JP2005535596A - Protein kinase inhibitor - Google Patents

Abstract

A compound of general formula I, or a pharmaceutically acceptable salt, hydrate, solvate, crystalline form or diastereomer thereof is described. Also described are methods of treating protein kinase related conditions 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 the phosphorylation of specific residues in proteins. In general, protein kinases fall into several groups. That is, those that preferentially phosphorylate serine and / or threonine residues, those that preferentially phosphorylate tyrosine residues, and those that phosphorylate both tyrosine and Ser / Thr residues. . Thus, protein kinases are important elements in signal transduction pathways that are responsible for the transmission of extracellular signals, including the actions of their receptors on the nucleus that trigger various biological phenomena. Many roles of protein kinases in normal cell physiology include cell cycle regulation and cell proliferation, differentiation, apoptosis, cell mobility and mitogenesis.

  Protein kinases contain multiple members of the protein tyrosine kinase family (PTK) and are divided into cytoplasmic PTK (CTK) and receptor PTK (RTK). Cytoplasmic PTK includes SRC family (BLK; FGR; FYN; HCK; LCK; LYN; SRC; YES and YRK included); BRK family (BRK; FRK, SAD; and SRM included); CSK family (CSK and CTK BTK family (including BTK; ITK; TEC; including MKK2 and TXK), Janus kinase family (including JAK1, JAK2, JAK3 and Tyk2), FAK family (including FAK and PYK2); Fes family (FES and FER), ZAP70 family (including ZAP70 and SYK); ACK family (including ACK1 and ACK2) and AbI 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, VEGF, including FLK2, VEGF-receptor family (including FLT1, FLK1 and FLT4); FGF-receptor family (including FGFR1, FGFR2, FGFR3 and FGFR4); CCK4 family (including CCK4); MET family (including TRK family (including TRKA, TRKB and TRKC); AXL family (including AXL, MER and SKY); TIE / TEK family (including TIE and TIE2 / TEK); EPH family (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 RET family (including RET); LTK family (including 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 are extracellular signal-regulated kinases (p42 / ERK2 and p44 / ERK1); c-JunNH2 terminal kinase (JNK); cAMP-responsive element-binding protein kinase (CREBK); cyclin-dependent Kinase (CDK); cAMP-dependent kinase (CAPK); Mitogen-activated protein kinase-activated protein kinase (MAPK and its analogs); Stress-activated protein kinase p38 / SAPK2; Mitogen- and stress-activated kinase (MSK); It contains a number of distinct subfamilies including protein kinases, especially PKA, PKB and PKC;

  In addition, the genomes of many pathogens have gene-encoded protein kinases. For example, Plasmodium falciparum fever and viruses such as HPV and hepatitis viruses appear to have kinase-related genes.

Inappropriately high protein kinase activity has been associated with many diseases resulting from abnormal cellular function. This may be directly or indirectly, for example, due to the failure of an appropriate regulatory mechanism for the kinase involved in enzyme mutation, overexpression or inappropriate activation, or upstream or downstream of the kinase signal. May be caused by overproduction or underproduction of cytokines or growth factors that are also involved in transmission to the body. In all these cases, selective inhibition of the action of the kinase may be expected to have a beneficial effect. Diseases that have been implicated in abnormal kinase activity include diabetes; restenosis; atherosclerosis; liver and kidney fibrosis; eye disease; myeloid and lymphoproliferative disorders; prostate cancer, colon Cancers such as cancer, breast cancer, head and neck cancer, leukemia and lymphoma; and atopic dermatitis, asthma, rheumatoid arthritis, Crohn's disease, psoriasis, Kurzon syndrome, chondrogenic dysplasia and fatal osteodysplasia Autoimmune diseases are included.
Physician Desk Reference (PDR) Miyaura, N. and Suzuki, Chem Rev. 1995, 952457 Stille, JK, Angew.Chem., Int.Ed.Engl., 1986, 25, 508 Spiotto MT and Chung TD, (2000) STAT3 mediates IL-6-induced growth inhibition in the human prostate cancer cell line LNCaP, Prostate 42 88-98

  The inventors have found that a group of compounds based on disubstituted pyrazine skeletons are inhibitors of protein kinases.

  Thus, the present invention provides compounds that potentially modulate protein kinase signaling by affecting RTK, CTK, and / or STK enzymatic activity, thereby interfering with the signal transmitted by such proteins. set to target. More specifically, the present invention is directed to compounds that modulate RTK, CTK and / or STK mediated signaling pathways as therapeutic approaches to cure many types of tumors.

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

(Where
R1 is H, C _1-4 alkyl,
Q is a bond or C _1-4 alkyl;
A is halogen, C _{1 to 4 alkyl, CH 2 F, CHF 2,} CF 3, CN, aryl, hetaryl, OCF _3, OC _{1 to 4} alkyl, OC _{2 to 5} alkyl NR @ 4 R @ 5, O aryl, O hetaryl, CO ₂ R4, CONR4R5, nitro, optionally substituted with NR @ 4 R @ 5, C _{1 to 4} alkyl _NR4R5, NR6C 1~4 alkyl NR4R5, NR4COR5, NR6CONR4R5, 0~3 substituents selected from NR4SO ₂ R5 independently aryl, hetaryl, R4, R5 are each independently H, C _{1 to 4} alkyl, C _{1 to 4} alkyl cycloalkyl, C _{1 to 4} alkyl cycloalkyl heta Le kills, aryl, hetaryl, C _{1 to 4} alkyl aryl, C _1-4 alkylhetaryl, or combine to form an optionally substituted 3- to 8-membered ring optionally containing an atom selected from O, S, NR7. can be, R6 is selected from H, C _{1 to 4} alkyl, R7 is H, C _{1 to 4} alkyl, aryl, het Lumpur, C _{1 to 4} alkyl aryl, is selected from C _{1 to 4} alkyl hetaryl,
R2 is halogen, C _{1 to 4} alkyl, OH, OC _{1 to 4 alkyl, CH 2 F, CHF 2,} CF 3, OCF 3, CN, C 1~4 alkyl NR8R9, OC _{1 to 4} alkyl NR8R9, CO ₂ R8 , CONR8R9, NR8R9, NR8COR9, NR10CONR8R9 , NR8SO 0-2 substituents selected from ₂ R9 independently, R8, R9 are each independently, H, C _{1 to 4} alkyl, C _{1 to 4} alkyl cycloalkyl, C _{1 to 4} alkyl cycloalkyl heta Le kills, aryl, hetaryl, C _{1 to 4} alkyl aryl, C _{1 to 4} alkyl hetaryl, or in combination, optionally O, and atom selected from S, NR11 containing the selection, it is possible to form a 3-membered ring to 8-membered ring which is optionally substituted, R10 is selected H, C _{1 to 4} alkyl, aryl or hetaryl, R11 is H, C _{1 to 4} alkyl is selected aryl, hetaryl, C _{1 to 4} alkyl aryl, C _{1 to 4} alkyl hetaryl,
Y is halogen, OH, NR12R13, NR12COR13, NR12CONR13 , N12SO 2 R13, R12 and R13 are each _{independently, H, CH 2 F, CHF} 2, CF 3, CN, C 1~4 alkyl, _{C. 1 to 4} alkyl cycloalkyl, C _{1 to 4} alkyl cycloalkyl heta Le kills, or bonded to, O, S, containing optionally an atom selected from NR14, 3-membered ring 6 an optionally substituted Can form a member ring, R14 is selected from H, C _1-4 alkyl;
n = 0-4,
W is H, C _{1 to 4} alkyl is selected from C _{2 to 6} alkenyl, C _{1 to 4} alkyl or C _{2 to 6} alkenyl C _{1 to 4} alkyl, OH, OC _{1 to 4} alkyl, optionally with NR15R16 may be substituted, the R15 and R16, each independently, H, a C _{1 to 4} alkyl, C _{1 to 4} alkyl cycloalkyl, C _{1 to 4} alkyl cycloalkyl heta Le kills, or bonded to, O, S, containing optionally an atom selected from NR17, can form a 3-membered ring to 8-membered ring which is optionally substituted, R17 is selected from H, C _{1 to 4} alkyl,
When Y is OH or NHCOCH _3, R2 is one to two substituents, when Y is absent is a NH ₂ R2, Y is in the para position)
Alternatively, it is in a pharmaceutically acceptable salt, hydrate, solvate, crystalline form or diastereomer.

  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 present invention is a method of treating a protein kinase related condition wherein said method comprises a therapeutically effective amount of at least one compound of the first aspect of the present invention, or a therapeutic A method comprising administering an effective amount of the composition of the second aspect of the invention.

  The present invention is directed to compounds that potentially modulate protein kinase signaling by affecting the enzyme activity of RTK, CTK, and / or STK, thereby interfering with the signal transmitted by such proteins. To do. More specifically, the present invention is directed to compounds that modulate RTK, CTK and / or STK mediated signaling pathways as therapeutic approaches to cure many types of tumors.

  Therefore, in the first aspect, the present invention provides the following general formula:

(Where
R1 is H, C _1-4 alkyl,
Q is a bond or C _1-4 alkyl;
A is halogen, C _{1 to 4 alkyl, CH 2 F, CHF 2,} CF 3, CN, aryl, hetaryl, OCF _3, OC _{1 to 4} alkyl, OC _{2 to 5} alkyl NR @ 4 R @ 5, O aryl, O hetaryl, CO ₂ R4, CONR4R5, nitro, optionally substituted with NR @ 4 R @ 5, C _{1 to 4} alkyl _NR4R5, NR6C 1~4 alkyl NR4R5, NR4COR5, NR6CONR4R5, 0~3 substituents selected from NR4SO ₂ R5 independently aryl, hetaryl, R4, R5 are each independently H, C _{1 to 4} alkyl, C _{1 to 4} alkyl cycloalkyl, C _{1 to 4} alkyl cycloalkyl heta Le kills, aryl, hetaryl, C _{1 to 4} alkyl aryl, C _1-4 alkylhetaryl, or combine to form an optionally substituted 3- to 8-membered ring optionally containing an atom selected from O, S, NR7. can be, R6 is selected from H, C _{1 to 4} alkyl, R7 is H, C _{1 to 4} alkyl, aryl, het Lumpur, C _{1 to 4} alkyl aryl, is selected from C _{1 to 4} alkyl hetaryl,
R2 is halogen, C _{1 to 4} alkyl, OH, OC _{1 to 4 alkyl, CH 2 F, CHF 2,} CF 3, OCF 3, CN, C 1~4 alkyl NR8R9, OC _{1 to 4} alkyl NR8R9, CO ₂ R8 , CONR8R9, NR8R9, NR8COR9, NR10CONR8R9 , NR8SO 0-2 substituents selected from ₂ R9 independently, R8, R9 are each independently, H, C _{1 to 4} alkyl, C _{1 to 4} alkyl cycloalkyl, C _{1 to 4} alkyl cycloalkyl heta Le kills, aryl, hetaryl, C _{1 to 4} alkyl aryl, C _{1 to 4} alkyl hetaryl, or in combination, optionally O, and atom selected from S, NR11 containing the selection, it is possible to form a 3-membered ring to 8-membered ring which is optionally substituted, R10 is selected H, C _{1 to 4} alkyl, aryl or hetaryl, R11 is H, C _{1 to 4} alkyl is selected aryl, hetaryl, C _{1 to 4} alkyl aryl, C _{1 to 4} alkyl hetaryl,
Y is halogen, OH, NR12R13, NR12COR13, NR12CONR13 , N12SO 2 R13, R12 and R13 are each _{independently, H, CH 2 F, CHF} 2, CF 3, CN, C 1~4 alkyl, _{C. 1 to 4} alkyl cycloalkyl, C _{1 to 4} alkyl cycloalkyl heta Le kills, or bonded to, O, S, containing optionally an atom selected from NR14, 3-membered ring 6 an optionally substituted Can form a member ring, R14 is selected from H, C _1-4 alkyl;
n = 0-4,
W is H, C _{1 to 4} alkyl is selected from C _{2 to 6} alkenyl, C _{1 to 4} alkyl or C _{2 to 6} alkenyl C _{1 to 4} alkyl, OH, OC _{1 to 4} alkyl, optionally with NR15R16 may be substituted, the R15 and R16, each independently, H, a C _{1 to 4} alkyl, C _{1 to 4} alkyl cycloalkyl, C _{1 to 4} alkyl cycloalkyl heta Le kills, or bonded to, O, S, containing optionally an atom selected from NR17, can form a 3-membered ring to 8-membered ring which is optionally substituted, R17 is selected from H, C _{1 to 4} alkyl,
When Y is OH or NHCOCH _3, R2 is one to two substituents, when Y is absent is a NH ₂ R2, Y is in the para position)
Alternatively, it is in a pharmaceutically acceptable salt, hydrate, solvate, crystalline form or diastereomer.

