in which thio-morphin-1,1-dioxide was substituted for 比 洛 bits to replace b〇cD-third white with Boc-D-cyclopropylglycine. Amino acid' and 2-(1-methyl-1H-pyrazol-4-yl)-5-((2-((trimethylindenyl)ethoxy)indolyl)-5H-pyrrole [3,2-b]pyrazine-7-carboxylic acid instead of 2-cyclopropyl-5-(2-trimethyldecyl-ethoxymethyl)_5H-pyrrolo[2,3-b] pyridin _7·Citrate. Use 2,2,2-trifluoroethanol in a microwave reactor to remove the N-Boc protecting group from step 2. The SEM protecting group in step 4 is removed using CsF in refluxing acetonitrile. MS: (M+H)+=458. Example 94. 154395.doc •162· 201134826 2-(1-Ethyl-1H-pyran-4-yl)_5H_pyrrolo[2,3-b Pyridin__7_decanoic acid [(R)-l-(4-cyano-slightly bite-1·yl)·3,3,3_trifluoropropyl]-bristamine and 2_(ι_ethyl-1Η -pyrazol-4-yl)-5Η-.pyrolo[2,3_b]pyr-_7·carboxylic acid [("-bu(4-cyano-piperidin-1-carbonyl)-3,3,3- Trifluoro-propyl decylamine

Step 1 To a suspension of 2-amino-4,4,4-trifluorobutyric acid (〇·5〇g, 3 2 mm〇1) K14 dioxane (8 mL) was added 1. 〇μ NaOH Aqueous solution (6.37 mL·, 6.4 mmol). Di-tert-butyl dicarbonate (764 mg, 35 mmol) was then added and vigorously stirred overnight at room temperature. The turbid reaction mixture was diluted with water (5 mL), EtOAc (EtOAc) The combined organics were dried over MgSO 4 and concentrated to a colourless oil. It was wet-milled with petroleum hydrazine to obtain 620 mg (76%) of 2-t-butoxycarbonylamino-4,4,4-trifluoro-butyric acid as a white powdery solid. Step 2 2-(1-Ethyl-1H-pyrazol-4-yl)-5H-indolo[2,3-b]pyrazine-7-carboxylic acid [(R)-l-(4-cyano) -Bite 1-carbonyl)-3,3,3-trifluoro-propyl]-bristamine and 2-(1-ethyl-1H-.pyridin-4-yl)-5Η-β ratio 11 And [2,3-b] 0 ratio _-7-decanoic acid [(S)-l-(4-cyano-succin-1-yl)-3,3,3-trifluoro-propyl] - guanamine. Prepared according to the procedure described in Example 1 154395.doc • 163·201134826, in which piperidine-4-carbonitrile was substituted for pyrrolidine, and 2_ second butoxycarbonylamino-4,4,4-trifluoro- Butyric acid replaces Boc-D-third-leucine with 2-(indolylpyrazol-4-yl)-5-((2-((trimethyldecyl)ethoxy)) Alkyl-[3,2-b]n replaces 2-cyclopropyl-5-(2-tridecylfluorenyl-ethoxyindolyl)_5H_pyrrolo[2,3_b Pyridin-7-decanoic acid. All steps of removing the protecting group are using trifluoroacetic acid instead of hydrochloric acid. In step 3, the separation of the SFC and the S enantiomer are carried out via a palmitic preparation type SFC. R enantiomer, (M+H)+= 489; s enantiomer, (M+H)+= 489. Example 95. 2-cyclopropyl-5H-pyrrolo[2,3- b]pyr-7-carboxylic acid [(R)-2-(3-cyano-3-indolyl-azetidin-1)yl-1 -cyclopropyl-2-sideoxy-B Amine

Step 1 3-Cyanoazetidinium-carboxylic acid tributyl acrylate (1.5 g, 8.2 mmol) was dissolved in THF (30 mL) in a 100 mL two-neck round bottom flask. The colorless solution was cooled to -76 ° C and bis((trimethyldecyl) guanamine clock (1.0 Μ solution in THF, 9.0 mL, 9.0 mmol) was added dropwise over 25 min. The yellow solution was stirred for 30 minutes, then iodonane (0.78 mL, 12.5 mmol) was slowly added. The reaction mixture was weighed at -76 C for 30 minutes, then warmed to room temperature over 1 154395.doc -164 - 201134826. The reaction mixture was quenched with 〇 mL saturated NHeCl and diluted with 10 mL of water and then extracted with about 1 mL of Et.sub.2Ac (2x). The combined organic layers were washed with about 10 mL of water and about 10 mL of brine. The mixture was dried over NaHCO3, filtered, and concentrated. EtOAcjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj Obtained 1.44 g (89 〇 / 〇) of 3 - cyano -3 - fluorenyl - azetidine-1-decanoic acid tert-butyl ester. φ Step 2 In a 20 mL microwave vial Cyano_3_methyl-azetidine 4 _ formic acid tert-butyl ketone (0.75 g, 3.82 mmol) and 2,2,2-trifluoroethanol (15.0 mL, 206 mm 〇l). Small air wash The bottle was closed. The colorless solution was heated under microwave irradiation at 150 ° C for 4 hours. The reaction mixture was cooled down and hydrogenation hydrogenated (in diethyl ether, 〇M solution, 4,6 6 _〇1) was added dropwise. The pale yellow solution was concentrated and the residue was triturated with diethyl ether to give &lt;RTI ID=0.0&gt;&gt; 5H-吼 并 [2,3_b]0 than tillage _7 formic acid _ 3 · methyl-azetidinyl small group) small cyclopropyl · 2 · pendant oxy-ethyl bromoamine. Prepared according to the procedure described in Example 1, which was replaced by 3-cyano-3-methyl-aza-hydroxy-hydrochloride, and each was bitten and replaced with cyclopropylglycine. _ leucine. The N_B〇c protecting group was removed in a microwave reactor using 2,2,2. trifluoroethanol V. Ms + Example 96. Soil 1Η·〇 ratio 0 sitting on ice base)_5H-pyrolo[2,3-bJ » 比井井·7_carboxylic acid 154395.doc •165· 201134826 [(R)-2-(3 -Cyano-3-methyl-azetidinylcycloprop-2-enyloxy-ethyl]-decylamine

Prepared according to the procedure described in Example 1, wherein 3: cyano-3 methyl-azetidine hydrochloride was substituted for the ratio of Boc-D-cyclopropylglycine to Boc-D- Third-leucine, and 2-(1-methyl-m-pyrazole-4-yl)5((2_((dimethyl sylylene))ethoxy)methyl)-5H-. And [3,2-b]&quot;Compared to whistle ^7-carboxylic acid instead of 2-cyclopropyl-5-(2-trimethylsulfonyl-ethoxymethyl)·5Η•pyrrolo[2,3 -b] pyridin-7-formic acid. The deprotected N-Boc protecting group in step 2 was achieved using 2,2,2-trifluoroethanol in a microwave reactor. MS: (M+H)+=419. 97 methyl-1H- 0 ratio "supple-4-yl)-5H- 0 piroxi[2,3-b] 0 ratio tillage-7_decanoic acid [(R)-1-(3-cyano) 3_Methyl-azetidine·i•carbonyl)_2,2-didecyl-propyl]•Taolin

154395.doc -166· 201134826 Prepared according to the procedure described in Example 1, in which pyrrolidine was replaced by 3-cyano-3-methylazetidine hydrochloride, and 2_(1_methyl_1H• Pyrazole _4_yl) 5-((2-((tridecyl decyl)ethoxy)methyl)_5H_D is more than argon [32b] 〇 耕 -7-7-carboxylic acid instead of 2-cyclopropyl _5_(2_Trimethyldecyl-ethoxymethyl)_ 5H-pyrrolo[2,3-b]pyridin-7-decanoic acid. Use 2,2,2_ tri I in a microwave reactor The ethanol was deprotected from the N-Boc protecting group in step 2. MS: (M+H)+ = 435. Example 98. 2-(1-ethyl-1H-pyrazol-4-yl)-5H-pyrrole [2,3-b]pyrazine-7-carboxylic acid [(R)-l-cyclopropyl-2-(4,4-difluoro-piperidinyl)-yloxy-ethyl] _ guanamine

Prepared according to the procedure described in Example 1, wherein 4,4-difluorosuccinic acid hydrochloride was substituted for pyrrolidine and Boc-D-cyclopropylglycine was substituted for Boc-D-third-leucine. And 2-(1-ethyl-iH-n-benzazol-4-yl)-5-((2-((trimethyl fluorenyl) ethoxy) fluorenyl)-5H-° ratio [3,2-b]. Substituting argon-7-nonanoic acid for 2-cyclopropyl-5-(2-trimethyldecyl-ethoxymethyl)_511_pyrrolo[2,3-1) Pyridin-7-formic acid. MS: (M+H)+=458. Example 99. 2-(1-Ethyl-1H-oxazol-4-yl)-5H-0piro[2,3-b]pyrazine-7-decanoic acid 154395.doc •167- 201134826 [(R )-l-cyclopropyl-2-(4-hydroxy-4-trifluoromethyl-piperidin-1-yl)-2-oxoethyl]-decylamine

Prepared according to the procedure described in Example 1, wherein 4-pyridyl-piperidin-4-ol (Example 74 Step 2) was substituted for pyrrolidine and Boc-D-cyclopropylglycine was substituted for Boc-D. -Third-leucine, and 2-(1-ethyl-1H-pyrazol-4-yl)-5((2-((tridecyl)alkyl)ethoxy)methylpyrrole [3,2-b]ni; t_-7-carboxylic acid instead of 2-cyclopropyl-5-(2-trimethyldecyl-ethoxymethyl)_5H_pyrrolo[2,3-b]pyrazine -7-formic acid. MS: (M+H)+ = 506 » Example 1〇〇 2-(1-ethyl-1H- 0 than -4-yl)-5H-&quot;Biluo[2, 3-b] 〇比ι»井-7_carboxylic acid [(R)-l-cyclopropyl-2-(3-carbyl-3.methyl-azetidinyl)_2_sideoxy- Ethyl]-bristamine

Step 1 J54395.doc • J68-201134826 l-Boc-3-azetidinone (〇7〇 g, 4 j mmol) was dissolved in THF (20 mL) in a dry round bottom flask. The solution was cooled to &&gt;c and methyl magnesium hydride (3.0 Μ solution in THF, 2 〇 mL, 6 〇 mm 〇 1) was added dropwise. The reaction mixture was stirred at 〇 C for 1 hour. The reaction mixture was quenched with 丨〇 mL saturated NH4Ci, diluted with 5 mL water and extracted with 100 mL Et EtOAc (2x). The combined organic layers were washed with 10 mL EtOAc EtOAc EtOAc (EtOAc) Alkyl hydrazine - tert-butyl formate. Step 2 In a round bottom flask, dibutyl 3-hydroxy-3-methyl-azetidincarboxylate (0.40 g, 2.13 mmol) was dissolved in di-methane (2 mL). The colorless solution was cooled to o ° c and trifluoroacetic acid (6 5 ml) was slowly added. After the addition was completed, the ice bath was removed and the reaction mixture was stirred at room temperature for 15 hours. The reaction mixture was concentrated to give the title compound (yield: EtOAc). Step 3 2-(1-Ethyl-1H-pyrazol-4-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-l-cyclopropyl-2- (3-Hydroxy-3-methyl-azetidinyl-indoleyl)_2_sideoxyethyl]-bristamine. Prepared according to the procedure described in Example 1, in which 3 - methyl-azetidin-3-ol difluoroacetate was substituted for the Lolo bite, and b〇c_d_cyclopropylglycine was substituted for Boc-D. -Third-leucine, and 2-((iethyl_1^..bazol-4-yl)-5-((2-((tridecyldecyl)ethoxy)methyl)-5H_pyrrole And [3,2-b]pyrazine-7-decanoic acid instead of 2·cyclopropyl-5-(2-trimethyldecyl-ethoxymethyl)-5H-pyrrolo[2,3-b Pyridin-7-decanoic acid. All the steps of deprotecting 8〇 (: 154 395. doc • 169- 201134826) were replaced with trifluoroacetic acid instead of hydrochloric acid e MS: (M+H)+=424. Example 101 2-cyclopropyl-5H-pyrrolo[2,3_b]pyrazine-7-cyano-piperidin-1-carbonyl)-2-methyl-butyl]-decylamine

Prepared according to the procedure described in Example 1, which was replaced with piperidine 4-indene. Bilo bites and replaces b〇c-D-third-leucine with Boc-D-isoleucine, and all steps to remove the N-Boc protecting group use trifluoroacetic acid instead of hydrochloric acid. MS: (M+H)+=409. Example 102. 2-Cyclopropyl-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(lR,2S)-l-(4.cyano-piperidin-1-carbonyl)-2 -methyl-butyl]-decylamine

Prepared according to the procedure described in Example 1, in which piperidine-4-carbonitrile was substituted for 'Bilo bite and Boc-D·iso-isoleucine was substituted for b〇cD-third-leucine, 154395. Doc • 170- 201134826 and all steps to remove the N-Boc protecting group use trifluoroacetic acid instead of salt hydrazine. MS: (M+H)+=409 〇 Example 103. 2-Cyclopropyl-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(4-cyano-base pyridine -1-yl)-1-cyclopropyl-decyl-2-oxo-ethyl]-decylamine

Step 1 To a suspension of (R)-2-amino-3-cyclopropylpropionic acid (0.57 g, 4.4 mmol) in 1,4-dioxane (8 mL) (4.0 mL '4.0 mmol). Di-tert-butyl dicarbonate (〇·96 g, 4.4 mmol) was then added and stirred vigorously at room temperature overnight. The turbid reaction mixture was diluted with water (5 mL) and EtOAc (EtOAc) The combined organics were dried with EtOAc (EtOAc) (EtOAc m. Step 2 2-Cyclopropyl-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(4-cyano-piperidin-1-yl)-1·cyclopropane Methyl-2-oxo-ethyl]-decylamine. Prepared according to the procedure described in Example 1 in which pyrrolidine was replaced by piperidine·4·carbonitrile and 154395.doc -171 - 201134826 (R)-2-tert-butoxycarbonylamino-3-cyclopropane The base-propionic acid replaces Boc-D-third-leucine, and all steps of removing the N-Boc protecting group use trifluoroacetic acid instead of hydrochloric acid. MS: (M+H)+=407. Example 104. 2-Cyclopropyl-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(4-cyano-piperidin-1-yl)-2 - side Oxy-1-phenyl-ethyl]-bristamine

Prepared according to the procedure described in Example 1, wherein piperidine-4-carbonitrile was substituted for 0 to slightly bite and B〇cD-phenylglycine was substituted for Boc-D-third-leucine, and all The step of removing the oxime-Boc protecting group uses trifluoroacetic acid instead of hydrochloric acid. MS: (M+H)+=429. Example 105. 2-(1-Methyl-1H-pyrazol-4-yl)_5H_. Bisolo[2,3-b]pyrazine-7-carboxylic acid [(R)-l-cyclopropyl-2-(3,3-difluoro-azetidin-i-yl)·2· Side oxy-ethyl]-bristamine 154395.doc -172· 201134826

Prepared according to the procedure described in Example 1, which was replaced with a 3,3 - 2 atmosphere heterocyclobutylene hydrochloride. Compared with bite, replace boc-D_cyclopropylglycine with b〇c_d_•·················· Methyl decyl)ethoxy)methyl)_5Η_pyrrolo[3,2b]pyrazine-7·carboxylic acid instead 2·cyclopropyl-5-(2-trimethyldecyl-ethoxymethyl) _5Η_〇比比和[2,3_b] pyridin-7-formic acid. All steps of removing the N_B〇c protecting group use trifluoroacetic acid instead of hydrochloric acid. MS: (M+H)+=416. Example 106 2-(1-Mercapto-1H-pyrazol-4-yl)-5H-pyrrolo[2,3-b]pyrazine-7-decanoic acid [(R)-2-(3-cyano- 3-ethyl-azetidine·ι·yl)·;[-cyclopropyl_2•sideoxy#yl-ethyl]-decylamine

Step 1 3-Cyanoazetidin-1-carboxylic acid tert-butyl ester (0-80 g, 4.4 mmol) was dissolved in THF (16 mL) in a 100 mL two-necked round bottom flask. The colorless 154395.doc -173·201134826 solution was cooled to -761 and bis((tridecyldecyl)decylamine (1.0 μ solution in THF, 4.8 mL, 4.8 mmol) was added dropwise over 20 min. The yellow solution was stirred at -76 ° C for 30 minutes, then slowly added ethyl iodide (0. 50 mL, 6.2 mmoip stirred at -70 ° C for 30 minutes) and then warmed to room temperature and stirred for 3 hours. The reaction mixture was diluted with 1 mL of mL, and the mixture was diluted with 10 mL of water and then extracted with EtOAc (2×). The combined organic layer was washed with about 1 mL of water and about 10 mL of brine. The mixture was dried over sodium sulfate, filtered and concentrated. EtOAc EtOAc EtOAc 0.84 g (91%) of 3-cyano-3-ethyl-azetidine·indole-carboxylic acid tert-butyl ester was obtained as a pale yellow oil. Step 2 In a round bottom flask, 3-cyano-3 was obtained. -Ethyl-azetidine-l-carboxylic acid tert-butyl ester (0.40 g, 1.9 mmol) was dissolved in di-methane (12 mL). The pale yellow solution was cooled to hydr. Trifluoroacetic acid (4 4 ml) was added. After the addition was completed, the ice bath was removed and the reaction mixture was stirred at room temperature for 15 hours. The reaction mixture was concentrated to give a pale yellow oil. Heterocyclic butyl fluoroacetic acid, which was used without further purification. Step 3 2-(1·Mercapto-1H-pyrazol-4-yl)_5H•pyrrolo[2 3_b]pyrazine_7_carboxylic acid [ (R)-2-(3-cyano-3-ethyl-azetidinyl)-cyclopropyl-2-epoxy-ethyl]-decylamine. According to Example 1 The procedure is prepared in which pyridinium is replaced by 3-cyano-3-ethyl-azetidine trifluoroacetic acid, and Boc-D-third-alkaline is replaced by b〇c_d_cyclopropylglycine. Acid, and 2-(1-mercapto- 154395.doc _ 174· 201134826 1 Η-.bazol-4-yl)-5-((2-((trimethyldecyl)ethoxy)) ))-5H-&quot;Birtho[3,2-b]pyrazine-7-decanoic acid instead of 2-cyclopropyl-5-(2-trimethyldecyl-ethoxyindenyl)-5H -pyrrolo[2,3-b]pyrazine-7-formic acid. All steps of removing the N-Boc protecting group use trifluoroacetic acid instead of hydrochloric acid. MS: (M+H)+=433 ° Example 107. 2 -(4-tris-decyl-phenyl-pyrrolo[2,3-b]. than p-well-7- Acid [(R) -l- (4- cyano - piperidine-1-carbonyl) -2,2-dimethyl - propyl] - amine Hai

Prepared according to the procedure described in Example 2, in the step 丨 · · · · -3 -3 -3 -3 -3 -3 -3 -3 _ _ _ _ _ _ _ _ _ _ _ _ _

Which alcohol ester. MS: (M+H)+=513. Example 108.

Guanamine 154395.doc -175- 201134826

Step 1 Combine Boc-D-alanine (500 mg, 2.64 mmol), azetidin-3-acetonitrile hydrochloride (376 mg, 3.17 mmol), HOBT (445 mg ' 2.91 mmol) in a round bottom flask. And HATU (1.11 g, 2.91 mmol). Then DMF (5 mL) and N,N-diisopropylethylamine (1.38 ml, 7.93 mmol) were added sequentially. The yellow reaction mixture was stirred at EtOAc (3 mL) The combined organics were washed with water (3 Torr) and dried over MgSO 4 and concentrated. The residue was purified by EtOAc EtOAc (EtOAc:EtOAc) 1-Base)_ι_曱yl_2_sideoxy-ethylglycolic acid tert-butyl ester. Step 2 to [(R)-2-(3-Cyanoazetidin-1-yl)-1-methyl-2-oxo-ethyl]-carbamic acid tert-butyl ester (860 Add a solution of trifluoroacetic acid (4·〇mL) to a solution of CH2C12 (20 mL). The reaction mixture was stirred at room temperature for 2 hours, then concentrated to give y-((11)-2-amino-propenyl)-azetidine-l-carbonitrile trifluoroacetate as a pale yellow oil. It was used without further purification. Step 3 154395.doc •176· 201134826 Combine 2-bromo-5-((2-((trimethyldecyl)ethoxy)methyl)-5H-pyrrolo[2,3- in a round bottom flask b] pyridinium _7_ decanoic acid (1.05 g, 2.82 mmol) (obtained by Procedure 1 Method B; about 3:1 Br:cl), amine propyl thiol) · azetidin -3- carbonitrile Trifluoroacetate (9 mg, 3.37 mmol) and HATU (1.18 g '3.1 mmo). Then DMF (1 mL) and N'N-diisopropylethylamine (148 ml, 8.46 mmol) were added sequentially. The reaction mixture was stirred at room temperature overnight, then quenched with water and extracted with EtOAc (EtOAc). The combined organics were washed with water (3×), dried over MgSO 4 and concentrated. The residue was purified by EtOAc (30% to EtOAc/EtOAc) elute曱 )))-5H-吼 并[2,3-b]° ratio tillage-7-decanoic acid [(R)-2-(3-cyano-azetidin-l-yl)-l - mercapto-2-yloxy-ethyl]-guanamine (approximately 3:1 mixture of Br and Cl compounds). Step 4 'In a round bottom flask' '2-bromo-5-(2-trimethyldecyl-ethoxymethylpyrolo[2,3-b]» than argon-7-decanoic acid [(R )-2-(3-cyano-azetidin-1-yl)-1-methyl-2-oxoethyl}-decylamine (125 mg, 0.25 mmol) and 3,4, 5-Trimethoxyphenyl tanning acid (78 mg, 0.37 mmol) was dissolved in DME (2.0 mL). K2C03 aqueous solution (2.0 Μ, 0.37 mL, 〇·74 mmol) and Pd(PPh3)4 (14 mg, The mixture was degassed with a gentle n.sub.2 stream for 15 min. The reaction mixture was heated at <RTI ID=0.0></RTI> </RTI> <RTIgt; It was dried over MgSO 4 and concentrated. EtOAc m. Colorless oily 2-(3'4,5-trimethoxy-phenyl)_5·(2_tridecylfluorenyl-ethoxymethyl)-5Η-»pyroloic acid [(R)_2_( 3. Cyano-azetidin-1-yl)]-methyl-2-indolylethyl]-bristamine Step 5 To the above 2-(3,4,5-trimethoxy- Phenyl)-5-(2-tridecylfluorenyl-ethoxy Methyl)-5H-»pyrolo[2,3_b]pyrazine-7-decanoic acid [(R)-2-(3-cyano-azetidin-1-yl)indenyl-2- TFA (〇75 mL) was added to a solution of CH2C12 (2.25 mL). The reaction mixture was stirred overnight and concentrated. The residue was dissolved in ammonium hydroxide, Me 〇H &amp; Mixture (1:10:60, 3.0 mi) and mix for 9 min at room temperature. The reaction mixture was then concentrated and purified by Si 〇 2 chromatography ( 〇 1 〇 % MeOH / CH 2 Cl 2 ) Obtained 97 mg (85%, 2 steps) of 2-(3,4,5-dimethoxy-phenyl)_5H_D in a white powder as a ratio of [2,3_b]n to argon-7-decanoic acid. [(R)-2-(3-Cyano-azetidinyl)-β-indolyl-2-yloxy-ethyl]-decylamine. MS: (Μ+Η)+=465 Example 109. 2-[3-(3,3-Dimethyl-pyrrolidin-1-yl)-phenyl]_5Η•pyrrolo[2 3 b]pyrazine-7-carboxylic acid [(R)-2 -(3-cyano-azetidin-4-yl)methyl_2·sideoxy-ethyl]-decylamine

• 178- 154395.doc 201134826 Step 1 3 / odor amine (i 〇〇 g, and 3 3 dimethyl ketone - 2,5-dione (8 · 2 g, 63 9 mm 〇 1 The suspension was suspended in 3 ° such as dcm. The reaction was stirred at 50 C for 3 hours. The reaction was allowed to cool to room temperature, and U-based dipyridinium (1)·3 g '69 7 mm〇1) was added portionwise. The reaction was again heated to 50 c and stirred overnight. The solvent was evaporated and the product was crystallized from isopropanol to give 9.3 g of 1-(3-bromophenyl)- 3,3-didecyl-pyrrolidine-2,5-dione. Concentrate the mother liquor and use 0% to 20 〇/. Chromatography on a gradient of ethyl acetate / hexane afforded a product. Step 2

1-(3-Bromophenyl)-3,3-dimercapto-pyrrolidine-2,5-dione (1 〇 6 g, 37.7 mmol) was suspended in 2 mL of THF. A borane sulfonium sulfide complex (33 ml ' 10.1 hydrazine solution) was added and the reaction was stirred at room temperature for 3 hours. The reaction was cooled in an ice bath. Methanol (100 ml) was added dropwise, followed by 300 ml of water. This mixture was transferred to a separatory funnel and DCM was added. The separated organic phase was washed with brine and filtered through Celite and concentrated. The product was chromatographed using a gradient of 0% to 5% ethyl acetate / hexanes, concentrated, EtOAc EtOAc (EtOAc) Base-pyrrolidine. Step 3 1-(3-Molyphenyl)-3,3-dimethyl is suspended in 132 ml of THF in each bit (6.7 g, 26.4 mmol) and cooled to _781 in a dry ice acetone bath. Tributyllithium (1.7 Μ solution in pentane, 46.6 ml, 79.2 mmol) was added dropwise and the reaction was stirred at -78 °C for 15 min. Add 2-isopropoxy-4,4,5,5-tetradecyl-[1,3,2]diboron (10.8 ml, 52.8 mmol) and 154395.doc -179- 201134826 at -7 8 The reaction was stirred for 2 hours under C. The reaction was quenched with saturated aqueous gas and heated to room temperature. Water was added and the layers were separated. The aqueous layer was back extracted twice with ethyl acetate. The combined organic layers were dried, filtered and concentrated. The crude product was chromatographed using 〇% to 10% ethyl acetate/hexanes to afford 6 〇g (75%) 3,3-dimethyl-l-[3(4,4,5,5- The base [1,3,2] dioxin _2·yl)-phenyl]pyrrolidine. Step 4 2-[3-(3,3-Dimethyl-0 is more than -1-yl)-phenyl]-5Η-° ratio π each [23 b] pyridin-7-carboxylic acid [(R -2-(3-cyano-azetidin-i-yl)_丨_methylglycol]oxy-ethyl]-guanamine. Prepared according to the procedure described in Steps 4 to 5 of Example 108, wherein 3,3-dimethyl-l-[3(4,4,5,5-tetradecyl[H2]dioxaborazole-2- The phenyl)-pyrrolidine is substituted for the 3,4,5-trimethoxyphenyl phthalic acid. Ms. (M+H)+=472. Example 110· and [2, 3_b]. Specific methyl 2- side gas 2-[3-(3,3-dimercapto-0-lolo-but-1-yl)-phenyl]-5H-. Ratio of 17 cultivable-7-carboxylic acid [(R)-2-(3-cyano-azetidin-1-yl)-1-yl-ethyl]-decylamine

