JP2005535597A - Kinase inhibitor - Google Patents

Abstract

Compounds of general formula (I), or pharmaceutically acceptable salts, hydrates, solvates, crystalline forms, or diastereomers thereof are described. Also described are methods of treating protein kinase related disease states using compounds of formula (I).

Description

  The present invention relates to the field of inhibitors of protein kinases.

  Protein kinases are a family of enzymes that catalyze phosphorylation of specific residues of proteins. In general, protein kinases are divided into several groups: groups that preferentially phosphorylate serine and / or threonine residues, groups that preferentially phosphorylate tyrosine residues, and both tyrosine and Ser / Thr residues. It is a group that phosphorylates. Protein kinases are therefore key elements of signal transduction pathways involved in extracellular signal transduction to the nucleus, including cytokine action at the receptor, and trigger various biological events. Many roles of protein kinases in normal cell physiology include cell cycle control and cell growth, differentiation, apoptosis, cell mobility, and mitogenesis.

  Protein kinases include, but are not limited to, for example, members of the protein tyrosine kinase family (PTK), which can be further classified into cytoplasmic PTK and receptor PTK (RTK). Cytoplasmic PTK includes SRC family (including BLK, FGR, FYN, HCK, LCK, LYN, SRC, YES, and YRK), BRK family (including BRK, FRK, SAD, and SRM), CSK family (CSK and CTK), BTK family (including BTK, ITK, TEC, MKK2, and TXK), Janus kinase family (including JAKI, JAK2, JAK3, and Tyk2), FAK family (including FAK and PYK2), Fes family (Including FES and FER), ZAP70 family (including ZAP70 and SYK), ACK family (including ACK1 and ACK2), and Abl family (including ABL and ARG). RTK family includes EGF receptor family (including EGFR, HER2, HER3, and HER4), insulin receptor family (including INS-R and IGF1-R), PDGF receptor family (PDGFRα, PDGFRβ, CSF1R, KIT , FLK2), VEGF receptor family (including FLT1, FLK1, and FLT4), FGF receptor family (including FGFR1, FGFR2, FGFR3, and FGFR4), CCK4 family (including CCK4), MET family (MET ), TRK family (including TRKA, TRKB, and TRKC), AXL family (including AXL, MER, and SKY), TIE / TEK family (including TIE and TIE2 / TEK family), EPH family (including EPHA1, EPHA2, EPHA3, EPHA4, EPHA5, EPHA6, EPHA7, EPHA8, EPHB1, EPHB2, EPHB3, EPHB4, EPHB5, EPHB6), RYK family (including RYK), MCK family (including MCK and TYRO10), ROS Family (including ROS), RET family (including RET), LTK family (LTK and ALK), ROR family (including ROR1 and ROR2), Musk family (including Musk), LMR family (including LMR1, LMR2, and LMR3), and SuRTK106 family (including SuRTK106).

  Similarly, serine / threonine specific kinases comprise several different subfamilies, including subcellular signal-regulated kinases (p42 / ERK2 and p44 / ERK1), c-Jun NH2 terminal kinase (JNK), cAMP response element binding protein kinase (CREBK), cAMP-dependent kinase (CAPK), mitogen-activated protein kinase-activated protein kinase (MAPK and related substances), stress-activated protein kinase p38 / SAPK2, mitogen and stress-activated kinase (MSK), protein kinases, especially PKA, PKB, and PKC.

  In addition, the genomes of some pathogens have genes that encode protein kinases. For example, the malaria parasite Plasmodium falciparum, and viruses such as HPV and hepatitis virus are believed to have kinase-related genes.

  Inappropriately high activity of protein kinases has been implicated in many diseases resulting from abnormal cellular function. This may be due to, for example, an excess of cytokines or growth factors involved in signal transduction upstream or downstream of the kinase, due to a failure of the appropriate regulatory mechanism of the kinase associated with enzyme mutation, overexpression, or inappropriate activation. Underproduction can occur directly or indirectly. In all these examples, selective inhibition of kinase action can be expected to have beneficial effects. Diseases that have been implicated in abnormal kinase activity include diabetes, restenosis, atherosclerosis, liver and kidney fibrosis, eye diseases, myeloproliferative and lymphoproliferative diseases, prostate cancer, Cancers such as colon cancer, breast cancer, head and neck cancer, leukemia, and lymphoma, and autoimmunity such as atopic dermatitis, asthma, rheumatoid arthritis, Crohn's disease, psoriasis, Kurzon syndrome, chondrogenic dysplasia, and lethal dysplasia Disease included.

  The JAK family of protein tyrosine kinases (PTKs) plays a central role in the cytokine-dependent regulation of proliferation and end function of several important cell types of the immune system.

  A direct comparison of the four members of the currently known mammalian JAK family reveals the existence of seven highly conserved domains (Harpur et al., 1992). In searching for the highly conserved domain nomenclature characteristic of this PTK family, the classification used followed the Pawson et al. Approach in the processing of SRC homology (SH) domains (Sadovski et al., 1986). These domains are listed according to the most C-terminal homology domain called JAK homology domain 1 (JH1). The next N-terminal domain of JH1 is a kinase-related domain, referred to herein as the JH2 domain. Each domain is then listed up to JH7 located at the N-terminus. The high conservation of these JAK homology (JH) domains suggests that each domain is likely to play an important role in the cellular processes in which these proteins function. However, the boundary of the JAK homology domain is arbitrary and may or may not define a functional domain. Nevertheless, their elucidation is a useful strategy that helps to consider the overall structural similarity of this type of protein.

  The most characteristic property of the JAK family of PTK is that it has two kinase-related domains (JH1 and JH2) (Wilks et al., 1991). This putative PTK domain (JH1) of JAK1 contains a highly conserved motif typical of PTK domains and is considered to be a member of the tyrosine-specific protein kinase species member of subdomain VII. It includes the presence of a tyrosine residue at position 1022, located 11 residues C-terminal. Alignment of the human JAK1PTK domain (255 amino acids) with other members of the PTK species protein revealed homology with other functional proteins PTK (e.g., 28% identical to c-fes (Wilks and Kurban 1988), 37% homology with TRK (Kozma et al., 1988)). The JH1 domain of each JAK family member has interesting properties in the highly conserved subdomain VIII motif (residues 1015 to 1027 of JAK2) located near the active site and thought to define substrate specificity . The phenylalanine and tyrosine residues adjacent to the conserved tryptophan of this motif are unique to the PAK JAK family. Except for this element, the JH1 domain of each member of the JAK family is a typical PTK domain.

  The JAK family of protein tyrosine kinases plays a central role in the cytokine-dependent regulation of the growth and end function of several important cell types, indicating that disease inhibitors in which JAK inhibitors depend on those enzymes It is useful for prevention and chemotherapy. Currently known effective and specific inhibitors of each of the four members of the JAK family include asthma (e.g. IL-13, JAK1, JAK2) and leukemia / lymphoma (e.g. IL-2, JAK1 and JAK3) It will provide a means of inhibiting the action of cytokines that promote immune diseases.

  In addition, certain cancers, such as prostate cancer, express the production by autocrine of certain cytokines as a selectable mechanism that enhances proliferation and / or metastatic potential. Examples include prostate cancer in which IL-6 is produced by growth of prostate cancer cell lines such as TSU and TC3, thereby stimulating growth (Spiotto MT and Chung TD, 2000). Interestingly, IL-6 levels are elevated in the serum of patients with metastatic prostate cancer.

Many references are directed to the field of cytokine signaling. We have focused on the JAK / STAT pathway involved in the direct binding of cytokine receptors to target genes (such as cell cycle regulators (eg p21) and anti-apoptotic genes (eg Bcl-X _L )).
Harpur et al., 1992 Sadovski et al., 1986 Wilks et al., 1991 Wilks and Kurban, 1988 Kozma et al., 1988 Spiotto MT and Chung TD, 2000

JAK / STAT pathway Recently, a particularly superior signaling pathway has been revealed downstream of non-protein tyrosine kinase cytokine receptors. The main components of this pathway are (i) cytokine receptor chains (or multiple chains) such as interleukin-4 receptor or interferon gamma receptor, (ii) members of the JAK family of PTK (or multiple members) ), (Iii) a member (or members) of the STAT family of transcription factors, and (iv) a sequence-specific DNA element to which activated STAT binds.

  The literature review on JAK / STAT strongly supports the notion that this pathway is important in increasing and leading the host immune response to external stimuli such as viral and bacterial infections. Tables 1 and 2 illustrate this. Information accumulated by gene knockout experiments highlights the importance of JAK family members in intracellular signaling induced by several important immunoregulatory cytokines. Therefore, there is a high possibility of treatment derived from inhibition (or enhancement) of the JAK / STAT pathway in the area of immunomodulation, and it is considered to be a promising drug for treating a series of diseases in this field. In addition to the diseases listed in Tables 1 and 2, inhibitors of JAKs include organ transplantation and lupus, multiple sclerosis, rheumatoid arthritis, type I diabetes, autoimmune thyroid disorders, Alzheimer's disease, and other autoimmunity It can be used as an immunosuppressant for autoimmune diseases such as diseases. Furthermore, treatment of cancers such as prostate cancer with JAK inhibitors has been suggested.

  The present inventor has found that a group of compounds based on the 2-substituted pyrazine skeleton I are inhibitors of protein kinases.

  Accordingly, in the first aspect, the present invention provides a compound of the following general formula:

In a pharmaceutically acceptable salt, hydrate, solvate, crystalline form, or diastereomer thereof,
Where D is a heterocycle selected from:

Wherein X ₁ , X ₂ , X ₃ , X ₄ are optionally substituted carbons, or _one of X ₁ , X ₂ , X ₃ , X ₄ is N and R 2 is H , Halogen, C _1-4 alkyl, CH ₂ F, CHF ₂ , CF ₃ , OCF ₃ , aryl, hetaryl, C _1-4 alkyl OC _1-4 alkyl, C _1-4 alkyl O aryl, C _1-4 alkyl NR3R4, CO ₂ R3, CONR3R4, CONR3SO ₂ R4, NR3R4, C _1-4 alkyl NR3R4, nitro, NR3COR4, NR5CONR3R4, NR3SO ₂ R4, C _1-4 alkyl NR3COR4, C _1-4 alkyl NR5CONR3R4, C _1-4 alkyl 0-4 substituents independently selected from NR3SO2R4, R3, R4 are each, independently, H, _{halogen, CH 2 F, CHF 2,} CF 3, C 1-4 alkyl, C _{1- 4} alkyl cycloalkyl, C _1-4 cyclohexylalkyl, aryl, C _1-4 alkyl aryl, hetaryl, C _1-4 alkyl hetaryl, or bonded to any atom selected from O, S, NR 6 Optional inclusion 3-8 membered substituted with selected may form a (saturated or unsaturated) ring, R5 is, H, C _1-4 alkyl, _{halogen, CH 2 F, CHF 2,} CF 3, aryl, or, Selected from hetaryl, R6 is selected from H, C _1-4 alkyl, aryl, hetaryl, C _1-4 alkylaryl, C _1-4 alkyl hetaryl,
R1 is H, C _1-4 alkyl, C _1-6 cycloalkyl,
Q is a bond, CH ₂ , C _1-4 alkyl,
A is halogen, C _1-4 alkyl, CH ₂ F, CHF ₂ , CF ₃ , OCF ₃ , CN, NR8R9, aryl, hetaryl, C _1-4 aryl, C _1-4 hetaryl, C _1-4 alkyl NR8R9 , 0C _1-4 alkyl NR8R9, nitro, NR10C _1-4 NR8R9, NR8COR9, NR10CONR8R9, NR8SO ₂ R9, CONR8R9, optionally substituted with 0 to 3 substituents independently selected from CO ₂ R8 Aryl, hetaryl, R8 and R9 are each independently H, C _1-4 alkyl, aryl, or optionally substituted, which can contain heteroatoms selected from O, S, NR11 Together with R 11 is C _1-4 alkyl, R 10 is selected from H, C _1-4 alkyl;
W is selected from H, C _1-4 alkyl, C _2-6 alkenyl, wherein C _1-4 alkyl or C _2-6 alkenyl is C _1-4 alkyl, OH, OC _1-4 alkyl, NR12R13 R12 and R13 are each independently H, C _1-4 alkyl, or joined to optionally select an atom selected from O, S, NR14. Optionally containing 3 to 8 membered rings containing it, NR14 is selected from H, _C1-4 alkyl.

  In a second aspect, the invention resides in a composition comprising a carrier and at least one compound of the first aspect of the invention.

  In a third aspect, the invention is a method of treating a protein kinase-related disease state, comprising a therapeutically effective amount of at least one compound of the first aspect of the invention, or a therapeutically effective amount of the invention. In a method comprising administering the composition of the second embodiment.

  In another aspect, the present invention provides the use of said compound in the preparation of a medicament for treating a protein kinase related disease state.

  In the first aspect, the present invention provides a compound of the following general formula:

In a pharmaceutically acceptable salt, hydrate, solvate, crystalline form, or diastereomer thereof,
Where D is a heterocycle selected from:

Wherein X ₁ , X ₂ , X ₃ , X ₄ are optionally substituted carbons, or _one of X ₁ , X ₂ , X ₃ , X ₄ is N and R 2 is H , Halogen, C _1-4 alkyl, CH ₂ F, CHF ₂ , CF ₃ , OCF ₃ , aryl, hetaryl, C _1-4 alkyl OC _1-4 alkyl, C _1-4 alkyl O aryl, C _1-4 alkyl NR3R4, CO ₂ R3, CONR3R4, CONR3SO ₂ R4, NR3R4, C _1-4 alkyl NR3R4, nitro, NR3COR4, NR5CONR3R4, NR3SO ₂ R4, C _1-4 alkyl NR3COR4, C _1-4 alkyl NR5CONR3R4, C _1-4 alkyl 0-4 substituents independently selected from NR3SO2R4, R3, R4 are each, independently, H, _{halogen, CH 2 F, CHF 2,} CF 3, C 1-4 alkyl, C _{1- 4} alkyl cycloalkyl, C _1-4 cyclohexylalkyl, aryl, C _1-4 alkyl aryl, hetaryl, C _1-4 alkyl hetaryl, or bonded to any atom selected from O, S, NR 6 Optional inclusion 3-8 membered substituted with selected may form a (saturated or unsaturated) ring, R5 is, H, C _1-4 alkyl, _{halogen, CH 2 F, CHF 2,} CF 3, aryl, or, Selected from hetaryl, R6 is selected from H, C _1-4 alkyl, aryl, hetaryl, C _1-4 alkylaryl, C _1-4 alkyl hetaryl,
R1 is H, C _1-4 alkyl, C _1-6 cycloalkyl,
Q is a bond, CH ₂ , C _1-4 alkyl,
A is halogen, C _1-4 alkyl, CH ₂ F, CHF ₂ , CF ₃ , OCF ₃ , CN, NR8R9, aryl, hetaryl, C _1-4 aryl, C _1-4 hetaryl, C _1-4 alkyl NR8R9 , 0C _1-4 alkyl NR8R9, nitro, optionally substituted with NR10C _1-4 alkyl _{NR8R9, NR8COR9, NR10CONR8R9, NR8SO 2} R9, CONR8R9, 0~3 substituents selected from CO ₂ R8 independently Aryl, hetaryl, and R8 and R9 are each independently H, _C1-4 alkyl, aryl, or can optionally contain a heteroatom selected from O, S, NR11 Together with a substituted 4-8 membered ring, R 11 is C _1-4 alkyl, R 10 is selected from H, C _1-4 alkyl;
W is selected from H, C _1-4 alkyl, C _2-6 alkenyl, wherein C _1-4 alkyl or C _2-6 alkenyl is C _1-4 alkyl, OH, OC _1-4 alkyl, NR12R13 R12 and R13 are each independently H, C _1-4 alkyl, or joined to optionally select an atom selected from O, S, NR14. Optionally containing 3 to 8 membered rings containing it, NR14 is selected from H, _C1-4 alkyl.

In the above,
C _1-4 alkyl means a straight or branched alkyl chain,
Aryl means unsubstituted or optionally substituted phenyl or naphthyl,
Hetaryl means an unsubstituted or optionally substituted 5 or 6 membered aromatic heterocycle containing one or more heteroatoms selected from O, N, S;
Cycloalkyl means a 3-8 membered saturated ring,
It is understood that cyclohetaryl refers to a 3-8 membered saturated ring containing 1-3 heteroatoms selected from O, S, NR13 and R13 is H, C _1-4 alkyl, aryl, hetaryl. Is done.

  In a further preferred embodiment, the compound is a compound of the general formula II

Selected from pharmaceutically acceptable salts, hydrates, solvates, crystalline forms, or diastereomers thereof,
Where D is a heterocycle selected from:

Wherein X ₁ , X ₂ , X ₃ , X ₄ are optionally substituted carbons, or _one of X ₁ , X ₂ , X ₃ , X ₄ is N and R 2 is H , Halogen, C _1-4 alkyl, CH ₂ F, CHF ₂ , CF ₃ , OCF ₃ , aryl, hetaryl, C _1-4 alkyl OC _1-4 alkyl, C _1-4 alkyl O aryl, C _1-4 alkyl NR3R4, CO ₂ R3, CONR3R4, CONR3SO ₂ R4, Nitro, NR3R4, C _1-4 alkyl NR3R4, NR3COR4, NR5CONR3R4, NR3SO ₂ R4, C _1-4 alkyl NR3COR4, C _1-4 alkyl NR5CONR3R4, C _1-4 alkyl 0-4 substituents from NR3SO ₂ R4 is independently selected, R3, R4 are each, independently, H, _{halogen, CH 2 F, CHF 2,} CF 3, C 1-4 alkyl, C Atoms selected from O, S, NR6, which are _1-4 alkyl cycloalkyl, C _1-4 cyclohetaryl, aryl, C _1-4 alkylaryl, hetaryl, C _1-4 alkyl hetaryl, or in combination Optionally contained 3-8 membered substituted with meaning selection may form a (saturated or unsaturated) ring, R5 is, H, C _1-4 alkyl, _{halogen, CH 2 F, CHF 2,} CF 3, aryl, Or selected from hetaryl, R6 is selected from H, C _1-4 alkyl, aryl, hetaryl, C _1-4 alkylaryl, C _1-4 alkyl hetaryl,
R1 is H, C _1-4 alkyl, C _1-6 cycloalkyl,
W is H, C _1-4 alkyl,
A is halogen, C _1-4 alkyl, CH ₂ F, CHF ₂ , CF ₃ , OCF ₃ , CN, nitro, NR8R9, aryl, hetaryl, C _1-4 aryl, C _1-4 hetaryl, C _1-4 Optionally substituted with 0 to 3 substituents independently selected from alkyl NR8R9, 0C _1-4 alkyl NR8R9, NR10C _1-4 alkyl NR8R9, NR8COR9, NR10CONR8R9, NR8SO ₂ R9, CONR8R9, CO ₂ R8 Aryl, hetaryl, and R8 and R9 are each independently H, _C1-4 alkyl, aryl, or can optionally contain a heteroatom selected from O, S, NR11 Forms a substituted 4-8 membered ring together, R 11 is C _1-4 alkyl, and R 10 is selected from H, C _1-4 alkyl.

