WO2010096619A1 - Process, purification and crystallization of 1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]urea - Google Patents

Abstract

The invention relates to a method of making compounds of formula VII: (see formula) or a pharmaceutically acceptable salt thereof, wherein the constituent variables are as defined herein.

Description

PROCESS, PURIFICATION AND CRYSTALLIZATION OF 1-(4-{[4- (DIMETHYLAMINO)PIPERIDIN-I-YL]CARBONYL)PHENYL)-S-[^e- DIMORPHOLIN-4-YL-1,3,5-TRIAZIN-2-YL)PHENYL]UREA

FIELD OF THE INVENTION

The invention relates to an improved process for the preparation of 1-(4-(4- (dimethylamino)piperidine-1-carbonyl)phenyl-3-(4-(4,6-dimorpholino-1 ,3,5-triazine-2- yl)phenyl) urea as a final product in the manufacture of biologically active mTOR and PI3K inhibitors. BACKGROUND OF THE INVENTION

Certain 3-{4-(4,6-dimorpholino-1 ,3,5-triazine-2-yl)phenyl}urea compounds of formula I:

wherein: R¹ is

R⁶, R⁷, R⁸, R⁹ are each independently selected from the group consisting of a hydrogen atom, and a Ci-C₆alkyl optionally substituted with C₂-C₆alkenyl, C₄- C₆alkadienyl, C₂-C₆alkynyl or C₄-C₆alkadiynyl; or R⁶ and R⁹ and/or R⁷ and R⁸ independently are attached by a (CH₂)_y or (CH₂-X-CH₂) linking group wherein one hydrogen atom in the linking group may be replaced by an OH; y is 2 or 3; X is O, S(O)_n, or NR¹⁰; n is O, 1 or 2;

R¹⁰ is selected from the group consisting of H, d-C₆alkyl-, (Ci-C₆alkyl)SO₂-, (Ci-C₆alkoxy)carbonyl-, (Ci-C₆alkyl)amido-, and R¹¹NHSO₂-;

R¹¹ is selected from the group consisting of H, d-C₆alkyl-, d-C₆heterocyclyl, C₆-Ci₄aryl, and d-Cgheteroaryl; or either R⁶ and R⁸ or R⁷ and R⁹ are attached by (CH₂)_Z or (CH₂-X-CH₂) linking group; z is 1 , 2 or 3; or one of R⁶ and R⁷ or R⁸ and R⁹, together with the carbon atoms to which they are attached form an optionally substituted 5-8 membered saturated or unsaturated ring containing O, 1 or 2 atoms independently selected from O, N and S;

R² is Ce-Cuaryl-NH-COR³, d-Cgheteroaryl-N H-COR³, -CH=CH-(C₆-Ci₄aryl)- NH-COR³ or -CH=CH-(d-C₉heteroaryl)-NH-COR³; wherein any C₆-d₄aryl, C₆- Ci₄aryl, or d-Cgheteroaryl is optionally substituted with 1 or 2 moieties selected from the group consisting of: a) d-C₆alkyl- optionally substituted with di(d-C₆alkyl)amino- , or d-Cgheterocyclyl; b) halogen; c) O₂N-; d) H₂NSO₂-; e) HOOC-; f) (C₁- C₆alkoxy)carbonyl-; g) (d-C₆alkyl)amido-; h) di(d-C₆alkyl)amino-; i) R^aR^bNC(0)-, wherein R^a is H or C_rC₆alkyl, and R^b is H, d-C₆alkyl, C₃-C₆cycloalkyl, C₁- Cgheterocyclyl, or di(d-C₆alkyl)amino-(CH₂)_a- wherein a is 2, 3 or 4; or R^a and R^b, when taken together with the nitrogen to which they are attached, form a 3- to 7- membered heterocycle wherein up to two of the carbon atoms of the heterocycle are optionally replaced with -N(d-C₆alkyl)-, -N(C₃- Cβcycloalkyl)-, -N(C₆-C₁₄aryl)-, -N(d-Cgheteroaryl)-, -S-, -SO-, -S(O)₂-, or -O- and wherein any carbon atom of the heterocycle is optionally substituted with from 1 or 2 substituents independently selected from d-C₆alkyl-, H₂N-, (d-C₆alkyl)amino-, di(d- C₆alkyl)amino-, and d-Cgheterocyclyl-; j) Q-Z-, wherein Z is O, NHSO₂, SO₂NH, NHCONH, S(0)_q, or is absent, q is O, 1 or 2, and Q is selected from C₆-C₁₄aryl, d-Cgheteroaryl, d-Cgheterocyclyl, C₃- docycloalkyl, d-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, (d-C₆alkyl)amino-(CH₂)_x- wherein x is 1 , 2, 3 or 4, di(d-C₆alkyl)amino-(CH₂)_x-, (C₆-C₁₄aryl)alkyl-, (C₁- Cgheteroaryl)alkyl-, and heterocyclyl(d-C₆alkyl)-; and k) R^CC(O)- wherein R^c is H, C₁- C₆alkyl, C₃-C₆cycloalkyl, or d-Cgheterocyclyl,

R³ is NHR⁵;

R⁵ is C₆-C₁₄aryl or d-Cgheteroaryl wherein the C₆-C₁₄aryl or d-Cgheteroaryl is optionally substituted with 1 or 2 moieties selected from the group consisting of: O₂N-, H₂NSO₂-, HOOC-, (C_rC₆alkoxy)carbonyl-, (Ci-C₆alkyl)amido-, CIi(C₁- C₆alkyl)amino-, R^aR^bNC(O)-, and Q-Z-;

R⁴ is selected from the group consisting of:

CrCgheterocyclyl- attached to the triazine moiety through a carbon or nitrogen atom and optionally substituted with:

