HK1211939B

HK1211939B - Imidazopyrazine syk inhibitors

Info

Publication number: HK1211939B
Application number: HK15112867.8A
Authority: HK
Inventors: Scott A. Mitchell; Kevin S. Currie; Peter A. Blomgren; Jeffrey E. Kropf; Seung H. Lee; Jianjun Xu; Douglas G. Stafford; James P. Harding; Jr. Antonio J. Barbosa; Zhongdong Zhao; David M. Armistead
Original assignee: 克洛诺斯生物股份有限公司
Priority date: 2008-12-08
Filing date: 2015-12-30
Publication date: 2018-04-27

Description

Imidazopyrazine SYK inhibitors

The application is a divisional application of an invention patent application with the application date of 2009, 12/7/10, the application number of 200980156331.1 and the name of 'imidazopyrazine SYK inhibitor'.

This application claims the benefit of U.S. provisional patent application 61/120,587 filed on 8.12.2008, U.S. provisional patent application No. 61/140,514 filed on 23.12.2008, and U.S. provisional patent application No. 61/240,979 filed on 9.9.2009, each of which is hereby incorporated by reference.

Technical Field

Provided herein are specific imidazopyrazines, compositions, and methods of their manufacture and use.

Background

The largest family of human enzymes, protein kinases, contain well over 500 proteins. Spleen tyrosine kinase (Syk) is a member of the Syk family of tyrosine kinases and is a regulator of early B cell development as well as mature B cell activation, signal transduction, and survival.

Syk is a non-receptor type tyrosine kinase that plays a key role in immunoreceptor and integrin-mediated signal transduction in a variety of cell types, including B cells, macrophages, monocytes, mast cells, eosinophils, basophils, neutrophils, dendritic cells, T cells, natural killer cells, thrombocytes, and osteoclasts. The immunoreceptors described herein include conventional immunoreceptors and molecules similar to immunoreceptors. Traditional immune receptors include B cell and T cell antigen receptors as well as various immunoglobulin receptors (Fc receptors). Molecules similar to immunoreceptors are either structurally related to immunoreceptors or participate in similar signal transduction pathways and are primarily involved in non-adaptive immune functions including neutrophil activation, natural killer cell recognition and osteoclast activity. Integrins are cell surface receptors that play a key role in the control of leukocyte adhesion and activation in both innate and adaptive immunity.

Ligand binding results in activation of both the immunoreceptor and integrin, and results in phosphorylation of immunoreceptor tyrosine-based activation motifs (ITAMs) in the cytoplasmic face of receptor-associated transmembrane adapter proteins, which leads to activation of Src family kinases. Syk binds to the phosphorylated ITAM motifs of the adaptor protein, resulting in activation of Syk and subsequent phosphorylation and activation of downstream signaling pathways.

Syk is essential for B cell activation through B Cell Receptor (BCR) signaling. SYK becomes activated upon binding to phosphorylated BCR, thereby initiating an early signaling event following BCR activation. B cell signaling through BCR can lead to a wide range of biological yields, which in turn depend on the developmental stage of the B cell. The magnitude and duration of the BCR signal must be precisely adjusted. Aberrant BCR-mediated signal transduction can lead to dysregulated B-cell activation and/or the formation of pathogenic autoantibodies leading to multiple autoimmune and/or inflammatory diseases. Mice lacking Syk show impaired maturation of B cells, reduced immunoglobulin production, compromised T cell-independent immune responses, and a significant attenuation of persistent calcium signaling upon BCR stimulation.

A large body of evidence supports the role of the B cell and humoral immune system in the etiology of autoimmune and/or inflammatory diseases. Protein-based therapies developed to deplete B cells (e.g., Rituxan) provide a method for treating a wide variety of autoimmune and inflammatory diseases. Autoantibodies and the immune complexes they produce are known to play pathogenic roles in autoimmune and/or inflammatory diseases. The pathogenic response to these antibodies relies on signal transduction through Fc receptors, which in turn are dependent on Syk. Because of the role of Syk in B cell activation and FcR-dependent signaling, inhibitors of Syk can be used as inhibitors of B cell-mediated pathogenic activity, including autoantibody production. Inhibition of Syk enzyme activity in cells has therefore been proposed for the treatment of autoimmune diseases through its effect on autoantibody production.

Syk also plays a key role in FCRI mediated mast cell degranulation and eosinophil activation. Thus, Syk is also implicated in allergic disorders including asthma. Syk binds to the phosphorylated gamma chain of FCRI through its SH2 domain and is essential for downstream signaling. Syk-deficient mast cells exhibit defective degranulation, arachidonic acid, and cytokine secretion. This is also shown for pharmacological agents that inhibit Syk activity in mast cells. Treatment with Syk antisense oligonucleotides inhibited antigen-induced infiltration of eosinophils and neutrophils in an animal model of asthma. Syk-deficient eosinophils also show impaired activation in response to FCRI stimulation. Therefore, small molecule inhibitors of Syk are useful for the treatment of allergy-induced inflammatory diseases including asthma.

Syk is also expressed in mast cells and monocytes and has been shown to be important for the function of these cells. For example, Syk deficiency in mice is associated with impaired lgE-mediated mast cell activation that results in a significant reduction in TNF-a and other inflammatory cytokine release. Syk kinase inhibitors have also been shown to inhibit mast cell degranulation in cell-based assays. In addition, Syk inhibitors have been shown to inhibit antigen-induced passive cutaneous allergic reactions, bronchoconstriction and bronchial edema in rats.

Inhibition of Syk activity may therefore be used to treat allergic disorders, autoimmune diseases and inflammatory diseases such as SLE, rheumatoid arthritis, multiple vasculitis, Idiopathic Thrombocytopenic Purpura (ITP), myasthenia gravis, allergic rhinitis, Chronic Obstructive Pulmonary Disease (COPD), Adult Respiratory Distress Syndrome (ARDs) and asthma. In addition, Syk has been reported to play an important role in ligand-independent tonic signal transduction through B cell receptors, which is known to be an important survival signal transduction in B cells. Thus, inhibition of Syk activity can be used to treat specific types of cancer, including B-cell lymphomas and leukemias.

Disclosure of Invention

There is provided at least one chemical entity selected from compounds of formula I and pharmaceutically acceptable salts thereof:

wherein the content of the first and second substances,

R₁is phenyl substituted with one or two groups selected from:

halogen;

a hydroxyl group;

a carboxyl group;

a cyano group;

cycloalkyl optionally substituted with one or two groups selected from hydroxy, lower alkoxy and lower alkyl;

cycloalkoxy optionally substituted with one or two groups selected from hydroxy, lower alkoxy and lower alkyl;

heterocycloalkyl optionally substituted with one or two groups selected from: acyl, halogen, optionally substituted amino, hydroxy, lower alkoxy, lower alkyl substituted with hydroxy, lower alkyl substituted with lower alkoxy, lower alkyl substituted with one, two or three halogen groups, optionally substituted amino, optionally substituted heterocycloalkyl, and oxo;

heterocycloalkoxy optionally substituted with one or two groups selected from: halogen, optionally substituted amino, hydroxy, lower alkoxy, lower alkyl substituted with hydroxy, lower alkyl substituted with lower alkoxy, lower alkyl substituted with one, two or three halogen groups, optionally substituted amino, optionally substituted heterocycloalkyl, and oxo;

a heteroaryl group;

amino optionally substituted with one or two groups selected from: lower alkyl, lower alkyl substituted with halogen, lower alkyl substituted with hydroxy and lower alkyl substituted with lower alkoxy;

-C(O)NR₆R₇wherein R is₆And R₇Independently selected from hydrogen, lower alkyl substituted with hydroxy, lower alkyl substituted with optionally substituted amino, cycloalkyl, aryl, heteroaryl and heterocycloalkyl, or R₆And R₇Together with the nitrogen to which they are attached form a 3-to 7-membered heterocycloalkyl ring optionally substituted with one or two groups selected from hydroxy, lower alkyl and lower alkyl substituted with hydroxy;

-S(O)₂NR₆R₇wherein R is₆And R₇Independently selected from hydrogen, lower alkyl substituted with hydroxy, lower alkyl substituted with optionally substituted amino, cycloalkyl, aryl, heteroaryl and heterocycloalkyl, or R₆And R₇Together with the nitrogen to which they are bound form a 3-to 7-membered heterocycloalkyl ring optionally substituted with one or two groups selected from hydroxy, lower alkyl and lower alkyl substituted with hydroxy, provided that R₆And R₇Is not hydrogen;

lower alkoxy optionally substituted with one or two groups selected from: hydroxy, lower alkoxy, optionally substituted aminocarbonyl, optionally substituted amino, carboxy, aminocarbonyl and heterocycloalkyl;

a heteroaryloxy group; and

lower alkyl optionally substituted with one or two groups selected from: hydroxy, lower alkoxy, halogen, trifluoromethyl, optionally substituted amino and heterocycloalkyl optionally substituted with lower alkyl; or

R₁Is thatWherein A is selected from the group consisting of aryl, cycloalkyl and heterocycloalkyl groups, each of which has from 5 to 7 ring atoms including atoms shared with the 6-membered aromatic ring, and each of which is optionally substituted;

R₂selected from optionally substituted aryl and optionally substituted heteroaryl;

R₃selected from hydrogen, lower alkyl and halogen;

R₄selected from hydrogen and lower alkyl; and

R₅is a hydrogen atom, and is,

with the following conditions:

if R is₃And R₄Is hydrogen and R₁Is 3-methoxy-4- (morpholin-4-ylcarbonyl) phenyl, 4- (morpholin-4-yl) phenyl, 3, 4-diethoxyphenyl, 3-fluoro-4-methoxyphenyl, 4- (4-ethylpiperazin-1-yl) phenyl, 4- (3-oxopiperazin-1-yl) phenyl, 4- (morpholin-4-yl) phenyl, 3-methoxy-4-methylphenyl, 4-methoxy-3-methylphenyl, 2- (dimethylamino) ethoxy-3-methoxyphenyl, 3-ethoxy-4-methoxyphenyl or 4-ethoxy-3-methoxyphenyl, then R is₂Instead of with- (CO) NHR₆Substituted phenyl, wherein R₆Is optionally substituted aryl;

if R is₃And R₄Is hydrogen and R₁Is 3, 4-dimethoxyphenyl, then R₂Not by the following- (CO) NR₈R₉Or- (SO)₂)NHR₁₀Substituted phenyl in said- (CO) NR₈R₉In, R₈And R₉Linked together to form an optionally substituted heterocycloalkyl or optionally substituted heteroaryl, or wherein R₈Is hydrogen, methyl or ethyl and R₉Is hydrogen, optionally substituted aryl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted alkyl or optionally substituted heteroaryl, wherein said phenyl is further optionally substituted with a group selected from methyl, methoxy and halogen, in said- (SO)₂)NHR₁₀In, R₁₀Is optionally substituted phenyl;

if R is₃And R₄Is hydrogen and R₁Is 4- (morpholin-4-yl) phenyl, then R₂Other than pyridyl, 2-fluorophenyl, benzo [ d][1,3]Dioxolyl, 2-methoxyphenyl, 2, 6-dimethoxyphenyl, 3-acetamidophenyl, 3-carboxyphenyl, 2- (hydroxymethyl) phenyl, furyl or 3- (hydroxyethylcarbamoyl) phenyl;

if R is₃And R₄Is hydrogen and R₁Is chlorophenyl, then R₂Instead of using piperidin-1-yl-carbonyl or NH (CO) NHR as described below₁₂Substituted phenyl on said NH (CO) NHR₁₂In, R₁₂Is phenyl substituted with trifluoromethyl or one or more halogens;

if R is₃And R₄Is hydrogen and R₁Is phenyl substituted with optionally substituted piperazinyl, then R₂Is not 3-aminophenyl;

if R is₃And R₄Is hydrogen and R₁Is 4-chlorophenyl, then R₂Is not 4-carboxyphenyl, 3- (2- (dimethylamino) ethylcarbamoyl) phenyl or 4- (2- (dimethylamino) ethylcarbamoyl) phenyl; and

if R is₃And R₄Is hydrogen and R₁Is 4- (2-hydroxy-ethyl) phenyl or 4- (hydroxyethyl) phenyl, then R₂Is not 2-methoxyphenyl or 2-fluorophenyl;

if R is₃And R₄Is hydrogen and R₁Is 4- [ (4-ethylpiperazin-1-yl) methyl]Phenyl or4- (2-hydroxypropan-2-yl) phenyl, then R₂Not by the following- (CO) NR₈R₉Substituted phenyl in said- (CO) NR₈R₉In, R₈Is hydrogen and R₉Is hydrogen, methyl or optionally substituted aryl, wherein the phenyl is further optionally substituted with a group selected from methyl;

if R is₃And R₄Is hydrogen and R₂Is 4-carbamoylphenyl, then R₁Is not 4- (hydroxymethyl) phenyl, 3- (1-hydroxyethyl) phenyl, 4- (1H-imidazol-2-yl) -3-methylphenyl, 3-methoxy-4- (piperidin-4-yloxy) phenyl, 3-methoxy-4- (2-methoxyethoxy) phenyl, 4- [2- (dimethylamino) ethoxy]-3-methoxyphenyl, 4- (2-hydroxyethoxy) -3-methoxyphenyl, 3-methoxy-4- (propan-2-yloxy) phenyl, 3-methoxy-4-propoxyphenyl, 4- (propylcarbamoyl) phenyl, 4-ethoxy-3-methoxyphenyl, 4- (1H-imidazol-2-yl) phenyl, 3-methoxy-4- (1H-pyrazol-5-yl) phenyl;

if R is₃And R₄Is hydrogen and R₂Is pyridin-3-yl substituted with carbamoyl, then R₁Is not 3, 4-dimethoxyphenyl;

if R is₃And R₄Is hydrogen and R₁Is 4-ethoxy-3-methoxyphenyl, then R₂Not substituted by methyl groups and further substituted by- (CO) NR described below₈R₉Substituted phenyl in said- (CO) NR₈R₉In, R₈Is hydrogen and R₉Is 4- (methylcarbamoyl) phenyl; and

with the further proviso that R₂Not with-NHC (O) R₁₁Substituted phenyl, wherein R₁₁Is an optionally substituted aryl group.

Also provided is at least one chemical entity selected from compounds of formula I:

wherein the content of the first and second substances,

R₁is phenyl substituted with one or two groups selected from:

halogen;

a hydroxyl group;

a carboxyl group;

heterocycloalkyl optionally substituted with one or two groups selected from: hydroxy, lower alkoxy, lower alkyl substituted with hydroxy, optionally substituted amino, and oxo;

a heteroaryl group;

-S(O)₂NR₆R₇wherein R is₆And R₇Independently selected from hydrogen, lower alkyl substituted with hydroxy, lower alkyl substituted with optionally substituted amino, cycloalkyl, aryl, heteroaryl and heterocycloalkyl, or R₆And R₇Together with the nitrogen to which they are attached form a 3-to 7-membered heterocycloalkyl ring selected fromOne or two groups of hydroxy, lower alkyl and lower alkyl substituted by hydroxy are optionally substituted, with the proviso that R₆And R₇Is not hydrogen;

lower alkoxy optionally substituted with one or two groups selected from: hydroxy, lower alkoxy, optionally substituted amino, carboxy, aminocarbonyl, and heterocycloalkyl;

a heteroaryloxy group; and

R₃is hydrogen;

R₄is hydrogen; and

R₅is a hydrogen atom, and is,

with the following conditions:

if R is₁Is 3-methoxy-4-methylphenyl, 4-methoxy-3-methylphenyl, 2- (dimethylamino) ethoxy-3-methoxyphenyl, 3-ethoxy-4-methoxyphenyl or 4-ethoxy-3-methoxyphenyl, then R₂Instead of with- (CO) NHR₆Substituted phenyl, wherein R₆Is optionally substituted aryl;

if R is₁Is 3, 4-dimethoxyphenyl, then R₂Not by the following- (CO) NR₈R₉Or- (SO)₂)NHR₁₀Substituted phenyl in said- (CO) NR₈R₉In, R₈And R₉Linked together to form an optionally substituted heterocycloalkyl or optionally substituted heteroaryl, or wherein R₈Is hydrogen and R₉Is optionally substituted aryl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted alkyl or optionally substituted heteroaryl, in said- (SO)₂)NHR₁₀In, R₁₀Is optionally substituted phenyl;

if R is₁Is 4- (morpholin-4-yl) phenyl, then R₂Other than pyridyl, 2-fluorophenyl, benzo [ d][1,3]Dioxolyl, 2-methoxyphenyl, 2, 6-dimethoxyphenyl, 3-acetamidophenyl, 3-carboxyphenyl, 2- (hydroxymethyl) phenyl, furyl or 3- (hydroxyethylcarbamoyl) phenyl;

if R is₁Is chlorophenyl, then R₂Instead of using piperidin-1-yl-carbonyl or the following NH (CO) NR₁₂Substituted phenyl at said NH (CO) NR₁₂In, R₁₂Is phenyl substituted with trifluoromethyl or one or more halogens;

if R is₁Is optionally substituted piperazinyl, then R₂Is not 3-aminophenyl;

if R is₁Is 4-chlorophenyl, then R₂Is not 4-carboxyphenyl, 3- (2- (dimethylamino) ethylcarbamoyl) phenyl or 4- (2- (dimethylamino) ethylcarbamoyl) phenyl; and

if R is₁Is 4- (2-hydroxy-ethyl) phenyl or 4- (hydroxyethyl) phenyl, then R₂Is not 2-methoxyphenyl or 2-fluorophenyl; and

wherein the content of the first and second substances,

R₁is phenyl substituted with one or two groups selected from:

halogen;

a hydroxyl group;

heterocycloalkyl optionally substituted with one or two groups selected from the group consisting of hydroxy, lower alkoxy and lower alkyl;

lower alkoxy optionally substituted with one or two groups selected from: hydroxy, lower alkoxy and optionally substituted amino; and

lower alkyl optionally substituted with one or two groups selected from: hydroxy, lower alkoxy, halogen, trifluoromethyl and optionally substituted amino; or

R₃is hydrogen;

R₄is hydrogen; and

R₅is a hydrogen atom, and is,

with the following conditions:

if R is₁Is 3, 4-dimethoxyphenyl, then R₂Not by the following- (CO) NR₈R₉Or- (SO)₂)NHR₁₀Substituted phenyl radicals, in- (CO) NR₈R₉In, R₈And R₉Linked together to form an optionally substituted heterocycloalkyl or optionally substituted heteroaryl, or wherein R₈Is hydrogen and R₉Is optionally substituted aryl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted alkyl or optionally substituted heteroaryl in- (SO)₂)NHR₁₀In, R₁₀Is optionally substituted phenyl;

if R is₁Is chlorophenyl, then R₂Instead of using piperidin-1-yl-carbonyl or the following NH (CO) NR₁₂Substituted phenyl radicals in NH (CO) NR₁₂In, R₁₂Is phenyl substituted with trifluoromethyl or one or more halogens;

if R is₁Is optionally substituted piperazinyl, then R₂Is not 3-aminophenyl;

Also provided is a pharmaceutical composition comprising at least one chemical entity described herein and at least one pharmaceutically acceptable vehicle selected from carriers, adjuvants, and excipients.

Also provided is a method for treating a patient having a disease responsive to (sensitive to) inhibition of Syk activity, comprising administering to the patient an effective amount of at least one chemical entity described herein.

Also provided is a method for treating a patient having a disease selected from cancer, autoimmune diseases, inflammatory diseases, acute inflammatory reactions, and allergic disorders, comprising administering to the patient an effective amount of at least one chemical entity described herein. Also provided is a method for treating a patient with polycystic kidney disease, the method comprising administering to the patient an effective amount of at least one chemical entity described herein.

Also provided is a method for increasing the sensitivity of a cancer cell to chemotherapy, the method comprising administering to a patient undergoing chemotherapy with a chemotherapeutic agent at least one chemical entity described herein in an amount sufficient to increase the sensitivity of a cancer cell to the chemotherapeutic agent.

Also provided is a method for inhibiting ATP hydrolysis, the method comprising contacting a cell expressing Syk with at least one chemical entity described herein in an amount sufficient to detectably reduce ATP hydrolysis levels in vitro.

Also provided is a method for determining the presence of Syk in a sample, the method comprising contacting the sample with at least one individual as described herein under conditions that allow detection of Syk activity, detecting the level of Syk activity in the sample, and thereby determining the presence or absence of Syk in the sample.

Also provided is a method for inhibiting B cell activity comprising contacting a cell expressing Syk with at least one chemical entity described herein in an amount sufficient to detectably reduce B cell activity in vitro.

Detailed Description

As used herein, when any variable occurs more than one time in a formula, its definition at each occurrence is independent of its definition at all other occurrences. According to the usual meaning of "a" and "an" in patents, references, for example, "a" kinase or "the" kinase comprises one or more kinases.

As used in this specification, the following words, phrases and symbols are generally intended to have the meanings as set forth below, unless to the extent that the context in which they are used indicates otherwise. The following abbreviations and terms have the indicated meanings throughout:

a dash ("-") that is not between two letters or symbols is used to indicate a point of attachment for a substituent. For example, -CONH₂Attached through a carbon atom.

Reference to "optional" or "optionally" means that the subsequently described event or circumstance may or may not occur, and that the description includes instances where the event or circumstance occurs and instances where it does not. For example, "optionally substituted alkyl" includes both "alkyl" and "substituted alkyl" as defined below. It will be understood by those skilled in the art that, with respect to any group containing one or more substituents, such groups are not intended to introduce any substitution or substitution pattern that is sterically impractical, synthetically non-feasible and/or inherently unstable.

"alkyl" includes straight and branched chains having the indicated number of carbon atoms, typically 1 to 20 carbon atoms, for example 1 to 8 carbon atoms, such as 1 to 6 carbon atoms. E.g. C₁-C₆Alkyl includes both straight and branched chain alkyl groups of 1 to 6 carbon atoms. Examples of alkyl groups include methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, pentyl, 2-pentyl, isopentyl, neopentyl, hexyl, 2-hexyl, 3-methylpentyl and the like. Alkylene is another subset of alkyl, which refers to the same residue as alkyl, but with two points of attachment. The alkylene group typically has 2 to 20 carbon atoms, for example 2 to 8 carbon atoms, such as 2 to 6 carbon atoms. E.g. C₀Alkylene means a covalent bond and C₁Alkylene is a methylene group. When naming alkyl residues having a particular carbon number, all geometric isomers having that carbon number are intended to be included; thus, for example, "butyl" is meant to include n-butyl, sec-butyl, isobutyl, and tert-butyl; "propyl" includes n-propyl and isopropyl. "lower alkyl" refers to an alkyl group having 1 to 4 carbons.

"alkenyl" refers to an unsaturated branched or straight chain alkyl group having at least one carbon-carbon double bond derived from the removal of one hydrogen molecule from the adjacent carbon atom of the parent alkyl group. The groups may be in either the cis or trans configuration with respect to the double bond. Typical alkenyl groups include, but are not limited to, vinyl; propenyl such as prop-1-en-1-yl (1-propen-1-yl), prop-1-en-2-yl, prop-2-en-1-yl (allyl), prop-2-en-2-yl; butenyl groups such as but-1-en-1-yl, but-1-en-2-yl, 2-methyl-prop-1-en-1-yl, but-2-en-2-yl, but-1, 3-dien-1-yl, but-1, 3-dien-2-yl and the like. In some embodiments, alkenyl groups have 2 to 20 carbon atoms and in other embodiments alkenyl groups have 2 to 6 carbon atoms.

"cycloalkyl" refers to a saturated hydrocarbon ring group having a specified number of carbon atoms, typically 3 to 7 ring carbon atoms. Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl as well as bridged and caged saturated cyclic groups such as norbornane.

The term "alkoxy" refers to an alkyl group indicating the number of carbon atoms bonded through an oxygen bridge, such as methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, pentyloxy, 2-pentyloxy, isopentyloxy, neopentyloxy, hexyloxy, 2-hexyloxy, 3-methylpentyloxy, and the like. Alkoxy groups typically have 1 to 6 carbon atoms attached through an oxygen bridge. "lower alkoxy" refers to an alkoxy group having 1 to 4 carbons.

"aminocarbonyl" includes the formula- (C ═ O) NR_aR_bWherein R is_aAnd R_bIndependently selected from hydrogen and optional substituents with respect to "substituted amino" described below.

"acyl" refers to the group (alkyl) -C (O) -; (cycloalkyl) -c (o) -; (aryl) -c (o) -; (heteroaryl) -c (o) -; and (heterocycloalkyl) -c (o) -, wherein the groups are linked to the parent structure through a carbonyl functional group, and wherein alkyl, cycloalkyl, aryl, heteroaryl, and heterocycloalkyl are as described herein. The acyl group has the indicated number of carbon atoms, with the carbon of the keto group being contained in the numbered carbon atoms. E.g. C₂Acyl is of the formula CH₃Acetyl of (C ═ O) -.

By "alkoxycarbonyl" is meant an ester group of formula (alkoxy) (C ═ O) attached through the carbonyl carbon, where the alkoxy group has the indicated number of carbon atoms. Thus, C₁-C₆An alkoxycarbonyl group is an alkoxy group having from 1 to 6 carbon atoms connected to the carbonyl bond through its oxygen.

By "amino" is meant the group-NH₂。

"aryl" includes:

5 and 6 membered carbocyclic aromatic rings, such as benzene;

bicyclic ring systems in which at least one ring is carbocyclic and aromatic, such as naphthalene, indane (indane) and tetralin; and

tricyclic ring systems in which at least one ring is carbocyclic and aromatic, such as fluorene.

For example, aryl includes 5 and 6 membered carbocyclic aromatic rings fused to a 5 to 7 membered heterocycloalkyl ring containing 1 or more heteroatoms selected from N, O and S. For such fused bicyclic ring systems where only one ring is a carbocyclic aromatic ring, the point of attachment may be at the carbocyclic aromatic ring or at the heterocycloalkyl ring. A divalent group formed of a substituted benzene derivative and having a free valence at a ring atom is named a substituted phenylene group. A divalent radical derived from a monovalent polycyclic hydrocarbon group whose name ends with a "radical" by removing one hydrogen atom from a carbon atom having a free valence is named by adding "idene" to the name of the corresponding monovalent radical, for example a naphthyl radical having two points of attachment is called naphthylene. However, aryl does not in any way include or overlap with heteroaryl as defined separately below. Thus, if one or more carbocyclic aromatic rings are fused to a heterocycloalkyl aromatic ring, as described herein, the resulting ring system is heteroaryl, not aryl.

The term "aryloxy" refers to the group-O-aryl.

The term "halo" includes fluoro, chloro, bromo and iodo, and the term "halogen" includes fluoro, chloro, bromo and iodo.

"heteroaryl" includes:

a 5 to 7 membered aromatic monocyclic ring comprising one or more, for example 1 to 4, or in some embodiments 1 to 3 heteroatoms selected from N, O and S, while the remaining ring atoms are carbon; and

bicyclic heterocycloalkyl rings containing one or more, e.g., 1 to 4, or in some embodiments, 1 to 3 heteroatoms selected from N, O and S, while the remaining ring atoms are carbon, and wherein at least one heteroatom is present in the aromatic ring.

For example, heteroaryl includes a 5-to 7-membered heterocycloalkyl aromatic ring fused to a 5-to 7-membered cycloalkyl ring. For such fused bicyclic heteroaryl ring systems wherein only one ring contains one or more heteroatoms, the point of attachment may be at the heteroaryl ring or at the heteroalkyl ring. When the total number of S and O atoms in the heteroaryl group exceeds 1, the above heteroatoms are not adjacent to each other. In some embodiments, the total number of S and O atoms in the heteroaryl group is no greater than 2. In some such embodiments, the total number of S and O atoms in the aromatic heterocycle is no greater than 1. Examples of heteroaryl groups include, but are not limited to (by numbering beginning with the attachment position of the indicated priority 1), 2-pyridyl, 3-pyridyl, 4-pyridyl, 2, 3-pyrazinyl, 3, 4-pyrazinyl, 2, 4-pyrimidinyl, 3, 5-pyrimidinyl, 2, 3-pyrazolinyl, 2, 4-imidazolinyl, isoxazolinyl, oxazolinyl, thiazolinyl, thiadiazolinyl, tetrazolyl, thienyl, benzothienyl, furyl, benzofuryl, benzimidazolinyl, dihydroindolyl, pyrazinyl (pyridizinyl), triazolyl, quinolinyl, pyrazolyl, and 5,6,7, 8-tetrahydroisoquinoline. Divalent radicals derived from monovalent heteroaryl radicals whose name ends with a "radical" by removing one hydrogen atom from the atom having a free valence are named by adding a "ene" to the name of the corresponding monovalent radical, e.g. a pyridyl radical having two points of attachment is a pyridylene radical. Heteroaryl does not include or overlap with aryl as defined above.

Substituted heteroaryl groups also include substituted heteroaryl groups with one or more oxides (-O)^-) Ring systems substituted by substituents, such as pyridyl N-oxides.

The term "heteroaryloxy" refers to the group-O-heteroaryl.

By "heterocycloalkyl" is meant an aliphatic monocyclic ring, typically having 3 to 7 ring atoms, which contains at least two carbon atoms in addition to 1-3 heteroatoms independently selected from oxygen, sulfur, and nitrogen, and combinations comprising at least one of the foregoing heteroatoms. Suitable heterocycloalkyl groups include, for example (by numbering starting from the attachment position of the indicated priority 1), 2-pyrrolinyl, 2, 4-imidazolinyl, 2, 3-pyrazolinyl, 2-piperidinyl, 3-piperidinyl, 4-piperidinyl and 2, 5-piperazinyl. Morpholinyl groups including 2-morpholinyl and 3-morpholinyl (wherein oxygen is the number designating priority 1) are also contemplated. Substituted heterocycloalkyl also includes ring systems substituted with one or more oxo moieties, such as piperidinyl N-oxide, morpholinyl-N-oxide, 1-oxo-thiomorpholinyl, and 1, 1-dioxo-thiomorpholinyl.