In the above description,
C _1-4 alkyl means a straight or branched alkyl chain,
It should be understood that aryl means unsubstituted or optionally substituted phenyl or naphthyl.

  Hetaryl refers to an unsubstituted or optionally substituted 5- or 6-membered heteroaromatic ring containing one or more heteroatoms selected from O, N, S.

Cycloalkyl means a 3-8 membered saturated ring,
Shikurohetarukiru is O, S, NR18 (R18 is H, C _{1 to 4} alkyl, aryl, a is hetaryl) refers to a saturated ring of 3-8 membered containing one to three heteroatoms selected from .

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

(Where
R1 is H, C _1-4 alkyl,
Q is a bond or C _1-4 alkyl;
A is halogen, C _{1 to 4 alkyl, CH 2 F, CHF 2,} CF 3, CN, aryl, hetaryl, OCF _3, OC _{1 to 4} alkyl, OC _{2 to 5} alkyl NR @ 4 R @ 5, O aryl, O hetaryl, CO _{2 R4, CONR4R5, NR4R5, C} 1~4 alkyl _NR4R5, NR6C 1~4 alkyl NR4R5, NR4COR5, NR6CONR4R5, aryl optionally substituted with 0-3 substituents selected from NR4SO ₂ R5 independently hetaryl, R4, R5 are each independently H, C _{1 to 4} alkyl, C _{1 to 4} alkyl cycloalkyl, C _{1 to 4} alkyl cycloalkyl heta Le kills, aryl, hetaryl, C _{1 to 4} alkyl aryl, C _{1 ~ 4} alkyl hetaryls or can be joined to form an optionally substituted 3- to 8-membered ring optionally containing an atom selected from O, S, NR7 , R6 is selected from H, C _{1 to 4} alkyl, R7 is H, C _{1 to 4} alkyl, aryl, hetaryl, C _1-4 alkylaryl, selected from C _1-4 alkyl hetaryl,
R2 is halogen, C _{1 to 4} alkyl, OH, OC _{1 to 4 alkyl, CH 2 F, CHF 2,} CF 3, OCF 3, CN, C 1~4 alkyl NR8R9, OC _{1 to 4} alkyl NR8R9, CO ₂ R8 , CONR8R9, NR8R9, NR8COR9, NR10CONR8R9 , NR8SO 0-2 substituents selected from ₂ R9 independently, R8, R9 are each independently, H, C _{1 to 4} alkyl, C _{1 to 4} alkyl cycloalkyl, C _{1 to 4} alkyl cycloalkyl heta Le kills, aryl, hetaryl, C _{1 to 4} alkyl aryl, C _{1 to 4} alkyl hetaryl, or in combination, optionally O, and atom selected from S, NR11 containing the selection, it is possible to form a 3-membered ring to 8-membered ring which is optionally substituted, R10 is selected H, C _{1 to 4} alkyl, aryl or hetaryl, R11 is H, C _{1 to 4} alkyl is selected aryl, hetaryl, C _{1 to 4} alkyl aryl, C _{1 to 4} alkyl hetaryl,
Y is halogen, OH, NR12R13, NR12COR13, NR12CONR13 , N12SO 2 R13, R12 and R13 are each _{independently, H, CH 2 F, CHF} 2, CF 3, CN, C 1~4 alkyl, _{C. 1 to 4} alkyl cycloalkyl, C _{1 to 4} alkyl cycloalkyl heta Le kills, or bonded to, O, S, containing optionally an atom selected from NR14, 3-membered ring 6 an optionally substituted Can form a member ring, R14 is selected from H, C _1-4 alkyl;
n = 0-4,
W is H, C _{1 to 4} alkyl is selected from C _{2 to 6} alkenyl, C _{1 to 4} alkyl or C _{2 to 6} alkenyl C _{1 to 4} alkyl, OH, OC _{1 to 4} alkyl, optionally with NR15R16 may be substituted, the R15 and R16, each independently, H, a C _{1 to 4} alkyl, C _{1 to 4} alkyl cycloalkyl, C _{1 to 4} alkyl cycloalkyl heta Le kills, or bonded to, O, S, containing optionally an atom selected from NR17, can form a 3-membered ring to 8-membered ring which is optionally substituted, R17 is selected from H, C _{1 to 4} alkyl,
When Y is OH or NHCOCH _3, R2 is one to two substituents, when Y is absent is a NH ₂ R2, Y is in the para position)
Alternatively, a pharmaceutically acceptable salt, hydrate, solvate, crystalline form or compound selected from diastereomers.

In the above description,
C _1-4 alkyl means a straight or branched alkyl chain,
It should be understood that aryl means unsubstituted or optionally substituted phenyl or naphthyl.

  Hetaryl refers to an unsubstituted or optionally substituted 5- or 6-membered heteroaromatic ring containing one or more heteroatoms selected from O, N, S.

Cycloalkyl means a 3-8 membered saturated ring,
Shikurohetarukiru mean O, S, NR18 (R18 is H, C _{1 to 4} alkyl, aryl, a is hetaryl) a saturated ring of 3-8 membered containing one to three heteroatoms selected from To do.

  The compounds of the present invention include all conformational isomers (eg, cis isomers and isomers). The compounds of the present invention have asymmetric centers. Therefore, it exists in various enantiomeric and diastereomeric forms. The invention relates to the use of all optical isomers and stereoisomers of the compounds of the invention and mixtures thereof and to all pharmaceutical compositions and methods of treatment using or including them. Compounds of formula I can also exist as tautomers. The present invention relates to the use of all such tautomers and mixtures thereof.

  The invention also encompasses a pharmaceutical composition comprising a prodrug of a compound of formula I. The invention also encompasses 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 into prodrugs. A prodrug is an amino acid residue, or a polypeptide chain of two or more (e.g., 2, 3 or 4) amino acid residues covalently bonded via a peptide bond to the free amino of a compound of formula I. Including compounds bonded to hydroxy and carboxylic acid groups. Amino acid residues include 20 naturally-occurring amino acids, usually represented by three letter symbols, and also 4-hydroxyproline, hydroxylysine, demosin, isodesomosin, 3-methylhistidine, norvlin, β- Also included are alanine, γ-aminobutyric acid, citrulline, homocystein, homoserine, ornithine and methionine sulfone. Prodrugs also include compounds in which carbonates, carbamates, amides and alkyl esters are covalently bonded to the above substituents of formula I via the carbonyl carbon prodrug side chain. Prodrugs also include phosphoric acid derivatives (acids, acid salts, esters, etc.) of the compounds of formula I which are linked to the free hydroxyl of the compound of formula I via a phosphorus-oxygen bond.

In a more preferred embodiment, the compound has S chirality at the asymmetric carbon with W being C _1-4 alkyl. The compounds can be used as purified isomers or as mixtures in any ratio of isomers. However, it is preferred that the mixture contains at least 70%, 80%, 90%, 95%, or 99% of the preferred isomer.

  In a further preferred embodiment, the compound is selected from the compounds shown in Table 1.

  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 condition, said method comprising a therapeutically effective amount of at least one compound of the first aspect of the invention, or a therapeutic A method comprising administering an effective amount of the composition of the second aspect of the invention.

  In a preferred embodiment, the condition is EGF, HER2, HER3, HER4, IR, IGF-1R, IRR, PDGFR.α, PDGFR.β, CSFIR, C-Kit, C-fms, Flk-1R, Flk4, KDR / Related to a receptor tyrosine kinase selected from the group consisting of Flk-1, Flt-1, FGFR-1R, FGFR-2R, FGFR-3R and FGFR-4R.

  In other preferred embodiments, the condition 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. Related to cellular tyrosine kinases.

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

  In still other preferred embodiments, the condition is ERK2, c-Jun, p38MAPK, PKA, PKB, PKC, cyclin dependent kinase, CDK1, CDK2, CDK3, CDK4, CDK5, CDK6, CDK7, CDK8, CDK9, CDK10 and Related to a serine / threonine kinase selected from the group consisting of CDK11.

  A preferred embodiment of the present invention is that the pathology is atopic, such as allergic asthma, atopic dermatitis (eczema) and 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, psoriatic arthritis, and other rheumatic diseases; such as type 1 diabetes, autoimmune thyroid disorders and Alzheimer's disease Other autoimmune diseases; viral diseases such as Epstein-Barr virus (EBV), hepatitis B, hepatitis C, HIV, HTLV1, chicken pox-zoster virus (VZV), human papilloma virus (HPV), leukemia, Selected from cancers such as lymphoma and prostate cancer.

  In one embodiment, the methods of the invention are used for the treatment of sarcomas, carcinomas and / or leukemias. Examples of disorders for which the subject method of the invention can be used alone or as part of a treatment regimen include fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, chordoma, Hemangiosarcoma, endothelial sarcoma, lymphangiosarcoma, lymphatic endothelial sarcoma, synovial, mesothelioma, Ewing sarcoma, leiomyosarcoma, rhabdomyosarcoma, colon carcinoma, pancreatic cancer, breast cancer, ovarian cancer, prostate cancer , Squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, sweat gland carcinoma, sebaceous carcinoma, papillary carcinoma, papillary adenocarcinoma, cystadenocarcinoma, medullary carcinoma, bronchial carcinoma, renal cell carcinoma, liver cancer, bile duct carcinoma, chorioallantoic membrane Carcinoma, seminoma, embryonal carcinoma, Wilms tumor, cervical cancer, testicular tumor, lung carcinoma, small cell lung carcinoma, bladder carcinoma, epithelial carcinoma, glioma, astrocytoma, medulloblastoma, craniopharynx Tumor, ependymoma, pineal gland, hemangioblastoma, acoustic nerve , Oligodendrocytes glioma, meningioma, melanoma, include neuroblastoma and retinoblastoma.

  In some embodiments, the methods of the invention are used to treat disorders such as carcinomas formed from breast, prostate, kidney, bladder or colon tissue.

  In other embodiments, the method of the invention is applied to adipose tissue such as adipocyte tumors such as lipomas, fibrolipomas, lipoblastomas, lipomatosis, hibemoma, hemangiomas and / or liposarcomas. Used to treat hyperplastic or neoplastic disorders that occur in it.

  As used herein, the term “protein kinase-related pathology” refers to disorders caused by abnormal protein kinase activity, particularly JAK activity, and / or disorders that are alleviated by inhibition of one or more of these enzymes.

  In another aspect, the invention provides the use of the compounds described in Pharmaceutical preparations for the treatment of protein kinase related conditions, including JAK related conditions.

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

  The present invention provides a pharmaceutical composition comprising an effective amount of at least one compound of Formula I or II and a pharmaceutically acceptable vehicle or diluent capable of treating a protein kinase related disorder. The compositions of the present invention can contain other therapeutic agents, as described below, such as conventional solid or liquid vehicles or dilutions by techniques such as those well known in the art of pharmaceutical formulation. The formulation can be made by using the agent, as well as the types of pharmaceutical additives (eg, excipients, binders, preservatives, stabilizers, flavoring agents, etc.) appropriate to the desired mode of administration.

  The compound of formula I or II is administered by suitable means, e.g. in the form of tablets, capsules, granules or powders; oral; sublingual; buccal; subcutaneous, intravenous, intramuscular or intracisternal injection or Parenteral, such as infusion techniques (e.g., sterile injectable aqueous or non-aqueous solutions or suspensions); nasal, such as inhalation spray; topical in the form of a cream or ointment; by rectal, such as in the form of a suppository, It can be administered in a dosage unit formulation containing a non-toxic, pharmaceutically acceptable vehicle or diluent. The compound can be administered, eg, in a form suitable for immediate release or extended release. Immediate release or extended release can be effected by use of a suitable pharmaceutical composition comprising a compound of the invention, or in particular in the case of extended release, by the use of a device such as a subcutaneous implant or an osmotic pump.

  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, mammals include, but are not limited to, cows, sheep, goats, horses, dogs, cats, guinea pigs, rats or other bovines, sheeps, horses, canines, felines, rodents Or you can treat murine seeds. However, the method can also be performed on other species such as avian species (eg, chicken).

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

  Targets of treatment by the above methods where JAK inhibition is desired include, but are not limited to, cows, sheep, goats, horses, dogs, cats, guinea pigs, rats or other bovines, sheeps, equines, canines , Mammals including feline, rodent or murine species, preferably male or female humans.

  The term “therapeutically effective amount” is a subject that will elicit the biological or medical response of a tissue, system, animal or human being studied by a researcher, veterinarian, physician or other clinician. It means the amount of the composition.

  As used herein, the term “composition” is obtained directly or indirectly by a product comprising a specified component in a specified amount, as well as a combination of a specified component in a specified amount. It shall include any product. “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 thereof.

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

  Pharmaceutical compositions for administration of the compounds of the present invention can be conveniently provided in dosage unit form and can be formulated in any manner well known in the pharmaceutical industry. All methods include the step of bringing the active ingredient into association with the carrier which constitutes one or more accessory ingredients. In general, a pharmaceutical composition is formulated 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 the product into the desired formulation. To do. In a 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 obtained directly or indirectly by a product comprising a specified component in a specified amount, as well as a combination of a specified component in a specified amount. It shall include any product.

  Pharmaceutical compositions containing the active ingredient are suitable for oral use, eg tablets, troches, drops, aqueous or oil suspensions, dispersible powders or granules, emulsions, hard or soft capsules or syrups It may be in the form of an agent or elixir. Compositions for oral use can be formulated by any method known in the art for the manufacture of pharmaceutical compositions, and such compositions can be formulated as a medicinal and palatable preparation. To provide, one or more agents selected from the group consisting of sweeteners, flavoring agents, coloring agents and preservatives can be included. Tablets may contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets. These excipients are inert diluents such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or potassium phosphate; granules and disintegrants such as corn starch or alginic acid; binders such as starch, gelatin or It may be acacia, as well as lubricants such as magnesium stearate, stearic acid or talc. The tablets may be uncoated, or the tablets may be coated with 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. These can also be coated to form osmotic therapeutic tablets for controlled release.

  Formulations for oral use are as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent such as calcium carbonate, calcium phosphate or kaolin, or the active ingredient is water or an oil vehicle such as peanut It can also be present as a soft gelatin capsule mixed with oil, liquid paraffin or olive oil.

  Aqueous suspensions contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients may be suspending agents such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinyl-pyrrolidone, gum tragacanth and gum arabic. The dispersant or wetting agent may be a naturally occurring phosphatide, for example, a product of condensation of lecithin, alkylene oxide with a fatty acid, such as polyoxyethylene stearate, or ethylene oxide with a long chain aliphatic alcohol, For example, heptadecaethyleneoxycetanol, or a condensation product of ethylene oxide with a partial ester derived from fatty acid and hexitol, such as polyoxyethylene sorbitol monooleate, or ethylene oxide, derived from fatty acid and hexitol anhydride. It may also be a condensation product with a partial ester such as polyethylene sorbitan monooleate. Aqueous suspensions contain 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 sucrose or saccharin. Sweeteners such as can also 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 liquid paraffin. Oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweet and flavoring agents such as those mentioned above can be added to provide a palatable oral preparation. These compositions can be preserved by the addition of an anti-oxidant such as ascorbic acid.

  Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives. . Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients, for example sweetening, flavoring and coloring agents, may also be present.

  The pharmaceutical composition of the present invention may be in the form of an oil-in-water emulsion. The oily phase may be a vegetable oil, for example olive oil or arachis oil, or a mineral oil, for example liquid paraffin or mixtures of these. Suitable emulsifiers are naturally derived gums such as gum arabic or tragacanth, natural phosphatides such as soy, lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides such as sorbitan monooleate, and said partial esters It may be a condensation product of ethylene oxide with, for example, polyoxyethylene sorbitan monooleate. The emulsion may contain sweetening and flavoring agents.

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

  The pharmaceutical composition may be in the form of a sterile injectable aqueous or oleagenous suspension. This suspension can be formulated by techniques known in the art using the dispersing or wetting agents and suspending agents described above. A sterile injectable preparation may 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. Acceptable vehicles and solvents used include water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are used as solvent or suspending vehicle. For this purpose any bland fixed oil can be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid are used 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. These compositions mix the drug with a suitable non-irritating excipient that is solid at normal temperature but liquid at rectal temperature and therefore will melt in the rectum to release the drug. Can be dispensed. Such materials are cocoa butter and polyethylene glycol.

  For topical use, creams, ointments, jellies, solutions or suspensions containing the compounds of the invention are used (for the purpose of this application, topical applications should include mouthwashes and mouthwashes). is there).

  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 vehicle. Any non-toxic, physiologically acceptable and metabolic lipid capable of forming liposomes can be used. The composition of the present invention in liposome form can contain, in addition to the compound of the present invention, stabilizers, preservatives, excipients and the like. Preferred lipids are phospholipids and phosphatidylcholines. Both of these are synthetic and natural. Methods for forming liposomes are known in the art.

  The pharmaceutical compositions and methods of the present invention can further comprise other pharmaceutically active compounds referred to herein that are usually applied in the treatment of the above pathological conditions. Selection of a suitable drug for use in combination therapy can be made by one of ordinary skill in the art, according to conventional pharmacological principles. Combinations of therapeutic agents can act synergistically to provide treatment or prevention of the various disorders described above. Using this approach, therapeutic effects can be achieved at lower doses of each drug, thereby reducing the potential for side effects.

  Examples of other therapeutic agents include the following: Cyclosporine (e.g., cyclosporin A), CTLA4-Ig, ICAM-3, anti-IL-2 receptor (anti-Tac), anti-CD45RB, anti-CD2, anti-CD3 (OKT-3 ), Drugs that block the interaction between CD40 and gp39, such as antibodies specific for anti-CD4, anti-CD80, anti-CD86, antibodies specific for CD40 and / or gp39 (ie CD154), CD40 and gp39 Fusion proteins made from (CD401g and CD8gp39), nuclear translocation inhibitors of NF-κB function such as deoxyspagarin (DSG), cholesterol biosynthesis inhibitors such as HMGCoA reductase inhibitors (lovastatin and simvastatin) Nonsteroidal anti-inflammatory drugs (NSAIDs) such as inhibitors, ibuprofen, aspirin, acetaminophen and cyclooxygenase inhibitors such as rofecoxib, steroids such as prednisolone or dexamethasone, gold compounds, methotrexate, FK50 6 (Tacrolimus, Prograf), antiproliferative substances such as mycophenolate mofetil, azathioprine, VP-16, etoposide, fludarabine, cisplatin and cyclophosamide and other cytotoxic drugs, tenidap, anti-TNF antibody or soluble TNF receptor TNF-α inhibitors such as the body, and rapamycin (Rapamune) or derivatives thereof.

  When other therapeutic agents are used in combination with the compounds of the present invention, these are described, for example, in the Physician Desk Reference (PDR), or one of ordinary skill in the art. Can be used in an amount determined by one.

  In the treatment or prevention of conditions requiring protein kinase inhibition, suitable dosage levels are generally about 0.01 to 500 mg per day per patient body weight, which can be administered in single or multiple doses. It is preferred that the dosage level be about 0.1 to about 250 mg / kg per day, more preferably about 0.5 to about 100 mg / kg per day. Suitable dosage levels may be about 0.01 to 250 mg / kg per day, about 0.05 to 100 mg / kg per day, or about 0.1 to 50 mg / kg per day. Within this range, the dosage may be 0.05 to 0.5, 0.5 to 5 or 5 to 50 mg / kg per day. For oral administration, the composition may be adjusted to 1.0 to 1000 milligrams of active ingredient, specifically 1.0, 5.0, 10.0, 15.0.20.0, 25.0, 50.0, for symptomatic adjustment of the dosage to the patient being treated. 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 is preferably provided in the form of a tablet. The compounds can be administered on a regimen of 1 to 4 times per day, preferably once or twice per day.

  However, the individual dosage level and frequency of administration for any individual patient may vary, including the activity of the individual compound used, the metabolic stability and length of action of the compound, age, weight, general health (general health), sex, diet, mode and time of administration, excretion rate, drug combination, severity of individual condition, and treatment being received by the host.

  Throughout this specification, the term “comprise” or variant terms such as “comprises” or “comprising” includes the elements, integers or steps, or groups of elements, integers or steps, but any other Should not be construed as excluding any elements, integers or steps, or groups of elements, integers or steps.

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

  Any discussion of documents, behaviors, materials, devices, articles, etc. included herein is solely for the purpose of providing a context for the present invention. Any or all of these matters form part of the prior art base or are relevant to the present invention as they existed in Australia prior to the priority claim date of each claim of this application. It should not be taken as advising as it was normal general knowledge.

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

Materials and Methods Compound Synthesis Compounds are generally prepared in a two step process starting from 2,6-dichloropyrazine.

  The first step is a nucleophilic aromatic substitution to generate a monoamino-monohalo intermediate (Scheme 1).

スキーム1

Scheme 1

  Nucleophilic aromatic substitution is generally performed by adding a primary amine to the dihalogenated heterocycle in a solvent such as ethanol, isopropanol, tert-butanol, dioxane, THF, DMF, toluene or xylene. The reaction is generally 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, amino substituents can be introduced by a transition metal catalyzed amination reaction. Common catalysts for such conversion include Pd (OAc) ₂ / P (t-Bu) ₃ , Pd ₂ (dba) ₃ / BINAP and Pd (OAc) ₂ / BINAP. These reactions are generally carried out in a solvent such as toluene or dioxane in the presence of cesium carbonate or a base such as sodium tert-butoxide or potassium tert-butoxide in the range of room temperature to reflux temperature.