NR¹¹R¹¹, or Ci-Cβheterocyclyl, with the proviso that 3 membered Cr C₆heterocyclyl is saturated and attached to the triazine moiety through a nitrogen atom, and the 5 membered Ci-C₆heterocyclyl is saturated;

wherein Z is CH₂, O, S(O)_n or NR¹⁰ wherein a and b are each independently -CH₂-, O, S, or NR -> 1'0^υ, and z is 1-3;

and R 1^η2"_DR1^η3^j _MN- .; R¹² and R¹³ are each independently selected from H, d-C₈alkyl, C₃- C₈alkenyl, and C₃-C₈alkynyl, the Ci-C₈alkyl, C₃-C₈alkenyl, and C₃-C₈alkynyl optionally substituted from the group selected from NR¹¹R¹¹ and Ci-C₆heterocyclyl, provided that an NR¹¹R¹¹ is not directly bonded to a carbon atom that is double- or triple- bonded to another carbon atom; or R¹² and R¹³ taken together with the nitrogen atom to which they are attached form a 3 to 8 membered ring system optionally substituted with d-C₆alkyl, which ring system is saturated or unsaturated and has, in addition to said nitrogen atom, 0 to 2 heteroatom ring members selected from O, S(O)_n and NR¹⁰; such as those disclosed in US Patent Application 12/470,521 , filed May 22, 2009 published as US Patent Publication 2009/0291079 A1 (the disclosure of which is hereby incorporated herein by reference in its entirety), inhibit the enzymes mTOR and PI3K. They are useful in preventing and treating mTOR-related disorders and PI3K-related disorders including, disorders with which abnormal cell growth is associated. Examples of such abnormal cell growth disorders are restenosis, atherosclerosis, bone disorders, arthritis, diabetic retinopathy, psoriasis, benign prostatic hypertrophy, atherosclerosis, inflammation, angiogenesis, immunological disorders, pancreatitis, kidney disease, cancer, etc. In particular, the 3-{4-(4,6- dimorpholino-1 ,3,5-triazine-2-yl)phenyl}urea compounds possess excellent cancer cell growth inhibiting effects and are effective in treating cancers, preferably all types of solid cancers and malignant lymphomas, and especially, leukemia, skin cancer, bladder cancer, breast cancer, uterine cancer, ovarian cancer, prostate cancer, lung cancer, colon cancer, pancreas cancer, renal cancer, gastric cancer, brain tumor, etc.

The earlier filed US Patent Application describes the preparation of 3-{4-(4,6- dimorpholino-1 ,3,5-triazine-2-yl)phenyl}urea compounds by reacting morpholine or any substituted morpholine with the commercially available cyanuric chloride in aqueous acetone solution and triethylamine as an acid binding agent. Two of the three chlorine atoms of cyanuric chloride were displaced by morpholine. The third chlorine atom in the triazine moiety was reacted with 4-aminoaryl boronic acid or 4- aminophenyl boronic acid pinacol ester in refluxing DME in the presence of catalytic amount of tetrakis(triphenylpnosphine)palladium(0)/aqueous Na₂CO₃. The product was purified by SiO₂ column chromatography. The aniline compound was further reacted with 4-carbomethoxy aniline and triphosgene to obtain the urea derivative. The ester group was subsequently hydrolyzed to carboxylic acid and coupled with N,N-dimethylpiperidin-4-amine in the presence of Hunig's base, HBTU (2-(1 H- benzotriazole-1-yl)-1 ,1 ,3,3-tetramethyluronium hexafluorophosphate) in a polar solvent such as NMP. The final product was obtained in 52% yield after SiO₂ column chromatography. The synthesis described herein eliminates the need to use triphosgene to make the initial urea intermediate, eliminates the need to use the hard to remove solvent NMP, eliminates the need to purify the intermediates, shortens the reaction times, eliminates the use of expensive HBTU, and avoids the use of SiO₂ column chromatography for purification. This procedure also gives products of high yields with high purity (>99%) and crystals of one form.

SUMMARY OF THE INVENTION

The present invention provides a method of making compounds of formula

VII:

VII or a pharmaceutically acceptable salt thereof, wherein the constituent variables are as defined below.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is an X-ray powder diffraction (XRD) scan of the amorphous form of 1- (4-(4-(dimethylamino)piperidine-1-carbonyl)phenyl-3-(4-(4,6-dimorpholino-1 ,3,5- triazine-2-yl)phenyl)urea.

FIG. 2 is an XRD scan of the crystalline form of 1-(4-(4- (dimethylamino)piperidine-1-carbonyl)phenyl-3-(4-(4,6-dimorpholino-1 ,3,5-triazine-2- yl)phenyl)urea. DETAILED DESCRIPTION

In one aspect, the present invention provides a method of making compounds of formula VII:

VII wherein: R¹ is

R⁶, R⁷, R⁸, R⁹ are each independently selected from the group consisting of a hydrogen atom, and a (VCealkyl optionally substituted with C₂-C₆alkenyl, C₄- C₆alkadienyl, C₂-C₆alkynyl or C₄-C₆alkadiynyl; or R⁶ and R⁹ and/or R⁷ and R⁸ independently are attached by a (CH₂)_y or (CH₂-X-CH₂) linking group wherein one hydrogen atom in the linking group may be replaced by an OH; y is 2 or 3;

X is O, S(O)_n, or NR¹⁰; n is O, 1 or 2;

R¹⁰ is selected from the group consisting of H, d-C₆alkyl-, (Ci-C₆alkyl)SO₂-, (Ci-C₆alkoxy)carbonyl-, (Ci-C₆alkyl)amido-, and R¹¹NHSO₂-;

