HK1104230A - Thiazole based inhibitors of atp-utilizing enzymes - Google Patents

Description

Thiazole-based inhibitors of ATP-utilizing enzymes

no marking

[001] This application claims the benefit of U.S. provisional patent application No.60/608,834 filed on 10/9/2004 and U.S. provisional patent application No.60/601,266 filed on 13/8/2004. All of which are incorporated herein by reference.

[002] The enzymes that utilize ATP catalyze the transfer of phosphate groups (phosphate groups) from Adenosine Triphosphate (ATP) molecules to biomolecules, such as proteins or carbohydrates. Examples of ATP-utilizing enzymes include, but are not limited to, synthetases, ligases, and kinases.

[003] Protein kinases encompass a large family of functionally and structurally related enzymes responsible for the control of a variety of cellular processes, including signal transduction, metabolism, transcription, cell cycle progression, cytoskeletal rearrangement and cell movement, apoptosis, and differentiation. In general, protein kinases control protein activity by catalyzing the addition of negatively charged phosphate groups to other proteins from phosphate-containing molecules, such as cyclic adenosine monophosphate (cAMP), Adenosine Diphosphate (ADP), and ATP. Phosphorylation of the protein can in turn regulate or modulate the functioning of the target protein. Phosphorylation of proteins is known to play a role in intercellular communication, physiological responses and homeostasis during development, as well as in the functioning of the nervous and immune systems.

[004] Dysregulated protein phosphorylation is known to be the cause or cause of a number of diseases, such as alzheimer's disease, stroke, diabetes, obesity, inflammation, cancer and rheumatoid arthritis. Deregulated protein kinase activity and overexpression of protein kinases have been implicated in the pathophysiology of a number of important human disorders. Furthermore, genetic mutations in protein kinases have been implicated in a number of disorders, many toxins and pathogens exert their effects by altering the phosphorylation of intracellular proteins.

[005] ATP-utilizing enzymes, such as protein kinases, therefore represent a broad class of pharmacological targets of interest for the treatment of human diseases. The identification and development of compounds that selectively inhibit the functioning of ATP-utilizing enzymes is therefore of interest.

[006] AKT/Protein Kinase B (PKB) is a key kinase in the phosphatidylinositol 3' -OH kinase (PI3K)/AKT pathway that regulates cell survival and apoptosis or apoptosis (Kauffmann-Zeh et al, Nature 385: 544-548 (1997); Hemmings, Science, 275: 628-630 (1997); Dudek et al, Science 275: 661-665 (1997)). The PI3K/AKT pathway is activated by a variety of factors, including growth factors such as platelet-derived growth factor and insulin-like growth factor-1, this activation involves the induction of PI3K activity to increase the level of its product phosphatidylinositol (3, 4, 5) -triphosphate (PIP3), and subsequent recruitment of AKT to PIP 3-enriched membranes via its Plekstrin Homology (PH) domain (Hemmings Science, 277: 534 (1997). AKT is subsequently activated via phosphorylation, two regulatory sites are Thr308 and ser473. tumor suppressor PTEN is a protein and lipid phosphatase that negatively regulates the PI3K/AKT pathway by removing the 3' phosphate of PIP 3. AKT has three isoforms, namely, AKT1(PKB α), AKT2(PKB β) and AKT3(PKB γ).

[007] A series of evidence has linked the PI3K/AKT pathway to human diseases, particularly Cancer (Vivanco and Sawyers, Nature Rev. Cancer 2: 489-. AKT is overexpressed to varying degrees in a number of human tumors (Sun et al, am. J. Pathol.159: 431- & 437 (2001); Yuan et al, Oncogene 19: 2324- & 2330 (2000); Nakatani et al, J. biol. chem. 274: 21528- & 21532(1999)), AKT1 and AKT2 have been shown to be amplified in several cancer types (Staal, Proc. Natl. Acad. Sci. USA 84: 5034- & 5037 (1987); Nicholsen and Anderson, cell Signaling 14, 381- & 395 (2002)). Furthermore, AKT activation in human cancers has been shown to occur by other means, including mutation of the tumor suppressor PTEN (Di Cristofano and Pandolfi, Cell 100: 387-620390 (2000); Sun et al, Proc. Natl. Acad. Sci. USA 96: 6199-6204 (1999)). One consequence of PTEN loss is overactivation of AKT and phosphorylation of downstream AKT substrates, including BAD, FOXO proteins, and GSK 3. Deletion of AKT1 has been shown to reverse the invasive growth phenotype of PTEN-free mouse embryonic stem cells (Stiles et al, mol.cell.biol.22: 3842-3851 (2002)). Loss-of-function mutations of the PTEN gene are very common in sporadic glioblastomas, melanomas, prostate and endometrial cancers, with the majority of breast, lung and lymphoma tumors harboring PTEN mutations (Cantley and Neel, Proc. Natl. Acad Sci. USA 96, 4240-. Mutation of PIK3CA, which encodes the p 110. alpha. catalytic subunit of class 1A PI3K, results in a mutation that activates PI3K (Samuels et al, Cancer Cell 7: 561-573 (2005)). PIK3CA appears to be one of the most highly mutated oncogenes, with somatic mutations seen in colorectal, gastric, breast and certain brain tumors (Samuels et al, Cancer Cell 7, 561-573(2005) and references therein). Taken together, these data indicate that AKT plays a key role in tumor biology and that the three AKT isoforms may exert different functions; thus, selective inhibition of one or more of the AKT isozymes may be a means of producing cancer therapeutics.

[008] Blocking the PI3K/AKT pathway can inhibit the proliferation of tumor cells and sensitize them to apoptosis. The resistance of many types of cancer to conventional chemotherapy is a major factor undermining successful cancer treatment, and inhibition of the PI3K/AKT pathway is being investigated as a strategy to overcome chemotherapeutic resistance (McCormick, Nature, 428, 267-269 (2004); Bellacosasa et al, cancer. biol. therapy, 3, 268-275 (2004); West et al, drug resistance Update 5, 234-248 (2002); Bianco et al, Oncogene 22, 2812-2822 (2003)). Thus, conventional targeted and cytotoxic antiproliferative and targeted antiangiogenic therapeutics would complement the pro-apoptotic mechanisms of AKT inhibitors.

[009] A number of cancers are associated with the activation of the PI3K/AKT pathway, including but not limited to glioblastoma, ovarian, breast, endometrial, hepatocellular, melanoma, digestive tract, lung, renal cell carcinoma, thyroid, lymphoid, prostate, and pancreatic cancers (Vivanco and Sawyer, Nature Rev. drug Disc., 2, 489-.

[010] Inappropriate activation of the phosphatidylinositol 3-kinase (PI3K)/AKT pathway is also associated with the development of diseases such as diabetes and autoimmunity.

[011] The PI3K/AKT pathway also functions in the growth and survival of normal tissues, and may regulate control of cellular and tissue functions during normal physiology. Thus, undesirable proliferation and survival of normal cells and tissues can lead to a number of disorders, such as immune cell disorders associated with expansion and prolonged survival of cell populations, resulting in prolonged or up-regulation of immune responses. For example, T and B lymphocytes activate the PI3K/AKT pathway in response to homogeneous antigens or growth factors, such as I1-2, responsible for maintaining the survival of antigen-specific lymphocyte clones during an immune response. Under conditions where lymphocytes and other immune cells respond to inappropriate self or foreign antigens or under conditions where other abnormalities cause prolonged activation, the PI3K/AKT pathway contributes an important survival signal that prevents the normal mechanism by which the immune response is terminated via apoptosis of the activated cell population. There is a great deal of evidence that in autoimmune disorders, such as multiple sclerosis and arthritis, there is expansion of lymphocyte populations in response to self-antigens. Expansion of lymphocyte populations in inappropriate response to foreign antigens is a feature of another group of disorders, such as allergy and asthma.

[012] Other examples of inappropriate expansion, growth, proliferation (hyperplasi) and survival of normal cells in which the PI3K/AKT pathway plays a role include, but are not limited to, atherosclerosis, cardiomyopathy and glomerulonephritis.

[013] In addition to a role in cell growth and survival, the PI3K/AKT pathway functions in the control of glucose metabolism by insulin. As a result, modulators of PI3K/AKT activity may also be applied to diseases in which dysfunction in glucose metabolism and energy storage exists, such as diabetes, metabolic diseases, and obesity.

[014] AKT was originally identified as a viral oncogene (Bellacosa et al 1991science 254, 274-277). Numerous studies have demonstrated the role of the PI3K/AKT pathway in a number of viral life cycles. Some viral proteins have been shown to activate the PI3K/AKT pathway, thereby providing an environment conducive to viral replication. These include the Tat protein of HIV (Borgatti et al 1997, Eur. J. immunol.27, 2805-ion 2811), the X protein of hepatitis B virus (Lee et al 2001J. biol. chem.276, 16969-ion 169977), NS5A of hepatitis C virus (He et al 2002J. Virol.76, 9207-ion 9217), human cytomegalovirus (Johnson et al 2001J. Virol.75, 6022-ion 6032) and Epstein Barr virus (Moody et al 2005J. Virol.79, 5499-ion 5506).

[015] ATP-utilizing enzymes, such as protein kinases, therefore represent a broad class of pharmacological targets of interest for the treatment of human diseases. The identification and development of compounds that selectively inhibit the functioning of ATP-utilizing enzymes is therefore of interest.

[016] The invention provides at least one chemical product (at least one chemical entity) selected from compounds of formula I:

(formula I)

And pharmaceutically acceptable salts, solvates, chelates, non-covalent complexes, prodrugs, and mixtures thereof, wherein

R³Selected from hydroxy, alkoxy (alkoxy), amino, substituted amino and Ar;

ar is selected from cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl and substituted heteroaryl;

l is selected from C₀-C₄Alkylene (alkylene), substituted C₁-C₄Alkylene group, - (C)₀-C₄Alkylene) -NH- (C ═ O) -and- (C)₀-C₄Alkylene) (C ═ O) -;

w is selected from the group consisting of hydrogen, halogen, alkyl (alkylene), substituted alkyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl;

q is selected from the group consisting of alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl;

Z is selected from the group consisting of hydrocarbyl and substituted hydrocarbyl,

provided that it is

If Q is optionally substituted pyridin-3-yl, L is a covalent bond, W is 3-methylphenyl, R³Is optionally substituted pyridin-4-yl, then Z is not methyl;

when Ar is pyridin-4-yl, W is hydrogen, Q is selected from benzyl, substituted benzyl, phenethyl and substituted phenethyl, then Z is not selected from lower alkyl and substituted lower alkyl;

when Ar is 2-oxo- (3-hydroquinolinyl), W is hydrogen, and Z is methyl, then Q is not phenyl;

when W is selected from 2- (cyclohexylamino) pyridin-4-yl and 2- (cyclopentylamino) pyridin-4-yl, Ar is 3-methylphenyl, and Z is methyl, then Q is not pyridin-3-yl or 6-methylpyridin-3-yl;

ar is not a substituted pyridone or benzoyloxypyridine;

if R is¹Or R²One is hydrogen, then Ar is other than 4-pivaloyloxyphenyl;

q is not a heteroaryl, substituted heteroaryl, heterocycloalkyi or substituted heterocycloalkyi group comprising one or more heteroatoms selected from S and N, fused to an aryl, substituted aryl, heteroaryl or substituted heteroaryl ring;

ar is not phenyl, 4-methoxyphenyl or 2, 5-dimethoxyphenyl if Z is lower alkyl or 3-morpholinopropyl;

When Ar is pyridinyl, L is a covalent bond, Z is hydrogen or methyl, W is phenyl substituted with one methoxy, methyl, chloro, fluoro or tert-butyl group, then Q is not methyl;

if Ar is 4-tert-butylphenyl, L is a covalent bond, Z is propyl and Q is 1-cyano-2-hydroxy-prop-1-enyl, W is not hydrogen.

[017] Also provided are pharmaceutical compositions comprising at least one pharmaceutically acceptable vehicle (vehicle) and a therapeutically effective amount of at least one chemical product of the invention.

[018] Also provided are packaged pharmaceutical formulations (packages) comprising a pharmaceutical composition comprising at least one pharmaceutically acceptable vehicle and a therapeutically effective amount of at least one chemical product of the invention and instructions for using the composition to treat a mammal (instructions).

[019] Also provided is a method of treating at least one disease in a patient in need thereof comprising administering to the patient a therapeutically effective amount of at least one chemical product of the invention.

[020] Additional inventive embodiments are described below in the description that follows, or may be learned by practice of the invention.

[021] Unless otherwise indicated, all numbers expressing quantities of ingredients, reaction conditions, and so forth used in the specification and claims are to be understood as being modified in all instances by the term "about". Accordingly, unless indicated to the contrary, the numerical parameters set forth in the following specification and claims are approximations that may vary depending upon the standard deviation of their respective experimental measurements. In no event, and in no way intended to limit the scope of the claims to which such equivalent versions of the teachings are applied, each numerical parameter should at least be construed in light of the number of reported significant digits and by applying ordinary rounding techniques.

[022] "acyl" represents the group-C (O) R, wherein R is hydrogen, alkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, or substituted heteroaryl, as defined herein. Representative examples include, but are not limited to, formyl, acetyl, cyclohexylcarbonyl, cyclohexylmethylcarbonyl, benzoyl, benzylcarbonyl, and the like.

[023] "alkyl" means a saturated branched, straight-chain or cyclic hydrocarbon radical derived from a parent alkane by the removal of one hydrogen atom from a single carbon atom. Typical alkyl groups include, but are not limited to, methyl; an ethyl group; propane groups such as propan-1-yl, propan-2-yl (isopropyl), cyclopropane-1-yl; butanes, such as butan-1-yl, butan-2-yl (sec-butyl), 2-methyl-propan-1-yl (isobutyl), 2-methylpropan-2-yl (tert-butyl), cyclobutane-1-yl; and so on.

[024] "alkenyl" means an unsaturated branched, straight chain or cyclic hydrocarbon radical having at least one carbon-carbon double bond derived from a parent olefin by the removal of one hydrogen atom from a single carbon atom. The group may be in either the cis or trans configuration with respect to the double bond. Typical alkenyl groups include, but are not limited to, vinyl; acryl groups such as prop-1-en-1-yl, prop-1-en-2-yl, prop-2-en-1-yl (allyl), prop-2-en-2-yl, prop-1-en-1-yl, prop-2-en-1-yl; butenyls, such as but-1-en-1-yl, but-1-en-2-yl, 2-methylprop-1-en-1-yl, but-2-en-2-yl, but-1, 3-dien-1-yl, but-1, 3-dien-2-yl, cyclobut-1-en-1-yl, cyclobut-1-en-3-yl, cyclobut-1, 3-dien-1-yl; and so on. In certain embodiments, alkenyl groups have from 2 to 20 carbon atoms, and in other embodiments from 2 to 6 carbon atoms.

[025] "hydrocarbyloxy" represents a group-OR, wherein R represents hydrocarbyl, substituted cycloalkyl, substituted heterocycloalkyi, substituted aryl OR substituted heteroaryl as defined herein. Representative examples include, but are not limited to, methoxy, ethoxy, propoxy, butoxy, cyclohexyloxy and the like.

[026] "hydrocarbyloxycarbonyl" means a group-C (O) -hydrocarbyloxy, wherein hydrocarbyloxy is as defined herein.

[027] "hydrocarbyl" means a saturated or unsaturated, branched, straight chain, or cyclic monovalent hydrocarbon group derived by the removal of one hydrogen atom from a single carbon atom of a parent alkane, alkene, or alkyne. Typical hydrocarbyl groups include, but are not limited to, methyl; ethyl groups such as ethyl, vinyl, ethynyl; propyls such as propan-1-yl, propan-2-yl, cyclopropane-1-yl, propan-1-en-2-yl, propan-2-en-1-yl (allyl), cycloprop-1-en-1-yl, cycloprop-2-en-1-yl, propan-1-yn-1-yl, propan-2-yn-1-yl; butyl radicals, e.g. butan-1-yl, butan-2-yl, 2-methyl-propan-1-yl, 2-methyl-propan-2-yl, cyclobutane-1-yl, but-1-en-2-yl, 2-methyl-prop-1-en-1-yl, but-2-en-2-yl, but-1, 3-dien-1-yl, but-1, 3-dien-2-yl, cyclobut-1-en-1-yl, cyclobut-1-en-3-yl, Cyclobut-1, 3-dien-1-yl, but-1-yn-3-yl, but-3-yn-1-yl; and so on.

[028] The term "hydrocarbyl" is specifically intended to include groups having any degree or level of saturation, i.e., groups having only single carbon-carbon bonds, groups having one or more double carbon-carbon bonds, groups having one or more triple carbon-carbon bonds, and groups having mixtures of single, double, and triple carbon-carbon bonds. When specifying the saturation level, the expressions "alkyl", "alkenyl" and "alkynyl" are used. In certain embodiments, the hydrocarbyl group comprises 1 to 20 carbon atoms. In other embodiments, the hydrocarbyl group contains 1 to 6 carbon atoms and is referred to as a lower hydrocarbyl group.

[029]The term "substituted amino" denotes the group-NHR^dor-NR^dR^dWherein each R is^dIndependently selected from: alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, acyl, substituted acyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycloalkyl, substituted heterocycloalkyl, alkoxycarbonyl, and sulfonyl. Representative examples include, but are not limited to, dimethylamino, methylethylamino, di- (1-methylethyl) amino, (cyclohexyl) (methyl) amino, (cyclohexyl) (ethyl) amino, (cyclohexyl) (propyl) amino, and the like.

[030]"Sulfonyl" represents the group-S (O) ₂R, wherein R is hydrocarbyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl or substituted heteroaryl as defined herein. Representative examples include, but are not limited to, methylsulfonyl, ethylsulfonyl, propylsulfonylButanesulfonyl and the like.

[031] "sulfinyl" represents the group-s (o) R, wherein R is hydrocarbyl, substituted cycloalkyl, substituted heterocycloalkenyl, substituted aryl or substituted heteroaryl as defined herein. Representative examples include, but are not limited to, methylsulfinyl, ethylsulfinyl, propylsulfinyl, butylsulfinyl, and the like.

[032] "thioalkyl" means a radical-SR where R is hydrocarbyl, substituted cycloalkyl, substituted heterocycloalkenyl, substituted aryl or substituted heteroaryl as defined herein. Representative examples include, but are not limited to, methylthio, ethylthio, propylthio, butylthio, and the like.

[033] "alkynyl" means an unsaturated branched, straight-chain or cyclic hydrocarbon group having at least one carbon-carbon triple bond derived by the removal of one hydrogen atom from a single carbon atom of a parent alkyne. Typical alkynyl groups include, but are not limited to, ethynyl; propynyl groups, such as prop-1-yn-1-yl, prop-2-yn-1-yl; butynyl groups, such as but-1-yn-1-yl, but-1-yn-3-yl, but-3-yn-1-yl; and so on. In certain embodiments, alkynyl groups have 2 to 20 carbon atoms, and in other embodiments 3 to 6 carbon atoms.

[034]"amino" denotes the group-NH₂。

[035] "aminocarbonyl" represents the group-C (O) NRR ' where R and R ' are independently selected from hydrogen, alkyl, substituted cycloalkyl, substituted heterocycloalkenyl, substituted aryl or substituted heteroaryl as defined herein, or optionally R and R ' together with the nitrogen atom to which they are attached form one or more heterocyclic or substituted heterocyclic rings.

[036] "aryl" encompasses:

5-and 6-membered carbocyclic aromatic rings, such as benzene;

bicyclic ring systems, wherein at least one ring is carbocyclic and aromatic, such as naphthalene, indane and tetrahydronaphthalene;

tricyclic ring systems in which at least one ring is carbocyclic and aromatic, such as fluorene.

For example, aryl includes 5-and 6-membered carbocyclic aromatic rings, fused to a 5-to 7-membered heterocyclic hydrocarbon ring containing one or more heteroatoms selected from N, O and S. For such fused bicyclic ring systems, wherein only one ring is a carbocyclic aromatic ring, the point of attachment may be located on a carbocyclic aromatic ring or a heterocyclic hydrocarbon ring. Divalent radicals which arise from substituted benzene derivatives and have a free valency on the ring atoms are designated as substituted phenylene radicals. Divalent radicals derived from monovalent polycyclic hydrocarbon radicals whose name ends in "-yl" by removing a hydrogen atom from a carbon atom with a free valence are named by adding "-ylidene" to the name of the corresponding monovalent radical, for example naphthyl radicals with two points of attachment are known as naphthylene radicals. However, aryl does not in any way encompass or cover heteroaryl, which is defined separately below. Thus, if one or more carbocyclic aromatic rings are fused to a heterocyclic hydrocarbyl aromatic ring, the resulting ring system is heteroaryl as defined herein, rather than aryl.

[037]"arylalkyl" or "arylalkyl" refers to a radical in which the carbon atoms are bonded, typically terminally or sp³An acyclic hydrocarbon group in which one of the hydrogen atoms of the carbon atoms is replaced by an aryl group. Typical arylalkyl groups include, but are not limited to, benzyl, 2-phenylethane-1-yl, 2-phenylethen-1-yl, naphthylmethyl, 2-naphthylethan-1-yl, 2-naphthylethen-1-yl, naphthobenzyl, 2-naphthophenylethane-1-yl, and the like. In designating hydrocarbyl moieties, the designations arylalkyl, arylalkenyl, and/or arylalkynyl are used. In certain embodiments, the arylalkyl group can be (C)_6-30) The arylalkyl radical, for example the alkyl, alkenyl or alkynyl fragment of the arylalkyl radical, may be (C)_1-10) The aryl moiety may be (C)_6-20)。

[038] "Aryloxycarbonyl" represents the group-C (O) -O-R, wherein R is selected from aryl and substituted aryl as defined herein.

[039] "carbonyl" represents the group-C (O).

[040] "carboxy" represents the group-C (O) OH.

[041] "cleavage" means the breaking of a chemical bond and is not limited to a chemical or enzymatic reaction or mechanism, unless the context clearly dictates otherwise.

[042] When a chemical structure and chemical name conflict, the chemical structure is a determinant of the identity of the compound. The chemical products of the invention may contain one or more chiral centers and/or double bonds and may therefore exist as stereoisomers, such as double bond isomers (i.e., geometric isomers), enantiomers or diastereomers. Thus, any chemical structure depicted in the specification, in whole or in part, with relative configuration, encompasses all possible enantiomers and stereoisomers of the compound, including stereomerically pure (e.g., geometrically pure, enantiomerically pure, or diastereomerically pure) forms, and mixtures of enantiomers and stereoisomers. Mixtures of enantiomers and stereoisomers may be resolved into the enantiomeric or stereoisomeric components using separation techniques or chiral synthesis techniques well known to the skilled artisan.

[043] The compounds of formula I include, but are not limited to, optical isomers, racemates and other mixtures of the compounds of formula I. In these cases, single enantiomers or diastereomers, i.e. optically active forms, can be obtained by means of asymmetric synthesis or racemate resolution. Resolution of the racemates can be accomplished, for example, by conventional methods such as crystallization in the presence of a resolving agent, or chromatography, for example, using a chiral High Pressure Liquid Chromatography (HPLC) column. In addition, the compounds of formula I include the Z-and E-forms (or cis-and trans-forms) of compounds with double bonds. Where various tautomeric forms exist for the compounds of formula I, the chemical products of the invention include all tautomeric forms of the compounds.

[044] The chemical products of the invention include, but are not limited to, compounds of formula I and all pharmaceutically acceptable forms thereof. Pharmaceutically acceptable forms of the compounds cited herein include pharmaceutically acceptable salts, solvates, crystal forms (including polymorphs and clathrates), chelates, non-covalent complexes, prodrugs, and mixtures thereof. In certain embodiments, the compounds described herein are in the form of a pharmaceutically acceptable salt. Thus, the term "chemical product" also encompasses pharmaceutically acceptable salts, solvates, chelates, non-covalent complexes, prodrugs, and mixtures.

[045] The term "chelate" refers to a chemical product formed by the coordination of a compound with a metal ion at two (or more) sites.

[046] The term "non-covalent complex" refers to a chemical product resulting from the interaction of a compound with another molecule, wherein no covalent bond is formed between the compound and the molecule. For example, complexation can occur through van der waals interactions, hydrogen bonding, and electrostatic interactions (also referred to as ionic bonding).

[047] Prodrugs also fall within the scope of chemical products, as described above, such as ester or amide derivatives of the compounds of formula I. The term "prodrug" includes any compound that upon administration to a patient, for example, becomes a compound of formula I after metabolic processing of the prodrug. Examples of prodrugs include, but are not limited to, acetate, formate, and benzoate derivatives of functional groups (e.g., alcohol or amine groups) in compounds of formula I.

[048] The term "solvate" refers to a compound that results from the interaction of a solvent with the compound. Suitable solvates are pharmaceutically acceptable solvates, such as hydrates, including mono-and hemihydrate.

[049] "valence bond" means a covalent linkage between two molecules.

[050] "cyano" represents the group-CN.

[051]"cycloalkyl" means a saturated or unsaturated (although not aromatic) cyclic hydrocarbon group. When a level of saturation is specified, the name "cycloalkyl" or "cycloalkenyl" is used. Typical cycloalkyl groups include, but are not limited to, groups derived from cyclopropane, cyclobutane, cyclopentane, cyclohexane, and the like. In certain embodiments, the cycloalkyl group may be C_3-10Cycloalkyl radicals, e.g.C_3-6A cyclic hydrocarbon group.

[052] "disease" means any disease, disorder, condition, symptom, or indication.

[053] "enzyme" means any naturally occurring or synthetic macromolecular substance, composed entirely or mostly of proteins, which catalyses one or more biochemical reactions somewhat specifically. The substance on which the enzyme acts is called the "substrate", for which the enzyme has a specific binding or "active site" or "catalytic domain". Enzymes can also act on macromolecular structures such as muscle fibers.

[054] By "extended release" is meant a dosage form that provides delayed, extended, continuous, discontinuous, or sustained release of the chemical product of the invention.

[055] "halogen" or "halogen" represents a fluorine, chlorine, bromine or iodine group.

[056] "heteroaryl" encompasses:

a 5-to 7-membered aromatic monocyclic ring containing one or more, e.g., 1 to 4, or in certain embodiments 1 to 3 heteroatoms selected from N, O and S, the remaining ring atoms being carbon;

bicyclic heterocyclic hydrocarbyl rings containing one or more, e.g., 1 to 4, or in certain embodiments 1 to 3, heteroatoms selected from N, O and S, the remaining ring atoms being carbon, and wherein at least one heteroatom is present in the aromatic ring.

[057] For example, heteroaryl includes a 5-to 7-membered heterocycloalkenyl aromatic ring fused to a 5-to 7-membered cycloalkylene ring. For such fused bicyclic heteroaryl ring systems, wherein only one ring contains one or more heteroatoms, the point of attachment may be in the heteroaromatic ring or the cycloalkyl ring. When the total number of S and O atoms in the heteroaryl group exceeds 1, these heteroatoms are not adjacent to each other. In certain embodiments, the total number of S and O atoms in the heteroaryl group is no more than 2. In certain embodiments, the total number of S and O atoms in the aromatic heterocycle is no more than 1. Examples of heteroaryl groups include, but are not limited to (the attachment position is preferably designated as position 1), 2-pyridyl, 3-pyridyl, 4-pyridyl, 2, 3-pyrazinyl, 3, 4-pyrazinyl, 2, 4-pyrimidinyl, 3, 5-pyrimidinyl, 2, 3-pyrazolinyl, 2, 4-imidazolinyl, isoxazolinyl, oxazolinyl, thiazolinyl, thiadiazolinyl, tetrazolyl, thienyl, benzothienyl, furyl, benzofuryl, benzimidazolinyl, dihydroindolyl, pyridazinyl, triazolyl, quinolyl, pyrazolyl, and 5, 6, 7, 8-tetrahydroisoquinoline. Divalent radicals derived from monovalent polycyclic hydrocarbon radicals whose name ends in "-yl" by removing a hydrogen atom from an atom with a free valence are named by adding "-ylidene" to the name of the corresponding monovalent radical, for example pyridyl with two points of attachment is known as pyridylidene. Heteroaryl does not encompass or cover aryl as defined above. In certain embodiments, heteroaryl groups may be those derived from thiophene, pyrrole, benzothiophene, benzofuran, indole, pyridine, quinoline, imidazole, oxazole, pyrazine, benzothiazole, isoxazole, thiadiazole, and thiazole.

[058]"Heteroarylalkyl" or "heteroarylalkyl" means a radical in which the carbon atoms are bonded, typically terminally or sp³Acyclic hydrocarbon radicals in which one of the hydrogen atoms of the carbon atoms is replaced by a heteroaryl radical. When specifying a hydrocarbyl fragment, the designations heteroarylalkyl, heteroarylalkenyl, and/or heteroarylalkynyl are used. In certain embodiments, the heteroarylalkyl group may be a 6 to 30 membered heteroarylalkyl group, for example the alkyl, alkenyl or alkynyl fragment of the heteroarylalkyl group may be 1 to 10 membered and the heteroaryl fragment may be a 5 to 20 membered heteroaryl.

[059]"Heterocycloalkyl" means a single aliphatic ring, typically having 3 to 7 ring atoms, containing at least 2 carbon atoms and 1-3 heteroatoms independently selected from oxygen, sulfur, and nitrogen, and combinations comprising at least one of the foregoing heteroatoms. Suitable heterocyclic hydrocarbon radicals include, for example (the attachment position is preferably designated as position 1), 2-pyrrolinyl, 2, 4-imidazolidinyl, 2, 3-pyrazolidinyl, 2-piperidinyl, 3-piperidinyl, 4-piperidinyl and 2, 5-piperazinyl. Morpholinyl is also contemplated, including 2-morpholinyl and 3-morpholinyl (oxygen is preferably designated as position 1).Substituted heterocyclic hydrocarbon radicals also include substituted heterocyclic hydrocarbon radicals substituted by one or more oxo (═ O) or oxo (-O) groups or by oxides (-O)^-) Ring systems substituted by substituents, for example piperidinyl N-oxide, morpholinyl N-oxide, 1-oxo-1-thiomorpholinyl and 1, 1-dioxo (oxo) -1-thiomorpholinyl.

[060] "leaving group" means an atom or group capable of being displaced by a nucleophile, including halogens such as chlorine, bromine, fluorine, and iodine; hydrocarbyloxycarbonyl groups such as acetoxy; an aryloxycarbonyl group; methanesulfonyloxy, toluenesulfonyloxy, trifluoromethanesulfonyloxy; aryloxy groups such as 2, 4-dinitrophenoxy; a methoxy group; n, O-dimethylhydroxyamino, and the like.

[061] "optional" or "optionally" means that the subsequently described event or circumstance may, but need not, occur, and that the description includes instances where the event or circumstance occurs and instances where it does not.

[062] "pharmaceutically acceptable" means either approved by a regulatory agency of the federal or a state government or listed in the U.S. pharmacopeia or other generally recognized pharmacopeia for use in animals, and more particularly in humans.

[063] "pharmaceutically acceptable salt" means a salt of a compound that is pharmaceutically acceptable and possesses the desired pharmacological activity of the parent compound. Such salts include: (1) acid addition salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or with organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3- (4-hydroxybenzoyl) benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1, 2-ethane-disulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, 4-methylbicyclo [2.2.2] oct-2-ene-1-carboxylic acid, glucoheptonic acid, 3-phenylpropionic acid, trimethylacetic acid, tert-butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid, and the like; or (2) salts formed by replacing an acidic proton present in the parent compound with a metal ion, such as an alkali metal ion, an alkaline earth metal ion, or an aluminum ion; or a salt formed by coordination combination with an organic base, for example, ethanolamine, diethanolamine, triethanolamine, N-methylglucamine, dicyclohexylamine, or the like.

[064] By "pharmaceutically acceptable excipient, carrier or adjuvant" is meant an excipient, carrier or adjuvant that is capable of being administered to a subject with at least one chemical product of the invention, does not destroy the pharmacological activity thereof, and is non-toxic when administered in a dosage sufficient to deliver a therapeutic amount of the compound.

[065] By "pharmaceutically acceptable vehicle" is meant a diluent, adjuvant, excipient, or carrier with which at least one chemical product of the invention is administered.

[066] "prodrug" means a derivative of a therapeutically effective compound that requires conversion in vivo to produce the therapeutically effective compound. A prodrug may be pharmacologically inactive until converted to the parent compound.

[067] "promoiety" refers to the form of a protecting group that, when used to mask a functional group within a drug molecule, converts the drug into a prodrug. For example, the precursor fragment may be linked to the drug via bonds that are cleaved enzymatically or non-enzymatically in vivo.

[068]"protecting group" means an atomic group that, when attached to a reactive group in a molecule, masks, reduces, or prevents its reactivity. Examples of protecting Groups can be found in Green et al, "Protective Groups in Organic Chemistry," (Wiley, 2) ^nded.1991) and Harrison et al, "company of Synthetic Organic Methods," Vols.1-8(John Wiley and sons, 1971-. Representative amino protecting groups include, but are not limited to, formyl, acetyl, trifluoroacetyl, benzyl, benzyloxycarbonyl (CBZ), tert-butoxycarbonyl (Boc), Trimethylsilyl (TMS), 2-trimethylsilyl-ethanesulfonyl (SES), triphenyleneMethyl and substituted trityl, allyloxycarbonyl, 9-Fluorenylmethoxycarbonyl (FMOC), Nitroveratryloxycarbonyl (NVOC), and the like. Representative hydroxyl protecting groups include, but are not limited to, those in which the hydroxyl group is acylated or hydrocarbylated, such as benzyl and trityl ethers as well as hydrocarbyl ethers, tetrahydropyranyl ethers, trihydrocarbylsilyl ethers and allyl ethers.

[069] "protein kinase", "kinase" and "human protein kinase" refer to any enzyme that phosphorylates one or more hydroxyl or phenolic groups in a protein, and ATP is the phosphoryl donor.

[070] "stereoisomers" refers to isomers that differ in the spatial arrangement of the constituent atoms. Stereoisomers that are mirror images of each other and optically active are referred to as "enantiomers", and stereoisomers that are not mirror images of each other are referred to as "diastereomers".

[071] "subject" includes mammals, such as humans. The terms "human" and "subject" are used interchangeably herein.

[072]"substituted" refers to groups in which one or more hydrogen atoms are each independently replaced by the same or different substituents. Typical substituents include, but are not limited to, -X, -R³³、-O^-、＝O、-OR³³、-SR³³、-S^-、＝S、-NR³³R³⁴、＝NR³³、-CX₃、-CF₃、-CN、-OCN、-SCN、-NO、-NO₂、＝N₂、-N₃、-S(O)₂O^-、-S(O)₂OH、-S(O)₂R³³、-OS(O₂)O^-、-OS(O)2R³³、-P(O)(O-)₂、-P(O)(OR³³)(O^-)、-OP(O)(OR³³)(OR³⁴)、-C(O)R³³、-C(S)R³³、-C(O)OR³³、-C(O)NR³³R³⁴、-C(O)O^-、-C(S)OR³³、-NR³⁵C(O)NR³³R³⁴、-NR³⁵C(S)NR³³R³⁴、-NR³⁵C(NR³³)NR³³R³⁴、-C(NR³³)NR³³R³⁴、-S(O)₂NR³³R³⁴、-NR³⁵S(O)₂R³³、-NR³⁵C(O)R³³and-S (O) R³³Wherein each X is independently halogen; each R³³And R³⁴Independently hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, -NR³⁵R³⁶、-C(O)R³⁵or-S (O)₂R³⁵Or optionally R³³And R³⁴Together with the atoms to which they are attached form one or more cycloheteroalkyl, substituted cycloheteroalkyl, heteroaryl, or substituted heteroaryl rings; r³⁵And R³⁶Independently is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl or substituted heteroarylalkyl, or optionally R ³⁵And R³⁶Together with the nitrogen atom to which they are attached, form one or more cycloheteroalkyl, substituted cycloheteroalkyl, heteroaryl or substituted heteroaryl rings. In certain embodiments, the tertiary amine or aromatic nitrogen may be substituted with one or more oxygen atoms to form the corresponding nitroxide.

[073]In certain embodiments, substituted aryl and substituted heteroaryl groups include one or more of the following substituents: F. cl, Br, C_1-3Hydrocarbyl, substituted hydrocarbyl, C_1-3Hydrocarbyloxy, -S (O)₂NR³³R³⁴、-NR³³R³⁴、-CF₃、-OCF₃、-CN、-NR³⁵S(O)₂R³³、-NR³⁵C(O)R³³、C_5-10Aryl, substituted C_5-10Aryl radical, C_5-10Heteroaryl, substituted C_5-10Heteroaryl, -C (O) OR³³、-NO₂、-C(O)R³³、-C(O)NR³³R³⁴、-OCHF₂、C_1-3Acyl, -SR³³、-S(O)₂OH、-S(O)₂R³³、-S(O)R³³、-C(S)R³³、-C(O)O^-、-C(S)OR³³、-NR³⁵C(O)NR³³R³⁴、-NR³⁵C(S)NR³³R³⁴、-C(NR³⁵)NR³³R³⁴、C_3-8Cycloalkyl and substituted C_3-8Cycloalkyl radical, C_3-8Heterocycloalkyl and substituted C_3-8Heterocyclic hydrocarbon groups, all as defined herein.

[074]In certain embodiments, substituted arylalkyl and substituted heteroarylalkyl groups include one or more of the following substituents: F. cl, Br, C_1-3Hydrocarbyl radical, C_1-3Hydrocarbyloxy, -S (O)₂NR³³R³⁴、-NR³³R³⁴、-CF₃、-OCF₃、CN、-NR³⁵S(O)₂R³³、-NR³⁵C(O)R³³、C_5-10Aryl, substituted hydrocarbyl, substituted C_5-10Aryl radical, C_5-10Heteroaryl, substituted C_5-10Heteroaryl, -C (O) OR³³、-NO₂、-C(O)R³³、-C(O)NR³³R³⁴、-OCHF₂、C_1-3Acyl, -SR³³、-S(O)₂OH、-S(O)₂R³³、-S(O)R³³、-C(S)R³³、-C(O)O^-、-C(S)OR³³、-NR³⁵C(O)NR³³R³⁴、-NR³⁵C(S)NR³³R³⁴、-C(NR³⁵)NR³³R³⁴、C_3-8Cycloalkyl and substituted C_3-8Cycloalkyl groups, all as defined herein.

[075]In certain embodiments, substituted hydrocarbyl groups include one or more of the following substituents: c_1-3Hydrocarbyloxy, -NR ³³R³⁴Substituted C_5-10Heteroaryl, -SR³³、C_1-3Hydrocarbyloxy, -S (O)₂NR³³R³⁴、CN、F、Cl、-CF₃、-OCF₃、-NR³⁵S(O)₂R³³、-NR³⁵C(O)R³³、C_5-10Aryl, substituted C_5-10Aryl radical, C_5-10Heteroaryl, substituted C_5-10Heteroaryl, -C (O) OR³³、-NO₂、-C(O)R³³、-C(O)NR³³R³⁴、-OCHF₂、C_1-3Acyl, -S (O)₂OH、-S(O)₂R³³、-S(O)R³³、-C(S)R、-C(O)O^-、-C(S)OR³³、-NR³⁵C(O)NR³³R³⁴、-NR³⁵C(S)NR³³R³⁴、-C(NR³⁵)NR³³R³⁴、C_3-8Cycloalkyl and substituted C_3-8Cycloalkyl groups, all as defined herein.

[076]In certain embodiments, substituted alkenyl groups include one or more of the following substituents: c_1-8Hydrocarbyl, substituted C_1-8Hydrocarbyl radical, C_5-10Aryl, substituted C_5-10Aryl radical, C_5-10Heteroaryl, substituted C_5-10Heteroaryl group, C_3-8Cycloalkyl, substituted C_3-8Cycloalkyl, cycloheteroalkyl, and substituted cycloheteroalkyl, all as defined herein.

[077] By "therapeutically effective amount" is meant an amount of a compound that is sufficient to effect such treatment of a disease or at least one clinical symptom of the disease or disorder when the compound is administered to a subject to treat the disease or disorder. A "therapeutically effective amount" may vary with the compound, the disease, disorder, and/or symptoms of the disease or disorder, the severity of the disease, disorder, and/or symptoms of the disease or disorder, the age of the subject to be treated, and/or the weight of the subject to be treated. Suitable amounts in any given case may be apparent to those skilled in the art or can be determined by routine experimentation.

[078] "treating" any disease or disorder means preventing or ameliorating the disease, disorder, or at least one clinical symptom of the disease or disorder, reducing the risk of acquiring the disease, disorder, or at least one clinical symptom of the disease or disorder, reducing the development of the disease, disorder, or at least one clinical symptom of the disease or disorder, or reducing the risk of developing the disease, disorder, or at least one clinical symptom of the disease or disorder. "treating" also means inhibiting the disease or disorder, either physically (e.g., stabilization of a detectable symptom), physiologically (e.g., stabilization of a physical parameter), or both, and inhibiting at least one physical parameter that may not be detectable by the subject. Further, "treating" means delaying the onset of a disease or disorder, or at least symptoms thereof, in a subject who may be exposed to or predisposed to the disease or disorder, even if the subject has not yet experienced or exhibited symptoms of the disease or disorder.

