CROSS REFERENCE TO RELATED APPLICATIONS

This non-provisional application filed under 37 CFR Â§1.53(b), claims the benefit under 35 USC Â§119(e) of U.S. Provisional Application Ser. No. 61/057,559 filed on 30 May 2008, which is incorporated by reference in entirety.

FIELD OF THE INVENTION

The invention relates generally to compounds with anti-cancer activity and more specifically to compounds which inhibit PI3 kinase activity. The invention also relates to methods of using the compounds for in vitro, in situ, and in vivo diagnosis or treatment of mammalian cells, or associated pathological conditions.

BACKGROUND OF THE INVENTION

Phosphatidylinositol (hereinafter abbreviated as â€œPIâ€ ) is one of a number of phospholipids found in cell membranes. In recent years it has become clear that PI plays an important role in intracellular signal transduction. Cell signaling via 3â€²-phosphorylated phosphoinositides has been implicated in a variety of cellular processes, e.g., malignant transformation, growth factor signaling, inflammation, and immunity (Rameh et al (1999) J. Biol Chem, 274:8347-8350). The enzyme responsible for generating these phosphorylated signaling products, phosphatidylinositol 3-kinase (also referred to as PI3 kinase, PI 3-kinase or PI3K), was originally identified as an activity associated with viral oncoproteins and growth factor receptor tyrosine kinases that phosphorylate phosphatidylinositol (PI) and its phosphorylated derivatives at the 3â€²-hydroxyl of the inositol ring (Panayotou et al (1992) Trends Cell Biol 2:358-60).

Phosphoinositide 3-kinases (PI3K) are lipid kinases that phosphorylate lipids at the 3-hydroxyl residue of the inositol ring of phosphoinositols (Whitman et al (1988) Nature, 332:664). The 3â€²-phosphorylated phospholipids (PIP3s) generated by PI3-kinases act as second messengers recruiting kinases with lipid binding domains (including plekstrin homology (PH) regions), such as Akt and phosphoinositide-dependent kinase-1 (PDK1). Binding of Akt to membrane PIP3s causes the translocation of Akt to the plasma membrane, bringing Akt into contact with PDK1, which is responsible for activating Akt. The tumor-suppressor phosphatase, PTEN, dephosphorylates PIP3 and therefore acts as a negative regulator of Akt activation. The PI3-kinases Akt and PDK1 are important in the regulation of many cellular processes including cell cycle regulation, proliferation, survival, apoptosis and motility and are significant components of the molecular mechanisms of diseases such as cancer, diabetes and immune inflammation (Vivanco et al (2002) Nature Rev. Cancer 2:489; Phillips et al (1998) Cancer 83:41).

PI3 kinase is a heterodimer consisting of p85 and p110 subunits (Otsu et al (1991) Cell 65:91-104; Hiles et al (1992) Cell 70:419-29). Four distinct Class I PI3Ks have been identified, designated PI3K Î± (alpha), Î² (beta), Î´ (delta), and Î³ (gamma), each consisting of a distinct 110 kDa catalytic subunit and a regulatory subunit. More specifically, three of the catalytic subunits, i.e., p110 alpha, p110 beta and p110 delta, each interact with the same regulatory subunit, p85; whereas p110 gamma interacts with a distinct regulatory subunit, p101. The patterns of expression of each of these PI3Ks in human cells and tissues are also distinct.

The main PI3-kinase isoform in cancer is the Class I PI3-kinase, p110Î± (alpha) (U.S. Pat. No. 5,824,492; U.S. Pat. No. 5,846,824; U.S. Pat. No. 6,274,327). Other isoforms are implicated in cardiovascular and immune-inflammatory disease (Workman P (2004) Biochem Soc Trans 32:393-396; Patel et al (2004) Proceedings of the American Association of Cancer Research (Abstract LB-247) 95th Annual Meeting, March 27-31, Orlando, Fla., USA; Ahmadi K and Waterfield M D (2004) Encyclopedia of Biological Chemistry (Lennarz W J, Lane M D eds) Elsevier/Academic Press).

The PI3 kinase/Akt/PTEN pathway is an attractive target for cancer drug development since such agents would be expected to inhibit proliferation, reverse the repression of apoptosis and surmount resistance to cytotoxic agents in cancer cells. PI3 kinase inhibitors have been reported (Yaguchi et al (2006) Jour. of the Nat. Cancer Inst. 98(8):545-556; U.S. Pat. No. 7,173,029; U.S. Pat. No. 7,037,915; U.S. Pat. No. 6,608,056; U.S. Pat. No. 6,608,053; U.S. Pat. No. 6,838,457; U.S. Pat. No. 6,770,641; U.S. Pat. No. 6,653,320; U.S. Pat. No. 6,403,588; U.S. Pat. No. 6,703,414; WO 97/15658; WO 2006/046031; WO 2006/046035; WO 2006/046040; WO 2007/042806; WO 2007/042810; WO 2004/017950; US 2004/092561; WO 2004/007491; WO 2004/006916; WO 2003/037886; US 2003/149074; WO 2003/035618; WO 2003/034997; US 2003/158212; EP 1417976; US 2004/053946; JP 2001247477; JP 08175990; JP 08176070). Certain thienopyrimidine compounds have p110 alpha binding, PI3 kinase inhibitory activity and inhibit the growth of cancer cells (WO 2006/046031; WO 2007/122410; WO 2007/127183; WO 2007/129161; US 2008/0269210; US 2008/0242665. Certain purine compounds have p110 delta binding, PI3 kinase inhibitory activity (WO 2009/053716).

SUMMARY OF THE INVENTION

The invention relates generally to purine compounds of Formula I with anti-cancer activity, and more specifically with PI3 kinase modulating or inhibitory activity. Certain hyperproliferative disorders are characterized by the modulation of PI3 kinase function, for example by mutations or overexpression of the proteins. Accordingly, the compounds of the invention may be useful in the treatment of hyperproliferative disorders such as cancer. The compounds may inhibit tumor growth in mammals and may be useful for treating human cancer patients.

The invention also relates to methods of using the purine compounds of Formula I for in vitro, in situ, and in vivo diagnosis or treatment of mammalian cells, organisms, or associated pathological conditions.

Formula I compounds include:

and stereoisomers, geometric isomers, tautomers, or pharmaceutically acceptable salts thereof. The various substituents R¹, R², R³, R⁴are as defined herein.

Another aspect of the invention provides a pharmaceutical composition comprising a purine compound of Formula I and a pharmaceutically acceptable carrier. The pharmaceutical composition may further comprise one or more additional therapeutic agent.

Another aspect of the invention provides methods of inhibiting PI3 kinase activity, comprising contacting a PI3 kinase with an effective inhibitory amount of a compound of Formula I, or a stereoisomer, geometric isomer, tautomer, or pharmaceutically acceptable salt thereof.

Another aspect of the invention provides methods of preventing or treating a hyperproliferative disease or disorder modulated by PI3 kinases, comprising administering to a mammal in need of such treatment an effective amount of a compound of Formula I, or a stereoisomer, geometric isomer, tautomer, or pharmaceutically acceptable salt thereof. Examples of such hyperproliferative disease or disorder include, but are not limited to, cancer.

