KR20040026657A - Inhibitors Of Protein Kinase For The Treatment Of Disease - Google Patents

Abstract

PURPOSE: An inhibitor of protein kinase is provided to prevent and treat protein kinase-related abnormal conditions in organisms, by using partly phenol- and hydroxynaphthalene-based compounds. CONSTITUTION: The inhibitor of protein kinase comprises a compound of formula 1 or a pharmaceutically acceptable salt, amide, ester, or prodrug thereof, wherein (a) R1 is selected from the group consisting of (i) a six-membered aromatic or heteroaromatic, or a five- or six-membered heteroaromatic ring, optionally substituted with one or more substituents, (ii) an acyl having a structure of -(X1)n1-C(O)-X2; and (iii) a substituent having a structure of -C(X4)=N-NX5-C(=E)-NX6X7, or of -C(X4)=N-N=C(EX5)-NX6X7; (b) R2, R3 and R4 are each independently selected from the group consisting of (i) hydrogen, (ii) lower alkyl, (iii) lower alkylene, (iv) halogen or perhaloalkyl, (v) an alkoxy having a structure of -(X13)n13-O-X14, and (vi) a five-membered or six-membered heteroaryl ring or a six-membered aryl or heteroaryl ring; (c) R5 is selected from the group consisting of hydrogen, lower alkyl, aryl, and heteroaryl; (d) R100 is selected from the group consisting of hydrogen, lower alkyl, lower alkene, lower alkyn, aryl, and heteroaryl; and (e) E1 is selected from the group consisting of hydrogen, sulfur, and -NR101-, provided that at least one of R1-R5 is not selected from the group consisting of hydrogen, lower alkyl, aryl, and heteroaryl.

Description

Inhibitors Of Protein Kinase For The Treatment Of Disease

At least 400 enzymes are present as protein kinases that catalyze the phosphate transfer reaction from adenine triphosphate (ATP) to the protein substrate. Since specific amino acids in the target substrate to which the phosphate group is transferred are tyrosine, serine or threonine, protein kinase enzymes are commonly referred to as protein tyrosine kinases (PTKs) or serine / troenine kinases (STKs).

Protein kinases are largely structurally relevant for regulating a wide variety of signaling pathways in cells, including proliferation, differentiation, killing, motility, transcription, translation, and many other signaling processes by delivery of phosphate groups to target proteins. It is composed of groups. These phosphorylation processes act as molecular on / off switches that can regulate the biological function of the target protein or protein complex. Proper function of protein kinases in the signaling pathway is to activate or deactivate metabolism enzymes, regulatory proteins, receptors, cytoskeleton proteins, ion channels and pumps, transcription factors and the like. Improper regulatory signaling due to defective regulation of protein phosphorylation is involved in a number of diseases including inflammation, cancer, allergy / asthma, diseases of the immune system, diseases of the central nervous system, angiogenesis, and the like.

Nearly all kinases contain similar 250-300 amino acid catalytic sites. Kinases can be classified into groups by the substrates they phosphorylate. Sequence motifs corresponding to each of these groups of kinases were identified.

Protein tyrosine kinases (PTKs) are enzymes that catalyze the phosphorylation of specific tyrosine residues in cellular proteins. Variants or excessive PTK activity have been observed in many diseases including proliferative abnormalities as well as diseases resulting from immune system, allograft rejection, and inappropriate activation of graft versus host response. PTKs may be either receptor tyrosine kinases (RTKs) having extracellular, transmembrane and intracellular sites or nonreceptor tyrosine kinases (or cellular tyrosine kinases: CTKs) that are entirely intracellular.

RTKs consist of a large group of transmembrane receptors with various activities. In fact, about 20 different subgroups of RTK were identified. Examples of these subgroups, referred to as the "HER" subgroups, include epithelial growth factor receptor (EGFR), HER2, HER3, and HER4. These RTKs consist of extracellular glycosylated ligands. Another subgroup of these RTKs are insulins, including INS-R, IGF-IR and IR-R. PDGF subgroups include PDGF-α and β receptors, CSFIR, c-kit and FLK-II and the like. The FLK group includes the kinase insert receptor (KDR), fetal liver kinase-1 (FLK-1), fetal liver kinase-4 (FLK-4), fms-like tyrosine kinase (flt-1) and the like. PDGF and FLK groups are usually considered together due to the similarity of these two groups.

A more complete listing of known RTK subgroups is described in Plowman et al., DN & P , 1994, 7 (6): 334-339.

Nonreceptor forms of tyrosine kinases or cellular tyrosine kinases (CTKs) also include numerous subgroups, including Src, Frk, Btk, Csk, Abl, Zap70, Fes / Fps, Fak, Jak, Ack and LIMK. have. Each of these subgroups is subdivided into various receptors. For example, the Src subgroup is one of the largest subgroups including Src, Yes, Fyn, Lyn, Lck, Blk, Hck, Fgr, and Yrk. Src subgroups of proteins are associated with tumorigenesis. See Bolen, Oncogene , 1993, 8: 2025-2031 for a more detailed description of CTKs.

Receptor-type and non-body-type tyrosine kinases are involved in cellular signaling pathways leading to numerous pathogenic conditions, including cancer, psoriasis and hyperimmune reactions.

Like non-receptor tyrosine kinases, serine / threonine kinases (STKs) are generally intracellular, even though some STK receptor kinases are present. STK is the most common case of cytoplasmic kinases. The cell substrate is the site within the cell where the metabolic and biosynthetic activity of the cell occurs.

Cyclin dependent kinases (CDKs) are known to play an important role in cellular processes, including cell circulation regulation, transcription, nerve and muscle function, and apoptosis. Some enzymes for cell cycle regulation include cyclinD / CDK4, cyclinD / CDK6, cyclinE / CDK2, cyclinE / CDK2 and cyclinB / CDK1 (also known as cyclinB / cdc2). CyclinD / CDK4, cyclinD / CDK6 and cyclinE / CDK2 control the processes in phase G1 and phase S to G1 by phosphorylation of retinoblastoma phosphoprotein (pRb). CyclinA / CDK2 controls the process on S, cyclinB / CDK1 controls the G2 checkpoint and regulates entry into mitosis. Thus, certain inhibitors are expected to be useful in the treatment of proliferative diseases such as cancer, neurodegenerative diseases, cardiovascular diseases, and tissue damage from injury. Extensive investigations into specific inhibitors have been of particular interest for the treatment of various diseases.

Aurora Kinases (AKs) have been identified as a new class of protein kinases that regulate the structure and function of mitotic spindles. There are three types, including aurora-A, aurora-B and aurora-C. aurora-A includes AIRK1, DmAurora, HsAurora-2, HsAIK, HsSTK15, CeAIR-1, MmARK1, MmAYK1, MmIAK1 and XIEg2. Aurora-B includes AIRK-2, DmIAL-1, HsAurora-1, HsAIK2, HsAIM-1, HsSTK12, CeAIR-2, MmARK2 and XAIRK2. Aurora-C contains HsAIK3 (Adams, et al ., Trends Cell Biol . 2001, 11, 49-54).

The composition of the aurora family of mitotically regulated serine / threonine kinases appears as key regulators of chromosome segregation and cytoplasmic division. Deregulation of Aks is associated with tumorigenesis as a result of chromosomal desegregation (Hsu, et al ., Cell , 2000, 102, 279-291).

RTKs, CTKs, CDKs, AKs and STKs are all contained within a host of diseased states, including cancer. Other onset conditions include psoriasis, cirrhosis, diabetes, atherosclerosis, hemocytosis, stenosis, visual disorders, immune diseases such as rheumatoid arthritis and other infectious diseases, autoimmune diseases, cardiovascular diseases such as atherosclerosis , And various kidney diseases, but are not limited to these. With respect to cancer, two of the main assumptions introduced to account for the excessive cellular proliferation that cause tumors are related to the functions by which PK is regulated. Malignant cell growth has been suggested to be the result of disruption of the mechanism of action that controls cell separation and / or differentiation. Protein products of numerous proto-oncogenes are known to be involved in signal transduction pathways that regulate cell growth and differentiation. These protein products of the proto-oncogene include extracellular growth factors, transmembrane growth factor PTK receptors (RTKs), cytoplasmic PTKs (CTKs) and cell substrate STKs.

In view of the clear association between PK-related cell activity and numerous human diseases, it is not surprising that much effort is being spent to identify ways to modulate PK activity. Some of these efforts include real cellular processes (eg, mutant ligands (US App. No. 4,966,849); water soluble receptors and antibodies (App. No. WO 94/10202, Kendall and Thomas, Proc. Natl Acad Sci). .., 1994, 90: 10705-09 , Kim, et al, Nature, 1993, 3 62: 841-844); RNA ligands to (Jelinek, et al, Biochemistry, 33:. 10450-56); Takano, et al. , Mol. Bio. Cell, 1993, 4: 358 A; Kinsella, et al ., Exp. Cell Res., 1992, 199: 56-62; Wright, et al. , J Cellular Phys . , 152: 448-57 ) And tyrosine kinase inhibitors (WO 94/03427; WO 92/21660; WO 91/15495; WO 94/14808; US Pat. No. 5,330,992; Mariani, et al. , Proc. Am. Assoc. Cancer Res., 1994, 35: 2268), a biomimetic approach using large molecules patterned with molecules related to this.

More recently, there have also been attempts to identify small molecules that act as PTK inhibitors. For example, bis-monocylic, bicyclic and heterocyclic aryl compounds (PCT WO 92/20642; PCT WO00 / 43373; PCT WO01 / 19828 A2; PCT WO01 / 17995), vinylene-azaindole derivatives (PCT WO 15 94/14808 ), And 1-cyclopropyl-4-pyridylquinolones (US Pat. No. 5,330,992) PTK inhibitors. Styryl compounds (US Pat. No. 5,217,999), styryl-substituted pyridyl compounds (US Pat. No. 5,302,606), quinazoline derivatives (EP App. No. 0 566 266 A1; Expert Opin. Ther. Pat., 1998 , 8 (4), 475-478), selenaindoles and selenides (PCT WO 94/03427), tricyclic polyhydroxylic compounds (PCT WO 92/21660) and benzylphosphonic acid compounds (PCT WO 91/15495) are also useful PTKs for cancer treatment. Inhibitors were identified. Anilinocinnolines (PCT WO97 / 34876) and quinazoline derivative compounds (PCT WO97 / 22596; PCT WO97 / 42187) have been identified as inhibitors of angiogenesis and vascular permeation.

In addition, attempts have been made to identify small molecules that act as STK inhibitors. For example, bis (indolylmaleimide) compounds have been shown to inhibit certain PKC STK isoforms that exhibit signal transduction function associated with altered vascular permeability in VEGF related diseases (PCT WO97 / 40830; PCT WO97 / 40831).

The following background description of the present invention is provided to aid the understanding of the present invention, and does not describe or constitute prior art of the present invention.

One aspect of the invention relates to a compound of Formula 1, or a pharmaceutically acceptable salt, amide, ester, or prodrug thereof.

Where

a) R ₁ is selected from the group consisting of

Iii) a 6-membered aromatic or heteroaromatic, 5- or 6-membered heteroaromatic ring, optionally substituted with one or more substituents selected from the group consisting of lower alkyl, hydroxy, alkoxy, amino and nitro;

Ii) acyl of the formula-(X ₁ ) _{n 1} -C (O) -X ₂ ,

Wherein X ₁ is selected from the group consisting of lower alkylene, lower alkenylene, lower alkynylene, aryl and heteroaryl;

X ₂ is selected from the group consisting of hydrogen, lower alkyl, aryl, heteroaryl, hydroxy, alkoxy, amino, and -NH-X ₃ ;

Wherein X ₃ is selected from the group consisting of hydrogen, alkyl, aryl, heteroaryl, amino, and amide; And

n1 is 0 or 1;

Iv) a substituent of formula -C (X ₄ ) = N-NX ₅ -C (= E) -NX ₆ X ₇ or a formula -C (X ₄ ) = NN = C (EX ₅ ) -NX ₆ X ₇ ,

Wherein X ₄ is selected from the group consisting of hydrogen, lower alkyl, aryl, alkaryl, heteroaryl and amino;

E is selected from the group consisting of oxygen, sulfur and -NR _101- , wherein R ₁₀₁ is selected from the group consisting of hydrogen hydrogen, lower alkyl, lower alkene, lower alkyne, aryl and heteroaryl; And

X ₅ , X ₆ and X ₇ are each independently selected from the group consisting of hydrogen, lower alkyl, aryl and heteroaryl;

Provided that R ₁ is -C ₆ H ₅ , -C (0) H, -C (O) CH ₃ , -C (O) -C ₆ H ₅ , -C (O) NH ₂ , or -C ₆ H _{Not 4} CH ₃ ;

b) R ₂ , R ₃ and R ₄ are each independently selected from the group consisting of:

Iii) hydrogen;

Ii) lower alkyl;

Iii) lower alkylene;

Iii) halogen or perhaloalkyl;

Ⅴ) alkoxy of the formula-(X ₁₃ ) _n13 -OX ₁₄ ,

Wherein X ₁₃ is selected from the group consisting of lower alkylene, lower alkenylene, lower alkynylene, allyl and heteroaryl;

X ₁₄ is selected from the group consisting of hydrogen, lower alkyl, aryl and heteroaryl; And

n13 is 0 or 1; And

V) 5- or 6-membered heteroaryl ring or 6-membered aryl ring or heteroaryl ring, optionally substituted with one or more substituents selected from the group consisting of the following;

A) optionally substituted C ₁ -C ₈ straight, branched, or cyclic saturated or unsaturated alkyl;

B) alkoxy of formula-(X ₁₃ ) _n13 -OX ₁₄ ,

Wherein X ₁₃ is selected from the group consisting of lower alkylene, lower alkenylene, lower alkynylene, aryl and heteroaryl;

X ₁₄ is selected from the group consisting of hydrogen, lower alkyl, aryl and heteroaryl; And

n13 is 0 or 1;

C) halogen or perhaloalkyl;

D) cyano;

E) nitro;

F) amino of the formula-(X ₁₅ ) _n15 -NX ₁₆ X ₁₇ ,

Wherein X ₁₅ is selected from the group consisting of lower alkylene, lower alkenylene, lower alkynylene, aryl and heteroaryl;

X ₁₆ and X ₁₇ are each independently selected from the group consisting of hydrogen, lower alkyl, aryl and heteroaryl; Or X ₁₆ and X ₁₇ are taken together with the nitrogen to which they are attached to form a 5- or 6-membered heteroaromatic or heteroaliphatic ring; n15 is 0 or 1;

G) a substituent of the _formula- (X ₁₈ ) _n18 -C (= E) -X ₁₉ ,

Wherein X ₁₈ is selected from the group consisting of lower alkylene, lower alkenylene, lower alkynylene, aryl and heteroaryl;

E is selected from the group consisting of oxygen, sulfur and -NR _101- , wherein R ₁₀₁ is selected from the group consisting of hydrogen hydrogen, lower alkyl, lower alkene, lower alkyne, aryl and heteroaryl;

X ₁₉ is selected from the group consisting of hydrogen, alkyl, aryl, heteroaryl, hydroxy, alkoxy, amino and -NX ₂₀ X ₂₁ ,

Wherein X ₂₀ and X ₂₁ are each independently selected from the group consisting of hydrogen, alkyl, aryl and heteroaryl;

n18 is 0 or 1; And

H) a thioether or thiol of the _formula- (X ₂₂ ) _{n22 -SX 23} ,

Wherein X ₂₂ is selected from the group consisting of lower alkylene, lower alkenylene, lower alkynylene, aryl and heteroaryl;

X ₂₃ is selected from the group consisting of hydrogen, lower alkyl, aryl and heteroaryl; And

n22 is 0 or 1; And

_{Amide of formula-} (X ₂₄ ) _n24 -NH-C (O) -X _{25 or-} (X ₂₆ ) _n26 -C (O) -NH-X ₂₇ ,

Wherein X ₂₄ and X ₂₆ are each independently selected from the group consisting of lower alkylene, lower alkenylene, lower alkynylene, aryl and heteroaryl;

X ₂₅ is selected from the group consisting of hydrogen, lower alkyl, lower alkenyl, aryl, heteroaryl, hydroxy, alkoxy and amide; And

X ₂₇ is selected from the group consisting of hydrogen, lower alkyl, lower alkenyl, aryl and heteroaryl;

Or R ₂ and R ₃ are taken together with the two ring carbons to which they are attached, or R ₄ and R ₃ are taken together with the two ring carbons to which they are attached, such that they are 6-membered aromatic or heteroaromatic, or 5- or 6-membered heteroaromatic ring, optionally substituted with one or more substituents selected from the group consisting of:

Iii) hydrogen;

Ii) optionally substituted C ₁ -C ₈ straight, branched or cyclic saturated or unsaturated alkyl;

Iii) optionally substituted aryl;

Iii) optionally substituted heterocycle;

Ⅴ) Formula -C (X ₄ ) = N-NX ₅ -C (= E) -NX ₆ X ₇ or -C (X ₄ ) = NN = C (EX ₅ ) -NX ₆ X ₇ ,

Wherein X ₄ is selected from the group consisting of hydrogen, lower alkyl, aryl, alkaryl, heteroaryl and amino;

E is selected from the group consisting of oxygen, sulfur and -NR _101- , wherein R ₁₀₁ is selected from the group consisting of hydrogen hydrogen, lower alkyl, lower alkene, lower alkyne, aryl and heteroaryl; And

X ₅ , X ₆ and X ₇ are each independently selected from the group consisting of hydrogen, lower alkyl, aryl and heteroaryl;

Iii) amino guanidine of formula -NX ₈ -NX ₉ -C (= NX ₁₀ ) -NX ₁₁ X ₁₂ ,

Wherein X ₈ , X ₉ , X ₁₀ , X ₁₁ and X ₁₂ are each independently selected from the group consisting of hydrogen, lower alkyl, aryl and heteroaryl;

Ⅶ) formula - (X _{13) n13} alkoxy of -OX _14,

Wherein X ₁₃ is selected from the group consisting of lower alkylene, lower alkenylene, lower alkynylene, aryl and heteroaryl;

X ₁₄ is selected from the group consisting of hydrogen, lower alkyl, aryl and heteroaryl;

n13 is 0 or 1;

Iii) halogen or perhaloalkyl;

Iii) cyano;

Iii) nitro;

xi) amino of the formula-(X ₁₅ ) _n15 -NX ₁₆ X ₁₇ ,

Wherein X ₁₅ is selected from the group consisting of lower alkylene, lower alkenylene, lower alkynylene, aryl and heteroaryl;

X ₁₆ and X ₁₇ are each independently selected from the group consisting of hydrogen, lower alkyl, aryl and heteroaryl; Or X ₁₆ and X ₁₇ are taken together with the nitrogen to which they are attached and are a 5- or 6-membered heteroaromatic or heteroaliphatic ring; And

n15 is 0 or 1;

xii) a substituent of the formula-(X ₁₈ ) _n18 -C (= E) -X ₁₉ ,

Wherein X ₁₈ is selected from the group consisting of lower alkylene, lower alkenylene, lower alkynylene, aryl and heteroaryl;

E is selected from the group consisting of oxygen, sulfur and -NR _101- , wherein R ₁₀₁ is selected from the group consisting of hydrogen hydrogen, lower alkyl, lower alkene, lower alkyne, aryl and heteroaryl;

X ₁₉ is selected from the group consisting of hydrogen, lower alkyl, aryl, heteroaryl, amino and -NX ₂₀ X ₂₁ ,

Wherein X ₂₀ and X ₂₁ are independently selected from the group consisting of hydrogen, alkyl, aryl and heteroaryl; And

n18 is 0 or 1;

xvi) thioether or thiol of the _formula- (X ₂₂ ) _{n22 -SX 23} ,

Wherein X ₂₂ is lower alkylene, lower alkenylene, lower alkynylene. Aryl and heteroaryl;

X ₂₃ is selected from the group consisting of hydrogen, lower alkyl, aryl and heteroaryl; And

n22 is 0 or 1;

c) R ₅ is selected from the group consisting of hydrogen, lower alkyl, aryl and heteroaryl; Or R ₄ and R ₅ are taken together with the two ring carbons to which they are attached such that a 6-membered aromatic or heteroaromatic, or 5- or 6-membered heteroaromatic ring, which is optionally selected from the group consisting of Or substituted with more substituents;

Iii) hydrogen;

Ii) optionally substituted C ₁ -C ₈ straight, branched or cyclic saturated or unsaturated alkyl;

Iii) optionally substituted aryl;

Iii) optionally substituted heterocycle;

Iv) a substituent of the formula -C (X ₄ ) = N-NX ₅ -C (= E) -NX ₆ X ₇ or -C (X ₄ ) = NN = C (EX ₅ ) -NX ₆ X ₇ ,

Wherein X ₄ is selected from the group consisting of hydrogen, lower alkyl, aryl, alkaryl, heteroaryl and amino;

E is selected from the group consisting of oxygen, sulfur and -NR _101- , wherein R ₁₀₁ is selected from the group consisting of hydrogen hydrogen, lower alkyl, lower alkene, lower alkyne, aryl and heteroaryl; And

X ₅ , X ₆ and X ₇ are each independently selected from the group consisting of hydrogen, lower alkyl, aryl and heteroaryl;

Iii) amino guanidine of formula -NX ₈ -NX ₉ -C (= NX ₁₀ ) -NX ₁₁ X ₁₂ ,

Wherein X ₈ , X ₉ , X ₁₀ , X ₁₁ and X ₁₂ are each independently selected from the group consisting of hydrogen, lower alkyl, aryl and heteroaryl;

Ⅶ) formula - (X _{13) n13} alkoxy of -OX _14,

Wherein X ₁₃ is selected from the group consisting of lower alkylene, lower alkenylene, lower alkynylene, aryl and heteroaryl;

X ₁₄ is selected from the group consisting of hydrogen, lower alkyl, aryl and heteroaryl;

n13 is 0 or 1;

Iii) halogen or perhaloalkyl;

Iii) cyano;

Iii) nitro;

xi) amino of the formula-(X ₁₅ ) _n15 -NX ₁₆ X ₁₇ ,

Wherein X ₁₅ is selected from the group consisting of lower alkylene, lower alkenylene, lower alkynylene, aryl or heteroaryl;

X ₁₆ and X ₁₇ are each independently selected from the group consisting of hydrogen, lower alkyl, aryl and heteroaryl; Or X ₁₆ and X ₁₇ are taken together with the nitrogen to which they are attached and are a 5- or 6-membered heteroaromatic or heteroaliphatic ring; And

n15 is 0 or 1;

xii) a substituent of the formula-(X ₁₈ ) _n18 -C (= E) -X ₁₉ ,

Wherein X ₁₈ is selected from the group consisting of lower alkylene, lower alkenylene, lower alkynylene, aryl and heteroaryl;

E is selected from the group consisting of oxygen, sulfur and -NR _101- , wherein R ₁₀₁ is selected from the group consisting of hydrogen hydrogen, lower alkyl, lower alkene, lower alkyne, aryl and heteroaryl;

X ₁₉ is selected from the group consisting of hydrogen, lower alkyl, aryl, heteroaryl, amino and -NX ₂₀ X ₂₁ ,

Wherein X ₂₀ and X ₂₁ are independently selected from the group consisting of hydrogen, alkyl, aryl and heteroaryl; And

n18 is 0 or 1;

xvi) thioether or thiol of the _formula- (X ₂₂ ) _{n22 -SX 23} ,

Wherein X ₂₂ is lower alkylene, lower alkenylene, lower alkynylene. Aryl and heteroaryl;

X ₂₃ is selected from the group consisting of hydrogen, lower alkyl, aryl and heteroaryl; And

n22 is 0 or 1;

d) R ₁₀₀ is selected from the group consisting of hydrogen, lower alkyl, lower alkene, lower alkyne, aryl and heteroaryl;

e) E ₁ is selected from the group consisting of hydrogen, sulfur and —NR ₁₀₁ —, where NR ₁₀₁ is selected from the group consisting of hydrogen hydrogen, lower alkyl, lower alkene, lower alkyne, aryl and heteroaryl;

Provided that at least one of R ₁ -R ₅ is not selected from the group consisting of hydrogen, lower alkyl, aryl and heteroaryl.

One aspect of the invention relates to a compound of Formula 2, or a pharmaceutically acceptable salt, amide, ester, or prodrug thereof.

Where

a) R ₁ is selected from the group consisting of

Iii) a 6-membered aromatic or heteroaromatic, 5- or 6-membered heteroaromatic ring, optionally substituted with one or more substituents selected from the group consisting of lower alkyl, hydroxy, alkoxy, amino and nitro;

Ii) acyl of the formula-(X ₁ ) _{n 1} -C (O) -X ₂ ,

Wherein X ₁ is selected from the group consisting of lower alkylene, lower alkenylene, lower alkynylene, aryl and heteroaryl;

X ₂ is selected from the group consisting of hydrogen, lower alkyl, aryl, heteroaryl, hydroxy, alkoxy, amino, and -NH-X ₃ ;

Wherein X ₃ is selected from the group consisting of hydrogen, alkyl, aryl, heteroaryl, amino and amide; And

n1 is 0 or 1;

Iv) a substituent of formula -C (X ₄ ) = N-NX ₅ -C (= E) -NX ₆ X ₇ or a formula -C (X ₄ ) = NN = C (EX ₅ ) -NX ₆ X ₇ ,

Wherein X ₄ is selected from the group consisting of hydrogen, lower alkyl, aryl, alkaryl, heteroaryl and amino;

E is selected from the group consisting of oxygen, sulfur and -NR _101- , wherein R ₁₀₁ is selected from the group consisting of hydrogen hydrogen, lower alkyl, lower alkene, lower alkyne, aryl and heteroaryl; And

X ₅ , X ₆ and X ₇ are each independently selected from the group consisting of hydrogen, lower alkyl, aryl and heteroaryl;

Provided that R ₁ is -C ₆ H ₅ , -C (0) H, -C (O) CH ₃ , -C (O) -C ₆ H ₅ , -C (O) NH ₂ , or -C ₆ H _{Not 4} CH ₃ ;

b) R ₂ , R ₃ and R ₄ are each independently selected from the group consisting of the following;

Iii) hydrogen;

Ii) lower alkyl;

Iii) lower alkylene;

Iii) halogen or perhaloalkyl;

Ⅴ) alkoxy of the formula-(X ₁₃ ) _n13 -OX ₁₄ ,

Wherein X ₁₃ is selected from the group consisting of lower alkylene, lower alkenylene, lower alkynylene, allyl and heteroaryl;

X ₁₄ is selected from the group consisting of hydrogen, lower alkyl, aryl and heteroaryl; And

n13 is 0 or 1; And

V) 5- or 6-membered heteroaryl ring or 6-membered aryl ring or heteroaryl ring, optionally substituted with one or more substituents selected from the group consisting of the following;

A) optionally substituted C ₁ -C ₈ straight, branched, or cyclic saturated or unsaturated alkyl;

B) alkoxy of formula-(X ₁₃ ) _n13 -OX ₁₄ ,

Wherein X ₁₃ is selected from the group consisting of lower alkylene, lower alkenylene, lower alkynylene, aryl and heteroaryl;

X ₁₄ is selected from the group consisting of hydrogen, lower alkyl, aryl and heteroaryl; And

n13 is 0 or 1;

C) halogen or perhaloalkyl;

D) cyano;

E) nitro;

F) amino of the formula-(X ₁₅ ) _n15 -NX ₁₆ X ₁₇ ,

Wherein X ₁₅ is selected from the group consisting of lower alkylene, lower alkenylene, lower alkynylene, aryl and heteroaryl;

X ₁₆ and X ₁₇ are each independently selected from the group consisting of hydrogen, lower alkyl, aryl and heteroaryl; Or X ₁₆ and X ₁₇ are taken together with the nitrogen to which they are attached to form a 5- or 6-membered heteroaromatic or heteroaliphatic ring; n15 is 0 or 1;

G) a substituent of the _formula- (X ₁₈ ) _n18 -C (= E) -X ₁₉ ,

Wherein X ₁₈ is selected from the group consisting of lower alkylene, lower alkenylene, lower alkynylene, aryl and heteroaryl;

E is selected from the group consisting of oxygen, sulfur and -NR _101- , wherein R ₁₀₁ is selected from the group consisting of hydrogen hydrogen, lower alkyl, lower alkene, lower alkyne, aryl and heteroaryl;

X ₁₉ is selected from the group consisting of hydrogen, alkyl, aryl, heteroaryl, hydroxy, alkoxy, amino and -NX ₂₀ X ₂₁ ,

Wherein X ₂₀ and X ₂₁ are each independently selected from the group consisting of hydrogen, alkyl, aryl and heteroaryl;

n18 is 0 or 1; And

H) a thioether or thiol of the _formula- (X ₂₂ ) _{n22 -SX 23} ,

Wherein X ₂₂ is selected from the group consisting of lower alkylene, lower alkenylene, lower alkynylene, aryl and heteroaryl; And

X ₂₃ is selected from the group consisting of hydrogen, lower alkyl, aryl and heteroaryl,

n22 is 0 or 1; And

_{Amide of formula-} (X ₂₄ ) _n24 -NH-C (O) -X _{25 or-} (X ₂₆ ) _n26 -C (O) -NH-X ₂₇ ,

Wherein X ₂₄ and X ₂₆ are each independently selected from the group consisting of lower alkylene, lower alkenylene, lower alkynylene, aryl and heteroaryl;

X ₂₅ is selected from the group consisting of hydrogen, lower alkyl, lower alkenyl, aryl, heteroaryl, hydroxy, alkoxy and amide; And

X ₂₇ is selected from the group consisting of hydrogen, lower alkyl, lower alkenyl, aryl and heteroaryl;

Or R ₂ and R ₃ are taken together with the two ring carbons to which they are attached, or R ₄ and R ₃ are taken together with the two ring carbons to which they are attached, such that they are 6-membered aromatic or heteroaromatic, or 5- or 6-membered heteroaromatic ring, which is optionally substituted with one or more substituents selected from the group consisting of:

Iii) hydrogen;

Ii) optionally substituted C ₁ -C ₈ straight, branched or cyclic saturated or unsaturated alkyl;

Iii) optionally substituted aryl;

Iii) optionally substituted heterocycle;

Ⅴ) Formula -C (X ₄ ) = N-NX ₅ -C (= E) -NX ₆ X ₇ or -C (X ₄ ) = NN = C (EX ₅ ) -NX ₆ X ₇ ,

Wherein X ₄ is selected from the group consisting of hydrogen, lower alkyl, aryl, alkaryl, heteroaryl and amino;

E is selected from the group consisting of oxygen, sulfur and -NR _101- , wherein R ₁₀₁ is selected from the group consisting of hydrogen hydrogen, lower alkyl, lower alkene, lower alkyne, aryl and heteroaryl; And

X ₅ , X ₆ and X ₇ are each independently selected from the group consisting of hydrogen, lower alkyl, aryl and heteroaryl;

Iii) amino guanidine of formula -NX ₈ -NX ₉ -C (= NX ₁₀ ) -NX ₁₁ X ₁₂ ,

Wherein X ₈ , X ₉ , X ₁₀ , X ₁₁ and X ₁₂ are each independently selected from the group consisting of hydrogen, lower alkyl, aryl and heteroaryl;

Ⅶ) formula - (X _{13) n13} alkoxy of -OX _14,

Wherein X ₁₃ is selected from the group consisting of lower alkylene, lower alkenylene, lower alkynylene, aryl and heteroaryl;

X ₁₄ is selected from the group consisting of hydrogen, lower alkyl, aryl and heteroaryl;

n13 is 0 or 1;

Iii) halogen or perhaloalkyl;

Iii) cyano;

Iii) nitro;

xi) amino of the formula-(X ₁₅ ) _n15 -NX ₁₆ X ₁₇ ,

Wherein X ₁₅ is selected from the group consisting of lower alkylene, lower alkenylene, lower alkynylene, aryl and heteroaryl;

X ₁₆ and X ₁₇ are each independently selected from the group consisting of hydrogen, lower alkyl, aryl and heteroaryl; Or X ₁₆ and X ₁₇ are taken together with the nitrogen to which they are attached and are a 5- or 6-membered heteroaromatic or heteroaliphatic ring; And

n15 is 0 or 1;

xii) a substituent of the formula-(X ₁₈ ) _n18 -C (= E) -X ₁₉ ,

Wherein X ₁₈ is selected from the group consisting of lower alkylene, lower alkenylene, lower alkynylene, aryl and heteroaryl;

E is selected from the group consisting of oxygen, sulfur and -NR _101- , wherein R ₁₀₁ is selected from the group consisting of hydrogen hydrogen, lower alkyl, lower alkene, lower alkyne, aryl and heteroaryl;

X ₁₉ is selected from the group consisting of hydrogen, lower alkyl, aryl, heteroaryl, amino and -NX ₂₀ X ₂₁ ,

Wherein X ₂₀ and X ₂₁ are independently selected from the group consisting of hydrogen, alkyl, aryl and heteroaryl; And

n18 is 0 or 1;

xvi) thioether or thiol of the _formula- (X ₂₂ ) _{n22 -SX 23} ,

Wherein X ₂₂ is lower alkylene, lower alkenylene, lower alkynylene. Aryl and heteroaryl;

X ₂₃ is selected from the group consisting of hydrogen, lower alkyl, aryl and heteroaryl; And

n22 is 0 or 1;

c) R ₅ is selected from the group consisting of hydrogen, lower alkyl, aryl and heteroaryl; Or R ₄ and R ₅ are taken together with the two ring carbons to which they are attached such that a 6-membered aromatic or heteroaromatic, or 5- or 6-membered heteroaromatic ring, which is optionally selected from the group consisting of Or substituted with more substituents;

Iii) hydrogen;

Ii) optionally substituted C ₁ -C ₈ straight, branched or cyclic saturated or unsaturated alkyl;

Iii) optionally substituted aryl;

Iii) optionally substituted heterocycle;

Iv) a substituent of the formula -C (X ₄ ) = N-NX ₅ -C (= E) -NX ₆ X ₇ or -C (X ₄ ) = NN = C (EX ₅ ) -NX ₆ X ₇ ,

Wherein X ₄ is selected from the group consisting of hydrogen, lower alkyl, aryl, alkaryl, heteroaryl and amino;

E is selected from the group consisting of oxygen, sulfur and -NR _101- , wherein R ₁₀₁ is selected from the group consisting of hydrogen hydrogen, lower alkyl, lower alkene, lower alkyne, aryl and heteroaryl; And

X ₅ , X ₆ and X ₇ are each independently selected from the group consisting of hydrogen, lower alkyl, aryl and heteroaryl;

Iii) amino guanidine of formula -NX ₈ -NX ₉ -C (= NX ₁₀ ) -NX ₁₁ X ₁₂ ,

Wherein X ₈ , X ₉ , X ₁₀ , X ₁₁ and X ₁₂ are each independently selected from the group consisting of hydrogen, lower alkyl, aryl and heteroaryl;

Ⅶ) formula - (X _{13) n13} alkoxy of -OX _14,

Wherein X ₁₃ is selected from the group consisting of lower alkylene, lower alkenylene, lower alkynylene, aryl and heteroaryl;

X ₁₄ is selected from the group consisting of hydrogen, lower alkyl, aryl and heteroaryl;

n13 is 0 or 1;

Iii) halogen or perhaloalkyl;

Iii) cyano;

Iii) nitro;

xi) amino of the formula-(X ₁₅ ) _n15 -NX ₁₆ X ₁₇ ,

Wherein X ₁₅ is selected from the group consisting of lower alkylene, lower alkenylene, lower alkynylene, aryl or heteroaryl;

X ₁₆ and X ₁₇ are each independently selected from the group consisting of hydrogen, lower alkyl, aryl and heteroaryl; Or X ₁₆ and X ₁₇ are taken together with the nitrogen to which they are attached and are a 5- or 6-membered heteroaromatic or heteroaliphatic ring; And

n15 is 0 or 1;

xii) a substituent of the formula-(X ₁₈ ) _n18 -C (= E) -X ₁₉ ,

Wherein X ₁₈ is selected from the group consisting of lower alkylene, lower alkenylene, lower alkynylene, aryl and heteroaryl;

E is selected from the group consisting of oxygen, sulfur and -NR _101- , wherein R ₁₀₁ is selected from the group consisting of hydrogen hydrogen, lower alkyl, lower alkene, lower alkyne, aryl and heteroaryl;

X ₁₉ is selected from the group consisting of hydrogen, lower alkyl, aryl, heteroaryl, amino and -NX ₂₀ X ₂₁ ,

Wherein X ₂₀ and X ₂₁ are independently selected from the group consisting of hydrogen, alkyl, aryl and heteroaryl; And

n18 is 0 or 1;

xvi) thioether or thiol of the _formula- (X ₂₂ ) _{n22 -SX 23} ,

Wherein X ₂₂ is lower alkylene, lower alkenylene, lower alkynylene. Aryl and heteroaryl;

X ₂₃ is selected from the group consisting of hydrogen, lower alkyl, aryl and heteroaryl; And

n22 is 0 or 1;

Provided that at least one of R ₁ -R ₅ is not selected from the group consisting of hydrogen, lower alkyl, aryl and heteroaryl.

One aspect of the invention relates to a compound of Formula 3, or a pharmaceutically acceptable salt, amide, ester, or prodrug thereof.

Where

a) R ₆ is selected from the group consisting of

Iii) a 6-membered aromatic or heteroaromatic, 5- or 6-membered heteroaromatic ring, optionally substituted with one or more substituents selected from the group consisting of lower alkyl, hydroxy, alkoxy, amino and nitro; And

Ii) acyl of the formula-(X ₁ ) _{n 1} -C (O) -X ₂ ,

Wherein X ₁ is selected from the group consisting of lower alkylene, lower alkenylene, lower alkynylene, aryl and heteroaryl;

X ₂ is selected from the group consisting of hydrogen, lower alkyl, aryl, heteroaryl, hydroxy, alkoxy, amino, and -NH-X ₃ ;

Wherein X ₃ is selected from the group consisting of hydrogen, alkyl, aryl, heteroaryl, amino and amide; And

n1 is 0 or 1;

Provided that R ₆ is -C ₆ H ₅ , -C (0) H, -C (O) CH ₃ , -C (O) -C ₆ H ₅ , -C (O) NH ₂ , or -C ₆ H _{Not 4} CH ₃ ;

b) R ₇ , R ₈ and R ₉ are each independently selected from the group consisting of the following;

Iii) hydrogen;

Ii) lower alkyl;

Iii) lower alkylene;

Iii) halogen or perhaloalkyl;

Ⅴ) alkoxy of the formula-(X ₁₃ ) _n13 -OX ₁₄ ,

Wherein X ₁₃ is selected from the group consisting of lower alkylene, lower alkenylene, lower alkynylene, allyl and heteroaryl;

X ₁₄ is selected from the group consisting of hydrogen, lower alkyl, aryl and heteroaryl; And

n13 is 0 or 1; And

V) 5- or 6-membered heteroaryl ring or 6-membered aryl ring or heteroaryl ring, optionally substituted with one or more substituents selected from the group consisting of the following;

A) optionally substituted C ₁ -C ₈ straight, branched, or cyclic saturated or unsaturated alkyl;

B) alkoxy of formula-(X ₁₃ ) _n13 -OX ₁₄ ,

Wherein X ₁₃ is selected from the group consisting of lower alkylene, lower alkenylene, lower alkynylene, aryl and heteroaryl;

X ₁₄ is selected from the group consisting of hydrogen, lower alkyl, aryl and heteroaryl; And

n13 is 0 or 1;

C) halogen or perhaloalkyl;

D) cyano;

E) nitro;

F) amino of the formula-(X ₁₅ ) _n15 -NX ₁₆ X ₁₇ ,

Wherein X ₁₅ is selected from the group consisting of lower alkylene, lower alkenylene, lower alkynylene, aryl and heteroaryl;

X ₁₆ and X ₁₇ are each independently selected from the group consisting of hydrogen, lower alkyl, aryl and heteroaryl; Or X ₁₆ and X ₁₇ are taken together with the nitrogen to which they are attached to form a 5- or 6-membered heteroaromatic or heteroaliphatic ring; And

n15 is 0 or 1;

G) a substituent of the _formula- (X ₁₈ ) _n18 -C (= E) -X ₁₉ ,

Wherein X ₁₈ is selected from the group consisting of lower alkylene, lower alkenylene, lower alkynylene, aryl and heteroaryl;

E is selected from the group consisting of oxygen, sulfur and -NR _101- , wherein R ₁₀₁ is selected from the group consisting of hydrogen hydrogen, lower alkyl, lower alkene, lower alkyne, aryl and heteroaryl;

X ₁₉ is selected from the group consisting of hydrogen, lower alkyl, aryl, heteroaryl, hydroxy, alkoxy, amino and -NX ₂₀ X ₂₁ ,

Wherein X ₂₀ and X ₂₁ are each independently selected from the group consisting of hydrogen, alkyl, aryl and heteroaryl;

n18 is 0 or 1; And

H) a thioether or thiol of the _formula- (X ₂₂ ) _{n22 -SX 23} ,

Wherein X ₂₂ is selected from the group consisting of lower alkylene, lower alkenylene, lower alkynylene, aryl and heteroaryl; And

X ₂₃ is selected from the group consisting of hydrogen, lower alkyl, aryl and heteroaryl,

n22 is 0 or 1; And

_{Amide of formula-} (X ₂₄ ) _n24 -NH-C (O) -X _{25 or-} (X ₂₆ ) _n26 -C (O) -NH-X ₂₇ ,

Wherein X ₂₄ and X ₂₆ are each independently selected from the group consisting of lower alkylene, lower alkenylene, lower alkynylene, aryl and heteroaryl;

X ₂₅ is selected from the group consisting of hydrogen, lower alkyl, lower alkenyl, aryl, heteroaryl, hydroxy, alkoxy and amide; And

X ₂₇ is selected from the group consisting of hydrogen, lower alkyl, lower alkenyl, aryl and heteroaryl;

c) R ₁₀ is selected from the group consisting of hydrogen, lower alkyl, aryl and heteroaryl; Provided that at least one of R ₆ -R ₁₀ is not selected from the group consisting of hydrogen, lower alkyl, aryl and heteroaryl.

Another aspect of the invention relates to a compound of formula 4, or a pharmaceutically acceptable salt, amide, ester, or prodrug thereof.

Where

a) R ₁₁ is selected from the group consisting of hydrogen, lower alkyl, aryl and heteroaryl;

b) R ₁₂ , R ₁₃ and R ₁₄ are each independently selected from the group consisting of the following;

Iii) hydrogen;

Ii) lower alkyl;

Iii) lower alkylene;

Iii) halogen or perhaloalkyl;

Ⅴ) alkoxy of the formula-(X ₁₃ ) _n13 -OX ₁₄ ,

Wherein X ₁₃ is selected from the group consisting of lower alkylene, lower alkenylene, lower alkynylene, allyl and heteroaryl;

X ₁₄ is selected from the group consisting of hydrogen, lower alkyl, aryl and heteroaryl; And

n13 is 0 or 1; And

Iii) a 5- or 6-membered heteroaryl ring or a 6-membered aryl or heteroaryl ring, optionally substituted with one or more substituents selected from the group consisting of:

A) optionally substituted C ₁ -C ₈ straight, branched, or cyclic saturated or unsaturated alkyl;

B) alkoxy of formula-(X ₁₃ ) _n13 -OX ₁₄ ,

Wherein X ₁₃ is selected from the group consisting of lower alkylene, lower alkenylene, lower alkynylene, aryl and heteroaryl;

X ₁₄ is selected from the group consisting of hydrogen, lower alkyl, aryl and heteroaryl; And

n13 is 0 or 1;

C) halogen or perhaloalkyl;

D) cyano;

E) nitro;

F) amino of the formula-(X ₁₅ ) _n15 -NX ₁₆ X ₁₇ ,

Wherein X ₁₅ is selected from the group consisting of lower alkylene, lower alkenylene, lower alkynylene, aryl and heteroaryl;

X ₁₆ and X ₁₇ are each independently selected from the group consisting of hydrogen, lower alkyl, aryl and heteroaryl; Or X ₁₆ and X ₁₇ are taken together with the nitrogen to which they are attached to form a 5- or 6-membered heteroaromatic or heteroaliphatic ring; And

n15 is 0 or 1;

G) a substituent of the _formula- (X ₁₈ ) _n18 -C (= E) -X ₁₉ ,

Wherein X ₁₈ is selected from the group consisting of lower alkylene, lower alkenylene, lower alkynylene, aryl and heteroaryl;

E is selected from the group consisting of oxygen, sulfur and -NR _101- , wherein R ₁₀₁ is selected from the group consisting of hydrogen hydrogen, lower alkyl, lower alkene, lower alkyne, aryl and heteroaryl;

X ₁₉ is selected from the group consisting of hydrogen, lower alkyl, aryl, heteroaryl, hydroxy, alkoxy, amino and -NX ₂₀ X ₂₁ ,

Wherein X ₂₀ and X ₂₁ are each independently selected from the group consisting of hydrogen, alkyl, aryl and heteroaryl;

n18 is 0 or 1; And

H) a thioether or thiol of the _formula- (X ₂₂ ) _{n22 -SX 23} ,

Wherein X ₂₂ is selected from the group consisting of lower alkylene, lower alkenylene, lower alkynylene, aryl and heteroaryl; And

X ₂₃ is selected from the group consisting of hydrogen, lower alkyl, aryl and heteroaryl,

n22 is 0 or 1; And

_{Amide of formula-} (X ₂₄ ) _n24 -NH-C (O) -X _{25 or-} (X ₂₆ ) _n26 -C (O) -NH-X ₂₇ ,

Wherein X ₂₄ and X ₂₆ are each independently selected from the group consisting of lower alkylene, lower alkenylene, lower alkynylene, aryl and heteroaryl;

X ₂₅ is selected from the group consisting of hydrogen, lower alkyl, lower alkenyl, aryl, heteroaryl, hydroxy, alkoxy and amide; And

X ₂₇ is selected from the group consisting of hydrogen, lower alkyl, lower alkenyl, aryl and heteroaryl;

c) R ₁₅ is selected from the group consisting of hydrogen, lower alkyl, aryl, alkaryl, heteroaryl and amino;

d) R ₁₆ and R ₁₇ are each independently selected from the group consisting of hydrogen, lower alkyl, aryl and heteroaryl; And

e) E is selected from the group consisting of oxygen, sulfur and —NR ₁₀₁ —, where R ₁₀₁ is selected from the group consisting of hydrogen hydrogen, lower alkyl, lower alkene, lower alkyne, aryl and heteroaryl.

Another aspect of the invention relates to a compound of formula 5 or 6, or a pharmaceutically acceptable salt, amide, ester, or prodrug thereof.

Where

a) R ₁₉ -R ₂₂ and R ₂₆ -R ₂₉ are each independently selected from the group consisting of

Iii) hydrogen;

Ii) optionally substituted C ₁ -C ₈ straight, branched or cyclic saturated or unsaturated alkyl;

Iii) optionally substituted aryl;

Iii) optionally substituted heterocycle;

Ⅴ) Formula -C (X ₄ ) = N-NX ₅ -C (= E) -NX ₆ X ₇ or -C (X ₄ ) = NN = C (EX ₅ ) -NX ₆ X ₇ ,

Wherein X ₄ is selected from the group consisting of hydrogen, lower alkyl, aryl, alkaryl, heteroaryl and amino;

E is selected from the group consisting of oxygen, sulfur and -NR _101- , wherein R ₁₀₁ is selected from the group consisting of hydrogen hydrogen, lower alkyl, lower alkene, lower alkyne, aryl and heteroaryl; And

X ₅ , X ₆ and X ₇ are each independently selected from the group consisting of hydrogen, lower alkyl, aryl and heteroaryl;

Iii) amino guanidine of formula -NX ₈ -NX ₉ -C (= NX ₁₀ ) -NX ₁₁ X ₁₂ ,

Wherein X ₈ , X ₉ , X ₁₀ , X ₁₁ and X ₁₂ are each independently selected from the group consisting of hydrogen, lower alkyl, aryl and heteroaryl;

Ⅶ) formula - (X _{13) n13} alkoxy of -OX _14,

Wherein X ₁₃ is selected from the group consisting of lower alkylene, lower alkenylene, lower alkynylene, aryl and heteroaryl;

X ₁₄ is selected from the group consisting of hydrogen, lower alkyl, aryl and heteroaryl;

n13 is 0 or 1;

Iii) halogen or perhaloalkyl;

Iii) cyano;

Iii) nitro;

xi) amino of the formula-(X ₁₅ ) _n15 -NX ₁₆ X ₁₇ ,

Wherein X ₁₅ is selected from the group consisting of lower alkylene, lower alkenylene, lower alkynylene, aryl and heteroaryl;

X ₁₆ and X ₁₇ are each independently selected from the group consisting of hydrogen, lower alkyl, aryl and heteroaryl; Or X ₁₆ and X ₁₇ are taken together with the nitrogen to which they are attached and are a 5- or 6-membered heteroaromatic or heteroaliphatic ring; And

n15 is 0 or 1;

xii) a substituent of the formula-(X ₁₈ ) _n18 -C (= E) -X ₁₉ ,

Wherein X ₁₈ is selected from the group consisting of lower alkylene, lower alkenylene, lower alkynylene, aryl and heteroaryl;

E is selected from the group consisting of oxygen, sulfur and -NR _101- , wherein R ₁₀₁ is selected from the group consisting of hydrogen hydrogen, lower alkyl, lower alkene, lower alkyne, aryl and heteroaryl;

X ₁₉ is selected from the group consisting of hydrogen, lower alkyl, aryl, heteroaryl, amino and -NX ₂₀ X ₂₁ ,

Wherein X ₂₀ and X ₂₁ are independently selected from the group consisting of hydrogen, alkyl, aryl and heteroaryl; And

n18 is 0 or 1;

xvi) thioether or thiol of the _formula- (X ₂₂ ) _{n22 -SX 23} ,

Wherein X ₂₂ is lower alkylene, lower alkenylene, lower alkynylene. Aryl and heteroaryl;

X ₂₃ is selected from the group consisting of hydrogen, lower alkyl, aryl and heteroaryl; And

n22 is 0 or 1;

b) R ₂₃ and R ₃₀ are each independently selected from the group consisting of the following;

Iii) hydrogen;

Ii) lower alkyl;

Iii) lower alkylene;

Iii) halogen or perhaloalkyl;

Ⅴ) alkoxy of the formula-(X ₁₃ ) _n13 -OX ₁₄ ,

Wherein X ₁₃ is selected from the group consisting of lower alkylene, lower alkenylene, lower alkynylene, allyl and heteroaryl;

X ₁₄ is selected from the group consisting of hydrogen, lower alkyl, aryl and heteroaryl; And

n13 is 0 or 1; And

Iii) a 5- or 6-membered heteroaryl ring or a 6-membered aryl or heteroaryl ring, optionally substituted with one or more substituents selected from the group consisting of:

A) optionally substituted C ₁ -C ₈ straight, branched, or cyclic saturated or unsaturated alkyl;

B) alkoxy of formula-(X ₁₃ ) _n13 -OX ₁₄ ,

Wherein X ₁₃ is selected from the group consisting of lower alkylene, lower alkenylene, lower alkynylene, aryl and heteroaryl;

X ₁₄ is selected from the group consisting of hydrogen, lower alkyl, aryl and heteroaryl; And

n13 is 0 or 1;

C) halogen or perhaloalkyl;

D) cyano;

E) nitro;

F) amino of the formula-(X ₁₅ ) _n15 -NX ₁₆ X ₁₇ ,

Wherein X ₁₅ is selected from the group consisting of lower alkylene, lower alkenylene, lower alkynylene, aryl and heteroaryl;

X ₁₆ and X ₁₇ are each independently selected from the group consisting of hydrogen, lower alkyl, aryl and heteroaryl; Or X ₁₆ and X ₁₇ are taken together with the nitrogen to which they are attached to form a 5- or 6-membered heteroaromatic or heteroaliphatic ring; And

n15 is 0 or 1;

G) a substituent of the _formula- (X ₁₈ ) _n18 -C (= E) -X ₁₉ ,

Wherein X ₁₈ is selected from the group consisting of lower alkylene, lower alkenylene, lower alkynylene, aryl and heteroaryl;

E is selected from the group consisting of oxygen, sulfur and -NR _101- , wherein R ₁₀₁ is selected from the group consisting of hydrogen hydrogen, lower alkyl, lower alkene, lower alkyne, aryl and heteroaryl;

X ₁₉ is selected from the group consisting of hydrogen, lower alkyl, aryl, heteroaryl, hydroxy, alkoxy, amino and -NX ₂₀ X ₂₁ ,

Wherein X ₂₀ and X ₂₁ are each independently selected from the group consisting of hydrogen, alkyl, aryl and heteroaryl;

n18 is 0 or 1; And

H) a thioether or thiol of the _formula- (X ₂₂ ) _{n22 -SX 23} ,

Wherein X ₂₂ is selected from the group consisting of lower alkylene, lower alkenylene, lower alkynylene, aryl and heteroaryl; And

X ₂₃ is selected from the group consisting of hydrogen, lower alkyl, aryl and heteroaryl,

n22 is 0 or 1; And

_{Amide of formula-} (X ₂₄ ) _n24 -NH-C (O) -X _{25 or-} (X ₂₆ ) _n26 -C (O) -NH-X ₂₇ ,

Wherein X ₂₄ and X ₂₆ are each independently selected from the group consisting of lower alkylene, lower alkenylene, lower alkynylene, aryl and heteroaryl;

X ₂₅ is selected from the group consisting of hydrogen, lower alkyl, lower alkenyl, aryl, heteroaryl, hydroxy, alkoxy and amide; And

X ₂₇ is selected from the group consisting of hydrogen, lower alkyl, lower alkenyl, aryl and heteroaryl; and

c) R ₂₄ , R ₂₅ , R ₃₁ and R ₃₂ are each independently selected from the group consisting of

Iii) a 6-membered aromatic or heteroaromatic, 5- or 6-membered heteroaromatic ring, optionally substituted with one or more substituents selected from the group consisting of lower alkyl, hydroxy, alkoxy, amino and nitro;

Ii) acyl of the formula-(X ₁ ) _{n 1} -C (O) -X ₂ ,

Wherein X ₁ is selected from the group consisting of lower alkylene, lower alkenylene, lower alkynylene, aryl and heteroaryl;

X ₂ is selected from the group consisting of hydrogen, lower alkyl, aryl, heteroaryl, hydroxy, alkoxy, amino and -NH-X ₃ ;

Wherein X ₃ is selected from the group consisting of hydrogen, alkyl, aryl, heteroaryl, amino and amide; And

n1 is 0 or 1;

Iv) a substituent of formula -C (X ₄ ) = N-NX ₅ -C (= E) -NX ₆ X ₇ or a formula -C (X ₄ ) = NN = C (EX ₅ ) -NX ₆ X ₇ ,

Wherein X ₄ is selected from the group consisting of hydrogen, lower alkyl, aryl, alkaryl, heteroaryl and amino;

E is selected from the group consisting of oxygen, sulfur and -NR _101- , wherein R ₁₀₁ is selected from the group consisting of hydrogen hydrogen, lower alkyl, lower alkene, lower alkyne, aryl and heteroaryl; And

X ₅ , X ₆ and X ₇ are each independently selected from the group consisting of hydrogen, lower alkyl, aryl and heteroaryl;

Provided that any of R ₂₄ , R ₂₅ , R ₃₁ or R ₃₂ is -C ₆ H ₅ , -C (0) H, -C (O) CH ₃ , -C (O) -C ₆ H ₅ , -C (O) NH ₂ , or -C ₆ H ₄ CH ₃ .

Another aspect of the invention relates to a compound selected from the group consisting of the compounds set forth in Table 1, pharmaceutically acceptable salts, esters, amides or prodrugs thereof.

Compounds of the present invention can inhibit the catalytic activity of protein kinases. Protein kinases may also be selected from the group consisting of receptor protein tyrosine kinases, cellular tyrosine kinases, and serine-troonine kinases.

In another aspect, the present invention relates to a method of modulating the catalytic activity of a protein kinase, comprising contacting certain compounds according to the invention with a protein kinase.

The invention also relates to a method of modulating a signal transduction pathway in a cell, comprising contacting any compound according to the invention with the cell.

Another aspect of the invention,

a) contacting any compound according to the invention with a cell expressing a protein kinase; And

b) monitoring the effect of said compound in the cell;

It relates to a method for identifying an aromatic compound consisting of, comprising a modulating protein kinase function.

In another aspect, the invention relates to a method for regulating an unregulated protein kinase signal transduction system by administering to a subject a pharmacologically effective amount of a compound according to the invention. Unregulated protein kinase signal transduction systems can cause disease or abnormal conditions in an organism, and the method can lead to the treatment or prevention of such diseases or abnormal conditions. Wherein the disease or abnormal condition is associated with an abnormality in the signal transduction pathway characterized by the interaction between the protein kinase and the binding partner, the method further comprising promoting or stopping this abnormal interaction. It may consist of.

In this method, the disease or abnormal condition may be selected from the group consisting of cell proliferative diseases, cerebrovascular injury, autoimmune diseases, degenerative neurological diseases, and degenerative diseases of the musculoskeletal system.

In a further aspect, the invention relates to a pharmaceutical composition comprising i) a physiologically acceptable carrier, diluent or excipient, or a combination thereof, and ii) a compound of the invention.

Detailed description of the preferred examples

I. Compounds of the Invention

A. General description of the compounds

One aspect of the invention relates to a compound of Formula 1, or a pharmaceutically acceptable salt, amide, ester, or prodrug thereof.

(One)

Where

a) R ₁ is selected from the group consisting of

Iii) a 6-membered aromatic or heteroaromatic, 5- or 6-membered heteroaromatic ring, optionally substituted with one or more substituents selected from the group consisting of lower alkyl, hydroxy, alkoxy, amino and nitro;

Ii) acyl of the formula-(X ₁ ) _{n 1} -C (O) -X ₂ ,

Wherein X ₁ is selected from the group consisting of lower alkylene, lower alkenylene, lower alkynylene, aryl and heteroaryl;

X ₂ is selected from the group consisting of hydrogen, lower alkyl, aryl, heteroaryl, hydroxy, alkoxy, amino, and -NH-X ₃ ;

Wherein X ₃ is selected from the group consisting of hydrogen, alkyl, aryl, heteroaryl, amino, and amide; And

n1 is 0 or 1;

Iv) a substituent of formula -C (X ₄ ) = N-NX ₅ -C (= E) -NX ₆ X ₇ or a formula -C (X ₄ ) = NN = C (EX ₅ ) -NX ₆ X ₇ ,

Wherein X ₄ is selected from the group consisting of hydrogen, lower alkyl, aryl, alkaryl, heteroaryl and amino;

E is selected from the group consisting of oxygen, sulfur and -NR _101- , wherein R ₁₀₁ is selected from the group consisting of hydrogen hydrogen, lower alkyl, lower alkene, lower alkyne, aryl and heteroaryl; And

X ₅ , X ₆ and X ₇ are each independently selected from the group consisting of hydrogen, lower alkyl, aryl and heteroaryl;

Provided that R ₁ is -C ₆ H ₅ , -C (0) H, -C (O) CH ₃ , -C (O) -C ₆ H ₅ , -C (O) NH ₂ , or -C ₆ H _{Not 4} CH ₃ ;

b) R ₂ , R ₃ and R ₄ are each independently selected from the group consisting of:

Iii) hydrogen;

Ii) lower alkyl;

Iii) lower alkylene;

Iii) halogen or perhaloalkyl;

Ⅴ) alkoxy of the formula-(X ₁₃ ) _n13 -OX ₁₄ ,

Wherein X ₁₃ is selected from the group consisting of lower alkylene, lower alkenylene, lower alkynylene, allyl and heteroaryl;

X ₁₄ is selected from the group consisting of hydrogen, lower alkyl, aryl and heteroaryl; And

n13 is 0 or 1; And

V) 5- or 6-membered heteroaryl ring or 6-membered aryl ring or heteroaryl ring, optionally substituted with one or more substituents selected from the group consisting of the following;

A) optionally substituted C ₁ -C ₈ straight, branched, or cyclic saturated or unsaturated alkyl;

B) alkoxy of formula-(X ₁₃ ) _n13 -OX ₁₄ ,

Wherein X ₁₃ is selected from the group consisting of lower alkylene, lower alkenylene, lower alkynylene, aryl and heteroaryl;

X ₁₄ is selected from the group consisting of hydrogen, lower alkyl, aryl and heteroaryl; And

n13 is 0 or 1;

C) halogen or perhaloalkyl;

D) cyano;

E) nitro;

F) amino of the formula-(X ₁₅ ) _n15 -NX ₁₆ X ₁₇ ,

Wherein X ₁₅ is selected from the group consisting of lower alkylene, lower alkenylene, lower alkynylene, aryl and heteroaryl;

X ₁₆ and X ₁₇ are each independently selected from the group consisting of hydrogen, lower alkyl, aryl and heteroaryl; Or X ₁₆ and X ₁₇ are taken together with the nitrogen to which they are attached to form a 5- or 6-membered heteroaromatic or heteroaliphatic ring; n15 is 0 or 1;

G) a substituent of the _formula- (X ₁₈ ) _n18 -C (= E) -X ₁₉ ,

Wherein X ₁₈ is selected from the group consisting of lower alkylene, lower alkenylene, lower alkynylene, aryl and heteroaryl;

E is selected from the group consisting of oxygen, sulfur and -NR _101- , wherein R ₁₀₁ is selected from the group consisting of hydrogen hydrogen, lower alkyl, lower alkene, lower alkyne, aryl and heteroaryl;

X ₁₉ is selected from the group consisting of hydrogen, alkyl, aryl, heteroaryl, hydroxy, alkoxy, amino and -NX ₂₀ X ₂₁ ,

Wherein X ₂₀ and X ₂₁ are each independently selected from the group consisting of hydrogen, alkyl, aryl and heteroaryl;

n18 is 0 or 1; And

H) a thioether or thiol of the _formula- (X ₂₂ ) _{n22 -SX 23} ,

Wherein X ₂₂ is selected from the group consisting of lower alkylene, lower alkenylene, lower alkynylene, aryl and heteroaryl;

X ₂₃ is selected from the group consisting of hydrogen, lower alkyl, aryl and heteroaryl; And

n22 is 0 or 1; And

_{Amide of formula-} (X ₂₄ ) _n24 -NH-C (O) -X _{25 or-} (X ₂₆ ) _n26 -C (O) -NH-X ₂₇ ,

Wherein X ₂₄ and X ₂₆ are each independently selected from the group consisting of lower alkylene, lower alkenylene, lower alkynylene, aryl and heteroaryl;

X ₂₅ is selected from the group consisting of hydrogen, lower alkyl, lower alkenyl, aryl, heteroaryl, hydroxy, alkoxy and amide; And

X ₂₇ is selected from the group consisting of hydrogen, lower alkyl, lower alkenyl, aryl and heteroaryl;

Or R ₂ and R ₃ are taken together with the two ring carbons to which they are attached, or R ₄ and R ₃ are taken together with the two ring carbons to which they are attached, such that they are 6-membered aromatic or heteroaromatic, or 5- or 6-membered heteroaromatic ring, which is optionally substituted with one or more substituents selected from the group consisting of:

Iii) hydrogen;

Ii) optionally substituted C ₁ -C ₈ straight, branched or cyclic saturated or unsaturated alkyl;

Iii) optionally substituted aryl;

Iii) optionally substituted heterocycle;

Ⅴ) Formula -C (X ₄ ) = N-NX ₅ -C (= E) -NX ₆ X ₇ or -C (X ₄ ) = NN = C (EX ₅ ) -NX ₆ X ₇ ,

Wherein X ₄ is selected from the group consisting of hydrogen, lower alkyl, aryl, alkaryl, heteroaryl and amino;

E is selected from the group consisting of oxygen, sulfur and -NR _101- , wherein R ₁₀₁ is selected from the group consisting of hydrogen hydrogen, lower alkyl, lower alkene, lower alkyne, aryl and heteroaryl; And

X ₅ , X ₆ and X ₇ are each independently selected from the group consisting of hydrogen, lower alkyl, aryl and heteroaryl;

Iii) amino guanidine of formula -NX ₈ -NX ₉ -C (= NX ₁₀ ) -NX ₁₁ X ₁₂ ,

Wherein X ₈ , X ₉ , X ₁₀ , X ₁₁ and X ₁₂ are each independently selected from the group consisting of hydrogen, lower alkyl, aryl and heteroaryl;

Ⅶ) formula - (X _{13) n13} alkoxy of -OX _14,

Wherein X ₁₃ is selected from the group consisting of lower alkylene, lower alkenylene, lower alkynylene, aryl and heteroaryl;

X ₁₄ is selected from the group consisting of hydrogen, lower alkyl, aryl and heteroaryl;

n13 is 0 or 1;

Iii) halogen or perhaloalkyl;

Iii) cyano;

Iii) nitro;

xi) amino of the formula-(X ₁₅ ) _n15 -NX ₁₆ X ₁₇ ,

Wherein X ₁₅ is selected from the group consisting of lower alkylene, lower alkenylene, lower alkynylene, aryl and heteroaryl;

X ₁₆ and X ₁₇ are each independently selected from the group consisting of hydrogen, lower alkyl, aryl and heteroaryl; Or X ₁₆ and X ₁₇ are taken together with the nitrogen to which they are attached and are a 5- or 6-membered heteroaromatic or heteroaliphatic ring; And

n15 is 0 or 1;

xii) a substituent of the formula-(X ₁₈ ) _n18 -C (= E) -X ₁₉ ,

Wherein X ₁₈ is selected from the group consisting of lower alkylene, lower alkenylene, lower alkynylene, aryl and heteroaryl;

E is selected from the group consisting of oxygen, sulfur and -NR _101- , wherein R ₁₀₁ is selected from the group consisting of hydrogen hydrogen, lower alkyl, lower alkene, lower alkyne, aryl and heteroaryl;

X ₁₉ is selected from the group consisting of hydrogen, lower alkyl, aryl, heteroaryl, amino and -NX ₂₀ X ₂₁ ,

Wherein X ₂₀ and X ₂₁ are independently selected from the group consisting of hydrogen, alkyl, aryl and heteroaryl; And

n18 is 0 or 1;

xvi) thioether or thiol of the _formula- (X ₂₂ ) _{n22 -SX 23} ,

Wherein X ₂₂ is lower alkylene, lower alkenylene, lower alkynylene. Aryl and heteroaryl;

X ₂₃ is selected from the group consisting of hydrogen, lower alkyl, aryl and heteroaryl; And

n22 is 0 or 1;

c) R ₅ is selected from the group consisting of hydrogen, lower alkyl, aryl and heteroaryl; Or R ₄ and R ₅ are taken together with the two ring carbons to which they are attached such that a 6-membered aromatic or heteroaromatic, or 5- or 6-membered heteroaromatic ring, which is optionally selected from the group consisting of Or substituted with more substituents;

Iii) hydrogen;

Ii) optionally substituted C ₁ -C ₈ straight, branched or cyclic saturated or unsaturated alkyl;

Iii) optionally substituted aryl;

Iii) optionally substituted heterocycle;

Iv) a substituent of the formula -C (X ₄ ) = N-NX ₅ -C (= E) -NX ₆ X ₇ or -C (X ₄ ) = NN = C (EX ₅ ) -NX ₆ X ₇ ,

Wherein X ₄ is selected from the group consisting of hydrogen, lower alkyl, aryl, alkaryl, heteroaryl and amino;

E is selected from the group consisting of oxygen, sulfur and -NR _101- , wherein R ₁₀₁ is selected from the group consisting of hydrogen hydrogen, lower alkyl, lower alkene, lower alkyne, aryl and heteroaryl; And

X ₅ , X ₆ and X ₇ are each independently selected from the group consisting of hydrogen, lower alkyl, aryl and heteroaryl;

Iii) amino guanidine of formula -NX ₈ -NX ₉ -C (= NX ₁₀ ) -NX ₁₁ X ₁₂ ,

Wherein X ₈ , X ₉ , X ₁₀ , X ₁₁ and X ₁₂ are each independently selected from the group consisting of hydrogen, lower alkyl, aryl and heteroaryl;

Ⅶ) formula - (X _{13) n13} alkoxy of -OX _14,

Wherein X ₁₃ is selected from the group consisting of lower alkylene, lower alkenylene, lower alkynylene, aryl and heteroaryl;

X ₁₄ is selected from the group consisting of hydrogen, lower alkyl, aryl and heteroaryl;

n13 is 0 or 1;

Iii) halogen or perhaloalkyl;

Iii) cyano;

Iii) nitro;

xi) amino of the formula-(X ₁₅ ) _n15 -NX ₁₆ X ₁₇ ,

Wherein X ₁₅ is selected from the group consisting of lower alkylene, lower alkenylene, lower alkynylene, aryl or heteroaryl;

X ₁₆ and X ₁₇ are each independently selected from the group consisting of hydrogen, lower alkyl, aryl and heteroaryl; Or X ₁₆ and X ₁₇ are taken together with the nitrogen to which they are attached and are a 5- or 6-membered heteroaromatic or heteroaliphatic ring; And

n15 is 0 or 1;

xii) a substituent of the formula-(X ₁₈ ) _n18 -C (= E) -X ₁₉ ,

Wherein X ₁₈ is selected from the group consisting of lower alkylene, lower alkenylene, lower alkynylene, aryl and heteroaryl;

E is selected from the group consisting of oxygen, sulfur and -NR _101- , wherein R ₁₀₁ is selected from the group consisting of hydrogen hydrogen, lower alkyl, lower alkene, lower alkyne, aryl and heteroaryl;

X ₁₉ is selected from the group consisting of hydrogen, lower alkyl, aryl, heteroaryl, amino and -NX ₂₀ X ₂₁ ,

Wherein X ₂₀ and X ₂₁ are independently selected from the group consisting of hydrogen, alkyl, aryl and heteroaryl; And

n18 is 0 or 1;

xvi) thioether or thiol of the _formula- (X ₂₂ ) _{n22 -SX 23} ,

Wherein X ₂₂ is lower alkylene, lower alkenylene, lower alkynylene. Aryl and heteroaryl;

X ₂₃ is selected from the group consisting of hydrogen, lower alkyl, aryl and heteroaryl; And

n22 is 0 or 1;

d) R ₁₀₀ is selected from the group consisting of hydrogen, lower alkyl, lower alkene, lower alkyne, aryl and heteroaryl;

e) E ₁ is selected from the group consisting of hydrogen, sulfur and —NR ₁₀₁ —, where NR ₁₀₁ is selected from the group consisting of hydrogen hydrogen, lower alkyl, lower alkene, lower alkyne, aryl and heteroaryl;

Provided that at least one of R ₁ -R ₅ is not selected from the group consisting of hydrogen, lower alkyl, aryl and heteroaryl.