R¹¹ is selected from the group consisting of H, d-C₆alkyl-, d-C₆heterocyclyl, C₆-Ci₄aryl, and d-Cgheteroaryl; or either R⁶ and R⁸ or R⁷ and R⁹ are attached by (CH₂)_Z or (CH₂-X-CH₂) linking group; z is 1 , 2 or 3; or one of R⁶ and R⁷ or R⁸ and R⁹, together with the carbon atoms to which they are attached form an optionally substituted 5-8 membered saturated or unsaturated ring containing O, 1 or 2 atoms independently selected from O, N and S; wherein Ar¹ is C₆-Ci₄aryl or d-Cgheteroaryl; wherein any C₆-d₄aryl or C₁- Cgheteroaryl is optionally substituted with 1 or 2 moieties selected from the group consisting of: a) d-C₆alkyl- optionally substituted with di(d-C₆alkyl)amino-, or C₁- Cgheterocyclyl; b) halogen; c) O₂N-; d) H₂NSO₂-; e) HOOC-; f) (d-C₆alkoxy)carbonyl- ; g) (d-C₆alkyl)amido-; h) di(d-C₆alkyl)amino-; i) R^aR^bNC(0)-, wherein R^a is H or C₁- C₆alkyl, and R^b is H, C_rC₆alkyl, C₃-C₆cycloalkyl, d-Cgheterocyclyl, or CIi(C₁- C₆alkyl)amino-(CH₂)_a- wherein a is 2, 3 or 4; or R^a and R^b, when taken together with the nitrogen to which they are attached, form a 3- to 7- membered heterocycle wherein up to two of the carbon atoms of the heterocycle are optionally replaced with -N(d-C₆alkyl)-, -N(C₃- Cβcycloalkyl)-, -N(C₆-C₁₄aryl)-, -N(d-Cgheteroaryl)-, -S-, -SO-, -S(O)₂-, or -O- and wherein any carbon atom of the heterocycle is optionally substituted with from 1 or 2 substituents independently selected from d-C₆alkyl-, H₂N-, (d-C₆alkyl)amino-, di(d- C₆alkyl)amino-, and d-Cgheterocyclyl-; j) Q-Z-, wherein Z is O, NHSO₂, SO₂NH, NHCONH, S(0)_q, or is absent, q is O, 1 or 2, and Q is selected from C₆-C₁₄aryl, d-Cgheteroaryl, d-Cgheterocyclyl, C₃- docycloalkyl, d-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, (d-C₆alkyl)amino-(CH₂)_x- wherein x is 1 , 2, 3 or 4, di(d-C₆alkyl)amino-(CH₂)_x-, (C₆-C₁₄aryl)alkyl-, (C₁- Cgheteroaryl)alkyl-, and heterocyclyl(d-C₆alkyl)-; and k) R^CC(O)- wherein R^c is H, C₁- C₆alkyl, C₃-C₆cycloalkyl, or d-Cgheterocyclyl,

R³ is NHR⁵;

R⁵ is C₆-C₁₄aryl or d-Cgheteroaryl wherein the C₆-C₁₄aryl or d-Cgheteroaryl is optionally substituted with 1 or 2 moieties selected from the group consisting of: O₂N-, H₂NSO₂-, HOOC-, (C_rC₆alkoxy)carbonyl-, (Ci-C₆alkyl)amido-, CIi(C₁- C₆alkyl)amino-, R^aR^bNC(O)-, and Q-Z-;

R⁴ is selected from the group consisting of:

CrCgheterocyclyl- attached to the triazine moiety through a carbon or nitrogen atom and optionally substituted with:

NR¹¹R¹¹, or Ci-Cβheterocyclyl, with the proviso that 3 membered Cr C₆heterocyclyl is saturated and attached to the triazine moiety through a nitrogen atom, and the 5 membered Ci-C₆heterocyclyl is saturated;

wherein Z is CH₂, O, S(O)_n or NR 1¹0

wherein a and b are each in O, S, or NR , and z is 1-3;

and R^η^R^ηjN-; R¹² and R¹³ are each independently selected from H, d-C₈alkyl, C₃- C₈alkenyl, and C₃-C₈alkynyl, the Ci-C₈alkyl, C₃-C₈alkenyl, and C₃-C₈alkynyl optionally substituted from the group selected from NR¹¹R¹¹ and Ci-C₆heterocyclyl, provided that an NR¹¹R¹¹ is not directly bonded to a carbon atom that is double- or triple- bonded to another carbon atom; or R¹² and R¹³ taken together with the nitrogen atom to which they are attached form a 3 to 8 membered ring system optionally substituted with d-C₆alkyl, which ring system is saturated or unsaturated and has, in addition to said nitrogen atom, 0 to 2 heteroatom ring members selected from O, S(O)_n and NR¹⁰; comprising reacting compound Vl:

Vl with R⁵-N=C=O to give compound VII:

VII and pharmaceutically acceptable salts thereof.

In another aspect, the present invention provides a method of making compounds of formula VII further comprising, when R⁵ is -C6-Ci₄aryl-carbonyl(d- C₆alkoxy) or -d-C₉heteroaryl-carbonyl(d-dialkoxy), saponifing the ester of formula VIII:

)

VIII to give acid IX:

IX wherein the C₆-C₁₄aryl or d-Cgheteroaryl is optionally substituted with 1 or 2 moieties selected from the group consisting of:

O₂N-, H₂NSO₂-, HOOC-, (C_rC₆alkoxy)carbonyl-, (C_rC₆alkyl)amido-, CIi(C₁- C₆alkyl)amino-, R^aR^bNC(O)-, and Q-Z-.

In another aspect, the present invention provides a method of making compounds of formula VII further comprising condensing the acid of formula IX:

IX with amine R^aR NH -to give amide X:

or a pharmaceutically acceptable salt thereof.