In the above,
C _1-4 alkyl means a straight or branched alkyl chain,
Aryl means unsubstituted or optionally substituted phenyl or naphthyl,
Hetaryl means an unsubstituted or optionally substituted 5 or 6 membered aromatic heterocycle containing one or more heteroatoms selected from O, N, S;
Cycloalkyl means a 3-8 membered saturated ring,
It is understood that cyclohetaryl refers to a 3-8 membered saturated ring containing 1-3 heteroatoms selected from O, S, NR13 and R13 is H, C _1-4 alkyl, aryl, hetaryl. Is done.

  The compounds of the present invention include all conformational isomers (eg, cis and trans isomers). The compounds of the present invention have asymmetric centers and therefore exist in various enantiomeric and diastereomeric forms. The present invention relates to the use of all optical isomers and stereoisomers of the compounds of the invention, and mixtures thereof, and further to all pharmaceutical compositions and methods of treatment that may use or contain them. In this regard, the present invention includes both E and Z configurations. The compounds of formula I can also exist as tautomers. The present invention relates to the use of all such tautomers and mixtures thereof.

  The present invention further encompasses pharmaceutical compositions containing prodrugs of compounds of Formula I. The invention further encompasses a method of treating or preventing a disorder that can be treated or prevented by inhibition of a protein kinase such as JAK, comprising administering a prodrug of a compound of formula I. Compounds of formula I having a free amino, amido, hydroxy, or carboxyl group can be converted to a prodrug. Prodrugs include amino acid residues, or a polypeptide chain of two or more (eg 2, 3, or 4) amino acid residues that are peptide-bonded to the free amino, hydroxy, and carboxylic acid groups of a compound of formula I. Compounds that are covalently bonded via are included. Amino acid residues include the 20 natural amino acids that are generally indicated by the three letter symbols, as well as 4-hydroxyproline, hydroxylysine, demosine (demosine), isodesmosine (isodemosine), 3-methylhistidine, norbulin (norvlin), beta alanine, gamma aminobutyric acid, citrulline, homocysteine, homoserine, ornithine, and methionine sulfone. Prodrugs further include compounds wherein carbonates, carbamates, amides, and alkyl esters are covalently bonded to the substituents of formula I above via the carbonyl carbon prodrug side chain. Prodrugs further include phosphoric acid derivatives (such as acids, acid salts, or esters) of the compound of formula I that are linked to the free hydroxyl of the compound of formula I via a phosphorus-oxygen bond.

In another preferred embodiment, the compound has S chirality at the chiral carbon with W, and W is C _1-4 alkyl. This compound can be used as a purified isomer or as a mixture of isomers in any ratio. However, it is preferred that the mixture comprises at least 70%, 80%, 90%, 95%, or 99% of the preferred isomer.

In another preferred embodiment, the compound is
6- (1H-benzimidazol-1-yl) -N-[(1R) -1-phenylethyl] pyrazin-2-amine, N-benzyl-6- (1H-imidazol-1-yl) pyrazin-2- Amine, 6- (1H-benzimidazol-1-yl) -N-[(1S) -1- (4-methoxyphenyl) ethyl] pyrazin-2-amine, N- (4-fluorobenzyl) -6- ( 1H-imidazol-1-yl) pyrazin-2-amine, 6- (1H-benzimidazol-1-yl) -N-[(1S) -1- (4-bromophenyl) ethyl] pyrazin-2-amine, 6- (1H-imidazol-1-yl) -N-[(1R) -1-phenylethyl] pyrazin-2-amine, 1- (6-{[(1S) -1-phenylethyl] amino} pyrazine- 2-yl) -1H-benzimidazole-6-carboxamide, 6- (1H-benzimidazol-1-yl) -N-benzylpyrazin-2-amine, 1- (6-{[(1S) -1-phenyl Ethyl] amino} pyrazin-2-yl) -1H-benzimidazol-5-carboxamide, 6- (1H-benzimidazol-1-yl) -N- (4-fluoro Nzyl) pyrazin-2-amine, 6- {5-[(morpholin-1-yl) carbonyl] -1H-benzimidazol-1-yl} -N-[(1S) -1-phenylethyl] pyrazin-2- Amines, 6- (1H-imidazo [4,5-b] pyridin-1-yl) -N-[(1R) -1-phenylethyl] pyrazin-2-amine, 6- {6-[(morpholino-1 -Yl) carbonyl] -1H-benzimidazol-1-yl} -N-[(1S) -1-phenylethyl] pyrazin-2-amine, 6- (1H-imidazol-1-yl) -N- (4 -Morpholin-4-ylphenyl) pyrazin-2-amine, N- [1- (6-{[(1S) -1-phenylethyl] amino} pyrazin-2-yl) -1H-benzimidazol-6-yl ] Cyclopropanecarboxamide, N- [1- (6-{[(1S) -1-phenylethyl] amino} pyrazin-2-yl) -1H-benzimidazol-5-yl] nicotinamide, N- [1- (6-{[(1S) -1-phenylethyl] amino} pyrazin-2-yl) -1H-benzimidazol-5-yl] cyclopropanecarboxamide, 6- ( 1H-benzimidazol-1-yl) -N-[(1R) -1-phenylethyl] pyrazin-2-amine, 6- [6- (4,5-dihydro-1,3-oxazol-2-yl) -1H-benzimidazol-1-yl] -N-[(1S) -1-phenylethyl] pyrazin-2-amine, N-[(1R) -1-phenylethyl] -6- (4-phenyl-1H -Imidazol-1-yl) pyrazin-2-amine, 1- [6-{[(1S) -1-phenylethyl] amino} pyrazin-2-yl] -N- (2-hydroxyethyl) -1H-benz Imidazole-6-carboxamide, N- [1- (6-{[(1S) -1-phenylethyl] amino} pyrazin-2-yl) -1H-benzimidazol-6-yl] methanesulfonamide, N- [ 1- (6-{[(1S) -1-phenylethyl] amino} pyrazin-2-yl) -1H-benzimidazol-5-yl] methanesulfonamide, N- [1- (6-{[(1S ) -1-Phenylethyl] amino} pyrazin-2-yl) -1H-benzimidazol-5-yl] isonicotinamide, 6- (1H-imidazol-1-yl) -N-[(1S) -1- Enylethyl] pyrazin-2-amine, N- [1- (6-{[(1S) -1-phenylethyl] amino} pyrazin-2-yl) -1H-benzimidazol-6-yl] isonicotinamide, 6 -(1H-benzimidazol-1-yl) -N-[(1S) -1-phenylethyl] pyrazin-2-amine, 6- [5- (4,5-dihydro-1,3-oxazole-2- Yl) -1H-benzimidazol-1-yl] -N-[(1S) -1-phenylethyl] pyrazin-2-amine, 1- [6-{[(1S) -1-phenylethyl] amino} pyrazine -2-yl] -N- (2-hydroxyethyl) -1H-benzimidazole-5-carboxamide, 6- (5-methyl-1H-benzimidazol-1-yl) -N-[(1S) -1- Phenylethyl] pyrazin-2-amine, N- [1- (6-{[(1S) -1-phenylethyl] amino} pyrazin-2-yl) -1H-benzimidazol-6-yl] nicotinamide, N -Methyl-1- (6-{[(1S) -1-phenylethyl] amino} pyrazin-2-yl) -1H-benzimidazole-5-carboxamide, N- [1- (6-{[(1S) -1-Phenylethyl] amino} pyrazin-2-yl) -1H-benzimidazol-6-yl] -2,2-dimethylpropanamide, N-methyl-1- (6- {[(1S) -1-phenylethyl] amino} pyrazin-2-yl) -1H-benzimidazole-6-carboxamide, N- [1- (6-{[(1S) -1-phenylethyl] amino} Pyrazin-2-yl) -1H-benzimidazol-5-yl] -2,2-dimethylpropanamide, 1- (6-{[(1S) -1-phenylethyl] amino} pyrazin-2-yl)- 1H-benzimidazol-5-amine, 2-methoxy-N- [1- (6-{[(1S) -1-phenylethyl] amino} pyrazin-2-yl) -1H-benzimidazol-5-yl] Acetamide, 1- (6-{[(1S) -1-phenylethyl] amino} pyrazin-2-yl) -1H-benzimidazol-6-amine, 2-methoxy-N- [1- (6-{[ (1S) -1-phenylethyl] amino} pyrazin-2-yl) -1H-benzimidazol-6-yl] acetamide, N-benzyl-1- [6-{[(1S) -1-phen Ruethyl] amino} pyrazin-2-yl] -1H-benzimidazol-5-carboxamide, N- [1- (6-{[(1S) -1-phenylethyl] amino} pyrazin-2-yl) -1H- Benzimidazol-5-yl] pyrazine-2-carboxamide, 1- (6-{[(1S) -1-phenylethyl] amino} pyrazin-2-yl) -N-phenyl-1H-benzimidazole-5-carboxamide N- [1- (6-{[(1S) -1-phenylethyl] amino} pyrazin-2-yl) -1H-benzimidazol-6-yl] pyrazin-2-carboxamide, N- [1- ( 6-{[(1S) -1-phenylethyl] amino} pyrazin-2-yl) -1H-benzimidazol-6-yl] acetamide, 6- {5-[(4-methylpiperazin-1-yl) methyl ] -1H-Benzimidazol-1-yl} -N-[(1S) -1-phenylethyl] pyrazin-2-amine, N- [1- (6-{[(1S) -1-phenylethyl] amino } Pyrazin-2-yl) -1H-benzimidazol-5-yl] acetamide, [1- (6-{[(1S) -1-phenylethyl Ru] amino} pyrazin-2-yl) -1H-benzimidazol-5-yl] methanol, N- [1- (6-{[(1S) -1-phenylethyl] amino} pyrazin-2-yl)- 1H-benzimidazol-6-yl] benzamide, [1- (6-{[(1S) -1-phenylethyl] amino} pyrazin-2-yl) -1H-benzimidazol-6-yl] methanol, N- [1- (6-{[(1S) -1-phenylethyl] amino} pyrazin-2-yl) -1H-benzimidazol-5-yl] benzamide, 1- (6-{[(1S) -1- Phenylethyl] amino} pyrazin-2-yl) -N- [2- (dimethylamino) ethyl] -1H-benzimidazole-5-carboxamide, 1- (6-{[(1S) -1-phenylethyl] amino } Pyrazin-2-yl) -N- (pyridin-3-ylmethyl) -1H-benzimidazol-5-amine, tert-butyl (2S) -2-({[1- (6-{[(1S)- 1-phenylethyl] amino} pyrazin-2-yl) -1H-benzimidazol-5-yl] amino} carbonyl) pyrrolidine-1-carboxylate 6- (3H-imidazo [4,5-c] pyridin-3-yl) -N-[(1S) -1-phenylethyl] pyrazin-2-amine, 6- (1H-benzimidazole-1- Yl) -N- [1- (4-fluorophenyl) ethyl] pyrazin-2-amine, 6- (1H-imidazo [4,5-c] pyridin-1-yl) -N-[(1S) -1 -Phenylethyl] pyrazin-2-amine, 6- (1H-benzimidazol-1-yl) -N-[(1S) -1- (4-pyridin-3-ylphenyl) ethyl] pyrazin-2-amine, (2S) -N- [1- (6-{[(1S) -1-phenylethyl] amino} pyrazin-2-yl) -1H-benzimidazol-5-yl] pyrrolidin-2-carboxamide, N- [ (1S) -1-phenylethyl] -6- (5-pyridin-4-yl-1H-benzimidazol-1-yl) pyrazin-2-amine, N-[(1S) -1-phenylethyl] -6 -(5-Pyridin-3-yl-1H-benzimidazol-1-yl) pyrazin-2-amine, 6- (5-bromo-1H-benzimidazol-1-yl) -N-[(1S) -1 -Phenylethyl] pyrazin-2-amine, N- [3- (1H- Imidazol-1-yl) propyl] -1- [6-([(1S) -1-phenylethyl] amino) pyrazin-2-yl] -1H-benzimidazole-6-carboxamide, N-1H-benzimidazole- 6-carboxamide, N- (3-morpholin-4-ylpropyl) -1- [6-([(1S) -1-phenylethyl] amino) pyrazin-2-yl] -1H-benzimidazole-6-carboxamide N- (3-morpholin-4-ylpropyl) -1- [6-([(1S) -1-phenylethyl] amino) pyrazin-2-yl] -1H-benzimidazole-5-carboxamide, N- [1- (6-{[(1S) -1-phenylethyl] amino} pyrazin-2-yl) -1H-benzimidazol-5-yl] piperidine-3-carboxamide, 6- (1H-benzimidazole-1 -Yl) -N-[(1S) -1-pyridin-3-ylethyl] pyrazin-2-amine, 6- (1H-benzimidazol-1-yl) -N-[(1S) -1- (1, 1'-biphenyl-4-yl) ethyl] pyrazin-2-amine, N- [1- (6-{[(1S) -1-phenylethyl] amino } Pyrazin-2-yl) -1H-benzimidazol-5-yl] benzenesulfonamide, and 6- (1H-benzimidazol-1-yl) -N-[(1S) -1- (1,1'- Biphenyl-4-yl) ethyl] pyrazin-2-amine is selected from the group consisting of

  In a second aspect, the invention resides in a composition comprising a carrier and at least one compound of the first aspect of the invention.

  In a third aspect, the invention is a method of treating a protein kinase-related disease state, comprising a therapeutically effective amount of at least one compound of the first aspect of the invention, or a therapeutically effective amount of the invention. In a method comprising administering the composition of the second embodiment.

  In preferred embodiments, the disease state is EGF, HER2, HER3, HER4, IR, IGF-1R, IRR, PDGFR.alpha., PDGFR.beta., CSFIR, C-Kit, C-fms, Flk-1R, Flk4 , A receptor tyrosine kinase selected from the group consisting of KDR / Flk-1, Flt-1, FGFR-1R, FGFR-2R, FGFR-3R, and FGFR-4R.

  In other preferred embodiments, the disease state is a group consisting of Src, Frk, Btk, Csk, Abl, ZAP70, Fes / Fps, Fak, Ack, Yes, Fyn, Lyn, Lck, Blk, Hck, Fgr, and Yrk. Associated with cellular tyrosine kinases selected from

  In another preferred embodiment, the disease state is associated with a tyrosine kinase selected from the group consisting of JAK1, JAK2, JAK3, and TYK2.

  In other preferred embodiments, the disease state is ERK2, c-Jun, p38 MAPK, PKA, PKB, PKC, cyclin dependent kinase, CDK1, CDK2, CDK3, CDK4, CDK5, CDK6, CDK7, CDK8, CDK9, CDK10 And a serine / threonine kinase selected from the group consisting of CDK11.

  In a preferred embodiment of the invention, the disease state is allergic asthma, atopic dermatitis (eczema), and atopy such as allergic rhinitis, cell-mediated hypersensitivity such as allergic contact dermatitis and hypersensitivity pneumonia, systemic Rheumatoid diseases such as lupus erythematosus (SLE), rheumatoid arthritis, juvenile arthritis, Sjogren's syndrome, scleroderma, polymyositis, ankylosing spondylitis, psoriatic arthritis, type I diabetes, autoimmune thyroid disorders, and Alzheimer's disease Other autoimmune diseases, Epstein-Barr virus (EBV), hepatitis B, hepatitis C, HIV, HTLV1, varicella-zoster virus (VZV), human papilloma virus (HPV) and other viral diseases, leukemia, lymphoma, And a group consisting of cancers such as prostate cancer.

  As used herein, the term “protein kinase-related disease state” refers to a disorder resulting from abnormal protein kinase activity, particularly JAK activity, and / or alleviated by inhibition of one or more of those enzymes.

  In another aspect, the present invention provides the use of said compound in the preparation of a medicament for treating a protein kinase related disease state.

  As used herein, the term “JAK”, “JAK kinase”, or “JAK family” refers to protein tyrosine kinases having the characteristic properties of JAK1, JAK2, JAK3, and TYK described herein.

  The present invention provides a pharmaceutical composition comprising an effective amount of at least one compound of the present invention capable of treating a protein kinase related disorder, such as a JAK related disorder, and a pharmaceutically acceptable vehicle or diluent. The compositions of the present invention may contain other therapeutic agents as described below, according to techniques well known in the pharmaceutical formulation art, for example conventional solid or liquid vehicles or diluents, as well as desired Can be formulated using drug additives of a type (for example, excipients, binders, preservatives, stabilizers, flavoring agents, etc.) suitable for these administration forms.

  The compounds of the present invention can be administered, for example, in the form of tablets, capsules, granules, or powders, orally, sublingually, intrabuccally, subcutaneously, intravenously, intramuscularly, or in the tank, or infusion techniques. Parenteral administration (for example, as a sterile injectable aqueous or non-aqueous solution or suspension), nasal administration by inhalation spray, etc., topical administration in the form of a cream or ointment, etc. Can be administered in dosage unit formulations containing a pharmaceutically acceptable non-toxic vehicle or diluent by any suitable means. The compound can be administered, for example, in a form suitable for immediate release or sustained release. Immediate or sustained release can be achieved using a suitable pharmaceutical composition comprising a compound of the invention, or in particular in the case of sustained release, using a device such as a subcutaneous implant or an osmotic pump. The compound can also be administered by liposome.

  In addition to primates, such as humans, a variety of other mammals can be treated according to the method of the present invention. For example, but not limited to, cows, sheep, goats, horses, dogs, cats, guinea pigs, rats, or other cattle, sheep, horses, dogs, cats, rodents Or mammals including mice can be treated. However, the method can also be practiced with other species such as birds (eg, chickens).

  Diseases and conditions associated with inflammation and infection can be treated using the methods of the present invention. In a preferred embodiment, the disease or condition is a disease or condition in which the action of eosinophils and / or lymphocytes is inhibited or promoted to modulate an inflammatory response.

  Subjects treated with the above method for which JAK inhibition is desired include, but are not limited to, cows, sheep, goats, horses, dogs, cats, guinea pigs, rats, or other cattle and sheep. Mammals including horses, dogs, cats, rodents, or mice, preferably human males or females.

  The term “therapeutically effective amount” refers to a subject composition that elicits a biological, medical response of a tissue, system, animal, or human that is sought by a researcher, veterinarian, physician, or other clinician. Means the amount.

  As used herein, the term “composition” is intended to encompass a product comprising a specified amount of a specified component, as well as any product obtained directly or indirectly from a combination of a specified amount of a specified component. “Pharmaceutically acceptable” means that the carrier, diluent, or excipient must be compatible with the other ingredients of the formulation and not deleterious to the recipient.

  The term “administration” of a compound and / or “administering” a compound should be understood to mean providing the compound of the invention to an individual in need of treatment.

  Pharmaceutical compositions for administering the compounds of the invention can conveniently be provided in dosage unit form and can be prepared by any method well known in the pharmaceutical art. All methods include the step of bringing the active ingredient into association with the carrier which constitutes one or more accessory ingredients. In general, the pharmaceutical compositions are prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping into the desired formulation. The In the pharmaceutical composition, the active subject compound is included in an amount sufficient to produce the desired effect upon the process or condition of diseases. As used herein, the term “composition” is intended to encompass a product comprising a specified amount of a specified component, as well as any product obtained directly or indirectly from a combination of a specified amount of a specified component.