Another aspect of the invention provides methods of preventing or treating a hyperproliferative disorder, comprising administering to a mammal in need of such treatment an effective amount of a compound of Formula I, or a stereoisomer, geometric isomer, tautomer, or pharmaceutically acceptable salt thereof, alone or in combination with one or more additional compounds having anti-hyperproliferative properties.

An additional aspect of the invention is the use of a compound of this invention in the preparation of a medicament for the treatment or prevention of a disease or condition modulated by PI3 kinase in a mammal.

Another aspect of the invention includes kits comprising a compound of Formula I, or a stereoisomer, geometric isomer, tautomer, solvate, metabolite, or pharmaceutically acceptable salt thereof, a container, and optionally a package insert or label indicating a treatment.

Another aspect of the invention includes methods of preparing, methods of separating, and methods of purifying compounds of Formula I.

Another aspect of the invention includes novel intermediates useful for preparing Formula I compounds.

Additional advantages and novel features of this invention shall be set forth in part in the description that follows, and in part will become apparent to those skilled in the art upon examination of the following specification or may be learned by the practice of the invention. The advantages of the invention may be realized and attained by means of the instrumentalities, combinations, compositions, and methods particularly pointed out in the appended claims.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows a general method for preparation of polyfunctionalized purines

FIG. 2 shows an alternate method for the synthesis of polyfunctionalized purines.

DETAILED DESCRIPTION OF EXEMPLARY EMBODIMENTS

Reference will now be made in detail to certain embodiments of the invention, examples of which are illustrated in the accompanying structures and formulas. While the invention will be described in conjunction with the enumerated embodiments, it will be understood that they are not intended to limit the invention to those embodiments. On the contrary, the invention is intended to cover all alternatives, modifications, and equivalents which may be included within the scope of the present invention as defined by the claims. One skilled in the art will recognize many methods and materials similar or equivalent to those described herein, which could be used in the practice of the present invention. The present invention is in no way limited to the methods and materials described. In the event that one or more of the incorporated literature, patents, and similar materials differs from or contradicts this application, including but not limited to defined terms, term usage, described techniques, or the like, this application controls.

DEFINITIONS

The term â€œalkylâ€ as used herein refers to a saturated linear or branched-chain monovalent hydrocarbon radical of one to twelve carbon atoms (C₁-C₁₂), wherein the alkyl radical may be optionally substituted independently with one or more substituents described below. In another embodiment, an alkyl radical is one to eight carbon atoms (C₁-C₈), or one to six carbon atoms (C₁-C₆). Examples of alkyl groups include, but are not limited to, methyl (Me, â€”CH₃), ethyl (Et, â€”CH₂CH₃), 1-propyl (n-Pr, n-propyl, â€”CH₂CH₂CH₃), 2-propyl (i-Pr, i-propyl, â€”CH(CH₃)₂), 1-butyl (n-Bu, n-butyl, â€”CH₂CH₂CH₂CH₃), 2-methyl-1-propyl (1-Bu, i-butyl, â€”CH₂CH(CH₃)₂), 2-butyl (s-Bu, s-butyl, â€”CH(CH₃)CH₂CH₃), 2-methyl-2-propyl (t-Bu, t-butyl, â€”C(CH₃)₃), 1-pentyl (n-pentyl, â€”CH₂CH₂CH₂CH₂CH₃), 2-pentyl (â€”CH(CH₃)CH₂CH₂CH₃), 3-pentyl (â€”CH(CH₂CH₃)₂), 2-methyl-2-butyl (â€”C(CH₃)₂CH₂CH₃), 3-methyl-2-butyl (â€”CH(CH₃)CH(CH₃)₂), 3-methyl-1-butyl (â€”CH₂CH₂CH(CH₃)₂), 2-methyl-1-butyl (â€”CH₂CH(CH₃)CH₂CH₃), 1-hexyl (â€”CH₂CH₂CH₂CH₂CH₂CH₃), 2-hexyl (â€”CH(CH₃)CH₂CH₂CH₂CH₃), 3-hexyl (â€”CH(CH₂CH₃)(CH₂CH₂CH₃)), 2-methyl-2-pentyl (â€”C(CH₃)₂CH₂CH₂CH₃), 3-methyl-2-pentyl (â€”CH(CH₃)CH(CH₃)CH₂CH₃), 4-methyl-2-pentyl (â€”CH(CH₃)CH₂CH(CH₃)₂), 3-methyl-3-pentyl (â€”C(CH₃)(CH₂CH₃)₂), 2-methyl-3-pentyl (â€”CH(CH₂CH₃)CH(CH₃)₂), 2,3-dimethyl-2-butyl (â€”C(CH₃)₂CH(CH₃)₂), 3,3-dimethyl-2-butyl (â€”CH(CH₃)C(CH₃)₃, 1-heptyl, 1-octyl, and the like.

The term â€œalkyleneâ€ as used herein refers to a saturated linear or branched-chain divalent hydrocarbon radical of one to twelve carbon atoms (C₁-C₁₂), wherein the alkylene radical may be optionally substituted independently with one or more substituents described below. In another embodiment, an alkylene radical is one to eight carbon atoms (C₁-C₈), or one to six carbon atoms (C₁-C₆). Examples of alkylene groups include, but are not limited to, methylene (â€”CH₂â€”), ethylene (â€”CH₂CH₂â€”), propylene (â€”CH₂CH₂CH₂â€”), and the like.

The term â€œalkenylâ€ refers to linear or branched-chain monovalent hydrocarbon radical of two to eight carbon atoms (C₂-C₈) with at least one site of unsaturation, i.e., a carbon-carbon, sp²double bond, wherein the alkenyl radical may be optionally substituted, and includes radicals having â€œcisâ€ and â€œtransâ€ orientations, or alternatively, â€œEâ€ and â€œZâ€ orientations. Examples include, but are not limited to, ethylenyl or vinyl (â€”CHâ• CH₂), allyl (â€”CH₂CHâ• CH₂), and the like.

The term â€œalkenyleneâ€ refers to linear or branched-chain divalent hydrocarbon radical of two to eight carbon atoms (C₂-C₈) with at least one site of unsaturation, i.e., a carbon-carbon, sp²double bond, wherein the alkenyl radical may be optionally substituted, and includes radicals having â€œcisâ€ and â€œtransâ€ orientations, or alternatively, â€œEâ€ and â€œZâ€ orientations. Examples include, but are not limited to, ethylenylene or vinylene (â€”CHâ• CHâ€”), allyl (â€”CH₂CHâ• CHâ€”), and the like.

The term â€œalkynylâ€ refers to a linear or branched monovalent hydrocarbon radical of two to eight carbon atoms (C₂-C₈) with at least one site of unsaturation, i.e., a carbon-carbon, sp triple bond, wherein the alkynyl radical may be optionally substituted. Examples include, but are not limited to, ethynyl (â€”Câ‰¡CH), propynyl (propargyl, â€”CH₂Câ‰¡CH), and the like.

The term â€œalkynyleneâ€ refers to a linear or branched divalent hydrocarbon radical of two to eight carbon atoms (C₂-C₈) with at least one site of unsaturation, i.e., a carbon-carbon, sp triple bond, wherein the alkynyl radical may be optionally. Examples include, but are not limited to, ethynylene (â€”Câ‰¡Câ€”), propynylene (propargylene, â€”CH₂Câ‰¡Câ€”), and the like.