In another aspect, the invention relates to a compound of Formula 2, or a pharmaceutically acceptable salt, amide, ester, or prodrug thereof.

(2)

Where

a) R ₁ is selected from the group consisting of

Iii) a 6-membered aromatic or heteroaromatic, 5- or 6-membered heteroaromatic ring, optionally substituted with one or more substituents selected from the group consisting of lower alkyl, hydroxy, alkoxy, amino and nitro;

Ii) acyl of the formula-(X ₁ ) _{n 1} -C (O) -X ₂ ,

Wherein X ₁ is selected from the group consisting of lower alkylene, lower alkenylene, lower alkynylene, aryl and heteroaryl;

X ₂ is selected from the group consisting of hydrogen, lower alkyl, aryl, heteroaryl, hydroxy, alkoxy, amino, and -NH-X ₃ ;

Wherein X ₃ is selected from the group consisting of hydrogen, alkyl, aryl, heteroaryl, amino and amide; And

n1 is 0 or 1;

Iv) a substituent of formula -C (X ₄ ) = N-NX ₅ -C (= E) -NX ₆ X ₇ or a formula -C (X ₄ ) = NN = C (EX ₅ ) -NX ₆ X ₇ ,

Wherein X ₄ is selected from the group consisting of hydrogen, lower alkyl, aryl, alkaryl, heteroaryl and amino;

E is selected from the group consisting of oxygen, sulfur and -NR _101- , wherein R ₁₀₁ is selected from the group consisting of hydrogen hydrogen, lower alkyl, lower alkene, lower alkyne, aryl and heteroaryl; And

X ₅ , X ₆ and X ₇ are each independently selected from the group consisting of hydrogen, lower alkyl, aryl and heteroaryl;

Provided that R ₁ is -C ₆ H ₅ , -C (0) H, -C (O) CH ₃ , -C (O) -C ₆ H ₅ , -C (O) NH ₂ , or -C ₆ H _{Not 4} CH ₃ ;

b) R ₂ , R ₃ and R ₄ are each independently selected from the group consisting of the following;

Iii) hydrogen;

Ii) lower alkyl;

Iii) lower alkylene;

Iii) halogen or perhaloalkyl;

Ⅴ) alkoxy of the formula-(X ₁₃ ) _n13 -OX ₁₄ ,

Wherein X ₁₃ is selected from the group consisting of lower alkylene, lower alkenylene, lower alkynylene, allyl and heteroaryl;

X ₁₄ is selected from the group consisting of hydrogen, lower alkyl, aryl and heteroaryl; And

n13 is 0 or 1; And

V) 5- or 6-membered heteroaryl ring or 6-membered aryl ring or heteroaryl ring, optionally substituted with one or more substituents selected from the group consisting of the following;

A) optionally substituted C ₁ -C ₈ straight, branched, or cyclic saturated or unsaturated alkyl;

B) alkoxy of formula-(X ₁₃ ) _n13 -OX ₁₄ ,

Wherein X ₁₃ is selected from the group consisting of lower alkylene, lower alkenylene, lower alkynylene, aryl and heteroaryl;

X ₁₄ is selected from the group consisting of hydrogen, lower alkyl, aryl and heteroaryl; And

n13 is 0 or 1;

C) halogen or perhaloalkyl;

D) cyano;

E) nitro;

F) amino of the formula-(X ₁₅ ) _n15 -NX ₁₆ X ₁₇ ,

Wherein X ₁₅ is selected from the group consisting of lower alkylene, lower alkenylene, lower alkynylene, aryl and heteroaryl;

X ₁₆ and X ₁₇ are each independently selected from the group consisting of hydrogen, lower alkyl, aryl and heteroaryl; Or X ₁₆ and X ₁₇ are taken together with the nitrogen to which they are attached to form a 5- or 6-membered heteroaromatic or heteroaliphatic ring; n15 is 0 or 1;

G) a substituent of the _formula- (X ₁₈ ) _n18 -C (= E) -X ₁₉ ,

Wherein X ₁₈ is selected from the group consisting of lower alkylene, lower alkenylene, lower alkynylene, aryl and heteroaryl;

E is selected from the group consisting of oxygen, sulfur and -NR _101- , wherein R ₁₀₁ is selected from the group consisting of hydrogen hydrogen, lower alkyl, lower alkene, lower alkyne, aryl and heteroaryl;

X ₁₉ is selected from the group consisting of hydrogen, alkyl, aryl, heteroaryl, hydroxy, alkoxy, amino and -NX ₂₀ X ₂₁ ,

Wherein X ₂₀ and X ₂₁ are each independently selected from the group consisting of hydrogen, alkyl, aryl and heteroaryl;

n18 is 0 or 1; And

H) a thioether or thiol of the _formula- (X ₂₂ ) _{n22 -SX 23} ,

Wherein X ₂₂ is selected from the group consisting of lower alkylene, lower alkenylene, lower alkynylene, aryl and heteroaryl; And

X ₂₃ is selected from the group consisting of hydrogen, lower alkyl, aryl and heteroaryl,

n22 is 0 or 1; And

_{Amide of formula-} (X ₂₄ ) _n24 -NH-C (O) -X _{25 or-} (X ₂₆ ) _n26 -C (O) -NH-X ₂₇ ,

Wherein X ₂₄ and X ₂₆ are each independently selected from the group consisting of lower alkylene, lower alkenylene, lower alkynylene, aryl and heteroaryl;

X ₂₅ is selected from the group consisting of hydrogen, lower alkyl, lower alkenyl, aryl, heteroaryl, hydroxy, alkoxy and amide; And

X ₂₇ is selected from the group consisting of hydrogen, lower alkyl, lower alkenyl, aryl and heteroaryl;

Or R ₂ and R ₃ are taken together with the two ring carbons to which they are attached, or R ₄ and R ₃ are taken together with the two ring carbons to which they are attached, such that they are 6-membered aromatic or heteroaromatic, or 5- or 6-membered heteroaromatic ring, which is optionally substituted with one or more substituents selected from the group consisting of:

Iii) hydrogen;

Ii) optionally substituted C ₁ -C ₈ straight, branched or cyclic saturated or unsaturated alkyl;

Iii) optionally substituted aryl;

Iii) optionally substituted heterocycle;

Ⅴ) Formula -C (X ₄ ) = N-NX ₅ -C (= E) -NX ₆ X ₇ or -C (X ₄ ) = NN = C (EX ₅ ) -NX ₆ X ₇ ,

Wherein X ₄ is selected from the group consisting of hydrogen, lower alkyl, aryl, alkaryl, heteroaryl and amino;

E is selected from the group consisting of oxygen, sulfur and -NR _101- , wherein R ₁₀₁ is selected from the group consisting of hydrogen hydrogen, lower alkyl, lower alkene, lower alkyne, aryl and heteroaryl; And

X ₅ , X ₆ and X ₇ are each independently selected from the group consisting of hydrogen, lower alkyl, aryl and heteroaryl;

Iii) amino guanidine of formula -NX ₈ -NX ₉ -C (= NX ₁₀ ) -NX ₁₁ X ₁₂ ,

Wherein X ₈ , X ₉ , X ₁₀ , X ₁₁ and X ₁₂ are each independently selected from the group consisting of hydrogen, lower alkyl, aryl and heteroaryl;

Ⅶ) formula - (X _{13) n13} alkoxy of -OX _14,

Wherein X ₁₃ is selected from the group consisting of lower alkylene, lower alkenylene, lower alkynylene, aryl and heteroaryl;

X ₁₄ is selected from the group consisting of hydrogen, lower alkyl, aryl and heteroaryl;

n13 is 0 or 1;

Iii) halogen or perhaloalkyl;

Iii) cyano;

Iii) nitro;

xi) amino of the formula-(X ₁₅ ) _n15 -NX ₁₆ X ₁₇ ,

Wherein X ₁₅ is selected from the group consisting of lower alkylene, lower alkenylene, lower alkynylene, aryl and heteroaryl;

X ₁₆ and X ₁₇ are each independently selected from the group consisting of hydrogen, lower alkyl, aryl and heteroaryl; Or X ₁₆ and X ₁₇ are taken together with the nitrogen to which they are attached and are a 5- or 6-membered heteroaromatic or heteroaliphatic ring; And

n15 is 0 or 1;

xii) a substituent of the formula-(X ₁₈ ) _n18 -C (= E) -X ₁₉ ,

Wherein X ₁₈ is selected from the group consisting of lower alkylene, lower alkenylene, lower alkynylene, aryl and heteroaryl;

E is selected from the group consisting of oxygen, sulfur and -NR _101- , wherein R ₁₀₁ is selected from the group consisting of hydrogen hydrogen, lower alkyl, lower alkene, lower alkyne, aryl and heteroaryl;

X ₁₉ is selected from the group consisting of hydrogen, lower alkyl, aryl, heteroaryl, amino and -NX ₂₀ X ₂₁ ,

Wherein X ₂₀ and X ₂₁ are independently selected from the group consisting of hydrogen, alkyl, aryl and heteroaryl; And

n18 is 0 or 1;

xvi) thioether or thiol of the _formula- (X ₂₂ ) _{n22 -SX 23} ,

Wherein X ₂₂ is lower alkylene, lower alkenylene, lower alkynylene. Aryl and heteroaryl;

X ₂₃ is selected from the group consisting of hydrogen, lower alkyl, aryl and heteroaryl; And

n22 is 0 or 1;

c) R ₅ is selected from the group consisting of hydrogen, lower alkyl, aryl and heteroaryl; Or R ₄ and R ₅ are taken together with the two ring carbons to which they are attached such that a 6-membered aromatic or heteroaromatic, or 5- or 6-membered heteroaromatic ring, which is optionally selected from the group consisting of Or substituted with more substituents;

Iii) hydrogen;

Ii) optionally substituted C ₁ -C ₈ straight, branched or cyclic saturated or unsaturated alkyl;

Iii) optionally substituted aryl;

Iii) optionally substituted heterocycle;

Iv) a substituent of the formula -C (X ₄ ) = N-NX ₅ -C (= E) -NX ₆ X ₇ or -C (X ₄ ) = NN = C (EX ₅ ) -NX ₆ X ₇ ,

Wherein X ₄ is selected from the group consisting of hydrogen, lower alkyl, aryl, alkaryl, heteroaryl and amino;

E is selected from the group consisting of oxygen, sulfur and -NR _101- , wherein R ₁₀₁ is selected from the group consisting of hydrogen hydrogen, lower alkyl, lower alkene, lower alkyne, aryl and heteroaryl; And

X ₅ , X ₆ and X ₇ are each independently selected from the group consisting of hydrogen, lower alkyl, aryl and heteroaryl;

Iii) amino guanidine of formula -NX ₈ -NX ₉ -C (= NX ₁₀ ) -NX ₁₁ X ₁₂ ,

Wherein X ₈ , X ₉ , X ₁₀ , X ₁₁ and X ₁₂ are each independently selected from the group consisting of hydrogen, lower alkyl, aryl and heteroaryl;

Ⅶ) formula - (X _{13) n13} alkoxy of -OX _14,

Wherein X ₁₃ is selected from the group consisting of lower alkylene, lower alkenylene, lower alkynylene, aryl and heteroaryl;

X ₁₄ is selected from the group consisting of hydrogen, lower alkyl, aryl and heteroaryl;

n13 is 0 or 1;

Iii) halogen or perhaloalkyl;

Iii) cyano;

Iii) nitro;

xi) amino of the formula-(X ₁₅ ) _n15 -NX ₁₆ X ₁₇ ,

Wherein X ₁₅ is selected from the group consisting of lower alkylene, lower alkenylene, lower alkynylene, aryl or heteroaryl;

X ₁₆ and X ₁₇ are each independently selected from the group consisting of hydrogen, lower alkyl, aryl and heteroaryl; Or X ₁₆ and X ₁₇ are taken together with the nitrogen to which they are attached and are a 5- or 6-membered heteroaromatic or heteroaliphatic ring; And

n15 is 0 or 1;

xii) a substituent of the formula-(X ₁₈ ) _n18 -C (= E) -X ₁₉ ,

Wherein X ₁₈ is selected from the group consisting of lower alkylene, lower alkenylene, lower alkynylene, aryl and heteroaryl;

E is selected from the group consisting of oxygen, sulfur and -NR _101- , wherein R ₁₀₁ is selected from the group consisting of hydrogen hydrogen, lower alkyl, lower alkene, lower alkyne, aryl and heteroaryl;

X ₁₉ is selected from the group consisting of hydrogen, lower alkyl, aryl, heteroaryl, amino and -NX ₂₀ X ₂₁ ,

Wherein X ₂₀ and X ₂₁ are independently selected from the group consisting of hydrogen, alkyl, aryl and heteroaryl; And

n18 is 0 or 1;

xvi) thioether or thiol of the _formula- (X ₂₂ ) _{n22 -SX 23} ,

Wherein X ₂₂ is lower alkylene, lower alkenylene, lower alkynylene. Aryl and heteroaryl;

X ₂₃ is selected from the group consisting of hydrogen, lower alkyl, aryl and heteroaryl; And

n22 is 0 or 1;

Provided that at least one of R ₁ -R ₅ is not selected from the group consisting of hydrogen, lower alkyl, aryl and heteroaryl.

The term "pharmaceutically acceptable salt" means a formulation of a compound that does not cause severe irritation to the organism to which the compound is administered and does not impair the biological activity and properties of the compound. Pharmaceutical salts can be obtained by reacting a compound of the invention with inorganic acids such as hydrochloric acid, bromic acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid and the like. The pharmaceutical salt is obtained by reacting a compound of the present invention with a base, such as alkali metal salts such as ammonium salts, sodium or potassium salts, and alkaline earth metal salts such as calcium or magnesium salts, dicyclohexylamine, and N-methyl-. It can be obtained by forming salts of organic bases such as D-glucamine, tris (hydroxymethyl) methylamine, and amino acid salts such as arginine and lysine.

The term “ester” means a compound species of the formula — (R) _n —COOR ′ wherein R and R ′ are independently alkyl, cycloalkyl, aryl, heteroaryl (bonded via a ring carbon) and Heteroalicyclic (defective through the ring carbon), n is 0 or 1;

"Amide" means a chemical species of the formula-(R) _n -C (O) NHR 'or-(R) _n -NHC (O) R', wherein R and R 'are independently Alkyl, cycloalkyl, aryl, heteroaryl (bonded via cyclic carbon) and heteroalicyclic (defective via cyclic carbon), n is 0 or 1. Amides may be amino acid or peptide molecules linked to the molecules of the invention, thereby forming prodrugs.

In the compounds of the present invention the amine, hydroxy or carboxyl side chains can be esterified or amidated. Processes and specific groups used to form such ends are known in the art and are described in references such as Greene and Wuts, Protective Groups in Organic Synthesis, 3rd Ed., John Wiley & Sons, New York, NY, 1999. It can be easily identified.

"Prodrug" means a substance that is transformed into a parent drug in vivo. Prodrugs are often used because, in some cases, they are easier to administer than the parent drug. For example, they may be bioavailable by oral administration, while the parent drug may not. Prodrugs may also have improved solubility in pharmaceutical compositions than the parent drug. One example of a prodrug is, but is not limited to, water solubility being detrimental to mobility, but in cells where water solubility is beneficial, the passage of cell membranes, which are hydrolyzed to carboxylic acids, which are active by metabolism, can be prevented. It will be a compound of the invention that is administered as an ester ("prodrug") to facilitate. Another example of a prodrug may be a short peptide (polyamino acid) that is bound to an acid group which is converted by metabolism to reveal the active site.

The term “aromatic” refers to an aromatic group having at least one ring having a shared pi electron field and comprising a carbocyclic aryl (eg phenyl) and a heterocyclic aryl group (eg pyridine) Means. The term includes monocyclic or fused ring polycyclic (ie rings that divide adjacent pairs of carbon atoms) groups. Thus, the term distinguishes a heterocyclic ring from a carbocyclic ring in which the ring backbone contains at least one atom other than carbon. The term "heteroaromatic" means an aromatic group comprising at least one heterocyclic ring.

The term "alkyl" as used herein, means an aliphatic hydrocarbon group. The alkyl moiety can be a "saturated alkyl" group, meaning that it does not contain any alkenes or alkyne moieties. The alkyl moiety may be an "unsaturated alkyl" moiety, meaning that it contains at least one alkene or alkyne moiety. "Alkene" moiety means a group consisting of at least two carbon atoms and at least one carbon-carbon double bond, and an "alkyne" moiety consisting of at least two carbon atoms and at least one triple bond Means a group. The alkyl moiety, whether saturated or unsaturated, may be branched, straight chain or cyclic.

An alkyl group may have 1 to 20 carbon atoms (whenever it is represented herein, a numerical range such as "1 to 20" means each integer in a given range; this definition does not specify a numerical range. Although covering the appearance of the term "alkyl", for example, "1 to 20 carbon atoms" means that the alkyl group includes 20 carbon atoms, including 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc. It can consist of carbon atoms up to that point). The alkyl group may be a medium sized alkyl having 1 to 10 carbon atoms. The alkyl group may be lower alkyl having 1 to 5 carbon atoms. The alkyl group of the compounds of the present invention may be designated with "C ₁ -C ₄ alkyl" or similar designations. By way of example only, “C ₁ -C ₄ alkyl” is one to four carbon atoms in the alkyl chain, ie the alkyl chain is methyl, ethyl, propyl, iso-propyl, n-butyl, iso-butyl, sec -Butyl and t-butyl.

Alkyl groups may be substituted or unsubstituted. When substituted, the substituents are cycloalkyl, aryl, heteroaryl, heteroalicyclic, hydroxy, alkoxy, aryloxy, merceto, alkylthio, arylthio, cyano, halo, carbonyl, thiocarbonyl, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido, N-amido, S-sulfonamido, N-sulfonamido, C-carboxy, O- Individually from carboxy, isocyanato, thiocyanato, isothiocyanato, amino including nitro, cyryl, trihalomethanesulfonyl, mono- and di-substituted amino groups, and protective derivatives thereof And one or more groups independently selected. Typical alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, pentyl, hexyl, ethenyl, propenyl, butenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc. It is not limited to these. Whenever a substituent is described as "optionally substituted", the substituent may be substituted with one of the above substituents.

Substituent "R" is selected from the group consisting of alkyl, cycloalkyl, aryl, heteroaryl (bonded through a cyclic carbon) and heteroalicyclic (bonded through a cyclic carbon) when not expressly indicated; It means a substituent to be.

"O-carboxy" group refers to a RC (= 0) O- group, wherein R is as defined herein.

A "C-carboxy" group refers to a -C (= 0) OR group, with R as defined herein.

An "acetyl" group refers to a -C (= 0) CH ₃ group.

"Trihalomethanesulfonyl" group refers to an X ₃ CS (= 0) ₂ -group, wherein X is halogen.

"Cyano" group refers to a -CN group.

"Isocyanato" group refers to the -NCO group.

A "thiocyanato" group refers to a -CNS group.

"Isothiocyanato" group refers to a -NCS group.

"Sulfinyl" group refers to the group -S (= 0) -R, wherein R is as defined herein.

"S-sulfonamido" group means a -S (= 0) ₂ NR group, wherein R is as defined herein.

"N-sulfonamido" group refers to the RS (= 0) ₂ NH- group, wherein R is as defined herein.

"Trihalomethanesulfonamido" group refers to the X ₃ CS (= 0) ₂ NR- group, wherein X and R are as defined herein.

"O-carbamyl" group refers to an -OC (= 0) -NR group, wherein R is as defined herein.

"N-carbamyl" group refers to the ROC (= 0) NH- group, with R as defined herein.

"O-thiocarbamyl" group refers to the group -OC (= S) -NR, wherein R is as defined herein.

"N-thiocarbamyl" group refers to the ROC (= S) NH- group, with R as defined herein.

A "C-amido" group refers to a -C (= 0) -NR ₂ group, where R is as defined herein.

"N-amido" group refers to the RC (= 0) NH- group, with R as defined herein.

The term "perhaloalkyl" refers to an alkyl group in which all hydrogen atoms have been replaced with halogen atoms.

When the substituents are taken together with two ring carbons to which two substituents are attached to form a ring, the structure

Represented by the following structure:

In this example, R ₁ and R ₂ form a six-membered aromatic ring when taken together with the two ring carbons to which they are attached.

Unless stated otherwise, when a substituent is considered to be "optionally substituted", it means that the substituent is cycloalkyl, aryl, heteroaryl, heteroalicyclic, hydroxy, alkoxy, aryloxy, merceto, Alkylthio, arylthio, cyano, halo, carbonyl, thiocarbonyl, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido, N-amido, S-sulfonamido, N-sulfonamido, C-carboxy, O-carboxy, isocyanato, thiocyanato, isothiocyanato, nitro, cyryl, trihalomethanesulfonyl, mono- and Amino, including di-substituted amino groups, and one or more groups individually and independently selected from protective derivatives thereof. Typical alkyl groups include individually from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, pentyl, hexyl, ethenyl, propenyl, butenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc. And it means that the group may be substituted with one or more groups selected independently. Protective groups capable of forming protective derivatives of the substituents are known in the art and can be found in the references of Greene and Wuts et al.

In one embodiment, the invention is directed to compounds of Formula 1 or Formula 2 wherein R ₁ is selected from the group consisting of

Iii) hydrogen;

Ii) 6-membered aromatic ring, which is optionally substituted with one or more substituents selected from the group consisting of lower alkyl, hydroxy, alkoxy, amine and nitro;

Iii) 6-membered heteroaromatic ring, which is optionally substituted with one or more substituents selected from the group consisting of lower alkyl, hydroxy and amine;

Iii) a 5-membered heteroaromatic ring, which is optionally substituted with one or more substituents selected from the group consisting of lower alkyl, hydroxy and amine;

아) acyl of the formula-(X ₁ ) _{n 1} -C (O) -X ₂ ,

Wherein X ₁ is lower alkylene or lower alkenylene;

X ₂ is selected from the group consisting of hydrogen, amino, hydroxy and -NH-X ₃ ,

Wherein X ₃ is selected from the group consisting of hydrogen, lower alkyl, amino and amide;

n is 0 or 1;

Iv) a substituent of the formula -C (X ₄ ) = N-NH-C (= E) -NX ₆ X ₇ or -C (X ₄ ) = NN = C (EX ₅ ) -NX ₆ X ₇ ,

Wherein X ₄ is selected from the group consisting of hydrogen, lower alkyl, aryl and alkaryl;

E is selected from the group consisting of oxygen, sulfur and -NR _101- , wherein R ₁₀₁ is selected from the group consisting of hydrogen hydrogen, lower alkyl, lower alkene, lower alkyne, aryl and heteroaryl; And

X ₅ , X ₆ and X ₇ are each independently selected from the group consisting of hydrogen and lower alkyl.

In another embodiment, R ₁ is selected from the group consisting of

Iii) hydrogen;

Ii) phenyl, which is optionally substituted with one or more hydroxy or -NH ₂ ;

Iii) a 6-membered heteroaromatic ring selected from the group consisting of pyridine, pyrazine, pyridazine, pyrimidine and 1,3,5-triazine, each independently and optionally with lower alkyl, hydroxy, alkoxy and amino Substituted with one or more substituents selected from the group consisting of;

Iii) 5-membered heteroaromatic rings selected from the group consisting of pyrrole, imidazole, 1,2,3-triazole, 1,2,4-triazole, tetrazole, thiophene, thiazole, and thiadiazole, which are Each independently and optionally hydroxy, an amide of the _formula- (X ₂₄ ) _n24 -NH-C (O) -X _{25 or-} (X ₂₆ ) _n26 -C (O) -NH-X ₂₇ , and -NH ₂ Substituted with one or more substituents selected from the group consisting of;

Iii) acyl of the formula -C (O) -X ₂ , wherein X ₂ is hydrogen or lower alkyl;

아) acyl of formula -X ₁ -C (O) -X ₂ ,

Wherein X ₁ is lower alkylene or lower alkenylene; And

X ₂ is -NH-X ₃ , wherein X ₃ is selected from the group consisting of hydrogen, amino and amide;

Iv) -C (X ₄ ) = N-NH-C (= E) -NH ₂ ,

Wherein X ₄ is selected from the group consisting of hydrogen, methyl, ethyl, phenyl and -CH ₂ CH ₂ -Ph; And

E is oxygen, sulfur, and -NR ₁₀₁ - it is selected from the group consisting of wherein R is hydrogen _1O1 hydrogen, lower alkyl, lower alkenyl, lower alkynyl, aryl, and is selected from the group consisting of-heteroaryl; And

Ⅷ) Formula -C (X ₄ ) = NN = C (SX ₅ ) -NH ₂ ,

Wherein X ₄ is selected from the group consisting of hydrogen, methyl, ethyl, phenyl and -CH ₂ CH ₂ -Ph;

X ₅ is hydrogen or methyl.

5- or 6-membered heteroaryl ring in R ₁ is optionally substituted , Optionally substituted , And optionally substituted Is selected from the group consisting of W, X, Y and Z are each independently CR or nitrogen, and U is selected from the group consisting of CR ₂ , oxygen, sulfur and NR; R is as defined herein.

In another embodiment of the present invention, the heteroaryl ring is a furan, thiophene, pyrrole, pyrroline, pyrrolidine, oxazole, thiazole, imidazole, imidazoline, imidazolidine, pyrazole, pyra Sleepy, pyrazolidine, isosazole, isothiazole, triazole, thiadiazole, pyran, pyridine, piperidine, morpholine, thiomorpholine, pyridazine, pyrimidine, pyrazine, piperazine, triazine, , , And It is selected from the group consisting of, wherein R relates to a compound of formula 1 or 2, as defined herein.

Heteroaryl ring is aminofuran, aminothiophene, aminopyrrole, aminopyrroline, aminopyrrolidine, aminooxazole, aminothiazole, aminoimidazole, aminoimidazoline, aminoimidazolidine, aminopyrazole, Aminopyrazoline, aminopyrazolidine, aminoisoxazole, aminoisothiazole, aminotriazole, aminothiadiazole, aminopyran, aminopyridine, aminopiperidine, aminomorpholine, aminothiomorpholine, aminopyridazine, Aminopyrimidine, aminopyrazine, aminopiperazine, aminotriazine, , , And It may be selected from the group consisting of, wherein R is as defined herein.

In embodiments of the present invention, R ₁ is -C (O) -CH ₃ , -C (O) -NH-CH ₂ -C (O) -NH ₂ , -CH = CH = C (O) -NH ₂ , -CH ₂ -CH ₂ -C (O) -NH-NH ₂ , -C (H) = N-NH-C (O) -NH ₂ , -C (CH ₃ ) = N-NH-C (O ) -NH ₂ , -C (H) = N-NH-C (S) -NH ₂ , -C (CH ₃ ) = N-NH-C (S) -NH ₂ , -C (Ph) = N- NH-C (S) -NH ₂ , -C (CH ₂ CH ₂ Ph) = N-NH-C (S) -NH ₂ , -C (H) = NN = C (SCH ₃ ) -NH ₂ , , , , , , , , , , , , , , , , , , , , And It is selected from the group consisting of wherein R is as defined herein.

The substituent R ₃ may be selected from the group consisting of the following in some embodiments.

Iii) hydrogen;

Ii) C ₂ -C ₆ alkenylene;

Iii) halogen or perhaloalkyl;

Iii) alkoxy of formula -OX ₁₄ ,

Wherein X ₁₄ is selected from the group consisting of hydrogen, lower alkyl and aryl; And

Iii) a 5-membered or 6-membered heteroaryl ring, or a 6-membered aryl or heteroaryl ring optionally substituted with one or more substituents selected from the group consisting of

A) optionally substituted C ₁ -C ₄ straight, branched or cyclic saturated or unsaturated alkyl;

B) alkoxy of formula -OX ₁₄ , wherein X ₁₄ is hydrogen or lower alkyl;

C) halogen or perhaloalkyl;

D) cyano;

E) nitro;

F) a substituent of the _formula- (X ₁₈ ) _{n 18} -C (O) -X ₁₉ ,

Wherein X ₁₈ is lower alkylene;

X ₁₉ is selected from the group consisting of hydrogen, lower alkyl, aryl, heteroaryl, hydroxy, alkoxy, amino and -NX ₂₀ X ₂₁ ,

Wherein X ₂₀ and X ₂₁ are each independently selected from the group consisting of hydrogen, alkyl and aryl; And

n18 is 0 or 1;

G) a thioether or thiol of the formula -SX ₂₃ , wherein X ₂₃ is selected from the group consisting of hydrogen, lower alkyl, aryl and heteroaryl; And

H) an amide of _formula- (X ₂₄ ) _n24 -NH-C (O) -X _{25 or-} (X ₂₆ ) _n26 -C (O) -NH-X ₂₇ ,

Wherein X ₂₄ and X ₂₆ are each independently lower alkylene; X ₂₅ is selected from the group consisting of hydrogen, lower alkyl, aryl, hydroxy and alkoxy;

X ₂₇ is selected from the group consisting of hydrogen, lower alkyl, aryl and heteroaryl.

In other embodiments, R ₃ may be selected from the group consisting of the following.

Iii) hydrogen;

Ii) C ₂ -C ₆ alkylene;

Iii) halogen or perhaloalkyl;

Iii) alkoxy of formula -OX ₁₄ ,

Wherein X ₁₄ is selected from the group consisting of hydrogen, methyl, ethyl and propyl;

Iii) 6-membered aryl ring, which is optionally substituted with one or more substituents selected from the group consisting of:

A) methyl, ethyl and propyl;

B) hydroxy, methoxy, ethoxy, phenoxy, hydroxymethyl, 2-hydroxyethyl and 3-hydroxypropyl;

C) halogen or perfluoroalkyl;

D) cyano;

E) nitro;

F) a substituent of the formula -C (O) -X ₁₉ ,

Wherein X ₁₉ is hydrogen, methyl, ethyl, propyl, phenyl, hydroxy, methoxy, ethoxy, propoxy, amino and -NX ₂₀ X ₂₁ ,

Wherein X ₂₀ and X ₂₁ are each independently selected from the group consisting of hydrogen, methyl, ethyl, propyl and phenyl;

Thioether or thiol of G) -SX ₂₃ , wherein X ₂₃ is selected from the group consisting of hydrogen, methyl, ethyl, propyl and phenyl;

H) an amide of _formula- (X ₂₄ ) _n24 -NH-C (O) -X _{25 or-} (X ₂₆ ) _n26 -C (O) -NH-X ₂₇ ,

Wherein X ₂₄ and X ₂₆ are each independently lower alkylene;

X ₂₅ is selected from the group consisting of hydrogen, methyl, ethyl, propyl, phenyl, hydroxy, methoxy and phenoxy; And

X ₂₇ is selected from the group consisting of hydrogen, methyl, ethyl, propyl and phenyl.

The 5- or 6-membered heteroaryl ring or 6-membered aryl or heteroaryl ring of R ₃ is optionally substituted , Optionally substituted , And optionally substituted It may be selected from the group consisting of wherein V, W, X, Y and Z are each independently CR or nitrogen, U is selected from the group consisting of CR ₂ , oxygen, sulfur and NR, wherein R is defined herein As it is.

In still other embodiments, the 5- or 6-membered heteroaryl ring or 6-membered aryl or heteroaryl ring of R _{3 may be selected from} the group consisting of phenyl, furan, thiophene, pyrrole, pyrroline, pyrrolidine, oxazole, thia Sol, imidazole, imidazoline, imidazolidine, pyrazole, pyrazoline, pyrazolidine, isosazole, isothiazole, triazole, thiadiazole, pyran, pyridine, piperidine, morpholine, thiomor It may also be selected from the group consisting of porin, pyridazine, pyrimidine, pyrazine, piperazine and triazine.

R ₃ substituents are hydrogen, chlorine, bromine, hydroxy, -CH = CH-CH ₂ CH ₂ CH ₂ CH ₃ , -CH = CH-C (O) -OH, -CH = CH-C (O)- OCH ₃ , -CH = CH-C (O) -NH ₂ , -CH ₂ CH (NH ₂ ) COOH, phenyl, -O-CH ₂ -phenyl, 2-methylphenyl, 3-methylphenyl, 2-methylthiophenyl, 3-methylthiopetyl, 4-methylthiophenyl, 4-methylphenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 2-hydroxyphenyl, 3-hydroxyphenyl, 4-hydrate Hydroxyphenyl, 2-hydroxymethylphenyl, 3-hydroxymethylphenyl, 4-hydroxymethylphenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2-cyanophenyl, 3-cyanophenyl , 4-cyanophenyl, 2-nitrophenyl, 3-nitrophenyl, 4-nitrophenyl, 2-hydroxycarbonylphenyl, 3-hydroxycarbonylphenyl, 4-hydroxycarbonylphenyl, 2-methoxy Carbonylphenyl, 3-methoxycarbonylphenyl, 4-methoxycarbonylphenyl, 2-trifluoromethylpetyl, 4-benzyloxyphenyl, 2-phenoxyphenyl, 2,4-dihydroxyphenyl, 3 , 4-dihydroxyl Cyphenyl, 2-hydroxy-4-methoxyphenyl, 4-hydroxy-2-methoxyphenyl, 2,4-dimethoxyphenyl, 3,4-dimethoxyphenyl, 3-fluoro-4-hydroxy Phenyl, 3-fluoro-4-methoxyphenyl, , , , , , , 2-pyridyl, 3-pyridyl, 4-pyridyl, , , , , , , , , , , , , And It may be selected from the group consisting of, wherein R is as defined herein.

In some embodiments, R ₂ and R ₃ substituents of the compound of Formula 1 or 2 are taken together with the two ring carbons to which they are attached, or R ₄ and R ₃ substituents of the compound of Formula 1 or 2 are attached Taken with two ring carbons, or R ₄ and R ₅ substituents of formula 1 or 2, taken with the two ring carbons to which they are attached, such as a 6-membered aromatic or heteroaromatic, or 5- or 6 -Form a heteroaromatic ring, which is optionally hydrogen, hydroxy, halogens, cyano, nitro, amino, carbonyl, hydroxycarbonyl, aminocarbonyl, aminothiocarbonyl, lower alkoxy, phenoxy, Amino-furan, amino-thiophene, amino-pyrrole, amino-pyrroline, amino-pyrrolodine, amino-oxazole, amino-thiazole, amino-imidazole, amino-imidazoline, amino-imidazolidine , Amino- Lazole, amino-pyrazoline, amino-pyrazolidine, amino-isoxazole, amino-isothiazole, amino-triazole, amino-thiadiazole, amino-pyran, amino-pyridine, amino-piperidine, amino- Morpholine, amino-thiomorpholine, amino-pyridazine, amino-pyrimidine, amino-pyrazine, amino-piperazine, amino-triazine, semicarbazone, thiosemicarbazone, and aminoguanidine It may be substituted with one or more substituents.

In some embodiments, R ₂ and R ₃ are taken with the remainder of the compound of formula 1 or 2, or R ₄ and R ₃ are taken with the rest of the compound of formula 1, or R ₄ and R ₅ are Taken together with the remainder of the compound of Formula 1 or 2, it may result in the formation of optionally substituted naphthalene. The resulting naphthalene molecule may be substituted with hydroxy.

B. Phenolic Derivatives

In another aspect, the invention relates to a compound of Formula 3, or a pharmaceutically acceptable salt, amide, ester, or prodrug thereof.

(3)

Where

a) R ₆ is selected from the group consisting of

Iii) 6-membered aromatic or heteroaromatic, 5- or 6-membered heteroaromatic rings, which are optionally substituted with one or more substituents selected from the group consisting of lower alkyl, hydroxy, alkoxy, amino and nitro; And

Ii) acyl of the formula-(X ₁ ) _{n 1} -C (O) -X ₂ ,

Wherein X ₁ is selected from the group consisting of lower alkylene, lower alkenylene, lower alkynylene, aryl and heteroaryl;

X ₂ is selected from the group consisting of hydrogen, lower alkyl, aryl, heteroaryl, hydroxy, alkoxy, amino, and -NH-X ₃ ;

Wherein X ₃ is selected from the group consisting of hydrogen, alkyl, aryl, heteroaryl, amino and amide; And

n1 is 0 or 1;

Provided that R ₆ is -C ₆ H ₅ , -C (0) H, -C (O) CH ₃ , -C (O) -C ₆ H ₅ , -C (O) NH ₂ , or -C ₆ H _{Not 4} CH ₃ ;

b) R ₇ , R ₈ and R ₉ are each independently selected from the group consisting of the following;

Iii) hydrogen;

Ii) lower alkyl;

Iii) lower alkylene;

Iii) halogen or perhaloalkyl;

Ⅴ) alkoxy of the formula-(X ₁₃ ) _n13 -OX ₁₄ ,

Wherein X ₁₃ is selected from the group consisting of lower alkylene, lower alkenylene, lower alkynylene, allyl and heteroaryl;

X ₁₄ is selected from the group consisting of hydrogen, lower alkyl, aryl and heteroaryl; And

n13 is 0 or 1; And

V) 5- or 6-membered heteroaryl ring or 6-membered aryl ring or heteroaryl ring, optionally substituted with one or more substituents selected from the group consisting of the following;

A) optionally substituted C ₁ -C ₈ straight, branched, or cyclic saturated or unsaturated alkyl;

B) alkoxy of formula-(X ₁₃ ) _n13 -OX ₁₄ ,

Wherein X ₁₃ is selected from the group consisting of lower alkylene, lower alkenylene, lower alkynylene, aryl and heteroaryl;

X ₁₄ is selected from the group consisting of hydrogen, lower alkyl, aryl and heteroaryl; And

n13 is 0 or 1;

C) halogen or perhaloalkyl;

D) cyano;

E) nitro;

F) amino of the formula-(X ₁₅ ) _n15 -NX ₁₆ X ₁₇ ,

Wherein X ₁₅ is selected from the group consisting of lower alkylene, lower alkenylene, lower alkynylene, aryl and heteroaryl;

X ₁₆ and X ₁₇ are each independently selected from the group consisting of hydrogen, lower alkyl, aryl and heteroaryl; Or X ₁₆ and X ₁₇ are taken together with the nitrogen to which they are attached to form a 5- or 6-membered heteroaromatic or heteroaliphatic ring; And

n15 is 0 or 1;

G) a substituent of the _formula- (X ₁₈ ) _n18 -C (= E) -X ₁₉ ,

Wherein X ₁₈ is selected from the group consisting of lower alkylene, lower alkenylene, lower alkynylene, aryl and heteroaryl;

E is selected from the group consisting of oxygen, sulfur and -NR _101- , wherein R ₁₀₁ is selected from the group consisting of hydrogen hydrogen, lower alkyl, lower alkene, lower alkyne, aryl and heteroaryl;

X ₁₉ is selected from the group consisting of hydrogen, lower alkyl, aryl, heteroaryl, hydroxy, alkoxy, amino and -NX ₂₀ X ₂₁ ,

Wherein X ₂₀ and X ₂₁ are each independently selected from the group consisting of hydrogen, alkyl, aryl and heteroaryl;

n18 is 0 or 1; And

H) a thioether or thiol of the _formula- (X ₂₂ ) _{n22 -SX 23} ,

Wherein X ₂₂ is selected from the group consisting of lower alkylene, lower alkenylene, lower alkynylene, aryl and heteroaryl; And

X ₂₃ is selected from the group consisting of hydrogen, lower alkyl, aryl and heteroaryl,

n22 is 0 or 1; And

_{Amide of formula-} (X ₂₄ ) _n24 -NH-C (O) -X _{25 or-} (X ₂₆ ) _n26 -C (O) -NH-X ₂₇ ,

Wherein X ₂₄ and X ₂₆ are each independently selected from the group consisting of lower alkylene, lower alkenylene, lower alkynylene, aryl and heteroaryl;

X ₂₅ is selected from the group consisting of hydrogen, lower alkyl, lower alkenyl, aryl, heteroaryl, hydroxy, alkoxy and amide; And

X ₂₇ is selected from the group consisting of hydrogen, lower alkyl, lower alkenyl, aryl and heteroaryl;

c) R ₁₀ is selected from the group consisting of hydrogen, lower alkyl, aryl and heteroaryl; Provided that at least one of R ₆ -R ₁₀ is not selected from the group consisting of hydrogen, lower alkyl, aryl and heteroaryl.

In some embodiments, R ₆ is selected from the group consisting of

Iii) hydrogen;

Ii) 6-membered aromatic ring, which is optionally substituted with one or more substituents selected from the group consisting of lower alkyl, hydroxy and amine;

Iii) a 6-membered heteroaromatic ring, which is optionally substituted with one or more substituents selected from the group consisting of lower alkyl, hydroxy, alkoxy, amino and nitro;

Iii) a 5-membered heteroaromatic ring, which is optionally substituted with one or more substituents selected from the group consisting of lower alkyl, hydroxy and amine;

아) acyl of the formula-(X ₁ ) _{n 1} -C (O) -X ₂ ,

Wherein X ₁ is lower alkylene or lower alkenylene;

X ₂ is selected from the group consisting of hydrogen, amino, hydroxy and -NH-X ₃ ,

Wherein X ₃ is selected from the group consisting of hydrogen, lower alkyl, amino and amide;

n is 0 or 1;

In another embodiment, R ₆ is selected from the group consisting of

Iii) hydrogen;

Ii) phenyl, which is optionally substituted with one or more hydroxy or -NH ₂ ;

Iii) a 6-membered heteroaromatic ring selected from the group consisting of pyridine, pyrazine, pyridazine, pyrimidine and 1,3,5-triazine, each independently and optionally with lower alkyl, hydroxy, alkoxy and amino Substituted with one or more substituents selected from the group consisting of;

Iii) 5-membered heteroaromatic rings selected from the group consisting of pyrrole, imidazole, 1,2,3-triazole, 1,2,4-triazole, tetrazole, thiophene, thiazole, and thiadiazole, which are Each independently and optionally hydroxy, an amide of the _formula- (X ₂₄ ) _n24 -NH-C (O) -X _{25 or-} (X ₂₆ ) _n26 -C (O) -NH-X ₂₇ , and -NH ₂ Substituted with one or more substituents selected from the group consisting of;

Iii) acyl of the formula -C (O) -X ₂ , wherein X ₂ is hydrogen or lower alkyl;

아) acyl of formula -X ₁ -C (O) -X ₂ ,

Wherein X ₁ is lower alkylene or lower alkenylene; And

X ₂ is -NH-X ₃ , wherein X ₃ is selected from the group consisting of hydrogen, amino and amide.

In R ₆ a 5- or 6-membered heteroaryl ring is optionally substituted , Optionally substituted , And optionally substituted Is selected from the group consisting of: wherein V, W, X, Y and Z are each independently CR or nitrogen, and U is selected from the group consisting of CR ₂ , oxygen, sulfur and NR; R is as defined herein.

The heteroaryl ring is furan, thiophene, pyrrole, pyrroline, pyrrolidine, oxazole, thiazole, imidazole, imidazoline, imidazolidine, pyrazole, pyrazoline, pyrazolidine, isocazole, Isothiazole, triazole, thiadiazole, oxadiazole ( ), Pyran, pyridine, piperidine, morpholine, thiomorpholine, pyridazine, pyrimidine, pyrazine, piperazine, and triazine. In addition, the heteroaryl ring, aminofuran, aminothiophene, aminopyrrole, aminopyrroline, aminopyrrolidine, aminooxazole, aminothiazole, aminoimidazole, aminoimidazoline, aminoimidazolidine, amino Pyrazole, aminopyrazoline, aminopyrazolidine, aminoisoxazole, aminoisothiazole, aminotriazole, aminothiadiazole, aminooxadiazole, aminopyran, aminopyridine, aminopiperidine, aminomorpholine, amino It may also be selected from the group consisting of thiomorpholine, aminopyridazine, aminopyrimidine, aminopyrazine, aminopiperazine, and aminotriazine.

In some embodiments, a R ₆ substituent is hydrogen, —C (O) —CH ₃ , —C (O) —NH—CH ₂ —C (O) —NH ₂ , —CH═CH═C (O) — NH ₂ , -CH ₂ CH ₂ -C (O) -NH-NH ₂ , , , , , , , , , , , , , , , , , , , And It is selected from the group consisting of wherein R is as defined herein.

Substituent R ₈ of the compound of formula 3 may be selected from the group consisting of

Iii) hydrogen;

Ii) C ₂ -C ₆ alkenylene;

Iii) halogen or perhaloalkyl;

Iii) alkoxy of formula -OX ₁₄ ,

Wherein X ₁₄ is selected from the group consisting of hydrogen, lower alkyl and aryl; And

Iii) a 5-membered or 6-membered heteroaryl ring, or a 6-membered aryl or heteroaryl ring optionally substituted with one or more substituents selected from the group consisting of

A) optionally substituted C ₁ -C ₄ straight, branched or cyclic saturated or unsaturated alkyl;

B) alkoxy of formula -OX ₁₄ , wherein X ₁₄ is hydrogen or lower alkyl;

C) halogen or perhaloalkyl;

D) cyano;

E) nitro;

F) a substituent of the _formula- (X ₁₈ ) _{n 18} -C (O) -X ₁₉ ,

Wherein X ₁₈ is lower alkylene;

X ₁₉ is selected from the group consisting of hydrogen, lower alkyl, aryl, heteroaryl, hydroxy, alkoxy, amino and -NX ₂₀ X ₂₁ ,

Wherein X ₂₀ and X ₂₁ are each independently selected from the group consisting of hydrogen, alkyl and aryl; And

n18 is 0 or 1;

G) a thioether or thiol of the formula -SX ₂₃ , wherein X ₂₃ is selected from the group consisting of hydrogen, lower alkyl, aryl and heteroaryl; And

H) an amide of _formula- (X ₂₄ ) _n24 -NH-C (O) -X _{25 or-} (X ₂₆ ) _n26 -C (O) -NH-X ₂₇ ,

Wherein X ₂₄ and X ₂₆ are each independently lower alkylene; X ₂₅ is selected from the group consisting of hydrogen, lower alkyl, aryl, hydroxy and alkoxy;

X ₂₇ is selected from the group consisting of hydrogen, lower alkyl, aryl and heteroaryl.

In other embodiments, R ₈ may be selected from the group consisting of

Iii) hydrogen;

Ii) C ₂ -C ₆ alkylene;

Iii) halogen or perhaloalkyl;

Iii) alkoxy of formula -OX ₁₄ ,

Wherein X ₁₄ is selected from the group consisting of hydrogen, methyl, ethyl and propyl;

Iii) 6-membered aryl ring, which is optionally substituted with one or more substituents selected from the group consisting of:

A) methyl, ethyl and propyl;

B) hydroxy, methoxy, ethoxy, phenoxy, hydroxymethyl, 2-hydroxyethyl and 3-hydroxypropyl;

C) halogen or perfluoroalkyl;

D) cyano;

E) nitro;

F) a substituent of the formula -C (O) -X ₁₉ ,

Wherein X ₁₉ is hydrogen, methyl, ethyl, propyl, phenyl, hydroxy, methoxy, ethoxy, propoxy, amino and -NX ₂₀ X ₂₁ ,

Wherein X ₂₀ and X ₂₁ are each independently selected from the group consisting of hydrogen, methyl, ethyl, propyl and phenyl;

G) a thioether or thiol of the formula -SX ₂₃ , wherein X ₂₃ is selected from the group consisting of hydrogen, methyl, ethyl, propyl and phenyl;

H) an amide of _formula- (X ₂₄ ) _n24 -NH-C (O) -X _{25 or-} (X ₂₆ ) _n26 -C (O) -NH-X ₂₇ ,

Wherein X ₂₄ and X ₂₆ are each independently lower alkylene;

X ₂₅ is selected from the group consisting of hydrogen, methyl, ethyl, propyl, phenyl, hydroxy, methoxy and phenoxy; And

X ₂₇ is selected from the group consisting of hydrogen, methyl, ethyl, propyl and phenyl.

The 5- or 6-membered heteroaryl ring or 6-membered aryl or heteroaryl ring of R ₈ is optionally substituted , Optionally substituted , And optionally substituted It may be selected from the group consisting of wherein V, W, X, Y and Z are each independently CR or nitrogen, U is selected from the group consisting of CR ₂ , oxygen, sulfur and NR, wherein R is defined herein As it is.

The 5- or 6-membered heteroaryl ring or 6-membered aryl or heteroaryl ring of R ₈ is phenyl, furan, thiophene, pyrrole, pyrroline, pyrrolidine, oxazole, thiazole, imidazole, imida Sleepy, imidazolidine, pyrazole, pyrazoline, pyrazolidine, isosazole, isothiazole, triazole, thiadiazole, pyran, pyridine, piperidine, morpholine, thiomorpholine, pyridazine, pyrimidine , Pyrazine, piperazine, triazine and benzimidazole.

In other embodiments, the R ₈ substituent of the compounds of formula 3 is hydrogen, chlorine, bromine, hydroxy, —CH═CH—CH ₂ CH ₂ CH ₂ CH ₃ , —CH═CH—C (O) —OH , -CH = CH-C (O) -OCH ₃ , -CH = CH-C (O) -NH ₂ , -CH ₂ CH (NH ₂ ) COOH, phenyl, -O-CH ₂ -phenyl, 2-methylphenyl , 3-methylphenyl, 2-methylthiophenyl, 3-methylthiophenyl, 4-methylthiophenyl, 4-methylphenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 2-hydroxy Phenyl, 3-hydroxyphenyl, 4-hydroxyphenyl, 2-hydroxymethylphenyl, 3-hydroxymethylphenyl, 4-hydroxymethylphenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2-cyanophenyl, 3-cyanophenyl, 4-cyanophenyl, 2-nitrophenyl, 3-nitrophenyl, 4-nitrophenyl, 2-hydroxycarbonylphenyl, 3-hydroxycarbonylphenyl, 4 -Hydroxycarbonylphenyl, 2-methoxycarbonylphenyl, 3-methoxycarbonylphenyl, 4-methoxycarbonylphenyl, 2-trifluoromethylfetyl, 4-benzyloxyphenyl, 2-feh Oxyphenyl, 2,4-dihydroxyphenyl, 3,4-dihydroxyphenyl, 2-hydroxy-4-methoxyphenyl, 4-hydroxy-2-methoxyphenyl, 2,4-dimethoxyphenyl , 3,4-dimethoxyphenyl, 3-fluoro-4-hydroxyphenyl, 3-fluoro-4-methoxyphenyl, , , , , , , 2-pyridyl, 3-pyridyl, 4-pyridyl, , , , , , , , , , , , , And It may be selected from the group consisting of, wherein R is as defined herein.

C. Carbazone derivatives

In another aspect the invention relates to a compound of formula 4, or a pharmaceutically acceptable salt, amide, ester, or prodrug thereof.

(4)

Where

a) R ₁₁ is selected from the group consisting of hydrogen, lower alkyl, aryl and heteroaryl;

b) R ₁₂ , R ₁₃ and R ₁₄ are each independently selected from the group consisting of the following;

Iii) hydrogen;

Ii) lower alkyl;

Iii) lower alkylene;

Iii) halogen or perhaloalkyl;

Ⅴ) alkoxy of the formula-(X ₁₃ ) _n13 -OX ₁₄ ,

Wherein X ₁₃ is selected from the group consisting of lower alkylene, lower alkenylene, lower alkynylene, allyl and heteroaryl;

X ₁₄ is selected from the group consisting of hydrogen, lower alkyl, aryl and heteroaryl; And

n13 is 0 or 1; And

Iii) a 5- or 6-membered heteroaryl ring or a 6-membered aryl or heteroaryl ring, optionally substituted with one or more substituents selected from the group consisting of:

A) optionally substituted C ₁ -C ₈ straight, branched, or cyclic saturated or unsaturated alkyl;

B) alkoxy of formula-(X ₁₃ ) _n13 -OX ₁₄ ,

Wherein X ₁₃ is selected from the group consisting of lower alkylene, lower alkenylene, lower alkynylene, aryl and heteroaryl;

X ₁₄ is selected from the group consisting of hydrogen, lower alkyl, aryl and heteroaryl; And

n13 is 0 or 1;

C) halogen or perhaloalkyl;

D) cyano;

E) nitro;

F) amino of the formula-(X ₁₅ ) _n15 -NX ₁₆ X ₁₇ ,

Wherein X ₁₅ is selected from the group consisting of lower alkylene, lower alkenylene, lower alkynylene, aryl and heteroaryl;

X ₁₆ and X ₁₇ are each independently selected from the group consisting of hydrogen, lower alkyl, aryl and heteroaryl; Or X ₁₆ and X ₁₇ are taken together with the nitrogen to which they are attached to form a 5- or 6-membered heteroaromatic or heteroaliphatic ring; And

n15 is 0 or 1;

G) a substituent of the _formula- (X ₁₈ ) _n18 -C (= E) -X ₁₉ ,

Wherein X ₁₈ is selected from the group consisting of lower alkylene, lower alkenylene, lower alkynylene, aryl and heteroaryl;

E is selected from the group consisting of oxygen, sulfur and -NR _101- , wherein R ₁₀₁ is selected from the group consisting of hydrogen hydrogen, lower alkyl, lower alkene, lower alkyne, aryl and heteroaryl;

X ₁₉ is selected from the group consisting of hydrogen, lower alkyl, aryl, heteroaryl, hydroxy, alkoxy, amino and -NX ₂₀ X ₂₁ ,

Wherein X ₂₀ and X ₂₁ are each independently selected from the group consisting of hydrogen, alkyl, aryl and heteroaryl;

n18 is 0 or 1; And

H) a thioether or thiol of the _formula- (X ₂₂ ) _{n22 -SX 23} ,

Wherein X ₂₂ is selected from the group consisting of lower alkylene, lower alkenylene, lower alkynylene, aryl and heteroaryl; And

X ₂₃ is selected from the group consisting of hydrogen, lower alkyl, aryl and heteroaryl,

n22 is 0 or 1; And

_{Amide of formula-} (X ₂₄ ) _n24 -NH-C (O) -X _{25 or-} (X ₂₆ ) _n26 -C (O) -NH-X ₂₇ ,

Wherein X ₂₄ and X ₂₆ are each independently selected from the group consisting of lower alkylene, lower alkenylene, lower alkynylene, aryl and heteroaryl;

X ₂₅ is selected from the group consisting of hydrogen, lower alkyl, lower alkenyl, aryl, heteroaryl, hydroxy, alkoxy and amide; And

X ₂₇ is selected from the group consisting of hydrogen, lower alkyl, lower alkenyl, aryl and heteroaryl;

c) R ₁₅ is selected from the group consisting of hydrogen, lower alkyl, aryl, alkaryl, heteroaryl and amino;

d) R ₁₆ and R ₁₇ are each independently selected from the group consisting of hydrogen, lower alkyl, aryl and heteroaryl; And

e) E is selected from the group consisting of oxygen, sulfur and —NR ₁₀₁ —, where R ₁₀₁ is selected from the group consisting of hydrogen hydrogen, lower alkyl, lower alkene, lower alkyne, aryl and heteroaryl.

In some embodiments, R ₁₃ in Formula 4 is selected from the group consisting of

Iii) hydrogen;

Ii) C ₂ -C ₆ alkenylene;

Iii) halogen or perhaloalkyl;

Iii) alkoxy of formula -OX ₁₄ ,

Wherein X ₁₄ is selected from the group consisting of hydrogen, lower alkyl and aryl; And

Iii) a 5-membered or 6-membered heteroaryl ring, or a 6-membered aryl or heteroaryl ring optionally substituted with one or more substituents selected from the group consisting of

A) optionally substituted C ₁ -C ₄ straight, branched or cyclic saturated or unsaturated alkyl;

B) alkoxy of formula -OX ₁₄ , wherein X ₁₄ is hydrogen or lower alkyl;

C) halogen or perhaloalkyl;

D) cyano;

E) nitro;

F) a substituent of the _formula- (X ₁₈ ) _{n 18} -C (O) -X ₁₉ ,

Wherein X ₁₈ is lower alkylene;

X ₁₉ is selected from the group consisting of hydrogen, lower alkyl, aryl, heteroaryl, hydroxy, alkoxy, amino and -NX ₂₀ X ₂₁ ,

Wherein X ₂₀ and X ₂₁ are each independently selected from the group consisting of hydrogen, alkyl and aryl; And

n18 is 0 or 1;

G) a thioether or thiol of the formula -SX ₂₃ , wherein X ₂₃ is selected from the group consisting of hydrogen, lower alkyl, aryl and heteroaryl; And

H) an amide of _formula- (X ₂₄ ) _n24 -NH-C (O) -X _{25 or-} (X ₂₆ ) _n26 -C (O) -NH-X ₂₇ ,

Wherein X ₂₄ and X ₂₆ are each independently lower alkylene; X ₂₅ is selected from the group consisting of hydrogen, lower alkyl, aryl, hydroxy and alkoxy;

X ₂₇ is selected from the group consisting of hydrogen, lower alkyl, aryl and heteroaryl.

In other embodiments, R ₁₃ is selected from the group consisting of

Iii) hydrogen;

Ii) C ₂ -C ₆ alkylene;

Iii) halogen or perhaloalkyl;

Iii) alkoxy of formula -OX ₁₄ ,

Wherein X ₁₄ is selected from the group consisting of hydrogen, methyl, ethyl and propyl;

Iii) 6-membered aryl ring, which is optionally substituted with one or more substituents selected from the group consisting of:

A) methyl, ethyl and propyl;

B) hydroxy, methoxy, ethoxy, phenoxy, hydroxymethyl, 2-hydroxyethyl and 3-hydroxypropyl;

C) halogen or perfluoroalkyl;

D) cyano;

E) nitro;

F) a substituent of the formula -C (O) -X ₁₉ ,

Wherein X ₁₉ is hydrogen, methyl, ethyl, propyl, phenyl, hydroxy, methoxy, ethoxy, propoxy, amino and -NX ₂₀ X ₂₁ ,

Wherein X ₂₀ and X ₂₁ are each independently selected from the group consisting of hydrogen, methyl, ethyl, propyl and phenyl;

G) a thioether or thiol of the formula -SX ₂₃ , wherein X ₂₃ is selected from the group consisting of hydrogen, methyl, ethyl, propyl and phenyl;

H) an amide of _formula- (X ₂₄ ) _n24 -NH-C (O) -X _{25 or-} (X ₂₆ ) _n26 -C (O) -NH-X ₂₇ ,

Wherein X ₂₄ and X ₂₆ are each independently lower alkylene;

X ₂₅ is selected from the group consisting of hydrogen, methyl, ethyl, propyl, phenyl, hydroxy, methoxy and phenoxy; And

X ₂₇ is selected from the group consisting of hydrogen, methyl, ethyl, propyl and phenyl.

5- or 6-membered heteroaryl ring or 6-membered aryl or heteroaryl ring of R ₁₃ is optionally substituted , Optionally substituted , And optionally substituted It may be selected from the group consisting of wherein V, W, X, Y and Z are each independently CR or nitrogen, U is selected from the group consisting of CR ₂ , oxygen, sulfur and NR, wherein R is defined herein As it is.

The 5- or 6-membered heteroaryl ring or 6-membered aryl or heteroaryl ring of R ₁₃ is phenyl, furan, thiophene, pyrrole, pyrroline, pyrrolidine, oxazole, thiazole, imidazole, imida Sleepy, imidazolidine, pyrazole, pyrazoline, pyrazolidine, isosazole, isothiazole, triazole, thiadiazole, pyran, pyridine, piperidine, morpholine, thiomorpholine, pyridazine, pyrimidine , Pyrazine, piperazine, and triazine.

In other embodiments, R ₁₃ is hydrogen, chlorine, bromine, hydroxy, -CH = CH-CH ₂ CH ₂ CH ₂ CH ₃ , -CH = CH-C (O) -OH, -CH = CH- C (O) -OCH ₃ , -CH = CH-C (O) -NH ₂ , -CH ₂ CH (NH ₂ ) COOH, phenyl, -O-CH ₂ -phenyl, 2-methylphenyl, 3-methylphenyl, 2 -Methylthiophenyl, 3-methylthiopetyl, 4-methylthiophenyl, 4-methylphenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 2-hydroxyphenyl, 3-hydroxy Phenyl, 4-hydroxyphenyl, 2-hydroxymethylphenyl, 3-hydroxymethylphenyl, 4-hydroxymethylphenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2-cyanophenyl, 3-cyanophenyl, 4-cyanophenyl, 2-nitrophenyl, 3-nitrophenyl, 4-nitrophenyl, 2-hydroxycarbonylphenyl, 3-hydroxycarbonylphenyl, 4-hydroxycarbonylphenyl , 2-methoxycarbonylphenyl, 3-methoxycarbonylphenyl, 4-methoxycarbonylphenyl, 2-trifluoromethylpetyl, 4-benzyloxyphenyl, 2-phenoxyphenyl, 2,4-di Hydroxyphenyl , 3,4-dihydroxyphenyl, 2-hydroxy-4-methoxyphenyl, 4-hydroxy-2-methoxyphenyl, 2,4-dimethoxyphenyl, 3,4-dimethoxyphenyl, 3- Fluoro-4-hydroxyphenyl, 3-fluoro-4-methoxyphenyl, , , , , , , 2-pyridyl, 3-pyridyl, 4-pyridyl, , , , , , , , , , , , , And It may be selected from the group consisting of, wherein R is as defined herein.

In some embodiments, R ₁₁ , R ₁₂ , R _13, and R ₁₄ of Formula 4 each independently represent (i) hydrogen, (ii) hydroxyl, (iii) halogens, (iii) cyano, (iii) ) Nitro, (iii) amino, (iii) hydroxycarbonyl, (iii) aminocarbonyl, (iii) aminothiocarbonyl, (iii) lower alkoxy, (xi) phenoxy, (xii) (C _1- C ₄ ) alkylamino, (x ′) arylamino, (x ′) C ₁ -C ₈ straight, branched, and cyclic saturated or unsaturated alkyl or alkenyl, (x ′) optionally substituted aryl and (x ′) optionally It may also be selected from the group consisting of substituted heterocycles.

In some embodiments, R ₁₅ is (i) hydrogen, (ii) cyano, (iii) amino, (iii) hydroxycarbonyl, (iii) aminocarbonyl, (iii) aminothiocarbonyl, (iii) (C ₁ -C ₄ ) alkylamino, (iii) arylamino, (iii) C ₁ -C ₈ straight, branched, and cyclic saturated or unsaturated alkyl or alkenyl, (iii) optionally substituted aryl, and (xi) relates to a compound of formula 4, which may be selected from the group consisting of optionally substituted heterocycles.

In some embodiments according to the present invention, R ₁₆ of the compound of formula 4 is selected from (i) hydrogen, (ii) amino, (iii) hydroxycarbonyl, (iii) aminocarbonyl, (iii) aminothiocarbonyl , (Iii) (C ₁ -C ₄ ) alkylamino, (iii) arylamino, (iii) C ₁ -C ₈ straight, branched, and cyclic saturated or unsaturated alkyl or alkenyl, (iii) optionally substituted Aryl, and (iii) optionally substituted heterocycle.

In some embodiments, R ₁₇ of the compound of formula 4 is (i) hydrogen, (ii) (C ₁ -C ₄ ) alkylamino, (iii) arylamino, (iii) C ₁ -C ₈ straight chain, branched And cyclic saturated or unsaturated alkyl, (iii) optionally substituted aryl, and (iii) optionally substituted heterocycle.

The heterocycle moieties mentioned in the description of the compound of formula 4 are furan, thiophene, pyrrole, pyrroline, pyrrolidine, oxazole, thiazole, imidazole, imidazoline, imidazolidine, pyrazole, pyra Consisting of sleepy, pyrazolidine, isosazole, isothiazole, triazole, thiadiazole, pyran, pyridine, piperidine, morpholine, thiomorpholine, pyridazine, pyrimidine, pyrazine, piperazine, and triazine It may be selected from the group.

D. Naphthalene derivatives

In another aspect, the invention relates to a compound of Formula 5 or 6, or a pharmaceutically acceptable salt, amide, ester, or prodrug thereof.

(5)

(6)

Where

a) R ₁₉ -R ₂₂ and R ₂₆ -R ₂₉ are each independently selected from the group consisting of

Iii) hydrogen;

Ii) optionally substituted C ₁ -C ₈ straight, branched or cyclic saturated or unsaturated alkyl;

Iii) optionally substituted aryl;

Iii) optionally substituted heterocycle;

Ⅴ) Formula -C (X ₄ ) = N-NX ₅ -C (= E) -NX ₆ X ₇ or -C (X ₄ ) = NN = C (EX ₅ ) -NX ₆ X ₇ ,

Wherein X ₄ is selected from the group consisting of hydrogen, lower alkyl, aryl, alkaryl, heteroaryl and amino;

E is selected from the group consisting of oxygen, sulfur and -NR _101- , wherein R ₁₀₁ is selected from the group consisting of hydrogen hydrogen, lower alkyl, lower alkene, lower alkyne, aryl and heteroaryl; And

X ₅ , X ₆ and X ₇ are each independently selected from the group consisting of hydrogen, lower alkyl, aryl and heteroaryl;

Iii) amino guanidine of formula -NX ₈ -NX ₉ -C (= NX ₁₀ ) -NX ₁₁ X ₁₂ ,

Wherein X ₈ , X ₉ , X ₁₀ , X ₁₁ and X ₁₂ are each independently selected from the group consisting of hydrogen, lower alkyl, aryl and heteroaryl;

Ⅶ) formula - (X _{13) n13} alkoxy of -OX _14,

Wherein X ₁₃ is selected from the group consisting of lower alkylene, lower alkenylene, lower alkynylene, aryl and heteroaryl;

X ₁₄ is selected from the group consisting of hydrogen, lower alkyl, aryl and heteroaryl;

n13 is 0 or 1;

Iii) halogen or perhaloalkyl;

Iii) cyano;

Iii) nitro;

xi) amino of the formula-(X ₁₅ ) _n15 -NX ₁₆ X ₁₇ ,

Wherein X ₁₅ is selected from the group consisting of lower alkylene, lower alkenylene, lower alkynylene, aryl and heteroaryl;

X ₁₆ and X ₁₇ are each independently selected from the group consisting of hydrogen, lower alkyl, aryl and heteroaryl; Or X ₁₆ and X ₁₇ are taken together with the nitrogen to which they are attached and are a 5- or 6-membered heteroaromatic or heteroaliphatic ring; And

n15 is 0 or 1;

xii) a substituent of the formula-(X ₁₈ ) _n18 -C (= E) -X ₁₉ ,

Wherein X ₁₈ is selected from the group consisting of lower alkylene, lower alkenylene, lower alkynylene, aryl and heteroaryl;

E is selected from the group consisting of oxygen, sulfur and -NR _101- , wherein R ₁₀₁ is selected from the group consisting of hydrogen hydrogen, lower alkyl, lower alkene, lower alkyne, aryl and heteroaryl;

X ₁₉ is selected from the group consisting of hydrogen, lower alkyl, aryl, heteroaryl, amino and -NX ₂₀ X ₂₁ ,

Wherein X ₂₀ and X ₂₁ are independently selected from the group consisting of hydrogen, alkyl, aryl and heteroaryl; And

n18 is 0 or 1;

xvi) thioether or thiol of the _formula- (X ₂₂ ) _{n22 -SX 23} ,

Wherein X ₂₂ is lower alkylene, lower alkenylene, lower alkynylene. Aryl and heteroaryl;

X ₂₃ is selected from the group consisting of hydrogen, lower alkyl, aryl and heteroaryl; And

n22 is 0 or 1;

b) R ₂₃ and R ₃₀ are each independently selected from the group consisting of the following;

Iii) hydrogen;

Ii) lower alkyl;

Iii) lower alkylene;

Iii) halogen or perhaloalkyl;

Ⅴ) alkoxy of the formula-(X ₁₃ ) _n13 -OX ₁₄ ,

Wherein X ₁₃ is selected from the group consisting of lower alkylene, lower alkenylene, lower alkynylene, allyl and heteroaryl;

X ₁₄ is selected from the group consisting of hydrogen, lower alkyl, aryl and heteroaryl; And

n13 is 0 or 1; And

Iii) a 5- or 6-membered heteroaryl ring or a 6-membered aryl or heteroaryl ring, optionally substituted with one or more substituents selected from the group consisting of:

A) optionally substituted C ₁ -C ₈ straight, branched, or cyclic saturated or unsaturated alkyl;

B) alkoxy of formula-(X ₁₃ ) _n13 -OX ₁₄ ,

Wherein X ₁₃ is selected from the group consisting of lower alkylene, lower alkenylene, lower alkynylene, aryl and heteroaryl;

X ₁₄ is selected from the group consisting of hydrogen, lower alkyl, aryl and heteroaryl; And

n13 is 0 or 1;

C) halogen or perhaloalkyl;

D) cyano;

E) nitro;

F) amino of the formula-(X ₁₅ ) _n15 -NX ₁₆ X ₁₇ ,

Wherein X ₁₅ is selected from the group consisting of lower alkylene, lower alkenylene, lower alkynylene, aryl and heteroaryl;

X ₁₆ and X ₁₇ are each independently selected from the group consisting of hydrogen, lower alkyl, aryl and heteroaryl; Or X ₁₆ and X ₁₇ are taken together with the nitrogen to which they are attached to form a 5- or 6-membered heteroaromatic or heteroaliphatic ring; And

n15 is 0 or 1;

G) a substituent of the _formula- (X ₁₈ ) _n18 -C (= E) -X ₁₉ ,

Wherein X ₁₈ is selected from the group consisting of lower alkylene, lower alkenylene, lower alkynylene, aryl and heteroaryl;

E is selected from the group consisting of oxygen, sulfur and -NR _101- , wherein R ₁₀₁ is selected from the group consisting of hydrogen hydrogen, lower alkyl, lower alkene, lower alkyne, aryl and heteroaryl;

X ₁₉ is selected from the group consisting of hydrogen, lower alkyl, aryl, heteroaryl, hydroxy, alkoxy, amino and -NX ₂₀ X ₂₁ ,

Wherein X ₂₀ and X ₂₁ are each independently selected from the group consisting of hydrogen, alkyl, aryl and heteroaryl;

n18 is 0 or 1; And

H) a thioether or thiol of the _formula- (X ₂₂ ) _{n22 -SX 23} ,

Wherein X ₂₂ is selected from the group consisting of lower alkylene, lower alkenylene, lower alkynylene, aryl and heteroaryl; And

X ₂₃ is selected from the group consisting of hydrogen, lower alkyl, aryl and heteroaryl,

n22 is 0 or 1; And

_{Amide of formula-} (X ₂₄ ) _n24 -NH-C (O) -X _{25 or-} (X ₂₆ ) _n26 -C (O) -NH-X ₂₇ ,

Wherein X ₂₄ and X ₂₆ are each independently selected from the group consisting of lower alkylene, lower alkenylene, lower alkynylene, aryl and heteroaryl;

X ₂₅ is selected from the group consisting of hydrogen, lower alkyl, lower alkenyl, aryl, heteroaryl, hydroxy, alkoxy and amide; And

X ₂₇ is selected from the group consisting of hydrogen, lower alkyl, lower alkenyl, aryl and heteroaryl; and

c) R ₂₄ , R ₂₅ , R ₃₁ and R ₃₂ are each independently selected from the group consisting of

Iii) a 6-membered aromatic or heteroaromatic, 5- or 6-membered heteroaromatic ring, optionally substituted with one or more substituents selected from the group consisting of lower alkyl, hydroxy, alkoxy, amino and nitro;

Ii) acyl of the formula-(X ₁ ) _{n 1} -C (O) -X ₂ ,

Wherein X ₁ is selected from the group consisting of lower alkylene, lower alkenylene, lower alkynylene, aryl and heteroaryl;

X ₂ is selected from the group consisting of hydrogen, lower alkyl, aryl, heteroaryl, hydroxy, alkoxy, amino and -NH-X ₃ ;

Wherein X ₃ is selected from the group consisting of hydrogen, alkyl, aryl, heteroaryl, amino and amide; And

n1 is 0 or 1;

Iv) a substituent of formula -C (X ₄ ) = N-NX ₅ -C (= E) -NX ₆ X ₇ or a formula -C (X ₄ ) = NN = C (EX ₅ ) -NX ₆ X ₇ ,

Wherein X ₄ is selected from the group consisting of hydrogen, lower alkyl, aryl, alkaryl, heteroaryl and amino;

E is selected from the group consisting of oxygen, sulfur and -NR _101- , wherein R ₁₀₁ is selected from the group consisting of hydrogen hydrogen, lower alkyl, lower alkene, lower alkyne, aryl and heteroaryl; And

X ₅ , X ₆ and X ₇ are each independently selected from the group consisting of hydrogen, lower alkyl, aryl and heteroaryl;

Provided that any of R ₂₄ , R ₂₅ , R ₃₁ or R ₃₂ is -C ₆ H ₅ , -C (0) H, -C (O) CH ₃ , -C (O) -C ₆ H ₅ , -C (O) NH ₂ , or -C ₆ H ₄ CH ₃ .

In some embodiments, R ₂₄ , R ₂₅ , R ₃₁ , and R ₃₂ may each be independently selected from the group consisting of

Iii) hydrogen;

Ii) 6-membered aromatic ring, which is optionally substituted with one or more substituents selected from the group consisting of lower alkyl, hydroxy and amine;

Iii) 6-membered heteroaromatic ring, which is optionally substituted with one or more substituents selected from the group consisting of lower alkyl, hydroxy, alkoxy, amino, nitro;

Iii) a 5-membered heteroaromatic ring, which is optionally substituted with one or more substituents selected from the group consisting of lower alkyl, hydroxy and amine;

아) acyl of the formula-(X ₁ ) _{n 1} -C (O) -X ₂ ,

Wherein X ₁ is lower alkylene or lower alkenylene;

X ₂ is selected from the group consisting of hydrogen, amino, hydroxy and -NH-X ₃ ,

Wherein X ₃ is selected from the group consisting of hydrogen, lower alkyl, amino and amide;

n is 0 or 1;

Iv) a substituent of the formula -C (X ₄ ) = N-NH-C (= E) -NX ₆ X ₇ or a formula -C (X ₄ ) = NN = C (EX ₅ ) -NX ₆ X ₇ ,

Wherein X ₄ is selected from the group consisting of hydrogen, lower alkyl, aryl and alkaryl;

E is selected from the group consisting of oxygen, sulfur and -NR _101- , wherein R ₁₀₁ is selected from the group consisting of hydrogen hydrogen, lower alkyl, lower alkene, lower alkyne, aryl and heteroaryl; And

X ₅ , X ₆ and X ₇ are each independently selected from the group consisting of hydrogen and lower alkyl.

R ₂₄ , R ₂₅ , R ₃₁ , and R ₃₂ may each independently be selected from the group consisting of

Iii) hydrogen;

Ii) phenyl, which is optionally substituted with one or more hydroxy or -NH ₂ ;

Iii) a 6-membered heteroaromatic ring selected from the group consisting of pyridine, pyrazine, pyridazine, pyrimidine and 1,3,5-triazine, each independently and optionally with lower alkyl, hydroxy, alkoxy and amino Substituted with one or more substituents selected from the group consisting of;

Iii) 5-membered heteroaromatic rings selected from the group consisting of pyrrole, imidazole, 1,2,3-triazole, 1,2,4-triazole, tetrazole, thiophene, thiazole, and thiadiazole, which are Each independently and optionally hydroxy, an amide of the _formula- (X ₂₄ ) _n24 -NH-C (O) -X _{25 or-} (X ₂₆ ) _n26 -C (O) -NH-X ₂₇ , and -NH ₂ Substituted with one or more substituents selected from the group consisting of;

Iii) acyl of the formula -C (O) -X ₂ , wherein X ₂ is hydrogen or lower alkyl;

Iv) -C (X ₄ ) = N-NH-C (= E) -NH ₂ ,

Wherein X ₄ is selected from the group consisting of hydrogen, methyl, ethyl, phenyl and -CH ₂ CH ₂ -Ph; And

E is oxygen, sulfur, and -NR ₁₀₁ - it is selected from the group consisting of wherein R is hydrogen _1O1 hydrogen, lower alkyl, lower alkenyl, lower alkynyl, aryl, and is selected from the group consisting of-heteroaryl; And

Ⅶ) Formula -C (X ₄ ) = NN = C (SX ₅ ) -NH ₂ ,

Wherein X ₄ is selected from the group consisting of hydrogen, methyl, ethyl, phenyl and -CH ₂ CH ₂ -Ph;

X ₅ is hydrogen or methyl.

The 5- or 6-membered heteroaryl ring in R ₂₄ , R ₂₅ , R ₃₁ , and R ₃₂ is, in some embodiments,

Optionally substituted , Optionally substituted , And optionally substituted It may be selected from the group consisting of wherein V, W, X, Y and Z are each independently CR or nitrogen, U is selected from the group consisting of CR ₂ , oxygen, sulfur and NR, wherein R is defined herein As it is.

In some other embodiments, the heteroaryl ring may be a furan, thiophene, pyrrole, pyrroline, pyrrolidine, oxazole, thiazole, imidazole, imidazoline, imidazolidine, pyrazole, pyrazoline, Pyrazolidine, isosazole, isothiazole, triazole, thiadiazole, oxadiazole, pyran, pyridine, piperidine, morpholine, thiomorpholine, pyridazine, pyrimidine, pyrazine, piperazine, and triazine It may be selected from the group consisting of.

More specifically, the heteroaryl ring is aminofuran, aminothiophene, aminopyrrole, aminopyrroline, aminopyrrolidine, aminooxazole, aminothiazole, aminoimidazole, aminoimidazoline, aminoimidazolidine, Aminopyrazole, aminopyrazoline, aminopyrazolidine, aminoisoxazole, aminoisothiazole, aminotriazole, aminothiadiazole, aminooxadiazole, aminopyran, aminopyridine, aminopiperidine, aminomorpholine, It may also be selected from the group consisting of aminothiomorpholine, aminopyridazine, aminopyrimidine, aminopyrazine, aminopiperazine, and aminotriazine.

Some embodiments of the invention include those wherein R ₂₄ , R ₂₅ , R ₃₁ and R ₃₂ are hydrogen, —C (O) —CH ₃ , —C (O) —NH—CH ₂ —C (O) —NH ₂ , -CH = CH = C (O) -NH ₂ , -CH ₂ CH ₂ -C (O) -NH-NH ₂ , -C (H) = N-NH-C (O) -NH ₂ , -C ( CH ₃ ) = N-NH-C (O) -NH ₂ , -C (H) = N-NH-C (S) -NH ₂ , -C (CH ₃ ) = N-NH-C (S)- NH ₂ , -C (Ph) = N-NH-C (S) -NH ₂ , -C (CH ₂ CH ₂ Ph) = N-NH-C (S) -NH ₂ , -C (H) = NN = C (SCH ₃ ) -NH ₂ , , , , , , , , , , , , , , , , , , , , And It may be selected from the group consisting of, relates to a compound of formula 5 or 6, wherein R is as defined herein.

In some embodiments R ₂₃ and R ₃₀ may be each independently selected from the group consisting of

Iii) hydrogen;

Ii) C ₂ -C ₆ alkenylene;

Iii) halogen or perhaloalkyl;

Iii) alkoxy of formula -OX ₁₄ ,

Wherein X ₁₄ is selected from the group consisting of hydrogen, lower alkyl and aryl; And

Iii) a 5-membered or 6-membered heteroaryl ring, or a 6-membered aryl or heteroaryl ring optionally substituted with one or more substituents selected from the group consisting of

A) optionally substituted C ₁ -C ₄ straight, branched or cyclic saturated or unsaturated alkyl;

B) alkoxy of formula -OX ₁₄ , wherein X ₁₄ is hydrogen or lower alkyl;

C) halogen or perhaloalkyl;

D) cyano;

E) nitro;

F) a substituent of the _formula- (X ₁₈ ) _{n 18} -C (O) -X ₁₉ ,

Wherein X ₁₈ is lower alkylene;

X ₁₉ is selected from the group consisting of hydrogen, lower alkyl, aryl, heteroaryl, hydroxy, alkoxy, amino and -NX ₂₀ X ₂₁ ,

Wherein X ₂₀ and X ₂₁ are each independently selected from the group consisting of hydrogen, alkyl and aryl; And

n18 is 0 or 1;

G) a thioether or thiol of the formula -SX ₂₃ , wherein X ₂₃ is selected from the group consisting of hydrogen, lower alkyl, aryl and heteroaryl; And

H) an amide of _formula- (X ₂₄ ) _n24 -NH-C (O) -X _{25 or-} (X ₂₆ ) _n26 -C (O) -NH-X ₂₇ ,

Wherein X ₂₄ and X ₂₆ are each independently lower alkylene; X ₂₅ is selected from the group consisting of hydrogen, lower alkyl, aryl, hydroxy and alkoxy;

X ₂₇ is selected from the group consisting of hydrogen, lower alkyl, aryl and heteroaryl.

In other embodiments, R ₂₃ and R ₃₀ may be selected from the group consisting of

Iii) hydrogen;

Ii) C ₂ -C ₆ alkylene;

Iii) halogen or perfluoroalkyl;

Iii) alkoxy of formula -OX ₁₄ ,

Wherein X ₁₄ is selected from the group consisting of hydrogen, methyl, ethyl and propyl;

Iii) 6-membered aryl ring, which is optionally substituted with one or more substituents selected from the group consisting of:

A) methyl, ethyl and propyl;

B) hydroxy, methoxy, ethoxy, phenoxy, hydroxymethyl, 2-hydroxyethyl and 3-hydroxypropyl;

C) halogen or perfluoroalkyl;

D) cyano;

E) nitro;

F) a substituent of the formula -C (O) -X ₁₉ ,

Wherein X ₁₉ is hydrogen, methyl, ethyl, propyl, phenyl, hydroxy, methoxy, ethoxy, propoxy, amino and -NX ₂₀ X ₂₁ ,

Wherein X ₂₀ and X ₂₁ are each independently selected from the group consisting of hydrogen, methyl, ethyl, propyl and phenyl;

Thioether or thiol of G) -SX ₂₃ , wherein X ₂₃ is selected from the group consisting of hydrogen, methyl, ethyl, propyl and phenyl;

H) an amide of _formula- (X ₂₄ ) _n24 -NH-C (O) -X _{25 or-} (X ₂₆ ) _n26 -C (O) -NH-X ₂₇ ,

Wherein X ₂₄ and X ₂₆ are each independently lower alkylene;

X ₂₅ is selected from the group consisting of hydrogen, methyl, ethyl, propyl, phenyl, hydroxy, methoxy and phenoxy; And

X ₂₇ is selected from the group consisting of hydrogen, methyl, ethyl, propyl and phenyl.

In some embodiments of the invention, the 5- or 6-membered heteroaryl ring or 6-membered aryl or heteroaryl of R ₂₃ and R ₃₀ is optionally substituted. , Optionally substituted , And optionally substituted It may be selected from the group consisting of W, X, Y and Z are each independently CR or nitrogen, U is selected from the group consisting of CR ₂ , oxygen, sulfur and NR; R is as defined herein.

The 5- or 6-membered heteroaryl ring or 6-membered aryl or heteroaryl of R ₂₃ and R ₃₀ is phenyl, furan, thiophene, pyrrole, pyrroline, pyrrolidine, oxazole, thiazole, imidazole , Imidazoline, imidazolidine, pyrazole, pyrazoline, pyrazolidine, isosazole, isothiazole, triazole, thiadiazole, pyran, pyridine, piperidine, morpholine, thiomorpholine, pyridazine It may also be selected from the group consisting of pyrimidine, pyrazine, piperazine and triazine.

In some embodiments, R ₂₃ and R ₃₀ are each independently hydrogen, chlorine, bromine, hydroxy, —CH═CH—CH ₂ CH ₂ CH ₂ CH ₃ , —CH═CH—C (O) —OH , -CH = CH-C (O) -OCH ₃ , -CH = CH-C (O) -NH ₂ , -CH ₂ CH (NH ₂ ) COOH, phenyl, -O-CH ₂ -phenyl, 2-methylphenyl , 3-methylphenyl, 2-methylthiophenyl, 3-methylthiophenyl, 4-methylthiophenyl, 4-methylphenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 2-hydroxy Phenyl, 3-hydroxyphenyl, 4-hydroxyphenyl, 2-hydroxymethylphenyl, 3-hydroxymethylphenyl, 4-hydroxymethylphenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2-cyanophenyl, 3-cyanophenyl, 4-cyanophenyl, 2-nitrophenyl, 3-nitrophenyl, 4-nitrophenyl, 2-hydroxycarbonylphenyl, 3-hydroxycarbonylphenyl, 4 -Hydroxycarbonylphenyl, 2-methoxycarbonylphenyl, 3-methoxycarbonylphenyl, 4-methoxycarbonylphenyl, 2-trifluoromethylphenyl, 4-benzyloxyphenyl, 2-phenoxy Phenyl, 2,4-dihydroxyphenyl, 3,4-dihydroxyphenyl, 2-hydroxy-4-methoxyphenyl, 4-hydroxy-2-methoxyphenyl, 2,4-dimethoxyphenyl, 3,4-dimethoxyphenyl, 3-fluoro-4-hydroxyphenyl, 3-fluoro-4-methoxyphenyl, , , , , , , 2-pyridyl, 3-pyridyl, 4-pyridyl, , , , , , , , , , , , , And It may be selected from the group consisting of, wherein R is as defined herein.

E. Compounds of the Invention

In another aspect, the present invention relates to the compounds disclosed in Table 1, their pharmaceutically acceptable salts, esters, amides or prodrugs.

TABLE 1

Example structure

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

31

32

33

34

35

36

37

38

39

40

41

42

43

44

45

46

47

48

49

50

51

52

53

54

55

56

57

58

59

60

61

62

63

64

65

66

67

68

69

70

71

72

73

74

75

76

77

78

79

80

81

82

83

84

85

86

87

88

89

90

91

92

93

94

95

96

97

98

99

100

101

102

103

104

105

106

107

108

109

110

111

112

113

114

115

116

117

118

119

II. Combinatorial configurations

In another aspect, the present invention provides a combination of at least 10 compounds that can be formed by reacting an acyl compound of formula 7 with an amine of formula 8.

Where

a) R ₅₀ is selected from the group consisting of hydrogen, lower alkyl, aryl, alkaryl, heteroaryl and amino;

b) R ₅₁ is selected from the group consisting of hydrogen, lower alkyl and hydroxy;

c) R ₅₂ is selected from the group consisting of hydrogen, optionally substituted lower alkyl, hydroxy, lower alkoxy, halogen and nitro;

d) R ₅₃ is selected from the group consisting of hydrogen, hydroxy, optionally substituted lower alkyl, and optionally substituted lower alkoxy;

e) R ₅₄ is selected from the group consisting of hydrogen, hydroxy, optionally substituted lower alkyl, optionally substituted lower alkoxy, optionally substituted aryl, optionally substituted cycloalkyl, halogen, and nitro;

f) R ₅₅ is selected from the group consisting of hydrogen, lower alkyl and hydroxy;

Or R ₅₃ and R ₅₄ are taken together with the two ring carbons to which they are attached, or R ₅₄ and R ₅₅ are taken together with the two ring carbons to which they are attached so that an optionally substituted 6-membered aromatic or hetero To form an aromatic, or optionally substituted 6-membered heteroaromatic ring,

g) M is selected from the group consisting of carbon and nitrogen, when M is nitrogen, R ₅₅ is absent,

h) T is selected from the group consisting of nitrogen and -CR _56- ;

i) R ₅₆ is selected from the group consisting of hydrogen and optionally substituted lower alkyl;

j) E is selected from the group consisting of oxygen, sulfur and NH;

Wherein at least one of R ₅₁ -R ₅₅ is not hydrogen and at least one of R ₅₁ , R ₅₂ or R ₅₅ is hydroxy.

By "combinatorial library" is meant all compounds formed by reacting each compound in one dimension with some or all of the other dimensional compounds in a multi-dimensional array of compounds. In the context of the present invention, the arrangement may be two-dimensional, where one dimension represents acyl compounds of formula 7 and the second dimension represents an amine of formula 8. Each acyl compound can react with each and all amines to form the compounds of the present invention. All compounds of the present invention formed in this way are within the scope of the present invention. Further smaller combinations formed by reaction of some acyl compounds with all amines, reaction of all acyl compounds with some amines, or reaction of some acyl compounds with some amines are also within the scope of the present invention. .

In some embodiments, R ₅₀ is (i) hydrogen, (ii) cyano, (iii) amino, (iii) hydroxycarbonyl, (iii) aminocarbonyl, (iii) aminothiocarbonyl, (iii) ) (C ₁ -C ₄ ) alkylamino, (iii) arylamino, (iii) C ₁ -C ₈ straight, branched, and cyclic saturated and unsaturated alkyl or akenyl, (iii) optionally substituted aryl and (xi) may be selected from the group consisting of optionally substituted heterocycles.

In other embodiments, R ₅₁ and R ₅₅ can each independently be hydrogen or hydroxy and R ₅₂ is a group consisting of hydrogen, hydroxy, chlorine, chlorine, bromine, iodine, halomethyl, methoxy, and nitro While R ₅₃ may be selected from hydrogen, hydroxy, methoxy, benzyloxy. In still other embodiments, R ₅₄ can be selected from the group consisting of hydrogen, methyl, ethyl, propyl, phenyl, cyclohexyl, hydroxy, fluorine, chlorine, bromine, iodine, methoxy and nitro.

Another embodiment of the present invention is an acyl compound of formula (7), , , , , , , , , , , , , , , , , , , , , , , , , , , , , And It is selected from the group consisting of;

The amine compound of formula (8), , , , , , And It is related to the combination configuration, selected from the group consisting of.

The reaction of the acyl compound of formula 7 with the amine of formula 8 may be carried out under the following general conditions. 0.05 M DMSO equivalent (volume units) of each of the acyl and amine compounds are combined in a combinatorial fashion with catalytic amounts of sulfonic acid. After 16 hours, thin layer chromatography analysis shows the completion of the reaction. The resulting product in DMSO can be used for analysis without further purification.

III. Synthesis of Compounds of the Invention

There are three synthetic methods used to prepare the phenol derivative compounds of the present invention having the following general formulas:

, And , Wherein U, W, X, Y and Z are as defined herein. The first method is to prepare boronic acid attached to the biaryl core structure as disclosed in Scheme 1 and Scheme 2. The second method is to construct heterocycle rings in biaryl using functional groups as described in Schemes 3-4. For the synthesis of the compound of the formula (2), as disclosed in Scheme 5, the amino aromatic pyrimidine ring is formed before the Suzuki reaction to introduce a second aromatic ring.

The semicarbazone / thiosemicarbazone compounds of the present invention are synthesized according to the following methods.

In Scheme 11, salicylaldehyde is reacted with semicarbazide hydrochloride or thiosemicarbazide in the presence of a catalytic amount of sulfonic acid to provide a high yield of semicarbazone / thiosemicarbazone product.

Preparation of 5-aryl salicyaldehyde was accomplished via Suzuki reaction (Miyaura, N .; Suzuki, A .: Chem. Rev. 1995, 95, 2457-2483). In this reaction, 1 equivalent of 5-bromo salicylaldehyde, 1.05 equivalent of arylboronic, and 0.02 equivalent of Tetrkis (triphenylphosphine) palladium are dissolved in ethylene glycol dimethyl (DME) ether to give 0.2-0.3 Obtain the final concentration of M To this mixture, 2.5 equivalents of liquid 2.0 M sodium carbonate are added and the mixture is refluxed for 2-16 hours in a nitrogen atmosphere. The resulting product was purified by column chromatography.

Following the reaction disclosed in Scheme 12, 1.05 equivalents of the obtained 5-aryl salicyaldehyde, 1 equivalent of semicarbazide or thiosemicarbazide are added and dissolved in dimethyl formamide at a final concentration of 0.5 mole. After addition of trace amounts of camphorsulfonic acid, the reaction solution is stirred at room temperature for 2-18 hours. Judging by thin layer chromatography, upon completion of the reaction, the solvent is removed in vacuo and the product is washed six times with diethyl ether and dried in vacuo.

When a methoxy group was attached to arylboronic acid, Suzuki reaction was carried out to first obtain methoxy substituted aryl salicylaldehyde (Scheme 13). The methyl group was removed at −78 ° C. using tribromoborane in DCM. The resulting hydroxyaryl substituted salicyaldehyde is reacted with hydrochloride or thiosemicarbazide in the presence of a catalytic amount of sulfonic acid to obtain a high yield of semicarbazone / thiosemicarbazone compound.

In order to synthesize 5- (5-pyrimidyl) salicyaldehyde thiosemicarbazone, boronate was introduced at a properly protected salicyaldehyde site (Murata, M .; Oyama, T .; Watanabe, S and Masuda, Y. J. Org.Chem . 2000, 65, 164-168 (Scheme 14). The boronate obtained was then reacted with 5-bromo-pyrimidine via Suzuki Reaction to give protected 5- (5-pyrimidyl) -salicylaldehyde in 72% yield. The protecting group was then removed using tribromoborane of dichloromethane at low temperature prior to conducting the semicarboservation reaction.

Starting from 5-bromosalicylaldehyde and the corresponding acrylates or acrylamides, cinnamate type compounds (Scheme 15, 16 and 17) were obtained via Heck reaction (Zebovitz, TC; Heck, RF J. Org. Chem. , 1997, 42, 3907-3909). The resulting aldehyde was further reacted with semicarbozide or thiosemicarbazide to give the corresponding semicarbazone and thiosemicarbazone products.

As shown in Scheme 18, 3- (4-hydroxyphenyl) propionic acid based on known methods (Russel, A. and Lockhart, L., B., Org.Syn . Coll., V3, 463-464). Was easily formed into hydroxy at the ortho position to give 3- (3-formyl-4-hydroxyphenyl) propionic acid. This aldehyde is further reacted with thiosemicarbazide to convert to the corresponding thiosemicarbazone product.

Processes and methods for preparing the naphthalene derivative compounds of the present invention are described in the following schemes.

In Scheme 19, naphthalene (I) is formed with phosphorus oxochloride and N, N-dimethylformamide and the aldehyde obtained is further reacted with semicarbazide or thiosemicarbazide in the presence of catalytic amount of sulfonic acid.

Scheme 20 provides a synthetic route to the pyrimidine compound (VII). 1 equivalent of ketone (IV) and 15 equivalents of N, N-dimethylformamide diethyl acetal were combined and heated to 100 ° C. overnight. The reaction mixture is concentrated in vacuo, with 3 equivalents of sodium ethoxide and then dissolved in salt butanol (0.1 M) with 1 equivalent of guanidine hydrochloride. The methyl ether is then readily converted to hydroxyl groups using tribromoborane of methylenedichloride.

The following schemes 21-26 illustrate novel methods for synthesizing some aromatic compounds of the present invention.

Ⅳ. Target diseases to be treated

The compounds described herein are useful for treating diseases associated with unregulated kinase-signaling, including cell proliferative diseases, fibrotic diseases, and metabolic diseases. The compounds of the present invention are useful in the same way as described in WO 00/56709.

Cell proliferative diseases that can be treated or further studied by the present invention include cancer, vascular proliferative diseases, and new cell proliferative diseases.

Blood vessel proliferative disorders generally refer to angiogenic and angiogenic diseases resulting in abnormal proliferation of blood vessels. Angiogenesis and expansion, or angiogenesis and angiogenesis, play an important role in various physiological processes, such as embryonic development, corpus luteum formation, wound healing and organ regeneration, respectively. They also play a pivotal role in cancer development. Other examples of vascular proliferative diseases include visual diseases, such as arthritis, in which new micro-vessels invade joints and destroy cartilage, and diabetic retinopathy, in which new capillaries in the retina invade the vitreous and cause blindness with its appearance. have. Conversely, diseases are also included, such as resteresis, associated with contraction, atrophy or obstruction of blood vessels.

Fibrotic disorders refer to abnormal formation of extracellular matrix. Examples of fibrotic diseases include cirrhosis of the liver and vasculature. Cirrhosis is characterized by an increase in extracellular matrix components that lead to the formation of liver scars. Liver cirrhosis can lead to diseases such as cirrhosis of the liver. Increased extracellular matrix that results in liver scars can also be caused by viral infections such as hepatitis. Adipocytes appear to play a major role in liver hardening. Other fibrotic diseases include atherosclerosis.

Mesenial cell proliferative disorders refer to diseases caused by abnormal proliferation of new cells. Renal proliferative diseases include renal disease such as glomerulonephritis, diabetic nephropathy, malignant atrophy, microvascular symptoms of thrombosis, transplant rejection and glomerulopathy. PDGF-R was involved in the maintenance of new cell proliferation. Floege et al., 1993, Kidney International 43: 47S-54S.

PKs have been associated with such cell proliferative diseases. For example, part of the receptor tyrosine kinase family has been involved in the development of cancer. EGFR (Tuzi et al., 1991, Br. J Cancer 63: 227-233; Torp et al., 1992, APMIS 100: 713-719), HER2 / neu (Slamon et al., 1989, Science 244: 707- 712) and some of these receptors, such as PDGF-R (Kumabe et al, 1992, Oncogene 7: 627-633), are overexpressed in many tumors and / or are constantly activated by self-secreting loops. In fact, in the most common and severe cancers, these receptor overexpression (Akbasak and Suner-Akbasak et al, 1992, J. Neurol. Sci. 119-133; Dickson et al, 1992, Cancer Treatment Res. 61: 249-273; Korc et al., 1992, J Clin. Invest. 90: 1352-1360) and self-secreting loops (Lee and Donoghue, 1992, J Cell. Biol 118: 1057-1070; Korc et al, supra; Akbasak and Suner-Akbasak et al, supra) has been demonstrated. For example, EGFR receptors are associated with squamous cell carcinoma, astrocytoma, glioblastoma, head and neck cancer, lung cancer and bladder cancer. HER2 is associated with breast, ovarian, stomach, lung, pancreatic and bladder cancers. PDGF-R is associated with glioplasma, lung, ovary, melanoma and prostate cancer. RK c-met is generally associated with liver carcinogenesis and consequent hepatocellular carcinoma. In addition, c-met is associated with malignant tumor formation. More specifically, RK c-met is associated with rectum, thyroid, pancreatic and gastric carcinoma, leukemia and lymphoma, among other sons. In addition, overexpression of the c-met gene is detected in patients with Hodgkin's disease, Burkitt's disease and seeding. Likewise, Flk is associated with a wide range of tumors including, but not limited to, glioma such as glioblastoma, as well as breast, ovarian and lung tumors.

In addition to being involved in nutritional support and type 2 diabetes, IGF-IR is also associated with several types of cancer. For example, IGF-I has been described in human breast cancer carcinoma cells (Azteaga et aL, 1989, J Clin. Invest. 84: 1418-1423) and bovine lung tumor cells (Macauley et aL, 1990, Cancer Res. 50: 2511-2517), and is involved as a self-secreting growth promoter for several types of tumors. In addition, it appears to be a self-secreting promoter of IGF-1 human gliaons that are absolutely involved in normal growth and differentiation of the nervous system (Sandberg-Nordqvist et aL, 1993, Cancer Res. 53: 2475-2478.). The importance of IGF-IF and its ligands in cell proliferation has been attributed to many types of cells (fibroblasts, epithelial cells, smooth muscle cells, T-lymphocytes, myeloid cells, chondrocytes, osteoblasts, the stem cells of the bone marrow) in culture. It is further supported by the fact that it is stimulated and grown by IGF-I (Goldring and Goldring, 1991, Eukaryotic Gene Expression 1: 301-326.). In a series of recent publications, Baserga even suggests that IGF-IR plays an important role in the pre-reactor reaction of metastasis, thereby making it a desirable target for therapeutic intervention in a wide range of human malignancies (Baserga, 1995, Cancer Res. 55: 249-252; Baserga, 1994, Cell 79: 927-930; Coppola et aL, 1994, MoL Cell. BioL 14: 4588-4595).

Some protein kinases (PKs) are involved in many types of cancers, especially breast cancer (Cance, et al., Int. J Cancer, 54: 571-77 (1993)).

However, the link between abnormalities in RKs and diseases is not limited to cancer alone. For example, RKs are associated with budding diseases such as psoriasis, diabetes, wound healing, infections and neurodegenerative diseases. These diseases include hypertension, suppression, systemic anxiety disorders, phobias, traumatic stress disorders, evasive personality disorders, sexual disability, eating disorders, obesity, drug dependence, cluster headaches, migraines, pain, Alzheimer's disease, obsessive compulsive disorders, Panic disorders, memory disorders, Parkinson's disease, endocrine disorders, vasospasm, ataxia, and gastrointestinal disorders, but are not limited to these. For example, EGF-R is seen in corneal and skin wound healing. More detailed relationships between specific RKs and their therapeutic indicators are described in Plowman et aL. 1994, DN & P 7: 334-339.

In addition to receptor type kinases, many cytoplasms, including src, abl, fps, yes, fyn, lyn, lck, blk, lick, fgr, yrk and others (reviewed by Bolen et al, 1992, FASEB J 6: 3403-3409) Kinases (CKs) are involved in proliferation and metabolic signal transduction pathways and thus are related to the indicators of the present invention. For example, the mutant src (v-src) has been identified as a cancer protein (pp60 ^v-src ) in chickens. In addition, its cellular allogene, the proto-oncogene pp60 ^c-src , carries tumor signals of many receptors. For example, overexpression of DGF-R or HER2 / neu in tumors induces constitutive activity of pp6 ^c-src , which is characteristic of malignant cells and absent in normal cells. On the other hand, mice lacking the expression of c-src exhibit an ossifying fossil phenotype, showing the significant involvement of c-src in osteoclasts and the potential for involvement in related disorders. Similarly, Zap 70 is involved in T-cell signaling.

In addition, identification of CTK modulatory compounds that increase or even upset the RIC-target blocker is one aspect of the present invention.

In addition, RKs and non-receptor type kinases are involved in highly immune disorders.

The compounds of the invention are also effective in treating diseases associated with PYK-2 protein.

Thus, the compounds and methods of the present invention are for treating a disease or abnormal condition selected from the group consisting of cell proliferative diseases, cerebrovascular injury, autoimmune diseases, degenerative neurological diseases, degenerative diseases of the musculoskeletal system It can be suitable for getting the enemy effect.

Examples of degenerative neurological diseases to be treated by the compounds and methods of the present invention include AIDS-related dementia, Alzheimer's disease, Parkinson's disease, Pick's disease, Huntington's disease, diffuse Lewy body disease, multiple system atrophy, amyotrophic lateral sclerosis, down Syndrome-related dementia, cerebrovascular dementia, Canine Motor Neuron Disease, Retinal Pigment Degeneration, Myelodystrophic Atrophy, Myelodysplastic Syndrome, Stroke and Repulsion Fusion, Aplastic Anemia, Myocardial Infarction-related Ischemia, Arrhythmia, Atherosclerosis, Toxin-induced or Alcoholic Related diseases, hematological diseases including chronic and aplastic anemia, and cerebrovascular degeneration, and the like, but are not limited thereto.

Examples of cerebrovascular damage to be treated by the compounds and methods of the present invention include, but are not limited to, cerebrovascular dementia, stroke, cerebral infarction and head trauma.

Some autoimmune diseases that can be treated by the compounds and methods of the present invention include systemic lupus, ertematosus, autoimmune mediated gluteruropritis, rheumatoid arthritis, psoriasis, inflammatory bowel disease, autoimmune diabetes , And the occurrence of AIDS in HIV-infected individuals, but are not limited to these.

Compounds and methods of the present invention include, but are not limited to, AIDS-related dementia, Alzheimer's disease, Parkinson's disease, Pick's disease, Huntington's disease, diffuse Lewy body disease, multiple system atrophy, Amyotrophic lateral sclerosis, Down syndrome It may also be effective in degenerative neurological diseases such as related dementia, cerebrovascular dementia, and dementia including Canine Moto neuron disease, retinal pigment degeneration, myelodystrophic atrophy, myelodysplastic syndrome, and cerebrovascular degeneration.

Compounds and methods of the present invention include, but are not limited to, osteoporosis, arthritis, aspirin-sensitive rhinosinusitis, cystic fibrosis, multiple sclerosis, kidney disease, chemotherapy-induced alopecia, baldness, and cancer pain It can also be considered to be effective against diseases.

Cell proliferative diseases to be treated by the compounds and methods of the invention include breast, lung, colon, kidney, liver, prostate, stomach, esophagus, gallbladder, ovary, pancreas, cervix, bladder, thyroid cartilage, skin Carcinoma, and squamous cell carcinoma; Hematopoietic tumors of the bone marrow selected from the group consisting of acute and chronic leukemia, prosthetic leukemia, and myelodysplastic syndromes; Hematopoietic tumors of lymphoid cells selected from the group consisting of B-cell lymphoma, T-cell lymphoma, Hodgkin lymphoma, non-Hodgkin lymphoma, hair cell lymphoma, Burkett lymphoma, leukemia, acute lymphocytic leukemia, and acute lymphoblastic leukemia; Tumors of mesenchymal organ selected from the group consisting of fibrosarcoma and rhabdomyosarcoma; Tumors of the central and peripheral nervous system selected from the group consisting of neuroblastoma, astrocytoma, glioma and schwannoma; Karposi sarcoma, melanoma, intestinal mesothelioma, teratocarcinoma, pigmentary dry skin disease, osteosarcoma, keratoktanoma, and thyroid vesicle cancer; Benign prostatic hyperplasia, hereditary adenomatous polyposis, myofioma, atherosclerosis, pulmonary fibrosis, arthritis, psoriasis, glomerulonephritis, resterosis after angioplasty or angioplasty, thickening scar formation, infectious bowel disease, transplant rejection, endogenous shock and Fungal infections, but are not limited to these.

Ⅴ. Target Proteins of the Invention

The invention features a method of modulating the function of a protein kinase with said compound, comprising contacting a compound of the invention with cells expressing a protein kinase.

Another aspect of the invention is that the receptor protein kinase whose catalytic activity is regulated by the compound of the invention is EGF, EGF receptor, HER2, HER3, HER4, IR, IGF-1R, IRR, PDGFR, PDGFR, CSFIR, C- Kit, C-fms, Flk-lR, Flk4, KDR / Flk-1, Flt-1, FGFR-1R, FGFR-2R, FGFR-3R, FGFR-4R, Protein Kinase C, MEK1, MAP Kinase, RAF1, PI3 Kinase, and wheel kinase. In addition, one aspect of the present invention is that the cellular tyrosine kinase whose catalytic activity is controlled by the compound of the present invention is Src, Frk, Btk, Csk, Abl, ZAP70, Fes / Fps, Fak, Jak, Ack, Yes, Fyn , Lyn, Lck, Blk, Hck, Fgr and Yrk. Another aspect of the invention is that serine-threonine protein kinases, whose catalytic activity is modulated by the compounds of the invention, include, but are not limited to, CDK1 (CDC2), CDK2, CDK3, CDK4, CDK5, CDK6, CDK7, Is selected from the group consisting of cyclin dependent kinase (CDK) groups of enzymes including CDK8, CDK9, and Raf. Cyclin dependent kinases may be selected from the group consisting of CDK2 and CDK5.

Protein kinase natural binding partners can bind to intracellular sites of protein kinases with high affinity. High affinity shows equilibrium binding constants in the order of 10 ⁻⁶ M or less. In addition, natural binding partners may also temporarily react with and chemically modify protein kinase intracellular sites. Protein kinase natural binding partners include, but are not limited to, the following: SRC homology 2 (SH2) or 3 (SH3) sites, other phosphoryl tyrosine binding (PTB) sites, guanine nucleotide exchange elements, protein phosphatase, and other Protein kinases. Methods of determining changes in interactions between protein kinases and their natural binding partners may readily be possible in the art.

The compounds of the present invention preferably modulate the activity of protein kinases in vitro. These compounds preferably show positive results in one or more in vitro assays for activity corresponding to the treatment of the diseases or disorders in question (as in the assay described later in the Examples).

The invention also comprises the steps of (a) contacting cells expressing protein tyrosine kinase with a compound; And (b) monitoring the effect on the cell, characterized by identifying compounds that modulate the function of protein kinases. The effect on the cells is preferably a change in the cell phenotype, more preferably a change or absence in change in cell proliferation, particularly preferably a change or absence in change in the catalytic activity of protein kinases, most preferably a protein A change or absence of a change in the interaction between the kinase and the natural binding partner described herein.

In one preferred embodiment, the invention comprises the steps of: (a) lysing cells into lysate consisting of protein tyrosine kinases; (b) adsorbing protein tyrosine kinase to the antibody; (c) culturing the adsorbed protein tyrosine kinase with the substrate or substrates; And (d) adsorbing the substrate or substrates to a solid support or antibody, wherein monitoring the effect on the cell comprises measuring the phosphate concentration of the substrate or substrates. It is characterized by a method for identifying the compounds.

In another aspect, the invention features a method of treating a disease associated with unregulated kinase signal transduction, comprising administering to a subject in need thereof a pharmacologically effective amount of a compound according to the invention as described herein. It is done.

The invention also features a method of modulating kinase signal transduction, comprising administering to a subject a pharmacologically effective amount of a compound according to the invention described herein.

Furthermore, the invention relates to (a) administering a compound according to the invention as described herein, when the abnormal state is associated with an abnormality in the signal transduction pathway characterized by the interaction between the protein kinase and the natural binding partner. Doing; And (b) promoting or stopping abnormal interactions. The organism may be a mammal and the abnormal conditions are those listed generally above, in particular those listed in item III above. Mammals may be selected from the group consisting of mice, mice, rabbits, morphotes, dogs, cats, sheep, goats, cattle, monkeys, primates such as chimpanzees and apes, and humans.

As used herein, "PK related disorder", "PK driven disorder" and "abnormal PK activity" all refer to conditions characterized or under improper PK catalytic activity. To; Herein, the specific PK may be RTK, CTK, or STK. Inappropriate catalytic activity includes (1) PK expression in cells that normally do not express PKs; (2) increased PK expression resulting in unwanted cell proliferation, differentiation and / or growth; Or (3) as a result of either reduced PK expression resulting in an unwanted decrease in cell proliferation, differentiation and / or growth. High-activity of PK produces one or more levels of PK activity that may be associated with cell proliferation, differentiation and / or growth disorders, or amplification of a gene encoding a particular PK (ie, as the level of PK increases, Increased severity of symptoms of the above cellular disorders). Low-activity, of course, is, on the contrary, an increase in the severity of the symptoms of one or more cellular disorders as the level of PK activity decreases.

As used herein, the term “therapeutically effective amount” means the amount of the compound administered to alleviate to some extent one or more of the symptoms of the disorder being treated. Thus, a pharmacologically effective amount can be obtained by (1) reversing the rate of progression of a disease or, in the case of cancer, reducing the size of a tumor; (2) the effect of inhibiting further progression of the disease to some extent and somewhat slowing in the case of cancer, or preferably stopping tumor metastasis; And / or (3) an amount having the effect of somewhat alleviating (preferably eliminating) one or more symptoms associated with the disease.

One aspect of the invention is selected from the group wherein the above mentioned protein kinase related disorders comprise receptor protein tyrosine kinase related disorders, cellular tyrosine kinase disorders and serine-threonine kinase related disorders.

In another aspect of the invention, the aforementioned protein kinase related disorders are selected from the group consisting of EGFR related disorders, PDGFR related disorders, IGFR related disorders and flk related disorders.

In addition to modulating PK activity, the compounds of the present invention can inhibit the activity of protein phosphatase, an enzyme that removes phosphate groups from phosphorylated proteins. Accordingly, the compounds disclosed herein are therapeutic compounds for diseases and disorders associated with abnormal phosphatase activity (eg, but not limited to diabetes, cell proliferative disorders and infectious disorders, etc.). It also shows a new generation of. The terms defined herein for PKs will be understood by those skilled in the art to have the same or similar means for phosphatases.

In another aspect, the invention provides a method of regulating a signal transduction pathway in a cell, comprising contacting the compound of the invention with the cell. In one embodiment, the cells express a protein kinase and the compound modulates the function of the protein kinase.

In another aspect, the invention provides a method for preparing a protein kinase, comprising the steps of: a) contacting cells expressing protein kinases with a compound of the invention; And b) monitoring the effect of the compound on the cell, providing a method of identifying an aromatic compound that modulates the function of a protein kinase.

The term "function" refers to the cellular role of protein kinases. The protein kinase family regulates many steps in a series of signaling processes, including regulating cell growth, transfer, differentiation, gene expression, muscle contraction, glucose metabolism, cellular protein synthesis, and cell cycle regulation. Include members.

The term "catalytic activity" in the context of the present invention defines the rate at which protein kinases phosphorylate a substrate. Catalytic activity can be measured, for example, by determining the amount of substrate conversion to product as a function of time. Phosphorylation of the substrate occurs at the active site of the protein kinase. The active portion is usually a cavity in which a substrate is bound to and phosphorylated to protein kinases.

As used herein, the term "substrate" refers to a molecule that is phosphorylated by protein kinases. The substrate is preferably a peptide, more preferably a protein.

The term "activates" means increasing the cellular function of protein kinases. Protein kinase function is preferably interaction with natural binding partners, more preferably catalytic activity.

The term "inhibit" means reducing the cellular function of protein kinases. Protein kinase function is preferably interaction with natural binding partners, more preferably catalytic activity.

The term "modulates" means altering the function of a protein kinase by increasing or decreasing the likelihood that a complex is formed between the protein kinase and the natural binding partner. The modulator may increase the likelihood that such complexes may form between the protein kinase and the natural binding partner, or increase or decrease the likelihood that the complex may be reduced between the protein kinase and the natural binding partner depending on the concentration of the compound exposed to the protein kinase. Can be formed, or can be reduced such that a complex can be formed between the protein kinase and the natural binding partner. The modulator may activate the catalytic activity of the protein kinase, or may activate or inhibit the catalytic activity of the protein kinase depending on the concentration of the compound exposed to the protein kinase, or may inhibit the catalytic activity of the protein kinase.

The term "complex" means a combination of at least two molecules bonded to one another. Signal transduction complexes often include at least two molecules bound to one another.

The term "natural binding partner" refers to a polypeptide that binds to a protein kinase intracellularly. Natural binding partners can play a role in propagating signals during protein kinase signal cleavage. Changes in the interaction between the protein kinase and the natural binding partner may manifest themselves as an increase or decrease in the likelihood that an interaction will form, or as an increase or decrease in the concentration of the protein kinase / natural binding partner complex.

As used herein, the term "contacting" means mixing a solution consisting of a compound of the invention with a solution medium moistened with the cells in the methods. The solution consisting of containing the compound may also be comprised of other components, such as dimethylsulfoxide (DMSO), which facilitate the introduction of the compound or compounds into cells in the methods. Solutions composed of containing the compounds of the present invention may be added to a medium moistened with cells using a delivery device such as a pipette-based or syringe-based device.

The term "monitoring" means observing the added effect of a compound on cells in a method. The effect can be observed as a change in cell phenotype, cell proliferation, protein kinase catalytic activity, or interaction between protein kinase and natural binding partner.

The term "effect" refers to a change or absence of change in cell phenotype or cell proliferation. "Effect" may also mean a change or absence of a change in the catalytic activity of a protein kinase. "Effect" may also mean a change or absence of a change in the interaction between a protein kinase and a natural binding partner.

The term "cell phenotype" refers to the appearance of a cell or tissue or the function of a cell or tissue. Examples of cell phenotypes include cell size (decrease or enlargement), cell proliferation (reduce or increase cell number), cell differentiation (change or absence of changes in cell shape), cell survival, necrosis (cell death), or metabolic nutrients (Eg glucose inhalation). Changes or absence of changes in the cell phenotype can be readily determined by techniques known in the art.

The term “antibody” refers to an antibody (eg monoclonal or polyclonal antibody) or antibody fraction having a specific binding affinity for a protein kinase or fraction thereof.

The term “specific binding affinity” means that an antibody binds to a target (protein kinase) polypeptide with a higher affinity than for other polypeptides under certain conditions. Antibodies that have a specific binding affinity for protein kinases are present in the sample by contacting the sample with the antibody and detecting the presence and / or amount of antibody conjugated to the protein kinase under conditions that allow an immune complex to form. And / or methods for detecting amounts. The diagnostic kit for carrying out such a method may comprise a first container containing the antibody, a junction of the binding partner of the antibody, and a second container having a label such as, for example, a radioisotope. have. The diagnostic kit may also include instructions for use under FDA approval and instructions for it.

The term "polyclonal" refers to antibodies that are a heterologous population of antibody molecules derived from the serum of an animal immunized with an antigen or antigenic functional derivatives thereof. For the production of polyclonal antibodies, various host animals can be immunized by antibody injection.

Various adjuvants may be used to increase the immune response depending on the host species.

The term "monoclonal" is substantially a homologous population of antibodies to a particular antigen. These may be obtained by techniques that provide for the production of antibody molecules by continuous cell lines in culture. Monoclonal antibodies can also be obtained by methods known in the art. See, for example, Kohler, et al., Nature 256: 495-497 (1975) and US Pat. No. 4,376,110.

The term “antibody fragment” refers to a portion of an antibody that exhibits specific binding affinity for a particular molecule, often highly variable regions and sites of the surrounding heavy and light chains. The highly variable region is the site of an antibody that physically binds to a polypeptide target.

With regard to the signal transduction process, the term “aberration” refers to an organism that has been mutated such that its catalytic activity is lower or higher than its native protein kinase activity, or that it can no longer interact with its natural binding partner. A protein kinase that is either high- or low-expressed, or which is no longer modified by another protein kinase or protein phosphatase, or which no longer interacts with a natural binding partner.

The term "promoting or disrupting the abnormal interaction" means a method that can be achieved by administering a compound of the invention to a cell or tissue in an organism. Compounds can facilitate interactions between protein kinases and natural binding partners by forming desirable interactions with multiple elements at the complex interface. In contrast, compounds can inhibit the interaction between protein kinases and natural binding partners by compromising the desired interactions formed between atoms at the complex interface.

"In vitro" means processes performed in an artificial environment, such as in a test tube, intracellular, or culture medium. As used herein, "in vivo" refers to processes performed in living organisms such as mice, mice or rabbits.

Thus, it will be understood by those skilled in the art that the methods and compounds described herein can be used to obtain therapeutic effects on unregulated protein kinase signal transduction that causes disease or abnormal conditions in living organisms. Additionally, the methods of the present invention result in the treatment or prevention of a disease or abnormal condition that is associated with an abnormality in the signal cleavage process characterized by the disease or abnormal condition being understood in the interaction between the protein kinase and the binding partner. Consists of further comprising steps to promote or prevent abnormal interactions.

Ⅵ. Pharmaceutical composition

The present invention also provides

a) a compound of the invention described herein; And

b) a pharmaceutically acceptable carrier, diluent, or excipient, or combination thereof;

It relates to a pharmaceutical composition consisting of.

The term "pharmaceutical composition" means a mixture of a compound of the invention with other chemical components such as diluents or carriers. The pharmaceutical composition facilitates administration of the compound into the organism. There are a variety of techniques for administering compounds, including but not limited to oral, injection, aerosol, parenteral, and topical administration. Pharmaceutical compositions may also be obtained by reacting compounds with inorganic acids such as hydrochloric acid, bromic acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid, p-toluenesulfonic acid, salicylic acid and the like.

The term "carrier" is defined as a compound that facilitates the addition of a compound into a cell or tissue. For example, dimethyl sulfoxide (DMSO) is a commonly used carrier that facilitates the incorporation of many organic compounds into organisms' cells or tissues.

The term "diluent" is defined as a compound that not only stabilizes the biologically active form of the compound of interest, but also is diluted in water to dissolve the compound. Salts dissolved in buffer solutions are used as diluents in the art. A commonly used buffer solution is phosphate buffered saline, because it mimics the salt state of human solutions. Because buffer salts can control the pH of a solution at low concentrations, buffer diluents rarely modify the biological activity of a compound.

The term "physiologically acceptable" is defined as a carrier or diluent that does not impair the biological activity and the properties of the compound.

The compounds used herein may be administered to human patients as such or as pharmaceutical compositions in combination with other active ingredients or with a suitable carrier or excipient, such as in a combination therapy. Techniques for formulation and administration of compounds in this application can be found in "Remington's Pharmaceutical Sciences," Mack Publishing Co., Easton, PA, 18th edition, 1990.

a) Route of administration

Suitable routes of administration include, for example, nasal, penetrating mucosal, or enteral administration; Parenteral delivery, including intramuscular, subcutaneous, intravenous, bone marrow injection, as well as intradiaphragmatic, direct intraventricular, intraperitoneal, or intraocular injection.

In addition, the compounds may also be administered in a local rather than systemic manner, for example by direct injection into solid tumors, often in immersion or sustained release formulations. Agents may also be administered as targeted drug delivery systems, eg, in liposomes coated with tumor-specific antibodies. Liposomes are targeted to and selectively taken by tumors.

b) Composition / Formulation

Pharmaceutical compositions of the invention can be prepared in a known manner, for example, by means of conventional mixing, dissolving, granulating, sugar-making, powdering, emulsifying, encapsulating, trapping and or lyophilizing processes. .

Thus, pharmaceutical compositions for use according to the present invention comprise one or more pharmacologically acceptable compositions comprising excipients or auxiliaries which facilitate the treatment of the active compounds into formulations which can be used pharmaceutically. It may also be prepared by conventional methods using a carrier. Proper formulation is dependent upon the route of administration chosen. Any of the known techniques, carriers and excipients can be used suitably and as understood in the art, for example in Remingston's Pharmaceutical Sciences described above.

For injection, the components of the invention may be formulated in liquid solutions, preferably in pharmacologically compatible buffers such as Hank's solution, Ringer's solution, or physiological saline buffalo. For mucosal permeation administration, noninvasive agents suitable for the barrier to pass through are used in the formulation. Such non-invasive agents are generally known in the art.

For oral administration, the compounds can be formulated readily by combining the active compounds with pharmacologically acceptable carriers known in the art. Such carriers allow the compounds of the present invention to be formulated into tablets, pills, sugars, capsules, liquids, gels, syrups, slurries, suspensions and the like. Pharmaceutical preparations for oral use may be achieved by mixing one or more compounds of the invention with one or more excipients, optionally grinding such mixtures and, if necessary, treating the mixture of granules after permeation of appropriate adjuvants. A tablet or sugar core can be obtained. Suitable excipients include fillers such as lactose, sucrose, mannitol, or sorbitol; Corn starch, wheat starch, rice starch, potato starch, gelatin, gum tragakens, methyl cellulose, hydroxypropylmethyl-cellulose, sodium carboxymethyl cellulose, and / or polyvinylpyrrolidone ( Cellulose-based materials such as PVP). If necessary, a disintergrating agent may be added, such as crosslinked polyvinyl pyrrolidone, butadiene, or salts thereof such as alginic acid or sodium alginate.

Sugar cores are supplied by appropriate coating. For this purpose, concentrated sugars, which optionally include arabide gum, talc, polyvinyl pyrrolidone, carbopol gel, polyethylene glycol, and / or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures Solutions can be used. Dyestuffs or pigments may be included in the tablets or sugars to characterize the identification of the active compound or to characterize other combinations thereof.

Pharmaceutical preparations that can be used orally may include soft sealing capsules made of gelatin and plasticizers such as glycol or sorbitol, as well as pushable capsules made of gelatin. The push-fix capsule may contain the active ingredients, as a mixture with a filler such as lactose, a binder such as starch, and / or a lubricant such as talc or magnesium stearate. In soft capsules, the active compounds may be dissolved or dispersed in suitable solvents such as fatty acids, liquid paraffin, or liquid polyethylene glycols. In addition, stabilizers may be included. All preparations for oral administration should be in amounts suitable for such administration.

For buccal administration, the compositions may take the form of tablets or lozenges formulated according to conventional methods.

For administration by inhalation, the compounds of use according to the invention typically use a suitable propellant such as, for example, dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas. Thus, it may be delivered in the form of aerosol injection provision from a pressurized pack or nebulisher. For use in inhalants or pulverulents, capsules and cartridges such as, for example, gelatin may be formulated comprising a powdered mixture of the compound and a suitable powder such as lactose or starch.

The compounds may be formulated for parenteral administration by injection, eg, by large pill injection or continuous infusion. Injectable formulations may be presented in unit dose form, for example, as ampoules or multi-dos containers, with preservatives added. The compositions may take the form of suspensions, solutions, emulsions on oily or liquid vehicles, and may include components for formulation such as suspensions, stabilizers and / or dispersants.

Liquid formulations for parenteral administration include liquid solutions of the active compounds in water-soluble form. In addition, suspensions of the active compounds may be prepared as appropriate oily injection suspensions. Suitable lipophilic solvents or vehicles include fatty acids such as sesame oil, synthetic fatty acid esters such as ethyl oleate or triglycerides, liposomes and the like. Liquid injection suspensions may include substances that increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, dextran, and the like. In some cases, suspensions may contain components or stabilizers that increase the solubility of the compound to allow for the preparation of highly concentrated solutions.

The active ingredient may also be in powder form for constitution with a suitable vehicle, such as sterile pyrogen-free water, before use.

The compounds may also be formulated in rectal dosage compositions, such as suppositories or retention enemas, including, for example, conventional suppository bases such as cocoa butter or other glycerides.

In addition to the formulations described above, the compounds may be formulated as deposits. Such long acting formulations may be administered by implantation (for example subcutaneously or intramuscularly) or by intramuscular infusion. Thus, the compounds may, for example, be formulated with a suitable polymer or hydrophobic material (such as an emulsion in an acceptable oil), or with an ion exchange resin, or as a low soluble derivative, for example a low soluble salt. have.

The formulation carrier for the hydrophobic compound of the present invention is a cosolvent system composed of benzyl alcohol, nonpolar surfactant, water-miscible organic polymer, and liquid phase. The cosolvent may be a VPD cosolvent. VPD is a solution of benzyl alcohol 3% w / v, nonpolar surfactant Polysorbate 80 (R) 85 w / v, and polyethylene glycol 300 65% w / v, made up to volume in anhydrous ethanol. VPD co-solvent system (VPD: D5W) consists of VPD diluted 1: 1 with 5% testrose in aqueous solution. This cosolvent system dissolves hydrophobic compounds well and provides itself with low toxicity upon systemic administration. Naturally, the proportion of cosolvent system may vary considerably without compromising its solubility and toxicological properties. Moreover, the identification of the cosolvent components can be varied: for example, other low toxicity nonpolar surfactants can be used in place of Polysorbate 80 ™; The fraction size of polyethylene glycol can vary; Other biocompatible polymers may replace polyethylene glycols such as, for example, polyvinyl pyrrolidone; And other parties and polysaccharides can replace dextrose.

In addition, other delivery systems for hydrophobic drug compounds may be employed. Liposomes and emulsions are known examples of delivery vehicles for hydrophobic agents. Any organic solvent, such as dimethylsulfoxide, may be employed, usually at the expense of higher toxicity. In addition, the compound may be delivered using a sustained release system, such as a semipermeable matrix of a solid hydrophobic polymer containing a therapeutic ingredient. Various sustained release materials have been developed and are known to those skilled in the art. Sustained release capsules can release the compound from 2 or 3 weeks to 100 days depending on its compound properties. Depending on the chemical nature and biological stability of the therapeutic agent, additional strategies for protein stability may be employed.

Many compounds of the present invention may also be provided as salts with pharmaceutically acceptable counterions. Pharmaceutically acceptable salts may be formed with many acids including, but not limited to, hydrochloric acid, sulfuric acid, acetic acid, lactic acid, tartaric acid, malic acid, succinic acid, and the like. Salts tend to dissolve better in aqueous or proton solutions than their corresponding acid free or base forms.

c) Effective amount

Pharmaceutical compositions suitable for use in the present invention include compositions in which the active ingredients are contained in an amount effective to achieve their intended purpose. More specifically, a therapeutically effective amount means an amount of a compound effective to prolong the survival of the subject to be treated or to prevent, alleviate or alleviate the symptoms of a disease. Determination of a therapeutically effective amount is within the capabilities of those skilled in the art, in particular in terms of the detailed disclosure provided herein.

A therapeutically effective amount for any compound used in the methods of the invention can be determined initially from cell culture assays. For example, the dose can be calculated in an animal model to obtain a range of circulating concentrations comprising an IC ₅₀ determined in cell culture. Such information can be used to more accurately determine useful doses in humans.

Toxicity and therapeutic efficiency of the compounds described herein can be determined, for example, to determine LD ₅₀ (lethal dose for 50% of the population) and ED ₅₀ (dose with therapeutic effect for 50% of the population). Estimates can be made by surface pharmaceutical procedures in culture or experimental animals. The dose ratio between toxic and therapeutic effects is the therapeutic index and it can be expressed as the ratio between LD ₅₀ and ED ₅₀ . Compounds showing high therapeutic indices are preferred. The data obtained from these cell culture assays can be used to estimate the range of doses used in humans. The dosage of such compounds is preferably in the range of circulating concentrations comprising ED ₅₀ in the absence or little toxicity. The dosage may vary within this range depending upon the dosage form employed and the route of administration utilized. The exact estimate, route of administration and dosage can be selected by the individual physician in view of the patient's condition (eg, Fingl et al. 1975, in "The Pharmacological Basis of Therapeutics", Ch. 1 p. 1 Typically, the dose range of the composition administered to the patient may be about 0.5 to 1000 mg / kg of the patient's body weight. Dosages may be given in a series of two or more, one at a time or in a day or more, depending on the extent required by the patient.

Dosages and intervals may be individually adjusted to provide plasma levels of the active site sufficient to maintain a kinase modulating effect or minimal effective concentration (MEC). The MEC depends on the individual compound, but may also be predicted from ex vivo data, such as, for example, the concentration required to achieve 50-90% inhibition of kinases using the assays described herein. Dosages necessary to achieve the MEC will depend on individual characteristics and route of administration. However, HPLC or biological quantification can be used to determine plasma concentration.

Dosage intervals may be determined using MEC values. Compounds should be administered using a dosing regimen that maintains blood serum levels above the MEC, such that 10-90%, preferably 30-90%, particularly preferably 50-90% at a time.

In the case of topical administration or selective uptake, the effective local concentration of the medicament may not be related to the plasma concentration.

Of course, the amount of composition to be administered will depend on the subject to be treated, on the weight of the subject, on the severity of pain, on the manner of administration and on the judgment of the physician.

d) Packing

The compositions may be provided in a pack or dispensing device, if desired, which may comprise one or more unit dosage forms containing the active ingredient. The bag may consist of a metal or plastic foil, for example a blister pack. The pack or dispenser may be accompanied by a notice relating to the container in a form granted by a government department regulating the production, use or sale of pharmaceutical companies. The notice reflects the agency's approval of the polynucleotide form for human or veterinary administration. Such notification may be, for example, a label or approved product insert approved by the US Food and Drug Administration for prescription drugs. Compositions comprising the compounds of the present invention formulated in an acceptable pharmaceutical carrier may be prepared and placed in appropriate containers and labeled for the treatment of the indicated conditions.

Iii. Embodiments of the Invention

Some embodiments of the invention are disclosed below. It is to be understood that the present invention includes embodiments other than the following.

In a first embodiment, the present invention relates to a compound of formula 1, a pharmaceutically acceptable salt, amide, ester or prodrug thereof,

(One)

Where

a) R ₁ is selected from the group consisting of

Iii) a 6-membered aromatic or heteroaromatic, 5- or 6-membered heteroaromatic ring, optionally substituted with one or more substituents selected from the group consisting of lower alkyl, hydroxy, alkoxy, amino and nitro;

Ii) acyl of the formula-(X ₁ ) _{n 1} -C (O) -X ₂ ,

Wherein X ₁ is selected from the group consisting of lower alkylene, lower alkenylene, lower alkynylene, aryl and heteroaryl;

X ₂ is selected from the group consisting of hydrogen, lower alkyl, aryl, heteroaryl, hydroxy, alkoxy, amino, and -NH-X ₃ ;

Wherein X ₃ is selected from the group consisting of hydrogen, alkyl, aryl, heteroaryl, amino, and amide; And

n1 is 0 or 1;

Iv) a substituent of formula -C (X ₄ ) = N-NX ₅ -C (= E) -NX ₆ X ₇ or a formula -C (X ₄ ) = NN = C (EX ₅ ) -NX ₆ X ₇ ,

Wherein X ₄ is selected from the group consisting of hydrogen, lower alkyl, aryl, alkaryl, heteroaryl and amino;

E is selected from the group consisting of oxygen, sulfur and -NR _101- , wherein R ₁₀₁ is selected from the group consisting of hydrogen hydrogen, lower alkyl, lower alkene, lower alkyne, aryl and heteroaryl; And

X ₅ , X ₆ and X ₇ are each independently selected from the group consisting of hydrogen, lower alkyl, aryl and heteroaryl;

Provided that R ₁ is -C ₆ H ₅ , -C (0) H, -C (O) CH ₃ , -C (O) -C ₆ H ₅ , -C (O) NH ₂ , or -C ₆ H _{Not 4} CH ₃ ;

b) R ₂ , R ₃ and R ₄ are each independently selected from the group consisting of:

Iii) hydrogen;

Ii) lower alkyl;

Iii) lower alkylene;

Iii) halogen or perhaloalkyl;

Ⅴ) alkoxy of the formula-(X ₁₃ ) _n13 -OX ₁₄ ,

Wherein X ₁₃ is selected from the group consisting of lower alkylene, lower alkenylene, lower alkynylene, allyl and heteroaryl;

X ₁₄ is selected from the group consisting of hydrogen, lower alkyl, aryl and heteroaryl; And

n13 is 0 or 1; And

V) 5- or 6-membered heteroaryl ring or 6-membered aryl ring or heteroaryl ring, optionally substituted with one or more substituents selected from the group consisting of the following;

A) optionally substituted C ₁ -C ₈ straight, branched, or cyclic saturated or unsaturated alkyl;

B) alkoxy of formula-(X ₁₃ ) _n13 -OX ₁₄ ,

Wherein X ₁₃ is selected from the group consisting of lower alkylene, lower alkenylene, lower alkynylene, aryl and heteroaryl;

X ₁₄ is selected from the group consisting of hydrogen, lower alkyl, aryl and heteroaryl; And

n13 is 0 or 1;

C) halogen or perhaloalkyl;

D) cyano;

E) nitro;

F) amino of the formula-(X ₁₅ ) _n15 -NX ₁₆ X ₁₇ ,

Wherein X ₁₅ is selected from the group consisting of lower alkylene, lower alkenylene, lower alkynylene, aryl and heteroaryl;

X ₁₆ and X ₁₇ are each independently selected from the group consisting of hydrogen, lower alkyl, aryl and heteroaryl; Or X ₁₆ and X ₁₇ are taken together with the nitrogen to which they are attached to form a 5- or 6-membered heteroaromatic or heteroaliphatic ring; n15 is 0 or 1;

G) a substituent of the _formula- (X ₁₈ ) _n18 -C (= E) -X ₁₉ ,

Wherein X ₁₈ is selected from the group consisting of lower alkylene, lower alkenylene, lower alkynylene, aryl and heteroaryl;

E is selected from the group consisting of oxygen, sulfur and -NR _101- , wherein R ₁₀₁ is selected from the group consisting of hydrogen hydrogen, lower alkyl, lower alkene, lower alkyne, aryl and heteroaryl;

X ₁₉ is selected from the group consisting of hydrogen, alkyl, aryl, heteroaryl, hydroxy, alkoxy, amino and -NX ₂₀ X ₂₁ ,

Wherein X ₂₀ and X ₂₁ are each independently selected from the group consisting of hydrogen, alkyl, aryl and heteroaryl;

n18 is 0 or 1; And

H) a thioether or thiol of the _formula- (X ₂₂ ) _{n22 -SX 23} ,

Wherein X ₂₂ is selected from the group consisting of lower alkylene, lower alkenylene, lower alkynylene, aryl and heteroaryl;

X ₂₃ is selected from the group consisting of hydrogen, lower alkyl, aryl and heteroaryl; And

n22 is 0 or 1; And

_{Amide of formula-} (X ₂₄ ) _n24 -NH-C (O) -X _{25 or-} (X ₂₆ ) _n26 -C (O) -NH-X ₂₇ ,

Wherein X ₂₄ and X ₂₆ are each independently selected from the group consisting of lower alkylene, lower alkenylene, lower alkynylene, aryl and heteroaryl;

X ₂₅ is selected from the group consisting of hydrogen, lower alkyl, lower alkenyl, aryl, heteroaryl, hydroxy, alkoxy and amide; And

X ₂₇ is selected from the group consisting of hydrogen, lower alkyl, lower alkenyl, aryl and heteroaryl;

Or R ₂ and R ₃ are taken together with the two ring carbons to which they are attached, or R ₄ and R ₃ are taken together with the two ring carbons to which they are attached, such that they are 6-membered aromatic or heteroaromatic, or 5- or 6-membered heteroaromatic ring, optionally substituted with one or more substituents selected from the group consisting of:

Iii) hydrogen;

Ii) optionally substituted C ₁ -C ₈ straight, branched or cyclic saturated or unsaturated alkyl;

Iii) optionally substituted aryl;

Iii) optionally substituted heterocycle;

Ⅴ) Formula -C (X ₄ ) = N-NX ₅ -C (= E) -NX ₆ X ₇ or -C (X ₄ ) = NN = C (EX ₅ ) -NX ₆ X ₇ ,

Wherein X ₄ is selected from the group consisting of hydrogen, lower alkyl, aryl, alkaryl, heteroaryl and amino;

E is selected from the group consisting of oxygen, sulfur and -NR _101- , wherein R ₁₀₁ is selected from the group consisting of hydrogen hydrogen, lower alkyl, lower alkene, lower alkyne, aryl and heteroaryl; And

X ₅ , X ₆ and X ₇ are each independently selected from the group consisting of hydrogen, lower alkyl, aryl and heteroaryl;

Iii) amino guanidine of formula -NX ₈ -NX ₉ -C (= NX ₁₀ ) -NX ₁₁ X ₁₂ ,

Wherein X ₈ , X ₉ , X ₁₀ , X ₁₁ and X ₁₂ are each independently selected from the group consisting of hydrogen, lower alkyl, aryl and heteroaryl;

Ⅶ) formula - (X _{13) n13} alkoxy of -OX _14,

Wherein X ₁₃ is selected from the group consisting of lower alkylene, lower alkenylene, lower alkynylene, aryl and heteroaryl;

X ₁₄ is selected from the group consisting of hydrogen, lower alkyl, aryl and heteroaryl;

n13 is 0 or 1;

Iii) halogen or perhaloalkyl;

Iii) cyano;

Iii) nitro;

xi) amino of the formula-(X ₁₅ ) _n15 -NX ₁₆ X ₁₇ ,

Wherein X ₁₅ is selected from the group consisting of lower alkylene, lower alkenylene, lower alkynylene, aryl and heteroaryl;

X ₁₆ and X ₁₇ are each independently selected from the group consisting of hydrogen, lower alkyl, aryl and heteroaryl; Or X ₁₆ and X ₁₇ are taken together with the nitrogen to which they are attached and are a 5- or 6-membered heteroaromatic or heteroaliphatic ring; And

n15 is 0 or 1;

xii) a substituent of the formula-(X ₁₈ ) _n18 -C (= E) -X ₁₉ ,

Wherein X ₁₈ is selected from the group consisting of lower alkylene, lower alkenylene, lower alkynylene, aryl and heteroaryl;

E is selected from the group consisting of oxygen, sulfur and -NR _101- , wherein R ₁₀₁ is selected from the group consisting of hydrogen hydrogen, lower alkyl, lower alkene, lower alkyne, aryl and heteroaryl;

X ₁₉ is selected from the group consisting of hydrogen, lower alkyl, aryl, heteroaryl, amino and -NX ₂₀ X ₂₁ ,

Wherein X ₂₀ and X ₂₁ are independently selected from the group consisting of hydrogen, alkyl, aryl and heteroaryl; And

n18 is 0 or 1;

xvi) thioether or thiol of the _formula- (X ₂₂ ) _{n22 -SX 23} ,

Wherein X ₂₂ is lower alkylene, lower alkenylene, lower alkynylene. Aryl and heteroaryl;

X ₂₃ is selected from the group consisting of hydrogen, lower alkyl, aryl and heteroaryl; And

n22 is 0 or 1;

c) R ₅ is selected from the group consisting of hydrogen, lower alkyl, aryl and heteroaryl; Or R ₄ and R ₅ are taken together with the two ring carbons to which they are attached such that a 6-membered aromatic or heteroaromatic, or 5- or 6-membered heteroaromatic ring, which is optionally selected from the group consisting of Or substituted with more substituents;

Iii) hydrogen;

Ii) optionally substituted C ₁ -C ₈ straight, branched or cyclic saturated or unsaturated alkyl;

Iii) optionally substituted aryl;

Iii) optionally substituted heterocycle;

Iv) a substituent of the formula -C (X ₄ ) = N-NX ₅ -C (= E) -NX ₆ X ₇ or -C (X ₄ ) = NN = C (EX ₅ ) -NX ₆ X ₇ ,

Wherein X ₄ is selected from the group consisting of hydrogen, lower alkyl, aryl, alkaryl, heteroaryl and amino;

E is selected from the group consisting of oxygen, sulfur and -NR _101- , wherein R ₁₀₁ is selected from the group consisting of hydrogen hydrogen, lower alkyl, lower alkene, lower alkyne, aryl and heteroaryl; And

X ₅ , X ₆ and X ₇ are each independently selected from the group consisting of hydrogen, lower alkyl, aryl and heteroaryl;

Iii) amino guanidine of formula -NX ₈ -NX ₉ -C (= NX ₁₀ ) -NX ₁₁ X ₁₂ ,

Wherein X ₈ , X ₉ , X ₁₀ , X ₁₁ and X ₁₂ are each independently selected from the group consisting of hydrogen, lower alkyl, aryl and heteroaryl;

Ⅶ) formula - (X _{13) n13} alkoxy of -OX _14,

Wherein X ₁₃ is selected from the group consisting of lower alkylene, lower alkenylene, lower alkynylene, aryl and heteroaryl;

X ₁₄ is selected from the group consisting of hydrogen, lower alkyl, aryl and heteroaryl;

n13 is 0 or 1;

Iii) halogen or perhaloalkyl;

Iii) cyano;

Iii) nitro;

xi) amino of the formula-(X ₁₅ ) _n15 -NX ₁₆ X ₁₇ ,

Wherein X ₁₅ is selected from the group consisting of lower alkylene, lower alkenylene, lower alkynylene, aryl or heteroaryl;

X ₁₆ and X ₁₇ are each independently selected from the group consisting of hydrogen, lower alkyl, aryl and heteroaryl; Or X ₁₆ and X ₁₇ are taken together with the nitrogen to which they are attached and are a 5- or 6-membered heteroaromatic or heteroaliphatic ring; And

n15 is 0 or 1;

xii) a substituent of the formula-(X ₁₈ ) _n18 -C (= E) -X ₁₉ ,

Wherein X ₁₈ is selected from the group consisting of lower alkylene, lower alkenylene, lower alkynylene, aryl and heteroaryl;

E is selected from the group consisting of oxygen, sulfur and -NR _101- , wherein R ₁₀₁ is selected from the group consisting of hydrogen hydrogen, lower alkyl, lower alkene, lower alkyne, aryl and heteroaryl;

X ₁₉ is selected from the group consisting of hydrogen, lower alkyl, aryl, heteroaryl, amino and -NX ₂₀ X ₂₁ ,

Wherein X ₂₀ and X ₂₁ are independently selected from the group consisting of hydrogen, alkyl, aryl and heteroaryl; And

n18 is 0 or 1;

xvi) thioether or thiol of the _formula- (X ₂₂ ) _{n22 -SX 23} ,

Wherein X ₂₂ is lower alkylene, lower alkenylene, lower alkynylene. Aryl and heteroaryl;

X ₂₃ is selected from the group consisting of hydrogen, lower alkyl, aryl and heteroaryl; And

n22 is 0 or 1;

d) R ₁₀₀ is selected from the group consisting of hydrogen, lower alkyl, lower alkene, lower alkyne, aryl and heteroaryl;

e) E ₁ is selected from the group consisting of hydrogen, sulfur and —NR ₁₀₁ —, where NR ₁₀₁ is selected from the group consisting of hydrogen hydrogen, lower alkyl, lower alkene, lower alkyne, aryl and heteroaryl;

Provided that at least one of R ₁ -R ₅ is not selected from the group consisting of hydrogen, lower alkyl, aryl and heteroaryl.

In a second embodiment, the present invention relates to a compound of formula (2), or a pharmaceutically acceptable salt, amide, ester, or prodrug thereof.

(2)

Where

a) R ₁ is selected from the group consisting of

Iii) a 6-membered aromatic or heteroaromatic, 5- or 6-membered heteroaromatic ring, optionally substituted with one or more substituents selected from the group consisting of lower alkyl, hydroxy, alkoxy, amino and nitro;

Ii) acyl of the formula-(X ₁ ) _{n 1} -C (O) -X ₂ ,

Wherein X ₁ is selected from the group consisting of lower alkylene, lower alkenylene, lower alkynylene, aryl and heteroaryl;

X ₂ is selected from the group consisting of hydrogen, lower alkyl, aryl, heteroaryl, hydroxy, alkoxy, amino, and -NH-X ₃ ;

Wherein X ₃ is selected from the group consisting of hydrogen, alkyl, aryl, heteroaryl, amino and amide; And

n1 is 0 or 1;

Iv) a substituent of formula -C (X ₄ ) = N-NX ₅ -C (= E) -NX ₆ X ₇ or a formula -C (X ₄ ) = NN = C (EX ₅ ) -NX ₆ X ₇ ,

Wherein X ₄ is selected from the group consisting of hydrogen, lower alkyl, aryl, alkaryl, heteroaryl and amino;

E is selected from the group consisting of oxygen, sulfur and -NR _101- , wherein R ₁₀₁ is selected from the group consisting of hydrogen hydrogen, lower alkyl, lower alkene, lower alkyne, aryl and heteroaryl; And

X ₅ , X ₆ and X ₇ are each independently selected from the group consisting of hydrogen, lower alkyl, aryl and heteroaryl;

Provided that R ₁ is -C ₆ H ₅ , -C (0) H, -C (O) CH ₃ , -C (O) -C ₆ H ₅ , -C (O) NH ₂ , or -C ₆ H _{Not 4} CH ₃ ;

b) R ₂ , R ₃ and R ₄ are each independently selected from the group consisting of the following;

Iii) hydrogen;

Ii) lower alkyl;

Iii) lower alkylene;

Iii) halogen or perhaloalkyl;

Ⅴ) alkoxy of the formula-(X ₁₃ ) _n13 -OX ₁₄ ,

Wherein X ₁₃ is selected from the group consisting of lower alkylene, lower alkenylene, lower alkynylene, allyl and heteroaryl;

X ₁₄ is selected from the group consisting of hydrogen, lower alkyl, aryl and heteroaryl; And

n13 is 0 or 1; And

V) 5- or 6-membered heteroaryl ring or 6-membered aryl ring or heteroaryl ring, optionally substituted with one or more substituents selected from the group consisting of the following;

A) optionally substituted C ₁ -C ₈ straight, branched, or cyclic saturated or unsaturated alkyl;

B) alkoxy of formula-(X ₁₃ ) _n13 -OX ₁₄ ,

Wherein X ₁₃ is selected from the group consisting of lower alkylene, lower alkenylene, lower alkynylene, aryl and heteroaryl;

X ₁₄ is selected from the group consisting of hydrogen, lower alkyl, aryl and heteroaryl; And

n13 is 0 or 1;

C) halogen or perhaloalkyl;

D) cyano;

E) nitro;

F) amino of the formula-(X ₁₅ ) _n15 -NX ₁₆ X ₁₇ ,

Wherein X ₁₅ is selected from the group consisting of lower alkylene, lower alkenylene, lower alkynylene, aryl and heteroaryl;

X ₁₆ and X ₁₇ are each independently selected from the group consisting of hydrogen, lower alkyl, aryl and heteroaryl; Or X ₁₆ and X ₁₇ are taken together with the nitrogen to which they are attached to form a 5- or 6-membered heteroaromatic or heteroaliphatic ring; n15 is 0 or 1;

G) a substituent of the _formula- (X ₁₈ ) _n18 -C (= E) -X ₁₉ ,

Wherein X ₁₈ is selected from the group consisting of lower alkylene, lower alkenylene, lower alkynylene, aryl and heteroaryl;

E is selected from the group consisting of oxygen, sulfur and -NR _101- , wherein R ₁₀₁ is selected from the group consisting of hydrogen hydrogen, lower alkyl, lower alkene, lower alkyne, aryl and heteroaryl;

X ₁₉ is selected from the group consisting of hydrogen, alkyl, aryl, heteroaryl, hydroxy, alkoxy, amino and -NX ₂₀ X ₂₁ ,

Wherein X ₂₀ and X ₂₁ are each independently selected from the group consisting of hydrogen, alkyl, aryl and heteroaryl;

n18 is 0 or 1; And

H) a thioether or thiol of the _formula- (X ₂₂ ) _{n22 -SX 23} ,

Wherein X ₂₂ is selected from the group consisting of lower alkylene, lower alkenylene, lower alkynylene, aryl and heteroaryl; And

X ₂₃ is selected from the group consisting of hydrogen, lower alkyl, aryl and heteroaryl,

n22 is 0 or 1; And

_{Amide of formula-} (X ₂₄ ) _n24 -NH-C (O) -X _{25 or-} (X ₂₆ ) _n26 -C (O) -NH-X ₂₇ ,

Wherein X ₂₄ and X ₂₆ are each independently selected from the group consisting of lower alkylene, lower alkenylene, lower alkynylene, aryl and heteroaryl;

X ₂₅ is selected from the group consisting of hydrogen, lower alkyl, lower alkenyl, aryl, heteroaryl, hydroxy, alkoxy and amide; And

X ₂₇ is selected from the group consisting of hydrogen, lower alkyl, lower alkenyl, aryl and heteroaryl;

Or R ₂ and R ₃ are taken together with the two ring carbons to which they are attached, or R ₄ and R ₃ are taken together with the two ring carbons to which they are attached, such that they are 6-membered aromatic or heteroaromatic, or 5- or 6-membered heteroaromatic ring, which is optionally substituted with one or more substituents selected from the group consisting of:

Iii) hydrogen;

Ii) optionally substituted C ₁ -C ₈ straight, branched or cyclic saturated or unsaturated alkyl;

Iii) optionally substituted aryl;

Iii) optionally substituted heterocycle;

Ⅴ) Formula -C (X ₄ ) = N-NX ₅ -C (= E) -NX ₆ X ₇ or -C (X ₄ ) = NN = C (EX ₅ ) -NX ₆ X ₇ ,

Wherein X ₄ is selected from the group consisting of hydrogen, lower alkyl, aryl, alkaryl, heteroaryl and amino;

E is selected from the group consisting of oxygen, sulfur and -NR _101- , wherein R ₁₀₁ is selected from the group consisting of hydrogen hydrogen, lower alkyl, lower alkene, lower alkyne, aryl and heteroaryl; And

X ₅ , X ₆ and X ₇ are each independently selected from the group consisting of hydrogen, lower alkyl, aryl and heteroaryl;

Iii) amino guanidine of formula -NX ₈ -NX ₉ -C (= NX ₁₀ ) -NX ₁₁ X ₁₂ ,

Wherein X ₈ , X ₉ , X ₁₀ , X ₁₁ and X ₁₂ are each independently selected from the group consisting of hydrogen, lower alkyl, aryl and heteroaryl;

Ⅶ) formula - (X _{13) n13} alkoxy of -OX _14,

Wherein X ₁₃ is selected from the group consisting of lower alkylene, lower alkenylene, lower alkynylene, aryl and heteroaryl;

X ₁₄ is selected from the group consisting of hydrogen, lower alkyl, aryl and heteroaryl;

n13 is 0 or 1;

Iii) halogen or perhaloalkyl;

Iii) cyano;

Iii) nitro;

xi) amino of the formula-(X ₁₅ ) _n15 -NX ₁₆ X ₁₇ ,

Wherein X ₁₅ is selected from the group consisting of lower alkylene, lower alkenylene, lower alkynylene, aryl and heteroaryl;

X ₁₆ and X ₁₇ are each independently selected from the group consisting of hydrogen, lower alkyl, aryl and heteroaryl; Or X ₁₆ and X ₁₇ are taken together with the nitrogen to which they are attached and are a 5- or 6-membered heteroaromatic or heteroaliphatic ring; And

n15 is 0 or 1;

xii) a substituent of the formula-(X ₁₈ ) _n18 -C (= E) -X ₁₉ ,

Wherein X ₁₈ is selected from the group consisting of lower alkylene, lower alkenylene, lower alkynylene, aryl and heteroaryl;

E is selected from the group consisting of oxygen, sulfur and -NR _101- , wherein R ₁₀₁ is selected from the group consisting of hydrogen hydrogen, lower alkyl, lower alkene, lower alkyne, aryl and heteroaryl;

X ₁₉ is selected from the group consisting of hydrogen, lower alkyl, aryl, heteroaryl, amino and -NX ₂₀ X ₂₁ ,

Wherein X ₂₀ and X ₂₁ are independently selected from the group consisting of hydrogen, alkyl, aryl and heteroaryl; And

n18 is 0 or 1;

xvi) thioether or thiol of the _formula- (X ₂₂ ) _{n22 -SX 23} ,

Wherein X ₂₂ is lower alkylene, lower alkenylene, lower alkynylene. Aryl and heteroaryl;

X ₂₃ is selected from the group consisting of hydrogen, lower alkyl, aryl and heteroaryl; And

n22 is 0 or 1;

c) R ₅ is selected from the group consisting of hydrogen, lower alkyl, aryl and heteroaryl; Or R ₄ and R ₅ are taken together with the two ring carbons to which they are attached such that a 6-membered aromatic or heteroaromatic, or 5- or 6-membered heteroaromatic ring, which is optionally selected from the group consisting of Or substituted with more substituents;

Iii) hydrogen;

Ii) optionally substituted C ₁ -C ₈ straight, branched or cyclic saturated or unsaturated alkyl;

Iii) optionally substituted aryl;

Iii) optionally substituted heterocycle;

Iv) a substituent of the formula -C (X ₄ ) = N-NX ₅ -C (= E) -NX ₆ X ₇ or -C (X ₄ ) = NN = C (EX ₅ ) -NX ₆ X ₇ ,

Wherein X ₄ is selected from the group consisting of hydrogen, lower alkyl, aryl, alkaryl, heteroaryl and amino;

E is selected from the group consisting of oxygen, sulfur and -NR _101- , wherein R ₁₀₁ is selected from the group consisting of hydrogen hydrogen, lower alkyl, lower alkene, lower alkyne, aryl and heteroaryl; And

X ₅ , X ₆ and X ₇ are each independently selected from the group consisting of hydrogen, lower alkyl, aryl and heteroaryl;

Iii) amino guanidine of formula -NX ₈ -NX ₉ -C (= NX ₁₀ ) -NX ₁₁ X ₁₂ ,

Wherein X ₈ , X ₉ , X ₁₀ , X ₁₁ and X ₁₂ are each independently selected from the group consisting of hydrogen, lower alkyl, aryl and heteroaryl;

Ⅶ) formula - (X _{13) n13} alkoxy of -OX _14,

Wherein X ₁₃ is selected from the group consisting of lower alkylene, lower alkenylene, lower alkynylene, aryl and heteroaryl;

X ₁₄ is selected from the group consisting of hydrogen, lower alkyl, aryl and heteroaryl;

n13 is 0 or 1;

Iii) halogen or perhaloalkyl;

Iii) cyano;

Iii) nitro;

xi) amino of the formula-(X ₁₅ ) _n15 -NX ₁₆ X ₁₇ ,

Wherein X ₁₅ is selected from the group consisting of lower alkylene, lower alkenylene, lower alkynylene, aryl or heteroaryl;

X ₁₆ and X ₁₇ are each independently selected from the group consisting of hydrogen, lower alkyl, aryl and heteroaryl; Or X ₁₆ and X ₁₇ are taken together with the nitrogen to which they are attached and are a 5- or 6-membered heteroaromatic or heteroaliphatic ring; And

n15 is 0 or 1;

xii) a substituent of the formula-(X ₁₈ ) _n18 -C (= E) -X ₁₉ ,

Wherein X ₁₈ is selected from the group consisting of lower alkylene, lower alkenylene, lower alkynylene, aryl and heteroaryl;

E is selected from the group consisting of oxygen, sulfur and -NR _101- , wherein R ₁₀₁ is selected from the group consisting of hydrogen hydrogen, lower alkyl, lower alkene, lower alkyne, aryl and heteroaryl;

X ₁₉ is selected from the group consisting of hydrogen, lower alkyl, aryl, heteroaryl, amino and -NX ₂₀ X ₂₁ ,

Wherein X ₂₀ and X ₂₁ are independently selected from the group consisting of hydrogen, alkyl, aryl and heteroaryl; And

n18 is 0 or 1;

xvi) thioether or thiol of the _formula- (X ₂₂ ) _{n22 -SX 23} ,

Wherein X ₂₂ is lower alkylene, lower alkenylene, lower alkynylene. Aryl and heteroaryl;

X ₂₃ is selected from the group consisting of hydrogen, lower alkyl, aryl and heteroaryl; And

n22 is 0 or 1;

Provided that at least one of R ₁ -R ₅ is not selected from the group consisting of hydrogen, lower alkyl, aryl and heteroaryl.

In a third example, the invention relates to the compound of the first example, selected from the group consisting of R1 and below.

Iii) hydrogen;

Ii) 6-membered aromatic ring, which is optionally substituted with one or more substituents selected from the group consisting of lower alkyl, hydroxy and amine;

Iii) a 6-membered heteroaromatic ring, which is optionally substituted with one or more substituents selected from the group consisting of lower alkyl, hydroxy, alkoxy, amino and nitro;

Iii) a 5-membered heteroaromatic ring, which is optionally substituted with one or more substituents selected from the group consisting of lower alkyl, hydroxy and amine;

아) acyl of the formula-(X ₁ ) _{n 1} -C (O) -X ₂ ,

Wherein X ₁ is lower alkylene or lower alkenylene;

X ₂ is selected from the group consisting of hydrogen, amino, hydroxy and -NH-X ₃ ,

Wherein X ₃ is selected from the group consisting of hydrogen, lower alkyl, amino and amide;

n is 0 or 1;

Iv) a substituent of the formula -C (X ₄ ) = N-NH-C (= E) -NX ₆ X ₇ or -C (X ₄ ) = NN = C (EX ₅ ) -NX ₆ X ₇ ,

Wherein X ₄ is selected from the group consisting of hydrogen, lower alkyl, aryl and alkaryl;

E is selected from the group consisting of oxygen, sulfur and -NR _101- , wherein R ₁₀₁ is selected from the group consisting of hydrogen hydrogen, lower alkyl, lower alkene, lower alkyne, aryl and heteroaryl; And

X ₅ , X ₆ and X ₇ are each independently selected from the group consisting of hydrogen and lower alkyl.

In a fourth embodiment, the invention relates to the compound of the first embodiment, wherein R ₁ is selected from the group consisting of

Iii) hydrogen;

Ii) phenyl, which is optionally substituted with one or more hydroxy or -NH ₂ ;

Iii) a 6-membered heteroaromatic ring selected from the group consisting of pyridine, pyrazine, pyridazine, pyrimidine and 1,3,5-triazine, each independently and optionally with lower alkyl, hydroxy, alkoxy and amino Substituted with one or more substituents selected from the group consisting of;

Iii) 5-membered heteroaromatic rings selected from the group consisting of pyrrole, imidazole, 1,2,3-triazole, 1,2,4-triazole, tetrazole, thiophene, thiazole, and thiadiazole, which are Each independently and optionally hydroxy, an amide of the _formula- (X ₂₄ ) _n24 -NH-C (O) -X _{25 or-} (X ₂₆ ) _n26 -C (O) -NH-X ₂₇ , and -NH ₂ Substituted with one or more substituents selected from the group consisting of;

Iii) acyl of the formula -C (O) -X ₂ , wherein X ₂ is hydrogen or lower alkyl;

아) acyl of formula -X ₁ -C (O) -X ₂ ,

Wherein X ₁ is lower alkylene or lower alkenylene; And

X ₂ is -NH-X ₃ , wherein X ₃ is selected from the group consisting of hydrogen, amino and amide;

Iv) -C (X ₄ ) = N-NH-C (= E) -NH ₂ ,

Wherein X ₄ is selected from the group consisting of hydrogen, methyl, ethyl, phenyl and -CH ₂ CH ₂ -Ph; And

E is oxygen, sulfur, and -NR ₁₀₁ - it is selected from the group consisting of wherein R is hydrogen _1O1 hydrogen, lower alkyl, lower alkenyl, lower alkynyl, aryl, and is selected from the group consisting of-heteroaryl; And

Ⅷ) Formula -C (X ₄ ) = NN = C (SX ₅ ) -NH ₂ ,

Wherein X ₄ is selected from the group consisting of hydrogen, methyl, ethyl, phenyl and -CH ₂ CH ₂ -Ph;

X ₅ is hydrogen or methyl.

In a fifth embodiment, the present invention provides a process wherein, in R ₁ , a 5- or 6-membered heteroaryl ring is optionally substituted , Optionally substituted , And optionally substituted Is selected from the group consisting of W, X, Y and Z are each independently CR or nitrogen, and U is selected from the group consisting of CR ₂ , oxygen, sulfur and NR; R relates to the compound of the first example, as defined herein.

In a sixth embodiment, the present invention provides that the heteroaryl ring is a furan, thiophene, pyrrole, pyrroline, pyrrolidine, oxazole, thiazole, imidazole, imidazoline, imidazolidine, pyrazole, Pyrazoline, pyrazolidine, isosazole, isothiazole, triazole, thiadiazole, pyran, pyridine, piperidine, morpholine, thiomorpholine, pyridazine, pyrimidine, pyrazine, piperazine, triazine, , , And Is selected from the group consisting of hydrogen, alkyl and aryl, the compound of the fifth embodiment.

In a seventh embodiment, the present invention provides that the heteroaryl ring is aminofuran, aminothiophene, aminopyrrole, aminopyrroline, aminopyrrolidine, aminooxazole, aminothiazole, aminoimidazole, aminoimidazoline, Aminoimidazolidine, aminopyrazole, aminopyrazoline, aminopyrazolidine, aminoisoxazole, aminoisothiazole, aminotriazole, aminothiadiazole, aminopyran, aminopyridine, aminopiperidine, aminomorpholine , Aminothiomorpholine, aminopyridazine, aminopyrimidine, aminopyrazine, aminopiperazine, aminotriazine, , , And It relates to a compound of the sixth embodiment selected from the group consisting of.

In an eighth embodiment, the invention provides that R ₁ is -C (O) -CH ₃ , -C (O) -NH-CH ₂ -C (O) -NH ₂ , -CH = CH = C (O) -NH ₂ , -CH ₂ -CH ₂ -C (O) -NH-NH ₂ , -C (H) = N-NH-C (O) -NH ₂ , -C (CH ₃ ) = N-NH- C (O) -NH ₂ , -C (H) = N-NH-C (S) -NH ₂ , -C (CH ₃ ) = N-NH-C (S) -NH ₂ , -C (Ph) = N-NH-C (S) -NH ₂ , -C (CH ₂ CH ₂ Ph) = N-NH-C (S) -NH ₂ , -C (H) = NN = C (SCH ₃ ) -NH ₂ , , , , , , , , , , , , , , , , , , , , And Is selected from the group consisting of hydrogen, alkyl and aryl, the compound of the first embodiment.

In a ninth embodiment, the invention relates to the compound of the first embodiment, wherein R ₃ is selected from the group consisting of

Iii) hydrogen;

Ii) C ₂ -C ₆ alkenylene;

Iii) halogen or perhaloalkyl;

Iii) alkoxy of formula -OX ₁₄ ,

Wherein X ₁₄ is selected from the group consisting of hydrogen, lower alkyl and aryl; And

Iii) a 5-membered or 6-membered heteroaryl ring, or a 6-membered aryl or heteroaryl ring optionally substituted with one or more substituents selected from the group consisting of

A) optionally substituted C ₁ -C ₄ straight, branched or cyclic saturated or unsaturated alkyl;

B) alkoxy of formula -OX ₁₄ , wherein X ₁₄ is hydrogen or lower alkyl;

C) halogen or perhaloalkyl;

D) cyano;

E) nitro;

F) a substituent of the _formula- (X ₁₈ ) _{n 18} -C (O) -X ₁₉ ,

Wherein X ₁₈ is lower alkylene;

X ₁₉ is selected from the group consisting of hydrogen, lower alkyl, aryl, heteroaryl, hydroxy, alkoxy, amino and -NX ₂₀ X ₂₁ ,

Wherein X ₂₀ and X ₂₁ are each independently selected from the group consisting of hydrogen, alkyl and aryl; And

n18 is 0 or 1;

G) a thioether or thiol of the formula -SX ₂₃ , wherein X ₂₃ is selected from the group consisting of hydrogen, lower alkyl, aryl and heteroaryl; And

H) an amide of _formula- (X ₂₄ ) _n24 -NH-C (O) -X _{25 or-} (X ₂₆ ) _n26 -C (O) -NH-X ₂₇ ,

Wherein X ₂₄ and X ₂₆ are each independently lower alkylene; X ₂₅ is selected from the group consisting of hydrogen, lower alkyl, aryl, hydroxy and alkoxy;

X ₂₇ is selected from the group consisting of hydrogen, lower alkyl, aryl and heteroaryl.

In a tenth embodiment, the invention relates to the compound of the first embodiment, wherein R ₃ is selected from the group consisting of

Iii) hydrogen;

Ii) C ₂ -C ₆ alkylene;

Iii) halogen or perhaloalkyl;

Iii) alkoxy of formula -OX ₁₄ ,

Wherein X ₁₄ is selected from the group consisting of hydrogen, methyl, ethyl and propyl;

Iii) 6-membered aryl ring, which is optionally substituted with one or more substituents selected from the group consisting of:

A) methyl, ethyl and propyl;

B) hydroxy, methoxy, ethoxy, phenoxy, hydroxymethyl, 2-hydroxyethyl and 3-hydroxypropyl;

C) halogen or perfluoroalkyl;

D) cyano;

E) nitro;

F) a substituent of the formula -C (O) -X ₁₉ ,

Wherein X ₁₉ is hydrogen, methyl, ethyl, propyl, phenyl, hydroxy, methoxy, ethoxy, propoxy, amino and -NX ₂₀ X ₂₁ ,

Wherein X ₂₀ and X ₂₁ are each independently selected from the group consisting of hydrogen, methyl, ethyl, propyl and phenyl;

Thioether or thiol of G) -SX ₂₃ , wherein X ₂₃ is selected from the group consisting of hydrogen, methyl, ethyl, propyl and phenyl;

H) an amide of _formula- (X ₂₄ ) _n24 -NH-C (O) -X _{25 or-} (X ₂₆ ) _n26 -C (O) -NH-X ₂₇ ,

Wherein X ₂₄ and X ₂₆ are each independently lower alkylene;

X ₂₅ is selected from the group consisting of hydrogen, methyl, ethyl, propyl, phenyl, hydroxy, methoxy and phenoxy; And

X ₂₇ is selected from the group consisting of hydrogen, methyl, ethyl, propyl and phenyl.

In an eleventh embodiment, the 5- or 6-membered heteroaryl ring or 6-membered aryl or heteroaryl ring of R ₃ is optionally substituted , Optionally substituted , And optionally substituted It may be selected from the group consisting of, wherein V, W, X, Y and Z are each independently CR or nitrogen, U is selected from the group consisting of CR ₂ , oxygen, sulfur and NR, wherein R is hydrogen, The compound of the first embodiment is selected from the group consisting of alkyl and aryl.

In a twelfth embodiment, the present invention relates to the above, wherein the 5- or 6-membered heteroaryl ring or 6-membered aryl or heteroaryl ring of R ₃ is selected from phenyl, furan, thiophene, pyrrole, pyrroline, pyrrolidine, Oxazole, thiazole, imidazole, imidazoline, imidazolidine, pyrazole, pyrazoline, pyrazolidine, isosazole, isothiazole, triazole, thiadiazole, pyran, pyridine, piperidine, mor The compound of the first embodiment is selected from the group consisting of porin, thiomorpholine, pyridazine, pyrimidine, pyrazine, piperazine and triazine.

In a thirteenth embodiment, the invention provides that R ₃ is hydrogen, chlorine, bromine, hydroxy, -CH = CH-CH ₂ CH ₂ CH ₂ CH ₃ , -CH = CH-C (O) -OH,- CH = CH-C (O) -OCH ₃ , -CH = CH-C (O) -NH ₂ , -CH ₂ CH (NH ₂ ) COOH, phenyl, -O-CH ₂ -phenyl, 2-methylphenyl, 3 -Methylphenyl, 2-methylthiophenyl, 3-methylthiopetyl, 4-methylthiophenyl, 4-methylphenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 2-hydroxyphenyl, 3-hydroxyphenyl, 4-hydroxyphenyl, 2-hydroxymethylphenyl, 3-hydroxymethylphenyl, 4-hydroxymethylphenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2- Cyanophenyl, 3-cyanophenyl, 4-cyanophenyl, 2-nitrophenyl, 3-nitrophenyl, 4-nitrophenyl, 2-hydroxycarbonylphenyl, 3-hydroxycarbonylphenyl, 4-hydrate Oxycarbonylphenyl, 2-methoxycarbonylphenyl, 3-methoxycarbonylphenyl, 4-methoxycarbonylphenyl, 2-trifluoromethylphenyl, 4-benzyloxyphenyl, 2-phenoxyphenyl, 2 , 4-Dhi Hydroxyphenyl, 3,4-dihydroxyphenyl, 2-hydroxy-4-methoxyphenyl, 4-hydroxy-2-methoxyphenyl, 2,4-dimethoxyphenyl, 3,4-dimethoxyphenyl , 3-fluoro-4-hydroxyphenyl, 3-fluoro-4-methoxyphenyl, , , , , , , 2-pyridyl, 3-pyridyl, 4-pyridyl, , , , , , , , , , , , , And Is selected from the group consisting of hydrogen, alkyl, and aryl, the compound of the first embodiment.

In a fourteenth embodiment, the invention provides that R ₂ and R ₃ substituents are taken with the two ring carbons to which they are attached, or R ₄ and R ₃ substituents are taken with the two ring carbons to which they are attached Or R ₄ and R ₅ substituents are taken together with the two ring carbons to which they are attached to form a 6-membered aromatic or heteroaromatic, or 5- or 6-membered heteroaromatic ring, which optionally is hydrogen, hydrate Hydroxy, halogens, cyano, nitro, amino, hydroxycarbonyl, aminocarbonyl, aminothiocarbonyl, lower alkoxy, phenoxy, amino-furan, amino-thiophene, amino-pyrrole, amino-pyrroline, Amino-pyrrolodine, amino-oxazole, amino-thiazole, amino-imidazole, amino-imidazoline, amino-imidazolidine, amino-pyrazole, amino-pyrazoline, amino-pyrazolidine, amino Isosazole, amino- Sothiazole, amino-triazole, amino-thiadiazole, amino-pyran, amino-pyridine, amino-piperidine, amino-morpholine, amino-thiomorpholine, amino-pyridazine, amino-pyrimidine, amino -A compound of the first embodiment, substituted with one or more substituents selected from the group consisting of pyrazine, amino-piperazine, amino-triazine, semicarbazone, thiosemicarbazone, and amino guanidine.

In a fifteenth embodiment, the invention provides that R ₂ and R ₃ are taken with the remainder of the compound of formula 2, or R ₄ and R ₃ are taken with the remainder of the compound of formula 2, or R ₄ and R ₅ relates to the compound of example 14, taken with the rest of the compound of formula 2, resulting in the formation of an optionally substituted naphthalene.

In a sixteenth embodiment, the invention relates to the compound of the fourteenth embodiment, wherein the substituent is hydroxy.

In a seventeenth embodiment, the invention relates to a compound of formula 3, or a pharmaceutically acceptable salt, amide, ester, or prodrug thereof,

(3)

Where

a) R ₆ is selected from the group consisting of

Iii) 6-membered aromatic or heteroaromatic, 5- or 6-membered heteroaromatic rings, which are optionally substituted with one or more substituents selected from the group consisting of lower alkyl, hydroxy, alkoxy, amino and nitro; And

Ii) acyl of the formula-(X ₁ ) _{n 1} -C (O) -X ₂ ,

Wherein X ₁ is selected from the group consisting of lower alkylene, lower alkenylene, lower alkynylene, aryl and heteroaryl;

X ₂ is selected from the group consisting of hydrogen, lower alkyl, aryl, heteroaryl, hydroxy, alkoxy, amino, and -NH-X ₃ ;

Wherein X ₃ is selected from the group consisting of hydrogen, alkyl, aryl, heteroaryl, amino and amide; And

n1 is 0 or 1;

Provided that R ₆ is -C ₆ H ₅ , -C (0) H, -C (O) CH ₃ , -C (O) -C ₆ H ₅ , -C (O) NH ₂ , or -C ₆ H _{Not 4} CH ₃ ;

b) R ₇ , R ₈ and R ₉ are each independently selected from the group consisting of the following;

Iii) hydrogen;

Ii) lower alkyl;

Iii) lower alkylene;

Iii) halogen or perhaloalkyl;

Ⅴ) alkoxy of the formula-(X ₁₃ ) _n13 -OX ₁₄ ,

Wherein X ₁₃ is selected from the group consisting of lower alkylene, lower alkenylene, lower alkynylene, allyl and heteroaryl;

X ₁₄ is selected from the group consisting of hydrogen, lower alkyl, aryl and heteroaryl; And

n13 is 0 or 1; And

V) 5- or 6-membered heteroaryl ring or 6-membered aryl ring or heteroaryl ring, optionally substituted with one or more substituents selected from the group consisting of the following;

A) optionally substituted C ₁ -C ₈ straight, branched, or cyclic saturated or unsaturated alkyl;

B) alkoxy of formula-(X ₁₃ ) _n13 -OX ₁₄ ,

Wherein X ₁₃ is selected from the group consisting of lower alkylene, lower alkenylene, lower alkynylene, aryl and heteroaryl;

X ₁₄ is selected from the group consisting of hydrogen, lower alkyl, aryl and heteroaryl; And

n13 is 0 or 1;

C) halogen or perhaloalkyl;

D) cyano;

E) nitro;

F) amino of the formula-(X ₁₅ ) _n15 -NX ₁₆ X ₁₇ ,

Wherein X ₁₅ is selected from the group consisting of lower alkylene, lower alkenylene, lower alkynylene, aryl and heteroaryl;

X ₁₆ and X ₁₇ are each independently selected from the group consisting of hydrogen, lower alkyl, aryl and heteroaryl; Or X ₁₆ and X ₁₇ are taken together with the nitrogen to which they are linked to form a 5- or 6-membered heteroaromatic or heteroaliphatic ring; And

n15 is 0 or 1;

G) a substituent of the _formula- (X ₁₈ ) _n18 -C (= E) -X ₁₉ ,

Wherein X ₁₈ is selected from the group consisting of lower alkylene, lower alkenylene, lower alkynylene, aryl and heteroaryl;

E is selected from the group consisting of oxygen, sulfur and -NR _101- , wherein R ₁₀₁ is selected from the group consisting of hydrogen hydrogen, lower alkyl, lower alkene, lower alkyne, aryl and heteroaryl;

X ₁₉ is selected from the group consisting of hydrogen, lower alkyl, aryl, heteroaryl, hydroxy, alkoxy, amino and -NX ₂₀ X ₂₁ ,

Wherein X ₂₀ and X ₂₁ are each independently selected from the group consisting of hydrogen, alkyl, aryl and heteroaryl;

n18 is 0 or 1; And

H) a thioether or thiol of the _formula- (X ₂₂ ) _{n22 -SX 23} ,

Wherein X ₂₂ is selected from the group consisting of lower alkylene, lower alkenylene, lower alkynylene, aryl and heteroaryl; And

X ₂₃ is selected from the group consisting of hydrogen, lower alkyl, aryl and heteroaryl,

n22 is 0 or 1; And

_{Amide of formula-} (X ₂₄ ) _n24 -NH-C (O) -X _{25 or-} (X ₂₆ ) _n26 -C (O) -NH-X ₂₇ ,

Wherein X ₂₄ and X ₂₆ are each independently selected from the group consisting of lower alkylene, lower alkenylene, lower alkynylene, aryl and heteroaryl;

X ₂₅ is selected from the group consisting of hydrogen, lower alkyl, lower alkenyl, aryl, heteroaryl, hydroxy, alkoxy and amide; And

X ₂₇ is selected from the group consisting of hydrogen, lower alkyl, lower alkenyl, aryl and heteroaryl;

c) R ₁₀ is selected from the group consisting of hydrogen, lower alkyl, aryl and heteroaryl; Provided that at least one of R ₆ -R ₁₀ is not selected from the group consisting of hydrogen, lower alkyl, aryl and heteroaryl.

In an eighteenth example, the invention relates to the compound of the seventeenth example, wherein R ₆ is selected from the group consisting of

Iii) hydrogen;

Ii) 6-membered aromatic ring, which is optionally substituted with one or more substituents selected from the group consisting of lower alkyl, hydroxy and amine;

Iii) a 6-membered heteroaromatic ring, which is optionally substituted with one or more substituents selected from the group consisting of lower alkyl, hydroxy, alkoxy, amino and nitro;

Iii) a 5-membered heteroaromatic ring, which is optionally substituted with one or more substituents selected from the group consisting of lower alkyl, hydroxy and amine;

아) acyl of the formula-(X ₁ ) _{n 1} -C (O) -X ₂ ,

Wherein X ₁ is lower alkylene or lower alkenylene;

X ₂ is selected from the group consisting of hydrogen, amino, hydroxy and -NH-X ₃ ,

Wherein X ₃ is selected from the group consisting of hydrogen, lower alkyl, amino and amide;

n is 0 or 1;

In a nineteenth embodiment, the invention relates to the compound of the seventeenth embodiment, wherein R ₆ is selected from the group consisting of

Iii) hydrogen;

Ii) phenyl, which is optionally substituted with one or more hydroxy or -NH ₂ ;

Iii) a 6-membered heteroaromatic ring selected from the group consisting of pyridine, pyrazine, pyridazine, pyrimidine and 1,3,5-triazine, each independently and optionally with lower alkyl, hydroxy, alkoxy and amino Substituted with one or more substituents selected from the group consisting of;

Iii) 5-membered heteroaromatic rings selected from the group consisting of pyrrole, imidazole, 1,2,3-triazole, 1,2,4-triazole, tetrazole, thiophene, thiazole, and thiadiazole, which are Each independently and optionally hydroxy, an amide of the _formula- (X ₂₄ ) _n24 -NH-C (O) -X _{25 or-} (X ₂₆ ) _n26 -C (O) -NH-X ₂₇ , and -NH ₂ Substituted with one or more substituents selected from the group consisting of;

Iii) acyl of the formula -C (O) -X ₂ , wherein X ₂ is hydrogen or lower alkyl;

아) acyl of formula -X ₁ -C (O) -X ₂ ,

Wherein X ₁ is lower alkylene or lower alkenylene; And

X ₂ is -NH-X ₃ , wherein X ₃ is selected from the group consisting of hydrogen, amino and amide.

In 20 examples, the invention relates to a compound wherein, in R ₆ , a 5- or 6-membered heteroaryl ring is optionally substituted , Optionally substituted , And optionally substituted Is selected from the group consisting of: wherein V, W, X, Y and Z are each independently CR or nitrogen, and U is selected from the group consisting of CR ₂ , oxygen, sulfur and NR; R is directed to the compound of example 17, selected from the group consisting of hydrogen, alkyl and aryl.

In a twenty-first embodiment, the present invention provides that the heteroaryl ring is selected from furan, thiophene, pyrrole, pyrroline, pyrrolidine, oxazole, thiazole, imidazole, imidazoline, imidazolidine, pyrazole, Pyrazoline, pyrazolidine, isosazole, isothiazole, triazole, thiadiazole, oxadiazole ( ), Pyran, pyridine, piperidine, morpholine, thiomorpholine, pyridazine, pyrimidine, pyrazine, piperazine, and triazine.

In a twenty-second embodiment, the invention provides that the heteroaryl ring is aminofuran, aminothiophene, aminopyrrole, aminopyrroline, aminopyrrolidine, aminooxazole, aminothiazole, aminoimidazole, aminoimidazoline , Aminoimidazolidine, aminopyrazole, aminopyrazoline, aminopyrazolidine, aminoisoxazole, aminoisothiazole, aminotriazole, aminothiadiazole, aminooxadiazole, aminopyran, aminopyridine, amino The compound of Example 21 is selected from the group consisting of piperidine, aminomorpholine, aminothiomorpholine, aminopyridazine, aminopyrimidine, aminopyrazine, aminopiperazine, and aminotriazine.

In twenty-third embodiments, the invention provides that R ₆ is hydrogen, -C (O) -CH ₃ , -C (O) -NH-CH ₂ -C (O) -NH ₂ , -CH = CH = C (O) -NH ₂ , -CH ₂ CH ₂ -C (O) -NH-NH ₂ , , , , , , , , , , , , , , , , , , , And It relates to the compound of the seventeenth embodiment selected from the group consisting of.

In a twenty-fourth example, the present invention relates to the compound of the seventeenth example, wherein R ₈ is selected from the group consisting of

Iii) hydrogen;

Ii) C ₂ -C ₆ alkenylene;

Iii) halogen or perhaloalkyl;

Iii) alkoxy of formula -OX ₁₄ ,

Wherein X ₁₄ is selected from the group consisting of hydrogen, lower alkyl and aryl; And

Iii) a 5-membered or 6-membered heteroaryl ring, or a 6-membered aryl or heteroaryl ring optionally substituted with one or more substituents selected from the group consisting of

A) optionally substituted C ₁ -C ₄ straight, branched or cyclic saturated or unsaturated alkyl;

B) alkoxy of formula -OX ₁₄ , wherein X ₁₄ is hydrogen or lower alkyl;

C) halogen or perhaloalkyl;

D) cyano;

E) nitro;

F) a substituent of the _formula- (X ₁₈ ) _{n 18} -C (O) -X ₁₉ ,

Wherein X ₁₈ is lower alkylene;

X ₁₉ is selected from the group consisting of hydrogen, lower alkyl, aryl, heteroaryl, hydroxy, alkoxy, amino and -NX ₂₀ X ₂₁ ,

Wherein X ₂₀ and X ₂₁ are each independently selected from the group consisting of hydrogen, alkyl and aryl; And

n18 is 0 or 1;

G) a thioether or thiol of the formula -SX ₂₃ , wherein X ₂₃ is selected from the group consisting of hydrogen, lower alkyl, aryl and heteroaryl; And

H) an amide of _formula- (X ₂₄ ) _n24 -NH-C (O) -X _{25 or-} (X ₂₆ ) _n26 -C (O) -NH-X ₂₇ ,

Wherein X ₂₄ and X ₂₆ are each independently lower alkylene; X ₂₅ is selected from the group consisting of hydrogen, lower alkyl, aryl, hydroxy and alkoxy;

X ₂₇ is selected from the group consisting of hydrogen, lower alkyl, aryl and heteroaryl.

In twenty-fifth embodiments, the present invention relates to the compound of the seventeenth embodiment, wherein R ₈ is selected from the group consisting of

Iii) hydrogen;

Ii) C ₂ -C ₆ alkylene;

Iii) halogen or perhaloalkyl;

Iii) alkoxy of formula -OX ₁₄ ,

Wherein X ₁₄ is selected from the group consisting of hydrogen, methyl, ethyl and propyl;

Iii) 6-membered aryl ring, which is optionally substituted with one or more substituents selected from the group consisting of:

A) methyl, ethyl and propyl;

B) hydroxy, methoxy, ethoxy, phenoxy, hydroxymethyl, 2-hydroxyethyl and 3-hydroxypropyl;

C) halogen or perfluoroalkyl;

D) cyano;

E) nitro;

F) a substituent of the formula -C (O) -X ₁₉ ,

Wherein X ₁₉ is hydrogen, methyl, ethyl, propyl, phenyl, hydroxy, methoxy, ethoxy, propoxy, amino and -NX ₂₀ X ₂₁ ,

Wherein X ₂₀ and X ₂₁ are each independently selected from the group consisting of hydrogen, methyl, ethyl, propyl and phenyl;

G) a thioether or thiol of the formula -SX ₂₃ , wherein X ₂₃ is selected from the group consisting of hydrogen, methyl, ethyl, propyl and phenyl;

H) an amide of _formula- (X ₂₄ ) _n24 -NH-C (O) -X _{25 or-} (X ₂₆ ) _n26 -C (O) -NH-X ₂₇ ,

Wherein X ₂₄ and X ₂₆ are each independently lower alkylene;

X ₂₅ is selected from the group consisting of hydrogen, methyl, ethyl, propyl, phenyl, hydroxy, methoxy and phenoxy; And

X ₂₇ is selected from the group consisting of hydrogen, methyl, ethyl, propyl and phenyl.

In a twenty sixth embodiment, the present invention provides that the 5- or 6-membered heteroaryl ring or 6-membered aryl or heteroaryl ring of R ₈ is optionally substituted. , Optionally substituted , And optionally substituted V, W, X, Y and Z are each independently CR or nitrogen, U is selected from the group consisting of CR ₂ , oxygen, sulfur and NR, wherein R is hydrogen, alkyl and The compound of Example 17 is selected from the group consisting of NR.

In a twenty-seventh embodiment, the invention provides that the 5- or 6-membered heteroaryl ring or 6-membered aryl or heteroaryl ring of R ₈ is a phenyl, furan, thiophene, pyrrole, pyrroline, pyrrolidine , Oxazole, thiazole, imidazole, imidazoline, imidazolidine, pyrazole, pyrazoline, pyrazolidine, isosazole, isothiazole, triazole, thiadiazole, pyran, pyridine, piperidine, The compound of the seventeenth embodiment is selected from the group consisting of morpholine, thiomorpholine, pyridazine, pyrimidine, pyrazine, piperazine, and triazine.

In a 28 th embodiment, the invention provides that R ₈ is hydrogen, chlorine, bromine, hydroxy, —CH═CH—CH ₂ CH ₂ CH ₂ CH ₃ , —CH═CH—C (O) —OH, — CH = CH-C (O) -OCH ₃ , -CH = CH-C (O) -NH ₂ , -CH ₂ CH (NH ₂ ) COOH, phenyl, -O-CH ₂ -phenyl, 2-methylphenyl, 3 -Methylphenyl, 2-methylthiophenyl, 3-methylthiopetyl, 4-methylthiophenyl, 4-methylphenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 2-hydroxyphenyl, 3-hydroxyphenyl, 4-hydroxyphenyl, 2-hydroxymethylphenyl, 3-hydroxymethylphenyl, 4-hydroxymethylphenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2- Cyanophenyl, 3-cyanophenyl, 4-cyanophenyl, 2-nitrophenyl, 3-nitrophenyl, 4-nitrophenyl, 2-hydroxycarbonylphenyl, 3-hydroxycarbonylphenyl, 4-hydrate Oxycarbonylphenyl, 2-methoxycarbonylphenyl, 3-methoxycarbonylphenyl, 4-methoxycarbonylphenyl, 2-trifluoromethylphenyl, 4-benzyloxyphenyl, 2-phenoxyphenyl, 2 , 4-Dhi Hydroxyphenyl, 3,4-dihydroxyphenyl, 2-hydroxy-4-methoxyphenyl, 4-hydroxy-2-methoxyphenyl, 2,4-dimethoxyphenyl, 3,4-dimethoxyphenyl , 3-fluoro-4-hydroxyphenyl, 3-fluoro-4-methoxyphenyl, , , , , , , 2-pyridyl, 3-pyridyl, 4-pyridyl, , , , , , , , , , , , , And Selected from the group consisting of hydrogen, alkyl and aryl, the compound of the seventeenth embodiment.

In a twenty-ninth embodiment, the present invention relates to a compound of formula 4, or a pharmaceutically acceptable salt, amide, ester, or prodrug thereof.

(4)

Where

a) R ₁₁ is selected from the group consisting of hydrogen, lower alkyl, aryl and heteroaryl;

b) R ₁₂ , R ₁₃ and R ₁₄ are each independently selected from the group consisting of the following;

Iii) hydrogen;

Ii) lower alkyl;

Iii) lower alkylene;

Iii) halogen or perhaloalkyl;

Ⅴ) alkoxy of the formula-(X ₁₃ ) _n13 -OX ₁₄ ,

Wherein X ₁₃ is selected from the group consisting of lower alkylene, lower alkenylene, lower alkynylene, allyl and heteroaryl;

X ₁₄ is selected from the group consisting of hydrogen, lower alkyl, aryl and heteroaryl; And

n13 is 0 or 1; And

Iii) a 5- or 6-membered heteroaryl ring or a 6-membered aryl or heteroaryl ring, optionally substituted with one or more substituents selected from the group consisting of:

A) optionally substituted C ₁ -C ₈ straight, branched, or cyclic saturated or unsaturated alkyl;

B) alkoxy of formula-(X ₁₃ ) _n13 -OX ₁₄ ,

Wherein X ₁₃ is selected from the group consisting of lower alkylene, lower alkenylene, lower alkynylene, aryl and heteroaryl;

X ₁₄ is selected from the group consisting of hydrogen, lower alkyl, aryl and heteroaryl; And

n13 is 0 or 1;

C) halogen or perhaloalkyl;

D) cyano;

E) nitro;

F) amino of the formula-(X ₁₅ ) _n15 -NX ₁₆ X ₁₇ ,

Wherein X ₁₅ is selected from the group consisting of lower alkylene, lower alkenylene, lower alkynylene, aryl and heteroaryl;

X ₁₆ and X ₁₇ are each independently selected from the group consisting of hydrogen, lower alkyl, aryl and heteroaryl; Or X ₁₆ and X ₁₇ are taken together with the nitrogen to which they are attached to form a 5- or 6-membered heteroaromatic or heteroaliphatic ring; And

n15 is 0 or 1;

G) a substituent of the _formula- (X ₁₈ ) _n18 -C (= E) -X ₁₉ ,

Wherein X ₁₈ is selected from the group consisting of lower alkylene, lower alkenylene, lower alkynylene, aryl and heteroaryl;

E is selected from the group consisting of oxygen, sulfur and -NR _101- , wherein R ₁₀₁ is selected from the group consisting of hydrogen hydrogen, lower alkyl, lower alkene, lower alkyne, aryl and heteroaryl;

X ₁₉ is selected from the group consisting of hydrogen, lower alkyl, aryl, heteroaryl, hydroxy, alkoxy, amino and -NX ₂₀ X ₂₁ ,

Wherein X ₂₀ and X ₂₁ are each independently selected from the group consisting of hydrogen, alkyl, aryl and heteroaryl;

n18 is 0 or 1; And

H) a thioether or thiol of the _formula- (X ₂₂ ) _{n22 -SX 23} ,

Wherein X ₂₂ is selected from the group consisting of lower alkylene, lower alkenylene, lower alkynylene, aryl and heteroaryl; And

X ₂₃ is selected from the group consisting of hydrogen, lower alkyl, aryl and heteroaryl,

n22 is 0 or 1; And

_{Amide of formula-} (X ₂₄ ) _n24 -NH-C (O) -X _{25 or-} (X ₂₆ ) _n26 -C (O) -NH-X ₂₇ ,

Wherein X ₂₄ and X ₂₆ are each independently selected from the group consisting of lower alkylene, lower alkenylene, lower alkynylene, aryl and heteroaryl;

X ₂₅ is selected from the group consisting of hydrogen, lower alkyl, lower alkenyl, aryl, heteroaryl, hydroxy, alkoxy and amide; And

X ₂₇ is selected from the group consisting of hydrogen, lower alkyl, lower alkenyl, aryl and heteroaryl;

c) R ₁₅ is selected from the group consisting of hydrogen, lower alkyl, aryl, alkaryl, heteroaryl and amino;

d) R ₁₆ and R ₁₇ are each independently selected from the group consisting of hydrogen, lower alkyl, aryl and heteroaryl; And

e) E is selected from the group consisting of oxygen, sulfur and —NR ₁₀₁ —, where R ₁₀₁ is selected from the group consisting of hydrogen hydrogen, lower alkyl, lower alkene, lower alkyne, aryl and heteroaryl.

In a thirty-first embodiment, the present invention relates to the compound of the twenty-ninth example, wherein R ₁₃ is selected from the group consisting of

Iii) hydrogen;

Ii) C ₂ -C ₆ alkenylene;

Iii) halogen or perhaloalkyl;

Iii) alkoxy of formula -OX ₁₄ ,

Wherein X ₁₄ is selected from the group consisting of hydrogen, lower alkyl and aryl; And

Iii) a 5-membered or 6-membered heteroaryl ring, or a 6-membered aryl or heteroaryl ring optionally substituted with one or more substituents selected from the group consisting of

A) optionally substituted C ₁ -C ₄ straight, branched or cyclic saturated or unsaturated alkyl;

B) alkoxy of formula -OX ₁₄ , wherein X ₁₄ is hydrogen or lower alkyl;

C) halogen or perhaloalkyl;

D) cyano;

E) nitro;

F) a substituent of the _formula- (X ₁₈ ) _{n 18} -C (O) -X ₁₉ ,

Wherein X ₁₈ is lower alkylene;

X ₁₉ is selected from the group consisting of hydrogen, lower alkyl, aryl, heteroaryl, hydroxy, alkoxy, amino and -NX ₂₀ X ₂₁ ,

Wherein X ₂₀ and X ₂₁ are each independently selected from the group consisting of hydrogen, alkyl and aryl; And

n18 is 0 or 1;

G) a thioether or thiol of the formula -SX ₂₃ , wherein X ₂₃ is selected from the group consisting of hydrogen, lower alkyl, aryl and heteroaryl; And

H) an amide of _formula- (X ₂₄ ) _n24 -NH-C (O) -X _{25 or-} (X ₂₆ ) _n26 -C (O) -NH-X ₂₇ ,

Wherein X ₂₄ and X ₂₆ are each independently lower alkylene; X ₂₅ is selected from the group consisting of hydrogen, lower alkyl, aryl, hydroxy and alkoxy;

X ₂₇ is selected from the group consisting of hydrogen, lower alkyl, aryl and heteroaryl.

In a thirty-first embodiment, the present invention relates to the compound of the twenty-ninth example, wherein R ₁₃ is selected from the group consisting of

Iii) hydrogen;

Ii) C ₂ -C ₆ alkylene;

Iii) halogen or perhaloalkyl;

Iii) alkoxy of formula -OX ₁₄ ,

Wherein X ₁₄ is selected from the group consisting of hydrogen, methyl, ethyl and propyl;

Iii) 6-membered aryl ring, which is optionally substituted with one or more substituents selected from the group consisting of:

A) methyl, ethyl and propyl;

B) hydroxy, methoxy, ethoxy, phenoxy, hydroxymethyl, 2-hydroxyethyl and 3-hydroxypropyl;

C) halogen or perfluoroalkyl;

D) cyano;

E) nitro;

F) a substituent of the formula -C (O) -X ₁₉ ,

Wherein X ₁₉ is hydrogen, methyl, ethyl, propyl, phenyl, hydroxy, methoxy, ethoxy, propoxy, amino and -NX ₂₀ X ₂₁ ,

Wherein X ₂₀ and X ₂₁ are each independently selected from the group consisting of hydrogen, methyl, ethyl, propyl and phenyl;

G) a thioether or thiol of the formula -SX ₂₃ , wherein X ₂₃ is selected from the group consisting of hydrogen, methyl, ethyl, propyl and phenyl;

H) an amide of _formula- (X ₂₄ ) _n24 -NH-C (O) -X _{25 or-} (X ₂₆ ) _n26 -C (O) -NH-X ₂₇ ,

Wherein X ₂₄ and X ₂₆ are each independently lower alkylene;

X ₂₅ is selected from the group consisting of hydrogen, methyl, ethyl, propyl, phenyl, hydroxy, methoxy and phenoxy; And

X ₂₇ is selected from the group consisting of hydrogen, methyl, ethyl, propyl and phenyl.

In a thirty-second embodiment, the present invention provides the above process wherein the 5- or 6-membered heteroaryl ring or 6-membered aryl or heteroaryl ring of R ₁₃ is optionally substituted. , Optionally substituted , And optionally substituted It may be selected from the group consisting of, wherein V, W, X, Y and Z are each independently CR or nitrogen, U is selected from the group consisting of CR ₂ , oxygen, sulfur and NR, wherein R is hydrogen, The compound of the twenty-ninth example is selected from the group consisting of alkyl and aryl.

In a thirty-third embodiment, the present invention provides that the 5- or 6-membered heteroaryl ring or 6-membered aryl or heteroaryl ring of R ₁₃ is a phenyl, furan, thiophene, pyrrole, pyrroline, pyrrolidine , Oxazole, thiazole, imidazole, imidazoline, imidazolidine, pyrazole, pyrazoline, pyrazolidine, isosazole, isothiazole, triazole, thiadiazole, pyran, pyridine, piperidine, The compound of Example 29 is selected from the group consisting of morpholine, thiomorpholine, pyridazine, pyrimidine, pyrazine, piperazine, and triazine.

In 34 th embodiments, the invention provides that R ₁₃ is hydrogen, chlorine, bromine, hydroxy, —CH═CH—CH ₂ CH ₂ CH ₂ CH ₃ , —CH═CH—C (O) —OH, — CH = CH-C (O) -OCH ₃ , -CH = CH-C (O) -NH ₂ , -CH ₂ CH (NH ₂ ) COOH, phenyl, -O-CH ₂ -phenyl, 2-methylphenyl, 3 -Methylphenyl, 2-methylthiophenyl, 3-methylthiopetyl, 4-methylthiophenyl, 4-methylphenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 2-hydroxyphenyl, 3-hydroxyphenyl, 4-hydroxyphenyl, 2-hydroxymethylphenyl, 3-hydroxymethylphenyl, 4-hydroxymethylphenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2- Cyanophenyl, 3-cyanophenyl, 4-cyanophenyl, 2-nitrophenyl, 3-nitrophenyl, 4-nitrophenyl, 2-hydroxycarbonylphenyl, 3-hydroxycarbonylphenyl, 4-hydrate Oxycarbonylphenyl, 2-methoxycarbonylphenyl, 3-methoxycarbonylphenyl, 4-methoxycarbonylphenyl, 2-trifluoromethylphenyl, 4-benzyloxyphenyl, 2-phenoxyphenyl, 2 , 4-d Hydroxyphenyl, 3,4-dihydroxyphenyl, 2-hydroxy-4-methoxyphenyl, 4-hydroxy-2-methoxyphenyl, 2,4-dimethoxyphenyl, 3,4-dimethoxyphenyl , 3-fluoro-4-hydroxyphenyl, 3-fluoro-4-methoxyphenyl, , , , , , , 2-pyridyl, 3-pyridyl, 4-pyridyl, , , , , , , , , , , , , And Selected from the group consisting of hydrogen, alkyl and aryl.

In a thirty-fifth embodiment, the present invention provides that R ₁₁ , R ₁₂ , R ₁₃ and R ₁₄ are each independently: (i) hydrogen, (ii) hydroxyl, (i) halogens, (i) cyano, ( (Iii) nitro, (iii) amino, (iii) hydroxycarbonyl, (iii) aminocarbonyl, (iii) aminothiocarbonyl, (iii) lower alkoxy, (xi) phenoxy, (xii) (C ₁ ) -C ₄₎ alkylamino, (xⅲ) arylamino, (xⅳ) C ₁ -C ₈ straight-chain, branched, and cyclic saturated or unsaturated alkyl or alkenyl, (xⅴ) and aryl (optionally substituted xⅵ) optionally It relates to a compound of the 29th example selected from the group consisting of heterocycle substituted with.

In a thirty-sixth embodiment, the invention provides that R ₁₅ is (i) hydrogen, (ii) cyano, (iii) amino, (iii) hydroxycarbonyl, (iii) aminocarbonyl, (iii) aminothiocar Carbonyl, (iii) (C ₁ -C ₄ ) alkylamino, (iii) arylamino, (iii) C ₁ -C ₈ straight, branched, and cyclic saturated or unsaturated alkyl or alkenyl, (iii) optionally The compound of example 29 is selected from the group consisting of substituted aryl, and (xi) optionally substituted heterocycle.

In a thirty-sixth embodiment, the invention provides that R ₁₆ represents (i) hydrogen, (ii) amino, (iii) hydroxycarbonyl, (iii) aminocarbonyl, (iii) aminothiocarbonyl, (iii) (C ₁ -C ₄ ) alkylamino, (iii) arylamino, (iii) C ₁ -C ₈ straight, branched, and cyclic saturated or unsaturated alkyl or alkenyl, (iii) optionally substituted aryl, and (Iii) the compound of the twenty-ninth example selected from the group consisting of optionally substituted heterocycles.

In a thirty eighth embodiment, the present invention relates to compounds of formula (I) wherein R ₁₇ is (i) hydrogen, (ii) (C ₁ -C ₄ ) alkylamino, (iii) arylamino, (iii) C ₁ -C ₈ straight chain, And cyclic saturated or unsaturated alkyl, (iii) optionally substituted aryl, and (iii) optionally substituted heterocycle.

In a thirty-ninth embodiment, the invention provides that the heterocycle is furan, thiophene, pyrrole, pyrroline, pyrrolidine, oxazole, thiazole, imidazole, imidazoline, imidazolidine, pyrazole, pyra Sleepy, pyrazolidine, isosazole, isothiazole, triazole, thiadiazole, pyran, pyridine, piperidine, morpholine, thiomorpholine, pyridazine, pyrimidine, pyrazine, piperazine, triazine, and benzo To compounds disclosed in the 35 th to 38 th examples selected from the group consisting of imidazoles.

In a fortyth embodiment, the invention relates to a compound of formula 5 or 6, or a pharmaceutically acceptable salt, amide, ester, or prodrug thereof.

(5)

(6)

Where

a) R ₁₉ -R ₂₂ and R ₂₆ -R ₂₉ are each independently selected from the group consisting of

Iii) hydrogen;

Ii) optionally substituted C ₁ -C ₈ straight, branched or cyclic saturated or unsaturated alkyl;

Iii) optionally substituted aryl;

Iii) optionally substituted heterocycle;

Ⅴ) Formula -C (X ₄ ) = N-NX ₅ -C (= E) -NX ₆ X ₇ or -C (X ₄ ) = NN = C (EX ₅ ) -NX ₆ X ₇ ,

Wherein X ₄ is selected from the group consisting of hydrogen, lower alkyl, aryl, alkaryl, heteroaryl and amino;

E is selected from the group consisting of oxygen, sulfur and -NR _101- , wherein R ₁₀₁ is selected from the group consisting of hydrogen hydrogen, lower alkyl, lower alkene, lower alkyne, aryl and heteroaryl; And

X ₅ , X ₆ and X ₇ are each independently selected from the group consisting of hydrogen, lower alkyl, aryl and heteroaryl;

Iii) amino guanidine of formula -NX ₈ -NX ₉ -C (= NX ₁₀ ) -NX ₁₁ X ₁₂ ,

Wherein X ₈ , X ₉ , X ₁₀ , X ₁₁ and X ₁₂ are each independently selected from the group consisting of hydrogen, lower alkyl, aryl and heteroaryl;

Ⅶ) formula - (X _{13) n13} alkoxy of -OX _14,

Wherein X ₁₃ is selected from the group consisting of lower alkylene, lower alkenylene, lower alkynylene, aryl and heteroaryl;

X ₁₄ is selected from the group consisting of hydrogen, lower alkyl, aryl and heteroaryl;

n13 is 0 or 1;

Iii) halogen or perhaloalkyl;

Iii) cyano;

Iii) nitro;

xi) amino of the formula-(X ₁₅ ) _n15 -NX ₁₆ X ₁₇ ,

Wherein X ₁₅ is selected from the group consisting of lower alkylene, lower alkenylene, lower alkynylene, aryl and heteroaryl;

X ₁₆ and X ₁₇ are each independently selected from the group consisting of hydrogen, lower alkyl, aryl and heteroaryl; Or X ₁₆ and X ₁₇ are taken together with the nitrogen to which they are attached and are a 5- or 6-membered heteroaromatic or heteroaliphatic ring; And

n15 is 0 or 1;

xii) a substituent of the formula-(X ₁₈ ) _n18 -C (= E) -X ₁₉ ,

Wherein X ₁₈ is selected from the group consisting of lower alkylene, lower alkenylene, lower alkynylene, aryl and heteroaryl;

E is selected from the group consisting of oxygen, sulfur and -NR _101- , wherein R ₁₀₁ is selected from the group consisting of hydrogen hydrogen, lower alkyl, lower alkene, lower alkyne, aryl and heteroaryl;

X ₁₉ is selected from the group consisting of hydrogen, lower alkyl, aryl, heteroaryl, amino and -NX ₂₀ X ₂₁ ,

Wherein X ₂₀ and X ₂₁ are independently selected from the group consisting of hydrogen, alkyl, aryl and heteroaryl; And

n18 is 0 or 1;

xvi) thioether or thiol of the _formula- (X ₂₂ ) _{n22 -SX 23} ,

Wherein X ₂₂ is lower alkylene, lower alkenylene, lower alkynylene. Aryl and heteroaryl;

X ₂₃ is selected from the group consisting of hydrogen, lower alkyl, aryl and heteroaryl; And

n22 is 0 or 1;

b) R ₂₃ and R ₃₀ are each independently selected from the group consisting of the following;

Iii) hydrogen;

Ii) lower alkyl;

Iii) lower alkylene;

Iii) halogen or perhaloalkyl;

Ⅴ) alkoxy of the formula-(X ₁₃ ) _n13 -OX ₁₄ ,

Wherein X ₁₃ is selected from the group consisting of lower alkylene, lower alkenylene, lower alkynylene, allyl and heteroaryl;

X ₁₄ is selected from the group consisting of hydrogen, lower alkyl, aryl and heteroaryl; And

n13 is 0 or 1; And

Iii) a 5- or 6-membered heteroaryl ring or a 6-membered aryl or heteroaryl ring, optionally substituted with one or more substituents selected from the group consisting of:

A) optionally substituted C ₁ -C ₈ straight, branched, or cyclic saturated or unsaturated alkyl;

B) alkoxy of formula-(X ₁₃ ) _n13 -OX ₁₄ ,

Wherein X ₁₃ is selected from the group consisting of lower alkylene, lower alkenylene, lower alkynylene, aryl and heteroaryl;

X ₁₄ is selected from the group consisting of hydrogen, lower alkyl, aryl and heteroaryl; And

n13 is 0 or 1;

C) halogen or perhaloalkyl;

D) cyano;

E) nitro;

F) amino of the formula-(X ₁₅ ) _n15 -NX ₁₆ X ₁₇ ,

Wherein X ₁₅ is selected from the group consisting of lower alkylene, lower alkenylene, lower alkynylene, aryl and heteroaryl;

X ₁₆ and X ₁₇ are each independently selected from the group consisting of hydrogen, lower alkyl, aryl and heteroaryl; Or X ₁₆ and X ₁₇ are taken together with the nitrogen to which they are attached to form a 5- or 6-membered heteroaromatic or heteroaliphatic ring; And

n15 is 0 or 1;

G) a substituent of the _formula- (X ₁₈ ) _n18 -C (= E) -X ₁₉ ,

Wherein X ₁₈ is selected from the group consisting of lower alkylene, lower alkenylene, lower alkynylene, aryl and heteroaryl;

E is selected from the group consisting of oxygen, sulfur and -NR _101- , wherein R ₁₀₁ is selected from the group consisting of hydrogen hydrogen, lower alkyl, lower alkene, lower alkyne, aryl and heteroaryl;

X ₁₉ is selected from the group consisting of hydrogen, lower alkyl, aryl, heteroaryl, hydroxy, alkoxy, amino and -NX ₂₀ X ₂₁ ,

Wherein X ₂₀ and X ₂₁ are each independently selected from the group consisting of hydrogen, alkyl, aryl and heteroaryl;

n18 is 0 or 1; And

H) a thioether or thiol of the _formula- (X ₂₂ ) _{n22 -SX 23} ,

Wherein X ₂₂ is selected from the group consisting of lower alkylene, lower alkenylene, lower alkynylene, aryl and heteroaryl; And

X ₂₃ is selected from the group consisting of hydrogen, lower alkyl, aryl and heteroaryl,

n22 is 0 or 1; And

_{Amide of formula-} (X ₂₄ ) _n24 -NH-C (O) -X _{25 or-} (X ₂₆ ) _n26 -C (O) -NH-X ₂₇ ,

Wherein X ₂₄ and X ₂₆ are each independently selected from the group consisting of lower alkylene, lower alkenylene, lower alkynylene, aryl and heteroaryl;

X ₂₅ is selected from the group consisting of hydrogen, lower alkyl, lower alkenyl, aryl, heteroaryl, hydroxy, alkoxy and amide; And

X ₂₇ is selected from the group consisting of hydrogen, lower alkyl, lower alkenyl, aryl and heteroaryl; and

c) R ₂₄ , R ₂₅ , R ₃₁ and R ₃₂ are each independently selected from the group consisting of

Iii) a 6-membered aromatic or heteroaromatic, 5- or 6-membered heteroaromatic ring, optionally substituted with one or more substituents selected from the group consisting of lower alkyl, hydroxy, alkoxy, amino and nitro;

Ii) acyl of the formula-(X ₁ ) _{n 1} -C (O) -X ₂ ,

Wherein X ₁ is selected from the group consisting of lower alkylene, lower alkenylene, lower alkynylene, aryl and heteroaryl;

X ₂ is selected from the group consisting of hydrogen, lower alkyl, aryl, heteroaryl, hydroxy, alkoxy, amino and -NH-X ₃ ;

Wherein X ₃ is selected from the group consisting of hydrogen, alkyl, aryl, heteroaryl, amino and amide; And

n1 is 0 or 1;

Iv) a substituent of formula -C (X ₄ ) = N-NX ₅ -C (= E) -NX ₆ X ₇ or a formula -C (X ₄ ) = NN = C (EX ₅ ) -NX ₆ X ₇ ,

Wherein X ₄ is selected from the group consisting of hydrogen, lower alkyl, aryl, alkaryl, heteroaryl and amino;

E is selected from the group consisting of oxygen, sulfur and -NR _101- , wherein R ₁₀₁ is selected from the group consisting of hydrogen hydrogen, lower alkyl, lower alkene, lower alkyne, aryl and heteroaryl; And

X ₅ , X ₆ and X ₇ are each independently selected from the group consisting of hydrogen, lower alkyl, aryl and heteroaryl;

Provided that any of R ₂₄ , R ₂₅ , R ₃₁ or R ₃₂ is -C ₆ H ₅ , -C (0) H, -C (O) CH ₃ , -C (O) -C ₆ H ₅ , -C (O) NH ₂ , or -C ₆ H ₄ CH ₃ .

In a forty-first embodiment, the present invention relates to a compound of a forty-fourth embodiment, wherein R ₂₄ , R ₂₅ , R ₃₁ and R ₃₂ are each independently selected from the group consisting of the following.

Iii) hydrogen;

Ii) 6-membered aromatic ring, which is optionally substituted with one or more substituents selected from the group consisting of lower alkyl, hydroxy and amine;

Iii) a six-membered heteroaromatic ring, which is optionally substituted with one or more substituents selected from the group consisting of lower alkyl, hydroxy, alkoxy, amino, and nitro;

Iii) a 5-membered heteroaromatic ring, which is optionally substituted with one or more substituents selected from the group consisting of lower alkyl, hydroxy and amine;

아) acyl of the formula-(X ₁ ) _{n 1} -C (O) -X ₂ ,

Wherein X ₁ is lower alkylene or lower alkenylene;

X ₂ is selected from the group consisting of hydrogen, amino, hydroxy and -NH-X ₃ ,

Wherein X ₃ is selected from the group consisting of hydrogen, lower alkyl, amino and amide;

n1 is 0 or 1;

Iv) a substituent of the formula -C (X ₄ ) = N-NH-C (= E) -NX ₆ X ₇ or a formula -C (X ₄ ) = NN = C (EX ₅ ) -NX ₆ X ₇ ,

Wherein X ₄ is selected from the group consisting of hydrogen, lower alkyl, aryl and alkaryl;

E is selected from the group consisting of oxygen, sulfur and —NR ₁₀₁ —, where R ₁₀₁ is selected from the group consisting of hydrogen hydrogen, lower alkyl, lower alkene, lower alkyne, aryl and heteroaryl; And

X ₅ , X ₆ and X ₇ are each independently selected from the group consisting of hydrogen and lower alkyl.

In a forty-second embodiment, the present invention relates to the compound of the forty-fourth embodiment, wherein R ₂₄ , R ₂₅ , R ₃₁ , and R ₃₂ are each independently selected from the group consisting of

Iii) hydrogen;

Ii) phenyl, which is optionally substituted with one or more hydroxy or -NH ₂ ;

Iii) a 6-membered heteroaromatic ring selected from the group consisting of pyridine, pyrazine, pyridazine, pyrimidine and 1,3,5-triazine, each independently and optionally with lower alkyl, hydroxy, alkoxy and amino Substituted with one or more substituents selected from the group consisting of;

Iii) 5-membered heteroaromatic rings selected from the group consisting of pyrrole, imidazole, 1,2,3-triazole, 1,2,4-triazole, tetrazole, thiophene, thiazole, and thiadiazole, which are Each independently and optionally hydroxy, an amide of the _formula- (X ₂₄ ) _n24 -NH-C (O) -X _{25 or-} (X ₂₆ ) _n26 -C (O) -NH-X ₂₇ , and -NH ₂ Substituted with one or more substituents selected from the group consisting of;

Iii) acyl of the formula -C (O) -X ₂ , wherein X ₂ is hydrogen or lower alkyl;

아) acyl of formula -X ₁ -C (O) -X ₂ ,

Wherein X ₁ is lower alkylene or lower alkenylene; And

X ₂ is -NH-X ₃ , wherein X ₃ is selected from the group consisting of hydrogen, amino and amide;

Iv) a substituent of the formula -C (X ₄ ) = N-NH-C (= E) -NH ₂ ,

Wherein X ₄ is selected from the group consisting of hydrogen, methyl, ethyl, phenyl and -CH ₂ CH ₂ -Ph; And

E is oxygen, sulfur, and -NR ₁₀₁ - it is selected from the group consisting of wherein R is hydrogen _1O1 hydrogen, lower alkyl, lower alkenyl, lower alkynyl, aryl, and is selected from the group consisting of-heteroaryl; And

Iv) a substituent of the formula -C (X ₄ ) = NN = C (SX ₅ ) -NH ₂ ,

Wherein X ₄ is selected from the group consisting of hydrogen, methyl, ethyl, phenyl and -CH ₂ CH ₂ -Ph;

X ₅ is hydrogen or methyl.

In a forty-third example, the present invention provides the above, wherein the 5- or 6-membered heteroaryl ring at R ₂₄ , R ₂₅ , R ₃₁ , and R ₃₂ is optionally substituted , Optionally substituted , And optionally substituted And V, W, X, Y and Z are each independently CR or nitrogen, U is selected from the group consisting of CR ₂ , oxygen, sulfur and NR, wherein R is hydrogen, alkyl or The compound of Example 40 is selected from the group consisting of aryl.

In a forty-fourth embodiment, the present invention provides that the heteroaryl ring is a furan, thiophene, pyrrole, pyrroline, pyrrolidine, oxazole, thiazole, imidazole, imidazoline, imidazolidine, pyrazole, Pyrazoline, pyrazolidine, isosazole, isothiazole, triazole, thiadiazole, oxadiazole, pyran, pyridine, piperidine, morpholine, thiomorpholine, pyridazine, pyrimidine, pyrazine, piperazine, And triazine, the compound of the forty th example.

In a 45 th embodiment, the invention provides that the heteroaryl ring is aminofuran, aminothiophene, aminopyrrole, aminopyrroline, aminopyrrolidine, aminooxazole, aminothiazole, aminoimidazole, aminoimidazoline , Aminoimidazolidine, aminopyrazole, aminopyrazoline, aminopyrazolidine, aminoisoxazole, aminoisothiazole, aminotriazole, aminothiadiazole, aminooxadiazole, aminopyran, aminopyridine, amino The compound of Example 44 is selected from the group consisting of piperidine, aminomorpholine, aminothiomorpholine, aminopyridazine, aminopyrimidine, aminopyrazine, aminopiperazine, and aminotriazine.

In a forty sixth embodiment, the invention provides that R ₂₄ , R ₂₅ , R ₃₁ and R ₃₂ are hydrogen, —C (O) —CH ₃ , —C (O) —NH—CH ₂ —C (O) —NH ₂ , -CH = CH = C (O) -NH ₂ , -CH ₂ CH ₂ -C (O) -NH-NH ₂ , -C (H) = N-NH-C (O) -NH ₂ ,- C (CH ₃ ) = N-NH-C (O) -NH ₂ , -C (H) = N-NH-C (S) -NH ₂ , -C (CH ₃ ) = N-NH-C (S ) -NH ₂ , -C (Ph) = N-NH-C (S) -NH ₂ , -C (CH ₂ CH ₂ Ph) = N-NH-C (S) -NH ₂ , -C (H) = NN = C (SCH ₃ ) -NH ₂ , , , , , , , , , , , , , , , , , , , , And Selected from the group consisting of R, wherein R is selected from the group consisting of hydrogen, alkyl and aryl.

In a forty-ninth example, the present invention relates to the compound of the fortyth example, wherein R ₂₃ and R ₃₀ are each independently selected from the group consisting of

Iii) hydrogen;

Ii) C ₂ -C ₆ alkenylene;

Iii) halogen or perhaloalkyl;

Iii) alkoxy of formula -OX ₁₄ ,

Wherein X ₁₄ is selected from the group consisting of hydrogen, lower alkyl and aryl; And

Iii) a 5-membered or 6-membered heteroaryl ring, or a 6-membered aryl or heteroaryl ring optionally substituted with one or more substituents selected from the group consisting of

A) optionally substituted C ₁ -C ₄ straight, branched or cyclic saturated or unsaturated alkyl;

B) alkoxy of formula -OX ₁₄ , wherein X ₁₄ is hydrogen or lower alkyl;

C) halogen or perhaloalkyl;

D) cyano;

E) nitro;

F) a substituent of the _formula- (X ₁₈ ) _{n 18} -C (O) -X ₁₉ ,

Wherein X ₁₈ is lower alkylene;

X ₁₉ is selected from the group consisting of hydrogen, lower alkyl, aryl, heteroaryl, hydroxy, alkoxy, amino and -NX ₂₀ X ₂₁ ,

Wherein X ₂₀ and X ₂₁ are each independently selected from the group consisting of hydrogen, alkyl and aryl; And

n18 is 0 or 1;

G) a thioether or thiol of the formula -SX ₂₃ , wherein X ₂₃ is selected from the group consisting of hydrogen, lower alkyl, aryl and heteroaryl; And

H) an amide of _formula- (X ₂₄ ) _n24 -NH-C (O) -X _{25 or-} (X ₂₆ ) _n26 -C (O) -NH-X ₂₇ ,

Wherein X ₂₄ and X ₂₆ are each independently lower alkylene; X ₂₅ is selected from the group consisting of hydrogen, lower alkyl, aryl, hydroxy and alkoxy;

X ₂₇ is selected from the group consisting of hydrogen, lower alkyl, aryl and heteroaryl.

In a forty-eighth embodiment, the present invention relates to the compound of the forty-eighth embodiment, wherein R ₂₃ and R ₃₀ are selected from the group consisting of

Iii) hydrogen;

Ii) C ₂ -C ₆ alkylene;

Iii) halogen or perfluoroalkyl;

Iii) alkoxy of formula -OX ₁₄ ,

Wherein X ₁₄ is selected from the group consisting of hydrogen, methyl, ethyl and propyl;

Iii) 6-membered aryl ring, which is optionally substituted with one or more substituents selected from the group consisting of:

A) methyl, ethyl and propyl;

B) hydroxy, methoxy, ethoxy, phenoxy, hydroxymethyl, 2-hydroxyethyl and 3-hydroxypropyl;

C) halogen or perfluoroalkyl;

D) cyano;

E) nitro;

F) a substituent of the formula -C (O) -X ₁₉ ,

Wherein X ₁₉ is hydrogen, methyl, ethyl, propyl, phenyl, hydroxy, methoxy, ethoxy, propoxy, amino and -NX ₂₀ X ₂₁ ,

Wherein X ₂₀ and X ₂₁ are each independently selected from the group consisting of hydrogen, methyl, ethyl, propyl and phenyl;

Thioether or thiol of G) -SX ₂₃ , wherein X ₂₃ is selected from the group consisting of hydrogen, methyl, ethyl, propyl and phenyl;

H) an amide of _formula- (X ₂₄ ) _n24 -NH-C (O) -X _{25 or-} (X ₂₆ ) _n26 -C (O) -NH-X ₂₇ ,

Wherein X ₂₄ and X ₂₆ are each independently lower alkylene;

X ₂₅ is selected from the group consisting of hydrogen, methyl, ethyl, propyl, phenyl, hydroxy, methoxy and phenoxy; And

X ₂₇ is selected from the group consisting of hydrogen, methyl, ethyl, propyl and phenyl.

In a 49th embodiment, the present invention relates to a compound wherein the 5- or 6-membered heteroaryl ring of R ₂₃ and R ₃₀ or the 6-membered aryl or heteroaryl is optionally substituted , Optionally substituted , And optionally substituted Is selected from the group consisting of W, X, Y and Z are each independently CR or nitrogen, and U is selected from the group consisting of CR ₂ , oxygen, sulfur and NR; Wherein R is directed to the compound of example 40, selected from the group consisting of hydrogen, alkyl and aryl.

In a fiftyth embodiment, the present invention provides that the 5- or 6-membered heteroaryl ring of R ₂₃ and R ₃₀ or the 6-membered aryl or heteroaryl is selected from the group consisting of phenyl, furan, thiophene, pyrrole, pyrroline, Pyrrolidine, oxazole, thiazole, imidazole, imidazoline, imidazolidine, pyrazole, pyrazoline, pyrazolidine, isosazole, isothiazole, triazole, thiadiazole, pyran, pyridine, The compound of Example 40 is selected from the group consisting of piperidine, morpholine, thiomorpholine, pyridazine, pyrimidine, pyrazine, piperazine and triazine.

In a 51 st embodiment, the present invention provides that R ₂₃ and R ₃₀ are each independently hydrogen, chlorine, bromine, hydroxy, —CH═CH—CH ₂ CH ₂ CH ₂ CH ₃ , —CH═CH—C (O ) -OH, -CH = CH-C (O) -OCH ₃ , -CH = CH-C (O) -NH ₂ , -CH ₂ CH (NH ₂ ) COOH, phenyl, -O-CH ₂ -phenyl, 2-methylphenyl, 3-methylphenyl, 2-methylthiophenyl, 3-methylthiopetyl, 4-methylthiophenyl, 4-methylphenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 2 -Hydroxyphenyl, 3-hydroxyphenyl, 4-hydroxyphenyl, 2-hydroxymethylphenyl, 3-hydroxymethylphenyl, 4-hydroxymethylphenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluoro Rophenyl, 2-cyanophenyl, 3-cyanophenyl, 4-cyanophenyl, 2-nitrophenyl, 3-nitrophenyl, 4-nitrophenyl, 2-hydroxycarbonylphenyl, 3-hydroxycarbonyl Phenyl, 4-hydroxycarbonylphenyl, 2-methoxycarbonylphenyl, 3-methoxycarbonylphenyl, 4-methoxycarbonylphenyl, 2-trifluoromethylpetyl, 4-benzyloxyfe , 2-phenoxyphenyl, 2,4-dihydroxyphenyl, 3,4-dihydroxyphenyl, 2-hydroxy-4-methoxyphenyl, 4-hydroxy-2-methoxyphenyl, 2,4 Dimethoxyphenyl, 3,4-dimethoxyphenyl, 3-fluoro-4-hydroxyphenyl, 3-fluoro-4-methoxyphenyl, , , , , , , 2-pyridyl, 3-pyridyl, 4-pyridyl, , , , , , , , , , , , , And Selected from the group consisting of R, wherein R is selected from the group consisting of hydrogen, alkyl and aryl.

In a fifty-second embodiment, the present invention relates to a compound selected from the group consisting of the compounds set forth in Table 1, or a pharmaceutically acceptable salt, ester, amide or prodrug thereof.

In a 53rd embodiment, the invention relates to a compound of any one of the 1st, 2nd, 28th, 40th or 52th embodiments, wherein said compound may inhibit the catalytic activity of a protein kinase.

In a 54th embodiment, the invention relates to the compound of embodiment 53, wherein said protein kinase is selected from the group consisting of receptor protein tyrosine kinases, cellular tyrosine kinases and serine-threonine kinases.

In a 55th embodiment, the invention relates to the compound of embodiment 53, wherein the protein kinase is a cyclin dependent kinase.

In a fifty sixth embodiment, the invention relates to a compound of the fifty-fifth embodiment, wherein the cyclin dependent kinase is selected from the group consisting of CDK1 (CDC2), CDK2, CDK3, CDK4, CDK5, CDK6, CDK7, CDK8 and CDK9 .

In a 57th embodiment, the invention relates to the compound of the 55th embodiment, wherein said cyclin dependent kinase is selected from the group consisting of CDK2 and CDK5.

In a 58th embodiment, the present invention, the protein kinase is a group consisting of protein kinase C, MEK1, MAP kinase, EGF receptor, PDGF receptor, IGF receptor, her2, raf1, PI3 kinase, wheel kinase, Src and Abl It relates to a compound of the 54th example, selected from.

In a 59th embodiment, the present invention comprises intracellularly contacting the protein kinase with a compound according to any one of the 1st, 2nd, 17th, 28th, 40th, or 52nd example The present invention relates to a method for adjusting a signal transmission path in.

In a sixtieth embodiment, the present invention comprises intracellularly contacting the cells with a compound according to any one of the first, second, seventeenth, twenty-eighth, forty-second, or fifty-second embodiment. The present invention relates to a method for adjusting a signal transduction pathway.

In a sixty sixth embodiment, the cells are directed to the method of embodiment 60, wherein the cells express a protein kinase and the compounds modulate the function of the protein kinase.

In a sixty-second embodiment, the present invention,

a) contacting cells expressing said protein kinase with a compound according to any one of the first, second, seventeenth, twenty-eighth, forty-second, or fifty-second embodiment; And

b) monitoring the effect of the compound on the cells;

It relates to a method for identifying an aromatic compound consisting of, comprising, regulating the function of a protein kinase.

In a sixty-third embodiment, the present invention is directed to a method wherein said effect consists of a change in cell phenotype, a change in cell proliferation, a change in catalytic activity of said protein kinase, and a change in interaction between said protein kinase and a binding partner. The method of the sixty-second embodiment, selected from the group.

In a sixtieth embodiment, the present invention comprises administering to a subject a pharmacologically effective amount of a compound according to any one of the first, second, seventeenth, twenty-eighth, forty-second, or fifty-second embodiment, A method of modulating unregulated kinase signal transduction.

In a sixty-ninth embodiment, the present invention relates to an embodiment of the invention, wherein unregulated kinase signal transduction causes a disease or an abnormal condition in an organism and the method leads to the treatment or prevention of the disease or abnormal condition;

The disease or abnormal condition is associated with an abnormality in the signal transduction pathway characterized by the interaction between the protein kinase and the binding partner;

The method relates to the method of embodiment 64, further comprising the step of facilitating or preventing the abnormal interaction.

In a sixty sixth embodiment, the invention provides a disease wherein the disease or abnormal condition is selected from the group consisting of cell proliferative diseases, cerebrovascular injury, autoimmune diseases, degenerative neurological diseases, degenerative diseases of the musculoskeletal system. The method of the first embodiment relates.

In a sixty seventh embodiment, the present invention relates to an embodiment of the present invention, wherein the degenerative neurological diseases include AIDS-related dementia, Alzheimer's disease, Parkinson's disease, Pick's disease, Huntington's disease, diffuse Lewy body disease, multiple system atrophy, amyotrophic lateral sclerosis, Down syndrome-related dementia, Cerebrovascular dementia, canine motor degeneration, retinitis pigmentosa, myelodysplastic atrophy, myelodysplastic syndrome, stroke and repulfusion damage, aplastic anemia, myocardial infarction related ischemia, arrhythmia, atherosclerosis, toxin-induced or alcohol-related diseases, The method of Example 66, which is selected from the group consisting of hematological diseases including chronic anemia and aplastic anemia, and cerebrovascular degeneration.

In a sixty eighth embodiment, the invention relates to the method of the sixty sixth embodiment, wherein the cerebrovascular injury is selected from the group consisting of cerebrovascular dementia, stroke, cerebral infarction, and head trauma.

In a sixty-ninth embodiment, the present invention relates to a system wherein the autoimmune disease is characterized by systemic lupus, hertematosus, autoimmune mediated gluteruropritis, rheumatoid arthritis, psoriasis, inflammatory bowel disease, autoimmune diabetes, and HIV-infection. The method of embodiment 66, selected from the group consisting of the occurrence of AIDS in an individual.

In a seventieth embodiment, the present invention provides AIDS-related dementia, Alzheimer's disease, Parkinson's disease, Pick's disease, Huntington's disease, diffuse Lewy body disease, multiple system atrophy, Amyotrophic lateral sclerosis, Down syndrome related dementia, cerebrovascular dementia, and The method of Example 66, selected from the group consisting of dementia including Canine Motor Neuron disease, retinal pigment degeneration, myelodystrophic atrophy, myelodysplastic syndrome, and cerebrovascular degeneration.

In the 71st embodiment, the present invention, the degenerative disease is selected from the group consisting of osteoporosis, arthritis, aspirin-sensitive rhinosinusitis, cystic fibrosis, multiple sclerosis, kidney disease, chemotherapy-induced hair loss, baldness, cancer pain, and the like, It relates to the method of the 66th embodiment.

In a seventy-second embodiment, the present invention, the cell proliferative disease,

Breast, lung, colon, kidney, liver, prostate, stomach, esophagus, gallbladder, ovary, pancreas, cervix, bladder, thyroid cartilage, carcinoma of the skin, and squamous cell carcinoma;

Hematopoietic tumors of the bone marrow selected from the group consisting of acute and chronic leukemia, prosthetic leukemia, and myelodysplastic syndromes;

Hematopoietic tumors of lymphoid cells selected from the group consisting of B-cell lymphoma, T-cell lymphoma, Hodgkin lymphoma, non-Hodgkin lymphoma, hair cell lymphoma, Burkett lymphoma, leukemia, acute lymphocytic leukemia, and acute lymphoblastic leukemia;

Tumors of mesenchymal organ selected from the group consisting of fibrosarcoma and rhabdomyosarcoma;

Tumors of the central and peripheral nervous system selected from the group consisting of neuroblastoma, astrocytoma, glioma and schwannoma;

Karposi sarcoma, melanoma, intestinal mesothelioma, teratocarcinoma, pigmentary dry skin disease, osteosarcoma, keratoktanoma, and thyroid vesicle cancer;

And the method of the sixtieth embodiment, selected from the group consisting of;

In a seventy-third embodiment, the present invention relates to a method in which the cell proliferative disease is benign prostatic hyperplasia, hereditary adenomatous polyposis, myofioma, atherosclerosis, pulmonary fibrosis, arthritis, psoriasis, glomerulonephritis, angioplasty or angioplasty after angioplasty, The method of Example 66, selected from the group consisting of hypertrophic scar formation, infectious bowel disease, transplant rejection, endotoxin shock, fungal infection, and the like.

In a 74th embodiment, the present invention,

i) a pharmaceutically acceptable carrier, diluent, or excipient, or combination thereof; And

ii) a compound according to any one of the first, second, seventeenth, 28th, 40th, or 52nd examples;

It relates to a pharmaceutical composition consisting of.

EXAMPLE

The following examples are merely representative of various aspects of the invention and are not limiting.

Synthesis of Compounds of the Invention

Example 1: General courses

General Course A: Semicarbazone / thiosemicarbazone formation (Mishra, B., Ali, R., J. Indian Chem. Soc ., 1989, 66 , 813-814):

One equivalent of aldehyde and 1.05 equivalent of thiosemicarbazide or semicarbazide hydrochloride are dissolved in N, N-dimethylformamide at a final concentration of 0.5 M. Trace amounts of camphorsulfonic acid are added and the reaction is stirred at room temperature for 2-18 hours. When the reaction is complete as determined by thin layer chromatography, the solvent is removed in vacuo and the product is washed six times with diethyl ether and dried in vacuo. The reaction yield was in the range of 90-100%.

General Course B: Biphenyl aldehydes and ketones:

These compounds were prepared via Suzuki reaction (Miyaura, N .; Suzuki, A., Chem. Rev. 1995, 95 , 2457-2483). In this reaction, 1 equivalent of arylbromide, 1.05 equivalent of arylboronic acid, and 0.02 equivalent of tetrakis (triphenylphosphine) palladium are dissolved in ethylene glycol dimethyl ether to produce a final concentration of 0.2-0.3 M. To this mixture, 2.5 equivalents of 2.0 M aqueous sodium carbonate solution are added and the mixture is heated to reflux under nitrogen for 2-16 hours. The mixture is then cooled to room temperature and partitioned between dichloromethane and water. The organic layer is washed back with saturated sodium chloride solution, filtered and concentrated. The obtained product was purified by column chromatography.

General Course C: Dimethylation (Vickery, E. H., Pahler, L. F., Eisenbraun, E. J., J. Org. Chem ., 1979, 44 , 4444):

One equivalent of methoxy substituted phenol is dissolved in dichloromethane and stirred at −78 ° C. under nitrogen. To this solution, 10 equivalents of boron triboramide are slowly added. The solution mixture is stirred at −78 ° C. for 15 minutes and then at room temperature for 8 hours. The reaction mixture is cooled to 0 ° C., 1/4 volume diethyl ether is carefully added and then saturated sodium dicarbonate solution is added until the mixture becomes base as measured by litmus paper. The resulting mixture is extracted with 6 parts of 4: 1 dichloromethane: methanol. The combined organic layers are dried over sodium sulphate, filtered and concentrated. The product is purified by preparative thin layer chromatography.

General Course D: Heck reaction (Zebovitz, T.C .; Heck, R.F. J. Org. Chem , 1997, 42 , 3907-3909):

A mixture of 0.0011 g (0.005 mmol) palladium acetate, 0.026 g (0.1 mmol) tri-o-toluylphosphine, 1.52 g (10 mmol) arylbromide, 11 mmol acrylate / acrylamide and 21 mmol triethylamine Heat at 15 ° C. After cooling, the reaction mixture was acidified with 0.1 M citric acid solution and extracted three or four times with ethyl acetate. The combined organic layers were dried over sodium sulphate, filtered and concentrated. The product was purified by column chromatography.

General Course E: Vilsmeier Formylation (Krishna-Rao, G. S., J. Org. Chem , 1981, 46 , 5371):

Corresponding hydroxy naphthalene is combined with 5 equivalents of N, N-dimethylformamide and the mixture is treated with 1.5 equivalents of POCl ₃ . The solid formed is dissolved and extracted with ethyl acetate and water. The organic phase is washed with sodium bicarbonate (10% aq.) And dried over sodium sulphate. Removal of the solvent gives a crude product which is purified on a silica-gel flash column using methylene chloride-methanol (1%) to give the desired aldehyde.

General Course F:

1 equivalent of aldehyde and 1.05 equivalent of thiosemicarbazide or semicarbazide hydrochloride obtained in General Procedure E are dissolved in N, N-dimethylformamide at a final concentration of 0.5 M. Trace amounts of camphorsulfonic acid are added and the reaction is stirred at room temperature for 2-18 hours. When the reaction is complete as determined by thin layer chromatography, the solvent is removed in vacuo and the product is washed six times with diethyl ether and dried in vacuo.

General Course G: Suzuki Reaction:

Biphenyl aldehyde and ketone were prepared via Suzuki Reaction ((Miyaura, N .; Suzuki, A. Chem. Rev. 1995, 95 , 2457-2483). In this reaction, 1 equivalent of aryl bromide, 1.05 equivalents Boronic acid or boronate, and 0.02 equivalent of tetrakis (triphenylphosphine) palladium are dissolved in ethylene glycol dimethyl ether to produce a final concentration of 0.2-0.3 M. In this mixture, 2.0 M aqueous solution of sodium carbonate 2.5 Equivalent weight is added and the mixture is heated to reflux under nitrogen for 2-16 hours, then the mixture is cooled to room temperature and partitioned between dichloromethane and water The organic layer is washed countercurrent with saturated sodium chloride solution and sodium Dry over sulphate, filter and concentrate The resulting product was purified by column chromatography to give 30-95% yield.

General Course H: Suzuki Reaction:

4,4'-dibenzyloxy-3-biphenylboronic acid or 4,4'-dimethoxymethylether-3-biphenyl-boronic acid (1 mmol), corresponding arylchloride or aryl bromide (1 mmol), Pd (PPh ₃ ) ₄ (0.03 mmol) and cesium fluoride (3 mmol, 1 M solution in degassed water) were dissolved in ethylene glycol dimethyl ether (30 ml) and heated to reflux overnight under nitrogen. The mixture was cooled, poured into cold water and extracted with CH ₂ Cl ₂ (3 × 50 ml). The combined organic layers were washed with water and saturated sodium chloride solution and dried over Na ₂ SO ₄ to vaporize the solvent. The residue was purified by column chromatography on silica gel (15 × 1 cm) and dissolved by hexanes: ethyl acetate to give a white product.

General Course I: Hydrogenation

The solution in THF: MeOH (1: 3) of the dibenzyloxybiphenyl product obtained in General Procedure H was stirred at room temperature for 4 hours in a hydrogen atmosphere in the presence of 10% Pd / C. The catalyst was filtered through celite and the filtrate was dried in vacuo. The residue was purified by column chromatography on silica gel (3 × 20 cm), which was dissolved by separating with CH ₂ Cl ₂ : MeOH (9: 1).

General Course J: Splitting of methoxymethyl ether (MOM) or methoxyethyl ether (MEM) (Corey, E. J., Danheiser, R. L., J. Am. Chem. Soc, 1978, 100, 8031);

One equivalent of disubstituted methoxymethyl phenyl is dissolved in dichloromethane (˜0.04 M) and stirred. To this solution, 8 equivalents of triethylsilane are added followed by trifluoroacetic acid (TFA) (10%). The reaction solution is stirred at room temperature for 5 hours and then dried under vacuum. The solid mixture obtained is treated with saturated sodium bicarbonate solution and extracted several times with 4: 1 dichloromethane: methanol. The combined organic layer is dried over sodium sulfate, filtered and concentrated. The product is purified by chromatography.

General Course K: Amidation:

A chloropyrimidine derivative (1 mmol) was heated at 120 ° C. overnight with 1.3 equivalents of amine and 4 equivalents of triethylamine in 5 ml n-butanol. No further purification was followed by General Procedure J, and the resulting mixture was treated with TFA.

General course L: Deprotection of methoxy groups:

One equivalent of methoxy substituted phenol is dissolved in dichloromethane (˜0.04 M) and stirred under nitrogen atmosphere at −78 ° C. To this solution, 10 equivalents of boron tribromide are slowly added. The reaction mixture is stirred at −78 ° C. for 15 minutes and then at room temperature for 8 hours. The reaction mixture is cooled to 0 ° C. and 1/4 volume diethyl ether is carefully added and saturated sodium dicarbonate solution is added until the mixture becomes base as measured by litmus paper. The resulting mixture is extracted with 6 parts of 4: 1 dichloromethane: methanol. The combined organic layers are dried over sodium sulphate, filtered and concentrated. The product is purified by preparative thin layer chromatography.

General course M: 4- [4- (2-methoxy-ethoxymethoxy) -3- (4,4,5,5-tetramethyl- [1,3,2] -dioxaborolan-2-yl-phenyl ]-Suzuki Reaction starting from pyrimidin-2-ylamine (Scheme 8)

1- (3-Bromo-4-hydroxy-phenyl) -ethanone

A 4-hydroxyacetophenone (13.6 g, 0.1 mol) solution of 65% acetic acid was treated with bromine (5.1 ml, 0.1 mol) dissolved in 80% acetic acid (50 ml) at room temperature. After addition of bromine, the solution was further stirred for 30 minutes at room temperature and poured into 200 ml of cold water. The by-product formed was filtered off and the filtrate was further diluted with 1 L of cold water. The white precipitate formed was filtered off, washed several times with water and dried in vacuo. Yield: (10.4 g, 35%).

¹ H NMR (CDCl 3) 2.57 (s, 3H), 6.46 (s, 1H), 7.08 (d, 1H), 7.85 (d, 1H), 8.21 (s, 1H).

MS 216 (M + H), C 8 H 7 O 2 Br

1- [3-Bromo-4- (2-methoxy-ethoxymethoxy) -phenyl] -ethanone

A solution of 1- (3-bromo-4-hydroxy-phenyl) -ethanone (15.5 g, 72.1 mmol) in anhydrous ether (100 ml) was dissolved in a NaH suspension (60% 3.46 g in mineral oil, under nitrogen at room temperature, 86.5 mmol). The suspension was stirred for 2 hours, then treated with MOM-Cl (2-methoxyethoxymethyl chloride, 9.86 ml, 86.5 mmol) and further stirred under nitrogen at room temperature for 1 hour. The solution was cooled to 0 ° C., treated with cold water and extracted with ether. The combined organic layers were washed successively with saturated NaHCO ₃ solution, water, and brine, then dried over Na ₂ SO ₄ and concentrated in vacuo to give a yellow oil (21.64 g, 99%).

¹ H NMR (CDCl 3) 2.56 (s, 3H), 2.96 (s, 3H), 3.56 (t, 2H), 3.82 (t, 2H), 4.42 (s, 2H), 7.25 (d, 1H), 7.86 ( d, 1 H), 8.17 (s, 1 H).

MS 304 (M + H), C ₁₂ H ₁₅ O ₄ Br

4- [3-Bromo-4- (2-methoxy-ethoxymethoxy) -phenyl] -pyrimidin-2-ylamine

N, N'-dimethylformamide diethylacetal (183 ml, 1069 mmol) of 1- [3-bromo-4- (2-methoxy-ethoxymethoxy) -phenyl] -ethanone (21.6 g, 71.28 mmol) solution was heated to reflux for 24 h and evaporated in vacuo to give a red oil. This oil was dissolved in ethanol (180 ml) and treated with sodium ethoxide (19.40 g, 285.28 mmol) and guanidine hydrochloride (10.21 g, 107 mmol) and heated to reflux overnight. The cooled solution was diluted with water, extracted with CH ₂ Cl ₂ , and the combined organic layers were concentrated to give a red viscous oil. The crude product was further purified by flash chromatography, which was dissolved in 0-5% MeOH with CH ₂ Cl ₂ and separated to give pale yellow crystals (12.5 g, 49%).

¹ H NMR (d ₆ -DMSO) 3.21 (s, 3H), 3.39 (t, 2H), 3.77 (t, 2H), 5.43 (s, 2H), 6.70 (s, 2H), 7.14 (d, 1H) , 7.33 (d, 1 H), 8.03 (dd, 1 H), 8.26 (d, 1 H), 8.35 (s, 1 H).

MS 355 (M + H), C ₁₄ H ₁₆ O ₃ N ₃ Br

4- [4- (2-methoxy-ethoxymethoxy) -3- (4,4,5,5-tetramethyl- [1,3,2] -dioxaborolan-2-yl-phenyl ] -Pyrimidin-2-ylamine

4- [3-bromo-4- (2-methoxy-ethoxymethoxy) -phenyl] -pyrimidin-2-ylamine (6.2 g, 17.65 mmol) in anhydrous DMF (125 ml), bis- ( A mixture of pinatorayto) diboron (4.93 g, 19.42 mmol), potassium acetate (5.197 g, 52.95 mmol) and Pd (dppf) Cl 2 was heated under nitrogen at 80 ° C. overnight. The cooled solution was partitioned between CH ₂ Cl ₂ and water. The combined organic phases were washed successively with water and brine, then dried over Na ₂ SO ₄ and concentrated. The crude product was purified by flash chromatography to give a yellow oil (this was kept at room temperature and solidified after a few days).

¹ H NMR (d ₆ -DMSO) 1.29 (s, 12H), 3.21 (s, 3H), 3.47 (t, 2H), 3.78 (t, 2H), 5.30 (s, 2H), 6.26 (s, 2H) , 7.04 (d, 1H), 7.16 (d, 1H), 8.08 (dd, 1H), 8.26 (d, 1H), 8.29 (s, 1H).

MS 402 (M + H), C ₂₀ H ₂₈ O ₅ N ₃ B.

Suzuki Reaction:

4- [4- (2-methoxy-ethoxymethoxy) -3- (4,4,5,5-tetramethyl- [1,3,2] -dioxaborolan-2-yl in DME -Phenyl] -pyrimidin-2-ylamine (1 mmol), heterocyclic arylbromide or chloride (1.5 mmol), aqueous 2N Na ₂ CO ₃ (2.5 ml) and Pd (PPh ₃ ) ₄ (40 mg) The mixture of was heated to reflux overnight and the solution was cooled, precipitated with water and extracted with CH ₂ Cl _{2. The} combined organic phases were washed successively with water and brine, then dried over Na ₂ SO ₄ and concentrated. The crude product was purified by flash chromatography, which was dissolved in 0.3% MeOH of CH ₂ Cl ₂ and separated to give a white solid.

Example 2: 5-bromosalicylaldehyde thiosemicarbazone

The title compound is prepared from 5-bromosalylsilaldehyde and thiosemicarbazide according to General Procedure A. Yields were calculated quantitatively.

¹ H NMR (d ₆ -DMSO): δ6.78 (d, 1H), 7.42 (dd, 1H), 8.144 (s, 1H), 8.26 (s, 1H), 10.16 (s, 1H), 11.36 (s , 1H).

MS 297 (M + Na), C ₈ H ₈ BrN ₃ OS.

Example 3: 5-bromosalicylaldehyde semicarbazone hydrochloride

The title compound is prepared from 5-bromosalicylaldehyde and semicarbazide hydrochloride according to General Procedure A. Yields were calculated quantitatively.

¹ H NMR (d ₆ -DMSO): δ6.78 (d, 1H), 7.42 (dd, 1H), 8.144 (s, 1H), 8.26 (s, 1H), 10.16 (s, 1H), 11.36 (s , 1H).

MS 297 (M + Na), C ₈ H ₈ BrN ₃ OS.

Example 4: 5-phenylsalicylaldehyde thiosemicarbazone

5-phenylsalicylaldehyde is prepared from 5-bromosalicylaldehyde and phenyl boronic acid according to General Procedure B. Yield 85%.

¹ H NMR (CDCl ₃ ): δ 7.08 (d, 1H), 7.26 (t, 1H), 7.52 (m, 2H), 7.68 (m, 2H), 7.82 (d, 2H), 10.04 (s, 1H ), 11.12 (s, 1 H).

The title compound is prepared from 5-phenylsalicylaldehyde and thiocarbazide according to General Procedure A. Yield is calculated quantitatively.

¹ H NMR (d6-DMSO): δ6.84 (d, 1H), 7.28 (t, 1H), 7.40 (t, 2H), 7.52 (d, 2H), 7.68 (d, 2H), 8.04 (d, 2H), 8.18 (s, 1H), 8.32 (s, 1H), 10.22 (s, 1H), 11.42 (s, 1H).

MS 272 (M + H), C ₁₄ H ₁₃ N ₃ OS.

Example 5: 5-phenylsalicylaldehyde semicarbazone hydrochloride

The title compound is made from 5-phenylsalicylaldehyde and semicarbazide hydrochloride, following General Procedure A. Yield was quantitative.

¹ H NMR (d ₆ -DMSO): δ 6.50 (br. 2H), 6.94 (d, 1H), 7.28 (t, 1H), 7.38 (t, 2H), 7.48 (d, 2H), 7.66 (d , 2H), 8.07 (s, 1H), 8.18 (s, 1H), 10.22 (s, 1H), 11.22 (s, 1H).

MS 256 (M + H), C ₁₄ H ₁₃ N ₃ O ₂ .

Example 6: 5- (3-methoxyphenyl) salicyaldehyde thiosemicarbazone

5- (3-methoxyphenyl) salicylaldehyde is prepared from 5-bromosalicylaldehyde and 3-methoxyphenyl boronic acid using the general procedure B.

The title compound is prepared from 5- (3-methoxyphenyl) salicylaldehyde and thiosemicarbazide according to General Procedure A.

¹ H NMR (d ₆ -DMSO) δ 3.81. (S, 3H) 6.87 (d, 1H) 6.94 (d, 1H) 7.18 (s, 1H) 7.25 (d, 1H) 7.33 (t, 1H) 7.54 (d , 1H) 8.14 (s, 2H) 8.22 (s, 1H) 8.41 (s, 1H) 10.11 (s, 1H) 11.41 (s, 1H).

MS (ESI +) 324 (M + Na) C ₁₅ H ₁₅ N ₃ O ₂ S

Example 7: 5- (3-cyanophenyl) salicyaldehyde thiosemicarbazone

5- (3-cyanophenyl) salicylaldehyde is prepared from 5-bromosalicylaldehyde and 3-cyanophenyl boronic acid using the general procedure B.

The title compound is prepared from 5- (3-cyanophenyl) salicylaldehyde and thiosemicarbazide according to General Procedure A.

¹ H NMR (d ₆ -DMSO) δ 6.98 (d, 1H) 7.62-7.65 (m, 2H) 7.76 (d, 1H) 8.05 (d, 1H) 8.16 (s, 1H) 8.19 (s, 1H) 8.22 ( s, 1 H) 8.35 (s, 1 H) 8.41 (s, 1 H) 10.28 (s, 1 H) 11.45 (s, 1 H).

MS (ESI +) 319 (M + Na) C ₁₅ H ₁₂ N ₄ OS.

Example 8: 5- (3-hydroxymethylphenyl) salicyaldehyde thiosemicarbazone

5- (3-hydroxymethylphenyl) salicylaldehyde is prepared from 5-bromosalicylaldehyde and 3-hydroxymethylphenyl boronic acid according to General Procedure B.

The title compound is prepared from 5- (3-hydroxymethylphenyl) salicyaldehyde and thiosemicarbazide according to General Procedure A.

¹ H NMR (d ₆ -DMSO) δ 4.55 (s, 2H) 5.22 (t, 1H) 6.96 (d, 1H) 7.26 (d, 1H) 7.38 (t, 1H) 7.53 (dd, 1H) 7.55 (d, 1H) 7.58 (s, 1H) 8.10 (s, 1H) 8.16 (s, 1H) 8.21 (s, 1H) 8.42 (s, 1H) 10.09 (s, 1H) 11.42 (s, 1H).

MS (ESI +) 324 (M + Na) C ₁₅ H ₁₅ N ₃ O ₂ S.

Example 9: 5- (3-hydroxymethylphenyl) salicyaldehyde semicarbazone hydrochloride

5- (3-hydroxymethylphenyl) salicylaldehyde is prepared from 5-bromo-salicylaldehyde and 3-hydroxymethylphenyl boronic acid according to General Procedure B.

The title compound is prepared from 5- (3-hydroxymethylphenyl) salicylaldehyde and semicarbazone hydrochloride according to General Procedure A.

¹ H NMR (d ₆ -DMSO): δ 4.56 (s, 2H), 6.40 (br. 2H), 6.94 (d, 1H), 7.23 (d, 1H), 7.37 (t, 1H), 7.45 (d , 1H), 7.50 (d, 1H), 7.54 (s, 1H), 8.02 (s, 1H), 8.18 (s, 1H), 10.22 (2s, 2H).

MS 286 (M + H), 308 (M + Na), C ₁₅ H ₁₅ N ₃ O ₃ .

Example 10: 5- (4-hydroxymethylphenyl) salicylaldehyde thiosemicarbazone

5- (4-hydroxymethylphenyl) salicylaldehyde is prepared from 5-bromosalicylaldehyde and 4-hydroxymethylphenyl boronic acid according to General Procedure B.

The title compound is prepared from 5- (4-hydroxymethylphenyl) salicyaldehyde and thiocarbazide according to General Procedure A.

¹ H NMR (d ₆ -DMSO) δ 4.52 (d, 2H) 5.19 (t, 1H) 6.94 (d, 1H) 7.36 (d, 2H) 7.54 (dd, 1H) 7.65 (d, 2H) 8.13 (s, 1H) 8.16 (s, 1 H) 8.23 (s, 1 H) 8.42 (s, 1 H) 10.06 (s, 1 H) 11.40 (s, 1 H).

MS (ESI +) 324 (M + Na) C ₁₅ H ₁₅ N ₃ O ₂ S.

Example 11: 5- (4-nitrophenyl) salicylaldehyde thiosemicarbazone

5- (4-nitrophenyl) salicylaldehyde is prepared from 5-bromosalylsilaldehyde and 4-nitrophenyl boronic acid according to General Procedure B.

The title compound is prepared from 5- (4-nitrophenyl) salicylaldehyde and thiosemicarbazide according to General Procedure A.

¹ H NMR (d ₆ -DMSO) δ 7.01 (d, 1H), 7.71 (dd, 1H), 8.01 (d, 2H), 8.20 (s, 1H) 8.24 (s, 1H), 8.26 (d, 2H) , 8.42 (s, 1H), 8.43 (s, 1H), 10.43 (s, 1H) 11.46 (s, 1H).

Example 12: 5- (3-methoxycarbonylphenyl) salicyaldehyde thiosemicarbazone

5- (3-methoxyphenyl) salicylaldehyde is prepared from 5-bromosalicylaldehyde and 4-methoxycarbonylphenyl boronic acid according to General Procedure B.

The title compound is prepared from 5- (3-methoxycarbonylphenyl) -salicyaldehyde and thiosemicarbazide according to General Procedure A.

¹ H NMR (d ₆ -DMSO) 3.88 (s, 3H), 6.99 (d, 1H), 7.55-7.60 (m, 2H), 7.90 (d, 1H), 7.96 (d, 1H), 8.16 (s, 1H), 8.17 (s, 2H), 8.29 (s, 1H), 8.42 (s, 1H), 10.19 (s, 1H), 11.42 (s, 1H).

MS (ESI +) 352 (M + Na) C ₁₆ H ₁₅ N ₃ O ₃ S.

Example 13: 5- (3-methoxycarbonylphenyl) salicyaldehyde semicarbazone hydrochloride

5- (3-methoxyphenyl) salicylaldehyde is prepared from 5-bromosalicylaldehyde and 4-methoxycarbonylphenyl boronic acid according to General Procedure B.

The title compound is prepared from 5- (3-methoxycarbonylphenyl) -salicyaldehyde and semicarbazide hydrochloride according to General Procedure A.

¹ H NMR (d ₆ -DMSO): δ3.82 (s, 3H), 6.50 (br. 2H), 7.04 (d, 1H), 7.48 (d, 1H), 7.53 (t, 1H), 7.84 (d , 1H), 7.92 (d, 1H), 8.07 (s, 1H), 8.12 (s, 1H), 8.20 (s, 1H), 8.84 (s, 1H), 9.92 (s, 1H).

MS 314 (M + H), 336 (M + Na), C ₁₆ H ₁₅ N ₃ O ₄ .

Example 14: 5- (3-fluoro-4-methoxyphenyl) salicyaldehyde thiosemicarbazone

5- (3-Fluoro-4-methoxyphenyl) salicylaldehyde is prepared from 5-bromo-salicylaldehyde and 3-fluoro-4-methoxyphenyl boronic acid using general procedure B.

The title compound is prepared from 5- (3-fluoroxy-4-methoxyphenyl) -salicylaldehyde and thiosemicarbazide according to General Procedure A.

¹ H NMR (d ₆ -DMSO) δ 3.86 (s, 3H), 6.93 (d, 1H), 7.19 (t, 1H), 7.47 (d, 1H), 7.53 (d, 1H), 7.59 (d, 1H ), 8.17 (s, 2H), 8.20 (s, 1H), 8.41 (s, 1H), 10.08 (s, 1H), 11.41 (s, 1H).

MS (APCI) 319 (M + H; M + Na) C ₁₅ H ₁₄ N ₃ O ₂ SF.

Example 15: 5- (3-fluorophenyl) salicyaldehyde thiosemicarbazone

5- (3-fluorophenyl) salicylaldehyde is prepared from 5-bromosalicylicaldehyde and 3-fluorophenyl boronic acid using the general procedure B.

The title compound is prepared from 5- (3-fluorofluorophenyl) salicylaldehyde and thiosemicarbazide according to General Procedure A.

¹ H NMR (d ₆ -DMSO) δ 6.96 (d, 1H), 7.12 (t, 1H), 7.45 (dd, 1H), 7.54 (d, 2H), 7.59 (dd, 1H), 8.15 (s, 2H ), 8.27 (s, 1H), 8.42 (s, 1H), 10.16 (s, 1H), 11.40 (s, 1H).

MS (APCI) 289 (M + Na) C ₁₄ H ₁₂ N ₃ OSF.

Example 16: 5- (4-fluorophenyl) salicyaldehyde thiosemicarbazone

5- (4-fluorophenyl) salicylaldehyde is prepared from 5-bromosalicylaldehyde and 4-fluorophenyl boronic acid using the general procedure B.

The title compound is prepared from 5- (4-fluoroxyphenyl) salicylaldehyde and thiosemicarbazide according to General Procedure A.

¹ H NMR (d ₆ -DMSO) δ 6.95 (d, 1H), 7.24 (t, 2H), 7.51 (d, 1H), 7.71 (t, 2H), 8.11 (s, 1H), 8.13 (s, 1H ), 8.21 (s, 1H), 8.41 (s, 1H), 10.06 (s, 1H), 11.39 (s, 1H).

MS (APCI) 289 (M + H; M + Na) C ₁₄ H ₁₂ N ₃ OSF.

Example 17: 5- (3-carboxyphenyl) salicylaldehyde thiosemicarbazone

5- (3-carboxyphenyl) salicylaldehyde is prepared from 5-bromosalicylaldehyde and 3-methoxycarbonylphenyl boronic acid using general procedure A. Methyl esters are readily hydrolyzed using aqueous LiOH to give free carboxylic acids.

The title compound is prepared from 5- (3-carboxyphenyl) salicylaldehyde and thiosemicarbazide using the general procedure A.

¹ H NMR (d ₆ -DMSO) δ 6.55 (m, 4H), 6.99 (d, 1H), 7.52 (d, 1H), 7.55 (t, 1H), 7.87 (d, 1H), 7.91 (d, 1H ), 8.13 (s, 1H), 8.14 (s, 1H), 8.21 (s, 1H), 8.74 (s, 1H), 13.5 (s, 1H).

MS (APCI) 316 (M + H); 322 (M + Na) C ₁₅ H ₁₃ N ₃ O ₃ S.

Example 18: 5- (3-carboxyphenyl) salicyaldehyde semicarbazone hydrochloride

5- (3-carboxyphenyl) salicylaldehyde is prepared from 5-bromosalicylaldehyde 3-methoxycarbonylphenyl boronic acid using general procedure B. Methyl esters are readily hydrolyzed using aqueous LiOH to give free carboxylic acids.

The title compound is prepared from 5- (3-carboxyphenyl) salicylaldehyde and semicarbazide hydrochloride using General Procedure A.

¹ H NMR (d ₆ -DMSO) δ 6.55 (m, 4H), 6.99 (d, 1H), 7.52 (d, 1H), 7.55 (t, 1H), 7.87 (d, 1H), 7.91 (d, 1H ), 8.13 (s, 1H), 8.14 (s, 1H), 8.21 (s, 1H), 8.74 (s, 1H), 12.0 13.5 (s, 1H).

MS (APCI) 300 (M + H); 322 (M + Na) C ₁₅ H ₁₃ N ₃ O ₄ .

Example 19: 5- (4-carboxyphenyl) salicylaldehyde thiosemicarbazone

5- (4-carboxyphenyl) salicylaldehyde is prepared from 5-bromosalicylaldehyde and 4-carboxyphenyl boronic acid using the general procedure B.

The title compound is prepared from 5- (4-carboxyphenyl) salicylaldehyde and thiosemicarbazide using general procedure A.

¹ H NMR (d ₆ -DMSO) δ 7.00 (d, 1H), 7.63 (d, 1H), 7.84 (d, 2H), 7.98 (d, 2H), 8.15 (s, 2H), 8.34 (s, 1H ), 8.43 (s, 1H), 10.24 (s, 1H), 11.41 (s, 1H), 12.90 (s, 1H).

MS (APCI) 315 (M + H; M + Na) C ₁₄ H ₁₃ N ₃ O ₃ S.

Example 20: 5- (3-hydroxyphenyl) salicyaldehyde thiosemicarbazone

5- (3-hydroxyphenyl) salicylaldehyde is free hydroxy from 5-bromosalicylaldehyde and 3-methoxyphenyl boronic acid using general procedure B, and then demethoxylated using general procedure C. It is made by leaving a group.

The title compound is prepared from 5- (3-hydroxyphenyl) salicylaldehyde and thiosemicarbazide according to General Procedure A.

¹ H NMR (d ₆ -DMSO) δ 6.70 (d, 1H), 6.94 (d, 1H), 7.01 (s, 1H), 7.08 (d, 1H), 7.20 (t, 1H), 7.45 (d, 1H ), 8.09 (d, 2H), 8.14 (s, 1H), 8.42 (s, 1H), 9.39 (s, 1H), 10.02 (s, 1H), 11.37 (s, 1H).

MS (APCI) 287 (M + H) C ₁₄ H ₁₃ N ₃ O ₂ S.

Example 21: 5- (4-hydroxyphenyl) salicylaldehyde thiosemicarbazone

5- (4-hydroxyphenyl) salicylaldehyde is free hydroxy from 5-bromosalylsilaldehyde and 4-methoxyphenyl boronic acid using general procedure B, and then by dimethoxylation using general procedure C. It is manufactured by leaving a hydroxy group.

The title compound is prepared from 5- (4-hydroxyphenyl) salicylaldehyde and thiosemicarbazide according to General Procedure A.

¹ H NMR (d ₆ -DMSO) δ, 6.80 (d, 2H), 6.90 (d, 1H), 7.43-7.49 (m, 3H), 8.06 (s, 1H), 8.10 (s, 2H), 8.40 ( s, 1H), 9.40 (s, 1H), 9.89 (s, 1H), 11.36 (s, 1H).

MS (APCI) 287 (M + H) C ₁₄ H ₁₃ N ₃ O ₂ S.

Example 22: 5- (4-hydroxyphenyl) salicyaldehyde semicarbazone hydrochloride

5- (4-hydroxyphenyl) salicylaldehyde is free hydroxy from 5-bromosalylsilaldehyde and 4-methoxyphenyl boronic acid using general procedure B, and then by dimethoxylation using general procedure C. It is prepared by leaving the oxy group.

The title compound is prepared from 5- (4-hydroxyphenyl) salicylaldehyde and thiosemicarbazide according to General Procedure A.

¹ H NMR (d ₆ -DMSO) δ 6.47 (s, 2H), 6.81 (d, 2H), 6.89 (d, 1H), 7.40 (d, 1H), 7.47 (d, 2H), 7.95 (s, 1H ), 8.18 (s, 1H), 9.41 (s, 1H), 9.93 (s, 1H), 10.19 (s, 1H).

MS (APCI) 271 (M + Na) C ₁₄ H ₁₃ N ₃ O ₃ .

Example 23: 5- (3-fluoro-4-hydroxyphenyl) salicylaldehyde thiosemicarbazone

5- (3-fluoror-4-hydroxyphenyl) salicylaldehyde is prepared from 5-bromosalicylaldehyde and 3-fluoro-4-methoxyphenyl boronic acid using general procedure B, followed by general procedure Prepared by using C to release free hydroxy groups by demethoxylation.

The title compound is prepared from 5- (3-fluoro-4-hydroxyphenyl) -salicylaldehyde and thiosemicarbazide according to General Procedure A.

¹ H NMR (d ₆ -DMSO) δ 6.91 (d, 1H), 6.98 (t, 1H), 7.32 (d, 1H), 7.49 (s, 1H), 7.51 (s, 1H), 8.16 (s, 3H ), 8.40 (s, 1H), 9.85 (s, 1H), 10.02 (s, 1H), 11.40 (s, 1H).

MS (APCI) 305 (M + H; M + Na) C ₁₄ H ₁₂ N ₃ O ₂ SF.

Example 24: 5- (3-fluoro-4-hydroxyphenyl) salicyaldehyde semicarbazone hydrochloride

5- (3-Fluoror-4-hydroxyphenyl) salicylaldehyde was then purified from 5-bromo-salicylaldehyde and 3-fluoro-4-methoxyphenyl boronic acid using general procedure B. Prepared by leaving the free hydroxy group by dimethoxylation using the general procedure C.

The title compound is prepared from 5- (3-fluoro-4-hydroxyphenyl) -salicylaldehyde and semicarbazide hydrochloride according to General Procedure A.

¹ H NMR (d ₆ -DMSO) δ 6.57 (d, 2H), 6.88 (d, 1H), 6.98 (t, 1H), 7.31 (d, 1H), 7.42 (d, 1H), 7.46 (d, 1H ), 7.99 (s, 1H), 8.16 (s, 1H), 9.84 (br., 2H), 10.05 (s, 1H), 10.20 (s, 1H).

MS (APCI) 305 (M + H; M + Na) C ₁₄ H ₁₂ N ₃ O ₂ SF.

Example 25: 5- (3,4-dihydroxyphenyl) salicylaldehyde thiosemicarbazone

5- (3,4-dihydroxyphenyl) salicylaldehyde is derived from 5-bromo-salicylaldehyde and 3,4-dimethoxyphenyl boronic acid using general procedure B, and then using general procedure C. It is prepared by leaving free hydroxy groups by dimethoxylation.

The title compound is prepared from 5- (3,4-dihydroxyphenyl) salicylaldehyde and thiosemicarbazide according to General Procedure A.

¹ H NMR (d ₆ -DMSO) δ 6.77 (d, 1H), 6.89 (d, 1H), 6.93 (d, 1H), 7.01 (s, 1H), 7.37 (d, 1H), 8.06 (s, 2H ), 8.12 (s, 1H), 8.40 (s, 1H), 8.90 (s, 1H), 8.94 (s, 1H), 9.90 (s, 1H), 11.38 (s, 1H).

MS (APCI) 304 (M + H); 326 (M + Na) C ₁₄ H ₁₃ N ₃ O ₃ S.

Example 26: 5- (3,4-dihydroxyphenyl) salicyaldehyde semicarbazone hydrochloride

5- (3,4-dihydroxyphenyl) salicylaldehyde is derived from 5-bromo-salicylaldehyde and 3,4-dimethoxyphenyl boronic acid using general procedure B, and then using general procedure C. It is prepared by leaving free hydroxy groups by dimethoxylation.

The title compound is prepared from 5- (3,4-dihydroxyphenyl) salicylaldehyde and semicarbazide hydrochloride according to General Procedure A.

¹ H NMR (d ₆ -DMSO) δ 6.47 (s, 2H), 6.81 (d, 2H), 6.89 (d, 1H), 7.40 (d, 1H), 7.47 (d, 2H), 7.95 (s, 1H ), 8.18 (s, 1H), 9.41 (s, 1H), 9.93 (s, 1H), 10.19 (s, 1H).

MS (APCI) 298 (M + Na) C ₁₄ H ₁₃ N ₃ O ₃ .

Example 27: 5- (2,4-dihydroxyphenyl) salicylaldehyde thiosemicarbazone

5- (2,4-dihydroxyphenyl) salicylaldehyde is derived from 5-bromo-salicylaldehyde and 2,4-dimethoxyphenyl boronic acid using general procedure B, followed by general procedure C. To free hydroxyl groups by dimethoxylation.

The title compound is prepared from 5- (2,4-dihydroxyphenyl) salicylaldehyde and thiosemicarbazide according to General Procedure A.

¹ H NMR (d ₆ -DMSO) δ 5.76 (s, 1H), 6.28 (d, 1H), 6.37 (s, 1H), 6.85 (d, 1H), 7.04 (d, 1H), 7.36 (d, 1H ), 7.86 (s, 1H), 7.88 (s, 1H), 8.07 (s, 1H), 8.40 (s, 1H), 9.24 (s, 1H), 9.77 (s, 1H), 11.35 (s, 1H) .

MS 304 (M + H), C ₁₄ H ₁₃ N ₃ O ₃ S.

Example 28: 4-hydroxy-5- (4-hydroxyphenyl) salicylaldehyde thiosemicarbazone

4-hydroxy-5- (4-hydroxyphenyl) salicyaldehyde is prepared from 5-bromo-2,4-dimethoxybenzoaldehyde and 4-methoxyphenyl boronic acid using general procedure B, followed by general Prepared by subjecting free hydroxy groups by demethoxylation using Procedure C.

The title compound is prepared from 4-hydroxy-5- (4-hydroxyphenyl) -salicylaldehyde and thiosemicarbazide according to General Procedure A.

¹ H NMR (d ₆ -DMSO) δ 4.47 (s, 1H), 6.44 (s, 1H), 6.72 (d, 2H), 7.29 (d, 2H), 7.67 (s, 1H), 7.95 (s, 1H ), 8.26 (s, 1 H), 9.26 (s, 1 H), 9.76 (d, 1 H), 11.15 (s, 1 H).

MS (APCI) 304 (M + H); 326 (M + Na) C ₁₄ H ₁₃ N ₃ O ₃ S.

Example 29: 4-hydroxy-5- (4-hydroxyphenyl) salicyaldehyde semicarbazone hydrochloride

5- (3,4-Dihydroxyphenyl) salicylaldehyde is derived from 5-bromosalylsilaldehyde and 3,4-dimethoxyphenyl boronic acid using general procedure B, and then dimethock using general procedure C. It is prepared by releasing free hydroxyl groups by aging.

The title compound is prepared from 5- (3,4-dihydroxyphenyl) salicylaldehyde and semicarbazide hydrochloride according to General Procedure A.

¹ H NMR (d ₆ -DMSO) δ 6.27 (s, 2H), 6.44 (d, 1H), 6.73 (d, 2H), 7.29 (d, 2H), 7.49 (s, 1H), 8.03 (s, 1H ), 8.63 (s, 2H), 9.27 (s, 1H), 9.93 (s, 1H).

MS (APCI) 288 (M + H); 310 (M + Na) C ₁₄ H ₁₃ N ₃ O ₄ .

Example 30: 5- (4-pyridyl) salicylaldehyde thiosemicarbazone

5- (4-Pyridyl) salicylaldehyde was obtained in 43% yield according to General Procedure B using 4-pyridyl boronic acid and 5-bromosalylsilaldehyde as starting materials.

The title compound is prepared from 5- (4-pyridyl) salicylaldehyde and thiosemicarbazide according to General Procedure A.

¹ H NMR (d ₆ -DMSO) δ 6.98 (d, 1H), 7.52 (d, 1H), 7.82 (d, 1H), 8.08 (bs, 2H), 8.42 (s, 1H), 8.46 (s, 1H ), 8.62 (d, 2H), 10.35 (s, 1H), 11.42 (s, 1H).

MS 273 (M + H), C ₁₃ H ₁₂ N ₄ OS.

Example 31: 5- (3-pyridyl) salicylaldehyde thiosemicarbazone

5- (3-pyridyl) salicylaldehyde was obtained in 40% yield according to General Procedure B using 3-pyridyl boronic acid and 5-bromo salicylaldehyde as starting materials.

The title compound is obtained from 5- (3-pyridyl) salicylaldehyde and thiosemicarbazide according to General Procedure A.

¹ H NMR (d ₆ -DMSO) δ 7.01 (d, 1H), 7.45 (t, 1H), 7.53 (d, 1H), 8.08 (d, 1H), 8.18 (d, 1H), 8.22 (s, 1H ), 8.32 (s, 1H), 8.42 (s, 1H), 8.53 (s, 1H), 8.95 (s, 1H), 10.25 (s, 1H), 11.42 (s, 1H).

MS 273 (M + H), C ₁₃ H ₁₂ N ₄ OS.

Example 32: 5- (5-pyrimidyl) salicylaldehyde thiosemicarbazone

To a 5-bromo-o-anisaldehyde (26 g) solution in benzene (300 mL) was added ethylene glycol (8.03 mL) and p-toluenesulfonic acid monohydrate (10 mg). The reaction mixture was heated to reflux for 6 hours and the water was removed. The resulting reaction mixture was washed with 1 N NaOH, dried over MgSO ₄ and concentrated. The residue was purified by silica gel column chromatography to give 25 g of acetal product.

1,4- of (2-bromo-6-methoxy) phenyl-1,3-dioxolane (2 g) obtained above together with triethylamine (3.34 mL) and pinacolborane (1.7 mL) was obtained. Dissolved in dioxane. [1,1'-bis (diphenylphosphino) ferrocene] dichloropalladium was added under nitrogen. The reaction mixture was stirred at 100 ° C. for 12 h, then extracted with dichloromethane, washed with water and then dried over MgSO ₄ and concentrated. The residue was purified by silica gel column chromatography to give 830 mg of boronate compound.

The boronate compound obtained above was then reacted with bromopyrimidine using general procedure B. A yield of 78% was obtained.

The title compound was obtained in 94% yield according to General Procedure A.

_{^{1 H NMR (DMSO- d 6)}} δ 7.02 (d, 1H), 7.07 (d, 1H), 8.09 (d, 2H), 8.40 (s, 1H), 8.42 (s, 1H), 9.12 (s, 1H ), 9.16 (s, 1H), 9.18 (s, 1H), 10.36 (s, 1H), 11.45 (s, 1H).

MS 274 (M + H) C ₁₂ H ₁₁ N ₅ OS.

Example 33: 5- (2-thienyl) salicylaldehyde thiosemicarbazone

5- (2-thienyl) salicylaldehyde is prepared from 5-bromosalicylaldehyde and 2-thienyl boronic acid according to General Procedure B.

The title compound is prepared from 5- (2-thienyl) salicylaldehyde and thiosemicarbazide according to General Procedure A.

¹ H NMR (d _6- DMSO) δ 6.91 (d, 1H), 7.09 (d, 1H), 7.44-7.48 (m, 3H), 8.08 (s, 1H), 8.17 (d, 2H), 8.39 (s , 1H), 10.13 (s, 1H), 11.40 (s, 1H).

MS (APCI) 278 (M + H); 300 (M + Na) C ₁₂ H ₁₁ N ₃ OS ₂ .

Example 34: 5- (3-thienyl) salicylaldehyde thiosemicarbazone

5- (3-thienyl) salicylaldehyde is prepared from 5-bromosalicylaldehyde and 3-thienyl boronic acid according to General Procedure B.

The title compound is prepared from 5- (3-thienyl) salicylaldehyde and thiosemicarbazide according to General Procedure A.

¹ H NMR (d ₆ -DMSO) δ 6.90 (d, 1H), 7.59 (m, 3H), 7.80 (s, 1H), 8.09 (s, 1H), 8.17 (s, 1H), 8.24 (d, 1H ), 8.40 (s, 1 H), 10.00 (s, 1 H), 11.39 (s, 1 H).

MS (APCI) 278 (M + H); 300 (M + Na) C ₁₂ H ₁₁ N ₃ OS ₂ .

Example 35: 5- [2- (5-chloro-thienyl)] salicylaldehyde thiosemicarbazone

5- [2- (5-chlorothienyl)] salicylaldehyde is prepared from 5-bromosalylsil-aldehyde and 5-chloro-2-thienyl boronic acid according to General Procedure B.

The title compound is prepared from 5- [2- (5-chlorothienyl)] salicylaldehyde and thiosemicarbazide according to General Procedure A.

¹ H NMR (d ₆ -DMSO) δ 6.91 (d, 1H), 7.11 (s, 1H), 7.44-7.48 (m, 3H), 8.11-8.17 (m, 3H), 8.37 (s, 2H), 10.23 (s, 1 H), 11.41 (s, 1 H).

MS (APCI) 335 (M + Na) C ₁₂ H10ClN ₃ OS ₂ .

Example 36: 5- (5-indolyl) salicylaldehyde thiosemicarbazone

5- (5-Indolyl) salicylaldehyde is prepared from 5-bromosalylsilaldehyde and 5-indolyl boronic acid according to General Procedure B.

The title compound is prepared from 5- (4-fluorooxyphenyl) salicylaldehyde and thiosemicarbazide according to General Procedure A.

¹ H NMR (d ₆ -DMSO) δ 6.32 (d, 1H), 6.90 (d, 1H), 7.34 (d, 1H), 7.38 (s, 1H), 7.40 (d, 1H), 7.54 (d, 1H ), 7.82 (d, 1H), 8.15 (bs, 2H), 8.23 (s, 1H), 8.48 (s, 1H), 9.91 (s, 1H), 11.07 (s, 1H), 11.38 (s, 1H) .

MS 311 (M + H), C ₁₆ H ₁₄ N ₄ OS.

Example 37: Methyl (3-formyl-4-hydroxy) cinnamate, thiosemicarbazone

Methyl (3-formyl-4-hydroxy) cinnamate is prepared from 5-bromosalicylaldehyde and methyl acrylate at 90% using General Procedure E.

The title compound is prepared from methyl (3-formyl-4-hydroxy) cinnamate and thiosemicarbazide following the general procedure A.

¹ H NMR (d ₆ -DMSO) δ 3.69 (s, 3H), 6.56 (d, 1H), 6.87 (d, 1H), 7.55-7.60 (m, 2H), 8.13 (d, 2H), 8.33 (d , 2H), 10.05 (s, 1H), 11.38 (s, 1H).

MS 302 (M + Na), C ₁₂ H ₁₃ N ₃ O ₃ S.

Example 38: 3-formyl-4-hydroxycinnamic acid, thiosemicarbazone

Methyl (3-formyl-4-hydroxy) cinnamate is hydrolyzed using aqueous LiOH solution (0.5 M).

The title compound is prepared from methyl (3-formyl-4-hydroxy) cinnamate and thiosemicarbazide according to General Procedure A.

_{^{1 H NMR (DMSO- d 6)}} δ 6.44 (d, 1H), 6.87 (d, 1H), 7.50 (d, 1H), 7.53 (d, 1H), 8.13 (d, 2H), 8.32 (d, 2H ), 8.61 (s, 1 H), 10.43 (s, 1 H), 11.38 (s, 1 H).

MS 288 (M + Na), C ₁₁ H ₁₁ N ₃ O ₃ S.

Example 39: 3-formyl-4-hydroxycinamide, thiosemicarbazone

3-formyl-4-hydroxycinamide is prepared from 5-bromosalylsilaldehyde and acrylamide in 70% using General Procedure E.

The title compound is prepared from methyl 3-formyl-4-hydroxycinamide and thiosemicarbazide using general procedure A.

¹ H NMR (d ₆ -DMSO) δ 6.46 (d, 1H), 6.88 (d, 1H), 6.93 (s, 1H), 7.37 (d, 1H), 7.43 (d, 1H), 7.92 (s, 1H ), 8.17 (d, 2H), 8.33 (d, 1H), 10.03 (s, 1H), 11.39 (s, 1H).

MS 287 (M + Na), C ₁₁ H ₁₂ N ₄ O ₂ S.

Example 40: 3- (3-formyl-4-hydroxyphenyl) propionic acid, thiosemicarbazone

To a solution of 3- (4-hydroxyphenyl) propionic acid (1 g) in CHCl ₃ (5 mL) was added 4 N NaOH (4 mL). After stirring at 80 ° C. for 6 hours, the mixture was extracted with water, dried over MgSO 4 and concentrated. The residue was purified by silica gel column chromatography to give 850 mg of aldehyde.

Thiosemicarbazone, the title compound 3- (3-formyl-4-hydroxyphenyl) propionic acid, was prepared from 3- (3-formyl-4-hydroxyphenyl) propionic acid and thiosemicarbazide according to General Procedure B. Are manufactured.

¹ H NMR (d ₆ -DMSO) δ 2.45 (t, 2H), 2.68 (t, 2H), 6.73 (d, 1H), 7.03 (d, 1H), 7.75 (s, 1H), 7.89 (s, 1H ), 8.12 (s, 1H), 8.32 (s, 1H), 9.65 (s, 1H), 11.32 (s, 1H), 12.12 (bs, 1H).

MS 268 (M + H), C ₁₁ H ₁₃ N ₃ O ₃ S.

Example 41: 2-[(2-hydroxy-1-naphthyl) methylidene] hydrazine-1-carbamide hydrochloride

Method of manufacture: General procedure F.

Starting material 2-hydroxy-1-naphthalaldehyde is obtained from commercially available products. Another starting material is semicarbazide hydrochloride.

¹ H NMR (d ₆ -DMSO): 7.20 (d, 1H), 7.36 (t, 1H), 7.62 (t, 1H), 7.80 (d, 1H), 7.85 (d, 1H), 7.84 (d, 1H ), 8.28 (s, 1 H), 8.46 (s, 1 H), 8.60 (s, 1 H), 9.05 (s, 1 H).

MS 230 (M + H), C ₁₂ H ₁₁ N ₃ O ₂ .

Example 42: 2-[(2-hydroxy-1-naphthyl) methylidene] hydrazine-1-carbothioamide

Method of manufacture: General procedure E.

Starting material 2-hydroxy-1-naphthalaldehyde is obtained from commercially available products. Another starting material is thiosemicarbazide.

¹ H NMR (d ₆ -DMSO): 7.18 (d, 1H), 7.36 (t, 1H), 7.58 (t, 1H), 7.80 (d, 1H), 7.85 (d, 1H), 7.88 (d, 1H ), 8.18 (s, 1H), 8.48 (s, 1H), 8.62 (s, 1H), 9.05 (s, 1H).

MS 246 (M + H), C ₁₂ H ₁₁ N ₃ OS.

Example 43: 2-[(2,7-Dihydroxy-1-naphthyl) methylidene] hydrazine-1-carbothioamide

The starting material of Example 3 (2,7-dihydroxy-3-naphthaldehydride) was prepared according to General Procedure E from 2,7-dihydroxy-naphthalene in a yield of 40%. The other formation product (2,7-dihydroxy-1-naphthaldehydride) is isolated in 20% yield, which is used in the synthesis of Example 44.

2,7-dihydroxy-3-naphthalaldehyde: ¹ H NMR (d ₆ -DMSO): δ 6.92 (m, 2H), 7.56 (d, 1H), 7.94 (s, 1H), 8.28 (s, 1H), 9,90 (s, 1H), 10.7 (s, 1H), 11.36 (s, 1H).

The compound of Example 43 was prepared according to General Procedure F with thiosemicarbazide. Yields were calculated quantitatively.

¹ H NMR (d ₆ -DMSO): δ 6.85 (dd, 1H), 6.92 (s, 1H), 7.52 (s, 1H), 7.64 (d, 1H), 7.68 (d, 1H), 8.94 (s, 1H), 9.90 (s, 1H), 10.36 (d, 1H), 11.36 (s, 1H).

MS 262 (M + H), C ₁₂ H ₁₁ N ₃ O ₂ S.

Example 44: 2-[(2,7-dihydroxy-1-naphthyl) methylidene] hydrazine-1-carbothioamide

The starting material of Example 4 (2,7-dihydroxy-1-naphthalde) was prepared according to General Procedure E with 2,7-dihydroxy-naphthalene in a yield of 20%.

2,7-dihydroxy-1-naphthaldehydride: ¹ H NMR (d ₆ -DMSO): 7.04-7.12 (m, 3H), 7.46 (d, 1H), 7.74 (d, 1H), 7.82 (d , 1H), 8.56 (s, 1 H), 10.7 (s, 1 H).

Another formylation product (2,7-dihydroxy-3-naphthaldehydride) is also isolated in a yield of 40%, which is used in the synthesis of Example 43.

The compound of Example 44 was prepared according to General Procedure F with thiosemicarbazide. Yield was quantitative.

¹ H NMR (d ₆ -DMSO): δ 7.50-7.52 (m, 4H), 7.6 ₆ -7.92 (m, 4H), 9.26 (s, 1H), 9.56 (d, 1H), 9.82 (s, 1H) .

MS 262 (M + H), C ₁₂ H ₁₁ N ₃ O ₂ S.

Example 45: 2-[(2,6-Dihydroxy-1-naphthyl) methylidene] hydrazine-1-carbothioamide

Starting material (2,6-dihydroxy-1-naphthaldehydride) is prepared from 2,6-dihydroxy-naphthalene in a yield of 30% according to General Procedure E.

2,6-dihydroxy-1-naphthaldehydride: 1H-NMR (d ₆ -DMSO): δ 7.04-7.12 (m, 3H), 7.46 (d, 1H), 7.74 (d, 1H), 7.82 ( d, 1 H), 8.56 (s, 1 H), 10.7 (s, 1 H).

The compound of Example 45 was prepared from thiosemicarbazide according to General Procedure F. Yield was quantitative.

1 H-NMR (d ₆ -DMSO): δ 6.78 (d, 1H), 6.86 (s, 1H), 7.48 (s, 1H), 7.56 (d, 1H), 7.88 (m, 1H), 9.20 (s, 2H), 9.46 (d, 2H), 9.82 (s, 2H).

MS 262 (M + H), C ₁₂ H ₁₁ N ₃ O ₂ S.

Example 46: 2-amino-4- [1- (2-hydroxynaphthyl)] pyrimidine

One equivalent of 2-methoxy-1-naphtone and 15 equivalents of N , N -dimethylformamide diethyl acetal are combined and heated to 120 ° C. overnight. The reaction mixture is concentrated in vacuo, dissolved in butanol (0.1 M) with 3 equivalents of sodium ethoxide, then 1.1 equivalents of guanidine hydrochloride are added. This mixture is heated to 120 ° C. overnight. The reaction mixture was extracted with dichloromethane, washed with water and then dried over sodium sulphate. After purification on a silica gel column, 2-amino-4- [1- (2-methoxynaphthyl)] pyrimidine was obtained.

The methoxy product is then dissolved in dichloromethane (˜0.04 molar) and stirred at −78 ° C. under nitrogen. To this solution, 10 equivalents of boron tribromide are slowly added. The reaction mixture is stirred at −78 ° C. for 15 minutes and then at room temperature for 8 hours. The reaction mixture is cooled to 0 ° C., 1/4 volume of diethyl ether is carefully added and saturated sodium bicarbonate solution is added until the mixture reaches a base as measured by litmus paper. The resulting mixture is extracted with 6 parts of 4: 1 dichloromethane: methanol. The combined organic layers are dried over sodium sulphate, filtered and concentrated. The product is purified by preparative thin layer chromatography.

1 H-NMR (d ₆ -DMSO): δ 5.18 (s, 2H), 5.29 (s, 1H), 7.19 (s, 1H), 7.22 (d, 1H), 7.25 (s, 1H), 7.35 (t, 1H), 7.47 (t, 1H), 7.79 (d, 1H), 7.81 (d, 1H), 8.16 (d, 1H), 8.43 (d, 1H), 12.20 (s, 1H).

MS 238 (M + H), C ₁₄ H ₁₁ N ₃ O.

Example 47: 3- (2-Amino-6-methyl-pyrimidin-4-yl) -biphenyl-4,4'-diol

4-methoxy-biphenyl-4-carboxyaldehyde was prepared from 4-bromobenzaldehyde and 4-methoxyphenyl boronic acid in a yield of 95% according to General Procedure G.

22.08 g (104 mmol) of 4-methoxy-biphenyl-4-carboxyaldehyde were dissolved in 300 ml of methylene chloride and stirred at 0 ° C. 5.36 mL of bromine dissolved in 100 mL of methylene chloride was added dropwise. The reaction mixture was stirred overnight and concentrated. The residue was dissolved again in methylene chloride and basified with sodium bicarbonate. The organic layer was further washed with water and dried over sodium sulphate. The crude product was purified by column chromatography (1: 1 hexanes / ethyl acetate) to afford the desired product in 58% yield.

10.92 g (37.5 mmol) of 3-bromo-4-methoxy-biphenyl-4-carboxyaldehyde was dissolved in 100 mL of methylene chloride and stirred at 0 ° C. 14.6 g (65 mmol; 1.7 equiv) of 77% purity 3-chlorobenzcarboperoxic acid were added. It was stirred for 18 hours at room temperature. The reaction mixture was cooled to 0 ° C. and treated with saturated sodium bicarbonate solution until no bubbles were observed. It was partitioned between saturated sodium bicarbonate solutions and 2 parts of methylene chloride and methanol (2: 1) and 100 mL of 1 N lithium hydroxide were added. Stir at room temperature for 2 hours. The organic layer was washed with bicarbonate and dried over sodium sulphate. The organic layer was washed with bicarbonate, dried over sodium sulfate, filtered and concentrated to yield 8.72 g of 3-bromo-4-hydroxy-4-methoxy-biphenyl in 80% yield.

The methoxy group of 3-bromo-4-hydroxy-4-methoxy-biphenyl was removed following the general procedure F to afford 3-bromo-4,4-biphenol in 80% yield.

6.2 g of anhydrous potassium carbonate was added to a solution of 3-bromo-4,4-biphenol (2 g, 7.5 mmol) and benzylbromide (1.8 mL, 15 mmol) in acetone. The mixture was refluxed for 4 hours and cooled. Acetone was evaporated in vacuo, water was added to the residue, and then acidified slowly with cold 10% HCl. The solid obtained was filtered, washed with H ₂ O and dried under vacuum overnight to give a white solid (96%).

¹ H NMR (d ₆ -DMSO) δ 5.14 (s, 2H), 5.24 (s, 2H), 6.65 (d, 2H), 7.22 (d, 1H), 7.33 (m, 2H), 7.40 (m, 4H ), 7.45 (d, 2H), 7.48 (d, 2H), 7.57 (m, 3H), 7.82 (d, 1H).

MS 446 (M + H), C ₂₆ H ₂₁ O ₂ Br.

4,4-Dibenzyloxy-3-biphenylboronic acid was obtained as follows:

To a solution of 3-bromo-4,4'-dibenzyloxybiphenol (2.88 g, 6.5 mmol) in dry THF (30 mL) was added dropwise BuLi (7.15 mmol) at -78 ° C under nitrogen and at -78 ° C. Stir for another 30 minutes. B (BuO) ₃ (20 mmol) solution in 20 mL THF was added slowly at the same temperature and further stirred at −78 ° C. for 6 hours. The mixture was left to warm and further stirred at room temperature overnight. It was then cooled to −0 ° C., treated with 1 N NaOH (10 mL) and water (50 mL), followed by extraction with ether (3 × 100 mL). The combined organic layer was washed with water, saturated sodium chloride solution, dried over Na ₂ SO ₄ and evaporated. The residue was purified by column chromatography on silicon gel (30 × 4 cm), which was dissolved by CH ₂ Cl ₂ and separated to give a white solid (27%).

¹ H NMR (d ₆ -DMSO) δ 5.17 (s, 2H), 5.20 (s, 2H), 7.06 (d, 2H), 7.11 (d, 1H), 7.36 (d, 2H), 7.41 (m, 4H ), 7.46 (d, 2H), 7.53 (m, 4H), 7.58 (d, 1H), 7.78 (d, 1H), 7.81 (s, 2H).

MS 410 (M + H), C ₂₆ H ₂₃ O ₄ B.

Starting material for the title compound (4- (4,4'-bis-benzyloxy-biphenyl-3-yl) -6-methyl-pyrimidin-2-ylamine) was prepared as 2-amino-4-chloro-6- Methylpyrimidine was used as a white solid (yield 84%) according to General Procedure H.

¹ H NMR (d ₆ -DMSO) δ 2.21 (s, 3H), 5.15 (s, 2H), 5.24 (s, 2H), 6.48 (s, 2H), 6.51 (s, 1H), 6.97 (s, 1H ), 7.08 (m, 3H), 7.28 (d, 1H), 7.35 (m, 3H), 7.41 (d, 2H), 7.48 (m, 2H), 7.56 (d, 2H), 7.63 (m, 2H) , 8.30 (s, 1 H).

MS 461 (M < + >), C ₃₀ H ₂₇ N ₃ O ₂ .

The title compound was obtained as a yellow solid (yield 69%) according to General Procedure I using 3- (2-amino-6-methyl-pyrimidin-4-yl) -biphenyl-4,4'-diol.

¹ H NMR (d ₆ -DMSO) δ 2.23 (s, 3H), 6.83 (d, 2H), 6.93 (d, 2H), 7.04 (s, 2H), 7.33 (s, 1H), 7.52 (d, 1H ), 7.56 (d, 1 H), 8.06 (d, 1 H), 9.45 (s, 1 H), 14.00 (s, 1 H).

MS 282 (M + H), C ₁₆ H ₁₅ N ₃ O ₂

Example 48: 3- (5-Amino-pyridin-2-yl) -biphenyl-4,4'-diol

Starting material for the title compound (6- (4,4'-bis-benzyloxy-biphenyl-3-yl) -pyridin-3-ylamine) was subjected to general procedure B using 5-amino-2-bromopyridine. To a pale yellow solid (yield 43%).

¹ H NMR (d ₆ -DMSO) δ 5.14 (s, 2H), 5.20 (s, 2H), 5.39 (s, 2H), 6.91 (d, 1H), 7.08 (d, 2H), 7.20 (d, 1H ), 7.32 (m, 2H), 7.37-7.41 (m, 4H), 7.44-7.50 (m, 5H), 7.56 (d, 2H), 7.69 (d, 1H), 7.92 (d, 1H), 8.04 ( s, 1 H).

MS 459 (M + H), C ₃₁ H ₂₆ N ₂ O ₂

The title compound was obtained as a yellow solid (yield 62%) according to general procedure C using 6- (4,4'-bis-benzyloxy-biphenyl-3-yl) -pyridin-2-ylamine.

¹ H NMR (d ₆ -DMSO) δ 5.75 (s, 2H), 6.82 (d, 2H), 6.86 (d, 1H), 7.18 (d, 1H), 7.34 (d, 1H), 7.48 (d, 2H ), 7.92 (s, 2H), 8.05 (d, 1H), 9.48 (s, 1H), 14.19 (s, 1H).

MS 279 (M + H), C ₁₇ H ₁₄ N ₂ O ₂

Example 49: 3- (6-amino-pyridin-2-yl) -biphenyl-4,4'-diol

Starting material for the title compound (6- (4,4'-bis-benzyloxy-biphenyl-3-yl) -pyridin-2-ylamine) was prepared in 2-amino-6-bromopyridine according to General Procedure H. To give a white solid (54%).

¹ H NMR (d ₆ -DMSO) δ 5.14 (s, 2H), 5.21 (s, 2H), 5.91 (s, 2H), 6.39 (d, 2H), 7.09 (d, 2H), 7.12 (d, 1H ), 7.22 (d, 1H), 7.33 (d, 1H), 7.37-7.41 (m, 5H), 7.44-7.47 (m, 5H), 7.55 (d, 2H), 7.93 (d, 1H).

MS 459 (M + H), C ₃₁ H ₂₆ N ₂ O ₂ .

The title compound was obtained as a yellow solid (yield 62%) using 6- (4,4'-bis-benzyloxy-biphenyl-3-yl) -pyridin-2-ylamine according to General Procedure I.

¹ H NMR (d ₆ -DMSO) δ 6.46 (d, 1H), 6.60 (s, 2H), 6.79 (d, 2H), 6.82 (d, 1H), 7.35 (d, 1H), 7.483 (d, 1H ), 7.48 (d, 2H), 7.57 (d, 1H), 7.97 (d, 1H), 9.44 (s, 1H), 14.47 (s, 1H).

MS 279 (M + H), C ₁₇ H ₁₄ N ₂ O ₂ .

Example 50: 3- (2-Amino-6-methoxy-pyrimidin-4-yl) -biphenyl-4,4'-diol

Starting material for the title compound (4- (4,4'-bis-benzyloxy-biphenyl-3-yl) -6-methoxy-pyrimidin-2-ylamine) was prepared according to General Procedure H. Obtained as a white solid (yield 75%) using 4-chloro-6-methoxypyrimidine.

¹ H NMR (d ₆ -DMSO) δ 3.87 (s, 3H), 5.10 (s, 2H), 5.18 (s, 2H), 6.76 (s, 2H), 6.88 (s, 1H), 6.97 (s, 1H ), 7.06 (m, 3H), 7.28 (d, 1H), 7.35 (m, 3H), 7.41 (d, 2H), 7.48 (m, 2H), 7.56 (d, 2H), 8.02 (m, 2H) , 8.05 (s, 1 H).

MS 490 (M + H), C ₃₁ H ₂₇ N ₃ O ₃ .

The title compound was obtained as a yellow solid (69%) using 3- (2-amino-6-methoxy-pyrimidin-4-yl) -biphenyl-4,4'-diol according to General Procedure I.

¹ H NMR (d ₆ -DMSO) δ 3.88 (s, 3H), 6.82 (d, 2H), 6.86 (s, 1H), 6.89 (d, 1H), 7.13 (s, 2H), 7.52 (d, 2H ), 7.54 (d, 1H), 8.00 (s, 1H), 9.41 (s, 1H), 14.09 (s, 1H).

MS 310 (M + H), C ₁₇ H ₁₅ N ₃ O ₃ .

Example 51: 3- (4,5-Diamino-pyrimidin-2-yl) -biphenyl-4,4'-diol

Starting material for the title compound (2- (4,4'-bis-benzyloxy-biphenyl-3-yl) -pyrimidine-4,5-diamine) was subjected to 2-chloro-4,5- according to General Procedure H. Diaminopyrimidine was used to obtain a white solid (yield 31%).

¹ H NMR (d ₆ -DMSO) δ 4.78 (s, 2H), 5.13 (s, 4H), 6.30 (s, 2H), 7.06 (d, 2H), 7.12 (d, 1H), 7.28 (d, 1H ), 7.33 (d, 2H), 7.35 (s, 1H), 7.40 (d, 2H), 7.46-7.53 (m, 4H), 7.53-7.55 (m, 3H), 7.64 (d, 1H), 7.70 ( s, 1 H).

MS 475 (M + H), C ₃₀ H ₂₆ N ₄ O ₂ .

The title compound was obtained as a yellow solid (yield 56%) using 2- (4,4'-bis-benzyloxy-biphenyl-3-yl) -pyrimidine-4,5-diamine according to General Procedure I.

¹ H NMR (d ₆ -DMSO) δ 5.06 (d, 2H), 6.75 (d, 2H), 6.83 (d, 1H), 6.88 (s, 2H), 7.39 (s, 1H), 7.40 (d, 2H ), 7.66 (s, 1H), 8.36 (s, 1H), 9.42 (s, 1H), 14.15 (s, 1H).

MS 295 (M + H), C ₁₆ H ₁₄ N ₄ O ₂ .

Example 52: 3- (2,6-Diamino-pyrimidin-4-yl) -biphenyl-4,4'-diol

Starting material for the title compound (6- (4,4'-bis-benzyloxy-biphenyl-3-yl) -pyrimidine-2,4-diamine) is 2-chloro-4,5- according to General Procedure H. Diaminopyrimidine was used as a white solid (yield 31%) according to General Procedure H.

¹ H NMR (d ₆ -DMSO) δ 4.62 (s, 2H), 4.86 (s, 2H), 5.10 (s, 2H), 5.16 (s, 2H), 6.48 (s, 1H), 7.01 (d, 2H ), 7.06 (d, 1H), 7.26 (s, 1H), 7.31 (m, 2H), 7.34-7.39 (m, 3H), 7.36 (d, 2H), 7.41 (s, 1H), 7.42 (d, 1H), 7.46 (d, 1H), 7.52 (d, 2H), 8.02 (d, 1H).

MS 475 (M + H), C ₃₀ H ₂₆ N ₄ O ₂ .

The title compound was obtained as a yellow solid (yield 86%) according to General Procedure I using 6- (4,4'-bis-benzyloxy-biphenyl-3-yl) -pyrimidine-2,4-diamine.

¹ H NMR (d ₆ -DMSO) δ 6.37 (s, 1H), 6.48 (s, 2H), 6.57 (s, 2H), 6.83 (d, 2H), 6.85 (d, 1H), 7.41 (d, 2H ), 7.47 (d, 2H), 7.74 (s, 1H), 9.44 (s, 1H), 14.77 (s, 1H).

MS 295 (M + H), C ₁₆ H ₁₄ N ₄ O ₂ .

Example 53: 3- (2-amino-pyrimidin-4-yl) -3'-fluoro-biphenyl-4,4'-diol

Starting material for the title compound (4- (4,4'-bis-benzyloxy-3'-fluoro-biphenyl-3-yl) -pyrimidin-2-ylamine) is 2-chloro-4,5- Diaminopyrimidine was used as a white solid according to General Procedure H.

The title compound was obtained as a yellow solid according to General Procedure I using 4- (4,4'-bis-benzyloxy-3'-fluoro-biphenyl-3-yl) -pyrimidin-2-ylamine.

¹ H NMR (d ₆ -DMSO) δ 6.95 (dd, 1H) 7.16 (s, 2H) 7.35 (d, 1H) 7.49 (dd, 1H) 7.55 (d, 1H) 7.62 (d, 1H) 8.01 (s, 1H) 8.10 (s, 1 H) 8.39 (dd, 1 H) 9.95 (s, 1 H) 13.89 (s, 1 H).

MS (ESI +) 321 (M + Na) C ₁₆ H ₁₃ N ₃ O ₂ F.

Example 54: 3- (2-Amino-6-chloro-pyrimidin-4-yl) -biphenyl-4,4'-diol

A solution of 4,4′-biphenol (1 mmol) in dry DMF (5 mL) was maintained at a temperature of 70 ° C. or lower, in a NaH suspension (2.5 mmol, 60% in mineral oil) in DMF (5 mL) under nitrogen. Added dropwise. After stirring at room temperature for 2 hours, the temperature was maintained at 50 ° C. or lower and added dropwise under nitrogen. The mixture was stirred at room temperature for 3 hours and quenched with cold water (10 mL). The aqueous layer was further extracted with ether (3 × 10 mL). The combined organic layer was washed with 1 N NaOH, water and saturated NaCl, dried over Na 2 SO 4 and evaporated to give a white solid 4,4-dimethoxymethyletherbiphenol (98%).

¹ H NMR (CDCl ₃ ) δ 3.48 (s, 6H), 5.20 (s, 4H), 7.09 (d, 4H), 7.47 (d, 4H).

MS 275 (M + H), C ₁₆ H ₁₈ O ₄ .

A solution of n-BuLi (7.3 mmol, 2 M in cyclohexane) was added to a solution of TMEDA (7.3 mmol) in anhydrous ether (10 mL) at −40 ° C. under nitrogen and stirred at room temperature for 30 minutes. The solution was cooled to −78 ° C. and the temperature was kept below −70 ° C. to slowly add a solution of 4,4′-dimethoxy-methyletherbiphenol (7.3 mmol) in 20 mL ether. After stirring at −78 ° C. for 2 hours, the mixture was allowed to slowly reach room temperature over 5 hours. The solution was again cooled to −78 ° C. and treated with trimethylborate (21.9 mmol). The mixture was cooled to 0 [deg.] C., treated with cold water (10 mL) and then stirred for 30 min. Finally, the organic layer was separated and the aqueous layer was extracted with ether (3 × 30 mL). The residue was purified by column chromatography on silica gel (3 × 20 cm) separated by 1% MeOH in CH ₂ Cl ₂ to give the title compound as a yield of 52% 4,4′-dimethoxymethylether-. Obtained as a colorless liquid of 3-biphenylboronic acid.

¹ H NMR (CDCl ₃ ) δ 3.38 (s, 3H), 3.40 (s, 3H), 5.21 (s, 2H), 5.26 (s, 2H), 7.04 (d, 2H), 7.12 (d, 1H), 7.52 (d, 2H), 7.57 (dd, 1H), 7.75 (d, 1H), 7.88 (s, 2H).

MS 318 (M + H), C ₁₆ H ₁₉ BO ₆ .

Starting material for the title compound (4- (4,4'-bis-methoxymethoxy-biphenyl-3-yl) -6-chloro-pyrimidin-2-ylamine) is for the title compound is 2-amino- 4,6-dichloropyrimidine was used as a white solid according to General Procedure H.

The title compound was obtained as a yellow solid according to General Procedure J using 4- (4,4'-bis-methoxymethoxy-biphenyl-3-yl) -6-chloro-pyrimidin-2-ylamine.

¹ H NMR (d ₆ -DMSO) δ 6.83 (d, 2H) 6.98 (d, 1H) 7.55-7.65 (m, 6H) 8.13 (s, 1H) 9.48 (s, 1H) 13.38 (s, 1H).

MS (ESI < + >) 314 (M + H) C ₁₆ H ₁₂ N ₃ 0 ₂ Cl.

Example 55: 3- [2-amino-6- (2-hydroxy-ethylamino) -pyrimidin-4-yl] -biphenyl-4,4'-diol

The title compound is prepared according to general procedure E from 2-aminoethanol and 4- (4,4'-bis-methoxymethoxy-biphenyl-3-yl) -6-chloro-pyrimidin-2-ylamine, and It is prepared by a deprotection step according to general procedure J.

¹ H NMR (d ₆ -DMSO) δ 3.52 (m, 2H), 4.77 (s, 1H), 5.15 (m, 2H), 6.51 (s, 1H), 6.87 (d, 1H), 7.08 (d, 2H ), 7.35 (d, 1H), 7.39-7.42 (m, 2H), 7.46-7.48 (m, 2H), 7.50 (d, 1H), 7.54 (s, 1H), 7.55 (s, 1H), 14.85 ( s 1H).

MS (ESI +) 339 (M + H) C ₁₈ H ₁₈ N ₄ O ₃ .

Example 56: 3- [2-amino-6- (2,3-dihydroxy-propylamino) -pyrimidin-4-yl] -biphenyl-4,4'-diol

The title compound is a general procedure from 2,3-dihydroxyethylamine and 4- (4,4'-bis-methoxymethoxy-biphenyl-3-yl) -6-chloro-pyrimidin-2-ylamine According to K and according to the general procedure J.

¹ H NMR (d ₆ -DMSO) δ 3.23 (d, 2H) 3.49 (d, 2H) 3.61 (s, 1H) 4.66 (s, 1H) 4.91 (s, 1H) 6.52-6.62 (m, 3H) 6.82- 6.85 (m, 3 H) 7.06 (s, 1 H) 7.43-7.47 (m, 3 H) 7.76 (s, 1 H) 9.53 (s, 1 H) 14.76 (s, 1 H).

MS (ESI +) 369 (M + H) C ₁₉ H ₂₀ N ₄ O ₄ .

Example 57: 3- (2-Amino-pyrimidin-4-yl) -biphenyl-4,4'-diol

One equivalent of 5-bromo-2-methoxy-acetophenone and 15 equivalents of N , N- dimethylformamide diethyl acetal were combined and heated at 120 ° C. overnight. The reaction mixture is concentrated in vacuo and dissolved in butanol (0.1 M) with 3 equivalents of sodium ethoxide followed by 1.1 equivalents of guanidine hydrochloride. This mixture is heated at 120 ° C. overnight. The reaction mixture is extracted with dichloromethane, washed with water and dried over sodium sulphate. After purification on a silica gel column, the result was 4- (2-methoxy-5-bromo-phenyl) -pyrimidin-2-ylamine. The Suzuki reaction is then carried out with 4-methoxyphenylboronic acid according to general procedure G, whereby 4- (4,4'-dimethoxy-biphenyl-3-yl) -pyrimidin-2-ylamine Obtained in 90% yield.

The title compound was obtained as a yellow solid using 4- (4,4'-Dimethoxy-biphenyl-3-yl) -pyrimidin-2-ylamine according to General Procedure L.

1 H-NMR (d ₆ -DMSO): δ 6.85 (d, 2H), 6.92 (d, 1H), 7.19 (s, 2H), 7.42 (d, 1H), 7.48 (d, 2H), 7.57 (d, 1H), 8.09 (d, 1H), 8.32 (d, 1H), 9.43 (d, 1H), 13.70 (s, 1H).

MS 280 (M + H), C ₁₆ H ₁₃ N ₃ O ₂ .

Example 58: 3- (4,6-diamino- [1,3,5] triazin-2-yl) -biphenyl-4,4'-diol

According to General Procedure G, 1 equivalent of 5-bromo-2-methoxy-benznitrile (1 mmol) is reacted with 4-methoxyphenylboronic acid (1.05 mmol) to give 4,4-dimethoxy-3- Cyanobiphenol is obtained in a yield of 90%. 5 equivalents of dicyandiamide are dissolved in methyl cellosolve together with 5 equivalents of potassium hydroxide. To this solution, 1 equivalent of 4,4-dimethoxy-3-cyanobiphenol is added at a final concentration of 0.5 M. The solution is heated to 100 ° C. overnight with stirring or until it is determined that the reaction is complete in thin layer chromatography. The precipitated product is filtered and dried in vacuo (Simons, JK and Saxton, MR Organic Synthesis 1963, 78.) Starting material for the title compound (6- (4,4'-dimethoxy-biphenyl-3-yl) -[1,3,5] triazine-2,4-diamine is obtained in a yield of 78%.

The title compound was obtained as a yellow solid according to general procedure L using 6- (4,4'-dimethoxy-biphenyl-3-yl)-[1,3,5] triazine-2,4-diamine.

¹ H NMR (CDCl ₃ ) δ 7.06 (d, 1H), 7.23 (bs, 1H), 7.31 (d, 1H), 7.43 (d, 1H), 7.57 (d, 1H), 7.63 (s, 1H), 7.83 (d, 1 H), 8.41 (s, 1 H), 8.46 (d, 1 H), 9.57 (s, 1 H).

MS 282 (M + H), C ₁₅ H ₁₁ N ₃ O ₃ .

Example 59: 5- [3- (2-Amino-pyrimidin-4-yl) -4-hydroxy-phenyl] -furan-2-carbaaldehyde

One equivalent of 5-bromo-2-benzyloxy-acetophenone and 15 equivalents of N , N- dimethyl-formamide diethyl acetal are combined and heated to 120 ° C. overnight. The reaction mixture is concentrated in vacuo and dissolved in butanol (0.1 M) with 3 equivalents of sodium ethoxide and then 1.1 equivalents of guanidine hydrochloride. This mixture is heated to 120 ° C. overnight. The reaction mixture was extracted with dichloromethane, washed with water and then dried over sodium sulphate. After purification on a silica gel column, the result was 4- (2-benzyloxy-5-bromo-phenyl) -pyrimidin-2-ylamine. The Suzuki reaction was then carried out with 2-propylic boronic acid according to the general procedure G, yielding 5- [3- (2-amino-pyrimidin-4-yl) -4-benzyloxy- in 60% yield. Phenyl] -furan-2-carbaaldehyde.

The title compound was obtained as a yellow solid according to General Procedure I using 5- [3- (2-amino-pyrimidin-4-yl) -4-benzyloxy-phenyl] -furan-2-carbaaldehyde.

¹ H NMR (d ₆ -DMSO) δ 6.81 (d, 2H), 6.88 (d, 1H), 7.01 (s, 2H), 7.26 (s, 2H), 7.39 (d, 2H), 7.56 (d, 1H ), 8.38 (d, 1 H), 9.44 (s, 1 H), 13.86 (s, 1 H).

MS (ESI +) 296 (M + H) C ₁₅ H ₁₃ N ₅ O ₂ .

Example 60: 2- (2-Amino-pyrimidin-4-yl) -4- (1H-indol-5-yl) -phenol

4- (2-benzyloxy-5-bromo-phenyl) -pyrimidin-2-ylamine obtained in Example 59 with 5-indolylboronic acid was used in the Suzuki reaction according to General Procedure G, to obtain 85% Yielded 4- [2-benzyloxy-5- ( 1H -indol-5-yl) -phenyl] -pyrimidin-2-ylamine.

The benzyl group is then removed according to general procedure I to afford the title compound in 90% yield.

¹ H NMR (d ₆ -DMSO) δ 6.46 (s, 1H), 6.98 (d, 1H), 7.16, (s, 2H), 7.36 (s, 1H), 7.41-7.46 (m, 3H), 7.66 ( d, 1H), 7.84 (s, 1H), 8.14 (s, 1H), 8.38 (d, 2H), 11.10 (s, 1H), 13.76 (s, 1H).

MS (ESI +) 303 (M + H) C ₁₈ H ₁₄ N ₄ O.

Example 61: 3- (2-amino-thiazol-4-yl) -biphenyl-4,4'-diol

Synthesis of the title compound is accomplished by dissolving 1 equivalent of ketone in glacial acetic acid at a final concentration of 0.2 M. To this solution, one equivalent of bromine (1 M) dissolved in glacial acetic acid is carefully added. The resulting solution is stirred at room temperature for 1 hour. The solution is partitioned between dichloromethane and water. The combined organic layers are washed with water, dried over sodium sulphate, filtered and concentrated. The resulting compound is dissolved again in dioxane (0.2 M) and 1 equivalent of thiourea is added. The mixture is stirred at room temperature for 18 hours. The reaction mixture is partitioned between dichloromethane and saturated sodium bicarbonate solution, dried over sodium sulphate, filtered and concentrated. The final product is purified by silica gel chromatography. The methyl groups are then cleaved according to general procedure L.

¹ H NMR (d ₆ -DMSO) δ 6.81 (d, 2H), 6.86 (d, 1H), 7.24 (s, 1H), 7.33-7.35 (dd, 1H), 7.44 (s, 1H), 7.45 (m , 3H), 7.88 (d, 1H), 9.41 (s, 1H), 11.89 (s, 1H).

MS (APCI) 307 (M + Na) C ₁₅ H ₁₂ N ₂ O ₂ S.

Example 62: 2- (2-Amino-pyrimidin-4-yl) -4-pyridin-4-yl-phenol

The title compound was subjected to the Suzuki reaction with 4-pyridylboronic acid described in General Procedure G, followed by deprotection using TFA with 5-10% thianiazole (Scheme 5), 4- ( Obtained from 2-benzyloxy-5-bromo-phenyl) -pyrimidin-2-ylamine.

¹ H NMR (DMSO-d ₆ ) δ 7.05 (d, J = 8.6 Hz, 1 H), 7.22 (br s, 2 H), 7.56 (d, J = 5.2 Hz, 1 H), 7.80 (d, J = 5.0 Hz, 2H), 7.84 (d, J = 8.6 Hz, 1H), 8.37 (s, 1H), 8.43 (d, J = 5.2 Hz, 1H), 8.60 (d, J = 5.0 Hz , 2H), 14.2 (br s, 1H).

ESI: m / z 265.40 (M + H < + >, C ₁₅ H ₁₂ N ₄ O requires 265.11).

Example 63: 2- (2-Amino-pyrimidin-4-yl) -4-pyridin-3-yl-phenol

The title compound was subjected to Suzuki reaction with 3-pyridylboronic acid described in General Procedure G, followed by deprotection using TFA with 5-10% thianizol (Scheme 5). Obtained as a yellow solid from (2-benzyloxy-5-bromo-phenyl) -pyrimidin-2-ylamine.

¹ H NMR (DMSO-d ₆ ) δ 7.04 (d, J = 8.5 Hz, 1 H), 7.20 (br s, 2 H), 7.46 (dd, J = 4.5, 7.5 Hz, 1 H), 7.54 (d , J = 5.3 Hz, 1 H), 7.75 (d, J = 8.5 Hz, 1 H), 8.13 (d, J = 7.5 Hz, 1 H), 8.28 (s, 1 H), 8.41 (d, J = 5.3 Hz, 1 H), 8.53 (d, J = 4.5 Hz, 1 H), 8.96 (s, 1 H), 14.1 (br s, 1 H).

ESI: m / z 265.41 (M + H < + >, C ₁₅ H ₁₂ N ₄ O requires 265.11).

Example 64: 4- (6-Amino-pyridin-2-yl) -2- (2-amino-pyrimidin-4-yl) -phenol

4- (2-benzyloxy-5-bromo-phenyl) -pyrimidin-2-ylamine (see Example 59) (17.65 mmol), bis- (pinacolato) diboron in anhydrous DMF (125 mL) (19.42 mmol), potassium acetate (52.95 mmol) and a mixture of Pd (dppf) Cl ₂ were heated overnight at 80 ° C. under nitrogen. The cooled solution was partitioned between CH ₂ Cl ₂ and water. The combined organic phases were washed successively with water and brine, then dried over Na ₂ SO ₄ and concentrated. The crude product was purified by flash chromatography to give the desired boronate.

The title compound was subjected to Suzuki reaction with 2-amino-6-bromopyridine described in General Procedure G, and then deprotected using TFA with 5-10% thianiazole (Scheme 6). Was obtained as a yellow solid from the boronate.

¹ H NMR (DMSO-d ₆ ) δ 5.96 (s, 2 H), 6.37 (d, J = 7.7 Hz, 1 H), 6.96 (d, J = 8.5 Hz, 1 H), 7.12 (d, J = 7.7 Hz, 1 H), 7.19 (br s, 2 H), 7.34 (d, J = 5.2 Hz, 1 H), 7.43 (t, J = 7.7 Hz, 1 H), 8.00 (d, J = 8.5 Hz , 1 H), 8.41 (d, J = 5.2 Hz, 1 H), 8.49 (s, 1 H), 14.0 (br s, 1 H).

ESI: m / z 280.50 (M + H < + >, C ₁₅ H ₁₃ N ₅ O requires 280.12).

Example 65: 4- (6-Amino-pyridin-3-yl) -2- (2-amino-pyrimidin-4-yl) -phenol

The title compound was subjected to boronate (execution) by deprotection (Scheme 6) with TFA with 2-amino-5-bromopyridine via Suzuki reaction and then with 5-10% thianiazole. As a yellow solid).

¹ H NMR (DMSO-d ₆ ) δ 5.97 (s, 2 H), 6.51 (d, J = 8.5 Hz, 1 H), 6.95 (d, J = 8.5 Hz, 1 H), 7.16 (br s, 2 H), 7.46 (d, J = 5.4 Hz, 1 H), 7.56 (d, J = 8.5 Hz, 1 H), 7.74 (d, J = 8.5 Hz, 1 H), 8.05 (s, 1 H), 8.27 (s, 1 H), 8.38 (d, J = 5.4 Hz, 1 H), 13.8 (br s, 1 H).

ESI: m / z 280.49 (M + H < + >, C ₁₅ H ₁₃ N ₅ O requires 280.12).

Example 66: 2- (2-Amino-pyrimidin-4-yl) -4- (2-amino-pyrimidin-5-yl) -phenol

The title compound was subjected to boronate (execution) by deprotection (Scheme 6) with TFA with 2-amino-5-bromopyridine via Suzuki reaction and then with 5-10% thianiazole. As a yellow solid).

¹ H NMR (DMSO-d ₆ ) δ 6.71 (br s, 2 H), 6.97 (d, J = 8.5 Hz, 1 H), 7.19 (br s, 2 H), 7.51 (d, J = 5.2 Hz, 1 H), 7.61 (d, J = 8.5 Hz, 1 H), 8.13 (s, 1 H), 8.40 (d, J = 5.2 Hz, 1 H), 8.61 (s, 1 H), 13.9 (s, 1 H).

ESI: m / z 281.60 (M + H < + >, C ₁₄ H ₁₂ N ₆ O requires 281.12).

Example 67: 4- (2-Amino-pyridin-4-yl) -2- (2-amino-pyrimidin-4-yl) -phenol

The title compound was subjected to boronate (exemplified by Deprotection (Scheme 6) using TFA with 5-10% thioanizol, via Suzuki reaction with 2-amino-4-bromopyridine). As a yellow solid).

¹ H NMR (DMSO-d ₆ ) δ 5.90 (s, 2 H), 6.73 (s, 1 H), 6.87 (d, J = 5.1 Hz, 1 H), 7.01 (d, J = 8.5 Hz, 1 H ), 7.21 (br s, 2H), 7.43 (d, J = 5.2 Hz, 1H), 7.64 (d, J = 8.5 Hz, 1H), 7.94 (d, J = 5.1 Hz, 1H), 8.16 (s, 1 H), 8.40 (d, J = 5.2 Hz, 1 H), 14.0 (s, 1 H).

ESI: m / z 280.41 (M + H < + >, C ₁₅ H ₁₃ N ₅ O requires 280.12).

Example 68: 2,4-bis- (2-amino-pyrimidin-4-yl) -phenol

The 6-hydroxy-2,4-diacetophenone solution in anhydrous THF was treated with MOM-Cl / NaH and further stirred for 1 hour at room temperature under nitrogen. Then, the mixture was extracted and dried. The MOM protective acetophenone solution (Scheme 7) in N, N'-dimethylformamide diethylacetal (15 equiv) was heated to reflux for 40 hours and evaporated under vacuum to give a yellow oil. This oil was dissolved in ethanol, treated with sodium ethoxide and guanidine hydrochloride, and then heated to reflux overnight. The cooled solution was diluted with water, extracted with CH ₂ Cl ₂ and the combined organic phases were concentrated to give a yellow viscous oil. This crude product was further purified by flash chromatography, which was dissolved in 0-5% MeOH in CH ₂ Cl ₂ and separated to give pale yellow-orange crystals. The MOM group was then removed using TFA as described in General Procedure I.

¹ H NMR (DMSOd ₆ ) δ 6.60 (s, 2 H), 7.00 (s, 1 H), 7.22 (br s, 3 H), 7.40 (s, 1 H), 8.01 (s, 1 H), 8.26 (s, 1 H), 8.42 (s, 1 H), 8.60 (s, 1 H), 14.30 (br s, 1 H).

ESI: m / z 281.51 (M + H < + >, C ₁₄ H ₁₂ N ₆ O requires 281.12).

Example 69: 2- (2-Amino-pyrimidin-4-yl) -4- (1H-pyrrole-2-yl) -phenol

The title compound was subjected to 4- (2) by deprotection (Scheme 6) via a Suzuki reaction with N-Boc protected 2-pyrroleylboronic acid and then using TFA with 5-10% thianiazole. Obtained as a yellow solid from -benzyloxy-5-bromo-phenyl) -pyrimidin-2-ylamine (see Example 59).

¹ H NMR (acetone-d ₆ ) δ 6.15 (s, 1 H), 6.48 (s, 1 H), 6.63 (br s, 2 H), 6.84 (s, 1 H), 6.92 (d, J = 8.5 Hz, 1 H), 7.41 (d, J = 5.4 Hz, 1 H), 7.65 (d, J = 8.5 Hz, 1 H), 8.18 (s, 1 H), 8.43 (d, J = 5.4 Hz, 1 H), 10.52 (br s, 1 H), 13.6 (s, 1 H).

ESI: m / z 253.49 (M + H < + >, C ₁₄ H ₁₂ N ₄ O requires 253.11).

Example 70: 5- [3- (2-Amino-pyrimidin-4-yl) -4-hydroxy-phenyl] -1 H-pyrimidine-2,4-dione

The title compound is subjected to Suprotection with Suzuki reaction with 2,4-dibenzyloxy-5-pyrimidylboronic acid as described in General Procedure G, and then deprotected using hydrogenation with palladium on charcoal ( By scheme 5), it was obtained as a yellow solid from 4- (2-benzyloxy-5-bromo-phenyl) -pyrimidin-2-ylamine.

¹ H NMR (DMSO-d ₆ ) δ 6.88 (d, J = 8.5 Hz, 1 H), 7.15 (br s, 2 H), 7.27 (d, J = 5.2 Hz, 1 H), 7.56 (d, J = 8.5 Hz, 1 H), 7.70 (s, 1 H), 8.04 (s, 1 H), 8.37 (d, J = 5.2 Hz, 1 H), 11.00 (bump), 13.80 (bump).

ESI: m / z 298.47 (M + H < + >, C ₁₄ H ₁₁ N ₅ O ₃ requires 298.09).

Example 71: 2- (2-Aminopyridin-6-yl) -4- (2-aminopyrimidin-4-yl) -phenol

4- [4- (2-methoxy-ethoxymethoxy) -3- (4,4,5,5-tetramethyl- [1,3,2] -dioxaborolane, according to general procedure M 2-yl-phenyl] -pyrimidin-2-ylamine is reacted with 2-amino-6-bromopyridine to give 4- [3- (2-aminopyridin-6-yl) -4- (2-meth Toxy-ethoxymethoxy) -phenyl] -pyrimidin-2-ylamine (54% yield) was obtained, which was then treated with TFA and triethylsilane in CH ₂ Cl ₂ at room temperature before conversion to the title compound. Yield 47%.

¹ H NMR (d ₆ -DMSO) 6.50 (d, 1H), 6.57 (s, 2H), 6.63 (s, 2H) 6.93 (d, 1H), 7.20 (d, 1H), 7.34 (d, 1H), 7.61 (t, 1 H), 7.98 (d, 1 H), 8.25 (d, 1 H), 8.56 (s, 1 H), 15.10 (s, 1 H).

MS 280 (M + H), C ₁₅ H ₁₃ N ₅ O.

Example 72: 2- (2-Amino-4-methyl-pyrimidin-6-yl) -4- (2-aminopyrimidin-4-yl) -phenol

4- [4- (2-methoxy-ethoxymethoxy) -3- (4,4,5,5-tetramethyl- [1,3,2] -dioxaborolane, according to general procedure M 2-yl-phenyl] -pyrimidin-2-ylamine is reacted with 2-amino-6-chloro-4-methylpyrimidine to give 4- [3- (2-amino-4-methyl-pyrimidine-6 -Yl) -4- (2-methoxy-ethoxymethoxy) -phenyl] -pyrimidin-2-ylamine was obtained, which was then treated with TFA and triethylsilane in CH ₂ Cl ₂ at room temperature and then titled Converted to compound.

¹ H NMR (d ₆ -DMSO) 2.35 (s, 3H), 6.67 (s, 2H), 6.99 (d, 1H), 7.20 (s, 2H), 7.24 (d, 1H), 7.33 (s, 1H) , 8.09 (d, 1H), 8.30 (d, 1H), 8.58 (s, 1H), 14.54 (s, 1H).

MS 295 (M + H), C ₁₅ H ₁₄ N ₆ O.

Example 73: 2- (2-Amino-4-chloro-pyrimidin-6-yl) -4- (2-aminopyrimidin-4-yl) -phenol

4- [4- (2-methoxy-ethoxymethoxy) -3- (4,4,5,5-tetramethyl- [1,3,2] -dioxaborolane, according to general procedure M 2-yl-phenyl] -pyrimidin-2-ylamine is reacted with 2-amino-4,6-dichloropyrimidine to give 4- [3- (2-amino-4-chloro-pyrimidine-6 -Yl) -4- (2-methoxy-ethoxymethoxy) -phenyl] -pyrimidin-2-ylamine was obtained, which was then treated with TFA and triethylsilane in CH ₂ Cl ₂ at room temperature and then titled Converted to compound.

¹ H NMR (d ₆ -DMSO) 6.58 (s, 2H), 7.03 (d, 1H), 7.30 (s, 1H), 7.57 (s, 1H), 7.69 (s, 2H), 8.16 (d, 1H) , 8.24 (d, 1 H), 8.59 (s, 1 H), 14.05 (s, 1 H).

MS 315 (M + H), C ₁₄ H ₁₁ N ₆ OCl.

Example 74: 2- (2,4-Diamino-pyrimidin-6-yl) -4- (2-aminopyrimidin-4-yl) -phenol

4- [4- (2-methoxy-ethoxymethoxy) -3- (4,4,5,5-tetramethyl- [1,3,2] -dioxaborolane, according to general procedure M 2-yl-phenyl] -pyrimidin-2-ylamine is reacted with 2,4-diamino-6-chloropyrimidine to give 4- [3- (2,4-diamino-pyrimidine-6- Il) -4- (2-methoxy-ethoxymethoxy) -phenyl] -pyrimidin-2-ylamine was obtained, and then treated with TFA and triethylsilin in CH ₂ Cl ₂ at room temperature, followed by the title Converted to compound.

¹ H NMR (d ₆ -DMSO) 6.38 (s, 1H), 6.60 (d, 4H), 6.71 (s, 2H), 6.86 (d, 1H), 7.06 (d, 1H), 7.95 (d, 1H) , 8.25 (d, 1 H), 8.36 (s, 1 H), 15.54 (s, 1 H).

MS 296 (M + H), C ₁₄ H ₁₃ N ₇ O.

Example 75: 2- (2-Amino-4-methoxy-pyrimidin-6-yl) -4- (2-aminopyrimidin-4-yl) -phenol

4- [4- (2-methoxy-ethoxymethoxy) -3- (4,4,5,5-tetramethyl- [1,3,2] -dioxaborolane, according to general procedure M 2-yl-phenyl] -pyrimidin-2-ylamine is reacted with 2-amino-6-chloro-4-methoxypyrimidine to give 4- [3- (2-amino-4-methoxy-pyrimidine -6-yl) -4- (2-methoxy-ethoxymethoxy) -phenyl] -pyrimidin-2-ylamine was obtained, which was then treated with TFA and triethylsilane in CH ₂ Cl ₂ at room temperature. Then it was converted to the title compound.

¹ H NMR (d ₆ -DMSO) 3.90 (s, 3H), 6.59 (s, 3H), 6.83 (d, 1H), 6.97 (d, 1H), 7.26 (d, 2H), 8.08 (d, 1H) , 8.25 (d, 1 H), 8.56 (s, 1 H), 14.66 (s, 1 H).

MS 211 (M + H), C ₁₅ H ₁₄ N ₆ O ₂ .

Example 76: 2- [2-amino-4- (piperazin-1-yl) -pyrimidin-6-yl] -4- (2-aminopyrimidin-4-yl)]-phenol

4- [2- (2-amino-4-chloro-pyrimidin-6-yl) -4- (2-aminopyrimidin-4-yl) -phenol (see Example 73) (120 mg, 0.38 mmol), t-butyl-1-piperazinecarboxylate (78.1 mg, 0.41 mmol) and DIPEA (0.2 mL, 1.14 mmol) were heated at 110 ° C. overnight. The solution was cooled and evaporated in vacuo to afford a residue, which was purified by flash chromatography, which was dissolved in 2-5% MeOH in CH ₂ Cl ₂ and separated, giving 2- [2-amino-4- (t-butoxy). Carbonylpiperazin-1-yl) -pyrimidin-6-yl] -4- (2-aminopyrimidin-4-yl) -phenol was obtained as a yellow solid (60 mg, 34%).

¹ H NMR (d ₆ -DMSO) δ 1.41 (s, 12H), 3.48 (t, 4H), 3.72 (t, 4H), 6.59 (s, 2H), 6.78 (s, 1H), 6.94 (d, 1H ), 7.22 (s, 2H), 7.27 (d, 1H), 8.06 (d, 1H), 8.26 (t, 1H), 8.52 (s, 1H), 15.44 (s, 1H).

MS 465 (M + H), C ₂₃ H ₂₃ N ₈ O ₃ .

The title compound is 2- [2-amino-4- (t-butoxycarbonylpiperazin-1-yl) -pyrimidin-6-yl] -4- (2-aminopyrimidine-4 according to General Procedure J. -Yl) -phenol.

¹ H NMR (d ₆ -DMSO) δ 2.75 (t, 4H), 3.63 (t, 4H), 6.58 (s, 2H), 6.66 (s, 1H), 6.70 (s, 1H), 6.91 (d, 1H ), 7.28 (d, 1H), 8.05 (d, 1H), 8.25 (d, 1H), 8.51 (s, 1H), 15.57 (s, 1H).

MS 365 (M + H), C ₁₈ H ₂₀ N ₈ O.

Example 77: 3- [2-Amino-6- (5-hydroxy-pentylamino) -pyrimidin-4-yl] -biphenyl-4,4'-diol

The title compound was reacted with 5-hydroxy 3- (2-amino-6-chloro-pyrimidin-4-yl) -biphenyl-4,4'-diol (see Scheme 9 and Example 54) according to General Procedure K. Obtained when treating with pentylamine.

¹ H NMR (d ₆ -DMSO) δ 1.38 (m, 2H) 1.47 (m, 2H) 1.52 (m, 2H) 3.31 (m, 2H) 4.43 (s, 1H) 6.44 (s, 1H) 6.60 (d, 2H) 6.84-6.88 (m, 3H) 7.15 (s, 1H) 7.45-7.49 (m, 3H) 7.76 (s, 1H) 9.49 (s, 1H) 14.80 (s, 1H)

MS (ESI +) 381 (M + H) C ₂ 1H ₂₄ N ₄ O ₃

Example 78: 3- (2-Amino-6-piperazin-1-yl-pyrimidin-4-yl) -biphenyl-4,4'-diol

The title compound is 3- (2-amino-6-chloro-pyrimidin-4-yl) -biphenyl-4,4'-diol (see Scheme 9 and Example 54) according to General Procedure K. Obtained upon treatment with 1-piperazinecarboxylate and deprotection as described in General Procedure J.

¹ H NMR (d ₆ -DMSO) δ 2.82 (m, 4H) 3.67 (m, 4H) 6.01 (s, 2H) 6.74 (s, 1H) 6.82 (d, 2H) 6.85 (d, 1H) 7.47 (dd, 1H) 7.50 (d, 2H) 8.06 (s, 1H) 9.43 (s, 1H)

MS (ESI +) 364 (M + H) C ₂ 0H ₂₁ N ₅ O ₂

Example 79: 3- [2-Amino-6- (2R-hydroxymethyl-pyrrolidin-1-yl) -pyrimidin-4-yl] -biphenyl-4,4'-diol

The title compound 3 in accordance with the following general procedure K 2 R (see Scheme 9 and Example 54), biphenyl-4,4'-diol - - (2-amino-6-chloro-pyrimidin-4-yl) hydroxy Obtained when treating with oxymethyl-pyrrolidinol.

¹ H NMR (d ₆ -DMSO) δ 1.90 (m, 2H) 2.00 (m, 2H) 3.33 (m, 1H) 3.40 (m, 2H) 3.57 (m, 2H) 6.79 (d, 1H) 6.83 (d, 2H) 6.85 (d, 1H) 7.37 (d, 1H) 7.45-7.48 (m, 3H) 7.95 (s, 2H) 9.44 (s, 1H) 14.83 (s, 1H)

MS (ESI +) 379 (M + H) C ₂ 1H22N ₄ O ₃

Example 80: 3- [2-Amino-6- (2S-hydroxymethyl-pyrrolidin-1-yl) -pyrimidin-4-yl] -biphenyl-4,4'-diol

The title compound 3 in accordance with the following general procedure K 2 S (see Scheme 9 and Example 54), biphenyl-4,4'-diol - - (2-amino-6-chloro-pyrimidin-4-yl) hydroxy Obtained when treating with oxymethyl-pyrrolidinol.

¹ H NMR (d ₆ -DMSO) δ 1.90 (m, 2H) 2.00 (bs, 2H) 3.17 (s, 1H) 3.39 (bs, 2H) 3.56 (bs, 2H) 4.11 (s, 1H) 6.55 (bs, 1H) 6.79 (d, 1H) 6.83 (d, 2H) 6.85 (d, 1H) 7.36 (d, 1H) 7.45-7.51 (m, 3H) 7.96 (bs, 1H) 9.44 (s, 1H) 14.81 (s, 1H)

MS (ESI +) 379 (M + H) C ₂ 1H22N ₄ O ₃

Example 81: 3- (2-Amino-6-morpholin-4-yl-pyrimidin-4-yl) -biphenyl-4,4'-diol

The title compound was treated with 3- (2-amino-6-chloro-pyrimidin-4-yl) -biphenyl-4,4'-diol (see Scheme 9 and Example 54) according to General Procedure K with morpholine. Was obtained when.

¹ H NMR (d ₆ -DMSO) δ 3.60-3.70 (m, 8H) 6.76-6.79 (m, 2H) 6.82 (d, 2H) 6.86 (d, 1H) 7.36 (d, 1H) 7.48 (dd, 1H) 7.50 (d, 2H) 8.07 (s, 1H) 9.43 (s, 1H) 14.78 (s, 1H)

MS (ESI +) 365 (M + H) C ₂ 0H ₂₀ N ₄ O ₃

Example 82: 3- [2-amino-6- (3-hydroxymethyl-piperidin-1-yl) -pyrimidin-4-yl] -biphenyl-4,4'-diol

The title compound is 3-hydroxymethyl 3- (2-amino-6-chloro-pyrimidin-4-yl) -biphenyl-4,4'-diol (Scheme 9 and Example 54) according to General Procedure K. Obtained when treated with piperidine.

¹ H NMR (d ₆ -DMSO) δ 3.17 (m, 4H) 3.34 (m, 4H) 4.12 (m, 1H) 4.59 (m, 2H) 6.55 (bs, 1H) 6.79 (d, 1H) 6.82-6.85 ( m, 4H) 7.45-7.50 (m, 3H) 8.02 (s, 1H) 9.42 (s, 1H) 14.85 (s, 1H)

MS (ESI +) 393 (M + H) C ₂₂ H ₂₄ N ₄ O ₃

Example 83: 3- [2-amino-6- (2-hydroxymethyl-phenyl) -pyrimidin-4-yl] -biphenyl-4,4'-diol

The title compound, 1) has 2-hydroxymethylphenylboronic acid according to general procedure G and has MEM protection 3- (2-amino-6-chloro-pyrimidin-4-yl) -biphenyl-4,4'-diol Suzuki Reaction (see Scheme 10 and Example 54), and 2) from the deprotection reaction according to General Procedure J.

¹ H NMR (d ₆ -DMSO) δ 4.61 (s, 2H) 5.25 (s, 1H) 6.81 (d, 2H) 6.97 (d, 1H) 7.30 (bs, 2H) 7.41 (t, 1H) 7.49 (t, 1H) 7.53 (d, 2H) 7.58-7.62 (m, 3H) 7.68 (s, 1H) 8.18 (d, 1H) 9.15 (s, 1H) 13.91 (s, 1H)

MS (ESI +) 386 (M + H) C ₂₃ H ₁₉ N ₃ O ₃

Example 84: 3- [2-amino-6- (3-hydroxymethyl-phenyl) -pyrimidin-4-yl] -biphenyl-4,4'-diol

The title compound, 1) has 3-hydroxymethylphenylboronic acid according to general procedure G and MEM protected 3- (2-amino-6-chloro-pyrimidin-4-yl) -biphenyl-4,4'-diol Suzuki reaction (see Scheme 10 and Example 54), and 2) from deprotection reaction according to general procedure J.

¹ H NMR (d ₆ -DMSO) δ 4.61 (s, 2H) 5.32 (s, 1H) 6.85 (d, 2H) 6.97 (d, 1H) 7.26 (bs, 2H) 7.50 (d, 2H) 7.59 (d, 1H) 7.93 (s, 1H) 8.17 (t, 1H) 8.23 (s, 1H) 8.30 (d, 1H) 9.52 (s, 1H) 14.05 (s, 1H)

MS (ESI +) 386 (M + H) C ₂₃ H ₁₉ N ₃ O ₃

Example 85: 3- [2-amino-6- (4-hydroxymethyl-phenyl) -pyrimidin-4-yl] -biphenyl-4,4'-diol

The title compound, 1) has 4-hydroxymethylphenylboronic acid according to general procedure G and MEM protected 3- (2-amino-6-chloro-pyrimidin-4-yl) -biphenyl-4,4'-diol Suzuki Reaction (see Scheme 10 and Example 54), and 2) from the deprotection reaction according to General Procedure J.

¹ H NMR (d ₆ -DMSO) δ 2.16 (s, 2H) 5.35 (s, 1H) 6.86 (d, 2H) 6.96 (d, 1H) 7.22 (bs, 2H) 7.48 (d, 2H) 7.56-7.58 ( m, 3H) 7.94 (s, 1H) 8.28 (d, 2H) 8.31 (d, 1H) 9.58 (s, 1H) 14.08 (s, 1H)

MS (ESI +) 386 (M + H) C ₂₃ H ₁₉ N ₃ O ₃

Example 86: 3- [2-Amino-6- (1R-benzyl-2-hydroxy-ethylamino) -pyrimidin-4-yl] -biphenyl-4,4'-diol

The title compound is treated with D-phenylalaninol for 3- (2-amino-6-chloro-pyrimidin-4-yl) -biphenyl-4,4'-diol (Example 54) according to General Procedure K. When obtained.

¹ H NMR (d ₆ -DMSO) δ 2.73-2.77 (m, 1H) 2.89-2.92 (m, 1H) 3.43 (m, 2H) 4.24 (bs, 1H) 4.87 (m, 1H) 6.49 (s, 1H) 6.55 (bs, 2H) 6.84-6.85 (m, 3H) 7.07 (d, 1H) 7.17 (t, 1H) 7.25-7.30 (m, 4H) 7.40-7.47 (m, 3H) 7.74 (s, 1H) 9.48 ( s, 1 H) 14.76 (s, 1 H)

MS (ESI +) 429 (M + H) C ₂₅ H ₂₄ N ₄ O ₃

Example 87: 3- [2-Amino-6- (1S-benzyl-2-hydroxy-ethylamino) -pyrimidin-4-yl] -biphenyl-4,4'-diol

The title compound was treated with L-phenylalaninol for 3- (2-amino-6-chloro-pyrimidin-4-yl) -biphenyl-4,4'-diol (Example 54) according to General Procedure K. When obtained.

¹ H NMR (d ₆ -DMSO) δ 2.76-2.77 (m, 1H) 2.89-2.92 (m, 1H) 3.43 (m, 2H) 4.25 (bs, 1H) 4.87 (m, 1H) 6.50 (s, 1H) 6.55 (bs, 2H) 6.83-6.85 (m, 3H) 7.06 (bs, 1H) 7.17 (bs, 1H) 7.27-7.30 (m, 4H) 7.43-7.47 (m, 3H) 7.74 (s, 1H) 9.48 ( s, 1 H) 14.76 (s, 1 H)

MS (ESI +) 429 (M + H) C ₂₅ H ₂₄ N ₄ O ₃

Example 88: 3- [2-amino-6- (3-nitro-phenyl) -pyrimidin-4-yl] -biphenyl-4,4'-diol

The title compound is prepared by 1) 3-nitrophenylboronic acid according to general procedure G and with MEM protection 3- (2-amino-6-chloro-pyrimidin-4-yl) -biphenyl-4,4'-diol ( From the deprotection method according to Suzuki Reaction of Example 54) and 2) General Procedure J.

¹ H NMR (d ₆ -DMSO) δ 6.89 (d, 2H) 7.00 (d, 1H) 7.47 (s, 2H) 7.61 (d, 2H) 7.64 (dd, 1H) 7.89 (t, 1H) 8.16 (s, 1H) 8.40 (d, 1H) 8.44 (dd, 1H) 8.84 (d, 1H) 9.11 (s, 1H) 9.53 (s, 1H) 13.95 (s, 1H)

MS (ESI +) 401 (M + H) C ₂₂ H ₁₆ N ₄ O ₄

Example 89: 3- [2-amino-6- (4-nitro-phenyl) -pyrimidin-4-yl] -biphenyl-4,4'-diol

The title compound is prepared by 1) 4-nitrophenylboronic acid according to general procedure G and with MEM protection 3- (2-amino-6-chloro-pyrimidin-4-yl) -biphenyl-4,4'-diol ( From the deprotection method according to Suzuki Reaction of Example 54) and 2) General Procedure J.

¹ H NMR (d ₆ -DMSO) δ 6.86 (m, 3H) 6.99 (d, 1H) 7.56-7.58 (m, 3H) 7.61 (d, 1H) 8.10 (s, 1H) 8.35 (s, 1H) 8.40 ( d, 2H) 8.56 (d, 2H) 9.53 (s, 1H) 13.87 (s, 1H)

MS (ESI +) 401 (M + H) C ₂₂ H ₁₆ N ₄ O ₄

Example 90: 3- [2-amino-6- (4-amino-phenyl) -pyrimidin-4-yl] -biphenyl-4,4'-diol

The title compound was obtained from hydrogenation of the compound of Example 89.

¹ H NMR (d ₆ -DMSO) δ 5.76 (s, 2H) 6.65 (d, 2H) 6.85 (d, 2H) 6.94 (d, 1H) 6.98 (s, 2H) 7.53-7.57 (m, 3H) 7.73 ( s, 1H) 8.06 (d, 2H) 8.25 (s, 1H) 9.46 (s, 1H) 14.33 (s, 1H)

MS (ESI +) 371 (M + H) C ₂₂ H ₁₈ N ₄ O ₂

Example 91: 3- [2-amino-6- (3-amino-phenyl) -pyrimidin-4-yl] -biphenyl-4,4'-diol

The title compound was obtained from hydrogenation of the compound of Example 88.

¹ H NMR (d ₆ -DMSO) δ 5.23 (s, 2H) 6.72 (d, 1H) 6.83-6.84 (m, 3H) 6.95 (d, 1H) 7.16 (t, 1H) 7.39 (m, 2H) 7.53- 7.54 (m, 4H) 7.78 (bs, 1H) 8.22 (s, 1H) 13.98 (s, 1H)

MS (ESI +) 371 (M + H) C ₂₂ H ₁₈ N ₄ O ₂

Example 92: 2- (2-amino-pyrimidin-4-yl) -4- [2- (2-amino-pyrimidin-4-yl) -vinyl] -phenol

In an inert atmosphere, to a mixture of NBu ₄ Cl (1 equiv), NaHCO ₃ (2.5 equiv) and Pd (OAc) ₂ (5 mole%), a solution of aryl bromide in DMF with a solution of aryl bromide (0.1 M) Vinyl ketone (1.5 equiv) was added. The reaction mixture was stirred at 100 ° C. for 21 hours and the solvent was evaporated. The crude product was taken up in EtOAc and the solution washed with water and brine, then dried over MgSO 4, filtered and evaporated. Purification by column chromatography (50% EtOAc-Hexane) gave pure Heck coupling product.

The Heck coupling product was then converted to enamines at reflux for 24 hours in N, N'-dimethylformamide diethylacetal. The resulting oil was dissolved in ethanol (180 mL), treated with sodium ethoxide (4 equiv) and guanidine hydrochloride (2 equiv) and then refluxed overnight. The cooled solution was diluted with water, extracted with CH ₂ Cl ₂ and the combined organic phases were concentrated to give a red viscous oil. The MEM group was then removed as described in General Procedure J.

Yellow solid; ¹ H NMR (DMSO-d ₆ ) δ 6.49 (s, 2 H), 6.66 (d, J = 4.8 Hz, 1 H), 6.95 (d, J = 8.6 Hz, 1 H), 7.02 (d, J = 16.0 Hz, 1 H), 7.22 (br s, 2 H), 7.43 (d, J = 5.2 Hz, 1 H), 7.69 (m, 2 H), 8.20 (d, J = 4.8 Hz, 1 H), 8.23 (s, 1 H), 8.42 (d, J = 5.2 Hz, 1 H), 14.2 (s, 1 H); ESI: m / z 307.08 (M + H < + >, C ₁₆ H ₁₄ N ₆ O requires 307.13).

Example 93: 2- [2-Amino-6- (2-hydroxy-1R-phenyl-ethylamino) -pyrimidin-4-yl] -4- (1H-indol-5-yl) -phenol

The synthesis of the title compound is described in Scheme 31.

1- (5-Bromo-2-methoxy-phenyl) -ethanone

1- (5-Bromo-2-hydroxy-phenyl) -ethanone (10 g, 47 mmol) in acetone (80 mL), methyl iodide (3.5 mL, 56 mmol), and potassium carbonate ( 10 g, 73 mmol) was heated to reflux for 4 hours. The reaction mixture was cooled to room temperature and the white solid obtained was filtered and washed almost with ethyl acetate. The filtered material was washed with water, brine, dried over MgSO ₄ and filtered. The filtered material was concentrated in vacuo to afford the title compound (10 g, 94%) as a white solid.

3- (5-Bromo-2-methoxy-phenyl) -3-oxo-propionic acid methyl ester

A mixture of 1- (5-bromo-2-methoxy-phenyl) -ethanone (10 g, 44 mmol) and 60% sodium hydroxide (2.8 g, 70.0 mmol) in dimethyl carbonate (100 mL) Heated to reflux for 2 h. To the brown suspension obtained, 0.5 M citric acid aqueous solution was added until a clear solution was obtained. The clear solution was extracted with ethyl acetate. The filtered material was concentrated in vacuo to give the title crude compound without purification in the next step.

2-amino-6- (5-bromo-2-methoxy-phenyl) -3 H -Pyrimidin-4-one

Crude 3- (5-bromo-2-methoxy-phenyl) -3-oxo-propionic acid methyl ester, guanidine hydrochloride (4.6 g, 48 mmol) in ethanol (100 mL), and sodium ethoxide (9.84 g, 145 mmol) was heated at reflux for 18 hours. The mixture was cooled to room temperature and diluted with water. The mixture was extracted with ethyl acetate and the combined organic layers were washed with brine, then dried over MgSO ₄ and filtered. The filtered material was concentrated in vacuo and the crude product was triturated in Et ₂ O. The solid obtained was filtered to give the title compound as a white solid (6.0 g, 46%).

4- (5-Bromo-2-methoxy-phenyl) -6-chloro-pyrimidin-2-ylamine

2-amino-6- (5-bromo-2-methoxy-phenyl) -3 H -pyrimidin-4-one (6.0 g, 20 mmol) was dissolved in phosphorus oxychloride (30 mL) and obtained The solution was heated at reflux for 16 h. The mixture was cooled to room temperature and poured slowly into ice water. It was carefully neutralized with aqueous sodium hydroxide solution and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with water and brine, dried over MgSO ₄ and filtered. The filtered material was concentrated in vacuo and the crude product was triturated in Et2O. The resulting solid was filtered to give the title compound (2.0 g) as a pale brown solid. Chromatography of the material filtered over silica gel (hexane / EtOAc = 6/1 gradient to 3/1) gave an additional product (0.5 g, 39% overall) as a white solid.

Title compound:

General procedure C was used to dimethylate 4- (5-bromo-2-methoxy-phenyl) -6-chloro-pyrimidin-2-ylamine. The resulting 4- (5-bromo-2-hydroxy-phenyl) -6-chloro-pyrimidin-2-ylamine was then reacted with D-phenylglycinol according to General Procedure K. Finally, the title compound was prepared via Suzuki coupling with 5-indolylboronic acid described in General Procedure H.

