Processes for preparing isoquinolinones and solid forms of isoquinolinones

Isoquinolinones and methods for preparing their solid forms

This invention claims priority to U.S. Provisional Application No. 61/431,304, filed on January 10, 2011, and U.S. Provisional Application No. 61/578,655, filed on December 21, 2011, both of which are incorporated herein by reference in their entirety. quoted as

Cell activity can be regulated by external signals that stimulate or inhibit endocytosis. The method by which a stimulatory or inhibitory signal is transmitted into and into a cell to induce an intracellular response is referred to as signal transduction. Over the past few decades, the cascade of signal transduction events has been elucidated and known to play important roles in a variety of biological responses. Defects in various elements of signaling pathways are known to be responsible for a variety of diseases, including various forms of cancer, inflammatory diseases, metabolic disorders, and vascular and neurological diseases (Gaestel et al.<i>Current</i><i></i><i>Medicinal</i><i></i><i>Chemistry</i>(2007) 14:2214-2234]).

Kinases represent a class of important signaling molecules. Kinases can be generally classified into protein kinases and lipid kinases, and certain kinases exhibit dual properties. Protein kinases are enzymes that phosphorylate other proteins and/or themselves (ie, autophosphorylation). Protein kinases can generally be classified into three main groups based on their substrate utilization: those that mostly phosphorylate substrates on tyrosine residues (e.g., erb2, PDGF receptor, EGF receptor, VEGF receptor, src, abl) Tyrosine kinases, serine/threonine kinases that mostly phosphorylate substrates on serine and/or threonine residues (e.g., mTorC1, mTorC2, ATM, ATR, DNA-PK, Akt), and phosphorylates substrates on tyrosine, serine and/or threonine residues A dual-specific kinase that makes

Lipid kinases are catalysts that promote phosphorylation of lipids. These enzymes, and the resulting phosphorylated lipids and lipid-derived biologically active organic molecules, play important roles in many different physiological functions, including cell proliferation, migration, adhesion, and differentiation. Certain lipid kinases are membrane-associated, which promote phosphorylation of lipids contained in or associated with cell membranes. Examples of such enzymes include phosphoinositide kinases (eg, PI3-kinase, PI4-kinase), diacylglycerol kinase, and sphingosine kinase.

Phosphoinositide 3-kinases (PI3Ks) constitute a unique, conserved family of intracellular lipid kinases that phosphorylate the 3'-OH group on phosphatidylinositol or phosphoinositide. The PI3K family includes 15 kinases with distinct substrate specificities, expression patterns, and modes of regulation. Class I PI3Ks (p110α, p110β, p110δ, and p110γ) are typically activated by tyrosine kinases or G-protein coupled receptors to activate PIP₃It produces lipid products called lipid products, which engage with downstream effectors such as in the Akt/PDK1 pathway, mTOR, Tec family kinases, and Rho family GTPases. Class II and III PI3Ks play important roles in intracellular transport through the synthesis of PI(3)P and PI(3,4)P2.

The PI3K signaling pathway is one of the most mutated systems in human cancer. In addition, PI3K signaling is a key factor in many other diseases in humans. PI3K signaling is involved in many diseases including allergic contact dermatitis, rheumatoid arthritis, degenerative arthritis, inflammatory bowel disease, chronic obstructive pulmonary disease, psoriasis, multiple sclerosis, asthma, diseases associated with diabetic complications and inflammatory complications of the cardiovascular system, such as acute coronary syndrome. is associated with

Many inhibitors of PI3K have emerged. When dissolved in solution, these compounds are often initially assessed for activity, and solid state characterization, such as polymorphization, plays an important role. Polymorphic forms of drug substances, such as inhibitors of PI3K, can have different chemical and physical properties, including crystallinity, melting point, chemical reactivity, solubility, dissolution rate, optical and mechanical properties, vapor pressure, and density. These properties can directly affect the ability to process or manufacture drug substances and drug products. In addition, polymorphism is often a factor under regulatory review of the 'identity' of drug products from various manufacturers. For example, polymorphism has been evaluated in compounds such as warfarin sodium, famotidine, and ranitidine. Polymorphism can affect the quality, safety, and/or efficacy of a drug product, such as a kinase inhibitor. Therefore, direct study of polymorphs of PI3K inhibitors and methods of preparing polymorphs of PI3K inhibitors show that it is a very useful research field in the development of active pharmaceutical ingredients (APIs).

In addition, PI3K inhibitors have been used to treat (eg, clinical trials) various diseases and disorders in humans. For the manufacture of drug substances intended for human use, current Good Manufacturing Practices (GMP) apply. The necessary procedures are created that can control the level of impurities and assure API products that consistently meet certain specifications. Accordingly, a significant need exists for a method for the preparation of a PI3K inhibitor suitable for human use, particularly on a commercial scale, inter alia, on a scale that is safe, scalable, efficient, economically realistic and/or has other desirable properties. Among other entities, the present invention addresses this need and discloses polymorphic forms of PI3K inhibitors that provide exemplary advantages.

In one embodiment, the invention provides a polymorphic form of a compound of Formula I: Form A, Form B, Form C, Form D, Form E, Form F, Form G, Form H, Form I, or Form J: , an amorphous form of the compound of formula I, or a salt, solvate or hydrate, or a mixture of two or more thereof:

[Formula I]

<img file="KR20140020249A_D0001.tif" />.

In one embodiment, the polymorphic form of the compound of formula (I) may be a crystalline form, a partially crystalline form, an amorphous form, or a mixture of crystalline and/or amorphous forms.

In one embodiment, the present invention provides a process for the preparation of a compound of formula (I):

[Formula I]

<img file="KR20140020249A_D0002.tif" />

In one embodiment, the method comprises any 1, 2, 3, 4, 5, 6, 7 or 8 or more of the following steps:

<img file="KR20140020249A_D0003.tif" />

<img file="KR20140020249A_D0004.tif" />

In the above formula,

X is fluoro, chloro, bromo, iodo, -O-SO₂-4-methylphenyl, and -O-SO₂-methyl;

PG¹silver benzyl, substituted benzyl, methoxycarbonyl, ethoxycarbonyl, substituted ethoxycarbonyl, 9-fluorenyloxycarbonyl, substituted 9-fluorenyloxycarbonyl, 2,2,2- Trichloroethoxycarbonyl, 2-trimethylsilylethoxycarbonyl, (2-phenyl-2-trimethylsilyl)ethoxycarbonyl, 2-phenylethoxycarbonyl, 1,1-dimethyl-2, 2-Dibromoethoxycarbonyl, 1,1-dimethyl-2,2,2-trichloroethoxycarbonyl, t-butoxycarbonyl, 1-adamantyloxycarbonyl, 2-adamantyl Oxycarbonyl, triisopropylsiloxycarbonyl, vinyloxycarbonyl, 1-isopropoxycarbonyl, 8-quinolyloxycarbonyl, 2,4-dimethylpent-3-yloxycarbonyl, benzyloxy carbonyl, and substituted benzyloxycarbonyl;

PG²is methylsulfonyl, substituted methylsulfonyl, benzenesulfonyl, substituted benzenesulfonyl, benzyloxycarbonyl, substituted benzyloxycarbonyl, 2,2,2-trichloroethoxycarbonyl, 2-trimethyl Silylethoxycarbonyl, t-butoxycarbonyl, 1-adamantyloxycarbonyl, 2-adamantyloxycarbonyl, alkyl, substituted alkyl, t-butyldimethylsilyl, triisopropylsilyl, allyl , benzyl, substituted benzyl, hydroxymethyl, methoxymethyl, diethoxymethyl, (2-chloroethoxy)methyl, t-butoxymethyl, t-butyldimethylsiloxymethyl, pivaloyloxymethyl, benzyloxymethyl, dimethylaminomethyl, 2-tetrahydropyranyl, substituted alkoxymethyl and substituted aryloxymethyl;

In this case, the substituent is alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, alkoxy, cycloalkoxy, heterocyclyloxy, aryloxy, heteroaryloxy , amido, amino, acyl, acyloxy, alkoxycarbonyl, ester, ether, thio, sulfinyl, sulfonyl, sulfonamido, halo, cyano, hydroxyl, nitro, phosphate, urea, carbamate and carbonate is selected from

In one embodiment, the present invention provides

(i) at least one non-Form C polymorph compound of Formula I, or a salt, solvate thereof, for a time sufficient to convert at least about 50% of the total amount of the non-Form C polymorph of the compound of Formula I to Form C or exposing the composition comprising the hydrate to non-anhydrous conditions; and

(ii) recovering polymorph Form C;

There is provided a process for the preparation of polymorph Form C of a compound of formula (I), comprising:

[Formula I]

<img file="KR20140020249A_D0005.tif" />

In one embodiment, the non-anhydrous condition comprises water, such as in the form of water vapor and/or liquid water. In one embodiment, the non-anhydrous condition comprises a solvent system comprising a non-aqueous solvent and liquid water. In one embodiment, the non-aqueous solvent is a water-miscible solvent. For example, liquid water can be about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9% by volume of the solvent system. % by volume, about 10% by volume, about 15% by volume, about 20% by volume, about 25% by volume, about 30% by volume, about 35% by volume, about 40% by volume, about 45% by volume, about 50% by volume, about 55% by volume % by volume, about 60% by volume, about 65% by volume, about 70% by volume, about 75% by volume, about 80% by volume, about 85% by volume, about 90% by volume, about 95% by volume, about 96% by volume, about 97 by volume % by volume, about 98% by volume, about 99% by volume, or about 100% by volume. In one embodiment, the liquid water is present in an amount from about 10 to about 50 volume percent of the solvent system.

In one embodiment, the non-anhydrous condition comprises a solvent system comprising water (eg, about 90% v/v) and isopropyl alcohol (eg, about 10% v/v). In one embodiment, the non-anhydrous condition comprises a solvent system comprising water and ethanol. In one embodiment, non-anhydrous conditions include water and a water-miscible solvent such as C₁-C₄ solvent systems including alcohol, acetone, acetonitrile, and the like. In one embodiment, the water-miscible solvent is an alcohol such as methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, t-butanol, ethylene glycol, and the like. In one embodiment, the ratio of water to water-miscible solvent in the solvent systems provided herein is about 50:1, about 40:1, about 30:1, about 20:1, about 10:1, about 9: 1, about 8:1, about 7:1, about 6:1, about 5:1, about 4:1, about 3:1, about 2:1, about 1:1, about 1:2, about 1: 3, about 1:4, about 1:5, about 1:6, about 1:7, about 1:8, about 1:9, about 1:10, about 1:20, about 1:30, about 1: 40, or about 1:50 v/v. In one embodiment, the ratio of water to water-miscible solvent in the solvent systems provided herein is from about 50:1 to about 1:1, from about 40:1 to about 1:1, from about 30:1 to about 1: 1, about 20:1 to about 1:1, about 10:1 to about 1:1, about 9:1 to about 1:1, about 8:1 to about 1:1, about 7:1 to about 1; 1, about 6:1 to about 1:1, about 5:1 to about 1:1, about 4:1 to about 1:1, about 3:1 to about 3:1, about 2:1 to about 1: 2, about 1:1 to about 1:4, about 1:1 to about 1:5, about 1:1 to about 1:6, about 1:1 to about 1:7, about 1:1 to about 1: 8, about 1:1 to about 1:9, about 1:1 to about 1:10, about 1:1 to about 1:20, about 1:1 to about 1:30, about 1:1 to about 1: 40, or from about 1:1 to about 1:50 v/v.

In one embodiment, the non-Form C polymorph is a compound of Formula I, or a salt, solvate, or hydrate thereof (such as a crystalline form, an amorphous form, or a crystalline form and / or a mixture of amorphous forms) in solid form. In one embodiment, the non-Form C polymorph is Form A, Form B, Form D, Form E, Form F, Form G, Form H, Form I, Form J, or an amorphous form of the compound of Formula I, or salts, solvates or hydrates thereof; or a mixture of two or more thereof. In one embodiment, the non-Form C polymorph may comprise at least about 50% by weight of polymorph Form A of the compound of formula (I). In one embodiment, a non-Form C polymorph (eg, Form A or Form B) can be obtained from a composition comprising Form C.

In one embodiment, the present invention provides

(i) combining a compound of formula la²to form a compound of formula (I); and

(ii) recovering polymorph Form C of the compound of formula (I), wherein at least one of steps (i) and (ii) occurs under non-anhydrous conditions.

There is provided a process for the preparation of polymorph Form C of a compound of formula (I), comprising:

[Formula Ia]

<img file="KR20140020249A_D0006.tif" />

[Formula I]

<img file="KR20140020249A_D0007.tif" />

In the above formula,

PG²is methylsulfonyl, substituted methylsulfonyl, benzenesulfonyl, substituted benzenesulfonyl, benzyloxycarbonyl, substituted benzyloxycarbonyl, 2,2,2-trichloroethoxycarbonyl, 2-trimethyl Silylethoxycarbonyl, t-butoxycarbonyl, 1-adamantyloxycarbonyl, 2-adamantyloxycarbonyl, alkyl, substituted alkyl, t-butyldimethylsilyl, triisopropylsilyl, allyl , benzyl, substituted benzyl, hydroxymethyl, methoxymethyl, diethoxymethyl, (2-chloroethoxy)methyl, t-butoxymethyl, t-butyldimethylsiloxymethyl, pivaloyloxymethyl, a protecting group selected from benzyloxymethyl, dimethylaminomethyl, 2-tetrahydropyranyl, substituted alkoxymethyl and substituted aryloxymethyl;

In this case, the substituent is alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, alkoxy, cycloalkoxy, heterocyclyloxy, aryloxy, heteroaryloxy , amido, amino, acyl, acyloxy, alkoxycarbonyl, ester, ether, thio, sulfinyl, sulfonyl, sulfonamido, halo, cyano, hydroxyl, nitro, phosphate, urea, carbamate and carbonate is selected from

In some embodiments, the protecting group PG²One or more reagents for removal include, but are not limited to, acids such as HCl, HBr and TFA; Carbonate bases such as Na₂CO₃ and K₂CO₃; hydroxyl bases such as NaOH and KOH; lithium bases such as methyl lithium, ethyl lithium, propyl lithium, n-butyl lithium, n-pentyl lithium, and n-hexyl lithium; oxidizing agents such as cerium ammonium nitrate; hydrogenation conditions such as cyclohexadiene/Pd black, and H₂/Pd/C; TBAF, and BF₃Et₂contains O. In one embodiment, the non-anhydrous condition comprises water, such as in the form of water vapor and/or liquid water. In one embodiment, the non-anhydrous condition comprises a solvent system comprising a non-aqueous solvent described herein and liquid water.

In certain embodiments, the polymorph provided herein is polymorph Form C of a compound of Formula (I). In certain embodiments, the present invention is a solid form of a compound of Formula (I), including Form C of the compound of Formula (I). In certain embodiments, the present invention provides a solid form of a compound of Formula (I), comprising Form C of the compound of Formula (I), which is substantially pure. In one embodiment, Form C can be characterized as having X-ray powder diffraction (XRPD) peaks at about 10.4, about 13.3, and about 24.3 degrees 2θ. In certain embodiments, Form C is characterized as having a differential scanning calorimetry (DSC) value that is endothermic at about 208°C. In another embodiment, Form C is characterized as having differential scanning calorimetry values that are endothermic at about 208°C, exothermic at about 222°C, and endothermic at about 280°C. In certain embodiments, Form C can be characterized by thermogravimetric analysis in which % weight loss is observed to be about 1.7% at about 80°C and about 0.2% at about 190°C.

In one embodiment, the present invention provides

(i) combining a compound of formula la²to form a compound of formula (I); and

(ii) recovering polymorph Form A of the compound of formula (I), wherein at least one of steps (i) and (ii) occurs under non-anhydrous conditions.

There is provided a process for the preparation of polymorph Form A of formula (I), comprising:

[Formula Ia]

<img file="KR20140020249A_D0008.tif" />

[Formula I]

<img file="KR20140020249A_D0009.tif" />

In the above formula,

PG²is methylsulfonyl, substituted methylsulfonyl, benzenesulfonyl, substituted benzenesulfonyl, benzyloxycarbonyl, substituted benzyloxycarbonyl, 2,2,2-trichloroethoxycarbonyl, 2-trimethyl Silylethoxycarbonyl, t-butoxycarbonyl, 1-adamantyloxycarbonyl, 2-adamantyloxycarbonyl, alkyl, substituted alkyl, t-butyldimethylsilyl, triisopropylsilyl, allyl , benzyl, substituted benzyl, hydroxymethyl, methoxymethyl, diethoxymethyl, (2-chloroethoxy)methyl, t-butoxymethyl, t-butyldimethylsiloxymethyl, pivaloyloxymethyl, a protecting group selected from benzyloxymethyl, dimethylaminomethyl, 2-tetrahydropyranyl, substituted alkoxymethyl and substituted aryloxymethyl;

In this case, the substituent is alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, alkoxy, cycloalkoxy, heterocyclyloxy, aryloxy, heteroaryloxy , amido, amino, acyl, acyloxy, alkoxycarbonyl, ester, ether, thio, sulfinyl, sulfonyl, sulfonamido, halo, cyano, hydroxyl, nitro, phosphate, urea, carbamate and carbonate is selected from

In some embodiments, step (ii) may comprise recrystallizing the compound of formula (I), or a salt, solvate or hydrate thereof, in a single-solvent system free of both ethyl acetate and hexane, or in a multi-solvent system. have. In certain embodiments, the method comprises dissolving a compound of formula (I), or a salt, solvate or hydrate thereof, in a single-solvent system or a multi-solvent system, removing residual solid material to obtain a liquid solution, said liquid cooling the solution at a rate sufficient to effect crystallization of Form A, and collecting Form A from the liquid solution.

In some embodiments, the protecting group PG²One or more reagents for removal include, but are not limited to, acids such as HCl, HBr and TFA; Carbonate bases such as Na₂CO₃ and K₂CO₃; hydroxyl bases such as NaOH and KOH; lithium bases such as methyl lithium, ethyl lithium, propyl lithium, n-butyl lithium, n-pentyl lithium, and n-hexyl lithium; oxides such as cerium ammonium nitrate; hydrogenation conditions such as cyclohexadiene/Pd black, and H₂/Pd/C; TBAF, and BF₃Et₂contains O.

In one embodiment, the present invention provides a composition comprising a compound of formula (I):

[Formula I]

<img file="KR20140020249A_D0010.tif" />

In one embodiment, the composition comprises polymorph Form C. In one embodiment, the composition comprises a mixture of polymorph Form C and one or more non-Form C polymorphs of a compound of Formula I, or a pharmaceutically acceptable salt, solvate or hydrate thereof. For example, in certain embodiments, the composition may comprise polymorph Form C and polymorph Form A. In other embodiments, the composition may comprise polymorph Form C and polymorph Form B. In other embodiments, the composition may comprise polymorph Form C and polymorph Form D. In other embodiments, the composition may comprise Polymorph Form C and Polymorph Form E. In other embodiments, the composition may comprise polymorph Form C and polymorph Form F. In other embodiments, the composition may comprise polymorph Form C and polymorph Form G. In other embodiments, the composition may comprise polymorph Form C and polymorph Form H. In other embodiments, the composition may comprise Polymorph Form C and Polymorph Form I. In other embodiments, the composition may comprise polymorph Form C and polymorph Form J. In another embodiment, the composition may comprise polymorph Form C and an amorphous form of a compound of Formula I, or a pharmaceutically acceptable salt, solvate or hydrate thereof. In one embodiment, the ratio of polymorph Form C to the total amount of non-Form C polymorph is greater than about 1:1, greater than about 2:1, greater than about 3:1, greater than about 4:1, about 5:1 greater than, greater than about 6:1, greater than about 7:1, greater than about 8:1, or greater than about 9:1. In one embodiment, the composition comprising Form C is a pharmaceutical composition. In one embodiment, the composition is at least about 98% by weight of the compound of Formula I, or a pharmaceutically acceptable salt, solvate or hydrate thereof.

In one embodiment, the composition comprises a mixture of polymorph Form A and one or more non-Form A polymorphs of a compound of Formula I, or a pharmaceutically acceptable salt, solvate or hydrate thereof. For example, in certain embodiments, a composition may include polymorph Form A and polymorph Form B. In other embodiments, the composition may comprise Polymorph Form A and Polymorph Form C. In other embodiments, the composition may comprise polymorph Form A and polymorph Form D. In other embodiments, the composition may comprise Polymorph Form A and Polymorph Form E. In other embodiments, the composition may comprise polymorph Form A and polymorph Form F. In other embodiments, the composition may comprise polymorph Form A and polymorph Form G. In other embodiments, the composition may comprise polymorph Form A and polymorph Form H. In other embodiments, the composition may comprise Polymorph Form A and Polymorph Form I. In other embodiments, the composition may comprise polymorph Form A and polymorph Form J. In another embodiment, the composition may comprise polymorph Form A and an amorphous form of a compound of Formula I, or a pharmaceutically acceptable salt, solvate or hydrate thereof. In one embodiment, the ratio of polymorph Form A to the total amount of non-Form A polymorph is greater than about 1:1, greater than about 2:1, greater than about 3:1, greater than about 4:1, about 5:1 greater than, greater than about 6:1, greater than about 7:1, greater than about 8:1, or greater than about 9:1. In one embodiment, the ratio of polymorph Form A to the total amount of non-Form A polymorph is less than about 1:1, less than about 2:1, less than about 3:1, less than about 4:1, about 5:1 less than, less than about 6:1, less than about 7:1, less than about 8:1, or less than about 9:1. In one embodiment, the composition comprising Form A is a pharmaceutical composition. In one embodiment, the composition is at least about 98% by weight of the compound of Formula I, or a pharmaceutically acceptable salt, solvate or hydrate thereof.

In one embodiment, a composition provided herein is a solid formulation comprising a polymorph of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate or hydrate thereof, and one or more pharmaceutically acceptable excipients. In one embodiment, a composition provided herein is a single unit dosage form comprising a polymorph of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate or hydrate thereof. In one embodiment, a composition provided herein is a tablet or capsule. In one embodiment, a composition provided herein is a capsule.

In one embodiment, a composition provided herein comprises a therapeutically effective amount of a polymorph of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate or hydrate thereof. In some embodiments, the therapeutically effective amount is about 0.5 mg, about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg , about 95 mg, about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, about 200 mg, about 210 mg, about 220 mg, about 230 mg, about 240 mg, about 250 mg, about 260 mg, about 270 mg, about 280 mg, about 290 mg, about 300 mg, about 325 mg, about 350 mg, about 375 mg , about 400 mg, about 425 mg, about 450 mg, about 475 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, or about 1000 mg or more. In one embodiment, a composition provided herein comprises one or more pharmaceutically acceptable carriers or excipients. In some embodiments, the compositions provided herein include one or more pharmaceutically acceptable carriers or excipients, such as, for example, microcrystalline cellulose, crospovidone, and/or magnesium stearate. In one embodiment, a composition provided herein is an immediate-release formulation. In some embodiments, a composition provided herein is a hard gelatin capsule. In some embodiments, a composition provided herein is a soft gelatin capsule. In some embodiments, a composition provided herein comprises Form C of a compound of Formula (I). In some embodiments, a composition provided herein comprises Form A of a compound of Formula (I). In some embodiments, a composition provided herein comprises an amorphous form of a compound of Formula (I). In some embodiments, a composition provided herein comprises a polymorph of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate or hydrate thereof, such as polymorphs A, B, C, D, E, F, described herein; and mixtures of two or more of G, H, I, and J.

In another embodiment, a composition provided herein is a suspension comprising carboxymethyl cellulose and water. In one embodiment, a composition provided herein comprises one or more excipients such as polysorbate, polyethylene glycol, cyclodextrin, dextrose, n-methylpyrrolidone, pH buffered solution, dilute hydrochloric acid, 12-hydroxystearic acid. polyoxyethylene esters, or mixtures of two or more thereof. Other excipients that may be used in the exemplary formulas include, but are not limited to, fillers such as lactose, mannitol, starch, sorbitol, sucrose, calcium diphosphate, and microcrystalline cellulose; disintegrants such as croscarmellose sodium and sodium starch glycolate; glidants such as colloidal silicon dioxide, silicon dioxide, magnesium silicate, and talc; lubricants such as sodium stearyl fumarate and stearic acid; and surfactants such as sodium lauryl sulfate, sodium dodecyl sulfate, Tween^&amp;#174; 80, and Lutrol^&amp;#174;may include

In one embodiment, a composition provided herein is used for the treatment of a PI3K-associated disease (eg, a disease or disorder described herein or known in the art). In one embodiment, a composition provided herein is used to inhibit PI3K kinase activity. The efficacy of compounds of formula (I) in the methods disclosed herein and the like are disclosed, for example, in US 2009/0312319.

In one embodiment, the present invention provides a method of treating a PI3K-associated disease (such as a disease or disorder described herein or known in the art), wherein said method comprises a polymorph of a compound of formula (I), or a method thereof and administering a pharmaceutically acceptable salt, solvate or hydrate to a subject in need thereof. In one embodiment, the present invention provides a method of treating a PI3K-associated disease, wherein the method comprises administering to a subject in need thereof a polymorph of a compound of formula (I), or a pharmaceutically acceptable salt, solvate or hydrate thereof. including administration to In one embodiment, the present invention provides a method of treating a PI3K-associated disease, comprising administering to an individual in need thereof a composition provided herein. In one embodiment, the method comprises orally, parenterally or topically administering to a patient in need of treatment a polymorph of a compound of formula (I), or a pharmaceutically acceptable salt, solvate or hydrate, or composition thereof. include that In one embodiment, the method comprises co-administering one or more additional therapeutic agents or treating the individual with one or more additional therapies (eg, radiation therapy or surgery).

1 depicts X-ray powder diffraction (XRPD) for polymorph Form A. Figure 2 shows the XRPD for polymorph Form B. Figure 3 shows the XRPD for polymorph Form C. 4 shows the XRPD for polymorph Form D. Figure 5 shows the XRPD for polymorph form E. 6 shows the XRPD for polymorph Form F. 7 shows the XRPD for polymorph form G. 8 shows the XRPD for polymorph Form H. 9 shows the XRPD for Polymorph Form I. 10 shows the XRPD for polymorph form J. 11 depicts the XRPD for an amorphous compound of formula I. 12 depicts a differential scanning calorimetry (DSC) thermogram for polymorph Form A. 13 shows the DSC for polymorph form B. 14 shows the DSC for polymorph Form C. 15 shows the DSC for polymorph form D. 16 shows the DSC for polymorph E. 17 shows the DSC for polymorph form F. 18 depicts the DSC for polymorph form G. 19 depicts the DSC for polymorph form H. 20 depicts the DSC for polymorph Form I. 21 shows the DSC for polymorph form J. 22 depicts a DSC thermogram and thermogravimetric analysis (TGA) for polymorph Form A. 23 shows two DSC thermograms for polymorph Form C. 24 depicts DSC and TGA for polymorph Form F. 25 depicts a panel of salts tested for the formation of crystalline solids in various solvents. Figure 26 depicts the single crystal X-ray structure of the polymorphic G MTBE (t-butyl methyl ether) solvate of the compound of formula (I). 27 shows the FT-IR spectrum of polymorph Form C. 28 is polymorph Form C. ¹The H-NMR spectrum is shown. 29 is polymorph Form C. ¹³The C-NMR spectrum is shown. 30 depicts a dynamic vapor adsorption (DVS) analysis of polymorph Form C. 31 depicts a representative dissolution profile of capsules containing polymorph Form C.

Certain features of the disclosure are set forth in particular in the appended claims. An understanding of various features and/or advantages of the disclosure may be obtained by reference to the following detailed description, which sets forth exemplary embodiments.

While various embodiments of the disclosure have been shown and described herein, it will be apparent to those skilled in the art that such embodiments are provided by way of illustration only. Many variables, changes, and substitutions will occur to those skilled in the art without departing from this disclosure. It should be understood that various alternatives to the embodiments described herein will be employed in light of the present invention.

<b>Justice</b>

Unless defined otherwise, all technical and scientific terms used herein have the same meaning and are commonly understood by one of ordinary skill in the art.

As used in the specification and claims, the singular forms include the plural forms, unless expressly indicated otherwise.

When ranges for physical properties, such as molecular weight, or chemical properties, such as chemical formula, are used herein, it is intended that all combinations and subcombinations of the ranges and specific embodiments herein be included. When referring to a number or range of numbers, the term "about" means an approximation within the experimental variability (or within statistical experimental error) of the stated number or range of numbers, so that the number or range of numbers is, for example, the number or range of numbers mentioned. 1 and 15%, 1 and 10%, 1 and 5%, 0.5 and 5%, and 0.5 and 1%. Also, for numbers or ranges of numbers modified by the term "about," as disclosed, all examples include the given number of embodiments. For example, "about 3° C." discloses a temperature embodiment of "3° C.". The term "about" is used fully interchangeably throughout the disclosure. The term "between" includes the number of endings on both limits of the range. For example, a range described as "3 to 5" includes "3" and "5".

As used herein, and unless otherwise specified, "agent" or "biologically active agent" or "second active agent" refers to a biological, pharmaceutical or chemical compound or other moiety. Non-limiting examples include simple or complex organic or inorganic molecules, peptides, proteins, oligonucleotides, antibodies, antibody derivatives, antibody fragments, vitamin derivatives, carbohydrates, toxins, or chemotherapeutic compounds. Various compounds can be synthesized, such as small molecules and oligomers (eg, oligopeptides and oligonucleotides), and synthetic organic compounds based on various central structures. In addition, various natural raw materials can provide compounds for screening, such as plant or animal extracts. One of ordinary skill in the art can readily recognize that the structural properties of the formulations disclosed herein are not limiting.

As used herein, and unless otherwise specified, the term "agent" refers to a compound that has the ability to initiate or enhance the biological function of a target protein, whether or not it enhances or initiates the activity or expression of the target protein. Thus, the term "agent" is defined in the context of the biological role of a target protein. Although an agent provided herein is capable of specifically interacting (eg, binding) a target, compounds that interact with other members of a signal transduction pathway of which the target protein is a member to initiate or enhance the biological activity of the target protein are also specifically included in this definition. Included.

As used herein, and unless otherwise specified, the terms "antagonist" and "inhibitor" are used interchangeably, which have the ability to inhibit a biological function of a target protein, regardless of inhibiting the activity or expression of the target protein. refers to compounds. Thus, the terms "antagonist" and "inhibitor" are defined in the context of the biological role of a target protein. Although antagonists provided herein are capable of specifically interacting (eg, binding) with a target, compounds that interact with other members of a signal transduction pathway of which the target protein is a member to initiate or enhance the biological activity of the target protein are also specifically included in this definition. Included. In one embodiment, the biological activity inhibited by the antagonist is associated with the development, growth or metastasis of a tumor, or an undesirable immune response, such as an immune response apparent in an autoimmune disease.

As used herein, and unless otherwise specified, "anti-cancer agent," "anti-tumor agent," or "chemotherapeutic agent" refers to any agent useful in the treatment of a neoplastic condition. One class of anticancer agents includes chemotherapeutic agents. As used herein, and unless otherwise specified, "chemotherapy" means administering one or more chemotherapeutic drugs and/or other agents in a variety of ways, such as intravenously, orally, intramuscularly, intraperitoneally, intravesically, subcutaneously, transdermally, buccal, buccal, or administration to cancer patients in the form of inhalation or suppositories.

As used herein, and unless otherwise specified, the term "cell proliferation" refers to a phenomenon in which the number of cells changes as a result of division. In one embodiment, the term also encompasses cell growth (eg, increase in size) in which cell morphology changes in agreement with a proliferative signal.

As used herein, and unless otherwise specified, the terms "co-administration", "administering in combination with" and grammatical equivalents thereof encompass administration of two or more agents to an animal simultaneously or sequentially. In one embodiment, both the agent and/or a metabolite thereof are present in the animal at the same time. In one embodiment, co-administration comprises administering separate compositions simultaneously, administering separate compositions at different times, or administering a composition in which both agents are present.

As used herein, and unless otherwise specified, the terms "effective amount" or "therapeutically effective amount" as used herein are sufficient to affect the intended application or effect, including but not limited to treating a disease as defined herein Refers to the amount of the compound. A therapeutically effective amount may vary depending on the intended application (in vitro or in vivo), which may be determined by one of ordinary skill in the art, or the subject and disease being treated, such as the subject's weight and age, the severity of the disease, and the method of administration. The term can also be applied to dosages that induce a specific response of a target cell, such as a decrease in platelet adhesion and/or cell migration. The particular dosage will vary depending on the particular compound chosen, the dosage regimen that follows, whether it is administered in combination with other compounds, the time of administration, the tissue to be administered, and the physical delivery system to be transported.

As used herein, and unless otherwise specified, the terms "treatment", "treat", "ameliorate" and "ameliorate" are used interchangeably herein, and do not refer to therapeutic benefit and/or prophylactic benefit. Refers to an approach for obtaining beneficial and desired results, including, but not limited to. In one embodiment, therapeutic benefit means eradication or amelioration of the underlying disorder being treated. In one embodiment, a therapeutic benefit is achieved by eradicating or ameliorating one or more physiological symptoms associated with the underlying disorder, such that improvement is observed in the patient even though the patient may still suffer from the underlying disorder. From a prophylactic advantage, the composition may be administered to a patient at risk of developing a particular disease, or a patient reporting one or more physiological symptoms of the disease in which a diagnosis of such disease may or may not be made.

As used herein, and unless otherwise specified, "therapeutic effect" encompasses the therapeutic and/or prophylactic benefits described herein. A prophylactic effect includes delaying or eliminating the appearance of a disease or symptom, delaying or eliminating the onset of a disease or symptom, delaying, stopping or reversing the progression of the disease or symptom, or any combination thereof.

As used herein, and unless otherwise specified, "signal transduction" is the sequence of processes in which a stimulatory or inhibitory signal is transmitted into and into a cell to elicit an intracellular response. A modulator of a signal transduction pathway refers to a compound that modulates the activity of one or more cellular proteins mapped to the same specific signal transduction pathway. A modulator may enhance (agonist) or inhibit (antagonist) the activity of a signaling molecule.

As used herein, and unless otherwise specified, the term "selective inhibition" or "selectively inhibit", as applied to a biologically active agent, selects a target signaling activity through direct or indirect interaction with the target as compared to off-target signaling activity. refers to the ability of an agent to reduce

As used herein, and unless otherwise specified, the term "in vivo" refers to an event occurring in an individual's body.

As used herein, and unless otherwise specified, the term "in vitro" refers to an event that occurs outside of a subject's body. For example, an in vitro assay encompasses any assay performed outside of a subject.<i>. </i>In vitro assays encompass cell-based assays using live or dead cells. In one embodiment, the in vitro assay also encompasses cell-free assays in which non-intact cells are used.

A "subject" contemplated for administration includes, but is not limited to, a human (ie, a male or female of any age group, such as a pediatric individual (eg, infant, child, adolescent) or adult individual (eg, young, middle-aged or elderly))). and/or other primates (eg, cynomolgus <i>monkey</i>), rhesus monkey; mammals, such as commercially relevant mammals such as cattle, pigs, horses, sheep, goats, cats, and/or dogs; and/or birds such as commercially related birds such as chickens, ducks, geese, quails, and/or turkeys.

As used herein, and unless otherwise specified, "radiation therapy" refers to treating a patient with a radiation emitter, such as an alpha-particle emitting radionuclide (eg, actinium and thorium radionuclides), using a general method and composition known to a physician Linear energy transfer (LET) radiation emitters (such as beta emitters), switched electron emitters (such as strontium-89 and samarium-153-EDTMP), or high energy radiation including, but not limited to, X-rays, gamma rays, and neutrons means to be exposed to

As used herein, the term "combining" refers to the transfer of one or more chemical substances into another one or more related substances. Combining involves adding one or more compounds to a solid, liquid, or gas mixture, or liquid solution or multiphase liquid mixture, of one or more compounds (the same or different chemical substances). The act of combining is the act of reacting (e.g., bond form or dissociation; salt form, solvate form, chelate, or other non-bond substitutional association) with one or more compounds (the same or different chemical substances). includes the process. The action of combining can include replacing one or more compounds, such as isomerization (eg, tautomerization, resolution of one isomer from another, racemization).

As used herein, the term "recover" includes, but is not limited to, the act of collecting one or more compounds during and/or after the process steps disclosed herein, and the act of collecting one or more compounds during and/or after the process steps disclosed herein. separation from one or more other chemical substances to yield one or more compounds. The term "collection" includes, but is not limited to, decanting a mother liquor from a solid to obtain one or more compounds and evaporating a liquid medium in solution or other mixture to obtain a solid, oil or other residue comprising one or more compounds. refers to any action known in the art for the purposes of the present invention, including making The solid may be crystalline, amorphous, partially crystalline, amorphous containing one or more polymorphs of constant particle size, powders, granules, varying particle sizes, among other properties known in the art. Oils may vary in color and viscosity and include one or more solid forms as heterogeneous mixtures, among other properties known in the art. The term "separation" includes, but is not limited to, the separation of one or more compounds by, for example, seeded or seedless crystallization or other precipitation techniques (eg, adding an antisolvent to a solution to induce compound precipitation; heating the solution and then cooling to precipitate the compound induction; inducing compound precipitation by scraping the solution surface with a tool), and isolating from a solution or mixture using distillation techniques. Recovering one or more compounds may involve preparing salts, solvates, hydrates, chelates or other complexes of the same materials, followed by collection or isolation as described herein.

As used herein, a "pharmaceutically acceptable form" of the disclosed Formula I includes, but is not limited to, pharmaceutically acceptable salts, hydrates, solvates, chelates, non-covalent complexes, isomers, prodrugs, and isotopically labeled derivatives, and mixtures thereof. Accordingly, the term "chemical entity" also encompasses pharmaceutically acceptable salts, hydrates, solvates, chelates, non-covalent complexes, isomers, prodrugs, and isotopically labeled derivatives, and mixtures thereof. In some embodiments, disclosed pharmaceutically acceptable forms of Formula I include salts, solvates or hydrates.

In certain embodiments, the pharmaceutically acceptable form is a pharmaceutically acceptable salt. As used herein, the term "pharmaceutically acceptable salt" refers to a salt useful for contacting tissue of an individual that has not suffered toxic, irritant, allergic reactions, etc. within the scope of sound medical judgment, and is proportional to an appropriate benefit/risk ratio. refers to Pharmaceutically acceptable salts are well known in the art. For example, Berge et al. described pharmaceutically acceptable salts [<i>J. </i><i>Pharmaceutical</i><i></i><i>Sciences</i>(1977) 66:1-19]. Pharmaceutically acceptable salts of the compounds provided herein are salts derived from suitable inorganic and organic acids and bases. Inorganic acids that can be derived from salts include, but are not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like. Organic acids that can be derived from salts include, but are not limited to, acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethane sulfonic acid,<i>p</i>-Contains toluenesulfonic acid, salicylic acid, and the like. Examples of pharmaceutically acceptable, non-toxic acid addition salts include inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or in the art salts of amino groups formed using other methods used in ion exchange, such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, besylate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate. Eate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulphate, heptanoate, hexanoate, hydroiodide, 2 -Hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate , oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p- toluenesulfonate, undecanoate, valerate salts and the like. In some embodiments, organic acids that can be derivatized into salts include, for example, acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid phonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like.

Pharmaceutically acceptable salts derived from suitable bases include alkali metals, alkaline earth metals, ammonium and N⁺(C₁_-4 alkyl)⁴- Contains salt. Inorganic bases from which salts can be derived include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, and the like. Organic bases from which salts can be derived include primary, secondary and tertiary amines, substituted amines such as naturally occurring substituted amines, cyclic amines, basic ion exchange resins and the like, such as, but not limited to, isopropylamine; trimethylamine, diethylamine, triethylamine, tripropylamine, and ethanolamine. In some embodiments, the pharmaceutically acceptable base addition salt is an ammonium, potassium, sodium, calcium, or magnesium salt. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, and the like. Where appropriate, additional pharmaceutically acceptable salts include non-toxic ammonium, quaternary ammonium, formed with counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkyl sulfonates and aryl sulfonates, and amine cations. Organic bases from which salts can be derived include, for example, primary, secondary and tertiary amines, substituted amines such as naturally substituted amines, cyclic amines, basic ion exchange resins and the like, such as isopropylamine, trimethyl amine, diethylamine, triethylamine, tripropylamine, and ethanolamine. In some embodiments, the pharmaceutically acceptable base addition salt is selected from ammonium, potassium, sodium, calcium, and magnesium salts. Bis salts (ie, two counterions) and higher salts (eg, three or more counterions) are encompassed within the meaning of pharmaceutically acceptable salts.

In addition, when the compound herein is obtained as an acid addition salt, the free base can be obtained by basifying the acid salt solution. Conversely, when the product is the free base, the acid addition salt, particularly a pharmaceutically acceptable addition salt, is dissolved in a suitable organic solvent in accordance with the conventional procedure for preparing acid addition salts from a base compound, and the solution is converted to an acid. It can be created by processing. One of ordinary skill in the art will recognize a variety of synthetic methods that can be used to prepare non-toxic, pharmaceutically acceptable addition salts.

In certain embodiments, the pharmaceutically acceptable form is a "solvate" (eg, a hydrate). As used herein, the term "solvate" refers to a compound that further comprises a stoichiometric or non-stoichiometric amount of a solvent bound by non-covalent intermolecular forces. The solvate may be a disclosed compound or a pharmaceutically acceptable salt thereof. When the solvent is water, the solvate is a "hydrate". Pharmaceutically acceptable solvates and hydrates are complexes that may include, for example, 1 to about 100, or 1 to about 10 or 1 to about 2, 3 or 4 molecules of solvent or water. In some embodiments, the hydrate may be a channel hydrate. It will be understood that the term "compound" as used herein encompasses compounds and solvates as well as mixtures thereof.

As used herein, and unless otherwise specified, "prodrug" refers to a compound that is capable of conversion under physiological conditions or by solvolysis of a biologically active compound described herein. Accordingly, the term "prodrug" refers to a pharmaceutically acceptable precursor of a biologically active compound. When administered to a subject, the prodrug may be inactive, but the active compound is converted in vivo, such as hydrolyzed. In some embodiments, prodrug compounds often offer advantages of solubility, tissue compatibility, or delayed release in mammalian organisms (see, e.g., Bundgard, H., Design of Prodrugs (1985), pp. 7-9, 21-24 (Elsevier, Amsterdam) A discussion of prodrugs can be found in Higuchi, T.,<i></i><i>et</i><i></i><i>al</i><i>.</i>, "Pro-drugs as Novel Delivery Systems," ACS Symposium Series, Vol. 14, and in Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987, both of which are incorporated herein by reference. Also, when such prodrugs are administered to a mammalian subject, the term "prodrug" includes any covalent carrier that releases the active compound in vivo. Prodrugs of the active compounds described herein can be prepared by modifying the functional groups present in the active formula (I) either by routine manipulation or by separation of the modifications into the parent active compound in vivo. When an active prodrug of formula (I) is administered to a mammalian subject and separated to form a free hydroxy, free amino or free mercapto group, respectively, the prodrug is a compound in which the hydroxy, amino or mercapto group is attached to any group. include Examples of prodrugs include, but are not limited to, acetate, formate, and benzoate derivatives of alcohols in the active compound; or acetamide, formamide, and benzamide derivatives of an amine functional group. Another example of a prodrug is -NO, -N_O2, -ONO, or -ON_O2 compounds comprising a moiety. Prodrugs are typically prepared by well-known methods, such as [<i>Burger's</i><i> Medicinal </i><i>Chemistry</i><i></i><i>and</i><i></i><i>Drug</i><i></i><i>Discovery</i>, 172-178, 949-982 (Manfred E. Wolff ed., 5th ed., 1995), and in the design of prodrugs (H. Bundgaard ed., Elselvier, New York, 1985). It can be prepared using the methods described.

For example, when a disclosed compound, or a pharmaceutically acceptable form thereof, contains a carboxylic acid functional group, the prodrug replaces the hydrogen atom of the acid group with a group such as (C₁-C₈)alkyl, (C₂-C₁₂) alkanoyloxymethyl, 1-(alkanyloxy)ethyl having 4 to 9 carbon atoms, 1-methyl-1-(alkanyloxy)-ethyl having 5 to 10 carbon atoms, 3 to 6 carbons alkoxycarbonyloxymethyl having atoms, 1-(alkoxycarbonyloxy)ethyl having 4 to 7 carbon atoms, 1-methyl-1-(alkoxycarbonyloxy)ethyl having 5 to 8 carbon atoms, 3 N-(alkoxycarbonyl)aminomethyl having to 9 carbon atoms, 1-(N-(alkoxycarbonyl)amino)ethyl having 4 to 10 carbon atoms, 3-phthalidyl, 4-crotonolactonyl , gamma-butyrolacton-4-yl, di-N,N-(C₁-C₂) Alkylamino (C₂-C₃) Alkyl (eg β-dimethylaminoethyl), carbamoyl-(C₁-C₂)alkyl, N,N-di(C₁-C₂) Alkylcarbamoyl-(C₁-C₂) alkyl and piperidino-, pyrrolidino- or morpholino (C₂-C₃) may include a pharmaceutically acceptable ester formed by substitution with an alkyl.

Similarly, when a disclosed compound, or a pharmaceutically acceptable form thereof, contains an alcohol functional group, the prodrug replaces the hydrogen atom of the alcohol group with a group such as (C₁-C₆) alkanoyloxymethyl, 1-((C₁-C₆) alkanoyloxy) ethyl, 1-methyl-1- ((C₁-C₆) alkanoyloxy) ethyl (C₁-C₆) Alkoxycarbonyloxymethyl, N- (C₁-C₆) Alkoxycarbonylaminomethyl, succinic oil, (C₁-C₆) alkanoyl, α-amino (C₁-C₄) alkanoyl, arylacyl and α-aminoacyl, or α-aminoacyl-α-aminoacyl, wherein each α-aminoacyl group is a naturally occurring L-amino acid, P(O) (OH)₂, -P(O)(O(C₁-C₆)alkyl)₂ or glycosyl (a radical formed by removal of a hydroxyl group in the hemiacetal form of a carbohydrate).

When a disclosed compound or pharmaceutically acceptable form thereof incorporates an amine functional group, a prodrug may be formed by substituting a hydrogen atom in the amine group with a group such as R-carbonyl, RO-carbonyl, NRR'-carbonyl. wherein R and R' are each independently (C₁-C₁₀)alkyl, (C₃-C₇) cycloalkyl, benzyl, natural α-aminoacyl or natural α-aminoacyl-natural α-aminoacyl, -C(OH)C(O)OY¹, where Y¹is H, (C₁-C₆)alkyl or benzyl, -C(OY²)Y³, where Y²is (C)₁-C₄) alkyl, Y³is (C)₁-C₆) Alkyl, carboxy (C₁-C₆) alkyl, amino (C₁-C₄)alkyl or mono-N- or di-N,N-(C₁-C₆)alkylaminoalkyl, -C(Y⁴)Y⁵, where Y⁴is H or methyl, Y⁵is mono-N- or di-N,N-(C₁-C₆) alkylamino, morpholino, piperidin-1-yl or pyrrolidin-1-yl.

In certain embodiments, the pharmaceutically acceptable form is an isomer. "Isomers" are different compounds having the same molecular formula. "Stereoisomers" are isomers that differ only in the way their atoms are arranged in space. As used herein, the term "isomer" includes any and all geometric isomers and stereoisomers. For example, "isomers" include, within the scope disclosed herein, geometric double bond cis- and trans-isomers, also named E- and Z-isomers; R- and S-enantiomers; diastereomers, (d)-isomers and (l)-isomers, racemic mixtures thereof; and other mixtures thereof.

Alternatively, a substituent around a carbon-carbon double bond may be referred to as "cis" or "trans", where "cis" refers to a substituent on the same side of the double bond and "trans" refers to a substituent on the opposite side of the double bond. represents a substituent. Also, the arrangement of substituents around a carbocyclic ring may be designated as "cis" or "trans". The term "cis" denotes substituents on the same side of the plate of the ring, and the term "trans" denotes a substituent on the opposite side of the plate of the ring. A mixture of compounds is designated "cis/trans" when the substituents are located on the same and different sides of the plate of the ring.

"Enantiomers" are pairs of stereoisomers that are non-superimposable mirror images of each other. A mixture of pairs of enantiomers in any fraction may be known as a "racemic" mixture. The term "(±)" is used to designate a racemic mixture, as appropriate. "Diastereomers" are stereoisomers that have two or more asymmetric atoms, but are not mirror images of each other. Absolute stereochemistry is specified by the Cahn-Ingold-Prelog RS system. When formula (I) is an enantiomer, the stereochemistry at each chiral carbon may be specified as R or S. A cleaved compound whose absolute configuration is unknown can be specified as (+) or (-) depending on the direction of rotation of the polarizer at the wavelength of the sodium D line (right-handedness or left-handedness). Certain compounds described herein contain one or more asymmetric centers and therefore enantiomers, diastereomers, and other stereoisomeric forms that can be defined with respect to absolute stereochemistry at each asymmetric atom as (R) or (S). can occur The chemical substances, pharmaceutical compositions and methods herein include all such possible isomers, including racemic mixtures, optically substantially pure forms and intermediate mixtures. The optically active (R) and (S) isomers can be prepared using, for example, chiral synthons or chiral reagents, or dissolved using conventional techniques.

As used herein, and unless otherwise specified, the term "stereomerically pure" means a composition or material comprising one stereoisomer of a compound and substantially free of other stereoisomers of the compound. For example, a stereomerically pure composition of a compound having one chiral center is substantially free of the opposite enantiomer of the compound. A stereomerically pure composition of a compound having two chiral centers is a composition that contains other stereoisomers of the compound (eg, diastereomers or enantiomers, or<i>syn</i> or <i>anti</i> isomers, or cis or trans isomers). Typically, a stereoisomerically pure compound is greater than about 80% by weight of the stereoisomers of the compound and less than about 20% by weight of the other stereoisomers of the compound, greater than about 90% by weight of the stereoisomers of the compound and greater than about 90% by weight of the other stereoisomers of the compound. less than 10% by weight, greater than about 95% by weight of the stereoisomers of the compound and less than about 5% by weight of the other stereoisomers of the compound, or greater than about 97% by weight of the stereoisomers of the compound and about 3% by weight of the other stereoisomers of the compound include less than

As used herein, and unless otherwise specified, the term "enantiomerically pure" means a stereoisomerically pure composition of a compound having one or more chiral centers.

As used herein, and unless otherwise specified, the terms "enantiomeric excess" and "diasteric excess" are used interchangeably herein. In some embodiments, a compound comprising a single stereocenter may be referred to as a compound that is in "enantiomeric excess", and a compound comprising two or more stereocenters is a compound that exists in "diasteric excess". may be referred to as For example, the term "enantiomeric excess" is well known in the art and is defined by the following equation:

[Equation 1]

<img file="KR20140020249A_D0011.tif" />

Thus, the term "enantiomeric excess" relates to the term "optical purity", both of which are measurands of the same phenomenon. The value of ee ranges from 0 to 100, with 0 in the racemate and 100 in the enantiomerically pure isomer. Compounds that were previously called 98% optically pure now more accurately characterize 96% ee. 90% ee reflects the presence of 95% of one enantiomer and 5% of the other enantiomer in the material.

Some compositions described herein contain an enantiomeric excess of at least about 50%, 75%, 90%, 95%, or 99% of the S enantiomer. In other words, the composition contains an enantiomeric excess in which the S enantiomer is greater than the R enantiomer. In other embodiments, some compositions described herein contain an enantiomeric excess of at least about 50%, 75%, 90%, 95%, or 99% of the R enantiomer. In other words, the composition contains an enantiomeric excess with more R enantiomer than S enantiomer.

For example, an isomer/enantiomer may, in some embodiments, be provided with the corresponding enantiomer substantially free of, and also as used interchangeably herein "optically enriched", "enantiomerically enriched" ", "enantiomerically pure" and "non-racemate". This term refers to a composition in which the % weight of one enantiomer is greater than the amount of one enantiomer in a controlled mixture (eg, greater than about 1:1 weight) of the racemic composition. For example, an enantiomerically enriched preparation of the S enantiomer means a compound preparation having greater than about 50% by weight, such as at least about 75%, further such as at least about 80% by weight, of the S enantiomer as compared to the R enantiomer. do. In some embodiments, the abundance may be greater than about 80% by weight, comprising at least about 85% by weight of one enantiomer, such as at least about 90% by weight, and further such as at least 95% by weight of one enantiomer as compared to the other enantiomer. "Substantially enantiomerically enriched", "substantially enantiomerically pure" or "substantially non-racemic" preparations, which refer to preparations of compositions having In certain embodiments, a compound provided herein consists of at least about 90% by weight of one enantiomer. In other embodiments, Formula I consists of at least about 95, 98, or 99 weight percent of one enantiomer.

In some embodiments, Formula I is a racemic mixture of (S)- and (R)-isomers. In another embodiment, the present invention provides a mixture of compounds, wherein the individual compounds of the mixture exist predominantly in (S)- or (R)-isomeric configurations. For example, a mixture of compounds may be greater than about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 96%, about 97%, about 98%, about 99%, about 99.5%, or greater (S)-enantiomeric excess. In other embodiments, the compound mixture is greater than about 55% to about 99.5%, greater than about 60% to about 99.5%, greater than about 65% to about 99.5%, greater than about 70% to about 99.5%, greater than about 75% to about 99.5%, greater than about 80% to about 99.5%, greater than about 85% to about 99.5%, greater than about 90% to about 99.5%, greater than about 95% to about 99.5%, greater than about 96% to about 99.5%, about 97 % to greater than about 99.5%, greater than about 98% to greater than about 99.5%, greater than about 99% to about 99.5%, or greater (S)-enantiomeric excess.

In other embodiments, the compound mixture is greater than about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 96%, about 97%, about 98%, about 99%, about 99.5%, or greater (R)-enantiomeric purity. In some other embodiments, the compound mixture is greater than about 55% to about 99.5%, greater than about 60% to about 99.5%, greater than about 65% to about 99.5%, greater than about 70% to about 99.5%, greater than about 75% to about 99.5%, greater than about 80% to about 99.5%, greater than about 85% to about 99.5%, greater than about 90% to about 99.5%, greater than about 95% to about 99.5%, greater than about 96% to about 99.5%, about greater than 97% to about 99.5%, greater than about 98% to greater than about 99.5%, greater than about 99% to about 99.5%, or greater (R)-enantiomeric excess.

In other embodiments, the compound mixture contains identical chemicals except for stereochemical orientation, i.e., the (S)- or (R)-isomer. For example, when a compound disclosed herein has a -CH(R)-unit and R is not hydrogen, then -CH(R)- is in the (S)- or (R)-stereochemical direction for the respective chemical entity. exist. In some embodiments, a mixture of the same chemical entity is a racemic mixture of (S)- and (R)- isomers. In another embodiment, a mixture of identical chemicals (except for their stereochemical orientation) contains predominantly (S)-isomers or predominantly (R)-isomers. For example, the (S)-isomer in a mixture of the same chemical is about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, compared to the (R)-isomer, about 90%, about 95%, about 96%, about 97%, about 98%, about 99%, about 99.5% or more. In some embodiments, the (S)-isomer in a mixture of the same chemical entity is greater than about 55 to about 99.5%, greater than about 60 to about 99.5%, greater than about 65 to about 99.5%, greater than about 70 to about 99.5%, about greater than 75 to about 99.5%, greater than about 80 to about 99.5%, greater than about 85 to about 99.5%, greater than about 90 to about 99.5%, greater than about 95 to about 99.5%, greater than about 96 to about 99.5%, greater than about 97 to about 99.5%, greater than about 98 to greater than about 99.5%, greater than about 99 to greater than about 99.5% (S)-enantiomeric excess.

In another embodiment, the (R)-isomer in a mixture of the same chemical entity (excluding their stereochemical orientation) is about 55%, about 60%, about 65%, about 70% compared to the (S)-isomer. , about 75%, about 80%, about 85%, about 90%, about 95%, about 96%, about 97%, about 98%, about 99%, about 99.5% or more. In some embodiments, the (R)-isomer in a mixture of the same chemical entity (excluding their stereochemical orientation) is greater than about 55 to about 99.5%, greater than about 60 to about 99.5%, greater than about 65 to about 99.5%, greater than about 70 to about 99.5%, greater than about 75 to about 99.5%, greater than about 80 to about 99.5%, greater than about 85 to about 99.5%, greater than about 90 to about 99.5%, greater than about 95 to about 99.5%, about 96 greater than about 99.5%, greater than about 97 to about 99.5%, greater than about 98 to greater than about 99.5%, greater than about 99 to greater than about 99.5% (R)-enantiomeric excess.

Enantiomers can be isolated from racemic mixtures by any method known to those of skill in the art, including chiral high pressure liquid chromatography (HPLC), chiral salt formation and crystallization, or prepared by asymmetric synthesis (see, e.g.,<i>Enantiomers</i><i>, Racemates </i><i>and</i><i> Resolutions</i>(Jacques, Ed., Wiley Interscience, New York, 1981)]; [Wilen et al.,<i>Tetrahedron</i> 33:2725(1977)]; [<i>stereochemistry</i><i></i><i>of</i><i> Carbon Compounds</i>(EL Eliel, Ed., McGraw-Hill, NY, 1962)]; and [<i>Tables</i><i> of </i><i>Resolving</i><i></i><i>Agents</i><i></i><i>and</i><i></i><i>Optical</i><i></i><i>Resolutions</i> p. 268] (see EL Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, IN 1972).

In certain embodiments, the pharmaceutically acceptable form is a tautomer. As used herein, the term "tautomer" refers to two or more interconvertible compounds resulting from one or more formal shifts of a hydrogen atom and one or more valence changes (eg, a single bond to a double bond, a triple bond to a single bond, or vice versa). isomeric type, including "Tautomerization" includes proton or proton transfer tautomerism which is considered a subset of acid-base chemistry. "Proton tautomerism" or "proton shift tautomerism" refers to the shift of protons accompanied by a change in the binding order. The exact proportions of tautomers depend on several factors including temperature, solvent, and pH. Where tautomerism is possible (eg, in solution), chemical equilibrium of the tautomer can be achieved. Tautomerization (ie, a reaction that gives a tautomeric pair) may be catalyzed with an acid or base, or may occur without the action or presence of an external agent. Exemplary tautomerizations include, but are not limited to, keto to enol; amide to imide; lactim from lactam; imine from enamines; and (different) enamine tautomerization from enamines. An example of ketoenol tautomerism is the interconversion of pentane-2,4-dione and 4-hydroxypent-3-en-2-one tautomers. Another example of tautomerism is phenolketo tautomerism. Another example of phenolketo tautomerism is the interconversion of pyridin-4-ol and pyridin-4-(1H)-one tautomers.

As used herein, the term "Formula I" refers to (S)-3-(1-() in the imide tautomer shown as a compound of Formula I-1 9H-purin-6-ylamino)ethyl)-8-chloro-2-phenylisoquinolin-1(2H)-one:

[Formula I-1]

<img file="KR20140020249A_D0012.tif" />

[Formula I-2]

<img file="KR20140020249A_D0013.tif" />

The term "Formula I" as described above refers to (S)-3-(1-(9H) in the imide tautomer shown as a compound of Formula I-1 and the lactim tautomer shown as a compound of Formula I-2 -purin-6-ylamino)ethyl)-8-chloro-2-phenylisoquinolin-1(2H)-one:

[Formula I-1]

<img file="KR20140020249A_D0014.tif" />

[Formula I-2]

<img file="KR20140020249A_D0015.tif" />

As used herein, and unless otherwise specified, structures depicted herein also include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, replacing hydrogen with deuterium or tritium, replacing carbon with¹³C- or ¹⁴C-rich carbon substitution, nitrogen ¹³N- or ¹⁵Substitution with N-rich nitrogen, oxygen ¹⁴O-, ¹⁵O-, ¹⁷O-, or ¹⁸O-rich oxygen substitution, chlorine ³⁵Cl-, ³⁶Cl-, or ³⁷Compounds other than substitution with Cl-rich chlorine are within the scope of this disclosure.

In one embodiment, compounds of the present invention may also contain unnatural moieties of atomic isotopes at one or more atoms of which such compounds are composed. For example, a compound may contain radioactive isotopes such as tritium (³H), iodine-125 (¹²⁵I), or carbon-14 (¹⁴C) can be radiolabeled. Certain isotopically-labeled disclosed compounds (eg,³H and ¹⁴C) is useful for analysis of compound and/or matrix tissue distribution. tritiated (i.e.,³H) and carbon-14 (i.e., ¹⁴C) Isotopes can facilitate preparation and detection. Also, heavy isotopes such as deuterium (i.e.,²Substituents comprising H) may yield certain therapeutic benefits resulting from better metabolic stability (eg, increased in vivo half-life or reduced dosage requirements). Isotopically labeled disclosed compounds can generally be prepared by substituting an isotopically labeled reagent for a non-isotopically labeled reagent. In some embodiments, the present invention provides compounds that may contain unnatural moieties of atomic isotopes at one or more atoms that make up such compounds. All isotopic variations of the compounds of the invention, whether radioactive or not, are encompassed within the scope of this application.

As used herein, and unless otherwise specified, the terms "solvent", "organic solvent" or "inert solvent" each refer to a solvent that is inert under the reaction conditions described with the material, including, but not limited to, benzene, toluene, aceto Nitrile, ethyl acetate, isopropyl acetate, hexane, heptane, dioxane, tetrahydrofuran ("THF"), dimethylformamide ("DMF"), dimethylacetamide ("DMA"), chloroform, methylene chloride (di chloromethane), diethyl ether, methanol, butanol, methyl t-butyl ether ("MTBE"), 2-butanone ("MEK"), N-methylpyrrolidone ("NMP"), pyridine, and the like. . Unless otherwise specified, the solvents used in the reactions described herein are inert organic solvents. Unless otherwise specified, one cc (or mL) of solvent for each g of limiting reagent consists of volume equivalents.

As used herein, and unless otherwise specified, "pharmaceutically acceptable carrier" or "pharmaceutically acceptable excipient" means any and all solvents, suspension media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents. etc. The use of such media and agents for pharmaceutically active substances is known in the art. Except insofar as any conventional medium or agent is incompatible with the active ingredient, its use in the therapeutic compositions of the present invention is contemplated. Supplementary active ingredients may also be incorporated into the compositions.

As used herein, and unless otherwise specified, "polymorph" may be used herein to describe a crystalline substance, such as a crystalline form. In certain embodiments, also, unless a specific crystalline or amorphous form is indicated, "polymorph" as used herein refers to all crystalline and amorphous forms of a compound or salts thereof, such as crystalline forms, polymorphs, pseudopolymorphs, solvents. cargoes, hydrates, co-crystals, unsolvated polymorphs (including anhydrides), coordination polymorphs, tautomeric forms, disordered crystalline forms, and amorphous forms, mixtures thereof. The compounds of the present invention may contain crystalline and amorphous forms of such compounds, such as crystalline forms, polymorphs, pseudopolymorphs, solvates, hydrates, co-crystals, unsolvated polymorphs (including anhydrides), coordination polymorphs, tautomers of the compounds. isomeric forms, disordered crystalline forms, and amorphous forms or salts thereof, as well as mixtures thereof.

As used herein, and unless otherwise specified, certain forms of the compounds of Formula (I) described herein (e.g.,<i></i>Form A, B, C, D, E, F, G, H, I, J, or an amorphous form of the compound of formula (I), or a mixture thereof) is a solid form of the compound of formula (I), or a salt, solvate thereof or hydrates and the like.

As used herein, and unless otherwise specified, the term "solid form" and terms related herein refer to a physical form, including a compound provided herein, or a salt or solvate or hydrate thereof, that is not in a liquid or gaseous state. The solid form may be crystalline, amorphous, disordered crystalline, partially crystalline, and/or partially amorphous.

As used herein, and unless otherwise specified, when used to describe a material, component, or product, the term "crystalline" means that the material, component, or product is not substantially crystalline, as measured, for example, by X-ray diffraction. (See, e.g., Remington: The Science and Practice of Pharmacy, Lippincott Williams &amp; Wilkins, 21^st ed. (2005)]).

As used herein, and unless otherwise specified, the terms "crystalline form", "crystal form" and terms related herein refer to a given material, including single-component crystal forms and multi-component crystal forms, and, without limitation, polymorphs; solvates, hydrates, co-crystals and other molecular complexes, as well as salts, solvates of salts, hydrates of salts, other molecular complexes of salts, and polymorphs thereof. In certain embodiments, the crystalline form of the component may be substantially free of an amorphous form and/or other crystalline form. In other embodiments, the crystalline form of the material is about 1%, about 2%, about 3%, about 4%, about 5% by weight of one or more amorphous forms and/or other crystalline forms by weight and/or molecular weight. %, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, or about 50% by weight. can

A particular crystalline form of a material can be obtained by many methods, including, but not limited to, melt recrystallization, melt cooling, solvent recrystallization, recrystallization in confined spaces such as nanopores or capillaries, recrystallization on a surface or template such as a polymer, additives such as balls -recrystallization, desolvation, dehydration, rapid evaporation, rapid cooling, slow cooling, vapor diffusion, sublimation, milling, solvent-droplet milling, microwave-induced precipitation, ultrasonic-induced precipitation, laser in the presence of crystal counter-molecules - induced precipitation, and/or precipitation from supercritical fluids. As used herein, and unless otherwise specified, the term "isolation" also encompasses purification.

Techniques for characterizing crystalline and amorphous forms include, but are not limited to, thermogravimetric analysis (TGA), differential scanning calorimetry (DSC), X-ray powder diffraction (XRPD), single crystal X-ray diffraction, vibrational spectroscopy such as infrared ( IR) and Raman Spectroscopy, Solid-State Nuclear Magnetic Resonance (NMR) Spectrometer, Optical Microscopy, Hyperthermic Optical Microscopy, Scanning Electron Microscopy (SEM), Electron Crystallography and Quantitative Analysis, Particle Size Analysis (PSA), Surface Area Analysis, Dissolution Studies and dissolution studies.

As used herein, and unless otherwise specified, when used in connection with a given spectrum or data in graphical form (e.g., XRPD, IR, Raman, and NMR spectra), the term "peak" is not recognized by those skilled in the art as a source of noise. It refers to a peak or other special characteristic that does not exist. The term "specific peak" refers to a peak in the background level of at least 1.5, 2, or 2.5 times the median size (eg, height) of at least another peak in the spectrum or data, or at least 1.5, 2, or 2.5 times in the spectrum or data.

As used herein, and unless otherwise specified, the terms "amorphous", "amorphous form" and related terms mean that the substance, component or product is not substantially crystalline as determined by X-ray diffraction. In certain embodiments, the amorphous form of the material may be substantially free of other amorphous forms and/or crystalline forms. In certain embodiments, an amorphous form of a material may comprise one or more disordered crystalline forms. In other embodiments, the amorphous form of the material is about 1%, about 2%, about 3%, about 4%, about 5% by weight of one or more other amorphous and/or crystalline forms on a weight and/or molar basis. %, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, or about 50% by weight. can Amorphous forms of substances can be obtained by methods known in the art. Such methods include, but are not limited to, heating, melt cooling, rapid melt cooling, solvent evaporation, rapid solvent evaporation, desolvation, sublimation, milling, freeze-milling, spray drying, and freeze drying.

As used herein, and unless otherwise indicated, a composition that is "substantially free of" a compound means that the composition is less than about 20%, less than about 10%, less than about 5%, or about 3% by weight of the compound by weight. less than, less than about 1% by weight.

As used herein, and unless otherwise specified, the term "substantially free of" includes the particular polymorph, when used to describe a polymorph, a crystalline form, or a solid form of a compound or complex described herein, means a solid form of a compound or complex that is substantially free of other polymorphic and/or amorphous forms of the compound. Representative and substantially pure polymorphs include greater than about 80% by weight of the polymorphic form of the compound and less than about 20% by weight of other polymorphic and/or amorphous forms of the compound; greater than about 90 weight percent of the polymorphic form of the compound and less than about 10 weight percent of other polymorphic and/or amorphous forms of the compound; greater than about 95 weight percent of the polymorphic form of the compound and less than about 5 weight percent of other polymorphic and/or amorphous forms of the compound; greater than about 97 weight percent of the polymorphic form of the compound and less than about 3 weight percent of other polymorphic and/or amorphous forms of the compound; or greater than about 99% by weight of the polymorphic form of the compound and less than about 1% by weight of other polymorphic and/or amorphous forms of the compound.

As used herein, and unless otherwise specified, a crystal form that is "substantially free of" water and/or solvent in a crystal lattice is defined as a specific In an embodiment, it has an amount of water and/or solvent that is close to the limit of detection, in other embodiments about the limit of detection, and in other embodiments, less than the limit of detection for solvent and/or water in the weak crystal lattice. . In certain embodiments, the solid-state analytical technique used to determine the amount of water and/or solvent in the crystal lattice is thermogravimetric analysis. In another embodiment, the solid-state analytical technique used to determine the amount of water and/or solvent in the crystal lattice is Karl Fischer analysis. In other embodiments, the crystalline form that is "substantially free" of water and/or solvent in the crystal lattice is less than about 5%, less than about 4%, less than about 3%, or about 2% by weight of the total weight of the crystalline form. Less than about 1 wt%, less than about 0.9 wt%, less than about 0.8 wt%, less than about 0.7 wt%, less than about 0.6 wt%, less than about 0.5 wt%, less than about 0.4 wt%, about 0.3 wt% less than, less than about 0.2%, less than about 0.1%, less than about 0.05%, less than about 0.01% by weight of water and/or solvent.

A crystalline or amorphous form, as used herein, is "pure," i.e., substantially free of other crystalline or amorphous forms, less than about 10% by weight of one or more other crystalline or amorphous forms, and about 5% by weight of one or more other crystalline or amorphous forms. less than about 3% by weight of one or more other crystalline or amorphous forms, less than about 1% by weight of one or more other crystalline or amorphous forms.

As used herein, and unless otherwise specified, the term "stable" refers to a compound or composition that does not undergo facile degradation or change in chemical treatment or physical state. Stable compositions or formulations provided herein do not degrade significantly under normal conditions of manufacture or storage. In some embodiments, when used in conjunction with a formulation or formulation, the term "stable" means that the active ingredient of the formulation or formulation does not change in chemical treatment or physical state for a specified period of time, does not significantly degrade, aggregate, or otherwise modified. means (e.g. determined by HPLC, FTIR or XRPD). In some embodiments, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 98%, or at least about 99% of the compound remains unchanged after a specified period of time. In one embodiment, a polymorph provided herein is stable upon long-term storage (eg, about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 18, 24, 30). , 36, 42, 48, 54, 60, or after more than about 60 months, no significant change in polymorphism).

Definitions of specific functional groups and chemical terms are described in more detail below. Chemical elements are identified according to Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75th ed., back cover, and specific functional groups are generally as described herein. In addition, general principles of organic chemistry, as well as specific functional moieties and reactants are described in [<i>Organic</i><i></i><i>Chemistry</i>, Thomas Sorrell, University Science Books, Sausalito, 1999]; [Smith and March<i>March's</i><i></i><i>Advanced</i><i> Organic </i><i>Chemistry</i>, 5th ed., John Wiley &amp; Sons, Inc., New York, 2001]; [Larock,<i>Comprehensive</i><i></i><i>Organic</i><i></i><i>Transformations</i>, VCH Publishers, Inc., New York, 1989]; and [Carruthers, Some<i>Modern</i><i></i><i>Methods</i><i></i><i>of</i><i></i><i>Organic</i><i></i><i>Synthesis</i>, 3rd ed., Cambridge University Press, Cambridge, 1987].