The terms â€œcarbocycleâ€ , â€œcarbocyclylâ€ , â€œcarbocyclic ringâ€ and â€œcycloalkylâ€ refer to a monovalent non-aromatic, saturated or partially unsaturated ring having 3 to 12 carbon atoms (C₃-C₁₂) as a monocyclic ring or 7 to 12 carbon atoms as a bicyclic ring. Bicyclic carbocycles having 7 to 12 atoms can be arranged, for example, as a bicyclo[4,5], [5,5], [5,6] or [6,6] system, and bicyclic carbocycles having 9 or 10 ring atoms can be arranged as a bicyclo[5,6] or [6,6] system, or as bridged systems such as bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane and bicyclo[3.2.2]nonane. Examples of monocyclic carbocycles include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopent-1-enyl, 1-cyclopent-2-enyl, 1-cyclopent-3-enyl, cyclohexyl, 1-cyclohex-1-enyl, 1-cyclohex-2-enyl, 1-cyclohex-3-enyl, cyclohexadienyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, cyclododecyl, and the like.

â€œArylâ€ means a monovalent aromatic hydrocarbon radical of 6-20 carbon atoms (C₆-C₂₀) derived by the removal of one hydrogen atom from a single carbon atom of a parent aromatic ring system. Some aryl groups are represented in the exemplary structures as â€œArâ€ . Aryl includes bicyclic radicals comprising an aromatic ring fused to a saturated, partially unsaturated ring, or aromatic carbocyclic ring. Typical aryl groups include, but are not limited to, radicals derived from benzene (phenyl), substituted benzenes, naphthalene, anthracene, biphenyl, indenyl, indanyl, 1,2-dihydronaphthalene, 1,2,3,4-tetrahydronaphthyl, and the like. Aryl groups are optionally substituted.

â€œAryleneâ€ means a divalent aromatic hydrocarbon radical of 6-20 carbon atoms (C₆-C₂₀) derived by the removal of two hydrogen atom from a two carbon atoms of a parent aromatic ring system. Some arylene groups are represented in the exemplary structures as â€œArâ€ . Arylene includes bicyclic radicals comprising an aromatic ring fused to a saturated, partially unsaturated ring, or aromatic carbocyclic ring. Typical arylene groups include, but are not limited to, radicals derived from benzene (phenylene), substituted benzenes, naphthalene, anthracene, biphenylene, indenylene, indanylene, 1,2-dihydronaphthalene, 1,2,3,4-tetrahydronaphthyl, and the like. Arylene groups are optionally substituted

The terms â€œheterocycle,â€ â€œheterocyclylâ€ and â€œheterocyclic ringâ€ are used interchangeably herein and refer to a saturated or a partially unsaturated (i.e., having one or more double and/or triple bonds within the ring) carbocyclic radical of 3 to about 20 ring atoms in which at least one ring atom is a heteroatom selected from nitrogen, oxygen, phosphorus and sulfur, the remaining ring atoms being C, where one or more ring atoms is optionally substituted, for example, with oxo (â• O), mercapto, or amino, etc. A heterocycle may be a monocycle having 3 to 7 ring members (2 to 6 carbon atoms and 1 to 4 heteroatoms selected from N, O, P, and S) or a bicycle having 7 to 10 ring members (4 to 9 carbon atoms and 1 to 6 heteroatoms selected from N, O, P, and S), for example: a bicyclo[4,5], [5,5], [5,6], or [6,6] system. Heterocycles are described in Paquette, Leo A.; â€œPrinciples of Modern Heterocyclic Chemistryâ€ (W. A. Benjamin, New York, 1968), particularly Chapters 1, 3, 4, 6, 7, and 9; â€œThe Chemistry of Heterocyclic Compounds, A series of Monographsâ€ (John Wiley & Sons, New York, 1950 to present), in particular Volumes 13, 14, 16, 19, and 28; and J. Am. Chem. Soc. (1960) 82:5566. â€œHeterocyclylâ€ also includes radicals where heterocycle radicals are fused with a saturated, partially unsaturated ring, or aromatic carbocyclic or heterocyclic ring. Examples of heterocyclic rings include, but are not limited to, pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, piperidino (piperidinyl), morpholino (morpholinyl), thiomorpholino, thioxanyl, piperazinyl, homopiperazinyl, azetidinyl, oxetanyl, thietanyl, homopiperidinyl, oxepanyl, thiepanyl, oxazepinyl, diazepinyl, thiazepinyl, 2-pyrrolinyl, 3-pyrrolinyl, indolinyl, 2H-pyranyl, 4H-pyranyl, dioxanyl, 1,3-dioxolanyl, pyrazolinyl, dithianyl, dithiolanyl, dihydropyranyl, dihydrothienyl, dihydrofuranyl, pyrazolidinylimidazolinyl, imidazolidinyl, 3-azabicyclo[3.1.0]hexanyl, 3-azabicyclo[4.1.0]heptanyl, azabicyclo[2.2.2]hexanyl, 3H-indolyl quinolizinyl 1H-benzo[d]imidazol-2(3H)-one-5-yl, and N-pyridyl ureas. Spiro moieties are also included within the scope of this definition. Examples of a heterocyclic group substituted with one or more oxo (â• O) moieties are pyrimidinonyl and 1,1-dioxo-thiomorpholinyl.

The term â€œheteroarylâ€ refers to a monovalent aromatic radical of 5-, 6-, or 7-membered rings, and includes fused ring systems (at least one of which is aromatic) of 5 to about 20 ring atoms, containing one or more heteroatoms independently selected from nitrogen, oxygen, and sulfur. Examples of heteroaryl groups are pyridinyl (including, for example, 2-hydroxypyridinyl), imidazolyl, imidazopyridinyl, pyrimidinyl (including, for example, 4-hydroxypyrimidinyl), pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxadiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolinyl, isoquinolinyl, tetrahydroisoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl, triazinyl, isoindolyl, pteridinyl, purinyl, oxadiazolyl, triazolyl, thiadiazolyl, thiadiazolyl, furazanyl, benzofurazanyl, benzothiophenyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, and furopyridinyl. Heteroaryl groups are optionally substituted.

The heterocycle or heteroaryl groups may be carbon (carbon-linked), or nitrogen (nitrogen-linked) bonded where such is possible. By way of example and not limitation, carbon bonded heterocycles or heteroaryls are bonded at position 2, 3, 4, 5, or 6 of a pyridine, position 3, 4, 5, or 6 of a pyridazine, position 2, 4, 5, or 6 of a pyrimidine, position 2, 3, 5, or 6 of a pyrazine, position 2, 3, 4, or 5 of a furan, tetrahydrofuran, thiofuran, thiophene, pyrrole or tetrahydropyrrole, position 2, 4, or 5 of an oxazole, imidazole or thiazole, position 3, 4, or 5 of an isoxazole, pyrazole, or isothiazole, position 2 or 3 of an aziridine, position 2, 3, or 4 of an azetidine, position 2, 3, 4, 5, 6, 7, or 8 of a quinoline or position 1, 3, 4, 5, 6, 7, or 8 of an isoquinoline.