"heterocycloalkyl" also includes bicyclic ring systems in which neither ring is aromatic and wherein at least one ring in the bicyclic ring system contains at least two carbon atoms in addition to 1-3 heteroatoms independently selected from oxygen, sulfur, and nitrogen.

The term "heterocycloalkoxy" refers to the group-O-heterocycloalkyl.

The term "nitro" refers to the group-NO₂。

The term "phosphono" refers to the group-PO₃H₂。

"thiocarbonyl" refers to the group-C (═ O) SH.

The term "optionally substituted thiocarbonyl" includes the following groups: -C (═ O) S- (optionally substituted (C)₁-C₆) Alkyl), -C (═ O) S- (optionally substituted aryl), -C (═ O) S- (optionally substituted heteroaryl), and C (═ O) S- (optionally substituted heterocycloalkyl).

The term "thioalkyl" includes the groups: -S- (optionally substituted (C)₁-C₆) Alkyl), -S- (optionally substituted aryl), -S- (optionally substituted heteroaryl), and-S- (optionally substituted heterocycloalkyl). Thus, a sulfanyl group includes the group C₁-C₆An alkylsulfanyl group.

The term "sulfinyl group"Comprising the group: -S (O) -H, -S (O) - (optionally substituted (C)₁-C₆) Alkyl), -s (o) - (optionally substituted aryl), -s (o) - (optionally substituted heteroaryl), -s (o) - (optionally substituted heterocycloalkyl); and-s (o) - (optionally substituted amino).

The term "sulfonyl" includes the groups: -S (O)₂)-H、-S(O₂) - (optionally substituted (C)₁-C₆) Alkyl), -S (O)₂) - (optionally substituted aryl), -S (O)₂) - (optionally substituted heteroaryl), -S (O)₂) - (optionally substituted heterocycloalkyl), -S (O)₂) - (optionally substituted alkoxy), -S (O)₂) - (optionally substituted aryloxy), -S (O)₂) - (optionally substituted heteroaryloxy), -S (O)₂) - (optionally substituted heterocyclyloxy); and-S (O)₂) - (optionally substituted amino).

The term "substituted" as used herein means that any one or more hydrogens on the designated atom or group is replaced with a selection from the indicated group, provided that the designated atom's normal valency is not exceeded. When the substituent is oxo (oxo) (i.e., ═ O), then 2 hydrogens on the atom are substituted. Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds or useful synthetic intermediates. A stable compound or stable structure refers to a compound that is sufficiently robust to survive isolation from a reaction mixture, and subsequent formulation as a reagent has at least one practical utility. Unless otherwise specified, substituents are named within the core structure. For example, it will be understood that when (cycloalkyl) alkyl is listed as a possible substituent, the point of attachment of such substituent to the core structure is in the alkyl moiety.

Unless otherwise specifically limited, the terms "substituted" alkyl, cycloalkyl, aryl, heterocycloalkyl, and heteroaryl (including, but not limited to, dihydrobenzoxazinyl, dihydroquinoxalinyl, dihydrobenzodiazolyl, indolinyl, pyrimidinyl, quinolinyl, indazolyl, indolyl, benzimidazolyl, benzothiazolyl, benzotriazolyl, quinoxalinyl, quinazolinyl, morpholinyl, azetidinyl, pyrrolidinyl, oxolanyl (oxanonyl), pyridinyl, oxazolyl, piperidinyl, and pyradazinyl) refer to alkyl, cycloalkyl, aryl, heterocycloalkyl, and heteroaryl (including, but not limited to, dihydrobenzoxazinyl, dihydroquinoxalinyl, dihydrobenzodiazolyl, indolinyl, pyrimidinyl, quinolinyl, indazolyl, indolyl, benzimidazolyl, benzothiazolyl, benzotriazolyl, quinoxalyl, quinazolinyl, and heteroaryl), respectively, to name a few, Morpholinyl, azetidinyl, pyrrolidinyl, oxacyclohexylyl, pyridinyl, oxazolyl, piperazinyl, and pyradazinyl groups), wherein one or more (such as up to 5, for example up to 3) hydrogen atoms are substituted with a substituent independently selected from:

-R^a、-OR^b、-O(C₁-C₂alkyl) O- (e.g. methylenedioxy-), -SR^bGuanidines, guanidines in which one or more guanidinium hydrogens are replaced by lower alkyl groups, -NR^bR^cHalogen, cyano, oxo (as substituents for heterocycloalkyl), nitro, -COR^b、-CO₂R^b、-CONR^bR^c、-OCOR^b、-OCO₂R^a、-OCONR^bR^c、-NR^cCOR^b、-NR^cCO₂R^a、-NR^cCONR^bR^c、-SOR^a、-SO₂R^a、-SO₂NR^bR^cand-NR^cSO₂R^a，

Wherein R is^aIs selected from optionally substituted C₁-C₆Alkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heterocycloalkyl, and optionally substituted heteroaryl;

R^bselected from H, optionally substituted C₁-C₆Alkyl, optionally substituted aryl, and optionally substituted heteroaryl; and

R^cselected from hydrogen and optionally substituted C₁-C₄An alkyl group; or

R^bAnd R^cAnd the nitrogen to which they are attached form an optionally substituted heterocycloalkyl group; and is

Wherein each optionally substituted group is unsaturated or independently substituted with one or more, such as one, two or three substituents independently selected from: c₁-C₄Alkyl radical, C₃-C₆Cycloalkyl, aryl, heteroaryl, aryl-C₁-C₄Alkyl-, heteroaryl-C₁-C₄Alkyl-, C₁-C₄Haloalkyl-, -OC₁-C₄Alkyl, -OC₁-C₄Alkylphenyl, -C₁-C₄alkyl-OH, -C₁-C₄alkyl-O-C₁-C₄Alkyl, -OC₁-C₄Haloalkyl, halogen, -OH, -NH_2、-C₁-C₄alkyl-NH_2、-N(C₁-C₄Alkyl) (C₁-C₄Alkyl), -NH (C)₁-C₄Alkyl), -N (C)₁-C₄Alkyl) (C₁-C₄Alkylphenyl), -NH (C)₁-C₄Alkylphenyl), cyano, nitro, oxo (as substituents for heteroaryl), -CO₂H、-C(O)OC₁-C₄Alkyl, -CON (C)₁-C₄Alkyl) (C₁-C₄Alkyl), -CONH (C)₁-C₄Alkyl), -CONH_2、-NHC(O)(C₁-C₄Alkyl), -NHC (O) (phenyl), -N (C)₁-C₄Alkyl radical C (O) (C)₁-C₄Alkyl), -N (C)₁-C₄Alkyl group C (O) (phenyl), -C (O) C₁-C₄Alkyl, -C (O) C₁-C₄Phenyl, -C (O) C₁-C₄Haloalkyl, -OC (O) C₁-C₄Alkyl, -SO₂(C₁-C₄Alkyl), -SO₂(phenyl), -SO₂(C₁-C₄Haloalkyl), -SO₂NH₂、-SO₂NH(C₁-C₄Alkyl), -SO₂NH (phenyl), -NHSO₂(C₁-C₄Alkyl), -NHSO₂(phenyl) and-NHSO₂(C₁-C₄Haloalkyl).

The term "substituted acyl" refers to the group (substituted alkyl) -c (o) -; (substituted cycloalkyl) -c (o) -; (substituted aryl) -c (o) -; (substituted heteroaryl) -c (o) -; and (substituted heterocycloalkyl) -c (o) -, wherein the groups are linked to the parent structure through a carbonyl functional group and wherein substituted alkyl, cycloalkyl, aryl, heteroaryl, and heterocycloalkyl are as described herein.

The term "substituted alkoxy" refers to an alkoxy group in which the alkyl component is substituted (i.e., -O- (substituted alkyl)), wherein "substituted alkyl" is as described herein.

The term "substituted alkoxycarbonyl" refers to the group (substituted alkyl) -O-c (O) -, wherein the group is attached to the parent structure through a carbonyl functionality, and wherein "substituted alkyl" is as described herein.

The term "substituted aryloxy" refers to aryloxy in which the aryl component is substituted (i.e., -O- (substituted aryl)), wherein "substituted aryl" is as described herein.

The term "substituted heteroaryloxy" refers to a heteroaryloxy group in which the aryl component is substituted (i.e., -O- (substituted heteroaryl)), wherein "substituted heteroaryl" is as described herein.

The term "substituted cycloalkoxy" refers to cycloalkoxy groups in which the cycloalkyl component is substituted (i.e., -O- (substituted cycloalkyl)), wherein "substituted cycloalkyl" is as described herein.

The term "substituted heterocycloalkoxy" refers to a heterocycloalkoxy in which the alkyl component is substituted (i.e., -O- (substituted heterocycloalkyi)), wherein "substituted heterocycloalkyi" is as described herein.

The term "substituted amino" refers to the group-NHR^dor-NR^dR^dWherein each R is^dIndependent of each otherIs selected from: hydroxy, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted acyl, aminocarbonyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycloalkyl, alkoxycarbonyl, sulfinyl, and sulfonyl, provided that only one R is present^dMay be hydroxy, and wherein substituted alkyl, cycloalkyl, aryl, heterocycloalkyl and heteroaryl refer respectively to alkyl, cycloalkyl, aryl, heterocycloalkyl and heteroaryl wherein one or more (such as up to 5, for example up to 3) hydrogen atoms are substituted by a substituent independently selected from the group consisting of:

-R^a、-OR^b、-O(C₁-C₂alkyl) O- (e.g. methylenedioxy-), -SR^bGuanidines, guanidines in which one or more guanidinium hydrogens are replaced by lower alkyl groups, -NR^bR^cHalogen, cyano, nitro, -COR^b、-CO₂R^b、-CONR^bR^c、-OCOR^b、-OCO₂R^a、-OCONR^bR^c、-NR^cCOR^b、-NR^cCO₂R^a、-NR^cCONR^bR^c、-SOR^a、-SO₂R^a、-SO₂NR^bR^cand-NR^cSO₂R^a，

Wherein R is^aIs selected from optionally substituted C₁-C₆Alkyl, optionally substituted aryl and optionally substituted heteroaryl;

R^bselected from H, optionally substituted C₁-C₆Alkyl, optionally substituted aryl and optionally substituted heteroaryl; and

Wherein each optionally substituted group is unsaturated or substituted withOne or more, such as one, two or three, substituents independently selected from the group consisting of: c₁-C₄Alkyl, aryl, heteroaryl, aryl-C₁-C₄Alkyl-, heteroaryl-C₁-C₄Alkyl-, C₁-C₄Haloalkyl-, OC₁-C₄Alkyl, -OC₁-C₄Alkylphenyl, -C₁-C₄alkyl-OH, -OC₁-C₄Haloalkyl, halogen, -OH, -NH₂、-C₁-C₄alkyl-NH₂、-N(C₁-C₄Alkyl) (C₁-C₄Alkyl), -NH (C)₁-C₄Alkyl), -N (C)₁-C₄Alkyl) (C₁-C₄Alkylphenyl), -NH (C)₁-C₄Alkylphenyl), cyano, nitro, oxo (as substituents for heteroaryl), -CO₂H、-C(O)OC₁-C₄Alkyl, -CON (C)₁-C₄Alkyl) (C₁-C₄Alkyl), -CONH (C)₁-C₄Alkyl), -CONH₂、-NHC(O)(C₁-C₄Alkyl), -NHC (O) (phenyl), -N (C)₁-C₄Alkyl radical C (O) (C)₁-C₄Alkyl), -N (C)₁-C₄Alkyl group C (O) (phenyl), -C (O) C₁-C₄Alkyl, -C (O) C₁-C₄Phenyl, -C (O) C₁-C₄Haloalkyl, -OC (O) C₁-C₄Alkyl, -SO₂(C₁-C₄Alkyl), -SO₂(phenyl), -SO₂(C₁-C₄Haloalkyl), -SO₂NH₂、-SO₂NH(C₁-C₄Alkyl), -SO₂NH (phenyl), -NHSO₂(C₁-C₄Alkyl), -NHSO₂(phenyl) and-NHSO₂(C₁-C₄Haloalkyl); and is

Wherein optionally substituted acyl, aminocarbonyl, alkoxycarbonyl, sulfinyl and sulfonyl are as described herein.

The term "substitutedAmino "also refers to the group-NHR each as described above^dAnd NR^dR^dN-oxide of (a). N-oxides can be prepared by treating the corresponding amino groups with, for example, hydrogen peroxide or m-chloroperoxybenzoic acid. Those skilled in the art are familiar with the reaction conditions for carrying out the N-oxidation.

The compounds described herein include, but are not limited to, their optical isomers, racemates and other mixtures thereof. In those cases, the individual enantiomers or diastereomers, i.e. the optically active forms, can be obtained by asymmetric synthesis or by resolution of the racemates. Resolution of the racemates can be accomplished, for example, by conventional methods such as crystallization in the presence of a resolving agent or chromatography using, for example, a chiral High Pressure Liquid Chromatography (HPLC) column. In addition, such compounds include Z-and E-forms (or cis and trans forms) of compounds having a carbon-carbon double bond. Where a compound described herein exists in multiple tautomeric forms, a chemical entity includes all tautomeric forms of the compound. Such compounds also include crystal forms including polymorphs and clathrates.

The compounds of formula I also include crystalline and amorphous forms of those compounds, including, for example, polymorphs, pseudopolymorphs, solvates, hydrates, unsolvated polymorphs (including anhydrates), conformational polymorphs, and amorphous forms of the compounds, and mixtures thereof. "crystalline forms," "polymorphs," and "novel forms" are used interchangeably herein and are intended to include all crystalline and amorphous forms of a compound, including, for example, polymorphs, pseudopolymorphs, solvates, hydrates, unsolvated polymorphs (including anhydrates), conformational polymorphs, and amorphous forms, and mixtures thereof, unless a particular crystalline or amorphous form is referred to. The compounds of formula I also include pharmaceutically acceptable forms of the compounds, including chelates, non-covalent complexes, prodrugs, and mixtures thereof.

Chemical entities include, but are not limited to, the compounds described herein and all pharmaceutically acceptable forms thereof. Thus, the terms "chemical entity" and "chemical entities" also include pharmaceutically acceptable salts.

"pharmaceutically acceptable salts" include, but are not limited to, salts with inorganic acids such as hydrochlorides, phosphates, diphosphates, hydrobromides, sulfates, sulfinates, nitrates, and the like; and salts with organic acids such as malate, maleate, fumarate, tartrate, succinate, citrate, acetate, lactate, methanesulfonate, p-toluenesulfonate, 2-isethionate, benzoate, salicylate, stearate and alkanoates such as acetate, HOOC- (CH) with n ═ 0 to 4₂)_n-COOH and similar salts. Similarly, pharmaceutically acceptable cations include, but are not limited to, sodium, potassium, calcium, aluminum, lithium, and ammonium.

Additionally, if the compounds described herein are obtained as acid addition salts, the free base may be obtained by basifying a solution of the acid salt. Conversely, if the product is a free base, addition salts, particularly pharmaceutically acceptable addition salts, may be produced by dissolving the free base in a suitable organic solvent and treating the solution with an acid in accordance with conventional procedures for the preparation of acid addition salts from basic compounds. Those skilled in the art will recognize a variety of synthetic methods that may be used to prepare non-toxic pharmaceutically acceptable addition salts.

Prodrugs also fall within the scope of the compounds of formula I, as described above. In some embodiments, "prodrug" as described herein includes any compound that becomes a compound of formula I when administered to a patient, e.g., upon metabolic processing of the prodrug. Examples of prodrugs include derivatives of functional groups, such as carboxylic acid groups, in the compounds of formula I. Exemplary prodrugs of carboxylic acid groups include, but are not limited to, carboxylic acid esters such as alkyl esters, hydroxyalkyl esters, arylalkyl esters, and aryloxyalkyl esters.

"solvates" are formed by the interaction of a solvent and a compound. The term "compound" is intended to include solvates of the compounds. Similarly, "salt" includes solvates of the salt. Suitable solvates are pharmaceutically acceptable solvates, such as hydrates including the monohydrate and the hemihydrate.

"chelates" are formed by the coordination of a compound to a metal ion at two (or more) points. The term "compound" is intended to include chelates of compounds. Similarly, "salt" includes chelates of salts.

A "non-covalent complex" is formed by the interaction of a compound and another molecule, wherein no covalent bond is formed between the compound and the molecule. For example, complexation can occur through van der waals interactions, hydrogen bonding, and electrostatic interactions (also known as ionic bonding). Such non-covalent complexes are also included in the term "compound".

The term "hydrogen bond" refers to the form of association between an electronegative atom (also known as a hydrogen bond acceptor) and a hydrogen atom (also known as a hydrogen bond donor) attached to a second, relatively electronegative atom. Suitable Hydrogen Bond donors and acceptors are well understood in medicinal chemistry (G.C. Pimentel and A.L. McClellan, The Hydrogen Bond, Freeman, SanFrancisco, 1960; R.Taylor and O.Kennard, "Hydrogen Bond Geometry in organic crystals", Accounts of Chemical Research (review), 17, pp.320-326 (1984)).

"Hydrogen bond acceptor" means an acceptor comprising oxygen or nitrogen, in particular sp²-groups of hybridized oxygen or nitrogen, ether oxygen or sulfoxide oxygen or N-oxides.

The term "hydrogen bond donor" refers to oxygen, nitrogen, or a heteroaromatic carbon bearing a ring nitrogen-containing hydrogen group or a ring nitrogen-containing heteroaryl group.

The terms "group," "group," or "fragment" as used herein are synonymous and are intended to indicate a functional group or fragment of a molecule or other fragment of a molecule that can be linked to a bond.

The term "activator" is used to indicate a chemical entity having biological activity. In some embodiments, an "activator" is a compound that has pharmaceutical utility. For example, the active agent may be an anti-cancer therapeutic agent.

The term "therapeutically effective amount" of a chemical entity described herein refers to an amount that is effective for providing a therapeutic benefit such as amelioration of symptoms, slowing of disease progression, or prevention of disease when administered to a human or non-human patient, e.g., a therapeutically effective amount can be an amount sufficient to reduce disease symptoms responsive to inhibition of Syk activity. In some embodiments, a therapeutically effective amount is an amount sufficient to reduce symptoms of cancer, symptoms of allergic disorders, symptoms of autoimmune and/or inflammatory diseases, or symptoms of acute inflammatory reactions. In some embodiments, a therapeutically effective amount is an amount sufficient to reduce the number of detectable cancer cells in an organism, detectably slow, or stop the growth of a cancerous tumor. In some embodiments, a therapeutically effective amount is an amount sufficient to shrink a cancerous tumor. In some cases, patients with cancer may not have symptoms of an attack. In some embodiments, a therapeutically effective amount of a chemical entity is an amount sufficient to prevent a significant increase in or to significantly reduce the detectable levels of cancer cells or cancer markers in the blood, serum or tissue of a patient. In the methods described herein for treating an allergic disorder and/or an autoimmune and/or inflammatory disease and/or an acute inflammatory response, a therapeutically effective amount may also be an amount sufficient to detectably slow the progression of the disease when administered to a patient, or to prevent the presence of symptoms of an allergic disorder and/or an autoimmune and/or inflammatory disease and/or an acute inflammatory response in a patient administered to a chemical entity. In the methods described herein for treating allergic disorders and/or autoimmune and/or inflammatory diseases and/or acute inflammatory reactions, the therapeutically effective amount may also be an amount sufficient to produce a detectable reduction in the amount of marker protein or cell type in the patient's blood or serum. For example, in some embodiments, a therapeutically effective amount is an amount of a chemical entity described herein sufficient to significantly reduce B cell activity. In another example, in some embodiments, a therapeutically effective amount is an amount of a chemical entity described herein sufficient to significantly reduce B cell numbers. In another example, in some embodiments, a therapeutically effective amount is an amount of a chemical entity described herein sufficient to reduce the level of anti-acetylcholine receptor antibodies in the blood of a patient having myasthenia gravis.

The term "inhibition" indicates a significant decrease in the baseline activity of a biological activity or process. By "inhibition of Syk activity" is meant a decrease in Syk activity when responding directly or indirectly to the presence of at least one chemical entity as described herein, relative to the activity of Syk in the absence of said at least one chemical entity. The reduction in activity may be due to direct interaction of the compound with Syk, or to interaction of one or more chemical entities described herein with one or more other factors which in turn affect Syk activity. For example, the presence of one or more chemical entities may reduce Syk activity by binding directly to Syk, by causing (directly or indirectly) another factor to reduce Syk activity, or by reducing (directly or indirectly) the amount of Syk present in a cell or organism.

Inhibition of Syk activity also involves the observable inhibition of Syk activity in standard biochemical assays for Syk activity, such as the ATP hydrolysis assay described below. In some embodiments, a chemical entity described herein has an IC of less than or equal to 1 micromolar₅₀The value is obtained. In some embodiments, the chemical entity has an IC of less than or equal to 100 nanomolar₅₀The value is obtained. In some embodiments, the chemical entity has an IC of less than or equal to 10 nanomolar₅₀The value is obtained.

"inhibition of B cell activity" refers to a decrease in B cell activity in direct or indirect response to the presence of at least one chemical entity described herein relative to B cell activity in the absence of the at least one chemical entity. The reduction in activity may be due to direct interaction of the compound with Syk, or with one or more other factors that in turn affect B cell activity.

Inhibition of B cell activity also involves observable inhibition of CD86 expression in a standard assay, such as the assay described below. In some embodiments, a chemical entity described herein has an IC of less than or equal to 10 micromolar₅₀The value is obtained. In some embodiments, the chemical entity has an IC of less than or equal to 1 micromolar₅₀The value is obtained. In some embodiments, the chemical entity has an IC of less than or equal to 500 nanomolar₅₀The value is obtained.

"B cell activity" also includes the activation, redistribution, recombination or capping (bridging) of more than one of a variety of B cell membrane receptors or membrane-bound immunoglobulins, such as IgM, IgG and IgD. Most B cells also have membrane receptors for the Fc portion of IgG in the form of antigen-antibody complexes or aggregated IgG. B cells also carry membrane receptors for the activating components of complements such as C3B, C3d, C4, and Clq. These different membrane receptors and membrane-bound immunoglobulins have membrane fluidity and are capable of undergoing redistribution and capping that can initiate signal transduction.

B cell activity also includes the synthesis or production of antibodies or immunoglobulins. Immunoglobulins are synthesized by B cell lines and have common structural features and building blocks. The five immunoglobulin classes, IgG, IgA, IgM, IgD and IgE, are recognized based on the structural differences of their heavy chains, including the amino acid sequences, and the length of the polypeptides. Antibodies to a given antigen may be detected in all or several classes of immunoglobulins or may be restricted to a single class or subclass of immunoglobulins. Autoantibodies or autoimmune antibodies can equally belong to one or more classes of immunoglobulins. For example, rheumatoid factor (an antibody to IgG) is most often recognized as an IgM immunoglobulin, but may also be composed of IgG or IgA.

In addition, B cell activity is also intended to include a series of events that lead to clonal expansion (proliferation) and differentiation of B cells from precursor B lymphocytes into antibody-synthesized plasma cells that occur with antigen binding and with cytokine signaling from other cells.

By "inhibition of B cell proliferation" is meant inhibition of proliferation of abnormal B cells such as cancer B cells, e.g., lymphoma B cells, and/or inhibition of normal, non-diseased B cells. The term "inhibition of B cell proliferation" indicates any significant reduction in B cell number in vitro or in vivo. Thus, inhibition of B cell proliferation in vitro would be any significant reduction in the number of B cells in an in vitro sample contacted with at least one chemical entity described herein, as compared to a counterpart sample not contacted with the chemical entity.

Inhibition of B cell proliferation also relates to the observable inhibition of B cell proliferation in a standard thymidine incorporation assay for B cell proliferation as described herein. In some embodiments, the chemical entity has an IC of less than or equal to 10 micromolar₅₀The value is obtained. In some embodiments, the chemical entity has an IC of less than or equal to 1 micromolar₅₀The value is obtained. In some embodiments, the chemical entity has an IC of less than or equal to 500 nanomolar₅₀The value is obtained.

"allergy" or "allergic disorder" refers to the acquired hypersensitivity to a substance (allergen). Allergic conditions include eczema, allergic rhinitis or nasal colds, hay fever, bronchial asthma, urticaria (hives), and food allergies, as well as other ectopic states.

"asthma" refers to a disorder of the respiratory system characterized by inflammation, narrowing of the lung airways and increased responsiveness of the lung airways to inhaled agents. Asthma is frequently associated with, but not exclusively with, atopic or allergic symptoms.

By "significant" is meant any detectable change that is statistically significant in a standard parametric test of statistical significance, such as the Student T test, where p < 0.05.

A "disease responsive to inhibition of Syk activity" is a disease in which inhibition of Syk kinase provides a therapeutic benefit, such as improvement in symptoms, reduction in disease progression, prevention or delay of onset of disease, or inhibition of abnormal activity of specific cell types (monocytes, B cells, and mast cells).

"treating or managing" refers to any treatment of a disease in a patient, including:

a) preventing disease, i.e., rendering the clinical symptoms of the disease unexposed;

b) inhibiting the disease;

c) slowing or stopping the development of clinical symptoms; and/or

d) Relief of the disease, i.e., recovery of clinical symptoms.

"patient" refers to an animal, such as a mammal, that has been or will be the subject of treatment, observation or experiment. The methods described herein can be used in both human therapy and veterinary applications. In some embodiments, the patient is a mammal; in some embodiments, the patient is a human; and in some embodiments, the patient is selected from a rat and a dog.

There is provided at least one chemical entity selected from compounds of formula I:

wherein the content of the first and second substances,

R₁is phenyl substituted with one or two groups selected from:

halogen;

a hydroxyl group;

a carboxyl group;

a cyano group;

heterocycloalkyl optionally substituted with one or two groups selected from: acyl, halogen, optionally substituted amino, hydroxy, lower alkoxy, lower alkyl substituted with hydroxy, lower alkyl substituted with lower alkoxy, lower alkyl substituted with one, two or three halogen groups, optionally substituted amino, optionally substituted heterocycloalkyl, and oxo (oxo);

a heteroaryl group;

a heteroaryloxy group; and

R₃selected from hydrogen, lower alkyl and halogen;

R₄selected from hydrogen and lower alkyl; and

R₅is a hydrogen atom, and is,

with the following conditions:

if R is₃And R₄Is hydrogen and R₁Is 3-methoxy-4- (morpholin-4-ylcarbonyl) phenyl, 4- (morpholin-4-yl) phenyl, 3, 4-diethoxyphenyl, 3-fluoro-4-methoxyphenyl, 4- (4-ethylpiperazin-1-yl) phenyl, 4- (3-oxopiperazin-1-yl) phenyl, 4- (morpholin-4-yl) phenyl, 3-methoxy-4-methylphenyl, 4-methoxy-3-methylphenyl, 2- (dimethylamino) ethoxy-3-methoxyphenyl, 3-ethoxy-4-methoxyphenyl or 4-ethoxy-3-methoxyphenyl, then R is₂Instead of with- (CO) NHR₆Substituted phenyl radicals, which areIn R₆Is optionally substituted aryl;

if R is₃And R₄Is hydrogen and R₁Is 4- [ (4-ethylpiperazin-1-yl) methyl]Phenyl or 4- (2-hydroxypropan-2-yl) phenyl, then R₂Not by the following- (CO) NR₈R₉Substituted phenyl in said- (CO) NR₈R₉In, R₈Is hydrogen and R₉Is hydrogen, methyl or optionally substituted aryl, wherein the phenyl is further optionally substituted with a group selected from methyl;

with the further proviso that R₂Not with-NHC (O) R₁₁A substituted phenyl group, which is substituted,wherein R is₁₁Is an optionally substituted aryl group.

In some embodiments, R₃Selected from hydrogen, methyl, ethyl and chlorine. In some embodiments, R₃Is hydrogen.

