KR101027426B1 - Protein kinase inhibitors - Google Patents

Abstract

The present invention relates to a compound of formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, crystalline form, or diastereomer thereof. The invention also relates to a method of treating protein kinase-related disease states using a compound of formula (I).

Kinases, inhibitors, pyrazine, pyridine, transformation

Description

Protein Kinase Inhibitor {PROTEIN KINASE INHIBITORS}

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

Protein kinases are a class of enzymes that catalyze the phosphorylation of certain residues in proteins. In general, protein kinases are classified into several groups: differentially phosphorylating serine and / or threonine residues, differentially phosphorylating tyrosine residues, and phosphorylating both tyrosine and Ser / Thr residues. . Therefore, protein kinases are key elements in the signal transduction pathway responsible for extracellular signal transduction, including the action of cytokines on their receptors on the nucleus, causing a variety of biological consequences. Many roles of protein kinases in normal cell physiology include cell cycle regulation and cell growth, differentiation, apoptosis, cell mobility, and mitogenesis.

Protein kinases include members of the protein tyrosine kinase class (PTK) that can be classified into cytoplasmic PTK and receptor PTK (RTK). Cytoplasmic PTKs include the following classes: SRC class (including BLK; FGR; FYN; HCK; LCK; LYN; SRC; YES, and YRK); BRK class (including BRK; FRK; SAD; and SRM); CSK class (including CSK and CTK); BTK classes (BTK; ITK; TEC; including MKK2 and TXK); Janus kinase classes (including JAKI, JAK2, JAK3, and Tyk2); FAK class (including FAK and PYK2); Fes class (including FES and FER), ZAP70 class (including ZAP70 and SYK); ACK class (including ACK1 and ACK2); And Abl classes (including ABL and ARG). RTK classes include EGF-receptor classes (including EGFR, HER2, HER3 and HER4); Insulin receptor classes (including INS-R and IGF1-R); PDGF-receptor classes (including PDGFRα, PDGFRβ, CSF1R, KIT, FLK2); VEGF-receptor classes (including FLT1, FLK1, and FLT4); FGF-receptor classes (FGFR1, FGFR2, FGFR3, and FGFR4); CCK4 class (including CCK4); MET class (including MET and RON); TRK classes (including TRKA, TRKB, and TRKC); AXL class (including AXL, MER, and SKY); TIE / TEK class (including TIE and TIE2 / TEK); EPH classes (including EPHA1, EPHA2, EPHA3, EPHA4, EPHA5, EPHA6, EPHA7, EPHA8, EPHB1, EPHB2, EPHB3, EPHB4, EPHB5, and EPHB6); RYK class (including RYK); MCK classes (MCK and TYRO10); ROS class (including ROS); RET class (including RET); LTK classes (including LTK and ALK); ROR class (including ROR1 and ROR2); Musk class (including musk); LMR classes (including LMR1, LMR2, and LMR3); And SuRTK106 class (SuRTK106).

Likewise, serine / threonine specific kinases include a number of individual subclasses: kinases (p42 / ERK2 and p44 / ERKI) regulated by extracellular signals; c-Jun NH2-terminal kinase (JNK); cAMP-reactive element-binding protein kinase (CREBK); cAMP-dependent kinase (CAPK); Protein kinases (MAPK and related substances) activated by protein kinases activated by mitogens; Protein kinase p38 / SAPK2 activated by stress; Mitase and kinase activated by stress (MSK); In particular protein kinases, PKA, PKB and PKC.

In addition, the genomes of many pathogenic organisms contain genes encoding protein kinases. For example, malaria parasite plasmodium Falsiparum ( Plasmodium falciparum, and viruses such as HPV and Hepatitis virus are believed to contain kinase related genes.

Abnormally high protein kinase activity is associated with many diseases resulting from abnormal cellular function. This is due to, for example, the failure of an appropriate regulatory mechanism for kinases associated with mutation, overexpression or abnormal activation of the kinase enzyme, or growth factors involved in the signal transduction upstream or downstream of the kinase. (growth factor) or cytokine overproduction or underproduction can be caused directly or indirectly. From all these instances, selective inhibition of the action of the kinase can be expected to have a beneficial effect. Diseases associated with abnormal kinase activity include diabetes; Restenosis; Atherosclerosis; Fibrosis of the liver and kidneys; Eye disease; Myeloproliferative disorders and lymphoid proliferative disorders; Cancers such as prostate cancer, colon cancer, breast cancer, brain and neck cancers, leukemias and lymphomas; And autoimmune diseases such as Atopic Dermatitis, asthma, rheumatoid arthritis, Crohn's disease, psoriasis, Crouzon syndrome, achondroplasia, and tanatoporic Dyatophoric dysplasia is included.

Summary of the Invention

We have found that a group of compounds based on a disubstituted pyrazine backbone is an inhibitor of protein kinase.

Accordingly, the present invention relates to compounds that effectively regulate protein kinase signal transduction by acting on the enzymatic activity of RTK, CTK, and / or STK and interfering with signals converted by these enzymes. More specifically, the present invention relates to compounds that modulate signal transduction pathways mediated by CTK and / or STK as therapeutic measures for healing various types of tumors.

Therefore, in a first aspect, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, crystal form or diastereomer thereof. diastereomer):

(I)

(I)

Where

R 1 is H or C _1-4 alkyl,

Q is a bond or C _1-4 alkyl,

A is halogen, C _1-4 alkyl, CH ₂ F, CHF ₂ , CF ₃ , CN, aryl, hetaryl, OCF ₃ , OC _1-4 alkyl, OC _2-5 alkylNR _{4 R 5} , Oaryl, O Hetaryl, CO ₂ R4, CONR4R5, nitro, NR4R5, C _1-4 alkylNR4R5, NR6C _1-4 alkylNR4R5, NR4COR5, NR6CONR4R5, and NR4SO ₂ R5, independently selected by 0-3 substituents Optionally substituted aryl or hetaryl; R 4 and R 5 are each independently H, C _1-4 alkyl, C _1-4 alkyl cycloalkyl, C _1-4 alkyl cyclohetalkyl, aryl, hetaryl, C _1-4 alkyl aryl, or C _{1 -4} alkyl hetaryl, or R4 and R5 join together to form an optionally substituted 3-8 membered ring optionally containing an atom selected from the group consisting of 0, S, and NR7 May be present; R 6 is selected from the group consisting of H and C _1-4 alkyl; R 7 is selected from the group consisting of H, C _1-4 alkyl, aryl, hetaryl, C _1-4 alkyl aryl, and C _1-4 alkyl hetaryl,

R2 is halogen, C _1-4 alkyl, OH, OC _1-4 alkyl, CH ₂ F, CHF ₂ , CF ₃ , OCF ₃ , CN, C _1-4 alkylNR8R9, OC _1-4 alkylNR8R9, CO ₂ R8 , CONR8R9, NR8R9, NR8COR9, NR10CONR8R9, and NR8SO ₂ R9 are 0-2 substituents independently selected from the group consisting of; R8 and R9 are each independently H, C _1-4 alkyl, C _1-4 alkyl cycloalkyl, C _1-4 alkyl cyclohetalkyl, aryl, hetaryl, C _1-4 alkyl aryl, or C _1-4 alkyl Hetaryl or R8 and R9 may be joined together to form an optionally substituted 3-8 membered ring optionally containing an atom selected from the group consisting of 0, S, and NR11; R 10 is selected from the group consisting of H, C _1-4 alkyl, aryl, and hetaryl; R 11 is selected from the group consisting of H, C _1-4 alkyl, aryl, hetaryl, C _1-4 alkyl aryl, and C _1-4 alkyl hetaryl,

Y is selected from the group consisting of halogen, OH, NR12R13, NR12COR13, NR12CONR13, and N12SO ₂ R13; R12 and R13 are each independently H, CH ₂ F, CHF ₂ , CF ₃ , CN, C _1-4 alkyl, C _1-4 alkyl cycloalkyl, or C _1-4 alkyl cyclohetalkyl, or R12 and R13 May be joined together to form an optionally substituted 3-6 membered ring optionally containing an atom selected from the group consisting of 0, S, and NR 14; R14 is selected from the group consisting of H and C _1-4 alkyl,

n is 0-4,

W is selected from the group consisting of H, C _1-4 alkyl, and C _2-6 alkenyl; Wherein C _1-4 alkyl or C _2-6 alkenyl may be optionally substituted by C _1-4 alkyl, OH, OC _1-4 alkyl, or NR 15 R 16; R 15 and R 16 are each independently H, C _1-4 alkyl, C _1-4 alkyl cycloalkyl, or C _1-4 alkyl cyclohetalkyl, or R 15 and R 16 join together to form O, S, and NR 17. May form an optionally substituted 3-8 membered ring optionally containing an atom selected from the group consisting of: R17 is selected from the group consisting of H and C _1-4 alkyl;

Here, when Y is OH or NHCOCH ₃ , R 2 is 1-2 substituents, and when Y is NH ₂ and R ₂ is absent, Y is in a para position.

In a second aspect, the invention relates to a composition comprising at least one compound and a carrier according to the first aspect of the invention.

In a third aspect, the invention provides a method of administering a therapeutically effective amount of one or more compounds according to the first aspect of the invention or a therapeutically effective amount of a composition according to the second aspect of the invention. It relates to a method for treating a protein kinase-associated disease state, characterized in that it comprises.

Detailed description of the invention

The present invention relates to compounds which act on the enzymatic activity of RTK, CTK, and / or STK to interfere with the signals converted by these enzymes, thereby effectively regulating protein kinase signal transduction. More specifically, the present invention relates to compounds that modulate signal transduction pathways mediated by CTK and / or STK as therapeutic measures for healing various types of tumors.                 