By way of example and not limitation, nitrogen bonded heterocycles or heteroaryls are bonded at position 1 of an aziridine, azetidine, pyrrole, pyrrolidine, 2-pyrroline, 3-pyrroline, imidazole, imidazolidine, 2-imidazoline, 3-imidazoline, pyrazole, pyrazoline, 2-pyrazoline, 3-pyrazoline, piperidine, piperazine, indole, indoline, 1H-indazole, position 2 of a isoindole, or isoindoline, position 4 of a morpholine, and position 9 of a carbazole, or Î²-carboline.

The term â€œmonocyclic heteroarylâ€ refers to a five- or six-membered, unsubstituted or substituted, monocyclic heteroaryl radical which contains 1, 2, 3 or 4 ring heteroatoms independently selected from N, O and S. The monocyclic heteroaryl may be attached to the C-4 and C-6 positions of the pyrimidine ring according to Formula I at any carbon (carbon-linked) atom of the monocyclic heteroaryl R³group. Monocyclic heteroaryl radicals include, but are not limited to: 2-pyridyl, 3-pyridyl, 4-pyridyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-imidazolyl, 4-imidazolyl, 3-pyrazolyl, 4-pyrazolyl, 2-pyrrolyl, 3-pyrrolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 3-pyridazinyl, 4-pyridazinyl, 5-pyridazinyl, 2-pyrimidinyl, 5-pyrimidinyl, 6-pyrimidinyl, 2-pyrazinyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, 2-furanyl, 3-furanyl, 2-thienyl, 3-thienyl, 3-triazolyl, 1-triazolyl, 5-tetrazolyl, 1-tetrazolyl, and 2-tetrazolyl. Monocyclic heteroaryls are optionally substituted.

â€œFused bicyclic C₄-C₂₀heterocyclylâ€ and â€œFused bicyclic C₁-C₂₀heteroarylâ€ containing one or more heteroatoms independently selected from nitrogen, oxygen, and sulfur, differ only by their aromatic character, and have two rings fused together, i.e. share a common bond. Fused bicyclic heterocyclyl and heteroaryl radicals may be unsubstituted or substituted, and attached to the C-4 and C-6 positions of the pyrimidine ring according to Formula I at any carbon (carbon-linked) atom of the fused bicyclic C₄-C₂₀heterocyclyl or fused bicyclic C₁-C₂₀heteroaryl group R³group. Fused bicyclic heterocyclyl and heteroaryl radicals include, but are not limited to: 1H-indazole, 1H-indole, indolin-2-one, 1-(indolin-1-yl)ethanone, 1H-benzo[d][1,2,3]triazole, 1H-pyrazolo[3,4-b]pyridine, 1H-pyrazolo[3,4-d]pyrimidine, 1H-benzo[d]imidazole, 1H-benzo[d]imidazol-2(3H)-one, 1H-pyrazolo[3,4-c]pyridine, 1H-pyrrolo[2,3-c]pyridine, 3H-imidazo[4,5-c]pyridine, 7H-pyrrolo[2,3-d]pyrimidine, 7H-purine, 1H-pyrazolo[4,3-d]pyrimidine, 5H-pyrrolo[3,2-d]pyrimidine, 2-amino-1H-purin-6(9H)-one, quinoline, quinazoline, quinoxaline, isoquinoline, isoquinolin-1(2H)-one, 3,4-dihydroisoquinolin-1(2H)-one, 3,4-dihydroquinolin-2(1H)-one, quinazolin-2(1H)-one, quinoxalin-2(1H)-one, 1,8-naphthyridine, pyrido[3,4-d]pyrimidine, pyrido[3,2-b]pyrazine, benzo[d][1,3]dioxole, and 2,3-dihydrobenzo[b][1,4]dioxine.

The terms â€œtreatâ€ and â€œtreatmentâ€ refer to both therapeutic treatment and prophylactic or preventative measures, wherein the object is to prevent or slow down (lessen) an undesired physiological change or disorder, such as the development or spread of cancer. For purposes of this invention, beneficial or desired clinical results include, but are not limited to, alleviation of symptoms, diminishment of extent of disease, stabilized (i.e., not worsening) state of disease, delay or slowing of disease progression, amelioration or palliation of the disease state, and remission (whether partial or total), whether detectable or undetectable. â€œTreatmentâ€ can also mean prolonging survival as compared to expected survival if not receiving treatment. Those in need of treatment include those already with the condition or disorder as well as those prone to have the condition or disorder or those in which the condition or disorder is to be prevented.

The phrase â€œtherapeutically effective amountâ€ means an amount of a compound of the present invention that (i) treats or prevents the particular disease, condition, or disorder, (ii) attenuates, ameliorates, or eliminates one or more symptoms of the particular disease, condition, or disorder, or (iii) prevents or delays the onset of one or more symptoms of the particular disease, condition, or disorder described herein. In the case of cancer, the therapeutically effective amount of the drug may reduce the number of cancer cells; reduce the tumor size; inhibit (i.e., slow to some extent and preferably stop) cancer cell infiltration into peripheral organs; inhibit (i.e., slow to some extent and preferably stop) tumor metastasis; inhibit, to some extent, tumor growth; and/or relieve to some extent one or more of the symptoms associated with the cancer. To the extent the drug may prevent growth and/or kill existing cancer cells, it may be cytostatic and/or cytotoxic. For cancer therapy, efficacy can be measured, for example, by assessing the time to disease progression (TTP) and/or determining the response rate (RR).

The terms â€œcancerâ€ and â€œcancerousâ€ refer to or describe the physiological condition in mammals that is typically characterized by unregulated cell growth. A â€œtumorâ€ comprises one or more cancerous cells. Examples of cancer include, but are not limited to, carcinoma, lymphoma, blastoma, sarcoma, and leukemia or lymphoid malignancies. More particular examples of such cancers include squamous cell cancer (e.g., epithelial squamous cell cancer), lung cancer including small-cell lung cancer, non-small cell lung cancer (â€œNSCLCâ€ ), adenocarcinoma of the lung and squamous carcinoma of the lung, cancer of the peritoneum, hepatocellular cancer, gastric or stomach cancer including gastrointestinal cancer, pancreatic cancer, glioblastoma, cervical cancer, ovarian cancer, liver cancer, bladder cancer, hepatoma, breast cancer, colon cancer, rectal cancer, colorectal cancer, endometrial or uterine carcinoma, salivary gland carcinoma, kidney or renal cancer, prostate cancer, vulval cancer, thyroid cancer, hepatic carcinoma, anal carcinoma, penile carcinoma, as well as head and neck cancer.