In some embodiments, R₄Selected from hydrogen and methyl. In some embodiments, R₄Is hydrogen.

wherein the content of the first and second substances,

R₁is phenyl substituted with one or two groups selected from:

halogen;

a hydroxyl group;

a carboxyl group;

heterocycloalkyl optionally substituted with one or two groups selected from: hydroxy, lower alkoxy, lower alkyl substituted with hydroxy, optionally substituted amino and oxo;

a heteroaryl group;

-C(O)NR₆R₇wherein R is₆And R₇Independently selected from hydrogen, lower alkyl substituted with hydroxy, amino substituted with optionally substitutedLower alkyl, cycloalkyl, aryl, heteroaryl and heterocycloalkyl of the generation, or R₆And R₇Together with the nitrogen to which they are attached form a 3-to 7-membered heterocycloalkyl ring optionally substituted with one or two groups selected from hydroxy, lower alkyl and lower alkyl substituted with hydroxy;

a heteroaryloxy group; and

R₃is hydrogen;

R₄is hydrogen; and

R₅is a hydrogen atom, and is,

with the following conditions:

if R is₁Is optionally substituted piperazinyl, then R₂Is not 3-aminophenyl;

In some embodiments, R₁Is phenyl substituted with one or two groups selected from:

halogen;

a hydroxyl group;

a carboxyl group;

a heteroaryl group;

-C(O)NR₆R₇wherein R is₆And R₇Independently selected from hydrogen, lower alkyl substituted with hydroxy, lower alkyl substituted with optionally substituted amino, cycloalkyl, aryl, heteroaryl and heterocycloalkyl, or R₆And R₇Together with the nitrogen to which they are attached form a 3-to 7-membered heterocycloalkyl ringOne or two groups selected from hydroxy, lower alkyl and lower alkyl substituted with hydroxy are optionally substituted;

a heteroaryloxy group; and

lower alkyl optionally substituted with one or two groups selected from: hydroxy, lower alkoxy, halogen, trifluoromethyl, optionally substituted amino and heterocycloalkyl optionally substituted with lower alkyl.

halogen;

a hydroxyl group;

heterocycloalkyl optionally substituted with one or two groups selected from: hydroxy, lower alkoxy, lower alkyl substituted with hydroxy;

amino optionally substituted with one or two groups selected from: lower alkyl, lower alkyl substituted with hydroxy and lower alkyl substituted with lower alkoxy;

lower alkoxy optionally substituted with one or two groups selected from: hydroxy, lower alkoxy and optionally substituted amino;

lower alkyl optionally substituted with one or two groups selected from: hydroxy, lower alkoxy, trifluoromethyl, optionally substituted amino and heterocycloalkyl; and

-C(O)NR₆R₇wherein R is₆And R₇Independently selected from hydrogen, lower alkyl substituted with hydroxy, lower alkyl substituted with optionally substituted amino, cycloalkyl, aryl, heteroaryl and heterocycloalkyl, or R₆And R₇Together with the nitrogen to which they are attached form a 3-to 7-membered heterocycloalkyl ring optionally substituted with one or two groups selected from hydroxy, lower alkyl and lower alkyl substituted with hydroxy.

a hydroxyl group;

heterocycloalkyl optionally substituted with one or two groups selected from: hydroxy, lower alkoxy, lower alkyl and lower alkyl substituted with hydroxy;

lower alkoxy optionally substituted with one or two groups selected from hydroxy and lower alkoxy; and

lower alkyl substituted with one or two groups selected from: hydroxy, lower alkoxy, trifluoromethyl, optionally substituted amino and heterocycloalkyl.

wherein the content of the first and second substances,

R₁is selected fromPhenyl substituted with one or two of the following groups:

halogen;

a hydroxyl group;

R₃is hydrogen;

R₄is hydrogen; and

R₅is a hydrogen atom, and is,

with the following conditions:

if R is₁Is optionally substituted piperazinyl, then R₂Is not 3-aminophenyl;

if R is₁Is 4- (2-hydroxy-ethyl) phenyl or 4- (hydroxyethyl)Phenyl, then R₂Is not 2-methoxyphenyl or 2-fluorophenyl; and

halogen;

a hydroxyl group;

lower alkoxy optionally substituted with optionally substituted amino; and

lower alkyl optionally substituted with one or two groups selected from: hydroxy, lower alkoxy and optionally substituted amino; or

R₁Is thatWherein A is selected from the group consisting of aryl, cycloalkyl and heterocycloalkyl groups, each of which has from 5 to 7 ring atoms including atoms shared with the 6-membered aromatic ring, and each of which is optionally substituted.

a hydroxyl group;

lower alkoxy optionally substituted with one or two groups selected from hydroxy and optionally substituted amino; and

lower alkyl optionally substituted with one or two groups selected from: hydroxy, lower alkoxy, trifluoromethyl and optionally substituted amino.

a hydroxyl group;

lower alkoxy; and

lower alkyl substituted with one or two groups selected from: hydroxy, lower alkoxy, trifluoromethyl and optionally substituted amino.

In some embodiments, R₁Selected from (1-hydroxycyclobutyl) phenyl, (1,1, 1-trifluoro-2-hydroxypropan-2-yl) phenyl, (2,2, 2-trifluoro-1-hydroxyethyl) phenyl, (1,1,1,3,3, 3-hexafluoro-2-hydroxypropan-2-yl) phenyl, (2-hydroxy-2-methylpropoxy) -3-methoxyphenyl, (2-hydroxyethyl) (methyl) amino) -3-methoxyphenyl, (2-methoxyethyl) (methyl) amino) -3-methoxyphenyl, (1-hydroxyethyl) phenyl, 3, 4-dimethoxyphenyl, 3-methoxyphenyl, 4-ethoxy-3-methoxyphenyl, 4-hydroxymethyl-3-methoxyphenyl group, 3-hydroxymethyl-4-methoxyphenyl group, 2-fluoro-4-methoxyphenyl group, 4- (dimethylamino) propoxy-3-methoxyphenyl group, 4-hydroxypropoxy-3-methoxyphenyl group, 4- (2-hydroxy-1, 1-dimethylethyl) phenyl group, 4- (1-hydroxy-1-methylethyl) phenyl group, 4-methoxy-3- (pyrrolidin-1-yl) phenyl group, 3-methoxy-4- (propan-2-yloxy) phenyl group, 3-methoxy-4- (morpholin-4-yl) phenyl group, and the like, 4- (pyrrolidin-1-yl) phenyl, 4- (3-hydroxypyrrolidinyl) phenyl, 4- (4-hydroxypiperidinyl) -3-methoxyphenyl, 4- (3-hydroxyazetidinyl) -3-methoxyphenyl, 4- (3-hydroxypyrrolidinyl) -3-Methoxyphenyl, 4- (2-methoxypropan-2-yl) phenyl, 4- (4-ethylpiperazin-1-yl) -3-methoxyphenyl, 4- (4-ethylpiperazin-1-yl) phenyl, 4- (3-hydroxy-3-methylpiperidinyl) phenyl and 3-hydroxymethylphenyl.

a hydroxyl group;

lower alkoxy optionally substituted with optionally substituted amino; and

lower alkyl optionally substituted with one or two groups selected from: hydroxy, lower alkoxy and optionally substituted amino.

a hydroxyl group;

lower alkoxy; and

lower alkyl substituted with one or two groups selected from: hydroxy, lower alkoxy and optionally substituted amino.

a hydroxyl group;

heterocycloalkyl optionally substituted with one or two groups selected from hydroxy and lower alkyl;

lower alkoxy; and

lower alkyl substituted with one or two groups selected from hydroxy and lower alkoxy.

In some embodiments, R₁Selected from the group consisting of (1-hydroxyethyl) phenyl, 3, 4-dimethoxyphenyl, 3-methoxyphenyl, 4-ethoxy-3-methoxyphenyl, 4-hydroxymethyl-3-methoxyphenyl, 3-hydroxymethyl-4-methoxyphenyl, 2-fluoro-4-methoxyphenyl, 4- (dimethylamino) propoxy-3-methoxyphenyl, 4-hydroxypropoxy-3-methoxyphenyl, 4- (2-hydroxy-1, 1-dimethylethyl) phenyl, 4- (1-hydroxy-1-methylethyl) phenyl, 4-methoxy-3- (pyrrolidin-1-yl) phenyl, 3-methoxy-4- (pyrrolidin-1-yl) phenyl, and mixtures thereof, 3-methoxy-4- (propan-2-yloxy) phenyl, 3-methoxy-4- (morpholin-4-yl) phenyl, 4- (pyrrolidin-1-yl) phenyl, 4- (3-hydroxypyrrolidinyl) phenyl, 4- (4-hydroxypiperidinyl) -3-methoxyphenyl, 4- (3-hydroxyazetidinyl) -3-methoxyphenyl, 4- (3-hydroxypyrrolidinyl) -3-methoxyphenyl, 4- (2-methoxypropan-2-yl) phenyl, 4- (4-ethylpiperazin-1-yl) -3-methoxyphenyl, 4- (4-ethylpiperazin-1-yl) phenyl, and mixtures thereof, 4- (3-hydroxy-3-methylpiperidinyl) phenyl and 3-hydroxymethylphenyl.

In some embodiments, R₁Is that

In some embodiments, a is an optionally substituted heterocycloalkyl group comprising one or more heteroatoms selected from O and N. In some embodiments, the heterocycloalkyl group is substituted with one or more groups selected from lower alkyl and oxo. In some embodiments, the heteroatom N is substituted with lower alkyl.

In some embodiments, R₁Selected from 3, 4-dihydro-2H-benzo [ b][1,4]Oxazin-6-yl, 4-methyl-3, 4-dihydro-2H-benzo [ b][1,4]Oxazin-6-yl, 2,3,4, 5-tetrahydrobenzo [ b ]][1,4]Oxazazepine-7-yl,5-methyl-2, 3,4, 5-tetrahydrobenzo [ b ]][1,4]Oxazazepine-7-yl, 2, 3-dihydro-1H-indol-2-one-6-yl and 2, 3-dihydro-1H-indol-2-one-5-yl.

In some embodiments, R₂Selected from:

optionally substituted heteroaryl;

a dihydrobenzoxazinyl group optionally substituted with one or more groups selected from lower alkyl, halogen and oxo;

a dihydroquinoxalinyl group optionally substituted with one or more groups selected from lower alkyl and oxo;

dihydrobenzodiazolyl optionally substituted with oxo;

indolinyl optionally substituted with one or more groups selected from lower alkyl and oxo;

and

phenyl substituted with one or more groups selected from: optionally substituted alkyl, cyano, nitro, lower alkoxy, halogen, sulfonyl, optionally substituted amino and optionally substituted heteroaryl.

In some embodiments, R₂Selected from:

an optionally substituted pyridyl group;

a pyrimidinyl group;

a phenylthio group;

quinolinyl optionally substituted with amino;

indazolyl optionally substituted with one or two groups selected from: carbamoyl, halogen, lower alkyl and amino;

indolyl optionally substituted with one or two groups selected from: lower alkyl, carbamoyl;

benzimidazolyl optionally substituted with methyl or amino;

benzothiazolyl optionally substituted with lower alkyl;

a benzoxazolyl group;

a benzotriazole group;

quinoxalinyl optionally substituted with amino;

(ii) an optionally substituted quinazolinyl group selected from: an amino group, a dihydrobenzoxazinyl group optionally substituted with one or more groups selected from methyl, halogen and oxo;

1H-pyrrolo [3,2-b ] pyridinyl;

indolinyl optionally substituted with one or more groups selected from lower alkyl and oxo; and

phenyl substituted with one or more groups selected from: optionally substituted alkyl, cyano, chloro, fluoro, nitro, methoxy, sulfonyl, heteroaryl, amino and NHC (O) R₁₂Wherein R is₁₂Is a lower alkyl group.

In some embodiments, R₂Selected from: 2, 3-dihydro-1, 4-benzodioxin-6-yl, 4-methyl-3, 4-dihydro-2H-1, 4-benzoxazin-6-yl, 1, 3-benzoxazol-5-yl, 2H-1, 3-benzodioxol-5-yl, 2, 3-dihydro-1H-indol-6-yl, 2-methyl-1, 2,3, 4-tetrahydroisoquinolin-6-yl, 1-methyl-2, 3-dihydro-1H-indol-2-one-6-yl, 1,2,3, 4-tetrahydroisoquinolin-2-yl-ethane-1-one-6-yl, and pharmaceutically acceptable salts thereof, 2-ethyl-1, 2,3, 4-tetrahydroisoquinolin-7-yl, 2-aminoquinazolin-6-yl, 2-hydroxyethyl-2H-indazol-6-yl, 1-hydroxyethyl-2H-indazol-6-yl 1H-indazol-7-yl, 1,2,3, 4-tetrahydroisoquinolin-6-yl, 3- (diethylamino) methyl-1H-indazol-6-yl, 1, 2-dihydroquinoxalin-2-one-6-yl, 1, 2-dihydroquinoxalin-6-yl, and pharmaceutically acceptable salts thereof,1, 2-dihydroquinolin-2-one-6-yl, 1H-pyrazol-4-yl, 1, 3-thiazol-5-yl, 2-methyl-1, 3-benzothiazol-5-yl, 1'2' -dihydrospiro [ cyclopropane-1, 3' -indole]-2' -keto-6-yl, 3-dimethyl-2-oxo-2, 3-dihydro-1H-indol-6-yl, 3- (1, 3-thiazol-4-ylmethylene) -2, 3-dihydro-1H-indol-2-one-6-yl, 1-methyl-1H-indazol-6-yl, (N, N-dimethylaminocarbonyl) indol-6-yl, 1, 3-benzothiazol-5-yl, 1, 3-benzothiazol-6-yl, 1H,2H, 3H-pyrido [2,3-b ] group][1,4]Oxazin-2-one-6-yl, 2-difluoro-3, 4-dihydro-2H-1, 4-benzoxazin-3-one-6-yl, 3-ethyl-1H-indazol-6-yl, 1H-indol-2-yl, 1H-indol-3-yl, 4-fluoro-1H-indazol-6-yl, 1H-1,2, 3-benzotriazol-6-yl, 2, 3-dihydro-1H-1, 3-benzodiazol-2-one-6-yl, 1H-1, 3-benzodiazol-6-yl, 1H-indol-6-yl, 2-difluoro-3, 4-dihydro-2H-indol-3-one-6-yl, 1H-indol-6-yl, and pharmaceutically, 1H-pyrrolo [3,2-b]Pyridin-6-yl, 1-methyl-1H-1, 3-benzooxadiazol-5-yl, 1-methyl-1H-1, 3-benzooxadiazol-6-yl, 1-methyl-1H-benzo [ d ]]Imidazol-5-yl, 2-methyl-1H-benzo [ d]Imidazol-5-yl, 2-oxoindolin-6-yl, 3-dimethyl-2-oxoindolin-6-yl, 3, 4-dihydro-2H-1, 4-benzoxazin-7-yl, 3-amino-1H-indazol-5-yl, 3-amino-1H-indazol-6-yl, 3-carbamoyl-1H-indazol-6-yl, 3-methyl-1H-indazol-6-yl, 3-oxo-3, 4-dihydro-2H-benzo [ b ].][1,4]Oxazin-6-yl, 4- (1-hydroxy-2-methylpropan-2-yl) phenyl, 5-fluoro-1H-indazol-6-yl and indolin-6-yl.

In some embodiments, R₂Selected from: optionally substituted heteroaryl, dihydrobenzoxazinyl optionally substituted with lower alkyl and oxo, and phenyl substituted with one or more groups selected from: optionally substituted alkyl, cyano, nitro, lower alkoxy, halogen, sulfonyl, optionally substituted amino and optionally substituted heteroaryl.

In some embodiments, R₂Selected from: optionally substituted pyridyl, pyrimidinyl, phenylthio, quinolinyl optionally substituted with amino, indazolyl optionally substituted with halogen, carbamoyl, methyl or amino, indolyl, indolinyl optionally substituted with one or two groups selected from lower alkyl and oxo,benzimidazolyl optionally substituted with methyl or amino, benzothiazolyl, benzoxazolyl, benzotriazolyl, quinoxalinyl optionally substituted with amino, quinazolinyl optionally substituted with amino, dihydrobenzoxazinyl optionally substituted with methyl and oxo, 1H-pyrrolo [3,2-b ]]A pyridyl group, and a phenyl group substituted with one or more groups selected from: optionally substituted alkyl, cyano, chloro, fluoro, nitro, methoxy, sulfonyl, heteroaryl, amino and NHC (O) R₁₂Wherein R is₁₂Is a lower alkyl group.

In some embodiments, R₂Selected from: 1H-1, 3-benzodiazol-6-yl, 1H-indol-6-yl, 1H-pyrrolo [3,2-b ] o]Pyridin-6-yl, 1-methyl-1H-1, 3-benzooxadiazol-5-yl, 1-methyl-1H-1, 3-benzooxadiazol-6-yl, 1-methyl-1H-benzo [ d ]]Imidazol-5-yl, 2-methyl-1H-benzo [ d]Imidazol-5-yl, 2-oxoindolin-6-yl, 3-dimethyl-2-oxoindolin-6-yl, 3, 4-dihydro-2H-1, 4-benzoxazin-7-yl, 3-amino-1H-indazol-5-yl, 3-amino-1H-indazol-6-yl, 3-carbamoyl-1H-indazol-6-yl, 3-methyl-1H-indazol-6-yl, 3-oxo-3, 4-dihydro-2H-benzo [ b ].][1,4]Oxazin-6-yl, 4- (1-hydroxy-2-methylpropan-2-yl) phenyl, 5-fluoro-1H-indazol-6-yl and indolin-6-yl.

In some embodiments, R₂Selected from: optionally substituted pyridyl, pyrimidinyl, thiophenyl, quinolinyl optionally substituted with amino, indazolyl optionally substituted with methyl or amino, indolyl, benzimidazolyl optionally substituted with methyl or amino, benzothiazolyl, benzoxazolyl, benzotriazolyl, quinoxalinyl optionally substituted with amino, quinazolinyl optionally substituted with amino, dihydrobenzoxazinyl optionally substituted with methyl and oxo, and phenyl substituted with one or more groups selected from: optionally substituted alkyl, cyano, chloro, fluoro, nitro, methoxy, sulfonyl, heteroaryl, amino and NHC (O) R₁₂Wherein R is₁₂Is a lower alkyl group.

In some embodiments, R₂Selected from: 3-methylphenyl, 4-methylphenyl, 3-nitrophenyl, 3- [ (ethylamino) methyl]Phenyl, 4- [ (ethylamino) methyl]Phenyl group, 3- (trifluoromethyl) phenyl group, 3-methoxyphenyl group, 4-pyridyl group, 3-pyridyl group, 4-cyanophenyl group, 3-cyanophenyl group, 4-chlorophenyl group, 3-chlorophenyl group, 4-chloro-3-methylphenyl group, 3-chloro-4-methylphenyl group, 4-fluorophenyl group, 3-fluorophenyl group, 4-fluoro-3-methylphenyl group, 3-fluoro-4-methylphenyl group, 3, 4-difluorophenyl group, 4-sulfonamidophenyl group (4-sulfonamidiophenyl group), 3-sulfonamidophenyl group (3-sulfonamidiophenyl group), 4-methanesulfonylphenyl group, 3-methanesulfonylphenyl group, 2-fluoropyridin-4-yl group, 5-methylpyridin-3-yl group, a salt thereof, a hydrate thereof, a salt thereof, and a mixture thereof, 5-chloropyridin-3-yl, pyrimidin-5-yl, (4-acetylpiperazin-1-yl) methylphenyl, (3-piperazin-1-ylmethyl) phenyl, (4-piperazin-1-ylmethyl) phenyl, 3-acetylaminophenyl, 4-aminophenyl, 3-aminophenyl, thiophen-3-yl, thiophen-2-yl, 1H-indazol-5-yl, 1H-indazol-6-yl, 3-amino-1H-indazol-5-yl, 1-methyl-1H-indazol-5-yl, pyrimidine-5-yl, 4-acetylpiperazin-1-yl) methylphenyl, (3-acetylaminophenyl, 4-aminophenyl, 3-aminophenyl, thiophen-3-, 1-methyl-1H-indazol-6-yl, 3-methyl-1H-indazol-5-yl, 2, 3-dimethyl-2H-indazol-5-yl, 3-amino-1H-indazol-6-yl, 3-amino-1H-indazol-5-yl, 4- (1H-imidazol-2-yl) phenyl, 4- (1H-imidazol-5-yl) phenyl, 3- (1H-imidazol-5-yl) phenyl, quinolin-6-yl, 2-aminoquinolin-6-yl, 3-aminoquinolin-6-yl, 1, 3-benzothiazol-5-yl, and pharmaceutically acceptable salts thereof, 1, 3-benzothiazol-6-yl, 2-aminoquinazolin-6-yl, 3- (1, 3-thiazol-2-yl) phenyl, 4- (1, 3-thiazol-2-yl) phenyl, 3- (1, 3-thiazol-2-yl) phenyl, 1, 2-dihydropyridin-2-one-5-yl, 4- (1, 3-oxazol-2-yl) phenyl, 3- (1, 3-oxazol-2-yl) phenyl, 2-aminopyridin-5-yl, 1H-1,2, 3-benzotriazol-6-yl, 1H-imidazo [4,5-b ] o]Pyridin-6-yl, 1, 3-benzoxazol-5-yl, 1, 3-benzoxazol-6-yl, 1H-indol-5-yl, 1-methyl-1H-1, 3-benzodiazol-5-yl, 2-amino-1H-1, 3-benzodiazol-6-yl, 1-methyl-1H-1, 3-benzodiazol-6-yl, 2H,3H, 4H-pyrido [3,2-b][1,4]Oxazin-3-one-6-yl, 1H,2H, 3H-pyrido [3,2-b][1,4]Oxazin-3-one-6-yl, 3, 4-dihydro-2H-1, 4-benzoxazin-3-one-7-yl, 4-methyl-3, 4-dihydro-2H-1, 4-benzoxazin-3-one-6-yl, 2-methyl-3, 4-dihydro-2H-1, 4-benzeneOxazin-3-one-6-yl, 2-dimethyl-3, 4-dihydro-2H-1, 4-benzoxazin-3-one-6-yl, 2-hydroxyquinolin-6-yl, 1-methyl-1, 2-dihydropyridin-2-one-5-yl and quinoxalin-2-ol-7-yl.

Also provided is at least one chemical entity selected from the group consisting of:

n- (3, 4-dimethoxyphenyl) -6- (3-methylphenyl) imidazo [1,2-a ] pyrazin-8-amine;

n- (3, 4-dimethoxyphenyl) -6- (3-nitrophenyl) imidazo [1,2-a ] pyrazin-8-amine;

n- (3, 4-dimethoxyphenyl) -6- {3- [ (ethylamino) methyl ] phenyl } imidazo [1,2-a ] pyrazin-8-amine;

n- (3, 4-dimethoxyphenyl) -6- [3- (trifluoromethyl) phenyl ] imidazo [1,2-a ] pyrazin-8-amine;

n- (3, 4-dimethoxyphenyl) -6- (3-methoxyphenyl) imidazo [1,2-a ] pyrazin-8-amine;

n- (3, 4-dimethoxyphenyl) -6- (pyridin-4-yl) imidazo [1,2-a ] pyrazin-8-amine;

n- (3, 4-dimethoxyphenyl) -6- (pyridin-3-yl) imidazo [1,2-a ] pyrazin-8-amine;

n- (3, 4-dimethoxyphenyl) -6-phenylimidazo [1,2-a ] pyrazin-8-amine;

3- {8- [ (3, 4-dimethoxyphenyl) amino ] imidazo [1,2-a ] pyrazin-6-yl } benzonitrile;

n- (3, 4-dimethoxyphenyl) -6- (4-fluorophenyl) imidazo [1,2-a ] pyrazin-8-amine;

4- {8- [ (3, 4-dimethoxyphenyl) amino ] imidazo [1,2-a ] pyrazin-6-yl } benzene-1-sulfonamide;

n- (3, 4-dimethoxyphenyl) -6- {4- [ (ethylamino) methyl ] phenyl } imidazo [1,2-a ] pyrazin-8-amine;

6- (4-chlorophenyl) -N- (3, 4-dimethoxyphenyl) imidazo [1,2-a ] pyrazin-8-amine;

6- (3-chlorophenyl) -N- (4-ethoxy-3-methoxyphenyl) imidazo [1,2-a ] pyrazin-8-amine;

n- (3, 4-dimethoxyphenyl) -6- (4-methanesulfonylphenyl) imidazo [1,2-a ] pyrazin-8-amine;

4- {8- [ (3, 4-dimethoxyphenyl) amino ] imidazo [1,2-a ] pyrazin-6-yl } benzonitrile;

n- (3, 4-dimethoxyphenyl) -6- (4-methylphenyl) imidazo [1,2-a ] pyrazin-8-amine;

n- (4-ethoxy-3-methoxyphenyl) -6- (3-methylphenyl) imidazo [1,2-a ] pyrazin-8-amine;

n- (4-ethoxy-3-methoxyphenyl) -6- (3-fluorophenyl) imidazo [1,2-a ] pyrazin-8-amine;

6- (3, 4-difluorophenyl) -N- (4-ethoxy-3-methoxyphenyl) imidazo [1,2-a ] pyrazin-8-amine;

6- (4-chloro-3-methylphenyl) -N- (4-ethoxy-3-methoxyphenyl) imidazo [1,2-a ] pyrazin-8-amine;

3- {8- [ (4-ethoxy-3-methoxyphenyl) amino ] imidazo [1,2-a ] pyrazin-6-yl } benzene-1-sulfonamide;

n- (4-ethoxy-3-methoxyphenyl) -6- (3-methanesulfonylphenyl) imidazo [1,2-a ] pyrazin-8-amine;

n- (4-ethoxy-3-methoxyphenyl) -6- (4-fluoro-3-methylphenyl) imidazo [1,2-a ] pyrazin-8-amine;

n- (4-ethoxy-3-methoxyphenyl) -6- (3-fluoro-4-methylphenyl) imidazo [1,2-a ] pyrazin-8-amine;

6- (3-chloro-4-methylphenyl) -N- (4-ethoxy-3-methoxyphenyl) imidazo [1,2-a ] pyrazin-8-amine;

n- (4-ethoxy-3-methoxyphenyl) -6- (2-fluoropyridin-4-yl) imidazo [1,2-a ] pyrazin-8-amine;

n- (4-ethoxy-3-methoxyphenyl) -6- (5-methylpyridin-3-yl) imidazo [1,2-a ] pyrazin-8-amine;

6- (5-chloropyridin-3-yl) -N- (4-ethoxy-3-methoxyphenyl) imidazo [1,2-a ] pyrazin-8-amine;

n- (4-ethoxy-3-methoxyphenyl) -6- (pyrimidin-5-yl) imidazo [1,2-a ] pyrazin-8-amine;

1- {4- [ (4- {8- [ (4-ethoxy-3-methoxyphenyl) amino ] imidazo [1,2-a ] pyrazin-6-yl } phenyl) methyl ] piperazin-1-yl } ethan-1-one;

1- {4- [ (3- {8- [ (3, 4-dimethoxyphenyl) amino ] imidazo [1,2-a ] pyrazin-6-yl } phenyl) methyl ] piperazin-1-yl } ethan-1-one;

n- (3, 4-dimethoxyphenyl) -6- [3- (piperazin-1-ylmethyl) phenyl ] imidazo [1,2-a ] pyrazin-8-amine;

n- (3, 4-dimethoxyphenyl) -6- [4- (piperazin-1-ylmethyl) phenyl ] imidazo [1,2-a ] pyrazin-8-amine;

6- (2, 3-dihydro-1, 4-benzodioxin-6-yl) -N- (3, 4-dimethoxyphenyl) imidazo [1,2-a ] pyrazin-8-amine;

n- (3- {8- [ (3, 4-dimethoxyphenyl) amino ] imidazo [1,2-a ] pyrazin-6-yl } phenyl) acetamide;

6- (3-aminophenyl) -N- (3, 4-dimethoxyphenyl) imidazo [1,2-a ] pyrazin-8-amine;

n- (4- {8- [ (3, 4-dimethoxyphenyl) amino ] imidazo [1,2-a ] pyrazin-6-yl } phenyl) acetamide;

n- (3, 4-dimethoxyphenyl) -6- (thiophen-3-yl) imidazo [1,2-a ] pyrazin-8-amine;

n- (3, 4-dimethoxyphenyl) -6- (1H-indazol-5-yl) imidazo [1,2-a ] pyrazin-8-amine;

n- (3, 4-dimethoxyphenyl) -6- [4- (1H-imidazol-2-yl) phenyl ] imidazo [1,2-a ] pyrazin-8-amine;

n- (3, 4-dimethoxyphenyl) -6- (quinolin-6-yl) imidazo [1,2-a ] pyrazin-8-amine;

n- (3, 4-dimethoxyphenyl) -6- (1H-indazol-6-yl) imidazo [1,2-a ] pyrazin-8-amine;

6- {8- [ (3, 4-dimethoxyphenyl) amino ] imidazo [1,2-a ] pyrazin-6-yl } -3, 4-dihydro-2H-1, 4-benzoxazin-3-one;

6- (1, 3-benzothiazol-5-yl) -N- (3, 4-dimethoxyphenyl) imidazo [1,2-a ] pyrazin-8-amine;

6- (1, 3-benzothiazol-6-yl) -N- (3, 4-dimethoxyphenyl) imidazo [1,2-a ] pyrazin-8-amine;

6- {8- [ (3, 4-dimethoxyphenyl) amino ] imidazo [1,2-a ] pyrazin-6-yl } quinazolin-2-amine;

n- (3, 4-dimethoxyphenyl) -6- (thiophen-2-yl) imidazo [1,2-a ] pyrazin-8-amine;

3-amino-5- {8- [ (3, 4-dimethoxyphenyl) amino ] imidazo [1,2-a ] pyrazin-6-yl } -1-methyl-1, 2-dihydropyridin-2-one;

6- {8- [ (3, 4-dimethoxyphenyl) amino ] imidazo [1,2-a ] pyrazin-6-yl } quinolin-2-amine;

6- (4-aminophenyl) -N- (3, 4-dimethoxyphenyl) imidazo [1,2-a ] pyrazin-8-amine;

6- (1H-1, 3-benzodiazol-5-yl) -N- (3, 4-dimethoxyphenyl) imidazo [1,2-a ] pyrazin-8-amine;

n- (3, 4-dimethoxyphenyl) -6- [3- (1H-imidazol-5-yl) phenyl ] imidazo [1,2-a ] pyrazin-8-amine;

7- {8- [ (3, 4-dimethoxyphenyl) amino ] imidazo [1,2-a ] pyrazin-6-yl } -3, 4-dihydro-2H-1, 4-benzoxazin-3-one;

n- (4-ethoxy-3-methoxyphenyl) -6- (1H-indazol-5-yl) imidazo [1,2-a ] pyrazin-8-amine;

n- (3, 4-dimethoxyphenyl) -6- [4- (1H-imidazol-5-yl) phenyl ] imidazo [1,2-a ] pyrazin-8-amine;

n- (4-ethoxy-3-methoxyphenyl) -6- (1H-indazol-6-yl) imidazo [1,2-a ] pyrazin-8-amine;

6- (1, 3-benzothiazol-6-yl) -N- (4-ethoxy-3-methoxyphenyl) imidazo [1,2-a ] pyrazin-8-amine;

n- (3, 4-dimethoxyphenyl) -6- [3- (1, 3-thiazol-2-yl) phenyl ] imidazo [1,2-a ] pyrazin-8-amine;

n- (3, 4-dimethoxyphenyl) -6- (1-methyl-1H-1, 3-benzooxadiazol-5-yl) imidazo [1,2-a ] pyrazin-8-amine;

5- {8- [ (3, 4-dimethoxyphenyl) amino ] imidazo [1,2-a ] pyrazin-6-yl } -1, 2-dihydropyridin-2-one;

6- (1, 3-benzothiazol-5-yl) -N- (4-ethoxy-3-methoxyphenyl) imidazo [1,2-a ] pyrazin-8-amine;

n- (3, 4-dimethoxyphenyl) -6- [4- (1, 3-oxazol-2-yl) phenyl ] imidazo [1,2-a ] pyrazin-8-amine;

(3- { [6- (1H-indazol-6-yl) imidazo [1,2-a ] pyrazin-8-yl ] amino } phenyl) methanol;