  Pharmaceutical compositions containing the active ingredient are, for example, tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, syrups or elixirs, etc. Can be in a form suitable for oral use. Orally used compositions can be prepared according to any method known in the art for the manufacture of pharmaceutical compositions, such compositions providing a aesthetically pleasing formulation as a drug. In order to do so, one or more agents selected from the group consisting of sweeteners, flavoring agents, coloring agents, and preservatives can be included. Tablets contain the active ingredient in admixture with pharmaceutically acceptable non-toxic excipients that are suitable for the manufacture of tablets. These excipients include, for example, inert diluents such as calcium carbonate, sodium carbonate, lactose, calcium phosphate, or sodium phosphate, granulating and disintegrating agents such as corn starch or alginic acid, bindings such as starch, gelatin, or acacia And lubricants such as magnesium stearate, stearic acid, or talc. The tablets may be uncoated or they may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate may be employed. They can also be coated to form osmotic therapeutic tablets that control release.

  Formulations for oral use include hard gelatin capsules with active ingredients mixed with an inert solid diluent such as calcium carbonate, calcium phosphate, or kaolin, or water, or such as peanut oil, paraffin oil, or olive oil It can also be provided as a soft gelatin capsule in which the active ingredient is mixed with an oily medium.

  Aqueous suspensions contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are for example suspending agents such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, tragacanth gum, acacia gum, and dispersing or wetting agents are natural sources such as lecithin With phosphatides or condensation products of alkylene oxides and fatty acids, such as polyoxyethylene stearate, or condensation products of ethylene oxide and long chain fatty alcohols, such as heptadecaethyleneoxycetanol, or partial esters derived from fatty acids and hexitol Condensation products of ethylene oxide, polyoxyethylene sorbitol monooleate, or partial esters derived from fatty acids and hexitol anhydrides Condensation products of ethylene oxide, for example polyethylene sorbitan monooleate. Aqueous suspensions can further include one or more preservatives, such as ethyl or n-propyl p-hydroxybenzoate, one or more colorants, one or more flavoring agents, and one or more sweetening agents. Agents such as sucrose or saccharin can be included.

  Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as paraffin oil. Oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. In order to provide a palatable oral preparation, sweeteners and flavoring agents as described above can be added. These compositions can be preserved by the addition of an anti-oxidant such as ascorbic acid.

  Dispersible powders and granules suitable for preparing aqueous suspensions with the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent, and one or more preservatives To do. Examples of suitable dispersing or wetting agents and suspending agents are those mentioned above. Other excipients can also be included, such as sweetening, flavoring, and coloring agents.

  The pharmaceutical composition of the present invention can also be in the form of an oil-in-water emulsion. The oily phase can be a vegetable oil, such as olive oil or arachis oil, or a mineral oil, such as paraffin oil, or a mixture of these. Suitable emulsifiers include natural gums such as gum acacia or tragacanth, natural phosphatides such as soybean, lecithin, esters or partial esters derived from fatty acids such as sorbitan monooleate and hexitol anhydride, polyoxyethylene sorbitan monooleate, etc. It may be a condensation product of ethylene oxide and the partial ester. The emulsion can further contain sweetening and flavoring agents.

  Syrups and elixirs can be formulated with sweetening agents, such as glycerol, propylene glycol, sorbitol or sucrose. Such formulations can further contain a demulcent, a preservative, flavoring and coloring agents.

  The pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleagenous suspension. This suspension may be formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents which have been mentioned above. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that can be employed are water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil may be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid are useful in the preparation of injectables.

  The compounds of the present invention can also be administered in the form of suppositories for rectal administration of the drug. Since these compositions are solid at ambient temperature but liquid at rectal temperature, they can be prepared by mixing the drug with a suitable non-irritating excipient that melts in the rectum to release the drug. Such materials are cocoa butter and polyethylene glycol.

  For topical use, creams, ointments, jellies, solutions, suspensions, or the like containing the compounds of the present invention are used (for this application, topical applications include oral and pharyngeal cleansing agents).

  The compounds of the present invention can also be administered in the form of liposomes. As is known in the art, liposomes are generally derived from phospholipids or other lipid substances. Liposomes are formed by mono- or multi-lamellar hydrated liquid crystals that are dispersed in an aqueous medium. Any physiologically acceptable and metabolizable non-toxic lipid capable of forming liposomes can be used. In addition to the compounds of the present invention, the composition of the present invention in liposome form can contain stabilizers, preservatives, excipients and the like. Preferred lipids are natural and synthetic phospholipids and phosphatidylcholines. Methods for forming liposomes are known in the art.

  The pharmaceutical compositions and methods of the present invention can further comprise other therapeutically active compounds described herein that are commonly used in the treatment of the above-mentioned disease states. Suitable agents for use in combination therapy can be selected by those skilled in the art according to normal pharmaceutical principles. This combination of therapeutic agents acts synergistically and may treat or prevent the various disorders described above. By using this approach, it is possible to obtain therapeutic effects while reducing the dose of each drug, thereby reducing the possibility of side effects.

  Examples of other therapeutic agents include: Cyclosporine (e.g., cyclosporin A), CTLA4-Ig, antibodies such as ICAM-3, anti-IL-2 receptor (anti-Tac), anti-CD45RB, anti-CD2, anti-CD3 (OKT-3), anti-CD4, anti-CD80, Agents that block the interaction of CD40 and gp39, such as anti-CD86, such as antibodies specific for CD40 and / or gp39 (i.e., CD154), fusion proteins constructed from CD40 and gp39 (CD401g and CD8gp39), For example, nuclear translocation inhibitors of NF-kappa B function such as deoxyspagarin (DSG), cholesterol biosynthesis inhibitors such as HMG CoA reductase inhibitors (lovastatin and simvastatin), non-substances such as ibuprofen, aspirin and acetaminophen Steroidal anti-inflammatory drugs (NSAIDs), cyclooxygenase inhibitors such as rofecoxib, steroids such as prednisolone or dexamethasone, gold compounds, methotrexate, FK506 Limus, Prograf), antiproliferative agents such as mycophenolate motifel, cytotoxic agents such as azathioprine, VP-16, etoposide, fludarabine, cisplatin, and cyclophosphamide, TNF-α inhibitors such as tenidap, anti TNF antibodies, or soluble TNF receptors, and rapamycin (sirolimus or rapamune), or derivatives thereof.

  When other therapeutic agents are used in combination with the compounds of the present invention, they are used in amounts described, for example, in the Physician Desk Reference (PDR), or otherwise determined by those skilled in the art. be able to.

  In the treatment or prevention of conditions requiring inhibition of protein tyrosine kinases, suitable dosage levels are generally about 0.01 to 500 mg / kg patient body weight per day, which can be administered in single or multiple doses. Preferably, the dose level will be about 0.1 to about 250 mg / kg / day, more preferably about 0.5 to about 100 mg / kg / day. Suitable dosage levels can be about 0.01 to 250 mg / kg / day, about 0.05 to 100 mg / kg / day, or about 0.1 to 50 mg / kg / day. Within this range, the dose can be 0.05 to 0.5, 0.5 to 5, or 5 to 50 mg / kg / day. For oral administration, the composition is preferably a tablet containing 1.0 to 1000 milligrams of active ingredient, especially 1.0, 5.0, 10.0, 15.0, 20.0, 25.0 to adjust the dosage to the condition of the patient being treated. , 50.0, 75.0, 100.0, 150.0, 200.0, 250.0, 300.0, 400.0, 500.0, 600.0, 750.0, 800.0, 900.0, and 1000.0 milligrams of the active ingredient are provided in the form of a tablet. The compounds can be administered on a regimen of 1 to 4 times daily, preferably once or twice daily.

  However, the specific dose level and frequency of administration for a specific patient is not uniform, the activity of the specific compound used, the metabolic stability and duration of action of the compound, age, weight, general health, sex, diet, It will be appreciated that it will depend on a variety of factors, including mode of administration and time, elimination rate, concomitant medications, severity of the particular condition, and the host being treated.

  Throughout this specification, the term “comprise” or variations such as “comprises” or “comprising” are used to refer to the elements, integers, or steps, or elements, integers, It is understood that it is meant to include a group of stages, but does not exclude any other elements, integers, or stages, or groups of elements, integers, or stages.

  All publications mentioned in this specification are herein incorporated by reference.

  Any discussion of documents, acts, materials, devices, articles, etc. contained herein is solely for the purpose of providing a context for the present invention. Any or all of these matters should not be understood as an admission that they form part of the basis of the prior art, or they existed in Australia prior to the priority date of each claim of this application It should not be understood as an admission that it was common general knowledge in the field relating to the present invention.

  In order that the nature of the present invention may be more clearly understood, preferred forms of the invention will be described by reference to the following non-limiting examples.

Materials and Methods Compound Synthesis Compounds are generally prepared from 2,6-dichloropyrazine in a two-step process.
The first step is a nucleophilic aromatic substitution that produces a monoamino-monohalo intermediate (Scheme 1).

スキーム1

Scheme 1

  Nucleophilic aromatic substitution is typically performed by adding a primary amine to a dihalogenated heterocycle in a solvent such as ethanol, isopropanol, tert-butanol, dioxane, THF, DMF, toluene, or xylene. This reaction is typically carried out at elevated temperatures in the presence of excess amine, or a non-nucleophilic base such as triethylamine or diisopropylethylamine, or an inorganic base such as potassium carbonate or sodium carbonate.

Alternatively, the amino substituent can be introduced by a transition metal catalyzed amination reaction. Typical catalysts for such conversion include Pd (OAc) ₂ / P (t-Bu) ₃ , Pd ₂ (dba) ₃ / BINAP, and Pd (OAc) ₂ / BINAP.

Amines used in the first step of the synthesis of these compounds are either obtained commercially or prepared using methods well known to those skilled in the art. Of particular note is α-methylbenzylamine which is commercially available or can be prepared by reduction of oximes (Scheme 2). Typical reducing agents include lithium aluminum hydride, hydrogen gas in the presence of activated carbon supported catalytic palladium, hydrogen in the presence of Lewis acids such as Zn, TiCl ₃ , ZrCl ₄ , NiCl ₂ , and MoO _{3 in the} presence of hydrochloric acid. Sodium borohydride, or sodium borohydride combined with Amberlyst H15 ion exchange resin and LiCl. The oxime is obtained in one step from the corresponding ketone by condensation with hydroxylamine. This reaction is generally performed at 0 ° C. to reflux temperature in a protic solvent such as water or ethanol. Hydroxylamine is generally used in its hydrochloride form, and thus the reaction is carried out in the presence of a base such as sodium hydroxide. Ketones used as starting materials are generally obtained commercially or obtained by procedures well known to those skilled in the art.

スキーム2

Scheme 2

  High optical purity α-methylbenzylamine can be prepared from chiral α-methylbenzyl alcohol using methods well known to those skilled in the art. Such methods include derivatizing the hydroxyl as mesylate or tosylate and replacing it with a nitrogen nucleophile such as phthalimide or azide, which is then converted to a primary amine using conventional synthetic methods. Or substitution of the hydroxyl with an appropriate nitrogen nucleophile under Mitsunobu conditions. Chiral α-methylbenzyl alcohol can be obtained by chiral reduction of the corresponding ketone. Chiral reduction methods are now well known in organic chemistry and include enzyme treatment, asymmetric hydrogenation procedures, and chiral oxazaborolidine.

  The second stage of the synthesis involves the nucleophilic aromatic substitution of monochloro-monoaminopyrazine with imidazole, benzimidazole, or indazole. This reaction is typically performed with a salt of imidazole, benzimidazole, or indazole in a solvent such as tetrahydrofuran, dimethylformamide, toluene, or xylene at room temperature to reflux temperature. The imidazole, benzimidazole, or indazole salt is prepared by reaction with a metal hydride such as sodium hydride or potassium hydride, or by reaction with cesium carbonate. Alternatively, metal-catalyzed coupling reactions can be used to introduce imidazole, benzimidazole, or indazole rings. This reaction is typically performed in a solvent such as xylene, toluene, and DMF at room temperature to reflux temperature with a base such as cesium carbonate, rubidium carbonate, potassium carbonate, tert-butoxide sodium, or potassium phosphate. . Auxiliary reagents such as phase transfer agents (eg, cetrimonium bromide) or copper complexing agents (eg, phenanthroline) can also be used in this reaction.

  The imidazole, benzimidazole, or indazole components used in this reaction are either commercially available or commercially available imidazoles, benzimidazoles, or by techniques well known to those skilled in the art. Prepared from indazoles.

  Alternatively, imidazole, benzimidazole, or indazole derivatives can be reacted with monoaminomonochloropyrazine and the product further derivatized using methods well known to those skilled in the art.

  A representative synthesis is shown below.

6-Chloro-N-[(1R) -1-phenylethyl] pyrazin-2-amine

A solution of R-α-methylbenzylamine (3.64 g, 30.0 mmol) and 2,6-dichloropyrazine (1.50 g, 10.0 mmol) in dioxane (5 mL) was heated to reflux under N ₂ for 48 hours. The solvent was removed and the product was crystallized from toluene-hexane.

¹ Hn.mr (CDCl ₃ ) δ1.59 (d, 3H, J = 6.9Hz, CH ₃ ), 4.88 (q, 1H, J = 6.6Hz, CH), 5.13 (br s, 1H, NH), 7.27 ~ 7.36 (m, 5H, ArH), 7.64 (s, 1H, pyrazine-H), 7.79 (s, 1H, pyrazine-H).

6- (1H-imidazol-1-yl) -N-[(1R) -1-phenylethyl] pyrazin-2-amine

To a stirred solution of imidazole (82 mg, 1.2 mmol) in anhydrous DMF (5 mL) was added sodium hydride (58 mg, 60% dispersion in oil, 1.45 mmol) at 0 ° C. under N ₂ . The mixture was stirred at 0 ° C. for 10 minutes and at room temperature for 30 minutes. To this mixture was added a solution of 6-chloro-N-[(1R) -1-phenylethyl] pyrazin-2-amine (280 mg, 1.2 mmol) in DMF (5 mL). The mixture was then stirred at room temperature for 62 hours and then heated to reflux for 18 hours. DMF was removed under reduced pressure and the residue was diluted with chloroform. The organic layer was washed with water, dried (Na ₂ SO ₄ ), and the solvent was removed under reduced pressure to obtain a crude product. The recovered starting material was separated from the product (177 mg, 56%) by column chromatography using dichloromethane-methanol (19: 1 → 10: 1) as the eluent.

¹ Hn.mr (CDCl ₃ ) δ 1.62 (d, 3H, J = 6.9Hz, CH ₃ ), 4.97 (m, 1H, CH), 5.46 (d, 1H, J = 6.0Hz, NH), 7.17 ( s, 1H, imidazol-H), 7.23-7.40 (m, 5H, Ph-H), 7.47 (s, 1H, imidazole-H), 7.76 (s, 1H, pyrazine-H), 7.91 (s, 1H, Pyrazine-H), 8.20 (s, 1H, imidazole-H).
m / z (ES) 266 ( M + + H), 162,105.

6-Chloro-N- (4-morpholin-4-ylphenyl) pyrazin-2-amine

  In a similar procedure to Example 1, the product (0.54 g, 37%) was obtained from the reaction of 4-morpholinoaniline (2.15 g, 12.1 mmol) and 2,6-dichloropyrazine (0.756 g, 5.03 mmol).

¹ Hn.mr (CDCl ₃ ) δ 3.25 (br s, 4H, CH ₂ ), 3.99 (br s, 4H, CH ₂ ), 7.05-7.17 (m, 2H, ArH), 7.42-7.54 (m, 2H , ArH), 7.94 (s, 1H, pyrazine-H), 8.04 (s, 1H, pyrazine-H), 8.06 (s, 1H, NH).

6-Chloro-N- (4-fluorobenzyl) pyrazin-2-amine

  In a procedure similar to Example 1, the product (2.35 g, 99%) was obtained from the reaction of 4-fluorobenzylamine (3.75 g, 30.0 mmol) and 2,6-dichloropyrazine (1.49 g, 10.0 mmol). .

¹ Hn.mr (CDCl ₃ ) δ4.53 (s, 2H, CH ₂ ), 5.08 (br s, 1H, NH), 7.01 ~ 7.07 (m, 2H, ArH), 7.30 ~ 7.34 (m, 2H, ArH ), 7.77 (s, 1H, pyrazine-H), 7.83 (s, 1H, pyrazine-H).

6- (1H-imidazol-1-yl) -N- (4-morpholin-4-ylphenyl) pyrazin-2-amine

  A product similar to that in Example 2 from the reaction of 6-chloro-N- (4-morpholin-4-ylphenyl) pyrazin-2-amine (100 mg, 0.34 mmol) and imidazole (126 mg, 0.38 mmol) ( 37 mg, 34%).

¹ Hn.mr (CDCl ₃ ) δ 3.18 (br s, 4H, 2CH ₂ ), 3.87-3.91 (m, 4H, 2CH ₂ ), 6.77 (s, 1H, imidazol-H), 6.94-6.98 (m, 2H, ArH), 7.36 (d, 2H, J = 8.7Hz, ArH), 7.62 (br s, 1H, imidazole-H), 8.03 (s, 1H, pyrazine-H), 8.08 (s, 1H, pyrazine- H), 8.39 (br s, 1H, imidazole-H).
m / z (ES) 323 ( M + + H).

N- (4-Fluorobenzyl) -6- (1H-imidazol-1-yl) pyrazin-2-amine

  The product (210 mg, 65%) from the reaction of 6-chloro-N- (4-fluorobenzyl) pyrazin-2-amine (240 mg, 1.01 mmol) and imidazole (76 mg, 1.11 mmol) in a procedure similar to Example 2. )

¹ Hn.mr (CDCl ₃ ) δ4.59 (d, 2H, J = 5.7Hz, CH ₂ ), 5.23 (t-like, 1H, NH), 7.03 ~ 7.08 (m, 2H, ArH), 7.20 (s , 1H, Imidazole-H), 7.32-7.37 (m, 2H, ArH), 7.55 (s, 1H, Imidazole-H), 7.85 (s, 1H, Pyrazine-H), 8.00 (s, 1H, Pyrazine-H) ), 8.29 (s, 1H, imidazole-H).
m / z (ES) 270 ( M + + H).

6- (2-Methyl-1H-imidazol-1-yl) -N-[(1R) -1-phenylethyl] pyrazin-2-amine

  From a reaction of 6-chloro-N-[(1R) -1-phenylethyl] pyrazin-2-amine (150 mg, 0.64 mmol) and 2-methylimidazole (58 mg, 0.71 mmol) in a procedure similar to Example 2. The product (172 mg, 40%) was obtained.

¹ Hn.mr (CDCl ₃ ) δ1.59 (d, 3H, J = 6.8Hz, CH ₃ ), 2.43 (s, 3H, CH ₃ ), 4.98 (m, 1H, CH), 5.45 (br s, 1H , NH), 6.98 (d, 1H, J = 1.3 Hz, imidazole-H), 7.17 (d, 1H, J = 1.3 Hz, imidazole-H), 7.22 to 7.35 (m, 5H, ArH), 7.82 (s , 1H, pyrazine-H), 7.84 (s, 1H, pyrazine-H).
m / z (ES) 280 ( M + + H).

N- (4-Fluorobenzyl) -6- (2-methyl-1H-imidazol-1-yl) pyrazin-2-amine

  The product (42 mg from the reaction of 6-chloro-N- (4-fluorobenzyl) pyrazin-2-amine (150 mg, 0.63 mmol) and 2-methylimidazole (57 mg, 0.69 mmol) in a procedure similar to Example 2. 23%).

¹ Hn.mr (CDCl ₃ ) δ2.56 (s, 3H, CH ₃ ), 4.57 (d, J = 5.7Hz, 1H, CH ₂ ), 5.34 (br s, 1H, NH), 7.01 ~ 7.07 (m , 3H, Ar-H), 7.26 (s, 1H, imidazole-H), 7.29-7.34 (m, 2H, ArH), 7.92 (s, 2H, pyrazine-H).
m / z (ES) 284 ( M + + H).