A â€œchemotherapeutic agentâ€ is a chemical compound useful in the treatment of cancer, regardless of mechanism of action. Classes of chemotherapeutic agents include, but are not limited to: alkylating agents, antimetabolites, spindle poison plant alkaloids, cytotoxic/antitumor antibiotics, topoisomerase inhibitors, antibodies, photosensitizers, and kinase inhibitors. Chemotherapeutic agents include compounds used in â€œtargeted therapyâ€ and conventional chemotherapy. Examples of chemotherapeutic agents include: erlotinib (TARCEVAÂ®, Genentech/OSI Pharm.), docetaxel (TAXOTEREÂ®, Sanofi-Aventis), 5-FU (fluorouracil, 5-fluorouracil, CAS No. 51-21-8), gemcitabine (GEMZARÂ®, Lilly), PD-0325901 (CAS No. 391210-10-9, Pfizer), cisplatin (cis-diamine, dichloroplatinum(II), CAS No. 15663-27-1), carboplatin (CAS No. 41575-94-4), paclitaxel (TAXOLÂ®, Bristol-Myers Squibb Oncology, Princeton, N.J.), trastuzumab (HERCEPTINÂ®, Genentech), temozolomide (4-methyl-5-oxo-2,3,4,6,8-pentazabicyclo[4.3.0]nona-2,7,9-triene-9-carboxamide, CAS No. 85622-93-1, TEMODARÂ®, TEMODALÂ®, Schering Plough), tamoxifen ((Z)-2-[4-(1,2-diphenylbut-1-enyl)phenoxy]-N,N-dimethyl-ethanamine, NOLVADEXÂ®, ISTUBALÂ®, VALODEXÂ®), and doxorubicin (ADRIAMYCINÂ®), Akti-1/2, HPPD, and rapamycin.

More examples of chemotherapeutic agents include: oxaliplatin (ELOXATINÂ®, Sanofi), bortezomib (VELCADEÂ®, Millennium Pharm.), sutent (SUNITINIBÂ®), SU11248, Pfizer), letrozole (FEMARAÂ®, Novartis), imatinib mesylate (GLEEVECÂ®, Novartis), XL-518 (MEK inhibitor, Exelixis, WO 2007/044515), ARRY-886 (MEK inhibitor, AZD6244, Array BioPharma, Astra Zeneca), SF-1126 (PI3K inhibitor, Semafore Pharmaceuticals), BEZ-235 (PI3K inhibitor, Novartis), XL-147 (PI3K inhibitor, Exelixis), PTK787/ZK 222584 (Novartis), fulvestrant (FASLODEXÂ®, AstraZeneca), leucovorin (folinic acid), rapamycin (sirolimus, RAPAMUNEÂ®, Wyeth), lapatinib (TYKERBÂ®, GSK572016, Glaxo Smith Kline), lonafarnib (SARASARâ„¢, SCH 66336, Schering Plough), sorafenib (NEXAVARÂ®, BAY43-9006, Bayer Labs), gefitinib (IRESSAÂ®, AstraZeneca), irinotecan (CAMPTOSARÂ®, CPT-11, Pfizer), tipifarnib (ZARNESTRAâ„¢, Johnson & Johnson), ABRAXANEâ„¢ (Cremophor-free), albumin-engineered nanoparticle formulations of paclitaxel (American Pharmaceutical Partners, Schaumberg, II), vandetanib (rINN, ZD6474, ZACTIMAÂ®, AstraZeneca), chloranmbucil, AG1478, AG1571 (SU 5271; Sugen), temsirolimus (TORISELÂ®, Wyeth), pazopanib (GlaxoSmithKline), canfosfamide (TELCYTAÂ®, Telik), thiotepa and cyclosphosphamide (CYTOXANÂ®, NEOSARÂ®); alkyl sulfonates such as busulfan, improsulfan and piposulfan; aziridines such as benzodopa, carboquone, meturedopa, and uredopa; ethylenimines and methylamelamines including altretamine, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphoramide and trimethylomelamine; acetogenins (especially bullatacin and bullatacinone); a camptothecin (including the synthetic analog topotecan); bryostatin; callystatin; CC-1065 (including its adozelesin, carzelesin and bizelesin synthetic analogs); cryptophycins (particularly cryptophycin 1 and cryptophycin 8); dolastatin; duocarmycin (including the synthetic analogs, KW-2189 and CB1-TM1); eleutherobin; pancratistatin; a sarcodictyin; spongistatin; nitrogen mustards such as chlorambucil, chlomaphazine, chlorophosphamide, estramustine, ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, novembichin, phenesterine, prednimustine, trofosfamide, uracil mustard; nitrosoureas such as carmustine, chlorozotocin, fotemustine, lomustine, nimustine, and ranimnustine; antibiotics such as the enediyne antibiotics (e.g., calicheamicin, calicheamicin gammall, calicheamicin omegaI1 (Angew Chem. Intl. Ed. Engl. (1994) 33:183-186); dynemicin, dynemicin A; bisphosphonates, such as clodronate; an esperamicin; as well as neocarzinostatin chromophore and related chromoprotein enediyne antibiotic chromophores), aclacinomysins, actinomycin, authramycin, azaserine, bleomycins, cactinomycin, carabicin, caminomycin, carzinophilin, chromomycinis, dactinomycin, daunorubicin, detorubicin, 6-diazo-5-oxo-L-norleucine, morpholino-doxorubicin, cyanomorpholino-doxorubicin, 2-pyrrolino-doxorubicin and deoxydoxorubicin), epirubicin, esorubicin, idarubicin, marcellomycin, mitomycins such as mitomycin C, mycophenolic acid, nogalamycin, olivomycins, peplomycin, porfiromycin, puromycin, quelamycin, rodorubicin, streptonigrin, streptozocin, tubercidin, ubenimex, zinostatin, zorubicin; anti-metabolites such as methotrexate and 5-fluorouracil (5-FU); folic acid analogs such as denopterin, methotrexate, pteropterin, trimetrexate; purine analogs such as fludarabine, 6-mercaptopurine, thiamiprine, thioguanine; pyrimidine analogs such as ancitabine, azacytidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine, doxifluridine, enocitabine, floxuridine; androgens such as calusterone, dromostanolone propionate, epitiostanol, mepitiostane, testolactone; anti-adrenals such as aminoglutethimide, mitotane, trilostane; folic acid replenisher such as frolinic acid; aceglatone; aldophosphamide glycoside; aminolevulinic acid; eniluracil; amsacrine; bestrabucil; bisantrene; edatraxate; defofamine; demecolcine; diaziquone; elformithine; elliptinium acetate; an epothilone; etoglucid; gallium nitrate; hydroxyurea; lentinan; lonidainine; maytansinoids such as maytansine and ansamitocins; mitoguazone; mitoxantrone; mopidanmol; nitraerine; pentostatin; phenamet; pirarubicin; losoxantrone; podophyllinic acid; 2-ethylhydrazide; procarbazine; PSKÂ® polysaccharide complex (JHS Natural Products, Eugene, Oreg.); razoxane; rhizoxin; sizofuran; spirogermanium; tenuazonic acid; triaziquone; 2,2â€²,2â€³-trichlorotriethylamine; trichothecenes (especially T-2 toxin, verracurin A, roridin A and anguidine); urethan; vindesine; dacarbazine; mannomustine; mitobronitol; mitolactol; pipobroman; gacytosine; arabinoside (â€œAra-Câ€ ); cyclophosphamide; thiotepa; 6-thioguanine; mercaptopurine; methotrexate; platinum analogs such as cisplatin and carboplatin; vinblastine; etoposide (VP-16); ifosfamide; mitoxantrone; vincristine; vinorelbine (NAVELBINEÂ®); novantrone; teniposide; edatrexate; daunomycin; aminopterin; capecitabine (XELODAÂ®, Roche); ibandronate; CPT-11; topoisomerase inhibitor RFS 2000; difluoromethylomithine (DMFO); retinoids such as retinoic acid; and pharmaceutically acceptable salts, acids and derivatives of any of the above.