5- {8- [ (3, 4-dimethoxyphenyl) amino ] imidazo [1,2-a ] pyrazin-6-yl } pyridin-2-amine;

n- (3, 4-dimethoxyphenyl) -6- [3- (1, 3-oxazol-2-yl) phenyl ] imidazo [1,2-a ] pyrazin-8-amine;

n- [6- (1H-indazol-6-yl) imidazo [1,2-a ] pyrazin-8-yl ] -3, 4-dihydro-2H-1, 4-benzoxazin-6-amine;

1- (4- { [6- (1H-indazol-6-yl) imidazo [1,2-a ] pyrazin-8-yl ] amino } phenyl) ethan-1-ol;

n- (3, 4-dimethoxyphenyl) -6- [4- (1, 3-thiazol-2-yl) phenyl ] imidazo [1,2-a ] pyrazin-8-amine;

(5- { [6- (1H-indazol-6-yl) imidazo [1,2-a ] pyrazin-8-yl ] amino } -2-methoxyphenyl) methanol;

n- (3, 4-dimethoxyphenyl) -6- (1H-indol-6-yl) imidazo [1,2-a ] pyrazin-8-amine;

n- (3, 4-dimethoxyphenyl) -6- (1-methyl-1H-1, 3-benzooxadiazol-6-yl) imidazo [1,2-a ] pyrazin-8-amine;

n- (4-ethoxy-3-methoxyphenyl) -6- (1-methyl-1H-indazol-5-yl) imidazo [1,2-a ] pyrazin-8-amine;

n- (4-ethoxy-3-methoxyphenyl) -6- (1-methyl-1H-indazol-6-yl) imidazo [1,2-a ] pyrazin-8-amine;

n- (3, 4-dimethoxyphenyl) -6- (1-methyl-1H-indazol-5-yl) imidazo [1,2-a ] pyrazin-8-amine;

6- (1H-1,2, 3-benzotriazol-6-yl) -N- (3, 4-dimethoxyphenyl) imidazo [1,2-a ] pyrazin-8-amine;

n- (3, 4-dimethoxyphenyl) -6- { 1H-imidazo [4,5-b ] pyridin-6-yl } imidazo [1,2-a ] pyrazin-8-amine;

6- (1, 3-benzoxazol-5-yl) -N- (3, 4-dimethoxyphenyl) imidazo [1,2-a ] pyrazin-8-amine;

6- (1, 3-benzoxazol-6-yl) -N- (3, 4-dimethoxyphenyl) imidazo [1,2-a ] pyrazin-8-amine;

6- {8- [ (3, 4-dimethoxyphenyl) amino ] imidazo [1,2-a ] pyrazin-6-yl } -4-methyl-3, 4-dihydro-2H-1, 4-benzoxazin-3-one;

n- (3, 4-dimethoxyphenyl) -6- (1-methyl-1H-indazol-6-yl) imidazo [1,2-a ] pyrazin-8-amine;

n- (3, 4-dimethoxyphenyl) -6- (1H-indol-5-yl) imidazo [1,2-a ] pyrazin-8-amine;

6- {8- [ (3, 4-dimethoxyphenyl) amino ] imidazo [1,2-a ] pyrazin-6-yl } quinolin-3-amine;

2- (4- { [6- (1H-indazol-6-yl) imidazo [1,2-a ] pyrazin-8-yl ] amino } phenyl) propan-2-ol;

5- {8- [ (3, 4-dimethoxyphenyl) amino ] imidazo [1,2-a ] pyrazin-6-yl } -1H-indazol-3-amine;

6- {8- [ (3, 4-dimethoxyphenyl) amino ] imidazo [1,2-a ] pyrazin-6-yl } -1H-1, 3-benzooxadiazol-2-amine;

6- {8- [ (3, 4-dimethoxyphenyl) amino ] imidazo [1,2-a ] pyrazin-6-yl } -2H,3H, 4H-pyrido [3,2-b ] [1,4] oxazin-3-one;

6- {8- [ (3, 4-dimethoxyphenyl) amino ] imidazo [1,2-a ] pyrazin-6-yl } -2-methyl-3, 4-dihydro-2H-1, 4-benzoxazin-3-one;

6- {8- [ (3, 4-dimethoxyphenyl) amino ] imidazo [1,2-a ] pyrazin-6-yl } -2, 2-dimethyl-3, 4-dihydro-2H-1, 4-benzoxazin-3-one;

7- {8- [ (3, 4-dimethoxyphenyl) amino ] imidazo [1,2-a ] pyrazin-6-yl } quinolin-2-ol;

2- (4- { [6- (1H-indazol-6-yl) imidazo [1,2-a ] pyrazin-8-yl ] amino } phenyl) -2-methylpropan-1-ol;

6- {8- [ (3, 4-dimethoxyphenyl) amino ] imidazo [1,2-a ] pyrazin-6-yl } -1H-indazol-3-amine;

(4- { [6- (1H-indazol-6-yl) imidazo [1,2-a ] pyrazin-8-yl ] amino } -2-methoxyphenyl) methanol;

6- (2, 3-dihydro-1H-indol-6-yl) -N- (3, 4-dimethoxyphenyl) imidazo [1,2-a ] pyrazin-8-amine;

n- [6- (3-amino-1H-indazol-5-yl) imidazo [1,2-a ] pyrazin-8-yl ] -3, 4-dihydro-2H-1, 4-benzoxazin-6-amine;

n- {4- [3- (dimethylamino) propoxy ] -3-methoxyphenyl } -6- (1H-indazol-6-yl) imidazo [1,2-a ] pyrazin-8-amine;

3- (4- { [6- (1H-indazol-6-yl) imidazo [1,2-a ] pyrazin-8-yl ] amino } -2-methoxyphenoxy) propan-1-ol;

6- (1H-indazol-6-yl) -N- [ 4-methoxy-3- (pyrrolidin-1-yl) phenyl ] imidazo [1,2-a ] pyrazin-8-amine;

5- { [6- (1H-indazol-6-yl) imidazo [1,2-a ] pyrazin-8-yl ] amino } -2, 3-dihydro-1H-indol-2-one;

7- {8- [ (3, 4-dimethoxyphenyl) amino ] imidazo [1,2-a ] pyrazin-6-yl } quinoxalin-2-ol;

7- {8- [ (3, 4-dimethoxyphenyl) amino ] imidazo [1,2-a ] pyrazin-6-yl } -1H,2H, 3H-pyrido [2,3-b ] [1,4] oxazin-2-one;

n- [6- (1H-indazol-6-yl) imidazo [1,2-a ] pyrazin-8-yl ] -4-methyl-3, 4-dihydro-2H-1, 4-benzoxazin-7-amine;

n- (2-fluoro-4-methoxyphenyl) -6- (1H-indazol-6-yl) imidazo [1,2-a ] pyrazin-8-amine;

6- (1H-indazol-6-yl) -N- [ 3-methoxy-4- (pyrrolidin-1-yl) phenyl ] imidazo [1,2-a ] pyrazin-8-amine;

n- [6- (1H-indazol-6-yl) imidazo [1,2-a]Pyrazin-8-yl radical]-2,3,4, 5-tetrahydro-1, 5-benzoxaazepine-7-amine;

1- (4- { [6- (3-amino-1H-indazol-6-yl) imidazo [1,2-a ] pyrazin-8-yl ] amino } phenyl) ethan-1-ol;

6- (3, 4-dihydro-2H-1, 4-benzoxazin-6-yl) -N- (3, 4-dimethoxyphenyl) imidazo [1,2-a ] pyrazin-8-amine;

n- [6- (1H-indazol-6-yl) imidazo [1,2-a ] pyrazin-8-yl ] -4-methyl-3, 4-dihydro-2H-1, 4-benzoxazin-6-amine;

6- { [6- (1H-indazol-6-yl) imidazo [1,2-a ] pyrazin-8-yl ] amino } -2, 3-dihydro-1H-indol-2-one;

n- (3, 4-dimethoxyphenyl) -6- { 1H-pyrrolo [3,2-b ] pyridin-6-yl } imidazo [1,2-a ] pyrazin-8-amine;

n- [6- (1H-indazol-6-yl) imidazo [1,2-a ] pyrazin-8-yl ] -3, 4-dihydro-2H-1, 4-benzoxazin-7-amine;

6- {8- [ (4-ethoxy-3-methoxyphenyl) amino ] imidazo [1,2-a ] pyrazin-6-yl } -1H-indazol-3-amine;

n- [6- (2-aminoquinazolin-6-yl) imidazo [1,2-a ] pyrazin-8-yl ] -4-methyl-3, 4-dihydro-2H-1, 4-benzoxazin-6-amine;

2-methyl-2- (4- { [6- (1-methyl-1H-1, 3-benzodiazol-5-yl) imidazo [1,2-a ] pyrazin-8-yl ] amino } phenyl) propan-1-ol;

6- (3, 4-dihydro-2H-1, 4-benzoxazin-6-yl) -N- (4-ethoxy-3-methoxyphenyl) imidazo [1,2-a ] pyrazin-8-amine;

n- [6- (2, 3-dihydro-1H-indol-6-yl) imidazo [1,2-a ] pyrazin-8-yl ] -3, 4-dihydro-2H-1, 4-benzoxazin-6-amine;

(2-methoxy-5- { [6- (1-methyl-1H-1, 3-benzodiazol-6-yl) imidazo [1,2-a ] pyrazin-8-yl ] amino } phenyl) methanol;

6- (1H-indazol-6-yl) -N- {4- [ 2-methyl-1- (morpholin-4-yl) propan-2-yl ] phenyl } imidazo [1,2-a ] pyrazin-8-amine;

n- [6- (1H-indol-6-yl) imidazo [1,2-a ] pyrazin-8-yl ] -3, 4-dihydro-2H-1, 4-benzoxazin-6-amine;

7- {8- [ (4-methyl-3, 4-dihydro-2H-1, 4-benzoxazin-7-yl) amino ] imidazo [1,2-a ] pyrazin-6-yl } quinoxalin-2-ol;

1- (4- { [6- (1, 3-benzothiazol-5-yl) imidazo [1,2-a ] pyrazin-8-yl ] amino } phenyl) ethan-1-ol;

6- (1H-1,2, 3-benzotriazol-6-yl) -N- [ 3-methoxy-4- (propan-2-yloxy) phenyl ] imidazo [1,2-a ] pyrazin-8-amine;

5- (8- { [ 3-methoxy-4- (pyrrolidin-1-yl) phenyl ] amino } imidazo [1,2-a ] pyrazin-6-yl) -1H-indazol-3-amine;

2- (4- { [6- (2-aminoquinazolin-6-yl) imidazo [1,2-a ] pyrazin-8-yl ] amino } phenyl) propan-2-ol;

6- (1H-indazol-6-yl) -N- [ 3-methoxy-4- (morpholin-4-yl) phenyl ] imidazo [1,2-a ] pyrazin-8-amine;

2- (4- { [6- (1, 3-benzothiazol-5-yl) imidazo [1,2-a ] pyrazin-8-yl ] amino } phenyl) propan-2-ol;

6- (8- { [4- (2-hydroxypropan-2-yl) phenyl ] amino } imidazo [1,2-a ] pyrazin-6-yl) -3, 4-dihydro-2H-1, 4-benzoxazin-3-one;

6- (1H-indazol-6-yl) -N- (3-methoxyphenyl) imidazo [1,2-a ] pyrazin-8-amine;

6- (1H-indazol-6-yl) -N- (4-methoxyphenyl) imidazo [1,2-a ] pyrazin-8-amine;

2- (4- { [6- (1-methyl-1H-1, 3-benzodiazol-5-yl) imidazo [1,2-a ] pyrazin-8-yl ] amino } phenyl) propan-2-ol;

2- (4- { [6- (1-methyl-1H-1, 3-benzodiazol-6-yl) imidazo [1,2-a ] pyrazin-8-yl ] amino } phenyl) propan-2-ol;

1- (4- { [6- (1H-indazol-6-yl) imidazo [1,2-a ] pyrazin-8-yl ] amino } -2-methoxyphenyl) piperidin-4-ol;

6- (1H-indazol-6-yl) -N- [4- (pyrrolidin-1-yl) phenyl ] imidazo [1,2-a ] pyrazin-8-amine;

1- (4- { [6- (1H-indazol-6-yl) imidazo [1,2-a ] pyrazin-8-yl ] amino } phenyl) pyrrolidin-3-ol;

2- (4- { [6- (4-methyl-3, 4-dihydro-2H-1, 4-benzoxazin-7-yl) imidazo [1,2-a ] pyrazin-8-yl ] amino } phenyl) propan-2-ol;

2- (4- { [6- (3, 4-dihydro-2H-1, 4-benzoxazin-6-yl) imidazo [1,2-a ] pyrazin-8-yl ] amino } phenyl) propan-2-ol;

2- (4- { [6- (1, 4-dimethyl-1, 2,3, 4-tetrahydroquinoxalin-6-yl) imidazo [1,2-a ] pyrazin-8-yl ] amino } phenyl) propan-2-ol;

1- (4- { [6- (1H-indazol-6-yl) imidazo [1,2-a ] pyrazin-8-yl ] amino } -2-methoxyphenyl) azetidin-3-ol;

2- (4- { [6- (1H-indol-6-yl) imidazo [1,2-a ] pyrazin-8-yl ] amino } phenyl) propan-2-ol

2- (4- { [6- (3, 4-dihydro-2H-1, 4-benzoxazin-7-yl) imidazo [1,2-a ] pyrazin-8-yl ] amino } phenyl) propan-2-ol;

2- (4- { [6- (4-methyl-3, 4-dihydro-2H-1, 4-benzoxazin-6-yl) imidazo [1,2-a ] pyrazin-8-yl ] amino } phenyl) propan-2-ol;

2- (4- { [6- (2, 3-dimethyl-2H-indazol-5-yl) imidazo [1,2-a ] pyrazin-8-yl ] amino } phenyl) propan-2-ol;

2- (4- { [6- (3-methyl-1H-indazol-5-yl) imidazo [1,2-a ] pyrazin-8-yl ] amino } phenyl) propan-2-ol;

n- [ 3-methoxy-4- (morpholin-4-yl) phenyl ] -6- (1-methyl-1H-1, 3-benzodiazol-6-yl) imidazo [1,2-a ] pyrazin-8-amine;

6- (8- { [ 3-methoxy-4- (morpholin-4-yl) phenyl ] amino } imidazo [1,2-a ] pyrazin-6-yl) quinazolin-2-amine;

1- (4- { [6- (1H-indazol-6-yl) imidazo [1,2-a ] pyrazin-8-yl ] amino } phenyl) azetidin-3-ol;

1- (4- { [6- (1H-indazol-6-yl) imidazo [1,2-a ] pyrazin-8-yl ] amino } -2-methoxyphenyl) pyrrolidin-3-ol;

6- (3, 4-dihydro-2H-1, 4-benzoxazin-6-yl) -N- [ 3-methoxy-4- (morpholin-4-yl) phenyl ] imidazo [1,2-a ] pyrazin-8-amine;

6- (1H-indazol-6-yl) -N- [4- (2-methoxypropan-2-yl) phenyl ] imidazo [1,2-a ] pyrazin-8-amine;

n- (4-ethoxy-3-methoxyphenyl) -6- (1H-indol-6-yl) imidazo [1,2-a ] pyrazin-8-amine;

n- [ 3-methoxy-4- (morpholin-4-yl) phenyl ] -6- (1-methyl-1H-1, 3-benzodiazol-5-yl) imidazo [1,2-a ] pyrazin-8-amine;

n- [4- (4-ethylpiperazin-1-yl) -3-methoxyphenyl ] -6- (1H-indazol-6-yl) imidazo [1,2-a ] pyrazin-8-amine;

1- (4- { [6- (1H-indazol-6-yl) imidazo [1,2-a ] pyrazin-8-yl ] amino } phenyl) -3-methylpiperidin-3-ol; and

n- [4- (4-ethylpiperazin-1-yl) phenyl ] -6- (1H-indazol-6-yl) imidazo [1,2-a ] pyrazin-8-amine.

6- (8- { [ 3-methoxy-4- (morpholin-4-yl) phenyl ] amino } imidazo [1,2-a ] pyrazin-6-yl) -1H-indazol-3-amine;

5- (8- { [ 3-methoxy-4- (morpholin-4-yl) phenyl ] amino } imidazo [1,2-a ] pyrazin-6-yl) -1H-indazol-3-amine;

6- (8- { [4- (2-hydroxypropan-2-yl) phenyl ] amino } imidazo [1,2-a ] pyrazin-6-yl) -2, 3-dihydro-1H-indol-2-one;

1- (4- { [6- (1H-indazol-6-yl) imidazo [1,2-a ] pyrazin-8-yl ] amino } phenyl) piperidin-4-ol;

1- (4- { [6- (1H-indazol-6-yl) imidazo [1,2-a ] pyrazin-8-yl ] amino } -2-methoxyphenoxy) -2-methylpropan-2-ol;

1- (4- { [6- (1H-indazol-6-yl) imidazo [1,2-a ] pyrazin-8-yl ] amino } -2-methoxyphenyl) -4-methylpiperidin-4-ol;

2- [ (4- { [6- (1H-indazol-6-yl) imidazo [1,2-a ] pyrazin-8-yl ] amino } -2-methoxyphenyl) (methyl) amino ] ethan-1-ol;

1- (4- { [6- (1H-indazol-6-yl) imidazo [1,2-a ] pyrazin-8-yl ] amino } phenyl) -4-methylpiperidin-4-ol;

4- { [6- (1H-indazol-6-yl) imidazo [1,2-a ] pyrazin-8-yl ] amino } phenol;

2- (4- { [6- (2, 3-dihydro-1H-indol-6-yl) imidazo [1,2-a ] pyrazin-8-yl ] amino } phenyl) propan-2-ol;

1- (4- { [6- (1H-indazol-6-yl) imidazo [1,2-a ] pyrazin-8-yl ] amino } phenyl) -3-methylpyrrolidin-3-ol;

n- [ 3-methoxy-4- (morpholin-4-yl) phenyl ] -6- (2-methyl-1H-1, 3-benzodiazol-5-yl) imidazo [1,2-a ] pyrazin-8-amine;

n- (4-ethoxy-3-methoxyphenyl) -6- (1-methyl-1H-1, 3-benzooxadiazol-5-yl) imidazo [1,2-a ] pyrazin-8-amine;

(3R) -1- (4- { [6- (1H-indazol-6-yl) imidazo [1,2-a ] pyrazin-8-yl ] amino } phenyl) pyrrolidin-3-ol;

(3R) -1- (4- { [6- (1H-indazol-6-yl) imidazo [1,2-a ] pyrazin-8-yl ] amino } -2-methoxyphenyl) pyrrolidin-3-ol;

(3S) -1- (4- { [6- (1H-indazol-6-yl) imidazo [1,2-a ] pyrazin-8-yl ] amino } -2-methoxyphenyl) pyrrolidin-3-ol;

[4- (4- { [6- (1H-indazol-6-yl) imidazo [1,2-a ] pyrazin-8-yl ] amino } phenyl) morpholin-2-yl ] methanol;

n- (4-ethoxy-3-methoxyphenyl) -6- (1-methyl-1H-1, 3-benzooxadiazol-6-yl) imidazo [1,2-a ] pyrazin-8-amine;

6- (5-fluoro-1H-indazol-6-yl) -N- [ 3-methoxy-4- (morpholin-4-yl) phenyl ] imidazo [1,2-a ] pyrazin-8-amine;

2- [1- (4- { [6- (1H-indazol-6-yl) imidazo [1,2-a ] pyrazin-8-yl ] amino } phenyl) piperidin-4-yl ] propan-2-ol;

(3S) -1- (4- { [6- (1H-indazol-6-yl) imidazo [1,2-a ] pyrazin-8-yl ] amino } phenyl) pyrrolidin-3-ol;

n- [ 3-methoxy-4- (morpholin-4-yl) phenyl ] -6- (3-methyl-1H-indazol-6-yl) imidazo [1,2-a ] pyrazin-8-amine;

1- (4- { [6- (1H-indazol-6-yl) imidazo [1,2-a ] pyrazin-8-yl ] amino } -2-methoxyphenyl) -3-methylpyrrolidin-3-ol;

6- (1H-1, 3-benzodiazol-6-yl) -N- (4-ethoxy-3-methoxyphenyl) imidazo [1,2-a ] pyrazin-8-amine;

6- (8- { [ 3-methoxy-4- (morpholin-4-yl) phenyl ] amino } imidazo [1,2-a ] pyrazin-6-yl) -2, 3-dihydro-1H-indol-2-one;

6- (8- { [ 3-methoxy-4- (morpholin-4-yl) phenyl ] amino } imidazo [1,2-a ] pyrazin-6-yl) -3, 3-dimethyl-2, 3-dihydro-1H-indol-2-one;

n- (4-ethoxy-3-methoxyphenyl) -6- { 1H-pyrrolo [3,2-b ] pyridin-6-yl } imidazo [1,2-a ] pyrazin-8-amine;

4-N- [6- (1H-indazol-6-yl) imidazo [1,2-a ] pyrazin-8-yl ] -2-methoxy-1-N- (2-methoxyethyl) -1-N-methylbenzene-1, 4-diamine;

4-methyl-1- (4- { [6- (1-methyl-1H-1, 3-benzodiazol-6-yl) imidazo [1,2-a ] pyrazin-8-yl ] amino } phenyl) piperidin-4-ol;

6- (3, 4-dihydro-2H-1, 4-benzoxazin-7-yl) -N- [ 3-methoxy-4- (morpholin-4-yl) phenyl ] imidazo [1,2-a ] pyrazin-8-amine;

6- (8- { [4- (1-hydroxy-2-methylpropan-2-yl) phenyl ] amino } imidazo [1,2-a ] pyrazin-6-yl) -3, 4-dihydro-2H-1, 4-benzoxazin-3-one;

1- (4- { [6- (1H-1, 3-benzodiazol-6-yl) imidazo [1,2-a ] pyrazin-8-yl ] amino } phenyl) -2-methylpropan-2-ol;

n- [ 3-methoxy-4- (morpholin-4-yl) phenyl ] -6- { 1H-pyrrolo [3,2-b ] pyridin-6-yl } imidazo [1,2-a ] pyrazin-8-amine;

2- (4- { [6- (1H-1, 3-benzodiazol-6-yl) imidazo [1,2-a ] pyrazin-8-yl ] amino } phenyl) -1,1,1,3,3, 3-hexafluoropropan-2-ol;

2-methyl-2- (4- { [6- (1-methyl-1H-1, 3-benzodiazol-6-yl) imidazo [1,2-a ] pyrazin-8-yl ] amino } phenyl) propan-1-ol;

2-methyl-2- {4- [ (6- { 1H-pyrrolo [3,2-b ] pyridin-6-yl } imidazo [1,2-a ] pyrazin-8-yl) amino ] phenyl } propan-1-ol;

2,2, 2-trifluoro-1- (4- { [6- (1H-indazol-6-yl) imidazo [1,2-a ] pyrazin-8-yl ] amino } phenyl) ethan-1-ol;

2- (4- { [6- (3, 4-dihydro-2H-1, 4-benzoxazin-6-yl) imidazo [1,2-a ] pyrazin-8-yl ] amino } phenyl) -2-methylpropan-1-ol;

6- (8- { [4- (4-hydroxy-4-methylpiperidin-1-yl) phenyl ] amino } imidazo [1,2-a ] pyrazin-6-yl) -3, 4-dihydro-2H-1, 4-benzoxazin-3-one;

4-methyl-1- {4- [ (6- { 1H-pyrrolo [3,2-b ] pyridin-6-yl } imidazo [1,2-a ] pyrazin-8-yl) amino ] phenyl } piperidin-4-ol;

1- (4- { [6- (1H-1, 3-benzodiazol-6-yl) imidazo [1,2-a ] pyrazin-8-yl ] amino } phenyl) -4-methylpiperidin-4-ol;

6- (1H-indazol-6-yl) -N- [4- (1-methoxy-2-methylpropan-2-yl) phenyl ] imidazo [1,2-a ] pyrazin-8-amine;

4-methyl-1- (4- { [6- (1-methyl-1H-1, 3-benzodiazol-5-yl) imidazo [1,2-a ] pyrazin-8-yl ] amino } phenyl) piperidin-4-ol;

6- (1H-1, 3-benzodiazol-6-yl) -N- [ 3-methoxy-4- (morpholin-4-yl) phenyl ] imidazo [1,2-a ] pyrazin-8-amine;

1,1, 1-trifluoro-2- (4- { [6- (1H-indazol-6-yl) imidazo [1,2-a ] pyrazin-8-yl ] amino } phenyl) propan-2-ol;

1- (4- { [6- (1H-indazol-6-yl) imidazo [1,2-a ] pyrazin-8-yl ] amino } phenyl) -2-methylpropan-2-ol;

1- (4- { [6- (1H-indazol-6-yl) imidazo [1,2-a ] pyrazin-8-yl ] amino } phenyl) cyclobutane-1-ol;

1- (4- { [6- (1H-indazol-6-yl) imidazo [1,2-a ] pyrazin-8-yl ] amino } -2-methoxyphenyl) -3-methylpiperidin-3-ol;

4-N- [6- (1H-indazol-6-yl) imidazo [1,2-a ] pyrazin-8-yl ] -1-N- (2-methoxyethyl) -1-N-methylbenzene-1, 4-diamine;

6- {8- [ (4-ethoxy-3-methoxyphenyl) amino ] imidazo [1,2-a ] pyrazin-6-yl } -1H-indazole-3-carboxamide;

2- [ (4- { [6- (1H-indazol-6-yl) imidazo [1,2-a ] pyrazin-8-yl ] amino } phenyl) (methyl) amino ] ethan-1-ol;

1- (4- { [6- (3, 4-dihydro-2H-1, 4-benzoxazin-6-yl) imidazo [1,2-a ] pyrazin-8-yl ] amino } phenyl) -4-methylpiperidin-4-ol;

6- (1H-indazol-6-yl) -N- [4- (morpholin-4-yl) phenyl ] imidazo [1,2-a ] pyrazin-8-amine;

n- [4- (morpholin-4-yl) phenyl ] -6- { 1H-pyrrolo [3,2-b ] pyridin-6-yl } imidazo [1,2-a ] pyrazin-8-amine;

1- (4- { [6- (1H-indazol-6-yl) imidazo [1,2-a ] pyrazin-8-yl ] amino } phenyl) piperidin-3-ol;

6- (1H-indol-6-yl) -N- [4- (morpholin-4-yl) phenyl ] imidazo [1,2-a ] pyrazin-8-amine;

2- (4- { [6- (1H-1, 3-benzodiazol-6-yl) imidazo [1,2-a ] pyrazin-8-yl ] amino } phenyl) -2-methylpropan-1-ol;

6- (8- { [4- (1-hydroxy-2-methylpropan-2-yl) phenyl ] amino } imidazo [1,2-a ] pyrazin-6-yl) -2, 3-dihydro-1H-indol-2-one;

2- (4- { [6- (1H-indol-6-yl) imidazo [1,2-a ] pyrazin-8-yl ] amino } phenyl) -2-methylpropan-1-ol;

6- {8- [ (4-ethoxy-3-methoxyphenyl) amino ] imidazo [1,2-a ] pyrazin-6-yl } -2, 3-dihydro-1H-indol-2-one;

2- (4- { [6- (3-amino-1H-indazol-6-yl) imidazo [1,2-a ] pyrazin-8-yl ] amino } phenyl) -2-methylpropan-1-ol;

5- {8- [ (4-ethoxy-3-methoxyphenyl) amino ] imidazo [1,2-a ] pyrazin-6-yl } -1H-indazol-3-amine; and

2- (4- { [6- (3-amino-1H-indazol-5-yl) imidazo [1,2-a ] pyrazin-8-yl ] amino } phenyl) -2-methylpropan-1-ol.