Step 1 3-bromoaniline (2.78 g, 16.2 mmol) and 3-oxabicyclo[3 ι 〇] 154395.doc -180· 201134826 alkane-2,4-dione (2.0 g, 17, 8 mmol) Suspended in 90 mL of dioxane. The reaction was stirred at 50 ° C for 3 hours. The reaction was allowed to cool to room temperature and U&apos;-carbonyldiimidazole (3.14 g, 19.4 mmol) was added portionwise. The reaction was again heated to 5 ° C and stirred overnight, then cooled to room temperature and evaporated. The residue was re-/solved in 90 mL of 1,2- chloroethene and then hydrazine, 1, and several groups were added. Mazole (1.13 g, 7.0 mmol). The reaction mixture was heated under reflux for 25 hours&apos; and then cooled to room temperature. The solvent was evaporated and the product was crystallized from isopropyl alcohol to afford 4. <RTI ID=0.0>#</RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; - Diketone. Step 2 3-(3-Bromo-phenyl)-3•aza-bicyclo[3.1_0]hexane-2,4-dione (4.25 g '16.0 mmol) was suspended in 80 mL THF. A borane sulfonate complex (14.2 ml, 10.1 hydrazine solution) was added and the reaction was heated at 50 ° C for 1 hour, and the reaction was cooled in an ice bath. Decanol (65 ml) was added slowly followed by 15 ml of water. The mixture was extracted with EtOAc (2×). The residue was dissolved in dioxane and the resulting suspension was transferred. The mash was concentrated and 〇% to 2 〇 was used by Si〇2 chromatography. The residue was purified with EtOAc / EtOAc (EtOAc)EtOAc. Step 3 3_(3_Bromo-phenyl)-3-aza-bicyclo[3.1.0]hexane (2.0 g, 8.4 mmol) was dissolved in 40 mL THF and cooled to -78 ° in dry ice acetone bath. C. Tributyllithium (1.7 Μ solution in pentane, 14_8 ml, 25.2 mmol) was added dropwise and the reaction was stirred at -78 °C for 15 min. Add 2-154395.doc -181 - 201134826 Isopropoxy-4,4,5,5-tetramethyl-[H2]dioxaboron (3 4 ,16 8 mmol) and stirred at -78 ° C Reaction for 2 hours. The reaction was quenched with saturated aqueous ammonium chloride and warmed to room temperature. Water was added and the layers were separated. The aqueous layer was extracted twice with ethyl acetate. The combined organic layers were dried, filtered and concentrated. Use 0〇/〇 to 10°/. Gradient chromatography of the crude residue from ethyl acetate / heptane to afford 1.93 g (81%) of white solids of 3-[[(4,4,5,5·tetramethyl-[1,3,2] Diboron-2-yl)-phenyl]-3-aza-bicyclo[3·1.〇]hexane. Step 4 2-[3-(3,3-Dimethyl-pyrrolidin-1-yl)-phenyl]-:5Η-α is compared with [2,3-b] pyridin-7-carboxylic acid [( R)-2-(3-Cyano-azetidin-1-yl)-1_methyl-2-oxo-ethyl]-decylamine. Prepared according to the procedure described in Steps 4 to 5 of Example 108, wherein 3-[3-(4,4,5,5-tetradecyl-[1,3,2]dioxaboran-2-yl) -Phenyl]-3-aza-bicyclo[3.1.0]hexane instead of 3,4,5-trimethoxyphenyl tanning acid. MS: (M+H)+=456. Example 111· 2-(4-Terbutyl-pyridin-2-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(4-cyano- Piperidin-1-yl)-1-cyclopropyl-2-oxo-ethyl]-decylamine

Step 1 Dissolve 4-tert-butyl 11 in a round bottom flask (1.5 g '丨1·1 mmo1). 154395.doc • 182- 201134826 in acetic acid (9 mL) with hydrogen peroxide (3〇) Aq. % aqueous solution, 6 〇 mL, 58.7 mmolp was stirred overnight at 9 (rc). The reaction mixture was cooled to room temperature and concentrated. The residue was poured into about 4 mL of saturated NaAO3 solution with 1 〇〇mL: Extraction with chloromethane (2 χ). The organic layer was combined, dried over sodium sulfate, filtered and concentrated to give EtOAc (EtOAc) In the bottom flask, phosphorus bromine oxide (5.0 g, 17.4 mmol) and 4-tert-butyl ratio N-oxide (0.85 g' 5.34 _〇ι) were dissolved in i,2_di-ethane (35). In mL), the reaction mixture was stirred at 70 ° C overnight, then cooled to warmness and slowly poured into ice. Slowly add sodium hydroxide (5 % aqueous solution) until pH ~ 10 » followed by about 1 mL mL The methane was extracted with a mixture of three times. The organic layer was combined, dried over sodium sulfate, filtered and concentrated. The residue was adsorbed on 4 g of SiO 2 Chromatography of c/hexane (gradient: 〇-1〇〇/0 φ Et〇Ac). All the fractions containing the product were combined and concentrated to give 157 mg (14%) as a colorless oil. - Ternary butyl pyridine. Step 3 2-Bromo-4-t-butylpyridine (149 mg, 7 〇mmol) was dissolved in THF (4 mL) in a round bottom flask. _76. Add n-butyllithium (1.6 μ solution in hexane, 0.57 mL, 0.91 mmol) dropwise. Stir the brown solution at -76 C for 3 min, then slowly add tributyl chlorostannane. (0.23 mL, 0.85 mmol). The reaction mixture was stirred at _76 ° C for 15 min then warmed to room temperature and stirred for 15 h. The mixture was quenched with saturated 154395.doc-183-201134826 NH4C1 aqueous solution with 50 mL Extracted with EtOAc (2x). EtOAc (EtOAc)EtOAc. Chromatography with EtOAc). </ RTI> </ RTI> ) Pyridine. Step 4 In a round bottom flask, 2-bromo-5- (2-ethoxy-Yue Yue alkyl group of silicon-yl) ·-5H. Ratio pyrrolo [2,3-b]. Specific tillage-7-formic acid [(R)-2-(4-cyano-piperidinyl)-1-cyclopropyl-2-oxo-ethyl]-bristamine (95 mg, 0.17 mmol) And 4-tert-butyl-2-(tributyltinyl) hydrazine is more soluble in DMF (1.6 mL) than bite (141 mg, 0.20 mmol). The reaction mixture was evacuated and backfilled with argon. Bismuth (triphenylphosphine) (0) (10 mg, 0.009 mmol) and copper (1) (7 mg '0.03 7 mmol) were added. The reaction mixture was stirred at 90 ° C overnight. The reaction mixture was cooled to rt EtOAc (EtOAc)EtOAc. The combined organic layers were washed twice with 5 mL of water and then washed &lt Residue on MeOH/CH2Cl2/0_5% NH4OH on 24 g SiO 2 (gradient: 0-2%)

MeOH) was chromatographed. All the fractions containing the product were combined and concentrated to obtain 68 mg (59 ° / 〇) 2-(4-t-butyl-pyridin-2-yl)-5-(2-trimethyldecyl-ethoxylate Methylpyrolo[2,3-b]indole-7-carboxylic acid [(R)-2-(4-cyanopiperidin-1-yl)-1-cyclopropyl-2-yloxy -ethyl]-decylamine. Step 5 'In the round bottom flask', make 2-(4-t-butyl-pyridin-2-yl)-5-(2-trimethyl 154395.doc • 184 - 201134826 --ethoxy fluorenyl)-5H-° ratio 咯[2,3-bp ratio till -7-decanoic acid [(R)-2-(4-cyano-substidine-1-yl)-1-cyclo Propyl 2_sideoxy-ethyl]-decylamine (62 mg, 0.091 mmol) was dissolved in di-methane (0.5 mL) and trifluoroacetic acid (0.28 mL). The reaction mixture was stirred for 2 hours, then concentrated under reduced pressure. The residue was dissolved in methylene chloride (5 mL) and ethyldiamine (0.37 mL). 5 mL of water was quenched and extracted with EtOAc (EtOAc) (EtOAc)EtOAc. /0.5〇/〇NH4〇H( Gradient: 0-4% MeOH) was chromatographed, and all the fractions containing product were combined and concentrated to give 28 mg (61%) of yellow foamy solid. )-5H-0 is more than [2,3-b]» than spray-7-formic acid [(R)-2_(4-cyano-slightly &quot;dine-1 -yl)-1 -cyclopropyl- 2-Sideoxy-ethyl]•decalamine. MS: (M+H)+= 486. Example 112. ® 2-(4-Phenyl-pyridin-2-yl)-5H-pyrrolo[2, 3-b]pyrazine_7-decanoic acid [(R)-2-(4-cyano-piperidin-1-yl)-1-cyclopropyl·2· sideoxy-ethyl decylamine

Prepared according to the procedure described in Steps 3 to 5 of Example 111, in which 2-bromo-4-phenylidenepyridine was replaced by 2-diethyl 154395.doc.185-201134826 4-phenylpyridine. MS: (M+H)+=506. Example 113· 2-(4-Thien-2-yl-pyridin-2-yl)-5H-pyrrolo[2,3-b]pyrazine-7-decanoic acid [(R)-2-(4-cyanide) Base-piperidin-1-yl)-1-cyclopropyl-2-isomethoxyethyl]-decylamine

Step 1 In a round bottom flask was charged 2-chloro-4-degradation 0 (600 mg, 2.5 mmol), thiophen-2-yl-acid (385 mg, 3.0 mmol), and trans-digas bis(triphenyl) Phosphine) palladium (11) (176 mg, 0.251 mmol), THF (9 mL), and EtOAc (EtOAc) The reaction mixture was stirred at 70 ° C overnight. The reaction mixture was cooled to rt. then was diluted with EtOAc EtOAc (EtOAc) The combined organic layers were washed with 20 mL of water and 20 mL brine then dried over sodium sulfate filtered and concentrated. The residue was taken up in ca. 2 g EtOAc (EtOAc:EtOAc) Combine all the fractions containing the product and concentrate to obtain 430 mg (88 ° /.) as a pale yellow solid. 2_chloro_4_thiophene-2-ylpyridine 0 Step 2 Add 2-gas to a 20 mL microwave vial _4·thiophene-2-yl-pyridine (428 mg, 2.19 mmol), sodium iodide (3.28 g, 219 mm〇i) and acetonitrile (3 5 154395.doc -186·201134826 mL). Ethylene gas (0.24 mL, 3.4 mmol) was added and the vial was flushed with argon and sealed. The reaction mixture was stirred at 80 ° C overnight. The reaction mixture was cooled to room temperature and quenched with 10 mL of sat. Na.sub.2 C.sub.3. The organic layer was washed with 10 mL of 10% Na2S 203 solution. The aqueous layer was extracted twice with 50 mL of dichloromethane. The organic layers were combined, dried over sodium sulfate, filtered and evaporated. The residue was chromatographed on EtOAc / EtOAc (EtOAc:EtOAc) All the fractions containing the product were combined and concentrated to give EtOAc (yield: EtOAc) Step 3 2-Button-4-exon-2-yl-indole ratio (150 mg, 0.52 mmol) was dissolved in THF (3.2 mL) in a round bottom flask. The pale yellow solution was cooled to -16 ° C (NaCI / ice bath) and isopropyl magnesium chloride (2.0 EtOAc in THF, 0.30 mL, 0.60 mmol). The reaction mixture was stirred at -16 °C for 20 min, then tributyl chlorostannane (〇17 mL, 0.63 mmol) was slowly added. After the addition, the reaction mixture was allowed to warm to room temperature and stirred for 1 hour. The reaction mixture was quenched with EtOAc (EtOAc) (EtOAc) The combined organic layers were washed with EtOAc (EtOAc) (EtOAc m. Pyridine, which was used without further purification. Step 4 2-(4-Thien-2-yl-pyridyl-2-yl)-5H-pyrrolo[2,3-b]pyridin-7-decanoic acid [(R)-2-(4-cyanide)基-娘唆_ι·基)cyclopropyl_2_sideoxy-ethyl]-醯154395.doc -187- 201134826 Amine. Prepared according to the procedure described in Example 111, Steps 4 to 5, in which 4·thien-2-yl-2-(tributylstannyl)pyridine was substituted for 4•t-butyl-2-(tributyltin) bite. MS: (Μ+Η)+=512. Example 114. 2-Pyridin-2-yl-5Η-pyrrolo[2,3-b]pyrho-7-decanoic acid [(Ryi·”·cyano-piperidin-1-carbonyl)-2,2· Dimethyl-propyl]-guanamine

Step 1 A round bottom flask was charged with Boc-D-third-leucine (2.5 g, 1 〇 8 mmol), HOBT (4.2 g, 24.9 mmol), EDC (4.77 g, 24.9 mmol) and piperidine- 4-carbonitrile (2.98 g, 27.0 mmol). Then DMF (50 mL) and N,N-diisopropylethylamine (10.7 m b 61.6 mmol) were added sequentially. The yellow reaction mixture was stirred at rt then EtOAc (EtOAc)EtOAc. The combined organic layers were washed twice with 10% citric acid twice 'salted with saturated LiCl' and washed once with brine, then dried over MgSO 4 , filtered and concentrated to yield 3.4 g (97 ° / 〇) beige A foamed solid [(R)-1-(4-cyano-11dept-1-yl)-2,2-dimethyl-propyl]-aminodecanoic acid tert-butyl ester. Step 2 To [(R)-l-(4-cyano-piperidin-1-carbonyl)-2,2-dimethyl-propyl-amino group 154395.doc •188· 201134826 tert-butyl formate ( 3.4 g, 10·5 mmol) Trifluoroacetic acid (20 mL) was added to a solution of CH2C1 (60 mL). The reaction mixture was stirred at rt overnight then concentrated to give EtOAc (md. The salt was used without further purification. Step 3 Combine 2-bromo-5-(2-trimethyldecyloxyethoxymethyl)_5H-portpyrolo[2,3-b]0 to p-well-7-decanoic acid in a flask (1.6 g, 4.3 mmol), l-((R)-2-amino-3,3-dimethyl-butanyl)-piperidine-4-carbonitrile trifluoroacetate (crude of step 2), EDC ( 1.89 g, 9.9 mmol) and HOBt (1.67 g, 9.9 mmol). DMF (40 mL) and i-Pr2NEt (5.2 mL, 30.1 mmol) were added sequentially. The reaction mixture was stirred overnight at room temperature and then hanked. The residue was dissolved in EtOAc and EtOAc (EtOAc)EtOAcEtOAcEtOAc. - Purification of the residue by chromatography on silica gel (40% / 1-1% EtOAc / hexanes) to obtain 1.46 g (59 ° / 〇) beige foam solid 2 bromo _5_ (2 _Trimethyldecyl-ethoxymethyl)-5-pyrrolo[2,3-b]pyridin-7-carboxylic acid [(R)-l-(4-cyano-piperidinyl)- 2,2-Dimercapto-propyl]-bristamine. Step 4 2-Pyridin-2-yl-5H-pyrrolo[2,3_b]pyrazine·7-carboxylic acid cyano-piperidin-1-carbonyl)·2,2-dimercapto-propyl]-decylamine . Prepared according to the procedure described in Example 1^Steps 4 to 5, wherein 2-bromo-5-(2-trimethyldecyl-ethoxymethyl)-5Η-pyrrolo[2,3_b]pyrazine was prepared. _7_carboxylic acid · piperidine • carbonyl) 2,2 dimethyl propyl] decylamine instead of 2 bromine _5_ (2_ three 154395.doc 201134826 fluorenyl fluorenyl-ethoxy fluorenyl -5H-pyrolo[2,3-b]0 ratio tillage-7-formic acid [(R)-2-(4-cyano-substrate-1-yl)-1-cyclopropyl-2-oxo Base-ethyl]-guanamine and 2-(tributylstannyl)pyridine in place of 4-t-butyl-2-(tributylstannyl). MS: (Μ+Η)+=446. Example 115. 2-(4-Trifluoromethyl-pyridin-2-yl)-5-pyrrolo[2,3-b]pyrazine-7-decanoic acid [(R)-l-(4-cyano substrate) Benzo-1-yl)-2,2-dimercapto-propyl]bristamine

Step 1 2-Bromo-4-(trifluoromethyl)pyridine (330 mg, 丨.46 mmol), bis(tributyltin) (1.44 mL, 2.85 mmol) and PdCl2(PPh3)2 (51) in a microwave vial Mg, 0.073 mmol) was suspended in 1,4-dioxane (15 mL). The mixture was degassed for 15 minutes with a gentle N2 stream. The vial was then sealed and heated at 140 ° C for 3 hours in a microwave reactor. The reaction mixture was allowed to cool to room temperature and concentrated. The residue was purified by EtOAc EtOAc (EtOAc:EtOAc) Step 2 2-(4-Trifluoromethyl-0-Bite-2-yl)-5H-» is more than [2,3-b]0 than p-well-7-decanoic acid [(R)-l- (4-Cyano-peptid-1-one)-2,2-dimercapto-propyl]-bristamine. Root 154395.doc • 190·201134826 Prepared according to the procedure described in Example 111, Steps 4 to 5, wherein 2-bromo-5-(2·didecyldecyl-ethoxymethyl)·5Η-pyrrolo[ 2,3-b]pyrrol-7-formic acid [(R)-l-(4-cyano-piperidin-indole-carbonyl)_2,2-diindolyl-propyl]-decylamine instead of 2_bromo 5-(2-trimethyldecyl-ethoxycarbonyl)·5Η_pyrrolo[^...pyr 11 well-7-decanoic acid [(R)-2-(4-cyano-slightly bite small base) Cyclopropyl-2-oxo-ethyl]-decylamine, and 2-tert-butyltin-4-yl-trifluoromethyl-pyridine as a substitute for 4-t-butyl-2-(dibutyltin) π Specific bite. ms: (m+H)+=5 14. Example 116. 2-(4-Methoxy-pyridin-2-yl)-5H-pyrrolo[2,3-b]pyrazine-7- Capric acid [(R)-1-(4-cyano-piperidin-1-carbonyl)_2,2-dimethyl-propyl]-decylamine

Step 1 2-Bromo-4-decyloxypyridine (315 mg, j 68 mm 〇1) was dissolved in TMF (6 mL) in a round bottom flask. The solution was cooled to 〇 ° C and «added isopropyl magnesium chloride vaporized lithium complex (J 3 M in THF, i 35 can, i % mm 〇 1). The reaction mixture was stirred at 〇 ° C for 30 minutes, then at room temperature for 1.5 hours. Add another __ part of the isopropyl chlorided complex (13 Μ in THF 〇. 15 mL, 〇 2 〇mm〇1) and continue to drop for 30 minutes at room temperature. Tributyltin chloride (0.50 mL·, 1.84 mm 〇i) was added and the reaction mixture was incubated at room temperature 154395.doc • 191 - 201134826 for 2 hours. Concentration (iv) 4 was reviewed for its % hydrazine mixture to give a white syrupy of 4-decyloxy-2- butylstannyl-pyridinium, which was used without further purification. Step 2 2-(4-decyloxy-2-yl)_5H_n ratio % gluten l2,3-b]pyrazine-7·decanoic acid [(R)-l-(4-cyano-piperidine- 1-carbonyl)_2 2_ _-T-propyl-propylamine. Prepared according to the procedure described in Example 111, Steps 4 to 5, wherein 2:5·(2_tris(tetra)ylethoxymethyl)_5Η♦ each [2,3_b(4) well-7-formic acid [(R)- 1-(4-Cyano-piperidin-1-carbonyl)_2,2-dimethyl-propyl]decylamine instead of 2·bromo-5-(2-tridecylfluorenyl-ethoxymethyl) _5Η(ΐ比咯和^...pyrazine-7·decanoic acid [(R)-2-(4-cyano-piperidinyl)cyclopropyl_2_sideoxy-ethyl]-decylamine and 4-methoxy-2-tributylstannyl-pyridine was substituted for 4-tert-butyl-2-(tributyltin). MS: (M+H)+=476. Example 117. 2-( 4-cyclopentyloxy-β ratio biti-2-yl)-5Η-° ratio &gt;» each [2,3-b]&quot; ratio p well-7-formic acid [(R)-1 - (4 ·Cyano group, bite _1_alkyl group,-2,2-dimethyl-propyl]-guanamine

Step 1 To 2-bromopyridine-4-ol (1.6 g, 9.2 mmol) in a microwave vial and bromine ring 154395.doc • 192-201134826 pentane (1.28 mL, 12.0 mmol) in DMF (12 mL) Carbonate planer (4.19 g, 12.9 mmol) was added to the solution. The vial was sealed and heated in a microwave reactor at 120 °C for 2 hours. The reaction mixture was cooled to EtOAc (EtOAc) The combined organics were washed with saturated LiCl and saturated NaCl, then dried over MgSO 4 and concentrated. The residue was purified by EtOAc (20% to 30%EtOAcEtOAc) elute Step 2 2-Bromo-4-cyclopentyloxypyridine (339 mg, 1.40 mmol) was dissolved in THF (6 mL). The solution was cooled to 〇 ° C and isopropylmagnesium chloride gasification clock mixture (1.3 Μ in THF, 1.1 mL, 1.47 mmol) was added dropwise. The reaction mixture was stirred at 〇 ° C for 15 minutes, followed by stirring at room temperature for 2 hours. A further part of the isopropylmagnesium chloride vaporized lithium complex (1.3 Μ ' in THF '0.27 mL, 0.35 mmol) was added and the mixture was continued for 30 minutes at room temperature. Tributyltin chloride (〇 42 mL, 1.54 mmol) was added and the mixture was stirred at room temperature for 2 hr. The reaction mixture was quenched with water and extracted with EtOAc. The organic phase was washed with brine, dried with EtOAc EtOAc EtOAc EtOAc EtOAc Step 3 2-(4-Cyclopentyloxypyridin-2-yl)_511_pyrrolo[2,3-7]pyrylene-7-decanoic acid [(R)_l-(4-cyano-piperidine_ 1_carbonyl)_2,2-dimethyl-propyl]•decylamine. Prepared according to the procedure described in Steps 4 to 5 of Example 111, wherein 2•bromo-5((2-trimethyldecyl-ethoxymethyl)_5Η-pyrrolo[2,3_b]pyrrolic acid 154395. Doc -193- 201134826 [(R)-1-(4-Cyano-piperidin-1-carbonyl)-2,2-dimethyl-propyl]-guanamine instead of 2-bromo-5-(2- Trimethyldecyl ethoxymethyl)·5Η-indolo[2,3-b]pyridin-7-carboxylic acid [(R)-2-(4-cyano-piperidin-1-yl) ) 丨 环 环 _2 _2 _2 _2 _2 _2 _2 , , , , , , , , , , , , , , , , , , , , , 4- 4- 4- 4- Butyltinyl). Bisidine. MS: (M+H)+=53〇. Example 118· 2-(4-Cyclopropylmethoxy-pyridin-2-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(4-cyanide) --Bistidin-1-yl)_1·cyclopropyl·2_sideoxy-ethyl]-decylamine

Step 1 Add a carbonation planer to a solution of 2-bromopyridin-4-ol (1.6 g, 9.2 mmol) and (bromomethyl)cyclopropane (1.61 g, 12.0 mmol) in DMF (12 mL) in a microwave vial. (4.19 g, 12.9 mmol). The vial was sealed and heated in a microwave reactor at 140 °C for 4 hours. The reaction mixture was cooled to EtOAc EtOAc (EtOAc) The combined organics were washed with saturated NaCl, then dried over MgSO 4 and concentrated. Purification of the residue by EtOAc (20% to 50%EtOAcEtOAc) elute Step 2 154395.doc -194- 201134826 2-Bromo-4-cyclopropyl decyloxy-pyridyl (315 mg, 1.38 mmol) was dissolved in THF (6 mL) in a round bottom flask.异丙c and isopropyl chloride chlorinated clock complex (1.3 Μ in THF, 1 1 inL, 1.45 mmol) was added dropwise. The reaction mixture was stirred at 0 ° C for 3 Torr, then at room temperature for 1.5 hr. Tributyltin hydride (〇 42 [ [, 丨 52 mm 〇 1) was added and the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was quenched with water and extracted with EtOAc. The organic phase was washed with EtOAc (EtOAc m. Step 3 2-(4-Cyclopropyldecyloxy"pyridin-2-yl)_5Η_pyrrolo[2,3刘pyrylene_7·carboxylic acid [(R)-2-(4-cyano) Pyridyl i-yl)cyclopropyl-2 oxo-ethyl]-decylamine. Prepared according to the procedure described in Example 1U, Steps 4 to 5, with 4-propylpropylmethoxy-2-dibutyltin. The base is replaced by 4·t-butyl-2-(dibutylstannyl)pyridine. Ms: (M+H)+=5〇〇.