Where ranges of values are recited, it is intended to encompass each value and subrange within the range. For example, "C₁_-6 Alkyl" is C₁, C₂, C₃, C₄, C₅, C₆, C₁_-6, C₁_-5, C₁_-4, C₁_-3, C₁_-2, C₂_-6, C₂_-5, C₂_-4, C₂_-3, C₃_-6, C₃_-5, C₃_-4, C₄_-6, C₄_-5, and C₅_-6 It is intended to encompass alkyl.

"Alkyl" refers to 1 to 10 carbon atoms (eg, C₁-C₁₀ alkyl) refers to a straight or branched hydrocarbon chain radical consisting simply of carbon and hydrogen atoms, containing no unsaturation. When referred to herein, a numerical range, such as "1 to 10," refers to each integer in the given range; For example, "1 to 10 carbon atoms" also means that, where no numerical range is specified, the alkyl group may contain 1 carbon atom, 2 carbon atoms, 3 carbon atoms, even if the present definition does not encompass the presence of the term "alkyl". may consist of n carbon atoms, etc., and is meant to contain up to 10 carbon atoms. In some embodiments, it is C₁-C₆ is an alkyl group. In some embodiments, the alkyl group has 1 to 10, 1 to 6, or 1 to 3 carbon atoms. Representative saturated straight chain alkyls include, but are not limited to, -methyl, -ethyl, -n-propyl, -n-butyl, -n-pentyl, and -n-hexyl; Saturated branched alkyl includes, but is not limited to, -isopropyl, -sec-butyl, -isobutyl, -tert-butyl, -isopentyl, 2-methylbutyl, 3-methylbutyl, 2-methylpentyl, 3- methylpentyl, 4-methylpentyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2,3-dimethylbutyl, and the like. The alkyl is attached to the parent molecule by a single bond. Unless stated otherwise herein, an alkyl group is optionally substituted with one or more substituents independently including: acyl, alkyl, alkenyl, alkynyl, alkoxy, alkylaryl, cycloalkyl, aralkyl, aryl, aryl Oxy, amino, amido, amidino, imino, azide, carbonate, carbamate, carbonyl, heteroalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, hydroxy, cyano, halo, haloalkoxy, Haloalkyl, ester, ether, mercapto, thio, alkylthio, arylthio, thiocarbonyl, nitro, oxo, phosphate, phosphonate, phosphinate, silyl, sulfinyl, sulfonyl, sulfonamidyl, sulfoxyl , sulfonate, urea, -Si(R^a)₃-, -OR^a, -SR^a, -OC(O)R^a, -N(R^a)₂, -C(O)R^a, -C(O)OR^a, -OC(O)N(R^a)₂, -C(O)N(R^a)₂, -N(R^a)C(O)OR^a, -N(R^a)C(O)R^a, -N(R^a)C(O)N(R^a)₂, -N(R^a)C(NR^a)N(R^a)₂, -N(R^a)S(O)_tR^a(In this case, t is 1 or 2), -S(O)_tOR^a(In this case, t is 1 or 2), -S(O)_tN(R^a)₂(where t is 1 or 2), or -OP(=O)(OR^a)₂(At this time, each R^ais independently hydrogen, alkyl, haloalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl or heteroarylalkyl, each of which moieties are as defined herein may be substituted arbitrarily).

"Perhaloalkyl" refers to an alkyl group in which all hydrogen atoms are replaced by a halogen selected from fluoro, chloro, bromo, and iodo. In some embodiments, all hydrogen atoms are each substituted with fluoro. In some embodiments, all hydrogen atoms are each substituted with chloro. An example of a perhaloalkyl group is -CF₃, -CF₂CF₃, -CF₂CF₂CF₃, -CCl₃, -CFCl₂, -CF₂Cl and the like.

"Alkenyl" means 2 to 10 carbon atoms (i.e.,<i></i>C₂-C₁₀ alkenyl) and containing at least one double bond, refers to a straight or branched hydrocarbon chain radical group consisting simply of carbon and hydrogen atoms. When referred to herein, a numerical range, such as "2 to 10", refers to each integer in the given range; For example, "2 to 10 carbon atoms" means that the alkenyl group can consist of 2 carbon atoms, 3 carbon atoms, etc., and contains up to 10 carbon atoms. In certain embodiments, alkenyl comprises 2 to 8 carbon atoms. In other embodiments, alkenyl has 2 to 5 carbon atoms (e.g.,<i></i>C₂-C₅ alkenyl). Alkenyl is attached to the parent molecular structure by a single bond, such as ethenyl (i.e. vinyl), prop-1-enyl (i.e.,<i></i>allyl), but-1-enyl, pent-1-enyl, penta-1,4-dienyl, and the like. One or more carbon-carbon double bonds may be internal (eg, 2-butenyl) or external (eg, 1-butenyl). C₂_-4 An example of an alkenyl group is ethenyl (C₂), 1-propenyl (C₃), 2-propenyl (C₃), 1-butenyl (C₄), 2-butenyl (C₄), butadienyl (C₄), etc. C₂_-6 Examples of alkenyl groups include the above-mentioned C₂_-4 alkenyl as well as pentenyl (C₅), pentadienyl (C₅), hexenyl (C₆), etc. Further examples of alkenyl are heptenyl (C₇), octenyl (C₈), octatrienyl (C₈), etc. Unless otherwise stated herein, an alkenyl group is optionally substituted with one or more substituents independently including: acyl, alkyl, alkenyl, alkynyl, alkoxy, alkylaryl, cycloalkyl, aralkyl, aryl, Aryloxy, amino, amido, amidino, imino, azide, carbonate, carbamate, carbonyl, heteroalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, hydroxy, cyano, halo, haloalkoxy , haloalkyl, ester, ether, mercapto, thio, alkylthio, arylthio, thiocarbonyl, nitro, oxo, phosphate, phosphonate, phosphinate, silyl, sulfinyl, sulfonyl, sulfonamidyl, sulfonyl Foxyl, sulfonate, urea, -Si(R^a)₃-, -OR^a, -SR^a, -OC(O)R^a, -N(R^a)₂, -C(O)R^a, -C(O)OR^a, -OC(O)N(R^a)₂, -C(O)N(R^a)₂, -N(R^a)C(O)OR^a, -N(R^a)C(O)R^a, -N(R^a)C(O)N(R^a)₂, -N(R^a)C(NR^a)N(R^a)₂, -N(R^a)S(O)_tR^a(In this case, t is 1 or 2), -S(O)_tOR^a(In this case, t is 1 or 2), -S(O)_tN(R^a)₂(where t is 1 or 2), or -OP(=O)(OR^a)₂(At this time, each R^ais independently hydrogen, alkyl, haloalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl or heteroarylalkyl, each of which moieties are as defined herein may be substituted arbitrarily).

"Alkynyl" means 2 to 10 carbon atoms (i.e., C₂-C₁₀ alkynyl) and containing at least one triple bond, refers to a straight-chain or branched hydrocarbon chain radical group consisting simply of carbon and hydrogen atoms. As used herein, a numerical range, such as "2 to 10", refers to each integer in the given range; For example, "2 to 10 carbon atoms" means that the alkynyl group may consist of 2 carbon atoms, 3 carbon atoms, etc., and contains up to 10 carbon atoms. In certain embodiments, alkynyl comprises 2 to 8 carbon atoms. In other embodiments, alkynyl has 2 to 5 carbon atoms (eg, C₂-C₅ alkynyl). Alkynyl is attached to the parent molecular structure by a single bond, such as ethynyl, propynyl, butynyl, pentynyl, hexynyl, and the like. Unless stated otherwise herein, an alkynyl group is optionally substituted with one or more substituents independently including: acyl, alkyl, alkenyl, alkynyl, alkoxy, alkylaryl, cycloalkyl, aralkyl, aryl, Aryloxy, amino, amido, amidino, imino, azide, carbonate, carbamate, carbonyl, heteroalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, hydroxy, cyano, halo, haloalkoxy , haloalkyl, ester, ether, mercapto, thio, alkylthio, arylthio, thiocarbonyl, nitro, oxo, phosphate, phosphonate, phosphinate, silyl, sulfinyl, sulfonyl, sulfonamidyl, sulfonyl Foxyl, sulfonate, urea, -Si(R^a)₃-, -OR^a, -SR^a, -OC(O)-R^a, -N(R^a)₂, -C(O)R^a, -C(O)OR^a, -OC(O)N(R^a)₂, -C(O)N(R^a)₂, -N(R^a)C(O)OR^a, -N(R^a)C(O)R^a, - N(R^a)C(O)N(R^a)₂, -N(R^a)C(NR^a)N(R^a)₂, -N(R^a)S(O)_tR^a(In this case, t is 1 or 2), -S(O)_tOR^a(In this case, t is 1 or 2), -S(O)_tN(R^a)₂(where t is 1 or 2), or -OP(=O)(OR^a)₂(At this time, each R^ais independently hydrogen, alkyl, haloalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl or heteroarylalkyl, each moiety of which is defined herein. may be optionally substituted as such).

The term "alkoxy" refers to the group O-alkyl, including those in which 1 to 10 carbon atoms in a straight chain, branched, cyclic arrangement, and combinations thereof are attached to the parent molecular structure through an oxygen. Examples include methoxy, ethoxy, propoxy, isopropoxy, cyclopropyloxy, cyclohexyloxy, and the like. "Lower alkoxy" refers to an alkoxy group containing 1 to 6 carbons. In some embodiments, C₁-C₄ Alkoxy is an alkoxy group encompassing straight and branched chain alkyls from 1 to 4 carbon atoms. Unless otherwise stated herein, an alkoxy group is optionally substituted with one or more substituents independently including: acyl, alkyl, alkenyl, alkynyl, alkoxy, alkylaryl, cycloalkyl, aralkyl, aryl, aryl Oxy, amino, amido, amidino, imino, azide, carbonate, carbamate, carbonyl, heteroalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, hydroxy, cyano, halo, haloalkoxy, Haloalkyl, ester, ether, mercapto, thio, alkylthio, arylthio, thiocarbonyl, nitro, oxo, phosphate, phosphonate, phosphinate, silyl, sulfinyl, sulfonyl, sulfonamidyl, sulfoxyl , sulfonate, urea, -Si(R^a)₃-, -OR^a, -SR^a, -OC(O)R^a, -N(R^a)₂, -C(O)R^a, -C(O)OR^a, -OC(O)N(R^a)₂, -C(O)N(R^a)₂, -N(R^a)C(O)OR^a, -N(R^a)C(O)R^a, -N(R^a)C(O)N(R^a)₂, -N(R^a)C(NR^a)N(R^a)₂, -N(R^a)S(O)_tR^a(In this case, t is 1 or 2), -S(O)_tOR^a(In this case, t is 1 or 2), -S(O)_tN(R^a)₂(where t is 1 or 2), or -OP(=O)(OR^a)₂(At this time, each R^ais independently hydrogen, alkyl, haloalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl or heteroarylalkyl, each moiety of which is defined herein. may be optionally substituted as follows). The terms "alkenoxy" and "alkynoxy" reflect the above description of "alkoxy", wherein the prefix "alk" is substituted with "alken" or "alkyne" respectively, and the parent "alkenyl" or "alkynyl" The terms are as described herein.

The term "alkoxycarbonyl" refers to a group of formula (alkoxy)(C=O)- attached to the parent molecular structure through a carbonyl carbon having 1 to 10 carbon atoms. Therefore, C₁-C₆ Alkoxycarbonyl groups are groups in which an alkoxy group having 1 to 6 carbon atoms is attached to a carbonyl linker through an oxygen. C₁-C₆ The designation does not include carbonyl carbon in the element count. "Lower alkoxycarbonyl" refers to an alkoxycarbonyl group, wherein the alkyl portion of the alkoxy group is a lower alkyl group. In some embodiments, C₁-C₄ Alkoxy is an alkoxy group, wherein it encompasses both straight and branched chain alkoxy groups from 1 to 4 carbon atoms. Unless otherwise stated herein, an alkoxycarbonyl group is optionally substituted with one or more substituents independently including: acyl, alkyl, alkenyl, alkynyl, alkoxy, alkylaryl, cycloalkyl, aralkyl, aryl , aryloxy, amino, amido, amidino, imino, azide, carbonate, carbamate, carbonyl, heteroalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, hydroxy, cyano, halo, halo Alkoxy, haloalkyl, ester, ether, mercapto, thio, alkylthio, arylthio, thiocarbonyl, nitro, oxo, phosphate, phosphonate, phosphinate, silyl, sulfinyl, sulfonyl, sulfonamidyl, sulfoxyl, sulfonate, urea, -Si(R^a)₃-, -OR^a, -SR^a, -OC(O)-R^a, -N(R^a)₂, -C(O)R^a, -C(O)OR^a, -OC(O)N(R^a)₂, -C(O)N(R^a)₂, -N(R^a)C(O)OR^a, -N(R^a)C(O)R^a, -N(R^a)C(O)N(R^a)₂, -N(R^a)C(NR^a)N(R^a)₂, -N(R^a)S(O)_tR^a(In this case, t is 1 or 2), -S(O)_tOR^a(In this case, t is 1 or 2), -S(O)_tN(R^a)₂(where t is 1 or 2), or -OP(=O)(OR^a)₂(At this time, each R^ais independently hydrogen, alkyl, haloalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl or heteroarylalkyl, each moiety of which is defined herein. may be optionally substituted as follows). The terms "alkenoxycarbonyl" and "alkyneoxycarbonyl" reflect the above description of "alkoxycarbonyl" wherein the prefix "alk" is substituted with "alken" or "alkyl" respectively, and the parent "alkenyl" or the term "alkynyl" as described herein.

"Acyl" refers to the group RC(O)-, such as, but not limited to, (alkyl)-C(O)-, (alkenyl)-C(O)-, (alkynyl)-C(O)-, (aryl)-C(O)-, (cycloalkyl)-C(O)-, (heteroaryl)-C(O)-, (heteroalkyl)-C(O)-, and (heterocycloalkyl)- C(O), wherein the group is attached to the parent molecular structure through a carbonyl functional group. In some embodiments, it is C₁-C₁₀ an acyl radical, which refers to the total number of chain or ring atoms of the acyl fraction plus the carbonyl carbons, such as alkyl, alkenyl, alkynyl, aryl, cyclohexyl, heteroaryl or heterocycloalkyl fraction. For example, C₄-acyl has 3 different ring or chain atoms including carbonyl. When the R radical is heteroaryl or heterocycloalkyl, the hetero ring or chain atoms contribute to the total number of chain or ring atoms. Unless stated otherwise herein, "R" of an aryloxy group may be optionally substituted with one or more substituents independently including: acyl, alkyl, alkenyl, alkynyl, alkoxy, alkylaryl, cyclo Alkyl, aralkyl, aryl, aryloxy, amino, amido, amidino, imino, azide, carbonate, carbamate, carbonyl, heteroalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, hydroxy, Cyano, halo, haloalkoxy, haloalkyl, ester, ether, mercapto, thio, alkylthio, arylthio, thiocarbonyl, nitro, oxo, phosphate, phosphonate, phosphinate, silyl, sulfinyl, sulfinyl Fonyl, sulfonamidyl, sulfoxyl, sulfonate, urea, -Si(R^a)₃-, -OR^a, -SR^a, -OC(O)-R^a, -N(R^a)₂, -C(O)R^a, -C(O)OR^a, -OC(O)N(R^a)₂, -C(O)N(R^a)₂, -N(R^a)C(O)OR^a, -N(R^a)C(O)R^a, - N(R^a)C(O)N(R^a)₂, -N(R^a)C(NR^a)N(R^a)₂, -N(R^a)S(O)_tR^a(In this case, t is 1 or 2), -S(O)_tOR^a(In this case, t is 1 or 2), -S(O)_tN(R^a)₂(where t is 1 or 2), or -OP(=O)(OR^a)₂(At this time, each R^ais independently hydrogen, alkyl, haloalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl or heteroarylalkyl, each moiety of which is defined herein. may be optionally substituted as follows).

"Acyloxy" refers to a R(C=O)O- radical, wherein "R" is alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, aryl, cyclo as described herein. hexyl, heteroaryl or heterocycloalkyl. The acyloxy group is attached to the parent molecular structure via an oxygen functional group. In some embodiments, an acyloxy group is C₁-C₄ an acyloxy radical and refers to the total amount of chain or ring atoms of the alkyl, alkenyl, alkynyl, aryl, cyclohexyl, heteroaryl or heterocycloalkyl portion of the acyloxy group plus the carbonyl carbons of the acyl, i.e. C₄-acyloxy has 3 different ring or chain atoms plus carbonyl. When the R radical is heteroaryl or heterocycloalkyl, the hetero ring or chain atoms contribute to the total number of chain or ring atoms. Unless otherwise stated herein, "R" of an acyloxy group is optionally substituted with one or more substituents independently including: acyl, alkyl, alkenyl, alkynyl, alkoxy, alkylaryl, cycloalkyl, Aralkyl, aryl, aryloxy, amino, amido, amidino, imino, azide, carbonate, carbamate, carbonyl, heteroalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, hydroxy, cyano , halo, haloalkoxy, haloalkyl, ester, ether, mercapto, thio, alkylthio, arylthio, thiocarbonyl, nitro, oxo, phosphate, phosphonate, phosphinate, silyl, sulfinyl, sulfonyl, Sulfonamidyl, sulfoxyl, sulfonate, urea, -Si(R^a)₃-, -OR^a, -SR^a, -OC(O)-R^a, -N(R^a)₂, -C(O)R^a, -C(O)OR^a, -OC(O)N(R^a)₂, -C(O)N(R^a)₂, -N(R^a)C(O)OR^a, -N(R^a)C(O)R^a, -N(R^a)C(O)N(R^a)₂, -N(R^a)C(NR^a)N(R^a)₂, -N(R^a)S(O)_tR^a(In this case, t is 1 or 2), -S(O)_tOR^a(In this case, t is 1 or 2), -S(O)_tN(R^a)₂(where t is 1 or 2), or -OP(=O)(OR^a)₂(At this time, each R^ais independently hydrogen, alkyl, haloalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl or heteroarylalkyl, each moiety of which is defined herein. may be optionally substituted as follows).

"Amino" or "amine" means -N(R^b)₂, -N(R^b)R^b-, or -R^bN(R^b)R^b- refers to a radical group, wherein each R^bis hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, heteroalkyl (bonded by chain carbons), cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocycloalkyl (bonded by ring carbons), heterocycloalkyl Independently selected from alkyl, heteroaryl (bonded by a ring carbon) or heteroarylalkyl, each moiety may be optionally substituted as described herein, unless otherwise stated herein. -N(R^b)₂ two Rs where the groups are not hydrogen^b, it may be combined with a nitrogen atom to form a 3-, 4-, 5-, 6-, or 7-membered ring. For example, -N(R^b)₂includes, but is not limited to, 1-pyrrolidinyl and 4-morpholinyl. Unless otherwise stated herein, an amino group is optionally substituted with one or more substituents independently including: acyl, alkyl, alkenyl, alkynyl, alkoxy, alkylaryl, cycloalkyl, aralkyl, aryl, aryl Oxy, amino, amido, amidino, imino, azide, carbonate, carbamate, carbonyl, heteroalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, hydroxy, cyano, halo, haloalkoxy, Haloalkyl, ester, ether, mercapto, thio, alkylthio, arylthio, thiocarbonyl, nitro, oxo, phosphate, phosphonate, phosphinate, silyl, sulfinyl, sulfonyl, sulfonamidyl, sulfoxyl , sulfonate, urea, -Si(R^a)₃-, -OR^a, -SR^a, -OC(O)-R^a, -N(R^a)₂, -C(O)R^a, -C(O)OR^a, -OC(O)N(R^a)₂, -C(O)N(R^a)₂, -N(R^a)C(O)OR^a, -N(R^a)C(O)R^a, -N(R^a)C(O)N(R^a)₂, -N(R^a)C(NR^a)N(R^a)₂, -N(R^a)S(O)_tR^a(In this case, t is 1 or 2), -S(O)_tOR^a(In this case, t is 1 or 2), -S(O)_tN(R^a)₂(where t is 1 or 2), or -OP(=O)(OR^a)₂(At this time, each R^ais independently hydrogen, alkyl, haloalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl or heteroarylalkyl, each moiety of which is defined herein. may be optionally substituted as follows).

Also, the terms "amine" and "amino" refer to the group -N⁺(H)(R)^a)O-, and -N⁺(R^a)(R^a) N-oxide of O- (R^ais described herein), wherein the N-oxide is bonded to the parent molecular structure through a nitrogen atom. N-oxides can be prepared by treatment of the corresponding amino group with, for example, hydrogen peroxide or m-chloroperoxybenzoic acid. The person skilled in the art is familiar with the reaction conditions for carrying out the N-oxidation.

"Amide" or "amido" refers to the formula -C(O)N(R^b)₂ or -NR^bC(O)R^brefers to a chemical moiety comprising^bis hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, heteroalkyl (bonded by chain carbons), cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocycloalkyl (bonded by ring carbons), heterocycloalkyl independently selected from alkyl, heteroaryl (bonded by a ring carbon) or heteroarylalkyl, each moiety of which may be optionally substituted as described herein, unless otherwise stated herein. In some embodiments, this radical is C₁-C₄ an amido or amide radical, which includes the amide carbonyl in the total number of carbons in the radical. -C(O)N(R^b)₂2 R instead of hydrogen^b, they may combine with a nitrogen atom to form a 3-, 4-, 5-, 6-, or 7-membered ring. For example, -C(O)N(R^b)₂ -N (R of the radical^b)₂ Fractions include, but are not limited to, 1-pyrrolidinyl and 4-morpholinyl. Unless otherwise stated herein, maybe R^b A group is optionally substituted with one or more substituents independently including: acyl, alkyl, alkenyl, alkynyl, alkoxy, alkylaryl, cycloalkyl, aralkyl, aryl, aryloxy, amino, amido, amidino, imino, azide, carbonate, carbamate, carbonyl, heteroalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, hydroxy, cyano, halo, haloalkoxy, haloalkyl, ester, ether, mercapto, Thio, alkylthio, arylthio, thiocarbonyl, nitro, oxo, phosphate, phosphonate, phosphinate, silyl, sulfinyl, sulfonyl, sulfonamidyl, sulfoxyl, sulfonate, urea, -Si(R^a)₃-, -OR^a, -SR^a, -OC(O)-R^a, -N(R^a)₂, -C(O)R^a, -C(O)OR^a, -OC(O)N(R^a)₂, -C(O)N(R^a)₂, -N(R^a)C(O)OR^a, -N(R^a)C(O)R^a, -N(R^a)C(O)N(R^a)₂, -N(R^a)C(NR^a)N(R^a)₂, -N(R^a)S(O)_tR^a(In this case, t is 1 or 2), -S(O)_tOR^a(In this case, t is 1 or 2), -S(O)_tN(R^a)₂(where t is 1 or 2), or -OP(=O)(OR^a)₂(At this time, each R^ais independently hydrogen, alkyl, haloalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl or heteroarylalkyl, each moiety of which is defined herein. may be optionally substituted as follows).

The term "amide" or "amido" includes amino acid or peptide molecules. Any amine, hydroxy, or carboxyl side chain on the compounds described herein can be converted to an amide group. Procedures and specifics for preparing such amides are known to those skilled in the art and are described in references such as Greene and Wuts,<i>Protective</i><i> Groups </i><i>in</i><i> O</i><i>rganic</i><i></i><i>Synthesis</i>, 3rd Ed., John Wiley &amp; Sons, New York, NY, 1999], which is incorporated herein by reference in its entirety.

"Amidino" is -C (=NR^b)N(R^b)₂ and -N(R^b)-C(=NR^b)- refers to both radicals, wherein each R^bis hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, heteroalkyl (bonded by chain carbons), cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocycloalkyl (bonded by ring carbons), heterocycloalkyl independently selected from alkyl, heteroaryl (bonded by a ring carbon) or heteroarylalkyl, each moiety of which may be optionally substituted as described herein, unless otherwise stated herein.

"Aromatic" or "aryl" refers to 6 to 10 ring atoms (eg, C₆-C₁₀ aromatic or C₆-C₁₀ aryl), wherein it is a carbocyclic (e.g., has one or more rings with a conjugated pi electron system that phenyl, fluorenyl, and naphthyl). For example, a divalent radical formed from a substituted benzene derivative and having a free valence at a ring atom is termed a substituted phenylene radical. In another embodiment, a divalent radical derived from a monovalent polycyclic hydrocarbon radical whose name ends with "one" by removal of one hydrogen atom from a carbon atom having a free valence is "idene" to the corresponding monovalent radical. Named by addition, for example, a naphthyl group having two points of attachment is named naphthylidene. When referred to herein, a number range, such as "6 to 10 aryl," refers to each integer within the given range; For example, "6 to 10 ring atoms" means an aryl group consisting of 6 ring atoms, 7 ring atoms, etc., and containing 10 or less ring atoms. The term includes monocyclic or fused-ring polycyclic (ie, rings shared with adjacent pairs of ring atoms) groups. Unless otherwise stated herein, an aryl moiety may be optionally substituted with one or more substituents independently including: acyl, alkyl, alkenyl, alkynyl, alkoxy, alkylaryl, cycloalkyl, aralkyl, aryl, aryloxy, amino, amido, amidino, imino, azide, carbonate, carbamate, carbonyl, heteroalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, hydroxy, cyano, halo, Haloalkoxy, haloalkyl, ester, ether, mercapto, thio, alkylthio, arylthio, thiocarbonyl, nitro, oxo, phosphate, phosphonate, phosphinate, silyl, sulfinyl, sulfonyl, sulfonamidyl , sulfoxyl, sulfonate, urea, -Si(R^a)₃-, -OR^a, -SR^a, -OC(O)-R^a, -N(R^a)₂, -C(O)R^a, -C(O)OR^a, -OC(O)N(R^a)₂, -C(O)N(R^a)₂, -N(R^a)C(O)OR^a, -N(R^a)C(O)R^a, -N(R^a)C(O)N(R^a)₂, -N(R^a)C(NR^a)N(R^a)₂, -N(R^a)S(O)_tR^a(In this case, t is 1 or 2), -S(O)_tOR^a(In this case, t is 1 or 2), -S(O)_tN(R^a)₂(where t is 1 or 2), or -OP(=O)(OR^a)₂(At this time, each R^ais independently hydrogen, alkyl, haloalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl or heteroarylalkyl, each moiety of which is defined herein. may be optionally substituted as follows).

"Aralkyl" or "arylalkyl" is an (aryl)alkyl- radical, wherein aryl and alkyl are as disclosed herein and are optionally substituted with one or more substituents described as suitable substituents for aryl and alkyl, respectively. "Aralkyl/arylalkyl" is an alkyl group attached to the parent molecular structure. The terms "aralkenyl/arylalkenyl" and "aralkynyl/arylalkynyl" reflect the above description of "aralkyl/arylalkyl", where "alkyl" is referred to as "alkenyl" or "alkynyl". Each is substituted, and the terms "alkenyl" or "alkynyl" are as described herein.

"azide" is -N₃ refers to radicals.

"Carbamate" refers to any of the following radicals: -O-(C=O)-N(R^b)-, -O-(C=O)-N(R^b)₂, -N(R^b)-(C=O)-O-, and -N(R^b)-(C=O)-OR^b(At this time, each R^bis alkyl, alkenyl, alkynyl, haloalkyl, heteroalkyl (bonded by chain carbons), cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocycloalkyl (bonded by ring carbons), heterocycloalkylalkyl, heteroaryl (bonded by a ring carbon) or heteroarylalkyl, each moiety of which may be optionally substituted as described herein, unless otherwise stated herein.

"Carbonate" refers to the radical -O-(C=O)-O-.

"Carbonyl" refers to a -(C=O)- radical.

"Carboxaldehyde" refers to the -(C=O)H radical.

"Carboxyl" refers to the -(C=O)OH radical.

"Cyano" refers to the -CN radical.

"Cycloalkyl" and "carbocyclyl" refer to monocyclic or polycyclic radicals containing only carbon and hydrogen, respectively, and which may be saturated or partially unsaturated. A partially unsaturated cycloalkyl group may be termed "cycloalkenyl" when the carbocycle contains one or more double bonds, or "cycloalkynyl" if the carbocycle contains one or more triple bonds. can A cycloalkyl group has 3 to 10 ring atoms (i.e., C₃-C₁₀ cycloalkyl). When referred to herein, a number range, such as "3 to 10", refers to each integer within the given range; For example, "3 to 10 carbon atoms" means that the cycloalkyl group can consist of 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, etc., and contains no more than 10 carbon atoms. The term "cycloalkyl" also includes bridged, spiro-fused cyclic structures containing no heteroatoms. The term also includes monocyclic or fused-ring polycyclic (ie, rings that share adjacent pairs of ring atoms) groups. In some embodiments, it is C₃-C₈ a cycloalkyl radical. In some embodiments, it is C₃-C₅ a cycloalkyl radical. Illustrative examples of cycloalkyl groups include, but are not limited to, the moieties: cyclopropyl (C₃), cyclobutyl (C₄), cyclopentyl (C₅), cyclopentenyl (C₅), cyclohexyl (C₆), cyclohexenyl (C₆), cyclohexadienyl (C₆), including but not limited to C₃_-6 Carbocycle Diary. C₃_-8 Examples of carbocyclyl groups include the above-mentioned C₃_-6 Carbocyclyl as well as cycloheptyl (C₇), cycloheptadienyl (C₇), cycloheptatrienyl (C₇), cyclooctyl (C₈), bicyclo[2.2.1]heptanyl, bicyclo[2.2.2]octanyl, and the like. C₃_-10 Examples of carbocyclyl groups include the above-mentioned C₃_-8 Octahydro-1 as well as carbocyclyl<i>H</i>-indenyl, decahydronaphthalenyl, spiro[4.5]decanyl, and the like. Unless otherwise stated herein, a cycloalkyl group is optionally substituted with one or more substituents independently including: acyl, alkyl, alkenyl, alkynyl, alkoxy, alkylaryl, cycloalkyl, aralkyl, aryl, Aryloxy, amino, amido, amidino, imino, azide, carbonate, carbamate, carbonyl, heteroalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, hydroxy, cyano, halo, haloalkoxy , haloalkyl, ester, ether, mercapto, thio, alkylthio, arylthio, thiocarbonyl, nitro, oxo, phosphate, phosphonate, phosphinate, silyl, sulfinyl, sulfonyl, sulfonamidyl, sulfonyl Foxyl, sulfonate, urea, -Si(R^a)₃-, -OR^a, -SR^a, -OC(O)-R^a, -N(R^a)₂, -C(O)R^a, -C(O)OR^a, -OC(O)N(R^a)₂, -C(O)N(R^a)₂, -N(R^a)C(O)OR^a, -N(R^a)C(O)R^a, -N(R^a)C(O)N(R^a)₂, -N(R^a)C(NR^a)N(R^a)₂, -N(R^a)S(O)_tR^a(In this case, t is 1 or 2), -S(O)_tOR^a(In this case, t is 1 or 2), -S(O)_tN(R^a)₂(where t is 1 or 2), or -OP(=O)(OR^a)₂(At this time, R^ais independently hydrogen, alkyl, haloalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl or heteroarylalkyl, each moiety of which is defined herein. may be optionally substituted as follows).

"Ester" refers to a radical of the formula -COOR, wherein R is alkyl, alkenyl, alkynyl, haloalkyl, heteroalkyl (bonded by a chain carbon), cycloalkyl, cycloalkylalkyl, aryl, aralkyl, hetero cycloalkyl (bonded by a ring carbon), heterocycloalkylalkyl, heteroaryl (bonded by a ring carbon) or heteroarylalkyl. Any amine, hydroxy, or carboxyl side chain on the compounds described herein may be esterified. Procedures and specifics for making such esters are known to those skilled in the art and are described in references such as Greene and Wuts,<i>Protective</i><i></i><i>Groups</i><i></i><i>in</i><i></i><i>Organic</i><i> Synthesis</i>, 3rd Ed., John Wiley &amp; Sons, New York, NY, 1999], which is incorporated herein by reference in its entirety. Unless otherwise stated herein, an ester group may be optionally substituted with one or more substituents independently including: acyl, alkyl, alkenyl, alkynyl, alkoxy, alkylaryl, cycloalkyl, aralkyl, aryl , aryloxy, amino, amido, amidino, imino, azide, carbonate, carbamate, carbonyl, heteroalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, hydroxy, cyano, halo, halo Alkoxy, haloalkyl, ester, ether, mercapto, thio, alkylthio, arylthio, thiocarbonyl, nitro, oxo, phosphate, phosphonate, phosphinate, silyl, sulfinyl, sulfonyl, sulfonamidyl, sulfoxyl, sulfonate, urea, -Si(R^a)₃-, -OR^a, -SR^a, -OC(O)-R^a, -N(R^a)₂, -C(O)R^a, -C(O)OR^a, -OC(O)N(R^a)₂, -C(O)N(R^a)₂, -N(R^a)C(O)OR^a, -N(R^a)C(O)R^a, -N(R^a)C(O)N(R^a)₂, -N(R^a)C(NR^a)N(R^a)₂, -N(R^a)S(O)_tR^a(In this case, t is 1 or 2), -S(O)_tOR^a(In this case, t is 1 or 2), -S(O)_tN(R^a)₂(where t is 1 or 2), or -OP(=O)(OR^a)₂(At this time, each R^ais independently hydrogen, alkyl, haloalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl or heteroarylalkyl, each moiety of which is defined herein. may be optionally substituted as follows).

"ether" is -R^b-OR^b- refers to a radical, wherein each R^bis hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, heteroalkyl (bonded by chain carbons), cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocycloalkyl (bonded by ring carbons), heterocycloalkyl independently selected from alkyl, heteroaryl (bonded by a ring carbon) or heteroarylalkyl, each moiety of which may be optionally substituted as described herein, unless otherwise stated herein.

"Halo", "halide", or alternatively, "halogen" means fluoro, chloro, bromo or iodo. The terms "haloalkyl," "haloalkenyl," "haloalkynyl," and "haloalkoxy" include alkyl, alkenyl, alkynyl and alkoxy structures substituted with one or more halo groups or combinations thereof. For example, the terms "fluoroalkyl" and "fluoroalkoxy" include haloalkyl and haloalkoxy groups, respectively, wherein halo is fluorine such as, but not limited to, trifluoromethyl, difluoromethyl, 2,2, 2-trifluoroethyl, 1-fluoromethyl-2-fluoroethyl, and the like. Each of the alkyl, alkenyl, alkynyl and alkoxy groups is as defined herein and may be optionally further substituted as defined herein.

"Heteroalkyl", "heteroalkenyl" and "heteroalkynyl" include alkyl, alkenyl and alkynyl radicals respectively, which are derived from atoms other than carbon, such as oxygen, nitrogen, sulfur, phosphorus, or combinations thereof. has one or more selected backbone chain atoms. A number range referring to the total chain length is, for example, C₁-C₄ Heteroalkyl may be given in this example 4 atoms in length. For example -CH₂OCH₂CH₃ The radical is "C₄"Referred to as "heteroalkyl," which includes heteroatoms on an atomic chain length basis. Links to the parent molecular structure can be through heteroatoms or carbons within the heteroalkyl chain. For example, an N-containing heteroalkyl moiety can be Refers to the group wherein at least one skeletal atom is nitrogen atom.One or more heteroatoms in the heteroalkyl radical can optionally be oxidized.Also, if present, at least one nitrogen atom can optionally be quaternized. For example, heteroalkyl includes a backbone chain substituted with one or more nitrogen oxide (O) substituents Exemplary heteroalkyl groups include, but are not limited to, ethers such as methoxyethanyl (-CH₂CH₂OCH₃), ethoxymethane (-CH₂OCH₂CH₃), (methoxymethoxy)ethanyl (-CH₂CH₂OCH₂OCH₃), (methoxymethoxy) methanyl (-CH₂OCH₂OCH₃) and (methoxyethoxy) methanyl (-CH₂OCH₂ CH₂OCH₃) etc; amines such as -CH₂CH₂NHCH₃, -CH₂CH₂N(CH₃)₂, -CH₂NHCH₂CH₃,-CH₂N(CH₂CH₃)(CH₃), etc. The heteroalkyl, heteroalkenyl, and heteroalkynyl groups may each be optionally substituted with one or more substituents independently including: acyl, alkyl, alkenyl, alkynyl, alkoxy, alkylaryl, cycloalkyl, aralkyl , aryl, aryloxy, amino, amido, amidino, imino, azide, carbonate, carbamate, carbonyl, heteroalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, hydroxy, cyano, halo , haloalkoxy, haloalkyl, ester, ether, mercapto, thio, alkylthio, arylthio, thiocarbonyl, nitro, oxo, phosphate, phosphonate, phosphinate, silyl, sulfinyl, sulfonyl, sulfonami Dill, sulfoxyl, sulfonate, urea, -Si(R^a)₃-, -OR^a, -SR^a, -OC(O)-R^a, -N(R^a)₂, -C(O)R^a, -C(O)OR^a, -OC(O)N(R^a)₂, -C(O)N(R^a)₂, -N(R^a)C(O)OR^a, -N(R^a)C(O)R^a, -N(R^a)C(O)N(R^a)₂, -N(R^a)C(NR^a)N(R^a)₂, -N(R^a)S(O)_tR^a(In this case, t is 1 or 2), -S(O)_tOR^a(In this case, t is 1 or 2), -S(O)_tN(R^a)₂(where t is 1 or 2), or -OP(=O)(OR^a)₂(At this time, each R^ais independently hydrogen, alkyl, haloalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl or heteroarylalkyl, each moiety of which is defined herein. may be optionally substituted as follows).

"Heteroaryl" or alternatively, "heteroaromatic" means 5 to 18 membered monocyclic or polycyclic (eg, bicyclic or tricyclic) having 1 to 6 ring heteroatoms and ring carbon atoms provided in the aromatic ring system. cyclic) refers to a radical of an aromatic ring system (e.g., having 6, 10 or 14 Π(pi) electrons shared in the cyclic arrangement), wherein each heteroatom is nitrogen, oxygen, phosphorus and sulfur ("5 to 18 membered heteroaryl"). Heteroaryl polycyclic ring systems may contain one or more heteroatoms in one or both rings. When referred to herein, a number range, such as "5 to 18", refers to each integer within the given range; For example, "5 to 18 ring atoms" means that the heteroaryl group may consist of 5 ring atoms, 6 ring atoms, etc., and contains up to 18 ring atoms. For example, a divalent radical derived from a monovalent heteroaryl radical whose name ends with "yl" by removal of one hydrogen atom from an atom having a free valence is named by adding "idene" to the corresponding monovalent radical, such as A pyridyl group with two points of attachment is termed pyridylidene. For example, an N-containing "heteroaromatic" or "heteroaryl" moiety refers to an aromatic group in which at least one backbone atom of the ring is a nitrogen atom. One or more heteroatoms in the heteroaryl radical may optionally be oxidized. Also, if present, one or more nitrogen atoms may optionally be quaternized. Heteroaryl also includes ring systems substituted with one or more nitrogen oxide (-O-) substituents, such as pyridinyl N-oxide. Heteroaryl is attached to the parent molecular structure through any ring atom.

"Heteroaryl" also includes ring systems wherein a heteroaryl ring as defined above is fused to one or more aryl groups, wherein the point of attachment to the parent molecular structure is on the aryl or heteroaryl ring, or as defined above. A heteroaryl ring is fused to one or more cycloalkyl or heterocyclyl groups, wherein the point of attachment to the parent molecular structure is on the heteroaryl ring.<b></b>In polycyclic heteroaryl groups, one ring does not contain a heteroatom (eg, indolyl, quinolinyl, carbazolyl, etc.) and the point of attachment to the parent molecular structure is at the point of attachment to the other ring, a heteroatom (eg, 2 -indolyl) or a ring that does not contain a heteroatom (eg 5-indolyl). In some embodiments, a heteroaryl group is a 5 to 10 membered aromatic ring system having 1 to 4 ring heteroatoms and ring carbon atoms provided in the aromatic ring system, wherein each heteroatom is nitrogen, oxygen, phosphorus, and sulfur ( "5-10 membered heteroaryl"). In some embodiments, a heteroaryl group is a 5 to 8 membered aromatic ring system having 1 to 4 ring heteroatoms and ring carbon atoms provided in the aromatic ring system, wherein each heteroatom is nitrogen, oxygen, phosphorus, and sulfur ( "5-8 membered heteroaryl"). In some embodiments, a heteroaryl group is a 5-6 membered aromatic ring system having 1 to 4 ring heteroatoms and ring carbon atoms provided in the aromatic ring system, wherein each heteroatom is nitrogen, oxygen, phosphorus, and sulfur ( "5-6 membered heteroaryl"). In some embodiments, a 5-6 membered heteroaryl has 1-3 ring heteroatoms selected from nitrogen, oxygen, phosphorus, and sulfur. In some embodiments, a 5-6 membered heteroaryl has 1-2 ring heteroatoms selected from nitrogen, oxygen, phosphorus, and sulfur. In some embodiments, the 5-6 membered heteroaryl has 1 ring heteroatom selected from nitrogen, oxygen, phosphorus, and sulfur.

Examples of heteroaryl include, but are not limited to, azepinyl, acridinyl, benzimidazolyl, benzindolyl, 1,3-benzodioxolyl, benzofuranyl, benzoxazolyl, benzo[d]thiazolyl, benzothia diazolyl, benzo[<i>b</i>][1,4]dioxepinyl, benzo[b][1,4]oxazinyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzox sazolyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzofurazanyl, benzothiazolyl, benzothienyl (benzothiophenyl), benzothieno[3,2-d]pyrimidinyl, Benzotriazolyl, benzo [4,6] imidazo [1,2-a] pyridinyl, carbazolyl, cinnolinyl, cyclopenta [d] pyrimidinyl, 6,7-dihydro-5H-cyclopenta [4,5] thieno [2,3-d] pyrimidinyl, 5,6-dihydrobenzo [h] quinazolinyl, 5,6-dihydrobenzo [h] cinnolinyl, 6,7- Dihydro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, furazanyl, furanonyl, furo [3,2-c ] pyridinyl, 5,6,7,8,9,10-hexahydrocycloocta[d]pyrimidinyl, 5,6,7,8,9,10-hexahydrocycloocta[d]pyridazinyl, 5,6,7,8,9,10-hexahydrocycloocta[d]pyridinyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoindoleyl, indolinyl, isoindolinyl , isoquinolyl, indolizinyl, isoxazolyl, 5,8-methano-5,6,7,8-tetrahydroquinazolinyl, naphthyridinyl, 1,6-naphthyridinonyl, oxadiazolyl, 2-oxazepinyl, oxazolyl, oxiranyl, 5,6,6a,7,8,9,10,10a-octahydrobenzo[h]quinazolinyl, 1-phenyl-1<i>H</i>-pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyranyl, pyrrolyl, pyrazolyl, pyrazolo[3,4-d]pyrimidinyl, pyridine yl, pyrido [3,2-d] pyrimidinyl, pyrido [3,4-d] pyrimidinyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrrolyl, quinazolinyl, quinoxalinyl, Quinolinyl, isoquinolinyl, tetrahydroquinolinyl, 5,6,7,8-tetrahydroquinazolinyl, 5,6,7,8-tetrahydrobenzo [4,5] thieno [2,3-d ] pyrimidinyl, 6,7,8,9-tetrahydro-5H-cyclohepta [4,5] thieno [2,3-d] pyrimidinyl, 5,6,7,8-tetrahydropyrido [4,5-c] pyridazinyl, thiazolyl, thiadiazolyl, thiapyranyl, triazolyl, tetrazolyl, triazinyl, thieno [2,3-d] pyrimidinyl, thieno [3 ,2-d]pyrimidinyl, thieno[2,3-c]pridinyl, and thiophenyl (ie, thienyl). Unless otherwise stated herein, a heteroaryl moiety is optionally substituted with one or more substituents independently including: acyl, alkyl, alkenyl, alkynyl, alkoxy, alkylaryl, cycloalkyl, aralkyl, aryl , aryloxy, amino, amido, amidino, imino, azide, carbonate, carbamate, carbonyl, heteroalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, hydroxy, cyano, halo, halo Alkoxy, haloalkyl, ester, ether, mercapto, thio, alkylthio, arylthio, thiocarbonyl, nitro, oxo, phosphate, phosphonate, phosphinate, silyl, sulfinyl, sulfonyl, sulfonamidyl, Sulfoxyl, sulfonate, urea, -Si(R^a)₃-, -OR^a, -SR^a, -OC(O)-R^a, -N(R^a)₂, -C(O)R^a, -C(O)OR^a, -OC(O)N(R^a)₂, -C(O)N(R^a)₂, -N(R^a)C(O)OR^a, -N(R^a)C(O)R^a, -N(R^a)C(O)N(R^a)₂, -N(R^a)C(NR^a)N(R^a)₂, -N(R^a)S(O)_tR^a(In this case, t is 1 or 2), -S(O)_tOR^a(In this case, t is 1 or 2), -S(O)_tN(R^a)₂(where t is 1 or 2), or -OP(=O)(OR^a)₂(At this time, each R^ais independently hydrogen, alkyl, haloalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl or heteroarylalkyl, each of which moieties is defined herein may be optionally substituted as follows).

"Heterocyclyl", "heterocycloalkyl" or "heterocarbocyclyl" means any 3 to 18 membered non-aromatic radical monocyclic or poly, respectively, containing one or more heteroatoms selected from nitrogen, oxygen, phosphorus and sulfur Refers to cyclic moiety.Heterocyclyl group can be monocyclic, bicyclic, tricyclic or tetracyclic ring system, wherein the polycyclic ring system can be fused, crosslinked or spiro ring system Heterocyclyl polycyclic ring system can contain one or more heteroatoms in one or two rings.Heterocyclyl group can be saturated or partially unsaturated.Heterocyclyl contains one or more double bonds In this case, a partially unsaturated heterocycloalkyl group may be referred to as "heterocycloalkenyl", or if the heterocyclyl contains one or more triple bonds, it may be referred to as "heterocycloalkynyl." When referred to herein, a number range, such as "5 to 18", refers to each integer in the given range; For example, "5 to 18 ring atoms" means that the heterocyclyl group may consist of 5 ring atoms, 6 ring atoms, etc., and contains up to 18 ring atoms. For example, a divalent radical derived from a monovalent heterocyclyl radical whose name ends with "yl" by removal of one hydrogen atom from an atom having a free valence is named by adding "idene" to the corresponding monovalent radical, For example, a piperidine having two points of attachment is termed piperidylidene.

An N-containing heterocyclyl moiety refers to a non-aromatic group in which at least one ring atom is a nitrogen atom. The heteroatoms in the heterocyclyl radical may be optionally oxidized. If present, one or more nitrogen atoms may optionally be quaternized. Heterocyclyl also includes ring systems substituted with one or more nitrogen oxide (O) substituents, such as piperidinyl N-oxide. Heterocyclyl is attached to the parent molecular structure through any atom of any ring.

"Heterocyclyl" also includes ring systems wherein the heterocyclyl ring as defined above is fused with one or more carbocyclyl groups and the point of attachment is on the carbocyclyl or heterocyclyl ring, or on the ring system. wherein the heterocyclyl ring as defined above is fused with one or more aryl or heteroaryl groups and the point of attachment to the parent molecule is on the heterocyclyl ring. In some embodiments, a heterocyclyl group is a 3 to 10 membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, wherein each heteroatom is nitrogen, oxygen, phosphorus, and sulfur ("3 to 10 one heterocyclyl"). In some embodiments, a heterocyclyl group is a 5 to 8 membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, wherein each heteroatom is nitrogen, oxygen, phosphorus, and sulfur ("5 to 8 one heterocyclyl"). In some embodiments, a heterocyclyl group is a 5-6 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is nitrogen, oxygen, phosphorus, and sulfur ("5-6" one heterocyclyl"). In some embodiments, a 5-6 membered heterocyclyl has 1-3 ring heteroatoms selected from nitrogen, oxygen, phosphorus, and sulfur. In some embodiments, the 5-6 membered heterocyclyl has 1-2 ring heteroatoms selected from nitrogen, oxygen, phosphorus, and sulfur. In some embodiments, a 5-6 membered heterocyclyl has 1 ring heteroatom selected from nitrogen, oxygen, phosphorus, and sulfur.

Exemplary 3-membered heterocyclyls containing one heteroatom include, but are not limited to, aziridinyl, oxiranyl, thiorenyl. Exemplary 4-membered heterocyclyls containing one heteroatom include, but are not limited to, azetidinyl, oxetanyl and thietanyl. Exemplary 5-membered heterocyclyls containing 1 heteroatom include, but are not limited to, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl and pyrrolyl- 2,5-dione. Exemplary 5-membered heterocyclyls containing two heteroatoms include, but are not limited to, dioxolanyl, oxathiolanyl and dithiolanyl. Exemplary 5-membered heterocyclyls containing 3 heteroatoms include, but are not limited to, triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary 6-membered heterocyclyl groups containing one heteroatom include, but are not limited to, piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl. Exemplary 6 membered heterocyclyl groups containing two heteroatoms include, but are not limited to, piperazinyl, morpholinyl, dithianyl, dioxanyl, and triazinanyl. Exemplary 7 membered heterocyclyl groups containing one heteroatom include, but are not limited to, azepanyl, oxepanyl and thiepanyl. Exemplary 8 membered heterocyclyl groups containing one heteroatom include, but are not limited to, azokanyl, oxecanyl and thiokanyl. Exemplary bicyclic heterocyclyl groups include, but are not limited to, indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, tetrahydrobenzothienyl, tetrahydrobenzofuranyl, tetrahydroindolyl, Tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, decahydroisoquinolinyl, octahydrochromenyl, octahydroisochromenyl, decahydronaphthyridinyl, decahydro-1,8-naphthyridinyl, Octahydropyrrolo [3,2-b] pyrrole, indolinyl, phthalimidyl, naphthalimidyl, chromanyl, chromenyl, 1H-benzo [e] [1,4] diazepinyl, 1,4, 5,7-tetrahydropyrano[3,4-b]pyrrolyl, 5,6-dihydro-4H-furo[3,2-b]pyrrolyl, 6,7-dihydro-5H-furo[3 ,2-b]pyranyl, 5,7-dihydro-4H-thieno[2,3-c]pyranyl, 2,3-dihydro-1H-pyrrolo[2,3-b]pyridinyl, 2,3-dihydrofuro [2,3-b] pyridinyl, 4,5,6,7-tetrahydro-1H-pyrrolo[2,3-b]pyridinyl, 4,5,6,7-tetrahydrofuro[3,2-c]pyridinyl, 4,5, 6,7-tetrahydrothieno[3,2-b]pyridinyl, 1,2,3,4-tetrahydro-1,6-naphthyridinyl, and the like.

Unless otherwise stated, a heterocyclyl moiety is optionally substituted with one or more substituents independently including: acyl, alkyl, alkenyl, alkynyl, alkoxy, alkylaryl, cycloalkyl, aralkyl, aryl, aryl oxy, amino, amido, amidino, imino, azide, carbonate, carbamate, carbonyl, heteroalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, hydroxy, cyano, halo, haloalkoxy, Haloalkyl, ester, ether, mercapto, thio, alkylthio, arylthio, thiocarbonyl, nitro, oxo, phosphate, phosphonate, phosphinate, silyl, sulfinyl, sulfonyl, sulfonamidyl, sulfoxyl , sulfonate, urea, -Si(R^a)₃-, -OR^a, -SR^a, -OC(O)R^a, -N(R^a)₂, -C(O)R^a, -C(O)OR^a, -OC(O)N(R^a)₂, -C(O)N(R^a)₂, -N(R^a)C(O)OR^a, -N(R^a)C(O)R^a, -N(R^a)C(O)N(R^a)₂, -N(R^a)C(NR^a)N(R^a)₂, -N(R^a)S(O)_tR^a(In this case, t is 1 or 2), -S(O)_tOR^a(In this case, t is 1 or 2), -S(O)_tN(R^a)₂(where t is 1 or 2), or -OP(=O)(OR^a)₂(At this time, each R^ais independently hydrogen, alkyl, haloalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl or heteroarylalkyl, each of which moieties are as defined herein may be substituted arbitrarily).

"Nitro" is -NO₂ refers to radicals.

"phosphate" is -OP(=O)(OR^b)₂ refers to a radical, wherein each R^bis hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, heteroalkyl (bonded by chain carbons), cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocycloalkyl (bonded by ring carbons), heterocycloalkyl independently selected from alkyl, heteroaryl (bonded by a ring carbon) or heteroarylalkyl, each of which moieties may be optionally substituted as described herein, unless otherwise stated herein. In some embodiments, R^aWhen is hydrogen and is pH dependent, the hydrogen may be substituted with a suitably charged counter ion.

"imino" means "-(C=N)-R^b" refers to a radical, wherein R^bis hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, heteroalkyl (bonded by chain carbons), cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocycloalkyl (bonded by ring carbons), heterocycloalkyl alkyl, heteroaryl (bonded by a ring carbon) or heteroarylalkyl, each of which moieties may be optionally substituted as described herein, unless otherwise stated herein.

"phosphonate" is -OP(=O)(R^b)(OR^b) refers to a radical, wherein each R^bis hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, heteroalkyl (bonded by chain carbons), cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocycloalkyl (bonded by ring carbons), heterocycloalkyl independently selected from alkyl, heteroaryl (bonded by a ring carbon) or heteroarylalkyl, each of which moieties may be optionally substituted as described herein, unless otherwise stated herein. In some embodiments, R^aWhen is hydrogen and is pH dependent, the hydrogen can be replaced with an appropriately charged counter ion.

"Phosphinate" means -P(=O)(R^b)(OR^b) refers to a radical, wherein each R^bis hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, heteroalkyl (bonded by chain carbons), cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocycloalkyl (bonded by ring carbons), heterocycloalkyl independently selected from alkyl, heteroaryl (bonded by a ring carbon) or heteroarylalkyl, each of which moieties may be optionally substituted as described herein, unless otherwise stated herein. In some embodiments, R^aWhen is hydrogen and is pH dependent, the hydrogen can be replaced with an appropriately charged counter ion.

As used herein, the term "substituted" or "substitution" means that one or more hydrogens present on a group atom (eg, a carbon or nitrogen atom) are replaced by an acceptable substituent, such as a hydrogen, for a stable compound, such as a compound spontaneously. to be substituted with a substituent that results in a compound that does not undergo conversion, such as rearrangement, cyclization, elimination, or other reaction. Unless otherwise stated, a "substituted" group may have a substituent at one or more substitutable positions of the group, and when more than one position in any given structure is substituted, the substituent is the same or different at each position. Substituents include individual one or more groups and are independently selected from: acyl, alkyl, alkenyl, alkynyl, alkoxy, alkylaryl, cycloalkyl, aralkyl, aryl, aryloxy, amino, amido, azide, Carbonate, carbonyl, heteroalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, hydroxy, cyano, halo, haloalkoxy, haloalkyl, ester, mercapto, thio, alkylthio, arylthio, thiocarbonyl , nitro, oxo, phosphate, phosphonate, phosphinate, silyl, sulfinyl, sulfonyl, sulfonamidyl, sulfoxyl, sulfonate, urea, -Si(R^a)₃, -OR^a, -SR^a, -OC(O)-R^a, -N(R^a)₂, -C(O)R^a, -C(O)OR^a, -OC(O)N(R^a)₂, -C(O)N(R^a)₂, -N(R^a)C(O)OR^a, -N(R^a)C(O)R^a, -N(R^a)C(O)N(R^a)₂, -N(R^a)C(NR^a)N(R^a)₂, -N(R^a)S(O)_tR^a(In this case, t is 1 or 2), -S(O)_tOR^a(In this case, t is 1 or 2), -S(O)_tN(R^a)₂(In this case, t is 1 or 2), -OP(=O)(OR^a)₂(At this time, each R^ais independently hydrogen, alkyl, haloalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl or heteroarylalkyl, each moiety of which is defined herein. may be optionally substituted as follows). For example, a cycloalkyl substituent may have a halide substituted with one or more ring carbons or the like. Protecting groups capable of forming protective derivatives of the above substituents are known to those skilled in the art and can be found, for example, in the literature of Greene and Wut, supra.

"Silyl" is -Si(R^b)₃ refers to a radical, wherein each R^bis alkyl, alkenyl, alkynyl, haloalkyl, heteroalkyl (bonded by chain carbons), cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocycloalkyl (bonded by ring carbons), heterocycloalkylalkyl, heteroaryl (bonded by a ring carbon) or heteroarylalkyl, each moiety of which may be optionally substituted as described herein, unless otherwise stated herein.

"Sulfanyl", "sulfide", and "thio" each represent the radical -SR^brefers to, where R^bis alkyl, alkenyl, alkynyl, haloalkyl, heteroalkyl (bonded by chain carbons), cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocycloalkyl (bonded by ring carbons), heterocycloalkylalkyl, heteroaryl (bonded by a ring carbon) or heteroarylalkyl, each moiety of which may be optionally substituted as described herein, unless otherwise stated herein. For example, "alkylthio" refers to the "alkyl-S-" radical and "arylthio" refers to the "aryl-S-" radical, each of which is bonded to the parent molecular group through an S atom. In addition, the terms "sulfide", "thiol", "mercapto", and "mercaptan" each refer to the group -R^bSH may be referred to.

"Sulfinyl" or "sulfoxide" is -S(O)-R^b refers to a radical, wherein when "sulfinyl", R^bis H and if "sulfoxide", then R^bis alkyl, alkenyl, alkynyl, haloalkyl, heteroalkyl (bonded by chain carbons), cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocycloalkyl (bonded by ring carbons), heterocycloalkylalkyl, heteroaryl (bonded by a ring carbon) or heteroarylalkyl, each moiety of which may be optionally substituted as described herein, unless otherwise stated herein.

"sulfonyl" or "sulfone" is -S (O₂)-R^b refers to a radical, where R^bis hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, heteroalkyl (bonded by chain carbons), cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocycloalkyl (bonded by ring carbons), heterocycloalkyl alkyl, heteroaryl (bonded by a ring carbon) or heteroarylalkyl, each moiety of which may be optionally substituted as described herein, unless otherwise stated herein.

"Sulphonamidyl" or "sulfonamido" is -S(=O)₂-N(R^b)₂, -N(R^b)-S(=O)₂-R^b, -S(=O)₂-N(R^b)-, or -N(R^b)-S(=O)₂- refers to a radical, wherein each R^bis hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, heteroalkyl (bonded by chain carbons), cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocycloalkyl (bonded by ring carbons), heterocycloalkyl independently selected from alkyl, heteroaryl (bonded by a ring carbon) or heteroarylalkyl, each moiety of which may be optionally substituted as defined herein, unless otherwise stated herein. -S(=O)₂-N(R^b)₂ R in^b Groups can be selected together with the nitrogen to be attached such that they form a 4-, 5-, 6-, or 7 membered heterocyclyl ring. In some embodiments, the term C₁-C₄ Sulfonamido is each R in the sulfonamido^bcontains 1, 2, 3 or 4 carbons in total.

"sulfoxyl" or "sulfoxide" is -S (=O)₂OH radical.

"Sulphonate" is -S (=O)₂-OR^b refers to a radical, where R^bis alkyl, alkenyl, alkynyl, haloalkyl, heteroalkyl (bonded by chain carbons), cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocycloalkyl (bonded by ring carbons), heterocycloalkylalkyl, heteroaryl (bonded by a ring carbon) or heteroarylalkyl, each moiety of which may be optionally substituted as described herein, unless otherwise stated herein.

"Thiocarbonyl" refers to a -(C=S)- radical.

"Urea" is -N(R^b)-(C=O)-N(R^b)₂ or -N(R^b)-(C=O)-N(R^b)- refers to a radical, wherein each R^bis alkyl, alkenyl, alkynyl, haloalkyl, heteroalkyl (bonded by chain carbons), cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocycloalkyl (bonded by ring carbons), heterocycloalkylalkyl, heteroaryl (bonded by a ring carbon) or heteroarylalkyl, each moiety of which may be optionally substituted as described herein, unless otherwise stated herein.

Substituent groups are characterized by conventional formulas written from left to right, and they equally encompass chemically identical substituents from structures written from right to left, for example -CH₂O- is -OCH₂- same as

<b>II</b><b>. Compounds, Compositions, and Methods of Making</b>

In one embodiment, the invention relates to Form A, Form B, Form C, Form D, Form E, Form F, Form G, Form H, Form I, Form J, or an amorphous form of a compound of Formula polymorphic forms of the compounds of I, or salts, solvates or hydrates thereof; or a mixture of two or more:

[Formula I]

<img file="KR20140020249A_D0016.tif" />.

In one embodiment, the polymorphic form of the compound of formula (I) may be a crystalline form, a partially crystalline form, an amorphous form, or a mixture of crystalline and/or amorphous forms.

In one embodiment, a polymorph provided herein is a Form A, Form B, Form C, Form D, Form E, Form F, Form G, Form H, Form I, Form J, or amorphous form of a compound of Formula I , or a pharmaceutically acceptable salt, solvate or hydrate thereof, or a mixture of two or more thereof. In one embodiment, the polymorph provided herein is a Form B, Form C, Form D, Form E, Form F, Form G, Form H, Form I, Form J, or amorphous form of a compound of Formula I, or It is a pharmaceutically acceptable salt, solvate or hydrate of In one embodiment, a polymorph provided herein is a Form A, Form B, Form C, Form D, Form E, Form F, Form G, Form H, Form I, Form J, or amorphous form of a compound of Formula I , or a pharmaceutically acceptable salt, solvate or hydrate thereof, or a substantially pure mixture of two or more thereof. In one embodiment, the polymorphs provided herein are thermally stable. In one embodiment, the polymorphs provided herein are subjected to long-term storage (e.g., about 1, about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, about 10, about 11, no significant change in polymorphism after more than about 12, about 18, about 24, about 30, about 36, about 42, about 48, about 54, about 60, or about 60 months). In one embodiment, after storage for a specified time, less than about 20%, less than about 10%, less than about 9%, less than about 8%, less than about 7%, less than about 6%, less than about 5%, less than about 4 Less than %, less than about 3%, less than about 2%, less than about 1% w/w of a polymorph provided herein is converted to another polymorph.

In certain embodiments, the polymorph provided herein is polymorph Form C of a compound of Formula (I). In certain embodiments, the present invention provides solid forms of a compound of Formula (I), including Form C of the compound of Formula (I). In certain embodiments, the present invention provides a solid form of a compound of Formula (I), comprising Form C of the compound of Formula (I), which is substantially pure. In one embodiment, Form C can be characterized as having X-ray powder diffraction (XRPD) peaks at about 10.4, about 13.3, and about 24.3 degrees 2θ. In certain embodiments, Form C is characterized as having differential scanning calorimetry (DSC) that is endothermic at about 208°C. In certain embodiments, Form C can be characterized by thermogravimetric analysis in which a % weight loss of about 1.7% by weight at about 80°C and about 0.2% by weight at about 190°C is observed.

In one embodiment, the non-Form C polymorph is a solid form of a compound of Formula (I), or a salt, solvate or hydrate (e.g., a crystalline form, an amorphous form, or a mixture of crystalline and/or amorphous forms) thereof , they are not polymorphic form C of the compound of formula (I). In one embodiment, the non-Form C polymorph is Form A, Form B, Form D, Form E, Form F, Form G, Form H, Form I, Form J, or an amorphous form of the compound of Formula I, or salts, solvates or hydrates thereof; or a mixture of two or more. In one embodiment, the non-Form C polymorph may comprise at least 50% by weight of polymorph Form A of the compound of formula (I). In one embodiment, a non-Form C polymorph (eg, Form A or Form B) can be obtained from a composition comprising Form C.

In certain embodiments, a salt of a compound of Formula (I) provided herein is L-tartaric acid, <i>p</i>-toluenesulfonic acid, <i>D</i>-glucaronic acid, ethane-1,2-disulfonic acid (EDSA), 2-naphthalenesulfonic acid (NSA), hydrochloric acid (HCl), hydrobromic acid (HBr), citric acid, naphthalene-1,5-disulfonic acid ( NDSA), <i>DL</i>-Mandelic acid, fumaric acid, sulfuric acid, maleic acid, methanesulfonic acid (MSA), benzenesulfonic acid (BSA), ethanesulfonic acid (ESA), <i>L</i>- Salts derived from malic acid, phosphoric acid, or aminoethanesulfonic acid (taurine). In certain embodiments, a salt of a compound of Formula (I) provided herein is a mono-acid salt or a bis-acid salt. In certain embodiments, a salt of a compound of Formula (I) provided herein is an HCl salt (eg, a mono-HCl salt or a bis-HCl salt), or a solvate or hydrate thereof. In certain embodiments, a salt, solvate or hydrate of a compound of Formula (I) provided herein is a crystalline material, partially crystalline material, or amorphous material or a mixture of one or more crystalline and/or amorphous forms.

In one embodiment, the present invention provides a composition comprising a compound of formula (I):

[Formula I]

<img file="KR20140020249A_D0017.tif" />

In one embodiment, the composition comprises polymorph Form C. In one embodiment, the composition comprises a mixture of polymorph Form C and one or more non-Form C polymorphs of a compound of Formula I, or a pharmaceutically acceptable salt, solvate or hydrate thereof. For example, in certain embodiments, the composition may comprise polymorph Form C and polymorph Form A. In other embodiments, the composition may comprise polymorph Form C and polymorph Form B. In other embodiments, the composition may comprise polymorph Form C and polymorph Form D. In other embodiments, the composition may comprise Polymorph Form C and Polymorph Form E. In other embodiments, the composition may comprise polymorph Form C and polymorph Form F. In other embodiments, the composition may comprise polymorph Form C and polymorph Form G. In other embodiments, the composition may comprise polymorph Form C and polymorph Form H. In other embodiments, the composition may comprise Polymorph Form C and Polymorph Form I. In other embodiments, the composition may comprise polymorph Form C and polymorph Form J. In another embodiment, the composition may comprise polymorph Form C and an amorphous form of a compound of Formula I, or a pharmaceutically acceptable salt, solvate or hydrate thereof. In one embodiment, the ratio of polymorph Form C to the total amount of non-Form C polymorph is greater than about 1:1, greater than about 2:1, greater than about 3:1, greater than about 4:1, about 5:1 greater than, greater than about 6:1, greater than about 7:1, greater than about 8:1, or greater than about 9:1. In one embodiment, the composition comprising Form C is a pharmaceutical composition. In one embodiment, the composition is at least about 98% by weight of the compound of Formula I, or a pharmaceutically acceptable salt, solvate or hydrate thereof.

In one embodiment, the composition comprises a mixture of polymorph Form A and one or more non-Form A polymorphs of a compound of Formula I, or a pharmaceutically acceptable salt, solvate or hydrate thereof. For example, in certain embodiments, a composition may include polymorph Form A and polymorph Form B. In other embodiments, the composition may comprise Polymorph Form A and Polymorph Form C. In other embodiments, the composition may comprise polymorph Form A and polymorph Form D. In other embodiments, the composition may comprise Polymorph Form A and Polymorph Form E. In other embodiments, the composition may comprise polymorph Form A and polymorph Form F. In other embodiments, the composition may comprise polymorph Form A and polymorph Form G. In other embodiments, the composition may comprise polymorph Form A and polymorph Form H. In other embodiments, the composition may comprise Polymorph Form A and Polymorph Form I. In other embodiments, the composition may comprise polymorph Form A and polymorph Form J. In another embodiment, the composition may comprise polymorph Form A and an amorphous form of a compound of Formula I, or a pharmaceutically acceptable salt, solvate or hydrate thereof. In one embodiment, the ratio of polymorph Form A to the total amount of non-Form A polymorph is greater than about 1:1, greater than about 2:1, greater than about 3:1, greater than about 4:1, about 5:1 greater than, greater than about 6:1, greater than about 7:1, greater than about 8:1, or greater than about 9:1. In one embodiment, the ratio of polymorph Form A to non-Form A polymorph is less than about 1:1, less than about 2:1, less than about 3:1, less than about 4:1, less than about 5:1; less than about 6:1, less than about 7:1, less than about 8:1, or less than about 9:1. In one embodiment, the composition comprising Form A is a pharmaceutical composition. In one embodiment, the composition is at least about 98% by weight of the compound of formula (I), or a pharmaceutically acceptable salt, solvate or hydrate.

In certain embodiments, the present invention provides a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt, solvate or hydrate thereof; and one or more pharmaceutically acceptable excipients:

[Formula I]

<img file="KR20140020249A_D0018.tif" />

In one embodiment, the composition comprises polymorph Form C of the compound of formula (I). In one embodiment, the composition may further comprise one or more non-Form C polymorphs of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate or hydrate thereof. In certain embodiments, the ratio of polymorph Form C to the total amount of non-Form C polymorph is greater than about 1:1, greater than about 2:1, greater than about 3:1, greater than about 4:1, greater than about 5:1 , greater than about 6:1, greater than about 7:1, greater than about 8:1, or greater than about 9:1. In one embodiment, the composition comprises polymorph Form A of the compound of formula (I). In one embodiment, the composition may further comprise one or more non-Form A polymorphs of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate or hydrate thereof. In certain embodiments, the ratio of polymorph Form A to the total amount of non-Form A polymorph is greater than about 1:1, greater than about 2:1, greater than about 3:1, greater than about 4:1, greater than about 5:1 , greater than about 6:1, greater than about 7:1, greater than about 8:1, or greater than about 9:1. In certain embodiments, the ratio of polymorph Form A to the total amount of non-Form A polymorph is less than about 1:1, less than about 2:1, less than about 3:1, less than about 4:1, less than about 5:1 , less than about 6:1, less than about 7:1, less than about 8:1, or less than about 9:1.

In one embodiment, the polymorphs provided herein are useful for the production of medical preparations and can be obtained by a crystallization process to produce crystalline and semi-crystalline forms or a solidification process to obtain an amorphous form. In certain embodiments, the compound of formula (I) is produced in the reaction mixture, the polymorph is recovered from the reaction mixture, or the compound of formula (I) is dissolved in a solvent, optionally heated, followed by cooling and/or half for a period of time. Crystallization is carried out by crystallization/solidification by adding a solvent. Crystallization or solidification may be followed by drying under controlled conditions until a specific water content is reached in the final polymorphic form.

In one embodiment, the invention provides a process for the preparation of one or more polymorphs of a compound of formula (I), or a pharmaceutically acceptable salt, solvate or hydrate thereof:

[Formula I]

<img file="KR20140020249A_D0019.tif" />

Polymorphs prepared according to the methods provided herein include Form A, Form B, Form C, Form D, Form E, Form F, Form G, Form H, Form I, Form J, or an amorphous form of a compound of Formula I; or mixtures of two or more thereof. In one embodiment, the polymorph provided herein is a solvate or hydrate of a compound of Formula (I). In one embodiment, a polymorph provided herein is a mono-acid or bis-acid addition salt, such as a mono-HCl salt or bis-HCl salt of a compound of Formula (I), or a solvate or hydrate thereof.

In one embodiment, the present invention provides a process for the preparation of a compound of formula (I):

[Formula I]

<img file="KR20140020249A_D0020.tif" />

In one embodiment, the method comprises at least any 1, 2, 3, 4, 5, 6, 7, or 8 of the following steps:

<img file="KR20140020249A_D0021.tif" />

<img file="KR20140020249A_D0022.tif" />

<img file="KR20140020249A_D0023.tif" />

In the above formula,

X is fluoro, chloro, bromo, iodo, -O-SO₂-4-methylphenyl, and -O-SO₂-methyl;

PG¹silver benzyl, substituted benzyl, methoxycarbonyl, ethoxycarbonyl, substituted ethoxycarbonyl, 9-fluorenyloxycarbonyl, substituted 9-fluorenyloxycarbonyl, 2,2,2- Trichloroethoxycarbonyl, 2-trimethylsilylethoxycarbonyl, (2-phenyl-2-trimethylsilyl)ethoxycarbonyl, 2-phenylethoxycarbonyl, 1,1-dimethyl-2, 2-Dibromoethoxycarbonyl, 1,1-dimethyl-2,2,2-trichloroethoxycarbonyl, t-butoxycarbonyl, 1-adamantyloxycarbonyl, 2-adamantyl Oxycarbonyl, triisopropylsiloxycarbonyl, vinyloxycarbonyl, 1-isopropoxycarbonyl, 8-quinolyloxycarbonyl, 2,4-dimethylpent-3-yloxycarbonyl, benzyloxy carbonyl, and substituted benzyloxycarbonyl;

PG²is methylsulfonyl, substituted methylsulfonyl, benzenesulfonyl, substituted benzenesulfonyl, benzyloxycarbonyl, substituted benzyloxycarbonyl, 2,2,2-trichloroethoxycarbonyl, 2-trimethyl Silylethoxycarbonyl, t-butoxycarbonyl, 1-adamantyloxycarbonyl, 2-adamantyloxycarbonyl, alkyl, substituted alkyl, t-butyldimethylsilyl, triisopropylsilyl, allyl , benzyl, substituted benzyl, hydroxymethyl, methoxymethyl, diethoxymethyl, (2-chloroethoxy)methyl, t-butoxymethyl, t-butyldimethylsiloxymethyl, pivaloyloxymethyl, benzyloxymethyl, dimethylaminomethyl, 2-tetrahydropyranyl, substituted alkoxymethyl and substituted aryloxymethyl;

In this case, the substituent is alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, alkoxy, cycloalkoxy, heterocyclyloxy, aryloxy, heteroaryloxy , amido, amino, acyl, acyloxy, alkoxycarbonyl, ester, ether, thio, sulfinyl, sulfonyl, sulfonamido, halo, cyano, hydroxyl, nitro, phosphate, urea, carbamate and carbonate is selected from

In one embodiment, the present invention provides a process for the preparation of a compound of formula (I), or a pharmaceutically acceptable salt, solvate or hydrate thereof, comprising the steps of:

<img file="KR20140020249A_D0024.tif" />

In the above formula,

PG¹silver benzyl, substituted benzyl, methoxycarbonyl, ethoxycarbonyl, substituted ethoxycarbonyl, 9-fluorenyloxycarbonyl, substituted 9-fluorenyloxycarbonyl, 2,2,2- Trichloroethoxycarbonyl, 2-trimethylsilylethoxycarbonyl, (2-phenyl-2-trimethylsilyl)ethoxycarbonyl, 2-phenylethoxycarbonyl, 1,1-dimethyl-2, 2-Dibromoethoxycarbonyl, 1,1-dimethyl-2,2,2-trichloroethoxycarbonyl, t-butoxycarbonyl, 1-adamantyloxycarbonyl, 2-adamantyl Oxycarbonyl, triisopropylsiloxycarbonyl, vinyloxycarbonyl, 1-isopropoxycarbonyl, 8-quinolyloxycarbonyl, 2,4-dimethylpent-3-yloxycarbonyl, benzyloxy carbonyl, and substituted benzyloxycarbonyl;

In this case, the substituent is alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, alkoxy, cycloalkoxy, heterocyclyloxy, aryloxy, heteroaryloxy , amido, amino, acyl, acyloxy, alkoxycarbonyl, ester, ether, thio, sulfinyl, sulfonyl, sulfonamido, halo, cyano, hydroxyl, nitro, phosphate, urea, carbamate and carbonate is selected from

In some embodiments, PG¹is a carbamate protecting group such as alkoxycarbonyl or aryloxycarbonyl. In one embodiment, PG¹is selected from t-butoxycarbonyl and benzyloxycarbonyl. In one embodiment, PG¹is t-butoxycarbonyl.

In one embodiment, the step comprises combining the protected amino acid starting material with N,O-dimethylhydroxylamine (eg, free base or salt form, such as HCl salt) in the presence of an amide coupling agent to obtain the amide product. includes steps. In some embodiments, the amide coupling agent optionally includes, but is not limited to, HOBt, HOAt, and/or a base (eg, an amine base, such as Et₃N) in the presence of EDCI, DCC, DIC, HATU, HBTU, HCTU, TBTU, and PyBOP. In one embodiment, the amide coupling agent is EDCI in the presence of HOBt.

In one embodiment, the present invention provides a process for the preparation of a compound of formula (I), or a pharmaceutically acceptable salt, solvate or hydrate thereof, comprising the steps of:

<img file="KR20140020249A_D0025.tif" />

In one embodiment, the step comprises combining 2-chloro-6-methylbenzoic acid, such as thionyl chloride or oxalyl chloride, optionally in the presence of a catalytic amount of DMF to obtain 2-chloro-6-methylbenzoyl chloride. includes steps.

In one embodiment, the present invention provides a process for the preparation of a compound of formula (I), or a pharmaceutically acceptable salt, solvate or hydrate thereof, comprising the steps of:

<img file="KR20140020249A_D0026.tif" />

In one embodiment, the step comprises combining 2-chloro-6-methylbenzoyl chloride with aniline to obtain 2-chloro-6-methyl-N-phenylbenzamide. In one embodiment, the step is performed with a base (eg, an amine base such as Et₃N) optionally in the presence of.

In one embodiment, the present invention provides a process for the preparation of a compound of formula (I), or a pharmaceutically acceptable salt, solvate or hydrate thereof, comprising the steps of:

<img file="KR20140020249A_D0027.tif" />

In one embodiment, the step comprises combining 2-chloro-6-methylbenzoic acid with aniline in the presence of an amide coupling agent to obtain 2-chloro-6-methyl-N-phenylbenzamide. In some embodiments, the amide coupling agent optionally includes, but is not limited to, HOBt, HOAt, and/or a base (eg, an amine base, such as Et₃N) in the presence of EDCI, DCC, DIC, HATU, HBTU, HCTU, TBTU, and PyBOP. In certain embodiments, first, 2-chloro-6-methylbenzoic acid is combined with an acyl halide (eg, SOCl₂) or anhydrides (e.g., using methods known in the art, such as, but not limited to, combining with a suitable acid such as alkyl-COOH, and one or more equivalents of a coupling agent), acyl halide or anhydride is combined with aniline to give 2-chloro-6-methyl-N-phenylbenzamide.

In one embodiment, the present invention provides a process for the preparation of a compound of formula (I), or a pharmaceutically acceptable salt, solvate or hydrate thereof, comprising the steps of:

<img file="KR20140020249A_D0028.tif" />

In the above formula,

PG¹silver benzyl, substituted benzyl, methoxycarbonyl, ethoxycarbonyl, substituted ethoxycarbonyl, 9-fluorenyloxycarbonyl, substituted 9-fluorenyloxycarbonyl, 2,2,2- Trichloroethoxycarbonyl, 2-trimethylsilylethoxycarbonyl, (2-phenyl-2-trimethylsilyl)ethoxycarbonyl, 2-phenylethoxycarbonyl, 1,1-dimethyl-2, 2-Dibromoethoxycarbonyl, 1,1-dimethyl-2,2,2-trichloroethoxycarbonyl, t-butoxycarbonyl, 1-adamantyloxycarbonyl, 2-adamantyl Oxycarbonyl, triisopropylsiloxycarbonyl, vinyloxycarbonyl, 1-isopropoxycarbonyl, 8-quinolyloxycarbonyl, 2,4-dimethylpent-3-yloxycarbonyl, benzyloxy carbonyl, and substituted benzyloxycarbonyl;

In this case, the substituent is alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, alkoxy, cycloalkoxy, heterocyclyloxy, aryloxy, heteroaryloxy , amido, amino, acyl, acyloxy, alkoxycarbonyl, ester, ether, thio, sulfinyl, sulfonyl, sulfonamido, halo, cyano, hydroxyl, nitro, phosphate, urea, carbamate and carbonate is selected from

In some embodiments, PG¹is a carbamate protecting group such as alkoxycarbonyl or aryloxycarbonyl. In one embodiment, PG¹is selected from t-butoxycarbonyl and benzyloxycarbonyl. In one embodiment, PG¹is t-butoxycarbonyl.

In one embodiment, the starting material of the step, 2-chloro-6-methyl-N-phenylbenzamide, is reacted with (S)-tert-butyl in the presence of an alkyllithium such as n-butyllithium or n-hexyllithium. Combination with (1-(methoxy(methyl)amino)-1-oxopropan-2-yl)carbamate affords the protected amine. In another embodiment, under similar conditions 2-chloro-6-methyl-N-phenylbenzamide is combined with Boc-Ala-OMe, or another C₁_-6 Combined with an alkyl ester, the protected amine is obtained. In another embodiment, (S)-tert-butyl(1-(methoxy(methyl)amino)-1-oxopropan-2-yl)carbamate is mixed with an alkyl Grignard reagent such as, but not limited to, isopropyl After combining with Grignard (eg iPrMgCl), it is added to the mixture containing 2-chloro-6-methyl-N-phenylbenzamide. Other suitable Grignard reagents include, but are not limited to, organomagnesium halides such as organomagnesium chloride and organomagnesium bromide. Non-limiting examples of Grignard reagents include methylmagnesium (chloride or bromide), substituted methylmagnesium (chloride or bromide), such as 2-naphthylenylmethylmagnesium (chloride or bromide), cyclohexylmethylmagnesium (chloride or bromide), and 1,3-dioxanylmethyl magnesium (chloride or bromide), ethyl magnesium (chloride or bromide), phenylmagnesium (chloride or bromide), substituted phenylmagnesium (chloride or bromide), and other materials known in the art. include

In one embodiment, the present invention provides a process for the preparation of a compound of formula (I), or a pharmaceutically acceptable salt, solvate or hydrate thereof, comprising the steps of:

<img file="KR20140020249A_D0029.tif" />

In the above formula,

PG¹silver benzyl, substituted benzyl, methoxycarbonyl, ethoxycarbonyl, substituted ethoxycarbonyl, 9-fluorenyloxycarbonyl, substituted 9-fluorenyloxycarbonyl, 2,2,2- Trichloroethoxycarbonyl, 2-trimethylsilylethoxycarbonyl, (2-phenyl-2-trimethylsilyl)ethoxycarbonyl, 2-phenylethoxycarbonyl, 1,1-dimethyl-2, 2-Dibromoethoxycarbonyl, 1,1-dimethyl-2,2,2-trichloroethoxycarbonyl, t-butoxycarbonyl, 1-adamantyloxycarbonyl, 2-adamantyl Oxycarbonyl, triisopropylsiloxycarbonyl, vinyloxycarbonyl, 1-isopropoxycarbonyl, 8-quinolyloxycarbonyl, 2,4-dimethylpent-3-yloxycarbonyl, benzyloxy carbonyl, and substituted benzyloxycarbonyl;

In this case, the substituent is alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, alkoxy, cycloalkoxy, heterocyclyloxy, aryloxy, heteroaryloxy , amido, amino, acyl, acyloxy, alkoxycarbonyl, ester, ether, thio, sulfinyl, sulfonyl, sulfonamido, halo, cyano, hydroxyl, nitro, phosphate, urea, carbamate and carbonate is selected from

In some embodiments, PG¹is a carbamate protecting group such as alkoxycarbonyl or aryloxycarbonyl. In one embodiment, PG¹is selected from t-butoxycarbonyl and benzyloxycarbonyl. In one embodiment, PG¹is t-butoxycarbonyl.

In one embodiment, the protected amine is combined with an inorganic acid such as HCl or trifluoroacetic acid to give the isoquinolinone. Other suitable acids include, but are not limited to, methanesulfonic acid, sulfuric acid, hydrobromic acid, nitric acid, phosphoric acid, perchloric acid, and camphorsulfonic acid.

In one embodiment, the present invention provides a process for the preparation of a compound of formula (I), or a pharmaceutically acceptable salt, solvate or hydrate thereof, comprising the steps of:

<img file="KR20140020249A_D0030.tif" />

In the above formula,

X is fluoro, chloro, bromo, iodo, -O-SO₂-4-methylphenyl, and -O-SO₂-methyl;

PG²is methylsulfonyl, substituted methylsulfonyl, benzenesulfonyl, substituted benzenesulfonyl, benzyloxycarbonyl, substituted benzyloxycarbonyl, 2,2,2-trichloroethoxycarbonyl, 2-trimethyl Silylethoxycarbonyl, t-butoxycarbonyl, 1-adamantyloxycarbonyl, 2-adamantyloxycarbonyl, alkyl, substituted alkyl, t-butyldimethylsilyl, triisopropylsilyl, allyl , benzyl, substituted benzyl, hydroxymethyl, methoxymethyl, diethoxymethyl, (2-chloroethoxy)methyl, t-butoxymethyl, t-butyldimethylsiloxymethyl, pivaloyloxymethyl, benzyloxymethyl, dimethylaminomethyl, 2-tetrahydropyranyl, substituted alkoxymethyl and substituted aryloxymethyl;

In this case, the substituent is alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, alkoxy, cycloalkoxy, heterocyclyloxy, aryloxy, heteroaryloxy , amido, amino, acyl, acyloxy, alkoxycarbonyl, ester, ether, thio, sulfinyl, sulfonyl, sulfonamido, halo, cyano, hydroxyl, nitro, phosphate, urea, carbamate and carbonate is selected from

In one embodiment, PG²is 2-tetrahydropyranyl. In some embodiments, X is selected from fluoro, chloro, bromo, and iodo. In one embodiment, X is chloro. In certain embodiments, the step comprises combining 6-chloro-9H-purine with 3,4-dihydro-2H-pyran to 6-chloro-9-(tetrahydro-2H-pyran-2-yl)-9H-purine comprising the steps of obtaining

In one embodiment, the present invention provides a process for the preparation of a compound of formula (I), or a pharmaceutically acceptable salt, solvate or hydrate thereof, comprising the steps of:

<img file="KR20140020249A_D0031.tif" />

In the above formula,

X is fluoro, chloro, bromo, iodo, -O-SO₂-4-methylphenyl, and -O-SO₂-methyl;

PG²is methylsulfonyl, substituted methylsulfonyl, benzenesulfonyl, substituted benzenesulfonyl, benzyloxycarbonyl, substituted benzyloxycarbonyl, 2,2,2-trichloroethoxycarbonyl, 2-trimethyl Silylethoxycarbonyl, t-butoxycarbonyl, 1-adamantyloxycarbonyl, 2-adamantyloxycarbonyl, alkyl, substituted alkyl, t-butyldimethylsilyl, triisopropylsilyl, allyl , benzyl, substituted benzyl, hydroxymethyl, methoxymethyl, diethoxymethyl, (2-chloroethoxy)methyl, t-butoxymethyl, t-butyldimethylsiloxymethyl, pivaloyloxymethyl, benzyloxymethyl, dimethylaminomethyl, 2-tetrahydropyranyl, substituted alkoxymethyl and substituted aryloxymethyl;

In this case, the substituent is alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, alkoxy, cycloalkoxy, heterocyclyloxy, aryloxy, heteroaryloxy , amido, amino, acyl, acyloxy, alkoxycarbonyl, ester, ether, thio, sulfinyl, sulfonyl, sulfonamido, halo, cyano, hydroxyl, nitro, phosphate, urea, carbamate and carbonate is selected from

In one embodiment, PG²is 2-tetrahydropyranyl. In some embodiments, X is selected from fluoro, chloro, bromo and iodo. In one embodiment, X is chloro. In one embodiment, a base, such as an amine base (eg, Et₃In the presence of N), the protected chloropurine is combined with isoquinolinone in an alcoholic solvent (eg, MeOH, EtOH, PrOH, and iPrOH).

In one embodiment, the present invention provides a process for the preparation of a compound of formula (I), or a pharmaceutically acceptable salt, solvate or hydrate thereof, comprising the steps of:

<img file="KR20140020249A_D0032.tif" />

In the above formula,

PG²is methylsulfonyl, substituted methylsulfonyl, benzenesulfonyl, substituted benzenesulfonyl, benzyloxycarbonyl, substituted benzyloxycarbonyl, 2,2,2-trichloroethoxycarbonyl, 2-trimethyl Silylethoxycarbonyl, t-butoxycarbonyl, 1-adamantyloxycarbonyl, 2-adamantyloxycarbonyl, alkyl, substituted alkyl, t-butyldimethylsilyl, triisopropylsilyl, allyl , benzyl, substituted benzyl, hydroxymethyl, methoxymethyl, diethoxymethyl, (2-chloroethoxy)methyl, t-butoxymethyl, t-butyldimethylsiloxymethyl, pivaloyloxymethyl, benzyloxymethyl, dimethylaminomethyl, 2-tetrahydropyranyl, substituted alkoxymethyl and substituted aryloxymethyl;

In this case, the substituent is alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, alkoxy, cycloalkoxy, heterocyclyloxy, aryloxy, heteroaryloxy , amido, amino, acyl, acyloxy, alkoxycarbonyl, ester, ether, thio, sulfinyl, sulfonyl, sulfonamido, halo, cyano, hydroxyl, nitro, phosphate, urea, carbamate and carbonate is selected from

In one embodiment, PG²is 2-tetrahydropyranyl. In one embodiment, the protected purine is combined with an inorganic acid such as, but not limited to, HCl, HBr, perchloric acid, sulfuric acid, nitric acid, and phosphoric acid in an alcoholic solvent (such as MeOH, EtOH, PrOH, and iPrOH). In one embodiment, the inorganic acid is HCl.

In one embodiment, the present invention provides a process for the preparation of a compound of formula (I), or a pharmaceutically acceptable salt, solvate or hydrate thereof, comprising the steps of:

<img file="KR20140020249A_D0033.tif" />

In the above formula,

X is fluoro, chloro, bromo, iodo, -O-SO₂-4-methylphenyl, and -O-SO₂-methyl.

In some embodiments, X is selected from fluoro, chloro, bromo, and iodo. In one embodiment, X is chloro. In one embodiment, the starting material is mixed with an amine base such as Et in an alcoholic solvent such as glycerol.₃In combination with N affects amine coupling.

In some embodiments, an intermediate for the synthesis of a compound of Formula I, or a salt, solvate, or hydrate thereof, is prepared according to one or more of the following schemes.

[Scheme 1]

<img file="KR20140020249A_D0034.tif" />

In one embodiment, the conversion of compound 1 to compound 2 may be performed according to any method in the art. In one embodiment, compound 1 is combined with MeNHOMe (HCl) in the presence of EDCI and HOBt. In certain embodiments, a base such as triethylamine may be present.

[Scheme 2]

<img file="KR20140020249A_D0035.tif" />

In one embodiment, the conversion of compound 3 to compound 4 occurs in the presence of para-toluenesulfonic acid. In another embodiment, the THP protecting group is generated using camphorsulfonic acid in 2-methyltetrahydrofuran.

[Scheme 3]

<img file="KR20140020249A_D0036.tif" />

In one embodiment, the conversion of compound 5 to compound 7 can be performed according to any method in the art. In one embodiment, compound 5 is combined with thionyl chloride and DMF to give compound 6, which is combined with aniline to give compound 7.

In one embodiment, compound 7 is <i>n</i>- After combining with hexyl lithium, convert to compound 8 by adding compound 2 previously combined with isopropyl Grignard (eg iPrMgCl). In one embodiment, compound 8 is converted to compound 9 in a solvent such as methanol or isopropyl alcohol in the presence of an acid such as hydrochloric acid, trifluoroacetic acid, or methanesulfonic acid. In one embodiment, the acid may be trifluoroacetic acid.

In one embodiment, compound 3 and compound 9 are combined to prepare a compound of formula I, or a salt, solvate or hydrate thereof, according to the following scheme:

[Scheme 4]

<img file="KR20140020249A_D0037.tif" />

In one embodiment, starting materials 3 and 9 are combined with an amine base such as Et in an alcoholic solvent such as glycerol.₃In combination with N affects furine coupling.

In one embodiment, a compound of Formula I, or a salt, solvate or hydrate thereof, can be prepared according to the following synthetic scheme:

[Scheme 5]

<img file="KR20140020249A_D0038.tif" />

In the above formula,

PG²is methylsulfonyl, substituted methylsulfonyl, benzenesulfonyl, substituted benzenesulfonyl, benzyloxycarbonyl, substituted benzyloxycarbonyl, 2,2,2-trichloroethoxycarbonyl, 2-trimethyl Silylethoxycarbonyl, t-butoxycarbonyl, 1-adamantyloxycarbonyl, 2-adamantyloxycarbonyl, alkyl, substituted alkyl, t-butyldimethylsilyl, triisopropylsilyl, allyl , benzyl, substituted benzyl, hydroxymethyl, methoxymethyl, diethoxymethyl, (2-chloroethoxy)methyl, t-butoxymethyl, t-butyldimethylsiloxymethyl, pivaloyloxymethyl, benzyloxymethyl, dimethylaminomethyl, 2-tetrahydropyranyl, substituted alkoxymethyl and substituted aryloxymethyl;

In this case, the substituent is alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, alkoxy, cycloalkoxy, heterocyclyloxy, aryloxy, heteroaryloxy , amido, amino, acyl, acyloxy, alkoxycarbonyl, ester, ether, thio, sulfinyl, sulfonyl, sulfonamido, halo, cyano, hydroxyl, nitro, phosphate, urea, carbamate and carbonate is selected from

Contrary to that shown in the two steps, the above synthetic scheme can be carried out as a one-pot reaction. In one embodiment, a base (eg, an amine base such as but not limited to Et₃The first step to obtain compound Ia can be carried out in an alcoholic solvent (eg, MeOH, EtOH, PrOH, and iPrOH) in the presence of N). PG² Depending on the nature of the protecting group, the following reagents can be used to deprotect compound Ia to give compound I. protector PG²One or more reagents for removal include, but are not limited to, acids such as HCl, HBr and TFA; Carbonate bases such as Na₂CO₃ and K₂CO₃; hydroxyl bases such as NaOH and KOH; lithium bases such as methyl lithium, ethyl lithium, propyl lithium, n-butyl lithium, n-pentyl lithium, and n-hexyl lithium; oxidizing agents such as cerium ammonium nitrate; hydrogenation conditions such as cyclohexadiene/Pd black, and H₂/Pd/C; TBAF, and BF₃Et₂contains O.

In one embodiment, a compound of Formula I, or a salt, solvate or hydrate thereof, is prepared using the following synthetic scheme:

<img file="KR20140020249A_D0039.tif" />

In one embodiment, a base (eg, an amine base such as but not limited to Et₃The first step to obtain compound 10 can be carried out in an alcoholic solvent (eg, MeOH, EtOH, PrOH, and iPrOH) in the presence of N). In certain embodiments, a compound of formula (I), or a salt, solvate or hydrate thereof, is obtained by treating the protected precursor (eg, compound 10) with hydrochloric acid in ethanol followed by treatment with dichloromethane. In certain embodiments, the product treated with dichloromethane is treated under aqueous conditions, such as about 90% water and about 10% 2-propanol.

In one embodiment, the recovery and purification of the chemicals and intermediates described herein is carried out by methods such as, but not limited to, filtration, extraction, crystallization, precipitation, silica gel column chromatography, high pressure liquid chromatography, thin layer chromatography or thick layer ( thick-layer) chromatography, or a combination of these methods. Non-limiting illustrative examples of suitable recovery and purification methods are provided in the Examples below. However, other recovery and purification methods known in the art may also be used.

Prior to preparation as an active pharmaceutical ingredient in a drug product, the compound of Formula I, or a salt, solvate or hydrate thereof, is greater than about 90% pure, greater than about 91% pure, greater than about 92% pure, about 93% pure. greater than about 94% pure, greater than about 95% pure, greater than about 96% pure, greater than about 97% pure, greater than about 98% pure, greater than about 99% pure, and 100% pure It can be isolated to near purity.

In some embodiments, the (R)- and (S)-isomers of a compound of Formula (I), when both present, can be separated by methods known to those skilled in the art, such as crystallization, to form diastereomeric salts or complexes; formation of diastereomeric derivatives which can be separated, for example, by crystallization, gas-liquid or liquid chromatography; selective reaction of one enantiomer with an enantiomer-specific reagent, such as enzymatic oxidation or reduction followed by separation of the modified and unmodified enantiomers; or by gas-liquid or liquid chromatography in a chiral environment, such as on a chiral support, such as silica comprising bound chiral ligands or in the presence of a chiral solvent. Alternatively, a particular enantiomer may be synthesized by asymmetric synthesis using an optionally active reagent, substrate, catalyst or solvent, or by converting one enantiomer to the other by asymmetric transformation. In certain embodiments, the compounds of formula (I) exist as racemic or non-racemic mixtures, including enantiomers. In one embodiment, the compound of formula (I) is greater than about 60%, greater than about 65%, greater than about 70%, greater than about 75%, greater than about 80%, greater than about 85%, greater than about 90%, greater than about 91% , greater than about 92%, greater than about 93%, greater than about 94%, greater than about 95%, greater than about 96%, greater than about 97%, greater than about 98%, and greater than about 99% enantiomeric excess (ee) exists as

In one embodiment, the present invention provides a process for preparing a polymorph of a compound of formula (I), or a pharmaceutically acceptable salt, solvate or hydrate thereof:

[Formula I]

<img file="KR20140020249A_D0040.tif" />

In one embodiment, the method comprises recovering the polymorph as the first solid form after synthesis of the compound of formula (I). In another embodiment, the method comprises first recovering a solid form of a compound of Formula I (e.g., a first polymorph of a compound of Formula I, or a salt, solvate or hydrate thereof, and preparing the recovered solid form under suitable conditions. 2 to recover the polymorph as a transition from the previous solid form of (converting to the polymorph). Transitions from one polymorphic form to another are within the scope of the present disclosure. In one embodiment, this transfer process can be used as a manufacturing method to obtain a form for the production of a medical agent.

In one embodiment, the present invention provides

i) combining a compound of formula la²to form a compound of formula (I); and

ii) recovering polymorph Form C of the compound of formula I, wherein at least one of steps i) and ii) occurs under non-anhydrous conditions.

There is provided a process for the preparation of polymorph Form C of a compound of formula (I), comprising:

[Formula Ia]

<img file="KR20140020249A_D0041.tif" />

[Formula I]

<img file="KR20140020249A_D0042.tif" />

In the above formula,

PG²is methylsulfonyl, substituted methylsulfonyl, benzenesulfonyl, substituted benzenesulfonyl, benzyloxycarbonyl, substituted benzyloxycarbonyl, 2,2,2-trichloroethoxycarbonyl, 2-trimethyl Silylethoxycarbonyl, t-butoxycarbonyl, 1-adamantyloxycarbonyl, 2-adamantyloxycarbonyl, alkyl, substituted alkyl, t-butyldimethylsilyl, triisopropylsilyl, allyl , benzyl, substituted benzyl, hydroxymethyl, methoxymethyl, diethoxymethyl, (2-chloroethoxy)methyl, t-butoxymethyl, t-butyldimethylsiloxymethyl, pivaloyloxymethyl, a protecting group selected from benzyloxymethyl, dimethylaminomethyl, 2-tetrahydropyranyl, substituted alkoxymethyl and substituted aryloxymethyl;

In this case, the substituent is alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, alkoxy, cycloalkoxy, heterocyclyloxy, aryloxy, heteroaryloxy , amido, amino, acyl, acyloxy, alkoxycarbonyl, ester, ether, thio, sulfinyl, sulfonyl, sulfonamido, halo, cyano, hydroxyl, nitro, phosphate, urea, carbamate and carbonate is selected from

In some embodiments, the protecting group PG²One or more reagents for removal include, but are not limited to, acids such as HCl, HBr and TFA; Carbonate bases such as Na₂CO₃ and K₂CO₃; hydroxyl bases such as NaOH and KOH; lithium bases such as methyl lithium, ethyl lithium, propyl lithium, n-butyl lithium, n-pentyl lithium, and n-hexyl lithium; oxidizing agents such as cerium ammonium nitrate; hydrogenation conditions such as cyclohexadiene/Pd black, and H₂/Pd/C; TBAF, and BF₃Et₂contains O. In one embodiment, the non-anhydrous condition comprises water, such as in the form of water vapor and/or liquid water. In one embodiment, the non-anhydrous condition comprises a solvent system comprising a non-aqueous solvent described herein and liquid water.

In one embodiment, the present invention provides a process for the preparation of polymorph Form C of a compound of formula (I), comprising the steps of:

[Formula I]

<img file="KR20140020249A_D0043.tif" />

(i) at least one non-Form C polymorph of the compound of Formula I, or a salt, solvent thereof, for a time sufficient to convert at least about 50% of the total amount of the non-Form C polymorph of the compound of Formula I to Form C exposing the cargo or composition comprising the hydrate to non-anhydrous conditions; and

(ii) recovering polymorph Form C.

In certain embodiments, the recovery step involves recrystallization of the reaction product from a single-solvent system. In certain embodiments, the recovery step involves recrystallization of the product from binary, ternary or more solvent systems, wherein binary, ternary or more solvent systems are collectively understood as multi-solvent systems. In certain embodiments, the recovery step involves crystallization from a single- or multi-solvent system, wherein the crystallization involves cooling a solution containing a compound of formula (I). In certain embodiments, the recovery step involves crystallization from a mono- or multi-solvent system, wherein the crystallization involves addition of an antisolvent with or without a cooling step leading to precipitation of Form C. In certain embodiments, the conditions for crystallization are non-anhydrous. When the conditions are non-anhydrous, water may be present in trace amounts, or less than about 1% of the solvent volume, or as water vapor. In certain embodiments, water may be present as a co-solvent (or anti-solvent), such as in an amount from about 1 to about 50%. For example, water may be present at about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, and about 50% of the volume of the solvent. have. In certain embodiments, water may be present in at least about 50% of the solvent volume. For example, water may be present in no more than about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, and 100% of the solvent volume. have. In certain embodiments, the liquid water is present in a multi-solvent system, such as in an amount from about 10% to about 50% by volume of the solvent system. In certain embodiments, the liquid water is present in the multi-solvent system in an amount of at least about 50% by volume of the solvent system. In certain embodiments, water may be present as water vapor or ambient humidity.

In one embodiment, the non-aqueous solvent is a water-miscible solvent. For example, liquid water can be about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9% by volume of the solvent system. % by volume, about 10% by volume, about 15% by volume, about 20% by volume, about 25% by volume, about 30% by volume, about 35% by volume, about 40% by volume, about 45% by volume, about 50% by volume, about 55% by volume % by volume, about 60% by volume, about 65% by volume, about 70% by volume, about 75% by volume, about 80% by volume, about 85% by volume, about 90% by volume, about 95% by volume, about 96% by volume, about 97% by volume % by volume, about 98% by volume, about 99% by volume, or about 100% by volume. In one embodiment, the liquid water is present in an amount from about 10% to about 50% by volume of the solvent system.

In one embodiment, the non-anhydrous condition comprises a solvent system comprising water (eg, about 90% v/v) and isopropyl alcohol (eg, about 10% v/v). In one embodiment, the non-anhydrous condition comprises a solvent system comprising water and ethanol. In one embodiment, non-anhydrous conditions include water and a water-miscible solvent such as C₁-C₄ solvent systems including alcohol, acetone, acetonitrile, and the like. In one embodiment, the water-miscible solvent is an alcohol such as methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, t-butanol, ethylene glycol, and the like. In one embodiment, the ratio of water and water-miscible solvent in a solvent system provided herein is about 50:1, about 40:1, about 30:1, about 20:1, about 10:1, about 9: 1, about 8:1, about 7:1, about 6:1, about 5:1, about 4:1, about 3:1, about 2:1, about 1:1, about 1:2, about 1: 3, about 1:4, about 1:5, about 1:6, about 1:7, about 1:8, about 1:9, about 1:10, about 1:20, about 1:30, about 1: 40, or about 1:50 v/v. In one embodiment, the ratio of water and water-miscible solvent in the solvent systems provided herein is from about 50:1 to about 1:1, from about 40:1 to about 1:1, from about 30:1 to about 1: 1, about 20:1 to about 1:1, about 10:1 to about 1:1, about 9:1 to about 1:1, about 8:1 to about 1:1, about 7:1 to about 1; 1, about 6:1 to about 1:1, about 5:1 to about 1:1, about 4:1 to about 1:1, about 3:1 to about 3:1, about 2:1 to about 1: 2, about 1:1 to about 1:4, about 1:1 to about 1:5, about 1:1 to about 1:6, about 1:1 to about 1:7, about 1:1 to about 1: 8, about 1:1 to about 1:9, about 1:1 to about 1:10, about 1:1 to about 1:20, about 1:1 to about 1:30, about 1:1 to about 1: 40, or from about 1:1 to about 1:50 v/v.

In one embodiment, the present invention provides

i) a compound of formula Ia with a protecting group PG²combining with one or more reagents to remove and

ii) recovering polymorph Form A of the compound of formula (I);

There is provided a process for the preparation of polymorph Form A of a compound of formula (I), comprising:

[Formula Ia]

<img file="KR20140020249A_D0044.tif" />

[Formula I]

<img file="KR20140020249A_D0045.tif" />

In the above formula,

PG²is methylsulfonyl, substituted methylsulfonyl, benzenesulfonyl, substituted benzenesulfonyl, benzyloxycarbonyl, substituted benzyloxycarbonyl, 2,2,2-trichloroethoxycarbonyl, 2-trimethyl Silylethoxycarbonyl, t-butoxycarbonyl, 1-adamantyloxycarbonyl, 2-adamantyloxycarbonyl, alkyl, substituted alkyl, t-butyldimethylsilyl, triisopropylsilyl, allyl , benzyl, substituted benzyl, hydroxymethyl, methoxymethyl, diethoxymethyl, (2-chloroethoxy)methyl, t-butoxymethyl, t-butyldimethylsiloxymethyl, pivaloyloxymethyl, a protecting group selected from benzyloxymethyl, dimethylaminomethyl, 2-tetrahydropyranyl, substituted alkoxymethyl and substituted aryloxymethyl;

In this case, the substituent is alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, alkoxy, cycloalkoxy, heterocyclyloxy, aryloxy, heteroaryloxy , amido, amino, acyl, acyloxy, alkoxycarbonyl, ester, ether, thio, sulfinyl, sulfonyl, sulfonamido, halo, cyano, hydroxyl, nitro, phosphate, urea, carbamate and carbonate is selected from

In some embodiments, the protecting group PG²One or more reagents for removal include, but are not limited to, acids such as HCl, HBr and TFA; Carbonate bases such as Na₂CO₃ and K₂CO₃; hydroxyl bases such as NaOH and KOH; lithium bases such as methyl lithium, ethyl lithium, propyl lithium, n-butyl lithium, n-pentyl lithium, and n-hexyl lithium; oxidizing agents such as cerium ammonium nitrate; hydrogenation conditions such as cyclohexadiene/Pd black, and H₂/Pd/C; TBAF, and BF₃Et₂contains O.

In some embodiments, step (ii) will involve recrystallization of a compound of Formula I, or a salt, solvate or hydrate thereof, from a single-solvent system, or a multi-solvent system free of both ethyl acetate and hexane. can In certain embodiments, the method comprises dissolving a compound of formula (I), or a salt, solvate or hydrate thereof, in a single-solvent system or a multi-solvent system, removing residual solid material to obtain a liquid solution, Form A cooling the liquid solution at a rate that affects the crystallization of , and recovering Form A from the liquid solution.

In certain embodiments, the recovered polymorph is Form A, and the recovery step involves recrystallization of the reaction product from a single-solvent system. In certain embodiments, the recovered polymorph is Form A, and the recovery step involves recrystallization of the product from binary, ternary or more solvent systems collectively understood as a multi-solvent system, wherein the multi-solvent system comprises: It does not contain both ethyl acetate and hexane. In certain embodiments, the recovered polymorph is Form A, and the recovery step involves crystallization from a mono- or multi-solvent system, wherein the crystallization involves cooling a solution containing the compound of formula (I). In certain embodiments, the recovered polymorph is Form A, and the recovery step involves crystallization from a mono- or multi-solvent system, wherein the crystallization is of the antisolvent in the presence or absence of a cooling step allowing recovery of Form A. related to addition.

In one embodiment, the present invention provides a polymorph of a compound of formula (I) A process for preparing Form B is provided:

[Formula I]

<img file="KR20140020249A_D0046.tif" />

In certain embodiments, the non-Form B polymorph is a solid form of a compound of Formula I, or a salt, solvate, or hydrate thereof (e.g., a crystalline form, an amorphous form, or a mixture of crystalline and/or amorphous forms), It is not polymorph form B of the compound of formula (I). In one embodiment, the non-Form B polymorph is Form A, Form C, Form D, Form E, Form F, Form G, Form H, Form I, Form J, or an amorphous form of the compound of Formula I, or salts, solvates or hydrates thereof, or mixtures of two or more thereof.

In certain embodiments, the present invention provides a process for preparing a polymorph of a compound of formula (I), or a pharmaceutically acceptable salt, solvate or hydrate thereof, wherein the process comprises a first polymorph or polymorph of a compound of formula (I) converting a mixture of forms, or a pharmaceutically acceptable salt, solvate or hydrate, into a second polymorph, or pharmaceutically acceptable salt, solvate or hydrate of a compound of formula (I). In certain embodiments, the method exposes a composition comprising one or more polymorphs to sufficient conditions such that the total amount of conversion of the original polymorph or the first polymorph to the second polymorph is at least about 50%, and optionally a second polymorph; recovering the polymorph.

In certain embodiments, the native solid form or first solid form of the compound of Formula (I), or a pharmaceutically acceptable salt, solvate or hydrate thereof, comprises more than about 50% of the non-Form A polymorph as the first polymorph. and the second polymorph is Form A.

In certain embodiments, the native solid form or first solid form of the compound of Formula (I), or a pharmaceutically acceptable salt, solvate or hydrate thereof, contains greater than about 50% of the non-Form C polymorph, and The polymorph is Form C. In one embodiment, the conversion to Form C is carried out under non-anhydrous conditions for a sufficient time such that the total amount of conversion from the non-Form C polymorph to Form C of the compound of Formula I is at least about 50%, in any ratio - recovery of Form C from the Form C polymorph. Non-anhydrous conditions may include exposing the original solid form or composition to water vapor or liquid water. For example, non-anhydrous conditions may include exposing the original solid form or composition to a substantial amount of liquid water alone or with additional liquids or other ingredients to form a slurry. In certain embodiments, the native solid form or composition may be exposed to water vapor or moisture conditions for a sufficient time and temperature to effect conversion to Form C. In certain embodiments, the original composition comprises at least one Form A, Form B, Form D, Form E, Form F, Form G, Form H, Form I, Form J, or amorphous form of a compound of Formula I, or a pharmaceutical thereof. commercially acceptable salts, solvates or hydrates or mixtures of two or more thereof. In certain embodiments, the original composition comprises greater than about 50% by weight of polymorph Form A.

In certain embodiments, the present invention provides a composition comprising a polymorph of a compound of formula (I). In some embodiments, the polymorph of the compound of Formula (I) is a pharmaceutically acceptable salt, solvate or hydrate. In certain embodiments, the composition comprises a first polymorph of a compound of formula (I), and one or more additional forms of a compound of formula (I), such as an amorphous form of a compound of formula (I), and/or one or more different polymorphs of a compound of formula (I) mixtures. In such mixtures, the first polymorph, the amorphous form, and the one or more different polymorphs can each independently be in the form of a pharmaceutically acceptable salt, solvate or hydrate disclosed herein, the two salts, solvates or hydrates are not necessarily the same as or different from each other.

In some embodiments, the composition comprises a mixture of the compound forms of Formula (I) disclosed herein, and has an amount of the first polymorph of the compound of Formula (I) as compared to one or more additional forms of the compound of Formula (I) in the mixture. In certain embodiments, the first polymorph of the compound of Formula I is selected from Form A, Form B, Form C, Form D, Form E, Form F, Form G, Form H, Form I, and Form J. In some embodiments, the at least one additional form of the compound of formula (I) is selected from one or more polymorphs of the compound of formula (I), which are non-identical polymorphs as the first polymorph, and an amorphous form of the compound of formula (I). In such mixtures, the first polymorph, the amorphous form, and the one or more different polymorphs may each independently be in the form of a pharmaceutically acceptable salt, solvate or hydrate disclosed herein, the two salts, solvates or hydrates are not necessarily the same as or different from each other.

In some embodiments, the composition comprises a first polymorph (eg, Form A, Form B, Form C, Form D, Form E, Form F, Form G, Form H) compared to one or more additional forms of the compound of Formula (I). , Form I, or Form J) greater than about 1:1, greater than about 2:1, greater than about 3:1, greater than about 4:1, greater than about 5:1, greater than about 6:1, greater than about 7:1 , greater than about 8:1, greater than about 9:1, greater than about 10:1, greater than about 20:1, greater than about 30:1, greater than about 40:1, greater than about 50:1, greater than about 60:1, about weight ratios greater than 70:1, greater than about 80:1, greater than about 90:1, or greater than about 99:1.

For example, in certain embodiments, the composition has a weight ratio of Form C to non-Form C polymorph greater than about 1:1, greater than about 2:1, greater than about 3:1, greater than about 4:1, about 5:1 greater than about 6:1, greater than about 7:1, greater than about 8:1, greater than about 9:1, greater than about 10:1, greater than about 20:1, greater than about 30:1, greater than about 40:1; greater than about 50:1, greater than about 60:1, greater than about 70:1, greater than about 80:1, greater than about 90:1, or greater than about 99:1. In certain embodiments, the composition comprises a first polymorph of the compound of formula (I), such as Form C, and is substantially free of other forms of the compound of formula (I). In certain embodiments, the composition comprises Form C and Form A. In certain embodiments, the composition comprises Form C and Form B. In certain embodiments, the composition comprises Form C and Form D. In certain embodiments, the composition comprises Form C and Form E. In certain embodiments, the composition comprises Form C and Form F. In certain embodiments, the composition comprises Form C and Form G. In certain embodiments, the composition comprises Form C and Form H. In certain embodiments, the composition comprises Form C and Form I. In certain embodiments, the composition comprises Form C and Form J. In certain embodiments, the composition comprises Form C and an amorphous form of a compound of Formula I, or a pharmaceutically acceptable salt, solvate or hydrate thereof.

In certain embodiments, the present invention provides a composition comprising Form A of a compound of Formula I and one or more non-Form A polymorphs, or one or more pharmaceutically acceptable salts, solvates or hydrates thereof. In certain embodiments, the present invention provides a composition comprising Form B of a compound of Formula I and one or more non-Form B polymorphs, or one or more pharmaceutically acceptable salts, solvates or hydrates thereof. In certain embodiments, the present invention provides a composition comprising Form C and one or more non-Form C polymorphs of a compound of Formula I, or one or more pharmaceutically acceptable salts, solvates or hydrates thereof. In certain embodiments, the present invention provides a composition comprising Form D and one or more non-Form D polymorphs of a compound of Formula I, or one or more pharmaceutically acceptable salts, solvates or hydrates thereof. In certain embodiments, the present invention provides a composition comprising Form E and one or more non-Form E polymorphs of a compound of Formula I, or one or more pharmaceutically acceptable salts, solvates or hydrates thereof. In certain embodiments, the present invention provides a composition comprising Form F and one or more non-Form F polymorphs of a compound of Formula I, or one or more pharmaceutically acceptable salts, solvates or hydrates thereof. In certain embodiments, the present invention provides a composition comprising Form G and one or more non-Form G polymorphs of a compound of Formula I, or one or more pharmaceutically acceptable salts, solvates or hydrates thereof. In certain embodiments, the present invention provides a composition comprising Form H and one or more non-Form H polymorphs of a compound of Formula I, or one or more pharmaceutically acceptable salts, solvates or hydrates thereof. In certain embodiments, the present invention provides a composition comprising Form I and one or more non-Form I polymorphs of a compound of Formula I, or one or more pharmaceutically acceptable salts, solvates or hydrates thereof. In certain embodiments, the present invention provides a composition comprising Form J and one or more non-Form J polymorphs of a compound of Formula I, or one or more pharmaceutically acceptable salts, solvates or hydrates thereof. In certain embodiments, the present invention provides a composition comprising an amorphous form of a compound of formula (I), or a pharmaceutically acceptable salt, solvate or hydrate thereof. In certain embodiments, the present invention provides amorphous forms of a compound of formula (I) and one or more polymorphs of a compound of formula (I) selected from Forms A, B, C, D, E, F, G, H, I, and J, or A composition comprising one or more pharmaceutically acceptable salts, solvates or hydrates thereof is provided. In certain embodiments, the invention relates to Forms A, B, C, D, E, F, G, H, I, J, or an amorphous form, or one or more pharmaceutically acceptable salts, solvates or hydrates thereof. A composition comprising one or more is provided.

In some embodiments, a polymorphic form of a compound of Formula I is prepared by dissolving a starting compound of Formula I (e.g., a different polymorphic form, amorphous form, or salt, solvate or hydrate of any of these chemicals) in a solvent. can be obtained. In some embodiments, small amounts of solvent may be required to dissolve the starting compound of formula (I) at room temperature or elevated temperature. Optionally, the solution can be filtered. In some instances, an antisolvent (eg, a solvent in which the starting compound is less soluble than the first solvent) may be added to the solution. In the case of an elevated temperature solution, the solution can be cooled relatively quickly (referred to herein as "rapid cooling"), eg, the solution can be left at about 4° C. overnight. Another method involves cooling the solution to ambient temperature at a rate of about 20° C./hour (referred to herein as "slow cooling"), followed by optionally equilibrating the solution at room temperature overnight (with or without stirring). can do. In some embodiments, the surface of the solution may be scraped with a tool known in the art, such as, but not limited to, a spatula. In other embodiments, the solution is prepared by methods known in the art, such as in vacuum, or with a gas (inert gas such as argon or nitrogen; ambient air, CO2).₂ etc.), and in some instances by evaporation to dryness. The solid obtained by the procedure or variation can be recovered, for example, by filtering or decanting any residual liquid. Identification of the resulting polymorphic form of a compound of Formula (I), or a salt, solvate or hydrate thereof, can be performed using any technique described herein and known in the art (e.g., XRPD, DSC, and TGA, etc.). have.

<b>form A</b>

In one embodiment is Form A of the polymorphic compound of Formula (I) provided herein.

1 depicts a representative X-ray powder diffraction (XRPD) for polymorph Form A.

In one embodiment, polymorph Form A is characterized by any 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more significant peaks of Figure 1 . can do. In one embodiment, polymorph Form A can be characterized as having one or more XRPD peaks selected from 2θ = 9.6° (±0.2°), 12.2° (±0.2°), and 18.3° (±0.2°). In one embodiment, polymorph Form A is 2θ = 9.6° (±0.2°), 12.2° (± 0.2°), and 18.3° (±0.2°). In another embodiment, polymorph Form A has 2θ = 9.1° (±0.2°), 9.4° (±0.2°), 12.4° (±0.2°), 14.8° (±0.2°), 16.3° (±0.2°) ), in combination with one or more XRPD peaks selected from 17.7° (±0.2°), 21.1° (±0.2°), 21.9° (±0.2°), 24.0° (±0.2°), and 26.9° (±0.2°) to obtain one or more XRPD peaks selected from 2θ = 9.6° (±0.2°), 12.2° (±0.2°), 15.6° (±0.2°), 18.3° (±0.2°), and 19.2° (±0.2°). can be characterized as having. In one embodiment, polymorph Form A can be characterized as having substantially all of the peaks in the XRPD pattern shown in FIG. 1 .

12 and 22 show differential scanning calorimetry (DSC) thermograms for polymorph Form A. In some embodiments, polymorph Form A can be characterized as having an endothermic peak at about 238°C or about 239°C. In another embodiment, polymorph Form A can be characterized as having an endothermic peak at about 238°C or about 239°C and an endothermic peak at about 280°C.

22 depicts thermogravimetric analysis (TGA) for polymorph Form A. The absence of features in the TGA trace indicates that no significant weight loss is observed upon heating.

In certain embodiments, Form A can be obtained by rapid and slow crystallization from a single solvent system produced by dissolving Form C in a solvent (including, but not limited to, including but not limited to acetonitrile and n-butanol). In certain embodiments, Form A can be obtained by crystallization from a binary solvent system comprising ethyl acetate and hexanes. In another embodiment, a binary solvent formed by dissolving Form C in a solvent (including, but not limited to, acetone, methylethyl ketone, DMF and dioxane) followed by addition of an anti-solvent (such as but not limited to dichloromethane). Form A can be obtained from the system by fast and slow cooling. In one embodiment, Form A can also be obtained from a slurry in dichloromethane, acetonitrile, ethanol, and/or isopropyl alcohol. In one embodiment, Form A can be obtained from a slurry of Form C, Form D, and/or Form E in acetonitrile.

In one embodiment, Form A is obtained by reslurrying into one or more non-Form A polymorphs in anhydrous solvent. In one embodiment, the non-Form A polymorph includes, but is not limited to, Form B, Form C, Form D, Form E, Form F, Form G, Form H, Form I, Form J, an amorphous form, and their mixtures. For example, in one embodiment, Form A is combined with one or more non-Form A polymorphs (such as, but not limited to, Form C or an amorphous form), such as chloroform, dichloromethane, isopropyl alcohol, ethanol, or mixtures thereof. It can be obtained by reslurrying with In another embodiment, Form A can be obtained by reslurrying a mixture of Form A, Form B, and Form C in acetonitrile. In one embodiment, Form A can be obtained by reslurrying a mixture of Form A, Form C, Form D, and Form E in isopropanol. In one embodiment, Form A can be obtained by crystallization from a multi-solvent system. In one embodiment, Form A may be anhydride.

<b>form B</b>

In one embodiment, the polymorph provided herein is Form B of a compound of Formula (I).

2 depicts a representative XRPD for polymorph Form B.

In one embodiment, polymorph Form B is characterized by any 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more significant peaks of Figure 2 can do. In one embodiment, polymorph Form B can be characterized as having one or more XRPD peaks selected from 2θ = 7.9° (±0.2°), 13.4° (±0.2°), and 23.4° (±0.2°). . In one embodiment, polymorph Form B is 2θ = 7.9° (±0.2°), 13.4° (± 0.2°), and 23.4° (±0.2°). In another embodiment, polymorph Form B has 2θ = 9.5° (±0.2°), 12.7° (±0.2°), 13.6° (±0.2°), 14.2° (±0.2°), 15.7° (±0.2°) ), in combination with one or more XRPD peaks selected from 19.0° (±0.2°), 22.3° (±0.2°), 24.2° (±0.2°), 24.8° (±0.2°), and 26.9° (±0.2°) to obtain one or more XRPD peaks selected from 2θ = 7.9° (±0.2°), 13.4° (±0.2°), 14.0° (±0.2°), 15.0° (±0.2°), and 23.4° (±0.2°). It can be characterized as having. In one embodiment, polymorph Form B can be characterized as having substantially all of the peaks in the XRPD pattern shown in FIG. 2 .

13 depicts a differential scanning calorimetry (DSC) thermogram for polymorph Form B. In some embodiments, polymorph Form B can be characterized as having an endothermic peak at about 280 to about 283 °C. In one embodiment, the DSC endothermic peak is about 281 °C. In one embodiment, the DSC endothermic peak is about 282°C. In one embodiment, the DSC endothermic peak is about 283°C.

In certain embodiments, Form B can be produced from Form A by holding isothermal at about 250° C. and then cooling to room temperature. In one embodiment, Form B can be generated from Form C following a similar thermal conversion procedure. In certain embodiments, Form B is combined with a non-Form B polymorph, such as, but not limited to,<i></i>produced by thermal conversion from Form A, Form C, Form D, Form E, Form F, Form G, Form H, Form I, Form J, amorphous forms, and mixtures thereof. In one embodiment, Form B may be anhydride.

<b>form C </b>

In one embodiment, the polymorph provided herein is Form C of the compound of Formula (I).

3 depicts a representative XRPD for polymorph Form C.

In one embodiment, polymorph Form C is characterized by any 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more significant peaks of Figure 3 can do. In one embodiment, Form C can be characterized as having one or more XRPD peaks selected from 2θ = 10.5° (±0.2°), 13.7° (±0.2°), and 24.5° (±0.2°). In another embodiment, Form C can be characterized as having one or more XRPD peaks from 2θ = 10.4° (±0.2°), 13.3° (±0.2°), and 24.3° (±0.2°).<b></b>In one embodiment, polymorph Form C is selected from 2θ = 10.4° (±0.2°), 13.3° (± 0.2°), and 24.3° (± 0.2°). In another embodiment, polymorph Form C has 2θ = 8.8° (±0.2°), 9.9° (±0.2°), 13.4° (±0.2°), 15.5° (±0.2°), 16.9° (±0.2°) ), 19.8° (±0.2°), 21.3° (±0.2°), 23.6° (±0.2°), 25.3° (±0.2°), and 27.9° (±0.2°) in combination with one or more XRPD peaks to obtain one or more XRPD peaks selected from 2θ = 6.6° (±0.2°), 10.4° (±0.2°), 12.5° (±0.2°), 13.3° (±0.2°), and 24.3° (±0.2°). It can be characterized as having. In one embodiment, polymorph Form C can be characterized as having substantially all of the peaks in the XRPD pattern shown in FIG. 3 .

14 and 23 show exemplary differential scanning calorimetry (DSC) thermograms for polymorph Form C. In some embodiments, polymorph Form C can be characterized as having an endothermic peak at about 203°C. In some embodiments, polymorph Form C can be characterized as having an endothermic peak at about 206°C or about 208°C. In another embodiment, polymorph Form C has one or more peaks selected from an endothermic peak ranging from about 203°C to about 208°C, an exothermic peak ranging from about 251°C to about 254°C, and an endothermic peak ranging from about 281°C to about 283°C. can be characterized . In one embodiment, polymorph Form C can be characterized as having an endothermic peak at about 208 °C, an exothermic peak at about 254 °C, and an endothermic peak at about 283 °C. The peak position variability is within the predicted rules using the thermographic analysis described below in the Examples section. For example, the peak position can be influenced by sample preparation, rate of temperature rise, and the instrument used, other factors known in the art.

In some embodiments, polymorph Form C can be characterized by thermogravimetric analysis (TGA). In one embodiment, a weight loss of about 1.7% by weight can be observed at about 80°C and a weight loss of about 0.2% by weight can be observed at about 190°C.

In certain embodiments, Form C is a non-Form C polymorph, such as, but not limited to, Form A, Form B, Form D, Form E, Form F, Form G, Form H, Form I, Form J, an amorphous form, and mixtures thereof. For example, in certain embodiments, Form C is present as a composition further comprising one or more non-Form C polymorphs. The amount of the non-Form C polymorph in the composition may vary. For example, in certain embodiments, the weight ratio of polymorph Form C to the total amount of one or more non-Form C polymorphs is greater than about 7:1, greater than about 8:1, greater than about 9:1, greater than about 9.5:1, or greater than about 99:1. Similarly, when a pharmaceutical composition is prepared, various amounts of the non-C polymorphic form may be present. In certain embodiments, the weight ratio of polymorph Form C to the total amount of one or more non-C polymorphs in the pharmaceutical composition is greater than about 7:1, greater than about 8:1, greater than about 9:1, greater than about 9.5:1, or greater than about 99:1.

In certain embodiments, Form C is obtained from direct work-up of a synthetic step that yields the compound of Formula I, and the non-C form is not obtained or is obtained as a minor component. In certain embodiments, the final work-up of the reaction mixture comprises water to remove any water-soluble salts formed during the reaction. In certain embodiments, seed crystals may be added to eliminate or reduce the compound of formula (I). Any type of seed crystal may be used. In one embodiment, seed crystals of polymorph Form C are present. In certain embodiments, one or more non-C forms are obtained in the presence or absence of recovery and/or purification, followed by subsequent conversion of one or more non-C forms to Form C.

In certain embodiments, Form C is produced by placing Form A in water to form a slurry for about 18 to 24 hours or until a certain amount of conversion of Form A to Form C occurs. In certain embodiments, Form C is replaced with Form A in water or a water-containing solvent system, resulting in Form C. Upon exposure to water or a water-containing solvent system, the combination can form a slurry. The combination of Form A and water or water-containing solvent system can be stirred and optionally heated until conversion of Form C occurs. In certain embodiments, Form A was exposed to water and other solvents excluded. In some embodiments, Form C can be obtained by slurrying Form D and/or Form E in water. In some embodiments, Form C can be obtained by slurrying a mixture of Form A, Form C, Form D, and Form E in water. In one embodiment, Form C can be obtained by slurrying a mixture of Form B and Form C in water.

In certain embodiments, the solvent system comprises C₁-C₆ It is alcohol. In certain embodiments, the solvent system is a water-miscible alcohol comprising water. In certain embodiments, the solvent system is a non-alcoholic water-miscible solvent comprising water. In certain embodiments, binary solvent systems (including, but not limited to, ethanol, isopropyl alcohol, tetrahydrofuran, acetone, dioxane, NMP, DME, and DMF as the primary solvent, and anti-solvents such as, but not limited to, water) Form C is produced by rapid or slow cooling by In certain embodiments, the solvent system is ethanol comprising water or 2-propanol. In some embodiments, Form C can be obtained by slurrying a mixture of Form A, Form B, and Form C with ethanol and water.

When a solvent other than water is used, the ratio of solvent to water can be varied from about 100/1 to about 1/100. For example, the ratio of solvent to water is about 100/1, about 90/1, about 80/1, about 70/1, about 60/1, about 50/1, about 40/1, about 30/1, about 20/1, about 10/1, about 9/1, about 8/1, about 7/1, about 6/1, about 5/1, about 4/1, about 3/1, about 2/1, about 1.5/1, about 1/1, about 1/1.5, about 1/2, about 1/3, about 1/4, about 1/5, about 1/6, about 1/7, about 1/8, about 1/9, about 1/10, about 1/20, about 1/30, about 1/40, about 1/50, about 1/60, about 1/70, about 1/80, about 1/90, and from about 1/100. In certain embodiments, the ratio of ethanol or isopropyl alcohol to water may be about 7/4, about 9/7, about 7/10, etc. The total amount of solvent or solvent system is about 0.1 volume (eg, L/kg), about 0.5 volume, about 1 volume, about 2 volume, about 3 volume, about 4 volume, about 5 volume, about 6 volume, about 7 volume, about 8 volumes, about 9 volumes, about 10 volumes, about 11 volumes, about 12 volumes, about 13 volumes, about 14 volumes, about 15 volumes, about 16 volumes, about 17 volumes, about 18 volumes, about 19 volumes, about 20 volumes volume, about 30 volumes, about 40 volumes, about 50 volumes or more. In certain embodiments, the solvent system is ethanol/water. In certain embodiments, the solvent system is isopropyl alcohol/water.

In some embodiments, a method for preparing Form C comprises preparing a slurry of Form C in dichloromethane to effect a polymorphic change on Form A. After filtration to recover the solid, polymorph Form A can be added to water to form a slurry. After stirring for some time (eg, about 3 to 12 hours), the slurry can be filtered and polymorph Form C can be recovered.

In certain embodiments, the non-C form (including the complete dissolution of the non-C form) is recrystallized, followed by filtration to remove any insoluble particles and subsequent crystallization to afford Form C. In certain embodiments, when a slurry is formed and converted to Form C without complete dissolution of one or more non-C forms, complete dissolution and filtration are not performed. In one embodiment, Form C can be obtained by crystallization in a multi-solvent system. In some embodiments, Form C exhibits better flow properties than Form A. In certain embodiments, Form C is a channel hydrate.

<b>form D</b>

In one embodiment, the polymorph provided herein is Form D of a compound of Formula (I).

4 depicts a representative XRPD for polymorph Form D.

In one embodiment, polymorph Form D is characterized by any 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more significant peaks of Figure 4 can do. In one embodiment, polymorph Form D can be characterized as having one or more XRPD peaks selected from 2θ = 11.4° (±0.2°), 17.4° (±0.2°), and 22.9° (±0.2°). . In one embodiment, polymorph Form D is 2θ = 11.4° (±0.2°), 17.4° (± 0.2°), and 22.9° (±0.2°). In another embodiment, polymorph Form D has 2θ = 9.8° (±0.2°), 12.2° (±0.2°), 15.8° (±0.2°), 16.2° (±0.2°), 16.8° (±0.2°) ), 18.9° (±0.2°), 19.9° (±0.2°), 20.0° (±0.2°), 24.9° (±0.2°), and 29.3° (±0.2°) in combination with one or more XRPD peaks to obtain one or more XRPD peaks selected from 2θ = 9.2° (±0.2°), 11.4° (±0.2°), 17.4° (±0.2°), 18.3° (±0.2°), and 22.9° (±0.2°). It can be characterized as having. In one embodiment, polymorph Form D can be characterized as having substantially all of the peaks in the XRPD pattern shown in FIG. 4 .

15 depicts a differential scanning calorimetry (DSC) thermogram for polymorph Form D. In some embodiments, polymorph Form D can be characterized as having an endothermic peak at about 260°C. In another embodiment, polymorph Form D can be characterized as having an endothermic peak at about 260 °C and an endothermic peak at about 283 °C.

In some embodiments, polymorph Form D can be characterized by thermogravimetric analysis (TGA). In one embodiment, a weight loss of about 0.2% by weight can be observed at about 150°C.

In certain embodiments, Form D can be obtained by rapid cooling crystallization from a single solvent system (including but not limited to, tetrahydrofuran, methyl ethyl ketone, dioxane, or dimethylformamide). In certain embodiments, Form D can be obtained from a single solvent system (including but not limited to, tetrahydrofuran, methyl ethyl ketone, or dioxane) by slow cooling crystallization. In one embodiment, Form D can be obtained by slurrying Form C and/or Form E in methyl ethyl ketone. In one embodiment, Form D can be obtained by slurrying a mixture of Form A, Form B and Form C in methyl ethyl ketone. In another embodiment, Form D can be obtained by slurrying a mixture of Form B and Form D in methyl ethyl ketone.

In certain embodiments, Form D can be obtained by rapid cooling crystallization from a binary solvent system, such as tetrahydrofuran, dioxane, or a binary solvent system comprising DMF as the primary solvent and an antisolvent such as but not limited to MTBE. have. In certain embodiments, Form D can be obtained by rapid cooling crystallization from a binary solvent system, such as tetrahydrofuran, isopropanol, or a binary solvent system comprising DMF as the primary solvent and an antisolvent such as but not limited to toluene. have. In one embodiment, Form D can be obtained by rapid cooling crystallization from a binary solvent system, such as a binary solvent system comprising tetrahydrofuran as the primary solvent and dichloromethane as the antisolvent. In certain embodiments, Form D can be obtained by slow cooling crystallization from a binary solvent system, such as methyl ethyl ketone or a binary solvent system comprising DMF as the primary solvent and MTBE as the antisolvent. In certain embodiments, Form D can be obtained by slow cooling crystallization from a binary solvent system such as tetrahydrofuran or a binary solvent system comprising DME as the primary solvent and dichloromethane as the antisolvent. In certain embodiments, Form D can be obtained by slow cooling crystallization from a binary solvent system, such as isopropanol, NNP, or a binary solvent system comprising DME as the primary solvent and toluene as the antisolvent.

In one embodiment, Form D can be obtained by crystallization from a multi-solvent system. In certain embodiments, Form D can be formed by slurrying a non-Form D polymorph, such as, but not limited to, Form A, B, C, or E with methyl ethyl ketone. In one embodiment, Form D may be anhydride.

<b>form E</b>

In one embodiment, the polymorph provided herein is Form E of the compound of Formula I.

5 depicts a representative XRPD for polymorph Form E.

In one embodiment, polymorph Form E is characterized by any 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more significant peaks of Figure 5. can do. In one embodiment, polymorph Form E can be characterized as having one or more XRPD peaks selected from 2θ = 6.7° (±0.2°), 9.3° (±0.2°), and 24.4° (±0.2°). . In one embodiment, polymorph Form E is 2θ = 6.7° (±0.2°), 9.3° (± 0.2°), and 24.4° (±0.2°). In another embodiment, polymorph Form E has 2θ = 12.4° (±0.2°), 13.3° (±0.2°), 14.3° (±0.2°), 15.5° (±0.2°), 17.4° (±0.2°) ), in combination with one or more XRPD peaks selected from 18.5° (±0.2°), 22.0° (±0.2°), 23.9° (±0.2°), 24.1° (±0.2°), and 26.4° (±0.2°) to obtain one or more XRPD peaks selected from 2θ = 6.7° (±0.2°), 9.3° (±0.2°), 12.7° (±0.2°), 13.9° (±0.2°), and 24.4° (±0.2°). It can be characterized as having. In one embodiment, polymorph Form E can be characterized as having substantially all of the peaks in the XRPD pattern shown in FIG. 5 .

16 depicts a differential scanning calorimetry (DSC) thermogram for polymorph Form E. In some embodiments, polymorph Form E can be characterized as having an endothermic peak at about 131 °C, an endothermic peak at about 263 °C, an exothermic peak at about 267 °C, and an endothermic peak at about 282 °C.

In some embodiments, polymorph Form E can be characterized by thermogravimetric analysis (TGA). In one embodiment, a weight loss of about 0.7% by weight can be observed at about 80°C and a weight loss of about 1.3% by weight can be observed at about 130°C.

In certain embodiments, Form E can be obtained by slow cooling crystallization from a single solvent system, such as a single solvent system comprising methanol. In certain embodiments, Form E can be obtained by rapid or slow cooling crystallization from a binary solvent system, such as a binary solvent system comprising methanol as the primary solvent and water as the antisolvent. In one embodiment, Form E can be obtained by crystallization from a multi-solvent system. In one embodiment, Form E may be anhydride.

<b>form F</b>

In one embodiment, the polymorph provided herein is Form F of a compound of Formula (I).

6 depicts a representative XRPD for polymorph Form F.

In one embodiment, polymorph Form F is characterized by any 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more significant peaks of Figure 6 can do. In one embodiment, polymorph Form F can be characterized as having one or more XRPD peaks selected from 2θ = 9.6° (±0.2°), 17.3° (±0.2°), and 24.6° (±0.2°). . In one embodiment, polymorph Form F is 2θ = 9.6° (±0.2°), 17.3° (± 0.2°), and 24.6° (± 0.2°). In another embodiment, polymorph Form F has 2θ = 12.4° (±0.2°), 16.1° (±0.2°), 16.6° (±0.2°), 17.1° (±0.2°), 20.8° (±0.2°) ), 21.5° (±0.2°), 22.0° (±0.2°), 24.3° (±0.2°), 25.2° (±0.2°), and 25.4° (±0.2°) in combination with one or more XRPD peaks to obtain one or more XRPD peaks selected from 2θ = 9.6° (±0.2°), 14.0° (±0.2°), 17.3° (±0.2°), 19.2° (±0.2°), and 24.6° (±0.2°). It can be characterized as having. In one embodiment, polymorph Form F can be characterized as having substantially all of the peaks in the XRPD pattern shown in FIG. 6 .

17 and 24 depict exemplary differential scanning calorimetry (DSC) endotherm analysis for Form F. In some embodiments, polymorph Form F can be characterized as having an endothermic peak at about 181 °C, an endothermic peak at about 160 °C, an exothermic peak at about 266 °C, and an endothermic peak at about 282 °C.

24 depicts thermogravimetric analysis (TGA) for polymorph Form F. In some embodiments, polymorph Form F may be characterized by TGA. In one embodiment, a weight loss of about 15.8% by weight can be observed at about 150°C and a weight loss of about 2.8% by weight can be observed at about 180°C.

In certain embodiments, Form F can be obtained by rapid cooling crystallization from a binary solvent system, such as a binary solvent system comprising NMP as the primary solvent and MBTE as the antisolvent. In certain embodiments, Form F can be obtained by slow cooling crystallization from a binary solvent system, such as a binary solvent system comprising NMP as the primary solvent and MBTE as the antisolvent. In some embodiments, Form F is an NMP solvate. In certain embodiments, MTBE may be present as an antisolvent. In one embodiment, Form F can be obtained by crystallization from a multi-solvent system.

<b>form G</b>

In one embodiment, the polymorph provided herein is Form G of a compound of Formula (I).

7 depicts a representative XRPD for polymorph Form G.

In one embodiment, polymorph Form G is characterized by any 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more significant peaks of Figure 7 can do. In one embodiment, polymorph Form G can be characterized as having one or more XRPD peaks selected from 2θ = 6.7° (±0.2°), 9.5° (±0.2°), and 19.0° (±0.2°). . In one embodiment, polymorph Form G is 2θ = 6.7° (±0.2°), 9.5° (± 0.2°), and 19.0° (±0.2°). In another embodiment, polymorph Form G is 2θ = 13.4° (±0.2°), 15.0° (±0.2°), 15.8° (±0.2°), 17.8° (±0.2°), 20.7° (±0.2°) ), 21.2° (±0.2°), 22.8° (±0.2°), 23.8° (±0.2°), 24.3° (±0.2°), and 25.6° (±0.2°) in combination with one or more XRPD peaks to obtain one or more XRPD peaks selected from 2θ = 6.7° (±0.2°), 9.5° (±0.2°), 10.6° (±0.2°), 19.0° (±0.2°), and 19.6° (±0.2°). It can be characterized as having. In one embodiment, polymorph Form G can be characterized as having substantially all of the peaks in the XRPD pattern shown in FIG. 7 .

18 depicts a differential scanning calorimetry (DSC) thermogram for polymorph Form G. In some embodiments, polymorph Form G can be characterized as having an endothermic peak at about 162°C. In another embodiment, polymorph Form G can be characterized as having an endothermic peak at about 162 °C, an exothermic peak at about 241 °C, and an endothermic peak at about 281 °C.

In some embodiments, polymorph Form G can be characterized by thermogravimetric analysis (TGA). In one embodiment, a weight loss of about 18.5% by weight can be observed at about 160°C.

In certain embodiments, Form G can be obtained by rapid cooling crystallization from a binary solvent system, such as ethanol, isopropyl alcohol, or methanol as the primary solvent. In certain embodiments, MTBE may be present as an antisolvent. In one embodiment, Form G is MTBE solvate. In one embodiment, Form G can be obtained by crystallization from a multi-solvent system.

<b>form H</b>

In one embodiment, the polymorph provided herein is Form H of a compound of Formula (I).

8 depicts a representative XRPD for polymorph Form H.

In one embodiment, polymorph Form H is characterized by any 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more significant peaks of Figure 8. can do. In one embodiment, polymorph Form H can be characterized as having one or more XRPD peaks selected from 2θ = 8.9° (±0.2°), 9.2° (±0.2°), and 14.1° (±0.2°). . In one embodiment, polymorph Form H is selected from 2θ = 8.9° (±0.2°), 9.2° (± 0.2°), and 14.1° (± 0.2°). In another embodiment, polymorph Form H has 2θ = 7.1° (±0.2°), 10.6° (±0.2°), 11.3° (±0.2°), 11.6° (±0.2°), 16.2° (±0.2°) ), 18.3° (±0.2°), 18.8° (±0.2°), 20.3° (±0.2°), 21.7° (±0.2°), and 24.7° (±0.2°) in combination with one or more XRPD peaks to obtain one or more XRPD peaks selected from 2θ = 8.9° (±0.2°), 9.2° (±0.2°), 14.1° (±0.2°), 17.3° (±0.2°), and 18.5° (±0.2°). It can be characterized as having. In one embodiment, polymorph Form H can be characterized as having substantially all of the peaks in the XRPD pattern shown in FIG. 8 .

19 depicts a differential scanning calorimetry (DSC) thermogram for polymorph Form H. In some embodiments, polymorph Form H can be characterized as having an endothermic peak at about 128 °C and an endothermic peak at about 258 °C. In another embodiment, polymorph Form H can be characterized as having an endothermic peak at about 128 °C, an endothermic peak at about 258 °C, and an endothermic peak at about 282 °C.

In some embodiments, polymorph Form H can be characterized by thermogravimetric analysis (TGA). In one embodiment, a weight loss of about 7.5% by weight can be observed at about 130°C.

In certain embodiments, Form H can be obtained by slow cooling crystallization from a binary solvent system, such as dioxane as the primary solvent, and an antisolvent such as, but not limited to, MTBE. In one embodiment, Form H is MTBE solvate. In one embodiment, Form H can be obtained by crystallization from a multi-solvent system.

<b>Form I</b>

In one embodiment, the polymorph provided herein is Form I of a compound of Formula (I).

9 depicts a representative XRPD for polymorph Form I.

In one embodiment, polymorph Form I is characterized by any 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more significant peaks of Figure 9 can do. In one embodiment, polymorph Form I can be characterized as having one or more XRPD peaks selected from 2θ = 9.7° (±0.2°), 19.3° (±0.2°), and 24.5° (±0.2°). . In one embodiment, polymorph Form I is 2θ = 9.7° (±0.2°), 19.3° (± 0.2°), and 24.5° (±0.2°). In another embodiment, polymorph Form I has 2θ = 9.2° (±0.2°), 14.7° (±0.2°), 15.5° (±0.2°), 16.7° (±0.2°), 17.3° (±0.2°) ), 18.4° (±0.2°), 21.4° (±0.2°), 22.9° (±0.2°), 29.1° (±0.2°), and 34.1° (±0.2°) in combination with one or more XRPD peaks to obtain one or more XRPD peaks selected from 2θ = 9.7° (±0.2°), 11.4° (±0.2°), 14.2° (±0.2°), 19.3° (±0.2°), and 24.5° (±0.2°). It can be characterized as having. In one embodiment, polymorph Form I can be characterized as having substantially all of the peaks in the XRPD pattern shown in FIG. 9 .

20 depicts a differential scanning calorimetry (DSC) thermogram for polymorph Form I. In some embodiments, polymorph Form I can be characterized as having an endothermic peak at about 208°C and an endothermic peak at about 263°C.

In some embodiments, polymorph Form I may be characterized by thermogravimetric analysis (TGA). In one embodiment, a weight loss of about 10.5% by weight can be observed at about 130°C and a weight loss of about 0.8% by weight can be observed at about 200°C.

In certain embodiments, Form I can be obtained by slow cooling crystallization from a binary solvent system comprising, but not limited to, acetone, MEK, or dioxane as the primary solvent, and an antisolvent such as, but not limited to, toluene. In one embodiment, Form I is hemi-toluene solvate. In one embodiment, Form I can be obtained by crystallization from a multi-solvent system.

<b>form J</b>

In one embodiment, the polymorph provided herein is Form J of the compound of Formula I.

10 depicts a representative XRPD for polymorph Form J.

In one embodiment, polymorph Form J is characterized by any 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more significant peaks of Figure 10 can do. In one embodiment, polymorph Form J is characterized as having one or more XRPD peaks selected from 2θ = 9.1° (±0.2°), 17.3° (±0.2°), and 18.3° (±0.2°). In one embodiment, polymorph Form J is 2θ = 9.1° (±0.2°), 17.3° (± 0.2°), and 18.3° (±0.2°). In another embodiment, polymorph Form J has 2θ = 9.4° (±0.2°), 10.1° (±0.2°), 10.7° (±0.2°), 14.0° (±0.2°), 14.3° (±0.2°) ), 15.5° (±0.2°), 16.9° (±0.2°), 19.9° (±0.2°), 24.0° (±0.2°), and 24.7° (±0.2°) in combination with one or more XRPD peaks to obtain one or more XRPD peaks selected from 2θ = 9.1° (±0.2°), 16.4° (±0.2°), 17.3° (±0.2°), 17.9° (±0.2°), and 18.3° (±0.2°). It can be characterized as having. In one embodiment, polymorph Form J can be characterized as having substantially all of the peaks in the XRPD pattern shown in FIG. 10 .

21 depicts a differential scanning calorimetry (DSC) thermogram for polymorph Form J. In some embodiments, polymorph Form J can be characterized as having an endothermic peak at about 259°C. In another embodiment, polymorph Form J is characterized as having an endothermic peak at about 121 °C, an endothermic peak at about 185 °C, an endothermic peak at about 259 °C, and an endothermic peak at about 282 °C.

In some embodiments, polymorph Form J is characterized by thermogravimetric analysis (TGA). In one embodiment, a weight loss of about 10.8% by weight can be observed at about 100°C.

In certain embodiments, Form J can be obtained by slow cooling crystallization from a binary solvent system comprising, but not limited to, DMF as the primary solvent, and an antisolvent such as, but not limited to, toluene. In one embodiment, Form J is hemi-toluene solvate. In one embodiment, Form J is obtainable by crystallization from a multi-solvent system.

<b>amorphous</b><b> form</b>

In one embodiment, provided herein is an amorphous form of a compound of Formula (I).

11 shows a representative XRPD for an amorphous form. The lack of diffraction peaks indicates a lack of crystallinity in the amorphous form.

In one embodiment, the amorphous form of a compound of formula (I), or a pharmaceutically acceptable salt, solvate or hydrate thereof, can be prepared by dissolving the crystalline form and then removing the solvent under conditions in which stable crystals are not formed. have. For example, solidification may occur by rapid removal of the solvent, rapid addition of an antisolvent (which causes precipitation of the solution in amorphous form), or physical cessation of the crystallization process. It is also possible to use a grinding process. In another embodiment, an amorphous form of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate or hydrate thereof, can be obtained using the processes or procedures described herein.

In certain embodiments, the amorphous form can be obtained by rapid cooling from a single solvent system such as ethanol, isopropyl alcohol, t-amyl alcohol, n-butanol, methanol, acetone, ethyl acetate, or acetic acid. In certain embodiments, the amorphous form can be obtained by slow cooling from a single solvent system such as ethanol, isopropyl alcohol, t-amyl alcohol, or ethyl acetate.

In certain embodiments, the amorphous form can be obtained by rapid cooling from a binary solvent system, such as acetone or DME as the primary solvent. In certain embodiments, the amorphous form can be obtained by slow cooling from a binary solvent system, such as ethanol, isopropyl alcohol, THF, acetone, or methanol as the primary solvent. In some embodiments, the amorphous form can be obtained by dissolving the compound of formula (I) in t-butanol and water at an elevated temperature, followed by cooling to obtain the amorphous solid form.

In some embodiments, the amorphous compound of Formula (I) is a salt, solvate, or hydrate thereof. In some embodiments, the amorphous compound of Formula I is a pharmaceutically acceptable salt, solvate or hydrate thereof. In one embodiment, the amorphous compound of formula (I) may contain an amount of one or more partially crystalline or crystalline compounds of formula (I). Non-limiting examples include less than about 10% of one or more partially crystalline or crystalline compounds of formula (I), less than about 9% of one or more partially crystalline or crystalline compounds of formula (I), less than about 8% of one or more partially crystalline or crystalline compounds of formula (I) compound, less than about 7% of one or more partially crystalline or crystalline compounds of formula (I), less than about 6% of one or more partially crystalline or crystalline compounds of formula (I), less than about 5% of one or more partially crystalline or crystalline compounds of formula (I), less than about 4% of one or more partially crystalline or crystalline compounds of formula (I), less than about 3% of one or more partially crystalline or crystalline compounds of formula (I), less than about 2% of one or more partially crystalline or crystalline compounds of formula (I), about 1 less than % of one or more partially crystalline or crystalline compounds of formula (I), less than about 0.5% of one or more partially crystalline or crystalline compounds of formula (I), amorphous compounds of formula (I) containing less than about 0.1% of one or more partially crystalline or crystalline compounds of formula (I), and less than about 0.01% of one or more partially crystalline or crystalline compounds of formula (I). In some embodiments, the amorphous compound of Formula (I), or salt, solvate or hydrate thereof, contains at least one partially crystalline compound, or salt, solvate or hydrate thereof. In some embodiments, the amorphous compound of Formula (I), or a salt, solvate, or hydrate thereof, contains one or more crystalline compounds of Formula (I), or a salt, solvate, or hydrate thereof.

<b>salt form</b>

In certain embodiments, a compound of Formula (I) provided herein is a pharmaceutically acceptable salt, or solvate or hydrate thereof. In one embodiment, a pharmaceutically acceptable acid addition salt of a compound provided herein can be formed with an inorganic acid and an organic acid. Inorganic acids that can be derived from salts include, but are not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like. Organic acids that can be derived from salts include, but are not limited to, acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethane. sulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like. In other embodiments, where applicable, pharmaceutically acceptable base addition salts of compounds provided herein can be formed with inorganic and organic bases. Inorganic bases that can be derived from salts include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, and the like. Organic bases that can be derived from salts include, but are not limited to, primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, basic ion exchange resins, and the like. Exemplary bases include, but are not limited to, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, and ethanolamine. In some embodiments, the pharmaceutically acceptable base addition salt is an ammonium, potassium, sodium, calcium, or magnesium salt. In one embodiment, bis salts (ie, two counter ions) and high salts (eg, three or more counter ions) are also encompassed within the meaning of pharmaceutically acceptable salts.

In certain embodiments, salts of compounds of formula (I) are, for example, L-tartaric acid, p-toluenesulfonic acid, D-glucaronic acid, ethane-1,2-disulfonic acid (EDSA), 2-naphthalenesulfonic acid (NSA) ), hydrochloric acid (HCl) (mono and bis), hydrobromic acid (HBr), citric acid, naphthalene-1,5-disulfonic acid (NDSA), DL-mandelic acid, fumaric acid, sulfuric acid, maleic acid, methanesulfonic acid (MSA) ), benzenesulfonic acid (BSA), ethanesulfonic acid (ESA), L-malic acid, phosphoric acid and aminoethanesulfonic acid (taurine).

<b>III</b><b>. composition</b>

The present invention relates to one or more polymorphic or amorphous forms of a compound of formula (I), or a pharmaceutically acceptable form thereof (e.g., a pharmaceutically acceptable salt, hydrate, solvate, chelate, non-covalent complex, isomer, prodrug, and an isotopically labeled derivative). In some embodiments, the present invention provides a pharmaceutical composition comprising Polymorph Form C, or a pharmaceutically acceptable salt, solvate, and hydrate thereof, and one or more pharmaceutically acceptable excipients. In some embodiments, the present invention provides a pharmaceutical composition comprising Polymorph Form C and Polymorph Form A, or pharmaceutically acceptable salts, solvates and hydrates thereof, and one or more pharmaceutically acceptable excipients, wherein The ratio of polymorph Form C to polymorph Form A is greater than about 9:1. In some embodiments, the present invention provides one or more polymorphs A, B, C, D, E, F, G, H, I, and J of Formula I, or an amorphous compound, or a pharmaceutically acceptable salt thereof, Provided are pharmaceutical compositions comprising solvates and hydrates, or mixtures thereof, and one or more pharmaceutically acceptable excipients. In another embodiment, the present invention provides polymorphic Form C selected from Form A, Form B, Form D, Form E, Form F, Form G, Form H, Form I, Form J and one or more non-forms of a compound of Formula I Provided is a pharmaceutical composition comprising polymorph C, or an amorphous form, or a salt, solvate or hydrate thereof, and one or more pharmaceutically acceptable excipients.

In certain embodiments, the ratio of a polymorph, such as Form C, to all other polymorphs in the compositions provided herein is greater than about 5:1, about 6:1, about 7:1, about 8:1, about 9:1 can be

In certain embodiments, the pharmaceutical compositions provided herein typically comprise a compound provided herein as an active ingredient (eg, a specific polymorph provided herein), or a pharmaceutically acceptable salt, hydrate, solvate, chelate, ester, non-covalent thereof. Complexes, isomers, prodrugs, and isotopically labeled derivatives are formulated to provide therapeutically effective amounts. In some embodiments, the pharmaceutical composition comprises one or more pharmaceutically acceptable salts, solvates, hydrates, and/or coordination complexes, and one or more pharmaceutically acceptable excipients such as carriers (including inert solid diluents and fillers), diluents. (including sterile aqueous solutions and various organic solvents), penetration enhancers, solubilizers, and/or adjuvants.

In certain embodiments, a pharmaceutical composition provided herein may be administered alone or in combination with one or more other agents, and is also administered in the form of a pharmaceutical composition. In some embodiments, the polymorphs and other agents provided herein can be mixed in a formulation, or both components can be combined individually or used simultaneously to compound into separate formulations.

In one embodiment, administration of a polymorph or pharmaceutical composition provided herein may be effected by any method capable of delivering the polymorph or pharmaceutical composition to the site of action. Such methods include, for example, oral routes, intraduodenal routes, parenteral infusions (including intravenous, intraarterial, subcutaneous, intramuscular, intravascular, intraperitoneal or infusion), topical routes (such as transdermal applications), rectal administration, local delivery or inhalation by catheter or stent. In one embodiment, the polymorph may also be administered intrathecally or intrathecally.

Pharmaceutical compositions may be formulated for administration particularly in solid or liquid form, including suitable forms for oral administration, such as drenches (aqueous or hydrophobic solutions or suspensions), tablets (eg, buccal, sublingual, and systemic absorption). ), capsules, lumps, powders, granules, pastes for application to the tongue, and intraduodenal routes; parenteral administration, such as intravenous, intraarterial, subcutaneous, intramuscular, intravascular, intraperitoneal or infusion, such as sterile solutions or suspensions, or sustained release formulations; topical application, such as creams, ointments, or controlled-release patches or sprays applied to the skin; vaginal or rectal, such as pessaries, creams, stents or foams; sublingual administration; ocular administration; pulmonary administration; local delivery by catheter or stent; intrathecal, or nasal administration.

Examples of suitable aqueous and non-aqueous carriers that can be used in the pharmaceutical composition include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, etc.), and suitable mixtures, vegetable oils such as olive oil, and injectable organic esters such as ethyl oligo. including eight. Proper fluidity can be maintained, for example, by the use of coating materials such as lecithin, maintenance of the required particle size in the case of dispersants, and the use of surfactants.

These compositions may also contain adjuvants such as preservatives, wetting agents, emulsifying agents, dispersing agents, lubricants, and/or antioxidants. Prevention of abiotic action in the compounds described herein can be prevented by injecting various antibacterial and antifungal agents, such as parabens, chlorobutanol, phenol sorbic acid, and the like. In some embodiments, a composition disclosed herein comprises an isotonic solution, such as a sugar, sodium chloride, and the like. Prolonged absorption of the injectable pharmaceutical form may also be brought about by infusion of agents which delay absorption, such as aluminum monostearate and gelatin.

Methods of making such agents or compositions include the step of incorporating a compound and/or chemotherapeutic agent described herein with a carrier, and optionally one or more additional ingredients. In general, formulations can be prepared uniformly and directly by incorporating the compounds disclosed herein into liquid carriers, or finely divided solid carriers, or all as necessary for shaping.

The preparation of such pharmaceutical compositions is well known in the art (Anderson, Philip O.; Knoben, James E.; Troutman, William G, eds., <i>handbook</i><i></i><i>of</i><i></i><i>Clinical</i><i> Drug </i><i>Data</i>, Tenth Edition, McGraw-Hill, 2002; Pratt and Taylor, eds.,<i>Principles </i><i>of</i><i></i><i>Drug</i><i></i><i>Action</i>, Third Edition, Churchill Livingston, New York, 1990; Katzung, ed.,<i>Basic</i><i></i><i>and</i><i></i><i>Clinical</i><i></i><i>Pharmacology</i>, Ninth Edition, McGraw Hill, 20037 ybg; Goodman and Gilman, eds.,<i>The</i><i></i><i>Pharmacological</i><i></i><i>Basis</i><i></i><i>of</i><i> Therapeutics</i>, Tenth Edition, McGraw Hill, 2001; <i>Remingtons</i><i></i><i>Pharmaceutical</i><i> Sciences</i>, 20th Ed., Lippincott Williams &amp; Wilkins., 2000; Martindale,<i>The</i><i> Extra </i><i>Pharmacopoeia</i>, Thirty-Second Edition (The Pharmaceutical Press, London, 1999)], which is incorporated herein by reference in its entirety. Where any conventional excipient medium is incompatible with the compounds provided herein, such as if it produces any undesirable biological effect or interacts with any other ingredient of the pharmaceutically acceptable composition in a deleterious manner. Except, it is contemplated that the use of excipients is within the scope of the present invention.

In some embodiments, the concentration of one or more polymorphs provided herein in a composition provided herein is less than about 100%, about 90%, about 80%, about 70%, about 60%, about 50%, about 40%, about 30%, about 20%, about 19%, about 18%, about 17%, about 16%, about 15%, about 14%, about 13%, about 12%, about 11%, about 10%, about 9% , about 8%, about 7%, about 6%, about 5%, about 4%, about 3%, about 2%, about 1%, about 0.5%, about 0.4%, about 0.3%, about 0.2%, about 0.1%, about 0.09%, about 0.08%, about 0.07%, about 0.06%, about 0.05%, about 0.04%, about 0.03%, about 0.02%, about 0.01%, about 0.009%, about 0.008%, about 0.007% , about 0.006%, about 0.005%, about 0.004%, about 0.003%, about 0.002%, about 0.001%, about 0.0009%, about 0.0008%, about 0.0007%, about 0.0006%, about 0.0005%, about 0.0004%, about 0.0003%, about 0.0002%, or about 0.0001% w/w, w/v, or v/v.

In some embodiments, the concentration of one or more polymorphs provided herein in a composition provided herein is about 90%, about 80%, about 70%, about 60%, about 50%, about 40%, about 30%, about 20 %, about 19.75%, about 19.50%, about 19.25%, about 19%, about 18.75%, about 18.50%, about 18.25%, about 18%, about 17.75%, about 17.50%, about 17.25%, about 17%, about 16.75%, about 16.50%, about 16.25%, about 16%, about 15.75%, about 15.50%, about 15.25%, about 15%, about 14.75%, about 14.50%, about 14.25%, about 14%, about 13.75 %, about 13.50%, about 13.25%, about 13%, about 12.75%, about 12.50%, about 12.25%, about 12%, about 11.75%, about 11.50%, about 11.25%, about 11%, about 10.75%, about 10.50%, about 10.25%, about 10%, about 9.75%, about 9.50%, about 9.25%, about 9%, about 8.75%, about 8.50%, about 8.25%, about 8%, about 7.75%, about 7.50%, about 7.25%, about 7%, about 6.75%, about 6.50%, about 6.25 %, about 6%, about 5.75%, about 5.50%, about 5.25%, about 5%, about 4.75%, about 4.50%, about 4.25%, about 4%, about 3.75%, about 3.50%, about 3.25%, about 3%, about 2.75%, about 2.50%, about 2.25%, about 2%, about 1.75%, about 1.50%, about 1.25%, about 1%, about 0.5%, about 0.4%, about 0.3%, about 0.2 %, about 0.1%, about 0.09%, about 0.08%, about 0.07%, about 0.06%, about 0.05%, about 0.04%, about 0.03%, about 0.02%, about 0.01%, about 0.009%, about 0.008%, about 0.007%, about 0.006%, about 0.005%, about 0.004%, about 0.003%, about 0.002%, about 0.001%, about 0.0009%, greater than about 0.0008%, about 0.0007%, about 0.0006%, about 0.0005%, about 0.0004%, about 0.0003%, about 0.0002%, or about 0.0001% w/w, w/v, or v/v.

In some embodiments, the concentration of one or more polymorphs provided herein in a composition provided herein is from about 0.0001 to about 50%, from about 0.001 to about 40%, from about 0.01 to about 30%, from about 0.02 to about 29%, about 0.03 to about 28%, about 0.04 to about 27%, about 0.05 to about 26%, about 0.06 to about 25%, about 0.07 to about 24%, about 0.08 to about 23%, about 0.09 to about 22%, about 0.1 to about 21%, about 0.2 to about 20%, about 0.3 to about 19%, about 0.4 to about 18%, about 0.5 to about 17%, about 0.6 to about 16%, about 0.7 to about 15%, about 0.8 to about 14%, about 0.9 to about 12%, about 1 to about 10% w/w, w/v, or v/v.

In some embodiments, the concentration of one or more polymorphs provided herein in a composition provided herein is from about 0.001 to about 10%, from about 0.01 to about 5%, from about 0.02 to about 4.5%, from about 0.03 to about 4%, about 0.04 to about 3.5%, about 0.05 to about 3%, about 0.06 to about 2.5%, about 0.07 to about 2%, about 0.08 to about 1.5%, about 0.09 to about 1%, about 0.1 to about 0.9% w/w, It is a range of w/v or v/v.

In some embodiments, the amount of one or more polymorphs provided herein in a composition provided herein is about 10 g, about 9.5 g, about 9.0 g, about 8.5 g, about 8.0 g, about 7.5 g, about 7.0 g, about 6.5 g. , about 6.0 g, about 5.5 g, about 5.0 g, about 4.5 g, about 4.0 g, about 3.5 g, about 3.0 g, about 2.5 g, about 2.0 g, about 1.5 g, about 1.0 g, about 0.95 g, about 0.9 g, about 0.85 g, about 0.8 g, about 0.75 g, about 0.7 g, about 0.65 g, about 0.6 g, about 0.55 g, about 0.5 g, about 0.45 g, about 0.4 g, about 0.35 g, about 0.3 g , about 0.25 g, about 0.2 g, about 0.15 g, about 0.1 g, about 0.09 g, about 0.08 g, about 0.07 g, about 0.06 g, about 0.05 g, about 0.04 g, about 0.03 g, about 0.02 g, about 0.01 g, about 0.009 g; about 0.008 g, about 0.007 g, about 0.006 g, about 0.005 g, about 0.004 g, about 0.003 g, about 0.002 g, about 0.001 g, about 0.0009 g, about 0.0008 g, about 0.0007 g, about 0.0006 g, about 0.0005 g, about 0.0004 g, about 0.0003 g, about 0.0002 g, or about 0.0001 g or less.

In some embodiments, the amount of one or more polymorphs provided herein in a composition provided herein is about 0.0001 g, about 0.0002 g, about 0.0003 g, about 0.0004 g, about 0.0005 g, about 0.0006 g, about 0.0007 g, about 0.0008 g , about 0.0009 g, about 0.001 g, about 0.0015 g, about 0.002 g, about 0.0025 g, about 0.003 g, about 0.0035 g, about 0.004 g, about 0.0045 g, about 0.005 g, about 0.0055 g, about 0.006 g, about 0.0065 g, about 0.007 g, about 0.0075 g, about 0.008 g, about 0.0085 g, about 0.009 g, about 0.0095 g, about 0.01 g, about 0.015 g, about 0.02 g, about 0.025 g, about 0.03 g, about 0.035 g , about 0.04 g, about 0.045 g, about 0.05 g, about 0.055 g, about 0.06 g, about 0.065 g, about 0.07 g, about 0.075 g, about 0.08 g, about 0.085 g, about 0.09 g, about 0.095 g, about 0.1 g, about 0.15 g, about 0.2 g, about 0.25 g, about 0.3 g, about 0.35 g, about 0.4 g, about 0.45 g, about 0.5 g, about 0.55 g, about 0.6 g, about 0.65 g, about 0.7 g, about 0.75 g, about 0.8 g, about 0.85 g, about 0.9 g, about 0.95 g, about 1 g, about 1.5 g, about 2 g, about 2.5 g, about 3 g, about 3.5 g, about 4 g, about 4.5 g, about 5 g, about 5.5 g, about 6 g, about 6.5 g, about 7 g, about 7.5 g, about 8 g, about 8.5 g, about 9 g, about 9.5 g, greater than about 10 g.

In some embodiments, the amount of one or more polymorphs provided herein in a composition provided herein is between about 0.0001 and about 10 g, between about 0.0005 and about 9 g, between about 0.001 and about 8 g, between about 0.005 and about 7 g, between about 0.01 and about 6 g, about 0.05 to about 5 g, about 0.1 to about 4 g, about 0.5 to about 4 g, or about 1 to about 3 g.

In one embodiment, the polymorphs provided herein are effective over a wide dosage range. For example, in the treatment of adults, dosages of about 0.01 to about 1000 mg, about 0.5 to about 100 mg, about 1 to about 50 mg, and about 5 to about 40 mg per day are examples of dosages that may be used. An exemplary dosage is from about 10 to about 30 mg per day. The exact dosage will depend on the route of administration, the form of the polymorph to be administered, the subject to be treated, the weight of the subject to be treated, and the preference and experience of the attending physician.

Non-limiting exemplary pharmaceutical compositions and methods of making them are described below.

<b>Pharmaceutical composition for oral administration</b>

In some embodiments, the present invention provides a pharmaceutical composition for oral administration, wherein the composition comprises a polymorph provided herein or a pharmaceutically acceptable form thereof (e.g., a pharmaceutically acceptable salt, hydrate, solvate, chelate, non-covalent complexes, isomers, prodrugs, and isotopically labeled derivatives), and pharmaceutically acceptable excipients (eg, excipients suitable for oral administration).

In one embodiment, a composition provided herein is a solid formulation comprising a polymorph of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate or hydrate thereof, and one or more pharmaceutically acceptable excipients. In one embodiment, a composition provided herein is a single unit dosage form comprising a polymorph of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate or hydrate thereof. In one embodiment, a composition provided herein is a tablet or capsule. In one embodiment, a composition provided herein comprises a therapeutically effective amount of a polymorph, or pharmaceutically acceptable salt, solvate or hydrate of a compound of Formula (I).

In one embodiment, a composition provided herein comprises a therapeutically effective amount of a polymorph of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate or hydrate thereof. In some embodiments, a therapeutically effective amount is about 0.5, about 1, about 2, about 3, about 4, about 5, about 10, about 15, about 20, about 25, about 30, about 35, about 40, about 45 , about 50, about 55, about 60, about 65, about 70, about 75, about 80, about 85, about 90, about 95, about 100, about 110, about 120, about 130, about 140, about 150, about 160, about 170, about 180, about 190, about 200, about 210, about 220, about 230, about 240, about 250, about 260, about 270, about 280, about 290, about 300, about 325, about 350, about 375, about 400, about 425, about 450, about 475, about 500, about 600, about 700, about 800, about 900, or about 1000 mg or more. In one embodiment, a composition provided herein comprises one or more pharmaceutically acceptable carriers or excipients. In some embodiments, the compositions provided herein include one or more pharmaceutically acceptable carriers or excipients including, for example, microcrystalline cellulose, crospovidone, and/or magnesium stearate. In one embodiment, a composition provided herein is an immediate-release formulation. In some embodiments, a composition provided herein is a hard gelatin capsule. In some embodiments, a composition provided herein is a soft gelatin capsule. In some embodiments, a composition provided herein comprises Form C of a compound of Formula (I). In some embodiments, a composition provided herein comprises Form A of a compound of Formula (I). In some embodiments, a composition provided herein comprises an amorphous form of a compound of Formula (I). In some embodiments, the compositions provided herein comprise a mixture of two or more polymorphs of a compound of Formula I, or a pharmaceutically acceptable salt, solvate or hydrate thereof, such as the polymorphs described herein.

In another embodiment, a composition provided herein is a suspension comprising one or more compounds of formula (I) and comprising carboxymethyl cellulose and water. In one embodiment, a composition provided herein comprises one or more excipients, such as polysorbate, polyethylene glycol, cyclodextrin, dextrose, n-methylpyrrolidone, pH buffered solution, dilute hydrochloric acid, 12-hydroxystearic acid. polyoxyethylene esters, or mixtures of two or more thereof. In one embodiment, the method for preparing a suspension comprises, but is not limited to, a pre-measured amount of a compound of formula (I) in powder form in a vehicle such as a commercially available medium strength USP carboxymethylcellulose sodium (SWFI) in sterile water for injection (SWFI) ( CMC).

In some embodiments, the present invention provides a solid pharmaceutical composition suitable for oral administration comprising: (i) a compound provided herein, or a pharmaceutically acceptable form thereof (e.g., a pharmaceutically acceptable salt, hydrate, a therapeutically effective amount of solvates, chelates, non-covalent complexes, isomers, prodrugs, and isotopically labeled derivatives); optionally (ii) a therapeutically effective amount of a second agent; and (iii) one or more pharmaceutical excipients suitable for oral administration. In some embodiments, the composition further contains: (iv) a therapeutically effective amount of a third agent.

In some embodiments, the present invention provides a liquid pharmaceutical composition suitable for oral administration. In some embodiments, the present invention provides capsule formulations suitable for oral administration.

In certain embodiments, the pharmaceutical compositions provided herein suitable for oral administration are formulated as separate formulations, such as capsules, pills, cachets, or tablets, or aerosol sprays each containing a pre-measured amount of the active ingredient as a liquid or powder or granules. , as a solution, or as a suspension in an aqueous or non-aqueous liquid, an oil-in-water emulsion, or a water-in-oil liquid emulsion. Generally, in solid form, the compositions are prepared by uniformly and directly mixing the active ingredient with a liquid carrier or finely divided solid carrier or both, and then, if necessary, shaping the product into a particular form. For example, tablets may be prepared by compression or molding, optionally with one or more additional ingredients. Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in free flowing form, such as a powder or granules, and optionally mixing with excipients such as, but not limited to, binders, lubricants, inert diluents, and/or surface active agents or dispersants. can Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid or semi-solid diluent.

Solid compositions of a similar type using such excipients as lactose or lactose as well as high molecular weight polyethylene glycols and the like can be used as fillers in soft and hard-filled gelatin capsules. Solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical compounding art. They may optionally include opacifying agents, and the composition may release the active substance alone, or preferentially to the intestinal tract, optionally, slowly. Examples of visceral compositions that may be used include polymeric materials and waxes. Solid compositions of a similar type using such excipients as lactose or lactose as well as high molecular weight polyethylene glycols and the like can be used as fillers in soft and hard-filled gelatin capsules.

The active ingredient may be in micro-encapsulated form and may optionally contain one or more excipients known herein. Solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical compounding art. In such solid formulations, the active substance may be admixed with one or more inert diluents, such as sucrose, lactose or starch. Such formulations may contain, as normal regimen, additional substances other than inert diluents such as tableted lubricants and other tableted acids such as magnesium stearate and microcrystalline cellulose. For capsules, tablets and pills, the dosage form may include a buffer. They may optionally contain opacifying agents and the composition may release the active substance alone, or preferentially to the intestinal tract, optionally, slowly. Examples of embedded compositions that can be used include polymer components and waxes.

The present invention also provides anhydrous pharmaceutical compositions and formulations comprising the active ingredient, since water enables the degradation of some compounds. For example, water may be added (eg, 5%) in the pharmaceutical arts as a means to stimulate long-term storage in order to determine the specificity, such as the quality shelf life or stability of a compound over time. Anhydrous pharmaceutical compositions and formulations provided herein can be prepared using anhydrous or low moisture containing ingredients and low moisture or low humidity conditions. Pharmaceutical compositions and formulations provided herein containing lactose can be rendered anhydrous if significant contact with moisture and/or moisture is expected during manufacture, packing, and/or storage. Anhydrous pharmaceutical compositions can be prepared and stored such that they retain their anhydrous properties. Accordingly, anhydrous compositions can be packaged using materials known to prevent exposure to water and can be included in suitable compound kits. Examples of suitable packing include, but are not limited to, sealed foil, plastic, and the like, single dose containers, blister packs, and strip packs.

In certain embodiments, the active ingredients may be combined by direct admixture with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques. Depending on the form of the preparation for which administration is intended, the carrier may take a variety of forms. In the preparation of compositions for oral dosage form, any conventional pharmaceutical medium is incorporated into oral liquid dosage forms (eg, suspensions, solutions, and elixirs) or, in the case of aerosols, carriers such as water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents. etc; or as a carrier such as starch, sugar, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, and disintegrants for oral solid formulations, in some embodiments lactose-free. For example, suitable carriers include powders, capsules, and tablets having solid oral dosage forms. In some embodiments, tablets may be coated by standard aqueous or non-aqueous techniques.

In one embodiment, the active ingredient is optionally combined with one or more inert, pharmaceutically acceptable excipients or carriers such as sodium citrate or dicalcium phosphate and/or a) fillers or extenders such as starch, lactose, sucrose, glucose , mannitol, and silicic acid, b) binders such as carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, c) wetting agents such as glycerol, d) disintegrating agents such as agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution delaying agents such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as cetyl alcohol and glycerol monostearate, h) absorbents such as kaolin and bentonite clay, and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. For capsules, tablets and pills, the dosage form may include a buffer.

In certain embodiments, suitable binders for use in pharmaceutical compositions and formulations include, but are not limited to, corn starch, potato starch, or other starches, gelatin, natural and synthetic gums such as acacia, sodium alginate, alginic acid, other alginates, powders tragacanth, guar gum, cellulose and its derivatives (eg ethyl cellulose, cellulose acetate, carboxymethyl cellulose calcium, sodium carboxymethyl cellulose), polyvinyl pyrrolidone, methyl cellulose, pre-gelatinized starch, hydroxypropyl methyl cellulose, microcrystalline cellulose, and mixtures of two or more thereof. In some embodiments, exemplary binders include, but are not limited to, starch (eg, cornstarch and starch paste); gelatin; sugars (eg, sucrose, glucose, dextrose, dextrin, molasses, lactose, lactitol, mannitol, etc.); Natural and synthetic gums (e.g., acacia, sodium alginate, Irish moss extract, panwa gum, gatti gum, isapol husk slime, carboxymethylcellulose, methylcellulose, ethylcellulose, hydroxy Ethylcellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, microcrystalline cellulose, cellulose acetate, poly(vinyl-pyrrolidone), magnesium aluminum silicate (veegum), and rachiarabogalactan; alginate; polyethylene oxide; polyethylene glycols; inorganic calcium salts; silicic acid; polymethacrylates; waxes; water; alcohols and the like, and mixtures of two or more thereof.

Examples of suitable fillers for use in the pharmaceutical compositions and formulations disclosed herein include, but are not limited to, talc, calcium carbonate (eg, granules or powder), microcrystalline cellulose, powdered cellulose, dextrate, kaolin, mannitol, silicic acid, sorbitol, starch, pre-gelatinized starch, and mixtures of the two.

In certain embodiments, disintegrants may be used in the compositions provided herein to provide tablets that disintegrate when exposed to an aqueous environment. Too much disintegrant can result in tablets that can disintegrate out of the bottle. Too little amount of disintegrant is not sufficient to disintegrate and can alter the rate range of release of the active ingredient from the formulation. Thus, a sufficient amount of disintegrant that is neither too little nor too much to adversely alter the release of the active ingredient can be used to form the formulations of the polymorphs disclosed herein. The amount of disintegrant used may vary depending on the type of formulation and mode of administration. In certain embodiments, from about 0.5 to about 15 weight percent of a disintegrant, or from about 1 to about 5 weight percent of a disintegrant may be used in the pharmaceutical compositions provided herein. Disintegrants that may be used in the pharmaceutical compositions and formulations provided herein include, but are not limited to, agar-agar, alginic acid, calcium carbonate, microcrystalline cellulose, croscarmellose sodium, crospovidone, polacrylline potassium, sodium starch glycolate, potato or tapioca starch, pre-gelatinized starch, other starches, clays, other algins, other celluloses, islets, and mixtures of two or more thereof.

In certain embodiments, lubricants that may be used to form the pharmaceutical compositions and formulations provided herein include, but are not limited to, calcium stearate, magnesium stearate, mineral oil, light mineral oil, glycerin, glyceryl behanate, sorbitol, mannitol , polyethylene glycol, other glycols, stearic acid, sodium lauryl sulfate, sodium benzoate, sodium acetate, sodium chloride, leucine, magnesium lauryl sulfate, talc, hydrogenated vegetable oils (such as peanut oil, cottonseed oil, sunflower oil, sesame oil) , olive oil, corn oil, and soybean oil), zinc stearate, ethyl oleate, ethyl laurate, agar, malt, and mixtures of two or more thereof. Additional lubricants include, for example, syloid silica gel, a coagulated aerosol of synthetic silica, or mixtures of two or more thereof. In certain embodiments, a lubricant may optionally be added in an amount of less than about 1% by weight of the pharmaceutical composition.

In some embodiments, a pharmaceutical composition or formulation provided herein comprises colloidal particles. In some cases, the colloidal particles comprise one or more cationizing agents and one or more nonionic surfactants such as poloxamers, tyloxapols, polysorbates, polyoxyethylene castor oil derivatives, sorbitan esters, or polyoxyl stearate. In some cases, the cationizing agent is an alkylamine, a tertiary alkyl amine, a quaternary ammonium compound, a cationic lipid, an amino alcohol, a biguanidine salt, a cationic compound, or a mixture of two or more thereof. In some cases, the cationizing agent is a biguanidine salt such as chlorhexidine, polyaminopropyl biguanidine, phenformine, alkylbiguanidine, or mixtures of the two. In some cases, quaternary ammonium formula I is a benzalkonium halide, lauralkonium halide, cetrimide, hexadecyltrimethylammonium halide, tetradecyltrimethyl-ammonium halide, dodecyltrimethylammonium halide, cetrimonium halide, benz Etonium halide, behenalkonium halide, cetalkonium halide, cetetyldimonium halide, cetylpyridinium halide, benzododecinium halide, chloroallyl methenamine halide, nyristylalkonium halide, stearalkonium halide, or their It is a mixture of two or more. In some cases, the cationizing agent is benzalkonium chloride, lauralkonium chloride, benzododecinium bromide, benzethenium chloride, hexadecyltrimethylammonium bromide, tetradecyltrimethylammonium bromide, dodecyltrimethylammonium bromide, or a combination thereof. It is a mixture of two or more. In some cases, the colloidal particles comprise an oil phase. In some cases, the oil phase is mineral oil, mild mineral oil, medium chain triglycerides (MCT), coconut oil, hydrogenated oils including hydrogenated cottonseed oil, hydrogenated palm oil, hydrogenated castor oil, hydrogenated soybean oil, polyoxyl- 40 hydrogenated castor oil, polyoxyl-60 hydrogenated castor oil, or polyoxyethylene hydrogenated castor oil derivatives comprising polyoxyl-100 hydrogenated castor oil.

In one embodiment, when aqueous suspensions and/or elixirs are for oral administration, the active ingredient is mixed with various sweetening or flavoring agents, coloring substances or dyes, in some embodiments emulsifying and/or suspending agents, with such diluents, such as It can be combined with water, ethanol, propylene glycol, glycerin, and various combinations.

In certain embodiments, tablets may be uncoated or coated by known techniques to delay disintegration and absorption in the gastrointestinal tract to provide sustained release over a longer period of time. For example, a time delay material such as glyceryl monostearate or glyceryl distearate may be used. Also, when the formulation for oral use is a hard gelatin capsule, the active ingredient is admixed with an inert solid diluent such as calcium carbonate, calcium phosphate, or kaolin; Or, in the case of soft gelatin capsules, the active ingredient may be mixed with water or an oil medium, such as peanut oil, liquid paraffin, or olive oil.

In certain embodiments, surfactants that can be used to form the pharmaceutical compositions and formulations provided herein include, but are not limited to, hydrophilic surfactants, lipophilic surfactants, and mixtures of two or more thereof. For example, a mixture of hydrophilic surfactants may be used, a mixture of lipophilic surfactants may be used, or a mixture of one or more hydrophilic surfactants and one or more lipophilic surfactants may be used.

In certain embodiments, suitable hydrophilic surfactants generally have an HLB value of 10 or greater, while suitable lipophilic surfactants may generally have an HLB value of about 10 or less. An empirical parameter used to characterize the relative hydrophilicity and hydrophobicity of nonionic amphoteric compounds is the hydrophilic-lipophilic balance ("HLB" value). Surfactants with low HLB values are more lipophilic or hydrophobic and have better solubility in oils, whereas surfactants with high HLB values are more hydrophilic and have better solubility in aqueous solutions. Hydrophilic surfactants are generally considered compounds having an HLB value greater than about 10, and HLB ranges for anionic, cationic, or amphoteric compounds are generally not applicable. Similarly, lipophilic (ie, non-aqueous) surfactants are compounds having an HLB value of about 10 or less. However, the values of the HLB of surfactants only play a rough role in enabling the formulation of emulsions for industrial, pharmaceutical and cosmetic uses in general use.

In certain embodiments, hydrophilic surfactants may be ionic or nonionic. Suitable ionic surfactants include, but are not limited to, alkylammonium salts; fusidic acid salt; fatty acid derivatives of amino acids, oligopeptides, and polypeptides; glyceride derivatives of amino acids, oligopeptides, and polypeptides; lecithin and hydrogenated lecithin; lysolecithin and hydrogenated lysolecithin; phospholipids and derivatives thereof; lysophospholipids and derivatives thereof; carnitine fatty acid ester salts; salts of alkyl sulfates; fatty acid salts; sodium docusate; acylacetylate; mono- and di-acetylated tartaric acid esters of mono- and di-glycerides; succilated mono- and di-glycerides; citric acid esters of mono- and di-glycerides; and mixtures of two or more thereof.

Within the aforementioned group, ionic surfactants include: lecithin, lysolecithin, phospholipids, lysophospholipids and derivatives thereof; carnitine fatty acid ester salts; salts of alkyl sulfates; fatty acid salts; sodium docusate; acylacetylate; mono- and di-acetylated tartaric acid esters of mono- and di-glycerides; succinylated mono- and di-glycerides; citric acid esters of mono- and di-glycerides; and mixtures of two or more thereof.

In certain embodiments, the ionic surfactant is lecithin, lysolecithin, phosphatidylcholine, phosphatidylethanolamine, phosphatidylglycerol, phosphatidic acid, phosphatidylserine, lysophosphatidylcholine, lysophosphatidylethanolamine, lysophosphatidylglycerol, lysophosphatidyl Diic acid, lysophosphatidylserine, PEG-phosphatidylethanolamine, PVP-phosphatidylethanolamine, lactyl esters of fatty acids, stearoyl-2-lactylate, stearoyl lactylate, succinate monoglycerides, mono/di Mono/diacetylated tartaric esters of glycerides, citric acid esters of mono/diglycerides, colylsarcosine, caproate, caprylate, caprate, laurate, myristate, palmitate, oleate, lysineoleate , linoleate, linolenate, stearate, lauryl sulfate, teracecyl sulfate, docusate, lauroyl carnitine, palmitoyl carnitine, myristoyl carnitine, salts thereof, and mixtures of two or more thereof. may be in the form

In certain embodiments, hydrophilic nonionic surfactants include, but are not limited to, alkylglucosides; alkyl maltoside; alkylthioglucoside; lauryl macrogolglyceride; polyoxyalkylene alkyl ethers such as polyethylene glycol alkyl ethers; polyoxyalkylene alkylphenols such as polyethylene glycol alkyl phenols; polyoxyalkylene alkyl phenol fatty acid esters such as polyethylene glycol fatty acid monoesters and polyethylene glycol fatty acid diesters; polyethylene glycol glycerol fatty acid esters; polyglycerol fatty acid esters; polyoxyalkylene sorbitan fatty acid esters such as polyethylene glycol sorbitan fatty acid esters; hydrophilic transesterification products of polyols comprising at least one member of the group consisting of glycerides, vegetable oils, hydrogenated vegetable oils, fatty acids, and sterols; polyoxyethylene sterols, derivatives, and analogs thereof; polyoxyethylated vitamins and derivatives thereof; polyoxyethylene-polyoxypropylene block copolymers; and mixtures thereof; polyethylene glycol sorbitan fatty acid esters and hydrophilic transesterification products of polyols comprising at least one member of the group consisting of triglycerides, vegetable oils, hydrogenated vegetable oils, and mixtures of two or more thereof. The polyol may be glycerol, ethylene glycol, polyethylene glycol, sorbitol, propylene glycol, pentaerythritol, or a saccharide.

Other hydrophilic-nonionic surfactants include, but are not limited to, PEG-10 laurate, PEG-12 laurate, PEG-20 laurate, PEG-32 laurate, PEG-32 dilaurate, PEG-12 oleate, PEG -15 Oleate, PEG-20 Oleate, PEG-20 Dioleate, PEG-32 Oleate, PEG-200 Oleate, PEG-400 Oleate, PEG-15 Stearate, PEG-32 Distearate, PEG -40 stearate, PEG-100 stearate, PEG-20 dilaurate, PEG-25 glyceryl trioleate, PEG-32 dioleate, PEG-20 glyceryl laurate, PEG-30 glyceryl laurate, PEG-20 Glyceryl Stearate, PEG-20 Glyceryl Oleate, PEG-30 Glyceryl Oleate, PEG-30 Glyceryl Laurate, PEG-40 Glyceryl Laurate, PEG-40 Palm Kernel Oil, PEG-50 hydrogenated castor oil, PEG-40 Castor Oil, PEG-35 Castor Oil, PEG-60 Castor Oil, PEG-40 Hydrogenated Castor Oil, PEG-60 Hydrogenated Castor Oil, PEG-60 Corn Oil, PEG-6 Caprate/Caprylate Glycer Ride, PEG-8 Caprate/Caprylate Glyceride, Polyglyceryl-10 Laurate, PEG-30 Cholesterol, PEG-25 Phytosterol, PEG-30 Soya Sterol, PEG-20 Trioleate, PEG-40 Sor bitan oleate, PEG-80 sorbitan laurate, polysorbate 20, polysorbate 80, POE-9 lauryl ether, POE-23 lauryl ether, POE-10 oleyl ether, POE-20 oleyl ether, POE-20 Stearyl Ether, Tocopheryl PEG-100 Succinate, PEG-24 Cholesterol, Polyglyceryl-10 Oleate, Tween^&amp;#174; 40, twin^&amp;#174; 60, sucrose monostearate, sucrose monolaurate, sucrose monopalmitate, PEG 10-100 nonyl phenol series, PEG 15-100 octyl phenol series, and poloxamers, and mixtures of two or more thereof. .

In certain embodiments, suitable lipophilic surfactants include fatty alcohols; glycerol fatty acid esters; acetylated glycerol fatty acid esters; lower alcohol fatty acid esters; propylene glycol fatty acid esters; sorbitan fatty acid esters; polyethylene glycol sorbitan fatty acid esters; sterols and sterol derivatives; polyoxyethylated sterols and sterol derivatives; polyethylene glycol alkyl ethers; sugar esters; sugar ether; lactic acid derivatives of mono- and di-glycerides; hydrophobic transesterification products of polyols comprising at least one member of the group consisting of glycerides, vegetable oils, hydrogenated vegetable oils, fatty acids and sterols; fat-soluble vitamins/vitamin derivatives; and mixtures of two or more thereof. Within this group, lipophilic surfactants include glycerol fatty acid esters, propylene glycol fatty acid esters, and mixtures of two or more thereof; hydrophobic transesterification products of polyols comprising at least one member of the group consisting of vegetable oils, hydrogenated vegetable oils, and triglycerides.

In one embodiment, the pharmaceutical composition may include a solubilizing agent to better dissolve and/or degrade the compound provided herein and/or minimize precipitation of the compound provided herein. It may be useful in compositions for parenteral use, such as injectable compositions. Solubilizers may also be added to increase the solubility of the hydrophilic drug and/or other ingredients, such as surfactants, or to maintain the composition as a stable or uniform solution or suspension.

Examples of suitable solubilizers include, but are not limited to, alcohols and polyols such as ethanol, isopropyl alcohol, butanol, benzyl alcohol, ethylene glycol, propylene glycol, butanediol and isomers thereof, glycerol, pentaerythritol , sorbitol, mannitol, transcutol, dimethyl isosorbide, polyethylene glycol, polypropylene glycol, polyvinyl alcohol, hydroxypropyl methylcellulose and other cellulose derivatives, cyclodextrin and cyclodextrin derivatives; ethers of polyethylene glycol having an average molecular weight of about 200 to about 6000, such as tetrahydrofurfuryl alcohol PEG ether (glycofurol) or methoxy PEG; Amides and other nitrogen-containing compounds such as 2-pyrrolidone, 2-piperidone, ε-caprolactam, N-alkylpyrrolidone, N-hydroxyalkylpyrrolidone, N-alkylpiperidone, N- alkylcaprolactam, dimethylacetamide and polyvinylpyrrolidone; esters such as ethyl propionate, tributylcitrate, acetyl triethylcitrate, acetyl tributyl citrate, triethylcitrate, ethyl oleate, ethyl caprylate, ethyl butyrate, triacetin, propylene glycol monoacetate, propylene glycol diacetate, ε-caprolactone and its isomers, δ-valerolactone and its isomers, β-butyrolactone and its isomers; and other solubilizing agents known in the art, such as dimethyl acetamide, dimethyl isosorbide, N-methyl pyrrolidone, monooctanoin, diethylene glycol monoethyl ether, water, and mixtures of two or more thereof. In certain embodiments, 12-hydroxystearic acid and about 30% free polyethylene glycol (Solutol^&amp;#174;) solubilizing agents, including polyglycol mono- and die-esters of (available as HS 15), are used in the compositions provided herein.

In certain embodiments, mixtures of solubilizers may be used. Examples include, but are not limited to, triacetin, triethylcitrate, ethyl oleate, ethyl caprylate, dimethylacetamide, N-methylpyrrolidone, N-hydroxyethylpyrrolidone, polyvinylpyrrolidone , hydroxypropyl methylcellulose, hydroxypropyl cyclodextrin, ethanol, polyethylene glycol 200-100, glycofurol, transcutol, propylene glycol, or a mixture of two or more of dimethyl isosorbide. In certain embodiments, solubilizing agents include sorbitol, glycerol, triacetin, ethyl alcohol, PEG-400, glycofurol, and propylene glycol.

In certain embodiments, the amount of solubilizer that may be included is not particularly limited. The amount of a given solubilizer may be limited to a biologically acceptable amount, which may be readily measurable to one of ordinary skill in the art. In some cases, it may be beneficial to include an amount of solubilizer in excess of a biologically acceptable amount, for example, the excess to be removed prior to providing the composition to a subject using conventional techniques such as distillation or evaporation. It is to maximize the concentration of the drug by including the solubilizer of Thus, if present, the solubilizing agent, based on the combined weight of the drug and other excipients, in a weight ratio of no more than about 10%, about 25%, about 50%, about 100%, or about 200% by weight. can be In some embodiments, also the smallest amounts of solubilizer may be used, such as about 5%, about 2%, about 1% or less. In certain embodiments, the solubilizer may be present in an amount from about 1 to about 100 weight percent, or from about 5 to about 25 weight percent.

In one embodiment, the compositions provided herein may further comprise one or more pharmaceutically acceptable additives and/or excipients. Such additives and excipients include, but are not limited to, anti-foaming agents, buffers, polymers, antioxidants, preservatives, chelating agents, viscosity modifiers, tonicity agents, flavoring agents, colorants, odorants, opacifiers, suspending agents, binders, fillers, plasticizers, lubricants, and mixtures of two or more thereof. In another embodiment, the compositions provided herein may contain one or more pharmaceutically acceptable additives and/or excipients such as, but not limited to, inert diluents, dispersing and/or granulating agents, surface active and/or emulsifying agents, disintegrating agents, binders. , preservatives, buffers, lubricants, and/or oils. For example, excipients such as cocoa butter and suppository waxes, coloring agents, coating agents, sweetening, flavoring, and perfuming agents may be present in the composition.

Exemplary surface active agents and/or emulsifiers include, but are not limited to, natural emulsifiers (eg, acacia, agar, alginic acid, sodium alginate, tragacanth, chondrux, cholesterol, xanthan, pectin, gelatin, egg yolk, casein, wool fat, cholesterol , waxes, and lecithin), colloidal clays (such as bentonite [aluminum silicate] and veegum [magnesium aluminum silicate]), long chain amino acid derivatives, high molecular weight alcohols (such as stearyl alcohol, cetyl alcohol, oleyl alcohol, tria) Cetine monostearate, ethylene glycol distearate, glyceryl monostearate, and propylene glycol monostearate, polyvinyl alcohol), carbomers (such as carboxy polymethylene, polyacrylic acid, acrylic acid polymers, and carboxyvinyl polymers), Carrageenan, cellulose derivatives (such as carboxymethylcellulose sodium, powdered cellulose, hydroxymethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, methylcellulose), sorbitan fatty acid esters (such as polyoxyethylene sorbitan monolaurate [twin^&amp;#174; 20], polyoxyethylene sorbitan [twin^&amp;#174; 60], polyoxyethylene sorbitan monooleate [twin^&amp;#174; 80], Sorbitan Monopalmitate [Span 40], Sorbitan Monostearate [Span 60], Sorbitan Tristearate [Span 65], Glyceryl Monooleate, Sorbitan Monooleate [Span 80] ]), polyoxyethylene esters such as polyoxyethylene monostearate [Myrj 45], polyoxyethylene hydrogenated castor oil, polyethoxylated castor oil, polyoxymethylene stearate, and solutol^&amp;#174;), sucrose fatty acid esters, polyethylene glycol fatty acid esters (e.g., Cremophor^&amp;#174;)), polyoxyethylene ethers (such as polyoxyethylene lauryl ether [Brij 30]), poly(vinyl-pyrrolidone), diethylene glycol monolaurate, triethanolamine oleate, sodium oleate, potassium oligo ate, ethyl oleate, oleic acid, ethyl laurate, sodium lauryl sulfate, pluronic acid F 68, Poloxamer 188, cetrimonium bromide, cetylpyridinium chloride, benzalkonium chloride, docusate sodium, etc. and/or combinations thereof.

Exemplary preservatives may include antioxidants, chelating agents, antimicrobial preservatives, antifungal preservatives, alcohol preservatives, acidic preservatives, and other preservatives. Exemplary antioxidants include, but are not limited to, alpha tocopherol, ascorbic acid, acorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene, monothioglycerol, potassium metabisulfite, propionic acid, propyl gallate , sodium ascorbate, sodium bisulfite, sodium metabisulfite, and sodium sulfite. Exemplary chelating agents include ethylenediaminetetraacetic acid (EDTA), citric acid monohydrate, disodium edetate, dipotassium edetate, edetic acid, fumaric acid, malic acid, phosphoric acid, sodium edetate, tartaric acid, and trisodium edetate. include Exemplary antimicrobial preservatives include, but are not limited to, benzalkonium chloride, benzethonium chloride, benzyl alcohol, bronopol, cetriimide, cetylpyridinium chloride, chlorhexidine, chlorobutanol, chlorocresol, chloroxyleneol, cre sol, ethyl alcohol, glycerin, hexetidine, imidurea, phenol, phenoxyethanol, phenylethyl alcohol, phenylmercury nitrate, propylene glycol, and thimerosal. Exemplary antifungal preservatives include, but are not limited to, butyl paraben, methyl paraben, ethyl paraben, propyl paraben, benzoic acid, hydroxybenzoic acid, potassium benzoate, potassium sorbate, sodium benzoate, sodium propionate, and sorbic acid. Exemplary alcohol preservatives include, but are not limited to, ethanol, polyethylene glycol, phenol, phenolic compounds, bisphenol, chlorobutanol, hydroxybenzoate, and phenylethyl alcohol. Exemplary acidic preservatives include, but are not limited to, vitamin A, vitamin C, vitamin E, beta-carotene, citric acid, acetic acid, dehydroacetic acid, ascorbic acid, sorbic acid, and phytic acid. Other preservatives include, but are not limited to, tocopherol, tocopherol acetate, diteroxime mesylate, cetriimide, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), ethylenediamine, sodium lauryl sulfate (SLS), Sodium Lauryl Ether Sulfate (SLES), Sodium Bisulfite, Sodium Metabisulfite, Potassium Sulfite, Potassium Metabisulfite, Glydant^&amp;#174;) Plus, Phenonip, Methylparaben, Low Molar (Germall)^&amp;#174;) 115, Germaben^&amp;#174;) II, Neolon^™), carton^™), and loss (Euxyl^&amp;#174;) is included. In certain embodiments, the preservative is an antioxidant. In other embodiments, the preservative is a chelating agent.

Exemplary oils include, but are not limited to, almond, apricot kernel, avocado, babassu, bergamot, blackcurrant seed, borage, cade, chamomile, canola, caraway, carnauba, castor, cinnamon, cocoa butter, coconut, Cord River, Coffee, Corn, Cottonseed, Emu, Eucalyptus, Evening Primrose, Fish, Plexidium, Geraniol, Gourd, Grape Seed, Hazelnut, Hyssop, Isopropyl Myristate, Jojoba, Cucui Nut, Lavandine, Lavender, Lemon, Lit Shia cubeba, macadamia nut, mallow, mango seed, meadowfoam seed, mink, nutmeg, olive, orange, orange rough, palm, palm kernel, peach kernel, peanut, poppy seed, pumpkin seed, rapeseed, rice bran, rosemary, safflower, sandalwood, saswana, savory, sea buckthorn, sesame, shea butter, silicone, soybean, sunflower, tea tree, thistle, camellia, vetiver, walnut, and wheat germ oil. Exemplary oils include, but are not limited to, butyl stearate, caprylic triglyceride, capric triglyceride, cyclomethicone, diethyl sebacate, dimethicone 360, isopropyl myristate, mineral oil, octyldodecane ol, oleyl alcohol, silicone oil, and combinations thereof.

Exemplary granulating and/or dispersing agents include, but are not limited to, potato starch, corn starch, tapioca starch, sodium starch glycolate, clay, alginic acid, guar gum, citrus pulp, agar, bentonite, cellulose and wood products, natural sponges, ion- Exchange resin, calcium carbonate, silicate, sodium carbonate, cross-linked poly(vinyl-pyrrolidone) (crospovidone), sodium carboxymethyl starch (sodium starch glycolate), carboxymethyl cellulose, cross-linked sodium carboxymethyl Cellulose (Crosscarmellose), Methylcellulose, Pregelatinized Starch (Starch 1500), Microcrystalline Starch, Water Insoluble Starch, Calcium Carboxymethyl Cellulose, Magnesium Aluminum Silicate (Vegum)^&amp;#174;), sodium lauryl sulfate, quaternary ammonium compounds, and the like, and combinations thereof.

Exemplary diluents include, but are not limited to, calcium carbonate, sodium carbonate, calcium phosphate, dicalcium phosphate, calcium sulfate, calcium hydrogen phosphate, sodium phosphate lactose, sucrose, cellulose, microcrystalline cellulose, kaolin, mannitol, sorbitol, inositol, chloride sodium, dry starch, corn starch, powdered sugar, and the like, and combinations thereof.

In another embodiment, acids or bases may be incorporated into the compositions provided herein to facilitate manufacturing processes, increase stability, or for other reasons. Examples of pharmaceutically acceptable bases include, but are not limited to, amino acids, amino acid esters, ammonium hydroxide, potassium hydroxide, sodium hydroxide, sodium hydrogen carbonate, aluminum hydroxide, calcium carbonate, magnesium hydroxide, magnesium aluminum silicate, synthetic aluminum silicate, synthetic hydro Calcite, magnesium aluminum hydroxide, diisopropylethylamine, ethanolamine, ethylenediamine, triethanolamine, triethylamine, triisopropanolamine, trimethylamine, tris(hydroxymethyl)aminomethane (TRIS), etc. do. In certain embodiments, a pharmaceutically acceptable base is a salt of a pharmaceutically acceptable acid. Examples of pharmaceutically acceptable acids include, but are not limited to, acetic acid, acrylic acid, adipic acid, alginic acid, alkanesulfonic acid, amino acids, ascorbic acid, benzoic acid, boric acid, butyric acid, carbonic acid, citric acid, fatty acid, formic acid, fumaric acid, gluconic acid , hydroquinosulfonic acid, isoascorbic acid, lactic acid, maleic acid, oxalic acid, para-bromophenylsulfonic acid, propionic acid, p-toluenesulfonic acid, salicylic acid, stearic acid, succinic acid, tannic acid, tartaric acid, thioglycolic acid, toluenesulfonic acid phonic acid, uric acid, and the like; and salts of polyprotic acids such as sodium phosphate, disodium hydrogen phosphate, and sodium dihydrogen phosphate. When the base is a salt, the cation can be any convenient, pharmaceutically acceptable cation, such as ammonium, alkali metals, alkaline earth metals, and the like. Examples may include, but are not limited to, sodium, potassium, lithium, magnesium, calcium and ammonium.

In one embodiment, the suitable acid is a pharmaceutically acceptable organic or inorganic acid. Examples of suitable inorganic acids include, but are not limited to, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, boric acid, phosphoric acid, and the like. Examples of suitable organic acids include, but are not limited to, acetic acid, acrylic acid, adipic acid, alginic acid, alkanesulfonic acid, amino acids, ascorbic acid, benzoic acid, boric acid, butyric acid, carbonic acid, citric acid, fatty acid, formic acid, fumaric acid, gluconic acid, hydroquinosulfonic acid Fonic acid, isoascorbic acid, lactic acid, maleic acid, methanesulfonic acid, oxalic acid, para-bromophenylsulfonic acid, propionic acid, p-toluenesulfonic acid, salicylic acid, stearic acid, succinic acid, tannic acid, tartaric acid, thioglycolic acid, toluenesulfonic acid phonic acid, uric acid, and the like.

<b>parenteral</b><b> Pharmaceutical composition for administration</b>

In some embodiments, the present invention relates to a polymorph provided herein or a pharmaceutically acceptable form thereof (e.g., a pharmaceutically acceptable salt, hydrate, solvate, chelate, non-covalent complex, isomer, prodrug, and isotopic) To provide a pharmaceutical composition for parenteral administration containing a derivative labeled with ), and a pharmaceutical excipient suitable for parenteral administration. In some embodiments, the present invention relates to (i) a disclosed compound, or a pharmaceutically acceptable form thereof (e.g., a pharmaceutically acceptable salt, hydrate, solvate, chelate, non-covalent complex, isomer, prodrug, and isotopic) an effective amount of a derivative labeled with optionally (ii) an effective amount of one or more second agents; and (iii) one or more pharmaceutical excipients suitable for parenteral administration. In some embodiments, the pharmaceutical composition further contains (iv) an effective amount of a third agent.

In certain embodiments, the forms in which the compositions provided herein can be incorporated for administration by infusion include aqueous or oil suspensions, or emulsions, including sesame oil, corn oil, cottonseed oil, or peanut oil, as well as elixirs, mannitol, dex Straws, or sterile aqueous solutions, and similar pharmaceutical vehicles are also included.

Liquid formulations for oral and parenteral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active ingredient, liquid formulations may contain inert diluents commonly used in the art, such as water or other solvents, solubilizers and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate. , propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (especially cottonseed, peanut, corn, sprout, olive, castor, and sesame oil), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycol and sorbitan fatty acid esters, and mixtures thereof. In certain embodiments for parenteral administration, a compound disclosed herein is combined with a solubilizing agent, such as Cremophor.^&amp;#174;, alcohols, oils, modified oils, glycols, polysorbates, cyclodextrins, polymers, and combinations thereof.

In certain embodiments, an aqueous solution in saline is used for infusion. In certain embodiments, ethanol, glycerol, propylene glycol, liquid polyethylene glycol and the like (and suitable mixtures thereof), cyclodextrin derivatives, or vegetable oils may be used. The sterile injectable formulation may be a sterile injectable solution, suspension or emulsion in a nontoxic parenterally acceptable diluent or solvent, such as a solution in 1,3-butanediol. Among the exemplary vehicles and solvents that may be used, water, Ringer's solution, USP, and isotonic sodium chloride solution may be used. In addition, sterile, fixed oils are conventionally employed as the solvent or suspending medium. For this purpose, any blend of fixed oils may be used, including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid are used in the preparation of injectables. In the case of suspensions, proper fluidity may be maintained, for example, by the use of coatings such as lecithin or surfactants to maintain a particular particle size. In certain embodiments, prevention of the action of microorganisms can be obtained with various antibacterial and antifungal agents, such as parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like.

In certain embodiments, sterile injectable solutions are prepared by incorporating a compound provided herein in a specified amount in an appropriate solvent into the various other ingredients enumerated herein, followed by filtered sterilization. In certain embodiments, suspensions are prepared by incorporating the various sterile active ingredients into a sterile vehicle which contains a basic suspension medium and various other ingredients enumerated herein. In the case of sterile powders for the preparation of sterile injectable solutions, suitable methods for preparation include, but are not limited to, vacuum-drying and freeze-drying to obtain a powder of the active ingredient plus any additional ingredients from a previously sterile-filtered solution. includes technology.

Formulations for injection may be sterilized, for example, by filtration through a bacterial-retaining filter or by incorporating a sterile agent in the form of a sterile solid composition that may be dissolved or suspended in sterile water or other sterile injectable medium prior to use. Compositions for injection may contain from about 0.1 to about 5% w/w of a compound disclosed herein.

<b>Pharmaceutical composition for topical administration</b>

In some embodiments, the present invention relates to a polymorph provided herein, or a pharmaceutically acceptable form thereof (e.g., a pharmaceutically acceptable salt, hydrate, solvate, chelate, non-covalent complex, isomer, prodrug, and isotopic) ) and a pharmaceutical excipient suitable for topical (eg, transdermal) delivery. In some embodiments, the present invention provides a pharmaceutical composition comprising (i) an effective amount of a disclosed compound; optionally (ii) an effective amount of one or more second agents; and (iii) one or more pharmaceutical excipients suitable for topical administration. In some embodiments, the pharmaceutical composition further contains (iv) an effective amount of a third agent.

In certain embodiments, the compositions provided herein are in solid, semi-solid, or liquid form suitable for partial and/or topical administration, such as gels, water-soluble jellies, creams, lotions, suspensions, foams, powders, slurries, ointments, solutions , oils, pastes, suppositories, sprays, emulsions, saline solutions, and dimethylsulfoxide (DMSO)-based solutions. In one embodiment, a carrier having a high density can provide an area with extended exposure to the active material. However, solution formulations may allow for more immediate exposure of the active ingredient to the selected area.

In some embodiments, the pharmaceutical composition may also include a suitable solid or gel phase carrier or excipient, which aids in the delivery or increases penetration of the therapeutic molecule into the stratum corneum permeation barrier of the skin. There are many such penetration-enhancing molecules known in the art of topical formulations. Examples of such carriers and excipients include, but are not limited to, wetting agents (eg, urea), glycols (eg, propylene glycol), alcohols (eg, ethanol), fatty acids (eg, oleic acid), surfactants (eg, isopropyl myristate and sodium lauryl sulfate), pyrrolidone, glycerol monolaurate, sulfoxide, terpenes (such as menthol), amines, amides, alkanes, alkanols, water, calcium carbonate, calcium phosphate, various sugars, starch, cellulose derivatives, gelatin, and polymers such as polyethylene glycol.

In another embodiment, a pharmaceutical composition or formulation for use in the methods provided herein employs a transdermal delivery device ("patch"). Such transdermal patches can be used to provide continuous or discontinuous infusion of a compound provided herein in controlled amounts with or without another agent.

The structure and use of transdermal patches for the delivery of pharmaceutical agents are known in the art. For example, US Pat. Nos. 5,023,252, 4,992,445, and 5,001,139 are incorporated herein by reference. Such patches may be configured for continuous, pulsatile or customized delivery of pharmaceutical agents.

Suitable devices for delivering a pharmaceutically acceptable composition within the epidermis described herein include short needle devices, such as those described in U.S. Patent Nos. 4,886,499; 5,190,521; 5,328,483; 5,527,288; 4,270,537; 5,015,235; 5,141,496; and 5,417,662. Devices that limit short needles of effective penetration length into the skin, such as those described in PCT application WO 99/34850, and functionally equivalents thereof, can be used to administer the composition in the epidermis. Jet injection devices that deliver a liquid vaccine to the dermis with a liquid jet syringe and/or a needle penetrating the stratum corneum and produce a jet reaching the dermis are suitable. Jet injection devices are described, for example, in U.S. Patent Nos. 5,480,381; 5,599,302; 5,334,144; 5,993,412; 5,649,912; 5,569,189; 5,704,911; 5,383,851; 5,893,397; 5,466,220; 5,339,163; 5,312,335; 5,503,627; 5,064,413; 5,520,639; 4,596,556; 4,790,824; 4,941,880; 4,940,460; and PCT applications WO 97/37705 and WO 97/13537. Ballistic powder/particle delivery devices that use compressed gas to accelerate the vaccine in powder form from the outer layers of the skin to the dermis are suitable. Alternatively, conventional injections may also be used in the classical tuberculosis method of intradermal administration.

Topically-administrable formulations include, for example, from about 1 to about 10% (w/w) of the compound of formula I, although the concentration of the compound of formula I may be high enough to limit the solubility of the compound of formula I in the solvent. can do. In some embodiments, the topically-administrable formulation comprises, for example, about 1 to about 9% (w/w) of a compound of Formula I, such as about 1 to about 8% (w/w), further such as about 1 to about 7% (w/w), further such as from about 1 to about 6% (w/w), further such as from about 1 to about 5% (w/w), further such as from about 1 to about 4% ( w/w), further such as from about 1 to about 3% (w/w), and further such as from about 1 to about 2% (w/w) of a compound of formula I. Formulations for topical administration may further comprise one or more additional pharmaceutically acceptable excipients described herein.

<b>Pharmaceutical composition for administration by inhalation </b>

In some embodiments, the present invention relates to polymorphs prepared herein or pharmaceutically acceptable forms thereof (e.g., pharmaceutically acceptable salts, hydrates, solvates, chelates, non-covalent complexes, isomers, prodrugs, and isotopes) A pharmaceutical composition for administration by inhalation is provided, which contains a chemically labeled derivative), and a pharmaceutical excipient suitable for topical administration. In some embodiments, the present invention relates to (i) a disclosed compound, or a pharmaceutically acceptable form thereof (e.g., a pharmaceutically acceptable salt, hydrate, solvate, chelate, non-covalent complex, isomer, prodrug, and isotopic) an effective amount of a derivative labeled with optionally (ii) an effective amount of one or more second agents; and (iii) one or more pharmaceutical excipients suitable for administration by inhalation. In some embodiments, the pharmaceutical composition further contains (iv) an effective amount of a third agent.

In some embodiments, the present invention provides solutions and suspensions in pharmaceutically acceptable aqueous or organic solvents, or mixtures thereof; and suitable powders. Liquid or solid compositions may contain suitable pharmaceutically acceptable excipients described herein. In some embodiments, the composition is administered by the oral or nasal respiratory route for partial and/or systemic effect. In certain embodiments, the composition in a pharmaceutically acceptable solvent may be nebulized using an inert gas. The nebulized solution may be inhaled directly from the nebulizer device, or the nebulizer device may be attached to a face mask tent, or intermittent positive pressure breathing machine. In certain embodiments, the solution, suspension, or spray composition may be administered from a device that delivers the formulation in a suitable manner, such as orally or nasally.

<b>Pharmaceutical composition for ocular administration</b>

In some embodiments, the present invention provides a pharmaceutical composition for treating an ophthalmic disease. In one embodiment, the composition is formulated for ophthalmic administration, which is a polymorph provided herein or a pharmaceutically acceptable form thereof provided herein (e.g., a pharmaceutically acceptable salt, hydrate, solvate) suitable for ophthalmic administration. , chelates, non-covalent complexes, isomers, prodrugs, and isotopically labeled derivatives) and pharmaceutical excipients. In certain embodiments, the pharmaceutical compositions provided herein suitable for ocular administration each contain a pre-measured amount of the active ingredient in separate formulations, such as solution, or suspension in an aqueous or non-aqueous liquid, oil-in-water emulsion, or water-in-oil liquid emulsion. may be presented as eye drops or sprays. Other dosage forms include the use of eye drops, intraocular injections, intravitreal injections, topical, or drug dissolution devices, microcapsules, implants, or microfluidic devices. In some instances, a compound disclosed herein is administered as a carrier or excipient that increases the intraocular penetration of the compound, such as an oil and water emulsion comprising colloidal particles having an oily core covered with an interfacial film.

In some cases, the colloidal particles comprise one or more cationizing agents and one or more nonionic surfactants, such as poloxamers, tyloxapols, polysorbates, polyoxyethylene castor oil derivatives, sorbitan esters, or polyoxyl stearate. In some cases, the cationizing agent is an alkylamine, a tertiary alkyl amine, a quaternary ammonium compound, a cationic lipid, an amino alcohol, a biguanidine salt, a cationic compound, or mixtures thereof. In some cases, the cationizing agent is a biguanidine salt such as chlorhexidine, polyaminopropyl biguanidine, phenformine, alkylbiguanidine, or mixtures thereof. In some cases, quaternary ammonium formula I is a benzalkonium halide, lauralkonium halide, cetriimide, hexadecyltrimethylammonium halide, tetradecyltrimethylammonium halide, dodecyltrimethylammonium halide, cetrimonium halide, benzeth tonium halide, behenalkonium halide, cetalkonium halide, cetetyldimonium halide, cetylpyridinium halide, benzododecinium halide, chloroallyl methenamine halide, nyristylalkonium halide, stearalkonium halide or two thereof It is a mixture. In some cases, the cationizing agent is benzalkonium chloride, lauralkonium chloride, benzododecinium bromide, benzethenium chloride, hexadecyltrimethylammonium bromide, tetradecyltrimethylammonium bromide, dodecyltrimethylammonium bromide, or two thereof. It is a mixture of more than one. In some cases, the oil phase is mineral oil and mild mineral oil, medium chain triglycerides (MCT), coconut oil; hydrogenated oils including hydrogenated cottonseed oil, hydrogenated palm oil, hydrogenated castor oil or hydrogenated soybean oil; polyoxyethylene hydrogenated castor oil derivatives comprising polyoxyl-40 hydrogenated castor oil, polyoxyl-60 hydrogenated castor oil or polyoxyl-100 hydrogenated castor oil.

It is contemplated that any partial route to the eye may be used, including topical, subconjunctival, periocular, posterior, subtenon, intraanterior, intravitreal, intraocular, subretinal, scleral, and suprachoroidal administration. . Systemic or parenteral administration including, but not limited to, intravenous, subcutaneous, and oral delivery may be feasible. Exemplary methods of administration include intravitreal or subtenon injection of a solution or suspension, or intravitreal or subtenon replacement of a biodegradable or non-biodegradable device, or topical ocular administration of a solution or suspension, or posteriorly in a gel or cream formulation. It will be scleral proximal administration.

In some embodiments, eye drops are prepared by dissolving the active ingredient in a sterile aqueous solution, such as physiological saline or buffer; The powder composition to be dissolved prior to use may be prepared by combining. Other vehicles known in the art may be selected including, but not limited to, saline solutions, saline solutions, water-soluble polyethers such as polyethylene glycol, polyvinyls such as polyvinyl alcohol and povidone, cellulose derivatives such as Methylcellulose and hydroxypropyl methylcellulose, petrolatum derivatives such as mineral oil and white petrolatum, animal fats such as lanolin, polymers of acrylic acid such as carboxypolymethylene gel, plant fats such as peanut oil, polysaccharides such as dextran, glycosa minoglycans such as sodium hyaluronate; and mixtures of two or more thereof. In some embodiments, additives commonly used in eye drops may be added. Such additives may include isotonic agents (eg sodium chloride), buffers (eg boric acid, sodium monohydrogen phosphate, sodium dihydrogen phosphate), preservatives (eg benzalkonium chloride, benzethonium chloride, chlorobutanol), thickeners (eg, saccharides such as lactose, mannitol, maltose; such as hyaluronic acid or salts thereof such as sodium hyaluronate, potassium hyaluronate; such as mucopolysaccharides such as chondroitin sulfate; such as sodium polyacrylate, carboxyvinyl polymer, cross-linked polyacrylates, polyvinyl alcohol, polyvinyl pyrrolidone, methyl cellulose, hydroxy propyl methylcellulose, hydroxyethyl cellulose, carboxymethyl cellulose, hydroxy propyl cellulose, or other agents known to those skilled in the art) include

<b>Alternative routes for administration</b>

In one embodiment, the compositions provided herein can also be delivered as infiltrated or coated devices, such as stents, such as or artery-inserted cylindrical polymers. This method of administration can help prevent or ameliorate restenosis following, for example, a procedure, such as instrumental vasodilation. Without wishing to be bound by any particular theory, the compounds provided herein may exhibit or inhibit the migration and proliferation of smooth muscle cells in the arterial wall that contributed to restenosis. The compounds provided herein can be administered by partial delivery, such as from the strut of a stent, stent graft, graft, or cover or sheath of a stent. In some embodiments, a compound provided herein is mixed into a matrix. This matrix may be a polymeric matrix and may serve to bind the compound to the stent. Polymeric matrices for this use include, for example, lactone-based polyesters or copolyesters such as polylactide, polycaprolactoneglycolide, polyorthoesters, polyanhydrides, polyamino acids, polysaccharides, polyphosphazenes, poly (ether-ester) copolymers (eg, PEO-PLLA); Polydimethylsiloxane, poly(ethylene-vinylacetate), acrylate-based polymers or copolymers (eg polyhydroxyethyl methylmethacrylate, polyvinyl pyrrolidinone), fluorinated polymers such as polytetrafluoro ethylene, and cellulose esters. Suitable matrices may not degrade or degrade to match the release time of the compound or compound. The compounds provided herein can be applied to the stent surface by a variety of methods, such as dip/spin coating, spray coating, dip-coating, and/or brush-coating. A compound provided herein can be applied to a solvent and the solvent can be evaporated to form a layer of the compound on the stent. Alternatively, the compound may be placed in the body of a stent or graft, such as a microchannel or micropore. When embedded, the compound leaves the body of the stent and contacts the artery wall. Stents prepared to contain such micropores or microchannels can be prepared by dipping in a solution of a compound provided herein in a suitable solvent, followed by evaporation of the solvent. Additional simple solvent washes can remove excess drug on the surface of the stent. In another embodiment, a compound provided herein can be covalently linked to a stent or graft. A covalent linker that degrades in vivo can be used to induce release of a compound provided herein. Any bio-labile linkage may be used for this purpose, such as an ester, amide or anhydride linkage. In addition, the compounds provided herein can be administered intravascularly from a balloon used during angioplasty. In addition, extravascular administration of a compound provided herein can be effected via pericardial or adventitial application of a formulation provided herein to reduce restenosis.

A variety of stent devices that may be used, such as those described in the following publications are disclosed and incorporated herein by reference in their entirety: US Pat. No. 5451233; US Patent No. 5040548; US Patent No. 5061273; US Pat. No. 5496346; US Patent No. 5292331; US Pat. No. 5674278; US Pat. No. 3657744; US Pat. No. 4739762; US Pat. No. 5195984; US Patent No. 5292331; US Pat. No. 5674278; US Pat. No. 5879382; and US Pat. No. 6344053.

<b>Formulation for sustained-release administration</b>

In some embodiments, the present invention relates to a polymorph provided herein or a pharmaceutically acceptable form thereof (eg, a pharmaceutically acceptable salt, hydrate, solvate, chelate, non-covalent complex, isomer, pro Provided is a pharmaceutical composition for sustained-release administration containing a drug, and an isotopically labeled derivative), and a pharmaceutical excipient. In some embodiments, the present invention relates to (i) a disclosed polymorph or a pharmaceutically acceptable form thereof (e.g., a pharmaceutically acceptable salt, hydrate, solvate, chelate, non-covalent complex, isomer, prodrug, and isotope) an effective amount of an antigenically labeled derivative); optionally (ii) an effective amount of one or more second agents; and (iii) one or more pharmaceutical excipients suitable for sustained-release administration. In some embodiments, the pharmaceutical composition further contains (iv) an effective amount of a third agent.

Active agents, such as compounds provided herein, can be administered by sustained-release means or delivery devices well known to those skilled in the art. Examples include, but are not limited to, US Pat. Nos. 3,845,770; 3,916,899; 3,536,809; 3,598,123; and 4,008,719; 5,674,533; 5,059,595; 5,591,767; 5,120,548; 5,073,543; 5,639,476; 5,354,556; 5,639,480; 5,733,566; 5,739,108; 5,891,474; 5,922,356; 5,972,891; 5,980,945; 5,993,855; 6,045,830; 6,087,324; 6,113,943; 6,197,350; 6,248,363; 6,264,970; 6,267,981; 6,376,461; 6,419,961; 6,589,548; 6,613,358; 6,699,500, each of which is incorporated herein by reference. Such formulations, such as hydropropylmethyl cellulose, other polymer matrices, gels, permeable membranes, osmotic systems, multilayer coatings, microparticles, liposomes, microspheres, or combinations thereof, are formulated to provide slow or sustained release of one or more active agents. can be used to provide a given release profile of various fractions. Suitable sustained release formulations known to those of skill in the art described herein can be readily selected for use with the active agents provided herein. Accordingly, provided pharmaceutical compositions encompass single unit dosage forms suitable for oral administration such as, but not limited to, tablets, capsules, gelatin capsules, and dragees adapted for sustained release.

All sustained-release pharmaceutical products have the general goal of improving drug treatment achieved by their uncontrolled counterparts. In some embodiments, the use of a sustained-release formulation in medical treatment is characterized by a minimal amount of drug substance used to treat or control a disease, disorder, or condition for a minimal amount of time. Advantages of sustained release formulations include prolonged activity of the drug, reduced dosing frequency, and increased subject compliance. In addition, sustained-release formulations may be used to affect the timing of onset of action or other characteristics, such as blood levels of the drug, so that side effects (eg, negative) may occur.

In some embodiments, the sustained release formulation comprises a compound disclosed herein (e.g., a polymorph) or a pharmaceutically acceptable form thereof (e.g., a pharmaceutically acceptable salt, hydrate, solvate, chelate, to initially release an amount of the non-covalent complex, isomer, prodrug, and isotopically labeled derivative) and gradually and continuously release different amounts of the compound to maintain the level of therapeutic or prophylactic effect over an extended period of time. is designed In order to maintain a constant level of the compound of formula (I) in the body, the compound must be released from the dosage form at a rate that displaces the amount of drug metabolized and excreted from the body. The sustained release of an active agent can be stimulated by a variety of conditions including, but not limited to, pH, temperature, enzymes, water, or other physiological conditions or compounds.

In certain embodiments, the pharmaceutical composition may be administered using intravenous infusion, insertable osmotic pumps, transdermal patches, liposomes, or other modes of administration. In one embodiment, a pump may be used (Sefton,<i>CRC</i><i></i><i>Crit</i><i>. </i><i>Ref</i><i>. </i><i>Biomed</i><i>. Eng</i>. 14:201 (1987); Buchwald<i>et</i><i></i><i>al</i><i>., </i><i>Surgery</i> 88:507 (1980); Saudek<i>et</i><i></i><i>al</i><i>., N. Engl. J.</i><i>Med</i>. 321:574 (1989))]. In another embodiment, polymeric materials may be used. In another embodiment, a sustained-release system can be placed on an individual in an appropriate portion as measured by the physician's skill, ie, a skill requiring only a portion of systemic administration (see, e.g., Goodson,<i>Medical</i><i></i><i>Applications</i><i></i><i>of</i><i></i><i>Controlled</i><i></i><i>Release</i>, 115-138 (vol. 2, 1984)]). Literature [Langer,<i>Science</i> 249:1527-1533 (1990) discusses other sustained-release systems to be reviewed. One or more active agents may be combined with a solid internal matrix such as polymethylmethacrylate, polybutylmethacrylate, plasticized or unplasticized polyvinylchloride, plasticized nylon, plasticized polyethyleneterephthalate, natural rubber, polyisoprene , polyisobutylene, polybutadiene, polyethylene, ethylene-vinylacetate copolymer, silicone rubber, polydimethylsiloxane, silicone carbonate copolymer, hydrophilic polymers such as hydrogels of esters of acrylic acid and methacrylic acid, outer polymer membrane , such as polyethylene, polypropylene, ethylene/propylene copolymer, ethylene/ethyl acrylate copolymer, ethylene/vinylacetate copolymer, silicone rubber, polydimethyl siloxane, neoprene rubber, chlorinated polyethylene, polyvinylchloride, vinyl acetate, Collagen, cross-linked polyvinyl alcohol and cross-linked partially hydrolyzed polyvinyl acetate, surrounded by vinylidene chloride, a vinyl chloride copolymer comprising ethylene and propylene, ionomer polyethylene terephthalate, butyl rubber epichlorohydrin rubber, ethylene/vinyl alcohol copolymer insoluble in body fluids, ethylene/vinyl acetate/vinyl alcohol terpolymer, and ethylene/vinyloxyethanol copolymer. The one or more pharmaceutical agents are then diffused through the outer polymer membrane in a release rate controlling step. The percentage of active agent in such parenteral compositions is highly dependent on the particular nature as well as the needs of the individual.

<b>Dosage</b>

Compounds described herein (e.g., polymorphs) or pharmaceutically acceptable forms thereof (e.g., pharmaceutically acceptable salts, hydrates, solvates, chelates, non-covalent complexes, isomers, prodrugs, and isotopically labeled derivatives) of one or more of the compounds described herein, or pharmaceutically acceptable forms thereof (e.g., pharmaceutically acceptable salts, hydrates, solvates, chelates, non-covalent complexes, isomers, prodrugs, and isotopically labeled derivatives) ) and/or one or more additional therapeutic agents, such as one or more pharmaceutically acceptable excipients, in combination with a therapeutically effective amount of a chemotherapeutic agent. In some cases, a compound described herein, or a pharmaceutically acceptable form thereof, and an additional therapeutic agent are administered in separate pharmaceutical compositions and by different routes (eg, one therapeutic agent is administered orally and the other therapeutic agent is administered intravenously). may be administered (eg due to different physical and/or chemical properties). In other cases, the compound described herein, or a pharmaceutically acceptable form thereof, and the additional therapeutic agent may be administered separately but by the same route (eg, both orally or both intravenously). In other cases, a compound described herein or a pharmaceutically acceptable form thereof and an additional therapeutic agent may be administered in the same pharmaceutical composition.

In one embodiment, a polymorph provided herein may be administered in a dosage. It is known in the art that, due to possible intersubjective variability in pharmacokinetics, individualization of dosing regimens can be used as the optimal therapy. Administration for the compounds provided herein may be found to be routine experimentation in light of the disclosure.

In one embodiment, the amount of compound administered is dependent on the mammal being treated, the severity of the disorder or condition, the route of administration, the rate of administration, the batch of the compound, the rate of excretion or metabolism of the particular compound to be used , the rate of the extent of absorption, the duration of treatment; Other drugs, compounds and/or substances used in combination with the particular compound employed, the age, sex, weight, condition, general health and previous medical history of the patient being treated, the prescribing discretion of the physician, and factors well known in the medical arts will depend on In one embodiment, an effective dosage ranges from about 0.001 to about 100 mg/kg/day, or from about 1 to about 35 mg/kg/day, in single or divided doses.<i></i>In one embodiment, for a 70 kg human, an effective dosage can be in the amount of about 0.05 to 7 g/day, or about 0.05 to about 2.5 g/day. In some cases, dosage levels below the lower limit of the aforementioned range may be more appropriate, while in other cases higher dosages may still be employed provided they do not cause any deleterious side effects, such as, in some embodiments, such higher doses. A case in which a dose is divided into several small doses to be administered throughout the day.

In general, a suitable daily dosage of a compound described herein and/or a chemotherapeutic agent may, in some embodiments, be the lowest dosage at which the amount of compound is effective to produce a therapeutically effective amount. Such effective dosages will generally depend on the factors described above. Generally, when used for the referred effect, a dosage of a compound described herein will be from about 0.0001 to about 100 mg/day, or from about 0.001 to about 100 mg/day, or from about 0.01 to about 100 mg/day, or about 0.1 to about 100 mg/day, or about 0.0001 to about 500 mg/day, or about 0.001 to about 500 mg/day, or about 0.01 to 1000 mg/day, or about 0.01 to about 500 mg/day, or about 0.1 to about 500 mg/day, or about 1 to 50 mg/day, or about 5 to 40 mg/day. An exemplary dosage is about 10 to 30 mg/day. In some embodiments, for a 70 kg human, a suitable dosage is from about 0.05 to about 7 g/day, such as from about 0.05 to about 2.5 g/day. Actual dosage levels of the active ingredient in the pharmaceutical compositions described herein may vary to achieve an active ingredient effective to achieve a therapeutic response for a particular patient, composition, and mode of administration without being toxic to the patient. In some cases, dosage levels below the lower limit of the ranges described above may be more appropriate, while in other cases higher dosages may still be used, such as in some embodiments, if they do not cause any deleterious side effects. It is a case in which a dose is divided into several small doses to be administered throughout the day.

In some embodiments, a compound provided herein is administered as a single dose. In some embodiments, such administration is an infusion, such as an intravenous infusion, because the agent is introduced rapidly. In other embodiments, such administration is administered orally, such as for ease of administration and patient compliance. Also, other routes may be used as appropriate. In some embodiments, a single dose of a compound provided herein may be used for the treatment of an acute condition.

In some embodiments, a compound provided herein is administered in multiple doses. In one embodiment, the dosage may be about 1, 2, 3, 4, 5, 6 or more times per day. In one embodiment, the dosage may be about once a month, once every two weeks, once a week, or once every two days. In another embodiment, the compound provided herein and the other agent are administered from about once per day to about 6 times per day. In another embodiment, administration of the compounds and formulations provided herein continues for less than about 7 days. In another embodiment, administration continues for more than about 6, 10, 14, or 28 days, 2 months, 6 months, or 1 year. In some embodiments, continued administration is achieved and maintained until necessary. In some embodiments, a compound provided herein is administered in cycles (eg, a treatment period followed by a non-treatment period, the cycle repeated until needed).

In some embodiments, the compound may be administered once per day, once every other day, three times a week, twice a week, once a week, or twice a week. The dosing schedule is a "drug holiday", i.e., drug is administered for 2 weeks, rest for 1 week, administration for 3 weeks, rest period for 1 week, administration for 4 weeks, drug rest for 1 week, etc. may be included or continued without a drug break. The compounds may be administered orally, intravenously, intraperitoneally, topically, transdermally, intramuscularly, subcutaneously, intranasally, sublingually, or by any other route.

In one embodiment, the formulation provided herein will continue to be administered for as long as necessary. In some embodiments, a formulation provided herein is administered for more than 1, 2, 3, 4, 5, 6, 7, 14, or 28 days. In some embodiments, the formulation provided herein is administered for less than 28, 14, 7, 6, 5, 4, 3, 2, or 1 day. In some embodiments, an agent provided herein is administered chronically on an ongoing basis, such as treatment of a chronic disease.

In one embodiment, an effective amount of a compound provided herein is administered orally, parenterally, subcutaneously, intravenously, intraperitoneally, intramuscularly, intraarterially, topically, rectal, buccal, intranasal, transdermal, or similar utility as an inhalant. It can be administered in single or multiple administrations by any acceptable mode of administration. In one embodiment, the compound is administered orally as a single dose once per day. In other embodiments, the compound is administered orally in multiple doses, such as two, three or more times per day.

In certain embodiments, the compound is administered orally, such as about 50 mg or less, about 40 mg or less, about 30 mg or less, about 25 mg or less, about 20 mg or less, about 15 mg or less, about 12.5 mg or less, about 10 mg or less. or less, about 5 mg or less, about 4 mg or less, about 3 mg or less, about 2 mg or less, or about 1 mg or less (e.g., about 0.9 mg, about 0.8 mg, about 0.7 mg, about 0.6 mg, about 0.5 mg, about 0.4 mg, about 0.3 mg, about 0.2 mg, about 0.1 mg, or about 0.05 mg or less) once a day as a single dose. In certain embodiments, the compound is administered orally, such as about 0.05 to about 50 mg, about 0.1 to about 45 mg, about 0.2 to about 40 mg, about 0.5 to about 35 mg, about 0.7 to about 30 mg, about 1 to about 30 mg, about 2 to about 25 mg, about 5 to about 20 mg, about 7 to about 15 mg, about 10 to about 12 mg, about 5 to about 10 mg, about 1 to about 5 mg, about 0.01 to about A single dose of 1 mg, about 0.01 to about 0.05 mg, or about 0.05 to about 1 mg, once daily.

In certain embodiments, the compound is administered in multiple doses per day (e.g., twice per day), such as orally, wherein each dose is about 50 mg or less, about 40 mg or less, about 30 mg or less, about 25 mg or less, about 20 mg or less, about 15 mg or less, about 12.5 mg or less, about 10 mg or less, about 5 mg or less, about 4 mg or less, about 3 mg or less, about 2 mg or less, or about 1 mg or less ( for example, about 0.9 mg, about 0.8 mg, about 0.7 mg, about 0.6 mg, about 0.5 mg, about 0.4 mg, about 0.3 mg, about 0.2 mg, about 0.1 mg, or about 0.05 mg or less). In certain embodiments, the compound is administered, e.g., orally, in multiple doses per day (e.g., twice per day), wherein each dose ranges from about 0.05 to about 50 mg, about 0.1 to about 45 mg, about 0.2 to about 40 mg, about 0.5 to about 35 mg, about 0.7 to about 30 mg, about 1 to about 30 mg, about 2 to about 25 mg, about 5 to about 20 mg, about 7 to about 15 mg, about 10 to about 12 mg, about 5 to about 10 mg, about 1 to about 5 mg, about 0.01 to about 1 mg, about 0.01 to about 0.05 mg, or about 0.05 to about 1 mg.

Because the compounds described herein may be administered in combination with other treatments (eg, additional chemotherapy, radiation or surgery), the dosage of each agent or therapeutic agent may be less than the corresponding dosage for a single-agent therapeutic agent. . Dosages for single-agent therapeutics may be, for example, from about 0.0001 to about 200 mg, or from about 0.001 to about 100 mg, or from about 0.01 to about 100 mg, or from about 0.1 to about 100 mg, or from about 0.05 to about 50 mg per day. , or from about 1 to about 50 mg.

When a compound provided herein is administered in a pharmaceutical composition comprising one or more agents and the agent has a shorter half-life than the compound provided herein, it may be adjusted according to the agent provided herein and the unit dosage form of the compound.

In one embodiment, the composition is characterized in that it comprises a compound of formula (I) (e.g., a composition comprising one or more polymorphic forms of a compound of formula (I), such as polymorph Form C), wherein the active compound is administered once per day (QD ) when administered in an amount of 0.05 to 50 mg twice per day (BID), at least about 0.5 ng*hr/mL, at least about 1 ng*hr/mL, at least about 2.5 ng*hr/mL, at least about 5 ng* hr/mL or greater, about 10 ng*hr/mL or greater, about 25 ng*hr/mL or greater, about 50 ng*hr/mL or greater, about 100 ng*hr/mL or greater, about 150 ng*hr/mL or greater, about 200 ng*hr/mL or more, about 250 ng*hr/mL or more, about 300 ng*hr/mL or more, about 500 ng*hr/mL or more, about 750 ng*hr/mL or more, about 850 ng*hr /mL or more, about 950 ng*hr/mL or more, about 1,000 ng*hr/mL or more, about 1,500 ng*hr/mL or more, About 2,000 ng*hr/mL or more, about 3,000 ng*hr/mL or more, about 5,000 ng*hr/mL or more, about 10,000 ng*hr/mL or more, about 12,000 ng*hr/mL or more, about 15,000 ng*hr /mL or more, about 20,000 ng*hr/mL or more, about 25,000 ng*hr/mL or more, about 30,000 ng*hr/mL or more, about 50,000 ng*hr/mL or more, about 75,000 ng*hr/mL or more, about A concentration time curve, AUC (e.g., AUC) of at least 100,000 ng*hr/mL, at least about 200,000 ng*hr/mL, or at least about 300,000 ng*hr/mL₀_-24 or AUC_tauss) to produce a sufficient amount of compound to achieve an average constant state region. In certain embodiments, when the active compound is administered in the range of about 0.05 mg QD to about 50 mg BID, the AUC (eg, AUC₀_-24 or AUC_tauss) is about 5 ng*hr/mL or more, about 50 ng*hr/mL or more, about 100 ng*hr/mL or more, about 150 ng*hr/mL or more, about 200 ng*hr/mL or more, about 300 ng*hr/mL or greater, about 400 ng*hr/mL or greater, about 500 ng*hr/mL or greater, about 600 ng*hr/mL or greater, about 700 ng*hr/mL or greater, about 800 ng*hr/mL or greater or more, about 900 ng*hr/mL or more, about 1,000 ng*hr/mL or more, about 1,500 ng*hr/mL or more, about 2,000 ng*hr/mL or more, about 2,500 ng*hr/mL or more, about 3,000 ng *hr/mL or more, about 5,000 ng*hr/mL or more, about 10,000 ng*hr/mL or more, about 15,000 ng*hr/mL or more, about 20,000 ng*hr/mL or more, about 25,000 ng*hr/mL or more , or about 30,000 ng*hr/mL or more. In other embodiments, when the active compound is administered in the range of about 0.05 mg QD to about 50 mg BID, the AUC (eg, AUC₀_-24 or AUC_tauss) is from about 0.5 to about 300,000 ng*hr/mL, from about 1 to about 200,000 ng*h/mL, from about 2.5 to about 250,000 ng*hr/mL, from about 5 to about 30,000 ng*hr/mL, from about 10 to about 200,000 ng*hr/mL, about 25 to about 100,000 ng*hr/mL, about 50 to about 75,000 ng*hr/mL, about 100 to about 50,000 ng*hr/mL, about 200 to about 40,000 ng*hr/mL mL, about 500 to about 30,000 ng*hr/mL, about 1,000 to about 25,000 ng*hr/mL, about 700 to about 15,000 ng*hr/mL, about 500 to about 10,000 ng*hr/mL, about 1,000 to about 5,000 ng*hr/mL, about 10,000 to about 50,000 ng*hr/mL, about 20,000 to about 40,000 ng*hr/mL, or about 25,000 to about 30,000 ng*hr/mL. In one embodiment, when the active compound is administered in the range of about 0.05 mg QD to about 50 mg BID, the AUC (eg, AUC₀_-24 or AUC_tau ss) is about 5 to about 30,000 ng*hr/mL, about 1000 to about 15,000 ng*hr/mL, about 2500 to about 10,000 ng*hr/mL, about 100 to about 3,500 ng*hr/mL, about 145 to about 3,000 ng*hr/mL, about 250 to about 2,500 ng*hr/mL, about 300 to about 2,500 ng*hr/mL, about 500 to about 2,300 ng*hr/mL, about 800 to about 2,200 ng*hr/mL mL, about 140 to about 900 ng*hr/mL, about 500 to about 10,000 ng*hr/mL, about 1,000 to about 5,000 ng*hr/mL, about 10,000 to about 50,000 ng*hr/mL, about 20,000 to about 40,000 ng*hr/mL, or from about 25,000 to about 30,000 ng*hr/mL.

In one embodiment, when the active compound is administered to a human in a single oral dose of from about 1 to about 30 mg once a day, a composition comprising a compound of formula (I) comprises at least about 40 ng*hr/mL, About 50 ng*hr/mL or more, about 75 ng*hr/mL or more, about 100 ng*hr/mL or more, about 150 ng*hr/mL or more, about 200 ng*hr/mL or more, about 300 ng*hr /mL or greater, about 400 ng*hr/mL or greater, about 500 ng*hr/mL or greater, about 600 ng*hr/mL or greater, about 700 ng*hr/mL or greater, about 800 ng*hr/mL or greater, about 900 ng*hr/mL or more, about 1,000 ng*hr/mL or more, about 1,500 ng*hr/mL or more, about 2,000 ng*hr/mL or more, about 2,500 ng*hr/mL or more, about 3,000 ng*hr/mL mL or more, about 5,000 ng*hr/mL or more, about 10,000 ng*hr/mL or more, An AUC of at least about 15,000 ng*hr/mL, at least about 20,000 ng*hr/mL, at least about 30,000 ng*hr/mL, or at least about 50,000 ng*hr/mL, such as an AUC₀_-24A sufficient amount of the compound can be produced to achieve In one embodiment, the AUC of the composition, such as the AUC, when the active compound is administered as a single oral, once per day (QD) in the range of about 1 to about 30 mg.₀_-24is about 5 to about 30,000 ng*hr/mL, about 100 to about 3,500 ng*hr/mL, about 145 to about 3,300 ng*hr/mL, about 200 to about 2,500 ng*hr/mL, about 300 to about 2,100 ng*hr/mL, about 500 to about 2,000 ng*hr/mL, about 500 to about 5,000 ng*hr/mL, about 1,000 to about 10,000 ng*hr/mL, about 10,000 to about 50,000 ng*hr/mL, from about 20,000 to about 40,000 ng*hr/mL, or from about 25,000 to about 30,000 ng*hr/mL.

In another embodiment, the active compound is administered at about 1 to about 10 mg (e.g., 1, 2, 5, and 10 mg repeated administrations (e.g., the dosage is QD on days 1 and 14, and 1 on days 2-13) When administered at a dose of at least twice daily (BID) evaluated on day 14), a composition comprising a compound of formula (I) is at least about 100 ng*hr/mL, at least about 200 ng*hr/mL, About 500 ng*hr/mL or more, about 700 ng*hr/mL or more, about 1,000 ng*hr/mL or more, about 1,200 ng*hr/mL or more, about 1,500 ng*hr/mL or more, about 2,000 ng*hr /mL or more, about 2,500 ng*hr/mL or more, about 3,000 ng*hr/mL or more, about 5,000 ng*hr/mL or more, about 10,000 ng*hr/mL or more, about 15,000 ng*hr/mL or more, about 20,000 ng*hr/mL or greater, about 25,000 ng*hr/mL or greater; or a concentration time curve of greater than or equal to about 30,000 ng*hr/mL (AUC_tau ss) to produce a sufficient amount of compound to achieve an average constant state region. In one embodiment, the active compound is administered at about 1 to about 10 mg (e.g., 1, 2, 5, and 10 mg repeated administrations (e.g., the dosage is QD on days 1 and 14, and 1 on days 2-13) The composition's AUC, e.g., AUC, when administered at a dose of twice daily (BID))_tau ss is about 5 to about 30,000 ng*hr/mL, about 100 to about 3,500 ng*hr/mL, about 150 to about 3,300 ng*hr/mL, about 200 to about 2,500 ng*hr/mL, about 300 to about 2,500 ng*hr/mL, about 500 to about 5,000 ng*hr/mL, about 1,000 to about 10,000 ng*hr/mL, about 10,000 to about 50,000 ng*hr/mL, about 20,000 to about 40,000 ng*hr/mL , or from about 25,000 to about 30,000 ng*hr/mL. As used herein, "AUC₀_-24" refers to the area post-administered for up to 24 hours under the mean steady-state serum concentration-time curve. "AUC_tauss" is the AUC for QD dose₀_-24, and AUC for the BID dose₀_-12refers to AUC corresponds to the area under plasma concentration-time over the interval. AUC values are given in ng hours per mL, abbreviated herein as ng hr/mL or ng*h/mL. AUC values can be found in the art, such as in Goodman and Gilman's The Pharmacological Basis of Therapeutics, 10th ed.; Hardman, JG, Limbird, LE, Eds.; McGraw-Hill: New York, 2001].

In another embodiment, a composition comprising a compound of formula (I) (eg, a composition comprising one or more polymorphic forms of a compound of formula (I), such as polymorph Form C), is disclosed, wherein the active compound is administered once per day (QD). When administered in the range of 0.05 mg to 50 mg twice daily (BID), it is about 0.05 ng/mL or greater, about 0.1 ng/mL or greater, about 0.5 ng/mL or greater, about 1 ng/mL or greater, about 10 ng/mL or greater, about 50 ng/mL or greater, about 100 ng/mL or greater, about 150 ng/mL or greater, about 200 ng/mL or greater, about 300 ng/mL or greater, about 400 ng/mL or greater, about 500 ng /mL or more, about 900 ng/mL or more, about 1,000 ng/mL or more, about 2,000 ng/mL or more, about 3,000 ng/mL or more, about 4,000 ng/mL or more, about 5,000 ng/mL or more, about 10,000 ng/mL or more mL or greater, about 20,000 ng/mL or greater, It can produce an observed maximum plasma concentration (Cmax) of about 30,000 ng/mL or greater, or about 40,000 ng/mL or greater. In other embodiments, when the active compound is administered in the range of from about 0.05 mg QD to about 50 mg BID, the Cmax of the composition is about 20 ng/mL or greater, about 40 ng/mL or greater, about 50 ng/mL or greater, about 80 ng/mL or more, about 100 ng/mL or more, about 200 ng/mL or more, about 500 ng/mL or more, about 750 ng/mL or more, about 1,000 ng/mL or more, about 1,500 ng/mL or more, about 5,000 ng/mL or greater, about 10,000 ng/mL or greater, about 15,000 ng/mL or greater, about 20,000 ng/mL or greater, about 30,000 ng/mL or greater, or about 40,000 ng/mL or greater. In other embodiments, when the active compound is administered in a range from about 0.05 mg QD to about 50 mg BID, the Cmax of the composition is from about 0.5 to about 40,000 ng/mL, from about 0.1 to about 20,000 ng/mL, from about 1 to about 20,000 ng/mL, about 0.5 to about 4,000 ng/mL, about 0.5 to about 10,000 ng/mL, about 1 to about 3,000 ng/mL, about 10 to about 2,000 ng/mL, about 40 to about 1,500 ng/mL, about 150 to about 1,000 ng/mL, about 200 to about 500 ng/mL, about 300 to about 400 ng/mL, about 500 to 1,000 ng/mL, about 1,000 to about 5,000 ng/mL, about 5,000 to about 10,000 ng /mL, about 10,000 to about 20,000 ng/mL, about 20,000 to about 30,000 ng/mL, or about 30,000 to about 40,000 ng/mL. In one embodiment, when the active compound is administered in the range of about 0.05 mg QD to about 50 mg BID, the Cmax of the composition is from about 0.5 to about 4,000 ng/mL, from about 20 to about 1,500 ng/mL, from about 40 to about 1,100 ng/mL, about 50 to about 1,000 ng/mL, about 80 to about 900 ng/mL, about 100 to about 500 ng/mL, about 200 to about 450 ng/mL, about 500 to about 1,000 ng/mL , about 1,000 to about 5,000 ng/mL, about 5,000 to about 10,000 ng/mL, about 10,000 to about 20,000 ng/mL, about 20,000 to about 30,000 ng/mL, or about 30,000 to about 40,000 ng/mL.

In one embodiment, when the active compound is administered to a human in a single oral administration of about 1 to about 30 mg once per day (QD), the composition comprising the compound of Formula I is at least about 20 ng/mL, about 40 ng/mL or greater, about 50 ng/mL or greater, about 80 ng/mL or greater, about 100 ng/mL or greater, about 200 ng/mL or greater, about 500 ng/mL or greater, about 750 ng/mL or greater, about 1,000 ng /mL or greater, or about 1,500 ng/mL or greater. In other embodiments, when the active compound is administered to a human at a single oral dose of about 1 to about 30 mg once per day (QD), the Cmax of the composition is from about 20 to about 1,500 ng/mL, from about 40 to about 1,200 ng. /mL, about 50 to about 1,000 ng/mL, about 80 to about 1,000 ng/mL, about 100 to about 500 ng/mL, about 200 to about 450 ng/mL, about 500 to about 1,000 ng/mL, about 1,000 to about 5,000 ng/mL, about 5,000 to about 10,000 ng/mL, about 10,000 to about 20,000 ng/mL, about 20,000 to about 30,000 ng/mL, or about 30,000 to about 40,000 ng/mL.

In another embodiment, the active compound is administered at about 1 to about 10 mg (e.g., 1, 2, 5, and 10 mg repeated administrations (e.g., the dosage is QD on days 1 and 14, and 1 on days 2-13) When administered at a dose of twice daily (BID)) evaluated on day 14), a composition comprising a compound of formula (I) is at least about 40 ng/mL, at least about 50 ng/mL, at least about 60 ng/mL mL or greater, about 100 ng/mL or greater, about 200 ng/mL or greater, about 300 ng/mL or greater, about 400 ng/mL or greater, about 500 ng/mL or greater, about 590 ng/mL or greater, about 750 ng/mL or greater or more, about 1,000 ng/mL or more, about 1,500 ng/mL or more, about 5,000 ng/mL or more, about 10,000 ng/mL or more, about 15,000 ng/mL or more, about 20,000 ng/mL or more, about 30,000 ng/mL or more , or an amount of compound sufficient to achieve a Cmax of at least about 40,000 ng/mL. In one embodiment, the active compound is administered in repeated doses of 1 mg (BID), 2 mg (BID), 5 mg (BID), or 10 mg (QD) (eg, repeated doses of 1, 2, 5, and 10 mg). When administered by dosing (e.g., the dose is QD on days 1 and 14, and twice daily (BID) on days 2-13), assessed on day 14), C) wherein the composition comprises about 50 to about 600 ng/mL, about 60 to about 400 ng/mL, about 100 to about 360 ng/mL, about 140 to about 250 ng/mL, about 250 to about 1,000 ng/mL mL, from about 1,000 to about 5,000 ng/mL, from about 5,000 to about 10,000 ng/mL, from about 10,000 to about 20,000 ng/mL, from about 20,000 to about 30,000 ng/mL, or from about 30,000 to about 40,000 ng/mL Cmax can be generated.

In one embodiment, when the active compound is administered to a human at a single oral dose of 1 to 30 mg once per day (QD), the composition comprising the compound of formula (I) is at least 3 hours, at least 5 hours, at least 6 hours. , a half-life of at least 7 hours, at least 8 hours, or at least 10 hours (t₁_/2) has In another embodiment, when the active compound is administered to a human at a single oral dose of 1 to 30 mg once per day (QD), a composition comprising a compound of formula (I) has a half-life (t) of about 3 to 10 hours.₁_/2) has

Cmax and half-life (t₁_/2) values are found in the art, such as in Goodman and Gilman's The Pharmacological Basis of Therapeutics, 10th ed.; Hardman, JG, Limbird, LE, Eds.; McGraw-Hill: New York, 2001]. In one embodiment, the half-life (t₁_/2) to 0.693/k_el(terminal removal).

<b>kit</b>

In another embodiment, the present invention provides a kit. In one embodiment, the kit comprises a compound or polymorph or a pharmaceutically acceptable form thereof (e.g., a pharmaceutically acceptable salt, hydrate, solvate, chelate, non-covalent complex, isomer, prodrug thereof) described herein in suitable packing. , and isotopically labeled derivatives), and written materials that may contain references for use, discussion of clinical studies, listed side effects, and the like. In addition, such kits may contain information that refers to the activity and/or benefits of a compound or composition and/or describes dosage, administration, side effects, drug interactions, such as scientific references, package inserts, clinical trial results, and/or or a summary thereof, etc. and/or other information useful to health care providers. Such information may be based on the results of various studies, such as studies using animal experiments involving in vivo models or studies based on human clinical trials.

In some embodiments, a memory aid is provided in the kit, such as in the form of a number next to a tablet or capsule, wherein the number corresponds to the number of days of the regimen in which the tablet or capsule specified above should be ingested. Another example of a memory aid is a calendar printed on a card, such as "first week, monday, tuesday, etc., second week, monday, tuesday, etc.". Other variations of the memory aid will be readily apparent. A "daily dose" may be a single tablet or capsule or several tablets or capsules administered for a given day.

Provided pharmaceutical packs and/or kits may include provided compositions and containers (eg, vials, ampoules, bottles, syringes and/or dispenser packages, or other suitable containers). In some embodiments, provided kits can optionally further comprise a second container comprising a suitable aqueous carrier for a dilution or suspension of a provided composition for administration to an individual. In some embodiments, the contents of a provided formulation container and solvent container are combined to form one or more single formulations.

In one embodiment, a single container may comprise one or more compartments containing a provided composition, and/or a suitable aqueous carrier for suspension or dilution. In some embodiments, a single vessel may be suitable for modification, such that the vessel may be subjected to a physical modification for combination of compartments and/or components of individual compartments. For example, a foil or plastic bag may include two or more compartments separated by a perforated seal that can break for combination of components of the two separate compartments when a signal to break the seal is generated. Accordingly, a pharmaceutical pack or kit may comprise such a multi-compartment container comprising a provided composition for suspension and an appropriate solvent and/or an appropriate aqueous carrier.

In some embodiments, the kit may contain another agent. In some embodiments, a compound provided herein, or a pharmaceutically acceptable form thereof (e.g., a pharmaceutically acceptable salt, hydrate, solvate, chelate, non-covalent complex, isomer, prodrug, and isotopically labeled derivative thereof) ) and the second agent are provided as separate compositions in separate containers within the kit. In some embodiments, a compound provided herein, or a pharmaceutically acceptable form thereof (e.g., a pharmaceutically acceptable salt, hydrate, solvate, chelate, non-covalent complex, isomer, prodrug, and isotopically labeled derivative thereof) ) and the second agent are provided as a single composition in a container in the kit. Suitable packages and additional articles for use (eg, measuring cups for liquid formulations, foil wraps to minimize exposure to air, etc.) are known in the art and can be included in kits. The kits described herein may be provided, sold, and/or promoted to health care providers, including doctors, nurses, pharmacists, chemical researchers, and the like. Also, in some embodiments, the kit may be sold directly to a consumer.

An example of such a kit is a so-called blister pack. Blister packs are well known in the packing industry and are widely used for packing pharmaceutical single dosage forms (tablets, capsules, etc.). Blister packs generally consist of a sheet of relatively stiff material covered with a foil of preferably transparent plastic material. During the packing process, a recess is formed in the plastic foil. The recess has the size and shape of the tablet or capsule to be packed. The tablet or capsule is then placed in the recess and the sheet of relatively stiff material is sealed in plastic foil with the foil side opposite to the direction in which the recess was formed. As a result, the tablet or capsule is sealed between the plastic foil and the sheet in the recess. The strength of the sheet is such that the tablet or capsule can be removed from the blister pack by applying pressure by hand over the recess so that a void is formed in the sheet at the face of the recess. The tablet or capsule may then be removed through the void.

Kits may also include a pharmaceutically acceptable vehicle that may be used to administer one or more active agents. For example, where the active agent is provided in solid form that must be reduced for parenteral administration, the kit may comprise a sealed container of a suitable vehicle, in which the active agent is dissolved and a sterile, particulate-free solution suitable for parenteral administration. can form. Examples of pharmaceutically acceptable vehicles include, but are not limited to, water for injection USP; aqueous vehicles such as, but not limited to, sodium chloride injection solution, Ringer's solution, dextrose injection solution, dextrose and sodium chloride injection solution, and lactated Ringer's solution; water-miscible vehicles such as, but not limited to, ethyl alcohol, polyethylene glycol, and polypropylene glycol; and non-aqueous vehicles such as, but not limited to, corn oil, cottonseed oil, peanut oil, sesame oil, ethyl oleate, isopropyl myristate, and benzyl benzoate.

The present invention also encompasses anhydrous pharmaceutical compositions and formulations comprising the active ingredient, since water may facilitate the degradation of some compounds. For example, in the pharmaceutical field, water may be added (eg, about 5%) as a means to stimulate long-term storage to determine properties such as half-life or stability of formulations over time. Anhydrous pharmaceutical compositions and formulations can be prepared using anhydrous or low moisture containing ingredients and low moisture or low humidity conditions. For example, pharmaceutical compositions and formulations containing lactose may be anhydrous if significant contact with moisture and/or moisture is expected during manufacture, packing and/or storage. Anhydrous pharmaceutical compositions can be prepared and stored to maintain anhydrous properties. Accordingly, anhydrous pharmaceutical compositions may be packaged using known materials to prevent exposure to water, which may be included in a suitable chemical kit. Examples of suitable packing include, but are not limited to, sealed foil, single dose containers such as plastic, blister packs, and strip packs.

In one embodiment, the polymorphs described herein, or pharmaceutically acceptable forms thereof (e.g., pharmaceutically acceptable salts, hydrates, solvates, chelates, non-covalent complexes, isomers, prodrugs, and isotopically labeled derivatives) may be used in combination with the agents disclosed herein or other suitable agents depending on the condition to be treated. Thus, in some embodiments, a polymorph provided herein, or a pharmaceutically acceptable form thereof (e.g., a pharmaceutically acceptable salt, hydrate, solvate, chelate, non-covalent complex, isomer, prodrug, and isotopically labeled derivatives) can be co-administered with other agents described herein. When using combination administration, the polymorphs described herein, or pharmaceutically acceptable forms thereof (e.g., pharmaceutically acceptable salts, hydrates, solvates, chelates, non-covalent complexes, isomers, prodrugs, and isotopically labeled derivative) may be administered simultaneously or separately with the second agent. Such combined administration may include simultaneous administration of two agents of the same formulation, simultaneous administration of separate formulations, and separate administration. In some embodiments, the polymorph described herein and any second agent described herein can be combined in the same formulation or administered simultaneously. Alternatively, in some embodiments, a polymorph described herein or a pharmaceutically acceptable form thereof (e.g., a pharmaceutically acceptable salt, hydrate, solvate, chelate, non-covalent complex, isomer, prodrug, and isotopic) ) and any of the second agents described herein may be administered simultaneously, wherein both agents are in separate formulations. In another alternative, the polymorphs described herein, or pharmaceutically acceptable forms thereof (e.g., pharmaceutically acceptable salts, hydrates, solvates, chelates, non-covalent complexes, isomers, prodrugs, and isotopically labeled derivative) may be administered after or prior to administration of any of the second agents described herein. In separate administration protocols, polymorphs provided herein or pharmaceutically acceptable forms thereof (e.g., pharmaceutically acceptable salts, hydrates, solvates, chelates, non-covalent complexes, isomers, prodrugs, and isotopically labeled derivative) and any second agent described herein may be administered several minutes apart, or several hours apart, or several days apart.

<b>IV</b><b>. treatment method</b>

Phosphoinositide 3-kinases (PI3Ks) are members of a conserved family of lipid kinases that regulate numerous cellular functions including proliferation, differentiation, cell survival and metabolism. class IA subpopulations that are normally activated by receptor tyrosine kinases (RTKs) (eg, PI3K-α, β, δ); Several classes of PI3Ks exist in mammalian cells, including class IB (eg, PI3K-γ) that are activated by G-protein coupled receptors and the like. PI3K is the second messenger phosphatidylinositol, 3,4,5-triphosphate at the cell membrane via the "PI3K-mediated signaling pathway", which involves several components that directly and/or indirectly transmit signals triggered by PI3K. (PIP3), the activation of heterotrimeric G protein signaling, and the production of additional second messengers such as cAMP, DAG, and IP3, all of which induce a broad cascade of protein kinase activity. (Vanhaesebroeck, B. <i>et</i><i></i><i>al</i>.(2001) <i>Annu</i><i></i><i>Rev</i><i></i><i>Biochem</i>. 70:535-602]. For example, PI3K-δ is activated by cellular receptors through interactions between the PI3K regulatory subunit (p85) SH2 domains, or directly with RAS. PIP3, produced by PI3K, activates a down-acting pathway through interaction with enzyme-containing plextrin homology (PH) domains (e.g., PDK-1 and AKT[PKB]) (Fung-Leung WP. 2011)<i>Cell</i><i></i><i>Signal</i>. 23(4):603-8]). Unlike PI3K-δ, PI3K-γ is not a class 1A PI3K and is not associated with regulatory subunits of the P85 family, but with regulatory subunits within the p101 family. PI3K-γ is associated with a G-protein coupled receptor (GPCR), is associated with the very rapid uptake of PIP3, and can also be activated by RAS.

In some embodiments, the invention provides a kinase to a compound, or a pharmaceutically acceptable form thereof (e.g., a pharmaceutically acceptable salt, hydrate, solvate, chelate, non-covalent complex, isomer, prodrug, and isotopically labeled derivative), or a pharmaceutical composition disclosed herein, in an effective amount. Modulation may inhibit or activate kinase activity. In some embodiments, the present invention provides methods of inhibiting kinase activity by contacting the kinase with an effective amount of a compound disclosed herein in solution. In some embodiments, the present invention provides a method of inhibiting kinase activity by contacting it with a cell, tissue, or organ expressing a kinase of interest. In some embodiments, the present invention provides methods of inhibiting kinase activity by administering to an individual an effective amount of a compound disclosed herein.

In some embodiments, the invention provides a method of inhibiting kinase activity in solution by contacting said solution with a compound provided herein in an amount sufficient to inhibit the activity of a kinase in solution. In some embodiments, the invention provides a method of inhibiting kinase activity in a cell by contacting said cell with a compound disclosed herein in an amount sufficient to inhibit the activity of a kinase in said cell. In some embodiments, the invention provides a method of inhibiting kinase activity in a tissue by contacting the tissue with a compound provided herein in an amount sufficient to inhibit kinase activity in said tissue. In some embodiments, the invention provides a method of inhibiting kinase activity in an organ by contacting the organ with a compound provided herein in an amount sufficient to inhibit kinase activity in the organ. In some embodiments, the invention provides a method of inhibiting kinase activity in an animal by contacting the animal with a compound provided herein in an amount sufficient to inhibit kinase activity in said animal. In some embodiments, the invention provides a method of inhibiting kinase activity in a mammal by contacting the mammal with a compound provided herein in an amount sufficient to inhibit kinase activity in said mammal. In some embodiments, the invention provides a method of inhibiting kinase activity in a human by contacting the human with a compound provided herein in an amount sufficient to inhibit kinase activity in said human.

In some embodiments, after contacting the kinase with a compound provided herein, the % of kinase activity is about 1, about 5, about 10, about 20, about 30, about 40, about 50, less than about 60, about 70, about 80, about 90, about 95, or about 99%. In some embodiments, the % inhibition is greater than about 25%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, or about 90%. In some embodiments, the invention provides a method of inhibiting PI3 kinase activity in an individual (including a mammal, such as a human) by contacting the individual with a compound disclosed herein in an amount sufficient to inhibit the activity of the PI3 kinase in the individual. provides

In some embodiments, the kinase is a lipid kinase or a protein kinase. In some embodiments, the kinase is in different isoforms, such as PI3 kinase α, PI3 kinase β, PI3 kinase γ, PI3 kinase δ; DNA-PK; mTor; Abl, VEGFR, ephrin receptor B4 (EphB4); TEK receptor tyrosine kinase (TIE2); FMS-associated tyrosine kinase 3 (FLT-3); platelet-derived growth factor receptor (PDGFR); RET; ATM; ATR; hSmg-1; Hck; Src; epidermal growth factor receptor (EGFR); KIT; PI3 kinases including insulin receptor (IR) and IGFR.

Also in one embodiment, the invention provides a method of modulating PI3 kinase activity by contacting the PI3 kinase with a compound provided herein in an amount sufficient to modulate the activity of the PI3 kinase. Modulation may inhibit or activate PI3 kinase activity. In some embodiments, the invention provides a method of inhibiting PI3 kinase activity by contacting the PI3 kinase with a compound provided herein in an amount sufficient to inhibit the activity of the PI3 kinase. In some embodiments, the present invention provides methods of inhibiting PI3 kinase activity. In some embodiments, such inhibition may occur in solution, in a cell expressing one or more PI3 kinases, in a tissue comprising cells expressing one or more PI3 kinases, or in an organ expressing one or more PI3 kinases. In some embodiments, the invention provides a method of inhibiting PI3 kinase activity in an animal (including a mammal, such as a human) by contacting the animal with a compound provided herein in an amount sufficient to inhibit the activity of the PI3 kinase in the animal. provides

As used herein, "PI3K-mediated disease" refers to a disease or condition associated with an aberrant PI3K-mediated signaling pathway. In one embodiment, the invention provides a method of treating a PI3K-mediated disease in an individual, the method comprising administering a therapeutically effective amount of a compound or pharmaceutical composition disclosed herein. In some embodiments, the present invention provides a method of treating a PI3K-δ or PI3K-γ mediated disease in an individual, the method comprising administering a therapeutically effective amount of a compound or pharmaceutical composition disclosed herein. In some embodiments, the present invention provides a method of inhibiting one or more PI3K-δ or PI3K-γ, comprising administering a therapeutically effective amount of a compound or composition disclosed herein in vitro or in vivo to a cell expressing PI3K; including contact. PI3K is associated with several conditions including immunity, cancer and thrombosis (Vanhaesebroeck, B.<i>et</i><i></i><i>al</i>.(2010) <i>Current</i><i></i><i>Topics</i><i></i><i>in</i><i></i><i>Microbiology</i><i></i><i>and</i><i> Immunology</i>, DOI 10.1007/82_2010_65]). For example, class I PI3Ks, particularly PI3K-γ and PI3K-δ isoforms, are highly expressed in leukocytes and are associated with adaptive and innate immunity; This PI3K is believed to be an important regulator in inflammatory diseases and hematologic tumors (Harris, SJ et al. (2009)).<i>Curr</i><i></i><i>Opin</i><i></i><i>Investig</i> Drugs 10(11):1151-62)]; [Rommel C. et al. (2007)<i>Nat</i><i></i><i>Rev</i><i></i><i>Immunol</i> 7(3):191-201]; [Durand CA<i>et</i><i> al</i>.(2009) <i>J </i><i>Immunol</i>. 183(9):5673-84]; [Dil N, Marshall AJ. (2009)<i>Mol</i><i></i><i>Immunol</i>. 46(10):1970-8]; [Al-Alwan MM<i>et</i><i></i><i>al</i>.(2007) <i>J </i><i>Immunol</i>. 178(4):2328-35]; [Zhang TT,<i>et</i><i></i><i>al</i>.(2008) <i>J Allergy Clin Immunol</i>. 2008;122(4):811-819.e2]; [Srinivasan L,<i>et</i><i></i><i>al</i>.(2009) <i>Cell</i> 139(3):573-86].

Numerous publications support a role for PI3K-δ, PI3K-γ, and PI3K-β in the differentiation, maintenance, and activity of immune and malignant cells, as detailed below.

The importance of PI3K-δ in the development and function of B-cells is supported by inhibitor studies and genetic models. PI3K-δ is an important mediator of B-cell receptor (BCR) signaling and upregulates AKT, calcium flux, PLCγ, MAP kinase, P70S6k, and FOXO3a activity. In addition, PI3K-δ is important in IL4R, S1P, and CXCR5 signaling and has been shown to modulate responses to toll-like receptors 4 and 9. Inhibitors of PI3K-δ inhibit PI3K- in the regulation of immunoglobulin floating switching leading to B-cell development (band and B1 cells), B-cell activity, chemotaxis, migration and homing to lymphoid tissue, and production of IgE. shows the importance of δ (Clayton E et al. (2002)<i>J </i><i>Exp</i><i></i><i>Med</i>. 196(6):753-63]; [Bilancio A, et al. (2006)<i>Blood</i> 107(2):642-50]; [Okkenhaug K. et al. (2002)<i>Science</i><i></i>297(5583):1031-4]; [Al-Alwan MM<i>et</i><i></i><i>al</i>.(2007) <i>J </i><i>Immunol</i>. 178(4):2328-35]; [Zhang TT,<i>et</i><i></i><i>al</i>.(2008) <i>J </i><i>Allergy</i><i></i><i>Clin</i><i></i><i>Immunol</i>. 2008;122(4):811-819.e2]; [Srinivasan L,<i>et</i><i></i><i>al</i>.(2009) <i>Cell</i> 139(3):573-86]).

In T-cells, PI3K-δ has been demonstrated to have a role in T-cell receptor and cytokine signaling and is upstream of AKT, PLCγ, and GSK3b. In PI3K-δ deletion or kinase-dead knock-in mice, or inhibitor studies, T-cell defects including proliferation, activation, and differentiation were observed, resulting in reduced T helper cells 2 (TH2) induces defects in response, memory T-cell specific defects (DTH reduction), defects in antigen-dependent cell trafficking, and chemokines (e.g., S1P, CCR7, CD62L) in chemotaxis/migration (Garcon F.<i>et</i><i></i><i>al</i>.(2008) <i>Blood</i> 111(3):1464-71]; [Okkenhaug K.<i>et</i><i></i><i>al</i><i>.(</i>2006). <i>J </i><i>Immunol</i>. 177(8):5122-8]; [Sound DR, et al. (2010)<i>Blood</i> 115(11):2203-13]; [Reif K, (2004). J Immunol. 2004;173(4):2236-40]; [Ji H.<i>et</i><i> al</i>.(2007) <i>Blood</i> 110(8):2940-7]; [Webb LM, et al. (2005))<i>J </i><i>Immunol</i>. 175(5):2783-7]; [Liu D,<i>et</i><i></i><i>al</i>.(2010) <i>J </i><i>Immunol</i>. 184(6):3098-105]; [Haylock-Jacobs S, et al. (2011)<i>J </i><i>autoimmune</i>. 2011;36(3-4):278-87]; [Jarmin SJ, et al. (2008)<i>J </i><i>Clin</i><i></i><i>Invest</i>. 118(3):1154-64]).

In neutrophils, PI3K-δ, like PI3K-γ, and PI3K-β, influences migration and response to immune complexes, FCgRII signals, including neutrophil respiratory rupture. Human neutrophils undergo rapid induction of PIP3 in response to formyl peptide receptor (FMLP) or complement binding C5a (C5a) in a PI3K-γ dependent manner, PI3K-δ dependent, and a long PIP3 production period critical for neutrophil respiratory rupture . The response to immune complexes is influenced by PI3K-δ, PI3K-γ, and PI3K-β and is an important mediator of temperamental damage in models of autoimmune diseases (Randis TM ).<i>et</i><i></i><i>al</i>.(2008) <i>Eur</i><i> J </i><i>Immunol</i>. 38(5): 1215-24]; [Pinho V, (2007)<i>J </i><i>Immunol</i>. 179(11):7891-8]; [Sadhu C.<i>et</i><i></i><i>al</i>.(2003) <i>J Immunol</i>. 170(5):2647-54]; [Condliffe AM et al. (2005))<i>Blood</i> 106(4):1432-40]).

In macrophages collected from patients with chronic obstructive pulmonary disease (COPD), glucocorticoid responsiveness can be restored by treating cells containing inhibitors of PI3K-δ. In addition, macrophages depend on PI3K-δ and PI3K-γ via Artus responses for responses to immune complexes (FCgR and C5a signals) (Randis TM, et al. (2008)).<i>Eur J </i><i>Immunol</i>. 38(5): 1215-24]; [Marwick J. A. et al. (2009)<i>Am</i><i> J </i><i>Respir</i><i></i><i>Crit</i><i></i><i>Care</i><i> Med</i>. 179(7):542-8]; [Konrad S,<i>et</i><i></i><i>al</i>.(2008) <i>J </i><i>Biol</i><i></i><i>Chem</i>. 283(48):33296-303).

In mast cells, stem cell factor- (SCF) and IL3-dependent proliferation, differentiation and function are PI3K-δ dependent and chemotactic. Allergen/IgE crosslinking of FCgR1, which produces cytokine release and degranulation of mast cells, is severely inhibited by treatment with PI3K-δ inhibitors in allergic diseases, suggesting a role for PI3K-δ (Ali K<i>et</i><i> al</i>.(2004) <i>Nature</i> 431(7011):1007-11]; [Lee K.S.,<i>et</i><i></i><i>al</i><i>.</i>(2006) <i>FASEB</i><i> J</i>. 20(3):455-65]; [Kim MS,<i>et</i><i></i><i>al</i><i>.(</i>2008) <i>Trends</i><i></i><i>Immunol</i>. 29(10):493-501]).

Natural killer (NK) cells are dependent on both PI3K-δ and PI3K-γ for efficient migration to chemokines including CXCL10, CCL3, S1P and CXCL12, or for response to LPS in the peritoneum (Guo H, et al. (2008) <i>J </i><i>Exp</i><i></i><i>Med</i>. 205(10):2419-35]; [Tassi I, et al. (2007)<i>Immunity</i><i></i>27(2):214-27]; [Saudemont A, (2009)<i>Proc</i><i></i><i>Natl</i><i> Acad </i><i>Sci</i><i> USA</i>. 106(14):5795-800]; [Kim N,<i>et</i><i></i><i>al</i>.(2007) <i>Blood</i> 110(9):3202-8]).

The role of PI3K-δ, PI3K-γ, and PI3K-β in the differentiation, maintenance, and activity of immune cells is important in autoimmune diseases (eg, rheumatoid arthritis, multiple sclerosis) and allergic inflammatory diseases such as asthma and COPD. Support the role of these enzymes in inflammatory diseases. Extensive evidence is available in experimental animal models, or can be assessed using art-recognized animal models. In an embodiment, the invention describes methods of treating allergic inflammatory diseases, such as asthma and inflammatory diseases, such as COPD, in autoimmune diseases (eg, rheumatoid arthritis, multiple sclerosis) using the compounds described herein.

For example, inhibitors of PI3K-δ and/or -γ have been shown to have anti-inflammatory activity in several autoimmune animal models for rheumatoid arthritis (Williams, O. et al. (2010) Chem Biol, 17). (2):123-34]; see WO 2009/088986; WO2009/088880; WO 2011/008302). PI3K-δ is expressed in RA lubricating tissues (particularly lubricating linings containing fibroblast-like synovial cells (FLS)), and selective PI3K-δ inhibitors are effective in inhibiting synovial cell growth and survival (Bartok<i>et</i><i></i><i>al</i>.(2010) <i>Arthritis</i><i> Rheum</i> 62 Suppl 10:362]). Several PI3K-δ and -γ inhibitors inhibit arthritis symptoms in art-recognized models for RA, such as collagen-induced arthritis and adjuvant-induced arthritis (WO 2009/088986; WO 2009/088880; WO 2011/008302). (eg, swelling of joints, reduction of serum-induced collagen levels, reduction of joint pathology and/or inflammation).

In addition, a role for PI3K-δ is shown in T-cell dependent response models, including the DTH model. In a murine experimental autoimmune encephalomyelitis (EAE) model of multiple sclerosis, PI3K-γ/δ-double mutant mice are resistant. In addition, PI3K-δ inhibitors block EAE diseases that show induction and development of TH-17 cells both in vitro and in vivo (Haylock-Jacobs, S.<i>et</i><i></i><i>al</i><i>.(</i>2011) <i>J. </i><i>autoimmunity</i> 36(3-4):278-87).

Systemic chronic lupus erythematosus (SLE) is a memory T-cell, B-cell polyclonal expansion and differentiation into plasma cells at different stages, an innate immune response to endogenous damage-associated molecular pattern molecules (DAMPS), and the complement system as well as not F_C It is a complex disease that requires an inflammatory response through a receptor or an inflammatory response to an immune complex. The role of PI3K-δ and PI3K-γ in these pathways and cell types suggests that blockade by inhibitors is effective in these diseases. In addition, the role of PI3K in lupus is predicted by two genetic models of lupus. Deletion of phosphatase and tensin homologues (PTEN) induces the transforming activity of class 1A PI3Ks, including a lupus-like phenotype, PI3K-δ. Deletion of PI3K-γ in the transformationally activated class 1A lupus model is protective, and lupus murine MLR/<i>lpr</i> Treatment with a PI3K-γ selective inhibitor in the model ameliorated symptoms (Barber, DF <i>et</i><i></i><i>al</i>.(2006) <i>J. </i><i>Immunol</i>. 176(1): 589-93]).

In allergic diseases, PI3K-δ shows an essential genetic model and inhibitor therapy for mast cell activation in a passive skin anaphylaxis assay (Ali K. <i>et</i><i> al</i>.(2008) <i>J </i><i>Immunol</i>. 180(4):2538-44]; [Ali K, (2004)<i>Nature</i> 431(7011):1007-11]). In lung measurements of response to immune complexes (Arthur's response), PI3K-δ knockouts are resistant and show defects in microphage activity and C5a production. Knockout studies and inhibitor studies for both PI3K-δ and PI3K-γ support a role for both these enzymes in ovalbumin-induced allergic airway inflammation and hypersensitivity response models (Lee KS).<i>et</i><i></i><i>al</i>.(2006) <i>FASEB</i><i> J</i>. 20(3):455-65]). Decreased infiltration of eosinophils, neutrophils, and lymphocytes as well as TH2 cytokines (IL4, IL5, and IL13) is shown using both PI3K-δ specific and dual PI3K-δ and PI3K-γ inhibitors in an oba-induced asthma model (Lee KS et al. (2006)<i>J </i><i>Allergy</i><i></i><i>Clin</i><i></i><i>Immunol</i> 118(2):403-9).

PI3K-δ and PI3K-γ inhibitors may be used to treat COPD. In a smoked mouse model of COPD, PI3K-δ non-knockout did not develop smoke-induced glucocorticoid resistance, whereas wild-type and PI3K-γ knockout mice did. Inhaled formulations of dual PI3K-δ and PI3K-γ inhibitors block inflammation in LPS or smoked COPD models as measured by neutropenia and glucocorticoid resistance (Doukas J, et al. (2009)<i>) J </i><i>Pharmacol</i><i></i><i>Exp</i><i></i><i>Ther</i>. 328(3):758-65]).

In addition, class I PI3Ks, particularly PI3K-δ and PI3K-γ isoforms, are associated with cancer (see, e.g., Vogt, PK et al. (2010) Curr Top Microbiol Immunol. 347:79-104; Fresno Vara); , J. A. et al. (2004) <i>Cancer</i><i></i><i>Treat</i><i></i><i>Rev</i>. 30(2):193-204]; [Zhao, L and Vogt, PK. (2008) Oncogene 27(41):5486-96]). Inhibitors of PI3K, such as PI3K-δ and/or -γ, have anticancer activity (see, eg, Courtney, KD et al. (2010)<i>J Clin </i><i>Oncol</i>. 28(6):1075-1083]; [Markman, B et al. (2010) Ann Oncol. 21(4):683-91]; [Kong, D and Yamori, T (2009) Curr Med Chem. 16(22):2839-54]; [Jimeno, A et al. (2009) J Clin Oncol. 27:156s(suppl; abstr 3542)]; [Flinn, IW et al. (2009))<i>J </i><i>Clin</i><i></i><i>Oncol</i>. 27:156s(suppl; abstr 3543)]; [Shapiro, G et al. (2009) J Clin Oncol. 27:146s(suppl; abstr 3500)]; [Wagner, AJ et al. (2009))<i>J </i><i>Clin</i><i> Oncol</i>. 27:146s(suppl; abstr 3501)]; [Vogt, PK et al. (2006) Virology 344(1):131-8]; [Ward, S et al. (2003)<i>Chem</i><i></i><i>Biol</i>. 10(3):207-13]; WO 2011/041399; US 2010/0029693; US 2010/0305096; see US 2010/0305084). In one embodiment, described herein is a method of treating cancer.

Types of cancer that can be treated with inhibitors of PI3K (particularly PI3K-δ and/or -γ) include, for example, leukemias (eg, chronic lymphocytic leukemia (CLL), acute myeloid leukemia (ALL), chronic myelogenous leukemia (CML)). (See, e.g., Salmena, L et al. (2008) <i>Cell</i> 133:403-414]; [Chapuis, N et al. (2010))<i>Clin</i><i></i><i>Cancer</i><i></i><i>Res</i>. 16(22):5424-35]; [Khwaja, A (2010)<i>Curr </i><i>Top</i><i></i><i>Microbiol</i><i></i><i>Immunol</i><i>. </i>347:169-88]); Lymphomas (eg, non-Hodgkin's lymphoma or Hodgkin's lymphoma) (eg, Salmena, L et al. (2008)<i>Cell</i> 133:403-414]); Lung cancer, such as non-small cell lung cancer, small cell lung cancer (see, e.g., Herrera, VA et al. (2011)<i>Anticancer </i><i>Res</i>. 31(3):849-54)]); Malignant melanoma (eg, Haluska, F et al. (2007))<i>Semi</i><i></i><i>Oncol</i>. 34(6):546-54]); Prostate cancer (see, e.g., Sarker, D et al. (2009)<i></i><i>Clin</i><i></i><i>Cancer</i><i></i><i>Res</i>. 15(15):4799-805]); malignant glioma (eg, Chen, JS et al. (2008) Mol Cancer Ther. 7:841-850); endometrial cancer (eg, Bansal, N et al. (2009) Cancer Control. 16(1):8-13); Pancreatic cancer (see, e.g., Furukawa, T (2008)<i>J </i><i>Gastroenterol</i>. 43(12):905-11]); Renal cancer (eg, Porta, C and Figlin, RA (2009))<i>J </i><i>Urol</i>. 182(6):2569-77]); colorectal cancer (eg Saif, MW and Chu, E(2010) Cancer J. 16(3):196-201); Breast cancer (see, e.g., Torbett, NE et al. (2008)<i>Biochem</i><i> J</i>. 415:97-100]); Thyroid cancer (eg, Brzezianska, E and Pastuszak-Lewandoska, D (2011)<i>Front</i><i></i><i>Biosci</i>. 16:422-39]); and ovarian cancer (eg, Mazzoletti, M and Broggini, M (2010))<i>Curr</i><i></i><i>Med</i><i> Chem.</i> 17(36):4433-47]).

Numerous publications support a role for PI3K-δ and PI3K-γ in the treatment of hematologic malignancies. PI3K-δ and PI3K-γ are highly expressed in the heme compartment and some solid tumors including prostate cancer, breast cancer and malignant gliomas (Chen JS<i>et</i><i></i><i>al</i>.(2008) <i>Mol</i><i></i><i>Cancer</i><i></i><i>Ther</i><i>.</i> 7(4):841-50; Ikeda H.<i>et</i><i></i><i>al</i>.(2010) <i>Blood</i> 116(9):1460-8]).

In hematologic cancers, including acute myeloid leukemia (AML), multiple myeloma (MM), and chronic lymphocytic leukemia (CLL), overexpression and component activity of PI3K-δ support a model in which PI3K-δ inhibitors are therapeutic agents. Billottet C, et al. (2006) <i>Oncogene</i><i></i>25(50):6648-59]; [Billottet C, et al. (2009))<i></i><i>Cancer</i><i></i><i>Res</i>. 69(3):1027-36]; [Meadows, SA, 52^nd Annual ASH Meeting and Exposition; 2010 Dec 4-7; Orlando, FL]; [Ikeda H, et al. (2010)<i>Blood</i> 116(9):1460-8]; [Herman SE<i>et</i><i></i><i>al</i>.(2010) <i>Blood</i> 116(12):2078-88]; [Herman SE<i>et</i><i></i><i>al</i><i>.</i>(2011). <i>Blood</i><i></i>117(16):4323-7]). In embodiments, the present invention provides methods of treating hematologic cancers, including but not limited to acute myeloid leukemia (AML), multiple myeloma (MM), and chronic lymphocytic leukemia (CLL).