(3S) -1- (4- { [6- (1H-indazol-6-yl) imidazo [1,2-a ] pyrazin-8-yl ] amino } -2-methoxyphenyl) -3-methylpyrrolidin-3-ol;

(3R) -1- (4- { [6- (1H-indazol-6-yl) imidazo [1,2-a ] pyrazin-8-yl ] amino } -2-methoxyphenyl) -3-methylpyrrolidin-3-ol;

7- (8- { [4- (morpholin-4-yl) phenyl ] amino } imidazo [1,2-a ] pyrazin-6-yl) -1, 2-dihydroquinoxalin-2-one;

n, N-dimethyl-6- (8- { [4- (morpholin-4-yl) phenyl ] amino } imidazo [1,2-a ] pyrazin-6-yl) -1H-indazole-3-carboxamide;

5- (8- { [4- (morpholin-4-yl) phenyl ] amino } imidazo [1,2-a ] pyrazin-6-yl) -2, 3-dihydro-1H-1, 3-benzodiazol-2-one;

1- (4- { [6- (3, 4-dihydro-2H-1, 4-benzoxazin-6-yl) imidazo [1,2-a ] pyrazin-8-yl ] amino } phenyl) -2-methylpropan-2-ol;

n-methyl-2- (4- { [6- (2-oxo-2, 3-dihydro-1H-indol-6-yl) imidazo [1,2-a ] pyrazin-8-yl ] amino } phenoxy) acetamide;

n- [3- (8- { [4- (morpholin-4-yl) phenyl ] amino } imidazo [1,2-a ] pyrazin-6-yl) phenyl ] methanesulfonamide;

n- [4- (8- { [4- (morpholin-4-yl) phenyl ] amino } imidazo [1,2-a ] pyrazin-6-yl) phenyl ] methanesulfonamide;

[ (2S) -4- (4- { [6- (1H-indazol-6-yl) imidazo [1,2-a ] pyrazin-8-yl ] amino } phenyl) morpholin-2-yl ] methanol;

[ (2R) -4- (4- { [6- (1H-indazol-6-yl) imidazo [1,2-a ] pyrazin-8-yl ] amino } phenyl) morpholin-2-yl ] methanol;

6- (8- { [4- (2-hydroxy-2-methylpropyl) phenyl ] amino } imidazo [1,2-a ] pyrazin-6-yl) -3, 4-dihydro-2H-1, 4-benzoxazin-3-one;

1- (4- { [6- (3, 4-dihydro-2H-1, 4-benzoxazin-7-yl) imidazo [1,2-a ] pyrazin-8-yl ] amino } -2-methoxyphenyl) -4-methylpiperidin-4-ol;

n- (2-hydroxyethyl) -N-methyl-6- (8- { [4- (morpholin-4-yl) phenyl ] amino } imidazo [1,2-a ] pyrazin-6-yl) -1H-indole-3-carboxamide;

6' - (8- { [4- (morpholin-4-yl) phenyl ] amino } imidazo [1,2-a ] pyrazin-6-yl) -1',2' -dihydrospiro [ cyclopropane-1, 3' -indol ] -2' -one;

3-methyl-1- (4- { [6- (1-methyl-1H-indazol-6-yl) imidazo [1,2-a ] pyrazin-8-yl ] amino } phenyl) azetidin-3-ol;

4- { [6- (1H-indazol-6-yl) imidazo [1,2-a ] pyrazin-8-yl ] amino } -2-methoxyphenol;

n- [ 3-methoxy-4- (morpholin-4-yl) phenyl ] -6- (6-methoxypyridin-3-yl) imidazo [1,2-a ] pyrazin-8-amine;

6- (1H-1,2, 3-benzotriazol-6-yl) -N- [4- (morpholin-4-yl) phenyl ] imidazo [1,2-a ] pyrazin-8-amine;

n, N-dimethyl-6- (8- { [4- (morpholin-4-yl) phenyl ] amino } imidazo [1,2-a ] pyrazin-6-yl) -1H-indole-3-carboxamide;

n- [ 3-methoxy-4- (morpholin-4-yl) phenyl ] -6- (5-methoxypyridin-3-yl) imidazo [1,2-a ] pyrazin-8-amine;

6- (8- { [4- (morpholin-4-yl) phenyl ] amino } imidazo [1,2-a ] pyrazin-6-yl) -1H-indazol-3-amine;

7- [8- ({4- [ (3S) -3-hydroxypyrrolidin-1-yl ] phenyl } amino) imidazo [1,2-a ] pyrazin-6-yl ] -1H,2H, 3H-pyrido [2,3-b ] [1,4] oxazin-2-one;

4- { [6- (1H-indazol-6-yl) imidazo [1,2-a ] pyrazin-8-yl ] amino } -N-methyl-N- (oxacyclohex-4-yl) benzamide;

6- (3-ethyl-1H-indazol-6-yl) -N- {4- [ 2-methyl-1- (morpholin-4-yl) propan-2-yl ] phenyl } imidazo [1,2-a ] pyrazin-8-amine;

2, 2-difluoro-6- (8- { [4- (morpholin-4-yl) phenyl ] amino } imidazo [1,2-a ] pyrazin-6-yl) -3, 4-dihydro-2H-1, 4-benzoxazin-3-one;

1- (4- { [6- (3, 4-dihydro-2H-1, 4-benzoxazin-7-yl) imidazo [1,2-a ] pyrazin-8-yl ] amino } -2-methoxyphenyl) -3-methylazetidin-3-ol;

6- (1H-indol-2-yl) -N- [4- (morpholin-4-yl) phenyl ] imidazo [1,2-a ] pyrazin-8-amine;

(3S) -1- (4- { [6- (3, 4-dihydro-2H-1, 4-benzoxazin-7-yl) imidazo [1,2-a ] pyrazin-8-yl ] amino } -2-methoxyphenyl) pyrrolidin-3-ol;

1- (4- { [6- (4-fluoro-1H-indazol-6-yl) imidazo [1,2-a ] pyrazin-8-yl ] amino } phenyl) -3-methylazetidin-3-ol;

6- (1H-indazol-6-yl) -N- [4- (2H-1,2,3, 4-tetrazol-5-yl) phenyl ] imidazo [1,2-a ] pyrazin-8-amine;

7- (8- { [4- (3-hydroxy-3-methylazetidin-1-yl) phenyl ] amino } imidazo [1,2-a ] pyrazin-6-yl) -1H,2H, 3H-pyrido [2,3-b ] [1,4] oxazin-2-one;

6- (1H-indazol-6-yl) -N- [ 3-methoxy-4- (2-methoxyethoxy) phenyl ] imidazo [1,2-a ] pyrazin-8-amine;

6- (2-ethyl-1, 2,3, 4-tetrahydroisoquinolin-6-yl) -N- [4- (morpholin-4-yl) phenyl ] imidazo [1,2-a ] pyrazin-8-amine;

4- { [6- (3, 3-dimethyl-2-oxo-2, 3-dihydro-1H-indol-6-yl) imidazo [1,2-a ] pyrazin-8-yl ] amino } -N-propylbenzamide;

6- (8- { [ 3-ethoxy-4- (morpholin-4-yl) phenyl ] amino } imidazo [1,2-a ] pyrazin-6-yl) -3, 3-dimethyl-2, 3-dihydro-1H-indol-2-one;

6- (1H-indol-3-yl) -N- [4- (morpholin-4-yl) phenyl ] imidazo [1,2-a ] pyrazin-8-amine;

6- (1, 3-benzothiazol-5-yl) -N- {4- [ 2-methyl-1- (morpholin-4-yl) propan-2-yl ] phenyl } imidazo [1,2-a ] pyrazin-8-amine;

(3E) -6- (8- { [4- (morpholin-4-yl) phenyl ] amino } imidazo [1,2-a ] pyrazin-6-yl) -3- (1, 3-thiazol-4-ylmethylene) -2, 3-dihydro-1H-indol-2-one;

4- { [6- (1H-indazol-6-yl) imidazo [1,2-a ] pyrazin-8-yl ] amino } -N- (oxacyclohex-4-yl) benzamide;

6- (2-methyl-1, 3-benzothiazol-5-yl) -N- {4- [ 2-methyl-1- (morpholin-4-yl) propan-2-yl ] phenyl } imidazo [1,2-a ] pyrazin-8-amine;

6- (2, 3-dihydro-1, 4-benzodioxin-6-yl) -N- [ 3-methoxy-4- (morpholin-4-yl) phenyl ] imidazo [1,2-a ] pyrazin-8-amine;

6- (1H-indazol-6-yl) -N- [4- (2-methoxyethoxy) phenyl ] imidazo [1,2-a ] pyrazin-8-amine;

6- (8- { [4- (morpholin-4-yl) phenyl ] amino } imidazo [1,2-a ] pyrazin-6-yl) quinazolin-2-amine;

6- (8- { [4- (4-hydroxy-4-methylpiperidin-1-yl) phenyl ] amino } imidazo [1,2-a ] pyrazin-6-yl) -3, 3-dimethyl-2, 3-dihydro-1H-indol-2-one;

6- (1H-indazol-6-yl) -N- {4- [ (2S) -oxolane-2-ylmethoxy ] phenyl } imidazo [1,2-a ] pyrazin-8-amine;

6- (3-ethyl-1H-indazol-6-yl) -N- [4- (morpholin-4-yl) phenyl ] imidazo [1,2-a ] pyrazin-8-amine;

n- (2, 3-dihydro-1, 4-benzodioxin-6-yl) -6- (1H-indazol-6-yl) imidazo [1,2-a ] pyrazin-8-amine;

n- (2H-1, 3-benzodioxol-5-yl) -6- (1H-indazol-6-yl) imidazo [1,2-a ] pyrazin-8-amine;

1- (2-ethoxy-4- { [6- (1H-indazol-6-yl) imidazo [1,2-a ] pyrazin-8-yl ] amino } phenyl) -4-methylpiperidin-4-ol;

6- [8- ({4- [ (3S) -3-hydroxypyrrolidin-1-yl ] phenyl } amino) imidazo [1,2-a ] pyrazin-6-yl ] -3, 3-dimethyl-2, 3-dihydro-1H-indol-2-one;

6- (8- { [4- (3-hydroxy-3-methylazetidin-1-yl) phenyl ] amino } imidazo [1,2-a ] pyrazin-6-yl) -3, 3-dimethyl-2, 3-dihydro-1H-indol-2-one;

6- (2H-1, 3-benzodioxol-5-yl) -N- [ 3-methoxy-4- (morpholin-4-yl) phenyl ] imidazo [1,2-a ] pyrazin-8-amine;

6- (1H-indol-6-yl) -N- {4- [ 2-methyl-1- (morpholin-4-yl) propan-2-yl ] phenyl } imidazo [1,2-a ] pyrazin-8-amine;

6- (1H-indazol-6-yl) -N- [4- (pyridin-4-yloxy) phenyl ] imidazo [1,2-a ] pyrazin-8-amine;

(3E) -6- (8- { [4- (morpholin-4-yl) phenyl ] amino } imidazo [1,2-a ] pyrazin-6-yl) -3- (pyridin-4-ylmethylene) -2, 3-dihydro-1H-indol-2-one;

4- { [6- (1H-indazol-6-yl) imidazo [1,2-a ] pyrazin-8-yl ] amino } -N- (oxetan-3-yl) benzamide;

6- {3- [ (diethylamino) methyl ] -1H-indazol-6-yl } -N- [4- (morpholin-4-yl) phenyl ] imidazo [1,2-a ] pyrazin-8-amine;

1- [ (4- { [6- (1H-indazol-6-yl) imidazo [1,2-a ] pyrazin-8-yl ] amino } phenyl) carbonyl ] -3-methylazetidin-3-ol;

[6- (8- { [4- (morpholin-4-yl) phenyl ] amino } imidazo [1,2-a ] pyrazin-6-yl) -1H-indazol-3-yl ] methanol;

n- [4- (morpholin-4-yl) phenyl ] -6- (1H-pyrazol-4-yl) imidazo [1,2-a ] pyrazin-8-amine;

6- (4-fluoro-1H-indazol-6-yl) -N- [4- (morpholin-4-yl) phenyl ] imidazo [1,2-a ] pyrazin-8-amine;

n- [4- (morpholin-4-yl) phenyl ] -6- {1H,2H, 3H-pyrido [2,3-b ] [1,4] oxazin-6-yl } imidazo [1,2-a ] pyrazin-8-amine;

n- [4- (morpholin-4-yl) phenyl ] -6- (1, 3-thiazol-5-yl) imidazo [1,2-a ] pyrazin-8-amine;

{4- [ (4- { [6- (1H-indazol-6-yl) imidazo [1,2-a ] pyrazin-8-yl ] amino } phenyl) carbonyl ] morpholin-2-yl } methanol;

1- [ (4- { [6- (1H-indazol-6-yl) imidazo [1,2-a ] pyrazin-8-yl ] amino } phenyl) carbonyl ] piperidin-4-ol;

N-ethyl-N- (2-hydroxyethyl) -4- { [6- (1H-indazol-6-yl) imidazo [1,2-a ] pyrazin-8-yl ] amino } benzamide;

2- (4- { [6- (3, 4-dihydro-2H-1, 4-benzoxazin-6-yl) imidazo [1,2-a ] pyrazin-8-yl ] amino } -2-methoxyphenoxy) -N-methylacetamide;

7- (8- { [4- (morpholin-4-yl) phenyl ] amino } imidazo [1,2-a ] pyrazin-6-yl) -1, 2-dihydroquinolin-2-one;

6- (2-ethyl-1, 2,3, 4-tetrahydroisoquinolin-7-yl) -N- [4- (morpholin-4-yl) phenyl ] imidazo [1,2-a ] pyrazin-8-amine;

1- [ (4- { [6- (1H-indazol-6-yl) imidazo [1,2-a ] pyrazin-8-yl ] amino } phenyl) carbonyl ] -4-methylpiperidin-4-ol;

4- { [6- (1H-indazol-6-yl) imidazo [1,2-a ] pyrazin-8-yl ] amino } -2-methoxybenzoic acid;

6- (1H-indazol-6-yl) -N- {4- [ (4-methylpiperazin-1-yl) carbonyl ] phenyl } imidazo [1,2-a ] pyrazin-8-amine;

1- [ (4- { [6- (1H-indazol-6-yl) imidazo [1,2-a ] pyrazin-8-yl ] amino } phenyl) carbonyl ] azetidin-3-ol;

3, 3-dimethyl-6- (8- { [4- (morpholin-4-yl) phenyl ] amino } imidazo [1,2-a ] pyrazin-6-yl) -2, 3-dihydro-1H-indol-2-one;

6- (1H-indazol-6-yl) -N- [4- (1-methylpiperidin-4-yl) phenyl ] imidazo [1,2-a ] pyrazin-8-amine;

2- (4- { [6- (4-fluoro-1H-indazol-6-yl) imidazo [1,2-a ] pyrazin-8-yl ] amino } phenyl) -2-methylpropan-1-ol;

2- [ ethyl (4- { [6- (4-fluoro-1H-indazol-6-yl) imidazo [1,2-a ] pyrazin-8-yl ] amino } phenyl) amino ] ethan-1-ol;

6- (1H-indazol-7-yl) -N- [4- (morpholin-4-yl) phenyl ] imidazo [1,2-a ] pyrazin-8-amine;

6- [8- ({4- [ ethyl (2-hydroxyethyl) amino ] phenyl } amino) imidazo [1,2-a ] pyrazin-6-yl ] -3, 3-dimethyl-2, 3-dihydro-1H-indol-2-one;

n- {4- [2- (dimethylamino) ethoxy ] phenyl } -6- (1H-indazol-6-yl) imidazo [1,2-a ] pyrazin-8-amine;

6- (3, 4-dihydro-2H-1, 4-benzoxazin-6-yl) -N- {4- [2- (dimethylamino) ethoxy ] phenyl } imidazo [1,2-a ] pyrazin-8-amine;

1- (4- { [6- (3, 4-dihydro-2H-1, 4-benzoxazin-6-yl) imidazo [1,2-a ] pyrazin-8-yl ] amino } phenyl) -3-methylazetidin-3-ol;

2- [6- (8- { [4- (morpholin-4-yl) phenyl ] amino } imidazo [1,2-a ] pyrazin-6-yl) -2H-indazol-2-yl ] ethan-1-ol;

3- (2-ethoxy-4- { [6- (1H-indazol-6-yl) imidazo [1,2-a ] pyrazin-8-yl ] amino } phenoxy) -2, 2-dimethylpropan-1-ol;

3- (4- { [6- (1H-indazol-6-yl) imidazo [1,2-a ] pyrazin-8-yl ] amino } phenoxy) -2, 2-dimethylpropan-1-ol;

2- (4- { [6- (1H-indazol-6-yl) imidazo [1,2-a ] pyrazin-8-yl ] amino } -2-methoxyphenoxy) -N-methylacetamide;

2- (4- { [6- (3, 4-dihydro-2H-1, 4-benzoxazin-6-yl) imidazo [1,2-a ] pyrazin-8-yl ] amino } phenoxy) -N-methylacetamide;

2- (4- { [6- (1H-indazol-6-yl) imidazo [1,2-a ] pyrazin-8-yl ] amino } phenoxy) -N-methylacetamide;

2- (4- { [6- (1H-indazol-6-yl) imidazo [1,2-a ] pyrazin-8-yl ] amino } phenoxy) acetic acid;

4- { [6- (1H-indazol-6-yl) imidazo [1,2-a ] pyrazin-8-yl ] amino } -2-methoxybenzamide;

6- (1, 3-benzothiazol-5-yl) -N- [ 3-ethoxy-4- (morpholin-4-yl) phenyl ] imidazo [1,2-a ] pyrazin-8-amine;

6- (1H-indazol-6-yl) -N- { 3-methoxy-4- [ (2R) -oxolane-2-ylmethoxy ] phenyl } imidazo [1,2-a ] pyrazin-8-amine;

6- (1H-indazol-6-yl) -N- {4- [ (2R) -oxolane-2-ylmethoxy ] phenyl } imidazo [1,2-a ] pyrazin-8-amine;

6- (8- { [4- (3-hydroxy-3-methylazetidin-1-yl) phenyl ] amino } imidazo [1,2-a ] pyrazin-6-yl) -3, 4-dihydro-2H-1, 4-benzoxazin-3-one;

6- (1H-indazol-6-yl) -N- [4- (morpholin-4-ylcarbonyl) phenyl ] imidazo [1,2-a ] pyrazin-8-amine;

4- { [6- (1H-indazol-6-yl) imidazo [1,2-a ] pyrazin-8-yl ] amino } -N-methylbenzamide;

2- [ (2-ethoxy-4- { [6- (1H-indazol-6-yl) imidazo [1,2-a ] pyrazin-8-yl ] amino } phenyl) (methyl) amino ] ethan-1-ol;

n- [2- (dimethylamino) ethyl ] -4- { [6- (1H-indazol-6-yl) imidazo [1,2-a ] pyrazin-8-yl ] amino } -N-methylbenzamide;

1- (2-fluoro-4- { [6- (1H-indazol-6-yl) imidazo [1,2-a ] pyrazin-8-yl ] amino } phenyl) -3-methylazetidin-3-ol;

(3S) -1- (4- { [6- (4-fluoro-1H-indazol-6-yl) imidazo [1,2-a ] pyrazin-8-yl ] amino } phenyl) pyrrolidin-3-ol;

2- [6- (8- { [4- (morpholin-4-yl) phenyl ] amino } imidazo [1,2-a ] pyrazin-6-yl) -1H-indazol-1-yl ] ethan-1-ol;

6- (8- { [4- (3-hydroxy-3-methylazetidin-1-yl) phenyl ] amino } imidazo [1,2-a ] pyrazin-6-yl) -2, 3-dihydro-1H-indol-2-one;

n- [6- (1H-indazol-6-yl) imidazo [1,2-a ] pyrazin-8-yl ] -2-methyl-1, 2,3, 4-tetrahydroisoquinolin-6-amine;

n- [ 3-ethoxy-4- (morpholin-4-yl) phenyl ] -6- (4-fluoro-1H-indazol-6-yl) imidazo [1,2-a ] pyrazin-8-amine;

1- (2-ethoxy-4- { [6- (1H-indazol-6-yl) imidazo [1,2-a ] pyrazin-8-yl ] amino } phenoxy) -2-methylpropan-2-ol;

(3R) -3- (4- { [6- (1H-indazol-6-yl) imidazo [1,2-a ] pyrazin-8-yl ] amino } phenyl) -1, 4-dimethylpiperazin-2-one;

4- { [6- (1H-indazol-6-yl) imidazo [1,2-a ] pyrazin-8-yl ] amino } benzamide;

6- (8- { [ 3-ethoxy-4- (morpholin-4-yl) phenyl ] amino } imidazo [1,2-a ] pyrazin-6-yl) -2, 3-dihydro-1H-indol-2-one;

6- (3, 4-dihydro-2H-1, 4-benzoxazin-6-yl) -N- [ 3-ethoxy-4- (morpholin-4-yl) phenyl ] imidazo [1,2-a ] pyrazin-8-amine;

1- (4- { [6- (1H-indazol-6-yl) imidazo [1,2-a ] pyrazin-8-yl ] amino } phenyl) -N, N-dimethylpiperidin-4-amine;

1- (4- { [6- (1, 3-benzothiazol-5-yl) imidazo [1,2-a ] pyrazin-8-yl ] amino } phenoxy) -2-methylpropan-2-ol;

(3R) -1- (2-ethoxy-4- { [6- (1H-indazol-6-yl) imidazo [1,2-a ] pyrazin-8-yl ] amino } phenyl) pyrrolidin-3-ol;

2- (4- { [6- (1H-indazol-6-yl) imidazo [1,2-a ] pyrazin-8-yl ] amino } phenoxy) ethan-1-ol;

1- (2-ethoxy-4- { [6- (1H-indazol-6-yl) imidazo [1,2-a ] pyrazin-8-yl ] amino } phenyl) -3-methylazetidin-3-ol;

1- (4- { [6- (1H-indazol-6-yl) imidazo [1,2-a ] pyrazin-8-yl ] amino } -2-methoxyphenyl) -3-methylazetidin-3-ol;

4- { [6- (1H-indazol-6-yl) imidazo [1,2-a ] pyrazin-8-yl ] amino } benzoic acid;

n- [ 3-ethoxy-4- (4-ethylpiperazin-1-yl) phenyl ] -6- (1H-indazol-6-yl) imidazo [1,2-a ] pyrazin-8-amine;

4- { [6- (1H-indazol-6-yl) imidazo [1,2-a ] pyrazin-8-yl ] amino } -N-propylbenzamide;

1- (4- { [6- (4-fluoro-1H-indazol-6-yl) imidazo [1,2-a ] pyrazin-8-yl ] amino } phenyl) -4-methylpiperidin-4-ol;

3- (4- { [6- (1H-indazol-6-yl) imidazo [1,2-a ] pyrazin-8-yl ] amino } -2-methoxyphenoxy) -2, 2-dimethylpropan-1-ol;

6- (4-fluoro-1H-indazol-6-yl) -N- [4- (1, 4-oxazepan-4-yl) phenyl ] imidazo [1,2-a ] pyrazin-8-amine;

6- (8- { [ 3-ethoxy-4- (morpholin-4-yl) phenyl ] amino } imidazo [1,2-a ] pyrazin-6-yl) -3, 4-dihydro-2H-1, 4-benzoxazin-3-one;

1- (4- { [6- (3, 4-dihydro-2H-1, 4-benzoxazin-6-yl) imidazo [1,2-a ] pyrazin-8-yl ] amino } phenoxy) -2-methylpropan-2-ol;

2-methyl-1- (4- { [6- (1-methyl-1H-1, 3-benzodiazol-6-yl) imidazo [1,2-a ] pyrazin-8-yl ] amino } phenoxy) propan-2-ol;

6- (8- { [4- (2-hydroxy-2-methylpropoxy) phenyl ] amino } imidazo [1,2-a ] pyrazin-6-yl) -2, 3-dihydro-1H-indol-2-one;

n- [ 3-fluoro-4- (morpholin-4-yl) phenyl ] -6- (1H-indazol-6-yl) imidazo [1,2-a ] pyrazin-8-amine;

1- (4- { [6- (1, 3-benzothiazol-5-yl) imidazo [1,2-a ] pyrazin-8-yl ] amino } phenyl) -3-methylazetidin-3-ol;

n- [6- (1H-indazol-6-yl) imidazo [1,2-a ] pyrazin-8-yl ] -1,2,3, 4-tetrahydroisoquinolin-6-amine;

n- [6- (1H-indazol-6-yl) imidazo [1,2-a ] pyrazin-8-yl ] -2, 3-dihydro-1H-indol-6-amine;

1- [6- (8- { [4- (morpholin-4-yl) phenyl ] amino } imidazo [1,2-a ] pyrazin-6-yl) -1,2,3, 4-tetrahydroisoquinolin-2-yl ] ethan-1-one;

1- [7- (8- { [4- (morpholin-4-yl) phenyl ] amino } imidazo [1,2-a ] pyrazin-6-yl) -1,2,3, 4-tetrahydroisoquinolin-2-yl ] ethan-1-one;

n- [4- (morpholin-4-yl) phenyl ] -6- {1H,2H, 3H-pyrido [2,3-b ] [1,4] oxazin-7-yl } imidazo [1,2-a ] pyrazin-8-amine;

6- (1-methyl-1H-indazol-6-yl) -N- [4- (morpholin-4-yl) phenyl ] imidazo [1,2-a ] pyrazin-8-amine;

n- [4- (morpholin-4-yl) phenyl ] -6- {2H,3H, 4H-pyrido [3,2-b ] [1,4] oxazin-7-yl } imidazo [1,2-a ] pyrazin-8-amine;

6- (8- { [4- (morpholin-4-yl) phenyl ] amino } imidazo [1,2-a ] pyrazin-6-yl) -1H,2H, 3H-pyrido [2,3-b ] [1,4] oxazin-2-one;

(3S) -1- (4- { [6- (3, 4-dihydro-2H-1, 4-benzoxazin-7-yl) imidazo [1,2-a ] pyrazin-8-yl ] amino } phenyl) -3-methylpiperidin-3-ol;

5- (8- { [4- (morpholin-4-yl) phenyl ] amino } imidazo [1,2-a ] pyrazin-6-yl) -2, 3-dihydro-1H-indol-2-one;

1-methyl-6- (8- { [4- (morpholin-4-yl) phenyl ] amino } imidazo [1,2-a ] pyrazin-6-yl) -2, 3-dihydro-1H-indol-2-one;

6- (8- { [4- (2-hydroxy-2-methylpropoxy) phenyl ] amino } imidazo [1,2-a ] pyrazin-6-yl) -3, 4-dihydro-2H-1, 4-benzoxazin-3-one;

2- [4- (4- { [6- (1H-indazol-6-yl) imidazo [1,2-a ] pyrazin-8-yl ] amino } phenyl) piperazin-1-yl ] ethan-1-ol;

6- (1H-indazol-4-yl) -N- [4- (morpholin-4-yl) phenyl ] imidazo [1,2-a ] pyrazin-8-amine;

n- [ 3-ethoxy-4- (morpholin-4-yl) phenyl ] -6- (1-methyl-1H-1, 3-benzodiazol-6-yl) imidazo [1,2-a ] pyrazin-8-amine;

6- (1H-indazol-6-yl) -N- [4- (piperazin-1-yl) phenyl ] imidazo [1,2-a ] pyrazin-8-amine;

n- [4- (morpholin-4-yl) phenyl ] -6- (1,2,3, 4-tetrahydroisoquinolin-7-yl) imidazo [1,2-a ] pyrazin-8-amine;

n- [4- (morpholin-4-yl) phenyl ] -6- (1,2,3, 4-tetrahydroisoquinolin-6-yl) imidazo [1,2-a ] pyrazin-8-amine;

7- (8- { [4- (morpholin-4-yl) phenyl ] amino } imidazo [1,2-a ] pyrazin-6-yl) -1H,2H, 3H-pyrido [2,3-b ] [1,4] oxazin-2-one;

6- { 1-methyl-1H-pyrrolo [3,2-b ] pyridin-6-yl } -N- [4- (morpholin-4-yl) phenyl ] imidazo [1,2-a ] pyrazin-8-amine;

6- (1-methyl-1H-indol-6-yl) -N- [4- (morpholin-4-yl) phenyl ] imidazo [1,2-a ] pyrazin-8-amine;

6- (1, 3-benzoxazol-5-yl) -N- [4- (morpholin-4-yl) phenyl ] imidazo [1,2-a ] pyrazin-8-amine;

6- (4-methyl-3, 4-dihydro-2H-1, 4-benzoxazin-7-yl) -N- [4- (morpholin-4-yl) phenyl ] imidazo [1,2-a ] pyrazin-8-amine;

6- (4-methyl-3, 4-dihydro-2H-1, 4-benzoxazin-6-yl) -N- [4- (morpholin-4-yl) phenyl ] imidazo [1,2-a ] pyrazin-8-amine;

6- [8- ({4- [ (3S) -3-hydroxypyrrolidin-1-yl ] phenyl } amino) imidazo [1,2-a ] pyrazin-6-yl ] -3, 4-dihydro-2H-1, 4-benzoxazin-3-one;

(3R) -1- (4- { [6- (3, 4-dihydro-2H-1, 4-benzoxazin-7-yl) imidazo [1,2-a ] pyrazin-8-yl ] amino } phenyl) -3-methylpiperidin-3-ol;

6- [8- ({4- [ (3S) -3-hydroxy-3-methylpiperidin-1-yl ] phenyl } amino) imidazo [1,2-a ] pyrazin-6-yl ] -3, 4-dihydro-2H-1, 4-benzoxazin-3-one;

6- [8- ({4- [ (3R) -3-hydroxy-3-methylpiperidin-1-yl ] phenyl } amino) imidazo [1,2-a ] pyrazin-6-yl ] -3, 4-dihydro-2H-1, 4-benzoxazin-3-one;

6- [8- ({4- [ (3S) -3-hydroxy-3-methylpiperidin-1-yl ] phenyl } amino) imidazo [1,2-a ] pyrazin-6-yl ] -2, 3-dihydro-1H-indol-2-one;

6- [8- ({4- [ (3R) -3-hydroxy-3-methylpiperidin-1-yl ] phenyl } amino) imidazo [1,2-a ] pyrazin-6-yl ] -2, 3-dihydro-1H-indol-2-one;

(3R) -1- (4- { [6- (3, 4-dihydro-2H-1, 4-benzoxazin-6-yl) imidazo [1,2-a ] pyrazin-8-yl ] amino } phenyl) -3-methylpiperidin-3-ol;

(3S) -3-methyl-1- (4- { [6- (1-methyl-1H-1, 3-benzodiazol-5-yl) imidazo [1,2-a ] pyrazin-8-yl ] amino } phenyl) piperidin-3-ol;

(3R) -3-methyl-1- (4- { [6- (1-methyl-1H-1, 3-benzodiazol-5-yl) imidazo [1,2-a ] pyrazin-8-yl ] amino } phenyl) piperidin-3-ol;

(3R) -3-methyl-1- (4- { [6- (1-methyl-1H-1, 3-benzodiazol-6-yl) imidazo [1,2-a ] pyrazin-8-yl ] amino } phenyl) piperidin-3-ol;

6- (8- { [4- (4-ethylpiperazin-1-yl) phenyl ] amino } imidazo [1,2-a ] pyrazin-6-yl) -3, 4-dihydro-2H-1, 4-benzoxazin-3-one;

6- (1, 3-benzothiazol-6-yl) -N- [4- (morpholin-4-yl) phenyl ] imidazo [1,2-a ] pyrazin-8-amine;

6- (1, 3-benzothiazol-5-yl) -N- [4- (morpholin-4-yl) phenyl ] imidazo [1,2-a ] pyrazin-8-amine;

6- (1, 3-benzoxazol-6-yl) -N- [4- (morpholin-4-yl) phenyl ] imidazo [1,2-a ] pyrazin-8-amine;

6- (1H-indazol-5-yl) -N- [4- (morpholin-4-yl) phenyl ] imidazo [1,2-a ] pyrazin-8-amine;

(3S) -1- (4- { [6- (3, 4-dihydro-2H-1, 4-benzoxazin-6-yl) imidazo [1,2-a ] pyrazin-8-yl ] amino } phenyl) -3-methylpiperidin-3-ol;

(3S) -3-methyl-1- (4- { [6- (1-methyl-1H-1, 3-benzodiazol-6-yl) imidazo [1,2-a ] pyrazin-8-yl ] amino } phenyl) piperidin-3-ol;

1- (4- { [6- (1H-indazol-6-yl) imidazo [1,2-a ] pyrazin-8-yl ] amino } phenyl) -3-methylazetidin-3-ol;

n- {4- [ (4-ethylpiperazin-1-yl) methyl ] phenyl } -6- (1-methyl-1H-1, 3-benzooxadiazol-6-yl) imidazo [1,2-a ] pyrazin-8-amine;

2- [ ethyl (4- { [6- (1H-indazol-6-yl) imidazo [1,2-a ] pyrazin-8-yl ] amino } phenyl) amino ] ethan-1-ol;

1- (4- { [6- (3, 4-dihydro-2H-1, 4-benzoxazin-7-yl) imidazo [1,2-a ] pyrazin-8-yl ] amino } phenyl) azetidin-3-ol;

7- (8- { [4- (morpholin-4-yl) phenyl ] amino } imidazo [1,2-a ] pyrazin-6-yl) -2H,3H, 4H-pyrido [3,2-b ] [1,4] oxazin-3-one;

6- (1-methyl-1H-indazol-5-yl) -N- [4- (morpholin-4-yl) phenyl ] imidazo [1,2-a ] pyrazin-8-amine;

1- (4- { [6- (1H-indazol-6-yl) imidazo [1,2-a ] pyrazin-8-yl ] amino } phenoxy) -2-methylpropan-2-ol;

6- (3, 4-dihydro-2H-1, 4-benzoxazin-6-yl) -N- [4- (morpholin-4-yl) phenyl ] imidazo [1,2-a ] pyrazin-8-amine;

4- (4- { [6- (1H-indazol-6-yl) imidazo [1,2-a ] pyrazin-8-yl ] amino } phenyl) piperazin-2-one;

6- (1-methyl-1H-1, 3-benzodiazol-6-yl) -N- [4- (morpholin-4-ylmethyl) phenyl ] imidazo [1,2-a ] pyrazin-8-amine;

6- (1H-1, 3-benzodiazol-6-yl) -N- [4- (morpholin-4-yl) phenyl ] imidazo [1,2-a ] pyrazin-8-amine;

1- (4- { [6- (3, 4-dihydro-2H-1, 4-benzoxazin-6-yl) imidazo [1,2-a ] pyrazin-8-yl ] amino } phenyl) azetidin-3-ol;

6- (1H-indazol-6-yl) -N- [4- (1, 4-oxazepan-4-yl) phenyl ] imidazo [1,2-a ] pyrazin-8-amine;

(3S) -1- (4- { [6- (1H-indazol-6-yl) imidazo [1,2-a ] pyrazin-8-yl ] amino } phenyl) -3-methylpiperidin-3-ol;

(3R) -1- (4- { [6- (1H-indazol-6-yl) imidazo [1,2-a ] pyrazin-8-yl ] amino } phenyl) -3-methylpiperidin-3-ol;

(3S) -1- (4- { [6- (1H-indazol-6-yl) imidazo [1,2-a ] pyrazin-8-yl ] amino } phenyl) -3-methylpyrrolidin-3-ol;

(3R) -1- (4- { [6- (1H-indazol-6-yl) imidazo [1,2-a ] pyrazin-8-yl ] amino } phenyl) -3-methylpyrrolidin-3-ol;

6- (8- { [4- (morpholin-4-yl) phenyl ] amino } imidazo [1,2-a ] pyrazin-6-yl) -3, 4-dihydro-2H-1, 4-benzoxazin-3-one;

6- (8- { [4- (3-hydroxyazetidin-1-yl) phenyl ] amino } imidazo [1,2-a ] pyrazin-6-yl) -2, 3-dihydro-1H-indol-2-one;

6- (8- { [4- (3-hydroxy-3-methylpyrrolidin-1-yl) phenyl ] amino } imidazo [1,2-a ] pyrazin-6-yl) -3, 4-dihydro-2H-1, 4-benzoxazin-3-one;

6- (1-methyl-1H-1, 3-benzodiazol-6-yl) -N- [4- (morpholin-4-yl) phenyl ] imidazo [1,2-a ] pyrazin-8-amine;

6- (3, 4-dihydro-2H-1, 4-benzoxazin-7-yl) -N- [4- (morpholin-4-yl) phenyl ] imidazo [1,2-a ] pyrazin-8-amine;

1- (4- { [6- (3, 4-dihydro-2H-1, 4-benzoxazin-7-yl) imidazo [1,2-a ] pyrazin-8-yl ] amino } phenyl) -4-methylpiperidin-4-ol;

1- (4- { [6- (1H-indol-6-yl) imidazo [1,2-a ] pyrazin-8-yl ] amino } phenyl) -4-methylpiperidin-4-ol;

1- (4- { [6- (1H-indol-6-yl) imidazo [1,2-a ] pyrazin-8-yl ] amino } phenyl) azetidin-3-ol;

1- (4- { [6- (1-methyl-1H-1, 3-benzodiazol-6-yl) imidazo [1,2-a ] pyrazin-8-yl ] amino } phenyl) azetidin-3-ol;

1- (4- { [6- (1-methyl-1H-1, 3-benzodiazol-5-yl) imidazo [1,2-a ] pyrazin-8-yl ] amino } phenyl) azetidin-3-ol;

6- (1-methyl-1H-1, 3-benzodiazol-5-yl) -N- [4- (morpholin-4-yl) phenyl ] imidazo [1,2-a ] pyrazin-8-amine;

6- (8- { [4- (morpholin-4-yl) phenyl ] amino } imidazo [1,2-a ] pyrazin-6-yl) -2, 3-dihydro-1H-indol-2-one;

6- (8- { [4- (3-hydroxyazetidin-1-yl) phenyl ] amino } imidazo [1,2-a ] pyrazin-6-yl) -3, 4-dihydro-2H-1, 4-benzoxazin-3-one;

5- (8- { [4- (morpholin-4-yl) phenyl ] amino } imidazo [1,2-a ] pyrazin-6-yl) -2, 3-dihydro-1, 3-benzoxazol-2-one;

4- { [6- (1H-indazol-6-yl) imidazo [1,2-a ] pyrazin-8-yl ] amino } -N, N-dimethylbenzene-1-sulfonamide;

6- (1H-indazol-6-yl) -N- {4- [4- (propan-2-yl) piperazin-1-yl ] phenyl } imidazo [1,2-a ] pyrazin-8-amine;

2- (4- { [6- (3, 4-dihydro-2H-1, 4-benzoxazin-7-yl) imidazo [1,2-a ] pyrazin-8-yl ] amino } phenyl) -2-methylpropan-1-ol;

4- (4- { [6- (1H-indazol-6-yl) imidazo [1,2-a ] pyrazin-8-yl ] amino } phenyl) thiomorpholine-1, 1-dione;

6- (1H-indazol-6-yl) -N- [4- (2-methylmorpholin-4-yl) phenyl ] imidazo [1,2-a ] pyrazin-8-amine.

n- (4-ethoxy-3-methoxyphenyl) -6- (1H-indazol-6-yl) -5-methylimidazo [1,2-a ] pyrazin-8-amine;

1- (4- { [6- (1H-indazol-6-yl) -5-methylimidazo [1,2-a ] pyrazin-8-yl ] amino } phenyl) -4-methylpiperidin-4-ol;

n, 6-bis [4- (morpholin-4-yl) phenyl ] imidazo [1,2-a ] pyrazin-8-amine;

2- [1- (4- { [6- (1H-indazol-6-yl) imidazo [1,2-a ] pyrazin-8-yl ] amino } phenyl) piperidin-4-yl ] ethan-1-ol;

6- [3- (morpholin-4-yl) phenyl ] -N- [4- (morpholin-4-yl) phenyl ] imidazo [1,2-a ] pyrazin-8-amine;

2- [6- (8- { [4- (morpholin-4-yl) phenyl ] amino } imidazo [1,2-a ] pyrazin-6-yl) -1H-indol-3-yl ] ethan-1-ol;

[1- (4- { [6- (1H-indazol-6-yl) imidazo [1,2-a ] pyrazin-8-yl ] amino } phenyl) piperidin-4-yl ] methanol;

1- [4- (4- { [6- (1H-indazol-6-yl) imidazo [1,2-a ] pyrazin-8-yl ] amino } phenyl) piperazin-1-yl ] ethan-1-one;

6- (5-chloro-8- { [ 3-methoxy-4- (morpholin-4-yl) phenyl ] amino } imidazo [1,2-a ] pyrazin-6-yl) -2, 3-dihydro-1H-indol-2-one;

5-chloro-N- [ 3-methoxy-4- (morpholin-4-yl) phenyl ] -6- { 1H-pyrrolo [3,2-b ] pyridin-6-yl } imidazo [1,2-a ] pyrazin-8-amine;

n-methyl-5- (8- { [4- (morpholin-4-yl) phenyl ] amino } imidazo [1,2-a ] pyrazin-6-yl) pyridin-3-amine;

6- (1H-indazol-6-yl) -N- (4- { 7-oxa-2-azaspiro [3.5] nonan-2-yl } phenyl) imidazo [1,2-a ] pyrazin-8-amine;

6- (2-methyl-1H-1, 3-benzodiazol-6-yl) -N- [4- (morpholin-4-yl) phenyl ] imidazo [1,2-a ] pyrazin-8-amine;

5- (8- { [4- (3-hydroxy-3-methylazetidin-1-yl) phenyl ] amino } imidazo [1,2-a ] pyrazin-6-yl) -1-methyl-2, 3-dihydro-1H-1, 3-benzodiazol-2-one;

n- {4- [ (2R,6S) -2, 6-dimethylmorpholin-4-yl ] phenyl } -6- (1H-indazol-6-yl) imidazo [1,2-a ] pyrazin-8-amine;

n- [6- (1H-indazol-6-yl) -5-methylimidazo [1,2-a ] pyridin-8-yl ] -5- (morpholin-4-yl) pyridin-2-amine;

[ (2R) -6- (8- { [4- (morpholin-4-yl) phenyl ] amino } imidazo [1,2-a ] pyrazin-6-yl) -3, 4-dihydro-2H-1, 4-benzoxazin-2-yl ] methanol;

6- (1H-indazol-6-yl) -N- [3- (methoxymethyl) -4- (morpholin-4-yl) phenyl ] imidazo [1,2-a ] pyrazin-8-amine;

7- (8- { [4- (morpholin-4-yl) phenyl ] amino } imidazo [1,2-a ] pyrazin-6-yl) -1,2,3, 4-tetrahydroquinoxalin-2-one;

5-chloro-6- (1H-indazol-6-yl) -N- [ 3-methoxy-4- (morpholin-4-yl) phenyl ] imidazo [1,2-a ] pyrazin-8-amine;

1- (4- { [6- (1H-indazol-6-yl) imidazo [1,2-a ] pyrazin-8-yl ] amino } phenyl) -3-methylazetidin-3-amine;

[ (2S) -6- (8- { [4- (morpholin-4-yl) phenyl ] amino } imidazo [1,2-a ] pyrazin-6-yl) -3, 4-dihydro-2H-1, 4-benzoxazin-2-yl ] methanol;

7- (8- { [4- (morpholin-4-yl) phenyl ] amino } imidazo [1,2-a ] pyrazin-6-yl) -1,2,3, 4-tetrahydroquinolin-2-one;

5- { [6- (1H-indazol-6-yl) imidazo [1,2-a ] pyrazin-8-yl ] amino } -2- (morpholin-4-yl) benzonitrile;

6- (3, 4-dihydro-2H-1, 4-benzoxazin-6-yl) -3-methyl-N- [4- (morpholin-4-yl) phenyl ] imidazo [1,2-a ] pyrazin-8-amine;

n- [ 3-methoxy-4- (morpholin-4-yl) phenyl ] -3-methyl-6- { 1H-pyrrolo [3,2-b ] pyridin-6-yl } imidazo [1,2-a ] pyrazin-8-amine;

5-methyl-6- (2-methyl-1H-1, 3-benzodiazol-6-yl) -N- [4- (morpholin-4-yl) phenyl ] imidazo [1,2-a ] pyrazin-8-amine;

5-ethyl-6- (1H-indazol-6-yl) -N- [4- (morpholin-4-yl) phenyl ] imidazo [1,2-a ] pyrazin-8-amine;

1-methyl-6- (8- { [4- (morpholin-4-yl) phenyl ] amino } imidazo [1,2-a ] pyrazin-6-yl) -2, 3-dihydro-1H-1, 3-benzodiazol-2-one;

6- (3-methyl-8- { [4- (morpholin-4-yl) phenyl ] amino } imidazo [1,2-a ] pyrazin-6-yl) -2, 3-dihydro-1H-indol-2-one;

1, 3-dimethyl-5- (8- { [4- (morpholin-4-yl) phenyl ] amino } imidazo [1,2-a ] pyrazin-6-yl) -2, 3-dihydro-1H-1, 3-benzodiazol-2-one;

2- [6- (8- { [4- (morpholin-4-yl) phenyl ] amino } imidazo [1,2-a ] pyrazin-6-yl) -1H-indazol-3-yl ] propan-2-ol;

6- (4-fluoro-1H-indol-6-yl) -N- [4- (morpholin-4-yl) phenyl ] imidazo [1,2-a ] pyrazin-8-amine;

5- { [6- (1H-indazol-6-yl) imidazo [1,2-a ] pyrazin-8-yl ] amino } -2- (morpholin-4-yl) benzamide;

5- (8- { [ 3-methoxy-4- (morpholin-4-yl) phenyl ] amino } -5-methylimidazo [1,2-a ] pyrazin-6-yl) -2, 3-dihydro-1H-1, 3-benzodiazol-2-one;

5- (5-methyl-8- { [4- (morpholin-4-yl) phenyl ] amino } imidazo [1,2-a ] pyrazin-6-yl) -2, 3-dihydro-1H-1, 3-benzodiazol-2-one;

[2- (8- { [4- (morpholin-4-yl) phenyl ] amino } imidazo [1,2-a ] pyrazin-6-yl) phenyl ] methanol;

1-methyl-5- (8- { [4- (morpholin-4-yl) phenyl ] amino } imidazo [1,2-a ] pyrazin-6-yl) -2, 3-dihydro-1H-1, 3-benzodiazol-2-one;

2- [6- (8- { [4- (morpholin-4-yl) phenyl ] amino } imidazo [1,2-a ] pyrazin-6-yl) -3, 4-dihydro-2H-1, 4-benzoxazin-4-yl ] ethan-1-ol;

(3R) -2, 2-dimethyl-6- (8- { [4- (morpholin-4-yl) phenyl ] amino } imidazo [1,2-a ] pyrazin-6-yl) -2, 3-dihydro-1H-indol-3-ol;

6- (1H-indazol-6-yl) -N- { 3-methoxy-4- [4- (2-methoxyethyl) piperazin-1-yl ] phenyl } imidazo [1,2-a ] pyrazin-8-amine;

2- (4- { 2-methoxy-4- [ (6- { 1H-pyrrolo [3,2-b ] pyridin-6-yl } imidazo [1,2-a ] pyrazin-8-yl) amino ] phenyl } piperazin-1-yl) ethan-1-ol;

1- [6- (8- { [4- (morpholin-4-yl) phenyl ] amino } imidazo [1,2-a ] pyrazin-6-yl) -1H-indazol-3-yl ] ethan-1-ol;

2- [6- (8- { [4- (morpholin-4-yl) phenyl ] amino } imidazo [1,2-a ] pyrazin-6-yl) -1H-indazol-3-yl ] ethan-1-ol;

2- { [5- (8- { [4- (morpholin-4-yl) phenyl ] amino } imidazo [1,2-a ] pyrazin-6-yl) pyridin-3-yl ] amino } ethan-1-ol;

n- [ 3-methoxy-4- (morpholin-4-yl) phenyl ] -5-methyl-6- { 1H-pyrrolo [3,2-b ] pyridin-6-yl } imidazo [1,2-a ] pyrazin-8-amine;

(3S) -2, 2-dimethyl-6- (8- { [4- (morpholin-4-yl) phenyl ] amino } imidazo [1,2-a ] pyrazin-6-yl) -2, 3-dihydro-1H-indol-3-ol;

n- {4- [4- (3-fluoropropyl) piperazin-1-yl ] phenyl } -6- (1H-indazol-6-yl) imidazo [1,2-a ] pyrazin-8-amine;

6- (1H-indazol-6-yl) -N- [4- (oxacyclohex-4-yl) phenyl ] imidazo [1,2-a ] pyrazin-8-amine;

n- [4- (4-fluoropiperidin-1-yl) phenyl ] -6- (1H-indazol-6-yl) imidazo [1,2-a ] pyrazin-8-amine;

6- (1H-indazol-6-yl) -N- [3- (2-methoxyethoxy) -4- (morpholin-4-yl) phenyl ] imidazo [1,2-a ] pyrazin-8-amine;

6- (1H-indazol-6-yl) -N- [4- (4H-1,2, 4-triazol-4-yl) phenyl ] imidazo [1,2-a ] pyrazin-8-amine;

n- [4- (3, 3-difluoropyrrolidin-1-yl) phenyl ] -6- (1H-indazol-6-yl) imidazo [1,2-a ] pyrazin-8-amine;

6- (1H-indazol-6-yl) -N- [ 3-methoxy-4- (morpholin-4-yl) phenyl ] -5-methylimidazo [1,2-a ] pyrazin-8-amine;

2, 2-dimethyl-6- (8- { [4- (morpholin-4-yl) phenyl ] amino } imidazo [1,2-a ] pyrazin-6-yl) -2, 3-dihydro-1H-indol-3-one;

6- (1H-indazol-6-yl) -N- [ 3-methoxy-4- (methoxymethyl) phenyl ] imidazo [1,2-a ] pyrazin-8-amine;

1- (4- { [6- (1H-indazol-6-yl) imidazo [1,2-a ] pyrazin-8-yl ] amino } -2-methoxyphenyl) -2-methylpropan-2-ol;

[ (2S) -4- (4- { [6- (3, 4-dihydro-2H-1, 4-benzoxazin-6-yl) imidazo [1,2-a ] pyrazin-8-yl ] amino } phenyl) morpholin-2-yl ] methanol;

n- [4- (4, 4-difluoropiperidin-1-yl) phenyl ] -6- (1H-indazol-6-yl) imidazo [1,2-a ] pyrazin-8-amine;

6- (1H-indazol-6-yl) -N- { 3-methoxy-4- [ (2-methoxyethoxy) methyl ] phenyl } imidazo [1,2-a ] pyrazin-8-amine;

2- [2- (morpholin-4-yl) -5- [ (6- { 1H-pyrrolo [3,2-b ] pyridin-6-yl } imidazo [1,2-a ] pyrazin-8-yl) amino ] phenoxy ] ethan-1-ol;

6- (1H-indazol-6-yl) -N- [4- (3-methoxy-3-methylazetidin-1-yl) phenyl ] imidazo [1,2-a ] pyrazin-8-amine;

5- (8- { [4- (morpholin-4-yl) phenyl ] amino } imidazo [1,2-a ] pyrazin-6-yl) pyridin-3-amine;

n- [4- (morpholin-4-yl) phenyl ] -6- (1, 5-naphthyridin-3-yl) imidazo [1,2-a ] pyrazin-8-amine;

3-ethyl-1- (4- { [6- (1H-indazol-6-yl) imidazo [1,2-a ] pyrazin-8-yl ] amino } phenyl) azetidin-3-ol;

n- [4- (3-fluoro-3-methylazetidin-1-yl) phenyl ] -6- (1H-indazol-6-yl) imidazo [1,2-a ] pyrazin-8-amine;

n- [4- (3, 3-difluoropiperidin-1-yl) phenyl ] -6- (1H-indazol-6-yl) imidazo [1,2-a ] pyrazin-8-amine;

[ (2R) -4- (4- { [6- (3, 4-dihydro-2H-1, 4-benzoxazin-6-yl) imidazo [1,2-a ] pyrazin-8-yl ] amino } phenyl) morpholin-2-yl ] methanol,

n- [4- (3, 3-difluoroazetidin-1-yl) phenyl ] -6- (1H-indazol-6-yl) imidazo [1,2-a ] pyrazin-8-amine;

(3S) -1- (4- { [6- (3, 4-dihydro-2H-1, 4-benzoxazin-6-yl) imidazo [1,2-a ] pyrazin-8-yl ] amino } -2-methoxyphenyl) pyrrolidin-3-ol;

(3R) -1- (4- { [6- (3, 4-dihydro-2H-1, 4-benzoxazin-6-yl) imidazo [1,2-a ] pyrazin-8-yl ] amino } -2-methoxyphenyl) pyrrolidin-3-ol;

n- [4- (3-fluoroazetidin-1-yl) phenyl ] -6- (1H-indazol-6-yl) imidazo [1,2-a ] pyrazin-8-amine;

6- (3, 4-dihydro-2H-1, 4-benzoxazin-6-yl) -N- [ 3-methoxy-4- (morpholin-4-yl) phenyl ] -5-methylimidazo [1,2-a ] pyrazin-8-amine;

n, N-diethyl-6- (8- { [4- (morpholin-4-yl) phenyl ] amino } imidazo [1,2-a ] pyrazin-6-yl) -1H-indazol-3-amine;

(3S) -3-hydroxy-3-methyl-6- (8- { [4- (morpholin-4-yl) phenyl ] amino } imidazo [1,2-a ] pyrazin-6-yl) -2, 3-dihydro-1H-indol-2-one;

n- [4- (morpholin-4-yl) phenyl ] -6- (quinoxalin-6-yl) imidazo [1,2-a ] pyrazin-8-amine;

(3R) -3-hydroxy-3-methyl-6- (8- { [4- (morpholin-4-yl) phenyl ] amino } imidazo [1,2-a ] pyrazin-6-yl) -2, 3-dihydro-1H-indol-2-one;

6- (1H-indazol-6-yl) -N- { 3-methoxy-4- [ (2S) -oxolanyl-2-ylmethoxy ] phenyl } imidazo [1,2-a ] pyrazin-8-amine;

6- (8- { [ 3-methoxy-4- (morpholin-4-yl) phenyl ] amino } -5-methylimidazo [1,2-a ] pyrazin-6-yl) -2, 3-dihydro-1H-indol-2-one;

6- (8- { [ 3-methoxy-4- (morpholin-4-yl) phenyl ] amino } -5-methylimidazo [1,2-a ] pyrazin-6-yl) -3, 4-dihydro-2H-1, 4-benzoxazin-3-one;

(3S) -1- {4- [ (6- {1H,2H, 3H-pyrido [2,3-b ] [1,4] oxazin-7-yl } imidazo [1,2-a ] pyrazin-8-yl) amino ] phenyl } pyrrolidin-3-ol;

(3R) -1- (4- { [6- (3, 4-dihydro-2H-1, 4-benzoxazin-6-yl) imidazo [1,2-a ] pyrazin-8-yl ] amino } phenyl) pyrrolidin-3-ol;

6- [8- ({4- [ (3R) -3-hydroxypyrrolidin-1-yl ] -3-methoxyphenyl } amino) imidazo [1,2-a ] pyrazin-6-yl ] -2, 3-dihydro-1H-indol-2-one;

n- [4- (1H-imidazol-1-yl) phenyl ] -6- (1H-indazol-6-yl) imidazo [1,2-a ] pyrazin-8-amine;

6- (1H-indazol-6-yl) -N- [4- (1H-pyrazol-1-yl) phenyl ] imidazo [1,2-a ] pyrazin-8-amine;

6- [8- ({4- [ (3R) -3-hydroxypyrrolidin-1-yl ] phenyl } amino) imidazo [1,2-a ] pyrazin-6-yl ] -2, 3-dihydro-1H-indol-2-one;

6- [8- ({4- [ (3S) -3-hydroxypyrrolidin-1-yl ] phenyl } amino) imidazo [1,2-a ] pyrazin-6-yl ] -2, 3-dihydro-1H-indol-2-one;

1- (4- { [6- (1H-indazol-6-yl) -5-methylimidazo [1,2-a ] pyrazin-8-yl ] amino } phenyl) -3-methylazetidin-3-ol;

(3S) -1- (4- { [6- (1H-indazol-6-yl) imidazo [1,2-a ] pyrazin-8-yl ] amino } phenyl) piperidin-3-ol;

(3R) -1- (4- { [6- (1H-indazol-6-yl) imidazo [1,2-a ] pyrazin-8-yl ] amino } phenyl) piperidin-3-ol;

2- [3- (8- { [4- (morpholin-4-yl) phenyl ] amino } imidazo [1,2-a ] pyrazin-6-yl) phenyl ] propan-2-ol;

6- (5-methyl-8- { [4- (morpholin-4-yl) phenyl ] amino } imidazo [1,2-a ] pyrazin-6-yl) -3, 4-dihydro-2H-1, 4-benzoxazin-3-one;

n-ethyl-6- (8- { [4- (morpholin-4-yl) phenyl ] amino } imidazo [1,2-a ] pyrazin-6-yl) -1H-indazol-3-amine;

2- [4- (4- { [6- (1H-indazol-6-yl) imidazo [1,2-a ] pyrazin-8-yl ] amino } -2-methoxyphenyl) piperazin-1-yl ] ethan-1-ol;

6- [8- ({4- [ (3S) -3-hydroxypyrrolidin-1-yl ] -3-methoxyphenyl } amino) imidazo [1,2-a ] pyrazin-6-yl ] -2, 3-dihydro-1H-indol-2-one;

2- (5- { [6- (1H-indazol-6-yl) imidazo [1,2-a ] pyrazin-8-yl ] amino } -2- (morpholin-4-yl) phenoxy) ethan-1-ol;

(3S) -1- (4- { [6- (1-methyl-1H-indazol-6-yl) imidazo [1,2-a ] pyrazin-8-yl ] amino } phenyl) pyrrolidin-3-ol;

6- (5-methyl-8- { [4- (morpholin-4-yl) phenyl ] amino } imidazo [1,2-a ] pyrazin-6-yl) -2, 3-dihydro-1H-indol-2-one;

2-methyl-1- [6- (8- { [4- (morpholin-4-yl) phenyl ] amino } imidazo [1,2-a ] pyrazin-6-yl) -2H-indazol-2-yl ] propan-2-ol;

2-methyl-1- {4- [ (6- { 1H-pyrrolo [3,2-b ] pyridin-6-yl } imidazo [1,2-a ] pyrazin-8-yl) amino ] phenyl } propan-2-ol;

(3S) -1- (4- { [6- (3, 4-dihydro-2H-1, 4-benzoxazin-6-yl) imidazo [1,2-a ] pyrazin-8-yl ] amino } phenyl) pyrrolidin-3-ol;

2- [4- (8- { [4- (morpholin-4-yl) phenyl ] amino } imidazo [1,2-a ] pyrazin-6-yl) phenyl ] propan-2-ol;

6- (1H-indazol-6-yl) -3-methyl-N- [4- (morpholin-4-yl) phenyl ] imidazo [1,2-a ] pyrazin-8-amine;

n- (2-hydroxyethyl) -N-methyl-6- (8- { [4- (morpholin-4-yl) phenyl ] amino } imidazo [1,2-a ] pyrazin-6-yl) -1H-indazole-3-carboxamide;

5-chloro-6- (1H-indazol-6-yl) -N- [4- (morpholin-4-yl) phenyl ] imidazo [1,2-a ] pyrazin-8-amine;

2- (4- { [6- (1H-indazol-6-yl) imidazo [1,2-a ] pyrazin-8-yl ] amino } phenoxy) acetamide;

1- (4- { [6- (1H-indol-6-yl) imidazo [1,2-a ] pyrazin-8-yl ] amino } -2-methoxyphenyl) -3-methylazetidin-3-ol;

1- (4- { [6- (1H-indol-6-yl) imidazo [1,2-a ] pyrazin-8-yl ] amino } phenyl) -3-methylazetidin-3-ol;

2-methyl-1- [6- (8- { [4- (morpholin-4-yl) phenyl ] amino } imidazo [1,2-a ] pyrazin-6-yl) -1H-indazol-1-yl ] propan-2-ol;

6- (1H-indazol-6-yl) -N- [ 3-methoxy-4- (oxacyclohex-4-yloxy) phenyl ] imidazo [1,2-a ] pyrazin-8-amine;

n- [ 3-methoxy-4- (morpholin-4-yl) phenyl ] -6- (1-methyl-1H-indazol-6-yl) imidazo [1,2-a ] pyrazin-8-amine;

6- (3, 4-dihydro-2H-1, 4-benzoxazin-6-yl) -5-methyl-N- [4- (morpholin-4-yl) phenyl ] imidazo [1,2-a ] pyrazin-8-amine;

2-methyl-2- (4- { [6- (1-methyl-1H-indazol-6-yl) imidazo [1,2-a ] pyrazin-8-yl ] amino } phenyl) propan-1-ol;

1- (3-hydroxy-3-methylazetidin-1-yl) -2- (4- { [6- (1H-indazol-6-yl) imidazo [1,2-a ] pyrazin-8-yl ] amino } phenoxy) ethan-1-one;

1- [6- (1, 3-benzothiazol-5-yl) imidazo [1,2-a ] pyridin-8-yl ] -3-methylurea;

1- [6- (1, 3-benzothiazol-5-yl) imidazo [1,2-a ] pyridin-8-yl ] -3-ethylurea;

1- { 2-ethoxy-4- [ (6- { 1H-pyrrolo [3,2-b ] pyridin-6-yl } imidazo [1,2-a ] pyrazin-8-yl) amino ] phenyl } -3-methylazetidin-3-ol;

1- { 2-methoxy-4- [ (6- { 1H-pyrrolo [3,2-b ] pyridin-6-yl } imidazo [1,2-a ] pyrazin-8-yl) amino ] phenyl } -3-methylazetidin-3-ol;

6- (1H-indol-6-yl) -N- [ 3-methoxy-4- (morpholin-4-yl) phenyl ] imidazo [1,2-a ] pyrazin-8-amine;