Also included in the definition of â€œchemotherapeutic agentâ€ are: (i) anti-hormonal agents that act to regulate or inhibit hormone action on tumors such as anti-estrogens and selective estrogen receptor modulators (SERMs), including, for example, tamoxifen (including NOLVADEXÂ®; tamoxifen citrate), raloxifene, droloxifene, 4-hydroxytamoxifen, trioxifene, keoxifene, LY117018, onapristone, and FARESTONÂ® (toremifine citrate); (ii) aromatase inhibitors that inhibit the enzyme aromatase, which regulates estrogen production in the adrenal glands, such as, for example, 4(5)-imidazoles, aminoglutethimide, MEGASEÂ® (megestrol acetate), AROMASINÂ® (exemestane; Pfizer), formestanie, fadrozole, RIVISORÂ® (vorozole), FEMARAÂ® (letrozole; Novartis), and ARIMIDEXÂ® (anastrozole; AstraZeneca); (iii) anti-androgens such as flutamide, nilutamide, bicalutamide, leuprolide, and goserelin; as well as troxacitabine (a 1,3-dioxolane nucleoside cytosine analog); (iv) protein kinase inhibitors such as MEK inhibitors (WO 2007/044515); (v) lipid kinase inhibitors; (vi) antisense oligonucleotides, particularly those which inhibit expression of genes in signaling pathways implicated in aberrant cell proliferation, for example, PKC-alpha, Raf and H-Ras, such as oblimersen (GENASENSEÂ®, Genta Inc.); (vii) ribozymes such as VEGF expression inhibitors (e.g., ANGIOZYMEÂ®) and HER2 expression inhibitors; (viii) vaccines such as gene therapy vaccines, for example, ALLOVECTINÂ®, LEUVECTINÂ®, and VAXIDÂ®; PROLEUKINÂ® rIL-2; topoisomerase 1 inhibitors such as LURTOTECANÂ®; ABARELIXÂ® rmRH; (ix) anti-angiogenic agents such as bevacizumab (AVASTINÂ®, Genentech); and pharmaceutically acceptable salts, acids and derivatives of any of the above.

Also included in the definition of â€œchemotherapeutic agentâ€ are therapeutic antibodies such as alemtuzumab (Campath), bevacizumab (AVASTINÂ®, Genentech); cetuximab (ERBITUXÂ®, Imclone); panitumumab (VECTIBIXÂ®, Amgen), rituximab (RITUXANÂ®, Genentech/Biogen Idec), pertuzumab (OMNITARGâ„¢, 2C4, Genentech), trastuzumab (HERCEPTINÂ®, Genentech), tositumomab (Bexxar, Corixia), and the antibody drug conjugate, gemtuzumab ozogamicin (MYLOTARGÂ®, Wyeth).

Humanized monoclonal antibodies with therapeutic potential as chemotherapeutic agents in combination with the PI3K inhibitors of the invention include: alemtuzumab, apolizumab, aselizumab, atlizumab, bapineuzumab, bevacizumab, bivatuzumab mertansine, cantuzumab mertansine, cedelizumab, certolizumab pegol, cidfusituzumab, cidtuzumab, daclizumab, eculizumab, efalizumab, epratuzumab, erlizumab, felvizumab, fontolizumab, gemtuzumab ozogamicin, inotuzumab ozogamicin, ipilimumab, labetuzumab, lintuzumab, matuzumab, mepolizumab, motavizumab, motovizumab, natalizumab, nimotuzumab, nolovizumab, numavizumab, ocrelizumab, omalizumab, palivizumab, pascolizumab, pecfusituzumab, pectuzumab, pertuzumab, pexelizumab, ralivizumab, ranibizumab, reslivizumab, reslizumab, resyvizumab, rovelizumab, ruplizumab, sibrotuzumab, siplizumab, sontuzumab, tacatuzumab tetraxetan, tadocizumab, talizumab, tefibazumab, tocilizumab, toralizumab, trastuzumab, tucotuzumab celmoleukin, tucusituzumab, umavizumab, urtoxazumab, and visilizumab.

A â€œmetaboliteâ€ is a product produced through metabolism in the body of a specified compound or salt thereof. Metabolites of a compound may be identified using routine techniques known in the art and their activities determined using tests such as those described herein. Such products may result for example from the oxidation, reduction, hydrolysis, amidation, deamidation, esterification, deesterification, enzymatic cleavage, and the like, of the administered compound. Accordingly, the invention includes metabolites of compounds of the invention, including compounds produced by a process comprising contacting a compound of this invention with a mammal for a period of time sufficient to yield a metabolic product thereof.

The term â€œpackage insertâ€ is used to refer to instructions customarily included in commercial packages of therapeutic products, that contain information about the indications, usage, dosage, administration, contraindications and/or warnings concerning the use of such therapeutic products.

The term â€œchiralâ€ refers to molecules which have the property of non-superimposability of the mirror image partner, while the term â€œachiralâ€ refers to molecules which are superimposable on their mirror image partner.

The term â€œstereoisomersâ€ refers to compounds which have identical chemical constitution, but differ with regard to the arrangement of the atoms or groups in space.

â€œDiastereomerâ€ refers to a stereoisomer with two or more centers of chirality and whose molecules are not mirror images of one another. Diastereomers have different physical properties, e.g. melting points, boiling points, spectral properties, and reactivities. Mixtures of diastereomers may separate under high resolution analytical procedures such as electrophoresis and chromatography.

â€œEnantiomersâ€ refer to two stereoisomers of a compound which are non-superimposable mirror images of one another.

Stereochemical definitions and conventions used herein generally follow S. P. Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S., â€œStereochemistry of Organic Compoundsâ€ , John Wiley & Sons, Inc., New York, 1994. The compounds of the invention may contain asymmetric or chiral centers, and therefore exist in different stereoisomeric forms. It is intended that all stereoisomeric forms of the compounds of the invention, including but not limited to, diastereomers, enantiomers and atropisomers, as well as mixtures thereof such as racemic mixtures, form part of the present invention. Many organic compounds exist in optically active forms, i.e., they have the ability to rotate the plane of plane-polarized light. In describing an optically active compound, the prefixes D and L, or R and S, are used to denote the absolute configuration of the molecule about its chiral center(s). The prefixes d and 1 or (+) and (âˆ’) are employed to designate the sign of rotation of plane-polarized light by the compound, with (âˆ’) or 1 meaning that the compound is levorotatory. A compound prefixed with (+) or d is dextrorotatory. For a given chemical structure, these stereoisomers are identical except that they are mirror images of one another. A specific stereoisomer may also be referred to as an enantiomer, and a mixture of such isomers is often called an enantiomeric mixture. A 50:50 mixture of enantiomers is referred to as a racemic mixture or a racemate, which may occur where there has been no stereoselection or stereospecificity in a chemical reaction or process. The terms â€œracemic mixtureâ€ and â€œracemateâ€ refer to an equimolar mixture of two enantiomeric species, devoid of optical activity.

The term â€œtautomerâ€ or â€œtautomeric formâ€ refers to structural isomers of different energies which are interconvertible via a low energy barrier. For example, proton tautomers (also known as prototropic tautomers) include interconversions via migration of a proton, such as keto-enol and imine-enamine isomerizations. Valence tautomers include interconversions by reorganization of some of the bonding electrons.