In some embodiments of the invention, R¹ and/or R⁴ are:

or a pharmaceutically acceptable salt thereof. In some embodiments of the invention, R¹ and/or R⁴ are:

or a pharmaceutically acceptable salt thereof.

In some embodiments of the invention, R¹ and/or R⁴ are:

or a pharmaceutically acceptable salt thereof.

In some embodiments of the invention, R¹ and/or R⁴ are independently selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.

In some embodiments, -Ar¹- is -C₆-Ci₄aryk

In some embodiments, -Ar¹- is -phenyl-.

In some embodiments, R⁵ is phenyl is substituted with C(O)NR^aR^b.

In some embodiments, the saponification is done with an alkali metal hydroxide.

In some embodiments, the alkali metal hydroxide is lithium hydroxide.

In some embodiments, the amide formation is done with a carboxyl-activating agent.

In some embodiments, the carboxyl activating agent is N, N'- carbonyldiimidazole or N-(3-dimethylaminopropyl)ethyl carbodiimide hydrochloride. In some embodiments, the compound made of formula VII has the structure:

or a pharmaceutically acceptable salt thereof.

In another aspect, the present invention provides the crystalline form of 1-(4- (4-(dimethylamino)piperidine-1-carbonyl)phenyl-3-(4-(4,6-dimorpholino-1 ,3,5-triazine- 2-yl)phenyl)urea.

In some embodiments, the crystalline form has an X-ray diffraction pattern having one or more characteristic peaks expressed in degrees 2Θ at 7.9, 9.2, 14.1 ,

15.7, 16.7, 17.2, 17.8, 18.7, 19.2, 21.2, 21.6, 22.0, 22.6, 23.0, 23.5, 24.3, 24.6, 26.4,

26.8, 28.2, 28.6, 29.5, 34.7, and 37.6 (±.0.2°).

In some embodiments, the crystalline form has an X-ray diffraction pattern substantially the same as that shown in FIG. 2.

Representative "pharmaceutically acceptable salts" include but are not limited to, e.g., water-soluble and water-insoluble salts, such as the acetate, aluminum, amsonate (4,4-diaminostilbene-2,2-disulfonate), benzathine (N₁N'- dibenzylethylenediamine), benzenesulfonate, benzoate, bicarbonate, bismuth, bisulfate, bitartrate, borate, bromide, butyrate, calcium, calcium edetate, camsylate (camphorsulfonate), carbonate, chloride, choline, citrate, clavulariate, diethanolamine, dihydrochloride, diphosphate, edetate, edisylate (camphorsulfonate), esylate (ethanesulfonate), ethylenediamine, fumarate, gluceptate (glucoheptonate), gluconate, glucuronate, glutamate, hexafluorophosphate, hexylresorcinate, hydrabamine (N,N'-bis(dehydroabietyl)ethylenediamine), hydrobromide, hydrochloride, hydroxynaphthoate, 1-hydroxy-2-naphthoate, 3-hydroxy-2-naphthoate, iodide, isothionate (2-hydroxyethanesulfonate), lactate, lactobionate, laurate, lauryl sulfate, lithium, magnesium, malate, maleate, mandelate, meglumine (1-deoxy-1- (methylamino)-D-glucitol), mesylate, methyl bromide, methylnitrate, methylsulfate, mucate, napsylate, nitrate, N-methylglucamine ammonium salt, oleate, oxalate, palmitate, pamoate (4,4'-methylenebis-3-hydroxy-2-naphthoate, or embonate), pantothenate, phosphate, picrate, polygalacturonate, potassium, propionate, p- toluenesulfonate, salicylate, sodium, stearate, subacetate, succinate, sulfate, sulfosaliculate, suramate, tannate, tartrate, teoclate (8-chloro-3,7-dihydro-1 ,3- dimethyl-1 H-purine-2,6-dione), triethiodide, tromethamine (2-amino-2- (hydroxymethyl)-1 ,3-propanediol), valerate, and zinc salts.

Different crystalline forms are frequently encountered among pharmaceutically useful compounds. Polymorphism is the ability of any element or compound to crystallize in more than one distinct crystalline form. Physical properties including solubility, melting point, density, hardness, crystalline shape and stability can be quite different for different polymorphic forms of the same chemical compound.

Crystalline forms are characterized by scattering techniques, e.g., x-ray diffraction powder pattern, by spectroscopic methods, e.g., infra-red, ¹³C nuclear magnetic resonance spectroscopy, and by thermal techniques, e.g., differential scanning calorimetry or differential thermal analysis. The compound of this invention is best characterized by the X-ray powder diffraction pattern determined in accordance with procedures that are known in the art. For a discussion of these techniques see J. Haleblian, J. Pharm. Sci. 1975 64:1269-1288, and J. Haleblain and W. McCrone, J. Pharm. Sci. 1969 58:911-929. Crystal forms of the invention can be further processed to modulate particle size. For example, the crystal forms of the invention can be milled to reduce average crystal size and/or to prepare a sample suitable for manipulation and formulation.

Generally, a diffraction angle (2Θ) in powder X-ray diffractometry may have an error in the range of ±.0.2°. Therefore, the aforementioned diffraction angle values should be understood as including values in the range of about ±.0.2°. Accordingly, the present invention includes not only crystals whose peak diffraction angles in powder X-ray diffractometry completely coincide with each other, but also crystals whose peak diffraction angles coincide with each other with an error of about ±.0.2°. Therefore, in the present specification, the phrase "having a diffraction peak at a diffraction angle (2Θ ±.0.2°) of 7.9°" means "having a diffraction peak at a diffraction angle (2Θ) of 7.7° to 8.1°. Although the intensities of peaks in the x-ray powder diffraction patterns of different batches of a compound may vary slightly, the peaks and the peak locations are characteristic for a specific polymorphic form. Alternatively, the term "about" means within an acceptable standard error of the mean, when considered by one of ordinary skill in the art. The relative intensities of the XRD peaks can vary depending on the sample preparation technique, crystal size distribution, various filters used, the sample mounting procedure, and the particular instrument employed. Moreover, instrument variation and other factors can affect the 2-theta values. Therefore, the term "substantially" in the context of XRD is meant to encompass that peak assignments can vary by plus or minus about 0.2. degree. Moreover, new peaks may be observed or existing peaks may disappear, depending on the type of the machine or the settings (for example, whether a Ni filter is used or not.