[079] Reference will now be made in detail to embodiments of the invention. While certain embodiments of the invention will be described, it will be understood that they are not intended to limit embodiments of the invention to those described. On the contrary, references to embodiments of the invention are intended to cover alternatives, modifications and equivalents, which may be included within the spirit and scope of the embodiments of the invention as defined by the appended claims.

[080] In the specification and claims, the singular forms "a", "an" and "the" include plural referents unless the context clearly dictates otherwise.

[081] The compounds of formula I may be named and numbered as follows (e.g. using the chemdawultra 9.0 Struct ═ Name algorithm). For example, the compound:

i.e. compounds according to formula I, wherein R³Is 3-phenylisoxazol-5-yl, L is C₀Alkylene (i.e., covalent bond), W is hydrogen, Z is 3-morpholinopropyl, Q is thiophen-2-yl, and can be named N- (3-morpholinopropyl) -N- (4- (3-phenylisoxazol-5-yl) thiazol-2-yl) thiophene-2-carboxamide (1- (4- (N- (4- (benzofuran-2-yl) thiazol-2-yl) thi)ophene-2-carboxamido)butanoyl)-N-(2-hydroxyethyl)piperidine-3-carboxamide)。

[082] Also, the compound:

i.e. compounds according to formula I, wherein R³Is benzofuran-2-yl, L is C₀Alkylene (i.e., covalent bond), W is hydrogen, Z is 4- (4- (2-hydroxyethylcarbamoyl) piperidin-1-yl) -4-oxobutyl-, Q is thiophen-2-yl, and may be designated 1- (4- (N- (4- (benzofuran-2-yl) thiazol-2-yl) thiophene-2-carboxamido) butyryl) -N- (2-hydroxyethyl) piperidine-3-carboxamide.

[083] Providing at least one chemical product selected from compounds of formula I:

(formula I)

And pharmaceutically acceptable salts, solvates, chelates, non-covalent complexes, prodrugs, and mixtures thereof, wherein

R³Selected from the group consisting of hydroxy, alkoxy, amino, substituted amino, and Ar;

ar is selected from cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl and substituted heteroaryl;

l is selected from C₀-C₄Alkylene, substituted C₁-C₄Alkylene group, - (C)₀-C₄Alkylene) -NH- (C ═ O) -and- (C)₀-C₄Alkylene) (C ═ O) -;

w is selected from the group consisting of hydrogen, halogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl;

q is selected from the group consisting of alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl;

z is selected from the group consisting of hydrocarbyl and substituted hydrocarbyl,

provided that it is

If Q is optionally substituted pyridin-3-yl, L is a covalent bond, W is 3-methylphenyl, R³Is optionally substituted pyridin-4-yl, then Z is not methyl;

when Ar is pyridin-4-yl, W is hydrogen, Q is selected from benzyl, substituted benzyl, phenethyl and substituted phenethyl, then Z is not selected from lower alkyl and substituted lower alkyl;

when Ar is 2-oxo- (3-hydroquinolinyl), W is hydrogen, and Z is methyl, then Q is not phenyl;

When W is selected from 2- (cyclohexylamino) pyridin-4-yl and 2- (cyclopentylamino) pyridin-4-yl, Ar is 3-methylphenyl, and Z is methyl, then Q is not pyridin-3-yl or 6-methylpyridin-3-yl;

ar is not a substituted pyridone or benzoyloxypyridine;

if R is¹Or R²One is hydrogen, then Ar is other than 4-pivaloyloxyphenyl;

q is not a heteroaryl, substituted heteroaryl, heterocycloalkyi or substituted heterocycloalkyi group comprising one or more heteroatoms selected from S and N, fused to an aryl, substituted aryl, heteroaryl or substituted heteroaryl ring;

ar is not phenyl, 4-methoxyphenyl or 2, 5-dimethoxyphenyl if Z is lower alkyl or 3-morpholinopropyl;

when Ar is pyridinyl, L is a covalent bond, Z is hydrogen or methyl, W is phenyl substituted with one methoxy, methyl, chloro, fluoro or tert-butyl group, then Q is not methyl;

if Ar is 4-tert-butylphenyl, L is a covalent bond, Z is propyl and Q is 1-cyano-2-hydroxy-prop-1-enyl, W is not hydrogen.

[084]In certain embodiments, R³Is C_1-8A hydrocarbyloxy group.

[085]In certain embodiments, R³Is Ar, wherein Ar is selected from the group consisting of cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl.

[086] In certain embodiments, Ar is selected from substituted aryl and substituted heteroaryl.

[087] In certain embodiments, Ar is selected from phenyl, substituted phenyl, benzo [ b ] thiophen-3-yl, substituted benzo [ b ] thiophen-3-yl, pyridin-2-yl, substituted pyridin-2-yl, pyridin-3-yl, substituted pyridin-3-yl, pyridin-4-yl, substituted pyridin-4-yl, thiophen-2-yl, substituted thiophen-2-yl, thiophen-3-yl, substituted thiophen-3-yl, 4-isoxazolyl, substituted 4-isoxazolyl, 5-isoxazolyl, substituted 5-isoxazolyl, 3-pyrazolyl, substituted 3-pyrazolyl, 4-pyrazolyl, substituted 3-pyrazolyl, and substituted 3-pyrazolyl, Naphthalen-2-yl, substituted naphthalen-2-yl, 2, 3-dihydro-1, 4-benzodioxan-6-yl, substituted 2, 3-dihydro-1, 4-benzodioxan-6-yl, 3, 4-dihydro-2H-1, 5-benzodioxan * -7-yl (3, 4-dihydro-2H-1, 5-benzodioxan-7-yl), substituted 3, 4-dihydro-2H-1, 5-benzodioxa * -7-yl, benzothiazol-2-yl, substituted benzothiazol-2-yl, benzofuran-2-yl, and substituted benzofuran-2-yl.

[088] In certain embodiments, Ar is selected from the group consisting of phenyl, substituted phenyl, 4-isoxazolyl, substituted 4-isoxazolyl, 5-isoxazolyl, substituted 5-isoxazolyl, 3-pyrazolyl, substituted 3-pyrazolyl, 4-pyrazolyl, substituted 4-pyrazolyl, benzofuran-2-yl, and substituted benzofuran-2-yl.

[089]In certain embodiments, when Ar is a substituted group (e.g., substituted phenyl, substituted 4-isoxazolyl, substituted 5-isoxazolyl, substituted benzofuran-2-yl or substituted pyridin-2-yl, substituted 3-pyrazolyl, substituted 4-pyrazolyl, etc.) which is substituted with at least one substituent, e.g. one, two or three substituents, independently selected from halogen, -CN, -OH, -COOH, -NO₂、C_1-8Hydrocarbyloxy, substituted C_1-8Hydrocarbyloxy, C_1-8Hydrocarbyl, substituted C_1-8Hydrocarbyl radical, C_5-10Aryl, substituted C_5-10Aryl radical, C_5-10Cycloalkyl, substituted C_5-10Cycloalkyl radical, C_1-8Sulfanyl, substituted C_1-8Sulfanyl, C_1-8Sulfinyl, substituted C_1-8Sulfinyl, substituted amino, C_1-8Aminocarbonyl, substituted C_1-8Aminocarbonyl group, C_1-8Hydrocarbyl carbonylamino, substituted C_1-8Hydrocarbyl carbonylamino group, C_1-8Sulfonyl, substituted C_1-8Sulfonyl radical, C_1-8Hydrocarbyl carbonyl, substituted C_1-8Hydrocarbyl carbonyl group, C_5-10Heteroaryl group, C_5-10Cycloheteroalkyl group and C_1-8A hydrocarbyloxycarbonyl group.

[090]In certain embodiments, when Ar is a substituted group (e.g., substituted phenyl, substituted 4-isoxazolyl, substituted 5-isoxazolyl, substituted 3-pyrazolyl, substituted 4-pyrazolyl, substituted benzofuran-2-yl, substituted pyridin-2-yl, etc.), the group is substituted with at least one substituent, e.g., one, two, or three substituents independently selected from methoxy, Cl, F, Br, nitro, methyl, pentyl, cyano, difluoromethoxy, trifluoromethyl, trifluoromethoxy, diethylamino, phenyl, substituted phenyl, morpholin-4-yl, methylsulfonyl, and-CO-O-CH ₃。

[091] In certain embodiments, L is a covalent bond. In certain embodiments, L is-NH- (C ═ O) - (wherein the carbonyl is attached to the thiazole core).

[092] In certain embodiments, W is selected from hydrogen, hydrocarbyl, and substituted hydrocarbyl. In certain embodiments, W is hydrogen.

[093] In certain embodiments, Q is selected from the group consisting of alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl.

[094] In certain embodiments, Q is selected from monocyclic cycloalkyl, substituted monocyclic cycloalkyl, monocyclic aryl, substituted monocyclic aryl, heteroaryl, and substituted monocyclic heteroaryl.

[095]In certain embodiments, Q is selected from monocyclic C_5-10Cycloalkyl, substituted monocyclic C_5-10Cycloalkyl, monocyclic C_5-10Aryl, substituted monocyclic C_5-10Aryl, monocyclic C_5-10Heteroaryl and substituted monocyclic C_5-10A heteroaryl group.

[096]In certain embodiments, Q is selected from C_5-10Monocyclic heteroaryl and substituted monocyclic C_5-10A heteroaryl group.

[097] In certain embodiments, Q is selected from the group consisting of phenyl, substituted phenyl, furyl, substituted furyl, cyclohexyl, substituted cyclohexyl, cyclopentenyl, substituted cyclopentenyl, 4-isoxazolyl, substituted 4-isoxazolyl, 5-isoxazolyl, substituted 5-isoxazolyl, thiophen-2-yl, substituted thiophen-2-yl, pyrimidin-2-yl, substituted pyrimidin-2-yl, 5-thiadiazolyl, substituted 5-thiadiazolyl, imidazolyl, substituted imidazolyl, 3-isothiazolyl, substituted thiazolyl, 3-pyrrolyl, and substituted 3-pyrrolyl.

[098] In certain embodiments, Q is selected from thiophene and substituted thiophenes.

[099]In certain embodiments, when Q is a substituted group (e.g., substituted thiophene, substituted phenyl, etc.), the group is substituted with at least one substituent, e.g., one, two, or three substituents independently selected from C_1-4Hydrocarbyl, halogen, nitro, C_1-4Acyl radical, C_1-4Sulfanyl and C_1-4A sulfonyl group. In certain embodiments, when Q is a substituted group (e.g., substituted thiophene, substituted phenyl, etc.), the group is substituted with at least one substituent, e.g., one, two, or threeAnd (b) substituents independently selected from F, Cl, methyl, cyano, Br, nitro, methylsulfonyl, acetyl and thiomethyl.

[0100] In certain embodiments, Z is a substituted hydrocarbyl group. In certain embodiments, Z is substituted lower alkyl.

[0101] Providing at least one chemical product selected from compounds of formula II:

(formula II)

And pharmaceutically acceptable salts, solvates, chelates, non-covalent complexes, prodrugs, and mixtures thereof, wherein Ar, W, and Q are as described for the compound of formula I,

a is selected from the group consisting of hydrocarbylene, substituted hydrocarbylene, alkenylene, and substituted alkenylene;

R¹And R²Independently selected from hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, heteroaryl and substituted heteroaryl, or R¹And R²Together with the nitrogen to which they are attached form a ring selected from cycloheteroalkyl, substituted cycloheteroalkyl, heteroaryl, and substituted heteroaryl.

[0102]In certain embodiments, a is selected from the group consisting of hydrocarbylene and substituted hydrocarbylene. In certain embodiments, A is selected from 1, 3-propylene, 1, 4-butylene or- (CH)₂)_m- (C ═ O) -, in which the carbonyl group is linked to-NR¹R²And wherein m is 2 or 3.

[0103]In certain embodiments, R¹And R²Independently selected from hydrocarbyl and substituted hydrocarbyl, or R¹And R²Together with the nitrogen to which they are attached form a monocyclic cycloheteroalkyl ring.

[0104]In certain embodiments, R¹And R²Independently selected from C_1-8Hydrocarbyl and substituted C_1-8A hydrocarbon group, or R¹And R²Together with the nitrogen to which they are attached form a monocyclic ring C_5-10A cycloheteroalkyl ring.

[0105]In certain embodiments, R¹And R²Independently selected from C_1-4A hydrocarbyl group.

[0106]In certain embodiments, R¹And R²Together with the nitrogen atom to which they are attached form a pyrrolidine, substituted pyrrolidine, piperidine, substituted piperidine, azepane, substituted azepane, piperazine, substituted piperazine, morpholine or substituted morpholine ring.

[0107]In certain embodiments, R¹And R²Together with the nitrogen atom to which they are attached form a morpholin-4-yl ring.

[0108] Providing at least one chemical product selected from compounds of formula III:

(formula III)

And pharmaceutically acceptable salts, solvates, chelates, non-covalent complexes, prodrugs, and mixtures thereof, wherein Ar, W, and Q are as described for the compound of formula I,

a is selected from the group consisting of hydrocarbylene, substituted hydrocarbylene, alkenylene, and substituted alkenylene;

R¹and R²Together with the nitrogen to which they are attached, form an optionally substituted 5-to 7-membered cycloheteroalkyl ring, which optionally includes 1 or 2 additional heteroatoms selected from O, S and N in the ring.

[0109]In certain embodiments, R¹And R²Together with the nitrogen atom to which they are attached form a pyrrolidine, substituted pyrrolidine, piperidine, substituted piperidine, azepane, substituted azepane, piperazine, substituted piperazine, morpholine or substituted morpholine ring.

[0110]In certain embodiments, R¹And R²Together with the nitrogen atom to which they are attached form a morpholin-4-yl ring.

[0111] Providing at least one chemical product selected from compounds of formula IV:

(formula IV)

And pharmaceutically acceptable salts, solvates, chelates, non-covalent complexes, prodrugs, and mixtures thereof, wherein Ar and Q are as described for the compound of formula I, and R is ¹And R²Is as described for compounds of formula II and wherein p is selected from 2, 3 and 4 and q is selected from 0 and 1.

[0112] In certain embodiments, p is selected from 2, 3 and 4 and q is 0. In certain embodiments, p is selected from 2 and 3 and q is 0.

[0113] In certain embodiments, p is selected from 2 and 3 and q is 1. In certain embodiments, p is 2 and q is 1.

[0114] In certain embodiments, the compound of formula I is selected from any of the compounds listed in table 1 and/or table 2.

[0115] Providing at least one chemical product selected from compounds of formula V:

(formula V)

And pharmaceutically acceptable salts, solvates, chelates, non-covalent complexes, prodrugs, and mixtures thereof, wherein W, Z and Q are as described for the compound of formula I, and wherein

E is selected from C₀-C₄Alkylene and substituted C₁-C₄A hydrocarbylene group;

R⁴selected from the group consisting of hydroxy, alkoxy, amino and substituted amino.

[0116]In certain embodiments, R⁴Is a hydrocarbyloxy group.

[0117] The chemical products of the invention as used herein may include pharmaceutically acceptable derivatives or prodrugs thereof. By "pharmaceutically acceptable derivative or prodrug" is meant any suitable pharmaceutically acceptable salt, ester, salt of an ester, hydrate, solvate or other derivative of a compound of the invention which, upon administration to a subject, is capable of providing, directly or indirectly, a compound of the invention. Particularly desirable derivatives and prodrugs include those that increase the bioavailability of the chemical products of the invention when such chemical products are administered to a subject, for example, by allowing an orally administered compound to be more readily absorbed into the blood relative to the parent species, or by enhancing delivery of the parent compound to a biological cavity, for example, the brain or lymphatic system. Prodrugs may include derivatives of formula (I) - (V) with the addition of groups that enhance aqueous solubility or active transport across the intestinal membrane. Other prodrugs may include precursor fragments that alter ADME (absorption, distribution, metabolism, and excretion) of the parent compound, thereby enhancing the therapeutic effectiveness of the parent compound.

[0118] In certain embodiments, the chemical products of the present invention may be modified by the addition of appropriate functionalities to enhance selective biological properties. Such modifications are known in the art and include those capable of increasing bio-penetration into a given biological cavity, such as the blood, lymphatic system, central nervous system, to increase oral bioavailability, to increase solubility for administration by injection, to alter metabolism, and to alter rate of excretion.

[0119] In some embodiments, modifying the chemical products of the present invention may facilitate application in biological assays, screening and analysis protocols. Such modifications may include, for example, derivatization to achieve or enhance binding to a physical surface, such as beads or arrays, or modifications to facilitate detection, such as via radioactive, affinity, or fluorescent labels.

[0120] The chemical product of the invention has inhibitory activity against at least one ATP-utilizing enzyme. An enzyme that utilizes ATP refers to an enzyme that catalyzes the transfer of phosphate groups from ATP molecules to biomolecules, such as proteins or carbohydrates. Examples of ATP-utilizing enzymes include, but are not limited to, synthetases, ligases, and kinases. The kinase can be an animal kinase, including mammalian protein kinases and human protein kinases.

[0121] Without being limited by theory, enzymes that utilize ATP may be inhibited by compounds that are structurally similar to the phosphoryl-containing compounds that serve as substrates for phosphorylation reactions. For example, a structurally similar compound may bind to the active site or catalytic domain of an ATP-utilizing enzyme, thereby preventing substrate binding.

[0122] In certain embodiments, the chemical product of the invention exhibits human protein kinase inhibitory activity.

[0123] Protein kinases are the largest and most functionally diverse gene families. The five hundred or more human protein kinases mostly belong to a single enzyme superfamily in which the catalytic domains are related in sequence and structure. Most human protein kinases can be further classified into seven major groups based on the identified deoxyribonucleic acid (DNA) sequence homology: CAMK (calcium/calmodulin-dependent protein kinase), AGC (including PKA (protein kinase a), PKG (protein kinase G), PKC (protein kinase C) kinase), CK1 (casein kinase), CMGC (containing CDK (cyclin-dependent), MAPK (mitogen-activated), GSK3 (glycogen synthase) and CLK (CDC 2-like) kinase), STE (homolog of yeast Sterile 7, Sterile 11 and Sterile 20 kinase), TK (tyrosine kinase) and TKL (tyrosine kinase-like).

[0124] The AGC protein kinase family includes AKT1, AKT2, AKT3, AURORA-A, MSK1, MSK2, P70S6K, PAK1, PKA and SGK1 protein kinases. The CMGC protein kinase family includes CDK1, CDK 2/cyclin A, CDK 2/cyclin E, CDK5, DYRK2, GSK 3-alpha, GSK 3-beta, P38-alpha, P38-beta, P38-delta, P38-gamma and MAPK1 protein kinases. The family of CAMK protein kinases includes DAPK1, MAPKAPK2, CHEK1, CHEK2, PRAK and c-TAK1 protein kinases. The TK protein kinase family includes ABL1, CSK, FLT3, FYN, HCK, INSR, KIT, LCK, PDGFR-alpha, LYNA, SYK and SRC protein kinases. The STE protein kinase family includes PAK2 protein kinases.

[0125] Certain chemical products of the invention exhibit selectivity for one or more protein kinases, wherein selectivity is as defined herein. Certain chemical products of the invention exhibit selective activity against at least one of the following protein kinases: AKT1, AKT2, AMP kinase, AXL, AURORA-A, BMX, CDK 2/cyclin A, CDK 2/cyclin E, CHEK1, CHEK2, CK2, DYRK2, EGFR, EPHB4, FLT3, GSK 3-alpha, GSK 3-beta, IGF1R, INSR, KDR, KIT, MAPKAPK2, MAPKPK 3, MET, MSK2, NEK2, P70S6K1, PAK2, PDGFR-alpha, PDK1, PIM1 kinase, PLK1, ROCK2, RSK2, SYK, TIE2, TRKB and ZAP 70. Certain of the inventive chemicals exhibited selective activity against AKT 1.

[0126] The chemical products of the invention may be prepared by methods well known in the art.

[0127] The chemical products of the present invention can be prepared from readily available starting materials using the following general methods and processes. It will be appreciated that while typical or preferred process conditions are given, such as reaction temperature, time, molar ratios of reactants, solvents, pressures, other process conditions may be employed unless otherwise specified. The reaction conditions may vary depending on the reactants or solvents used, but such conditions can be determined by one skilled in the art with the aid of customary optimization procedures.

[0128]In addition, as will be apparent to those skilled in the art, conventional protecting groups may be necessary to prevent certain functional groups from undergoing unwanted reactions. Protecting groups suitable for a variety of functional groups and conditions suitable for protecting and deprotecting a particular functional group are well known in the art. For example, a number of Protecting Groups are described in T.W.Greene and G.M.Wuts, Protecting Groups in organic Synthesis, 3^rd Edition，John Wiley &Sons, 1999 and references cited therein.

[0129] Furthermore, the chemical products of the invention may contain one or more chiral centers. Thus, such compounds may be prepared or isolated as pure stereoisomers, i.e. individual enantiomers or diastereomers, or stereoisomer-enriched mixtures, if desired. All such stereoisomers and enriched mixtures thereof are included within the scope of the invention unless otherwise indicated. Pure stereoisomers and enriched mixtures thereof may be prepared using, for example, optically active starting materials or stereoselective reagents well known in the art. Alternatively, racemic mixtures of such compounds can be separated using, for example, chiral column chromatography, chiral resolving agents, and the like.

[0130] General synthetic schemes and specific reaction schemes for preparing the chemical products of the invention are presented in the reaction schemes and examples provided herein.

[0131] The chemical product of the present invention can be prepared as described in scheme 1 below. The reaction of an appropriately substituted alpha-bromoketone 4 with thiourea 5 can give aminothiazoles 6 or 7 via known procedures (e.g., Hantzsch, A.R., et al, Ber.1887, 20, 3118; Metzer, J.V., Thiazol and Its Derivatives, Wiley, 1979 and references cited therein). Bromoketones of structure 4 can also be prepared by brominating the appropriate α -methanone via known processes (e.g., Langley, w.d.org.syn.1932, 122; Corey, e.j.j.j.am.chem.soc.1954, 75, 2301; King, l.c., et al.j.org.chem.1964, 3459). The thioureas of structure 5 can be prepared from the corresponding amines by known procedures, such as reaction with thiophosgene followed by treatment of the resulting chloride with ammonia, reaction with FMOC-isothiocyanate, followed by deprotection with piperidine, reaction with TMS-isocyanate, followed by deprotection and with Lawesson's reagent ionization, or reaction with benzoyl isothiocyanate, followed by acidic hydrolysis. The preparation of the compound of structure 7 can also be accomplished by alkylation of 6 with a suitable reagent, such as Z-X (where X is a leaving group, such as Cl, Br, I, mesylate or triflate), or via reductive alkylation with a suitable aldehyde under reductive amination conditions. Aminothiazoles 6 and 7 can be acylated with the appropriate acid chloride, carboxylic acid or carboxylic acid anhydride under standard conditions to give the amidothiazole 8 or compound of formula I. Alkylation of 8 with an appropriate Z-X alkylating agent also affords compounds of formula I.

[0132] Solid phase reaction methods have been developed for the synthesis of aminothiazoles, such as 7, and can be applied to the preparation of the chemical products of the present invention (see, e.g., Kearney, p.c., et al.j.org.chem.1998, 63, 196).

Scheme 1

[0133] The chemical products of the present invention can be prepared by the process of scheme 1. The necessary diamine starting materials are known or can be prepared by methods known in the art. Alternatively, the chemical products of the invention can be prepared via the route described in scheme 2. Alcohol 7a can be prepared via the process of scheme 1. Compounds of structure 7a, wherein L is a substituted or unsubstituted alkylene or alkenylene group, may be protected with an alcohol protecting group, such as a trimethylsilyl group, and then acylated to provide compounds wherein G is-C (═ O) Q or protected with an amine protecting group, such as 4-methoxybenzyl or t-butoxycarbonyl, or the protecting group may be a solid phase polymer resin containing a readily cleavable linker. Removal of the alcohol protecting group affords compound 9. Alcohol 9 may be oxidized to provide carbonyl compound 10 or may be converted to alkylating agent 11. Alternatively, the acetal/ketal of structure 7b can be acylated or protected, followed by acid hydrolysis, to afford compound 10. Alkylating agent 11 may also be prepared via alkylation of aminothiazole 12. The preparation of the amine 13 can be accomplished by reductive amination of the appropriate amine with the carbonyl compound 10 or alkylation of the appropriate amine with the compound 11. Acylation with an appropriate acylating agent can convert the amine 13 into an amide, carbamate, or urea to give the compound of formula 2a, or via sulfonylation to a sulfonamide to give the compound of formula 2 b. Reductive amination using an appropriate aldehyde or ketone, or alkylation with an appropriate alkyl halide, for example, can yield an amine of formula II. Alternatively, the chemical product of the present invention may be prepared by reductive alkylation of the appropriate amine with compound 10 or by reaction of the appropriate amine with alkylating agent 11. In the reaction of compounds 10, 11 and 13, when G is a protecting group, additional deprotection is required followed by an acylation sequence to attach a-C (═ O) Q group to the aminothiazole core to give compounds of formulae 2a, 2b and II.

Scheme 2

[0134] Certain amides of formula IV may be prepared as shown in scheme 3. The ester of structure 14 can be converted to carboxylic acid 15, for example, by acid or base hydrolysis. The amide of formula 3a can be obtained by coupling the amide using methods known to those skilled in the art and using the appropriate amine.

Scheme 3

[0135]Certain compounds of formula V, wherein R is as shown in scheme 4, can be prepared alternatively^bAre substituents such as alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, heteroaryl and substituted heteroaryl. Hydrolysis of the compound of structure 4a can yield the acid of structure 4 b. The preparation of the amide 4c can be accomplished by reacting the acid 4b with an amine under standard conditions known to those skilled in the art.

Scheme 4

[0136] According to certain embodiments, the chemical product of the invention exhibits inhibitory activity of an ATP-utilizing enzyme. Thus, one important application of the chemical products of the present invention includes the administration of at least one chemical product of the present invention to a subject, such as a human. Such administration serves to prevent, ameliorate, reduce the risk of acquiring, reduce the formation or at least one clinical symptom of, or reduce the risk of formation or at least one clinical symptom of a disease or condition modulated by an ATP-utilizing enzyme, such as a protein kinase.

[0137] For example, dysregulated or inappropriately high protein kinase activity has been implicated in a number of diseases caused by abnormal cellular function. Dysregulated or inappropriately high protein kinase activity can result, directly or indirectly, for example, from failure of the normal control mechanisms of the protein kinase, for example involving mutation, overexpression or inappropriate activation of the enzyme; or from overproduction or underproduction of cytokines or growth factors which are also involved in signal transduction upstream or downstream of the protein kinase. In all of these cases, selective inhibition of the action of protein kinases can be expected to have beneficial effects.

[0138] According to certain embodiments, the present invention relates to methods of treating a disease modulated by at least one ATP-utilizing enzyme in a subject. ATP-utilizing enzyme-modulated diseases include, for example, those in which ATP-utilizing enzymes are involved in signaling, mediating, regulating, controlling, or otherwise participating in biochemical processes affecting disease manifestations. In certain embodiments, these methods are useful for treating diseases modulated by protein kinases. Protein kinase-modulated diseases include, for example, the following general classes of diseases: cancer, autoimmune, metabolic, inflammatory, infectious, central nervous system diseases, degenerative neurological diseases, allergy/asthma, angiogenesis, neovascularization, angiogenesis, cardiovascular and the like. Without being limited by theory, specific examples of diseases known or believed to be modulated by protein kinases include transplant rejection, osteoarthritis, rheumatoid arthritis, multiple sclerosis, diabetes (diabets), diabetic retinopathy, asthma, inflammatory bowel diseases (e.g., crohn's disease and ulcerative colitis), renal disease cachexia, septic shock, lupus, diabetes (diabets mellitis), myasthenia gravis, psoriasis, dermatitis, eczema, seborrhea, alzheimer's disease, parkinson's disease, stem cell protection during chemotherapy, ex vivo selection or ex vivo clearance for autologous or allogeneic bone marrow transplantation (ex vivo selection or ex vivo prediction for autoimmune or allogeneic bone marrow transplantation), leukemias (including but not limited to acute myelogenous leukemia, chronic myelogenous leukemia, and acute lymphoblastic leukemia), Cancer (including but not limited to breast cancer, lung cancer, colorectal cancer, ovarian cancer, prostate cancer, kidney cancer, squamous cell carcinoma, glioblastoma, melanoma, pancreatic cancer, and kaposi's sarcoma), ocular diseases, corneal diseases, glaucoma, bacterial infections, viral infections, fungal infections, heart disease, stroke, obesity, endometriosis, atherosclerosis, graft vein stenosis (vein graft stenosis), peri-anastomosis prosthetic graft stenosis (peri-anatomical prosthetic graft stenosis), prostate hyperplasia, chronic obstructive pulmonary disease, nerve damage suppression by tissue repair, scar tissue formation, wound healing, lung disease, tumors, macular degeneration.

[0139] The chemical products of the invention are particularly useful in the treatment of cancers including, but not limited to: glioblastoma, ovarian cancer, breast cancer, endometrial cancer, hepatocellular cancer, melanoma, colorectal cancer, colon cancer, digestive tract, lung cancer, renal cell carcinoma, thyroid, lymphoid, prostate and pancreatic cancer, advanced tumors (advanced melanomas), hairy cell leukemia, melanoma, chronic myelogenous leukemia, advanced head and neck, squamous cell carcinoma, metastatic renal cells (metastic renal cells), non-hodgkin's lymphoma, metastatic breast, breast adenocarcinoma, advanced melanoma, pancreas, stomach, non-small cell lung, renal cell carcinoma, various solid tumors, multiple myeloma, metastatic prostate, malignant glioma, kidney cancer, lymphoma, refractory metastatic disease, refractory multiple myeloma, cervical cancer, kaposi's sarcoma, recurrent degenerative glioma, and metastatic colon cancer.

[0140] More specifically, cancers that may be treated with the chemical products of the invention include, but are not limited to: heart: sarcomas (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyoma, fibroma, lipoma, teratoma; lung: bronchial carcinoma (squamous cell, undifferentiated small cell, undifferentiated large cell, adenocarcinoma), alveolar cell (bronchioloalveolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, chondromatous hamartoma, mesothelioma; gastrointestinal tract: esophagus (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (carcinoma, lymphoma, leiomyosarcoma), pancreas (ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumor, kaposi's sarcoma, leiomyosarcoma, hemangioma, lipoma, neurofibroma, fibroma), large intestine (adenocarcinoma, tubular adenoma (tubular adenoma), villous adenoma, hamartoma, leiomyosarcoma); urogenital tract: kidney (adenocarcinoma, wilm's tumor (nephroblastoma), lymphoma, leukemia), bladder and urethra (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate (adenocarcinoma, sarcoma), testis (seminoma, teratoma, embryonal carcinoma, teratocarcinoma, choriocarcinoma, sarcoma, interstitial cell carcinoma, fibroma, fibroadenoma, adenomatoid tumors, lipoma); liver: liver tumors (hepatocellular carcinoma), cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma; bone: osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibrosarcoma, chondrosarcoma, ewing's sarcoma, malignant lymphoma (reticulosarcoma), multiple myeloma, malignant giant cell tumor chordoma, osteochondroma (osteochondral exostosis), osteochronosarcoma (osteoarthamalogenousexostoses), benign chondroma (benign chromoma), chondroblastoma fibroma (chondromas), osteoid tumor, and giant cell tumor; the nervous system: cranium (osteoma, hemangioma, granuloma, xanthoma, osteitis deformans, meninges (meningioma, meningiosarcoma (meniosarcoma), glioma), brain (astrocytoma, medulloblastoma, glioma, ependymoma, germ cell tumor (pinealoma), glioblastoma multiforme, oligodendroglioma, schwannoma, retinoblastoma, congenital tumor), spinal cord, neurofibroma, meningioma, glioma, sarcoma); gynecological: uterus (endometrial carcinoma), cervix (cervix carcinoma, pre-tumor cervical dysplasia), ovary (ovarian carcinoma (serous cystadenocarcinoma, mucinous cystadenocarcinoma), granulose-thecal cell tumors), Sertoli-Leydig cell tumors (Sertoli-Leydig cell tumors), dysgerminoma, malignant teratoma), vulva (squamous cell carcinoma, intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma), vagina (clear cell carcinoma), squamous cell carcinoma, botryoid sarcoma (embryonal rhabdomyosarcoma), fallopian tube carcinoma); hematology: blood (myeloid leukemia (acute and chronic), acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative diseases, multiple myeloma, myelodysplastic syndrome), hodgkin's disease, non-hodgkin's lymphoma (malignant lymphoma); skin: malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, moles dysplastic nevi, lipoma, hemangioma, dermatofibrosarcoma, keloid, psoriasis; and adrenal gland: neuroblastoma.

[0141] The chemical product of the invention may also be used to treat tuberous sclerosis complex.

[0142] The chemical products of the invention may also be used to treat other conditions (e.g. inflammatory diseases) including, but not limited to, rheumatoid arthritis, osteoarthritis, endometriosis, atherosclerosis, graft vein stenosis, peri-anastomosis prosthetic graft stenosis, prostate hyperplasia, chronic obstructive pulmonary disease, psoriasis, inhibition of nerve damage resulting from tissue repair (inhibition of nerve graft to tissue repair), scar tissue formation (scar tissue formation), wound healing (wind healing), multiple sclerosis, inflammatory bowel disease, infection (specifically bacterial, viral, retroviral or parasitic infection (by increased apoptosis)), lung disease, tumors, parkinson's disease, transplant rejection (as an immunosuppressant), macular degeneration and septic shock (septic shock).

[0143] The chemical products of the invention may also be used to treat diseases mediated by, but not limited to, modulation or regulation of AKT protein kinases, tyrosine kinases, additional serine/threonine kinases, and/or bispecific kinases.

[0144] In certain embodiments, the pharmaceutical composition may comprise at least one chemical product of the invention and at least one additional therapeutic agent suitable for effecting combination therapy. The chemical products of the invention may also be used in combination with known therapeutic and anti-cancer agents. Those skilled in the art will be able to determine which drug combinations will be useful based on the particular characteristics of the drugs involved and the cancer. Many chemotherapeutic agents are currently known in the art. Such anti-cancer agents include, but are not limited to, estrogen receptor modulators (estrogen receptor modulators), cytostatic/cytotoxic agents (cytostatic/cytoxic agents), anti-proliferative agents (anti-proliferative agents), cell cycle checkpoint inhibitors (cell cycle checkpoint inhibitors), angiogenesis inhibitors, monoclonal antibody targeted therapeutics (monoclonal anti-proliferative therapeutic agents), tyrosine kinase inhibitors, serine-threonine kinase inhibitors, histone deacetylase inhibitors, heat shock protein inhibitors, and farnesyl transferase inhibitors. The chemical products of the invention may also be used in combination with radiation therapy.

[0145] Examples of cytostatic/cytotoxic agents, antiproliferative agents, and cell cycle checkpoint inhibitors include, but are not limited to, sertenef, cachectin (cachectin), ifosfamide (ifosfamide), tasolinamine (tasonemin), lonidamine (lonidamine), carboplatin (carboplatin), aclatomide (altramine), prednimustine (prednimustine), dibromostrigoside (dibro-modutol), ranimustine (ranimustine), fotemustine (fotemustine), nedaplatin, oxaliplatin (oxallatin), temozolomide (temozolomide), heptapeptatin, estramustine (estramustine), amipramine tosylate (prosulfate), chloroacetoamide (trosfamide), nitrosourea (mitomycin), nictine (diclomezine), spidrosine (loplatin), cisplatin (clopyramide), cisplatin (cisplatin), spidromycin (spidromycin), cisplatin (spidromycin), spidromycin (spidromycin), benzylguanidine, glufosfamide (glufosfamide), GPX1OO, (trans ) -bis-m μ - (hexane-1, 6-diamine) -m μ [ di-amine-platinum (II) ] bis [ diamine (chloro) platinum (II) ] tetrachloride), diethyleneiminospermine (diarylimine), arsenic trioxide, 1- (11-dodecylamino-10-hydroxyundecyl) -3, 7-dimethylxanthine, zocubicin, idarubicin (idarubicin), daunorubicin (daunorubicin), bisantrene (bisantrene), mitoxantrone (mitoxantrone), pyrarubicin (pirarubicin), pyrazorubicin (pinafide), valrubicin, amrubicin, anticancer peptides (antipeton), 3 '-deamino-3' -morpholino-13-10-hydroxy-daunorubicin, annamycin, galanubicin, eliofade, MENI0755 and 4-desmethoxy-3-desamino-3-oximino-4-methylsulfonyl-daunorubicin.

[0146] An example of a hypoxia activatable compound is tirapazamine.

[0147] Examples of proteosome inhibitors include, but are not limited to, lactacystin and MLN-341 (Velcade).

[0148] Examples of microtubule inhibitors/microtubule-stabilizing agents include paclitaxel, vindesine sulfate, 3 ', 4' -didehydro-4 '-deoxy-8' -catharanthine (3 ', 4' -didehydro-4 '-deoxy-8' -nonvincaleukobtaine), docetaxel, rhizoxin, dolastatin, mivobulin isethionate, auristatin, cemadotin, RPRI09881, BMS184476, vinflunine and BMS 188797.

[0149] Some examples of topoisomerase inhibitors are aureomycin (topotecan), bycapamine, irinotecan, robitecan, 6-ethoxypropionyl-3 ', 4' -O-exo-benzylidene-tebucin.

[0150] "kinase inhibitors" involved in mitotic progression include, but are not limited to, Aurora kinase inhibitors, Polo-like kinase inhibitors (PLK, specifically PLK-1 inhibitors), bub-1 inhibitors, and bub-R1 inhibitors.

[0151] "antiproliferative agents" include antisense RNA and DNA oligonucleotides, such as G3139, ODN698, RVASKRAS, GEM231 and INX3001, and antimetabolites, such as enocarbenes (enocitabine), carmofur (carmofur), flurouracil (tegafur), pentostatin, doxifluoridine (trimetrexate), fludarabine (fludarabine), capecitabine, galecitabine, cytarabine (cytarabine ocfosfate), fosetabonate hydrate, polytripted, polytrexid, emitexur, tiazofurin, decitabine, nollatrexed, pem-etrexed, and nezarabine.

[0152] Examples of monoclonal antibody targeted therapeutic agents include those that attach a cytotoxic agent or a radioisotope to a cancer cell-specific or target cell-specific monoclonal antibody. Examples can be found in a number of references (Krause and Van Etten, 2005 New Eng. J. Med.353, 172184), including but not limited to Bexxar, trastuzumab (herceptin), cetuximab (erbitux), ABX-EGF, 2C4, bevacizumab (avastin), bortezomib, rituxan.

[0153] Some specific examples of tyrosine inhibitors can be found in a number of references (Krause and Van Etten, 2005 New Eng. J. Med.353, 172184; Brown and Small 2004 Eur. J. cancer 40, 707-721; Fabian et al 2005 Nat. Biotech.23, 329-336), including imatinib (Gleevec, STI571), gefitnib (Iressa), BMS-354825, PKC412, PD0173074, SU5402, MLN-518, CEP-701, SU5416, erlotinib (tarceva), CI-1033, CT2923, sunitinib (SU11248), GW-2016, EKB-569, ZD-6474, vatalanib (PTK-787), AMN107, ZD6474, CHIR-258, CHIR-930, AZD 788, AEE 0530, OSI-336.

[0154] Some specific examples of serine/threonine kinase inhibitors can be found in a number of references (Jackman et al 2004 Drug Disc Today: the der Strategies 1, 445-Asahs 454; Fabian et al 2005 Nat Biotech.23, 329-336; Pearson and Fabbro 2004, Expert Rev. Anactancer The.4, 1113-1124), including but not limited to LY-333531, sorafenib (BAY-43-9006), roscovitine (CYC202), CI-1040, 447439, CCI-779, RAD001, UNC01, VX680, AP 73.

[0155] Examples of heat shock protein inhibitors include, but are not limited to, 17-AAG and 17-DMAG.

[0156] Examples of histone deacetylase inhibitors include, but are not limited to, MS-275, AN-9, apicidin derivatives, Baceca, CBHA, CHAPs, chlamydocin, CS-00028, CS-055, EHT-0205, FK-228, FR-135313, G2M-777, HDAC-42, LBH-589, MGCD-0103, NSC-3852, PXD-101, pyroxamide, SAHA derivatives, suberanilic hydroxyl acid, tacedine, VX-563, and zebularine.

[0157] Examples of farnesyl transferase inhibitors include, but are not limited to, lonafamib.

[0158] Certain embodiments of the present invention relate to methods of treating a disease in a subject comprising the step of administering to a subject in need of such treatment a therapeutically effective amount of at least one chemical product of the present invention. In some embodiments, the disease can be modulated by at least one ATP-utilizing enzyme, such as a protein kinase. Certain diseases may be modulated by one or more enzymes that utilize ATP. In such cases, treatment of the disease or disorder may comprise administering a therapeutically effective amount of at least one chemical product of the invention that inhibits one or more ATP utilizing enzyme activities, or more than one compound of the invention, wherein each compound inhibits at least one different ATP utilizing enzyme.