N- (4-fluorobenzyl) -6- (4-methyl-1H-imidazol-1-yl) pyrazin-2-amine and N- (4-fluorobenzyl) -6- (5-methyl-1H-imidazole- 1-yl) pyrazin-2-amine

  In a procedure similar to Example 2, the reaction of 2- (4-fluorobenzylamino) -6-chloro-pyrazine (190 mg, 0.80 mmol) and 4-methylimidazole (72 mg, 0.88 mmol) yielded the following product, 4 A methyl derivative (100 mg, 44%) and a 5-methyl derivative (19 mg, 8%) were obtained.

(4-Methyl derivative) ¹ Hn.mr (CDCl ₃ ) δ2.31 (s, 3H, CH ₃ ), 4.58 (d, 2H, J = 5.7Hz, CH ₂ ), 5.40 (br s, 1H, NH) 6.92 (s, 1H, imidazole-H), 7.00 to 7.08 (m, 2H, ArH), 7.25 (s, 1H, imidazole-H5), 7.31 to 7.36 (m, 2H, ArH), 7.84 (s, 1H , Pyrazine-H5), 7.93 (s, 1H, pyrazine-H3), 8.24 (br s, 1H, imidazole-H2).
m / z (ES) 284 ( M + + H).

(5-methyl derivative) ¹ Hn.mr (CDCl ₃ ) δ 2.34 (s, 3H, CH ₃ ), 4.57 (d, 2H, J = 5.7Hz, CH ₂ ), 5.44 (br s, 1H, NH) 6.92 (s, 1H, imidazole-H), 7.00 to 7.07 (m, 2H, ArH), 7.28 to 7.34 (m, 2H, ArH), 7.93 (s, 1H, pyrazine-H), 7.95 (s, 1H , Pyrazine-H), 7.98 (br s, 1H, imidazole-H).
m / z (ES) 284 ( M + + H).

N-[(1R) -1-phenylethyl] -6- (4-phenyl-1H-imidazol-1-yl) pyrazin-2-amine

  From a reaction of 6-chloro-N-[(1R) -1-phenylethyl] pyrazin-2-amine (180 mg, 0.77 mmol) and 4-phenylimidazole (122 mg, 0.85 mmol) in a procedure similar to Example 2. The product (176 mg, 67%) was obtained.

¹ Hn.mr (CDCl ₃ ) δ 1.63 (d, 3H, J = 6.9Hz, CH ₃ ), 4.93 to 5.02 (m, 1H, CH), 5.26 (d, 1H, J = 6.0Hz, NH), 7.25-7.44 (m, 8H, ArH), 7.72 (d, 1H, J = 1.2Hz, imidazole-H), 7.77 (s, 1H, pyrazine-H), 7.82-7.86 (m, 2H, ArH), 7.92 (s, 1H, pyrazine-H), 8.22 (s, 1H, imidazole-H).
m / z (ES) 342 ( M + + H).

N-Benzyl-6-chloropyrazin-2-amine

  In a similar procedure to Example 1, the product (2.15 g, 98%) was obtained from the reaction of benzylamine (3.21 g, 30.0 mmol) and 2,6-dichloropyrazine (1.49 g, 10.0 mmol).

¹ Hn.mr (CDCl ₃ ) δ4.55 (d, 2H, J = 5.7Hz, CH ₂ ), 7.28-7.40 (m, 5H, ArH), 7.76 (s, 1H, pyrazine-H), 7.83 (s , 1H, pyrazine-H) ,.

6- (1H-Benzimidazol-1-yl) -N-benzylpyrazin-2-amine

Sodium hydride (56 mg, 60% dispersion in oil, 1.45 mmol) was added in portions over 2 minutes to a stirred solution of benzimidazole (130 mg, 1.1 mmol) in anhydrous DMF (5 mL) at 0 ° C. under N ₂ . The mixture was stirred at 0 ° C. for 15 minutes and at room temperature for 60 minutes. To this was added a solution of (6-chloro-pyrazin-2-yl)-(1-benzyl) -amine (220 mg) in DMF (5 mL) and the resulting mixture was heated to reflux for 18 hours. DMF was removed under reduced pressure and the residue was diluted with chloroform. The organic layer was washed with water, dried (Na ₂ SO ₄ ), and the solvent was removed under reduced pressure to obtain a crude product. The product (100 mg) was separated by column chromatography using dichloromethane-methanol (20: 1 → 10: 1) as eluent.

¹ Hn.mr (CDCl ₃ ) δ 4.66 (d, 2H, J = 5.7Hz, CH ₂ ), 5.56 (m, 1H, NH), 7.29-7.39 (m, 7H, Ar-H), 7.78-7.89 (m, 2H, Ar-H), 7.92 (s, 1H, pyrazine-H), 8.16 (s, 1H, pyrazine-H), 8.48 (s, 1H, benzimidazole-H2).
m / z (ES) 302 ( M + + H).

6- (1H-Benzimidazol-1-yl) -N-[(1R) -1-phenylethyl] pyrazin-2-amine

  The product from the reaction of 6-chloro-N-[(1R) -1-phenylethyl] pyrazin-2-amine (240 mg, 1.03 mmol) and benzimidazole (130 mg, 1.10 mmol) with a procedure similar to Example 12. (187 mg, 59%) was obtained.

¹ Hn.mr (CDCl ₃ ) δ 1.63 (d, 3H, J = 6.6Hz, CH ₃ ), 4.98 to 5.20 (m, 1H, CH), 5.58 (d, 1H, J = 6.0Hz, NH), 7.25-7.42 (m, 6H, Ph-H, benzimidazole-H), 7.70 (dd, 1H, J = 7.2, 1.0Hz, benzimidazole-H), 7.82 (dd, 1H, J = 8.0, 1.2Hz, Benzimidazole-H), 7.87 (s, 1H, pyrazine-H), 8.11 (s, 1H, pyrazine-H), 8.38 (s, 1H, benzimidazole-H).
m / z (ES) 315 ( M + + H), 212,105.

6- (1H-Benzimidazol-1-yl) -N-[(1S) -1-phenylethyl] pyrazin-2-amine

  The product from the reaction of 6-chloro-N-[(1S) -1-phenylethyl] pyrazin-2-amine (140 mg, 0.60 mmol) and benzimidazole (78 mg, 0.66 mmol) in a procedure similar to Example 12. (71 mg, 38%) was obtained.

¹ Hn.mr (CDCl ₃ ) δ1.57 (d, 3H, J = 6.9Hz, CH ₃ ), 4.95 (m, 1H, CH), 5.29 (d, 1H, J = 6.0Hz, NH), 7.19 ~ 7.35 (m, 7H, Ph-H, benzimidazole-H), 7.63-7.66 (m, 1H, benzimidazole-H), 7.74-7.77 (m, 1H, benzimidazole-H), 7.78 (s, 1H, Pyrazine-H), 8.06 (s, 1H, pyrazine-H), 8.31 (s, 1H, benzimidazole-H).
m / z (ES) 316 ( M + + H), 212,105

6- (1H-Benzimidazol-1-yl) -N- (4-morpholin-4-ylphenyl) pyrazin-2-amine

  The product from the reaction of 6-chloro-N- (4-morpholin-4-ylphenyl) pyrazin-2-amine (150 mg, 0.52 mmol) and benzimidazole (67 mg, 0.57 mmol) in a procedure similar to Example 12. (60 mg, 31%) was obtained.

¹ Hn.mr (CDCl ₃ ) δ 3.19 (br s, 4H, 2CH ₂ ), 3.90 (t, 4H, J = 4.6Hz, 2CH ₂ ), 6.69 (s, 1H, NH), 6.98 (d, 2H , J = 8.4 Hz, ArH), 7.37 to 7.41 (m, 4H, ArH), 7.87 to 7.90 (m, 1H, ArH), 8.00 to 8.03 (m, 1H, ArH), 8.08 (s, 1H, pyrazine- H), 8.31 (s, 1H, pyrazine-H), 8.59 (s, 1H, benzimidazole-H2).
m / z (ES) 373 ( M + + H).

6- (1H-Benzimidazol-1-yl) -N- (4-fluorobenzyl) pyrazin-2-amine

  In a procedure similar to Example 12, the product (170 mg, 53 mmol) from the reaction of 6-chloro-N- (4-fluorobenzyl) pyrazin-2-amine (240 mg, 1.01 mmol) and benzimidazole (130 mg, 1.1 mmol). %).

¹ Hn.mr (CDCl ₃ ) δ 4.64 (d, 2H, J = 5.7Hz, CH ₂ ), 5.46 (br s, 1H, NH), 7.06 (m, 2H, ArH), 7.30-7.38 (m, 4H, ArH), 7.82-7.88 (m, 2H, ArH), 7.93 (s, 1H, pyrazine-H), 8.20 (s, 1H, benzimidazole-H), 8.49 (s, 1H, pyrazine-H).
m / z (ES) 320 ( M + + H).

6- (1H-imidazo [4,5-b] pyridin-1-yl) -N-[(1S) -1-phenylethyl] pyrazin-2-amine and 6- (3H-imidazo [4,5-b ] Pyridin-3-yl) -N-[(1S) -1-phenylethyl] pyrazin-2-amine

  Reaction of 6-chloro-N-[(1S) -1-phenylethyl] pyrazin-2-amine (240 mg, 1.03 mmol) and 4-azabenzimidazole (130 mg, 1.09 mmol) in a procedure similar to Example 12. Gave the product (7 mg, 2%) as a 1: 1 mixture of regioisomers.

¹ Hn.mr (1: 1 mixture) (CDCl ₃ ) δ 1.54 (d, 3H, CH ₃ ), 1.63 (d, 3H, CH ₃ ), 4.63 (br s, 1H, NH), 4.82 to 4.91 ( m, 1H, CH), 4.95 to 5.04 (m, 1H, NH), 5.16 (m, 1H, NH), 7.07 (s, 1H, ArH), 7.22 to 7.43 (m, 16H, ArH), 7.87 (s , 1H, ArH), 8.11 (dd, 1H, J = 8.1, 1.5 Hz, ArH), 8.48 (dd, 1H, J = 4.8, 1.2 Hz, ArH), 8.80 (s, 1H, ArH).
m / z (ES) 317 ( M + + H).

6- (5-Methyl-1H-benzimidazol-1-yl) -N-[(1S) -1-phenylethyl] pyrazin-2-amine and 6- (6-Methyl-1H-benzimidazol-1-yl ) -N-[(1S) -1-Phenylethyl] pyrazin-2-amine

  Reaction of 6-chloro-N-[(1S) -1-phenylethyl] pyrazin-2-amine (91 mg, 0.39 mmol) and 5-methylbenzimidazole (57 mg, 0.43 mmol) in a procedure similar to Example 12. Gave the product (61 mg, 148%) as a 1: 1 mixture.

¹ Hn.mr (1: 1 mixture) (CDCl ₃ ) δ 1.65 (d, 3H, CH ₃ ), 1.66 (d, 3H, CH ₃ ), 2.49 (s, 3H, CH ₃ ), 2.50 (s, _{3H, CH 3), 5.01 (} m, 1H, CH), 5.04 (m, 1H, CH), 5.56 (d, 1H, NH), 5.62 (d, 1H, NH), 7.27~7.45 (m, 10H, Ph-H), 7.56-7.85 (m, 4H, benzimidazole-H), 7.94 (s, 1H, pyrazine-H), 7.97 (s, 1H, pyrazine-H), 8.02 (s, 2H, benzimidazole- H), 8.16 (s, 1H, pyrazine-H), 8.17 (s, 1H, pyrazine-H), 8.59 (s, 1H, benzimidazole-H), 8.70 (s, 1H, benzimidazole-H).
m / z (ES) 330 ( M + + H).

6- (2-Methyl-1H-benzimidazol-1-yl) -N-[(1S) -1-phenylethyl] pyrazin-2-amine

  Reaction of 6-chloro-N-[(1S) -1-phenylethyl] pyrazin-2-amine (120 mg, 0.51 mmol) and 2-methylbenzimidazole (75 mg, 0.57 mmol) in a procedure similar to Example 12. Gave the product (18 mg, 11%).

¹ Hn.mr (CDCl ₃ ) δ1.63 (d, 3H, J = 6.9Hz, CH ₃ ), 2.59 (s, 3H, CH ₃ ), 4.93 (m, 1H, CH), 5.89 (br s, 1H , NH), 7.16-7.49 (m, 7H, ArH), 7.93 (d, 2H, J = 8.1Hz, Ar-H), 8.00 (br s, 1H, pyrazine-H), 8.23 (br s, 1H, Pyrazine-H).
m / z (ES) 330 ( M + + H).

N- (2-hydroxyethyl) -1H-benzimidazole-5-carboxamide

  To a stirred suspension of benzimidazole-5-carboxylic acid (0.40 g, 2.50 mmol) in benzene (8 mL) was added thionyl chloride (2 mL) dropwise at room temperature. The entire mixture was then heated to reflux for 5 hours. Benzene and thionyl chloride were removed by evaporation under reduced pressure and the resulting acid chloride was suspended in tetrohydrofuran. To this, 2-hydroxyethylamine was added dropwise at 0 ° C., and the resulting mixture was stirred overnight at room temperature. The solvent was then decanted and the residue was washed with diethyl ether (40 mL). The residual oil was then treated with cold water (5 mL) and the aqueous solution was carefully decanted. This step was repeated to give 0.19 g (37%) of the amide as a light brown solid.

¹ Hn.mr (CDCl ₃ ) δ 3.30-3.37 (m, 2H, CH ₂ ), 3.51-3.55 (m, 2H, CH ₂ ), 4.69 (s, 1H, OH), 7.59 (d, 1H, J = 8.1Hz, ArH), 7.73 (d, 1H, J = 8.4Hz, ArH), 8.13 (br s, 1H, NH), 8.30 (s, 1H, H-4), 8.35 (br s, 1H, H -2), 12.47 (br s, 1H, CONH).

1- [6-{[(1S) -1-Phenylethyl] amino} pyrazin-2-yl] -N- (2-hydroxyethyl) -1H-benzimidazole-5-carboxamide

  In a procedure analogous to Example 12, 6-chloro-N-[(1S) -1-phenylethyl] pyrazin-2-amine (91 mg, 0.39 mmol) and benzimidazole 5-carboxylic acid (2-hydroxyethyl) amide The product was obtained from the reaction (88 mg, 0.43 mmol) and was purified by column chromatography (22 mg, 14%).

¹ Hn.mr (CDCl ₃ ) δ1.63 (d, 3H, J = 6.9Hz, CH ₃ ), 3.68 (2H, dt, J = 5.1Hz, CH ₂ NH), 3.91 (2H, t, J = 5.1 _{Hz, CH 2 OH), 4.98} (m, 1H, CH), 5.50 (d, 1H, J = 6.0Hz, NH), 7.15 (1H, t, J = 5.1Hz, CONH), 7.28~7.41 (m, 5H, Ar-H), 7.60 (d, 1H, J = 8.4Hz, benzimidazole-H), 7.73 (d, 1H, J = 8.4Hz, benzimidazole-H), 7.88 (s, 1H, pyrazine-H) ), 8.05 (s, 1H, pyrazine-H), 8.20 (s, 1H, benzimidazole-H), 8.40 (s, 1H, benzimidazole-H). m / z (ES) 403 ( M + + H).

[1- (6-{[(1S) -1-phenylethyl] amino} pyrazin-2-yl) -1H-benzimidazol-5-yl] methanol and [1- (6-{[(1S) -1 -Phenylethyl] amino} pyrazin-2-yl) -1H-benzimidazol-6-yl] methanol

  In a procedure analogous to Example 12, 6-chloro-N-[(1S) -1-phenylethyl] pyrazin-2-amine (1.07 g, 4.6 mmol) and 5-hydroxymethylbenzimidazole (0.68 g, Y4. From the reaction of 60 mmol), two products separated by column chromatography were obtained. 5-hydroxymethyl isomer (34 mg, 2%), 6-hydroxymethyl isomer (36 mg, 2%).

(5-hydroxymethyl isomer) ¹ Hn.mr (CDCl ₃ ) δ 1.65 (d, 3H, J = 6.9 Hz, CH ₃ ), 4.82 (s, 2H, CH ₂ OH), 5.03 (m, 1H, CH), 5.26 (d, 1H, J = 6.0 Hz, NH), 7.25-7.40 (m, 6H, Ar-H), 7.68 (d, 1H, J = 8.4 Hz, benzimidazole-H), 7.81 (s , 1H, benzimidazole-H), 7.85 (s, 1H, pyrazine-H), 8.12 (s, 1H, pyrazine-H), 8.39 (s, 1H, benzimidazole-H). m / z (ES) 346 ( M + + H).

(6-hydroxymethyl isomer) ¹ Hn.mr (CDCl ₃ ) δ 1.63 (d, 3H, J = 6.9Hz, CH ₃ ), 4.79 (s, 2H, CH ₂ OH), 5.03 (m, 1H, CH), 5.42 (d, 1H, J = 6.3 Hz, NH), 7.25-7.42 (m, 6H, Ar-H), 7.78 (d, 1H, J = 8.4 Hz, benzimidazole-H), 7.81 (s , 1H, pyrazine-H), 7.90 (s, 1H, benzimidazole-H), 8.10 (s, 1H, pyrazine-H), 8.35 (s, 1H, benzimidazole-H). m / z (ES) 346 ( M + + H).

N-methyl-1H-benzimidazole-5-carboxamide

  In a similar procedure to Example 20, the product was obtained in 67% yield from the reaction of benzimidazole-5-carboxylic acid and aqueous methylamine.

¹ Hn.mr (CDCl ₃ ) δ2.79 (s, 3H, CH ₃ ), 7.59 (d, 1H, J = 8.4Hz, H-6), 7.71 (dd, 1H, J = 8.4,1.2Hz, H -7), 8.10 (s, 1H, H-4), 8.29 (s, 1H, H-2), 8.36 (br s, 1H, NH), 12.56 (br s, 1H, CONH).

N-methyl-1- (6-{[(1S) -1-phenylethyl] amino} pyrazin-2-yl) -1H-benzimidazole-5-carboxamide and N-methyl-1- (6-{[( 1S) -1-Phenylethyl] amino} pyrazin-2-yl) -1H-benzimidazole-6-carboxamide

  In a procedure analogous to Example 12, 6-chloro-N-[(1S) -1-phenylethyl] pyrazin-2-amine (91 mg, 0.39 mmol) and 5-carboxybenzimidazole N-methylamide (75 mg, 0.43 mmol) ) To give two products separated by column chromatography. 5-isomer (23 mg, 16%), 6-isomer (38 mg, 26%).

(5-isomer) ¹ Hn.mr (CDCl ₃ ) δ 1.67 (d, 3H, J = 6.9 Hz, CH ₃ ), 3.06 (d, 3H, J = 4.5 Hz, NCH ₃ ), 5.01 (m, 1H, CH), 5.58 (br s, 1H, NH), 6.43 (br s, 1H, CONH), 7.30-7.43 (m, 5H, Ph-H), 7.71 (d, 1H, J = 8.4Hz, benz Imidazole-H), 7.84-7.88 (m, 2H, benzimidazole-H, pyrazine-H), 8.19 (s, 1H, pyrazine-H), 8.53 (s, 1H, benzimidazole-H), 8.57 (s, 1H, benzimidazole-H).
m / z (ES) 373 ( M + + H).