Some compounds within the present invention possess one or more chiral centers, and the present invention includes each separate enantiomer of such compounds as well as mixtures of the enantiomers. Where multiple chiral centers exist in compounds of the present invention, the invention includes each combination as well as mixtures thereof. All chiral, diastereomeric, and racemic forms of a structure are intended, unless the specific stereochemistry or isomeric form is specifically indicated. It is well known in the art how to prepare optically active forms, such as by resolution of racemic forms or by synthesis from optically active starting materials. Definitions

The following definitions are used in connection with the compounds of the present invention unless the context indicates otherwise. In general, the number of carbon atoms present in a given group is designated "C_x-C_y", where x and y are the lower and upper limits, respectively. For example, a group designated as "CrC₆" contains from 1 to 6 carbon atoms. The carbon number as used in the definitions herein refers to carbon backbone and carbon branching, but does not include carbon atoms of the substituents, such as alkoxy substitutions and the like.

"Alkadienyl-" refer to a straight or branched chain unsaturated hydrocarbon containing at least two double bonds. Examples of a C₄-C6alkadienyl- group include, but are not limited to, buta-1 ,3-dienyl, penta-1 ,3-dienyl, penta-1 ,4-dienyl, penta-2,4- dienyl, hexa-1 ,3-dienyl, hexa-1 ,4-dienyl, hexa-1 ,5-dienyl, hexa-2,4-dienyl, and hexa- 2,5-dienyl. An alkadienyl- group can be unsubstituted or substituted with one or more of the following groups: halogen, H₂N-, (Ci-C6alkyl)amino-, di(Ci-C6alkyl)amino- , (Ci-C₆alkyl)C(O)N(Ci-C₃alkyl)-, (C_rC₆alkyl)carboxyamido-, HC(O)NH-, H₂NC(O)-, (Ci-C₆alkyl)NHC(O)-, di(C_rC₆alkyl)NC(O)-, NC-, hydroxyl, Ci-C₆alkoxy-, Ci-C₆alkyl-, HO₂C-, (Ci-C₆alkoxy)carbonyl-, (C_rC₆alkyl)C(O)-, C₆-Ci₄aryl-, Ci-Cgheteroaryl-, and C₃-C₈cycloalkyk

"Alkadiynyl-" refer to a straight or branched chain unsaturated hydrocarbon containing at least two triple bonds. Examples of a C₄-C₆alkadiynyl- group include, but are not limited to, buta-1 ,3-diynyl, penta-1 ,3-diynyl, penta-1 ,4-diynyl, penta-2,4- diynyl, hexa-1 ,3-diynyl, hexa-1 ,4-diynyl, hexa-1 ,5-diynyl, hexa-2,4-diynyl, and hexa- 2,5-diynyl. An alkadiynyl- group can be unsubstituted or substituted with one or more of the following groups: halogen, H₂N-, (d-C₆alkyl)amino-, di(Ci-C₆alkyl)amino-, (d- C₆alkyl)C(O)N(Ci-C₃alkyl)-, (Ci-C₆alkyl)carboxyamido-, HC(O)NH-, H₂NC(O)-, (d- C₆alkyl)NHC(O)-, di(C_rC₆alkyl)NC(O)-, NC-, hydroxyl, d-C₆alkoxy-, d-C₆alkyl-, HO₂C-, (Ci-C₆alkoxy)carbonyl-, (C_rC₆alkyl)C(O)-, C₆-Ci₄aryl-, Ci-Cgheteroaryl-, and C₃-C₈cycloalkyl-.

"Alkoxy-" refers to the group R-O- where R is an alkyl group, as defined below. Exemplary d-C₆alkoxy- groups include but are not limited to methoxy, ethoxy, n-propoxy, 1-propoxy, n-butoxy and t-butoxy. An alkoxy group can be unsubstituted or substituted with one or more of the following groups: halogen, hydroxyl, d-C₆alkoxy-, H₂N-, (d-C₆alkyl)amino-, di(d-C₆alkyl)amino-, (d- C₆alkyl)C(O)N(Ci-C₃alkyl)-, (Ci-CealkyOcarboxyamido-, HC(O)NH-, H₂NC(O)-, (d- C₆alkyl)NHC(O)-, di(Ci-C₆alkyl)NC(O)-, NC-, d-C₆alkoxy-, HO₂C-, (d- C₆alkoxy)carbonyl-, (d-C₆alkyl)C(O)-, C₆-Ci₄aryl-, Ci-Cgheteroaryl-, C₃-C₈cycloalkyl-, d-C₆haloalkyl-, amino(C₁-C₆alkyl)-, (d-C₆alkyl)carboxyl-, d-Cecarboxyamidoalkyl-, Or O₂N-.

"(Alkoxy)carbonyl-" and "-carbonyl(alkoxy)" both refer to the group alkyl-O- C(O)-. Exemplary (d-C₆alkoxy)carbonyl- groups include but are not limited to methoxy, ethoxy, n-propoxy, 1-propoxy, n-butoxy and t-butoxy. An (alkoxy )carbonyl group can be unsubstituted or substituted with one or more of the following groups: halogen, hydroxyl, H₂N-, (d-C₆alkyl)amino-, di(d-C₆alkyl)amino-, (d- C₆alkyl)C(O)N(Ci-C₃alkyl)-, (Ci-C₆alkyl)carboxyamido-, HC(O)NH-, H₂NC(O)-, (d- C₆alkyl)NHC(O)-, di(d-C₆alkyl)NC(O)-, NC-, d-C₆alkoxy-, HO₂C-, (d- C₆alkoxy)carbonyl-, (d-C₆alkyl)C(O)-, C₆-Ci₄aryl-, Ci-Cgheteroaryl-, C₃-C₈cycloalkyl-, Ci-C₆haloalkyl-, amino(d-C₆alkyl)-, (d-C₆alkyl)carboxyl-, d-Cβcarboxyamidoalkyl-, Or O₂N-.

"Alkenyl-" refer to a straight or branched chain unsaturated hydrocarbon containing at least one double bond. Examples of a C₂-C6alkenyl- group include, but are not limited to, ethylene, propylene, 1-butylene, 2-butylene, isobutylene, sec- butylene, 1-pentene, 2-pentene, isopentene, 1-hexene, 2-hexene, 3-hexene, and isohexene. An alkenyl- group can be unsubstituted or substituted with one or more of the following groups: halogen, H₂N-, (d-C₆alkyl)amino-, di(d-C₆alkyl)amino-, (d- C₆alkyl)C(O)N(C_rC₃alkyl)-, (d-C₆alkyl)carboxyamido-, HC(O)NH-, H₂NC(O)-, (C₁- C₆alkyl)NHC(O)-, di(C_rC₆alkyl)NC(O)-, NC-, hydroxyl, C_rC₆alkoxy-, C_rC₆alkyl-, HO₂C-, (Ci-C₆alkoxy)carbonyl-, (C_rC₆alkyl)C(O)-, C₆-C₁₄aryl-, C_rC₉heteroaryl-, and C₃-C₈cycloalkyl-.

"Alkyl-" refers to a hydrocarbon chain that may be a straight chain or branched chain, containing the indicated number of carbon atoms, for example, a Cr C|_Oalkyl- group may have from 1 to 10 (inclusive) carbon atoms in it. In the absence of any numerical designation, "alkyl" is a chain (straight or branched) having 1 to 6 (inclusive) carbon atoms in it. Examples of Ci-C₆alkyl- groups include, but are not limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert- butyl, isopentyl, neopentyl, and isohexyl. An alkyl- group can be unsubstituted or substituted with one or more of the following groups: halogen, H₂N-, (d- C₆alkyl)amino-, di(C_rC₆alkyl)amino-, (Ci-C₆alkyl)C(O)N(Ci-C₃alkyl)-, (C_r C₆alkyl)carboxyamido-, HC(O)NH-, H₂NC(O)-, (Ci-C₆alkyl)NHC(O)-, CIi(C₁- C₆alkyl)NC(O)-, NC-, hydroxyl, C_rC₆alkoxy-, d-C₆alkyl-, HO₂C-, (d- C₆alkoxy)carbonyl-, (d-C₆alkyl)C(O)-, C₆-Ci₄aryl-, d-Cgheteroaryl-, C₃-C₈cycloalkyl-, Ci-C₆haloalkyl-, amino(d-C₆alkyl)-, (d-C₆alkyl)carboxyl-, d-Cβcarboxyamidoalkyl-, Or O₂N-.

"(Alkyl)amido-" refers to a -C(O)NH- group in which the nitrogen atom of said group is attached to a d-C₆alkyl group, as defined above. Representative examples of a (d-C₆alkyl)amido- group include, but are not limited to, -C(O)NHCH₃, - C(O)NHCH₂CH₃, -C(O)NHCH₂CH₂CH₃, -C(O)NHCH₂CH₂CH₂CH₃,

C(O)NHCH₂CH₂CH₂CH₂CH₃, -C(O)NHCH(CH_S)₂, -C(O)NHCH₂CH(CH₃)₂, C(O)NHCH(CH₃)CH₂CH₃, -C(O)NH-C(CH₃)₃ and -C(O)NHCH₂C(CH₃)₃.

"(Alkyl)amino-" refers to an -NH group, the nitrogen atom of said group being attached to an alkyl group, as defined above. Representative examples of an (Ci- C6alkyl)amino- group include, but are not limited to CH₃NH-, CH₃CH₂NH-, CH₃CH₂CH₂NH-, CH₃CH₂CH₂CH₂NH-, (CH₃)₂CHNH-, (CH₃)₂CHCH₂NH-, CH₃CH₂CH(CH₃)NH- and (CH₃)₃CNH-. An (alkyl)amino group can be unsubstituted or substituted with one or more of the following groups: halogen, H₂N-, (d- C₆alkyl)amino-, di(d-C₆alkyl)amino-, (d-C₆alkyl)C(O)N(d-C₃alkyl)-, (C_r C₆alkyl)carboxyamido-, HC(O)NH-, H₂NC(O)-, (d-C₆alkyl)NHC(O)-, di(d- C₆alkyl)NC(O)-, NC-, hydroxyl, d-C₆alkoxy-, d-C₆alkyl-, HO₂C-, (d- C₆alkoxy)carbonyl-, (d-C₆alkyl)C(O)-, C₆-d₄aryl-, d-Cgheteroaryl-, C₃-C₈cycloalkyl-, Ci-C₆haloalkyl-, amino(d-C₆alkyl)-, (d-C₆alkyl)carboxyl-, d-Cβcarboxyamidoalkyl-, Or O₂N-.

"Alkynyl-" refers to a straight or branched chain unsaturated hydrocarbon containing at least one triple bond. Examples of a C₂-C₆alkynyl- group include, but are not limited to, acetylene, propyne, 1-butyne, 2-butyne, isobutyne, sec-butyne, 1- pentyne, 2-pentyne, isopentyne, 1-hexyne, 2-hexyne, 3-hexyne, and isohexyne. An alkynyl group can be unsubstituted or substituted with one or more of the following groups: halogen, H₂N-, (d-C₆alkyl)amino-, di(Ci-C₆alkyl)amino-, (d- C₆alkyl)C(O)N(Ci-C₃alkyl)-, (d-C₆alkyl)carboxyamido-, HC(O)NH-, H₂NC(O)-, (d- C₆alkyl)NHC(O)-, di(d-C₆alkyl)NC(O)-, NC-, hydroxyl, d-C₆alkoxy-, d-C₆alkyl-, HO₂C-, (Ci-C₆alkoxy)carbonyl-, (C_rC₆alkyl)C(O)-, C₆-Ci₄aryl-, Ci-Cgheteroaryl-, and C₃-C₈cycloalkyl-.

The term "amorphous form" denotes a material that lacks long-range order and as such does not show sharp X-ray peaks. The XRD pattern of an amorphous material is characterized by one or more amorphous halos.

"Aryl-" refers to an aromatic hydrocarbon group. Examples of a Cβ-C-_Haryl- group include, but are not limited to, phenyl, 1-naphthyl, 2-naphthyl, 3-biphen-1-yl, anthryl, tetrahydronaphthyl, fluorenyl, indanyl, biphenylenyl, and acenaphthenyl. An aryl group can be unsubstituted or substituted with one or more of the following groups: d-C₆alkyl-, halogen, haloalkyl-, hydroxyl, hydroxyl(d-C₆alkyl)-, H₂N-, amino(d-C₆alkyl)-, di(d-C₆alkyl)amino-, HO₂C-, (C₁-C₆alkoxy)carbonyl-, (C₁- C₆alkyl)carboxyl-, di(C_rC₆alkyl)amido-, H₂NC(O)-, (d-C₆alkyl)amido-, or O₂N-.

"(Aryl)alkyl-" refers to an alkyl group, as defined above, wherein one or more of the alkyl group's hydrogen atoms have been replaced with an aryl group as defined above. Examples of (C6-C10aryl) alkyl- moieties include benzyl, benzhydryl, 1-phenylethyl, 2-phenylethyl, 3-phenylpropyl, 2-phenylpropyl, 1-naphthylmethyl, 2- naphthylmethyl and the like. An (aryl)alkyl group can be unsubstituted or substituted with one or more of the following groups: halogen, H₂N-, hydroxyl, (d-C₆alkyl)amino- , di(Ci-C₆alkyl)amino-, (d-C₆alkyl)C(O)N(Ci-C₃alkyl)-, (Ci-CealkyOcarboxyamido-, HC(O)NH-, H₂NC(O)-, (C_rC₆alkyl)N HC(O)-, di(d-C₆alkyl)NC(O)-, NC-, hydroxyl, d- C₆alkoxy-, d-C₆alkyl-, HO₂C-, (d-C₆alkoxy)carbonyl-, (d-C₆alkyl)C(O)-, C₆-d₄aryl-, d-Cgheteroaryl-, C₃-C₈cycloalkyl-, d-C₆haloalkyl-, amino(d-C₆alkyl)-, (d- C₆alkyl)carboxyl-, Ci-Cβcarboxyamidoalkyl-, or O₂N-.

"Carboxyl-activating agent" refers to a compound, molecule, or substance, capable of activating carboxylic acids with respect to nucleophilic attack. In some embodiments, the carboxyl-activating agents are capable of activating carboxylic acids where the attacking nucleophile is an amine or alcohol, resulting in amide or ester formation. Non-limiting examples of such carboxyl-activating agents include carbodiimide compounds (e.g. N,N'-dicyclohexylcarbodiimide (DCC), N, N'- diisopropylcarbodiimide (DIC), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC HCI), and the like). Carbodiimide compounds may be either used alone or in combination with HOAt, HOBt, or HODhbt. Further examples of carboxyl-activating agents include alkyl chloroformate compounds (e.g. ethyl chloroformate, isobutyl chloroformate, and the like) that are generally used with a tertiary amine like triethyl amine, diethyl azodicarboxylate (DEAD) with triphenylphosphine (the Mitsunobu reaction), various chlorosilanes, chlorosulfonyl isocyanate, N,N'-carbonyldiimidazole (CDI), phosphonium reagents (e.g. BOP, AOP, PyBOP, PyAOP, BroP, PyBroP, CF₃-NO₂-PyBOP and the like), in situ acid fluoride generators (e.g. TFFH, BTFFH, DAST, cyanuric fluoride, and the like), aminium reagents (e.g. HBTU, HATU, HBPyU, HAPyU, and the like) phosphinyls (e.g. DPPA, DEPC, and the like), pentafluorophenyl active ester generators (e.g. PfTU, PfPyU, FDPP, PFP-trifluoroacetate, FPFOH plus DCC, and the like), mixed carbon anhydrides (e.g. EEDQ, NDQ, and the like), CIP, and BOP-CI.

The phrase "crystalline form" means crystal structures in which a compound can crystallize in different crystal packing arrangements, all of which have the same molecular composition. Different crystalline forms usually have different X-ray diffraction patterns, infrared spectra, melting points, density hardness, crystal shape, optical properties, electrical properties, stability, and solubility. Recrystallization solvent, rate of crystallization, storage temperature, and other factors may cause one crystal form to dominate.