[0159] Other embodiments of the invention relate to methods of inhibiting at least one ATP utilizing enzyme, including, for example, a protein kinase. In certain embodiments, the method of inhibiting an ATP-utilizing enzyme is administering to a subject at least one chemical product of the invention or a composition comprising at least one chemical product of the invention.

[0160] In certain embodiments, the invention relates to a method of inhibiting an ATP-utilizing enzyme activity by contacting at least one ATP-utilizing enzyme with at least one chemical product of the invention. ATP-utilizing enzymes include phosphotransferases that catalyze the phosphorylation of biomolecules by transferring phosphate groups from ATP substrates. ATP-utilizing enzymes include, for example, synthetases, ligases and kinases. Certain methods of the invention are useful for inhibiting protein kinases, including, for example, the following protein kinases: AKT1, AKT2, AMP kinase, AXL, AURORA-A, BMX, CDK 2/cyclin A, CDK 2/cyclin E, CHEK1, CHEK2, CK2, DYRK2, EGFR, EPHB4, FLT3, GSK 3-alpha, GSK 3-beta, IGF1R, INSR, KDR, KIT, MAPKAPK2, MAPKPK 3, MET, MSK2, NEK2, P70S6K1, PAK2, PDGFR-alpha, PDK1, PIM1 kinase, PLK1, ROCK2, RSK2, SYK, TIE2, TRKB and ZAP 70. Certain methods of the invention are useful for inhibiting AKT 1.

[0161] Some methods of the invention can be used to inhibit ATP-utilizing enzymes that are present in living organisms, such as mammals; contained in a biological sample, such as a cell, cell culture or extract thereof; biopsy material obtained from mammals or extracts thereof, and blood, saliva, stool, semen, tears or other body fluids or extracts thereof; contained within the reagent or bound to a physical carrier. In certain embodiments, the ATP-utilizing enzyme is capable of modulating a disease or disorder, and in other embodiments, the ATP-utilizing enzyme may not modulate the disease or disorder.

[0162] Contacting at least one chemical product of the invention according to the methods of the invention inhibits at least one ATP-utilizing enzyme. Administration of a composition comprising at least one chemical product of the invention can inhibit ATP-utilizing enzymes in the body. For in vitro systems, contacting the ATP-utilizing enzyme with at least one chemical product of the invention may comprise, for example, combining a liquid reagent or combining a reagent with the ATP-utilizing enzyme and/or a compound of the invention attached to a solid support. The ATP-utilizing enzyme and the compound of the invention may be contacted in any suitable device, such as an affinity chromatography column, a microarray, a microfluidic device, an assay plate, or other chemical or biotechnological instrument suitable for performing biochemical analysis, assays, screens, and the like.

[0163] In certain embodiments, the pharmaceutical compositions of the present invention may be administered by the following route: oral, parenteral, inhalation spray, topical, rectal, nasal, buccal (buccally), vaginal, implant depot (reservoir), or any other suitable route. The pharmaceutical compositions of the present invention may contain one or more pharmaceutically acceptable vehicles. In some embodiments, the pH of the formulation can be adjusted with pharmaceutically acceptable acids, bases, or buffers to enhance the stability of the formulated compound or delivery form. The term parenteral as used herein includes subcutaneous, intradermal, intravenous, intramuscular, intraarticular, intraarterial, intrasynovial, intrasternal, intrathecal, intralesional and intracranial injection or infusion techniques.

[0164] In certain embodiments, the compounds disclosed herein can be delivered orally. The dosage range suitable for oral administration may depend on the potency of the compound, but may generally be from 0.1mg to 20mg of compound per kilogram of body weight. Appropriate doses may range from 25 to 500 mg/day, and the dose of compound administered may be adjusted to provide an equivalent molar amount of the compound in the plasma of the subject. Dosage ranges are readily determined by methods known to those skilled in the art.

[0165] The dosage may be delivered in the composition by a single administration, multiple administrations, sustained or controlled release, or any other suitable release interval and/or rate.

[0166] The desired therapeutic or prophylactic activity of the chemical products of the invention can be determined in vitro and in vivo prior to therapeutic application to a mammal. For example, in vitro assays may be used to determine whether administration of a particular compound of the invention or a combination of such compounds is effective in inhibiting the activity of certain ATP-utilizing enzymes or in treating at least one disease. The chemical products of the invention may also be demonstrated to be effective and safe using animal model systems. A therapeutically effective dose of at least one chemical product of the invention may, in certain embodiments, provide a therapeutic benefit without causing substantial toxicity. The toxicity of the chemical products of the present invention can be determined and readily determined by the skilled artisan using standard pharmaceutical procedures. The dose ratio between toxic and therapeutic effects is the therapeutic index. The chemical products of the invention can exhibit a high therapeutic index when used to treat diseases and disorders. The dosage of the compounds of the invention may be within the range of circulating concentrations, including effective dosages, with little or no toxicity.

[0167] When used as a medicament, the chemical product of the invention may be administered in the form of a pharmaceutical composition. Such compositions may be prepared in a manner well known in the pharmaceutical arts and may contain at least one chemical product of the invention.

[0168] The pharmaceutical compositions of the invention may comprise a therapeutically effective amount of at least one chemical product of the invention and at least one pharmaceutically acceptable vehicle. The pharmaceutical compositions of the present invention may additionally comprise at least one additional compound that enhances the therapeutic efficacy of one or more of the chemical products of the present invention. For example, such compounds can enhance the therapeutic efficacy of the chemical products of the present invention by effectively increasing the plasma concentration of the compound. Without being limited by theory, certain compounds may reduce the degradation of the chemical products of the invention prior to administration or during transport to or within the plasma. Certain compounds may increase plasma concentrations by increasing absorption of the compound in the gastrointestinal tract. The pharmaceutical compositions of the present invention may also include additional therapeutic agents that are normally administered to treat a disease or disorder.

[0169] In certain embodiments, the pharmaceutical composition may comprise at least one chemical product of the invention and at least one additional therapeutic agent suitable for effecting combination therapy.

[0170] In some embodiments, the chemical products and compositions of the present invention may be administered via the oral route. The compositions may be prepared in a manner well known in the pharmaceutical arts and may contain at least one chemical product of the invention. In some embodiments, the compositions of the invention comprise a therapeutically effective amount of at least one chemical product of the invention, which may be in purified form, and a therapeutically effective amount of at least one additional therapeutic agent, and an appropriate amount of at least one pharmaceutically acceptable excipient, to provide a form suitable for administration to a subject.

[0171] Some embodiments of the invention relate to compositions containing one or more chemical products of the invention as active ingredients, together with pharmaceutically acceptable excipients. In preparing certain compositions of the present invention, the active ingredient may be mixed with an excipient, diluted with an excipient, or enclosed within such a carrier, which may be in the form of a capsule, sachet, paper, or other container. When the excipient serves as a diluent, the excipient may be a solid, semi-solid, or liquid material that serves as a vehicle, carrier, or medium for the active ingredient. Thus, for example, the compositions may be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions and syrups, e.g., containing 1 to 90% by weight of at least one chemical product of the invention, e.g., using soft and hard gelatin capsules.

[0172] In preparing the composition, it may be necessary to grind the active compound prior to combining with the other ingredients to provide the appropriate particle size. If the active compound is insoluble, the active compound may generally be ground to a particle size of less than 200 mesh. If the active compound is water soluble, the particle size may be adjusted by milling to provide a uniform distribution in the formulation, for example 40 mesh.

[0173] Examples of suitable excipients include, but are not limited to, lactose, dextrose, sucrose, sorbitol, mannitol, starch, acacia gum, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, modified cyclodextrins, cellulose, water, syrup, and methyl cellulose. Some compositions may additionally include lubricating agents, such as talc, magnesium stearate, and mineral oil; a humectant; emulsifying and suspending agents; preservatives, such as methyl-and propylhydroxy-benzoate; a sweetener; and a flavoring agent. The compositions of the present invention are formulated to provide rapid, sustained or delayed release of the active ingredient after administration to a subject using techniques known in the art.

[0174] Some of the compositions of the present invention may be formulated in unit dosage forms, each containing, for example, from 0.1mg to 2g of active ingredient. As used herein, "unit dosage form" means physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient, diluent, carrier and/or adjuvant. In certain embodiments, the compositions of the present invention may be formulated in a multiple dosage form. The amount of the chemical product of the invention that can be combined with other materials and therapeutic agents in a single dosage form to produce the composition of the invention will vary depending on the subject and the particular mode of administration.

[0175] In the treatment of disease, the chemical product of the invention may be administered in a therapeutically effective amount. It will be understood, however, that the amount of the compound administered will depend upon the physician, and will depend upon the relevant circumstances, including the condition to be treated, the chosen route of administration, the actual compound administered, the age, weight and response of the individual subject, the severity of the subject's symptoms, etc.

[0176] For preparing solid compositions, such as tablets, the principal active ingredient may be mixed with pharmaceutical excipients to form a solid preformulation composition containing a homogeneous mixture of the compound of the present invention. When referring to these preformulation compositions as homogeneous, this means that the active ingredient is dispersed evenly throughout the composition so that the composition can be readily subdivided into equally effective unit dosage forms such as tablets, pills and capsules. The solid preformulation compositions may then be subdivided into unit dosage forms of the type described above containing, for example, from 0.1mg to 2g of a therapeutically effective compound of the invention.

[0177] Tablets or pills comprising certain compositions of the present invention may be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action. For example, a tablet or pill may comprise an inner dosage and an outer dosage component, the latter being in the form of a capsule other than the former. The two components may be separated by an enteric layer which acts to resist disintegration in the stomach, allowing the inner component to pass intact into the duodenum or to be delayed in release. A variety of materials may be used for such enteric layers or coatings, including a wide variety of polymeric acids and mixtures of polymeric acids with shellac, cetyl alcohol and cellulose acetate, among others.

[0178] Liquid forms in which the compositions of the present invention may be incorporated for administration orally or by injection include aqueous solutions, suitably flavored syrups, aqueous or oil suspensions, and flavored emulsions with edible oils, such as cottonseed oil, sesame oil, coconut oil, or peanut oil, as well as elixirs and similar pharmaceutical vehicles.

[0179] As used herein, "pharmaceutically acceptable derivative or prodrug" means any pharmaceutically acceptable salt, ester, salt of an ester, or other derivative of a compound of the invention which, upon administration to a recipient, is capable of providing, directly or indirectly, a compound of the invention or an inhibitory active metabolite or residue thereof. Examples of such derivatives or prodrugs include those which increase the bioavailability of the chemical product of the invention when such compound is administered to a mammal, for example by allowing an orally administered compound to be more readily absorbed into the blood relative to the parent species, or by enhancing the delivery of the parent compound to a biological cavity, for example the brain or lymphatic system.

[0180] In certain embodiments, acceptable formulation materials are non-toxic to recipients at the dosages and concentrations employed.

[0181]In certain embodiments, the pharmaceutical compositions of the present invention may contain formulation materials that alter, maintain or preserve the following parameters of the composition, such as pH, osmolarity, viscosity, clarity, color, isotonicity, odor, sterility, stability, rate of dissolution or release, absorption or permeation. In certain embodiments, suitable formulation materials include, but are not limited to, amino acids such as glycine, glutamine, asparagine, arginine, or lysine; an antimicrobial agent; antioxidants, such as ascorbic acid, sodium sulfite or sodium bisulfite; buffers such as borate, bicarbonate, Tris-HCl, citrate, phosphate or other organic acids; bulking agents, such as mannitol or glycine; chelating agents, such as ethylenediaminetetraacetic acid (EDTA); complexing agents, such as caffeine, polyvinylpyrrolidone, beta-cyclodextrin, hydroxypropyl-beta-cyclodextrin or sulfobutylether beta-cyclodextrin; a filler; sheet A sugar; a disaccharide; and other carbohydrates, such as glucose, mannose, or dextrins; proteins, such as serum albumin, gelatin, or immunoglobulins; coloring, flavoring and diluting agents; an emulsifier; hydrophilic polymers such as polyvinylpyrrolidone; a low molecular weight polypeptide; salt-forming counterions, such as sodium; preservatives, for example benzalkonium chloride, benzoic acid, salicylic acid, thimerosal, phenethyl alcohol, methylparaben, propylparaben, chlorhexidine, sorbic acid or hydrogen peroxide; solvents such as glycerol, propylene glycol or polyethylene glycol; sugar alcohols, such as mannitol or sorbitol; suspending agents, surfactants or wetting agents, such as polyoxypropylene (pluronics), PEG, sorbitan esters, polysorbates (e.g. polysorbate 20, polysorbate 80), trinitrotoluene, tromethamine, lecithin, cholesterol, tyloxapol (tyloxapal); stability enhancers, such as sucrose or sorbitol; tonicity enhancing agents such as alkali metal halides (e.g., sodium or potassium chloride), mannitol, sorbitol; a delivery vehicle; a diluent; excipients and/or pharmaceutical adjuvants (Remington's pharmaceutical sciences, 18) ^th Edition，A.R.Gennaro，ed.，Mack Publishing Company(1990))。

[0182] In certain embodiments, one skilled in the art is able to determine the optimal pharmaceutical composition, depending on, for example, the desired route of administration, delivery format, and required dosage. See, for example, Remington's Pharmaceutical Sciences, supra. In certain embodiments, such compositions can affect the physical state, stability, rate of in vivo release, and rate of in vivo clearance of the antibodies of the invention.

[0183] In certain embodiments, the primary vehicle or carrier in the pharmaceutical composition may be aqueous or non-aqueous. For example, in certain embodiments, a suitable vehicle or carrier may be water for injection, a physiological saline solution, or artificial cerebrospinal fluid, possibly supplemented with other materials commonly found in parenterally administered compositions. In certain embodiments, neutral buffered saline or saline mixed with serum albumin is a further exemplary vehicle. In certain embodiments, the pharmaceutical composition comprises a Tris buffer at pH 7 to 8.5, or an acetate buffer at pH 4 to 5.5, which may further comprise sorbitol or a suitable substitute thereof. In certain embodiments, the buffer is used to maintain the composition at physiological pH or slightly lower pH, typically in the pH range of 5 to 8.

[0184] In certain embodiments, the pharmaceutical compositions of the present invention may be selected for parenteral delivery. In other embodiments, the composition may be selected for inhalation or for delivery through the digestive tract, e.g., orally. The preparation of such pharmaceutically acceptable compositions is within the skill of the art.

[0185] In certain embodiments, the composition contains components at concentrations that are acceptable at the site of administration. In certain embodiments, when parenteral administration is contemplated, the therapeutic composition may be in the form of a pyrogen-free, parenterally acceptable aqueous solution comprising at least one chemical product of the invention in a pharmaceutically acceptable vehicle, with or without the addition of an additional therapeutic agent. In other embodiments, the parenteral injection vehicle may be sterile distilled water, wherein at least one chemical product of the invention, and optionally at least one additional therapeutic agent, is formulated as a sterile isotonic solution, and suitably preserved. In other embodiments, the pharmaceutical composition may comprise microencapsulation of at least one chemical product of the invention with an agent, such as injectable microspheres, bioerodible particles, polymeric compounds (e.g., polyacetic or polyglycolic acid), beads or liposomes, which may provide controlled or sustained release of the compounds of the invention, and thus may be delivered via depot injection. In certain embodiments, the compounds of the present invention are introduced into the plasma of a subject, into a target organ, or at a specific site in the subject using an implantable drug delivery device.

[0186] In certain embodiments, the pharmaceutical composition may be formulated as an inhalation dosage form. In certain embodiments, the compounds of the present invention, and optionally at least one additional therapeutic agent, may be formulated as a dry powder for inhalation. In certain embodiments, an inhalation solution comprising a compound of the present invention and, optionally, at least one additional therapeutic agent may be formulated with a propellant for aerosol delivery. In other embodiments, the solution may be atomized. In other embodiments, solutions, powders, or dry films of the chemical products of the present invention may be aerosolized or vaporized for pulmonary delivery.

[0187] In certain embodiments, the formulations may be administered orally. In certain embodiments, the compounds of the present invention, and optionally at least one additional therapeutic agent, may be administered orally, with or without carriers customarily used in complex solid dosage forms, such as tablets and capsules. In other embodiments, the capsule may be designed to release the active portion of the formulation in the gastrointestinal tract in areas that maximize bioavailability and minimize pre-systemic degradation. In other embodiments, at least one additional ingredient may be included in the formulation to facilitate absorption of the compounds of the present invention and/or any additional therapeutic agents into the systemic circulation. In certain embodiments, diluents, flavoring agents, low melting waxes, vegetable oils, lubricants, suspending agents, tablet disintegrating agents, and binding agents may be employed.

[0188] In certain embodiments, the pharmaceutical compositions of the invention may comprise an effective amount of the chemical product of the invention, with or without at least one additional therapeutic agent, in admixture with at least one pharmaceutically acceptable vehicle suitable for tablet manufacture. In certain embodiments, solutions in unit dosage form may be prepared by dissolving the tablets in sterile water or other suitable vehicle. In certain embodiments, suitable excipients include inert diluents, such as calcium carbonate, sodium carbonate or bicarbonate, lactose, or calcium phosphate; or a binder, such as starch, gelatin or acacia; and lubricating agents, such as magnesium stearate, stearic acid or talc.

[0189] In certain embodiments, the frequency of dosing will take into account the pharmacokinetic parameters of the chemical product of the invention and/or any additional therapeutic agents in the pharmaceutical composition used. In certain embodiments, the clinician is able to administer the compositions until a dosage is reached that achieves the desired effect. The compositions may be administered as a single dose or as two or more doses, which may or may not contain equal amounts of the therapeutically active compound over time, or as a continuous infusion via an implanted device or catheter. Further definition of appropriate dosages may be routinely made by those of ordinary skill in the art. For example, by using appropriate dose-response data, therapeutically effective amounts and regimes can be determined.

[0190] In certain embodiments, the route of administration of the pharmaceutical composition may conform to known methods, such as oral administration; by intravenous, intraperitoneal, intracerebral (intraparenchymal), intracerebroventricular, intramuscular, intraocular, intraarterial, intraportal or intralesional routes; by means of a sustained release system or an implanted device. In certain embodiments, the compositions may be administered by bolus injection (bolus injection) or continuous infusion or implant devices.

[0191] In certain embodiments, the compositions may be administered topically, via implantation of a membrane, sponge, or another suitable material, onto which the desired compound of the invention has been absorbed or encapsulated. In certain embodiments, where an implant device is used, the device may be implanted into any suitable tissue or organ and the desired molecule delivered via diffusion, timed release bolus, or continuous administration.

[0192] In certain embodiments, it may be desirable to use a pharmaceutical composition comprising a compound of the invention in an ex vivo (ex vivo) manner, with or without at least one additional therapeutic agent. For example, cells, tissues and/or organs are removed from a subject, exposed to a pharmaceutical composition comprising a compound of the invention with or without at least one additional therapeutic agent, and then implanted back into the subject.

[0193] The pharmaceutical compositions according to the invention may take a form suitable for oral, buccal, parenteral, nasal, topical or rectal administration, or for administration by inhalation or insufflation.

[0194] If desired, the compositions of the present invention may be presented in a pack or dispenser device which may contain one or more unit dosage forms containing the active ingredient. The packaging or dispensing device may carry instructions for administration.

[0195] The amount of a compound of the invention required to treat a particular condition may vary depending on the condition of the compound and the subject to be treated. In general, the daily dose may be from 100ng/kg to 100mg/kg, for example from 0.01mg/kg to 40mg/kg of body weight, for oral or buccal administration; from 10ng/kg to 50mg/kg body weight, for example from 0.001mg/kg to 20mg/kg body weight, for parenteral administration; from 0.05mg to 1,000mg, for nasal administration or administration by inhalation or insufflation.

[0196] Certain chemical products of the invention and/or compositions of the invention may be administered as a sustained release system. In certain embodiments, the chemical products of the present invention may be delivered via oral sustained release administration. In such embodiments, the chemical product of the invention may be administered, for example, twice daily and once daily.

[0197] The chemical products of the invention may be formulated in a variety of different dosage forms which may be adapted to provide sustained and/or extended release of the compound following oral administration. Examples of sustained and/or extended release dosage forms include, but are not limited to, beads comprising dissolved or diffusional release compositions and/or structures, oral sustained release pumps, enteric coating preparations, compound-releasing lipid matrices, compound-releasing waxes, osmotic delivery systems, bioerodible polymer matrices, diffusible polymer matrices, various timed release particles, and osmotic dosage forms.

[0198] Regardless of the particular form of sustained release oral dosage form employed, the compounds and compositions of the present invention may be released from the dosage form over an extended period of time. In certain embodiments, a sustained release oral dosage form can provide a therapeutically effective amount of a compound of the invention over a period of at least several hours. In certain embodiments, an extended release dosage form can provide a constant therapeutically effective concentration of a compound of the invention in the plasma of a subject for an extended period of time, e.g., at least several hours. In other embodiments, sustained release oral dosage forms can provide a controlled and constant concentration of a therapeutically effective amount of a compound of the invention in the plasma of a subject.

[0199] Dosage forms comprising the compositions and chemical products of the invention may be administered at certain intervals, for example twice daily or once daily.

[0200] An exemplary dosage range for oral administration depends on the potency of the compounds of the invention, but may be from 0.1mg to 20mg of compound per kilogram of body weight. Dosage ranges can be readily determined by methods known to those skilled in the art.

[0201] Packaged pharmaceutical formulations are also provided. Such packaged formulations include pharmaceutical compositions comprising at least one chemical product of the invention and instructions for using the compositions to treat a mammal, typically a human patient. In some embodiments, the instructions relate to treating a patient having a disease responsive to inhibition of at least one ATP utilizing enzyme, e.g., human protein kinase, e.g., AKT1, AKT2, AMP kinase, AXL, AURORA-a, BMX, CDK 2/cyclin A, CDK 2/cyclin E, CHEK1, CHEK2, CK2, DYRK2, EGFR, EPHB4, FLT3, GSK 3-a, GSK3- β, IGF1R, INSR, KDR, KIT, MAPKAPK2, MAPKAPK3, MET, MSK2, NEK2, P70S6K1, PAK2, PDGFR-a, PDK1, PLK1 kinase, PLK1, ROCK2, RSK2, sykb, TIE2, trk 70, and ZAP70, with a pharmaceutical composition. Prescription information is also provided; for example, to a patient or health care provider, or as a label in a packaged pharmaceutical formulation. Prescription information may include, for example, information regarding the efficacy, dosage and administration, contraindications, and adverse reactions of the pharmaceutical preparation.

[0202] The chemical products of the invention can be used in vitro and in vivo assays to determine and optimize therapeutic or prophylactic activity prior to use in a subject. For example, in vitro assays may be used to determine whether a particular compound of the invention or combination of such compounds exhibits therapeutic efficacy. The chemical products of the invention may also be demonstrated to be effective and safe using animal model systems.

[0203] It is desirable that a therapeutically effective dose of a compound of the present invention provide therapeutic benefit without causing substantial toxicity. The toxicity of the chemical products of the present invention can be determined and readily determined by the skilled artisan using standard pharmaceutical procedures. The dose ratio between toxic and therapeutic effects is the therapeutic index. In certain embodiments, the chemical products of the invention are capable of exhibiting particularly high therapeutic indices in the treatment of diseases and disorders. In certain embodiments, the dosage of the compounds of the invention may be within the range of circulating concentrations, exhibit therapeutic efficacy, and have little or no toxicity.

Examples

[0204] Embodiments of the invention may be further defined by reference to the following examples describing in detail the preparation of the chemical products of the invention and assays using the chemical products of the invention. It will be apparent to those skilled in the art that many modifications, both to materials and methods, may be practiced without departing from the scope of the invention.

[0205] In the following examples, the following abbreviations have the following meanings. If an abbreviation is not defined, it has its accepted meaning.

AcOH ═ acetic acid

Atms being atmospheric air

Adenosine Triphosphate (ATP)

Boc ═ tert-butoxycarbonyl

br ═ broad peak

BSA ═ bovine serum albumin

d ═ double peak

Da ═ Dalton

double peak

DMF ═ N, N-dimethylformamide

DMSO ═ dimethyl sulfoxide

DTT ═ R, R-dithiothreitol

EDTA-EDTA

ESI-electrospray ionization

EtOAc ═ ethyl acetate

EtOH ═ ethanol

FMOC ═ fluorenylmethoxycarbonyl

g is g ═ g

HCl ═ hydrochloric acid

h is hour

HEPES (HEPES) -1-piperazineethanesulfonic acid

HPLC ═ high performance liquid chromatography

HTS high throughput screening (high throughput screen)

Hz-Hz

i-PrOH ═ isopropanol

J is a coupling constant

kDa ═ kilodaltons

K₂CO₃Arbutine potassium carbonate

L is liter

LC/MS liquid chromatography/mass spectrometry

M is molar concentration

MeOH ═ methanol

MgSO₄Magnesium sulfate ═ magnesium sulfate

MHz-MHz

mg ═ mg

min is minutes

mL to mL

mm-mm

mmol ═ mmol

mM to millimolar concentration

MS mass spectrum

m/z-mass-to-charge ratio

nM as nanomolar concentration

NMR (nuclear magnetic resonance)

NaHCO₃Sodium bicarbonate

NaOH (sodium hydroxide)

NMP ═ N-methylpyrrolidone

psi pounds per square inch

RT ═ room temperature

s ═ singlet

t is triplet

TCB groove circulation buffer (trough circulating buffer)

THF ═ tetrahydrofuran

TFA ═ trifluoroacetic acid

TLC ═ thin layer chromatography

TMS ═ trimethylsilyl

UV ═ ultraviolet

v/v-volume ratio

W ═ watt

μ L ═ microliter

Micromolar concentration of

Method 1

General procedure for solid phase parallel synthesis

[0206]Will Synphase^TMAminomethylated (TFA salt) lanterns (lanters) (60 units, 2.28mmol) were placed in a capped plastic container (100mL) and swelled in NMP (50mL) for 30 min. A mixture of benzotriazol-1-yloxy-tris (dimethylamino) phosphonium hexafluorophosphate (1512mg, 3.42mmol), (3-formyl-1-indolyl) acetic acid (720mg, 3.42mmol) and 1-hydroxybenzotriazole (280mg, 5.7mmol) was added, followed by N, N-diisopropylethylamine (1190. mu.L, 6.84 mmol). The vessel was shaken overnight at room temperature and then the liquid was removed. The lantern was washed with DMF (2X 100mL), MeOH (100mL), and dichloromethane (3X 100mL) and then dried under vacuum at room temperature.

[0207] The lanterns were divided into 6 groups of 9 units (0.342 mmol). Each group was placed in a plastic syringe (20mL) with plastic glaze and swollen in a DMF/EtOH mixture (3: 1, 10 mL). To each syringe was added the appropriate amine (3.42mmol) and borane-pyridine complex (318mg, 3.42 mmol). The syringe was fitted with a plunger (plunger) and cap and shaken overnight at room temperature. The liquid was removed and the lantern was washed with DMF (2X 10mL), MeOH (10mL), and dichloromethane (3X 10mL) and then swollen in dichloromethane (10 mL). FMOC-isothiocyanate (578mg, 2.05mmol) was added to each syringe. The syringe was fitted with a plunger and cap and shaken overnight at room temperature. The liquid was removed and the lantern was washed with DMF (2X 10mL), MeOH (10mL), and dichloromethane (3X 10mL), then treated with 20% piperidine in DMF (10mL) at room temperature for 20 min. The liquid was removed and the lantern was treated again with 20% piperidine in DMF (10mL) at room temperature for 20 min. The liquid was removed and the lantern was washed with DMF (2X 10mL), MeOH (10mL), and dichloromethane (3X 10mL) and then dried under vacuum at room temperature.

[0208] Each group was divided into 3 subgroups of 3 units (0.114mmol) per subgroup. Each panel was placed in a plastic syringe (50mL) with plastic glaze and swelled in dioxane (10 mL). To each syringe was added the appropriate bromomethyl ketone (6.84 mmol). The syringe was fitted with a plunger and cap and shaken overnight at room temperature. The liquid was removed and the lantern was washed with DMF (2X 10mL), MeOH (10mL), and dichloromethane (3X 10mL) and then dried under vacuum at room temperature.

[0209] The lanterns were distributed in 96-deep well polypropylene plates (1 unit per well), treated with 60% TFA/dichloromethane for 2h (400. mu.L per well) at room temperature, and the solvent was removed in vacuo. The contents of the wells were extracted with N, N-dimethylacetamide (500. mu.L per well) with stirring at room temperature for 16 h. The resulting solution from each well was transferred to a 96-deep well polypropylene plate and concentrated under vacuum. The residue from each well was dissolved in MeOH (100. mu.L) and treated with 1M HCl/ether (ether) (500. mu.L). The plates were centrifuged to remove the liquid and the precipitated solid residue was dried in vacuo to give the hydrochloride salt of the crude intermediate amine.

[0210] The crude intermediate amine was dissolved in a dichloromethane/N, N-dimethylacetamide mixture (2: 1, 150. mu.L) followed by the addition of N, N-diisopropylethylamine (13. mu.L, 0.076mmol) and the appropriate acid chloride (0.057 mmol). The reaction mixture was maintained at room temperature for 2h and then concentrated under vacuum. The resulting residue was dissolved in DMSO (200. mu.L) and purified by HPLC (method Z) to give the desired acylate.

Example 1

N- (4- (3, 4-dimethoxyphenyl) thiazol-2-yl) -N- (3-morpholinopropyl) thiophene-2-carboxamide

[0211] A mixture of 2-bromo-1- (3, 4-dimethoxyphenyl) ethanone (2-bromo-1- (3, 4-dimethoxyphenyl) ethanone) (259mg, 1mmol) and (3-morpholin-4-yl-propyl) -thiourea (203mg, 1mmol) in dry dioxane (10mL) was heated at reflux for 1h and then cooled to room temperature. The solvent was evaporated to give the crude aminothiazole as a colorless oil.

[0212]A mixture of crude aminothiazole, N-diisopropylethylamine (522. mu.L, 3mmol) and 2-thiophenecarbonyl chloride (220. mu.L, 1.5mmol) in dichloromethane (3mL) was maintained at room temperature for 16 h. The reaction mixture was concentrated in vacuo and the resulting residue was dissolved in DMSO (2mL) and purified by HPLC (method Y). The fractions containing the desired product were combined and concentrated in vacuo. The residue was dissolved in MeOH (1mL) and 1M HCl/ether (50mL) was added. The resulting precipitate was filtered and dried in vacuo to give the title compound (382mg, 75%) as an off-white solid as the hydrochloride salt. LC/MS (ESI) M/z 474.3[ M + H ]]HPLC retention time (method a) ═ 2.59min.¹H NMR(DMSO-d₆)δ2.36(m，2H)，3.04(m，2H)，3.23(m，2H)，3.40(m，3H)，3.76(m，1H)，3.79(s，3H)，3.85(s，3H)，3.91(br d，J＝12.1Hz，2H)，4.44(t，J＝7.3Hz，2H)，7.00(d，J＝8.4Hz，1H)，7.23(dd，J＝4.7，4.0Hz，1H)，7.49(d，J＝1.8Hz，1H)，7.53(dd，J＝8.2，1.8Hz，1H)，7.68(d，J＝3.4Hz，1H)，7.73(s，1H)，7.98(d，J＝4.9Hz，1H).

Example 2

N- (4- (benzofuran-2-yl) thiazol-2-yl) -N- (3-morpholinopropyl) thiophene-2-carboxamide

[0213] A mixture of 1- (benzofuran-2-yl) -2-bromoethanone (239mg, 1mmol) and (3-morpholin-4-yl-propyl) -thiourea (203mg, 1mmol) in anhydrous dioxane (10mL) was heated at reflux for 1h and then cooled to room temperature. The solvent was evaporated to give the crude aminothiazole as a colorless oil.

[0214]A mixture of the crude intermediate, N-diisopropylethylamine (522. mu.L, 3mmol) and 2-thiophenecarbonyl chloride (220. mu.L, 1.5mmol) in dichloromethane (3mL) was maintained at room temperature for 16 h. The reaction mixture was concentrated in vacuo and the resulting residue was dissolved inDMSO (2mL) was purified by HPLC (method Y). The fractions containing the desired product were combined and concentrated in vacuo. The residue was dissolved in MeOH (1mL) and 1M HCl/ether (50mL) was added. The resulting precipitate was filtered and dried in vacuo to give the title compound (303mg, 62%) as an off-white solid as the hydrochloride salt. LC/MS (ESI) M/z 454.3[ M + H ]]HPLC retention time (method a) ═ 3.02min.¹H NMR(500MHz，CD₃OD)δ2.39(m，2H)，3.17-3.95(br m，10H)，4.54(t，J＝7.2Hz，2H)，7.18(dd，J＝5.0，3.8Hz，1H)，7.37(m，2H)，7.57(m，2H)，7.67(s，1H)，7.80(dd，J＝5.0，1.0Hz，1H)，8.02(dd，J＝7.0，1.4Hz，1H)，8.29(s，1H).

Example 3

N- (3-morpholinopropyl) -N- (4-phenylthiazol-2-yl) thiophene-2-carboxamide

[0215] A mixture of 2-bromoacetophenone (60mg, 0.3mmol) and (3-morpholin-4-yl-propyl) -thiourea (61mg, 0.3mmol) in dry ethanol (3mL) was heated at reflux for 10min, cooled to room temperature, and concentrated in vacuo. The resulting residue was suspended in dichloromethane (3mL) followed by the addition of N, N-diisopropylethylamine (105. mu.L, 0.6mmol) and thiophene-2-carbonyl chloride (34. mu.L, 0.32 mmol). The reaction mixture was maintained at room temperature overnight and then concentrated in vacuo. The resulting residue was dissolved in DMSO (1.5mL) and purified by HPLC (method Y). The resulting free amine was dissolved in MeOH (1mL) and 1M HCl/ether (50mL) was added. The precipitate was filtered and dried in vacuo to give the title compound (67mg) as an off-white solid as the hydrochloride salt. LC/ms (esi) M/z 413.9[ M + H ] HPLC retention time (method a) ═ 2.78min.

Example 4

N- (4- (3-chlorophenyl) thiazol-2-yl) -N- (3-morpholinopropyl) thiophene-2-carboxamide

[0216] A mixture of 3-chlorobenzoylmethyl bromide (467mg, 2mmol) and (3-morpholin-4-yl-propyl) -thiourea (407mg, 2mmol) in absolute ethanol (4mL) was heated at reflux for 2min, cooled to room temperature and concentrated in vacuo. The resulting residue was suspended in dichloromethane (5mL) followed by the addition of N, N-diisopropylethylamine (554. mu.L, 3mmol) and thiophene-2-carbonyl chloride (160. mu.L, 1.5 mmol). The reaction mixture was maintained at room temperature overnight and then concentrated in vacuo. The resulting residue was dissolved in DMSO (3mL) and purified by HPLC (method Y). The resulting free amine was dissolved in MeOH (2mL) and 1M HCl/ether (75mL) was added. The precipitate was filtered and dried in vacuo to give the title compound (367mg) as an off-white solid as the hydrochloride salt. LC/ms (esi) M/z 447.9[ M + H ] HPLC retention time (method a) ═ 2.95min.

Example 5

N- (4- (5-chlorothien-2-yl) thiazol-2-yl) -N- (3-morpholinopropyl) thiophene-2-carboxamide

[0217] A mixture of 2-bromo-1- (5-chloro-thiophen-2-yl) -ethanone (72mg, 0.3mmol) and (3-morpholin-4-yl-propyl) -thiourea (61mg, 0.3mmol) in absolute ethanol (3mL) was heated at reflux for 10min, cooled to room temperature and dried in vacuo. The resulting residue was suspended in dichloromethane (3mL) followed by the addition of N, N-diisopropylethylamine (105. mu.L, 0.6mmol) and thiophene-2-carbonyl chloride (34. mu.L, 0.32 mmol). The reaction mixture was maintained at room temperature overnight and then concentrated in vacuo. The resulting residue was dissolved in DMSO (1.5mL) and purified by HPLC (method Y). The resulting free amine was dissolved in MeOH (1mL) and 1M HCl/ether (50mL) was added. The precipitate was filtered and dried in vacuo to give the title compound (61mg) as a yellow solid as the hydrochloride salt. LC/ms (esi) M/z 453.9[ M + H ] HPLC retention time (method a) ═ 2.93min.

Example 6

Methyl 4- (2- (N- (3-morpholinopropyl) thiophene-2-carboxamido) thiazol-4-yl) benzoate

[0218] A mixture of 4- (2-bromo-acetyl) -benzoic acid methyl ester (77mg, 0.3mmol) and (3-morpholin-4-yl-propyl) -thiourea (61mg, 0.3mmol) in absolute ethanol (3mL) was heated at reflux for 10 min. Cooled to room temperature and dried in vacuo. The resulting residue was suspended in dichloromethane (3mL) followed by the addition of N, N-diisopropylethylamine (105. mu.L, 0.6mmol) and thiophene-2-carbonyl chloride (34. mu.L, 0.32 mmol). The reaction mixture was maintained at room temperature overnight and then concentrated in vacuo. The resulting residue was dissolved in DMSO (1.5mL) and purified by HPLC (method Y). The resulting free amine was dissolved in MeOH (1mL) and 1M HCl/ether (50mL) was added. The precipitate was filtered and dried in vacuo to give the title compound (52mg) as an off-white solid as the hydrochloride salt. LC/ms (esi) M/z 472.3[ M + H ] HPLC retention time (method a) ═ 2.80min.

Example 7

N- (4- (2, 3-dihydrobenzo [ b ] [1, 4] dioxadien-6-yl) thiazol-2-yl) -N- (3-morpholinopropyl) thiophene-2-carboxamide

[0219] A mixture of 3, 4- (ethylenedioxy) phenacyl bromide (77mg, 0.3mmol) and (3-morpholin-4-yl-propyl) -thiourea (61mg, 0.3mmol) in dry ethanol (3mL) was heated at reflux for 10 min. Cooled to room temperature and concentrated in vacuo. The resulting residue was suspended in dichloromethane (3mL) followed by the addition of N, N-diisopropylethylamine (105. mu.L, 0.6mmol) and thiophene-2-carbonyl chloride (34. mu.L, 0.32 mmol). The reaction mixture was maintained at room temperature overnight and then concentrated in vacuo. The resulting residue was dissolved in DMSO (1.5mL) and purified by HPLC (method Y). The resulting free amine was dissolved in MeOH (1mL) and 1M HCl/ether (50mL) was added. The precipitate was filtered and dried in vacuo to give the title compound (72mg) as an off-white solid as the hydrochloride salt. LC/ms (esi) M/z 472.3[ M + H ] HPLC retention time (method a) ═ 2.72min.

Example 8

N- (4- (2, 4-dimethoxyphenyl) thiazol-2-yl) -N- (3-morpholinopropyl) thiophene-2-carboxamide

[0220] A mixture of 2-bromo-2 ', 4' -dimethoxyacetophenone (156mg, 0.6mmol) and (3-morpholin-4-yl-propyl) -thiourea (122mg, 0.6mmol) in anhydrous dioxane (5mL) was heated at 80 ℃ for 2 h. Cooled to room temperature and concentrated in vacuo. The resulting residue was suspended in dichloromethane (5mL) followed by the addition of N, N-diisopropylethylamine (209. mu.L, 1.2mmol) and thiophene-2-carbonyl chloride (96. mu.L, 0.9 mmol). The reaction mixture was maintained at room temperature overnight and then concentrated in vacuo. The resulting residue was dissolved in DMSO (2.5mL) and purified by HPLC (method Y). The resulting free amine was dissolved in MeOH (1mL) and 1M HCl/ether (50mL) was added. The precipitate was filtered and dried in vacuo to give the title compound (207mg) as a yellow solid as the hydrochloride salt. LC/ms (esi) M/z 474.3[ M + H ] HPLC retention time (method a) ═ 2.81min.

Example 9

N- (3-morpholinopropyl) -N- (4- (3-phenylisoxazol-5-yl) thiazol-2-yl) thiophene-2-carboxamide

[0221] A mixture of 2-bromo-1- (3-phenylisoxazol-5-yl) ethan-1-one (160mg, 0.6mmol) and (3-morpholin-4-yl-propyl) -thiourea (122mg, 0.6mmol) in anhydrous dioxane (5mL) was heated at 80 ℃ for 2 h. Cooled to room temperature and concentrated in vacuo. The resulting residue was suspended in dichloromethane (5mL) followed by the addition of N, N-diisopropylethylamine (209. mu.L, 1.2mmol) and thiophene-2-carbonyl chloride (96. mu.L, 0.9 mmol). The reaction mixture was maintained at room temperature overnight and then concentrated in vacuo. The resulting residue was dissolved in DMSO (2.5mL) and purified by HPLC (method Y). The resulting free amine was dissolved in MeOH (1mL) and 1M HCl/ether (50mL) was added. The precipitate was filtered and dried in vacuo to give the title compound (155mg) as an off-white solid as the hydrochloride salt. LC/ms (esi) M/z 481.1[ M + H ] HPLC retention time (method B) ═ 2.94min.