The phrase â€œpharmaceutically acceptable saltâ€ as used herein, refers to pharmaceutically acceptable organic or inorganic salts of a compound of the invention. Exemplary salts include, but are not limited, to sulfate, citrate, acetate, oxalate, chloride, bromide, iodide, nitrate, bisulfate, phosphate, acid phosphate, isonicotinate, lactate, salicylate, acid citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucuronate, saccharate, formate, benzoate, glutamate, methanesulfonate â€œmesylateâ€ , ethanesulfonate, benzenesulfonate, p-toluenesulfonate, and pamoate (i.e., 1,1â€²-methylene-bis(2-hydroxy-3-naphthoate)) salts. A pharmaceutically acceptable salt may involve the inclusion of another molecule such as an acetate ion, a succinate ion or other counter ion. The counter ion may be any organic or inorganic moiety that stabilizes the charge on the parent compound. Furthermore, a pharmaceutically acceptable salt may have more than one charged atom in its structure. Instances where multiple charged atoms are part of the pharmaceutically acceptable salt can have multiple counter ions. Hence, a pharmaceutically acceptable salt can have one or more charged atoms and/or one or more counter ion.

If the compound of the invention is a base, the desired pharmaceutically acceptable salt may be prepared by any suitable method available in the art, for example, treatment of the free base with an inorganic acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, methanesulfonic acid, phosphoric acid and the like, or with an organic acid, such as acetic acid, trifluoroacetic acid, maleic acid, succinic acid, mandelic acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid, salicylic acid, a pyranosidyl acid, such as glucuronic acid or galacturonic acid, an alpha hydroxy acid, such as citric acid or tartaric acid, an amino acid, such as aspartic acid or glutamic acid, an aromatic acid, such as benzoic acid or cinnamic acid, a sulfonic acid, such as p-toluenesulfonic acid or ethanesulfonic acid, or the like.

If the compound of the invention is an acid, the desired pharmaceutically acceptable salt may be prepared by any suitable method, for example, treatment of the free acid with an inorganic or organic base, such as an amine (primary, secondary or tertiary), an alkali metal hydroxide or alkaline earth metal hydroxide, or the like. Illustrative examples of suitable salts include, but are not limited to, organic salts derived from amino acids, such as glycine and arginine, ammonia, primary, secondary, and tertiary amines, and cyclic amines, such as piperidine, morpholine and piperazine, and inorganic salts derived from sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminum and lithium.

The phrase â€œpharmaceutically acceptableâ€ indicates that the substance or composition must be compatible chemically and/or toxicologically, with the other ingredients comprising a formulation, and/or the mammal being treated therewith.

A â€œsolvateâ€ refers to an association or complex of one or more solvent molecules and a compound of the invention. Examples of solvents that form solvates include, but are not limited to, water, isopropanol, ethanol, methanol, DMSO, ethyl acetate, acetic acid, and ethanolamine. The term â€œhydrateâ€ refers to the complex where the solvent molecule is water.

The term â€œprotecting groupâ€ refers to a substituent that is commonly employed to block or protect a particular functionality while other functional groups on the compound undergo reaction. For example, an â€œamino-protecting groupâ€ is a substituent attached to an amino group that blocks or protects the amino functionality in the compound. Suitable amino-protecting groups include acetyl, trifluoroacetyl, t-butoxycarbonyl (BOC), benzyloxycarbonyl (CBZ) and 9-fluorenylmethylenoxycarbonyl (Fmoc). Similarly, a â€œhydroxy-protecting groupâ€ refers to a substituent of a hydroxy group that blocks or protects the hydroxy functionality. Suitable protecting groups include acetyl and silyl. A â€œcarboxy-protecting groupâ€ refers to a substituent of the carboxy group that blocks or protects the carboxy functionality. Common carboxy-protecting groups include phenylsulfonylethyl, cyanoethyl, 2-(trimethylsilyl)ethyl, 2-(trimethylsilyl)ethoxymethyl, 2-(p-toluenesulfonyl)ethyl, 2-(p-nitrophenylsulfenyl)ethyl, 2-(diphenylphosphino)-ethyl, nitroethyl and the like. For a general description of protecting groups and their use, see T. W. Greene, Protective Groups in Organic Synthesis, John Wiley & Sons, New York, 1991.

The terms â€œcompound of this invention,â€ and â€œcompounds of the present inventionâ€ and â€œcompounds of Formula Iâ€ include compounds of Formulas I and stereoisomers, geometric isomers, tautomers, solvates, metabolites, and pharmaceutically acceptable salts and prodrugs thereof

Purine Compounds

The present invention provides purine compounds, and pharmaceutical formulations thereof, which are potentially useful in the treatment of diseases, conditions and/or disorders modulated by PI3 kinases. More specifically, the present invention provides compounds of Formula I

and stereoisomers, geometric isomers, tautomers, or pharmaceutically acceptable salts thereof, wherein:

R¹is selected from H, C₁-C₁₂alkyl, C₂-C₈alkenyl, C₂-C₈alkynyl, C₆-C₂₀aryl, â€”(C₁-C₁₂alkylene)-(C₃-C₁₂carbocyclyl), â€”(C₁-C₁₂alkylene)-(C₂-C₂₀heterocyclyl), â€”(C₁-C₁₂alkylene)-C(â• O)â€”(C₂-C₂₀heterocyclyl), â€”(C₁-C₁₂alkylene)-(C₆-C₂₀aryl), and â€”(C₁-C₁₂alkylene)-(C₁-C₂₀heteroaryl), where alkyl, alkenyl, alkynyl, alkylene, carbocyclyl, heterocyclyl, aryl, and heteroaryl are optionally substituted with one or more groups independently selected from F, Cl, Br, I, â€”CH₃, â€”CH₂OH, â€”CN, â€”CF₃, â€”CO₂H, â€”COCH₃, â€”CO₂CH₃, â€”CONH₂, â€”CONHCH₃, â€”CON(CH₃)₂, â€”NO₂, â€”NH₂, â€”NHCH₃, â€”NHCOCH₃, â€”NHS(O)₂CH₃, â€”OH, â€”OCH₃, â€”S(O)₂N(CH₃)₂, â€”SCH₃, â€”CH₂OCH₃, and â€”S(O)₂CH₃;

R²is selected from C₁-C₁₂alkyl, C₂-C₈alkenyl, C₂-C₈alkynyl, â€”(C₁-C₁₂alkylene)-(C₃-C₁₂carbocyclyl), â€”(C₁-C₁₂alkylene)-(C₂-C₂₀heterocyclyl), â€”(C₁-C₁₂alkylene)-C(â• O)â€”(C₂-C₂₀heterocyclyl), â€”(C₁-C₁₂alkylene)-(C₆-C₂₀aryl), and â€”(C₁-C₁₂alkylene)-(C₁-C₂₀heteroaryl), where alkyl, alkenyl, alkynyl, alkylene, carbocyclyl, heterocyclyl, aryl, and heteroaryl are optionally substituted with one or more groups independently selected from F, Cl, Br, I, â€”CH₃, â€”CH₂OH, â€”CN, â€”CF₃, â€”CO₂H, â€”COCH₃, â€”CO₂CH₃, â€”CONH₂, â€”CONHCH₃, â€”CON(CH₃)₂, â€”NO₂, â€”NH₂, â€”NHCH₃, â€”NHCOCH₃, â€”NHS(O)₂CH₃, â€”OH, â€”OCH₃, â€”S(O)₂N(CH₃)₂, â€”SCH₃, â€”CH₂OCH₃, and â€”S(O)₂CH₃;