In a first aspect, the invention relates to a compound of formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, crystalline or diastereomer thereof:

(I)

(I)

Where

R 1 is H or C _1-4 alkyl,

Q is a bond or C _1-4 alkyl,

A is halogen, C _1-4 alkyl, CH ₂ F, CHF ₂ , CF ₃ , CN, aryl, hetaryl, OCF ₃ , OC _1-4 alkyl, OC _2-5 alkylNR _{4 R} 5, Oaryl, O hetaryl, Optionally substituted by 0-3 substituents independently selected from the group consisting of CO ₂ R4, CONR4R5, nitro, NR4R5, C _1-4 alkylNR4R5, NR6C _1-4 alkylNR4R5, NR4COR5, NR6CONR4R5, and NR4SO ₂ R5 Aryl or hetaryl; R 4 and R 5 are each independently H, C _1-4 alkyl, C _1-4 alkyl cycloalkyl, C _1-4 alkyl cyclohetalkyl, aryl, hetaryl, C _1-4 alkyl aryl, or C _1-4 alkyl Hetaryl or R4 and R5 may be joined together to form an optionally substituted 3-8 membered ring optionally containing an atom selected from the group consisting of 0, S, and NR7; R 6 is selected from the group consisting of H and C _1-4 alkyl; R 7 is selected from the group consisting of H, C _1-4 alkyl, aryl, hetaryl, C _1-4 alkyl aryl, and C _1-4 alkyl hetaryl,

R2 is halogen, C _1-4 alkyl, OH, OC _1-4 alkyl, CH ₂ F, CHF ₂ , CF ₃ , OCF ₃ , CN, C _1-4 alkylNR8R9, OC _1-4 alkylNR8R9, CO ₂ R8 , CONR8R9, NR8R9, NR8COR9, NR10CONR8R9, and NR8SO ₂ R9 are 0-2 substituents independently selected from the group consisting of; R8 and R9 are each independently H, C _1-4 alkyl, C _1-4 alkyl cycloalkyl, C _1-4 alkyl cyclohetalkyl, aryl, hetaryl, C _1-4 alkyl aryl, or C _1-4 alkyl Hetaryl or R8 and R9 may be joined together to form an optionally substituted 3-8 membered ring optionally containing an atom selected from the group consisting of 0, S, and NR11; R 10 is selected from the group consisting of H, C _1-4 alkyl, aryl, and hetaryl; R 11 is selected from the group consisting of H, C _1-4 alkyl, aryl, hetaryl, C _1-4 alkyl aryl, and C _1-4 alkyl hetaryl,

Y is selected from the group consisting of halogen, OH, NR12R13, NR12COR13, NR12CONR13, and N12SO ₂ R13; R12 and R13 are each independently H, CH ₂ F, CHF ₂ , CF ₃ , CN, C _1-4 alkyl, C _1-4 alkyl cycloalkyl, or C _1-4 alkyl cyclohetalkyl, or R12 and R13 May be joined together to form an optionally substituted 3-6 membered ring optionally containing an atom selected from the group consisting of 0, S, and NR 14; R14 is selected from the group consisting of H and C _1-4 alkyl,

n is 0-4,

W is selected from the group consisting of H, C _1-4 alkyl, and C _2-6 alkenyl; Wherein C _1-4 alkyl or C _2-6 alkenyl may be optionally substituted by C _1-4 alkyl, OH, OC _1-4 alkyl, or NR 15 R 16; R 15 and R 16 are each independently H, C _1-4 alkyl, C _1-4 alkyl cycloalkyl, or C _1-4 alkyl cyclohetalkyl, or R 15 and R 16 join together to form O, S, and NR 17. May form an optionally substituted 3-8 membered ring optionally containing an atom selected from the group consisting of: R17 is selected from the group consisting of H and C _1-4 alkyl;

Here, when Y is OH or NHCOCH ₃ , R 2 is 1-2 substituents, and when Y is NH ₂ and R ₂ is absent, Y is in the para position.

In the above disclosure,

C _1-4 alkyl refers to a linear or branched alkyl chain,

Aryl means unsubstituted or optionally substituted phenyl or naphthyl,

Hetaryl means an unsubstituted or optionally substituted 5 or 6 membered heterocyclic ring containing one or more heteroatoms selected from the group consisting of O, N, and S,

Cycloalkyl means a 3-8 membered saturated ring,

Cyclohetalkyl means a 3-8 membered saturated ring containing 1-3 heteroatoms selected from the group consisting of O, S, and NR18, wherein R18 is H, C _1-4 alkyl, aryl, or het It is understood to be aryl.

In another preferred embodiment, the compound is selected from compounds of formula (II), or pharmaceutically acceptable salts, hydrates, solvates, crystalline or diastereomers thereof:

( II )

( II )

Where

R 1 is H or C _1-4 alkyl,

Q is a bond or C _1-4 alkyl,

A is halogen, C _1-4 alkyl, CH ₂ F, CHF ₂ , CF ₃ , CN, aryl, hetaryl, OCF ₃ , OC _1-4 alkyl, OC _2-5 alkylNR _{4 R} 5, Oaryl, O hetaryl, Aryl optionally substituted by 0-3 substituents independently selected from the group consisting of CO ₂ R4, CONR4R5, NR4R5, C _1-4 alkylNR4R5, NR6C _1-4 alkylNR4R5, NR4COR5, NR6CONR4R5, and NR4SO ₂ R5 Or hetaryl; R 4 and R 5 are each independently H, C _1-4 alkyl, C _1-4 alkyl cycloalkyl, C _1-4 alkyl cyclohetalkyl, aryl, hetaryl, C _1-4 alkyl aryl, or C _1-4 alkyl Hetaryl or R4 and R5 may be joined together to form an optionally substituted 3-8 membered ring optionally containing an atom selected from the group consisting of 0, S, and NR7; R 6 is selected from the group consisting of H and C _1-4 alkyl; R 7 is selected from the group consisting of H, C _1-4 alkyl, aryl, hetaryl, C _1-4 alkyl aryl, and C _1-4 alkyl hetaryl,

R2 is halogen, C _1-4 alkyl, OH, OC _1-4 alkyl, CH ₂ F, CHF ₂ , CF ₃ , OCF ₃ , CN, C _1-4 alkylNR8R9, OC _1-4 alkylNR8R9, CO ₂ R8 , CONR8R9, NR8R9, NR8COR9, NR10CONR8R9, and NR8SO ₂ R9 are 0-2 substituents independently selected from the group consisting of; R8 and R9 are each independently H, C _1-4 alkyl, C _1-4 alkyl cycloalkyl, C _1-4 alkyl cyclohetalkyl, aryl, hetaryl, C _1-4 alkyl aryl, or C _1-4 alkyl Hetaryl or R8 and R9 may be joined together to form an optionally substituted 3-8 membered ring optionally containing an atom selected from the group consisting of 0, S, and NR11; R 10 is selected from the group consisting of H, C _1-4 alkyl, aryl, and hetaryl; R 11 is selected from the group consisting of H, C _1-4 alkyl, aryl, hetaryl, C _1-4 alkyl aryl, and C _1-4 alkyl hetaryl,

Y is selected from the group consisting of halogen, OH, NR12R13, NR12COR13, NR12CONR13, and N12SO ₂ R13; R12 and R13 are each independently H, CH ₂ F, CHF ₂ , CF ₃ , CN, C _1-4 alkyl, C _1-4 alkyl cycloalkyl, or C _1-4 alkyl cyclohetalkyl, or R12 and R13 May be joined together to form an optionally substituted 3-6 membered ring optionally containing an atom selected from the group consisting of 0, S, and NR 14; R14 is selected from the group consisting of H and C _1-4 alkyl,

n is 0-4,

W is selected from the group consisting of H, C _1-4 alkyl, and C _2-6 alkenyl; Wherein C _1-4 alkyl or C _2-6 alkenyl may be optionally substituted by C _1-4 alkyl, OH, OC _1-4 alkyl, or NR 15 R 16; R 15 and R 16 are each independently H, C _1-4 alkyl, C _1-4 alkyl cycloalkyl, or C _1-4 alkyl cyclohetalkyl, or R 15 and R 16 join together to form O, S, and NR 17. May form an optionally substituted 3-8 membered ring optionally containing an atom selected from the group consisting of: R17 is selected from the group consisting of H and C _1-4 alkyl;

Here, when Y is OH or NHCOCH ₃ , R 2 is 1-2 substituents, and when Y is NH ₂ and R ₂ is absent, Y is in the para position.

In the above disclosure,                 

C _1-4 alkyl refers to a linear or branched alkyl chain,

Aryl means unsubstituted or optionally substituted phenyl or naphthyl,

Hetaryl means an unsubstituted or optionally substituted 5 or 6 membered heterocyclic ring containing one or more heteroatoms selected from the group consisting of O, N, and S,

Cycloalkyl means a 3-8 membered saturated ring,

Cyclohetalkyl means a 3-8 membered saturated ring containing 1-3 heteroatoms selected from the group consisting of O, S, and NR18, wherein R18 is H, C _1-4 alkyl, aryl, or het It is understood to be aryl.

Compounds of the invention include all conformational isomers (eg, cis and trans isomers). The compounds of the present invention have asymmetric centers and therefore exist in the form of different enantiomers and diastereomers. The present invention relates to all optical isomers and stereoisomers of the compounds of the present invention, as well as mixtures thereof, and to all pharmaceutical compositions and methods of treatment that can use or contain them. In this regard, the present invention encompasses both E and Z configurations. The compounds of general formula (I) may also exist as tautomers. The present invention relates to the use of all such tautomers and mixtures thereof.