Example 10

N- (4- (5-methyl-1-phenyl-1H-pyrazol-4-yl) thiazol-2-yl) -N- (3-morpholinopropyl) thiophene-2-carboxamide

[0222] A mixture of 2-bromo-1- (5-methyl-1-phenyl-1H-pyrazol-4-yl) -1-ethanone (167mg, 0.6mmol) and (3-morpholin-4-yl-propyl) -thiourea (122mg, 0.6mmol) in anhydrous dioxane (5mL) was heated at 80 ℃ for 2H. Cooled to room temperature and dried in vacuo. The resulting residue was suspended in dichloromethane (5mL) followed by the addition of N, N-diisopropylethylamine (209. mu.L, 1.2mmol) and thiophene-2-carbonyl chloride (96. mu.L, 0.9 mmol). The reaction mixture was maintained at room temperature overnight and then concentrated in vacuo. The resulting residue was dissolved in DMSO (2.5mL) and purified by HPLC (method Y). The resulting free amine was dissolved in MeOH (1mL) and 1M HCl/ether (50mL) was added. The precipitate was filtered and dried in vacuo to give the title compound (193mg) as a yellow solid as the hydrochloride salt. LC/ms (esi) M/z 494.3[ M + H ] HPLC retention time (method B) ═ 2.72min.

Example 11

N- (3-morpholinopropyl) -N- (4- (5- (pyridin-2-yl) thiophen-2-yl) thiazol-2-yl) thiophene-2-carboxamide

[0223] A mixture of 2-bromo-1- [5- (2-pyridyl) -2-thienyl ] -1-ethanone (169mg, 0.6mmol) (167mg, 0.6mmol) and (3-morpholin-4-yl-propyl) -thiourea (122mg, 0.6mmol) in anhydrous dioxane (5mL) was heated at 80 ℃ for 2 h. Cooled to room temperature and dried in vacuo. The resulting residue was suspended in dichloromethane (5mL) followed by the addition of N, N-diisopropylethylamine (209. mu.L, 1.2mmol) and thiophene-2-carbonyl chloride (96. mu.L, 0.9 mmol). The reaction mixture was maintained at room temperature overnight and then concentrated in vacuo. The resulting residue was dissolved in DMSO (2.5mL) and purified by HPLC (method Y). The resulting free amine was dissolved in MeOH (1mL) and 1M HCl/ether (50mL) was added. The precipitate was filtered and dried in vacuo to give the title compound (320mg) as an off-white solid as the hydrochloride salt. LC/ms (esi) M/z 497.5[ M + H ] HPLC retention time (method B) ═ 2.55min.

Example 12

2- (N- (3-morpholinopropyl) thiophene-2-carboxamido) -N- (1, 3, 4-thiadiazol-2-yl) thiazole-4-carboxamide

[0224] 2- (N- (3-morpholinopropyl) thiophene-2-carboxamido) thiazole-4-carboxylic acid was obtained using 3-bromopyruvic acid according to the procedure of example 1.

[0225] A mixture of the acid (990mg, 2mmol) and pentafluorophenol (368mg, 2mmol) was dissolved in NMP (8mL) followed by N, N' -diisopropylcarbodiimide (314 μ L, 2 mmol). The reaction mixture was maintained at room temperature for 20 min. A portion of the above mixture (100. mu.L, 0.02mmol) was added to a solution of 2-amino-1, 3, 4-thiazole (2mg, 0.02mmol) in NMP (100. mu.L), and the reaction mixture was maintained at room temperature overnight. The resulting reaction mixture was purified by HPLC (method Z) to give the desired coupled product (1.1mg) as a brown oil as trifluoroacetate salt. LC/ms (esi) M/z 465.1[ M + H ] HPLC retention time (method B) ═ 2.22min.

Example 13

N- (4- (3, 4-dimethoxyphenyl) thiazol-2-yl) -N- (5-morpholinopentyl) thiophene-2-carboxamide

[0226] A mixture of N- (5-bromopentyl) phthalimide (1.49g, 5mmol) and N, N-diisopropylethylamine (870 μ L, 5mmol) was dissolved in NMP (2mL) followed by morpholine (870 μ L, 5.5 mmol). The reaction mixture was stirred at room temperature overnight, the precipitate formed was filtered and the filtrate was evaporated. The crude product was triturated from EtOAc, filtered and dried in vacuo to give the alkylated morpholine intermediate (939mg) as a white solid. This intermediate was dissolved in ethanol (20mL) and treated with hydrazine hydrate (155. mu.L, 3.1 mmol). The reaction mixture was heated at reflux for 2h, cooled to room temperature and the resulting precipitate was filtered. The filtrate was concentrated in vacuo, and the resulting residue was dissolved in chloroform (5mL) followed by treatment with N- (9-fluorenylmethoxycarbonyl) -isothiocyanate (872mg, 3.1 mmol). The reaction mixture was maintained at room temperature for 2h, then concentrated in vacuo. The resulting oil was dissolved in EtOAc (5mL), treated with piperidine (614 μ L, 6.2mmol), stirred at room temperature for 30min, and concentrated in vacuo. The resulting residue was dissolved in dichloromethane (10mL), and the resulting precipitate was filtered and dried in vacuo to give 1- (5-morpholinopentyl) thiourea (287mg, 58%) as a yellow amorphous solid.

[0227] Following the procedure of example 1, 2-bromo-1- (3, 4-dimethoxyphenyl) ethanone was reacted with 1- (5-morpholinopentyl) thiourea to give the title compound (1.5mg) as a colorless film. LC/ms (esi) M/z 502.3[ M + H ] HPLC retention time (method B) ═ 2.75min.

Example 14

N- (3- (2-oxopyrrolidin-1-yl) propyl) -N- (4- (3-phenylisoxazol-5-yl) thiazol-2-yl) thiophene-2-carboxamide

[0228] A mixture of 1- (3-aminopropyl) -2-pyrrolidone (560. mu.L, 4mmol) and benzoyl isothiocyanate (536. mu.L, 4mmol) was dissolved in chloroform (3mL), stirred at room temperature for 30min, and then concentrated in vacuo. The resulting residue was dissolved in concentrated HCl (3mL), heated at 95 ℃ for 2h, and then concentrated in vacuo. The resulting residue was dissolved in water, washed with dichloromethane (2X 30mL), then basified with 2M NaOH and extracted with dichloromethane (2X 30 mL). The combined extracts were dried over MgSO4 and concentrated to give 1- (3- (2-oxopyrrolidin-1-yl) propyl) thiourea (638mg) as a pale yellow oil.

[0229] Following the procedure of example 1, 5- (bromoacetyl) -3-phenylisoxazole was reacted with 1- (3- (2-oxopyrrolidin-1-yl) propyl) thiourea to give the title compound (1.5mg) as a colorless film. LC/ms (esi) M/z 479.1[ M + H ]. HPLC retention time (method C) ═ 3.59min.

Example 15

N- (4- (2, 6-Dimethoxypyridin-3-yl) thiazol-2-yl) -N- (3-morpholinopropyl) thiophene-2-carboxamide

[0230] A mixture of 2, 6-dimethoxynicotinic acid (1.1g, 6mmol) and N, N-diisopropylethylamine (1.01mL, 6.3mmol) was dissolved in 1, 2-dichloroethane (10mL), treated with thionyl chloride (460. mu.L, 6.3mmol) and stirred at room temperature for 2 h. The reaction mixture was concentrated in vacuo and the resulting oil was extracted with diethyl ether (10 mL). The supernatant was separated and used in the next step without any further purification.

[0231]The ethereal solution of the acid chloride was cooled to-30 ℃ and a solution of diazomethane in ether (25mL, 25mmol) was added dropwise. The reaction mixture was stirred at-30 ℃ for an additional 30min, then at 0 ℃ for 3 h. The reaction mixture was concentrated in vacuo, the resulting oil was dissolved in THF (5mL), cooled to 0 deg.C, and treated dropwise with 48% HBr (2 mL). The reaction mixture was stirred at 0 ℃ for 20min with saturated aqueous NaHCO₃Neutralized and then extracted with dichloromethane (2 × 50 mL). The organic layers were combined and washed with Na₂SO₄Dried and concentrated in vacuo to give 2-bromo-1- (2, 6-dimethoxypyridin-3-yl) ethanone (1.1g) as a yellow solidAnd (3) a body.

[0232] Following the procedure of example 1, 2-bromo-1- (2, 6-dimethoxypyridin-3-yl) ethanone was reacted with (3-morpholin-4-yl-propyl) -thiourea to give the title compound (1.9mg) as a colorless film. LC/ms (esi) M/z 475.1[ M + H ] HPLC retention time (method B) ═ 2.87min.

Example 16

N- (4- (4- (2- (dimethylamino) ethylcarbamoyl) phenyl) thiazol-2-yl) -N- (3-morpholinopropyl) thiophene-2-carboxamide

[0233] A mixture of 4- (2-bromoacetyl) benzoic acid (100mg, 0.41mmol) and pentafluorophenol (75mg, 0.41mmol) was dissolved in THF (1mL) and cooled to 0 deg.C. N, N' -diisopropylcarbodiimide (64. mu.L, 0.41mmol) was added and the reaction mixture was stirred at 0 ℃ for 10min, then at room temperature for an additional 30 min. N, N-dimethylethylenediamine (36mg, 0.41mmol) was added and the reaction mixture was stirred at room temperature for 3h, then concentrated in vacuo. The resulting 4- (2-bromoacetyl) -N- (2- (dimethylamino) ethyl) benzamide was dissolved in absolute ethanol (4mL) and used immediately for the next reaction.

[0234] Following the procedure of example 1, 4- (2-bromoacetyl) -N- (2- (dimethylamino) ethyl) benzamide was reacted with (3-morpholin-4-yl-propyl) -thiourea to give the title compound (0.3mg) as a colorless film. LC/ms (esi) M/z 528.3[ M + H ] HPLC retention time (method B) ═ 2.08min.

Example 17

2- (3- (2- (N- (3-morpholinopropyl) thiophene-2-carboxamido) thiazol-4-yl) phenoxy) acetic acid

[0235]A mixture of methyl bromoacetate (690. mu.L, 7.3mmol) and 4-hydroxyacetophenone (1g, 7.3mmol) was dissolved in acetone (100mL) followed by the addition of anhydrous K ₂CO₃(10g, 73 mmol). The reaction mixture was stirred at room temperature overnight, filtered and the filtrate was concentrated in vacuo. The resulting residue was dissolved in dioxane (21mL) and a portion of the resulting solution (3.2mL, 1.03mmol) was combined with a solution of NaOH (64mg, 1.6mmol) in water (3 mL). Maintaining the reaction mixtureFor 1h at room temperature, then concentrated in vacuo. The residue was dissolved in water (3mL) and neutralized with 1M HCl. The mixture was extracted with EtOAc (10mL) and the organic layer was MgSO₄Dried and concentrated in vacuo. The crude acid was dissolved in THF (36mL) and a portion of the resulting solution (5.2mL, 0.14mmol) was combined with phenyltrimethylammonium tribromide (93mg, 0.14 mmol). The reaction mixture was heated at reflux for 1h, cooled, stirred at room temperature overnight, and then concentrated in vacuo. The resulting residue was dissolved in water (15mL) and extracted with dichloromethane (2X 30 mL). The combined organic extracts were then dried over MgSO₄Dried and concentrated in vacuo. The crude bromoketone was dissolved in anhydrous dioxane (1mL) followed by the addition of (3-morpholin-4-yl-propyl) -thiourea (28mg, 0.14 mmol). The reaction mixture was heated at 80 ℃ for 1h, cooled to room temperature, and then concentrated in vacuo. The resulting crude aminothiazole was suspended in anhydrous chloroform (600. mu.L) followed by the addition of N, N-diisopropylethylamine (52. mu.L, 0.3mmol) and thiophene-2-carbonyl chloride (24. mu.L, 0.22 mmol). The reaction mixture was stirred at room temperature for 30min, then concentrated in vacuo. The resulting residue was dissolved in AcOH/water (1: 1, 5mL), heated at reflux for 30min, cooled to room temperature, and then concentrated in vacuo. The crude product was dissolved in DMSO (800. mu.L), and a portion of the resulting solution (200. mu.L, 0.035mmol) was purified by HPLC (method Z) to give the title compound (2.4mg) as a colorless amorphous solid. LC/MS (ESI) M/z 488.3[ M + H ] ]HPLC retention time (method B) ═ 2.58min.

Example 18

N- (4- (4- (2- (dimethylamino) ethoxy) phenyl) thiazol-2-yl) -N- (3-morpholinopropyl) thiophene-2-carboxamide

[0236]A mixture of 2- (dimethylamino) ethyl chloride hydrochloride (1.05g, 7.3mmol) and 4-hydroxyacetophenone (1g, 7.3mmol) was dissolved in acetone (100mL) followed by the addition of anhydrous K₂CO₃(10g, 73 mmol). The reaction mixture was stirred at room temperature overnight, filtered and the filtrate was concentrated in vacuo. The resulting residue was dissolved in THF (20mL), and a portion of the resulting solution (7.4mL, 2.7mmol) was combined with phenyltrimethylammonium tribromide (1.05g, 2.7 mmol). The reaction mixture was heated at reflux for 1h and cooledStirred at room temperature overnight, then concentrated in vacuo. The resulting residue was dissolved in water (15mL) and extracted with dichloromethane (2X 30 mL). The organic layers were combined and MgSO₄Dried and concentrated in vacuo. The resulting crude bromoketone was dissolved in anhydrous dioxane (25mL) and a portion of this solution (1mL, 0.11mmol) was combined with (3-morpholin-4-yl-propyl) -thiourea (21mg, 0.11 mmol). The reaction mixture was heated at 80 ℃ for 1h, cooled, stirred at room temperature overnight, and then concentrated in vacuo. The resulting residue was suspended in anhydrous chloroform (600. mu.L) followed by the addition of N, N-diisopropylethylamine (52. mu.L, 0.3mmol) and thiophene-2-carbonyl chloride (24. mu.L, 0.22 mmol). The reaction mixture was maintained at room temperature for 30min, then concentrated in vacuo. The resulting residue was dissolved in AcOH (5mL), heated at reflux for 30min, cooled, and concentrated in vacuo. The residue was dissolved in DMSO (600. mu.L) and a portion of this solution (200. mu.L, 0.035mmol) was purified by HPLC (method Z) to give the title compound (0.8mg) as a yellow amorphous solid. LC/MS (ESI) M/z 501.1[ M + H ] ]HPLC retention time (method B) ═ 2.21min.

Example 19

1- (3- (N- (4- (benzofuran-2-yl) thiazol-2-yl) thiophene-2-carboxamido) propionyl) piperidine-3-carboxamide

[0237] A mixture of beta-alanine tert-butyl ester hydrochloride (1.09g, 6mmol) and N, N-diisopropylethylamine (1.04mL, 6mmol) was dissolved in chloroform (6mL) followed by the addition of N- (9-fluorenylmethoxycarbonyl) -isothiocyanate (1.67g, 6 mmol). The reaction mixture was stirred at room temperature for 2h, concentrated, and the resulting residue was dissolved in EtOAc (10mL) followed by the addition of piperidine (1.1mL, 11 mmol). The reaction mixture was maintained at room temperature for 30min, then concentrated in vacuo. The resulting residue was dissolved in dichloromethane (3mL) and hexane (30mL) was added. The resulting precipitate was filtered and dried in vacuo to give thiourea (1.1g) as a yellow solid.

[0238]A mixture of 1- (1-benzofuran-2-yl) -2-bromoethane-1-one (360mg, 1.5mmol) and thiourea prepared as above (300mg, 1.5mmol) was dissolved in anhydrous dioxane (3mL) followed by the addition of N, N-diisopropylethylamine (261 μL, 1.5 mmol). The reaction mixture was heated at 80 ℃ for 1h, cooled, and then concentrated in vacuo. The residue obtained is dissolved in chloroform (3mL) and purified by flash chromatography (Teledyne Isco Combiflash) ^®) Elution was with chloroform/AcOH mixture (95: 3) and MeOH. The product fractions were combined, concentrated in vacuo, dissolved in EtOAc (25mL) and washed with 5% aqueous NaHCO₃And brine, then over MgSO₄And (5) drying. Concentration in vacuo afforded the aminothiazole (400mg) as an off-white solid.

[0239] A mixture of aminothiazole (140mg, 0.41mmol) and N, N-diisopropylethylamine (710. mu.L, 4.1mmol) prepared as above was dissolved in anhydrous chloroform (1mL) followed by the addition of 2-thiophenecarbonyl chloride (430. mu.L, 4.1 mmol). The reaction mixture was irradiated in a microwave oven (maximum power 250W, 140 ℃ C.) for 10min, cooled to room temperature, and concentrated in vacuo. The resulting residue was dissolved in DMSO (500. mu.L) and purified by HPLC (method Y). The fractions containing the desired product were combined and concentrated in vacuo. The resulting ester was dissolved in TFA/dichloromethane mixture (60: 40, 10mL), stirred at room temperature for 30min, concentrated in vacuo, and the resulting residue was dried in vacuo to give the carboxylic acid (163mg) as a yellow solid.

[0240] A mixture of the acid prepared as above (159mg, 0.4mmol) and pentafluorophenol (74mg, 0.4mmol) was dissolved in chloroform (4mL) followed by the addition of N, N' -diisopropylcarbodiimide (63 μ L, 0.4 mmol). The reaction mixture was maintained at room temperature for 20min, then a portion (200. mu.L, 0.02mmol) was added to a solution of piperidine formamide (2.6mg, 0.02mmol) in chloroform (100. mu.L). The reaction mixture was maintained at room temperature overnight and then concentrated in vacuo. The resulting residue was dissolved in DMSO (200 μ L) and purified by HPLC (method Z) to give the title compound (1.8mg) as a yellow solid. LC/ms (esi) M/z 509.1[ M + H ] HPLC retention time (method C) ═ 3.40min.

Example 20

1-acetyl-N- (3- (N- (4- (benzofuran-2-yl) thiazol-2-yl) thiophene-2-carboxamido) propyl) piperidine-4-carboxamide

[0241] Following the procedure of example 19, (3-amino-propyl) carbamic acid tert-butyl ester was converted to tert-butyl 3- (N- (4- (benzofuran-2-yl) thiazol-2-yl) thiophene-2-carboxamido) propyl carbamate, reacted with TFA/dichloromethane (3: 2), stirred at room temperature for 30min, concentrated in vacuo, then dissolved in MeOH and treated with 1M HCl/ether. The resulting precipitate was filtered and dried in vacuo to give N- (3-aminopropyl) -N- (4- (benzofuran-2-yl) thiazol-2-yl) thiophene-2-carboxamide (220mg) as a white solid.

[0242] A mixture of the amine (77mg, 0.2mmol) prepared above and N, N-diisopropylethylamine (139. mu.L, 0.8mmol) was dissolved in chloroform (2mL) and a portion of this solution (200. mu.L, 0.02mmol) was added to a solution of 1-acetyl-hexahydroisonicotinoyl chloride (1-acetyl-isonicotinoyl chloride; 7.6mg, 0.04mmol) in chloroform (200. mu.L). The reaction mixture was maintained at room temperature overnight and then concentrated in vacuo. The resulting residue was dissolved in DMSO (200 μ L) and purified by HPLC (method Z) to give the title compound (4.5mg) as a yellow solid. LC/ms (esi) M/z 537.1[ M + H ]. HPLC retention time (method C) ═ 3.44min.

Example 21

N- (4- (benzofuran-2-yl) thiazol-2-yl) -N- (3- (3- (piperidin-1-yl) propionylamino) propyl) thiophene-2-carboxamide

[0243] A mixture of 1-piperidinepropanoic acid (3mg, 0.02mmol) and tris (dimethylamino) phosphonium chloride perchlorate (7mg, 0.02mmol) was dissolved in NMP (200. mu.L) followed by the addition of N, N-diisopropylethylamine (17. mu.L, 0.1 mmol). The reaction mixture was maintained at room temperature for 20min, then N- (3-aminopropyl) -N- (4- (benzofuran-2-yl) thiazol-2-yl) thiophene-2-carboxamide (7.7mg, 0.02mmol) was added and the reaction mixture was stirred at room temperature overnight. The resulting mixture was purified by HPLC (method Z) to give the title compound (3.2mg) as a pale yellow solid. LC/ms (esi) M/z 523.5[ M + H ] HPLC retention time (method C) ═ 3.15min.

Example 22

N- (4- (benzofuran-2-yl) thiazol-2-yl) -N- (3- (4, 4-dihydroxypiperidin-1-yl) propyl) thiophene-2-carboxamide

[0244] Following the procedure of example 19, 3-amino-1-propanol was converted to aminotriazole, which was dissolved in i-PrOH and treated with 1M HCl/ether to give 3- (4- (benzofuran-2-yl) thiazol-2-ylamino) propan-1-ol (437mg) as a white solid as the hydrochloride salt.

[0245] A mixture of aminotriazole hydrochloride (423mg, 1.36mmol) prepared above and N, O-bis (trimethylsilyl) acetamide (674 μ L, 2.73mmol) was dissolved in anhydrous chloroform (32 mL). The reaction mixture was heated in a pressure vessel at 80 ℃ for 30min and cooled to room temperature. N, N-diisopropylethylamine (1.07mL, 6.12mmol) was added followed by 2-thiophenecarbonyl chloride (945. mu.L, 8.84 mmol). The reaction mixture was irradiated (maximum power 250W, 120 ℃ C.) in a microwave oven for 45min and then cooled to room temperature. The resulting solution was washed with water (2 × 30mL) and concentrated in vacuo. The resulting residue was dissolved in DMSO (2mL) and purified by HPLC (method X) to give the amide (347mg) as an off-white solid.

[0246] A mixture of the amide (318mg, 0.83mmol) and N, N-diisopropylethylamine (432. mu.L, 2.48mmol) was dissolved in dichloromethane (28mL), cooled to 0 ℃ and treated with methanesulfonyl chloride (192. mu.L, 2.48 mmol). The ice bath was removed and the reaction mixture was stirred at room temperature for 2h, washed with water (2X 30mL) and azeotropically evaporated with toluene (2X 20mL) to give the desired mesylate. The residual oil was used in the next step without further purification.

[0247] A mixture of 4-piperidone monohydrate hydrochloride (3mg, 0.2mmol) and N, N-diisopropylethylamine (35. mu.L, 0.2mmol) was dissolved in NMP (200. mu.L) in a glove box under nitrogen, followed by the addition of 4 Å molecular sieves. The reaction mixture was maintained at room temperature overnight. The solution was decanted and a solution of the mesylate (0.2mmol) prepared above in NMP (100. mu.L) was added. The reaction mixture was maintained at room temperature overnight and then purified by HPLC (method Z) to give the desired coupling product (0.4mg) as an off-white solid. LC/ms (esi) M/z 484.3[ M + H ] HPLC retention time (method C) ═ 2.95min.

Example 23

N- (4- (benzofuran-2-yl) thiazol-2-yl) -N- (3- (2- (hydroxymethyl) pyrrolidin-1-yl) propyl) thiophene-2-carboxamide

[0248] Following the procedure of example 19, using 1-amino-3, 3-diethoxypropane, purification by flash chromatography instead of HPLC, eluting with an EtOAc/hexane mixture containing 1% triethylamine gave N- (4- (benzofuran-2-yl) thiazol-2-yl) -N- (3, 3-diethoxypropyl) thiophene-2-carboxamide as an off-white solid.

[0249]A solution of the acetal (880mg, 1.93mmol) in dioxane (5mL) was cooled to 0 deg.C and 1M HCl/ether (8mL) was added. The ice bath was removed and the reaction mixture was stirred at room temperature for 30min, diluted with ether (100mL) and extracted with water. The aqueous layer was washed with saturated aqueous NaHCO₃Neutralized and extracted with ether (3X 30 mL). The organic layers were combined and washed with Na₂SO₄Drying and concentration gave the aldehyde (735mg, 99%) as an off-white solid.

[0250] A mixture of the aldehyde (8mg, 0.024mmol) and (S) - (+) -2-pyrrolidinemethanol (12mg, 0.12mmol) was dissolved in 1, 2-dichloroethane (500. mu.L) followed by treatment with sodium borohydride (1.1mg, 0.029 mmol). The reaction mixture was maintained at room temperature for 1h, then concentrated in vacuo. The resulting residue was extracted with DMSO (250 μ L) and filtered. The resulting filtrate was purified by HPLC (method Z) to give the title compound (1mg) as a pale yellow solid. LC/ms (esi) M/z 468.3[ M + H ] HPLC retention time (method B) ═ 3.08min.

Example 24

[0251] The following compounds of table 1 were prepared by the general procedure for solid phase parallel synthesis (method 1) or as exemplified in the examples using the appropriate starting materials.

TABLE 1

Name of Compound	LC/MSm/z[M+H]	HPLC retention time (min)	HPLC method	Synthesis method
					N- (4- (4-methoxyphenyl) thiazol-2-yl) -3, 3-dimethyl-N- (3-morpholinopropyl) butanamide	432.3	3.05	A	Example 1 or method 1

Name of Compound	LC/MSm/z[M+H]	HPLC retention time (min)	HPLC method	Synthesis method
					2- (2-chlorophenyl) -N- (4- (4-methoxyphenyl) thiazol-2-yl) -N- (3-morpholinopropyl) acetamide	486.3	2.96	A	Example 1 or method 1
2- (3-chlorophenyl) -N- (4- (4-methoxyphenyl) thiazol-2-yl) -N- (3-morpholinopropyl) acetamide	486.3	3.08	A	Example 1 or method 1
					N- (3- (diethylamino) propyl) -N- (4- (2, 5-dimethoxyphenyl) thiazol-2-yl) benzamide	454.3	3.02	A	Example 1 or method 1
N- (3- (diethylamino) propyl) -N- (4- (2, 5-dimethoxyphenyl) thiazol-2-yl) thiophene-2-carboxamide	460.3	2.99	A	Example 1 or method 1
					N- (4-phenylthiazol-2-yl) -N- (3- (pyrrolidin-1-yl) propyl) thiophene-2-carboxamide	397.9	2.88	A	Example 1 or method 1
N- (4- (4-methoxyphenyl) thiazol-2-yl) -N- (3- (pyrrolidin-1-yl) propyl) benzamide	421.9	2.96	A	Example 1 orMethod 1
					N- (4- (4-methoxyphenyl) thiazol-2-yl) -N- (3- (pyrrolidin-1-yl) propyl) thiophene-2-carboxamide	428.3	2.92	A	Example 1 or method 1
N- (4- (4-methoxyphenyl) thiazol-2-yl) -N- (3- (pyrrolidin-1-yl) propyl) furan-2-carboxamide	411.9	2.86	A	Example 1 or method 1
					N- (4- (2, 5-dimethoxyphenyl) thiazol-2-yl) -N- (3- (pyrrolidin-1-yl) propyl) benzamide	452.3	3.00	A	Example 1 or method 1

Name of Compound	LC/MSm/z[M+H]	HPLC retention time (min)	HPLC method	Synthesis method
					N- (4- (2, 5-dimethoxyphenyl) thiazol-2-yl) -N- (3- (pyrrolidin-1-yl) propyl) thiophene-2-carboxamide	458.3	2.98	A	Example 1 or method 1
N- (4- (2, 5-dimethoxyphenyl) thiazol-2-yl) -N- (3- (pyrrolidin-1-yl) propyl) furan-2-carboxamide	442.3	2.92	A	Example 1 or method 1
					N- (4- (4-methoxyphenyl) thiazol-2-yl) -N- (3- (piperidin-1-yl) propyl) thiophene-2-carboxamide	442.3	2.95	A	Example 1 or method 1
N- (4- (2, 5-dimethoxyphenyl) thiazol-2-yl) -N- (3- (piperidin-1-yl) propyl) benzamide	466.3	3.06	A	Example 1 or method 1
					N- (4- (2, 5-dimethoxyphenyl) thiazol-2-yl) -N- (3- (piperidin-1-yl) propyl) thiophene-2-carboxamide	472.3	3.03	A	Example 1 or method 1
N- (4- (2, 5-dimethoxyphenyl) thiazol-2-yl) -N- (3- (piperidin-1-yl) propyl) furan-2-carboxamide	456.3	2.98	A	Example 1 or method 1
					N- (3- (azepan-1-yl) propyl) -N- (4-phenylthiazol-2-yl) benzamide	420.3	3.12	A	Example 1 or method 1
N- (3- (azepan-1-yl) propyl) -N- (4-phenylthiazol-2-yl) thiophene-2-carboxamide	426.3	3.11	A	Example 1 or method 1
					N- (3- (azepan-1-yl) propyl) -N- (4-phenylthiazol-2-yl) furan-2-carboxamide	410.3	3.03	A	Example 1 or method 1

Name of Compound	LC/MSm/z[M+H]	HPLC retention time (min)	HPLC method	Synthesis method
					N- (3- (azepan-1-yl) propyl) -N- (4- (4-methoxyphenyl) thiazol-2-yl) benzamide	450.3	3.11	A	Example 1 or method 1
N- (3- (azepan-1-yl) propyl) -N- (4- (4-methoxyphenyl) thiazol-2-yl) thiophene-2-carboxamide	456.3	3.06	A	Example 1 or method 1
					N- (3- (azepan-1-yl) propyl) -N- (4- (4-methoxyphenyl) thiazol-2-yl) furan-2-carboxamide	440.3	3.02	A	Example 1 or method 1
N- (3- (azepan-1-yl) propyl) -N- (4- (2, 5-dimethoxyphenyl) thiazol-2-yl) benzamide	480.3	3.18	A	Example 1 or method 1
					N- (3- (azepan-1-yl) propyl) -N- (4- (2, 5-dimethoxyphenyl) thiazol-2-yl) thiophene-2-carboxamide	486.3	3.12	A	Example 1 or method 1
N- (3- (azepan-1-yl) propyl) -N- (4- (2, 5-dimethoxyphenyl) thiazol-2-yl) furan-2-carboxamide	470.3	3.06	A	Example 1 or method 1
					N- (3- (4-methylpiperazin-1-yl) propyl) -N- (4-phenylthiazol-2-yl) benzamide	421.1	2.53	A	Example 1 or method 1
N- (3- (4-methylpiperazin-1-yl) propyl) -N- (4-phenylthiazol-2-yl) thiophene-2-carboxamide	427.1	2.49	A	Example 1 or method 1
					N- (3- (4-methylpiperazin-1-yl) propyl) -N- (4-phenylthiazol-2-yl) furan-2-carboxamide	411.1	2.42	A	Example 1 or method 1

Name of Compound	LC/MSm/z[M+H]	HPLC retention time (min)	HPLC method	Synthesis method
					N- (4- (4-methoxyphenyl) thiazol-2-yl) -N- (3- (4-methylpiperazin-1-yl) propyl) benzamide	451.1	2.55	A	Example 1 or method 1
N- (4- (4-methoxyphenyl) thiazol-2-yl) -N- (3- (4-methylpiperazin-1-yl) propyl) thiophene-2-carboxamide	457.1	2.50	A	Example 1 or method 1
					N- (4- (4-methoxyphenyl) thiazol-2-yl) -N- (3- (4-methylpiperazin-1-yl) propyl) furan-2-carboxamide	441.1	2.45	A	Example 1 or method 1
N- (4- (2, 5-dimethoxyphenyl) thiazol-2-yl) -N- (3- (4-methylpiperazin-1-yl) propyl) benzamide	481.1	2.61	A	Example 1 or method 1
					N- (4- (2, 5-dimethoxyphenyl) thiazol-2-yl) -N- (3- (4-methylpiperazin-1-yl) propyl) thiophene-2-carboxamide	487.1	2.55	A	Example 1 or method 1
N- (4- (2, 5-dimethoxyphenyl) thiazol-2-yl) -N- (3- (4-methylpiperazin-1-yl) propyl) furan-2-carboxamide	471.5	2.50	A	Example 1 or method 1
					N- (4- (4-methoxyphenyl) thiazol-2-yl) -N- (3-morpholinopropyl) cyclopent-1-enecarboxamide	428.3	2.73	A	Example 1 or method 1
4-chloro-N- (4- (4-methoxyphenyl) thiazol-2-yl) -N- (3-morpholinopropyl) benzamide	472.3	2.90	A	Example 1 or method 1
					3-fluoro-N- (4- (4-methoxyphenyl) thiazol-2-yl) -N- (3-morpholinopropyl) benzamide	456.3	2.81	A	Example 1 or method 1

Name of Compound	LC/MSm/z[M+H]	HPLC retention time (min)	HPLC method	Synthesis method
					N- (4- (4-methoxyphenyl) thiazol-2-yl) -3-methyl-N- (3-morpholinopropyl) benzamide	452.3	2.88	A	Example 1 or method 1
2-fluoro-N- (4- (4-methoxyphenyl) thiazol-2-yl) -N- (3-morpholinopropyl) benzamide	456.3	2.81	A	Example 1 or method 1
					N- (4- (4-methoxyphenyl) thiazol-2-yl) -4-methyl-N- (3-morpholinopropyl) benzamide	452.3	2.85	A	Example 1 or method 1
2-cyano-N- (4- (4-methoxyphenyl) thiazol-2-yl) -N- (3-morpholinopropyl) benzamide	463.1	2.69	A	Example 1 or method 1
					N- (4- (4-methoxyphenyl) thiazol-2-yl) -5-methyl-N- (3-morpholinopropyl) furan-2-carboxamide	442.3	2.78	A	Example 1 or method 1
N- (4- (4-methoxyphenyl) thiazol-2-yl) -3-methyl-N- (3-morpholinopropyl) furan-2-carboxamide	442.3	2.84	A	Example 1 or method 1
					N- (4- (4-methoxyphenyl) thiazol-2-yl) -N- (3-morpholinopropyl) thiophene-2-carboxamide	444.3	2.79	A	Example 1 or method 1
N- (4- (4-chlorophenyl) thiazol-2-yl) -N- (3-morpholinopropyl) thiophene-2-carboxamide	447.9	2.98	A	Example 1 or method 1
					N- (3-morpholinopropyl) -N- (4-p-tolylthiazol-2-yl) thiophene-2-carboxamide	428.3	2.88	A	Example 1 or method 1

Name of Compound	LC/MSm/z[M+H]	HPLC retention time (min)	HPLC method	Synthesis method
					N- (4- (2, 3-dihydrobenzo [ b ]][1，4]Dioxadien-6-yl) thiazol-2-yl) -N- (3-morpholinopropyl) thiophene-2-carboxamide	472.3	2.72	A	Example 1 or method 1
N- (4- (4-chloro-3-nitrophenyl) thiazol-2-yl) -N- (3-morpholinopropyl) thiophene-2-carboxamide	493.1	3.03	A	Example 1 or method 1
					N- (4- (2-methoxyphenyl) thiazol-2-yl) -N- (3-morpholinopropyl) thiophene-2-carboxamide	444.3	2.78	A	Example 1 or method 1
N- (4- (2, 4-dimethylphenyl) thiazol-2-yl) -N- (3-morpholinopropyl) thiophene-2-carboxamide	442.3	2.95	A	Example 1 or method 1
					N- (4- (4-cyanophenyl) thiazol-2-yl) -N- (3-morpholinopropyl) thiophene-2-carboxamide	439.1	2.73	A	Example 1 or method 1
Methyl 4- (2- (N- (3-morpholinopropyl) thiophene-2-carboxamido) thiazol-4-yl) benzoate	472.3	2.80	A	Example 1 or method 1
					N- (4- (4- (methylsulfonyl) phenyl) thiazol-2-yl) -N- (3-morpholinopropyl) thiophene-2-carboxamide	492.3	2.48	A	Example 1 or method 1
N- (4- (2, 4-dimethoxyphenyl) thiazol-2-yl) -N- (3-morpholinopropyl) thiophene-2-carboxamide	474.3	2.81	A	Example 1 or method 1
					N- (4- (benzofuran-3-yl) thiazol-2-yl) -N- (3-morpholinopropyl) thiophene-2-carboxamide	454.3	2.93	A	Example 1 or method 1

Name of Compound	LC/MSm/z[M+H]	HPLC retention time (min)	HPLC method	Synthesis method
					N- (4- (2-chlorophenyl) thiazol-2-yl) -N- (3-morpholinopropyl) thiophene-2-carboxamide	447.9	2.83	A	Example 1 or method 1
N- (4- (3-chlorophenyl) thiazol-2-yl) -N- (3-morpholinopropyl) thiophene-2-carboxamide	447.9	2.95	A	Example 1 or method 1
					N- (4- (benzo [ b ]]Thien-3-yl) thiazol-2-yl) -N- (3-morpholinopropyl) thiophene-2-carboxamide	470.3	2.99	A	Example 1 or method 1
N- (3-morpholinopropyl) -N- (4- (pyridin-2-yl) thiazol-2-yl) thiophene-2-carboxamide	415.1	1.92	A	Example 1 or method 1
					N- (3-morpholinopropyl) -N- (4- (pyridin-3-yl) thiazol-2-yl) thiophene-2-carboxamide	415.1	1.92	A	Example 1 or method 1
N- (3-morpholinopropyl) -N- (4- (pyridin-4-yl) thiazol-2-yl) thiophene-2-carboxamide	415.1	1.93	A	Example 1 or method 1
					N- (3-morpholinopropyl) -N- (4- (thien-2-yl) thiazol-2-yl) thiophene-2-carboxamide	420.3	2.69	A	Example 1 or method 1
N- (4- (5-chlorothien-2-yl) thiazol-2-yl) -N- (3-morpholinopropyl) thiophene-2-carboxamide	453.9	2.93	A	Example 1 or method 1
					N- (4- (5-chlorothien-2-yl) thiazol-2-yl) -N- (3-morpholinopropyl) thiophene-2-carboxamide	4203	2.65	A	Example 1 or method 1

Name of Compound	LC/MSm/z[M+H]	HPLC retention time (min)	HPLC method	Synthesis method
					N- (4- (3, 4-dichlorophenyl) thiazol-2-yl) -N- (3-morpholinopropyl) thiophene-2-carboxamide	482.3	3.13	A	Example 1 or method 1
N- (4- (4-fluorophenyl) thiazol-2-yl) -N- (3-morpholinopropyl) thiophene-2-carboxamide	432.3	2.78	A	Example 1 or method 1
					N- (4- (4- (difluoromethoxy) phenyl) thiazol-2-yl) -N- (3-morpholinopropyl) thiophene-2-carboxamide	479.9	2.93	A	Example 1 or method 1
N- (3-morpholinopropyl) -N- (4- (2- (trifluoromethyl) phenyl) thiazol-2-yl) thiophene-2-carboxamide	482.3	2.89	A	Example 1 or method 1
					N- (4- (2-fluorophenyl) thiazol-2-yl) -N- (3-morpholinopropyl) thiophene-2-carboxamide	432.3	2.83	A	Example 1 or method 1
N- (4- (3, 4-difluorophenyl) thiazol-2-yl) -N- (3-morpholinopropyl) thiophene-2-carboxamide	450.3	2.90	A	Example 1 or method 1
					N- (4- (3-bromophenyl) thiazol-2-yl) -N- (3-morpholinopropyl) thiophene-2-carboxamide	491.9	3.00	A	Example 1 or method 1
N- (3-morpholinopropyl) -N- (4- (4- (trifluoromethoxy) phenyl) thiazol-2-yl) thiophene-2-carboxamide	498.3	3.15	A	Example 1 or method 1
					N- (4- (3-fluorophenyl) thiazol-2-yl) -N- (3-morpholinopropyl) thiophene-2-carboxamide	432.3	2.80	A	Example 1 or method 1

Name of Compound	LC/MSm/z[M+H]	HPLC retention time (min)	HPLC method	Synthesis method
					N- (4- (3-methylbenzo [ b ]]Thien-2-yl) thiazol-2-yl) -N- (3-morpholinopropyl) thiophene-2-carboxamide	484.3	3.16	A	Example 1 or method 1
N- (4- (3-cyanophenyl) thiazol-2-yl) -N- (3-morpholinopropyl) thiophene-2-carboxamide	439.1	2.72	A	Example 1 or method 1
					N- (3-morpholinopropyl) -N- (4- (4-pentylphenyl) thiazol-2-yl) thiophene-2-carboxamide	484.3	3.56	A	Example 1 or method 1
N- (4- (4- (diethylamino) phenyl) thiazol-2-yl) -N- (3-morpholinopropyl) thiophene-2-carboxamide	485.5	2.15	A	Example 1 or method 1
					N- (3-morpholinopropyl) -N- (4- (4- (pyrrolidin-1-yl) phenyl) thiazol-2-yl) thiophene-2-carboxamide	483.5	2.72	A	Example 1 or method 1
N- (4- (3, 4-dimethoxyphenyl) thiazol-2-yl) -N- (3-morpholinopropyl) thiophene-2-carboxamide	474.3	2.59	A	Example 1 or method 1
					N- (4- (benzo [ d ])][1，3]Dioxolen-5-yl) thiazol-2-yl-N- (3-morpholinopropyl) thiophene-2-carboxamide	458.3	2.73	A	Example 1 or method 1
N- (4- (benzo [ d ])]Thiazol-2-yl) thiazol-2-yl) -N- (3-morpholinopropyl) thiophene-2-carboxamide	471.5	2.80	A	Example 1 or method 1
					N- (4- (3-methoxyphenyl) thiazol-2-yl) -N- (3-morpholinopropyl) thiophene-2-carboxamide	444.3	2.75	A	Example 1 or method 1

Name of Compound	LC/MSm/z[M+H]	HPLC retention time (min)	HPLC method	Synthesis method
					N- (3-morpholinopropyl) -N- (4- (2-nitrophenyl) thiazol-2-yl) thiophene-2-carboxamide	459.1	2.69	A	Example 1 or method 1
N- (3-morpholinopropyl) -N- (4- (naphthalen-2-yl) thiazol-2-yl) thiophene-2-carboxamide	464.3	3.06	A	Example 1 or method 1
					N- (4- (benzofuran-2-yl) thiazol-2-yl) -N- (3-morpholinopropyl) thiophene-2-carboxamide	454.3	3.02	A	Example 1 or method 1
N- (4- (4-morpholinophenyl) thiazol-2-yl) -N- (3-morpholinopropyl) thiophene-2-carboxamide	499.1	2.46	A	Example 1 or method 1
					N- (4- (3, 4-dihydro-2H-benzo [ b ]][1，4]Dioxa * (dioxapin) -7-yl) thiazol-2-yl) -N- (3-morpholinopropyl) thiophene-2-carboxamide	486.3	2.76	A	Example 1 or method 1
N- (4- (2-chloropyridin-4-yl) thiazol-2-yl) -N- (3-morpholinopropyl) thiophene-2-carboxamide	449.1	2.59	A	Example 1 or method 1
					N- (4- (4-methoxyphenyl) thiazol-2-yl) -3-methyl-N- (3-morpholinopropyl) thiophene-2-carboxamide	458.3	2.81	A	Example 1 or method 1
2, 5-dichloro-N- (4- (4-methoxyphenyl) thiazol-2-yl) -N- (3-morpholinopropyl) thiophene-3-carboxamide	512.3	3.06	A	Example 1 or method 1
					3-bromo-N- (4- (4-methoxyphenyl) thiazol-2-yl) -N- (3-morpholinopropyl) thiophene-2-carboxamide	522.3	2.86	A	Example 1 or method 1

Name of Compound	LC/MSm/z[M+H]	HPLC retention time (min)	HPLC method	Synthesis method
					N- (4- (4-methoxyphenyl) thiazol-2-yl) -N- (3-morpholinopropyl) -5-nitrothiophene-2-carboxamide	489.1	2.86	A	Example 1 or method 1
5-chloro-N- (4- (4-methoxyphenyl) thiazol-2-yl) -N- (3-morpholinopropyl) thiophene-2-carboxamide	477.9	2.95	A	Example 1 or method 1
					5-acetyl-N- (4- (4-methoxyphenyl) thiazol-2-yl) -N- (3-morpholinopropyl) thiophene-2-carboxamide	486.3	2.69	A	Example 1 or method 1
5-bromo-N- (4- (4-methoxyphenyl) thiazol-2-yl) -N- (3-morpholinopropyl) thiophene-2-carboxamide	522.3	2.96	A	Example 1 or method 1
					N- (4- (4-methoxyphenyl) thiazol-2-yl) -5- (methylthio) -N- (3-morpholinopropyl) thiophene-2-carboxamide	490.3	2.96	A	Example 1 or method 1
N- (3-morpholinopropyl) -N- (4- (3- (trifluoromethyl) phenyl) thiazol-2-yl) thiophene-2-carboxamide	482.3	3.06	A	Example 1 or method 1
					N- (4- (4-methoxyphenyl) thiazol-2-yl) -1-methyl-N- (3-morpholinopropyl) -1H-pyrrole-2-carboxamide	441.1	2.72	A	Example 1 or method 1
N- (4- (4-methoxyphenyl) thiazol-2-yl) -N- (3-morpholinopropyl) isoxazole-5-carboxamide	429.1	2.58	A	Example 1 or method 1
					N- (4- (4-methoxyphenyl) thiazol-2-yl) -3, 5-dimethyl-N- (3-morpholinopropyl) isoxazole-4-carboxamide	457.5	2.62	A	Example 1 or method 1

Name of Compound	LC/MSm/z[M+H]	HPLC retention time (min)	HPLC method	Synthesis method
					N- (4- (4-methoxyphenyl) thiazol-2-yl) -4-methyl-N- (3-morpholinopropyl) -1, 2, 3-thiadiazole-5-carboxamide	460.3	2.60	A	Example 1 or method 1
N- (4- (4-methoxyphenyl) thiazol-2-yl) -2, 4-dimethyl-N- (3-morpholinopropyl) thiazole-5-carboxamide	473.1	2.59	A	Example 1 or method 1
					4-chloro-N- (4- (4-methoxyphenyl) thiazol-2-yl) -N- (3-morpholinopropyl) picolinamide	473.1	2.83	A	Example 1 or method 1
N- (4- (4-methoxyphenyl) thiazol-2-yl) -3-methyl-N- (3-morpholinopropyl) isoxazole-4-carboxamide	443.5	2.59	A	Example 1 or method 1
					6-chloro-N- (4- (4-methoxyphenyl) thiazol-2-yl) -N- (3-morpholinopropyl) picolinamide	473.1	2.80	A	Example 1 or method 1
N- (4- (4-methoxyphenyl) thiazol-2-yl) -1-methyl-N- (3-morpholinopropyl) -1H-imidazole-2-carboxamide	442.3	2.62	A	Example 1 or method 1
					4, 5-dichloro-N- (4- (4-methoxyphenyl) thiazol-2-yl) -N- (3-morpholinopropyl) isothiazole-3-carboxamide	513.1	3.01	A	Example 1 or method 1
N- (4- (4-methoxyphenyl) thiazol-2-yl) -1, 2, 5-trimethyl-N- (3-morpholinopropyl) -1H-pyrrole-3-carboxamide	469.5	2.83	A	Example 1 or method 1
					Ethyl 2- (N- (3-morpholinopropyl) thiophene-2-carboxamido) thiazole-4-carboxylate	410.3	2.39	A	Example 1 or method 1

Name of Compound	LC/MSm/z[M+H]	HPLC retention time (min)	HPLC method	Synthesis method
					Ethyl 3-methyl-3- (2- (N- (3-morpholinopropyl) thiophene-2-carboxamido) thiazol-4-yl) butanoate	466.3	2.69	A	Example 1 or method 1
N- (4- (biphenyl-4-yl) thiazol-2-yl) -N- (3-morpholinopropyl) thiophene-2-carboxamide	490.3	3.20	B	Example 1 or method 1
					N- (4- (5-methyl-1-phenyl-1H-pyrazol-4-yl) thiazol-2-yl) -N- (3-morpholinopropyl) thiophene-2-carboxamide	494.3	2.72	B	Example 1 or method 1
N- (4- (2, 4-dichlorophenyl) thiazol-2-yl) -N- (3-morpholinopropyl) thiophene-2-carboxamide	481.9	3.08	B	Example 1 or method 1
					3- (2- (N- (3-morpholinopropyl) thiophene-2-carboxamido) thiazol-4-yl) benzoic acid	458.3	2.50	B	Example 1 or method 1
N- (3-Morpholinopropyl) -N- (4- (3-oxo-3, 4-dihydro-2H-benzo [ b ]][1，4]Oxazin-6-yl) thiazol-2-yl) thiophene-2-carboxamide	485.1	2.42	B	Example 1 or method 1
					N- (3-morpholinopropyl) -N- (4- (3-phenylisoxazol-5-yl) thiazol-2-yl) thiophene-2-carboxamide	481.1	2.94	B	Example 1 or method 1
N- (3-morpholinopropyl) -N- (4- (5- (pyridin-2-yl) thiophen-2-yl) thiazol-2-yl) thiophene-2-carboxamide	497.5	2.55	B	Example 1 or method 1
					N- (4 ' -methyl-2 ' - (pyrazin-2-yl) -4, 5 ' -bithiazol-2-yl) -N- (3-morpholinopropyl) thiophene-2-carboxamide	513.1	2.72	B	Example 1 or method 1

Name of Compound	LC/MSm/z[M+H]	HPLC retention time (min)	HPLC method	Synthesis method
					2- (5- (2- (N- (3-morpholinopropyl) thiophene-2-carboxamido) thiazol-4-yl) thiophen-2-yl) acetic acid	477.9	2.48	B	Example 1 or method 1
N- (4- (4-chloro-3-methylphenyl) thiazol-2-yl) -N- (3-morpholinopropyl) thiophene-2-carboxamide	462.3	3.06	B	Example 1 or method 1
					N- (4- (3, 4-dimethoxyphenyl) thiazol-2-yl) -N- (3-morpholinopropyl) benzamide	468.3	2.58	B	Example 1 or method 1
N- (4- (3, 4-Dimethoxyphenyl) thiazol-2-yl) -N- (3-morpholinopropyl) furan-2-carboxamide	458.3	2.48	B	Example 1 or method 1
					N- (4- (benzofuran-2-yl) thiazol-2-yl) -N- (3-morpholinopropyl) furan-2-carboxamide	438.3	2.89	B	Example 1 or method 1
N- (4- (benzofuran-2-yl) thiazol-2-yl) -N- (3-morpholinopropyl) nicotinamide	449.1	2.55	B	Example 1 or method 1
					N- (4- (3, 4-Dimethoxyphenyl) thiazol-2-yl) -N- (3-morpholinopropyl) cyclopentanecarboxamide	460.3	2.73	B	Example 1 or method 1
N- (4- (3, 4-Dimethoxyphenyl) thiazol-2-yl) -N- (3-morpholinopropyl) cyclobutanecarboxamide	446.3	2.60	B	Example 1 or method 1
					N- (4- (benzofuran-2-yl) thiazol-2-yl) -N- (3-morpholinopropyl) cyclobutanecarboxamide	426.4	3.08	A	Example 1 or method 1

Name of Compound	LC/MSm/z[M+H]	HPLC retention time (min)	HPLC method	Synthesis method
					N- (4- (3, 4-Dimethoxyphenyl) thiazol-2-yl) -N- (3-morpholinopropyl) picolinamide	469.5	2.44	B	Example 1 or method 1
N- (4- (benzofuran-2-yl) thiazol-2-yl) -N- (3-morpholinopropyl) picolinamide	449.1	2.83	B	Example 1 or method 1
					N- (4- (3- (4-chlorophenyl) isoxazol-5-yl) thiazol-2-yl) -N- (3-morpholinopropyl) thiophene-2-carboxamide	515.1	3.20	C	Example 1 or method 1
N- (3-morpholinopropyl) -N- (4- (3-phenylisoxazol-5-yl) thiazol-2-yl) furan-2-carboxamide	465.1	2.85	C	Example 1 or method 1
					1-methyl-N- (3-morpholinopropyl) -N- (4- (3-phenylisoxazol-5-yl) thiazol-2-yl) -1H-pyrrole-2-carboxamide	478.3	2.94	C	Example 1 or method 1
4- (2- (N- (3-morpholinopropyl) thiophene-2-carboxamido) thiazol-4-yl) benzoic acid	458.3	2.47	B	Example 1 or method 1
					N- (3-morpholinopropyl) -N- (4- (trifluoromethyl) thiazol-2-yl) thiophene-2-carboxamide	406.3	2.51	B	Example 1 or method 1
Ethyl 5- (2- (N- (3-morpholinopropyl) thiophene-2-carboxamido) thiazol-4-yl) isoOxazole-3-carboxylic acid esters	477.1	2.67	B	Example 1 or method 1
					2- (N- (3-morpholinopropyl) thiophene-2-carboxamido) -N- (1, 3, 4-thiadiazol-2-yl) thiazole-4-carboxamide	465.1	2.22	B	Example 12

Name of Compound	LC/MSm/z[M+H]	HPLC retention time (min)	HPLC method	Synthesis method
					2- (N- (3-morpholinopropyl) thiophene-2-carboxamido) -N- (thiazol-2-yl) thiazole-4-carboxamide	463.9	2.38	B	Example 12
N- (3-methoxyphenyl) -2- (N- (3-morpholinopropyl) thiophene-2-carboxamido) thiazole-4-carboxamide	487.1	2.49	B	Example 12
					N- (3-methoxybenzyl) -2- (N- (3-morpholinopropyl) thiophene-2-carboxamido) thiazole-4-carboxamide	501.1	2.39	B	Example 12
N- (3-chlorobenzyl) -2- (N- (3-morpholinopropyl) thiophene-2-carboxamido) thiazole-4-carboxamide	505.1	2.59	B	Example 12
					N- (2, 3-dihydrobenzo [ b ]][1，4]Dioxadien-6-yl) -2- (N- (3-morpholinopropyl) thiophene-2-carboxamido) thiazole-4-carboxamide	515.1	2.46	B	Example 12
N- (5-Ethyl-1, 3, 4-thiadiazol-2-yl) -2- (N- (3-morpholinopropyl) thiophene-2-carboxamido) thiazole-4-carboxamide	493.1	2.46	B	Example 12
					N- (benzo [ d ]]Thiazol-6-yl) -2- (N- (3-morpholinopropyl) thiophene-2-carboxamido) thiazole-4-carboxamide	514.3	2.42	B	Example 12
N- (3-carbamoylphenyl) -2- (N- (3-morpholinopropyl) thiophene-2-carboxamido) thiazole-4-carboxamide	500.3	2.15	B	Example 12

Name of Compound	LC/MSm/z[M+H]	HPLC retention time (min)	HPLC method	Synthesis method
					Ethyl 2- (2- (2- (N- (3-morpholinopropyl) thiophene-2-carboxamido) thiazole-4-carboxamido) thiazol-4-yl) acetate	550.3	2.62	B	Example 12
N- (3- (methylsulfonylamino) phenyl) -2- (N- (3-morpholinopropyl) thiophene-2-carboxamido) thiazole-4-carboxamide	550.3	2.30	B	Example 12
					N- (4- (benzofuran-2-yl) thiazol-2-yl) -N- (3- (2-oxopyrrolidin-1-yl) propyl) furan-2-carboxamide	436.3	3.65	C	Examples 13 and 14
N- (4- (benzofuran-2-yl) thiazol-2-yl) -N- (3- (2-oxopyrrolidin-1-yl) propyl) thiophene-2-carboxamide	451.9	3.69	C	Examples 13 and 14
					N- (4- (benzofuran-2-yl) thiazol-2-yl) -1-methyl-N- (3- (2-oxopyrrolidin-1-yl) propyl) -1H-pyrrole-2-carboxamide	449.1	3.69	C	Examples 13 and 14
N- (3- (2-oxopyrrolidin-1-yl) propyl) -N- (4- (3-phenylisoxazol-5-yl) thiazol-2-yl) furan-2-carboxamide	463.1	3.56	C	Examples 13 and 14
					N- (3- (2-oxopyrrolidin-1-yl) propyl) -N- (4- (3-phenylisoxazol-5-yl) thiazol-2-yl) thiophene-2-carboxamide	479.1	3.59	C	Examples 13 and 14
1-methyl-N- (3- (2-oxopyrrolidin-1-yl) propyl) -N- (4- (3-phenylisoxazol-5-yl) thiazol-2-yl) -1H-pyrrole-2-carboxamide	476.3	3.56	C	Examples 13 and 14
					N- (3- (4-methylpiperazin-1-yl) propyl) -N- (4- (3-phenylisoxazol-5-yl) thiazol-2-yl) furan-2-carboxamide	478.3	2.55	C	Examples 13 and 14

Name of Compound	LC/MSm/z[M+H]	HPLC retention time (min)	HPLC method	Synthesis method
					N- (4-morpholinobutyl) -N- (4- (3-phenylisoxazol-5-yl) thiazol-2-yl) furan-2-carboxamide	479.1	2.92	C	Examples 13 and 14
N- (4-morpholinobutyl) -N- (4- (3-phenylisoxazol-5-yl) thiazol-2-yl) thiophene-2-carboxamide	495.1	2.98	C	Examples 13 and 14
					N- (3- (diethylamino) propyl) -N- (4- (3, 4-dimethoxyphenyl) thiazol-2-yl) thiophene-2-carboxamide	460.3	2.61	B	Examples 13 and 14
N- (4- (3, 4-dimethoxyphenyl) thiazol-2-yl) -N- (3- (2-oxopyrrolidin-1-yl) propyl) thiophene-2-carboxamide	472.3	3.11	B	Examples 13 and 14
					N- (4- (3, 4-dimethoxyphenyl) thiazol-2-yl) -N- (3- (4-methylpiperazin-1-yl) propyl) thiophene-2-carboxamide	487.1	2.32	B	Examples 13 and 14
N- (4- (3, 4-dimethoxyphenyl) thiazol-2-yl) -N- (3- (piperidin-1-yl) propyl) thiophene-2-carboxamide	472.3	2.66	B	Examples 13 and 14
					N- (4- (3, 4-dimethoxyphenyl) thiazol-2-yl) -N- (5-morpholinopentyl) thiophene-2-carboxamide	502.3	2.75	B	Examples 13 and 14
N- (4- (3, 4-dimethoxyphenyl) thiazol-2-yl) -N- (2-morpholinoethyl) thiophene-2-carboxamide	460.3	2.41	B	Examples 13 and 14
					N- (4- (3, 4-dimethoxyphenyl) thiazol-2-yl) -N- (3-phenylpropyl) thiophene-2-carboxamide	465.1	4.04	B	Examples 13 and 14

Name of Compound	LC/MSm/z[M+H]	HPLC retention time (min)	HPLC method	Synthesis method
					N- (4- (benzofuran-2-yl) thiazol-2-yl) -N- (3- (diethylamino) propyl) thiophene-2-carboxamide	440.3	3.05	B	Examples 13 and 14
N- (3- (1H-imidazol-1-yl) propyl) -N- (4- (benzofuran-2-yl) thiazol-2-yl) thiophene-2-carboxamide	435.1	2.79	B	Examples 13 and 14
					N- (4- (benzofuran-2-yl) thiazol-2-yl) -N- (3- (4-methylpiperazin-1-yl) propyl) thiophene-2-carboxamide	467.1	2.68	B	Examples 13 and 14
N- (4- (benzofuran-2-yl) thiazol-2-yl) -N- (3- (piperidin-1-yl) propyl) thiophene-2-carboxamide	451.9	3.07	B	Examples 13 and 14
					N- (4- (benzofuran-2-yl) thiazol-2-yl) -N- (4-morpholinobutyl) thiophene-2-carboxamide	468.3	3.01	B	Examples 13 and 14
N-(4- (benzofuran-2-yl) thiazol-2-yl) -N- (5-morpholinopentyl) thiophene-2-carboxamide	482.3	3.16	B	Examples 13 and 14
					N- (4- (benzofuran-2-yl) thiazol-2-yl) -N- (3-phenylpropyl) thiophene-2-carboxamide	445.1	4.60	B	Examples 13 and 14
N- (4- (benzofuran-2-yl) thiazol-2-yl) -N-propylthiophene-2-carboxamide	369.1	4.34	B	Examples 13 and 14
					N- (4- (5-methylthiophen-2-yl) thiazol-2-yl) -N- (3-morpholinopropyl) thiophene-2-carboxamide	434.3	2.78	B	Example 15

Name of Compound	LC/MSm/z[M+H]	HPLC retention time (min)	HPLC method	Synthesis method
					N- (4- (6-methoxypyridin-3-yl) thiazol-2-yl) -N- (3-morpholinopropyl) thiophene-2-carboxamide	445.1	2.42	B	Example 15
N- (4- (2, 6-Dimethoxypyridin-3-yl) thiazol-2-yl) -N- (3-morpholinopropyl) thiophene-2-carboxamide	475.1	2.87	B	Example 15
					N- (4-Cyclopentylthiazol-2-yl) -N- (3-morpholinopropyl) thiophene-2-carboxamide	406.3	2.63	B	Example 15
N- (4-Cyclohexylthiazol-2-yl) -N- (3-morpholinopropyl) thiophene-2-carboxamide	420.3	2.80	B	Example 15
					Methyl 6- (2- (N- (3-morpholinopropyl) thiophene-2-carboxamido) thiazol-4-yl) nicotinate	473.1	2.50	B	Example 15
N- (4- (1H-indol-2-yl) thiazol-2-yl) -N- (3-morpholinopropyl) thiophene-2-carboxamide	453.1	2.93	C	Example 15
					N- (4- (7-methoxybenzofuran-2-yl) thiazol-2-yl) -N- (3-morpholinopropyl) thiophene-2-carboxamide	484.3	2.94	C	Example 15
N- (4- (5-methoxybenzofuran-2-yl) thiazol-2-yl) -N- (3-morpholinopropyl) thiophene-2-carboxamide	484.3	3.03	C	Example 15
					N- (3-Morpholinopropyl) -N- (4- (5-nitrobenzofuran-2-yl) thiazol-2-yl) thiophene-2-carboxylic acidAmines as pesticides	499.1	3.09	C	Example 15

Name of Compound	LC/MSm/z[M+H]	HPLC retention time (min)	HPLC method	Synthesis method
					N- (4- (4- (2-hydroxyethylcarbamoyl) phenyl) thiazol-2-yl) -N- (3-morpholinopropyl) thiophene-2-carboxamide	501.1	2.17	B	Example 16
N- (4- (4- (2-morpholinoethylcarbamoyl) phenyl) thiazol-2-yl) -N- (3-morpholinopropyl) thiophene-2-carboxamide	570.4	2.09	B	Example 16
					N- (4- (4- (methylcarbamoyl) phenyl) thiazol-2-yl) -N- (3-morpholinopropyl) thiophene-2-carboxamide	471.5	2.29	B	Example 16
N- (4- (4- (2- (dimethylamino) ethylcarbamoyl) phenyl) thiazol-2-yl) -N- (3-morpholinopropyl) thiophene-2-carboxamide	528.3	2.08	B	Example 16
					N- (4- (4- (3- (dimethylamino) propylcarbamoyl) phenyl) thiazol-2-yl) -N- (3-morpholinopropyl) thiophene-2-carboxamide	542.3	2.09	B	Example 16
N- (4- (4- (3-hydroxypropylcarbamoyl) phenyl) thiazol-2-yl) -N- (3-morpholinopropyl) thiophene-2-carboxamide	515.1	2.21	B	Example 16
					N- (4- (4-carbamoylphenyl) thiazol-2-yl) -N- (3-morpholinopropyl) thiophene-2-carboxamide	457.1	2.22	B	Example 16
N- (4- (4- (dimethylcarbamoyl) phenyl) thiazol-2-yl) -N- (3-morpholinopropyl) thiophene-2-carboxamide	485.5	2.38	B	Example 16
					2- (4- (2- (N- (3-morpholinopropyl) thiophene-2-carboxamido) thiazol-4-yl) benzoylamino) acetic acid	515.1	2.22	B	Example 16

Name of Compound	LC/MSm/z[M+H]	HPLC retention time (min)	HPLC method	Synthesis method
					N- (4- (4- (4-methylpiperazine-1-carbonyl) phenyl) thiazol-2-yl) -N- (3-morpholinopropyl) thiophene-2-carboxamide	540.3	2.01	B	Example 16
N- (4- (4- (morpholine-4-carbonyl) phenyl) thiazol-2-yl) -N- (3-morpholinopropyl) thiophene-2-carboxamide	527.1	2.37	B	Example 16
					2- (3- (2- (N- (3-morpholinopropyl) thiophene-2-carboxamido) thiazol-4-yl) phenoxy) acetic acid	488.3	2.58	B	Example 17
3- (3- (2- (N- (3-morpholinopropyl) thiophene-2-carboxamido) thiazol-4-yl) phenoxy) propanoic acid	502.3	2.64	B	Example 17
					2- (4- (2- (N- (3-morpholinopropyl) thiophene-2-carboxamido) thiazol-4-yl) phenoxy) acetic acid	488.3	2.58	B	Example 17
3- (4- (2- (N- (3-morpholinopropyl) thiophene-2-carboxamido) thiazol-4-yl) phenoxy) propanoic acid	502.3	2.60	B	Example 17
					N- (4- (3- (3- (dimethylamino) propoxy) phenyl) thiazol-2-yl) -N- (3-morpholinopropyl) thiophene-2-carboxamide	515.5	2.30	B	Example 18
N- (4- (3- (2- (dimethylamino) ethoxy) phenyl) thiazol-2-yl) -N- (3-morpholinopropyl) thiophene-2-carboxamide	501.1	2.22	B	Example 18
					N- (4- (4- (3- (dimethylamino) propoxy) phenyl) thiazol-2-yl) -N- (3-morpholinopropyl) thiophene-2-carboxamide	515.5	2.31	B	Example 18

Name of Compound	LC/MSm/z[M+H]	HPLC retention time (min)	HPLC method	Synthesis method
					N- (4- (4- (2- (dimethylamino) ethoxy) phenyl) thiazol-2-yl) -N- (3-morpholinopropyl) thiophene-2-carboxamide	501.1	2.21	B	Example 18
N- (4- (benzofuran-2-yl) thiazol-2-yl) -N- (3- (2-hydroxyethylamino) -3-oxopropyl) thiophene-2-carboxamide	442.3	3.23	B	Example 19
					N- (4- (benzofuran-2-yl) thiazol-2-yl) -N- (3- (2- (hydroxymethyl) pyrrolidin-1-yl) -3-oxopropyl) thiophene-2-carboxamide	482.3	3.62	B	Example 19
N- (4- (benzofuran-2-yl) thiazol-2-yl) -N- (3- (2- (dimethylamino) ethylamino) -3-oxopropyl) thiophene-2-carboxamide	469.1	2.93	B	Example 19
					N- (4- (benzofuran-2-yl) thiazol-2-yl) -N- (3- (3-hydroxypiperidin-1-yl) -3-oxopropyl) thiophene-2-carboxamide	482.3	3.54	B	Example 19
N- (4- (benzofuran-2-yl) thiazol-2-yl) -N- (3- ((2-hydroxyethyl) (methyl) amino) -3-oxopropyl) thiophene-2-carboxamide	456.3	3.43	B	Example 19
					N- (4- (benzofuran-2-yl) thiazol-2-yl) -N- (3- (bis (2-hydroxyethyl) amino) -3-oxopropyl) thiophene-2-carboxamide	486.3	3.06	B	Example 19
N- (4- (benzofuran-2-yl) thiazol-2-yl) -N-(3-oxo-3- (piperazin-1-yl) propyl) thiophene-2-carboxamide	467.1	2.95	B	Example 19
					N- (4- (benzofuran-2-yl) thiazol-2-yl) -N- (3- ((2- (dimethylamino) ethyl) (methyl) amino) -3-oxopropyl) thiophene-2-carboxamide	483.1	3.04	B	Example 19

Name of Compound	LC/MSm/z[M+H]	HPLC retention time (min)	HPLC method	Synthesis method
					N- (4- (benzofuran-2-yl) thiazol-2-yl) -N- (3- (methyl (2- (methylamino) ethyl) amino) -3-oxopropyl) thiophene-2-carboxamide	469.1	3.04	B	Example 19
N- (4- (benzofuran-2-yl) thiazol-2-yl) -N- (3- (3-hydroxypyrrolidin-1-yl) -3-oxopropyl) thiophene-2-carboxamide	468.3	3.36	B	Example 19
					N- (4- (benzofuran-2-yl) thiazol-2-yl) -N- (3- (3- (dimethylamino) pyrrolidin-1-yl) -3-oxopropyl) thiophene-2-carboxamide	495.1	2.95	B	Example 19
N- (4- (benzofuran-2-yl) thiazol-2-yl) -N- (3- ((2, 3-dihydroxypropyl) (methyl) amino) -3-oxopropyl) thiophene-2-carboxamide	486.3	3.23	C	Example 19
					Methyl 2- (3- (N- (4- (benzofuran-2-yl) thiazole-2-yl) thiophene-2-formamido) propionylamino) acetate	470.3	3.62	C	Example 19
1- (3- (N- (4- (benzofuran-2-yl) thiazol-2-yl) thiophene-2-carboxamido) propionyl) piperidine-3-carboxamide	509.1	3.40	C	Example 19
					N- (4- (benzofuran-2-yl) thiazol-2-yl) -N- (3-oxo-3- (thiazolidin-3-yl) propyl) thiophene-2-carboxamide	470.3	3.98	C	Example 19
N- (4- (benzofuran-2-yl) thiazol-2-yl) -N- (3-morpholino-3-oxopropyl) thiophene-2-carboxamide	468.3	3.75	C	Example 19
					N- (4- (benzofuran-2-yl) thiazol-2-yl) -N- (3- ((2-cyanoethyl) (methyl) amino) -3-oxopropyl) thiophene-2-carboxamide	465.1	3.76	C	Example 19

Name of Compound	LC/MSm/z[M+H]	HPLC retention time (min)	HPLC method	Synthesis method
					N- (4- (benzofuran-2-yl) thiazol-2-yl) -N- (3- (3- (hydroxymethyl) piperidin-1-yl) -3-oxopropyl) thiophene-2-carboxamide	496.3	3.66	C	Example 19
1- (3- (N- (4- (benzofuran-2-yl) thiazol-2-yl) thiophene-2-carboxamido) propionyl) piperidine-3-carboxylic acid	510.3	362	C	Example 19
					N- (3- (3-Acylaminopyrrolidin-1-yl) -3-oxopropyl) -N- (4- (benzofuran-2-yl) thiazol-2-yl) thiophene-2-carboxamide	509.1	3.28	C	Example 19
1- (3- (N- (4- (benzofuran-2-yl) thiazol-2-yl) thiophene-2-carboxamido) propionyl) pyrrolidine-2-carboxamide	495.1	3.34	C	Example 19
					N- (4- (benzofuran-2-yl) thiazol-2-yl) -N- (3-oxo-3- (3-oxopiperazin-1-yl) propyl) thiophene-2-carboxamide	481.1	3.25	C	Example 19
1- (3- (N- (4- (benzofuran-2-yl) thiazol-2-yl) thiophene-2-carboxamido) propionyl) piperidine-2-carboxamide	509.1	3.59	C	Example 19
					N- (4- (benzofuran-2-yl) thiazol-2-yl) -N- (3-oxo-3- (2-phenoxyethylamino) propyl) thiophene-2-carboxamide	517.9	4.11	C	Example 19
1- (3- (N- (4- (benzofuran-2-yl) thiazol-2-yl) thiophene-2-carboxamido) propionyl) -N- (2-hydroxyethyl) piperidine-3-carboxamide	553.2	3.29	C	Example 19
					N- (4- (benzofuran-2-yl) thiazol-2-yl) -N- (3- (isobutyl (1, 1-dioxo-tetrahydrothiophen-3-yl) amino) -3-oxopropyl) thiophene-2-carboxamide	572.4	4.10	C	Example 19

Name of Compound	LC/MSm/z[M+H]	HPLC retention time (min)	HPLC method	Synthesis method
					N- (4- (benzofuran-2-yl) thiazol-2-yl) -N- (4- (4- (2- (dimethylamino) ethyl) piperazin-1-yl) -4-oxobutyl) thiophene-2-carboxamide	552.3	2.83	C	Example 19
N- (4- (benzofuran-2-yl) thiazol-2-yl) -N- (4- ((2, 3-dihydroxypropyl) (methyl) amino) -4-oxobutyl) thiophene-2-carboxamide	500.3	3.32	C	Example 19
					Methyl 2- (4- (N- (4- (benzofuran-2-yl) thiazole-2-yl) thiophene-2-formamido) butyrylamino) acetate	484.3	3.67	C	Example 19
N- (4- (benzofuran-2-yl) thiazol-2-yl) -N- (4- ((5-methylpyrazin-2-yl) methylamino) -4-oxobutyl) thiophene-2-carboxamide	517.9	3.57	C	Example 19
					N- (4- (benzofuran-2-yl) thiazol-2-yl) -N- (4- (1-hydroxypropan-2-ylamino) -4-oxobutyl) thiophene-2-carboxamide	470.3	3.42	C	Example 19
N- (4- (benzofuran-2-yl) thiazol-2-yl) -N- (4-oxo-4- (piperidin-1-yl) butyl) thiophene-2-carboxamide	479.9	4.26	C	Example 19
					1- (4- (N- (4- (benzofuran-2-yl) thiazol-2-yl) thiophene-2-carboxamido) butyryl) piperidine-4-carboxamide	523.5	3.37	C	Example 19
N- (4- (benzofuran-2-yl) thiazol-2-yl) -N- (4- ((2-hydroxyethyl) (phenyl) amino) -4-oxobutyl) thiophene-2-carboxamide	531.9	3.97	C	Example 19
					N- (4- (benzofuran-2-yl) thiazol-2-yl) -N- (4-oxo-4- (2- (pyridin-4-yl) ethylamino) butyl) thiophene-2-carboxamide	517.1	3.01	C	Example 19

Name of Compound	LC/MSm/z[M+H]	HPLC retention time (min)	HPLC method	Synthesis method
					Tert-butyl 4- (4- (N- (4- (benzofuran-2-yl) thiazol-2-yl) thiophene-2-carboxamido) butyryl) piperazine-1-carboxylate	581.2	4.30	C	Example 19
N- (4- (benzofuran-2-yl) thiazol-2-yl) -N- (4-oxo-4- (pyridin-3-ylmethyl-amino) butyl) thiophene-2-carboxamide	503.1	3.04	C	Example 19
					N- (4- (benzofuran-2-yl) thiazol-2-yl) -N- (4- (5- (methylsulfonyl) indolin-1-yl) -4-oxobutyl) thiophene-2-carboxamide	592.4	4.06	C	Example 19
Tert-butyl 1- (4- (N- (4- (benzofuran-2-yl) thiazol-2-yl) thiophene-2-carboxamido) butyryl) pyrrolidin-3-ylcarbamate	581.2	4.07	C	Example 19
					N- (4- (3-Acylaminopyrrolidin-1-yl) -4-oxobutyl) -N- (4- (benzofuran-2-yl) thiazol-2-yl) thiophene-2-carboxamide	523.5	3.39	C	Example 19
Methyl 1- (4- (N- (4- (benzofuran-2-yl) thiazol-2-yl) thiophene-2-carboxamido) butyryl) piperidine-4-carboxylate	538.3	4.02	C	Example 19
					1- (4- (N- (4- (benzofuran-2-yl) thiazol-2-yl) thiophene-2-carboxamido) butyryl) -N-methylpiperidine-4-carboxamide	537.1	3.46	C	Example 19
N- (4- (benzofuran-2-yl) thiazol-2-yl) -N- (4- (4- (N, N-dimethylsulfamoyl) piperazin-1-yl) -4-oxobutyl) thiophene-2-carboxamide	588.4	3.92	C	Example 19
					Ethyl 2- (1- (4- (N- (4- (benzofuran-2-yl) thiazol-2-yl) thiophene-2-carboxamido) butyryl) piperidin-3-yl) acetate	566.4	4.31	C	Example 19

Name of Compound	LC/MSm/z[M+H]	HPLC retention time (min)	HPLC method	Synthesis method
					Ethyl 2- (1- (4- (N- (4- (benzofuran-2-yl) thiazol-2-yl) thiophene-2-carboxamido) butyryl) piperidin-4-yl) acetate	566.4	4.24	C	Example 19
N- (4- (benzofuran-2-yl) thiazol-2-yl) -N- (4)- (4- (diethylamino) piperidin-1-yl) -4-oxobutyl) thiophene-2-carboxamide	551.5	3.18	C	Example 19
					1- (4- (N- (4- (benzofuran-2-yl) thiazole-2-yl) thiophene-2-carboxamido) butyryl) pyrrolidine-2-carboxamide	509.1	3.43	C	Example 19
Methyl 1- (4- (N- (4- (benzofuran-2-yl) thiazol-2-yl) thiophene-2-carboxamido) butyryl) pyrrolidine-2-carboxylate	524.3	3.98	C	Example 19
					N- (4- (benzofuran-2-yl) thiazol-2-yl) -N- (4-oxo-4- (3-oxopiperazin-1-yl) butyl) thiophene-2-carboxamide	495.1	3.34	C	Example 19
N- (4- (2-amino-2-oxoethylamino) -4-oxobutyl) -N- (4- (benzofuran-2-yl) thiazol-2-yl) thiophene-2-carboxamide	469.1	3.21	C	Practice ofExample 19
					1- (4- (N- (4- (benzofuran-2-yl) thiazol-2-yl) thiophene-2-carboxamido) butyryl) -N- (2-hydroxyethyl) piperidine-3-carboxamide	567.2	3.35	C	Example 19
1- (4- (N- (4- (benzofuran-2-yl) thiazol-2-yl) thiophene-2-carboxamido) butyryl) -N- (2-hydroxyethyl) piperidine-4-carboxamide	567.2	3.25	C	Example 19
					N- (4- (benzofuran-2-yl) thiazol-2-yl) -N- (4- (2- (methylsulfinyl) ethylamino) -4-oxobutyl) thiophene-2-carboxamide	502.3	3.24	C	Example 19

Name of Compound	LC/MSm/z[M+H]	HPLC retention time (min)	HPLC method	Synthesis method
					N- (4- (benzofuran-2-yl) thiazol-2-yl) -N- (4- ((2-hydroxyethyl) (pyridin-4-ylmethyl) amino) -4-oxobutyl) thiophene-2-carboxamide	547.1	2.98	C	Example 19
N- (4- (benzofuran-2-yl) thiazol-2-yl) -N- (4- (cyclohexyl (4-hydroxybutyl) amino) -4-oxobutyl) thiophene-2-carboxamide	566.4	4.25	C	Example 19
					N- (4- (benzofuran-2-yl) thiazol-2-yl) -N- (4- ((2-cyanoethyl) ((tetrahydrofuran-2-yl) methyl) amino) -4-oxobutyl) thiophene-2-carboxamide	549.1	4.02	C	Example 19
N- (4- (benzofuran-2-yl) thiazol-2-yl) -N- (4-oxo-4- (2- (pyridin-3-yl) pyrrolidin-1-yl) butyl) thiophene-2-carboxamide	543.1	3.21	C	Example 19
					N- (4- (benzofuran-2-yl) thiazol-2-yl) -N- (3- (1-hydroxypropan-2-ylamino) -3-oxopropyl) thiophene-2-carboxamide	456.3	3.34	C	Example 19
N- (4- (benzofuran-2-yl) thiazol-2-yl) -N- (3- (2-methoxyethylamino) -3-oxopropyl) thiophene-2-carboxamide	456.3	3.59	C	Example 19
					N- (4- (benzofuran-2-yl) thiazol-2-yl) -N- (3- (furan-3-ylmethyl-amino) -3-oxopropyl) thiophene-2-carboxamide	477.9	3.84	C	Example 19
Methyl 1- (3- (N- (4- (benzofuran-2-yl) thiazol-2-yl) thiophene-2-carboxamido) propionyl) pyrrolidine-2-carboxylate	510.3	3.95	C	Example 19

Name of Compound	LC/MSm/z[M+H]	HPLC retention time (min)	HPLC method	Synthesis method
					N- (4- (benzofuran-2-yl) thiazol-2-yl) -N- (3- (isoindolin-2-yl) -3-oxopropyl) thiophene-2-carboxamide	500.3	4.27	C	Example 19
N- (3- ((1, 4-dioxan-2-yl) methylamino) -3-oxopropyl) -N- (4- (benzofuran-2-yl) thiazol-2-yl) thiophene-2-carboxamide	498.3	3.53	C	Example 19
					N- (4- (benzofuran-2-yl) thiazol-2-yl) -N- (3- (cyclohexyl (4-hydroxybutyl) amino) -3-oxopropyl) thiophene-2-carboxamide	552.3	3.55	C	Example 19
N- (4- (benzofuran-2-yl) thiazol-2-yl) -N- (3- (methyl (pyridin-4-yl) amino) -3-oxopropyl) thiophene-2-carboxamide	489.1	3.20	C	Example 19
					1- (4- (N- (4- (benzofuran-2-yl) thiazol-2-yl) thiophene-2-carboxamido) butyryl) piperidine-3-carboxamide	523.5	3.47	C	Example 19
N- (4- (benzofuran-2-yl) thiazol-2-yl) -N- (4-oxo-4- (pyridin-2-ylmethyl-amino) butyl) thiophene-2-carboxamide	503.1	3.08	C	Example 19
					N- (4- (benzofuran-2-yl) thiazol-2-yl) -N- (4-oxo-4- (thiazolidin-3-yl) butyl) thiophene-2-carboxamide	484.3	4.03	C	Example 19
Tert-butyl 2- (4- (N- (4- (benzofuran-2-yl) thiazol-2-yl) thiophene-2-carboxamido) butyrylamino) ethylcarbamate	555.2	3.91	C	Example 19
					(S) -N- (4- (benzofuran-2-yl) thiazol-2-yl) -N- (4- (2- (hydroxymethyl) indolin-1-yl) -4-oxobutyl) thiophene-2-carboxamide	544.3	3.85	C	Example 19

Name of Compound	LC/MSm/z[M+H]	HPLC retention time (min)	HPLC method	Synthesis method
					N- (4- (benzofuran-2-yl) thiazol-2-yl) -N- (4- (isoindolin-2-yl) -4-oxobutyl) thiophen-2-yl-carboxamides	514.3	4.28	C	Example 19
N- (3-Acylaminopropyl) -N- (4- (benzofuran-2-yl) thiazol-2-yl) thiophene-2-carboxamide	426.3	3.50	B	Examples 20 and 21
					1-acetyl-N- (3- (N- (4- (benzofuran-2-yl) thiazol-2-yl) thiophene-2-carboxamido) propyl) piperidine-4-carboxamide	537.1	3.44	C	Examples 20 and 21
N- (4- (benzofuran-2-yl) thiazol-2-yl) -N- (3- (3- (piperidin-1-yl) propionylamino) propyl) thiophene-2-carboxamide	523.5	3.15	C	Examples 20 and 21
					N- (4- (benzofuran-2-yl) thiazol-2-yl) -N- (3- (4- (dimethylamino) butyrylamino) propyl) thiophene-2-carboxamide	497.5	3.04	C	Examples 20 and 21
N- (3- (N- (4- (benzofuran-2-yl) thiazol-2-yl) thiophene-2-carboxamido) propyl) isonicotinamide	489.1	3.12	C	Examples 20 and 21
					N- (3- (4-Acylaminobutylamino) propyl) -N- (4- (benzofuran-2-yl) thiazol-2-yl) thiophene-2-carboxamide	511.5	3.29	C	Examples 20 and 21
N- (4- (benzofuran-2-yl) thiazol-2-yl) -N- (3- (3-hydroxy-2- (hydroxymethyl) -2-methylpropionylamino) propyl) thiophene-2-carboxamide	500.3	3.30	C	Examples 20 and 21
					N- (4- (benzofuran-2-yl) thiazol-2-yl) -N- (3- (2- (2, 5-dioxoimidazolidin-4-yl) acetylamino) propyl) thiophene-2-carboxamide	524.3	3.57	C	Examples 20 and 21

Name of Compound	LC/MSm/z[M+H]	HPLC retention time (min)	HPLC method	Synthesis method
					N- (4- (benzofuran-2-yl) thiazol-2-yl) -N- (3- (3-morpholinopropionylamino) propyl) thiophene-2-carboxamide	525.1	3.03	C	Examples 20 and 21
N- (3- (N- (4- (benzofuran-2-yl) thiazol-2-yl) thiophene-2-carboxamido) propyl) -1, 5-dimethyl-1H-pyrazole-3-carboxamide	505.9	3.75	C	Examples 20 and 21
					N- (4- (benzofuran-2-yl) thiazol-2-yl) -N- (3- (2-morpholinoacetamido) propyl) thiophene-2-carboxamide	511.5	3.02	C	Examples 20 and 21
(S) -tert-butyl 1- (3- (N- (4- (benzofuran-2-yl) thiazol-2-yl) thiophene-2-carboxamido) propyl) pyrrolidine-2-carboxylic acid ester	538.3	3.53	C	Examples 22 and 23
					1- (3- (N- (4- (benzofuran-2-yl) thiazol-2-yl) thiophene-2-carboxamido) propyl) piperidine-3-carboxamide	495.1	3.02	C	Examples 22 and 23
Ethyl 1- (3- (N- (4- (benzofuran-2-yl) thiazol-2-yl) thiophene-2-carboxamido) propyl) piperidine-2-carboxylate	524.3	3.40	C	Examples 22 and 23
					N- (4- (benzofuran-2-yl) thiazol-2-yl) -N- (3- (3-hydroxypiperidin-1-yl) propyl) thiophene-2-carboxamide	468.3	3.03	C	Examples 22 and 23
N- (4- (benzofuran-2-yl) thiazol-2-yl) -N- (3- (4- (2- (2-hydroxyethoxy) ethyl) piperazin-1-yl) propyl) thiophene-2-carboxamide	541.1	273	C	Examples 22 and 23
					N- (4- (benzofuran-2-yl) thiazol-2-yl) -N- (3- (4- (2-hydroxyethyl) piperidin-1-yl) propyl) thiophene-2-carboxamide	496.3	3.04	C	Examples 22 and 23

Name of Compound	LC/MSm/z[M+H]	HPLC retention time (min)	HPLC method	Synthesis method
					N- (4- (benzofuran-2-yl) thiazol-2-yl) -N- (3- (4- (2-cyanoethyl) piperazin-1-yl) propyl) thiophene-2-carboxamide	505.9	3.11	C	Examples 22 and 23
N- (4- (benzofuran-2-yl) thiazol-2-yl) -N- (3- (4- (hydroxymethyl) piperidin-1-yl) propyl) thiophene-2-carboxamide	482.3	3.00	C	Examples 22 and 23
					N- (4- (benzofuran-2-yl) thiazol-2-yl) -N- (3- (3- (dimethylamino) pyrrolidin-1-yl) propyl) thiophene-2-carboxamide	481.1	2.73	C	Examples 22 and 23
Ethyl 1- (3- (N- (4- (benzofuran-2-yl) thiazol-2-yl) thiophene-2-carboxamido) propyl) piperidine-3-carboxylate	524.3	3.36	C	Examples 22 and 23
					N- (4- (benzofuran-2-yl) thiazol-2-yl) -N- (3- (4-hydroxypiperidin-1-yl) propyl) thiophene-2-carboxamide	468.3	3.01	C	Examples 22 and 23
N- (4- (benzofuran-2-yl) thiazol-2-yl) -N- (3- (3- (N-ethylacetamido) pyrrolidin-1-yl) propyl) thiophene-2-carboxamides	523.5	3.24	C	Examples 22 and 23
					N- (4- (benzofuran-2-yl) thiazol-2-yl) -N- (3- (3- (N-methylacetamido) pyrrolidin-1-yl) propyl) thiophene-2-carboxamide	509.1	3.10	C	Examples 22 and 23
Tert-butyl 1- (3- (N- (4- (benzofuran-2-yl) thiazol-2-yl) thiophene-2-carboxamido) propyl) pyrrolidin-3-ylcarbamate	553.2	3.44	C	Examples 22 and 23
					(S) -N- (4- (benzofuran-2-yl) thiazol-2-yl) -N- (3- (2- (methoxymethyl) pyrrolidin-1-yl) propyl) thiophene-2-carboxamide	482.3	3.28	C	Examples 22 and 23

Name of Compound	LC/MSm/z[M+H]	HPLC retention time (min)	HPLC method	Synthesis method
					N- (3- (3-acetamidopyrrolidin-1-yl) propyl) -N- (4- (benzofuran-2-yl) thiazol-2-yl) thiophene-2-carboxamide	495.1	2.99	C	Examples 22 and 23
Ethyl 4- (3- (N- (4- (benzofuran-2-yl) thiazol-2-yl) thiophene-2-carboxamido) propyl) piperazine-1-carboxylate	525.1	3.23	C	Examples 22 and 23
					N- (4- (benzofuran-2-yl) thiazol-2-yl) -N- (3- (4- (morpholine-4-carbonyl) piperazin-1-yl) propyl) thiophene-2-carboxamide	566.4	3.02	C	Examples 22 and 23
N- (4- (benzo)Furan-2-yl) thiazol-2-yl-N- (3- (4, 4-dihydroxypiperidin-1-yl) propyl) thiophene-2-carboxamide	484.3	2.95	C	Examples 22 and 23
					N- (4- (benzofuran-2-yl) thiazol-2-yl) -N- (3- (4- (tetrahydrofuran-2-carbonyl) piperazin-1-yl) propyl) thiophene-2-carboxamide	551.5	3.05	C	Examples 22 and 23
(R) -1- (3- (N- (4- (benzofuran-2-yl) thiazol-2-yl) thiophene-2-carboxamido) propyl) -N-methylpyrrolidine-2-carboxamide	495.1	3.12	C	Examples 22 and 23
					1- (3- (N- (4- (benzofuran-2-yl) thiazole-2-yl) thiophene-2-formamido) propyl) pyrrolidine-2-carboxamide	481.1	3.04	C	Examples 22 and 23
Methyl 1- (3- (N- (4- (benzofuran-2-yl) thiazol-2-yl) thiophene-2-carboxamido) propyl) pyrrolidine-2-carboxylate	496.3	3.26	C	Examples 22 and 23
					Methyl 1- (3- (N- (4- (benzofuran-2-yl) thiazol-2-yl) thiophene-2-carboxamido) propyl) piperidine-2-carboxylate	510.3	3.31	C	Examples 22 and 23

Name of Compound	LC/MSm/z[M+H]	HPLC retention time (min)	HPLC method	Synthesis method
					(S) -1- (3- (N- (4- (benzofuran-2-yl) thiazol-2-yl) thiophene-2-carboxamido) propyl) -N, N-dimethylpyrrolidine-2-carboxamide	509.1	3.20	C	Examples 22 and 23
N- (4- (benzofuran-2-yl) thiazol-2-yl) -N- (3- (2- (pyrrolidin-1-ylmethyl) piperidin-1-yl) propyl) thiophene-2-carboxamide	535.1	2.85	C	Examples 22 and 23
					N- (4- (benzofuran-2-yl) thiazol-2-yl) -N- (3- (3-oxopiperazin-1-yl) propyl) thiophene-2-carboxamide	467.1	2.91	C	Examples 22 and 23
1- (3- (N- (4- (benzofuran-2-yl) thiazol-2-yl) thiophene-2-carboxamido) propyl) piperidine-2-carboxamide	495.1	3.05	C	Examples 22 and 23
					Ethyl 2- (4- (3- (N- (4- (benzofuran-2-yl) thiazol-2-yl) thiophene-2-carboxamido) propyl) piperazin-1-yl) acetate	539.1	3.21	C	Examples 22 and 23
Tert-butyl 4- (3- (N- (4- (benzofuran-2-yl) thiazol-2-yl) thiophene-2-carboxamido) propyl) piperazine-1-carboxylate	553.2	3.43	C	Examples 22 and 23
					N- (4- (benzofuran-2-yl) thiazol-2-yl) -N- (3- (4-morpholinopiperidin-1-yl) propyl) thiophene-2-carboxamide	537.1	2.72	C	Examples 22 and 23
N- (4- (benzofuran-2-yl) thiazol-2-yl) -N- (3- (4- (2- (dimethylamino) ethyl) piperazin-1-yl) propyl) thiophene-2-carboxamide	524.3	2.71	C	Examples 22 and 23
					N- (4- (benzofuran-2-yl) thiazol-2-yl) -N- (3- (2- (hydroxymethyl) pyrrolidin-1-yl) propyl) thiophene-2-carboxamide	468.3	3.08	B	Examples 22 and 23

Name of Compound	LC/MSm/z[M+H]	HPLC retention time (min)	HPLC method	Synthesis method
					N- (4- (benzofuran-2-yl) thiazol-2-yl) -N- (3- (2- (2-hydroxyethyl) piperidin-1-yl) propyl) thiophene-2-carboxamide	496.3	3.14	B	Examples 22 and 23
N- (4- (benzofuran-2-yl) thiazol-2-yl) -N- (3- (3- (hydroxymethyl) piperidin-1-yl) propyl) thiophene-2-carboxamide	482.3	3.05	B	Examples 22 and 23
					N- (4- (benzofuran-2-yl) thiazol-2-yl) -N- (3- (2- (hydroxymethyl) piperidin-1-yl) propyl) thiophene-2-carboxamide	482.3	3.13	B	Examples 22 and 23
N- (4- (benzofuran-2-yl) thiazol-2-yl) -N- (3- (3-hydroxypyrrolidin-1-yl) propyl) thiophene-2-carboxamide	454.3	3.00	B	Examples 22 and 23
					(S) -N- (4- (benzofuran-2-yl) thiazol-2-yl) -N- (3- (2- (hydroxymethyl) pyrrolidin-1-yl) propyl) thiophene-2-carboxamide	468.3	3.09	B	Examples 22 and 23
N- (3- (4-acetylpiperazin-1-yl) propyl) -N- (4- (benzofuran-2-yl) thiazol-2-yl) thiophene-2-carboxamide	495.5	2.98	B	Examples 22 and 23
					1- (3- (N- (4- (benzofuran-2-yl) thiazol-2-yl) thiophene-2-carboxamido) propyl) -N, N-diethylpiperidine-3-carboxamide	551.5	3.39	B	Examples 22 and 23
N- (4- (benzofuran-2-yl) thiazol-2-yl) -N- (3- (4- (2-hydroxyethyl) piperazin-1-yl) propyl) thiophene-2-carboxamide	497.5	2.70	B	Examples 22 and 23
					N- (4- (benzofuran-2-yl) thiazol-2-yl) -N- (3- (4- (2-methoxyethyl) piperazin-1-yl) propyl) thiophene-2-carboxamide	511.5	2.82	B	Examples 22 and 23

Name of Compound	LC/MSm/z[M+H]	HPLC retention time (min)	HPLC method	Synthesis method
					N- (4- (benzofuran-2-yl) thiazol-2-yl) -N- (3- (3- (diethylamino) pyrrolidin-1-yl) propyl) thiophene-2-carboxamide	509.5	2.82	B	Examples 22 and 23
1- (3- (N- (4- (benzofuran-2-yl) thiazol-2-yl) thiophene-2-carboxamido) propyl) -N-methylpiperidine-4-carboxamide	509.1	2.93	C	Examples 22 and 23
					N- (4- (benzofuran-2-yl) thiazol-2-yl) -N- (3- (4- (diethylamino) piperidin-1-yl) propyl) thiophene-2-carboxamide	523.5	2.72	C	Examples 22 and 23
(R) -1- (3- (N- (4- (benzofuran-2-yl) thiazol-2-yl) thiophene-2-carboxamido) propyl) pyrrolidine-2-carboxylic acid	482.3	3.06	B	Examples 22 and 23
					1- (3- (N- (4- (benzofuran-2-yl) thiazol-2-yl) thiophene-2-carboxamido) propyl) piperidine-4-carboxamide	495.5	2.88	C	Examples 22 and 23
N- (4- (benzofuran-2-yl) thiazol-2-yl) -N- (3- (4- (2- (dimethylamino) -2-oxoethyl) piperazin-1-yl) propyl) thiophene-2-carboxamide	538.3	2.84	B	Examples 22 and 23
					N- (4- (benzofuran-2-yl) thiazol-2-yl) -N- (3- (4- (methylsulfonyl) piperazin-1-yl) propyl) thiophene-2-carboxamide	531.1	3.13	B	Examples 22 and 23

Example 25

Identification of Compounds

[0252] The following analytical HPLC conditions were used to identify the chemical products of the invention. MS ions were detected using a Sciex API-100 electrospray single quadrupole mass spectrometer with an HPLC system interface.

[0253] The method A comprises the following steps: phenomenex Chromolith SpeedRod RP-18e C18 analytical column (4.6 mm. times.50 mm); the flow rate is 1.5 mL/min; the injection volume is 15-20 mu L; mobile phase A: 100% water, 0.1% trifluoroacetic acid (TFA); a mobile phase B: 100% acetonitrile, 0.1% trifluoroacetic acid (TFA); gradient elution took 4.4min from 5% B to 100% B, stayed at 100% B for 1min, and then equilibrated to 5% B for 0.6min.

[0254] The method B comprises the following steps: phenomenex Chromolith SpeedRod RP-18e C18 analytical column (4.6 mm. times.50 mm); the flow rate is 1.5 mL/min; the injection volume is 15-20 mu L; mobile phase A: 100% water, 0.1% trifluoroacetic acid (TFA); a mobile phase B: 100% acetonitrile, 0.1% trifluoroacetic acid (TFA); gradient elution took 4.3min from 5% B to 100% B, stayed at 100% B for 1min, and then equilibrated to 5% B for 0.7min.

[0255] The method C comprises the following steps: phenomenex Chromolith SpeedRod RP-18e C18 analytical column (4.6 mm. times.50 mm); the flow rate is 1.5 mL/min; the injection volume is 15-20 mu L; mobile phase A: 100% water, 0.1% trifluoroacetic acid (TFA); a mobile phase B: 100% acetonitrile, 0.1% trifluoroacetic acid (TFA); gradient elution was from 5% B to 100% B over 4.2min, stopped at 100% B for 1min, and then equilibrated to 5% B over 0.8min.

[0256] The chemical product of the invention was purified using the following preparative HPLC method:

[0257] method X: YMC-Pack ODS-A C-18 column (30 mm. times.100 mm); the flow rate is 45 mL/min; the injection volume is 2 mL; mobile phase A: 100% water, 0.1% trifluoroacetic acid (TFA); a mobile phase B: 100% acetonitrile, 0.1% TFA; gradient elution was from 0% B to 90% B over 90min.

[0258] Method Y: YMC-Pack ODS-A C-18 column (30 mm. times.100 mm); the flow rate is 36 mL/min; the injection volume is 1.5-2.5 mL; mobile phase A: 100% water, 0.1% trifluoroacetic acid (TFA); a mobile phase B: 100% acetonitrile, 0.1% TFA; gradient elution was from 0% B to 70% B over 70min.

[0259] Method Z: phenomenex Synergi 4 μm Max-RP column (10 mm. times.50 mm); the flow rate is 6 mL/min; the injection volume is 100 mL; mobile phase A: 100% water, 0.1% trifluoroacetic acid (TFA); a mobile phase B: 100% acetonitrile, 0.1% trifluoroacetic acid (TFA); gradient elution was from 5% B to 100% B over 6min.

Example 26

HTS ATP-utilizing enzyme assay

[0260] The following procedures describe the preparation of a plate and reagents for an enzyme using ATP, e.g., HTS of protein kinase, according to an off-chip mobility-shift assay format. The following provides an HTS protocol for protein kinase HTS screening on Caliper HTS 250 microfluidics systems. The following parameters depend on the protein kinase used and can be determined by those skilled in the art as part of a typical assay development process. For example, the peptide substrates used can be identified from the current literature, by screening peptide libraries for potential protein kinase substrates, or by other available means accepted in the art.

[0261]The table below provides typical screening assay parameters suitable for the Caliper HTS 250 microfluidics system used to assay AKT 1. One skilled in the art can determine parameters for the determination of other protein kinases.

Reaction concentration
			Inhibitor concentration	10	μM
Enzyme concentration	0.9	nM
			Substrate/peptide concentration	1	μM
ATP	50	μM

Nature of reaction
			Volume of inhibitor	5	μL
Volume of enzyme	10	μL
			Volume of substrate	10	μL
Termination volume	45	μL
			Reaction time	3	h
Reaction temperature	20-25	℃

Sipper properties
			Initial delay	20	sec
Buffer	20	sec
			Sample (I)	0.2	sec
Final delay	120	sec

Dye pores
			Dye	0.2	sec

Script Property
			Electrode 1	-250	A device

Electrode 2	-2000	A device
			Electrode 3	-2000	A device
Electrode 4	-250	A device

Laser properties	Yes/no
			UV	Whether or not
Blue (B)	Is that
			Red wine	Whether or not

Data collection	Yes/no
			CCD1	Whether or not
CCD2	Is that
			CCD3	Whether or not

Inhibitor concentration
			Inhibitor (B): EDTA
100％	20	mM
			Inhibitor (B): staurosporine
50％	32	nM

Pressure driven flow
			Pressure of	-2	psi
Pressure of foundation	-2	psi

[0262]The reagents and buffers listed in the table below are generally available for development and human protein kinase HTS screening using the Caliper HTS 250 system.

Reagent	Name of reagent	Manufacturer(s)	Directory #	MW	Storage of
						4 sipperLABCHIP	FS266	Caliper Tech.Inc.	760077-0266	-	2-8℃
Enzyme	Aktl/PKB alpha, Activity	Upstate	14-276	-	-20℃
						Substrate	Peptide 2	BioPeptide	-	1528Da	-20℃
Control inhibitors	Staurosporine	Calbiochem	569397	466.5	20℃
						Buffer component	HEPES (free acid)	Calbiochem	391338	238.3	RT
	HEPES (Na salt)	Calbiochem	391333	260.3	RT
							DMSO	Sigma	D8418	-	RT
	Triton X-100	Sigma	T8787	-	RT
							BSA	Sigma	A8806	-	2-8℃
	DTT (Cleland's reagent)	Calbiochem	233153	154.2	2-8℃
							EDTA(0.5M)	Sigma	E7889	n/a	RT
	Coating agent 3	Caliper Tech.Inc.	760050	n/a	2-8℃
							6N HCl	VWR	JT5619-2	n/a	RT
	ATP disodium salt	Sigma	A7699	551.1	-20℃
							Na3VO4	Calbiochem	567540	183.9	-20℃
	Beta-glycerophosphate	Calbiochem	35675	306.1	-20℃
							MgCl2 6H2O	Sigma	M2670	203.3	RT

[0263] The following reagents were prepared using the aforementioned buffers.

[0264]The 2 XMaster buffer solution was prepared by combining 200mL of 1M HEPES, pH 7.5, 2mL of 10% Triton X-100, 20mL of 10% BSA and 778mL of H₂O。

[0265]2.5 Xenzyme buffer solution was prepared by combining 177.408mL of 2 Xmain buffer, 0.887mL of 1M DTT, 0.089mL of 100mM ATP, 8.870mL of 1M MgCl₂0.089mL100mM beta-glycerophosphate, 0.089mL100mM Na₃VO₄0.254mL of 62.8. mu.M enzyme and 167.13mL of H₂O。

[0266]2.5 Xsubstrate buffer solution was prepared by combining 177.408mL of 2 Xmain buffer, 0.887mL of 1mM peptide-X, and 176.521mL of H₂O。

[0267]1.55 Xstop buffer solution was prepared by combining 762.05mL of 2 Xmain buffer, 95.1mL of 0.5M EDTA, and 666.94mL of H₂O。

[0268]TCB buffer solution was prepared by combining 125mL of 2 Xmain buffer, 10mL of 0.5M EDTA, 6.25mL of 4% coating agent, 1.01mL of 100% DMSO, and 107.74mL of H₂O。

[0269] Dye Trough solutions (Dye Trough solution) were prepared as follows, combining 0.5. mu.L peptide-X and 2,999.5. mu.L 1 Xmain buffer.

[0270]1.06 Xassay buffer solution was prepared by combining 205.15mL of 2 Xmain buffer and 181.92mL of H₂O。

[0271] Assays for determining kinase inhibitory activity of the chemical products of the invention were performed using a Caliper HTS250 microfluidics device, Greiner U-bottom assay plate, Multidrop for transfer reagents and Biomek FX (AMNCBM03) software. First, 2.4 μ L of a 1mM test compound in 100% DMSO solution was added to the well of a Greiner U-shaped bottom plate. A single 24X 16 well Greiner U-shaped bottom plate may contain multiple test compounds. Next, 40. mu.L of 1.06 Xassay buffer was added to each well of the assay plate. Using Biomek FX, 10. mu.L of 0.5M EDTA, span 8, was added to the wells as a 100% control, and 2.4. mu.L of 100% DMSO, span 8, was added to the wells as a 0% control. Using Multidrop, 10. mu.L of 2.5 Xenzyme buffer followed by 10. mu.L of 2.5 Xsubstrate buffer was added to each well of the assay plate. The total reaction volume in each well was 25. mu.L, and the concentration of test compound was 10. mu.M. The assay plates were incubated at 20 ℃ to 22 ℃ for 2.5 hr. After the incubation period, 45 μ L of 1.55X stop buffer was added to each well of the assay plate using Multidrop to stop the reaction. The inhibition of ATP-utilizing enzymes, such as specific protein kinases, is determined by measuring the ratio of peptide substrate to phosphorylated product per well of the assay plate using the Caliper HTS250 system.

[0272]Compounds are considered active if they exhibit an activity towards a specific target ATP utilizing enzyme that is 3 σ greater than the average activity of the main inactive compound species towards the same target ATP utilizing enzyme. The use of a 3 σ statistical limit represents a conservative approach to determining the potential target hit rate. The 3 σ activity as well as the average population activity may be different for each target enzyme. This method predicts one million false positive rates from the in-control measurement process. If the activity of the compound against the primary target (e.g.inhibition%; IC)₅₀、K_i、EC₅₀Etc.) differ significantly from other targets within the error of the activity measurement, then these compounds are considered to exhibit selectivity between the primary target and one or more other targets.

[0273] Each of the chemical products in table 2 was tested for protein kinase inhibitory activity according to the definition of protein kinase inhibitory activity and bioassay described herein. For each of the exemplary compounds listed in table 2, the inhibitory activity for at least one protein kinase, as defined by the bioassays and protein kinase inhibitory activities described herein, is indicated. Also provided in table 2 are one or more human protein kinases for which the compounds exhibit selectivity as defined herein.

TABLE 2

Compound (I)	Activity of
		N- (4- (2, 5-di)Methoxyphenyl) thiazol-2-yl) -N- (3- (dimethylamino) propyl) acetamide	GSK-3-α
4- ((4- (4-methoxyphenyl) thiazol-2-yl) ((tetrahydrofuran-2-yl) methyl) amino) -4-oxobutanoic acid	DYRK2
		N- (3-morpholinopropyl) -N- (4-phenylthiazol-2-yl) acetamide	GSK-3-α
4- ((4- (2, 5-dimethoxyphenyl) thiazol-2-yl) (furan-2-ylmethyl) amino) -4-oxobutanoic acid	AURORA-AGSK-3-α
		4- (butyl (4- (2, 5-dimethoxyphenyl) thiazol-2-yl) amino) -4-oxobutanoic acid	AURORA-AGSK-3-α
N- (furan-2-ylmethyl) -N- (4- (4-methoxyphenyl) thiazol-2-yl) thiophene-2-carboxamide	AKT1
		N-ethyl-N- (4- (4-methoxyphenyl) thiazol-2-yl) propanamide	DYRK2
4- (Ethyl (4- (4-methoxyphenyl) thiazol-2-yl) amino) -4-oxobutanoic acid	DYRK2

Compound (I)	Activity of
		4- ((3, 4-Dimethoxyphenethyl) (4- (4-methoxyphenyl) thiazol-2-yl) amino) -4-oxobutanoic acid	DYRK2
N- (4- (4-methoxyphenyl) thiazol-2-yl) -N- ((tetrahydrofuran-2-yl) methyl) propanamide	DYRK2
		4- (benzyl (4- (4-methoxyphenyl) thiazol-2-yl) amino) -4-oxobutanoic acid	DYRK2
4- ((3, 4-Dimethoxyphenethyl) (4- (2, 5-dimethoxyphenyl) thiazol-2-yl) amino) -4-oxobutanoic acid	GSK-3-α
		4- ((furan-2-ylmethyl) (4- (4-methoxyphenyl) thiazol-2-yl) amino) -4-oxobutanoic acid	DYRK2
4- (benzyl (4- (2, 5-dimethoxyphenyl) thiazol-2-yl) amino) -4-oxobutanoic acid	AYRORA-A
		4- ((4- (4-methoxyphenyl) thiazol-2-yl) (3-methoxypropyl) amino) -4-oxobutanoic acid	DYRK2
4- ((2-methoxyethyl) (4- (4-methoxyphenyl) thiazol-2-yl) amino) -4-oxobutanoic acid	DYRK2
		4- (isobutyl (4- (4-methoxyphenyl) thiazol-2-yl) amino) -4-oxobutanoic acid	DYRK2AURORA-A
4- ((4- (4-methoxyphenyl) thiazol-2-yl) (methyl) amino) -4-oxobutanoic acid	DYRK2
		N- (3- (diethylamino) propyl) -N- (4- (4-methoxyphenyl) thiazol-2-yl) -2- (p-tolyloxy) acetamide	DYRK2
4- ((4- (4-methoxyphenyl) thiazol-2-yl) (phenethyl) amino) -4-oxobutanoic acid	DYRK2
		N- (2-methoxyethyl)) -N- (4- (4-methoxyphenyl) thiazol-2-yl) acetamide	DYRK2

Compound (I)	Activity of
		N- (4- (4-methoxyphenyl) thiazol-2-yl) -N-methylacetamide	DYRK2
N- (4- (4-methoxyphenyl) thiazol-2-yl) -N- (3-methoxypropyl) propanamide	DYRK2
		N- (4- (4-methoxyphenyl) thiazol-2-yl) -N- (3-morpholinopropyl) -2-phenoxyacetamide	DYRK2GSK-3-α
N- (4- (4-methoxyphenyl) thiazol-2-yl) -N- (3-morpholinopropyl) acetamide	DYRK2
		N- (4- (4-methoxyphenyl) thiazol-2-yl) -3, 3-dimethyl-N- (3-morpholinopropyl) butanamide	DYRK2
2- (2-chlorophenyl) -N- (4- (4-methoxyphenyl) thiazol-2-yl) -N- (3-morpholinopropyl) acetamide	BMX
		2- (3-chlorophenyl) -N- (4- (4-methoxyphenyl) thiazol-2-yl) -N- (3-morpholinopropyl) acetamide	DYRK2
N- (4- (2, 5-dimethoxyphenyl) thiazol-2-yl) -N- (3- (dimethylamino) propyl) benzamide	CASPASE-7CHEK2
		N- (3- (dimethylamino) propyl) -2-fluoro-N- (4-phenylthiazol-2-yl) benzamide	AKT1CHEK2
N- (3- (diethylamino) propyl) -N- (4-phenylthiazol-2-yl) furan-2-carboxamide	AKT1
		N- (4- (2, 5-dimethoxyphenyl) thiazol-2-yl) -N- (3- (dimethylamino) propyl) -2-fluorobenzamide	CHEK2AKT1
N- (4- (2, 5-dimethoxyphenyl) thiazol-2-yl) -N- (3- (dimethylamino) propyl) thiophene-2-carboxamide	CHEK2AKT1
		N- (3- (diethylamino) propyl) -N- (4-phenylthiazol-2-yl) thiophene-2-carboxamide	AKT1

Compound (I)	Activity of
		2-chloro-N- (3- (diethylamino) propyl) -N- (4- (2, 5-dimethoxyphenyl) thiazol-2-yl) benzamide	CHEK2
N- (3- (diethylamino) propyl) -N- (4- (2, 5-dimethoxyphenyl) thiazol-2-yl) furan-2-carboxamide	AKT1
		N- (3- (diethylamino) propyl) -N- (4- (4-methoxyphenyl) thiazole-2 -yl) benzamides	AKT1
N- (3- (diethylamino) propyl) -N- (4- (2, 5-dimethoxyphenyl) thiazol-2-yl) -2-fluorobenzamide	CHEK2AKT1
		N- (3- (diethylamino) propyl) -N- (4- (2, 5-dimethoxyphenyl) thiazol-2-yl) benzamide	AKT1
N- (3- (diethylamino) propyl) -N- (4- (2, 5-dimethoxyphenyl) thiazol-2-yl) thiophene-2-carboxamide	AKT1
		N- (4-phenylthiazol-2-yl) -N- (3- (pyrrolidin-1-yl) propyl) thiophene-2-carboxamide	AKT1
N- (4- (4-methoxyphenyl) thiazol-2-yl) -N- (3- (pyrrolidin-1-yl) propyl) benzamide	AKT1
		N- (4- (4-methoxyphenyl) thiazol-2-yl) -N- (3- (pyrrolidin-1-yl) propyl) thiophene-2-carboxamide	AKT1
N- (4- (4-methoxyphenyl) thiazol-2-yl) -N- (3- (pyrrolidin-1-yl) propyl) furan-2-carboxamide	AKT1
		N- (4- (2, 5-dimethoxyphenyl) thiazol-2-yl) -N- (3- (pyrrolidin-1-yl) propyl) benzamide	AKT1
N- (4- (2, 5-dimethoxyphenyl) thiazol-2-yl) -N- (3- (pyrrolidin-1-yl) propyl) thiophene-2-carboxamide	AKT1
		N- (4- (2, 5-dimethoxyphenyl) thiazol-2-yl) -N- (3- (pyrrolidin-1-yl) propyl) furan-2-carboxamide	AKT1
N- (4- (4-methoxyphenyl) thiazol-2-yl) -N- (3- (piperidin-1-yl) propyl) thiophene-2-carboxamide	AKT1

Compound (I)	Activity of
		N- (4- (2, 5-dimethoxyphenyl) thiazol-2-yl) -N- (3- (piperidin-1-yl) propyl) benzamide	AKT1
N- (4- (2, 5-dimethoxyphenyl) thiazol-2-yl) -N- (3- (piperidin-1-yl) propyl) thiophene-2-carboxamide	AKT1
		N- (4- (2, 5-dimethoxyphenyl) thiazol-2-yl) -N- (3- (piperidin-1-yl) propyl) furan-2-carboxamide	AKT1
N- (3- (azepan-1-yl) propyl) -N- (4-phenylthiazol-2-yl) benzamide	AKT1
		N- (3- (azepan-1-yl) propyl) -N- (4-phenylthiazol-2-yl) thiophene-2-carboxamide	AKT1
N- (3- (azepan-1-yl) propyl) -N- (4-phenylthiazol-2-yl) furan-2-carboxamide	AKT1
		N- (3- (azacyclic ring)Heptane-1-yl) propyl) -N- (4- (4-methoxyphenyl) thiazol-2-yl) benzamide	AKT1
N- (3- (azepan-1-yl) propyl) -N- (4- (4-methoxyphenyl) thiazol-2-yl) thiophene-2-carboxamide	AKT1
		N- (3- (azepan-1-yl) propyl) -N- (4- (4-methoxyphenyl) thiazol-2-yl) furan-2-carboxamide	AKT1
N- (3- (azepan-1-yl) propyl) -N- (4- (2, 5-dimethoxyphenyl) thiazol-2-yl) benzamide	AKT1
		N- (3- (azepan-1-yl) propyl) -N- (4- (2, 5-dimethoxyphenyl) thiazol-2-yl) thiophene-2-carboxamide	AKT1
N- (3- (azepan-1-yl) propyl) -N- (4- (2, 5-dimethoxyphenyl) thiazol-2-yl) furan-2-carboxamide	AKT1
		N- (3- (4-methylpiperazin-1-yl) propyl) -N- (4-phenylthiazol-2-yl) benzamide	AKT1
N- (3- (4-methylpiperazin-1-yl) propyl) -N- (4-phenylthiazol-2-yl) thiophene-2-carboxamide	AKT1CHEK2

Compound (I)	Activity of
		N- (3- (4-methylpiperazin-1-yl) propyl) -N- (4-phenylthiazol-2-yl) furan-2-carboxamide	AKT1
N- (4- (4-methoxyphenyl) thiazol-2-yl) -N- (3- (4-methylpiperazin-1-yl) propyl) benzamide	AKT1CHEK2
		N- (4- (4-methoxyphenyl) thiazol-2-yl) -N- (3- (4-methylpiperazin-1-yl) propyl) thiophene-2-carboxamide	AKT1INSR
N- (4- (4-methoxyphenyl) thiazol-2-yl) -N- (3- (4-methylpiperazine-1)-yl) propyl) furan-2-carboxamide	AKT1MAPKAPK-2CHEK2
		N- (4- (2, 5-dimethoxyphenyl) thiazol-2-yl) -N- (3- (4-methylpiperazin-1-yl) propyl) benzamide	AKT1
N- (4- (2, 5-dimethoxyphenyl) thiazol-2-yl) -N- (3- (4-methylpiperazin-1-yl) propyl) thiophene-2-carboxamide	AKT1
		N- (4- (2, 5-dimethoxyphenyl) thiazol-2-yl) -N- (3- (4-methylpiperazin-1-yl) propyl) furan-2-carboxamide	AKT1CHEK2
N- (4- (4-methoxyphenyl) thiazol-2-yl) -N- (3-morpholinopropyl) cyclohexanamide	AKT1
		N- (4- (4-methoxyphenyl) thiazol-2-yl) -N- (3-morpholinopropyl) cyclopent-1-enecarboxamide	AKT1
4-fluoro-N- (4- (4-methoxyphenyl) thiazol-2-yl) -N- (3-morpholinopropyl) benzamide	AKT1
		N- (4- (4-methoxyphenyl) thiazol-2-yl) -N- (3-morpholinopropyl) benzamide	AKT1
4-methyl-N- (3-morpholinopropyl) -N- (4-phenylthiazol-2-yl) benzamide	AKT1
		4-fluoro-N- (3-morpholinopropyl) -N- (4-phenylthiazol-2-yl) benzamide	AKT1
N- (3-morpholinopropyl) -N- (4-phenylthiazol-2-yl) benzamide	AKT1

Compound (I)	Activity of
		3-methyl-N- (3-morpholinopropyl) -N- (4-phenylthiazol-2-yl) benzamide	AKT1
4-chloro-N- (4- (4-methoxyphenyl) thiazol-2-yl) -N- (3-morpholinopropyl) benzamide	AKT1
		3-fluoro-N- (4- (4-methoxyphenyl) thiazol-2-yl) -N- (3-morpholinopropyl) benzamide	AKT1
N- (4- (4-methoxyphenyl) thiazol-2-yl) -3-methyl-N- (3-morpholinopropyl) benzamide	AKT1
		2-fluoro-N- (4- (4-methoxyphenyl) thiazol-2-yl) -N- (3-morpholinopropyl) benzamide	AKT1
N- (4- (4-methoxyphenyl) thiazol-2-yl) -4-methyl-N- (3-morpholinopropyl) benzamide	FLT-3
		2-cyano-N- (4- (4-methoxyphenyl) thiazol-2-yl) -N- (3-morpholinopropyl) benzamide	ZAP70
N- (3-morpholinopropyl) -N- (4-phenylthiazol-2-yl) furan-2-carboxamide	AKT1
		N- (4- (2, 5-dimethoxyphenyl) thiazol-2-yl) -N- (3-morpholinopropyl) furan-2-carboxamide	AKT1
N- (4- (4-methoxyphenyl) thiazol-2-yl) -N- (3-morpholinopropyl) furan-2-carboxamide	AKT1DYRK2
		N- (4- (4-methoxyphenyl) thiazol-2-yl) -5-methyl-N- (3-morpholinopropyl) furan-2-carboxamide	AKT1KIT
N- (4- (4-methoxyphenyl) thiazol-2-yl) -3-methyl-N- (3-morpholinopropyl) furan-2-carboxamide	AKT1
		N- (3-morpholinopropyl) -N- (4-phenylthiazol-2-yl) thiophene-2-carboxamide	AKT1
N- (4- (2, 5-dimethoxyphenyl) thiazol-2-yl) -N- (3-morpholinopropyl) thiophene-2-carboxamide	AKT1

Compound (I)	Activity of
		N- (4- (4-methoxyphenyl) thiazol-2-yl) -N- (3-morpholinopropyl) thiophene-2-carboxamide	AKT1
N- (4- (4-chlorophenyl) thiazol-2-yl) -N- (3-morpholinopropyl) thiophene-2-carboxamide	AKT1
		N- (3-morpholinopropyl) -N- (4-p-tolylthiazol-2-yl) thiophene-2-carboxamide	AKT1
N- (4- (2, 3-dihydrobenzo [ b ]][1，4]Dioxadien-6-yl) thiazol-2-yl) -N- (3-morpholinopropyl) thiophene-2-carboxamide	AKT1
		N- (4- (4-chloro-3-nitrophenyl) thiazol-2-yl) -N- (3-morpholinopropyl) thiophene-2-carboxamide	AKT1
N- (4- (2-methoxyphenyl) thiazol-2-yl) -N- (3-morpholinopropyl) thiophene-2-carboxamide	AKT1
		N- (4- (2, 4-dimethylphenyl) thiazol-2-yl) -N- (3-morpholinopropyl) thiophene-2-carboxamide	AKT1
N- (4- (4-cyanophenyl) thiazol-2-yl) -N- (3-morpholinopropyl) thiophene-2-carboxamide	AKT1
		Methyl 4- (2- (N- (3-morpholinopropyl) thiophene-2-carboxamido) thiazol-4-yl) benzoate	AKT1
N- (4- (4- (methylsulfonyl) phenyl) thiazol-2-yl) -N- (3-morpholinopropyl) thiophene-2-carboxamide	AKT1
		N- (4- (2, 4-dimethoxyphenyl) thiazol-2-yl) -N- (3-morpholinopropyl) thiophene-2-carboxamide	AKT1
N- (4- (benzofuran-3-yl) thiazol-2-yl) -N- (3-morpholinopropyl) thiophene-2-carboxylic acidAmines as pesticides	AKT1
		N- (4- (2-chlorophenyl) thiazol-2-yl) -N- (3-morpholinopropyl) thiophene-2-carboxamide	AKT1
N- (4- (3-chlorophenyl) thiazol-2-yl) -N- (3-morpholinopropyl) thiophene-2-carboxamide	AKT1

Compound (I)	Activity of
		N- (4- (benzo [ b ]]Thien-3-yl) thiazol-2-yl) -N- (3-morpholinopropyl) thiophene-2-carboxamide	AKT1
N- (3-morpholinopropyl) -N- (4- (pyridin-2-yl) thiazol-2-yl) thiophene-2-carboxamide	AKT1
		N- (3-morpholinopropan)Yl) -N- (4- (pyridin-3-Yl) Thiazol-2-Yl) thiophene-2-carboxamide	AKT1CDK 2/cyclin E
N- (3-morpholinopropyl) -N- (4- (pyridin-4-yl) thiazol-2-yl) thiophene-2-carboxamide	AKT1KIT
		N- (3-morpholinopropyl) -N- (4- (thien-2-yl) thiazol-2-yl) thiophene-2-carboxamide	AKT1
N- (4- (5-chlorothien-2-yl) thiazol-2-yl) -N- (3-morpholinopropyl) thiophene-2-carboxamide	AKT1
		N- (4- (5-chlorothien-2-yl) thiazol-2-yl) -N- (3-morpholinopropyl) thiophene-2-carboxamide	AKT1
N- (4- (3, 4-dichlorophenyl) thiazol-2-yl) -N- (3-morpholinopropyl) thiophene-2-carboxamide	AKT1
		N- (4- (4-fluorophenyl) thiazol-2-yl) -N- (3-morpholinopropyl) thiophene-2-carboxamide	AKT1
N- (4- (4- (difluoromethoxy) phenyl) thiazol-2-yl) -N- (3-morpholinopropyl) thiophene-2-carboxamide	AKT1
		N- (3-morpholinopropyl) -N- (4- (2- (trifluoromethyl) phenyl) thiazol-2-yl) thiophene-2-carboxamide	AKT1
N- (4- (2-fluorophenyl) thiazol-2-yl) -N- (3-morpholinopropyl) thiophene-2-carboxamide	AKT1
		N- (4- (3, 4-difluorophenyl) thiazol-2-yl) -N- (3-morpholinopropyl) thiophene-2-carboxamide	AKT1
N- (4- (3-bromophenyl) thiazol-2-yl) -N- (3-morpholinopropyl) thiophene-2-carboxamide	AKT1

Compound (I)	Activity of
		N- (3-morpholinopropyl) -N- (4- (4- (trifluoromethoxy) phenyl) thiazol-2-yl) thiophene-2-carboxamide	AKT1
N- (4- (3-fluorophenyl) thiazol-2-yl) -N- (3-morpholinopropyl) thiophene-2-carboxamide	AKT1
		N- (4- (3-methylbenzo [ b ]]Thien-2-yl) thiazol-2-yl) -N- (3-morpholinopropyl) thiophene-2-carboxamide	AKT1
N- (4- (3-cyanophenyl) thiazol-2-yl) -N- (3-morpholinopropyl) thiophene-2-carboxamide	AKT1GSK-3-αKIT
		N- (3-morpholinopropyl) -N- (4- (4-pentylphenyl) thiazol-2-yl) thiophene-2-carboxamide	AKT1
N- (4- (4- (diethylamino) phenyl) thiazol-2-yl) -N- (3-morpholinopropyl) thiophene-2-carboxamide	AKT1SYK
		N- (3-Morpholinopropyl) -N- (4- (4- (pyrrolidin-1-yl) phenyl) thiazol-2-yl) thiophene-2-carboxamides	AKT1
N- (4- (3, 4-dimethoxyphenyl) thiazol-2-yl) -N- (3-morpholinopropyl) thiophene-2-carboxamide	AKT1
		N- (4- (benzo [ d ])][1，3]Dioxolen-5-yl) thiazol-2-yl-N- (3-morpholinopropyl) thiophene-2-carboxamide	AKT1
N- (4- (benzo [ d ])]Thiazol-2-yl) thiazol-2-yl) -N- (3-morpholinopropyl) thiophene-2-carboxamide	AKT1
		N- (4- (3-methoxyphenyl) thiazol-2-yl) -N- (3-morpholinopropyl) thiophene-2-carboxamide	AKT1
N- (3-morpholinopropyl) -N- (4- (2-nitrophenyl) thiazol-2-yl) thiophene-2-carboxamide	AKT1
		N- (3-morpholinopropyl) -N- (4- (naphthalen-2-yl) thiazol-2-yl) thiophene-2-carboxamide	AKT1
N- (4- (benzofuran-2-yl) thiazol-2-yl) -N- (3-morpholinopropyl) thiophene-2-carboxamide	AKT1

Compound (I)	Activity of
		N- (4- (4-morpholinophenyl) thiazol-2-yl) -N- (3-morpholinopropyl) thiophene-2-carboxamide	AKT1
N- (4- (3, 4-dihydro-2H-benzo [ b ]][1，4]Dioxa * -7-yl) thiazol-2-yl) -N- (3-morpholinopropyl) thiophene-2-carboxamide	AKT1KIT
		N- (4- (2-chloropyridin-4-yl) thiazol-2-yl) -N- (3-morpholinopropyl) thiophene-2-carboxamide	AKT1KIT
N- (4- (4-methoxyphenyl) thiazol-2-yl) -3-methyl-N- (3-morpholinopropyl) thiophene-2-carboxamide	AKT1
		2, 5-dichloro-N- (4- (4-methoxyphenyl) thiazol-2-yl) -N- (3-morpholinopropyl) thiophene-3-carboxamide	CDK2
3-bromo-N- (4- (4-methoxyphenyl) thiazol-2-yl) -N- (3-morpholinopropyl) thiophene-2-carboxamide	AKT1ZAP70
		N- (4- (4-methoxyphenyl) thiazol-2-yl) -N- (3-morpholinopropyl) -5-nitrothiophene-2-carboxamide	ZAP70KITFLT-3
5-chloro-N- (4- (4-methoxyphenyl) thiazol-2-yl) -N- (3-morpholinopropyl) thiophene-2-carboxamide	AKT1
		5-acetyl-N- (4- (4-methoxyphenyl) thiazol-2-yl) -N- (3-morpholinopropyl) thiophene-2-carboxamide	ZAP70
5-bromo-N- (4- (4-methoxyphenyl) thiazol-2-yl) -N- (3-morpholinopropyl) thiophene-2-carboxamide	AKT1ZAP70
		N- (4- (4-methoxyphenyl) thiazol-2-yl) -5- (methylthio) -N-, (methylthio)3-morpholinopropyl) thiophene-2-carboxamide	KITZAP70
N- (3-morpholinopropyl) -N- (4- (3- (trifluoromethyl) phenyl) thiazol-2-yl) thiophene-2-carboxamide	AKT1
		N- (4- (4-methoxyphenyl) thiazol-2-yl) -1-methyl-N- (3-morpholinopropyl) -1H-pyrrole-2-carboxamide	AKT1

Compound (I)	Activity of
		N- (4- (4-methoxyphenyl) thiazol-2-yl) -N- (3-morpholinopropyl) isoxazole-5-carboxamide	AKT1AURORA-A
N- (4- (4-methoxyphenyl) thiazol-2-yl) -3, 5-dimethyl-N- (3-morpholinopropyl) isoxazole-4-carboxamide	ZAP70KIT
		N- (4- (4-methoxyphenyl) thiazol-2-yl) -4-methyl-N- (3-morpholinopropyl) -1, 2, 3-thiadiazole-5-carboxamide	KITZAP70PDGFR-αFLT-3DYRK2
N- (4- (4-methoxyphenyl) thiazol-2-yl) -2, 4-dimethyl-N- (3-morpholinopropyl) thiazole-5-carboxamide	PDK1
		4-chloro-N- (4- (4-methoxyphenyl) thiazol-2-yl) -N- (3-morpholinopropyl) picolinamide	AKT1
N- (4- (4-methoxyphenyl) thiazol-2-yl) -3-methyl-N- (3-morpholinopropyl) isoxazole-4-carboxamide	ZAP70DYRK2
		6-chloro-N- (4- (4-methoxyphenyl) thiazol-2-yl) -N- (3-morpholinopropyl) picolinamide	ZAP70AKT1
N- (4- (4-methoxyphenyl) thiazol-2-yl) -1-methyl-N- (3-morpholinopropyl) -1H-imidazole-2-carboxamide	AKT1
		4, 5-dichloro-N- (4- (4-methoxyphenyl) thiazol-2-yl)) -N- (3-morpholinopropyl) isothiazole-3-carboxamide	ZAP70
N- (4- (4-methoxyphenyl) thiazol-2-yl) -1, 2, 5-trimethyl-N- (3-morpholinopropyl) -1H-pyrrole-3-carboxamide	CDK 2/cyclin E
		Ethyl 2- (N- (3-morpholinopropyl) thiophene-2-carboxamido) thiazole-4-carboxylate	AKT1
Ethyl 3-methyl-3- (2- (N- (3-morpholinopropyl) thiophene-2-carboxamido) thiazol-4-yl) butanoate	AKT1
		N- (4- (biphenyl-4-yl) thiazol-2-yl) -N- (3-morpholinopropyl) thiophene-2-carboxamide	AKT1

Compound (I)	Activity of
		N- (4- (5-methyl-1-phenyl-1H-pyrazol-4-yl) thiazol-2-yl) -N- (3-morpholinopropyl) thiophene-2-carboxamide	AKT1
N- (4- (2, 4-dichlorophenyl) thiazol-2-yl) -N- (3-morpholinopropyl) thiophene-2-carboxamide	AKT1
		3- (2- (N- (3-morpholinopropyl) thiophene-2-carboxamido) thiazol-4-yl) benzoic acid	AKT1
N- (3-Morpholinopropyl) -N- (4- (3-oxo-3, 4-dihydro-2H-benzo [ b ]][1，4]Oxazin-6-yl) thiazol-2-yl) thiophene-2-carboxamide	AKT1
		N- (3-morpholinopropyl) -N- (4- (3-phenylisoxazol-5-yl) thiazol-2-yl) thiophene-2-carboxamide	AKT1
N- (3-morpholinopropyl) -N- (4- (5- (pyridin-2-yl) thiophen-2-yl) thiazol-2-yl) thiophene-2-carboxamide	AKT1
		N- (4 ' -methyl-2 ' - (pyrazin-2-yl) -4, 5 ' -bithiazole-2-yl) -N- (3-morpholinopropyl) thiophene-2-carboxamide	AKT1
2- (5- (2- (N- (3-morpholinopropyl) thiophene-2-carboxamido) thiazol-4-yl) thiophen-2-yl) acetic acid	AKT1
		N- (4- (4-chloro-3-methylphenyl) thiazol-2-yl) -N- (3-morpholinopropyl) thiophene-2-carboxamide	AKT1
N- (4- (3, 4-dimethoxyphenyl) thiazol-2-yl) -N- (3-morpholinopropyl) benzamide	AKT1
		N- (4- (3, 4-Dimethoxyphenyl) thiazol-2-yl) -N- (3-morpholinopropyl) furan-2-carboxamide	AKT1
N- (4- (benzofuran-2-yl) thiazol-2-yl) -N- (3-morpholinopropyl) furan-2-carboxamide	AKT1
		N- (4- (benzofuran-2-yl) thiazol-2-yl) -N- (3-morpholinopropyl) nicotinamide	AKT1
N- (4- (3, 4-Dimethoxyphenyl) thiazol-2-yl) -N- (3-morpholinopropyl) cyclopentanecarboxamide	AKT1

Compound (I)	Activity of
		N- (4- (3, 4-Dimethoxyphenyl) thiazol-2-yl) -N- (3-morpholinopropyl) cyclobutanecarboxamide	AKT1
N- (4- (benzofuran-2-yl) thiazol-2-yl) -N- (3-morpholinopropyl) cyclobutanecarboxamide	AKT1
		N- (4- (3, 4-Dimethoxyphenyl) thiazol-2-yl) -N- (3-morpholinopropyl) picolinamide	AKT1
N- (4- (benzofuran-2-yl) thiazol-2-yl) -N- (3-morpholinopropyl) picolinamide	AKT1
		N- (4- (3- (4-chlorophenyl) isoxazol-5-yl) thiazol-2-yl) -N- (3-morpholinopropyl) thiophene-2-carboxamide	AKT1
N- (3-morpholinopropyl) -N- (4- (3-phenylisoxazol-5-yl) thiazol-2-yl) furan-2-carboxamide	AKT1
		1-methyl-N- (3-morpholinopropyl) -N- (4- (3-phenylisoxazol-5-yl) thiazol-2-yl) -1H-pyrrole-2-carboxamide	AKT1
4- (2- (N- (3-morpholinopropyl) thiophene-2-carboxamido) thiazol-4-yl) benzoic acid	AKT1
		N- (3-morpholinopropyl) -N- (4- (trifluoromethyl) thiazol-2-yl) thiophene-2-carboxamide	AKT1
Ethyl 5- (2- (N- (3-morpholinopropyl) thiophene-2-carboxamido) thiazol-4-yl) isoxazole-3-carboxylic acid ester	AKT1
		2- (N- (3-morpholinopropan)Yl) thiophene-2-carboxamido) -N- (1, 3, 4-thiadiazol-2-yl) thiazole-4-carboxamide	AKT1
2- (N- (3-morpholinopropyl) thiophene-2-carboxamido) -N- (thiazol-2-yl) thiazole-4-carboxamide	AKT1
		N- (3-methoxyphenyl) -2- (N- (3-morpholinopropyl) thiophene-2-carboxamido) thiazole-4-carboxamide	AKT1
N- (3-methoxybenzyl) -2- (N- (3-morpholinopropyl) thiophene-2-carboxamido) thiazole-4-carboxamide	AKT1

Compound (I)	Activity of
		N- (3-chlorobenzyl) -2- (N- (3-morpholinopropyl) thiophene-2-carboxamido) thiazole-4-carboxamide	AKT1
N- (2, 3-dihydrobenzo [ b ]][1，4]Dioxadien-6-yl) -2- (N- (3-morpholinopropyl) thiophene-2-carboxamido) thiazole-4-carboxamide	AKT1
		N- (5-Ethyl-1, 3, 4-thiadiazol-2-yl) -2- (N- (3-morpholinopropyl) thiophene-2-carboxamido) thiazole-4-carboxamide	AKT1
N- (benzo [ d ]]Thiazol-6-yl) -2- (N- (3-morpholinopropyl) thiophene-2-carboxamido) thiazole-4-carboxamide	AKT1
		N- (3-carbamoylphenyl) -2- (N- (3-morpholinopropyl) thiophene-2-carboxamido) thiazole-4-carboxamide	AKT1
Ethyl 2- (2- (2- (N- (3-morpholinopropyl) thiophene-2-carboxamido) thiazole-4-carboxamido) thiazol-4-yl) acetate	AKT1
		N- (3- (methylsulfonylamino) phenyl) -2- (N- (3-morpholinopropyl) thiophene-2-carboxamido) thiazole-4-carboxamide	AKT1
N- (4- (benzofuran-2-yl) thiazol-2-yl) -N- (3- (2-oxopyrrolidin-1-yl) propyl) furan-2-carboxamide	AKT1
		N- (4- (benzofuran-2-yl) thiazol-2-yl) -N- (3- (2-oxopyrrolidin-1-yl) propyl) thiophene-2-carboxamide	AKT1
N- (4- (benzofuran-2-yl) thiazol-2-yl) -1-methyl-N- (3- (2-oxopyrrolidin-1-yl) propyl) -1H-pyrrole-2-carboxamide	AKT1
		N- (3- (2-oxopyrrolidin-1-yl) propyl) -N- (4- (3-phenylisoxazol-5-yl) thiazol-2-yl) furan-2-carboxamide	AKT1
N- (3- (2-oxopyrrolidin-1-yl) propyl) -N- (4- (3-phenylisoxazol-5-yl) thiazol-2-yl) thiophene-2-carboxamide	AKT1

Compound (I)	Activity of
		1-methyl-N- (3- (2-oxopyrrolidin-1-yl) propyl) -N- (4- (3-phenylisoxazol-5-yl) thiazol-2-yl) -1H-pyrrole-2-carboxamide	AKT1
N- (3- (4-methylpiperazin-1-yl) propyl) -N- (4- (3-phenylisoxazol-5-yl) thiazol-2-yl) furan-2-carboxamide	AKT1
		N- (4-morpholinobutyl) -N- (4- (3-phenylisoxazol-5-yl) thiazol-2-yl) furan-2-carboxamide	AKT1
N- (4-morpholinobutyl) -N- (4- (3-phenylisoxazol-5-yl) thiazol-2-yl) thiophene-2-carboxamide	AKT1
		N- (3- (diethylamino) propyl) -N- (4- (3, 4-dimethoxyphenyl) thiazol-2-yl) thiophene-2-carboxamide	AKT1
N- (4- (3, 4-dimethoxyphenyl) thiazol-2-yl) -N- (3- (2-oxopyrrolidin-1-yl) propyl) thiophene-2-carboxamide	AKT1
		N- (4- (3, 4-dimethoxyphenyl) thiazol-2-yl) -N- (3- (4-methylpiperazin-1-yl) propyl) thiophene-2-carboxamide	AKT1
N- (4- (3, 4-dimethoxyphenyl) thiazol-2-yl) -N- (3- (piperidin-1-yl) propyl) thiophene-2-carboxamide	AKT1
		N- (4- (3, 4-dimethoxyphenyl) thiazol-2-yl) -N- (5-morpholinopentyl) thiophene-2-carboxamide	AKT1
N- (4- (3, 4-dimethoxyphenyl) thiazol-2-yl) -N- (2-morpholinoethyl) thiophene-2-carboxamide	AKT1
		N- (4- (3, 4-dimethoxyphenyl) thiazol-2-yl) -N- (3-phenylpropyl) thiophene-2-carboxamide	AKT1
N- (4- (benzofuran-2-yl) thiazol-2-yl) -N- (3- (diethylamino) propyl) thiophene-2-carboxamide	AKT1
		N- (3- (1H-imidazol-1-yl) propyl) -N- (4- (benzofuran)-2-yl) thiazol-2-yl) thiophene-2-carboxamide	AKT1
N- (4- (benzofuran-2-yl) thiazol-2-yl) -N- (3- (4-methylpiperazin-1-yl) propyl) thiophene-2-carboxamide	AKT1

Compound (I)	Activity of
		N- (4- (benzofuran-2-yl) thiazol-2-yl) -N- (3- (piperidin-1-yl) propyl) thiophene-2-carboxamide	AKT1
N- (4- (benzofuran-2-yl) thiazol-2-yl) -N- (4-morpholinobutyl) thiophene-2-carboxamide	AKT1
		N- (4- (benzofuran-2-yl) thiazol-2-yl) -N- (5-morpholinopentyl) thiophene-2-carboxamide	AKT1
N- (4- (benzofuran-2-yl) thiazol-2-yl) -N- (3-phenylpropyl) thiophene-2-carboxamide	AKT1
		N- (4- (benzofuran-2-yl) thiazol-2-yl) -N-propylthiophene-2-carboxamide	AKT1
N- (4- (5-methylthiophen-2-yl) thiazol-2-yl) -N- (3-morpholinopropyl) thiophene-2-carboxamide	AKT1
		N- (4- (6-methoxypyridin-3-yl) thiazol-2-yl) -N- (3-morpholinopropyl) thiophene-2-carboxamide	AKT1
N- (4- (2, 6-Dimethoxypyridin-3-yl) thiazol-2-yl) -N- (3-morpholinopropyl) thiophene-2-carboxamide	AKT1
		N- (4-Cyclopentylthiazol-2-yl) -N- (3-morpholinopropyl) thiophene-2-carboxamide	AKT1
N- (4-Cyclohexylthiazol-2-yl) -N- (3-morpholinopropyl) thiophene-2-carboxamide	AKT1
		Methyl 6- (2- (N- (3-morpholinopropyl) thiophene-2-carboxamido) thiazol-4-yl) nicotinate	AKT1
N- (4- (1H-indol-2-yl) thiazol-2-yl) -N- (3-morpholinopropyl) thiophene-2-carboxamide	AKT1
		N- (4- (7-methoxybenzofuran-2-yl) thiazol-2-yl) -N- (3-morpholinopropyl) thiophene-2-carboxamide	AKT1
N- (4- (5-methoxybenzofuran-2-yl) thiazol-2-yl) -N- (3-morpholinopropyl) thiophene-2-carboxamide	AKT1

Compound (I)	Activity of
		N- (3-morpholinopropyl)) -N- (4- (5-nitrobenzofuran-2-yl) thiazol-2-yl) thiophene-2-carboxamide	AKT1
N- (4- (4- (2-hydroxyethylcarbamoyl) phenyl) thiazol-2-yl) -N- (3-morpholinopropyl) thiophene-2-carboxamide	AKT1
		N- (4- (4- (2-morpholinoethylcarbamoyl) phenyl) thiazol-2-yl) -N- (3-morpholinopropyl) thiophene-2-carboxamide	AKT1
N- (4- (4- (methylcarbamoyl) phenyl) thiazol-2-yl) -N- (3-morpholinopropyl) thiophene-2-carboxamide	AKT1
		N- (4- (4- (2- (dimethylamino) ethylcarbamoyl) phenyl) thiazol-2-yl) -N- (3-morpholinopropyl) thiophene-2-carboxamide	AKT1
N- (4- (4- (3- (dimethylamino) propylcarbamoyl) phenyl) thiazol-2-yl) -N- (3-morpholinopropyl) thiophene-2-carboxamide	AKT1
		N- (4- (4- (3-hydroxypropylcarbamoyl) phenyl) thiazol-2-yl) -N- (3-morpholinopropyl) thiophene-2-carboxamide	AKT1
N- (4- (4-carbamoylphenyl) thiazol-2-yl) -N- (3-morpholinopropyl) thiophene-2-carboxamide	AKT1
		N- (4- (4- (dimethylcarbamoyl) phenyl) thiazol-2-yl) -N- (3-morpholinopropyl) thiophene-2-carboxamide	AKT1
2- (4- (2- (N- (3-morpholinopropyl) thiophene-2-carboxamido) thiazol-4-yl) benzoylamino) acetic acid	AKT1
		N- (4- (4- (4-methylpiperazine-1-carbonyl) phenyl) thiazol-2-yl) -N- (3-morpholinopropyl) thiophene-2-carboxamide	AKT1
N- (4- (4- (morpholine-4-carbonyl) phenyl) thiazol-2-yl) -N- (3-morpholinopropyl) thiophene-2-carboxamide	AKT1
		2- (3- (2- (N- (3-morpholinopropyl) thiophene-2-carboxamido) thiazol-4-yl) phenoxy) acetic acid	AKT1

Compound (I)	Activity of
		3- (3- (2- (N- (3-morpholinopropyl) thiophene-2-carboxamido) thiazol-4-yl) phenoxy) propanoic acid	AKT1
2- (4- (2- (N- (3-morpholinopropyl) thiophene-2-carboxamido) thiazol-4-yl) phenoxy) acetic acid	AKT1
		3- (4- (2- (N- (3-morpholinopropyl) thiophene-2-carboxamido) thiazol-4-yl) phenoxy) propanoic acid	AKT1
N- (4- (3- (3- (dimethylamino) propoxy) phenyl) thiazol-2-yl) -N- (3-morpholinopropyl) thiophene-2-carboxamide	AKT1
		N- (4- (3- (2- (dimethylamino) ethoxy) phenyl) thiazol-2-yl) -N- (3-morpholinopropyl) thiophene-2-carboxamide	AKT1
N- (4- (4- (3- (dimethylamino) propoxy) phenyl) thiazol-2-yl) -N- (3-morpholinopropyl) thiophene-2-carboxamide	AKT1
		N- (4- (4- (2- (dimethylamino) ethoxy) phenyl) thiazol-2-yl) -N- (3-morpholinopropyl) thiophene-2-carboxamide	AKT1
N- (4- (benzofuran-2-yl) thiazol-2-yl) -N- (3- (2-hydroxyethylamino) -3-oxopropyl) thiophene-2-carboxamide	AKT1
		N- (4- (benzofuran-2-yl) thiazol-2-yl) -N- (3- (2- (hydroxymethyl) pyrrolidin-1-yl) -3-oxopropyl) thiophene-2-carboxamide	AKT1
N- (4- (benzofuran-2-yl) thiazol-2-yl) -N- (3- (2- (dimethylamino) ethylamino) -3-oxopropyl) thiophene-2-carboxamide	AKT1
		N- (4- (benzofuran-2-yl) thiazol-2-yl) -N- (3- (3-hydroxypiperidin-1-yl) -3-oxopropyl) thiophene-2-carboxamide	AKT1
N- (4- (benzofuran-2-yl) thiazol-2-yl) -N- (3- ((2-hydroxyethyl) (methyl) amino) -3-oxopropyl) thiophene-2-carboxamide	AKT1

Compound (I)	Activity of
		N- (4- (benzofuran-2-yl) thiazol-2-yl) -N- (3- (bis (2-hydroxyethyl) amino) -3-oxopropyl) thiophene-2-carboxamide	AKT1
N- (4- (benzofuran-2-yl) thiazol-2-yl) -N- (3-oxo-3- (piperazin-1-yl) propyl) thiophene-2-carboxamide	AKT1
		N- (4- (benzofuran-2-yl) thiazol-2-yl) -N- (3- ((2- (dimethylamino) ethyl) (methyl) amino) -3-oxopropyl) thiophene-2-carboxamide	AKT1
N-(4- (benzofuran-2-yl) thiazol-2-yl) -N- (3- (methyl (2- (methylamino) ethyl) amino) -3-oxopropyl) thiophene-2-carboxamide	AKT1
		N- (4- (benzofuran-2-yl) thiazol-2-yl) -N- (3- (3-hydroxypyrrolidin-1-yl) -3-oxopropyl) thiophene-2-carboxamide	AKT1
N- (4- (benzofuran-2-yl) thiazol-2-yl) -N- (3- (3- (dimethylamino) pyrrolidin-1-yl) -3-oxopropyl) thiophene-2-carboxamide	AKT1
		N- (4- (benzofuran-2-yl) thiazol-2-yl) -N- (3- ((2, 3-dihydroxypropyl) (methyl) amino) -3-oxopropyl) thiophene-2-carboxamide	AKT1
Methyl 2- (3- (N- (4- (benzofuran-2-yl) thiazole-2-yl) thiophene-2-formamido) propionylamino) acetate	AKT1
		1- (3- (N- (4- (benzofuran-2-yl) thiazol-2-yl) thiophene-2-carboxamido) propionyl) piperidine-3-carboxamide	AKT1
N- (4- (benzofuran-2-yl) thiazol-2-yl) -N- (3-oxo-3- (thiazolidin-3-yl)) Propyl) thiophene-2-carboxamide	AKT1
		N- (4- (benzofuran-2-yl) thiazol-2-yl) -N- (3-morpholino-3-oxopropyl) thiophene-2-carboxamide	AKT1

Compound (I)	Activity of
		N- (4- (benzofuran-2-yl) thiazol-2-yl) -N- (3- ((2-cyanoethyl) (methyl) amino) -3-oxopropyl) thiophene-2-carboxamide	AKT1
N- (4- (benzofuran-2-yl) thiazol-2-yl) -N- (3- (3- (hydroxymethyl) piperidin-1-yl) -3-oxopropyl) thiophene-2-carboxamide	AKT1
		1- (3- (N- (4- (benzofuran-2-yl) thiazol-2-yl) thiophene-2-carboxamido) propionyl) piperidine-3-carboxylic acid	AKT1
N- (3- (3-Acylaminopyrrolidin-1-yl) -3-oxopropyl) -N- (4- (benzofuran-2-yl) thiazol-2-yl) thiophene-2-carboxamide	AKT1
		1- (3- (N- (4- (benzofuran-2-yl) thiazol-2-yl) thiophene-2-carboxamido) propionyl) pyrrolidine-2-carboxamide	AKT1
N- (4- (benzofuran-2-yl) thiazol-2-yl) -N- (3-oxo-3- (3-oxopiperazin-1-yl) propyl) thiophene-2-carboxamide	AKT1
		1- (3- (N- (4- (benzofuran-2-yl) thiazol-2-yl) thiophene-2-carboxamido) propionyl) piperidine-2-carboxamide	AKT1
N- (4- (benzofuran-2-yl) thiazol-2-yl) -N- (3-oxo-3- (2-phenoxyethylamino) propyl) thiophene-2-carboxamide	AKT1
		1- (3- (N- (4- (benzofuran-2-yl) thiazol-2-yl) thiophene-2-carboxamido) propionyl) -N- (2-hydroxyethyl) piperidine-3-carboxamide	AKT1
N- (4- (benzofuran-2-yl) thiazol-2-yl) -N- (3- (isobutyl (1, 1-dioxo-tetrahydrothiophen-3-yl) amino) -3-oxopropyl) thiophene-2-carboxamide	AKT1

Compound (I)	Activity of
		N- (4- (benzofuran-2-yl) thiazol-2-yl) -N- (4- (4- (2- (dimethylamino) ethyl) piperazin-1-yl) -4-oxobutyl) thiophene-2-carboxamide	AKT1
N- (4- (benzofuran-2-yl) thiazol-2-yl) -N- (4- ((2, 3-dihydroxypropyl) (methyl) amino) -4-oxobutyl) thiophene-2-carboxamide	AKT1
		Methyl 2- (4- (N- (4- (benzofuran-2-yl) thiazole-2-yl) thiophene-2-formamido) butyrylamino) acetate	AKT1
N- (4- (benzofuran-2-yl) thiazol-2-yl) -N- (4- ((5-methylpyrazin-2-yl) methylamino) -4-oxobutyl) thiophene-2-carboxamide	AKT1
		N- (4- (benzofuran-2-yl) thiazol-2-yl) -N- (4- (1-hydroxypropan-2-ylamino) -4-oxobutyl) thiophene-2-carboxamide	AKT1
N- (4- (benzofuran-2-yl) thiazol-2-yl) -N- (4-oxo-4- (piperidin-1-yl) butyl) thiophene-2-carboxamide	AKT1
		1- (4- (N- (4- (benzofuran-2-yl) thiazol-2-yl) thiophene-2-carboxamido) butyryl) piperidine-4-carboxamide	AKT1
N- (4- (benzofuran-2-yl) thiazol-2-yl) -N- (4- ((2-hydroxyethyl) (phenyl) amino) -4-oxobutyl) thiophene-2-carboxamide	AKT1
		N- (4- (benzofuran-2-yl) thiazol-2-yl) -N- (4-oxo-4- (2- (pyridin-4-yl) ethylamino) butyl) thiophene-2-carboxamide	AKT1
Tert-butyl 4- (4- (N- (4- (benzofuran-2-yl) thiazole-2)-yl) thiophene-2-carboxamido) butyryl) piperazine-1-carboxylate	AKT1

Compound (I)	Activity of
		N- (4- (benzofuran-2-yl) thiazol-2-yl) -N- (4-oxo-4- (pyridin-3-ylmethyl-amino) butyl) thiophene-2-carboxamide	AKT1
N- (4- (benzofuran-2-yl) thiazol-2-yl) -N- (4- (5- (methylsulfonyl) indolin-1-yl) -4-oxobutyl) thiophene-2-carboxamide	AKT1
		Tert-butyl 1- (4- (N- (4- (benzofuran-2-yl) thiazol-2-yl) thiophene-2-carboxamido) butyryl) pyrrolidin-3-ylcarbamate	AKT1
N- (4- (3-Acylaminopyrrolidin-1-yl) -4-oxobutyl) -N- (4- (benzofuran-2-yl) thiazol-2-yl) thiophene-2-carboxamide	AKT1
		Methyl 1- (4- (N- (4- (benzofuran-2-yl) thiazol-2-yl) thiophene-2-carboxamido) butyryl) piperidine-4-carboxylate	AKT1
1- (4- (N- (4- (benzofuran-2-yl) thiazol-2-yl) thiophene-2-carboxamido) butyryl) -N-methylpiperidine-4-carboxamide	AKT1
		N- (4- (benzofuran-2-yl) thiazol-2-yl) -N- (4- (4- (N, N-dimethylsulfamoyl) piperazin-1-yl) -4-oxobutyl) thiophene-2-carboxamide	AKT1
Ethyl 2- (1- (4- (N- (4- (benzofuran-2-yl) thiazol-2-yl) thiophene-2-carboxamido) butyryl) piperidin-3-yl) acetate	AKT1
		Ethyl 2- (1- (4- (N- (4- (benzofuran-2-yl) thiazol-2-yl) thiophene-2-carboxamido) butyryl) piperidin-4-yl) acetate	AKT1
N- (4- (benzofuran-2-yl) thiazol-2-yl) -N- (4- (4- (diethylamino) piperidin-1-yl) -4-oxobutyl) thiophene-2-carboxamide	AKT1

Compound (I)	Activity of
		1- (4- (N- (4- (benzofuran-2-yl) thiazole-2-yl) thiophene-2-carboxamido) butyryl) pyrrolidine-2-carboxamide	AKT1
Methyl 1- (4- (N- (4- (benzofuran-2-yl) thiazol-2-yl) thiophene-2-carboxamido) butyryl) pyrrolidine-2-carboxylate	AKT1
		N- (4- (benzofuran-2-yl) thiazol-2-yl) -N- (4-oxo-4- (3-oxopiperazin-1-yl) butyl) thiophene-2-carboxamide	AKT1
N- (4- (2-amino-2-oxoethylamino) -4-oxobutyl) -N- (4- (benzofuran-2-yl) thiazol-2-yl) thiophene-2-carboxamide	AKT1
		1- (4- (N- (4- (benzofuran-2-yl) thiazol-2-yl) thiophene-2-carboxamido) butyryl) -N- (2-hydroxyethyl) piperidine-3-carboxamide	AKT1
1- (4- (N- (4- (benzofuran-2-yl) thiazol-2-yl) thiophene-2-carboxamido) butyryl) -N- (2-hydroxyethyl) piperidine-4-carboxamide	AKT1
		N- (4- (benzofuran-2-yl) thiazol-2-yl) -N- (4- (2- (methylsulfinyl) ethylamino) -4-oxobutyl) thiophene-2-carboxamide	AKT1
N- (4- (benzofuran-2-yl) thiazol-2-yl) -N- (4- ((2-hydroxyethyl) (pyridin-4-ylmethyl) amino) -4-oxobutyl) thiophene-2-carboxamide	AKT1
		N- (4- (benzofuran-2-yl) thiazol-2-yl) -N- (4- (cyclohexyl (4-hydroxybutyl) amino) -4-oxobutyl) thiophene-2-carboxamide	AKT1
N- (4- (benzofuran-2-yl) thiazol-2-yl) -N- (4- ((2-cyanoethyl) ((tetrahydrofuran-2-yl) methyl) amino) -4-oxobutyl) thiophene-2-carboxamide	AKT1

Compound (I)	Activity of
		N- (4- (benzofuran-2-yl) thiazol-2-yl) -N- (4-oxo-4- (2- (pyridin-3-yl) pyrrolidin-1-yl) butyl) thiophene-2-carboxamide	AKT1
N- (4- (benzofuran-2-yl) thiazol-2-yl) -N- (3- (1-hydroxypropan-2-ylamino) -3-oxopropyl) thiophene-2-carboxamide	AKT1
		N- (4- (benzofuran-2-yl) thiazol-2-yl) -N- (3- (2-methoxyethylamino) -3-oxopropyl) thiophene-2-carboxamide	AKT1
N- (4- (benzofuran-2-yl) thiazol-2-yl) -N- (3- (furan-3-ylmethyl-amino) -3-oxopropyl) thiophene-2-carboxamide	AKT1
		Methyl 1- (3- (N- (4- (benzofuran-2-yl) thiazol-2-yl) thiophene-2-carboxamido) propionyl) pyrrolidine-2-carboxylate	AKT1
N- (4- (benzofuran-2-yl) thiazol-2-yl) -N- (3- (isoindolin-2-yl) -3-oxopropyl) thiophene-2-carboxamide	AKT1
		N- (3- ((1, 4-dioxan-2-yl) methylamino) -3-oxopropyl) -N- (4- (benzofuran-2-yl) thiazol-2-yl) thiophene-2-carboxamide	AKT1
N- (4- (benzofuran-2-yl) thiazol-2-yl) -N- (3- (cyclohexyl (4-hydroxybutyl) amino) -3-oxopropyl) thiophene-2-carboxamide	AKT1
		N- (4- (benzofuran-2-yl) thiazol-2-yl) -N- (3- (methyl (pyridin-4-yl) amino) -3-oxopropyl) thiophene-2-carboxamide	AKT1
1- (4- (N- (4- (benzofuran-2-yl) thiazol-2-yl) thiophene-2-carboxamido) butyryl) piperidine-3-carboxamide	AKT1

Compound (I)	Activity of
		N- (4- (benzofuran-2-yl) thiazol-2-yl) -N- (4-oxo-4- (pyridin-2-ylmethyl-amino) butyl) thiophene-2-carboxamide	AKT1
N- (4- (benzofuran-2-yl) thiazol-2-yl) -N- (4-oxo-4- (thiazolidin-3-yl) butyl) thiophene-2-carboxamide	AKT1
		Tert-butyl 2- (4- (N- (4- (benzofuran-2-yl) thiazol-2-yl) thiophene-2-carboxamido) butyrylamino) ethylcarbamate	AKT1
(S) -N- (4- (benzofuran-2-yl) thiazol-2-yl) -N- (4- (2- (hydroxymethyl) indolin-1-yl) -4-oxobutyl) thiophene-2-carboxamide	AKT1
		N- (4- (benzofuran-2-yl) thiazol-2-yl) -N- (4- (isoindolin-2-yl) -4-oxobutyl) thiophene-2-carboxamide	AKT1
N- (3-Acylaminopropyl) -N- (4- (benzofuran-2-yl) thiazol-2-yl) thiophene-2-carboxamide	AKT1
		1-acetyl-N- (3- (N- (4- (benzofuran-2-yl) thiazol-2-yl) thiophene-2-carboxamido) propyl) piperidine-4-carboxamide	AKT1
N- (4- (benzofuran-2-yl) thiazol-2-yl) -N- (3- (3- (piperidin-1-yl) propionylamino) propyl) thiophene-2-carboxamide	AKT1
		N- (4- (benzofuran-2-yl) thiazol-2-yl) -N- (3- (4- (dimethylamino) butyrylamino) propyl) thiophene-2-carboxamide	AKT1
N- (3- (N- (4- (benzofuran-2-yl) thiazol-2-yl) thiophene-2-carboxamido) propyl) isonicotinamide	AKT1
		N- (3- (4-Acylaminobutylamino) propyl) -N- (4- (benzofuran-2-yl) thiazol-2-yl) thiophene-2-carboxamide	AKT1

Compound (I)	Activity of
		N- (4- (benzofuran-2-yl) thiazol-2-yl) -N- (3- (3-hydroxy-2- (hydroxymethyl) -2-methylpropionylamino) propyl) thiophene-2-carboxamide	AKT1
N- (4- (benzofuran-2-yl) thiazol-2-yl) -N- (3- (2- (2, 5-dioxoimidazolidin-4-yl) acetylamino) propyl) thiophene-2-carboxamide	AKT1
		N- (4- (benzofuran-2-yl) thiazol-2-yl) -N- (3- (3-morpholinopropionylamino) propyl) thiophene-2-carboxamide	AKT1
N- (3- (N- (4- (benzofuran-2-yl) thiazol-2-yl) thiophene-2-carboxamido) propyl) -1, 5-dimethyl-1H-pyrazole-3-carboxamide	AKT1
		N- (4- (benzofuran-2-yl) thiazol-2-yl) -N- (3- (2-morpholinoacetamido) propyl) thiophene-2-carboxamide	AKT1
(S) -tert-butyl 1- (3- (N- (4- (benzofuran-2-yl) thiazol-2-yl) thiophene-2-carboxamido) propyl) pyrrolidine-2-carboxylic acid ester	AKT1
		1- (3- (N- (4- (benzofuran-2-yl) thiazol-2-yl) thiophene-2-carboxamido) propyl) piperidine-3-carboxamide	AKT1
Ethyl 1- (3- (N- (4- (benzofuran-2-yl) thiazol-2-yl) thiophene-2-carboxamido) propyl) piperidine-2-carboxylate	AKT1
		N- (4- (benzofuran-2-yl) thiazol-2-yl) -N- (3- (3-hydroxypiperidin-1-yl) propyl) thiophene-2-carboxamide	AKT1
N- (4- (benzofuran-2-yl) thiazol-2-yl) -N- (3- (4- (2- (2-hydroxyethoxy) ethyl) piperazin-1-yl) propyl) thiophene-2-carboxamide	AKT1
		N- (4- (benzofuran-2-yl) thiazol-2-yl) -N- (3- (4- (2-hydroxyethyl) piperidin-1-yl) propyl) thiophene-2-methylAmides of carboxylic acids	AKT1

Compound (I)	Activity of
		N- (4- (benzofuran-2-yl) thiazol-2-yl) -N- (3- (4- (2-cyanoethyl) piperazin-1-yl) propyl) thiophene-2-carboxamide	AKT1
N- (4- (benzofuran-2-yl) thiazol-2-yl) -N- (3- (4- (hydroxymethyl) piperidin-1-yl) propyl) thiophene-2-carboxamide	AKT1
		N- (4- (benzofuran-2-yl) thiazol-2-yl) -N- (3- (3- (dimethylamino) pyrrolidin-1-yl) propyl) thiophene-2-carboxamide	AKT1
Ethyl 1- (3- (N- (4- (benzofuran-2-yl) thiazol-2-yl) thiophene-2-carboxamido) propyl) piperidine-3-carboxylate	AKT1
		N- (4- (benzofuran-2-yl) thiazol-2-yl) -N- (3- (4-hydroxypiperidin-1-yl) propyl) thiophene-2-carboxamide	AKT1
N- (4- (benzofuran-2-yl) thiazol-2-yl) -N- (3- (3- (N-ethylacetamido) pyrrolidin-1-yl) propyl) thiophene-2-carboxamide	AKT1
		N- (4- (benzofuran-2-yl) thiazol-2-yl) -N- (3- (3- (N-methylacetamido) pyrrolidin-1-yl) propyl) thiophene-2-carboxamide	AKT1
Tert-butyl 1- (3- (N- (4- (benzofuran-2-yl) thiazol-2-yl) thiophene-2-carboxamido) propyl) pyrrolidin-3-ylcarbamate	AKT1
		(S) -N- (4- (benzofuran-2-yl) thiazol-2-yl) -N- (3- (2- (methoxymethyl) pyrrolidin-1-yl) propyl) thiophene-2-carboxamide	AKT1
N- (3- (3-acetamidopyrrolidin-1-yl) propyl) -N- (4- (benzofuran-2-yl) thiazol-2-yl) thiophene-2-carboxamide-	AKT1
		Ethyl 4- (3- (N- (4- (benzofuran-2-yl) thiazol-2-yl) thiophene-2-carboxamido) propyl) piperazine-1-carboxylate	AKT1

Compound (I)	Activity of
		N- (4- (benzofuran-2-yl) thiazol-2-yl) -N- (3- (4- (morpholine-4-carbonyl) piperazin-1-yl) propyl) thiophene-2-carboxamide	AKT1
N- (4- (benzofuran-2-yl) thiazol-2-yl) -N- (3- (4, 4-dihydroxypiperidin-1-yl) propyl) thiophene-2-carboxamide	AKT1
		N- (4- (benzofuran-2-yl) thiazol-2-yl) -N- (3- (4- (tetrahydrofuran-2-carbonyl) piperazin-1-yl) propyl) thiophene-2-carboxamide	AKT1
(R) -1- (3- (N- (4- (benzofuran))-2-yl) thiazol-2-yl) thiophene-2-carboxamido) propyl) -N-methylpyrrolidine-2-carboxamide	AKT1
		1- (3- (N- (4- (benzofuran-2-yl) thiazole-2-yl) thiophene-2-formamido) propyl) pyrrolidine-2-carboxamide	AKT1
Methyl 1- (3- (N- (4- (benzofuran-2-yl) thiazol-2-yl) thiophene-2-carboxamido) propyl) pyrrolidine-2-carboxylate	AKT1
		Methyl 1- (3- (N- (4- (benzofuran-2-yl) thiazol-2-yl) thiophene-2-carboxamido) propyl) piperidine-2-carboxylate	AKT1
(S) -1- (3- (N- (4- (benzofuran-2-yl) thiazol-2-yl) thiophene-2-carboxamido) propyl) -N, N-dimethylpyrrolidine-2-carboxamide	AKT1
		N- (4- (benzofuran-2-yl) thiazol-2-yl) -N- (3- (2- (pyrrolidin-1-ylmethyl) piperidin-1-yl) propyl) thiophene-2-carboxamide	AKT1
N- (4- (benzofuran-2-yl) thiazol-2-yl) -N- (3- (3-oxopiperazin-1-yl) propyl) thiophene-2-carboxamide	AKT1
		1- (3- (N- (4- (benzofuran-2-yl) thiazol-2-yl) thiophene-2-carboxamido) propyl) piperidine-2-carboxamide	AKT1

Compound (I)	Activity of
		Ethyl 2- (4- (3- (N- (4- (benzofuran-2-yl) thiazol-2-yl) thiophene-2-carboxamido) propyl) piperazin-1-yl) acetate	AKT1
Tert-butyl 4- (3- (N- (4- (benzofuran-2-yl) thiazol-2-yl) thiophene-2-carboxamido) propyl) piperazine-1-carboxylate	AKT1
		N- (4- (benzofuran-2-yl) thiazol-2-yl) -N- (3- (4-morpholinopiperidin-1-yl) propyl) thiophene-2-carboxamide	AKT1
N- (4- (benzofuran-2-yl) thiazol-2-yl) -N- (3- (4- (2- (dimethylamino) ethyl) piperazin-1-yl) propyl) thiophene-2-carboxamide	AKT1
		N- (4- (benzofuran-2-yl) thiazol-2-yl) -N- (3- (2- (hydroxymethyl) pyrrolidin-1-yl) propyl) thiophene-2-carboxamide	AKT1
N- (4- (benzofuran-2-yl) thiazol-2-yl) -N- (3- (2- (2-hydroxyethyl) piperidin-1-yl) propyl) thiophene-2-carboxamide	AKT1
		N- (4- (benzofuran-2-yl) thiazol-2-yl) -N- (3- (3- (hydroxymethyl) piperidin-1-yl) propyl) thiophene-2-carboxamide	AKT1
N- (4- (benzofuran-2-yl) thiazol-2-yl) -N- (3- (2- (hydroxymethyl) piperidin-1-yl) propyl) thiophene-2-carboxamide	AKT1
		N- (4- (benzofuran-2-yl) thiazol-2-yl) -N- (3- (3-hydroxypyrrolidin-1-yl) propyl) thiophene-2-carboxamide	AKT1
(S) -N- (4- (benzofuran-2-yl) thiazol-2-yl) -N- (3- (2- (hydroxymethyl) pyrrolidin-1-yl) propyl) thiophene-2-carboxamide	AKT1
		N- (3- (4-acetylpiperazin-1-yl) propyl) -N- (4- (benzofuran-2-yl) thiazol-2-yl) thiophene-2-carboxamide	AKT1

Compound (I)	Activity of
		1- (3- (N- (4- (benzofuran-2-yl) thiazol-2-yl) thiophene-2-carboxamido) propyl) -N, N-diethylpiperidine-3-carboxamide	AKT1
N- (4- (benzofuran-2-yl) thiazol-2-yl) -N- (3- (4- (2-hydroxyethyl) piperazin-1-yl) propyl) thiophene-2-carboxamide	AKT1
		N- (4- (benzofuran-2-yl) thiazol-2-yl) -N- (3- (4- (2-methoxyethyl) piperazin-1-yl) propyl) thiophen-2-yl-carboxamides	AKT1
N- (4- (benzofuran-2-yl) thiazol-2-yl) -N- (3- (3- (diethylamino) pyrrolidin-1-yl) propyl) thiophene-2-carboxamide	AKT1
		1- (3- (N- (4- (benzofuran-2-yl) thiazol-2-yl) thiophene-2-carboxamido) propyl) -N-methylpiperidine-4-carboxamide	AKT1
N- (4- (benzofuran-2-yl) thiazol-2-yl) -N- (3- (4- (diethylamino) piperidin-1-yl) propyl) thiophene-2-carboxamide	AKT1
		(R) -1- (3- (N- (4- (benzofuran-2-yl) thiazol-2-yl) thiophene-2-carboxamido) propyl) pyrrolidine-2-carboxylic acid	AKT1
1- (3- (N- (4- (benzofuran-2-yl) thiazol-2-yl) thiophene-2-carboxamido) propyl) piperidine-4-carboxamide	AKT1
		N- (4- (benzofuran-2-yl) thiazol-2-yl) -N- (3- (4- (2- (dimethylamino) -2-oxoethyl) piperazin-1-yl) propyl) thiophene-2-carboxamide	AKT1
N- (4- (benzofuran-2-yl) thiazol-2-yl) -N- (3- (4- (methylsulfonyl) piperazin-1-yl) propyl) thiophene-2-carboxamide	AKT1

Example 27

Cell assay

[0274] One skilled in the art can determine the cellular activity of the inhibitor compounds in a number of assays. Sources of cells include, but are not limited to, human peripheral blood mononuclear cells and transformed cell lines, available from standard cell banks, such as The American Type Culture Collection (Bethesda, Md.). Cells genetically processed to express one or more specific kinases are also suitable for use in determining cell activity.

[0275]Compounds can be tested for activity in cell proliferation assays using target cells (e.g., LNCaP, HT-29, U87MG, PC3, MV4-11, RS 4: 11, H1299, H526, K562, and others). Cells are plated at the optimal density for each cell line (typically 1000-. Growth factors and/or cytokines may be used to stimulate cell proliferation. Utilizing Alamar Blue ^TM(Biosource International, Camarillo, Calif.) cell viability was measured. Typical controls for proliferation inhibition include, but are not limited to, paclitaxel and doxorubicin (Calbiochem, San Diego CA).

[0276] The induction of apoptosis in target cells by compounds can be tested by measuring the induction of Caspase 3 using the Promega Caspase-Glo 3/7 assay system (Madison, Wis.). The induction of caspase 3 by the compound can be compared to that of caspase 3 by the vehicle (1% DMSO) and known inducers of apoptosis, such as LY294002(calbiochem. san Diego, CA).

[0277] The activity of intracellular signaling proteins can be measured by assessing the phosphorylation state using techniques such as western blot and solution bead assay. Reagents for measuring Akt (S473), PRAS40(T246), GSK3beta (S9) and other phosphorylation were from Biosource International (Camarillo, CA). Cells at optimal density can be treated with the compound for 2-24 hours and then dissolved in standard hypotonic lysis buffer (50mM Tris, pH 7.4, 250mM NaCl, 5mM EDTA, 50mM NaF, 1mM NaVO3, 1% Nonidet P40, 1mM PMSF, Roche inhibitor cocktail reagent, Cat # 1836170). The lysates can be centrifuged and the supernatants used for SDS/PAGE or phosphoprotein assessment with bead reagents and detected on a Luminex 100 assay system (Luminex, Austin, TX).

[0278]Certain chemical products of the invention that exhibit an IC of less than or equal to 30 micromolar are tested in the cell proliferation assay described herein₅₀The value is obtained.

[0279]Some of the chemical products of the invention were tested for their induction of apoptosis in target cells and exhibited an EC of less than or equal to 30 micromolar₅₀The value is obtained.

Example 2

In vivo xenograft tumor model

[0280] Animals: female athymic nude mice (Harlan) were used. Animals were 9-10 weeks old on day 1 of the study.

[0281]Tumor: HT29 human colon tumors were maintained in athymic nude mice by serial engraftment. Tumor fragments (1 mm) were implanted subcutaneously in the right flank of the animal³). Tumors were monitored twice weekly and then daily until their volume reached 80-120mm³. On day 1, mice were randomized into control groups and tumors of 62.5-196.0mm in size³The treatment group and the average tumor size of 91.1-155.3mm³The treatment group of (1). Initial tumor size and body weight of the animals were recorded.

[0282]Treatment: control (no treatment). Vehicle control (30% CAPTISOL)^®Aqueous solution), 0.2 mL/mouse, i.p. twice daily, days 1-10 (b.i.d.x 10). The chemical product of the invention, 150 mg/kg/time, i.p., twice daily, on days 1-10 (b.i.d.x 10). Paclitaxel, 30 mg/kg/dose, i.v., once daily, days 1, 3, 5, 7 and 9 (qod x 5). In all groups, the dosing volume was determined based on 0.2 or 0.3mL/20g mouse and body weight of each animal. Animals were weighed daily on days 1-5 and then twice weekly until the end of the study. The study was monitored daily to observe any unusual behavior of the animals.

[0283]When the tumor reaches a predetermined endpoint size (1,500 mm)³) Each animal was euthanized at the time. The Time To Endpoint (TTE) was calculated for each mouse by means of the following equation:

where TTE is expressed in days and endpoint volume in mm³Expressed, b is the intercept of a straight line from a linear regression of a set of log-transformed tumor growth data, and m is the slope. The set of data included the first observation that exceeded the study endpoint volume and the last three consecutive observations before the endpoint volume was reached. Animals that did not reach the endpoint were assigned a TTE value equal to the last day of the study (60 days). The significance of the difference between the two sets of TTE values was analyzed using a log-scale test.

[0284] Treatment efficacy was determined from Tumor Growth Delay (TGD), which is defined as the increase in median TTE in the treated group compared to the control group:

TGD＝T-C，

expressed in days, or as a percentage of median TTE in the control group:

wherein: t-median TTE in the treatment group, C-median TTE in the treatment group.

[0285]Treatment can result in Partial Regression (PR) or Complete Regression (CR) of the tumor in the animal. In the PR response, tumor volume was 50% or less of its day 1 volume for three consecutive measurements during the course of the study, and equal to or greater than 13.5mm for one or more of these three measurements ³. In the CR response, tumor volume was less than 13.5mm for three consecutive measurements during the course of the study³。

[0286] Other embodiments of the invention will be apparent to those skilled in the art from consideration of the specification and practice of the invention disclosed herein. It is intended that the specification and examples be considered as exemplary only, with a true scope and spirit of the invention being indicated by the following claims.

Claims (63)

1. At least one chemical product selected from compounds of formula I:

(formula I)

And pharmaceutically acceptable salts, solvates, chelates, non-covalent complexes, prodrugs, and mixtures thereof, wherein

R³Selected from the group consisting of hydroxy, alkoxy, amino, substituted amino, and Ar;

ar is selected from cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl and substituted heteroaryl;

l is selected from C₀-C₄Alkylene, substituted C₁-C₄Alkylene group, - (C)₀-C₄Alkylene) -NH- (C ═ O) -and- (C)₀-C₄Alkylene) (C ═ O) -;

w is selected from the group consisting of hydrogen, halogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl;

q is selected from the group consisting of alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl;

z is selected from the group consisting of hydrocarbyl and substituted hydrocarbyl,

provided that it is

If Q is optionally substituted pyridin-3-yl, L is a covalent bond, W is 3-methylphenyl, R³Is optionally substituted pyridin-4-yl, then Z is not methyl;

when Ar is pyridin-4-yl, W is hydrogen, Q is selected from benzyl, substituted benzyl, phenethyl and substituted phenethyl, then Z is not selected from lower alkyl and substituted lower alkyl;

When Ar is 2-oxo- (3-hydroquinolinyl), W is hydrogen, and Z is methyl, then Q is not phenyl;

when W is selected from 2- (cyclohexylamino) pyridin-4-yl and 2- (cyclopentylamino) pyridin-4-yl, Ar is 3-methylphenyl, and Z is methyl, then Q is not pyridin-3-yl or 6-methylpyridin-3-yl;

ar is not a substituted pyridone or benzoyloxypyridine;

if R is¹Or R²One is hydrogen, then Ar is other than 4-pivaloyloxyphenyl;

q is not a heteroaryl, substituted heteroaryl, heterocycloalkyi or substituted heterocycloalkyi group comprising one or more heteroatoms selected from S and N, fused to an aryl, substituted aryl, heteroaryl or substituted heteroaryl ring;

ar is not phenyl, 4-methoxyphenyl or 2, 5-dimethoxyphenyl if Z is lower alkyl or 3-morpholinopropyl;

when Ar is pyridyl, L is a covalent bond, Z is hydrogen or methyl, W is phenyl substituted with one methoxy, methyl, chloro, fluoro or tert-butyl group, then Q is not methyl;

if Ar is 4-tert-butylphenyl, L is a covalent bond, Z is propyl and Q is 1-cyano-2-hydroxy-prop-1-enyl, W is not hydrogen.

2. At least one chemical entity of claim 1 wherein L is a covalent bond.

3. At least one chemical entity of claim 1 wherein L is-NH- (C ═ O) -.

4. At least one chemical entity of any one of claims 1 to 3 wherein R is³Is C_1-8A hydrocarbyloxy group.

5. At least one chemical entity of any one of claims 1 to 3 wherein R is³Is Ar.

6. At least one chemical entity of claim 1 wherein the compound of formula I is selected from compounds of formula II:

(formula II)

Wherein

A is selected from the group consisting of hydrocarbylene, substituted hydrocarbylene, alkenylene, and substituted alkenylene;

R¹and R²Independently selected from hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, heteroaryl and substituted heteroaryl, or R¹And R²Together with the nitrogen to which they are attached form a ring selected from cycloheteroalkyl, substituted cycloheteroalkyl, heteroaryl, and substituted heteroaryl.

7. At least one chemical entity of claim 6 wherein A is selected from the group consisting of hydrocarbylene and substituted hydrocarbylene.

8. At least one chemical entity of claim 7 wherein A is selected from 1, 3-propylene, 1, 4-butylene or- (CH)₂)_m- (C ═ O) -, where m is 2 or 3.

9. At least one chemical entity of any one of claims 1 to 8 wherein W is selected from hydrogen, hydrocarbyl and substituted hydrocarbyl.

10. At least one chemical entity of claim 9 wherein W is hydrogen.

11. At least one chemical entity of claim 6 wherein the compound of formula I is selected from compounds of formula III:

(formula III)

Wherein R is¹And R²Together with the nitrogen to which they are attached, form an optionally substituted 5-to 7-membered ring heterohydrocarbyl ring optionally including 1 or 2 additional heteroatoms selected from O, S and N in the ring.

12. At least one chemical entity of claim 7 wherein the compound of formula I is selected from compounds of formula IV:

(formula IV)

Wherein p is selected from 2, 3 and 4 and q is selected from 0 and 1.

13. At least one chemical entity of claim 12 wherein p is selected from 2, 3 and 4 and q is 0.

14. At least one chemical entity of claim 13 wherein p is selected from 2 and 3 and q is 0.

15. At least one chemical entity of claim 12 wherein p is selected from 2 and 3 and q is 1.

16. At least one chemical entity of claim 15 wherein p is 2 and q is 1.

17. At least one chemical entity of any one of claims 6 to 10 or 12 to 16 wherein R is¹And R²Independently selected from hydrocarbyl and substituted hydrocarbyl, or R¹And R²Together with the nitrogen to which they are attached form a monocyclic cycloheteroalkyl ring.

18. At least one chemical entity of claim 17 wherein R is ¹And R²Independently selected from C_1-4A hydrocarbyl group.

19. At least one chemical entity of claim 11 or 17 wherein R is¹And R²Together with the nitrogen atom to which they are attached form a pyrrolidine, substituted pyrrolidine, piperidine, substituted piperidine, azepane, substituted azepane, piperazine, substituted piperazine, morpholine or substituted morpholine ring.

20. At least one chemical entity of claim 19 wherein R is¹And R²Together with the nitrogen atom to which they are attached form a morpholin-4-yl ring.

21. At least one chemical entity of any one of claims 1 to 20 wherein Ar is selected from substituted aryl and substituted heteroaryl.

22. At least one chemical entity of claim 21 wherein Ar is selected from the group consisting of phenyl, substituted phenyl, benzo [ b ] thiophen-3-yl, substituted benzo [ b ] thiophen-3-yl, pyridin-2-yl, substituted pyridin-2-yl, pyridin-3-yl, substituted pyridin-3-yl, pyridin-4-yl, substituted pyridin-4-yl, thiophen-2-yl, substituted thiophen-2-yl, thiophen-3-yl, substituted thiophen-3-yl, 4-isoxazolyl, substituted 4-isoxazolyl, 5-isoxazolyl, substituted 5-isoxazolyl, 3-pyrazolyl, substituted 3-pyrazolyl, 4-pyrazolyl, and mixtures thereof, Substituted 4-pyrazolyl, naphthalen-2-yl, substituted naphthalen-2-yl, 2, 3-dihydro-1, 4-benzodioxadien-6-yl, substituted 2, 3-dihydro-1, 4-benzodioxadien-6-yl, 3, 4-dihydro-2H-1, 5-benzodioxa * -7-yl, substituted 3, 4-dihydro-2H-1, 5-benzodioxa * -7-yl, benzothiazol-2-yl, substituted benzothiazol-2-yl, benzofuran-2-yl, and substituted benzofuran-2-yl.

23. At least one chemical entity of claim 22 wherein Ar is selected from the group consisting of phenyl, substituted phenyl, 4-isoxazolyl, substituted 4-isoxazolyl, 5-isoxazolyl, substituted 5-isoxazolyl, 3-pyrazolyl, substituted 3-pyrazolyl, 4-pyrazolyl, substituted 4-pyrazolyl, benzofuran-2-yl, and substituted benzofuran-2-yl.

24. At least one chemical entity of claim 1 wherein the compound of formula I is selected from compounds of formula V:

(formula V)

Wherein

E is selected from C₀-C₄Alkylene and substituted C₁-C₄A hydrocarbylene group;

R⁴selected from the group consisting of hydroxy, alkoxy, amino and substituted amino.

25. At least one chemical entity of claim 24 wherein R is⁴Is a hydrocarbyloxy group.

26. At least one chemical entity of any one of claims 1 to 25 wherein Q is selected from the group consisting of hydrocarbyl, substituted hydrocarbyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl.

27. At least one chemical entity of claim 26 wherein Q is selected from the group consisting of monocyclic cycloalkyl, substituted monocyclic cycloalkyl, monocyclic aryl, substituted monocyclic aryl, heteroaryl, and substituted monocyclic heteroaryl.

28. At least one chemical entity of claim 27 wherein Q is selected from C_5-10Monocyclic heteroaryl and substituted monocyclic C _5-10A heteroaryl group.

29. At least one chemical entity of claim 28 wherein Q is selected from the group consisting of phenyl, substituted phenyl, furyl, substituted furyl, cyclohexyl, substituted cyclohexyl, cyclopentenyl, substituted cyclopentenyl, 4-isoxazolyl, substituted 4-isoxazolyl, 5-isoxazolyl, substituted 5-isoxazolyl, thiophen-2-yl, substituted thiophen-2-yl, pyrimidin-2-yl, substituted pyrimidin-2-yl, 5-thiadiazolyl, substituted 5-thiadiazolyl, imidazolyl, substituted imidazolyl, 3-isothiazolyl, substituted thiazolyl, 3-pyrrolyl, and substituted 3-pyrrolyl.

30. At least one chemical entity of claim 29 wherein Q is selected from thiophene and substituted thiophenes.

31. At least one chemical entity of any one of claims 1 to 30 wherein the compound is an inhibitor of at least one ATP-utilizing enzyme.

32. At least one chemical entity of claim 31 wherein said at least one ATP utilizing enzyme is selected from the group consisting of human protein kinases.

33. At least one chemical entity of claim 32 wherein said human protein kinase is selected from the group consisting of AKT1, AKT2, AMP kinase, AXL, AURORA-a, BMX, CDK 2/cyclin A, CDK 2/cyclin E, CHEK1, CHEK2, CK2, DYRK2, EGFR, EPHB4, FLT3, GSK 3-a, GSK3- β, IGF1R, KDR, KIT, MAPKAPK2, MAPKAPK3, MET, MSK2, NEK2, P70S6K1, PAK2, PDGFR-a, PDK1, PIM1 kinase, PLK1, ROCK2, RSK2, SYK, TIE2, TRKB, and ZAP 70.

34. At least one chemical entity of claim 33 wherein said human protein kinase is AKT 1.

35. At least one chemical entity of claim 1 wherein the compound of formula I is selected from the compounds shown in tables I and/or II.

36. A pharmaceutical composition comprising at least one pharmaceutically acceptable vehicle and a therapeutically effective amount of at least one chemical product of any one of claims 1 to 35.

37. The pharmaceutical composition of claim 36, wherein the at least one chemical product is present in an amount effective to treat at least one disease in the patient selected from transplant rejection, osteoarthritis, rheumatoid arthritis, multiple sclerosis, diabetes (diabets), diabetic retinopathy, asthma, inflammatory bowel disease, kidney disease cachexia, septic shock, lupus, diabetes (diabets mellitis), myasthenia gravis, psoriasis, dermatitis, eczema, seborrhea, alzheimer's disease, parkinson's disease, stem cell protection during chemotherapy, ex vivo selection or ex vivo clearance for autologous or allogeneic bone marrow transplantation, leukemia, cancer, ocular diseases, corneal diseases, glaucoma, bacterial infections, viral infections, fungal infections, heart disease, stroke, obesity, endometriosis, atherosclerosis, graft vein stenosis, cancer, stenosis of peri-anastomosis prosthetic grafts, prostatic hyperplasia, chronic obstructive pulmonary disease, inhibition of nerve damage resulting from tissue repair, scar tissue formation, wound healing, pulmonary disease, tumors, and macular degeneration.

38. The pharmaceutical composition of claim 37, wherein the cancer is selected from at least one of: glioblastoma, ovarian cancer, breast cancer, endometrial cancer, hepatocellular carcinoma, melanoma, colorectal cancer, colon cancer, digestive tract, lung cancer, renal cell carcinoma, thyroid, lymphoid, prostate and pancreatic cancer, advanced tumors, hairy cell leukemia, melanoma, chronic myelogenous leukemia, advanced head and neck, squamous cell carcinoma, metastatic renal cells, non-hodgkin's lymphoma, metastatic breast, breast adenocarcinoma, advanced melanoma, pancreas, stomach, non-small cell lung, renal cell carcinoma, various solid tumors, multiple myeloma, metastatic prostate, malignant glioma, renal cancer, lymphoma, refractory metastatic disease, refractory multiple myeloma, cervical cancer, kaposi's sarcoma, recurrent degenerative glioma, and metastatic colon cancer.

39. The pharmaceutical composition of claim 38, wherein the cancer is selected from at least one of: breast cancer, lung cancer, colorectal cancer, ovarian cancer, prostate cancer, renal cancer, squamous cell carcinoma, glioblastoma, melanoma, pancreatic cancer, and kaposi's sarcoma.

40. The pharmaceutical composition of claim 37, wherein the cancer is selected from at least one of: heart: sarcomas (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyoma, fibroma, lipoma, teratoma; lung: bronchial carcinoma (squamous cell, undifferentiated small cell, undifferentiated large cell, adenocarcinoma), alveolar cell (bronchioloalveolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, chondromatous hamartoma, mesothelioma; gastrointestinal tract: esophagus (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (carcinoma, lymphoma, leiomyosarcoma), pancreas (ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumor, kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), large intestine (adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyosarcoma); urogenital tract: kidney (adenocarcinoma, wilm's tumor (nephroblastoma), lymphoma, leukemia), bladder and urethra (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate (adenocarcinoma, sarcoma), testis (seminoma, teratoma, embryonal carcinoma, teratocarcinoma, choriocarcinoma, sarcoma, interstitial cell carcinoma, fibroma, fibroadenoma, adenomatoid tumors, lipoma); liver: liver tumors (hepatocellular carcinoma), cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma; bone: osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibrosarcoma, chondrosarcoma, ewing's sarcoma, malignant lymphoma (reticulosarcoma), multiple myeloma, malignant giant cell tumor chordoma, osteochondrosoma (osteochondral exostosis), benign chondroma, chondroblastoma, osteoid osteoma, and giant cell tumor; the nervous system: cranium (osteoma, hemangioma, granuloma, xanthoma, osteitis deformans, meninges (meningioma, meningosarcoma, glioma disease), brain (astrocytoma, medulloblastoma, glioma, ependymoma, germ cell tumor (pinealoma), glioblastoma multiforme, oligodendroglioma, schwannoma, retinoblastoma, congenital tumor), spinal cord, neurofibroma, meningioma, glioma, sarcoma); gynecological: uterus (endometrial carcinoma), cervix (cervical carcinoma, pre-tumor cervical dysplasia), ovaries (ovarian carcinoma (serous cystadenocarcinoma, mucinous cystadenocarcinoma), granulose-thecal cell tumor, Semliki-Leydig cell tumor, dysgerminoma, malignant teratoma), vulva (squamous cell carcinoma, intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma), vagina (renal carcinoma, squamous cell carcinoma, botryoid sarcoma (embryonal rhabdomyosarcoma), fallopian tube carcinoma); hematology: blood (myeloid leukemia (acute and chronic), acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative disorders, multiple myeloma, myelodysplastic syndrome), hodgkin's disease, non-hodgkin's lymphoma (malignant lymphoma); skin: malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, moles dysplastic nevi, lipoma, hemangioma, dermatofibrosarcoma, keloid, psoriasis; and adrenal gland: neuroblastoma.

41. The pharmaceutical composition of claim 36, wherein the at least one chemical product is present in an amount effective to treat a tuberous sclerosis complex in a patient.

42. The pharmaceutical composition of claim 36, further comprising at least one additional therapeutic agent suitable for effecting combination therapy.

43. The pharmaceutical composition of claim 42, wherein the at least one additional therapeutic agent suitable for effecting combination therapy is selected from the group consisting of estrogen receptor modulators, cytostatic/cytotoxic agents, antiproliferative agents, cell cycle checkpoint inhibitors, angiogenesis inhibitors, monoclonal antibody targeted therapeutic agents, tyrosine kinase inhibitors, serine-threonine kinase inhibitors, histone deacetylase inhibitors, heat shock protein inhibitors, and farnesyl transferase inhibitors.

44. A method of treating at least one disease in a patient in need of such treatment, comprising administering to the patient a therapeutically effective amount of at least one chemical product of any one of claims 1 to 35.

45. The method of claim 44, wherein the at least one chemical product is present in an amount effective to treat at least one disorder selected from transplant rejection, osteoarthritis, rheumatoid arthritis, multiple sclerosis, diabetes (diabets), diabetic retinopathy, asthma, inflammatory bowel disease, kidney disease cachexia, septic shock, lupus, diabetes (diabets mellitis), myasthenia gravis, psoriasis, dermatitis, eczema, seborrhea, Alzheimer's disease, Parkinson's disease, stem cell protection during chemotherapy, ex vivo selection or ex vivo clearance for autologous or allogeneic bone marrow transplantation, leukemia, cancer, ocular disorders, corneal diseases, glaucoma, bacterial infections, viral infections, fungal infections, heart disease, stroke, obesity, endometrial disorders, atherosclerosis, graft vein stenosis, vascular disease, and/or other diseases in the patient, Stenosis of peri-anastomosis prosthetic grafts, prostatic hyperplasia, chronic obstructive pulmonary disease, inhibition of nerve damage resulting from tissue repair, scar tissue formation, wound healing, pulmonary disease, tumors, and macular degeneration.

46. The method of claim 45, wherein the cancer is selected from at least one of: glioblastoma, ovarian cancer, breast cancer, endometrial cancer, hepatocellular carcinoma, melanoma, colorectal cancer, colon cancer, digestive tract, lung cancer, renal cell carcinoma, thyroid, lymphoid, prostate and pancreatic cancer, advanced tumors, hairy cell leukemia, melanoma, chronic myelogenous leukemia, advanced head and neck, squamous cell carcinoma, metastatic renal cells, non-hodgkin's lymphoma, metastatic breast, breast adenocarcinoma, advanced melanoma, pancreas, stomach, non-small cell lung, renal cell carcinoma, various solid tumors, multiple myeloma, metastatic prostate, malignant glioma, renal cancer, lymphoma, refractory metastatic disease, refractory multiple myeloma, cervical cancer, kaposi's sarcoma, recurrent degenerative glioma, and metastatic colon cancer.

47. The method of claim 46, wherein the cancer is selected from at least one of: breast cancer, lung cancer, colorectal cancer, ovarian cancer, prostate cancer, renal cancer, squamous cell carcinoma, glioblastoma, melanoma, pancreatic cancer, and kaposi's sarcoma.

48. The method of claim 45, wherein the cancer is selected from at least one of: heart: sarcomas (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyoma, fibroma, lipoma, teratoma; lung: bronchial carcinoma (squamous cell, undifferentiated small cell, undifferentiated large cell, adenocarcinoma), alveolar cell (bronchioloalveolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, chondromatous hamartoma, mesothelioma; gastrointestinal tract: esophagus (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (carcinoma, lymphoma, leiomyosarcoma), pancreas (ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumor, kaposi's sarcoma, leiomyosarcoma, hemangioma, lipoma, neurofibroma, fibroma), large intestine (adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyosarcoma); urogenital tract: kidney (adenocarcinoma, wilm's tumor (nephroblastoma), lymphoma, leukemia), bladder and urethra (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate (adenocarcinoma, sarcoma), testis (seminoma, teratoma, embryonal carcinoma, teratocarcinoma, choriocarcinoma, sarcoma, interstitial cell carcinoma, fibroma, fibroadenoma, adenomatoid tumors, lipoma); liver: liver tumors (hepatocellular carcinoma), cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma; bone: osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibrosarcoma, chondrosarcoma, ewing's sarcoma, malignant lymphoma (reticulosarcoma), multiple myeloma, malignant giant cell tumor chordoma, osteochondrosoma (osteochondral exostosis), benign chondroma, chondroblastoma, osteoid osteoma, and giant cell tumor; the nervous system: cranium (osteoma, hemangioma, granuloma, xanthoma, osteitis deformans, meninges (meningioma, meningosarcoma, glioma disease), brain (astrocytoma, medulloblastoma, glioma, ependymoma, germ cell tumor (pinealoma), glioblastoma multiforme, oligodendroglioma, schwannoma, retinoblastoma, congenital tumor), spinal cord, neurofibroma, meningioma, glioma, sarcoma); gynecological: uterus (endometrial carcinoma), cervix (cervical carcinoma, pre-tumor cervical dysplasia), ovaries (ovarian carcinoma (serous cystadenocarcinoma, mucinous cystadenocarcinoma), granulose-thecal cell tumor, Semliki-Leydig cell tumor, dysgerminoma, malignant teratoma), vulva (squamous cell carcinoma, intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma), vagina (renal carcinoma, squamous cell carcinoma, botryoid sarcoma (embryonal rhabdomyosarcoma), fallopian tube carcinoma); hematology: blood (myeloid leukemia (acute and chronic), acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative disorders, multiple myeloma, myelodysplastic syndrome), hodgkin's disease, non-hodgkin's lymphoma (malignant lymphoma); skin: malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, moles dysplastic nevi, lipoma, hemangioma, dermatofibrosarcoma, keloid, psoriasis; and adrenal gland: neuroblastoma.

49. The method of claim 44, wherein the at least one chemical product is present in an amount effective to treat a tuberous sclerosis complex in the patient.

50. The method of claim 44, further comprising at least one additional therapeutic agent suitable for effecting combination therapy.

51. The method of claim 44, wherein the at least one additional therapeutic agent suitable for effecting combination therapy is selected from the group consisting of estrogen receptor modulators, cytostatic/cytotoxic agents, antiproliferative agents, cell cycle checkpoint inhibitors, angiogenesis inhibitors, monoclonal antibody targeted therapeutics, tyrosine kinase inhibitors, serine-threonine kinase inhibitors, histone deacetylase inhibitors, heat shock protein inhibitors, and farnesyl transferase inhibitors.

52. A method of inhibiting at least one ATP-utilizing enzyme in a subject, comprising administering to the subject at least one chemical product of any one of claims 1 to 35.

53. The method of claim 52, wherein the at least one ATP-utilizing enzyme is selected from the group consisting of human protein kinases.

54. The method of claim 53, wherein the human protein kinase is selected from the group consisting of AKT1, AKT2, AMP kinase, AXL, AURORA-A, BMX, CDK 2/cyclin A, CDK 2/cyclin E, CHEK1, CHEK2, CK2, DYRK2, EGFR, EPHB4, FLT3, GSK 3-a, GSK3- β, IGF1R, INSR, KDR, KIT, MAPKAKK 2, MAPKAKK 3, MET, MSK2, NEK2, P70S6K1, PAK2, PDGFR-a, PDK1, PIM1 kinase, PLK1, ROCK2, RSK2, SYK, TIE2, TRKB, and P70.

55. The method of claim 54, wherein the human protein kinase is AKT 1.

56. A packaged pharmaceutical preparation comprising a pharmaceutical composition according to any one of claims 36 to 43 and instructions for using the composition to treat a mammal.

57. The packaged pharmaceutical preparation of claim 56, wherein the instructions are for using the pharmaceutical composition to treat a patient having a disease responsive to inhibition of at least one ATP-utilizing enzyme.

58. The packaged drug formulation of claim 57, wherein the at least one ATP utilizing enzyme is selected from the group consisting of AKT1, AKT2, AMP kinase, AXL, AURORA-A, BMX, CDK 2/cyclin A, CDK 2/cyclin E, CHEK1, CHEK2, CK2, DYRK2, EGFR, EPHB4, FLT3, GSK 3-a, GSK3- β, IGF1R, INSR, KDR, KIT, MAPKAKK 2, MAPKAKK 3, MET, MSK2, NEK2, P70S6K1, PAK2, PDGFR-a, PDK1, PIM1 kinase, PLK1, ROCK2, RSK2, SYK, TIE2, TRKB, and TRP 70.

59. The packaged drug formulation of claim 58, wherein the at least one ATP-utilizing enzyme is AKT 1.

60. Use of at least one chemical product according to any one of claims 1 to 35 in the manufacture of a medicament for the treatment of at least one disease selected from transplant rejection, osteoarthritis, rheumatoid arthritis, multiple sclerosis, diabetes (diabets), diabetic retinopathy, asthma, inflammatory bowel disease, kidney disease cachexia, septic shock, lupus, diabetes (diabets mellitis), myasthenia gravis, psoriasis, dermatitis, eczema, seborrhea, alzheimer's disease, parkinson's disease, stem cell protection during chemotherapy, ex vivo selection or ex vivo clearance for autologous or allogeneic bone marrow transplantation, leukemia, cancer, ocular diseases, corneal diseases, glaucoma, bacterial infections, viral infections, fungal infections, heart disease, stroke, obesity, endometriosis, atherosclerosis, graft vein stenosis, atherosclerosis, cancer, bone marrow transplantation, bone marrow, kidney, bone marrow, Stenosis of peri-anastomosis prosthetic grafts, prostatic hyperplasia, chronic obstructive pulmonary disease, inhibition of nerve damage resulting from tissue repair, scar tissue formation, wound healing, pulmonary disease, tumors, and macular degeneration.

61. The use of claim 60, wherein the cancer is selected from at least one of: glioblastoma, ovarian cancer, breast cancer, endometrial cancer, hepatocellular carcinoma, melanoma, colorectal cancer, colon cancer, digestive tract, lung cancer, renal cell carcinoma, thyroid, lymphoid, prostate and pancreatic cancer, advanced tumors, hairy cell leukemia, melanoma, chronic myelogenous leukemia, advanced head and neck, squamous cell carcinoma, metastatic renal cells, non-hodgkin's lymphoma, metastatic breast, breast adenocarcinoma, advanced melanoma, pancreas, stomach, non-small cell lung, renal cell carcinoma, various solid tumors, multiple myeloma, metastatic prostate, malignant glioma, renal cancer, lymphoma, refractory metastatic disease, refractory multiple myeloma, cervical cancer, kaposi's sarcoma, recurrent degenerative glioma, and metastatic colon cancer.

62. The use of claim 61, wherein the cancer is selected from at least one of: breast cancer, lung cancer, colorectal cancer, ovarian cancer, prostate cancer, renal cancer, squamous cell carcinoma, glioblastoma, melanoma, pancreatic cancer, and kaposi's sarcoma.

63. The use of claim 60, wherein the cancer is selected from at least one of: heart: sarcomas (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyoma, fibroma, lipoma, teratoma; lung: bronchial carcinoma (squamous cell, undifferentiated small cell, undifferentiated large cell, adenocarcinoma), alveolar cell (bronchioloalveolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, chondromatous hamartoma, mesothelioma; gastrointestinal tract: esophagus (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (carcinoma, lymphoma, leiomyosarcoma), pancreas (ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumor, kaposi's sarcoma, leiomyosarcoma, hemangioma, lipoma, neurofibroma, fibroma), large intestine (adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyosarcoma); urogenital tract: kidney (adenocarcinoma, wilm's tumor (nephroblastoma), lymphoma, leukemia), bladder and urethra (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate (adenocarcinoma, sarcoma), testis (seminoma, teratoma, embryonal carcinoma, teratocarcinoma, choriocarcinoma, sarcoma, interstitial cell carcinoma, fibroma, fibroadenoma, adenomatoid tumors, lipoma); liver: liver tumors (hepatocellular carcinoma), cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma; bone: osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibrosarcoma, chondrosarcoma, ewing's sarcoma, malignant lymphoma (reticulosarcoma), multiple myeloma, malignant giant cell tumor chordoma, osteochondrosoma (osteochondral exostosis), benign chondroma, chondroblastoma, osteoid osteoma, and giant cell tumor; the nervous system: cranium (osteoma, hemangioma, granuloma, xanthoma, osteitis deformans, meninges (meningioma, meningosarcoma, glioma disease), brain (astrocytoma, medulloblastoma, glioma, ependymoma, germ cell tumor (pinealoma), glioblastoma multiforme, oligodendroglioma, schwannoma, retinoblastoma, congenital tumor), spinal cord, neurofibroma, meningioma, glioma, sarcoma); gynecological: uterus (endometrial carcinoma), cervix (cervical carcinoma, pre-tumor cervical dysplasia), ovaries (ovarian carcinoma (serous cystadenocarcinoma, mucinous cystadenocarcinoma), granulose-thecal cell tumor, Semliki-Leydig cell tumor, dysgerminoma, malignant teratoma), vulva (squamous cell carcinoma, intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma), vagina (renal carcinoma, squamous cell carcinoma, botryoid sarcoma (embryonal rhabdomyosarcoma), fallopian tube carcinoma); hematology: blood (myeloid leukemia (acute and chronic), acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative disorders, multiple myeloma, myelodysplastic syndrome), hodgkin's disease, non-hodgkin's lymphoma (malignant lymphoma); skin: malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, moles dysplastic nevi, lipoma, hemangioma, dermatofibrosarcoma, keloid, psoriasis; and adrenal gland: neuroblastoma.