HK1183490A

HK1183490A - Pyrrolo [2, 3 - b] pyrazine - 7 - carboxamide derivatives and their use as jak and syk inhibitors

Info

Publication number: HK1183490A
Application number: HK13110944.1A
Authority: HK
Inventors: Robert Than Hendricks; Johannes Cornelius Hermann; Saul Jaime-Figueroa; Rama K. Kondru; Yan Lou; Stephen M. Lynch; Timothy D. Owens; Michael Soth; Calvin Wesley Yee
Original assignee: F. Hoffmann-La Roche Ag
Priority date: 2010-05-20
Filing date: 2011-05-17
Publication date: 2013-12-27

Description

Pyrrolo [2,3-b ] pyrazine-7-carboxamide derivatives as JAK and SYK inhibitors and their use

The present invention relates to the use of novel pyrrolopyrazine derivatives which are JAK and SYK inhibitors and which selectively inhibit JAK3 and which may be useful in the treatment of autoimmune and inflammatory diseases.

Protein kinases constitute one of the largest families of human enzymes and regulate many different signaling processes by adding phosphate groups to proteins; in particular tyrosine kinases phosphorylate proteins on the alcohol moiety of tyrosine residues. The tyrosine kinase family includes members that control cell growth, migration, and differentiation. Abnormal kinase activity has been implicated in a variety of human diseases including cancer, autoimmune and inflammatory diseases. Since protein kinases belong to key regulators of cell signaling, they provide a means to modulate cellular function with small molecule inhibitors of kinase activity and are therefore good drug design targets. In addition to treating kinase-mediated disease processes, selective and potent inhibitors of kinase activity may also be used to study cell signaling processes and identify other cellular targets of therapeutic interest.

JAK (janus kinases) is a family of cytoplasmic protein tyrosine kinases including JAK1, JAK2, JAK3 and TYK 2. Each JAK associates preferentially with the intracytoplasmic portion of a discrete cytokine receptor (annu. rev. immunol.16(1998), pp.293-322). JAKs are activated upon ligand binding and initiate signaling by phosphorylating cytokine receptors, which themselves lack intrinsic kinase activity. This phosphorylation creates docking sites on the receptor for other molecules called STAT proteins (signal transducers and activators of transcription), and phosphorylated JAKs bind to a variety of STAT proteins. STAT proteins, or STATs, are DNA binding proteins that are activated by phosphorylation of tyrosine residues and function both as signaling molecules and transcription factors and ultimately bind to specific DNA sequences present in the promoters of cytokine-responsive genes (Leonard et al, (2000), J.allergy Clin. immunol.105: 877-888).

JAK/STAT signaling has been implicated in the mediation of many abnormal immune responses such as allergy, asthma, autoimmune diseases such as transplant (allograft) rejection, rheumatoid arthritis, amyotrophic lateral sclerosis and multiple sclerosis, as well as in solid and hematologic cancers such as leukemia and lymphoma.

Thus, JAKs and STATs are components of a variety of potentially tangled signaling pathways (Oncogene19(2000), pp.5662-5679), suggesting that it is difficult to specifically target one element of the JAK-STAT pathway without interfering with other signaling pathways.

JAK kinases, including JAK3, are abundantly expressed in primary leukemia cells of children with acute lymphoblastic leukemia, the most common form of pediatric cancer, and studies have linked STAT activation in certain cells to signal-regulated apoptosis (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). They are also known to be important for lymphocyte differentiation, function and survival. JAK3 plays a fundamental role in the function of lymphocytes, macrophages and mast cells, among others. Given the importance of this JAK kinase, compounds that modulate the JAK pathway, including those selective for JAK3, may be useful in the treatment of diseases or disorders involving lymphocyte, macrophage, or mast cell function (Kudlacz et al, (2004) am.j. transplant 4: 51-57; Changelian (2003) Science 302: 875. 878). Conditions in which targeting of the JAK pathway or modulation of JAK kinases (particularly JAK3) is expected to be therapeutically useful include: leukemias, lymphomas, transplant rejection (e.g., islet transplant rejection, bone marrow transplant applications (e.g., graft versus host disease), autoimmune diseases (e.g., diabetes), and inflammation (e.g., asthma, allergy).

However, in contrast to the relatively ubiquitous expression of JAK1, JAK2, and Tyk2, JAK3 has more restricted and regulated expression. Although some JAKs (JAK1, JAK2, Tyk2) are used by various cytokine receptors, JAK3 is used only by cytokines that contain yc in their receptors. Thus, common gamma chain cytokines have been used for receptors shown to date; IL-2, IL-4, IL-7, IL-9, IL-15 and IL-21, JAK3 play a role in cytokine signaling. Wherein JAK1 interacts with receptors for the cytokines IL-2, IL-4, IL-7, IL-9, and IL-21, and wherein JAK2 interacts with receptors for IL-9 and TNF- α. Receptor oligomerization occurs through the binding of certain cytokines to their receptors (e.g., IL-2, IL-4, IL-7, IL-9, IL-15, and IL-21), resulting in the initial access of the cytoplasmic tail of the associated JAK kinase and favoring phosphotransfer of tyrosine residues on the JAK kinase. This phosphate transfer leads to the activation of JAK kinases.

Animal studies suggest: not only does JAK3 play a key role in B and T lymphocyte maturation, JAK3 is constitutively required for maintenance of T cell function. Modulation of immune activity by this novel mechanism may prove useful in the treatment of T cell proliferative disorders such as transplant rejection and autoimmune diseases.

In particular, JAK3 has been implicated in a variety of biological processes. For example, IL-4 and IL-9-induced proliferation and survival of murine mast cells has been shown to be dependent on JAK 3-and γ chain-signaling (Suzuki et al, (2000), Blood 96: 2172-. JAK3 also plays a key role in IgE receptor-mediated mast cell degranulation responses (Malaviya et al, (1999), biochem. biophysis. res. comm.257: 807-813) and inhibition of JAK3 kinase has been shown to prevent type I hypersensitivity reactions, including anaphylaxis (Malaviya et al, (1999), j. biol. chem.274: 27028-27038). JAK3 was also shown to inhibit immunosuppression leading to allograft rejection (Kirken, (2001), Transpl. Proc.33: 3268-. JAK3 kinase is also implicated in mechanisms involved in the following diseases: early and late rheumatoid arthritis (Muller-Ladner et al, (2000), J.Immunal.164: 3894-3901); familial 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).

JAK3 inhibitors are useful therapeutics as immunosuppressive agents for: organ transplantation, xenotransplantation, lupus, multiple sclerosis, rheumatoid arthritis, psoriasis, type I diabetes and complications from diabetes, cancer, asthma, atopic dermatitis, autoimmune thyroid disorders, ulcerative colitis, crohn's disease, alzheimer's disease, leukemia and other conditions where immunosuppression is appropriate.

Non-hematopoietic expression of JAK3 has also been reported, although the functional significance is unclear (j. immunol.168(2002), pp.2475-2482). Since bone marrow transplantation for SCID is curative (Blood 103(2004), pp.2009-2018), it seems unlikely that JAK3 has the necessary non-redundant function in other tissues or organs. Therefore, in contrast to other targets for immunosuppressive drugs, the restricted distribution of JAK3 is attractive. Active agents acting on molecular targets with expression limited to the immune system may result in an optimal pharmacodynamic to toxicity ratio. Thus, in theory, targeting JAK3 would provide immunosuppression in situations where it is needed (i.e., on cells actively involved in the immune response) without causing any effect outside of these cell populations. Although in various STATs ^-/-Defective immune responses have been described in strains (J.Investig.Med.44(1996), pp.304-311; Curr.Opin.cell biol.9: (C.1997) Pp.233-239), but their non-selectivity as key targets for immunosuppression has been contributed by the widespread distribution of STATs and the fact that these molecules lack enzymatic activity that can be targeted with small molecule inhibitors.

SYK (spleen tyrosine kinase) is a non-receptor tyrosine kinase that is essential for B-cell activation by BCR signaling. SYK becomes activated by binding to phosphorylated BCR, thus initiating an early signaling event following BCR activation. Mice lacking SYK show early blockade in B-cell development (Cheng et al Nature 378: 303, 1995; Turner et al Nature 378: 298, 1995). Thus, inhibition of SYK enzyme activity in cells has been proposed as a treatment for autoimmune diseases through its effect on autoantibody production.

In addition to its role in BCR signaling and B-cell activation, SYK plays a key role in fceri-mediated mast cell degranulation and eosinophil activation. Thus, SYK has been implicated in allergic disorders, including asthma (reviewed in Wong et al Expert Opin Investig Drugs 13: 743, 2004). SYK binds via its SH2 domain to the phosphorylated gamma chain of Fc epsilon RI and is essential for downstream signaling (Taylor et al mol.cell.biol.15: 4149, 1995). SYK-deficient mast cells show defective degranulation, arachidonic acid and cytokine secretion (Costello et al Oncogene 13: 2595, 1996). This has also been shown for pharmacologically active agents that inhibit SYK activity in mast cells (Yamamoto et al J Pharmacol Exp Ther 306: 1174, 2003). Treatment with SYK antisense oligonucleotides inhibited eosinophil and neutrophil antigen-induced infiltration in animal models of asthma (Stenton et al J Immunol 169: 1028, 2002). SYK-deficient eosinophils also show impaired activation in response to Fc ε R stimulation (Lach-Trifilefiffe et al Blood 96: 2506, 2000). Therefore, small molecule inhibitors of SYK would be useful in the treatment of allergy-induced inflammatory diseases, including asthma.

In view of the large number of conditions that are expected to benefit from treatment including modulation of the JAK and/or SYK pathways, it is immediately apparent that novel compounds that modulate JAK and/or SYK pathways and methods of using these compounds should provide substantial therapeutic benefits to a wide variety of patients. Provided herein are novel pyrrolopyrazine derivatives useful in the treatment of disorders in which JAK and/or SYK pathways are targeted or JAK or SYK kinases (particularly JAK3) are inhibited, and therapeutically useful in the treatment of autoimmune and inflammatory diseases.

The novel pyrrolopyrazine derivatives provided herein selectively inhibit JAK3 and may be useful in the treatment of autoimmune and inflammatory diseases. The compounds of the present invention modulate the JAK and/or SYK pathway and are useful novel pyrrolopyrazine derivatives for the treatment of autoimmune and inflammatory diseases, with preferred compounds selectively inhibiting JAK 3. For example, the compounds of the invention may inhibit JAK3 and SYK, with preferred compounds being selective for JAK3 in JAK kinases and being useful novel pyrrolopyrazine derivatives for the treatment of autoimmune and inflammatory diseases. The amide linker at the 7-position of the 5H-pyrrolo [2, 3-b ] pyrazines provides surprisingly increased potency of the compounds of formulae I and I' in inhibiting JAK and Syk kinase compared to 5H-pyrrolo [2, 3-b ] pyrazines having other moieties at this position. Furthermore, the compounds of the present invention can inhibit JAK3 and JAK2, with preferred compounds being selective for JAK3 of the JAK kinases and being useful novel pyrrolopyrazine derivatives for the treatment of autoimmune and inflammatory diseases. Similarly, the compounds of the invention may inhibit JAK3 and JAK1, with preferred compounds being selective for JAK3 of the JAK kinases and being useful novel pyrrolopyrazine derivatives for the treatment of autoimmune and inflammatory diseases.

The present application provides compounds of formula I

Wherein:

r is H, cyano, lower alkyl, R' or

R' is cycloalkyl, heterocycloalkyl, heteroaryl, or phenyl, each of which is optionally substituted with one or more R ";

each R "is independently halogen, hydroxy, cyano, lower alkyl, lower haloalkyl, lower alkoxy, lower hydroxyalkyl, cycloalkyl, C (═ O) R'" or S (═ O)₂R”’；

Each R' "is independently OH or lower alkyl;

R^1aand R^1bEach independently is H, hydroxy, halogen, lower alkyl, lower alkenyl, lower alkynyl, lower haloalkyl, lower alkoxy, lower haloalkoxy, lower hydroxyalkyl, amino, lower alkylamino, lower dialkylamino, cyano, C (═ O) R' ", S (═ O)₂R' "or CH₂S(＝O)₂R；

R^1cIs phenyl, cycloalkyl, heterocycloalkyl or heteroaryl, optionally substituted with one or more R^1dSubstitution;

R^1deach independently is hydroxy, halogen, lower alkyl, lower hydroxyalkyl, lower haloalkyl or lower alkoxy;

R²is H, hydroxy lower alkyl, lower haloalkyl or lower alkyl;

R³is H, hydroxy, cyano lower alkyl or R³’；

R³' are each independently lower alkyl, hydroxy lower alkyl, lower alkoxy, lower haloalkyl, lower haloalkoxy, phenyl lower alkyl, cycloalkyl or cycloalkyl lower alkyl, each optionally substituted with one or more R ³"substituted;

R³"are each independently lower alkyl, halogen, hydroxy, lower alkoxy, lower haloalkyl, lower hydroxyalkyl, oxo, amino, cyano lower alkyl, S (═ O)₂R³”’、C(＝O)R³"', cycloalkyl, heterocycloalkyl, heteroaryl, or heterocycloalkenyl;

R³"' are each independently H, hydroxy or lower alkyl;

q is Q²、Q³Or Q⁴；

Q²Is heterocycloalkyl, cycloalkyl, cycloalkenyl, heterocycloalkylphenyl, heteroaryl, biaryl or heterobiaryl, optionally substituted with one or more Q^2aSubstitution;

Q^2ais Q^2bOr Q^2c；

Q^2bEach independently halogen, oxo, hydroxy, -CN, -SCH₃、-S(O)₂CH₃or-S (═ O) CH₃；

Q^2cEach independently is Q^2dOr Q^2e；

Or two of Q^2aTogether form a bicyclic ring system, optionally substituted with one or more Q^2bOr Q^2cSubstitution;

Q^2deach independently is-O (Q)^2e)、-S(＝O)₂(Q^2e)、-C(＝O)N(Q^2e)₂、-S(O)₂(Q^2e)、-C(＝O)(Q^2e)、-C(＝O)O(Q^2e)、-N(Q^2e)C(＝O)(Q^2e)-N(Q^2e)C(＝O)O(Q^2e) or-N (Q)^2e)C(＝O)N(Q^2e)₂；

Q^2eEach independently is H or Q^2e’；

Q^2e' are each independently lower alkyl, phenyl, benzyl, 5, 6, 7, 8-tetrahydro-naphthalene, lower haloalkylLower alkoxy, cycloalkyl, cycloalkenyl, heterocycloalkyl, spiroheterocycloalkyl or heteroaryl, optionally substituted with one or more Q^2fSubstitution;

Q^2feach independently is Q^2gOr Q^2h；

Q^2gEach independently is halogen, hydroxy, cyano, oxo, -S (═ O)₂(Q²ⁱ’)、-S(＝O)₂N(Q²ⁱ’)₂、-C(＝O)OH、C(＝O)N(Q²ⁱ’)₂or-C (═ O) (Q) ²ⁱ’)；

Q^2hEach independently is lower alkyl, lower alkenyl, lower haloalkyl, lower alkoxy, amino, phenyl, benzyl, cycloalkyl, heterocycloalkyl, or heteroaryl, optionally substituted with one or more Q²ⁱSubstitution; and is

Q²ⁱEach independently is halogen, hydroxy, cyano, lower alkyl, lower haloalkyl or lower alkoxy;

Q²ⁱ' are each independently H or lower alkyl;

Q³is-O-Q^3a、-S-Q^3a、-C(＝O)(Q^3a)、-O(CH₂)_mC(＝O)(Q^3a)、-S(＝O)(Q^3a)、-S(＝O)₂(Q^3a)、-N(Q^3a)₂、-N(Q^3a)S(＝O)₂(Q^3a)、-N(Q^3a)C(＝O)(Q^3a)、-C(＝O)N(Q^3a)₂、N(Q^3a)C(＝O)N(Q^3a)₂or-N (Q)^3a)(CH₂)_mC(＝O)N(Q^3a)₂；

Q^3aEach independently is Q^3bOr Q^3c；

Each m is independently 0, 1 or 2;

Q^3beach independently is H;

Q^3ceach independently is lower alkyl, lower haloalkyl, phenyl, 5, 6, 7, 8-tetrahydro-naphthalene, 2-dimethyl-2, 3-dihydro-benzofuranyl, indanyl, indenyl, indolyl, cycloalkyl, heterocycloalkyl, or heteroaryl, optionally substituted with one or more Q^3dSubstitution; and is

Q^3dEach independently is Q^3eOr Q^3f；

Q^3eEach independently is halogen, oxo, cyano, hydroxy, -NHS (═ O)₂(Q^3f)、-NHC(＝O)(Q^3f)、NHC(＝O)N(Q^3f)₂Or N (Q)^3f)₂；

Q^3fEach independently is H or Q^3f’；

Q^3f' are each independently lower alkyl, lower alkoxy, lower haloalkyl, phenyl, benzyl, cycloalkyl, heterocycloalkyl, or heteroaryl, optionally substituted with one or more Q^3gSubstitution; and is

Q^3gEach independently is halogen, hydroxy, lower alkyl, lower hydroxyalkyl, lower haloalkyl or lower alkoxy;

Q⁴Is Q^4aOr Q^4b；

Q^4aIs hydroxy, halogen or cyano;

Q^4bis lower alkyl, lower alkoxy, lower alkynyl, lower alkenyl, lower hydroxyalkyl, amino or lower haloalkyl, optionally substituted with one or more Q^4cSubstitution;

Q^4ceach independently is Q^4dOr Q^4e；

Q^4dEach independently is halogen, hydroxy or cyano;

Q^4eeach independently is lower alkyl, lower haloalkyl, lower alkoxy, amino, cyclicAlkyl, phenyl, heterocycloalkyl or heteroaryl, optionally substituted with one or more Q^4fSubstitution;

Q^4feach independently is hydroxy, halogen, lower alkyl, lower alkenyl, oxo, lower haloalkyl, lower alkoxy, lower hydroxyalkyl or amino;

with the proviso that the compound of formula I is not 2-thiophen-2-yl-5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid isopropylamide, 2-cyclopropyl-5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid (4-hydroxy-3, 3-dimethyl-butyl) -amide, tert-butyl 2- [1- (7-isopropylcarbamoyl-5H-pyrrolo [2, 3-b ] pyrazin-2-yl) -piperidin-3-yl ] -propionate, 2-cyclopropyl-5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid tert-butylamide, 2-cyclohexyl-5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid isopropylamide, 2-cyclohex-1-enyl-5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid isopropylamide, 2-chloro-5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid isopropylamide, 2-isopropyl-5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid isopropylamide, 2-isopropenyl-5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid isopropylamide, 2- (cyclopentyl-methyl-amino) -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid isopropylamide, and mixtures thereof, [1- (7-isopropylcarbamoyl-5H-pyrrolo [2, 3-b ] pyrazin-2-yl) -piperidin-3-yl ] -methyl-carbamic acid tert-butyl ester, 2- (3-methylamino-piperidin-1-yl) -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid isopropylamide, 2- (cyclopentyl-methyl-amino) -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid isopropylamide, 2-chloro-5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid isopropylamide, 2-isopropenyl-5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid isopropylamide, 2-isopropyl-5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid isopropylamide, 2-cyclohex-1-enyl-5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid isopropylamide, 2-cyclopropyl-5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid (3-hydroxy-2, 2-dimethyl-propyl) -amide, 2-cyclopropyl-5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ((S) -2-hydroxy-1, 2-dimethyl-propyl) -amide, and mixtures thereof, 2-cyclopropyl-5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid tert-butylamide, 2-cyclohexyl-5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid isopropylamide, 2-thiophen-2-yl-5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid (3-hydroxy-2, 2-dimethyl-propyl) -amide, [1- (7-isopropylcarbamoyl-5H-pyrrolo [2, 3-b ] pyrazin-2-yl) -piperidin-3-yl ] -methyl-carbamic acid tert-butyl ester, 2- (3-methylamino-piperidin-1-yl) -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid isopropylamide; a compound having trifluoro-acetic acid, [1- (7-isopropylcarbamoyl-5H-pyrrolo [2, 3-b ] pyrazin-2-yl) -piperidin-3-yl ] -methyl-carbamic acid tert-butyl ester or 2- (3-methylamino-piperidin-1-yl) -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid isopropylamide; a compound having trifluoro-acetic acid;

Or a pharmaceutically acceptable salt thereof.

The present application provides a method of treating an inflammatory or autoimmune disorder comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula I.

The present application provides pharmaceutical compositions comprising a compound of formula I in admixture with at least one pharmaceutically acceptable carrier, excipient or diluent.

Definition of

As used herein, the phrase "an" or "an" entity refers to one or more of that entity; for example, a compound refers to one or more compounds or at least one compound. Thus, the terms "a" (or "an)", "one or more" and "at least one" may be used interchangeably herein.

The phrase "as defined above" refers to the broadest definition of each group as provided in the summary of the invention or the broadest claims. In all other embodiments provided below, substituents that may be present in each embodiment and are not explicitly defined remain with the broadest definition provided in the summary of the invention.

As used in this specification, the terms "comprises" and "comprising," whether in transitional phrases or in the main body of the claims, should be construed to have an open-ended meaning. That is, the term should be interpreted synonymously with the phrases "having at least" or "including at least". When used in the context of a method, the term "comprising" means that the method includes at least the recited steps, but may include additional steps. The term "comprising" when used in the context of a compound or composition means that the compound or composition includes at least the recited features or ingredients, but may also include additional features or ingredients.

As used herein, unless specifically indicated otherwise, the use of the word "or" is used in the "inclusive" sense of "and/or" and not in the "exclusive" sense of "or/and".

The term "independently" as used herein means that the variables are used in either case regardless of the presence or absence of variables having the same or different definitions within the same compound. Thus, in a compound where R "occurs twice and is defined as" independently carbon or nitrogen ", two R" can be carbon, two R "can be nitrogen, or one R" can be carbon and the other nitrogen.

When any variable (e.g., R', or Q) occurs more than one time in any moiety or formula depicting or describing compounds employed or claimed in the present invention, its definition on each occurrence is independent of its definition at every other occurrence. Furthermore, combinations of substituents and/or variables are permissible only if such compounds result in stable compounds.

The symbol ". ang" at the end of a bond or "- - - - -" across a bond refers to the point of attachment of a functional group or other chemical moiety to the remainder of the molecule of which it is a part, respectively. Thus, for example:

A bond drawn into a ring system (as opposed to being attached at a distinct vertex) means that the bond can be attached to any suitable ring atom.

The term "optional" or "optionally" as used herein means that the subsequently described event or circumstance may, but need not, occur, and that the description includes instances where the event or circumstance occurs and instances where it does not. For example, "optionally substituted" means that the optionally substituted moiety may incorporate hydrogen or a substituent.

The phrase "together form a bicyclic ring system" as used herein means that the rings combine to form a bicyclic ring system, wherein each ring may be composed of 4 to 7 carbon atoms or 4 to 7 carbons and heteroatoms, and may be saturated or unsaturated.

The phrase "together form a spirocyclic ring system" as used herein means that two substituents on a single carbon atom combine to form a spirocyclic ring system, wherein the ring formed may be composed of 3 to 7 carbon atoms or 4 to 7 carbons and heteroatoms, and may be saturated or unsaturated.

The term "about" as used herein means approximately, near. When the term "about" is used in conjunction with a numerical range, it modifies that range by extending the boundaries above and below the numerical values set forth. Generally, the term "about" is used herein to change a numerical value to a variance of 20% above and below the stated value.

The definitions described herein may be appended to form chemically relevant combinations such as "heteroalkylaryl," "haloalkylheteroaryl," "arylalkyl heterocyclyl," "alkylcarbonyl," "alkoxyalkyl," "cycloalkylalkyl," and the like. When the term "alkyl" is used as a suffix following another term, as in "phenylalkyl" or "hydroxyalkyl", it is intended to indicate an alkyl group, as defined above, substituted with one or two substituents selected from the group of the other specified nomenclature. Thus, for example, "phenylalkyl" refers to an alkyl group having 1 to 2 phenyl substituents, and thus includes benzyl, phenylethyl and biphenyl. "alkylaminoalkyl" is an alkyl group having 1 to 2 alkylamino substituents. "hydroxyalkyl" includes 2-hydroxyethyl, 2-hydroxypropyl, 1- (hydroxymethyl) -2-methylpropyl, 2-hydroxybutyl, 2, 3-dihydroxybutyl, 2- (hydroxymethyl), 3-hydroxypropyl and the like. Thus, as used herein, the term "hydroxyalkyl" is used to define a subset of heteroalkyl groups defined below. The term- (ar) alkyl refers to unsubstituted alkyl or aralkyl groups. The term (hetero) aryl or (hetero) aryl refers to aryl or heteroaryl.

The compounds of formula I may exhibit tautomerism. Tautomeric compounds may exist as two or more species that can be interconverted. Tautomers of proton transfer result from the migration of a covalently bound hydrogen atom between two atoms. Tautomers generally exist in equilibrium and attempts to isolate individual tautomers generally produce mixtures whose chemical and physical properties are consistent with mixtures of compounds. The position of equilibrium depends on the chemical characteristics within the molecule. For example, in the case of many aliphatic aldehydes and ketones, such as acetaldehyde, the keto form predominates, while in the phenols, the enol form predominates. Common tautomers of proton transfer include keto/enolAmide/imide acidAnd amidinesTautomers. The latter two are particularly common in heteroaryl and heterocyclic rings, and the present invention includes all tautomeric forms of the compounds.

Technical and scientific terms used herein have the meanings commonly understood by one of ordinary skill in the art to which this invention belongs, unless otherwise defined. Reference is made herein to various methods and materials known to those skilled in the art. Standard reference works listing general principles of pharmacology include The Pharmacological Basis of Therapeutics, 10 th edition, McGraw Hill companies Inc., New York (2001), Goodman and Gilman. Any suitable materials and/or methods known to those skilled in the art may be used in the practice of the present invention. However, preferred materials and methods are described. Materials, reagents, etc. referred to in the following description and examples are available from commercial sources unless otherwise indicated.

The term "acyl" as used herein denotes a group of formula-C (═ O) R, wherein R is hydrogen or lower alkyl as defined herein. The term or "alkylcarbonyl" as used herein denotes a group of formula C (═ O) R, wherein R is alkyl as defined herein. Term C_1-6Acyl refers to the group-C (═ O) R, which contains 6 carbon atoms. The term "arylcarbonyl" as used herein denotes a group of formula C (═ O) R, wherein R is aryl; the term "benzoyl" as used herein refers to an "arylcarbonyl" group wherein R is phenyl. The term "carbonyl" as used herein refers to a group of formula C (═ O). The term "oxo" as used herein refers to a group of formula (═ O), which may be attached to a carbon atom or a heteroatom.

The term "alkyl" as used herein denotes an unbranched or branched saturated monovalent hydrocarbon residue containing from 1 to 10 carbon atoms. The term "lower alkyl" denotes a straight or branched chain hydrocarbon residue containing 1 to 6 carbon atoms. "C" as used herein_1-10Alkyl "refers to an alkyl group consisting of 1 to 10 carbons. Examples of alkyl groups include, but are not limited to, lower alkyl groups, including: methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl or pentyl, isopentyl, neopentyl, hexyl, heptyl and octyl.

When the term "alkyl" is used as a suffix following another term, as in "phenylalkyl" or "hydroxyalkyl", it is intended to indicate an alkyl group, as defined above, substituted with one or two substituents selected from the group of the other specified nomenclature. Thus, for example, "phenylalkyl" denotes the group R 'R "-, where R' is phenyl and R" is alkylene as defined herein, with the understanding that the attachment point of the phenylalkyl moiety will be on the alkylene. Examples of arylalkyl groups include, but are not limited to, benzyl, phenylethyl, 3-phenylpropyl. The terms "arylalkyl", "arylalkyl" or "aralkyl" are to be construed analogously, with the difference that R' is an aryl group. The term "heteroarylalkyl" or "heteroarylalkyl" is similarly construed, except that R' is optionally aryl or heteroaryl.

The term "haloalkyl" as used herein denotes an unbranched or branched alkyl group as defined above wherein 1, 2, 3 or more hydrogen atoms are substituted by halogen. The term "lower haloalkyl" denotes a straight or branched chain hydrocarbon residue containing 1 to 6 carbon atoms, wherein 1, 2, 3 or more hydrogen atoms are substituted by halogen. Examples are 1-fluoromethyl, 1-chloromethyl, 1-bromomethyl, 1-iodomethyl, difluoromethyl, trifluoromethyl, trichloromethyl, tribromomethyl, triiodomethyl, 1-fluoroethyl, 1-chloroethyl, 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 denotes a divalent saturated straight chain hydrocarbon radical of 1 to 10 carbon atoms (e.g., (CH)₂)_n) Or a branched saturated divalent hydrocarbon radical of 2 to 10 carbon atoms (e.g. -CHMe-or-CH)₂CH(i-Pr)CH₂-) unless otherwise indicated. Except in the case of methylene, the open valences of the alkylene groups are not attached to the same atom. Examples of alkylene groups include, but are not limited to: methylene, ethylene, propylene, 2-methyl-propylene, 1-dimethyl-ethylene, butylene, 2-ethylbutylene.

The term "alkoxy" as used herein denotes-O-alkyl, wherein alkyl is as defined above, such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, pentyloxy, hexyloxy, including isomers thereof. "lower alkoxy" as used herein denotes alkoxy having a "lower alkyl" group as defined above. "C" as used herein_1-10Alkoxy "means an-O-alkyl group wherein alkyl is C_1-10。

The term "hydroxyalkyl" as used herein denotes an alkyl group as defined herein wherein 1 to 3 hydrogen atoms on different carbon atoms are replaced by a hydroxyl group.

The term "cycloalkyl" as used herein refers to a saturated carbocyclic ring containing 3 to 8 carbon atoms, i.e. cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl. "C" as used herein_3-7Cycloalkyl "refers to a cycloalkyl group consisting of 3 to 7 carbons in a carbocyclic ring.

The term "cycloalkenyl" refers to a partially unsaturated carbocyclic ring containing 5 to 7 carbon atoms and having a carbon-carbon double bond within the ring, unless otherwise indicated. E.g. C_5-6Cycloalkenyl refers to cycloalkenyl groups having 5 to 6 member atoms. In certain embodiments, cycloalkenyl groups have one carbon-carbon double bond within the ring. In other embodiments, cycloalkenyl groups have more than one carbon-carbon double bond within the ring. However, cycloalkenyl groups are not aromatic. The cycloalkenyl group can be optionally substituted with one or more substituents. Examples of cycloalkenyl groups include, but are not limited to, cyclopentenyl and cyclohexenyl.

The term "halogen" or "halo" as used herein refers to fluorine, chlorine, bromine or iodine.

The term "amino" as used herein includes-NR₂Wherein each R group is independently H or lower alkyl, wherein lower alkyl is as defined herein. Examples of the amino group include dimethylamino group, methylamino group and NH group ₂。

The term "aryl" as used herein refers to a monocyclic or bicyclic (also referred to as "biaryl"), substituted or unsubstituted carbocyclic aromatic group. Examples of aryl groups are phenyl, naphthyl and the like.

The term "heteroaryl" as used herein refers to a monocyclic, bicyclic ("heterobiaryl") or tricyclic group of 5 to 18 ring atoms having at least one aromatic ring, each aromatic ring containing 4 to 8 atoms, to which is bonded one or more N, O or S heteroatoms, the remaining ring atoms being carbon, with the understanding that the attachment point of the heteroaryl group will be on the aromatic ring. As is well known to those skilled in the art, heteroaryl rings have less aromatic character than their all-carbon counterparts. Thus, for the purposes of the present invention, heteroaryl groups need only have some degree of aromatic character. Examples of heteroaryl moieties include monocyclic aromatic heterocycles having 5 to 6 ring atoms and 1 to 3 heteroatoms, including but not limited to pyridyl, pyrimidinyl, pyrazinyl, pyrrolyl, pyrazolyl, imidazolyl, indolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolinyl, triazolyl, thienyl, furyl, thiadiazolyl, and oxadiazolinyl (oxadixoline), which may be optionally substituted with one or more, preferably one or two substituents selected from the group consisting of: hydroxy, cyano, alkyl, alkoxy, thio, lower haloalkoxy, alkylthio, halo, haloalkyl, alkylsulfinyl, alkylsulfonyl, halogen, amino, alkylamino, dialkylamino, aminoalkyl, alkylaminoalkyl and dialkylaminoalkyl, nitro, alkoxycarbonyl and carbamoyl, alkylcarbamoyl, dialkylcarbamoyl, arylcarbamoyl, alkylcarbonylamino and arylcarbonylamino. Examples of bicyclic moieties, also referred to as "heterobiaryl" include, but are not limited to, quinolinyl, indazolyl, isoquinolinyl, benzofuranyl, benzothienyl, benzoxazole, benzisoxazole, benzothiazole, pyrrolopyridinyl, pyrrolopyrazinyl, 1H-pyrrolo [2, 3-b ] pyridine, and benzisothiazole.

The term "heterocycloalkyl", "heterocyclyl" or "heterocycle" as used herein denotes a monovalent saturated cyclic group consisting of one or more rings, preferably 1 to 2 rings or 3 rings, each ring having 3 to 8 atoms, to which are bound one or more ring carbon atoms and one or more ring heteroatoms (selected from N, O or S (═ O)_0-2) Wherein the point of attachment may be through a carbon or heteroatom and which may optionally be independently substituted with one or more, preferably 1 or 2 or 3 substituents selected from: hydroxy, oxo, cyano, lower alkyl, lower alkoxy, lower haloalkoxy, alkylthio,Halo, haloalkyl, hydroxyalkyl, nitro, alkoxycarbonyl, amino, alkylamino, alkylsulfonyl, arylsulfonyl, alkylaminosulfonyl, arylaminosulfonyl, alkylsulfonylamino, arylsulfonylamino, alkylaminocarbonyl, arylaminocarbonyl, alkylcarbonylamino, arylcarbonylamino, unless otherwise indicated. Examples of heterocyclyl groups include, but are not limited to, azetidinyl, pyrrolidinyl, hexahydroazepinyl, oxetanyl, tetrahydrofuranyl, tetrahydrothienyl, oxazolidinyl, thiazolidinyl, isoxazolidinyl, pyrrolidinyl, morpholinyl, piperazinyl, piperidinyl, isoindolinyl, dihydroisoquinolinyl, tetrahydropyranyl, tetrahydrocarbolinyl, imidazolinyl, thiomorpholinyl, and quinuclidinyl.

The phrase "organ rejection" includes acute allograft or xenograft rejection and chronic allograft or xenograft rejection in the setting of vascularized and/or non-vascularized (e.g., bone marrow, pancreatic islet cells) transplants.

Inhibitors of JAK and Syk

The invention provides compounds of formula I or I' with the proviso that when Q is cyclopropyl or thienyl, R²And R³Is H or methyl, R^1a、R^1bAnd R^1cWhen any two of (a) are H or methyl, the other is not H, hydroxy or hydroxymethyl;

with the proviso that when Q is chloro, isopropyl, isopropenyl, piperidinyl, methyl-piperidin-3-yl-amine, methyl-piperidin-3-yl-carbamic acid tert-butyl ester, cyclohexyl, cyclopentyl-methyl-amino or cyclohexenyl, R²And R³When it is H or methyl, R^1a、R^1bAnd R^1cAre not all H; and is

With the proviso that the compound of formula I is not 2- (cyclopentyl-methyl-amino) -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid isopropylamide, 2-chloro-5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid isopropylamide, 2-isopropenyl-5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid isopropylamide, 2-isopropyl-5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid isopropylamide, 2-cyclohex-1-enyl-5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid isopropylamide, 2-cyclopropyl-5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid isopropylamide, 3-b ] pyrazine-7-carboxylic acid (3-hydroxy-2, 2-dimethyl-propyl) -amide, 2-cyclopropyl-5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ((S) -2-hydroxy-1, 2-dimethyl-propyl) -amide, 2-cyclopropyl-5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid tert-butylamide, 2-cyclohexyl-5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid isopropylamide, 2-thiophen-2-yl-5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid (3-hydroxy-2, 2-dimethyl-propyl) -amide, [1- (7-isopropylcarbamoyl-5H-pyrrolo [2, 3-b ] pyrazin-2-yl) -piperidin-3-yl ] -methyl-carbamic acid tert-butyl ester, 2- (3-methylamino-piperidin-1-yl) -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid isopropylamide; a compound having trifluoro-acetic acid, [1- (7-isopropylcarbamoyl-5H-pyrrolo [2, 3-b ] pyrazin-2-yl) -piperidin-3-yl ] -methyl-carbamic acid tert-butyl ester, or 2- (3-methylamino-piperidin-1-yl) -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid isopropylamide; a compound having trifluoro-acetic acid;

Or a pharmaceutically acceptable salt thereof.

In one variation of formula I or I ', R is H, cyano, R' or

Each R' "is independently OH or lower alkyl;

R^1aand R^1bEach independently is H, hydroxy, halogen, lower alkylAlkyl, lower alkenyl, lower alkynyl, lower haloalkyl, lower alkoxy, lower haloalkoxy, lower hydroxyalkyl, amino, lower alkylamino, lower dialkylamino, cyano, C (═ O) R' ", S (═ O)₂R' "or CH₂S(＝O)₂R；

R^1deach independently is hydroxy, halogen, lower alkyl, lower hydroxyalkyl, lower haloalkyl or lower alkoxy.

In one variation of formula I or I ', R is H, methyl, or R'.

In one variation of formula I or I ', R' is cycloalkyl, piperidinyl, pyrrolidinyl, or tetrahydropyranyl, each of which is optionally substituted with one or more R ".

In one variant of formula I or I', R²Is H or lower alkyl.

In one variant of formula I or I', R³Is H, hydroxy, cyano lower alkyl or R³’；

R³' are each independently lower alkyl, hydroxy lower alkyl, lower alkoxy, lower haloalkyl, lower haloalkoxy, phenyl lower alkyl or cycloalkyl lower alkyl, each of which is optionally substituted with one or more R³"substituted;

R³"are each independently lower alkyl, halogen, hydroxy, lower alkoxy, lower haloalkyl, lower hydroxyalkyl, oxo, cyano lower alkyl, S (═ O)₂R³”’、C(＝O)R³"', cycloalkyl, heterocycloalkyl, heteroaryl, or heterocycloalkenyl;

R³"'s are each independently H or lower alkyl.

In one variant of formula I or I', R³Is H, cyano lower alkyl or R³’；

R³' are each independently lower alkyl, hydroxy lower alkyl, lower alkoxy, lower haloalkyl, lower haloalkoxy, cycloalkyl or cycloalkyl lower alkyl, each of which is optionally substituted with one or more R³"substitution".

In one variant of formula I or I', R²Or R³Is methyl.

In one variant of formula I or I', R ²Or R³Is lower alkyl and the other is H.

In one variation of formula I or I', Q is cycloalkyl, heterocycloalkyl, or heteroaryl, each of which is optionally substituted with one or more Q^2aIs substituted, and R²Or R³Is methyl.

In one variant of formula I or I', R^1aIs lower alkyl, hydroxy, lower haloalkyl, lower alkoxy, cyano or lower hydroxyalkyl.

In one variant of formula I or I', R^1aIs lower alkyl, hydroxy, lower haloalkyl, lower alkoxy, cyano or lower hydroxyalkyl, and Q is cycloalkyl, heterocycloalkyl or heteroaryl, each of which is optionally substituted with one or more Q^2aAnd (4) substitution.

In one variant of formula I or I', R^1aIs lower alkyl, hydroxy, lower haloalkyl, lower alkoxy, cyano or lower hydroxyalkyl, and R²Or R³Is methyl.

In one variant of formula I or I', R^1aIs lower alkyl, hydroxy, lower haloalkyl, lower alkoxy, cyano or lower hydroxyalkyl, Q is cycloalkyl, heterocycloalkyl or heteroaryl, each of which is optionally substituted by one or more Q^2aIs substituted, and R²Or R³Is methyl.

In one variant of formula I or I', R^1bIs lower alkyl or lower haloalkyl.

In one variant of formula I or I', R^1bIs lower alkyl or lower haloalkyl, and R^1aIs lower alkyl, hydroxy, lower haloalkyl, lower alkoxy, cyano or lower hydroxyalkyl.

In one variant of formula I or I', R^1bIs lower alkyl or lower haloalkyl, and Q is cycloalkyl, heterocycloalkyl or heteroaryl, each of which is optionally substituted with one or more Q^2aAnd (4) substitution.

In one variant of formula I or I', R^1bIs lower alkyl or lower haloalkyl, and R²Or R³Is methyl.

In one variant of formula I or I', R^1bIs lower alkyl or lower haloalkyl, R^1aIs lower alkyl, hydroxy, lower haloalkyl, lower alkoxy, cyano or lower hydroxyalkyl, Q is cycloalkyl, heterocycloalkyl or heteroaryl, each of which is optionally substituted by one or more Q^2aIs substituted, and R²Or R³Is methyl.

In one variant of formula I or I', R^1cIs H, hydroxy or lower alkyl.

In one variant of formula I or I', R^1cIs H, hydroxy or lower alkyl and R^1aIs lower alkyl, hydroxy, lower haloalkyl, lower alkoxy, cyano or lower hydroxyalkyl.

In one variant of formula I or I', R ^1cIs H, hydroxy or lower alkyl, and Q is cycloalkyl, heterocycloalkyl or heteroaryl, each of which is optionally substituted by one or more Q^2aAnd (4) substitution.

In one variant of formula I or I', R^1cIs H, hydroxy or lower alkyl, and R²Or R³Is methyl.

In one variant of formula I or I', R^1cIs H, hydroxy or lower alkyl, R^1aIs lower alkyl, hydroxy, lower haloalkyl, lower alkoxy, cyano or lower hydroxyalkyl, Q is cycloalkyl, heterocycloalkyl or heteroaryl, each of which is optionally substituted by one or more Q^2aIs substituted, and R²Or R³Is methyl.

In one variant of formula I or I', R^1aAnd R^1bTogether form a spirocycloalkyl or spiroheterocycloalkyl group.

In one variation of formula I or I', Q is Q²、Q³Or Q⁴；

Q²Is cycloalkyl, cycloalkenyl, pyrrolidinyl, thiazolyl, thienyl, pyridyl, pyrazolyl or dihydropyranyl, optionally substituted with one or more Q^2aSubstitution;

Q^2aindependently is Q^2dOr Q^2e；

Q^2dEach independently is-C (═ O) N (Q)^2e)₂or-C (═ O) (Q)^2e)-；

Q^2eEach independently is H or Q^2e’；

Q^2e' are each independently lower alkyl, phenyl, benzyl, 5, 6, 7, 8-tetrahydro-naphthalene, lower haloalkyl, lower alkoxy, cycloalkyl, cycloalkenyl, heterocycloalkyl, spiroheterocycloalkyl, or heteroaryl, optionally substituted with one or more Q ^2fSubstitution;

Q^2feach independently is Q^2gOr Q^2h；

Q^2gEach independently is halogen, hydroxy, cyano, oxo, -S (═ O)₂(Q²ⁱ’)、-S(＝O)₂N(Q²ⁱ’)₂、-C(＝O)OH、C(＝O)N(Q²ⁱ’)₂or-C (═ O) (Q)²ⁱ’)；

Q³is-O-Q^3a、-N(Q^3a)₂or-N (Q)^3a)(CH₂)_mC(＝O)N(Q^3a)₂；

Q^3aEach independently is H or Q^3c；

Each m is independently 0, 1 or 2;

Q^3dEach independently is halogen, oxo, cyano, hydroxy, -NHS (═ O)₂(Q^3f)、-NHC(＝O)(Q^3f)、NHC(＝O)N(Q^3f)₂Or N (Q)^3f)₂；

Q^3fEach independently is H or Q^3f’；

Q⁴Is Q^4aOr Q^4b；

Q^4aIs halogen or cyano;

Q^4bis lower alkyl, lower alkenyl or lower haloalkyl;

in one variation of formula I or I', Q is cyclopropyl, thienyl, or pyrazolyl.

In one variation of formula I or I', Q is cyclopropyl, thienyl or pyrazolyl, each optionally substituted with one or more Q^2eAnd (4) substitution.

The present application provides compounds of formula I',

wherein:

r is H, cyano, R' or

r 'is halogen, hydroxy, cyano, lower alkyl, lower haloalkyl, lower alkoxy, lower hydroxyalkyl, cycloalkyl, C (═ O) R' or S (═ O)₂R”’；

R' "is OH or lower alkyl;

R^1a、R^1band R^1cEach independently is H, hydroxy, halogen, lower alkyl, lower alkenyl, lower alkynyl, lower haloalkyl, lower alkoxy, lower haloalkoxy, lower hydroxyalkyl, amino, lower alkylamino, lower dialkylamino, cyano, cycloAlkyl, heterocycloalkyl, C (═ O) R' "or S (═ O)₂R”’；

R²Is H or lower alkyl;

R³is H, hydroxy, cyano lower alkyl or R³’；

R³' is lower alkyl, hydroxy lower alkyl, lower alkoxy, lower haloalkyl, lower haloalkoxy, phenyl lower alkyl or cycloalkyl lower alkyl, each of which is optionally substituted with one or more R ³"substituted;

R³"' is H or lower alkyl;

q is Q²、Q³Or Q⁴；

Q^2ais Q^2bOr Q^2c；

Q^2bIs halogen, oxo, hydroxy, -CN, -SCH₃、-S(O)₂CH₃or-S (═ O) CH₃；

Q^2cIs Q^2dOr Q^2e；

Q^2dis-O (Q)^2e)、-S(＝O)₂(Q^2e)、-C(＝O)N(Q^2e)₂、-S(O)₂(Q^2e)、-C(＝O)(Q^2e)、-C(＝O)O(Q^2e)、-N(Q^2e)C(＝O)(Q^2e)、-N(Q^2e)C(＝O)O(Q^2e) or-N (Q)^2e)C(＝O)N(Q^2e)₂；

Q^2eEach independently is H or Q^2e’；

Q^2e' are each independently lower alkyl, phenyl, benzyl, lower haloalkyl, lower alkoxy, cycloalkyl, cycloalkenyl, heterocycloalkyl, or heteroaryl, optionally substituted with one or more Q^2fSubstitution;

Q^2fis Q^2gOr Q^2h；

Q^2gIs halogen, hydroxy, cyano, oxo or-C (═ O) (Q)^2h)；

Q^2hIs lower alkyl, lower haloalkyl, lower alkoxy, amino, phenyl, benzyl, cycloalkyl, heterocycloalkyl or heteroaryl, optionally substituted with one or more Q²ⁱSubstitution; and is

Q²ⁱIs halogen, hydroxy, cyano, lower alkyl, lower haloalkyl or lower alkoxy;

Q^3aEach independently is Q^3bOr Q^3c；

m is 0, 1 or 2;

Q^3bis H;

Q^3cis lower alkyl, lower haloalkyl, phenyl, cycloalkyl, heterocycloalkyl or heteroaryl, optionally substituted with one or more Q^3dSubstitution; and is

Q^3dEach independently is Q^3eOr Q^3f；

Q^3eIs halogen or hydroxy;

Q^3fis lower alkyl, lower alkoxy, lower haloalkyl, phenyl, cycloalkyl, heterocycloalkyl or heteroaryl, optionally substituted with one or more Q^3gSubstitution; and is

Q⁴is Q^4aOr Q^4b；

Q^4aIs hydroxy, halogen or cyano;

Q^4cis Q^4dOr Q^4e；

Q^4dEach independently is halogen, hydroxy or cyano;

Q^4eeach independently is lower alkyl, lower haloalkyl, lower alkoxy, amino, cycloalkyl, phenyl, heterocycloalkyl, or heteroaryl, optionally substituted with one or more Q^4fSubstitution;

With the proviso that when Q is cyclopropyl or thienyl, R²And R³Is H or methyl, R^1a、R^1bAnd R^1cWhen any two of (a) are H or methyl, the other is not H, hydroxy or hydroxymethyl; and is

With the proviso that when Q is chloro, isopropyl, isopropenyl, piperidinyl, methyl-piperidin-3-yl-amine, methyl-piperidin-3-yl-carbamic acid tert-butyl ester, cyclohexyl, cyclopentyl-methyl-amino or cyclohexenyl, and R²And R³When it is H or methyl, R^1a、R^1bAnd R^1cAre not all H;

or a pharmaceutically acceptable salt thereof.

The present application provides a method of treating an inflammatory or autoimmune disease comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula I or I'.

The present application provides the above method further comprising administering an additional therapeutic agent selected from a chemotherapeutic or anti-proliferative agent, an anti-inflammatory agent, an immunomodulatory or immunosuppressive agent, a neurotrophic factor, an agent for treating cardiovascular disease, an agent for treating diabetes, or an agent for treating immunodeficiency disorders.

The present application provides a method of treating an inflammatory disorder comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula I or I'.

The present application 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 or I'.

The present application provides a method of treating asthma comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula I or I'.

The present application provides a method of inhibiting a T-cell proliferative disorder comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula I or I'.

The present application provides the above method, wherein the proliferative disorder is cancer.

The present application provides a method of treating a B-cell proliferative disorder comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula I or I'.

The present application provides methods of treating immune disorders including lupus, multiple sclerosis, rheumatoid arthritis, psoriasis, type I diabetes, complications resulting from organ transplantation, foreign body transplantation, diabetes, cancer, asthma, atopic dermatitis, autoimmune thyroid disease, ulcerative colitis, crohn's disease, alzheimer's disease, and leukemia comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula I or I '.

The present application provides methods of preventing or treating all forms of organ rejection, including acute allograft or xenograft rejection and chronic allograft or xenograft rejection, vascular or non-vascular graft rejection, comprising administering a compound of formula I or I' to a patient in need thereof.

The present application provides methods of inhibiting JAK3 activity comprising administering a compound of formula I or I', wherein the compound exhibits an IC of 50 nanomolar or less in an in vitro biochemical assay of JAK3 activity₅₀。

The present application provides the above method wherein the compound exhibits an IC of 100 nanomolar or less in an in vitro biochemical assay of JAK3 activity₅₀。

The present application provides the above method wherein the compound exhibits an IC of 10 nanomolar or less in an in vitro biochemical assay of JAK3 activity₅₀。

The present application provides methods of inhibiting SYK activity comprising administering formula I orA compound of I', wherein the compound exhibits an IC of 50 nanomolar or less in an in vitro biochemical assay of SYK activity₅₀。

The present application provides the above method, wherein the compound exhibits an IC of 100 nanomolar or less in an in vitro biochemical assay of SYK activity ₅₀。

The present application provides the above method, wherein the compound exhibits an IC of 10 nanomolar or less in an in vitro biochemical assay of SYK activity₅₀。

The present application provides a method of treating an inflammatory disorder comprising co-administering to a patient in need thereof a therapeutically effective amount of an anti-inflammatory compound with a compound of formula I or I'.

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 with a compound of formula I or I'.

The present application provides pharmaceutical compositions comprising a compound of formula I or I' admixed with at least one pharmaceutically acceptable carrier, excipient or diluent.

The present application provides a pharmaceutical compound of formula I or I' above, further comprising an additional therapeutic agent selected from a chemotherapeutic or anti-proliferative agent, an anti-inflammatory agent, an immunomodulatory or immunosuppressive agent, a neurotrophic factor, an agent for treating cardiovascular disease, an agent for treating diabetes, or an agent for treating immunodeficiency disorders.

The present application provides compounds as described above for the treatment of inflammatory or autoimmune disorders.

The present application provides compounds as described above for the treatment of any one of the conditions listed above.

The present application provides the use of a compound of formula I or I' in the manufacture of a medicament for the treatment of an inflammatory disorder.

The present application provides the use of a compound of formula I or I' in the manufacture of a medicament for the treatment of an autoimmune disease.

The present application provides a compound or method as described herein.

Examples of representative compounds encompassed by and within the scope of the present invention are provided in the following tables. The following examples and preparations are provided to enable those skilled in the art to more clearly understand and practice the present invention. They should not be considered as limiting the scope of the invention, but merely as being exemplary and representative thereof.

Generally, the nomenclature used in this application is based on AUTONOMTM v.4.0, a Beilstein Institute computerized system for generating IUPAC system nomenclature. If there is a difference between the drawn structure and the name giving it, the drawn structure will be given more weight. Further, if the stereochemistry of a structure or a portion of a structure is not indicated with, for example, bold or dashed lines, the structure or portion of the structure is to be interpreted as encompassing all stereoisomers of it.

Table I describes the embodied compounds of formula I.

TABLE I

The following schemes, preparations and examples illustrate the preparation and biological evaluation of compounds within the scope of the present invention. The following preparations and examples are provided to enable those skilled in the art to more clearly understand and practice the present invention. They should not be considered as limiting the scope of the invention, but merely as being exemplary and representative thereof.

Synthesis of

Different sections of the incorporation on pyrrolopyrazines are disclosed in U.S. application serial No. 12/378,837 filed on 2-20-2009, 12/378,869 filed on 2-20-2009, 12/378,971 filed on 2-20-2009, 12/378,977 filed on 2-20-2009, and 12/378,978 filed on 2-20-2009, the contents of each of these references being incorporated herein by reference.

In particular, the synthetic disclosures in the above-cited applications and in scheme 1 and those methods and examples set forth below describe a detailed description of the synthesis of some species that can be introduced at the Q position including the following general structural formula I:

for example, U.S. application serial No. 12/378,837 discloses pyrrolopyrazine compounds wherein Q may be H, hydroxy, cyano, or halogen; or lower alkyl, lower alkenyl, lower alkynyl, lower hydroxyalkyl, amino or lower haloalkyl, each of which is optionally substituted.

For example, U.S. application serial No. 12/378,869 discloses pyrrolopyrazine compounds wherein Q may be phenyl, which may be substituted with two substituents that together form a heterocyclic or heteroaryl ring system, each of which is optionally substituted.

For example, U.S. application Ser. No. 12/378,971 discloses pyrrolopyrazine compounds wherein Q may be-O-Q^3a、-S-Q^3a、-C(＝O)(Q^3a)、-O(CH₂)_mC(＝O)(^3a)、-S(＝O)(^3a)、-S(＝O)₂(Q^3a)、-N(Q^3a)₂、-N(Q^3a)S(＝O)₂(Q^3a)、-N(Q^3a)C(＝O)(Q^3a)、-C(＝O)N(Q^3a)₂or-N (Q)^3a)C(＝O)N(Q^3a)₂Wherein m is 0, 1 or 2, and Q^3aEach independently may be lower alkyl, lower haloalkyl, phenyl, cycloalkyl, heterocycloalkyl, or heteroaryl, each of which is optionally substituted, or is H.

For example, U.S. application serial No. 12/378,977 discloses pyrrolopyrazine compounds wherein Q may be phenyl or indolyl, each of which is optionally substituted.

For example, U.S. application serial No. 12/378,978 pyrrolopyrazine compounds wherein Q may be cycloalkyl, cycloalkenyl, heterocycloalkyl, or heteroaryl, each of which is optionally substituted.

This synthesis is detailed in scheme 1, and those methods and examples provided below describe the synthetic preparation, which can be found in the above general structure R, R²And R³The included moiety is introduced locally.

A representative preparation of the compounds of the invention is outlined in scheme 1 below:

Reaction scheme 1.

As shown in scheme 1 above, R may be H, cyano, R' or

R' may be cycloalkyl, heterocycloalkyl, or phenyl, each of which may be optionally substituted with one or more R "; r "may be halogen, hydroxy, cyano, lower alkyl, lower haloalkyl, lower alkoxy, lower hydroxyalkyl, cycloalkyl, C (═ O) R'" or S (═ O)₂R' "; r' "can be OH, lower alkyl, lower alkoxy, lower haloalkyl, lower hydroxyalkyl, cycloalkyl, or amino; r^1a、R^1bAnd R^1cEach independently is H, hydroxy, halogen, lower alkyl, lower alkenyl, lower alkynyl, lower haloalkyl, lower alkoxy, lower haloalkoxy, lower hydroxyalkyl, amino, lower alkylamino, lower dialkylamino, cyano, cycloalkyl, lower alkylamino, lower haloalkyloxy, lower haloalkyl, lower alkylamino, lower haloalkyloxy, lower dialkylamino, lower haloalkyloxy, lower alkylamino, lower dialkylamino, lower haloalkyloxy, lower haloalk,Heterocycloalkyl, C (═ O) R' "or S (═ O)₂R' "; or R^1aAnd R^1bTogether form a spirocycloalkyl or spiroheterocycloalkyl, each of which may be optionally substituted with one or more R³' substitution; r²May be H or lower alkyl; r³May be H, lower alkyl, hydroxy lower alkyl, lower alkoxy, lower haloalkyl, lower haloalkoxy, phenyl lower alkyl, cycloalkyl lower alkyl, cyano lower alkyl or heterocycloalkyl; or R ³And R' together form a spiro ring system, each of which may optionally be substituted by one or more R³' substitution; r³' are each independently lower alkyl, halogen, hydroxy, lower alkoxy, lower haloalkyl, lower hydroxyalkyl, oxo, cyano lower alkyl, S (═ O)₂R³”、C(＝O)R³', cycloalkyl, heterocycloalkyl, heteroaryl, or heterocycloalkenyl; r³"may be H or lower alkyl; q may be Q²、Q³Or Q⁴；Q²Can be heterocycloalkyl, cycloalkyl, cycloalkenyl, heterocycloalkylphenyl, heteroaryl, biaryl, or heterobiaryl, optionally substituted with one or more Q^2aSubstitution; q^2aMay be Q^2bOr Q^2c；Q^2bCan be halogen, oxo, hydroxy, -CN, -SCH₃、-S(O)₂CH₃or-S (═ O) CH₃；Q^2cMay be Q^2dOr Q^2e(ii) a Or two of Q^2aTogether form a bicyclic ring system, optionally substituted with one or more Q^2bOr Q^2cSubstitution; q^2dMay be-O (Q)^2e)、-S(＝O)₂(Q^2e)、-C(＝O)N(Q^2e)₂、-S(O)₂(Q^2e)、-C(＝O)(Q^2e)、-C(＝O)O(Q^2e)、-N(Q^2e)C(＝O)(Q^2e)、-N(Q^2e)C(＝O)O(Q^2e) or-N (Q)^2e)C(＝O)N(Q^2e)₂；Q^2eEach of which may be independently H or Q^2e’；Q^2e' Each may be independently lower alkyl, phenyl, benzyl, lower halogenLower alkoxy, cycloalkyl, cycloalkenyl, heterocycloalkyl or heteroaryl, optionally substituted with one or more Q^2fSubstitution; q^2fMay be Q^2gOr Q^2h；Q^2gMay be halogen, hydroxy, cyano, oxo or-C (═ O) (Q)^2h)；Q^2hMay be lower alkyl, lower haloalkyl, lower alkoxy, amino, phenyl, benzyl, cycloalkyl, heterocycloalkyl or heteroaryl, optionally substituted with one or more Q ²ⁱSubstitution; q²ⁱMay be halogen, hydroxy, cyano, lower alkyl, lower haloalkyl or lower alkoxy; q³May be-O-Q^3a、-S-Q^3a、-C(＝O)(Q^3a)、-O(CH₂)_mC(＝O)(Q^3a)、-S(＝O)(Q^3a)、-S(＝O)₂(Q^3a)、-N(Q^3a)₂、-N(Q^3a)S(＝O)₂(Q^3a)、-N(Q^3a)C(＝O)(Q^3a)、-C(＝O)N(Q^3a)₂、N(Q^3a)C(＝O)N(Q^3a)₂or-N (Q)^3a)(CH₂)_mC(＝O)N(Q^3a)₂；Q^3aMay each independently be Q^3bOr Q^3c(ii) a m may be 0, 1 or 2; q^3bMay be H; q^3cMay be lower alkyl, lower haloalkyl, phenyl, cycloalkyl, heterocycloalkyl or heteroaryl, optionally substituted with one or more Q^3dSubstitution; q^3dMay each independently be Q^3dMay be Q^3eOr Q^3f；Q^3eMay be halogen or hydroxy; q^3fMay be lower alkyl, lower alkoxy, lower haloalkyl, phenyl, cycloalkyl, heterocycloalkyl or heteroaryl, optionally substituted with one or more Q^3gSubstitution; q^3gMay each independently be halogen, hydroxy, lower alkyl, lower hydroxyalkyl, lower haloalkyl or lower alkoxy; q⁴May be Q^4aOr Q^4b；Q^4aMay be hydroxy, halogen or cyano; q^4bMay be lower alkyl, lower alkoxy, lower alkynyl, lower alkenyl, lower hydroxyalkyl, amino or lower halogenAlkyl substituted, optionally substituted with one or more Q^4cSubstitution; q^4cMay be Q^4dOr Q^4e；Q^4dMay each independently be halogen, hydroxy or cyano; q^4eMay each independently be lower alkyl, lower haloalkyl, lower alkoxy, amino, cycloalkyl, phenyl, heterocycloalkyl, or heteroaryl, optionally substituted with one or more Q ^4fSubstitution; q^4fMay each independently be hydroxy, halogen, lower alkyl, lower alkenyl, oxo, lower haloalkyl, lower alkoxy, lower hydroxyalkyl or amino; with the proviso that when Q is cyclopropyl or thienyl, R²And R³Is H or methyl, R^1a、R^1bAnd R^1cWhen any two of (a) are H or methyl, the other cannot be H, hydroxy or hydroxymethyl; and with the proviso that when Q is chloro, isopropyl, isopropenyl, piperidinyl, cyclohexyl or cyclohexenyl, R²And R³When it is H or methyl, R^1a、R^1bAnd R^1cNot all are H.

Method of producing a composite material

The following methods detail the chemical synthesis of intermediates used to provide the final compounds disclosed in the examples.

Method 1.

Step 1

To a partial suspension of 2-bromo-5H-pyrrolo [2, 3-b ] pyrazine (5.0g, 25.2mmol) in 1, 4-dioxane (100mL) was added 2.0M aqueous NaOH (25mL, 50.0mmol) and 37% aqueous formaldehyde (19mL, 252 mmol). The dark homogeneous reaction mixture was stirred at room temperature overnight. The organic layer was evaporated under reduced pressure. The aqueous layer was neutralized with 1.0M HCl and extracted with EtOAc (2X). The combined organic layers were concentrated to give 2.6g of an orange solid. Upon standing, a thick brown precipitate formed in the aqueous layer. The precipitate was collected by filtration and dried. The brown solid was extracted hot with 10% MeOH/EtOAC (3X 200 mL). The extracts were combined and evaporated to give a further 3.05g of an orange solid. The total yield of (2-bromo-7-hydroxymethyl-pyrrolo [2, 3-b ] pyrazin-5-yl) -methanol was 5.65g (87%).

Step 2

To (2-bromo-7-hydroxymethyl-pyrrolo [2, 3-b)]To a suspension of pyrazin-5-yl) -methanol (5.65g, 21.9mmol) in THF (150mL) was added 2.0M aqueous NaOH (33mL, 66 mmol). The homogeneous reaction mixture was stirred overnight and then the organic layer was removed under reduced pressure. The aqueous residue was brought to pH 4 with 1.0M aqueous HCl. Collecting the obtained precipitate by filtration, and purifying with H₂O rinse to give 3.68g of a yellow solid, the filtrate extracted with EtOAc (2 ×), and the organic layer concentrated under reduced pressure to provide an additional 0.92g of a yellow solid. (2-bromo-5H-pyrrolo [2, 3-b)]Total yield of pyrazin-7-yl) -methanol was 4.60g (92%).

Step 3

By adding concentrated H₂SO₄(2.3mL) carefully added to CrO₃(2.67g) with H₂Stock solutions of jones reagent (2.67M) were prepared by dilution of O to 10 mL. To (2-bromo-5H-pyrrolo [2, 3-b)]To a partial suspension of pyrazin-7-yl) -methanol (4.6g, 20.1mmol) in acetone (300mL) was slowly added jones reagent (9mL, 24.0 mmol). During the addition process, the raw materials are gradually dissolved to form a thick green precipitate. The reaction mixture was stirred for 15min, then quenched with i-PrOH (2mL), filtered through celite, and rinsed with acetone. The filtrate was concentrated to give 4.76g of 2-bromo-5H-pyrrolo [2, 3-b ] ]Pyrazine-7-carbaldehyde, a yellow-orange solid, was used without further purification. To a DMF solution (50mL) of this solid was added NaH (60% in mineral oil, 1.2g, 30.1mmol) at 0 ℃. The reaction mixture was stirred at room temperature for 30min, then cooled back to 0 ℃ and 2- (trimethylsilyl) ethoxymethyl chloride (4.3mL, 24.1mmol) was added slowly. The reaction mixture was warmed to room temperature, stirred for 1H, then taken up with H₂O quenched and extracted with EtOAc (3 ×). By H₂The combined organic layers were washed with O (3X) and brine, then MgSO₄Drying and concentrating. By SiO₂The residue was chromatographed (20% -30% EtOAc/hexanes) to isolate 3.82g (53%) of 2-bromo-5- (2-trimethylsilyl-ethoxymethyl) -5H-pyrrolo [2, 3-b ]]Pyrazine-7-carbaldehyde as a yellow solid.

Method 2.

In a flask 2-bromo-5- (2-trimethylsilylethoxymethyl) -5H-pyrrolo [2, 3-b ]]Pyrazine-7-carbaldehyde (3.11g, 8.74mmol) was dissolved in dioxane (120mL) and H₂O (30mL), and the mixture was cooled at 0 ℃. Sulfamic acid (5.09g, 52.4mmol) was added followed by sodium chlorite (1.28g, 11.4mmol) and potassium dihydrogen phosphate (14.3g, 104.9mmol) in H over 15min via a dropping funnel₂O (75mL) solution. The mixture was warmed to room temperature over 2 h. The resulting yellow solid was filtered off and washed with H ₂And washing with O and hexane and drying. The filtrate was then extracted with EtOAc and the combined organic layers were washed with brine, MgSO₄Drying and concentrating to obtain another product. In total, 3.71g of 2-bromo-5- (2-trimethylsilylethoxymethyl) -5H-pyrrolo [2, 3-b ] are obtained]Pyrazine-7-carboxylic acid as a yellow solid.

Method 3.

Step 1

A mixture of 2-bromo-5- (2-trimethylsilyl-ethoxymethyl) -5H-pyrrolo [2, 3-b ] pyrazine-7-carbaldehyde (0.33g, 0.93mmol), cyclopropylboronic acid (0.12g, 1.39mmol), tricyclohexylphosphine (0.026g, 0.09mmol), palladium (II) acetate (0.01g, 0.046mmol), and tripotassium phosphate (0.63g, 2.97mmol) in 4mL of toluene and 0.5mL of water was purged with argon for 5min and then heated at 100 ℃ for 18H. The cooled mixture was filtered through a pad of celite, washed with EtOAc, and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with 10% EtOAc/hexanes, to give 0.24g (81%) of 2-cyclopropyl-5- (2-trimethylsilyl-ethoxymethyl) -5H-pyrrolo [2, 3-b ] pyrazine-7-carbaldehyde as a yellow powder.

Step 2

To a solution of 2-cyclopropyl-5- (2-trimethylsilyl-ethoxymethyl) -5H-pyrrolo [2, 3-b ] pyrazine-7-carbaldehyde (0.24g, 0.75mmol) in 1, 4-dioxane (10mL) and water (2mL) was added sulfamic acid (0.44g, 4.54mmol) at 0 ℃. Then, a 6mL aqueous solution of sodium chlorite (0.09g, 0.98mmol) and potassium dihydrogen phosphate (1.22g, 9.0mmol) was added dropwise. After addition, the reaction mixture was warmed to room temperature, stirred for 2h, and then partitioned between water and ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate and concentrated under reduced pressure. The residue was triturated with hexanes to give 0.22g (87%) of 2-cyclopropyl-5- (2-trimethylsilyl-ethoxymethyl) -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid as a light yellow powder.

Method 4.

Step 1

To 2-bromo-5- ((2- (trimethylsilyl) ethoxy) methyl) -5H-pyrrolo [2, 3-b]To a solution of pyrazine-7-carbaldehyde (1.33g, 3.73mmol) and 1-ethyl-4- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazole (995mg, 4.48mmol) in 1, 2-DME (20mL) was added Pd (Ph)₃P)₄(0.22g, 0.19mmol) and 2.0M of K₂CO₃Aqueous solution (5.6ml, 11.2 mmol). By making N₂The reaction mixture was degassed by foaming for 15min and then heated at 100 ℃ overnight. Cooling the resulting purplish red reaction mixture with H₂Diluted O and then extracted with EtOAc (2 ×). With MgSO₄The combined organic layers were dried and concentrated. By SiO₂The crude residue was purified by chromatography (30% -80% EtOAc/hexanes) to give 1.12g (81%) of 2-(1-Ethyl-1H-pyrazol-4-yl) -5- ((2- (trimethylsilyl) ethoxy) methyl) -5H-pyrrolo [2, 3-b]Pyrazine-7-carbaldehyde as a light orange-brown solid.

Step 2

To 2- (1-ethyl-1H-pyrazol-4-yl) -5- ((2- (trimethylsilyl) ethoxy) methyl) -5H-pyrrolo [2, 3-b ] at 0 deg.C]Pyrazine-7-carbaldehyde (1.12g, 3.01mmol) in 1, 4-dioxane (50mL) and H₂To a solution in O (10mL) was added sulfamic acid (1.76g, 18.1 mmol). Then NaClO is added through a dropping funnel within 15min ₂(0.44g, 3.92mmol) and KH₂PO₄(4.92g, 36.2mmol) of H₂O (30mL) solution. The ice bath was removed and the yellow cloudy reaction mixture was stirred at room temperature for 2.5 h. By H₂The reaction mixture was diluted with EtOAc (2 ×). With MgSO₄The combined organic layers were dried and concentrated to give an oily yellow solid which was triturated with 5% EtOAc/hexanes to give 1.05g (90%) of 2- (1-ethyl-1H-pyrazol-4-yl) -5- ((2- (trimethylsilyl) ethoxy) methyl) -5H-pyrrolo [3, 2-b]Pyrazine-7-carboxylic acid as a light yellow solid.

Pharmaceutical compositions and administration

The compounds of the present invention may be formulated in a wide variety of oral administration dosage forms and carriers. Oral administration may be in the form of tablets, coated tablets, dragees, hard and soft gelatin capsules, solutions, emulsions, syrups or suspensions. The compounds of the present invention are effective when administered by other routes of administration, including sustained (intravenous drip) topical parenteral, intramuscular, intravenous, subcutaneous, transdermal (which may contain a penetration enhancer), buccal, nasal, inhalation, and suppository administration, among other routes of administration. The preferred mode of administration is generally oral using a conventional daily dosage regimen which may be adjusted according to the degree of affliction and the patient's response to the active ingredient.

The compound or compounds of the present invention and their pharmaceutically acceptable salts, together with one or more conventional excipients, carriers or diluents, may be placed in the form of pharmaceutical compositions and unit dosages. The pharmaceutical compositions and unit dosage forms may comprise the usual ingredients in conventional proportions, with or without additional active compounds or principles, and may contain any suitable effective amount of the active ingredient commensurate with the intended daily dosage range of use. The pharmaceutical compositions may be administered orally as a solid such as a tablet or filled capsule, a semi-solid, a powder, a sustained release formulation, or a liquid such as a solution, suspension, emulsion, elixir, or filled capsule; or in the form of suppositories for rectal or vaginal administration; or in the form of a sterile injectable solution for parenteral use. Typical formulations contain from about 5% to about 95% of the active compound or compounds (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 understand that the active ingredient may be present in different formulations depending on the target organ or tissue and depending on the desired dosage and pharmacokinetic parameters.

The term "excipient" as used herein refers to a compound that is generally safe, non-toxic, and biologically or otherwise undesirable for use in preparing a pharmaceutical composition, and includes excipients that are useful for veterinary use as well as human pharmaceutical applications. 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 selected with regard to the intended route of administration and standard pharmaceutical practice.

By "pharmaceutically acceptable" it is meant that it can be used to prepare pharmaceutical compositions that are generally safe, non-toxic, and not biologically or otherwise undesirable, and includes that it is acceptable for veterinary as well as human pharmaceutical use.

The "pharmaceutically acceptable salt" form of the active ingredient may also initially impart desirable pharmacokinetic properties to the active ingredient which are lacking in the non-salt form and may even positively affect the pharmacodynamics of the active ingredient with respect to its in vivo therapeutic activity. The phrase "pharmaceutically acceptable salt" of a compound refers to a salt that is pharmaceutically acceptable and has the desired pharmacological activity of the parent compound. The salt comprises: (1) acid addition salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or with organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3- (4-hydroxybenzoyl) benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1, 2-ethane-disulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, 4-methylbicyclo [2.2.2] -oct-2-ene-1-carboxylic acid, glucoheptonic acid, 3-phenylpropionic acid, trimethylacetic acid, tert-butylacetic acid, laurylsulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid, and the like; or (2) a salt formed when an acid proton present in the parent compound is replaced with a metal ion, such as an alkali metal ion, an alkaline earth ion, or an aluminum ion; or salts coordinated with organic bases such as ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine, etc.

Solid form preparations include powders, tablets, pills, capsules, cachets, suppositories, and dispersible granules. A solid carrier can be one or more substances that may also act as diluents, flavoring agents, solubilizers, lubricants, suspending agents, binders, preservatives, tablet disintegrating agents, or an encapsulating material. In powders, the carrier is typically a finely divided solid which is in admixture with the finely divided active ingredient. In tablets, the active ingredient is usually mixed with a carrier having the necessary binding capacity in suitable proportions and compacted in the shape and size desired. Suitable carriers include, but are not limited to, magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methyl cellulose, sodium carboxymethyl cellulose, a low melting wax, cocoa butter, and the like. Formulations in solid form may contain, in addition to the active ingredient, colorants, flavors, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizing agents, and the like.

Liquid formulations are also suitable for oral administration, including liquid formulations including emulsions, syrups, elixirs, aqueous solutions, aqueous suspensions. These include solid form preparations which are intended to be converted, shortly before use, to liquid form preparations. Emulsions may be prepared in the form of solutions, for example in the form of aqueous propylene glycol solutions, or may contain emulsifying agents, for example lecithin, sorbitan monooleate, or acacia. Aqueous solutions may be prepared by dissolving the active ingredient in water and adding suitable colorants, fragrances, stabilizers and thickeners. Aqueous suspensions may be formulated by dispersing the finely divided active ingredient in water together with viscous materials such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose and other well-known suspending agents.

The compounds of the invention may be formulated for parenteral administration (e.g., by injection, e.g., bolus injection or continuous infusion) and may be presented in unit dosage form in ampoules, pre-filled syringes, small volume infusion solutions or in multi-dose containers with an added preservative. The compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, for example, solutions in aqueous polyethylene glycol. Examples of oily or nonaqueous carriers, diluents, solvents or vehicles include propylene glycol, polyethylene glycol, vegetable oils (e.g., olive oil) and injectable organic esters (e.g., ethyl oleate) and may contain formulatory agents such as preservatives, wetting, emulsifying or suspending agents, stabilizers and/or dispersants. Alternatively, the active ingredient may be presented in powder form, obtained by aseptic isolation of sterile solid or by lyophilization from solution, for constitution with a suitable vehicle, e.g., sterile, pyrogen-free water, before use.

The compounds of the present invention may be formulated for topical administration to the epidermis as an ointment, cream or lotion, or as a transdermal patch. Ointments and creams may, for example, be formulated with an aqueous or oily base with the addition of suitable thickening and/or gelling agents. Lotions may be formulated with an aqueous or oily base and will in general also contain one or more emulsifying agents, stabilizing agents, dispersing agents, suspending agents, thickening agents, or coloring agents. Formulations suitable for topical administration in the mouth include: lozenges comprising the active ingredient in a flavoured base, usually sucrose and acacia or tragacanth; pastilles comprising the active ingredient in an inert base such as gelatin and glycerin or sucrose and acacia; and mouthwashes comprising the active ingredient in a suitable liquid carrier.

The compounds of the present invention may be formulated for administration as suppositories. A low melting wax, such as a mixture of fatty acid glycerides or cocoa butter, is first melted and the active ingredient is dispersed homogeneously, for example by stirring. The molten homogeneous mixture is then poured into a suitably sized mould, allowed to cool and solidify.

The compounds of the present invention may be formulated for vaginal administration. Pessaries, tampons, creams, gels, pastes, foams or sprays containing in addition to the active ingredient such carriers as are known in the art to be suitable.

The compounds of the present invention may be formulated for nasal administration. The solution or suspension is applied directly to the nasal cavity by conventional means, for example with a dropper, pipette or nebulizer. The formulations may be provided in single or multiple dose forms. In the latter case of a dropper or pipette, this may 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 a metered nebulization spray pump.

The compounds of the invention may be formulated for aerosol administration, particularly to the respiratory tract, and include intranasal administration. The compounds typically have small particle sizes, for example about five (5) microns or less. Such particle sizes may be obtained by means known in the art, for example by micronization. The active ingredient is provided in a pressurised container with a suitable propellant, such as a chlorofluorocarbon (CFC), for example dichlorodifluoromethane, trichlorofluoromethane or dichlorotetrafluoroethane, or carbon dioxide or other suitable gas. The aerosol may also conveniently contain a surfactant such as lecithin. The dosage of the medicament may be controlled by a metering valve. Alternatively, the active ingredient may be provided in the form of a dry powder, for example a powder mix of the compound in a suitable powder base such as lactose, starch derivatives such as hydroxypropylmethyl cellulose and polyvinylpyrrolidone (PVP). The powder carrier will form a gel in the nasal cavity. The powder compositions may be presented in unit dosage form, for example in capsules or cartridges of, for example, gelatin, or blister packs, from which the powder may be administered by means of an inhaler.

When desired, the formulations can be prepared with an enteric coating suitable for sustained or controlled release administration of the active ingredient. For example, the compounds of the present invention may be formulated in a transdermal or subcutaneous drug delivery device. These delivery systems are advantageous when sustained release of the compound is desired and when patient compliance with a treatment regimen is important. The compounds in transdermal delivery systems are often attached to a skin-adherent solid support. The compound of interest may also be combined with a penetration enhancer such as lauryl nitrogenA ketone (1-dodecylaza-cycloheptan-2-one) combination. The sustained release delivery system is inserted subcutaneously into the subcutaneous layer by surgery or injection. Subcutaneous implants encapsulate compounds in a lipid soluble membrane such as silicone rubber or a biodegradable polymer such as polylactic acid.

In Remington: suitable formulations are described in The Science and Practice of Pharmacy 1995, edited by e.w. martin, Mack publishing company, 19 th edition, Easton, pa, along with pharmaceutical carriers, diluents and excipients. The skilled formulation scientist is able to modify the formulation within the scope of the present specification to provide a variety of formulations for the specific route of administration without destabilizing the compositions of the present invention or compromising their therapeutic activity.

Modifications of the compounds of the invention to increase their solubility in water or other excipients, for example, can be readily accomplished by minor modifications (salt formation, esterification, etc.), which are within the ordinary skill in the art. It is also within the ordinary skill in the art to modify the route of administration and dosage regimen of a particular compound in order to maximize the beneficial effect of the pharmacokinetics of the compounds of the present invention in the patient.

As used herein, the term "therapeutically effective amount" refers to the amount required to alleviate the symptoms of a disease in an individual. In each particular case, the dosage is adjusted to the individual needs. The dosage may vary within a wide range depending on a number of factors, such as the severity of the disease to be treated, the age and general health of the patient, the other drugs being treated, the route and form of administration, and the preference and experience of the practitioner involved. For oral administration, daily dosages of between about 0.01 and about 1000mg/kg body weight per day should be appropriate in monotherapy and/or in combination therapy. Preferred daily dosages are between about 0.1 and about 500mg/kg body weight per day, more preferably between about 0.1 and about 100mg/kg body weight per day, and most preferably between about 1.0 and about 10mg/kg body weight per day. Thus, for administration to a 70kg human, the dosage range is about 7mg to 0.7 g/day. The daily dose may be administered as a single dose or in divided doses, typically in the range of 1-5 doses per day. In general, treatment is initiated with smaller doses that are less than the optimal dose of the compound. Subsequently, the dose is increased by small increments until the optimum effect is achieved for the individual patient. One of ordinary skill in the art of treating the diseases described herein will be able to determine, without undue experimentation and based on personal knowledge and experience and the disclosure of this application, a therapeutically effective amount of a compound of the present invention for 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 may be a packaged preparation, the package containing discrete quantities of preparation, such as tablets, capsules, and powders in vials or ampoules. In addition, the unit dosage form can be a capsule, tablet, cachet, or lozenge itself, or it can be the appropriate number of any of these in packaged form.

Indications and treatment methods

The novel pyrrolopyrazine derivatives provided herein selectively inhibit JAK3 and are useful in the treatment of autoimmune and inflammatory diseases. The compounds of the present invention modulate the JAK and/or SYK pathway and are useful novel pyrrolopyrazine derivatives for the treatment of autoimmune and inflammatory diseases, with preferred compounds selectively inhibiting JAK 3. For example, the compounds of the invention may inhibit JAK3 and SYK, with preferred compounds being selective for JAK3 of JAK kinases and being useful novel pyrrolopyrazine derivatives for the treatment of autoimmune and inflammatory diseases. The amide linker at the 7-position of the 5H-pyrrolo [2, 3-b ] pyrazines provides a surprising increase in potency of compounds of formulae I and I' in inhibiting JAK and Syk kinase over 5H-pyrrolo [2, 3-b ] pyrazines with an additional moiety at that position. Furthermore, the compounds of the present invention may inhibit JAK3 and JAK2, with preferred compounds being selective for JAK3 of the JAK kinase and being useful novel pyrrolopyrazine derivatives for the treatment of autoimmune and inflammatory diseases. Similarly, the compounds of the invention may inhibit JAK3 and JAK1, with preferred compounds being selective for JAK3 of the JAK kinase and being useful novel pyrrolopyrazine derivatives for the treatment of autoimmune and inflammatory diseases.

The present application provides methods of preventing or treating all forms of organ rejection, including acute and chronic allograft or xenograft rejection, vascular or non-vascular graft rejection, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula I or I'.

The present application provides methods of inhibiting JAK3 activity comprising administering a compound of formula I or I', wherein the compound exhibits an IC of 50 micromolar or less in an in vitro biochemical assay of JAK3 activity₅₀。

The present application provides the above method wherein the compound is shown in an in vitro biochemical assay for JAK3 activity IC of less than 100 nanomolar₅₀。

The present application provides a method of inhibiting SYK activity comprising administering a compound of formula I or I', wherein the compound exhibits an IC of less than 50 micromolar in an in vitro biochemical assay for SYK activity₅₀。

The present application provides the above method, wherein the compound exhibits an IC of 100 nanomolar or less in an in vitro biochemical assay of SYK activity₅₀。

The following examples illustrate the preparation and biological evaluation of compounds within the scope of the present invention. The following examples and preparations are provided for the purpose of enabling those skilled in the art to more clearly understand and practice the present invention. They should not be considered as limiting the scope of the invention, but merely as being exemplary and representative thereof.

Examples

Abbreviations

Common abbreviations include: acetyl (Ac), azo-bis-isobutyronitrile (AIBN), atmospheric pressure (Atm), 9-borabicyclo [3.3.1]Nonane (9-BBN or BBN), tert-butyloxycarbonyl (Boc), di-tert-butylpyrocarbonate or Boc anhydride (BOC)₂O), benzyl (Bn), butyl (Bu), chemical abstracts accession number (CASRN), benzyloxycarbonyl (CBZ or Z), Carbonyldiimidazole (CDI), 1, 4-diazabicyclo [2.2.2]Octane (DABCO), diethylaminosulfur trifluoride (DAST), dibenzylideneacetone (dba), 1, 5-diazabicyclo [4.3.0]Non-5-ene (DBN), 1, 8-diazabicyclo [5.4.0]Undec-7-ene (DBU), N, N ' -Dicyclohexylcarbodiimide (DCC), 1, 2-Dichloroethane (DCE), Dichloromethane (DCM), diethyl azodicarboxylate (DEAD), di-isopropyl azodicarboxylate (DIAD), hydrogenated di-iso-butylaluminum (DIBAL or DIBAL-H), di-iso-propylethylamine (DIPEA), N, N-Dimethylacetamide (DMA), 4-N, N-Dimethylaminopyridine (DMAP), N, N-Dimethylformamide (DMF), dimethyl sulfoxide (DMSO), 1, 1 ' -bis- (diphenylphosphino) ethane (dppe), 1, 1 ' -bis- (diphenylphosphino) ferrocene (dppf), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDCI), ethyl (Et), ethyl acetate (EtOAc), ethanol (EtOH), 2-ethoxy-2H-quinoline-1-carboxylic acid Ethyl Ester (EEDQ), diethyl ether (Et) ₂O), O- (7-azabenzotriazol-1-yl) -N, N, N 'N' -tetramethyluronium hexafluorophosphate acetic acid (HATU), acetic acid (HOAc), 1-N-hydroxybenzotriazole (HOBt), High Pressure Liquid Chromatography (HPLC), Isopropanol (IPA), lithium hexamethyldisilazane (LiHMDS), methanol (MeOH), melting point (MP or MP), MeSO₂- (methanesulfonyl or Ms), methyl (Me), acetonitrile (MeCN), m-chloroperbenzoic acid (MCPBA), mass spectrometry (Ms or MS), methyl t-butyl ether (MTBE), N-bromosuccinimide (NBS), N-carboxy anhydride (NCA), N-chlorosuccinimide (NCS), N-methylmorpholine (NMM), N-methylpyrrolidone (NMP), pyridinium chlorochromate (PCC), Pyridinium Dichromate (PDC), phenyl (Ph), propyl (Pr), iso-propyl (i-Pr), pounds per square inch (psi), pyridine (pyr), room temperature (RT or RT), 2- (trimethylsilyl) ethoxymethyl chloride (SEMCl), t-butyldimethylsilyl or t-BuMe₂Si (TBDMS), triethylamine (TEA or Et)₃N), 2, 2, 6, 6-tetramethylpiperidine 1-oxyl (TEMPO), trifluoromethanesulfonate or CF₃SO₂- (Tf), trifluoroacetic acid (TFA), 1, 1 ' -bis-2, 2, 6, 6-tetramethylheptane-2, 6-dione (TMHD), O-benzotriazol-1-yl-N, N, N ', N ' -tetramethyluronium tetrafluoroborate (TBTU), thin layer chromatography Method (TLC), Tetrahydrofuran (THF), trimethylsilyl or Me₃Si (TMS), p-methanesulfonic acid monohydrate (TsOH or pTsOH), 4-Me-C₆H₄SO₂-or tosyl (Ts), N-urethane-N-carboxy anhydride (UNCA). Common Nomenclature includes the prefixes positive (n), iso (i-), secondary (sec-), tertiary (tert-), and new have their usual meaning when used with alkyl moieties (j.rigaudy and d.p.klesney, Nomenclature in Organic Chemistry, IUPAC1979 Pergamon Press, Oxford.).

Example 1.

2-cyclopropyl-5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid [ (R) -1- (1-hydroxy-cyclopentyl) -ethyl ] -amide

Step 1

To a solution of Boc-D-alanine methyl ester (2.03g, 10.0mmol) in THF (20mL) at 0 deg.C was slowly added allylmagnesium bromide (1.0M Et₂O solution, 35mL, 35.0 mmol). The resulting white slurry was stirred at 0 ℃ for 1h, then at room temperature for 2 h. The reaction mixture was cooled to 0 ℃ with saturated NH₄Aqueous Cl solution was quenched and then with H₂Diluted with O and extracted with EtOAc. By H₂The combined organic layers were washed with MgSO₄Dried and concentrated to give a viscous colorless oil. The oil was dissolved in CH₂Cl₂(200mL) and a second generation Grubbs catalyst (0.17g, 0.2mmol) was added. The purplish red reaction was mixed and heated at reflux overnight. A further amount of catalyst (0.085g, 0.1mmol) was added and heating continued for 6 h. Concentrating the reaction mixture through SiO ₂Chromatography (10% -40% EtOAc/hexanes) afforded 1.46g (64%) of [ (R) -1- (1-hydroxycyclopent-3-enyl) -ethyl]Tert-butyl carbamate as a light brown oil.

Step 2

To [ (R) -1- (1-hydroxy ring)Pent-3-enyl) -ethyl]To a solution of tert-butyl carbamate (0.62g, 2.7mmol) in MeOH (20mL) was added 10% Pd on carbon (65 mg). The reaction mixture is reacted in H₂The mixture was stirred overnight under an atmosphere (1atm), then filtered through celite, rinsing with EtOAc. Concentrating the filtrate through SiO₂Chromatography (10% -25% EtOAc/hexanes) afforded 336mg of [ (R) -1- (1-hydroxycyclopentyl) -ethyl]-tert-butyl carbamate as colorless oil.

Step 3

The above oil was dissolved in 1.0M HCl in MeOH (10mL) and stirred at room temperature overnight. The reaction mixture is concentrated to give 218mg (50%) of 1- ((R) -1-amino-ethyl) -cyclopentanol hydrochloride as a hygroscopic white solid.

Step 4

In a flask, combine 2-cyclopropyl-5- (2-trimethylsilyl-ethoxymethyl) -5H-pyrrolo [2, 3-b]Pyrazine-7-carboxylic acid (120mg, 0.36mmol), 1- ((R) -1-amino-ethyl) -cyclopentanol hydrochloride (70mg, 0.43mmol), EDC (77mg, 0.40mmol) and HOBt (54mg, 0.40 mmol). DMF (2mL) was then added followed by i-Pr ₂NEt (0.16mL, 0.90 mmol). The reaction mixture was stirred at room temperature for 4H, then H₂O quenched and extracted with EtOAc (3 ×). By H₂The combined organic layers were washed with O (3X) and then MgSO₄Drying and concentration gave 153mg (96%) of 2-cyclopropyl-5- (2-trimethylsilylethoxymethyl) -5H-pyrrolo [2, 3-b ]]Pyrazine-7-carboxylic acid [ (R) -1- (1-hydroxy-cyclopentyl) -ethyl]Amides, as light yellow foams.

Step 5

To 2-cyclopropyl-5- (2-trimethylsilylethoxymethyl) -5H-pyrrolo [2, 3-b ]]Pyrazine-7-carboxylic acid [ (R) -1- (1-hydroxy-cyclopentyl) -ethyl]Amide (153mg, 0.34mmol) in CH₂Cl₂To the solution in (3mL) was added TFA (1 mL). The reaction mixture was stirred for 3h and then concentrated. The residue was dissolved in CH₂Cl₂(5mL), ethylenediamine (1mL) was added. The reaction mixture was stirred for 1h, then concentrated. The residue is taken up with 10% MeOH/EtOAc co-triturates. The resulting white solid was collected by filtration to give 73mg (68%) of 2-cyclopropyl-5H-pyrrolo [2, 3-b ]]Pyrazine-7-carboxylic acid [ (R) -1- (1-hydroxy-cyclopentyl) -ethyl]-an amide. MS: (M + H)⁺＝315；mp＝287.0-290.0。

Example 2.

2-cyclopropyl-5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid [ (S) -1- (1-hydroxy-cyclopentyl) -ethyl ] -amide

Prepared according to the procedure outlined in example 1, substituting Boc-L-alanine methyl ester for Boc-D-alanine methyl ester in step 1. MS: (M + H) ⁺＝315；mp 292.0-294.0。

Example 3.

2-cyclopropyl-5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ((S) -1, 2, 2-trimethylpropyl) -amide

Prepared according to the procedure outlined in example 1, steps 4-5, substituting (S) -1, 2, 2-trimethylpropylamine for 1- ((R) -1-amino-ethyl) -cyclopentanol hydrochloride. MS: (M + H)⁺＝287；mp＞300。

Example 4.

2-cyclopropyl-5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ((S) -3, 3, 3-trifluoro-1, 2, 2-trimethyl-propyl) -amide

Step 1

To a solution of 3, 3, 3-trifluoro-2, 2-dimethylpropionic acid (2.5g, 16.0mmol) in dichloromethane (35mL) was added N, O-dimethylhydroxylamine hydrochloride (2.34g, 24mmol), N-methylmorpholine (4.9mL, 45mmol) and 1-hydroxybenzotriazole hydrate (2.45g, 16 mmol). The mixture was stirred vigorously for 5 minutes, then 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (5.22g, 27.2mmol) was added in one portion. The mixture was stirred for 72 hours. The crude product was dissolved in 4% aqueous HCl (150mL) and methylene chloride (150mL) and transferred to a separatory funnel. The dichloromethane phase was collected and washed successively with equal volumes of 5% aqueous sodium bicarbonate solution followed by brine solution. The aqueous phase was back-extracted with dichloromethane (2X80 mL). The organic phases were combined, dried (magnesium sulfate), filtered and carefully reduced in volume using a rotary evaporator. The crude product remaining in dichloromethane (20mL) was filtered through a short pad of silica gel, and the solvent was carefully removed in partial vacuum to give the desired pale yellow oil (2.25g) which was used directly in the next step.

Step 2

To a cold (ice bath, 0 ℃) solution of 3, 3, 3-trifluoro-N-methoxy-2, 2, N-trimethyl-propionamide (1.25g, 6.3mmol) in tetrahydrofuran (10mL) was added a solution of 3M methylmagnesium bromide (4.2mL, 12.6mmol) in diethyl ether slowly dropwise under an argon atmosphere (balloon). The material was stirred at ambient temperature overnight and then quenched by the addition of saturated ammonium chloride solution (15 mL). Water (20mL) and ether (25mL) were added and the material shaken in a separatory funnel. The ether phase was collected and washed with brine (25 mL). The aqueous phase was back-extracted with diethyl ether (2X25 mL). The combined organic phases were dried over magnesium sulfate and filtered. The solvent was removed by careful distillation. The remaining material was dissolved in dry dichloromethane (20mL) and the solvent was distilled off (repeated more than once). A clear, flowing oil (presumably 6mmol) was obtained, which was dried over molecular sieves and used directly in the next step.

Step 3

To a mixture of titanium (IV) ethoxide (1.06mL, 5.1mmol) and (R) - (+) -2-methyl-2-propanesulfinamide (303mg, 2.5mmol) in dry tetrahydrofuran (5mL) was added 4, 4, 4-trifluoro-3, 3-dimethyl-butan-2-one (1/2, material from step 2, presumably 3mmol) under an argon atmosphere. The mass was heated to 75 ℃ for 18 h. The mixture was cooled to-45 ℃ and lithium tri-sec-butylborohydride (1M in THF, 8mL, 8mmol) was added dropwise. After 5 minutes at-45 ℃, the cooling bath was removed and the mass was stirred for 3 hours. The mixture was cooled in an ice bath, methanol was added and added dropwise until bubbling ceased. The material was stirred vigorously and brine (10mL) was added to give a solid suspension. The material was filtered through a pad of celite, washing well with ethyl acetate. The filtrate was collected and washed with an equal volume of brine. The aqueous phase was back-extracted with ethyl acetate (2X30 mL). The organic phases were combined, dried over magnesium sulfate, filtered and evaporated. The remaining material was purified by column flash silica gel (30g) chromatography, eluting with 25-75% ethyl acetate/hexanes to give 2-methyl-propane-2-sulfinic acid ((S) -3, 3, 3-trifluoro-1, 2, 2-trimethyl-propyl) -amide as a white crystalline solid (70 mg).

Step 4

2-methyl-propane-2-sulfinic acid ((S) -3, 3, 3-trifluoro-1, 2, 2-trimethyl-propyl) -amide (70mg, 0.27mmol) was dissolved in 30% ethanol hydrochloride solution (1mL) and the capped solution was stirred for 2 hours. The volatiles were evaporated and the remaining material was dissolved in dichloromethane (15 mL). The solvent was again evaporated and the material was placed under high vacuum for 30 minutes to give (S) -3, 3, 3-trifluoro-1, 2, 2-trimethylpropylamine hydrochloride, which was used without further purification.

Step 5

2-cyclopropyl-5H-pyrrolo [2, 3-b ]]Pyrazine-7-carboxylic acid ((S) -3, 3, 3-trifluoro-1, 2, 2-trimethyl-propyl) -amide. Prepared according to the procedure outlined in example 1, steps 4-5, substituting (S) -3, 3, 3-trifluoro-1, 2, 2-trimethylpropylamine hydrochloride for 1- ((R) -1-amino-ethyl) -cyclopentanol hydrochloride. MS: (M + H)⁺＝341；mp＞300。

Example 5.

2-cyclopropyl-5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid (2-hydroxy-1, 1, 2-trimethyl-propyl) -amide

Step 1

N-Boc-aminoisobutyric acid (1.20g, 5.90mmol) was dissolved in dichloromethane (22mL) and MeOH (11mL) in a round bottom flask. (trimethylsilyl) diazomethane (2.0M in hexane, 5.0mL, 10.0mmol) was added dropwise and the reaction mixture was stirred at room temperature for 2.5 h. The reaction mixture was quenched with a small portion of acetic acid and concentrated under reduced pressure. The residue was dissolved in dichloromethane and saturated Na ₂CO₃And (4) washing with an aqueous solution. The aqueous layer was extracted with dichloromethane and Na₂SO₄The combined organic layers were dried and concentrated to give 1.3g (99%) of methyl N-Boc-aminoisobutyrate as a yellow-white solid.

Step 2

To a solution of N-Boc-aminoisobutyric acid methyl ester (0.60g, 2.76mmol) in THF (20mL) was slowly added methylmagnesium bromide (3.0M in ether, 3.6mL, 10.8mmol) at 0 ℃. The reaction mixture was stirred at 0 ℃ for 1h, then at room temperature for 5 h. The reaction was cooled back to 0 ℃ with saturated NH₄Aqueous Cl was quenched and then extracted with EtOAc (2 ×). The combined organic layers were washed with water and brine, then Na₂SO₄Drying and concentrating. Passing 24g SiO₂The residue was purified by chromatography, eluting with 0% to 20% EtOAc/hexanes, to give 0.41g (68%) of (2-hydroxy-1, 1, 2-trimethyl-propyl) -carbamic acid tert-butyl ester as a white solid.

Step 3

In a round bottom flask, (2-hydroxy-1, 1, 2-trimethyl-propyl) -carbamic acid tert-butyl ester (100mg, 0.46mmol) is dissolved in 1.0M HCl in MeOH (3.0mL, 3.0 mmol). The reaction mixture was stirred at 50 ℃ for 4h, then cooled to room temperature and concentrated to give 70mg (99%) of 3-amino-2, 3-dimethyl-butan-2-ol hydrochloride as an off-white solid.

Step 4

2-cyclopropyl-5H-pyrrolo [2, 3-b ]]Pyrazine-7-carboxylic acid (2-hydroxy-1, 1, 2-trimethyl-propyl) -amide. Prepared according to the procedure outlined in example 1, steps 4-5, substituting 3-amino-2, 3-dimethyl-but-2-ol hydrochloride for 1- ((R) -1-amino-ethyl) -cyclopentanol hydrochloride. MS: (M + H)⁺＝303；mp＝270.0-273.0。

Example 6.

2-cyclopropyl-5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ((S) -2-cyano-1, 2, 2-trimethyl-ethyl) -amide

Step 1

In a flask, 2-methyl-propane-2-sulfinic acid amide (2.00g, 16.5mmol) was dissolved in CH₂Cl₂(7.0 mL). Acetaldehyde (6.70mL, 119mmol) and MgSO was added₄(4.79g, 39.8mmol) and pyridinium tosylate (100mg, 0.398 mmol). The reaction mixture was stirred at room temperature overnight, filtered and concentrated to give 2.48g of 2-methyl-propane-2-sulfinic acid (E) -ethylideneamide as a brown oil which was used without further purification.

Step 2

In a flask, isobutyronitrile (0.91mL, 10.2mmol) was dissolved in THF (20mL) and cooled at-78 ℃. LiHMDS (1.0M in THF, 11.2mL, 11.2mmol) was added and the mixture was stirred at-78 ℃ for 30 min. A solution of 2-methyl-propane-2-sulfinic acid (E) -ethylene amide (1.00g, 6.8mmol) in THF (5.0mL) was added slowly. The mixture was stirred at-78 ℃ for 2h, 0 ℃ for 2h and then warmed to room temperature overnight. The reaction mixture was quenched with saturated aqueous ammonium chloride and extracted with EtOAc. The combined organic layers were washed with brine, MgSO ₄Drying and concentrating. By SiO₂The residue was purified by chromatography (20-100% EtOAc/hexanes) to give 714mg (49%) of 2-methyl-prop-2-sulfinic acid (2-cyano-1, 2, 2-trimethyl-ethyl) -amide as a yellow viscous oil.

Step 3

2-methyl-propane-2-sulfinic acid (2-cyano-1, 2, 2-trimethyl-ethyl) -amide (714mg, 3.30mmol) was dissolved in 0.70M HCl (10.0mL) and stirred at room temperature for 2 h. Concentration gave 525mg of 3-amino-2, 2-dimethyl-butyronitrile hydrochloride as a light brown solid, which was used without further purification.

Step 4

In a flask, combine 2-cyclopropyl-5- (2-trimethylsilylethoxymethyl) -5H-pyrrolo [2, 3-b ]]Pyrazine-7-carboxylic acid (200mg, 0.60mmol), 3-amino-2, 2-methyl-butyronitrile hydrochloride (223mg, 1.50mmol), EDC (264mg, 1.38mmol) and HOBt (186mg, 1.38 mmol). DMF (4.0mL) was added followed by i-Pr₂NEt (0.33mL, 1.92 mmol). The reaction mixture was stirred at room temperature for 1h, then concentrated. By SiO₂The residue was purified by chromatography (20-100% EtOAc/hexanes) and the enantiomers were separated by preparative chiral HPLC (Chiralcel OJ-H, hexanes/EtOH) to give 63mg (24%) of 2-cyclopropyl-5- (2-trimethylsilyl-ethoxymethyl) -5H-pyrrolo [2, 3-b% ]Pyrazine-7-carboxylic acid ((S) -2-cyano-1, 2, 2-trimethyl-ethyl) -amide as a colorless viscous oil; and 67mg (26%) of 2-cyclopropyl-5- (2-trimethylsilyl-ethoxymethyl) -5H-pyrrolo [2, 3-b]Pyrazine-7-carboxylic acid ((R) -2-cyano-1, 2, 2-trimethyl-ethyl) -amide as a colorless viscous oil.

Step 5

In a flask, 2-cyclopropyl-5- (2-trimethylsilyl-ethoxymethyl) -5H-pyrrolo [2, 3-b ] was placed]Pyrazine-7-carboxylic acid ((S) -2-cyano-1, 2, 2-trimethyl-ethyl) -amide (63mg, 0.146mmol) was dissolved in CH₂Cl₂(1.5mL) and TFA (0.50mL) was added. The reaction mixture was stirred for 2h and concentrated. The residue was dissolved in CH₂Cl₂(2.5mL) followed by ethylenediamine (0.50mL, 7)48mmol) the mixture was stirred at room temperature overnight. The reaction mixture is then concentrated through SiO₂The residue was purified by chromatography (20-100%% EtOAc/hexanes) to give 32.5mg (75%) of 2-cyclopropyl-5H-pyrrolo [2, 3-b ]]Pyrazine-7-carboxylic acid ((S) -2-cyano-1, 2, 2-trimethyl-ethyl) -amide as a white powder. MS: (M + H)⁺＝298。

Example 7.

2-cyclopropyl-5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ((R) -2-cyano-1, 2, 2-trimethyl-ethyl) -amide

Prepared according to the method outlined in example 6, step 5, using 2-cyclopropyl-5- (2-trimethylsilyl-ethoxymethyl) -5H-pyrrolo [2, 3-b ] ]Pyrazine-7-carboxylic acid ((R) -2-cyano-1, 2, 2-trimethyl-ethyl) -amide substituted 2-cyclopropyl-5- (2-trimethylsilyl-ethoxymethyl) -5H-pyrrolo [2, 3-b)]Pyrazine-7-carboxylic acid ((S) -2-cyano-1, 2, 2-trimethyl-ethyl) -amide. MS: (M + H)⁺＝298。

Example 8.

2-cyclopropyl-5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid [ (S) -1- (1-cyano-cyclopentyl) -ethyl ] -amide and 2-cyclopropyl-5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid [ (R) -1- (1-cyano-cyclopentyl) -ethyl ] -amide

Prepared according to the procedure outlined in example 6 substituting isobutyronitrile with cyclopentanenitrile. The enantiomers were separated by preparative chiral HPLC in step 4. (S) -enantiomer MS: (M + H)⁺324; mp 220.0-223.0. (R) -enantiomer MS: (M + H)⁺＝324；mp 220.0-223.0。

Example 9.

2-cyclopropyl-5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid [ (S) -1- (1-cyano-cyclohexyl) -ethyl ] -amide and 2-cyclopropyl-5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid [ (R) -1- (1-cyano-cyclohexyl) -ethyl ] -amide

Prepared according to the procedure outlined in example 6 substituting isobutyronitrile with cyclohexanenitrile. The enantiomers were separated by preparative chiral HPLC in step 4. (S) -enantiomer MS: (M + H)⁺338. (R) -enantiomer MS: (M + H)⁺＝338。

Example 10.

2-cyclopropyl-5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid [1- (tetrahydro-pyran-4-yl) -ethyl ] -amide

Step 1

Tetrahydropyran-4-carbaldehyde (5.00g, 43.8mmol) in Et at 0 deg.C₂To a solution of methylmagnesium bromide (3.0M Et) in O (100mL) was added dropwise₂O solution, 18.9mL, 56.9 mmol). The reaction mixture was warmed to room temperature and stirred overnight. With 50% saturated NH₄The mixture was quenched with Cl and extracted with EtOAc. The organic extract was washed with saturated aqueous NaCl solution and MgSO₄Drying and evaporation gave 4.34g of 1- (tetrahydropyran-4-yl) -ethanol as a colorless oil.

Step 2

The oil from step 1 was dissolved in CH₂Cl₂(50mL) Triethylamine (9.8mL, 70mmol) was added. The mixture was cooled to 0 ℃ and methanesulfonyl chloride was added dropwise(4.07mL, 52.6mmol) of CH₂Cl₂(25 mL). The reaction mixture was warmed to room temperature and stirred overnight. By H₂Quenching the mixture with O and CH₂Cl₂The aqueous layer was extracted. With 1M HCl, 50% saturated NaHCO₃And saturated NaCl and then with MgSO 2₄Drying and evaporation gave 6.38g (70%) of 1- (tetrahydro-pyran-4-yl) -ethyl methanesulfonate as a colorless oil.

Step 3

To a solution of methanesulfonic acid 1- (tetrahydro-pyran-4-yl) -ethyl ester (1.0g, 4.80mmol) in DMF (10.0mL) was added sodium azide (624mg, 9.60mmol) and the mixture was stirred at 70 ℃ overnight. The reaction mixture was cooled to room temperature and H was added ₂And O. The aqueous layer was extracted with EtOAc, then the combined organic layers were washed with saturated LiCl, saturated NaCl, MgSO₄Drying and evaporation gave 0.77g of 4- (1-azido-ethyl) -tetrahydro-pyran as a light yellow oil.

Step 4

The oil from step 3 was dissolved in MeOH (10mL) and 10% Pd/carbon (40mg) was added. The mixture is reacted with hydrogen₂(1atm) stirring for 1.5h, then filtering and evaporating, gives 412mg (66%) of 1- (tetrahydropyran-4-yl) -ethylamine as a pale yellow oil.

Step 5

2-cyclopropyl-5H-pyrrolo [2, 3-b ]]Pyrazine-7-carboxylic acid [1- (tetrahydro-pyran-4-yl) -ethyl]-an amide. Prepared according to the procedure outlined in step 4 of example 1 from 2-cyclopropyl-5H-pyrrolo [2, 3-b ]]Pyrazine-7-carboxylic acid substituted 2-cyclopropyl-5- (2-trimethylsilyl-ethoxymethyl) -5H-pyrrolo [2, 3-b]Pyrazine-7-carboxylic acid and 1- ((R) -1-amino-ethyl) -cyclopentanol hydrochloride was substituted with 1- (tetrahydropyran-4-yl) -ethylamine. MS: (M + H)⁺＝315；mp 260.0-262.0。

Example 11.

2-bromo-5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid (3-hydroxy-2, 2-dimethyl-propyl) -amide

Step 1

2-bromo-5- (2-trimethylsilyl-ethoxymethyl) -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid (2.0g, 5.39mmol) was suspended in 36mL acetonitrile. N, N-diisopropylethylamine (2.8mL, 16.2mmol), O-benzotriazol-1-yl-N, N, N ', N' -tetramethyluronium tetrafluoroborate (1.9g, 5.93mmol) and 3-amino-2, 2-dimethyl-propan-1-ol (0.56g, 5.39mmol) were added and the reaction mixture was stirred for 1.5 h. Water and ethyl acetate were added and the layers were separated. The aqueous layer was extracted once more with ethyl acetate, the combined organic layers were washed with sodium chloride solution, dried over sodium sulfate and concentrated. The residue was purified by silica gel chromatography (EtOAc/hexanes) to give 2.0g (81%) of 2-bromo-5- (2-trimethylsilyl-ethoxymethyl) -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid (3-hydroxy-2, 2-dimethyl-propyl) -amide.

Step 2

2-bromo-5H-pyrrolo [2, 3-b ] was prepared according to the procedure outlined in example 1, step 5]Pyrazine-7-carboxylic acid (3-hydroxy-2, 2-dimethyl-propyl) -amide with 2-bromo-5- (2-trimethylsilyl-ethoxymethyl) -5H-pyrrolo [2, 3-b ]]Pyrazine-7-carboxylic acid (3-hydroxy-2, 2-dimethyl-propyl) -amide substituted 2-cyclopropyl-5- (2-trimethylsilylethoxymethyl) -5H-pyrrolo [2, 3-b ] -amide]Pyrazine-7-carboxylic acid [ (R) -1- (1-hydroxy-cyclopentyl) -ethyl]-an amide. MS: (M + H)⁺＝328；mp＝248.0-250.0。

Example 12

2-cyclopropyl-5H-pyrrolo [2, 3b ] pyrazine-7-carboxylic acid (3-methanesulfonyl-2, 2-dimethyl-propyl) -amide

Step 1

Step 2

Reacting 2-bromo-5- (2-trimethylsilyl-ethoxymethyl) -5H-pyrrolo [2, 3-b]Pyrazine-7-carboxylic acid (3-hydroxy-2, 2-dimethyl-propyl) -amide (0.47g, 1.02mmol) was dissolved in 4.9ml toluene and 0.25ml water. The solution was purged with argon and palladium acetate (12mg, 0.05mmol), tricyclohexylphosphine (29mg, 0.102mmol), cyclopropylboronic acid (0.114g, 1.33mmol) and tripotassium phosphate (0.76g, 3.57mmol) were added. The reaction was stirred at 100 ℃ for 16h and then cooled to room temperature. Aqueous sodium bicarbonate and ethyl acetate were added and the layers were separated. The aqueous layer was extracted with ethyl acetate and the combined organic layers were washed with sodium chloride solution, dried over sodium sulfate and evaporated. The residue was purified by chromatography on silica gel (MeOH/CH)₂Cl₂) To yield 0.34g (79%) of 2-cyclopropyl-5- (2-trimethylsilyl-ethoxymethyl) -5H-pyrrolo [2, 3-b]Pyrazine-7-carboxylic acid (3-hydroxy-2, 2-dimethyl-propyl) -amide.

Step 3

2-cyclopropyl-5- (2-trimethylsilyl-ethoxymethyl) -5H-pyrrolo [2, 3-b]Pyrazine-7-carboxylic acid (3-hydroxy-2, 2-dimethyl-propyl) -amide (0.34g,0.81mmol) was dissolved in 4ml of CH₂Cl₂And cooling with ice bath. N, N-diisopropylethylamine (0.21mL, 1.2mmol) was added, followed by slow addition of methanesulfonyl chloride (0.076mL, 0.97 mmol). The reaction mixture was warmed to room temperature over 16 h. Ethyl acetate and aqueous hydrochloric acid were added and the layers were separated. The aqueous layer was extracted with ethyl acetate and the combined organic layers were washed with sodium bicarbonate solution, dried over sodium sulfate and evaporated to give 0.38g of 3- { [ 2-cyclopropyl-5- (2-trimethylsilyl-ethoxymethyl) -5H-pyrrolo [2, 3-b ] methanesulfonic acid ]Pyrazine-7-carbonyl]-amino } -2, 2-dimethyl-propyl ester.

Step 4

Methanesulfonic acid 3- { [ 2-cyclopropyl-5- (2-trimethylsilyl-ethoxymethyl) -5H-pyrrolo [2, 3-b ] pyrazine-7-carbonyl ] -amino } -2, 2-dimethyl-propyl ester (0.28g, 0.56mmol) was dissolved in 8ml DMF. Sodium thiomethoxide (157mg, 2.24mmol) was added, the reaction vessel sealed and stirred in a microwave reactor at 100 ℃ for 30 min. Aqueous sodium bicarbonate and dichloromethane were added and the layers were separated. The aqueous layer was extracted with dichloromethane (2 ×), the combined organic layers were washed with water and sodium chloride solution, then dried over sodium sulfate and evaporated. The residue was purified by silica gel chromatography (ethyl acetate/hexane) to give 94mg (37%) of 2-cyclopropyl-5- (2-trimethylsilyl-ethoxymethyl) -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid (2, 2-dimethyl-3-methylsulfanyl-propyl) -amide.

Step 5

2-cyclopropyl-5- (2-trimethylsilyl-ethoxymethyl) -5H-pyrrolo [2, 3-b]Pyrazine-7-carboxylic acid (2, 2-dimethyl-3-methylsulfanyl-propyl) -amide (102mg, 0.226mmol) was dissolved in 0.9ml THF. Potassium hydrogen persulfate (0.418g, 0.682mmol) was slowly added dissolved in 0.9ml H₂O solution, the mixture was stirred at rt for 16 h. Ethyl acetate and water were added to the reaction system. The layers were separated and the aqueous layer was extracted with ethyl acetate (3 ×). The combined organic layers were washed with sodium chloride solution, dried over sodium sulfate and evaporated. The residue was purified by silica gel chromatography (ethyl acetate/hexane) to give 80mg (73%) of 2-cyclopropyl-5- (2-trimethylsilyl-ethoxy) Methyl) -5H-pyrrolo [2, 3-b]Pyrazine-7-carboxylic acid (3-methanesulfonyl-2, 2-dimethyl-propyl) -amide.

Step 6

2-cyclopropyl-5H-pyrrolo [2, 3b ]]Pyrazine-7-carboxylic acid (3-methanesulfonyl-2, 2-dimethyl-propyl) -amide. Prepared according to the method outlined in example 1, step 5, using 2-cyclopropyl-5- (2-trimethylsilyl-ethoxymethyl) -5H-pyrrolo [2, 3-b ]]Pyrazine-7-carboxylic acid (3-methanesulfonyl-2, 2-dimethyl-propyl) -amide substituted 2-cyclopropyl-5- (2-trimethylsilylethoxymethyl) -5H-pyrrolo [2, 3-b [ -E]Pyrazine-7-carboxylic acid [ (R) -1- (1-hydroxy-cyclopentyl) -ethyl]-an amide. MS: (M + H)⁺351，mp＝206.0-208.0。

Example 13.

2- (3, 3-dimethyl-pyrrolidin-1-yl) -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid (3-hydroxy-2, 2-dimethyl-propyl) -amide

Step 1

Reacting 2-bromo-5- (2-trimethylsilyl-ethoxymethyl) -5H-pyrrolo [2, 3-b]Pyrazine-7-carboxylic acid (3-hydroxy-2, 2-dimethyl-propyl) -amide (0.15g, 0.33mmol) was dissolved in 3.3ml of dimethyl sulfoxide and purged with argon. Potassium carbonate (0.113g, 0.82mmol), 3-dimethylpyrrolidine (0.16g, 1.64mmol), DL-proline (11mg, 0.098mmol) and then copper (I) iodide (9mg, 0.049mmol) were added. The reaction was sealed and stirred in a 100 ℃ oil bath for 16 h. The reaction was cooled and water and ethyl acetate were added. The layers were separated and the organic layer was extracted more than once with ethyl acetate. The combined organic layers were then washed with water and saturated sodium chloride solution, dried over sodium sulfate and evaporated. The resulting residue was purified by silica gel chromatography (methanol/dichloromethane) to yield 130mg (83%) of 2- (3, 3-dimethyl-pyrrolidin-1-yl) -5- (2-trimethylsilyl-ethoxymethyl) -5H-pyrrolo [2，3-b]Pyrazine-7-carboxylic acid (3-hydroxy-2, 2-dimethyl-propyl) -amide. (M + H)⁺＝476。

Step 2

Reacting 2- (3, 3-dimethyl-pyrrolidin-1-yl) -5- (2-trimethylsilyl-ethoxymethyl) -5H-pyrrolo [2, 3-b]Pyrazine-7-carboxylic acid (3-hydroxy-2, 2-dimethyl-propyl) -amide (0.13g, 0.27mmol) was dissolved in 1.3ml methanol. Then 1.7ml of 6M aqueous HCl was slowly added and the reaction was stirred in a hot block for 30min at 90 ℃. The reaction was cooled, sodium bicarbonate solution was added, and then extracted twice with ethyl acetate. The combined organic layers were washed with sodium chloride solution, dried over sodium sulfate and concentrated. The resulting residue was redissolved in 10ml ethanol and sodium acetate (0.73g, 5.4mmol) was added. The reaction was stirred at 60 ℃ for 16 h. After cooling, water was added and the solution was extracted 3 times with ethyl acetate. The combined organic layers were washed with sodium chloride solution, dried over sodium sulfate and evaporated. The residue was purified by silica gel chromatography (methanol/dichloromethane) to give 51mg (54%) of 2- (3, 3-dimethyl-pyrrolidin-1-yl) -5H-pyrrolo [2, 3-b ]]Pyrazine-7-carboxylic acid (3-hydroxy-2, 2-dimethyl-propyl) -amide. MS: (M + H)⁺346; mp is 223.0-225.0; elemental analysis: calcd for C69.59, H7.88, N20.27, found C69.22, H7.70, N20.07.

Example 14.

2-dimethylamino-5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid (3-hydroxy-2, 2-dimethyl-propyl) -amide

Prepared according to the procedure outlined in example 13 substituting dimethylamine hydrochloride for 3, 3-dimethylpyrrolidine. MS: (M + H)⁺＝292；mp＝222.0-224.0。

Example 15.

2-pyrrolidin-1-yl-5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid (3-hydroxy-2, 2-dimethyl-propyl) -amide

Prepared according to the procedure outlined in example 13 substituting pyrrolidine for 3, 3-dimethylpyrrolidine. MS: (M + H)⁺＝318；mp＝220.0-222.0。

Example 16.

2-phenylamino-5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid (3-hydroxy-2, 2-dimethyl-propyl) -amide

Prepared according to the procedure outlined in example 13 substituting aniline for 3, 3-dimethylpyrrolidine. MS: (M + H)⁺＝340；mp＝280.0-282.0。

Example 17.

2- (methylcarbamoylmethyl-amino) -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid (3-hydroxy-2, 2-dimethyl-propyl) -amide

Step 1

2- (methylcarbamoylmethyl-amino) -5- (2-trimethylsilyl-ethoxymethyl) -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid (3-hydroxy-2, 2-dimethyl-propyl) -amide was prepared according to the procedure outlined in example 13, step 1. 3, 3-dimethylpyrrolidine was substituted with 2-amino-N-methylacetamide.

Step 2

Reacting 2- (methylcarbamoylmethyl-amino) -5- (2-trimethylsilyl-ethoxymethyl) -5H-pyrrolo [2, 3-b]Pyrazine-7-carboxylic acid (3-hydroxy-2, 2-dimethyl-propyl) -amide (90mg, 0.193mmol) was dissolved in 2ml of a 1M solution of tetrabutylammonium fluoride in THF. The solution was stirred at 60 ℃ for 24 h. After cooling the reaction, sodium bicarbonate solution was added and the reaction was extracted 3 times with ethyl acetate. The combined organic layers were washed with sodium chloride solution, dried over sodium sulfate and concentrated. The residue was purified by silica gel chromatography (ammonia/methanol/dichloromethane) to give 15mg (21%) of 2- (methylcarbamoylmethyl-amino) -5H-pyrrolo [2, 3-b ]]Pyrazine-7-carboxylic acid (3-hydroxy-2, 2-dimethyl-propyl) -amide. MS: (M + H)⁺＝335；mp＝270.0-275.0。

Example 18.

2-trifluoromethyl-5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid (3-hydroxy-2, 2-dimethyl-propyl) -amide

Step 1

2-bromo-5- (2-trimethylsilyl-ethoxymethyl) -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid (3-hydroxy-2, 2-dimethyl-propyl) -amide (0.5g, 1.08mmol) was dissolved in 5ml dichloromethane. N, N-diisopropylethylamine (1.5ml, 8.7mmol) was added and the reaction cooled with an ice bath. 2-Trimethylsilylethoxymethyl chloride (0.39ml, 2.18mmol) was added slowly and the reaction stirred at room temperature for 16 h. Dilute aqueous HCl and ethyl acetate were added. The layers were separated and the aqueous layer was extracted more than once with ethyl acetate. The combined organic layers were washed with sodium chloride solution and dried over sodium sulfate. After evaporation, the residue was purified by silica gel chromatography (ethyl acetate/hexane) to give 0.6g (93%) of 2-bromo-5- (2-trimethylsilyl-ethoxymethyl) -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid [2, 2-dimethyl-3- (2-trimethylsilyl-ethoxymethoxy) -propyl ] -amide.

Step 2

Reacting 2-bromo-5- (2-trimethylsilyl-ethoxymethyl) -5H-pyrrolo [2, 3-b]Pyrazine-7-carboxylic acid [2, 2-dimethyl-3- (2-trimethylsilyl-ethoxymethoxy) -propyl]The amide (0.18g, 0.306mmol) was dissolved in 0.6ml of N, N-dimethylacetamide. The solution was purged with argon and then cooled with an ice bath. Copper (116mg, 1.83mmol) and dibromodifluoromethane (0.113ml, 1.22mmol) were added, the reaction vessel sealed and stirred at 100 ℃ for 16 h. After cooling, sodium bicarbonate solution and ethyl acetate were added to the reaction. The layers were separated and the aqueous layer was extracted more than once with ethyl acetate. The combined organic layers were washed with sodium chloride solution and dried over sodium sulfate. After concentration, the residue was purified by silica gel chromatography (ethyl acetate/hexane) to give 41mg (23%) of 2-trifluoromethyl-5- (2-trimethylsilyl-ethoxymethyl) -5H-pyrrolo [2, 3-b ]]Pyrazine-7-carboxylic acid [2, 2-dimethyl-3- (2-trimethylsilyl-ethoxymethoxy) -propyl]-an amide. (M + H)⁺＝577。

Step 3

Reacting 2-trifluoromethyl-5- (2-trimethylsilyl-ethoxymethyl) -5H-pyrrolo [2, 3-b]Pyrazine-7-carboxylic acid [2, 2-dimethyl-3- (2-trimethylsilyl-ethoxymethoxy) -propyl ]Amide (41mg, 0.071mmol) was dissolved in 0.4ml methanol. Then 0.5ml of 6M aqueous HCl was slowly added and the reaction was stirred in a hot block for 45min at 90 ℃. The reaction was cooled, sodium bicarbonate solution was added, and then extracted 2 times with ethyl acetate. The combined organic layers were washed with sodium chloride solution, dried over sodium sulfate and concentrated. The residue was purified by silica gel chromatography (methanol/dichloromethane) to give 15.7mg (70%) of 2-trifluoromethyl-5H-pyrrolo [2, 3-b ]]Pyrazine-7-carboxylic acid (3-hydroxy-2, 2-dimethyl-propyl) -amide. MS: (M + H)⁺＝317；mp＝221.0-223.0。

Example 19.

2-cyclopropyl-5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid (2-methoxy-2-methyl-propyl) -amide

Prepared according to the procedure outlined in example 12, steps 1-2 and 6, substituting 3-amino-2, 2-dimethyl-propan-1-ol with 2-methoxy-2-methylpropylamine in step 1. MS: (M + H)⁺＝289；mp＝259.0-262.0。

Example 20.

2-cyclopropyl-5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid (3-methoxy-2, 2-dimethyl-propyl) -amide

Prepared according to the procedure outlined in example 1, steps 4-5, substituting 2, 2-dimethyl-3-methoxypropylamine for 1- ((R) -1-amino-ethyl) -cyclopentanol hydrochloride. (M + H)⁺＝303；mp＝230.0-232.0。

Example 21.

2-cyclopropyl-5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid dicyclopropylmethyl-amide

Prepared according to the procedure outlined in example 12, steps 1-2 and 6, substituting 3-amino-2, 2-dimethyl-propan-1-ol with dicyclopropylmethylamine hydrochloride in step 1. MS: (M + H)⁺＝297；mp＝224.0-226.0。

Example 22.

2-cyclopropyl-5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ((R) -1-methoxymethyl-2, 2-dimethyl-propyl) -amide

Step 1

R-tert-leucinol (0.23g, 1.96mmol) and di-tert-butyl dicarbonate (0.85g, 3.9mmol) were dissolved in 10ml of dichloromethane and stirred for 3 days. Aqueous HCl and ethyl acetate were then added, the layers separated, and the aqueous layer was extracted more than once with ethyl acetate. The combined organic layers were washed with sodium chloride solution and dried over sodium sulfate. After evaporation, the residue was purified by silica gel chromatography (ethyl acetate/hexane) to give 0.38g (88%) of ((R) -1-hydroxymethyl-2, 2-dimethyl-propyl) -carbamic acid tert-butyl ester.

Step 2

((R) -1-hydroxymethyl-2, 2-dimethyl-propyl) -carbamic acid tert-butyl ester (0.38g, 1.74mmol) was dissolved in 17ml acetonitrile and iodomethane (1.6ml, 26.1mmol) followed by addition of silver oxide (0.65g, 2.78 mmol; as prepared in org.Syn.Coll.Vol.VII, p.386). The reaction flask was covered with light and the reaction was heated at reflux for 24 h. Methyl iodide (6.4ml) and silver oxide (0.65g) were added in portions and then heated until the reaction was judged to be complete by standard reverse phase LC/MS. The reaction mixture was filtered through celite, rinsing with ethyl acetate. After evaporation, the residue was purified by silica gel chromatography (ethyl acetate/hexane) to give 0.28g (69%) of ((R) -1-methoxymethyl-2, 2-dimethyl-propyl) -carbamic acid tert-butyl ester.

Step 3

((R) -1-methoxymethyl-2, 2-dimethyl-propyl) -carbamic acid tert-butyl ester (0.28g, 1.2mmol) was dissolved in 6ml dichloromethane and then cooled with an ice bath. 4ml of trifluoroacetic acid were added and the reaction was stirred to room temperature. The reaction solution was evaporated to give (R) -1-methoxymethyl-2, 2-dimethyl-propylamine trifluoroacetate, which was used without further purification.

Step 4

2-cyclopropyl-5H-pyrrolo [2, 3-b ] is prepared according to the procedure outlined in example 1, Steps 4-5]Pyrazine-7-carboxylic acid ((R) -1-methoxymethyl-2, 2-dimethyl-propyl) -amide, 1- ((R) -1-amino-ethyl) -cyclopentanol hydrochloride was substituted with (R) -1-methoxymethyl-2, 2-dimethyl-propylamine trifluoroacetate. MS: (M + H)⁺＝317；mp＝265.0-270.0。

Example 23.

2-cyclopropyl-5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ((S) -1-methoxymethyl-2, 2-dimethyl-propyl) -amide

Prepared according to the procedure outlined in example 22 substituting S-tert-leucinol for R-tert-leucinol. MS: (M + H)⁺＝317；mp＝268.0-270.0。

Example 24.

2-cyclopropyl-5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid (1-cyclohexyl-propyl) -amide

Step 1

In a flask was combined 2-methyl-2-propanesulfinamide (5.0g, 41.2mmol), cyclohexane aldehyde (9.9ml, 82.5mmol), pyridinium p-toluenesulfonate (0.52g, 2.06mmol) and 25g magnesium sulfate with 70ml dichloromethane. The reaction mixture was stirred for 16h and then filtered through celite. After evaporation, the residue was purified by silica gel chromatography (ether/hexane) to give 7.79g (87%) of 2-methyl-propane-2-sulfinic acid 1-cyclohexyl-methyleneamide.

Step 2

2-methyl-propane-2-sulfinic acid 1-cyclohexyl-methyleneamide (0.5g, 2.3mmol) was dissolved in 12ml of diethyl ether. The reaction solution was cooled to-40 ℃ and ethylmagnesium bromide (3M in ether, 1.5ml, 4.5mmol) was added dropwise and the reaction stirred to 25 ℃. Ammonium chloride solution was added followed by ethyl acetate, the layers were separated and the aqueous layer was extracted with ethyl acetate more than 2 times. The combined organic layers were washed with sodium chloride solution, dried over sodium sulfate and concentrated to give 0.45g (85%) of 2-methyl-propane-2-sulfinic acid (1-cyclohexyl-propyl) -amide.

Step 3

2-methyl-propane-2-sulfinic acid (1-cyclohexyl-propyl) -amide (0.45g, 1.95mmol) was dissolved in 1ml of methanol and 1ml of 4M HCl in 1, 4-dioxane was added. The reaction solution was stirred for 30 min. Diethyl ether was added to the solution and the reaction solvent was partially evaporated, resulting in the formation of a precipitate. The solid was filtered, washed with hexane and dried to give 200mg (57%) of 1-cyclohexyl-propyl-amine hydrochloride.

Step 4

2-cyclopropyl-5H-pyrrolo [2, 3-b ] is prepared according to the procedure outlined in example 1, Steps 4-5]Pyrazine-7-carboxylic acid (1-cyclohexyl-propyl) -amide, 1- ((R) -1-amino-ethyl) -cyclopentanol hydrochloride was substituted with 1-cyclohexyl-propyl-amine hydrochloride. MS: (M + H) ⁺327; mp is 208.0-210.0; elemental analysis: calcd for C69.91, H8.03, N17.16, found C69.57, H7.96, N16.97.

Example 25.

2-cyclopropyl-5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid (cyclohexyl-cyclopropyl-methyl) -amide

Prepared according to the procedure outlined in example 24 substituting cyclopropylmagnesium bromide for ethylmagnesium bromide in step 2. MS: (M + H)⁺339; mp-174.0-176.0; elemental analysis: calculated values of C70.98, H7.74,n16.55, found C70.68, H7.54, N16.46.

Example 26.

2-cyclopropyl-5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ((S) -1-cyanomethyl-2, 2-dimethyl-propyl) -amide

Step 1

((R) -1-hydroxymethyl-2, 2-dimethyl-propyl) -carbamic acid tert-butyl ester (example 22, step 1; 0.157g, 7.2mmol) was dissolved in 2ml tetrahydrofuran. Triethylamine (0.13ml, 0.935mmol) was added and the reaction cooled with an ice bath. Methanesulfonyl chloride (0.073ml, 0.935mmol) was added slowly and the reaction stirred to 25 ℃ over 16 h. Dichloromethane and water were added and the layers were separated. The aqueous layer was extracted 1 more times with dichloromethane, then the combined organic layers were washed with sodium chloride solution and dried over sodium sulfate. After evaporation, 0.21g (83%) of (R) -2-tert-butoxycarbonylamino-3, 3-dimethyl-butyl methanesulfonate were obtained.

Step 2

Methanesulfonic acid (R) -2-tert-butoxycarbonylamino-3, 3-dimethyl-butyl ester (0.21g, 0.71mmol) was dissolved in 2ml of N, N-dimethylformamide. Sodium cyanide (104mg, 2.13mmol) was added and the mixture was stirred at 35 ℃ for 4 days. Water and ethyl acetate were added and the layers were separated. The aqueous layer was extracted 2 more times with ethyl acetate, and the combined organic layers were washed with water and sodium chloride solution and then dried over sodium sulfate. After evaporation, the residue was purified by silica gel chromatography (ethyl acetate/hexane) to give 0.1g (62%) of ((S) -1-cyanomethyl-2, 2-dimethyl-propyl) -carbamic acid tert-butyl ester.

Step 3

((S) -1-cyanomethyl-2, 2-dimethyl-propyl) -carbamic acid tert-butyl ester (0.1g, 0.44mmol) was cooled with an ice bath and a cold 4M HCl in 1, 4-dioxane was added to dissolve the ester. After 1h, the reaction solution was carefully evaporated to give (S) -3-amino-4, 4-dimethyl-valeronitrile hydrochloride, which was used without further purification.

Step 4

2-cyclopropyl-5H-pyrrolo [2, 3-b ] is prepared according to the procedure outlined in example 1, Steps 4-5]Pyrazine-7-carboxylic acid ((S) -1-cyanomethyl-2, 2-dimethyl-propyl) -amide, substituting (S) -3-amino-4, 4-dimethyl-valeronitrile hydrochloride for 1- ((R) -1-amino-ethyl) -cyclopentanol hydrochloride. MS: (M + H) ⁺＝312；mp＝258.0-260.0。

Example 27.

2-cyclopropyl-5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ((R) -1-cyanomethyl-2, 2-dimethyl-propyl) -amide

Prepared according to the procedure outlined in example 26 substituting ((R) -1-hydroxymethyl-2, 2-dimethyl-propyl) -carbamic acid tert-butyl ester with ((S) -1-hydroxymethyl-2, 2-dimethyl-propyl) -carbamic acid tert-butyl ester. (M + H)⁺＝312；mp＝259.0-261.0。

Example 28.

2-cyclopropyl-5H-pyrrolo [2, 3b ] pyrazine-7-carboxylic acid (2-hydroxy-2-methyl-1-trifluoromethyl-propyl) -amide

Step 1

Methyl 3, 3, 3-Trifluoroalanine hydrochloride (1.0g, 5.16mmol) was dissolved in 26ml dichloromethane. Triethylamine (0.72ml, 5.16mmol) was added and the reaction cooled with an ice bath. Di-tert-butyl dicarbonate (2.2g, 10.3mmol) was added slowly and the reaction stirred for 18 h. Ethyl acetate and ammonium chloride solution were added, the layers were separated and the aqueous layer was extracted more than once with ethyl acetate. The combined organic layers were washed with sodium chloride solution and dried over sodium sulfate. After evaporation, the residue was purified by silica gel chromatography to give 2-tert-butoxycarbonylamino-3, 3, 3-trifluoro-propionic acid methyl ester.

Step 2

Methyl 2-tert-butoxycarbonylamino-3, 3, 3-trifluoro-propionate (0.16g, 0.55mmol) was dissolved in 5ml of tetrahydrofuran and then cooled with an ice bath. Methylmagnesium chloride (3.0M in ether, 0.73ml, 2.18mmol) was added dropwise to the solution, which was then stirred for 16 h. Ammonium chloride solution and ethyl acetate were added to the reaction and the layers were separated. The aqueous layer was extracted once more with ethyl acetate and the combined organic layers were washed with sodium chloride solution, dried over sodium sulfate and evaporated to give 0.11g of (2-hydroxy-2-methyl-1-trifluoromethyl-propyl) -carbamic acid tert-butyl ester.

Step 3

(2-hydroxy-2-methyl-1-trifluoromethyl-propyl) -carbamic acid tert-butyl ester (0.11g, 0.43mmol) was cooled with an ice bath and a cold 4M HCl in 1, 4-dioxane was added to dissolve the ester. After 1h, the reaction solution was carefully evaporated to give 3-amino-4, 4, 4-trifluoro-2-methyl-butan-2-ol hydrochloride, which was used without further purification.

Step 4

2-cyclopropyl-5H-pyrrolo [2, 3b ] is prepared according to the procedure outlined in example 1, Steps 4-5]Pyrazine-7-carboxylic acid (2-hydroxy-2-methyl-1-trifluoromethyl-propyl) -amide, 1- ((R) -1-amino-ethyl) -cyclopentanol hydrochloride, substituted with 3-amino-4, 4, 4-trifluoro-2-methyl-but-2-ol hydrochloride. MS: (M + H)⁺＝343；mp＝258.0-260.0。

Example 29.

2-cyclopropyl-5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ((S) -1-cyclohexyl-2-hydroxy-2-methyl-propyl) -amide

Step 1

(S) -amino-cyclohexyl-acetic acid, hydrochloride salt (1.0g, 5.16mmol) was dissolved in 17ml 2: 11, 4-dioxane: water and cooled with an ice bath. Sodium hydroxide solution (10.4ml of 1M aqueous solution) was slowly added to the reaction solution followed by the addition of sodium bicarbonate solid (0.43g, 5.16 mmol). Di-tert-butyl dicarbonate (1.68g, 7.74mmol) was added and the reaction mixture was stirred for 16 h. The reaction mixture was partially separated, then dissolved in ethyl acetate and water and acidified to pH 2 with potassium hydrogen sulfate solution. The layers were separated and the aqueous layer was extracted 2 more times with ethyl acetate. The combined ethyl acetate layers were washed with sodium chloride solution, dried over sodium sulfate and evaporated to give 1.52g of crude (S) -tert-butoxycarbonylamino-cyclohexyl-acetic acid.

Step 2

(S) -tert-Butoxycarbonylamino-cyclohexyl-acetic acid (1.52g, 5.16mmol) was dissolved in 39ml toluene and 11ml methanol. Trimethylsilyldiazomethane (2.0M in hexane, 12.9ml, 25.8mmol) was added slowly and the reaction mixture was stirred for 16 h. The reaction was evaporated to give a solid which was purified by silica gel chromatography (ethyl acetate/hexane) to give 1.26g (79%) of (S) -tert-butoxycarbonylamino-cyclohexyl-acetic acid methyl ester.

Step 3

2-cyclopropyl-5H-pyrrolo [2, 3-b ] was prepared according to the procedure outlined in example 28, Steps 2-4]Pyrazine-7-carboxylic acid ((S) -1-cyclohexyl-2-hydroxy-2-methyl-propyl) -amide, 2-tert-butoxycarbonylamino-3, 3, 3-trifluoro-propionic acid methyl ester was substituted with (S) -tert-butoxycarbonylamino-cyclohexyl-acetic acid methyl ester. MS: (M + H)⁺＝357；mp＝251.0-253.0。

Example 30.

2-cyclopropyl-5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ((R) -2-cyano-cyclopropyl-ethyl) -amide

Step 1

(R) -2-methyl-propane-2-sulfinic acid 1-cyclopropyl-methyleneamide was prepared as described in example 24, step 1, substituting (R) -2-methylpropane-2-sulfinamide for 2-methyl-2-propanesulfinamide and cyclopropanealdehyde for cyclopropanealdehyde.

Step 2

(R) -2-methyl-propane-2-sulfinic acid 1-cyclopropyl-methyleneamide (0.3g, 1.73mmol) was dissolved in 17ml tetrahydrofuran. Tetrabutylammonium phenolate (0.58g, 1.73mmol, prepared as described in Bull. chem. Soc. Jpn.2003, 76(11), 2191) was added and the reaction solution was cooled with a dry ice/acetone bath. Trimethylsilylacetonitrile (0.356ml, 2.6mmol) was added dropwise and the reaction stirred in the bath for 2 h. The ammonium chloride solution was added to the reaction solution at about 0 ℃. Ethyl acetate was added, water was then added, the layers were separated, and the aqueous layer was extracted with ethyl acetate 2 times more. The combined organic layers were washed with brine and dried over sodium sulfate. After evaporation, the residue was purified by silica gel chromatography (ethyl acetate/hexane) to give 0.14g (38%) of (R) -N- ((R) -2-cyano-1-cyclopropylethyl) -2-methylpropan-2-sulfinamide.

Step 3

Preparation of 2-cyclopropyl-5H-pyrrolo [2, 3-b ] as in example 24, Steps 3-4]Pyrazine-7-carboxylic acid ((R) -2-cyano-cyclopropyl-ethyl) -amide, 2-methyl-propane-2-sulfinic acid (1-cyclohexyl-propyl) -amide substituted with (R) -N- ((R) -2-cyano-1-cyclopropylethyl) -2-methylpropane-2-sulfinamide. MS: (M + H)⁺＝296；[α]_D＝-23。

Example 31.

2-cyclopropyl-5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ((S) -2-cyano-1-cyclopropyl-ethyl) -amide

Prepared according to the procedure outlined in example 30, substituting (R) -2-methylpropan-2-sulfinamide with (S) - (-) -t-butylsulfinamide. MS: (M + H)⁺＝296；[α]_D＝23.7；mp＝230.0-232.0。

Example 32.

Step 1

To a solution of Boc-D-alanine methyl ester (5.00g, 24.6mmol) in THF (100mL) at 0 deg.C was slowly added methylmagnesium bromide (3.0M Et₂Solution O, 28.7mL, 86.1 mmol). The resulting white slurry was stirred at 0 ℃ for 1h, then at room temperature for 2 h. With saturated NH₄The reaction mixture was quenched with aqueous Cl and H₂Diluted with O and extracted with EtOAc. The combined organic layers were washed with brine, MgSO₄Drying and concentration gave 4.93g (99%) of tert-butyl ((R) -2-hydroxy-1, 2-dimethyl-propyl) -carbamate as a colorless viscous oil.

Step 2

((R) -2-hydroxy-1, 2-dimethyl-propyl) -carbamic acid tert-butyl ester (4.93g, 24.2mmol) was dissolved in 1.0M HCl (150mL) and stirred at 50 ℃ for 4 h. Concentration afforded 4.01g of (R) -3-amino-2-methyl-butan-2-ol hydrochloride as a light brown solid, which was used without further purification.

Step 3

In a flask, combine 2-bromo-5- (2-trimethylsilylethoxymethyl) -5H-pyrrolo [2, 3-b ]]Pyrazine-7-carboxylic acid (3.25g, 8.74mmol), (R) -3-amino-2-methyl-but-2-ol hydrochloride (3.05g, 21.9mmol), EDC(3.85g, 20.1mmol) and HOBt (2.72g, 20.1 mmol). DMF (50mL) was then added followed by i-Pr₂NEt (4.87mL, 28.0 mmol). The mixture was stirred at room temperature overnight and then concentrated under reduced pressure. By SiO₂The residue was purified by chromatography (20-100% EtOAc/hexanes) to give 2.40g (60%) of 2-bromo-5- (2-trimethylsilyl-ethoxymethyl) -5H-pyrrolo [2, 3-b ]]Pyrazine-7-carboxylic acid ((R) -2-hydroxy-1, 2-dimethyl-propyl) -amide, which is a yellow solid.

Step 4

In a pressure test tube, 2-bromo-5- (2-trimethylsilyl-ethoxymethyl) -5H-pyrrolo [2, 3-b ] is added]Pyrazine-7-carboxylic acid ((R) -2-hydroxy-1, 2-dimethyl-propyl) -amide (120mg, 0.26mmol) and 1-ethyl-1H-pyrazole-4-boronic acid pinacol ester (70mg, 0.32mmol) were dissolved in DME (2.0 mL). Adding K₂CO₃(2.0M, 0.39mL, 0.78mmol) and Pd (PPh)₃)₄(15mg, 0.013mmol) in water, using slow N₂The mixture was degassed with a gas stream for 15 min. The tube was then sealed and heated at 90 ℃ for 3 h. The reaction mixture was cooled to room temperature and washed with H ₂Quench O and extract with EtOAc. The organic extract was washed with brine, MgSO₄Drying and concentrating. By SiO₂The residue was purified by chromatography (20-100% EtOAc/hexanes) to give 111mg (90%) of 2- (1-ethyl-1H-pyrazol-4-yl) -5- (2-trimethylsilyl-ethoxymethyl) -5H-pyrrolo [2, 3-b ]]Pyrazine-7-carboxylic acid ((R) -2-hydroxy-1, 2-dimethyl-propyl) amide, which is a light yellow foam.

Step 5

To 2- (1-ethyl-1H-pyrazol-4-yl) -5- (2-trimethylsilyl-ethoxymethyl) -5H-pyrrolo [2, 3-b]Pyrazine-7-carboxylic acid ((R) -2-hydroxy-1, 2-dimethyl-propyl) -amide in CH₂Cl₂To a solution in (2.25mL) was added TFA (0.75 mL). The reaction mixture was stirred for 2.5h and concentrated. The residue was dissolved in CH₂Cl₂(3.75mL), ethylenediamine (0.75mL, 11.2mmol) was added and the mixture was stirred at room temperature overnight. Concentrating the reaction mixture through SiO₂Chromatography (0-10% MeOH/CH)₂Cl₂) The residue was purified to give 59mg (74%) of 2- (1-ethyl-1H-pyrazol-4-yl) -5H-pyrrolo [2, 3-b ]]Pyrazine-7-carboxylic acid ((R) -2-hydroxy-1, 2-dimethyl-propyl) -amide as a light yellow powder. MS: 343(M + H)⁺；mp＝270.0-272.0。

Example 33.

2- (1-methyl-1H-pyrazol-4-yl) -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ((R) -2-hydroxy-1, 2-dimethyl-propyl) -amide

Prepared according to the procedure outlined in steps 4-5 of example 32, substituting 1-methyl-1H-pyrazole-4-boronic acid pinacol ester for 1-ethyl-1H-pyrazole-4-boronic acid pinacol ester. MS: (M + H)⁺＝329；mp285.0-288.0。

Example 34.

2-thiophen-2-yl-5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ((R) -2-hydroxy-1, 2-dimethyl-propyl) -amide

Prepared according to the procedure outlined in steps 4-5 of example 32, substituting thiophene-2-boronic acid pinacol ester for 1-ethyl-1H-pyrazole-4-boronic acid pinacol ester. MS: (M + H)⁺＝331；mp 272.0-275.0。

Example 35.

2- (3, 6-dihydro-2H-pyran-4-yl) -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ((R) -2-hydroxy-1, 2-dimethyl-propyl) -amide

Prepared according to the procedure outlined in example 32, steps 4-5, substituting 1-ethyl-1H-pyrazole-4-boronic acid pinacol ester with 3, 6-dihydro-2H-pyran-4-ylboronic acid pinacol ester. MS: (M + H)⁺＝331。

Example 36.

2-thiazol-2-yl-5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ((R) -2-hydroxy-1, 2-dimethyl-propyl) -amide

Step 1

In a pressure test tube, 2-bromo-5- (2-trimethylsilyl-ethoxymethyl) -5H-pyrrolo [2, 3b]Pyrazine-7-carboxylic acid ((R) -2-hydroxy-1, 2-dimethyl-propyl) -amide (120mg, 0.26mmol) and 2-tributylstannyl thiazole (0.10mL, 0.32mmol) were dissolved in DMF (2.0 mL). Adding Pd (PPh) ₃)₄(15.2mg, 0.013mmol) and copper (I) iodide (10.0mg, 0.052mmol), the tube was sealed and heated at 80 ℃ for 1.5 h. The reaction mixture was cooled and concentrated. By SiO₂Chromatography (0-10% MeOH/CH)₂Cl₂) The residue was purified to give 125mg of 2-thiazol-2-yl-5- (2-trimethylsilyl-ethoxymethyl) -5H-pyrrolo [2, 3-b ]]Pyrazine-7-carboxylic acid ((R) -2-hydroxy-1, 2-dimethyl-propyl) -amide, which is a brown viscous oil.

Step 2

2-thiazol-2-yl-5H-pyrrolo [2, 3-b ]]Pyrazine-7-carboxylic acid ((R) -2-hydroxy-1, 2-dimethyl-propyl) -amide. Prepared according to the method outlined in example 32, step 5, using 2-thiazol-2-yl-5- (2-trimethylsilyl-ethoxymethyl) -5H-pyrrolo [2, 3-b ]]Pyrazine-7-carboxylic acid ((R) -2-hydroxy-1, 2-dimethyl-propyl) -amide substituted 2- (1-ethyl-1H-pyrazol-4-yl) -5- (2-trimethylsilyl-ethoxymethyl) -5H-pyrrolo [2, 3-b [ -5 [ -methyl ] -amide]Pyrazine-7-carboxylic acid ((R) -2-hydroxy-)1, 2-dimethyl-propyl) -amide. MS: (M + H)⁺＝332。

Example 37.

2-pyridin-2-yl-5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ((R) -2-hydroxy-1, 2-dimethyl-propyl) -amide

Prepared according to the procedure outlined in example 36 substituting 2- (tributylstannyl) pyridine for 2-tributylstannyl thiazole. MS: (M + H) ⁺＝326。

Example 38.

2-cyano-5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ((R) -2-hydroxy-1, 2-dimethyl-propyl) -amide

Step 1

Combine 2-bromo-5- (2-trimethylsilyl-ethoxymethyl) -5H-pyrrolo [2, 3b ] in DMF (5.0mL) in a microwave tube]Pyrazine-7-carboxylic acid ((R) -2-hydroxy-1, 2-dimethyl-propyl) -amide (250mg, 0.55mmol), zinc cyanide (97mg, 0.82mmol), and Pd (PPh)₃)₄(191mg, 0.165mmol) and heated at 140 ℃ for 15 min. Evaporating the reaction mixture directly through SiO₂Chromatography (20-100% EtOAc/heptane) afforded 186mg (84%) of 2-cyano-5- (2-trimethylsilyl-ethoxymethyl) -5H-pyrrolo [2, 3-b ]]Pyrazine-7-carboxylic acid ((R) -2-hydroxy-1, 2-dimethyl-propyl) -amide, which is a yellow paste.

Step 2

2-cyano-5H-pyrrolo [2, 3-b ]]Pyrazine-7-carboxylic acid ((R) -2-hydroxy-1, 2-dimethyl-propyl) -amide. Root of herbaceous plantPrepared according to the method outlined in example 32, step 5, using 2-cyano-5- (2-trimethylsilyl-ethoxymethyl) -5H-pyrrolo [2, 3-b ]]Pyrazine-7-carboxylic acid ((R) -2-hydroxy-1, 2-dimethyl-propyl) -amide substituted 2- (1-ethyl-1H-pyrazol-4-yl) -5- (2-trimethylsilyl-ethoxymethyl) -5H-pyrrolo [2, 3-b [ -5 [ -methyl ] -amide ]Pyrazine-7-carboxylic acid ((R) -2-hydroxy-1, 2-dimethyl-propyl) -amide. MS: (M + H)⁺＝274。

Example 39.

2-cyclopent-1-enyl-5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ((S) -2-hydroxy-1, 2-dimethyl-propyl) -amide

Prepared according to the method outlined in example 32, steps 3-5, substituting (R) -3-amino-2-methyl-but-2-ol hydrochloride with (S) -3-amino-2-methyl-but-2-ol hydrochloride in step 3 (Tetrahedron: Asymmetry 1995, 6, 671) and 1-ethyl-1H-pyrazole-4-boronic acid pinacol ester with cyclopenten-1-ylboronic acid in step 4. MS: (M + H)⁺＝315。

Example 40.

2-cyclopentyl-5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ((S) -2-hydroxy-1, 2-dimethyl-propyl) -amide

From 2-cyclopent-1-enyl-5H-pyrrolo [2, 3-b]Pyrazine-7-carboxylic acid ((S) -2-hydroxy-1, 2-dimethyl-propyl) -amide (example 39) was prepared by treatment with 10% palladium on carbon in a 40psi hydrogen atmosphere for 24 hours. The reaction mixture was filtered through celite and a Whatman syringe filter and the product was purified by trituration with ethyl acetate. MS: (M + H)⁺＝317。

Example 41.

2-isopropenyl-5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ((S) -2-hydroxy-1, 2-dimethyl-propyl) -amide

Prepared according to the method outlined in example 32, steps 3-5, substituting (R) -3-amino-2-methyl-butan-2-ol hydrochloride with (S) -3-amino-2-methyl-butan-2-ol hydrochloride (tetra edron: Asymmetry 1995, 6, 671) in step 3 and 2-isopropenyl-4, 4, 5, 5-tetramethyl- [1, 3, 2 ] in step 4 ]Dioxolane substituted 1-ethyl-1H-pyrazole-4-boronic acid pinacol ester. MS: (M + H)⁺＝289。

Example 42.

2-isopropyl-5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ((S) -2-hydroxy-1, 2-dimethyl-propyl) -amide

From 2-isopropenyl-5H-pyrrolo [2, 3-b ]]Pyrazine-7-carboxylic acid ((S) -2-hydroxy-1, 2-dimethyl-propyl) -amide (example 41) was prepared by treatment with 10% palladium on carbon in a 40psi hydrogen atmosphere overnight. The reaction mixture was filtered through celite and a Whatman syringe filter and the product was purified by crystallization from ethyl acetate. MS: (M + H)⁺＝291。

Example 43.

2-cyclohex-1-enyl-5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ((S) -2-hydroxy-1, 2-dimethyl-propyl) -amide

Prepared according to the method outlined in example 32, steps 3-5, substituting (R) -3-amino-2-methyl-but-2-ol hydrochloride with (S) -3-amino-2-methyl-but-2-ol hydrochloride in step 3 (Tetrahedron: Asymmetry 1995, 6, 671) and 1-ethyl-1H-pyrazole-4-boronic acid pinacol ester with cyclohexen-1-ylboronic acid in step 4. MS: (M + H)⁺＝329。

Example 44.

2-cyclohexyl-5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ((S) -2-hydroxy-1, 2-dimethyl-propyl) -amide

From 2-cyclohex-1-enyl-5H-pyrrolo [2, 3-b ]Pyrazine-7-carboxylic acid ((S) -2-hydroxy-1, 2-dimethyl-propyl) -amide, was prepared by treatment with 10% palladium on carbon in a 50psi hydrogen atmosphere for 48 hours. The reaction mixture was filtered through celite and a Whatman syringe filter and the product was purified by crystallization from ethyl acetate. MS: (M + H)⁺＝331。

Example 45.

2-thiophen-2-yl-5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ((S) -2-hydroxy-1, 2-dimethyl-propyl) -amide

Prepared according to the method outlined in example 32, steps 3-5, substituting (R) -3-amino-2-methyl-butan-2-ol hydrochloride with (S) -3-amino-2-methyl-butan-2-ol hydrochloride in step 3 (Tetrahedron: Asymmetry 1995, 6, 671) and 4, 4, 5, 5-tetramethyl-2-thiophen-2-yl- [1, 3, 2-l ] in step 4]Dioxolane substituted 1-ethyl-1H-pyrazole-4-boronic acid pinacol ester. The catalyst used in step 4 was Pd (dppf) Cl₂And the solvent is toluene. MS: (M + H)⁺＝331。

Example 46.

2- (2-methyl-pyridin-4-yl) -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ((S) -2-hydroxy-1, 2-dimethyl-propyl) -amide hydrochloride

Prepared according to the method outlined in example 32, steps 3-5, substituting (R) -3-amino-2-methyl-butan-2-ol hydrochloride with (S) -3-amino-2-methyl-butan-2-ol hydrochloride in step 3 (Tetrahedron: Asymmetry 1995, 6, 671) and 2-methyl-4- (4, 4, 5, 5-tetramethyl- [1, 3, 2-methyl- [1, 3, 2 ] in step 4 ]Dioxopentaborane-2-yl) -pyridine substituted 1-ethyl-1H-pyrazole-4-boronic acid pinacol ester. The catalyst used in step 4 is Pd₂(dba)₃And the solvent is toluene. The hydrochloride salt was prepared by dissolving the free base in boiling dioxane and treating with 4MHCl in dioxane. MS: (M + H)⁺＝340。

Example 47.

2- (6-methyl-pyridin-3-yl) -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ((S) -2-hydroxy-1, 2-dimethyl-propyl) -amide hydrochloride

Prepared according to the method outlined in example 32, steps 3-5, substituting (R) -3-amino-2-methyl-butan-2-ol hydrochloride with (S) -3-amino-2-methyl-butan-2-ol hydrochloride in step 3 (Tetrahedron: Asymmetry 1995, 6, 671) and 2-methyl-5- (4, 4, 5, 5-tetramethyl- [1, 3, 2-l-o-methyl- [1, 3, 2 ] in step 4]Dioxolane-2-yl-pyridine substituted 1-ethyl-1H-pyrazole-4-boronic acid pinacol ester. The catalyst used in step 4 is Pd₂(dba)₃And the solvent is toluene. The hydrochloride salt was prepared by dissolving the free base in boiling dioxane and treating with 4MHCl in dioxane. MS: (M + H)⁺＝340。

Example 48.

2-vinyl-5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid (3-hydroxy-2, 2-dimethyl-propyl) -amide

Step 1

2-bromo-5- (2-trimethylsilyl-ethoxymethyl) -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid (3-hydroxy-2, 2-dimethyl-propyl) -amide was prepared according to the procedure outlined in example 32, step 3, substituting (R) -3-amino-2-methyl-but-2-ol hydrochloride with 3-amino-2, 2-dimethyl-propan-1-ol.

Step 2

Combining 2-bromo-5- (2-trimethylsilyl-ethoxymethyl) -5H-pyrrolo [2, 3-b ] in a pressure tube]Pyrazine-7-carboxylic acid (3-hydroxy-2, 2-dimethyl-propyl) -amide (250mg, 0.55mmol), potassium vinyltrifluoroborate (110mg, 0.83mmol), cesium carbonate (627mg, 1.90mmol), Pd (dppf) Cl₂(22mg, 0.03mmol), THF (1.8mL), and water (0.2 mL). The tube was purged with argon, sealed and heated at 85 ℃ overnight. Evaporating the solvent through SiO₂The crude residue was chromatographed, eluting with 25% -50% EtOAc/hexanes, to give 157mg (71%) of 5- (2-trimethylsilyl-ethoxymethyl) -2-vinyl-5H-pyrrolo [2, 3-b ]]Pyrazine-7-carboxylic acid (3-hydroxy-2, 2-dimethyl-propyl) -amide.

Step 3

2-vinyl-5H-pyrrolo [2, 3-b ] was prepared according to the procedure outlined in step 5 of example 32]Pyrazine-7-carboxylic acid (3-hydroxy-2, 2-dimethyl-propane)Base) -amide from 5- (2-trimethylsilyl-ethoxymethyl) -2-vinyl-5H-pyrrolo [2, 3-b]Pyrazine-7-carboxylic acid (3-hydroxy-2, 2-dimethyl-propyl) -amide substituted 2- (1-ethyl-1H-pyrazol-4-yl) -5- (2-trimethylsilyl-ethoxymethyl) -5H-pyrrolo [2, 3-b [ -5]Pyrazine-7-carboxylic acid ((R) -2-hydroxy-1, 2-dimethyl-propyl) -amide. MS: (M + H) ⁺＝275。

Example 49.

2-ethyl-5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid (3-hydroxy-2, 2-dimethyl-propyl) -amide

From 2-vinyl-5H-pyrrolo [2, 3-b]Pyrazine-7-carboxylic acid (3-hydroxy-2, 2-dimethyl-propyl) -amide was prepared by treatment with 10% palladium on carbon in a 50psi hydrogen atmosphere overnight. The reaction mixture was filtered through celite and a Whatman syringe filter and the product was purified by trituration with ethyl acetate. MS: (M + H)⁺＝277。

Example 50.

2- (2, 2-dimethyl-cyclopropyl) -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid (3-hydroxy-2, 2-dimethyl-propyl) -amide

Step 1

Step 2

Combining 2-bromo-5- (2-trimethylsilyl-ethoxymethyl) -5H-pyrrolo [2, 3-b ] in a pressure tube]Pyrazine-7-carboxylic acid (3-hydroxy-2, 2-dimethyl-propyl) -amide (100mg, 0.22mmol), (2, 2-dimethyl-cyclopropyl) -potassium trifluoroborate (58mg, 0.33mmol), cesium carbonate (251mg, 0.77mmol), Pd (dppf) Cl ₂(18mg, 0.02mmol), THF (0.75mL), and water (0.25 mL). The tube was purged with argon and heated at 100 ℃ overnight. Evaporating the solvent through SiO₂The crude residue was chromatographed, eluting with 25% -50% EtOAc/hexanes, to give 63mg (64%) of 2- (2, 2-dimethyl-cyclopropyl) -5- (2-trimethylsilyl-ethoxymethyl) -5H-pyrrolo [2, 3-b ]]Pyrazine-7-carboxylic acid (3-hydroxy-2, 2-dimethyl-propyl) -amide.

Step 3

2- (2, 2-dimethyl-cyclopropyl) -5H-pyrrolo [2, 3-b ] was prepared according to the procedure outlined in example 32, step 5]Pyrazine-7-carboxylic acid (3-hydroxy-2, 2-dimethyl-propyl) -amide, substituting ethylenediamine with 1N sodium hydroxide. MS: (M + H)⁺＝317；mp＝261.0-263.0。

Example 51.

2- ((trans) -2-methyl-cyclopropyl) -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid (3-hydroxy-2, 2-dimethyl-propyl) -amide

Step 1

A solution of trans-1-propen-1-ylboronic acid (1.0g, 11.6mmol), pinacol (1.5g, 12.8mmol) and magnesium sulphate (0.7g, 5.8mmol) in diethyl ether (23mL) was stirred at room temperature for 1h and then concentrated to give 4, 4, 5, 5-tetramethyl-2- ((E) -propenyl) - [1, 3, 2] dioxaborolan which was used without further purification.

Step 2

In a nitrogen atmosphereTo 4, 4, 5, 5-tetramethyl-2- ((E) -propenyl) - [1, 3, 2 ]Dioxolane (1.9g, 11.6mmol, crude from step 1) in toluene (11.6mL) Diethylzinc (1.1M in toluene, 10.5mL, 11.6mmol) was carefully added followed by diiodomethane (1.3mL, 16.2 mmol). The reaction mixture was stirred at 50 ℃ for 4 h. Diethyl zinc (1.1M in toluene, 10.5mL, 11.6mmol) and diiodomethane (1.3mL, 16.2mmol) were added and heating continued overnight. The reaction was cooled, 1.0M HCl (25mL) was added, followed by saturated NaHCO₃(100 mL). The reaction was filtered and the filtrate was extracted with ether (2 ×). The combined organic layers were washed with water, dried over sodium sulfate, and concentrated to give 4, 4, 5, 5-tetramethyl-2- ((trans) -2-methyl-cyclopropyl) - [1, 3, 2 ]]Dioxolane. The purity was determined to be 80% by NMR analysis and the isolated product was used without further purification.

Step 3

Mixing KHF₂(6.0g, 77mmol) in water (7.7mmol) was added 4, 4, 5, 5-tetramethyl-2- ((trans) -2-methyl-cyclopropyl) - [1, 3, 2]Dioxolane (2.0g, 11mmol, crude from step 2) in MeOH (40 mL). The reaction mixture was stirred at room temperature overnight and then concentrated. The residue was extracted with acetonitrile (3 ×). The combined organic layers were concentrated and the residue triturated with ether. The resulting solid was collected by filtration and washed with diethyl ether. 787mg (44%, 3 steps) of trans-2-methylcyclopropanepotassium-1-trifluoroborate was isolated and the purity was 80% by NMR analysis. The main contaminant is the similar alkene. Used without further purification.

Step 4

2- ((trans) -2-methyl-cyclopropyl) -5- (2-trimethylsilyl-ethoxymethyl) -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid (3-hydroxy-2, 2-dimethyl-propyl) -amide was prepared according to the procedure outlined in example 50, step 2, substituting potassium (2, 2-dimethyl-cyclopropyl) -trifluoroborate with potassium trans-1-trifluoroborate-2-methylcyclopropane.

Step 5

Preparation of 2- ((trans) -2-methyl-cyclopropyl) -5H-pyrrolo [2, 3-b ] according to the procedure outlined in example 32, step 5]Pyrazine-7-carboxylic acid (3-hydroxy-2, 2-dimethyl-propyl) -amide, substituting ethylenediamine with 1N sodium hydroxide. MS: (M + H)⁺＝303。

Example 52.

2- ((cis) -2-methyl-cyclopropyl) -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid (3-hydroxy-2, 2-dimethyl-propyl) -amide

Prepared according to the procedure outlined in example 51 substituting cis-1-propen-1-ylboronic acid for trans-1-propen-1-ylboronic acid. MS: (M + H)⁺＝303。

Example 53.

2-cyclopropyl-5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ((R) -1, 2, 2-trimethyl-propyl) -amide

Prepared according to the procedure outlined in example 1, steps 4-5, substituting (R) -1, 2, 2-trimethylpropylamine for 1- ((R) -1-amino-ethyl) -cyclopentanol hydrochloride. MS: (M + H)⁺＝287；mp＝298.0-300.0。

Example 54.

2-cyclopropyl-5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid isopropylamide

Step 1

To 2-cyclopropyl-5- (2-trimethylsilyl-ethoxymethyl) -5H-pyrrolo [2, 3-b]Pyrazine-7-carboxylic acid (0.20g, 0.59mmol) in CH₂Cl₂To a solution in (5mL) was added EDC (0.14g, 0.72mmol), 4- (dimethylamino) pyridine (0.088g, 0.72mmol) and isopropylamine (0.042g, 0.72 mmol). The reaction mixture was stirred at room temperature overnight and then with H₂Diluting with O and CH₂Cl₂And (4) extracting. The combined organic layers were washed with brine, Na₂SO₄Drying and concentrating. By SiO₂The residue was purified by chromatography (30% EtOAc/hexanes) to give 0.18g (81%) of 2-cyclopropyl-5- (2-trimethylsilyl-ethoxymethyl) -5H-pyrrolo [2, 3-b ]]Pyrazine-7-carboxylic acid isopropylamide as an oil.

Step 2

To 2-cyclopropyl-5- (2-trimethylsilyl-ethoxymethyl) -5H-pyrrolo [2, 3-b]Pyrazinyl-7-carboxylic acid isopropylamide (0.18g, 0.48mmol) in CH₂Cl₂To the solution in (5mL) was added trifluoroacetic acid (1.0 mL). The reaction mixture was stirred at room temperature overnight and then concentrated. The residue was dissolved in MeOH (10mL) and H₂O (2mL), Et was added₃N (2mL), the reaction mixture was stirred at room temperature overnight and then concentrated. By SiO₂Chromatography (2% MeOH/CH)₂Cl₂) The residue was purified to give 0.0.75g (64%) of 2-cyclopropyl-5H-pyrrolo [2, 3-b ] ]Pyrazine-7-carboxylic acid isopropylamide as a white solid. MS: (M + H)⁺＝245；mp＞300.0。

Example 55.

2-cyclopropyl-5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid (2-methoxy-1-methyl-ethyl) -amide

According to the method outlined in example 54The preparation method comprises the step of substituting 2-amino-1-methoxy propane for isopropylamine. MS: (M + H)⁺＝275；mp＝238.0-240.0。

Example 56.

2-cyclopropyl-5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid (3-hydroxy-1, 1-dimethyl-butyl) -amide

Prepared according to the procedure outlined in example 54 substituting isopropylamine with 4-amino-4-methyl-pentan-2-ol. MS: (M + H)⁺＝303；mp＝230.0-232.0。

Example 57.

2-cyclopropyl-5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid (2-cyanoethyl) -amide

Step 1

To 2-cyclopropyl-5- (2-trimethylsilyl-ethoxymethyl) -5H-pyrrolo [2, 3-b]Pyrazine-7-carboxylic acid (0.26g, 0.77mmol) in CH₂Cl₂To the solution (10mL) was added trifluoroacetic acid (1.5 mL). The reaction mixture was stirred at room temperature overnight and then concentrated. The residue was dissolved in MeOH (10mL) and H₂O (1mL), Et was added₃N (2 mL). The reaction mixture was stirred at room temperature overnight, then concentrated and dried under high vacuum to give 2-cyclopropyl-5H-pyrrolo [2, 3-b ]]Pyrazine-7-carboxylic acid, which was used without further purification.

Step 2

To 2-cyclopropyl-5H-pyrrolo [2, 3-b ]]Pyrazine-7-carboxylic acid (0.156g, 0.77mmol, crude from step 1) in CH₂Cl₂(10mL) ofEDC (0.176g, 0.92mmol), 4- (dimethylamino) pyridine (0.11g, 0.92mmol) and 3-aminopropionitrile (0.065g, 0.92mmol) were added to the solution. The reaction mixture was stirred at room temperature overnight and then with H₂Diluting with O and CH₂Cl₂And (4) extracting. The combined organic layers were washed with brine, Na₂SO₄Drying and concentrating. The residue was taken up in 50% EtOH/Et₂O trituration together gave 0.059g (30%) of 2-cyclopropyl-5H-pyrrolo [2, 3-b ]]Pyrazine-7-carboxylic acid (2-cyano-ethyl) -amide as an off-white solid. MS: (M + H)⁺＝256；mp＝236.0-238.0。

Example 58.

2-cyclopropyl-5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid cyanomethyl-amides

Prepared according to the procedure outlined in example 57 substituting aminoacetonitrile for 3-aminopropionitrile. MS: (M + H)⁺＝242；mp＝240.0-242.0。

Example 59.

2-cyclopropyl-5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid (3-cyanopropyl) -amide

Prepared according to the procedure outlined in example 57 substituting 4-aminobutyronitrile for 3-aminopropionitrile. MS: (M + H)⁺＝270；mp＝232.0-234.0。

Example 60.

2-cyclopropyl-5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ((S) -1-ethyl-2-hydroxy-2-methyl-propyl) -amide

Prepared according to the procedure outlined in example 54, substituting isopropylamine with (S) -3-amino-2-methyl-pentan-2-ol hydrochloride. MS: (M + H) ⁺＝303；mp＝229.0-231.0。

Example 61.

2-cyclopropyl-5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid (3-hydroxy-1, 1-dimethyl-propyl) -amide

Prepared according to the procedure outlined in example 54 substituting isopropylamine with 3-amino-3-methyl-butan-1-ol. MS: (M + H)⁺＝289；mp＝250.0-252.0。

Example 62.

2-cyclopropyl-5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ((S) -1-hydroxymethyl-2, 2-dimethyl-propyl) -amide

Prepared according to the procedure outlined in example 54 substituting isopropylamine with (S) -tert-leucinol. MS: (M + H)⁺＝303；mp＝259.0-261.0。

Example 63.

2-cyclopropyl-5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid (2-hydroxy-1-hydroxymethyl-ethyl) -amide

Prepared according to the procedure outlined in example 57 substituting 2-amino-1, 3-propanediol for 3-aminopropionitrile. MS: (M + H)⁺＝277；mp＝255.0-256.7。

Example 64.

2-cyclopropyl-5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ((R) -1-hydroxymethyl-2, 2-dimethyl-propyl) -amide

Prepared according to the procedure outlined in example 54 substituting isopropylamine with (R) -tert-leucinol. MS: (M + H)⁺＝303；mp＝270.0-273.0。

Example 65.

2-cyclopropyl-5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ((R) -1-hydroxymethyl-2-methyl-propyl) -amide

Prepared according to the procedure outlined in example 54 substituting D-valinol for isopropylamine. MS: (M + H)⁺＝289；mp＝250.0-253.0。

Example 66.

2-cyclopropyl-5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ((S) -2-hydroxy-1-methyl-ethyl) -amide

Prepared according to the method outlined in example 54 substituting isopropylamine with L-alaninol。MS：(M+H)⁺＝261；mp＝274.0-276.0。

Example 67.

2-cyclopropyl-5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ((R) -1-hydroxymethyl-propyl) -amide

Prepared according to the procedure outlined in example 54 substituting isopropylamine with (R) - (-) -2-amino-1-butanol. MS: (M + H)⁺＝275；mp＝250.0-253.0。

Example 68.

2-cyclopropyl-5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ((R) -1-cyclohexylethyl) -amide

Prepared according to the procedure outlined in example 54 substituting isopropylamine with (R) - (-) -1-cyclohexylethylamine. MS: (M + H)⁺＝313；mp＝253.0-255.0。

Example 69.

2-cyclopropyl-5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid (2-cyano-1, 2, 2-trimethyl-ethyl) -amide

Step 1

To 3-hydroxy-3-methyl-2-butanone (1.9g, 18.6mmol) and Et at 0 deg.C₃N (3.9mL, 27.9mmol) in CH₂Cl₂(20mL) to a solution of methanesulfonyl chloride (1.6mL, 20.5mmol) in CH₂Cl₂(10 mL). Stirred at room temperature for 2h, then poured into water and treated with CH₂Cl₂And (4) extracting. With 10% aqueous HCl and 5% NaHCO₃The organic layer was washed with aqueous solution and then MgSO₄Drying and concentration gave 1.8g (54%) of 1, 1-dimethyl-2-oxo-propyl methanesulfonate as a white solid.

Step 2

To a solution of methanesulfonic acid 1, 1-dimethyl-2-oxo-propyl ester (1.8g, 10mmol) in DMSO (10mL) was added NaCN (1.47g, 30 mmol). The reaction mixture was stirred at 45 ℃ overnight, then quenched with water and extracted with ether (2 ×). The combined organic layers were washed with brine, MgSO₄Drying and concentration gave 0.52g (25%) of 2, 2-dimethyl-3-oxo-butyronitrile as an oil, which was used without further purification.

Step 3

To a solution of 2, 2-dimethyl-3-oxo-butyronitrile (0.52g, 4.72mmol) in MeOH (10mL) was added ammonium acetate (3.64g, 47.2mmol) and NaCNBH₃(0.296g, 4.72 mmol). The reaction mixture was stirred at rt for 5 days, then cooled to 0 ℃, slowly treated with concentrated HCl to pH 2, and stirred at rt for 15 min. The reaction mixture was concentrated, the residue diluted with water and CH₂Cl₂And (4) extracting. With concentrated NH₄OH alkalinizes the aqueous layer (pH 10) and then CH₂Cl₂And (4) extracting. With MgSO₄The organic layer was dried and concentrated to give 0.031g (6%) of 3-amino-2, 2-dimethyl-butyronitrile as an oil.

Step 4

2-cyclopropyl-5H-pyrrolo [2, 3-b ] is prepared according to the procedure outlined in example 54]Pyrazine-7-carboxylic acid (2-cyano-1, 2, 2-trimethyl-ethyl) -amide, isopropylamine substituted with 3-amino-2, 2-dimethyl-butyronitrile. MS: (M + H) ⁺＝298；mp＝295.0-297.0。

Example 70.

2-cyclopropyl-5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid (3-hydroxy-1, 2, 2-trimethyl-propyl) -amide

Step 1

Ethyl 2, 2-dimethyl-3-oxo-butanoate was prepared according to the method reported in j.am.chem.soc.1988, 110, 1539.

Step 2

To a solution of ethyl 2, 2-dimethyl-3-oxo-butyrate (0.74g, 4.67mmol) in MeOH (10mL) was added ammonium acetate (3.61g, 46.7mmol) and NaCNBH₃(0.29g, 4.67 mmol). The reaction mixture was then stirred at rt overnight, cooled to 0 ℃, slowly treated with concentrated HCl to pH 2 and stirred at rt for 15 min. The reaction mixture was concentrated, the residue diluted with water and CH₂Cl₂And (4) extracting. With concentrated NH₄OH alkalinizes the aqueous layer (pH 10) and then CH₂Cl₂And (4) extracting. With MgSO₄The organic layer was dried and concentrated to give 0.18g (24%) of ethyl 3-amino-2, 2-dimethyl-butyrate as an oil, which was used without further purification.

Step 3

To a solution of 3-amino-2, 2-dimethyl-butyric acid ethyl ester (0.18g, 1.1mmol) in dry THF (3mL) at-78 deg.C was slowly added LiAlH₄(1.0M in THF, 1.2mL, 1.2 mmol). The reaction mixture was warmed to room temperature, stirred for 2h, then quenched with water and CH₂Cl₂And (4) extracting. With MgSO₄The organic layer was dried and concentrated to give 0.85g (66%) of 3-amino-2, 2-dimethyl-butan-1-ol as an oil, which was used without further purification.

Step 4

2-cyclopropyl-5H-pyrrolo [2, 3-b ] is prepared according to the procedure outlined in example 54]Pyrazine-7-carboxylic acid (3-hydroxy-1, 2, 2-trimethyl-propane)Yl) -amide, isopropylamine substituted with 3-amino-2, 2-dimethyl-butan-1-ol. MS: (M + H)⁺＝303；mp＝228.0-270.0。

Example 71.

2-cyclopropyl-5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ((S) -sec-butyl) -amide

Prepared according to the procedure outlined in example 54 substituting isopropylamine with (S) - (+) -2-aminobutane. MS: (M + H)⁺＝259；mp＝280.0-282.0。

Example 72.

2-cyclopropyl-5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ((S) -2-hydroxy-1-isopropyl-2-methyl-propyl) -amide

Step 1

To a solution of N-Boc-L-valine methyl ester (1.5g, 6.49mmol) in THF (10mL) at 0 deg.C was added methylmagnesium bromide (3.0M Et₂Solution O, 9.3mL, 27.9 mmol). The reaction mixture was stirred at room temperature overnight, then quenched with water and CH₂Cl₂(2x) extraction. With MgSO₄The combined organic layers were dried and concentrated to give 1.71g of ((S) -2-hydroxy-1-isopropyl-2-methyl-propyl) -carbamic acid tert-butyl ester as a colorless oil, which was used without further purification.

Step 2

((S) -2-hydroxy-1-isopropyl-2-methyl-propyl) -carbamic acid tert-butyl ester (1.71g, crude from step 1) was dissolved in hydrogen chloride (1.0M in MeOH, 20mL, 20 mmol). The solution was allowed to stand at room temperature Stirred overnight, then concentrated and treated with Et₂O treatment, high vacuum drying, gives 1.42g of (S) -3-amino-2, 4-dimethyl-pentan-2-ol hydrochloride as a light brown oil, which is used without further purification.

Step 3

To 2-cyclopropyl-5- (2-trimethylsilyl-ethoxymethyl) -5H-pyrrolo [2, 3-b]Pyrazine-7-carboxylic acid (100mg, 0.30mmol) in CH₂Cl₂To the solution in (3mL) was added trifluoroacetic acid (1 mL). The reaction mixture was stirred at room temperature for 2h, then concentrated. The residue was dissolved in DMF (5mL) and (S) -3-amino-2, 4-dimethyl-pentan-2-ol hydrochloride (100mg, 0.36mmol), BOP (160mg, 0.36mmol) and Et were added₃N (0.21mL, 1.5 mmol). The reaction mixture was stirred at rt overnight, then diluted with EtOAc and with NaHCO₃Aqueous solution (3 ×) and brine wash. The organic layer was dried and concentrated. By SiO₂The residue was chromatographed, eluting with 0% -100% EtOAc/hexanes, to give 35mg (37%) of 2-cyclopropyl-5H-pyrrolo [2, 3-b ]]Pyrazine-7-carboxylic acid ((S) -2-hydroxy-1-isopropyl-2-methyl-propyl) -amide as a white solid. MS: (M + H)⁺＝317；mp＝232.0-234.0。

Example 73.

2-cyclopropyl-5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ((S) -1, 2-dimethyl-propyl) -amide

Prepared according to the procedure outlined in example 72, step 3, substituting (S) -3-amino-2, 4-dimethyl-pentan-2-ol hydrochloride with (S) - (+) -3-methyl-2-butylamine. MS: (M + H)⁺＝273；mp＝281.0-283.0。

Example 74.

2-cyclopropyl-5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ((R) -2-hydroxy-1, 2-dimethyl-propyl) -amide

Prepared according to the procedure outlined in example 72 substituting N-Boc-D-alanine methyl ester for N-Boc-L-valine methyl ester. MS: (M + H)⁺＝289；mp＝269.0-271.0。

Example 75.

2-cyclopropyl-5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ((R) -1-ethyl-2-hydroxy-2-methyl-propyl) -amide

Prepared according to the procedure outlined in example 72 substituting (R) -2-tert-butoxycarbonylamino-butyric acid methyl ester for N-Boc-L-valine methyl ester. MS: (M + H)⁺＝303；mp＝218.0-222.0。

Example 76.

2-cyclopropyl-5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid (2-hydroxy-1, 1-dimethyl-ethyl) -amide

Prepared according to the procedure outlined in example 72, step 3, substituting 2-amino-2-methyl-1-propanol for (S) -3-amino-2, 4-dimethyl-pentan-2-ol hydrochloride. MS: (M + H)⁺＝275；mp＝293.0-295.0。

Example 77.

2-cyclopropyl-5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid [ (S) -1- (1-hydroxy-1-methyl-ethyl) -pentyl ] -amide

Prepared according to the procedure outlined in example 72 substituting N-Boc-L-norleucine methyl ester for N-Boc-L-valine methyl ester. MS: (M + H) ⁺＝331；mp＝170.0-172.0。

Example 78.

2-cyclopropyl-5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid (1-cyclopropyl-ethyl) -amide

Prepared according to the procedure outlined in example 54 substituting isopropylamine with 1-cyclopropyl-ethylamine. MS: (M + H)⁺＝271；mp＝269.0-272.0。

Example 79.

2-cyclopropyl-5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid (1-ethyl-propyl) -amide

Prepared according to the procedure outlined in example 54 substituting isopropylamine with 1-ethylpropylamine. MS: (M + H)⁺＝273；mp＝245.0-246.0。

Example 80.

2-cyclopropyl-5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid (2-dimethylamino-1-methyl-ethyl) -amide

Prepared according to the procedure outlined in example 54 substituting isopropylamine with 1-dimethylamino-2-propylamine. MS: (M + H)⁺＝288；mp＝225.0-229.0。

Example 81.

2-cyclopropyl-5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ((S) -1-cyclohexylethyl) -amide

Prepared according to the procedure outlined in example 54 substituting isopropylamine with (S) - (+) -1-cyclohexylethylamine. MS: (M + H)⁺＝313；mp＝246.0-249.0。

Example 82.

2-cyclopropyl-5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ((R) -2-hydroxy-1-methyl-ethyl) -amide

Prepared according to the procedure outlined in example 54 substituting isopropylamine with D-alaninol. MS: (M + H)⁺＝261；mp＝265.0-268.0。

Example 83.

2-cyclopropyl-5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ((S) -1-hydroxymethyl-propyl) -amide

Prepared according to the procedure outlined in example 54 substituting isopropylamine with (S) - (+) -2-amino-1-butanol. MS: (M + H)⁺＝275；mp＝250.0-252.0。

Example 84.

2-cyclopropyl-5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid methylamide

Prepared according to the procedure outlined in example 54 substituting isopropylamine with methylamine hydrochloride. MS: (M + H)⁺＝217；mp＝283.0-286.0。

Example 85.

2-cyclopropyl-5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid (2, 2-dimethyl-propyl) -amide

Prepared according to the procedure outlined in example 54 substituting 2, 2-dimethyl-propylamine for isopropylamine. MS: (M + H)⁺＝273。

Example 86.

2-cyclopropyl-5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid [ 2-hydroxy-1- (2-hydroxy-ethyl) -2-methyl-propyl ] -amide

Step 1

To a solution of tert-butyl- (tetrahydro-2-oxo-3-furanyl) -carbamate (2.1g, 10.4mmol) in THF (12mL) at 0 deg.C was slowly added methylmagnesium bromide (3.0M Et₂O solution, 14.5mL, 43.5 mmol). The reaction mixture was stirred at room temperature overnight and then carefully quenched with water. By passingFiltering the mixture with celite and adding CH₂Cl₂Washing, washing the filtrate with brine, drying over sodium sulfate and concentrating gave 1.65g (68%) of 2-hydroxy-1- (2-hydroxy-ethyl) -2-methyl-propyl]Tert-butyl carbamate, as a white solid, which is used without further purification.

Step 2

In a microwave vial, 2-hydroxy-1- (2-hydroxy-ethyl) -2-methyl-propyl ] -carbamic acid tert-butyl ester (100mg, 0.43mmol) was dissolved in hexafluoroisopropanol (5 mL). The vial was sealed and heated at 150 ℃ for 1h under microwave irradiation. The solvent was removed in vacuo to give 83mg of 3-amino-4-methyl-pentane-1, 4-diol as a light brown oil, which was used without further purification.

Step 3

2-cyclopropyl-5H-pyrrolo [2, 3-b ] is prepared according to the procedure outlined in example 54]Pyrazine-7-carboxylic acid [ 2-hydroxy-1- (2-hydroxy-ethyl) -2-methyl-propyl]Amides of isopropylamine substituted with 3-amino-4-methyl-pentane-1, 4-diol. MS: (M + H)⁺＝319；mp＝195.0-198.0。

Example 87.

2-cyclopropyl-5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid [ (S) -1- (1H-pyrazol-3-yl) -ethyl ] -amide

Step 1

2-cyclopropyl-5- (2-trimethylsilyl-ethoxymethyl) -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid [ (S) -1- (1H-pyrazol-3-yl) -ethyl ] -amide was prepared according to the procedure outlined in example 54, step 1, substituting isopropylamine with (S) -1- (1H-pyrazol-3-yl) -ethylamine.

Step 2

To 2-cyclopropyl-5- (2-trimethylsilyl-ethoxymethyl group) -5H-pyrrolo [2, 3-b]Pyrazine-7-carboxylic acid [ (S) -1- (1H-pyrazol-3-yl) -ethyl ]To a solution of amide (230mg, 0.54mmol) in MeOH (9mL) was added 6M aqueous HCl (2 mL). The reaction mixture was stirred at room temperature for 4h and then heated at 80 ℃ overnight. The reaction was cooled to room temperature and K was added₂CO₃(2g) In that respect The reaction was stirred at rt overnight and then concentrated. The residue was diluted with water and extracted with EtOAc. Dried over MgSO4 and concentrated. The residue was triturated with EtOAc/hexanes to give 130mg (81%) of 2-cyclopropyl-5H-pyrrolo [2, 3-b ]]Pyrazine-7-carboxylic acid [ (S) -1- (1H-pyrazol-3-yl) -ethyl]-an amide. MS: (M + H)⁺＝297。

Example 88.

2-cyclopropyl-5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ((R) -1-phenyl-ethyl) -amide

Prepared according to the procedure outlined in example 54 substituting isopropylamine with (R) - (+) -1-phenylethylamine. In step 2, 1.0M NaOH and THF were used instead of MeOH, H₂O and Et₃N。MS：(M+H)⁺＝307；mp＝278.0-280.0。

Example 89.

2-cyclopropyl-5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ((S) -1-phenyl-ethyl) -amide

Prepared according to the procedure outlined in example 54 substituting isopropylamine with (S) - (-) -1-phenylethylamine. In step 2, 1.0M NaOH and THF were used instead of MeOH, H₂O and Et₃N。MS：(M+H)⁺＝307；mp＝272.0-274.0。

Example 90.

2-cyclopropyl-5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid (3-hydroxy-butyl) -amide

Prepared according to the procedure outlined in example 54 substituting isopropylamine with 4-amino-2-butanol. In step 2, 1.0M NaOH and THF were used instead of MeOH, H₂O and Et₃N。MS：(M+H)⁺＝275；mp＝228.0-230.0。

Example 91.

2-cyclopropyl-5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid (3-hydroxy-2-methyl-propyl) -amide

Prepared according to the procedure outlined in example 54 substituting 3-amino-2-methyl-1-propanol for isopropylamine. In step 2, 1.0M NaOH and THF were used instead of MeOH, H₂O and Et₃N。MS：(M+H)⁺＝275；mp＝252.0-254.0。

Example 92.

2-cyclopropyl-5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid (1-pyridin-2-yl-ethyl) -amide

Prepared according to the procedure outlined in example 54 substituting isopropylamine with 1-pyridin-2-yl-ethylamine. In step 2, 1.0M NaOH and THF were used instead of MeOH, H₂O and Et₃N。MS：(M+H)⁺＝308；mp＝217.0-219.0。

Example 93.

2-pyridin-2-yl-5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ((S) -1, 2, 2-trimethyl-propyl) -amide

Step 1

To 2-bromo-5- (2-trimethylsilyl-ethoxymethyl) -5H-pyrrolo [2, 3-b]To a solution of pyrazine-7-carboxylic acid methyl ester (105mg, 0.27mmol) in THF (1mL) was added Pd (PPh)₃)₄(16mg, 0.014 mmol). The reaction mixture was degassed with argon and then 2-pyridylzinc bromide (0.5M in THF, 1.35mL, 0.675mmol) was added. The reaction mixture was heated at 50 ℃ overnight. Cooled to room temperature and then treated with NaHCO ₃The aqueous solution was quenched and extracted with EtOAc. With MgSO₄The organic layer was dried and concentrated. By SiO₂Chromatography (1% -10% MeOH/CH)₂Cl₂) The residue was purified to give 120mg of 2-pyridin-2-yl-5- (2-trimethylsilyl-ethoxymethyl) -5H-pyrrolo [2, 3-b]Pyrazine-7-carboxylic acid methyl ester, a yellow oil, which contains some minor impurities.

Step 2

To 2-pyridin-2-yl-5- (2-trimethylsilyl-ethoxymethyl) -5H-pyrrolo [2, 3-b]To a solution of pyrazine-7-carboxylic acid methyl ester (120mg, 0.27mmol) in THF (2.5mL) was added 1.0M aqueous NaOH solution (1.0 mL). The reaction mixture was stirred at room temperature overnight. The reaction was neutralized to pH 7 with 1.0M aqueous HCl. The resulting precipitate was collected by filtration and then dissolved in 10% MeOH/CH₂Cl₂Dried and concentrated to give 65mg of 2-pyridin-2-yl-5- (2-trimethylsilyl-ethoxymethyl) -5H-pyrrolo [2, 3-b ]]Pyrazine-7-carboxylic acid as a yellow oil.

Step 3

According to implementationPreparation of 2-pyridin-2-yl-5H-pyrrolo [2, 3-b ] by the procedure outlined in example 54]Pyrazine-7-carboxylic acid ((S) -1, 2, 2-trimethyl-propyl) -amide with 2-pyridin-2-yl-5- (2-trimethylsilyl-ethoxymethyl) -5H-pyrrolo [2, 3-b [ ]]Pyrazine-7-carboxylic acid substituted 2-cyclopropyl-5- (2-trimethylsilyl-ethoxymethyl) -5H-pyrrolo [2, 3-b ]Pyrazine-7-carboxylic acid and isopropylamine substituted with (S) -1, 2, 2-trimethyl-propylamine. In step 2, 1.0M NaOH and THF were used instead of MeOH, H₂O and Et₃N。MS：(M+H)⁺＝324；mp＞300.0。

Example 94

2-cyclopropyl-5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ((S) -1-cyclopropyl-2-hydroxy-2-methyl-propyl) -amide

Step 1

(S) -cyclopropyl- ((S) -1-phenyl-ethylamino) -acetic acid was prepared from cyclopropanealdehyde according to the procedure outlined in US 6191306.

Step 2

To a suspension of (S) -cyclopropyl- ((S) -1-phenyl-ethylamino) -acetic acid (0.50g, 2.28mmol) in MeOH (20mL) was slowly added (trimethylsilyl) diazomethane (2.0M Et₂O solution, 5.0mL, 10mmol), the temperature was adjusted periodically using an ice bath. The homogeneous reaction mixture was stirred at room temperature for 1h and then poured into NaHCO₃Aqueous solution of CH₂Cl₂(3x) extracting. With MgSO₄The combined organic layers were dried and concentrated to give 0.42g (79%) of (S) -cyclopropyl- ((S) -1-phenyl-ethylamino) -acetic acid methyl ester as an orange oil, which was used without further purification.

Step 3

To (S) -cyclopropyl- ((S) -1-phenyl-ethylamino) -acetic acid methyl ester (0.42g, 1.8mmol) in THF (8mL) at 0 deg.CTo the solution was slowly added methylmagnesium bromide (3.0M Et)₂O solution, 1.5mL, 4.5 mmol). The reaction mixture was stirred at 0 ℃ for 1h and then with NH ₄Aqueous Cl was quenched, diluted with water, and extracted with EtOAc (2 ×). With MgSO₄The combined organic layers were dried and concentrated. By SiO₂The residue was purified by chromatography (20% -50% EtOAc/hexanes) to give 0.25g (60%) of (S) -1-cyclopropyl-2-methyl-1- ((S) -1-phenyl-ethylamino) -propan-2-ol as a light yellow oil.

Step 4

To a solution of (S) -1-cyclopropyl-2-methyl-1- ((S) -1-phenyl-ethylamino) -propan-2-ol (0.25g, 1.07mmol) in MeOH (8mL) was added 20% Pd (OH)₂Carbon (30 mg). The reaction mixture is reacted in H₂(1atm, balloon) atmosphere stirred for 18h, then filtered through celite, rinsing with EtOAc. The filtrate was concentrated to give 0.16g of (S) -1-amino-1-cyclopropyl-2-methyl-propan-2-ol as a pale yellow oil, which was used without further purification.

Step 5

In a flask, combine 2-cyclopropyl-5H-pyrrolo [2, 3-b ]]Pyrazine-7-carboxylic acid (150mg, 0.74mmol), (S) -1-amino-1-cyclopropyl-2-methyl-propan-2-ol (115mg, 0.89mmol), EDC (155mg, 0.81mmol) and HOBt (109mg, 0.81 mmol). DMF (2mL) was then added followed by i-Pr₂NEt (0.19mL, 1.11 mmol). The reaction mixture was stirred at room temperature overnight and then with H₂O quenched and extracted with EtOAc (3 ×). By H ₂The combined organic layers were washed with O (3X) and then MgSO₄Drying and concentrating. By SiO₂The residue was purified by chromatography (50% -100% EtOAc/hexanes) to give 30mg (13%) of 2-cyclopropyl-5H-pyrrolo [2, 3-b ]]Pyrazine-7-carboxylic acid ((S) -1-cyclopropyl-2-hydroxy-2-methyl-propyl) -amide as a white solid. MS: (M + H)⁺＝315；mp＝238.0-240.0。

Example 95.

2-cyclopropyl-5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ((R) -1-cyclopropyl-2-hydroxy-2-methyl-propyl) -amide

Step 1

To a solution of N-Boc-D-cyclopropylglycine (0.50g, 2.32mmol) in MeOH (20mL) at 0 deg.C was slowly added (trimethylsilyl) diazomethane (2.0M Et)₂O solution, 5.0mL, 10 mmol). The reaction mixture was stirred at room temperature for 1h, then quenched with a small portion of acetic acid and concentrated to give 0.56g of Boc-D-cyclopropylglycine methyl ester as a colorless oil, which was used without further purification.

Step 2

To a solution of N-Boc-D-cyclopropylglycine methyl ester (0.56g, 2.32mmol) in THF (10mL) was slowly added methylmagnesium bromide (3.0M in ether, 2.7mL, 8.1mmol) at 0 deg.C. The reaction mixture was stirred at 0 ℃ for 1h and then saturated NH₄Aqueous Cl was quenched and then extracted with EtOAc (2 ×). The combined organic layers were washed with water and brine, then MgSO ₄Drying and concentrating. Through 24gSiO₂The residue was chromatographed, eluting with 10% -30% EtOAc/hexanes, to give 0.44g (82%) of ((R) -1-cyclopropyl-2-hydroxy-2-methyl-propyl) -carbamic acid tert-butyl ester as a colorless oil.

Step 3

In a round bottom flask ((R) -1-cyclopropyl-2-hydroxy-2-methyl-propyl) -carbamic acid tert-butyl ester (0.44g, 1.92mmol) was dissolved in 1.0M HCl in MeOH (10.0mL, 10.0 mmol). The reaction mixture was stirred at 50 ℃ for 4h, then cooled to room temperature and concentrated to give 0.26g (82%) of (R) -1-amino-1-cyclopropyl-2-methyl-propan-2-ol hydrochloride as a pale pink solid.

Step 4

In a flask, combine 2-cyclopropyl-5H-pyrrolo [2, 3-b ]]Pyrazine-7-carboxylic acid (150mg, 0.74 mm)ol), (R) -1-amino-1-cyclopropyl-2-methyl-propan-2-ol hydrochloride (147mg, 0.89mmol), EDC (155mg, 0.81mmol) and HOBt (109mg, 0.81 mmol). DMF (2mL) was then added followed by i-Pr₂NEt (0.32mL, 1.85 mmol). The reaction mixture was stirred at room temperature overnight and then with H₂O quenched and extracted with EtOAc (3 ×). By H₂The combined organic layers were washed with O (3X) and then MgSO₄Drying and concentrating. The residue was triturated with EtOAc/hexanes to give 69mg (30%) of 2-cyclopropyl-5H-pyrrolo [2, 3-b ] ]Pyrazine-7-carboxylic acid ((R) -1-cyclopropyl-2-hydroxy-2-methyl-propyl) -amide as a white solid. MS: (M + H)⁺＝315；mp＝235.0-237.0。

Example 96.

2-cyclopropyl-5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid (2-cyano-1-cyclopropyl-2, 2-dimethyl-ethyl) -amide

Step 1

To a solution of isobutyronitrile (0.30g, 4.35mmol) in THF (8mL) was added LiHMDS (1.0M in THF, 4.8mL, 4.8mmol) at-78 ℃. The pale yellow reaction mixture was stirred at-78 ℃ for 30min, then 2-methyl-prop-2-sulfinic acid 1-cyclopropyl-methylene- (E) -ylamide (0.50g, 2.90mmol) [ prepared according to WO2008/147800 ]]Solution in THF (2 mL). The reaction mixture was stirred at-78 ℃ for 2h, then saturated NH was added₄Aqueous Cl was quenched and warmed to room temperature. The mixture was diluted with water and extracted with EtOAc (2 ×). With MgSO₄The combined organic layers were dried and concentrated to give 0.70g of 2-methylpropane-2-sulfinic acid (2-cyano-1-cyclopropyl-2, 2-dimethyl-ethyl) -amide as a viscous colorless oil.

Step 2

To a solution of 2-methylpropane-2-sulfinic acid (2-cyano-1-cyclopropyl-2, 2-dimethyl-ethyl) -amide (0.70g, 2.90mmol) in MeOH (5mL) was added a 4.0M HCl in dioxane (1.5mL, 6.0mmol) at room temperature. The reaction mixture was stirred at room temperature for 15min, then concentrated to give 0.45g (89%, 2 steps) of 3-amino-3-cyclopropyl-2, 2-dimethyl-propionitrile hydrochloride as a white solid.

Step 3

In a flask, combine 2-cyclopropyl-5- ((2- (trimethylsilyl) ethoxy) methyl) -5H-pyrrolo [2, 3-b]Pyrazine-7-carboxylic acid (120mg, 0.36mmol), 3-amino-3-cyclopropyl-2, 2-dimethyl-propionitrile hydrochloride (75mg, 0.43mmol), HOBt (54mg, 0.40mmol) and EDC (77mg, 0.40 mmol). DMF (2mL) was then added followed by diisopropylethylamine (0.16mL, 0.90 mmol). The reaction mixture was stirred at rt overnight, then quenched with water and extracted with EtOAc (3 ×). The combined organic layers were washed with water (3 ×), then MgSO₄Drying and concentrating. By SiO₂The residue was purified by chromatography (30% -50% EtOAc/hexanes) to give 121mg (74%) of 2-cyclopropyl-5- (2-trimethylsilyl-ethoxymethyl) -5H-pyrrolo [2, 3-b ]]Pyrazine-7-carboxylic acid (2-cyano-1-cyclopropyl-2, 2-dimethyl-ethyl) -amide as an off-white foam.

Step 4

To 2-cyclopropyl-5- (2-trimethylsilyl-ethoxymethyl) -5H-pyrrolo [2, 3-b]Pyrazine-7-carboxylic acid (2-cyano-1-cyclopropyl-2, 2-dimethyl-ethyl) -amide (110mg, 0.24mmol) in CH₂Cl₂To the solution in (4mL) was added TFA (1 mL). The yellow reaction mixture was stirred for 3h and then concentrated. The residue was redissolved in MeOH (8mL) and water (1mL) and triethylamine (1mL) was added. The reaction mixture was stirred at room temperature overnight and then concentrated. By SiO ₂The residue was purified by chromatography (50% -80% EtOAc/hexanes) and then triturated with EtOAc to give 45mg (58%) of 2-cyclopropyl-5H-pyrrolo [2, 3-b ]]Pyrazine-7-carboxylic acid (2-cyano-1-cyclopropyl-2, 2-dimethyl-ethyl) -amide as a white solid. MS: (M + H)⁺＝324；mp＝230.0-232.0。

Example 97.

3-cyclopropyl-3- [ (2-cyclopropyl-5H-pyrrolo [2, 3-b ] pyrazine-7-carbonyl) -amino ] -2, 2-dimethyl-propionic acid

Step 1

To a solution of methyl isobutyrate (1.18g, 11.5mmol) in THF (15mL) at-78 deg.C was added LiHMDS (1.0M in THF, 12.7mL, 12.7 mmol). The pale yellow reaction mixture was stirred at-78 ℃ for 30min, then 2-methyl-prop-2-sulfinic acid 1-cyclopropyl-methylene- (E) -ylamide (1.0g, 5.8mmol) [ prepared according to WO2008/147800 ]]Solution in THF (5 mL). The reaction mixture was stirred at-78 ℃ for 2h, then brought to room temperature over 1h, with saturated NH₄Aqueous Cl solution was quenched. The mixture was diluted with water and extracted with EtOAc (2 ×). With MgSO₄The combined organic layers were dried and concentrated. By SiO₂The residue was purified by chromatography (30% -50% EtOAc/hexanes) to give 1.15g (72%) of methyl 3-cyclopropyl-2, 2-dimethyl-3- (2-methyl-propane-2-sulfinylamino) -propionate as a colorless oil.

Step 2

To a solution of 3-cyclopropyl-2, 2-dimethyl-3- (2-methyl-propane-2-sulfinylamino) -propionic acid methyl ester (1.15g, 4.17mmol) in MeOH (10mL) was added 4.0M HCl in dioxane (2.1mL, 8.4mmol) at room temperature. The reaction mixture was stirred at room temperature for 30min, then concentrated to give 0.81g (94%) of 3-amino-3-cyclopropyl-2, 2-dimethyl-propionic acid methyl ester hydrochloride as a white solid.

Step 3

In a flask, combine 2-cyclopropyl-5- ((2- (trimethylsilyl) ethoxy) methyl) -5H-pyrrolo [2, 3-b]Pyrazine-7-carboxylic acid (200mg, 0.60mmol), 3-amino-3-cyclopropyl-2, 2-dimethyl-propionic acid methyl ester hydrochloride (150mg, 0.72mmol), HOBt (90mg, 0.66mmol) and EDC(127mg, 0.66 mmol). DMF (3mL) was then added followed by diisopropylethylamine (0.26mL, 1.50 mmol). The reaction mixture was stirred at rt overnight, then quenched with water and extracted with EtOAc (3 ×). The combined organic layers were washed with water (3 ×), then MgSO₄Drying and concentrating. By SiO₂The residue was purified by chromatography (30% EtOAc/hexanes) to give 264mg (90%) of 3-cyclopropyl-3- { [ 2-cyclopropyl-5- (2-trimethylsilyl-ethoxymethyl) -5H-pyrrolo [2, 3-b ] ]Pyrazine-7-carbonyl]-amino } -2, 2-dimethyl-propionic acid methyl ester as viscous colorless oil.

Step 4

To 3-cyclopropyl-3- { [ 2-cyclopropyl-5- (2-trimethylsilyl-ethoxymethyl) -5H-pyrrolo [2, 3-b]Pyrazine-7-carbonyl]-amino } -2, 2-dimethyl-propionic acid methyl ester (110mg, 0.23mmol) in CH₂Cl₂To the solution in (4mL) was added TFA (1 mL). The yellow reaction mixture was stirred for 3h and then concentrated. Redissolving the residue in CH₂Cl₂(4mL), ethylenediamine (0.5mL) was added. The reaction mixture was stirred at room temperature for 1h, then concentrated. By SiO₂The residue was purified by chromatography (50% -80% EtOAc/hexanes) to isolate 56mg (70%) of 3-cyclopropyl-3- [ (2-cyclopropyl-5H-pyrrolo [2, 3-b ])]Pyrazine-7-carbonyl) -amino]-methyl 2, 2-dimethyl-propionate as white solid.

Step 5

3-cyclopropyl-3- [ (2-cyclopropyl-5H-pyrrolo [2, 3-b ]]Pyrazine-7-carbonyl) -amino]A sample of methyl-2, 2-dimethyl-propionate (56mg, 0.157mmol) was dissolved in MeOH (1.5mL), THF (1.5mL), and H₂O (0.75 mL). Then adding LiOH & H₂O (20mg, 0.471mmol), stirred at 50 ℃ for 18 h. Cooled to room temperature and concentrated. The residue was diluted with water and acidified to pH 4 with 1.0M HCl. The mixture was extracted with EtOAc (2 ×). The combined organic layers were dried with MgSO4 and concentrated to give 54mg (99%) of 3-cyclopropyl-3- [ (2-cyclopropyl-5H-pyrrolo [2, 3-b ] ]Pyrazine-7-carbonyl) -amino]2, 2-dimethyl-propionic acid as white solid. MS: (M + H)⁺＝343；mp＝265.0-267.0。

Example 98.

2-cyclopropyl-5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid (1-cyclopentyl-ethyl) -amide

Prepared according to the procedure outlined in example 1, steps 4-5, substituting 1- ((R) -1-amino-ethyl) -cyclopentanol hydrochloride with 1-cyclopentylethylamine. MS: (M + H)⁺＝299。

Example 99.

2-cyclopropyl-5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ((1S, 2R, 3S) -1-cyclohexylmethyl-3-cyclopropyl-2, 3-dihydroxy-propyl) -amide

Prepared according to the method outlined in steps 4-5 of example 1, using (1S, 2R, 3S) -3-amino-4-cyclohexyl-1-cyclopropyl-butane-1, 2-diol [ as prepared in bioorg.med.chem.lett.2005, 15, 3292]Substituted 1- ((R) -1-amino-ethyl) -cyclopentanol hydrochloride. MS: (M + H)⁺＝413。

Example 100.

2-cyclopropyl-5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid (1-cyano-2-methyl-propyl) -amide

Prepared according to the procedure outlined in example 1, steps 4-5, substituting 2-amino-3-methyl-butyronitrile for 1- ((R) -1-amino-ethyl) -cyclopentanol hydrochloride. MS: (M + H)⁺＝284。

Example 101.

2-cyclopropyl-5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid (cyano-cyclopropyl-methyl) -amide

Prepared according to the procedure outlined in steps 3-5 of example 1, substituting (cyano-cyclopropyl-methyl) -carbamic acid tert-butyl ester for [ (R) -1- (1-hydroxycyclopentyl) -ethyl ]-carbamic acid tert-butyl ester. MS: (M + H)⁺＝282。

Example 102.

2-cyclopropyl-5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid [ (R) -cyclopropyl- (1-hydroxy-cyclopentyl) -methyl ] -amide

Step 1

(R) -cyclopropyl- ((R) -1-phenyl-ethylamino) -acetic acid was prepared from cyclopropane aldehyde according to the procedure outlined in US 6191306.

Step 2

To a suspension of (R) -cyclopropyl- ((R) -1-phenyl-ethylamino) -acetic acid (0.50g, 2.28mmol) in MeOH (20mL) at 0 ℃ was slowly added thionyl chloride (1.66mL, 22.8 mmol). The homogeneous reaction mixture was stirred at room temperature for 4h and then heated to 60 ℃ overnight. The reaction was cooled to room temperature and concentrated. The residue was diluted with water and brought to pH 9 with 1.0M NaOH. With Et₂O (2X) extraction followed by MgSO₄The organic layer was dried and concentrated to give 0.37g (70%) of (R) -cyclopropyl- ((R) -1-phenyl-ethylamino) -acetic acid methyl ester as a light brown oil, which was used without further purification.

Step 3

To a solution of (R) -cyclopropyl- ((R) -1-phenyl-ethylamino) -acetic acid methyl ester (0.37g, 1.58mmol) in THF (12mL) at 0 deg.C was slowly added allylmagnesium bromide (1.0M Et₂O solution, 5.5mL, 5.5 mmol). The resulting white slurry was stirred at 0 ℃ for 1h, then at room temperature for 3 h. The reaction mixture was cooled to 0 ℃ with saturated NH ₄Aqueous Cl solution was quenched and then with H₂Diluted with O and extracted with EtOAc. By H₂The combined organic layers were washed with MgSO₄Drying and concentrating. By SiO₂The residue was purified by chromatography (10% -25% EtOAc/hexanes) to give 0.37g (82%) of 4- [ (R) -cyclopropyl- ((R) -1-phenyl-ethylamino) -methyl]-hepta-1, 6-dien-4-ol as a colorless oil.

Step 4

To 4- [ (R) -cyclopropyl- ((R) -1-phenyl-ethylamino) -methyl]To a solution of hepta-1, 6-dien-4-ol (0.37g, 1.3mmol) in toluene (40mL) was added a second generation Grubbs catalyst (0.044g, 0.05 mmol). The purplish red reaction mixture was heated at 100 ℃ overnight. Concentrating the reaction mixture through SiO₂Purification by chromatography (20% -50% EtOAc/hexanes) provided 134mg (40%) of 1- [ (R) -cyclopropyl- ((R) -1-phenyl-ethylamino) -methyl]Cyclopent-3-enol, which is a brown oil.

Step 5

To 1- [ (R) -cyclopropyl- ((R) -1-phenyl-ethylamino) -methyl]Addition of 20% Pd (OH) to a solution of cyclopent-3-enol (134mg, 0.52mmol) in MeOH (8mL)₂Carbon (20 mg). The reaction mixture is reacted in H₂(1atm) stirring overnight under an atmosphere, then filtering through celite, rinsing with EtOAc. The filtrate was concentrated to give 74mg (90%) of 1- ((R) -amino-cyclopropyl-methyl) -cyclopentanol as a light brown oil.

Step 6

2-cyclopropyl-5H-pyrrolo [2, 3-b ] is prepared according to the procedure outlined in example 1, Steps 4-5]Pyrazine-7-carboxylic acid [ (R) -cyclopropyl- (1-hydroxy-cyclopentyl)Methyl radical) -methyl radical]Amide, 1- ((R) -1-amino-ethyl) -cyclopentanol hydrochloride by 1- ((R) -amino-cyclopropyl-methyl) -cyclopentanol. MS: (M + H)⁺＝341；mp＝195.0-197.0。

Example 103.

2-cyclopropyl-5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ((1S, 2S) -2-hydroxy-1, 2-dimethyl-butyl) -amide

Step 1

A solution of N- (tert-butoxycarbonyl) -L-alanine-N '-methoxy-N' -methylamide (5.49g, 23.64mmol) in dry THF (100ml) was cooled to-25 ℃ under an argon atmosphere. To this was added a solution of methylmagnesium bromide (22ml, 66mmol, 3M in ether). The mixture was stirred at-25 ℃ for 1 hour and then warmed to room temperature overnight. The mixture was cooled in an ice bath and treated dropwise with a 1N hydrochloric acid solution (60ml, aqueous solution). Water (60ml) and ethyl acetate (60ml) were added and the material was shaken in a separatory funnel. The ethyl acetate phase was collected and washed successively with 2X120ml water. The aqueous phase was back-extracted with ethyl acetate (2X80 mL). The organic phases were combined, dried (magnesium sulfate), filtered and concentrated on a rotary evaporator. The crude material was purified by filtration through a short pad of silica gel eluting with 20% ethyl acetate/hexane to give 4.34g of ((S) -1-methyl-2-oxo-propyl) -carbamic acid tert-butyl ester as a white solid. ¹H NMR (300MHz, chloro FORM-d) δ ppm 1.35(d, J ═ 7.2Hz, 3H)1.44(s, 9H)1.61(s, 3H)4.28-4.37(m, 1H)5.27(br s, 1H).

Step 2

To a cold (ice bath, 0 ℃) solution of ((S) -1-methyl-2-oxo-propyl) -carbamic acid tert-butyl ester (600mg, 3.2mmol) in tetrahydrofuran (20mL) was added a solution of 1M ethyl magnesium bromide (9.6mL, 9.6mmol) in ether by slow dropwise addition under an argon atmosphere. The material was stirred at 0 ℃ for 20 minutes, thenWarm to ambient temperature overnight. 0.5N hydrochloric acid solution (60ml, aq.) and ethyl acetate (60ml) were added and the material shaken in a separatory funnel. The ethyl acetate phase was collected and washed with brine (60 ml). The aqueous phase was back-extracted with ethyl acetate (2X40 mL). The combined organic phases were dried over magnesium sulfate and filtered. The solvent was removed and the remaining material was filtered through a short pad of silica gel eluting with 20% ethyl acetate/hexanes to give 630mg of ((1S, 2S) -2-hydroxy-1, 2-dimethyl-butyl) -carbamic acid tert-butyl ester as a yellow-brown semi-viscous oil (major diastereomer: 3: 1 mixture). (M + H)⁺＝218。

Step 3

To a solution of ((1S, 2S) -2-hydroxy-1, 2-dimethyl-butyl) -carbamic acid tert-butyl ester (620mg, 3.2mmol) in dry dichloromethane (4ml) was added trifluoroacetic acid (4ml) dropwise. The flask was capped and stirred for about 30 minutes. The volatile materials were removed, the resulting material was dissolved in toluene (25ml), and the solvent was removed by a rotary evaporator. This procedure was repeated once more and the remaining material was evacuated with a mechanical pump to give the product (2S, 3S) -2-amino-3-methyl-pentan-3-ol trifluoroacetate as a viscous brownish red oil which was used without further purification.

Step 4

(2S, 3S) -2-amino-3-methyl-pentan-3-ol trifluoroacetate from step 3 is reacted with 2-cyclopropyl-5- (2-trimethylsilyl-ethoxymethyl) -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid under the conditions shown in step 4 of example 1 to give 2-cyclopropyl-5- (2-trimethylsilyl-ethoxymethyl) -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ((1S, 2S) -2-hydroxy-1, 2-dimethyl-butyl) -amide.

Step 5

2-cyclopropyl-5- (2-trimethylsilyl-ethoxymethyl) -5H-pyrrolo [2, 3-b ] from step 4]Deprotection of pyrazine-7-carboxylic acid ((1S, 2S) -2-hydroxy-1, 2-dimethyl-butyl) -amide under the conditions described in example 1, step 5 gave 2-cyclopropyl-5H-pyrrolo [2, 3-b ] -c]Pyrazine-7-carboxylic acid ((1S, 2S) -2-hydroxy-1,2-dimethyl-butyl) -amide as a white crystalline solid. MS: (M + H)⁺＝303；mp＝243.0-245.0。

Example 104.

2-cyclopropyl-5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ((1S, 2R) -2-hydroxy-1, 2-dimethyl-butyl) -amide

Prepared according to the method outlined in example 103 substituting methyl magnesium bromide with ethyl magnesium bromide in step 1 and ethyl magnesium bromide with methyl magnesium bromide in step 2. The product of step 2 is a 3: 2 mixture of diastereomers in favor of the desired (1S, 2R) configuration. The final product contained 18% of the (1S, 2S) diastereomer. MS: (M + H) ⁺＝303；mp＝262.0-264.0。

Example 105.

2-cyclopropyl-5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ((1S, 2S) -3-cyclopropyl-2-hydroxy-1, 2-dimethyl-propyl) -amide

Step 1

((1S, 2S) -2-hydroxy-1, 2 dimethyl-pent-4-enyl) -carbamic acid tert-butyl ester was prepared according to the method outlined in example 103, step 2, substituting allylmagnesium bromide for ethylmagnesium bromide.

Step 2

(2S, 3S) -2-amino-3-methylhexan-5-en-3-ol trifluoroacetate was prepared according to the procedure outlined in example 103, step 3, substituting ((1S, 2S) -2-hydroxy-1, 2 dimethyl-pent-4-enyl) -carbamic acid tert-butyl ester with ((1S, 2S) -2-hydroxy-1, 2 dimethyl-butyl) -carbamic acid tert-butyl ester.

Step 3

2-cyclopropyl-5- (2-trimethylsilyl-ethoxymethyl) -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ((1S, 2S) -2-hydroxy-1, 2-dimethyl-pent-4-enyl) -amide was prepared according to the procedure outlined in example 103 step 4, substituting (2S, 3S) -2-amino-3-methylhexan-5-en-3-ol trifluoroacetate for (2S, 3S) -2-amino-3-methyl-pent-3-ol trifluoroacetate.

Step 4

To a solution of 2-cyclopropyl-5- (2-trimethylsilyl-ethoxymethyl) -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ((1S, 2S) -2-hydroxy-1, 2-dimethyl-pent-4-enyl) -amide (98mg, 0.23mmol) in tetrahydrofuran (2mL) and diethyl ether (0.5mL) was added palladium acetate (5mg. catalyst) and the mixture was cooled with an ice bath. Diazomethane solution (6-8mL, 0.5M in ether) was added dropwise and the material was allowed to stand for 30 minutes while cooling and stirring occasionally. Additional diazomethane solution (4mL) was added with occasional stirring. After 10 minutes, the material was filtered through a pad of celite, rinsing well with ethyl acetate. The volatiles were evaporated to give 132mg of crude 2-cyclopropyl-5- (2-trimethylsilyl-ethoxymethyl) -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ((1S, 2S) -3-cyclopropyl-2-hydroxy-1, 2-dimethyl-propyl) -amide, which was used in the next step without further purification.

Step 5

2-cyclopropyl-5H-pyrrolo [2, 3-b ] was prepared according to the procedure outlined in step 5, example 103]Pyrazine-7-carboxylic acid ((1S, 2S) -3-cyclopropyl-2-hydroxy-1, 2-dimethyl-propyl) -amide with 2-cyclopropyl-5- (2-trimethylsilyl-ethoxymethyl) -5H-pyrrolo [2, 3-b ]]Pyrazine-7-carboxylic acid ((1S, 2S) -3-cyclopropyl-2-hydroxy-1, 2-dimethyl-propyl) -amide substituted 2-cyclopropyl-5- (2-trimethylsilyl-ethoxymethyl) -5H-pyrrolo [2, 3-b)]Pyrazine-7-carboxylic acid ((1S, 2S) -2-hydroxy-1, 2-dimethyl-butyl) -amide. The product was isolated as a light yellow solid. MS: (M + H)⁺＝329。

Example 106.

2-cyclopropyl-5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ((1S, 2R) -3-cyclopropyl-2-hydroxy-1, 2-dimethyl-propyl) -amide

Step 1

((S) -1-methyl-2-oxo-pent-4-enyl) -carbamic acid tert-butyl ester was prepared according to the method outlined in example 103, step 1, substituting allylmagnesium bromide for methylmagnesium bromide.

Step 2

((1S, 2R) -2-hydroxy-1, 2-dimethyl-pent-4-enyl) -carbamic acid tert-butyl ester was prepared according to the method outlined in example 103, step 2, substituting methyl magnesium bromide for ethyl magnesium bromide.

Step 3

(2S, 3R) -2-amino-3-methylhexan-5-en-3-ol trifluoroacetate was prepared according to the procedure outlined in example 103 step 3 substituting ((1S, 2S) -2-hydroxy-1, 2-dimethyl-pent-4-enyl) -carbamic acid tert-butyl ester with ((1S, 2R) -2-hydroxy-1, 2-dimethyl-butyl) -carbamic acid tert-butyl ester.

Step 4

2-cyclopropyl-5- (2-trimethylsilyl-ethoxymethyl) -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ((1S, 2R) -2-hydroxy-1, 2-dimethyl-pent-4-enyl) -amide was prepared according to the procedure outlined in example 103 step 4, substituting (2S, 3S) -2-amino-3-methylhexan-5-en-3-ol trifluoroacetate for (2S, 3S) -2-amino-3-methyl-pent-3-ol trifluoroacetate.

Step 5

2-cyclopropyl-5- (2-trimethylsilyl-ethoxymethyl) -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ((1S, 2R) -3-cyclopropyl-2-hydroxy-1, 2-dimethyl-propyl) -amide was prepared according to the procedure outlined in example 105, step 4, substituting 2-cyclopropyl-5- (2-trimethylsilyl-ethoxymethyl) -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ((1S, 2R) -2-hydroxy-1, 2-dimethyl-pent-4-enyl) -amide for 2-cyclopropyl-5- (2-trimethylsilyl-ethoxymethyl) -5H-penten-4-enyl) -amide -pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ((1S, 2S) -2-hydroxy-1, 2-dimethyl-pent-4-enyl) -amide.

Step 6

2-cyclopropyl-5H-pyrrolo [2, 3-b ] was prepared according to the procedure outlined in step 5, example 103]Pyrazine-7-carboxylic acid ((1S, 2R) -3-cyclopropyl-2-hydroxy-1, 2-dimethyl-propyl) -amide with 2-cyclopropyl-5- (2-trimethylsilyl-ethoxymethyl) -5H-pyrrolo [2, 3-b ] ]Pyrazine-7-carboxylic acid ((1S, 2R) -3-cyclopropyl-2-hydroxy-1, 2-dimethyl-propyl) -amide substituted 2-cyclopropyl-5- (2-trimethylsilyl-ethoxymethyl) -5H-pyrrolo [2, 3-b)]Pyrazine-7-carboxylic acid ((1S, 2S) -2-hydroxy-1, 2-dimethyl-butyl) -amide. MS: (M + H)⁺＝329。

Example 107.

2-cyclopropyl-5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ((1S, 2R) -3, 3, 3-trifluoro-2-hydroxy-1, 2-dimethyl-propyl) -amide

According to Andres, j.m.; pedrosa, r.; (2R, 3S) -3-amino-1, 1, 1-trifluoro-2-methyl-butan-2-ol was prepared from (S) -2-dibenzylamino-propionaldehyde by the method of Perez-Encabo, A.Eur.J.org.chem.2004, 1558-za-1566 and references therein. 2-cyclopropyl-5H-pyrrolo [2, 3-b ] is prepared according to the procedure outlined in example 1, Steps 4-5]Pyrazine-7-carboxylic acid ((1S, 2R) -3, 3, 3-trifluoro-2-hydroxy-1, 2-dimethyl-propyl) -amide, 1- ((R) -1-amino-ethyl) -cyclopentanol hydrochloride substituted with (2R, 3S) -3-amino-1, 1, 1-trifluoro-2-methyl-butan-2-ol. MS: (M + H)⁺＝343；mp＝280.0-283.0。

Example 108.

2-cyclopropyl-5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ((1S, 2S) -3, 3, 3-trifluoro-2-hydroxy-1, 2-dimethyl-propyl) -amide

Step 1

(S) -2-dibenzylamino-N-methoxy-N-methyl-propionamide (492mg, 1.57mmol) [ synthesis described in: josop Bonj och et al, tetra hour 2006, 62, 9166- ]Dissolved in dry tetrahydrofuran (10 mL). The reaction mixture was stirred at 0 ℃ for 3 h by adding dropwise a 3M solution of methylmagnesium bromide (2.1mL, 6.3 mmol). Saturated ammonium chloride solution (20mL, aq) was added, followed by water (40mL) and ethyl acetate (60 mL). The mixture was transferred to a separatory funnel and shaken. The ethyl acetate phase was collected and washed with brine (60 mL). The aqueous phase was back-extracted with ethyl acetate (2X40mL), dried over magnesium sulfate, filtered, and removed to give the crude product. The residue was dissolved in dichloromethane and filtered through a short silica gel column to give 401mg of (S) -3-dibenzylamino-butan-2-one as a yellowish brown oil. (M + H)⁺＝268。

Step 2

To a solution of (S) -3-dibenzylamino-butan-2-one (400mg, 1.5mmol) in dry tetrahydrofuran (7mL) was added tetra-N-butylammonium fluoride (0.08mL, 1.0M in THF), and the reaction mixture was cooled to 0 deg.C under an argon atmosphere (ice bath). Trimethyl (trifluoromethyl) silane (0.35mL, 2.25mmol) was added dropwise and stirred at 0 ℃ for 30 min. Saturated ammonium chloride solution (20mL, aq) was added and most of the solvent was removed using a rotary evaporator. The remaining material was dissolved in ether (40mL) and water (40mL) and transferred to a separatory funnel. The mixture was shaken and the ether phase was collected and washed with brine. Back-extracting the aqueous phase with diethyl ether (2X30mL), and combining And dried over magnesium sulfate, filtered, and removed to give a crude silyl ether intermediate. The material was purified by preparative TLC (using 2 plates, eluting with 30% ethyl acetate/hexanes) to give a semi-flowing oil (462 mg). This material was dissolved in dry tetrahydrofuran (5mL) and tetra-N-butylammonium fluoride solution (0.4mL, 1.0M in THF) was added. The material was stirred for 1 hour and then worked up as described above. The crude product was dissolved in dichloromethane and filtered through a short pad of silica gel. The solvent was removed to give 402mg of the desired (2S, 3S) -3-dibenzylamino-1, 1, 1-trifluoro-2-methyl-butan-2-ol as a clear semi-viscous oil. (M + H)⁺＝338。

Step 3

(2S, 3S) -3-dibenzylamino-1, 1, 1-trifluoro-2-methyl-butan-2-ol (130mg, 0.42mmol) was dissolved in methanol (4ml) and Pearlmann catalyst (40mg) was added. The flask was evacuated and placed in a hydrogen balloon. The mixture was stirred overnight, then filtered through a pad of celite, rinsing well with methanol. To this material was added hydrochloric acid solution (1.5ml, about 50% ethanol solution). The solvent was removed with a rotary evaporator to give (2S, 3S) -3-amino-1, 1, 1-trifluoro-2-methyl-butan-2-ol hydrochloride as an off-white semi-solid (82mg), which was used without further purification.

Step 4

2-cyclopropyl-5H-pyrrolo [2, 3-b ] is prepared according to the procedure outlined in example 1, Steps 4-5]Pyrazine-7-carboxylic acid ((1S, 2S) -3, 3, 3-trifluoro-2-hydroxy-1, 2-dimethyl-propyl) -amide, 1- ((R) -1-amino-ethyl) -cyclopentanol hydrochloride was substituted with (2S, 3S) -3-amino-1, 1, 1-trifluoro-2-methyl-butan-2-ol hydrochloride. MS: (M + H)⁺＝343；mp＝290.0-292.0。

Example 109.

2-cyclopropyl-5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ((1R, 2R) -2-hydroxy-1, 2-dimethyl-butyl) -amide

Prepared according to the procedure outlined in example 103 substituting N- (tert-butoxycarbonyl) -L-alanine-N '-methoxy-N' -methylamide with N- (tert-butoxycarbonyl) -D-alanine-N '-methoxy-N' -carboxamide in step 1. The product of step 2 was a 4: 1 mixture of diastereomers in favor of the desired (1R, 2R) configuration. In step 3, HCl/MeOH was used instead of TFA to deprotect the Boc group. Diastereoisomers were separated using preparative HPLC after step 4. MS: (M + H)⁺＝303；mp＝245.0-247.0。

Example 110.

2-cyclopropyl-5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ((1R, 2R) -2-hydroxy-1, 2-dimethyl-pentyl) -amide

Prepared according to the procedure outlined in example 103 substituting N- (tert-butoxycarbonyl) -L-alanine-N '-methoxy-N' -methylamide with N- (tert-butoxycarbonyl) -D-alanine-N '-methoxy-N' -methylamide in step 1 and ethylmagnesium bromide with propylmagnesium chloride in step 2. The product of step 2 is a 4: 1 mixture of diastereomers in favor of the desired (1R, 2R) configuration. In step 3, HCl/MeOH was used in place of TFA to deprotect the Boc group. Diastereoisomers were separated using preparative HPLC after step 4. MS: (M + H) ⁺＝317；mp＝222.0-224.0。

Example 111.

2-cyclopropyl-5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ((1R, 2R) -3-cyano-2-hydroxy-1, 2-dimethyl-propyl) -amide

Step 1

((R) -1-methyl-2-oxo-propyl) -carbamic acid tert-butyl ester was prepared according to the method outlined in example 21 step 1, substituting N- (tert-butoxycarbonyl) -L-alanine-N '-methoxy-N' -methylamide with N- (tert-butoxycarbonyl) -D-alanine-N '-methoxy-N' -carboxamide.

Step 2

To a solution of acetonitrile (0.50mL, 9.5mmol) in THF (25mL) was added lithium bis (trimethylsilyl) amide (1.0M in THF, 9.5mL, 9.5mmol) at-78 ℃. The reaction mixture was stirred at-78 ℃ for 30min, then a solution of ((R) -1-methyl-2-oxo-propyl) -carbamic acid tert-butyl ester (400mg, 2.1mmol) in THF (5mL) was added dropwise. The reaction mixture was stirred at-78 ℃ for 2h, then saturated NH was added₄Aqueous Cl was quenched and warmed to room temperature. The mixture was diluted with water and extracted with EtOAc (2 ×). The combined organic layers were washed with water and brine, then dried over sodium sulfate and concentrated. Passing 24g of SiO₂The residue was chromatographed, eluting with 0% to 40% EtOAc in hexanes, to give 453mg (93%) of ((1R, 2R) -3-cyano-2-hydroxy-1, 2-dimethyl-propyl) -carbamic acid tert-butyl ester as a light yellow oil with 95: 5dr as judged by NMR analysis.

Step 3

((1R, 2R) -3-cyano-2-hydroxy-1, 2-dimethyl-propyl) -carbamic acid tert-butyl ester (180mg, 0.78mmol) was dissolved in hydrogen chloride (1.0 in MeOH, 5mL, 5 mmol). The solution was stirred at room temperature overnight and then concentrated to give 87mg of (3R, 4R) -4-amino-3-hydroxy-3-methyl-valeronitrile hydrochloride as a brown solid which was used without further purification.

Step 4

2-cyclopropyl-5H-pyrrolo [2, 3-b ] is prepared according to the procedure outlined in example 1, Steps 4-5]Pyrazine-7-carboxylic acid ((1R, 2R) -3-cyano-2-hydroxy-1, 2-dimethyl-propyl) -amide substituted by (3R, 4R) -4-amino-3-hydroxy-3-methyl-valeronitrile hydrochloride((R) -1-amino-ethyl) -cyclopentanol hydrochloride. MS: (M + H)⁺＝314；mp＝234.0-236.0。

Example 112.

2-cyclopropyl-5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid cyclohexylmethyl-amide

Step 1

To 2-cyclopropyl-5- (2-trimethylsilyl-ethoxymethyl) -5H-pyrrolo [2, 3-b]To a solution of pyrazine-7-carboxylic acid (80mg, 0.24mmol) in THF (2mL) was added 1, 1' -carbonyldiimidazole (47mg, 0.29 mmol). The reaction mixture was stirred at 60 ℃ for 45min, then cooled to room temperature and cyclohexane methylamine (0.31mL, 2.4mmol) was added. The reaction mixture was stirred at rt for 3h, then quenched with water and extracted with EtOAc (2 ×). The combined organic layers were washed with water and brine, then dried over sodium sulfate and concentrated. Passing through 8g of SiO ₂The residue was purified by chromatography, eluting with 0% -40% EtOAc/hexanes, to give 102mg (99%) of 2-cyclopropyl-5- (2-trimethylsilyl-ethoxymethyl) -5H-pyrrolo [2, 3-b ]]Pyrazine-7-carboxylic acid cyclohexylmethyl-amide, which is an off-white solid.

Step 2

2-cyclopropyl-5H-pyrrolo [2, 3-b ] is prepared according to the procedure outlined in step 5 of example 1]Pyrazine-7-carboxylic acid cyclohexylmethyl-amide from 2-cyclopropyl-5- (2-trimethylsilyl-ethoxymethyl) -5H-pyrrolo [2, 3-b]Pyrazine-7-carboxylic acid cyclohexylmethyl-amide substituted 2-cyclopropyl-5- (2-trimethylsilylethoxymethyl) -5H-pyrrolo [2, 3-b]Pyrazine-7-carboxylic acid [ (R) -1- (1-hydroxy-cyclopentyl) -ethyl]-an amide. MS: (M + H)⁺＝299；mp＝284.2.0-284.7。

Example 113.

2-cyclopropyl-5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid (1-methanesulfonyl-piperidin-3-ylmethyl) -amide

Step 1

A10 mL round bottom flask was charged with 2-cyclopropyl-5- ((2- (trimethylsilyl) ethoxy) methyl) -5H-pyrrolo [2, 3-b ]]Pyrazine-7-carboxylic acid (250mg, 0.75mmol), 3- (aminomethyl) -1-N-Boc-piperidine (241mg, 1.12mmol), HOBT (111mg, 0.82mmol) and EDC (158mg, 0.82 mmol). DMF (3.3mL) was then added followed by N, N-diisopropylethylamine (0.20mL, 1.12 mmol). The yellow reaction mixture was stirred at room temperature overnight and then with H ₂Quenching with O (5mL) and Et₂O (2 × 50 mL). By H₂The combined organic layers were washed 2 times with brine 1 time, then with Na₂SO₄Drying, filtering and concentrating. By using EtOAc/hexanes (gradient: 0-40% EtOAc) 24g SiO₂The residue was purified by chromatography to give 393mg (99%) of 3- ({ [ 2-cyclopropyl-5- (2-trimethylsilyl-ethoxymethyl) -5H-pyrrolo [2, 3-b ]]Pyrazine-7-carbonyl]-amino } -methyl) -piperidine-1-carboxylic acid tert-butyl ester as a light yellow oil.

Step 2

In a 25mL round bottom flask, 3- ({ [ 2-cyclopropyl-5- (2-trimethylsilyl-ethoxymethyl) -5H-pyrrolo [2, 3-b ] pyrazine-7-carbonyl ] -amino } -methyl) -piperidine-1-carboxylic acid tert-butyl ester (0.39g, 0.74mmol) was dissolved in MeOH (6.0 mL). The solution was cooled to 0 ℃ and acetyl chloride (1.05mL, 14.8mmol) was added dropwise over 10 min. The ice bath was removed and the reaction mixture was stirred at room temperature for 1.5 h. The solvent was evaporated at room temperature and the residue dried under high vacuum to give 339mg (98%) of 2-cyclopropyl-5- (2-trimethylsilyl-ethoxymethyl) -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid (piperidin-3-ylmethyl) -amide hydrochloride as a light yellow foam.

Step 3

In a 15mL round bottom flask, 2-cyclopropyl-5- (2-trimethylsilyl-ethoxymethyl) -5H-pyrrolo [2, 3-b ]Pyrazine-7-carboxylic acid (piperidin-3-ylmethyl) -amide hydrochloride (160mg, 0.34mmol) was dissolved in CH₂Cl₂(3mL), cool to 0 ℃. Triethylamine (0.11mL, 0.75mmol) was added followed by methanesulfonyl chloride (0.032mL, 0.41 mmol). The reaction mixture was stirred at room temperature for 7h, then with 25ml CH₂Cl₂Dilute and wash with water (5 mL). By CH₂Cl₂The aqueous layer was extracted (25mL) and Na was added₂SO₄The combined organic layers were dried, filtered, and concentrated. By using EtOAc/hexanes (gradient: 0-100% EtOAc) 8g SiO₂The residue is purified by chromatography to yield 171mg (98%) of 2-cyclopropyl-5- (2-trimethylsilyl-ethoxymethyl) -5H-pyrrolo [2, 3-b ]]Pyrazine-7-carboxylic acid (1-methanesulfonyl-piperidin-3-ylmethyl) -amide as an off-white foam.

Step 4

In a 10mL round bottom flask, 2-cyclopropyl-5- (2-trimethylsilyl-ethoxymethyl) -5H-pyrrolo [2, 3-b]Pyrazine-7-carboxylic acid (1-methanesulfonyl-piperidin-3-ylmethyl) -amide (159mg, 0.32mmol) was dissolved in CH₂Cl₂(1.3 mL). Trifluoroacetic acid (1.0mL, 13.0mmol) was added and the pale yellow reaction mixture was stirred at room temperature for 2h, then concentrated. The residue was dissolved in toluene (3mL), concentrated, and then dried under high vacuum. The residue was dissolved in CH₂Cl₂(1.3mL) and ethylenediamine (1.3mL, 19.3mmol) was added. The reaction mixture was stirred at room temperature for 2.5H, then H was added ₂O and EtOAc. Filtering the resulting suspension with H₂O and EtOAc rinse, and dry under high vacuum to yield 59mg (50%) of 2-cyclopropyl-5H-pyrrolo [2, 3-b ]]Pyrazine-7-carboxylic acid (1-methanesulfonyl-piperidin-3-ylmethyl) -amide as a light yellow solid. MS: (M + H)⁺＝378；mp＝247.6-248.4。

Example 114.

2-cyclopropyl-5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid (1-acetyl-piperidin-3-ylmethyl) -amide

Step 1

Step 2

In a 15mL round bottom flask, 2-cyclopropyl-5- (2-trimethylsilyl-ethoxymethyl) -5H-pyrrolo [2, 3-b]Pyrazine-7-carboxylic acid (piperidin-3-ylmethyl) -amide hydrochloride (175mg, 0.38mmol, from example 31 step 2) was dissolved in CH ₂Cl₂(3mL), cool to 0 ℃. Triethylamine (0.12mL, 0.83mmol) was added followed by acetyl chloride (0.032mL, 0.45 mmol). The reaction mixture was stirred at room temperature for 7.5h, then with 30ml CH₂Cl₂Dilute and wash with water (5 mL). By CH₂Cl₂The aqueous layer was extracted (30mL) and Na was added₂SO₄The combined organic layers were dried, filtered, and concentrated. By using EtOAc/hexanes (gradient: 50-100% EtOAc) followed by MeOH/EtOAc (gradient: 0-10% MeOH) 8gSiO₂The residue was purified by chromatography to give 159mg (90%) of 2-cyclopropyl-5- (2-trimethylsilyl-ethoxymethyl) -5H-pyrrolo [2, 3-b ]]Pyrazine-7-carboxylic acid (1-acetyl-piperidin-3-ylmethyl) -amide as a light yellow oil.

Step 3

Example 113 procedure4 preparation of 2-cyclopropyl-5H-pyrrolo [2, 3-b ]]Pyrazine-7-carboxylic acid (1-acetyl-piperidin-3-ylmethyl) -amide with 2-cyclopropyl-5- (2-trimethylsilyl-ethoxymethyl) -5H-pyrrolo [2, 3-b [ -methyl ] -amide]Pyrazine-7-carboxylic acid (1-acetyl-piperidin-3-ylmethyl) -amide substituted 2-cyclopropyl-5- (2-trimethylsilyl-ethoxymethyl) -5H-pyrrolo [2, 3-b]Pyrazine-7-carboxylic acid (1-methanesulfonyl-piperidin-3-ylmethyl) -amide. MS: (M + H)⁺＝342；mp＝198.4-199.1。

Example 115.

2-cyclopropyl-5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid (1-methanesulfonyl-pyrrolidin-3-ylmethyl) -amide

Step 1

A10 mL round bottom flask was charged with 2-cyclopropyl-5- ((2- (trimethylsilyl) ethoxy) methyl) -5H-pyrrolo [2, 3-b ]]Pyrazine-7-carboxylic acid (260mg, 0.78mmol), 3- (aminomethyl) -1-N-Boc-pyrrolidine (234mg, 1.17mmol), HOBT (116mg, 0.86mmol) and EDC (164mg, 0.86 mmol). DMF (3.4mL) was then added followed by N, N-diisopropylethylamine (0.20mL, 1.12 mmol). The yellow reaction mixture was stirred at room temperature overnight and then with H₂Quenching with O (5mL) and Et₂O (2 × 50 mL). By H₂The combined organic layers were washed 2 times with brine 1 time, then with Na₂SO₄Drying, filtering and concentrating. By using EtOAc/hexanes (gradient: 0-50% EtOAc) 24g SiO₂The residue was purified by chromatography to give 339mg (84%) of 3- ({ [ 2-cyclopropyl-5- (2-trimethylsilyl-ethoxymethyl) -5H-pyrrolo [2, 3-b ]]Pyrazine-7-carbonyl]-amino } -methyl) -pyrrolidine-1-carboxylic acid tert-butyl ester as light yellow oil.

Step 2

Preparation 2-cyclopropyl-5H-pyrrolo [2, 3-b ]]Pyrazine-7-carboxylic acid (1-methanesulfonyl-pyrrolidin-3-ylmethyl) -amide with 3- ({ [ 2-cyclopropyl-5- (2-trimethylsilyl-ethoxymethyl) -5H-pyrrolo [2, 3-b ] ]Pyrazine-7-carbonyl]-amino } -methyl) -pyrrolidine-1-carboxylic acid tert-butyl ester substitution 3- ({ [ 2-cyclopropyl-5- (2-trimethylsilyl-ethoxymethyl) -5H-pyrrolo [2, 3-b]Pyrazine-7-carbonyl]-amino } -methyl) -piperidine-1-carboxylic acid tert-butyl ester. MS: (M + H)⁺＝364；mp＝248.0-249.0。

Example 116.

2-cyclopropyl-5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid (1-acetyl-pyrrolidin-3-ylmethyl) -amide

Prepared according to the procedure outlined in example 114 from 3- ({ [ 2-cyclopropyl-5- (2-trimethylsilyl-ethoxymethyl) -5H-pyrrolo [2, 3-b ]]Pyrazine-7-carbonyl]-amino } -methyl) -pyrrolidine-1-carboxylic acid tert-butyl ester substitution 3- ({ [ 2-cyclopropyl-5- (2-trimethylsilyl-ethoxymethyl) -5H-pyrrolo [2, 3-b]Pyrazine-7-carbonyl]-amino } -methyl) -piperidine-1-carboxylic acid tert-butyl ester. MS: (M + H)⁺＝328；mp＝233.8-235.0。

Example 117.

2-phenoxy-5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid (1-cyclopropyl-ethyl) -amide

Step 1

Reacting 2-bromo-5- (2-trimethylsilyl-ethoxymethyl) -5H-pyrrolo [2, 3-b]Pyrazine-7-carboxylic acid (0.276g, 0.741mmol), 7ml dichloromethane, 4-dimethylaminopyridine (0.0850g, 0.696mmol), 1-cyclopropylethylamine (0).151g, 1.77mmol) and (3-dimethylamino-propyl) -ethyl-carbonyldiimidazole (0.285g, 1.49mmol) were stirred for 20h and then concentrated to a yellow oil. The oil was partitioned between 10ml ethyl acetate and 10ml 10% citric acid solution, washed successively with 10ml water and 10ml saturated aqueous NaCl solution; with MgSO ₄Dried, filtered and concentrated to a yellow oil. Column chromatography (0- > 33% EtOAc/hexanes) afforded 0.190g (58%) of 2-bromo-5- (2-trimethylsilyl-ethoxymethyl) -5H-pyrrolo [2, 3-b ]]Pyrazine-7-carboxylic acid (1-cyclopropyl-ethyl) -amide as a white solid.

Step 2

Reacting 2-bromo-5- (2-trimethylsilyl-ethoxymethyl) -5H-pyrrolo [2, 3-b]Pyrazine-7-carboxylic acid (1-cyclopropyl-ethyl) -amide (0.092g, 0.210mmol), phenol (0.0246g, 0.261mmol), K₃PO₄(0.106g, 0.498mmol), [ 2' - (di-tert-butyl-phosphanyl) -biphenyl-2-yl]Dimethyl-amine (0.0036g, 0.011mmol), Pd (OAc)₂(0.0018g, 0.0080mmol) and 2ml of toluene were stirred in a sealed tube under nitrogen at 150 ℃ for 38h, then cooled and partitioned between 10ml of ethyl acetate and 10ml of water. The aqueous layer was extracted with 10ml ethyl acetate, MgSO₄The combined organic layers were dried, filtered, and concentrated to give an orange residue. Column chromatography (0- > 33% EtOAc/hexanes) afforded 0.047g (46%) of 2-phenoxy-5- (2-trimethylsilyl-ethoxymethyl) -5H-pyrrolo [2, 3-b ]]Pyrazine-7-carboxylic acid (1-cyclopropyl-ethyl) -amide as a light yellow oil.

Step 3

2-phenoxy-5- (2-trimethylsilyl-ethoxymethyl) -5H-pyrrolo [2, 3-b]A solution of pyrazine-7-carboxylic acid (1-cyclopropyl-ethyl) -amide (0.047g, 0.105mmol) in 1ml dichloromethane and 1ml trifluoroacetic acid was stirred for 2h, then concentrated and separated with toluene to give a yellow residue. The residue was treated with 0.6ml dichloromethane and 0.6ml ethylenediamine. The resulting solution was stirred for 1h and then partitioned between 10ml ethyl acetate and 5ml water. The aqueous layer was extracted with 10ml of ethyl acetate, the combined organic layers were concentrated,a yellow solid was obtained. Column chromatography (20- > 100% EtOAc/hexanes) afforded 0.024g (70%) of 2-phenoxy-5H-pyrrolo [2, 3-b ]]Pyrazine-7-carboxylic acid (1-cyclopropyl-ethyl) -amide as a light yellow solid. MS: (M + H)⁺＝323；mp＝242.0-245.0。

Example 118.

2- (2, 4-difluoro-phenoxy) -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid (1-cyclopropyl-ethyl) -amide

Prepared according to the method outlined in example 117 substituting 2, 4-difluorophenol for phenol in step 2. MS: (M + H)⁺＝359。

Example 119.

2- (4-fluoro-phenoxy) -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid (1-cyclopropyl-ethyl) -amide

Prepared according to the procedure outlined in example 117 substituting phenol with 4-fluorophenol in step 2. MS: (M + H) ⁺＝341。

Example 120.

2- (2-fluoro-phenoxy) -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid (1-cyclopropyl-ethyl) -amide

Prepared according to the procedure outlined in example 117 substituting phenol with 2-fluorophenol in step 2. MS:(M+H)⁺＝341。

example 121.

2-phenoxy-5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ((R) -2-hydroxy-1, 2-dimethyl-propyl) -amide

Prepared according to the method outlined in example 117, steps 2-3, using 2-bromo-5- (2-trimethylsilyl-ethoxymethyl) -5H-pyrrolo [2, 3-b ]]Pyrazine-7-carboxylic acid ((R) -2-hydroxy-1, 2-dimethyl-propyl) -amide [ from example 32, step 3]Substituted 2-bromo-5- (2-trimethylsilyl-ethoxymethyl) -5H-pyrrolo [2, 3-b]Pyrazine-7-carboxylic acid (1-cyclopropyl-ethyl) -amide. MS: (M + H)⁺＝341。

Example 122.

2-phenoxy-5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid isopropylamide

Step 1

2-bromo-5- (2-trimethylsilyl-ethoxymethyl) -5H-pyrrolo [2, 3-b ] at 150 deg.C]Pyrazine-7-carbaldehyde (3.29g, 9.23mmol), phenol (1.04g, 11.08mmol), K₃PO₄(3.92g, 18.46mmol), [ 2' - (di-tert-butyl-phosphanyl) -biphenyl-2-yl]Dimethyl-amine (0.157g, 0.46mmol), Pd (OAc)₂A mixture of (0.103g, 0.46mmol) and degassed toluene (50mL) was stirred in a sealed tube overnight under a nitrogen atmosphere. The reaction mixture was cooled to room temperature and partitioned between ethyl acetate and water. The aqueous layer was extracted with ethyl acetate and MgSO ₄The combined organic layers were dried, filtered, and concentrated. By SiO₂Column chromatography (0-30% EtOAc/hexanes) neatThe residue was digested to give 2.09g (61%) of 2-phenoxy-5- (2-trimethylsilyl-ethoxymethyl) -5H-pyrrolo [2, 3-b ]]Pyrazine-7-carbaldehyde, which is a light brown solid.

Step 2

By adding concentrated H₂SO₄(2.3mL) carefully added to CrO₃(2.67g) with H₂Stock solutions of jones reagent (2.67M) were prepared by dilution of O to 10 mL. To 2-phenoxy-5- (2-trimethylsilyl-ethoxymethyl) -5H-pyrrolo [2, 3-b ] at 0 deg.C]To a solution of pyrazine-7-carbaldehyde (2.35g, 6.37mmol) in acetone (75mL) was added dropwise jones reagent (5mL, 13.4 mmol). The reaction mixture was stirred at rt for 2h, then quenched with i-PrOH (2mL), diluted with EtOAc, filtered through celite, and rinsed with EtOAc. The filtrate was washed with cold water (3X) and brine, then MgSO₄Drying and concentrating. By SiO₂The residue was purified by column chromatography (30-70% EtOAc/hexanes) to give 1.59g (65%) of 2-phenoxy-5- (2-trimethylsilyl-ethoxymethyl) -5H-pyrrolo [2, 3-b ]]Pyrazine-7-carboxylic acid as a light yellow solid.

Step 3

To 2-phenoxy-5- (2-trimethylsilyl-ethoxymethyl) -5H-pyrrolo [2, 3-b ]Pyrazine-7-carboxylic acid (0.115g, 0.30mmol), 4-dimethylaminopyridine (0.048g, 0.39mmol) and (3-dimethylamino-propyl) -ethyl-carbodiimide (0.075g, 0.39mmol) in CH₂Cl₂(2mL) to a solution of isopropylamine (0.023g, 0.39mmol) in CH was added₂Cl₂(0.5 mL). The reaction mixture was stirred at room temperature overnight, then quenched with water and extracted with ethyl acetate (3 ×). The organic layer was washed with water and saturated aqueous NaCl solution, and MgSO₄Drying, filtering and concentrating to obtain 2-phenoxy-5- (2-trimethylsilyl-ethoxymethyl) -5H-pyrrolo [2, 3-b]Pyrazine-7-carboxylic acid isopropylamide, which was used without further purification.

Step 4

To the 2-phenoxy-5- (2-trimethylsilyl-ethoxysilyl) from step 3Radical) -5H-pyrrolo [2, 3-b]Trifluoroacetic acid (0.7mL) was added to a solution of pyrazine-7-carboxylic acid isopropylamide in dichloromethane (0.7 mL). The reaction mixture was stirred at room temperature overnight and then concentrated. The residue was taken up in THF (1mL), water (0.5mL) and Et₃N (0.5mL) was stirred together for 2h, then concentrated. The residue was partitioned between ethyl acetate and water, and the aqueous layer was extracted with ethyl acetate. With MgSO₄The combined organic layers were dried and concentrated. By SiO ₂Column chromatography (5% MeOH/CH)₂Cl₂) The residue was purified to give 0.070g (78%, 2 steps) of 2-phenoxy-5H-pyrrolo [2, 3-b ]]Pyrazine-7-carboxylic acid isopropylamide as a yellow solid. MS: (M + H)⁺＝297；mp＝263.0-265.0。

Example 123.

2-phenoxy-5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ((S) -1, 2, 2-trimethyl-propyl) -amide

Prepared according to the procedure outlined in example 122 substituting isopropylamine with (S) -1, 2, 2-trimethyl-propylamine in step 3. MS: (M + H)⁺＝339；mp＝270.0-273.0。

Example 124.

2-phenoxy-5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ((S) -sec-butyl) -amide

Prepared according to the procedure outlined in example 122 substituting isopropylamine with (S) -sec-butylamine in step 3. MS: (M + H)⁺＝311；mp＝227.0-229.0。

Example 125.

2-phenoxy-5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ((S) -1, 2-dimethyl-propyl) -amide

Prepared according to the method outlined in example 122, substituting isopropylamine with (S) -1, 2-dimethyl-propylamine in step 3. MS: (M + H)⁺＝325；mp＝234.0-235.0。

Example 126.

2-phenoxy-5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ((S) -1-cyclohexyl-ethyl) -amide

Prepared according to the procedure outlined in example 122 substituting isopropylamine with (S) - (+) -1-cyclohexylethylamine in step 3. MS: (M + H)⁺＝365；mp＝227.0-230.0。

Example 127.

2-phenoxy-5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ((S) -2-hydroxy-1, 2-dimethyl-propyl) -amide

Prepared according to the method outlined in example 122, substituting isopropylamine with (S) -3-amino-2-methyl-butan-2-ol in step 3. MS: (M + H)⁺＝341；mp＝232.0-232.0。

Example 128.

2-phenoxy-5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ((R) -1-cyclohexyl-ethyl) -amide

Prepared according to the procedure outlined in example 122, substituting isopropylamine with (R) - (-) -1-cyclohexylethylamine in step 3. MS: (M + H)⁺＝365；mp＝231.0-232.0。

Example 129.

2-phenoxy-5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ((R) -1, 2, 2-trimethyl-propyl) -amide

Prepared according to the procedure outlined in example 122, substituting isopropylamine with (R) -1, 2, 2-trimethyl-propylamine in step 3. MS: (M + H)⁺＝339；mp＝273.0-274.0。

Example 130.

2-phenoxy-5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ethylamide

Prepared according to the procedure outlined in example 122 substituting isopropylamine with 70% aqueous ethylamine in step 3. MS: (M + H)⁺＝283；mp＝230.0-232.0。

Example 131.

2- (2, 4-difluoro-phenoxy) -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid isopropylamide

Prepared according to the method outlined in example 122 substituting 2, 4-difluorophenol for phenol in step 1. MS: (M + H)⁺＝333。

Example 132.

2- (2, 4-difluoro-phenoxy) -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ((S) -1, 2, 2-trimethyl-propyl) -amide

Prepared according to the method outlined in example 122 substituting phenol with 2, 4-difluorophenol in step 1 and isopropylamine with (S) -1, 2, 2-trimethyl-propylamine in step 3. MS: (M + H)⁺＝375。

Example 133.

2- (2, 4-difluoro-phenoxy) -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ((R) -1, 2, 2-trimethyl-propyl) -amide

Prepared according to the method outlined in example 122 substituting phenol with 2, 4-difluorophenol in step 1 and isopropylamine with (R) -1, 2, 2-trimethyl-propylamine in step 3. MS: (M + H)⁺＝375。

Example 134.

2- (2, 4-difluoro-phenoxy) -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ethylamide

Prepared according to the method outlined in example 122 substituting 2, 4-difluorophenol for phenol in step 1 and ethylamine for isopropylamine in step 3. MS: (M + H)⁺＝319。

Example 135.

2- (2, 4-difluoro-phenoxy) -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ((S) -1-cyclohexyl-ethyl) -amide

Prepared according to the method outlined in example 122 substituting phenol with 2, 4-difluorophenol in step 1 and isopropylamine with (S) - (+) -1-cyclohexylethylamine in step 3. MS: (M + H)⁺＝401；mp＝233.0-235.0。

Example 136.

2- (2, 4-difluoro-phenoxy) -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ((R) -1-cyclohexyl-ethyl) -amide

Prepared according to the method outlined in example 122 substituting phenol with 2, 4-difluorophenol in step 1 and isopropylamine with (R) - (+) -1-cyclohexylethylamine in step 3. MS: (M + H)⁺＝401；mp＝233.0-235.0。

Example 137.

2- (2, 4-difluoro-phenoxy) -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ((R) -sec-butyl) -amide

Prepared according to the method outlined in example 122 substituting phenol with 2, 4-difluorophenol in step 1 and isopropylamine with (R) -sec-butylamine in step 3. MS: (M + H)⁺＝347；mp＝246.0-248.0。

Example 138.

2- (2, 4-difluoro-phenoxy) -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ((S) -2-hydroxy-1, 2-dimethyl-propyl) -amide

Prepared according to the method outlined in example 122 substituting 2, 4-difluorophenol for phenol in step 1 and (S) -3-amino-2-methyl-butan-2-ol for isopropylamine in step 3. MS: (M + H)⁺＝377；mp＝224.0-226.0。

Example 139.

2- (2, 4-difluoro-phenoxy) -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ((R) -1, 2-dimethyl-propyl) -amide

Prepared according to the method outlined in example 122 substituting phenol with 2, 4-difluorophenol in step 1 and isopropylamine with (R) -1, 2-dimethyl-propylamine in step 3. MS: (M + H)⁺＝361；mp＝235.0-237.0。

Example 140.

2- (1-ethyl-1H-pyrazol-4-yl) -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid [ (S) -1- (1-hydroxy-cyclopentyl) -ethyl ] -amide

Prepared according to the procedure outlined in example 1, substituting Boc-L-alanine methyl ester for Boc-D-alanine methyl ester in step 1 and 2- (1-ethyl-1H-pyrazol-4-yl) -5- (2-trimethylsilyl-ethoxymethyl) -5H-pyrrolo [2, 3-b ] in step 4]Pyrazine-7-carboxylic acid substituted 2-cyclopropyl-5- (2-trimethylsilyl-ethoxymethyl) -5H-pyrrolo [2, 3-b]Pyrazine-7-carboxylic acid. MS: (M + H)⁺＝369。

Example 141.

Step 1

In a flask, (R) -2-methyl-propane-2-sulfinic acid amide (4.00g, 33.0mmol) was dissolved in CH₂Cl₂(14.0 mL). Acetaldehyde (16.7mL, 297mmol) and MgSO was added₄(11.9g, 99.0mmol) and pyridinium tosylate (415mg, 1.65 mmol). The reaction mixture was stirred at room temperature overnight, filtered, and concentrated to give 5.21g of (R) -2-methyl-propane-2-sulfinic acid (E) -ethylideneamide as a yellow oil, which was used without further purification.

Step 2

In a flask, isobutyronitrile (6.39g, 92.4mmol) was dissolved in diethyl ether (190mL) and cooled at-78 ℃. NaHMDS (1.0M in THF, 99.0mL, 99.0mmol) was added and the mixture was stirred at-78 deg.C for 30 min. A solution of (R) -2-methyl-propane-2-sulfinic acid (E) -ethylene amide (crude from step 1, 5.21g, 33.0mmol) in THF (50.0mL) was added slowly. The mixture was stirred at-78 ℃ for 2h, then warmed to room temperature overnight. The reaction mixture was quenched with saturated aqueous ammonium chloride and extracted with EtOAc. The combined organic layers were washed with brine, MgSO₄Drying and concentrating. By SiO₂The residue was purified by chromatography (20-100% EtOAc/hexanes) to give 2.93g (41%) of (R) -2-methyl-propane-2-sulfinic acid ((S) -2-cyano-1, 2, 2-trimethyl-ethyl) -amide as a light yellow oil.

Step 3

(R) -2-methyl-propane-2-sulfinic acid (2-cyano-1, 2, 2-trimethyl-ethyl) -amide (2.93g, 13.6mmol) was dissolved in MeOH and HCl (4.0M solution in 1, 4-dioxane, 6.8mL, 27.2mmol) was added. The reaction mixture was stirred at room temperature for 1h, then concentrated to give 1.90g (94%) of (S) -3-amino-2, 2-dimethyl-butyronitrile hydrochloride as a white solid, which was used without further purification.

Step 4

2- (1-methyl-1H-pyrazol-4-yl) -5- (2-trimethylsilyl-ethoxymethyl) -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid was prepared according to method 4, substituting 1-methyl-4- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazole for 1-ethyl-4- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazole in step 1.

Step 5

In a flask, combine 2- (1-methyl-1H-pyrazol-4-yl) -5- (2-trimethylsilyl-ethoxymethyl) -5H-pyrrolo [2, 3-b ] ]Pyrazine-7-carboxylic acid (120mg, 0.32mmol), (S) -3-amino-2, 2-dimethyl-butyronitrile hydrochloride (72mg, 0.48mmol), EDC (142mg, 0.74mmol) and HOBt (125mg, 0.74 mmol). DMF (4.0mL) was added followed by i-Pr₂NEt (0.39mL, 2.25 mmol). The reaction mixture was stirred at rt for 18h, then quenched with water and extracted with EtOAc. With 10% citric acid, saturated NaHCO₃The organic layer was washed with saturated LiCl and saturated NaCl, and then MgSO₄Drying and concentrating. By SiO₂The residue was purified by chromatography (50-100% EtOAc/hexanes) to give 150mg (99%) of 2- (1-methyl-1H-pyrazol-4-yl) -5- (2-trimethylSilyl-ethoxymethyl) -5H-pyrrolo [2, 3-b]Pyrazine-7-carboxylic acid ((S) -2-cyano-1, 2, 2-trimethyl-ethyl) -amide as a light yellow viscous oil.

Step 6

In a flask, 2- (1-methyl-1H-pyrazol-4-yl) -5- (2-trimethylsilyl-ethoxymethyl) -5H-pyrrolo [2, 3-b ] was placed]Pyrazine-7-carboxylic acid ((S) -2-cyano-1, 2, 2-trimethyl-ethyl) -amide (150mg, 0.32mmol) was dissolved in CH₂Cl₂(2.25mL) and TFA (0.75mL) was added. The reaction mixture was stirred for 2h and concentrated. The residue was dissolved in CH₂Cl₂/MeOH/NH₄OH (60: 10: 1) (3mL) was stirred at room temperature overnight. The reaction mixture is then concentrated through SiO ₂Chromatography (0-10% MeOH/CH)₂Cl₂) The residue was purified to give 72mg (67%) of 2- (1-methyl-1H-pyrazol-4-yl) -5H-pyrrolo [2, 3-b)]Pyrazine-7-carboxylic acid ((S) -2-cyano-1, 2, 2-trimethyl-ethyl) -amide as a white powder. MS: (M + H)⁺＝338。

Example 142.

2- (1-methyl-1H-pyrazol-4-yl) -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ((S) -1-cyclohexyl-ethyl) -amide

Prepared according to the method outlined in example 1, steps 4-5, substituting 1- ((R) -1-amino-ethyl) -cyclopentanol hydrochloride with (S) - (+) -1-cyclohexylethylamine in step 4 and 2- (1-methyl-1H-pyrazol-4-yl) -5- (2-trimethylsilyl-ethoxymethyl) -5H-pyrrolo [2, 3-b ] amine]Pyrazine-7-carboxylic acid substituted 2-cyclopropyl-5- (2-trimethylsilyl-ethoxymethyl) -5H-pyrrolo [2, 3-b]Pyrazine-7-carboxylic acid. MS: (M + H)⁺＝353。

Example 143.

2- (1-methyl-1H-pyrazol-4-yl) -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ((S) -1, 2, 2-trimethyl-propyl) -amide

Step 1

2-bromo-5- (2-trimethylsilyl-ethoxymethyl) -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid (1.5g, 4.8mmol) was partially dissolved in dichloromethane (40 mL). 1-Ethyl-3- (3- (dimethylamino) propyl) carbodiimide (1.54g, 8.06mmol), 4-dimethylaminopyridine (0.49g, 4mmol), N-diisopropylethylamine (1.4mL, 8.06mmol) and then (S) -3, 3-dimethylbut-2-amine (0.49g, 4.8mmol) were added and the reaction stirred for 16 h. The reaction mixture was diluted with HCl solution and the aqueous layer was extracted 2 times with dichloromethane. The combined organic layers were washed with sodium bicarbonate solution, dried over sodium sulfate and concentrated. The residue was purified by silica gel chromatography (ethyl acetate/hexane) to give 1.23g (67%) of 2-bromo-5- (2-trimethylsilyl-ethoxymethyl) -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ((S) -1, 2, 2-trimethyl-propyl) -amide.

Step 2

In a microwave vial, a mixture of 1, 4-dioxane (1.8mL) and water (0.4mL) was purged with argon. 2-bromo-5- (2-trimethylsilyl-ethoxymethyl) -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ((S) -1, 2, 2-trimethyl-propyl) -amide (100mg, 0.22mmol), 1-methyl-4- (4, 4, 5, 5-tetramethyl- [1, 3, 2] dioxaborolan-2-yl) -1H-pyrazole (50mg, 0.24mmol), tetrakis (triphenylphosphine) palladium (12.7mg, 0.011mmol) were added, followed by potassium carbonate (91mg, 0.66 mmol). The vial was sealed and heated in a microwave reactor at 140 ℃ for 1 h. The reaction was cooled and water, sodium bicarbonate solution and ethyl acetate were added. The aqueous layer was extracted 2 times with ethyl acetate, then the combined organic layers were washed with brine, dried over sodium sulfate, and concentrated. The residue was purified by silica gel chromatography (ethyl acetate/hexane) to give 89mg (88%) of 2- (1-methyl-1H-pyrazol-4-yl) -5- (2-trimethylsilyl-ethoxymethyl) -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ((S) -1, 2, 2-trimethyl-propyl) -amide.

Step 3

2- (1-methyl-1H-pyrazol-4-yl) -5- (2-trimethylsilyl-ethoxymethyl) -5H-pyrrolo [2, 3-b)]Pyrazine-7-carboxylic acid ((S) -1, 2, 2-trimethyl-propyl) -amide (87mg, 0.19mmol) was dissolved in dichloromethane (1.3mL) and then stirred in an ice bath. Trifluoroacetic acid (0.6mL) was added slowly and the ice bath removed. The reaction was stirred for 3h and then cooled again in an ice bath. Sodium bicarbonate solution was added and the mixture was extracted 3 times with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate and concentrated. The residue was dissolved in absolute ethanol (8mL), and sodium acetate (313mg, 3.8mmol) was added. The reaction mixture was stirred at 60 ℃ for 20h, then cooled, water and ethyl acetate were added. The aqueous layer was extracted 2 times with ethyl acetate, then the combined organic layers were washed with brine, dried over sodium sulfate, and concentrated. The residue was purified by silica gel chromatography to give 36mg (57%) of 2- (1-methyl-1H-pyrazol-4-yl) -5H-pyrrolo [2, 3-b ] ]Pyrazine-7-carboxylic acid ((S) -1, 2, 2-trimethyl-propyl) -amide. MS: (M + H)⁺＝327；mp＝296-297℃。

Example 144.

2-thiophen-2-yl-5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ((S) -1, 2, 2-trimethyl-propyl) -amide

Prepared according to the method outlined in steps 2-3 of example 143, substituting 1-methyl-4- (4, 4, 5, 5-tetramethyl- [1, 3, 2 ] with thiophen-2-ylboronic acid in step 2]Dioxolane-2-yl) -1H-pyrazole. MS: (M + H)⁺＝329；mp＝311-312℃。

Example 145.

2- (4-trifluoromethyl-phenyl) -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ((S) -1, 2, 2-trimethyl-propyl) -amide

Prepared according to the method outlined in example 143, steps 2-3, substituting 4- (trifluoromethyl) phenylboronic acid for 1-methyl-4- (4, 4, 5, 5-tetramethyl- [1, 3, 2 ] in step 2]Dioxolane-2-yl) -1H-pyrazole. MS: (M + H)⁺＝391；mp＞300℃。

Example 146.

2-cyclopropyl-5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ((S) -3-methanesulfonyl-1, 2, 2-trimethyl-propyl) amide

Step 1

(S) -3- (tert-Butoxycarbonylamino) butanoic acid (1.0g, 4.9mmol) was dissolved in toluene (38mL) and methanol (11 mL). The solution was cooled with an ice/water bath and trimethylsilyldiazomethane (2M in hexane, 12.3mL, 24.6mmol) was added slowly. The reaction was stirred at 20 ℃ for 18h and then concentrated. The residue was adsorbed on silica gel and purified by silica gel chromatography (ethyl acetate/hexane) to give 1.06g (99%) of methyl (S) -3-tert-butoxycarbonylamino-butyrate.

Step 2

(S) -methyl 3-tert-Butoxycarbonylamino-butyrate (1.06g, 2.9mmol) was dissolved in THF (29mL) and stirred in a dry ice/acetone bath. Lithium diisopropylamide was prepared by adding a butyl lithium solution (2.6M in hexane, 4.2mL, 10.8mmol) to a dry ice/acetone bath cooled solution of diisopropylamine (1.54mL, 10.8mmol) in THF (4mL) in a separatory funnel, followed by stirring for 45 min. The lithium diisopropylamide solution was added to the ester solution via a catheter within 20min and the reaction was stirred at dry ice/acetone temperature for a further 30 min. Methyl iodide (0.7mL, 10.8mmol) was added to the reaction and the mixture was stirred for 2 h. Additional methyl iodide (0.7mL, 10.8mmol) was added over 20min, and the reaction was then allowed to warm to 0 ℃ over 16h while stirring. Ammonium chloride solution was added and the mixture was extracted 2 times 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 (ether/hexane) to give 0.49g (39%) of (S) -3-tert-butoxycarbonylamino-2, 2-dimethyl-butyric acid methyl ester.

Step 3

(S) -3-tert-Butoxycarbonylamino-2, 2-dimethyl-butyric acid methyl ester (0.47g, 1.92mmol) was dissolved in THF (11mL) and cooled to-35 ℃. Lithium aluminum hydride (1.0M in THF, 1.9mL, 1.9mmol) was added dropwise. The reaction was stirred and after 2h the temperature gradually reached 5 ℃. Then carefully add about 75uL of water, then 120uL of 10% NaOH solution, then 190uL of water. The resulting solid was filtered, washed with diethyl ether and evaporated to give 0.37g (88%) of tert-butyl ((S) -3-hydroxy-1, 2, 2-trimethyl-propyl) -carbamate as a white solid.

Step 4

((S) -3-hydroxy-1, 2, 2-trimethyl-propyl) -carbamic acid tert-butyl ester (244mg, 1.12mmol) was dissolved in dichloromethane (7.5mL) and stirred in an ice bath. Trifluoroacetic acid (3.5mL) was slowly added and the reaction warmed to room temperature, stirred for 1h, then evaporated to dryness to give (S) -3-amino-2, 2-dimethyl-butan-1-ol trifluoroacetate salt, which was used without further purification.

Step 5

(S) -3-amino-2, 2-dimethyl-butan-1-ol trifluoroacetate (crude from step 4) is dissolved in acetonitrile (3.75 mL). 2-cyclopropyl-5- (2-trimethylsilyl-ethoxymethyl) 5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid (250mg, 0.75mmol) and O-benzotriazol-1-yl-N, N, N ', N' -tetramethyluronium tetrafluoroborate (361mg, 1.12mmol) and N, N-diisopropylethylamine (0.46mL, 2.62mmol) were added and the mixture was stirred at room temperature for 18H. Water and ethyl acetate were added, the layers were separated and the aqueous layer was extracted 2 times with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate and concentrated. The residue was purified by silica gel chromatography (ethyl acetate/dichloromethane) to give 130mg (40%) of 2-cyclopropyl-5- (2-trimethylsilyl-ethoxymethyl) -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ((S) -3-hydroxy-1, 2, 2-trimethyl-propyl) -amide.

Step 6

2-cyclopropyl-5- (2-trimethylsilyl-ethoxymethyl) -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ((S) -3-hydroxy-1, 2, 2-trimethyl-propyl) -amide (0.13g, 0.3mmol) was dissolved in 1.5ml dichloromethane and cooled with an ice bath. N, N-diisopropylethylamine (0.08mL, 0.45mmol) was added, followed by slow addition of methanesulfonyl chloride (0.041mL, 0.36 mmol). The reaction was allowed to warm to room temperature over 5 h. Ammonium chloride solution was added to the reaction, which was then extracted 3 times with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate and evaporated to give methanesulfonic acid (S) -3- { [ 2-cyclopropyl-5- (2-trimethylsilyl-ethoxymethyl) -5H-pyrrolo [2, 3-b ] pyrazine-7-carbonyl ] -amino } -2, 2-dimethyl-butyl ester, which was used without further purification.

Step 7

In a microwave vial, (S) -3- { [ 2-cyclopropyl-5- (2-trimethylsilyl-ethoxymethyl) -5H-pyrrolo [2, 3-b ] pyrazine-7-carbonyl ] -amino } -2, 2-dimethyl-butyl methanesulfonate (crude from step 6) was dissolved in DMF (3 mL). Sodium thiomethoxide (0.2g, 2.8mmol) was added followed by 0.3ml of water. The vial was sealed and heated in a microwave reactor at 110 ℃ for 1 h. The reaction was cooled and poured into ethyl acetate and sodium bicarbonate solution. The aqueous layer was extracted more than once with ethyl acetate. The combined organic layers were washed with water and brine, dried over sodium sulfate and concentrated. The residue was purified by silica gel chromatography (methanol/ethyl acetate) to give 35mg (32%) of 2-cyclopropyl-5- (2-trimethylsilyl-ethoxymethyl) -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ((S) -1, 2, 2-trimethyl-3-methylsulfanyl-propyl) -amide.

Step 8

2-cyclopropyl-5- (2-trimethylsilyl-ethoxymethyl) -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ((S) -1, 2, 2-trimethyl-3-methylsulfanyl-propyl) -amide (45mg, 0.097mmol) was dissolved in THF (0.35 mL). Potassium hydrogen persulfate (0.18g, 0.29mmol) suspended in THF (1.3mL) was added and the reaction stirred for 5h before being stored in a refrigerator overnight. Water and ethyl acetate were added. The aqueous layer was extracted 2 more times with ethyl acetate. The combined organic layers were washed with sodium bicarbonate solution, dried over sodium sulfate and evaporated to give 45mg of 2-cyclopropyl-5- (2-trimethylsilyl-ethoxymethyl) -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ((S) -3-methanesulfonyl-1, 2, 2-trimethyl-propyl) -amide, which was used without further purification.

Step 9

2-cyclopropyl-5- (2-trimethylsilyl-ethoxymethyl) -5H-pyrrolo [2, 3-b]Pyrazine-7-carboxylic acid ((S) -3-methanesulfonyl-1, 2, 2-trimethyl-propyl) -amide (45mg, 0.097mmol) was dissolved in dichloromethane (0.7mL) and then stirred in an ice bath. Trifluoroacetic acid (0.3mL) was added slowly and the ice bath removed. The reaction was stirred for 3h and then cooled again in an ice bath. Sodium bicarbonate solution was added and the mixture was extracted 3 times with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate and concentrated. The residue was dissolved in absolute ethanol (4mL), and sodium acetate (159mg, 1.94mmol) was added. The reaction mixture was stirred at 60 ℃ for 16h, then cooled, water and ethyl acetate were added. The aqueous layer was extracted 2 more times with ethyl acetate, then the combined organic layers were washed with brine, dried over sodium sulfate, and concentrated. The residue was purified by silica gel chromatography (MeOH/dichloromethane) to give 17mg (47%) of 2-cyclopropyl-5H-pyrrolo [2, 3-b ] ]Pyrazine-7-carboxylic acid ((S) -3-methanesulfonyl-1, 2, 2-trimethyl-propyl) amide. MS: (M + H)⁺＝365；mp＝232-234℃。

Example 147.

2- [1- (3-chlorophenyl) -1H-imidazol-4-yl ] -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ((S) -1, 2, 2-trimethyl-propyl) -amide

Step 1

4-iodo-1H-imidazole (1.0g, 5.16mmol) was dissolved in THF (32 mL). Copper TMEDA catalyst (480mg, 1.03mmol, Aldrich) was added followed by 3-chlorophenylboronic acid (0.56g, 3.6 mmol). Oxygen was bubbled through the reaction mixture for 20min, then the mixture was stirred for 90 min. 0.28g of 3-chlorophenylboronic acid was added thereto, followed by oxygen bubbling for 20min and stirring at room temperature for 75 min. 0.28g of 3-chlorophenylboronic acid was added thereto, followed by oxygen bubbling for another 20min and then stirring at room temperature for 20 hours. The reaction mixture was filtered through a neutral alumina bed and the filtrate was concentrated. The residue was purified by silica gel chromatography (ethyl acetate/hexane) to give 0.76g (48%) of 4-iodo-1- (3-chlorophenyl) -1H-imidazole.

Step 2

4-iodo-1- (3-chlorophenyl) -1H-imidazole (0.76g, 2.5mmol) was dissolved in anhydrous THF (13 mL). Isopropylmagnesium chloride (2.0M in THF, 1.56mL, 3.12mmol) was added dropwise. The reaction was stirred at rt for 1 h. Tributylstannyl chloride (0.71mL, 2.6mmol) was added slowly. After completion of the reaction as judged by TLC, ammonium chloride solution and ethyl acetate were added. The aqueous layer was extracted 2 more times with ethyl acetate and the combined organic layers were washed with brine, dried over sodium sulfate and concentrated. The residue was purified by silica gel chromatography (triethylamine/ethyl acetate/hexane) to give 0.45g (38%) of 1- (3-chlorophenyl) -4-tributylstannyl-1H-imidazole.

Step 3

Reacting 2-bromo-5- (2-trimethylsilyl-ethoxymethyl) -5H-pyrrolo [2, 3-b]Pyrazine-7-carboxylic acid ((S) -1, 2, 2-trimethyl-propyl) -amide (100mg, 0.19mmol) and 1- (3-chlorophenyl) -4-tributylstannyl-1H-imidazole (107mg, 0.229mmol) were dissolved in DMF (1.9mL) and the solution was purged with ArThe reaction mixture. Tetrakis (triphenylphosphine) palladium (11mg, 0.010mmol) was added followed by copper (I) iodide (7mg, 0.038mmol) and the reaction was sealed and stirred in an oil bath at 100 ℃ for 2 h. The reaction was cooled and water, ethyl acetate and sodium bicarbonate solution were added. The aqueous layer was extracted 2 more times with ethyl acetate. The combined organic layers were washed with water and brine, then dried over sodium sulfate and concentrated. The residue was purified by silica gel chromatography (ethyl acetate/hexane) to give 70mg (68%) of 2- [1- (3-chloro-phenyl) -1H-imidazol-4-yl]-5- (2-trimethylsilyl-ethoxymethyl) -5H-pyrrolo [2, 3-b]Pyrazine-7-carboxylic acid ((S) -1, 2, 2-trimethyl-propyl) -amide. (M + H)⁺＝553。

Step 4

Reacting 2- [1- (3-chloro-phenyl) -1H-imidazol-4-yl]-5- (2-trimethylsilyl-ethoxymethyl) -5H-pyrrolo [2, 3-b]Pyrazine-7-carboxylic acid ((S) -1, 2, 2-trimethyl-propyl) -amide (145mg, 0.26mmol) was dissolved in dichloromethane (1.6mL) and then stirred in an ice bath. Trifluoroacetic acid (0.8mL) was added slowly and the ice bath removed. The reaction was stirred for 2.5h and then cooled with an ice bath. Sodium bicarbonate solution was added and the mixture was extracted 3 times with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate and concentrated. The residue was dissolved in absolute ethanol (10mL), and sodium acetate (430mg, 5.24mmol) was added. The reaction mixture was stirred at 60 ℃ for 16h, then cooled, water and ethyl acetate were added. The aqueous layer was extracted 2 more times with ethyl acetate, then the combined organic layers were washed with brine, dried over sodium sulfate, and concentrated. The residue was purified by silica gel chromatography (MeOH/dichloromethane) to give 75mg (68%) of 2- [1- (3-chlorophenyl) -1H-imidazol-4-yl ]-5H-pyrrolo [2, 3-b]Pyrazine-7-carboxylic acid ((S) -1, 2, 2-trimethyl-propyl) -amide. MS: (M + H)⁺＝423；mp＝337-339℃。

Example 148.

2- [1- (3-trifluoromethylphenyl) -1H-imidazol-4-yl ] -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ((S) -1, 2, 2-trimethyl-propyl) -amide

Prepared according to the method outlined in example 147 substituting 3- (trifluoromethyl) phenylboronic acid for 3-chlorophenylboronic acid in step 1. MS: (M + Na)⁺＝479；mp＝332-333℃。

Example 149.

2- [1- (5-chloro-2-fluorophenyl) -1H-imidazol-4-yl ] -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ((S) -1, 2, 2-trimethyl-propyl) -amide

Prepared according to the method outlined in example 147 substituting 2-fluoro-5-chlorophenylboronic acid for 3-chlorophenylboronic acid in step 1. MS: (M + Na)⁺＝463；mp＝337-339℃。

Example 150.

2- [1- (2-fluoro-5-methylphenyl) -1H-imidazol-4-yl ] -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ((S) -1, 2, 2-trimethyl-propyl) -amide

Prepared according to the method outlined in example 147 substituting 2-fluoro-5-methylphenylboronic acid for 3-chlorophenylboronic acid in step 1. MS: (M + Na)⁺＝443；mp＝331-332℃。

Example 151.

2- [1- (2-fluoro-5-trifluoromethylphenyl) -1H-imidazol-4-yl ] -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ((S) -1, 2, 2-trimethyl-propyl) -amide

Prepared according to the method outlined in example 147 substituting 2-fluoro-5- (trifluoromethyl) phenylboronic acid for 3-chlorophenylboronic acid in step 1. MS: (M + Na) ⁺＝497；mp＞300℃。

Example 152.

2- (1- (3-methylphenyl) -1H-imidazol-4-yl) -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ((S) -1, 2, 2-trimethyl-propyl) -amide

Prepared according to the method outlined in example 147 substituting 3-chlorophenylboronic acid with 3-methylphenylboronic acid in step 1. MS: (M + Na)⁺＝425；mp＝314-316℃。

Example 153.

2- (1- (3-ethylphenyl) -1H-imidazol-4-yl) -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ((S) -1, 2, 2-trimethyl-propyl) -amide

Prepared according to the method outlined in example 147 substituting 3-chlorophenylboronic acid with 3-ethylphenylboronic acid in step 1. MS: (M + Na)⁺＝439；mp＝284-287℃。

Example 154.

2- [1- (3-isopropylphenyl) -1H-imidazol-4-yl ] -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ((S) -1, 2, 2-trimethyl-propyl) -amide

Prepared according to the method outlined in example 147 substituting 3-isopropylphenylboronic acid for 3-chlorophenyl boronic acid in step 1. MS: (M + Na)⁺＝453；mp＝242-245℃。

Example 155.

2- [1- (3-tert-butylphenyl) -1H-imidazol-4-yl ] -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ((S) -1, 2, 2-trimethyl-propyl) -amide

Prepared according to the method outlined in example 147 substituting 3-chlorophenyl boronic acid with 3-tert-butylphenyl boronic acid in step 1. MS: (M + H)⁺＝445；mp＝226-228℃。

Example 156.

2- [1- (3-vinylphenyl) -1H-imidazol-4-yl ] -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ((S) -1, 2, 2-trimethyl-propyl) -amide

Prepared according to the method outlined in example 147 substituting 3-chlorophenylboronic acid with 3-vinylphenylboronic acid in step 1. MS: (M + H)⁺＝415；mp＝253-257℃。

Example 157.

2- (1, 3-dimethyl-1H-pyrazol-4-yl) -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ((S) -2-methoxy-1-methyl-ethyl) -amide

Step 1

In a 25mL pressure vessel, combine 1, 3-dimethyl-4- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazole (439mg, 1.98mmol), lithium chloride (52mg, 1.23mmol), and 2-bromo-5- (2-trimethylsilyl-ethoxymethyl) -5H-pyrrolo [2, 3-b ]]Pyrazine-7-carbaldehyde (440mg, 1.23mmol) was reacted with ethanol (7mL) and toluene (7mL) with N₂The mixture is purified. Tripotassium phosphate (917mg, 4.32mmol) was dissolved in 4mL of water and added to the mixture. Reuse of N₂After purging, bis (triphenylphosphine) palladium (II) dichloride (87mg, 0.12mmol) was added, the vessel capped and stirred at 60-65 ℃ for 20 h. The reaction was cooled and then diluted with ethyl acetate and water. The organic layer was washed with brine, dried and evaporated. The crude material was purified by flash chromatography (silica gel, 80g, 100% EtOAc-20% THF/EtOAc) to give 360mg (71% yield; 90% purity) of 2- (1, 3-dimethyl-1H-pyrazol-4-yl) -5- (2-trimethylsilyl-ethoxymethyl) -5H-pyrrolo [2, 3-b ] ]Pyrazine-7-carbaldehyde.

Step 2

To 2- (1, 3-dimethyl-1H-pyrazol-4-yl) -5- (2-trimethylsilyl-ethoxymethyl) -5H-pyrrolo [2, 3-b ] at 5 deg.C]To a solution of pyrazine-7-carbaldehyde (440mg, 1.18mmol) in 1, 4-dioxane (20mL) was added a solution of sulfamic acid (690mg, 7.11mmol) in water (7 mL). Then NaClO is slowly added within 5min₂(139mg, 1.54mmol) and KH₂PO₄(161mg, 1.18mmol) in water (4 mL). The ice bath was removed and the yellow cloudy reaction mixture was stirred at r.t. for 2 h. Half of the solvent was evaporated, the remaining material poured into brine and extracted with 80% EtOAc/hexanes (2 ×). The combined organic layers were washed with brine and concentrated. The residue was purified by chromatography on silica gel (MeOH/dichloromethane) and triturated with cold ether/hexane to give 320mg (66%) of 2- (1, 3-dimethyl-1H-pyrazol-4-yl) -5- (2-trimethylsilyl-ethoxymethyl) -5H-pyrrolo[2，3-b]Pyrazine-7-carboxylic acid, which is a white solid.

Step 3

In a round bottom flask, (S) - (+) -1-methoxy-2-propylamine (23.2. mu.L, 0.22mmol), N-diisopropylethylamine (38. mu.L, 0.22mmol) and HATU (83mg, 0.22mmol) and 2- (1, 3-dimethyl-1H-pyrazol-4-yl) -5- (2-trimethylsilyl-ethoxymethyl) -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid (85mg, 0.22mmol) were combined with DMF (10mL) and stirred at room temperature for 20H. The reaction mixture was diluted with EtOAc (50mL) and hexanes (10mL), poured into 30% brine/water and extracted with EtOAc (2X). The combined organic layers were washed with brine and concentrated. The residue was purified by silica gel chromatography (MeOH/dichloromethane) to give 2- (1, 3-dimethyl-1H-pyrazol-4-yl) -5- (2-trimethylsilyl-ethoxymethyl) -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ((S) -2-methoxy-1-methyl-ethyl) -amide.

Step 4

2- (1, 3-dimethyl-1H-pyrazol-4-yl) -5H-pyrrolo [2, 3-b]Pyrazine-7-carboxylic acid ((S) -2-methoxy-1-methyl-ethyl) -amide. Prepared according to the method outlined in example 1, step 5, using 2- (1, 3-dimethyl-1H-pyrazol-4-yl) -5- (2-trimethylsilyl-ethoxymethyl) -5H-pyrrolo [2, 3-b ]]Pyrazine-7-carboxylic acid ((S) -2-methoxy-1-methyl-ethyl) -amide substituted 2-cyclopropyl-5- (2-trimethylsilylethoxymethyl) -5H-pyrrolo [2, 3-b [ ]]Pyrazine-7-carboxylic acid [ (R) -1- (1-hydroxy-cyclopentyl) -ethyl]-an amide. MS: (M + H)⁺＝329。

Example 158.

2- (5-ethylcarbamoyl-thiophen-2-yl) -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ((S) -1, 2, 2-trimethyl-propyl) -amide

Step 1

2-bromo-5- (2-trimethylsilyl-ethoxymethyl) -5H-pyrrolo [2, 3-b ] stirred inside a pressure tube]To a solution of pyrazine-7-carboxylic acid ((S) -1, 2, 2-trimethyl-propyl) -amide (500mg, 1.10mmol) in 4: 1 dioxane/water (15mL) was added 2-formylthiophene-5-boronic acid (274mg, 1.76mmol) and K₂CO₃(455mg, 3.29 mmol). The reaction mixture was purged with argon for 15min, then PdCl was added₂dppf·CH₂Cl₂(90mg, 0.11 mmol). The tube was sealed, heated at 120 ℃ for 18h, then cooled to room temperature and partitioned between water and EtOAc. With Na ₂SO₄The organic layer was dried and evaporated under reduced pressure. The crude residue was purified by silica gel column chromatography using EtOAc/hexanes ═ 1: 5 as eluent to give 0.32g (60%) of 2- (5-formyl-thiophen-2-yl) -5- (2-trimethylsilyl-ethoxymethyl) -5H-pyrrolo [2, 3-b ], (60%)]Pyrazine-7-carboxylic acid ((S) -1, 2, 2-trimethyl-propyl) -amide as a light yellow solid. LC-MS: 487(M + H)⁺。

Step 2

To a stirred solution of 2- (5-formyl-thiophen-2-yl) -5- (2-trimethylsilyl-ethoxymethyl) -5H-pyrrolo [2, 3-b]To a solution of pyrazine-7-carboxylic acid ((S) -1, 2, 2-trimethyl-propyl) -amide (1.5g, 3.09mmol) in 1: 1 dioxane/water (50mL) was added sulfamic acid (1.8g, 18.51mmol), sodium chlorite (0.36g, 4.01mmol) and KH₂PO₄(5.04g, 37.03 mmol). The reaction mixture was stirred at 25 ℃ for 30h, then partitioned between water and EtOAc. With Na₂SO₄The organic layer was dried and evaporated under reduced pressure to give 1.3g (84%) of 5- [7- ((S) -1, 2, 2-trimethyl-propylcarbamoyl) -5- (2-trimethylsilyl-ethoxymethyl) -5H-pyrrolo [2, 3-b ]]Pyrazin-2-yl radicals]-thiophene-2-carboxylic acid as a light yellow solid, which was used without further purification. LC-MS: 503[ M + H]⁺。

Step 3

To a stirred solution of 5- [7- ((S) -1, 2, 2-trimethyl-propylcarbamoyl) -5- (2-trimethylsilyl-ethoxymethyl) -5H-pyrrolo [2, 3-b ] ]Pyrazin-2-yl radicals]-thiophene-2-carboxylic acid (200mg, 0.40 m)mol) to a solution in THF were added triethylamine (0.22mL, 1.6mmol), PyBOP (416mg, 0.80mmol) and ethylamine (2.0M in THF, 0.90mL, 1.80 mmol). The reaction mixture was stirred at 25 ℃ for 18h, then partitioned between water and EtOAc. With Na₂SO₄The organic layer was dried and evaporated under reduced pressure. The crude residue was purified by silica gel column chromatography (EtOAc/hexanes) to give 160mg (76%) of 2- (5-ethylcarbamoyl-thiophen-2-yl) -5- (2-trimethylsilyl-ethoxymethyl) -5H-pyrrolo [2, 3-b ]]Pyrazine-7-carboxylic acid ((S) -1, 2, 2-trimethyl-propyl) -amide as a light yellow solid. LC-MS: 530[ M + H]⁺。

Step 4

Stirring 2- (5-ethylcarbamoyl-thiophen-2-yl) -5- (2-trimethylsilyl-ethoxymethyl) -5H-pyrrolo [2, 3-b ]]A solution of pyrazine-7-carboxylic acid ((S) -1, 2, 2-trimethyl-propyl) -amide (150mg, 0.28mmol) in 1.0M HC1 in AcOH was heated at 60 ℃ for 3 h. The reaction mixture was concentrated under reduced pressure and the residue was dissolved in 1: 1MeOH/CH₂Cl₂(3mL), ethylenediamine (0.3mL) was added. The reaction mixture was stirred at 25 ℃ for 16h and then concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography (MeOH/CH) ₂C1₂) 100mg (89%) of 2- (5-ethylcarbamoyl-thiophen-2-yl) -5H-pyrrolo [2, 3-b ] are obtained]Pyrazine-7-carboxylic acid ((S) -1, 2, 2-trimethyl-propyl) -amide as an off-white solid. MS: (M + H)⁺＝400。

Example 159.

2- (5-isopropylcarbamoyl-thiophen-2-yl) -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ((S) -1, 2, 2-trimethyl-propyl) -amide

Prepared according to the procedure outlined in example 158 substituting isopropylamine for ethylamine in step 3. MS: (M + H)⁺＝414。

Example 160.

2- (5-tert-butylcarbamoyl-thiophen-2-yl) -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ((S) -1, 2, 2-trimethyl-propyl) -amide

Prepared according to the method outlined in example 158 substituting tert-butylamine for ethylamine in step 3. MS: (M + H)⁺＝428。

Example 161.

2- [5- (1-methyl-2-pyrazol-1-yl-ethylcarbamoyl) -thiophen-2-yl ] -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ((S) -1, 2, 2-trimethyl-propyl) -amide

Prepared according to the procedure outlined in example 158 substituting ethylamine with 1-methyl-2-pyrazol-1-yl-ethylamine in step 3. MS: (M + H)⁺＝480。

Example 162.

2- {5- [2- (4-fluoro-phenyl) -1-methyl-ethylcarbamoyl ] -thiophen-2-yl } -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ((S) -1, 2, 2-trimethyl-propyl) -amide

Prepared according to the method outlined in example 158 substituting ethylamine with 2- (4-fluoro-phenyl) -1-methyl-ethylamine in step 3. MS: (M + H)⁺＝508。

Example 163.

2- (5-diethylcarbamoyl-thiophen-2-yl) -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ((S) -1, 2, 2-trimethyl-propyl) -amide

Prepared according to the method outlined in example 158 substituting ethylamine with diethylamine in step 3. MS: (M + H)⁺＝428。

Example 164.

2- [5- (4-methyl-piperazine-1-carbonyl) -thiophen-2-yl ] -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ((S) -1, 2, 2-trimethyl-propyl) -amide

Prepared according to the procedure outlined in example 158 substituting ethylamine with 1-methylpiperazine in step 3. MS: (M + H)⁺＝455。

Example 165.

2- [5- ((R) -1-cyclopropylethylcarbamoyl) -thiophen-2-yl ] -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ((S) -1, 2, 2-trimethyl-propyl) -amide

Prepared according to the procedure outlined in example 158 substituting ethylamine with (R) -1-cyclopropylethylamine in step 3. MS: (M + H)⁺＝440。

Example 166.

2- {5- [ (pyridin-3-ylmethyl) -carbamoyl ] -thiophen-2-yl } -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ((S) -1, 2, 2-trimethyl-propyl) -amide

Prepared according to the method outlined in example 158 substituting 3- (aminomethyl) pyridine for ethylamine in step 3. MS: (M + H) ⁺＝463。

Example 167.

2- {5- [ (pyridin-4-ylmethyl) -carbamoyl ] -thiophen-2-yl } -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ((S) -1, 2, 2-trimethyl-propyl) -amide

Prepared according to the method outlined in example 158 substituting ethylamine with 4- (aminomethyl) pyridine in step 3. MS: (M + H)⁺＝463。

Example 168.

2- {5- [ (pyridin-2-ylmethyl) -carbamoyl ] -thiophen-2-yl } -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ((S) -1, 2, 2-trimethyl-propyl) -amide

Prepared according to the method outlined in example 158 substituting ethylamine with 2- (aminomethyl) pyridine in step 3. MS: (M + H)⁺＝463。

Example 169.

2- [5- (4-cyano-piperidine-1-carbonyl) -thiophen-2-yl ] -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ((S) -1, 2, 2-trimethyl-propyl) -amide

Prepared according to the procedure outlined in example 158 substituting piperidine-4-carbonitrile for ethylamine in step 3. MS: (M + H)⁺＝465。

Example 170.

2- [5- (cyclopentylmethyl-carbamoyl) -thiophen-2-yl ] -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ((S) -1, 2, 2-trimethyl-propyl) -amide

Prepared according to the procedure outlined in example 158 substituting cyclopentylmethylamine for ethylamine in step 3. MS: (M + H)⁺＝454。

Example 171.

2- [5- ((R) -2-hydroxy-1-methyl-ethylcarbamoyl) -thiophen-2-yl ] -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ((S) -1, 2, 2-trimethyl-propyl) -amide

Prepared according to the procedure outlined in example 158 substituting ethylamine with (R) -2-aminopropan-1-ol in step 3. MS: (M + H)⁺＝430。

Example 172.

2- [5- ((R) -1-methyl-2-phenyl-ethylcarbamoyl) -thiophen-2-yl ] -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ((S) -1, 2, 2-trimethyl-propyl) -amide

Prepared according to the procedure outlined in example 158 substituting ethylamine with (R) -1-methyl-2-phenylethylamine hydrochloride in step 3. MS: (M + H)⁺＝490。

Example 173.

2- [5- (1-pyridin-3-yl-ethylcarbamoyl) -thiophen-2-yl ] -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ((S) -1, 2, 2-trimethyl-propyl) -amide

Prepared according to the procedure outlined in example 158 substituting ethylamine with 1-pyridin-3-yl-ethylamine in step 3. MS: (M + H)⁺＝477。

Example 174.

2- [5- (cyanomethyl-carbamoyl) -thiophen-2-yl ] -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ((S) -1, 2, 2-trimethyl-propyl) -amide

Prepared according to the procedure outlined in example 158 substituting aminoacetonitrile for ethylamine in step 3. SEM deprotection in step 4 was performed in THF using TBAF (1.0M solution in THF) at reflux for 16h, followed by treatment with ethylenediamine. MS: (M + H)⁺＝411。

Example 175.

2- [5- (2-sulfamoyl-ethylcarbamoyl) -thiophen-2-yl ] -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ((S) -1, 2, 2-trimethyl-propyl) -amide

Prepared according to the procedure outlined in example 158 substituting ethylamine with 2-amino-ethanesulfonamide in step 3. SEM deprotection in step 4 was performed in THF using TBAF (1.0M solution in THF) at reflux for 16h, followed by treatment with ethylenediamine. MS: (M + H)⁺＝479。

Example 176.

2- [5- (2-imidazol-1-yl-1-methyl-ethylcarbamoyl) -thiophen-2-yl ] -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ((S) -1, 2, 2-trimethyl-propyl) -amide

Prepared according to the procedure outlined in example 158 substituting ethylamine with 2-imidazol-1-yl-1-methylethylamine in step 3. MS: (M + H)⁺＝480。

Example 177.

2- [5- (4-hydroxy-4-methyl-piperidine-1-carbonyl) -thiophen-2-yl ] -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ((S) -1, 2, 2-trimethyl-propyl) -amide

Prepared according to the procedure outlined in example 158 substituting ethylamine with 4-methyl-piperidin-4-ol hydrochloride in step 3. MS: (M + H)⁺＝470。

Example 178.

2- [5- (1-methyl-2-pyridin-2-yl-ethylcarbamoyl) -thiophen-2-yl ] -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ((S) -1, 2, 2-trimethyl-propyl) -amide

Prepared according to the procedure outlined in example 158 substituting ethylamine with 1-methyl-2-pyridin-2-yl-ethylamine in step 3. MS: (M + H) ⁺＝491。

Example 179.

2- [5- (7-aza-bicyclo [2.2.1] heptane-7-carbonyl) -thiophen-2-yl ] -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ((S) -1, 2, 2-trimethyl-propyl) -amide

Prepared according to the method outlined in example 158 using 7-aza-bicyclo [2.2.1] in step 3]Heptane hydrochloride substituted ethylamine. MS: (M + H)⁺＝452。

Example 180.

2- [5- (3-cyano-azetidine-1-carbonyl) -thiophen-2-yl ] -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ((S) -1, 2, 2-trimethyl-propyl) -amide

Prepared according to the procedure outlined in example 158 substituting azetidine-3-carbonitrile for ethylamine in step 3. SEM deprotection in step 4 was performed in THF using TBAF (1.0M solution in THF) at reflux for 16h, followed by treatment with ethylenediamine. MS: (M + H)⁺＝437。

Example 181.

2- [5- (3-carbamoyl-azetidine-1-carbonyl) -thiophen-2-yl ] -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ((S) -1, 2, 2-trimethyl-propyl) -amide

Additional product was isolated from example 180, step 4. MS: (M + H)⁺＝455。

Example 182.

2- [5- (azetidine-1-carbonyl) -thiophen-2-yl ] -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ((S) -1, 2, 2-trimethyl-propyl) -amide

Prepared according to the procedure outlined in example 158 substituting azetidine hydrochloride for ethylamine in step 3. SEM deprotection in step 4 was performed in THF using TBAF (1.0M solution in THF) at reflux for 16h, followed by treatment with ethylenediamine. MS: (M + H) ⁺＝412。

Example 183.

2- [5- (2, 6-dimethylpiperidine-1-carbonyl) -thiophen-2-yl ] -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ((S) -1, 2, 2-trimethyl-propyl) -amide

Prepared according to the procedure outlined in example 158 substituting ethylamine with 2, 6-dimethylpiperidine in step 3. MS: (M + H)⁺＝468。

Example 184.

1- {5- [7- ((S) -1, 2, 2-trimethyl-propylcarbamoyl) -5H-pyrrolo [2, 3-b ] pyrazin-2-yl ] -thiophene-2-carbonyl } -piperidine-4-carboxylic acid

Prepared according to the procedure outlined in example 158 substituting piperidine-4-carboxylic acid methyl ester for ethylamine in step 3. Hydrolysis of the methyl ester after coupling gives the acid. MS: (M + H)⁺＝484。

Example 185.

2- [5- (4-acetylamino-piperidine-1-carbonyl) -thiophen-2-yl ] -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ((S) -1, 2, 2-trimethyl-propyl) -amide

Prepared according to the procedure outlined in example 158 substituting ethylamine with N-piperidin-4-yl-acetamide in step 3. MS: (M + H)⁺＝497。

Example 186.

2- [5- (4-methylbenzylcarbamoyl) -thiophen-2-yl ] -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ((S) -1, 2, 2-trimethyl-propyl) -amide

Prepared according to the procedure outlined in example 158 substituting ethylamine with 4-methylbenzylamine in step 3. MS: (M + H) ⁺＝476。

Example 187.

2- [5- (4-fluorobenzylcarbamoyl) -thiophen-2-yl ] -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ((S) -1, 2, 2-trimethyl-propyl) -amide

Prepared according to the procedure outlined in example 158 substituting ethylamine with 4-fluorobenzylamine in step 3. MS: (M + H)⁺＝480。

Example 188.

2- [5- (2, 3-dichlorobenzylcarbamoyl) -thiophen-2-yl ] -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ((S) -1, 2, 2-trimethyl-propyl) -amide

Prepared according to the procedure outlined in example 158 substituting ethylamine with 2, 3-dichlorobenzylamine in step 3. MS: (M + H)⁺＝531。

Example 189.

2- [5- (2-methylbenzylcarbamoyl) -thiophen-2-yl ] -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ((S) -1, 2, 2-trimethyl-propyl) -amide

Prepared according to the procedure outlined in example 158 substituting ethylamine with 2-methylbenzylamine in step 3. MS: (M + H)⁺＝476。

Example 190.

2- [5- (2, 6-difluorobenzylcarbamoyl) -thiophen-2-yl ] -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ((S) -1, 2, 2-trimethyl-propyl) -amide

Prepared according to the procedure outlined in example 158 substituting ethylamine with 2, 6-difluorobenzylamine in step 3. MS: (M + H)⁺＝498。

Example 191.

2- [5- (2-chloro-6-fluorobenzylcarbamoyl) -thiophen-2-yl ] -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ((S) -1, 2, 2-trimethyl-propyl) -amide

Prepared according to the procedure outlined in example 158 substituting ethylamine with 2-chloro-6-fluorobenzylamine in step 3. MS: (M + H)⁺＝515。

Example 192.

2- [5- (2-methylcyclohexylcarbamoyl) -thiophen-2-yl ] -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ((S) -1, 2, 2-trimethyl-propyl) -amide

Prepared according to the procedure outlined in example 158 substituting ethylamine with 2-methylcyclohexylamine in step 3. MS: (M + H)⁺＝468。

Example 193.

2- [5- ((1S, 2R) -2-phenylcyclopropylcarbamoyl) -thiophen-2-yl ] -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ((S) -1, 2, 2-trimethyl-propyl) -amide

Prepared according to the method outlined in example 158 substituting ethylamine with (1S, 2R) -2-phenylcyclopropylamine hydrochloride in step 3. MS: (M + H)⁺＝488。

Example 194.

2- {5- [ (4-Methylthion-2-ylmethyl) -carbamoyl ] -thiophen-2-yl } -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ((S) -1, 2, 2-trimethyl-propyl) -amide

Prepared according to the method outlined in example 158 substituting ethylamine with (4-methylthiophen-2-yl) -methylamine in step 3. SEM deprotection in step 4 was performed using TBAF (1.0M in THF) for 16h in reflux, followed by treatment with ethylenediamine. MS: (M + H)⁺＝482。

Example 195.

2- {5- [ (5-Methylfuran-2-ylmethyl) -carbamoyl ] -thiophen-2-yl } -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ((S) -1, 2, 2-trimethyl-propyl) -amide

Prepared according to the procedure outlined in example 158 substituting ethylamine with (5-methylfuran-2-yl) -methylamine in step 3. SEM deprotection 1 in step 4 was performed in reflux using TBAF (1.0M in THF) in THFFor 6h, then treated with ethylenediamine. MS: (M + H)⁺＝466。

Example 196.

2- [5- (adamantan-1-ylcarbamoyl) -thiophen-2-yl ] -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ((S) -1, 2, 2-trimethyl-propyl) -amide

Prepared according to the procedure outlined in example 158 substituting ethylamine with adamantan-1-amine hydrochloride in step 3. MS: (M + H)⁺＝504。

Example 197.

2- {5- [1- (4-fluoro-phenyl) -ethylcarbamoyl ] -thiophen-2-yl } -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ((S) -1, 2, 2-trimethyl-propyl) -amide

Prepared according to the method outlined in example 158 substituting ethylamine with 1- (4-fluorophenyl) -ethylamine in step 3. MS: (M + H)⁺＝494。

Example 198.

2- [5- (methoxymethylcarbamoyl) -thiophen-2-yl ] -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ((S) -1, 2, 2-trimethyl-propyl) -amide

Prepared according to the method outlined in example 158 substituting ethylamine with N, O-dimethylhydroxylamine hydrochloride in step 3. MS: (M+H)⁺＝416。

Example 199.

2- (5-Methoxycarbarbamoylthiophen-2-yl) -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ((S) -1, 2, 2-trimethyl-propyl) -amide

Prepared according to the method outlined in example 158 substituting ethylamine with O-methylhydroxylamine hydrochloride in step 3. MS: (M + H)⁺＝402。

Example 200.

2- (5-prop-2-ynylcarbamoyl-thiophen-2-yl) -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ((S) -1, 2, 2-trimethyl-propyl) -amide

Prepared according to the procedure outlined in example 158 substituting propargylamine for ethylamine in step 3. MS: (M + H)⁺＝410。

Example 201.

2- {5- [ (R) -2- (3H-imidazol-4-yl) -1-methyl-ethylcarbamoyl ] -thiophen-2-yl } -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ((S) -1, 2, 2-trimethyl-propyl) -amide

Prepared according to the procedure outlined in example 158 substituting ethylamine with (R) -2- (3H-imidazol-4-yl) -1-methylethylamine dihydrochloride in step 3. MS: (M + H)⁺＝480。

Example 202.

2- [5- (5, 6, 7, 8-tetrahydronaphthalen-2-ylcarbamoyl) -thiophen-2-yl ] -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ((S) -1, 2, 2-trimethyl-propyl) -amide

Prepared according to the method outlined in example 158 substituting ethylamine with 5, 6, 7, 8-tetrahydronaphthalen-2-ylamine in step 3. MS: (M + H)⁺＝502。

Example 203.

2- (5-phenylcarbamoyl-thiophen-2-yl) -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ((S) -1, 2, 2-trimethyl-propyl) -amide

Prepared according to the procedure outlined in example 158 substituting ethylamine with aniline in step 3. MS: (M + H)⁺＝448。

Example 204.

2- [5- ((R) -1-p-tolylethylcarbamoyl) -thiophen-2-yl ] -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ((S) -1, 2, 2-trimethyl-propyl) -amide

Prepared according to the procedure outlined in example 158 substituting ethylamine with (R) -1- (4-methylphenyl) -ethylamine in step 3. MS: (M + H)⁺＝490。

Example 205.

2- [5- (2-methoxybenzylcarbamoyl) -thiophen-2-yl ] -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ((S) -1, 2, 2-trimethyl-propyl) -amide

Prepared according to the procedure outlined in example 158 substituting ethylamine with 2-methoxybenzylamine in step 3. MS: (M + H)⁺＝492。

Example 206.

2- [5- (2, 5-Dimethoxybenzylcarbamoyl) -thiophen-2-yl ] -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ((S) -1, 2, 2-trimethyl-propyl) -amide

Prepared according to the procedure outlined in example 158 substituting ethylamine with 2, 5-dimethoxybenzylamine in step 3. MS: (M + H) ⁺＝522。

Example 207.

2- {5- [ (4-fluorobenzyl) -methyl-carbamoyl ] -thiophen-2-yl } -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ((S) -1, 2, 2-trimethyl-propyl) -amide

Prepared according to the procedure outlined in example 158 substituting ethylamine with (4-fluorobenzyl) -methylamine in step 3. MS: (M + H)⁺＝494。

Example 208.

2- [5- (3-methoxybenzylcarbamoyl) -thiophen-2-yl ] -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ((S) -1, 2, 2-trimethyl-propyl) -amide

Prepared according to the procedure outlined in example 158 substituting ethylamine with 3-methoxybenzylamine in step 3. MS: (M + H)⁺＝492。

Example 209.

2- [5- (3-trifluoromethylbenzylcarbamoyl) -thiophen-2-yl ] -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ((S) -1, 2, 2-trimethyl-propyl) -amide

Prepared according to the procedure outlined in example 158 substituting ethylamine with 3-trifluoromethylbenzylamine in step 3. MS: (M + H)⁺＝530。

Example 210.

2- [5- (2-chloro-4-iodophenylcarbamoyl) -thiophen-2-yl ] -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ((S) -1, 2, 2-trimethyl-propyl) -amide

Step 1

To a stirred solution of 5- [7- ((S) -1, 2, 2-trimethyl-propylcarbamoyl) -5- (2-trimethylsilyl-ethoxymethyl) -5H-pyrrolo [2, 3-b ] ]Pyrazin-2-yl radicals]To a solution of-thiophene-2-carboxylic acid (150mg, 0.30mmol) in dry pyridine was added HATU (228 mg)0.60mmol) and 2-chloro-4-iodoaniline (380mg, 1.50 mmol). The reaction mixture was stirred at rt for 72h, then evaporated under reduced pressure and partitioned between water and EtOAc. With Na₂SO₄The organic layer was dried and concentrated. The crude residue was purified by silica gel column chromatography (EtOAc/hexane) to give 80mg (36%) of 2- [5- (2-chloro-4-iodo-phenylcarbamoyl) -thiophen-2-yl]-5- (2-trimethylsilyl-ethoxymethyl) -5H-pyrrolo [2, 3-b]Pyrazine-7-carboxylic acid ((S) -1, 2, 2-trimethyl-propyl) -amide as a yellow solid.

Step 2

2- [5- (2-chloro-4-iodophenylcarbamoyl) -thiophen-2-yl]-5H-pyrrolo [2, 3-b]Pyrazine-7-carboxylic acid ((S) -1, 2, 2-trimethyl-propyl) -amide. Prepared according to the method outlined in example 170, step 4, using 2- [5- (2-chloro-4-iodo-phenylcarbamoyl) -thiophen-2-yl]-5- (2-trimethylsilyl-ethoxymethyl) -5H-pyrrolo [2, 3-b]Pyrazine-7-carboxylic acid ((S) -1, 2, 2-trimethyl-propyl) -amide substituted 2- (5-ethylcarbamoyl-thiophen-2-yl) -5- (2-trimethylsilyl-ethoxymethyl) -5H-pyrrolo [2, 3-b [ -5]Pyrazine-7-carboxylic acid ((S) -1, 2, 2-trimethyl-propyl) -amide. MS: (M + H) ⁺＝608。

Example 211.

2- [5- ((R) -1, 2, 2-trimethyl-propylcarbamoyl) -thiophen-2-yl ] -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ((S) -1, 2, 2-trimethyl-propyl) -amide

Step 1

Reacting 5- [7- ((S) -1, 2, 2-trimethyl-propylcarbamoyl) -5- (2-trimethylsilyl-ethoxymethyl) -5H-pyrrolo [2, 3-b ]]Pyrazin-2-yl radicals]Thiophene-2-carboxylic acid (0.042g, 0.084mmol), 2mL of anhydrous dichloromethane, (R) -3, 3-dimethylbut-2-amine (0.025mL, 0.19mmol), 4-dimethylaminopyridine (0.012g, 0.101 mmol)mmol)) and N- (3-dimethylaminopropyl) -N' -ethylcarbodiimide hydrochloride (0.037g, 0.190mmol) were stirred at room temperature for 4 h. Dichloromethane (10mL) was added, and the solution was washed successively with 10mL of 1M citric acid solution, 10mL of water, 10mL of 10% NaOH solution, and 10mL of water, and then with Na₂SO₄Drying, filtration and concentration gave 0.074g (> 100%) of 2- [5- ((R) -1, 2, 2-trimethyl-propylcarbamoyl) -thiophen-2-yl]-5- (2-trimethylsilyl-ethoxymethyl) -5H-pyrrolo [2, 3-b]Pyrazine-7-carboxylic acid ((S) -1, 2, 2-trimethyl-propyl) -amide, as a yellow film, was used without further purification. MS: (M + Na)⁺＝608。

Step 2

Crude 2- [5- ((R) -1, 2, 2-trimethyl-propylcarbamoyl) -thiophen-2-yl prepared above ]-5- (2-trimethylsilyl-ethoxymethyl) -5H-pyrrolo [2, 3-b]Pyrazine-7-carboxylic acid ((S) -1, 2, 2-trimethyl-propyl) -amide, 1ml CH₂Cl₂And 1ml of trifluoroacetic acid, and then concentrated to a yellow residue. To the residue were added 0.5ml of dichloromethane and 0.5ml of ethylenediamine. The yellow solution was stirred for 90min and then partitioned between 10ml ethyl acetate and 5ml water. The aqueous layer was extracted with 10ml of ethyl acetate. With Na₂SO₄The combined organic layers were dried, filtered, and concentrated to give a yellow oily residue. Column chromatography (80-100% EtOAc/hexanes) afforded 0.018g (46%, 2 steps) of 2- [5- ((R) -1, 2, 2-trimethyl-propylcarbamoyl) -thiophen-2-yl]-5H-pyrrolo [2, 3-b]Pyrazine-7-carboxylic acid ((S) -1, 2, 2-trimethyl-propyl) -amide as a light yellow solid. MS: (M + Na)⁺＝478。

Example 212.

2- [5- (2, 2-dimethyl-propylcarbamoyl) -thiophen-2-yl ] -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ((S) -1, 2, 2-trimethyl-propyl) -amide

Prepared according to the method outlined in example 211, substituting 2, 2-dimethyl-propylamine for (R) -3, 3-dimethylbut-2-amine in step 1. MS: (M + Na)⁺＝464。

Example 213.

2- [5- ((R) -2-methanesulfonyl-1-methyl-ethylcarbamoyl) -thiophen-2-yl ] -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ((S) -1, 2, 2-trimethyl-propyl) -amide

Prepared according to the method outlined in example 158 substituting ethylamine with (R) -1- (methylsulfonyl) propan-2-amine hydrochloride in step 3. Using TFA followed by CH₂Cl₂/MeOH/NH₄OH (80: 19: 1) was subjected to SEM deprotection in step 4. MS: (M + H)⁺＝492。

Example 214.

2- [5- (1, 1-dioxo-hexahydro-1-thiopyran-4-ylcarbamoyl) -thiophen-2-yl ] -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ((S) -1, 2, 2-trimethyl-propyl) -amide

Prepared according to the method outlined in example 158 substituting ethylamine with (1, 1-tetrahydro-2H-thiopyran-4-yl) -amine hydrochloride in step 3. Using TFA followed by CH₂Cl₂/MeOH/NH₄OH (80: 19: 1) was subjected to SEM deprotection in step 4. MS: (M + H)⁺＝504。

Example 215.

2- [5- (1, 1-dioxo-1-thiomorpholine-4-carbonyl) -thiophen-2-yl ] -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ((S) -1, 2, 2-trimethyl-propyl) -amide

Prepared according to the procedure outlined in example 158 substituting ethylamine with thiomorpholine 1, 1-dioxide in step 3. Using TFA followed by CH₂Cl₂/MeOH/NH₄OH (80: 19: 1) was subjected to SEM deprotection in step 4. MS: (M + H)⁺＝490。

Example 216.

2- [5- (2-methoxy-1-methylethylcarbamoyl) -thiophen-2-yl ] -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ((S) -1, 2, 2-trimethyl-propyl) -amide

Prepared according to the procedure outlined in example 158 substituting ethylamine with 1-methoxypropan-2-amine in step 3. Using TFA followed by CH₂Cl₂/MeOH/NH₄OH (80: 19: 1) was subjected to SEM deprotection in step 4. MS: (M + H)⁺＝444。

Example 217.

2- (5-carbamoyl-thiophen-2-yl) -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ((S) -1, 2, 2-trimethyl-propyl) -amide

Prepared according to the method outlined in example 158 using 1, 1, 1-trifluoropropan-2-amine in step 3A substituted ethylamine. The title compound is presumed to be the result of hydrolysis of the initially formed 1, 1, 1-trifluoro-2-propylamide or an impure 1, 1, 1-trifluoropropan-2-amine starting material. Using TFA followed by CH₂Cl₂/MeOH/NH₄OH (80: 19: 1) was subjected to SEM deprotection in step 4. MS: (M + H)⁺＝372。

Example 218.

2- [5- (3, 3, 3-trifluoropropylcarbamoyl) -thiophen-2-yl ] -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ((S) -1, 2, 2-trimethyl-propyl) -amide

Prepared according to the method outlined in example 158 substituting 3, 3, 3-trifluoropropan-1-amine hydrochloride for ethylamine in step 3. Using TFA followed by CH₂Cl₂/MeOH/NH₄OH (80: 19: 1) was subjected to SEM deprotection in step 4. MS: (M + H)⁺＝468。

Example 219.

2- [5- (2-oxa-6-azaspiro [3.3] heptane-6-carbonyl) -thiophen-2-yl ] -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ((S) -1, 2, 2-trimethyl-propyl) -amide

Prepared according to the method outlined in example 158 using 2-oxa-6-azaspiro [3.3 ] in step 3]Heptane hemioxalate substituted ethylamine. Using TFA followed by CH₂Cl₂/MeOH/NH₄OH (80: 19: 1) was subjected to SEM deprotection in step 4. MS: (M + H)⁺＝454。

Example 220.

2- [5- (3, 3-dihydroxymethyl-azetidine-1-carbonyl) -thiophen-2-yl ] -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ((S) -1, 2, 2-trimethyl-propyl) -amide

Isolated as a byproduct from example 219, step 4. MS: (M + H)⁺＝472。

Example 221.

2- [ 4-methyl-5- (tetrahydropyran-4-ylcarbamoyl) -thiophen-2-yl ] -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ((S) -1, 2, 2-trimethyl-propyl) -amide

Prepared according to the method outlined in example 158, 2-formylthiophene-5-boronic acid was substituted with 5-formyl-4-methylthiophen-2-ylboronic acid in step 1 and ethylamine was substituted with tetrahydro-2H-pyran-4-amine hydrochloride in step 3. Using TFA followed by CH₂Cl₂/MeOH/NH₄OH (80: 19: 1) was subjected to SEM deprotection in step 4. MS: (M + H)⁺＝470。

Example 222.

2- [5- (1, 1-dioxo-1-thiomorpholine-4-carbonyl) -4-methyl-thiophen-2-yl ] -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ((S) -1, 2, 2-trimethyl-propyl) -amide

Prepared according to the method outlined in example 158 substituting 2-formyl with 5-formyl-4-methylthiophen-2-ylboronic acid in step 1 Thiophene-5-boronic acid and substituting thiomorpholine 1, 1-dioxide for ethylamine in step 3. Using TFA followed by CH₂Cl₂/MeOH/NH₄OH (80: 19: 1) was subjected to SEM deprotection in step 4. MS: (M + H)⁺＝504。

Example 223.

2- [ 4-methyl-5- (2-oxa-6-aza-spiro [3.3] heptane-6-carbonyl) -thiophen-2-yl ] -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ((S) -1, 2, 2-trimethyl-propyl) -amide

Prepared according to the method outlined in example 158, 2-formylthiophene-5-boronic acid was substituted with 5-formyl-4-methylthiophen-2-ylboronic acid in step 1 and 2-oxa-6-azaspiro [3.3] in step 3]Heptane hemioxalate substituted ethylamine. Using TFA followed by CH₂Cl₂/MeOH/NH₄OH (80: 19: 1) was subjected to SEM deprotection in step 4. MS: (M + H)⁺＝468。

Example 224.

2- [5- (3, 3-bishydroxymethyl-azetidine-1-carbonyl) -4-methyl-thiophen-2-yl ] -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ((S) -1, 2, 2-trimethyl-propyl) -amide

Isolated as a byproduct from example 223, step 4. MS: (M-H)^-＝484。

Example 225.

2- [5- (tetrahydropyran-4-ylcarbamoyl) -thiophen-2-yl ] -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ((S) -2-cyano-1, 2, 2-trimethyl-ethyl) -amide

Step 1

(S) -3-amino-2, 2-dimethyl-butyronitrile hydrochloride was prepared according to example 141, steps 1-3.

Step 2

In a flask, combine 2-bromo-5- (2-trimethylsilylethoxymethyl) -5H-pyrrolo [2, 3-b ]]Pyrazine-7-carboxylic acid (1.10g, 2.95mmol), (S) -3-amino-2, 2-dimethyl-butyronitrile hydrochloride (439mg, 2.95mmol), EDC (1.30g, 6.80mmol) and HOBt (1.15g, 6.80 mmol). DMF (27mL) was added followed by i-Pr₂NEt (3.6mL, 20.7 mmol). The reaction mixture was stirred at rt for 1.5h, then quenched with water and extracted with EtOAc. With 10% citric acid, saturated NaHCO₃The organic layer was washed with saturated LiCl and saturated NaCl, and then MgSO₄Drying and concentrating. By SiO₂The residue was purified by chromatography (20-100% EtOAc/hexanes) to give 1.32g (96%) of 2-bromo-5- (2-trimethylsilyl-ethoxymethyl) -5H-pyrrolo [2, 3-b ]]Pyrazine-7-carboxylic acid ((S) -2-cyano-1, 2, 2-trimethyl-ethyl) -amide as an off-white solid.

Step 3

2- [5- (tetrahydropyran-4-ylcarbamoyl) -thiophen-2-yl ] is prepared according to the procedure outlined in example 158]-5H-pyrrolo [2, 3-b]Pyrazine-7-carboxylic acid ((S) -2-cyano-1, 2, 2-trimethyl-ethyl) -amide with 2-bromo-5- (2-trimethylsilyl-ethoxymethyl) -5H-pyrrolo [2, 3-b ] in step 1]Pyrazine-7-carboxylic acid ((S) -2-cyano-1, 2, 2-trimethyl-ethyl) -amide substituted 2-bromo-5- (2-trimethylsilyl-ethoxymethyl) -5H-pyrrolo [2, 3-b [ ] ]Pyrazine-7-carboxylic acid ((S) -1, 2, 2-trimethyl-propyl) -amide and in step 3 ethylamine was substituted with tetrahydro-2H-pyran-4-amine hydrochloride. SEM deprotection in step 4 was performed using TFA followed by ethylenediamine. MS: (M + H)⁺＝467。

Example 226.

2- [5- (piperidine-1-carbonyl) -thiophen-2-yl ] -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ((S) -2-cyano-1, 2, 2-trimethyl-ethyl) -amide

Prepared according to the method outlined in example 158 using 2-bromo-5- (2-trimethylsilyl-ethoxymethyl) -5H-pyrrolo [2, 3-b ] in step 1]Pyrazine-7-carboxylic acid ((S) -2-cyano-1, 2, 2-trimethyl-ethyl) -amide substituted 2-bromo-5- (2-trimethylsilyl-ethoxymethyl) -5H-pyrrolo [2, 3-b [ ]]Pyrazine-7-carboxylic acid ((S) -1, 2, 2-trimethyl-propyl) -amide, and substituting piperidine for ethylamine in step 3. Using TFA followed by CH₂Cl₂/MeOH/NH₄OH (90: 9: 1) was subjected to SEM deprotection in step 4. MS: (M + H)⁺＝467；mp＝253-257。

Example 227.

2- [5- (tetrahydro-pyran-4-ylcarbamoyl) -thiophen-2-yl ] -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ((S) -1, 2, 2-trimethyl-propyl) -amide

Step 1

2-bromo-5- (2-trimethylsilyl-ethoxymethyl) -5H-pyrrolo [2, 3-b ] in a microwave vial ]Pyrazine-7-carboxylic acid ((S) -1, 2, 2-trimethyl-propyl) -amide (100mg, 0.22mmol) was dissolved in 5: 1 dioxane/water (6 mL). The vial was purged with argon and then 5- (methoxycarbonyl) thiophen-2-ylboronic acid (45mg, 0.24mmol), Na were added₂CO₃(70mg, 0.66mmol) and Pd (PPh)₃)₄(13mg，0011 mmol). The vial was sealed and heated in a microwave reactor at 140 ℃ for 1 h. Additional amounts of 5- (methoxycarbonyl) thiophen-2-ylboronic acid (23mg, 0.12mmol) and Pd (PPh) were added₃)₄(6mg, 0.005mmol), heated again in the microwave reactor at 140 ℃ for 1 h. The reaction was repeated isocratically and the crude reaction mixtures from both reactions were combined and partitioned between water and EtOAc. Adding saturated NaHCO₃The aqueous layer was extracted with EtOAc (2 ×). The combined organic layers were washed with brine and then Na₂SO₄Drying and evaporating under reduced pressure. The crude residue was purified by silica gel column chromatography (0-50% EtOAc/hexane) to give 90mg (40%, 2 times combined) of 5- [7- ((S) -1, 2, 2-trimethyl-propylcarbamoyl) -5- (2-trimethylsilyl-ethoxymethyl) -5H-pyrrolo [2, 3-b ]]Pyrazin-2-yl radicals]-thiophene-2-carboxylic acid methyl ester as a yellow-white solid.

Step 2

Methyl 5- [7- ((S) -1, 2, 2-trimethyl-propylcarbamoyl) -5- (2-trimethylsilyl-ethoxymethyl) -5H-pyrrolo [2, 3-b ] pyrazin-2-yl ] -thiophene-2-carboxylate (90mg, 0.17mmol) was dissolved in THF (1mL) and methanol (0.5 mL). A solution of lithium hydroxide (29mg, 0.70mmol) in water (1mL) was added slowly. The solution was stirred for 2h, then water and ethyl acetate were added. The pH was adjusted to 3, the layers were separated and the aqueous layer was extracted 2 more times with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, and concentrated to give 5- [7- ((S) -1, 2, 2-trimethyl-propylcarbamoyl) -5- (2-trimethylsilyl-ethoxymethyl) -5H-pyrrolo [2, 3-b ] pyrazin-2-yl ] -thiophene-2-carboxylic acid, which was used without further purification.

Step 3

5- [7- ((S) -1, 2, 2-trimethyl-propylcarbamoyl) -5- (2-trimethylsilyl-ethoxymethyl) -5H-pyrrolo [2, 3-b ] pyrazin-2-yl ] -thiophene-2-carboxylic acid (87mg, 0.17mmol), O-benzotriazol-1-yl-N, N, N ', N' -tetramethyluronium tetrafluoroborate (61mg, 0.19mmol), and N, N-diisopropylethylamine (0.10mL, 0.52mmol) were dissolved in acetonitrile (1.7 mL). tetrahydro-2H-pyran-4-amine hydrochloride (26mg, 0.19mmol) was added and the mixture was stirred at room temperature for 18H. Water, dilute HCl solution and ethyl acetate were added, the layers were separated and the aqueous layer was extracted 2 more times with ethyl acetate. The combined organic layers were washed with sodium bicarbonate solution, dried over sodium sulfate and concentrated. The residue was purified by silica gel chromatography (ethyl acetate/hexane) to give 80mg (76%) of 2- [5- (tetrahydro-pyran-4-ylcarbamoyl) -thiophen-2-yl ] -5- (2-trimethylsilyl-ethoxymethyl) -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ((S) -1, 2, 2-trimethyl-propyl) -amide.

Step 4

Reacting 2- [5- (tetrahydro-pyran-4-ylcarbamoyl) -thiophen-2-yl]-5- (2-trimethylsilyl-ethoxymethyl) -5H-pyrrolo [2, 3-b]Pyrazine-7-carboxylic acid ((S) -1, 2, 2-trimethyl-propyl) -amide (80mg, 0.137mmol) was dissolved in dichloromethane (1mL) and then stirred in an ice bath. Trifluoroacetic acid (0.4mL) was added slowly and the ice bath removed. The reaction was stirred for 3h and then cooled with an ice bath. Sodium bicarbonate solution was added and the mixture was extracted 3 times with ethyl acetate. The combined organic layers were washed with brine and dried over sodium sulfate. After evaporation, the residue was dissolved in absolute ethanol (6mL) and sodium acetate (224mg, 2.7mmol) was added. The mixture was stirred at 60 ℃ for 20 h. The reaction was cooled and water and ethyl acetate were added. The aqueous layer was extracted 2 more times 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 give 49mg (79%) of 2- [5- (tetrahydro-pyran-4-ylcarbamoyl) -thiophen-2-yl ]-5H-pyrrolo [2, 3-b]Pyrazine-7-carboxylic acid ((S) -1, 2, 2-trimethyl-propyl) -amide as an off-white solid. MS: (M + H)⁺＝456；mp＝333-334℃。

Example 228.

2- (5-benzylcarbamoyl-thiophen-2-yl) -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ((S) -1, 2, 2-trimethyl-propyl) -amide

Step 1

Thiophene formate boronic acid (0.5g, 2.9mmol) was dissolved in THF (12 mL). 1, 1' -carbonyldiimidazole (0.47g, 2.9mmol) was added and the reaction was stirred at room temperature for 1 h. Benzylamine (0.32mL, 2.9mmol) was added slowly and the reaction stirred for 18 h. The solvent was evaporated and the residue partitioned between ethyl acetate and water. The organic layer was washed with ammonium chloride solution, dried over sodium sulfate and evaporated to give 0.55g of 5- (benzylcarbamoyl) thiophen-2-ylboronic acid, which was used without further purification. LCMS: (M + Na)⁺＝284。

Step 2

2-bromo-5- (2-trimethylsilyl-ethoxymethyl) -5H-pyrrolo [2, 3-b ] in a microwave vial]Pyrazine-7-carboxylic acid ((S) -1, 2, 2-trimethyl-propyl) -amide (100mg, 0.22mmol) was dissolved in 5: 1 dioxane/water (6 mL). The vial was purged with argon and then 5- (benzylcarbamoyl) thiophen-2-ylboronic acid (86mg, 0.33mmol), Na were added₂CO₃(70mg, 0.66mmol) and Pd (PPh) ₃)₄(13mg, 0.011 mmol). The vial was sealed and heated in a microwave reactor at 150 ℃ for 0.5 h. Additional amounts of 5- (benzylcarbamoyl) thiophen-2-ylboronic acid (40mg, 0.15mmol) and Pd (PPh) were added₃)₄(6mg, 0.005mmol) and the reaction was heated in a microwave reactor at 140 ℃ for an additional 1 h. The reaction mixture was cooled and partitioned between water and EtOAc. Adding saturated NaHCO₃The aqueous layer was extracted with EtOAc (2 ×). The combined organic layers were washed with brine and then Na₂SO₄Drying and evaporating under reduced pressure. The crude residue was purified by silica gel column chromatography (EtOAc/hexane) to give 68mg (52%) of 2- (5-benzylcarbamoyl-thiophen-2-yl) -5- (2-trimethylsilyl-ethoxymethyl) -5H-pyrrolo [2, 3-b ]]Pyrazine-7-carboxylic acid ((S) -1, 2, 2-trimethyl-propyl) -amide as an off-white solid.

Step 3

Reacting 2- (5-benzylcarbamoyl-thiophen-2-yl) -5-(2-trimethylsilyl-ethoxymethyl) -5H-pyrrolo [2, 3-b]Pyrazine-7-carboxylic acid ((S) -1, 2, 2-trimethyl-propyl) -amide (65mg, 0.11mmol) was dissolved in dichloromethane (0.8mL) and then stirred in an ice bath. Trifluoroacetic acid (0.4mL) was added slowly and the ice bath removed. The reaction was stirred for 3h and then cooled with an ice bath. Sodium bicarbonate solution was added and the mixture was extracted 3 times with ethyl acetate. The combined organic layers were washed with brine and dried over sodium sulfate. After evaporation, the residue was dissolved in absolute ethanol (7mL) and sodium acetate (180mg, 2.2mmol) was added. The mixture was stirred at 60 ℃ for 20 h. The reaction was cooled and water and ethyl acetate were added. The aqueous layer was extracted 2 more times 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 give 40mg (79%) of 2- (5-benzylcarbamoyl-thiophen-2-yl) -5H-pyrrolo [2, 3-b ] ]Pyrazine-7-carboxylic acid ((S) -1, 2, 2-trimethyl-propyl) -amide as an off-white solid. MS: (M + H)⁺＝462；mp＝225-226℃。

Example 229.

2- [5- (3-cyanobenzylcarbamoyl) -thiophen-2-yl ] -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ((S) -1, 2, 2-trimethyl-propyl) -amide

Prepared according to the procedure outlined in example 228 substituting benzylamine with 3-cyanobenzylamine in step 1. MS: (M + H)⁺＝487；mp＝171-174℃。

Example 230.

2- (3-cyanophenoxy) -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid isopropylamide

Step 1

Stirring 2-bromo-5- (2-trimethylsilyl-ethoxymethyl) -5H-pyrrolo [2, 3-b ] in a pressure tube]To a solution of pyrazine-7-carboxylic acid isopropylamide (200mg, 0.48mmol) in toluene (5mL) was added 3-cyanophenol (87mg, 0.73mmol), K₃PO₄(204mg, 0.96mmol) and 2-di-tert-butylphosphino-2' - (N, N-dimethylamino) biphenyl (24mg, 0.07 mmol). The reaction mixture was purged thoroughly with argon for 20min, then Pd (OAc) was added₂(11mg, 0.05 mmol). The tube was sealed and the reaction mixture was heated at 140 ℃ for 18h, then cooled to room temperature, quenched with water (20mL), and extracted with EtOAc (3X 15 mL). The combined organic layers were washed with brine, dried over anhydrous Na₂SO₄Drying, and concentrating under reduced pressure. The residue was purified by silica gel column chromatography (100-200 mesh) using 20-60% EtOAc/hexane as eluting solvent to give 160mg (73%) of 2- (3-cyano-phenoxy) -5- (2-trimethylsilyl-ethoxymethyl) -5H-pyrrolo [2, 3-b ] ]Pyrazine-7-carboxylic acid isopropylamide as a yellow-brown oil.

Step 2

Stirring 2- (3-cyano-phenoxy) -5- (2-trimethylsilyl-ethoxymethyl) -5H-pyrrolo [2, 3-b]A solution of pyrazine-7-carboxylic acid isopropylamide (160mg, 0.35mmol) in 1.0M HCl in AcOH (5mL) was heated at 65 ℃ for 3 h. The reaction mixture was concentrated under reduced pressure and the residue was dissolved in MeOH/Et₃N/H₂O (8: 1, 3mL), ethylenediamine (0.1mL) was added at 0 ℃. The reaction mixture was stirred at 25 ℃ for 18h and then concentrated under reduced pressure. Chromatography on silica gel (MeOH/CH)₂Cl₂) The crude residue was purified to give 50mg (44%) of 2- (3-cyanophenoxy) -5H-pyrrolo [2, 3-b ]]Pyrazine-7-carboxylic acid isopropylamide as a yellow-white solid. MS: (M + H)⁺＝322。

Example 231.

2- (3-methoxyphenoxy) -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid isopropylamide

Prepared according to the method outlined in example 230 substituting 3-methoxyphenol for 3-cyanophenol in step 1. MS: (M + H)⁺＝327。

Example 232.

2- (3-trifluoromethoxy-phenoxy) -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid isopropylamide

Prepared according to the method outlined in example 230 substituting 3- (trifluoromethoxy) phenol for 3-cyanophenol in step 1. MS: (M + H) ⁺＝381。

Example 233.

2- (3-tert-butylphenoxy) -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid isopropylamide

Prepared according to the method outlined in example 230 substituting 3-tert-butylphenol for 3-cyanophenol in step 1. MS: (M + H)⁺＝353。

Example 234.

2- (3-methylphenoxy) -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid isopropylamide

Prepared according to the method outlined in example 230 substituting 3-methylphenol for 3-cyanophenol in step 1. MS: (M + H)⁺＝311。

Example 235.

2- (3-ethylphenoxy) -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid isopropylamide

Prepared according to the method outlined in example 230 substituting 3-ethylphenol for 3-cyanophenol in step 1. MS: (M + H)⁺＝325。

Example 236.

2- (3-isopropylphenoxy) -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid isopropylamide

Prepared according to the method outlined in example 230 substituting 3-isopropylphenol for 3-cyanophenol in step 1. MS: (M + H)⁺＝339。

Example 237.

2- (3-trifluoromethylphenoxy) -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid isopropylamide

Prepared according to the method outlined in example 230 substituting 3- (trifluoromethyl) phenol for 3-cyanophenol in step 1. MS: (M + H)⁺＝365。

Example 238.

2- (2-trifluoromethylphenoxy) -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid isopropylamide

Prepared according to the method outlined in example 230 substituting 2- (trifluoromethyl) phenol for 3-cyanophenol in step 1. MS: (M + H)⁺＝365。

Example 239.

2- (2-benzylphenoxy) -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid isopropylamide

Prepared according to the method outlined in example 230 substituting 2-benzylphenol for 3-cyanophenol in step 1. MS: (M + H)⁺＝387。

Example 240.

2- (2-ethylphenoxy) -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid isopropylamide

Prepared according to the method outlined in example 230 substituting 2-ethylphenol for 3-cyanophenol in step 1. MS: (M + H)⁺＝325。

Example 241.

2- (5, 6, 7, 8-tetrahydronaphthalen-1-yloxy) -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid isopropylamide

Prepared according to the method outlined in example 230 substituting 5, 6, 7, 8-tetrahydronaphthalen-1-ol for 3-cyanophenol in step 1. MS: (M + H)⁺＝351。

Example 242.

2- (5, 6, 7, 8-tetrahydronaphthalen-2-yloxy) -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid isopropylamide

Prepared according to the method outlined in example 230 substituting 5, 6, 7, 8-tetrahydronaphthalen-2-ol for 3-cyanophenol in step 1. MS: (M + H) ⁺＝351。

Example 243.

2- (naphthalen-1-yloxy) -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid isopropylamide

Prepared according to the method outlined in example 230 substituting naphthalene-1-ol for 3-cyanophenol in step 1. MS: (M + H)⁺＝347。

Example 244.

2- (naphthalen-2-yloxy) -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid isopropylamide

Prepared according to the method outlined in example 230 substituting naphthalene-2-ol for 3-cyanophenol in step 1. MS: (M + H)⁺＝347。

Example 245.

2- (3-chlorophenoxy) -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid isopropylamide

Prepared according to the method outlined in example 230 substituting 3-chlorophenol for 3-cyanophenol in step 1. MS: (M + H)⁺＝332。

Example 246.

2- (3-chlorophenoxy) -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ethylamide

Prepared according to the method outlined in example 230 using 2-bromo-5- (2-trimethylsilyl-ethoxymethyl) -5H-pyrrolo [2, 3-b ] in step 1]Pyrazine-7-carboxylic acid ethylamide substituted 2-bromo-5- (2-trimethylsilyl-ethoxymethyl) -5H-pyrrolo [2, 3-b]Pyrazine-7-carboxylic acid isopropylamide and 3-cyanophenol substituted with 3-chlorophenol. MS: (M + H)⁺＝318。

Example 247.

2- (3-cyanophenoxy) -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ethylamide

Prepared according to the method outlined in example 230 using 2-bromo-5- (2-trimethylsilyl-ethoxymethyl) -5H-pyrrolo [2, 3-b ] in step 1]Pyrazine-7-carboxylic acid ethylamide substituted 2-bromo-5- (2-trimethylsilyl-ethoxymethyl) -5H-pyrrolo [2, 3-b]Pyrazine-7-carboxylic acid isopropylamide. MS: (M + H)⁺＝308。

Example 248.

2- (3-trifluoromethoxy-phenoxy) -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ethylamide

Prepared according to the method outlined in example 230 using 2-bromo-5- (2-trimethylsilyl-ethoxymethyl) -5H-pyrrolo [2, 3-b ] in step 1]Pyrazine-7-carboxylic acid ethylamide substituted 2-bromo-5- (2-trimethylsilyl-ethoxymethyl) -5H-pyrrolo [2, 3-b]Pyrazine-7-carboxylic acid isopropylamide and 3-cyanophenol substituted with 3- (trifluoromethoxy) phenol. MS: (M + H)⁺＝367。

Example 249.

2- (3-tert-butylphenoxy) -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ethylamide

Prepared according to the method outlined in example 230 using 2-bromo-5- (2-trimethylsilyl-ethoxymethyl) -5H-pyrrolo [2, 3-b ] in step 1]Pyrazine-7-carboxylic acid ethylamide substituted 2-bromo-5- (2-trimethylsilyl-ethoxymethyl) -5H-pyrrolo [2, 3-b]Pyrazine-7-carboxylic acid isopropylamide and 3-cyanophenol substituted with 3-tert-butylphenol. MS: (M + H) ⁺＝339。

Example 250.

2- (3-methylphenoxy) -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ethylamide

Prepared according to the method outlined in example 230 using 2-bromo-5- (2-trimethylsilyl-ethoxymethyl) -5H-pyrrolo [2, 3-b ] in step 1]Pyrazine-7-carboxylic acid ethylamide substituted 2-bromo-5- (2-trimethylsilyl-ethoxymethyl) -5H-pyrrolo [2, 3-b]Pyrazine-7-carboxylic acid isopropylamide and 3-cyanophenol substituted with 3-methylphenol. MS: (M + H)⁺＝297。

Example 251.

2- (3-ethylphenoxy) -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ethylamide

Prepared according to the method outlined in example 230 using 2-bromo-5- (2-trimethylsilyl-ethoxymethyl) -5H-pyrrolo [2, 3-b ] in step 1]Pyrazine-7-carboxylic acid ethylamide substituted 2-bromo-5- (2-trimethylsilyl-ethoxymethyl) -5H-pyrrolo [2, 3-b]Pyrazine-7-carboxylic acid isopropylamide and 3-cyanophenol substituted with 3-ethylphenol. MS: (M + H)⁺＝311。

Example 252.

2- (3-isopropylphenoxy) -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ethylamide

Prepared according to the method outlined in example 230 using 2-bromo-5- (2-trimethylsilyl-ethoxymethyl) -5H-pyrrolo [2, 3-b ] in step 1 ]Pyrazine-7-carboxylic acid ethylamide substituted 2-bromo-5- (2-trimethylsilyl-ethoxymethyl) -5H-pyrrolo [2, 3-b]Pyrazine-7-carboxylic acid isopropylamide and 3-cyanophenol substituted with 3-isopropylphenol. MS: (M + H)⁺＝325。

Example 253.

2- (3-trifluoromethylphenoxy) -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ethylamide

Prepared according to the method outlined in example 230 using 2-bromo-5- (2-trimethylsilyl-ethoxymethyl) -5H-pyrrolo [2, 3-b ] in step 1]Pyrazine-7-carboxylic acid ethylamide substituted 2-bromo-5- (2-trimethylsilyl-ethoxymethyl) -5H-pyrrolo [2, 3-b]Pyrazine-7-carboxylic acid isopropylamide and 3-cyanophenol substituted with 3- (trifluoromethyl) phenol. MS: (M + H)⁺＝351。

Example 254.

2- (2-methylphenoxy) -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid isopropylamide

Prepared according to the method outlined in example 230 substituting 2-methylphenol for 3-cyanophenol in step 1. MS: (M + H)⁺＝311。

Example 255.

2- (2-trifluoromethoxy-phenoxy) -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid isopropylamide

Prepared according to the method outlined in example 230 substituting 2- (trifluoromethoxy) phenol for 3-cyanophenol in step 1. MS: (M + H) ⁺＝381。

Example 256.

2- (2, 2-dimethyl-2, 3-dihydrobenzofuran-7-yloxy) -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid isopropylamide

Prepared according to the method outlined in example 230 substituting 2, 2-dimethyl-2, 3-dihydro-benzofuran-7-ol for 3-cyanophenol in step 1. MS: (M + H)⁺＝367。

Example 257.

2- (2-chlorophenoxy) -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid isopropylamide

Prepared according to the method outlined in example 230 substituting 2-chlorophenol for 3-cyanophenol in step 1. MS: (M + H)⁺＝332。

Example 258.

2- (2-methoxyphenoxy) -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid isopropylamide

Prepared according to the method outlined in example 230 substituting 2-methoxyphenol for 3-cyanophenol in step 1. MS: (M + H)⁺＝327。

Example 259.

2- (2-methylphenoxy) -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ethylamide

Prepared according to the method outlined in example 230 using 2-bromo-5- (2-trimethylsilyl-ethoxymethyl) -5H-pyrrolo [2, 3-b ] in step 1]Pyrazine-7-carboxylic acid ethylamide substituted 2-bromo-5- (2-trimethylsilyl-ethoxymethyl) -5H-pyrrolo [2, 3-b]Pyrazine-7-carboxylic acid isopropylamide and 3-cyanophenol was substituted with 2-methylphenol. MS: (M + H) ⁺＝297。

Example 260.

2- (3, 5-Dimethoxyphenoxy) -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid isopropylamide

Prepared according to the method outlined in example 230 substituting 3, 5-dimethoxyphenol for 3-cyanophenol in step 1. MS: (M + H)⁺＝357。

Example 261.

2- (5, 6, 7, 8-tetrahydronaphthalen-1-yloxy) -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ethylamide

Prepared according to the method outlined in example 230 using 2-bromo-5- (2-trimethylsilyl-ethoxymethyl) -5H-pyrrolo [2, 3-b ] in step 1]Pyrazine-7-carboxylic acid ethylamide substituted 2-bromo-5- (2-trimethylsilyl-ethoxymethyl) -5H-pyrrolo [2, 3-b]Pyrazine-7-carboxylic acid isopropylamide and 3-cyanophenol substituted with 5, 6, 7, 8-tetrahydronaphthalen-1-ol. MS: (M + H)⁺＝337。

Example 262.

2- (5, 6, 7, 8-tetrahydronaphthalen-2-yloxy) -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ethylamide

Prepared according to the method outlined in example 230 using 2-bromo-5- (2-trimethylsilyl-ethoxymethyl) -5H-pyrrolo [2, 3-b ] in step 1]Pyrazine-7-carboxylic acid ethylamide substituted 2-bromo-5- (2-trimethylsilyl-ethoxymethyl) -5H-pyrrolo [2, 3-b]Pyrazine-7-carboxylic acid isopropylamide and 3-cyanophenol substituted with 5, 6, 7, 8-tetrahydronaphthalen-2-ol. MS: (M + H) ⁺＝337。

Example 263.

2- (naphthalen-1-yloxy) -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ethylamide

Prepared according to the method outlined in example 230 using 2-bromo-5- (2-trimethylsilyl-ethoxymethyl) -5H-pyrrolo [2, 3-b ] in step 1]Pyrazine-7-carboxylic acid ethylamide substituted 2-bromo-5- (2-trimethylsilyl-ethoxymethyl) -5H-pyrrolo [2, 3-b]Pyrazine-7-carboxylic acid isopropylamide and 3-cyanophenol substituted with naphthalen-1-ol. MS: (M + H)⁺＝333。

Example 264.

2- (naphthalen-2-yloxy) -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ethylamide

Prepared according to the method outlined in example 230 using 2-bromo-5- (2-trimethylsilyl-ethoxymethyl) -5H-pyrrolo [2, 3-b ] in step 1]Pyrazine-7-carboxylic acid ethylamide substituted 2-bromo-5- (2-trimethylsilyl-ethoxymethyl) -5H-pyrrolo [2, 3-b]Pyrazine-7-carboxylic acid isopropylamide and 3-cyanophenol substituted with naphthalen-2-ol. MS: (M + H)⁺＝333。

Example 265.

2- (3, 5-Dimethoxyphenoxy) -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ethylamide

Prepared according to the method outlined in example 230 using 2-bromo-5- (2-trimethylsilyl-ethoxymethyl) -5H-pyrrolo [2, 3-b ] in step 1]Pyrazine-7-carboxylic acid ethylamide substituted 2-bromo-5- (2-trimethylsilyl-ethoxymethyl) -5H-pyrrolo [2, 3-b ]Pyrazine-7-carboxylic acid isopropylamide and 3-cyanophenol substituted with 3, 5-dimethoxyphenol. MS: (M + H)⁺＝343。

Example 266.

2- (3-methoxyphenoxy) -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ethylamide

Prepared according to the method outlined in example 230 using 2-bromo-5- (2-trimethylsilyl-ethoxymethyl) -5H-pyrrolo [2, 3-b ] in step 1]Pyrazine-7-carboxylic acid ethylamide substituted 2-bromo-5- (2-trimethylsilyl-ethoxymethyl) -5H-pyrrolo [2, 3-b]Pyrazine-7-carboxylic acid isopropylamide and 3-cyanophenol substituted with 3-methoxyphenol. MS: (M + H)⁺＝313。

Example 267.

2- (2-chlorophenoxy) -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ethylamide

Prepared according to the method outlined in example 230 using 2-bromo-5- (2-trimethylsilyl-ethoxymethyl) -5H-pyrrolo [2, 3-b ] in step 1]Pyrazine-7-carboxylic acid ethylamide substituted 2-bromo-5- (2-trimethylsilyl-ethoxymethyl) -5H-pyrrolo [2, 3-b]Pyrazine-7-carboxylic acid isopropylamide, and 3-cyanophenol was substituted with 2-chlorophenol. MS: (M + H)⁺＝318。

Example 268.

2- (4-cyanophenoxy) -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid isopropylamide

Prepared according to the method outlined in example 230 substituting 4-cyanophenol for 3-cyanophenol in step 1. MS: (M + H) ⁺＝322。

Example 269.

2- (4-cyanophenoxy) -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ethylamide

Prepared according to the method outlined in example 230 using 2-bromo-5- (2-trimethylsilyl-ethoxymethyl) -5H-pyrrolo [2, 3-b ] in step 1]Pyrazine-7-carboxylic acid ethylamide substituted 2-bromo-5- (2-trimethylsilyl-ethoxymethyl) -5H-pyrrolo [2, 3-b]Pyrazine-7-carboxylic acid isopropylamide and 3-cyanophenol substituted with 4-cyanophenol. MS: (M + H)⁺＝308。

Example 270.

2- ((R) -3-methanesulfonylaminoindan-5-yloxy) -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid isopropylamide

Step 1

To a solution of (R) -3-aminoindan-5-ol (100mg, 0.67mmol) in THF (4mL) was added di-tert-butyl dicarbonate (0.13mL, 0.60mmol) and triethylamine (0.11mL, 0.80 mmol). The reaction mixture was stirred at room temperature for 18h, then the solvent was evaporated. The residue was partitioned between water and EtOAc. Extract the aqueous layer with EtOAc and use Na₂SO₄The combined organic layers were dried and concentrated under reduced pressure. The residue was purified by silica gel chromatography using EtOAc/hexanes as the eluting solvent to give 100mg (60%) of tert-butyl ((R) -6-hydroxyindan-1-yl) -carbamate as a white solid.

Step 2

To a stirred solution of 2-bromo-5- (2-trimethylsilyl-ethoxymethyl) -5H-pyrrolo [2, 3-b]Pyrazine-7-carboxylic acid isopropylamide (250mg, 0.60 mm)ol) to a solution in toluene (5mL) were added ((R) -6-hydroxyindan-1-yl) -carbamic acid tert-butyl ester (190mg, 0.78mmol), K₃PO₄(250mg, 1.20mmol) and 2-di-tert-butylphosphino-2' - (N, N-dimethylamino) biphenyl (41mg, 0.12 mmol). The reaction mixture was purged thoroughly with argon for 20min, then Pd (OAc) was added₂(13mg, 0.06 mmol). The reaction mixture was heated at 140 ℃ for 18h, then cooled to room temperature, quenched with water (20mL), and extracted with EtOAc (3X 15 mL). The combined organic layers were washed with brine, dried over anhydrous Na₂SO₄Drying, and concentrating under reduced pressure. The residue was purified by silica gel column chromatography (100-200 mesh) using 20-60% EtOAc/hexane as the eluting solvent to give 220mg (65%) of { (R) -6- [ 7-isopropylcarbamoyl-5- (2-trimethylsilyl-ethoxymethyl) -5H-pyrrolo [2, 3-b ]]Pyrazin-2-yloxy]-indan-1-yl } -carbamic acid tert-butyl ester as brown solid.

Step 3

To a stirred solution of { (R) -6- [ 7-isopropylcarbamoyl-5- (2-trimethylsilyl-ethoxymethyl) -5H-pyrrolo [2, 3-b ] pyrazin-2-yloxy ] -indan-1-yl } -carbamic acid tert-butyl ester (450mg, 0.77mol) in dry MeOH (10mL) was added acetyl chloride (1.09mL, 15.46mmol) dropwise at 0 deg.C. After addition, the reaction was warmed to room temperature and stirred for 2 h. The reaction mixture was concentrated under reduced pressure and at room temperature to give 2- ((R) -3-amino-indan-5-yloxy) -5- (2-trimethylsilyl-ethoxymethyl) -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid isopropylamide hydrochloride as a brown solid, which was used without further purification.

Step 4

Stirring 2- ((R) -3-amino-indan-5-yloxy) -5- (2-trimethylsilyl-ethoxymethyl) -5H-pyrrolo [2, 3-b ] at 0 deg.C]To a solution of pyrazine-7-carboxylic acid isopropylamide hydrochloride (200mg, 0.38mmol) in dichloromethane (8mL) was added diisopropylethylamine (0.29mL, 1.66mmol) followed by methanesulfonyl chloride (0.038mL, 0.49 mmol). The reaction mixture was stirred at 0 ℃ for 10min, at room temperature for 16h, then quenched with water and extracted with EtOAc (3 ×). With Na₂SO₄The combined organic layers were dried and concentrated. The residue was purified by silica gel column chromatography (100-200 mesh) using EtOAc/hexane as eluting solvent to give 170mg (73%) of 2- ((R) -3-methanesulfonylamino-indan-5-yloxy) -5- (2-trimethylsilyl-ethoxymethyl) -5H-pyrrolo [2, 3-b ]]Pyrazine-7-carboxylic acid isopropylamide as a grey solid.

Step 5

To a stirred solution of 2- ((R) -3-methanesulfonylamino-indan-5-yloxy) -5- (2-trimethylsilyl-ethoxymethyl) -5H-pyrrolo [2, 3-b ]]To a solution of pyrazine-7-carboxylic acid isopropylamide (170mg, 0.30mmol) in anhydrous THF (5mL) were added tetrabutylammonium fluoride (1.0M solution in THF, 6.0mL, 6mmol) and ethylenediamine (0.40mL, 6.0 mmol). The reaction mixture was heated at reflux for 18h and then cooled to room temperature. Quench with water and extract with ethyl acetate (3 ×). With Na ₂SO₄The combined organic layers were dried and concentrated. Chromatography on silica gel (100-200 mesh) using 2-5% MeOH/CH₂Cl₂The residue was purified as elution solvent to give 43mg (34%) of 2- ((R) -3-methanesulfonylaminoindan-5-yloxy) -5H-pyrrolo [2, 3-b ]]Pyrazine-7-carboxylic acid isopropylamide as a yellow-white solid. MS: (M + H)⁺＝430。

Example 271.

2- ((R) -3-Acetylaminoindan-5-yloxy) -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid isopropylamide

Prepared according to the method outlined in example 270 substituting methanesulfonyl chloride and diisopropylethylamine with acetic anhydride and pyridine in step 4. MS: (M + H)⁺＝394。

Example 272.

2- ((R) -3-methanesulfonylaminoindan-5-yloxy) -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ethylamide

Prepared according to the method outlined in example 270 using 2-bromo-5- (2-trimethylsilyl-ethoxymethyl) -5H-pyrrolo [2, 3-b ] in step 2]Pyrazine-7-carboxylic acid ethylamide substituted 2-bromo-5- (2-trimethylsilyl-ethoxymethyl) -5H-pyrrolo [2, 3-b]Pyrazine-7-carboxylic acid isopropylamide. MS: (M + H)⁺＝416。

Example 273.

2- ((R) -3-Acetylaminoindan-5-yloxy) -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ethylamide

Prepared according to the method outlined in example 270 using 2-bromo-5- (2-trimethylsilyl-ethoxymethyl) -5H-pyrrolo [2, 3-b ] in step 2 ]Pyrazine-7-carboxylic acid ethylamide substituted 2-bromo-5- (2-trimethylsilyl-ethoxymethyl) -5H-pyrrolo [2, 3-b]Pyrazine-7-carboxylic acid isopropylamide, substituting methanesulfonyl chloride and diisopropylethylamine with acetic anhydride and pyridine in step 4. MS: (M + H)⁺＝380。

Example 274.

2- (1H-indol-6-yloxy) -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid isopropylamide

Step 1

To a stirred solution of 6-hydroxyindole (0.40g, 3.00mmol) in MeCN (15mL) were added di-tert-butyl dicarbonate (1.9mL, 9.00mmol), DMAP (0.184g, 1.5mmol) and triethylamine (1.2mL, 9.00 mmol). The reaction mixture was stirred at 25 ℃ for 16h, and then the solvent was completely distilled off. The residue was purified by silica gel column chromatography (100-200 mesh) using 10-20% EtOAc/hexanes as the eluting solvent to give 0.87g (87%) of tert-butyl 6-tert-butoxycarbonyloxy-indole-1-carboxylate as a colorless oil.

Step 2

To a stirred solution of tert-butyl 6-tert-butoxycarbonyloxy-indole-1-carboxylate (1.0g, 3.00mmol) in dichloromethane (20mL) was added morpholine (7.8mL, 90.1 mmol). The reaction mixture was stirred at 25 ℃ for 20h, and then the solvent was completely distilled off. The residue was purified by column chromatography on silica gel (100-200 mesh) using 10-20% EtOAc/hexanes as the eluting solvent to give 0.35g (50%) of tert-butyl 6-hydroxyindole-1-carboxylate as a colorless oil.

Step 3

To a stirred solution of 2-bromo-5- (2-trimethylsilyl-ethoxymethyl) -5H-pyrrolo [2, 3-b]To a solution of pyrazine-7-carboxylic acid isopropylamide (550mg, 1.33mmol) in toluene (10mL) was added tert-butyl 6-hydroxyindole-1-carboxylate (466mg, 2.00mmol), K₃PO₄(564mg, 2.66mmol) and 2-di-tert-butylphosphino-2' - (N, N-dimethylamino) biphenyl (136mg, 0.40 mmol). The reaction mixture was purged thoroughly with argon for 20min, then Pd (OAc) was added₂(58mg, 0.26 mmol). The reaction mixture was heated at 140 ℃ for 18h, then cooled to room temperature, quenched with water (20mL), and extracted with EtOAc (3X 15 mL). The combined organic layers were washed with brine, dried over anhydrous Na₂SO₄Drying, and concentrating under reduced pressure. The residue was purified by column chromatography on silica gel (100-200 mesh) using 20-60% EtOAc/hexane as eluting solvent to give 320mg (52%) of 2- (1H-indol-6-yloxy) -5- (2-trimethylsilyl-ethoxymethyl) -5H-pyrrolo [2, 3-b ]]Pyrazine-7-carboxylic acid isopropylamide as a yellow-brown oil.

Step 4

Stirring 2- (1H-indol-6-yloxy) -5- (2-trimethylsilyl-ethoxymethyl) -5H-pyrrolo [2, 3-b ] at 0 deg.C]To a solution of pyrazine-7-carboxylic acid isopropylamide (63mg, 0.135mmol) in dichloromethane (5mL) was added trifluoroacetic acid (1 mL). The reaction mixture was stirred at room temperature for 4h, then the solvent was removed under reduced pressure. The residue was dissolved in 1: 1 MeOH/dichloromethane (5mL) and ethylenediamine (0.2mL) was added at 0 ℃. The reaction mixture was stirred at room temperature for 18h, then concentrated under reduced pressure. The crude residue was purified by preparative HPLC to give 3.8mg (8%) of 2- (1H-indol-6-yloxy) -5H-pyrrolo [2, 3-b ] ]Pyrazine-7-carboxylic acid isopropylamide. MS: (M + H)⁺＝336。

Example 275.

2- (1H-indol-6-yloxy) -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ethylamide

Prepared according to the method outlined in example 274 using 2-bromo-5- (2-trimethylsilyl-ethoxymethyl) -5H-pyrrolo [2, 3-b ] in step 3]Pyrazine-7-carboxylic acid ethylamide substituted 2-bromo-5- (2-trimethylsilyl-ethoxymethyl) -5H-pyrrolo [2, 3-b]Pyrazine-7-carboxylic acid isopropylamide. MS: (M + H)⁺＝322。

Example 276.

2- (1H-indol-4-yloxy) -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid isopropylamide

Prepared according to the method outlined in example 274 substituting 4-hydroxyindole for 6-hydroxyindole in step 1. MS: (M + H)⁺＝336。

Example 277.

2- (1H-indol-4-yloxy) -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ethylamide

Prepared according to the method outlined in example 274 substituting 4-hydroxyindole for 6-hydroxyindole in step 1 and 2-bromo-5- (2-trimethylsilyl-ethoxymethyl) -5H-pyrrolo [2, 3-b ] in step 3]Pyrazine-7-carboxylic acid ethylamide substituted 2-bromo-5- (2-trimethylsilyl-ethoxymethyl) -5H-pyrrolo [2, 3-b]Pyrazine-7-carboxylic acid isopropylamide. MS: (M + H)⁺＝322。

Example 278.

2- (1-methyl-1H-indol-6-yloxy) -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid isopropylamide

Step 1

To a stirred suspension of NaH (60% in mineral oil, 36mg, 0.90mmol) in anhydrous DMF (10mL) was added a solution of 2- (1H-indol-6-yloxy) -5- (2-trimethylsilyl-ethoxymethyl) -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid isopropylamide (275mg, 0.59mmol) in anhydrous DMF (5mL) at 0 ℃. The reaction mixture was stirred at 25 ℃ for 30min, then cooled to 0 ℃ and methyl iodide (44uL, 0.70mmol) was added slowly. The reaction mixture was stirred at 25 ℃ for 3h, and then DMF was distilled off. The crude residue was purified by silica gel column chromatography with 7% ethyl acetate in hexane to give 160mg (56%) of 2- (1-methyl-1H-indol-6-yloxy) -5- (2-trimethylsilyl-ethoxymethyl) -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid isopropylamide as a yellow oil.

Step 2

To a stirred solution of 2- (1-methyl-1H-indol-6-yloxy) -5- (2-trimethylsilyl-ethoxymethyl) -5H-pyrrolo [2, 3-b]To a solution of pyrazine-7-carboxylic acid isopropylamide (160mg, 0.33mmol) in anhydrous THF (5mL) were added tetrabutylammonium fluoride (1.0M in THF, 6.6mL, 6.6mmol) and ethylenediamine (0.44mL, 6.6 mmol). The reaction mixture was heated at reflux for 16h, then cooled to room temperature, quenched with water, and extracted with ethyl acetate (4 ×). With Na ₂SO₄The combined organic layers were dried and concentrated. Chromatography on silica gel (100-200 mesh) using 2-6% MeOH/CH₂Cl₂The residue was purified as eluting solvent to give 59mg (52%) of 2- (1-methyl-1H-indol-6-yloxy) -5H-pyrrolo [2, 3-b ]]Pyrazine-7-carboxylic acid isopropylamide as a light yellow solid. MS: (M + H)⁺＝350。

Example 279.

2- (1H-indol-5-yloxy) -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid isopropylamide

Step 1

To a stirred solution of 5-hydroxyindole (1.0g, 7.50mmol) in MeCN (35mL) were added di-tert-butyl dicarbonate (4.9g, 22.5mmol), DMAP (0.46g, 3.75mmol) and triethylamine (3.2mL, 22.5 mmol). The reaction mixture was stirred at 25 ℃ for 16h, and then the solvent was completely distilled off. The residue was purified by column chromatography on silica gel (100-200 mesh) using 10-20% EtOAc/hexane as the eluting solvent to give 2.5g (100%) of tert-butyl 5-tert-butoxycarbonyloxy-indole-1-carboxylate as a colorless oil.

Step 2

To a stirred solution of tert-butyl 5-tert-butoxycarbonyloxy-indole-1-carboxylate (1.5g, 4.50mmol) in dichloromethane (30mL) was added morpholine (11.8mL, 135 mmol). The reaction mixture was stirred at 25 ℃ for 16h, and then the solvent was completely distilled off. The residue was purified by column chromatography on silica gel (100-200 mesh) using 10-20% EtOAc/hexanes as the eluting solvent to give 0.8g (77%) of tert-butyl 5-hydroxyindole-1-carboxylate as a colorless oil.

Step 3

Stirring of 2-bromo-5- (2-trimethylsilyl-ethoxymethyl) -5H-pyrrolo [2, 3-b ] in a microwave vial]To a solution of pyrazine-7-carboxylic acid isopropylamide (100mg, 0.24mmol) in DMF (4mL) was added tert-butyl 5-hydroxyindole-1-carboxylate (68mg, 0.29mmol) and Cs₂CO₃(235mg, 0.72 mmol). The vial was sealed and heated with a microwave reactor at 120 ℃ for 1 h. The reaction was quenched with water (20mL) and extracted with EtOAc (3X). The combined organic layers were washed with brine, Na₂SO₄Drying, and concentrating under reduced pressure. The residue was purified by column chromatography on silica gel (100-200 mesh) using 20-60% EtOAc/hexane as eluting solvent to give 60mg (36%) of 2- (1H-indol-5-yloxy) -5- (2-trimethylsilyl-ethoxymethyl) -5H-pyrrolo [2, 3-b ]]Pyrazine-7-carboxylic acid isopropylamide as a brown oil.

Step 4

To a stirred solution of 2- (1H-indol-5-yloxy) -5- (2-trimethylsilyl-ethoxymethyl) -5H-pyrrolo [2, 3-b]To a solution of pyrazine-7-carboxylic acid isopropylamide (60mg, 0.13mmol) in anhydrous THF (4mL) was added tetrabutylammonium fluoride (1.0M in THF, 2.6mL, 2.6 mmol). The reaction mixture was heated at reflux for 16h, then cooled to room temperature, quenched with water, and extracted with ethyl acetate (4 ×). With Na ₂SO₄The combined organic layers were dried and concentrated. By column chromatography using MeOH/CH₂Cl₂The residue was purified as eluting solvent to give 3.4mg (8%) of 2- (1H-indol-5-yloxy) -5H-pyrrolo [2, 3-b ]]Pyrazine-7-carboxylic acid isopropylamide as a yellow-white solid. MS: (M + H)⁺＝336。

Example 280.

2- (6-methylpyridin-2-yloxy) -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid isopropylamide

Step 1

Stirring 2-bromo-5- (2-trimethylsilyl-ethoxymethyl) -5H-pyrrolo [2, 3-b ] in a pressure tube]To a solution of pyrazine-7-carboxylic acid isopropylamide (145mg, 0.35mmol) in DMF (4mL) was added 6-methylpyridin-2-ol (115mg, 1.05mmol) and Cs₂CO₃(342mg, 1.05 mmol). The tube was sealed and heated at 140 ℃ for 18 h. The reaction was cooled, then quenched with water (20mL) and extracted with EtOAc (4X). The combined organic layers were washed with brine, Na₂SO₄Drying, and concentrating under reduced pressure. The residue was purified by column chromatography on silica gel (100-200 mesh) using 20-60% EtOAc/hexane as eluent to give 95mg (61%) of 2- (6-methylpyridin-2-yloxy) -5- (2-trimethylsilyl-ethoxymethyl) -5H-pyrrolo [2, 3-b ]]Pyrazine-7-carboxylic acid isopropylamide as a colorless oil.

Step 4

To a stirred solution of 2- (6-methylpyridin-2-yloxy) -5- (2-trimethylsilyl-ethoxymethyl) -5H-pyrrolo [2, 3-b]To a solution of pyrazine-7-carboxylic acid isopropylamide (160mg, 0.36mmol) in anhydrous THF (4mL) were added tetrabutylammonium fluoride (1.0M in THF, 7.2mL, 7.2mmol) and ethylenediamine (0.48mL, 7.2 mmol). The reaction mixture was heated at reflux for 16h, then cooled to room temperature, quenched with water, and extracted with ethyl acetate (4 ×). With Na₂SO₄The combined organic layers were dried and concentrated. By column chromatography, using 2-10% MeOH/CH₂Cl₂The residue was purified as an eluting solvent to give 65mg (58%) of 2- (6-methylpyridin-2-yloxy) -5H-pyrrolo [2, 3-b ]]Pyrazine-7-carboxylic acid isopropylamide as a yellow-white solid. MS: (M + H)⁺＝312。

Example 281.

2- (4, 6-dimethylpyridin-2-yloxy) -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid isopropylamide

Prepared according to the method outlined in example 280, substituting 4, 6-dimethylpyridin-2-ol for 6-methylpyridin-2-ol in step 1. MS: (M + H)⁺＝326。

Example 282.

2- (2-methylpyridin-3-yloxy) -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid isopropylamide

Prepared according to the method outlined in example 280, substituting 2-methylpyridin-3-ol for 6-methylpyridin-2-ol in step 1. MS: (M + H) ⁺＝312。

Example 283.

2- ((R) -3-aminoindan-5-yloxy) -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid isopropylamide

Prepared according to the method outlined in example 270, but without using step 4. MS: (M + H)⁺＝352。

Example 284.

2- ((R) -3-propionylaminoindan-5-yloxy) -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid isopropylamide

Prepared according to the procedure outlined in example 270, but substituting methanesulfonyl chloride and diisopropylethylamine with propionyl chloride and pyridine in step 4. MS: (M + H)⁺＝408。

Example 285.

2- { (R) -3- [ (tetrahydropyran-4-carbonyl) -amino ] -indan-5-yloxy } -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid isopropylamide

Prepared according to the procedure outlined in example 270, but substituting tetrahydropyran-4-carbonyl chloride and pyridine for methanesulfonyl chloride and diisopropylethylamine in step 4. MS: (M + H)⁺＝464。

Example 286.

2- [ (R) -3- (cyclopropanecarbonyl-amino) -indan-5-yloxy ] -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid isopropylamide

Prepared according to the method outlined in example 270, but substituting cyclopropanecarbonyl chloride and pyridine for methanesulfonyl chloride and diisopropylethylamine in step 4. MS: (M + H)⁺＝420。

Example 287.

2- [ (R) -3- (2, 2-dimethyl-propionylamino) -indan-5-yloxy ] -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid isopropylamide

Prepared according to the method outlined in example 270, but substituting trimethylacetyl chloride and pyridine for methanesulfonyl chloride and diisopropylethylamine in step 4. MS: (M + H)⁺＝436。

Example 288.

2- ((R) -3-benzoylaminoindan-5-yloxy) -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid isopropylamide

Prepared according to the procedure outlined in example 270, but substituting methanesulfonyl chloride and diisopropylethylamine with benzoyl chloride and pyridine in step 4. MS: (M + H)⁺＝456。

Example 289.

2- ((R) -3-Acetylaminoindan-5-yloxy) -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ((S) -1, 2, 2-trimethyl-propyl) -amide

Prepared according to the method outlined in example 270, but using 2-bromo-5- (2-trimethylsilyl-ethoxymethyl) -5H-pyrrolo [2, 3-b ] in step 2]Pyrazine-7-carboxylic acid ((S) -1, 2, 2-trimethyl-propyl) -amide substituted 2-bromo-5- (2-trimethylsilyl-ethoxymethyl) -5H-pyrrolo [2, 3-b]Pyrazine-7-carboxylic acid isopropylamide, substituting methanesulfonyl chloride and diisopropylethylamine with acetyl chloride and pyridine in step 4. MS:(M+H)⁺＝436。

example 290.

2- ((S) -3-Acetylaminoindan-5-yloxy) -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid isopropylamide

Prepared according to the method outlined in example 270, but substituting (R) -3-aminoindan-5-ol with (S) -3-aminoindan-5-ol in step 1 and methanesulfonyl chloride and diisopropylethylamine with acetyl chloride and pyridine in step 4. MS: (M + H) ⁺＝394。

Example 291.

2- ((S) -3-aminoindan-5-yloxy) -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid isopropylamide

Prepared according to the method outlined in example 270, but substituting (R) -3-aminoindan-5-ol with (S) -3-aminoindan-5-ol in step 1, without using step 4. MS: (M + H)⁺＝352。

Example 292.

2- (indan-5-yloxy) -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid isopropylamide

Prepared according to the method outlined in example 270, steps 2 and 5, but substituting in step 2 ((R) -6-hydroxyindan-1-yl) -carbamic acid tert-butyl ester with indan-5-ol. MS: (M+H)⁺＝337。

Example 293.

2- ((R) -1-Acetylaminoindan-5-yloxy) -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ((S) -1, 2, 2-trimethyl-propyl) -amide

Prepared according to the method outlined in example 270, but substituting (R) -3-aminoindan-5-ol with (R) -1-amino-indan-5-ol hydrochloride in step 1 and 2-bromo-5- (2-trimethylsilyl-ethoxymethyl) -5H-pyrrolo [2, 3-b ] in step 2]Pyrazine-7-carboxylic acid ((S) -1, 2, 2-trimethyl-propyl) -amide substituted 2-bromo-5- (2-trimethylsilyl-ethoxymethyl) -5H-pyrrolo [2, 3-b]Pyrazine-7-carboxylic acid isopropylamide, substituting methanesulfonyl chloride and diisopropylethylamine with acetyl chloride and pyridine in step 4. MS: (M + H) ⁺＝436。

Example 294.

2- ((R) -1-Acetylaminoindan-5-yloxy) -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ((S) -sec-butyl) -amide

Step 1

To 2-bromo-5- (2-trimethylsilyl-ethoxymethyl) -5H-pyrrolo [2, 3-b ] in a pressure tube]To a stirred solution of pyrazine-7-carbaldehyde (0.25g, 0.70mmol) in toluene were added ((R) -6-hydroxyindan-1-yl) -carbamic acid tert-butyl ester (0.209g, 0.84mmol), 2-di-tert-butylphosphino-2' - (N, N-dimethylamino) biphenyl (0.072g, 0.210mmol), and K₃PO₄(0.298g, 1.404 mmol). The reaction was purged with nitrogen for 20 minutes, Pd (OAc) was added₂(0.032g，0.140mmol). The tube was sealed and stirred at 90 ℃ for 16 h. The reaction was cooled and the solvent evaporated in vacuo. The crude residue was purified by silica gel (100-200 mesh) column chromatography using EtOAc/hexane (10-15%) as eluent to give 0.10g (27%) of { (R) -6- [ 7-formyl-5- (2-trimethylsilyl-ethoxymethyl) -5H-pyrrolo [2, 3-b%]Pyrazin-2-yloxy]-indan-1-yl } -carbamic acid tert-butyl ester as brown solid. LC-MS: (M + H)⁺＝525。

Step 2

To a stirred solution of { (R) -6- [ 7-formyl-5- (2-trimethylsilyl-ethoxymethyl) -5H-pyrrolo [2, 3-b ] pyrazin-2-yloxy ] -indan-1-yl } -carbamic acid tert-butyl ester (1.0g, 1.91mmol) in methanol was added acetyl chloride (2.71mL, 38.1mmol) at 0 ℃. The reaction mixture was stirred at 0 ℃ for 10min and then at 25 ℃ for 2 h. Evaporation of the solvent at room temperature under reduced pressure gave 0.90g of 2- ((R) -3-aminoindan-5-yloxy) -5- (2-trimethylsilyl-ethoxymethyl) -5H-pyrrolo [2, 3-b ] pyrazine-7-carbaldehyde hydrochloride as a brown solid, which was used without further purification.

Step 3

2- ((R) -3-Aminoindan-5-yloxy) -5- (2-trimethylsilyl-ethoxymethyl) -5H-pyrrolo [2, 3-b ] was reacted with pyridine (0.671g, 8.492mmol) at 0 deg.C]Pyrazine-7-carbaldehyde) hydrochloride (0.90g, 2.12mmol) in a stirred solution in dichloromethane was neutralized to pH 7 and stirred at 0 ℃ for 20 min. Addition of Ac₂O (0.325g, 3.18mmol), and the reaction mixture was stirred at 25 ℃ for 16 h. The solvent was evaporated under reduced pressure and the crude residue was purified by column chromatography on silica gel (100-200 mesh) using EtOAc/hexane (10-15%) as eluent to give 0.45g (45%) of N- { (R) -6- [ 7-formyl-5- (2-trimethylsilyl-ethoxymethyl) -5H-pyrrolo [2, 3-b ]]Pyrazin-2-yloxy]-indan-1-yl } -acetamide, as a light yellow solid. LC-MS: (M + H)⁺＝467。

Step 4

To a stirred solution of N- { (R) -6- [ 7-formyl-5- (2-trimethylsilyl-ethoxymethyl) -5H-pyrrolo [2, 3-b]Pyrazin-2-yloxy]-indan-1-yl } -acetamide (0.45g, 0.97mmol) in dioxane (10mL) NH was added₂SO₃H (0.56g, 5.80mmol), then NaClO is added₂(0.114g, 1.25mmol) and KH₂PO₄(1.57g, 11.592mmol) in water (5 mL). The reaction mixture was stirred at 25 ℃ for 16h, then diluted with water and extracted with EtOAc (3X 50 mL). With Na ₂SO₄The combined organic layers were dried and concentrated under reduced pressure to give 0.35g (75%) of 2- ((R) -3-acetylaminoindan-5-yloxy) -5- (2-trimethylsilyl-ethoxymethyl) -5H-pyrrolo [2, 3-b ]]Pyrazine-7-carboxylic acid, which was a white solid, was used without further purification.

Step 5

To a stirred solution of 2- ((R) -3-acetylaminoindan-5-yloxy) -5- (2-trimethylsilyl-ethoxymethyl) -5H-pyrrolo [2, 3-b ]]To a solution of pyrazine-7-carboxylic acid (0.20g, 0.41mmol) in dichloromethane (10mL) was added (S) -1-sec-butylamine (0.033g, 0.46mmol) and HATU (175mg, 0.46 mmol). Diisopropylethylamine (0.21mL, 1.23mmol) was added at 0 ℃. The reaction mixture was stirred at 25 ℃ for 12h, then quenched with water and extracted with dichloromethane. With Na₂SO₄The combined organic layers were dried and concentrated under reduced pressure. The crude residue was purified by column chromatography on silica gel (100-200 mesh) to give 0.12g (54%) of 2- ((R) -3-acetylaminoindan-5-yloxy) -5- (2-trimethylsilyl-ethoxymethyl) -5H-pyrrolo [2, 3-b ]]Pyrazine-7-carboxylic acid ((S) -sec-butyl) -amide, which is a yellow sticky solid.

Step 6

Stirring 2- ((R) -3-acetylaminoindan-5-yloxy) -5- (2-trimethylsilyl-ethoxymethyl) -5H-pyrrolo [2, 3-b ]A solution of pyrazine-7-carboxylic acid ((S) -sec-butyl) -amide (0.12g, 0.22mmol)) in 1.0M HCl in acetic acid (5mL) was heated at 65 ℃ for 3 h. The solvent was completely distilled off under reduced pressure. The residue was dissolved in MeOH/dichloromethane (1: 1) and ethylenediamine (20.0eqv) was added at 0 ℃. The reaction mixture was stirred at 25 ℃ for 18h, then the solvent was completely evaporated under reduced pressure, andthe crude residue was purified by column chromatography over silica gel (100-200 mesh) using MeOH/DCM (2-6%) as eluent to yield 17mg (19%) of 2- ((R) -3-acetylaminoindan-5-yloxy) -5H-pyrrolo [2, 3-b ]]Pyrazine-7-carboxylic acid ((S) -sec-butyl) -amide as an off-white solid. MS: (M + H)⁺＝408。

Example 295.

2- ((R) -1-Acetylaminoindan-5-yloxy) -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ((R) -1-cyclopropyl-ethyl) -amide

Prepared according to the method outlined in example 294, substituting (S) -1-sec-butylamine with (R) -1-cyclopropyl-ethylamine in step 5. MS: (M + H)⁺＝420。

Example 296.

2- ((R) -1-Acetylaminoindan-5-yloxy) -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ((S) -1-cyclopropyl-ethyl) -amide

Prepared according to the method outlined in example 294 substituting (S) -1-sec-butylamine in step 5 with (S) -1-cyclopropyl-ethylamine. MS: (M + H) ⁺＝420。

JAK assay information

IC for Janus kinase (JAK) inhibition₅₀The determination of (1):

the enzymes and peptide substrates used are as follows:

JAK 1: recombinant human kinase domain from Invitrogen (Cat # PV4774)

JAK 3: recombinant human kinase domain, from Millipore (Cat #14-629) or prepared.

JAK 2: recombinant human kinase domain from Millipore (Cat #14-640)

Substrate: n-terminal biotinylated 14-mer peptides, activation loop derived from JAK1

(activation loop), the peptide substrate sequence: Biotin-KAIETDKEYYTVKD the assay conditions used are described below:

determination of buffer: JAK kinase buffer: 50mM Hepes [ pH 7.2]，10mM MgCl₂1mM DTT, 1mg/ml BSA. The assay was performed in this buffer.

Assay format: kinase activity of all three JAK kinases is an endpoint assay using radioactivity and with trace amounts³³P-ATP measurement. The assay was performed in 96-well polypropylene plates.

The experimental method comprises the following steps:

all concentrations were final concentrations in the reaction mixture and all incubations were performed at room temperature.

The assay procedure is described below:

compounds were serially diluted in 100% DMSO, typically 10x at 1mM starting concentration. The final concentration of DMSO in the reaction was 10%.

Compounds were preincubated with enzyme (0.5nM JAK3 (commercially available), 0.2nM JAK3 (prepared), 1nM JAK2, 5nM JAK1) for 10 min.

The reaction was initiated by adding a mixture of the two substrates (ATP and peptide premixed in JAK kinase buffer). In the JAK2/JAK3 assay, ATP and peptide were used at concentrations of 1.5uM and 50uM, respectively. JAK1 assays were performed at ATP concentrations of 10uM and peptide concentrations of 50 uM.

The duration of the assay for JAK2 and JAK3 was 20 minutes. JAK1 assay was performed for 40 minutes. In the case of all three enzymes, the reaction was stopped by adding 0.5M EDTA to a final concentration of 100 mM.

Transfer 25ul of the terminated reaction to streptavidin-coated agarose beads in 96-well 1.2um MultiScreen-BV filter plates in MgCl-free containing 50mM EDTA₂And CaCl₂150ul of 7.5% (v/v) slurry in 1 Xphosphate buffered saline. After 30-minute incubation, the beads were washed under vacuum with the following buffers:

three to four washes were performed with 200ul of 2M NaCl.

Three to four washes were performed with 200ul of 2M NaCl plus 1% (v/v) phosphoric acid.

Water is adopted for washing once.

The washed plates were dried in a 60 ℃ drying cabinet for between 1 and 2 hours.

70ul of Microscint 20 scintillation fluid was added to each well of the filter plate and after at least 30 minutes of incubation, the radioactivity counts were measured in a Perkinelmer microplate scintillation counter.

Representative IC₅₀The results are in table II below:

table II.

SYK assay information

Spleen tyrosine kinase (SYK) inhibited IC₅₀The determination of (1):

the SYK kinase assay is a standard kinase assay suitable for 96-well plate format. The assay is for IC₅₀The defined 96-well format was performed with 8 samples representing 10 sesqui-log dilutions and 40 μ L reaction volumes. The assay measuring radioisotope labels³³Binding of P γ ATP to an N-terminal biotinylated peptide substrate derived from a naturally occurring phosphate receptor (phosphonacceptor) consensus sequence (biotin-11 aa DY E). Phosphorylated products were detected by stopping the reaction with EDTA and adding streptavidin-coated beads. Representative results are in table II above.

Plate determination: 96-well MultiScreen 0.65um filter plate (Millipore catalog number: MADVNOB10)

Streptavidin-coated beads: streptavidin Sepharose TM, suspension 5.0mL, diluted with 50mM EDTA/PBS (1: 100), (Amersham, Cat: 17-5113-01)

A compound: 10mM in 100% Dimethylsulfoxide (DMSO), final concentration: compounds 0.003-100uM in 10% DMSO

Enzyme: SYK RPA purified spleen tyrosine kinase truncation construct aa 360-635, stock solution 1mg/mL, MW: 31.2KDa, final concentration: 0.0005. mu.M

Peptide 1: biotinylated peptides were derived from the naturally occurring phosphate receptor consensus sequence (biotin-EPEGDYEEVLE), specifically ordered from QCB, stock solution 20mM, final concentration: 5.0. mu.M.

ATP: adenosine-5' -triphosphate 20mM, (ROCHE catalog No. 93202720), final concentration: 20 μ M

Buffer solution: HEPES (high efficiency particulate air): 2-Hydroxyethylpiperazine-2-ethanesulfonic acid (Sigma, cat # H-3375), final concentration: 50mM HEPES pH7.5

BSA: bovine serum albumin fraction V, no fatty acids (Roche Diagnostics GmbH, Cat. No. 9100221) diluted to a final concentration of 0.1%

EDTA: EDTA stock solution 500mM, (GIBCO, Cat. No.: 15575-038), final concentration: 0.1mM

DTT: 1, 4-dithiothreitol (Roche Diagnostics GmbH, Cat. No: 197777), final concentration: 1mM

MgCl₂x 6H₂O: MERCK, Cat No.: 105833.1000, final concentration: 10mM

Assay Dilution Buffer (ADB): 50mM HEPES, 0.1mM EGTA, 0.1mM sodium vanadate, 0.1mM beta-glycerophosphate, 10mM MgCl₂、1mM DTT、0，1％BSA，pH 7.5

Bead wash buffer: 10g/L PBS (phosphate buffered saline) containing 2M NaCl + 1% phosphoric acid

The experimental method comprises the following steps:

in a 40 μ L volume, 26 μ L of ADB diluted purified recombinant human SYK360-635[0.5nM ] were mixed with 4 μ L of 10X concentration of test compound, [ typically 100 μ M-0.003 μ M ] in [ 10% ] DMSO, and the mixture was incubated at RT for 10 min.

By adding a substrate containing a DYE peptide [0 or 5. mu.M ]]、ATP[20μM]And³³PγATP[2μCi/rxn]10 μ L of 4x substrate mixture, the kinase reaction was initiated. After 15min incubation at 30 ℃, the reaction was stopped by transferring 25 μ Ι _ of reaction sample to a 96 well 0.65 μ η Millipore madpnob membrane/plate containing 200 μ Ι _ of 5mM EDTA and 20% streptavidin coated beads in PBS.

Unbound radionucleotide was applied under vacuum with 3 × 250 μ L2M NaCl; 2 × 250 μ L2M NaCl + 1% phosphoric acid; 1X 250. mu. L H₂And O washing. After the final wash, the membrane/plate was transferred to a loading template (adaptor plate), heat dried at 60 ℃ for 15min, and 50 μ Ι _ of scintillation cocktail was added to each well and after 4h the amount of radioactivity was counted in an overhead counter.

Percent inhibition was calculated based on the uninhibited enzyme ratio:

% inhibition of 100/(1+ (IC)₅₀Inhibitor concentration)ⁿ)

IC was calculated using XLFit software (ID Business Solution Ltd., Guilford, Surrey, UK) using non-linear curve fitting₅₀。

The foregoing invention has been described in some detail by way of illustration and example for purposes of clarity and understanding. It will be apparent to those skilled in the art that changes and modifications may be made within the scope of the appended claims. Accordingly, it is to be understood that the above description is intended to be illustrative, and not restrictive. The scope of the invention should, therefore, be determined not with reference to the above description, but instead should be determined with reference to the following appended claims, along with the full scope of equivalents to which such claims are entitled.

All patents, patent applications, and publications cited in this application are hereby incorporated by reference in their entirety for all purposes to the same extent as if each individual patent, patent application, or publication were so individually indicated.

Claims

1. A compound of formula I

Wherein:

r is H, cyano, lower alkyl, R' or

Each R' "is independently OH or lower alkyl;

R^1aand R^1bEach independently is H, hydroxy, halogen, lower alkyl, lower alkenyl, lower alkynyl, lower haloalkyl, lower alkoxy, lower haloalkoxy, lower hydroxyalkyl, amino, lower alkylamino, lower dialkylamino, cyano, C (═ O) R' ", S (═ O)₂R' "or CH₂S(＝O)₂R”’；

R²is H, hydroxy lower alkyl, lower haloalkyl or lower alkyl;

R³is H, hydroxy, cyano lower alkyl or R³’；

R³' are each independently lower alkyl, hydroxy lower alkyl, lower alkoxy, lower haloalkyl, lower haloalkoxy, phenyl lower alkyl, cycloalkyl or cycloalkyl lower alkyl, each of which is optionally substituted with one or more R ³"substituted;

R³"' are each independently H, hydroxy or lower alkyl;

q is Q²、Q³Or Q⁴；

Q^2ais Q^2bOr Q^2c；

Q^2bEach independently halogen, oxo, hydroxy, -CN, -SCH₃、-S(O)₂CH₃

or-S (═ O) CH₃；

Q^2cEach independently is Q^2dOr Q^2e；

Or two of Q^2aTogether form a bicyclic ring system, optionally substituted with one or more Q^2bOr

Q^2cSubstitution;

Q^2deach independently is-O (Q)^2e)、-S(＝O)₂(Q^2e)、-C(＝O)N(Q^2e)₂、-S(O)₂(Q^2e)、-C(＝O)(Q^2e)、-C(＝O)O(Q^2e)、-N(Q^2e)C(＝O)(Q^2e)、-N(Q^2e)C(＝O)O(Q^2e) or-N (Q)^2e)C(＝O)N(Q^2e)₂；

Q^2eEach independently is H or Q^2e’；

Q^2e' are each independently lower alkyl, phenyl, benzyl, 5, 6, 7, 8-tetrahydro-naphthalene, lower haloalkyl, lower alkoxy, cycloalkyl, cycloalkenyl, heterocycloalkyl, spiroheterocycloalkyl, or heteroaryl, optionally substituted with one or more Q^2fSubstitution;

Q^2feach independently is Q^2gOr Q^2h；

Q^2gEach independently is halogen, hydroxy, cyano, oxo, -S (═ O)₂(Q²ⁱ’)、-S(＝O)₂N(Q²ⁱ’)₂、-C(＝O)OH、C(＝O)N(Q²ⁱ’)₂Or

-C(＝O)(Q²ⁱ’)；

Q^2hEach independently is lower alkyl, lower alkenyl, lower haloalkyl, lower alkoxy, amino, phenyl, benzyl, cycloalkyl, heterocycloalkyl, or heteroaryl, optionally substituted with one or more Q ²ⁱSubstitution; and is

Q²ⁱ' are each independently H or lower alkyl;

Q^3aEach independently is Q^3bOr Q^3c；

Each m is independently 0, 1 or 2;

Q^3beach independently is H;

Q^3dEach independently is Q^3eOr Q^3f；

Q^3eEach independently is halogen, oxo, cyano, hydroxy,

-NHS(＝O)₂(Q^3f)、-NHC(＝O)(Q^3f)、NHC(＝O)N(Q^3f)₂Or N (Q)^3f)₂；

Q^3fEach independently is H or Q^3f’；

Q⁴is Q^4aOr Q^4b；

Q^4aIs hydroxy, halogen or cyano;

Q^4bis lower alkyl, lower alkoxy, lower alkynyl, lower alkenyl, lower hydroxyalkyl, amino or lower haloalkyl, optionally substituted with one or more Q ^4cSubstitution;

Q^4ceach independently is Q^4dOr Q^4e；

Q^4dEach independently is halogen, hydroxy or cyano;

Q^4feach independently is hydroxy, halogen, lower alkyl, lower alkenyl, oxo, lower haloalkyl, lower alkoxy, lower hydroxyalkyl or amino; with the proviso that the compound of formula I is not 2-thiophen-2-yl-5H-pyrrolo [2, 3-b ]]Pyrazine-7-carboxylic acid isopropylamide, 2-cyclopropyl-5H-pyrrolo [2, 3-b ]]Pyrazine-7-carboxylic acid (4-hydroxy-3, 3-dimethyl-butyl) -amide, 2- [1- (7-isopropylcarbamoyl-5H-pyrrolo [2, 3-b ]]Pyrazin-2-yl) -piperidin-3-yl]-propionic acid tert-butyl ester, 2-cyclopropyl-5H-pyrrolo [2, 3-b ]]Pyrazine-7-carboxylic acid tert-butylamide, 2-cyclohexyl-5H-pyrrolo [2, 3-b ]]Pyrazine-7-carboxylic acid isopropylamide, 2-cyclohex-1-enyl-5H-pyrrolo [2, 3-b ] amine]Pyrazine-7-carboxylic acid isopropylamide, 2-chloro-5H-pyrrolo [2, 3-b ]]Pyrazine-7-carboxylic acid isopropylamide, 2-isopropyl-5H-pyrrolo [2, 3-b ]]Pyrazine-7-carboxylic acid isopropylamide, 2-isopropenyl-5H-pyrrolo [2, 3-b ] ]7-Pyrazinyl carboxylic acid isopropylamide, 2- (cyclopentyl)Yl-methyl-amino) -5H-pyrrolo [2, 3-b]Pyrazine-7-carboxylic acid isopropylamide, [1- (7-isopropylcarbamoyl-5H-pyrrolo [2, 3-b ]]Pyrazin-2-yl) -piperidin-3-yl]-methyl-carbamic acid tert-butyl ester, 2- (3-methylamino-piperidin-1-yl) -5H-pyrrolo [2, 3-b]Pyrazine-7-carboxylic acid isopropylamide, 2- (cyclopentyl-methyl-amino) -5H-pyrrolo [2, 3-b]Pyrazine-7-carboxylic acid isopropylamide, 2-chloro-5H-pyrrolo [2, 3-b ]]Pyrazine-7-carboxylic acid isopropylamide, 2-isopropenyl-5H-pyrrolo [2, 3-b ]]Pyrazine-7-carboxylic acid isopropylamide, 2-isopropyl-5H-pyrrolo [2, 3-b ]]Pyrazine-7-carboxylic acid isopropylamide, 2-cyclohex-1-enyl-5H-pyrrolo [2, 3-b ] amine]Pyrazine-7-carboxylic acid isopropylamide, 2-cyclopropyl-5H-pyrrolo [2, 3-b ]]Pyrazine-7-carboxylic acid (3-hydroxy-2, 2-dimethyl-propyl) -amide, 2-cyclopropyl-5H-pyrrolo [2, 3-b]Pyrazine-7-carboxylic acid ((S) -2-hydroxy-1, 2-dimethyl-propyl) -amide, 2-cyclopropyl-5H-pyrrolo [2, 3-b)]Pyrazine-7-carboxylic acid tert-butylamide, 2-cyclohexyl-5H-pyrrolo [2, 3-b ]]Pyrazine-7-carboxylic acid isopropylamide, 2-thiophen-2-yl-5H-pyrrolo [2, 3-b ]]Pyrazine-7-carboxylic acid (3-hydroxy-2, 2-dimethyl-propyl) -amide, [1- (7-isopropylcarbamoyl-5H-pyrrolo [2, 3-b ] ]Pyrazin-2-yl) -piperidin-3-yl]-methyl-carbamic acid tert-butyl ester, 2- (3-methylamino-piperidin-1-yl) -5H-pyrrolo [2, 3-b]Pyrazine-7-carboxylic acid isopropylamide; compound having trifluoro-acetic acid, [1- (7-isopropylcarbamoyl-5H-pyrrolo [2, 3-b ]]Pyrazin-2-yl) -piperidin-3-yl]-methyl-carbamic acid tert-butyl ester or 2- (3-methylamino-piperidin-1-yl) -5H-pyrrolo [2, 3-b]Pyrazine-7-carboxylic acid isopropylamide; a compound having trifluoro-acetic acid;

or a pharmaceutically acceptable salt thereof.

2. The compound of claim 1, wherein

R' "is OH or lower alkyl;

R^1a、R^1band R^1cEach independently is H, hydroxy, halogen, lower alkyl, lower alkenyl, lower alkynyl, lower haloalkyl, lower alkoxy, lower haloalkoxy, lower hydroxyalkyl, amino, lower alkylamino, lower dialkylamino, cyano, cycloalkyl, heterocycloalkyl, C (═ O) R' "or S (═ O) ₂R”’；

R²Is H or lower alkyl;

R³is H, hydroxy, cyano lower alkyl or R³’；

R³' is lower alkyl, hydroxy lower alkyl, lower alkoxy, lower haloalkyl, lower haloalkoxy, phenyl lower alkyl or cycloalkyl lower alkyl, each of which is optionally substituted with one or more R³"substituted;

R³"' is H or lower alkyl;

q is Q²、Q³Or Q⁴；

Q^2ais Q^2bOr Q^2c；

Q^2bIs halogen, oxo, hydroxy, -CN, -SCH₃、-S(O)₂CH₃or-S (═ O) CH₃；

Q^2cIs Q^2dOr Q^2e；

Q^2eEach independently is H or Q^2e’；

Q^2e' are each independently lower alkyl, phenyl, benzyl, lower haloalkyl, lower alkoxy, cycloalkyl, cycloalkenyl, heterocycloalkyl, or heteroaryl, optionally substituted with one or more Q ^2fSubstitution;

Q^2fis Q^2gOr Q^2h；

Q^2gIs halogen, hydroxy, cyano, oxo or-C (═ O) (Q)^2h)；

Q²ⁱIs halogen, hydroxy, cyano, lower alkyl, lower haloalkyl or lower alkoxy;

Q^3aEach independently is Q^3bOr Q^3c；

m is 0, 1 or 2;

Q^3bis H;

Q^3cis lower alkyl, lower alkyl halideAryl, phenyl, cycloalkyl, heterocycloalkyl or heteroaryl, optionally substituted with one or more Q^3dSubstitution; and is

Q^3dEach independently is Q^3eOr Q^3f；

Q^3eIs halogen or hydroxy;

Q⁴is Q^4aOr Q^4b；

Q^4aIs hydroxy, halogen or cyano;

Q^4bis lower alkyl, lower alkoxy, lower alkynyl, lower alkenyl, lower hydroxyalkyl, amino or lower haloalkyl, which is optionally substituted by one or more Q^4c；

Q^4cIs Q^4dOr Q ^4e；

Q^4dEach independently is halogen, hydroxy or cyano;

Q^4feach independently is hydroxy, halogen, lower alkyl, lower alkenyl, oxo, lower haloalkyl, lower alkoxy, lower hydroxyalkyl or amino; with the proviso that when Q is cyclopropyl or thienyl, and R²And R³Is H or methyl, and R^1a、R^1bAnd R^1cWhen any two of (a) are H or methyl, the other is not H, hydroxy or hydroxymethyl; and with the proviso that when Q is chloro, isopropyl, isopropenyl, piperidinyl, methyl-piperidin-3-yl-amine, methyl-piperidin-3-yl-carbamic acid tert-butyl ester, cyclohexyl, cyclopentyl-methyl-amino or cyclohexenyl, and R²And R³When is H or methyl，R^1a、R^1bAnd R^1cAre not all H;

or a pharmaceutically acceptable salt thereof.

3. The compound of claim 1 or 2, wherein Q is cycloalkyl, heterocycloalkyl, or heteroaryl, each of which is optionally substituted with one or more Q^2aAnd (4) substitution.

4. The compound of any one of claims 1-3, wherein R²Or R³Is lower alkyl and the other is H.

5. A compound according to any one of claims 1 to 4, wherein R ²And R³Are all methyl.

6. A compound according to any one of claims 1 to 5, wherein R^1aIs lower alkyl, hydroxy, lower haloalkyl, lower alkoxy, cyano or lower hydroxyalkyl.

7. A compound according to any one of claims 1 to 6, wherein R^1aIs methyl.

8. Compounds according to any one of claims 1 to 7, wherein R^1bIs methyl.

9. Compounds according to any one of claims 1 to 8, wherein R^1cIs lower alkyl, hydroxy, lower hydroxyalkyl, lower alkoxy, lower haloalkyl, cyano or methylsulfonylmethylene.

10. Compounds according to any one of claims 1-9, wherein R^1cIs H, hydroxy or lower alkyl.

11. Compounds according to any one of claims 1-10, wherein R^1cIs methyl or hydroxy.

12. Compounds according to any one of claims 1-11, wherein R^1bIs lower alkyl or lower haloalkyl.

13. Compounds according to any one of claims 1-12, wherein R^1aAnd R^1bTogether form spirocycloalkyl or spiroheterocycloalkyl 3. the compound of claim 2, wherein R²Or R³Is methyl.

14. A compound according to any one of claims 1 to 13, wherein Q is cyclopropyl, thienyl or pyrazolyl, each optionally substituted with one or more Q ^2aAnd (4) substitution.

15. A compound according to claim 1, selected from:

2-bromo-5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid (3-hydroxy-2, 2-dimethyl-propyl) -amide;

2-cyclopent-1-enyl-5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ((S) -2-hydroxy-1, 2-dimethyl-propyl) -amide;

2-isopropenyl-5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ((S) -2-hydroxy-1, 2-dimethyl-propyl) -amide;

2-dimethylamino-5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid (3-hydroxy-2, 2-dimethyl-propyl) -amide;

2-isopropyl-5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ((S) -2-hydroxy-1, 2-dimethyl-propyl) -amide;

2-cyclopentyl-5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ((S) -2-hydroxy-1, 2-dimethyl-propyl) -amide;

2-cyclohex-1-enyl-5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ((S) -2-hydroxy-1, 2-dimethyl-propyl) -amide;

2-cyclopropyl-5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid isopropylamide;

2-cyclopropyl-5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid (2-methoxy-1-methyl-ethyl) -amide;

2-pyrrolidin-1-yl-5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid (3-hydroxy-2, 2-dimethyl-propyl) -amide;

2-cyclohexyl-5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ((S) -2-hydroxy-1, 2-dimethyl-propyl) -amide;

2-cyclopropyl-5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid (3-hydroxy-1, 1-dimethyl-butyl) -amide;

2-cyclopropyl-5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid (2-cyano-ethyl) -amide;

2- (3, 3-dimethyl-pyrrolidin-1-yl) -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid (3-hydroxy-2, 2-dimethyl-propyl) -amide;

2-phenylamino-5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid (3-hydroxy-2, 2-dimethyl-propyl) -amide;

2- (methylcarbamoylmethyl-amino) -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid (3-hydroxy-2, 2-dimethyl-propyl) -amide;

2-cyclopropyl-5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid [ 2-hydroxy-1- (2-hydroxy-ethyl) -2-methyl-propyl ] -amide;

2-thiophen-2-yl-5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ((S) -2-hydroxy-1, 2-dimethyl-propyl) -amide;

2-cyclopropyl-5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid (1-cyclopropyl-ethyl) -amide;

2- (2-methyl-pyridin-4-yl) -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ((S) -2-hydroxy-1, 2-dimethyl-propyl) -amide;

2- (6-methyl-pyridin-3-yl) -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ((S) -2-hydroxy-1, 2-dimethyl-propyl) -amide;

2-cyclopropyl-5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ((S) -sec-butyl) -amide;

2-cyclopropyl-5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ((S) -1, 2, 2-trimethyl-propyl) -amide;

2-cyclopropyl-5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ((S) -2-hydroxy-1-isopropyl-2-methyl-propyl) -amide;

2-cyclopropyl-5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ((S) -1, 2-dimethyl-propyl) -amide;

2-cyclopropyl-5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid (1-ethyl-propyl) -amide;

2-cyclopropyl-5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid (2-dimethylamino-1-methyl-ethyl) -amide;

2-cyclopropyl-5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid cyanomethyl-amide;

2-cyclopropyl-5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ((S) -1-ethyl-2-hydroxy-2-methyl-propyl) -amide;

2-cyclopropyl-5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ((R) -2-hydroxy-1, 2-dimethyl-propyl) -amide;

2-cyclopropyl-5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ((1S, 2S) -2-hydroxy-1, 2-dimethyl-butyl) -amide;

2-cyclopropyl-5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ((S) -1-cyclohexyl-ethyl) -amide;

2-cyclopropyl-5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid (3-cyano-propyl) -amide;

2-cyclopropyl-5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ((1S, 2R) -2-hydroxy-1, 2-dimethyl-butyl) -amide;

2-trifluoromethyl-5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid (3-hydroxy-2, 2-dimethyl-propyl) -amide;

2-vinyl-5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid (3-hydroxy-2, 2-dimethyl-propyl) -amide;

2-cyclopropyl-5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid [ (S) -1- (1H-pyrazol-3-yl) -ethyl ] -amide;

2-cyclopropyl-5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ((1S, 2S) -3-cyclopropyl-2-hydroxy-1, 2-dimethyl-propyl) -amide;

2-ethyl-5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid (3-hydroxy-2, 2-dimethyl-propyl) -amide;

2-cyclopropyl-5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ((S) -1-hydroxymethyl-propyl) -amide;

2-cyclopropyl-5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ((R) -2-hydroxy-1-methyl-ethyl) -amide;

2-cyclopropyl-5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid (3-hydroxy-1, 1-dimethyl-propyl) -amide;

2- ((1R, 2R) -2-methyl-cyclopropyl) -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid (3-hydroxy-2, 2-dimethyl-propyl) -amide;

2-cyclopropyl-5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ((R) -1-ethyl-2-hydroxy-2-methyl-propyl) -amide;

2-cyclopropyl-5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid (2-hydroxy-1, 1-dimethyl-ethyl) -amide;

2- ((1R, 2S) -2-methyl-cyclopropyl) -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid (3-hydroxy-2, 2-dimethyl-propyl) -amide;

2-cyclopropyl-5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ((S) -1-hydroxymethyl-2, 2-dimethyl-propyl) -amide;

2-cyclopropyl-5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ((1S, 2R) -3-cyclopropyl-2-hydroxy-1, 2-dimethyl-propyl) -amide;

2-cyclopropyl-5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid [ (S) -1- (1-hydroxy-1-methyl-ethyl) -pentyl ] -amide;

2-cyclopropyl-5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid (2-methoxy-2-methyl-propyl) -amide;

2-cyclopropyl-5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid (2-hydroxy-1-hydroxymethyl-ethyl) -amide;

2-cyclopropyl-5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ((R) -1-hydroxymethyl-2, 2-dimethyl-propyl) -amide;

2-cyclopropyl-5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ((1S, 2R) -3, 3, 3-trifluoro-2-hydroxy-1, 2-dimethyl-propyl) -amide;

2-cyclopropyl-5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ((S) -3, 3, 3-trifluoro-1, 2, 2-trimethyl-propyl) -amide;

2-cyclopropyl-5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid (2, 2-dimethyl-propyl) -amide;

2-cyclopropyl-5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ((R) -1-hydroxymethyl-2-methyl-propyl) -amide;

2-cyclopropyl-5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ((S) -2-hydroxy-1-methyl-ethyl) -amide;

2-cyclopropyl-5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ((R) -1-hydroxymethyl-propyl) -amide;

2-cyclopropyl-5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid (3-methoxy-2, 2-dimethyl-propyl) -amide;

2-cyclopropyl-5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ((R) -1-cyclohexyl-ethyl) -amide;

2-cyclopropyl-5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid (2-cyano-1, 2, 2-trimethyl-ethyl) -amide;

2-cyclopropyl-5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ((R) -1, 2, 2-trimethyl-propyl) -amide;

2-cyclopropyl-5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ((1S, 2S) -3, 3, 3-trifluoro-2-hydroxy-1, 2-dimethyl-propyl) -amide;

2-cyclopropyl-5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ((R) -1-methoxymethyl-2, 2-dimethyl-propyl) -amide;

2-cyclopropyl-5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ((S) -1-methoxymethyl-2, 2-dimethyl-propyl) -amide;

2-cyclopropyl-5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ((R) -1-phenyl-ethyl) -amide;

2-cyclopropyl-5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ((S) -1-phenyl-ethyl) -amide;

2-cyclopropyl-5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid (3-hydroxy-butyl) -amide;

2-cyclopropyl-5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid (3-hydroxy-2-methyl-propyl) -amide;

2-cyclopropyl-5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid (1-pyridin-2-yl-ethyl) -amide;

2-cyclopropyl-5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid (3-hydroxy-1, 2, 2-trimethyl-propyl) -amide;

2-pyridin-2-yl-5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ((S) -1, 2, 2-trimethyl-propyl) -amide;

2-cyclopropyl-5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ((S) -1-cyclopropyl-2-hydroxy-2-methyl-propyl) -amide;

2-cyclopropyl-5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ((R) -1-cyclopropyl-2-hydroxy-2-methyl-propyl) -amide;

2-cyclopropyl-5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid (1-cyclohexyl-propyl) -amide;

2-cyclopropyl-5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ((R) -1-cyanomethyl-2, 2-dimethyl-propyl) -amide;

2-cyclopropyl-5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ((S) -1-cyanomethyl-2, 2-dimethyl-propyl) -amide;

2-cyclopropyl-5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid (cyclohexyl-cyclopropyl-methyl) -amide;

2-cyclopropyl-5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid (2-hydroxy-1, 1, 2-trimethyl-propyl) -amide;

2-cyclopropyl-5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid dicyclopropylmethyl-amide;

2-cyclopropyl-5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid (2-cyano-1-cyclopropyl-2, 2-dimethyl-ethyl) -amide;

2-cyclopropyl-5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid [ (R) -1- (1-hydroxy-cyclopentyl) -ethyl ] -amide;

2-cyclopropyl-5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ((1R, 2R) -2-hydroxy-1, 2-dimethyl-butyl) -amide;

2-cyclopropyl-5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ((1R, 2R) -2-hydroxy-1, 2-dimethyl-pentyl) -amide;

2-cyclopropyl-5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid [1- (tetrahydro-pyran-4-yl) -ethyl ] -amide;

2-cyclopropyl-5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ((R) -2-cyano-1, 2, 2-trimethyl-ethyl) -amide;

2-cyclopropyl-5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ((S) -2-cyano-1, 2, 2-trimethyl-ethyl) -amide;

2-cyclopropyl-5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ((1S, 2R, 3S) -1-cyclohexylmethyl-3-cyclopropyl-2, 3-dihydroxy-propyl) -amide;

2-cyclopropyl-5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid (1-cyano-2-methyl-propyl) -amide;

2-cyclopropyl-5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid (cyano-cyclopropyl-methyl) -amide;

2-cyclopropyl-5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ((1R, 2R) -3-cyano-2-hydroxy-1, 2-dimethyl-propyl) -amide;

3-cyclopropyl-3- [ (2-cyclopropyl-5H-pyrrolo [2, 3-b ] pyrazine-7-carbonyl) -amino ] -2, 2-dimethyl-propionic acid;

2-cyclopropyl-5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid (2-hydroxy-2-methyl-1-trifluoromethyl-propyl) -amide;

2-cyclopropyl-5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ((S) -1-cyclohexyl-2-hydroxy-2-methyl-propyl) -amide;

2-cyclopropyl-5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid (1-cyclopentyl-ethyl) -amide;

2-phenoxy-5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid (1-cyclopropyl-ethyl) -amide;

2-cyclopropyl-5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid [ (S) -1- (1-hydroxy-cyclopentyl) -ethyl ] -amide;

2-cyclopropyl-5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid (3-methanesulfonyl-2, 2-dimethyl-propyl) -amide;

2- (1-ethyl-1H-pyrazol-4-yl) -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ((R) -2-hydroxy-1, 2-dimethyl-propyl) -amide;

2-cyclopropyl-5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid [ (R) -1- (1-cyano-cyclopentyl) -ethyl ] -amide;

2-cyclopropyl-5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid [ (S) -1- (1-cyano-cyclopentyl) -ethyl ] -amide;

2- (1-methyl-1H-pyrazol-4-yl) -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ((R) -2-hydroxy-1, 2-dimethyl-propyl) -amide;

2-thiophen-2-yl-5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ((R) -2-hydroxy-1, 2-dimethyl-propyl) -amide;

2-cyclopropyl-5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid [ (R) -cyclopropyl- (1-hydroxy-cyclopentyl) -methyl ] -amide;

2- (2, 4-difluoro-phenoxy) -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid (1-cyclopropyl-ethyl) -amide;

2-cyclopropyl-5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid (2-cyano-1-cyclopropyl-ethyl) -amide;

2-cyclopropyl-5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid cyclohexylmethyl-amide;

2-cyclopropyl-5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid (1-methanesulfonyl-piperidin-3-ylmethyl) -amide;

2-cyclopropyl-5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid (1-methanesulfonyl-pyrrolidin-3-ylmethyl) -amide;

2- (3, 6-dihydro-2H-pyran-4-yl) -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ((R) -2-hydroxy-1, 2-dimethyl-propyl) -amide;

2-thiazol-2-yl-5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ((R) -2-hydroxy-1, 2-dimethyl-propyl) -amide;

2-pyridin-2-yl-5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ((R) -2-hydroxy-1, 2-dimethyl-propyl) -amide;

2- (4-fluoro-phenoxy) -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid (1-cyclopropyl-ethyl) -amide;

2- (2-fluoro-phenoxy) -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid (1-cyclopropyl-ethyl) -amide;

2-cyano-5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ((R) -2-hydroxy-1, 2-dimethyl-propyl) -amide;

2-phenoxy-5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ((R) -2-hydroxy-1, 2-dimethyl-propyl) -amide;

2-cyclopropyl-5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid [ (R) -1- (1-cyano-cyclohexyl) -ethyl ] -amide;

2-cyclopropyl-5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid [ (S) -1- (1-cyano-cyclohexyl) -ethyl ] -amide;

2-phenoxy-5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid isopropylamide;

2-phenoxy-5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ((S) -1, 2, 2-trimethyl-propyl) -amide;

2-phenoxy-5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ((S) -sec-butyl) -amide;

2-phenoxy-5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ((S) -1, 2-dimethyl-propyl) -amide;

2-phenoxy-5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ((S) -1-cyclohexyl-ethyl) -amide;

2- (2, 4-difluoro-phenoxy) -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ((R) -1-cyclohexyl-ethyl) -amide;

2- (2, 4-difluoro-phenoxy) -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ((S) -2-hydroxy-1, 2-dimethyl-propyl) -amide;

2- (2, 4-difluoro-phenoxy) -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ((R) -sec-butyl) -amide;

2- (2, 4-difluoro-phenoxy) -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ((R) -1, 2-dimethyl-propyl) -amide;

2-phenoxy-5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ((S) -2-hydroxy-1, 2-dimethyl-propyl) -amide;

2-phenoxy-5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ((R) -1-cyclohexyl-ethyl) -amide;

2-phenoxy-5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ((R) -1, 2, 2-trimethyl-propyl) -amide;

2-phenoxy-5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ethylamide;

2- (2, 4-difluoro-phenoxy) -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid isopropylamide;

2- (2, 4-difluoro-phenoxy) -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ((S) -1, 2, 2-trimethyl-propyl) -amide;

2- (2, 4-difluoro-phenoxy) -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ((R) -1, 2, 2-trimethyl-propyl) -amide;

2-cyclopropyl-5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ((R) -2-cyano-1-cyclopropyl-ethyl) -amide;

2-cyclopropyl-5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid (1-acetyl-piperidin-3-ylmethyl) -amide;

2-cyclopropyl-5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid (1-acetyl-pyrrolidin-3-ylmethyl) -amide;

2- (1-ethyl-1H-pyrazol-4-yl) -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid [ (S) -1- (1-hydroxy-cyclopentyl) -ethyl ] -amide;

2- (1-methyl-1H-pyrazol-4-yl) -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ((S) -2-cyano-1, 2, 2-trimethyl-ethyl) -amide;

2- (1-methyl-1H-pyrazol-4-yl) -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ((S) -1-cyclohexyl-ethyl) -amide;

2- (1-methyl-1H-pyrazol-4-yl) -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ((S) -1, 2, 2-trimethyl-propyl) -amide;

2-thiophen-2-yl-5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ((S) -1, 2, 2-trimethyl-propyl) -amide;

2- (4-trifluoromethyl-phenyl) -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ((S) -1, 2, 2-trimethyl-propyl) -amide;

2-cyclopropyl-5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ((S) -3-methanesulfonyl-1, 2, 2-trimethyl-propyl) -amide;

2- [1- (3-chloro-phenyl) -1H-imidazol-4-yl ] -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ((S) -1, 2, 2-trimethyl-propyl) -amide;

2- [1- (3-trifluoromethyl-phenyl) -1H-imidazol-4-yl ] -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ((S) -1, 2, 2-trimethyl-propyl) -amide;

2- [1- (5-chloro-2-fluoro-phenyl) -1H-imidazol-4-yl ] -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ((S) -1, 2, 2-trimethyl-propyl) -amide;

2- [1- (2-fluoro-5-methyl-phenyl) -1H-imidazol-4-yl ] -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ((S) -1, 2, 2-trimethyl-propyl) -amide;

2- [1- (2-fluoro-5-trifluoromethyl-phenyl) -1H-imidazol-4-yl ] -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ((S) -1, 2, 2-trimethyl-propyl) -amide;

2- (1-m-tolyl-1H-imidazol-4-yl) -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ((S) -1, 2, 2-trimethyl-propyl) -amide;

2- [1- (3-ethyl-phenyl) -1H-imidazol-4-yl ] -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ((S) -1, 2, 2-trimethyl-propyl) -amide;

2- [1- (3-isopropyl-phenyl) -1H-imidazol-4-yl ] -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ((S) -1, 2, 2-trimethyl-propyl) -amide;

2- [1- (3-tert-butyl-phenyl) -1H-imidazol-4-yl ] -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ((S) -1, 2, 2-trimethyl-propyl) -amide;

2- (1, 3-dimethyl-1H-pyrazol-4-yl) -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ((S) -2-methoxy-1-methyl-ethyl) -amide;

2- (5-ethylcarbamoyl-thiophen-2-yl) -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ((S) -1, 2, 2-trimethyl-propyl) -amide;

2- (5-isopropylcarbamoyl-thiophen-2-yl) -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ((S) -1, 2, 2-trimethyl-propyl) -amide;

2- (5-tert-butylcarbamoyl-thiophen-2-yl) -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ((S) -1, 2, 2-trimethyl-propyl) -amide;

2- [5- (1-methyl-2-pyrazol-1-yl-ethylcarbamoyl) -thiophen-2-yl ] -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ((S) -1, 2, 2-trimethyl-propyl) -amide;

2- {5- [2- (4-fluoro-phenyl) -1-methyl-ethylcarbamoyl ] -thiophen-2-yl } -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ((S) -1, 2, 2-trimethyl-propyl) -amide;

2- (5-diethylcarbamoyl-thiophen-2-yl) -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ((S) -1, 2, 2-trimethyl-propyl) -amide;

2- [5- (4-methyl-piperazine-1-carbonyl) -thiophen-2-yl ] -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ((S) -1, 2, 2-trimethyl-propyl) -amide;

2- [5- ((R) -1-cyclopropyl-ethylcarbamoyl) -thiophen-2-yl ] -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ((S) -1, 2, 2-trimethyl-propyl) -amide;

2- [1- (3-vinyl-phenyl) -1H-imidazol-4-yl ] -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ((S) -1, 2, 2-trimethyl-propyl) -amide;

2- {5- [ (pyridin-3-ylmethyl) -carbamoyl ] -thiophen-2-yl } -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ((S) -1, 2, 2-trimethyl-propyl) -amide;

2- {5- [ (pyridin-4-ylmethyl) -carbamoyl ] -thiophen-2-yl } -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ((S) -1, 2, 2-trimethyl-propyl) -amide;

2- {5- [ (pyridin-2-ylmethyl) -carbamoyl ] -thiophen-2-yl } -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ((S) -1, 2, 2-trimethyl-propyl) -amide;

2- [5- (4-cyano-piperidine-1-carbonyl) -thiophen-2-yl ] -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ((S) -1, 2, 2-trimethyl-propyl) -amide;

2- [5- (cyclopentylmethyl-carbamoyl) -thiophen-2-yl ] -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ((S) -1, 2, 2-trimethyl-propyl) -amide;

2- [5- ((R) -2-hydroxy-1-methyl-ethylcarbamoyl) -thiophen-2-yl ] -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ((S) -1, 2, 2-trimethyl-propyl) -amide;

2- [5- ((R) -1-methyl-2-phenyl-ethylcarbamoyl) -thiophen-2-yl ] -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ((S) -1, 2, 2-trimethyl-propyl) -amide;

2- [5- (1-pyridin-3-yl-ethylcarbamoyl) -thiophen-2-yl ] -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ((S) -1, 2, 2-trimethyl-propyl) -amide;

2- [5- (cyanomethyl-carbamoyl) -thiophen-2-yl ] -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ((S) -1, 2, 2-trimethyl-propyl) -amide;

2- [5- (2-sulfamoyl-ethylcarbamoyl) -thiophen-2-yl ] -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ((S) -1, 2, 2-trimethyl-propyl) -amide;

2- [5- (2-imidazol-1-yl-1-methyl-ethylcarbamoyl) -thiophen-2-yl ] -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ((S) -1, 2, 2-trimethyl-propyl) -amide;

2- [5- (4-hydroxy-4-methyl-piperidine-1-carbonyl) -thiophen-2-yl ] -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ((S) -1, 2, 2-trimethyl-propyl) -amide;

2- [5- (1-methyl-2-pyridin-2-yl-ethylcarbamoyl) -thiophen-2-yl ] -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ((S) -1, 2, 2-trimethyl-propyl) -amide;

2- [5- (7-aza-bicyclo [2.2.1] heptane-7-carbonyl) -thiophen-2-yl ] -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ((S) -1, 2, 2-trimethyl-propyl) -amide;

2- [5- (3-cyano-azetidine-1-carbonyl) -thiophen-2-yl ] -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ((S) -1, 2, 2-trimethyl-propyl) -amide;

2- [5- (3-carbamoyl-azetidine-1-carbonyl) -thiophen-2-yl ] -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ((S) -1, 2, 2-trimethyl-propyl) -amide;

2- [5- (azetidine-1-carbonyl) -thiophen-2-yl ] -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ((S) -1, 2, 2-trimethyl-propyl) -amide;

2- [5- (2, 6-dimethyl-piperidine-1-carbonyl) -thiophen-2-yl ] -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ((S) -1, 2, 2-trimethyl-propyl) -amide;

1- {5- [7- ((S) -1, 2, 2-trimethyl-propylcarbamoyl) -5H-pyrrolo [2, 3-b ] pyrazin-2-yl ] -thiophene-2-carbonyl } -piperidine-4-carboxylic acid;

2- [5- (4-acetylamino-piperidine-1-carbonyl) -thiophen-2-yl ] -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ((S) -1, 2, 2-trimethyl-propyl) -amide;

2- [5- (4-methyl-benzylcarbamoyl) -thiophen-2-yl ] -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ((S) -1, 2, 2-trimethyl-propyl) -amide;

2- [5- (4-fluoro-benzylcarbamoyl) -thiophen-2-yl ] -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ((S) -1, 2, 2-trimethyl-propyl) -amide;

2- [5- (2, 3-dichloro-benzylcarbamoyl) -thiophen-2-yl ] -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ((S) -1, 2, 2-trimethyl-propyl) -amide;

2- [5- (2-methyl-benzylcarbamoyl) -thiophen-2-yl ] -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ((S) -1, 2, 2-trimethyl-propyl) -amide;

2- [5- (2, 6-difluoro-benzylcarbamoyl) -thiophen-2-yl ] -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ((S) -1, 2, 2-trimethyl-propyl) -amide;

2- [5- (2-chloro-6-fluoro-benzylcarbamoyl) -thiophen-2-yl ] -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ((S) -1, 2, 2-trimethyl-propyl) -amide;

2- [5- (2-methyl-cyclohexylcarbamoyl) -thiophen-2-yl ] -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ((S) -1, 2, 2-trimethyl-propyl) -amide;

2- [5- ((1S, 2R) -2-phenyl-cyclopropylcarbamoyl) -thiophen-2-yl ] -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ((S) -1, 2, 2-trimethyl-propyl) -amide;

2- {5- [ (4-methyl-thiophen-2-ylmethyl) -carbamoyl ] -thiophen-2-yl } -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ((S) -1, 2, 2-trimethyl-propyl) -amide;

2- {5- [ (5-methyl-furan-2-ylmethyl) -carbamoyl ] -thiophen-2-yl } -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ((S) -1, 2, 2-trimethyl-propyl) -amide;

2- [5- (adamantan-1-ylcarbamoyl) -thiophen-2-yl ] -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ((S) -1, 2, 2-trimethyl-propyl) -amide;

2- {5- [1- (4-fluoro-phenyl) -ethylcarbamoyl ] -thiophen-2-yl } -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ((S) -1, 2, 2-trimethyl-propyl) -amide;

2- [5- (methoxy-methyl-carbamoyl) -thiophen-2-yl ] -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ((S) -1, 2, 2-trimethyl-propyl) -amide;

2- (5-methoxycarbamoyl-thiophen-2-yl) -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ((S) -1, 2, 2-trimethyl-propyl) -amide;

2- (5-prop-2-ynylcarbamoyl-thiophen-2-yl) -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ((S) -1, 2, 2-trimethyl-propyl) -amide;

2- {5- [ (R) -2- (3H-imidazol-4-yl) -1-methyl-ethylcarbamoyl ] -thiophen-2-yl } -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ((S) -1, 2, 2-trimethyl-propyl) -amide;

2- [5- (5, 6, 7, 8-tetrahydro-naphthalen-2-ylcarbamoyl) -thiophen-2-yl ] -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ((S) -1, 2, 2-trimethyl-propyl) -amide;

2- (5-phenylcarbamoyl-thiophen-2-yl) -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ((S) -1, 2, 2-trimethyl-propyl) -amide;

2- [5- ((R) -1-p-tolyl-ethylcarbamoyl) -thiophen-2-yl ] -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ((S) -1, 2, 2-trimethyl-propyl) -amide;

2- [5- (2-methoxy-benzylcarbamoyl) -thiophen-2-yl ] -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ((S) -1, 2, 2-trimethyl-propyl) -amide;

2- [5- (2, 5-dimethoxy-benzylcarbamoyl) -thiophen-2-yl ] -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ((S) -1, 2, 2-trimethyl-propyl) -amide;

2- {5- [ (4-fluoro-benzyl) -methyl-carbamoyl ] -thiophen-2-yl } -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ((S) -1, 2, 2-trimethyl-propyl) -amide;

2- [5- (3-methoxy-benzylcarbamoyl) -thiophen-2-yl ] -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ((S) -1, 2, 2-trimethyl-propyl) -amide;

2- [5- (3-trifluoromethyl-benzylcarbamoyl) -thiophen-2-yl ] -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ((S) -1, 2, 2-trimethyl-propyl) -amide;

2- [5- (2-chloro-4-iodo-phenylcarbamoyl) -thiophen-2-yl ] -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ((S) -1, 2, 2-trimethyl-propyl) -amide;

2- [5- ((R) -1, 2, 2-trimethyl-propylcarbamoyl) -thiophen-2-yl ] -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ((S) -1, 2, 2-trimethyl-propyl) -amide;

2- [5- (2, 2-dimethyl-propylcarbamoyl) -thiophen-2-yl ] -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ((S) -1, 2, 2-trimethyl-propyl) -amide;

2- [5- ((R) -2-methanesulfonyl-1-methyl-ethylcarbamoyl) -thiophen-2-yl ] -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ((S) -1, 2, 2-trimethyl-propyl) -amide;

2- [5- (1, 1-dioxo-hexahydro-1 λ 6-thiopyran-4-ylcarbamoyl) -thiophen-2-yl ] -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ((S) -1, 2, 2-trimethyl-propyl) -amide;

2- [5- (1, 1-dioxo-1 λ 6-thiomorpholine-4-carbonyl) -thiophen-2-yl ] -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ((S) -1, 2, 2-trimethyl-propyl) -amide;

2- [5- (2-methoxy-1-methyl-ethylcarbamoyl) -thiophen-2-yl ] -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ((S) -1, 2, 2-trimethyl-propyl) -amide;

2- (5-carbamoyl-thiophen-2-yl) -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ((S) -1, 2, 2-trimethyl-propyl) -amide;

2- [5- (3, 3, 3-trifluoro-propylcarbamoyl) -thiophen-2-yl ] -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ((S) -1, 2, 2-trimethyl-propyl) -amide;

2- [5- (2-oxa-6-aza-spiro [3.3] heptane-6-carbonyl) -thiophen-2-yl ] -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ((S) -1, 2, 2-trimethyl-propyl) -amide;

2- [5- (3, 3-bis-hydroxymethyl-azetidine-1-carbonyl) -thiophen-2-yl ] -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ((S) -1, 2, 2-trimethyl-propyl) -amide;

2- [ 4-methyl-5- (tetrahydro-pyran-4-ylcarbamoyl) -thiophen-2-yl ] -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ((S) -1, 2, 2-trimethyl-propyl) -amide;

2- [5- (1, 1-dioxo-1 λ 6-thiomorpholine-4-carbonyl) -4-methyl-thiophen-2-yl ] -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ((S) -1, 2, 2-trimethyl-propyl) -amide;

2- [ 4-methyl-5- (2-oxa-6-aza-spiro [3.3] heptane-6-carbonyl) -thiophen-2-yl ] -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ((S) -1, 2, 2-trimethyl-propyl) -amide;

2- [5- (3, 3-bis-hydroxymethyl-azetidine-1-carbonyl) -4-methyl-thiophen-2-yl ] -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ((S) -1, 2, 2-trimethyl-propyl) -amide;

2- [5- (tetrahydro-pyran-4-ylcarbamoyl) -thiophen-2-yl ] -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ((S) -2-cyano-1, 2, 2-trimethyl-ethyl) -amide;

2- [5- (piperidine-1-carbonyl) -thiophen-2-yl ] -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ((S) -2-cyano-1, 2, 2-trimethyl-ethyl) -amide;

2- [5- (tetrahydro-pyran-4-ylcarbamoyl) -thiophen-2-yl ] -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ((S) -1, 2, 2-trimethyl-propyl) -amide;

2- (5-benzylcarbamoyl-thiophen-2-yl) -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ((S) -1, 2, 2-trimethyl-propyl) -amide;

2- [5- (3-cyano-benzylcarbamoyl) -thiophen-2-yl ] -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ((S) -1, 2, 2-trimethyl-propyl) -amide;

2- (3-cyano-phenoxy) -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid isopropylamide;

2- (3-methoxy-phenoxy) -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid isopropylamide;

2- (3-trifluoromethoxy-phenoxy) -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid isopropylamide;

2- (3-tert-butyl-phenoxy) -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid isopropylamide;

2-m-tolyloxy-5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid isopropylamide;

2- (3-ethyl-phenoxy) -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid isopropylamide;

2- (3-isopropyl-phenoxy) -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid isopropylamide;

2- (3-trifluoromethyl-phenoxy) -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid isopropylamide;

2- (2-trifluoromethyl-phenoxy) -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid isopropylamide;

2- (2-benzyl-phenoxy) -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid isopropylamide;

2- (2-ethyl-phenoxy) -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid isopropylamide;

2- (5, 6, 7, 8-tetrahydro-naphthalen-1-yloxy) -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid isopropylamide;

2- (5, 6, 7, 8-tetrahydro-naphthalen-2-yloxy) -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid isopropylamide;

2- (naphthalen-1-yloxy) -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid isopropylamide;

2- (naphthalen-2-yloxy) -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid isopropylamide;

2- (3-chloro-phenoxy) -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid isopropylamide;

2- (3-chloro-phenoxy) -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ethylamide;

2- (3-cyano-phenoxy) -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ethylamide;

2- (3-trifluoromethoxy-phenoxy) -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ethylamide;

2- (3-tert-butyl-phenoxy) -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ethylamide;

2-m-tolyloxy-5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ethylamide;

2- (3-ethyl-phenoxy) -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ethylamide;

2- (3-isopropyl-phenoxy) -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ethylamide;

2- (3-trifluoromethyl-phenoxy) -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ethylamide;

2-o-tolyloxy-5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid isopropylamide;

2- (2-trifluoromethoxy-phenoxy) -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid isopropylamide;

2- (2, 2-dimethyl-2, 3-dihydro-benzofuran-7-yloxy) -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid isopropylamide;

2- (2-chloro-phenoxy) -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid isopropylamide;

2- (2-methoxy-phenoxy) -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid isopropylamide;

2-o-tolyloxy-5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ethylamide;

2- (3, 5-dimethoxy-phenoxy) -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid isopropylamide;

2- (5, 6, 7, 8-tetrahydro-naphthalen-1-yloxy) -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ethylamide;

2- (5, 6, 7, 8-tetrahydro-naphthalen-2-yloxy) -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ethylamide;

2- (naphthalen-1-yloxy) -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ethylamide;

2- (naphthalen-2-yloxy) -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ethylamide;

2- (3, 5-dimethoxy-phenoxy) -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ethylamide;

2- (3-methoxy-phenoxy) -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ethylamide;

2- (2-chloro-phenoxy) -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ethylamide;

2- (4-cyano-phenoxy) -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid isopropylamide;

2- (4-cyano-phenoxy) -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ethylamide;

2- ((R) -3-methanesulfonylamino-indan-5-yloxy) -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid isopropylamide;

2- ((R) -3-acetylamino-indan-5-yloxy) -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid isopropylamide;

2- ((R) -3-methanesulfonylamino-indan-5-yloxy) -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ethylamide;

2- ((R) -3-acetylamino-indan-5-yloxy) -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ethylamide;

2- (1H-indol-6-yloxy) -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid isopropylamide;

2- (1H-indol-6-yloxy) -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ethylamide;

2- (1H-indol-4-yloxy) -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid isopropylamide;

2- (1H-indol-4-yloxy) -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ethylamide;

2- (1-methyl-1H-indol-6-yloxy) -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid isopropylamide;

2- (1H-indol-5-yloxy) -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid isopropylamide;

2- (6-methyl-pyridin-2-yloxy) -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid isopropylamide;

2- (4, 6-dimethyl-pyridin-2-yloxy) -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid isopropylamide;

2- (2-methyl-pyridin-3-yloxy) -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid isopropylamide;

2- ((R) -3-amino-indan-5-yloxy) -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid isopropylamide

2- ((R) -3-propionylamino-indan-5-yloxy) -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid isopropylamide;

2- { (R) -3- [ (tetrahydro-pyran-4-carbonyl) -amino ] -indan-5-yloxy } -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid isopropylamide;

2- [ (R) -3- (cyclopropanecarbonyl-amino) -indan-5-yloxy ] -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid isopropylamide;

2- [ (R) -3- (2, 2-dimethyl-propionylamino) -indan-5-yloxy ] -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid isopropylamide;

2- ((R) -3-benzoylamino-indan-5-yloxy) -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid isopropylamide;

2- ((R) -3-acetylamino-indan-5-yloxy) -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ((S) -1, 2, 2-trimethyl-propyl) -amide;

2- ((S) -3-acetylamino-indan-5-yloxy) -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid isopropylamide;

2- ((S) -3-amino-indan-5-yloxy) -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid isopropylamide;

2- (indan-5-yloxy) -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid isopropylamide;

2- ((R) -1-acetylamino-indan-5-yloxy) -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ((S) -1, 2, 2-trimethyl-propyl) -amide;

2- [ (R) -3- (3-methyl-ureido) -indan-5-yloxy ] -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid isopropylamide;

2- (3-hydroxy-indan-5-yloxy) -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid isopropylamide;

2- ((R) -3-acetylamino-indan-5-yloxy) -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ((R) -1-cyclopropyl-ethyl) -amide;

2- ((R) -3-acetylamino-indan-5-yloxy) -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ((S) -1-cyclopropyl-ethyl) -amide;

2- ((R) -3-acetylamino-indan-5-yloxy) -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ((S) -sec-butyl) -amide;

2- (3-oxo-indan-5-yloxy) -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid isopropylamide;

2- ((R) -3-acetylamino-indan-5-yloxy) -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid (cyano-methyl) -amide;

2- ((R) -3-ureido-indan-5-yloxy) -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid isopropylamide;

2- (2-acetylamino-indan-5-yloxy) -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid isopropylamide;

2- ((R) -3-formylamino-indan-5-yloxy) -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid isopropylamide;

2- (1H-inden-5-yloxy) -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid isopropylamide;

2- ((R) -3-hydroxy-indan-5-yloxy) -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid isopropylamide;

2- ((S) -3-hydroxy-indan-5-yloxy) -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid isopropylamide;

2- ((R) -1-amino-indan-5-yloxy) -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ((S) -1, 2, 2-trimethyl-propyl) -amide;

2- ((R) -8-acetylamino-5, 6, 7, 8-tetrahydro-naphthalen-2-yloxy) -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ((S) -1, 2, 2-trimethyl-propyl) -amide;

2- ((R) -8-amino-5, 6, 7, 8-tetrahydro-naphthalen-2-yloxy) -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ((S) -1, 2, 2-trimethyl-propyl) -amide;

2- ((R) -8-acetylamino-5, 6, 7, 8-tetrahydro-naphthalen-2-yloxy) -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ((R) -1-cyclopropyl-ethyl) -amide;

2- ((R) -8-formylamino-5, 6, 7, 8-tetrahydro-naphthalen-2-yloxy) -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ((R) -1-cyclopropyl-ethyl) -amide;

2- ((R) -8-amino-5, 6, 7, 8-tetrahydro-naphthalen-2-yloxy) -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ((R) -1-cyclopropyl-ethyl) -amide;

2- ((R) -3-acetylamino-indan-5-yloxy) -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid dicyclopropylmethyl-amide;

2- ((R) -1-acetylamino-indan-5-yloxy) -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ((R) -1-cyclopropyl-ethyl) -amide; and

2- ((R) -8-acetylamino-5, 6, 7, 8-tetrahydro-naphthalen-2-yloxy) -5H-pyrrolo [2, 3-b ] pyrazine-7-carboxylic acid ((S) -2-methoxy-1-methyl-ethyl) -amide.

16. A method of treating an inflammatory or autoimmune condition comprising administering to a patient in need thereof a therapeutically effective amount of a compound of any one of claims 1-15.

17. The method of claim 16, further comprising administering an additional therapeutic agent selected from a chemotherapeutic or anti-proliferative agent, an anti-inflammatory agent, an immunomodulatory or immunosuppressive agent, a neurotrophic factor, an agent for treating cardiovascular disease, an agent for treating diabetes, or an agent for treating immunodeficiency disorders.

18. A method of treating rheumatoid arthritis comprising administering to a patient in need thereof a therapeutically effective amount of a compound of any one of claims 1-15.

19. A method of treating asthma, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of any one of claims 1-15.

20. A method of treating an immune disorder including lupus, multiple sclerosis, rheumatoid arthritis, psoriasis, type I diabetes, complications from organ transplantation, foreign body transplantation, diabetes, cancer, asthma, atopic dermatitis, autoimmune thyroid disease, ulcerative colitis, crohn's disease, alzheimer's disease, and leukemia, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of any one of claims 1-15.

21. A pharmaceutical composition comprising a compound of any one of claims 1-15 and at least one pharmaceutically acceptable carrier, excipient, or diluent.

22. The pharmaceutical composition of claim 21, further comprising administering an additional 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 disease, an agent for treating diabetes, and an agent for treating immunodeficiency disorders.

23. A compound according to any one of claims 1 to 15 for use in the treatment of an inflammatory or autoimmune disorder.

24. A compound according to any one of claims 1 to 15 for use in the treatment of any one of the conditions mentioned in claims 17, 20 or 22.

25. Use of a compound according to any one of claims 1 to 15 in the manufacture of a medicament for the treatment of an inflammatory or autoimmune disorder.

26. The invention as hereinbefore described.