6- (1H-indazol-6-yl) -N- [4- (oxacyclohex-4-yloxy) phenyl ] imidazo [1,2-a ] pyrazin-8-amine;

6- (8- { [ 3-methoxy-4- (morpholin-4-yl) phenyl ] amino } imidazo [1,2-a ] pyrazin-6-yl) -3, 4-dihydro-2H-1, 4-benzoxazin-3-one;

6- (1H-indazol-6-yl) -N- [3- (morpholin-4-yl) phenyl ] imidazo [1,2-a ] pyrazin-8-amine;

2- (4- { [6- (1H-indazol-6-yl) imidazo [1,2-a ] pyrazin-8-yl ] amino } phenoxy) -N, N-dimethylacetamide;

3-methyl-1- {4- [ (6- { 1H-pyrrolo [3,2-b ] pyridin-6-yl } imidazo [1,2-a ] pyrazin-8-yl) amino ] phenyl } azetidin-3-ol;

1-methyl-5- (5-methyl-8- { [4- (morpholin-4-yl) phenyl ] amino } imidazo [1,2-a ] pyrazin-6-yl) -2, 3-dihydro-1H-1, 3-benzodiazol-2-one;

1-ethyl-5- (8- { [4- (morpholin-4-yl) phenyl ] amino } imidazo [1,2-a ] pyrazin-6-yl) -2, 3-dihydro-1H-1, 3-benzodiazol-2-one;

6- (3, 4-dihydro-2H-1, 4-benzoxazin-6-yl) -5-ethyl-N- [4- (morpholin-4-yl) phenyl ] imidazo [1,2-a ] pyrazin-8-amine;

6- (5-ethyl-8- { [4- (morpholin-4-yl) phenyl ] amino } imidazo [1,2-a ] pyrazin-6-yl) -2, 3-dihydro-1H-indol-2-one;

(3S) -1- {4- [ (6- { 1H-pyrrolo [3,2-b ] pyridin-6-yl } imidazo [1,2-a ] pyrazin-8-yl) amino ] phenyl } piperidin-3-ol;

(3S) -1- { 2-methoxy-4- [ (6- { 1H-pyrrolo [3,2-b ] pyridin-6-yl } imidazo [1,2-a ] pyrazin-8-yl) amino ] phenyl } piperidin-3-ol;

2- (1- {4- [ (6- { 1H-pyrrolo [3,2-b ] pyridin-6-yl } imidazo [1,2-a ] pyrazin-8-yl) amino ] phenyl } piperidin-4-yl) ethan-1-ol;

2- [6- (5-methyl-8- { [4- (morpholin-4-yl) phenyl ] amino } imidazo [1,2-a ] pyrazin-6-yl) -1H-indazol-3-yl ] ethan-1-ol;

1- [4- ({6- [3- (2-hydroxyethyl) -1H-indazol-6-yl ] imidazo [1,2-a ] pyrazin-8-yl } amino) phenyl ] -3-methylazetidin-3-ol;

6- [8- ({4- [ (2R) -2- (hydroxymethyl) morpholin-4-yl ] phenyl } amino) imidazo [1,2-a ] pyrazin-6-yl ] -2, 3-dihydro-1H-indol-2-one;

6- [8- ({4- [ (2S) -2- (hydroxymethyl) morpholin-4-yl ] phenyl } amino) imidazo [1,2-a ] pyrazin-6-yl ] -2, 3-dihydro-1H-indol-2-one;

5- (5-ethyl-8- { [4- (morpholin-4-yl) phenyl ] amino } imidazo [1,2-a ] pyrazin-6-yl) -1-methyl-2, 3-dihydro-1H-1, 3-benzodiazol-2-one;

5-ethyl-N- [4- (morpholin-4-yl) phenyl ] -6- { 1H-pyrrolo [3,2-b ] pyridin-6-yl } imidazo [1,2-a ] pyrazin-8-amine;

(3R) -1- (4- { [6- (3, 4-dihydro-2H-1, 4-benzoxazin-6-yl) imidazo [1,2-a ] pyrazin-8-yl ] amino } -2-methoxyphenyl) piperidin-3-ol;

n- [4- (morpholin-4-yl) phenyl]-6- (1,2,3, 5-tetrahydro-4, 1-benzoxaazepine-8-yl) imidazo [1,2-a]Pyrazin-8-amine;

[ (3R) -4- (4- { [6- (1H-indazol-6-yl) imidazo [1,2-a ] pyrazin-8-yl ] amino } phenyl) morpholin-3-yl ] methanol;

[ (3S) -4- (4- { [6- (1H-indazol-6-yl) imidazo [1,2-a ] pyrazin-8-yl ] amino } phenyl) morpholin-3-yl ] methanol;

(3S) -1- (4- { [6- (3, 4-dihydro-2H-1, 4-benzoxazin-6-yl) imidazo [1,2-a ] pyrazin-8-yl ] amino } -2-methoxyphenyl) piperidin-3-ol;

(1- {4- [ (6- { 1H-pyrrolo [3,2-b ] pyridin-6-yl } imidazo [1,2-a ] pyrazin-8-yl) amino ] phenyl } piperidin-4-yl) methanol;

[ (2R) -4- (4- { [6- (3, 4-dihydro-2H-1, 4-benzoxazin-6-yl) imidazo [1,2-a ] pyrazin-8-yl ] amino } -2-methoxyphenyl) morpholin-2-yl ] methanol;

[ (2S) -4- (4- { [6- (3, 4-dihydro-2H-1, 4-benzoxazin-6-yl) imidazo [1,2-a ] pyrazin-8-yl ] amino } -2-methoxyphenyl) morpholin-2-yl ] methanol;

4- (4- { [6- (1H-indazol-6-yl) imidazo [1,2-a ] pyrazin-8-yl ] amino } phenoxy) cyclohexan-1-ol;

6- (1H-indazol-6-yl) -N- (4- { 2-oxa-6-azaspiro [3.3] heptan-6-yl } phenyl) imidazo [1,2-a ] pyrazin-8-amine;

2- [6- (8- { [ 3-methoxy-4- (morpholin-4-yl) phenyl ] amino } imidazo [1,2-a ] pyrazin-6-yl) -1H-indazol-3-yl ] ethan-1-ol;

[ (2S) -4- (4- { [6- (1H-indazol-6-yl) imidazo [1,2-a ] pyrazin-8-yl ] amino } -2-methoxyphenyl) morpholin-2-yl ] methanol;

[ (2R) -4- (4- { [6- (1H-indazol-6-yl) imidazo [1,2-a ] pyrazin-8-yl ] amino } -2-methoxyphenyl) morpholin-2-yl ] methanol;

2- [1- (4- { [6- (3, 4-dihydro-2H-1, 4-benzoxazin-6-yl) imidazo [1,2-a ] pyrazin-8-yl ] amino } phenyl) piperidin-4-yl ] ethan-1-ol;

6- (1H-indazol-6-yl) -N- (4- { 8-oxa-3-azabicyclo [3.2.1] oct-3-yl } phenyl) imidazo [1,2-a ] pyrazin-8-amine;

[ (3R) -1- (4- { [6- (1H-indazol-6-yl) imidazo [1,2-a ] pyrazin-8-yl ] amino } phenyl) pyrrolidin-3-yl ] methanol;

[ (3S) -1- (4- { [6- (1H-indazol-6-yl) imidazo [1,2-a ] pyrazin-8-yl ] amino } phenyl) pyrrolidin-3-yl ] methanol;

5-chloro-6- (3, 4-dihydro-2H-1, 4-benzoxazin-6-yl) -N- [ 3-methoxy-4- (morpholin-4-yl) phenyl ] imidazo [1,2-a ] pyrazin-8-amine;

2- [6- (8- { [ 3-methoxy-4- (morpholin-4-yl) phenyl ] amino } imidazo [1,2-a ] pyrazin-6-yl) -1H-indol-3-yl ] ethan-1-ol;

(3R) -1- (4- { [6- (3, 4-dihydro-2H-1, 4-benzoxazin-6-yl) imidazo [1,2-a ] pyrazin-8-yl ] amino } phenyl) piperidin-3-ol;

[1- (4- { [6- (3, 4-dihydro-2H-1, 4-benzoxazin-6-yl) imidazo [1,2-a ] pyrazin-8-yl ] amino } phenyl) piperidin-4-yl ] methanol;

(3S) -1- (4- { [6- (3, 4-dihydro-2H-1, 4-benzoxazin-6-yl) imidazo [1,2-a ] pyrazin-8-yl ] amino } phenyl) piperidin-3-ol;

[ (2S) -4- {4- [ (6- { 1H-pyrrolo [3,2-b ] pyridin-6-yl } imidazo [1,2-a ] pyrazin-8-yl) amino ] phenyl } morpholin-2-yl ] methanol;

[ (2R) -4- {4- [ (6- { 1H-pyrrolo [3,2-b ] pyridin-6-yl } imidazo [1,2-a ] pyrazin-8-yl) amino ] phenyl } morpholin-2-yl ] methanol;

2- [1- (4- { [6- (1H-indazol-6-yl) imidazo [1,2-a ] pyrazin-8-yl ] amino } phenyl) pyrrolidin-3-yl ] ethan-1-ol;

6- (1H-indazol-6-yl) -N- [4- (oxacyclohex-4-ylmethoxy) phenyl ] imidazo [1,2-a ] pyrazin-8-amine;

n- [5- (8- { [4- (morpholin-4-yl) phenyl ] amino } imidazo [1,2-a ] pyrazin-6-yl) pyridin-3-yl ] acetamide;

6- (8- { [ 3-methoxy-4- (oxacyclohex-4-yloxy) phenyl ] amino } imidazo [1,2-a ] pyrazin-6-yl) -2, 3-dihydro-1H-indol-2-one;

6- (1H-indol-6-yl) -N- [ 3-methoxy-4- (morpholin-4-yl) phenyl ] -5-methylimidazo [1,2-a ] pyrazin-8-amine;

6- (1H-indol-6-yl) -5-methyl-N- [4- (morpholin-4-yl) phenyl ] imidazo [1,2-a ] pyrazin-8-amine;

1- (4- { [6- (3, 4-dihydro-2H-1, 4-benzoxazin-6-yl) -5-methylimidazo [1,2-a ] pyrazin-8-yl ] amino } phenyl) -4-methylpiperidin-4-ol;

n- [ 3-methoxy-4- (oxacyclohex-4-yloxy) phenyl ] -6- { 1H-pyrrolo [3,2-b ] pyridin-6-yl } imidazo [1,2-a ] pyrazin-8-amine;

6- (1H-indazol-6-yl) -N- (4- { 2-oxa-7-azaspiro [3.5] nonan-7-yl } phenyl) imidazo [1,2-a ] pyrazin-8-amine; and

6- (1H-indazol-6-yl) -N- [ 3-methoxy-4- (oxacyclohex-4-ylmethoxy) phenyl ] imidazo [1,2-a ] pyrazin-8-amine;

1- (4- {4- [ (6- { 1H-pyrrolo [3,2-b ] pyridin-6-yl } imidazo [1,2-a ] pyrazin-8-yl) amino ] phenyl } piperazin-1-yl) ethan-1-one;

5- (8- { [3- (2-hydroxyethoxy) -4- (morpholin-4-yl) phenyl ] amino } imidazo [1,2-a ] pyrazin-6-yl) -1-methyl-2, 3-dihydro-1H-1, 3-benzodiazol-2-one;

[ (3S) -1- { 2-methoxy-4- [ (6- { 1H-pyrrolo [3,2-b ] pyridin-6-yl } imidazo [1,2-a ] pyrazin-8-yl) amino ] phenyl } pyrrolidin-3-yl ] methanol;

5- (8- { [ 3-methoxy-4- (morpholin-4-yl) phenyl ] amino } imidazo [1,2-a ] pyrazin-6-yl) -N-methylpyridin-3-amine;

5- (8- { [ 3-methoxy-4- (morpholin-4-yl) phenyl ] amino } imidazo [1,2-a ] pyrazin-6-yl) -1-methyl-2, 3-dihydro-1H-1, 3-benzodiazol-2-one;

5- [8- ({4- [ (3R) -3-hydroxypiperidin-1-yl ] phenyl } amino) imidazo [1,2-a ] pyrazin-6-yl ] -1-methyl-2, 3-dihydro-1H-1, 3-benzodiazol-2-one;

(3R) -1- { 2-methoxy-4- [ (6- { 1H-pyrrolo [3,2-b ] pyridin-6-yl } imidazo [1,2-a ] pyrazin-8-yl) amino ] phenyl } piperidin-3-ol;

4-methyl-7- (8- { [4- (morpholin-4-yl) phenyl ] amino } imidazo [1,2-a ] pyrazin-6-yl) -1,2,3, 4-tetrahydroquinoxalin-2-one;

[ (2R) -4- { 2-methoxy-4- [ (6- { 1H-pyrrolo [3,2-b ] pyridin-6-yl } imidazo [1,2-a ] pyrazin-8-yl) amino ] phenyl } morpholin-2-yl ] methanol; and

(3R) -1- {4- [ (6- { 1H-pyrrolo [3,2-b ] pyridin-6-yl } imidazo [1,2-a ] pyrazin-8-yl) amino ] phenyl } piperidin-3-ol.

In all of the above examples, the chemical entities may be administered alone, as a mixture, or in combination with other active agents.

Methods for obtaining the novel compounds described herein will be apparent to one of ordinary skill in the art, for example, suitable procedures are described in the following reaction schemes and examples, and in the references cited herein.

Reaction scheme 1

Referring to reaction scheme 1, step 1, a compound of formula 100 in which L is an excess (e.g., about 3.5 equivalents) of a leaving group such as bromide is combined with an aqueous solution of an acid (e.g., 48% aqueous hydrogen bromide) and the mixture is stirred under reflux for about 2 hours. The mixture is cooled to about 40 ℃ and a base (e.g., solid sodium bicarbonate) is added. The reaction mixture is filtered and a compound of formula 101 wherein L is a leaving group such as bromide is added and the reaction mixture is stirred under reflux for about 16 hours. The product, a compound of formula 102, is isolated and optionally purified.

Referring to reaction scheme 1, step 2, to a compound of formula 102 wherein L is a leaving group such as bromide, is added an excess (e.g., about 1.3 equivalents) of a solution of a compound of formula 103 in a polar solvent such as N, N-dimethylformamide. An organic base such as N, N-diisopropylethylamine is added and the mixture is stirred at about 120 ℃ for about 13 hours. The product, a compound of formula 104, is isolated and optionally purified.

Referring to reaction scheme 1, step 3, a mixture of the compound of formula 105, wherein L is a leaving group such as bromide, is combined with an excess of bis (pinacolato) diboron (e.g., about 1.1 equivalents) and an excess of an inorganic base (e.g., about 3.0 equivalents) such as potassium acetate in a polar solvent such as dimethyl sulfoxide. The reaction mixture was bubbled with nitrogen and stirred for about 5 minutes. The reaction mixture was treated with about 0.2 equivalents of dichloro-1, 1-bis (diphenylphosphino) ferrocene palladium (II) dichloromethane and stirred at about 80 ℃ for about 3 hours. The product, a compound of formula 106, is isolated and optionally purified.

Referring to reaction scheme 1, step 4, an excess of a compound of formula 106 (e.g., about 1.1 equivalents) and a compound of formula 104 wherein L is a leaving group such as bromide are placed in an aqueous solution of a base (e.g., 1M sodium carbonate) and an inert solvent such as 1, 4-dioxane. The reaction mixture was bubbled with nitrogen and stirred for about 5 minutes. The resulting mixture was treated with about 0.1 equivalents of tetrakis (triphenylphosphine) palladium (0) and allowed to react under microwave irradiation at about 135 ℃ for about 30 minutes. The resulting product, a compound of formula 107, is isolated and optionally purified.

Accordingly, there is provided a method of treating a patient, e.g. a mammal such as a human, having a response to inhibition of Syk activity, the method comprising administering to a patient having such a disease an effective amount of at least one chemical entity as described herein.

In some embodiments, chemical entities described herein may also inhibit other kinases, such that diseases, disorders, and conditions associated with these kinases are also treated.

The treatment methods further comprise inhibiting Syk activity and/or inhibiting B cell activity by: ATP binding or hydrolysis due to Syk or due to some other mechanism is inhibited in a patient suffering from a disease responsive to inhibition of Syk activity by administering an effective concentration of at least one chemical entity selected from those described herein. An example of an effective concentration would be a concentration sufficient to inhibit Syk activity in vitro. Effective concentrations can be determined experimentally, for example by analyzing blood concentrations of chemical entities, or theoretically by calculating bioavailability.

In some embodiments, the disease (condition) responsive to inhibition of Syk activity and/or B cell activity is cancer, an allergic disorder and/or an autoimmune and/or inflammatory disease, and/or an acute inflammatory response.

Also provided is a method of treating a patient having cancer, an allergic disorder and/or an autoimmune and/or inflammatory disease, and/or an acute inflammatory response by administering an effective amount of at least one chemical entity as described herein.

In some embodiments, conditions and diseases that can be effected using the chemical entities described herein include, but are not limited to: allergic disorders including, but not limited to, eczema, allergic rhinitis or nasal colds, hay fever, bronchial asthma, urticaria (hives), and food allergies, as well as other ectopic states; autoimmune and/or inflammatory diseases including, but not limited to, psoriasis, Crohn's disease, irritable bowel disease, Sjogren's disease, tissue transplant rejection, and hyperacute rejection of transplanted organs, asthma, systemic lupus erythematosus (and associated glomerulonephritis), dermatomyositis, multiple sclerosis, scleroderma, vasculitis (ANCA-associated and other vasculitis), autoimmune hemolytic and thrombocytopenic states, goodpasture's syndrome (and associated glomerulonephritis and pulmonary hemorrhage), arteriosclerosis, rheumatoid arthritis, chronic Idiopathic Thrombocytopenic Purpura (ITP), edison's disease, parkinson's disease, alzheimer's disease, diabetes, septic shock, myasthenia gravis, and the like; acute inflammatory reactions including, but not limited to, skin sunburn, inflammatory pelvic diseases, inflammatory bowel disease, urethritis, uveitis (uvitis), sinusitis, local acute pneumonia, encephalitis, meningitis, myocarditis, nephritis, osteomyelitis, myositis, hepatitis, gastritis, enteritis, dermatitis, gingivitis, appendicitis, pancreatitis, and cholecystitis (cholecystitis); polycystic kidney disease, and cancers including, but not limited to, B-cell lymphoma, lymphoma (including hodgkin and non-hodgkin lymphomas), hairy cell leukemia, multiple myeloma, chronic and acute myelogenous leukemia, and chronic and acute lymphocytic leukemia.

Syk is a known inhibitor of apoptosis in lymphoma B cells. Defects in apoptosis contribute to the etiology and resistance of human leukemias and lymphomas. Thus, there is further provided a method of promoting or inducing apoptosis in a cell expressing Syk, the method comprising contacting the cell with at least one chemical entity as described herein.

Also provided are methods of treatment wherein at least one chemical entity described herein is the only active agent administered to a patient, and further comprising methods of treatment wherein at least one chemical entity described herein is administered to a patient in conjunction with one or more additional active agents.

Thus, in some embodiments, a method of treating cancer, an allergic disorder and/or an autoimmune and/or inflammatory disease, and/or an acute inflammatory response comprises administering to a patient in need thereof an effective amount of at least one chemical entity as described herein and a second agent that can be used to treat cancer, an allergic disorder and/or an autoimmune and/or inflammatory disease, and/or an acute inflammatory response. For example, the second agent may be an anti-inflammatory agent. Treatment with the second active agent may be prior to, concomitant with, or subsequent to treatment with at least one chemical entity described herein. In some embodiments, at least one chemical entity described herein is combined with another active agent in a single dosage form. Suitable anti-tumor therapeutic agents that may be used in combination with at least one chemical entity described herein include, but are not limited to: a chemotherapeutic agent, such as mitomycin C, carboplatin, taxol, cisplatin, paclitaxel, etoposide, doxorubicin, or a combination comprising at least one of the foregoing chemotherapeutic agents. Radiation therapy antineoplastic agents may also be used alone or in combination with chemotherapeutic agents.

The chemical entities described herein can be used as chemosensitizers, whereby combinations with other chemotherapeutic drugs, in particular drugs that induce apoptosis, can be useful.

Also provided herein are methods for increasing the sensitivity of a cancer cell to chemotherapy, comprising administering to a patient undergoing chemotherapy a chemotherapeutic agent and at least one chemical entity described herein in an amount sufficient to increase the sensitivity of the cancer cell to the chemotherapeutic agent.

Examples of other chemotherapeutic drugs that can be used in combination with the chemical entities described herein include topoisomerase I inhibitors (camptothecin or topotecan), topoisomerase II inhibitors (e.g., to norubicin and etoposide), alkylating agents (e.g., cyclophosphamide, melphalan, and BCNU), tubulin-directing agents (e.g., taxol and vinblastine), and biologicals (e.g., antibodies such as anti-CD 20 antibodies, IDEC8, immunotoxins, and cytokines).

In some embodiments, a chemical entity described herein is reacted with(Rituximab)) or other agents that act by selectively depleting CD20+ B cells.

Included herein are methods of treatment wherein at least one chemical entity described herein is administered in combination with an anti-inflammatory agent. Anti-inflammatory agents include, but are not limited to, NSAIDs, non-specific and COX-2 specific cyclooxygenase inhibitors, gold compounds, corticosteroids, methotrexate, tumor necrosis factor receptor (TNF) receptor antagonists, immunosuppressants, and methotrexate (methotrexate).

Examples of NSAIDs include, but are not limited to, ibuprofen, flurbiprofen, naproxen and naproxen sodium, diclofenac, a combination of diclofenac sodium and misoprostol, sulindac, oxaprozin, diflunisal, piroxicam, indomethacin, etodolac, fenoprofen calcium, ketoprofen (ketoprofen), nabumetone sodium (sodium nabumetone), sulfasalazine, tolmetin sodium, and hydroxychloroquine. Examples of NSAIDs also include COX-2 specific inhibitors (i.e., compounds that inhibit COX-2 wherein the IC50 is at least 50-fold lower than the IC50 of COX-1) such as celecoxib, valdecoxib, lumiracoxib, etoxib, and/or rofecoxib.

In a further embodiment, the anti-inflammatory agent is a salicylate. Salicylates include, but are not limited to, acetylsalicylic acid or aspirin, sodium salicylate, and choline salicylate and magnesium salicylate.

The anti-inflammatory agent may also be a corticosteroid. For example, the corticosteroid may be selected from cortisone, dexamethasone, methylprednisolone, prednisolone sodium phosphate, and prednisone.

In some embodiments, the anti-inflammatory therapeutic agent is a gold compound such as disodium aurothioate or auranofin.

In some embodiments, the anti-inflammatory agent is a metabolic inhibitor, such as a dihydrofolate reductase inhibitor, e.g., methotrexate, or a dihydroorotate dehydrogenase inhibitor, e.g., leflunomide.

In some embodiments, a combination is used wherein the at least one anti-inflammatory compound is an anti-C5 monoclonal antibody (such as eculizumab or peclizumab), a TNF antagonist that is an anti-TNF-alpha monoclonal antibody such as etanercept (entanercept), or infliximab.

In some embodiments, the following combinations are used: wherein at least one active agent is an immunosuppressant compound such as methotrexate, leflunomide, cyclosporine, tacrolimus, azathioprine or mycophenolate mofetil.

For example, dosage levels of about 0.1mg to 140mg per kilogram body weight per day can be useful in the treatment of the diseases (conditions) indicated above (0.5 mg to 7g per patient per day). The amount of active ingredient that may be combined with the vehicle to produce a single dosage form will vary depending upon the host treated and the particular mode of administration. Unit dosage forms typically contain from 1mg to 500mg of the active ingredient.

The frequency of dosing can also vary depending on the compound used and the particular disease being treated. In some embodiments, for example, for the treatment of allergic disorders and/or autoimmune and/or inflammatory diseases, a dosing regimen of less than 4 times per day is used. In some embodiments, a dosing regimen of 1 or 2 times per day is used. It will be understood, however, that the specific dose level for any particular patient will depend upon a variety of factors including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, route and rate of administration, drug combination and the severity of the particular disease in the patient undergoing treatment.

The labeled forms of the chemical entities described herein can be used as diagnostics for identifying and/or obtaining compounds that function to modulate kinase activity as described herein. In addition, the chemical entities described herein can be used to verify, optimize, and standardize bioassays.

By "labeled" in this context is meant a compound that is directly or indirectly labeled with a label that provides a detectable signal, e.g., a radioisotope, a fluorescent label, an enzyme, an antibody, a particle such as a magnetic particle, a chemiluminescent label, or a specific binding molecule, and the like. Specific binding molecules include those against e.g. biotin and streptavidin, digoxin and digoxin resistant drugs, etc. For a particular binding member, the complementary member is labelled, as described above, with a molecule ready for detection, typically following known procedures. The label is capable of providing a detectable signal, either directly or indirectly.

Examples

The invention is further illustrated by the following non-limiting examples.

In the examples which follow, the following abbreviations have the following meanings. Abbreviations have their usual meaning if not defined.

DME ═ dimethyl ether

DMEM-Darber's modified eagle's medium

DMF ═ N, N-dimethylformamide

DMSO ═ dimethyl sulfoxide

Et₂Diethyl ether (O ═ C)

g is g ═ g

h is hour

mg ═ mg

min is minutes

mL to mL

mmol ═ mmol

millimolar mM

ng-nanogram

nm-nm

nM as nanomolar

PBS-phosphate buffered saline

μ L ═ microliter

Micromolar on a μ M basis

Example 1

Preparation of 6- (benzo [ d ] thiazol-5-yl) -N- (3, 4-dimethoxy-phenyl) imidazo [1,2-a ] pyrazin-8-amine (4)

Preparation of 6, 8-dibromoimidazo [1,2-a ] pyrazine (1)

A1L four-necked round bottom flask equipped with a temperature sensor, mechanical stirrer and reflux condenser was charged with 2-bromo-1, 1-diethoxyethane (68.1g, 346mmol) and 48% aqueous hydrogen bromide (11.3mL, 99.2mmol) and the reaction mixture was stirred under reflux for 2 hours. The resulting mixture was cooled to 40 ℃ and solid sodium bicarbonate (8.50g,101mmol) was added in small portions (in small fractions) until cessation of gas evolution was observed. Note that: the initial addition of sodium bicarbonate to the mild solution resulted in a vigorous gas evolution (bubbling). The resulting suspension was filtered into a 1L four-necked round bottom flask and the filter cake was washed with ethanol (200 mL). The flask was equipped with a temperature sensor, mechanical stirrer and reflux condenser. 3, 5-dibromopyrazin-2-amine (50) was added.0g, 198mmol) and the reaction mixture is heated under vigorous stirring at reflux for 16 hours. After this time, the suspension was cooled to 0 ℃ and filtered. The filter cake was washed with cold ethanol (50mL), dried under vacuum and added to a 1L three-necked round bottom flask equipped with a mechanical stirrer. Water (200mL) was added and the vigorously stirred suspension was treated with solid potassium carbonate (27.4g, 198mmol) in portions (transition-wise). Note that: gas evolution was observed upon addition of potassium carbonate. After stirring for 30 minutes, the resulting precipitate was isolated by filtration and the filter cake was washed with water (100mL), followed by ethanol (50 mL). The filter cake was dried to constant weight at 50 ℃ under vacuum to provide 6, 8-dibromoimidazo [1,2-a ] as a pale yellow solid]Pyrazine (1) (52.0g, 94%):¹H NMR(300MHz,DMSO-d₆)9.02(s,1H)，8.23(s,1H)，7.90(s,1H)。

preparation of 6-bromo-N- (3, 4-dimethoxyphenyl) imidazo [1,2-a ] pyrazin-8-amine (2)

3, 4-Dimethoxyaniline (18.0g, 118mmol), 6, 8-dibromoimidazo [1,2-a ] is reacted at 120 deg.C]A mixture of pyrazine (25.0g, 90.4mmol) and N, N-diisopropylethylamine (11.7g, 90.4mmol) in DMF (500mL) was stirred overnight. After this time, the reaction was cooled to room temperature and concentrated under reduced pressure to about 100 mL. The dark brown reaction mixture was poured into ice-cold water (300mL) and stirred for 10 min. The resulting brown precipitate was filtered and the filter cake was washed with water (100 mL). The filter cake was dried under vacuum and recrystallized from methanol (-800 mL) to provide 6-bromo-N- (3,4, 5-trimethoxyphenyl) imidazo [1,2-a as a light brown needle-like solid]Pyrazin-8-amine (2) (23.3g, 74%):¹H NMR(300MHz,DMSO-d₆)9.81(s,1H)，8.22(s,1H)，7.93(s,1H)，7.75(d,J＝2.4Hz,1H)，7.62(s,1H)，7.53(dd,J＝8.7,2.4,1H)，6.94(d,J＝8.7Hz,1H)，3.77(s,3H)，3.75(s,3H)；ESI MS m/z 349.2[M+H]⁺(ii) a HPLC,6.92 min,>99％(AUC)。

preparation of 5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) benzo [ d ] thiazole (3)

By treatment of 5-bromobenzo [ d ] with nitrogen]A mixture of thiazole (428mg, 2.00mmol), bis (pinacolato) diboron (558mg, 2.20mmol) and potassium acetate (588mg, 6.00mmol) in dimethyl sulfoxide (7mL) was bubbled while stirring for 5 minutes, then dichloro-1, 1-bis (diphenylphosphino) ferrocene palladium (II) dichloromethane (293mg, 0.40mmol) was added and the reaction was stirred at 85 ℃ for 3 hours after which time the mixture was filtered through a pad of Celite (Celite) and the cake was washed with water (20mL), the filtrate was diluted with ethyl acetate (100mL) and water (2 × 75mL), then the filtrate was washed with brine (75mL), the organic phase was dried with anhydrous sodium sulfate, filtered and concentrated under reduced pressure to provide a light brown solid which was purified by chromatography (silica gel, gradient 0% to 50% ethyl acetate in dichloromethane) to afford a residue of 5- (4-tetramethyl-5-3 d, 5-tetramethyl-3-dioxaborolan, 5-tetramethyl-2 d, 5-3-2-bis (diphenylphosphino) ferrocene palladium (II) and potassium acetate (II) was added to the reaction mixture to provide a brown solid which was purified by column chromatography]Thiazole (3) (200mg, 38%):¹H NMR(300MHz,DMSO-d₆)9.41(s,1H)，8.32(s,1H)，8.18(d,1H,J＝8.0Hz)，7.72(d,1H,J＝8.0Hz)，1.33(s,12H)；ESI MS m/z 262.1[M+H]⁺。

preparation of 6- (benzo [ d ] thiazol-5-yl) -N- (3, 4-dimethoxyphenyl) imidazo [1,2-a ] pyrazin-8-amine (4)

6-bromo-N- (3, 4-dimethoxyphenyl) imidazo [1,2-a ] with nitrogen]Pyrazin-8-amine (2) (209mg, 0.601mmol) and 5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) benzo [ d]A mixture of thiazole (3) (180mg, 0.689mmol) in 1M aqueous sodium carbonate (0.76mL) and 1, 4-dioxane (2.4mL) was bubbled with stirring for 5 minutes. Tetrakis (triphenylphosphine) palladium (0) (69mg, 0.06mmol) was then added and the resulting mixture was reacted for 30 min at 135 ℃ under microwave irradiation. After this time, the reaction was cooled to ambient temperature, diluted with 1:9 methanol/ethyl acetate (75mL), and washed with water (50mL) then brine (50 mL). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. By chromatography (silica gel, silica), gradient 0% to 1 in dichloromethane0% methanol) to provide 6- (benzo [ d ] as an off-white solid]Thiazol-5-yl) -N- (3, 4-dimethoxyphenyl) imidazo [1,2-a]Pyrazin-8-amine (4) (169mg, 70%): mp 179-181 ℃;¹H NMR(300MHz,DMSO-d₆)9.56(s,1H)，9.45(s,1H)，8.78(s,1H)，8.76(d,1H,J＝1.2Hz)，8.26(d,1H,J＝8.7Hz)，8.14(m,2H)，8.00(s,1H)，7.66(s,1H)，7.58(dd,1H,J＝8.7,2.4Hz)，6.99(d,1H,J＝8.7Hz)，3.87(s,3H)，3.76(s,3H)；MS m/z 404.6[M+H]⁺(ii) a HPLC, 6.475 min, 98.6% (AUC).