The amines used in the first step of the synthesis of these compounds are obtained from commercial sources or prepared using methods well known to those skilled in the art. Of particular interest is α-methylbenzylamine which can be prepared by reduction of the oxime (Scheme 2). Common reducing agents include lithium aluminum hydride, hydrogen gas in the presence of palladium on charcoal catalyst, Zn in the presence of hydrochloric acid, or Lewis acids such as TiCl ₃ , ZrCl ₄ , NiCl ₂ and MoO ₃ This includes sodium borohydride below or sodium borohydride combined with Amberlyst H15 ion exchange resin and LiCl.

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 derivatization of hydroxyl as mesylate or tosylate and substitution with nitrogen nucleophilic atoms such as phthalimide or azide, which are then converted to primary amines using conventional synthetic methods, or Mitsunobu. ) Substitution of the hydroxyl with an appropriate nitrogen nucleophilic atom. 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 enzymatic processes, asymmetric hydrogenation procedures and chiral oxaborolidine.

  The second step of the synthesis uses palladium mediated cross coupling of a monoamino-monochloro intermediate with an appropriately functionalized coupling partner. Typical coupling partners are boronic acid (Suzuki coupling: see, for example, Miyaura, N. and Suzuki, Chem Rev. 1995, page 952457) or stannane (Still coupling: such as Still, JK, Angew. ., Int. Ed. Engl., 1986, 25, 508) (Scheme 3).

スキーム3

Scheme 3

Suzuki coupling is the preferred coupling method, generally in a solvent such as DME, THF, DMF, ethanol, propanol, toluene or 1,4-dioxane, potassium carbonate, lithium hydroxide, cesium carbonate, sodium hydroxide, It is carried out in the presence of a base such as potassium fluoride or potassium phosphate. The reaction can be performed at a high temperature, and the palladium catalyst used is [Pd (PPh ₃ ) ₄ ], Pd (OAc) ₂ , [PdCl ₂ (dppf)], Pd ₂ (dba) ₃ / P (t-Bu) ₃ Selected from.

  The product formed by this series of reactions can be further derivatized using techniques well known to those skilled in the art. Alternatively, monoaminomonochloropyrazine can be derivatized prior to substitution of the 6-chloro substituent. This derivatization generally uses functional groups that are naturally present in the amine species and are well known to those skilled in the art.

  A representative synthesis is described below.

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

A solution of R-α-methylbenzylamine (0.57 g, 4.7 mmol) and 2,6-dichloropyrazine (0.6388 g, 4.29 mmol) in dioxane (2.5 ml) was heated at reflux for 48 hours under N ₂ atmosphere. The solvent was removed and crystallized from toluene-hexane to give the product (0.82 g, 82%).
¹ Hn.mr (CDCl ₃ ) δ1.58 (d, J = 6.6Hz, 3H, CH ₃ ), 4.88 (m, 1H, CH), 5.07 (d, 1H, NH), 7.24-7.36 (m, 5H , Ar-H), 7.61 (s, 1H, Pyraz-H), 7.79 (s, 1H, Pyraz-H).

2-Methoxy-4- (6-{[(1R) -1-phenylethyl] amino} pyrazin-2-yl) phenol

6-chloro-N-[(1R) -1-phenylethyl] pyrazin-2-amine (0.611 g, 2.61 mmol), 4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolane -2-yl) phenol (0.785 g, 3.14 mmol), tetrakis (triphenylphosphine) palladium (0) (0.30 g, 0.26 mmol) and toluene (3 mL) were mixed with 2M aqueous sodium carbonate ( 1.6 ml, 2.6 mmol). The resulting mixture was heated under reflux for 24 hours with vigorous stirring. After cooling, ethyl acetate was added and the mixture was dried (MgSO ₄ ) and filtered. The solvent was then removed under vacuum to give a crude product. Purification by column chromatography using dichloromethane: diethyl ether (99: 1 → 90: 10) as eluent (0.619 g, 74%).
¹ Hn.mr (CDCl ₃ ) δ1.72 (d, 3H, J = 6.9Hz, CH ₃ ), 4.06 (s, 3H, OCH ₃ ), 4.90 (m, 1H, CH), 5.75 (br s, 1H , NH), 6.98 (d, 1H, J = 8.1 Hz, ArH), 7.26-7.46 (m, 7H, Ar-H), 7.97 (s, 1H, Pilaz-H), 8.20 (s, 1H, Pilaz- H).

6-Chloro-N-[(1R) -1- (3-methoxyphenyl) ethyl] pyrazin-2-amine

In a similar procedure as Example 1, the product was obtained by reaction of R-α-methylbenzylamine (1.Og, 6.6 mmol) with 2,6-dichloropyrazine (0.440 g, 2.95 mmol) (517 mg, 67 %).
¹ Hn.mr (CDCl ₃ ) δ1.59 (d, J = 6.9Hz, 3H, CH ₃ ), 3,81 (s, 3H, OCH ₃ ), 4.87 (m, 1H, CH), 5.47 (br s , 1H, NH), 6.79-7.30 (m, 4H, Ar-H), 7.66 (s, 1H, Pyraz-H), 7.79 (s, 1H, Pyraz-H).

2-Methoxy-4- (6-{[(1R) -1- (3-methoxyphenyl) ethyl] amino} pyrazin-2-yl) phenol

In a similar procedure as in Example 2, 2- (R-α-methyl-3-methoxy-benzylamino) -6-chloro-pyrazine (137-2 mg, 0.52 mmol) and 2-methoxy-4- (4,4 , 5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl) phenol (143 mg, 0.57 mmol) gave the product (32 mg, 18%).
¹ Hn.mr (CDCl ₃ ) δ1.61 (d, J = 6.6Hz, 3H, CH3), 3.79 (s, 3H, OCH ₃ ), 3.94 (s, 3H, OCH ₃ ), 4.94 (m, 1H, CH), 5.02 (d, J = 6Hz, 1H, NH), 6.04 (br s, 1H, OH), 6.77-7.48 (m, 7H, Ar-H), 7.69 (s, 1H, Pyraz-H), 8.23 (s, 1H, Pilaz-H).
m / z (ES) 352 ( M + + H).

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

In the same manner as in Example 1, reaction of R-α-methylbenzylamine (1.0 g, 6.6 mmol) with 2,6-dichloropyrazine (0.4355 g, 2.92 mmol) gave the product (0.72 g, 93 %).
¹ Hn.mr (CDCl ₃ ) δ1.56 (d, 3H, J = 6.9Hz, CH ₃ ), 3.80 (s, 3H, OCH ₃ ), 4.84 (m, 1H, CH), 5.25 (br s, 1H , NH), 6.88 (AA'XX ', 2H, Ar-H), 7.28 (AA'XX', 2H, Ar-H), 7.64 (s, 1H, Pilaz-H), 7.78 (s, 1H, Pilaz -H).

2-Methoxy-4- (6-{[(1R) -1- (4-methoxyphenyl) ethyl] amino} pyrazin-2-yl) phenol

In a similar procedure as in Example 2, 2- (R-α-methyl-4-methoxybenzylamino) -6-chloro-pyrazine (127.1 mg, 0.48 mol) and 2-methoxy-4- (4,4,5 , 5-Tetramethyl-1,3,2-dioxaborolan-2-yl) phenol (145 mg, 0.58 mmol) gave the product (59.5 mg, 35%).
¹ Hn.mr (CDCl ₃ ) δ1.59 (d, 3H, J = 6.6Hz, CH ₃ ), 3.79 (s, 3H, OCH ₃ ), 3.95 (s, 3H, OCH ₃ ), 4.97 (m, 2H , CH and NH), 5.95 (br s, 1H, OH), 6.87 (AA'XX ', 2H, ArH), 6.97 (d, 1H, J = 8.1 Hz, ArH), 7.32 (AA'XX', 2H , Ar-H), 7.46 (m, 2H, ArH), 7.66 (s, 1H, Pilaz-H), 8.22 (s, 1H, Pilaz-H).
m / z (ES) 352 ( M + + H).

6-Chloro-N-[(1R) -1,2,3,4-tetrahydronaphthalen-1-yl] pyrazin-2-amine

In a similar procedure as in Example 1, by reaction of (1R) -1,2,3,4-tetrahydronaphthalen-1-amine (441 mg, 3.0 mmol) with 2,6-dichloropyrazine (0.4055 g, 2.72 mmol). The product was obtained (521 mg, 74%).
¹ Hn.mr (CDCl ₃ ) δ1.89 (m, 2H, CH ₂ CH ₂ Ar), 1.97 (m, 1H, H-CHCH ₂ CH ₂ Ar), 2.08 (m, 1H, HC-H-CH ₂ CH ₂ Ar), 2.83 (m, 2H, CH ₂ Ar), 4.94 (br s, 1H, NH), 5.15 (m, 1H, CH), 7.12 to 7.31 (m, 4H, Ar-H), 7.76 ( s, 1H, pyraz-H), 7.81 (s, 1H, pyraz-H).

2-methoxy-4- {6-[(1R) -1,2,3,4-tetrahydronaphthalen-1-ylamino] pyrazin-2-yl} phenol

In a similar procedure as Example 2, 6-chloro-N-[(1R) -1,2,3,4-tetrahydronaphthalen-1-yl] pyrazin-2-amine (139 mg, 0.536 mmol) and 2-methoxy Reaction with -4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenol (147 mg, 0.59 mmol) gave the product (87 mg, 47%).
¹ Hn.mr (CDCl ₃ ) δ1.91 (m, 2H, C H ₂ CH ₂ Ar), 2.09 (m, 2H, C H ₂ CH ₂ CH ₂ Ar), 2.85 (m, 2H, CH ₂ Ar) , 3.96 (s, 3H, OCH ₃ ), 4.87 (d, J = 7.8Hz, 1H, NH), 5.28 (m, 1H, CH), 6.04 (br s, 1H, OH), 6.98-7.73 (m, 7H, Ar-H), 7.79 (s, 1H, Pyraz-H), 8.26 (s, 1H, Pyraz-H).
m / z (ES) 348 ( M + + H).

6-Chloro-N-[(1R) -2,3-dihydro-1H-inden-1-yl] pyrazin-2-amine

Reaction of (1R) -2,3-dihydro-1H-inden-1-ylamine (1.Og, 7.6 mmol) with 2,6-dichloropyrazine (0.452 g, 3.04 mmol) in the same procedure as in Example 1. Gave the product (673.8 mg, 90%).
¹ Hn.mr (CDCl ₃ ) δ1.91 (m, 1H, H -CHCH ₂ Ar), 2.68 (m, 1H, HC- H -CHCH ₂ Ar), 3.00 (m, 2H, CH ₂ Ar), 5.03 (br s, 1H, NH), 5.45 (m, 1H, CH), 7.18 to 7.33 (m, 4H, Ar-H), 7.82 (br s, 2H, 2x pyraz-H).

4- {6-[(1R) -2,3-Dihydro-1H-inden-1-ylamino] pyrazin-2-yl} -2-methoxyphenol

In a similar procedure as in Example 2, 6-chloro-N-[(1R) -2,3-dihydro-1H-inden-1-yl] pyrazin-2-amine (136.8 mg, 0.56 mmol) and 2-methoxy Reaction with 4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenol (153 mg, X 0.61 mmol) gave the product (130 mg, 70%) .
¹ Hn.mr (CDCl ₃ ) δ2.00 (m, 1H, HC- H -CH ₂ Ar), 2.71 (m, 1H, H -CHCH ₂ Ar), 3.01 (m, 2H, CH ₂ Ar), 3.96 (s, 3H, OCH ₃ ), 4.90 (d, J = 7.8Hz, 1H, NH), 5.57 (m, 1H, CH), 6.06 (br s, 1H, OH), 6.98 to 7.82 (m, 7H, Ar-H), 7.85 (s , 1H, Pirazu -H), 8.29 (s, 1H , Pirazu -H); m / z (ES ) 334 (M + + H).

6-Chloro-N-[(1R) -1- (4-methylphenyl) ethyl] pyrazin-2-amine

The product was obtained by reaction of α- (R) -4-dimethylbenzylamine (250 mg, 1.85 mmol) with 2,6-dichloropyrazine (0.251 g, 1.67 mmol) in a similar procedure as Example 1. mg, 48%).
¹ Hn.mr (CDCl ₃ ) δ1.56 (d, 3H, J = 6.9Hz, CH ₃ ), 2.33 (s, 3H, CH ₃ ), 4.84 (m, 1H, CH), 5.05 (br s, 1H , NH), 7.15 (AA'XX ', 2H, Ar-H), 7.24 (AA'XX', 2H, Ar-H), 7.60 (s, 1H, Pilaz-H), 7.78 (s, 1H, Pilaz -H).

2-Methoxy-4- (6-{[(1R) -1- (4-methylphenyl) ethyl] amino} pyrazin-2-yl) phenol

In a similar procedure as in Example 2, 6-chloro-N-[(1R) -1- (4-methylphenyl) ethyl] pyrazin-2-amine (56.8 mg, 0.229 mmol) and 2-methoxy-4- ( Reaction of 4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenol (63 mg, 0.25 mmol) gave the product (5 mg, 6%).
¹ Hn.mr (CDCl ₃ ) δ 1.60 (d, 3H, J = 6.6Hz, CH ₃ ), 2.33 (s, 3H, CH ₃ ), 3.95 (s, 3H, OCH ₃ ), 4.96 (m, 2H , CH and NH), 5.59 (br s, 1H, OH), 6.97 (d, 1H, J = 8.4Hz, ArH), 7.14 (AA'XX ', 2H, ArH), 7.30 (AA'XX', 2H , Ar-H), 7.42-7.48 (m, 2H, Ar-H), 7.67 (s, 1H, pyraz-H), 8.62 (s, 1H, pyraz-H).
m / z (ES) 336 ( M + + H).

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

In a similar procedure to Example 1, the product was obtained by reaction of S-α-methylbenzylamine (568.8 mg, 4.72 mmol) with 2,6-dichloropyrazine (0.6388 g, 4.29 mmol) (821 mg, 82% ).
¹ Hn.mr (CDCl ₃ ) δ1.58 (d, J = 6.6Hz, 3H, CH ₃ ), 4.88 (m, 1H, CH), 5.07 (d, 1H, NH), 7.24-7.36 (m, 5H , Ar-H), 7.61 (s, 1H, Pyraz-H), 7.79 (s, 1H, Pyraz-H).

2-Methoxy-4- (6-{[(1S) -1-phenylethyl] amino} pyrazin-2-yl) phenol

In a similar procedure as in Example 2, 6-chloro-N-[(1S) -1-phenylethyl] pyrazin-2-amine (717.3 mg, 3.07 mmol) and 2-methoxy-4- (4,4,5 , 5-Tetramethyl-1,3,2-dioxaborolan-2-yl) phenol (845 mg, 3.38 mmol) gave the product (689 mg, 70%).
¹ Hn.mr (CDCl ₃ ) δ1.63 (d, 3H, J = 6.6Hz, CH ₃ ), 3.95 (s, 3H, OCH ₃ ), 4.99 (m, 2H, CH + NH), 5.74 (br s , 1H, OH), 6.97 (d, 1H, J = 8.1 Hz, Ar-H), 7.24-7.46 (m, 7H, Ar-H), 7.69 (s, 1H, Pyraz-H), 8.23 (s, 1H, Pilaz-H).

6-Chloro-N-[(1S) -1-phenylpropyl] pyrazin-2-amine

In a similar procedure as Example 1, the product was obtained by reaction of S-α-ethylbenzylamine (558 mg, 4.21 mmol with 2,6-dichloropyrazine (570 mg, 3.82 mmol) (655 mg, 73%).
¹ Hn.mr (CDCl ₃ ) δ0.96 (t, 3H, CH ₃ ), 1.90 (m, 2H, CH ₂ ), 4.59 (m, 1H, CH), 5.12 (d, 1H, NH), 7.24- 7.37 (m, 5H, Ar-H), 7.60 (s, 1H, Pyraz-H), 7.78 (s, 1H, Pyraz-H).

2-Methoxy-4- (6-{[(1S) -1-phenylpropyl] amino} pyrazin-2-yl) phenol

In a similar procedure to Example 2, 6-chloro-N-[(1S) -1-phenylpropyl] pyrazin-2-amine (135 mg, 0.57 mmol) and 2-methoxy-4- (4,4,5, Reaction of 5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenol (158 mg, 0.63 mmol) gave the product (87 mg, 45%).
¹ Hn.mr (CDCl ₃ ) δ1.00 (t, 3H, J = 7.5Hz, CH ₃ ), 1.94 (dq, 2H, J = 7.5Hz, CH ₂ ), 3.96 (s, 3H, OCH ₃ ), 4.71 (dt, 1H, J = 7.5Hz, CH), 5.00 (br s, 1H, NH), 5.75 (br s, 1H, OH), 6.97 (d, 1H, J = 8.4Hz, ArH), 7.24 ( m, 1H, ArH), 7.30-7.47 (m, 6H, ArH), 7.67 (s, 1H, Pilaz-H), 8.21 (s, 1H, Pilaz-H).
m / z (ES) 336 ( M + + H).

(2R) -2-[(6-Chloropyrazin-2-yl) amino] -2-phenylethanol

In a similar procedure to Example 1, the product was obtained by reaction of (2R) -2-amino-2-phenylethanol (420 mg, 3.1 mmol) and 2,6-dichloropyrazine (415 mg, 2.79 mmol) (261 mg 37%).
¹ Hn.mr (CDCl ₃ ) δ0.91 (d, 1H, OH), 3.97 (m, 2H, CH ₂ ), 4.94 (m, 1H, CH), 5.56 (d, 1H, NH), 7.30 to 7.44 (m, 5H, Ar-H), 7.70 (s, 1H, Pyraz-H), 7.81 (s, 1H, Pyraz-H).

4- (6-{[(1R) -2-hydroxy-1-phenylethyl] amino} pyrazin-2-yl) -2-methoxyphenol

In the same manner as in Example 2, (2R) -2-[(6-chloropyrazin-2-yl) amino] -2-phenylethanol (137 mg, 0.55 mmol) and 2-methoxy-4- (4,4 , 5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl) phenol (151 mg, 0.60 mmol) gave the product (70 mg, 38%).
¹ Hn.mr (CDCl ₃ ) δ1.16 (s, 1H, OH), 382 (s, 3H, OCH ₃ ), 3.90 (m, 2H, CH ₂ ), 4.92 (m, 1H, CH), 5.50 ( br s, 1H, NH), 6.87 (d, 1H, J = 9Hz, ArH), 7.15-7.66 (m, 8H, ArH), 8.14 (s, 1H, Pyraz-H).
m / z (ES) 338 ( M + + H).

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

The product was obtained by reaction of 4-methoxy-α- (S) -methylbenzylamine (0.70 mg, 4.6 mmol) and 2,6-dichloropyrazine (0.6259 g, 4.20 mmol) in the same procedure as Example 1. (873 mg, 79%).
¹ Hn.mr (CDCl ₃ ) δ1.56 (d, 3H, J = 6.9Hz, CH ₃ ), 3.80 (s, 3H, OCH ₃ ), 4.84 (m, 1H, CH), 5.01 (br s, 1H , NH), 6.88 (AA'XX ', 2H, Ar-H), 7.28 (AA'XX', 2H, Ar-H), 7.61 (s, 1H, Pilaz-H), 7.79 (s, 1H, Pilaz -H).

2-Methoxy-4- (6-{[(1S) -1- (4-methoxyphenyl) ethyl] amino} pyrazin-2-yl) phenol

In a similar procedure as in Example 2, 6-chloro-N-[(1S) -1- (4-methoxyphenyl) ethyl] pyrazin-2-amine (149.4 mg, 0.57 mmol) and 2-methoxy-4- ( Reaction of 4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenol (156 mg, 0.62 mmol) gave the product (71 mg, 35%).
¹ Hn.mr (CDCl ₃ ) δ1.59 (d, 3H, J = 6.6Hz, CH ₃ ), 3.79 (s, 3H, OCH ₃ ), 3.95 (s, 3H, OCH ₃ ), 4.95 (m, 2H CH and NH), 5.98 (br s, 1H, OH), 6.87 (AA'XX ', 2H, ArH), 6.97 (d, 1H, J = 8.1 Hz, ArH), 7.33 (AA'XX', 2H, Ar-H), 7.43-7.49 (m, 2H, ArH), 7.66. (S, 1H, pyraz-H), 8.22 (s, 1H, pyraz-H).
m / z (ES) 352 ( M + + H).

6-Chloro-N- (pyridin-3-ylmethyl) pyrazin-2-amine

A mixture of 2,6-dichloropyrazine (0.671 mmol) and 3-picolylamine (2.014 mmol) in xylene (25 ml) was refluxed overnight. After evaporation of the solvent, the resulting residue was suspended in CH ₂ Cl ₂ (100 ml) and water (100 ml). The organic layer was separated and the aqueous layer was extracted with CH ₂ Cl ₂ (3 × 50 ml). The combined organic extracts were washed with brine (1 × 100 ml), dried (Na ₂ SO ₄ ) and the solvent removed in vacuo. The residue was then purified by column chromatography eluting with a hexane: ethyl acetate gradient mixture to give the desired product (93%).
¹ Hn.mr (CDCl ₃ ) δ4.61. (D, J = 5.7Hz, 2H, NCH ₂ ), 5.29 (s, broad, 1H, NH), 7.27 (m, 1H, pyrido-H), 7.30 ( m, 1H, pyrido-H), 7.71 (d, J = 7.8Hz, 1H, pyrido-H), 7.85 (s, 1H, pyrido-H), 8.54 (s, broad, 1H, pyraz-H), 8.61 (s, broad, 1H, Pilaz-H).

2-Methoxy-4- {6-[(pyridin-3-ylmethyl) amino] pyrazin-2-yl} phenol

6-Chloro-N- (pyridin-3-ylmethyl) pyrazin-2-amine (49 mg, 0.22 mmol), 2-methoxy-4- (4,4,5,5-tetramethyl-1 in toluene (10 ml) , 3,2-dioxaborolan-2-yl) phenol (52 mg, 0.20 mmol), (PPh ₃ ) ₄ Pd (23 mg, 0.020 mmol) and Na ₂ CO ₃ solution (0.22 mmol in 2M solution) under reflux. Heated overnight. After removing the solvent, the residue was dissolved in CH ₂ Cl ₂ (150 ml), dried (Na ₂ SO ₄ ) and filtered to remove CH ₂ Cl ₂ under vacuum. The residue was purified by column chromatography eluting with a n-hexane: ethyl acetate gradient mixture to give the desired product (62 mg, 75%).
¹ Hn.mr (CDCl ₃ ) δ3.94 (br s, 3H, CH ₃ ), 4.70 (d, 2H, J = 6.0 Hz, CH ₂ ), 5.01 (br s, 1H, NH), 5.83 (br s , 1H, OH), 6.98 (d, 1H, J = 8.7Hz, ArH), 7.29 (m, 1H, Ar-H), 7.48 (m, 2H, ArH), 7.73 (br d, 1H, J = 8.7 Hz, ArH), 7.83 (s, 1H, Pilaz-H), 8.30 (s, 1H, Pilaz-H), 8.54 (m, 1H, ArH), 8.70 (s, 1H, ArH).
m / z (ES) 309 ( M + + H).

N-Benzyl-6-chloro-N-methylpyrazin-2-amine

In the same manner as in Example 21, the product was obtained by reaction of N-methylbenzylamine with 2,6-dichloropyrazine (70%).
¹ Hn.mr (CDCl ₃ ) δ3.11 (s, 3H, NCH ₃ ), 4.78 (s, 2H, ArCH ₂ N), 7.24 (d, J = 6.9Hz, 2H, ArH), 7.37 to 7.28 (m , 4H, ArH), 7.81 (s, 1H, Pyraz-H), 7.88 (s, 1H, Pyraz-H).

4- {6- [Benzyl (methyl) amino] pyrazin-2-yl} -2-methoxyphenol

In the same procedure as in Example 22, N-benzyl-6-chloro-N-methylpyrazin-2-amine and 2-methoxy-4- (4,4,5,5-tetramethyl-1,3,2- The product was obtained by reaction of (dioxaborolan-2-yl) phenol (51%).
¹ Hn.mr (CDCl ₃ ) δ3.20 (br s, 3H, NCH ₃ ), 3.91 (s, 3H, OCH ₃ ), 4.89 (s, 2H, CH ₂ ), 5.83 (br s, 1H, OH) , 6.98 (d, 1H, J = 8.1Hz, ArH), 7.27 (m, 5H, Ar-H), 7.53 (m, 2H, ArH), 7.93 (s, 1H, Pilaz-H), 8.28 (s, 1H, Pilaz-H).
m / z (ES) 322 ( M + + H).

2- (6-Chloropyrazin-2-yl) -1,2,3,4-tetrahydroisoquinoline

In a similar procedure to Example 21, the product was obtained by reaction of tetrahydroisoquinoline with 2,6-dichloropyrazine (95%).
¹ Hn.mr (CDCl ₃ ) δ2.99 (t, J = 5.7Hz, 2H, ArCH ₂ CH ₂ N), 3.86 (t, J = 5.7Hz, 2H, ArCH ₂ CH ₂ N), 4.73 (s, _{2H ArCH 2 N), 7.27~7.19 (} m, 4H, ArH), 7.82 (s, 1H, Pirazu -H), 8.01 (s, 1H , Pirazu -H).

4- [6- (3,4-Dihydroisoquinolin-2 (1H) -yl) pyrazin-2-yl] -2-methoxyphenol

In the same procedure as in Example 22, 2- (6-chloropyrazin-2-yl) -1,2,3,4-tetrahydroisoquinoline and 2-methoxy-4- (4,4,5,5-tetramethyl The product was obtained by reaction of -1,3,2-dioxaborolan-2-yl) phenol (44%).
¹ Hn.mr (CDCl ₃ ) δ3.03 (m, 2H, CH ₂ ), 3.96 (m, 2H, CH ₂ ), 4.01 (s, 3H, OCH ₃ ), 4.83 (s, 2H, CH ₂ ), 5.87 (br s, 1H, OH), 7.04 (m, 1H, ArH), 7.21 (m, 3H, Ar-H), 7.56 (m, 2H, ArH), 8.07 (br s, 1H, Pilaz-H) 8.28 (br s, 1H, Pilaz-H).
m / z (ES) 374 (M + H + K) ⁺ .

6-Chloro-N- (3,4-dichlorobenzyl) pyrazin-2-amine

In a similar procedure as Example 21, the product was obtained by reaction of 3,4-dichlorobenzylamine and 2,6-dichloropyrazine (89%).
¹ Hn.mr (CDCl ₃ ) δ4.55 (d, J = 6Hz, 2H, NCH ₂ ), 5.01 (s, broad, 1H, NH), 7.18 (dd, J = 2.1, 2.1Hz, 1H, ArH) 7.20 (dd, J = 2.1, 2.1 Hz, 1H, ArH), 7.45-7.41 (m, 2H, ArH), 7.77 (s, 1H, Pilaz-H), 7.86 (s, 1H, Pilaz-H).

4- {6-[(3,4-Dichlorobenzyl) amino] pyrazin-2-yl} -2-methoxyphenol

In the same manner as in Example 22, 6-chloro-N- (3,4-dichlorobenzyl) pyrazin-2-amine and 2-methoxy-4- (4,4,5,5-tetramethyl-1,3 , 2-Dioxaborolan-2-yl) phenol gave the product (57%).
¹ Hn.mr (CDCl ₃ ) δ3.93 (s, 3H, CH ₃ ), 4.62 (d, 2H, J = 6.0 Hz, CH ₂ ), 5.01 (br s, 1H, NH), 5.79 (br s, 1H, OH), 6.98 (d, 1H, J = 8.7Hz, ArH), 7.45 (m, 4H, ArH), 7.68 (m, 1H, ArH), 7.95 (s, 1H, Pilaz-H), 6.29 ( s, 1H, Pilaz-H).
m / z (ES) 376 (M ⁺ ).

6-Chloro-N- (3,5-dimethoxybenzyl) pyrazin-2-amine

In a similar procedure as Example 21, the product was obtained by reaction of 3,5-dimethoxybenzylamine and 2,6-dichloropyrazine (91%).
¹ Hn.mr (CDCl ₃ ) δ3.78 (s, 6H, OCH ₃ ), 4.49 (d, J = 5.4Hz, 2H, NCH ₂ ), 5.12 (br s, 1H, NH), 6.39 (t, J = 2.1 Hz, 1H, ArH), 6.50 (d, J = 2.1 Hz, 2H, ArH), 7.75 (s, 1H, Pilaz-H), 7.82 (s, 1H, Pilaz-H).

4- {6-[(3,5-Dimethoxybenzyl) amino] pyrazin-2-yl} -2-methoxyphenol

In the same manner as in Example 22, 6-chloro-N- (3,5-dimethoxybenzyl) pyrazin-2-amine and 2-methoxy-4- (4,4,5,5-tetramethyl-1,3 , 2-Dioxaborolan-2-yl) phenol gave the product (88%).
¹ Hn.mr (as mesylate salt) (d6-DMSO) δ 2.39 (s, 3H, CH ₃ SO ₃ ), 3.69 (s, 6H, OCH ₃ ), 3.80 (s, 3H, OCH ₃ ), 4.51 ( s, 2H, CH ₂ ), 6.36 (d, 1H, J = 2.1Hz, ArH), 6.57 (d, 2H, J = 2.1Hz, ArH), 6.83 (d, 1H, J = 8.1Hz, ArH), 7.54 (m, 2H, ArH), 7.87 (s, 1H, Pyraz-H), 8.29 (s, 1H, Pyraz-H).
m / z (ES) 368 ( M + + H).

6-Chloro-N- (2-furylmethyl) pyrazin-2-amine

The product was obtained by reaction of furfurylamine and 2,6-dichloropyrazine in the same procedure as Example 21 (98%).
¹ Hn.mr (CDCl ₃ ) δ4.57 (d, J = 5.7Hz, 2H, NCH ₂ ), 5.01 (s, broad, 1H, NH), 6.30 (d, J = 3.3Hz, 1H, furanyl-H ), 6.35-6.33 (m, 2H, furanyl-H), 7.81 (s, 1H, pyraz-H), 7.84 (s, 1H, pyraz-H).

4- {6-[(2-Furylmethyl) amino] pyrazin-2-yl} -2-methoxyphenol

In the same manner as in Example 2, 6-chloro-N- (2-furylmethyl) pyrazin-2-amine and 2-methoxy-4- (4,4,5,5-tetramethyl-1,3,2 The product was obtained by reaction of -dioxaborolan-2-yl) phenol (92%).
¹ Hn.mr (as mesylate salt) (d6-DMSO) δ 2.38 (s, 3H, CH ₃ SO ₃ ), 3.84 (s, 3H, OCH ₃ ), 4.59 (s, 2H, CH ₂ ), 6.33 ( s, 1H, ArH), 6.38 (s, 1H, ArH), 6.87 (d, 2H, J = 8.1Hz, ArH), 7.52 (m, 3H, ArH), 7.86 (br s, 1H, Pilaz-H) 8.30 (br s, 1H, Pilaz-H).
m / z (ES) 298 ( M + + H).

2-Chloro-4- (6-{[(1S) -1-phenylethyl] amino} pyrazin-2-yl) phenol

4-Bromo-2-chlorophenol (246 mg, 1.18 mmol), bis (pinacolato) diboron (332 mg, 1.3 mmol), [1,1′-bis (diphenylphosphino) ferrocene] palladium II in dry methanol (4 mL) ) A solution of chloride (26 mg, 0.035 mmol) and potassium acetate (222 mg, 2.26 mmol) was degassed and heated at 65 ° C. for 24 hours. After cooling, the reaction mixture was diluted with ether and filtered through Celite. The solvent was removed under reduced pressure and the residue was chromatographed using dichloromethane-hexane (90:10) as eluent. Next, under the same conditions as in Example 2, the obtained boronate (50 mg) was combined with 6-chloro-N-[(1S) -1-phenylethylpyrazin-2-amine (50 mg, 0.2 mmol). The reaction was chromatographed eluting with dichloromethane-ether (90:10) to give the pure product (44 mg, 68%).
¹ Hn.mr δδ1.59 (d, 3H, J = 6.0Hz, CH ₃ ), 4.88 (m, 1H, CH), 5.08 (br s, 1H, NH), 5.69 (br s, 1H NH), 7.07 (d, 1H, J = 8.5Hz, ArH), 7.27-7.36 (m, 6H, Ar-H), 7.48 (d, 1H, J = 1.5Hz, ArH), 7.52 (s, 1H, Pilaz-H) 7.80 (s, 1H, Pilaz-H).

6- (4-Aminophenyl) -N-[(1S) -1-phenylethyl] pyrazin-2-amine

6-chloro-N-[(1S) -1-phenylethyl] pyrazin-2-amine (1.10 g, 4.71 mmol), 4- (4,4,5,5-tetramethyl-1 in toluene (20 ml) , 3,2-dioxaborolan-2-yl) aniline (1.10 g, 5.02 mmol), (PPh ₃ ) ₄ Pd (580 mg, 0.5 mmol) and Na ₂ CO ₃ solution (2.6 ml, 2M solution) were refluxed. Heated under for 40 hours. After cooling, the mixture was diluted with water (30 mL) and the product was extracted with ethyl acetate (3 × 40 ml). The combined organic layers were washed with brine (30 ml), dried (Na ₂ SO ₄ ) and the solvent removed in vacuo. The residue was purified by column chromatography eluting with hexane-ethyl acetate (2: 3) to give the desired product from the polar fraction (0.86 g, 63%).
¹ Hn.mr (CDCl ₃ ) δ1.57 (d, 3H, J = 6.2Hz, CH ₃ ), 3.80 (br s, 2H, NH ₂ ), 4.92 to 4.99 (m 2H, CH + NH), 6.69 ( d, 2H, J = 6.7Hz, ArH), 7.21-7.40 (m, 5H, ArH), 7.72 (d, 2H, J = 6.7Hz, ArH), 7.57 (s, 1H, Pilaz-H), 8.16 ( s, 1H, Pilaz-H).
m / z (ES) 291 (M ⁺ + H)

6- [4- (Ethylamino) phenyl] -N-[(1S) -1-phenylethyl] pyrazin-2-amine

A solution of amide (40 mg, 0.12 mmol) in THF (5 mL) was treated with solid LiAlH ₄ (38 mg, 1 mmol) and the mixture was stirred at room temperature for 4 h. The reaction was then treated sequentially with H ₂ O (5 ml), 2M NaOH (5 ml) and water (10 ml), then the resulting suspension was extracted with ethyl acetate (3 × 15 ml). The combined organic layers were dried (Na ₂ SO ₄ ) and concentrated under reduced pressure. The resulting crude product was then purified by column chromatography using ethyl acetate-hexane (3: 1) as eluent to give the product as a colorless solid (22 mg, 58%).
¹ Hn.mr (CDCl ₃ ) δ1.25 (t, 3H, J = 7.0Hz, CH ₃ ), 1.57 (d, 3H, J = 6.8Hz, CH ₃ ), 3.18 (q, 2H, J = 7.0Hz , CH ₂ ), 3.74 (br s. 1H, NH), 4.85 to 5.01 (m, 2H, CH + NH), 6.59 to 6.63 (m, 2H, ArH), 7.21 to 7.40 (m, 5H, ArH), 7.54 (s, 1H, Pyraz-H), 7.73-7.77 (m, 2H, ArH), 8.16 (s, 1H, Pyraz-H).
m / z (ES) 319 (M ⁺ + H)

N- [4- (6-{[(1S) -1-phenylethyl] amino} pyrazin-2-yl) phenyl] methanesulfonamide

To a stirred solution of 6- (4-aminophenyl) -N-[(1S) -1-phenylethyl] pyrazin-2-amine (58 mg, 0.2 mmol) in dry THF (3 ml) triethylamine (70 μL, 0.5 mmol) Was added. The solution was cooled to 0 ° C. and methanesulfonyl chloride (18.6 μL, 0.24 mmol) was added dropwise. The mixture was warmed to room temperature, stirred overnight and then diluted with water (15 ml). The product was extracted into ethyl acetate (2 × 15 mL) and the combined extracts were washed with 10% aqueous Na ₂ CO ₃ solution and brine, then dried (Na ₂ SO ₄ ). The solvent was removed under reduced pressure and the product was chromatographed eluting with ethyl acetate-hexane (3: 2) to give the product as a pale yellow solid (54 mg, 73%).
¹ Hn.mr (CDCl ₃ ) δ1.59 (d, 3H, J = 6.2Hz, CH ₃ ), 3.01 (s, 3H, CH ₃ ), 4.96 to 5.01 (m, 2H, CH + NH), 6.52 ( br s, 1H, NHSO ₂ ), 7.22-7.40 (m, 7H, ArH), 7.70 (s, 1H, Pyraz-H), 7.85-7.89 (m, 2H, ArH), 8.20 (s, 1H, Pyraz- H).
m / z (ES) 369 ( M + + H).

N- [4- (6-{[(1S) -1-phenylethyl] amino} pyrazin-2-yl) phenyl] cyclopropanecarboxamide

In a manner similar to that shown in Example 39, 6- (4-aminophenyl) -N-[(1S) -1-phenylethyl] pyrazin-2-amine (58 mg, 0.2 mmol) and cyclopropanecarbonyl chloride (25 mg, 0.24 mmol) was reacted and chromatographically purified using ethyl acetate-hexane (3: 2) to give a highly pure product (46 mg, 64%).
¹ Hn.mr (CDCl ₃ ) δ 0.82 to 0.88 (m, 2H, CH ₂ ), 1.05 to 1.10 (m, 2H, CH ₂ ), 1.49 to 1.60 (m, 4H, CH, CH ₃ ), 4.91 to 4.9 (m, 2H, CH + NH), 7.23-7.40 (m, 5H, ArH), 7.56 (AA'XX ', 2H, ArH), 7.65 (s, 1H, Pyraz-H), 7.85 (AA'XX ', 2H, ArH), 8.21 (s, 1H, Pilaz-H).
m / z (ES) 359 ( M + + H).

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 in one portion and the resulting mixture was stirred at room temperature until the disappearance of residual ketone was exhibited by TLC. The solvent was distilled off under vacuum and the residue was extracted with CH ₂ Cl ₂ (3 × 100 ml) and dried (Na ₂ SO ₄ ). After removing the solvent by filtration, recrystallization from CH ₂ Cl ₂ / n-hexane gave a crude ketoxime.
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 under reflux for 2 hours. . After cooling in ice, ketoxime precipitated and was collected by suction filtration. Recrystallization from CH ₂ Cl ₂ / N-hexane gave the crude product (1.88 g, 86%).
¹ Hn.mr (CDCl ₃ ) δ 2.28 (s, 3H, CH3), 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 at reflux overnight under a dry N ₂ atmosphere. 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 0.5 h, followed by filtration through Celite®. The 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 vacuum gave a high purity 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 hydrochloric acid (50 ml) was gradually added to a mixture of ketoxime (4.85 g, 36 mmol) and Zn powder (12 g) at 0 ° C. with vigorous stirring. When the initial vigorous reaction had ceased, the mixture was heated under reflux until the disappearance of all ketoximes was exhibited by TLC. After cooling to room temperature, the strongly acidic mixture was extracted with CH ₂ Cl ₂ (2 × 75 ml). The reaction mixture was then made strong base 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. This was used in subsequent reactions 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).

screening
Establishment of TEL: JAK cell line
The translation region encompassing nucleotides 1 to 487 of TEL is 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 BamH I site was provided in the 5TEL primer and a Sal I 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 to be generated was generated by PCR using Taq DNA polymerase (Gibco / BRL) and U937 mRNA as template. The SAII site was incorporated into the JAK2 and JAK3 forward primers, the Not I site was incorporated into the JAK2 reverse primer, and the Xba I site was added to the JAK3 reverse primer.

  TEL / Jak2 fusion is a digestion of TELPCR product with BamH I / Sal I, digestion of JAK2 PCR product with Sal I / Not I, followed by mammalian expression digested with BamH I-Not I (pTELJAK2) Produced by binding to the vector pTRE2 (Clontech) and subcloning. For JAK3, the Sal I / Not I cleaved kinase domain PCR product was ligated with a BamH I / Sal I cleaved TEL product followed by ligation to BamH I / Not I cleaved pTRE2 (pTELJAK3).

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

Cell assays were performed as follows:
Cell suspensions were prepared by harvesting cells from media cultures (cells used in this study must later be of logarithmic growth and high viability). Cells were diluted to 1.1 × final concentration (50000 cells / mL to 200,000 cells / mL depending on the cell line) in a reasonable growth vehicle.

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 / ml in PBS) was added and the plate was returned to the incubator for an additional 6 hours. Lysis buffer (100 μL per well, 10% SDS, 0.01N HCl) was added and the plates were stored in the incubator overnight. The plate was then read at 590 nm.

Kinase assays were performed in either a 96 well capture based ELISA assay or a 384 well Optiplates (Packard) using an alpha screen protein tyrosine kinase kit. In both cases, 50 mM HEPES, in the presence of pH7.5,10mM MgCl _2, 150mM NaCl and 10mM~1mM ATP, using PTK domain affinity purified about 1.5 mg. The biotinylated substrate biotin? EGPWLEEEEEAYGWMDF? NH2 (final concentration 5 mM) was used as the substrate. In the ELISA assay, tyrosine phosphorylation was quantified following transfer to an avidin-coated ELISA plate using peroxidase conjugated with anti-phospho-tyrosine antibody PY20. For the alpha screen assay, alpha screen phosphotyrosine acceptor beads were added followed by streptavidin donor beads under soft light. ELISA plates were read with BMG Fluorostar and alpha screen plates were read with Packard Fusion Alpha. Inhibitors were added to the assay 15 minutes prior to the addition of ATP. Inhibitors were added to the DMSO aqueous solution without ever increasing the DMSO concentration above 1%.

Results The activity of a range of compounds is shown in Table 1. Compounds that showed the ability to inhibit 50% of cell proliferation at a concentration of 50 μM (measured under standard conditions, see “Methods”) are indicated by “+”.

  Those skilled in the art will appreciate that many changes 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. Let's be done. Accordingly, the embodiments of the invention are to be considered in all respects only as illustrative and not restrictive.

[参考文献]

Table 1: 2-Amino-6-carba-disubstituted pyrazines and 2-amino- having growth inhibitory activity (> 50%) at 50 μM in transformed cell lines (Tel-Jak2 and Tel-Jak3) 6-carba-disubstituted pyridine

[References]

FIG. 1 is a graph showing dose-response curves for R and S enantiomers of the processing inhibitory activity of representative 2- (α-methylbenzylamino) -pyrazine in Tel-Jak2 transformed cell lines. It is. FIG. 2A shows kinase inhibitory activity of representative 2- (α-methylbenzylamino) -pyrazine. Kinase assays were performed as described in the methods section. CYC10124 (exemplified as compound 141 in Table 1) shows potent inhibitory activity against c-KIT, TIE2 and ABL protein kinases. FIG. 2B shows the kinase inhibitory activity of representative 2- (α-methylbenzylamino) -pyrazine. Kinase assays were performed as described in the methods section. CYC10268 (exemplified as compound 268 in Table 1) shows potent inhibitory activity against c-FMS. FIG. 2C shows the kinase inhibitory activity of representative 2- (α-methylbenzylamino) -pyrazine. Kinase assays were performed as described in the methods section. CYC10119 (exemplified as compound 136 in Table 1) shows potent inhibitory activity against JAK2 and c-KIT.