A PI3K-δ inhibitor (CAL-101) has been evaluated in Phase 1 clinical trials in patients with hematologic malignancies and is active in patients with poor prognostic characteristics in CLL. In CLL, inhibition of PI3K-δ not only affects tumor cells directly, but also affects the ability of tumor cells to interact in this microenvironment. This microenvironment includes factors from and contact with stem cells, T-cells, nurse-like cells, as well as other tumor cells. CAL-101 inhibits expression of factors including CCL3, CCL4, and CXCL13, as well as stem cells and T-cells induced by the ability of CLL tumor cells to respond to these factors. CAL-101 treatment in CLL patients induces rapid lymph node reduction and redistribution of lymphocytes to circulation, affects tonic survival signaling through the BCR, and induces decreased cell survival, and increased apoptosis. In addition, single agent CAL-101 treatment is active in mantle cell lymphoma and refractory non-Hodgkin's lymphoma (Furman, RR, et al. 52).^nd Annual ASH Meeting and Exposition; 2010 Dec 4-7; Orlando, FL]; [Hoellenriegel,J, et al. 52^nd Annual ASH Meeting and Exposition; 2010 Dec 4-7; Orlando, FL]; [Webb, HK, et al. 52^nd Annual ASH Meeting and Exposition; 2010 Dec 4-7; Orlando, FL]; [Meadows, et al. 52^nd Annual ASH Meeting and Exposition; 2010 Dec 4-7; Orlando, FL]; [Kahl, B, et al. 52^nd Annual ASH Meeting and Exposition; 2010 Dec 4-7; Orlando, FL]; [Lannutti BJ, et al. (2011))<i>Blood</i> 117(2):591-4]).

PI3K-δ inhibitors show activity against PI3K-δ positive gliomas in vitro (Kashishian A, <i>et</i><i></i><i>al</i>. Poster presented at: The American Association of Cancer Research 102^nd Annual Meeting; 2011 Apr 2-6; Orlando, FL]). When the PTEN tumor suppressor is mutated, PI3K-β is the most commonly activated PI3K isoform in tumors (Ward S, et al. (2003)).<i>Chem</i><i></i><i>Biol</i>. 10(3):207-13]). In this subset of tumors, treatment with PI3K-δ inhibitors alone or in combination with cytotoxic agents may be effective.

Another mechanism for effective PI3K-δ inhibitors in solid tumors involves the interaction of tumor cells with the microenvironment. PI3K-δ, PI3K-γ and PI3K-β are expressed in tumor-infiltrating immune cells, including tumor infiltrating lymphocytes, microphages, and neutrophils. PI3K-δ inhibitors may modify the function of these tumor-associated immune cells and the way they respond to signals from the stroma, tumor, and each other and in this way affect tumor cells and metastases (see [Hoellenriegel,J, <i>et</i><i></i><i>al</i>. 52^nd Annual ASH Meeting and Exposition; 2010 Dec 4-7; Orlando, FL]).

In addition, PI3K-δ is expressed in endothelial cells. It has been shown that tumors in mice treated with PI3K-δ selective inhibitors are readily removed by radiation therapy. In this same study, capillary network formation is impaired by PI3K inhibitors, and it is believed that this damage helps to clear more with radiation. PI3K-δ inhibitors can affect how tumors interact with the microenvironment, including stromal cells, immune cells, and endothelial cells, and can be therapeutic on their own or in combination with other therapies (Meadows, SA,<i>et</i><i></i><i>al</i>. Paper presented at: 52^nd Annual ASH Meeting and Exposition; 2010 Dec 4-7; Orlando, FL]; [Geng L, et al. (2004))<i>Cancer</i><i></i><i>Res</i>. 64(14):4893-9].

In other embodiments, inhibitors of PI3K (such as PI3K-δ and/or -γ) may be used to treat neuropsychiatric disorders, such as autoimmune encephalopathy. Infectious and immune factors are responsible for the pathogenesis of several neuropsychiatric disorders, including but not limited to: Sidnam Chorea (SC) (Garvey, MA<i>et</i><i></i><i>al</i>.(2005) <i>J. </i><i>Child</i><i></i><i>Neurol</i>. 20:424-429), Tourette's syndrome (TS), obsessive compulsive disorder (OCD) (Asbahr, FR<i>et</i><i></i><i>al</i>.(1998) <i>Am</i><i>. J. Psychiatry</i> 155:1122-1124), attention deficit disorder (AD/HD) (Hirschtritt, ME <i>et</i><i> al</i>.(2008) <i>Child</i><i></i><i>Neuropsychol</i>. 1:1-16]; [Peterson, B.S.<i>et</i><i></i><i>al</i>.(2000) <i>Arch</i><i>. Gen.</i><i>Psychiatry</i> 57:364-372), anorexia nervosa (Sokol, MS (2000)) <i>J. Child </i><i>Adolesc</i><i>. </i><i>Psychopharmacol</i>. 10:133-145]; [Sokol, MS<i>et</i><i></i><i>al</i>.(2002) <i>Am</i><i>. J. Psychiatry</i> 159:1430-1432), depression (Leslie, DL <i>et</i><i></i><i>al</i>.(2008) <i>J. </i><i>Am</i><i>. Acad.</i><i>Child</i><i></i><i>Adolesc</i><i>. </i><i>Psychiatry</i> 47:1166-1172), and autism spectrum disease (ASD) (Hollander, E. <i>et</i><i></i><i>al</i>.(1999) <i>Am</i><i>. J.</i><i>Psychiatry</i> 156:317-320]; [Margutti, P.<i>et </i><i>al</i>.(2006) <i>Curr</i><i>. </i><i>Neurovasc</i><i>. </i><i>Res</i>. 3:149-157]). A subset of pediatric obsessive compulsive disorder and tic disorders are classified as pediatric autoimmune neuropsychiatric disorders (PANDAS) associated with streptococcus. PANDAS disease provides an example of a disease in which neuropsychiatric disorders are initiated and exacerbated by streptococcal infection (Kurlan, R., Kaplan, EL (2004)).<i>Pediatrics</i> 113:883-886; Garvey, MA<i>et</i><i></i><i>al</i>.(1998) <i>J. </i><i>Clin</i><i>. </i><i>Neurol</i>. 13:413-423]). Many PANDAS diseases share a general mechanism of action resulting from antibody responses to streptococcal associated epitopes, such as GlcNAc, which produce neuronal effects (Kirvan. CA).<i>et</i><i></i><i>al</i>.(2006) <i>J. </i><i>Neuroimmunol</i><i>. </i>179:173-179]). In addition, autoantibody recognition central nervous system (CNS) epitopes are mostly found in the serum of PANDAS individuals (Yaddanapudi, K.<i>et</i><i></i><i>al</i>.(2010) <i>Mol</i><i>. </i><i>Psychiatry</i> 15:712-726]). Thus, several neuropsychiatric disorders are associated with immune and autoimmune components that make them suitable for treatment involving PI3K-δ and/or -γ inhibition.

In certain embodiments, methods (eg, reducing or alleviating one or more symptoms) of a neuropsychiatric disorder (eg, autoimmune encephalopathy) using PI3K-δ and/or -γ inhibitors, alone or in combination, are described. . For example, one or more of the PI3K-δ and/or -γ inhibitors described herein can be used alone or in combination with any suitable therapeutic agent and/or modality, such as a dietary supplement to treat a neuropsychiatric disorder. Exemplary neuropsychiatric disorders that may be treated with the PI3K-δ and/or -γ inhibitors described herein include, but are not limited to, PANDAS disease, Sidnam chorea, Tourette's syndrome, obsessive compulsive disorder, attention deficit disorder, anorexia nervosa, depression, and autism spectrum disorders. Pervasive Developmental Disorder (PDD) is an exemplary class of autism spectrum disorders, including autism, Asperger's Disorder, Childhood Disintegrative Disorder (CDD), Rett's Disease, and Pervasive Developmental Disorder not elsewhere classified (PDD-NOS). Animal models for evaluating the activity of PI3K-δ and/or -γ inhibitors are known in the art. For example, mouse models of PANDAS disease are described, eg, in Yaddanapudi, K.<i>et</i><i></i><i>al</i>.(2010) <i>supra</i>]; and [Hoffman, KI et al. (2004))<i>J. </i><i>Neurosci</i><i>.</i> 24:1780-1791].

The present invention provides, but is not limited to, methods of treatment using a compound or pharmaceutical composition provided herein to treat a disease associated with dysfunction of one or more types of PI3 kinase. For example, a detailed description of symptoms and diseases mediated by p110δ kinase activity can be found in Sadu<i>et</i><i></i><i>al</i><i>.</i>, WO 01/81346, which is incorporated herein by reference in its entirety.

In one embodiment, a method of treatment provided herein comprises administering to an individual a therapeutically effective amount of a compound provided herein. In one embodiment, the present invention provides a method of treating an inflammatory disease, including an autoimmune disease, in a mammal. In one embodiment, the method comprises administering to the mammal a therapeutically effective amount of a compound provided herein, or a pharmaceutically acceptable salt, ester, prodrug, solvate, hydrate, or derivative thereof. Examples of autoimmune diseases include, but are not limited to, acute transverse myelitis (ADEM), Addison's disease, antiphospholipid antibody syndrome (APS), aplastic anemia, autoimmune hepatitis, chronic digestive disorders, Crohn's disease, diabetes (type 1). , Goodpesture syndrome, Graves disease, Guillain-Barré syndrome (GBS), Hashimoto's disease, chronic lupus erythematosus, multiple sclerosis, myasthenia gravis, myoclonus syndrome (OMS), optic neuritis, thyroiditis, pemphigus, polyarthritis, primary biliary cirrhosis, psoriasis, skin blister pemphigus bullae, rheumatoid arthritis, Reiter's syndrome, Takayasu's arteritis, temporal arteritis (also known as "giant cell arteritis"), warm autoimmune hemolytic anemia, Wegener's granuloma, systemic alopecia, Chagas disease, chronic fatigue syndrome, autonomic ataxia, endometriosis, chrysitis suppurative, interstitial cystitis, neuromuscular dystonia, sarcoidosis, scleroderma, ulcerative colitis, vitiligo, and vulvar pain. In other embodiments, the disorder or disease condition comprises bone-resorption disorders and thrombosis.

Inflammation exists in many forms, including but not limited to acute inflammation, adhesion inflammation, atrophic inflammation, catarrhal inflammation, chronic inflammation, cirrhosis inflammation, diffuse inflammation, disseminated inflammation, exudative inflammation, fibrinous inflammation, fibrotic inflammation, central inflammation. Inflammation, granulomatous inflammation, hyperplastic inflammation, hypertrophic inflammation, interstitial inflammation, metastatic inflammation, gangrene inflammation, obstructive inflammation, parenchymal inflammation, pseudoinflammation, productive inflammation, proliferative inflammation, pseudomembranous inflammation, suppurative inflammation, sclerosing inflammation , serous inflammation, serous inflammation, simple inflammation, specific inflammation, subacute inflammation, purulent inflammation, toxic inflammation, traumatic inflammation, and/or ulcerative inflammation.

Exemplary inflammatory conditions include, but are not limited to, acne, anemia (eg, aplastic anemia, autoimmune hemolytic anemia), asthma, arteritis (eg, polyarteritis, temporal arteritis, periarteritis nodosa, Takayasu's arteritis), arthritis (eg, crystalline arthritis, degenerative arthritis, psoriatic arthritis, gouty arthritis, reactive arthritis, rheumatoid arthritis and Reiter's arthritis), ankylosing spondylitis, bursitis, Lou Gehrig's disease, autoimmune disease, allergic or allergic reaction, atherosclerosis, bronchitis, bursitis, Chronic prostatitis, conjunctivitis, Chagas disease, chronic obstructive pulmonary disease, dermatomyositis, diverticulitis, diabetes (eg type 1 diabetes and type 2 diabetes), skin conditions (eg psoriasis, eczema, burns, dermatitis, pruritus (itch)) ), endometriosis, Len-Barré syndrome, infection, ischemic heart disease, Kawasaki disease, glomerulonephritis, gingivitis, hypersensitivity, headache (e.g. migraine, tension headache), ileus (e.g., postoperative ileus and ileus during sepsis), idiopathic thrombocytopenic purpura, Interstitial cystitis (bladder pain syndrome), gastrointestinal disorders (e.g. gastric ulcer, fatty enteritis, diverticulitis, gastrointestinal bleeding, eosinophilic gastrointestinal disease (e.g. eosinophilic esophagitis, eosinophilic gastritis, eosinophilic gastroenteritis, eosinophilic colitis), gastritis, Diarrhea, gastroesophageal reflux disease (GORD, or GERD), inflammatory bowel disease (IBD) (eg, Crohn's disease, ulcerative colitis, collagen colitis, lymphocytic colitis, ischemic colitis, conversion colitis, Behcet's disease, indeterminate colitis ) and irritable bowel syndrome (IBS)), lupus, multiple sclerosis, scleroderma, myasthenia gravis, myocardial ischemia, nephrotic syndrome, pemphigus vulgaris, pernicious anemia, gastric ulcer, polymyositis, inflammation associated with primary biliary cirrhosis, brain disease Neuroinflammation associated with (eg, Parkinson's disease, Huntington's disease, and Alzheimer's disease), prostatitis, cranial radiation injury, pelvic inflammatory disease, reperfusion injury, fatty enteritis, rheumatic fever, systemic chronic lupus erythematosus, cutaneous chronic lupus erythematosus , scleroderma, cyeroma, Includes sarcoidosis, arthritis, Sjogren's syndrome, thyroiditis, transplant rejection, tendinitis, trauma or injury (e.g., frostbite, chemical irritation, toxins, scars, burns, physical damage), vasculitis, vitiligo, and chronic inflammation associated with Wegener's granuloma do. In certain embodiments, the inflammatory disease is selected from arthritis (eg, rheumatoid arthritis), inflammatory bowel disease, irritable bowel syndrome, asthma, psoriasis, endometriosis, interstitial cystitis and prostatitis. In certain embodiments, the inflammatory condition is an acute inflammatory condition (eg, inflammation resulting from an infection). In certain embodiments, the inflammatory condition is a chronic inflammatory condition (eg, symptoms resulting from asthma, arthritis, and inflammatory bowel disease). The compounds may also be useful in treating inflammation associated with trauma and non-inflammatory myalgia.

Immune diseases such as autoimmune diseases include, but are not limited to, arthritis (rheumatoid arthritis, arthritis, gouty arthritis, degenerative joint diseases such as degenerative arthritis, systemic chronic lupus erythematosus, Sjogren's syndrome, ankylosing spondylitis, undifferentiated spondylitis, Behcet's disease, Autoimmune hemolytic anemia, multiple sclerosis, Lou Gehrig's disease, curvature, acute shoulder pain, psoriasis, and arthritis in children), asthma, atherosclerosis, osteoporosis, bronchitis, tendinitis, bursitis, skin conditions (e.g., psoriasis, eczema) , burns, dermatitis, pruritus (itch), enuresis, eosinophilic disease, gastrointestinal disease (eg, gastric ulcer, fatty enteritis, diverticulitis, gastrointestinal bleeding, eosinophilic gastrointestinal disease (eg, eosinophilic esophagitis, eosinophilic gastritis, eosinophilic gastroenteritis) , eosinophilic colitis), gastritis, diarrhea, gastroesophageal reflux disease (GORD, or GERD), inflammatory bowel disease (IBD) (eg Crohn's disease, ulcerative colitis, collagen colitis, lymphocytic colitis, ischemic colitis, Conversion colitis, Behcet's disease, uncertain colitis) and irritable bowel syndrome (IBS)), and dyspepsia treatment (e.g., ileus, post-surgical ileus and intestinal obstruction during sepsis; gastroesophageal reflux disease (GORD, or synonymously GERD); eosinophilic esophagitis, gastric hypofunction, such as diabetic hypofunction; food intolerance and food allergy and other functional bowel diseases such as non-ulcer dyspepsia (NUD) and non-cardiogenic chest pain (including NCCP, costochondritis)). .

In some embodiments, the method of treating an inflammatory or autoimmune disease comprises administering a therapeutically effective amount of a compound provided herein to an individual (e.g., mammals). Such selective inhibition of PI3K-δ and/or PI3K-γ may be beneficial in treating any disease or condition described herein. For example, and not wishing to be bound by a particular theory, selective inhibition of PI3K-δ may be inhibited by autologous, inflammatory diseases including, but not limited to, asthma, emphysema, allergy, dermatitis, rheumatoid arthritis, psoriasis, chronic lupus erythematosus, or graft-versus-host disease. It can inhibit the inflammatory response associated with an immune disease, or a disease associated with an undesirable immune response. Without wishing to be bound by any particular theory, selective inhibition of PI3K-δ would further provide a reduction in inflammatory or undesirable immune responses without the concomitant decrease in the ability to reduce bacterial, viral, and/or fungal infection. can Without wishing to be bound by any particular theory, selective inhibition of both PI3K-δ and PI3K-γ may be beneficial in inhibiting the inflammatory response in an individual more than that provided by an inhibitor that selectively inhibits PI3K-δ or PI3K-γ alone. can In one embodiment, one or more methods provided herein increase antigen-specific antibody production in vivo by about 2-fold, 3-fold, 4-fold, 5-fold, 7.5-fold, 10-fold, 25-fold, 50-fold, 100-fold, It is effective in reducing 250-fold, 500-fold, 750-fold, or about 1000-fold or more. In another embodiment, one or more methods provided herein increase antigen-specific IgG3 and/or IgGM production in vivo by about 2-fold, about 3-fold, about 4-fold, about 5-fold, about 7.5-fold, about 10-fold, about 25 times, about 50 times, about 100 times, about 250 times, about 500 times, about 750 times, or about 1000 times or more.

In one embodiment, one or more of the methods provided herein include, but are not limited to, reducing joint swelling, reducing serum anti-collagen levels, and/or joint pathologies such as bone resorption, cartilage damage, pannus, and/or or for alleviation of symptoms associated with rheumatoid arthritis, including reduction of inflammation. In another embodiment, the methods provided herein comprise about 2%, about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 50%, or about 60%, or about effective in reducing ankle inflammation by 75 to about 90% or more. In another embodiment, the methods provided herein comprise about 2%, about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 50%, or about 60%, or about effective in reducing knee inflammation by at least 75 to about 90%. In another embodiment, the methods provided herein comprise about 10%, about 12%, about 15%, about 20%, about 24%, about 25%, about 30%, about 35%, about 50%, about 60% , about 75%, about 80%, about 86%, about 87%, or about 90% or more of serum antitype II collagen levels. In another embodiment, the methods provided herein comprise about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 40%, about 50%, about 60%, about 75% , about 80%, or about 90% or more of the ankle histopathology score. In another embodiment, the methods provided herein comprise about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 40%, about 50%, about 60%, about 75% , about 80%, or about 90% or more of the ankle histopathology score.

In another embodiment, the present invention provides a compound provided herein for treating a respiratory disease, including, but not limited to, the lobe of the lung, the chest cavity, the bronchi, the trachea, the upper airway, or the nerves and muscles for breathing. or a method of using a pharmaceutical composition thereof. For example, the method provides a method for treating obstructive pulmonary disease, including COPD. Chronic obstructive pulmonary disease (COPD) is an umbrella term for a group of respiratory tract diseases characterized by airway obstruction or limitation. Symptoms include generic terms such as chronic bronchitis, emphysema and bronchiectasis.

In another embodiment, the compounds described herein are used for the treatment of asthma. In addition, a compound described herein or a pharmaceutical composition thereof may be used for the treatment of endotoxemia and sepsis. In one embodiment, a compound described herein, or a pharmaceutical composition thereof, is used for the treatment of rheumatoid arthritis (RA). In another embodiment, a compound described herein, or a pharmaceutical composition thereof, is used in the treatment of contact or atopic dermatitis. Contact dermatitis includes irritant dermatitis, phototoxic dermatitis, allergic dermatitis, photoallergic dermatitis, contact urticaria, systemic contact type dermatitis, and the like. If you use too many substances on your skin or if your skin is sensitive to certain substances, irritant dermatitis may occur. Atopic dermatitis, sometimes called eczema, is a type of dermatitis, atopic skin disease.

The invention also provides a method of treating a hyperproliferative disease comprising administering to a mammal a therapeutically effective amount of a compound provided herein or a pharmaceutically acceptable salt, ester, prodrug, solvate, hydrate or derivative thereof. . In some embodiments, the hyperproliferative disease is myeloid disease, myelodysplastic syndrome (MDS), myeloproliferative disease (MPD), or mast cell disease. In some embodiments, the method comprises a cancer, such as acute myeloid leukemia, retinoblastoma, malignant melanoma in the eye, or thymus cancer, brain cancer, lung cancer, squamous cell cancer, skin cancer, eye cancer, oral cancer and oropharyngeal cancer, bladder cancer, gastric cancer, Pancreatic cancer, breast cancer, cervical cancer, head cancer, cervical cancer, kidney cancer, liver cancer, ovarian cancer, prostate cancer, colon cancer, esophageal cancer, testicular cancer, gynecological cancer, thyroid cancer, CNS, or PNS, or AIDS-related cancers (such as lymphoma and Kaposi sarcoma) or virus-induced cancer. In some embodiments, the method relates to treatment of a noncancerous hyperproliferative disease, such as benign hyperplasia of the skin (eg, psoriasis), restenosis, or prostate (eg, enlarged prostate (BPH)).

The present invention also provides a method for treating diseases associated with angiogenesis or angiogenesis comprising administering to a mammal a therapeutically effective amount of a compound provided herein or a pharmaceutically acceptable salt, ester, prodrug, solvate, hydrate or derivative thereof. treatment methods are provided. In some embodiments, the method comprises a disease selected from the group consisting of tumor angiogenesis, a chronic inflammatory disease such as rheumatoid arthritis, atherosclerosis, inflammatory bowel disease, skin diseases such as psoriasis, eczema, and scleroderma, diabetes, diabetic retinopathy. , retinopathy of prematurity, age-related macular degeneration, hemangioma, glioma, malignant melanoma, Kaposi's sarcoma, and ovarian cancer, breast cancer, lung cancer, pancreatic cancer, prostate cancer, colorectal cancer, and epidermal cancer.

In one embodiment, patients who may be treated with a compound provided herein, or a pharmaceutically acceptable salt, ester, prodrug, solvate, hydrate, or derivative thereof according to the methods provided herein, include, for example, psoriasis; restenosis; atherosclerosis; BPH; breast cancer, such as ductal carcinoma in duct tissue in the mammary gland, hydrocephalus, colloidal carcinoma, tubular carcinoma, and inflammatory breast cancer; ovarian cancer, including epithelial ovarian tumors, such as adenocarcinoma in the ovary and adenocarcinoma migrating from the ovary into the abdominal cavity; uterine cancer; cervical cancer such as adenocarcinoma in the cervical epithelium, including squamous cell carcinoma and adenocarcinoma; prostate cancer, such as a prostate cancer selected from adenocarcinoma or adenocarcinoma migrating to the bone; pancreatic cancer such as epithelial carcinoma in pancreatic duct tissue and adenocarcinoma in pancreatic duct; bladder cancer such as transitional epithelial cancer in the bladder, renal pelvic urothelial cancer (transitional epithelial cancer), tumors in the bladder cells lining the bladder, squamous cell carcinoma, adenocarcinoma, and small cell cancer; Leukemias such as acute myeloid leukemia (AML), acute lymphocytic leukemia, chronic lymphocytic leukemia, chronic myelogenous leukemia, hairy cell leukemia, myelodysplasia, myeloproliferative disease, acute myeloid leukemia (AML), chronic myelogenous leukemia (CML), mastocytosis, chronic lymphocytic leukemia (CLL), multiple myeloma (MM), and myelodysplastic syndrome (MDS); bone cancer; lung cancer, such as squamous cell carcinoma, adenocarcinoma, and large cell undifferentiated carcinoma, and non-small cell lung cancer (NSCLC) separated into small cell lung cancer; actinic keratosis, a skin condition that develops into skin cancers such as basal cell carcinoma, malignant melanoma, squamous cell carcinoma and squamous cell carcinoma; ocular retinoblastoma; malignant melanoma in the skin or in the eye; primary liver cancer (cancer that begins in the liver); kidney cancer; thyroid cancer such as papillary, follicular, medullary and malignant tumors; AIDS-related lymphomas such as diffuse large B-cell lymphoma, B-cell immunoblastic lymphoma and bovine non-segmented cell lymphoma; Kaposi's sarcoma; virus-induced cancers, including hepatitis B virus (HBV), hepatitis C virus (HCV), and hepatocellular carcinoma; human lymphocytic virus-type 1 (HTLV-1) and adult T-cell leukemia/lymphoma; and human papillomavirus (HPV) and cervical cancer; cancers of the central nervous system (CNS) such as primary brain tumors, including gliomas (astrocytoma, malignant astrocytoma, or malignant glioma polymorphism), oligodendroglioma, ependymoma, meningioma, lymphoma, schwannoma, and medulloblastoma; Peripheral nervous system (PNS) cancers such as auditory nerve tumors and malignant peripheral nerve sheath tumors (MPNST), including neurofibromas and schwannomas, malignant fibrous cytoma, malignant fibrous histiocytoma, malignant meningioma, malignant mesothelioma, and malignant mixed Müller tumor ; cancers of the oral cavity and oropharynx, such as cancer of the esophagus, cancer of the larynx, cancer of the nasopharynx, and cancer of the oropharynx; gastric cancer such as lymphoma, gastric stromal tumor, and carcinoid; testicular cancers such as germ cell tumors (GCT), including seminothelioma and non-seminoma, and gonadal stromal tumors, including Leydig cell carcinoma and Sertoli cell carcinoma; thymic cancer such as thrombocytoma, thymic carcinoma, Hodgkin's disease, non-Hodgkin's lymphoma carcinoid or carcinoid; rectal cancer; and/or patients with colorectal cancer.

In one embodiment, a patient that can be treated with a compound provided herein, or a pharmaceutically acceptable salt, ester, prodrug, solvate, hydrate, or derivative thereof according to a method provided herein, includes, but is not limited to, an auditory nerve. Tumor, adenocarcinoma, adrenal cancer, anal cancer, angiosarcoma (e.g. lymphangiosarcoma, lymphangioendothelial sarcoma, angiosarcoma), benign monoclonal gamma pathology, cholangiocarcinoma (e.g. biliary tract cancer), bladder cancer, breast cancer (e.g. adenocarcinoma of the breast, papillary carcinoma of the breast, mammary gland cancer, hydrocephalus of the breast), brain cancer (eg, meningioma; glioma such as astrocytoma, oligodendroglioma; medulloblastoma), bronchial cancer, cervical cancer (eg cervical adenocarcinoma), villous cancer, chordoma, craniopharyngoma, colon cancer (eg colorectal cancer, rectal cancer, colon adenocarcinoma), epithelial carcinoma, ependymoma, endothelial sarcoma (eg, Kaposi's sarcoma, multiple idiopathic hemorrhagic sarcoma), endometrial cancer, esophageal cancer (eg, adenocarcinoma of the esophagus, Barrett's gastric adenocarcinoma), Ewing's sarcoma, pseudohypereosinophilia, gastric cancer (eg, gastric adenocarcinoma), gastrointestinal stromal tumor (GIST), head and neck cancer (eg head and neck squamous cell carcinoma, oral cancer (eg oral squamous cell carcinoma (OSCC)), heavy chain disease (eg alpha chain disease, gamma chain disease, achain disease), hemangioblastoma, inflammatory muscle fibers blastic tumor, immunocytic amyloidosis, kidney cancer (eg, nephroblastoma, also known as Wilms' tumor, kidney cancer), liver cancer (eg, hepatocellular carcinoma (HCC), malignant liver cancer), lung cancer (eg, bronchial carcinoma, small cell lung cancer (SCLC) ), non-small cell lung cancer (NSCLC), adenocarcinoma of the lung), leukemia (such as Acute lymphocytic leukemia (ALL), including B-lineage ALL and T-lineage ALL, chronic lymphocytic leukemia (CLL), prolymphocytic leukemia (PLL), hairy cell leukemia (HLL) and Waldenstrom's macroglobulinemia (WM) ); Peripheral T-cell lymphoma (PTCL), adult T-cell leukemia/lymphoma (ATL), cutaneous T-cell lymphoma (CTCL), macrogranular lymphocytic leukemia (LGF), Hodgkin's disease and Reed-Sternberg Stemberg) disease; Acute myeloid leukemia (AML), chronic myelogenous leukemia (CML), chronic lymphocytic leukemia (CLL)), lymphoma (eg, Hodgkin's lymphoma (HL), non-Hodgkin's lymphoma (NHL), cystic lymphoma, diffuse large B-cell) Lymphoma (DLBCL), mantle cell lymphoma (MCL)), leiomyosarcoma (LMS), mastocytosis (eg, systemic mastocytosis), multiple myeloma (MM), myelodysplastic syndrome (MDS), mesothelioma, myeloproliferative disease (MPD) ) (e.g., polycythemia vera (PV), essential thrombocythemia (ET), chronic myelomonocytic leukemia (CMML), myelofibrosis of unknown cause (AMM), also called myelofibrosis (MF), chronic idiopathic myelofibrosis, chronic myeloid Leukemia (CML), chronic neutrophilic leukemia (CNL), hypereosinophilic syndrome (HES)), neuroblastoma, neurofibroma (eg, neurofibromatosis (NF) type 1 or 2, schwannomatosis), neuroendocrine cancer (eg, Gastrointestinal pancreatic neuroendocrine tumor (GEP-NET), carcinoid), osteosarcoma, ovarian cancer (eg, cyst cancer, ovarian germ cell carcinoma, ovarian adenocarcinoma), Paget's disease of the vulva, Paget's disease of the genitals, papillary adenocarcinoma, pancreatic cancer (eg, pancreatic adenocarcinoma, papillary mucinous tumor in the pancreatic duct (IPMN)), pineal tumor, primitive neuroectodermal tumor (PNT) , prostate cancer (eg, prostate adenocarcinoma), rhabdomyosarcoma, retinoblastoma, salivary gland cancer, skin cancer (eg, squamous cell carcinoma (SCC), keratocytoma (KA), malignant melanoma, basal cell carcinoma (BCC)), small intestine Cancer (eg, appendicitis), soft tissue sarcoma (eg, malignant fibrous histiocytoma (MFH), liposarcoma, malignant peripheral nerve sheath tumor (MPNST), chondrosarcoma, fibrosarcoma, myxosarcoma), sebaceous gland carcinoma, sweat gland carcinoma, synovial membrane tumors, testicular cancer (e.g., seminomas, testicular germ cell carcinoma), thyroid cancer (e.g., papillary carcinoma of the thyroid, papillary thyroid carcinoma (PTC), medullary thyroid cancer), and Waldenstrom's macroglobulinemia.

In some embodiments, the present invention provides a method of treating a heme malignancy comprising administering to an individual a therapeutically effective amount of a compound provided herein or a pharmaceutically acceptable salt, ester, prodrug, solvate, hydrate or derivative thereof. provides In some embodiments, the heme malignancy is a myeloid malignancy. Exemplary myeloid malignancies that can be treated using the compounds provided herein include leukemia (eg, acute myeloid leukemia (AML) or chronic myelogenous leukemia (CML)); myelodysplastic syndrome (MDS) (eg, high-grade MDS or low-grade MDS); myeloproliferative diseases (MPD) (eg, essential thrombocythemia (ET), myelofibrosis (MF), polycythemia vera (PV), or chronic myelomonocytic leukemia (CMML)) and mast cell diseases.

In some embodiments, the heme malignancy is a myeloid malignancy, such as a lymphoma. Exemplary lymphomas that can be treated using the compounds provided herein are Hodgkin's lymphoma, non-Hodgkin's lymphoma (eg, B-cell or T-cell), leukemia (eg, acute lymphocytic leukemia (ALL) or chronic lymphocytic leukemia) (CLL)), and post-transplant lymphoproliferative disease (PLD). Exemplary B-cell lymphomas include diffuse large B-cell lymphoma (DLBCL), mentle cell lymphoma, and indolent non-Hodgkin's lymphoma (iNHL). Exemplary T-cell lymphomas include peripheral T-cell lymphoma (PTCL) and cutaneous T-cell lymphoma (CTCL). Exemplary acute lymphocytic leukemia (ALL) includes T-cell ALL and B-cell ALL. Exemplary PLDs include multiple myeloma, Waldenstrom PLD, and amyloid PLD.

In another embodiment, the compounds and compositions provided herein can be used to prevent a PI3K-mediated cancer in an individual having or at risk of having a PI3K-mediated cancer. In one embodiment, the compounds and compositions provided herein can be used as chemopreventive agents, such as agents that inhibit, delay or reverse the development of PI3K-mediated cancer. This role is supported, at least in part, by a broad spectrum of anti-inflammatory agents, such as COX-2 inhibitors, showing the effectiveness of anti-inflammatory agents, such as COX-2 inhibitors, as chemopreventive agents that reduce or inhibit the development of cancers, including colorectal cancer and the like. Since both COX-2 inhibitors and PI3K inhibitors have broad anti-inflammatory activity, PI3K inhibition is expected to have chemopreventive activity that reduces or inhibits the development of various cancers.

In certain embodiments, methods of treating or preventing recurrence and/or recurrence of a PI3K-mediated cancer (eg, a PI3K-mediated cancer described herein) in an individual are provided. The method comprises administering to the individual an amount of a PI3K inhibitor sufficient to reduce or inhibit the regrowth or recurrence of a tumor or cancer in the individual, such as one or more PI3K inhibitors described herein. In certain embodiments, the individual is undergoing or is undergoing treatment for cancer (eg, treatment with other anticancer agents, surgery, and/or radiation). PI3K inhibitors before, concurrently with, after, and with other cancer treatments; or during remission of cancer. Treatment or prophylaxis delays recurrence and/or recurrence (eg, 1 week, 1 month, 1 year) or regrowth (eg, PI3K-mediated cancer, eg, as compared to a subject not administered with a PI3K inhibitor) (eg, a PI3K inhibitor). Inhibition of recurrence or recurrence need not be absolute as long as it reduces or delays about 10%, about 20%, about 30%, about 40%, about 50% or more).

Accordingly, in one embodiment, disclosed is a method of prolonging recurrence-free survival in a cancer patient undergoing or receiving cancer therapy in which a therapeutically effective amount of a PI3K inhibitor is administered to the individual. "Relapse-free survival" as understood by one of ordinary skill in the art is the clinically defined length of time that cancer is free of recurrence, depending on a particular point in time in cancer treatment. In some embodiments, the PI3K inhibitor is administered concurrently in the treatment of cancer. In other embodiments, the PI3K inhibitor is administered sequentially (in any order) in the treatment of cancer. In the case of simultaneous administration, the PI3K inhibitor may be continued after the cancer treatment is stopped. In other embodiments, the PI3K inhibitor is administered after cancer treatment is discontinued (eg, a period of non-overlapping cancer treatment). After the cancer treatment is stopped, the PI3K inhibitor may be administered immediately, or the time difference between the end of cancer treatment and administration of the PI3K inhibitor (eg, several hours or less, about 1 day, about 1 week, about 1 month, about 6 months, or a year). PI3K as long as relapse-free survival is maintained (e.g., about 1 day or less, about 1 week, about 1 month, about 6 months, about 1 year, about 2 years, about 3 years, about 4 years, about 5 years or more) Inhibitor administration may be continued.

The invention also provides a method of treating diabetes comprising administering to a mammal a therapeutically effective amount of a compound provided herein or a pharmaceutically acceptable salt, ester, prodrug, solvate, hydrate or derivative thereof.

In addition, the compounds described herein can be used to treat acne. In certain embodiments, the inflammatory disease and/or immune disease is a skin condition. In some embodiments, the skin condition is pruritus (itchiness), psoriasis, eczema, burns, or dermatitis. In certain embodiments, the skin condition is psoriasis. In certain embodiments, the skin condition is pruritus.

In addition, the compounds described herein can be used to treat arteriosclerosis, including atherosclerosis. Atherosclerosis is a general term describing any hardening of the middle or aorta. Atherosclerosis is particularly hardening of the arteries due to atheromatous plaque.

In some embodiments, the invention provides an individual with a compound disclosed herein, or a pharmaceutically acceptable form thereof (e.g., a pharmaceutically acceptable salt, hydrate, solvate, chelate, non-covalent complex, isomer, prodrug, and isotope thereof). It provides a method for treating cardiovascular disease, comprising administering a therapeutically effective amount of the derivative). Examples of cardiovascular disease include, but are not limited to, atherosclerosis, restenosis, vascular occlusion and carotid occlusive disease.

In certain embodiments, the inflammatory disease and/or immune disease is a gastrointestinal disease. In some embodiments, the gastrointestinal disease is a gastrointestinal disease (eg, gastric ulcer, fatty enteritis, diverticulitis, gastrointestinal bleeding, eosinophilic gastrointestinal disease (eg, eosinophilic esophagitis, eosinophilic gastritis, eosinophilic gastroenteritis, eosinophilic colitis), gastritis, diarrhea , gastroesophageal reflux disease (GORD, or synonymous GERD), inflammatory bowel disease (IBD) (eg, Crohn's disease, ulcerative colitis, collagen colitis, lymphocytic colitis, ischemic colitis, conversion colitis, Behcet's disease, colitis indefinite) and irritable bowel syndrome (IBS)). In certain embodiments, the gastrointestinal disease is inflammatory bowel disease (IBD).

In addition, the compounds described herein, or pharmaceutically acceptable forms thereof (e.g., pharmaceutically acceptable salts, hydrates, solvates, chelates, non-covalent complexes, isomers, prodrugs, and isotopically labeled derivatives) are glomerular It can be used to treat nephritis. Glomerulonephritis is a primary or secondary autoimmune kidney disease characterized by inflammation of the glomeruli. It may be asymptomatic or present with hematuria and/or proteinuria. Many recognized types exist and are divided into acute, subacute or chronic glomerulonephritis. It can be caused by an infectious (bacterial, viral or parasitic disease), autoimmune, or paratumour.

In some embodiments, the present invention provides a compound disclosed herein, or a pharmaceutically acceptable form thereof (e.g., a pharmaceutically acceptable salt, hydrate, solvate, chelate, non-covalent complex, isomer, prodrugs, and isotopically labeled derivatives), or pharmaceutical compositions. The invention also provides a compound disclosed herein for treating liver disease (including diabetes), gallbladder disease (including gallstones), pancreatitis or kidney disease (including proliferative glomerulonephritis and diabetes-induced kidney disease) or pain in a subject, or a pharmaceutically acceptable form thereof (eg, a pharmaceutically acceptable salt, hydrate, solvate, chelate, non-covalent complex, isomer, prodrug, and isotopically labeled derivative), or a pharmaceutical composition.

In some embodiments, the present invention provides a compound disclosed herein, or a pharmaceutically acceptable form thereof (eg, a pharmaceutically acceptable salt, hydrate, solvate, chelate, non-covalent complex, isomer) thereof, for preventing blastocyst insertion in an individual. , prodrugs, and isotopically labeled derivatives), or pharmaceutical compositions.

In some embodiments, the present invention provides, but is not limited to, idiopathic thrombocytopenic purpura, Bernard-Soulier syndrome, Glanzmann thrombocytopenia, Scott syndrome, von Willebrand ) disease, Hermansky-Pudlak syndrome, and a disease associated with platelet coagulation or platelet aggregation, including Gray platelet syndrome, or a pharmaceutically acceptable compound disclosed herein; forms (eg, pharmaceutically acceptable salts, hydrates, solvates, chelates, non-covalent complexes, isomers, prodrugs, and isotopically labeled derivatives), or pharmaceutical compositions.

In some embodiments, a compound disclosed herein, or a pharmaceutically acceptable form thereof (e.g., a pharmaceutically acceptable salt, hydrate, solvate, chelate, non-covalent complex) thereof, for treating skeletal muscle atrophy, skeletal or muscular hypertrophy, a disease. , isomers, prodrugs, and isotopically labeled derivatives), or pharmaceutical compositions. In some embodiments, the present invention relates to, but is not limited to, cancer, transplant-related diseases (eg, reduced rejection, graft-versus-host disease, etc.), muscle sclerosis (MS), allergic diseases (eg, arthritis, allergy) discussed herein. encephalomyelitis) and other immunosuppression-related diseases, metabolic diseases (eg diabetes), decreased intima thickness due to vascular damage, and misfolded protein diseases (eg, Alzheimer's disease, Gaucher's Disease, Parkinson's disease) A compound provided herein for the treatment of a disease, including mTOR inhibition, which can mitigate the effects of misfolded protein aggregation, or pharmaceutically acceptable forms thereof (eg, pharmaceutically acceptable salts, hydrates, solvates, chelates, non-covalent complexes, isomers, prodrugs, and isotopically labeled derivatives), or pharmaceutical compositions. The disease also includes hamartoma syndromes, such as tuberous sclerosis and Cowden's disease (also referred to as Cowden's syndrome and multiple hamartomas).

In other embodiments, bursitis, lupus, acute transverse myelitis (ADEM), Addison's disease, antiphospholipid antibody syndrome (APS), aplastic anemia, autoimmune hepatitis, chronic digestive disorder, Crohn's disease, diabetes (type 1) , Goodpesture syndrome, Graves disease, Guillain-Barré syndrome (GBS), Hashimoto's disease, inflammatory bowel disease, chronic lupus erythematosus, myasthenia gravis, myoclonus syndrome (OMS), optic neuritis, thyroiditis, degenerative arthritis, uvea Retinitis, pemphigus, polyarthritis, primary biliary cirrhosis, Reiter's syndrome, Takayasu's arteritis, temporal arteritis, warm autoimmune hemolytic anemia, Wegener's granuloma, generalized alopecia, Chagas disease, chronic fatigue syndrome, ataxia, endometriosis, purulent Gastroenteritis, interstitial cystitis, neuromuscular dystonia, sarcoidosis, scleroderma, ulcerative colitis, vitiligo, vulvar pain, appendicitis, arteritis, arthritis, blepharitis, bronchiolitis, bronchitis, cervicitis, cholangitis, cholecystitis, chorioamnionitis, colitis , conjunctivitis, cystitis, laryngitis, Dermatomyositis, endocarditis, endometritis, enteritis, enterocolitis, epididymitis, epididymitis, fasciitis, connective tissueitis, gastritis, gastroenteritis, gingivitis, hepatitis, tonsillitis, ileitis, iritis, laryngitis, mastitis, meningitis, myelitis, myocarditis, myositis , nephritis, umbilical corditis, oophoritis, orchitis, osteitis, otitis, pancreatitis, parotitis, pericarditis, peritonitis, pharyngitis, pleurisy, phlebitis, pneumonia, proctitis, prostatitis, pyelonephritis, rhinitis, salpingitis, sinusitis, stomatitis, tendonitis, tendinitis , tonsillitis, uveitis, vaginitis, vasculitis, or vulvitis.

In other embodiments, a compound provided herein is administered to a compound provided herein for treatment of chronic allergic rhinitis, mesenteritis, peritonitis, acrosome dermatitis, cutaneous vasculitis, atopic dermatitis, contact dermatitis, eczema, erythema multiforme, interlimal dermatitis, Stevens-Johnson syndrome, toxic epidermal necrolysis, Skin allergy, severe allergic reaction/anaphylaxis, allergic granulomatosis, Wegener's granulomatosis, allergic conjunctivitis, chorioretinitis, conjunctivitis, infectious keratoconjunctivitis, keratoconjunctivitis, neonatal ophthalmitis, trachoma, uveitis, ocular inflammation, blepharoconjunctivitis, mastitis, gingivitis , paronychia, pharyngitis, nasopharyngitis, salivary glanditis, musculoskeletal inflammation, adult onset Still's disease, Behcet's disease, bursitis, cartilage calcification, pharyngitis, Pelty syndrome, gout, infectious arthritis, Lyme disease, inflammatory degenerative arthritis, periarthritis, Reiter's syndrome, Ross River virus infection, acute respiratory distress syndrome, acute bronchitis, acute sinusitis, allergic rhinitis, asthma, severe intractable asthma, pharyngitis, pleurisy, nasopharyngitis, seasonal allergic rhinitis, sinusitis, persistent asthma, Bronchitis, rhinitis, serousitis, meningitis, optic neuromyelitis, poliovirus infection, Alport syndrome, balanitis, epididymitis, epididymal orchitis, focal segmental glomerulosclerosis, glomerulonephritis, IgA nephropathy (Berger's disease), orchitis, periuterine histitis, pelvic inflammatory Diseases, prostatitis, pyelitis, pyelonephritis, pyelonephritis, Wegener's granulomatosis, hyperuricemia, aortitis, arteritis, chylopericarditis, Dressler's syndrome, endarteritis, endocarditis, extracranial temporal arteritis, HIV associated arteritis, intracranial temporal arteritis , Kawasaki disease, lymph node phlebitis, Mondor's disease, periarteritis, or pericarditis.

In other embodiments, a compound provided herein is an autoimmune hepatitis, enterocolitis, mesenteritis, mucositis, nonalcoholic steatohepatitis, nonviral hepatitis, autoimmune pancreatitis, interstitial gastritis, peritonitis, appendicitis, proctitis, pseudomembranous colitis , proctocolitis, salphingoperitonitis, stomatitis, steatohepatitis, ulcerative colitis, Chug-Strauss syndrome, ulcerative proctitis, irritable bowel syndrome, gastrointestinal inflammation, acute enterocolitis, proctitis, plantar necrosis, cholecystitis, colitis, Crohns disease, diverticulitis, enterocolitis, enterocolitis, enterohepatitis, eosinophilic esophagitis, esophagitis, gastritis, hemorrhagic enteritis, hepatitis, hepatitis virus infection, hepatocholangitis, hypertrophic gastritis, ileitis, ileal appendicitis, sarcoidosis, inflammatory bowel disease, ankylosing spondylitis, Rheumatoid arthritis, juvenile rheumatoid arthritis, psoriasis, psoriatic arthritis, lupus (skin/systemic/nephritis), AIDS, agammaglobulinemia, AIDS-related complications, Bruton's disease, Chediak Higashi syndrome, common variable immunodeficiency, DiGeorge syndrome , dysgamma globulinemia, immunoglobulin deficiency, job syndrome, Nezelov's syndrome, phagocytic bacterial disease, Biscott-Aldrich syndrome, asepsis, epithelial disease, hyperfunction, Kawasaki disease, lymphadenitis, lymphedema, lymph cyst, non-Millois Meiji syndrome, spleen disease, splenomegaly, thymoma, thymic disease , pericarditis, phlebitis, pleural pericarditis, polyarteritis fibrils, vasculitis, Takayasu arteritis, temporal arteritis, thrombangiitis, thromboangiitis obstructive, thrombophlebitis, thrombophlebitis, or COPD.

In some embodiments, the invention provides an inflammatory or autoimmune disease comprising administering to an individual a therapeutically effective amount of a compound provided herein, or a pharmaceutically acceptable salt, ester, prodrug, solvate, hydrate, or derivative thereof. treatment methods are provided. In some embodiments, the inflammatory or autoimmune disease comprises asthma, rheumatoid arthritis, Crohn's disease, lupus, and multiple sclerosis.

In some embodiments, the inflammatory or autoimmune disease is idiopathic thrombocytopenic purpura; anemia, such as aplastic anemia; lupus such as cutaneous chronic lupus erythematosus; and pemphigus such as skin blister bullous pemphigus.

The present invention also provides a method of treating cardiovascular disease comprising administering to a mammal a therapeutically effective amount of a compound provided herein, or a pharmaceutically acceptable salt, ester, prodrug, solvate, hydrate, or derivative thereof. provides Examples of cardiovascular disease include, but are not limited to, atherosclerosis, restenosis, vascular occlusion and carotid occlusive disease.

In another embodiment, the invention provides a method of disrupting the function of a white blood cell or an osteoclast. In one embodiment, the method comprises contacting the leukocytes or osteoclasts with an interfering amount of a compound provided herein.

In another embodiment, the invention provides a method of treating an ophthalmic disease by administering to the eye of an individual a compound provided herein or a pharmaceutical composition provided herein.

<b>V. Combination Therapy</b>

In addition, the present invention provides combination therapies, wherein agents known to modulate different pathways, or other components of similar pathways, or overlapping sets of target enzymes, include a compound provided herein, or a pharmaceutically acceptable salt, ester thereof. , used in combination with a prodrug, solvate, hydrate or derivative. In one embodiment, such therapy includes, but is not limited to, therapy in which a subject compound is combined with a chemotherapeutic agent, a therapeutic antibody, and radiation therapy to provide a synergistic or additional therapeutic effect.

In one embodiment, a compound or pharmaceutical composition provided herein may exhibit synergistic or additive efficacy when administered in combination with an agent that inhibits IgE production or activity. Such combinations may reduce the undesirable effects of high levels of IgE (if such effects occur) associated with the use of one or more PI3Kδ inhibitors. In some embodiments, it may be particularly useful for the treatment of autoimmune and inflammatory diseases (AIIDs), such as rheumatoid arthritis. Also, without limitation to a particular therapy, administration of a PI3Kδ or PI3Kδ/γ inhibitor provided herein in combination with an inhibitor of mTOR may show synergy through improved inhibition of the PI3K pathway.

In another embodiment, the invention provides combination treatment of a disease associated with PI3Kδ comprising administering to the individual a PI3Kδ inhibitor and an agent that inhibits IgE production or activity. Other exemplary PI3Kδ inhibitors are available and are described, for example, in US Pat. No. 6,800,620, incorporated by reference. In some embodiments, such combination therapy is particularly useful for the treatment of autoimmune and inflammatory diseases (AIIDs), including but not limited to rheumatoid arthritis.

Agents that inhibit IgE production are known in the art and include, but are not limited to, TEI-9874, 2-(4-(6-cyclohexyloxy-2-naphthyloxy)phenylacetamide)benzoic acid, rapamycin, rapamycin analogs (ie, rapalogs), TORC1 inhibitors, TORC2 inhibitors, and any other compound that inhibits mTORC1 and mTORC2. Agents that inhibit IgE activity include, for example, anti-IgE antibodies such as omalizumab and TNX-901.

For the treatment of an autoimmune disease, a compound or pharmaceutical composition provided herein, without limitation, Enbrel^&amp;#174;, Remicade^&amp;#174;, Fumira^&amp;#174;, Avonex^&amp;#174;, and levif^&amp;#174;It can be used in combination with commonly prescribed drugs, including For the treatment of respiratory disorders, a compound or pharmaceutical composition provided herein can be administered to^&amp;#174;, advisor^&amp;#174;, singular^&amp;#174;, and Spiriva^&amp;#174;It can be used in combination with commonly prescribed drugs, including

In one embodiment, the compounds provided herein may be combined or administered with other agents that alleviate the symptoms of inflammatory diseases, such as encephalomyelitis, asthma, and other diseases described herein. Such agents include, but are not limited to, nonsteroidal anti-inflammatory drugs (NSAIDs) such as acetylsalicylic acid; ibuprofen; naproxen; indomethacin; nabumetone; and tolmethine. In some embodiments, corticosteroids are used to reduce inflammation and inhibit the activity of the immune system. For example, this type of drug that is usually prescribed is prednisone. In addition, chloroquine (aralene^&amp;#174;) or hydroxychloroquine (plaquinyl^&amp;#174;) can be very useful for some patients with lupus. It is often prescribed for skin and joint symptoms of lupus. Azathioprine (Imuran) and cyclophosphamide (Cytoxane)^™) suppresses inflammation and tends to suppress the immune system. Other agents, such as methotrexate and cyclosporine, may be used to control the symptoms of lupus. Anticoagulants are used to prevent the blood from clotting rapidly. For example, those that prevent platelets from sticking at very low doses range from aspirin to heparin/coumadin. Another compound used to treat lupus is belimumab (Benilista^&amp;#174;) is included.

In another embodiment, the present invention provides a compound provided herein in combination with an anti-cancer agent (eg, a biotherapeutic agent or a chemotherapeutic agent), or a pharmaceutically acceptable salt, ester, prodrug, solvate, hydrate or derivative thereof. A pharmaceutical composition for inhibiting abnormal cell growth in a mammal is provided. Many chemotherapy methods are now known in the art and can be used in combination with the compounds provided herein. In addition, other cancer therapies that can be used in combination with the compounds provided herein include, but are not limited to, surgery, surgical treatment, and radiation therapy.

In some embodiments, the chemotherapeutic agent is a mitotic inhibitor, an alkylating agent, an anti-metabolite, an intercalating agent, a growth factor inhibitor, a cell cycle inhibitor, an enzyme, a topoisomerase inhibitor, a bioresponse modulator, an anti-hormonal, an angiogenesis inhibitor , and anti-androgens. Non-limiting examples of anticancer agents include, for example, chemotherapeutic agents, cytotoxic agents, and non-peptide small molecules such as Gleevec (Gleevec).^&amp;#174;) (imatinib mesylate), Velcade (Velcade)^&amp;#174;) (bortezomib), CASODEX^™) (baicalutamide), Iressa^™) (gefitinib), and adriamycin as well as a host of chemotherapeutic agents. Non-limiting examples of chemotherapeutic agents include, but are not limited to, alkylating agents such as thiotepa and cyclophosphamide (CYTOXAN^™)); alkyl sulfonates such as busulfan, improsulfan and piposulfan; aziridines such as benzodopa, carboquone, meturedopa, and uredopa; ethylenimine and methylamelamine, including altretamine, triethylenemelamine, triethylenephosphoamide, triethylenethiophosphaoramide and trimethylolomelamine; nitrogen mustards such as chlorambucil, clonapazine, chlorophosphamide, estramustine, ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, novembicin, phenesterine, prednimu Steen, trophosphamide, uracil mustard; nitroureas such as carmustine, chlorozotocin, fotemustine, lomustine, nimustine, ranimustine; Antibiotics such as aclasinomycin, actinomycin, automycin, azaserine, bleomycin, cactinomycin, calicheamicin, carabicin, caminomycin, carzinophylline, CASODEX^™), chromomycin, dactinomycin, daunorubicin, detorubicin, 6-diazo-5-oxo-L-noreucin, doxorubicin, epirubicin, esorubicin, idarubicin, marcelomycin, mito Mycin, mycophenolic acid, nogalamicin, olibomycin, peflomycin, poppyromycin, puromycin, quelamycin, rhodorubicin, streptonigrin, streptozocin, tubersidin, ubenimex, genostatin , premature bicin; 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, azacitidine, 6-azauridine, chamofer, cytarabine, dideoxyuridine, doxyfluridine, enocitabine, flosuridine, androgens such as calusterone, dromostanolone propionate, epithiostanol, mepitiostan, testolactone; anti-adrenal such as aminoglutethimide, mitotan, trirostan; folic acid supplements such as prolinic acid; aceglatone; aldophosphamide glycoside; aminolevulinic acid; amsacrine; bestlabucil; bisantrene; edatraxate; depopamine; demecholcin; diaziquione; elformitin; elliptinium acetate; etoglucide; gallium nitrate; hydroxyurea; lentinan; Ronidamine; mitoguazone; mitoxantrone; fur damol; nitracrine; pentostatin; phenamet; pyrarubicin; podophyllic acid; 2-ethylhydrazide; procarbazine; PSK.R^™; Lazoxic acid; sijopiran; spirogermanium; tenuazonic acid; triaziquione; 2,2',2"-Trichlorotriethylamine; Urethane; Vindesine; Dacarbazine; Mannomustine; Mitobronitol; Mitolactol; Pipobroman; Gacytosine; Arabinoside ("Ara-C") ); cyclophosphamide; thiotepa; Tarzan such as paclitaxel (Taxol^™), Bristol-Myers Squibb Oncology, Princeton, NJ) and docetaxel (Taxotere^&amp;#174;), Rhone-Poulenc Rorer, Antony, France); retinoic acid; esperamycin; and capecitabine; and pharmaceutically acceptable salts, solvates, or derivatives. Also, for example, anti-estrogens such as tamoxifen (Novaldex^™)), raloxifen, aromatase inhibitor 4(5)-imidazole, 4-hydroxytamoxifen, trioxifene, keosifen, LY 117018, onapristone, and toremifene (Fareston); and anti-androgens such as flutamide, nirutamide, bicalutamide, leuprolide, and goserelin; chlorambucil; Gemicitabine; 6-thioguanine; mercaptopurine; methotrexate; platinum analogs such as cisplatin and carboplatin; vinblastine; platinum; etoposide (VP-16); ifosfamide; mitomycin C; mitoxantrone; vincristine; vinorelbine; Nabelbin; novantron; teniposide; daunomycin; aminopterin; zero^&amp;#174;; ibandronate; camptothecin-11 (CPT-11); topoisomerase inhibitor RFS 2000; and anti-hormones that act by modulating or inhibiting tumor-acting hormones, including difluoromethylornithine (DMFO), as suitable chemotherapeutic cell conditioners. In some embodiments, a compound or pharmaceutical composition provided herein is a commonly prescribed anticancer agent, such as Herceptin.^&amp;#174;, Avastin^&amp;#174;, Erbitus^&amp;#174;, Lituzan^&amp;#174;, Taxol^&amp;#174;, Arimidex^&amp;#174;, Taxotere^&amp;#174;, and velcade^&amp;#174;can be used in combination with

Non-limiting examples include chemotherapeutic agents, cytotoxic agents, and non-peptide small molecules such as ABVD, avicin, abagobomab, acridine carboxamide, adecatumumab, 17-N-allylamino-17-demethoxygeldanamycin , alpharadin, albocidib, 3-aminopyridine-2-carboxaldehyde thiosemicarbazone, amonapide, anthracendione, anti-CD22 immunotoxin, anti-tumor drug, anti-tumor herb, apaziquione^&amp;#174;, atiprimod, azathioprine, belotecan, bendamustine, BIBW 2992, vircoder, brostalysin, bryostatin, butionine sulfoximin, CBV (chemotherapeutic agent), caliculin, crizotinib, cell cycle Non-specific anti-neoplastic agents, dichloroacetic acid, discordermolide, elsamitrucin, enocitabine, epothilone, eribulin, everolimus, exatecan, exisulind, feruginol, porodecin, phosgestrol, ICE Chemotherapy Regimen, IT-101, Imexone, Imiquimod, Indolocarbazole, Irofulvene, Raniquider, Larotaxel, Lenalidomide, Lucanthone, Rutotecan, Maposphamide, Mitozolomide, Napo cidin, nedaplatin, olaparib, ortataxel, PAC-1, faupau, pizantrone, proteasome inhibitor, lebecamycin, resiquimod, rubitecan, SN-38, salinosporamide A, sapaci Tabine, Stanford V, Swainsonicin, Talaporfin, Tariquider, Tegafer-uracil, Temodar^&amp;#174;), tecetaxel, triplatin tetranitrate, tris(2-chloroethyl)amine, troxacitabine, uramustine, bodymezan, vinflunin, ZD6126, and zosquider.

In some embodiments, the chemotherapy is selected from hedgehog inhibitors including, but not limited to, IPI-926 (see US Pat. No. 7,812,164). Other suitable hedgehog inhibitors include, for example, inhibitors described and published in US Pat. is incorporated herein by reference in its entirety. Examples of other suitable hedgehog inhibitors include US Patent Application Publication Nos. 2002/0006931, US 2007/0021493 and US 2007/0060546, and International Publication Nos. WO 2001/19800, WO 2001/26644, WO 2001/27135 , WO 2001/49279, WO 2001/74344, WO 2003/011219, WO 2003/088970, WO 2004/020599, WO 2005/013800, WO 2005/033288, WO 2005/032343, WO 2005/042700, WO 2006/028958 , WO 2006/050351, WO 2006/078283, WO 2007/054623, WO 2007/059157, WO 2007/120827, WO 2007/131201, WO 2008/070357, WO 2008/110611, WO 2008/112913, and WO 2008/ 131354. Additional examples of hedgehog inhibitors include, but are not limited to, Von Hoff D. <i>et</i><i></i><i>al</i>., <i>N. </i><i>Engl</i><i>. J.</i><i>Med</i>. 2009; 361(12):1164-72; Robarge KD<i>et</i><i></i><i>al</i><i>.</i>, <i>Bioorg</i><i></i><i>Med</i><i></i><i>Chem</i><i></i><i>Lett</i><i>.</i> 2009; 19(19):5576-81; Yauch, RL et al. (2009)<i>Science</i><i></i>326: 572-574; Sciencexpress: 1-3 (10.1126/science.1179386); Rudin, C.<i>et</i><i></i><i>al</i>.(2009) <i>New</i><i></i><i>England</i><i> J </i><i>of</i><i></i><i>Medicine</i> 361-366 (10.1056/nejma0902903); GDC-0449 (also known as RG3616 or bismodegib); See Siu L.<i>et</i><i></i><i>al</i><i>.</i>, <i>J. </i><i>Clin</i><i>. </i><i>Oncol</i><i>.</i> 2010; 28:15s(suppl; abstr 2501); and National Institute of Health Clinical Trial Identifier No. NCT006701891 (also known as XL139); The literature [Pan S.<i>et</i><i></i><i>al</i><i>.</i>, <i>ACS </i><i>Med</i><i>. </i><i>Chem</i><i>. </i><i>Lett</i><i>.</i>, 2010; 1(3): 130-134; See National Institute of Health Clinical Trial Identifier No. LEQ-506 described in NCT01106508; See National Institute of Health Clinical Trial Identifier No. PF-04449913 described in NCT00953758; Hedgehog pathway antagonists disclosed in US Patent Application Publication No. 2010/0286114; SMOi2-17 described in US Patent Application Publication No. 2010/0093625; Rominger CM et al.,<i>J. </i><i>Pharmacol</i><i>. </i><i>Exp</i><i>. </i><i>Ther</i><i>.</i> 2009; 329(3):995-1005; Lucas BS et al.,<i>Bioorg</i><i>. Med.</i><i>Chem</i><i>. </i><i>Lett</i>. 2010; 20(12):3618-22, or an analog thereof.

Other chemotherapeutic agents include, but are not limited to, anti-estrogens (eg, tamoxifen, raloxifene, and megestrol), LHRH agonists (eg, goscrylline and leuprolide), anti-androgens (eg, flutamide and bicaluta) amide), photodynamic therapeutics (eg, vertopophine (BPD-MA), phthalocyanine, photosensitizer Pc4, and dimethoxy-hypocrelin A (2BA-2-DMHA)), nitrogen mustard (eg, cyclophosphama) id, ifosfamide, trophosphamide, chlorambucil, estramustine, and melphalan), nitrosoureas (such as carmustine (BCNU) and lomustine (CCNU)), alkylsulfonates (such as busulfan) and threosulfan), triazines (such as dacarbazine, temozolomide), platinum-containing compounds (such as cisplatin, carboplatin, oxaliplatin), vinca alkaloids (such as vincristine, vinblastine, vindesine, and vinocine) relvin), taxoids (such as paclitaxel or paclitaxel equivalents such as nanoparticle albumin-bound paclitaxel (Abrazan), Docosahexaenoic acid bound-paclitaxel (DHA-paclitaxel, Taxoprexin^&amp;#174;)), polyglutamate bound-paclitaxel (PG-paclitaxel, paclitaxel polyglomex, CT-2103, XYOTAX^™)), the tumor-activated prodrug (TAP) ANG1005 (anjiopep-2 binds to 3 molecules of paclitaxel), paclitaxel-EC-1 (paclitaxel binds to the erbB2-recognizing peptide EC-1), and glucose-conjugated paclitaxel such as 2'-paclitaxel methyl 2-glucopyranosyl succinate; docetaxel, taxol), epipodophylline (e.g., etoposide, etoposide phosphate, teniposide, topotecan, 9-aminocamptothecin, camptoirinotecan, irinotecan, cristol, mitomycin C), anti-metabolite, DHFR inhibitor (e.g., methotrexate, dichloromethotrexate, trimetrexate, edatrexate), IMP dehydrogenase inhibitors (e.g., mycophenolic acid, thiazopurine, ribavirin, and EICAR), ribonucleotide reductase inhibitors (e.g., hydroxy urea and deferoxamine), uracil analogues (eg, 5-fluorouracil (5-FU), flosuridine, doxyfluridine, latitrexed, tegafer-uracil, capecitabine), cytosine analogues (eg, cytarabine (ara C), cytosine arabinoside, and fludarabine), purine analogs (eg, mercaptopurine and thioguanine), vitamin D3 analogues (eg, EB 1089, CB 1093, and KH 1060), isoprenylation inhibitors (eg, lovastatin), dopaminergic neurotoxins (eg, 1-methyl-4-phenylpyridinium ion), cell cycle inhibitors (eg staurosporin), actinomycins (eg actinomycin D, dactinomycin), bleomycins (eg bleomycin A2, bleomycin) B2, peflomycin), anthracyclines (e.g. daunorubicin, doxorubicin, peglylated liposomal doxorubicin, idarubicin, epirubicin, pyrarubicin, zorubicin, mitoxantrone), MDR inhibitors (e.g. , verapamil), Ca²⁺ ATPase inhibitors (eg, thapsigagin), imatinib, thalidomide, lenalidomide, tyrosine kinase inhibitors (eg, axitinib (AG013736), bosutinib (SKI-606), cediranib (RECENTIN)^™), AZD2171), Dasatinib (SPRYCEL^&amp;#174;), BMS-354825), erlotinib (TARCEVA^&amp;#174;)), gefitinib (IRESSA^&amp;#174;)), imatinib (Gleevec^&amp;#174;, CGP57148B, STI-571), lapatinib (TYKERB^&amp;#174;), TYVERB^&amp;#174;)), restautinib (CEP-701), neratinib (HKI-272), nilotinib (TASIGNA^&amp;#174;)), semazanib (semazanib, SU5416), sunitinib (sutent^&amp;#174;, SU11248), toceranib (PALLADIA^&amp;#174;)), vandetanib (Zaktima^&amp;#174;, ZD6474), vatalanib (PTK787, PTK/ZK), trastuzumab (Herceptin)^&amp;#174;), bevacizumab (Avastin^&amp;#174;), rituximab (rituzan^&amp;#174;), cetusimab (Erbitux^&amp;#174;), panitumumab (Vectivix^&amp;#174;), ranibizumab (Lucentis^&amp;#174;), nilotinib (Tasigna^&amp;#174;), sorafenib (Nexavar^&amp;#174;), everolimus (AFINITOR^&amp;#174;)), alemtuzumab (CAMPATH)^&amp;#174;)), gemtuzumab ozogamicin (MYLOTARG^&amp;#174;)), temsirolimus (TORISEL^&amp;#174;)), ENMD-2076, PCI-32765, AC220, dovitinib lactate (TKI258, CHIR-258), BIBW 2992 (TOVOKTM), SGX523, PF-04217903, PF-02341066, PF-299804, BMS-777607, ABT -869, MP470, BIBF 1120 (VARGATEF^&amp;#174;)), AP24534, JNJ-26483327, MGCD265, DCC-2036, BMS-690154, CEP-11981, tivozanib (AV-951), OSI-930, MM-121, XL-184, XL-647, and/or or XL228), a proteasome inhibitor (eg, bortezomib (Velcade)^&amp;#174;), mTOR inhibitors (e.g., rapamycin, temsirolimus (CCI-779), everolimus (RAD-001), ridaforolimus, AP23573 (Ariad), AZD8055 (AstraZeneca) , BEZ235 (Novatis), BGT226 (Novatis), XL765 (Sanofi Aventis), PF-4691502 (Pfizer), GDC0980 (Genentech), SF1126 (Semafoe) and OSI-027 (OSI)); Oblimersen, gemcitabine, caminomycin, leucovorin, pemetrexd, cyclophosphamide, dacarbazine, procarbazine, prednisolone, dexamethasone, campathecin, plicamycin, asparaginase, aminopterin, meth topterin, porphyromycin, melphalan, leurocidin, leurocin, chlorambucil, trabectedine, procarbazine, discordermolide, caminomycin, aminopterin, and hexamethyl melamine.

Exemplary biotherapeutic agents include, but are not limited to, cytokines (eg, tumor necrosis factor, interferon α, interferon γ), vaccines, hematopoietic growth factors, monoclonal serum therapy, immune stimulants and/or immune modulators (eg, IL-1, 2, 4, 6, or 12), immune cell growth factor (eg GM-CSF) and antibodies (eg Herceptin)^&amp;#174;(trastuzumab), T-DM1, Avastin^&amp;#174;(bevacizumab), Erbitus^&amp;#174;(cetusimab), Vectibix^&amp;#174;(panitumumab), rituzan^&amp;#174;(rituximab), and Bexar^&amp;#174;(tositumomab)).

In some embodiments, the chemotherapeutic agent is selected from an HSP90 inhibitor. The HSP90 inhibitor may be a geldanamycin derivative such as a benzoquinone or hydroquinone ansamycin HSP90 inhibitor (eg, IPI-493 and/or IPI-504). Non-limiting examples of HSP90 inhibitors include IPI-493, IPI-504, 17-AAG (also known as tanespimycin or CNF-1010), BIIB-021 (CNF-2024), BIIB-028, AUY-922 ( Also known as VER-49009), SNX-5422, STA-9090, AT-13387, XL-888, MPC-3100, CU-0305, 17-DMAG, CNF-1010, Macbesin (e.g. Macbesin I) , Macbesin II), CCT-018159, CCT-129397, PU-H71, or PF-04928473 (SNX-2112).

In some embodiments, the chemotherapeutic agent is selected from a PI3K inhibitor (eg, including a PI3K inhibitor disclosed herein and a PI3K inhibitor not disclosed herein). In some embodiments, the PI3K inhibitor is an inhibitor of the delta and gamma isoforms of PI3K. In some embodiments, the PI3K inhibitor is an inhibitor of the alpha isoform of PI3K. In other embodiments, the PI3K inhibitor is an inhibitor of one or more of the alpha, beta, delta and gamma isoforms of PI3K. Exemplary PI3K inhibitors that may be used in combination include, for example, WO 09/088990, WO 09/088086, WO 2011/008302, WO 2010/036380, WO 2010/006086, WO 09/114870, WO 05/113556; US 2009/0312310, and US 2011/0046165. Additional PI3K inhibitors that may be combined with the pharmaceutical composition include, but are not limited to, GSK 2126458, GDC-0980, GDC-0941, Sanofi XL147, XL756, XL147, PF-46915032, BKM 120, CAL-101, CAL 263, SF1126, PX -886, and a dual PI3K inhibitor (eg, Novartis BEZ235). In one embodiment, the PI3K inhibitor is isoquinolinone.

The present invention also provides a compound disclosed herein, or a pharmaceutically acceptable form thereof (eg, a pharmaceutically acceptable salt, hydrates, solvates, chelates, non-covalent complexes, isomers, prodrugs, and isotopically labeled derivatives), or methods of using the pharmaceutical compositions disclosed herein. Techniques for administering radiation are known in the art, and such techniques can be used in combination with the therapies described herein. In such combination therapy, the compounds provided herein may be administered as described herein.

In one embodiment, radiation therapy is one of several methods, or without limitation external beam therapy, internal radiation therapy, implanted radiation, stereotactic radiosurgery, systemic radiation therapy, radiotherapy, and permanent or temporary intra-tissue brachytherapy radiation. It may be administered in combination with a method comprising treatment. As used herein, the term "brachytherapy" refers to radiation therapy in which a spatially defined radioactive material is inserted and delivered into a tumor or near or other site of proliferative tissue disease. The term includes, but is not limited to, radioactive isotopes (e.g., At-211, I-131, I-125, Y-90, Re-186, Re-188, Sm-153, Bi-212, P-32, and Lu exposure to radioactive isotopes of Suitable radioactive sources described herein for use as cell conditioners include both solids and liquids. In a non-limiting embodiment, the radiation source is a radionuclide, such as I-125, I-131, Yb-169, or Ir-192 as a solid source, I-125 as a solid source, or photons, beta particles, gamma rays, or other sources. It may be other radionuclides that emit therapeutic radiation. In addition, the radioactive material may be a fluid made from any solution of a radionuclide, such as a solution of I-125 or I-131, or a slurry of a suitable fluid containing small particles of a solid radionuclide, such as Au-198, or Y-90. It may be a radioactive fluid that can be prepared using In addition, radionuclides may be contained in gels or radioactive microspheres.

Without being limited by any theory, the compounds provided herein can treat abnormal cells to make them more sensitive to radiation in order to kill and/or inhibit the growth of such cells. Accordingly, the present invention provides for sensitizing abnormal cells to radiation treatment comprising administering to a mammal an amount of a compound provided herein, or a pharmaceutically acceptable salt, ester, prodrug, solvate, hydrate or derivative thereof. A method is provided for making, wherein the amount is effective to sensitize the abnormal cells to radiation treatment. The amount of a compound, salt, or solvate in this method can be determined according to the means for ascertaining an effective amount of such a compound as described herein.

In one embodiment, a compound or pharmaceutical composition provided herein can be combined with an amount of one or more substances selected from anti-angiogenic agents, signal transduction inhibitors, antiproliferative agents, glycolysis inhibitors, or autophagy inhibitors.

In one embodiment, anti-angiogenic agents, such as MMP-2 (matrix-metalloproteinase 2) inhibitors, MMP-9 (matrix-metalloproteinase 9) inhibitors, and COX-11 (cyclic Oxygenase 11) inhibitors may be used in conjugation with a compound provided herein or a pharmaceutical composition described herein. An example of a useful COX-II inhibitor is Celebrex^&amp;#174;(allekosip), valdekosip, and lopecosip. Examples of useful matrix-metalloproteinase inhibitors are WO 96/33172, WO 96/27583, European Patent Application No. 97304971.1, European Patent Application No. 99308617.2, WO 98/07697, WO 98/03516, WO 98/ 34918, WO 98/34915, WO 98/33768, WO 98/30566, European Patent Application No. 606,046, European Patent Application No. 931,788, WO 90/05719, WO 99/52910, WO 99/52889, WO 99/29667 , PCT International Application No. PCT/IB98/01113, European Patent Application No. 99302232.1, British Patent Application No. 9912961.1, U.S. Patent No. 7,030,242, U.S. Patent No. 5,863,949, U.S. Patent No. 5,861,510, and European Patent Application No. 780,386 , which is incorporated herein by reference in its entirety. In one embodiment, the MMP-2 and MMP-9 inhibitors are other matrix-metalloproteinases (i.e., MMP-1, MMP-3, MMP-4, MMP-5, MMP-6, MMP-7, It is an inhibitor that inhibits the activity of MMP-1, or inhibits MMP-2 and/or MMP-9, compared to MMP-8, MMP-10, MMP-11, MMP-12, and MMP-13). Some non-limiting examples of MMP inhibitors useful herein are AG-3340, RO 32-3555, and RS 13-0830.

Autophagy inhibitors include, but are not limited to, chloroquine, 3-methyladenine, hydroxychloroquine (plaquienyl^™), bafilomycin A1, 5-amino-4-imidazole carboxamide riboside (AICAR), okadaic acid, an autophagy-inhibiting algal toxin that inhibits type 2A or type 1 protein phosphatase, cAMP analogs, and drugs that increase cAMP levels, such as adenosine, LY204002, N6-mercaptopurine riboside, and vinblastine. In addition, antisense or siRNAs that inhibit the expression of proteins including, but not limited to, ATG5 (associated with autophagy) may be used.

The invention also encompasses amounts of a compound provided herein, or a pharmaceutically acceptable salt, ester, prodrug, solvate, hydrate or derivative thereof, and an amount of one or more second therapeutic agents useful for the treatment of cardiovascular disease. It provides a method for treating cardiovascular disease in mammals with a pharmaceutical composition comprising:

Examples of second therapeutic agents for use in the treatment of cardiovascular disease include, but are not limited to, anti-thrombotic agents such as prostacyclins and salicylates, thrombolytic agents such as streptokinase, urokinase, tissue plasminogen activator ( TPA) and anisoylated plasminogen-streptokinase activating complex (APSAC), anti-platelet agents such as acetyl-salicylic acid (ASA) and clopitrogel, vasodilators such as nitrates, calcium channel blocking drugs, anti- Proliferative agents such as colchicine and alkylating agents, septating agents, growth regulators such as interleukins, transforming growth factor-beta and homologs of platelet-derived growth factors, monoclonal antibodies to growth factors, steroidal and non-steroidal anti- inflammatory agents, and other agents that can modulate vascular tone, action, atherosclerosis, and treat response to interventions after vascular or organ damage. In one embodiment, the coating can be used to precisely affect the site of therapeutic delivery within the vessel wall. In one embodiment, antibiotics may also be combined or included with a coating provided herein. In one embodiment, an activator may be incorporated in the swellable polymer and released into the swelling of the polymer.

In one embodiment, the compounds described herein may be formulated or administered in conjugation with liquid or solid tissue barriers known as lubricants. Examples of tissue barriers include, but are not limited to, polysaccharides, polyglycans, sefrafilm, anti-adhesive agents, and hyaluronic acid.

In one embodiment, the medicament that can be administered in conjugate with the compound described herein is a suitable drug that can be delivered by inhalation, such as an analgesic such as codeine, dihydromorphine, ergotamine, pentanyl or morphine; angina agents such as diltiazem; antiallergic agents such as chromoglycate, ketotifen or nedocromil; anti-infective agents such as cephalosporins, penicillins, streptomycin, sulfonamides, tetracyclines or pentamidines; antihistamines such as metapyrylene; anti-inflammatory agents such as beclomethasone, flunisolide, budesonide, tipredan, triamcinolone acetonide or fluticasone; antitussives such as noscapine; Bronchodilators such as ephedrine, adrenaline, phenoterol, formoterol, isoprenaline, metaproterenol, phenylephrine, phenylpropanolamine, perbuterol, leproterol, limiterol, salbutamol, salmeterol, tabu Talin, isoetharin, tulobuterol, osiprenaline or (-)-4-amino-3,5-dichloro-α-[[[6-[2-(2-pyridinyl)ethoxy]hexyl] -amino]methyl]benzenemethanol; diuretics such as amiloride; anticholinergic agents such as ipratropium, atropine or oxytropium; hormonal agents such as cortisone, hydrocortisone or prednisolone; xanthines such as aminophylline, choline theophylline, lysine theophylinate or theophylline; and therapeutic proteins and peptides such as insulin or glucagon. In one embodiment, where appropriate, the medicament is used in the form of a salt (eg, alkali metal or amine salt or acid addition salt) or ester (eg, lower alkyl ester) or solvate (eg, hydrate) so that the activity of the medicament is and/or to optimize stability.

Other exemplary therapeutic agents useful in combination therapy include, but are not limited to, the agents described herein, radiation therapy, hormone antagonists, hormones and their releasing factors, thyroid and antithyroid drugs, estrogens and progestins, androgens, adrenocorticotropic hormones; adrenocortical steroids and synthetic analogs thereof; Inhibitors of the synthesis and action of corticosteroids, insulin, oral hypoglycemic agents, and agents of the endocrine pancreas, calcium, phosphate, agents affecting calcification and bone replacement, vitamin D, calcitonin, vitamins such as water-soluble vitamins, vitamin B complexes, ascorbic acid, fat soluble vitamins, vitamins A, K, and E, growth factors, cytokines, chemokines, muscarinic receptor agonists and antagonists; anticholinesterase agents; agents acting at the neuromuscular junction and/or autonomic ganglia; catecholamines, sympathomimetic agents, and adrenergic receptor agonists or antagonists; and 5-hydroxytryptamine (5-HT, serotonin) receptor agonists and antagonists.

In one embodiment, the therapeutic agent is also one or more agents for pain and inflammation, such as histamine and histamine antagonists, bradykinin and bradykinin antagonists, 5-hydroxytryptamine (serotonin), selective hydrolysis of membrane phospholipids. Lipid substances produced by biotransformation of products, eicosanoids, prostaglandins, thromboxanes, leukotrienes, aspirins, nonsteroidal anti-inflammatory agents, analgesic-antipyretics, agents inhibiting the synthesis of prostaglandins and thromboxanes, inducible Selective inhibitors of cyclic oxygenases, selective inhibitors of inducible cyclic oxygenase-2, otacoids, paracrine hormones, somatostatin, gastrin, cytokines, lipids that mediate interactions related to humoral and cellular immune responses -Including induced otacoids, eicosanoids, β-adrenergic agonists, ipratropium, glucocorticoids, methylxanthine, sodium channel blockers, opioid receptor agonists, calcium channel blockers, membrane stabilizers, and leukotriene inhibitors can do.

In one embodiment, the additional therapeutic agents contemplated herein are diuretics, vasopressin, agents that affect renal preservation of water, renin, angiotensin, agents useful for treating myocardial ischemia, anti-hypertensive agents, angiotensin converting enzyme inhibitors, β-adrenergic receptor antagonists, therapeutic agents for hypercholesterolemia, and therapeutic agents for dyslipidemia.

In one embodiment, the other therapeutic agent contemplated herein is a drug used to control gastric acidity, a drug used to treat gastric ulcer, an agent to treat gastroesophageal reflux disease, a gastrointestinal motility agent, an antiemetic agent, an agent used for irritable bowel syndrome, use for diarrhea Agents used to treat protozoan infections, agents used for constipation, agents used for inflammatory bowel disease, agents used for gallbladder disease, agents used for pancreatic disease, agents used to treat protozoan infections, malaria, amoebic dysentery, trichomoniasis , drugs used to treat trichomoniasis, sleeping sickness, and/or leishmaniasis, and/or drugs used for chemotherapy of parasitic diseases. In one embodiment, the other therapeutic agent is an antimicrobial agent, sulfonamide, trimethoprim-sulfamethoxazole quinolone, and agents for urinary tract infections, penicillins, cephalosporins, and other beta-lactam antibiotics, aminoglycosides. preparations containing, protein synthesis inhibitors, drugs used for the chemotherapy of tuberculosis, Mycobacterium avium complex disease, and Hansen's disease, antifungal agents, and antiviral agents including nonretroviral agents and antiretroviral agents.

In one embodiment, examples of therapeutic antibodies that can be combined with a compound provided herein include, but are not limited to, anti-receptor tyrosine kinase antibodies (cetuximab, panitumumab, trastuzumab), anti-CD20 antibodies (rituximab) Mab, tositumomab), and other antibodies such as alemtuzumab, bevacizumab, and gemtuzumab.

In other embodiments, therapeutic agents used in immune modulation, such as immune modulators, immunosuppressants, tolerogens, and immune stimulants, are contemplated by the methods provided herein. In further embodiments, therapeutic agents that act on blood and blood-forming organs, hematopoietic agents, growth factors, minerals, vitamins, anticoagulants, thrombolytic agents, and antiplatelet drugs are contemplated by the methods provided herein.

In one embodiment, a compound disclosed herein, or a pharmaceutically acceptable form (eg, a pharmaceutically acceptable salt, hydrate, solvate, chelate, non-covalent complex, isomer, prodrug thereof) thereof, is used for the treatment of renal cancer. , and isotopically labeled derivatives), or a pharmaceutical composition disclosed herein, may be combined with sorafenib and/or avastin. To treat endometrial disease, a compound disclosed herein may be combined with doxorubincin, taxotere (Taxol), and/or cisplatin (carboplatin). To treat ovarian cancer, a compound disclosed herein may be combined with cisplatin (carboplatin), taxotere, doxorubincin, topotecan, and/or tamoxifen. To treat breast cancer, a compound disclosed herein is administered with Taxotere (Taxol).^&amp;#174;), Gemcitabine (Capecitabine), Tamoxifen, Letrozole, Tarceva^&amp;#174;, Lapatinib, PD0325901, Avastin^&amp;#174;, Herceptin^&amp;#174;, OSI-906, and/or OSI-930. To treat lung cancer, a compound disclosed herein may be combined with Taxotere (Taxol), Gemcitabine, Cisplatin, Pemetrexd, Tarceva^&amp;#174;, PD0325901, and/or Avastin^&amp;#174;can be combined with

In one embodiment, additional therapeutic agents that may be combined with the subject compound are described in Goodman and Gilman's "The Pharmacological Basis of Therapeutics" Eleventh Edition; or in the Physician's Desk Reference, which is incorporated herein by reference in its entirety.

In one embodiment, a compound described herein may be used in combination with an agent described herein or other suitable agent depending on the condition being treated. Accordingly, in some embodiments, a compound provided herein will be administered in combination with other agents described herein. When used in combination therapy, the compounds described herein may be administered simultaneously or separately with a second agent. Such combined administration may include simultaneous administration of the two agents in the same formulation, simultaneous administration in separate formulations, and separate administration. In one embodiment, a compound described herein and any additional agent described herein can be formulated together in the same formulation and administered simultaneously. Alternatively, a compound provided herein and any additional agent described herein can be administered simultaneously, wherein the compound and agent are in separate formulations. In another alternative, a compound provided herein can be administered before or after administration of any additional agent provided herein. In separate dosing protocols, a compound provided herein and any additional agent described herein can be administered at intervals after a few minutes, or hours, or days.

The examples and methods of preparation provided below illustrate the compounds, polymorphs and compositions provided herein, and methods of making such compounds, polymorphs, and compositions. It is understood that the scope of the present invention will not in any way limit the scope of the following examples and preparation methods. In the examples below, unless otherwise noted, molecules comprising a single chiral center exist as racemic mixtures. Unless otherwise known, molecules having two or more chiral centers exist as racemic mixtures of diastereomers. Single enantiomers/diastereomers can be obtained by methods known to those skilled in the art.

Bibliography Citation

All publications, patents, and patent applications mentioned herein are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was expressly and individually indicated to be incorporated by reference. In case of conflict, the present application, including any definitions, will control.

<b>Example</b>

<b><u>chemical </u></b><b><u>Example</u></b>

Unless specifically opposed, the reactions described herein occur at atmospheric pressure, generally in the temperature range of -10 to 200°C. Also, unless otherwise specified, reaction times and conditions are intended to occur over a temperature range of from about -10 to about 110° C., such as from about 1 to about 24 hours, such as at about atmospheric pressure; In some embodiments, the average overnight lasting response is about 16 hours. As used herein, the term "volume" or "vol" refers to 1 L of solvent per kg of limiting reagent.

Isolation and purification of the chemicals and intermediates described herein may be optionally effected by any suitable separation or purification procedure, such as filtration, extraction, crystallization, column chromatography, thin layer chromatography or thick film chromatography, or a combination of procedures thereof. can go crazy Specific examples of suitable separation and isolation procedures are incorporated by reference in the Examples set forth below. However, other equivalent separation or isolation procedures may also be used.

In some embodiments, if present, the (R)- and (S)-isomers of the non-limiting exemplary compounds can be separated by methods known to those skilled in the art, such as by crystallization, by combining diastereomeric salts or complexes; diastereomeric derivatives which can be separated by crystallization, gas-liquid or liquid chromatography; selective reaction of one enantiomer with an enantiomer-specific reagent, such as enzymatic oxidation or reduction followed by separation of the modified and unmodified enantiomers; or by gas-liquid or liquid chromatography in a chiral environment, such as on a chiral support, such as in a silica environment comprising bound chiral ligands or in the presence of a chiral solvent. Alternatively, certain enantiomers can be synthesized by asymmetric synthesis using optically active reagents, substrates, catalysts or solvents, or by converting one enantiomer to the other by asymmetric transformation.

The compounds described herein can optionally be contacted with a pharmaceutically acceptable acid to form the corresponding acid addition salt. In addition, the compounds described herein can optionally be contacted with a pharmaceutically acceptable base to form the corresponding base addition salt.

In some embodiments, the disclosed compounds can generally be synthesized by appropriate combinations of well-known synthetic methods. Techniques useful for synthesizing these chemicals are readily apparent and accessible to those skilled in the art on the basis of their immediate disclosure. Many optionally substituted starting compounds and other reactants are commercially available, such as from Aldrich Chemical Company, Milwaukee, Wis., or can be readily prepared by one of ordinary skill in the art using commercially used synthetic methods.

The following description illustrates several specific methods available for use in making the disclosed compounds, and is not intended to limit the scope of the reactions or reaction sequences that can be used to prepare the compounds provided herein.

Polymorphs made according to the methods provided herein can be characterized by any method known in the art. For example, polymorphs made according to the methods provided herein can be obtained from X-ray powder diffraction (XRPD), differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), dynamic vapor adsorption (DVS), hotness speculum, light microscopy, knife Fisher analysis, melting point, spectroscopy (e.g., Raman, solid state nuclear magnetic resonance (ssNMR), liquid state nuclear magnetic resonance (¹H- and ¹³C-NMR), and FT-IR), thermal stability, grinding stability, and solubility, and the like.

<b>XRPD</b>

The compounds and polymorphs provided herein can be characterized by an X-ray powder diffraction pattern (XRPD). The relative intensities of the XRPD peaks may vary depending on the sample preparation technique, the sample mounting procedure, and the particular instrument used. In addition, instrumental variables and other factors can affect the 2θ peak value. Thus, in certain embodiments, the XRPD peak designation can vary by a θ greater than or equal to about 0.2° plus or minus, and is referred to as "(±0.2°)."

XRPD patterns for each of Forms A to J and the amorphous form of the compound of Formula (I) were analyzed using PANalytical CubiX using an incident beam of CU radiation produced using an Optix long, fine-focus raw material. Collected with an XPert PRO MPD diffractometer. An elliptically graded multilayer mirror was used to focus Cu Kα X-rays through the sample and onto the detector. The sample was placed in a Si zero-return ultramicro sample holder. The analysis was performed using a 10 mm irradiated width and the following parameters were set in hardware/software:

X-ray tube: Cu Kα, 45 kV, 40 mA

Detector: X'celerator

Slit: ASS Primary Slit: Fixed 1°

Divergence Slit (Prog): Auto - 5 mm irradiated length

Solar slit: 0.02 radians

Scatter Slit (PASS): Auto - 5 mm Observed Length

<u>scanning</u>

Scan range: 3.0 to 45.0°

Scan Mode: Continuous

Step size: 0.03°

Time per step: 10 seconds

Active Length: 2.54°

<b>DSC</b>

The compounds and polymorphs provided herein can be characterized by certain differential scanning calorimetry (DSC) thermograms. It is known in the art that in DSC, the observed peak temperature depends on the rate of temperature change, the sample preparation technique, and the particular instrumentation used, and the like. Thus, the peak values in the DSC thermograms reported herein can vary by at least ± about 2 °C, ± about 3 °C, ± about 4 °C, ± about 5 °C, ± about 6 °C, to ± about 7 °C or more. In some polymorphs, DSC analysis was performed on more than one sample, exemplified by the known variability in peak positions, such as the factors mentioned above. As an indicator of different samples of a single polymorphic form of the compound of formula (I), the observed peak position differences were maintained, as would be expected of a person skilled in the art.

Also, impurities in the sample can affect the observed peaks on any given DSC thermogram. In some embodiments, at least one chemical entity that is not a polymorph of a compound of Formula (I) in a sample analyzed by DSC may produce at least one peak at a temperature lower than the peak associated with the transition temperature of a given polymorph disclosed herein.

DSC analysis was performed using a Mettler 822e differential scanning calorimeter. Samples were weighed in an aluminum pan, covered with a perforated lid and crimped. Typical assay conditions were from about 300 to about 350° C. at about 30 ramping at about 10° C./min. Several additional ramp rates, including about 2° C./min, about 5° C./min, and about 20° C./min, were utilized as part of observing high melt Form B. Samples were analyzed at multiple ramp rates to determine the thermal and dynamic transitions observed.

In addition, an isothermal maintenance experiment was performed using DSC. The sample was ramped to a temperature (about 100° C. to about 250° C.) at about 10° C./min, held at this temperature for about 5 minutes, and then rapidly cooled to room temperature. In this case, samples were analyzed by XRPD or re-analyzed by DSC.

<b>TGA</b>

Polymorphic forms provided herein may exhibit different thermal behavior than amorphous materials or other polymorphic forms. The thermal behavior can be measured in the laboratory by thermogravimetric analysis (TGA), which can be used to distinguish some polymorphic forms from others. In one embodiment, the polymorphs disclosed herein can be characterized by thermogravimetric analysis.

TGA analysis was performed using a METTLER 851e SDTA/TGA thermogravimetric analyzer. Samples were weighed into an alumina crucible and analyzed at about 30 to about 230°C, and a ramp rate of about 10°C/min.

<b>DVS</b>

The compounds and polymorphs provided herein can be characterized by water absorption assays. This analysis was performed using a Hiden IGAsorp moisture absorption instrument. Water absorption experiments were performed at about 25° C. with an adsorption scan of about 40 to about 90% RH in a step of about 10% RH and a desorption scan of about 85 to about 0% RH in a step of about -10% RH. A second adsorption scan from about 10 to about 40% RH was performed to determine the moisture uptake at the starting humidity from the dry state. Samples were equilibrated at each point for about 4 hours or until an asymptotic weight was reached. After the isothermal absorption scan, the sample was dried at an elevated temperature (about 60° C.) for about 1 hour to obtain a dry weight. XRPD analysis was performed on the material that followed water absorption to determine the solid form.

<b>light microscope</b>

The compounds and polymorphs provided herein can be characterized by a microscope, such as an optical microscope. Light microscopy analysis was performed using a Leica DMRB polarized microscope. Samples were observed under a polarizing microscope equipped with a digital camera (1600×1200 resolution). A small sample was suspended in mineral oil on a glass slide to cover the cover slide and viewed at 100x magnification.

<b>Karl Fisher Analysis</b>

The compounds and polymorphs provided herein can be characterized by a Karl Fischer assay to determine water content. Karl Fischer analysis was performed using a Metrohm 756 KF coulometer. A Karl Fischer titration was performed by adding water (50 μg), material sufficient to obtain a sample (about 10 to about 50 mg), to the AD coulometer.

<b>Raman spectroscopy</b>

The compounds and polymorphs provided herein can be characterized by Raman spectroscopy. Raman spectroscopic analysis was performed using a Kaiser Raman RXN1 instrument containing samples in glass wells. Raman spectra were collected using a PhAT macroscope at an irradiation frequency of about 785 nm and a spot size of about 1.2 mm. Samples were analyzed using 12 to 16 cumulative values including exposure times of about 0.5 to about 12 seconds and cosmic ray filtering utilized. Data were processed by background isolation of empty wells collected under the same conditions. Baseline adjustments and smoothing were performed to obtain interpretable data, if necessary.

<b>FT</b><b>-</b><b>IR</b><b></b>

The compounds and polymorphs provided herein can be characterized by FT-IR spectroscopy. FT-IR spectroscopy was performed using a Nicolet Nexus 470 or Avatar 370 infrared spectrometer and OMNIC software. Samples were analyzed using a diamond attenuated total reflection (ATR) accessory. The compound sample was applied to the diamond crystal surface, and the appropriate pressure was applied by turning the ATR knob. Spectra were then obtained and analyzed using Omnic software. Alternative sample preparations include solution cells, mull, thin film, and compressed disks, such as disks made of KBr known in the art.

<b>NMR</b>

The compounds and polymorphs provided herein can be characterized by nuclear magnetic resonance (NMR). NMR spectra were obtained using a 500 MHz Bruker AVANCE with a 5 mm BBO probe instrument. Samples (about 2 to about 10 mg) were run in DMSO-d with 0.05% tetramethylsilane (TMS) to internal standard.₆was dissolved in ¹H-NMR spectra were obtained using a broadband observe (1H-X) Z gradient probe (5 mm) at 500 MHz. A 30° pulse with a spectral width of 20 ppm, a repetition rate of 1.0 s, and a transient signal of 32 to 64 was used to obtain the spectrum.

<b>high performance liquid </b><b>chromatography</b><b></b>

The compounds and polymorphs provided herein can be analyzed by high performance liquid chromatography using an Agilent 1100 instrument. The instrument parameters for achiral HPLC are as follows:

Column: Sunfire C18 4.6 x 150 mm

Column temperature: ambient temperature

Autosampler Temperature: Ambient Temperature

Detection: UV at 250 nm

Mobile phase A: 0.05% trifluoroacetic acid in water

Mobile phase B: 0.05% trifluoroacetic acid in MeCN

Flow rate: 1.0 mL/min

Injection volume: 10 μL

Data collection time: 20 minutes

Re-equilibration time: 5 minutes

Diluent and needle wash: MeOH

<b>gradient</b><b> condition</b>

<img file="KR20140020249A_D0047.tif" />

The compounds and polymorphs provided herein can be analyzed by high performance liquid chromatography using a chiral HPLC column to determine the %ee value:

Column: Chiralpak IC, 4.6 mm × 250 mm, 5 μm

Column temperature: room temperature

Sample temperature: room temperature

Detection: UV at 254 nm

Mobile phase A: 40% 60% hexane with 0.2% acetic acid and 0.1% DEA (IPA:EtOH = 2:3)

Isocratic: 100% A

Flow rate: 1 mL/min

Diluent: Methanol

Injection volume: 10 μL

Analysis time: 25 minutes

Example 1

Synthesis of (S)-3-(1-aminoethyl)-8-chloro-2-phenylisoquinolin-1(2H)-one

Example 1A

<img file="KR20140020249A_D0048.tif" />

Compound 1 (6.00 kg) was mixed with 1-hydroxybenzotriazole monohydrate (HOBt-H) in dimethylacetamide (DMA) at 10°C.₂O), triethylamine, N,O-dimethylhydroxylamine hydrochloride, and EDCI. The reaction was monitored by proton NMR and deemed complete after 2.6 h to afford compound 2 as a white solid in 95% yield.<i>R</i>-Enantiomers were not detected by proton NMR using (R)-(-)-alpha-acetylmandelic acid as a chiral-transfer agent.

Example 1B

<img file="KR20140020249A_D0049.tif" />

Compound 3 (4.60 kg) was treated with p-toluenesulfonic acid monohydrate and 3,4-dihydro-2H-pyran (DHP) in ethyl acetate at 75° C. for 2.6 h. The reaction was monitored by HPLC. Upon completion of the reaction, compound 4 was obtained as a yellow solid with a purity greater than 99% (AUC) by HPLC analysis in 80% yield.

Example 1C

<img file="KR20140020249A_D0050.tif" />

Compound 5 (3.30 kg) was treated with thionyl chloride in methylene chloride and a catalytic amount of DMF for 5 h at 25°C. The reaction was monitored by HPLC and showed conversion of 97.5% (AUC) to compound 6. Compound 6 was treated in situ with aniline in methylene chloride at 25° C. for 15 h. The reaction was monitored by HPLC and compound 7 was obtained as a brown solid in 81% yield with a purity greater than 99% (AUC) by HPLC analysis.

Compound 2 was treated with 2.0 M isopropyl Grignard in THF at -20°C. The resulting solution at -15°C was added to compound 7 (3.30 kg) pretreated with n-hexyl lithium (2.3 M) in tetrahydrofuran. The reaction was monitored by HPLC until conversion of 99% (AUC) to compound 8 was observed. Compound 8 was treated in situ with concentrated HCl in isopropyl alcohol at 70° C. for 8 hours. The reaction was monitored by HPLC and compound 9 was obtained as a brown solid in 85% yield with 98% (AUC) purity and 84% (AUC) ee by HPLC analysis.

Example 1D

Compound 9 (3.40 kg) was treated with D-tartaric acid in methanol at 55° C. for 1-2 h. The batch was filtered and treated with ammonium hydroxide in deionized water to give enantiomerically enriched compound 9 as a tan solid in 71% yield with &gt;99% (AUC) purity and 91% (AUC) ee by HPLC analysis. did.

Example 2

Synthesis of (S)-3-(1-aminoethyl)-8-chloro-2-phenylisoquinolin-1(2H)-one

<img file="KR20140020249A_D0051.tif" />

Example 2A

To compound 7 (20.1 g) was charged anhydrous THF (100 mL). The resulting solution was cooled to about 10° C. and n-hexyl lithium (80 mL, 2.3 M in hexanes, 2.26 eq) was added slowly (eg, over about 20 minutes). The resulting solution was stirred at about 10° C. for about 20 minutes.

To compound 2 (26.5 g; 1.39 equiv) was charged anhydrous THF (120 mL). The resulting mixture was cooled to about 10° C. and isopropyl magnesium chloride (60 mL, 2.0 M in THF, 1.47 equiv) was added slowly (eg, over about 15-20 minutes). The resulting mixture was then stirred at about 10° C. for about 20 minutes. While the mixture prepared from compound 2 was added to the solution prepared from compound 7, the internal temperature was maintained at about -10 to about 0°C. After the addition was complete (about 5 minutes), the cooling batch was removed and the resulting mixture was stirred at ambient temperature for about 1 hour before cooling.

A solution of anisole (100 mL) and isobutyric acid (33 mL, 4.37 equiv) was prepared. The anisole solution was cooled to an internal temperature of about -3°C. The reaction mixture was added to the anisole solution to maintain the internal temperature of the anisole solution below about 5°C. The cooling batch was then removed (after about 15 minutes, the internal temperature was about 7° C.). To the mixture was rapidly added 10 wt % aqueous NaCl solution (100 mL) (increasing the internal temperature to about 7 to about 15 °C). After stirring for about 30 minutes, the two phases were separated. The organic phase was washed with another 10 wt % aqueous NaCl (100 mL). The organic phase was transferred to a flask using anisole (25 mL) to facilitate transfer. The anisole solution was then concentrated to 109 g. Then anisole (100 mL) was added.

TFA (50 mL, 8 equiv) was added to the anisole solution (ca. 200 mL) while maintaining the internal temperature below about 45-50 °C. The resulting solution was warmed to about 45-50° C., stirred for about 15 hours, and then cooled to 20-25° C. MTBE (300 mL) was added dropwise to this solution, and the resulting mixture was left at 20-25° C. for 1 hour. The mixture was filtered and the wet cake was washed with MTBE (ca. 50 mL). The wet cake was conditioned on the filter under nitrogen for about 1 hour. The wet cake was mixed periodically and mixed well again during conditioning. The wet cake was then washed with MTBE (200 mL). The wet cake was further conditioned for about 2 hours (wet cake was mixed and mixed well again after about 1.5 hours). The wet cake was dried in a vacuum oven at about 40° C. for about 18 hours to give compound 9-TFA salt with a purity (AUC) of about 97.3%, which was about 99.1% of the S-enantiomer (e.g., about 99.1% of the chiral purity).

Compound 9-TFA salt (3 g) was suspended in EtOAc (30 mL) at about 20°C. To the EtOAc suspension was added 14% aqueous ammonium hydroxide solution (4.5 mL, 2.2 equiv) and the internal temperature was reduced to about 17°C. Water (5 mL) was added to the biphasic mixture. The biphasic mixture was stirred for 30 minutes. The mixture was stopped and the phases were separated. The aqueous phase was removed. To the organic phase (combined with EtOAc (5 mL)) was added 10% aqueous NaCl (10 mL). The biphasic mixture was stirred for about 30 minutes. The aqueous phase was removed. The organic layer was concentrated to 9 g. To this EtOAc mixture was added i-PrOAc (20 mL). The resulting mixture was concentrated to 14.8 g. While stirring, n-heptane (10 mL) was added dropwise. After the suspension was stirred for about 30 minutes, additional n-heptane (10 mL) was added. The resulting suspension was stirred for 1 h. The suspension was filtered and the wet cake was washed with additional heptane. The wet cake was conditioned under nitrogen for 20 minutes and then dried in a vacuum oven at about 40° C. to add compound 9 (free base) to a purity of about 99.3% (AUC), which contained about 99.2% of the S-enantiomer ( for example, about 99.2% chiral purity).

Example 2B

A mixture of compound 7 (100 g, 0.407 mol, 1 weight) and THF (500 mL, 5 vol) was prepared and cooled to about 3°C. n-Hexyllithium (2.3 M in hexanes, 400 mL, 0.920 mol, 2.26 equiv) was charged over about 110 minutes while maintaining the temperature below about 6°C. The resulting solution was stirred at 0±5° C. for about 30 minutes. Simultaneously, a mixture of compound 2 (126 g, 0.541 mol, 1.33 equiv) and THF (575 mL, 5.8 vol) was prepared. The resulting slurry was charged with isopropylmagnesium chloride (2.0 M in THF, 290 mL, 0.574 mol, 1.41 equiv) over about 85 minutes while maintaining a temperature below about 5°C. The resulting mixture was stirred at 0±5° C. for about 35 minutes. The compound 2 magnesium salt mixture was transferred to the compound 7 lithium salt mixture over about 1 hour, maintaining a temperature of 0±5°C. Upon transfer, the solution was stirred for about 6 minutes.

For a period of time such that the temperature does not exceed about 6 °C over about 20 minutes, the solution is stirred solution of isobutyric acid (165 mL, 1.78 mol, 4.37 equiv) in anisole (500 mL, 5 vol) at about -5 °C. was added to The resulting solution was warmed to about 14° C. while stirring for about 40 minutes. Then 10% sodium chloride solution (500 mL, 5 vol) was added rapidly to the reaction. The temperature rose to about 21°C. After stirring the mixture for about 6 minutes, the stirring was stopped and the lower aqueous layer was removed (ca. 700 mL). A second portion of 10% sodium chloride solution (500 mL, 5 vol) was added and the mixture was stirred for 5 minutes. The stirring was then stopped and the lower aqueous layer was removed. The volume of the organic layer was reduced by vacuum distillation to about 750 mL (7.5 volumes).

Trifluoroacetic acid (250 mL, 3.26 mol, 8.0 equiv) was added and the resulting mixture was stirred at about 45° C. for about 15 hours. The mixture was cooled to about 35° C. and MTBE (1.5 L, 15 vol) was added over about 70 minutes. Upon completion of the addition, the mixture was stirred at about 25-30° C. for about 45 minutes. The solid was collected by vacuum filtration and conditioned under nitrogen for about 20 hours to give compound 9-TFA salt with a purity (AUC) of about 97.5%, which has a chiral purity of about 99.3%.

Compound 9-TFA salt (100 g) was suspended in EtOAc (1 L, 10 vol) and 14% aqueous ammonia (250 mL, 2.5 vol). After the mixture was stirred for about 30 minutes, the lower aqueous layer was removed. A second portion of 14% aqueous ammonia (250 mL, 2.5 vol) was added to the organic layer. After the mixture was stirred for 30 minutes, the lower aqueous layer was removed. Isopropyl acetate (300 mL, 3 vol) was added and more isopropyl acetate (1 L, 10 vol) was added periodically while the mixture was distilled under vacuum to 500 mL (5 vol).

Then, after vacuum distillation to a volume of 600 mL (6 vol), heptane (1.5 L, 15 vol) was added over about 110 minutes while maintaining a temperature of about 20 to about 30 °C. The resulting slurry was stirred for about 1 hour and then the solids were collected by vacuum filtration. The cake was washed with heptane (330 mL, 3.3 vol) and conditioned for about 1 hour. The solid is dried in a vacuum oven at about 45° C. for about 20 hours to give compound 9 (free base) with a purity (AUC) of about 99.23%, which has a chiral purity of about 99.4%.

Example 3

Chiral resolution of (S)-3-(1-aminoethyl)-8-chloro-2-phenylisoquinolin-1(2H)-one (compound 9)

In some instances, synthetically obtained (S)-3-(1-aminoethyl)-8-chloro-2-phenylisoquinolin-1(2H)-one (Compound 9) contains trace amounts of the corresponding (R) -Contains isomers. A chiral resolution procedure is used to improve the enantiomeric purity of (S)-3-(1-aminoethyl)-8-chloro-2-phenylisoquinolin-1(2H)-one specific samples.

In one experiment, compound 9 (3.40 kg) was treated with D-tartaric acid in methanol at about 55° C. for about 1 to about 2 hours. The mixture was filtered and treated with ammonium hydroxide in deionized water to give compound 9 with a purity greater than about 99% (AUC), which had a chiral purity of about 91% (AUC).

In another procedure, MeOH (10 vol) and compound 9 (1 eq) were stirred at 55±5° C. D-tartaric acid (0.95 equiv) was charged. The mixture was allowed to stand at 55±5° C. for about 30 minutes and then cooled to about 20 to about 25° C. over about 3 hours. The mixture was allowed to stand for about 30 minutes and then filtered. The filter cake was washed with MeOH (2.5 vol) and then adjusted. The cake was placed back into the reactor and charged with water (16 vol). The mixture was stirred at 25±5°C. Then, NH₄OH adjusted the pH to about 8 to about 9 over about 1 hour. The mixture was then filtered and the cake washed with water (4 vol) followed by heptane (4 vol). After adjusting the cake, it was vacuum dried at 45-50° C. to obtain compound 9 (free base) with a chiral purity of about 99.0%.

Example 4

Synthesis of (S)-3-(1-(9H-purin-6-ylamino)ethyl)-8-chloro-2-phenylisoquinolin-1(2H)-one

<img file="KR20140020249A_D0052.tif" />

A mixture of compound 7 (1 eq) and anhydrous THF (5 vol) was prepared. Separately, a mixture of compound 2 (1.3 eq) and anhydrous THF (5 vol) was prepared. Both mixtures were stirred at about 20 to about 25° C. for about 15 minutes and then cooled to -25±15° C. n-Hexyl lithium (2.05 equiv) was added to the compound 7 mixture and maintained at a temperature above 5°C. i-PrMgCl (1.33 equiv) was added to the compound 2 mixture and maintained at a temperature above 5°C. The compound 2 mixture was transferred to the compound 7 mixture at 0±5° C. under anhydrous conditions. The resulting mixture was warmed to 20±2° C. and allowed to stand for about 1 hour. The reaction was then cooled to -5±5° C. and 6 N HCl (3.5 equiv) was added to quench the reaction and maintained at a temperature below about 25° C. The aqueous layer was drained and the organic layer was distilled under reduced pressure to 2-3 volumes. IPA (3 vol) was added and vacuum distillation continued until 2-3 vol. IPA (8 vol) was added and the mixture temperature was adjusted to about 60 to about 75°C. After addition of concentrated HCl (1.5 vol), the mixture was allowed to stand for 4 h. The mixture was distilled under reduced pressure to 2.5 to 3.5 volumes. The mixture temperature was adjusted to 30±10°C. Deionized water (3 vol) and DCM (7 vol) were each added to the mixture. Then, NH₄OH was added to the mixture and the pH was adjusted to about 7.5 to about 9. The temperature was adjusted to about 20 to about 25°C. The layers were separated and the aqueous layer was washed with DCM (0.3 vol). The combined DCM layers were distilled to 2 volumes. i-PrOAc (3 vol) was added and vacuum distillation continued until 3 vol. The temperature was adjusted to about 15 to about 30 °C. Heptane (12 vol) was charged to the organic layer and the mixture was allowed to stand for 30 minutes. The mixture was filtered and the filter cake was washed with heptane (3 vol). The cake was vacuum dried at about 45° C. to give compound 9.

Then, MeOH (10 vol) and compound 9 (1 eq) were combined and the temperature was adjusted to 55±5° C. while stirring. D-tartaric acid (0.95 equiv) was charged. The mixture was allowed to stand at 55±5° C. for about 30 minutes and then cooled at about 20 to about 25° C. over about 3 hours. The mixture was allowed to stand for 30 minutes and then filtered. The filter cake was washed with MeOH (2.5 vol) and then adjusted. Water (16 vol) was added to the cake and the mixture was stirred at 25±5°C. NH₄OH was charged over 1 hour to adjust the pH to about 8 to about 9. The mixture was then filtered and the resulting cake was washed with water (4 vol) followed by heptane (4 vol). After adjusting the cake, the compound 9 was obtained by vacuum drying at 45 to 50°C.

To a mixture of i-PrOH (4 vol) and compound 9 (1 equiv), compound 4 (1.8 equiv), Et₃N (2.5 eq) and i-PrOH (4 vol) were added. The mixture was stirred and the temperature was adjusted to 82±5°C. The mixture was allowed to stand for 24 hours. The mixture was then cooled to about 20 to about 25° C. over 2 hours. The mixture was filtered and the cake was washed with i-PrOH (2 vol), deionized water (25 vol) and n-heptane (2 vol), respectively. After adjusting the cake, the compound 10 was obtained by vacuum drying at 50±5°C.

To a mixture of EtOH (2.5 vol) and compound 10 (1 eq) was added EtOH (2.5 vol) and deionized water (2 vol). The mixture was stirred at about 20 to about 25 °C. Concentrated HCl (3.5 eq) was added and the temperature was adjusted to 35±5°C. The mixture was allowed to stand for about 1.5 hours. After the mixture was cooled to 25±5° C., it was polished filtered in a non-particulate container. NH₄OH was added to adjust the pH to about 8 to about 9. A crystalline seed of Form C of the compound of formula I (0.3% by weight) was added to the mixture, which was allowed to stand for 30 minutes. Deionized water (13 vol) was added over about 2 hours. The mixture was allowed to stand for 1 hour and then filtered. The resulting cake was washed with deionized water (4 vol) and n-heptane (2 vol), respectively. After the cake was conditioned for about 24 hours, DCM (5 vol) was added. The mixture was stirred at about 20 to about 25° C. for about 12 hours. The mixture was filtered and the cake washed with DCM (1 vol). The cake was conditioned for about 6 hours. The cake was then vacuum dried at 50±5°C. To the cake was added deionized water (10 vol), and i-PrOH (0.8 vol), and the mixture was stirred at 25±5° C. for about 6 hours. XRPD samples confirmed that the compound of formula (I) was in Form C. The mixture was filtered and the cake was washed with deionized water (5 vol) followed by n-heptane (3 vol). After adjusting the cake, vacuum drying at 50±5° C. gave the compound of formula I as polymorph form C.

Example 5

Synthesis of (S)-3-(1-(9H-purin-6-ylamino)ethyl)-8-chloro-2-phenylisoquinolin-1(2H)-one

<img file="KR20140020249A_D0053.tif" />

Example 5A

Compound 9 (2.39 kg) was treated with compound 4 and triethylamine in isopropyl alcohol at 80° C. for 24 h. The reaction was monitored by HPLC until completion, 8-chloro-2-phenyl-3-((1S)-1-(9-(tetrahydro-2H) with a purity of 98% (AUC) by HPLC analysis. -Pyran-2-yl)-9H-purin-6-ylamino)ethyl)isoquinolin-1(2H)-one (Compound 10) was obtained as a tan solid in 94% yield.

8-chloro-2-phenyl-3-((1S)-1-(9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-ylamino)ethyl) at 30° C. for 2.3 hours -Isoquinolin-1(2H)-one (compound 10) (3.63 kg) was treated with HCl in ethanol. To completion, the reaction was monitored by HPLC to give the compound of formula I in 92% yield as a tan solid with a purity greater than 99% (AUC) and 90.9% (AUC) ee by HPLC analysis.

Example 5B

3-(1-Aminoethyl)-8-chloro-2-phenylisoquinolin-1(2H)-one (compound 9) (0.72 mmol), 6-chloro-9-(tetrahydro-2H-pyran-2- yl)-9H-purine (compound 4) (344 mg, 1.44 mmol) and DIPEA (279 mg, 2.16 mmol) <i>n-</i>It was dissolved in BuOH (20 mL) and the resulting mixture was stirred at reflux for 16 h. The reaction mixture was concentrated in vacuo and purified by flash column chromatography on silica gel (eluting with 30-50% Hex/EA) to give the product 8-chloro-2-phenyl-3-((1S)-1-( Obtained 9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-ylamino)ethyl)isoquinolin-1(2H)-one (compound 10) as a white solid (60% yield). .

8-Chloro-2-phenyl-3-((1S)-1-(9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-ylamino)ethyl)-isoquinoline-1 ( 2H)-one(compound 10) (0.42 mmol) was dissolved in HCl/EtOH (3 M, 5 mL) and the resulting mixture was stirred for 1 h at room temperature. The reaction mixture was saturated with NaHCO₃ Quench with aqueous solution and adjust pH to about 7-8. CH the mixture₂Cl₂(50 mL X 3), anhydrous Na₂SO₄ dried over and filtered. The filtrate was concentrated in vacuo and the residue was recrystallized from ethyl acetate and hexanes (1:1). The solid was collected by filtration and dried in vacuo to give the product (S)-3-(1-(9H-purin-6-ylamino)ethyl)-8-chloro-2-phenylisoquinoline-1(2H)- One (formula I) (90% yield) was obtained as polymorph Form A as a white solid.

Example 5C

3-(1-aminoethyl)-8-chloro-2-phenylisoquinolin-1(2H)-one (compound 9) and 6-chloro-9-(tetrahydro-) in the presence of triethylamine and isopropyl alcohol 2H-pyran-2-yl)-9H-purine (compound 4) was combined. The reaction solution was heated at 82° C. for 24 hours to obtain compound 10. (S)-3-(1-(9H-purin-6-ylamino)ethyl)-8-chloro-2 by treatment of intermediate compound 10 with concentrated HCl and ethanol under aqueous conditions at 35°C to remove the tetrahydropyranyl group -Phenylisoquinolin-1(2H)-one was obtained. Polymorph Form C was obtained by isolation/purification under aqueous conditions.

Example 6

Synthesis of (S)-3-(1-(9H-purin-6-ylamino)ethyl)-8-chloro-2-phenylisoquinolin-1(2H)-one

<img file="KR20140020249A_D0054.tif" />

3-(1-Aminoethyl)-8-chloro-2-phenylisoquinolin-1(2H)-one (compound 9) (150 g; 90% ee) and 6-chloro-9-(tetrahydro-2H- Pyran-2-yl)-9H-purine (compound 4) (216 g, 1.8 equiv) was charged to a round bottom flask, followed by IPA (1.2 L; 8 vol) and triethylamine (175 mL; 2.5 equiv) added. The resulting slurry was stirred at reflux for 1 day. Heptane (1.5 L; 10 vol) was added dropwise over 2 h. The batch was then cooled to 0-5° C., left standing for 1 hour and filtered. The cake was washed with heptane (450 mL; 3 vol) and placed back into the reactor. IPA (300 mL; 2 vol) and water (2.25 L; 15 vol) were added, and the resulting slurry was stirred at 20-25° C. for 3.5 hours, followed by filtration. The cake was washed with water (1.5 L; 10 vol) and heptane (450 mL; 3 vol) and then vacuum dried at 48° C. for 2.5 days to give the intermediate (227 g, 90.1%, compound 10) 99% (AUC) Obtained as an off-white solid with greater than purity and greater than 94% ee (chiral HPLC). The cake sample was converted to the final product to determine the ee, which was analyzed by chiral HPLC.

The intermediate (compound 10) (200 g) was slurried in an ethanol (900 mL; 4.5 vol)/water (300 mL; 1.5 vol) mixture at 22° C., then concentrated HCl (300 mL; 1.5 vol) was added, It was allowed to stand at 25-35°C for 1.5 hours. Addition of HCl led to the decomposition of all solids resulting in a dark brown solution. Ammonium hydroxide (260 mL) was added to adjust the pH to 8-9. The product seeds of polymorph Form C (0.5 g) (also Form A seeds may be used) are then added, the batch is allowed to stand for 10 minutes, then water (3 L; 15 vol) is added over 2 hours. to obtain crystallization of the product. The batch was allowed to stand at 20-25° C. for 3.5 hours and then filtered. The cake was washed with water (1 L; 5 vol) followed by heptane (800 mL; 4 vol) and vacuum dried at 52° C. for 23 h to a product with 99.6% (AUC) purity and 93.8% ee (chiral HPLC). (155.5 g, 93.5%) was obtained.

Example 7

Synthesis of (S)-3-(1-(9H-purin-6-ylamino)ethyl)-8-chloro-2-phenylisoquinolin-1(2H)-one

<img file="KR20140020249A_D0055.tif" />

A mixture of isopropanol (20.20 kg, 8 vol), compound 9 (3.17 kg, 9.04 mol, 1 equiv), compound 4 (4.61 kg, 16.27 mol, 1.8 equiv) and triethylamine (2.62 kg, 20.02 mol, 2.4 equiv) was prepared and heated to an internal temperature of 82 ± 5 °C. The mixture was stirred at that temperature for an additional about 24 hours. The temperature was slowly adjusted to 20±5° C. over about 2 hours and the solids were isolated by vacuum filtration of the solids through a 24 polypropylene table top filter equipped with Sharkskin paper. Subsequently, the filter cake was washed with IPA. (5.15 kg, 3 vol), purified water (80.80 kg, 25 vol) and n-heptane (4.30 kg, 2 vol) The cake was further dried in vacuo at 50±5° C. for about 4 days to compound 10 was obtained.

To a mixture of ethanol (17.7 kg, 5 vol) and compound 10 (4.45 kg, 8.88 mol. 1.0 equiv) was added purified water (8.94 kg, 2 vol). Concentrated HCl (3.10 kg, 3.5 eq) was slowly added to this mixture while maintaining the temperature below about 35°C. The mixture is stirred at 30±5° C. for about 1.5 hours and HPLC analysis shows the presence of the compound of formula I at a purity of 99.8% (AUC) relative to compound 10.

The compound mixture of formula (I) was then cooled to 25±5°C. The pH of the mixture was adjusted to about 8 using pre-filtered ammonium hydroxide (1.90 kg). After stirring for about 15 minutes, Form C crystal seeds (13.88 g) were added. After stirring for about 15 minutes, purified water (58.0 kg, 13 vol) was charged over about 2 hours. The mixture was stirred at 25±5° C. for 15 hours and then the solid was isolated by vacuum filtration through a 24" polypropylene table top filter fitted with PTFE cloth over sharkskin paper. The filter cake was washed with purified water (18.55 kg, 4 volume), followed by rinsing with pre-filtered n-heptane (6.10 kg, 2 vol.) After conditioning the filter cake for about 24 hours, HPLC analysis of the filter cake showed that compound presence was indicated.

To the filter cake was added dichloromethane (29.9 kg, 5 vol) and the slurry was stirred at 25±5° C. for about 24 hours. The solids were isolated by vacuum filtration with a 24" polypropylene table top filter fitted with PTFE cloth on sharkskin paper and the filter cake rinsed with DCM (6.10 kg, 1 vol). Filter cake conditioned for approximately 22 hours. After drying, the filter cake was dried in vacuum at 50±5° C. for about 2 days to obtain the compound of formula I with a purity of 99.6% (AUC). Referring to XRPD, the compound of formula I is consistent with Form A.

To this solid was added purified water (44.6 kg, 10 vol) and pre-filtered 2-propanol (3.0 kg, 0.8 vol). After stirring for about 6 hours, a solid sample in the slurry is analyzed by XRPD and is consistent with the Form C sample. The solids were isolated by vacuum filtration with a 24" polypropylene table top filter equipped with PTFE cloth on sharkskin paper and the filter cake was purified with purified water (22.35 kg, 5 vol) followed by pre-filtered n-heptane (9.15 kg, 3 volumes) After conditioning the filter cake for about 18 hours, the filter cake was dried in vacuo at 50±5° C. for about 5 days.

This procedure affords the compound of formula (I) with a purity of about 99.6% (AUC) and greater than about 99% (AUC) of a chiral purity. The XRPD of the solid is consistent with the Form C standard sample. of product¹H NMR (DMSO-<i>d</i><i>₆</i>) and IR were confirmed with standard samples.

Example 8

Analytical data of (S)-3-(1-(9H-purin-6-ylamino)ethyl)-8-chloro-2-phenylisoquinolin-1(2H)-one

The present invention relates to various purified compounds of formula I, which is (S)-3-(1-(9H-purin-6-ylamino)ethyl)-8-chloro-2-phenylisoquinolin-1(2H)-one Analytical data of the sample is provided. Identification of the structure of the compound of formula (I) is carried out by single crystal X-ray diffraction, FT-IR,¹H-NMR and ¹³obtained by C-NMR spectrum.

of (S)-3-(1-(9H-purin-6-ylamino)ethyl)-8-chloro-2-phenylisoquinolin-1(2H)-one (eg polymorph Form G) <i>3rd grade</i>A single crystal structure of -butyl methyl ether solvate was generated and single crystal X-ray data were collected. The structure is shown in Fig. 26, which<i>S</i>- Additional confirmation of absolute stereochemistry as enantiomers.

Obtaining an FT-IR spectrum of Form C of (S)-3-(1-(9H-purin-6-ylamino)ethyl)-8-chloro-2-phenylisoquinolin-1(2H)-one, 27 shows.

of a sample of Form C of (S)-3-(1-(9H-purin-6-ylamino)ethyl)-8-chloro-2-phenylisoquinolin-1(2H)-one ¹H-NMR and ¹³C-NMR spectra were obtained and are provided in FIGS. 28 and 29 respectively.

Example 9

General Processes for the Preparation of Polymorph Forms A, B, C, D, E, F, G, H, I and J of the Compounds of Formula I

General Method A: Single Solvent Crystallization with Fast Cooling or Slow Cooling

A sample of a compound of Formula I (eg, Form A or Form C) is placed in a vial equipped with a stir bar and dissolved with a minimal amount of solvent (eg, about 0.2 to about 0.3 mL) at elevated temperature. The resulting solution was polished filtered through an injection filter (0.45 μm) into a clean preheated vial. After warm filtration, place the vials in a refrigerator (eg, about 4° C.) overnight in a fast cooling procedure or cool to ambient temperature at a rate of about 20° C./hr in a slow cooling procedure and equilibrate overnight at ambient temperature without stirring. Optionally, the solid-free sample may be scraped with a tool known in the art (eg, a spatula) to initiate crystallization. The solution can be equilibrated for a period of time, such as about 8 hours. In the slow cooling sample, if scraping does not yield solids after about 8 hours, a stir bar can be added and the sample is then stirred overnight. The precipitate-free sample may be evaporated to dryness under a mild gas stream such as argon, nitrogen, ambient air, or the like. The precipitated solid may be recovered by vacuum filtration, centrifugal filtration, or appropriately decanted to obtain the form referred to below.

General Method B: Multi-solvent crystallization with fast cooling or slow cooling

Multi-solvent (eg binary) solvent crystallization can be performed. Primary solvents include, but are not limited to, ethanol, isopropyl alcohol, methanol, tetrahydrofuran, acetone, methyl ethyl ketone, dioxane, NMP, DME, and DMF. Anti-solvents include, but are not limited to, MTBE, DCM, toluene, heptane, and water.

A sample of a compound of Formula I (eg, Form A or Form C) is placed in a vial equipped with a stir bar and dissolved with a small amount of solvent (eg, about 0.2 to about 0.3 mL) at elevated temperature. The resulting solution was polished filtered into a clean preheated vial with an injection filter (0.45 μm). After hot filtration, antisolvent was added until cloudiness was observed. After hot filtration, the vials were placed in a refrigerator (eg, about 4° C.) overnight in a fast cooling procedure, or cooled to ambient temperature at a rate of about 20° C./hour, and equilibrated overnight at ambient temperature without stirring in a slow cooling procedure. Optionally, the solid-free sample can be scraped with a tool known in the art (eg, a spatula) to initiate crystallization. The solution can be equilibrated for a period of time, such as about 8 hours. In the slow cooling sample, if scraping does not yield solids after about 8 hours, a stir bar can be added and the sample is then stirred overnight. The precipitate-free sample may be evaporated to dryness under a mild gas stream such as argon, nitrogen, ambient air, or the like. The precipitated solid may be recovered by vacuum filtration, centrifugal filtration or may be appropriately decanted to obtain the form referred to below.

General Method C: Slurry Procedure to Obtain the Formula I Polymorph

A mixture of one or more forms of the compound of formula (I) (eg, Form A or Form C) is placed in a vial equipped with a stir bar. A small amount of solvent (eg, a single solvent or a mixture/solution of two or more solvents) was added to the vial to form a non-uniform slurry. Optionally, the vial can be sealed to prevent evaporation. The slurry is maintained for a period of time, less than about 1 hour, to about 6 hours, to about 12 hours, to about 24 hours, to about 2 days, to about 4 days, to about 1 week, to about 1.5 weeks, to about 2 weeks or more. stirred for a while. An aliquot can be taken while stirring and the morphology of the solid can be assessed using, for example, XRPD analysis. Optionally, additional solvent may be added while stirring. Optionally, seeds of a given polymorphic form of the compound of formula (I) may be added. In some cases, the slurry was then stirred for an additional period of time, such as the ranges described above. The recovered solid may be recovered by vacuum filtration, centrifugal filtration, or appropriately decanted to obtain the form described below.

Example 10

Preparation of polymorphic forms A, B, C, D, E, F, G, H, I and J of a compound of formula (I)

<b><u>form A</u></b>

Single solvent crystallization to obtain Formula I Form A

One. Rapid cooling procedure from MeCN: Formula I Form A (ca. 23 mg) was placed in a glass vial (2-dram) equipped with a stir bar. A small amount of acetonitrile (7.4 ml) was added to the vial to dissolve the solid at 70°C. The resulting solution was polished filtered into a clean preheated vial with an injection filter (0.45 μm). After hot filtration, the vial was placed in the refrigerator (4° C.) overnight. At 4°C, the contents of the vial were periodically scraped with a spatula to induce crystallization, followed by equilibration for about 8 hours. The crystals were collected by decanting the liquid and dried at ambient temperature under vacuum (30 inches Hg) overnight. The dried solid was evaluated for crystallinity and morphology by XRPD, indicating that the crystalline material was polymorph A.

2. Slow cooling procedure from MeCN: Formula I Form A (ca. 24 mg) was placed in a glass vial (2-dram) equipped with a stir bar. A small amount of acetonitrile (8 ml) was added to the vial to dissolve the solid at 70°C. The resulting solution was polished filtered into a clean preheated vial with an injection filter (0.45 μm). After hot filtration, the vial was cooled to ambient temperature at a rate of 20° C./hour and allowed to equilibrate at ambient temperature overnight without stirring. After equilibration at ambient temperature, the contents of the vial were periodically scraped with a spatula to induce crystallization, followed by equilibration for approximately 8 hours. The crystals were collected by decanting the liquid and dried overnight at ambient temperature under vacuum (30 inches Hg). The dried solid was evaluated for crystallinity and morphology by XRPD, which indicated that the crystalline material was polymorph A.

3. Slow cooling procedure from n-butanol: Formula I Form A (ca. 23 mg) was placed in a glass vial (2-dram) equipped with a stir bar. A small amount of n-butanol (0.6 ml) was added to the vial to dissolve the solid at 70°C. The resulting solution was polished filtered into a clean preheated vial with an injection filter (0.45 μm). After hot filtration, the vial was cooled to ambient temperature at a rate of 20° C./hour and allowed to equilibrate at ambient temperature overnight without stirring. After equilibration at ambient temperature, the contents of the vial were periodically scraped with a spatula to induce crystallization, followed by equilibration for approximately 8 hours. To induce further crystallization, a stir bar was added to the vial and the contents stirred overnight. The resulting crystals were collected by filtration and dried overnight at ambient temperature under vacuum (30 inches Hg). The dried solid was evaluated for crystallinity and morphology by XRPD, which indicated that the crystalline material was polymorph A.

Binary Solvent Crystallization to Obtain Formula I Form A

One. Rapid cooling procedure from acetone/DCM: Formula I Form A (ca. 23.5 mg) was placed in a glass vial (2-dram) equipped with a stir bar. A small amount of acetone (2.6 ml) was added to the vial to dissolve the solid at 50°C. The resulting solution was polished filtered into a clean preheated vial with an injection filter (0.45 μm). After hot filtration, DCM (5.0 ml) was added in portions. After anti-solvent addition, the vial was placed in the refrigerator (4° C.) overnight. At 4°C, the contents of the vial were periodically scraped with a spatula to induce crystallization, followed by equilibration for about 8 hours. The crystals were collected by filtration and dried overnight at ambient temperature under vacuum (30 inches Hg). The dried solid was evaluated for crystallinity and morphology by XRPD, indicating that the crystalline material was polymorph A.

2. Rapid cooling procedure from MEK/DCM: Formula I Form A (ca. 23 mg) was placed in a glass vial (2-dram) equipped with a stir bar. A minimal amount of MEK (2.2 ml) was added to the vial to dissolve the solid at 70°C. The resulting solution was polished filtered into a clean preheated vial with an injection filter (0.45 μm). After hot filtration, DCM (5.0 ml) was added in portions. After addition of the anti-solvent, the vial was placed in the refrigerator (4° C.) overnight. At 4°C, the contents of the vial were periodically scraped with a spatula to induce crystallization, followed by equilibration for about 8 hours. The crystals were collected by filtration and dried overnight at ambient temperature under vacuum (30 inches Hg). The dried solid was evaluated for crystallinity and morphology by XRPD, indicating that the crystalline material was polymorph A.

3. Rapid cooling procedure from DMF/DCM: Formula I Form A (ca. 24 mg) was placed in a glass vial (2-dram) equipped with a stir bar. A minimal amount of DCM (0.2 ml) was added to the vial to dissolve the solid at 70°C. The resulting solution was polished filtered into a clean preheated vial with an injection filter (0.45 μm). After hot filtration, DCM (7.0 ml) was added in portions. After addition of the anti-solvent, the vial was placed in the refrigerator (4° C.) overnight. At 4°C, the contents of the vial were periodically scraped with a spatula to induce crystallization, followed by equilibration for about 8 hours. The crystals were collected by filtration and dried overnight at ambient temperature under vacuum (30 inches Hg). The dried solid was evaluated for crystallinity and morphology by XRPD, indicating that the crystalline material was polymorph A.

4. Rapid cooling procedure from dioxane/DCM: Formula I Form A (ca. 24.4 mg) was placed in a glass vial (2-dram) equipped with a stir bar. A minimum amount of dioxane (0.8 ml) was added to the vial to dissolve the solid at 70°C. The resulting solution was polished filtered into a clean preheated vial with an injection filter (0.45 μm). After hot filtration, DCM (7.0 ml) was added in portions. After addition of the anti-solvent, the vial was placed in the refrigerator (4° C.) overnight. At 4°C, the contents of the vial were periodically scraped with a spatula to induce crystallization, followed by equilibration for about 8 hours. The crystals were collected by filtration and dried overnight at ambient temperature under vacuum (30 inches Hg). The dried solid was evaluated for crystallinity and morphology by XRPD, which indicated that the crystalline material was polymorph A.

5. Slow cooling procedure from acetone/DCM: Formula I Form A (ca. 22 mg) was placed in a glass vial (2-dram) equipped with a stir bar. A minimal amount of acetone (2.5 ml) was added to the vial to dissolve the solid at 50°C. The resulting solution was polished filtered into a clean preheated vial with an injection filter (0.45 μm). After hot filtration, DCM (5.0 ml) was added in portions. After addition of the anti-solvent, the vial was cooled to ambient temperature at a rate of 20° C./hour and allowed to equilibrate at ambient temperature overnight without stirring. After equilibration was maintained at ambient temperature, the contents of the vial were periodically scraped with a spatula to induce crystallization, followed by equilibration for approximately 8 hours. To further induce crystallization, a stir bar was added to the vial and the contents stirred overnight. The resulting crystals were collected by filtration and dried overnight at ambient temperature under vacuum (30 inches Hg). The dried solid was evaluated for crystallinity and morphology by XRPD, indicating that the crystalline material was polymorph A.

6. Slow cooling procedure from MEK/DCM: Formula I Form A (ca. 23.4 mg) was placed in a glass vial (2-dram) equipped with a stir bar. A minimal amount of MEK (2.2 ml) was added to the vial to dissolve the solid at 70°C. The resulting solution was polished filtered into a clean preheated vial with an injection filter (0.45 μm). After hot filtration, DCM (5.0 ml) was added in portions. After addition of the anti-solvent, the vial was cooled to ambient temperature at a rate of 20° C./hour and allowed to equilibrate at ambient temperature overnight without stirring. After equilibration was maintained at ambient temperature, the contents of the vial were periodically scraped with a spatula to induce crystallization, followed by equilibration for approximately 8 hours. The resulting crystals were collected by filtration and dried overnight at ambient temperature under vacuum (30 inches Hg). The dried solid was evaluated for crystallinity and morphology by XRPD, which indicated that the crystalline material was polymorph A.

7. Slow cooling procedure from dioxane/DCM: Formula I Form A (ca. 24 mg) was placed in a glass vial (2-dram) equipped with a stir bar. A minimum amount of dioxane (0.8 ml) was added to the vial to dissolve the solid at 70°C. The resulting solution was polished filtered into a clean preheated vial with an injection filter (0.45 μm). After hot filtration, DCM (7.0 ml) was added in portions. After addition of the anti-solvent, the vial was cooled to ambient temperature at a rate of 20° C./hour and allowed to equilibrate at ambient temperature overnight without stirring. After equilibration was maintained at ambient temperature, the contents of the vial were periodically scraped with a spatula to induce crystallization, followed by equilibration for approximately 8 hours. To further induce crystallization, a stir bar was added to the vial and the contents stirred overnight. The resulting crystals were collected by filtration and dried overnight at ambient temperature under vacuum (30 inches Hg). The dried solid was evaluated for crystallinity and morphology by XRPD, indicating that the crystalline material was polymorph A.

8. Slow cooling procedure from DMF/DCM: Formula I Form A (ca. 23.5 mg) was placed in a glass vial (2-dram) equipped with a stir bar. A minimum amount of DMF (0.2 ml) was added to the vial to dissolve the solid at 70°C. The resulting solution was polished filtered into a clean preheated vial with an injection filter (0.45 μm). After hot filtration, DCM (7.0 ml) was added in portions. After addition of the anti-solvent, the vial was cooled to ambient temperature at a rate of 20° C./hour and allowed to equilibrate at ambient temperature overnight without stirring. After equilibration was maintained at ambient temperature, the contents of the vial were periodically scraped with a spatula to induce crystallization and allowed to equilibrate for approximately 8 hours. To further induce crystallization, a stir bar was added to the vial and the contents stirred overnight. To further induce crystallization, the contents of the vial were concentrated under a gentle stream of nitrogen to dryness. The resulting crystals were collected by filtration and dried overnight at ambient temperature under vacuum (30 inches Hg). The dried solid was evaluated for crystallinity and morphology by XRPD, which indicated that the crystalline material was polymorph A.

Slurry Procedure for Obtaining Formula I Form A

One. CH₂Cl₂ and Procedure from IPA: Form C (1 g) was slurried with dichloromethane (5 vol). After standing for 15 hours, filtration and drying, Form A was isolated in 82% yield. Scale-up was performed on a scale (20 g) containing a water-wet cake of Form C to give Form A in 92% yield. Drying at 70° C. for 6 days showed no degradation in chemical or chiral purity. Also, using a similar method, anhydrous Form C was slurried in isopropyl alcohol to give Form A.

2. Procedure for Competitive Slurry Experiments (Using Forms A, B, and C): A competitive slurry was mixed with an approximately 50/50 mixture of Forms A and C (11.2 mg of Form A and 11.7 mg of Form C) equipped with a glass stir bar. It was carried out by filling into an old glass vial (1-dram). MeCN (600 μL) was added to the vial. The vial cap was covered with parafilm to prevent evaporation. The slurry was stirred for 1 day and an aliquot was taken. The contents of the vial were stirred for an additional week, and another aliquot was taken. Both aliquots were centrifugally filtered at 8000 RPM for 5 minutes. XRPD analysis was performed on the solid phase from each aliquot to show the conversion of Formula I to Form A at two time points. After 1 week, an aliquot was taken and additional acetonitrile (300 μL) was added to the remaining slurry and allowed to equilibrate for 1 day. The slurry was then seeded with Form B (ca. 3.2 mg) and allowed to equilibrate for an additional 3 days. The solid was isolated by centrifugal filtration (5 min at 8000 RPM) and dried under vacuum overnight. The dried solid was evaluated for crystallinity and morphology by XRPD, which indicated that the crystalline material was polymorph A.

3. Procedure for Competitive Slurry Experiments (Using Forms A, C, D, and E): The competitive slurries were mixed with each form (7.8 mg of Form A, 7.7 mg of Form C, 7.7 mg of Form D, and 8.2 mg of Form). E) was carried out by filling an equivalence of the mixture into a glass vial (1-dram) equipped with a glass stir bar. To the vial was added 2-propanol (1 ml). The vial cap was covered with parafilm to prevent evaporation. The slurry was mixed for 1 day and an aliquot was taken. The contents of the vial were stirred for an additional week, and another aliquot was taken. Both aliquots were centrifuged at 8000 RPM for 5 minutes. XRPD analysis was performed on the solid phase from each aliquot to show the conversion of Formula I to Form A at two time points. After 1 week, an aliquot was taken and the remaining solid was isolated by centrifugal filtration (8000 RPM for 5 min) and dried under vacuum overnight. The dried solid was evaluated for crystallinity and morphology by XRPD, indicating that the crystalline material was polymorph A.

<b><u>form B</u></b>

The pan for a thermogravimetric analysis (TGA) instrument was loaded with Formula I Form A (15-20 mg). Form C can also be used in this process. The crystalline sample was rapidly heated to 250° C. and the temperature inside the TGA instrument was maintained for 5 minutes. After completion of the hold, the sample was rapidly cooled to room temperature as quickly as possible. The resulting samples were evaluated for crystallinity and morphology by XRPD, indicating that the crystalline material is polymorphic form B.

<b><u>form C</u></b>

Binary solvent crystallization to obtain Formula I Form C

Using General Method B of Example 9, the following experiments described in Tables 1 and 2 were performed to obtain Formula I Form C. Table 1 experiments were performed using a fast cooling procedure, while Table 2 experiments were performed using a slow cooling procedure.

[Table 1]

quick cooling procedure

<img file="KR20140020249A_D0056.tif" />

[Table 2]

slow cooling procedure

<img file="KR20140020249A_D0057.tif" />

Slurry Procedure for Obtaining Formula I Form C

One. Procedure for Competitive Slurry Experiments (Using Forms A, C, D, and E): Competitive slurry was mixed with each form (7.9 mg of Form A, 7.8 mg of Form C, 7.8 mg of Form D, and 8.1 mg of Form E). ) was filled into a glass vial (1-dram) equipped with a glass stir bar. Water (1 ml) was added to the vial. The vial cap was covered with parafilm to prevent evaporation. The slurry was mixed for 1 day and an aliquot was taken. The contents of the vial were stirred for an additional week, and another aliquot was taken. Both aliquots were centrifugally filtered at 8000 RPM for 5 minutes. XRPD analysis was performed on the solid phase to show the conversion of Formula I to Form C at two time points. After 1 week an aliquot was taken and the remaining solid isolated by centrifugal filtration (8000 RPM for 5 min) and dried under vacuum overnight. The dried solid was evaluated for crystallinity and morphology by XRPD, indicating that the crystalline material is polymorphic form C.

2. Procedure for Competitive Slurry Experiments (Using Forms B and C): Form C (approximately 4.9 mg) was weighed into a vial (1-dram) equipped with a magnetic stir bar. To this vial was added water (0.3 mL) to form a slurry, which was equilibrated at ambient temperature for about 24 hours. An equal amount (about 5.4 mg) of Form B was added to the vial and the slurry was equilibrated at ambient temperature for 4 days. The resulting solid was isolated by centrifugal filtration (8000 RPM for 5 min) and dried under vacuum overnight. The dried solid was evaluated for crystallinity and morphology by XRPD, indicating that the crystalline material is polymorphic form C.

3. Procedure for Competitive Slurry Experiments (Using Forms A, B, and C): A competitive slurry was prepared by mixing approximately 50/50 mixtures of Forms A and C (10.6 mg of Form A and 12 mg of Form C) to a glass stir bar mounted on a glass stir bar. Filling in glass vials (1-dram) was carried out. To the vial was added a solution of water and ethanol (50/50 v/v, 600 μL). The vial cap was covered with parafilm to prevent evaporation. The slurry was mixed for 1 day and an aliquot was taken. The contents of the vial were stirred for an additional week, and another aliquot was taken. Both aliquots were centrifugally filtered at 8000 RPM for 5 minutes. XRPD analysis was performed on the solid phase, showing that all formula I was converted to Form C at two time points. After 1 week, an aliquot was taken and additional water and ethanol (50/50 v/v, 300 μL) solution was added to the remaining slurry and allowed to equilibrate for 1 day. The slurry was then seeded with Form B (ca. 3.6 mg) and allowed to equilibrate for an additional 3 days before isolation by centrifugal filtration (8000 RPM for 5 min). The solid was dried under vacuum at ambient temperature overnight. The dried solid was evaluated for crystallinity and morphology by XRPD, indicating that the crystalline material is polymorphic form C.

4. (S)-3-(1-(9H-purin-6-ylamino)ethyl)-8-chloro-2 in isopropyl alcohol (1.2 L) and deionized water (12 L) in a round bottom flask (22 L) Form A of -phenylisoquinolin-1(2H)-one (1.20 kg) was charged and stirred at 20±5°C. After stirring for 3 hours, analysis of the sample by XRPD showed that the sample was Form C. The mixture was filtered through a Buchner funnel equipped with sharkskin filter paper, which was then rinsed with deionized water (6 L) and heptane (3.6 L). The cake was held for 1 hour and dried to equal weights in a vacuum oven at 50° C. to afford 98% by weight of the compound of formula I as Form C (1.18 kg). Using the following reaction condition parameters according to this procedure shown in Table 3, (S)-3-(1-(9H-purin-6-ylamino)ethyl)-8-chloro-2-phenylisoquinoline-1 Additional samples of Form C were prepared starting from Form A of (2H)-one:

[Table 3]

<img file="KR20140020249A_D0058.tif" />

<b><u>form D</u></b>

Single solvent crystallization to obtain Formula I Form D

One. Rapid cooling procedure from tetrahydrofuran (THF): Formula I Form A (ca. 23 mg) was placed in a glass vial (2-dram) equipped with a stir bar. A minimum amount of THF (1.2 ml) was added to the vial to dissolve the solid at 60°C. The resulting solution was polished filtered into a clean preheated vial with an injection filter (0.45 μm). After hot filtration, the vial was placed in the refrigerator (4° C.) overnight. At 4°C, the contents of the vial were periodically scraped with a spatula to induce crystallization and allowed to equilibrate for about 8 hours. The crystals were collected by decanting the liquid and dried overnight at ambient temperature under vacuum (30 inches Hg). The dried solid was evaluated for crystallinity and morphology by XRPD, indicating that the crystalline material is polymorphic form D.

2. Rapid cooling procedure from 2-butanone (MEK): Formula I Form A (ca. 23 mg) was placed in a glass vial (2-dram) equipped with a stir bar. A minimal amount of MEK (2.0 ml) was added to the vial to dissolve the solid at 70°C. The resulting solution was polished filtered into a clean preheated vial with an injection filter (0.45 μm). After hot filtration, the vial was placed in the refrigerator (4° C.) overnight. At 4° C., the contents of the vial were periodically scraped with a spatula to induce crystallization and allowed to equilibrate for about 8 hours. The crystals were collected by decanting the liquid and dried overnight at ambient temperature under vacuum (30 inches Hg). The dried solid was evaluated for crystallinity and morphology by XRPD, indicating that the crystalline material is polymorphic form D.

3. Rapid cooling procedure from dioxane: Form A (ca. 25 mg) was placed in a glass vial (2-dram) equipped with a stir bar. A minimum amount of THF (1.5 ml) was added to the vial to dissolve the solid at 70°C. The resulting solution was polished filtered into a clean preheated vial with an injection filter (0.45 μm). After hot filtration, the vial was placed in the refrigerator (4° C.) overnight. At 4°C, the contents of the vial were periodically scraped with a spatula to induce crystallization and allowed to equilibrate for about 8 hours. To further induce crystallization, the contents of the vial were evaporated to dryness under a gentle stream of nitrogen. The crystals were collected by decanting any residual liquid and dried overnight at ambient temperature under vacuum (30 inches Hg). The dried solid was evaluated for crystallinity and morphology by XRPD, indicating that the crystalline material is polymorphic form D.

4. Rapid cooling procedure from N,N-dimethylformamide (DMF): Formula I Form A (ca. 23.5 mg) was placed in a glass vial (2-dram) equipped with a stir bar. A minimum amount of DMF (0.3 ml) was added to the vial to dissolve the solid at 70°C. The resulting solution was polished filtered into a clean preheated vial with an injection filter (0.45 μm). After hot filtration, the vial was placed in the refrigerator (4° C.) overnight. At 4° C., the contents of the vial were periodically scraped with a spatula to induce crystallization and allowed to equilibrate for about 8 hours. To further induce crystallization, the contents of the vial were evaporated to dryness under a gentle stream of nitrogen. The crystals were collected by decanting any residual liquid and dried overnight at ambient temperature under vacuum (30 inches Hg). The dried solid was evaluated for crystallinity and morphology by XRPD, indicating that the crystalline material is polymorphic form D.

5. Slow cooling procedure from tetrahydrofuran (THF): Formula I Form A (ca. 25 mg) was placed in a glass vial (2-dram) equipped with a stir bar. A minimum amount of THF (1.1 ml) was added to the vial to dissolve the solid at 60°C. The resulting solution was polished filtered into a clean preheated vial with an injection filter (0.45 μm). After hot filtration, the vial was cooled to ambient temperature at a rate of 20° C./hour and allowed to equilibrate at ambient temperature overnight without stirring. After equilibration was maintained at ambient temperature, the contents of the vial were periodically scraped with a spatula to induce crystallization and allowed to equilibrate for approximately 8 hours. The crystals were collected by decanting the liquid and dried overnight at ambient temperature under vacuum (30 inches Hg). The dried solid was evaluated for crystallinity and morphology by XRPD, indicating that the crystalline material is polymorphic form D.

6. Slow cooling procedure from 2-butanone (MEK): Formula I Form A (ca. 24.5 mg) was placed in a glass vial (2-dram) equipped with a stir bar. A minimum amount of MEK (4 ml) was added to the vial to dissolve the solid at 70°C. The resulting solution was polished filtered into a clean preheated vial with an injection filter (0.45 μm). After hot filtration, the vial was cooled to ambient temperature at a rate of 20° C./hour and allowed to equilibrate at ambient temperature overnight without stirring. After equilibration was maintained at ambient temperature, the contents of the vial were periodically scraped with a spatula to induce crystallization and allowed to equilibrate for approximately 8 hours. The crystals were collected by decanting the liquid and dried overnight at ambient temperature under vacuum (30 inches Hg). The dried solid was evaluated for crystallinity and morphology by XRPD, indicating that the crystalline material is polymorphic form D.

7. Slow cooling procedure from dioxane: Formula I Form A (ca. 24 mg) was placed in a glass vial (2-dram) equipped with a stir bar. A minimum amount of dioxane (1.1 ml) was added to the vial to dissolve the solid at 70°C. The resulting solution was polished filtered into a clean preheated vial with an injection filter (0.45 μm). After hot filtration, the vial was cooled to ambient temperature at a rate of 20° C./hour and allowed to equilibrate at ambient temperature overnight without stirring. After equilibration was maintained at ambient temperature, the contents of the vial were periodically scraped with a spatula to induce crystallization and allowed to equilibrate for approximately 8 hours. The crystals were collected by decanting the liquid and dried overnight at ambient temperature under vacuum (30 inches Hg). The dried solid was evaluated for crystallinity and morphology by XRPD, indicating that the crystalline material is polymorphic form D.

Binary Solvent Crystallization to Obtain Formula I Form D

Using General Method B of Example 9, the following experiments described in Tables 4 and 5 below were carried out to obtain Formula I Form C. The experiments in Table 4 below were performed using the fast cooling procedure, but the experiments in Table 5 below were performed using the slow cooling procedure.

[Table 4]

quick cooling procedure

<img file="KR20140020249A_D0059.tif" />

[Table 5]

slow cooling procedure

<img file="KR20140020249A_D0060.tif" />

Slurry Procedure for Obtaining Formula I Form D

One. Formula I, Form A (ca. 122 mg) was weighed into a vial (8 mL) equipped with a magnetic stir bar. To the vial was added 2-butanone (MEK) (3.0 mL) to form a slurry. The contents of the vial were heated to 50° C. and held for about 1.5 hours. After holding, the contents of the vial were slowly cooled to room temperature at a rate of 20° C./hr. The mixture was then stirred overnight. The product was isolated by vacuum filtration and dried in vacuo overnight. The dried solid was evaluated for crystallinity and morphology by XRPD, indicating that the crystalline material is polymorphic form D.

2. Procedure for Competitive Slurry Experiments (Using Forms A, B, and C): The competitive slurry was mixed with approximately 50/50 mixtures of Forms A and C (10.3 mg of Form A and 11.7 mg of Form C) with a glass stir bar. Filling in glass vials (1-dram) was carried out. MEK (600 μL) was added to the vial. The vial cap was covered with parafilm to prevent evaporation. The slurry was mixed for 1 day and an aliquot was taken. The contents of the vial were stirred for an additional week, and another aliquot was taken. Both aliquots were centrifugally filtered at 8000 RPM for 5 minutes. XRPD analysis was performed on the solid phase showing the conversion of Formula I to Form D at two time points. After 1 week, an aliquot was taken and additional MEK (300 μL) was added to the remaining slurry and allowed to equilibrate for 1 day. The slurry was then seeded with Form B (ca. 4.5 mg) and equilibrated for an additional 3 days before isolation by centrifugal filtration (8000 RPM for 5 min). The solid was dried under vacuum at ambient temperature overnight. The dried solid was evaluated for crystallinity and morphology by XRPD, indicating that the crystalline material is polymorphic form D.

3. Procedure for Competitive Slurry Experiments (Using Forms B and D): Formula I Form D (ca. 6 mg) was weighed into a vial (1-dram) equipped with a magnetic stir bar. To the vial was added MEK (0.3 mL) to form a slurry and allowed to equilibrate at ambient temperature for about 24 hours. An equal amount (about 6 mg) of Form B was added to the vial and allowed to equilibrate at ambient temperature for 4 days. The resulting solid was isolated by centrifugal filtration (8000 RPM for 5 min) and dried under vacuum overnight. The dried solid was evaluated for crystallinity and morphology by XRPD, indicating that the crystalline material is polymorphic form D.

<b><u>Forms A, C, and D</u></b>

Slurry Procedure to Obtain Formula I Forms A, C, and D

Using General Method C of Example 9, the following experiments described in Table 6 below were carried out to obtain the polymorphic forms of the compounds of formula I referred to.

[Table 6]

<img file="KR20140020249A_D0061.tif" />

<b><u>form E</u></b>

Single solvent crystallization to obtain Formula I Form E

Slow cooling procedure from methanol: Formula I Form A (ca. 23.5 mg) was placed in a glass vial (2-dram) equipped with a stir bar. A minimum amount of methanol (0.53 ml) was added to the vial to dissolve the solid at 60°C. The resulting solution was polished filtered into a clean preheated vial with an injection filter (0.45 μm). After hot filtration, the vial was cooled to ambient temperature at a rate of 20° C./hour and allowed to equilibrate at ambient temperature overnight without stirring. After equilibration was maintained at ambient temperature, the crystals were collected by decanting the liquid and dried overnight at ambient temperature under vacuum (30 inches Hg). The dried solid was evaluated for crystallinity and morphology by XRPD, indicating that the crystalline material is polymorph E.

Binary Solvent Crystallization to Obtain Formula I Form E

One. Rapid cooling procedure from methanol/water: Formula I Form A (ca. 23.4 mg) was placed in a glass vial (2-dram) equipped with a stir bar. A minimum amount of methanol (0.6 ml) was added to the vial to dissolve the solid at 60°C. The resulting solution was polished filtered into a clean preheated vial with an injection filter (0.45 μm). After hot filtration, water (0.85 ml) was added in portions. After addition of the anti-solvent, the vial was placed in the refrigerator (4° C.) overnight. The crystals were collected by filtration and dried overnight at ambient temperature under vacuum (30 inches Hg). The dried solid was evaluated for crystallinity and morphology by XRPD, indicating that the crystalline material is polymorph E.

2. Slow cooling procedure from methanol/water: Formula I Form A (ca. 23 mg) was placed in a glass vial (2-dram) equipped with a stir bar. A minimum amount of methanol (0.6 ml) was added to the vial to dissolve the solid at 60°C. The resulting solution was polished filtered into a clean preheated vial with an injection filter (0.45 μm). After hot filtration, water (0.83 ml) was added in portions. After addition of the anti-solvent, the vial was cooled to ambient temperature at a rate of 20° C./hour and allowed to equilibrate at ambient temperature overnight without stirring. The resulting crystals were collected by filtration and dried overnight at ambient temperature under vacuum (30 inches Hg). The dried solid was evaluated for crystallinity and morphology by XRPD, indicating that the crystalline material is polymorph E.

Slurry Procedure for Obtaining Formula I Form E

One. Formula I, Form A (ca. 127 mg) was weighed into a vial (8 mL) mounted on a magnetic stir bar. Methanol (3.0 mL) was added to the vial to form a slurry. The contents of the vial were heated to 50° C. and held for about 1.5 hours. After holding, the contents of the vial were slowly cooled to room temperature at a rate of 20° C./hr. The mixture was then stirred overnight. The product was isolated by vacuum filtration and dried in vacuo overnight. The dried solid was evaluated for crystallinity and morphology by XRPD, indicating that the crystalline material is polymorph E.

2. Formula I Form E (ca. 5.6 mg) was weighed into a vial (1-dram) equipped with a magnetic stir bar. To this vial was added methanol (0.3 mL) to form a slurry and allowed to equilibrate at ambient temperature for about 24 hours. An equal amount (about 5.7 mg) of Form B was added to the vial and allowed to equilibrate at ambient temperature for 4 days. The resulting solid was isolated by centrifugal filtration (8000 RPM for 5 min) and dried under vacuum overnight. The dried solid was evaluated for crystallinity and morphology by XRPD, indicating that the crystalline material is polymorph E.

<b><u>form F</u></b>

Binary Solvent Crystallization to Obtain Formula I Form F

One. Rapid cooling procedure from NMP/MTBE: Formula I Form A (ca. 23 mg) was placed in a glass vial (2-dram) equipped with a stir bar. A minimal amount of NMP (0.2 ml) was added to the vial to dissolve the solid at 70°C. The resulting solution was polished filtered into a clean preheated vial with an injection filter (0.45 μm). After hot filtration, MTBE (1.0 ml) was added in portions. After addition of the anti-solvent, the vial was placed in the refrigerator (4° C.) overnight. The crystals were collected by filtration and dried overnight at ambient temperature under vacuum (30 inches Hg). The dried solid was evaluated for crystallinity and morphology by XRPD, indicating that the crystalline material is polymorphic form F.

2. Slow cooling procedure from NMP/MTBE: Formula I Form A (ca. 23 mg) was placed in a glass vial (2-dram) equipped with a stir bar. A minimal amount of NMP (0.2 ml) was added to the vial to dissolve the solid at 70°C. The resulting solution was polished filtered into a clean preheated vial with an injection filter (0.45 μm). After hot filtration, MTBE (1.0 ml) was added in portions. After addition of the anti-solvent, the vial was cooled to ambient temperature at a rate of 20° C./hour and allowed to equilibrate at ambient temperature overnight without stirring. The resulting crystals were collected by filtration and dried overnight at ambient temperature under vacuum (30 inches Hg). The dried solid was evaluated for crystallinity and morphology by XRPD, indicating that the crystalline material is polymorphic form F.

<b><u>form G</u></b>

Binary Solvent Crystallization to Obtain Formula I Form G

One. Rapid cooling procedure from ethanol/MTBE: Formula I Form A (ca. 24.3 mg) was placed in a glass vial (2-dram) equipped with a stir bar. A minimum amount of ethanol (0.78 ml) was added to the vial to dissolve the solid at 70°C. The resulting solution was polished filtered into a clean preheated vial with an injection filter (0.45 μm). After hot filtration, MTBE (7.0 ml) was added in portions. After addition of the anti-solvent, the vial was placed in the refrigerator (4° C.) overnight. At 4° C., the contents of the vial were periodically scraped with a spatula to induce crystallization and allowed to equilibrate for about 8 hours. The crystals were collected by decanting any liquid and dried overnight at ambient temperature under vacuum (30 inches Hg). The dried solid was evaluated for crystallinity and morphology by XRPD, indicating that the crystalline material is polymorphic form G.

2. Rapid cooling procedure from IPA/MTBE: Formula I Form A (ca. 23.7 mg) was placed in a glass vial (2-dram) equipped with a stir bar. A minimum amount of IPA (0.60 ml) was added to the vial to dissolve the solid at 70°C. The resulting solution was polished filtered into a clean preheated vial with an injection filter (0.45 μm). After hot filtration, MTBE (6.0 ml) was added in portions. After addition of the anti-solvent, the vial was placed in the refrigerator (4° C.) overnight. At 4° C., the contents of the vial were periodically scraped with a spatula to induce crystallization and allowed to equilibrate for about 8 hours. The crystals were collected by vacuum filtration and dried under vacuum (30 inches Hg) at ambient temperature overnight. The dried solid was evaluated for crystallinity and morphology by XRPD, indicating that the crystalline material is polymorphic form G.

3. Rapid cooling procedure from methanol/MTBE: Formula I Form A (ca. 24 mg) was placed in a glass vial (2-dram) equipped with a stir bar. A minimum amount of methanol (0.6 ml) was added to the vial to dissolve the solid at 60°C. The resulting solution was polished filtered into a clean preheated vial with an injection filter (0.45 μm). After hot filtration, MTBE (6.0 ml) was added in portions. After addition of the anti-solvent, the vial was placed in the refrigerator (4° C.) overnight. At 4° C., the contents of the vial were periodically scraped with a spatula to induce crystallization and allowed to equilibrate for about 8 hours. The crystals were collected by decanting any liquid and dried overnight at ambient temperature under vacuum (30 inches Hg). The dried solid was evaluated for crystallinity and morphology by XRPD, indicating that the crystalline material is polymorphic form G.

<b><u>form H</u></b>

Binary Solvent Crystallization to Obtain Formula I Form H

Slow cooling procedure from dioxane/MTBE: Formula I Form A (ca. 23.2 mg) was placed in a glass vial (2-dram) equipped with a stir bar. A minimum amount of dioxane (0.6 ml) was added to the vial to dissolve the solid at 70°C. The resulting solution was polished filtered into a clean preheated vial with an injection filter (0.45 μm). After hot filtration, MTBE (1.0 ml) was added in portions. After addition of the anti-solvent, the vial was cooled to ambient temperature at a rate of 20° C./hour and allowed to equilibrate at ambient temperature overnight without stirring. The resulting crystals were collected by filtration and dried overnight at ambient temperature under vacuum (30 inches Hg). The dried solid was evaluated for crystallinity and morphology by XRPD, indicating that the crystalline material is polymorphic form H.

<b><u>Form I</u></b>

Binary Solvent Crystallization to Obtain Formula I Form I

One. Slow cooling procedure from acetone/toluene: Formula I Form A (ca. 23.3 mg) was placed in a glass vial (2-dram) equipped with a stir bar. A minimal amount of acetone (2.5 ml) was added to the vial to dissolve the solid at 50°C. The resulting solution was polished filtered into a clean preheated vial with an injection filter (0.45 μm). After hot filtration, toluene (5.0 ml) was added in portions. After addition of the anti-solvent, the vial was cooled to ambient temperature at a rate of 20° C./hour and allowed to equilibrate at ambient temperature overnight without stirring. The resulting crystals were collected by filtration and dried overnight at ambient temperature under vacuum (30 inches Hg). The dried solid was evaluated for crystallinity and morphology by XRPD, indicating that the crystalline material is polymorphic form I.

2. Slow cooling procedure from MEK/toluene: Formula I Form A (ca. 24.1 mg) was placed in a glass vial (2-dram) equipped with a stir bar. A minimal amount of MEK (2.1 ml) was added to the vial to dissolve the solid at 70°C. The resulting solution was polished filtered into a clean preheated vial with an injection filter (0.45 μm). After hot filtration, toluene (6.0 ml) was added in portions. After addition of the anti-solvent, the vial was cooled to ambient temperature at a rate of 20° C./hour and allowed to equilibrate at ambient temperature overnight without stirring. The resulting crystals were collected by filtration and dried overnight at ambient temperature under vacuum (30 inches Hg). The dried solid was evaluated for crystallinity and morphology by XRPD, indicating that the crystalline material is polymorphic form I.

3. Slow cooling procedure from dioxane/toluene: Formula I Form A (ca. 24.5 mg) was placed in a glass vial (2-dram) equipped with a stir bar. A minimum amount of dioxane (0.8 ml) was added to the vial to dissolve the solid at 70°C. The resulting solution was polished filtered into a clean preheated vial with an injection filter (0.45 μm). After hot filtration, toluene (1.0 ml) was added in portions. After addition of the anti-solvent, the vial was cooled to ambient temperature at a rate of 20° C./hour and allowed to equilibrate at ambient temperature overnight without stirring. The resulting crystals were collected by filtration and dried overnight at ambient temperature under vacuum (30 inches Hg). The dried solid was evaluated for crystallinity and morphology by XRPD, indicating that the crystalline material is polymorphic form I.

<b><u>form J</u></b>

Binary Solvent Crystallization to Obtain Formula I Form J

Slow cooling procedure with DMF/toluene: Formula I Form A (ca. 24.2 mg) was placed in a glass vial (2-dram) equipped with a stir bar. A minimum amount of DMF (0.2 ml) was added to the vial to dissolve the solid at 70°C. The resulting solution was polished filtered into a clean preheated vial with an injection filter (0.45 μm). After hot filtration, toluene (2.0 ml) was added in portions. After addition of the anti-solvent, the vial was cooled to ambient temperature at a rate of 20° C./hour and allowed to equilibrate at ambient temperature overnight without stirring. The resulting crystals were collected by filtration and dried overnight at ambient temperature under vacuum (30 inches Hg). The dried solid was evaluated for crystallinity and morphology by XRPD, indicating that the crystalline material is polymorphic form J.

Example 11

Preparation of an amorphous compound of formula (I)

To polymorph Form A of the compound of formula I (2.0 g) was added t-butanol (50 mL) and water (25 mL). The mixture was heated to 40° C. for 0.5 h with stirring. After sonication for about 20 minutes, t-butanol (25 mL) was added. The mixture was then cooled to room temperature to obtain a homogeneous solution. After filtration, the resulting solution was lyophilized for 2 days to obtain a foamy solid. The amorphous quality of the solid was confirmed by XRPD (see FIG. 11), DSC and TGA analysis.

Example 12

XRPD Research

Using the XRPD instrumentation and parameters described above, the following XRPD peaks were observed for Formula I Polymorph Forms A, B, C, D, E, F, G, H, I, and J. XRPD targets for these ten polymorphisms are given in Figures 1-10, respectively. In Table 7, the peak position unit is °2θ. In one embodiment, a given polymorph can be characterized as having one or more of the five XRPD peaks given in Set 1 of Table 7 below. In another embodiment, a given form can be characterized as having one or more of the five XRPD peaks given in set 1 in combination with one or more of the XRPD peaks given in set 2 of Table 7 below. In some embodiments, one or more peak position values may be defined as modified by the term "about" as described herein. In other embodiments, any given peak position has ±0.2 2θ (eg, 9.6±0.2 2θ).

[Table 7]

<img file="KR20140020249A_D0062.tif" />

Example 13

Differential Scanning Calorimetry (DSC) Studies

Using the DSC instrumentation and parameters described herein, the following DSC peaks were observed for compounds of Formula I Polymorph Forms A, B, C, D, E, F, G, H, I, and J. The DSC thermograms for these nine polymorphisms are given in FIGS. 12 to 24, respectively, and the peak positions are given in Table 8 below. Additional DSC data for polymorph forms A, B, C, D, E, F, G, H, I, and J are given in Table 9 below. If ^ indicating an exothermic peak is not included, then all peaks are endothermic.

[Table 8]

<img file="KR20140020249A_D0063.tif" />

12 to 23, the DSC thermograms for polymorphs A, B, C, D, E, F, G, H, and J have endothermic peaks at about 280 to about 282°C, respectively. This peak appears upon heating and crystallizes from a given form to Form B (if Form A or Form C is heated to about 250° C. and then cooled to give Form B, see Example 10), then from about 280 to about It has a specific endothermic peak at 282°C.

Example 14

Thermogravimetric Analysis (TGA) Studies

Using the TGA instrumentation and parameters described below, the following TGA peaks summarized in Table 9 below for Formula I Polymorph Forms C-J were observed. Corresponds to the peak when the sample is heated and a weight loss (wt%) is observed at a given temperature.

Example 15

Summary of Preparation and Analysis of Polymorph Forms A-J of Formula I

Table 9 below summarizes non-limiting exemplary preparation techniques and representative analytical data described below for Formula I Polymorph Forms A-J.

[Table 9]

<img file="KR20140020249A_D0064.tif" />

Example 16

Stability study

For polymorph Form A and Form C, stability studies were performed, packing several samples of each given form and subjecting given temperature and humidity conditions, as described in Table 10 below. At each time point, samples for study were opened and evaluated using HPLC for purity, Karl Fischer for moisture content, and XRPD for polymorphism. In all studies listed in Table 10 below at each evaluation time point, no indication of polymorphic form instability was observed.

[Table 10]

<img file="KR20140020249A_D0065.tif" />

Example 17

Dynamic Vapor Adsorption Analysis

Dynamic vapor adsorption (DVS) analysis was performed on polymorph Forms A, B, C, D, and E using the DVS instrumentation and parameters described herein. Form A was slightly hygroscopic and showed a moisture absorption of 0.7% by weight at 60% RH and a moisture absorption of 2.6% by weight at 90% RH. Hysteresis of the hemi-hydrate formulation was observed. Form B was slightly hygroscopic and showed a moisture absorption of 1.0% by weight at 60% RH and a moisture absorption of 1.7% by weight at 90% RH. Form C is moderately hygroscopic and exhibits moisture absorption of 4.2% by weight at 60% RH and 4.9% by weight at 90% RH (see FIG. 30 below). Form D was slightly hygroscopic and showed an inspiratory absorption of 0.4% by weight at 60% RH and an intake absorption of 1.7% by weight at 90% RH. Form E is slightly hygroscopic and exhibits moisture absorption of 1.9% by weight at 60% RH and 2.2% by weight at 90% RH. Forms A and C were both placed in a thermo-hygrostat at 9% RH and 95% RH, and the form did not change even after 1 week.

Example 18

thermal stability

Forms A, B, C, D, and E were stored at 60° C. for 10 days and then analyzed by XRPD. In each case, vials (8 mL) were filled with material (approximately 20 mg), with the exception of Form B, which filled only 10 mg of material. Samples were equilibrated in an oven for 10 days. No polymorphic changes were observed with XRPD. All forms were observed to be stable.

Example 19

grinding stability

Forms A, C, D, and E were subjected to grinding experiments by hand using a mortar and pestle. Samples were ground gently for 2 minutes and then analyzed by XRPD. The material was then transferred back to a mortar and pestle, ground for an additional 3 minutes, and milling was performed for a total of 5 minutes before reanalysis by XRPD. Form A remained constant at both 2 min and 5 min grinding. Form C also remained constant at 2 min and 5 min grinding.

Example 20

Summary of Examples 17-19

Table 11 below summarizes non-limiting representative analytical data for Formula I Polymorph Forms A-E described herein.

[Table 11]

<img file="KR20140020249A_D0066.tif" />

Example 21

salt screening

The salts of the compounds of formula (I) were prepared with L-tartaric acid, p-toluenesulfonic acid, D-glucaronic acid, ethane-1,2-disulfonic acid (EDSA), 2-naphthalenesulfonic acid (NSA), hydrochloric acid (HCl) ( mono and bis), hydrobromic acid (HBr), citric acid, naphthalene-1,5-disulfonic acid (NDSA), DL-mandelic acid, fumaric acid, sulfuric acid, maleic acid, methanesulfonic acid (MSA), benzenesulfonic acid (BSA) ), ethanesulfonic acid (ESA), L-malic acid, phosphoric acid, and aminoethanesulfonic acid (taurine). Various salts and free bases were tested against various solvents for the formulation of the crystalline solid shown in FIG. 25 . Tables 12 and 13 summarize representative data for exemplary salts of compounds of Formula (I). Compounds of formula (I) include semi-crystalline to crystalline mono-salts including ethane-1,2-disulfonic acid (EDSA), 2-naphthalenesulfonic acid (NSA), hydrochloric acid (HCl), hydrobromic acid (HBr), citric acid, and naphthalene-1,5-disulfonic acid (NDSA) were observed to form amorphous single-salts and amorphous bis-salts including HCl from various solvents.

[Table 12]

<img file="KR20140020249A_D0067.tif" />

[Table 13]

<img file="KR20140020249A_D0068.tif" />

Example 22

Formulations and Formulations

Example 22A: Capsule Formulation for Formula I Form C Polymorph

Capsules containing the Compound Form C polymorph (API) of Formula I were prepared according to the following procedure. Capsules include hard capsules filled with a combined dry blend powder charge of the Formula I Form C polymorph and one or more excipients. In some examples, the capsule component comprises the Formula I Form C polymorph (about 1 to about 30% w/w); fillers/glidants such as silicified microcrystalline cellulose (about 70 to about 99% w/w); disintegrants such as crospovidone (0 to about 7% w/w); and lubricants such as magnesium stearate (0 to about 2% w/w).

Other excipients that may be used in the exemplary capsule formulation include, but are not limited to, fillers such as lactose, mannitol, starch, sorbitol, sucrose, dicalcium phosphate, and microcrystalline cellulose; disintegrants such as croscarmellose sodium and sodium starch glycolate; glidants such as colloidal silicon dioxide, silicon dioxide, magnesium silicate, and talc; lubricants such as sodium stearyl fumarate and stearic acid; and surfactants such as sodium lauryl sulfate, sodium dodecyl sulfate, Tween^&amp;#174; 80, and root roll^&amp;#174;includes The choice and percentage of filler/glidant can be based on the flowability of the blend. The choice and percentage of disintegrant can be based on the release profile of the capsules in 0.1N hydrochloric acid, without surfactant.

In a given formulation, portions of filler/glidant and disintegrant were each individually passed through a # 30 mesh screen. The Formula I Form C polymorph and portions of the filler/glidant were combined and passed through a # 30 mesh screen. The lubricant was passed through a #40 mesh screen. Each ingredient, except for the lubricant, was weighed, transferred individually to a Patterson Kelley's V-blender, added each, and blended for about 5 to about 15 minutes. The mixture was then Quadro using a 0.039R mesh screen at a speed of about 40 rpm.^&amp;#174;) Comil^&amp;#174;) through milling. Finally, the lubricant was added and the mixture was blended for about 5 minutes. The mixture was then used to fill the appropriate capsules using an IN-CAP encapsulation machine.

Non-limiting examples of formulations and capsule preparations are given in Table 14 below. A low strength formulation was prepared in 1 mg/5 mg capsules and a high strength formulation at 25 mg/100 mg strength. The 1 mg and 25 mg strengths are size 2, opaque white, hard gelatin capsules, the 5 mg strength is size 2, opaque Swedish orange, hard gelatin capsules, and the 100 mg strength is size 0, opaque white, hard gelatin capsules.

[Table 14]

capsule formulation

<img file="KR20140020249A_D0069.tif" />

Example 22B: Extensive Capsule Formulation for Formula I Form C Polymorph

Formulations were evaluated for manufacturability, scalability to automated encapsulation equipment, ingredient uniformity, dissolution, and stability. To evaluate the factors mentioned above, a wide range of batches were prepared for all intensities. At the 1/5 mg blend, an API formulation (about 2 kg) was prepared as described in Example 22A, and about 9000 capsules were produced at each strength. At the 25/100 mg blend, an API formulation (about 2.5 kg) was prepared as described in Example 22A, and about 6000 capsules were produced at each strength. Tables 15 and 16 below summarize the results of several analyzes of these formulations.

[Table 15]

1/5 mg Formulation Characteristics

<img file="KR20140020249A_D0070.tif" />

[Table 16]

25/100 mg Formulation Characteristics

<img file="KR20140020249A_D0071.tif" />

The stability of the capsule in the container closure was evaluated under long-term and rapid acceleration conditions. Container closure conditions were: (i) 60-cc high density polyethylene (HDPE), wide opening, round, white bottle; and (ii) a child-safe 33-mm white plastic lid including a heat induction foil inner sealing liner. The container containing the capsules is subject to the following conditions: (1) -20±5° C.; (2) 5±3° C.; (3) 25±2°C, 60±5% RH; (4) 40±2°C, 75±5% RH; (5) 25±2°C, 60±5% RH, open bottle; (6) 40±2°C, 75±5% RH, open bottle; and (7) 30±2° C., 65±5% RH. Samples of the capsule formulation were analyzed at specific time intervals. The API maintained stability for at least 6 months at 25±2° C., 60±5% RH and 40±2° C., 45±5% RH. When stored in induction-sealed HDPE bottles, the API maintained stability at -20±5° C., 5±3° C. for at least 6 months. In an open HDPE bottle, the API maintained stability at 25±2° C., 60±5% RH and 40±2° C., 75±5% RH for at least 6 months.

Manufacturing, packing, labeling, storage and testing of capsules were performed in accordance with current good manufacturing practices (cGMP). The capsules were packed into high density polyethylene (HDPE) bottles. Other suitable packing containers include, but are not limited to, glass bottles, low density polyethylene bottles/drums, fiber drums, HDPE drums, and aluminum foil, Aclar^&amp;#174;), and/or blister packing that may contain materials such as PVC/PVdC/PE films.

Karl Fischer analysis of API in capsules refers to a water content of about 4 to about 5% w/w (e.g., about 4.2%, about 4.3%, about 4.5%, about 4.7%, about 4.9%, and about 5.0%) did.

Representative capsule dissolution profiles for 1, 5, 25, and 100 mg capsules are shown in FIG. 31 . The dissolution of the capsule was equivalent to that of the immediate-release solid oral dosage form. At 60 minutes, more than about 90% of the API had dissolved. Dissolution conditions were USP Apparatus II (pedal), 0.1 N HCl at 37° C., 500 mL (at 1, 5, 25 mg) or 900 mL (at 100 mg), 50 RPM pedal speed.

Example 23

Biological activity evaluation

PI3-kinase HTRF purchased from Millipore Corporation^&amp;#174; The compounds disclosed herein were screened using an assay kit (Catalog No. 33-016). This assay used specific high affinity binding of the GRP1 plextrin homology (PH) domain to PIP3, which is the product of class 1A or 1B PI3 kinases acting on the physiological substrate PIP2. During the detection phase of the assay, a complex was generated between the GST-tagged PH domain and the biotinylated single chain PIP3. Biotinylated PIP3 and GST-tagged PH domains aggregate fluorophores (streptavidin-allophycocyanin and europium-labeled anti-GST, respectively) to form a fluorescence resonance energy transfer (FRET) structure, and stable time- The resolution produces a FRET signal. The FRET complex was disrupted in a competitive manner by the product formed in the PI3 kinase assay, which is non-biotinylated PIP3.

PI3 kinase α, β, γ and δ activity was purchased from Millipore Corporation PI3 kinase HTRF^&amp;#174; The assay was performed using an assay kit (Catalog No. 33-016). Purified recombinant PI3Kα (Cat. No. 14-602-K), PI3Kβ (Cat. No. 14-603-K), PI3Kγ (Cat. No. 14-558-K) and PI3Kδ (Cat. No. 14-604-K) was obtained from Milcore Corporation. The phosphorylation of phosphatidylinositol 4,5-bisphosphate (PIP2 at 10 μM) and phosphatidylinositol 3,4,5-triphosphate (PIP3) was catalyzed using purified recombinant PI3K enzyme in the presence of ATP (10 μM). . Assays were performed in a 384-well format and detected using a Perkin Elmer EnVision Xcite Multilabel Reader. Toggle the emission rate to %inhibit, GraphPad Prism^&amp;#174;) imported into the software. 50% (IC₅₀) were calculated using concentrations ranging from 20 μM to 0.1 nM (12-point curve). IC₅₀ value in graphpad prism^&amp;#174; 5 was determined using the available nonlinear regression analysis.

Example 24

chemical stability

The chemical stability of one or more subject compounds was determined according to standard procedures known in the art. Exemplary procedures for the identified chemical stability of the subject compounds are detailed below. The default buffer solution used for chemical stability analysis is phosphate-buffered solution (PBS) at pH 7.4; Other suitable buffer solutions may be used. From the stock solution (100 µM), the subject compound was added to an aliquot of PBS (2x) containing the test compound (5 µM) and 1% DMSO (for half-life determination, a total sample volume of 700 µL was prepared). A final assay volume (400 μL) was obtained. The reaction was incubated with shaking at 37° C. for 24 hours; Samples were incubated for 0, 2, 4, 6, and 24 hours for half-life measurements. The culture mixture (100 μL) was immediately added to acetonitrile (100 μL) to stop the reaction and vortexed for 5 min. Samples were then stored at -20°C until analyzed by HPLC-MS/MS. Optionally, a control compound or a reference compound such as chlorambucil (5 μM) is tested with the subject compound of interest, while the compound is significantly hydrolyzed over 24 hours. Samples were analyzed by (RP)HPLC-MS/MS using selected reaction monitoring (SRM). HPLC conditions consisted of an automatic sampler, mixed-mode, C12, 2 x 20 mm column and a binary LC pump with a gradient program. The peak areas corresponding to the analytes were recorded by HPLC-MS/MS. The proportion (expressed in %) of the parent compound remaining after 24 hours compared to the amount remaining at 0 hours was reported as chemical stability. For half-life measurements, half-life was determined as the slope of the initial linear range of the logarithmic curve of residual compound (%) versus time (estimated by a linear equation).

Example 25

Expression and inhibition analysis of p110α/p85α, p110β/p85α, p110δ/p85α, and p110γ

Class I PI3-K can be purchased (p110α/p85α, p110β/p85α, p110δ/p85α, and p110γ from Sigma from Upstate) or expressed as previously described (Knight et al. ., 2004]). IC₅₀ Values were determined using standard TLC assays or high throughput membrane capture assays for lipid kinase activity (described below). Kinase reactions were performed with kinase, inhibitor (2% DMSO final concentration), buffer solution (25 mM HEPES, pH 7.4, 10 mM MgCl).₂), and directly sonicated phosphatidylinositol (100 μg/ml). The reaction was initiated by adding ATP containing 10 μCi of γ-32P-ATP to a final concentration of 10 or 100 μM, and allowed to proceed at room temperature for 5 minutes. In TLC analysis, 1N HCl (105 μl) followed by CHCl₃:MeOH (1:1, 160 μl) was added to quench the reaction. The biphasic mixture was vortexed, centrifuged briefly, and CHCl₃The organic phase was transferred to a new tube using a gel-loaded pipette tip precoated with . This extract was dropped onto a TLC plate and developed in a solution of n-propanol: 1 M acetic acid (65:35) for 3-4 hours. The TLC plates were then dried, exposed to a phosphoimaging screen (Storm, Amersham) and quantified. For each compound, kinase activity was measured at inhibitor concentrations of 10 to 12 representing a 2-fold dilution from the highest concentration tested (typically 200 μM). In compounds with significant activity, the IC₅₀ Measurements are repeated 2 to 4 times and the reported value is the average of these independent measurements.

Other commercial kits or systems for measuring PI3-K activity are available. Commercially available kits or systems can be used to screen inhibitors and/or agonists of PI3-K, including but not limited to PI3-kinases α, β, δ and γ. Exemplary systems include PI3-kinase (human) HTRF from Upstate^&amp;#174; analysis. The analysis may be performed according to the procedure suggested by the manufacturer. Briefly, the assay is a time-resolved FRET assay that indirectly measures the PIP3 product formed by the activity of PI3-K. Kinase reactions are performed in microtiter plates (eg, 384 well microtiter plates). The total reaction volume is approximately 20 μL per well. In the first step, each well contains test compound (2 μL) in 20% dimethylsulfoxide, resulting in a final concentration of 2% DMSO. Next, a kinase/PIP2 mixture (diluted in reaction buffer (1X), approximately 14.5 μL) was added per well to final concentrations of kinase (0.25 to 0.3 μg/ml) and PIP2 (10 μM). The plate was sealed and incubated for 15 min at room temperature. To start the reaction, ATP (diluted in reaction buffer (1X), 3.5 µL) was added per well to a final concentration of ATP (10 µM). The plate was sealed and incubated for 1 hour at room temperature. The reaction was stopped by adding stop solution (5 μL) per well, followed by addition of detection mixture (5 μL) per well. Plates were sealed and incubated at room temperature for 1 hour before reading with an appropriate plate reader. Analyze data, GraphPad Prism^&amp;#174; 5 using IC₅₀was created.

Example 26

B cell activity and proliferation assay

The ability of one or more subject compounds to inhibit B cell activity and proliferation was determined according to standard procedures known in the art. For example, in vitro cell proliferation assays measure the metabolic activity of living cells. Analyze the AlamarBlue^&amp;#174;) was performed in 96 well microtiter plates using reduction. Balb/c splenic B cells were subjected to Ficoll-Paque^™) after purification on a plus gradient, magnetic cells were isolated using a MACS B cell isolation kit (Miletenyi). Cells were plated in 90 μL in B cell medium (RPMI+10% FBS+Pen/Strep+50 μM bME+5 mM HEPES) at 50,000 cells/well. Compounds disclosed herein were diluted with B cell medium and added in volume (10 μL). Plate at 37° C. and 5% CO₂incubated for 72 hours. allama blue^&amp;#174; Add reagents (volume of 15 μL) to each well and incubate the plate at 37 °C and 5% CO2.₂incubated for 5 hours. allama blue^&amp;#174; Fluorescence was read at 560Ex/590Em, IC₅₀ or EC₅₀ value in graphpad prism^&amp;#174; 5 was used to calculate.

Example 27

Tumor Cell Line Proliferation Assay

The ability of one or more subject compounds to inhibit tumor cell line proliferation can be determined according to standard procedures known in the art. For example, an in vitro cell proliferation assay can be performed to measure the metabolic activity of living cells. allama blue^&amp;#174; Assays were performed in 96 well microtiter plates using reduction. Human tumor cell lines were obtained from ATCC (eg, MCF7, U-87 MG, MDA-MB-468, PC-3), combined in T75 flasks, trypsinized with trypsin (0.25%), and tumor cell medium (DMEM + 10% FBS) and plated at 90 μL at 5,000 cells/well in tumor cell medium. Compounds disclosed herein were diluted with tumor cell media and added in a 10 ul volume. Plate at 37° C. and 5% CO₂incubated for 72 hours. allama blue^&amp;#174; Add reagent (10 μL) to each well and place the plate at 37°C and 5% CO2.₂incubated for 3 hours. allama blue^&amp;#174; Fluorescence was read at 560Ex/590Em, IC₅₀ value in graphpad prism^&amp;#174; 5 was used to calculate.

Example 28

Antitumor activity in vivo

The compounds described herein can be evaluated in a panel of human and murine tumor models.

<u>paclitaxel</u><u>-refractory tumor model</u>

<i>One. Clinically-Induced Ovarian Tumor Model</i>

This tumor model was created from a tumor biopsy of a patient with ovarian cancer. Tumor biopsies were performed from patients. Compounds described herein were administered to nude mice bearing developed tumors using a schedule of 5 times every 2 days.

<i>2. A2780Tax human ovarian cancer xenograft (mutated tubulin).</i>

A2780Tax is a paclitaxel-resistant human ovarian cancer model. Cells from the sensitive parental A2780 line were induced by co-culture with the MDR-inverse agents paclitaxel and verapamil. The resistance mechanism showed an associated non-MDR and provided a mutation in the gene encoding the beta-tubulin protein. Compounds described herein can be administered to nude mice bearing developed tumors using a schedule of 5 times every 2 days.

<i>3. </i><i>HCT116</i><i>/</i><i>VM46</i><i> Human Colon Cancer Xenograft (Multi-Drug Resistance). </i>

HCT116/VM46 is an MDR-resistant colon cancer developed from a sensitive HCT116 parental line. In vivo, HCT116/VM46 grown in nude mice is highly resistant to paclitaxel. The compounds described herein can be administered to mice bearing developed tumors using a schedule of 5 times every 2 days.

<i>4. </i><i>M5076</i><i> Rat breeding model</i>

M5076 is a murine fibrosarcoma that is inherently refractory to paclitaxel in vivo. The compounds described herein can be administered to mice bearing developed tumors using a schedule of 5 times every 2 days.

One or more compounds disclosed herein may be used in combination with other therapeutic agents in vivo in multidrug resistant human colon cancer xenograft HCT/VM46 or any other model known in the art described herein.

Example 29

Microsomal Stability Analysis

The stability of one or more subject compounds was determined according to standard procedures known in the art. For example, the stability of one or more subject compounds was performed in an in vitro assay. For example, an in vitro microsomal stability assay measures the stability of one or more subject compounds upon reaction with mouse, rat or human microsomes from the liver. The microsomal reaction with the compound was carried out in an Eppendorf tube (1.5 mL). Each tube contains NADPH (10.0 mg/ml, 0.1 μL); mouse, rat or human liver microsomes (20.0 mg/ml, 75 μL); 0.2 M phosphate buffer solution (0.4 µL), and ddH₂O (425 µL). Negative control (except NADPH) tubes contain mouse, rat or human liver microsomes (20.0 mg/ml, 75 μL); 0.2 M phosphate buffer solution (0.4 µL), and ddH₂O (525 µL). The reaction was started by addition of test compound (10.0 mM, 1.0 μL). The reaction tube was incubated at 37°C. Samples (100 μL) at 0, 5, 10, 15, 30, and 60 min reactions were collected in new Eppendorf tubes containing cold methanol (300 μL). Samples were centrifuged at 15,000 rpm to remove proteins. The supernatant of the centrifuged sample was transferred to a new tube. After reaction with the microsomes, the concentration of stable compounds in the supernatant was determined by liquid chromatography/mass spectrometry (LC-MS).

Example 30

Plasma Stability Analysis

The stability of one or more subject compounds in plasma was determined according to standard procedures known in the art (see, e.g.,<i>Rapid</i><i></i><i>Commun</i><i>. </i><i>Mass</i><i></i><i>Spectrom</i>., <b>10</b>: 1019-1026]). In addition, the following procedure is performed in human plasma; HPLC-MS/MS analyzes using other species such as monkeys, dogs, rats, and mice are available. Frozen and heparinized human plasma was thawed in a cold water bath and spun at 2000 rpm at 4° C. for 10 minutes prior to use. Add the subject compound from the stock solution (400 µM) to an aliquot of pre-warmed plasma to a final assay volume of 400 µL (or 800 µL in half-life measurements) containing the test compound (5 µM) and DMSO (0.5%). was obtained. Reactions were incubated with shaking for 0 to 60 min at 37°C, or 0, 15, 30, 45 and 60 min at 37°C in half-life measurements. The culture mixture (50 μL) was transferred to ice-water acetonitrile (200 μL) to stop the reaction and mixed by shaking for 5 min. Samples were centrifuged at 6000 x g for 15 min at 4 °C, and the supernatant (120 μL) was removed from a clean tube. The samples were then evaporated to dryness and analyzed by HPLC-MS/MS.

In one embodiment, one or more control or reference compounds (5 μM) were tested simultaneously with the following test compounds: propoxycaine, one compound with low plasma stability, and propantheline, another compound with intermediate plasma stability.

Samples were placed in acetonitrile/methanol/water (1/1/2, v/v/v) and analyzed by (RP)HPLC-MS/MS using selected reaction monitoring (SRM). HPLC conditions consist of an automatic sampler, mixed mode, C12, 2 x 20 mm column, and a binary LC pump with gradient program. The peak areas corresponding to the analytes were recorded by HPLC-MS/MS. The proportion of parent compound remaining (expressed as %) after 60 minutes compared to the amount remaining at 0 hours was recorded as plasma stability. For half-life measurements, half-life was determined as the slope of the initial linear range of the logarithmic curve of residual compound (%) versus time (estimated by a first-order equation).

Example 31

Kinase signaling in the blood

PI3K/Akt/mTor signals in blood cells were measured using the phosflow method (see [<i>Methods</i><i></i><i>Enzymol</i><i>.</i> (2007) 434:131-54)]. As this method is inherently a single cell assay, it is capable of detecting cellular heterogeneity above the average population. This allows for coexisting differences in signal status in different populations defined by different markers. In addition, phosflow is very quantitative. To test the effect of one or more compounds disclosed herein, unfractionated splenocytes, or peripheral blood mononuclear cells, stimulate anti-CD3 to initiate T-cell receptor signaling. Cells were then fixed and stained with surface markers and intracellular phosphoproteins. The inhibitors disclosed herein inhibit anti-CD3-mediated phosphorylation of Akt-S473 and S6, whereas rapamycin inhibits S6 phosphorylation and enhances Akt phosphorylation under the conditions tested.

Similarly, aliquots of whole blood are incubated with vehicle (e.g., 0.1% DMSO) or kinase inhibitors at various concentrations for 15 minutes, followed by the addition of stimulation to T cells using anti-kappa light chain antibody (Fab'2 fragment). Receptor (TCR) (anti-CD3 with secondary antibody) or B cell receptor (BCR) was cross-linked. After about 5 and 15 minutes, the samples are fixed (eg, added cold 4% paraformaldehyde) and used in Phosflow. Surface staining was used to differentiate between T and B cells using antibodies against cell surface markers known in the art. The phosphorylation levels of kinase substrates such as Akt and S6 were then measured by incubation with immobilized cells containing labeled antibodies specific for the phosphorylated isoform of these proteins. The population of cells was then analyzed by flow cytometry.

Example 32

Colony Formation Assay

Murine bone marrow cells directly transformed with the p190 BCR-Abl retrovirus (referred to as p190 transformed cells) were medicated in the presence of various drugs in combination with M3630 methylcellulose medium containing recombinant human IL-7 in about 30% serum. Plated for 7 days and the number of colonies formed was counted by visual examination using a microscope.

Alternatively, upon initial diagnosis or relapse, human peripheral blood mononuclear cells were obtained from Philadelphia chromosome positive (Ph+) and negative (Ph-) patients. Live cells were isolated and enriched in CD19+ CD34+ B hepatocytes. After incubating the liquid overnight, cells were harvested at various concentrations in combination with cytokines (IL-3, IL-6, IL-7, G-CSF, GM-CSF, CF, Flt3 ligand, and erythropoietin) and a compound disclosed herein. was plated in methocult GF+ H4435 (Stem Cell Technologies) augmented with known chemotherapeutic agents. Colonies were counted 12 to 14 days after microscopic observation. This method can be used to test evidence for additive or synergistic activity.

Example 33

In vivo effect of kinase inhibitors on leukemia cells

Female recipient mice were lethally irradiated with γ-rays twice, at approximately 4 hour intervals, each at approximately 5 Gy. About 1 hour after the second irradiation, the mice were treated about 1x10⁶ Leukemia cells (eg, Ph+ human or murine cells, or p190 transformed bone marrow cells) are injected intravenously. These cells were harvested from about 5x10 cells from 3 to 5 week old donor mice.⁶ It was administered together with the radiation protection dose of normal bone marrow cells. Recipients were given antibiotics in water and monitored daily. After about 14 days diseased mice were euthanized and lymphatic organs were collected for analysis. Kinase inhibitors were treated approximately 10 days after injection of leukemia cells, and treatment continued until mice became ill or transplanted up to approximately 35 days later. Inhibitors were given by oral lavage.

Peripheral blood cells were collected for approximately 10 days (pre-treatment), euthanized (post-treatment), contacted with labeled anti-hCD4 antibody, and counted by flow counting. Known chemotherapeutic agents (eg, Gleevec^&amp;#174;)) may explain that the synergistic effect of one or more compounds disclosed herein in combination with a known chemotherapeutic agent compared to treatment alone may reduce the leukemia blood cell count.

Example 34

Treatment of Lupus Disease Model Mice

Mice deficient in the inhibitory receptor FcγRIIb, which opposes PI3K signaling in B cells, developed lupus with high penetrance. FcγRIIb knockout mice (R2KO, Jackson Labs) are considered a valid model of human disease, and some lupus patients have reduced expression or function of FcγRIIb (S. Bolland and JV Ravtech 2000.<i>Immunity</i> 12:277-285]).

Within about 4-6 months, R2KO mice developed lupus-like disease with antinuclear antibodies, glomerulonephritis and proteinurea. In these experiments, rapamycin-like RAD001 (available from LC Laboratories) was used as a reference compound and administered orally. This compound has been shown to ameliorate lupus symptoms in the B6.Sle 1z.Sle 3z model (T. Wu et al.<i>J. </i><i>Clin</i><i></i><i>Invest</i>. 117:2186-2196]).

Lupus disease model mice, such as R2KO, BXSB or MLR/lpr, were treated at about 2 months of age and about 2 months of age. Mice were administered the following: vehicle, RAD001 (about 10 mg/kg), or a compound disclosed herein (about 1 to about 500 mg/kg). Blood and urine samples were obtained during the drug trial and tested for antinuclear antibody (dilution of serum) or protein concentration (urine). In addition, sera were tested for anti-ssDNA and anti-dsDNA antibodies by ELISA. Animals were euthanized for 60 days and tissues were collected to check for splenic weight and kidney disease. Glomerulonephritis was measured in kidney areas stained with H&amp;E. After treatment was discontinued using the same endpoint, another animal was studied for approximately 2 months.

Using these identified art models, the kinase inhibitors disclosed herein can inhibit or delay the onset of lupus symptoms in lupus disease model mice.

Example 35

Rat Bone Marrow Transplant Assay

Female recipient mice were lethally irradiated with γ-rays. About 1 hour after irradiation, mice are cultured in an early passage p190 transformed culture (eg,<i>Cancer</i><i></i><i>Genet</i><i> Cytogenet</i>. 2005 Aug;161(1):51-6) from about 1×10⁶ Leukemia cells were injected. These cells were harvested from about 5x10 cells from 3 to 5 week old donor mice.⁶ It was administered together with the radiation protection dose of normal bone marrow cells. Recipients were given antibiotics in water and monitored daily. After approximately 14 days diseased mice were euthanized and lymph organs were collected for flow counting and/or magnetic enrichment. Treatment was continued for about 10 days and treated daily until the mice became ill or transplanted up to about 35 days later. Drugs were given by oral feeding (po). In preliminary trials, amounts of chemotherapeutic agents that are not curative but delay the onset of leukemia for up to about 1 week are identified; Controls were either vehicle-treated or treated with previously shown chemotherapeutic agents that did not treat but delay the development of leukemia in this model (eg, imatinib at about 70 mg/kg twice per day). In the first phase using p190 cells expressing eGFP, post hoc analysis was limited to flow counting the percentage of leukemia cells in the bone marrow, spleen and lymph nodes (LN). In the second phase, p190 cells expressing the tailless form of human CD4 are used and post hoc analysis involves electronic sorting of hCD4+ cells from the spleen, followed by immunoblot analysis of the following key signal endpoints: pAkt-T308 and S473; pS6 and p4EBP-1. In a control for immunoblot detection, sorted cells were cultured in the presence or absence of a kinase inhibitor of an inhibitor of the present invention and then lysed. Optionally, "phosflow" was used to detect pAkt-S473 and pS6-S235/236 in hCD4-open cells without prior sorting. Such signaling studies are particularly useful, for example, when drug-treated mice do not develop clinical leukemia at the 35-day time point. Kaplan-Meier plots of survival were generated and statistical analysis was performed according to methods known in the art. Results from p190 cells were analyzed individually and incrementally.

Samples of peripheral blood (100-200 μL) were obtained from all mice for 1 week and were performed immediately 10 days prior to treatment. Plasma was used to determine drug concentrations and cells were analyzed for leukemia markers (eGFP or hCD4) and the signal biomarkers described herein.

This general assay known in the art has been used to demonstrate that a therapeutically effective amount of a compound disclosed herein can be used to inhibit proliferation of leukemia cells.

Example 36

Matrigel plug angiogenesis assay

Matrigel containing the test compound is injected subcutaneously or intraocularly, which solidifies to form a plug. After 7 to 21 days, the plugs were recovered from the animals and histologically observed to determine the extent of passage through the blood vessels. Angiogenesis was determined by quantifying blood vessels in the histological section. Alternatively, fluorescence measurements of plasma volumes were performed using fluorescein isothiocyanate (FITC)-labeled dextran 150. One or more compounds disclosed herein inhibit angiogenesis, leading to promising results that are useful for treating ophthalmic diseases associated with abnormal blood vessel formation and/or vascular infiltration.

Example 37

Corneal angiogenesis assay

A pocket is made in the cornea, and a plug containing an angiogenesis-inducing formulation (eg, VEGF, FGF, or tumor cells), which, when introduced into the pocket, prevents the internal growth of new blood vessels from peripheral limbal vasculature. induce Long-acting substances such as Elvax^&amp;#174;) (ethylene vinyl copolymer) or Hydron was used to introduce angiogenesis-inducing substances into the corneal pocket. Alternatively, a sponge material was used.

The effect of a local putative inhibitor induces an angiogenic response in the cornea (eg, by FGF, VEGF, or tumor cells) (eg, a sponge implant). Test compounds were administered orally, systemically, or directly to the eye. Systemic administration includes bolus injection, more effectively, sustained-release methods such as infusion of an osmotic pump loaded with a test inhibitor. Administration to the eye includes, but is not limited to, topical administration of eye drops, creams, emulsions, or gels by any method, intravitreal injection.

Vascular responses were monitored in mice by directly observing the experimental process using a stereoscopic microscope. Conclusive visualization of corneal vasculature is achieved by administration of fluorochrome-labeled high molecular weight dextran. Quantification was performed by measuring the area of vascular infiltration, the progression of the vessel to angiogenic stimulus over time, or, in the case of fluorescence, histogram analysis or pixel counts on specific (background) thresholds.

The results may indicate that one or more compounds disclosed herein may be useful for treating ophthalmic diseases associated with abnormal blood vessel formation and/or vascular penetration by inhibiting angiogenesis.

Example 38

Microtiter-Plate Angiogenesis Assay

Assay plates were prepared by placing collagen plugs under each well containing 5-10 cell spheroids per collagen plug each spheroid containing 400-500 cells. Cover each collagen plug with storage medium (1100 µL) per well and use for further use (37 °C, 5% CO2).₂1 to 3 days). The plate was sealed with a sealant. Test compounds were dissolved in assay medium (200 μL) containing a VEGF positive control, one or more wells without VEGF, or one or more wells containing a test compound as a negative control. The assay plate was removed from the incubator and the storage medium was removed by carefully pipetting it. Assay medium containing test compounds was pipetted onto collagen plugs. Plug in (37°C, 5% CO₂) were placed in an incubator for 24-48 hours. Angiogenesis was quantified by counting the number of spouts, and average spout lengths were determined or cumulative spout lengths were determined. The assay can be preserved for later analysis by removing the assay medium, adding 10% paraformaldehyde (1 ml) in Hank BSS per well, and storing at 4°C. Results were expected that the compound inhibited angiogenesis in the various cell types tested, including ocular causative cells.

Example 39

Combination use of PI3K-δ inhibitors and agents that inhibit IgE production or activity

When administered in combination with agents that inhibit IgE production or activity, the compounds disclosed herein may exhibit synergistic or additive efficacy. Agents that inhibit IgE production include, for example, TEI-9874, 2-(4-(6-cyclohexyloxy-2-naphthyloxy)phenylacetamide)benzoic acid, rapamycin, rapamycin analogues (ie, rapalog). , TORC1 inhibitors, TORC2 inhibitors, and any other compounds that inhibit mTORC1 and mTORC2. Agents that inhibit IgE activity include, for example, anti-IgE antibodies such as omalizumab and TNX-901.

One or more subject compounds capable of inhibiting PI3K-δ may be effective in the treatment of autoimmune and inflammatory diseases (AIIDs), such as rheumatoid arthritis. If any compound induces IgE production at undesirable levels, one may be administered in combination with an agent that inhibits IgE production or IgE activity. In addition, administration of a PI3K-δ or PI3K-δ/γ inhibitor disclosed herein in combination with an inhibitor of mTOR may be synergistic through enhanced inhibition of the PI3K pathway. (a) in vitro<i></i>A variety of in vivo and in vitro models are used to treat AIID, including, but not limited to, B-cell antibody production assays, (b) in vivo TNP assays, and (c) murine collagen induced arthritis models. can be seen

<i>(a) B-cell analysis</i>

Mice were euthanized, spleens removed, and suspended in nylon mesh to create single-cell suspensions. Splenic cells were washed (removal of red blood cells by subsequent osmotic shock) and incubated with anti-CD43 and anti-Mac-1 antibody-conjugated microbeads (Miltenyi Biotec). Bead-bound cells were separated into unbound cells using a magnetic cell fractionator. The magnetized column retained undesired cells and the remaining B cells were collected in the flow-through. Purified B-cells were stimulated with lipopolysaccharide or anti-CD40 antibody and interleukin 4. Stimulated B-cells were treated with vehicle alone or with a PI3K-δ inhibitor disclosed herein in the presence and absence of an mTOR inhibitor such as rapamycin, rapalog, or an mTORC1/C2 inhibitor. Results showed no substantial effect on IgG and IgE responses when mTOR inhibitors (eg, rapamycin) were present alone. However, in the presence of PI3K-δ and mTOR inhibitor, B-cells show a reduced IgG response compared to B-cells treated with vehicle alone, and B-cells from B-cells treated with PI3K-δ inhibitor alone Compared with the response of , it showed a reduced IgE response.

<i>(b) </i><i>TNP</i><i> analysis </i>

Mice were immunized with TNP-Ficoll or TNP-KHL and treated with vehicle, a PI3K-δ inhibitor, an mTOR inhibitor such as rapamycin, or a PI3K-δ inhibitor in combination with an mTOR inhibitor such as rapamycin. Antigen specific serum IgE was determined by ELISA using TNP-BSA coated plates and allogeneic specific labeled antibodies. Mice treated with mTOR inhibitor alone did not show a substantial effect on antigen specific IgG3 response compared to vehicle control and were not expected to show a statistically significant elevation in IgE response. In addition, mice treated with both the PI3K-δ inhibitor and the mTOR inhibitor were expected to show a decrease in antigen-specific IgG3 responses compared to mice treated with vehicle alone. In addition, mice treated with both the PI3K-δ inhibitor and the mTOR inhibitor showed reduced IgE responses compared to mice treated with the PI3K-δ inhibitor alone.

<i>(c) </i><i>rat</i><i> Collagen-induced arthritis model </i>

Female Lewis rats were anesthetized and injected with collagen prepared and administered as previously described on day 0. On day 6 the animals were anesthetized and a second injection of collagen was made. Caliper measurements of normal (pre-disease) right and left ankle joints were performed on Day 9. Arthritis typically developed on days 10-11, and rats were randomized into treatment groups. Randomization was performed after ankle joint swelling had already developed and provided good evidence of reciprocal disease.

After animals were selected for enrollment in the study, treatment was initiated. Animals were injected with vehicle, a PI3K-δ inhibitor, or a PI3K-δ inhibitor in combination with rapamycin. Doses were administered on days 1-6. After weighing the rats on days 1-7, arthritis was confirmed, and caliper measurements of the joints were performed daily. Final body weights were weighed on day 7 and animals were euthanized.

Combination treatment with a compound disclosed herein and rapamycin may provide greater efficacy than treatment with a PI3K-δ inhibitor alone.

Example 40

Delayed type hypersensitivity model

0 and DTH induced by sensitizing 60 BALB/c male mice on day 1 to a solution of 2,4-dinitrofluorobenzene (DNFB, 0.05%) in an acetone/olive oil mixture (4:1). While gently restraining the mice, the solution (20 μL) was applied to the hindfoot pad of each mouse. Mice's hindfoot pads were used to show anatomical sites that could be easily isolated and immobilized without anesthesia. On day 5, mice were administered a single dose of vehicle, a compound disclosed herein at 10, 3, 1, or 0.3 mg/kg, or dexamethasone at a dose of 5 mg/kg by oral tube. After 30 min, mice were anesthetized and a solution of DNFB (0.25%) in acetone/olive oil solution (4:1) was applied to the left inner and outer ear surfaces. This application induced swelling in the left ear, and under these conditions, all animals responded to treatment of the swelling of the ear. A vehicle control solution of acetone/olive oil (4:1) was applied to the right inner and outer ears. After 24 hours, the mice were anesthetized and the left and right ears were measured using a digital micrometer. The difference between the two ears was recorded as the amount of swelling induced by DNFB. The drug-treated group showed a reduction (%) of ear swelling compared to the vehicle-treated group. Dexamethasone is generally used as a positive control with broad anti-inflammatory activity.

Example 41

Peptidoglycan-Polysaccharide Rat Arthritis Model

(a) systemic arthritis model

All injections were performed under anesthesia. Sixty female Lewis rats (150-170) were anesthetized by inhalation of isoflurane using a small animal anesthesia machine. O₂ Animals were placed in the induction chamber until anesthetized by delivery of isoflurane in 4-5% of the solution, then maintained there using a nose cone on the progress table. Levels of isoflurane were maintained at 1-2%. Animals were injected intraperitoneally (ip) with a single injection of purified PG-PS 10S group A, the D58 strain (concentration of 25 μg/g of body weight) suspended in sterile 0.85% saline. Each animal was administered a total of 500 μl in the lower left quadrant of the abdomen using a 1 ml syringe containing 23 gauge needles. The position of the needle is important to avoid injecting PG-PS 10S into the stomach or cecum. Animals were continuously observed until fully recovered from anesthesia and roaming the cage. Prominent acute responses in joint measurements may peak at 3 to 5 days post infusion with baseline measurements typically greater than 20%. Treatment with the test compound may be PO, SC, IV or IP. Rats were dosed only twice in a 24-hour cycle. Treatment can be started on any day after day 0 or 30 days.<i></i>Animals were weighed on days 0, 1, 2, 3, 4, 5, 6, 7, restarted on days 12-30, or waited until the study was terminated before weighing. The foot/ankle diameters of the left and right sides were measured with digital caliper on day 0 before injection, and again on days 1, 2, 3, 4, 5, 6 and 7. Measurements were restarted on day 12 and continued until day 30. During this period, animals may be anesthetized with isoflurane as described above, and termination blood samples may be obtained by tail vein draw to assess compound blood levels, clinical chemistry, or hematological parameters. The animals were then euthanized with excess carbon dioxide. A thoracotomy may be performed as a means of confirming death.

(b) monoarticular arthritis model

All injections were performed under anesthesia. Sixty female Lewis rats (150-170) were anesthetized by inhalation of isoflurane using a small animal anesthesia machine. O₂ Animals were placed in the induction chamber until anesthetized by delivery of isoflurane in 4-5% of the solution, then maintained there using a nose cone on the progress table. Levels of isoflurane were maintained at 1-2%. Animals were injected intra-articularly (ia) with a single injection of purified PG-PS 100P group A, the D58 strain (concentration of 500 μg/mL) suspended in sterile 0.85% saline. Each rat was administered a total of 10 μl into the tibiotalar joint space using a 1 ml syringe containing 27 gauge needles. Animals were continuously observed until fully recovered from anesthesia and roaming the cage. Animals with a flare in joint measurements, responding after 2-3 days, are included in the study, typically with a baseline measurement of greater than 20% at the time of the first intra-articular injection. On day 14, all responding animals were re-anesthetized using the previously described procedure. Animals were injected intravenously (IV) of PG-PS (250 uL/mL concentration). Each rat was slowly administered a total of 400 μl into the lateral tail vein using a 1 ml syringe containing 27 gauge needles. Baseline joint measurements were taken prior to IV infusion, and the extent of inflammation was continued until day 10. Treatment with the test compound will be PO, SC, IV or IP. Rats were dosed only twice in a 24-hour cycle. Treatment can be started on any day after day 0 or day 24.<i></i>Animals were weighed on days 0, 1, 2, 3, 4, 5, restarted on days 14-24, or waited until the study was terminated before weighing. The left and right side paw/ankle diameters were measured with digital caliper on day 0 prior to injection, re-measured on days 1, 2, 3, 4, 5, resumed on days 14-24 or the study was terminated. Wait until weighed. During this period, animals may be anesthetized with isoflurane as described above, and termination blood samples may be obtained by tail vein drapes to assess compound blood levels, clinical chemistry, or hematology parameters. The animals were then euthanized with excess carbon dioxide. A thoracotomy may be performed as a means of confirming death.

Example 42

Pharmacokinetic data for single and repeated administration

Randomized, double-blind, placebo-controlled, single and repeat-dose studies to evaluate the pharmacokinetics (PK) of the Compound Form C polymorph of Formula I upon oral administration to healthy adult male and female subjects did. The subject received a single oral administration of the Compound Form C polymorph of Formula I on an empty stomach at doses of 1 mg, 2 mg, 5 mg, 10 mg, 20 mg, and 30 mg. Plasma Analysis Blood samples were collected at 0.5, 1, 1.5, 2, 3, 4, 6, 9, 12, 16, and 24 hours for pre-dose. Doses of 1 mg, 2 mg, 5 mg, 10 mg, 20 mg, and 30 mg have a C of greater than 10 and less than 1,500 ng/mL in a dose dependent manner._max Value range, AUC greater than 100 to less than 4,000 ng*h/mL₀_-24 values, and half-life values ranging from greater than 3 hours to less than 10 hours.

Repeat oral dose administration of the Compound Form C polymorph of Formula I was administered once daily in the morning (QD) on days 1 and 14 and twice daily (BID) on days 2-13. Compounds were administered on days 1 and 14 after an overnight fast. Blood samples were collected on day 14 for plasma analysis at 1, 2, 5 and 10 mg repeated doses. Blood samples were collected 14 days prior to dosing and administered to determine plasma concentrations of the compound Form C polymorph of Formula I and 0.5, 1, 1.5, 2, 3, 4, 6, 9, 12, 16 and 24 collected after an hour. Doses of 1 mg, 2 mg, 5 mg, and 10 mg have a C of greater than 10 and less than 1,000 ng/mL in a dose dependent method._max had a range of values. In addition, dosages of 1 mg, 2 mg, 5 mg, and 10 mg have an AUC greater than 100 and less than 2,500 ng*h/mL in a dose dependent method._tau,ss has a range of values. In the BID regimen, AUC over a 24-hour interval_tau, was obtained by multiplying ss by 2.

While various embodiments of the invention have been shown and described herein, it will be apparent to those skilled in the art that such embodiments are provided by way of example only. Various variables, changes, and substitutions will occur to those skilled in the art without departing from the scope of the present invention. It should be understood that various modifications and embodiments described herein may be employed in light of the present invention.