Yellow solid; ¹ H NMR (d ₆ -DMSO) δ 3.69 (m, 2H) 5.28 (bs, 1H) 5.66 (bs, 1H) 6.51 (bs, 2H) 6.45-7.80 (m, 17H) 11.04 (s, 1H) 11.6- 12.4 (bs, 1 H); ESI: m / z 438.19 (M + H < + >).

Example 94: 3'-Amino-3- (2-amino-pyrimidin-4-yl) -biphenyl-4-ol

The title compound was subjected to deprotection (Scheme 6) with 2-bromoaniline via Suzuki Reaction (see Example 64) as described in General Procedure G and then using 5-10% thioanisole. Obtained from boronate.

¹ H NMR (CDCl ₃ ) δ 3.82 (bs, 2H), 5.22 (s, 2H), 6.68 (d, 2H), 6.87 (s, 1H), 6.95 (d, 1H), 7.03 (t, 1H), 7.05 (d, 1H), 7.06 (d, 1H), 7.58 (d, 1H), 7.93 (s, 1H), 8.42 (d, 1H)

ESI: m / z 278 (M + H +)

Example 95: 2- [3- (2-Amino-pyrimidin-4-yl) -4-hydroxy-phenyl] -pyrrole-1-carboxylic acid t-butyl ester

The title compound has 4- (2-benzyloxy-5-bromo-phenyl) -pyrimidine-2- via Suzuki Reaction with N-Boc protected 2-pyrroleylboronic acid as described in General Procedure G. Obtained as a yellow solid from monoamine (see Example 59) (Scheme 5).

ESI: m / z 381 (M + H +)

Example 96: 3- {2-amino-6- [2-hydroxy-1R- (1H-indol-3-ylmethyl) -ethylamino] -pyrimidin-4-yl} -biphenyl-4,4'-diol

The title compound was synthesized starting from D-tryptophanol and chloropyrimidine derivatives using the general procedure K.

Yellow solid; ¹ H NMR (d ₆ -DMSO) δ 2.83-2.87 (m, 1H) 3.40-3.48 (m, 4H) 4.83 (s, 1H) 6.51 (bs, 2H) 6.82-6.86 (m, 3H) 6.96-7.05 ( m, 3H) 7.15 (s, 1H) 7.31 (d, 1H) 7.42 (d, 2H) 7.46 (d, 1H) 7.61 (d, 1H) 7.74 (s, 1H) 9.47 (s, 1H) 10.79 (s, 1H) 14.74 (bs, 1 H); ESI: m / z 468.19 (M + H < + >).

Example 97: 3- [2-Amino-6- (2-hydroxy-1S-phenyl-ethylamino) -pyrimidin-4-yl] -biphenyl-4,4'-diol

The title compound was synthesized starting from L-phenylglycinol and chloropyrimidine derivatives using general procedure K.

Yellow solid; ¹ H NMR (d ₆ -DMSO) δ 3.55 (m, 2H) 3.66 (m, 1H) 4.94 (bs, 1H) 6.81-6.85 (m, 4H) 6.97 (d, 1H) 7.30-7.34 (m, 5H) 7.56 (d, 2H) 7.62 (d, 1H) 7.64 (s, 1H) 8.12 (s, 1H) 9.48 (s, 1H) 13.36 (s, 1H) 14.71 (bs, 1H); ESI: m / z 415.17 (M + H < + >).

Example 98: 3- [2-amino-6- (4-methoxy-phenylamino) -pyrimidin-4-yl] -biphenyl-4,4'-diol

The title compound was synthesized starting from p-methoxyaniline and chloropyrimidine derivatives using general procedure K.

Yellow solid; ¹ H NMR (d ₆ -DMSO) δ 3.74 (s, 1H) 6.61 (s, 1H) 6.79-6.85 (m, 4H) 6.89 (d, 2H) 7.44 (d, 2H) 7.50 (d, 1H) 7.56 ( d, 1 H) 7.65 (d, 2 H) 7.78 (s, 1 H) 9.49 (s, 1 H) 9.50 (s, 1 H) 14.54 (s, 1 H); ESI: m / z 401.15 (M + H < + >).

Example 99: 3- [2-Amino-6- (2-benzylsulfanyl-1R-hydroxymethyl-ethylamino) -pyrimidin-4-yl] -biphenyl-4,4'-diol

The title compound was synthesized starting from S-benzyl-L-cysteinol and chloropyrimidine derivatives using formula K.

Yellow solid; ¹ H NMR (d ₆ -DMSO) δ 3.45-3.49 (m, 2H) 3.57 (m, 1H) 3.79 (s, 1H) 4.89 (s, 1H) 6.54 (s, 1H) 6.59 (bs, 2H) 6.82- 6.87 (m, 3H) 7.23-7.32 (m, 5H) 7.43 (d, 2H) 7.47 (d, 1H) 7.56 (d, 1H) 7.76 (s, 1H) 9.48 (s, 1) 14.74 (bs, 1H) ; ESI: m / z 475.17 (M + H < + >).

Example 100: 3- {2-amino-6- [2- (1-indol-3-yl) -ethylamino] -pyrimidin-4-yl} biphenyl-4,4'-diol

The title compound was synthesized starting from tryptamine and chloropyrimidine derivatives using general procedure K.

Yellow solid; ¹ H NMR (d ₆ -DMSO) δ 2.95 (m, 2H) 3.62 (m, 2H) 6.44 (s, 1H) 6.56 (bs, 2H) 6.82 (d, 2H) 6.85 (d, 1H) 6.98 (t, 1H) 7.06 (t, 1H) 7.19 (s, 1H) 7.34 (d, 1H) 7.42 (d, 2H) 7.46 (d, 1H) 7.58 (d, 1H) 7.74 (bs, 1H) 9.46 (s, 1H) 10.83 (s, 1 H) 14.81 (s, 1 H); ESI: m / z 438.18 (M + H < + >).

Example 101 3- [2-amino-6- (4-benzyl-piperazin-1-yl) -pyrimidin-4-yl] -biphenyl-4,4'-diol

The title compound was synthesized starting from 4-benzylpiperazine and chloropyrimidine derivatives using general procedure K.

Yellow solid; ¹ H NMR (d ₆ -DMSO) δ 2.43 (m, 4H) 3.53 (s, 2H) 3.70 (m, 4H) 6.60 (bs, 2H) 6.74 (s, 1H) 6.81-6.86 (m, 3H) 7.27 ( m, 1H) 7.34 (m, 4H) 7.45-7.49 (m, 3H) 8.04 (s, 1H) 9.43 (s, 1H) 14.80 (s, 1H); ESI: m / z 454.21 (M + H < + >).

Example 102: 3- {2-amino-6- [2-hydroxy-1R- (1H-indol-3-ylmethyl) -ethylamino] -pyrimidin-4-yl} -biphenyl-4,4'-diol

The title compound was synthesized starting from L-tryptophanol and chloropyrimidine derivatives using general procedure K.

Yellow solid; ¹ H NMR (d ₆ -DMSO) δ 2.82-2.84 (m, 1H) 3.41-3.48 (m, 4H) 4.83 (s, 1H) 6.50 (bs, 2H) 6.82-6.85 (m, 3H) 6.96-7.05 ( m, 3H) 7.15 (s, 1H) 7.31 (d, 1H) 7.42 (d, 2H) 7.46 (d, 1H) 7.61 (d, 1H) 7.74 (s, 1H) 9.48 (s, 1H) 10.79 (s, 1H) 14.78 (bs, 1 H); ESI: m / z 468.19 (M + H < + >).

Example 103: 3- [2-amino-6- (1-hydroxymethyl-2-methyl-propylamino) pyrimidin-4-yl] -biphenyl-4,4'-diol

The title compound was synthesized starting from L-valinol and chloropyrimidine derivatives using general procedure K.

ESI: m / z 353 (M + H +)

Example 104: 3- [2-Amino-6- (4-methyl-piperazin-1-yl) -pyrimidin-4-yl] -biphenyl-4,4'-diol

The title compound was synthesized starting from p-methylpiperazine and chloropyrimidine derivatives using general procedure K.

Yellow solid; ¹ H NMR (DMSO-d ₆ ) δ 2.22 (s, 3 H), 2.36 (s, 4 H), 3.69 (s, 4 H), 6.60 (s, 3H), 6.76 (s, 1 H), 6.82 -6.86 (m, 3H), 7.46-7.50 (m, 1H), 8.06 (s, 1H), 9.43 (s, 1H), 14.8 (br s, 1H); ESI: m / z 378.18 (M + H < + >).

Example 105: 3- [2-Amino-6- (2-morpholin-4-yl-ethylamino) -pyrimidin-4-yl] -biphenyl-4,4'-diol

The title compound was synthesized starting from N- (2-aminoethyl) morpholine and chloropyrimidine derivatives using general procedure K.

Yellow solid; ¹ H NMR (DMSO-d ₆ ) δ 2.43-2.47 (m, 8 H), 3.44-3.59 (m, 8 H), 6.50 (br s, 1 H), 6.56 (s, 2 H), 6.84 (m , 3H), 7.01 (s, 1H), 7.45 (m, 3H), 7.77 (s, 1H), 9.46 (s, 1H), 14.80 (br s, 1H); ESI: m / z 452.14 (M + H < + >).

Example 106: 3- [2-Amino-6- (2-pyridin-2-yl-ethylamino) -pyrimidin-4-yl] -biphenyl-4,4'-diol

The title compound was synthesized starting from 2-aminoethylpyridine and chloropyrimidine derivatives using general procedure K.

Yellow solid; ¹ H NMR (DMSO-d ₆ ) δ 3.44-3.46 (m, 2 H), 3.68 (br.s, 1 H), 6.43 (s, 1 H), 6.59 (br.s, 2 H), 6.82- 6.86 (m, 3H), 7.23-7.25 (m, 3H), 7.42-7.45 (m, 3H), 7.71 (s, 2H), 7.97-8.05 (m, 2H), 8.50 (m, 1 H), 14.79 (br s, 1 H); ESI: m / z 400.10 (M + H < + >).

Example 107: 3- (2-Amino-6-thiomorpholin-4-yl-pyrimidin-4-yl) -biphenyl-4,4'-diol

The title compound was synthesized starting from thiomorpholine and chloropyrimidine derivatives using general procedure K.

Yellow solid; ¹ H NMR (DMSO-d ₆ ) δ 2.62 (s, 4 H), 4.03 (br s, 4 H), 6.65 (br. S, 2 H), 6.76 (s, 1 H), 6.82-7.50 (m , 4H), 8.07 (s, 1H), 9.48 (s, 1H), 14.77 (s, 1H); ESI: m / z 381.09 (M + H < + >).

Example 108: 3- {2-amino-6-[(biphenyl-2-ylmethyl) -amino] -pyrimidin-4-yl} -biphenyl-4,4'-diol

The title compound was synthesized starting from 2-phenylbenzylamine and chloropyrimidine derivatives using general procedure K.

Yellow solid; ¹ H NMR (DMSO-d ₆ ) δ 4.43 (s, 2 H), 6.55 (br. S, 2 H), 6.82-6.76 (s, 3 H), 7.25-7.27 (d, 1 H), 7.35- 7.65 (m, 12 H), 9.48 (s, 1 H), 14.70 (s, 1 H); ESI: m / z 461.15 (M + H < + >).

Example 109: 3- [2-amino-6- (3-chloro-phenylamino) -pyrimidin-4-yl] -biphenyl-4,4'-diol

The title compound was synthesized starting from m-chloroaniline and chloropyrimidine derivatives using general procedure K.

Yellow solid; ¹ H NMR (d ₆ -DMSO) δ 5.76 (s, 1H) 6.69 (s, 1H) 6.84 (d, 2H) 6.91 (d, 1H) 6.99-7.02 (m, 3H) 7.31 (t, 1H) 7.45 ( d, 2H) 7.52 (d, 1 H) 7.65 (d, 1 H) 7.81 (s, 1 H) 8.00 (s, 1 H) 9.58 (s, 1 H) 14.33 (s, 1 H); ESI: m / z 405.10 (M + H < + >).

Example 110: 3- [2-amino-6- (4-chloro-phenylamino) -pyrimidin-4-yl] -biphenyl-4,4'-diol

The title compound was synthesized starting from p-chloroaniline and chloropyrimidine derivatives using general procedure K.

Yellow solid; ¹ H NMR (d ₆ -DMSO) δ 6.68 (d, 1H) 6.84 (d, 2H) 6.90-6.95 (m, 3H) 7.33 (d, 2H) 7.45 (d, 2H) 7.52 (d, 1H) 7.81 ( s, 1 H) 7.84 (d, 2 H) 9.50 (s, 1 H) 9.55 (s, 1 H) 14.40 (s, 1 H); ESI: m / z 405.10 (M + H < + >).

Example 111: 3- [2-amino-6- (3-methoxy-phenylamino) -pyrimidin-4-yl] -biphenyl-4,4'-diol

The title compound was synthesized starting from m-methoxyaniline and chloropyrimidine derivatives using general procedure K.

Yellow solid; ¹ H NMR (d ₆ -DMSO) δ 3.77 (s, 3H) 6.56 (s, 1H) 6.68 (d, 1H) 6.85 (d, 2H) 6.90-6.92 (m, 3H) 7.19 (t, 1H) 7.27 ( s, 1H) 7.45 (d, 2H) 7.50-7.53 (m, 2H) 7.80 (s, 1H) 9.39 (s, 1H) 9.50 (s, 1H) 14.45 (s, 1H); ESI: m / z 401.15 (M + H < + >).

Example 112: 3- [2-Amino-6- (2-hydroxy-1-phenyl-ethylamino) -pyrimidin-4-yl] -biphenyl-4,4'-diol

The title compound was synthesized starting from D-phenylglycinol and chloropyrimidine derivatives using general procedure K.

Yellow solid; ¹ H NMR (d ₆ -DMSO) δ 3.66 (d, 2H) 4.95 (t, 1H) 5.23 (s, 1H) 6.50 (bs, 2H) 6.63 (s, 1H) 6.83-6.84 (m, 3H) 7.24 ( t, 1 H) 7.33 (d, 2 H) 7.37-7.47 (m, 5 H) 7.55 (s, 1 H) 7.77 (s, 1 H) 9.48 (s, 1 H) 14.67 (s, 1 H); ESI: m / z 415.17 (M + H < + >).

Example 113: 3- (2-Amino-6-thiophen-3-yl-pyrimidin-4-yl) -biphenyl-4,4'-diol

The title compound was synthesized starting from 3-thienylboronic acid and chloropyrimidine derivatives using general procedure K.

Yellow solid; ¹ H NMR (d ₆ -DMSO) δ 6.86 (d, 2H) 6.96 (d, 1H) 7.16 (bs, 2H) 7.56-7.59 (m, 3H) 7.69 (d, 1H) 7.85 (s, 1H) 7.94 ( d, 1H) 8.27 (s, 1 H) 8.53 (s, 1 H) 9.50 (s, 1 H) 14.06 (s, 1 H); ESI: m / z 362.09 (M + H < + >).

Example 114: 3- [2-amino-6- (1H-indol-5-yl) -pyrimidin-4-yl] -biphenyl-4,4'-diol

The title compound was synthesized starting from 3-thienylboronic acid and chloropyrimidine derivatives using General Procedure H.

Yellow solid; ¹ H NMR (d ₆ -DMSO) δ 6.58 (s, 1H) 6.86 (d, 2H) 6.96 (d, 1H) 7.10 (bs, 2H) 7.43 (s, 1H) 7.50 (d, 1H) 7.57-7.59 ( m, 3H) 7.95 (s, 1 H) 8.10 (d, 1 H) 8.31 (s, 1 H) 8.59 (s, 1 H) 9.62 (bs, 1 H) 11.34 (s, 1 H) 14.24 (s, 1 H); ESI: m / z 395.14 (M + H < + >).

Example 115: 3- [2-amino-6- (3-fluoro-benzylamino) -pyrimidin-4-yl] -biphenyl-4,4'-diol

The title compound was synthesized starting from 3-fluoro-benzylamine and chloropyrimidine derivatives using general procedure K.

Yellow solid; ¹ H NMR (d ₆ -DMSO) δ 4.57 (s, 2H) 6.50 (s, 1H) 6.60 (bs, 2H) 6.82 (d, 2H) 6.85 (d, 1H) 7.06 (t, 1H) 7.19 (s, 1H) 7.36 (d, 1H) 7.42 (d, 2H) 7.48 (d, 1H) 7.64 (d, 1H) 7.78 (bs, 1H) 9.45 (s, 1H) 14.65 (s, 1H); ESI: m / z 403.16 (M + H < + >).

Example 116: 3- [2-amino-6- (2-fluoro-benzylamino) -pyrimidin-4-yl] -biphenyl-4,4'-diol

The title compound was synthesized starting from 2-fluoro-benzylamine and chloropyrimidine derivatives using general procedure K.

Yellow solid; ¹ H NMR (d ₆ -DMSO) δ 4.59 (s, 2H) 6.45 (s, 1H) 6.53 (bs, 2H) 6.73 (d, 2H) 6.85 (d, 1H) 7.06 (t, 1H) 7.19 (s, 1H) 7.32 (d, 1H) 7.43 (d, 2H) 7.48 (d, 1H) 7.57 (d, 1H) 7.77 (bs, 1H) 9.60 (s, 1H) 14.65 (s, 1H); ESI: m / z 403.16 (M + H < + >).

Example 117: 3- [2-Amino-6- (3-methoxy-benzylamino) -pyrimidin-4-yl] -biphenyl-4,4'-diol

The title compound was synthesized starting from 3-methoxy-benzylamine and chloropyrimidine derivatives using general procedure K.

Yellow solid; ¹ H NMR (d ₆ -DMSO) δ 3.73 (s, 3H) 4.53 (s, 2H) 6.50 (s, 1H) 6.60 (bs, 2H) 6.82 (d, 2H) 6.85 (d, 1H) 6.92 (bs, 2H) 7.23 (t, 1 H) 7.42 (d, 2 H) 7.47 (d, 1 H) 7.57 (d, 1 H) 7.76 (bs, 1 H) 9.45 (s, 1 H) 14.65 (s, 1 H); ESI: m / z 415.18 (M + H < + >).

Example 118: 3- [2-Amino-6- (4-methoxy-benzylamino) -pyrimidin-4-yl] -biphenyl-4,4'-diol

The title compound was synthesized starting from 4-methoxy-benzylamine and chloropyrimidine derivatives using general procedure K.

Yellow solid; ¹ H NMR (d ₆ -DMSO) δ 3.72 (s, 3H) 4.47 (s, 2H) 6.47 (s, 1H) 6.58 (bs, 2H) 6.82 (d, 2H) 6.85 (d, 1H) 6.90 (d, 2H) 7.28 (d, 2H) 7.42 (d, 2H) 7.46 (d, 1H) 7.50 (d, 1H) 7.76 (bs, 1H) 9.45 (s, 1H) 14.71 (s, 1H); ESI: m / z 415.18 (M + H < + >).

Example 119: 3- [2-amino-6- (2-fluoro-4-hydroxyphenylamino) -pyrimidin-4-yl] -biphenyl-4,4'-diol

The title compound was synthesized starting from 2-fluoro-4-hydroxyaniline and chloropyrimidine derivatives using general procedure K.

Yellow solid; ¹ H NMR (d ₆ -DMSO) δ 6.60 (d, 1H) 6.64-6.70 (m, 4H) 6.83 (d, 2H) 6.89 (d, 1H) 7.42 (d, 2H) 7.49 (d, 1H) 7.65 ( d, 1 H) 7.76 (s, 1 H) 8.69 (s, 1 H) 9.46 (s, 1 H) 9.74 (s, 1 H) 14.49 (s, 1 H); ESI: m / z 405.16 (M + H < + >).

Biological analysis

Example 129: Analysis condition

Analysis of cyclin dependent kinase activity was determined by monitoring the phosphorylation of the synthetic peptide PKTPKKAKKLRRR. The assay mixture contained 0.1 mM cold ATP, ³³ P-γ-ATP (2000-4000 cpm / μL), 0.1 mM peptide, 1 mM DTT, and 10 mM MgCl ₂ in 100 mM HEPES buffer pH 7.4. The assay mixture was sealed by mixing together with the inhibitor and the CDK enzyme (0.3-0.4 U / mL; CDK5 complexed with p25 or CDK2 complexed with cyclin A) to a microtiter plate in a final volume of 40 μl, 30 Incubated for 2 hours at ℃. After incubation, 15 μl aliquots were added to Whatman P81 filter plates containing 100 μl 0.5% phosphoric acid. This mixture was left for 5 minutes prior to filtration in a vacuum manifold. The filter plate was washed by continuously adding 300 μl of 0.5% phosphoric acid. The filter plate was air dried for 10 minutes before sealing the bottom. After addition of the scintillation fluid to the sealed plate, the phosphorylated peptide was quantitated with scintillation meter.

The experimental results are shown in the table below.

Example Structure CDK 2 Activity ^* CDK 5 Activity ^*

2 CB

3 CB

4 BA

5 BA

6 CC

7 DC

8 DD

9 CB

10 DD

11 DC

12 DB

13 CD

14 CB

15 BB

16 CB

17 BC

18 BA

19 DA

20 BA

21 AA

22 AA

23 AA

24 AA

25 AA

26 AA

27 AA

28 BC

29 BD

30 CA

31 BA

32 CC

33 AB

34 AB

35 BD

36 AA

37 DB

38 AA

39 BD

40 AA

41 AA

42 AA

43 AA

44 CB

45 DC

46 DC

47 AA

48 AA

49 AA

50 AA

51 AA

52 AA

53 AA

54 AA

55 AA

56 AA

57 AA

58 AA

59 BB

60 CA

61 AA

62 AA

63 DA

64 AA

65 AB

66 BB

67 ANA

68 AA

69 AA

70 DC

71 AA

72 ANA

73 ANA

74 ANA

75 NANA

76 NANA

77 AA

78 DA

79 AA

80 AA

81 AA

82 AA

83 AA

84 AA

85 AA

86 AA

87 AA

88 AA

89 AA

90 AA

91 AA

*: The activity of the compounds is defined as follows:

A: IC ₅₀ = 0-0.5 μM

B: IC ₅₀ = 0.5-2.0 μM

C: IC ₅₀ = 2.0-5.0 μM

D: IC ₅₀ > 5.0 μM

NA: No valid active data

Example 130: Specificity studies

Analysis of kinases was determined by monitoring phosphorylation of the appropriate substrate. The assay mixture contains 0.1 mM cold ATP ³³ P-γ-ATP (2000-4000 cpm / μL), 0.1 mM substrate, 1 mM DTT, and 10 mM MgCl ₂ in 100 mM HEPES buffer pH 7.4. The assay mixture, combined with inhibitor and kinase enzyme (0.3-0.4 U / ml), was sealed together in a microtiter 96-well plate at a final volume of 40 μl and incubated at 30 ° C. for 1 hour. After incubation, 15 μl aliquots were added to Whatman P81 filter plates containing 100 μl 0.5% phosphoric acid. This mixture was left for 5 minutes before filtration in a vacuum manifold. The filter plate was washed with 5 successive additions of 300 μl 0.5% phosphoric acid. The filter plate was naturally dried for 10 minutes before sealing the bottom. After flashing fluid was added to the sealed plate, the phosphorylated substrate was quantitatively calculated on a scintillation meter.

3- (2-amino-pyrimidin-4-yl) -biphenyl-4,4'-diol has proven to be very specific for CDK5 and CDK2. It showed little inhibition against a panel of protein kinases as described in the table below.

enzyme 10% inhibition at μM BMI0000869 Analysis reference Protein Kinase A (Bovine Heart) NI Chijiwa et al. (1990) Protein Kinase C (Rat Brain) NI Humble et al. (1985) Protein Kinase C- (Human) 12 Martiny-Baron et al. (1993) Protein Kinase C-1 (Human) NI Martiny-Baron et al. (1993) Protein Kinase C-2 (Human) 49 Martiny-Baron et al. (1993) Protein Kinase C- (Rabbit Brain) NI Humble et al. (1985) Protein Kinase C- (Human) 25 Humble et al. (1985) EGF-tyrosine kinase (human) 25 Carpenter et al. (1979) Protein kinase p56lck (bovine thymus) 29 Cheng et al. (1992) Protein kinase p55fyn (bovine thymus) 83 Cheng et al. (1992) MAP kinase, ERK 42 (rat) NI Robbins et al. (1993)

Chijiwa et al. J Biol Chem. 1990 Mar 25; 265 (9): 5267-72.

Martiny-Baron et al. J Biol Chem. 1993 May 5; 268 (13): 9194-7.

Carpenter et al. J Biol Chem. 1979 Jun 10; 254 (11): 4884-91.

Cheng et al. J Biol Chem. 1992 May 5; 267 (13): 9248-56.

Robbins et al. J Biol Chem. 1993 Mar 5; 268 (7): 5097-106.

Humble E et al Arch Biochem Biophys 1985 Aug 15; 241 (1): 225-31

Example 131: In vitro tumor cell efficacy test

Inhibition of cell growth was measured using a cell viability assay based on the use of sulforhodamine B (SRB), a protein-binding dye. Different cancer cell tumors were seeded in 96-well plates at 2000 cells / 100 μl per well in RPMI medium containing 10% FBS. The following day, cells were treated with the set doses of compounds and incubated for 72 hours at 37 ° C. in the presence of 5% CO ₂ . Cells were then fixed with 10% ice cold trichloroacetic acid (TCA) and incubated at 4 ° C. for one hour. The plates were washed 4-5 times with tap water and then naturally dried. After dissolving the boundary stain by adding 100 μl of 10 mM unbuffered Tris base, the optical density was measured at 574 nm using Analytical Victor (1420 Multi-label Counter, Wallace). IC50 (50% growth inhibition concentration) values were calculated from dose-response curve fit.

In addition, 3- (2-amino-pyrimidin-4-yl) -biphenyl-4,4'-diol was tested for ex vivo tumor cell efficacy against several cancers.

Cell line log (GI ₅₀ ) (M) Log (LC ₅₀ ) (M) Leukemia CCRF-CEM -6.7 -4.1 HL-60 (TB) -6.9 -4.1 K-562 -6.4 > -4 MOLT-4 -6.6 > -4 RPMI-8226 -6.7 > -4 SR -8.0 > -4 Non-Small Cell Lung Cancer A549 / ATCC -6.5 > -4 EKVX -6.6 > -4 HOP-62 -7.1 -5.1 HOP-92 -6.4 > -4 NCI-H23 -6.6 > -4 NCI-H322M -6.5 > -4 NCI-H460 -6.6 > -4 NCI-H522 -6.7 > -4 Colon cancer COLO 205 -5.1 > -4 HCC-2998 -5.9 > -4 HCT-116 -6.8 > -4 HCT-15 -6.9 > -4 HT29 -5.5 > -4 KM12 -6.9 > -4 SW-620 -6.5 > -4 CNS Cancer SF-268 -6.6 > -4 SF-295 -6.6 > -4 SF-539 -6.7 > -4 SNB-19 -6.7 -4.7 SNB-75 -5.7 > -4 U251 -6.7 > -4 Melanoma LOX IMVI -6.7 > -4 MALME-3M -6.3 > -4 M14 -6.4 > -4 SK-MEL-2 -6.7 -5.5 SK-MEL-28 -6.6 > -4 SK-MEL-5 -7.0 -4.7 UACC-257 -5.9 > -4 UACC-62 -6.7 -4.9

Ovarian Cancer IGROV1 -6.6 > -4 OVCAR-3 -6.6 > -4 OVCAR-4 -6.5 > -4 OVCAR-5 -5.7 > -4 OVCAR-8 -6.7 > -4 SK-OV-3 -6.3 > -4 Renal Cancer 786-0 -6.6 > -4 A498 -5.8 > -4 ACHN -6.6 > -4 CAKI-1 -6.4 > -4 RXF 393 -6.0 -5.2 SN12C -6.6 > -4 TK-10 -5.7 > -4 UO-31 -6.6 > -4 Prostate cancer PC-3 -6.6 > -4 DU-145 -6.1 > -4 Breast cancer MCF7 -6.6 > -4 NCI / ADR-RES -6.5 > -4 MDA-MB-231 / ATCC -6.6 > -4 HS 578T -6.4 > -4 MDA-MB-435 -6.6 > -4 MDA-N -6.6 > -4 BT-549 -6.6 > -4 T-47D -5.7 -4.3 Mean -6.5 > -4 St.Dev. 0.4

Example 132: Analytical Conditions for EGFR2 (KDR)

Enzyme analysis for IC ₅₀ determinations was done in 96-well titer plates with 50 μl total reaction volume. Each reaction solution contains 1.5 μl of appropriate inhibitor diluent, 50 mM Hepes, pH 7.4, 1 mM DTT, 10 mM magnesium chloride, 2 mM phospho-poly (E ₄ Y) (Sigma Chemical Company), 500 μΜ unlabeled ATP, 0.0025 μM [ ³³ P] ATP (Amersham Pharmacia Biotech), and 50 nM KDR. All components except KDR were added to the wells and the enzyme was added to initiate the reaction. After the reactions were mixed and incubated for 1 hour at room temperature, 50 μl of 8% phosphoric acid was added to stop the reaction. At this time, a 90 μl aliquot of the sample was added to a positively charged DEAE 96-well filter plate (Millipore Corporation MADENOB 10). The plate was incubated for 30 minutes at room temperature. Samples were sucked and wells washed three times with 200 μl of 0.5% phosphoric acid. To each well, 50 μl of flash mixed solution was added and counted for 60 seconds on a Top Count Microplate Scintillation Instrument (Packard Instrument Company). The concentration of compound (IC ₅₀ ) that inhibits KDR activity by 50% was determined based on its curve.

The test results are given in the table below.

Example rescue KDR: IC ₅₀ (nM)

22 B

23 B

24 B

25 A

26 A

36 C

57 B

58 A

59 A

60 A

61 B

67 A

79 B

80 B

81 B

83 A

84 A

85 A

86 B

87 B

88 B

89 B

90 A

91 A

92 B

93 A

94 B

95 B

96 B

97 A

98 A

99 A

100 A

101 B

102 B

103 B

104 B

105 B

106 A

107 B

108 A

109 A

110 A

111 A

112 A

113 B

114 A

115 B

116 A

117 A

118 A

119 B

*: The activity of the compounds is defined as follows:

A: IC ₅₀ = 0-1 μM

B: IC ₅₀ = 1-20 μM

C: IC ₅₀ = 20-50 μM

D: IC ₅₀ > 50 μM

NA: No active data available

Thus, those skilled in the art will appreciate that the various compounds, methods and pharmaceutical compositions of the present invention can modulate protein kinase activity and are useful as therapeutic agents for CDK-related diseases. Protein kinase activity of any particular compound can be readily identified, for example, as disclosed in Example 100.

Those skilled in the art will understand that the invention is well suited to achieving the stated objects and achieving the objectives and advantages as well as being implied herein. The molecular complexes, methods, processes, processes, molecules, specific compounds described herein are merely representative and illustrate preferred embodiments, and are not intended as limitations on the scope of the invention. Various changes and other uses, which are within the scope of the invention and defined in the scope of the claims, will be apparent to those skilled in the art.

It will be apparent to those skilled in the art that various permutations and modifications can be made to the invention disclosed herein without departing from the scope and spirit of the invention.

The invention suitably described herein by way of example may be practiced in the absence of any element, limitation or limitation that is not specifically required herein. Thus, for example, each of the terms "comprising", "consisting essentially of", and "consisting of" is in two different terms. It may be replaced. The terms and expressions employed are for the purpose of description and not of limitation, and the use of such terms and descriptions is disclosed and indicates the exclusion of equivalents to the features or portions thereof described. It is not intended to be.

Various modifications may be possible within the scope of the claimed invention. Thus, although the invention has been specifically disclosed by preferred embodiments and optional features, variations and modifications of the concepts disclosed herein may be made by those skilled in the art, and such variations and modifications are defined in the claims It is to be understood that the present invention is considered to be within the scope of the present invention.

Further, when features or aspects of the invention are described as Markush groups, those skilled in the art will understand that the invention is based on what is described in terms of any individual component or subgroup of components of the Markush group. For example, if X is selected from the group consisting of bromine, chlorine and iodine, then claims for X being bromine and claims for X being chlorine and chlorine are all described.

Claims (77)