The present invention also encompasses pharmaceutical compositions containing a prodrug of a compound of formula (I). The invention also includes a method of treating or preventing a disease 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 free amino, amido, hydroxy or carboxyl groups can be converted to prodrugs. Prodrugs allow polypeptide chains of amino acid residues or two or more (eg, two, three or four) amino acid residues to bind peptides to the free amino, hydroxy and carboxyl groups of the compound of formula (I). Compounds covalently bound through. The amino acid residues comprise 20 natural amino acids, usually designated by three letter symbols, and also 4-hydroxyproline, hydroxylysine, democin, isodemosin, 3-methylhistidine, norvlin, beta -Alanine, gamma-aminobutyric acid, citrulline, homocysteine, homoserine, ornithine and methionine sulfone. Prodrugs also include compounds in which carbonates, carbamates, amides, and alkyl esters are covalently bonded to the substituents of formula (I) through a carbonyl carbon prodrug side chain. Prodrugs are also bound to the free hydroxy groups of the compounds of formula (I) via phosphorus-acid linkages, phosphate derivatives of the compounds of formula (I) (e.g., acids, salts, or esters) It includes.

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

In another preferred aspect, the compound is selected from the group consisting of the compounds set forth in Table 1 below.

In a second aspect, the invention relates to a composition comprising a carrier and at least one compound according to the first aspect of the invention.

In a third aspect, the invention comprises administering a therapeutically effective amount of one or more compounds according to the first aspect of the invention or a therapeutically effective amount of a composition according to the second aspect of the invention. A method of treating protein kinase-related disease states.

In a preferred embodiment, the 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-1, Flt-1, FGFR-1R, FGFR-2R, FGFR-3R, and FGFR-4R are associated with receptor tyrosine kinases selected from the group.

In another preferred embodiment, the disease state is from the group consisting of Src, Frk, Btk, Csk, Abl, ZAP70, Fes / Fps, Fak, Ack, Yes, Fyn, Lyn, Lck, Blk, Hck, Fgr, and Yrk. It is associated with the cell tyrosine kinase of choice.

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

In another preferred embodiment, 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 CDK11 are associated with serine / threonine kinases selected from the group.

In a preferred aspect of the present invention, the disease state may include atopic diseases including allergic asthma, atopic dermatitis (eczema), and allergic rhinitis (Atopy); Cell mediated hypersensitivity including Allergic Contact Dermatitis and Hypersensitivity Pneumonitis; Systemic Lupus Erythematosus (SLE), Rheumatoid Arthritis, Juvenile Arthritis, Sjogren's Syndrome, Scleroderma, Polymyositis, Polymyositis, Ankylosing Spondylitis, and tendonitis Rheumatic diseases including Psoriatic Arthritis; Other autoimmune diseases, including type I diabetes, autoimmune thyroid disease, and Alzheimer's disease; Epstein Barr Virus (EBV), Hepatitis B Virus, Hepatitis C Virus, HIV, HTLV 1, Varicella-Zoster Virus (VZV), and Human Papilloma Virus Viral diseases including HPV); And cancers such as leukemia, lymphoma, and prostate cancer.

In one embodiment, the methods of the invention are used for the treatment of sarcoma, carcinoma, and leukemia. Examples of diseases in which the methods of the present invention may be used alone or as part of a treatment regimen include fibrosarcoma, myxosarcoma, lymphosarcoma, chondrosarcoma, osteosarcoma. ), Chordoma, angiosarcoma, endotheliosarcoma, lymphangiosarcoma, lymphangioendotheliosarcoma, lymphangioendotheliosarcoma, synovioma, mesothelioma, Ewing's tumor tumor, smooth muscle sarcoma (leiomyosarcoma), rhabdomyosarcoma, colon carcinoma, pancreatic cancer, breast cancer, ovarian cancer, prostate cancer, squamous cell Squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, sweat gland carcinoma, sebaceous gland carcinoma, papillary carcinoma, papillary adenocarcinoma pillary adenocarcinoma, cystadenocarcinoma, myeloid carcinoma, bronchogenic carcinoma, renal cell carcinoma, hepatoma, bile duct carcinoma, chorionic carcinoma choriocarcinoma, seminoma, embryonic carcinoma, Wilm's tumor, cervical cancer, testicular tumor, lung carcinoma, small cell lung carcinoma lung carcinoma, bladder carcinoma, epithelial carcinoma, glioma, astrocytoma, medulloblastoma, craniopharyngioma, cerebral medullary cell tumor (ependymoma) Species include hepatic, hemangioblastoma, acoustic neuroma, oligodendroglioma, meningioma, melanoma, neuroblastoma, and retinoblastoma.

In another embodiment, the methods of the present invention are used to treat a disease, such as a carcinoma formed from breast, prostate, kidney, bladder, or colon tissue.

In another aspect, the invention relates to, for example, lipoma, fibrolipoma, lipoblastoma, lipomatosis, hibemoma, hemangioma, and liposarcoma It is used for the treatment of hyperplastic or neoplastic diseases that occur in adipose tissue, such as adipose cell carcinoma such as (liposarcoma).

As used herein, the term "protein kinase-related disease state" refers to a disease caused by abnormal protein kinase activity, in particular JAK activity, or alleviated by inhibition of one or more protein kinases.

In another aspect of the invention, the invention provides the use of a compound of the present invention for the manufacture of a medicament for the treatment of protein kinase-related disease states.

As used herein, the terms "JAK", "JAK kinase" or "JAK class" refer to protein tyrosine kinases having the unique characteristics of JAK1, JAK2, JAK3, and TYK disclosed herein.

The present invention provides a pharmaceutical composition comprising an effective amount of at least one compound of the invention and a pharmaceutically acceptable carrier or diluent capable of treating protein kinase-related diseases such as JAK-related diseases. The compositions of the present invention may contain other therapeutic agents as set forth below, according to techniques known in the art of pharmaceutical formulation, such as, for example, conventional solid or liquid carriers or diluents, and types suitable for the desired mode of administration. Pharmaceutical additives (e.g., excipients, binders, preservatives, stabilizers, flavors, etc.).

The compounds of the present invention may be administered in the form of unit dose formulations containing pharmaceutically acceptable non-toxic carriers or diluents, by oral administration in any suitable means, such as in the form of tablets, capsules, granules, or powders; Sublingually administration; Buccally administration; Parenterally administration (eg, sterile injectable), for example, by subcutaneous, intravenous, intramuscular, or intraracisternal injection or infusion techniques. Aqueous or non-aqueous solutions or suspensions); Nasal administration by, for example, inhalation spray; Topical administration, eg as a cream or ointment form; Or rectally, for example, in the form of suppositories. The compound may be administered, eg, in a form suitable for immediate release or extended release. Immediate or sustained release formulations can be achieved by using suitable pharmaceutical compositions, and in the case of sustained release, in particular by means of devices such as subcutaneous implants or osmotic pumps. The compound may also be administered via liposomes.

In addition to primates such as humans, various other mammals can be treated according to the methods of the present invention. Such as, but not limited to, cows, sheep, goats, horses, dogs, cats, guinea pigs, rats, or other bovines, sheeps, horses, canines, felines, rodents or rats Mammals can be treated. However, the method may also be practiced for other species, such as bird species (eg chickens).

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 one that modulates the inflammatory response by inhibiting or promoting the action of eosinophils and / or lymphocytes.

Subjects treated in the above methods, which require JAK inhibition, include, but are not limited to, cows, sheep, goats, horses, dogs, cats, guinea pigs, rats, or other bovines, sheeps, horses, canines, felines Mammals, including rodent or murine species, preferably male or female humans.

The term "therapeutically effective amount" means the amount of a subject composition that induces a biological or medical response in a tissue, system, animal, or human studied by a researcher, veterinarian, physician, or other clinician.

The term "composition", as used herein, encompasses a product comprising a predetermined amount of a predetermined component, and any product obtained directly or indirectly through a combination of the predetermined amount of the predetermined component. "Pharmaceutically acceptable" means that the carrier, diluent or excipient is compatible with the other ingredients of the formulation and should not be harmful to its recipient.                 

"Administration" of a compound and / or its parental translation is to be understood as meaning providing the compound of the invention to an individual in need thereof.

Pharmaceutical compositions for the administration of the compounds of the present invention may conveniently be presented in unit dosage form and may be prepared by any method known in the art of pharmacy. All methods include the step of combining the active ingredient with the carrier to form one or more accessory ingredients. In general, the pharmaceutical compositions are prepared by uniformly and intimately combining the active ingredients with liquid carriers or finely divided solid carriers or both, and if necessary, the product can be formulated into the desired dosage form. In the pharmaceutical composition, the active subject compound is included in an amount sufficient to induce a desired effect on the progress or symptom of the disease. As used herein, the term “composition” encompasses a product comprising a predetermined amount of a given component, and any product obtained directly or indirectly through a combination of the predetermined amount of the predetermined component.

Pharmaceutical compositions containing such active ingredients can be used for oral use, such as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs It may be in a form suitable for elixir. Compositions for oral use may be prepared according to any method known in the art of preparing pharmaceutical compositions, which compositions may include sweetening agents, to provide pharmaceutical preparations of good taste, It may contain one or more agents selected from the group consisting of flavoring agents, coloring agents, and preserving agents. Tablets contain the active ingredient in admixture with pharmaceutically acceptable non-toxic excipients which 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 agents and disintegrating agents such as corn starch, or alginic acid; Binding agents such as starch, gelatin or acacia, and lubricating agents such as magnesium stearate, stearic acid, or talc. The tablets may or may not be coated by known techniques to provide long lasting action by delaying disintegration and absorption in the gastrointestinal tract. For example, a time delay material such as glyceryl monostearate or glyceryl distearate can be used. They may also be coated to form osmotic therapeutic tablets for controlled release.

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

Aqueous suspensions contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients include suspending agents such as sodium carboxymethylcellulose, methylcellulose, hydroxy-propylmethylcellulose, sodium alginate, polyvinyl-pyrrolidone, gum tragacanth and acacia rubber Dispersing agents or wetting agents are natural phosphatides, such as lecithin, or condensation products of alkylene oxides and fatty acids, such as polyoxyethylene stearate. Or partial esters derived from fatty acids such as ethylene oxide and long chain aliphatic alcohols such as heptadecaethyleneoxycetanol, or hexitol and fatty acids such as polyoxyethylene sorbitol monooleate. Condensation products of ethylene oxide with fatty acids and hexitol anhydrides, such as Condensation products of ethylene oxide with partial esters derived from polyethylene sorbitan monooleate. The aqueous suspension may also 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 sweetening agents such as sucrose or saccharin. .

Oil-based suspensions can be formulated by suspending the active ingredient in vegetable oils such as arachis oil, olive oil, sesame oil or coconut oil, or mineral oils such as liquid paraffin. The oily suspension may contain a thickening agent such as beeswax, hard paraffin or cetyl alcohol. Sweeteners and flavoring agents as set forth above may be added to provide oral pharmaceutical preparations of good taste. These compositions can be preserved by the addition of an anti-oxidant such as ascorbic acid.                 

Dispersible powders and granules suitable for preparing an aqueous suspension by adding water provide the active ingredient in admixture with the dispersing or wetting agent, suspending agent, and one or more preservatives. Suitable dispersing or wetting agents and suspending agents have already been exemplified above. Additional excipients such as sweetening, flavoring, and coloring agents may also be contained.

The pharmaceutical composition of the present invention may also be in the form of an oil-in-water emulsion. The oily phase may be a vegetable oil such as olive oil or arachis oil, or a mineral oil such as liquid paraffin or mixtures thereof. Suitable emulsifying agents are natural rubbers such as acacia rubber or gum tragacanth, natural phosphides such as soy bean, lecithin, and hexitol with fatty acids such as sorbitan monooleate, for example. Partial esters or esters derived from anhydrides, and condensation products of such partial esters with ethylene oxide such as polyoxyethylene sorbitan monooleate. The emulsion may also contain sweetening and flavoring agents.

Syrups and elixirs may be formulated in combination with sweetening agents such as glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain analgesics, preservatives, flavors, and coloring agents.

The pharmaceutical compositions may be in the form of sterile injectable aqueous or oleaginnous suspensions. This suspension may be formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents as described above. Injectable sterile preparations may also be injectable sterile solutions or suspensions in a non-oral acceptable non-toxic diluent or solvent, such as a 1,3-butane diol solution. Acceptable carriers and solvents that may be used include water, Ringer's solution, and sodium chloride isotonic solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland coagulating oil may be used including synthetic monoglycerides or diglycerides. In addition, fatty acids such as oleic acid may be used in the preparation of injectable solutions.

The compounds of the present invention can also be administered in the form of suppositories for rectal administration of the drug. These compositions can be prepared by mixing the drug with a non-irritating suitable excipient which becomes solid at ordinary temperature but liquid at rectal temperature and thereby melts in the rectum to release the drug. Such materials include cocoa butter and polyethylene glycols.

For topical use, creams, ointments, jelly, solutions or suspensions containing the compounds of the invention are used. (For the purpose of this application, topical application will include mouthwash and gargle.)

Compounds of the 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 monolayered or multilamellar hydrated liquid crystal dispersed in an aqueous medium. Any physiologically acceptable and metabolizable non-toxic lipid capable of forming liposomes can be used. Compositions of the present invention in liposome form may contain, in addition to the compounds of the present invention, stabilizers, preservatives, excipients, and the like. Preferred lipids are natural and synthetic phospholipids and phosphatidyl choline. Liposomal preparation methods are known in the art.

The pharmaceutical compositions and methods of the present invention may further comprise other therapeutically active compounds not disclosed herein, which are commonly applied to the treatment of the above pathological symptoms. The selection of a suitable agent for use in combination therapy can be made by one skilled in the art, according to conventional pharmaceutical principles. Combinations of therapeutic agents may act synergistically for the treatment or prophylactic action of the various diseases described above. By using this method, anyone will be able to achieve therapeutic efficacy using fewer doses of each agent, thus reducing the likelihood of side effects.

Examples of other therapeutic agents include the following: cyclosporin (eg 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, anti-CD86, agents that block the interaction between CD40 and gp39, such as antibodies specific for CD40 and / or gp39 (ie, CD154), Inhibitors of NF-kappa B functions, such as fusion proteins consisting of CD40 and gp39 (CD401g and CD8gp39), nuclear translocation inhibitors, such as deoxyspergualin (DSG), cholesterol Biosynthetic inhibitors such as HMG CoA reductase inhibitors (lovastatin and simvastatin), non-steroidal antiinflammatory drugs (NSAIDs) such as ibuprofen, aspirin, Acetaminophen, and cyclooxygenase inhibitors such as rofecock Rofecoxib, steroids such as prednisolone or dexamethasone, gold compounds, antiproliferative agents such as methotrexate, FK506 (tacrolimus, prograph) Prograf)), mycophenolate mofetil, cytotoxic drugs such as azathioprine, VP-16, etoposide, fludarabine, cisplatin and cyclophosph Pamide, TNF-α inhibitors such as tenidap, anti-TNF antibodies or soluble TNF receptors, and rapamycin (sirolimus or Rapamune) or theirs derivative.

When other therapeutic agents are used with the compounds of the present invention, they may be used in the amounts set forth in the Physician Desk Reference (PDR) and may be determined by one skilled in the art.

In the treatment or prevention of a condition requiring inhibition of protein tyrosine kinase, an appropriate dosage level will generally be from about 0.01 to 500 mg / kg body weight of the patient, which may be administered in a single dose or in multiple doses. It may be administered separately. Preferably, the dose level is about 0.1 to about 250 mg / kg / day; More preferably about 0.5 to about 100 mg / kg / day. Appropriate dose 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 may be 0.05 to 0.5, 0.5 to 5, or 5 to 50 mg / kg / day. In the case of oral administration, the composition is adjusted to a dose depending on the condition of the patient to be treated, so that 1.0 to 1000 mg of the active ingredient, in particular 1.0, 5.0, 10.0, 15.0, 20.0, 25.0, 50.0, 75.0, 100.0, 150.0, It is preferably provided in the form of tablets containing 200.0, 250.0, 300.0, 400.0, 500.0, 600.0, 750.0, 800.0, 900.0, and 1000.0 mg of active ingredient. The compound may be administered in a regimen once to four times daily, preferably once or twice daily.

However, the specific dosage dose level and number of doses for any particular patient may vary, and the activity of the specific compound used, its metabolic stability and duration of action, age, weight, general health, sex , Diet, mode and time of administration, rate of secretion, drug combination, the severity of certain symptoms, and the host on which the therapy is being applied will vary.

Throughout this application, the terms "comprises" and "comprises" or a parent translation thereof include any element, integer or step, or group of elements, integers or steps mentioned, but elements, integers or steps, or elements, integers or It will be understood in the sense that it does not exclude a group of steps.

All publications mentioned herein are incorporated herein by reference.

References to documents, articles, materials, devices, articles, etc., described herein are also merely to provide a background for the present invention. All of these contents, which existed in Australia before the priority date of each claim herein, are not to be tolerated as forming part of the prior art or as general knowledge common in the relevant field of the invention.

1: Dose-response curves for R and S enantiomers of representative 2- (α-methyl benzylamino) -pyrazine with inhibitory activity in Tel-Jak2 transformed cell line.

Figure 2: Kinase inhibitory activity of representative 2- (α-methyl benzylamino) -pyrazine. Kinase evaluation was performed as disclosed in the method description. A, CYC10124 of FIG. 2 (illustrated as Chemistry 141 in Table 1) shows effective inhibitory activity against c-KIT, TIE2, and ABL protein kinase. 2, B, CYC10268 (illustrated as Chemistry 268 in Table 1) shows an effective inhibitory activity against c-FMS. C, CYC10119 of FIG. 2 (illustrated as Chemistry 136 in Table 1) shows effective inhibitory activity against Jak2 and c-KIT.

Hereinafter, in order to provide a more in-depth understanding of the present invention, preferred embodiments of the present invention are presented with reference to the following non-limiting examples.

Substances 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 process to prepare a monoamino-monohalo intermediate (Chemical Scheme 1).                 

[Chemical Scheme 1]

The nucleophilic aromatic substitution is usually carried out in a solvent such as ethanol, isopropanol, tert-butanol, dioxane, THF, DMF, toluene or xylene, to the primary amine in a di-halogenated heterocycle. It is carried out by addition. The reaction is usually carried out at elevated temperature in the presence of excess amine or non-nucleophilic base such as triethylamine or diisopropylethylamine, or inorganic base such as potassium carbonate or sodium carbonate. .

Alternatively, the amino substituents can be introduced via an amination reaction catalyzed by a transition metal. Representative catalysts for such transformations include Pd (OAc) ₂ / P (t-Bu) ₃ , Pd ₂ (dba) ₃ / BINAP and Pd (OAc) ₂ / BINA. These reactions are usually carried out at room temperature to reflux temperature in a solvent such as toluene and dioxane in the presence of cesium carbonate or a base such as sodium or potassium tert-butoxide.

The amines used in the first step of the synthesis of these compounds can be obtained commercially or prepared using methods known in the art. Of particular interest is α-methylbenzylamine, which is either commercially available or can be prepared via an oxime reaction. Representative reducing agents are lithium aluminum hydride, hydrogen gas in the presence of catalytic palladium on charcoal, sodium borohydride in the presence of Lewis acid such as Zn, TiCl ₃ , ZrCl ₄ , NiCl ₂ and MoO _{3 in the} presence of hydrochloric acid Ryde, or Amberlyst H15 ion exchange resin and sodium borohydride in the presence of LiC1.

[Chemical Scheme 2]

High optical purity α-methyl benzylamine can be prepared from chiral α-methyl benzyl alcohol using methods known in the art. Such methods include, for example, nitrophile, such as phthalates, which can be converted into primary amines by derivatisation of hydroxyls and conventional synthetic methods as mesylate or tosylate. Substitution with an imide or azide, or substitution of a hydroxyl with an appropriate nitrogen nucleophile under Mitsunobu conditions. The chiral α-methyl benzyl alcohol can be obtained through chiral reduction of the ketone. Chiral reduction methods are known in the art of organic chemistry and include enzymatic processes, asymmetric hydrogenation procedures, and chiral oxazaborolidine.

The second step of synthesis typically involves a palladium mediated cross-coupling process of a monoamino-monochloro intermediate and a suitably well-coupled coupling partner. Representative coupling partners include, but are not limited to, boronic acid (Suzuki coupling (see, eg, Miyaura, N. and Suzuki, Chem Rev. 1995, 952457) or stannane (see Stille, JK, Angew , Chem ., Int. Ed. Engl . , 1986, 25, 508).

[Chemical Scheme 3]

Suzuki coupling is the preferred coupling method, typically DME, THF, DMF, in the presence of a base such as potassium carbonate, lithium hydroxide, cesium carbonate, sodium hydroxide, potassium fluoride or potassium phosphate, It is preferably carried out in a solvent such as ethanol, propanol, toluene, or 1,4-dioxane. The reaction can be carried out at elevated temperatures and the palladium catalysts used are [Pd (PPh ₃ ) ₄ ], Pd (OAc) ₂ , [PdCl ₂ (dppf)], and Pd ₂ (dba) ₃ / P (t− Bu) ₃ can be selected from the group consisting of.

The product formed from this reaction sequence can be further derivatized using techniques known in the art. Alternatively, mono-amino mono-chloropyrazine can be derivatized prior to substitution of the 6-chloro substituent. Such derivatization typically involves the use of functional groups inherently present on the amine species and employs methods known in the art.

Representative synthesis methods are shown below.

Example  One

6- Chloro -N-[(1 R )-One- Phenylethyl ] Pyrazine 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 (5 mL) was heated at reflux under N ₂ for 48 h. Solvent was removed and the product was recrystallized from toluene-hexane (0.82 g, 82%).

Example  2

2- Methoxy -4- (6-{[(1 R )-One- Phenylethyl ] Amino} Pyrazine -2-yl) phenol

In an atmosphere of nitrogen, 6-chloro -N - [(1 R) -1- phenylethyl] pyrazin-2-amine (0.611 g, 2.61 mmol), 4- (4,4,5,5- tetramethyl-1, A mixture of 3,2-dioxaborolan-2-yl) phenol (0.785 g, 3.14 mmol), tetrakis (triphenylphosphine) palladium (0) (0.30 g, 0.26 mmol), and toluene (3 mL) Was treated with 2M aqueous sodium carbonate solution (1.6 mL, 2.6 mmol). The resulting mixture was stirred vigorously with heating under reflux for 24 hours. Cold ethyl acetate was added and the mixture was dried (MgSO ₄ ) and filtered. The solvent was then removed in vacuo to afford the crude product which was then purified by column chromatography using dichloromethane: diethyl ether (99: 1 to 90:10) as eluent (0.619 g, 74%).

Example  3

6- Chloro -N-[(1 R ) -1- (3- Methoxyphenyl )ethyl] Pyrazine 2-amine

Following a procedure similar to Example 1, the product was obtained through the reaction of R-α-methylbenzylamine (1.0 g, 6.6 mmol) and 2,6-dichloropyrazine (0.440 g. 2.95 mmol) (517 mg, 67). %).

Example  4

2- Methoxy -4- (6-{[(1 R ) -1- (3- Methoxyphenyl ) Ethyl] amino} Pyrazine -2-yl) phenol

Following a procedure similar to Example 2, 2- (R-α-methyl-3-methoxy-benzylamino) -6-chloro-pyrazine (137.2 mg, 0.52 mmol) and 2-methoxy-4- (4, The product was obtained (32 mg, 18%) through the reaction of 4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenol (143 mg, 0.57 mmol).

Example  5

6- Chloro -N-[(1 R ) -1- (4- Methoxyphenyl )ethyl] Pyrazine 2-amine

According to a procedure similar to Example 1, the product was obtained through the reaction of R-α-methylbenzylamine (1.0 g, 6.6 mmol) and 2,6-dichloropyrazine (0.4355 g, 2.92 mmol) (0.72 g, 93 %).

Example  6

2- Methoxy -4- (6-{[(1 R ) -1- (4- Methoxyphenyl ) Ethyl] amino} Pyrazine -2-yl) phenol

Following a procedure similar to Example 2, 2- (R-α-methyl-4-methoxy-benzylamino) -6-chloro-pyrazine (127.1 mg, 0.48 mmol) and 2-methoxy-4- (4, The product was obtained (59.5 mg, 35%) through the reaction of 4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenol (145 mg, 0.58 mmol).

Example  7

6- Chloro -N-[(1R) -1,2,3,4- Tetrahydronaphthalene -1 day] Pyrazine 2-amine

Following a procedure similar to Example 1, of (1R) -1,2,3,4-tetrahydronaphthalen-1-amine (441 mg, 3.0 mmol) and 2,6-dichloropyrazine (0.4055 g, 2.72 mmol) The reaction gave the product (521 mg, 74%).

Example  8

2- Methoxy -4- [6-[(1R) -1,2,3,4- Tetrahydronaphthalene -One- Monoamino ] Pyrazine -2-yl} phenol

6-Chloro-N-[(1 R ) -1,2,3,4-tetrahydronaphthalen-1-yl] pyrazin-2-amine (139 mg, 0.536 mmol) according to a similar procedure as in Example 2 and The product was obtained through reaction of 2-methoxy-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenol (147 mg, 0.59 mmol). (87 mg, 47%).

Example  9

6- Chloro -N-[(1 R ) -2,3- Dehydro -1H- Inden -1 day] Pyrazine 2-amine

Following a procedure similar to Example 1, (1 R ) -2,3-dihydro-1H-inden-1-ylamine (1.0 g, 7.6 mmol) and 2,6-dichloropyrazine (0.452 g, 3.04 mmol) The reaction afforded the product (673.8 mg, 90%).

Example  10

4- (6-[(1 R ) -2,3- Dehydro -1H- Inden -One- Monoamino ] Pyrazine -2- day] -2- Methoxyphenol

6-Chloro-N-[(1-2,3-dihydro-1H-inden-l-yl] pyrazin-2-amine (136.8 mg, 0.56 mmol) and 2-methine, according to a procedure similar to Example 2 The product was obtained through the reaction of oxy-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenol (153 mg, X0.61 mmol) ( 130 mg, 70%).

Example  11

6- Chloro -N-[(1 R ) -1- (4- Methylphenyl )ethyl] Pyrazine 2-amine

Following a procedure similar to Example 1, the product was obtained through the reaction of α- (R) -4-dimethylbenzylamine (250 mg, 1.85 mmol) and 2,6-dichloropyrazine (0.251 g, 1.67 mmol) ( 199.5 mg, 48%).

Example  12

2- Methoxy -4- (6-{[(1 R ) -1- (4- Methylphenyl ) Ethyl] amino} Pyrazine -2-yl) phenol

6-Chloro-N-[( 1R ) -1- (4-methylphenyl) ethyl] pyrazin-2-amine (56.8 mg, 0.229 mmol) and 2-methoxy-4-, according to a procedure similar to Example 2 The product was obtained through the reaction of (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenol (63 mg, 0.25 mmol) (5 mg, 6%) .

Example  13

6- Chloro -N-[(1 S )-One- Phenylethyl ] Pyrazine 2-amine

Following a procedure similar to Example 1, the product was obtained through the reaction of S-α-methylbenzylamine (568 mg, 4.72 mmol) and 2,6-dichloropyrazine (0.6388 g, 4.29 mmol) (821 mg, 82 %).

Example  14

2- Methoxy -4- (6-{[(1 S )-One- Phenylethyl ] Amino} Pyrazine -2-yl) phenol

According to a procedure similar to Example 2, 6-chloro-N-[(1S) -phenylethyl) pyrazin-2-amine (717.3 mg, 3.07 mmol) and 2-methoxy-4- (4,4,5, The product was obtained (689 mg, 70%) through reaction of 5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenol (845 mg, 3.38 mmol).

Example  15

6- Chloro -N-[(1 S )-One- Phenylpropyl ] Pyrazine 2-amine

Following a procedure similar to Example 1, the product was obtained through the reaction of S-α-ethylbenzylamine (558 mg, 4.21 mmol and 2,6-dichloropyrazine (570 mg, 3.82 mmol) (655 mg, 73%). ).

Example  16

2- Methoxy -4- (6-{[(1 S )-One- Phenylpropyl ] Amino} Pyrazine -2-yl) phenol

According to a procedure similar to Example 2, 6-chloro-N-[(1S) -1-phenylpropyl] pyrazin-2-amine (135 mg, 0.57 mmol) and 2-methoxy-4- (4,4, The product was obtained (87 mg, 45%) through the reaction of 5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenol (158 mg, 0.63 mmol).

Example  17

(2R) -2-[(6- Chloropyrazine -2-yl) amino] -2- Phenylethanol

Following a procedure similar to Example 1, the product was obtained through the reaction of (2R) -2-amino-2-phenylethanol (420 mg, 3.1 mmol) and 2,6-dichloropyrazine (415 mg, 2.79 mmol). (261 mg, 37%).

Example  18

4- (6-{[(1 R )-2- Hydroxy -One- Phenylethyl ] Amino} Pyrazine -2- days) -2- Methoxyphenol

Following a similar procedure as in Example 2, (2R) -2-[(6-chloropyrazin-2-yl) amino] -2-phenylethanol (137 mg, 0.55 mmol) and 2-methoxy-4- (4 The product was obtained (70 mg, 38%) through the reaction of, 4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenol (151 mg, 0.60 mmol).

Example  19

6- Chloro -N-[(1 S ) -1- (4- Methoxyphenyl )ethyl] Pyrazine 2-amine

Following a procedure similar to Example 1, the product was reacted through the reaction of 4-methoxy-α- (S) -methylbenzylamine (0.70 mg, 4.6 mmol) and 2,6-dichloropyrazine (0.6259 g, 4.20 mmol). Obtained (873 mg, 79%).

Example  20

2- Methoxy -4- (6-{[(1 S ) -1- (4- Methoxyphenyl ) Ethyl] amino} Pyrazine -2-yl) phenol

6-Chloro-N-[( 1S ) -1- (4-methoxyphenyl) ethyl] pyrazin-2-amine (149.4 mg, 0.57 mmol) and 2-methoxy-, according to a procedure similar to Example 2 The product was obtained through the reaction of 4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenol (156 mg, 0.62 mmol) (71 mg, 35 %).

Example  21

6- Chloro -N- ( Pyridine -3- Yl methyl ) Pyrazine 2-amine

A mixture of 2,6-dichloropyrazine (0.671 mmol) and 3-picolinylamine (2, 014 mmol) in xylene (25 mL) was refluxed overnight. The residue obtained after evaporation of the solvent was suspended between CH ₂ Cl ₂ (100 mL) and water (100 mL). The organic phase 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 using a hexane: ethyl acetate gradient mixture as eluent to afford the desired product (93%).

Example  22

2- Methoxy -4- {6-[( Pyridine -3- Yl methyl ) Amino] Pyrazine -2-yl} phenol

6-chloro-N- (pyridin-3-ylmethyl) pyrazin-2-amine (49 mg, 0.22 mmol) in toluene (10 mL), 2-methoxy-4- (4,4,5,5-tetra Methyl-1,3,2-dioxaborolan-2-yl) phenol (52 mg, 0.20 mmol), (PPh ₃ ) ₄ Pd (23 mg, 0.020 mmol), and Na ₂ CO ₃ solution (2 M solution) 0.22 mmol) was heated under reflux overnight. After removal of the solvent, the residue was dissolved in CH ₂ Cl ₂ (150 mL), dried (NaSO ₄ ), filtered and CH ₂ Cl ₂ was removed in vacuo. The residue was purified via column chromatography using an n-hexane: ethyl acetate gradient mixture as eluent to afford the desired product (62 mg, 75%).

Example  23

N- benzyl -6- Chloro -N- Methylpyrazine 2-amine

Following a procedure similar to Example 21, the product was obtained (70%) through the reaction of N-methyl benzylamine and 2,6-dichloropyrazine.

Example  24

4- {6- [ benzyl ( methyl ) Amino] Pyrazine -2-day} -2- Methoxyphenol

N-benzyl-6-chloro-N-methylpyrazin-2-amine and 2-methoxy-4- (4,4,5,5-tetramethyl-1,3,2 according to a procedure similar to Example 22 The product was obtained (51%) through the reaction of dioxaborolan-2-yl) phenol.

Example  25

2- (6- Chloropyrazine -2-yl) -1,2,3,4- Tetrahydroisoquinoline

Following a procedure similar to Example 21, the product was obtained (95%) through the reaction of tetrahydroisoquinoline and 2,6-dichloropyrazine.

Example  26

4- [6- (3,4- Dihydroisoquinoline -2 (1H) -day) Pyrazine -2- day] -2- Methoxyphenol

Following a procedure similar to Example 22, 2- (6-chloropyrazin-2-yl) -1,2,3,4-tetrahydroisoquinoline and 2-methoxy-4- (4,4,5,5 The product was obtained (44%) through the reaction of -tetramethyl-1,3,2-dioxaborolan-2-yl) phenol.

Example  27

6- Chloro -N- (3,4- Dichlorobenzyl ) Pyrazine 2-amine

Following a procedure similar to Example 21, the product was obtained (89%) through the reaction of 3,4-dichlorobenzylamine and 2,6-dichloropyrazine.

Example  28

4- {6-[(3,4- Dichlorobenzyl ) Amino] Pyrazine -2-day} -2- Methoxyphenol

According to a procedure similar to Example 22, 6-chloro-N- (3,4-dichlorobenzyl) pyrazin-2-amine and 2-methoxy-4- (4,4,5,5-tetramethyl-1, The product was obtained (57%) through the reaction of 3,2-dioxaborolan-2-yl) phenol.

Example  29

6- Chloro -N- (3,5- Dimethoxybenzyl ) Pyrazine 2-amine

Following a procedure similar to Example 21, the product was obtained (91%) through the reaction of 3,5-dimethoxybenzylamine and 2,6-dichloropyrazine.

Example  30

4- {6-[(3,5- Dimethoxybenzyl ) Amino] Pyrazine -2-day} -2- Methoxyphenol

6-Chloro-N- (3,5-dimethoxybenzyl) pyrazin-2-amine and 2-methoxy-4- (4,4,5,5-tetramethyl-1, according to a procedure similar to Example 22 The product was obtained (88%) through the reaction of, 3,2-dioxaborolan-2-yl) phenol.

Example  31

6- Chloro -N- (2- Furylmethyl ) Pyrazine 2-amine

Following a procedure similar to Example 21, the product was obtained (98%) through the reaction of furfurylamine and 2,6-dichloropyrazine.

Example  32

4- {6-[(2- Furylmethyl ) Amino] Pyrazine -2-day} -2- Methoxyphenol

According to a procedure similar to Example 2, 6-chloro-N- (2-furylmethyl) pyrazin-2-amine and 2-methoxy-4- (4,4,5,5-tetramethyl-1,3, The product was obtained through the reaction of 2-dioxaborolan-2-yl) phenol (92%).

Example  33

2- Chloro -4- (6-{[(1 S )-One- Phenylethyl ] Amino} Pyrazine -2-yl) phenol

4-bromo-2-chlorophenol (246 mg, 1.18 mmol), bis (pinacolato) diboron (332 mg, 1.3 mmol) in anhydrous methanol (4 mL), [1,1'-bis (diphenyl) The gas was removed from a solution of phosphino) ferrocene] palladium (II) chloride (26 mg, 0.035 mmol), and potassium acetate (222 mg, 2.26 mmol) and heated at 65 ° C. for 24 hours. After cooling, the reaction mixture was diluted with ether and filtered through celite. After removing the solvent under reduced pressure, the residue was purified by chromatography using dichloromethane-hexane (90:10) as eluent. The thus-obtained boronate (50 mg) a, under conditions similar to the conditions used in Example 2, 6-chloro -N - [(1 S) -1- phenylethyl] pyrazin-2-amine (50 mg, 0.2 mmol ), And then purified by chromatography using dichloromethane-ether (90:10) as eluent to give the pure product (44 mg, 68%).

Example  34

6- (4- Aminophenyl ) -N-[(1S) -1- Phenylethyl ] Pyrazine 2-amine

Toluene (20 ㎖) 6- chloro within -N - [(1 S) -1- phenylethyl] pyrazin-2-amine (1.10 g, 4.71 mmol), 4- (4,4,5,5- tetramethyl- 1,3,2-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) ) Was heated at reflux for 40 h. Upon cooling, the mixture was diluted with water (30 mL) and the product obtained was extracted with ethyl acetate (3 x 40 mL). The combined organic phases were washed with brine (30 mL), then dried (Na ₂ SO ₄ ) and the solvent removed in vacuo. The residue was purified via column chromatography using hexane-ethyl acetate (2: 3) as eluent to afford the desired product from the polar fraction (0.86 g, 63%).

Example  35

6- [4- (ethylamino) phenyl] -N-[(1 S )-One- Phenylethyl ] Pyrazine 2-amine

After treatment with solid LiAlH ₄ (38 mg, 1 mmol) in a solution of amide (40 mg, 0.12 mmol) in THF (5 mL), the resulting mixture was stirred at RT for 4 h. The reaction was then sequentially treated with H ₂ O (5 mL), 2M NaOH (5 mL) and water (10 mL), and the suspension obtained was extracted with ethyl acetate (3 × 15 mL). The combined organic phases were dried (Na ₂ SO ₄ ) and concentrated under reduced pressure. The crude product thus obtained was purified by column chromatography using ethyl acetate-hexane (3: 1) as eluent to afford the product as a colorless solid (22 mg, 58%).

Example  36

N- [4- (6-{[(1 S )-One- Phenylethyl ] Amino} Pyrazine -2-yl) phenyl] Methanesulfonamide

6- (4-aminophenyl) -N in anhydrous THE (3 ㎖) - [( 1 S) -1- phenylethyl] pyrazin-2-amine (58 mg, 0.2 mmol), triethylamine (70 ㎕ the solution. 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 RT and stirred overnight then diluted with water (15 mL). The product thus obtained was extracted with ethyl acetate (2 × 15 mL), and the combined extracts were washed with 10% Na ₂ CO ₃ aqueous solution and brine and dried (Na ₂ SO ₄ ). The solvent was removed under reduced pressure and the product was purified by chromatography using ethyl acetate-hexane (3: 2) as eluent to give the product as a pale yellow solid (54 mg, 73%).

Example  37

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

Exemplary method similar to the method set out in Example 39, the 6- (4-aminophenyl) -N - [(1 S) -1- phenylethyl] pyrazin-2-amine (58 mg, 0.2 mmol) and cyclopropane carbonyl The product was obtained through the reaction of chloride (25 mg, 0.24 mmol) and purified by chromatography with ethyl acetate-hexane (3: 2) as eluent (46 mg, 64%).

Example  38

One- Pyridine -3- Il Ethanon Oxime

NaOH (20%, 30 mL) was added to an aqueous solution (20 mL) of hydroxylamine hydrochloride (3.44 g). Ketone (5 g, 41 mmol) was added in one portion, and the resulting mixture was stirred at RT until no ketone remained through TLC. The solvent was evaporated in vacuo and the residue was extracted with CH ₂ Cl ₂ (3 × 100 mL) and then dried (Na ₂ SO ₄ ). After filtration and removal of the solvent, the crude ketoxime was recrystallized from CH ₂ Cl ₂ / n-hexane.

Example  39

1- (3- Chlorophenyl ) Ethanon 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 refluxed for 2 hours. Heated during. Upon cooling the ice bath, ketoxime precipitated out and was collected via suction filtration. The crude product was recrystallized from CH ₂ Cl ₂ / n-hexane (1.88 g, 86%).

Example  40

1- (3- Chlorophenyl Ethanamine

A mixture of ketoxime (1 g, 6 mmol) and LiA1H ₄ (0.27 g) in anhydrous THF (100 mL) was heated overnight at reflux temperature under N ₂ . The reaction mixture was cooled in an ice-water bath and carefully cooled with H ₂ O (60 mL). The mixture was stirred for 30 min at RT temperature and then filtered through Celite ^(R) . The inorganic salt was washed with EtOAc (3 x 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 solution and the product obtained was extracted with Et ₂ O (3 × 50 mL). The combined organic phases were washed with brine (50 mL) and dried (MgSO ₄ ). The solvent was removed in vacuo to give pure amine (0.65 g, 71%).

Example  41

One- Pyridine -3- Monoethanamine

Concentrated HCl (50 mL) was slowly added to the mixture of ketoxime (4.85 g, 36 mmol) and Zn powder (12 g) at 0 ° C. with vigorous stirring. After the initial vigorous reaction had decayed, the mixture was heated under reflux until all ketoxime was found to have been consumed via TLC. After cooling to RT, the strong acidic mixture was extracted with CH ₂ Cl ₂ (2 × 75 mL). The reaction mixture was then made strong basic with 50% KOH solution. After removal of the solvent, the residue was extracted with boiling MeOH (4 x 100 mL). After evaporating MeOH, a crude amine was obtained. The crude amine was used for the next reaction without further purification.

Selection

TEL: JAK  Cell line production

The coding region containing nucleotides 1-487 of TEL was used as the template using U937 mRNA, and oligonucleotide 5TEL (5'-GGA GGA Amplification was by PCR using TCC TGA TCT CTC TCG CTG TGA GAC-3 ') and 3TEL (5'-AGGC GTC GAC TTC TTC TTC ATG GTT CTG-3'). The BamH I site was placed into the 5TEL primer and the Sal I site was introduced into the 3TEL primer. Using the U937 mRNA as a template, Taq DNA polymerase (Gibco / BRL), JAK2 (nucleotides 2994-3914 by PCR using; JAK2F 5'-ACGC GTC GAC GGT GCC TTT GAA GAC CGG GAT-3 '; JAK 2R 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 '; A region comprising the kinase domain of JAK 3R 5'-GGA TCT AGA CTA TGA AAA GGA CAG GGA GTG GTG TTT-3 ') was constructed. Sail sites were introduced into forward primers of JAK2 and JAK3, Not I sites were introduced into reverse primers of JAK2, and Xba I sites were introduced into reverse primers of JAK3.

The TELPCR product was digested with BamHI / Sal I, the JAK2 PCR product was digested with Sal I / Not I and then digested with BamHI-Not I (pTELJAK2) into the mammalian expression vector pTRE 2 (Clontech). Subcloning was done. For JAK3, the kinase domain PCR product cleaved by Sal I / Not I was ligated to the TEL product cleaved by BamHI / Sal I and then ligated into pTRE2 (pTELJAK3) cleaved by BamH I / Not I.

Growth factor dependent myelomonocytic cell line BaF3 (Clontech) containing a pTET-off plasmid was transfected with pTELJAK2 or pTELJAK3 and the cells were selected for factor dependent growth. BaF3 normal cells were cultured in DMEM 10% FCS, 10% WEHI 3B conditioned medium. BaF3 TELJAK cells were cultured in DMEM 10% Tet-System Approved FBS (does not contain WEHI conditioned medium).

Cell evaluation was performed in the following manner:

Cell suspensions were prepared by harvesting cells from the culture. (Cells used in this test should be in late log phase growth and have high viability.) Cells are 1.1 × final concentration in the normal growth medium (50000 cells / ml to 200,000 cells, depending on the cell line). / Ml).

Compounds to be treated were added to a flat bottom 96 well plate (10 μl, 10 × final concentration). A suspension of the cells (90 μl / well) was added to the plate and it was incubated for 40 hours at 37 ° C. and 5% CO ₂ . MTT (20 μl / well, 5 mg / ml in PBS) was added and the plate was returned to the incubator and incubated for an additional 6 hours. Lysis buffer (100 L / well, 10% SDS, 0.01 N HCl) was added and the plate was stored overnight in the incubator. The plate was then read at 590 nm.

Kinase assessments were performed in ELISA assays based on 96 well capture or 384 well Optiplates using a Alphascreen Protein Tyrosine Kinase kit. . In either case, PTK was purified in the presence of 50 mM HEPES, pH7.5, 10 mM MgCl ₂ , 150 mM NaCl, and 10 mM-1 mM ATP, using approximately 1.5 mg of affinity. Biotinylated Substrate Biotin-EGPWLEEEEEAYGWMDF-NH ₂ (final concentration 5 mM) was used as substrate. In ELISA evaluation, oxidase-linked anti-phospho-tyrosine antibody PY20 was used to transfer to avidin coated ELISA plates, followed by quantification of tyrosine phosphorylation. In alphascreen evaluation, alphascreen phosphotyrosine acceptor beads and then streptavidin donor beads were added under soft light. ELISA plates were read on BMG Fluorostar and alphascreen plates were read on Packard Fusion Alpha. 15 minutes before the addition of ATP, the inhibitor was added to the evaluation. Inhibitors were added to aqueous DMSO so that the DMSO concentration did not exceed 1%.

result

The activities of a wide variety of compounds are shown in Table 1. Compounds that exhibited the ability to inhibit 50% of cell growth at a concentration of 50 μM (measured under standard conditions, see the “method” description above) were designated as “+”.

Those skilled in the art will appreciate that numerous changes and / or modifications can be made to the invention presented in particular aspects without departing from the spirit or scope of the invention as broadly disclosed. Accordingly, the aspects presented herein are to be considered in all respects only as illustrative and not restrictive.                 

Table 1: 50 μ At M concentration Transformed Cell line (Tel- Jak 2 and Tel- Jak 3) 2-amino-6- with growth inhibitory activity (> 50%) in Carba -Double substituted Pyrazine  And 2-amino-6-carba-double substituted Pyridine

references

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.

Claims (24)

A compound of formula (I), a pharmaceutically acceptable salt thereof, or a diastereomer thereof:

(I) [Wherein, R 1 is H or C _1-4 alkyl, Q is a bond or C _1-4 alkyl, A is halogen, C _1-4 alkyl, CH ₂ F, CHF ₂ , CF ₃ , CN, aryl, hetaryl, OCF ₃ , OC _1-4 alkyl, CO ₂ R4, CONR4R5, NR4R5, C _{1- 4} alkyl, NR4R5, NR6C _1-4 alkyl, NR4R5, NR4COR5, NR6CONR4R5, and each substituted aryl or het aryl by 0 to 3 substituents independently selected from the group consisting of a; R 4 and R 5 are each independently H, C _1-4 alkyl, C _1-4 alkyl cycloalkyl, C _1-4 alkyl cyclohetalkyl, aryl, hetaryl, C _1-4 alkyl aryl, or C _{1 -4} alkyl hetaryl, or R4 and R5 can be joined together to form an optionally substituted 3-8 membered ring optionally containing an atom selected from the group consisting of 0, S, and NR7. Can be; R 6 is selected from the group consisting of H and C _1-4 alkyl; R 7 is selected from the group consisting of H, C _1-4 alkyl, aryl, hetaryl, C _1-4 alkyl aryl, and C _1-4 alkyl hetaryl, R2 is halogen, C _1-4 alkyl, OH, OC _1-4 alkyl, CH ₂ F, CHF ₂ , CF ₃ , OCF ₃ , CN, C _1-4 alkylNR8R9, OC _1-4 alkylNR8R9, CO ₂ R8 , CONR8R9, NR8R9, NR8COR9, NR10CONR8R9, and NR8SO ₂ R9 are 0-2 substituents independently selected from the group consisting of; R8 and R9 are each independently H, C _1-4 alkyl, C _1-4 alkyl cycloalkyl, C _1-4 alkyl cyclohetalkyl, aryl, hetaryl, C _1-4 alkyl aryl, or C _1-4 alkyl Hetaryl, or R 8 and R 9 may be joined together to form an optionally substituted 3-8 membered ring optionally containing an atom selected from the group consisting of 0, S, and NR 11; R 10 is selected from the group consisting of H, C _1-4 alkyl, aryl, and hetaryl; R 11 is selected from the group consisting of H, C _1-4 alkyl, aryl, hetaryl, C _1-4 alkyl aryl, and C _1-4 alkyl hetaryl, Y is selected from the group consisting of halogen, OH, NR12R13, NR12COR13, NR12CONR13, and N12SO ₂ R13; R12 and R13 are each independently H, C _1-4 alkyl, C _1-4 alkyl cycloalkyl, or C _1-4 alkyl cyclohetalkyl, or R12 and R13 join together to 0, S, and NR14 To form an optionally substituted 3-6 membered ring optionally containing an atom selected from the group consisting of: R14 is selected from the group consisting of H and C _1-4 alkyl, n is 0-2, W is selected from the group consisting of H and C _1-4 alkyl; Wherein C _1-4 alkyl may be optionally substituted by C _1-4 alkyl, OH, and OC _1-4 alkyl; Wherein aryl is phenyl or naphthyl and hetaryl is a 5- or 6-membered heteroaromatic ring containing one or more heteroatoms selected from O, N, and S; Wherein when Y is OH or NHCOCH ₃ , R 2 is 1-2 substituents, and when Y is NH ₂ and R ₂ is absent, Y is in a para position], Or the following compound:

or

. The method of claim 1, Wherein said compound is a compound of formula (II), a pharmaceutically acceptable salt thereof, or a diastereomer thereof:

(II) Where R 1 is H or C _1-4 alkyl, Q is a bond or C _1-4 alkyl, A is halogen, C _1-4 alkyl, CH ₂ F, CHF ₂ , CF ₃ , CN, aryl, hetaryl, OCF ₃ , OC _1-4 alkyl, CO ₂ R4, CONR4R5, NR4R5, C _1-4 alkylNR4R5 Aryl or hetaryl, each substituted by 0-3 substituents independently selected from the group consisting of NR6C _1-4 alkylNR4R5, NR4COR5, NR6CONR4R5, and NR4SO ₂ R5; R 4 and R 5 are each independently H, C _1-4 alkyl, C _1-4 alkyl cycloalkyl, C _1-4 alkyl cyclohetalkyl, aryl, hetaryl, C _1-4 alkyl aryl, or C _1-4 alkyl Hetaryl, or R 4 and R 5 may be joined together to form an optionally substituted 3-8 membered ring optionally containing an atom selected from the group consisting of 0, S, and NR 7; R 6 is selected from the group consisting of H and C _1-4 alkyl; R 7 is selected from the group consisting of H, C _1-4 alkyl, aryl, hetaryl, C _1-4 alkyl aryl, and C _1-4 alkyl hetaryl, R2 is halogen, C _1-4 alkyl, OH, OC _1-4 alkyl, CH ₂ F, CHF ₂ , CF ₃ , OCF ₃ , CN, C _1-4 alkylNR8R9, OC _1-4 alkylNR8R9, CO ₂ R8 , CONR8R9, NR8R9, NR8COR9, NR10CONR8R9, and NR8SO ₂ R9 are 0-2 substituents independently selected from the group consisting of; R8 and R9 are each independently H, C _1-4 alkyl, C _1-4 alkyl cycloalkyl, C _1-4 alkyl cyclohetalkyl, aryl, hetaryl, C _1-4 alkyl aryl, or C _1-4 alkyl Hetaryl or R8 and R9 may be joined together to form an optionally substituted 3-8 membered ring optionally containing an atom selected from the group consisting of 0, S, and NR11; R 10 is selected from the group consisting of H, C _1-4 alkyl, aryl, and hetaryl; R 11 is selected from the group consisting of H, C _1-4 alkyl, aryl, hetaryl, C _1-4 alkyl aryl, and C _1-4 alkyl hetaryl, Y is selected from the group consisting of halogen, OH, NR12R13, NR12COR13, NR12CONR13, and N12SO ₂ R13; R12 and R13 are each independently H, C _1-4 alkyl, C _1-4 alkyl cycloalkyl, or C _1-4 alkyl cyclohetalkyl, or R12 and R13 join together to 0, S, and NR14 May form an optionally substituted 3-6 membered ring optionally containing an atom selected from the group consisting of: R14 is selected from the group consisting of H and C _1-4 alkyl, n is 0-2, W is selected from the group consisting of H, and C _1-4 alkyl; Wherein C _1-4 alkyl may be optionally substituted by C _1-4 alkyl, OH, and OC _1-4 alkyl; Wherein aryl is phenyl or naphthyl and hetaryl is a 5- or 6-membered heteroaromatic ring containing one or more heteroatoms selected from O, N, and S; Wherein when Y is OH or NHCOCH ₃ , R 2 is 1-2 substituents, and when Y is NH ₂ and R ₂ is absent, Y is in the para position. The method of claim 1, W is C _1-4 alkyl and the compound has S chirality at the chiral carbon to which W is bonded. The method of claim 3, The compound is a mixture of R and S isomers, the mixture comprising at least 70% S isomers. The method of claim 4, wherein And said compound comprises at least 80% S isomers. The method of claim 4, wherein And said compound comprises at least 90% S isomers. The method of claim 4, wherein And wherein said compound comprises at least 95% S isomers. The method of claim 4, wherein And wherein said compound comprises at least 99% S isomers. The method of claim 1, Compounds characterized in that the compound is selected from the group consisting of:

delete Tyrosine selected from the group consisting of Janus Kinase 2 (JAK2) and Janus Kinase 3 (JAK3) comprising a therapeutically effective amount of at least one compound according to claim 1 A composition for the treatment of a protein kinase-associated disease state, which is a disease state associated with tyrosine kinase, Atopy diseases wherein the disease state includes allergic asthma, atopic dermatitis (eczema), and allergic rhinitis; Cell mediated hypersensitivity including Allergic Contact Dermatitis and Hypersensitivity Pneumonitis; Systemic Lupus Erythematosus (SLE), Rheumatoid Arthritis, Juvenile Arthritis, Sjogren's Syndrome, Scleroderma, Polymyositis, Polymyositis, Ankylosing Spondylitis, and tendonitis Rheumatic diseases including Psoriatic Arthritis; Autoimmune diseases, including type I diabetes, and autoimmune thyroid disease; And protein kinase- selected from the group consisting of leukemia, Lymphoma, sarcoma, carcinoma, hyperplastic or neoplastic disease, and cancer, including prostate cancer. Compositions for the treatment of related disease states. delete delete delete delete delete The method of claim 11, Wherein said protein kinase-related disease state is selected from the group consisting of one or more sarcoma, carcinoma, and leukemia. The method of claim 17, The protein kinase-related disease state is one or more fibrosarcoma, myxar sarcoma, myxosarcoma, lymphosarcoma, chondrosarcoma, osteogenic sarcoma, chordoma, angiosarcoma (angiosarcoma), endothelial sarcoma, lymphangiosarcoma, lymphangioendotheliosarcoma, synovioma, mesothelioma, Ewing's tumor, smooth muscle sarcoma, leiomyosarcoma Sarcoma, colon carcinoma, pancreatic cancer, breast cancer, ovarian cancer, prostate cancer, squamous cell carcinoma, basal cell carcinoma (basal cell carcinoma), adenocarcinoma, sweat gland carcinoma, sebaceous gland carcinoma, papillary carcinoma, papillary adenocarcinoma, cystadenocarcinoma carcinoma, medullary carcinoma, bronchogenic carcinoma, renal cell carcinoma, hepatoma, bile duct carcinoma, choriocarcinoma, normal carcinoma ), Embryonic carcinoma, Wilm's tumor, cervical cancer, testicular tumor, lung carcinoma, small cell lung carcinoma, bladder carcinoma ( bladder carcinoma, epithelial carcinoma, glioma, astrocytoma, medulloblastoma, craniopharyngioma, ependymoma, pinealoma, hemangioblastoma protein selected from the group consisting of hemangioblastoma, acoustic neuroma, oligodendroglioma, meningioma, melanoma, neuroblastoma, and retinoblastoma. Kinase-related compositions for the treatment of disease states. The method of claim 11, A composition for the treatment of a protein kinase-related disease state wherein said protein kinase-related disease state is a carcinoma formed from breast, prostate, kidney, bladder, or colon tissue. The method of claim 11, A composition for the treatment of a protein kinase-related disease state wherein said protein kinase-related disease state is a hyperplastic or neoplastic disease occurring in adipose tissue. 21. The method of claim 20, A composition for the treatment of a protein kinase-related disease state wherein said proliferative or neoplastic disease is a fat cell tumor. The method of claim 21, The fat cell tumor is at least one lipoma, fibrolipoma, lipoblastoma, lipomatosis, hibemoma, hemangioma, and liposarcoma. Compositions for the treatment of protein kinase-related disease states. Protein kinase-associated disease, a disease state associated with tyrosine kinase selected from the group consisting of Janus Kinase 2 (JAK2) and Janus Kinase 3 (JAK3). A method of using at least one compound according to claim 1 or 2 to prepare a medicament for the treatment of Atopy diseases wherein the disease condition includes allergic asthma, atopic dermatitis (eczema), and allergic rhinitis; Cell mediated hypersensitivity including Allergic Contact Dermatitis and Hypersensitivity Pneumonitis; Systemic Lupus Erythematosus (SLE), Rheumatoid Arthritis, Juvenile Arthritis, Sjogren's Syndrome, Scleroderma, Polymyositis, Polymyositis, Ankylosing Spondylitis, and tendonitis Rheumatic diseases including Psoriatic Arthritis; Autoimmune diseases, including type I diabetes, and autoimmune thyroid disease; And a protein kinase-related that is selected from the group consisting of leukemia, Lymphoma, sarcoma, carcinoma, hyperplastic or neoplastic disease, and prostate cancer. Use of at least one compound according to claim 1 or 2 for the manufacture of a medicament for the treatment of a disease state. 23. The composition of any one of claims 11 and 17-22, further comprising a carrier.

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