(6-Isomer) ¹ Hn.mr (CDCl ₃ ) δ 1.65 (d, 3H, J = 6.9 Hz, CH ₃ ), 3.07 (d, 3H, J = 4.5 Hz, NCH ₃ ), 5.02 (m, 1H, CH), 5.31 (d, 1H, J = 4.8Hz, NH), 6.30 (br s, 1H, CONH), 7.31-7.41 (m, 5H, Ph-H), 7.68 (d, 1H, J = 8.4 Hz, benzimidazole-H), 7.81 (d, 1 H, J = 8.4 Hz, benzimidazole-H), 7.92 (s, 1 H, pyrazine-H), 8.13 (s, 1 H, pyrazine-H), 8.18 ( s, 1H, benzimidazole-H), 8.49 (s, 1H, benzimidazole-H).
m / z (ES) 373 ( M + + H).

1- (6-{[(1S) -1-phenylethyl] amino} pyrazin-2-yl) -1H-benzimidazol-5-amine and 1- (6-{[(1S) -1-phenylethyl] Amino} pyrazin-2-yl) -1H-benzimidazol-6-amine

5-amino-benzimidazole (290 mg, 2.2 mmol) in anhydrous DMF (10 mL) stirred solution of, N ₂ under, was added cesium carbonate (980 mg). The resulting mixture was stirred at 70 ° C. for 60 minutes. To this was added a solution of 6-chloro-N-[(1S) -1-phenylethyl] pyrazin-2-amine (470 mg) in DMF (5 mL), and the resulting mixture was heated to reflux for 48 hours. DMF was removed under reduced pressure and the residue was diluted with chloroform. The organic layer was washed with an aqueous Na ₂ CO ₃ solution, dried (Na ₂ SO ₄ ), and the solvent was removed under reduced pressure to obtain a crude product. Two fractions were separated from unreacted starting material by column chromatography using dichloromethane-methanol (95: 5 → 92: 8) as eluent. The higher frequency fraction was made 6-isomer (276 mg, 42%). ¹ Hn.mr (CDCl ₃ ) δ1.64 (d, 3H, J = 6.9Hz, CH ₃ ), 2.90 (br s, 2H, NH ₂ ), 5.05 (m, 1H, CH), 5.21 (d, 1H , NH), 6.70 (dd, 1H, J = 8.7, 2.1 Hz, benzimidazole-H), 6.97 (d, 1H, J = 1.8 Hz, benzimidazole-H), 7.28 to 7.43 (m, 5H, Ph- H), 7.58 (d, 1H, J = 8.4 Hz, benzimidazole-H), 7.84 (s, 1H, pyrazine-H), 8.08 (s, 1H, pyrazine-H), 8.21 (s, 1H, benzimidazole) -H). m / z (ES) 331 ( M + + H). The lower fraction was the 5-isomer (170 mg, 26%). ¹ Hn.mr (CDCl ₃ ) δ 1.64 (d, 3H, J = 6.9Hz, CH), 2.85 (br s, 2H, NH ₂ ), 5.01 (m, 1H, CH), 5.19 (d, 1H, NH), 6.70 (dd, 1H, J = 8.7, 2.1 Hz, benzimidazole-H), 7.11 (d, 1H, J = MHz, benzimidazole-H), 7.29-7.40 (m, 5H, Ph-H) 7.51 (d, 1H, J = 8.7 Hz, benzimidazole-H), 7.81 (s, 1H, pyrazine-H), 8.10 (s, 1H, pyrazine-H), 8.32 (s, 1H, benzimidazole-H) ).
m / z (ES) 331 ( M + + H).

N-Benzyl-1H-benzimidazole-5-carboxamide

  In a similar procedure to Example 20, the product (410 mg, 66%) was obtained from the reaction of benzimidazole-5-carboxylic acid (400 mg, 2.50 mmol) and benzylamine.

¹ Hn.mr (CDCl ₃ ) δ4.56 (d, 2H, J = 5.8Hz, CH ₂ ), 7.13 ~ 7.31 (m, 5H, Ph-H), 7.59 (d, 1H, J = 8.5Hz, H -6), 7.79 (dd, 1H, J = 8.5Hz, H-7), 7.96 (br s, 1H, CONH), 8.21 (s, 1H, H-4), 8.29 (s, 1H, H-2) ).

N-benzyl-1- [6-{[(1S) -1-phenylethyl] amino} pyrazin-2-yl] -1H-benzimidazole-5-carboxamide and N-benzyl-1- [6-{[( 1S) -1-Phenylethyl] amino} pyrazin-2-yl-1H-benzimidazole-6-carboxamide

  In a procedure similar to Example 25, 6-chloro-N-[(1S) -1-phenylethyl] pyrazin-2-amine (91 mg, 0.39 mmol) and N-benzyl-1H-benzimidazole-5-carboxamide ( 108 mg, 0.43 mmol) gave the product (132 mg, 75%) as a 3: 1 mixture of regioisomers.

¹ Hn.mr (3: 1 mixture) (CDCl ₃ ) δ 1.62 (d, 3H, J = 6.9Hz, CH ₃ ), 1.63 (d, 3H, J = 6.9Hz, CH ₃ ), 4.68 (d, _{2H, J = 5.4Hz, CH 2} ), 4.70 (d, 2H, J = 5.4Hz, CH 2), 4.95~5.04 (m, 1H, CH), 5.55 (d, 1H, NH), 5.61 (d, 1H, NH), 6.80 (t-like, 1H, CONH), 6.92 (t-like, 1H, CONH), 7.22 to 7.40 (m, Ph-H, Ph-H), 7.66 (d, 1H, J = 8.4 Hz, benzimidazole-H), 7.71 (d, 1H, J = 8.4 Hz, benzimidazole-H), 7.80-7.85 (m, benzimidazole-H), 7.91 (s, 1H, benzimidazole-H), 8.05 (s, 1H, pyrazine-H), 8.13 (s, 1H, pyrazine-H), 8.25 (s, 1H, benzimidazole-H), 8.38 (s, 1H, pyrazine-H), 8.46 (s, 1H , Benzimidazole-H), 8.59 (s, 1H, pyrazine-H).
m / z (ES) 449 ( M + + H).

N-phenyl-1H-benzimidazole-5-carboxamide

  In a similar procedure to Example 20, the product (370 mg, 63%) was obtained from the reaction of benzimidazole-5-carboxylic acid (400 mg, 5.50 mmol) and aniline (510 mg, 5.50 mmol).

¹ Hn.mr (CDCl ₃ ) δ6.83 (m, 1H, Ar-H), 7.08 (m, 2H, Ar-H), 7.53-7.74 (m, 4H, Ar-H), 8.13-8.31 (m , 2H, Ar-H + CONH), 9.57 (s, 1H, H-2).

1- (6-{[(1S) -1-phenylethyl] amino} pyrazin-2-yl) -N-phenyl-1H-benzimidazole-5-carboxamide and 1- (6-{[(1S) -1 -Phenylethyl] amino} pyrazin-2-yl) -N-phenyl-1H-benzimidazole-6-carboxamide

  In a procedure similar to Example 25, 6-chloro-N-[(1S) -1-phenylethyl] pyrazin-2-amine (91 mg, 0.39 mmol) and N-phenyl-1H-benzimidazole-5-carboxamide ( 102 mg, 0.43 mmol) gave the product as a 2: 1 mixture of regioisomers (100 mg, 59%).

¹ Hn.mr (2: 1 mixture) (CDCl ₃ ) δ 1.61 (d, 3H, J = 6.9Hz, CH ₃ ), 1.62 (d, 3H, J = 6.9Hz, CH ₃ ), 4.94 to 5.03 ( m, CH, CH), 5.55 (d, 1H, NH), 5.62 (d, 1H, NH), 7.18-7.45 (m, Ph-H, Ph-H), 7.61-7.83 (m, benzimidazole-H And Ph-H)), 7.85 (s, 1H, pyrazine-H), 7.90 (s, 1H, pyrazine-H), 8.06 (s, 1H, pyrazine-H), 8.12 (s, 1H, pyrazine-H) 8.33 (s, 1H, benzimidazole-H), 8.36 (s, 1H, benzimidazole-H), 8.46 (s, 1H, benzimidazole-H), 8.49 (s, 1H, CONH), 8.52 (s, 1H, CONH), 8.57 (s, 1H, benzimidazole-H).
m / z (ES) 435 ( M + + H).

5-[(4-Methylpiperazin-1-yl) carbonyl] -1H-benzimidazole

  In a similar procedure to Example 20, the product (380 mg, 63%) was obtained from the reaction of benzimidazole-5-carboxylic acid (400 mg, 2.50 mmol) and N-methylpiperazine (550 mg, 5.0 mmol).

¹ Hn.mr (CDCl ₃ ) δ2.33 (s, 3H, CH ₃ ), 2.44 (br s, 4H, CH ₂ ), 3.70 (br s, 4H, CH ₂ ), 7.25 (s, 1H, ArH) 7.66 (br s, 1H, ArH), 7.87 (s, 1H, ArH), 11.88 (s, 1H, H-2).
m / z (ES) 245 ( M + + H).

6- {5-[(4-Methylpiperazin-1-yl) carbonyl] -1H-benzimidazol-1-yl} -N-[(1S) -1-phenylethyl] pyrazin-2-amine and 6- { 6-[(4-Methylpiperazin-1-yl) carbonyl] -1H-benzimidazol-1-yl} -N-[(1S) -1-phenylethyl] pyrazin-2-amine

  In a procedure analogous to Example 25, 6-chloro-N-[(1S) -1-phenylethyl] pyrazin-2-amine (91 mg, 0.39 mmol) and 5-[(4-methylpiperazin-1-yl) Reaction of carbonyl] -1H-benzimidazole (105 mg, 0.43 mmol) gave the product as a mixture of regioisomers, which were separated by column chromatography. 6-isomer (58 mg, 34%), 5-isomer (68 mg, 40%).

(5-Isomer) ¹ Hn.mr (CDCl ₃ ) δ1.63 (d, 3H, J = 6.9Hz, CH ₃ ), 2.33 (s, 3H, NCH ₃ ), 2.44 (br s, 4H, CH ₂ ), 3.67 (br s, 4H, CH ₂ ), 5.01 (m, 1H, CH), 5.48 (d, 1H, J = 6.0 Hz, NH), 7.26-7.38 (m, 6H, Ar-H), 7.65 (d, 1H, J = 8.4 Hz, benzimidazole-H), 7.85 (s, 1H, benzimidazole-H), 7.89 (s, 1H, pyrazine-H), 8.09 (s, 1H, pyrazine-H), 8.41 (s, 1H, benzimidazole-H).
m / z (ES) 442 ( M + + H).

(6-Isomer) ¹ Hn.mr (CDCl ₃ ) δ1.63 (d, 3H, J = 6.9Hz, CH ₃ ), 2.31 (s, 3H, NCH), 2.43 (br s, 4H, CH ₂ ) , 3.4~3.9 (br m, 4H, CH 2), 4.99 (m, 1H, CH), 5.54 (d, 1H, J = 6.0Hz, NH), 7.23~7.39 (m, 6H, Ar-H), 7.83-7.85 (m, 2H, Ar-H, pyrazine-H), 8.07 (s, 1H, benzimidazole-H), 8.12 (s, 1H, pyrazine-H), 8.44 (s, 1H, benzimidazole-H) ). m / z (ES) 442 ( M + + H).

N- [1- (6-{[(1S) -1-Phenylethyl] amino} pyrazin-2-yl) -1H-benzimidazol-5-yl] acetamide

To a stirred solution of 2- (S-α-methylbenzylamino) -6- (5-aminobenzimidazol-1-yl) -pyrazine (66 mg, 0.2 mmol) in anhydrous THF (2 mL) was added triethylamine (41 mg under N _2. 0.4 mmol) was added. The solution was cooled at 0 ° C., acetyl chloride (17 mg, 0.22 mmol) was added and the resulting mixture was stirred at room temperature. After 18 hours, the solution was poured into water (30 mL) and the product was extracted into chloroform (2 × 20 mL). The combined organic layers were dried (Na ₂ SO ₄ ) and the solvent was removed under reduced pressure to give the crude product as a pale yellow solid. The product was isolated as a pale yellow solid (38 mg) by column chromatography using dichloromethane-methanol (200: 15) as the eluent.

¹ Hn.mr (CDCl ₃ ) δ1.63 (d, 3H, J = 6.6Hz, CH ₃ ), 2.21 (s, 3H, CH ₃ ), 5.00 (m, 1H, CH), 5.43 (d, 1H, J = 5.7 Hz, NH), 7.27-7.38 (m, 5H, ArH), 7.49 (d, 1H, J = 9.0 Hz, benzimidazole-H), 7.61 (d, 1H, J = 9.0 Hz, benzimidazole) H), 7.74 (br s, 1H, CONH), 7.84 (s, 1H, pyrazine-H), 7.90 (s, 1H, benzimidazole-H), 8.11 (s, 1H, pyrazine-H), 8.36 (s , 1H, benzimidazole-H).
m / z (ES) 373 ( M + + H).

N- [1- (6-{[(1S) -1-Phenylethyl] amino} pyrazin-2-yl) -1H-benzimidazol-6-yl] acetamide

  In a procedure similar to Example 32, 2- (S-α-methylbenzylamino) -6- (6-aminobenzimidazol-1-yl) -pyrazine (66 mg, 0.20 mmol) and acetyl chloride (17 mg, 0.22 mmol) ) Gave the product (70 mg, 94%) after chromatography.

¹ Hn.mr (CDCl ₃ ) δ1.65 (d, 3H, J = 6.9Hz, CH ₃ ), 2.22 (s, 3H, CH), 5.07 (m, 1H, CH), 5.29 (d, 1H, J = 6.3 Hz, NH), 7.28 to 7.43 (m, 6H, ArH, benzimidazole-H), 7.72 (d, 1H, J = 8.7 Hz, benzimidazole-H), 7.84 (s, 1H, pyrazine-H) 8.12 (s, 1H, pyrazine-H), 8.27 (s, 1H, benzimidazole-H), 8.34 (s, 1H, benzimidazole-H).
m / z (ES) 373 ( M + + H).

N- [1- (6-{[(1S) -1-Phenylethyl] amino} pyrazin-2-yl) -1H-benzimidazol-5-yl] benzamide

  In a procedure analogous to Example 32, 1- (6-{[(1S) -1-phenylethyl] amino} pyrazin-2-yl) -1H-benzimidazol-5-amine (33 mg, 0.10 mmol) and chloride Reaction of benzoyl (14 mg, 0.10 mmol) gave the product (23 mg, 53%) after chromatography.

¹ Hn.mr (CDCl ₃ ) δ 1.64 (d, 3H, J = 6.8Hz, CH ₃ ), 5.02 (m, 1H, CH), 5.33 (d, 1H, J = 4.5Hz, NH), 7.27- 7.68 (m, 10H, ArH), 7.85 (s, 1H, pyrazine-H), 7.90-7.93 (m, 2H, benzimidazole-H), 8.03 (s, 1H, benzimidazole-H), 8.06 (s, 1H, CONH), 8.10 (s, 1H, pyrazine-H), 8.38 (s, 1H, benzimidazole-H).
m / z (ES) 435 ( M + + H).

N- [1- (6-{[(1S) -1-Phenylethyl] amino} pyrazin-2-yl) -1H-benzimidazol-6-yl] benzamide

  In a procedure analogous to Example 32, 1- (6-{[(1S) -1-phenylethyl] amino} pyrazin-2-yl) -1H-benzimidazol-6-amine (50 mg, 0.15 mmol) and chloride Reaction of benzoyl (21 mg, 0.15 mmol) gave the product (50 mg, 76%) after chromatography.

¹ Hn.mr (CDCl ₃ ) δ 1.64 (d, 3H, J = 6.6Hz, CH ₃ ), 5.11 (m, 1H, CH), 5.31 (d, 1H, J = 6.6Hz, NH), 7.16- 7.58 (m, 10H, ArH), 7.78 (d, 1H, J = 8.4Hz, benzimidazole-H), 7.83 (s, 1H, benzimidazole-H), 7.90 (d, 1H, J = 8.1Hz, benz Imidazole-H), 7.97 (s 1H, CONH), 8.15 (s, 1H, pyrazine-H), 8.35 (s, 1H, pyrazine-H), 8.51 (s, 1H, benzimidazole-H).
m / z (ES) 435 ( M + + H).

N- [1- (6-{[(1S) -1-Phenylethyl] amino} pyrazin-2-yl) -1H-benzimidazol-5-yl] isonicotinamide

  In a procedure analogous to Example 32, 1- (6-{[(1S) -1-phenylethyl] amino} pyrazin-2-yl) -1H-benzimidazol-5-amine (33 mg, 0.10 mmol) and chloride Reaction of isonicotinoyl hydrochloride (20 mg, 0.11 mmol) gave the product (10 mg, 23%) after chromatography.

¹ Hn.mr (CDCl ₃ ) δ1.56 (d, 3H, J = 6.9Hz, CH ₃ ), 4.98 (m, 1H, CH), 6.21 (d, 1H, J = 6.0Hz, NH), 7.11 ~ 7.37 (m, 5H, ArH), 7.59 (d, 1H, J = 9.0Hz, benzimidazole-H), 7.65 (d, 1H, J = 8.7Hz, benzimidazole-H), 7.81 (d, 2H, J = 5.7Hz, pyridine-H), 7.87 (s, 1H, pyrazine-H), 8.01 (s, 1H, pyrazine-H), 8.10 (s, 1H, benzimidazole-H), 8.32 (s, 1H, benz) Imidazole-H), 8.72 (d, 2H, J = 5.7 Hz, pyridine-H), 9.58 (s, 1H, CONH).
m / z (ES) 436 ( M + + H).

N- [1- (6-{[(1S) -1-Phenylethyl] amino} pyrazin-2-yl) -1H-benzimidazol-6-yl] isonicotinamide

  In a procedure analogous to Example 32, 1- (6-{[(1S) -1-phenylethyl] amino} pyrazin-2-yl) -1H-benzimidazol-6-amine (33 mg, 0.10 mmol) and chloride Reaction of isonicotinoyl hydrochloride (20 mg, 0.11 mmol) gave the product (10 mg, 23%) after chromatography.

¹ Hn.mr (CDCl ₃ ) δ1.63 (d, 3H, J = 6.9Hz, CH ₃ ), 5.11 (m, 1H, CH), 5.40 (d, 1H, J = 6.3Hz, NH), 7.18 ~ 7.42 (m, 6H, ArH, CONH), 7.73-7.79 (m, 3H, benzimidazole-H), 7.83 (s, 1H, pyrazine-H), 8.10 (s, 1H, pyrazine-H), 8.36 (br s, 2H, pyridine-H), 8.48 (s, 1H, benzimidazole-H), 8.79 (d, 2H, J = 5.7 Hz, pyridine-H).
m / z (ES) 436 ( M + + H).

N- [1- (6-{[(1S) -1-Phenylethyl] amino} pyrazin-2-yl) -1H-benzimidazol-5-yl] nicotinamide

  In a procedure analogous to Example 32, 1- (6-{[(1S) -1-phenylethyl] amino} pyrazin-2-yl) -1H-benzimidazol-5-amine (33 mg, 0.10 mmol) and chloride Reaction of nicotinoyl hydrochloride (20 mg, 0.11 mmol) gave the product (17 mg, 39%) after chromatography.