Example 119. 2_(4_cyclopropylmethoxy-° ratio _2. base)-5 士&quot;Bildo[2,3-b]pyroxycetic acid [W-2-(3-cyano) ·azetidine]•yl)small methyl I-oxy-ethyl]-decylamine

154395.doc 195· 201134826 Prepared according to the procedure described in Example 1 Π Steps 4 to 5, wherein 2_-_ 5-(2-tridecyl decyl ethoxymethyl)_5H_pyrrolo[2 ,3_b]pyridinium_7_carboxylic acid [(R)-2-(3-cyano-azetidinyl"-yl)methyl_2_sideoxyethyl]-nitramine instead of 2-bromo-5 -(2-trimethylglyoxime-ethoxymethyl)_5^_11 pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)_2_(4-cyano-piperidinyl) )_丨_cyclopropyl-2-oxo-ethyl]-decylamine and replacing 4-tert-butyl_2 with 4·cyclopropylmethoxy-2-tributylstannyl-n-pyridinium -(tributylstannyl)pyridine. MS: (M+H)+ = 446. Example 120. 2-(4-pyrazol-1-yl-pyridin-2-yl)-5H-pyrrolo[2,3- b]pyrazine-1-7-formic acid [(R)-2-(3-cyano-azetidinyl)·〗 _ mercapto-2-epoxyethyl]-bristamine

CN Step 1 2-Bromo-4-(l-pyrazol-l-yl)pyridine (0.15 g, 0.67 mmol) was dissolved in thf (44 mL). The pale yellow solution was cooled to 0 C and isopropyl magnesium sulphide vaporized lithium complex (1.3 Μ solution in THF, 0.57 mL, 0.74 mmol) was added dropwise. The reaction mixture was stirred at 〇 °c for 25 minutes and at room temperature for 15 hours. Add another portion of the isopropylated gasification gasification complex (1·3 Μ solution in THF, 〇·29 mL, 154395.doc 201134826 0·38 mmol) and stir the reaction mixture for 3 〇 at room temperature. . The reaction mixture was cooled to 〇 ° C and tributyl succinimide (0.21 mL, 0.77 mmol) was slowly added. After the addition was completed, the ice bath was removed and the reaction mixture was taken up at room temperature for 1 hour. The reaction mixture was quenched with saturated aq. EtOAc (EtOAc) The combined organic layers were washed with ca. 5 mL EtOAc (EtOAc) EtOAc (EtOAc) It was used without further purification. Step 2 2-(4-Pyrazol-1-yl-pyridin-2-yl)-5H-pyrrolo[2,3-b]pyrazine-7-decanoic acid [(R)-2-(3-cyanide) Base-azetidine-i-yl)_ι_methyl_2_sideoxy-ethyl]•decylamine. Prepared according to the procedure described in Steps 4 to 5 of Example 111, wherein 2-bromo-5-(2-trimethyl-stone-ethoxymethyl)-511-° ratio '1 each [2,3- 13] Pyridin-7-formic acid [(R)-2-(3-cyano-azetidin-1yl)- 1 methyl-2-oxo-ethyl]-decylamine substitute 2 -Bromo-5-(2-tridecyldecyl-ethoxycarbonyl)-5Η-0-pyrolo[2,3-b]indole-7-carboxylic acid [(R)-2-(4- Cyano-piperidin-1-yl)-1-cyclopropyl-2-sideoxy-ethyl]-bristamine and in a ratio of 4 -°&lt;» sit-1-yl-2-tributyltin -β is more specific than β-buttering 4-tert-butyl-2-(tributyltin). MS: (Μ+Η)+=442. Example 121· 2-(4-&quot;Bilo-1-yl-pyridin-2-yl)-5-pyrido[2,3-b]pyridin-7-carboxylic acid [(R)-2-( 3-cyano-azetidin-1-yl)-1-methyl-2-oxo-ethyl]-decylamine 154395.doc • 197- 201134826

.CN

Step 1 2-Bromo-4-(1H-pyrrol-1-yl)pyridine (0.20 g, 0.90 mmol) was dissolved in THF (6 mL). The light yellow solution was cooled to 〇 °c and isopropyl magnesium sulphate lithium chloride complex (1.3 Μ solution in THF, 0.78 mL, 1.0 mmol) was added dropwise. The reaction mixture was stirred at Ot: for 40 minutes' and stirred at room temperature for 2 hours. The reaction mixture was cooled to 〇 ° C and dibutyl sulphide (0.28 mL, 1.03 mmol) was slowly added. After the addition was completed, the ice bath was removed and the reaction mixture was stirred at room temperature for 1.5 hours. The reaction mixture was quenched with saturated NH.sub.1 solution. The combined organic layers were washed with ca. 5 mL EtOAc (EtOAc) EtOAc (EtOAc) It is used immediately after purification. Step 2 2-(4-pyrrole-fluorenyl-pyridyl-2-yl)·5Η_pyrrolo[2,3_b]pyrazine-'carboxylic acid [(R)-2-(3-cyano-nitrogen heterocycle) Butane•yl)_丨_methyl_2_sideoxy-ethyl]-decylamine. Prepared according to the procedure described in Steps 4 to 5 of Example 111, wherein 2-bromo-5-(2-trimethyldecyl-ethoxymethyl)-5H-pyrrolo[2 3 b] was compared to - 7-carboxylic acid [(R)-2-(3-cyano-decahydrocyclobutanyl) small methyl '2_sideoxy-ethyl]•••=========== Trimethyldecyl _ethoxy hydrazine 154395.doc • 198- 201134826 yl)-5H-»Bilobut[2,3,b]pyrrol _7·formic acid [(R)_2-(4·cyano) - piperidine-hydrazino-ylcycloprop-2-enyl-yl-ethyl]-decylamine and substituted 4-_t-butyl-2_ with 4-pyrrol-1-yl-2-tributyltin (Tributylstannyl)pyridine MS: (M+H)+=44l. Example 122. 2-(4-cyclopent-1-enyl-D-pyridin-2-yl)_5Η_pyrrolo[2, 3_b]pyrazine_7•formic acid [(R)-2-(3-cyano-azetidin-1-yl)-1-methyl-2-oxo-ethyl]·guanamine

Step 1 to 2-cyclopentenyl·4,4,5,5-tetramethyl-1,3,2-diboron (681 mg, 3.51 mmol) and 2-gas-4-A η ratio bite (700 mg, 2.92 mmol) in 1,4-two.恶炫&lt;(12 1111〇) added 2_〇]^\&amp;2 (:03 aqueous solution (4.39 mL, 8.77 mmol) and hydrazine (triphenylphosphine) palladium (0) (67·6 mg, The reaction mixture was heated at 9.0 ° C for 3-5 hours, then cooled to EtOAc EtOAc EtOAc (EtOAc) Chromatography (〇% to 1% 〇% 〇Ac/hexane) The residue was purified to give a white powder (yield: &lt;RTI ID=0.0&gt;&gt; .doc -199- 201134826 The flask was charged with sodium iodide (3.75 g, 25.0 mmol), 2-chloro-4-cyclopenta-1-ene group (450 mg, 2.5 mmol) and acetonitrile (8 mL). The mixture was stirred with EtOAc (3×), EtOAc (EtOAc)EtOAc. The combined organics were dried <RTI ID=0.0></RTI> to <RTI ID=0.0> Set. Step 3 Add n-BuLi (1.6 Μ to a solution of 2-methyl-cyclo-4-penta-l-yl-β-bit (15 〇 mg, 0.55 mmol) in THF (3 mL) at -78C '0.38 mL '0.61 mmol) in the alkane. The resulting deep-draw color solution was stirred at -78 °C for 15 min, then tributylstannane (0.17 mL, 61 mmol) was added dropwise at -78 °C. The mixture was stirred and stirred for 30 minutes, then warmed to room temperature &lt;~&gt;&lt;[&gt;&gt;&lt;[&gt;&gt;&gt;戊_ι_稀基_2_ Tributylstannyl-pyridine, which was used without further purification. Step 4 2-(4-Cyclopent-1-enyl-buty-2-yl)-5H-. Each [2,3-b]β-pyrrolic acid [(R)-2-(3-cyano-azetidin-1yl)methyl_2_sideoxy-ethyl]-oxime Amine prepared according to the procedure described in Steps 4 to 5 of Example 111, wherein 2-bromo-5-(2-trimethyldecyl-ethoxymethyl)-5H-pyrrolo[23_b]. 7-decanoic acid [(R)-2-(3-cyano-azetidine-i-yl H•methyl-2_sideoxy-ethyl]-decylamine instead of 2-bromo-5- (2-trimethylsulfanyl-ethoxymethyl 154395 .doc 200· 201134826 yl)-5H-pyrrolo[2,3_b]pyrrole_7•decanoic acid [(r)-2_(4cyano-piperidinyl)-1-cyclopropyl-2- The pendant oxy-ethyl; decylamine and 4- 4-cyclopentenyl-2-dibutylstannyl-pyridine in place of 4-t-butyl-2-(tributylstannyl)pyridine. MS: (M+H)+=442. Example 123.

2 (3 ratios each. Determine small base _ phenyl) _5 Η π π 咯 [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( Oxo-ethyl]-decylamine

According to the procedure of Example 1 〇8, Step 4 5 Λ &amp;, +. and traits, the towel is 3·(〇比献(_), 444. Generation, 5·dimethoxyphenyl butterfly acid.

Example 124. 2-(1-Cyclopentyl·1Η-[ι,2 carboxylic acid [(R)-2-(4 cyano)]]amine 3]triazol-4-yl)-5H-pyrrolo[ 2,3_b]pyrazine-piperidin-1-yl)-1-cyclopropyl_2_sideoxy B

154395.doc 201134826 Step 1 to 2-bromo-5·(2-trimethyldecyl-ethoxymethyl)-5H 0 0-pyrrolo[2,3-b]pyrazine-7-decanoic acid [(R) )-2-(4-cyano-piperidin-1-yl)cyclopropyl_2· oxo-ethyl]-decylamine (〇.5〇g '0.89 mmol) (5-Br and 5- Addition of triethylamine (〇5〇mL, 3.56 mmol), ethynyltridecyldecane (0.15 mL, 1.07 mmol), Pd (PPh3) to a solution of C1 5:1 mixture in DMF (3 mL) 2Cl2 (31.2 mg, 0.045 mmol) and copper iodide (1) (8.5 mg, 0.045 mmol). All solids were dissolved after the addition of Cul. The reaction mixture was stirred at room temperature for 30 minutes, followed by 5 Torr. (The mixture was heated for 1 h. The reaction mixture was cooled to EtOAc EtOAc (EtOAc)EtOAc. The residue was purified by chromatography (50% to 100%EtOAcEtOAcEtOAc) Trimethyl hydrazinoalkylethynyl _5H_pyrrolo[2,3_b]pyrazine-7-decanoic acid [(R)-2-(4-cyano-piperidinyl-1-yl)-cyclopropyl _ 2_Sideoxy-ethyl bromoamine. NMR showed the presence of traces of unreacted 5_C1 pyrrolopyrazine. Step 2 to 5-(2-trimethyldecyl-ethoxymethyl) at room temperature _2_Trimethyl fluorenyl ethynyl-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(4-cyano-0 bottoming-1-yl)- Add a ruler 2 (: 〇3 (10 mg, 0.072 mmol) to a solution of 1-cyclopropyl-2· oxo-ethyldoxime (4 mg, 〇69 mmol) in MeOH (8 mL) The reaction mixture was allowed to stand at room temperature for 3 minutes, then concentrated. The residue was dissolved in CH2C12 and washed with water. The organic layer was dried and concentrated with EtOAc. % to 100% EtOAc / hexane) Purified residue 154395.doc 201134826 Residue, obtained 310 mg (89%) of light brown foamy solid 2-ethynyl-5-(2-trimethyldecyl-ethoxy Methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(4-cyano-piperidin-1-yl)-1-cyclopropyl_2_ The pendant oxy-ethyl]-nonylamine. NMR showed the presence of traces of 5-Cl ° ratio β and ° ratio p. Step 3 Prepare azido cyclopentane according to the procedure described in 1997, 413: Solid sodium azide (192 mg, 2.95 mmol) was added to a solution of odorant (0.40 g, 2.68 mmol) in DMSO (6 mL) at room temperature. The solution was gradually dissolved over about 1 hour. The reaction mixture was stirred overnight at room temperature, then quenched with water and extracted with Et20 (2×). The combined organics were washed with water (3×) and then dried at &lt;RTI ID=0.0&gt; Concentrate carefully to give a colorless oily azidylcyclopentane which was used without further purification. Step 4 </ RTI> </ RTI> </ RTI> 2- ethynyl-5-(2-tridecyl fluorenyl-ethoxy) in a microwave vial曱 ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) _1 _ yl)-1-cyclopropyl-2-oxo-ethyl]-chiral amine (1 〇〇 mg, 0.20 mmol), azidocyclopentanol (32.9 mg, 0.3 mmol), t-BuOH (0.6 mL) and H2 〇 (0.6 mL). To this viscous mixture, ί ο μ copper sulphate (39.5 pL, 0.04 mmol) and copper powder (1 〇.〇 mg, 〇·ΐ 6 mm〇i) were added. The vial was sealed and the heterogeneous reaction mixture was heated in a microwave reactor at 125 °C for 5 minutes. The reaction mixture was cooled to room temperature and filtered and washed with EtOAc. The filtrate was washed with water &lt;RTI ID=0.0&gt;&gt;&&&&&&&&&&&&&&&&&&&&&&&&&& 201134826 Foamed solid 2·(1-cyclopentyl_1Η·[12 3]trisin-4-yl)_5_(2·trimethyldecyl-ethoxymethyl)_5Η-pyrrolo[2 3_b] Pyridinium-7-formic acid [(r)_2_(4-cyano-piperidin-1-yl)-indole_cyclopropyl-2 sideoxyethyl]decylamine. Step 5 To 2-(1-cyclopentyl-1H-[1,2,3]triazol-4-yl)-5-(2-trimethyldecyl-ethoxymethyl)-5Η-η咯 并 [2,3_bp ratio tillage_7_carboxylic acid [(R)-2-(4-cyano-piperidin-1-yl)-1-cyclopropyl-2-oxo-ethyl]_ To a solution of decylamine (85 mg, EtOAc (EtOAc) (EtOAc) The reaction mixture was stirred at room temperature for 3 hours' then concentrated. The residue was redissolved in CH2C12 (4 mL) and ethyldiamine (5 mL). The reaction mixture was removed at room temperature for 0.5 hour and then concentrated. By gelatin chromatography (5% to 100% EtOAc / hexane to 5% MeOH / EtOAc, then 〇〇 / to 5%

Purify the residue twice with MeOH/CH 2 Cl 2 (0.5 〇 / 〇 NH 4 OH), then use

EhO wet grinding, separation of 35 mg (52 ° /.) white powder of 2-(1_cyclopentyl-1 s[1,2,3]trisul-4-yl)-5H_0 to 0 and [2, 3-b]n than well -7-formic acid [(R)_2-(4-cyano-D-diyl-1-yl)-1-cyclopropyl-2-oxo-ethyl] amine. Ms: (M+H)+=488. Example 125. 2-(1-Phenyl-1H-[1,2,3]tris(4-yl)-5H-° ratio d[2,3_b]n ratio p-well-7-carboxylic acid [ (R)-2-(4-cyano-piperidin-1-yl)-bucyclopropyl.2_sideoxy-ethyl]_ decylamine 154395.doc •204- 201134826

Step 1 Slowly add sodium nitrite (289 mg, 4.19 mmol) to water (1 mL) at 0 ° C to aniline (300 mg, 3.22 mmol) in water (2 mL) and concentrated EtOAc (1 mL) Solution in ). The reaction mixture was stirred at 〇 °c for 10 min then a solution of sodium azide (25 1 mg, 3.87 mmol) in water (1 mL) was slowly added. The reaction mixture was stirred at room temperature for 1 hour, then extracted with Et20 (2x). The combined organics were washed with water, dried <RTI ID=0.0>(M </RTI> <RTI ID=0.0></RTI> </ RTI> </ RTI> </ RTI> and concentrated carefully at 300 Torr and ambient temperature to afford 350 mg (91%) of pale orange oily azidobenzene. Step 2 2-(1-Phenyl-1H-[1,2,3]triazol-4-yl)-5H-n than argonium [2,3-b] ° than tillage 7-carboxylic acid [(R -2-(4-cyano-D-decyl small group) small cyclopropyl _2_sideoxy-ethyl]-guanamine. Prepared according to the procedure described in Example 124, Steps 4 to 5, in which azidocyclopentane was replaced with azidobenzene. MS: (M+H)+=496. Example 126. 2-(3-Methylaminoindenyl-phenyl)·5Η_pyrrolo[2,3_b]pyrazine·7-carboxylic acid [(R)-2-(3-cyano-nitrogen heterocycle) Butane·丨·基)·〗 〖曱 base_2_sideoxy-ethyl]_ decyl 154395.doc •205- 201134826

,CN

Hn^ N

Prepared according to the procedure described in Steps 4 to 5 of Example 108, in which 3,4,5-trimethoxyphenyl phthalic acid was replaced by tris(methylcarbamoyl)phenyl-acid. MS: (M+H)+=432. Example 127. φ 2-(3-Isopropylamine-mercapto-phenyl)_5H-0 pyrrole ratio tillage_7_carboxylic acid [(R)-2-(3-cyano-azetidinyl) Methyl-2-oxo-ethyl decylamine

To 2-bromo-5-(2-tridecyldecyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(3-cyanide) Alkyl-heterocyclobutane-(yl)-yl-2-yloxy-ethyl]•decylamine (2〇〇mg' 0.39 mmol) (a mixture of 5-Br and 5-C1 of about 3:1) And 3-carboxyphenyl g-p-acid (85·〇mg, 0.51 mmol)

Add Pd(Ph3P;) 4 (22.8 mg, 0.02 mmol) and 2.0 M Na2C〇3 in water (0.8 mL, 1.6 mmol) to a solution in 1,2-DME (4 mL) at 90 ° C 154395.doc • The reaction mixture was heated overnight at 206-201134826, then cooled to room temperature and diluted with water. It was adjusted to pH 6 with 1.0 M HCl and then extracted with EtOAc (2x). The combined organics were dried over MgSO 4 and concentrated. The residue was purified by silica gel chromatography ( 〇% to 4% Me 〇H/CH2Cl2 (0.5% NH4OH) to afford 145 mg (67 / 〇) white foam solid 3-[7-[(r)_2- (3-cyano-azetidinyl)-1-indolyl-2-yloxy-ethylaminoindenyl]_5_(2-trimethyldecyl-ethoxymethyl)-5H -° is more than [2,3-b]n than chlorin-2-yl]-benzoic acid. Step 2 to 3-[7-[(R)-2-(3-cyano-azetidinyl)-indenyl-yl-2-yloxy-ethylamine-methylhydrazine] -5-(2-tridecyldecyl-ethoxymethyl)·5Η_〇Λ 嘻[2,3-b] 0 ratio ρ  -2-yl]·benzoic acid (7 〇 mg, Add isopropylamine (44, 0.51 mmol) to a solution of 0.13 mmol) and HATU (53.4 mg, 0.14 mmol) in DMF (1.5 mL). The reaction mixture was stirred at rt EtOAc (EtOAc) The organics combined with water (3 Torr) and brine were then dried over MgSO 4 and concentrated. Use 50〇/. To 100. /. Chromatography of EtOAc/hexanes eluting 52 mg (69%) of EtOAc (EtOAc: EtOAc)曱 )))-5Η·η ratio 咯[2,3-b]. Specific tillage-7_carboxylic acid [(R)-2-(3-cyano-azetidin-1·yl)·1-methyl_2-sideoxy-ethyl]-decylamine Step 3 To 2-(3-isopropylaminoindenyl-phenyltrimethylsulfonyl-ethoxymethyl)-5Η-pyrrolo[2,3-b]pyrazine-7-decanoic acid [(R 2-(3-cyano-azetidin-1-yl)-1-indenyl-2-oxo-ethyl]-decylamine (52 mg, 0.088 mmol) in CH2C12 (4 mL TFA (1.5 mL) was added to the solution. The reaction mixture was stirred at room temperature 154395.doc -207-201134826 for 3 hours, followed by concentration. The residue was redissolved in CH2C12 (4 mL) and ethyldiamine (5 mL). The reaction mixture was stirred at room temperature for 0.5 hr then concentrated. The residue was purified by chrome chromatography to 100% EtOAc / hexanes to 5% EtOAc (EtOAc) EtOAc EtOAc EtOAc EtOAc笨基基)-5H-吼 并[2,3-b]吼耕-7_曱酸[(R)_2_(3·cyano-azetidin-1-yl M-methyl-2 -Sideoxy-ethyl]-decylamine. Ms: (m+h)+:= 460 ° Example 128. 2-[3-(cyclopropylmethyl-aminocarbamoyl)-phenyl]_5Η_η ratio咯[2,3_b]D is more than 7-carboxylic acid [(R)-2-(3-cyano-azetidinyl)-yl)methyl-2-oxo-ethyl]- Amine

Prepared according to the procedure described in Example 127, steps 2 to 3, in which isopropylamine was replaced by cyclopropylmethylamine. MS: (M+H)+=472. Example 129. 2-(4-Mercapto-aminomethylpyridinylpyridine-2-yl)-51^pyrrolo[2,3_b]pyrrolic acid [(R)-2-(3-cyano-azetidine) Alkyl small group) methyl 2 • pendant oxy-ethyl] aryl amine 154395.doc -208- 201134826 h&lt;

Step 1 In a round bottom flask was charged 2-iodoisonicotinic acid (0.70 g, 2.81).

HOBt (474 mg, 3.09 mmol) and EDC (593 mg, 3_〇9 mm〇i). DMF (4 mL) and decylamine (2.0 M solution in THF, 8.0 mL, 16.0 mmol) were then weighed. The reaction mixture was quenched with water and extracted with EtOAc EtOAc. The combined organic layers were washed twice with ca. 5 mL water and washed with EtOAc (EtOAc) EtOAc. The residue was chromatographed on EtOAc / EtOAc (EtOAc:EtOAc All the fractions containing the product were combined and concentrated to give &lt;RTI ID=0.0&gt;&gt; Step 2 In a round bottom flask, 2-iodo-N-mercaptoisonicoinamide (〇18 g' 〇69 mmol) was dissolved in THF (3.9 mL) and sodium hydride (60% in mineral oil) was added. Dispersion, 33 mg, 0.83 mmol). The reaction mixture was stirred at room temperature for 10 minutes, then cooled to -16t: (NaCI / ice bath) and isopropyl was added dropwise.

The reaction mixture was stirred at -16 °C for 40 min then tributylstannane (0.22 mL, 0.81 mmol) was slowly added. The reaction mixture was allowed to warm to room temperature and stirred for 2 hours, then quenched with saturated aqueous solution of &lt;RTI ID=0.0&gt;&gt;

Extracted with EtOAc (2x). The combined organic layers were washed with brine (5 mL) and then brine. The residue was chromatographed on EtOAc / hexane (EtOAc: EtOAc (EtOAc) All product-containing fractions were combined and concentrated to give &lt;RTI ID=0.0&gt;&gt;&gt; Step 3 2-(4-Mercaptoamine thiol- η than hexane-2-yl)-5Η·°Biluo[2,3-1?]0 ratio _-7· formic acid [(R)-2 -(3-Cyano-azetidinyl)_indenyl-2-yloxy-ethyl]-bristamine. Prepared according to the procedure described in Steps 4 to 5 of Example 111, wherein 2-bromo-5-(2-tridecylfluorenyl-ethoxymethyl)-5Hpyrrolo[2 3 b]pyrazine-7- Formic acid [(R)-2-(3-cyano-azetidinyl-indenyl)_jmethyl-2-oxo-ethyl]-decylamine instead of 2-bromo-5-(2 -三曱基石夕院基_ethoxycarbonyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(r)_2_(4-cyano-piperidine.bu) 1-cyclopropyl-2-oxo-ethyl]-decylamine, and replaced by 4-t-butyltin- 2 -(butyl butyl sulphate) with methyl 2 -t-butyltin-based-iso-final amine Base) indole. MS: (M+H)+=433. Example 130. 2-[1-(4-Fluorophenyl)-1Η-°Bizozol-4-yl]-5H-pyrrolo[2,3_b]pyrazine-7-carboxylic acid [(R)-l-( 4-cyano-l-pyridine-1-carbonyl)·2,2-dimercapto-propyl]-decylamine

154395.doc -210- 201134826 Prepared according to the procedure described in Example 2, in the step of replacing W(8)-2-amino-3U-yl-butyl-branol)4 with 4-fluorenyltrifluoroacetate ((iv)amine Base-3,3-methyl-l-bite _] 萁丁, 丞-but-1-鲖 hydrochloride and in step 2 with 1-(4-fluorophenyl) Butyric acid replaces ethyl ethyl (1) _ 吼嗤 _4 · carboxylic acid pinacol ester. MS: (M + H) + = 529. Example 131. 2-(1-cyclopropylmethyl) H-flavor. 4_基)·5Η_pyrrolo[2,3_b]pyrazine citrate [(R)-l-(4-cyano-nine bite+yl)_2,2•dimercapto-propyl] amine