A compound of formula 1, a pharmaceutically acceptable salt, amide, ester or prodrug thereof, (One) Where a) R ₁ is selected from the group consisting of Iii) a 6-membered aromatic or heteroaromatic, 5- or 6-membered heteroaromatic ring, optionally substituted with one or more substituents selected from the group consisting of lower alkyl, hydroxy, alkoxy, amino and nitro; Ii) acyl of the formula-(X ₁ ) _{n 1} -C (O) -X ₂ , Wherein X ₁ is selected from the group consisting of lower alkylene, lower alkenylene, lower alkynylene, aryl and heteroaryl; X ₂ is selected from the group consisting of hydrogen, lower alkyl, aryl, heteroaryl, hydroxy, alkoxy, amino, and -NH-X ₃ ; Wherein X ₃ is selected from the group consisting of hydrogen, alkyl, aryl, heteroaryl, amino, and amide; And n1 is 0 or 1; Iv) a substituent of formula -C (X ₄ ) = N-NX ₅ -C (= E) -NX ₆ X ₇ or a formula -C (X ₄ ) = NN = C (EX ₅ ) -NX ₆ X ₇ , Wherein X ₄ is selected from the group consisting of hydrogen, lower alkyl, aryl, alkaryl, heteroaryl and amino; E is selected from the group consisting of oxygen, sulfur and -NR _101- , wherein R ₁₀₁ is selected from the group consisting of hydrogen hydrogen, lower alkyl, lower alkene, lower alkyne, aryl and heteroaryl; And X ₅ , X ₆ and X ₇ are each independently selected from the group consisting of hydrogen, lower alkyl, aryl and heteroaryl; Provided that R ₁ is -C ₆ H ₅ , -C (0) H, -C (O) CH ₃ , -C (O) -C ₆ H ₅ , -C (O) NH ₂ , or -C ₆ H _{Not 4} CH ₃ ; b) R ₂ , R ₃ and R ₄ are each independently selected from the group consisting of: Iii) hydrogen; Ii) lower alkyl; Iii) lower alkylene; Iii) halogen or perhaloalkyl; Ⅴ) alkoxy of the formula-(X ₁₃ ) _n13 -OX ₁₄ , Wherein X ₁₃ is selected from the group consisting of lower alkylene, lower alkenylene, lower alkynylene, allyl and heteroaryl; X ₁₄ is selected from the group consisting of hydrogen, lower alkyl, aryl and heteroaryl; And n13 is 0 or 1; And V) 5- or 6-membered heteroaryl ring or 6-membered aryl ring or heteroaryl ring, optionally substituted with one or more substituents selected from the group consisting of the following; A) optionally substituted C ₁ -C ₈ straight, branched, or cyclic saturated or unsaturated alkyl; B) alkoxy of formula-(X ₁₃ ) _n13 -OX ₁₄ , Wherein X ₁₃ is selected from the group consisting of lower alkylene, lower alkenylene, lower alkynylene, aryl and heteroaryl; X ₁₄ is selected from the group consisting of hydrogen, lower alkyl, aryl and heteroaryl; And n13 is 0 or 1; C) halogen or perhaloalkyl; D) cyano; E) nitro; F) amino of the formula-(X ₁₅ ) _n15 -NX ₁₆ X ₁₇ , Wherein X ₁₅ is selected from the group consisting of lower alkylene, lower alkenylene, lower alkynylene, aryl and heteroaryl; X ₁₆ and X ₁₇ are each independently selected from the group consisting of hydrogen, lower alkyl, aryl and heteroaryl; Or X ₁₆ and X ₁₇ are taken together with the nitrogen to which they are attached to form a 5- or 6-membered heteroaromatic or heteroaliphatic ring; n15 is 0 or 1; G) a substituent of the _formula- (X ₁₈ ) _n18 -C (= E) -X ₁₉ , Wherein X ₁₈ is selected from the group consisting of lower alkylene, lower alkenylene, lower alkynylene, aryl and heteroaryl; E is selected from the group consisting of oxygen, sulfur and -NR _101- , wherein R ₁₀₁ is selected from the group consisting of hydrogen hydrogen, lower alkyl, lower alkene, lower alkyne, aryl and heteroaryl; X ₁₉ is selected from the group consisting of hydrogen, alkyl, aryl, heteroaryl, hydroxy, alkoxy, amino and -NX ₂₀ X ₂₁ , Wherein X ₂₀ and X ₂₁ are each independently selected from the group consisting of hydrogen, alkyl, aryl and heteroaryl; n18 is 0 or 1; And H) a thioether or thiol of the _formula- (X ₂₂ ) _{n22 -SX 23} , Wherein X ₂₂ is selected from the group consisting of lower alkylene, lower alkenylene, lower alkynylene, aryl and heteroaryl; X ₂₃ is selected from the group consisting of hydrogen, lower alkyl, aryl and heteroaryl; And n22 is 0 or 1; And _{Amide of formula-} (X ₂₄ ) _n24 -NH-C (O) -X _{25 or-} (X ₂₆ ) _n26 -C (O) -NH-X ₂₇ , Wherein X ₂₄ and X ₂₆ are each independently selected from the group consisting of lower alkylene, lower alkenylene, lower alkynylene, aryl and heteroaryl; X ₂₅ is selected from the group consisting of hydrogen, lower alkyl, lower alkenyl, aryl, heteroaryl, hydroxy, alkoxy and amide; And X ₂₇ is selected from the group consisting of hydrogen, lower alkyl, lower alkenyl, aryl and heteroaryl; Or R ₂ and R ₃ are taken together with the two ring carbons to which they are attached, or R ₄ and R ₃ are taken together with the two ring carbons to which they are attached, such that they are 6-membered aromatic or heteroaromatic, or 5- or 6-membered heteroaromatic ring, optionally substituted with one or more substituents selected from the group consisting of: Iii) hydrogen; Ii) optionally substituted C ₁ -C ₈ straight, branched or cyclic saturated or unsaturated alkyl; Iii) optionally substituted aryl; Iii) optionally substituted heterocycle; Ⅴ) Formula -C (X ₄ ) = N-NX ₅ -C (= E) -NX ₆ X ₇ or -C (X ₄ ) = NN = C (EX ₅ ) -NX ₆ X ₇ , Wherein X ₄ is selected from the group consisting of hydrogen, lower alkyl, aryl, alkaryl, heteroaryl and amino; E is selected from the group consisting of oxygen, sulfur and -NR _101- , wherein R ₁₀₁ is selected from the group consisting of hydrogen hydrogen, lower alkyl, lower alkene, lower alkyne, aryl and heteroaryl; And X ₅ , X ₆ and X ₇ are each independently selected from the group consisting of hydrogen, lower alkyl, aryl and heteroaryl; Iii) amino guanidine of formula -NX ₈ -NX ₉ -C (= NX ₁₀ ) -NX ₁₁ X ₁₂ , Wherein X ₈ , X ₉ , X ₁₀ , X ₁₁ and X ₁₂ are each independently selected from the group consisting of hydrogen, lower alkyl, aryl and heteroaryl; Ⅶ) formula - (X _{13) n13} alkoxy of -OX _14, Wherein X ₁₃ is selected from the group consisting of lower alkylene, lower alkenylene, lower alkynylene, aryl and heteroaryl; X ₁₄ is selected from the group consisting of hydrogen, lower alkyl, aryl and heteroaryl; n13 is 0 or 1; Iii) halogen or perhaloalkyl; Iii) cyano; Iii) nitro; xi) amino of the formula-(X ₁₅ ) _n15 -NX ₁₆ X ₁₇ , Wherein X ₁₅ is selected from the group consisting of lower alkylene, lower alkenylene, lower alkynylene, aryl and heteroaryl; X ₁₆ and X ₁₇ are each independently selected from the group consisting of hydrogen, lower alkyl, aryl and heteroaryl; Or X ₁₆ and X ₁₇ are taken together with the nitrogen to which they are attached and are a 5- or 6-membered heteroaromatic or heteroaliphatic ring; And n15 is 0 or 1; xii) a substituent of the formula-(X ₁₈ ) _n18 -C (= E) -X ₁₉ , Wherein X ₁₈ is selected from the group consisting of lower alkylene, lower alkenylene, lower alkynylene, aryl and heteroaryl; E is selected from the group consisting of oxygen, sulfur and -NR _101- , wherein R ₁₀₁ is selected from the group consisting of hydrogen hydrogen, lower alkyl, lower alkene, lower alkyne, aryl and heteroaryl; X ₁₉ is selected from the group consisting of hydrogen, lower alkyl, aryl, heteroaryl, amino and -NX ₂₀ X ₂₁ , Wherein X ₂₀ and X ₂₁ are independently selected from the group consisting of hydrogen, alkyl, aryl and heteroaryl; And n18 is 0 or 1; xvi) thioether or thiol of the _formula- (X ₂₂ ) _{n22 -SX 23} , Wherein X ₂₂ is lower alkylene, lower alkenylene, lower alkynylene. Aryl and heteroaryl; X ₂₃ is selected from the group consisting of hydrogen, lower alkyl, aryl and heteroaryl; And n22 is 0 or 1; c) R ₅ is selected from the group consisting of hydrogen, lower alkyl, aryl and heteroaryl; Or R ₄ and R ₅ are taken together with the two ring carbons to which they are attached such that a 6-membered aromatic or heteroaromatic, or 5- or 6-membered heteroaromatic ring, which is optionally selected from the group consisting of Or substituted with more substituents; Iii) hydrogen; Ii) optionally substituted C ₁ -C ₈ straight, branched or cyclic saturated or unsaturated alkyl; Iii) optionally substituted aryl; Iii) optionally substituted heterocycle; Iv) a substituent of the formula -C (X ₄ ) = N-NX ₅ -C (= E) -NX ₆ X ₇ or -C (X ₄ ) = NN = C (EX ₅ ) -NX ₆ X ₇ , Wherein X ₄ is selected from the group consisting of hydrogen, lower alkyl, aryl, alkaryl, heteroaryl and amino; E is selected from the group consisting of oxygen, sulfur and -NR _101- , wherein R ₁₀₁ is selected from the group consisting of hydrogen hydrogen, lower alkyl, lower alkene, lower alkyne, aryl and heteroaryl; And X ₅ , X ₆ and X ₇ are each independently selected from the group consisting of hydrogen, lower alkyl, aryl and heteroaryl; Iii) amino guanidine of formula -NX ₈ -NX ₉ -C (= NX ₁₀ ) -NX ₁₁ X ₁₂ , Wherein X ₈ , X ₉ , X ₁₀ , X ₁₁ and X ₁₂ are each independently selected from the group consisting of hydrogen, lower alkyl, aryl and heteroaryl; Ⅶ) formula - (X _{13) n13} alkoxy of -OX _14, Wherein X ₁₃ is selected from the group consisting of lower alkylene, lower alkenylene, lower alkynylene, aryl and heteroaryl; X ₁₄ is selected from the group consisting of hydrogen, lower alkyl, aryl and heteroaryl; n13 is 0 or 1; Iii) halogen or perhaloalkyl; Iii) cyano; Iii) nitro; xi) amino of the formula-(X ₁₅ ) _n15 -NX ₁₆ X ₁₇ , Wherein X ₁₅ is selected from the group consisting of lower alkylene, lower alkenylene, lower alkynylene, aryl or heteroaryl; X ₁₆ and X ₁₇ are each independently selected from the group consisting of hydrogen, lower alkyl, aryl and heteroaryl; Or X ₁₆ and X ₁₇ are taken together with the nitrogen to which they are attached and are a 5- or 6-membered heteroaromatic or heteroaliphatic ring; And n15 is 0 or 1; xii) a substituent of the formula-(X ₁₈ ) _n18 -C (= E) -X ₁₉ , Wherein X ₁₈ is selected from the group consisting of lower alkylene, lower alkenylene, lower alkynylene, aryl and heteroaryl; E is selected from the group consisting of oxygen, sulfur and -NR _101- , wherein R ₁₀₁ is selected from the group consisting of hydrogen hydrogen, lower alkyl, lower alkene, lower alkyne, aryl and heteroaryl; X ₁₉ is selected from the group consisting of hydrogen, lower alkyl, aryl, heteroaryl, amino and -NX ₂₀ X ₂₁ , Wherein X ₂₀ and X ₂₁ are independently selected from the group consisting of hydrogen, alkyl, aryl and heteroaryl; And n18 is 0 or 1; xvi) thioether or thiol of the _formula- (X ₂₂ ) _{n22 -SX 23} , Wherein X ₂₂ is lower alkylene, lower alkenylene, lower alkynylene. Aryl and heteroaryl; X ₂₃ is selected from the group consisting of hydrogen, lower alkyl, aryl and heteroaryl; And n22 is 0 or 1; d) R ₁₀₀ is selected from the group consisting of hydrogen, lower alkyl, lower alkene, lower alkyne, aryl and heteroaryl; e) E ₁ is selected from the group consisting of hydrogen, sulfur and —NR ₁₀₁ —, where NR ₁₀₁ is selected from the group consisting of hydrogen hydrogen, lower alkyl, lower alkene, lower alkyne, aryl and heteroaryl; Provided that at least one of R ₁ -R ₅ is not selected from the group consisting of hydrogen, lower alkyl, aryl and heteroaryl. A compound of Formula 2, or a pharmaceutically acceptable salt, amide, ester, or prodrug thereof, (2) Where a) R ₁ is selected from the group consisting of Iii) a 6-membered aromatic or heteroaromatic, 5- or 6-membered heteroaromatic ring, optionally substituted with one or more substituents selected from the group consisting of lower alkyl, hydroxy, alkoxy, amino and nitro; Ii) acyl of the formula-(X ₁ ) _{n 1} -C (O) -X ₂ , Wherein X ₁ is selected from the group consisting of lower alkylene, lower alkenylene, lower alkynylene, aryl and heteroaryl; X ₂ is selected from the group consisting of hydrogen, lower alkyl, aryl, heteroaryl, hydroxy, alkoxy, amino, and -NH-X ₃ ; Wherein X ₃ is selected from the group consisting of hydrogen, alkyl, aryl, heteroaryl, amino and amide; And n1 is 0 or 1; Iv) a substituent of formula -C (X ₄ ) = N-NX ₅ -C (= E) -NX ₆ X ₇ or a formula -C (X ₄ ) = NN = C (EX ₅ ) -NX ₆ X ₇ , Wherein X ₄ is selected from the group consisting of hydrogen, lower alkyl, aryl, alkaryl, heteroaryl and amino; E is selected from the group consisting of oxygen, sulfur and -NR _101- , wherein R ₁₀₁ is selected from the group consisting of hydrogen hydrogen, lower alkyl, lower alkene, lower alkyne, aryl and heteroaryl; And X ₅ , X ₆ and X ₇ are each independently selected from the group consisting of hydrogen, lower alkyl, aryl and heteroaryl; Provided that R ₁ is -C ₆ H ₅ , -C (0) H, -C (O) CH ₃ , -C (O) -C ₆ H ₅ , -C (O) NH ₂ , or -C ₆ H _{Not 4} CH ₃ ; b) R ₂ , R ₃ and R ₄ are each independently selected from the group consisting of the following; Iii) hydrogen; Ii) lower alkyl; Iii) lower alkylene; Iii) halogen or perhaloalkyl; Ⅴ) alkoxy of the formula-(X ₁₃ ) _n13 -OX ₁₄ , Wherein X ₁₃ is selected from the group consisting of lower alkylene, lower alkenylene, lower alkynylene, allyl and heteroaryl; X ₁₄ is selected from the group consisting of hydrogen, lower alkyl, aryl and heteroaryl; And n13 is 0 or 1; And V) 5- or 6-membered heteroaryl ring or 6-membered aryl ring or heteroaryl ring, optionally substituted with one or more substituents selected from the group consisting of the following; A) optionally substituted C ₁ -C ₈ straight, branched, or cyclic saturated or unsaturated alkyl; B) alkoxy of formula-(X ₁₃ ) _n13 -OX ₁₄ , Wherein X ₁₃ is selected from the group consisting of lower alkylene, lower alkenylene, lower alkynylene, aryl and heteroaryl; X ₁₄ is selected from the group consisting of hydrogen, lower alkyl, aryl and heteroaryl; And n13 is 0 or 1; C) halogen or perhaloalkyl; D) cyano; E) nitro; F) amino of the formula-(X ₁₅ ) _n15 -NX ₁₆ X ₁₇ , Wherein X ₁₅ is selected from the group consisting of lower alkylene, lower alkenylene, lower alkynylene, aryl and heteroaryl; X ₁₆ and X ₁₇ are each independently selected from the group consisting of hydrogen, lower alkyl, aryl and heteroaryl; Or X ₁₆ and X ₁₇ are taken together with the nitrogen to which they are attached to form a 5- or 6-membered heteroaromatic or heteroaliphatic ring; n15 is 0 or 1; G) a substituent of the _formula- (X ₁₈ ) _n18 -C (= E) -X ₁₉ , Wherein X ₁₈ is selected from the group consisting of lower alkylene, lower alkenylene, lower alkynylene, aryl and heteroaryl; E is selected from the group consisting of oxygen, sulfur and -NR _101- , wherein R ₁₀₁ is selected from the group consisting of hydrogen hydrogen, lower alkyl, lower alkene, lower alkyne, aryl and heteroaryl; X ₁₉ is selected from the group consisting of hydrogen, alkyl, aryl, heteroaryl, hydroxy, alkoxy, amino and -NX ₂₀ X ₂₁ , Wherein X ₂₀ and X ₂₁ are each independently selected from the group consisting of hydrogen, alkyl, aryl and heteroaryl; n18 is 0 or 1; And H) a thioether or thiol of the _formula- (X ₂₂ ) _{n22 -SX 23} , Wherein X ₂₂ is selected from the group consisting of lower alkylene, lower alkenylene, lower alkynylene, aryl and heteroaryl; And X ₂₃ is selected from the group consisting of hydrogen, lower alkyl, aryl and heteroaryl, n22 is 0 or 1; And _{Amide of formula-} (X ₂₄ ) _n24 -NH-C (O) -X _{25 or-} (X ₂₆ ) _n26 -C (O) -NH-X ₂₇ , Wherein X ₂₄ and X ₂₆ are each independently selected from the group consisting of lower alkylene, lower alkenylene, lower alkynylene, aryl and heteroaryl; X ₂₅ is selected from the group consisting of hydrogen, lower alkyl, lower alkenyl, aryl, heteroaryl, hydroxy, alkoxy and amide; And X ₂₇ is selected from the group consisting of hydrogen, lower alkyl, lower alkenyl, aryl and heteroaryl; Or R ₂ and R ₃ are taken together with the two ring carbons to which they are attached, or R ₄ and R ₃ are taken together with the two ring carbons to which they are attached, such that they are 6-membered aromatic or heteroaromatic, or 5- or 6-membered heteroaromatic ring, which is optionally substituted with one or more substituents selected from the group consisting of: Iii) hydrogen; Ii) optionally substituted C ₁ -C ₈ straight, branched or cyclic saturated or unsaturated alkyl; Iii) optionally substituted aryl; Iii) optionally substituted heterocycle; Ⅴ) Formula -C (X ₄ ) = N-NX ₅ -C (= E) -NX ₆ X ₇ or -C (X ₄ ) = NN = C (EX ₅ ) -NX ₆ X ₇ , Wherein X ₄ is selected from the group consisting of hydrogen, lower alkyl, aryl, alkaryl, heteroaryl and amino; E is selected from the group consisting of oxygen, sulfur and -NR _101- , wherein R ₁₀₁ is selected from the group consisting of hydrogen hydrogen, lower alkyl, lower alkene, lower alkyne, aryl and heteroaryl; And X ₅ , X ₆ and X ₇ are each independently selected from the group consisting of hydrogen, lower alkyl, aryl and heteroaryl; Iii) amino guanidine of formula -NX ₈ -NX ₉ -C (= NX ₁₀ ) -NX ₁₁ X ₁₂ , Wherein X ₈ , X ₉ , X ₁₀ , X ₁₁ and X ₁₂ are each independently selected from the group consisting of hydrogen, lower alkyl, aryl and heteroaryl; Ⅶ) formula - (X _{13) n13} alkoxy of -OX _14, Wherein X ₁₃ is selected from the group consisting of lower alkylene, lower alkenylene, lower alkynylene, aryl and heteroaryl; X ₁₄ is selected from the group consisting of hydrogen, lower alkyl, aryl and heteroaryl; n13 is 0 or 1; Iii) halogen or perhaloalkyl; Iii) cyano; Iii) nitro; xi) amino of the formula-(X ₁₅ ) _n15 -NX ₁₆ X ₁₇ , Wherein X ₁₅ is selected from the group consisting of lower alkylene, lower alkenylene, lower alkynylene, aryl and heteroaryl; X ₁₆ and X ₁₇ are each independently selected from the group consisting of hydrogen, lower alkyl, aryl and heteroaryl; Or X ₁₆ and X ₁₇ are taken together with the nitrogen to which they are attached and are a 5- or 6-membered heteroaromatic or heteroaliphatic ring; And n15 is 0 or 1; xii) a substituent of the formula-(X ₁₈ ) _n18 -C (= E) -X ₁₉ , Wherein X ₁₈ is selected from the group consisting of lower alkylene, lower alkenylene, lower alkynylene, aryl and heteroaryl; E is selected from the group consisting of oxygen, sulfur and -NR _101- , wherein R ₁₀₁ is selected from the group consisting of hydrogen hydrogen, lower alkyl, lower alkene, lower alkyne, aryl and heteroaryl; X ₁₉ is selected from the group consisting of hydrogen, lower alkyl, aryl, heteroaryl, amino and -NX ₂₀ X ₂₁ , Wherein X ₂₀ and X ₂₁ are independently selected from the group consisting of hydrogen, alkyl, aryl and heteroaryl; And n18 is 0 or 1; xvi) thioether or thiol of the _formula- (X ₂₂ ) _{n22 -SX 23} , Wherein X ₂₂ is lower alkylene, lower alkenylene, lower alkynylene. Aryl and heteroaryl; X ₂₃ is selected from the group consisting of hydrogen, lower alkyl, aryl and heteroaryl; And n22 is 0 or 1; c) R ₅ is selected from the group consisting of hydrogen, lower alkyl, aryl and heteroaryl; Or R ₄ and R ₅ are taken together with the two ring carbons to which they are attached such that a 6-membered aromatic or heteroaromatic, or 5- or 6-membered heteroaromatic ring, which is optionally selected from the group consisting of Or substituted with more substituents; Iii) hydrogen; Ii) optionally substituted C ₁ -C ₈ straight, branched or cyclic saturated or unsaturated alkyl; Iii) optionally substituted aryl; Iii) optionally substituted heterocycle; Iv) a substituent of the formula -C (X ₄ ) = N-NX ₅ -C (= E) -NX ₆ X ₇ or -C (X ₄ ) = NN = C (EX ₅ ) -NX ₆ X ₇ , Wherein X ₄ is selected from the group consisting of hydrogen, lower alkyl, aryl, alkaryl, heteroaryl and amino; E is selected from the group consisting of oxygen, sulfur and -NR _101- , wherein R ₁₀₁ is selected from the group consisting of hydrogen hydrogen, lower alkyl, lower alkene, lower alkyne, aryl and heteroaryl; And X ₅ , X ₆ and X ₇ are each independently selected from the group consisting of hydrogen, lower alkyl, aryl and heteroaryl; Iii) amino guanidine of formula -NX ₈ -NX ₉ -C (= NX ₁₀ ) -NX ₁₁ X ₁₂ , Wherein X ₈ , X ₉ , X ₁₀ , X ₁₁ and X ₁₂ are each independently selected from the group consisting of hydrogen, lower alkyl, aryl and heteroaryl; Ⅶ) formula - (X _{13) n13} alkoxy of -OX _14, Wherein X ₁₃ is selected from the group consisting of lower alkylene, lower alkenylene, lower alkynylene, aryl and heteroaryl; X ₁₄ is selected from the group consisting of hydrogen, lower alkyl, aryl and heteroaryl; n13 is 0 or 1; Iii) halogen or perhaloalkyl; Iii) cyano; Iii) nitro; xi) amino of the formula-(X ₁₅ ) _n15 -NX ₁₆ X ₁₇ , Wherein X ₁₅ is selected from the group consisting of lower alkylene, lower alkenylene, lower alkynylene, aryl or heteroaryl; X ₁₆ and X ₁₇ are each independently selected from the group consisting of hydrogen, lower alkyl, aryl and heteroaryl; Or X ₁₆ and X ₁₇ are taken together with the nitrogen to which they are attached and are a 5- or 6-membered heteroaromatic or heteroaliphatic ring; And n15 is 0 or 1; xii) a substituent of the formula-(X ₁₈ ) _n18 -C (= E) -X ₁₉ , Wherein X ₁₈ is selected from the group consisting of lower alkylene, lower alkenylene, lower alkynylene, aryl and heteroaryl; E is selected from the group consisting of oxygen, sulfur and -NR _101- , wherein R ₁₀₁ is selected from the group consisting of hydrogen hydrogen, lower alkyl, lower alkene, lower alkyne, aryl and heteroaryl; X ₁₉ is selected from the group consisting of hydrogen, lower alkyl, aryl, heteroaryl, amino and -NX ₂₀ X ₂₁ , Wherein X ₂₀ and X ₂₁ are independently selected from the group consisting of hydrogen, alkyl, aryl and heteroaryl; And n18 is 0 or 1; xvi) thioether or thiol of the _formula- (X ₂₂ ) _{n22 -SX 23} , Wherein X ₂₂ is lower alkylene, lower alkenylene, lower alkynylene. Aryl and heteroaryl; X ₂₃ is selected from the group consisting of hydrogen, lower alkyl, aryl and heteroaryl; And n22 is 0 or 1; Provided that at least one of R ₁ -R ₅ is not selected from the group consisting of hydrogen, lower alkyl, aryl and heteroaryl. The compound according to claim 1, which is selected from the group consisting of R _{1 and} below. Iii) hydrogen; Ii) 6-membered aromatic ring, which is optionally substituted with one or more substituents selected from the group consisting of lower alkyl, hydroxy and amine; Iii) a 6-membered heteroaromatic ring, which is optionally substituted with one or more substituents selected from the group consisting of lower alkyl, hydroxy, alkoxy, amino and nitro; Iii) a 5-membered heteroaromatic ring, which is optionally substituted with one or more substituents selected from the group consisting of lower alkyl, hydroxy and amine; 아) acyl of the formula-(X ₁ ) _{n 1} -C (O) -X ₂ , Wherein X ₁ is lower alkylene or lower alkenylene; X ₂ is selected from the group consisting of hydrogen, amino, hydroxy and -NH-X ₃ , Wherein X ₃ is selected from the group consisting of hydrogen, lower alkyl, amino and amide; n is 0 or 1; Iv) a substituent of the formula -C (X ₄ ) = N-NH-C (= E) -NX ₆ X ₇ or -C (X ₄ ) = NN = C (EX ₅ ) -NX ₆ X ₇ , Wherein X ₄ is selected from the group consisting of hydrogen, lower alkyl, aryl and alkaryl; E is selected from the group consisting of oxygen, sulfur and -NR _101- , wherein R ₁₀₁ is selected from the group consisting of hydrogen hydrogen, lower alkyl, lower alkene, lower alkyne, aryl and heteroaryl; And X ₅ , X ₆ and X ₇ are each independently selected from the group consisting of hydrogen and lower alkyl. A compound according to claim 1, wherein R ₁ is selected from the group consisting of Iii) hydrogen; Ii) phenyl, which is optionally substituted with one or more hydroxy or -NH ₂ ; Iii) a 6-membered heteroaromatic ring selected from the group consisting of pyridine, pyrazine, pyridazine, pyrimidine and 1,3,5-triazine, each independently and optionally with lower alkyl, hydroxy, alkoxy and amino Substituted with one or more substituents selected from the group consisting of; Iii) 5-membered heteroaromatic rings selected from the group consisting of pyrrole, imidazole, 1,2,3-triazole, 1,2,4-triazole, tetrazole, thiophene, thiazole, and thiadiazole, which are Each independently and optionally hydroxy, an amide of the _formula- (X ₂₄ ) _n24 -NH-C (O) -X _{25 or-} (X ₂₆ ) _n26 -C (O) -NH-X ₂₇ , and -NH ₂ Substituted with one or more substituents selected from the group consisting of; Iii) acyl of the formula -C (O) -X ₂ , wherein X ₂ is hydrogen or lower alkyl; 아) acyl of formula -X ₁ -C (O) -X ₂ , Wherein X ₁ is lower alkylene or lower alkenylene; And X ₂ is -NH-X ₃ , wherein X ₃ is selected from the group consisting of hydrogen, amino and amide; Iv) -C (X ₄ ) = N-NH-C (= E) -NH ₂ , Wherein X ₄ is selected from the group consisting of hydrogen, methyl, ethyl, phenyl and -CH ₂ CH ₂ -Ph; And E is oxygen, sulfur, and -NR ₁₀₁ - it is selected from the group consisting of wherein R is hydrogen _1O1 hydrogen, lower alkyl, lower alkenyl, lower alkynyl, aryl, and is selected from the group consisting of-heteroaryl; And Ⅷ) Formula -C (X ₄ ) = NN = C (SX ₅ ) -NH ₂ , Wherein X ₄ is selected from the group consisting of hydrogen, methyl, ethyl, phenyl and -CH ₂ CH ₂ -Ph; X ₅ is hydrogen or methyl. The compound of claim 1, wherein the 5- or 6-membered heteroaryl ring in R ₁ is optionally substituted. , Optionally substituted , And optionally substituted Selected from the group consisting of W, X, Y and Z are each independently CR or nitrogen, U is selected from the group consisting of CR ₂ , oxygen, sulfur and NR; wherein R is hydrogen, alkyl or aryl A compound selected from the group consisting of. The heteroaryl ring according to claim 5, wherein the heteroaryl ring is a furan, thiophene, pyrrole, pyrroline, pyrrolidine, oxazole, thiazole, imidazole, imidazoline, imidazolidine, pyrazole, pyrazoline, pyra. Zolidine, isosazole, isothiazole, triazole, thiadiazole, pyran, pyridine, piperidine, morpholine, thiomorpholine, pyridazine, pyrimidine, pyrazine, piperazine, triazine, , , And A compound selected from the group consisting of hydrogen, alkyl and aryl. 7. The heteroaryl ring according to claim 6, wherein the heteroaryl ring is aminofuran, aminothiophene, aminopyrrole, aminopyrroline, aminopyrrolidine, aminooxazole, aminothiazole, aminoimidazole, aminoimidazoline, aminoimidazoli Dean, aminopyrazole, aminopyrazoline, aminopyrazolidine, aminoisoxazole, aminoisothiazole, aminotriazole, aminothiadiazole, aminopyrane, aminopyridine, aminopiperidine, aminomorpholine, aminothiomor Porin, aminopyridazine, aminopyrimidine, aminopyrazine, aminopiperazine, aminotriazine, , , And Compound selected from the group consisting of. The compound of claim 1, wherein R ₁ is —C (O) —CH ₃ , —C (O) —NH—CH ₂ —C (O) —NH ₂ , —CH═CH═C (O) —NH ₂ , -CH ₂ -CH ₂ -C (O) -NH-NH ₂ , -C (H) = N-NH-C (O) -NH ₂ , -C (CH ₃ ) = N-NH-C (O) -NH ₂ , -C (H) = N-NH-C (S) -NH ₂ , -C (CH ₃ ) = N-NH-C (S) -NH ₂ , -C (Ph) = N-NH -C (S) -NH ₂ , -C (CH ₂ CH ₂ Ph) = N-NH-C (S) -NH ₂ , -C (H) = NN = C (SCH ₃ ) -NH ₂ , , , , , , , , , , , , , , , , , , , , And A compound selected from the group consisting of hydrogen, alkyl and aryl. A compound according to claim 1, wherein R ₃ is selected from the group consisting of Iii) hydrogen; Ii) C ₂ -C ₆ alkenylene; Iii) halogen or perhaloalkyl; Iii) alkoxy of formula -OX ₁₄ , Wherein X ₁₄ is selected from the group consisting of hydrogen, lower alkyl and aryl; And Iii) a 5-membered or 6-membered heteroaryl ring, or a 6-membered aryl or heteroaryl ring optionally substituted with one or more substituents selected from the group consisting of A) optionally substituted C ₁ -C ₄ straight, branched or cyclic saturated or unsaturated alkyl; B) alkoxy of formula -OX ₁₄ , wherein X ₁₄ is hydrogen or lower alkyl; C) halogen or perhaloalkyl; D) cyano; E) nitro; F) a substituent of the _formula- (X ₁₈ ) _{n 18} -C (O) -X ₁₉ , Wherein X ₁₈ is lower alkylene; X ₁₉ is selected from the group consisting of hydrogen, lower alkyl, aryl, heteroaryl, hydroxy, alkoxy, amino and -NX ₂₀ X ₂₁ , Wherein X ₂₀ and X ₂₁ are each independently selected from the group consisting of hydrogen, alkyl and aryl; And n18 is 0 or 1; G) a thioether or thiol of the formula -SX ₂₃ , wherein X ₂₃ is selected from the group consisting of hydrogen, lower alkyl, aryl and heteroaryl; And H) an amide of _formula- (X ₂₄ ) _n24 -NH-C (O) -X _{25 or-} (X ₂₆ ) _n26 -C (O) -NH-X ₂₇ , Wherein X ₂₄ and X ₂₆ are each independently lower alkylene; X ₂₅ is selected from the group consisting of hydrogen, lower alkyl, aryl, hydroxy and alkoxy; X ₂₇ is selected from the group consisting of hydrogen, lower alkyl, aryl and heteroaryl. A compound according to claim 1, wherein R ₃ is selected from the group consisting of Iii) hydrogen; Ii) C ₂ -C ₆ alkylene; Iii) halogen or perhaloalkyl; Iii) alkoxy of formula -OX ₁₄ , Wherein X ₁₄ is selected from the group consisting of hydrogen, methyl, ethyl and propyl; Iii) 6-membered aryl ring, which is optionally substituted with one or more substituents selected from the group consisting of: A) methyl, ethyl and propyl; B) hydroxy, methoxy, ethoxy, phenoxy, hydroxymethyl, 2-hydroxyethyl and 3-hydroxypropyl; C) halogen or perfluoroalkyl; D) cyano; E) nitro; F) a substituent of the formula -C (O) -X ₁₉ , Wherein X ₁₉ is hydrogen, methyl, ethyl, propyl, phenyl, hydroxy, methoxy, ethoxy, propoxy, amino and -NX ₂₀ X ₂₁ , Wherein X ₂₀ and X ₂₁ are each independently selected from the group consisting of hydrogen, methyl, ethyl, propyl and phenyl; Thioether or thiol of G) -SX ₂₃ , wherein X ₂₃ is selected from the group consisting of hydrogen, methyl, ethyl, propyl and phenyl; H) an amide of _formula- (X ₂₄ ) _n24 -NH-C (O) -X _{25 or-} (X ₂₆ ) _n26 -C (O) -NH-X ₂₇ , Wherein X ₂₄ and X ₂₆ are each independently lower alkylene; X ₂₅ is selected from the group consisting of hydrogen, methyl, ethyl, propyl, phenyl, hydroxy, methoxy and phenoxy; And X ₂₇ is selected from the group consisting of hydrogen, methyl, ethyl, propyl and phenyl. The compound of claim 1, wherein the 5- or 6-membered heteroaryl ring or 6-membered aryl or heteroaryl ring of R ₃ is optionally substituted. , Optionally substituted , And optionally substituted It may be selected from the group consisting of, wherein V, W, X, Y and Z are each independently CR or nitrogen, U is selected from the group consisting of CR ₂ , oxygen, sulfur and NR, wherein R is hydrogen, A compound selected from the group consisting of alkyl and aryl. 2. The compound of claim 1, wherein the 5- or 6-membered heteroaryl ring or 6-membered aryl or heteroaryl ring of R ₃ is selected from the group consisting of phenyl, furan, thiophene, pyrrole, pyrroline, pyrrolidine, oxazole, thia Sol, imidazole, imidazoline, imidazolidine, pyrazole, pyrazoline, pyrazolidine, isosazole, isothiazole, triazole, thiadiazole, pyran, pyridine, piperidine, morpholine, thiomor Compound selected from the group consisting of porin, pyridazine, pyrimidine, pyrazine, piperazine and triazine. The compound of claim 1, wherein R ₃ is hydrogen, chlorine, bromine, hydroxy, —CH═CH—CH ₂ CH ₂ CH ₂ CH ₂ CH ₃ , —CH═CH—C (O) —OH, —CH═CH— C (O) -OCH ₃ , -CH = CH-C (O) -NH ₂ , -CH ₂ CH (NH ₂ ) COOH, phenyl, -O-CH ₂ -phenyl, 2-methylphenyl, 3-methylphenyl, 2 -Methylthiophenyl, 3-methylthiopetyl, 4-methylthiophenyl, 4-methylphenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 2-hydroxyphenyl, 3-hydroxy Phenyl, 4-hydroxyphenyl, 2-hydroxymethylphenyl, 3-hydroxymethylphenyl, 4-hydroxymethylphenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2-cyanophenyl, 3-cyanophenyl, 4-cyanophenyl, 2-nitrophenyl, 3-nitrophenyl, 4-nitrophenyl, 2-hydroxycarbonylphenyl, 3-hydroxycarbonylphenyl, 4-hydroxycarbonylphenyl , 2-methoxycarbonylphenyl, 3-methoxycarbonylphenyl, 4-methoxycarbonylphenyl, 2-trifluoromethylpetyl, 4-benzyloxyphenyl, 2-phenoxyphenyl, 2,4-di Hydroxyphenyl, 3 , 4-dihydroxyphenyl, 2-hydroxy-4-methoxyphenyl, 4-hydroxy-2-methoxyphenyl, 2,4-dimethoxyphenyl, 3,4-dimethoxyphenyl, 3-fluoro -4-hydroxyphenyl, 3-fluoro-4-methoxyphenyl, , , , , , , 2-pyridyl, 3-pyridyl, 4-pyridyl, , , , , , , , , , , , , And A compound selected from the group consisting of hydrogen, alkyl, and aryl. The compound of claim 1, wherein the R ₂ and R ₃ substituents are taken with the two ring carbons to which they are attached, or the R ₄ and R ₃ substituents are taken with the two ring carbons to which they are attached, or R ₄ And R ₅ substituents are taken together with the two ring carbons to which they are attached to form a 6-membered aromatic or heteroaromatic, or 5- or 6-membered heteroaromatic ring, which optionally contains hydrogen, hydroxy, halogens , Cyano, nitro, amino, hydroxycarbonyl, aminocarbonyl, aminothiocarbonyl, lower alkoxy, phenoxy, amino-furan, amino-thiophene, amino-pyrrole, amino-pyrroline, amino-pyrrolodine , Amino-oxazole, amino-thiazole, amino-imidazole, amino-imidazoline, amino-imidazolidine, amino-pyrazole, amino-pyrazoline, amino-pyrazolidine, amino-isoazole, Amino-isothiazole, sub Mino-triazole, amino-thiadiazole, amino-pyran, amino-pyridine, amino-piperidine, amino-morpholine, amino-thiomorpholine, amino-pyridazine, amino-pyrimidine, amino-pyrazine, amino A compound substituted with one or more substituents selected from the group consisting of piperazine, amino-triazine, semicarbazone, thiosemicarbazone, and amino guanidine. The compound of claim 14, wherein R ₂ and R ₃ are taken with the remainder of the compound of formula 2, or R ₄ and R ₃ are taken with the remainder of the compound of formula 2, or R ₄ and R ₅ are Taken together with the remainder of the compound of, the compound results in the formation of an optionally substituted naphthalene. 15. The compound of claim 14, wherein said substituent is hydroxy. A compound of Formula 3, or a pharmaceutically acceptable salt, amide, ester, or prodrug thereof, (3) Where a) R ₆ is selected from the group consisting of Iii) 6-membered aromatic or heteroaromatic, 5- or 6-membered heteroaromatic rings, which are optionally substituted with one or more substituents selected from the group consisting of lower alkyl, hydroxy, alkoxy, amino and nitro; And Ii) acyl of the formula-(X ₁ ) _{n 1} -C (O) -X ₂ , Wherein X ₁ is selected from the group consisting of lower alkylene, lower alkenylene, lower alkynylene, aryl and heteroaryl; X ₂ is selected from the group consisting of hydrogen, lower alkyl, aryl, heteroaryl, hydroxy, alkoxy, amino, and -NH-X ₃ ; Wherein X ₃ is selected from the group consisting of hydrogen, alkyl, aryl, heteroaryl, amino and amide; And n1 is 0 or 1; Provided that R ₆ is -C ₆ H ₅ , -C (0) H, -C (O) CH ₃ , -C (O) -C ₆ H ₅ , -C (O) NH ₂ , or -C ₆ H _{Not 4} CH ₃ ; b) R ₇ , R ₈ and R ₉ are each independently selected from the group consisting of the following; Iii) hydrogen; Ii) lower alkyl; Iii) lower alkylene; Iii) halogen or perhaloalkyl; Ⅴ) alkoxy of the formula-(X ₁₃ ) _n13 -OX ₁₄ , Wherein X ₁₃ is selected from the group consisting of lower alkylene, lower alkenylene, lower alkynylene, allyl and heteroaryl; X ₁₄ is selected from the group consisting of hydrogen, lower alkyl, aryl and heteroaryl; And n13 is 0 or 1; And V) 5- or 6-membered heteroaryl ring or 6-membered aryl ring or heteroaryl ring, optionally substituted with one or more substituents selected from the group consisting of the following; A) optionally substituted C ₁ -C ₈ straight, branched, or cyclic saturated or unsaturated alkyl; B) alkoxy of formula-(X ₁₃ ) _n13 -OX ₁₄ , Wherein X ₁₃ is selected from the group consisting of lower alkylene, lower alkenylene, lower alkynylene, aryl and heteroaryl; X ₁₄ is selected from the group consisting of hydrogen, lower alkyl, aryl and heteroaryl; And n13 is 0 or 1; C) halogen or perhaloalkyl; D) cyano; E) nitro; F) amino of the formula-(X ₁₅ ) _n15 -NX ₁₆ X ₁₇ , Wherein X ₁₅ is selected from the group consisting of lower alkylene, lower alkenylene, lower alkynylene, aryl and heteroaryl; X ₁₆ and X ₁₇ are each independently selected from the group consisting of hydrogen, lower alkyl, aryl and heteroaryl; Or X ₁₆ and X ₁₇ are taken together with the nitrogen to which they are linked to form a 5- or 6-membered heteroaromatic or heteroaliphatic ring; And n15 is 0 or 1; G) a substituent of the _formula- (X ₁₈ ) _n18 -C (= E) -X ₁₉ , Wherein X ₁₈ is selected from the group consisting of lower alkylene, lower alkenylene, lower alkynylene, aryl and heteroaryl; E is selected from the group consisting of oxygen, sulfur and -NR _101- , wherein R ₁₀₁ is selected from the group consisting of hydrogen hydrogen, lower alkyl, lower alkene, lower alkyne, aryl and heteroaryl; X ₁₉ is selected from the group consisting of hydrogen, lower alkyl, aryl, heteroaryl, hydroxy, alkoxy, amino and -NX ₂₀ X ₂₁ , Wherein X ₂₀ and X ₂₁ are each independently selected from the group consisting of hydrogen, alkyl, aryl and heteroaryl; n18 is 0 or 1; And H) a thioether or thiol of the _formula- (X ₂₂ ) _{n22 -SX 23} , Wherein X ₂₂ is selected from the group consisting of lower alkylene, lower alkenylene, lower alkynylene, aryl and heteroaryl; And X ₂₃ is selected from the group consisting of hydrogen, lower alkyl, aryl and heteroaryl, n22 is 0 or 1; And _{Amide of formula-} (X ₂₄ ) _n24 -NH-C (O) -X _{25 or-} (X ₂₆ ) _n26 -C (O) -NH-X ₂₇ , Wherein X ₂₄ and X ₂₆ are each independently selected from the group consisting of lower alkylene, lower alkenylene, lower alkynylene, aryl and heteroaryl; X ₂₅ is selected from the group consisting of hydrogen, lower alkyl, lower alkenyl, aryl, heteroaryl, hydroxy, alkoxy and amide; And X ₂₇ is selected from the group consisting of hydrogen, lower alkyl, lower alkenyl, aryl and heteroaryl; c) R ₁₀ is selected from the group consisting of hydrogen, lower alkyl, aryl and heteroaryl; Provided that at least one of R ₆ -R ₁₀ is not selected from the group consisting of hydrogen, lower alkyl, aryl and heteroaryl. 18. The compound of claim 17, wherein R ₆ is selected from the group consisting of Iii) hydrogen; Ii) 6-membered aromatic ring, which is optionally substituted with one or more substituents selected from the group consisting of lower alkyl, hydroxy and amine; Iii) a 6-membered heteroaromatic ring, which is optionally substituted with one or more substituents selected from the group consisting of lower alkyl, hydroxy, alkoxy, amino and nitro; Iii) a 5-membered heteroaromatic ring, which is optionally substituted with one or more substituents selected from the group consisting of lower alkyl, hydroxy and amine; 아) acyl of the formula-(X ₁ ) _{n 1} -C (O) -X ₂ , Wherein X ₁ is lower alkylene or lower alkenylene; X ₂ is selected from the group consisting of hydrogen, amino, hydroxy and -NH-X ₃ , Wherein X ₃ is selected from the group consisting of hydrogen, lower alkyl, amino and amide; n is 0 or 1; 18. A compound according to claim 17, wherein R ₆ is selected from the group consisting of Iii) hydrogen; Ii) phenyl, which is optionally substituted with one or more hydroxy or -NH ₂ ; Iii) a 6-membered heteroaromatic ring selected from the group consisting of pyridine, pyrazine, pyridazine, pyrimidine and 1,3,5-triazine, each independently and optionally with lower alkyl, hydroxy, alkoxy and amino Substituted with one or more substituents selected from the group consisting of; Iii) 5-membered heteroaromatic rings selected from the group consisting of pyrrole, imidazole, 1,2,3-triazole, 1,2,4-triazole, tetrazole, thiophene, thiazole, and thiadiazole, which are Each independently and optionally hydroxy, an amide of the _formula- (X ₂₄ ) _n24 -NH-C (O) -X _{25 or-} (X ₂₆ ) _n26 -C (O) -NH-X ₂₇ , and -NH ₂ Substituted with one or more substituents selected from the group consisting of; Iii) acyl of the formula -C (O) -X ₂ , wherein X ₂ is hydrogen or lower alkyl; 아) acyl of formula -X ₁ -C (O) -X ₂ , Wherein X ₁ is lower alkylene or lower alkenylene; And X ₂ is -NH-X ₃ , wherein X ₃ is selected from the group consisting of hydrogen, amino and amide. 18. The compound of claim 17, wherein the 5- or 6-membered heteroaryl ring in R ₆ is optionally substituted , Optionally substituted , And optionally substituted Is selected from the group consisting of: wherein V, W, X, Y and Z are each independently CR or nitrogen, and U is selected from the group consisting of CR ₂ , oxygen, sulfur and NR; R is selected from the group consisting of hydrogen, alkyl and aryl. The heteroaryl ring according to claim 20, wherein the heteroaryl ring is a furan, thiophene, pyrrole, pyrroline, pyrrolidine, oxazole, thiazole, imidazole, imidazoline, imidazolidine, pyrazole, pyrazoline, pyra. Zolidine, isosazole, isothiazole, triazole, thiadiazole, oxadiazole ( ), Pyran, pyridine, piperidine, morpholine, thiomorpholine, pyridazine, pyrimidine, pyrazine, piperazine, and triazine. 21. The heteroaryl ring according to claim 20, wherein the heteroaryl ring is aminofuran, aminothiophene, aminopyrrole, aminopyrroline, aminopyrrolidine, aminooxazole, aminothiazole, aminoimidazole, aminoimidazoline, aminoimida. Zolidine, aminopyrazole, aminopyrazoline, aminopyrazolidine, aminoisoxazole, aminoisothiazole, aminotriazole, aminothiadiazole, aminooxadiazole, aminopyran, aminopyridine, aminopiperidine, amino A compound selected from the group consisting of morpholine, aminothiomorpholine, aminopyridazine, aminopyrimidine, aminopyrazine, aminopiperazine, and aminotriazine. 18. The compound of claim 17, wherein R ₆ is hydrogen, —C (O) —CH ₃ , —C (O) —NH—CH ₂ —C (O) —NH ₂ , —CH═CH═C (O) —NH. ₂ , -CH ₂ CH ₂ -C (O) -NH-NH ₂ , , , , , , , , , , , , , , , , , , , And Compound selected from the group consisting of. 18. A compound according to claim 17, wherein R ₈ is selected from the group consisting of Iii) hydrogen; Ii) C ₂ -C ₆ alkenylene; Iii) halogen or perhaloalkyl; Iii) alkoxy of formula -OX ₁₄ , Wherein X ₁₄ is selected from the group consisting of hydrogen, lower alkyl and aryl; And Iii) a 5-membered or 6-membered heteroaryl ring, or a 6-membered aryl or heteroaryl ring optionally substituted with one or more substituents selected from the group consisting of A) optionally substituted C ₁ -C ₄ straight, branched or cyclic saturated or unsaturated alkyl; B) alkoxy of formula -OX ₁₄ , wherein X ₁₄ is hydrogen or lower alkyl; C) halogen or perhaloalkyl; D) cyano; E) nitro; F) a substituent of the _formula- (X ₁₈ ) _{n 18} -C (O) -X ₁₉ , Wherein X ₁₈ is lower alkylene; X ₁₉ is selected from the group consisting of hydrogen, lower alkyl, aryl, heteroaryl, hydroxy, alkoxy, amino and -NX ₂₀ X ₂₁ , Wherein X ₂₀ and X ₂₁ are each independently selected from the group consisting of hydrogen, alkyl and aryl; And n18 is 0 or 1; G) a thioether or thiol of the formula -SX ₂₃ , wherein X ₂₃ is selected from the group consisting of hydrogen, lower alkyl, aryl and heteroaryl; And H) an amide of _formula- (X ₂₄ ) _n24 -NH-C (O) -X _{25 or-} (X ₂₆ ) _n26 -C (O) -NH-X ₂₇ , Wherein X ₂₄ and X ₂₆ are each independently lower alkylene; X ₂₅ is selected from the group consisting of hydrogen, lower alkyl, aryl, hydroxy and alkoxy; X ₂₇ is selected from the group consisting of hydrogen, lower alkyl, aryl and heteroaryl. 18. A compound according to claim 17, wherein R ₈ is selected from the group consisting of Iii) hydrogen; Ii) C ₂ -C ₆ alkylene; Iii) halogen or perhaloalkyl; Iii) alkoxy of formula -OX ₁₄ , Wherein X ₁₄ is selected from the group consisting of hydrogen, methyl, ethyl and propyl; Iii) 6-membered aryl ring, which is optionally substituted with one or more substituents selected from the group consisting of: A) methyl, ethyl and propyl; B) hydroxy, methoxy, ethoxy, phenoxy, hydroxymethyl, 2-hydroxyethyl and 3-hydroxypropyl; C) halogen or perfluoroalkyl; D) cyano; E) nitro; F) a substituent of the formula -C (O) -X ₁₉ , Wherein X ₁₉ is hydrogen, methyl, ethyl, propyl, phenyl, hydroxy, methoxy, ethoxy, propoxy, amino and -NX ₂₀ X ₂₁ , Wherein X ₂₀ and X ₂₁ are each independently selected from the group consisting of hydrogen, methyl, ethyl, propyl and phenyl; G) a thioether or thiol of the formula -SX ₂₃ , wherein X ₂₃ is selected from the group consisting of hydrogen, methyl, ethyl, propyl and phenyl; H) an amide of _formula- (X ₂₄ ) _n24 -NH-C (O) -X _{25 or-} (X ₂₆ ) _n26 -C (O) -NH-X ₂₇ , Wherein X ₂₄ and X ₂₆ are each independently lower alkylene; X ₂₅ is selected from the group consisting of hydrogen, methyl, ethyl, propyl, phenyl, hydroxy, methoxy and phenoxy; And X ₂₇ is selected from the group consisting of hydrogen, methyl, ethyl, propyl and phenyl. 18. The compound of claim 17, wherein the 5- or 6-membered heteroaryl ring or 6-membered aryl or heteroaryl ring of R ₈ is optionally substituted. , Optionally substituted , And optionally substituted V, W, X, Y and Z are each independently CR or nitrogen, U is selected from the group consisting of CR ₂ , oxygen, sulfur and NR, wherein R is hydrogen, alkyl and Compound selected from the group consisting of NR. 18. The compound of claim 17, wherein the 5- or 6-membered heteroaryl ring of R ₈ or the 6-membered aryl or heteroaryl ring is selected from phenyl, furan, thiophene, pyrrole, pyrroline, pyrrolidine, oxazole, Thiazole, imidazole, imidazoline, imidazolidine, pyrazole, pyrazoline, pyrazolidine, isosazole, isothiazole, triazole, thiadiazole, pyran, pyridine, piperidine, morpholine, thio A compound selected from the group consisting of morpholine, pyridazine, pyrimidine, pyrazine, piperazine, and triazine. 18. The compound of claim 17, wherein R ₈ is hydrogen, chlorine, bromine, hydroxy, -CH = CH-CH ₂ CH ₂ CH ₂ CH ₃ , -CH = CH-C (O) -OH, -CH = CH-. C (O) -OCH ₃ , -CH = CH-C (O) -NH ₂ , -CH ₂ CH (NH ₂ ) COOH, phenyl, -O-CH ₂ -phenyl, 2-methylphenyl, 3-methylphenyl, 2 -Methylthiophenyl, 3-methylthiopetyl, 4-methylthiophenyl, 4-methylphenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 2-hydroxyphenyl, 3-hydroxy Phenyl, 4-hydroxyphenyl, 2-hydroxymethylphenyl, 3-hydroxymethylphenyl, 4-hydroxymethylphenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2-cyanophenyl, 3-cyanophenyl, 4-cyanophenyl, 2-nitrophenyl, 3-nitrophenyl, 4-nitrophenyl, 2-hydroxycarbonylphenyl, 3-hydroxycarbonylphenyl, 4-hydroxycarbonylphenyl , 2-methoxycarbonylphenyl, 3-methoxycarbonylphenyl, 4-methoxycarbonylphenyl, 2-trifluoromethylpetyl, 4-benzyloxyphenyl, 2-phenoxyphenyl, 2,4-di Hydroxyphenyl, 3,4-dihydroxyphenyl, 2-hydroxy-4-methoxyphenyl, 4-hydroxy-2-methoxyphenyl, 2,4-dimethoxyphenyl, 3,4-dimethoxyphenyl, 3-fluor Rho-4-hydroxyphenyl, 3-fluoro-4-methoxyphenyl, , , , , , , 2-pyridyl, 3-pyridyl, 4-pyridyl, , , , , , , , , , , , , And A compound selected from the group consisting of hydrogen, alkyl and aryl. A compound of formula 4, or a pharmaceutically acceptable salt, amide, ester, or prodrug compound thereof. (4) Where a) R ₁₁ is selected from the group consisting of hydrogen, lower alkyl, aryl and heteroaryl; b) R ₁₂ , R ₁₃ and R ₁₄ are each independently selected from the group consisting of the following; Iii) hydrogen; Ii) lower alkyl; Iii) lower alkylene; Iii) halogen or perhaloalkyl; Ⅴ) alkoxy of the formula-(X ₁₃ ) _n13 -OX ₁₄ , Wherein X ₁₃ is selected from the group consisting of lower alkylene, lower alkenylene, lower alkynylene, allyl and heteroaryl; X ₁₄ is selected from the group consisting of hydrogen, lower alkyl, aryl and heteroaryl; And n13 is 0 or 1; And Iii) a 5- or 6-membered heteroaryl ring or a 6-membered aryl or heteroaryl ring, optionally substituted with one or more substituents selected from the group consisting of: A) optionally substituted C ₁ -C ₈ straight, branched, or cyclic saturated or unsaturated alkyl; B) alkoxy of formula-(X ₁₃ ) _n13 -OX ₁₄ , Wherein X ₁₃ is selected from the group consisting of lower alkylene, lower alkenylene, lower alkynylene, aryl and heteroaryl; X ₁₄ is selected from the group consisting of hydrogen, lower alkyl, aryl and heteroaryl; And n13 is 0 or 1; C) halogen or perhaloalkyl; D) cyano; E) nitro; F) amino of the formula-(X ₁₅ ) _n15 -NX ₁₆ X ₁₇ , Wherein X ₁₅ is selected from the group consisting of lower alkylene, lower alkenylene, lower alkynylene, aryl and heteroaryl; X ₁₆ and X ₁₇ are each independently selected from the group consisting of hydrogen, lower alkyl, aryl and heteroaryl; Or X ₁₆ and X ₁₇ are taken together with the nitrogen to which they are attached to form a 5- or 6-membered heteroaromatic or heteroaliphatic ring; And n15 is 0 or 1; G) a substituent of the _formula- (X ₁₈ ) _n18 -C (= E) -X ₁₉ , Wherein X ₁₈ is selected from the group consisting of lower alkylene, lower alkenylene, lower alkynylene, aryl and heteroaryl; E is selected from the group consisting of oxygen, sulfur and -NR _101- , wherein R ₁₀₁ is selected from the group consisting of hydrogen hydrogen, lower alkyl, lower alkene, lower alkyne, aryl and heteroaryl; X ₁₉ is selected from the group consisting of hydrogen, lower alkyl, aryl, heteroaryl, hydroxy, alkoxy, amino and -NX ₂₀ X ₂₁ , Wherein X ₂₀ and X ₂₁ are each independently selected from the group consisting of hydrogen, alkyl, aryl and heteroaryl; n18 is 0 or 1; And H) a thioether or thiol of the _formula- (X ₂₂ ) _{n22 -SX 23} , Wherein X ₂₂ is selected from the group consisting of lower alkylene, lower alkenylene, lower alkynylene, aryl and heteroaryl; And X ₂₃ is selected from the group consisting of hydrogen, lower alkyl, aryl and heteroaryl, n22 is 0 or 1; And _{Amide of formula-} (X ₂₄ ) _n24 -NH-C (O) -X _{25 or-} (X ₂₆ ) _n26 -C (O) -NH-X ₂₇ , Wherein X ₂₄ and X ₂₆ are each independently selected from the group consisting of lower alkylene, lower alkenylene, lower alkynylene, aryl and heteroaryl; X ₂₅ is selected from the group consisting of hydrogen, lower alkyl, lower alkenyl, aryl, heteroaryl, hydroxy, alkoxy and amide; And X ₂₇ is selected from the group consisting of hydrogen, lower alkyl, lower alkenyl, aryl and heteroaryl; c) R ₁₅ is selected from the group consisting of hydrogen, lower alkyl, aryl, alkaryl, heteroaryl and amino; d) R ₁₆ and R ₁₇ are each independently selected from the group consisting of hydrogen, lower alkyl, aryl and heteroaryl; And e) E is selected from the group consisting of oxygen, sulfur and —NR ₁₀₁ —, where R ₁₀₁ is selected from the group consisting of hydrogen hydrogen, lower alkyl, lower alkene, lower alkyne, aryl and heteroaryl. The compound of claim 29, wherein R ₁₃ is selected from the group consisting of Iii) hydrogen; Ii) C ₂ -C ₆ alkenylene; Iii) halogen or perhaloalkyl; Iii) alkoxy of formula -OX ₁₄ , Wherein X ₁₄ is selected from the group consisting of hydrogen, lower alkyl and aryl; And Iii) a 5-membered or 6-membered heteroaryl ring, or a 6-membered aryl or heteroaryl ring optionally substituted with one or more substituents selected from the group consisting of A) optionally substituted C ₁ -C ₄ straight, branched or cyclic saturated or unsaturated alkyl; B) alkoxy of formula -OX ₁₄ , wherein X ₁₄ is hydrogen or lower alkyl; C) halogen or perhaloalkyl; D) cyano; E) nitro; F) a substituent of the _formula- (X ₁₈ ) _{n 18} -C (O) -X ₁₉ , Wherein X ₁₈ is lower alkylene; X ₁₉ is selected from the group consisting of hydrogen, lower alkyl, aryl, heteroaryl, hydroxy, alkoxy, amino and -NX ₂₀ X ₂₁ , Wherein X ₂₀ and X ₂₁ are each independently selected from the group consisting of hydrogen, alkyl and aryl; And n18 is 0 or 1; G) a thioether or thiol of the formula -SX ₂₃ , wherein X ₂₃ is selected from the group consisting of hydrogen, lower alkyl, aryl and heteroaryl; And H) an amide of _formula- (X ₂₄ ) _n24 -NH-C (O) -X _{25 or-} (X ₂₆ ) _n26 -C (O) -NH-X ₂₇ , Wherein X ₂₄ and X ₂₆ are each independently lower alkylene; X ₂₅ is selected from the group consisting of hydrogen, lower alkyl, aryl, hydroxy and alkoxy; X ₂₇ is selected from the group consisting of hydrogen, lower alkyl, aryl and heteroaryl. The compound of claim 29, wherein R ₁₃ is selected from the group consisting of Iii) hydrogen; Ii) C ₂ -C ₆ alkylene; Iii) halogen or perhaloalkyl; Iii) alkoxy of formula -OX ₁₄ , Wherein X ₁₄ is selected from the group consisting of hydrogen, methyl, ethyl and propyl; Iii) 6-membered aryl ring, which is optionally substituted with one or more substituents selected from the group consisting of: A) methyl, ethyl and propyl; B) hydroxy, methoxy, ethoxy, phenoxy, hydroxymethyl, 2-hydroxyethyl and 3-hydroxypropyl; C) halogen or perfluoroalkyl; D) cyano; E) nitro; F) a substituent of the formula -C (O) -X ₁₉ , Wherein X ₁₉ is hydrogen, methyl, ethyl, propyl, phenyl, hydroxy, methoxy, ethoxy, propoxy, amino and -NX ₂₀ X ₂₁ , Wherein X ₂₀ and X ₂₁ are each independently selected from the group consisting of hydrogen, methyl, ethyl, propyl and phenyl; G) a thioether or thiol of the formula -SX ₂₃ , wherein X ₂₃ is selected from the group consisting of hydrogen, methyl, ethyl, propyl and phenyl; H) an amide of _formula- (X ₂₄ ) _n24 -NH-C (O) -X _{25 or-} (X ₂₆ ) _n26 -C (O) -NH-X ₂₇ , Wherein X ₂₄ and X ₂₆ are each independently lower alkylene; X ₂₅ is selected from the group consisting of hydrogen, methyl, ethyl, propyl, phenyl, hydroxy, methoxy and phenoxy; And X ₂₇ is selected from the group consisting of hydrogen, methyl, ethyl, propyl and phenyl. 30. The compound of claim 29, wherein the 5- or 6-membered heteroaryl ring of R ₁₃ or the 6-membered aryl or heteroaryl ring is optionally substituted. , Optionally substituted , And optionally substituted It may be selected from the group consisting of, wherein V, W, X, Y and Z are each independently CR or nitrogen, U is selected from the group consisting of CR ₂ , oxygen, sulfur and NR, wherein R is hydrogen, A compound selected from the group consisting of alkyl and aryl. 30. The compound of claim 29, wherein the 5- or 6-membered heteroaryl ring of R ₁₃ or the 6-membered aryl or heteroaryl ring is selected from phenyl, furan, thiophene, pyrrole, pyrroline, pyrrolidine, oxazole, Thiazole, imidazole, imidazoline, imidazolidine, pyrazole, pyrazoline, pyrazolidine, isosazole, isothiazole, triazole, thiadiazole, pyran, pyridine, piperidine, morpholine, thio A compound selected from the group consisting of morpholine, pyridazine, pyrimidine, pyrazine, piperazine, and triazine. The compound of claim 29, wherein R ₁₃ is hydrogen, chlorine, bromine, hydroxy, —CH═CH—CH ₂ CH ₂ CH ₂ CH ₃ , —CH═CH—C (O) —OH, —CH═CH—C (O) -OCH ₃ , -CH = CH-C (O) -NH ₂ , -CH ₂ CH (NH ₂ ) COOH, phenyl, -O-CH ₂ -phenyl, 2-methylphenyl, 3-methylphenyl, 2- Methylthiophenyl, 3-methylthiopetyl, 4-methylthiophenyl, 4-methylphenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 2-hydroxyphenyl, 3-hydroxyphenyl , 4-hydroxyphenyl, 2-hydroxymethylphenyl, 3-hydroxymethylphenyl, 4-hydroxymethylphenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2-cyanophenyl, 3 Cyanophenyl, 4-cyanophenyl, 2-nitrophenyl, 3-nitrophenyl, 4-nitrophenyl, 2-hydroxycarbonylphenyl, 3-hydroxycarbonylphenyl, 4-hydroxycarbonylphenyl, 2-methoxycarbonylphenyl, 3-methoxycarbonylphenyl, 4-methoxycarbonylphenyl, 2-trifluoromethylpetyl, 4-benzyloxyphenyl, 2-phenoxyphenyl, 2,4-dihydrate Oxyphenyl, 3,4-dihydroxyphenyl, 2-hydroxy-4-methoxyphenyl, 4-hydroxy-2-methoxyphenyl, 2,4-dimethoxyphenyl, 3,4-dimethoxyphenyl, 3-fluor Rho-4-hydroxyphenyl, 3-fluoro-4-methoxyphenyl, , , , , , , 2-pyridyl, 3-pyridyl, 4-pyridyl, , , , , , , , , , , , , And And R is selected from the group consisting of hydrogen, alkyl and aryl. 30. The compound of claim 29, wherein R ₁₁ , R ₁₂ , R ₁₃ and R ₁₄ are each independently selected from (i) hydrogen, (ii) hydroxyl, (iii) halogens, (iii) cyano, (iii) nitro, (Iii) amino, (iii) hydroxycarbonyl, (iii) aminocarbonyl, (iii) aminothiocarbonyl, (iii) lower alkoxy, (xi) phenoxy, (xii) (C ₁ -C ₄ ) Alkylamino, (x ') arylamino, (x') C ₁ -C ₈ straight, branched, and cyclic saturated or unsaturated alkyl or alkenyl, (x ') optionally substituted aryl and (x') optionally substituted hetero A compound selected from the group consisting of cycles. 30. The compound of claim 29, wherein R ₁₅ represents (i) hydrogen, (ii) cyano, (iii) amino, (iii) hydroxycarbonyl, (iii) aminocarbonyl, (iii) aminothiocarbonyl, ) (C ₁ -C ₄ ) alkylamino, (iii) arylamino, (iii) C ₁ -C ₈ straight chain, branched, and cyclic saturated or unsaturated alkyl or alkenyl, (iii) optionally substituted aryl, And (xi) an optionally substituted heterocycle. 30. The compound of claim 29, wherein R ₁₆ represents (i) hydrogen, (ii) amino, (iii) hydroxycarbonyl, (iii) aminocarbonyl, (iii) aminothiocarbonyl, (iii) (C _1- C ₄ ) alkylamino, (iii) arylamino, (iii) C ₁ -C ₈ straight, branched, and cyclic saturated or unsaturated alkyl or alkenyl, (iii) optionally substituted aryl, and (iii) optional A compound selected from the group consisting of heterocycles substituted with. 30. The process of claim 29, wherein R ₁₇ is (i) hydrogen, (ii) (C ₁ -C ₄ ) alkylamino, (iii) arylamino, (iii) C ₁ -C ₈ straight chain, branched, and cyclic saturation Or unsaturated alkyl, (iii) optionally substituted aryl, and (iii) optionally substituted heterocycle. 39. The composition of any one of claims 35 to 38, wherein the heterocycle is furan, thiophene, pyrrole, pyrroline, pyrrolidine, oxazole, thiazole, imidazole, imidazoline, imidazolidine, pyra. Sol, pyrazoline, pyrazolidine, isosazole, isothiazole, triazole, thiadiazole, pyran, pyridine, piperidine, morpholine, thiomorpholine, pyridazine, pyrimidine, pyrazine, piperazine, triazine , And benzoimidazole. A compound of formula 5 or 6, or a pharmaceutically acceptable salt, amide, ester, or prodrug thereof, (5) (6) Where a) R ₁₉ -R ₂₂ and R ₂₆ -R ₂₉ are each independently selected from the group consisting of Iii) hydrogen; Ii) optionally substituted C ₁ -C ₈ straight, branched or cyclic saturated or unsaturated alkyl; Iii) optionally substituted aryl; Iii) optionally substituted heterocycle; Ⅴ) Formula -C (X ₄ ) = N-NX ₅ -C (= E) -NX ₆ X ₇ or -C (X ₄ ) = NN = C (EX ₅ ) -NX ₆ X ₇ , Wherein X ₄ is selected from the group consisting of hydrogen, lower alkyl, aryl, alkaryl, heteroaryl and amino; E is selected from the group consisting of oxygen, sulfur and -NR _101- , wherein R ₁₀₁ is selected from the group consisting of hydrogen hydrogen, lower alkyl, lower alkene, lower alkyne, aryl and heteroaryl; And X ₅ , X ₆ and X ₇ are each independently selected from the group consisting of hydrogen, lower alkyl, aryl and heteroaryl; Iii) amino guanidine of formula -NX ₈ -NX ₉ -C (= NX ₁₀ ) -NX ₁₁ X ₁₂ , Wherein X ₈ , X ₉ , X ₁₀ , X ₁₁ and X ₁₂ are each independently selected from the group consisting of hydrogen, lower alkyl, aryl and heteroaryl; Ⅶ) formula - (X _{13) n13} alkoxy of -OX _14, Wherein X ₁₃ is selected from the group consisting of lower alkylene, lower alkenylene, lower alkynylene, aryl and heteroaryl; X ₁₄ is selected from the group consisting of hydrogen, lower alkyl, aryl and heteroaryl; n13 is 0 or 1; Iii) halogen or perhaloalkyl; Iii) cyano; Iii) nitro; xi) amino of the formula-(X ₁₅ ) _n15 -NX ₁₆ X ₁₇ , Wherein X ₁₅ is selected from the group consisting of lower alkylene, lower alkenylene, lower alkynylene, aryl and heteroaryl; X ₁₆ and X ₁₇ are each independently selected from the group consisting of hydrogen, lower alkyl, aryl and heteroaryl; Or X ₁₆ and X ₁₇ are taken together with the nitrogen to which they are attached and are a 5- or 6-membered heteroaromatic or heteroaliphatic ring; And n15 is 0 or 1; xii) a substituent of the formula-(X ₁₈ ) _n18 -C (= E) -X ₁₉ , Wherein X ₁₈ is selected from the group consisting of lower alkylene, lower alkenylene, lower alkynylene, aryl and heteroaryl; E is selected from the group consisting of oxygen, sulfur and —NR ₁₀₁ —, where R ₁₀₁ is selected from the group consisting of hydrogen hydrogen, lower alkyl, lower alkene, lower alkyne, aryl and heteroaryl; X ₁₉ is selected from the group consisting of hydrogen, lower alkyl, aryl, heteroaryl, amino and -NX ₂₀ X ₂₁ , Wherein X ₂₀ and X ₂₁ are independently selected from the group consisting of hydrogen, alkyl, aryl and heteroaryl; And n18 is 0 or 1; xvi) thioether or thiol of the _formula- (X ₂₂ ) _{n22 -SX 23} , Wherein X ₂₂ is lower alkylene, lower alkenylene, lower alkynylene. Aryl and heteroaryl; X ₂₃ is selected from the group consisting of hydrogen, lower alkyl, aryl and heteroaryl; And n22 is 0 or 1; b) R ₂₃ and R ₃₀ are each independently selected from the group consisting of the following; Iii) hydrogen; Ii) lower alkyl; Iii) lower alkylene; Iii) halogen or perhaloalkyl; Ⅴ) alkoxy of the formula-(X ₁₃ ) _n13 -OX ₁₄ , Wherein X ₁₃ is selected from the group consisting of lower alkylene, lower alkenylene, lower alkynylene, allyl and heteroaryl; X ₁₄ is selected from the group consisting of hydrogen, lower alkyl, aryl and heteroaryl; And n13 is 0 or 1; And Iii) a 5- or 6-membered heteroaryl ring or a 6-membered aryl or heteroaryl ring, optionally substituted with one or more substituents selected from the group consisting of: A) optionally substituted C ₁ -C ₈ straight, branched, or cyclic saturated or unsaturated alkyl; B) alkoxy of formula-(X ₁₃ ) _n13 -OX ₁₄ , Wherein X ₁₃ is selected from the group consisting of lower alkylene, lower alkenylene, lower alkynylene, aryl and heteroaryl; X ₁₄ is selected from the group consisting of hydrogen, lower alkyl, aryl and heteroaryl; And n13 is 0 or 1; C) halogen or perhaloalkyl; D) cyano; E) nitro; F) amino of the formula-(X ₁₅ ) _n15 -NX ₁₆ X ₁₇ , Wherein X ₁₅ is selected from the group consisting of lower alkylene, lower alkenylene, lower alkynylene, aryl and heteroaryl; X ₁₆ and X ₁₇ are each independently selected from the group consisting of hydrogen, lower alkyl, aryl and heteroaryl; Or X ₁₆ and X ₁₇ are taken together with the nitrogen to which they are attached to form a 5- or 6-membered heteroaromatic or heteroaliphatic ring; And n15 is 0 or 1; G) a substituent of the _formula- (X ₁₈ ) _n18 -C (= E) -X ₁₉ , Wherein X ₁₈ is selected from the group consisting of lower alkylene, lower alkenylene, lower alkynylene, aryl and heteroaryl; E is selected from the group consisting of oxygen, sulfur and -NR _101- , wherein R ₁₀₁ is selected from the group consisting of hydrogen hydrogen, lower alkyl, lower alkene, lower alkyne, aryl and heteroaryl; X ₁₉ is selected from the group consisting of hydrogen, lower alkyl, aryl, heteroaryl, hydroxy, alkoxy, amino and -NX ₂₀ X ₂₁ , Wherein X ₂₀ and X ₂₁ are each independently selected from the group consisting of hydrogen, alkyl, aryl and heteroaryl; n18 is 0 or 1; And H) a thioether or thiol of the _formula- (X ₂₂ ) _{n22 -SX 23} , Wherein X ₂₂ is selected from the group consisting of lower alkylene, lower alkenylene, lower alkynylene, aryl and heteroaryl; And X ₂₃ is selected from the group consisting of hydrogen, lower alkyl, aryl and heteroaryl, n22 is 0 or 1; And _{Amide of formula-} (X ₂₄ ) _n24 -NH-C (O) -X _{25 or-} (X ₂₆ ) _n26 -C (O) -NH-X ₂₇ , Wherein X ₂₄ and X ₂₆ are each independently selected from the group consisting of lower alkylene, lower alkenylene, lower alkynylene, aryl and heteroaryl; X ₂₅ is selected from the group consisting of hydrogen, lower alkyl, lower alkenyl, aryl, heteroaryl, hydroxy, alkoxy and amide; And X ₂₇ is selected from the group consisting of hydrogen, lower alkyl, lower alkenyl, aryl and heteroaryl; and c) R ₂₄ , R ₂₅ , R ₃₁ and R ₃₂ are each independently selected from the group consisting of Iii) a 6-membered aromatic or heteroaromatic, 5- or 6-membered heteroaromatic ring, optionally substituted with one or more substituents selected from the group consisting of lower alkyl, hydroxy, alkoxy, amino and nitro; Ii) acyl of the formula-(X ₁ ) _{n 1} -C (O) -X ₂ , Wherein X ₁ is selected from the group consisting of lower alkylene, lower alkenylene, lower alkynylene, aryl and heteroaryl; X ₂ is selected from the group consisting of hydrogen, lower alkyl, aryl, heteroaryl, hydroxy, alkoxy, amino and -NH-X ₃ ; Wherein X ₃ is selected from the group consisting of hydrogen, alkyl, aryl, heteroaryl, amino and amide; And n1 is 0 or 1; Iv) a substituent of formula -C (X ₄ ) = N-NX ₅ -C (= E) -NX ₆ X ₇ or a formula -C (X ₄ ) = NN = C (EX ₅ ) -NX ₆ X ₇ , Wherein X ₄ is selected from the group consisting of hydrogen, lower alkyl, aryl, alkaryl, heteroaryl and amino; E is selected from the group consisting of oxygen, sulfur and -NR _101- , wherein R ₁₀₁ is selected from the group consisting of hydrogen hydrogen, lower alkyl, lower alkene, lower alkyne, aryl and heteroaryl; And X ₅ , X ₆ and X ₇ are each independently selected from the group consisting of hydrogen, lower alkyl, aryl and heteroaryl; Provided that any of R ₂₄ , R ₂₅ , R ₃₁ or R ₃₂ is -C ₆ H ₅ , -C (0) H, -C (O) CH ₃ , -C (O) -C ₆ H ₅ , -C (O) NH ₂ , or -C ₆ H ₄ CH ₃ . 41. The compound of claim 40, wherein R ₂₄ , R ₂₅ , R ₃₁ and R ₃₂ are each independently selected from the group consisting of the following. Iii) hydrogen; Ii) 6-membered aromatic ring, which is optionally substituted with one or more substituents selected from the group consisting of lower alkyl, hydroxy and amine; Iii) a six-membered heteroaromatic ring, which is optionally substituted with one or more substituents selected from the group consisting of lower alkyl, hydroxy, alkoxy, amino, and nitro; Iii) a 5-membered heteroaromatic ring, which is optionally substituted with one or more substituents selected from the group consisting of lower alkyl, hydroxy and amine; 아) acyl of the formula-(X ₁ ) _{n 1} -C (O) -X ₂ , Wherein X ₁ is lower alkylene or lower alkenylene; X ₂ is selected from the group consisting of hydrogen, amino, hydroxy and -NH-X ₃ , Wherein X ₃ is selected from the group consisting of hydrogen, lower alkyl, amino and amide; n1 is 0 or 1; Iv) a substituent of the formula -C (X ₄ ) = N-NH-C (= E) -NX ₆ X ₇ or a formula -C (X ₄ ) = NN = C (EX ₅ ) -NX ₆ X ₇ , Wherein X ₄ is selected from the group consisting of hydrogen, lower alkyl, aryl and alkaryl; E is selected from the group consisting of oxygen, sulfur and -NR _101- , wherein R ₁₀₁ is selected from the group consisting of hydrogen hydrogen, lower alkyl, lower alkene, lower alkyne, aryl and heteroaryl; And X ₅ , X ₆ and X ₇ are each independently selected from the group consisting of hydrogen and lower alkyl. 41. The compound of claim 40, wherein R ₂₄ , R ₂₅ , R ₃₁ , and R ₃₂ are each independently selected from the group consisting of Iii) hydrogen; Ii) phenyl, which is optionally substituted with one or more hydroxy or -NH ₂ ; Iii) a 6-membered heteroaromatic ring selected from the group consisting of pyridine, pyrazine, pyridazine, pyrimidine and 1,3,5-triazine, each independently and optionally with lower alkyl, hydroxy, alkoxy and amino Substituted with one or more substituents selected from the group consisting of; Iii) 5-membered heteroaromatic rings selected from the group consisting of pyrrole, imidazole, 1,2,3-triazole, 1,2,4-triazole, tetrazole, thiophene, thiazole, and thiadiazole, which are Each independently and optionally hydroxy, an amide of the _formula- (X ₂₄ ) _n24 -NH-C (O) -X _{25 or-} (X ₂₆ ) _n26 -C (O) -NH-X ₂₇ , and -NH ₂ Substituted with one or more substituents selected from the group consisting of; Iii) acyl of the formula -C (O) -X ₂ , wherein X ₂ is hydrogen or lower alkyl; 아) acyl of formula -X ₁ -C (O) -X ₂ , Wherein X ₁ is lower alkylene or lower alkenylene; And X ₂ is -NH-X ₃ , wherein X ₃ is selected from the group consisting of hydrogen, amino and amide; Iv) a substituent of the formula -C (X ₄ ) = N-NH-C (= E) -NH ₂ , Wherein X ₄ is selected from the group consisting of hydrogen, methyl, ethyl, phenyl and -CH ₂ CH ₂ -Ph; And E is oxygen, sulfur, and -NR ₁₀₁ - it is selected from the group consisting of wherein R is hydrogen _1O1 hydrogen, lower alkyl, lower alkenyl, lower alkynyl, aryl, and is selected from the group consisting of-heteroaryl; And Iv) a substituent of the formula -C (X ₄ ) = NN = C (SX ₅ ) -NH ₂ , Wherein X ₄ is selected from the group consisting of hydrogen, methyl, ethyl, phenyl and -CH ₂ CH ₂ -Ph; X ₅ is hydrogen or methyl. 41. The compound of claim 40, wherein the 5- or 6-membered heteroaryl ring of R ₂₄ , R ₂₅ , R ₃₁ and R ₃₂ is optionally substituted. , Optionally substituted , And optionally substituted And V, W, X, Y and Z are each independently CR or nitrogen, U is selected from the group consisting of CR ₂ , oxygen, sulfur and NR, wherein R is hydrogen, alkyl or A compound selected from the group consisting of aryl. The method of claim 40, wherein the heteroaryl ring is furan, thiophene, pyrrole, pyrroline, pyrrolidine, oxazole, thiazole, imidazole, imidazoline, imidazolidine, pyrazole, pyrazoline, pyra With zolidine, isosazole, isothiazole, triazole, thiadiazole, oxadiazole, pyran, pyridine, piperidine, morpholine, thiomorpholine, pyridazine, pyrimidine, pyrazine, piperazine, and triazine A compound selected from the group consisting of. 45. The heteroaryl ring according to claim 44, wherein the heteroaryl ring is aminofuran, aminothiophene, aminopyrrole, aminopyrroline, aminopyrrolidine, aminooxazole, aminothiazole, aminoimidazole, aminoimidazoline, aminoimida Zolidine, aminopyrazole, aminopyrazoline, aminopyrazolidine, aminoisoxazole, aminoisothiazole, aminotriazole, aminothiadiazole, aminooxadiazole, aminopyran, aminopyridine, aminopiperidine, amino A compound selected from the group consisting of morpholine, aminothiomorpholine, aminopyridazine, aminopyrimidine, aminopyrazine, aminopiperazine, and aminotriazine. 41. The compound of claim 40, wherein R ₂₄ , R ₂₅ , R ₃₁ and R ₃₂ are hydrogen, —C (O) —CH ₃ , —C (O) —NH—CH ₂ —C (O) —NH ₂ , —CH = CH = C (O) -NH ₂ , -CH ₂ CH ₂ -C (O) -NH-NH ₂ , -C (H) = N-NH-C (O) -NH ₂ , -C (CH ₃ ) = N-NH-C (O) -NH ₂ , -C (H) = N-NH-C (S) -NH ₂ , -C (CH ₃ ) = N-NH-C (S) -NH ₂ , -C (Ph) = N-NH-C (S) -NH ₂ , -C (CH ₂ CH ₂ Ph) = N-NH-C (S) -NH ₂ , -C (H) = NN = C (SCH ₃ ) -NH ₂ , , , , , , , , , , , , . , , , , , , , And And R is selected from the group consisting of hydrogen, alkyl and aryl. 41. The compound of claim 40, wherein R ₂₃ and R ₃₀ are each independently selected from the group consisting of Iii) hydrogen; Ii) C ₂ -C ₆ alkenylene; Iii) halogen or perhaloalkyl; Iii) alkoxy of formula -OX ₁₄ , Wherein X ₁₄ is selected from the group consisting of hydrogen, lower alkyl and aryl; And Iii) a 5-membered or 6-membered heteroaryl ring, or a 6-membered aryl or heteroaryl ring optionally substituted with one or more substituents selected from the group consisting of A) optionally substituted C ₁ -C ₄ straight, branched or cyclic saturated or unsaturated alkyl; B) alkoxy of formula -OX ₁₄ , wherein X ₁₄ is hydrogen or lower alkyl; C) halogen or perhaloalkyl; D) cyano; E) nitro; F) a substituent of the _formula- (X ₁₈ ) _{n 18} -C (O) -X ₁₉ , Wherein X ₁₈ is lower alkylene; X ₁₉ is selected from the group consisting of hydrogen, lower alkyl, aryl, heteroaryl, hydroxy, alkoxy, amino and -NX ₂₀ X ₂₁ , Wherein X ₂₀ and X ₂₁ are each independently selected from the group consisting of hydrogen, alkyl and aryl; And n18 is 0 or 1; G) a thioether or thiol of the formula -SX ₂₃ , wherein X ₂₃ is selected from the group consisting of hydrogen, lower alkyl, aryl and heteroaryl; And H) an amide of _formula- (X ₂₄ ) _n24 -NH-C (O) -X _{25 or-} (X ₂₆ ) _n26 -C (O) -NH-X ₂₇ , Wherein X ₂₄ and X ₂₆ are each independently lower alkylene; X ₂₅ is selected from the group consisting of hydrogen, lower alkyl, aryl, hydroxy and alkoxy; X ₂₇ is selected from the group consisting of hydrogen, lower alkyl, aryl and heteroaryl. 41. The compound of claim 40, wherein R ₂₃ and R ₃₀ are selected from the group consisting of Iii) hydrogen; Ii) C ₂ -C ₆ alkylene; Iii) halogen or perfluoroalkyl; Iii) alkoxy of formula -OX ₁₄ , Wherein X ₁₄ is selected from the group consisting of hydrogen, methyl, ethyl and propyl; Iii) 6-membered aryl ring, which is optionally substituted with one or more substituents selected from the group consisting of: A) methyl, ethyl and propyl; B) hydroxy, methoxy, ethoxy, phenoxy, hydroxymethyl, 2-hydroxyethyl and 3-hydroxypropyl; C) halogen or perfluoroalkyl; D) cyano; E) nitro; F) a substituent of the formula -C (O) -X ₁₉ , Wherein X ₁₉ is hydrogen, methyl, ethyl, propyl, phenyl, hydroxy, methoxy, ethoxy, propoxy, amino and -NX ₂₀ X ₂₁ , Wherein X ₂₀ and X ₂₁ are each independently selected from the group consisting of hydrogen, methyl, ethyl, propyl and phenyl; Thioether or thiol of G) -SX ₂₃ , wherein X ₂₃ is selected from the group consisting of hydrogen, methyl, ethyl, propyl and phenyl; H) an amide of _formula- (X ₂₄ ) _n24 -NH-C (O) -X _{25 or-} (X ₂₆ ) _n26 -C (O) -NH-X ₂₇ , Wherein X ₂₄ and X ₂₆ are each independently lower alkylene; X ₂₅ is selected from the group consisting of hydrogen, methyl, ethyl, propyl, phenyl, hydroxy, methoxy and phenoxy; And X ₂₇ is selected from the group consisting of hydrogen, methyl, ethyl, propyl and phenyl. 41. The compound of claim 40, wherein the 5- or 6-membered heteroaryl ring of R ₂₃ and R ₃₀ or the 6-membered aryl or heteroaryl is optionally substituted , Optionally substituted , And optionally substituted Is selected from the group consisting of W, X, Y and Z are each independently CR or nitrogen, and U is selected from the group consisting of CR ₂ , oxygen, sulfur and NR; Wherein R is selected from the group consisting of hydrogen, alkyl and aryl. 41. The compound of claim 40, wherein the 5- or 6-membered heteroaryl ring of R ₂₃ and R ₃₀ or the 6-membered aryl or heteroaryl is selected from phenyl, furan, thiophene, pyrrole, pyrroline, pyrrolidine, Oxazole, thiazole, imidazole, imidazoline, imidazolidine, pyrazole, pyrazoline, pyrazolidine, isosazole, isothiazole, triazole, thiadiazole, pyran, pyridine, piperidine, mor Compound selected from the group consisting of porin, thiomorpholine, pyridazine, pyrimidine, pyrazine, piperazine and triazine. The compound of claim 40, wherein R ₂₃ and R ₃₀ are each independently hydrogen, chlorine, bromine, hydroxy, —CH═CH—CH ₂ CH ₂ CH ₂ CH ₃ , —CH═CH—C (O) —OH, -CH = CH-C (O) -OCH ₃ , -CH = CH-C (O) -NH ₂ , -CH ₂ CH (NH ₂ ) COOH, phenyl, -O-CH ₂ -phenyl, 2-methylphenyl, 3-methylphenyl, 2-methylthiophenyl, 3-methylthiopetyl, 4-methylthiophenyl, 4-methylphenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 2-hydroxyphenyl , 3-hydroxyphenyl, 4-hydroxyphenyl, 2-hydroxymethylphenyl, 3-hydroxymethylphenyl, 4-hydroxymethylphenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2 -Cyanophenyl, 3-cyanophenyl, 4-cyanophenyl, 2-nitrophenyl, 3-nitrophenyl, 4-nitrophenyl, 2-hydroxycarbonylphenyl, 3-hydroxycarbonylphenyl, 4- Hydroxycarbonylphenyl, 2-methoxycarbonylphenyl, 3-methoxycarbonylphenyl, 4-methoxycarbonylphenyl, 2-trifluoromethylphenyl, 4-benzyloxyphenyl, 2-phenoxype Neyl, 2,4-dihydroxyphenyl, 3,4-dihydroxyphenyl, 2-hydroxy-4-methoxyphenyl, 4-hydroxy-2-methoxyphenyl, 2,4-dimethoxyphenyl, 3,4-dimethoxyphenyl, 3-fluoro-4-hydroxyphenyl, 3-fluoro-4-methoxyphenyl, , , , , , , 2-pyridyl, 3-pyridyl, 4-pyridyl, , , , , , , , , , , , , And And R is selected from the group consisting of hydrogen, alkyl and aryl. A compound selected from the group consisting of the compounds disclosed in Table 1, or a pharmaceutically acceptable salt, ester, amide or prodrug thereof. 53. The compound of claim 1, 2, 28, 40 or 52, wherein said compound is capable of inhibiting the catalytic activity of protein kinases. 54. The compound of claim 53, wherein said protein kinase is selected from the group consisting of receptor protein tyrosine kinases, cellular tyrosine kinases and serine-threonine kinases. 54. The compound of claim 53, wherein said protein kinase is a cyclin dependent kinase. The compound of claim 55, wherein said cyclin dependent kinase is selected from the group consisting of CDK1 (CDC2), CDK2, CDK3, CDK4, CDK5, CDK6, CDK7, CDK8, and CDK9. 56. The compound of claim 55, wherein said cyclin dependent kinase is selected from the group consisting of CDK2 and CDK5. 55. The compound of claim 54, wherein said protein kinase is selected from the group consisting of protein kinase C, MEK1, MAP kinase, EGF receptor, PDGF receptor, IGF receptor, her2, raf1, PI3 kinase, wheel kinase, Src and Abl . A method of regulating a signal transduction pathway in a cell, comprising contacting a protein kinase with a compound according to any one of claims 1, 2, 28, 40, and 52. 52. A method of regulating an intracellular signal transduction pathway, comprising contacting cells with a compound according to any one of claims 1, 2, 28, 40, and 52. 61. The method of claim 60, wherein said cells express protein kinases and said compounds modulate the function of said protein kinases. a) contacting cells expressing said protein kinase with a compound according to any one of the first, second, seventeenth, twenty-eighth, forty-second, or fifty-second embodiment; And b) monitoring the effect of the compound on the cells; Consisting of, comprising an aromatic compound that modulates the function of protein kinases. 63. The method of claim 62, wherein said effect is selected from the group consisting of a change in cell phenotype, a change in cell proliferation, a change in catalytic activity of said protein kinase, and a change in interaction between said protein kinase and a binding partner. Way. 52. A method of modulating unregulated kinase signal transduction, comprising administering to a subject a pharmacologically effective amount of a compound according to any one of claims 1, 2, 28, 40 and 52. . 65. The method of claim 64, wherein unregulated kinase signal transduction causes a disease or abnormal condition in the organism and the method leads to the treatment or prevention of the disease or abnormal condition; The disease or abnormal condition is associated with an abnormality in the signal transduction pathway characterized by the interaction between the protein kinase and the binding partner; The method further comprises promoting or preventing the abnormal interaction. 66. The method of claim 65, wherein said disease or abnormal condition is selected from the group consisting of cell proliferative diseases, cerebrovascular injury, autoimmune diseases, degenerative neurological diseases, degenerative diseases of the musculoskeletal system. 67. The method of claim 66, wherein the neurodegenerative diseases are AIDS-related dementia, Alzheimer's disease, Parkinson's disease, Pick's disease, Huntington's disease, diffuse Lewy body disease, multiple system atrophy, muscular dystrophy, Down's syndrome related dementia, cerebrovascular dementia, Cainine Motor Neuron Disease, Retinal Pigment Degeneration, Myelodystrophic Atrophy, Myelodysplastic Syndrome, Stroke and Repulfusion Injury, Aplastic Anemia, Myocardial Infarction-related Fever, Arrhythmia, Atherosclerosis, Toxin-Induced or Alcohol-Related Diseases, Chronic Anemia and Aplastic Hematologic diseases, including anemia, and cerebrovascular degeneration. 67. The method of claim 66, wherein said cerebrovascular injury is selected from the group consisting of cerebrovascular dementia, stroke, cerebral infarction and head trauma. 67. The AIDS of claim 66, wherein the autoimmune disease is systemic lupus, ertematosus, autoimmune mediated glutomerropritis, rheumatoid arthritis, psoriasis, inflammatory bowel disease, autoimmune diabetes, and HIV-infected individuals. Selected from the group consisting of 67. The moto-neuron of claim 66, wherein the AIDS-related dementia, Alzheimer's disease, Parkinson's disease, Pick's disease, Huntington's disease, diffuse Lewy body disease, multiple system atrophy, amyotrophic lateral sclerosis, Down's syndrome related dementia, cerebrovascular dementia, and kinemoto And dementia including disease, retinal pigmentation, myelodystrophic atrophy, myelodysplastic syndrome, and cerebrovascular degeneration. 67. The method of claim 66, wherein said degenerative disease is selected from the group consisting of osteoporosis, arthritis, aspirin-sensitive rhinosinusitis, cystic fibrosis, multiple sclerosis, kidney disease, chemotherapy induced hair loss, baldness, cancer pain, and the like. 67. The method of claim 66, wherein the cell proliferative disorder is Breast, lung, colon, kidney, liver, prostate, stomach, esophagus, gallbladder, ovary, pancreas, cervix, bladder, thyroid cartilage, carcinoma of the skin, and squamous cell carcinoma; Hematopoietic tumors of the bone marrow selected from the group consisting of acute and chronic leukemia, prosthetic leukemia, and myelodysplastic syndromes; Hematopoietic tumors of lymphoid cells selected from the group consisting of B-cell lymphoma, T-cell lymphoma, Hodgkin lymphoma, non-Hodgkin lymphoma, hair cell lymphoma, Burkett lymphoma, leukemia, acute lymphocytic leukemia, and acute lymphoblastic leukemia; Tumors of mesenchymal organ selected from the group consisting of fibrosarcoma and rhabdomyosarcoma; Tumors of the central and peripheral nervous system selected from the group consisting of neuroblastoma, astrocytoma, glioma and schwannoma; Karposi sarcoma, melanoma, intestinal mesothelioma, teratocarcinoma, pigmentary dry skin disease, osteosarcoma, keratoktanoma, and thyroid vesicle cancer; And the like. 67. The method according to claim 66, wherein said cell proliferative disease is benign prostatic hyperplasia, hereditary adenomatous polyposis, myofioma, atherosclerosis, pulmonary fibrosis, arthritis, psoriasis, glomerulonephritis, resterosis, hypertrophic scar formation after angioplasty or angioplasty. , Infectious bowel disease, transplant rejection, endotoxin shock and fungal infection. i) a pharmaceutically acceptable carrier, diluent, or excipient, or combination thereof; And ii) a compound according to any one of claims 1, 2, 28, 40 and 52; Pharmaceutical composition comprising a. 5-bromosalicylaldehyde semicarbazone hydrochloride; 5-phenylsalicylaldehyde thiosemicarbazone; 5-phenylsalicylaldehyde semicarbazone hydrochloride; 5- (3-methoxyphenyl) salicyaldehyde thiosemicarbazone; 5- (3-cyanophenyl) salicyaldehyde thiosemicarbazone; 5- (3-hydroxymethylphenyl) salicyaldehyde thiosemicarbazone; 5- (3-hydroxymethylphenyl) salicyaldehyde semicarbazone hydrochloride; 5- (4-hydroxymethylphenyl) salicyaldehyde thiosemicarbazone; 5- (4-nitrophenyl) salicylaldehyde thiosemicarbazone; 5- (3-methoxycarbonylphenyl) salicyaldehyde thiosemicarbazone; 5- (3-methoxycarbonylphenyl) salicyaldehyde semicarbazone hydrochloride; 5- (3-fluoro-4-methoxyphenyl) salicyaldehyde thiosemicarbazone; 5- (3-fluorophenyl) salicyaldehyde thiosemicarbazone; 5- (4-fluorophenyl) salicyaldehyde thiosemicarbazone; 5- (3-carboxyphenyl) salicyaldehyde thiosemicarbazone; 5- (3-carboxyphenyl) salicyaldehyde semicarbazone hydrochloride; 5- (4-carboxyphenyl) salicyaldehyde thiosemicarbazone; 5- (3-hydroxyphenyl) salicyaldehyde thiosemicarbazone; 5- (4-hydroxyphenyl) salicyaldehyde thiosemicarbazone; 5- (4-hydroxyphenyl) salicyaldehyde semicarbazone hydrochloride; 5- (3-fluoro-4-hydroxyphenyl) salicyaldehyde thiosemicarbazone; 5- (3-fluoro-4-hydroxyphenyl) salicyaldehyde semicarbazone hydrochloride; 5- (3,4-dihydroxyphenyl) salicyaldehyde thiosemicarbazone; 5- (3,4-dihydroxyphenyl) salicyaldehyde semicarbazone hydrochloride; 5- (2,4-dihydroxyphenyl) salicyaldehyde thiosemicarbazone; 4-hydroxy-5- (4-hydroxyphenyl) salicyaldehyde thiosemicarbazone; 4-hydroxy-5- (4-hydroxyphenyl) salicyaldehyde semicarbazone hydrochloride; 5- (4-pyridyl) salicyaldehyde thiosemicarbazone; 5- (3-pyridyl) salicyaldehyde thiosemicarbazone; 5- (5-pyrimidyl) salicylaldehyde thiosemicarbazone; 5- (2-thienyl) salicylaldehyde thiosemicarbazone; 5- (3-thienyl) salicylaldehyde thiosemicarbazone; 5- [2- (5-chloro-thienyl)] salicylaldehyde thiosemicarbazone; 5- (5-indolyl) -salicyaldehyde thiosemicarbazone; Methyl (3-formyl-4-hydroxy) cinnamate, thiosemicarbazone; 3-formyl-4-hydroxycinnamic acid, thiosemicarbazone; 3-formyl-4-hydroxycinamide, thiosemicarbazone; 3- (3-formyl-4-hydroxyphenyl) propionic acid, thiosemicarbazone; 2-[(2-hydroxy-1-naphthyl) methylidene] hydrazine-1-carbamide hydrochloride; 2-[(2-hydroxy-1-naphthyl) -methylidene] hydrazine-1-carbothioamide; 2-[(2,7-dihydroxy-1-naphthyl) methylidene] hydrazine-1-carbothioamide; 2-[(2,7-dihydroxy-1-naphthyl) methylidene] hydrazine-1-carbothioamide; 2-[(2,6-dihydroxy-1-naphthyl) methylidene] hydrazine-1-carbothioamide; 2-amino-4- [1- (2-hydroxy-naphthyl)] pyrimidine; 3- (2-amino-pyrimidin-4-yl) -biphenyl-4,4'-diol; 2- (2-amino-pyrimidin-4-yl) -4 [2- (2-amino-pyrimidin-4-yl) -vinyl] phenol. 3- (2-amino-6-methyl-pyrimidin-4-yl) -biphenyl-4,4'-diol; 3- (5-amino-pyridin-2-yl) -biphenyl-4,4'-diol; 3- (6-amino-pyridin-2-yl) -biphenyl-4,4'-diol; 3- (2-amino-6-methoxy-pyrimidin-4-yl) -biphenyl-4,4'-diol; 3- (4,5-diamino-2-yl) -biphenyl-4,4'-diol; 3- (2,6-diamino-pyrimidin-4-yl) -biphenyl-4,4'-diol; 3- (2-amino-pyrimidin-4-yl) -3'-fluoro-biphenyl-4,4'-diol; 3- (2-amino-6-chloro-pyrimidin-4-yl) -biphenyl-4,4'-diol; 3- [2-amino-6- (2-hydroxy-ethylamino) -pyrimidin-4-yl) -biphenyl-4,4'-diol; 3- [2-amino-6- (2,3-dihydroxy-propylamino) -pyrimidin-4-yl) -biphenyl-4,4'-diol; 3- (4,6-diamino- [1,3,5] triazin-2-yl) -biphenyl-4,4'-diol; 3- (2-amino-thiazol-4-yl) -biphenyl-4,4'-diol; 3- [2-amino-6- (5-hydroxy-pentylamino) -pyrimidin-4-yl) -biphenyl-4,4'-diol; 3- (2-amino-6-piperazin-1-yl-pyrimidin-4-yl) -biphenyl-4,4'-diol; 3- [2-amino-6- (2R-hydroxymethyl-pyrrolidin-1-yl) -pyrimidin-4-yl] -biphenyl-4,4'-diol; 3- [2-amino-6- (2S-hydroxymethyl-pyrrolidin-1-yl) -pyrimidin-4-yl] -biphenyl-4,4'-diol; 3- (2-amino-6-morpholin-4-yl-pyrimidin-4-yl) -biphenyl-4,4'-diol; 3- [2-amino-6- (3-hydroxymethyl-piperidin-1-yl) -pyrimidin-4-yl] -biphenyl-4,4'-diol; 3- [2-amino-6- (2-hydroxymethyl-phenyl) -pyrimidin-4-yl] -biphenyl-4,4'-diol; 3- [2-amino-6- (3-hydroxymethyl-phenyl) -pyrimidin-4-yl] -biphenyl-4,4'-diol; 3- [2-amino-6- (4-hydroxymethyl-phenyl) -pyrimidin-4-yl] -biphenyl-4,4'-diol; 3- [2-amino-6- (1R-benzyl-2-hydroxy-ethylamino) -pyrimidin-4-yl] -biphenyl-4,4'-diol; 3- [2-amino-6- (1S-benzyl-2-hydroxy-ethylamino) -pyrimidin-4-yl] -biphenyl-4,4'-diol; 3- [2-amino-6- (3-nitro-phenyl) -pyrimidin-4-yl] -biphenyl-4,4'-diol; 3- [2-amino-6- (4-nitro-phenyl) -pyrimidin-4-yl] -biphenyl-4,4'-diol; 3- [2-amino-6- (4-amino-phenyl) -pyrimidin-4-yl] -biphenyl-4,4'-diol; 3- [2-amino-6- (3-amino-phenyl) -pyrimidin-4-yl] -biphenyl-4,4'-diol; 3- {2-amino-6- [2-hydroxy-1R- (1H-indol-3-ylmethyl) -ethylamino] -pyrimidin-4-yl} -biphenyl-4,4'-diol; 3- [2-amino-6- (2-hydroxy-1S-phenyl-ethylamino) -pyrimidin-4-yl] -biphenyl-4,4'-diol; 3- [2-amino-6- (4-methoxy-phenylamino) -pyrimidin-4-yl] -biphenyl-4,4'-diol; 3- [2-amino-6- (2-benzyl-sulfanyl-1R-hydroxymethyl-ethylamino) -pyrimidin-4-yl] -biphenyl-4,4'-diol; 3- {2-amino-6- [2- (1-indol-3-yl) -ethylamino] -pyrimidin-4-yl} -biphenyl-4,4'-diol; 3- [2-amino-6- (4-benzyl-piperazin-1-yl) -pyrimidin-4-yl] -biphenyl-4,4'-diol; 3- {2-amino-6- [2-hydroxy-1R- (1H-indol-3-ylmethyl) -ethylamino] -pyrimidin-4-yl} -biphenyl-4,4'-diol; 3- [2-amino-6- (4-methyl-piperazin-1-yl) -pyrimidin-4-yl] -biphenyl-4,4'-diol; 3- [2-amino-6- (2-morpholin-4-yl-ethylamino) -pyrimidin-4-yl] -biphenyl-4,4'-diol; 3- [2-amino-6- (2-pyridin-2-yl-ethylamino) -pyrimidin-4-yl] -biphenyl-4,4'-diol; 3- (2-amino-6-thiomorpholin-4-yl-pyrimidin-4-yl) -biphenyl-4,4'-diol; 3- {2-amino-6-[(biphenyl-2-ylmethyl) -amino] -pyrimidin-4-yl} -biphenyl-4,4'-diol; 3- [2-amino-6- (3-chloro-phenylamino) -pyrimidin-4-yl] -biphenyl-4,4'-diol; 3- [2-amino-6- (4-chloro-phenylamino) -pyrimidin-4-yl] -biphenyl-4,4'-diol; 3- [2-amino-6- (3-methoxy-phenylamino) -pyrimidin-4-yl] -biphenyl-4,4'-diol; 3- [2-amino-6- (2-hydroxy-1-phenyl-ethylamino) -pyrimidin-4-yl] -biphenyl-4,4'-diol; 3- (2-amino-6-thiophen-3-yl-pyrimidin-4-yl) -biphenyl-4,4'-diol; 3- [2-amino-6- (1H-indol-5-yl) -pyrimidin-4-yl] -biphenyl-4,4'-diol; 3- [2-amino-6- (3-fluoro-benzylamino) -pyrimidin-4-yl] -biphenyl-4,4'-diol; 3- [2-amino-6- (2-fluoro-benzylamino) -pyrimidin-4-yl] -biphenyl-4,4'-diol; 3- [2-amino-6- (3-methoxy-benzylamino) -pyrimidin-4-yl] -biphenyl-4,4'-diol; 3- [2-amino-6- (4-methoxy-benzylamino) -pyrimidin-4-yl] -biphenyl-4,4'-diol; And 3- [2-amino-6- (2-fluoro-4-hydroxyphenylamine) -pyrimidin-4yl] -biphenyl-4,4'-diol. 5- [3- (2-amino-pyrimidin-4-yl) -4-hydroxy-phenyl] -furan-2-carbaldehyde; 2- (2-amino-pyrimidin-4-yl) -4- (1H-indol-5-yl) -phenol; 2- (2-amino-pyrimidin-4-yl) -4-pyrimidin-4-yl-phenol; 2- (2-amino-pyrimidin-4-yl) -4-pyridin-3-yl-phenol; 4- (6-amino-pyridin-2-yl) -2- (2-amino-pyrimidin-4-yl) -phenol; 4- (6-amino-pyridin-3-yl) -2- (2-amino-pyrimidin-4-yl) -phenol; 2- (2-amino-pyrimidin-4-yl) -4- (2-amino-pyrimidin-5-yl) -phenol; 4- (2-amino-pyridin-4-yl) -2- (2-amino-pyrimidin-4-yl) -phenol; 2,4-bis- (2-amino-pyrimidin-4-yl) -phenol; 2- (2-amino-pyrimidin-4-yl) -4- (1H-pyrrol-2-yl) -phenol; 5- [3- (2-amino-pyrimidin-4-yl) -4-hydroxy-phenyl] -1 H-pyrimidine-2,4-dione; 2- (2-aminopyridin-6-yl) -4- (2-aminopyrimidin-4-yl) -phenol; 2- (2-amino-4-methyl-pyrimidin-6-yl) -4- (2-amino-pyrimidin-4-yl) -phenol; 2- (2-amino-4-chloro-pyrimidin-6-yl) -4- (2-aminopyrimidin-4-yl) -phenol; 2- (2,4-diamino-pyrimidin-6-yl) -4- (2-aminopyrimidin-4-yl) -phenol; 2- (2-amino-4-methoxy-pyrimidin-6-yl) -4- (2-aminopyrimidin-4-yl) -phenol; 2- [2-amino-4- (piperazin-1-yl) -pyrimidin-6-yl] -4- (2-aminopyrimidin-4-yl)]-phenol; And 2- [2-amino-6- (2-hydroxy-IR-phenyl-ethylamino) -pyrimidin-4-yl] -4- (1H-indol-5-yl) -phenol compound.