Claims (24)

Compounds of the following general formula

(Where
R1 is H, C _1-4 alkyl,
Q is a bond or C _1-4 alkyl;
A is halogen, C _{1 to 4 alkyl, CH 2 F, CHF 2,} CF 3, CN, aryl, hetaryl, OCF _3, OC _{1 to 4} alkyl, OC _{2 to 5} alkyl NR @ 4 R @ 5, O aryl, O hetaryl, CO ₂ R4, CONR4R5, nitro, optionally substituted with NR @ 4 R @ 5, C _{1 to 4} alkyl _NR4R5, NR6C 1~4 alkyl NR4R5, NR4COR5, NR6CONR4R5, 0~3 substituents selected from NR4SO ₂ R5 independently aryl, hetaryl, R4, R5 are each independently H, C _{1 to 4} alkyl, C _{1 to 4} alkyl cycloalkyl, C _{1 to 4} alkyl cycloalkyl heta Le kills, aryl, hetaryl, C _{1 to 4} alkyl aryl, C _1-4 alkylhetaryl, or combine to form an optionally substituted 3- to 8-membered ring optionally containing an atom selected from O, S, NR7. can be, R6 is selected from H, C _{1 to 4} alkyl, R7 is H, C _{1 to 4} alkyl, aryl, het Lumpur, C _{1 to 4} alkyl aryl, is selected from C _{1 to 4} alkyl hetaryl,
R2 is halogen, C _{1 to 4} alkyl, OH, OC _{1 to 4 alkyl, CH 2 F, CHF 2,} CF 3, OCF 3, CN, C 1~4 alkyl NR8R9, OC _{1 to 4} alkyl NR8R9, CO ₂ R8 , CONR8R9, NR8R9, NR8COR9, NR10CONR8R9 , NR8SO 0-2 substituents selected from ₂ R9 independently, R8, R9 are each independently, H, C _{1 to 4} alkyl, C _{1 to 4} alkyl cycloalkyl, C _{1 to 4} alkyl cycloalkyl heta Le kills, aryl, hetaryl, C _{1 to 4} alkyl aryl, C _{1 to 4} alkyl hetaryl, or in combination, optionally O, and atom selected from S, NR11 containing the selection, it is possible to form a 3-membered ring to 8-membered ring which is optionally substituted, R10 is selected H, C _{1 to 4} alkyl, aryl or hetaryl, R11 is H, C _{1 to 4} alkyl is selected aryl, hetaryl, C _{1 to 4} alkyl aryl, C _{1 to 4} alkyl hetaryl,
Y is halogen, OH, NR12R13, NR12COR13, NR12CONR13 , N12SO 2 R13, R12 and R13 are each _{independently, H, CH 2 F, CHF} 2, CF 3, CN, C 1~4 alkyl, _{C. 1 to 4} alkyl cycloalkyl, C _{1 to 4} alkyl cycloalkyl heta Le kills, or bonded to, O, S, containing optionally an atom selected from NR14, 3-membered ring 6 an optionally substituted Can form a member ring, R14 is selected from H, C _1-4 alkyl;
n = 0-4,
W is H, C _{1 to 4} alkyl is selected from C _{2 to 6} alkenyl, C _{1 to 4} alkyl or C _{2 to 6} alkenyl C _{1 to 4} alkyl, OH, OC _{1 to 4} alkyl, optionally with NR15R16 may be substituted, the R15 and R16, each independently, H, a C _{1 to 4} alkyl, C _{1 to 4} alkyl cycloalkyl, C _{1 to 4} alkyl cycloalkyl heta Le kills, or bonded to, O, S, containing optionally an atom selected from NR17, can form a 3-membered ring to 8-membered ring which is optionally substituted, R17 is selected from H, C _{1 to 4} alkyl,
When Y is OH or NHCOCH _3, R2 is one to two substituents, when Y is absent is a NH ₂ R2, Y is in the para position)
Alternatively, a pharmaceutically acceptable salt, hydrate, solvate, crystalline form or diastereomer thereof. Compounds of general formula II

(Where
R1 is H, C _1-4 alkyl,
Q is a bond or C _1-4 alkyl;
A is halogen, C _{1 to 4 alkyl, CH 2 F, CHF 2,} CF 3, CN, aryl, hetaryl, OCF _3, OC _{1 to 4} alkyl, OC _{2 to 5} alkyl NR @ 4 R @ 5, O aryl, O hetaryl, CO _{2 R4, CONR4R5, NR4R5, C} 1~4 alkyl _NR4R5, NR6C 1~4 alkyl NR4R5, NR4COR5, NR6CONR4R5, aryl optionally substituted with 0-3 substituents selected from NR4SO ₂ R5 independently hetaryl, R4, R5 are each independently H, C _{1 to 4} alkyl, C _{1 to 4} alkyl cycloalkyl, C _{1 to 4} alkyl cycloalkyl heta Le kills, aryl, hetaryl, C _{1 to 4} alkyl aryl, C _{1 ~ 4} alkyl hetaryls or can be joined to form an optionally substituted 3- to 8-membered ring optionally containing an atom selected from O, S, NR7 , R6 is selected from H, C _{1 to 4} alkyl, R7 is H, C _{1 to 4} alkyl, aryl, hetaryl, C _1-4 alkylaryl, selected from C _1-4 alkyl hetaryl,
R2 is halogen, C _{1 to 4} alkyl, OH, OC _{1 to 4 alkyl, CH 2 F, CHF 2,} CF 3, OCF 3, CN, C 1~4 alkyl NR8R9, OC _{1 to 4} alkyl NR8R9, CO ₂ R8 , CONR8R9, NR8R9, NR8COR9, NR10CONR8R9 , NR8SO 0-2 substituents selected from ₂ R9 independently, R8, R9 are each independently, H, C _{1 to 4} alkyl, C _{1 to 4} alkyl cycloalkyl, C _{1 to 4} alkyl cycloalkyl heta Le kills, aryl, hetaryl, C _{1 to 4} alkyl aryl, C _{1 to 4} alkyl hetaryl, or in combination, optionally O, and atom selected from S, NR11 containing the selection, it is possible to form a 3-membered ring to 8-membered ring which is optionally substituted, R10 is selected H, C _{1 to 4} alkyl, aryl or hetaryl, R11 is H, C _{1 to 4} alkyl is selected aryl, hetaryl, C _{1 to 4} alkyl aryl, C _{1 to 4} alkyl hetaryl,
Y is halogen, OH, NR12R13, NR12COR13, NR12CONR13 , N12SO 2 R13, R12 and R13 are each _{independently, H, CH 2 F, CHF} 2, CF 3, CN, C 1~4 alkyl, _{C. 1 to 4} alkyl cycloalkyl, C _{1 to 4} alkyl cycloalkyl heta Le kills, or bonded to, O, S, containing optionally an atom selected from NR14, 3-membered ring 6 an optionally substituted Can form a member ring, R14 is selected from H, C _1-4 alkyl;
n = 0-4,
W is H, C _{1 to 4} alkyl is selected from C _{2 to 6} alkenyl, C _{1 to 4} alkyl or C _{2 to 6} alkenyl C _{1 to 4} alkyl, OH, OC _{1 to 4} alkyl, optionally with NR15R16 may be substituted, the R15 and R16, each independently, H, a C _{1 to 4} alkyl, C _{1 to 4} alkyl cycloalkyl, C _{1 to 4} alkyl cycloalkyl heta Le kills, or bonded to, O, S, containing optionally an atom selected from NR17, can form a 3-membered ring to 8-membered ring which is optionally substituted, R17 is selected from H, C _{1 to 4} alkyl,
When Y is OH or NHCOCH _3, R2 is one to two substituents, when Y is absent is a NH ₂ R2, Y is in the para position)
Alternatively, the compound of claim 1 selected from a pharmaceutically acceptable salt, hydrate, solvate, crystalline form or diastereomer thereof. The compound according to claim 1, wherein W is C _1-4 alkyl, and the compound has S chirality at an asymmetric carbon having W.   4. The compound of claim 3, wherein the compound is a mixture of R and S isomers, and the mixture comprises at least 70% S isomers.   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. The compound of claim 4, wherein the compound contains at least 95% S isomer.   5. The compound of claim 4, wherein the compound contains at least 99% S isomer. The compound is

2. The compound of claim 1, selected from the group consisting of:   10. A composition comprising a carrier and at least one compound according to any one of claims 1-9.   10. A method of treating a protein kinase-related condition, wherein the method is a therapeutically effective amount of at least one compound according to any one of claims 1 to 9, or a therapeutically effective amount. 11. A method comprising administering the composition of claim 10.   The pathological condition is EGF, HER2, HER3, HER4, IR, IGF-1R, IRR, PDGFR.α, PDGFR.β, CSFIR, C-Kit, C-fms, Flk-1R, Flk4, KDR / Flk-1, 12. The compound according to claim 11, which is related to a receptor tyrosine kinase selected from the group consisting of Flt-1, FGFR-1R, FGFR-2R, FGFR-3R and FGFR-4R.   A cellular tyrosine kinase 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 12. A compound according to claim 11 concerned.   12. The compound of claim 11, wherein the pathological condition is associated with a tyrosine kinase selected from the group consisting of JAKI, JAK2, JAK3 and TYK2.   The pathological condition is selected from the group consisting of ERK2, c-Jun, p38MAPK, PKA, PKB, PKC, cyclin dependent kinase, CDK1, CDK2, CDK3, CDK4, CDK5, CDK6, CDK7, CDK8, CDK9, CDK10 and CDK11 12. The compound according to claim 11, which is related to serine / threonine kinase.   The pathology is atopic, such as allergic asthma, atopic dermatitis (eczema) and allergic rhinitis; cell-mediated hypersensitivity, such as allergic contact dermatitis and hypersensitivity pneumonia; systemic lupus erythematosus (SLE), rheumatoid arthritis Rheumatic diseases such as juvenile arthritis, Sjogren's syndrome, scleroderma, polymyositis, ankylosing spondylitis, psoriatic arthritis; other Alzheimer's disease; Epstein-Barr virus (EBV), hepatitis B, hepatitis C 12. The method of claim 11, selected from the group consisting of HIV, HTLV1, varicella-zoster virus (VZV), viral diseases such as human papilloma virus (HPV), cancers such as leukemia, lymphoma and prostate cancer .   12. The method of claim 11, wherein the protein kinase-related condition is selected from the group consisting of one or more of sarcoma, carcinoma and leukemia.   Protein kinase-related pathologies include fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, chordoma, hemangiosarcoma, endothelial sarcoma, lymphangiosarcoma, lymphovascular endothelial sarcoma, synovial tumor, mesothelioma Ewing sarcoma, leiomyosarcoma, rhabdomyosarcoma, colon carcinoma, pancreatic cancer, breast cancer, ovarian cancer, prostate cancer, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, sweat gland carcinoma, sebaceous carcinoma, papillary carcinoma, nipple Adenocarcinoma, cystadenocarcinoma, medullary carcinoma, bronchial carcinoma, renal cell carcinoma, liver cancer, cholangiocarcinoma, chorioallantoic carcinoma, seminoma, embryonal carcinoma, Wilms tumor, cervical cancer, testicular tumor, lung carcinoma, small Cell lung carcinoma, bladder carcinoma, epithelial carcinoma, glioma, astrocytoma, medulloblastoma, craniopharyngioma, ependymoma, pineal tumor, hemangioblastoma, acoustic neuroma, oligodendroma glioma , Meningiomas, melanomas, neuroblastomas and retinoblastomas The method of claim 17 which is selected from the group consisting of one or more.   12. The method according to claim 11, wherein the protein kinase-related pathological condition is a carcinoma formed from a tissue of the breast, prostate, kidney, bladder or large intestine.   12. The method according to claim 11, wherein the protein kinase-related pathological condition is a hyperplastic or neoplastic disorder occurring in adipose tissue.   21. The method of claim 20, wherein the hyperplastic or neoplastic disorder is an adipocyte tumor.   22. The method of claim 21, wherein the adipocyte tumor is one or more of lipoma, fibrolipoma, lipoblastoma, lipomatosis, hibema, hemangioma and liposarcoma.   10. Use of at least one of the compounds according to any one of claims 1 to 9 in the preparation of a medicament for treating a protein kinase associated condition. A protein kinase related disorder comprising at least one of the compounds according to any one of claims 1 to 9 capable of being treated in an effective amount therefor and a pharmaceutically acceptable vehicle or diluent. Pharmaceutical composition.

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