R³is selected from C₆-C₂₀aryl, carbon-linked C₂-C₂₀heterocyclyl and carbon-linked C₁-C₂₀heteroaryl, each of which are optionally substituted with one or more groups independently selected from F, Cl, Br, I, â€”CH₃, â€”CN, â€”CF₃, â€”CH₂OH, â€”CO₂H, â€”CONH₂, â€”CON(CH₃)₂, â€”NO₂, â€”NH₂, â€”NHCH₃, â€”NHCOCH₃, â€”OH, â€”OCH₃, â€”SH, â€”NHC(â• O)NHCH₃, â€”NHC(â• O)NHCH₂CH₃, and â€”S(O)₂CH₃;

R⁴is selected from â€”NR¹⁰R¹³, â€”NR¹²C(â• O)R¹⁰, â€”NR¹⁰(C₁-C₁₂alkyl)NR¹⁰R¹³, â€”NR¹⁰(C₁-C₁₂alkylene)OR¹⁰, â€”NR¹⁰(C₁-C₁₂alkylene)C(â• O)NR¹⁰R¹³, â€”NR¹⁰(C₁-C₁₂alkylene)-(C₃-C₁₂carbocyclyl), â€”NR¹⁰(C₁-C₁₂alkylene)-(C₂-C₂₀heterocyclyl), â€”NR¹⁰(C₁-C₁₂alkylene)-(C₆-C₂₀aryl), and â€”NR¹⁰(C₁-C₁₂alkylene)-(C₁-C₂₀heteroaryl), where alkyl, alkylene, carbocyclyl, heterocyclyl, aryl, and heteroaryl are optionally substituted with one or more groups independently selected from F, Cl, Br, I, â€”CH₃, â€”CH₂OH, â€”CN, â€”CF₃, â€”CO₂H, â€”COCH₃, â€”CONH₂, â€”CONHCH₃, â€”CON(CH₃)₂, â€”NO₂, â€”NH₂, â€”NHCH₃, â€”NHCOCH₃, â€”NHS(O)₂CH₃, â€”OH, â€”OCH₃, â€”S(O)₂N(CH₃)₂, â€”SCH₃, â€”CH₂OCH₃, and â€”S(O)₂CH₃;

R¹⁰, R¹¹and R¹²are independently selected from H, C₁-C₁₂alkyl, C₂-C₈alkenyl, C₂-C₈alkynyl, C₃-C₁₂carbocyclyl, C₂-C₂₀heterocyclyl, C₆-C₂₀aryl, and C₁-C₂₀heteroaryl, where alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl are optionally substituted with one or more groups independently selected from F, Cl, Br, I, â€”CH₂OH, â€”CH₂C₆H₅, â€”CN, â€”CF₃, â€”CO₂H, â€”CONH₂, â€”CONHCH₃, â€”NO₂, â€”N(CH₃)₂, â€”NHCOCH₃, â€”NHS(O)₂CH₃, â€”OH, â€”OCH₃, â€”OCH₂CH₃, â€”S(O)₂NH₂, â€”SCH₃, â€”S(O)CH₃, â€”CH₂OCH₃, â€”CH₃, and â€”S(O)₂CH₃;

or R¹⁰and R¹¹together with the nitrogen atom to which they are attached form a C₂-C₂₀heterocyclyl ring; and

R¹³is selected from C₁-C₁₂alkyl, C₂-C₈alkenyl, C₂-C₈alkynyl, C₃-C₁₂carbocyclyl, C₂-C₂₀heterocyclyl, C₆-C₂₀aryl, and C₁-C₂₀heteroaryl, where alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl are optionally substituted with one or more groups independently selected from F, Cl, Br, I, â€”CH₂OH, â€”CH₂C₆H₅, â€”CN, â€”CF₃, â€”CO₂H, â€”CONH₂, â€”CONHCH₃, â€”NO₂, â€”N(CH₃)₂, â€”NHCOCH₃, â€”NHS(O)₂CH₃, â€”OH, â€”OCH₃, â€”OCH₂CH₃, â€”S(O)₂NH₂, â€”SCH₃, â€”S(O)CH₃, â€”OCH₂CH₂â€”N(CH₃)₂, and â€”S(O)₂CH₃;

or R¹⁰and R¹³together with the nitrogen atom to which they are attached form a C₂-C₂₀heterocyclyl ring;

with the proviso that when R¹is â€”(C₁-C₁₂alkylene)-(C₂-C₂₀heterocyclyl), then R³is not an indole which is unsubstituted or substituted.

Exemplary embodiments of R¹include H, C₁-C₁₂alkyl such as CH₃, â€”CH₂CH₃, â€”CH₂CH₂CH₃, â€”CH(CH₃)₂, â€”CH₂CH₂CH₂CH₃, and â€”CH₂CH(CH₃)₂, C₁-C₁₂alkyl substituted with one or more â€”OH or F, such as â€”C(CH₃)₂OH, â€”CH₂CH₂OH, â€”CH₂CH₂CH₂OH, and â€”CH₂CH₂CO₂H, and 2-morpholinoethyl.

Exemplary embodiments of R¹also include optionally substituted phenyl.

Exemplary embodiments of R¹also include â€”(C₁-C₁₂alkylene)-(C₂-C₂₀heterocyclyl) such as â€”CH₂â€” (piperazin-1-yl) where piperazin-1-yl is optionally substituted such as â€”CH₂-(4-(methylsulfonyl)piperazin-1-yl)

Exemplary embodiments R²include C₁-C₁₂alkyl such as CH₃, â€”CH₂CH₃, â€”CH₂CH₂CH₃, â€”CH(CH₃)₂, â€”CH₂CH₂CH₂CH₃, and â€”CH₂CH(CH₃)₂, C₁-C₁₂alkyl substituted with one or more â€”OH or F, such as â€”C(CH₃)₂OH, â€”CH₂CH₂OH, â€”CH₂CH₂CH₂OH, and â€”CH₂CH₂CO₂H, and 2-morpholinoethyl.

Exemplary embodiments of R²also include â€”(C₁-C₁₂alkylene)-(C₂-C₂₀heterocyclyl) such as â€”CH₂â€” (piperazin-1-yl) where piperazin-1-yl is optionally substituted such as â€”CH₂-(4-(methylsulfonyl)piperazin-1-yl).

Exemplary embodiments include wherein R³is optionally substituted C₆-C₂₀aryl. The C₆-C₂₀aryl groups include phenyl, naphthalene, anthracene, biphenyl, indenyl, indanyl, 1,2-dihydronaphthalene, and 1,2,3,4-tetrahydronaphthyl, such as phenyl substituted with one or more â€”OH.

Exemplary embodiments include wherein R³is a monocyclic heteroaryl selected from pyridyl, isoxazolyl, imidazolyl, pyrazolyl, pyrrolyl, thiazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, oxazolyl, oxadiazolyl, furanyl, thienyl, triazolyl, and tetrazolyl.

Exemplary embodiments include wherein R³is a monocyclic heteroaryl selected from the structures: