heterocyclic compounds and their uses

专利摘要:
HETEROCYCLIC COMPOUNDS AND USE OF THEM. Described herein are heterocyclic compounds that modulate PI3 kinase activities, compositions containing the heterocyclic pharmaceutical compounds for the treatment of diseases and conditions associated with PI3 kinase activity.
公开号:BR112012003709B1
申请号:R112012003709-9
申请日:2010-08-17
公开日:2021-05-18
发明作者:Pingda Ren；Yi Liu；Liansheng Li；Katrina Chan；Troy Edward Wilson；Simon Fraser Campbell
申请人:Intellikine Llc；
IPC主号:

专利说明:

[001] This application claims the benefit of U.S. Provisional Application Serial No. 61/234, 617, filed August 17, 2009, which is incorporated herein by reference in its entirety. BACKGROUND OF THE INVENTION
[002] Cell activity can be regulated by external signals that stimulate or inhibit intracellular events. The process by which stimulatory or inhibitory signals are transmitted into and within a cell to elicit an intracellular response is referred to as signal transduction. In recent decades, cascades of signal transduction events have been elucidated and found to play a central role in a variety of biological responses. Defects in various components of signal transduction pathways have been found to contribute to a large number of diseases, including numerous forms of cancer, inflammatory disorders, metabolic disorders, vascular and neuronal diseases (Gaestel et al. Current Medicinal Chemistry (2007) 14 :22142234).
[003] Kinases represent a class of important signaling molecules. Kinases can generally be classified into protein kinases and lipid kinases, and some kinases have dual specificities. Protein kinases are enzymes that phosphorylate other proteins and/or themselves (ie, autophosphorylation). Protein kinases can be generally classified into three broad groups based on their substrate usage: tyrosine kinases that phosphorylate substrates predominantly on tyrosine residues (eg, erb2, PDGF receptor, EGF receptor, VEGF receptor, src, abl ), serine/threonine kinases that phosphorylate substrates predominantly on serine and/or threonine residues (e.g., mTorC1, mTorC2, ATM, ATR, DNA-PK, Akt), and dual-specific kinases that phosphorylate substrates on serine, tyrosine, and/or threonine residues.
[004] Lipid kinases are enzymes that catalyze the phosphorylation of lipids within cells. These enzymes, and the resulting phosphorylated lipids and lipid-derived biologically active organic molecules, play a role in several physiological processes, including cell proliferation, migration, adhesion and differentiation. A particular group of lipid kinases comprises membrane lipid kinases, that is, kinases that catalyze the phosphorylation of lipids contained in or associated with cell membranes. Examples of such enzymes include phosphoinositide kinases (such as PI3-kinases, PI4-kinases), diacylglycerol kinases, and sphingosine kinases.
The phosphoinositide 3-kinase (PI3Ks) signaling pathway is one of the most highly mutated systems in human cancers. PI3K signaling is involved in many disease states including allergic contact dermatitis, rheumatoid arthritis, osteoarthritis, inflammatory bowel disease, chronic obstructive pulmonary disease, psoriasis, multiple sclerosis, asthma, disorders related to diabetic complications, and inflammatory system complications cardiovascular, such as acute coronary syndrome.
[006] PI3Ks are members of a unique and conserved family of intracellular lipid kinases that phosphorylate the 3'-OH group on phosphatidylinositols or phosphoinositides. The family comprises 15 PI3K kinases with distinct substrate specificities, expression patterns and modes of regulation (Katso et al., 2001). Class I PI3Ks (p110, p110, p110, and p110) are normally activated by tyrosine kinases or G protein-coupled receptors to generate PIP3, which involves downstream effectors such as those in the Akt/PDK1 pathways, mTOR , the Tec family kinases, and the Rho families of GTPases. Class II and III PI3-Ks play a role in intracellular trafficking through the synthesis of PI(3)P and PI(3,4)P2.
[007] The alpha (α) isoform of PI3K has been involved, for example, in a variety of human cancers. Angiogenesis has been demonstrated to selectively require the α isoform of PI3K in controlling endothelial cell migration. (Graupera et al, Nature 2008; 453; 662-6). Mutations in the gene encoding PI3K α or mutations leading to up-regulation of PI3K α are believed to occur in many human cancers such as lung, stomach, endometrial, ovarian, bladder, breast, colon, brain and cancers. skin. Often, mutations in the gene encoding PI3K α are point mutations within several areas in the kinase domains, such as E542K, E545K, and H1047R. Many of these mutations have been shown to be oncogenic gain-of-function mutations. Due to the high rate of PI3K α mutations, tagging this pathway can provide many valuable therapeutic opportunities. While other PI3K isoforms such as PI3K δ or PI3K y are expressed primarily in hematopoietic cells, PI3K α, along with PI3K β, is expressed constitutively.
[008] The delta (δ) isoform of PI3K class I has been involved, in particular, in a number of diseases and biological processes. PI3K δ is primarily expressed in hematopoietic cells including leukocytes such as T cells, dendritic cells, neutrophils, mast cells, B cells, and macrophages. PI3K δ is integrally involved in mammalian immune system functions such as T cell function, B cell activation, mast cell activation, dendritic cell function, and neutrophil activity. Due to its essential role in immune system function, PI3K δ is also involved in a number of diseases related to undesirable immune response, such as allergic reactions, inflammatory diseases, inflammation-mediated angiogenesis, rheumatoid arthritis, autoimmune diseases such as lupus, asthma, emphysema and other respiratory diseases. Other class I PI3K involved in immune system function includes PI3K y, which plays a role in leukocyte signaling and has been implicated in inflammation, rheumatoid arthritis, and autoimmune diseases such as lupus.
[009] Downstream mediators of the PI3K and Akt signal transduction pathway include mammalian targeting of rapamycin (mTOR). Akt has a domain of homology to pleckstrin (PH), which binds to PIP3, leading to activation of Akt kinase. Akt phosphorylates several substrates and is a central downstream effector of PI3K for several cellular responses. An important function of Akt is to increase mTOR activity, through phosphorylation of TSC2 and other mechanisms. mTOR is a serine threonine kinase related to the lipid kinases of the PI3K family. mTOR has been involved in a wide range of biological processes, including cell growth, cell proliferation, cell motility and survival. Dysregulation of the mTOR pathway has been reported in several types of cancer. mTOR is a multifunctional kinase that integrates growth factor and nutrient signals to regulate protein translation, nutrient uptake, autophagy, and mitochondrial function.
[0010] The dysregulation of signaling pathways mediated by many other kinases is a key factor in the development of human diseases. Aberrant or excessive protein kinase activity or expression has been observed in many disease states including benign and malignant proliferative diseases, disorders such as allergic contact dermatitis, rheumatoid arthritis, osteoarthritis, inflammatory bowel diseases, chronic obstructive pulmonary disorders, psoriasis, sclerosis multiple, asthma, disorders related to diabetic complications and inflammatory complications of the cardiovascular system, such as acute coronary syndrome.
[0011] as such, kinases particularly lipid kinases like PI3Ks and protein kinase like mTor are prime targets for drug development. The present invention addresses a need in the art by providing a new class of kinase inhibitors.
[0012] SUMMARY OF THE INVENTION
[0013] In one embodiment, the invention provides a compound of formula I:
or pharmaceutically acceptable salts thereof, wherein X is O or S or N; W1 is N, NR3, CR3, or C=O, W2 is N, NR4, CR4, or C=O, W3 is N, NR5 or CR5, W4 is N, C=O or CR6, where no more than two atoms of N and no more than two. Two C=O groups are adjacent; W5 is N or CR7; W6 is N or CR8; R1 and R2 are independently hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, alkoxy, heterocycloalkyloxy, amido, amino, acyl, acyloxy, alkoxycarbonyl, sulfonamido, halo, cyano, hydroxy, nitro , phosphate, urea, carbonate, or NR'R'' where R' and R'' are taken together with nitrogen to form a cyclic fraction; R3and R4 are independently hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, alkoxy, heterocycloalkyloxy, amido, amino, acyl, acyloxy, alkoxycarbonyl, sulfonamido, halo, cyano, hydroxy, nitro, phosphate, urea, carbonate, or NR'R'' where R' and R" are taken together with nitrogen to form a cyclic moiety; or R3 and R4 taken together form a cyclic moiety; and R5, R6 , R7 and R8 are independently hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, alkoxy, heterocycloalkyloxy, amido, amino, acyl, acyloxy, alkoxycarbonyl, sulfonamido, halo, cyano, hydroxy,nitro, phosphate, urea, carbonate, or NR'R'' where R' and R" are taken together with nitrogen to form a cyclic fraction.
[0014] In some embodiments, the compound has the formula:

In yet other embodiments of compounds of Formula I, W1 is CR3, W2 is CR4, W3 is CR5, W4 is N, W5 is CR7, and W6 is CR8; W1 is N, W2 is CR4, W3 is CR5, W4 is N, W5 is CR7, and W6 is CR8; or W1 is CR3, W2 is N, W3 is CR5, W4 is N, W5 is CR7, and W6 is CR8. In some modes, W5 and W6 are CH. In other embodiments, R2 is amino. In still other embodiments, R1 is H.
In some embodiments of compounds of Formula I, W1 is CR3 and R3 is alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, alkoxy, heterocycloalkyloxy, starch, amino, acyl, acyloxy, alkoxycarbonyl, sulfonamido, halo, cyano, hydroxy, nitro, phosphate, urea, carbonate, or NR'R'' where R' and R'' are taken together with nitrogen to form a cyclic moiety. In some embodiments, R3 is aryl, heteroaryl, heterocycloalkyl, or NR'R' where R' and R' are taken together with nitrogen to form a cyclic moiety. In other embodiments, W1 is CR3 and W2 is CR4; and R3 and R4 taken together form a cyclic fraction. In one embodiment, R3 and R4 taken together form a 5-membered heterocyclic ring. In some modes, W4 is N. In other modes, X is O.
Compounds of Formula I are further provided wherein the cyclic moiety is further substituted with alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, alkoxy, heterocycloalkyloxy, starch, amino, acyl, acyloxy , alkoxycarbonyl, sulfonamido, halo, cyano, hydroxy, nitro, phosphate, urea, carbonate, or NR'R'' where R' and R'' are taken together with nitrogen to form a cyclic moiety.
[0018] In another aspect, the invention provides a compound of Formula II:
or the pharmaceutically acceptable salts thereof, wherein X is O or S or N; W1 is S, N, NR3 or CR3, W2 is N or CR4, W3 is S, N or CR5, W4 is N or C, and W7 is N or C, where no more than two N atoms and no more than two C=O groups are adjacent; W5 is N or CR7; W6 is N or CR8; R1 and R2 are independently hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, alkoxy, heterocycloalkyloxy, starch, amino, acyl, acyloxy, alkoxycarbonyl, sulfonamido, halo, cyano, hydroxy, nitro, phosphate, urea, carbonate, or NR'R'' where R' and R'' are taken together with nitrogen to form a cyclic fraction; R3 and R4 are independently hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, alkoxy, heterocycloalkyloxy, starch, amino, acyl, acyloxy, alkoxycarbonyl, sulfonamido, halo, cyano, hydroxy, nitro, phosphate, urea, carbonate, or NR'R'' where R' and R'' are taken together with nitrogen to form a cyclic fraction; or R3 and R4 taken together form a cyclic moiety; and R5, R7 and R8 are independently hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, alkoxy, heterocycloalkyloxy, starch, amino, acyl, acyloxy, alkoxycarbonyl, sulfonamido, halo, cyano, hydroxy , nitro, phosphate, urea, carbonate, or NR'R'' where R' and R'' are taken together with nitrogen to form a cyclic fraction.
[0019] In one embodiment, the compound of the present invention has the formula:

[0020] In other embodiments, W1 is CR3, W2 is CR4, W3 is N, W4 is N, W5 is CR7, and W6 is CR8; W1 is CR3, W2 is CR4, W3 is N, W4 is N, W5 is CR7, and W6 is CR8; W1 is CR3, W2 is CR4, W3 is N, W4 is N, W5 is N, and W6 is CR8; W1 is NR3, W2 is CR4, W3 is N, W4 is C, W5 is CR7, and W6 is CR8; W1 is S, W2 is CR4, W3 is N, W4 is C, W5 is CR7, and W6 is CR8; or W1 is CR3, W2 is CR4, W3 is S, W4 is C, W5 is N, and W6 is N. In some modes, W5 and W6 are CH. In other embodiments, R2 is amino. In still other modalities, R1 is H.
In some embodiments, W1 is CR3 and R3 is alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, alkoxy, heterocycloalkyloxy, starch, amino, acyl, acyloxy, alkoxycarbonyl, sulfonamido, halo, cyano , hydroxy, nitro, phosphate, urea, carbonate, or NR'R'' where R' and R'' are taken together with nitrogen to form a cyclic fraction. In other embodiments, R3 is aryl, heteroaryl, heterocycloalkyl, or NR'R' where R' and R'' are taken together with nitrogen to form a cyclic moiety. In some embodiments, W1 is CR3 and W2 is CR4, and R3 and R4 taken together form a cyclic fraction. In other embodiments, R3 and R4 taken together form a 5-membered heterocyclic ring.
In some embodiments, W4 is N. In other embodiments, the cyclic moiety is further substituted with alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, alkoxy, heterocycloalkyloxy, starch, amino, acyl , acyloxy, alkoxycarbonyl, sulfonamido, halo, cyano, hydroxy, nitro, phosphate, urea, carbonate, or NR'R'' where R' and R'' are taken together with nitrogen to form a cyclic moiety. In still other embodiments, R1 is alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, alkoxy, heterocycloalkyloxy, starch, amino, acyl, acyloxy, alkoxycarbonyl, sulfonamido, halo, cyano, hydroxy, nitro , phosphate, urea, carbonate, or NR'R'' where R' and R'' are taken together with nitrogen to form a cyclic fraction. In some embodiments of the Formula II compound, X is O. In other embodiments of the Formula II compound, W7 is C.
[0023] The invention further provides a compound of Formula III:
or the pharmaceutically acceptable salts thereof, wherein W1 is CR3, W2 is C-benzoxazolyl substituted with R2 and W3 is S; W1 is CR3, W2 is C-benzoxazolyl substituted with R2 and W3 is CR5; W1 is N or NR3, W2 is CR4, and W3 is C-benzoxazolyl substituted with R2; W1 is CR3, W2 is CR4, and W3 is C-benzoxazolyl substituted with R2; or W1 is N or NR3, W2 is NR4, and W3 is C-benzoxazolyl substituted with R2; X is N; R1 and R2 are independently hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, alkoxy, heterocycloalkyloxy, starch, amino, acyl, acyloxy, alkoxycarbonyl, sulfonamido, halo, cyano, hydroxy, nitro, phosphate, urea, carbonate, or NR'R'' where R' and R'' are taken together with nitrogen to form a cyclic fraction; R3 and R4 are independently hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, alkoxy, heterocycloalkyloxy, starch, amino, acyl, acyloxy, alkoxycarbonyl, sulfonamido, halo, cyano, hydroxy, nitro, phosphate, urea, carbonate, or NR'R'' where R' and R'' are taken together with nitrogen to form a cyclic fraction; R5, R6 , R7 and R8 are independently hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, alkoxy, heterocycloalkyloxy, starch, amino, acyl, acyloxy, alkoxycarbonyl, sulfonamido, halo, cyano, hydroxy, nitro, phosphate, urea, carbonate, or NR'R'' where R' and R'' are taken together with nitrogen to form a cyclic fraction.
[0024] In some embodiments of the compound of Formula III, the compound is:
where W1 is CR3 or NR3 and W2 is CR4.
[0025] In one modality, the compound is:
where W1 is CR3 or NR3 and W3 is CR5.
[0026] In another aspect, the invention provides a compound of Formula IV:
or the pharmaceutically acceptable salts thereof, wherein: W1 is N, NR3, CR3, or C=O; W2 is N, NR4, CR4, or C=O; W3 is N, NR5 or CR5; W4 is N, C=O or CR6, where no more than two N atoms and no more than two C=O groups are adjacent; W5 is N or CR7; W6 is N or CR8; Wa and Wb are independently N or CR9; one of Wc and Wdé N, and the other is O, NR10, or S; R1 and R2 are independently hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, alkoxy, heterocycloalkyloxy, starch, amino, acyl, acyloxy, alkoxycarbonyl, sulfonamido, halo, cyano, hydroxy, nitro, phosphate, urea, carbonate, or NR'R'' where R' and R'' are taken together with nitrogen to form a cyclic fraction; R3 and R4 are independently hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, alkoxy, heterocycloalkyloxy, starch, amino, acyl, acyloxy, alkoxycarbonyl, sulfonamido, halo, cyano, hydroxy, nitro, phosphate, urea, carbonate, or NR'R'' where R' and R'' are taken together with nitrogen to form a cyclic fraction; or R3 and R4 taken together form a cyclic moiety; R5, R6 , R7 and R8 are independently hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, alkoxy, heterocycloalkyloxy, starch, amino, acyl, acyloxy, alkoxycarbonyl, sulfonamido, halo, cyano, hydroxy, nitro, phosphate, urea, carbonate, or NR'R'' where R' and R'' are taken together with nitrogen to form a cyclic fraction; R9 is alkyl or halo; and R10 is hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, alkoxy, heterocycloalkyloxy, starch, amino, acyl, acyloxy, alkoxycarbonyl, sulfonamido, halo, cyano, hydroxy, nitro, phosphate, urea, carbonate, or NR'R'' where R' and R'' are taken together with nitrogen to form a cyclic fraction.
In some embodiments of the compound of Formula IV, W1 is CR3, W2 is CR4, W3 is CR5, W4 is N, W5 is CR7, and W6 is CR8; W1 is N, W2 is CR4, W3 is CR5, W4 is N, W5 is CR7, and W6 is CR8; or W1 is CR3, W2 is N, W3 is CR5, W4 is N, W5 is CR7, and W6 is CR8. In some embodiments of the compound of Formula IV, Wb is N. In other embodiments, Wa is CR9 and R9 is alkyl.
[0028] The invention also provides a compound of Formula V:
or the pharmaceutically acceptable salts thereof, wherein W1 is S, N, NR3 or CR3, W2 is N or CR4, W3 is S, N or CR5, W4 is N or C, and W7 is N or C, wherein not more than two N atoms and no more than two C=O groups are adjacent; W5 is N or CR7; W6 is N or CR8; Wa and Wb are independently N or CR9; one of Wc and Wdé N, and the other is O, NR10, or S; R1 and R2 are independently hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, alkoxy, heterocycloalkyloxy, starch, amino, acyl, acyloxy, alkoxycarbonyl, sulfonamido, halo, cyano, hydroxy, nitro, phosphate, urea, carbonate, or NR'R'' where R' and R'' are taken together with nitrogen to form a cyclic fraction; R3 and R4 are independently hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, alkoxy, heterocycloalkyloxy, starch, amino, acyl, acyloxy, alkoxycarbonyl, sulfonamido, halo, cyano, hydroxy, nitro, phosphate, urea, carbonate, or NR'R'' where R' and R'' are taken together with nitrogen to form a cyclic fraction; or R3 and R4 taken together form a cyclic moiety; R5, R7 and R8 are independently hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, alkoxy, heterocycloalkyloxy, amido, amino, acyl, acyloxy, alkoxycarbonyl, sulfonamido, halo, cyano, hydroxy, nitro, phosphate, urea, carbonate, or NR'R'' where R' and R'' are taken together with nitrogen to form a cyclic fraction; R9 is alkyl or halo; and R10 is hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, alkoxy, heterocycloalkyloxy, starch, amino, acyl, acyloxy, alkoxycarbonyl, sulfonamido, halo, cyano, hydroxy, nitro, phosphate , urea, carbonate, or NR'R'' where R' and R'' are taken together with nitrogen to form a cyclic fraction.
[0029] In some embodiments of the compound of Formula V, W1 is CR3, W2 is CR4, W3 is N, W4 is N, W5 is CR7, and W6 is CR8. In other embodiments, W1 is CR3, W2 is CR4, W3 is N, W4 is N, W5 is CR7, and W6 is CR8. In other embodiments, W1 is CR3, W2 is CR4, W3 is N, W4 is N, W5 is N, and W6 is CR8. In still other embodiments, W1 is NR3, W2 is CR4, W3 is N, W4 is C, W5 is CR7, and W6 is CR8. In other embodiments, W1 is S, W2 is CR4, W3 is N, W4 is C, W5 is CR7, and W6 is CR8. In other embodiments, W1 is CR3, W2 is CR4, W3 is S, W4 is C, W5 is N, and W6 is N.
In some embodiments of the compound of Formula V, Wb is N. In other embodiments, Wa is CR9 and R9 is alkyl.
[0031] The invention further provides compounds of Formula VA and VB:
or the pharmaceutically acceptable salts thereof, wherein W1 is CR3; R1 and R2 are independently hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, alkoxy, heterocycloalkyloxy, starch, amino, acyl, acyloxy, alkoxycarbonyl, sulfonamido, halo, cyano, hydroxy, nitro, phosphate, urea, carbonate, or NR′R′′ where R′ and R'′are taken together with nitrogen to form a cyclic fraction; and R3 is hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, alkoxy, heterocycloalkyloxy, starch, amino, acyl, acyloxy, alkoxycarbonyl, sulfonamido, halo, cyano, hydroxy, nitro, phosphate , urea, carbonate, or NR′R′′ where R′ and R'′are taken together with nitrogen to form a cyclic fraction.
[0032] Also provided herein are compounds of Formula VC and VD:
or the pharmaceutically acceptable salts thereof, wherein W1 is CR3; W5 is N or CR7; Wa and Wb are independently N or CR9; one of Wc and Wd is N, and the other is O, NR10, or S; R1 and R2 are independently hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, alkoxy, heterocycloalkyloxy, starch, amino, acyl, acyloxy, alkoxycarbonyl, sulfonamido, halo, cyano, hydroxy, nitro, phosphate, urea, carbonate, or NR'R'' where R' and R'' are taken together with nitrogen to form a cyclic fraction; R3 is hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, alkoxy, heterocycloalkyloxy, starch, amino, acyl, acyloxy, alkoxycarbonyl, sulfonamido, halo, cyano, hydroxy, nitro, phosphate, urea, carbonate, or NR'R'' where R' and R'' are taken together with nitrogen to form a cyclic fraction; R7 is hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, alkoxy, heterocycloalkyloxy, starch, amino, acyl, acyloxy, alkoxycarbonyl, sulfonamido, halo, cyano, hydroxy, nitro, phosphate, urea, carbonate, or NR'R'' where R' and R'' are taken together with nitrogen to form a cyclic fraction; R9 is alkyl or halo; and R10 is hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, alkoxy, heterocycloalkyloxy, starch, amino, acyl, acyloxy, alkoxycarbonyl, sulfonamido, halo, cyano, hydroxy, nitro, phosphate , urea, carbonate, or NR'R'' where R' and R'' are taken together with nitrogen to form a cyclic fraction.
In some embodiments of the compound of Formula V-C or V-D, Wb is N. In other embodiments, Wa is CR9 and R9 is alkyl.
[0034] Also provided herein is a compound of Formula VI:
or the pharmaceutically acceptable salts thereof, wherein W1 is CR3; W2 is CR4; Wa is CH or N; R1is hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, alkoxy, heterocycloalkyloxy, starch, amino, acyl, acyloxy, alkoxycarbonyl, sulfonamido, halo, cyano, hydroxy, nitro, phosphate, urea , carbonate, or NR'R'' where R' and R'' are taken together with nitrogen to form a cyclic fraction; R3 is alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroarylalkyl, alkoxy, heterocycloalkyloxy, starch, amino, acyl, acyloxy, alkoxycarbonyl, sulfonamido, halo, cyano, hydroxy, nitro, phosphate, urea, carbonate, or NR'R'' where R' and R'' are taken together with nitrogen to form a cyclic fraction; R4 is hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, alkoxy, heterocycloalkyloxy, starch, amino, acyl, acyloxy, alkoxycarbonyl, sulfonamido, halo, cyano, hydroxy, nitro, phosphate, urea, carbonate, or NR'R'' where R' and R'' are taken together with nitrogen to form a cyclic fraction; or R3 and R4 taken together form a cyclic moiety; and R10 and R11 are independently hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, alkoxy, heterocycloalkyloxy, amido, amino, acyl, acyloxy, alkoxycarbonyl, sulfonamido, halo, cyano, hydroxy, nitro , phosphate, urea, carbonate, or NR'R'' where R' and R'' are taken together with nitrogen to form a cyclic fraction.
[0035] The invention further provides a compound of Formula VII:
or a pharmaceutically acceptable salt thereof, wherein X1 is CR3, NR3, or S; X2 is CR4, NR4, X--X., or CR-^XR; X3 and X4 are independently C or N; X5 is CR6, NR6, or S; X4 is CR7, NR7, CR1CR, or CR1XR; Wa and Wb are independently N or CR9; one of Wc and Wd is X, and the other is O, XR10, or S; R1 and R2 are independently hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, alkoxy, heterocycloalkyloxy, starch, amino, acyl, acyloxy, alkoxycarbonyl, sulfonamido, halo, cyano, hydroxy, nitro, phosphate, urea, carbonate, or NR'R'' where R' and R'' are taken together with nitrogen to form a cyclic fraction; R3 and R4 are independently hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, alkoxy, heterocycloalkyloxy, starch, amino, acyl, acyloxy, alkoxycarbonyl, sulfonamido, halo, cyano, hydroxy, nitro, phosphate, urea, carbonate, or NR'R'' where R' and R'' are taken together with nitrogen to form a cyclic fraction; or R3 and R4 taken together form a cyclic moiety; R5, R6 , R7, and R8 are independently hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, alkoxy, heterocycloalkyloxy, starch, amino, acyl, acyloxy, alkoxycarbonyl, sulfonamido, halo, cyano , hydroxy, nitro, phosphate, urea, carbonate, or NR'R'' where R' and R'' are taken together with nitrogen to form a cyclic fraction; R9 is alkyl or halo; and R10 is hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, alkoxy, heterocycloalkyloxy, starch, amino, acyl, acyloxy, alkoxycarbonyl, sulfonamido, halo, cyano, hydroxy, nitro, phosphate , urea, carbonate, or NR'R'' where R' and R'' are taken together with nitrogen to form a cyclic fraction.
In some embodiments of the compound of Formula VII, Wb is N. In other embodiments, Wa is CR9 and R9 is alkyl.
[0037] In yet another embodiment, the present invention provides a composition comprising a pharmaceutically acceptable excipient and one or more compounds disclosed herein. In some embodiments, the composition is in liquid, solid, semi-solid, gel, or aerosol form.
In yet another embodiment, the present invention provides a method for inhibiting a phosphatidyl inositol-3 kinase (PI3 kinase) comprising: contacting the PI3 kinase with an effective amount of a compound disclosed herein. In some embodiments, the PI3 kinase is PI3 kinase alpha. The step of contacting may further comprise contacting a cell that expresses one or more types of type I PI3 kinases, including PI3 kinase alpha. In some embodiments, the method further comprises administering a second therapeutic agent to a cell.
The present invention further provides a method of treating a condition associated with PI3 kinase, comprising administering to a subject in need thereof an effective amount of the compound disclosed herein. In some embodiments, the PI3 kinase-associated condition is selected from the group consisting of asthma, emphysema, bronchitis, psoriasis, allergy, anaphylaxis, rheumatoid arthritis, graft-host disease, lupus erythematosus, psoriasis, restenosis, benign prostatic hypertrophy, diabetes , pancreatitis, proliferative glomerulonephritis, diabetes-induced kidney disease, inflammatory bowel disease, atherosclerosis, eczema, scleroderma, diabetes, diabetic retinopathy, retinopathy of prematurity, age-related macular degeneration, hemangioma, glioma, melanoma, Kaposi's sarcoma, and ovarian cancer , breast, lung, pancreatic, prostate, colon and epidermoid. INCORPORATION AS A REFERENCE
[0040] All publications, patents and patent applications mentioned in this report are hereby incorporated by reference to the same extent as if each individual publication, patent or patent application were specifically and individually indicated by being incorporated by reference. BRIEF DESCRIPTION OF THE DRAWINGS
[0041] The new features of the invention are set out with particularity in the appended claims. A better understanding of the features and advantages of the present invention will be obtained with reference to the following detailed description which sets forth the illustrative embodiments in which the principles of the invention are used, and the accompanying drawings of which:
[0042] Figure 1 illustrates the selectivity and inhibiting potency of an exemplary compound of the invention (eg, compound 54) with respect to a number of kinases.
[0043] Figure 2 shows that an exemplary compound of the invention (eg, compound 54) inhibits the PI3K pathway and the proliferation of tumor cells with a mutation in PI3Kα.
[0044] Figure 3 shows the inhibition of the inhibition of angiogenesis by a compound of the invention, and comparison to the activity of a non-specific inhibitor of PI3Ks (Pan-PI3K Inh).
Figure 4 shows the in vivo efficacy of a compound of the invention compared to a Pan-PI3K inhibitor, as measured by tumor weight and downstream markers of kinase activity, as well as comparison of the effect on blood glucose.
[0046] Figure 5 shows the impact of a compound of the invention on tumor size, and that the location and viability of marginal zone B cells derived from the spleen is not affected by the compound, in contrast to the Pan-PI3K inhibitor.
Figure 6 shows the in vivo efficacy of a compound of the invention against a tumor devoid of PI3Kα mutation, compared to a kinase inhibitor with specificity for mTor.
[0048] Figure 7 shows the synergistic effect of combining a compound of the invention with an MEK inhibitor.
[0049] Detailed description of the invention
[0050] While preferred embodiments of the present invention are shown and described herein, it will be clear to those skilled in the art that such embodiments are provided by way of example only. Numerous variations, alterations and substitutions will now occur to those skilled in the art without departing from the invention. It should be understood that various alternatives to the embodiments of the invention described herein can be employed in practicing the invention. It is intended that the appended claims define the scope of the invention and that methods and structures within the scope of these claims and their equivalents are covered therein.
[0051] Unless defined otherwise, all technical and scientific terms used herein have the same meanings as commonly understood by one of ordinary skill in the art to which this invention belongs. All patents and publications referenced herein are incorporated by reference.
[0052] As used in the specification and claims, the singular form "a", "an" and "the" includes plural references unless the context clearly defines otherwise.
[0053] As used herein, "agent" or "biologically active agent" refers to a biological, pharmaceutical or chemical compound or other fraction. Non-limiting examples include simple or complex molecules, organic or inorganic, a peptide, a protein, an oligonucleotide, an antibody, an antibody derivative, antibody fragment, a vitamin derivative, a carbohydrate, a toxin, or a chemotherapeutic compound. Various compounds can be synthesized, for example, small molecules and oligomers (eg, oligopeptides and oligonucleotides), and synthetic organic compounds based on various core structures. In addition, various natural sources can provide compounds for screening, such as plant or animal extracts, and the like. One of skill will readily recognize that there is no limit to the structural nature of the agents of the present invention.
The term "agonist" as used herein refers to a compound having the ability to initiate or enhance a biological function of a target protein, either by inhibiting the activity or expression of the target protein. Thus, the term "agonist" is defined in the context of the biological role of the target polypeptide. While preferred agonists specifically interact with (eg, bind to) the target, compounds that initiate or enhance a biological activity of the target polypeptide through interaction with other members of the signal transduction pathway of which the target polypeptide is a member , are also specifically included within this definition.
The terms "antagonist" and "inhibitor" are used interchangeably, and refer to a compound having the ability to inhibit a biological function of a target protein, whether by inhibiting the activity or expression of the target protein. Thus, the terms "antagonist" and "inhibitors" are defined in the context of the biological role of the target protein. While preferred antagonists specifically interact with (e.g., bind to) the target, compounds that inhibit a target protein's biological activity through interaction with other members of the signal transduction pathway of which the target protein is a member are also specifically included within this definition. A preferential biological activity inhibited by an antagonist is associated with the development, growth, or spread of a tumor, or an unwanted immune response as manifested in autoimmune disease.
An "anticancer agent", "antitumor agent" or "chemotherapeutic agent" refers to any agent useful in the treatment of a neoplastic condition. One class of anticancer agents comprises chemotherapeutic agents. "Chemotherapy" means the administration of one or more chemotherapy drugs and/or other agents to a cancer patient by various methods, including intravenous, oral, intramuscular, intraperitoneal, intravesical, subcutaneous, transdermal, buccal, or inhalation or in the form of a suppository.
[0057] The term “cell proliferation” refers to a phenomenon whereby the number of cells has changed as a result of division. This term also includes cell growth whereby cell morphology has been altered (eg, increase in size) consistent with a proliferative signal.
[0058] The terms "co-administration," "administered in combination with," and their grammatical equivalents, include the administration of two or more agents to an animal such that both agents and/or their metabolites are present in the animal at the same time . Co-administration includes simultaneous administration in separate compositions, administration at different times in separate compositions, or administration in a composition in which both agents are present.
[0059] The term "effective amount" or "therapeutically effective amount" refers to that amount of a compound described herein that is sufficient to effect the intended application including but not limited to the treatment of disease, as defined below. The therapeutically effective amount may vary depending on the intended application (in vitro or in vivo), or the subject and disease condition being treated, for example, the subject's weight and age, the severity of the disease condition, the mode of administration and similar, which can be readily determined by one skilled in the art. The term also applies to a dose that will produce a particular response in target cells, for example, reduced platelet adhesion and/or cell migration. The specific dose will vary depending on the particular compounds chosen, the dose regimen to be followed, whether it is administered in combination with other compounds, time of administration, the tissue to which it is administered, and the physical delivery system in which it is conducted.
[0060] “Treat”, “treat”, “palliative” and “improve”, as used herein, are used interchangeably. These terms refer to an approach to obtaining desired benefit or results including but not limited to therapeutic benefit and/or a prophylactic benefit. By therapeutic benefit is meant the eradication or amelioration of the underlying disorder being treated. Furthermore, a therapeutic benefit is achieved by eradicating or ameliorating one or more of the physiological symptoms associated with the underlying disorder so that an improvement is seen in the patient, notwithstanding that the patient may still be afflicted with the underlying disease. For a prophylactic benefit, the compositions can be administered to a patient at risk of developing a particular disease, or to a patient who reports one or more of the physiological symptoms of a disease, even though a diagnosis of that disease may not have been made.
A "therapeutic effect," as used herein, includes a therapeutic benefit and/or a prophylactic benefit as described above. A prophylactic effect includes delaying or eliminating the onset of a disease or condition, delaying or eliminating the onset of symptoms of a disease or condition, slowing, stopping, or reversing the progress of a disease or condition, or any combination thereof.
[0062] The term "pharmaceutically acceptable salt" refers to salts derived from a variety of organic and inorganic counterions well known in the art. Pharmaceutically acceptable acid addition salts can be formed with inorganic acids and organic acids. Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like. Organic acids from which the salts can be derived may include, for example, acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid , cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like. Pharmaceutically acceptable base addition salts can be formed with inorganic and organic bases. Inorganic bases from which salts can be derived include, for example, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, and the like. Organic bases from which salts can be derived include, for example, primary, secondary and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, basic ion exchange resins, and the like, specifically as isopropylamine, trimethylamine, diethylamine, triethylamine , tripropylamine, and ethanolamine. In some embodiments, the pharmaceutically acceptable base addition salt is chosen from ammonium, potassium, sodium, calcium, and magnesium salts.
[0063] "Pharmaceutically acceptable carrier" or "pharmaceutically acceptable excipient" includes any and all solvents, dispersion media, coating agents, antibacterials and antifungals, isotonic and absorption retarding agents, and the like. The use of said media and agents for pharmaceutically active substances is well known in the art. Except while any conventional media or agent is incompatible with the active ingredient, its use in the therapeutic compositions of the invention is contemplated. Complementary active ingredients can also be incorporated into the compositions.
[0064] "Signal transduction" is a process during which stimulatory or inhibitory signals are transmitted into and within a cell to induce an intracellular response. A signal transduction pathway modulator refers to a compound that modulates the activity of one or more cellular proteins mapped to the same specific signal transduction pathway. A modulator can increase (agonist) or suppress (antagonist) the activity of a signaling molecule.
[0065] The term "selective inhibition" or "selectively inhibit" as applied to a biologically active agent refers to the ability of the agent to selectively reduce target signaling activity when compared to off-target signaling activity, through direct or indirect interaction with the target.
[0066] The term "B-ALL" as used herein refers to a B-Cell Acute Lymphoblastic Leukemia.
[0067] "Subject" refers to an animal, such as a mammal, eg, a human. The methods described here can be useful in both human and veterinary applications. In some embodiments, the patient is a mammal, and in some embodiments, the patient is human.
[0068] "Radiotherapy" means to expose a patient, using routine methods and compositions known to the practitioner, to radiation emissions such as alpha particle emitting radionucleotides (for example, actinium and thorium radionuclides), low linear energy transfer radiation emitters (LET) (ie, beta emitters), converting electron emitters (eg, strontium-89 and samarium-153-EDTMP, or high energy radiation, including but not limited to X-rays, gamma rays, and neutrons.
[0069] "Prodrug" is meant to indicate a compound that can be converted under physiological conditions or by solvolysis to a biologically active compound described herein. Thus, the term "prodrug" refers to a precursor of a biologically active compound that is pharmaceutically acceptable. A prodrug may be inactive when administered to a subject, but is converted in vivo to an active compound, for example, by hydrolysis. The prodrug compound generally offers advantages of solubility, tissue compatibility, or sustained release in a mammalian organism (see, for example, Bundgard, H., Design of Prodrugs (1985), pp. 7-9, 21-24 ( Elsevier, Amsterdam). A discussion of prodrugs is provided in Higuchi, T., et al., "Prodrugs as Novel Delivery Systems," ACS Symposium Series, Vol. 14, and in Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987, both of which are fully incorporated by reference herein. The term "prodrug" is also intended to include any covalently linked carrier, which releases the active compound in vivo when it says pro -drug is administered to a mammalian subject. Prodrugs of an active compound, as described herein, can be prepared by modifying functional groups present in the active compound such that the modifications are cleaved, in routine manipulation in vivo, upon compound relative asset. Prodrugs include compounds in which hydroxy, amino or mercapto groups are attached to any group which, when the prodrug of the active compound is administered to a mammalian subject, cleaves the free form of the hydroxy, amino or mercapto group, respectively. Examples of prodrugs include, among others, acetate, formate and benzoate derivatives of an alcohol or acetamide, formamide and formamide derivatives of an amine functional group in the active compound and the like.
[0070] The term "in vivo" refers to an event that occurs in the subject's body.
[0071] The term "invitro" refers to an event that occurs outside the subject's body. For example, an in vitro test includes any test run outside an in-subject test. In vitro assays include cell-based assays in which living or dead cells are employed. In vitro assays also include a cell-free assay in which no intact cells are employed.
[0072] Unless otherwise stated, the structures described here also mean compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds containing the structures present in which hydrogen is replaced by deuterium or tritium, or in which carbon atom is replaced by 13C- or 14C enriched carbon, are within the scope of this invention.
[0073] The compounds of the present invention may further contain unnatural proportions of atomic isotopes in one or more atoms that constitute said compounds. For example, the compounds can be radiolabeled with radioactive isotopes such as tritium (3H), iodine-125 (125I) or carbon-14 (14C). All isotopic variations of the compounds of the present invention, whether radioactive or not, are included within the scope of the present invention.
[0074] When ranges are used for physical properties, such as molecular weight, or chemical properties, such as chemical formula, all combinations and subcombinations of specific ranges and modalities in that are intended to be included. The term "about" when referring to a number or numerical range means that the number or numerical range a is an approximation within experimental variability (or within experimental statistical error), and thus the number or numerical range may vary from , for example, between 1% and 15% of the declared number or numerical range. The term "comprising" (and related terms such as "comprise" or "comprises" or "containing" or "including") includes those embodiments, for example, an embodiment of any composition of matter, composition, method or process or the like, which "consists of" or "consists essentially of" the characteristics described.
[0075] The following abbreviations and terms have the meanings indicated throughout the text. PI3-K = Phosphoinositide 3-kinase; PI = phosphatidylinositol; PDK = Phosphoinositide-dependent kinase; DNA-PK = Deoxyribonucleic acid dependent protein kinase; PIKK = Phosphoinositide Kinase-Type Kinase; AIDS = Acquired Human Immunodeficiency Syndrome; TLC = Thin Layer Chromatography; MeOH = Methanol; and CHCl3 = Chloroform.
[0076] The abbreviations used here have their conventional meaning within the techniques of chemistry and biology.
[0077] "Alkyl" refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, containing no unsaturation, containing one to ten carbon atoms (eg, C1-C10 alkyl). Whenever it appears here, a numerical range such as "1 to 10" refers to each integer in that range; for example, "1 to 10 carbon atoms" means that the alkyl group may consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc. , up to and including 10 carbon atoms, although the present definition still covers the occurrence of the term "alkyl" where no numerical range is designated. In some embodiments, this is a C1-C4 alkyl group. Typical alkyl groups include, among others, methyl, ethyl, propyl, isopropyl, n-butyl, iso-butyl, sec-butyl isobutyl, tertiary butyl, pentyl, isopentyl, neopentyl, hexyl, septyl, octyl, nonyl, decyl, and similar. The alkyl is attached to the rest of the molecule by a single bond, eg methyl (Me), ethyl (Et), n-propyl, 1-methylethyl (iso-propyl), n-butyl, n-pentyl, 1.1 -dimethylethyl (t-butyl), 3-methylhexyl, 2-methylhexyl, and the like. Unless specifically stated otherwise in the specification, an alkyl group is optionally substituted by one or more of substituents which independently are: alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, trifluoromethyl, trifluoromethoxy, nitro, trimethylsilanyl, -ORa, Sra, -OC(O)-Ra, -N(Ra)2, -C(O)Ra, -C(O)ORa, -OC(O)N (Ra)2, -C(O)N(Ra)2, -N(Ra)C(O)ORa, -N(Ra)C(O)Ra, -N(Ra)C(O)N(Ra )2, N(Ra)C(NRa)N(Ra)2, -N(Ra)S(O)tRa (where t is 1 or 2), -S(O)tORa (where t is 1 or 2) , -S(O)tN(Ra)2 (where t is 1 or 2), or PO3(Ra)2 where each Ra is independently hydrogen, alkyl, fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl or heteroarylalkyl.
[0078] An "alkene" moiety refers to a group consisting of at least two carbon atoms and at least one carbon-carbon double bond, and an "alkyne" moiety refers to a group consisting of at least two carbon atoms and at least one carbon-carbon triple bond. The alkyl moiety, saturated or unsaturated, can be branched-chain, linear or cyclic.
[0079] "Alkenyl" refers to a straight or branched hydrocarbon group chain radical consisting solely of carbon and hydrogen atoms, containing at least one double bond, and containing from two to ten carbon atoms (ie, C2-C10 alkenyl). Whenever it appears here, a numerical range such as "2 to 10" refers to each integer in that range; for example, "2 to 10 carbon atoms" means that the alkenyl group may consist of 2 carbon atoms, 3 carbon atoms, etc. , up to and including 10 carbon atoms. In certain embodiments, an alkenyl comprises two to eight carbon atoms. In other embodiments, an alkenyl comprises two to five carbon atoms (eg, C2-C5 alkenyl). Alkenyl is attached to the rest of the molecule by a single bond, eg ethenyl (ie vinyl), prop-1-enyl (ie allyl), but-1-enyl, pent-1-enyl, penta- 1,4-dienyl, and the like. Unless specifically stated otherwise in the specification, an alkenyl group is optionally substituted by one or more substituents which independently are: alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano , trifluoromethyl, trifluoromethoxy, nitro, trimethylsilanyl, -ORa, -SRa, -OC(O)-Ra, -N(Ra)2, -C(O)Ra, -C(O)ORa, -OC(O)N (Ra)2, -C(O)N(Ra)2, -N(Ra)C(O)ORa, -N(Ra)C(O)Ra, -N(Ra)C(O)N(Ra )2, N(Ra)C(NRa)N(Ra)2, -N(Ra)S(O)tRa (where t is 1 or 2), -S(O)tORa (where t is 1 or 2) , -S(O)tN(Ra)2 (where t is 1 or 2), or PO3(Ra)2, where each Ra is independently hydrogen, alkyl, fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl or heteroarylalkyl.
[0080] "Alkynyl" refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, containing at least one triple bond, containing two to ten carbon atoms (ie, C2-C10alkynyl ). Whenever it appears here, a numerical range such as "2 to 10" refers to each integer in that range; for example, "2 to 10 carbon atoms" means that the alkenyl group may consist of 2 carbon atoms, 3 carbon atoms, etc. , up to and including 10 carbon atoms. In certain embodiments, an alkynyl comprises two to eight carbon atoms. In other embodiments, an alkynyl has two to five carbon atoms (eg, C2-C5alkynyl). The alkynyl is attached to the rest of the molecule by a single bond, for example, ethynyl, propynyl, butynyl, pentynyl, hexynyl, and the like. Unless specifically stated otherwise in the specification, an alkynyl group is optionally substituted by one or more substituents which independently are: alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano , trifluoromethyl, trifluoromethoxy, nitro, trimethylsilanyl, -ORa,SRa, -OC(O)-Ra, -N(Ra)2, -C(O)Ra, -C(O) ORa, -OC(O)N( Ra)2, -C(O)N(Ra)2, -N(Ra)C(O)ORa, -N(Ra)C(O)Ra, -N(Ra)C(O)N(Ra) 2, N(Ra)C(NRa)N(Ra)2, -N(Ra)S(O)tRa (where t is 1 or 2), -S(O)tORa (where t is 1 or 2), -S(O)tN(Ra)2 (where t is 1 or 2), or PO3(Ra)2, where each Ra is independently hydrogen, alkyl, fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl or heteroarylalkyl.
[0081] "Carboxaldehyde" refers to a (C=O)H-radical.
[0082] "Carboxyl" refers to a (C=O)OH-radical.
[0083] "Cyan" refers to a CN-radical.
[0084] "Cycloalkyl" refers to a monocyclic or polycyclic radical that contains only carbon and hydrogen, and may be saturated, or partially unsaturated. Cycloalkyl groups include groups containing from 3 to 10 ring atoms (i.e., C2-C10cycloalkyl). Whenever it appears here, a numeric range such as "3 to 10" refers to each integer in that range; for example, "3 to 10 carbon atoms" means that the cycloalkyl group may consist of 3 carbon atoms, etc. , up to and including 10 carbon atoms. In some embodiments, this is the C3-C8cycloalkyl radical. In some embodiments, this is a C3C5 cycloalkyl radical. Illustrative examples of cycloalkyl groups include, among others, the following moieties: cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloseptyl, cyclooctyl, cyclononyl, cyclodecyl, norbornyl, and the like. Unless specifically stated otherwise in the specification, a cycloalkyl group is optionally substituted by one or more substituents which independently are: alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano , trifluoromethyl, trifluoromethoxy, nitro, trimethylsilanyl, -ORa, Sra, -OC(O)-Ra, -N(Ra)2, -C(O)Ra, -C(O)ORa, -OC(O)N( Ra)2, -C(O )N(Ra)2, -N(Ra)C(O)ORa, -N(Ra)C(O)Ra, -N(Ra)C(O)N(Ra) 2, N(Ra)C(NRa)N(Ra)2, -N(Ra)S(O)tRa (where t is 1 or 2), -S(O)tORa (where t is 1 or 2), -S(O)tN(Ra)2 (where t is 1 or 2), or PO3(Ra)2, where each Ra is independently hydrogen, alkyl, fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl or heteroarylalkyl.
[0085] The term "alkoxy" refers to the -O-alkyl group, including from 1 to 8 carbon atoms of a linear, branched or cyclic configuration and combinations thereof attached to the parent structure through an oxygen. Examples include methoxy, ethoxy, propoxy, isopropoxy, cyclopropyloxy, cyclohexyloxy and the like. "Lower alkoxy" refers to alkoxy groups containing one to six carbons. In some embodiments, C1-C4alkyl is an alkyl group that includes both straight and branched chain alkyls of 1 to 4 carbon atoms.
[0086] The term "substituted alkoxy" refers to alkoxy in which the alkyl constituent is substituted (i.e., -O-(substituted alkyl)). Unless specifically stated otherwise in the specification, the alkyl moiety of an alkoxy group is optionally substituted by one or more substituents which independently are: alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy , halo, cyano, trifluoromethyl, trifluoromethoxy, nitro, trimethylsilanyl, -ORa, SRa, -OC(O)-Ra, -N(Ra)2, -C(O)Ra, -C(O)ORa, -OC( O)N(Ra)2, -C(O)N (Ra)2, -N(Ra)C(O)ORa, -N(Ra)C(O)Ra, -N(Ra)C(O) N(Ra)2, N(Ra)C(NRa)N(Ra)2, -N(Ra)S(O)tRa (where t is 1 or 2), -S(O)tORa (where t is 1 or 2), -S(O)tN(Ra)2 (where t is 1 or 2), or PO3(Ra)2, where each Ra is independently hydrogen, alkyl, fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl , heterocycloalkylalkyl, heteroaryl or heteroarylalkyl.
The term "alkoxycarbonyl" refers to a group of the formula (alkoxy)(C=O)- bonded through the carbonyl carbon wherein the alkoxy group has the indicated number of carbon atoms. Thus, a C1-C6alkoxycarbonyl group is an alkoxy group containing 1 to 6 carbon atoms bonded through oxygen to a carbonyl linker. "Lower alkoxycarbonyl" refers to an alkoxycarbonyl group where the alkoxy group is a lower alkoxy group. In some embodiments, C1-C4alkoxy is an alkoxy group that includes both straight and branched chain alkoxy groups of 1 to 4 carbon atoms.
[0088] The term "substituted alkoxycarbonyl" refers to the group (substituted alkyl)-O-C(O)-wherein the group is attached to the parent structure through the carbonyl functionality. Unless specifically stated otherwise in the specification, the alkyl moiety of an alkoxycarbonyl group is optionally substituted by one or more substituents which independently are: alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy , halo, cyano, trifluoromethyl, trifluoromethoxy, nitro, trimethylsilanyl, -ORa, -SRa, -OC(O)-Ra, -N(Ra)2, -C(O)Ra, -C(O)ORa, -OC (O)N(Ra)2, - C(O)N(Ra)2, -N(Ra)C(O)ORa, -N(Ra)C(O)Ra, - N(Ra)C(O )N(Ra)2, N(Ra)C(NRa)N(Ra)2, -N(Ra)S(O)tRa (where t is 1 or 2), -S(O)tORa (where t is 1 or 2), -S(O)tN(Ra)2 (where t is 1 or 2), or PO3(Ra)2, where each Ra is independently hydrogen, alkyl, fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl , heterocycloalkylalkyl, heteroaryl or heteroarylalkyl.
[0089] "Acyl" refers to the groups (alkyl)-C(O)-, (aryl)-C(O)-, (heteroaryl)-C(O)-, (heteroalkyl)-C(O)- , and (heterocycloalkyl)-C(O)-, wherein the group is attached to the parent structure through the carbonyl functionality. In some embodiments, this is a C1-C10 acyl radical which refers to the total number of chain or ring atoms of the alkyl, aryl, heteroaryl or heterocycloalkyl portion of the acyloxy group plus the carbonyl carbon of acyl, i.e. three other rings or atoms. more carbonyl chain. If the radical R is heteroaryl or heterocycloalkyl, the hetero ring or chain atoms contribute to the total number of the chain or ring atoms. Unless specifically stated otherwise in the specification, the "R" of an acyloxy group is optionally substituted by one or more substituents which independently are: alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, trifluoromethyl, trifluoromethoxy, nitro, trimethylsilanyl, -ORa,SRa, -OC(O)-Ra, -N(Ra)2, -C(O)Ra, -C(O)OR a, - OC(O)N(Ra)2, -C(O)N(Ra)2, -N(Ra)C(O)ORa, -N(Ra)C(O)Ra, -N(Ra)C( O)N(Ra)2, N(Ra)C(NRa)N(Ra)2, -N(Ra)S(O)tRa (where t is 1 or 2), -S(O)tORa (where t is 1 or 2), -S(O)tN(Ra)2 (where t is 1 or 2), or PO3(Ra)2, where each Ra is independently hydrogen, alkyl, fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl or heteroarylalkyl.
"Acyloxy" refers to an R(C=O)O- radical where "R" is alkyl, aryl, heteroaryl, heteroalkyl, or heterocycloalkyl, which are as described herein. In some embodiments, this is a C1-C4acyloxy radical which refers to the total number of chain or atoms in the ring of the alkyl, aryl, heteroaryl or heterocycloalkyl portion of the acyloxy group plus the carbonyl atom of acyl, i.e. three other rings or atoms more carbonyl chain. If the radical R is heteroaryl or heterocycloalkyl, the hetero ring or chain atoms contribute to the total number of the chain or ring atoms. Unless specifically stated otherwise in the specification, the "R" of an acyloxy group is optionally substituted by one or more substituents which independently are: alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, trifluoromethyl, trifluoromethoxy, nitro, trimethylsilanyl, -ORa, -SRa, -OC(O)-Ra, -N(Ra)2, -C(O)Ra, -C(O)ORa, - OC(O)N(Ra)2, - C(O)N(Ra)2, -N(Ra)C(O)ORa, -N(Ra)C(O)Ra, - N(Ra)C( O)N(Ra)2, N(Ra)C(NRa)N(Ra)2, -N(Ra)S(O)tRa (where t is 1 or 2-S(O)tORa (where t is 1 or 2), -S(O)tN(Ra)2 (where t is 1 or 2), or PO3(Ra)2, where each Ra is independently hydrogen, alkyl, fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl or heteroarylalkyl.
[0091] "Amino" or "amine" refers to a radical group -N(Ra)2, where each Ra is independently hydrogen, alkyl, fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl or heteroarylalkyl, unless specifically stated otherwise in the specification. When an -N(Ra)2 group has two Ra plus hydrogen they can be combined with the nitrogen atom to form a 4-, 5-, 6-, or 7-membered ring. For example, -N(Ra)2 is intended to include, among others, 1-pyrrolidinyl and 4-morpholinyl. Unless specifically stated otherwise in the specification, an amino group is optionally substituted by one or more substituents which independently are: alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano , trifluoromethyl, trifluoromethoxy, nitro, trimethylsilanyl, -ORa, -SRa, -OC(O)-Ra, -N(Ra)2, -C(O)Ra, -C(O)ORa, -OC(O)N (Ra)2, -C(O )N(Ra)2, -N(Ra)C(O)ORa, -N(Ra)C(O)Ra, -N(Ra)C(O)N(Ra )2, - N(Ra)C(NRa)N(Ra)2, -N(Ra)S(O)tRa (where t is 1 or 2), -S(O)tORa (where t is 1 or 2 ), -S(O)tN(Ra)2 (where t is 1 or 2), or PO3(Ra)2, where each Ra is independently hydrogen, alkyl, fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl or heteroarylalkyl and each of these moieties may be optionally substituted as defined herein.
[0092] The term "substituted amino" also refers to the N-oxides of the groups -NHRa, and NRaRa each as described above. N-oxides can be prepared by treating the corresponding amino group with, for example, hydrogen peroxide or m-chloroperoxybenzoic acid. The person skilled in the art is familiar with reaction conditions for carrying out N-oxidation.
[0093] "Amide" or "starch" refers to a chemical moiety with the formula -C(O)N(R)2 or -NHC(O)R, where R is selected from the group consisting of hydrogen, alkyl, cycloalkyl , aryl, heteroaryl (attached via a ring carbon) and heteroalicyclic (attached via a ring carbon), each of the moieties may be its own or optionally substituted. In some embodiments this is a C1-C4 amido or amide radical, which includes the carbonyl amide in the total number of carbons in the radical. The R2 of -N(R)2 of the amide can optionally be taken together with the nitrogen to which it is attached to form a 4-, 5-, 6- or 7-membered ring. Unless specifically stated otherwise in the specification, an amido group is optionally independently substituted by one or more of the substituents as described herein for alkyl, cycloalkyl, aryl, heteroaryl, or heterocycloalkyl. An amide can be an amino acid molecule or a peptide linked to a compound of Formula (I), thus forming the prodrug. Any amine, hydroxy, or carboxyl side chain in the compounds described herein can be amidified. Procedures and specific groups for creating such amides are known to those skilled in the art and can readily be found in reference sources such as Greene and Wuts, Protective Groups in Organic Synthesis, 3rd Ed., John Wiley & Sons, New York, NY, 1999, which is incorporated herein by reference in its entirety.
[0094] "Aromatic" or "aryl" refers to an aromatic radical having six to ten ring atoms (eg, C6-C10 aromatic or C6-C10aryl) that has at least one ring containing a conjugated pi electron system which is carbocyclic (for example, phenyl, fluorenyl, and naphthyl). Divalent radicals formed from substituted benzene derivatives and containing free valences on ring atoms are named as substituted phenylene radicals. Bivalent radicals derived from univalent polycyclic hydrocarbon radicals whose terminal names in "-il" by removing a hydrogen atom from the carbon atom with the free valence are named by adding "-idene" to the name of the corresponding univalent radical, eg, a naphthyl group with two points of attachment is called naphthylidene. Whenever this appears here, a numerical range such as "6 to 10" refers to each integer in that range; for example, "6 to 10 ring atoms" means that the aryl group may consist of 6 ring atoms, 7 ring atoms, etc. , up to and including 10 ring atoms. The term includes groups of monocyclic rings or fused polycyclic rings (that is, rings that share adjacent pairs of ring atoms). Unless specifically stated otherwise in the specification, an aryl moiety is optionally substituted by one or more substituents which are independently: alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano , trifluoromethyl, trifluoromethoxy, nitro, trimethylsilanyl, -ORa, -SRa, -OC(O)-Ra, -N(Ra)2, -C(O)Ra, -C(O)ORa, -OC(O)N (Ra)2, -C(O)N(Ra)2, -N(Ra)C(O)ORa, -N(Ra)C(O)Ra, -N(Ra)C(O)N(Ra )2, N(Ra)C(NRa)N(Ra)2, -N(Ra)S(O)tRa (where t is 1 or 2), -S(O)tORa (where t is 1 or 2) , -S(O)tN(Ra)2 (where t is 1 or 2), or PO3(Ra)2, where each Ra is independently hydrogen, alkyl, fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl or heteroarylalkyl.
[0095] "Aralkyl" or "arylalkyl" refers to an (aryl)alkyl radical—wherein the arylalkyl moiety is attached to the alkyl portion of the moiety. Aryl and alkyl are as disclosed herein and are optionally substituted by one or more of the substituents described as suitable substituents for aryl and alkyl respectively.
[0096] "Ester" refers to a chemical radical of the formula -COOR, where R is selected from the group consisting of alkyl, cycloalkyl, aryl, heteroaryl (bonded through a ring carbon) and heteroalicyclic (bonded through a carbon of the ring). Any amine, hydroxy, or carboxyl side chain in the compounds described herein can be esterified. Procedures and specific groups for creating such esters are known to those skilled in the art and can readily be found in reference sources such as Greene and Wuts, Protective Groups in Organic Synthesis, 3rd Ed., John Wiley & Sons, New York, NY, 1999, which is incorporated herein by reference in its entirety. Unless specifically stated otherwise in the specification, an ester group is optionally substituted by one or more substituents which independently are: alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano , trifluoromethyl, trifluoromethoxy, nitro, trimethylsilanyl, -ORa, -SRa, -OC(O)-Ra, -N(Ra)2, -C(O)Ra, -C(O)ORa, -OC(O)N (Ra)2, - C(O)N(Ra)2, -N(Ra)C(O)ORa, N(Ra)C(O)Ra, - N(Ra)C(O)N(Ra) 2, N(Ra)C(NRa)N(Ra)2, -N(Ra)S(O)tRa (where t is 1 or 2), -S(O)tORa (where t is 1 or 2), -S(O)tN(Ra)2 (where t is 1 or 2), or PO3(Ra)2, where each Ra is independently hydrogen, alkyl, fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl or heteroarylalkyl.
[0097] "Fluoralkyl" refers to an alkyl radical as defined above that is substituted by one or more fluoro radicals as defined above, for example, trifluoromethyl, difluoromethyl, 2,2,2-trifluoroethyl, 1- fluoromethyl-2-fluoroethyl, and the like. The alkyl part of the fluoroalkyl radical may be optionally substituted as defined above for an alkyl group.
[0098] "Halo", "halide", or alternatively "halogen" means fluorine, chlorine, bromine or iodine. The terms "haloalkyl," "haloalkenyl," "haloalkynyl" and "haloalkoxy" include alkyl, alkenyl, alkynyl and alkoxy structures that are substituted with one or more halo groups or combinations thereof. For example, the terms "fluoroalkyl" and "fluoroalkoxy" include haloalkyl and haloalkoxy groups, respectively, in which halo is fluorine.
[0099] "Heteroalkyl", "heteroalkenyl" and "heteroalkynyl" include optionally substituted alkyl, alkenyl and alkynyl radicals and which have one or more last in structure selected from an atom other than carbon, e.g. oxygen, nitrogen, sulfur, phosphorus or combinations thereof. A numerical range can be conferred, for example, C1-C4 heteroalkyl which refers to the chain length in total, which in this example is 4 atoms in length. For example, a -CH2OCH2CH3 radical is referred to as a "C4" heteroalkyl, which includes the heteroatom center in the chain length description. Connection to the rest of the molecule can be through a heteroatom or a carbon in the heteroalkyl chain. A heteroalkyl group may be substituted with one or more substituents which independently are: alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, nitro, oxo, thioxo, trimethylsilanyl, - ORa, -SRa, -OC(O)-Ra, -N(Ra)2, -C(O)Ra, -C(O)ORa, -C(O)N(Ra)2, -N(Ra) C(O)ORa, -N(Ra)C(O)Ra, -N(Ra)S(O)tRa (where t is 1 or 2), -S(O)tORa (where t is 1 or 2) , -S(O)tN(Ra)2 (where t is 1 or 2), or PO3(Ra)2, where each Ra is independently hydrogen, alkyl, fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl or heteroarylalkyl.
"Heteroalkylaryl" refers to "a -(heteroalkyl)aryl radical where heteroalkyl and aryl are as disclosed herein and which are optionally substituted by one or more of the substituents described as suitable substituents for heteroalkyl and aryl respectively.
[00101] "Heteroaryl" or, alternatively, "heteroaromatic" refers to a 5- to 18-membered aromatic radical (eg, C5-C13 heteroaryl) that includes one or more ring heteroatoms selected from nitrogen, oxygen and sulfur, and which can be a monocyclic, bicyclic, tricyclic or tetracyclic ring system. Whenever appearing here, a numerical range such as "5 to 18" refers to each integer in that range; for example, "5 to 18 ring atoms" means that the heteroaryl group may consist of 5 ring atoms, 6 ring atoms, etc. , up to and including 18 ring atoms. Bivalent radicals derived from univalent heteroaryl radicals whose names end in "-il" by removing one hydrogen atom from the atom with free avalence are named by adding "-idene" to the name of the corresponding univalent radical radical, eg, a pyridyl group with two connecting points is a pyridylidene. An N-containing "heteroaromatic" or "heteroaryl" moiety refers to an aromatic group in which at least one of the atoms of the ring structure is a nitrogen atom. The polycyclic heteroaryl group can be fused or unfused. The heteroatoms in the heteroaryl radical are optionally oxidized. One or more nitrogen atoms, if present, are optionally quaternized. Heteroaryl is attached to the rest of the molecule through any atom on the rings. Examples of heteroaryls include, among others, azepinyl, acridinyl, benzimidazolyl, benzindolyl, 1,3-benzodioxolyl, benzofuranyl, benzooxazolyl, benzo[d]thiazolyl, benzothiadiazolyl, benzo[b][1,4]dioxepinyl, benzo[b][ 1,4]oxazinyl, 1,4-benzodioxanil, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzoxazolyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzofurazanyl, benzothiazolyl, benzothiene, benzotriazolyl ([3]) , benzo[4,6]imidazo[1,2-a]pyridinyl, carbazolyl, cinnolinyl, cyclopenta[d]pyrimidinyl, 6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-d]pyrimidinyl , 5,6-dihydrobenzo[h]quinazolinyl, 5,6-dihydrobenzo[h]cinnolinyl, 6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazinyl, dibenzofuranyl, dibenzothiophenyl, furanyl , furazanil, furanonil, furo[3,2-c]pyridinyl, 5,6,7,8,9,10-hexahydrocycloocta[d]pyrimidinyl, 5,6,7,8,9,10-hexahydrocycloocta[d]pyridazinyl , 5,6,7,8,9,10-hexahydrocycloocta[d]pyridinyl,isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, indolinyl, isoindolinyl, isoquinolyl, indolizinyl, isoxazolyl, 5,8-methane-5,6,7,8-tetrahydroquinazolinyl, naphthyridinyl, 1,6-naphthyridinonyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl oxiranil, 5,6,6a,7,8,9,10,10a-octahydrobenzo[h]quinazolinyl, 1-phenyl-1H-pyrrolyl, phenazinyl, phenothiazinyl, fenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyranyl, pyrrolyl, pyrazolyl, pyrazolo[3,4-d]pyrimidinyl, pyridinyl, pyrido[3,2-d]pyrimidinyl, pyrido[3,4-d]pyrimidinyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrrolyl, quinazolinyl, quinoxalinyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, 5,6,7,8-tetrahydroquinazolinyl, 5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidinyl, 6,7,8,9-tetrahydro-5H-cyclohepta[4, 5]thieno[2,3-d]pyrimidinyl, 5,6,7,8-tetrahydropyrido[4,5-c]pyridazinyl, thiazolyl, thiadiazolyl, thiapyranil, triazolyl, tetrazolyl, triazinyl, thieno[2,3-d ]pyrimidinyl, thieno[3,2-d]pyrimidinyl, thieno[2,3-c]pridinyl, and thiophenyl (i.e. thienyl). Unless specifically stated otherwise in the specification, a heteroaryl moiety is optionally substituted by one or more substituents which are independently: alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano , nitro, oxo, thioxo, trimethylsilanyl, -ORa, -SRa, -OC(O)-Ra, -N(Ra)2, -C(O)Ra, -C(O)ORa, -C(O)N (Ra)2, -N(Ra )C(O)ORa, -N(Ra)C(O)Ra, -N(Ra)S(O)tRa (where t is 1 or 2), -S(O) )tORa (where t is 1 or 2), -S(O)tN(Ra)2 (where t is 1 or 2), or PO3(Ra)2, where each Ra is independently hydrogen, alkyl, fluoroalkyl, carbocyclyl, carbocyclylalkyl , aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl or heteroarylalkyl.
[00102] Substituted heteroaryl also includes ring systems substituted with one or more oxide (-O-) substituents, such as pyridinyl N-oxides.
[00103] "Heteroarylalkyl" refers to a moiety containing a heteroaryl moiety, as described herein, connected to an alkyl moiety as described herein, wherein the attachment to the remainder of the molecule is through the alkyl group. Heteroaryl and alkyl are as disclosed herein optionally substituted by one or more of the substituents described as suitable substituents for heteroaryl and alkyl respectively.
[00104] "Heterocycloalkyl" refers to a stable 3- to 18-membered non-aromatic ring radical comprising two to twelve carbon atoms and one to six heteroatoms selected from nitrogen, oxygen and sulfur. Whenever it appears here, a numeric range such as "3 to 18" refers to each integer in that range; for example, "3 to 18 ring atoms" means that the heterocycloalkyl group may consist of 3 ring atoms, 4 ring atoms, etc. , up to and including 18 ring atoms. In some embodiments, this is a C5-C10 heterocycloalkyl. In some embodiments, this is a C4-C10 heterocycloalkyl. In some embodiments, this is a C3-C10 heterocycloalkyl. Unless specifically stated otherwise in the specification, the heterocycloalkyl radical is a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which may include fused or bridged ring systems. The heteroatoms in the heterocycloalkyl radical can optionally be oxidized. One or more nitrogen atoms, if present, are optionally quaternized. The heterocycloalkyl radical is partially or completely saturated. The heterocycloalkyl can be attached to the remainder of the molecule through any atom on the ring or rings. Examples of said heterocycloalkyl radicals include, among others, dioxolanyl, thienyl[1,3]dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopyrazolidinyl, 2-oxopyrazolidinyl, 2-oxopyrazolidinyl, 2-oxopyrazolidinyl, 2- piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, and 1,1-dioxo-thiomorpholinyl. Unless specifically stated otherwise in the specification, a heterocycloalkyl moiety is optionally substituted by one or more substituents which independently are: alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano , nitro, oxo, thioxo, trimethylsilanyl, -ORa, -SRa, -OC(O)-Ra, -N(Ra)2, -C(O)Ra, -C(O)ORa, -C(O)N (Ra)2, -N(Ra )C(O)ORa, -N(Ra)C(O)Ra, -N(Ra)S(O)tRa (where t is 1 or 2), -S(O) )tORa (where t is 1 or 2), -S(O)tN(Ra)2 (where t is 1 or 2), or PO3(Ra)2, where each Ra is independently hydrogen, alkyl, fluoroalkyl, carbocyclyl, carbocyclylalkyl , aryl, aralkyl, heterocycloalkyl, heteroaryl or heteroarylalkyl.
[00105] "Heterocycloalkyl" also includes bicyclic ring systems in which a non-aromatic atom, usually 3 to 7 ring atoms, contains at least 2 carbon atoms in addition to 1-3 heteroatoms independently selected from oxygen, sulfur, and nitrogen , as well as combinations comprising at least one of the above heteroatoms; and the other ring, generally with 3 to 7 ring atoms, optionally contains 1-3 heteroatoms independently selected from oxygen, sulfur, and nitrogen and is non-aromatic.
[00106] "Heterocycloalkyloxy" refers to a moiety (heterocycloalkyl)-O-, where the heterocycloalkyl moiety is attached through a carbon atom to oxygen, where oxygen acts as a linker to link the moiety to a compound. Heterocycloalkyl is as described herein and is optionally substituted by one or more substituents described herein as appropriate for heterocycloalkyl.
[00107] "Isomers" are different compounds that have the same molecular formula. "Stereoisomers" are isomers that only differ in the way atoms are arranged in space. "Enantiomers" are a pair of stereoisomers that are not superimposed mirror images of each other. A 1:1 mixture of a pair of enantiomers is a "racemic" mixture. The term "(±)" is used to designate a racemic mixture where appropriate. "Diastereoisomers" are stereoisomers that have at least two asymmetric atoms, but that are not mirror images of the other. Absolute stereochemistry is specified according to the R-S system of Cahn-Ingold-Prelog. When a compound is a pure enantiomer the stereochemistry at each chiral carbon can be specified by R or S. Resolved compounds whose absolute configuration is unknown can be designated (+) or (-) depending on the direction (dextro- or levorotatory) they rotate the plane of light polarized at the wavelength of the sodium D line. Some of the compounds described herein contain one or more asymmetric centers and may thus generate enantiomers, diastereoisomers, and other stereoisomeric forms that may be defined, in terms of absolute stereochemistry, as (R)- or (S)-. The present chemical entities, pharmaceutical compositions and methods are intended to include all said possible isomers, including racemic mixtures, optically pure forms and intermediate mixtures. Optically active (R)- and (S)-isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. The optical activity of a compound can be analyzed by any suitable method, including but not limited to chiral chromatography and polarimetry, and the degree of predominance of one stereoisomer over the other isomer can be determined.
[00108] When the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, and unless otherwise specified, the compounds are intended to include geometric E and Z isomers.
[00109] "Fraction" refers to a specific segment or functional group of a molecule. Chemical fractions are usually rearranged chemical entities embedded or attached to a molecule.
[00110] "Nitro" refers to the radical-NO2.
[00111] "Oxa" refers to the radical -O-.
[00112] "Oxo" refers to the radical =O.
[00113] "Tautomers" are structurally distinct isomers that interconvert by tautomerization. "Tautomerization" is a form of isomerization and includes prototropic or proton shift tautomerization, which is considered a subset of acid-base chemistry. "Prototropic tautomerization" or "proton-change tautomerization" involves the migration of a proton accompanied by changes in bond order, usually exchange of a single bond with an adjacent double bond. Where tautomerization is possible (eg in solution), a chemical equilibrium of tautomers can be achieved. An example of tautomerization is keto-enol tautomerization. A specific example of keto-enol tautomerization is the interconversion of pentane-2,4-dione and 4-hydroxypent-3-en-2-one tautomers. Another example of tautomerization is phenol-keto tautomerization. A specific example of phenol-keto tautomerization is interconversion of pyridin-4-ol and pyridin-4(1H)-one tautomers.
[00114] The compounds of the present invention may also contain unnatural proportions of atomic isotopes in one or more of the atoms that constitute said compounds. For example, the compounds can be radiolabeled with radioactive isotopes such as, for example, tritium (3H), iodine-125 (125I) or carbon-14 (14C). All isotopic variations of the compounds of the present invention, whether radioactive or not, are included within the scope of the present invention.
[00115] A "leaving group or atom" is any group or atom that will, under reaction conditions, cleave the starting material, thus promoting reaction at a specific site. Suitable examples of each group, unless otherwise specified, are halogen atoms, mesiloxy, p-nitrobenzenesulfonyloxy and tosyloxy groups.
[00116] "Protection group" has the meaning conventionally associated with this in organic syntheses, that is, a group that selectively blocks one or more reaction sites on a multifunctional compound so that a chemical reaction can be selectively conducted at another site unprotected reactive and so that the group can readily be removed after the selective reaction is complete. A variety of protecting groups are disclosed, for example, in T.H. Greene and P.G.M. Wuts, Protective Groups in Organic Synthesis, Third Edition, John Wiley & Sons, New York (1999). For example, a protected hydroxy form is at least one of the hydroxy groups present in a compound is protected with a hydroxy protecting group. Likewise, amines and other reactive groups can similarly be protected.
"Solvate" refers to a compound (for example, a compound selected from Formula I or the pharmaceutically acceptable salt thereof) in physical association with one or more molecules of a pharmaceutically acceptable solvent. It will be understood that "a compound of Formula I" includes the compound of Formula I and solvates of the compound, as well as mixtures thereof.
[00118] "Substituted" means that the referenced group may be substituted with one or more additional groups individually and independently selected from acyl, alkyl, alkylaryl, cycloalkyl, aralkyl, aryl, carbohydrate, carbonate, heteroaryl, heterocycloalkyl, hydroxy, alkoxy, aryloxy , mercapto, alkylthio, arylthio, cyano, halo, carbonyl, ester, thiocarbonyl, isocyanate, thiocyanate, isothiocyanate, nitro, oxo, perhaloalkyl, perfluoroalkyl, phosphate, silyl, sulfinyl, sulfonyl, sulfonamidyl, sulfoxyl, sulfonate, urea, and including mono- and di-substituted amino groups, and the protected derivatives thereof. Substituted di-amino groups include those that form a ring together with the nitrogen of the amino group, such as morpholino. The substituents themselves may be substituted, for example, a cycloalkyl substituent may have a halide substituted on one or more carbon rings, and the like. Protecting groups which can form the protective derivatives of the above substituents are known to those skilled in the art and can be found in references such as Greene and Wuts, above.
[00119] "Sulfonyl" refers to the groups: -S(O2)-H, -S(O2)-(optionally substituted alkyl), -S(O2)-(optionally substituted amino), -S(O2)- (optionally substituted aryl), -S(O2)-(optionally substituted heteroaryl), and -S(O2)-(optionally substituted heterocycloalkyl).
[00120] "Sulphonamidyl" or "sulfonamido" refers to a radical-S(=O) 2 -NRR, where each R is independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl, heteroaryl (bonded through a ring carbon) and heteroalicyclic (bonded through a ring carbon). The R groups in -NRR of the -S(=O)2-NRR radical can be taken together with the nitrogen to which it is attached to form a ring of 4, 5, 6, or 7-membered. In some embodiments, this is a C1-C10 sulfonamido, where each R in the sulfonamido contains 1 carbon, 2 carbons, 3 carbons, or 4 carbons total. A sulfonamido group is optionally substituted by one or more of the described substituents for alkyl, cycloalkyl, aryl, heteroaryl respectively.
[00121] "Sulphoxyl" refers to an S(=O)2OH-radical.
[00122] "Sulfonate" refers to a radical -S(=O)2-OR, where R is selected from the group consisting of alkyl, cycloalkyl, aryl, heteroaryl (bonded through a ring carbon) and heteroalicyclic (bonded through a ring carbon). A sulfonate group is optionally substituted on R by one or more of the substituents described for alkyl, cycloalkyl, aryl, heteroaryl respectively.
[00123] Where the substituent groups are specified by their conventional chemical formulas, written from left to right, they also include chemically identical substituents that would result from writing the structure from right to left, eg -CH2O- is equivalent to -OCH2-.
Compounds of the present invention also include crystalline and amorphous forms of those compounds, including, for example, polymorphs, pseudopolymorphs, solvates, hydrates, unsolvated polymorphs (including anhydrates), conformational polymorphs, and amorphous forms of the compounds, as well as mixtures of the compounds. same. "Crystal form," "polymorph," and "new form" may be used interchangeably herein, and are intended to include all crystalline and amorphous forms of the compound, including, for example, polymorphs, pseudopolymorphs, solvates, hydrates, unsolvated polymorphs (including anhydrates), conformational polymorphs, and amorphous forms, as well as mixtures thereof, unless a crystalline or amorphous form is referenced.
[00125] "Solvent," "organic solvent," and "inert solvent" each mean a solvent inert under the reaction conditions being described in conjunction therewith including, for example, benzene, toluene, acetonitrile, tetrahydrofuran ("THF" ), dimethylformamide ("DMF"), chloroform, methylene chloride (or dichloromethane), diethyl ether, methanol, N-methylpyrrolidone ("NMP"), pyridine, and the like. Unless otherwise specified, solvents used in the reactions described herein are inert organic solvents. Unless otherwise specified, for each gram of limiting reagent, one cc (or mL) of solvent constitutes one equivalent in volume.
[00126] Isolation and purification of the chemical entities and intermediates described herein can be carried out, if desired, by any separation or purification procedure such as, for example, filtration, extraction, crystallization, column chromatography, thin layer chromatography or layer chromatography thick, or a combination of these procedures. Specific illustrations of separation and isolation procedures can be obtained by referring to the examples herein below. However, other equivalent separation and isolation procedures can still be used.
[00127] When desired, the (R)- and (S)- isomers of the compounds of the present invention, if present, can be resolved by methods known to those skilled in the art, for example by the formation of diastereoisomeric salts or complexes which can be separated , for example, by crystallization; through the formation of diastereoisomeric derivatives which can be separated, for example, by crystallization, gas-liquid or liquid chromatography; selective reaction of an enantiomer-specific reagent, eg oxidation or enzymatic reduction, followed by separation of the modified and unmodified enantiomers; or gas-liquid or liquid chromatography in a chiral environment, for example on a chiral support such as silica with a chiral bonding ligand or in the presence of a chiral solvent. Alternatively, a specific enantiomer can be synthesized by asymmetric synthesis using optically active reagents, substrates, catalysts or solvents, or by converting one enantiomer to another by asymmetric transformation.
The compounds described herein may optionally be contacted with a pharmaceutically acceptable acid to form the corresponding acid addition salts. Pharmaceutically acceptable forms of the compounds mentioned herein include pharmaceutically acceptable salts, chelates, non-covalent complexes, prodrugs, and mixtures thereof. In certain embodiments, the compounds described herein are in pharmaceutically acceptable salt form. Furthermore, if the compound described here is obtained as an acid addition salt, the free base can be obtained by basifying the acid salt. Conversely, if the product is the free base, an addition salt, particularly a pharmaceutically acceptable addition salt, can be produced by dissolving the free base in an appropriate organic solvent and treating the solution with an acid, in accordance with conventional procedures for preparing acid addition salts from base compounds. Those skilled in the art will recognize the various synthetic methodologies that can be used to prepare pharmaceutically acceptable non-toxic acid addition salts.
[00129] As noted above, the present invention provides various compounds that are useful as antagonists to one or more lipid kinases and/or protein kinases.
[00130] In one aspect, the present invention provides a compound of Formula I:
or the pharmaceutically acceptable salts thereof, wherein: X is O or S or N; W1 is N, NR3, CR3, or C=O, W2 is N, NR4, CR4, or C=O, W3 is N, NR5 or CR5, W4 is N, C=O or CR6, where no more than two N atoms and no more than two C=O groups are adjacent; W5 is N or CR7; W6 is N or CR8; R1 and R2 are independently hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, alkoxy, heterocycloalkyloxy, starch, amino, acyl, acyloxy, alkoxycarbonyl, sulfonamido, halo, cyano, hydroxy, nitro, phosphate, urea, carbonate, or NR'R'' where R' and R'' are taken together with nitrogen to form a cyclic fraction; R3 and R4 are independently hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, alkoxy, heterocycloalkyloxy, amido, amino, acyl, acyloxy, alkoxycarbonyl, sulfonamido, halo, cyano, hydroxy, nitro , phosphate, urea, carbonate, or NR'R'' where R' and R'' are taken together with nitrogen to form a cyclic fraction; or R3 and R4 taken together form a cyclic moiety; and R5, R6 , R7 and R8 are independently hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, alkoxy, heterocycloalkyloxy, starch, amino, acyl, acyloxy, alkoxycarbonyl, sulfonamido, halo, cyano, hydroxy, nitro, phosphate, urea, carbonate, or NR'R'' where R' and R'' are taken together with nitrogen to form a cyclic fraction.
[00131] In some embodiments, the compound of Formula I exists as a tautomer, and such tautomers are contemplated by the present invention.
[00132] In some embodiments, the compound of Formula I has the formula:

[00133] For example, a compound of Formula I is:

In some embodiments of the compound of Formula I, W1 is CR3, W2 is CR4, W3 is CR5, W4 is N, W5 is CR7, and W6 is CR8; W1is N, W2is CR4, W3is CR5, W4is N, W5is CR7, and W6is CR8; or W1is CR3, W2is N, W3is CR5, W4is N, W5is CR7, and W6is CR8. Formulas for these modalities are shown below.

[00135] In some modalities, X is O. In other modalities, X is S.
[00136] In some embodiments, R1 is hydrogen. In other embodiments, R1 is alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, alkoxy, heterocycloalkyloxy, starch, amino, acyl, acyloxy, alkoxycarbonyl, sulfonamido, halo, cyano, hydroxy, nitro, phosphate , urea, carbonate, or NR'R", where R' and R'' are taken together with nitrogen to form a cyclic fraction.
[00137] In some embodiments, R2 is hydrogen. In other embodiments, R2 is, for example, unsubstituted or substituted alkyl (including but not limited to CH3, -CH2CH3, n-propyl, isopropyl, n-butyl, tert-butyl, sec-butyl, pentyl, hexyl, and heptyl). In other embodiments, R2 is unsubstituted or substituted alkenyl (including but not limited to unsubstituted or substituted C2-C5alkenyl such as, for example, vinyl, allyl, 1-methyl propen-1-yl, butenyl, or pentenyl) or unsubstituted or substituted alkynyl (including but not limited to unsubstituted or substituted C2-C5alkynyl such as acetylenyl, propargyl, butynyl, or pentynyl). Alternatively, R2 is unsubstituted or substituted aryl (including but not limited to monocyclic or bicyclic aryl) or unsubstituted or substituted arylalkyl (including but not limited to monocyclic or bicyclic aryl linked to alkyl wherein alkyl includes, but not limited to, CH3, -CH2CH3, n- propyl, isopropyl, n-butyl, sec-butyl, and pentyl). In some other embodiments, R2 is unsubstituted or substituted heteroaryl, including but not limited to monocyclic and bicyclic bicyclic heteroaryl heteroaryl. Monocyclic heteroaryl R2 includes, among others, pyrrolyl, thienyl, furyl, pyridinyl, pyranyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, thiazolyl, pyrazolyl, and oxazolyl. Bicyclic heteroaryl R2 includes, but is not limited to, benzothiophenyl, benzofuryl, indolyl, quinolinyl, isoquinolinyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, quinazolinyl, azaindolyl, pyrazolopyrimidinyl, purinyl, pyrrolo[1,2-b]pyridazoylidinyl, pyrroloidinyl, pyrroloidinyl, pyrroloidinyl[1,2-b]pyridazoylidinyl, pyrroloinyl 1,2-a]pyridinyl, and pyrrolo[1,2-f][1,2,4]triazinyl. The present invention also provides compounds wherein R2 is unsubstituted or substituted heteroarylalkyl, including but not limited to monocyclic and bicyclic bicyclicheteroaryl heteroaryl as described above, which are linked to alkyl, which in turn includes, but not limited to, CH3, -CH2CH3, n- propyl, isopropyl, n-butyl, sec-butyl, and pentyl. In some embodiments, R2 is unsubstituted or substituted cycloalkyl (including but not limited to cyclopropyl, cyclobutyl, and cyclopentyl) or unsubstituted or substituted heteroalkyl (non-limiting examples include ethoxymethyl, methoxymethyl, and diethylaminomethyl). In some other embodiments, R2 is unsubstituted or substituted heterocycloalkyl which includes, among others, pyrrolidinyl, tetrahydrofuranoyl, piperidinyl, tetrahydropyranyl, thiazolidinyl, imidazolidinyl, morpholinyl, and piperazinyl. In yet other embodiments of the compounds of Formula I, R 2 is unsubstituted or substituted alkoxy including but not limited to C 1 -C 4 alkoxy such as methoxy, ethoxy, propoxy or butoxy. R2 may further be unsubstituted or substituted heterocycloalkyloxy, including among others 4-NH-piperidin-1-yl-oxy, 4-methyl piperidin-1-yl-oxy, 4-ethyl piperidin-1-yl-oxy, 4-isopropyl- piperidin-1-yl-oxy, and pyrrolidin-3-yl-oxy. In other embodiments, R2 is unsubstituted or substituted amino, where substituted amino includes, among others, dimethylamino, diethylamino, diisopropylamino, N-methyl N-ethylamino, and dibutylamino. In some embodiments, R2 is unsubstituted or substituted acyl, unsubstituted or substituted acyloxy, unsubstituted or substituted C1-C4 acyloxy, unsubstituted or substituted alkoxycarbonyl, unsubstituted or substituted amido, or unsubstituted or substituted sulfonamido. In other embodiments, R2 is halo, which is -I, -F, -Cl, or -Br. In some embodiments, R2 is selected from the group consisting of cyano, hydroxy, nitro, phosphate, urea, and carbonate. Also contemplated are R2 being -CH3, -CH2CH3, n-propyl, isopropyl, n-butyl, tert-butyl, sec-butyl, pentyl, hexyl, heptyl, -OCH3, -OCH2CH3, or -CF3.
[00138] In some embodiments of the compound of Formula I, W1 is CR3. R3 can be, for example, hydrogen, unsubstituted or substituted alkyl (including but not limited to CH3, -CH2CH3, n-propyl, isopropyl, n-butyl, tert-butyl, sec-butyl, pentyl, hexyl, and heptyl). In other embodiments, R3 is unsubstituted or substituted alkenyl (including but not limited to unsubstituted or substituted C2-C5alkenyl such as, for example, vinyl, allyl, 1-methyl propen-1-yl, butenyl, or pentenyl) or unsubstituted or substituted alkynyl (including but not limited to unsubstituted or substituted C2-C5alkynyl such as acetylenyl, propargyl, butynyl, or pentynyl). Alternatively, R3 is unsubstituted or substituted aryl (including but not limited to monocyclic or bicyclic aryl) or unsubstituted or substituted arylalkyl (including but not limited to monocyclic or bicyclic aryl linked to alkyl wherein alkyl includes, but not limited to, CH3, -CH2CH3, n -propyl, isopropyl, n-butyl, sec-butyl, and pentyl). In some other embodiments, R3 is unsubstituted or substituted heteroaryl, including but not limited to monocyclic and bicyclic bicyclic heteroaryl heteroaryl. Monocyclic heteroaryl R3 includes, among others, pyrrolyl, thienyl, furyl, pyridinyl, pyranyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, thiazolyl, pyrazolyl, and oxazolyl. Bicyclic heteroaryl R3 includes, but is not limited to, benzothiophenyl, benzofuryl, indolyl, quinolinyl, isoquinolinyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, quinazolinyl, azaindolyl, pyrazolopyrimidinyl, purinyl, pyrrolo[1,2-b]pyridazoylidinyl, pyrroloinyl, pyrroloidinyl, pyrroloidinyl[1,2-b]pyridazoylidinyl, pyrroloinyl 1,2-a]pyridinyl, and pyrrolo[1,2-f][1,2,4]triazinyl. The present invention also provides compounds of Formula I wherein R3 is unsubstituted or substituted heteroarylalkyl, including but not limited to monocyclic and bicyclic bicyclic heteroaryl heteroaryl heteroaryl as described above, which are linked to alkyl, which in turn includes, but not limited to, CH3, -CH2CH3, n-propyl, isopropyl, n-butyl, sec-butyl, and pentyl. In some embodiments, R3 is unsubstituted or substituted cycloalkyl (including but not limited to cyclopropyl, cyclobutyl, and cyclopentyl) or unsubstituted or substituted heteroalkyl (non-limiting examples include ethoxymethyl, methoxymethyl, and diethylaminomethyl). In some other embodiments, R3 is unsubstituted or substituted heterocycloalkyl which includes, among others, pyrrolidinyl, tetrahydrofuranoyl, piperidinyl, tetrahydropyranyl, thiazolidinyl, imidazolidinyl, morpholinyl, and piperazinyl. In yet other embodiments of the compounds of Formula I, R3 is unsubstituted or substituted alkoxy including but not limited to C1-C4alkoxy such as methoxy, ethoxy, propoxy or butoxy. R3 may further be unsubstituted or substituted heterocycloalkyloxy, including among others 4-NH-piperidin-1-yl-oxy, 4-methyl piperidin-1-yl-oxy, 4-ethyl piperidin-1-yl-oxy, 4-isopropyl- piperidin-1-yl-oxy, and pyrrolidin-3-yl-oxy. In other embodiments, R3 is unsubstituted or substituted amino, where substituted amino includes, among others, dimethylamino, diethylamino, diisopropylamino, N-methyl N-ethylamino, and dibutylamino. In some embodiments, R3 is unsubstituted or substituted acyl, unsubstituted or substituted acyloxy, unsubstituted or substituted C1-C4 acyloxy, unsubstituted or substituted alkoxycarbonyl, unsubstituted or substituted amido, or unsubstituted or substituted sulfonamido. In other embodiments, R3 is halo, which is -I, -F, -Cl, or -Br. In some embodiments, R3 is selected from the group consisting of cyano, hydroxy, nitro, phosphate, urea, and carbonate. Further contemplated are R3 being -CH3, -CH2CH3, n-propyl, isopropyl, n-butyl, tert-butyl, sec-butyl, pentyl, hexyl, heptyl, -OCH3, -OCH2CH3, or -CF3.
[00139] R3 of the compounds of Formula I, may further be NR'R'' where R' and R'' are taken together with nitrogen to form a cyclic moiety containing from 3 to 8 ring atoms. The cyclic moiety so formed may further include one or more heteroatoms which are selected from the group consisting of S, O, and N. The cyclic moiety so formed is unsubstituted or substituted, including but not limited to morpholinyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, 1,2 isothiazolidinyl, dioxide, and thiomorpholinyl. Other exemplary non-limiting cyclic fractions are as follows:

The invention also provides compounds of Formula I, wherein when R3 is a member of the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, heteroalkyl, heterocycloalkyl, heterocycloalkyloxy, aryl, arylalkyl, heteroaryl, heteroarylalkyl, acyl, alkoxy, starch , amino, sulfonamido, acyloxy, alkoxycarbonyl, and NR'R'' (where R' and R'' are taken together with nitrogen to form a cyclic moiety), then R3 is optionally substituted with one or more of the following substituents: alkyl, alkenyl, alkynyl, cycloalkyl, heteroalkyl, heterocycloalkyl, heterocycloalkyloxy, aryl, arylalkyl, heteroaryl, heteroarylalkyl, acyl, heterocycloalkyloxy, alkoxy, starch, amino, sulfonamido, acyloxy, alkoxycarbonyl, halo, cyano, hydroxy, nitro, phosphate, urea, carbonate, or NR'R'' where R' and R'' are taken together with nitrogen to form a cyclic fraction. Each of the above substituents may be further substituted with one or more substituents selected from the group consisting of alkyl, alkoxy, amido, amino, sulfonamido, acyloxy, alkoxycarbonyl, halo, cyano, hydroxy, nitro, oxo, phosphate, urea, and carbonate.
[00141] For example, the invention provides compounds wherein when R3 is alkyl, the alkyl is substituted with NR'R'' where R' and R'' are taken together with nitrogen to form a cyclic moiety. The cyclic fraction thus formed can be unsubstituted or substituted. Exemplary non-limiting cyclic moieties include but are not limited to morpholinyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, and thiomorpholinyl. In other examples of the compounds of Formula I, when R3 is alkyl, the alkyl is substituted with heterocycloalkyl, which includes oxetanyl, azetidinyl, tetrahydrofuranoyl, pyrrolyl, tetrahydropyranyl, piperidinyl, morpholinyl, and piperazinyl. All of the above listed heterocycloalkyl substituents may be unsubstituted or substituted.
In still other examples of the compounds of Formula I, when R3 is alkyl, the alkyl is substituted with a 5-, 6-, 7, 8, 9, or 10-membered monocyclic or bicyclic heteroaryl which is unsubstituted or substituted. Monocyclic heteroaryl includes, among others, pyrrolyl, thienyl, furyl, pyridinyl, pyranyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, thiazolyl, pyrazolyl, and oxazolyl. Bicyclic heteroaryl includes, but is not limited to, benzothiophenyl, benzofuryl, indolyl, quinolinyl, isoquinolinyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, quinazolinyl, azaindolyl, pyrazolopyrimidinyl, purinyl, pyrrolo[1,2-b]pyridazinyl, pyridazinyl, pyrazolididinyl, inrazolidinyl 1,2-a]pyridinyl, and pyrrolo[1,2-f][1,2,4]triazinyl.
In other embodiments of the compound of Formula I, R3 is -NHR3', -N(CHs)R3', -N(CH2CH3)R3', -N(CH(CH3)2)R3', or -OR3' , wherein R3' is unsubstituted or substituted heterocycloalkyl (non-limiting examples thereof include 4-NH piperidin-1-yl, 4-methyl piperidin-1-yl, 4-ethyl piperidin-1-yl, 4-isopropyl-piperidine -1-yl, and pyrrolidin-3-yl), unsubstituted or substituted monocyclic aryl, or unsubstituted or substituted monocyclic heteroaryl (including but not limited to pyrrolyl, thienyl, furyl, pyridinyl, pyranyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, thiazolyl, pyrazolyl, and oxazolyl). In one example, R3 is -O-aryl, meaning phenoxy. In another example, R3 is -O-(4-methyl)piperidin-1-yl or -O-(4-isopropyl)piperidin-1-yl.
[00144] In some embodiments of the compound of Formula I, R3 is one of the following fractions:



[00145] In some embodiments of the compound of Formula I, W1 is NR3, where R3 is hydrogen, unsubstituted or substituted C1-C10alkyl (which includes, among others, -CH3, -CH2CH3, n-propyl, isopropyl, n-butyl, tert-butyl, sec-butyl, pentyl, hexyl, and heptyl), or unsubstituted or substituted C3-C7cycloalkyl (which includes, among others, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl). In other embodiments of the compound of Formula I, R3 is unsubstituted or substituted heterocycloalkyl (which includes, but is not limited to, oxetanyl, tetrahydrofuranoyl, pyrrolidinyl, tetrahydropyranyl, piperidinyl, and piperazinyl), or unsubstituted or substituted C2-C10heteroalkyl (which includes, but is not limited to, , methoxyethoxy, methoxymethyl, and diethylaminoethyl). Alternatively, R3 is unsubstituted or substituted monocyclic heteroaryl (which includes, among others, pyrrolyl, thienyl, furyl, pyridinyl, pyranyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, thiazolyl, pyrazolyl, and oxazolyl) or unsubstituted or substituted monocyclic aryl.
[00146] Still in other modalities, W1 is C=O.
[00147] In some embodiments of the compound of Formula I, W2 is CR4. R4 can be, for example, hydrogen, or unsubstituted or substituted alkyl (including among others CH3, -CH2CH3, n-propyl, isopropyl, n-butyl, tert-butyl, sec-butyl, pentyl, hexyl, and heptyl). In other embodiments, R4 is unsubstituted or substituted alkenyl (including but not limited to unsubstituted or substituted C2-C5alkenyl such as, for example, vinyl, allyl, 1-methyl propen-1-yl, butenyl, or pentenyl) or unsubstituted or substituted alkynyl (including but not limited to unsubstituted or substituted C2-C5alkynyl such as acetylenyl, propargyl, butynyl, or pentynyl). Alternatively, R4 is unsubstituted or substituted aryl (including but not limited to monocyclic or bicyclic aryl) or unsubstituted or substituted arylalkyl (including but not limited to monocyclic or bicyclic aryl linked to alkyl wherein alkyl includes, but not limited to, CH3, -CH2CH3, n-propyl , isopropyl, n-butyl, sec-butyl, and pentyl). In some other embodiments, R4 is unsubstituted or substituted heteroaryl, including but not limited to monocyclic and bicyclic bicyclic heteroaryl heteroaryl. Monocyclic heteroaryl R4 includes, among others, pyrrolyl, thienyl, furyl, pyridinyl, pyranyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, thiazolyl, pyrazolyl, and oxazolyl. . Bicyclic heteroaryl R4 includes, but is not limited to, benzothiophenyl, benzofuryl, indolyl, quinolinyl, isoquinolinyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, quinazolinyl, azaindolyl, pyrazolopyrimidinyl, purinyl, pyrrolo[1,2-b]pyridazoylidinyl, pyrroloidinyl, pyrroloidinyl, pyrroloidinyl[1,2-b]pyridazoylidinyl, pyrroloinyl 1,2-a]pyridinyl, and pyrrolo[1,2-f][1,2,4]triazinyl.
[00148] The present invention also provides compounds of Formula I wherein R4 is unsubstituted or substituted heteroarylalkyl, including but not limited to bicyclic heteroaryl monocyclic and bicyclic heteroaryl as described above, which are linked to alkyl, which in turn includes, but not limited to, CH3, -CH2CH3, n-propyl, isopropyl, n-butyl, sec-butyl, and pentyl. In some embodiments, R4 is unsubstituted or substituted cycloalkyl (including but not limited to cyclopropyl, cyclobutyl, and cyclopentyl) or unsubstituted or substituted heteroalkyl (non-limiting examples include ethoxymethyl, methoxymethyl, and diethylaminomethyl). In some other embodiments, R4 is unsubstituted or substituted heterocycloalkyl which includes, among others, pyrrolidinyl, tetrahydrofuranoyl, piperidinyl, tetrahydropyranyl, thiazolidinyl, imidazolidinyl, morpholinyl, and piperazinyl. In yet other embodiments of the compounds of Formula I, R4 is unsubstituted or substituted alkoxy including but not limited to C1-C4alkoxy such as methoxy, ethoxy, propoxy or butoxy. R4 may further be unsubstituted or substituted heterocycloalkyloxy, including among others 4-NH-piperidin-1-yl-oxy, 4-methyl piperidin-1-yl-oxy, 4-ethyl piperidin-1-yl-oxy, 4-isopropyl- piperidin-1-yl-oxy, and pyrrolidin-3-yl-oxy. In other embodiments, R4 is unsubstituted or substituted amino, where substituted amino includes, among others, dimethylamino, diethylamino, diisopropylamino, N-methyl N-ethylamino, and dibutylamino. In some embodiments, R4 is unsubstituted or substituted acyl, unsubstituted or substituted acyloxy, unsubstituted or substituted C1-C4 acyloxy, unsubstituted or substituted alkoxycarbonyl, unsubstituted or substituted amido, or unsubstituted or substituted sulfonamido. In some embodiments, R4 is halo, which is -I, -F, -Cl, or -Br. In some embodiments, R4 is selected from the group consisting of cyano, hydroxy, nitro, phosphate, urea, or carbonate. Further contemplated are R4 being -CH3, -CH2CH3, n-propyl, isopropyl, n-butyl, tert-butyl, sec-butyl, pentyl, hexyl, heptyl, -OCH3, -OCH2CH3, or -CF3.
[00149] R4 of the compounds of Formula I, may further be NR'R'' where R' and R'' are taken together with nitrogen to form a cyclic moiety containing from 3 to 8 ring atoms. The cyclic moiety so formed may further include one or more heteroatoms which are selected from the group consisting of S, O, and N. The cyclic moiety so formed is unsubstituted or substituted, including but not limited to morpholinyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, 1,2 isothiazolidinyl, dioxide, and thiomorpholinyl. Other exemplary non-limiting cyclic fractions are as follows:

The invention also provides compounds of Formula I, wherein when R4 is a member of the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, heteroalkyl, heterocycloalkyl, heterocycloalkyloxy, aryl, arylalkyl, heteroaryl, heteroarylalkyl, acyl, alkoxy, amido, amino, sulfonamido, acyloxy, alkoxycarbonyl, and NR'R'' (wherein R' and R'' are taken together with nitrogen to form a cyclic moiety), then R4 is optionally substituted with one or more of the following substituents : alkyl, alkenyl, alkynyl, cycloalkyl, heteroalkyl, heterocycloalkyl, heterocycloalkyloxy, aryl, arylalkyl, heteroaryl, heteroarylalkyl, acyl, alkoxy, starch, amino,sulfonamido, acyloxy, alkoxycarbonyl, halo, cyano, hydroxy, nitro, phosphate, urea, carbonate , or NR'R'' where R' and R'' are taken together with nitrogen to form a cyclic fraction. Each of the above substituents may be further substituted with one or more substituents selected from the group consisting of alkyl, alkoxy, amido, amino, sulfonamido, acyloxy, alkoxycarbonyl, halo, cyano, hydroxy, nitro, oxo, phosphate, urea, and carbonate.
[00151] For example, the invention provides compounds wherein when R4 is alkyl, the alkyl is substituted with NR'R'' where R' and R'' are taken together with nitrogen to form a cyclic moiety. The cyclic moiety thus formed can be unsubstituted or substituted. Exemplary non-limiting cyclic moieties include but are not limited to morpholinyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, isothiazolidinyl 1,2, dioxide, and thiomorpholinyl. In other examples of the compounds of Formula I, when R4 is alkyl, the alkyl is substituted with heterocycloalkyl, which includes oxetanyl, azetidinyl, tetrahydrofuranoyl, pyrrolyl, tetrahydropyranyl, piperidinyl, morpholinyl, and piperazinyl. All of the above listed heterocycloalkyl substituents may be unsubstituted or substituted.
[00152] In still other examples of the compounds of Formula I, when R4 is alkyl, the alkyl is substituted by 5, 6, 7, 8, 9, or 10-membered monocyclic or bicyclic heteroaryl, which is unsubstituted or substituted. Monocyclic heteroaryl includes, among others, pyrrolyl, thienyl, furyl, pyridinyl, pyranyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, thiazolyl, pyrazolyl, and oxazolyl. Bicyclic heteroaryl includes but is not limited to benzothiophenyl, benzofuryl, indolyl, quinolinyl, isoquinolinyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, quinazolinyl, azaindolyl, pyrazolopyrimidinyl, purinyl, pyrrolo[1,2-b]pyridazoylidinyl, pyrolopyrimidine [1,2-a]pyridinyl, and pyrrolo[1,2-f][1,2,4]triazinyl.
[00153] In some embodiments of the compound of Formula I, W2is NR4, wherein R4is hydrogen, unsubstituted or substituted C1-C10alkyl (which includes, among others, -CH3, -CH2CH3, n-propyl, isopropyl, n-butyl, tert-butyl, sec-butyl, pentyl, hexyl, and heptyl), or unsubstituted or substituted C3-C7cycloalkyl (which includes, among others, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl). In other embodiments of the compound of Formula I, R4 is unsubstituted or substituted heterocycloalkyl (which includes, but is not limited to, oxetanyl, tetrahydrofuranoyl, pyrrolidinyl, tetrahydropyranyl, piperidinyl, and piperazinyl), or unsubstituted or substituted C2-C10heteroalkyl (which includes, but is not limited to, , methoxyethoxy, methoxymethyl, and diethylaminoethyl). Alternatively, R4 is unsubstituted or substituted monocyclic heteroaryl (which includes, among others, pyrrolyl, thienyl, furyl, pyridinyl, pyranyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, thiazolyl, pyrazolyl, and oxazolyl) or unsubstituted or substituted monocyclic aryl.
[00154] In some embodiments R3 and R4 taken together form a cyclic fraction. Said fraction may have, for example, from 3 to 8 ring atoms. The cyclic moiety so formed may further include one or more heteroatoms which are selected from the group consisting of S, O, and N. The cyclic moiety so formed is unsubstituted or substituted. In some embodiments, the substituent is C1-C10alkyl (which includes, but is not limited to, -CH3, -CH2CH3, n-propyl, isopropyl, n-butyl, tert-butyl, sec-butyl, pentyl, hexyl, and heptyl), or C3-C7cycloalkyl (which includes, but is not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl); heterocycloalkyl (which includes, but is not limited to, oxetanyl, tetrahydrofuranoyl, pyrrolidinyl, tetrahydropyranyl, piperidinyl, and piperazinyl), C2-C10heteroalkyl (which includes, but is not limited to, methoxyethoxy, methoxymethyl, and diethylaminoethyl); monocyclic heteroaryl (which includes, but is not limited to, pyrrolyl, thienyl, furyl, pyridinyl, pyranyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, thiazolyl, pyrazolyl, and oxazolyl) or unsubstituted or substituted monocyclic aryl. The cyclic moiety can have one or more substituents, which can be the same or different.
[00155] In some embodiments, the cyclic moiety formed by R3 and R4 is substituted with at least one of the following substituents:


[00156] In some embodiments of the compound of Formula I, W3 is CR5. R5 can be, for example, hydrogen, or unsubstituted or substituted alkyl (including but not limited to CH3, -CH2CH3, n-propyl, isopropyl, n-butyl, tert-butyl, sec-butyl, pentyl, hexyl, and heptyl). In one embodiment, R 5 is H. In other embodiments, R 5 is unsubstituted or substituted alkenyl (including but not limited to unsubstituted or substituted C 2 -C 5 alkenyl such as, for example, vinyl, allyl, 1-methyl propen-1-yl, butenyl, or pentenyl) or unsubstituted or substituted alkynyl (including but not limited to unsubstituted or substituted C2-C5alkynyl such as acetylenyl, propargyl, butynyl, or pentynyl). Alternatively, R5 is unsubstituted or substituted aryl (including but not limited to monocyclic or bicyclic aryl) or unsubstituted or substituted arylalkyl (including but not limited to monocyclic or bicyclic aryl linked to alkyl wherein alkyl includes, but not limited to, CH3, -CH2CH3, n- propyl, isopropyl, n-butyl, sec-butyl, and pentyl). In some other embodiments, R5 is unsubstituted or substituted heteroaryl, including but not limited to monocyclic and bicyclic bicyclic heteroaryl heteroaryl. Monocyclic heteroaryl R5 includes, among others, pyrrolyl, thienyl, furyl, pyridinyl, pyranyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, thiazolyl, pyrazolyl, and oxazolyl. Bicyclic heteroaryl R5 includes, but is not limited to, benzothiophenyl, benzofuryl, indolyl, quinolinyl, isoquinolinyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, quinazolinyl, azaindolyl, pyrazolopyrimidinyl, purinyl, pyrrolo[1,2-b]pyridazoylidinyl, pyrroloidinyl, pyrroloidinyl, pyrroloidinyl[1,2-b]pyridazoylidinyl, pyrroloinyl 1,2-a]pyridinyl, and pyrrolo[1,2-f][1,2,4]triazinyl.
[00157] In some embodiments the compound of Formula I, W3 is N or NR5, wherein R5 is hydrogen, unsubstituted or substituted C1-C10alkyl (which includes, among others, -CH3, -CH2CH3, n-propyl, isopropyl, n - butyl, tert-butyl, sec-butyl, pentyl, hexyl, and heptyl), or unsubstituted or substituted C3-C7cycloalkyl (which includes, among others, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl). In other embodiments of the compound of Formula I, R 5 is unsubstituted or substituted heterocycloalkyl (which includes, but is not limited to, oxetanyl, tetrahydrofuranoyl, pyrrolidinyl, tetrahydropyranyl, piperidinyl, and piperazinyl), or unsubstituted or substituted C 2 -C 10 heteroalkyl (which includes, but is not limited to, , methoxyethoxy, methoxymethyl, and diethylaminoethyl). Alternatively, R5 is unsubstituted or substituted monocyclic heteroaryl (which includes, but is not limited to, pyrrolyl, thienyl, furyl, pyridinyl, pyranyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, thiazolyl, pyrazolyl, and oxazolyl) or unsubstituted or substituted monocyclic aryl.
[00158] In some embodiments of the compound of Formula I, W4 is CR6. R6 can be, for example, hydrogen, or unsubstituted or substituted alkyl (including among others CH3, -CH2CH3, n-propyl, isopropyl, n-butyl, tert-butyl, sec-butyl, pentyl, hexyl, and heptyl). In one embodiment, R 6 is H. In other embodiments, R 6 is unsubstituted or substituted alkenyl (including but not limited to unsubstituted or substituted C 2 -C 5 alkenyl such as, for example, vinyl, allyl, 1-methyl propen-1-yl, butenyl, or pentenyl) or unsubstituted or substituted alkynyl (including but not limited to unsubstituted or substituted C2-C5alkynyl such as acetylenyl, propargyl, butynyl, or pentynyl). Alternatively, R6 is unsubstituted or substituted aryl (including, but not limited to, monocyclic or bicyclic aryl) or unsubstituted or substituted arylalkyl (including, but not limited to, alkyl-linked monocyclic or bicyclic aryl wherein alkyl includes, but not limited to, CH3, -CH2CH3 , n-propyl, isopropyl, n-butyl, sec-butyl, and pentyl). In some other embodiments, R6 is unsubstituted or substituted heteroaryl, including, but not limited to, monocyclic and bicyclic bicyclic heteroaryl heteroaryl. Monocyclic heteroaryl R6 includes, among others, pyrrolyl, thienyl, furyl, pyridinyl, pyranyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, thiazolyl, pyrazolyl, and oxazolyl. Bicyclic heteroaryl R6 includes, but is not limited to, benzothiophenyl, benzofuryl, indolyl, quinolinyl, isoquinolinyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, quinazolinyl, azaindolyl, pyrazolopyrimidinyl, purinyl, pyrrolo[1,2-b]pyridazoylidinyl, pyrroloidinyl, pyrroloidinyl, pyrroloidinyl[1,2-b]pyridazoylidinyl, pyrroloinyl 1,2-a]pyridinyl, and pyrrolo[1,2-f][1,2,4]triazinyl.
[00159] In some embodiments of the compound of Formula I, W4 is N or NR6, wherein R6 is hydrogen, unsubstituted or substituted C1-C10alkyl (which includes, among others, -CH3, -CH2CH3, n-propyl, isopropyl, n- butyl, tert-butyl, sec-butyl, pentyl, hexyl, and heptyl), or unsubstituted or substituted C3-C7cycloalkyl (which includes, among others, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl). In other embodiments of the compound of Formula I, R6 is unsubstituted or substituted heterocycloalkyl (which includes, but is not limited to, oxetanyl, tetrahydrofuranoyl, pyrrolidinyl, tetrahydropyranyl, piperidinyl, and piperazinyl), or unsubstituted or substituted C2-C10heteroalkyl (which includes, but is not limited to, , methoxyethoxy, methoxymethyl, and diethylaminoethyl). Alternatively, R6 is unsubstituted or substituted monocyclic heteroaryl (which includes, among others, pyrrolyl, thienyl, furyl, pyridinyl, pyranyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, thiazolyl, pyrazolyl, and oxazolyl) or unsubstituted or substituted monocyclic aryl.
[00160] In other embodiments, W4 is C=O.
In some embodiments of the compound of Formula I, W5 is N. In other embodiments of the compound of Formula I, W5 is CR7. R7 can be, for example, hydrogen, or unsubstituted or substituted alkyl (including among others CH3, -CH2CH3, n-propyl, isopropyl, n-butyl, tert-butyl, sec-butyl, pentyl, hexyl, and heptyl). In one embodiment, R7 is H. In other embodiments, R7 is unsubstituted or substituted alkenyl (including but not limited to unsubstituted or substituted C2-C5alkenyl such as, for example, vinyl, allyl, 1-methyl propen-1-yl, butenyl, or pentenyl) or unsubstituted or substituted alkynyl (including but not limited to unsubstituted or substituted C2-C5alkynyl such as acetylenyl, propargyl, butynyl, or pentynyl). Alternatively, R7 is unsubstituted or substituted aryl (including, but not limited to, monocyclic or bicyclic aryl) or unsubstituted or substituted arylalkyl (including, but not limited to, alkyl-linked monocyclic or bicyclic aryl wherein alkyl includes, but not limited to, CH3, -CH2CH3 , n-propyl, isopropyl, n-butyl, sec-butyl, and pentyl). In some other embodiments, R7 is unsubstituted or substituted heteroaryl, including, but not limited to, monocyclic and bicyclic heteroaryl. Monocyclic heteroaryl R7 includes, among others, pyrrolyl, thienyl, furyl, pyridinyl, pyranyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, thiazolyl, pyrazolyl, and oxazolyl. Bicyclic heteroaryl R7 includes, but is not limited to, benzothiophenyl, benzofuryl, indolyl, quinolinyl, isoquinolinyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, quinazolinyl, azaindolyl, pyrazolopyrimidinyl, purinyl, pyrrolo[1,2-b]pyridazoylidinyl, pyrroloidinyl, pyrroloidinyl, pyrroloidinyl[1,2-b]pyridazolidinyl, pyrroloinyl 1,2-a]pyridinyl, and pyrrolo[1,2-f][1,2,4]triazinyl.
In some embodiments of the compound of Formula I, W6 is N. In other embodiments of the compound of Formula I, W6 is CR8. R8 can be, for example, hydrogen, or unsubstituted or substituted alkyl (including but not limited to CH3, -CH2CH3, n-propyl, isopropyl, n-butyl, tert-butyl, sec-butyl, pentyl, hexyl, and heptyl). In one embodiment, R 8 is H. In other embodiments, R 8 is unsubstituted or substituted alkenyl (including but not limited to unsubstituted or substituted C 2 -C 5 alkenyl such as, for example, vinyl, allyl, 1-methyl propen-1-yl, butenyl, or pentenyl) or unsubstituted or substituted alkynyl (including but not limited to unsubstituted or substituted C2-C5alkynyl such as acetylenyl, propargyl, butynyl, or pentynyl). Alternatively, R8 is unsubstituted or substituted aryl (including, but not limited to, monocyclic or bicyclic aryl) or unsubstituted or substituted arylalkyl (including, but not limited to, alkyl-linked monocyclic or bicyclic aryl wherein alkyl includes, but not limited to, CH3, -CH2CH3 , n-propyl, isopropyl, n-butyl, sec-butyl, and pentyl). In some other embodiments, R8 is unsubstituted or substituted heteroaryl, including, but not limited to, monocyclic and bicyclic heteroaryl. Monocyclic heteroaryl R8 includes, among others, pyrrolyl, thienyl, furyl, pyridinyl, pyranyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, thiazolyl, pyrazolyl, and oxazolyl. Bicyclic heteroaryl R8 includes, but is not limited to, benzothiophenyl, benzofuryl, indolyl, quinolinyl, isoquinolinyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, quinazolinyl, azaindolyl, pyrazolopyrimidinyl, purinyl, pyrrolo[1,2-b]pyridazoylidinyl, pyrroloidinyl, pyrroloidinyl, pyrroloidinyl[1,2-b]pyridazolidinyl, pyrroloinyl 1,2-a]pyridinyl, and pyrrolo[1,2-f][1,2,4]triazinyl.

In another aspect, the invention provides compounds of Subformula Ia and Ib, where W1 is CR3, W2 is CR4, W3 is CR5, W4 is N, W5 is CR7, and W6 is CR8. In one embodiment, R1, R3, R4, R5, R7 and R8 are hydrogens. In another embodiment, R1, R4, R5, R7 and R8 are hydrogens and R3 is alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, alkoxy, heterocycloalkyloxy, starch, amino, acyl, acyloxy, alkoxycarbonyl, sulfonamido, halo, cyano, hydroxy, nitro, phosphate, urea, carbonate, or NR'R'' where R' and R'' are taken together with nitrogen to form a cyclic moiety. R3 can be, for example, hydrogen, unsubstituted or substituted alkyl (including among others CH3, -CH2CH3, n-propyl, isopropyl, n-butyl, tert-butyl, sec-butyl, pentyl, hexyl, and heptyl). In other embodiments, R3 is unsubstituted or substituted alkenyl (including but not limited to unsubstituted or substituted C2-C5alkenyl such as, for example, vinyl, allyl, 1-methyl propen-1-yl, butenyl, or pentenyl) or unsubstituted or substituted alkynyl (including but not limited to unsubstituted or substituted C2-C5alkynyl such as acetylenyl, propargyl, butynyl, or pentynyl). Alternatively, R3 is unsubstituted or substituted aryl (including, but not limited to, monocyclic or bicyclic aryl) or unsubstituted or substituted arylalkyl (including, but not limited to, alkyl-linked monocyclic or bicyclic aryl wherein alkyl includes, but not limited to, CH3, -CH2CH3 , n-propyl, isopropyl, n-butyl, sec-butyl, and pentyl). In some other embodiments, R3 is unsubstituted or substituted heteroaryl, including, but not limited to, monocyclic and bicyclic heteroaryl. Monocyclic heteroaryl R3 includes, among others, pyrrolyl, thienyl, furyl, pyridinyl, pyranyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, thiazolyl, pyrazolyl, and oxazolyl. Bicyclic heteroaryl R3 includes, but is not limited to, benzothiophenyl, benzofuryl, indolyl, quinolinyl, isoquinolinyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, quinazolinyl, azaindolyl, pyrazolopyrimidinyl, purinyl, pyrrolo[1,2-b]pyridazoylidinyl, pyrroloinyl, pyrroloidinyl, pyrroloidinyl[1,2-b]pyridazoylidinyl, pyrroloinyl 1,2-a]pyridinyl, and pyrrolo[1,2-f][1,2,4]triazinyl. The present invention also provides compounds of Formula I wherein R3 is unsubstituted or substituted heteroarylalkyl, including, but not limited to, monocyclic and bicyclic heteroaryl as described above, which are linked to alkyl, which in turn includes, but not limited to, CH3, - CH2CH3, n-propyl, isopropyl, n-butyl, sec-butyl, and pentyl. In some embodiments, R3 is unsubstituted or substituted cycloalkyl (including but not limited to cyclopropyl, cyclobutyl, and cyclopentyl) or unsubstituted or substituted heteroalkyl (non-limiting examples include ethoxymethyl, methoxymethyl, and diethylaminomethyl). In some other embodiments, R3 is unsubstituted or substituted heterocycloalkyl which includes, among others, pyrrolidinyl, tetrahydrofuranoyl, piperidinyl, tetrahydropyranyl, thiazolidinyl, imidazolidinyl, morpholinyl, and piperazinyl. In yet other embodiments of the compounds of Formula I, R3 is unsubstituted or substituted alkoxy including but not limited to C1-C4alkoxy such as methoxy, ethoxy, propoxy or butoxy. R3 may further be unsubstituted or substituted heterocycloalkyloxy, including among others 4-NH-piperidin-1-yl-oxy, 4-methyl piperidin-1-yl-oxy, 4-ethyl piperidin-1-yl-oxy, 4-isopropyl- piperidin-1-yl-oxy, and pyrrolidin-3-yl-oxy. In other embodiments, R3 is unsubstituted or substituted amino, where substituted amino includes, among others, dimethylamino, diethylamino, diisopropylamino, N-methyl N-ethylamino, and dibutylamino. In some embodiments, R3 is unsubstituted or substituted acyl, unsubstituted or substituted acyloxy, unsubstituted or substituted C1 -C4 acyloxy, unsubstituted or substituted alkoxycarbonyl, unsubstituted or substituted amido, or unsubstituted or substituted sulfonamido. In other embodiments, R3 is halo, which is -I, -F, -Cl, or -Br. In some embodiments, R3 is selected from the group consisting of cyano, hydroxy, nitro, phosphate, urea, and carbonate. Further contemplated are R3 being -CH3, -CH2CH3, n-propyl, isopropyl, n-butyl, tert-butyl, sec-butyl, pentyl, hexyl, heptyl, -OCH3, -OCH2CH3, or -CF3. In some embodiments R3 may further be NR'R'' where R' and R'' are taken together with nitrogen to form a cyclic moiety containing 3 to 8 ring atoms. The cyclic moiety so formed may further include one or more heteroatoms which are selected from the group consisting of S, O, and N. The cyclic moiety so formed is unsubstituted or substituted, including but not limited to morpholinyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, 1,2 isothiazolidinyl, dioxide, and thiomorpholinyl. Other exemplary non-limiting cyclic fractions are as follows:

[00164] In another aspect, the invention provides compounds of Subformula Ic and Id, where W1 is N, W2 is CR4, W3 is CR5, W4 is N, W5 is CR7, and W6 is CR8. In one embodiment, R1, R4, R5, R7 and R8 are hydrogen. In another embodiment, R1, R5, R7 and R8 are hydrogen and R4 is alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, alkoxy, heterocycloalkyloxy, starch, amino, acyl, acyloxy, alkoxycarbonyl, sulfonamido, halo, cyano, hydroxy, nitro, phosphate, urea, carbonate, or NR'R'' where R' and R'' are taken together with nitrogen to form a cyclic moiety. R4 can be, for example, hydrogen, unsubstituted or substituted alkyl (including but not limited to CH3, -CH2CH3, n-propyl, isopropyl, n-butyl, tert-butyl, sec-butyl, pentyl, hexyl, and heptyl). In other embodiments, R4 is unsubstituted or substituted alkenyl (including but not limited to unsubstituted or substituted C2-C5alkenyl such as, for example, vinyl, allyl, 1-methyl propen-1-yl, butenyl, or pentenyl) or unsubstituted or substituted alkynyl (including but not limited to unsubstituted or substituted C2-C5alkynyl such as acetylenyl, propargyl, butynyl, or pentynyl). Alternatively, R4 is unsubstituted or substituted aryl (including, but not limited to, monocyclic or bicyclic aryl) or unsubstituted or substituted arylalkyl (including, but not limited to, alkyl-linked monocyclic or bicyclic aryl wherein alkyl includes, but not limited to, CH3, -CH2CH3 , n-propyl, isopropyl, n-butyl, sec-butyl, and pentyl). In some other embodiments, R4 is unsubstituted or substituted heteroaryl, including, but not limited to, monocyclic and bicyclic heteroaryl. Monocyclic heteroaryl R4 includes, among others, pyrrolyl, thienyl, furyl, pyridinyl, pyranyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, thiazolyl, pyrazolyl, and oxazolyl. Bicyclic heteroaryl R4 includes, but is not limited to, benzothiophenyl, benzofuryl, indolyl, quinolinyl, isoquinolinyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, quinazolinyl, azaindolyl, pyrazolopyrimidinyl, purinyl, pyrrolo[1,2-b]pyridazoylidinyl, pyrroloidinyl, pyrroloidinyl, pyrroloidinyl[1,2-b]pyridazoylidinyl, pyrroloinyl 1,2-a]pyridinyl, and pyrrolo[1,2-f][1,2,4]triazinyl. The present invention also provides compounds of Formula I wherein R4 is unsubstituted or substituted heteroarylalkyl, including, but not limited to, monocyclic and bicyclic heteroaryl as described above, which are linked to alkyl, which in turn includes, but is not limited to, CH3, - CH2CH3, n-propyl, isopropyl, n-butyl, sec-butyl, and pentyl. In some embodiments, R4 is unsubstituted or substituted cycloalkyl (including but not limited to cyclopropyl, cyclobutyl, and cyclopentyl) or unsubstituted or substituted heteroalkyl (non-limiting examples include ethoxymethyl, methoxymethyl, and diethylaminomethyl). In some other embodiments, R4 is unsubstituted or substituted heterocycloalkyl which includes, among others, pyrrolidinyl, tetrahydrofuranoyl, piperidinyl, tetrahydropyranyl, thiazolidinyl, imidazolidinyl, morpholinyl, and piperazinyl. In yet other embodiments of the compounds of Formula I, R4 is unsubstituted or substituted alkoxy including but not limited to C1-C4alkoxy such as methoxy, ethoxy, propoxy or butoxy. R3 may further be unsubstituted or substituted heterocycloalkyloxy, including among others 4-NH-piperidin-1-yl-oxy, 4-methyl piperidin-1-yl-oxy, 4-ethyl piperidin-1-yl-oxy, 4-isopropyl- piperidin-1-yl-oxy, and pyrrolidin-3-yl-oxy. In other embodiments, R4 is unsubstituted or substituted amino, where substituted amino includes, among others, dimethylamino, diethylamino, diisopropylamino, N-methyl N-ethylamino, and dibutylamino. In some embodiments, R4 is unsubstituted or substituted acyl, unsubstituted or substituted acyloxy, unsubstituted or substituted C1 -C4 acyloxy, unsubstituted or substituted alkoxycarbonyl, unsubstituted or substituted amido, or unsubstituted or substituted sulfonamido. In other embodiments, R4 is halo, which is -I, -F, -Cl, or -Br. In some embodiments, R4 is selected from the group consisting of cyano, hydroxy, nitro, phosphate, urea, and carbonate. Further contemplated are R4 being -CH3, -CH2CH3, n-propyl, isopropyl, n-butyl, tert-butyl, sec-butyl, pentyl, hexyl, heptyl, -OCH3, -OCH2CH3, or -CF3.
[00165] In some embodiments R4 may further be NR'R'' where R' and R'' are taken together with nitrogen to form a cyclic moiety containing from 3 to 8 ring atoms. The cyclic moiety so formed may further include one or more heteroatoms which are selected from the group consisting of S, O, and N. The cyclic moiety so formed is unsubstituted or substituted, including but not limited to morpholinyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, 1,2 isothiazolidinyl, dioxide, and thiomorpholinyl. Other exemplary non-limiting cyclic fractions are as follows:

In another aspect, the invention provides compounds of Subformula Ie and If, where W1 is CR3, W2 is N, W3 is CR5, W4 is N, W5 is CR7, and W6 is CR8.
[00167] In one embodiment, R1, R3, R5, R7 and R8 are hydrogens. In another embodiment, R1, R5, R7 and R8 are hydrogens and R3 is alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, alkoxy, heterocycloalkyloxy, starch, amino, acyl, acyloxy, alkoxycarbonyl, sulfonamido, halo, cyano, hydroxy, nitro, phosphate, urea, carbonate, or NR'R'' where R' and R'' are taken together with nitrogen to form a cyclic moiety. R3 can be, for example, hydrogen, unsubstituted or substituted alkyl (including but not limited to CH3, -CH2CH3, n-propyl, isopropyl, n-butyl, tert-butyl, sec-butyl, pentyl, hexyl, and heptyl). In other embodiments, R3 is unsubstituted or substituted alkenyl (including but not limited to unsubstituted or substituted C2-C5alkenyl such as, for example, vinyl, allyl, 1-methyl propen-1-yl, butenyl, or pentenyl) or unsubstituted or substituted alkynyl (including but not limited to unsubstituted or substituted C2-C5alkynyl such as acetylenyl, propargyl, butynyl, or pentynyl). Alternatively, R3 is unsubstituted or substituted aryl (including, but not limited to, monocyclic or bicyclic aryl) or unsubstituted or substituted arylalkyl (including, but not limited to, alkyl-linked monocyclic or bicyclic aryl wherein alkyl includes, but not limited to, CH3, - CH2CH3, n-propyl, isopropyl, n-butyl, sec-butyl, and pentyl). In some other embodiments, R3 is unsubstituted or substituted heteroaryl, including, but not limited to, monocyclic and bicyclic heteroaryl. Monocyclic heteroaryl R3 includes, among others, pyrrolyl, thienyl, furyl, pyridinyl, pyranyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, thiazolyl, pyrazolyl, and oxazolyl. Bicyclic heteroaryl R3 includes, but is not limited to, benzothiophenyl, benzofuryl, indolyl, quinolinyl, isoquinolinyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, quinazolinyl, azaindolyl, pyrazolopyrimidinyl, purinyl, pyrrolo[1,2-b]pyridazoylidinyl, pyrroloinyl, pyrroloidinyl, pyrroloidinyl[1,2-b]pyridazoylidinyl, pyrroloinyl 1,2-a]pyridinyl, and pyrrolo[1,2-f][1,2,4]triazinyl. The present invention also provides compounds of Formula I wherein R3 is unsubstituted or substituted heteroarylalkyl, including, but not limited to, monocyclic and bicyclic heteroaryl as described above, which are linked to alkyl, which in turn includes, but not limited to, CH3, -CH2CH3 , n-propyl, isopropyl, n-butyl, sec-butyl, and pentyl. In some embodiments, R3 is unsubstituted or substituted cycloalkyl (including but not limited to cyclopropyl, cyclobutyl, and cyclopentyl) or unsubstituted or substituted heteroalkyl (non-limiting examples include ethoxymethyl, methoxymethyl, and diethylaminomethyl). In some other embodiments, R3 is unsubstituted or substituted heterocycloalkyl which includes, among others, pyrrolidinyl, tetrahydrofuranoyl, piperidinyl, tetrahydropyranyl, thiazolidinyl, imidazolidinyl, morpholinyl, and piperazinyl. In yet other embodiments of the compounds of Formula I, R3 is unsubstituted or substituted alkoxy including but not limited to C1-C4alkoxy such as methoxy, ethoxy, propoxy or butoxy. R3 may further be unsubstituted or substituted heterocycloalkyloxy, including among others 4-NH-piperidin-1-yl-oxy, 4-methyl piperidin-1-yl-oxy, 4-ethyl piperidin-1-yl-oxy, 4-isopropyl- piperidin-1-yl-oxy, and pyrrolidin-3-yl-oxy. In other embodiments, R3 is unsubstituted or substituted amino, where substituted amino includes, among others, dimethylamino, diethylamino, diisopropylamino, N-methyl N-ethylamino, and dibutylamino. In some embodiments, R3 is unsubstituted or substituted acyl, unsubstituted or substituted acyloxy, unsubstituted or substituted C1 -C4 acyloxy, unsubstituted or substituted alkoxycarbonyl, unsubstituted or substituted amido, or unsubstituted or substituted sulfonamido. In other embodiments, R3 is halo, which is -I, -F, -Cl, or -Br. In some embodiments, R3 is selected from the group consisting of cyano, hydroxy, nitro, phosphate, urea, and carbonate. Further contemplated are R3 being -CH3, -CH2CH3, n-propyl, isopropyl, n-butyl, tert-butyl, sec-butyl, pentyl, hexyl, heptyl, -OCH3, -OCH2CH3, or -CF3. In some embodiments R3 may further be NR'R'' where R' and R'' are taken together with nitrogen to form a cyclic moiety containing 3 to 8 ring atoms. The cyclic moiety so formed may further include one or more heteroatoms which are selected from the group consisting of S, O, and N. The cyclic moiety so formed is unsubstituted or substituted, including but not limited to morpholinyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, 1,2 isothiazolidinyl, dioxide, and thiomorpholinyl. Other exemplary non-limiting cyclic fractions are as follows:

In some embodiments, the R 3 , R 4 , R 5 , or R 6 substituents can be any of the substituents shown in Table 1: Table 1. R 3 , R 4 , R 5 , R 6 moieties of the compounds of Formula I each independently include, among others, the following:



[00169] In another aspect, the invention provides a compound of Formula II:
or the pharmaceutically acceptable salts thereof, where: X is O or S or N; W1is S, N, NR3 or CR3, W2is N or CR4, W3is S, N or CR5, W4is N or C, and W7is N or C, where no more than two N atoms and no more than two C=O groups are adjacent; W5 is N or CR7; W6 is N or CR8; R1 and R2 are independently hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, alkoxy, heterocycloalkyloxy, starch, amino, acyl, acyloxy, alkoxycarbonyl, sulfonamido, halo, cyano, hydroxy, nitro, phosphate, urea, carbonate, or NR'R'' where R' and R'' are taken together with nitrogen to form a cyclic fraction; R3 and R4 are independently hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, alkoxy, heterocycloalkyloxy, amido, amino, acyl, acyloxy, alkoxycarbonyl, sulfonamido, halo, cyano, hydroxy, nitro , phosphate, urea, carbonate, or NR'R'' where R' and R'' are taken together with nitrogen to form a cyclic fraction; or R3 and R4 taken together form a cyclic moiety; and R5, R7, and R8 are independently hydrogen, alkyl, heteroarylalkyl, alkoxy, heterocycloalkyloxy, amido, amino, acyl, acyloxy, alkoxycarbonyl, sulfonamido, halo, cyano, hydroxy, nitro, phosphate, urea, carbonate, or NR'R' in that R' and R'' are taken together with nitrogen to form a cyclic fraction.
[00170] In some embodiments, the compound of Formula II exists as a tautomer, and such tautomers are contemplated by the present invention.
[00171] In some embodiments, the compound of Formula II has the formula:

[00172] In still other embodiments, W1 is CR3, W2 is CR4, W3 is N, W4 is N, W5 is CR7, and W6 is CR8. In other embodiments, W1 is CR3, W2 is CR4, W3 is N, W4 is N, W5 is CR7, and W6 is CR8. In other embodiments, W1 is CR3, W2 is CR4, W3 is N, W4 is N, W5 is N, and W6 is CR8. In still other embodiments, W1 is NR3, W2 is CR4, W3 is N, W4 is C, W5 is CR7, and W6 is CR8. In other embodiments, W1 is S, W2 is CR4, W3 is N, W4 is C, W5 is CR7, and W6 is CR8. In other embodiments, W1 is CR3, W2 is CR4, W3 is S, W4 is C, W5 is N, and W6 is N.
[00173] In other embodiments, a compound of Formula II is a compound according to one of the formulas:

[00174] In some embodiments, X is O. In other embodiments, X is S.
[00175] In some embodiments, R1 is hydrogen. In other embodiments, R1 is alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, alkoxy, heterocycloalkyloxy, starch, amino, acyl, acyloxy, alkoxycarbonyl, sulfonamido, halo, cyano, hydroxy,nitro, phosphate , urea, carbonate, or NR'R", where R' and R'' are taken together with nitrogen to form a cyclic fraction.
[00176] In some embodiments, R2 is hydrogen. In other embodiments, R2 is, for example, unsubstituted or substituted alkyl (including but not limited to CH3, -CH2CH3, n-propyl, isopropyl, n-butyl, tert-butyl, sec-butyl, pentyl, hexyl, and heptyl). In other embodiments, R2 is unsubstituted or substituted alkenyl (including but not limited to unsubstituted or substituted C2-C5alkenyl such as, for example, vinyl, allyl, 1-methyl propen-1-yl, butenyl, or pentenyl) or unsubstituted or substituted alkynyl (including but not limited to unsubstituted or substituted C2-C5alkynyl such as acetylenyl, propargyl, butynyl, or pentynyl). Alternatively, R2 is unsubstituted or substituted aryl (including, but not limited to, monocyclic or bicyclic aryl) or unsubstituted or substituted arylalkyl (including, but not limited to, alkyl-linked monocyclic or bicyclic aryl wherein alkyl includes, but not limited to, CH3, - CH2CH3, n-propyl, isopropyl, n-butyl, sec-butyl, and pentyl). In some other embodiments, R2 is unsubstituted or substituted heteroaryl, including, but not limited to, monocyclic and bicyclic heteroaryl. Monocyclic heteroaryl R2 includes, among others, pyrrolyl, thienyl, furyl, pyridinyl, pyranyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, thiazolyl, pyrazolyl, and oxazolyl. Bicyclic heteroaryl R2 includes, but is not limited to, benzothiophenyl, benzofuryl, indolyl, quinolinyl, isoquinolinyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, quinazolinyl, azaindolyl, pyrazolopyrimidinyl, purinyl, pyrrolo[1,2-b]pyridazoylidinyl, pyrroloidinyl, pyrroloidinyl, pyrroloidinyl[1,2-b]pyridazoylidinyl, pyrroloinyl 1,2-a]pyridinyl, and pyrrolo[1,2-f][1,2,4]triazinyl. The present invention also provides compounds wherein R2 is unsubstituted or substituted heteroarylalkyl, including, but not limited to, monocyclic and bicyclic heteroaryl as described above, which are linked to alkyl, which in turn includes, but not limited to, CH3, -CH2CH3, n- propyl, isopropyl, n-butyl, sec-butyl, and pentyl. In some embodiments, R2 is unsubstituted or substituted cycloalkyl (including but not limited to cyclopropyl, cyclobutyl, and cyclopentyl) or unsubstituted or substituted heteroalkyl (non-limiting examples include ethoxymethyl, methoxymethyl, and diethylaminomethyl). In some other embodiments, R2 is unsubstituted or substituted heterocycloalkyl which includes, among others, pyrrolidinyl, tetrahydrofuranoyl, piperidinyl, tetrahydropyranyl, thiazolidinyl, imidazolidinyl, morpholinyl, and piperazinyl. In yet other embodiments of the compounds of Formula II, R 2 is unsubstituted or substituted alkoxy including but not limited to C 1 -C 4 alkoxy such as methoxy, ethoxy, propoxy or butoxy. R2 may further be unsubstituted or substituted heterocycloalkyloxy, including among others 4-NH-piperidin-1-yl-oxy, 4-methyl piperidin-1-yl-oxy, 4-ethyl piperidin-1-yl-oxy, 4-isopropyl- piperidin-1-yl-oxy, and pyrrolidin-3-yl-oxy. In other embodiments, R2 is unsubstituted or substituted amino, where substituted amino includes, among others, dimethylamino, diethylamino, diisopropylamino, N-methyl N-ethylamino, and dibutylamino. In some embodiments, R2 is unsubstituted or substituted acyl, unsubstituted or substituted acyloxy, unsubstituted or substituted C1-C4 acyloxy, unsubstituted or substituted alkoxycarbonyl, unsubstituted or substituted amido, or unsubstituted or substituted sulfonamido. In other embodiments, R2 is halo, which is -I, -F, -Cl, or -Br. In some embodiments, R2 is selected from the group consisting of cyano, hydroxy, nitro, phosphate, urea, and carbonate. Further contemplated are R2 being -CH3, -CH2CH3, n-propyl, isopropyl, n-butyl, tert-butyl, sec-butyl, pentyl, hexyl, heptyl, -OCH3, -OCH2CH3, or -CF3.
[00177] In some embodiments of the compound of Formula II, W1 is CR3. R3 can be, for example, hydrogen, unsubstituted or substituted alkyl (including but not limited to CH3, -CH2CH3, n-propyl, isopropyl, n-butyl, tert-butyl, sec-butyl, pentyl, hexyl, and heptyl). In other embodiments, R3 is unsubstituted or substituted alkenyl (including but not limited to unsubstituted or substituted C2-C5alkenyl such as, for example, vinyl, allyl, 1-methyl propen-1-yl, butenyl, or pentenyl) or unsubstituted or substituted alkynyl (including but not limited to unsubstituted or substituted C2-C5alkynyl such as acetylenyl, propargyl, butynyl, or pentynyl). Alternatively, R3 is unsubstituted or substituted aryl (including, but not limited to, monocyclic or bicyclic aryl) or unsubstituted or substituted arylalkyl (including, but not limited to, alkyl-linked monocyclic or bicyclic aryl wherein alkyl includes, but not limited to, CH3, -CH2CH3 , n-propyl, isopropyl, n-butyl, sec-butyl, and pentyl). In some other embodiments, R3 is unsubstituted or substituted heteroaryl, including, but not limited to, monocyclic and bicyclic heteroaryl. Monocyclic heteroaryl R3 includes, among others, pyrrolyl, thienyl, furyl, pyridinyl, pyranyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, thiazolyl, pyrazolyl, and oxazolyl. Bicyclic heteroaryl R3 includes, but is not limited to, benzothiophenyl, benzofuryl, indolyl, quinolinyl, isoquinolinyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, quinazolinyl, azaindolyl, pyrazolopyrimidinyl, purinyl, pyrrolo[1,2-b]pyridazoylidinyl, pyrroloinyl, pyrroloidinyl, pyrroloidinyl[1,2-b]pyridazoylidinyl, pyrroloinyl 1,2-a]pyridinyl, and pyrrolo[1,2-f][1,2,4]triazinyl. The present invention also provides compounds of Formula II wherein R3 is unsubstituted or substituted heteroarylalkyl, including, but not limited to, monocyclic and bicyclic bicyclic heteroaryl heteroaryl as described above, which are linked to alkyl, which in turn includes, but not limited to, CH3, - CH2CH3, n-propyl, isopropyl, n-butyl, sec-butyl, and pentyl. In some embodiments, R3 is unsubstituted or substituted cycloalkyl (including but not limited to cyclopropyl, cyclobutyl, and cyclopentyl) or unsubstituted or substituted heteroalkyl (non-limiting examples include ethoxymethyl, methoxymethyl, and diethylaminomethyl). In some other embodiments, R3 is unsubstituted or substituted heterocycloalkyl which includes, among others, pyrrolidinyl, tetrahydrofuranoyl, piperidinyl, tetrahydropyranyl, thiazolidinyl, imidazolidinyl, morpholinyl, and piperazinyl. In yet other embodiments of the compounds of Formula II, R3 is unsubstituted or substituted alkoxy including but not limited to C1-C4alkoxy such as methoxy, ethoxy, propoxy or butoxy. R3 may further be unsubstituted or substituted heterocycloalkyloxy, including among others 4-NH-piperidin-1-yl-oxy, 4-methyl piperidin-1-yl-oxy, 4-ethyl piperidin-1-yl-oxy, 4-isopropyl- piperidin-1-yl-oxy, and pyrrolidin-3-yl-oxy. In other embodiments, R3 is unsubstituted or substituted amino, where substituted amino includes, among others, dimethylamino, diethylamino, diisopropylamino, N-methyl N-ethylamino, and dibutylamino. In some embodiments, R3 is unsubstituted or substituted acyl, unsubstituted or substituted acyloxy, unsubstituted or substituted C1-C4 acyloxy, unsubstituted or substituted alkoxycarbonyl, unsubstituted or substituted amido, or unsubstituted or substituted sulfonamido. In other embodiments, R3 is halo, which is -I, -F, -Cl, or -Br. In some embodiments, R3 is selected from the group consisting of cyano, hydroxy, nitro, phosphate, urea, and carbonate. Further contemplated are R3 being -CH3, -CH2CH3, n-propyl, isopropyl, n-butyl, tert-butyl, sec-butyl, pentyl, hexyl, heptyl, -OCH3, -OCH2CH3, or -CF3.
[00178] R3 of the compounds of Formula II, may further be NR'R'' where R' and R'' are taken together with nitrogen to form a cyclic moiety containing from 3 to 8 ring atoms. The cyclic moiety so formed may further include one or more heteroatoms which are selected from the group consisting of S, O, and N. The cyclic moiety so formed is unsubstituted or substituted, including but not limited to morpholinyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, 1,2 isothiazolidinyl, dioxide, and thiomorpholinyl. Other exemplary non-limiting cyclic fractions are as follows:

The invention also provides compounds of Formula II, wherein when R3 is a member of the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, heteroalkyl, heterocycloalkyl, heterocycloalkyloxy, aryl, arylalkyl, heteroaryl, heteroarylalkyl, acyl, alkoxy, starch , amino, sulfonamido, acyloxy, alkoxycarbonyl, and NR'R'' (wherein R' and R'' are taken together with nitrogen to form a cyclic moiety), then R3 is optionally substituted with one or more of the following substituents: alkyl, alkenyl, alkynyl, cycloalkyl, heteroalkyl, heterocycloalkyl, heterocycloalkyloxy, aryl, arylalkyl, heteroaryl, heteroarylalkyl, acyl, heterocycloalkyloxy, alkoxy, starch, amino,sulfonamido, acyloxy, alkoxycarbonyl, halo, cyano, hydroxy, nitro, phosphate, urea, carbonate, or NR'R'' where R' and R'' are taken together with nitrogen to form a cyclic fraction. Each of the above substituents may be further substituted with one or more substituents selected from the group consisting of alkyl, alkoxy, amido, amino, sulfonamido, acyloxy, alkoxycarbonyl, halo, cyano, hydroxy, nitro, oxo, phosphate, urea, and carbonate.
[00180] For example, the invention provides compounds wherein when R3 is alkyl, the alkyl is substituted with NR'R'' where R' and R'' are taken together with nitrogen to form a cyclic moiety. The cyclic moiety thus formed can be unsubstituted or substituted. Exemplary non-limiting cyclic moieties include but are not limited to morpholinyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, and thiomorpholinyl. In other examples of the compounds of Formula II, when R3 is alkyl, the alkyl is substituted with heterocycloalkyl, which includes oxetanyl, azetidinyl, tetrahydrofuranoyl, pyrrolyl, tetrahydropyranyl, piperidinyl, morpholinyl, and piperazinyl. All of the above listed heterocycloalkyl substituents may be unsubstituted or substituted.
[00181] In still other examples of the compounds of Formula II, when R3 is alkyl, the alkyl is substituted with a 5-, 6, 7, 8, 9, or 10-membered monocyclic or bicyclic heteroaryl, which is unsubstituted or substituted. Monocyclic heteroaryl includes, among others, pyrrolyl, thienyl, furyl, pyridinyl, pyranyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, thiazolyl, pyrazolyl, and oxazolyl. Bicyclic heteroaryl includes, but is not limited to, benzothiophenyl, benzofuryl, indolyl, quinolinyl, isoquinolinyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, quinazolinyl, azaindolyl, pyrazolopyrimidinyl, purinyl, pyrrolo[1,2-b]pyridazinyl, pyridazinyl, pyrazolididinyl, inrazolidinyl 1,2-a]pyridinyl, and pyrrolo[1,2-f][1,2,4]triazinyl.
In other embodiments of the compound of Formula II, R3 is -NHR3', -N(CHs)R3', -N(CH2CH3)R3', -N(CH(CH3)2)R3', or -OR3' , wherein R3' is unsubstituted or substituted heterocycloalkyl (non-limiting examples thereof include 4-NH piperidin-1-yl, 4-methyl piperidin-1-yl, 4-ethyl piperidin-1-yl, 4-isopropyl-piperidine -1-yl, and pyrrolidin-3-yl), unsubstituted or substituted monocyclic aryl, or unsubstituted or substituted monocyclic heteroaryl (including but not limited to pyrrolyl, thienyl, furyl, pyridinyl, pyranyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, thiazolyl , pyrazolyl, and oxazolyl). In one example, R3 is -O-aryl, meaning phenoxy. In another example, R3 is -O-(4-methyl)piperidin-1-yl or -O-(4-isopropyl)piperidin-1-yl.
[00183] In some embodiments of the compound of Formula II, R3 is one of the following fractions:
[00184]



[00185] In some embodiments of the compound of Formula II, W1 is NR3, where R3 is hydrogen, unsubstituted or substituted C1-C10alkyl (which includes, among others, -CH3, -CH2CH3, n-propyl, isopropyl, n-butyl, tert-butyl, sec-butyl, pentyl, hexyl, and heptyl), or unsubstituted or substituted C3-C7cycloalkyl (which includes, among others, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl). In other embodiments of the compound of Formula II, R3 is unsubstituted or substituted heterocycloalkyl (which includes, but is not limited to, oxetanyl, tetrahydrofuranoyl, pyrrolidinyl, tetrahydropyranyl, piperidinyl, and piperazinyl), or unsubstituted or substituted C2-C10heteroalkyl (which includes, among others, , methoxyethoxy, methoxymethyl, and diethylaminoethyl). Alternatively, R3 is unsubstituted or substituted monocyclic heteroaryl (which includes, among others, pyrrolyl, thienyl, furyl, pyridinyl, pyranyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, thiazolyl, pyrazolyl, and oxazolyl) or unsubstituted or substituted monocyclic aryl.
[00186] In other modalities, W1 is N. In still other modalities, W1 is S.
[00187] In some embodiments of the compound of Formula II, W2 is CR4. R4 can be, for example, hydrogen, or unsubstituted or substituted alkyl (including among others CH3, -CH2CH3, n-propyl, isopropyl, n-butyl, tert-butyl, sec-butyl, pentyl, hexyl, and heptyl). In other embodiments, R4 is unsubstituted or substituted alkenyl (including but not limited to unsubstituted or substituted C2-C5alkenyl such as, for example, vinyl, allyl, 1-methyl propen-1-yl, butenyl, or pentenyl) or unsubstituted or substituted alkynyl (including but not limited to unsubstituted or substituted C2-C5alkynyl such as acetylenyl, propargyl, butynyl, or pentynyl). Alternatively, R4 is unsubstituted or substituted aryl (including, but not limited to, monocyclic or bicyclic aryl) or unsubstituted or substituted arylalkyl (including, but not limited to, alkyl-linked monocyclic or bicyclic aryl wherein alkyl includes, but not limited to, CH3, -CH2CH3, n-propyl, isopropyl, n-butyl, sec-butyl, and pentyl). In some other embodiments, R4 is unsubstituted or substituted heteroaryl, including, but not limited to, monocyclic and bicyclic heteroaryl. Monocyclic heteroaryl R4 includes, among others, pyrrolyl, thienyl, furyl, pyridinyl, pyranyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, thiazolyl, pyrazolyl, and oxazolyl. . Bicyclic heteroaryl R4 includes, but is not limited to, benzothiophenyl, benzofuryl, indolyl, quinolinyl, isoquinolinyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, quinazolinyl, azaindolyl, pyrazolopyrimidinyl, purinyl, pyrrolo[1,2-b]pyridazoylidinyl, pyrroloidinyl, pyrroloidinyl, pyrroloidinyl[1,2-b]pyridazoylidinyl, pyrroloinyl 1,2-a]pyridinyl, and pyrrolo[1,2-f][1,2,4]triazinyl.
[00188] The present invention also provides compounds of Formula II wherein R4 is unsubstituted or substituted heteroarylalkyl, including, but not limited to, monocyclic and bicyclic heteroaryl as described above, which are linked to alkyl, which in turn includes, but is not limited to, CH3 , -CH2CH3, n-propyl, isopropyl, n-butyl, sec-butyl, and pentyl. In some embodiments, R4 is unsubstituted or substituted cycloalkyl (including but not limited to cyclopropyl, cyclobutyl, and cyclopentyl) or unsubstituted or substituted heteroalkyl (non-limiting examples include ethoxymethyl, methoxymethyl, and diethylaminomethyl). In some other embodiments, R4 is unsubstituted or substituted heterocycloalkyl which includes, among others, pyrrolidinyl, tetrahydrofuranoyl, piperidinyl, tetrahydropyranyl, thiazolidinyl, imidazolidinyl, morpholinyl, and piperazinyl. In yet other embodiments of the compounds of Formula II, R4 is unsubstituted or substituted alkoxy including but not limited to C1-C4alkoxy such as methoxy, ethoxy, propoxy or butoxy. R4 may further be unsubstituted or substituted heterocycloalkyloxy, including among others 4-NH piperidin-1-yl-oxy, 4-methyl piperidin-1-yl-oxy, 4-ethyl piperidin-1-yl-oxy, 4-isopropyl - piperidin-1-yl-oxy, and pyrrolidin-3-yl-oxy. In other embodiments, R4 is unsubstituted or substituted amino, where substituted amino includes, among others, dimethylamino, diethylamino, diisopropylamino, N-methyl N-ethylamino, and dibutylamino. In some embodiments, R4 is unsubstituted or substituted acyl, unsubstituted or substituted acyloxy, unsubstituted or substituted C1-C4 acyloxy, unsubstituted or substituted alkoxycarbonyl, unsubstituted or substituted amido, or unsubstituted or substituted sulfonamido. In some embodiments, R4 is halo, which is -I, -F, -Cl, or -Br. In some embodiments, R4 is selected from the group consisting of cyano, hydroxy, nitro, phosphate, urea, or carbonate. Further contemplated are R4 being -CH3, -CH2CH3, n-propyl, isopropyl, n-butyl, tert-butyl, sec-butyl, pentyl, hexyl, heptyl, -OCH3, -OCH2CH3, or -CF3.
[00189] R4 of the compounds of Formula II may further be NR'R'' where R' and R'' are taken together with nitrogen to form a cyclic moiety containing from 3 to 8 ring atoms. The cyclic moiety so formed may further include one or more heteroatoms which are selected from the group consisting of S, O, and N. The cyclic moiety so formed is unsubstituted or substituted, including but not limited to morpholinyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, 1,2 isothiazolidinyl, dioxide, and thiomorpholinyl. Other exemplary non-limiting cyclic fractions are as follows:

[00190] The invention also provides compounds of Formula II, wherein when R4 is a member of the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, heteroalkyl, heterocycloalkyl, heterocycloalkyloxy, aryl, arylalkyl, heteroaryl, heteroarylalkyl, acyl, alkoxy, amido, amino, sulfonamido, acyloxy, alkoxycarbonyl, and NR'R'' (wherein R' and R'' are taken together with nitrogen to form a cyclic moiety), then R4 is optionally substituted with one or more of the following substituents : alkyl, alkenyl, alkynyl, cycloalkyl, heteroalkyl, heterocycloalkyl, heterocycloalkyloxy, aryl, arylalkyl, heteroaryl, heteroarylalkyl, acyl, alkoxy, starch, amino, sulfonamido, acyloxy, alkoxycarbonyl, halo, cyano, hydroxy, nitro, phosphate, urea, carbonate , or NR'R'' where R' and R'' are taken together with nitrogen to form a cyclic fraction. Each of the above substituents may be further substituted with one or more substituents selected from the group consisting of alkyl, alkoxy, amido, amino, sulfonamido, acyloxy, alkoxycarbonyl, halo, cyano, hydroxy, nitro, oxo, phosphate, urea, and carbonate.
[00191] For example, the invention provides compounds wherein when R4 is alkyl, the alkyl is substituted with NR'R'' where R' and R'' are taken together with nitrogen to form a cyclic moiety. The cyclic moiety thus formed can be unsubstituted or substituted. Exemplary non-limiting cyclic moieties include but are not limited to morpholinyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, isothiazolidinyl 1, 2, dioxide, and thiomorpholinyl. In other examples of the compounds of Formula II, when R4 is alkyl, the alkyl is substituted with heterocycloalkyl, which includes oxetanyl, azetidinyl, tetrahydrofuranoyl, pyrrolyl, tetrahydropyranyl, piperidinyl, morpholinyl, and piperazinyl. All of the above listed heterocycloalkyl substituents may be unsubstituted or substituted.
[00192] In still other examples of the compounds of Formula II, when R4 is alkyl, the alkyl is substituted with a 5-, 6, 7, 8, 9, or 10-membered monocyclic or bicyclic heteroaryl, which is unsubstituted or substituted. Monocyclic heteroaryl includes, among others, pyrrolyl, thienyl, furyl, pyridinyl, pyranyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, thiazolyl, pyrazolyl, and oxazolyl. Bicyclic heteroaryl includes but is not limited to benzothiophenyl, benzofuryl, indolyl, quinolinyl, isoquinolinyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, quinazolinyl, azaindolyl, pyrazolopyrimidinyl, purinyl, pyrrolo[1,2-b]pyridazoylidinyl, pyridazinyl, pyrrolopyrimidinyl, pyrrolopyrimidinyl [1,2-a]pyridinyl, and pyrrolo[1,2-f][1,2,4]triazinyl. In some embodiments of the compound of Formula II, W2 is N.
[00193] In some embodiments R3 and R4 taken together form a cyclic fraction. Said fraction may have, for example, from 3 to 8 ring atoms. The cyclic moiety so formed may further include one or more heteroatoms which are selected from the group consisting of S, O, and N. The cyclic moiety so formed is unsubstituted or substituted. In some embodiments, the substituent is C1-C10alkyl (which includes, but is not limited to, -CH3, -CH2CH3, n-propyl, isopropyl, n-butyl, tert-butyl, sec-butyl, pentyl, hexyl, and heptyl), or C3-C7cycloalkyl (which includes, but is not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl); heterocycloalkyl (which includes, but is not limited to, oxetanyl, tetrahydrofuranoyl, pyrrolidinyl, tetrahydropyranyl, piperidinyl, and piperazinyl), C2-C10heteroalkyl (which includes, but is not limited to, methoxyethoxy, methoxymethyl, and diethylaminoethyl); monocyclic heteroaryl (which includes, but is not limited to, pyrrolyl, thienyl, furyl, pyridinyl, pyranyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, thiazolyl, pyrazolyl, and oxazolyl) or unsubstituted or substituted monocyclic aryl. The cyclic moiety can have one or more substituents, which can be the same or different.
[00194] In some embodiments, the cyclic moiety formed by R3 and R4 is substituted with at least one of the following substituents:



[00195] In some embodiments of the compound of Formula II, W3 is CR5. R5 can be, for example, hydrogen, or unsubstituted or substituted alkyl (including but not limited to CH3, -CH2CH3, n-propyl, isopropyl, n-butyl, tert-butyl, sec-butyl, pentyl, hexyl, and heptyl). In one embodiment, R5 is H. In other embodiments, R5 is unsubstituted or substituted alkenyl (including but not limited to unsubstituted or substituted C2-C5alkenyl such as, for example, vinyl, allyl, 1-methyl propen-1-yl, butenyl, or pentenyl) or unsubstituted or substituted alkynyl (including but not limited to unsubstituted or substituted C2-C5alkynyl such as acetylenyl, propargyl, butynyl, or pentynyl). Alternatively, R5 is unsubstituted or substituted aryl (including, but not limited to, monocyclic or bicyclic aryl) or unsubstituted or substituted arylalkyl (including, but not limited to, alkyl-linked monocyclic or bicyclic aryl wherein alkyl includes, but not limited to, CH3, -CH2CH3 , n-propyl, isopropyl, n-butyl, sec-butyl, and pentyl). In some other embodiments, R5 is unsubstituted or substituted heteroaryl, including, but not limited to, monocyclic and bicyclic heteroaryl. Monocyclic heteroaryl R5 includes, among others, pyrrolyl, thienyl, furyl, pyridinyl, pyranyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, thiazolyl, pyrazolyl, and oxazolyl. . Bicyclic heteroaryl R5 includes, but is not limited to, benzothiophenyl, benzofuryl, indolyl, quinolinyl, isoquinolinyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, quinazolinyl, azaindolyl, pyrazolopyrimidinyl, purinyl, pyrrolo[1,2-b]pyridazoylidinyl, pyrroloidinyl, pyrroloidinyl, pyrroloidinyl[1,2-b]pyridazoylidinyl, pyrroloinyl 1,2-a]pyridinyl, and pyrrolo[1,2-f][1,2,4]triazinyl. In some embodiments of the compound of Formula II, W3 is N. In other embodiments, W3 is S.
[00196] In some embodiments of the compound of Formula II, W4 is C. In other embodiments, W4 is N.
In some embodiments of the compound of Formula II, W5 is N. In other embodiments of the compound of Formula II, W5 is CR7. R7 can be, for example, hydrogen, or unsubstituted or substituted alkyl (including among others CH3, -CH2CH3, n-propyl, isopropyl, n-butyl, tert-butyl, sec-butyl, pentyl, hexyl, and heptyl). In one embodiment, R7 is H. In other embodiments, R7 is unsubstituted or substituted alkenyl (including but not limited to unsubstituted or substituted C2-C5alkenyl such as, for example, vinyl, allyl, 1-methyl propen-1-yl, butenyl, or pentenyl) or unsubstituted or substituted alkynyl (including but not limited to unsubstituted or substituted C2-C5alkynyl such as acetylenyl, propargyl, butynyl, or pentynyl). Alternatively, R7 is unsubstituted or substituted aryl (including, but not limited to, monocyclic or bicyclic aryl) or unsubstituted or substituted arylalkyl (including, but not limited to, alkyl-linked monocyclic or bicyclic aryl wherein alkyl includes, but not limited to, CH3, -CH2CH3 , n-propyl, isopropyl, n-butyl, sec-butyl, and pentyl). In some other embodiments, R7 is unsubstituted or substituted heteroaryl, including, but not limited to, monocyclic and bicyclic heteroaryl. Monocyclic heteroaryl R7 includes, among others, pyrrolyl, thienyl, furyl, pyridinyl, pyranyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, thiazolyl, pyrazolyl, and oxazolyl. Bicyclic heteroaryl R7 includes, but is not limited to, benzothiophenyl, benzofuryl, indolyl, quinolinyl, isoquinolinyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, quinazolinyl, azaindolyl, pyrazolopyrimidinyl, purinyl, pyrrolo[1,2-b]pyridazoylidinyl, pyrroloidinyl, pyrroloidinyl, pyrroloidinyl[1,2-b]pyridazolidinyl, pyrroloinyl 1,2-a]pyridinyl, and pyrrolo[1,2-f][1,2,4]triazinyl.
In some embodiments of the compound of Formula II, W6 is N. In other embodiments of the compound of Formula II, W6 is CR8. R8 can be, for example, hydrogen, or unsubstituted or substituted alkyl (including but not limited to CH3, -CH2CH3, n-propyl, isopropyl, n-butyl, tert-butyl, sec-butyl, pentyl, hexyl, and heptyl). In one embodiment, R 8 is H. In other embodiments, R 8 is unsubstituted or substituted alkenyl (including but not limited to unsubstituted or substituted C 2 -C 5 alkenyl such as, for example, vinyl, allyl, 1-methyl propen-1-yl, butenyl, or pentenyl) or unsubstituted or substituted alkynyl (including but not limited to unsubstituted or substituted C2-C5alkynyl such as acetylenyl, propargyl, butynyl, or pentynyl). Alternatively, R8 is unsubstituted or substituted aryl (including, but not limited to, monocyclic or bicyclic aryl) or unsubstituted or substituted arylalkyl (including, but not limited to, alkyl-linked monocyclic or bicyclic aryl wherein alkyl includes, but not limited to, CH3, -CH2CH3 , n-propyl, isopropyl, n-butyl, sec-butyl, and pentyl). In some other embodiments, R8 is unsubstituted or substituted heteroaryl, including, but not limited to, monocyclic and bicyclic heteroaryl. Monocyclic heteroaryl R8 includes, among others, pyrrolyl, thienyl, furyl, pyridinyl, pyranyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, thiazolyl, pyrazolyl, and oxazolyl. Bicyclic heteroaryl R8 includes, but is not limited to, benzothiophenyl, benzofuryl, indolyl, quinolinyl, isoquinolinyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, quinazolinyl, azaindolyl, pyrazolopyrimidinyl, purinyl, pyrrolo[1,2-b]pyridazoylidinyl, pyrroloidinyl, pyrroloidinyl, pyrroloidinyl[1,2-b]pyridazolidinyl, pyrroloinyl 1,2-a]pyridinyl, and pyrrolo[1,2-f][1,2,4]triazinyl.
[00199] In some embodiments of the compound of Formula II, W7 is C. In other embodiments, W7 is N.
The invention also provides compounds of Formula II which are defined by the following subclasses.


[00201] In some embodiments of compounds of Subclasses IIa - IIj, R1 is hydrogen. In other embodiments of compounds of Subclasses IIa - IIl, R2 is NH2 of NHCO(alkyl). In other embodiments of compounds of Subclass IIa - IIIl, R4 is hydrogen. In other embodiments of compounds of Subclasses IIc - IIf and III - III, R7 is hydrogen. In other modalities of compounds of Subclass IIa - IIh and IIk - IIIl, R8 is hydrogen.
In some embodiments of compounds of Subclasses IIa to IIl, R3 is alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, alkoxy, heterocycloalkyloxy, starch, amino, acyl, acyloxy, alkoxycarbonyl, sulfonamido , halo, cyano, hydroxy, nitro, phosphate, urea, carbonate, or NR'R" where R' and R'' are taken together with nitrogen to form a cyclic moiety. R3 can be, for example, hydrogen, alkyl unsubstituted or substituted (including but not limited to CH3, -CH2CH3, n-propyl, isopropyl, n-butyl, tert-butyl, sec-butyl, pentyl, hexyl, and heptyl). In other embodiments, R3 is unsubstituted or substituted alkenyl (including but not limited to unsubstituted or substituted C2-C5alkenyl such as, for example, vinyl, allyl, 1-methyl propen-1-yl, butenyl, or pentenyl) or unsubstituted or substituted alkynyl (including but not limited to unsubstituted or substituted ones C2-C5alkynyl such as acetylenyl, propargyl, butynyl, or u pentynyl). Alternatively, R3 is unsubstituted or substituted aryl (including, but not limited to, monocyclic or bicyclic aryl) or unsubstituted or substituted arylalkyl (including, but not limited to, alkyl-linked monocyclic or bicyclic aryl wherein alkyl includes, but not limited to, CH3, -CH2CH3 , n-propyl, isopropyl, n-butyl, sec-butyl, and pentyl). In some other embodiments, R3 is unsubstituted or substituted heteroaryl, including, but not limited to, monocyclic and bicyclic heteroaryl. Monocyclic heteroaryl R3 includes, among others, pyrrolyl, thienyl, furyl, pyridinyl, pyranyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, thiazolyl, pyrazolyl, and oxazolyl. Bicyclic heteroaryl R3 includes, but is not limited to, benzothiophenyl, benzofuryl, indolyl, quinolinyl, isoquinolinyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, quinazolinyl, azaindolyl, pyrazolopyrimidinyl, purinyl, pyrrolo[1,2-b]pyridazoylidinyl, pyrroloinyl, pyrroloidinyl, pyrroloidinyl[1,2-b]pyridazoylidinyl, pyrroloinyl 1,2-a]pyridinyl, and pyrrolo[1,2-f][1,2,4]triazinyl. The present invention also provides compounds of Formula I wherein R3 is unsubstituted or substituted heteroarylalkyl, including, but not limited to, monocyclic and bicyclic heteroaryl as described above, which are linked to alkyl, which in turn includes, but not limited to, CH3, - CH2CH3, n-propyl, isopropyl, n-butyl, sec-butyl, and pentyl. In some embodiments, R3 is unsubstituted or substituted cycloalkyl (including but not limited to cyclopropyl, cyclobutyl, and cyclopentyl) or unsubstituted or substituted heteroalkyl (non-limiting examples include ethoxymethyl, methoxymethyl, and diethylaminomethyl). In some other embodiments, R3 is unsubstituted or substituted heterocycloalkyl which includes, among others, pyrrolidinyl, tetrahydrofuranoyl, piperidinyl, tetrahydropyranyl, thiazolidinyl, imidazolidinyl, morpholinyl, and piperazinyl. In yet other embodiments of the compounds of Formula I, R3 is unsubstituted or substituted alkoxy including but not limited to C1-C4alkoxy such as methoxy, ethoxy, propoxy or butoxy. R3 may further be unsubstituted or substituted heterocycloalkyloxy, including among others 4-NH-piperidin-1-yl-oxy, 4-methyl piperidin-1-yl-oxy, 4-ethyl piperidin-1-yl-oxy, 4-isopropyl- piperidin-1-yl-oxy, and pyrrolidin-3-yl-oxy. In other embodiments, R3 is unsubstituted or substituted amino, where substituted amino includes, among others, dimethylamino, diethylamino, diisopropylamino, N-methyl N-ethylamino, and dibutylamino. In some embodiments, R3 is unsubstituted or substituted acyl, unsubstituted or substituted acyloxy, unsubstituted or substituted C1 -C4 acyloxy, unsubstituted or substituted alkoxycarbonyl, unsubstituted or substituted amido, or unsubstituted or substituted sulfonamido. In other embodiments, R3 is halo, which is -I, -F, -Cl, or -Br. In some embodiments, R3 is selected from the group consisting of cyano, hydroxy, nitro, phosphate, urea, and carbonate. Further contemplated are R3 being -CH3, -CH2CH3, n-propyl, isopropyl, n-butyl, tert-butyl, sec-butyl, pentyl, hexyl, heptyl, -OCH3, -OCH2CH3, or -CF3. In some embodiments R3 may further be NR'R'' where R' and R'' are taken together with nitrogen to form a cyclic moiety containing 3 to 8 ring atoms. The cyclic moiety so formed may further include one or more heteroatoms which are selected from the group consisting of S, O, and N. The cyclic moiety so formed is unsubstituted or substituted, including but not limited to morpholinyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, 1,2 isothiazolidinyl, dioxide, and thiomorpholinyl. Other exemplary non-limiting cyclic fractions are as follows:

[00203] The invention further provides a compound of Formula III:
or the pharmaceutically acceptable salts thereof, wherein W1 is CR3, W2 is C-benzoxazolyl substituted with R2 and W3 is S; W1 is CR3, W2 is C-benzoxazolyl substituted with R2 and W3 is CR5; W1 is N or NR3, W2 is CR4, and W3 is C-benzoxazolyl substituted with R2; W1 is CR3, W2 is CR4, and W3 is C-benzoxazolyl substituted with R2; or W1 is N or NR3, W2 is NR4, and W3 is C-benzoxazolyl substituted with R2; X is N; R1 and R2 are independently hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, alkoxy, heterocycloalkyloxy, amido, amino, acyl, acyloxy, alkoxycarbonyl, sulfonamido, halo, cyano, hydroxy, nitro , phosphate, urea, carbonate, or NR'R'' where R' and R'' are taken together with nitrogen to form a cyclic fraction; R3 and R4 are independently hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, alkoxy, heterocycloalkyloxy, amido, amino, acyl, acyloxy, alkoxycarbonyl, sulfonamido, halo, cyano, hydroxy, nitro , phosphate, urea, carbonate, or NR'R'' where R' and R'' are taken together with nitrogen to form a cyclic fraction; R5, R6 , R7 and R8 are independently hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, alkoxy, heterocycloalkyloxy, starch, amino, acyl, acyloxy, alkoxycarbonyl, sulfonamido, halo, cyano , hydroxy, nitro, phosphate, urea, carbonate, or NR'R'' where R' and R'' are taken together with nitrogen to form a cyclic fraction.
[00204] In some embodiments of the compound of Formula III, the compound is:
and where W1 is CR3 or NR3 and W2 is CR4.
[00205] In another aspect, the invention provides a compound of Formula IV:
or the pharmaceutically acceptable salts thereof, wherein: W1 is N, NR3, CR3, or C=O; W2 is N, NR4, CR4, or C=O; W3 is N, NR5 or CR5; W4 is N, C=O or CR6, where no more than two N atoms and no more than two C=O groups are adjacent; W5 is N or CR7; W6 is N or CR8; Wa and Wb are independently N or CR9; one of Wc and Wd is N, and the other is O, NR10, or S; R1 and R2 are independently hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, alkoxy, heterocycloalkyloxy, amido, amino, acyl, acyloxy, alkoxycarbonyl, sulfonamido, halo, cyano, hydroxy, nitro , phosphate, urea, carbonate, or NR'R'' where R' and R'' are taken together with nitrogen to form a cyclic fraction; R3 and R4 are independently hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, alkoxy, heterocycloalkyloxy, amido, amino, acyl, acyloxy, alkoxycarbonyl, sulfonamido, halo, cyano, hydroxy, nitro , phosphate, urea, carbonate, or NR'R'' where R' and R'' are taken together with nitrogen to form a cyclic fraction; or R3 and R4 taken together form a cyclic moiety; R5, R6 , R7 and R8 are independently hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, alkoxy, heterocycloalkyloxy, starch, amino, acyl, acyloxy, alkoxycarbonyl, sulfonamido, halo, cyano , hydroxy, nitro, phosphate, urea, carbonate, or NR'R'' where R' and R'' are taken together with nitrogen to form a cyclic fraction; R9 is alkyl or halo; and R10 is hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, alkoxy, heterocycloalkyloxy, starch, amino, acyl, acyloxy, alkoxycarbonyl, sulfonamido, halo, cyano, hydroxy, nitro, phosphate , urea, carbonate, or NR'R'' where R' and R'' are taken together with nitrogen to form a cyclic fraction.
In some embodiments of the compound of Formula IV, W1 is CR3, W2 is CR4, W3 is CR5, W4 is N, W5 is CR7, and W6 is CR8; W1 is N, W2 is CR4, W3 is CR5, W4 is N, W5 is CR7, and W6 is CR8; or W1is CR3, W2is N, W3is CR5, W4is N, W5is CR7, and W6is CR8. In some embodiments of the compound of Formula IV, Wbe is N. In other embodiments, Wa is CR9 and R9 is alkyl.
[00207] The invention also provides a compound of Formula V:
or the pharmaceutically acceptable salts thereof, wherein W1 is S, N, NR3 or CR3, W2 is N or CR4, W3 is S, N or CR5, W4 is N or C, and W7 is N or C, where no more than two atoms of N and no more than two C=O groups are adjacent; W5 is N or CR7; W6 is N or CR8; Wa and Wb are independently N or CR9; one of Wc and Wdé N, and the other is O, NR10, or S; R1 and R2 are independently hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, alkoxy, heterocycloalkyloxy, starch, amino, acyl, acyloxy, alkoxycarbonyl, sulfonamido, halo, cyano, hydroxy, nitro, phosphate, urea, carbonate, or NR'R'' where R' and R'' are taken together with nitrogen to form a cyclic fraction; R3 and R4 are independently hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, alkoxy, heterocycloalkyloxy, amido, amino, acyl, acyloxy, alkoxycarbonyl, sulfonamido, halo, cyano, hydroxy, nitro , phosphate, urea, carbonate, or N^R" where R' and R'' are taken together with nitrogen to form a cyclic moiety; or R3 and R4 taken together form a cyclic moiety; R5, R7 and R8 are independently hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, alkoxy, heterocycloalkyloxy, starch, amino, acyl, acyloxy, alkoxycarbonyl, sulfonamido, halo, cyano, hydroxy, nitro, phosphate, urea, carbonate, or NR'R'' where R' and R'' are taken together with nitrogen to form a cyclic moiety; R9 is alkyl or halo; and R10 is hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl , aryl, arylalkyl, heteroar yl, heteroarylalkyl, alkoxy, heterocycloalkyloxy, starch, amino, acyl, acyloxy, alkoxycarbonyl, sulfonamido, halo, cyano, hydroxy, nitro, phosphate, urea, carbonate, or NR'R'' where R' and R'' are taken together with nitrogen to form a cyclic fraction.
In some embodiments of the compound of Formula V, W1 is CR3, W2 is CR4, W3 is N, W4 is N, W5 is CR7, and W6 is CR8. In other embodiments, W1 is CR3, W2 is CR4, W3 is N, W4 is N, W5 is CR7, and W6 is CR8. In other modes, W1is CR3, W2is CR4, W3is N, W4is N, W5is N, and W6is CR8. In still other modes, W1 is NR3, W2 is CR4, W3 is N, W4 is C, W5 is CR7, and W6 is CR8. In other modes, W1 is S, W2 is CR4, W3 is N, W4 is C, W5 is CR7, and W6 is CR8. In other embodiments, W1 is CR3, W2 is CR4, W3 is N, W4 is N, W5 is N, and W6 is CR8. In still other embodiments, W1 is NR3, W2 is CR4, W3 is N, W4 is C, W5 is CR7, and W6 is CR8. In other embodiments, W1 is S, W2 is CR4, W3 is N, W4 is C, W5 is CR7, and W6 is CR8. In other embodiments, W1 is CR3, W2 is CR4, W3 is S, W4 is C, W5 is N, and W6 is N.
In some embodiments of the compound of Formula V, Wb is N. In other embodiments, Wa is CR9 and R9 is alkyl.
[00210] The invention further provides compounds of Formula VA and VB:
or the pharmaceutically acceptable salts thereof, wherein W1 is CR3; R1 and R2 are independently hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, alkoxy, heterocycloalkyloxy, starch, amino, acyl, acyloxy, alkoxycarbonyl, sulfonamido, halo, cyano, hydroxy, nitro, phosphate, urea, carbonate, or NR'R'' where R' and R'' are taken together with nitrogen to form a cyclic fraction; and R3 is hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, alkoxy, heterocycloalkyloxy, starch, amino, acyl, acyloxy, alkoxycarbonyl, sulfonamido, halo, cyano, hydroxy, nitro, phosphate , urea, carbonate, or NR'R'' where R' and R'' are taken together with nitrogen to form a cyclic fraction.
[00211] Also provided herein are compounds of Formula VC and VD:
or the pharmaceutically acceptable salts thereof, wherein W1 is CR3; W5 is N or CR7; Wa and Wb are independently N or CR9; one of Wc and Wd is N, and the other is O, NR10, or S; R1 and R2 are independently hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, alkoxy, heterocycloalkyloxy, amido, amino, acyl, acyloxy, alkoxycarbonyl, sulfonamido, halo, cyano, hydroxy, nitro , phosphate, urea, carbonate, or NR'R'' where R' and R'' are taken together with nitrogen to form a cyclic fraction; R3 is hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, alkoxy, heterocycloalkyloxy, starch, amino, acyl, acyloxy, alkoxycarbonyl, sulfonamido, halo, cyano, hydroxy, nitro, phosphate, urea, carbonate, or NR'R'' where R' and R'' are taken together with nitrogen to form a cyclic fraction; R7 is hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, alkoxy, heterocycloalkyloxy, starch, amino, acyl, acyloxy, alkoxycarbonyl, sulfonamido, halo, cyano, hydroxy, nitro, phosphate, urea, carbonate, or NR'R'' where R' and R'' are taken together with nitrogen to form a cyclic fraction; R9 is alkyl or halo; and R10 is hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, alkoxy, heterocycloalkyloxy, starch, amino, acyl, acyloxy, alkoxycarbonyl, sulfonamido, halo, cyano, hydroxy, nitro, phosphate , urea, carbonate, or NR'R'' where R' and R'' are taken together with nitrogen to form a cyclic fraction.
[00212] In some embodiments of the compound of Formula V-C or V-D, Wb is N. In other embodiments, Wa is CR9 and R9 is alkyl.
[00213] Also provided herein is a compound of Formula VI:
or the pharmaceutically acceptable salts thereof, wherein W1 is CR3; W2 is CR4; Wa is CH or N; R1is hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, alkoxy, heterocycloalkyloxy, starch, amino, acyl, acyloxy, alkoxycarbonyl, sulfonamido, halo, cyano, hydroxy, nitro, phosphate, urea , carbonate, or NR'R'' where R' and R'' are taken together with nitrogen to form a cyclic fraction; R3 is alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroarylalkyl, alkoxy, heterocycloalkyloxy, starch, amino, acyl, acyloxy, alkoxycarbonyl, sulfonamido, halo, cyano, hydroxy, nitro, phosphate, urea, carbonate, or NR'R'' where R' and R'' are taken together with nitrogen to form a cyclic fraction; R4 is hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, alkoxy, heterocycloalkyloxy, starch, amino, acyl, acyloxy, alkoxycarbonyl, sulfonamido, halo, cyano, hydroxy, nitro, phosphate, urea, carbonate, or NR'R'' where R' and R'' are taken together with nitrogen to form a cyclic fraction; or R3 and R4 taken together form a cyclic moiety; and R10 and R11 are independently hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, alkoxy, heterocycloalkyloxy, amido, amino, acyl, acyloxy, alkoxycarbonyl, sulfonamido, halo, cyano, hydroxy, nitro, phosphate, urea, carbonate, or NR'R'' where R' and R'' are taken together with nitrogen to form a cyclic fraction.
[00214] The invention further provides a compound of Formula VII:
or a pharmaceutically acceptable salt thereof, wherein X1 is CR3, NR3, or S; X2 is CR4, NR4, CR4—CR55, or CR4-^XR. ; X3 and X4 are independently C or N; X5 is CR6, NR6, or S; X4 is CR7, NR7, CR1CR, or CR1XR; Wa and Wb are independently N or CR9; one of Wc and Wd is N, and the other is O, NR10, or S; R1 and R2 are independently hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, alkoxy, heterocycloalkyloxy, amido, amino, acyl, acyloxy, alkoxycarbonyl, sulfonamido, halo, cyano, hydroxy, nitro , phosphate, urea, carbonate, or N1 R" where R' and R'' are taken together with nitrogen to form a cyclic moiety; R3 and R4 are independently hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl , aryl, arylalkyl, heteroaryl, heteroarylalkyl, alkoxy, heterocycloalkyloxy, amido, amino, acyl, acyloxy, alkoxycarbonyl, sulfonamido, halo, cyano, hydroxy, nitro, phosphate, urea, carbonate, or NR'R'' where R' and R'' are taken together with nitrogen to form a cyclic moiety; or R3 and R4 taken together form a cyclic moiety; R5, R6 , R7, and R8 are independently hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, h eteroaryl, heteroarylalkyl, alkoxy, heterocycloalkyloxy, starch, amino, acyl, acyloxy, alkoxycarbonyl, sulfonamido, halo, cyano, hydroxy, nitro, phosphate, urea, carbonate, or NR'R'' where R' and R'' are taken together with nitrogen to form a cyclic fraction; R9 is alkyl or halo; and R10 is hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, alkoxy, heterocycloalkyloxy, starch, amino, acyl, acyloxy, alkoxycarbonyl, sulfonamido, halo, cyano, hydroxy, nitro, phosphate , urea, carbonate, or NR'R'' where R' and R'' are taken together with nitrogen to form a cyclic fraction.
In some embodiments of the compound of Formula VII, Wb is N. In other embodiments, Wa is CR9 and R9 is alkyl.
[00216] In some embodiments, the compounds of the present invention exhibit one or more functional characteristics disclosed herein. For example, one or more subject compounds specifically bind a PI3 kinase. In some embodiments, the IC50 of a subject compound for p110a, p110β, p110y, or p110δ is less than about 1 µM, less than about 100 nM, less than about 50 nM, less than about 10 nM , less than about 1 nM, less than about 0.5nM, less than about 100pM, or less than about 50 pM.
[00217] In some embodiments, one or more of the subject compound can selectively inhibit one or more class I or I members of phosphatidylinositol 3-kinases (PI3 kinase) with an IC50 value of about 100 nM, 50 nM, 10 nM, 5 nM, 100 pM, 10 pM or 1 pM, or less as measured in an in vitro kinase assay.
[00218] In some embodiments, one or more of the subject compound can selectively inhibit one or two members of type I or class I phosphatidylinositol 3-kinases (PI3-kinases) consisting of PI3-kinase α, PI3-kinase β, PI3 - kinase y, and PI3 kinase δ. In some respects, some of the object compounds selectively inhibit PI3-kinase α as compared to all other type I types of PI3-kinases. In other aspects, some of the subject compounds selectively inhibit PI3-kinase α and PI3-kinase y as compared to the rest of type I PI3-kinases. In still other aspects, some of the subject compounds selectively inhibit PI3-kinase α and PI3-kinase β as compared to the rest of type I PI3-kinases. In yet some other aspects, some of the subject compounds selectively inhibit PI3-kinase α and PI3-kinase δ as compared to the rest of type I PI3-kinases. In yet some other aspects, some of the subject compounds selectively inhibit PI3-kinase δ and PI3-kinase β as compared to the type I remnant of PI3-kinases, or selectively inhibit PI3-kinase δ and PI3-kinase α as compared to the remnant of PI3-kinases type I PI3-kinases, or selectively inhibits PI3-kinaseα and PI3-kinase as compared to the type I remnant of PI3-kinases, or selectively inhibits PI3-kinaseα and PI3-kinaseβ as compared to the type I remnant of PI3-kinases .
[00219] In yet another aspect, an inhibitor that selectively inhibits one or more members of type I PI3-kinases, or an inhibitor that selectively inhibits one or more signaling pathways mediated by type I PI3-kinase, may alternatively be understood as refers to a compound having an inhibitory concentration of 50% (IC50) with respect to a certain type I PI3 kinase, which is at least 10-fold, at least 20-fold, at least 50-fold, at least 100-fold, at least 1000 times, at least 10, 100 times, or less than the inhibitory IC50 with respect to the rest of other types I of PI3-kinases.
[00220] The chemical entities described herein may be synthesized in accordance with one or more illustrative schemes herein and/or known techniques.
[00221] Unless otherwise specified, the reactions described here take place at atmospheric pressure, generally within a temperature range of -10 °C to 200 °C. Others, unless otherwise specified, reaction times and conditions are intended to be approximate, for example, occurring at about atmospheric pressure within the temperature range of about -10 °C to about 110 °C over a period of about 1 to about 24 hours; the reactions left to occur overnight for a period of about 16 hours.
[00222] In general, compounds of the invention can be prepared by the following reaction schemes:

The compounds of the invention can be synthesized via a reaction scheme depicted generically in Schemes A and B. Synthesis processes by coupling a compound of Formula A with a compound of Formula B to generate a compound of Formula C. The coupling step is typically catalyzed by the use of a palladium catalyst, including among others palladium tetrakis (triphenylphosphine). Coupling is generally carried out in the presence of an appropriate base, a non-limiting example being sodium carbonate. An example of a suitable solvent for the reaction is aqueous dioxane.
[00224] A compound of Formula A for use in Scheme A has a structure of formula A, where T1 is halo including bromine, chlorine, fluorine, and iodine, and where other substituents are defined for Formulas I and II of compounds of the invention. For boronic acids and acid derivatives as described in Formula B, X is O or S, and the benzoxazol or benzothiazol moiety can be attached at the 4-, 5-, 6- or 7-position.
[00225] For a compound of Formula B, G is hydrogen or RG1, where RG1 is alkyl, alkenyl, or aryl. Alternatively, B(OG)2 is taken together to form a 5- or 6-membered cyclic moiety. In some embodiments, the compound of Formula B is a compound having the structure of Formula E:

[00226] wherein G is H or RG1; RG1 is alkyl, alkenyl, or aryl. Alternatively, B(OG)2 is taken together to form the 5- or 6-membered cyclic fraction; and RG2 is H, tert-butyl carbamate, oracyl.

[00227] Scheme C depicts an exemplary scheme for the synthesis of a compound of Formula B' or optionally Formula B'' for use in Reaction Scheme C. M is the benzoxazolyl or benzothiazolyl moiety as described by Formula B. This reaction occurs by reacting a compound of Formula D with a trialkyl borate or a boronic acid derivative to produce a compound of Formula B'. Trialkyl borate includes, but is not limited to, triisopropyl borate, and the boronic acid derivative includes, but is not limited to, bis(pinacolato)diboron. The reaction typically takes place in the presence of a base, a non-limiting example being potassium acetate. The reaction can take place in a solvent such as dioxane or tetrahydrofuran.
[00228] A compound of Formula D for use in Scheme C is a compound where T2 is halo or another leaving group, and M is as defined above. The compound of Formula B' can be further converted to a compound of Formula B'' by treatment with an acid such as hydrochloric acid.
[00229] Some examples of compounds of Formula B that can be synthesized via Scheme C include among other compounds of the following formulas:

[00230] Where desired, deprotection of a substituent (eg removal of Boc protection from an amino substituent) in the benzoxazolyl moiety (i.e. M1 of formula C) is carried out after coupling the compound of Formula B to the compound of Formula THE.
[00231] Some examples of compounds with said protecting groups, include among other compounds of the following formulas:

[00232] The following Reaction Schemes illustrate the preparation of various compounds of the invention.
















The invention provides pharmaceutical compositions comprising one or more compounds of the present invention.
In some embodiments, the invention provides pharmaceutical compositions for the treatment of disorders such as hyperproliferative disorder including but not limited to cancer such as acute myeloid leukemia, thymus, brain, lung, squamous cell, skin, eye, retinoblastoma, intraocular melanoma, oral cavity and oropharyngeal, bladder, gastric, stomach, pancreatic, bladder, breast, cervical, head, neck, renal, kidney, hepatic, ovarian, prostate, colorectal, esophageal, testicular, gynecological, thyroid, CNS, PNS, AIDS-related (by eg, Lymphoma and Kaposi's Sarcoma) or Virus-induced cancer. In some embodiments, said pharmaceutical composition is for the treatment of non-cancerous hyperproliferative disorder such as benign skin hyperplasia (eg, psoriasis), restenosis, or prostate (eg, benign prostatic hypertrophy (BPH)).
[00235] In some embodiments, the invention provides pharmaceutical compositions to treat diseases or conditions related to an undesirable, overreactive, harmful or deleterious immune response in a mammal. Such undesirable immune response can be associated with or result in, for example, asthma, emphysema, bronchitis, psoriasis, allergy, anaphylaxis, autoimmune diseases, rheumatoid arthritis, graft-host disease, transplant rejection, lung lesions, and lupus erythematosus. The pharmaceutical compositions of the present invention can be used to treat other respiratory diseases including but not limited to diseases affecting the lung lobes, pleural cavity, bronchial tubes, trachea, upper respiratory tract, or the nerves and muscles for breathing. The compositions of the invention can be used to treat multiple organ failure.
The invention also provides compositions for the treatment of liver disease (including diabetes), pancreatitis or kidney disease (including proliferative glomerulonephritis and diabetes-induced kidney disease) or pain in a mammal.
[00237] The invention also provides compositions for the treatment of sperm motility. The invention further provides compositions for the treatment of neurological or neurodegenerative diseases including, but not limited to, Alzheimer's disease, Huntington's disease, CNS trauma, and stroke.
[00238] The invention further provides a composition for preventing blastocyst implantation in a mammal.
[00239] The invention further relates to a composition for treating a disease related to vasculogenesis or angiogenesis in a mammal that may manifest as tumor angiogenesis, chronic inflammatory disease such as rheumatoid arthritis, inflammatory bowel disease, atherosclerosis, skin diseases such as psoriasis , eczema, and scleroderma, diabetes, diabetic retinopathy, retinopathy of prematurity, age-related macular degeneration, hemangioma, glioma, melanoma, Kaposi's sarcoma, and ovarian, breast, lung, pancreatic, prostate, colon and epidermoid cancer.
The invention further provides compositions for the treatment of disorders involving platelet aggregation or platelet adhesion, including but not limited to Bernard-Soulier syndrome, Glanzmann thrombasthenia, Scott syndrome, von Willebrand disease, Hermansky-Pudlak syndrome, and Gray platelet syndrome.
[00241] In some embodiments, compositions are provided to treat a disease that is skeletal muscle atrophy, skeletal muscle hypertrophy, leukocyte recruitment into cancer tissue, invasive metastasis, melanoma, Kaposi's sarcoma, acute and chronic bacterial and viral infections, sepsis, glomerulus sclerosis, glomerulonephritis, or progressive renal fibrosis.
[00242] The subject pharmaceutical compositions are typically formulated to provide a therapeutically effective amount of a compound of the present invention as the active ingredient, or the pharmaceutically acceptable salt, ester, prodrug, solvate, hydrate or derivative thereof. Where desired, pharmaceutical compositions contain a pharmaceutically acceptable salt and/or coordination complex thereof, and one or more pharmaceutically acceptable excipients, carriers, including sodium inert diluents and fillers, diluents, including sterile aqueous solution and various organic solvents, permeation enhancers , solubilizers and adjuvants.
[00243] The subject pharmaceutical compositions can be administered alone or in combination with one or more other agents, which are typically administered in the form of pharmaceutical compositions. Where desired, the subject compounds and other agents can be mixed in the preparation or both components can be formulated into separate preparations to use the same in combinations separately or at the same time.
[00244] In some embodiments, the concentration of one or more of the compounds provided in the pharmaceutical compositions of the present invention is less than 100%, 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, 19%, 18%, 17%, 16%, 15%,14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4% , 3%, 2%, 1%, 0.5%, 0.4%, 0.3%, 0.2%, 0.1%, 0.09%, 0.08%, 0.07%, 0.06%, 0.05%, 0.04%, 0.03%, 0.02%, 0.01%, 0.009%, 0.008%, 0.007%, 0.006%, 0.005%, 0.004%, 0.003% , 0.002%, 0.001%, 0.0009%, 0.0008%, 0.0007%, 0.0006%, 0.0005%, 0.0004%, 0.0003%, 0.0002%, or 0. 0001% w/w, p/v or v/v.
[00245] In some embodiments, the concentration of one or more of the compounds of the present invention is greater than 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, 19.75% , 19.50%, 19.25% 19%, 18.75%, 18.50%, 18.25% 18%, 17.75%, 17.50%, 17.25% 17%, 16.75 %, 16.50%, 16.25% 16%, 15.75%, 15.50%, 15.25% 15%, 14.75%, 14.50%, 14.25% 14%, 13. 75%, 13.50%, 13.25% 13%, 12.75%, 12.50%, 12.25% 12%, 11.75%, 11.50%, 11.25% 11%, 10 .75%, 10.50%, 10.25% 10%, 9.75%, 9.50%, 9.25% 9%, 8.75%, 8.50%, 8.25% 8%, 7.75%, 7.50%, 7.25% 7%, 6.75%, 6.50%, 6.25% 6%, 5.75%, 5.50%, 5.25%5% , 4.75%, 4.50%, 4.25%, 4%, 3.75%, 3.50%, 3.25%, 3%, 2.75%, 2.50%, 2.25 %, 2%, 1.75%, 1.50%, 125%, 1%, 0.5%, 0.4%, 0.3%, 0.2%, 0.1%, 0.09% , 0.08%, 0.07%, 0.06%, 0.05%, 0.04%, 0.03%, 0.02%, 0.01%, 0.009%, 0.008%, 0.007%, 0.006%, 0.005%, 0.004%, 0.003%, 0.002%, 0.001%, 0.0009%, 0.0008%, 0.0007%, 0.0006%, 0.0005%, 0.0004%, 0, 0003%, 0.0002%, or 0.0001% w/w, w/v, or v/v.
[00246] In some embodiments, the concentration of one or more of the compounds of the present invention is in the range of approximately 0.0001% to approximately 50%, approximately 0.001% to approximately 40%, approximately 0.01% to approximately 30%, approximately 0.02% to approximately 29%, approximately 0.03% to approximately 28%, approximately 0.04% to approximately 27%, approximately 0.05% to approximately 26%, approximately 0.06% to approximately 25%, approximately 0.07% to approximately 24%, approximately 0.08% to approximately 23%, approximately 0.09% to approximately 22%, approximately 0.1% to approximately 21%, approximately 0.2% to approximately 20%, approximately 0.3% to approximately 19%, approximately 0.4% to approximately 18%, approximately 0.5% to approximately 17%, approximately 0.6% to approximately 16%, approximately 0.7% to approximately 15%, approximately 0.8% to approximately 14%, approximately 0.9% to approximately te 12%, approximately 1% to approximately 10% w/w, w/v or v/v. v/v.
[00247] In some embodiments, the concentration of one or more of the compounds of the present invention is in the range of approximately 0.001% to approximately 10%, approximately 0.01% to approximately 5%, approximately 0.02% to approximately 4.5 %, approximately 0.03% to approximately 4%, approximately 0.04% to approximately 3.5%, approximately 0.05% to approximately 3%, approximately 0.06% to approximately 2.5%, approximately 0.07 % to approximately 2%, approximately 0.08% to approximately 1.5%, approximately 0.09% to approximately 1%, approximately 0.1% to approximately 0.9% w/w, p/v or v/v .
[00248] In some embodiments, the amount of one or more of the compounds of the present invention is equal to or less than 10 g, 9.5 g, 9.0 g, 8.5 g, 8.0 g, 7, 5g, 7.0g, 6.5g, 6.0g, 5.5g, 5.0g, 4.5g, 4.0g, 3.5g, 3.0g, 2, 5g, 2.0g, 1.5g, 1.0g, 0.95g, 0.9g, 0.85g, 0.8g, 0.75g, 0.7g, 0. 65g, 0.6g, 0.55g, 0.5g, 0.45g, 0.4g, 0.35g, 0.3g, 0.25g, 0.2g, 0. 15 g, 0.1 g, 0.09 g, 0.08 g, 0.07 g, 0.06 g, 0.05 g, 0.04 g, 0.03 g, 0.02 g, 0.0 01 g, 0.009 g, 0.008 g, 0.007 g, 0.006 g, 0.005 g, 0.004 g, 0.003 g, 0.002 g, 0.001 g, 0.0009 g, 0.0008 g, 0.0007 g, 0.0006 g, 0.0005 g, 0.0004 g, 0.0003 g, 0.0002 g, or 0.0001 g,
[00249] In some embodiments, the amount of one or more of the compounds of the present invention is more than 0.0001 g, 0.0002 g, 0.0003 g, 0.004 g, 0.0005 g, 0.0006 g, 0.0007 g, 0.0008 g, 0.0009 g, 0.001 g, 0.0015 g, 0.002 g, 0.0025 g, 0.003 g, 0.0035 g, 0.004 g, 0.0045 g, 0.005 g, 0.0055 g, 0.006 g, 0.0065 g, 0.007 g, 0.0075 g, 0.008 g, 0.0085 g, 0.009 g, 0.0095 g, 0.01 g, 0.015 g, 0.02 g, 0.025g, 0.03g, 0.035g, 0.04g, 0.045g, 0.05g, 0.055g, 0.06g, 0.065g, 0.07g, 0.075g, 0.08g, 0.085g, 0.09g, 0.095g, 0.1g, 0.15g, 0.2g, 0.25g, 0.3g, 0.35g, 0.4g, 0.45g 0.5g, 0.55g, 0.6g, 0.65g, 0.7g, 0.75g, 0.8g, 0.85g, 0.9g, 0.95g , 1 g, 1.5 g, 2 g, 2.5, 3 g, 3.5, 4 g, 4.5 g, 5 g, 5.5 g, 6 g, 6.5 g, 7 g, 7 .5g, 8g, 8.5g, 9g, 9.5g, or 10g.
[00250] In some embodiments, the amount of one or more of the compounds of the present invention is in the range of 0.0001-10 g, 0.0005-9 g, 0.001-8 g, 0.005-7 g, 0.01- 6g, 0.05-5g, 0.1-4g, 0.5-4g, or 1-3g.
[00251] The compounds according to the invention are effective over a wide dosage range. For example, in the treatment of adult humans, dosages of 0.01 to 1000 mg, 0.5 to 100 mg, 1 to 50 mg per day, and 5 to 40 mg per day are examples of dosages that can be used . An exemplary dosage is 10 to 30 mg per day. The exact dosage will depend on the route of administration, the form in which the compound is administered, the subject to be treated, the body weight of the subject to be treated, and the preference and experience of the attending physician.
[00252] The pharmaceutical composition of the present invention typically contains an active ingredient (for example, a compound of the present invention or the pharmaceutically acceptable salt and/or coordination complex thereof, and one or more pharmaceutically acceptable excipients, carriers, including among others inert solid diluents and fillers, thinners, sterile aqueous solution and various organic solvents, permeation enhancers, solubilizers and adjuvants.
[00253] Below are described non-limiting exemplary pharmaceutical compositions and methods for preparing the same.
[00254] Pharmaceutical compositions for oral administration. In some embodiments, the invention provides a pharmaceutical composition for oral administration containing a compound of the present invention, and a pharmaceutical excipient suitable for oral administration.
In some embodiments, the invention provides a solid pharmaceutical composition for oral administration containing: (i) an effective amount of a compound of the present invention; optionally (ii) an effective amount of a second agent; and (iii) a pharmaceutical excipient suitable for oral administration. In some embodiments, the composition further contains: (iv) an effective amount of a third agent.
[00256] In some embodiments, the pharmaceutical composition may be a liquid pharmaceutical composition suitable for oral consumption. Pharmaceutical compositions of the invention suitable for oral administration may be presented as discrete dosage forms such as capsules, cachets, or tablets, or liquids or aerosol sprays each containing a predetermined amount of an active ingredient as a powder or granules, a solution, or a suspension in an aqueous or non-aqueous liquid, an oil-in-water emulsion, or a water-in-oil emulsion. Said dosage forms can be prepared by any method of pharmacy, but all methods include the step of bringing the active ingredient into association with the carrier, which constitutes one or more required ingredients. In general, compositions are prepared by intimately and uniformly mixing the active ingredient with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product into the desired presentation. For example, a tablet can be prepared by compression or molding, optionally with one or more accessory ingredients. Compressed tablets can be prepared by compressing in a machine the active ingredient in a free-flowing form as a powder or granules, optionally mixed with an excipient such as, among others, a binder, a lubricant, an inert diluent, and/or a active surface or dispersing agent. Molded tablets can be made by molding in a suitable machine mixing the powdered compound moistened with an inert liquid diluent.
[00257] This invention further comprises anhydrous pharmaceutical compositions and dosage forms comprising an active ingredient, since water can facilitate the degradation of some compounds. For example, water can be added (eg 5%) in pharmaceutical techniques as a means of simulating long-term storage to determine characteristics such as shelf life or the stability of formulations over time. Anhydrous pharmaceutical compositions and dosage forms of the invention can be prepared using anhydrous or low-moisture ingredients and containing low-moisture conditions. Pharmaceutical compositions and dosage forms of the invention that contain lactose can be made anhydrous if substantial contact with moisture during manufacturing, packaging, and/or storage is expected. An anhydrous pharmaceutical composition can be prepared and stored so that its anhydrous nature is maintained. Thus, anhydrous compositions can be packaged using materials known to prevent exposure to water so that they can be included in appropriate form kits. Examples of suitable packaging include, among others, hermetically sealed sheets, plastics or the like, unit dose containers, blister packs, and strip packs.
[00258] An active ingredient can be combined in an intimate mixture with a pharmaceutical carrier according to conventional techniques of pharmaceutical manipulation. The carrier can take a wide variety of forms depending on the form of preparation desired for administration. In preparing the compositions for oral dosage form, any of the pharmaceutical media may be employed as carriers, such as, for example, water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents, and the like in the case of liquid preparations oral (such as suspensions, solutions, and elixirs) or aerosols; or carriers such as starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, and disintegrating agents can be used in the case of solid oral preparations, in some embodiments without employing the use of lactose. For example, suitable carriers include powders, capsules, and tablets, with solid oral preparations. If desired, tablets can be coated by standard aqueous or non-aqueous techniques.
Suitable binders for use in pharmaceutical compositions and dosage forms include, among others, corn starch, potato starch, or other starches, gelatin, natural and synthetic gums such as acacia, sodium alginate, alginic acid, other alginates, powdered tragacanth, guar gum, cellulose and its derivatives (eg, ethyl cellulose, cellulose acetate, calcium carboxymethyl cellulose, sodium carboxymethyl cellulose), polyvinyl pyrrolidone, methyl cellulose, pregelatinized starch, hydroxypropyl methyl cellulose, microcrystalline cellulose, and mixtures thereof.
[00260] Examples of fillers suitable for use in the pharmaceutical compositions and dosage forms disclosed herein include, among others, talc, calcium carbonate (e.g., granules or powder), microcrystalline cellulose, powdered cellulose, dextrates, kaolin, mannitol, silicic acid, sorbitol, starch, pregelatinized starch, and mixtures thereof.
[00261] Disintegrants can be used in the compositions of the invention to provide tablets that disintegrate when exposed to an aqueous environment. Too much disintegrant can produce pills that can disintegrate in the bottle. Little may be insufficient for disintegration to occur and may thus alter the rate and extent of release of the active ingredients from the dosage form. Thus, a sufficient amount of disintegrant that is neither too little nor too much to detrimentally alter the release of the active ingredients can be used to form dosage forms of the compounds disclosed herein. The amount of disintegrant used may vary based on the type of formulation and mode of administration, and may be readily discernible to one of skill in the art. About 0.5 to about 15 percent by weight of disintegrant, or about 1 to about 5 percent by weight of disintegrant, can be used in the pharmaceutical composition. Disintegrants that can be used to form pharmaceutical compositions and dosage forms of the invention include, among others, agar-agar, alginic acid, calcium carbonate, microcrystalline cellulose, croscarmellose sodium, crospovidone, polacrylin potassium, sodium starch glycolate, starch potato or cassava, other starches, pregelatinized starch, other starches, clays, other algins, other celluloses, gums or mixtures thereof.
[00262] Lubricants that can be used to form the pharmaceutical compositions and dosage forms of the invention include, among others, calcium stearate, magnesium stearate, mineral oil, light mineral oil, glycerin, sorbitol, mannitol, polyethylene glycol, other glycols, stearic acid, sodium lauryl sulfate, talc, hydrogenated vegetable oil (eg peanut oil, cottonseed oil, sunflower oil, safflower oil, olive oil, corn oil, and soybean oil), stearate of zinc, ethyl, ethyl ureate, agar, or mixtures thereof. Additional lubricants include, for example, a siloid silica gel, a coagulated synthetic silica aerosol, or mixtures thereof. A lubricant may optionally be added, in an amount of less than about 1 weight percent of the pharmaceutical composition.
[00263] When aqueous suspensions and/or elixirs are desired for oral administration, the essential active ingredient in these can be combined with various sweetening or flavoring agents, coloring or coloring substances and, if so desired, emulsifying and/or suspending agents, together with such diluents as water, ethanol, propylene glycol, glycerin and various combinations thereof.
Tablets may be uncoated or coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thus provide a sustained action over a longer period of time. For example, one that delays time such as glyceryl monostearate or glyceryl distearate may be employed. Formulations for oral use may further be presented as hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent, for example calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules in which the ingredient active is mixed with water or an oily medium, eg peanut oil, liquid paraffin or olive oil.
[00265] Surfactants that can be used to form pharmaceutical compositions and dosage forms of the invention include, among others, hydrophilic surfactants, lipophilic surfactants, and mixtures thereof. That is, a mixture of hydrophilic surfactants can be employed, a mixture of lipophilic surfactants can be employed, or a mixture of at least one hydrophilic surfactant and at least one lipophilic surfactant can be employed.
[00266] A suitable hydrophilic surfactant may generally have an HLB value of at least 10, while suitable lipophilic surfactants may generally have an HLB value of or less than about 10. An empirical parameter used to characterize the relative hydrophilicity and hydrophobicity of compounds nonionic amphiphilic is the hydrophilic-lipophilic balance ("HLB value"). Surfactants with low HLB values are more lipophilic or hydrophobic, and have greater solubility in oils, while surfactants with higher HLB values are more hydrophilic, and have greater solubility in aqueous solutions. Hydrophilic surfactants are generally considered to be those compounds having an HLB value greater than about 10, as well as anionic, cationic, or zwitterionic compounds for which the HLB scale is not generally applicable. Similarly, lipophilic (ie, hydrophobic) surfactants are compounds having an HLB value equal to or less than about 10. However, a surfactant's HLB value is merely an approximate guide generally used to enable formulation of industrial emulsions, pharmaceuticals and cosmetics.
[00267] Hydrophilic surfactants can be ionic or non-ionic. Suitable ionic surfactants include, among others, alkylammonium salts; fusidic acid salts; fatty acid derivatives of amino acids, oligopeptides, and polypeptides; glyceride derivatives of amino acids, oligopeptides, and polypeptides; hydrogenated lecithins and lecithins; lysolecithins and hydrogenated lysolecithins; phospholipids and derivatives thereof; lysophospholipids and derivatives thereof; carnitine fatty acid ester salts; salts of alkyl sulfates; fatty acid salts; docusate sodium; acylactylates; mono- and di-acetylated tartaric acid esters of mono- and di-glycerides; succinylated mono- and di-glycerides; citric acid esters of mono- and di-glycerides; and mixtures thereof.
[00268] Within the aforementioned group, ionic surfactants include, by way of example: lecithins, lysolecithin, phospholipids, lysophospholipids and derivatives thereof; fatty acid ester salts of carnitine; salts of alkyl sulfates; fatty acid salts; docusate sodium; acylactylates; mono- and di-acetylated tartaric acid esters of mono- and di-glycerides; succinylated mono- and di-glycerides; citric acid esters of mono- and di-glycerides; and mixtures thereof.
[00269] Ionic surfactants may be the ionized forms of lecithin, lysolecithin, phosphatidylcholine, phosphatidylethanolamine, phosphatidylglycerol, phosphatidic acid, phosphatidylserine, lysophosphatidylcholine, lysophosphatidylethanolamine, lysophosphatidylglycerol, lysophosphatidylethanolamine, lysophosphatidyl phosphatylamine, lysophosphatidyl phosphatylamine acid , stearoyl-2-lactylate, stearoyl lactylate, succinylated monoglycerides, mono/diacetylated tartaric acid esters of mono/diglycerides, citric acid esters mono/diglyceride esters, colilsarcosine, caproate, caprylate, caprate, palmite oleate, laurate , ricinoleate, linoleate, linolenate, stearate, lauryl sulfate, teracecyl sulfate, docusate, lauroyl carnitines, palmitoyl carnitines, myristoyl carnitines, and salts and mixtures thereof.
[00270] Nonionic hydrophilic surfactants may include, but are not limited to, alkylglycosides; alkyl maltosides; alkylthioglycosides; lauryl macrogolglycerides; polyoxyalkylene alkyl ethers such as polyethylene glycol alkyl ethers; polyoxyalkylene alkylphenols such as polyethylene glycol alkyl phenols; polyoxyalkylene alkyl phenol fatty acid esters such as polyethylene glycol monoester fatty acids and polyethylene glycol diester fatty acids; polyethylene glycol glycerol fatty acid esters; polyglycerol fatty acid esters; polyoxyalkylene sorbitan fatty acid esters such as polyethylene glycol sorbitan; hydrophilic transesterification products of a polyol with at least one member of the group consisting of glycerides, vegetable oils, hydrogenated vegetable oil, fatty acids, and sterols; polyoxyethylene sterols, derivatives and the like; polyoxyethylated vitamins and derivatives thereof; polyoxyethylene-polyoxypropylene block copolymers; and mixtures thereof; fatty acid esters of polyethylene glycol sorbitan and hydrophilic transesterification products of a polyol with at least one member of the group consisting of triglycerides, vegetable oils, and hydrogenated vegetable oil. The polyol can be glycerol, ethylene glycol, polyethylene glycol, sorbitol, propylene glycol, pentaerythritol, or a saccharide.
[00271] Other nonionic hydrophilic surfactants include, but are not limited to, PEG-10 laurate, PEG-12 laurate, PEG-20 laurate, PEG-32 laurate, PEG-32 dilaurate, PEG-12 oleate, PEG-15 oleate, PEG- 20 oleate, PEG-20 dioleate, PEG-32 oleate, PEG-200 oleate, PEG-400 oleate, PEG-15 stearate, PEG-32 distearate, PEG-40 stearate, PEG-100 stearate, PEG-20 dilaurate, PEG- 25 glyceryl trioleate, PEG-32 dioleate, PEG-20 glyceryl laurate, PEG-30 glyceryl laurate, PEG-20 glyceryl stearate, PEG-20 glyceryl oleate, PEG-30 glyceryl oleate, PEG-30 glyceryl laurate, PEG-40 glyceryl laurate , PEG-40 palm kernel oil, PEG-50 hydrogenated castor oil, PEG-40 castor oil, PEG-35 castor oil, PEG-60 castor oil, PEG-40 hydrogenated castor oil, hydrogenated PEG-60 castor oil, PEG-60 corn oil, PEG-6 caprate/caprylate glycerides, PEG-8 caprate/caprylate glycerides, polyglyceryl-10 laurate, PEG-30 cholesterol, PEG-25 phytosterol, PEG-30 soy sterol, PEG -20 trioleate, PEG-40 sorbite in oleate, PEG-80 sorbitan laurate, polysorbate 20, polysorbate 80, POE-9 lauriether, POE-23 lauriether, POE-10 oleyl ether, POE-20 oleyl ether, POE-20 stearyl ether, tocopheryl PEG-100 succinate , PEG-24 cholesterol, polyglyceryl-10oleate, Tween 40, Tween 60, sucrose monostearate, sucrose monolaurate, sucrose monopalmitate, PEG 10-100 nonyl phenol series, PEG 15100 octyl phenol series, and poloxamers.
[00272] Suitable lipophilic surfactants include, by way of example only: fatty alcohols; glycerol fatty acid esters; acetylated glycerol fatty acid esters; lower alcohol fatty acid esters; propylene glycol fatty acid esters; sorbitan fatty acid esters; polyethylene glycol sorbitan fatty acid esters; etherols and sterol derivatives; polyoxyethylated sterols and sterol derivatives; polyethylene glycol alkyl ethers; sugar esters; sugar ethers; lactic acid derivatives of mono- and di-glycerides; hydrophobic transesterification products of a polyol with at least one member of the group consisting of glycerides, vegetable oils, hydrogenated vegetable oil, fatty acids and sterols; oil-soluble vitamins/vitamin derivatives; and mixtures thereof. Within this group, preferred lipophilic surfactants include fatty acid esters of glycerol, fatty acid esters of propylene glycol, and mixtures thereof, or are hydrophobic transesterification products of a polyol with at least one member of the group consisting of vegetable oils, oil hydrogenated vegetable, and triglycerides.
[00273] In one embodiment, the composition may include a solubilizer to ensure good solubilization and/or dissolution of a compound of the present invention and to minimize precipitation of the compound of the present invention. This can be especially important for compositions for non-oral use, for example compositions for injection. A solubilizer can further be added to increase the solubility of the hydrophilic drug and/or other components, such as surfactants, or to maintain the composition as a stable solution or dispersion.
[00274] Examples of suitable solubilizers include, among others, the following: alcohols and polyols such as ethanol, isopropanol, butanol, benzyl alcohol, ethylene glycol, propylene glycol, butanediols and isomers thereof, glycerol, pentaerythritol, sorbitol, mannitol, transcutol, dimethyl isosorbide, polyethylene glycol, polypropylene glycol, polyvinyl alcohol, hydroxypropyl methylcellulose and other cellulose derivatives, cyclodextrins and cyclodextrin derivatives; polyethylene glycol ethers having an average molecular weight of about 200 to about 6000, such as tetrahydrofurfuryl alcohol PEG ether (glycofurol) or methoxy PEG; amides and other nitrogen-containing compounds such as 2-pyrrolidone, 2-piperidone, . epsilon. -caprolactam, N-alkylpyrrolidone, N-hydroxyalkylpyrrolidone, N-alkylpiperidone, N-alkylcaprolactam, dimethylacetamide and polyvinylpyrrolidone; esters such as ethyl propionate, tributylcitrate, acetyl triethylcitrate, acetyl tributyl citrate, triethylcitrate, ethyl oleate, ethyl caprylate, ethyl butyrate, triacetin, propylene glycol monoacetate, propylene glycol diacetate, ε-caprolactone and isomers thereof, δ-valerolactone - butyrolactone and its isomers; and other solubilizers known in the art, such as dimethylacetamide, dimethyl isosorbide, N-methyl pyrrolidones, monooctanoin, diethylene glycol monoethyl ether, and water.
[00275] Mixtures of solubilizers can be further used. Examples include, but are not limited to, triacetin, triethylcitrate, ethyl oleate, ethyl caprylate, dimethylacetamide, N-methylpyrrolidone, N-hydroxyethylpyrrolidone, polyvinylpyrrolidone, hydroxypropyl methylcellulose, hydroxypropylcyclodextrins, ethanol, polyethylene glycol 200-100, glycofurol, transpropyl dimethyl sorbitol. Particularly preferred solubilizers include sorbitol, glycerol, triacetin, ethyl alcohol, PEG-400, glycofurol and propylene glycol.
[00276] The amount of solubilizer that can be included is not particularly limited. The amount of certain solubilizer can be limited to a bioacceptable amount, which can be readily determined by one of skill in the art. In some cases, it may be advantageous to include amounts of solubilizers in excess of bioacceptable amounts, for example to maximize drug concentration, with excess solubilizer removed before providing the composition to a patient using conventional techniques such as distillation or evaporation. Thus, if present, the solubilizer can be in a weight ratio of 10%, 25%, 50%, 100%, or up to about 200% by weight, based on the combined weight of the drug, and other excipients. If desired, very small amounts of solubilizer can still be used, such as 5%, 2%, 1% or even less. Typically, the solubilizer can be present in an amount of from about 1% to about 100%, more typically about 5% to about 25% by weight.
[00277] The composition may further include one or more pharmaceutically acceptable additives and excipients. Said additives and excipients include, among others, viscosity reducer, anti-foaming agents, buffering agents, polymers, antioxidants, preservatives, chelating agents, viscomodulators, tonics, flavorings, dyes, odorants, opacifiers, suspending agents, binders, diluents, plasticizers, lubricants, and mixtures thereof.
[00278] Additionally, an acid or base may be incorporated into a composition to facilitate processing, enhance stability, or for other reasons. Examples of pharmaceutically acceptable bases include amino acids, amino acid esters, ammonium hydroxide, potassium hydroxide, sodium hydroxide, sodium hydrogen sulfonate, aluminum hydroxide, calcium carbonate, magnesium hydroxide, magnesium aluminum silicate, synthetic aluminum silicate, synthetic hydrocalce , magnesium aluminum hydroxide, diisopropylethylamine, ethanolamine, ethylenediamine, triethanolamine, triethylamine, triisopropanolamine, trimethylamine, tris(hydroxymethyl)aminomethane (TRIS) and the like. Also suitable are bases which are pharmaceutically salts of a stable acid, such as acetic acid, acrylic acid, adipic acid, alginic acid, alkanesulfonic acid, amino acids, ascorbic acid, benzoic acid, boric acid, butyric acid, carbonic acid, citric acid, acids fatty acids, formic acid, fumaric acid, gluconic acid, hydroquinesulfonic acid, isoascorbic acid, lactic acid, maleic acid, oxalic acid, para-bromophenylsulfonic acid, propionic acid, p-toluenesulfonic acid, salicylic acid, stearic acid, succinic acid, tannic acid , tartaric acid, thioglycolic acid, toluenesulfonic acid, uric acid, and the like. Polyprotic acid salts such as sodium phosphate, disodium hydrogen sulfate, and sodium hydrogen phosphate can also be used. When the base is a salt, the cation can be any convenient and pharmaceutically acceptable cation, such as ammonium, alkali metals, alkaline earth metals, and the like. Examples may include, but are not limited to, sodium, potassium, lithium, magnesium, calcium, and ammonium.
[00279] Suitable acids are pharmaceutically acceptable inorganic or organic acids. Examples of suitable inorganic acids include hydrochloric acid, hydrobromic acid, hydrotic acid, sulfuric acid, nitric acid, boric acid, phosphoric acid and the like. Examples of suitable organic acids include acetic acid, acrylic acid, adipic acid, alginic acid, alkanesulfonic acid, amino acids, ascorbic acid, benzoic acid, boric acid, butyric acid, carbonic acid, citric acid, fatty acids, formic acid, fumaric acid, gluconic acid, hydroquinosulfonic acid, isoascorbic acid, lactic acid, maleic acid, methanesulfonic acid, oxalic acid, para-bromophenylsulfonic acid, propionic acid, p-toluenesulfonic acid, salicylic acid, stearic acid, succinic acid, tannic acid, tartaric acid, acid thioglycolic, toluenesulfonic acid, uric acid and the like.
[00280] Pharmaceutical compositions for injection. In some embodiments, the invention provides pharmaceutical composition for injection containing a compound of the present invention and a pharmaceutical excipient suitable for injection. Components and amounts of agents in compositions are as described herein.
[00281] The forms in which the novel compositions of the present invention may be incorporated for administration by injection include aqueous or oily suspensions, or emulsions, with sesame oil, corn oil, cottonseed oil, or peanut oil, as well as elixirs, mannitol, dextrose, or a sterile aqueous solution, and the like pharmaceutical carriers.
[00282] Aqueous solutions in saline are also conventionally used for injection. Glycerol, ethanol, propylene glycol, liquid polyethylene glycol, and the like (and suitable mixtures thereof), cyclodextrin derivatives, vegetable oils may also be employed. Proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by maintenance of the required particle size in the case of dispersion, and by the use of surfactants. Prevention of the action of microorganisms can be brought about by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like.
Sterile injectable solutions are prepared by incorporating the compound of the present invention in the required amount in the appropriate solvent with various other ingredients as enumerated above, as required, followed by filter sterilization. Generally, dispersions are prepared by incorporating the various sterilized active ingredients into a sterile vehicle which contains the basic dispersion medium and the required other ingredients from those enumerated above. In the case of sterile powders for preparing sterile injectable solutions, certain desirable methods of preparation are vacuum drying or lyophilization techniques which produce a powder of the active ingredient plus any additional desired ingredient from a solution previously sterilized by filtration.
[00284] Pharmaceutical compositions for topical (eg transdermal) delivery. In some embodiments, the inventio provides a pharmaceutical composition for transdermal administration containing a present compound of the invention and the pharmaceutical excipient suitable for transdermal administration.
[00285] The compositions of the present invention can be formulated into preparations in solid, semi-solid, or liquid form suitable for topical or local administration, such as gels, jellies, water-soluble, creams, lotions, suspensions, powders, foams, pastes, ointments, solutions, oils, pastes, suppositories, sprays, emulsions, saline solutions, dimethylsulfoxide (DMSO) based solutions. In general, carriers with higher density are able to provide an area with prolonged exposure to the active ingredients. In contrast, a solution formulation can provide more immediate exposure of the active ingredient to the chosen area.
[00286] Pharmaceutical compositions may also comprise suitable solid or gel-phase carriers or excipients, which are compounds that allow increased penetration of, or assist in the delivery of therapeutic molecules across the skin's stratum corneum permeability barrier. There are many such penetration enhancing molecules known to those trained in the art of topical formulation. Examples of such excipients and carriers include, but are not limited to, humectants (eg, urea), glycols (eg, propylene glycol), alcohols (eg, ethanol), fatty acids (eg, oleic acid), surfactants (eg, isopropyl myristate and sodium lauryl sulfate), pyrrolidones, glycerol monolaurate, sulfoxides, terpenes (eg, menthol), amines, amides, alkanes, alkanols, water, calcium carbonate, calcium phosphate, various sugars , starches, cellulose derivatives, gelatin, and polymers such as polyethylene glycols.
[00287] Another exemplary formulation for use in the methods of the present invention employs transdermal delivery devices ("stickers"). Such transdermal systems can be used to provide continuous or discontinuous infusion of a compound of the present invention in controlled amounts, with or without another agent.
[00288] The use and construction of transdermal systems for the delivery of pharmaceutical agents is well known in the art. See, for example, US Patents 5,023,252, 4,992,445 and 5,001,139. Such adhesives can be constructed for discontinuous or discontinuous, pulsatile, on-demand delivery of pharmaceutical agents.
[00289] Pharmaceutical compositions for inhalation. Compositions for insufflation or inhalation include suspensions in pharmaceutically acceptable aqueous or organic solvents, or mixtures thereof, and powders. Suitable solid or liquid compositions may contain pharmaceutically acceptable excipients as described above. Preferably, the compositions are administered by the oral, respiratory or nasal routes for systemic or local effect. Compositions in pharmaceutically acceptable solvents can preferably be nebulized using inert gases. Nebulized solutions can be inhaled directly from the nebulizing device or the nebulizing device can be attached to a face mask tent, or intermittent positive pressure breathing machine. The solution, suspension, or powder compositions can be administered, preferably, orally or nasally, from devices that deliver the formulation in a suitable manner.
[00290] Other pharmaceutical compositions. Pharmaceutical compositions can also be prepared from compositions described herein and one or more pharmaceutically acceptable excipients suitable for sublingual, buccal, rectal, intraosseous, intraocular intranasal, epidural, or intraspinal administration. Preparations for such pharmaceutical compositions are well known in the art. See, for example, Anderson, Philip O.; Knoben, James E.; Troutman, William G, eds. , Handbook of Clinical Drug Data, Tenth Edition, McGraw-Hill, 2002; Pratt and Taylor, eds. , Principles of Drug Action, Third Edition, Churchill Livingston, New York, 1990; Katzung, ed. , Basic and Clinical Pharmacology, Ninth Edition, McGraw Hill, 20037ybg; Goodman and Gilman, eds. , The Pharmacological Basis of Therapeutics, Tenth Edition, McGraw Hill, 2001; Remingtons Pharmaceutical Sciences, 20th Ed., Lippincott Williams & Wilkins., 2000; Martindale, The Extra Pharmacopoeia, Thirty-Second Edition (The Pharmaceutical Press, London, 1999); all of which being incorporated by reference in their entirety.
[00291] The administration of the compounds or pharmaceutical composition of the present invention can be carried out by any method that enables delivery of the compounds to the site of action. These methods include oral routes, intraduodenal routes, parenteral injection (including intravenous, intraarterial, subcutaneous, intramuscular, intravascular, intraperitoneal or infusion), topical (eg, transdermal application), rectal administration, via local delivery by catheter or stent or through inhalation. The compounds can also be administered intraadipose or intrathecally.
The amount of compound administered will be dependent on the mammal being treated, the severity of the disorder or condition, the rate of administration, the disposition of the compound and the judgment of the prescribing physician. However, an effective dosage is in the range of about 0.001 to about 100 mg per kg of body weight per day, preferably about 1 to about 35 mg/kg/day, in single or divided doses. For a 70 kg human, this would be the amount of from about 0.05 to 7 g/day, preferably about 0.05 to about 2.5 g/day. In some cases, dosage levels below the lower limit of the above range may be more than adequate, while in other cases even larger doses may be employed without causing any harmful side effects, for example, by dividing these larger doses into several small doses for administration throughout the day.
In some embodiments, a compound of the invention is administered in a single dose. Typically, such administration will be by injection, for example, intravenously, in order to introduce the agent rapidly. However, other routes can be used as appropriate. A single dose of a compound of the invention can also be used to treat an acute condition.
In some embodiments, a compound of the invention is administered in multiple doses. The dosage can be about once, twice, three times, four times, five times, six times, or more than six times a day. The dosage can be about once a month, once every two weeks, once a week, or once every other day. In another embodiment a compound of the invention and another agent are administered together about once a day to about 6 times a day. In another embodiment, administration of a compound of the invention and an agent continues for less than about 7 days. In yet another mode of administration continues for more than about 6, 10, 14, 28 days, two months, six months, or a year. In some cases, continuous dosing is achieved and maintained for as long as necessary.
[00295] Administration of the agents of the invention may continue for as long as necessary. In some embodiments, an agent of the invention is administered for more than 1, 2, 3, 4, 5, 6, 7, 14, or 28 days. In some embodiments, an agent of the invention is administered for less than 28, 14, 7, 6, 5, 4, 3, 2 or 1 day. In some embodiments, an agent of the invention is chronically administered on a continuous basis, for example, to treat chronic effects.
An effective amount of a compound of the invention can be administered either in single or multiple doses, by any of the accepted modes of administration of agents that have similar utilities, including the rectal, buccal, intranasal and transdermal route, by intraarterial injection , intravenous, intraperitoneal, parenteral, intramuscular, subcutaneous, oral, topical, or as an inhalation.
[00297] The compositions of the invention can also be delivered through an impregnated or coated device, such as a stent, for example, or a cylindrical polymer inserted into the artery. Such a method of administration can, for example, aid in preventing or ameliorating restenosis after procedures such as balloon angioplasty. Without being limited by theory, the compounds of the invention may delay or inhibit the migration and proliferation of smooth muscle cells in the arterial wall that contribute to restenosis. A compound of the invention can be administered, for example, by local delivery from a stent strut, from a stent graft, from grafts, or from a stent cap or sheath. In some embodiments, a compound of the invention is mixed with a matrix. This matrix can be a polymeric matrix, and can serve to bond the compound to the stent. Suitable polymeric matrices for such use include, for example, lactone-based polyesters or copolyesters such as polylactide, polycaprolacton glycolide, polyorthoesters, polyanhydrides, polyamino acids, polysaccharides, polyphosphazenes, poly(ether-ester) copolymers (for example, PEO-PLLA ); polydimethylsiloxane, poly(ethylene vinyl acetate), acrylate-based polymers or copolymers (e.g., polyhydroxyethyl methylmethacrylate, polyvinyl pyrrolidinone), fluorinated polymers such as polytetrafluoroethylene and cellulose esters. Suitable matrices may be non-degrading or may degrade over time, releasing the compound or compounds. The compounds of the invention can be applied to the stent surface by various methods, such as dip/spin coating, spray coating, dip coating, and/or brush coating. The compounds can be applied in a solvent and the solvent allowed to evaporate, thus forming a layer of compound on the stent. Alternatively, the compound can be located in the body of the stent or graft, for example, in microchannels or micropores. When implanted, the compound diffuses out of the stent body to contact the arterial wall. Such stents can be prepared by dipping a stent fabricated to contain such micropores or microchannels in a solution of the compound of the invention in a suitable solvent, followed by evaporation of the solvent. Excess drug on the stent surface can be removed by an additional brief solvent wash. In still other embodiments, compounds of the invention can be covalently attached to a stent or graft. A covalent linker that degrades in vivo can be used, leading to the release of the compound of the invention. Any bio-labile linkages can be used for this purpose, such as ester, amide, or anhydride linkages. The compounds of the invention can additionally be administered intravascularly from a balloon used during angioplasty. Extravascular administration of the compounds via the pericardium or via advential application of formulations of the invention can also be performed to decrease restenosis.
[00298] A variety of stent devices that can be used as described are disclosed, for example, in the following references, all of which are incorporated herein by reference: US Patent No. 5,451,233; US Patent No. 5,040,548; US Patent No. 5,061,273; US Patent No. 5,496,346; US Patent No. 5,292,331; US Patent No. 5,674,278; US Patent No. 3,657,744; US Patent No. 4,739,762; US Patent No. 5,195,984; US Patent No. 5,292,331; US Patent No. 5,674,278; US Patent No. 5,879,382; US Patent No. 6,344,053.
The compounds of the invention can be administered in dosages. It is known in the art that, due to inter-individual variability in the pharmacokinetics of compounds, individualization of dosage regimen is necessary for optimal therapy. The dosage for a compound of the invention can be found by routine experimentation, taking into account the present disclosure.
[00300] When a compound of the invention is administered in a composition comprising one or more agents, and the agent has a shorter half-life than the compound of the invention, single dose forms of the agent and the compound of the invention may be adjusted accordingly.
[00301] The pharmaceutical composition in question, for example, may be in a form suitable for oral administration as a tablet, capsule, pill, powder, sustained release formulations, solution, suspension, for parenteral injection as a solution, suspension or emulsion sterile, for topical administration as an ointment or cream or for rectal administration as a suppository. The pharmaceutical composition can be in unitary dosage forms suitable for single administration of precise dosages. The pharmaceutical composition will include a conventional pharmaceutical carrier or excipient and a compound according to the invention as an active ingredient. In addition, they may include other medicinal or pharmaceutical agents, carriers, adjuvants, etc.
[00302] Examples of parenteral administration forms include solutions or suspensions of the active compound in sterile aqueous solutions, for example, aqueous dextrose or propylene glycol solutions. Such dosage forms can be suitably buffered if desired.
[00303] The invention also provides kits. Kits include a compound or compounds of the present invention as described herein, in appropriate packaging, and written material which may include instructions for use, discussion of clinical studies, lists of side effects, and the like. These kits may also include information, such as scientific literature references, package insert materials, results of clinical trials and/or summaries thereof and the like, that indicate or establish the activities and/or advantages of the composition, and/or that describe the dosage, administration, side effects, drug interactions, or other information useful to the health care professional. Such information can be based on the results of various studies, for example, studies using experimental animals involving in vivo models and studies based on human clinical trials. The kit may also contain another agent. In some embodiments, the compound of the present invention and the agent are provided as separate compositions in separate containers within the kit. In some embodiments, the compound of the present invention and the agent are provided as a single composition within a container in the kit. Suitable packaging and additional items for use (e.g., measuring cup for liquid preparations, wrapping sheet to minimize exposure to air, and the like) are known in the art and can be included in the kit. The Kits described in this document may be provided, marketed and/or promoted by the healthcare professional, including physicians, nurses, pharmacists, form employees, and the like. Kits can also, in some modalities, be sold directly to the consumer.
The invention also provides methods of using the compounds or pharmaceutical compositions of the present invention to treat diseases, including but not limited to diseases associated with malfunction of one or more types of PI3 kinase (particularly PI3α kinase), and/or mTOR . A detailed description of conditions and disorders mediated by p110δ kinase activity is set forth in Sadu et al., WO 01/81346, which is incorporated herein by reference in its entirety for all purposes.
The invention also relates to a method of treating a hyperproliferative disorder in a mammal which comprises administering to said mammal a therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt, ester, pro. drug, solvate, or hydrate thereof. In some modalities, said method relates to the treatment of cancer, such as leukemia, thymus, brain, lung, squamous cell breast, skin, eye, retinoblastoma, intraocular melanoma, oral cavity and oropharyngeal cancer , bladder, gastric, stomach, pancreas, bladder, breast, cervical, head, neck, renal, kidney, liver, ovary, prostate, colorectal, esophagus, testicle, thyroid, gynecological, CNS, PNS, AIDS related (eg , lymphoma and Kaposi's sarcoma) or virus-induced cancer. In some modalities the cancer is cerebral glioma, glioblastoma, leukemia, Bannayan-Zonana syndrome, Cowden disease, Lhermitte-Duclos disease, breast cancer, inflammatory breast cancer, Wilm's tumor, Ewing's sarcoma, rhabdomyosarcoma, ependymoma, medulloblastoma, sarcoma, osteosarcoma, or a giant cell tumor of the bone or thyroid. In other embodiments, a compound of the invention is used to treat T lymphoblastic leukemia, chronic myelogenous leukemia, chronic lymphocytic leukemia, hairy cell leukemia, acute lymphoblastic leukemia, acute myelogenous leukemia, chronic neutrophilic leukemia, acute T lymphoblastic leukemia , plasmacytoma, large immunoblastic cell leukemia, multiple myeloma, mantle cell leukemia, megakaryoblastic leukemia, acute megakaryocytic leukemia, promyelocytic leukemia, or erythroleukemia. In still other embodiments, the invention provides compounds for the treatment of malignant lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, lymphoblastic T-cell lymphoma, Burkitt's lymphoma or follicular lymphoma. In other embodiments, the invention relates to the treatment of a cancer that is neuroblastoma, bladder cancer, urothelial cancer, vulvar cancer, endometrial cancer, mesothelioma, salivary gland cancer, hepatocellular carcinoma, nasopharyngeal cancer, oral cancer, and tumors gastrointestinal stromals.
[00306] In some embodiments, said method relates to the treatment of a non-cancerous hyperproliferative disorder such as benign hyperplasia of the skin (eg, psoriasis), restenosis, or prostate (eg, benign prostatic hypertrophy (BPH)) .
The methods of treatment provided herein comprise administering to the subject a therapeutically effective amount of a compound of the invention. In one embodiment, the present invention provides a method of treating a disorder of inflammation, including autoimmune diseases, in a mammal. The method comprises administering to said mammal a therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt, ester, prodrug, solvate, hydrate or derivative thereof. Examples of autoimmune diseases include, but are not limited to acute disseminated encephalomyelitis (ADEM), Addison's disease, antiphospholipid antibody syndrome (APS), aplastic anemia, autoimmune hepatitis, celiac disease, Crohn's disease, diabetes mellitus (type 1) , Goodpasture's syndrome, Graves' disease, Guillain-Barré syndrome (GBS), Hashimoto's disease, lupus erythematosus, multiple sclerosis, myasthenia gravis, opsoclonus myoclonus syndrome (WHO), otic neuritis, Ord's thyroiditis, oemphigus, polyarthritis, primary biliary cirrhosis, psoriasis, rheumatoid arthritis, Reiter's syndrome, Takayasu's arteritis, temporal arteritis (also known as "giant cell arteritis"), warm autoimmune hemolytic anemia, Wegener's granulomatosis, alopecia universalis, Chagas' disease syndrome from chronic fatigue, dysautonomia, endometriosis, hidradenitis suppurativa, interstitial cystitis, neuromyotonia, sarcoidosis, colitis, ulcerative scleroderma, vitiligo, and vulvodynia. Other diseases include bone resorption, disorders, thrombosis, lung inflammation, brain infection/inflammation, meningitis and encephalitis.
[00308] In one aspect, one or more of the subject methods may be effective in relieving symptoms associated with rheumatoid arthritis including, but not limited to, a reduction in joint swelling, a reduction in anti-collagen serum levels, and/or a reduction in joint pathology, such as bone resorption, cartilage damage, pannus, and/or inflammation. In another aspect, the methods in question are effective in reducing ankle inflammation by at least about 2%, 5%, 10%, 15%, 20%, 25%, 30%, 50%, 60%, or about 75-90%%. In another aspect, the methods in question are effective in reducing knee inflammation by at least about 2%, 5%, 10%, 15%, 20%, 25%, 30%, 50%, 60%, or about 75-90%% or more. In yet another aspect, the subject methods are effective in reducing serum anti-type II collagen serum levels by at least about 10%, 12%, 15%, 20%, 24%, 25%, 30%, 35%, 50%, 60%, 75%, 80%, 86%, 87%, or about 90% or more. In another aspect, the methods in question are effective in reducing ankle histopathology scores by about 5%, 10%, 15%, 20%, 25%, 30%, 40%, 50%, 60%, 75% , 80%, 90% or more. In yet another aspect, the methods in question are effective in reducing knee histopathology scores by about 5%, 10%, 15%, 20%, 25%, 30%, 40%, 50%, 60%, 75 %, 80%, 90% or more.
[00309] In other embodiments, the present invention provides methods for using the compounds or pharmaceutical compositions for treating respiratory diseases, including, but not limited to, diseases affecting the lung lobes, pleural cavity, bronchi, trachea, the upper respiratory tract, or the nerves and muscles for breathing. For example, methods for treating obstructive pulmonary disease are provided. Chronic Obstructive Pulmonary Disease (COPD) is a generic term for a group of respiratory tract diseases that are characterized by obstruction or limitation. Conditions included in this key term are: chronic bronchitis, emphysema, and bronchiectasis.
[00310] In another embodiment, the compounds described herein are used for the treatment of asthma. Furthermore, the compounds or pharmaceutical compositions described herein can be used for the treatment of endotoxemia and sepsis. In one embodiment, the compounds or pharmaceutical compositions described herein are used for the treatment of rheumatoid arthritis (RA). In yet another embodiment, the compounds or pharmaceutical compositions described herein are used for the treatment of atopic or contact dermatitis. Contact dermatitis includes irritant dermatitis, phototoxic dermatitis, allergic dermatitis, photoallergic dermatitis, contact urticaria, systemic-type contact dermatitis, and the like. Irritant dermatitis can occur when too much of a substance is used on the skin when the skin is sensitive to that substance. Atopic dermatitis, sometimes called eczema, is a type of dermatitis, an atopic skin disease.
In other embodiments, the compounds described herein are used for the treatment of cardiac conditions, including atherosclerosis, cardiac hypertrophy, cardiac myocyte dysfunction, high blood pressure and vasoconstriction. The invention also relates to a method of treating diseases related to vasculogenesis or angiogenesis in a mammal which comprises administering to said mammal a therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt, ester, prodrug. , solvate, or hydrate derived therefrom. In some embodiments, said method is for treating a disease selected from the group consisting of tumor angiogenesis, chronic inflammatory disease such as rheumatoid arthritis, atherosclerosis, inflammatory bowel disease, skin diseases such as psoriasis, eczema, and scleroderma, diabetes, diabetic retinopathy, retinopathy of prematurity, age-related macular degeneration, hemangioma, glioma, melanoma, Kaposi's sarcoma, and ovarian, breast, lung, pancreas, prostate, colon and epidermoid cancer.
[00312] Patients who can be treated with the compounds of the present invention, or a pharmaceutically acceptable salt, ester, prodrug, solvate, hydrate or derivative of said compounds, according to the methods of the present invention include, for example, patients who have been diagnosed as having psoriasis, restenosis, atherosclerosis; BPH, breast cancer, such as a ductal carcinoma in the duct tissue in a mammary gland, medullary carcinomas, colloid carcinomas, tubular carcinomas, and inflammatory breast cancer; ovarian cancer, including epithelial ovarian tumors such as adenocarcinoma in the ovary and an adenocarcinoma that has migrated from the ovary into the abdominal cavity; uterine cancer; cervical cancer, such as epithelial cervical adenocarcinoma, including squamous cell carcinoma and adenocarcinoma; prostate cancer, such as a prostate cancer selected from the following: an adenocarcinoma or an adenocarinoma that has migrated to bone; pancreatic cancer such as epithelioid carcinomas in the pancreatic duct tissue and an adenocarcinoma in a pancreatic duct, bladder carcinoma such as a transitional cell carcinoma in the urinary bladder, urothelial carcinomas (transition cell carcinomas), tumors in the urothelial cells lining the bladder, squamous cell carcinoma, adenocarcinoma and small cell cancer and leukemia such as acute myelogenous leukemia (AML), acute lymphocytic leukemia, chronic lymphocytic leukemia, chronic myelogenous leukemia, hairy cell leukemia, myelodysplasia, acute rheumatic diseases, myeloid leukemia (AML), chronic myelogenous leukemia (CML), mastocytosis, chronic lymphocytic leukemia (CLL), multiple myeloma (MM), and myelodysplastic syndrome (MDS); bone cancer, lung cancer such as non-small cell lung (NSCLC), which is divided into squamous cell carcinomas, adenocarcinomas, large cell and undifferentiated cell carcinomas, and small cell lung cancer; skin cancers such as basal cell carcinoma, melanoma, squamous cell carcinoma and actinic keratosis, which is a skin condition that sometimes develops into squamous cell carcinoma; retinoblastoma of the eye; cutaneous or intraocular (eye) melanoma, primary liver cancer (cancer that starts in the liver); kidney cancer, thyroid cancer such as follicular, papillary, medullary, and anaplastic, AIDS-related such as diffuse large B-cell lymphoma, B-cell lymphoma, immunoblastic lymphoma, and cleaved non-small cell lymphoma; Kaposi's sarcoma; virus-induced cancers including hepatitis B virus (HBV), hepatitis C virus (HCV), and hepatocellular carcinoma; human lymphotropic virus type 1 (HTLV-1) and adult T-cell leukemia/lymphoma, and human papilloma virus (HPV) and cervical cancer; central cancers of the central nervous system (CNS), such as primary brain tumor, which includes gliomas (astrocytoma, anaplastic astrocytoma, or glioblastoma multiforme), Oligodendroglioma, ependymoma, meningioma, lymphoma, Schwannoma, and medulloblastoma; Peripheral Nervous System (PNS) cancers, such as acoustic neuromas and peripheral nerve sheath malignant tumor (MPNST), including neurofibromas and schwannomas, malignant fibrous cytoma, malignant fibrous histiocytoma, malignant meningioma, malignant mesothelioma, and mixed malignant mullerian tumor, oral cavity and oropharyngeal cancer such as hypopharyngeal cancer, laryngeal cancer, nasopharyngeal cancer, and oropharyngeal cancer, stomach cancer such as lymphomas, gastric stromal tumors and carcinoid tumors, testicular cancer such as cell tumors germ cells (GCTs), which include seminomas and non-seminomas, and gonadal stromal tumors, which include Leydig cell tumors and Sertoli cell tumors, thymus cancer such as thymomas, thymus carcinomas, Hodgkin's disease, non-lymphoma carcinoids -Hodgkin or carcinoid tumors; rectal cancer, and colon cancer.
The invention also relates to a method of treating diabetes in a mammal comprising administering to said mammal a therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt, ester, prodrug, solvate, hydrate or its derivative thereof.
[00314] In addition, the compounds described here can be used to treat acne.
[00315] In addition, the compounds described herein can be used for the treatment of arteriosclerosis, including atherosclerosis. Arteriosclerosis is a general term that describes any hardening of the medium or large arteries. Atherosclerosis is a hardening of an artery specifically due to an atheromatous plaque.
[00316] In addition, the compounds described here can be used for the treatment of glomerulonephritis. Glomerulonephritis is a primary or secondary autoimmune kidney disease characterized by inflammation of the glomeruli. It may be asymptomatic, or present with hematuria and/or proteinuria. There are many recognized types, divided into acute, subacute, or chronic glomerulonephritis. Causes are infectious (bacterial, viral or parasitic pathogens), autoimmune or paraneoplastic.
[00317] In addition, the compounds described herein can be used for the treatment of bursitis, lupus, acute disseminated encephalomyelitis (ADEM), Addison's disease, antiphospholipid antibody syndrome (APS), aplastic anemia, autoimmune hepatitis, celiac disease, disease Crohn's disease, diabetes mellitus (type 1), Goodpasture's syndrome, Graves' disease, Guillain-Barré syndrome (GBS), Hashimoto's disease, inflammatory bowel disease, lupus erythematosus, myasthenia gravis, opsoclonous myoclonus syndrome (OMS), neuritis optic, ord's thyroiditis, osteoarthritis, uveoretinitis, pemphigus, polyarthritis, primary biliary cirrhosis, sarcoidosis, Reiter's syndrome, Takayasu's arteritis, temporal arteritis, warm hemolytic autoimmune anemia, Wegener's granulomatosis, alopecia universalis, Chagas' disease, fatigue syndrome chronic, dysautonomia, endometriosis, hidradenitis suppurativa, interstitial cystitis, neuromyotonia, sarcoidosis, scleroderma, ulcerative colitis, vitiligo, vulvodynia, appendicitis, a rhritis, arthritis, blepharitis, bronchiolitis, bronchitis, cervicitis, cholangitis, cholecystitis, chorioamnionitis, colitis, conjunctivitis, cystitis, dacryoadenitis, dermatomyositis, endocarditis, endometritis, enteritis, enterocolitis, epicondylitis, epididymitis, gastricitis, fasciitis, gastricitis hepatitis, hidradenitis, ileitis, iritis, laryngitis, mastitis, meningitis, myelitis, myocarditis, myositis, nephritis, omphalitis, oophoritis, orchitis, osteitis, otitis, pancreatitis, mumps, pericarditis, peritonitis, pharyngitis, pleuritis, pneumonia, prophlebitis prostatitis, pyelonephritis, rhinitis, salpingitis, sinusitis, stomatitis, synovitis, tendinitis, tonsillitis, uveitis, vaginitis, vasculitis, or vulvitis.
The invention also relates to a method of treating a cardiovascular disease in a mammal comprising administering to said mammal a therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt, ester, prodrug thereof. , solvate, or hydrate derived therefrom. Examples of cardiovascular conditions include, but are not limited to, atherosclerosis, restenosis and vascular occlusion conditions, carotid obstructive disease, or ischemia.
[00319] In another aspect, the present invention provides methods for disrupting the function of a leukocyte or disrupting a function of one of the osteoclasts. The method includes contacting leukocytes or osteoclasts with an amount that disrupts the function of a compound of the invention.
[00320] In another aspect of the present invention, methods are provided for treating ophthalmic disease by administering one or more of the compounds or pharmaceutical compositions in question to the eye of a subject.
[00321] Methods are further provided for administering the compounds of the present invention through eye drops, intraocular injection, intravitreal injection, topically, or through the use of a drug elution device, implant microcapsule, or microfluidic. In some cases, the compounds of the present invention are administered with a carrier or excipient that enhances the intraocular penetration of the compound, such as an oil and water emulsion with colloidal particles having an oil core surrounded by an interfacial film.
[00322] In some cases, colloidal particles include at least one cationic agent and at least one nonionic surfactant, such as a poloxamer, tyloxapol, a polysorbate, a polyoxyethylene castor oil derivative, a sorbitan ester, or a polyoxy stearate. In some cases, the cationic agent is an alkylamine, a tertiary alkyl amine, a quaternary ammonium compound, a cationic lipid, an amine alcohol, a biguanide salt, a cationic compound, or a mixture of these. In some cases, the cationic agent is a biguanide salt such as chlorhexidine, polyaminopropyl biguanidine, phenformin, alkylbiguanidine, or a mixture thereof. In some cases, the quaternary ammonium compound is a benzalkonium halide, lauralkonium halide, hexadecyltrimethylammonium halide, cetrimide halide, tetradecyltrimethylammonium halide, dodecyltrimethylammonium halide, cetrimonium halide, benzethonium halide, debehenalkonium halide, deketone halide cetethyldimonium, cetylpyridinium halide, benzododecinium halide, chloralkyl methenamine halide, myristylalkonium halide, stearalkonium halide or a mixture of two or more of these. In some cases, the cationic agent is a benzalkonium chloride, lauralkonium chloride, benzododecinium bromide, benzthenium chloride, hexadecyltrimethylammonium bromide, tetradecyltrimethylammonium bromide, dodecyltrimethylammonium bromide, or a mixture of two or more of these. In some cases, the oil phase is mineral oil and light mineral oil, medium chain triglycerides (MCT), coconut oil; hydrogenated oils comprising hydrogenated cottonseed oil, hydrogenated palm oil, hydrogenated castor oil, or hydrogenated soybean oil; hydrogenated polyoxyethylene castor oil derivatives comprising polyoxyl-40 hydrogenated castor oil, polyoxyl-60 hydrogenated castor oil or polyoxyl-100 hydrogenated castor oil.
The invention further provides methods for modulating a PI3K and/or mTOR kinase activity by contacting the kinase with an amount of an effective amount of compound of the invention. Modular may be the inhibition or activation of kinase activity. In some embodiments, the invention provides methods for inhibiting kinase activity by contacting the kinase with an amount of an effective amount of a compound of the invention in solution. In some embodiments, the invention provides methods for inhibiting kinase activity by contacting a cell, tissue, or organ expressing the kinase of interest. In some embodiments, the invention provides methods of inhibiting the subject kinase activity including, but not limited to, rodents and mammals (e.g., humans) by administering to the subject an effective amount of a compound of the invention. In some embodiments, the percent inhibition exceeds 50%, 60%, 70%, 80%, or 90%.
[00324] In some embodiments, the kinase is selected from the group consisting of PI3 kinase including different isorforms such as PI3α kinase, PI3β kinase, PI3Y kinase, PI3δ kinase; DNA-PK; mTOR; Abl, VEGFR, Ephrin B4 receptor (EphB4); TEK receptor tyrosine kinase (TIE2); FMS-related tyrosine kinase 3 (FLT-3); platelet-derived growth factor receptor (PDGFR); RET; ATM; ATR; hSmg-1; Hck; Src; Epidermal Growth Factor Receptor (EGFR); KIT; Inulsin receptor (IR) and IGFR.
[00325] The present invention also provides methods for combination therapies in which an agent known to modulate other pathways, or other components of the same pathway, or even overlapping sets of target enzymes are used in combination with a compound of the present invention, or a pharmaceutically acceptable salt, ester, prodrug, solvate, hydrate or derivative thereof. In one aspect, such therapy includes, but is not limited to, combining the title compound with chemotherapeutic agents, therapeutic antibodies, and radiation treatment, to provide a synergistic or additive therapeutic effect.
[00326] For the treatment of autoimmune diseases, the subject compounds or pharmaceutical compositions can be used in combination with commonly prescribed drugs, including, but not limited to, Enbrel®, Remicade®, Humira®, Avonex®, and Rebif®. For the treatment of respiratory diseases, the subject compounds or pharmaceutical compositions can be administered in combination with commonly described drugs, including, but not limited to, Xolair®, Advair®, Singulair®, and Spiriva®.
The compounds of the invention can be formulated or administered in conjunction with other agents that act to alleviate the symptoms of inflammatory conditions such as encephalomyelitis, asthma and other diseases described herein. These agents include non-steroidal anti-inflammatory drugs (NSAIDs), for example, acetylsalicylic acid; ibuprofen; naproxen; indomethacin; nabumetone; tolmetin; etc. Corticosteroids are used to reduce inflammation and suppress immune system activity. The most commonly prescribed drug of this type is Prednisone. Chloroquine (Aralen) or hydroxychloroquine (Plaquenil) may also be very helpful in some people with lupus. They are most often prescribed for lupus symptoms of the skin and joints. Azathioprine (Imuran) and cyclophosphamide (Cytoxan) suppress inflammation and tend to suppress the immune system. Other agents, eg methotrexate, and cyclosporine are used to control lupus symptoms. Anticoagulants are used to prevent blood from clotting quickly. They range from very low-dose aspirin, which prevents platelets from clumping, to heparin/coumadin.
[00328] In another aspect, this invention also relates to methods and pharmaceutical compositions for inhibiting abnormal cell growth in a mammal comprising an amount of a compound of the present invention, or a pharmaceutically acceptable salt, ester, prodrug, solvate, hydrate or derivative thereof, in combination with an amount of an anti-cancer agent (for example, a chemotherapeutic agent). Many chemotherapeutic agents are presently known in the art and can be used in combination with the compounds of the invention.
[00329] In some embodiments, the chemotherapeutic is selected from the group consisting of mitotic inhibitors, alkylating agents, antimetabolites, intercalating antibiotics, growth factor inhibitors, cell cycle inhibitors, enzymes, topoisomerase inhibitors, biological response modifiers, anti-hormones, angiogenesis inhibitors, immunotherapeutic agents, proapoptotic agents and anti-androgens. Non-limiting examples are chemotherapeutic agents, cytotoxic agents, and small non-peptide molecules such as Gleevec (Imatinib mesylate), Velcade (bortezomib), Casodex (bicalutamide), Iressa (gefitinib), and adriamycin, as well as a number of chemotherapeutic agents. Non-limiting examples of chemotherapeutic agents include alkylating agents such as thiotepa and cyclophosphamide (CYTOXANTM); alkyl sulfonates such as busulfan, improsulfan and piposulfan; aziridines, such as benzodopa and carboquone, meturedopa, and uredopa; ethylenimines and methylamelamines including Altretamine, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphoramide and trimethylolomelamine; nitrogen mustards such as chlorambucil, chlornaphazine, clolophosphamide, estramustine, ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, novembichina, phenesterine, prednimustine, trofosfamide, uracil mustard; nitrosoureas such as carmustine, chlorozotocin, fotemustine, lomustine, nimustine, ranimustine; oxazaphosphorines; nitrosoureas; Triazenes, antibiotics such as anthracyclines and actinomycins and Bleomycins including aclacinomysins, actinomycin, Anthramycin, azaserine, Bleomycins, cactinomycin, calicheamicin, carabicin, carminomycin, carzinophylline, CasodexTM, Chromomycins, dactinomycin, daunoxorubicin-5, 6 L-norleucine, doxorubicin, epirubicin, esorubicin, idarubicin, marcelomycin, mitomycins, mycophenolic acid, nogalamycin, Olivomycin, peplomycin, potfiromycin, puromycin, chelamycin, rhodorubicin, streptonigrin, streptozocin, tubetarimexidin, anti-benequine as methotrexate and 5-fluorouracil (5-FU); folic acid analogues such as denopterin, methotrexate, pteropterin, trimetrexate; purine analogues such as fludarabine, 6-mercaptopurine, thiamiprine, thioguanine; pyrimidine analogues such as ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine, doxifluridine, enocitabine, floxuridine, androgens such as calusterone, dromostalonone propionate, epithiostanol, mepitiostan, testolactone; anti-adrenals such as aminoglutethimide, mitotane, trilostane; strengthening folic acid such as frolinic acid; aceglatone; aldophosphamide glycoside; aminolevulinic acid; amsacrine; bestrabucil; bisantrene; edatraxate; defofamin; demecolcine; diaziquone; elfomitine; elliptinium acetate; ethoglucide; gallium nitrate; hydroxyurea; lentinan; lonidamine; mitoguazone; mitoxantrone; mopidamol; nitracrine; pentostatin; phenamet; pyrarubicin; podophylinic acid; 2-ethylhydrazide; procarbazine; PSK.RTM;. razoxane; sizophiran; spirogermanium; tenuazonic acid; triaziquone; 2,2',2''-trichlorotriethylamine; urethane; vindesine; dacarbazine; Manomustine; mitobronitol; mitolactol; pipobroman; gacitosin; arabinoside ("Ara-C"); cyclophosphamide; thiotepa; taxanes, for example paclitaxel (TAXOL™, Bristol-Myers Squibb Oncology, Princeton, NJ) and docetaxel (TAXOTERE™, Rhone-Poulenc Rorer, Antony, France); retinoic acid; Esperamycins; capecitabine; gemcitabine and pharmaceutically acceptable salts, acids or derivatives of any of the above. Also included as suitable chemotherapeutic cell conditioners are anti-hormonal agents that act to regulate or inhibit hormone action on tumors, such as anti-estrogens, including, for example, tamoxifen (NolvadexTM), raloxifene, 4(5)-imidazoles aromatase inhibitors, 4-hydroxytamoxifen, trioxifene, keoxifene, LY 117018, onapristone and toremifene (Fareston); and antiandrogens such as flutamide, bicalutamide, nilutamide and leuprolide, goserelin; and chlorambucil; gemcitabine; 6-thioguanine; mercaptopurine, methotrexate; platinum and platinum analogues and complexes such as cisplatin and carboplatin; anti-microtubules, such as diterpenoids, including paclitaxel and docetaxel, or Vinca alkaloids, including vincristine, vinblastine, vinflunine, vindesine, and vinorelbine; etoposide (VP-16); ifosfamide; mitomycin C; mitoxantrone; vincristine; vinorelbine; Navelbine; Novantrone; teniposide; daunomycin; aminopterin; Xeloda; ibandronate; topoisomerase I and II, including inhibitors of camptothecins (for example camptothecin-11), topotecan, irinotecan and epipodophyllotoxins; RFS 2000 topoisomerase inhibitor; epothilone A or B; difluoromethylornithine (DMFO); histone deacetylase inhibitors; compounds that induce cell differentiation processes; gonadorelin agonists; methionine aminopeptidase inhibitors; compounds targeting/decreasing an activity of protein or lipid kinases; compounds that target, decrease or inhibit the activity of a protein or lipid phosphatase; anti-androgens; bisphosphonates; biological response modifiers; anti-proliferative antibodies, heparanase inhibitors; inhibitors of oncogenic Ras isoforms; telomerase inhibitors; proteasome inhibitors, compounds used to treat hematologic malignancies; compounds that target, decrease or inhibit Flt-3 activity; Hsp90 inhibitors; temozolomide (TEMODAL®); Hsp90 inhibitors such as 17-AAG (17-allylaminogeldanamycin, NSC330507), 17-DMAG (17-dimethylaminoethylamino-17-desmethoxy-geldanamycin, NSC707545), IPI-504, CNF1010, CNF2024, CNF1010 from Conforma Therapeutics; temozolomide (TEMODAL®); kinesin spindle protein inhibitors, such as SB715992 or SB743921 from GlaxoSmithKline, or pentamidine/chlorpromazine from CombinatoRx; MEK inhibitors such as ARRY142886 from PioPharma matrix, AZD6244 from AstraZeneca, PD181461 or PD0325901 from Pfizer, leucovorin, EDG ligands, anti-leukemia compounds, ribonucleotide reductase inhibitors, S-adenosylmethionine decarboxylase inhibitors, anti-proliferative antibodies or other chemotherapeutic compounds. When desired, the compounds or pharmaceutical composition of the present invention can be used in combination with frequently prescribed anticancers, such as Herceptin®, Avastin®, Erbitux®, Rituxan®, Taxol®, Arimidex®, Taxotere®, and Velcade® drugs. Further information on compounds that can be used in conjunction with the compounds of the invention is provided below.
Proteasome inhibitors include compounds that target, decrease or inhibit the activity of the proteasome. Compounds that target, decrease or inhibit proteasome activity include, for example, Bortezomid (Velcade™) and MLN 341. Matrix metalloproteinase inhibitors ("MMP" inhibitors) include, but are not limited to, peptidomimetic inhibitors and non-peptidomimetics of collagen, tetracycline derivatives, eg the peptidomimetic inhibitor hydroxamate batimastat and its orally bioavailable analogue marimastat (BB-2516) and prinomastat (AG3340) and metastat (NSC 683551) BMS-279251, BAY 12-9566, TAA211 , MMI270B or AAJ996. Compounds used in the treatment of hematologic malignancies include, but are not limited to, FMS-tyrosine such as, for example, kinase inhibitors, compounds that target, decrease or inhibit the activity of FMS-type receptor tyrosine kinase (Flt- 3R); interferon, 1-b-D -arabinofuransylcytosine (ara-C) and bisulfan; and ALK inhibitors, for example those compounds that target, decrease or inhibit anaplastic lymphoma kinase. Compounds that target, decrease or inhibit the activity of FMS-type receptor tyrosine kinase (Flt-3R) are especially compounds, proteins or antibodies that inhibit members of the Flt-3R receptor kinase family, eg, PKC412, midostaurin, a staurosporine derivative, SU11248 and MLN518.
Hsp90 inhibitors include compounds such as 17-AAG (17-allylaminogeldanamycin, NSC330507), 17-DMAG (17-dimethylaminoethylamino-17-desmethoxy-geldanamycin, NSC707545), IPI-504, CNF1010, CNF2024, CNF1010 from Conforma Therapeutics ; temozo-lomide (TEMODAL®); kinesin spindle protein inhibitors such as SB715992 or SB743921 from GlaxoSmithKline, or pentamidine/chlorpromazine from CombinatoRx; MEK inhibitors such as ARRY142886 from PioPharma Array, AZD6244 from AstraZeneca, PD181461 from Pfizer, leucovorin, EDG ligands, anti-leukemia compounds, ribonucleotide reductase inhibitors, S-adenosylmethionine decarboxylase inhibitors, anti-proliferative antibodies or other chemotherapeutic compounds.
Histone inhibitors (or "HDAC inhibitors") include compounds that inhibit a histone deacetylase and that have antiproliferative activity. This includes compounds disclosed in WO 02/22577, especially N-hydroxy-3-[4-[[(2-hydroxyethyl) [2-(1H-indol-3-yl)-ethyl]-amino]-methyl]-phenyl ]-2E-2-propenamide, N-hydroxy-3-[4-[[[2-(2-methyl-1H-indol-3-yl)-ethyl]amino]methyl]phenyl]-2E-2-propenamide and their pharmaceutically acceptable salts. It even more especially include Suberoylanilide Hydroxamic Acid (SAHA).
Bisphosphonates for use in combination with the compounds of the invention include, but are not limited to, etridonic, clodronic, tiludronic, pamidronic, alendronic, ibandronic, risedronic and zoledronic acid.
The compounds of the invention can also be used in conjunction with compounds targeting or decreasing a protein or lipid kinase activity, a protein or lipid phosphatase activity, or other anti-angiogenic compounds. Such compounds include, but are not limited to, protein tyrosine kinase and/or serine and/or threonine kinase inhibitors or lipid kinase inhibitors, for example: compounds targeting, decreasing or inhibiting the activity of growth factor-derived receptors of platelets - (PDGFR), such as compounds that target, decrease or inhibit the activity of PDGFR, especially compounds that inhibit the PDGF receptor, e.g., an N-phenyl-2-pyrimidine-amine derivative, e.g. , imatinib, SU101, SU6668 and GFB-11; compounds that target, decrease or inhibit the activity of fibroblast growth factor receptors (FGFR); compounds that target, decrease or inhibit the activity of the insulin growth factor I receptor (IGF-IR), such as compounds that target, decrease or inhibit the activity of IGF-IR, especially compounds that inhibit the kinase activity of the IGF-I receptor, such as those compounds disclosed in WO 02/092599 or as OSI906, or antibodies that target the extracellular domain of IGF-I receptors such as CP-751871, R1507, AVE1642, IMC- A12, AMG479, MK-0646, SCH717454 or their growth factors; compounds that target, decrease or inhibit the activity of the Trk receptor tyrosine kinase family, or Ephrin B4 inhibitors; compounds that target, decrease or inhibit the activity of the Axi receptor tyrosine kinase family; compounds that target, decrease or inhibit Ret receptor tyrosine kinase activity; compounds that target, decrease or inhibit Kit/SCFR receptor tyrosine kinase activity, e.g., imatinib; compounds that target, decrease or inhibit the activity of C-kit receptor tyrosine kinases (part of the PDGF-R family), such as compounds that target, decrease or inhibit the activity of the c-receptor tyrosine kinase family -Kit, especially compounds which inhibit the c-Kit receptor, for example, imatinib; compounds that target, decrease or inhibit the activity of members of the c-Abl family, their fusion gene products (eg, BCR-ABI kinase) and mutants, such as compounds that target, decrease or inhibit the activity of c-abl family members and their fusion gene products, for example an N-phenyl-2-pyrimidine-amine derivative, for example imatinib or nilotinib (AMN107); PD180970; AG957; NSC 680410; PD173955 from ParkeDavis; or dasatinib (BMS-354825); compounds that target, decrease or inhibit the activity of members of protein kinase C (PKC) and the Raf family of serine/threonine kinases, members of MEK, SRC, Jak, FAK, PDK1, PKB/Akt, and members of the Ras/MAPK family and/or cyclin dependent kinase (CDK) family members and are especially those derivatives of staurosporine disclosed in US 5,093,330, for example, midostaurin; examples of other compounds include, for example, UCN-01, safingol, BAY 43-9006, bryostatin 1, Perifosine; llmofosin; RO 318220 and RO 320432; GO 6976; Isis 3521; LY333531/LY379196; isoquinoline compounds such as those disclosed in WO 00/09495; FTIs; PD184352 or QAN697 (a P13K inhibitor) or AT7519 (CDK inhibitor); compounds that target, decrease or inhibit the activity of protein-tyrosine kinase inhibitors, such as compounds that target, decrease or inhibit the activity of protein-tyrosine kinase inhibitors include mesylate (Gleevec) or tyrphostin. A tyrphostin is preferably a low molecular weight compound (Mr < 15000), or a pharmaceutically acceptable salt thereof, especially a compound selected from the benzylidenomalonitrile class or from the class of S-arylbenzenemaloniryl or quinoline bisubstrate compounds, more especially a compound selected from the group consisting of Tyrphostin A23/RG-50810, AG 99, Tyrphostin AG 213; Tyrphostin AG 1748; Tyrphostin AG 490; Tyrphostin B44; (+) enantiomer of Tyrphostin B44; Tyrphostin AG 555, AG 494, Tyrphostin AG 556, AG957 and adafostine (4-{[(2,5-dihydroxyphenyl)-methyl]-amino}-benzoic adamantyl ester; NSC 680410, adafostine).
[00335] The compounds of the invention can also be used in combination with compounds targeting, decreasing or inhibiting the activity of the epidermal growth factor receptor tyrosine kinase family (EGFR, ErbB2, ErbB3, ErbB4 as homo or heterodimers) and their mutants , such as compounds that target, decrease or inhibit the activity of the epidermal growth factor receptor family are especially compounds, proteins or antibodies that inhibit members of the EGF receptor tyrosine kinase family, e.g. EGF, ErbB2 and ErbB3 and ErbB4 or bind to related EGF or EGF linkers, and are in particular those compounds, proteins or monoclonal antibodies generically and specifically described in EP 0 564 409, WO 99/03854, EP 0520722, EP 0 566 226 , EP 0 787 722, EP 0 837 063, US 5,747,498, WO 98/10767, WO 97/30034, WO 97/49688, WO 97/38983 and specifically WO 96/30347 (for example compounds known as CP 358774 ), WO 96/33980 (by example, compound ZD 1839) and WO 95/03283 (for example compound ZM105180); for example, trastuzumab (Herceptin™), cetuximab (Erbitux™), Iressa, Tarceva, OSI-774, Cl-1033, EKB-569, GW-2016, E1. 1 AND 2. 4, E2. 5, E6. 2, E6. 4, E2. 1 1 , E6. 3 or E7. 6.3, and 7H-pyrrolo-[2,3-d]pyrimidine derivatives which are shown in WO 03/013541; and compounds targeting, decreasing or inhibiting c-Met receptor activity, such as compounds that target, decrease or inhibit c-Met activity, especially compounds that inhibit c-Met receptor kinase activity, or antibodies that target the extracellular domain of c-Met or bind to HGF. Other anti-angiogenic compounds include compounds that have another mechanism for their activity, eg unrelated to protein or lipid, eg kinase inhibition, thalidomide (Thalomid) and TNP-470.
Non-receptor kinase angiogenesis inhibitors may also be useful in conjunction with the compounds of the present invention. Angiogenesis, in general, is linked to erbB21EGFR signaling since erbB2 and EGFR inhibitors have been shown to inhibit angiogenesis, essentially the expression of VEGF. Consequently, non-receptor tyrosine kinase inhibitors can be used in combination with the compounds of the present invention. For example, anti-VEGF antibodies, which do not recognize VEGFR (the receptor tyrosine kinase) but bind to the ligand; small molecule integrin inhibitors (alphav beta3) that will inhibit angiogenesis; endostatin and angiostatin (non-RTK) may also prove useful in combination with the described compounds. (See Bruns CJ et al (2000), Cancer Res., 60:2926-2935; Schreiber AB, Winkler ME, and Derynck R. (1986), Science, 232:1250-1253; L Yen et al (2000), Oncogene 19:3.460-3.469).
Compounds that target, decrease or inhibit the activity of a protein or lipid phosphatase include, for example, inhibitors of phosphatase 1, phosphatase 2A, or cdc25, for example, okadaic acid or derivative thereof. Compounds that induce cell differentiation processes are, for example, retinoic acid, α-y- or δ-tocopherol or α-y- or δ-tocotrienol. Cyclooxygenase inhibitors include, but are not limited to, for example, COX-2 inhibitors, 5-alkyl substituted 2-arylaminophenylacetic acid and derivatives thereof, such as celecoxib (CELEBREX), rofecoxib (VIOXX), etoricoxib, valdecoxib or a 5 -alkyl-2-arylaminophenylacetic acid, for example 5-methyl-2-(2'-chloro-6'-fluoroanilino)-phenylacetic acid, and lumiracoxib.
Heparanase inhibitors include compounds that target, decrease or inhibit the degradation of heparin sulfate, including, but not limited to, PI-88. Biological response modifiers include lymphokines and interferons, e.g., interferon Y. Inhibitors of oncogenic Ras isoforms include H-Ras, K-Ras, N-Ras, and other compounds that target, decrease or inhibit oncogenic Ras activity. Farnesyl transferase inhibitors include, but are not limited to, for example, L-744832, DK8G557 and R115777 (Zarnestra).
[00339] Telomerase inhibitors include compounds that target, decrease or inhibit telomerase activity. Compounds that target, decrease or inhibit telomerase activity are especially compounds that inhibit the telomerase receptor, for example telomerase. Methionine aminopeptidase inhibitors are, for example, compounds that target, decrease or inhibit the activity of methionine aminopeptidase. Compounds that target, decrease or inhibit the activity of methionine aminopeptidase are bengamide, for example, or derivatives thereof.
Anti-proliferative antibodies include, but are not limited to, trastuzumab (Herceptin™), trastuzumab-DM1, Erbitux, bevacizumab (Avastin™), rituximab (Rituxan®), PRO64553 (anti-CD40) and 2C4 antibody. By antibodies is meant, for example, intact monoclonal antibodies, polyclonal antibodies, multispecific antibodies formed from at least 2 intact antibodies, and antibody fragments, as long as they exhibit the desired biological activity.
For the treatment of acute myeloid leukemia (AML), the compounds of the invention can be used in combination with standard leukemia therapies, especially in combination with therapies used for the treatment of AML. In particular, the compounds of the invention can be administered in combination with, for example, inhibitors of farnesyl transferase and/or other drugs useful for the treatment of acute myeloid leukemia, such as daunorubicin, adriamycin, Ara-C, VP-16, teniposide , mitoxantrone, idarubicin, Carboplatin and PKC412.
Antileukemic compounds for use in combination with the compounds of the invention include, for example, Ara-C, a pyrimidine analogue, which is the 2'-alpha-hydroxy ribose derivative (arabinoside) of deoxycytidine. Also included are the purine analogue of hypoxanthine, 6-mercaptopurine (6-MP) and fludarabine phosphate. Compounds that target, decrease or inhibit histone deacetylase (HDAC) activity, such as sodium butyrate and suberoylanilide hydroxamic acid (SAHA) inhibit the activity of enzymes known as histone deacetylases. Specific inhibitors include HDAC MS275, Saha, FK228 (formerly FR901228), Trichostatin A and compounds disclosed in US 6,552,065, in particular, A/-hydroxy-3-[4-[[[2-(2-methyl-1H) - indol-3-yl)-ethyl]-amino]methyl]phenyl]-2E-2-propenamide, or a pharmaceutically acceptable salt thereof and A/-hydroxy-3-[4 - [(2-hydroxyethyl){2 - (1/-/-indol-3-yl)ethyl]-amino]-methyl]-phenyl]-2E-2-propenamide, or a pharmaceutically acceptable salt thereof, for example the lactate salt.
Somatostatin receptor antagonists include compounds that target, treat or inhibit the somatostatin receptor such as octreotide, and SOM230 (pasireotide). Harmful tumor cell approaches include approaches such as ionizing radiation, eg ionizing radiation that occurs with electromagnetic rays, (such as X-rays and gamma rays) or particles (such as alpha and beta particles). Ionizing radiation is provided in, but not limited to, radiation therapy and is known in the art. See Hellman, Principles of Radiotherapy, Cancer, in Principles and practice of Oncology, Devita et al., Eds., 4th edition, vol. 1, pp 248275 (1993). EDG ligands include immunosuppressants that modulate lymphocyte recirculation, such as FTY720.
Ribonucleotide reductase inhibitors include nucleoside analogues of pyrimidine or purine, including, but not limited to, fludarabine and/or cytosine arabinoside (Ara-C), 6-thioguanine, 5-fluorouracil, cladribine, 6-mercaptopurine (especially in combination with ara -C against ALL) and/or pentostatin. Ribonucleotide reductase inhibitors are, for example, derivatives of hydroxyurea or 2-hydroxy-1/-/-isoindole-1,3-dione, such as PL-1, PL-2, PL-3, PL-4, PL- 5, PL-6, PL-7 or PL-8 mentioned in Nandy et al., Acta Oncologica, vol. 33, No. 8, pp 953-961 (1994).
S-adenosylmethionine decarboxylase inhibitors include, but are not limited to the compounds described in US 5,461,076.
Also included in particular are those VEGF monoclonal compounds, proteins or antibodies disclosed in WO 98/35958, for example, 1-(4-chloroanilino)-4-(4-pyridylmethyl)phthalazine or a pharmaceutically acceptable salt thereof, for example the succinate, or in WO 00/09495, WO 00/27820, WO 00/59509, WO 98/11223, WO 00/27819 and EP 0 769 947; those as described by Prewett et al, Cancer Res, Vol. 59, pp. 5209-5218 (1999); Yuan et al. , Proc Natl Acad Sci USA, Vol. 1476514770 (1996); Zhu et al. , Cancer Res, Vol. 58, pp. 32093214 (1998); and Mordenti et al. , Toxicol Pathol, Vol. 27, No. 1, pp. 14-21 (1999); in WO 00/37502 and WO 94/10202; ANGIOSTATIN, described by O'Reilly et al., Cell, Vol. 315-328 (1994); ENDOSTATIN, described by O'Reilly et al. , Cell, Vol. 88, pp. 277-285 (1997); anthranilic acid amides; ZD4190; ZD6474; SU5416; SU6668; bevacizumab; or anti-VEGF antibodies or anti-VEGF receptor antibodies, e.g. rhuMAb and RHUFab, VEGF aptamer, e.g. Macugon; FLT-4 inhibitors, FLT-3 inhibitors, VEGFR-2 IgGI antibody, Angiozyme (RPI 4610) and Bevacizumab (Avastin™).
The compounds of the invention are also useful as cotherapeutic compounds for use in combination with other drug substances, such as anti-inflammatory, bronchodilatory or antihistamine drug substances, particularly in the treatment of inflammatory or obstructive airway diseases such as those herein mentioned above, for example, as enhancers of the therapeutic activity of such drugs or as a means of reducing required dosage or potential side effects of such drugs. A compound of the invention can be mixed with another drug substance in a fixed pharmaceutical composition or it can be administered separately, before, simultaneously with, or after the other drug substance. Thus the invention includes a combination of a compound of the invention as described with an anti-inflammatory, antihistamine, bronchodilator or anti-cough drug substance, said compound of the invention and said drug substance are in the same or different pharmaceutical compositions. Suitable anti-inflammatory drugs include steroids, in particular glucocorticosteroids, such as budesonide, beclamethasone dipropionate, fluticasone propionate, ciclesonide or mometasone furoate, or steroids described in WO 02/88167, WO 02/12266, WO 02/100879, WO 02/00679 (specifically those of examples 3, 11, 14, 17, 19, 26, 34, 37, 39, 51, 60, 67, 72, 73, 90, 99 and 101), WO 03/035668, WO 03 /048181, WO 03/062259, WO 03/064445, WO 03/072592, non-steroidal glucocorticoid receptor agonists such as those described in WO 00/00531, WO 02/10143, WO 03/082280, WO 03/082787, WO 03/104195, WO 04/005229; LTB4 antagonists such as LY293111, CGS025019C, CP-195543, SC-53228, BIIL 284, ONO 4057, SB 209247 and those described in US 5451700; LTD4 antagonists such as montelukast and zafirlukast; PDE4 inhibitors such as cilomilast (Ariflo® GlaxoSmithKline), Roflumilast (Byk Gulden), V-1 1294A (Napp), BAY19-8004 (Bayer), SCH-351591 (Schering-Plough), Arofylline (Almirall Prodesfarma), PD189659 / PD168787 (Parke-Davis), AWD-12-281 (Asta Medica), CDC-801 (Celgene), SeICID(TM) CC-10004 (Celgene), VM554/UM565 (Vernalis), T-440 (Tanabe), KW- 4490 (Kyowa Hakko Kogyo), and those disclosed in WO 92/19594, WO 93/19749, WO 93/19750, WO 93/19751, WO 98/18796, WO 99/16766, WO 01/13953, WO 03/104204 WO 03/104205, WO 03/39544, WO 04/000814, WO 04/000839, WO 04/005258, WO 04/018450, WO 04/018451, WO 04/018457, WO 04/018465, WO 04/018431 WO 04/018449, WO 04/018450, WO 04/018451, WO 04/018457, WO 04/018465, WO 04/019944, WO 04/019945, WO 04/045607 and WO 04/037805; A2a agonists such as those disclosed in EP 409595A2, EP 1052264, EP 1241176, WO 94/17090, WO 96/02543, WO 96/02553, WO 98/28319, WO 99/24449, WO 99/24450, WO 99/24451 , WO 99/38877, WO 99/41267, WO 99/67263, WO 99/67264, WO 99/67265, WO 99/67266, WO 00/23457, WO 00/77018, WO 00/78774, WO 01/23399 WO 01/27130, WO 01/27131, WO 01/60835, WO 01/94368, WO 02/00676, WO 02/22630, WO 02/96462, WO 03/086408, WO 04/039762, WO 04/039766 , WO 04/045618 and WO 04/046083; A2b antagonists such as those described in WO 02/42298; and beta-2 adrenoceptor agonists such as albuterol (salbutamol), metaproterenol, terbutaline, salmeterol fenoterol, procaterol, and especially, formoterol and pharmaceutically acceptable salts thereof, and compounds (in solvate or salt or free form) of WO Formula I 0075114, which document is incorporated herein by reference, preferably compounds of the Examples thereof, as well as compounds (in solvate or salt or free form) of Formula I of WO 04/16601, and also compounds of WO 04/033412. Suitable brochodilator drugs include anticholinergic or antimuscarinic compounds, in particular ipratropium bromide, oxitropium bromide, tiotropium sia and CHF 4226 (Chiesi), and glycopyrrolate, but also those described in WO 01/04118, WO 02/51841, WO 02/ 53564, WO 03/00840, WO 03/87094, WO 04/05285, WO 02/00652, WO 03/53966, EP 424021, US 5171744, US 3714357, WO 03/33495 and WO 04/018422.
Suitable antihistaminic drug substances include cetirizine hydrochloride, acetaminophen, clemastine fumarate, promethazine, loratidine, desloratidine, diphenhydramine and fexofenadine hydrochloride, activatin, astemizole, azelastine, ebastine, mitrazine and epinastine disclosed in WO 03/099807, WO 04/026841 and JP 2004107299.
[00349] Other useful combinations of compounds of the invention with anti-inflammatory drugs are those with chemokine receptor antagonists, e.g., CCR-1, CCR-2, CCR-3, CCR-4, CCR-5, CCR -6, CCR-7, CCR-8, CCR-9 and CCR10, CXCR1, CXCR2, CXCR3, CXCR4, CXCR5, particularly CCR-5 antagonists such as Schering-Plough antagonists SC-351 125, SCH-55700 and SCH-D, Takeda antagonists such as TAK-770, and 5-CCR antagonists described in US 6,166,037 (particularly claim 18 and 19), WO 00/66558 (particularly claim 8), WO 00/66559 (particularly claim 9), WO 04/018425 and WO 04/026873.
Antimicrotubule or antimitotic agents include phase-specific agents active against the microtubules of tumor cells during the M or mitotic phase of the cell cycle. Examples of anti-microtubule agents include, but are not limited to, diterpenoids and vinca alkaloids. Diterpenoids, which are derived from natural sources, are phase-specific anticancer agents that operate in the G2/M phases of the cell cycle. Diterpenoids are believed to stabilize the β-tubulin subunit of microtubules by binding to this protein. Disassembly of the protein then appears to be inhibited with mitosis being arrested and then cell death. Examples of diterpenoids include, but are not limited to, paclitaxel and its analogue docetaxel. Paclitaxel, 5β,20-epoxy-1,2α, 4.7 β, 10β, 13α-hexahydroxytax-11-en-9-one 4,10 13-ester diacetate-2-benzoate with (2R, 3S) -N-benzoyl-3-phenylisoserine; is a natural diterpene product isolated from the Pacific yew tree Taxus brevifolia, and is commercially available as an injectable solution of Taxol®. It is a member of the terpene taxane family. One mechanism for its activity refers to the ability of paclitaxel to bind to tubulin, thus inhibiting cancer cell growth. Paclitaxel has been approved for clinical use in the treatment of refractory ovarian cancer in the United States and for the treatment of breast cancer. It is a potential candidate for the treatment of neoplasms of the skin and head and neck. The compound also shows the potential for treating polycystic kidney disease, lung cancer and malaria. Treatment of patients with paclitaxel results in bone marrow suppression (multiple cell lines, Ignoff, RJ et. al, Cancer Chemotherapy Pocket Guide, 1998) related to dosing duration above a threshold concentration (50 nM) (Kearns , CM et.al., Seminars in Oncology, 3(6) p. 16-23, 1995). Docetaxel, (2R,3S)--N-carboxy-3-phenylisoserine, N-tert-butyl ester, 13-ester with 5β-20-epoxy-1,2α,4,7β,10β,13α-hexahydroxytax-1- 1-en-9-one 4-acetate 2-benzoate, trihydrate; it is commercially available as an injectable solution such as TAXOTERE®. Docetaxel is indicated for the treatment of breast cancer. Docetaxel is a semi-synthetic derivative of paclitaxel q.v., prepared using a natural precursor, 10-deacetyl-baccatin III, extracted from the needle of European yew. The dose-limiting toxicity of docetaxel is neutropenia.
Vinca alkaloids include phase-specific antineoplastic agents derived from the periwinkle plant. Vinca alkaloids act in the M phase (mitosis) of the cell cycle by specifically binding to tubulin. Therefore, the bound tubulin molecule is unable to polymerize into microtubules. Mitosis is believed to be trapped in the metaphase with consequent cell death. Examples of vinca alkaloids include, but are not limited to, vinblastine, vincristine, and vinorelbine. Vinblastine, vincaleukoblastine sulfate, is commercially available as VELBAN® as an injectable solution. Although it has possible indication as a second-line therapy for several solid tumors, it is mainly indicated in the treatment of testicular cancer and several lymphomas including Hodgkin's disease, lymphomas and lymphocytic and histiocytic. Myelosuppression is the dose-limiting side effect of vinblastine. Vincaleukoblastine, vincristine, 22-oxo-, sulfate, is commercially available as Oncovin® as an injectable solution. Vincristine is indicated for the treatment of acute leukemias and also finds use in treatment regimens for malignant Hodgkin's and non-Hodgkin's lymphomas. Alopecia and neurological effects are the most frequent side effect of vincristine and to a lesser extent the effects of gastrointestinal mucositis and myelosuppression occur. Vinorelbine, 3',4'-didehydro-4'-deoxy-C'-norvincaleucoblastin-[R - (R*, R*) -2,3-dihydroxybutanedioate (1:2) (salt)], commercially available as a vinorelbine tartrate solution for injection (Navelbine®), is a semi-synthetic vinca alkaloid. Vinorelbine is indicated as a single agent or in combination with other chemotherapeutic agents, such as cisplatin, in the treatment of various solid tumors, especially non-small cell lung cancer, advanced breast cancer, and hormone-refractory prostate cancers. Myelosuppression is the most common dose-limiting side effect of vinorelbine.
Platinum coordination complexes include non-phase-specific anticancer agents, which interact with DNA. The platinum a complexes enter tumor cells, undergo aquation and form intra- and inter-strand cross-links with DNA causing adverse biological effects to the tumor. Examples of platinum coordination complexes include, but are not limited to, cisplatin and carboplatin. Cisplatin, cis-diaminodichloroplatinum, is commercially available as PLANITOL® as an injectable solution. Cisplatin is primarily indicated in the treatment of metastatic testicular and ovarian cancer and advanced bladder cancer. The primary dose-limiting side effects of cisplatin are nephrotoxicity, which can be controlled by hydration and diuresis, and ototoxicity. Platinum, carboplatin, diamine[1,1-cyclobutane-dicarboxylate (2-)-O,O'], is commercially available as Paraplatin®) as an injectable solution. Carboplatin is primarily indicated for the first- and second-line treatment of advanced ovarian carcinoma. Bone marrow suppression is the dose-limiting toxicity of carboplatin
[00353] Alkylating agents include non-phase-specific and strong electrophilic anticancer agents. Typically, alkylating agents form covalent bonds, by alkylation, to DNA via nucleophilic moieties of the DNA molecule, such as phosphate, amino, sulfhydryl, hydroxyl, carboxyl, and imidazole groups. Alkylation destroys the nucleic acid function that leads to cell death. Examples of alkylating agents include, but are not limited to, nitrogen mustards such as cyclophosphamide, melphalan, and chlorambucil; alkyl sulfonates such as busulfan; nitrosoureas such as carmustine, and Triazenes such as dacarbazine. Cyclophosphamide, 2-[bis(2-chloroethyl)amino]tetrahydro-2H-1,3,2-oxazaphosphorine 2-oxide monohydrate, is commercially available as an injectable solution or tablets, such as CYTOXAN®. Cyclophosphamide is indicated as a single agent or in combination with other chemotherapeutic agents, in the treatment of malignant lymphomas, multiple myeloma, and leukemias. Alopecia, nausea, vomiting, and leukopenia are the most common dose-limiting side effects of cyclophosphamide. Melphalan, 4-[bis(2-chloroethyl)amino]-L-phenylalanine, is commercially available as an injectable solution or tablets, such as ALKERAN®. Melphalan is indicated for the palliative treatment of multiple myeloma and unresectable ovarian epithelial carcinomas. Bone marrow suppression is the most common dose-limiting side effect of melphalan. Chlorambucil, 4-[bis(2-chloroethyl)amino]benzenebutanoic acid, is commercially available in the form of LEUKERAN® tablets. Chlorambucil is indicated for the palliative treatment of chronic lymphatic leukemia, and malignant lymphomas such as lymphosarcoma, giant follicular lymphoma, and Hodgkin's disease. Bone marrow suppression is the most common dose-limiting side effect of chlorambucil. Busulfan, 1,4-butanediol dimethanesulfonate, is commercially available in the form of MYLERAN® TABLETS tablets. Busulfan is indicated for the palliative treatment of chronic myeloid leukemia. Bone marrow suppression is the most common dose-limiting side effect of busulfan. Carmustine, 1,3-[bis(2-chloroethyl)-1-nitrosourea, is commercially available as individual vials of lyophilized material such as BiCNU®. Carmustine is indicated for palliative treatment as a single agent or in combination with other agents for brain tumors, multiple myeloma, Hodgkin's disease, and non-Hodgkin's lymphomas. Later myelosuppression is the most common dose-limiting side effect of carmustine. Dacarbazine, 5-(3,3-dimethyl-1-triazene)-imidazole-4-carboxamide, is commercially available as individual vials of material such as DTIC-Dome®. Dacarbazine is indicated for the treatment of metastatic malignant melanoma and in combination with other agents for the second-line treatment of Hodgkin's disease. Nausea, vomiting, and anorexia are the most common dose-limiting side effects of dacarbazine.
Anti-cancer antibiotics include non-phase-specific agents that bind or intercalate with DNA. Typically, this action results from stable DNA complexes or strand breaks, which disrupt the normal function of nucleic acids that lead to cell death. Examples of antineoplastic antibiotic agents include, but are not limited to, actinomycins such as dactinomycin, anthrocyclines such as daunorubicin and doxorubicin, and Bleomycins. Dactinomycin, also known as actinomycin D, is commercially available in injectable form as COSMEGEN®. Dactinomycin is indicated for the treatment of Wilm's tumor and rhabdomyosarcoma. Nausea, vomiting, and anorexia are the most common dose-limiting side effects of dactinomycin. Daunorubicin, naftacenedione hydrochloride, is commercially available as a liposomal injectable form like DAUNOXOME® or as an injectable like CERUBIDINE®. Daunorubicin is indicated for the induction of remission in the treatment of acute non-lymphocytic leukemia and advanced HIV-associated Kaposi's sarcoma. Myelosuppression is the most common dose-limiting side effect of daunorubicin. Doxorubicin, (8s, 10S)-10-[(3-amino-2,3,6-trideoxy-α-L-lixohexopyranosyl)-oxy]-8-glycoyl, 7,8,9,10-tetra- hydro-6,8,11-trihydroxy-1-methoxy-5,12, Naphthacenedione hydrochloride, is commercially available as an injectable form as RUBEX® or ADRIAMICIN RDF®. Doxorubicin is primarily indicated for the treatment of acute lymphoblastic leukemia and acute myeloblastic leukemia, but it is also a useful component in the treatment of some solid tumors and lymphomas. Myelosuppression is the most common dose-limiting side effect of doxorubicin. Bleomycin, a mixture of cytotoxic glycopeptide antibiotics isolated from a strain of Streptomyces verticillus, is commercially available as BLENOXANE®. Bleomycin is indicated as a palliative treatment, as a single agent or in combination with other agents, for squamous cell carcinoma, lymphomas, and testicular carcinomas. Pulmonary and cutaneous toxicities are the most common dose-limiting side effects of bleomycin.
Topoisomerase II inhibitors include, but are not limited to, epipodophyllotoxins. Epipodophyllotoxins are phase-specific antineoplastic agents derived from the mandrake plant. Epipodophyllotoxins normally affect cells in the G2 and S phase of the cell cycle by forming a tertiary complex with DNA topoisomerase II and causing DNA breaks. Filament breaks accumulate and cell death ensues. Examples of epipodophyllotoxins include, but are not limited to, etoposide and teniposide. Etoposide,4'-demethyl epipodophyllotoxin-9[4,6-0-(R)-ethylidene-β-D-glucopyranoside], is commercially available as an injectable solution or capsules as VePESID® and is commonly known as VP-16. Etoposide is indicated as a single agent or in combination with other chemotherapeutic agents in the treatment of testicular and non-small cell lung cancers. Myelosuppression is the most common side effect of etoposide. The incidence of leukopenia tends to be more severe than thrombocytopenia. Teniposide, 4'-demethyl epipodophyllotoxin-9 [4,6-0-(R)-thenylidene-β-D-glucopyranoside], is commercially available as an injectable solution as VUMON® and is commonly known as VM-26. Teniposide is indicated as a single agent or in combination with other chemotherapeutic agents in the treatment of acute leukemia in children. Myelosuppression is the most common dose-limiting side effect of teniposide. Teniposide can induce both leukopenia and thrombocytopenia. Other topoisomerase II inhibitors include epirubicin, idarubicin, nemorubicin, mitoxantrone, and losoxantrone.
[00356] Antimetabolite neoplastic agents include phase-specific antineoplastic agents that act in the S phase (DNA synthesis) of the cell cycle by inhibiting DNA synthesis or by inhibiting purine and pyrimidine base synthesis and thereby limiting synthesis of DNA. Therefore, the S phase does not proceed and cell death ensues. Examples of antimetabolite antineoplastic agents include, but are not limited to, fluorouracil methotrexate, cytarabine, mercaptopurine, thioguanine, and gemcitabine. 5-fluorouracil, 5-fluoro-2,4-(1H, 3H) pyrimidinedione, is commercially available as fluorouracil. Administration of 5-fluorouracil leads to inhibition of thymidylate synthesis and is also incorporated into RNA and DNA. The result is typically cell death. 5-Fluorouracil is indicated as a single agent or in combination with other chemotherapeutic agents in the treatment of carcinomas of the breast, colon, rectum, stomach and pancreas. Myelosuppression and mucositis are dose-limiting side effects of 5-fluorouracil. Other fluoropyrimidine analogs include 5-fluorodeoxyuridine (floxuridine) and 5-fluorodeoxouridine monophosphate. Cytarabine, 4-amino-1-β-D-arabinofuranosyl-2(1H)-pyrimidinone, is commercially available as CYTOSAR-U® and is commonly known as Ara-C. Cytarabine is believed to exhibit cell phase specificity in S phase by inhibiting elongation of the DNA strand by incorporating the cytarabine terminus into the growing DNA strand. Cytarabine is indicated as a single agent or in combination with other chemotherapeutic agents in the treatment of acute leukemia. Other cytidine analogues include 5-azacytidine and 2',2'-difluorodeoxycytidine (gemcitabine). Cytarabine induces leukopenia, thrombocytopenia, mucositis e. Mercaptopurine, 1,7-dihydro-6H-purine-6-thione monohydrate, is commercially available as PURINETHOL®. Mercaptopurine exhibits cell-phase specificity in S-phase by inhibiting DNA synthesis by an as-yet-unspecified mechanism. Mercaptopurine is indicated as a single agent or in combination with other chemotherapeutic agents in the treatment of acute leukemia. Myelosuppression and gastrointestinal mucositis are expected side effects of mercaptopurine at high doses. A useful mercaptopurine analogue is azathioprine. Thioguanine, 2-amino-1,7-dihydro-6H-purine-6-thione, is commercially available as TABLOIDE®. Thioguanine exhibits cell-phase specificity in S-phase by inhibiting DNA synthesis by an as-yet-unspecified mechanism. Thioguanine is indicated as a single agent or in combination with other chemotherapeutic agents in the treatment of acute leukemia. Myelosuppression, including leukopenia, thrombocytopenia, and anemia, is the most common dose-limiting side effect of thioguanine administration. However, gastrointestinal side effects do occur and may be dose-limiting. Purine analogues include pentostatin, erythrohydroxynonyladenine, fludarabine phosphate, and cladribine. Gemcitabine, 2'-deoxy-2',2'-difluorocytidine monohydrochloride (β-isomer), is commercially available as GEMZAR®. Gemcitabine exhibits cell phase specificity in S phase and blocking cell progression across the G1/S boundary. Gemcitabine is indicated in combination with cisplatin in the treatment of locally advanced non-small cell lung cancer and individually in the treatment of locally advanced pancreatic cancer. Myelosuppression, including leukopenia, thrombocytopenia, and anemia, is the most common dose-limiting side effect of gemcitabine administration. Methotrexate, N-[4-[[(2,4-diamino-6-pteridinyl)methyl] methylamino]benzoyl]-L-glutamic acid, is commercially available as sodium methotrexate. Methotrexate exhibits cell-phase effects specifically S-phase through inhibition of DNA synthesis, repair and/or replication through inhibition of dihydrofolic acid reductase which is required for purine and thymidylate nucleotide synthesis. Methotrexate is indicated as a single agent or in combination with other chemotherapeutic agents in the treatment of choriocarcinoma, meningeal leukemia, non-Hodgkin's lymphoma, and carcinomas of the breast, head, neck, ovary, and bladder. Myelosuppression (leukopenia, thrombocytopenia, and anemia) and mucositis are expected side effects of methotrexate administration.
Topoisomerase I inhibitors include camptothecins such as camptothecin and its camptothecin derivatives. The cytotoxic activity of camptothecin is believed to be related to its topoisomerase I inhibitory activity. Examples of camptothecins include, but are not limited to irinotecan and topotecan. Irinotecan HCl, (4S)-4,11-diethyl-4-hydroxy-9-[(4-piperidinopiperidino)carbonyloxy]-1H-pyrano[3',4',6,7]indolizino[1,2- b]quinoline-3,14(4H,12H)-dione, is commercially available as a CAMPTOSAR® injectable solution. Irinotecan is a derivative of camptothecin, which binds, together with its active metabolite SN-38, to the DNA-complex topoisomerase I. Cytotoxicity is believed to occur as a result of irreparable double-stranded breaks caused by topoisomerase I:DNA:irinotecan or SN-38 ternary complex interaction with replication enzymes. Irinotecan is indicated for the treatment of metastatic cancer of the colon or rectum. Dose-limiting side effects of irinotecan HCl are myelosuppression, including neutropenia, and gastrointestinal effects, including diarrhea. Topotecan HCl, (S)-10-[(dimethylamino)methyl]-4-ethyl-4,9-dihydroxy-1H-pyrano[3',4',6,7]-indolizino[1,2-b] monohydrochloride ]quinoline-3,14-(4H,12H)-dione is commercially available as a HYCAMTIN® injectable solution. Topotecan is a camptothecin derivative that binds to complex DNA-topoisomerase I and prevents religation of simple strand breaks caused by topoisomerase I in response to the DNA molecule's torsional stress. Topotecan is indicated for second-line treatment of metastatic ovarian carcinoma and small cell lung cancer. The dose limiting side effect of topotecan HCl is myelosuppression, mainly neutropenia.
[00358] Hormones and hormone analogues are compounds useful for the treatment of cancers in which there is a relationship between the hormone and the growth and/or absence of cancer growth. Examples of hormones and hormonal analogues useful in treating cancer include, but are not limited to, adrenocorticosteroids such as prednisone and prednisolone, which are useful in treating malignant lymphoma, acute leukemia in children; aminoglutethimide and other aromatase inhibitors such as aminoglutethimide, roglethimide, pyridoglutethimide, trilostane, testolactone, ketoconazole, vorozole, Fadrozole, anastrozole, letrazol, formestane, atamestane and exemestane useful in the treatment of adrenostrogen receptor-dependent breast carcinoma and breast carcinoma progestrins such as megestrol acetate, useful in the treatment of hormone-dependent breast cancer and endometrial carcinoma; estrogens, androgens, and anti-androgens, such as flutamide, nilutamide and bicalutamide, cyproterone acetate and 5α reductases, such as finasteride and dutasteride, useful in the treatment of prostate carcinoma and benign prostatic hypertrophy; anti-estrogens such as fulvestrant, tamoxifen, toremifene, raloxifene, droloxifene, iodoxifene, as well as selective estrogen receptor modulators (SERMs) such as those described in US Patents 5,681,835, 5,877,219, and 6,207,716 , useful in treating hormone-dependent breast cancer and other susceptible cancers; and gonadotropin-releasing hormones (GnRH) and their analogues which stimulate the release of luteinizing hormone (LH) and/or follicle-stimulating hormone (FSH) for the treatment of prostate cancer, eg LHRH agonists and antagonists such as such as abarelix, goserelin, goserelin and luprolide acetate. SH2/SH3 domain blockers are agents that disrupt the SH2 or SH3 binding domain in a variety of adapter enzymes or proteins, including, PI3-K p85 subunit, Src family kinases, adapter molecules (Shc, Crk, NCK, Grb2) and GAP-Ras. SH2/SH3 domains as targets for anticancer drugs are discussed in Smithgall, T.E. (1995), Journal of Pharmacological and Toxicological Methods. 34(3) 125-32. Serine/threonine kinase inhibitors, including MAP kinase cascade blockers which include RAF (rafk) and mitogen kinase blockers or regulated extracellular kinase (MEKs) and Regulated extracellular kinases (ERKs); and blockers from members of the protein kinase C family, such as PKC blockers (alpha, beta, gamma, epsilon, mu, lambda, iota, zeta). IkB family kinases (Ikka, IKKb), PKB family kinases, Akt family kinases, and TGF beta receptor kinases. Such serine/reonine kinases and inhibitors thereof are described in Yamamoto, T., Taya, S., Kaibuchi, K., (1999), Journal of Biochemistry. 126 (5) 799-803; Brodt, P, Samani, A., and Navab, R. (2000), Biochemical Pharmacology, 60, 11011107; Massague, J., Weis-Garcia, F. (1996) Cancer Surveys. 27:41-64; Philip, P.A., and Harris, A.L. (1995), Cancer Treatment and Research. 78: 3-27, Lackey, K. et al Bioorganic and Medicinal Chemistry Letters, (10), 2000, 223-226; US Patent No. 6,268,391; and Martinez-Iacaci, L., et al, Int. J. Cancer (2000), 88(1), 44-52.
Also of interest for use with the compounds of the invention are inhibitors of myo-inositol signaling, such as phospholipase C blockers and myoinositol analogues. Such signal inhibitors are described in Powis, G., and Kozikowski A., (1994) New Molecular Targets for Cancer Chemotherapy ed., Paul Workman and David Kerr, CRC press 1994, London.
[00360] Another group of inhibitors are inhibitors of the signal transduction pathway, such as Ras oncogene inhibitors. Such inhibitors include inhibitors of farnesyltransferase and geranyl-geranyl transferase, and CAAX protease, as well as antisense oligonucleotides, ribozymes and immunotherapy. Such inhibitors have been shown to block Ras activation in wild-type cells that contain mutant Ras, thus acting as antiproliferative agents. Ras oncogene inhibition is discussed in Scharovsky, O.G., Rozados, V.R., Gervasoni, S.I. Matar, P. (2000), Journal of Biomedical Science. 7(4) 292-8; Ashby, M.N. (1998), Current Opinion in Lipidology. 9(2) 99-102; and BioChim. Biophys. Acta, (1999) 1423(3):19-30.
[00361] This invention further relates to a method for using the compounds or pharmaceutical composition in combination with other approaches to treating tumors, including surgery, ionizing radiation, photodynamic therapy, or implants, for example, with corticosteroids, hormones, or used as radiosensitizers.
Such an approach may be, for example, radiation therapy in the inhibition of abnormal cell growth or treatment of the hyperproliferative disorder in the mammal. Techniques for administering radiation therapy are known in the art, and these techniques can be used in the combination therapy described herein. Administration of the compound of the invention in the present combination therapy can be determined as described herein.
[00363] Radiation therapy can be administered by one of several methods, or a combination of methods, including, without limitation, external beam therapy, internal radiation therapy, implant radiation, radiosurgery, systemic radiation therapy , radiotherapy and permanent or temporary interstitial brachytherapy. The term "brachytherapy" as used herein refers to radiation therapy emitted by a spatially confined radioactive material inserted into the body at or near a disease site of tumor or other proliferative tissue. The term is intended, without limitation, to include exposure to radioactive isotopes (eg, At-211, I-131, I-125, Y-90, Re-186, Re-188, Sm-153, Bi-212, P32 and radioactive isotopes of Lu). Suitable radiation sources for use as a cell conditioner of the present invention include both solids and liquids. By way of non-limiting example, the radiation source can be a radionuclide, such as I-125, I-131, Yb-169, IR-192 as a solid source, I-125 as a solid source, or other radionuclides which emit photons, beta particles, gamma radiation, or other therapeutic rays. The radioactive material can also be a fluid made from any solution of radionuclide(s), for example a solution of I-125 or I131, or a radioactive fluid can be produced using a suspension of a suitable fluid containing small particles of solid radionuclides such as Au-198, Y-90. In addition, the radionuclide(s) can be incorporated into a gel or radioactive microsphere.
[00364] Without being limited by any theory, the compounds of the present invention may make abnormal cells more sensitive to radiation treatment for the purpose of killing and/or inhibiting the growth of such cells. Thus, the present invention further relates to a method for sensitizing abnormal cells in a mammal to radiation treatment which comprises administering to the mammal an amount of a compound of the present invention or a pharmaceutically acceptable salt, ester, pro. drug, solvate, hydrate or derivative thereof, the amount of which is effective to sensitize abnormal cells to radiation treatment. The amount of the compound, salt or solvate of this method can be determined in accordance with the means for determining effective amounts of such compounds described herein.
[00365] Photodynamic therapy includes therapy that uses certain chemicals known as photosensitizing compounds to treat or prevent cancers. Examples of photodynamic therapy include treatment with compounds such as, for example, VISUDYNE and porfimer sodium. Angiostatic steroids include compounds that block or inhibit angiogenesis, such as, for example, anecortave, triamcinolone, hydrocortisone, 11-α-epihydrocotisol, cortexolone, 17α-hydroxyprogesterone, corticosterone, deoxycorticosterone, testosterone estrone, and dexamethasone.
Corticosteroid-containing implants include compounds such as, for example, fluocinolone and dexamethasone. Other chemotherapeutic compounds include, but are not limited to, plant alkaloids, hormonal compounds and antagonists; biological response modifiers, preferably lymphokines or interferons; antisense oligonucleotides or oligonucleotide derivatives; Lentiviruses or siRNA; or various compounds or compounds with another mechanism or unknown action.
[00367] The compounds or pharmaceutical compositions of the present invention can be used in combination with an amount of one or more substances selected from anti-angiogenesis, signal transduction inhibitory agents, and anti-proliferative agents.
[00368] Anti-angiogenesis agents, such as MMP-2 inhibitors (matrix metalloproteinases 2) MMP-9 inhibitors (matrix metalloproteinases 9), and COX-11 inhibitors (cyclooxygenase 11), can be used in conjunction with a compound of the present invention and the pharmaceutical compositions described herein. Examples of useful COX-II inhibitors include CELEBREX™ (alecoxib), valdecoxib and rofecoxib. Examples of useful matrix metalloproteinase inhibitors are described in WO 96/33172 (published October 24, 1996), WO 96/27583 (published March 7, 1996), European Patent Application No. 97304971.1 (filed at 8 of July 1997), European Patent Application No. 99308617.2 (filed 29 October 1999), WO 98/07697 (published 26 February 1998), WO 98/03516 (published 29 January 1998), WO 98/34918 (published 13th August 1998), WO 98/34915 (published 13th August 1998), WO 98/33768 (published 6th August 1998), WO 98/30566 (published 16th July 1998) , European Patent Publication 606,046 (published 13 July 1994), European Patent Publication 931,788 (published 28 July 1999), WO 90/05719 (published 31 May 1990), WO 99/52910 ( published October 21, 1999), WO 99/52889 (published October 21, 1999), WO 99/29667 (published June 17, 1999), PCT International Application No. PCT/IB98/0111 3 (filed July 21, 1998), European Patent Application No. 99302232.1 (filed March 25, 1999), Great Britain Patent Application No. 9912961.1 (filed June 3, 1999) , US Provisional Application 60/148, 464 (filed August 12, 1999), United States Patent US 5,863,949 (issued January 26, 1999), United States Patent 5,861,510 (issued January 19, 1999) , and European Patent Publication 780,386 (published June 25, 1997), all of which are incorporated herein by reference in their entirety. In some embodiments, MMP-2 and MMP-9 inhibitors have little or no MMP-1 inhibitory activity, or selectively inhibit MMP-2 and/or AMP-9 relative to other matrix metalloproteinase (i.e., the MAP-1, MMP-3, MMP-4, MMP-5, MMP-6, MMP-7, MMP-8, MMP-10, MMP-11, MMP-12, and MMP-13). Some specific examples of MMP inhibitors useful in the present invention are AG-3340, RO 32-3555, 13-0830 and RS.
The invention also relates to a method for, and a pharmaceutical composition for, treating a cardiovascular disease in a mammal, which comprises an amount of a compound of the present invention, or a pharmaceutically acceptable salt, ester, prodrug , solvate, hydrate or derivative thereof, or an isotopically labeled derivative thereof, and an amount of one or more therapeutic agents useful for the treatment of cardiovascular disease.
[00370] Exemplary agents for use in cardiovascular disease applications are antithrombotic agents, for example, prostacyclin, and salicylates, thrombolytic agents, for example, streptokinase, urokinase, tissue plasminogen activator (TPA) and anisoylated streptokinase-plasminogen activator complex (APSAC), antiplatelet agents, for example, acetylsalicylic acid (ASA) and clopidrogel, vasodilating agents, for example, nitrates, calcium channel blocking drugs, antiproliferative agents, for example, colchicine, and alkylating agents, intercalating agents, modulating growth factors such as interleukins, transforming growth factor beta and platelet-derived growth factor congeners, monoclonal antibodies directed against growth factors, steroidal and non-steroidal anti-inflammatory agents, and other agents that may modulate blood vessels, function, arteriosclerosis, and the healing response of the injured vessels or organs after intervention. Antibiotics can also be included in combinations or coatings encompassed by the invention. In addition, a liner can be used to effect therapeutic delivery focally within the vessel wall. By incorporating the active agent into a swellable polymer, the active agent will be released upon polymer swelling.
[00371] The compounds described herein can be formulated or administered in conjunction with liquid or solid tissue barriers also known as lubricants. Examples of tissue barriers include, but are not limited to, polysaccharides, polyglycans and Seprafilm, hyaluronic acid and interceed.
Medicines which may be administered in conjunction with the compounds described in the present invention include any suitable drugs usefully delivered by inhalation, for example analgesics, for example codeine, dihydromorphine, fentanyl, ergotamine or morphine; anginal preparations, for example diltiazem; antiallergics, for example cromoglycate, ketotifen or nedocromil; anti-infectives, for example cephalosporins, penicillins, streptomycin, sulfonamides, tetracyclines or pentamidine; antihistamines, for example, Metapyrilene; anti-inflammatories, for example beclomethasone, flunisolide, budesonide, tipredane, triamcinolone acetonide or fluticasone; cough suppressants, for example, noscapine; bronchodilators, e.g., ephedrine, adrenaline, fenoterol, formoterol, isoprenaline, metaproterenol, phenylephrine, phenylpropanolamine, pirbuterol, reproterol, rimiterol, salbutamol, salmeterol, terbutaline, isoetharine, tulobuterol, orciprenaline or (-,5-4) - -dichloro-α-[[[6-[2-(2-pyridinyl)ethoxy]hexyl]amino]methyl]benzenemethanol; diuretics, for example amiloride; anticholinergics, for example ipratropium, atropine or oxitropium; hormones, for example hydrocortisone, cortisone or prednisolone; xanthines for example aminophylline, choline theophyllinate, lysine theophyllinate or theophylline; and therapeutic proteins and peptides, for example, insulin, or glucagon. It will be apparent to a person skilled in the art that, where appropriate, medicines can be used in the form of salts (eg as alkali metal or amine salts or as acid addition salts) or as esters (eg esters of lower alkyl) or as solvates (eg hydrates) to optimize drug activity and/or stability.
[00373] Other exemplary therapeutic agents useful for a combination therapy include, but are not limited to, agents as described above, radiation therapy, antagonists of hormones, hormones and their thyroid releasing factors, and antithyroid drugs, estrogens and progestins, androgens, adrenocorticotropic hormone; adrenocortical steroids and their synthetic analogues; inhibitors of the synthesis and actions of adrenocortical hormones, insulin, oral hypoglycemic agents, and of pancreas pharmacology, agents that affect calcification and bone volume: calcium, phosphate, parathyroid hormone, vitamin D, calcitonin, vitamins such as water-soluble vitamins , B complex vitamins, ascorbic acid, fat-soluble vitamins, vitamins A, K, and E, growth factors, cytokines, chemokines, muscarinic receptor agonists and antagonists; anticholinesterases; agents that act at the neuromuscular junction and/or autonomic ganglia; catecholamines, sympathomimetic drugs, and adrenergic receptor agonists or antagonists, and 5-hydroxytryptamine (5-HT, serotonin) receptor agonists and antagonists.
Therapeutic agents may also include agents for pain and inflammation, such as histamine and histamine antagonists, bradykinin and bradykinin antagonists, 5-hydroxytryptamine (serotonin), lipid substances that are generated by biotransformation of the products of selective hydrolysis of phospholipids of membranes, eicosanoids, prostaglandins, thromboxanes, leukotrienes, aspirin, anti-inflammatory drugs, antipyretic analgesic agents, agents that inhibit the synthesis of prostaglandins and thromboxanes, selective inhibitors of inducible cyclooxygenase, selective inhibitors of inducible cyclooxygenase-2, autacoids and paracrine hormones somatostatin, gastrin, cytokines that mediate interactions involved in humoral and cellular immune system responses, lipids derived from autacoids and eicosanoids, e-adrenergic agonists, ipratropium, glucocorticoids, methylxanthines, sodium channel blockers, opioid receptor agonists, channel blockers of lime opium, membrane stabilizers and leukotriene inhibitors.
[00375] Additional therapeutic agents contemplated by the present invention include diuretics, vasopressin, agents that affect renal water conservation, renin, angiotensin, agents useful in the treatment of myocardial ischemia, antihypertensive agents, angiotensin-converting enzyme inhibitors, α-adrenergic antagonists, agents for treating hypercholesterolemia, and agents for treating dyslipidemia.
[00376] Other therapeutic agents contemplated include drugs used to control gastric acidity, agents to treat peptic ulcers, agents to treat gastroesophageal reflux disease, prokinetic agents, antiemetics, agents used in irritable bowel syndrome, agents used for diarrhea, agents used for constipation, agents used for inflammatory bowel disease, agents used for biliary disease, agents used for pancreas disease. Therapeutic agents used to treat protozoan infections, drugs used to treat malaria, amoebiasis, giardiasis, trichomoniasis, trypanosomiasis, and/or leishmaniasis, and/or drugs used in chemotherapy of helminths. Other therapeutic agents include antimicrobial agents, sulfonamides and trimethoprim sulfamethoxazole-quinolones, and agents for urinary tract infections, penicillins, cephalosporins and others, 3-lactams, an agent comprising an aminoglycoside, protein synthesis inhibitors, drugs used in chemotherapy of tuberculosis, Mycobacterium avium complex disease, and leprosy, antifungals, antivirals, including non-retroviral agents and antiretroviral agents.
[00377] Examples of therapeutic antibodies that can be combined with a subject compound include, but are not limited to, anti-receptor tyrosine kinase (cetuximab, panitumumab, trastuzumab), anti-CD20 (rituximab, tositumomab) antibodies, and other such antibodies. such as alemtuzumab, bevacizumab, and ozogamycin.
[00378] In addition, therapeutic agents used for immunomodulation, such as immunomodulators, immunosuppressive agents, tolerogens, and immunostimulants are contemplated by the methods described herein. In addition, therapeutic agents that act on the blood and blood-forming organs, hematopoietic agents, growth factors, mineral salts and vitamins, anticoagulant, thrombolytic, and antiplatelet drugs.
[00379] Other therapeutic agents that can be combined with a subject compound can be found in Goodman and Gilman's "The Pharmacological Basis of Therapeutics" Tenth Edition edited by Hardman, Limbird and Gilman or the Physician's Desk Reference, both of which are incorporated herein by reference in its entirety.
[00380] The compounds described herein can be used in combination with the agents described herein or other suitable agents, depending on the condition being treated. Thus, in some embodiments the compounds of the invention will be co-administered with other agents, as described above. When used in combination therapy, the compounds described herein can be administered with the second agent simultaneously or separately. Such combination administration can include simultaneous administration of two agents in the same dosage form, simultaneous administration in separate dosage forms, and separate administration. That is, a compound described herein and any of the agents described above can be formulated together in the same dosage form and administered simultaneously. Alternatively, a compound of the present invention and any of the agents described above can be administered simultaneously, as both agents are present in separate formulations. In another alternative, a compound of the present invention can be administered alone followed by any of the agents described above, or vice versa. In the separate administration protocol, a compound of the present invention and any of the agents described above may be administered a few minutes apart, or a few hours apart, or a few days apart.
[00381] The administration of the compounds of the present invention can be carried out by any method that allows the delivery of the compounds to the site of action. An effective amount of a compound of the invention can be administered in either single or multiple doses, by any of the accepted modes of administration of agents that have similar utilities, including rectal, buccal, intranasal and transdermal, by intra-arterial injection, intravenously. , intraperitoneal, parenteral, intramuscular, subcutaneous, oral, topical, such as an inhalant, or through an impregnated or coated device, such as a stent, for example, or a cylindrical polymer inserted into the artery.
The amount of compound administered will be dependent on the mammal being treated, the severity of the disorder or condition, the rate of administration, the disposition of the compound and the judgment of the prescribing physician. However, an effective dosage is in the range of about 0.001 to about 100 mg per kg of body weight per day, preferably about 1 to about 35 mg/kg/day, in single or divided doses. For a 70 kg human, this would be about 0.05 to 7 g/day, preferably, about 0.05 to about 2.5 g/day. In some cases, dosage levels below the lower limit of the above range may be more than adequate, while in other cases even larger doses can be employed without causing any harmful side effects, for example by dividing these larger doses into several small doses for administration throughout the day.
In some embodiments, a compound of the invention is administered in a single dose. Typically, such administration will be by injection, for example, intravenously, in order to introduce the agent rapidly. However, other routes can be used as appropriate. A single dose of a compound of the invention can also be used to treat an acute condition.
In some embodiments, a compound of the invention is administered in multiple doses. Administration can be about once, twice, three times, four times, five times, six times, or more than six times a day. Administration can be about once a month, once every two weeks, once a week, or once every other day. In another embodiment a compound of the invention and another agent are administered together about once a day to about 6 times a day. In another embodiment, administration of a compound of the invention and an agent continues for less than about 7 days. In yet another modality, administration continues for more than about 6, 10, 14, 28 days, two months, six months, or a year. In some cases, continuous dosing is achieved and maintained for as long as necessary.
[00385] Administration of the agents of the invention may continue for as long as necessary. In some embodiments, an agent of the invention is administered for more than 1, 2, 3, 4, 5, 6, 7, 14, or 28 days. In some embodiments, an agent of the invention is administered for less than 28, 14, 7, 6, 5, 4, 3, 2 or 1 day. In some embodiments, an agent of the invention is chronically administered on a continuous basis, for example, to treat chronic effects.
When a compound of the invention is administered in a composition comprising one or more agents, and the agent has a shorter half-life than the compound of the invention, unit dosage forms of the agent and the compound of the invention may be adjusted accordingly.
[00387] In some embodiments, compounds of the invention are tested to estimate pharmacokinetic properties and expected side effect profile. Various assays are known in the art for this purpose. For example, oral availability can be estimated during the early stages of drug development by performing a Caco-2 permeability assay. Furthermore, oral pharmacokinetics in humans can be approximated by extrapolation from the results of tests in mice, rats or monkeys. In some embodiments, compounds of the invention show good oral availability across multiple species of organisms.
[00388] Other trials examine the effect of a drug candidate on liver function and metabolism. Cytochrome P450 (CYP) proteins are the major enzyme involved in the metabolism of drugs delivered to mammalian organisms. As such, when unwanted a drug candidate can be a significant source of adverse drug interactions. Generally, it is desirable that a drug not interact with CYP isoenzymes such as CYP1A2, CYP2C9, CYP2C19, CYP2D6 or CYP3A4. In some embodiments, a compound of the invention exhibits an IC50 greater than 10 uM for CYP1A2, CYP2C9, CYP2C19, CYP2D6 or CYP3A4. In addition, microsome and hepatocyte metabolism assays using human preparations can be used to estimate the in vitro half life of a drug candidate.
[00389] Cardiac toxicity is also an important consideration in evaluating drug candidates. For example, hERG is the gene that codes for the Kv11.1 potassium ion channel, a protein that is involved in mediating repolarizing current in the cardiac action potential in the heart. Inhibition of the hERG gene product by a drug candidate can lead to an increased risk of sudden death and is therefore an undesirable property. In some embodiments, a compound of the invention exhibits less than 10% hERG inhibition when administered at a suitable concentration.
The mutagenicity of drug candidate compounds can be assayed by an Ames test or a modified Ames test using, for example, the liver S9 system. In some embodiments, compounds of the invention show negative activity in such a test.
[00391] Other undesirable interactions of a drug candidate can also be determined through a receptor panel screen. In some embodiments, there are significant interactions that are detected for the compounds of the invention.
The examples and preparations provided below further illustrate and exemplify the compounds of the present invention and methods of preparing such compounds. It is to be understood that the scope of the present invention is in no way limited by the scope of the following examples and preparations. In the following examples, molecules with a single chiral center, unless otherwise noted, exist as a racemic mixture. Those molecules with two or more chiral centers, unless otherwise noted, exist as a racemic mixture of diastereoisomers. Individual enantiomers/diastereomers can be obtained by methods known to those skilled in the art. EXAMPLES Example 1: Synthesis of 5-(3-(pyridin-4-yl)imidazo[1,2 a]pyridin-6-yl)benzo[d]oxazol-2-amine

[00393] The above scheme describes the synthesis of a compound of the invention. A pyridine substituted as compound 1-1 is reacted with 2-chloroacetaldehyde, resulting in the halogenated imidazopyridinium compound compound 1-2. Compound 1-2 is coupled to a benzoxazolyl boronic acid ester under Suzuki conditions to produce compound 1-4. Further derivatization of compound 1-4 using, for example, NBS, DMF results in halogenation of the imidazopyridine moiety, which is then further reacted in an additional Suzuki coupling using pyridine boronic acid to yield compound 1-6. Example 2: Synthesis of 2-(4-(8-(2-aminobenzo[d]oxazol-5-yl)-3-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]quinolin-1- yl)phenyl)-2-methylpropanenitrile.

[00394] The above Reaction Scheme illustrates the synthesis of a compound of the invention 2-13. Methylation of starting material 2-1 generates compound 2-2, which is subsequently reduced to amine 2-3. In a separate reaction, compound 2-4 is converted to a salt, such as an HCl salt, which is then reacted, for example, with 2-nitrovinylhydroxylamine to generate compound 2-6. Another cyclization generates compound 2-7. Halogenation with a reagent such as POCl3 results in compound 2-8, which can be coupled with intermediate 2-3 to generate 2-9. The nitro moiety of 2-9 is subsequently reduced to an amine, and another reaction with 4-nitrophenyl carbonhydrochloride results in the 2-11 heterocycle. The desired compound 2-13 is then prepared by coupling to the benzoxazolyl boronate 2-12, for example in a Suzuki coupling. Example 3: Synthesis of 6-(4-(pyridin-4-yl)quinolin-6-yl)benzo[d]thiazol-2-amine.

The bicyclic compound 3-2 is prepared from bromoaniline 3-1 using diethyl 2-(ethoxymethylene)malonate or a similar reagent. Deprotection and removal of carboxylic acid, followed by halogenation using a reagent such as phosphorus oxychloride generates compound 3-5. Derivatization with pyridine boronate under Suzuki coupling conditions generates 3-6, which is reacted in a second Suzuki reaction with a benzothiazolyl boronate to generate compound 3-7. Subsequent heating in hydrochloric acid in a solvent such as methanol results in the removal of an acetyl group. Example 4: IC50 Values for Selected Compounds. Table 2. In Vitro IC50 data for selected compounds of the invention. The following symbols are used: + (more than 10 microMolar), ++ (less than 10 microMolar), +++ (less than 1 microMolar), and ++++ (less than 100 nM).









































































*Starting with compound 438, proliferation data was obtained using an MDA-MB-361 cell line. Example 5: Expression and Inhibition of p110α/p85α, p110β/p85α, p110δ/p85α, and p110Y Assay:
[00396] Kits or commercial systems to assess PI3-K activities are available. Commercially available kits or systems can be used to screen for inhibitors and/or agonists of PI3-Ks including but not limited to PI 3-Kinase a, β, δ, and Y. Any exemplary system is PI 3-Kinase (human) HTRF™ Upstate Assay. The test can be performed according to the procedures suggested by the manufacturer. Briefly, the assay is a time-resolved FRET assay that indirectly measures the PIP3 product formed by activity of a PI3-K. The kinase reaction is performed in a microtiter plate plate (eg a 384-well microtiter plate). Total reaction volume is approximately 20ul per well. In the first step, each well will receive 2ul of test compound in 20% dimethylsulfoxide resulting in a final concentration of 2% DMSO. Then approximately 14.5ul of a kinase/PIP2 mixture (diluted in 1X reaction buffer) is added per well for a final concentration of 0.25-0.3ug/ml kinase and 10μM PIP2. The plate is sealed and incubated for 15 minutes at room temperature. To start the reaction, 3.5ul of ATP (diluted in 1X reaction buffer) is added per well to a final concentration of 10μM ATP. The plate is sealed and incubated for 1 hour at room temperature. The reaction is stopped by adding 5ul of Stop Solution per well and then 5ul of Detection Mix is added per well. The plate is sealed, incubated for 1 hour at room temperature, and then read in an appropriate plate reader. Data are analyzed and IC50s are generated using GraphPad Prism 5. Fig. 1 shows the results for an example analysis of kinase activities. For PI3K α, β, δ, and y, the nM concentration of inhibitor to achieve IC50 is given. Inhibition of α PI3K at concentrations lower than those for β, δ, and y provides evidence of specificity within this group of kinases. Similar assays, and others known in the art, can be used to measure the percent inhibition of other kinases, including but not limited to PI3K class II kinases, phosphoinositide 4 kinases (PI4K), and phosphoinositide 5 kinases (PI5K). Fig. 1 shows a percent inhibition analysis at 1000nm concentration of the same compound, compound 54, including PDK class II kinases PI3K2Cβ and PI3KC2Y; the PI4Kβ PI4K; and from PI5s PI5K1α, PI5K1C, PI5k2β, and PI5K2C. Both percent inhibition and IC50 for DYRK1A, HIPK3, CLK1 kinases are also provided. The results shown in Fig. 1 show the relative degree of specificity of compound 54. Example 6: Abl Expression Inhibition Assays
[00397] The cross-activity or lack thereof of one or more compounds of the present invention against Abl kinase can be measured according to any procedure known in the art or methods disclosed below. For example, the compounds described herein can be evaluated in triplicate against full-length recombinant Abl or Abl (T315I) (Upstate) in an assay containing 25 mM HEPES, pH 7.4, 10 mM MgCl2, 200 μM ATP (2.5 µCi of Y-32P-ATP), and 0.5 mg/ml BSA. The optimized Abl peptide substrate EAIYAAPFAKKK is used as a phosphoaceptor (200 μM). Reactions are terminated by smearing on the phosphocellulose sheets, which are washed with 0.5% phosphoric acid (approximately 6 times, 5-10 minutes each). Leaves are dried and transferred radioactivity quantified by phosphorimaging. Example 7: Hck Expression Inhibition Assays
The cross-activity or lack thereof of one or more compounds of the present invention against Hck kinase can be measured according to any procedure known in the art or methods disclosed below. The compounds described here can be assayed against full-length recombinant Hck in an assay containing 25 mM HEPES, pH 7.4, 10 mM MgCl2, 200 μM ATP (2.5 μCi Y-32P-ATP), and 0.5 mg/ml BSA. The EIYGEFKKK kinase kinase Src family peptide optimized substrate is used as a phosphoacceptor (200 μM). Reactions are terminated by spotting them on phosphocellulose sheets, which are washed with 0.5% phosphoric acid (approximately 6 times, 5-10 minutes each). Leaves are dried and transferred radioactivity quantified by phosphorimaging. Example 8: Insulin Receptor (IR) Expression and Inhibition Assays
The cross-activity or lack thereof of one or more compounds of the present invention against IR receptor kinase can be measured according to any procedure known in the art or methods disclosed below. The compounds described herein can be evaluated in triplicate against recombinant insulin receptor kinase domain (Upstate) in an assay containing 25 mM HEPES, pH 7.4, 10 mM MgCl2, 10 mM MnCl2, 200 μM ATP (2.5 μCi of Y-32P-ATP), and 0.5 mg/ml BSA. Poly E-Y (Sigma; 2mg/ml) is used as a substrate. Reactions are terminated by smearing them onto nitrocellulose, which is washed with 1M NaCl/1% phosphoric acid (approximately 6 times, 5-10 minutes each). Leaves are dried and transferred radioactivity quantified by phosphorimaging. Example 9: Src Expression and Inhibition Assays
The cross-activity or lack thereof of one or more compounds of the present invention against Src kinase can be measured according to any procedure known in the art or methods disclosed below. The compounds described here can be evaluated in triplicate against recombinant full-length Src or Src (T338I) in an assay containing 25 mM HEPES, pH 7.4, 10 mM MgCl2, 200 μM ATP (2.5 μCi Y—32P— ATP), and 0.5 mg/ml BSA. Substrate-optimized peptide from the Src kinase family EIYGEFKKK is used as a phosphoacceptor (200 µM). Reactions are terminated by spotting them on phosphocellulose sheets, which are washed with 0.5% phosphoric acid (approximately 6 times, 5-10 minutes each). The leaves were dried and the transferred radioactivity was quantified by phosphorimaging. Example 10: DNA-PK Expression and Inhibition Assays (DNAK)
The cross-activity or lack thereof of one or more compounds of the present invention against DNAK kinase can be measured according to any procedure known in the art. DNA-PK can be purchased from Promega and evaluated using the DNA-PK Assay System (Promega) according to the manufacturer's instructions. Example 11: mTOR Expression Assays.
The cross-activity or lack thereof of one or more compounds of the present invention against mTor can be measured according to any procedure known in the art or methods disclosed below. The compounds described here can be tested against recombinant mTOR (Invitrogen) in an assay containing 50 mM HEPES, pH 7.5, 1 mM EGTA, 10 mM MgCl2, 2.5 mM, 0.01% Tween, 10 μM ATP (2, 5 μCi of O-32P-ATP), and 3 μg/ml BSA. Recombinant mouse PHAS-1/4EBP1 (Calbiochem; 2 mg/ml) is used as a substrate. Reactions are terminated by applying them to nitrocellulose, which is washed with 1M NaCl/1% phosphoric acid (approximately 6 times, 510 minutes each). Leaves are dried and transferred radioactivity quantified by phosphorimaging.
[00403] Other kits or systems for assessing mTOR activity are commercially available. For example, one can use the Invitrogen's LanthaScreen™ Kinase Assay to test the mTOR inhibitors disclosed herein. This assay is a time-resolved FRET platform that measures the phosphorylation of 4EBP1-labeled GFP by mTOR kinase. The kinase reaction is performed in a 384-well microtiter plate. The total reaction volume is 20ul per well and the composition of the reaction buffer is 50mM HEPES pH7.5, 0.01% Polysorbate 20, 1mM EGTA, 10mM MnCl2, and 2mM DTT. In the first step, each well receives 2ul of test compound in 20% dimethylsulfoxide resulting in a final concentration of 2% DMSO. Then 8ul of mTOR diluted in reaction buffer is added per well for a final concentration of 60ng/ml. To start the reaction, 10ul of an ATP/GFP-4EBP1 mixture (diluted in reaction buffer) is added per well for a final concentration of 10μM ATP and 0.5μM GFP-4EBP1. The plate is sealed and incubated for 1 hour at room temperature. The reaction is stopped by adding 10ul per well of a Tb-anti-pT46 antibody 4EBP1/EDTA mix (diluted in TR-FRET buffer) to a final concentration of 1.3nM antibody and 6.7mM EDTA. The plate is sealed, incubated for 1 hour at room temperature, and then read in a plate reader set for LanthaScreen™ TR-FRET. Data is analyzed and IC50s are generated using GraphPad Prism 5. Example 12: Vascular Endothelial Growth Receptor Expression and Inhibition Assays
The cross-activity or lack thereof of one or more compounds of the present invention against VEGF receptor can be measured according to any procedure known in the art or methods disclosed below. The compounds described here can be tested against KDR receptor kinase domain (Invitrogen) in an assay containing 25 mM HEPES, pH 7.4, 10 mM MgCl2, 0.1% BME, 10 μM ATP (2.5 QCi of □ -32P-ATP), and 3 ug/ml BSA. Poly EY (Sigma; 2 mg/ml) is used as a substrate. Reactions are terminated by application to nitrocellulose, which is washed with 1M NaCl/1% phosphoric acid (approximately 6 times, 5-10 minutes each). Leaves are dried and transferred radioactivity quantified by phosphorimaging. Example 13: Ephrin B4 Receptor (EphB4) Expression and Inhibition Assays
[00405] The cross-activity or lack thereof of one or more compounds of the present invention against EphB4 can be measured according to any procedure known in the art or methods disclosed below. The compounds described herein can be tested against recombinant Ephrin receptor B4 receptor kinase domain (Invitrogen) in an assay containing 25 mM HEPES, pH 7.4, 10 mM MgCl2, 0.1% BME, 10 DM ATP (2.5 DCi of Ü-32P-ATP), and 3 Dg/ml BSA.Poli EY (Sigma; 2 mg/ml) is used as a substrate. Reactions are terminated by applying over nitrocellulose, which is washed with 1M NaCl/1% phosphoric acid (approximately 6 times, 5-10 minutes each). Leaves are dried and transferred radioactivity quantified by phosphorimaging. Example 14: Epidermal Growth Factor Receptor (EGFR) Expression and Inhibition Assays
[00406] The cross-activity or lack thereof of one or more compounds of the present invention against EGFR kinase can be measured according to any procedure known in the art or methods disclosed below. The compounds described herein can be tested against recombinant receptor kinase domain of EGF (Invitrogen) in an assay containing 25 mM HEPES, pH 7.4, 10 mM MgCl2, 0.1% BME, 10 DM ATP (2.5 DCi of Ü-32P-ATP), and 3 µg/ml BSA . Poly E-Y (Sigma; 2 mg/ml) is used as a substrate. Reactions are terminated by applying them to nitrocellulose, which is washed with 1M NaCl/1% phosphoric acid (approximately 6 times, 5-10 minutes each). Leaves are dried and transferred radioactivity quantified by phosphorimaging. Example 15: Expression and Inhibition Assays KIT Assay
[00407] The cross-activity or lack thereof of one or more compounds of the present invention against KIT kinase can be measured according to any procedure known in the art or methods disclosed below. The compounds described here can be tested against KIT recombinant kinase domain (Invitrogen) in an assay containing 25 mM HEPES, pH 7.4, 10 mM MgCl2, 1 mM DTT, 10 mM MnCl2, 10 DM ATP (2.5 DCi of D- 32P-ATP), and 3 Dg/ml BSA. Poly EY (Sigma; 2 mg/ml) is used as a substrate. Reactions are terminated by applying them to nitrocellulose, which is washed with 1M NaCl/1% phosphoric acid (approximately 6 times, 5-10 minutes each). Leaves are dried and transferred radioactivity quantified by phosphorimaging. Example 16: RET Expression and Inhibition Assays
[00408] The cross-activity or lack thereof of one or more compounds of the present invention against RET kinase can be measured according to any procedure known in the art or methods disclosed below. The compounds described here can be tested against recombinant RET kinase domain (Invitrogen) in an assay containing 25 mM HEPES, pH 7.4, 10 mM MgCl2, 2.5 mM DTT, 10 DM ATP (2.5 OCi of □ -32P -ATP), and 3 Ug/ml BSA. The substrate-optimized Abl peptide EAIYAAPFAKKK is used as a phosphoaceptor (200 DM). Reactions are terminated by spotting them on phosphocellulose sheets, which are washed with 0.5% phosphoric acid (approximately 6 times, 5-10 minutes each). Leaves are dried and transferred radioactivity quantified by phosphorimaging. Example 17: Platelet Derived Growth Factor Receptor (PDGFR) Expression and Inhibition Assays
The cross-activity or lack thereof of one or more compounds of the present invention against PDGFR kinase can be measured according to any procedure known in the art or methods disclosed below. The compounds described herein can be tested against kinase domain of the PDG receptor recombinant (Invitrogen) in an assay containing 25 mM HEPES, pH 7.4, 10 mM MgCl2, 2.5 mM DTT, 10 DM ATP (2.5 □ Ci D-32P-ATP), and 3 Dg/ml BSA. The optimized Abl peptide substrate EAIYAAPFAKKK is used as a phosphoaceptor (200 □M). Reactions are terminated by smearing them onto phosphocellulose sheets, which are washed with 0.5% phosphoric acid (approximately 6 times, 5-10 minutes each). Leaves are dried and transferred radioactivity quantified by phosphorimaging. Example 18: FMS-related Tyrosine Kinase 3 (FLT-3) Expression and Inhibition Assays
The cross-activity or lack thereof of one or more compounds of the present invention against FLT-3 kinase can be measured according to any procedure known in the art or methods disclosed below. The compounds described herein can be tested against kinase domain of Recombinant FLT-3 (Invitrogen) in an assay containing 25 mM HEPES, pH 7.4, 10 mM MgCl2, 2.5 mM DTT, 10 DM ATP (2.5 DCi of □ -32P-ATP), and 3 Dg/ml BSA. The substrate-optimized Abl peptide EAIYAAPFAKKK is used as a phosphoaceptor (200 DM). Reactions are terminated by spotting them on phosphocellulose sheets, which are washed with 0.5% phosphoric acid (approximately 6 times, 5-10 minutes each). Leaves are dried and transferred radioactivity quantified by phosphorimaging. Example 19: TEK receptor tyrosine kinase (TIE2) Expression and Inhibition Assays
The cross-activity or lack thereof of one or more compounds of the present invention against TIE2 kinase can be measured according to any procedure known in the art or methods disclosed below. The compounds described herein can be tested against TIE2 kinase domain recombinant (Invitrogen) in an assay containing 25 mM HEPES, pH 7.4, 10 mM MgCl2, 2 mM DTT, 10 mM MnCl2, 10 DM ATP (2.5 DCi D-32P-ATP), and 3 Dg/ml BSA. Poly EY (Sigma; 2mg/ml) is used as a substrate. Reactions are terminated by applying them to nitrocellulose, which is washed with 1M NaCl/1% phosphoric acid (approximately 6 times, 5-10 minutes each). Leaves are dried and transferred radioactivity quantified by phosphorimaging. Example 20: B-Cell Activation and Proliferation Assay
[00412] The ability of one or more subject compounds to inhibit B cell activation and proliferation is determined according to standard procedures known in the art. For example, an in vitro cell proliferation assay is established that measures the metabolic activity of living cells. The assay is performed in a 96-well microtiter plate using Alamar Blue reduction. Balb/c splenic B cells are purified on a Ficoll-Paque™ PLUS gradient followed by magnetic cell separation using a MACS B cell isolation kit (Miletenyi). Cells are plated at 90ul at 50,000 cells/well in B Cell Medium (RPMI + 10%FBS + Penic/Estrep + 50μM bME + 5mM HEPES). A compound disclosed here is dilution in B Cell Medium and added in one volume of 10ul. Plates are incubated for 30min at 37C and 5% CO2 (final concentration of 0.2% DMSO). 50ul of B cell stimulation cocktail is then added containing 10ug/ml LPS or 5ug/ml F(ab')2 Donkey anti-mouse IgM plus 2ng/ml recombinant mouse IL4 in B Cell Medium. Plates are incubated for 72 hours at 37°C and 5% CO2. A 1ML volume of Alamar reagent is added to each well and the plates are incubated for 5 hours at 37°C and 5% CO2. Alamar Blue fluorescence is read at 560Ex/590Em, and IC50 or EC50 values are calculated using GraphPad Prism 5. Example 21: Tumor Cell Line Proliferation Assay
[00413] The ability of one or more subject compounds to inhibit the proliferation of tumor cell lineages is determined according to procedures known in the art. For example, an in vitro cell proliferation assay can be performed to measure the metabolic activity of living cells. The assay is performed in a 96-well microtiter plate using Alamar Blue reduction. Human tumor cell lines are obtained from ATCC (eg, MCF7, U-87 MG, MDA-MB-468, PC-3), grown confluent in T75 flasks, trypsinized with 0.25% trypsin, washed with a time with Tumor Cell Medium (DMEM + 10%FBS), and plated in 90ul at 5,000 cells/well in Tumor Cell Medium. A compound disclosed here is diluted in Tumor Cell Medium and added in 10ul volume. Plates are incubated for 72 hours at 37C and 5% CO2. A 10uL volume of Alamar Blue reagent is added to each well and the plates are incubated for 3 hours at 37°C and 5% CO2. Alamar Blue fluorescence is read at 560Ex/590Em, and IC50 values are calculated using GraphPad Prism 5. The results are expected to show that some of the compounds of the present invention are potent inhibitors of tumor cell lineage proliferation under the conditions tested . Example 22: In vivo Antitumor Activity
The compounds described herein can be evaluated in a group of human and murine tumor models.
[00415] Paclitaxel Refractory Tumor Models
[00416] 1. Clinically derived Ovarian Carcinoma Model.
[00417] This tumor model is established from a tumor biopsy of a patient with ovarian cancer. Tumor biopsy is taken from the patient.
[00418] The compounds described here are administered to nude mice bearing tumors staged on a 2 x 5 schedule.
2. A2780Tax Human Ovarian Carcinoma Xenograft (Mutated Tubulin).
[00420] A2780Tax is a paclitaxel-resistant human ovarian carcinoma model. It is derived from the sensitive parent lineage A2780 by co-incubating the cells with paclitaxel and verapamil, an MDR reversal agent. Its resistance mechanism has been shown to be unrelated to MDR and is attributed to a mutation in the gene encoding the beta-tubulin protein.
[00421] The compounds described here can be administered to mice bearing tumors staged on a schedule every 2 days x 5.
[00422] 3. HCT116/VM46 Human Cervical Carcinoma Xenograft (Multi-Drug Resistant).
[00423] HCT116/VM46 is an MDR-resistant colon carcinoma developed from the sensitive parent lineage HCT116. In vivo, grown in nude mice, HCT116/VM46 has consistently demonstrated resistance to paclitaxel.
[00424] The compounds described here can be administered to mice bearing tumors staged on a schedule of every 2 days x 5.
[00425] 5. M5076 Murine Sarcoma Model
[00426] M5076 is a mouse fibrosarcoma that is inherently refractory to paclitaxel in vivo.
[00427] The compounds described here can be administered to mice bearing staging tumors on a schedule of every 2 days x 5.
One or more compounds of the invention can be used in combination with other therapeutic agents in vivo in the HCT/VM46 multi-drug resistant human colon carcinoma xenografts or any other model known in the art including those described herein.
The results are expected to show that one or more compounds of the present invention are potent inhibitors of tumor growth in vivo under the conditions tested. Example 23: Microsome stability test
[00430] The stability of one or more object compounds is determined according to standard procedures known in the art. For example, the stability of one or more subject compounds is established in an in vitro assay. In particular, an in vitro microsome stability assay is established which measures the stability of one or more subject compounds when reacting with mouse, rat or human liver microsomes. The microsome reaction with compounds is carried out in a 1.5 mL Eppendorf tube. Each tube contains 0.1 μL of 10.0 mg/ml NADPH; 75 μL of 20.0 mg/ml of mouse, rat or human liver microsome; 0.4 μL of 0.2 M phosphate buffer, and 425 μL of ddH2O. Negative control tubes (without NADPH) contain 75 μL of 20.0 mg/ml mouse, rat or human liver microsome; 0.4 μL of 0.2 M phosphate buffer, and 525 μL of ddH2O. The reaction is started by adding 1.0 μL of 10.0 mM tested compound. Reaction tubes are incubated at 37°C. 100 μL of sample is collected in new Eppendorf tubes containing 300 μL of cold methanol in 0, 5, 10, 15, 30 and 60 minutes of reaction. Samples are centrifuged at 15,000 rpm to remove protein. The centrifuged sample supernatant is transferred to a new tube. The concentration of stable compound after the microsome reaction in the supernatant is measured by Liquid Chromatography/Mass Spectrometry (LC-MS). Example 24: Plasma Stability Assay
[00431] The stability of one or more object compounds in plasma is determined according to standard procedures known in the art. See, for example, Rapid Commun. Mass Spectrom., 10: 1019-1026. The following procedure is an HPLC-MS/MS assay using human plasma; other species including monkey, dog, rat, and mouse are still available. Frozen, heparinized human plasma is thawed in an ice-cold water bath and rotated for 10 minutes at 2000 rpm at 4°C before use. A subject compound is added from a 400 μM stock solution to an aliquot of prewarmed plasma to generate a final assay volume of 400 μL (or 800 μL for half-life determination), containing 5 μM of test compound and 0 .5% DMSO. Reactions are incubated, with shaking, for 0 minutes and 60 minutes at 37 °C, or for 0, 15, 30, 45 and 60 minutes at 37 °C to determine half-life. Reactions are stopped by transferring 50 μL of incubation mix to 200 μL of ice-cold acetonitrile and mixed by shaking for 5 minutes. Samples are centrifuged at 6000 x g for 15 minutes at 4°C and 120 μL of supernatant removed in clean tubes. The samples are then evaporated to dryness and submitted for analysis by HPLC-MS/MS.
[00432] Where desired, one or more control or reference compounds (5 μM) are tested simultaneously with the test compounds: one compound, propoxycaine, with low stability in plasma and another compound, propantheline, with intermediate stability in plasma.
[00433] Samples are reconstituted in acetonitrile/methanol/water (1/1/2, v/v/v) and analyzed via (RP)HPLC-MS/MS using selected reaction monitoring (SRM). The HPLC conditions consist of a binary LC pump with autosampler, a mixing mode, C12 column, 2 x 20 mm, and a gradient program. Peak areas corresponding to analytes are recorded by HPLC-MS/MS. The proportion of parent compound remaining after 60 minutes to the amount remaining at time zero, expressed as a percentage, is reported as stability in plasma. In the case of half-life determination, the half-life is estimated from the slope of the initial linear range of the logarithmic curve of the compound remaining (%) vs. time, assuming first-order kinetics. Example 25: Chemical Stability
[00434] The chemical stability of one or more object compounds is determined according to standard procedures known in the art. The following details an exemplary procedure for checking the chemical stability of an object compound. The standard buffer used for the chemical stability assay is phosphate saline buffer (PBS) at pH 7.4; other suitable buffers can be used. A subject compound is added from a 100 μM stock solution to an aliquot of PBS (in duplicate) to generate a final assay volume of 400 μL, containing 5 μM of test compound and 1% DMSO (for half-life determination in a total sample volume of 700 µL is prepared). Reactions are incubated, with shaking for 0 minutes and 24 hours at 37°C; for half-life determination samples are incubated for 0, 2, 4, 6, and 24 hours. Reactions are stopped by immediately adding 100 µL of the incubation mixture to 100 µL of acetonitrile and vortexing for 5 minutes. Samples are then stored at -20oC until analysis by HPLC-MS/MS. Where desired, a control compound or a reference compound such as chlorambucil (5 μM) is tested simultaneously with an object compound of interest, as this compound is extensively hydrolyzed over the course of 24 hours. Samples are analyzed by (RP)HPLC-MS/MS using selected reaction monitoring (SRM). The HPLC conditions consist of a binary LC pump with autosampler, a mixed mode, C12 column, 2 x 20 mm, and a gradient program. Peak areas corresponding to analytes are recorded by HPLC-MS/MS. The proportion of parent compound remaining after 24 hours to the amount remaining at time zero, expressed as a percentage, is reported as chemical stability. In the case of half-life determination, the half-life is estimated from the slope of the initial linear range of the logarithmic curve of the compound remaining (%) vs. time, assuming first-order kinetics. Example 26: Akt Kinase Assay
Cells comprising components of the Akt/mTOR pathway, including but not limited to L6 myoblasts, B-ALL cells, B cells, T cells, leukemia cells, bone marrow cells, p190 transduced cells, philladelphia chromosome positive cells (Ph+ ), and mouse embryonic fibroblasts, are typically grown in cell growth medium such as DMEM supplemented with fetal bovine serum and/or antibiotics, and grown to confluence.
[00436] To compare the effect of one or more compounds disclosed herein on Akt activation, said cells are left serum-free overnight and incubated with one or more compounds disclosed herein or about 0.1% DMSO for approximately 1 minute at about 1 hour before insulin stimulation (eg 100 nM) for about 1 minute to about 1 hour. Cells are lysed by scraping in ice-cold lysis buffer containing detergents such as sodium dodecyl sulfate and protease inhibitors (eg PMSF). After contacting the cells with lysis buffer, the solution is briefly sonicated, clarified by centrifugation, resolved by SDS-PAGE, transferred to nitrocellulose or PVDF, and immunoblotted using antibodies to phospho-Akt S473, phospho-Akt T308, Akt, and β-actin (Cell Signaling Technologies). Example 27: Blood Kinase Signaling
PI3K/Akt /mTor signaling is measured in blood cells using the phosflow method (Methods Enzymol. 2007;434:131-54). The advantage of this method is that it is by nature a single cell assay so that heterogeneity can be detected rather than population means. This allows for the concurrent distinction of signaling states in different populations defined by other markers. Phosflow is also highly quantitative. To test the effects of testing one or more compounds disclosed herein, unfractionated splenocytes, or peripheral mononuclear cells are stimulated with anti-CD3 to initiate T cell receptor signaling. The cells are then fixed to surface markers and intracellular phosphoproteins . Inhibitors disclosed herein are expected to inhibit anti-CD3-mediated phosphorylation of Akt -S473 and S6, whereas rapamycin inhibits S6 phosphorylation and increases Akt phosphorylation under the conditions tested.
Similarly, aliquots of whole blood are incubated for 15 minutes with vehicle (eg 0.1%DMSO) or kinase inhibitors at various concentrations, prior to addition of stimulus for T cell receptor cross-linking (TCR) (anti-CD3 with secondary antibody) or B cell receptor (BCR) using anti-kappa light chain antibody (Fab'2 fragments). After approximately 5 and 15 minutes the samples are fixed (eg with cold 4% paraformaldehyde) and used for phosflow. Surface staining is used to distinguish T and B cells using antibodies directed to cell surface markers that are known in the art. The level of phosphorylation of kinase substrates such as Akt and S6 are then measured by incubating fixed cells with labeled antibodies specific for the phosphorylated isoforms of these proteins. The cell population is then analyzed by flow cytometry.
The results are expected to show that one or more of the compounds of the present invention are potent and selective inhibitors of one or more members of one or more of PI3K, mTOR, and Akt signaling in blood cells under the conditions tested. Example 28: Colony Formation Assay
[00440] Murine bone marrow cells newly transformed with a p190 BCR-Abl retrovirus (referred to herein as p190 transduced cells) are plated in the presence of various drug combinations in M3630 methylcellulose medium for about 7 days with recombinant human IL-7 on about 30% serum, and the number of colonies formed is counted by visual assessment under a microscope.
[00441] Alternatively, peripheral blood mononuclear cells are obtained from patients positive (Ph+) and negative (Ph-) for the Philadelphia chromosome at initial diagnosis or recurrence. Live cells are isolated and enriched for CD19+ CD34+ B cell progenitors. After overnight liquid culture, cells are plated in methocult GF+ H4435, Stem Cell Technologies) supplemented with cytokines (IL-3, IL-6, IL- 7, G-CSF, GM-CSF, CF, Flt3 linker, and erythropoietin) and various concentrations of known chemotherapeutic agents in combination with the compounds of the present disclosure. Colonies are counted by microscopy 12-14 days later. This method can be used to test for evidence of synergistic or additive activity.
[00442] The results are expected to show that one or more of the compounds of the present invention are potent and selective inhibitors of p190 transduced cell colony formation under the condition tested. Example 29: In vivo Effect of Kinase Inhibitors on Leukemic Cells
[00443] Recipient female mice are lethally irradiated from a y source in two doses approximately 4 hr apart, with approximately 5Gy each. About 1hr after the second radiation dose, mice are injected i.v. with about 1x106 leukemic cells (eg, human or murine Ph+ cells, or p190) transduced bone marrow cells. These cells are administered along with a radioprotective dose of about 5x106 normal bone marrow cells from 35-week-old donor mice. Recipients are given antibiotics in water and monitored daily. Mice that became ill after about 14 days are sacrificed and lymphoid organs are harvested for analysis. Kinase inhibitor treatment begins ten days after leukemic cell injection and continues daily until the mouse becomes ill or a maximum of approximately 35 days after transplantation. Inhibitors are administered by oral lavage.
[00444] Peripheral blood cells are collected at approximately day 10 (pre-treatment) and at euthanasia (post-treatment), contacted with labeled anti-hCD4 antibodies and counted by flow cytometry. This method can be used to demonstrate that the synergistic effect of one or more compounds disclosed herein in combination with known chemotherapeutic agents significantly reduces leukemic blood cell counts as compared to treatment with known chemotherapeutic agents (eg, Gleevec) isolated under the condition tested. Example 30: Mouse Treatment with Lupus Disease Model
[00445] Mice that are devoid of FcYRIIb inhibitory receptor that opposes PI3K signaling in B cells develop high-penetration lupus. Mice devoid of FcYRIIb (R2KO, Jackson Labs) are considered a valid model of human disease as some lupus patients show decreased expression or function of FcYRIIb (S. Bolland and J.V. Ravtech 2000. Immunity 12:277285).
[00446] R2KO mice develop lupus-like disease with anti-nuclear antibodies, glomerulonephritis, and proteinurea within about 4-6 months of age. For these experiments, the rapamycin analogue RAD001 (available from LC Laboratories) is used as a reference compound, and administered orally. This compound has been shown to alleviate lupus symptoms in the B6.Sle1z.Sle3z model (T. Wu et al. J. Clin Invest. 117:2186-2196).
[00447] Lupus disease model mice such as R2KO, BXSB or MLR/lpr are treated at about 2 months of age, approximately for about two months. Mice receive administration of: vehicle, RAD001 at about 10mg/kg, or compounds disclosed herein at approximately 1mg/kg to about 500mg/kg. Blood and urine samples are taken approximately throughout the test period, and tested for antinuclear antibodies (in serum dilutions) or protein concentration (in urine). Serum is further tested for anti-ssDNA and anti-dsDNA antibodies by ELISA. Animals are sacrificed on day ay 60 and tissues collected for measurement of spleen weight and kidney disease. Glomerulonephritis is evaluated in H&E stained kidney sections. Other animals are studied for about two months after stopping treatment, using the same assessment parameters.
[00448] This established model in the art can be employed to test that the kinase inhibitors disclosed here can suppress or delay the onset of lupus symptoms in lupus disease model mice. Example 31: Murine Bone Marrow Transplant Assay
[00449] Recipient female mice are lethally irradiated from a y-ray source. About 1hr after dose completion, mice received about 1x106 leukemic cells from early passage p190 translated cell cultures (eg, as described in Cancer Genet Cytogenet. 2005 Aug;161(1):51-6). These cells are administered along with a radioprotective dose of approximately 5x106 normal bone marrow cells from 3-5 week old donors. Recipients are given antibiotics in water and monitored daily. Mice that became ill after about 14 days are sacrificed and lymphoid organs are harvested by flow cytometry and/or magnetic enrichment. Treatment starts at approximately day 10 and continues until the mice become ill, or after a maximum of about 35 days after transplantation. Drugs are administered by oral gavage (p.o.). In a pilot experiment a dose of chemotherapy that is not curative but delays the onset of leukemia for about a week or less is identified; controls are treated with vehicle or treated with a chemotherapeutic agent, previously shown to delay but not cure leukogenesis in this model (eg, imatinib at about 70mg/kg twice daily). For the first stage p190 cells expressing eGFP are used, and the postmortem analysis is limited to enumeration of the percentage of leukemic cells in bone marrow, spleen and lymph node (LN) by flow cytometry. In the second phase, p190 cells expressing a tailless form of human CD4 are used for postmortem analysis including spleen hCD4+ cell screening followed by immunoblot analysis of a key signaling endpoint: p Akt -T308 and S473; pS6 and p4EBP-1. With immunoblot detection controls, sorted cells are incubated in the presence or absence of kinase inhibitors of the inhibitors of the present disclosure prior to lysis. Optionally, “phosflow” is used to detect p Akt -S473 and pS6-S235/236 in hCD4-gated cells without prior screening. These signaling studies are particularly useful if, for example, drug-treated mice have not developed clinical leukemia at the day 35 time point. Kaplan-Meier survival plots are generated and statistical analysis done according to methods known in the art. Results from p190 cells are analyzed separately as well as cumulatively.
[00450] Peripheral blood samples (100-200μl) are obtained weekly from all mice, starting on day 10 immediately before the start of treatment. Plasma is used to measure drug concentrations, and cells are analyzed for leukemia markers (eGFP or hCD4) and signaling biomarkers as described here.
[00451] This general assay known in the art can be used to test that effective therapeutic doses of the compounds disclosed herein can be used to inhibit the proliferation of leukemic cells. Example 32: Type II Collagen-Induced Arthritis Developing in Rat Assay
[00452] To study the effects of compounds of the present invention on autoimmune arthritis disease, a collagen-induced arthritis model developing is used. Female Lewis rats are given collagen injections on day 0. Bovine type II collagen is prepared as a 4mg/ml solution in 0.01N acetic acid. Equal volumes of collagen and incomplete Freund's adjuvant are emulsified by hand mixing until a granule of the emulsified material retains its shape in the water. Each rodent receives an injection of 300 μl of the mixture at each separate injection time spread over three subcutaneous sites in the posterior part.
[00453] Oral compound administration begins on day 0 and continues through day 16 with vehicle (5% NMP, 85% PEG 400, 10% Solutol) or compounds of the present invention in vehicle or control (e.g., methotrexate) in 12-hour daily intervals. Rats are weighed on days 0, 3, 6, 9-17 and ankle caliper measurements are taken on days 9-17. Final body weight is measured, and then animals are sacrificed on day 17. After euthanasia, blood is drawn and the hind legs and knees are removed. Blood is further processed for pharmacokinetic experiments as well as an anti-type II collagen antibody ELISA assay. The hind legs are weighed and then, with the knees, preserved in 10% formalin. The paws and knees are subsequently processed for microscopy. Liver, spleen and thymus are heavy. Sciatic nerves are prepared for histopathology.
The knee and ankle joints are fixed for 1-2 days and decalcified for 4-5 days. Ankle joints are cut in halves longitudinally, and only knees are cut in half along the frontal plane. Joints are processed, embedded, sectioned and stained with toluidine blue. The classification of joints is made according to the following criteria: Knee and Ankle Inflammation 0=Normal 1= Minimal infiltration of inflammatory cells in synovial/periarticular tissue 2= Mild infiltration 3= Moderate infiltration with moderate edema 4= Marked infiltration with marked edema 5 = severe infiltration with severe edema Pannus Ankle 0=Normal 1=Minimum infiltration of pannus into cartilage and subchondral bone 2= mild infiltration (<1/4 of tibia or tarsi in marginal areas) 3= moderate infiltration (1/4 to 1 /3 of tibia or tarsi affected in marginal zones 4= marked infiltration (1/2-3/4 of tibia or tarsi affected in marginal zones) 5=Severe infiltration (>3/4 of tibia or tarsi affected in marginal zones) , severe distortion of general architecture) Knee Pannus 0=Normal 1=Minimum infiltration of pannus into cartilage and subchondral tissue 2=Mild infiltration (extending to 1/4 of the surface or subchondral area of the tibia or femur) 3= Moderate infiltration (extends up to >1/ 4 but < 1/2 the surface or subchondral area of the tibia or femur) 4=Marked infiltration (extends up to 1/2 to 3/4 of the tibial or femoral surface) 5=Severe infiltration (copper > 3/4 surface) Cartilage Damage (Ankle, emphasis on small tarsi) 0=Normal 1=minimal=minimal to moderate loss of toluidine blue staining with no obvious loss of chondrocyte or interruption of collagen 2=Slight=mild loss of toulidine blue staining with loss mild focal (superficial) dechondrocyte and/or collagen disruption 3=Moderate=moderate loss of toulidine blue stain with moderate multifocal (depth to medial zoma) loss of chondrocyte and/or collagen disruption, smaller tarsi affected 1/2- 3/4 depth 4=marked=marked loss of toulidine blue staining with marked multifocal loss (deep to deep zoma) chondrocyte and/or collagen disruption, 1 or more small tarsi have full-thickness cartilage loss 5=severe= severe diffuse loss of blue color of toulidine with severe multifocal loss (depth to tide mark) chondrocyte and/or collagen disruption Cartilage damage (Knee, emphasis on femoral condyles) 0=Normal 1=minimum=minimal to slight loss of toulidine blue stain without obvious loss of chondrocyte or collagen disruption 2=Mild=mild loss of toulidine blue staining with mild focal (superficial) chondrocyte loss and/or collagen disruption 3=Moderate=moderate loss of toulidine blue staining with moderate multifocal to diffuse (depth) loss for middle zone) chondrocyte and/or collagen disruption 4=marked=marked loss of toulidine blue staining with marked multifocal to diffuse loss (depth to deep zone) chondrocyte and/or collagen disruption or simple femoral surface with total or almost total 5=severe =severe diffuse loss of toulidine blue stain with severe multifocal loss (depth to tide mark) chondrocyte and/or collagen disruption in both femurs and/or u tibias Bone Resorption (Ankle) 0=Normal 1=Minimum=small areas of resorption, not readily apparent at low magnification, rare osteoclasts 2=Mild=more numerous areas of resorption, not readily apparent at low magnification, more numerous osteoclasts, < 1/4 of the tibia or tarsi in marginal areas resorbed 3=Moderate=obvious resorption of medullary and cortical trabecular bone without full thickness defects in the cortex, loss of some medullary trabeculae, apparent low amplification lesion, more numerous osteoclasts, 1/4 1/3 of affected tibia or tarsi in marginal zones 4=marked = marked defects in full thickness in cortical bone, usually with profile distortion on remaining cortical surface, marked loss of medullary bone, numerous osteoclasts, 1/2-3/ 4 of the tibia or tarsi affected in marginal zones 5=Severe =Severe thickness defects in cortical bone, usually with profile distortion of remaining cortical surface, marked loss of lower bone. edular, numerous osteoclasts, >3/4 of tibia or tarsi affected in marginal zones, severe distortion of general architecture Bone Resorption (Knee) 0=Normal 1=Minimum=small areas of resorption, not readily apparent at low amplification, rare osteoclasts 2 =Slight=more numerous areas of resorption, definite loss of subchondral tissue involving 1/4 of the tibial or femoral surface (medial or lateral) 3=Moderate=obvious resorption of subchondral tissue involving >1/4 but <1/2 of the tibial surface or femoral (medial or lateral) 4=marked = obvious resorption of subchondral tissue involving >1/2 but <3/4 of tibial or femoral surface (medial or lateral) 5=Severe = Distortion of complete joint due to destruction involving >3 /4 tibial or femoral surface (medial or lateral)
[00455] Statistical analysis of body/paw weight, paw AUC parameters and histopathological parameters were evaluated using Student's t-test or other appropriate (ANOVA with post-test) with significance set at 5% significance level . Percent inhibition of paw weight and AUC were calculated using the following formula: % Inhibition =A - B/A X 100 A=Mean Disease Control-Mean Normal B=Mean Treated-Mean Normal
[00456] The results are expected to show, in relation to vehicle only control or for methotrexate control, that the compounds of the present invention show a significant reduction in arthritis-induced ankle diameter increase over time, and reduction in ankle histopathology in at least one or more of the following categories of inflammation, pannus, cartilage damage, and bone resorption as described above. The results are expected to show that one or more compounds of the present invention may be useful for treating and reducing the symptoms of arthritis disease.
[00457] Results are still expected to show a reduction of 10, 20, and 60mg/kg serum levels of anti-collagen type II serum levels for selected test compounds, suggesting that one or more compounds of the present invention may not only be useful for treating and reducing symptoms of arthritis, but may still be useful for inhibiting an autoimmune reaction itself. Example 33: Rat Established Type II Collagen-Induced Arthritis Assay
[00458] To assess the dose-responsive efficacy of compounds of the present invention in inhibiting inflammation, cartilage destruction and bone resorption from day 10 established in type II collagen-induced arthritis in rats, compounds are administered orally daily or twice daily for 6 days.
Female Lewis rats are anesthetized and administered with collagen injections prepared and administered as described above on day 0. On day 6, the animals are anesthetized and administered with a second collagen injection. Pachymeter measurements of normal right and left ankle joints (pre-disease) are performed on day 9. On days 10-11, arthritis typically occurs and rats are randomized into treatment groups. Randomization is performed after knee joint swelling is obviously established and there is evidence of bilateral disease.
[00460] After an animal is selected for inclusion in the study, treatment is started orally. Animals receive vehicle, control (Enbrel) or compound doses twice daily or once daily (BID or QD respectively). Administration is performed on days 1-6 using a volume of 2.5ml/kg (BID) or 5ml/kg (QD) for oral solutions. Rats are weighed on days 1-7 after onset of arthritis and ankle caliper measurements taken each day. Final body weights are taken on day 7 and animals are sacrificed.
[00461] Results are expected to show reduction reduction in mean ankle diameter increase over time for selected test compounds under the tested condition. Example 34: Adjuvant-Induced Arthritis Assay Intrathecal Catheterization of Rats
[00462] Lewis rats anesthetized with isoflurane (200-250 g) are implanted with an intrathecal (IT) catheter. After a 6 d recovery period, all animals except those that appeared to have sensory or motor abnormalities (generally less than 5% of the total number) are used for the experiments. For IT administration, 10 μL of the drug or saline followed by 10 μL of isotonic saline is injected through the catheter. Drug Treatment and Adjuvant Arthritis
Lewis rats are immunized at the base of the tail with 0.1 ml complete Freund's helper (CFA) on day 0 several days after catheter implantation (n=6/group). Treatment with drug (e.g., one or more compounds of the present invention or vehicle) is generally initiated on day 8 and is continued daily through day 20. Clinical signs of arthritis generally begin on day 10, and paw swelling is determined every second day by water displacement plethysmmetry.
[00464] The results are expected to show that one or more compounds of the present invention prove to be useful for the treatment of one or more of these diseases or conditions described herein. Example 35: Rodent Pharmacokinetic Assay
[00465] To study the pharmacokinetics of the compounds of the present invention a set of 4-10 week old mice are grouped according to the following table:


Compounds of the present invention are dissolved in an appropriate vehicle (eg 5% 1-methyl-2-pyrrolidinone, 85% polyethylene glycol 400, 10% Solutor) and administered orally at 12 hour daily intervals. All animals are sacrificed in CO2 2 hours after the final compound is administered. Blood is collected immediately and kept on ice for plasma isolation. Plasma is isolated by centrifugation at 5000 rpm for 10 minutes. Collected plasma is frozen for pharmacokinetic detection.
[00467] The results are expected to demonstrate the pharmacokinetic parameters such as absorption, distribution, metabolism, excretion and toxicity for the compounds of the present invention. Example 36: Basotest Assay
[00468] The basotest assay is performed using the Orpegen Pharma Basotest reagent kit. Heparinized whole blood is pre-incubated with test compound or solvent at 37°C for 20 min. Blood is then incubated with assay kit stimulation buffer (to prime cells for response) followed by allergen (dust mite extract or grass) for 20min. The degranulation process is stopped by incubating the blood samples on ice. The cells are then labeled with anti-IgE-PE to detect basophilic granulocytes, and anti-gp53-FITC to detect gp53 (a glycoprotein expressed on activated basophils). After staining, the red cells are lysed by adding Lysis Solution. Cells are washed, and analyzed by flow cytometry. The test compounds, when evaluated in this assay, inhibit the allergy activation of basophilic granulocytes in the micromolar range. These results are expected to demonstrate that under the condition tested one or more compounds of the present invention are capable of inhibiting allergen-induced basophil activation. Example 37: Use of Compounds of the Present Invention to Inhibit Tumor Growth Cell Lines
Cell lines of interest (A549, U87, ZR-75-1 and 786-O) are obtained from the American Type Culture Collection (ATCC, Manassas, VA). Cells are proliferated and cryogenically preserved at early passage (eg, passage 3). An aliquot is used for further proliferation to obtain enough cells for a TGI study (at about passage 9). Animals
[00470] Athymic female nude mice are provided by Harlan. Mice were received at 4 to 6 weeks of age. All mice are acclimated for about a day to two weeks before handling. The mice are housed in microisolated cages and kept in conditions free from specific pathogens. The mice are fed irradiated mouse chow and freely available autoclaved water is provided. Tumor Xenograft Model
[00471] Mice are inoculated subcutaneously on the right flank with 0.01 to 0.5 ml of tumor cells (approximately 1.0 x 105 to 1.0 x 108 cells/mouse). Five to 10 days after inoculation, tumors are measured using calipers and tumor weight is calculated, for example using animal study management software such as Study Director V,1.6.70 (Study Log). Mice with tumor sizes of about 120 mg are paired into desired groups using Study Director (Day 1). Body weights are recorded when mice are matched in pairs. Tumor volume and body weight measurements are taken one to four times weekly and crude observations are made at least once daily. On Day 1, compounds of the present invention and reference compounds as well as vehicle control are administered by oral gavage or IV as indicated. On the last day of the experiment, mice are sacrificed and their tumors are collected 1-4 hours after the final dose. Tumors are removed and cut into two sections. One third of the tumor is fixed in formalin and embedded in paraffin blocks and the remaining two thirds of the tumor is snap frozen and stored at -80°C. Data and Statistical Analysis
[00472] Mean tumor growth inhibition
(TGI) is calculated using the following formulas:
[00473] Tumors that regress from Day 1 of initial size are removed from the calculations. Individual tumor reduction (TS) is calculated using the Formula below for tumors that show relative regression to Day 1 tumor weight. The mean tumor reduction for each group is calculated and reported.
[00474]

[00475] The model can be employed to show whether the compounds of the present invention can inhibit tumor cell growth such as renal carcinoma cell growth, breast cancer cell growth, lung cancer cell growth, or glioblastoma cell growth under the condition tested. Example 38: PI3K pathway inhibition and PI3Kα mutated tumor cell proliferation
Cells comprising one or more mutations in PI3Kα, including but not limited to breast cancer cells (eg MDA-MB-361 and T47D), and cells comprising one or more mutations in PTEN including but not limited to breast cancer cells prostate cancers (eg, PC3), are typically grown in cell growth media such as DMEM supplemented with fetal bovine serum and/or antibiotics, grown to confluence. Cells are then treated with various concentrations of test compound for about 2 hours and subsequently lysed in cell lysis buffer. Lysates are subjected to SDS-PAGE followed by Western blot analysis to detect downstream signaling markers, including among others pAKT(S473), pAKT(T308), pS6, and p4E-BP1. The degree of proliferation (and inhibition of proliferation) can further be measured for cells at various doses of the compound of the present invention as compound 54. Based on the percent inhibition of pAKT and proliferation indicated by these results, IC50 values are calculated. Fig. 2 provides sample Western blots for downstream signaling markers of PI3K activity for a compound of the present invention at concentrations of 0.1μM, 1μM, and 10μM, as well as calculated results for pAKT IC50 and proliferation inhibition, which exhibits inhibition of the PI3K pathway. Example 39: In vitro inhibition of angiogenesis
[00477] Inhibition of angiogenesis in the presence of test compound is assessed using a tube formation assay, such as using a tube formation assay kit (eg, commercially available from Invitrogen). Angiogenic capacity can be measured in vitro using an endothelial cell line such as human umbilical vein endothelial cells (HUVEC). The assay is conducted according to the kit instructions, in the presence or absence of compound. Briefly, a gel matrix is applied to the cell culture surface, the cells are added to the surface covered with the matrix along with growth factors, with some samples also receiving an inhibitor compound, the cells are incubated at 37°C and 5 % CO2 enough for control samples (no compound added) to form tube structures (such as overnight), cells are stained using a cell-permeable dye (eg calcein), and cells are visualized to identify the degree of formation of tubes. Any reduction in tube formation relative to uninhibited control cells is indicative of angiogenic inhibition. Fig. 3 shows the results of a sample tube formation assay, comparing the control (no compound added), cells receiving a non-specific PI3K inhibitor (Pan-PI3K Inh), and cells receiving a compound from invention as compound 54. Based on the n doses tested and corresponding degree of inhibition of tube formation, IC50 values for tube formation are calculated. Fig. 3 also provides IC50 values for cell viability, which can be measured using any number of methods known in the art, such as staining methods that distinguish live from dead cells (e.g., commercially available Image-iT DEAD Green viability staining of Invitrogen). Fig. 3 further shows IC50 values for compound 54 and Pan-PI3K inhibitor molecules with respect to PI3K α, β, y, δ, which are determined using methods described above, as in example 5. Generally, the results show that compound 54 has a comparable greater potency with respect to inhibition of angiogenesis compared to the Pan-PI3K inhibitor, and is achieved with a compound having specificity for inhibition of α PI3K. Example 40: In vivo efficacy in xenogenic mouse model of breast cancer
[00478] Nude mice bearing tumors derived from implantation of human breast MDA-MB-361 cells (PI3Kα/HER2 carcinoma) are separated into untreated control (vehicle only) and treatment groups. The mice in the treatment group are further divided into mice that receive 70mg/kg (70 mpk) of a Pan-PI3K inhibitor, or 30 mpk or 60 mpk of test compound. Mice in the treatment group receive the defined dose daily by oral lavage for 20 to 50 days, during which time the tumor weight is calculated as described in example 37. Blood glucose is monitored periodically after treatment administration. 2 hours after the final treatment, tumors are harvested and proteins are analyzed by Western blot as described above. The effect of compounds on the location/viability of marginal zone B cells in the spleen is further evaluated at the conclusion of treatment. Fig. 4 shows sample results for tumor size, glucose levels, and levels of various markers for kinase activity. In general, the results indicate that a compound of the present invention including compound 54 has tumor growth inhibition and kinase activity comparable to Pan-PI3K inhibitor, without the blood glucose impact observed for the latter. The results of a similar experiment with regard to tumor size are redrawn in Fig. 5, followed by a longer period of time. Fig. 5 further shows that, in contrast to Pan-PI3K inhibitor, a compound of the present invention including compound 54 does not affect the location/viability of marginal zone B cells.
[00479] A similar experiment using 786-O cells, a human renal carcinoma cell line containing a non-mutated PI3Kα, to MDA cells is used to further demonstrate the specificity of the test compounds. For example, a test compound is compared to a kinase inhibitor with specificity for mTor. The inhibitor with affinity for mTor is effective in inhibiting kinase activity (as measured by Western blot analysis of downstream markers) and tumor growth in this model, whereas a compound of the present invention including compound 54, while still having some anti-cancer activity. -tumor, reduced activity compared to that observed in MDA-derived tumors (compare Fig. 4 and Fig. 6). Fig. 6 also provides biochemical potency data for the two compared inhibitors. Example 41: Synergistic combination with other kinase inhibitors
In some embodiments, a compound of the present invention is combined with another kinase inhibitor. In some embodiments, the combined kinase inhibitor is an MEK inhibitor. A mean effect analysis is used to determine the synergism, antagonism, or additivity of a compound of the present invention when combined with an MEK inhibitor. The combination index (CI) is determined using the Chou/Talalay equation. IC50 values for each individual compound is determined in a 72 hr CellTiter-Glo assay. For combination trials, drugs are used in their equipotent proportions (eg, in proportion to their IC50's). CalcuSyn software (by Biosoft) is used for dose effect analysis.
[00481] To further demonstrate the synergy between kinase inhibitors, a cell capture assay is used to determine the effects of inhibitors alone and in combination in the treated cell cycle stage. HCT116 cells, a human colon cancer cell line, are treated with DMSO (carrier), 3μM of a compound of the present invention including compound 54, 0.3μM of PD0325901, or a combination of both 3μM of compound 54 and 0 .3μM of a MEK inhibitor. Cells are then incubated in the presence of DMSO or inhibitor for 20 hours. The number of cells at each stage in the cell cycle is determined as a percentage of the total, with an increase in the number of cells captured in pre-G0/G1 indicating effective inhibition of cell cycle progression. Fig. 7 shows sample results from said experiment. While all samples receiving inhibitor showed some increase in cell cycle disruption compared to DMSO control, samples receiving both inhibitors showed a greater number of captured cells than expected by merely adding the individual effects (55% compared to 40 %). Thus, these results indicate that the combination of a compound of the present invention including compound 54 with other inhibitors may be synergistic.

权利要求:
Claims (23)
[0001]
1. Compound of Formula II:
[0002]
2. A pharmaceutically acceptable compound or salt, according to claim 1, characterized in that: W1 is CR3, W2 is CR4, W3 is N, W4 is N, W5 is CR7, and W6 is CR8.
[0003]
3. Compound or pharmaceutically acceptable salt, according to claim 1, characterized in that W5 and W6 are CH.
[0004]
4. Compound or pharmaceutically acceptable salt, according to claim 1, characterized in that R1 is H.
[0005]
5. A pharmaceutically acceptable compound or salt, according to claim 1, characterized in that W1 is CR3 and R3 is alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, alkoxy, heterocycloalkyloxy, starch, amino , acyl, acyloxy, alkoxycarbonyl, sulfonamido, halo, cyano, hydroxy, nitro, phosphate, urea or carbonate.
[0006]
6. Compound according to claim 5, characterized in that R3 is aryl, heteroaryl or heterocycloalkyl.
[0007]
7. A compound, according to claim 1, or a pharmaceutically acceptable salt thereof, characterized in that the compound has the Formula VB:
[0008]
8. Compound or pharmaceutically acceptable salt, according to claim 7, characterized in that R3 is alkyl, heteroalkyl, alkenyl, alkynyl, heteroaryl, heteroarylalkyl, alkoxy, heterocycloalkyloxy, starch, amino, acyl, acyloxy, alkoxycarbonyl, sulfonamido, halo, cyano, hydroxy, nitro, phosphate, urea or carbonate.
[0009]
9. Compound or pharmaceutically acceptable salt, according to claim 8, characterized in that R1 is H.
[0010]
10. A compound or pharmaceutically acceptable salt, according to claim 7, characterized in that R3 is starch of the formula -C(O)N(R)2 or -NHC(O)R, wherein R is selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl, heteroaryl bonded through a ring carbon and heteroalicyclic bonded through a ring carbon, each of the moieties optionally being substituted.
[0011]
11. Compound or pharmaceutically acceptable salt, according to claim 7, characterized in that R3 is starch of the formula -C(O)N(R)2, and said (R)2 groups taken together with the nitrogen to which are attached form an optionally substituted 4-, 5-, 6- or 7-membered ring.
[0012]
12. Compound or pharmaceutically acceptable salt, according to claim 1, characterized in that the compound is selected from the group consisting of:
[0013]
13. Compound or pharmaceutically acceptable salt, according to claim 1, characterized in that the compound is:
[0014]
14. Use of a compound or pharmaceutically acceptable salt, as defined in any one of the preceding claims, characterized in that it is in the manufacture of a medicine for the treatment of a condition mediated by a phosphatidyl inositol-3 kinase (PI3 kinase).
[0015]
15. Use according to claim 14, characterized in that PI3 kinase is PI3 kinase alpha.
[0016]
16. Use according to claim 14, characterized in that the condition is selected from the group consisting of asthma, emphysema, bronchitis, psoriasis, allergy, anaphylaxis, rheumatoid arthritis, graft versus host disease, lupus erythematosus, psoriasis, restenosis, benign prostatic hypertrophy, diabetes, pancreatitis, proliferative glomerulonephritis, diabetes-induced kidney disease, inflammatory bowel disease, atherosclerosis, eczema, scleroderma, diabetes, diabetic retinopathy, retinopathy of prematurity, age-related macular degeneration, hemangioma, glioma, melanoma , Kaposi's sarcoma and ovarian, breast, lung, pancreatic, prostate, colon and epidermoid cancers.
[0017]
17. Use according to claim 14, characterized in that the gene encoding PI3 kinase alpha comprises a mutation.
[0018]
18. Use according to claim 17, characterized in that the mutation is E542K, E545K or H1047R.
[0019]
19. Use according to claim 14, characterized in that the condition is lung cancer.
[0020]
20. Use according to claim 19, characterized in that lung cancer is non-small cell lung cancer.
[0021]
21. Use according to claim 19, characterized in that lung cancer is small cell lung cancer.
[0022]
22. Use according to claim 14, characterized by the fact that the condition is gastric cancer.
[0023]
23. Use according to claim 14, characterized in that the condition is selected from the group consisting of invasive breast carcinoma, prostate adenocarcinoma, colon adenocarcinoma, thyroid carcinoma, urothelial bladder carcinoma, lung adenocarcinoma, uterine carcinosarcoma, cervical squamous cell carcinoma and endocervical adenocarcinoma, testicular germ cell tumors, lung squamous cell carcinoma, stomach adenocarcinoma, glioblastoma multiforme, hepatocellular carcinoma of the liver and pancreatic adenocarcinoma.

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法律状态:
2018-01-23| B07D| Technical examination (opinion) related to article 229 of industrial property law [chapter 7.4 patent gazette]|

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2018-02-06| B25F| Entry of change of name and/or headquarter and transfer of application, patent and certif. of addition of invention: change of name on requirement|Owner name: INTELLIKINE, INC. (US) |

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2018-04-10| B06F| Objections, documents and/or translations needed after an examination request according [chapter 6.6 patent gazette]|

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2018-05-15| B25D| Requested change of name of applicant approved|Owner name: INTELLIKINE LLC (US) |

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2019-05-28| B07E| Notice of approval relating to section 229 industrial property law [chapter 7.5 patent gazette]|Free format text: NOTIFICACAO DE ANUENCIA RELACIONADA COM O ART 229 DA LPI |

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2019-09-03| B06U| Preliminary requirement: requests with searches performed by other patent offices: procedure suspended [chapter 6.21 patent gazette]|

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2019-12-31| B06A| Notification to applicant to reply to the report for non-patentability or inadequacy of the application [chapter 6.1 patent gazette]|

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2020-05-12| B06A| Notification to applicant to reply to the report for non-patentability or inadequacy of the application [chapter 6.1 patent gazette]|

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2020-09-15| B09A| Decision: intention to grant [chapter 9.1 patent gazette]|

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2021-03-16| B09X| Decision of grant: republication|

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2021-05-18| B16A| Patent or certificate of addition of invention granted|Free format text: PRAZO DE VALIDADE: 20 (VINTE) ANOS CONTADOS A PARTIR DE 17/08/2010, OBSERVADAS AS CONDICOES LEGAIS. PATENTE CONCEDIDA CONFORME ADI 5.529/DF |

优先权:

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申请号 | 申请日 | 专利标题

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US23461709P| true| 2009-08-17|2009-08-17|

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US61/234,617|2009-08-17|

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PCT/US2010/045816|WO2011022439A1|2009-08-17|2010-08-17|Heterocyclic compounds and uses thereof|

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