Step 1 To a solution of 4-fill-1H-imidazole (800 mg, 4.12 mmol) in DMF (50 mL) was added cesium carbonate (5.37 g, &lt;RTI ID=0.0&gt; 16.5 mmol). The reaction mixture was stirred at rt EtOAc (EtOAc)EtOAc. The organic layer was dried over MgSO 4 and concentrated. The residue was purified by gelatin chromatography (50% to 100% EtOAc/heptane) to isolate the first batch of 590 mg (58%) as a light yellow oil, 1-cyclopropyl-mercapto-4-iodo-1H-imidazole. Then 227 mg (22%) of 1-cyclopropylmethyl-5-iodo-1H-imidazole as a pale yellow oil was isolated. 154395.doc -211- 201134826 Step 2 In a round bottom flask, 1-cyclopropyl hydrazino-4-moth-1 Η-11 m was obtained. Sitting (570 mg, 2.3 mmol) was dissolved in THF (10 mL). Allow the solution to cool to hydrazine. Isopropylmagnesium chloride (2.0 Torr in THF, 1.15 mL, 2.3 mmol) was added dropwise. The reaction mixture was allowed to warm to rt and stirred for 1.5 h. Tributylstannane (0.62 mL, 2.3 mmol) was added and the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was quenched with a saturated aqueous solution of ?? The combined organics were washed with brine, dried over MgSO 4 and evaporated. The residue was purified by silica gel chromatography eluting with 20% to 50% EtOAc / EtOAc (EtOAc: EtOAc) Butyltin alkyl _ 1H-0 m. sit. Step 3 'To 2-bromo-5-(2-trimethyldecyl-ethoxymethyl)-5Η-»bi-[2,3-]pyrazine-7-carboxylic acid in a round bottom flask [ (R)-i_(4-cyano-piperidinyl-yl)- 2,2-monomethyl-propyl]-chiral amine (150 mg, 0.26 mmol) and 1-cyclopropyldecyl- 4-Tributylstannyl-1H-imidazole (160 mg, 0.39 mmol) was dissolved in DMF (2 mL). Pd(PPh3)4 (15 mg, 0.013 mmol) and Cul (10 mg, 0.052 mmol) were added. The reaction mixture was heated at 80 ° C for 1 h then cooled to EtOAc EtOAc EtOAc. The organic extract was washed with a saturated aqueous solution of LiCl and brine, dried over MgSO 4 and concentrated. The residue was purified by EtOAc (EtOAc (EtOAc) 5-(2-trimethyldecyl-ethoxymethyl)_5H_„比比和[231)]11比耕-7-carboxylic acid [(R)-l-(4-cyano-piperidine·ι _carbonyl)_22_dimethyl-propyl]· 154395.doc -212· 201134826 guanamine. Step 4 to 2-(1-cyclopropylf-group·1Η_imisin+yl) 5-(2-trimethyl stone夕烧基_ ethoxymethyl)-5Η"比嘻和^-小比味^carboxylic acid (tetra)+(4) aryl. Bottom bite base)-2,2-dimercapto-propyl]_ Amine oxime 6. Post, 〇26 _〇1) Trifluoroacetic acid (〇75) was added to a solution of CH2C12 (2.25 mL). The reaction mixture was stirred at room temperature for 2 hr and concentrated. The residue was dissolved in a mixture of ammonium hydroxide, MeOH and CH.sub.2 C.sub.2 (1:1 〇: 6 〇, 3 〇ml) and stirred at room temperature for 30 minutes. The reaction mixture was then concentrated and chromatographed by SiO 2 . The residue was purified twice (0-5% MeOH / EtOAc then EtOAc &lt;RTI ID=0.0&gt;&gt; -4 -yl)-5H-0 ratio 0 each [one-匕^ ratio spray---formic acid [(R)-l-(4-cyano-0 bottom bit-1-yl)_2,2 _Dimethyl-propyl]-bristamine. MS: (M+H)+=489. Example 132. 2-[1-(2,2,2-Tris-ethyl)-1Η-imidol-4-yl]-5Η-»比略和[2,3-b]«&gt; -7-carboxylic acid [(R)-l-(4-cyano-piperidin-1-carbonyl)-2,2-dimethyl-propyl]-decylamine

154395.doc · 213· 201134826 Prepared according to the procedure described in Example 13 1 'In step 1 with 4-methylbenzoic acid 2,2,2-dilactyl S as a substitute (, / skunk) ring B hospital. : (m+h)+= 517 » Example 133. 2-(1-Cyclopentyl-1H-imidazol-4-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [( R)-l-(4-cyano-bristidin-1-yl)-2,2-dimethyl-propyl]-decylamine

Prepared according to the procedure described in Example 13 1 in which the (bromomethyl)cyclopropane was replaced with bromocyclopentane. MS: (M+H)+=503. Example 134. 2-(1-Cyclopentyl-1H-mio-4-yl)-5H-&quot;Biloze[2,3-b]0 is compared to 啫7-carboxylic acid [(R)-2- (4_Cyanide base bit-1-yl)-1-cyclopropyl·2-o-oxy-ethyl]-decylamine

Prepared according to the procedure described in Example 131, substituting bromocyclopentane 154395.doc •214-201134826 for (bromomethyl)cyclopropane in step 1 and 2-bromo-5-(2- in step 3) Trimethyldecyl-ethoxymethylpyrolo[2,3-b]. Tillage-7-decanoic acid [(R)_2-(4-cyano-piperidin-1-yl)-1 -cyclopropyl-2-oxo-ethyl]-decylamine in place of 2-bromo-5-(2-trimethyldecyl-ethoxymethylhydrazine-. Well-7-formic acid [(R)-l-(4-cyano-0-bottom-1-yl)-2,2-dimethyl-propyl]-decylamine MS: (M+H) += 487. Example 135. 2-(2-mercapto-1-phenyl-1H-0 m. sit-4-yl)-5H-° ratio 0 and [2,3_b]n ratio p well-7 · Formic acid [(R)-2-(3-cyano-azetidin-1-yl)_1·cyclopropyl_2_sideoxy·ethyl]-decylamine

Step 1 (R)-2-(Tertibutoxycarbonylamino)-2-cyclopropylacetic acid (2.25 g, 10.5 mmol) and tetra-n-indole-benzotris-l-yl-N , N, N', N'-tetramethyl (3.69 g, 11.5 mmol) was dissolved in dioxane (105 mL). 3·Cyanoazetidine hydrochloride (1.36 g, 11.5 mmol) and hydrazine, hydrazine-diisopropylethylamine (4.5 mL ' 26.1 mmol) were then added and the mixture was stirred at room temperature for 5 hr. Water, dilute HC1 and more monochlorohydrazine were added, the layers were separated and the aqueous layer was extracted with _ methane for more than one time. The combined layers of 154395.doc • 215-201134826 were washed with a sodium carbonate solution and dried over sodium sulfate and concentrated. Purification of the residue by gelatin chromatography (methanol / methylene chloride) afforded 2.45 g (83%) [(R)-2-(3-cyano-azetidin-1-yl)-1- Cyclopropyl-2-oxo-ethyl]-aminobutyric acid tert-butyl ester. Step 2 [(R)-2-(3-Cyano-azetidinyl)-p-cyclopropyl-2-oxo-ethyl]-amino decanoic acid tert-butyl ester (〇99) g, 3 54 mm 〇l) was dissolved in 24 mL of dioxane and cooled in an ice bath. Trifluoroacetic acid (1 〇 6 mL) was added slowly. Then the reaction was stirred at room temperature. After 3 hours, the reaction was judged to be completed by TLC' followed by evaporation under high vacuum. The residue was dissolved in 34 mL of acetonitrile' and then added (1.28 g, 3.44 mmol), tetrafluoro-borate-benzoxazol-1-yl-N,N,N,N,·tetradecyl锞 (1.21 g, 3.78 mmol) and N,N-diisopropylethylamine (2 mL, 12 mmol). The reaction was stirred for 18 hours, then water and ethyl acetate were added. The layers were separated and the aqueous layer was extracted with ethyl acetate more than once. The combined organic layers were washed with brine and dried over sodium sulfate. After evaporation, the residue was purified by silica gel chromatography (methanol / dichloromethane). The obtained viscous oil was wet-milled with hexane to obtain 0.93 g (5 % by weight) of 2 bromo-5-(2-didecyl fluorenyl-ethoxymethyl)_5H-pyrrolo[2,3-b]pyridine as a white solid. Plough-7-decanoic acid [(R)-2-(3-cyano-azetidinyl)-hydrazine-cyclopropyl-2-oxacyloxyethyl]-bristamine. Step 3a Hydrazine (18.5 g, 73.1 mmol) was dissolved in 90 mL of trioxane. 2-Methylimidazole (3. 〇 g, 36 5 mmol) was added slowly in 90 mL of 2 M NaOH solution. As of 2.5 hours, the turbid mixture clearly formed two phases. The layers were separated and acetic acid (10.5 mL, 183 mm 〇1) was added to the organic layer to 154395.doc • 216·201134826 and the reaction (up to pH ～5-6). The solid which appeared was filtered off and recrystallized from warm acetonitrile to give 8.5 g (69%) of 4,5·diiodo-2-mercapto-1H-imidazole. (M+H)+=334. Step 3b 4,5-Diiodomethyl-1H-imidazole (8.5 g, 25.5 mmol) was dissolved in 430 mL of 3:7 ethanol: water. Sodium sulfite (25 7 g, 2 〇 4 was added and the reaction was refluxed (about 1 〇〇〇c) for 24 hours. The reaction mixture was concentrated to about half of its volume. The solid that appeared was filtered off and rinsed with water to isolate 5.3 g (66). 〇/〇) 4-iodo-2-indenyl_iH-imidazole. (m+H)+=209. Step 4 4-Iodo-2-Tyl]H-imidazole (1·〇g, 4.8 mm〇 1) Dissolved in 3 mL of THF. Add copper TMEDA catalyst (447 tons, 〇% 〇 Al Al Aldrich) and phenyl phthalic acid (0·41 g, 3 35 〇1). Use oxygen in the reaction mixture. The mixture was bubbled for 20 minutes, then the mixture was stirred at room temperature for 90 minutes. Further, 0.21 g of phenylflavic acid was added, followed by bubbling with oxygen for 2 minutes, and stirring at room temperature for 75 minutes. Further adding 0.21 § phenyl The acid was then bubbled with oxygen for 20 minutes and then stirred at room temperature for 2 hours. The reaction mixture was filtered through a pad of neutral alumina, concentrated and purified by silica gel chromatography (ethyl acetate /hexane) , 0.55 g (40 ° / 〇) 4-anthracene-2-methylphenyl·1H•imidazole and 0.47 g (35%) 5·iodo-2-methyl·1_phenyl-1H-imidazole were obtained. 5 will be 4-moth-2-methyl-1-phenyl_1 H-salt (〇55 g, i% brewed in 9 mL of anhydrous THF and isopropylmagnesium chloride (2 m τ HF solution, 1.2 mL, 2.4 mmol) was added dropwise. The reaction was stirred at room temperature for more than 丨 hours. 154395.doc •217- 201134826

Tributyltin-based base gas (0.55 mL, 2.03 mmol) was added slowly. After the completion of the reaction by TLC, 'NH 2 Cl solution and ethyl acetate were added. The layers were separated&apos; and the aqueous layer was extracted twice with ethyl acetate. The combined organic layers were washed with brine and dried over sodium sulfate and then evaporated. The residue was purified by silica gel chromatography (triethylamine / ethyl acetate / hexanes) to afford y 2 g (23 ° / 〇) 2-methyl-1-phenyl-4-tributylstannyl -1H-imidazole. Step 6 2·Bromo-5-(2-trimethyldecyl-ethoxymethyl)_5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(3) -cyano-azetidinyl)-indole-cyclopropyl-2-oxo-ethyl]-decylamine (115 mg, 0.188 mmol) and 2-methyl-1-phenyl-4- Tributylstannyl-1H-imidazole (101 mg, 0.225 mmol) was dissolved in 1 mL of DMF and the mixture was purified using argon. Strontium (triphenylphosphine) (10.8 mg, 0.0094 mmol) and copper (1) (7.1 mg, 0.03 8 mmol) were added sequentially, and the reaction was sealed and stirred in an oil bath at 80 ° C for 18 hours. The reaction was cooled, and water, di-methane and sodium hydrogencarbonate solution were added to separate the layers&apos; and the aqueous layer was extracted twice with dichloromethane. The combined organic layers were washed sequentially with water and brine and dried over sodium sulfate. After evaporation, the residue was purified by EtOAc (EtOAc/EtOAc) -1 phenyl-1H-imidazol-4-yl)-5-(2-tridecylsulfanyl-ethoxymethyl)-5H-indolo[2,3-b] «比耕- 7-Formic acid [(R)-2-(3-cyano-azetidin-1-yl)-1.cyclopropyl-2-oxo-ethyl]-decylamine. (M+H)+=611. Step 7 2-(2-Methyl-1-phenyl-1H-imidazol-4-yl)-5-(2-tridecylsulfonyl-ethoxycarbonyl)-5H-n ratio [2,3-b]e than tillage-7-decanoic acid [(R)-2-(3-cyano-154395.doc •218- 201134826 azetidin-1-yl)-1-cyclopropane The keto-2-oxoethyl]-decylamine (68 mg, 0.111 mmol) was dissolved in EtOAc EtOAc (EtOAc)EtOAc. Trifluoroacetic acid (0.4 mL) was added slowly and the ice bath was removed. The reaction was stirred for 3 hours' followed by cooling in an ice bath. A sodium bicarbonate solution was added and the mixture was extracted three times with ethyl acetate. The combined organic layers were washed with brine and dried over sodium sulfate. After evaporation, the residue was dissolved in 4 mL of absolute ethanol, sodium acetate (183 mg) was added, and the mixture was stirred at 60 ° C for 20 hours. The reaction was cooled, and water and ethyl acetate were added. The layers were separated&apos; and the aqueous layer was extracted twice more with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate and evaporated. The residue was purified by silica gel chromatography (MeOH/dichloromethane) to afford &lt;RTI ID=0.0&gt;&gt; And [2,3-b]pyrazine-7-carboxylic acid [(R)_2_(3-cyano-azetidin-1-yl)-1-cyclopropyl-2-oxo-ethyl ]-nonylamine. MS: (M+H)+=481; mp=l75-179〇C. Example 136. 2-[l-(3,5-difluoro-phenyl)-2-methyl-1H -Mimosa _4_yl]_5H-0 is more than 11 [2,3-b]D than -7-carboxylic acid [(R)-i_(3-cyano-azetidinylcarbonyl)_2, 2-dimethyl-propyl]-guanamine

154395.doc -219- 201134826 Prepared according to the procedure described in Example 135, substituted in step i with (11)_2_t-butoxyphenylamino-3,3-dimercapto-butyric acid (R) 2-(Tert-butoxycarbonylamino)-2-cyclopropylacetic acid and in step 5 is 1-(3,5-diphenyl)-4-moth-2-methylmethane. Sit in place of 4-indol-2-methyl-1-phenyl-1H-imidazole. MS: (Μ+Η)+=533; ιηρ = 187-19(Γ(:. Example 137. 2-[1-(3-1 phenyl)-2 -indolyl-1Η-°m. Sit-4 -yl]-5Η-. The ratio of each [2,3-b]°lt plough-7-decanoic acid [(R)-l-(3-cyano-azetidin-1-carbonyl)_2 ,2·dimethyl-propyl]-guanamine

Prepared according to the procedure described in Example 135, substituting (r)_2-t-butoxycarbonylamino-3,3-dimercapto-butyric acid for (R)_2_(t-butoxy) in step 1. Carbonylamino)-2-cyclopropylacetic acid, and in step 4, phenyl Iponic acid is replaced by 3-fluorophenyl tanning acid. MS: (M+H)+=515; 11^=171-1761. Example 138. 2-[2-Indolyl- l-(2,2,2-tris-ethyl)-1Η-imidin-4-yl]_5H-0 ratio p and [2,3-b] Pyridin-7-decanoic acid [(R)-2-(3-cyano-azetidinyl)q•cyclopropyl-2-oxo-ethyl]-decylamine 154395.doc -220 - 201134826

Step 1 4-Methyl-2-methyl _ih_0 m. Sitting (1·0 g, 4.8 mmol) was dissolved in i〇 mL DMF. Trifluoroethyl p-toluenesulfonate (4.89 g ' 19.2 mmol) and cesium carbonate (1.57 g, 4.8 mmol) were added and the mixture was stirred in a 50 t: oil bath for 18 hours. The reaction was cooled and dissolved in ethyl acetate and water. The layers were separated and the aqueous layer was extracted twice with ethyl acetate. The combined organic layers were washed with water and brine and dried over sodium sulfate. After evaporation, the residue was purified by silica gel chromatography (ethyl acetate / hexane) to afford 6 g (43%) of 4- Ethyl) - 1 Η - sodium saliva. (m+H)+=291. Step 2 2-[2-Methyl-l-(2,2,2-trifluoro-ethyl)-1Η-imidazol-4-yl]-5H-pyrho[2,3-b] 7-Formic acid [(R)_2_(3-cyano-azetidin-yl)cycloprop-2-yloxy-ethyl decylamine. Prepared according to the procedure described in Example 135. In step 5, 4-anthracene-2-methyl-1-(2,2,2-tris-ethyl-methane-sodium is substituted for 4-iodo-2-methyl-1-phenyl-1indole-imidazole. Ms: (M+H)+=487; mp=255-256°C. Example 139. 2-[l-(2,5-H-phenyl)-1Η-°米°-4-yl] -5H-° ratio [2,3-b]. Ratio 154395.doc -221 - 201134826 Plough-7-formic acid [(R)-2-(3-cyano-azetidine small group ^• Cyclopropyl·2_sideoxy-ethyl]-decylamine

According to a procedure similar to that described in C/iew. Cowm. 2004, 188-189: 2,5-difluorophenyl-folic acid (47 mg, 0.30 mmol), 4-iodo-1H at 60 C under air A solution of imidazole (46 mg, 0.24 mmol), copper (1) (1.8 mg, 0.018 mmol) and 1 mL of methanol was stirred for 3 hr then concentrated. Column chromatography (0-33% EtOAc/hexanes) afforded 14.5 mg (20%) of 1-(2,5-difluorophenyl)-4-iodo-1H-imidazole as a white solid. Step 2 A solution of 1-(2,5-difluorophenyl)-4-iodo-111-imidazole (〇.115 §, 0.38 mmol) in 2 mL of tetrahydrofuran was chilled for 5 min in an ice/water bath. A solution of isopropyl chloride (2.0 Torr in tetrahydro beta ketone, ο"% mL '0.38 mmol) was added in one portion. The bath was removed and the pale yellow solution was stirred for 1 5 hours. Tributyltin chloride (0.1 〇 5 mL, 0.39 mmol) was added in one portion, and the pale yellow solution was mixed for 1 hour. A saturated aqueous NH4C1 solution (1 mL) was added and mixture was extracted with two portions of 1 mL of ethyl acetate. The combined organic layers were washed with 20 mL of aq. sat. aq. Na.sub.sub.sub.sub.sub.[sub.sub.sub.sub.sub.sub.sub. 4-Tributylstannyl-1 Η-imidazole' was used without further purification. MS: (Μ+Η)+= 471 ° Step 3 2-bromo-5-(2-tridecyldecyl-ethoxycarbonyl)-511-pyrrole in 3 mL of DMF in a pressure tube And [2,3-1)] 吼耕-7-furfural (0.1108, 0.31 mmol), Pd(PPh3)4 (0.020 g, 0.017 mmol), Cul (0.012 g, 0.063 mmol) and the crude preparation above Product (0.198 g). The tube was capped under Ar and the orange-yellow mixture was stirred at 80 ° C for 1.5 hours, followed by cooling. The mixture was partitioned between 20 mL of ethyl acetate and 20 mL of water + 20 mL of saturated aqueous NHUC1. The organic layer was washed with 20 mL of aq. sat. NaCI. Column chromatography (20°/. to 100% EtOAc/hexanes) afforded 0.087 g (yield: 62%). )-1Η-imidazol-4-yl]-5-(2-tridecyldecyl-ethoxycarbonyl)-5H-pyrrolo[2,3-b]pyrrol-7-formaldehyde, which is not Further purification is used. MS: (M+Na)+=478. Step 4 Treatment of 2-[l-(2,5-difluoro-phenyl) with a mixture of sodium sulfite (0.031 g, 0.27 mmol) and KH2P〇4 (0.335 g, 2.46 mmol) in 1 mL water -1Η-imidazol-4-yl]-5-(2-tridecylfluorenyl-ethoxyindenyl)_5H-0 ratio B and [2,3-b]0 ratio ρ well-7-decanoic acid (0.087 g, 0.19 mmol) and a mixture of aminic acid (0.127 g, 1.30 mmol) in 2 mL of 1,4-dioxin and 0.2 mL water, rinsed with 1 mL water. The pale yellow solution was stirred for 1.25 hours while forming a white precipitate. The mixture was partitioned between 10 mL of water and 1 〇 mL of ethyl acetate 154395.doc -223 - 201134826. The organic layer was washed with 10 mL of aq. EtOAc (EtOAc) (EtOAc (EtOAcjjjjjjjj -imidazol-4-yl]-5-(2-trimethyldecyl-ethoxyphenyl)-5H-pyrrolo[2,3-b]pyrazine-7-decanoic acid, without further purification That is to use. MS: (M+H)+=472. Step 5 2-[1-(2,5-Difluoro-indolyl)_ih-imidazol-4-yl]-5-(2-trimethyldecyl-ethoxymethyl)-5H-pyrrole [2,3-b]0 ratio tillage-7-decanoic acid (0.067 g, _ 〇·14 mmol), (R)-i_(2-amino-2-cyclopropylethylhydrazino)azetidine A solution of alkyl-3-carbonitrile (0.038 g, 0.21 mmol), DMAP (0.021 g '0·17 mmol) and EDC (0.036 g &quot; </ RTI> 9 mmol) in 2 mL of methane methane was stirred for 13.5 hours. Dioxane (i〇 mL)' was added and the solution was washed sequentially with i〇 mL 1 Μ Μ 样 acid solution, 10 mL of water and 1 mL of saturated NaCl aqueous solution, followed by drying through NaJO 4 'filtered and concentrated. The residue was purified by column chromatography (EtOAc EtOAc) (EtOAc) )_1H-imidazolyl]_5_(2_tridecyldecane ruthenyl-ethoxymethyl)-5H-«bibromo[2,3-b]&quot;specific tillage-7-decanoic acid [(R) -2-(3-Vinyl-azetidin-1-yl)-indole_cyclopropyl_2_sideoxy-ethyl]-decylamine. Ms: (M+Na)+=655. Step 6 2-[1-(2,5-Difluoro-phenyl)_1H-imidazole_4_ylbu 5-(2-trimethyldecyl-ethoxycarbonyl)·5Η at 75 °C _pyrrolo[2,3b]pyridinium_7_decanoic acid [(R)-2-(3-carbyl-azetidinyl)-yl)-hydrazinyl-2-yloxyethyl --Amine (0.037 g, 〇〇58 mmol), 18_crown_6 (〇〇16 g, 〇〇58 154395.doc •224·201134826 mmol) and cesium fluoride (0 093 g, 〇58 mm〇) 1) The solution in i mL acetonitrile was dropped for 5 days' followed by concentration. The resulting residue was partitioned between $ mL 1 μ citric acid solution and 5 mL of di-methane. Water was extracted with two portions of 5 ml of dioxane. The combined organic layers were dried over NazSO4, filtered and concentrated. EtOAc (1 mL) and 1 mL of trifluoroacetic acid were added, and the yellow solution was stirred for 2 hours, then concentrated. dichloromethane (〇 5 mL) and 〇 5 mL of ethylenediamine, and stir the yellow-orange solution for 1 hour. Dispense the solution between 丨〇mL ethyl acetate and 5 mL # water, and extract the aqueous layer with 10 mL of ethyl acetate. The layer was filtered and concentrated. Column chromatography (〇% to &gt; 1% MeOH/EtOAc) was obtained. .0055 g (19%) of pale yellow solid... (2,5-difluoro-phenyl)-lH-imidazol-4-yl; μ5Η_pyrrolo[2,3_b]pyrazine_7_decanoic acid [ (R)-2-(3-cyano-azetidinyl)-hydrazine-cyclopropyl-2-phenoxy-ethyl]-decylamine. MS: (Μ-Η)· = 501. Example 140. 2-[1-(2,3,5-Trifluoro-phenyl)_1Η_imidazole_4yl]_5Ηpyrrolo[2 3^]〇比鲁&quot;井_7_carboxylic acid [ (Κ)·2_(3-cyano-azetidin-1-yl)-1-cyclopropyl_2_sideoxy-ethyl]-bristamine

154395.doc -225 201134826 2-Bromo-5-(2-trimethyldecyl-ethoxymethyl)_5H_pyrrolo[2,3-1&gt;]«1 than plough-7-formic acid [( 11) -2-(3-cyano-azetidin-1-yl)-1_cyclopropyl-2-oxo-ethyl]-decylamine (0.104 g, 〇195 mm〇i, The solution containing some 2-gas impurities), 1 mL of dioxane and 1 mL of TFA was mixed for 3 hours, then concentrated to a pale yellow oil. The oil was dissolved in 5 mL of dichloromethane and 0.5 mL of ethylenediamine. 'The yellow solution was stirred for 1.25 hours and then partitioned between 5 mL water and 10 mL ethyl acetate. The aqueous layer was extracted with 1 mL of ethyl acetate. The combined organic layers were dried over Na 2 S 〇 4, filtered and concentrated to afford s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s 7-decanoic acid [(R)-2·(3-aryl-azetidin-1-yl)_ι_cyclopropyl_2_sideoxy-ethyl]-decylamine' without further It is used immediately after purification. MS: (M+Na)+=427. The main impurity is 2-gas-5H-0 to 0 and [2,3-b]pyrene ratio p-well-7-formic acid [(r)_2_(3-cyano-azetidin-1-yl) 1-cyclopropyl-2-oxo-ethyl]-decylamine. Ms: (M+Na)+=381. The ratio of Br:Cl is about 3:1. Step 2 According to the procedure similar to that described in 2008, 795-799, 2,3,5-trifluorophenyl-tanoic acid (0.302 g, 1.72 mmol), 4-disc-1H "rice" (under the gas) 0.498 g, 2.57 mmol), 2 mL of decyl alcohol and a mixture of Cu 2 hydrazine (〇〇49 g, 0.34 mmol) were stirred for 21 hours, then passed through a celite and concentrated to an oily white solid. To &gt;33% £tQAe/hexane), 4-150-(27%) 4-iodo-i-(2,3,5-tris-phenyl)-1 Η-imidazole as a white solid. MS: (M +H)+=325. Step 3 154395.doc •226- 201134826 4_Iodo_1_(2,35-trifluorophenyl)-indole-imidazole (0.140 g, 0.43) in an ice/water bath Methyl) solution in 2 mL THF was chilled for 5 min. Add isopropylmagnesium chloride (2.0 Μ in tetrahydrofuran, 〇225 m]L, 〇45 mm〇l) 'Remove the bath and stir the light yellow solution 1.5 An hour was added. Dibutyltin chloride (0.055 mL '0.20 mmol) was added in one portion, and light yellow and hexanes were mixed for 1 hour. A saturated aqueous solution of NH.sub.4Cl.sub.1 (10 mL) was added and mixture was extracted with two portions of 10 mL EtOAc. Washed with 1 mL of saturated NaC1 aqueous solution The layers were dried over EtOAc (EtOAc m. Step 4 Add the crude product 2_bromo-511 from 3 mL of DMF to the crude product 4-tributylstannyl 4-(2,3,5-trifluoro-phenyl)-1Η-imidazole from step 3. _pyrrolo[2,3-b]pyrazine-7·decanoic acid [(R)-2_(3-cyano-azetidinyl small) small cyclopropyl-2-sideoxy-ethyl ]-guanamine (0.087 g from step 丨), Lu Pd(PPh3) 4 (0 032 g, 0.027 mmol) and Cul (0.021 g, 〇·11〇mmol). Distracted dark yellow at 8 °C The mixture was allowed to stand for 6 hours, then allowed to cool. The mixture was partitioned between 2 mL of ethyl acetate and 20 mL of saturated aqueous NH.sub.4Cl. Filtration and concentration of the residue were subjected to column chromatography (〇_10% Me〇H/Et〇Ac) to obtain 〇〇〇5 g (5%) as a yellow solid 2-[1·(2,3, 5-(trifluoro-phenyl)-1Η-imidazol-4-yl]·5Η-pyrrolo[2,3-b]pyrazine-7·carboxylic acid [(R)_2_(3_cyano-azetidine Alkane·丨· ) _ _ Shu-cyclopropyl-2-oxo - ethyl] • Amides, about 85% pure. Ms: (M+Na), 154395.doc •227- 201134826 543 » Example 141. 2-(2-Chlorothiazol-5-yl)-5H-pyrrolo[2,3-b]pyrazine-7-曱Acid [(R)-l-(4-cyano-piperidin-1-carbonyl)_2,2-dimethyl-propyl decylamine

Step 1 Diisopropylamine (0.66 mL, 4.6 mmol) and triisopropyl borate (1.26 mL, 5.44 mmol) were dissolved in EtOAc (EtOAc) n-Butyllithium (2.6 Μ in benzene, 1.77 mL, 4.6 mmol) was slowly added to the reaction and the mixture was stirred for 30 min. Add 2-chlorothiazide. Sitting (0.5 g, 4.18 mmol) and gradually bringing the reaction to room temperature over 3 hours. A solution of pinacol (0.69 g' 5.85 mmol) in 5 mL of acetamidine was added. After 15 minutes, 'acetic acid (0.26 mL, 4.6 mmol) was then taken and then the mixture was filtered and filtered and evaporated. The filtrate was evaporated, and the residue was distilled using a Kugelrohr apparatus at a temperature of from 120 ° C to 130 ° C to obtain 〇84 ü(820/〇) 2-Ga-5-(4,4,5,5-tetramethyl- [1,3,2] Dioxo side 0 East_2-yl) 〇 CT CT sitting 0 Step 2 Purify M-dioxane (3 mL) with argon in a microwave vial. Add 2_ 154395.doc -228· 201134826 Bromo-5-(2-trimethyldecyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyr-7-decanoic acid [( R) - l-(4-cyano-1 yl-o- bottom π-l-?-yl)-2,2-dimethyl-propyl]-decylamine (100 mg, 0·173 mmol), 2-gas- 5-(4,4,5,5-tetramethyl·[1,3,2]dioxaboroin-2-yl)-thiazole (128 mg, 0.519 mmol), hydrazine (triphenylphosphine) l £ ( 10 mg ' 0.009 mmol) followed by the addition of carbonic acid (in mg, 0.346 mmol). The reaction vessel was sealed and heated in a microwave reactor under pot: for 1 hour. Add 2-gas-5-(4,4,5,5-tetradecyl-[1,3,2]dioxaborom-2-yl)-° saponin (90 mg, 0.366 mmol) and hydrazine (Triphenylphosphine) (6 mg, 0.005 mmol) and reacted again at 170 ° C for 2 hours. The reaction was cooled and water and ethyl acetate were added. The layers were separated and the aqueous layer was extracted twice with ethyl acetate. The combined organic layers were washed with brine and dried over sodium sulfate. After evaporation, the residue was purified by silica gel chromatography (MeOH / di-hexane) to yield 39 (3 6%) of 2-(2-chlorothiazol-5-yl)-5-(2-trimethyldecane -Ethoxymethyl)-5H-. Bisolo[2,3-b]pyrazine-7-decanoic acid [(R)-l-(4-cyano-piperidin-1-carbonyl)·2,2-monomethyl-13⁄4yl]- Amine amine. (M+Na)+=63 8. Step 3 2-(2-AZ-thiazol-5-yl)-5-(2-trimethyldecyl-ethoxycarbonyl)-5H-indolo[2,3-b]pyrid-7 -formic acid [(R)-i-(4-cyano-piperidine-i •carbonyl)· 2,2-dimercapto-propyl]•decylamine (39 mg' 0.063 mmol) dissolved in 〇.8 mL In dichlorohydrazine, 'thir is then stirred in an ice bath. Trifluoroacetic acid (〇 4 mL) was added slowly and the ice bath was removed. The reaction was stirred for 25 hours and then cooled in an ice bath. A sodium bicarbonate solution was added and the mixture was extracted three times with ethyl acetate. The combined organic layers were washed with brine and dried over sodium sulfate. After evaporation, the residue was dissolved in 4 mL of absolute ethanol, sodium acetate (104 mg, 1.27 mmol) and 154 395. doc </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; • Cool the reaction and add water and ethyl acetate. The layers were separated and the aqueous layer was extracted twice with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate and evaporated. Purification by reverse phase chromatography gave 8 mg (26%) of 2-(2-chlorothiazol-5-yl)-5H-pyrrolo[2,3-b]pyrinoic acid [(R)-l- (4-Cyano-piperidin-1-carbonyl)-2,2-dimethyl-propyl]-nonylamine MS: (M+Na)+=509. Example 142. 2-(4-Trifluoromethyl-phenyl)-5H-pyrrolo[2,3-b]pyrazine-7-decanoic acid [(R)_2-(3-cyano-gas heterocycle) Ding Xuan-1-yl)-1-cyclopropyl-2-methoxyethyl]-bristamine

Step 1 (R)-2-(Tertibutoxyamino)-2-cyclopropylacetic acid (2.25 g, 10.5 mmol) and tetrakisole-p-benzoic acid. Sodium-1-yl-N,N,N',N'-tetramethyl hydrazine (3.69 g '11.5 mmol) was dissolved in dioxane (1 〇 5 mL). 3-Cyanoazetidine hydrochloride (1.36 g, 11.5 mmol) and N,N-diisopropylethylamine (4.5 mL, 26.1 mmol) were added sequentially, and the mixture was stirred at room temperature for 5 hours. Water, dilute HC1 and more digas methane were added, the layers were separated and the aqueous layer was extracted more than once with two gas. The combined organic layers were washed with a sodium carbonate solution, dried over sodium sulfate and concentrated. Purification of the residue by gelatin chromatography (methanol / two gas 154395.doc -230 - 201134826 alkane) gave 2.4sg (83%) [(R)_2_(3_cyano-azetidin-1- ))-1-cyclopropyl-2·sideoxy-ethyl]-aminobutyric acid tert-butyl ester. Step 2

Dissolve the third ester of cyano-azetidin-1-yl)-1-cyclopropyl-2-oxo-ethyl]-carbamic acid (〇99 g, 3.54 mmol) in 24 mL One gas was burned and cooled in an ice bath. Trifluoroacetic acid (丨 0.6 mL) was slowly added, followed by stirring at room temperature. After 3 hours, the reaction was judged by TLC to evaporate under vacuum. The residue was dissolved in 34 mL of acetonitrile' followed by the addition of 2-bromo-5-(2-trimethyldecyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine- 7-formic acid (1.28 g, 3.44 mmol), bismuth tetrafluoroborate-benzotriazole_1_yl_team;^,1^,&gt;1'-tetrazole (1.21 LV, 3.78 mmol) and N , N-isopropylethylamine (2.1 mL, 12 mmol). The reaction was stirred for 18 hours, followed by the addition of water and ethyl acetate. The layers were separated and the aqueous layer was extracted with EtOAc (EtOAc). After evaporation, the residue was purified by silica gel chromatography (methanol / dichloromethane). The obtained viscous oil was wet-milled with hexane to obtain 2-bromo-5-(2-trimethyldecyl-ethoxymethyl)_5η·pyrrolo[2, 〇·93 g (50%) as a white solid. 3_b]pyrazine-7-decanoic acid [(R)-2-(3-cyano-azetidin-1-yl)-1-cyclopropyl_2-sideoxy-ethyl]- amine. Step 3 In a microwave vial, 2-bromo-5-(2-trifosylalkyl-ethoxyindolyl)-5H-indolo[2,3-b]indole-7-decanoic acid [ (R)-2-(3-Cyano-azetidin-1-yl)-1-cyclopropyl_2_p-oxy-ethyl]-decylamine (8 〇 mg, 0.15 mmol) dissolved In 1.5 mL 1,4-two-degree hospital and 0.35 mL water. Using argon net 154395.doc -231 - 201134826 solution - followed by the addition of 4-(trifluoromethyl)phenyl Iponic acid (31 mg, 0.165 mmol), bis-(diphenylphosphino)ferrocene The two gas smoldering complex (6.1 mg ' 0.008 mm 〇i) and the carbonic acid slant (62 mg '0.45 mmol). The reaction vessel was sealed and placed at 15 Torr in a microwave reactor. Heat under the arm for 30 minutes. The reaction was cooled and water and ethyl acetate were added. The mixture was poured into ethyl acetate and sodium hydrogen carbonate solution. The layers were separated and the aqueous layer was extracted twice with ethyl acetate. The combined organic layers were washed with brine and dried over sodium sulfate. After evaporation, the residue was purified by silica gel chromatography (MeOH / di-hexane) to afford 6 g (66%) of 2-(4-trifluoromethylphenyl)-5-(2-trimethyldecyl- Ethoxymethyl)-5H-»pyrho[2,3-b]&quot;比〃井-7-carboxylic acid [(R)-2-(3-cyano-azetidin-1- ))-1-cyclopropyl-2-sided oxy-ethyl]-decylamine. Step 4 2-(4-Trifluorodecylphenyl)_5·(2-trimethyldecyl-ethoxymethyl 5H-indolo[2,3-b]pyrazine-7-carboxylic acid [ (R)-2-(3-cyano-azetidin-1-yl)-1-cyclopropyl-2-oxo-ethyl]-bristamine (62 mg, 0.104 mmol) dissolved in 0.8 mL of di-gas methane, followed by stirring in an ice bath. Slowly add trifluoroacetic acid (0.4 mL) and remove the ice bath. Stir the reaction for 2.5 hours, then cool in an ice bath. Add sodium bicarbonate solution and use acetic acid The mixture was extracted three times. The combined organic layers were washed with brine and dried over sodium sulfate. After evaporation, the residue was dissolved in 4 mL absolute ethanol, sodium acetate (170 mg, 2.07 mmol) and at 60 ° C The mixture was stirred overnight, the reaction was cooled, and water and ethyl acetate were evaporated, and the layers were separated, and the layers were separated, and the aqueous layer was extracted twice with ethyl acetate. The combined organic layer was washed with brine, dried over sodium sulfate and evaporated. The residue was purified (methanol/di-methane) to afford 34 154395.doc - 232 · 201134826 mg (70%) 2-(4-trifluoromethyl-phenyl)-5H-n ratio [2, 3-b]&quot;比耕-7-carboxylic acid [(R)-2-(3 Cyano-azetidin-1 -yl)-1 -cyclopropyl-2-oxo-ethyl]-indolamine MS: (M+H)+=469; mp=207-209° C. Example 143· 2-[4-(4-Ethyl-piperidin-1-yl)-phenyl]-5H-° than bromo[2,3-b]. [(R)-2-(3-.Cyano-azetidin-1-yl)-1-cyclopropyl-2-oxo-ethyl]-decylamine

Prepared according to the procedure described in Example 142, in step 3 as l-丨4-[4·(4,4,5,5-tetradecyl-[l,3,2]dioxaboron-2- Base)-phenyl]-piperidinyl-1-ethyl ketone instead of 4-(trifluoromethyl)phenylidene. MS: (M+H)+= 527; mp </ RTI> </ RTI> 85-188. Example 144. 2-[4-(4-Mercapto-piperazin-1-yl)-styl]-5H-«tb-[2,3-b]&quot; than plough-7-formic acid [(R) )-2-(3-cyano-azetidin-1-yl)-1-cyclopropyl-2-oxo-ethyl]-decylamine 154395.doc •233- 201134826

Prepared according to the procedure described in Example 142, in step 3 as the methyl 4-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborin-2-yl )-Phenyl]-piperiding instead of 4-(trifluoromethyl)phenyl tartaric acid. MS: (M+H)+=499; mp=178-185〇C. Example 145. 2-(4-Methyl- 4-yl-phenyl-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(3-cyano-azetidine) Alkyl-1-yl)-cyclocyclopropyl-2-oxo-ethyl]-decylamine

制备 Prepared according to the procedure described in Example 142, substituting 4-[4-(4,4,5,5-tetradecyldioxaborin-2-yl)-phenylmorpholine for 4_ (in step 3) Monofluoromethyl) stupid base acid. MS. (M+H)+= 486; mp= 186-192 °C. 154395.doc •234· 201134826 Example 146. 2-(4-Dimethylamino-phenyl)·5Η-pyrrolo[2,3-b]pyridin-7-carboxylic acid [(R)_ 2-( 3-cyano-azetidine_ι_yl)-1_cyclopropyl_2_sideoxy-ethyl]-decylamine

Prepared according to the procedure described in Example 142, in step 3 as dimethyl-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborom-2-yl )-Phenyl]-amine instead of 4-(trifluoromethyl)phenyl tanning acid. MS: (M+H)+=444; 1!^=175-180. (:. Example 147. 2-Phenyl-5H-»pyrho[2,3-b]&quot; than plough-7-formic acid [(R)-2-(3-cyano-azetidin) -1 -yl)-1 -cyclopropyl-2-o-oxy-ethyl]-bristamine

Prepared according to the procedure described in Example 142 to replace 4-(trifluoromethyl)phenyl lysate with phenyl crotonic acid in step 3. MS: (M+H)+=4〇1; mp=200-202 °C. 154395.doc •235- 201134826 Example 148. 2-Cyclohexyloxy-5H-pyrrolo[2,3-b]pyrazole_7-carboxylic acid [(R)-i_(4-cyanopyridin-1- Carbonyl)-2,2-dimethyl-propyl]-decylamine

Step 1 In a 10 mL flask, a 2-mL bromo-5-(2-trimethyldecyl-ethoxymethyl)-5H-° ratio [2,3-b]« was placed under an argon atmosphere. Specific tillage-7-decanoic acid [(R)-l-(4-cyano-piperidin-1-carbonyl)-2,2-dimethyl-propyl oxime (1 mg, 〇17 mmol ), copper iodide (1) (1.7 mg ' 0.009 mm 〇l), 8-hydroxyquinoline (2.5 mg, 0.017 mmol) and tripotassium citrate (74 mg '0.34 mmol). Cyclohexanol (1.82 mL, 17.3 mmol) was added at 120. (The reaction mixture was heated for 24 hours. The reaction mixture was taken to room temperature then diluted with EtOAc (10 mL). EtOAc EtOAc (EtOAc) : EtOAc 1:1 x 2) The crude residue was purified to give 52 mg (50%) of 2-cyclohexyloxy-5-(2-trimethyldecyloxyethyloxy)-5H-pyrrolo[2 , 3-b] pyridin-7-decanoic acid [(R)_l-(4-cyano-piperidin-1-carbonyl)-2,2-dimercapto-propyl]-decylamine. (M+ Na)+=619. Step 2 to 2-cyclohexyloxy-5-(2-tridecylfluorenyl-ethoxymethyl)·5Η-«&gt; at the room temperature [2,3 -b]pyrazine-7-formic acid [(R)-l-(4-cyano-piperidine-1-carbonyl 154395.doc •236- 201134826

Add 18 crowns _6 (37 mg, oM mmol) and fluorinated planer to a solution of 2,2,2-dimethyl-propyl]-decylamine (84 mg, 0.14 mmol) in acetonitrile (30 mL) 214 mg, 1.41 mmol). The reaction mixture was heated under reflux for 72 hours, then cooled to room temperature and filtered thru a pad. The filtrate was evaporated under vacuum and the crude residue was purified by column chromatography (Si.sub.2.sub.24 g, CH.sub.2Cl.sub.sup..sup..sup. 36 mg (55%) 2-cyclohexyloxy_5H_pyrrolo[2,3 b]pyrazine·7-formic acid [(8) small • (4-cyano-piperidin-1·carbonyl)-2,2- Dimethyl-propyl decylamine. Ms: (M+H)+=467. Example 149. 2-(2,2,2-Difluoro-ethoxy oxime-. Ratio of [2,3-b]0 to spray-7-carboxylic acid [(r)-1-(4-cyano) -piperidin-1-carbonyl)-2,2-dimethyl-propyl]-decylamine

Prepared according to the procedure described in Example 148, substituting 222-fluoroethanol for cyclohexanol in step 1. MS: (M+Na)+=489. Example 150. 2-(3,3,3-Trifluoro-propoxy)-5H-n than indeno[2,3-b]indole-7-carboxylic acid 1-(4-cyano-indole bite -1-rebase)-2,2-dimercapto-propyl]-decylamine 154395.doc • 237· 201134826

F Prepared according to the procedure described in Example 148, in step 3 3 - fluoropropanol instead of cyclohexanol. MS: (M+H)+=481. Example '151. 2-Cyclopentyloxy-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)_1(4-cyanoguanidine-1-carbonyl)-2,2 -dimercapto-propyl]-guanamine

Prepared according to the procedure described in Example 148, in which the cyclohexanol was replaced by cyclohexane. MS: (M+Na)+=475. Example 152. 2. Isopropoxy-5H-pyrrolo[2,3-b]pyrazine-7-decanoic acid [(R)-1-(4.a.g.-piperidin-1-carbonyl)-2 ,2-dimercapto-propyl]-guanamine

154395.doc -238- 201134826 Prepared according to the procedure described in Example 148, in which the cyclohexanol was replaced with isopropanol in step 1. MS: (M+H)+=427. Example 153. 2-(4-Ga-1-oneoxy-1,3-dihydro-isoindole-2-yl)_5H•pyrrolo[2,3 ton] pyridin-7-decanoic acid [( R)-2-(3-cyano-azetidine-indole-based fluorene cyclopropyl-oxyl-ethyl]-decylamine

Step 1 Under a argon atmosphere, a 10 mL flask was charged with 2_bromo-5-(2_trimethylsulfanylethoxymethyl)-5H-°bi[2,3-b]pyridin. Plowing -7-furfural (7 〇〇 mg, 1.96 mmol), 4-chloro-2,3-dihydro-isoindole ketone (395 mg, 2% mmol), N,N-- fluorenyl Amine (42 μιη, 0.39 mmol) and a carbonic acid clock (543 mg, 3.93 mmol). Copper iodide (1) (37 mg, 〇 2〇 mm〇1) was added and the reaction mixture was heated at 100 ° C for 24 hours. The reaction mixture was allowed to reach rt then EtOAc (EtOAc) The slurry was filtered through a pad of celite and the filtrate was evaporated in vacuo. The crude product was purified by column chromatography (Si </RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; 1-tertiary oxy-oxime, 3·dihydro-iso"anthracene-2-yl)-5-(2-trimethylsulfonyl-ethoxymethyl)_5Η·&quot;Biro and [2 , 3-b]. Specific starting material than 154395.doc -239· 201134826 p well-7-wake and 400 rag recovery. Step 2 2-(4-Ga-1-oneoxy-1,3-dihydro-isoindol-2-yl)-5-(2-didecylcarbazide-ethoxylate) at 〇 °C The base )5)-° ratio is slightly [2,3-b]. Add alkalic acid (349 mg '3.59 mmol) to water (4.35 mL) in a solution of p-well-7-decanoic acid (265 mg, 0.60 mmol) in 1,4-dioxane (35 mL). Solution. A solution of NaC 102 (88 mg, 0.78 mmol) and ΚΗ2Ρ〇4 (977 mg, 7.18 mmol) in water (8·7 mL) was then added via a dropping funnel over 15 min. The ice bath was removed and the yellow turbid reaction mixture was stirred at room temperature for 18 h. The reaction mixture was diluted with EtOAc (EtOAc) The combined organic layers were dried over MgSO.sub.4 and concentrated to afford </RTI> </RTI> </RTI> </RTI> </RTI> <RTIgt; 5-(2-Tridecyldecyl-ethoxymethyl)_ 5H-indolo[2,3-b]pyridinium-7-decanoic acid, which was used without further purification. Step 3 to 2-(4·Ga-1-oneoxy-i,3-dihydro-isoindol-2-yl)-5-(2-tridecylfluorenyl-ethoxyl) at room temperature Add methyltriethylamine (73 0 〇.52〇) to a solution of methyl)_5Η·pyrrolo[2,3-b]pyrazine-7-decanoic acid (80 mg, 0.17 mmol) in DMF (2.4 mL) 1111〇1), 1-((尺)-2-amino-2-cyclopropyl-ethenyl)-azetidin-3-indolecarbonitrile (31.2 mg, 0.17 mmol) and PyBOP (l〇 9 mg '0·21 mmoip was stirred at the same temperature for 16 hours, then poured into Et 〇Ac (50 mL) and washed with water (4×50 mL). Dry (Na; jS 〇 4) organic extract and vacuum Evaporation. Purification of crude residue 154395.doc -240 - 201134826 by column chromatography (SiO 2 ' 23 g ' Hex: EtOAc 0% to 6:4 ' 35 min) afforded 42 mg (39%) 2 -(4_Chloro-small oxy-u-u-dichloro-iso-decyl _ 2-yl)-5-(2-trimethyl-stone-ethoxy ethoxymethyl)·5Η_[2,3 Exo-pyridin-7-formic acid [(R)-2_(3. cyano.azetidinyl)"cyclopropyl_2_ oxo-ethyl]• nitamine. Step 4 at room temperature Downward 2-(4-chloro-sideoxy-153_diaza-iso(tetra)_2-yl)^ (2-trimethylcene Ethyl ethoxymethyl) _5H ♦ each [2, 3 handsome than spray ·? - A • acid [(R)-2-(3-cyano-azetidin-1-yl)-1- Add triacetic acid (0.30 mL, 3.87) to a solution of cyclopropyl-2-oxo.ethyl]-decylamine (4 〇 mg, 〇.〇65 〇 )1) in dioxane oxime) Mm〇1). The solution was allowed to stand for 3 hours at room temperature and then concentrated under vacuum. The residue was dissolved in dioxane (1 mL) and ethylenediamine (〇 43 mL, 6 45 min.) was added. The reaction mixture was stirred at room temperature for 2 hr then concentrated under vacuum. The crude product was suspended in EtOAc (2 mLEtOAc (EtOAc)EtOAc. --1,3-dihydro-isoindole-2-yl)_5Η_β is more than [2,3_b]n than h-7-carboxylic acid [(R)-2-(3·cyano.azetidine) +Base) Small cyclopropyl-2-epoxy-ethyl]-guanamine. MS: (M+Na)+=512. Example 154. 2·(7-Chloropheno[3,2-]pyridin-2-yl)-5H-.咯 并 [2,3_b]n ratio spray_7_ formic acid [(R)-2-(3-cyano-azetidinyl) small cyclopropyl _2_sideoxy_ethyl]-醯amine 154395.doc -241 · 201134826

Step 1 7-Chloro-2-iodothieno[3,2-b]pyridine (200 mg, 〇·68 mmol) was suspended in THF (6 mL). The reaction mixture was cooled with aq. EtOAc (EtOAc EtOAc (EtOAc) (EtOAc) The reaction mixture was searched for 1 hour at the same temperature, followed by the slow addition of tributyltin chloride (0.29 mL, 1.08 mmol). The reaction mixture was warmed to EtOAc EtOAc (EtOAc)EtOAc. The crude residue was purified by column chromatography (EtOAc EtOAc (EtOAc:EtOAc:EtOAc 7-Gas-2-tributylstannyl-thieno[3,2-b]pyridine. Step 2 Under the murine gas atmosphere, 2-mur-5-(2-trimethyl-stone-ethoxymethyl)-5H-indole[2,3_b]pyrazine_7-carboxylic acid [(R) _2_(3_Cyano-azetidin-1-yl)-1-cyclopropyl_2-sideoxy-ethyl]-bristamine (180 mg, 0.34 mmol) and 7-gas-2 Addition of copper iodide (1) to a solution of dibutyltin-11-sepeno[3,2-1)]°° (162 111, 〇35 mmol) in DMF (3 mL) 135 mg, 154395.doc •242- 201134826 0.071 mmol) and hydrazine (triphenylphosphine) palladium (0) (20.4 mg, 0.018 mmol). The reaction mixture was stirred at <RTI ID=0.0></RTI> <RTIgt; </RTI> <RTIgt; The organic extract was dried over Na 2 SO 4 and evaporated in vacuo. The crude residue was purified by column chromatography (EtOAc, EtOAc (EtOAc:EtOAc:EtOAc) Gas-excitation [3,2-13]'1 than bit-2-yl)-5-(2-trimethyl-stone-ethoxymethyl)-5H-°Bilo[2,3 -1)]° ratio tillage-7-formic acid [(R)-2-(3-cyano-yl-azetidin-1yl)-1_cyclopropyl-2-oxo-ethyl ]_醯amine. Step 3 To 2-(7-Gas-thieno[3,2-b]pyridin-2-yl)-5-(2-tridecylfluorenyl-ethoxymethyl)-5H-.咯和和[2,3-b]&quot;比耕-7-decanoic acid [(R)-2-(3-cyano-azetidin-1-yl)-1-cyclopropyl_2 To a solution of _ oxo-ethyl]- decylamine (3 〇 mg, 0.048 mmol) in dichloromethane (2 mL), trifluoroacetic acid (············ The reaction mixture was stirred at room temperature for 3 hours, then concentrated and dried under high vacuum for hrs. The residue was dissolved in 3 mL of π 2α 2 : Μ 6 〇Η: ΝΗ 4 〇Η (8 (): 19:1) 1 ? and mixed for 8 hours at room temperature, followed by evaporation to dryness under actual work. The crude product residue was washed with fflMe〇H (3×3 mL) to obtain 丨7 mg (72%) 2♦chloro-嗟 并[Hb]pyridine-2-yl)-5H-[2,3 帅比喷_7 _Citrate [(R)_2_(3_Alityl-heterocyclobutane-1-yl) small cyclopropyl-2-_2 oxo-ethyl]• decylamine. Ms: (M+H)+=492. Example 155. 2-(7" 比比.定小基等[3,2_b]nn2·基)·5η•.和和[2,% b]pyrazine-7-formic acid[(R)_2_(3 _cyano-azetidinylbubupropyl _ 154395.doc -243- 201134826 2-sided oxy-ethyl]-guanamine

Step 1 2-(7-Gas-thieno[3,2-b]pyridin-2-yl)-5-(2-tridecylfluorenyl-ethoxyl) at 100 ° C in a microwave reactor Methyl)_5H_.咯 并 [23_b]I^ 耕-7- decanoic acid [(R)-2-(3-cyano-azetidinyl)-yl)-cyclopropyl-2-oxo-ethoxy A solution of the hydrazide (40 mg, 0.064 mmol) in pyrrolidine (5.32 ml, 64.3 mmol) was heated for 2 h. The reaction mixture was evaporated to dryness under vacuum. The crude product residue was suspended in EtOAc (0.5 mL). EtOAcjjjjjjjjjjjjjjjjj b]pyridin-2-yl)-5-(2-tridecyldecyl-ethoxymethyl)-5H-pyha[2,3-b]pyrazine-7-decanoic acid [(R) -2-(3-Cyano-azetidin-1-yl)-1_cyclopropyl_2_sideoxy-ethyl]-decylamine. Step 2 2-(7-Pyrrolidin-1-yl-thieno[3,2-b]pyridin-2-yl)-5H-pyrrolo[2,3-b]pyrazole-7-carboxylic acid [(R - 2 - (3 - cyano-azetidinyl hydrazinyl) hydrazine - cyclopropyl side oxy-ethyl] decylamine. Prepared according to the procedure described in Step 3 of Example 154, wherein 2-(7-pyrrolidin-1-yl-thieno[3,2-b]pyridin-2-yl)-5-(2-tridecylfluorenyl) _Ethoxymethyl)_5Hpyrrolo[2,3b]pyridyl 154395.doc •244- 201134826 Well-7-formic acid [(R)-2-(3-cyano-azetidinyl)_ι_ Cyclopropyl 2_sideoxy-ethyl]-bristamine instead of 2·(7-gas-thieno[3,2_b]1J-pyridyl-2-yl)_5_ (2-trimethylglycine-B Oxidyl)-5H-0 to 0 and [2,3_b]pyrene -7-decanoic acid [(R)-2-(3-cyano-azetidin-1-yl)- 1-Cyclopropyl_2_sideoxy-ethyl]-guanamine. The free assay was treated with 1.0 M HCl/MeOH to isolate the hydrochloride. MS: (M+H)+=527. Example 156. φ 2_[7-(2'2,2-Trifluoroethoxy)-0-propenyl [3, 2-1)]. Than bite_2_yl]_511-° piroxi[2,3-bp ratio tillage-7-formic acid [(R)-2-(3-cyano-azetidinyl)]-cyclopropane Keto-2-oxy-ethyl]-decylamine

Step 1 To a suspension of sodium hydride (60% dispersion, 9.6 mg, 0.24 mmol) in DMF (3 mL) was added 2,2,2-trifluoroethanol (59 μί, 〇8〇mmol) and 2·(7-gas-sighing [3,2-b]&quot;Bite-2-yl)-5-(2-trimethylsulfanyl-ethoxyl-yl)-5H-&quot; Specific ratio of [2,3-b]° to -7-decanoic acid [(R)-2-(3-cyano-azetidin-i-yl)-oxime-cyclopropyl_2_ Oxy-oxyethyl] decylamine (5 〇 mg, 0. 08 mmol). The reaction mixture was stirred under microwave-assisted conditions for 1 hour at EtOAc (20 mL) and washed with water (5×20 mL) 154395.doc 245. The organic phase was evaporated in vacuo and the crude residue was purified mjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj 2-Trifluoroethoxy)+分分[Μ中比 bit_2 base]· 5-(2-tridecylfluorenyl-ethoxyindenyl)_5H_吼 吼[2,3b] 〇 ratio Plowing _7_ decanoic acid [(R)-2-(3-cyano-azetidinyl)-yl)_i·cyclopropyl_2_sideoxy·ethyl]-decylamine. Step 2 2-[7-(2,2,2-Di|1ethoxy)_snap[3,2-1)]. More than bite 2 -yl]-511-0 than argon [2,3-b]pyrazine-7-carboxylic acid [(R)-2-(3-cyano-azetidin 1-cyclopropyl) -2-Sideoxy-ethyl]-guanamine. Prepared according to the procedure described in Step 3 of Example 154, wherein 2-[7-(2,2,2-trifluoroethoxy)-indole was used. [3,2-b] ° than bit-2-yl]-5-(2-trimethyl-stone-ethoxymethyl 11 and [2,3-b]° ratio of spray-7-formic acid [ (R)-2-(3·cyano-azetidinyl-yl)- 1·cyclopropyl-2-oxo-ethyl]-decylamine in place of 2-(7-chlorocerob And [3,2-b] 0 is more than 2 -yl)-5-(2-trimethyl-stone-ethoxymethyl)_5H-0biol[2,3-b] ° ratio -7-carboxylic acid [(R)-2-(3-cyano-azetidin-j-yl)cyclopropyl-2-oxo-ethyl]-decylamine. MS: (Μ+Η +=556. Example 157. 2-(7-Methoxy-thieno[3,2-b]pyridine-2.yl)-5-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(3-cyano-azetidin-1-yl)-i-cyclopropyl_2_sideoxy-ethyl]-decylamine 154395.doc -246- 201134826

Step 1 Add 2-(7-gas-thieno[3,2-b]pyridin-2-yl)-5_ to a solution of sodium methoxide in MeOH (0.5 Μ, 0.97 mL, 〇.49 mm 〇1) (2·Trimethyldecyl-ethoxycarbonyl)_5Η_Π比比和[2,3-b]° ratio tillage-7-formic acid [(r)_2-(3_cyano-azetidine-丨-yl)_i_cyclopropyl·2_sideoxy·ethyl]-decylamine (35 mg, 0.056 mm 〇l) and the reaction mixture was stirred under microwave-assisted conditions at 1 ° C for 1 hour. The reaction mixture was evaporated to dryness and purified title m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m -(7-decyloxy)"»塞eno[3,2_b] 11 bite 2-yl)-5-(2-tridecylfluorenyl-ethoxyindolylpyrylene [2,3 -b]0 to 11 well-7-monoamino]-amino}-acetic acid. MS: (M+H)+=554; (MH))· =552. Step 2 To (R)- at room temperature Cyclopropyl-{[2-(7-methoxy-thieno[3,2-b]pyridin-2-yl)-5-(2-trimethyldecyl-ethoxycarbonyl)·5Η Add-triethylamine (34.0 pL) to a solution of pyrrolo[2,3-b]n than 11 -7-hexyl]-amino}-acetic acid (27 mg, 0.049 mmol) in DMF (2 mL) , 0.24 mmol), azetidine-3-carbonitrile hydrochloride (6 mg, 0.049 mmol) and PyBOP (31 154395.doc -247-201134826 mg '0.059 mmol). The reaction mixture was stirred at the same temperature 16 The mixture was washed with EtOAc (EtOAc) (EtOAc) 1 to 100%, 30 minutes) Purify the crude residue to obtain 26 mg ( 64%) 2-(7-Methoxy-thieno[3,2-b]pyridin-2-yl)-5-(2-trimethyldecyl-ethoxycarbonyl)_5H-pyrrolo[ 2,3-b]pyrazine-7-decanoic acid [(R)-2-(3-cyanoazetidin-1-yl)-1-cyclopropyl_2_sideoxy-ethyl ]-guanamine. Step 3 2-(7-Methoxy-thieno[3,2-b]pyridin-2-yl)-5H-pyrrolo[2,3-b]. Acid [(R)-2-(3-cyano-azetidin-1-yl)-1-cyclopropyl_2_ oxo-ethyl]-decylamine. According to Example 154, Step 3 The procedure described is 'in which 2-(7-methoxy-thieno[3,2-b]pyridin-2-yl)-5-(2-trimethyl-stone-ethoxymethyl) 5Η-°Biluo[2,3-b]. Tillage-7-decanoic acid [(R)-2-(3-cyano-azetidinyl)-indole-cyclopropyl _2_Sideoxy-ethyl]-bristamine in place of 2-(7-chloro-indeno[3,2-b]° ratio -2-yl)-5-(2-trimethyl-stone -ethoxymethyl)-5H-0piro[2,3-b]0 to h-7-carboxylic acid [(R)-2-(3-cyano-azetidin-i-yl) )-1_cyclopropyl_2_sideoxy-ethyl]-decylamine. MS: (M+H)+=488. Example 158. 2-(7-Chloro-zexo[3,2-b]° ratio. Defen-2-yl)-5H-°Biluo[2,3-1)]&quot; ratio, well-7 - decanoic acid [(R)-2-(3-cyano-azetidine small) fluorenyl 2 oxo-ethyl]-decylamine 154395.doc -248* 201134826

CN was prepared according to the procedure described in Example 154, in step 2 as 2-bromo-5-(2-trimethyldecyl-ethoxymethyl)-5H-pyrrolo[2,3b]pyrazole-7 _A S夂[(R)_ 2-(3 - gas-gas-heterocyclic ketone-1-yl)_1·methyl-2_sideoxy-ethyl]-guanamine instead of 2-bromo-5 -(2-tridecylfluorenyl-ethoxymethyl)_51{_pyrrolo[2,3-b]pyr-7-carboxylic acid [(R)-2-(3-cyano-indole heterocycle) Butane•yl)_ 1-cyclopropyl-2-oxo-ethyl]-bristamine. MS: (M+H)+=467. Example 159. 2-(7-Pyrrolidin-1-yl-thieno[3,2-b]pyridin-2-yl)-5H-pyrrolo[2,3-b]indole-7-carboxylic acid [( R)-2-(3-cyano-azetidine-buyl^•methyl_2_sideoxy-ethyl]-decylamine

Prepared according to the procedure described in Example 155, in step 1 as 2-(7- gas-thieno[3,2-b]pyridin-2-yl)-5-(2-tridecylfluorenyl) Oxyfluorenyl)_ 5H-&quot;bibromo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(3-indolyl-azetidine- 154395.doc-249 - 201134826 1-yl)-1-methyl-2-oxo-ethyl]-decylamine in place of 2-(7-chloro-.seceno[3,2-b]°pyridin-2-yl -5-(2-trimethyldecyl-ethoxycarbonyl)_5Η-« ratio 0 and [2,3-b] ° ratio tillage-7-formic acid [(R)_2_(3_cyano) -azetidin-1-yl)- 1-cyclopropyl-2-oxo-ethyl]-bristamine. MS: (M+H)+=501. Example 160·2-[7-(2,2,2-Trifluoro-ethoxy)-0-sepeno[3,2-b] 〇bite·2_yl]_51^ ratio 0 and [2 , 3-b] ° ratio spray-7·carboxylic acid [(R)-2-(3-cyano-azetidinyl)-l-methyl-2-oxo-ethyl]- Guanamine

Prepared according to the procedure described in Example 156, in step 1 as 2-(7-qi·thieno[3,2-b]pyridin-2-yl)-5-(2-trimethyldecyl-ethoxy Methyl 5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(3-cyano-azetidin-1-yl)-1-methyl-2 -Sideoxy-ethyl]-decylamine in place of 2-(7-a-puro[3,2-b].pyridin-2-yl)-5-(2-trimethyl-stone-base-B Oxymethyl) _5H 〇 比洛和[2,3-b] 〇 啡 -7 -7-7-曱 [ [(R)-2-(3-cyano-azetidinyl]_丨_基)_ 1 - Cyclopropyl-2-oxo-ethyl]-guanamine. MS: (M+H)+ = 530. Example 161. 2-(7-methoxy-thieno[3,2-b] Pyridine_2_yl)_5H_pyrrolo[2 3 b]pyrazine-7-decanoic acid [(R)-2-(3-cyano-azetidinyl H•methyl_2• side oxygen 154395.doc •250- 201134826 base ·ethyl] drink amine

[3,2-b]pyridine_2_yl)_5_(2_trimethyldecyl-ethoxymethyl)·5Ηpyrido[2,3-b]pyrazine-7-carboxylic acid [(R - 2 - (3-cyano-azetidine-bu)- 1-cyclopropyl-2-oxo-ethyl]-decylamine. MS: (M+H)+=462. Example 162. 2-(1,3-Dimercapto-1H-pyrazol-4-yl)-5H-pyrrolo[2,3-b]. Specific cultivating · 7_ formic acid [(R)-2-(3-cyano-azetidinyl-bu)-1-indenyl-2-oxo-ethyl] decylamine

Step 1 154395.doc • 251 · 201134826 Combine ι,3-dimercapto-4-(4,4,5,5-tetradecyl _ 1,3,2-dioxo silane in a 25 mL pressure vessel - 2-base)-1Η·° ratio saliva (439 mg, 1.98 mmol), gasification (52 mg, 1.23 mmol) and 2-bromo-5-(2-tridecyldecyl-ethoxycarbonyl) -5H-pyrrolo[2,3-b]pyrazine-7-carboxaldehyde (440 mg, 1.23 mmol) with ethanol (7 mL) and toluene (7 mL), and the mixture was purified with N2. Tripotassium phosphate (917 mg ' 4.32 mmol) was dissolved in 4 mL of water and added to the mixture. After purging with Ns, bis(triphenylphosphine) di-palladium (π) (87 ^, 0.12 mmol) was added, and the vessel was capped and stirred at 6 to 65 for 2 hours. The reaction was cooled and then diluted with ethyl acetate and water. The organic layer was washed with brine, dried and evaporated <~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ Purity) 2-(1,3-didecylsyl-4-yl)_5_(2_trimethylsulfanylethoxymethyl)-5 H-pyrrolo[2,3-b]pyrazine -7-formaldehyde. Step 2 2-(1,3-Dimercapto-1H-pyrazole-4-yl)-5H-pyrrolo[2,3_b]pyrazine_7_carboxylic acid [(R)-2-(3·cyano)- Azetidinated small base) methyl-2-oxoethyl]-decylamine. According to the second step described in the steps 2 to 4 of Example 153, 2·(1,3-dimethyl·1Η·_.4_yl)-external trimethyl-stone-based ethoxymethyl)-5Η- η ratio slightly [2,3 仲比Ρ井·7_甲酿替2·(4_氯小侧氧-1,3-Dihydro· 异,朵_2·基)_5-(2_三甲基石夕烧基·ethoxymethyl)-5Η_«比嘻和[2,3帅比喷_7_carboxylic acid, referred to as 2-aminopropyl aryl in step 3)·azetidine _3_ acetonitrile trifluoroacetate instead of 2, amine-2 - cyclopropyl · ethyl aryl) _ azetidin _3 · Acha triacetate acetate, and in step 3 with HATU Replace ρ_ρ. He (μ+η)+=393. 154395.doc -252· 201134826 Biological Examples JAK Assay Information Determination of IC50 for Janus Kinase (JAK) Inhibition: The enzymes and peptides used are described as follows: JAK1: Recombinant Human Kinase Domain JAK3 from Invitrogen (Cat. No. PV4774) : Recombinant human φ kinase domain JAK2 from Millipore (Catalog No. 14-629) or self-made: Recombinant human kinase domain from Millipore (Catalog No. 14-640): Derived from peptide-bearing sequence: Biotin- The assay conditions used for the biotin-labeled 14-mer peptide at the N-terminus of the JAK1 activation loop of KAIETDKEYYTVKD are described below: Assay buffer: JAK kinase buffer: 50 mM Hepes [pH 7.2], 10 mM MgCl2, 1 mM DTT, 1 mg/ml BSA. Check in this buffer #. Assay format: The kinase activity of all three JAK kinases was measured using a radioactive endpoint assay and using a trace amount of 33p-atp. The assay was performed in a 96-well polypropylene plate. Experimental method: All concentrations were in the final concentration in the reaction mixture and all incubations were carried out at room temperature. The assay procedure is described as follows: The compound is typically serially diluted in 100% DMSO at a 10 fold initial concentration of 1 mM. The final concentration of DMSO in the reaction was 10%. 154395.doc -253 - 201134826 The compound was pre-incubated with the enzyme (〇·5 nM JAK3 (commercially available), 0.2 nM JAK2 (prepared), 1 nM JAK2, 5 nM JAK1) for 1 min. The reaction was initiated by the addition of a mixture of two receptors (ATP and peptide premixed in JAK kinase buffer). In the JAK2/JAK3 assay, ATP and peptide were used at concentrations of 1.5 μΜ and 50 μΜ, respectively. The JAK1 assay was performed at an ATP concentration of 10 μΜ and a peptide concentration of 50 μΜ. The duration of the JAK2 and JAK3 tests is 20 minutes. The JAK1 test takes 40 minutes. For all three enzymes, the reaction was stopped by the addition of 〇.5 M EDTA until the final concentration was 100 mM. Transfer 25 μΐ of the terminated reaction to streptavidin-coated agarose beads in 96-well 1.2 μιη MultiScreen-BV filter plates in 1x phosphate buffered saline without MgCl2 and CaCl2 (containing 50 mM EDTA) In a 150 μΐ 7.5°/〇 (v/v) slurry. After 30 minutes of incubation, the beads were washed under vacuum with the following buffer: Washed 3 to 4 times with 200 μL of 2 M NaCl. Wash 3 to 4 times with 200 μM 2 M NaCl plus 1% (ν/ν) phosphoric acid. Wash the Su for 1 time with water. The washed plates were dried in an oven at 60 ° C for 1 to 2 hours. 70 μM Microscint 20 scintillation fluid was added to each well of the filter plate, and after incubation for at least 30 minutes, the radioactivity count was measured in a Perkinelmer micro-quantitative plate scintillation counter. Representative IC50 results are given in Table II below: I54395.doc -254· 201134826 Table II.

Compound Ic50 h-jak3(810-1124)-sf9-c: no additive 1-1 0.05159 1-2 0.04579 1-3 0.01171 1-4 0.00486 1-5 0.00172 1-6 3.03651 1-7 0.00656 1-8 0.01234 1 -9 0.05294 1-10 0.00218 1-11 0.09151 1-12 0.99241 1-13 0.00453 1-14 0.00802 1-15 0.05495 1-16 0.07248 1-17 0.14793 1-18 0.44311 1-19 0.02700 1-20 0.00705 1-21 0.01494 1-22 0.00534 1-23 0.00953 1-24 0.07276 1-25 0.01612 1-26 0.00398 1-27 0.00194 1-28 0.00051 154395.doc -255 - 201134826 1-29 0.01362 1-30 0.00124 1-31 0.00080 1- 。 。 。 。 。 。 。 。 1-51 0.11095 1-52 0.44049 1-53 0.27888 1-54 0.01491 1-55 0.00152 1-56 0.00077 1-57 0.00032 1-58 0.00049 1-60 0.00079 1-61 0.00042 1-64 0.09493 1-65 0.00087 1- 68 0.00058 1-69 0.00032 1-71 0.00392 154395.doc -256- 201134826

1-73 0.00334 1-74 0.00113 1-76 0.01182 1-77 0.00032 1-78 0.00032 1-79 0.00032 1-81 0.00032 1-82 0.00032 1-83 0.00032 1-84 0.00075 1-85 0.00085 1-86 0.00402 1- 87 0.00449 1-88 0.00123 1-89 0.00423 1-90 0.00973 1-91 0.01701 1-92 0.01091 1-93 0.01635 1-94 0.00366 1-95 0.00273 1-96 0.00069 1-97 0.00391 1-98 0.00216 1-99 0.00078 I-100 0.01605 1-101 0.03700 1-102 0.04312 1-103 0.00834 1-105 2.26468 1-106 0.00261 154395.doc •257 - 201134826 1-107 0.00657 1-108 0.00605 1-109 0.00061 1-110 0.00122 1-111 0.00571 1-112 0.00097 1-113 0.00371 1-114 0.01628 1-115 0.00292 1-116 0.00273 1-117 0.00101 1-118 0.00605 1-119 0.00274 1-120 0.00370 1-121 0.00167 1-122 0.00405 1-123 0.00062 1 -124 0.00137 1-125 0.00035 1-126 0.00057 1-127 0.00356 1-128 0.00281 1-129 0.00118 1-130 0.11280 1-131 0.00258 1-132 0.00049 1-133 0.00167 1-135 0.00611 1-136 0.00711 1-137 0.53864 1-138 0.01905 154395.doc •258 · 201134826 1-139 0.00032 1-140 0.00068 1-142 0.00047 1-143 0.00042 1-144 0.00062 1-145 0.01520 1-146 0.00038 1-147 0.00446 1-148 0.00198 1-149 0.00127 1-150 0.00200 1-151 0.00032 1-152 0.00952 1-153 0.00902 1-154 0.00306 1 -155 0.01051 1-156 0.00597 1-157 0.00328 1-158 0.00234 1-159 0.00266 1-160 0.00038 1-161 0.00032 1-163 0.00032 1-164 0.00032 1-165 0.00068 1-166 0.00032

SYK assay information Determination of spleen tyrosine kinase (SYK) inhibition by ICS0: The SYK kinase assay is a standard kinase assay suitable for 96-well plate format. This assay was performed in 96-well format for IC50 assay using 8 representations of 10 154395.doc -259-201134826 semi-log dilutions and 40 μί reaction volume. This assay incorporates a radiolabeled 33ΡγΑΤΡ from the biotinylated peptide receptor (biotin-llaa DY*E) at the end of the naturally occurring phosphoacceptor consensus sequence. Phosphorylated products were detected when the reaction was stopped with EDTA and beads coated with streptavidin were added. Calibration plate: 96-well Multiscreen 0.65 μηι filter plate (Millipore, catalog number: MADVNOB10) Beads coated with antibiotic proteomycin: streptavidin agaroseTM, suspension 5.0 mL, diluted (1: 100) in 50 mM EDTA/PBS (Amersham, Cat. No.: 17-5113-01) Compound: 10 mM in 100% dimethyl sulfoxide (DMS0), final concentration: 0.003-100 μΜ compound at 10% DMS0 Medium enzyme: purified truncated SYK RPA construct of spleen tyrosine kinase aa 360-635, 1 mg/mL stock solution, MW: 31.2 KDa, final concentration: 0.0005 μΜ ° peptide 1: biotinylated peptide It is derived from the naturally occurring phosphate receptor consensus sequence (Biotin-EPEGDYEEVLE), custom-made from QCB, 20 mM stock solution, final concentration: 5.0 μΜ. ΑΤΡ: adenosine-5'-triphosphate, 20 mM (R0CHE catalog number: 93202720), final concentration: 20 μΜ buffer: HEPES: 2-hydroxyethylpiperidine-2-ethanesulfonic acid (Sigma, catalog number: H-33 75), final concentration: 50 mM HEPES pH 7.5 BSA: Fatty acid-free bovine serum albumin Part V (Roche Diagnostics GmbH, Cat. No. 9100221), diluted to final concentration 154395.doc -260- 201134826 0.1%

EDTA : EDTA stock solution 500 mM (GIBCO, catalog number: 15575-038), final concentration: 0.1 mM

DTT: 1,4-dithiothreitol (Roche Diagnostics GmbH, catalog number: 197777), final concentration: 1 mM

MgCl2x6H20 : MERCK, catalog number: 105833.1000, final concentration: 10 mM

φ assay dilution buffer (ADB): 50 mM HEPES, 0.1 mM EGTA, 0.1 mM sodium vanadate, 0.1 mM β-glycerophosphate, 10 mM MgCl2, 1 mM DTT, 0.1% BSA, pH 7.5 Bead Wash Buffer: 10 g/L PBS (phosphate buffered saline) containing 2 M NaCl + 1% phosphoric acid. Experimental method: 26 pL of ADB-diluted purified recombinant human SYK360-635 [0.5 nM] was mixed with a concentration of 4 μιηx of test compound [usually Φ 100 μΜ-0·003 μΜ] in a volume of 40 pL [10% The mixture was incubated in DMSO for 10 minutes at room temperature. The kinase reaction was initiated by the addition of 10 pL of DYE peptide-bearing [0 or 5 μΜ], ATP [20 μΜ], and 33ΡγΑΤΡ [2 μ(:ί/reaction) 4 χ substrate mixture at 30 ° C. After 15 minutes of incubation, the 25 μί reaction sample was transferred to a 96-well 0.65 μη Millipore MADVN0B membrane/plate containing 200 pL of 5 mM EDTA and 20% streptavidin-coated beads in PBS. The unbound radionucleotide was washed under vacuum with 3x250 μm 2 M NaCl, 2x250 pL 2 M NaCl+1% 154395.doc -261- 201134826 phosphoric acid '1x250 μί H20. After the last knee wash, the membrane/ The plate was transferred to an adaptor plate 'heated at 60 ° C for 15 minutes, and 5 〇 scintillation cocktail was added to each well, and after 4 hours, the radioactivity was applied to the top counter (top c〇unter). The amount is counted. The percent inhibition is calculated based on the uninhibited enzyme rate: % inhibition = 100 / (1 + (IC5 / inhibitor concentration) η)

Use nonlinear curve fitting with XLfit software (ID Business

Solution Ltd. ’ Guilford, Surrey, UK) calculates IC50. The present invention has been described in considerable detail with the aid of the description and examples for the purpose of understanding and understanding. It is to be understood that the above description is intended to be illustrative and not restrictive. The invention (4) should be determined with reference to the above description, and should refer to all the scopes of the following patent application and the equivalents of the patent application scope to determine all patents cited in this application.

The search for a case and the case of the open case are quoted in full text. You are included in this article for all purposes.

The degree is like that of each patent. #利application or public case individual expression 154395.doc -262-

Claims (1)

201134826 VII. Patent application scope: 1. A compound of formula I, Stomach I, wherein: Y is (: 1); R1 is Η or Rla; Rla is a lower alkyl, lower alkoxy, phenyl, phenyl fluorenyl group, optionally substituted by one or more Rla· a heteroaryl group, a cycloalkyl group, a heterocycloalkyl group or a cycloalkylalkyl group; Rla' is a halogen, a lower alkyl group, a lower carbon lialkyl group, a lower alkoxy alkoxy group, a lower hydroxyalkyl group, and a lower Carbohaloalkyl, pendant oxy, hydroxy or -CN; X is C(R2)(R3), N(R2), s(=0)2 or Ο; each R2 is independently Η or R2a; each R is independent The ground is a low carbon alkyl group, a low carbon tooth base, a dentate, a lower alkoxy group, a lower hydroxyalkyl group, a cyano group, a cyano lower alkyl group, a hydroxyl group, a C(=0)R2a· or S ( =0) 2R2a·; each Ra2' is independently hydrazine or lower alkyl; each X is independently dentate, lower alkyl, cyano, hydroxy, lower sec-alkyl, lower hydroxyalkyl, Heteroaryl, spiroheterocycloalkyl, spirocycloalkyl, 154395.doc 201134826 lower alkoxy, lower alkylamino or lower dialkylamino; or X' and R2 together form By one or more R2, instead of the bicyclic system; R2, is a dentate, a lower alkyl group, a lower alkoxy group, a hydroxyl group, a lower hydroxyl group Alkyl, lower halohaloalkyl, lower hydroxyalkylcyano or -S(0)2CH3; R3 is hydrazine, hydroxy, halogen or lower alkyl; or R2 and R3 together form one or more a R2' substituted spiro ring system; q is 0, 1, 2, 3 or 4; η is 0 or 1; ρ is 0 or 1; Q is Η, halogen, hydroxy, cyano or Q'; Q' is Lower alkyl, lower alkenyl, lower alkynyl, lower alkoxy, cycloalkyl, cycloalkoxy, phenoxy, phenyl, cycloalkenyl substituted by one or more Qa, as appropriate , heterocycloalkyl or heteroaryl; Qa is Qb or Qe; Qb is a hydroxyl, pendant oxy, hydroxy, -CN, -SCH3, -s(o)2ch3 or -S(=〇)CH3; Qe is Q^Qe' ; or two Qa - forming a bicyclic system that is replaced by one or more Qb or Qe as appropriate; Ql - 〇 (Qe), _s (=0) 2 (Qe), _C (= 〇) N (Qe)2, -S(0)2(Qe), -C(=〇)(Qe), -C(=0)0(Qe), -N(Qe)2, -N(Qe)c( =〇)(Qe), _N(Qe)c(=〇)0(Qe) or _N(Qe)c 154395.doc 201134826 (=0)N(Qe)2 ; each Qlf is H or Qe'; Each Qe' is independently a lower alkyl, phenyl, benzyl, lower haloalkyl, lower carbon by one or more QfS as appropriate Oxy, cycloalkyl, cycloalkyl lower alkyl, cycloalkenyl, heterocycloalkyl or heteroaryl; Q^Qg or Qh; Φ Qg is a hydroxyl, hydroxy, cyano, pendant oxy or C(=0)(Qh); Qh is a lower alkyl group, a lower alkoxy group, a lower alkoxy group, an amine group, a phenyl group, a phenyl fluorenyl group, a cycloalkane substituted by one or more Qi as the case may be. a heterocyclic alkyl group or a heteroaryl group; and Q1 is a gerberin, a thiol group, a cyano group, a lower alkyl group, a lower alkyl group or a lower alkoxy group; ^ or a pharmaceutically acceptable salt thereof . 2. A compound according to claim 1, wherein Y is CH(R!); R1 is hydrazine or Rla; and Rla is lower alkyl, lower alkoxy, phenyl optionally substituted by one or more Rla' , phenyl fluorenyl, heteroaryl, cycloalkyl, heterocycloalkyl or cycloalkyl; Rla' is iS, lower alkyl, lower carboalkyl, lower alkoxy, lower hydroxy Alkyl, lower halohaloalkyl, pendant oxy, hydroxy or -CN; 154395.doc 201134826 X is C(R2)(R3), n(R2), s(=o)2 or ο; each R2 independently Is H or R2a; each R is independently a lower alkoxy group, a lower carboalkyl group, a olefin, a lower alkoxy group, a lower hydroxyalkyl group, a cyano group, a cyano lower alkyl group, a hydroxyl group, a C ( =0) R2a' or S(=0)2R2a·; each Ra2_ is independently hydrazine or lower alkyl; each X' is independently halogen, lower alkyl, cyano, hydroxy, lower haloalkyl , lower hydroxyalkyl, heteroaryl, spiroheterocycloalkyl, spirocycloalkyl, lower alkoxy, lower alkylamino or lower dialkylamino; or hydrazine and R2 a bicyclic ring system substituted with one or more R 2 ' as appropriate; R 2 'is halogen, lower alkyl, lower alkoxy, hydroxy, a lower alkylene group, a lower halohaloalkyl group, a lower hydroxyalkyl cyano group or a -S(0)2CH3; R3 is a hydrazine, a hydroxy group, a halogen or a lower alkyl group; or R2 and R3 together form a form One or more R 2 'substituted spiro ring systems; q is 0, 1, 2, 3 or 4; η is 0 or 1; ρ is 0 or 1; Q is deuterium, halogen, hydroxy, cyano or Q'; Q' is a lower alkyl group, a lower alkenyl group, a lower alkynyl group, a lower alkoxy group, a cycloalkyl group, a cycloalkoxy group, a phenyl group, a cycloalkenyl group, optionally substituted with one or more Qa groups. Heterocycloalkyl or heteroaryl; Qa is Qb or Qc; 154395.doc 4·201134826 Qb is halogen, pendant oxy, hydroxy, _CN, -SCH3, -s(o)2ch3 or -s(=〇)ch3 ; for Qd or Qe'; or two Qa together form a bicyclic system that is replaced by one or more Qb or QC as appropriate; Qd is -0 (Qe), -S (=0) 2 (Qe), -C (=〇)N(Qe)2, -S(0)2(Qe), -C(=0)(Qe), -C(=0)0(Qe), -N(Qe)2 ' -N (Qe)C( = 〇)(Qe) . -N(Qe)C( = 0)0(Qe) or -N(Qe)C(=〇)N(Qe)2 ; each (^ is independently H Or Qe'; each Qe' is independently one or more (lower alkyl, phenyl, benzyl, lower halothane substituted by ^) , lower alkoxy, cycloalkyl, cycloalkyl lower alkyl, % dilute, heterorubbery or heteroaryl; Q^Qg4Qh; Qg is halogen, trans-cyano, oxo or -C(=0)(Qh); Qh is a lower alkyl group, a lower alkoxy group, a lower alkoxy group, an amine group, a phenyl group, a phenyl fluorenyl group, a ring substituted by one or more β as the case may be. An alkyl group, a heterocycloalkyl group or a heteroaryl group; and (i is iS, hydroxy, cyano, lower alkyl, lower haloalkyl or lower alkoxy; or a pharmaceutically acceptable salt thereof . 154395.doc 201134826 3. The compound of claim 2 or 2, wherein tQ is a cycloalkyl, phenyl or heteroaryl group optionally substituted with one or more Qa. 4. The compound of claim 1 or 2, wherein X is c(r) (r%. 5. The compound of claim 2 or 2, wherein R2 is lower alkyl, cyano, arginine, low carbon institute A compound of claim 1 or 2 wherein η is 〇 and p is 〇. 7. A compound of claim 1 or 2, wherein η Is a compound of claim 1 or 2, wherein η is 1 and 卩 is 1. 9. The compound of claim 1 or 2, wherein R 2 is cyano. Or a compound of 2, wherein q is hydrazine. 11. The compound 'R' as claimed is a lower alkyl, lower alkoxy group substituted by one or more Rla' as defined in claim 1 or 2, as appropriate. a compound, a cycloalkyl group, a lower halohaloalkyl group or a lower carboalkylcycloalkyl group. 12. The compound 'Rla.' of claim 1 or 2 is a lower alkyl group or a lower carboalkyl group. The compound of item 1 or 2 wherein R1 is lower alkyl, lower alkoxy, cycloalkyl, lower haloalkyl or lower alkalicycloalkyl. 14. The compound of claim 1 or 2 'wherein R1 is lower alkyl or cycloalkyl. The compound of claim 1, wherein R3 is η. 16. The compound of claim 1 or 2, wherein R3 is lower alkyl. 17. The compound of claim 1 or 2, Q is optionally one or more 1-a-oxy-1,3-dihydro-isoindol-2-yl, cycloalkyl, imidazolyl, cycloalkoxy, lower alkoxy, substituted by Qa as defined in claim 1 or 2, Phenyl, present oxy, "n-substituent, β-bite-based, β-beta-spinyl η-septo[3,2-6]n ratio bite-2-154395.doc -6- 201134826 base or three嗤基。 1 8. According to the compound of claim 1 or 2, Qa is replaced by one or more Qfs as defined in claim 1 or 2, 〇Qe, -N(Qe)2, -C( =0)N(Qe)2, aza-bicyclo[3.1.0]hex-3-yl, lower carboalkyl, lower alkyl, cycloalkyl, phenyl, morpholinyl, lower alkoxy Alkyl, cycloalkyl lower alkyl, piperino, pyrazolyl, pyrrolyl, pyridyl, thiophene, 19. Compound of claim 1 or 2, (^ is _ Or _c(=0)(Qh), wherein Qh is a lower alkyl group. 2 0 · a compound selected from the group consisting of: 2-cyclopropyl-5//-° than haha [ 2,3-6]° ratio p well·7·capric acid ((R) small methyl-2_ sideoxy-2-pyrrolidin-1-yl-ethyl)-guanamine; 2-cyclopropyl- 5//-pyrrolo[2,3-6]pyrazine_7_formic acid (chemically sulphonyl 2· oxo-2-piperidin-1-yl-ethyl)-decylamine; 2_cyclopropane -5-5-open-pyrrolo[2,3-gong]pyridinium-7-decanoic acid [chemical dipyridamole (pyrrole-1-yl)-propyl]-guanamine; 2-cyclopropyl-5/ /-. Biluo[2,3-do]0 is more than 7·carboxylic acid [(R)_2_mercapto_ι_(pyrrolidin-1-carbonyl)-propyl]-decylamine; 2-cyclopropyl-5仏pyrrolo[2,3 work]pyrazine_7•carboxylic acid ((R) i_cyclopropyl_2-o-oxy-2-pyrrolidine-i-yl-ethyl decylamine; 2-cyclopropyl -5 good-pyrrolo[2,3 work]pyrazine·7_decanoic acid ((s) i_methyl·2_ sideoxy-2-°bipyridyl-i-yl-ethyl)-decylamine ; 2-ί propyl propyl 匕 并 [2,3_6] 0 than 〇 _7_ decanoic acid (10) _2 · fluorenyl small (Biridine-1-carbonyl)-propyl] • decylamine; 5//-. 比比和[2,3_6]Pyreoic acid [(R)_2·曱基·卜154395.doc 201134826 (morpholine-4_carbonyl)-propyl]-decylamine; 2- Cyclopropyl-5//-β piroxi[2,3-6]pyr-7-carboxylic acid [(R)-2-(3-methoxy·°-pyrrolidin-1-yl)-1 -methyl-2-oxo-ethyl]-decylamine; 2-cyclopropyl-5//-pyrrolo[2,3-6]pyrazine-7-carboxylic acid [(R)-2,2 - dimethyl-1-(pyrrolidin-1-carbonyl)-propyl oxime; 2-cyclopropyl-ST/-pyrrolo[2,3·ό]pyrazine-7-decanoic acid [(R 2-(3-hydroxy-0-pyridin-1-yl)-1-indolyl-2-oxo-ethyl]-decylamine; 2-cyclopropyl-5//-pyrrolo[ 2,3-6]pyrazine-7-formic acid ((S)-l- Benzyl-2-oxo-2 -. butyl-1-yl-ethyl) decylamine; 2-(1-ethyl-1^/--pyrazol-4-yl)-5//- Pyrrolo[2,3-do]pyrazine-7-carboxylic acid [(R)-2,2-dimercapto-1-(pyrrolidinylcarbonyl)-propyl]-decylamine; 2-cyclopropyl-5 /f-pyrrolo[2,3-6]pyridin-7-decanoic acid [(R)-2-(3-cyano-pyrrolidin-1-yl)-1-methyl-2-oxooxy -ethyl]-guanamine; 2-cyclopropyl-5i/-pyrrolo[2,3-6]pyrazine-7-carboxylic acid [(R)-l-methyl-2-(3-methyl- Pyrrrolidin-1-yl)·2_sideoxy-ethyl]-decylamine; 2-cyclopropyl-5//-° ratio 嘻[2,3-6]. Ratio 11 Well-7-carboxylic acid [(R)-l-methyl_2_(2-methyl-pyrrolidin-1-yl)·2·sideoxy-ethyl]-decylamine; 2-cyclopropyl-5//-pyrrole [2,3-6]pyrazine-7-formic acid ((R)-2-azetidin-1-yl-1-methyl-2-oxo-ethyl)-decylamine; 2- Phenoxy-5 ugly than argon [2,34] 〇 耕 -7-carboxylic acid [(R)-2-methyl-indololbine-1-yl)-propyl]-bristamine; 2 -cyclopropyl-5//~0biluo[2,3-6]t&gt; ratio ρ well-7-formic acid [2,2,2-three gas-1· (° ratio 11 each bite -1- Alkyl)-ethyl]-bristamine; 2-cyclopropyl-5i/-pyrrolopyrene 4-7-decanoic acid [(R)-2-(3-cyano-I54395.doc 20113 4826 azetidin-1-yl)-1·indol-2-yloxy-ethyl]-decylamine; 2-cyclopropyl-5//-pyrrolo[2,3-do]pyrr Plough-7-decanoic acid [(R)-2-(3,3-difluoro-pyrrolidin-1yl)·1·methyl-2-oxo-ethyl]-decylamine; 2-ring Propyl-5//-pyrrolo[2,3-6]pyrazine-7-carboxylic acid [(R)-2-((S)-3-fluoro-pyrrolidin-1yl)-i-methyl -2-Sideoxy-ethyl]-decylamine; 2-cyclopropyl-5//-&quot;bibromo[2,3-Z&gt;]nb plough-7-formic acid [(R)-2- ((R)-3-fluoro-pyrrolidin-1-yl)-1-methyl-2-oxo-ethyl]-decylamine; φ 2-cyclopropyl-5//-pyrrolo[2 , 3_6] pyridin-7-formic acid [(R)-bumethyl-2-(2-oxa-6-aza-spiro[3.3]hept-6-yl)-2-yloxy-ethyl]- Indoleamine; 2-cyclopropylpyrrolo[2,3-6]pyrazine-7-carboxylic acid [(R)-l-methyl-2-oxo-2-(3-trifluorodecyl)啶·卜基)·ethyl]_decylamine; 2-cyclopropyl-5//-pyrrolo[2,3-Z&gt;]°tb cultivable-7-decanoic acid ((R)-l-cyclopentane 2-ethyloxy-2-pyrrolidin-1-yl-ethyl)-decylamine; 2-(1-ethyl-1//-pyrazol-4-ylpyrrolo[2,3-Z ?]pyrazine-7-formic acid ((R)-l-cyclopropyl-2-oxooxy-2-pyrrolidin-1-yl-hexyl)-decylamine; Φ 2-(1-ethyl- 1//-pyrazole_4_yl)-5//-pyrrolo[2,3-pyridyl 11 well_7_carboxylic acid [(R)-l-(3-cyano-3-methyl-pyrrole Acridine-fluorene-carbonyl)_2,2-dimethyl-propyl]-bristamine; 2-cyclopropyl-5//-pyrrolo[2,3-6]pyrazine-7-carboxylic acid [(R) -l-(3-cyano-piperidin-1-carbonyl)-2,2-dimethyl-propyl]•decalamine; 2_cyclopropylpyrho[2,3-W〇tb rigic acid [(R)-1-((S)_3-cyano-°Pilo-1-yl)-2,2-dimercapto-propyl]-bristamine; 2·cyclopropyl-5 ugly -°Biluo[2,3-&] 〇比耕-7-decanoic acid [(R)-1-((r)-3_cyano-pyrrolidine-1-carbonyl)-2,2-di Mercapto-propyl]-decylamine; 154395.doc • 9. 201134826 2-cyclopropyl-5H-pyrrolo[2,3-6]pyridyl-7-carboxylic acid [(r)-2,2- Dimethyl-1-(piperidine_1-carbonyl)-propyl]-decylamine; 2·cyclopropyl-5H-pyrrolo[2,3-do]pyrazine-7-decanoic acid [(R) -l-(3-cyano-azetidin-1-carbonyl)-2,2-dimercapto-propyl]-guanamine; 2-(1-ethyl-li/-pyrazole-4 -base)-5 ugly-° ratio 11 and [2,3-δρ ratio tillage-7-decanoic acid [(R)-l-(l-fluorenyl-cyclopropyl)-2- oxo-2 -pyrrolidin-1-yl-ethyl]-decylamine; 2-cyclopropyl-5&quot;-° ratio 咯[2,3-do]pyrazine-7-decanoic acid [(R)-1 -(4-cyano-oxaridin-1-carbonyl)-2,2-dimercapto-propyl]-guanamine; 2-(1-ethyl-1 ugly-pyrazol-4-yl)- 5/ί-pyrrolo[2,3-cis pyridin-7-decanoic acid [(R)-1-(3-cyano-3-fluoro-pyrrolidin-1-carbonyl)-2,2-dimethyl --propyl]-guanamine; 2-cyclopropyl-5-pyrrolo[2,3-6]pyrazine-7-decanoic acid ((R)-l-cyclohexyl-2-yloxy- 2-pyrrolidin-1-yl-ethyl)·guanamine; 2-(1-ethyl-Ι/f·pyrazole-4-yl)-5//-pyrrolo[2,3-do]pyrr Plough-7-formic acid {(R)-l-[3-(4,5-dihydro-1//-imidazol-2-yl)-3-fluoropyrrolidine-1-carbonyl]-2,2- Monomethyl-propyl}-bristamine; 2-cyclopropyl-5//-pyrrolo[2,3-6]pyrazine-7-decanoic acid [(R)-l-(3-cyano- 3_Indolyl-azetidine-1-carbonyl)-2,2-dimethyl-propyl]-bristamine; 2-cyclopropyl-5//-.咯比和[2,3-6]&quot;比耕-7-carboxylic acid [(R)_2-(3-cyano-azetidin-l-yl)-l-cyclopentyl_2_ side Oxy-ethyl]-decylamine; 2·cyclopropyl-57/-pyrrolo[2,3·6]pyrazine·7-carboxylic acid [(R)-l-(3,3-difluoro-pyrrole Pyridin-1-carbonyl)·2,2·didecyl-propyl]-decylamine; 2-cyclopropyl-5//-pyrrolo[2,3-6]pyrazine-7-carboxylic acid [(R )-M3,4-di 154395.doc 201134826 Argon-17/-isoquinolin-2-carbonyl)-2,2-dimethyl-propyl]-guanamine; 2-cyclopropyl-5//- Pyrrolo[2,3-6]. Ratio 4-7-formic acid [(R)·1 -(4-cyano-piperidin-1-carbonyl)-3-methyl-butyl]-decylamine; 2-cyclopropyl-57/-&quot; Bis-[2,3-6]吼耕-7-carboxylic acid [(R)-l-(4-cyano-4-indolyl-piperidin-1-carbonyl)-2,2-didecyl- Propyl]-nonylamine; 2-cyclopropyl-5 ugly-n ratio argon [2,3-6]&quot; than plough-7-formic acid [(R)-2-(4-cyano-0 bottom) Benzo-1-yl)-1-cyclopentyl-2-oxo-ethyl]-bristamine, φ 2-cyclopropyl-5-pyrrolo[2,3-6]pyrazine-7- Formic acid [(S)-2-(4-cyano-pyrylene-1-yl)-2-oxo-oxime-(ι-trifluoromethyl-cyclopropyl)ethyl] 2-cyclopropyl-5//-pyrrolo[2,3-6]pyrazine-7-carboxylic acid [(R)-2-(4-cyano-piperidin-1-yl)-2-sideoxy Ϊ́-ΐ_(ι_Trifluoromethyl-cyclopropyl)-ethyl μ decylamine; 2-cyclopropyl-5//-pyrrolo[2,3-6]pyridyl well-7-carboxylic acid [( R)-l-stupyl-methyl 2-(4-cyano-piperidin-1-yl)-2. oxo-ethyl]-decylamine; #2·cyclopropylpyrrolo[2,3 ·Do]Pemide _7·carboxylic acid [(R)-l-(4-cyano_0 bottom bite-1-weiyl)-3,3-dimethyl-butyl]-bristamine·, 2- (3,5-bis-difluoromethyl-stupyl)_57/-11 than 0 each [2,3_do]1&gt; than 1» well_7_capric acid [(R)-l-(4 -Cyanide Alkyl)-2,2-dimethyl-propyl]-bristamine; 2-(3-pyrrolidin-1-yl-phenyl b 5 ugly-pyrrolo[2,3 work]pyrazine_7· Formic acid [(R)-l-(4-cyano-piperidine-i-carbonyl)_2,2-dimethyl-propyl]-decylamine; 2-cyclopropyl-5//-pyrrolo[2 , 3-0] pyridin-7-decanoic acid [(foot)_b (4,4-difluoro-piperidin-1-carbonyl)-2,2-dimethylpropyl]-decylamine; 2 -(1-methyl-1//-pyrazol-4-yl)-5 ugly-pyrrolo[2,3_5]pyrrole__7-methyl 154395.doc -11· 201134826 acid [(R)-l-( 3-cyano-azetidine j • carbonyl) _22 dimethyl propyl] decylamine; 2-(1//-pyrazol-4-yl)·5&quot;·pyrrolo[2 3 Pyridin_7·formic acid [(r) i·(4-cyano-piperidin-1-carbonyl)·2,2-dimethyl-propyl]•decylamine; 2-(1-mercapto- 1 ugly-pyrazole_4_yl)·5/ί-pyrrolo[2,3 work]pyrylene_7_decanoic acid [(R)-l-(4-cyano-pyrene + carbene) ^-Dimercapto-propyl]-bristamine; 2-(1-ethyl-1//-. Biazole _4_yl)_5 ugly-pyrrolo[2 3 6]pyrazine_7-formic acid [(R)-l-(4-cyano-p-pyridyl)-yl)_2,2-didecyl-propion 2-arylpropyl-5//-pyrrolo[2,3 work]pyrazine·7_carboxylic acid [(foot)^ _(4_ethylhydrazine-piperidin-1-carbonyl) -2,2-dimercapto-propyl decylamine; 2-cyclopropyl-5open-pyrrolo[2 3·ό]pyrazine_7_carboxylic acid [(R)_2,2 dimethyl-1- (4-trifluoromethyl-piperidine-hydrazine-carbonyl)-propyl]-decylamine; 2-(1-methylazole·4•yl)·5//•pyrrolo[2 3•small taste _7-formic acid [(R)-l-((S)-3.cyano-pyrrolidinium-fluorene-carbonyl)·2 2 dimethyl-propyl oxime; 2-(1·methyl-1 ugly -pyrazole_4_yl)-5-open-pyrrolo[2 3-Rapyrid _7·carboxylic acid [(R)-l-((R)-3-cyano·. than singly] base 2) 2-dimercapto-propyl bromide; 2-cyclopropyl-5/f-pyrrolo[2,3 work]pyrazine_7_carboxylic acid [(R)_2_(4-cyano-piperidine-1 -yl)-1-cyclopropyl·2_sideoxyethylidene; 2-(ι·ethyl m4·yl)5-pyrrolo[23-pyrazolecarboxylic acid [(R)-2- (3-cyano-azetidinium _ j-based) fluorenyl 2·sideoxy-ethyl]-bristamine; 2-(1-methyl-1//-.biazole _4· Base)·5仄pyrrolo[2, 3 external ratio spray 7 A 154395.doc •12· 201134826 Acid [(R)-2-(4-azyl-c-bottom-1·yl)-1-cyclopropyl-2-sideoxy-ethyl ]-guanamine; 2-(3,4,5-trimethoxy-phenyl)-5-pyrrolo[2,3-6]pyrazine-7-carboxylic acid [(R)-l-(4- Cyano-piperidin-1-carbonyl)-2,2-dimercapto-propyl]-guanamine; 2-cyclopropyl-5//-pyrrolo[2,3-6]pyrazine-7- Formic acid [(R)-l-(4-hydroxy-4-phenyl-piperidin-1-carbonyl)-2,2-dimercapto-propyl]-nonylamine; 2-(2,5-dimethyl Oxy-phenyl)-5 ugly-pyrrolo[2,3-6]pyrazine-7-carboxylic acid [(R)-1-(4- disordered-based base--1-wei)-2, 2-dimercapto-propyl]-decylamine; 2-(1-ethyl-1//-pyrazol-4-ylpyrrolo[2,3-6]pyrazine-7-carboxylic acid [(R) -2-(4-cyano-piperidin-1·yl)-1-indenyl-2-sideoxy-ethyl]-decylamine; 2-cyclopropyl-5//-° ratio 2,3-6]. Specific tillage-7-formic acid [(R)_2-(3-cyano-azetidin-l-yl)-l-cyclopropyl-2-o-oxy-ethyl ]_Benamine; 2-(1-mercapto-1孖-° than sal-4-yl)-5--.咯和和[2,3-6]»比耕-7-carboxylic acid [(R)-1-(3-cyano-azetidin-1-ylcarbonyl)_3_methyl-butyl]_醯Amine; 2-(1-mercapto-1//-pyrazol-4-yl)-5ii-pyrrolo[2,3-fc]pyrazine-7-decanoic acid [(R)-2-(3- Cyano-azetidine_ι_yl)_丨·cyclopropyl_2_sideoxy_ethyl]-guanamine; 2-(1-ethyl-li/-pyrazol-4-yl )-5//-pyrrolo[2,3_办]pyr _7_decanoic acid [(R)-2-(4-cyano-piperidinyl] 〖-kesing oxime-cyclopropyl side oxy group -ethyl]-decylamine; 2-cyclopropyl-5//-pyrrolo[2,3·6]pyridin-7-carboxylic acid [(r)_i_(4-hydroxy-4-trifluoromethyl)- Piperidine-1-carbonyl)-2,2-dimercaptopropyl]-decylamine; *13· 154395.doc 201134826 2-cyclopropyl-5/ί-pyrrolo[2 3]pyrazine_ 7 decanoic acid hydroxy 4- 4-indolyl-piperidine-1·carbonyl)_2,2-dimethyl-propyl]• decylamine; 2-(1-ethyl-1//-pyrazole·4_ Base)_5 ugly _pyrrolo[2,3_ 吡 呼 _7_ decanoic acid [(S)-2-(4. cyano-piperidin-1-yl)-2- oxo-1 ( 1-trifluoromethyl-cyclopropyl)-ethyl]-guanamine; 2-(1-ethyl-1//-pyrazolyl)_5-open-pyrrolo[2 3]pyrazine_7-formic acid [(R)-2-(4-carbyl-anthracene)•yl)2 oxo 1 (1trifluoromethyl) Cyclopropyl)-ethyl]-guanamine; 2-(1-indolyl-1//-. oxazol-4-yl)_57/_pyrrolo[2,3^pyridin-7-carboxylic acid [( R)-2-(3-cyano-indolebutane_丨_yl)_丨_cyclohexyl_2_sideoxy_ethyl]-guanamine; 2-(1-methyl-1/ /-isazole_4•yl)5-pyrido[2 3 ^pyrrol_7-decanoic acid [(R)-l-(4-cyano-audio nMi) 2 2 dimercaptopropyl] decylamine ; 2-(1-cyclopropylpyrazole-4-yl)5//pyrrolo[23...pyrazine_7·carboxylic acid [(R)-l-(4-cyano]n-yl) 2 2 Mercapto-propyl bromoamine; 2-[1-(2,2,2-trifluoro-ethyl}1-open pyrazole-4-yl]5孖pyrrolo[2'3-6]n-specific- 7-Methylcyano_Brigade bite base) · 2,2 dimethyl-propyl]-guanamine; 2-% propyl-5//-.咯 并 [2,3_6] 〇 喷 _7_ carboxylic acid [(R)_2-((s)_3_ cyano-吼格咬-1-yl)-K cyclopropyl-2_sideoxy-ethyl ]_醢amine; 2-(1-indenyl·1//,. sit_4•yl)-5 ugly-pyrrolo[2 3 6]pyrylene_7_carboxylic acid [(R)-2-(( S)-3-cyano-0 ratio 0 each small base w cyclopropyl 2 side oxy _ ethyl]-decylamine; 154395.doc 201134826 2-(bu methyl-1 open-pyrazol-4-yl -5H-pyrrolo[2,3-6]pyrazine-7-decanoic acid [(R)-2-((R)_3-cyano-«&gt;pyrrolidin-1-yl)_ι_环Propyl 2_sideoxy·ethyl]-decylamine; 2-cyclopropyl-5open-°pyrho[2,3-6]0 than tillage-7-formic acid [(11)-2- ((11)-3-cyanopyrrolidin-1-yl)-1-cyclopropyl-2-oxooxyethyl]-decylamine; 2_cyclopropyl-5/Γ-pyrrolo[ 2,3 work]pyrazine-7-formic acid [(R)-l-cyclopropyl·2-(2-oxa-6-aza-spiro[3.3]hept-6-yl)-2-side oxygen 2-ethyl]-decylamine; 2-(1-methyl-1 open ratio 0 sit-4-yl)-57/-° than 〇[2,3-Z)]〇比井-7- Formic acid [(R)-cyclocyclopropyl-2-(2-oxa-6-aza-spiro[3.3]hept-6-yl)-2-oxo-ethyl]-decylamine; 2- Cyclopropyl-57/-° ratio 0 and [2,3-6]° ratio _-7-carboxylic acid [(R)_i_cyclopropyl_ 2-((13,5 ft, 611)-6_ Methyl-3-aza-bicyclo[3.1.〇]hex-3-yl)-2-oxo-ethyl]-decylamine; 2-(1-methyl-l/ί-pyrazole-4 - pipyrrolo[2,3·&amp;]pyrazine_7-decanoic acid [(R)-l-cyclopropyl-2-((1 S,5R,6R)-6- via methyl_3_ Aza-bicyclo[3.1.0]hex-3-yl)-2-yloxyethyl]-guanamine; 2-cyclopropyl-5//-pyrrolo[2,3-6]pyrrole -7-decanoic acid [(foot)_1_cyclopropyl·2-(1,1-di-oxy-1,6-thio- phenothin-4-yl)-2-oxo-ethyl]-醯Amine; 2-(1-methyl-1/f-pyrazol-4-yl)-5//-pyrrolo[2,3-6]pyrazine-7-carboxylic acid [(R)-l-cyclopropane Benzyl-2-(1,1-di-oxy-1λ6-thio- phenanthrene-4-yl)_2_ oxo-ethyl]-guanamine; 2-cyclohexyloxy-5/ί-.咯[2,3-6]pyrazine-7-decanoic acid [(r)-i_(4-cyano 154395.doc -15- 201134826 keto-chito-1-yl)-2,2-di Benzyl-propyl]-bristamine; 2-(3,3,3-trifluoro-propoxy)-5//-pyrrolo[2,3-6]pyrazine-7-carboxylic acid [(11)- 1-(4-cyano-p-[&gt;--1-reradyl)_2,2_didecyl-propyl]-nonylamine; 2-cyclopentyloxy-5i/-0 ratio 11 each [ 2,3-6]. Ratio whistle: _7_carboxylic acid [(R)-l-(4-cyano-** bottom bite-1-reactive)-2,2-dimethyl-propyl]-bristamine; 2-(2, 2,2-Trifluoro-ethoxy)-5//- »Biha and [2,3-6]. Ratio p-well-7-formic acid [(R)-l-(4-cyano-bristidin-1-yl)-2,2-dimercapto-propyl]-decylamine; 2-isopropoxy -5/ί-0 is a little more than [2,3-&amp;]. Specific tillage-7-formic acid [(r)_i_(4-nitro-piperidin-1-carbonyl)-2,2-dimercapto-propyl]-decylamine; 2-(4- gas-1-side Oxy-1·3-dihydro-isoindol-2-yl)_5//·pyrolo[2,3 work]pyridin-7-decanoic acid [(R)-2-(3-cyano) -azetidinyl-yl)cyclopropyl-2-oxo-ethyl]-bristamine; 2-(7-a-thio-thieno[3,2-6]pyridin-2-yl) -5//-pyrrolo[2,3-6]0 ratio tillage-7-decanoic acid [(R)-2-(3-cyano-azetidin-1-yl)-1-cyclopropane 2-_2-oxo-ethyl]-guanamine; 2-(7-pyrrolidin-1-yl-thieno[3,2-6]pyridin-2-yl)-5 ugly-pyrrolo[2, 3-Z&gt;]pyrazine-7-formic acid [(R)-2-(3-cyano-azetidin-1-yl)_ι_cyclopropyl-2-oxo-ethyl]- Indoleamine; 2-[7-(2,2,2-trifluoro-ethoxy)-thieno[3,2-yl]pyridin-2-yl]-5-open-pyrrolo[2,3-0 Pyridin-7-formic acid [(foot)-2-(3-cyano-azetidin-1-yl)-1-cyclopropyl-2-oxo-ethyl]-bristamine; 2-(7-decyloxy-thieno[3,2·do]0 to 0-but-2-yl)-5-pyrrolo[2,3-6]pyrazine-7-carboxylic acid [(R) -2-(3-cyano-azetidin-1-yl)-1-cyclopropyl-2-oxo-ethyl]-decylamine; 154395.doc •16- 20113482 6 2-(7-氪- 吩 并 [3,2-Ai„,. ~3]0 ratio '2-sided oxy-ethyl}-decylamine; [2,3-0]pyrazine-7-formic acid [(仗)-2-(3-ylyl 7] α ratio. 1,4-yl)-5/f- n piroxicam-azetidine Alkyl-1-yl)yl-2-oxo-ethyl]-indolyl; 2-[7-(2,2,2-difluoro-ethoxy)-deutero[326] indoleidine ·2_基] Lu 5//-pyrrolo[2,3-6]pyrazine-7·carboxylic acid [(R)_2_(3·cyano-azetidin-1-yl)·1-A 2-yloxy-ethyl]-bristamine; 2-(7-decyloxy-thieno[3,2-6].pyridin-2-yl)-5//-pyridinium [2,3-6]pyrazine-7-carboxylic acid [(R)-2-(3-cyano-azetidinyl-2-yloxy-ethyl]-decylamine; 2-( 1,3-Dimethyl-1//-pyrazol-4-yl)-57/-pyrrolo[2,3_6]pyr _7_ decanoic acid [(R)-2-(3-cyano- Azetidin-1-yl)-1-methyl-2. oxo_ethyl]-bristamine; # 2-(1-ethyl-1H-pyrazol-4-yl)-5/ /-pyrrolo[2,3-fc]pyrazine_7•carboxylic acid [(S)-l-(4-cyano-piperidin-1-carbonyl)-3,3,3-trifluoro-propyl] _ guanamine; 2-(1-ethyl-l/ί-pyrazol-4-yl)-5//-pyrrolo[2,3-6]pyrazine_7-carboxylic acid [(R)-1- (4-cyano-β-bottom-1-yl)-3,3,3-trifluoro-propyl]-bristamine; 2-(1-cyclopentyl-1/ί-[1,2, 3] three-degree sitting-4-base)-57/-〇biha [2,3 _6]0 ratio ° well-7-formic acid [(R)-2-(4-cyano-0 bottomed-1-yl)-1-cyclopropyl_2_sideoxy_ethyl ]-decylamine; 2-(1-phenyl-1/^-[1,2,3]triazin-4-yl)-5-dan-pyrene-[2,3_6] mouth ratio p-well-7 - decanoic acid [(R)-2-(4-cyano-substrate-1-yl)-1-cyclopropyl_2•sideoxy_ 154395.doc -17- 201134826 ethyl]-guanamine; (3-Pyrrolidinyl-l-yl.[(R)-2-(3-cyano-azalyl)-decylamine; phenyl)H-indolo[2,3-extra-rho- 7-carboxylic acid cyclobutane- 1-yl)·1-methyl-2j-oxy-ethyl 2-(3-methylaminoindenyl)-phenylpyr-[2,3·small-ratio_carboxylic acid [(R)-2- (3-cyano-azacyclobutane oxime small group η methyl 2·sideoxyethyl)-guanamine; 2-(3-isopropylaminecarbamyl·stupyl)_5 ugly_pyrrole And [23] p-cultivated formic acid [(R)-2-(3-cyano-azetidinyl-indoleyl)·j _indolyloxy-ethyl]-nonylamine; soil 2-[ 3-(cyclopropylindenyl-amine fluorenyl)·phenyl]_5 ugly ratio [2 3·do] pyridin-7-formic acid [(R)-2-(3-cyano-aza) Cyclobutane 丨 基 基 ) 丨 曱 曱 _2 _2 · · 侧 侧 侧 侧 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2-.比 _2 _ _ _ 好 好 好 好 2 2 2 2 2 2 2 2 2 2 2 2 2 _ _ _ _ ( ( ( ( ( ( ( ( ( ( ( ( ( ( _ _ _ _ _ _丨_Methyl 2_sideoxy·ethyl]-decylamine; 2-cyclopropyl-5-pyrido[2,3-6]pyr-7-carboxylic acid [(R)-2-( 4-cyano-piperidin-1-yl)-2-oxo-1-phenylethyl]-decylamine; 2-pyridin-2-yl-5//-pyrrolo[2,3- 0] pyridin-7-formic acid [(R)_i_(4-cyano-bunken-1-yl)-2,2-dimethyl-propyl]-bristamine; 2-cyclopropyl-5 --pyrrolo[2,3-Z&gt;]pyrazine-7-carboxylic acid [(R)-2-(4-cyano-piperidin-1-yl)-cyclocyclopropylmethyl-2-oxo Base-ethyl]•guanamine; 2-[1-(4-fluoro-phenyl)-1 ugly-. Bizozol-4-yl]-57/-&quot;bibromo[2,3-6]&quot; than plough-7-formic acid [(R)-bu (4-cyano-piperidin-1-carbonyl) -2,2-dimethyl-propyl]_ 154395.doc •18· 201134826 decylamine; 2-(4-trifluoromethyl-pyridin-2-yl)-5//-pyrrolo[2,34 Pyridin _7_carboxylic acid [(R)-1-(4-cyano-indenyl-1-yl)-2,2-dimethyl-propyl bromoamine. 2-(1-ring Propylmethyl-1 tastes salino-4-yl)-5//-.比比和[2 3_办]„比耕-7-carboxylic acid [(R)-l-(4-cyano-piperidin-1-carbonyl)-2,2-dimercapto-propyl]·醯amine; 2-(1-Cyclopentyl-1//-imidazol-4-yl)-5 ugly-pyrrolo[2,3-6]pyrr. Well-7· formic acid [(R)-l-(4-cyano-piperidin-1-carbonyl)-2,2-dimethyl-propyl]-decylamine; 2-(1-cyclodecyl- 1//-imidazol-4-yl)-5//-pyrrolo[2,3-6]. The ratio is called [-7]-formic acid [(R)-2-(4-amino-Nanthene-l-yl)-1-3⁄4 propyl-2-sideoxy-ethyl]-guanamine; 2-[ 1-(2,2,2-trifluoro-ethyl)-1//-imidazol-4-yl]-5-pyrrolo[2,3-6]pyrazine-7-carboxylic acid [(R)- 1-(4-cyano-piperidinyl-p-carbonyl)-2,2-dimethyl-propyl]-bristamine; 2-[3-(3,3-dimethyl-d-r. -i_yl)-phenyl]-577- °biluo[[一力力耕耕-了-formic acid ^化^-^-cyano-azetidin-buji^-mercapto-2- Side oxy-ethyl]-guanamine; 2-cyclopropyl-57/-pyrrolo[2,3-6]pyrazine-7-carboxylic acid [(111,28)_1_(4_cyano-piperidine- 1-carbonyl)-2-mercapto-butyl]• decylamine; 2-(3,4,5-trimethoxy-phenyl)_5//_pyrrolo[2,34]吼'1 well-7 - decanoic acid [(R)-2-(3-cyano-azetidinyl small) small methyl-2-oxo-ethyl]-decylamine; 2-[(lS,5R)- 3-(3·aza-bicyclo[no]hex-3-yl)_phenyl]_5 is better than 154395.doc • 19·201134826 咯[2,3-H pyridin-7-formic acid [(R)- 2-(3-cyano-azetidinyl)-1-indolyl-2-oxo-ethyl]-decylamine; 2-(4-methoxy-pyridin-2-yl)-5 -pyrrolo[2,3-6]pyrazine_7_carboxylic acid [(R)-l-(4·cyano-piperidin-1- Base)·2,2·dimethyl-propyl]•decalamine; 2-(4-difluoromethyl-phenyl)·5//-pyrrolo[2,3-do]pyrazine_7_ [(R)-l-(4-cyano-piperidin-1-carbonyl)_2,2·dimethyl-propyl]-decylamine; 2-(4-cyclopropylmethoxy-pyridyl) Bite·2_base) ratio slightly [2,3_&amp;]α ratio tillage_7-formic acid [(R)-2-(4-cyano-piperidinyl)_丨_cyclopropyl_2• side oxygen 2-ethyl]-guanamine; 2-(4-cyclopentyloxy-pyridin-2-yl)_5//_pyrrolo[2,3]pyrazole·7-carboxylic acid [(R)-l- (4-Alkyl-Brigade bite small carbonyl)_2,2·Di-f-propyl]-bristamine; 2-(4-cyclopropylmethoxy-tonidine _2·yl)·5/^倍比和[2,3_办]pyrazine _ 7-decanoic acid [(R)-2-(3-cyano-azetidinylmethyl-2·sideoxy-ethyl]-decylamine ; 2-[1-(2,5-Difluoro-phenyl)-1//-imidazole·4_ylpyrrolo[2 3 ^pyrazine-7·carboxylic acid [(R)-2-(3- Cyano-azetidine-丨-ylcyclopropyl-2-2-oxo-ethyl]-guanamine; 2-[1-(2,3,5-difluoro-phenyl)·ι _ imidazole _4 base]-5 仏. Biha and [2,3 sec-pyrrol-7-carboxylic acid [(R)-2-(3. cyano-nitroheterocyclic succinylpyridin-2-yloxy-ethyl]- Amine; 2-(1-ethyl-1//-pyrazol-4-yl)·5//_pyrrolo[2,3·6]pyridinium-7-decanoic acid[(8)小从二襄" Biting a small base) · 2,2_dimethyl-propyl]•-bristamine; 2-cyclopropyl-5//-pyrrolo[2,3-6]pyrazine·7·carboxylic acid [(r) 1(7,8 154395.doc •20· 201134826 Hydrogen-5-[1,6]acridine-6-carbonyl)-2,2-diindolylpropylamine 2-cyclopropyl-5 //-pyrrolo[2,3_6]pyridinium-7-carboxylic acid [(R)j azetidin-1-yl)-2-yloxy·ι_(tetrahydro-piperane-cyano-bristamine ; mouth 4 are ethyl]-2-cyclopropyl-5//-pyrrolo[2,3 work]pyrazine_7_carboxylic acid [(s)_2 azetidin-1-yl)-2- Side oxy_ι_(tetrahydro-pyran-4-yl decylamine; violent) ethyl μ 2-cyclopropyl-5//-pyrrolo[2,3_ypyrrole_7_carboxylic acid [(R)"3 hydrogen-inden-1-carbonyl)-2,2-dimethyl-propyl]_ Indoleamine; 2-(1-ethyl-indole/f-pyrazole-4-yl)_5 ugly-pyrrolo[2 3 hepta-7-acid [(R)-l-cyclopropyl-2-( 3,3·difluoro-hydrazide bite small base 2_side gas methyl]-guanamine; 2-(1-ethyl-1//-pyrazole_4_yl)_5仏pyrrolo[2 3·小比呼·' Acid [(R)-l-(4-hydroxy-4-methyl-piperidinyl)carbonyl]- decylamine; ,-methyl-propyl 2-cyclopropyl -5/f-pyrrolo[2,3_external ratio, well_7_formic acid [called 2 octagonal 3-methyl-azetidinylcycloprop-2-enyloxy-ethyl]• Brewed amine; 2-U-fluorenyl _ 4_yl)·decorated and [2,3 gyphonic acid [(R)-2-(3-cyano-3-methyl-azetidinyl) Small cyclopropyl J-side oxy-ethyl]-decylamine; &lt; soil _-mercapto-propyl]-bristamine; 2-(1) fluorenyl group 4·yl)_ W each[2呼acid [(R)-1-(3-cyano-3-methyl·氡 heterocyclobutane-buji) 乂2_ 154395.doc -21 · 201134826 2-(1-ethyl-1// -pyrazole·4·yl)_5//-pyrrolo[2,3_fe]pyrrole_7_carboxylic acid [(R)-l-cyclopropyl-2·(4,4-difluoro-«» -i_base)_2•side oxygen -ethyl]-guanamine; 2-(4-t-butyl-pyridin-2-ylpyrho[2,3-indenyl]]ι&gt; than tillage-7-decanoic acid [(R)-2 -(4-cyano-piperidin-1-yl)-1-cyclopropyl-oxyl-ethyl]-decylamine; 2-(1-ethyl-I//-0 ratio 0 sitting-4 - Base) -57/- 0 piroxi[2,3-6] 〇比》»井-7-decanoic acid [(R)-l-cyclopropyl-2-(4-pyridyl-4-trifluoro)曱Substrate. _1_1 yl)_2_sideoxy-ethyl]-bristamine, 2-(4-phenyl-° ratio -2-yl)-5//- ° 3-6] »Bigen-7-formic acid [(R)-2-(4-cyano-pyridin-1-yl)-1-cyclopropyl·2_sideoxy-ethyl]-decylamine ; 2-(1-ethyl-1//-° ratio 0 to 4-base)-5//-. 〇[2,3_办]η比耕-7-carboxylic acid [(R)-l-cyclopropyl-2-(3-hydroxy-3-methyl-azetidinyl) )_2_ oxo-ethyl]-decylamine; 2-cyclopropyl-5//-0 ratio each [2,3-6]0 ratio "well-7-carboxylic acid [(lR, 2R)- L-(4-cyano-0 bottom bit-1-cutting)-2-methyl-butyl]-bristamine; 2-(1-methyl-1 ugly-0 ratio. sit-4-base ratio Luohe [2,3-do] 0 to p well-7-formic acid [(R)-1 -cyclopropyl-2-(3,3-one gas-azetidin-1-yl)-2- Side oxy-ethyl]-guanamine; 2-(1-methyl-1 孖-pyrazol-4-yl)-5-p-pyrrolo[2,3-6]pyrazine-7-decanoic acid [ (R)-2-(3-cyano-3-ethyl-azetidinyl-2-ylcyclopropyl-2-yloxy-ethyl)-decylamine; 2-(4- praquino- 1-kibbit bite_2_gibylol[2,3-6]° than tillage-7-曱154395.doc -22· 201134826 acid [(R)-2-(3-cyano-nitrogen heterocycle Dibutyl"·base) small methyl 2__oxy-ethyl]-decylamine; 2_(4_°bi Loki·ki)-5 heart ratio slightly [2,3·small than -7- Capric acid [(R)-2-(3-cyano-azetidinyl), fluorenyl-2-yloxy-ethyl]-guanamine; 2-(4-purine-2- Base-ton bite_2_base)_5 heart than mouth each [2,3 secondary than brown · 7_A Acid [W-2-(4. cyano "bottom bite + base" small cyclopropyl _2 _ oxoethyl] decylamine; 2 · (4 · methylamine carbaryl "bipyridine" 2-yl)_5仏pyrrolo[2,3-palapyryl-7-decanoic acid [(R)-2-(3-cyano-azetidinyl)-indolyl-2-yloxy -ethyl]-guanamine; 2-(2-gas oxime. sit-5-yl) _5//pyrrolo[2,3_6]pyridin-7-carboxylic acid [(8)- 1-(4-cyano-pyrene Biting a small base) _2,2·dimethyl-propyl]-decylamine; 2-[1-(3,5-diI-phenyl)·2·indolyl-1H 〇比比和[2,3 is more than +7-carboxylic acid [(R) small (3-cyano-azetidinyl)/2,2-dimethyl-propyl]-decylamine; 2_[1-(3- I-phenyl)-2·methylimidazole·4·yl]-he^比比和[2,3-external ratio_-7 f &amp; [(8) small...cyano] Azetidinium acetonyl) 2,2-dimercapto-propyl]-guanamine; 2-(2-methyl-1-phenyl-cardiacyl)_5仏pyrrolo[2 3 secondary morphine-7-formic acid [(R)-2-(3-cyano-azetidinyl) small cyclopropyl _2_ oxo-ethyl] decylamine; 2-(4 -Tri-Il-methyl-styl)-5仏, bis-[2,3_6]pyrazine_7_decanoic acid [(R)W gas-based gas-heterocyclobutane small fluorenylcyclopropyl winterside oxy group - B 154395.doc -23- 201134826 base]-bristamine; 2-[4-(4-ethyl fluorenyl-. bottom 小 well small base) _ phenyl]_5 open · η ratio 咯 [2, 3 secondary ratio Spray-7-decanoic acid [(R)-2-(3-cyano-azetidinyl)-cyclopropanyl-2-yloxy-ethyl]-guanamine; 2-[4- (4-methyl-Pei u well·Buji)_Stupid base]_5//β ratio 咯[2,3_十比呼·7-decanoic acid [(R)-2-(3-cyano) Azetidine-indenyl)-i•cyclopropyl·2_sideoxy-ethyl]-guanamine; 2-(4·morpholin-4-ylphenyl)-5//-吼And [2,3-6] D ratio tillage-7_decanoic acid [(R)-2-(3-cyano-azetidinyl) small cyclopropyl_2_sideoxy-ethyl] - guanamine; 2-(4·monomethylamino-phenyl)_5 〇 〇 并 ο ο 〇 〇 耕 耕 曱 曱 曱 曱 曱 曱 曱 曱 曱 ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( Butane·丨·yl)_丨·cyclopropyl_2 sideoxy·ethyl]-decylamine; 2·[2·methyl-1_(2,2,2-trifluoro-ethyl)-1 //-Imidazol-4-yl]-5//-pyrrolo[2,3-6]pyrazine-7-carboxylic acid [(R)_2_(3-cyano-azetidinyl)"_ Cyclopropyl-2-oxo-ethyl]-bristamine; and 2-phenyl-5//-pyrrolo[2,34]n ratio tillage_7_carboxylic acid [(R)_2-(3 -cyano-azetidin-1-yl)-1-cyclopropyl·2- Ethyl oxy _] _ Amides. 21. Use of a compound according to any one of claims 1 to 20 for the manufacture of a medicament for the treatment of an inflammatory condition or an autoimmune condition. 22. The use of claim 21, wherein the drug is used in combination with another therapeutic agent selected from the group consisting of a chemotherapeutic or anti-proliferative agent, an anti-inflammatory agent, an immunomodulator or an immunosuppressive agent, a neurotrophic factor, a therapeutic heart An agent for vascular disease, an agent for treating diabetes, or an agent for treating immunodeficiency. The use of a compound according to any one of claims 1 to 20 for the manufacture of a medicament for the treatment of an immune disorder comprising lupus, multiple sclerosis, a genus Rheumatoid arthritis, psoriasis, type 1 diabetes, organ transplant complications, xenografts, diabetes, cancer, asthma, atopic dermatitis, autoimmune sputum gland disorders, ulcerative colitis, Crohn's disease ( Crohn's disease), Alzheimer's disease and leukemia. A pharmaceutical composition comprising a mixture of a reconstituted substance according to any one of claims 1 to 20 and a pharmaceutically acceptable carrier, excipient or diluent. The pharmaceutical composition according to claim 24, which further comprises a further therapeutic agent selected from the group consisting of a chemotherapeutic or antiproliferative agent, an anti-inflammatory agent, an immunomodulator or an immunosuppressive agent, a neurotrophic factor, and a cardiovascular disease. An agent, an agent for treating diabetes, and an agent for treating an immunodeficiency disorder. '26. The compound of claim </RTI> is used to treat an inflammatory condition or a self-inflammation condition. 27. The compound of claim 2 or 2 for use in the treatment of any of the conditions as recited in claims a to. 154395.doc •25- 201134826 IV. Designated representative map: (1) The representative representative of the case is: (none) (2) The symbolic symbol of the representative figure is simple: • 5. If there is a chemical formula in this case, please reveal the best Chemical formula showing the characteristics of the invention: 154395.doc