Example 2

The following compounds were prepared using procedures similar to those described above. One of ordinary skill in the art of organic synthesis will recognize when starting materials or reaction conditions should be altered to obtain the desired compound.

The MS data reported in this example was obtained as follows:

MS conditions: electrospray mass spectrometry (Electrospray MS) was performed on a MICROMASS LCT equipped with a LockSpray source for accurate mass determination. Spectra were obtained from 100-1000Da in positive ion mode at an acquisition speed of 1 spectrum/0.9 s with an inter-scan delay of 0.1 s. The device is tuned to a resolution of 5000 (FWHM). Each 5 th scan is obtained from the reference position of the Lockspray source. Leucine enkephalin (556.2771[ M + H) was used]⁺) As a reference or lock mass.

Example 3

Biochemical Syk assay

A general procedure for one standard biochemical Syk kinase assay that can be used for the test compounds disclosed in this application is as follows.

A negative Syk enzyme mixture (master mix minus Syk enzyme) was prepared containing 1 Xcell signal transduction kinase buffer (25mM Tris (hydroxymethyl) aminomethane hydrochloride (Tris-HCl), pH 7.5, 5mM β -glycerophosphate, 2mM dithiothreitol, 0.1mM Na₃VO₄，10mM MgCl₂) 0.5 μ M Promega PTK Biotinylated peptide substrate (Biotinylated peptide substrate)1, 0.01% casein, 0.01% Triton-X100 (polyethylene glycol octylphenyl ether), and 0.25% glycerol. A positive Syk enzyme mixture (master mix plus Syk enzyme) was prepared containing 1X cell signal transduction kinase buffer, 0.5. mu.M PTK Biotinylated peptide substrate (Biotinylated peptide) 1, 0.01% casein, 0.01% Triton-X100 (polyethylene glycol octylphenyl ether), 0.25% glycerol, and 0.4 ng/well Syk enzyme. The Syk enzyme was purchased from Cell signalling Technologies, Inc., full-length human wild-type Syk expressed as baculovirus and labeled with N-terminal GST (accession No. NM-00377). The Syk protein was purified in one step using glutathione sepharose. The purity of the final protein preparation was assessed by SDS-PAGE and Coomassie staining. A solution of 200. mu.M ATP was prepared in water and adjusted to pH7.4 with 1N NaOH. An amount of 1.25. mu.L of compound in 5% DMSO was transferred to a 96-well 1/2 zone Costar polystyrene plateIn (1). An 11-point dose response curve (starting concentration 10) was used^-1Mu M; 1:2 dilution) compounds were tested individually. An amount of 18.75. mu.L of negative enzyme mix (master mix minus enzyme) and positive enzyme mix (master mix plus enzyme) were transferred to appropriate wells in 96-well 1/2-zone Costar polystyrene plates. mu.L of 200. mu.M ATP was added to the above mixture in the 96-well 1/2-zone Costar polystyrene plate to give a final ATP concentration of 40. mu.M. The reaction was allowed to develop (incubate) at room temperature for 1 hour. The reaction was stopped with Perkin Elmer (Perkin Elmer) 1 Xdetection buffer containing 30mM EDTA, 80nM SA-APC and 4nM PT66 Ab. The plates were read using time-resolved fluorescence using a Perkin Elmer Envision using an excitation filter (excitation filter)330nm, an emission filter 665nm, and a second emission filter 615 nm. Then using linear regression algorithm to IC₅₀The value is calculated.

Example 4

Ramos cell pBLNK (Y96) assay

Another general procedure for Syk kinase assay for standard cells that can be used for the test compounds disclosed in this application is as follows.

In a vertical T175Falcon TC flask, 2 × 10 in serum-free RPMI⁶Ramos cells were serum depleted for 1 hour per ml cells were centrifuged (1100rpm × 5 min) and incubated at 37 ℃ in the presence of test compounds or DMSO controls at 0.5 × 10⁷The cells/ml were incubated at a density of 1 hour. Then, by using 10. mu.g/ml of anti-human IgM F (ab) at 37 ℃₂Cells were stimulated by incubation for 5 minutes. Cells were pelleted, lysed in 40 μ l cell lysis buffer, and mixed with Invitrogen SDS-PAGE loading buffer. Anti-phospho BLNK (phosphorylated T lymphocyte connexin antibody, anti-phosphoBLNK) (Tyr96) antibody (Cell Signaling Technology #3601) for the evaluation of Syk activity and anti Syk antibody (BD Transduction Labs # 611) for the control of total protein load in various lysates were utilized116) SDS-PAGE and Western blotting were performed on 20. mu.l of cell lysates for each sample. The images were detected using a fluorescent secondary detection system and LiCor Odyssey software.

Example 5

B cell proliferation assay

A general procedure for a standard cellular B cell proliferation assay that can be used for the test compounds disclosed in this application is as follows.

B cells were purified from the spleens of 8-16 week old Balb/c mice using the B cell isolation kit (Miltenyi Biotech, Cat # 130-⁵Purified mouse splenic B cells were incubated for 30 minutes. After 24 hours incubation, 1. mu. Ci was added³H-thymidine, and use thereof in SPA [2 ]³H]Plates were incubated for an additional 36 hours prior to harvest as agreed by the manufacturer of the thymidine uptake assay system (amersham biosciences # RPNQ 0130). SPA pellet-based fluorescence was counted using a microplate scintillation counter (microbeta counter) (Wallace Triplex1450, Perkin Elmer).

Example 6

T cell proliferation assay

A general procedure for a standard T cell proliferation assay that can be used for the test compounds disclosed in this application is as follows.

T cells were purified from the spleens of 8-16 week old Balb/c mice using a Pan T cell isolation kit (Miltenyi Biotech, Cat # 130-⁵The purified mouse spleen T is thinThe cells were incubated and the plates were pre-coated with 10. mu.g/ml of each of anti-CD 3(BD #553057) and anti-CD 28(BD # 553294) antibodies for 90 minutes at 37 ℃. After 24 hours incubation, 1. mu. Ci was added³H-thymidine, and use thereof in SPA [2 ]³H]Plates were incubated for an additional 36 hours prior to harvest as agreed by the manufacturer of the thymidine uptake assay system (Amersham Biosciences # RPNQ 0130). SPA pellet-based fluorescence was counted using a microplate scintillation counter (microbeta counter) (Wallace Triplex1450, Perkin Elmer).

Example 7

CD69 inhibition assay

A general procedure for a standard assay for inhibiting B cell activity that can be used for the test compounds disclosed in this application is as follows.

Total mouse splenocytes were purified from the spleens of 8-16 week old Balb/c mice by red blood cell lysis (BD Pharmingen #555899) test compounds were diluted to 0.5% DMSO and used in a final volume of 200 μ l of 1.25 × 10 in a flat, transparent bottom plate (Falcon 353072) at 37 deg.C⁶Individual splenocytes were incubated for 60 minutes. Then, the cells were stimulated under the condition of adding 15. mu.g/ml IgM (Jackson ImmunoResearch 115-₂Following 16 hours of incubation, cells were transferred to conical bottom clear 96-well plates and pelleted by centrifugation at 1200 × g × 5 min after 16 hours of incubation, cells were prebaked by CD16/CD32(BD Pharmingen #553142), followed by triple staining using CD19-FITC (BD Pharmingen #553785), CD69-PE (BD Pharmingen #553237), and 7AAD (BD Pharmingen #51-68981E), cells were sorted on BD FACSCalibur and stained on CD19⁺/7AAD^-It is gated on the group. The surface expression level of CD69 on the gated population relative to the concentration of test compound was measured.

Example 8

Degranulation of BMMC

A general procedure for standard assays for degranulation of bone marrow-derived mouse mast cells (BMMC) that can be used for the test compounds disclosed in this application is as follows.

Bone marrow-derived mast cell cultures Using IL-3(10ng/ml) and SCF (10ng/ml)>4 weeks. The cells were determined by FACS analysis at the time of use to be>90％ cKit⁺/FceRI⁺Cells were grown in T150 cell culture flasks (6X 10) in the absence of IL-3 and SCF containing IgE α -DNP at 1ug/ml⁷Individual cells/50 ml) lacking serum for 16 hours overnight sensitized cells were washed twice in Tyrodes buffer and resuspended to 5 × 10⁶Cell/ml. 5 × 10⁵Individual cells (100ul) were placed in 96-well microtiter plates (Falcon 353072) and incubated at 37 ℃ with 5% CO₂Test compounds were serially diluted in plates to a final concentration of 0.25% DMSO for 1 hour. The wells were treated with DNP-BSA antigen challenge (50ng/ml) at 37 ℃ and incubated for an additional 30 minutes. Supernatants were analyzed for hexosaminidase release (hexosamimidase release) relative to control wells. The cell pellet was simultaneously lysed and all hexosaminidase release was analyzed to calculate specific release. Dose response curves were generated using a 4-parameter logistic fit and calculated IC 50.

Example 9

Passive skin allergic reaction (PCA)

The following is a procedure for a standard PCA model for measuring IgE anti-DNP Ab sensitization in vivo, DNP-BSA antigen for triggering mast cell degranulation, and release of immunomodulators responsible for acute vascular permeability monitored by Evan's blue dye (Evan's blue dye) into the inflamed region of the mouse ear.

1.2mg/ml in phosphate buffer solutionProviding a reagent: anti-DNP IgE, buffered with BSA for additional proteins and azide for sterility. It was diluted 1:100 in sterile PBS to 12 μ g/ml working stock, which can be further diluted in PBS to the appropriate concentration for injection. Further 1:5 dilution gave a final 1:500 solution (10 μ l/l 24ng) of 2.4ng/μ l. Sterile PBS alone was used as a negative control. Will be in sterile ddH₂the-DNP-BSA was formulated at 4mg/ml in O and stored as a 40 ℃ solution. It was further diluted 1:1 with sterile saline prior to use. This solution or further dilutions in saline were 1:1 diluted with 2% evans blue in sterile saline that had been filtered through 0.02 μm filter paper and refiltered prior to injection. For these experiments, a final solution of 0.5mg/ml of DNP-BSA in 1% Evans blue can be used. Tail vein injection was kept constant at 200 μ Ι ═ 100 μ g in 1% evans blue. Evans's blue dye (Evan's blue dye) A2% stock in saline was sterile filtered and 1:1 diluted with DNP-BSA saline solution to obtain a 1% final concentration for injection.

General PCA protocol using intracutaneous ear sensitization

1) Animals anesthetized with isoflurane (isoflurorine) were passively sensitized at d0 (on d0) by intradermal injection of IgE anti-DNP using a No. 29 metered insulin syringe. By convention, the left ear received a 10 μ l intradermal injection of anti-DNP IgE while the right ear received PBS. 2) Sensitization was performed after 20 hours and antigen challenge was given by tail vein injection of DNP-BSA in 200 μ l of 1% evans blue dye solution in saline. The tail was immersed in warm water prior to intravenous injection to increase success. 3) The drug is administered subcutaneously or orally 30 minutes to 2 hours prior to challenge with the antigen, in 10% EtOH/20% cremophor/70% saline. 4) Passing CO for 30-60 min₂Animals were sacrificed by antigen challenge after inhalation and the ears were removed to extract the evans blue dye in 500 μ l formamide overnight at 65 ℃. 5) Just prior to the final cervical dislocation, blood was obtained by cardiac puncture and its plasma was processed to provide a PK scoreAnd (6) analyzing. 6) The amount of evans blue dye was determined by reading the absorbance at 620nm of 200 μ l of extract in a microtiter plate.

Study design of experiments

Each animal had one anti-DNP IgE sensitized ear (right ear by convention) and one PBS control ear (left ear by convention). Groups 1-8: support and compound test arms (arms); group 9: represents a non-antigenic negative control; group 10: negative controls representing non-sensitized excitations; panel 11 represents a non-antigen primed, non-sensitized negative control group (panels 9-11 represent negative controls for background levels only and require only a minimum number of animals per group).

The compounds disclosed in the above examples were tested in the Syk biochemical assay described herein (example 3), and some of those compounds showed an IC of less than or equal to 1 micromolar₅₀The value is obtained. Some of those compounds showed an IC of less than or equal to 100nM₅₀The value is obtained. Some of those compounds exhibit an IC of less than or equal to 10nM₅₀The value is obtained. Some of those compounds exhibit an IC of less than or equal to 1nM₅₀The value is obtained.

Some of the compounds disclosed in example 2 were tested in a B cell proliferation assay (as described in example 5) and showed an IC of less than or equal to 10 micromolar₅₀The value is obtained. Some of those compounds exhibit an IC of less than or equal to 1 micromolar₅₀The value is obtained.

Some of those compounds do not inhibit T cell proliferation and have an IC greater than or equal to 5 micromolar when assayed under the conditions described herein₅₀Values (as described in example 6).

Some of the compounds described herein show IC for inhibiting T cell proliferation₅₀Value of IC over those compounds used to inhibit B cell proliferation₅₀The value is at least 3 times greater, and in some cases 5 times greater.

In assays for inhibiting B cell activitySome of the compounds described herein were tested (under the conditions described in example 7) and showed an IC of less than or equal to 10 micromolar₅₀The value is obtained. Some of those compounds exhibit an IC of less than or equal to 1 micromolar₅₀The value is obtained.

Some of the compounds disclosed in the description herein exhibit both biochemical and cell-based activities. For example, some of the compounds described herein exhibit an IC of less than or equal to 10 micromolar in the Syk biochemical assay described herein (example 3)₅₀Values, and exhibits an IC of less than or equal to 10 micromolar in at least one cell-based assay (other than a T cell assay) described herein₅₀Value (example 4,5, 7 or 8). Some of those compounds showed an IC of less than or equal to 1 micromolar in the Syk biochemical assay described herein (example 4)₅₀Values, and exhibits an IC of less than or equal to 10 micromolar in at least one cell-based assay (other than a T cell assay) described herein₅₀Value (example 4,5, 7 or 8). Some of those compounds exhibit an IC of less than or equal to 0.1 micromolar₅₀Values, and exhibits an IC of less than or equal to 10 micromolar in at least one cell-based assay (other than a T cell assay) described herein₅₀Value (example 4,5, 7 or 8).

Although a few embodiments have been shown and described, various modifications and substitutions may be made thereto without departing from the spirit and scope of the invention. For example, for the purposes of claim interpretation, it is not intended to interpret the claims set forth below in any way narrower than the literal language thereof, and thus it is not intended to display exemplary embodiments from the specification in the claims. Accordingly, it is to be understood that the present invention has been described by way of illustration and not limitation of the scope of the claims.

Claims

1. Use of a compound having the structure:

2. use of a compound having the structure:

3. use of a compound having the structure:

4. a compound of formula I:

wherein R is₁Selected from (1-hydroxycyclobutyl) phenyl, (1,1, 1-trifluoro-2-hydroxypropan-2-yl) phenyl, (2,2, 2-trifluoro-1-hydroxyethyl) phenyl, (2-hydroxy-2-methylpropoxy) -3-methoxyphenyl, (2-hydroxyethyl) (methyl) amino) -3-methoxyphenyl, (2-methoxyethyl) (methyl) amino) -3-methoxyphenyl, (1-hydroxyethyl) phenyl, 3, 4-dimethoxyphenyl, 3-methoxyphenyl, 4-ethoxy-3-methoxyphenyl, 4-hydroxymethyl-3-methoxyphenyl, 3-hydroxymethyl-4-methoxyphenyl, 2-fluoro-4-methoxyphenyl, 4- (dimethylamino) propoxy-3-methoxyphenyl, 4-hydroxypropoxy-3-methoxyphenyl, 4- (2-hydroxy-1, 1-dimethylethyl) phenyl, 4- (1-hydroxy-1-methylethyl) phenyl, 4-methoxy-3- (pyrrolidin-1-yl) phenyl, 3-methoxy-4- (propan-2-yloxy) phenyl, 3-methoxy-4- (morpholin-4-yl) phenyl, 4- (pyrrolidin-1-yl) phenyl, and mixtures thereof, 4- (3-hydroxypyrrolidinyl) phenyl, 4- (4-hydroxypiperidinyl) -3-methoxyphenyl, 4- (3-hydroxyazetidinyl) -3-methoxyphenyl, 4- (3-hydroxypyrrolidinyl) -3-methoxyphenyl, 4- (2-methoxypropan-2-yl) phenyl, 4- (4-ethylpiperazin-1-yl) -3-methoxyphenyl and 4- (4-ethylpiperazin-1-yl) phenyl, 4- (3-hydroxy-3-methylpiperidinyl) phenyl and 3-hydroxymethylphenyl; or

R₂Selected from the group consisting of 1, 3-benzoxazol-5-yl, 2-aminoquinazolin-6-yl, 2-hydroxyethyl-2H-indazol-6-yl, 1H-indazol-7-yl, 3- (diethylamino) methyl-1H-indazol-6-yl, 1, 2-dihydroquinoxalin-2-one-6-yl, 1, 2-dihydroquinolin-2-one-6-yl, 2-methyl-1, 3-benzothiazol-5-yl, 3- (1, 3-thiazol-4-ylmethylene) -2, 3-dihydro-1H-indol-2-one-6-yl, and mixtures thereof, 1-methyl-1H-indazol-6-yl, (N, N-dimethylaminocarbonyl) indol-6-yl, 1, 3-benzothiazol-5-yl, 1, 3-benzothiazol-6-yl, 3-ethyl-1H-indazol-6-yl, 1H-indol-2-yl, 1H-indol-3-yl, 4-fluoro-1H-indazol-6-yl, 1H-1,2, 3-benzotriazol-6-yl, 1H-1, 3-benzodiazol-6-yl, 1H-indol-6-yl, 1H-pyrrolo [3,2-b ] group]Pyridin-6-yl, 1-methyl-1H-1, 3-benzooxadiazol-5-yl, 1-methyl-1H-1, 3-benzooxadiazol-6-yl, 1-methyl-1H-benzo [ d ]]Imidazol-5-yl, 2-methyl-1H-benzo [ d]Imidazol-5-yl, 3-amino-1H-indazol-6-yl, 3-carbamoyl-1H-indazol-6-yl, 3-methyl-1H-indazol-6-yl, 5-fluoro-1H-indazol-6-yl, 1H-indazol-5-yl, 1H-indazol-6-yl, 3-amino-1H-indazol-5-yl, 1-methyl-1H-indazol-6-yl, 3-methyl-1H-indazol-5-yl, 3-amino-1H-indazol-5-yl, 2, 3-dimethyl-2H-indazol-5-yl, 3-amino-1H-indazol-5-yl, quinolin-6-yl, 2-aminoquinolin-6-yl, 3-aminoquinolin-6-yl, 2-aminoquinazolin-6-yl, 1H-1,2, 3-benzotriazol-6-yl, 1H-imidazo [4,5-b]Pyridin-6-yl, 1, 3-benzoxazol-6-yl, 1H-indol-5-yl, 2-amino-1H-1, 3-benzodiazol-6-yl, 2H,3H, 4H-pyrido [3,2-b][1,4]Oxazin-3-one-6-yl, 1H,2H, 3H-pyrido [3,2-b][1,4]Oxazin-3-on-6-yl, 2-methyl-3, 4-dihydro-2H-1, 4-benzoxazin-3-on-6-yl, 2-hydroxyquinolin-6-yl and quinoxalin-2-ol-7-yl;

R₃selected from hydrogen, lower alkyl and halogen;

R₄selected from hydrogen and lower alkyl; and

R₅is hydrogen.

5. The method of claim 4A compound or a pharmaceutically acceptable salt thereof, wherein R₃Selected from hydrogen, methyl, ethyl and chlorine.

6. A compound or pharmaceutically acceptable salt thereof according to claim 5, wherein R₃Is hydrogen.

7. A compound according to any one of claims 4 to 6, or a pharmaceutically acceptable salt thereof, wherein R₄Selected from hydrogen and methyl.

8. A compound or pharmaceutically acceptable salt thereof according to claim 7, wherein R₄Is hydrogen.

9. A compound having the structure:

10. a compound selected from the group consisting of:

n- (3, 4-dimethoxyphenyl) -6- (3-nitrophenyl) imidazo [1,2-a ] pyrazin-8-amine;

n- (3, 4-dimethoxyphenyl) -6- (pyridin-4-yl) imidazo [1,2-a ] pyrazin-8-amine;

n- (3, 4-dimethoxyphenyl) -6- (pyridin-3-yl) imidazo [1,2-a ] pyrazin-8-amine;

n- (3, 4-dimethoxyphenyl) -6-phenylimidazo [1,2-a ] pyrazin-8-amine;

6- (3-aminophenyl) -N- (3, 4-dimethoxyphenyl) imidazo [1,2-a ] pyrazin-8-amine;

n- (3, 4-dimethoxyphenyl) -6- (thiophen-3-yl) imidazo [1,2-a ] pyrazin-8-amine;

n- (3, 4-dimethoxyphenyl) -6- (quinolin-6-yl) imidazo [1,2-a ] pyrazin-8-amine;

n- (3, 4-dimethoxyphenyl) -6- (thiophen-2-yl) imidazo [1,2-a ] pyrazin-8-amine;

6- (4-aminophenyl) -N- (3, 4-dimethoxyphenyl) imidazo [1,2-a ] pyrazin-8-amine;

n- (3, 4-dimethoxyphenyl) -6- (1H-indol-6-yl) imidazo [1,2-a ] pyrazin-8-amine;

n- (3, 4-dimethoxyphenyl) -6- (1H-indol-5-yl) imidazo [1,2-a ] pyrazin-8-amine;

6- (1H-indazol-6-yl) -N- (3-methoxyphenyl) imidazo [1,2-a ] pyrazin-8-amine;

6- (1H-indazol-6-yl) -N- (4-methoxyphenyl) imidazo [1,2-a ] pyrazin-8-amine;

1- (4- { [6- (1H-indazol-6-yl) imidazo [1,2-a ] pyrazin-8-yl ] amino } phenyl) -3-methylpiperidin-3-ol;

n- [4- (4-ethylpiperazin-1-yl) phenyl ] -6- (1H-indazol-6-yl) imidazo [1,2-a ] pyrazin-8-amine;

4- { [6- (1H-indazol-6-yl) imidazo [1,2-a ] pyrazin-8-yl ] amino } phenol;

5- {8- [ (4-ethoxy-3-methoxyphenyl) amino ] imidazo [1,2-a ] pyrazin-6-yl } -1H-indazol-3-amine;

2- (4- { [6- (3-amino-1H-indazol-5-yl) imidazo [1,2-a ] pyrazin-8-yl ] amino } phenyl) -2-methylpropan-1-ol;

4- { [6- (1H-indazol-6-yl) imidazo [1,2-a ] pyrazin-8-yl ] amino } benzamide;

6- (1H-indazol-6-yl) -N- [4- (2-methylmorpholin-4-yl) phenyl ] imidazo [1,2-a ] pyrazin-8-amine;

n, 6-bis [4- (morpholin-4-yl) phenyl ] imidazo [1,2-a ] pyrazin-8-amine;

1- [6- (1, 3-benzothiazol-5-yl) imidazo [1,2-a ] pyridin-8-yl ] -3-methylurea;

1- [6- (1, 3-benzothiazol-5-yl) imidazo [1,2-a ] pyridin-8-yl ] -3-ethylurea;

6- (1H-indazol-6-yl) -N- (4- { 2-oxa-7-azaspiro [3.5] nonan-7-yl } phenyl) imidazo [1,2-a ] pyrazin-8-amine;

[ (2R) -4- { 2-methoxy-4- [ (6- { 1H-pyrrolo [3,2-b ] pyridin-6-yl } imidazo [1,2-a ] pyrazin-8-yl) amino ] phenyl } morpholin-2-yl ] methanol; or

11. A compound selected from the group consisting of:

n- (3, 4-dimethoxyphenyl) -6- (quinolin-6-yl) imidazo [1,2-a ] pyrazin-8-amine;

n- (3, 4-dimethoxyphenyl) -6- (1H-indol-6-yl) imidazo [1,2-a ] pyrazin-8-amine;

n- (3, 4-dimethoxyphenyl) -6- (1H-indol-5-yl) imidazo [1,2-a ] pyrazin-8-amine;

6- (1H-indazol-6-yl) -N- (3-methoxyphenyl) imidazo [1,2-a ] pyrazin-8-amine;

2- (4- { [6- (1H-indol-6-yl) imidazo [1,2-a ] pyrazin-8-yl ] amino } phenyl) propan-2-ol;

6- (1H-indol-6-yl) -N- [ 3-methoxy-4- (morpholin-4-yl) phenyl ] imidazo [1,2-a ] pyrazin-8-amine; and

6- (1H-indol-6-yl) -N- [ 3-methoxy-4- (morpholin-4-yl) phenyl ] -5-methylimidazo [1,2-a ] pyrazin-8-amine.

12. A pharmaceutical composition comprising a compound according to any one of claims 4 to 11, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable vehicle selected from carriers, adjuvants and excipients.

13. Use of a compound according to any one of claims 4 to 11, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of a disease responsive to inhibition of spleen tyrosine kinase activity in a human in need thereof.

14. Use according to claim 1 or 13, wherein the compound or a pharmaceutically acceptable salt thereof is administered parenterally to a human.

15. Use according to claim 1 or 13, wherein the compound or a pharmaceutically acceptable salt thereof is administered to the human intravenously, intramuscularly or orally.

16. Use according to claim 1 or 13, wherein the disease responsive to inhibition of spleen tyrosine kinase activity is cancer.

17. Use according to claim 1 or 13, wherein the disease responsive to inhibition of spleen tyrosine kinase activity is an inflammatory disease.

18. The use according to claim 1 or 13, wherein the disease responsive to inhibition of spleen tyrosine kinase activity is rheumatoid arthritis, allergic rhinitis, Chronic Obstructive Pulmonary Disease (COPD), Adult Respiratory Distress Syndrome (ARDs), allergy-induced inflammatory diseases, multiple sclerosis, autoimmune diseases, acute inflammatory responses, allergic disorders, polycystic kidney disease, B-cell lymphoma, hodgkin's lymphoma, non-hodgkin's lymphoma, hairy cell leukemia, multiple myeloma, chronic myelogenous leukemia, acute myelogenous leukemia, chronic lymphocytic leukemia or acute lymphocytic leukemia.

19. Use according to claim 1 or 13, wherein the disease responsive to inhibition of spleen tyrosine kinase activity is leukemia.

20. The use according to claim 19, wherein the disease responsive to inhibition of spleen tyrosine kinase activity is B-cell leukemia.

21. The use according to claim 19, wherein the disease responsive to inhibition of spleen tyrosine kinase activity is chronic lymphocytic leukemia, acute lymphocytic leukemia, chronic myelogenous leukemia, acute myelogenous leukemia, or hairy cell leukemia.

22. The use according to claim 21, wherein the disease responsive to inhibition of spleen tyrosine kinase activity is chronic lymphocytic leukemia.

23. The use according to claim 21, wherein the disease responsive to inhibition of spleen tyrosine kinase activity is acute lymphocytic leukemia.

24. The use according to claim 21, wherein the disease responsive to inhibition of spleen tyrosine kinase activity is acute myelogenous leukemia.

25. Use according to claim 1 or 13, wherein the disease responsive to inhibition of spleen tyrosine kinase activity is lymphoma.

26. The use of claim 25, wherein the disease responsive to inhibition of spleen tyrosine kinase activity is B-cell lymphoma.

27. The use of claim 25, wherein the disease responsive to inhibition of spleen tyrosine kinase activity is non-hodgkin's lymphoma.

28. Use of a compound according to any one of claims 4 to 11, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for inhibiting B cell activity in a human in need thereof.

29. Use of a compound according to any one of claims 4 to 11, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for inhibiting ATP hydrolysis in a human in need thereof.