¹ Hn.mr (CDCl ₃ ) δ 1.48 (d, 3H, J = 6.9Hz, CH ₃ ), 4.91 (m, 1H, CH), 6.59 (d, 1H, J = 5.7Hz, NH), 7.11 ~ 7.32 (m, 6H, ArH, pyridine-H), 7.58 (d, 1H, J = 9.0Hz, benzimidazole-H), 7.83 (s, 1H, benzimidazole-H), 7.91 (s, 1H, pyrazine- H), 8.07 (s, 1H, benzimidazole-H), 8.20 (d, 1H, J = 8.1 Hz, pyridine-H), 8.24 (s, 1H, pyrazine-H), 8.61 (d, 1H, J = 4.6 Hz, pyridine-H), 9.12 (s, 1H, pyridine-H), 9.80 (s, 1H, CONH).
m / z (ES) 436 ( M + + H).

N- [1- (6-{[(1S) -1-Phenylethyl] amino} pyrazin-2-yl) -1H-benzimidazol-6-yl] nicotinamide

  In a procedure analogous to Example 32, 1- (6-{[(1S) -1-phenylethyl] amino} pyrazin-2-yl) -1H-benzimidazol-6-amine (33 mg, 0.10 mmol) and chloride Reaction of isonicotinoyl hydrochloride (20 mg, 0.11 mmol) gave the product (27 mg, 62%) after chromatography.

¹ Hn.mr (CDCl ₃ ) δ 1.62 (d, 3H, J = 6.6Hz, CH ₃ ), 5.12 (m, 1H, CH), 5.41 (d, 1H, J = 6.0Hz, NH), 7.17- 7.21 (m, 1H, Ar-H), 7.26-7.29 (m, 1H, Ar-H), 7.39-7.45 (m, 4H, ArH, pyridine-H), 7.76 (d, 1H, J = 8.7Hz, Benzimidazole-H), 7.82 (s, 1H, pyrazine-H), 8.11 (s, 1H, pyrazine-H), 8.21 (d, 1H, J = 8.1 Hz, pyridine-H), 8.33 (s, 1H, CONH), 8.35 (s, 1H, Ar-H), 8.47 (3, 1H, pyridine-H), 8.76 (1H, d, J = 4.5Hz, pyridine-H), 9.13 (s, 1H, pyridine-H) ).
m / z (ES) 436 ( M + + H).

N- [1- (6-{[(1S) -1-phenylethyl] amino} pyrazin-2-yl) -1H-benzimidazol-5-yl] pyrazin-2-carboxamide

  In a procedure analogous to Example 32, 1- (6-{[(1S) -1-phenylethyl] amino} pyrazin-2-yl) -1H-benzimidazol-5-amine (33 mg, 0.10 mmol) and chloride Reaction of pyrazine-2-carbonyl (0.11 mmol) (prepared by reacting oxalyl chloride and pyrazine-2-carboxylic acid in dichloromethane at room temperature) gave the product (24 mg, 55%) after chromatography.

¹ Hn.mr (CDCl ₃ ) δ 1.65 (d, 3H, J = 6.9Hz, CH ₃ ), 5.04 (m, 1H, CH), 5.35 (d, 1H, J = 6.0Hz, NH), 7.28- 7.41 (m, 5H, Ar-H, pyridine-H), 7.71 (s, 1H, pyrazine-H), 7.87 (s, 1H, pyrazine-H), 8.12 (s, 1H, pyrazine-H), 8.21 ( s, 1H, benzimidazole-H), 8.40 (s, 1H, pyrazine-H), 8.61-8.62 (m, 1H, benzimidazole-H), 8.81 (d, 1H, J = 2.4Hz, benzimidazole-H ), 9.55 (d, 1H, J = 1.2 Hz, benzimidazole-H), 9.78 (s, 1H, CONH).
m / z (ES) 437 ( M + + H).

N- [1- (6-{[(1S) -1-phenylethyl] amino} pyrazin-2-yl) -1H-benzimidazol-6-yl] pyrazin-2-carboxamide

  In a procedure analogous to Example 32, 1- (6-{[(1S) -1-phenylethyl] amino} pyrazin-2-yl) -1H-benzimidazol-6-amine (33 mg, 0.10 mmol) and chloride Reaction of isonicotinoyl hydrochloride (0.11 mmol) (prepared by reacting oxalyl chloride and pyrazine-2-carboxylic acid in dichloromethane at room temperature) gave the product (28 mg, 64%) after chromatography.

¹ Hn.mr (CDCl ₃ ) δ 1.67 (d, 3H, J = 6.9Hz, CH ₃ ), 5.18 (m, 1H, CH), 5.39 (d, 1H, J = 6.3Hz, NH), 7.23- 7.46 (m, 6H, Ar-H, Pyridine-H), 7.82 (d, 1H, J = 9.0Hz, Benzimidazole-H), 7.84 (s, 1H, Pyrazine-H), 8.18 (s, 1H, Pyrazine -H), 8.39 (s, 1H, pyrazine-H), 8.61-8.62 (m, 1H, pyrazine-H), 8.81-8.84 (m, 2H, Ar-H), 9.52 (d, 1H, J = 1.2 Hz, benzimidazole-H), 9.81 (s, 1H, CONH).
m / z (ES) 437 ( M + + H).

2-Methoxy-N- [1- (6-{[(1S) -1-phenylethyl] amino} pyrazin-2-yl) -1H-benzimidazol-5-yl] acetamide

  In a procedure analogous to Example 32, 1- (6-{[(1S) -1-phenylethyl] amino} pyrazin-2-yl) -1H-benzimidazol-5-amine (33 mg, 0.10 mmol) and chloride Reaction of methoxyacetyl (12 mg, 0.11 mmol) gave the product (20 mg, 50%) after chromatography.

¹ Hn.mr (CDCl ₃ ) δ1.64 (d, 3H, J = 6.9Hz, CH ₃ ), 3.55 (s, 3H, OCH ₃ ), 4.07 (s, 2H, CH ₂ ), 5.02 (m, 1H , CH), 5.27 (d, 1H, J = 6.3 Hz, NH), 7.30-7.40 (m, 5H, Ar-H), 7.54 (dd, 1H, J = 8.7, 1.5 Hz, benzimidazole-H), 7.66 (d, 1H, J = 8.7Hz, benzimidazole-H), 7.85 (s, 1H, pyrazine-H), 8.01 (s, 1H, benzimidazole-H), 8.11 (s, 1H, pyrazine-H) 8.35 (s, 1H, CONH), 8.38 (s, 1H, benzimidazole-H).
m / z (ES) 403 ( M + + H).

2-Methoxy-N- [1- (6-{[(1S) -1-phenylethyl] amino} pyrazin-2-yl) -1H-benzimidazol-6-yl] acetamide

  In a procedure analogous to Example 32, 1- (6-{[(1S) -1-phenylethyl] amino} pyrazin-2-yl) -1H-benzimidazol-6-amine (33 mg, 0.10 mmol) and chloride Reaction of methoxyacetyl (20 mg, 0.11 mmol) gave the product (10 mg, 25%) after chromatography.

¹ Hn.mr (CDCl ₃ ) δ 1.64 (d, 3H, J = 6.9Hz, CH), 3.54 (s, 3H, OCH ₃ ), 4.06 (s, 2H, CH ₂ ), 5.08 (m, 1H, CH), 5.36 (d, 1H, J = 6.3 Hz, NH), 7.24-7.42 (m, 6H, Ar-H), 7.76 (d, 1H, J = 8.7 Hz, benzimidazole-H), 7.81 (s , 1H, pyrazine-H), 8.14 (s, 1H, pyrazine-H), 8.35 (s, 1H, benzimidazole-H), 8.39 (s, 1H, CONH), 8.52 (d, 1H, J = 1.5Hz Benzimidazole-H).
m / z (ES) 403 ( M + + H).

N- [1- (6-{[(1S) -1-Phenylethyl] amino} pyrazin-2-yl) -1H-benzimidazol-6-yl] -2,2-dimethylpropanamide

To a stirred solution of 2- (benzylamino) -6- (5-amino-benzimidazol-1-yl) -pyrazine (33 mg, 0.1 mmol) in anhydrous THF (2 mL) under N ₂ , triethylamine (38 l, 0.3 mmol) Was added. The solution was cooled to 0 ° C., pivalic acid (12 mg, 0.11 mmol) and EDC (23 mg, 0.12 mmol) were added, and then the resulting mixture was stirred at room temperature. After 64 hours, the solution was diluted with H ₂ O and the mixture was extracted with CHCl ₃ (2 × 15 mL). The combined organic layers were washed with 10% aqueous Na ₂ CO ₃ solution, dried (Na ₂ SO ₄ ), and the solvent was removed under reduced pressure. The residue was purified by column chromatography using dichloromethane-methanol (100: 6) as eluent to separate the pure product (15 mg).

¹ Hn.mr (CDCl ₃ ) δ 1.35 (s, 9H, 3CH ₃ ), 1.65 (d, 3H, J = 6.6Hz, CH ₃ ), 5.14 (m, 1H, CH), 5.24 (d, 1H, J = 5.7Hz, NH), 7.13 (d, 1H, J = 8.7Hz, Ar-H), 7.29-7.47 (m, 5H, ArH), 7.75 (d, 1H, J = 8.7Hz, benzimidazole-H ), 7.81 (s, 1H, pyrazine-H), 8.17 (s, 1H, pyrazine-H), 8.35 (s, 1H, benzimidazole-H), 8.69 (s, 1H, CONH).
m / z (ES) 415 ( M + + H).

N- [1- (6-{[(1S) -1-Phenylethyl] amino} pyrazin-2-yl) -1H-benzimidazol-5-yl] -2,2-dimethylpropanamide

  In a procedure analogous to Example 44, 1- (6-{[(1S) -1-phenylethyl] amino} pyrazin-2-yl) -1H-benzimidazol-5-amine (33 mg, 0.10 mmol) and pivalin Reaction of the acid (12 mg, 0.11 mmol) gave the product (12 mg, 29%) after chromatography.

¹ Hn.mr (CDCl ₃ ) δ 1.35 (s, 9H, CH ₃ ), 1.66 (d, 3H, J = 6.9Hz, CH ₃ ), 5.14 (m, 1H, CH), 5.24 (d, 1H, J = 6.3Hz, NH), 7.13 (d, 1H, J = 8.7Hz, Ar-H), 7.29-7.47 (m, 6H, ArH), 7.75 (d, 1H, J = 8.7Hz, benzimidazole-H ), 7.81 (s, 1H, pyrazine-H), 8.17 (s, 1H, pyrazine-H), 8.35 (s, 1H, benzimidazole-H), 8.69 (s, 1H, CONH).
m / z (ES) 415 ( M + + H).

6- {5-[(4-Methylpiperazin-1-yl) methyl] -1H-benzimidazol-1-yl} -N-[(1S) -1-phenylethyl] pyrazin-2-amine

6- {5-[(4-Methylpiperazin-1-yl) carbonyl] -1H-benzimidazol-1-yl} -N-[(1S) -1-phenylethyl] pyrazin-2-amine (22 mg, 0.05 To a solution of mmol) in anhydrous THF (1 mL) was added a suspension of LiAlH ₄ (4 mg, 0.1 mmol) in THF (1 mL) and the mixture was heated to reflux for 4 hours. Cool to room temperature and treat sequentially with H ₂ O (1 mL), aqueous NaOH (1 mL, 2M), and H ₂ O (5 mL). The resulting mixture was extracted with CHCl ₃ (2 × 10 ml) and the combined organic layers were dried (Na ₂ SO ₄ ). The solvent was removed under reduced pressure and the product was purified by flash chromatography using CH ₂ Cl ₂ -MeOH (10: 1 → 1: 1) as eluent to give the product as a yellow solid (11 mg , 52%).

¹ Hn.mr (CDCl ₃ ) δ1.65 (d, 3H, J = 6.9Hz, CH), 2.58 (s, 3H, NCH), 2.81 (br s, 4H, CH ₂ ), 2.90 (br s, 4H , CH ₂ ), 3.74 (s, 2H, NCH ₂ ), 5.03 (m, 1H, CH), 5.33 (d, 1H, J = 6.0 Hz, NH), 7.25 to 7.42 (m, 6H, Ar-H) 7.67 (d, 1H, J = 8.4 Hz, benzimidazole-H), 7.77 (s, 1H, benzimidazole-H), 7.87 (s, 1H, pyrazine-H), 8.12 (s, 1H, pyrazine-H) ), 8.39 (s, 1H, benzimidazole-H).
m / z (ES) 428 ( M + + H).

1- (6-{[(1S) -1-phenylethyl] amino} pyrazin-2-yl) -N- (pyridin-3-ylmethyl) -1H-benzimidazol-5-amine

In a procedure similar to that of Example 46, N- {1- (6-{[(1S) -1-phenylethyl] amino} pyrazin-2-yl) -1H-benzimidazol-5-yl} nicotinamide (33 mg , 0.10 mmol) and LiAlH ₄ (5.7 mg, 0.15 mmol) gave the product (10 mg, 24%) after chromatography.

¹ Hn.mr (CDCl ₃ ) δ1.64 (d, J = 6.9Hz, 3H, CH ₃ ), 4.42 (s, 2H, CH ₂ ), 5.01 (m, 1H, CH), 5.20 (d, J = 6.0Hz, 1H, NH), 6.66 (dd, J = 8.7, 2.1Hz, 1H, H-7 '), 7.01 (d, J = 2.1Hz, 1H, H-4'), 7.25 to 7.45 (m, 6H, ArH), 7.51 (d, J = 8.7Hz, 1H, H-6 '), 7.74 (d, J = 7.8Hz, pyridine-H), 7.80 (s, 1H, pyrazine-H), 8.09 (s , 1H, pyrazine-H), 8.30 (s, 1H, H-2 ′), 8.53 (d, J = 3.6 Hz, 1H, pyridine-H), 8.68 (s, 1H, pyridine-H).
m / z (ES) 422 ( M + + H).

N-[(1S) -1- (4-Bromophenyl) ethyl] -6-chloropyrazin-2-amine

  The product (835 mg, 67%) from the reaction of 4-bromo-α-S-methylbenzylamine (877 mg, 4.4 mmol) and 2,6-dichloropyrazine (597 mg, 4.0 mmol) in a procedure similar to Example 1. Got.

¹ Hn.mr (CDCl ₃ ) δ1.56 (d, J = 6.9Hz, 3H, CH ₃ ), 4.86 (m, 1H, CH), 5.0 (d, 1H, NH), 7.24 (AA'XX ', 2H, Ar-H), 7.60 (s, 1H, pyrazine-H), 7.81 (s, 1H, pyrazine-H).

6-Chloro-N-[(1S) -1- (4-methoxyphenyl) ethyl] pyrazin-2-amine

  The product (873 mg, 79%) from the reaction of 4-methoxy-α-S-methylbenzylamine (700 mg, 4.6 mmol) and 2,6-dichloropyrazine (626 mg, 4.2 mmol) with a procedure similar to Example 1. Got.

¹ Hn.mr (CDCl ₃ ) δ1.56 (d, J = 6.9Hz, 3H, CH ₃ ), 3.80 (s, 3H, OCH ₃ ), 4.84 (m, 1H, CH), 5.01 (d, 1H, NH), 6.88 (AA'XX ', 2H, Ar-H), 7.28 (AA'XX', 2H, Ar-H), 7.621 (s, 1H, pyrazine-H), 7.79 (s, 1H, pyrazine- H).

6- (1H-Benzimidazol-1-yl) -N-[(1S) -1- (4-bromophenyl) ethyl] pyrazin-2-amine

  In a procedure similar to Example 25, N-[(1S) -1- (4-bromophenyl) ethyl] -6-chloropyrazin-2-amine (125 mg, 0.40 mmol) and benzimidazole (52 mg, 0.44 mmol) The product (66 mg, 42%) was obtained from the reaction.

¹ Hn.mr (CDCl ₃ ) δ1.63 (d, 3H, J = 6.9Hz, CH ₃ ), 4.99 (m, 1H, CH), 5.19 (d, 1H, J = 5.1Hz, NH), 7.26〜 7.37 (m, 3H, Ar-H), 7.51 (AA'XX ', 2H, Ar-H), 7.65 (d, 1H, J = 8.1Hz, benzimidazole-H), 7.83-7.86 (m, 2H, Benzimidazole-H + pyrazine-H), 8.17 (s, 1H, pyrazine-H), 8.39 (s, 1H, benzimidazole-H).
m / z (ES) 396,394 ( M + + H).

6- (1H-Benzimidazol-1-yl) -N-[(1S) -1- (4-methoxyphenyl) ethyl] pyrazin-2-amine

  In a procedure analogous to Example 25, 6-chloro-N-[(1S) -1- (4-methoxyphenyl) ethyl] pyrazin-2-amine (105 mg, 0.40 mmol) and benzimidazole (52 mg, 0.44 mmol) The product (57 mg, 41%) was obtained from the reaction.

¹ Hn.mr (CDCl ₃ ) δ1.62 (d, 3H, J = 6.8Hz, CH ₃ ), 3.80 (s, 3H, CH ₃ ), 4.99 (m, 1H, CH), 5.31 (br d, 1H , J = 6.2Hz, NH), 6.91 (AA'XX ', 2H, Ar-H), 7.28-7.36 (m, 4H, Ar-H), 7.77 (d, 1H, J = 2.0Hz, Ar-H ), 7.78 (s, 2H, benzimidazole-H + pyrazine-H), 8.13 (s, 1H, pyrazine-H), 8.44 (s, 1H, benzimidazole-H).
m / z (ES) 346 ( M + + H)

2- (S-α-Methylbenzylamino) -6- (5- (N-methylpiperazin-4-yl-methyl) -benzimidazol-1-yl) -pyrazine

3- [6- (S-α-methylbenzylamino) -pyrazin-2-yl] -3H-benzimidazole-5-carboxylic acid N-methylpiperazinylamide (22 mg, 0.05 mmol) in anhydrous THF (1 mL) To the solution was added a suspension of LiAlH ₄ (4 mg, 0.1 mmol) in THF (1 mL) and the mixture was heated to reflux for 4 hours. Cool to room temperature and treat sequentially with H ₂ O (1 mL), aqueous NaOH (1 mL, 2M), and H ₂ O (5 mL). The resulting mixture was extracted with CHCl ₃ (2 × 10 ml) and the combined organic layers were dried (Na ₂ SO ₄ ). The solvent was removed under reduced pressure and the product was purified by flash chromatography using CH ₂ Cl ₂ -MeOH (10: 1 → 1: 1) as eluent to give the product as a yellow solid (11 mg, 52% )

¹ Hn.mr (CDCl ₃ ) δ1.65 (d, 3H, J = 6.9Hz, CH ₃ ), 2.58 (s, 3H, NCH ₃ ), 2.81 (br s, 4H, CH ₂ ), 2.90 (br s _{, 4H, CH 2), 3.74} (s, 2H, NCH 2), 5.03 (m, 1H, CH), 5.33 (d, 1H, J = 6.0Hz, NH), 7.25~7.42 (m, 6H, Ar- H), 7.67 (d, 1H, J = 8.4 Hz, benzimidazole-H), 7.77 (s, 1H, benzimidazole-H), 7.87 (s, 1H, pyrazine-H), 8.12 (s, 1H, pyrazine -H), 8.39 (s, 1H, benzimidazole-H).
m / z (ES) 428 ( M + + H).

1- {4- [2- (Diethylamino) ethoxy] phenyl} ethanone

4-bromoacetophenone (5 g, 25 mmol), diethylaminoethanol (3.5 g, 38 mmol), K ₂ CO ₃ (2 g), copper powder (0.5 g), copper (I) iodide (2.5 g) in DMSO (30 ml) Was heated at 120 ° C. until TLC indicated that the starting material was consumed. After cooling to room temperature, the mixture was poured into aqueous NH ₃ (28%, 100 ml) and extracted with CH ₂ Cl ₃ (3 × 100 ml). The combined organic extracts were dried (Na ₂ SO ₄ ), filtered and distilled under reduced pressure with CH ₂ Cl ₂ . The crude product was purified by silica gel column chromatography eluting with EtOAc-MeOH (95: 5) to give the pure compound (4.85 g, 82%).

¹ Hn.mr (CDCl ₃ ) δ0.98 (t, J = 7.2Hz, 6H, NCH ₂ CH ₃ ), 2.43 (s, 3H, Ar-C-CH ₃ ), 2.57 ~ 2.50 (m, 4H, NCH _{2 CH 3), 2.78 (t} , J = 6.3Hz, 2H, ArOCH 2 CH 2 N), 4.00 (t, J = 6.3Hz, 2H, ArOCH 2), 6.85 (d, J = 9Hz, 2H, ArH), 7.83 (d, J = 9 Hz, 2H, ArH).

1- [4- (4-Methylpiperazin-1-yl) phenyl] ethanone

  In a procedure similar to Example 53, 4-bromoacetophenone was reacted with N-methylpiperazine in the presence of potassium carbonate, copper, and copper iodide to give the desired product in 82% yield.

¹ Hn.mr (CDCl ₃ ) δ 2.35 (s, 3H, Ar-C-CH ₃ ), 2.52 (s, 3H, N-CH ₃ ), 2.55 (t, J = 5.1Hz, 4H, CH _{2- N-CH 3), 3.37 (} dd, J = 5.1,5.1Hz, 4H, ArNCH 2), 6.89 (AA'XX ', 2H, ArH), 7.89 (AA'XX', 2H, ArH).

1-Pyridin-3-yl ethanone oxime

To a solution of hydroxylamine hydrochloride (3.44 g) in water (20 ml) was added NaOH (20%, 30 ml). Ketone (5 g, 41 mmol) was added simultaneously and the resulting mixture was stirred at room temperature until TLC indicated no ketone remained. The solvent was removed under reduced pressure and the residue was extracted with CH ₂ Cl ₂ (3 × 100 ml) and dried (Na ₂ SO ₄ ). After filtration and removal of the solvent, the crude ketoxime was recrystallized from CH ₂ Cl ₂ / n-hexane.

¹ Hn.mr (CDCl ₃ ) δ2.31 (s, 3H, CH ₃ ), 7.33 (dd, J = 4.8,4.8Hz, 1H, ArH), 7.97 (ddd, J = 8.1,1.8,1.8Hz, 1H , ArH), 8.61 (dd, J = 5.1, 1.8 Hz, 1H, ArH), 8.96 (d, J = 1.8 Hz, 1H, ArH), 10.62 (s, 1H, OH).

1- (3-Chlorophenyl) ethanone oxime

A mixture of ketone (2.0 g, 13 mmol), hydroxylamine hydrochloride (0.98 g, 14 mmol), NaOH (10%, 4 ml), water (6.2 ml), and EtOH (25 ml) was heated to reflux for 2 hours. On cooling in ice, the ketoxime was precipitated and collected by suction filtration. The crude product was recrystallized from CH ₂ Cl ₂ / n-hexane (1.88 g, 86%).

¹ Hn.mr (CDCl ₃ ) δ 2.28 (s, 3H, CH ₃ ), 7.51 (s, 4H, ArH), 8.67 (s, 1H, OH).

1- (3-Chlorophenyl) ethanamine

A mixture of ketoxime (1 g, 6 mmol) and LiAlH ₄ (0.27 g) in anhydrous THF (100 ml) was heated to reflux overnight under dry N ₂ . The reaction mixture was cooled in ice water and carefully quenched with H ₂ O (60 mL). The mixture was stirred at room temperature for 30 minutes and then filtered through Celite®. This inorganic salt was washed with EtOAc (3 × 100 ml). The filtrate was concentrated under reduced pressure, diluted with 2M HCl (50 ml) and the aqueous phase was washed with Et ₂ O (2 × 70 ml). The aqueous phase was basified with 40% aqueous NaOH and the product was extracted with Et ₂ O (3 × 50 ml). The combined organic layers were washed with brine (50 ml) and dried (MgSO ₄ ). Removal of the solvent under reduced pressure gave pure amine (0.65 g, 71%).

¹ Hn.mr (CDCl ₃ ) δ1.38 (d, J = 6.6Hz, 3H, CH-CH ₃ ), 1.63 (br s, 2H, NH ₂ ), 4.13 ~ 4.06 (m, 1H, CH-CH ₃ ), 7.23-7.18 (m, 3H, ArH), 7.35 (s, 1H, ArH).

1-Pyridin-3-ylethanamine

Concentrated HCl (50 ml) was slowly added to a mixture of ketoxime (4.85 g, 36 mmol) and Zn powder (12 g) with vigorous stirring at 0 ° C. When the first strong reaction was over, the reaction was heated to reflux until TLC indicated that all ketoxime was consumed. After cooling to room temperature, the strongly acidic mixture was extracted with CH ₂ Cl ₂ (2 × 75 ml). The reaction mixture was then basified with 50% KOH solution. After removing the solvent, the residue was extracted with boiling MeOH (4 × 100 ml). MeOH was distilled off to give the crude amine, which was used in the next reaction without further purification.

¹ Hn.mr (CDCl ₃ ) δ1.07 (d, J = 6.6Hz, 3H, CH ₃ ), 1.37 (br s, 2H, NH ₂ ), 3.84 (q, J = 4.6Hz, 1H, CH-CH ₃ ), 6.93 (dd, J = 7.8, 4.8Hz, 1H, ArH), 7.38 (ddd, J = 7.8, 2.1, 1.5Hz, 1H, ArH), 8.15 (dd, J = 4.8, 1.5Hz, 1H, ArH), 8.27 (d, J = 2.1 Hz, 1H, ArH).

6-Chloro-N-[(1S) -1- (4-pyridin-3-ylphenyl) ethyl] pyrazin-2-amine

N-[(1S) -1- (4-bromophenyl) ethyl] -6-chloropyrazin-2-amine (0.117 g, 0.37 mmol), 1,3-propanediol pyridine-3-boronic acid under nitrogen atmosphere A mixture of cyclic ester (67 mg, 0.41 mmol), tetrakis (triphenylphosphine) palladium (0) (65 mg, 0.06 mmol), and toluene (4 mL) was treated with 2M aqueous sodium carbonate (0.2 mL). The resulting mixture was heated to reflux with vigorous stirring for 24 hours. Upon cooling, the solution was diluted with methanol and dichloromethane and the mixture was dried (MgSO ₄ ) and filtered. The solvent was removed under reduced pressure to give the crude product which was purified by column chromatography (50 mg) using dichloromethane-diethyl ether (90:10) and then dichloromethane-methanol (99: 1) as eluent.

¹ Hn.mr (CDCl ₃ ) δ 1.61 (d, 3H, J = 6.9Hz, CH ₃ ), 4.97 (m, 1H, CH), 5.42 (d, 1H, J = 6.3Hz, NH), 7.33- 7.37 (m, 1H, ArH), 7.42-7.56 (m, 4H, ArH), 7.66 (m, 1H, pyrazine-H), 7.78 (s, 1H, pyrazine-H), 7.83-7.86 (m, 1H, ArH), 8.58 (br s, 1H, pyridine-H), 8.83 (br s, 1H, pyridine-H).
m / z (ES) 313,311 ( M + + H).

N- [1- (6-{[(1S) -1-Phenylethyl] amino} pyrazin-2-yl) -1H-benzimidazol-5-yl] methanesulfonamide

To a stirred solution of 2- (S-α-methylbenzylamino) -6- (5-aminobenzimidazol-1-yl) -pyrazine (33 mg, 0.1 mmol) in anhydrous THF (2 mL) was added triethylamine (40 mg under N _2. 0.4 mmol) was added. The solution was cooled at 0 ° C., methanesulfonyl chloride (25 mg, 0.2 mmol) was added and the resulting mixture was stirred at room temperature. After 16 hours, the solution was poured into water (30 mL) and the product was extracted into chloroform (2 × 15 mL). The combined organic layers were washed with 10% Na ₂ CO ₃ , dried (Na ₂ SO ₄ ), and the solvent was removed under reduced pressure to give the crude product as a pale yellow solid. The product was separated from the most polar fraction as a pale yellow solid (16 mg) by column chromatography using dichloromethane-methanol (100: 6) as the eluent.

¹ Hn.mr (CDCl ₃ ) δ 1.65 (d, 3H, J = 6.9Hz, CH ₃ ), 3.00 (s, 3H, CH ₃ ), 5.02 (m, 1H, CH), 5.27 (d, 1H, J = 6.0 Hz, NH), 7.21-7.40 (m, 6H, ArH), 7.64 (d, 1H, J = 8.7 Hz, benzimidazole-H), 7.69 (d, 1H, J = 1.9 Hz, benzimidazole- H), 7.88 (s, 1H, pyrazine-H), 8.10 (s, 1H, pyrazine-H), 8.41 (s, 1H, benzimidazole-H).
m / z (ES) 409 ( M + + H).

N-[(1S) -1-phenylethyl] -6- (5-pyridin-4-yl-1H-benzimidazol-1-yl) pyrazin-2-amine and N-[(1S) -1-phenylethyl ] -6- (6-Pyridin-4-yl-1H-benzimidazol-1-yl) pyrazin-2-amine

  6- (5-Bromo-1H-benzimidazol-1-yl) -N-[(1S) -1-phenylethyl] pyrazin-2-amine and 6- (6-Bromo-1H-benzimidazol-1-yl ) -N-[(1S) -1-phenylethyl] pyrazin-2-amine 1: 1 mixture (160 mg, 0.4 mmol), pyridine-4-boronic acid pinacol cyclic ester (91 mg, 0.44 mmol) in toluene (5 mL) ) To the stirred solution was added tetrakis (triphenylphosphine) palladium (46 mg, 0.04 mmol) followed by aqueous sodium carbonate (0.22 mL, 2M). The solution was then heated to reflux for 24 hours. After standard treatment (see Example 60), flash chromatography using dichloromethane-methanol (100: 6) as the eluent gave the product as a 1: 1 mixture.

¹ Hn.mr (1: 1 mixture) (CDCl ₃ ) δ 1.66 (d, J = 6.9Hz, 3H, CH ₃ ), 5.07 (m, 1H, CH), 5.25 (d, J = 6.0Hz, 1H , NH), 7.29-7.42 (m, 5H, ArH), 7.52-7.64 (m, 3H), 7.78 (d, J = 8.7 Hz), 7.88 and 7.90 (s, 1H, pyrazine-H), 7.94 (d , 1H, J = 8.4Hz) 8.12 (s, 1H), 8.16 (s, 1H), 8.19 and 8.20 (s, 1H, pyrazine-H), 8.44 and 8.45 (s, 1H, H-2 '), 8.68 (d, J = 3.6 Hz, 1H, pyridine-H), 8.68 and 8.71 (d, 1H, J = 8.7 Hz, pyridine-H).
m / z (ES) 393 ( M + + H).

Screening Compound Dilution For screening, compounds were diluted to a concentration of 20 μM in 96 well plates. Prior to the assay, the plates were warmed for 30 minutes at 37 ° C.

JAK tyrosine kinase domain production
The JAK kinase domain was produced as follows.
JAK1
The kinase domain of human JAK1 was amplified from U937 mRNA using the polymerase chain reaction with the following primers:
XHOI-J1 5'-CCG CTC GAG ACT GAA GTG GAC CCC ACA CAT-3 '
J1-KPNI 5'-CGG GGT ACC TTA TTT TAA AAG TGC TTC AAA-3 '

  The JAK1 PCR product was cloned into the pFastBacHTb expression vector (Gibco) via the XhoI and KpnI sites. The JAK1 plasmid was then transformed into competent DH10Bac cells (Gibco) and the produced recombinant baculovirus was prepared for transfection into Sf9 insect cells.

JAK2
The kinase domain of human JAK2 was amplified from U937 mRNA using the polymerase chain reaction with the following primers:
SALI-jk2 5'-ACG CGT CGA CGG TGC CTT TGA AGA CCG GGA T-3 '
jk2-NOTI 5'-ATA GTT TAG CGG CCG CTC AGA ATG AAG GTC ATT T-3 '

  The JAK2 PCR product was cloned into the pFastBacHTc expression vector (Gibco) via the SAlI and NotI sites. The JAK2 plasmid was then transformed into competent DH10Bac cells (Gibco) and the produced recombinant baculovirus was prepared for transfection into Sf9 insect cells.

JAK3
The kinase domain of human JAK3 was amplified from U937 mRNA using the polymerase chain reaction with the following primers:
XHOI-J3 5'-CCG CTC GAG TAT GCC TGC CAA GAC CCC ACG-3 '
J3-KPNI 5'-CGG GGT ACC CTA TGA AAA GGA CAG GGA GTG-3 '

  The JAK3 PCR product was cloned into the pFastBacHTb expression vector (Gibco) via the XhoI and KpnI sites. The JAK3 plasmid was then transformed into competent DH10Bac cells (Gibco) and the produced recombinant baculovirus was prepared for transfection into Sf9 insect cells.

TYK2
The kinase domain of human TYK2 was amplified from A549 mRNA using the polymerase chain reaction with the following primers:
HT2EK 5'-GGA GCA CTC GAG ATG GTA GCA CAC AAC CAG GTG-3 '
ITY2.2R 5'-GGA GCA GGA ATT CCG GCG CTG CCG GTC AAA TCT GG-3 '

  The TYK2 PCR product was cloned into pBlueBacHis2A (Invitrogen) via the EcoRI site. The produced recombinant TYK2 baculovirus was prepared for transfection into Sf9 insect cells.

Mass production of kinase domains
Baculovirus products from each member of the JAK family were infected with 5 liters of High Five cells (Invitrogen) grown to a cell density of about 1-2 × 10 ⁶ cells / ml in High Five serum-free medium (Invitrogen) . Cells were infected with virus at MOI 0.8-3.0. Cells were harvested and lysed. The JAK kinase domain was purified by affinity chromatography on a Probond (Invitrogen) nickel chelate affinity column.

Assay protocol
Kinase assays were performed in 96 well capture based ELISA assays or 384 well Optiplate (Packard) using Alphascreen protein tyrosine kinase kit. In all cases, about 1.5 μg of affinity purified PTK domain was used in the presence of 50 mM HEPES, pH 7.5 10 mM MgCl ₂ , 150 mM NaCl, and 10 μM-1 mM ATP. As a substrate, the biotinylated substrate biotin-EGPWLEEEEEAYGWMDF-NH ₂ (final concentration 5 μM) was used. In the ELISA assay, peroxidase-conjugated anti-phosphotyrosine antibody PY20 was used to quantify tyrosine phosphorylation after transfer to an avidin-coated ELISA plate. In the Alphascreen assay, Alphascreen phosphotyrosine acceptor beads were added followed by streptavidin donor beads under inhibitory light. ELISA plates were read on BMG Fluorostar and Alphascreen plates on Packard Fusion Alpha. Inhibitors were added to the assay 15 minutes before adding ATP. The inhibitor was added to the DMSO aqueous solution so that the DMSO concentration did not exceed 1%.

Establishment of TEL: JAK cell line
The coding region containing nucleotides 1 to 487 of TEL is designated as oligonucleotide 5TEL (5'-GGA GGA TCC TGA TCT CTC TCG CTG TGA GAC-3 ') and 3TEL (5'-AGGC GTC GAC TTC TTC TTC ATG GTT CTG-3 ') And amplified by PCR using U937 mRNA as template. A BamHI site was presented to the 5TEL primer and a SalI site was incorporated into the 3TEL primer. JAK2 (nucleotides 2994-3914, JAK2F 5'-ACGC GTC GAC GGT GCC TTT GAA GAC CGG GAT-3 ', JAK2R 5'-ATA GTT TA G CGG CC G CTC AGA ATG AAG GTC ATT T-3') and JAK3 ( Nucleotides 2520-3469, JAK3F 5'-GAA GTC GAC TAT GCC TGC CAA GAC CCC ACG ATC TT-3 ', JAK3R 5'-GGA TCT AGA CTA TGA AAA GGA CAG GGA GTG GTG TTT-3') The region was produced by PCR using Taq DNA polymerase (Gibco / BRL) and U937 mRNA as a template. The SalI site was incorporated into the JAK2 and JAK3 forward primers, the NotI site was incorporated into the JAK2 reverse primer, and the XbaI site was added to the JAK3 reverse primer.

  TEL / Jak2 fusion was generated by digestion of TELPCR product with BamHI / SalI, digestion of JAK2PCR product with SalI / NotI, followed by ligation and ligation and subcloning into the mammalian expression vector pTRE2 (Clontech) digested with BamHI-NotI (pTELJAK2). In the case of JAK3, the SalI / NotI cleavage kinase domain PCR product was ligated using the BamHI / SalI cleavage TEL product and then ligated to BamHI / NotI cleavage pTRE2 (pTELJAK3).

  Growth factor-dependent myelomonocytic cell line BaF3 carrying the pTET off plasmid (Clontech) was transfected with pTELJAK2 or pTELJAK3 and cells were selected for factor-dependent proliferation. BaF3 wild type cells were cultured in DMEM 10% FCS, 10% WEHI 3B conditioned medium. BaF3 TELJAK cells were cultured in DMEM10% Tet-System Approved FBS (without WEHI 3B conditioned medium).

Cell assays were performed as follows.
Cell suspensions were prepared by harvesting cells from the culture (cells used in this study should be in late logarithmic growth phase and highly viable). Cells were diluted in conditioned growth medium to a 1.1 × final concentration (50000 cells / ml to 200,000 cells / mL depending on the cell line).

The compound to be tested was added to a flat bottom 96 well plate (10 μL, 10 × final concentration). Cell suspension (90 μL per well) was added and the plates were incubated at 37 ° C., 5% CO ₂ for 40 hours. MTT (20 μL per well, 5 mg / PBSmL) was added and the plate returned to the incubator for an additional 6 hours. Lysis buffer (100 μL per well, 10% SDS, 0.01N HCl) was added and the plate was placed in the incubator overnight. Thereafter, the plate was read at 590 nm.

Results The activity of a series of compounds is shown in Table 3. A compound showing the ability to inhibit 50% of JAK activity at a concentration of 50 μM is designated as “+” (measured under standard conditions, see method).

  Those skilled in the art will appreciate that many variations and / or modifications can be made to the invention shown in the specific embodiments without departing from the spirit or scope of the invention as broadly described. Accordingly, the embodiments of the invention are to be considered in all respects as illustrative and not restrictive.

FIG. 1 is a graph showing a dose response curve of a representative pyrazine having inhibitory activity in a Tel-Jak2 transformed cell line. FIG. 2 is a graph showing a dose response curve of a representative pyrazine having inhibitory activity in a Tel-Jak3 transformed cell line. FIG. 3 is a graph showing dose response curves of R and S enantiomers of representative 2- (α-methylbenzylamino) pyrazine having inhibitory activity in Tel-Jak2 transformed cell lines.

Claims (19)

A compound of the general formula:

A pharmaceutically acceptable salt, hydrate, solvate, crystalline form, or diastereomer thereof,
[Wherein D is a heterocycle selected from

Wherein X ₁ , X ₂ , X ₃ , X ₄ are optionally substituted carbons, or _one of X ₁ , X ₂ , X ₃ , X ₄ is N and R 2 is H , Halogen, C _1-4 alkyl, CH ₂ F, CHF ₂ , CF ₃ , OCF ₃ , aryl, hetaryl, C _1-4 alkyl OC _1-4 alkyl, C _1-4 alkyl O aryl, C _1-4 alkyl NR3R4, CO ₂ R3, CONR3R4, CONR3SO ₂ R4, NR3R4, C _1-4 alkyl NR3R4, nitro, NR3COR4, NR5CONR3R4, NR3SO ₂ R4, C _1-4 alkyl NR3COR4, C _1-4 alkyl NR5CONR3R4, C _1-4 alkyl 0-4 substituents independently selected from NR3SO2R4, R3, R4 are each, independently, H, _{halogen, CH 2 F, CHF 2,} CF 3, C 1-4 alkyl, C _{1- 4} alkyl cycloalkyl, C _1-4 cyclohexylalkyl, aryl, C _1-4 alkyl aryl, hetaryl, C _1-4 alkyl hetaryl, or bonded to any atom selected from O, S, NR 6 Optional inclusion 3-8 membered substituted with selected may form a (saturated or unsaturated) ring, R5 is, H, C _1-4 alkyl, _{halogen, CH 2 F, CHF 2,} CF 3, aryl, or, Selected from hetaryl, R6 is selected from H, C _1-4 alkyl, aryl, hetaryl, C _1-4 alkylaryl, C _1-4 alkyl hetaryl,
R1 is H, C _1-4 alkyl, C _1-6 cycloalkyl,
Q is a bond, CH ₂ , C _1-4 alkyl,
A is halogen, C _1-4 alkyl, CH ₂ F, CHF ₂ , CF ₃ , OCF ₃ , CN, NR8R9, aryl, hetaryl, C _1-4 aryl, C _1-4 hetaryl, C _1-4 alkyl NR8R9 , 0C _1-4 alkyl NR8R9, nitro, NR10C _1-4 NR8R9, NR8COR9, NR10CONR8R9, NR8SO ₂ R9, CONR8R9, optionally substituted with 0 to 3 substituents independently selected from CO ₂ R8 Aryl, hetaryl, R8, R9 can each independently be H, C _1-4 alkyl, aryl, or together can contain a heteroatom selected from O, S, NR11 Forms an optionally substituted 4- to 8-membered ring, R 11 is C _1-4 alkyl, R 10 is selected from H, C _1-4 alkyl;
W is selected from H, C _1-4 alkyl, C _2-6 alkenyl, wherein C _1-4 alkyl or C _2-6 alkenyl is C _1-4 alkyl, OH, OC _1-4 alkyl, NR12R13 R12 and R13 are each independently H, C _1-4 alkyl, or are bonded to optionally select an atom selected from O, S, NR14. Optionally substituted 3- to 8-membered rings containing R14 is selected from H, C _1-4 alkyl]. The compound according to claim 1, which is the following general formula II, or

A pharmaceutically acceptable salt, hydrate, solvate, crystalline form, or diastereomer thereof,
[Wherein D is a heterocycle selected from

Wherein X ₁ , X ₂ , X ₃ , X ₄ are optionally substituted carbons, or _one of X ₁ , X ₂ , X ₃ , X ₄ is N and R 2 is H , Halogen, C _1-4 alkyl, CH ₂ F, CHF ₂ , CF ₃ , OCF ₃ , aryl, hetaryl, C _1-4 alkyl OC _1-4 alkyl, C _1-4 alkyl O aryl, C _1-4 alkyl NR3R4, CO ₂ R3, CONR3R4, CONR3SO ₂ R4, Nitro, NR3R4, C _1-4 alkyl NR3R4, NR3COR4, NR5CONR3R4, NR3SO ₂ R4, C _1-4 alkyl NR3COR4, C _1-4 alkyl NR5CONR3R4, C _1-4 alkyl 0-4 substituents from NR3SO ₂ R4 is independently selected, R3, R4 are each, independently, H, _{halogen, CH 2 F, CHF 2,} CF 3, C 1-4 alkyl, C Atoms selected from O, S, NR6, which are _1-4 alkyl cycloalkyl, C _1-4 cyclohetaryl, aryl, C _1-4 alkylaryl, hetaryl, C _1-4 alkyl hetaryl, or in combination Optionally contained 3-8 membered substituted with meaning selection may form a (saturated or unsaturated) ring, R5 is, H, C _1-4 alkyl, _{halogen, CH 2 F, CHF 2,} CF 3, aryl, Or selected from hetaryl, R6 is selected from H, C _1-4 alkyl, aryl, hetaryl, C _1-4 alkylaryl, C _1-4 alkyl hetaryl,
R1 is H, C _1-4 alkyl, C _1-6 cycloalkyl,
W is H, C _1-4 alkyl,
A is halogen, C _1-4 alkyl, CH ₂ F, CHF ₂ , CF ₃ , OCF ₃ , CN, nitro, NR8R9, aryl, hetaryl, C _1-4 aryl, C _1-4 hetaryl, C _1-4 Alkyl NR8R9, 0C _1-4 alkyl NR8R9, NR10C _1-4 NR8R9, NR8COR9, NR10CONR8R9, NR8SO ₂ R9, CONR8R9, optionally substituted with 0 to 3 substituents independently selected from CO ₂ R8 Aryl, hetaryl, and R8 and R9 are each independently H, _C1-4 alkyl, aryl, or together contain a heteroatom selected from O, S, NR11 Can form an optionally substituted 4-8 membered ring where R 11 is C _1-4 alkyl and R 10 is selected from H, C _1-4 alkyl]. The compound according to claim 1 or 2, wherein W is C _1-4 alkyl, and the compound has S chirality at a chiral carbon having W.   4. The compound of claim 3, wherein the compound is a mixture of R and S isomers, the mixture comprising at least 70% S isomer.   5. A compound according to claim 4, wherein the compound comprises at least 80% S isomer.   5. A compound according to claim 4, wherein the compound comprises at least 90% S isomer.   5. A compound according to claim 4, wherein the compound comprises at least 95% S isomer.   5. A compound according to claim 4, wherein the compound comprises at least 99% S isomer.   The compound is 6- (1H-benzimidazol-1-yl) -N-[(1R) -1-phenylethyl] pyrazin-2-amine, N-benzyl-6- (1H-imidazol-1-yl) pyrazine -2-amine, 6- (1H-benzimidazol-1-yl) -N-[(1S) -1- (4-methoxyphenyl) ethyl] pyrazin-2-amine, N- (4-fluorobenzyl)- 6- (1H-imidazol-1-yl) pyrazin-2-amine, 6- (1H-benzimidazol-1-yl) -N-[(1S) -1- (4-bromophenyl) ethyl] pyrazine-2 -Amine, 6- (1H-imidazol-1-yl) -N-[(1R) -1-phenylethyl] pyrazin-2-amine, 1- (6-{[(1S) -1-phenylethyl] amino } Pyrazin-2-yl) -1H-benzimidazole-6-carboxamide, 6- (1H-benzimidazol-1-yl) -N-benzylpyrazin-2-amine, 1- (6-{[(1S)- 1-phenylethyl] amino} pyrazin-2-yl) -1H-benzimidazol-5-carboxamide, 6- (1H-benzimidazol-1-yl) -N- (4 -Fluorobenzyl) pyrazin-2-amine, 6- {5-[(morpholino-1-yl) carbonyl] -1H-benzimidazol-1-yl} -N-[(1S) -1-phenylethyl] pyrazine- 2-Amine, 6- (1H-imidazo [4,5-b] pyridin-1-yl) -N-[(1R) -1-phenylethyl] pyrazin-2-amine, 6- {6-[(morpholino -1-yl) carbonyl] -1H-benzimidazol-1-yl} -N-[(1S) -1-phenylethyl] pyrazin-2-amine, 6- (1H-imidazol-1-yl) -N- (4-morpholin-4-ylphenyl) pyrazin-2-amine, N- [1- (6-{[(1S) -1-phenylethyl] amino} pyrazin-2-yl) -1H-benzimidazole-6 -Yl] cyclopropanecarboxamide, N- [1- (6-{[(1S) -1-phenylethyl] amino} pyrazin-2-yl) -1H-benzimidazol-5-yl] nicotinamide, N- [ 1- (6-{[(1S) -1-phenylethyl] amino} pyrazin-2-yl) -1H-benzimidazol-5-yl] cyclopropanecarboxyl Samid, 6- (1H-benzimidazol-1-yl) -N-[(1R) -1-phenylethyl] pyrazin-2-amine, 6- [6- (4,5-dihydro-1,3-oxazole) -2-yl) -1H-benzimidazol-1-yl] -N-[(1S) -1-phenylethyl] pyrazin-2-amine, N-[(1R) -1-phenylethyl] -6- ( 4-Phenyl-1H-imidazol-1-yl) pyrazin-2-amine, 1- [6-{[(1S) -1-phenylethyl] amino} pyrazin-2-yl] -N- (2-hydroxyethyl ) -1H-benzimidazole-6-carboxamide, N- [1- (6-{[(1S) -1-phenylethyl] amino} pyrazin-2-yl) -1H-benzimidazol-6-yl] methanesulfone Amido, N- [1- (6-{[(1S) -1-phenylethyl] amino} pyrazin-2-yl) -1H-benzimidazol-5-yl] methanesulfonamide, N- [1- (6 -{[(1S) -1-phenylethyl] amino} pyrazin-2-yl) -1H-benzimidazol-5-yl] isonicotinamide, 6- (1H-imidazol-1-yl ) -N-[(1S) -1-phenylethyl] pyrazin-2-amine, N- [1- (6-{[(1S) -1-phenylethyl] amino} pyrazin-2-yl) -1H- Benzimidazol-6-yl] isonicotinamide, 6- (1H-benzimidazol-1-yl) -N-[(1S) -1-phenylethyl] pyrazin-2-amine, 6- [5- (4, 5-dihydro-1,3-oxazol-2-yl) -1H-benzimidazol-1-yl] -N-[(1S) -1-phenylethyl] pyrazin-2-amine, 1- [6-{[ (1S) -1-phenylethyl] amino} pyrazin-2-yl] -N- (2-hydroxyethyl) -1H-benzimidazole-5-carboxamide, 6- (5-methyl-1H-benzimidazole-1- Yl) -N-[(1S) -1-phenylethyl] pyrazin-2-amine, N- [1- (6-{[(1S) -1-phenylethyl] amino} pyrazin-2-yl) -1H -Benzimidazol-6-yl] nicotinamide, N-methyl-1- (6-{[(1S) -1-phenylethyl] amino} pyrazin-2-yl) -1H-benzimidazol-5-carboxy N- [1- (6-{[(1S) -1-phenylethyl] amino} pyrazin-2-yl) -1H-benzimidazol-6-yl] -2,2-dimethylpropanamide, N- Methyl-1- (6-{[(1S) -1-phenylethyl] amino} pyrazin-2-yl) -1H-benzimidazole-6-carboxamide, N- [1- (6-{[(1S)- 1-phenylethyl] amino} pyrazin-2-yl) -1H-benzimidazol-5-yl] -2,2-dimethylpropanamide, 1- (6-{[(1S) -1-phenylethyl] amino} Pyrazin-2-yl) -1H-benzimidazol-5-amine, 2-methoxy-N- [1- (6-{[(1S) -1-phenylethyl] amino} pyrazin-2-yl) -1H- Benzimidazol-5-yl] acetamide, 1- (6-{[(1S) -1-phenylethyl] amino} pyrazin-2-yl) -1H-benzimidazol-6-amine, 2-methoxy-N- [ 1- (6-{[(1S) -1-phenylethyl] amino} pyrazin-2-yl) -1H-benzimidazol-6-yl] acetamide, N-benzyl-1- [6-{[ (1S) -1-phenylethyl] amino} pyrazin-2-yl] -1H-benzimidazol-5-carboxamide, N- [1- (6-{[(1S) -1-phenylethyl] amino} pyrazine- 2-yl) -1H-benzimidazol-5-yl] pyrazine-2-carboxamide, 1- (6-{[(1S) -1-phenylethyl] amino} pyrazin-2-yl) -N-phenyl-1H -Benzimidazole-5-carboxamide, N- [1- (6-{[(1S) -1-phenylethyl] amino} pyrazin-2-yl) -1H-benzimidazol-6-yl] pyrazine-2-carboxamide , N- [1- (6-{[(1S) -1-phenylethyl] amino} pyrazin-2-yl) -1H-benzimidazol-6-yl] acetamide, 6- {5-[(4-methyl Piperazin-1-yl) methyl] -1H-benzimidazol-1-yl} -N-[(1S) -1-phenylethyl] pyrazin-2-amine, N- [1- (6-{[(1S)] -1-phenylethyl] amino} pyrazin-2-yl) -1H-benzimidazol-5-yl] acetamide, [1- (6-{[(1S) -1-fur Enylethyl] amino} pyrazin-2-yl) -1H-benzimidazol-5-yl] methanol, N- [1- (6-{[(1S) -1-phenylethyl] amino} pyrazin-2-yl)- 1H-benzimidazol-6-yl] benzamide, [1- (6-{[(1S) -1-phenylethyl] amino} pyrazin-2-yl) -1H-benzimidazol-6-yl] methanol, N- [1- (6-{[(1S) -1-phenylethyl] amino} pyrazin-2-yl) -1H-benzimidazol-5-yl] benzamide, 1- (6-{[(1S) -1- Phenylethyl] amino} pyrazin-2-yl) -N- [2- (dimethylamino) ethyl] -1H-benzimidazole-6-carboxamide, 1- (6-{[(1S) -1-phenylethyl] amino } Pyrazin-2-yl) -N- (pyridin-3-ylmethyl) -1H-benzimidazol-5-amine, tert-butyl (2S) -2-({[1- (6-{[(1S)- 1-phenylethyl] amino} pyrazin-2-yl) -1H-benzimidazol-5-yl] amino} carbonyl) pyrrolidine-1-carb Boxylate, 6- (3H-imidazo [4,5-c] pyridin-3-yl) -N-[(1S) -1-phenylethyl] pyrazin-2-amine, 6- (1H-benzimidazole-1- Yl) -N- [1- (4-fluorophenyl) ethyl] pyrazin-2-amine, 6- (1H-imidazo [4,5-c] pyridin-1-yl) -N-[(1S) -1 -Phenylethyl] pyrazin-2-amine, 6- (1H-benzimidazol-1-yl) -N-[(1S) -1- (4-pyridin-3-ylphenyl) ethyl] pyrazin-2-amine, (2S) -N- [1- (6-{[(1S) -1-phenylethyl] amino} pyrazin-2-yl) -1H-benzimidazol-5-yl] pyrrolidin-2-carboxamide, N- [ (1S) -1-phenylethyl] -6- (5-pyridin-4-yl-1H-benzimidazol-1-yl) pyrazin-2-amine, N-[(1S) -1-phenylethyl] -6 -(5-Pyridin-3-yl-1H-benzimidazol-1-yl) pyrazin-2-amine, 6- (5-bromo-1H-benzimidazol-1-yl) -N-[(1S) -1 -Phenylethyl] pyrazine-2-amino N- [3- (1H-imidazol-1-yl) propyl] -1- [6-([(1S) -1-phenylethyl] amino) pyrazin-2-yl] -1H-benzimidazole-6 -Carboxamide, N-1H-benzimidazole-6-carboxamide, N- (3-morpholin-4-ylpropyl) -1- [6-([(1S) -1-phenylethyl] amino) pyrazin-2-yl ] -1H-Benzimidazole-6-carboxamide, N- (3-morpholin-4-ylpropyl) -1- [6-([(1S) -1-phenylethyl] amino) pyrazin-2-yl] -1H -Benzimidazole-5-carboxamide, N- [1- (6-{[(1S) -1-phenylethyl] amino} pyrazin-2-yl) -1H-benzimidazol-5-yl] piperidine-3-carboxamide 6- (1H-benzimidazol-1-yl) -N-[(1S) -1-pyridin-3-ylethyl] pyrazin-2-amine, 6- (1H-benzimidazol-1-yl) -N- [(1S) -1- (1,1′-biphenyl-4-yl) ethyl] pyrazin-2-amine, N- [1- (6-{[(1S) -1-phenylethyl Til] amino} pyrazin-2-yl) -1H-benzimidazol-5-yl] benzenesulfonamide, and 6- (1H-benzimidazol-1-yl) -N-[(1S) -1- (1, 2. The compound of claim 1 selected from the group consisting of [1'-biphenyl-4-yl) ethyl] pyrazin-2-amine. 2. The compound of claim 1, wherein the compound is selected from the group consisting of:

  A composition comprising a carrier and at least one compound according to any one of claims 1 to 10.   A method of treating a protein kinase-related disease state, comprising a therapeutically effective amount of at least one compound according to any one of claims 1 to 10, or a therapeutically effective amount of a composition according to claim 11. Administering a product.   Disease state is EGF, HER2, HER3, HER4, IR, IGF-1R, IRR, PDGFR.Alpha., PDGFR.beta., CSFIR, C-Kit, C-fms, Flk-1R, Flk4, KDR / Flk- 13. The compound of claim 12, wherein the compound is related to a receptor tyrosine kinase selected from the group consisting of 1, Flt-1, FGFR-1R, FGFR-2R, FGFR-3R, and FGFR-4R.   A cellular tyrosine kinase in which the disease state is selected from the group consisting of Src, Frk, Btk, Csk, Abl, ZAP70, Fes / Fps, Fak, Ack, Yes, Fyn, Lyn, Lck, Blk, Hck, Fgr, and Yrk 13. A compound according to claim 12 related to   13. The compound according to claim 12, wherein the disease state is associated with a tyrosine kinase selected from the group consisting of JAK1, JAK2, JAK3, and TYK2.   The disease state is from the group consisting of ERK2, c-Jun, p38 MAPK, PKA, PKB, PKC, cyclin-dependent kinase, CDK1, CDK2, CDK3, CDK4, CDK5, CDK6, CDK7, CDK8, CDK9, CDK10, and CDK11 13. A compound according to claim 12 relating to a selected serine / threonine kinase.   Disease states include allergic asthma, atopic dermatitis (eczema), and atopy such as allergic rhinitis, cell-mediated hypersensitivity such as allergic contact dermatitis and hypersensitivity pneumonia, systemic lupus erythematosus (SLE), rheumatoid arthritis, Juvenile arthritis, Sjogren's syndrome, scleroderma, polymyositis, ankylosing spondylitis, rheumatic diseases such as psoriatic arthritis, other autoimmune diseases such as type I diabetes, autoimmune thyroid disorders, and Alzheimer's disease, Epstein Barr Viral diseases such as virus (EBV), hepatitis B, hepatitis C, HIV, HTLV1, varicella-zoster virus (VZV), human papilloma virus (HPV), and cancers such as leukemia, lymphoma, and prostate cancer 13. A method according to claim 12, selected from a group.   Use of at least one compound according to any one of claims 1 to 10 in the preparation of a medicament for treating a protein kinase related disease state. 11. A pharmaceutical composition comprising an effective amount of at least one compound according to any one of claims 1 to 10 and a pharmaceutically acceptable vehicle or diluent capable of treating a protein kinase related disorder.

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