"Cycloalkyl-" refers to a monocyclic, non-aromatic, saturated hydrocarbon ring. Representative examples of a C₃-C₈cycloalkyl- include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. A cycloalkyl can be unsubstituted or independently substituted with one or more of the following groups: halogen, H₂N-, (d-C₆alkyl)amino-, di(Ci-C₆alkyl)amino-, (d- C₆alkyl)C(O)N(Ci-C₃alkyl)-, (d-C₆alkyl)carboxyamido-, HC(O)NH-, H₂NC(O)-, (d- C₆alkyl)NHC(O)-, di(d-C₆alkyl)NC(O)-, NC-, hydroxyl, d-C₆alkoxy-, d-C₆alkyl-, HO₂C-, (Ci-C₆alkoxy)carbonyl-, (C_rC₆alkyl)C(O)-, C₆-Ci₄aryl-, Ci-Cgheteroaryl-, or C₃-C₈cycloalkyl-, d-C₆haloalkyl-, amino(d-C₆alkyl)-, (d-C₆alkyl)carboxyl-, d- C₆carboxyamidoalkyl-, or O₂N-. Additionally, each of any two hydrogen atoms on the same carbon atom of the carbocyclic ring can be replaced by an oxygen atom to form an oxo (=0) substituent or the two hydrogen atoms can be replaced by an alkylenedioxy group so that the alkylenedioxy group, when taken together with the carbon atom to which it is attached, form a 5- to 7-membered heterocycle containing two oxygen atoms. "Di(alkyl)amino-" refers to a nitrogen atom attached to two alkyl groups, as defined above. Each alkyl group can be independently selected. Representative examples of an di(Ci-C₆alkyl)amino- group include, but are not limited to, -N(CH₃)₂, - N(CH₂CH₃)(CH₃), -N(CH₂CH₃)₂, -N(CH₂CH₂CHs)₂, -N(CH₂CH₂CH₂CHs)₂, - N(CH(CH₃)₂)₂, -N(CH(CHS)₂)(CH₃), -N(CH₂CH(CH₃)₂)₂, -NH(CH(CH₃)CH₂CH₃)₂, - N(C(CH₃)s)₂, -N(C(CH₃)s)(CH₃), and -N(CH₃)(CH₂CH₃). The two alkyl groups on the nitrogen atom, when taken together with the nitrogen to which they are attached, can form a 3- to 7- membered nitrogen containing heterocycle wherein up to two of the carbon atoms of the heterocycle can be replaced with -N(H)-, -N(d-C₆alkyl)-, -N(C₃- Cβcycloalkyl)-, -N(C₆-Ci₄aryl)-, -N(Ci-C₉heteroaryl)-, -N(amino(C_rC₆alkyl))-, -N(C₆- Ci₄arylamino)-, -O-, -S-, -S(O)-, or -S(O)₂-.

"Halo" or "halogen" refers to fluorine, chlorine, bromine, or iodine.

Ηeteroaryl-" refers to 5-10-membered mono and bicyclic aromatic groups containing at least one heteroatom, e.g. 1-4 heteroatoms, selected from oxygen, sulfur and nitrogen. Examples of monocyclic d-Cgheteroaryl- radicals include, but are not limited to, oxazinyl, thiazinyl, diazinyl, triazinyl, thiadiazoyl, tetrazinyl, imidazolyl, tetrazolyl, isoxazolyl, furanyl, furazanyl, oxazolyl, thiazolyl, thiophenyl, pyrazolyl, triazolyl, pyrimidinyl, N-pyridyl, 2-pyridyl, 3-pyridyl and 4-pyridyl. Examples of bicyclic d-Cgheteroaryl- radicals include but are not limited to, benzimidazolyl, indolyl, isoquinolinyl, benzofuranyl, benzothiophenyl, indazolyl, quinolinyl, quinazolinyl, purinyl, benzisoxazolyl, benzoxazolyl, benzthiazolyl, benzodiazolyl, benzotriazolyl, isoindolyl, and indazolyl. The contemplated heteroaryl- rings or ring systems have a minimum of 5 members. Therefore, for example, C-iheteroaryl- radicals would include but are not limited to tetrazolyl, C₂heteroaryl- radicals include but are not limited to triazolyl, thiadiazoyl, and tetrazinyl, Cgheteroaryl- radicals include but are not limited to quinolinyl and isoquinolinyl. A heteroaryl group can be unsubstituted or substituted with one or more of the following groups: CrCβalkyl-, halogen, d-C₆haloalkyl-, hydroxyl, Ci-C₆hydroxylalkyl-, H₂N-, amino(Ci-C₆alkyl), di(Ci-C₆alkyl)amino-, -COOH, (C_rC₆alkoxy)carbonyl-, (d-C₆alkyl)carboxyl-, di(d- C₆alkyl)amido-, H₂NC(O)-, (d-C₆alkyl)amido-, or O₂N-.

"(Heteroaryl)alkyl-" refers to an alkyl group, as defined above, wherein one or more of the alkyl group's hydrogen atoms have been replaced with a heteroaryl- group as defined above. Examples of (Ci-Cgheteroaryl)alkyl- moieties include 2- pyridylmethyl, 2-thiophenylethyl, 3-pyridylpropyl, 2-quinolinylmethyl, 2-indolylmethyl, and the like. A (heteroaryl)alkyl group can be unsubstituted or substituted with one or more of the following groups: halogen, H₂N-, hydroxyl, (d-C₆alkyl)amino-, CIi(C₁- C₆alkyl)amino-, (C₁-C₆alkyl)C(O)N(C₁-C₃alkyl)-, (Ci-C₆alkyl)carboxyamido-, HC(O)NH-, H₂NC(O)-, (C_rC₆alkyl)N HC(O)-, di(d-C₆alkyl)NC(O)-, NC-, hydroxyl, C₁- C₆alkoxy-, C_rC₆alkyl-, HO₂C-, (C_rC₆alkoxy)carbonyl-, (d-C₆alkyl)C(O)-, C₆-Ci₄aryl-, d-Cgheteroaryl-, C₃-C₈cycloalkyl-, d-C₆haloalkyl-, amino(d-C₆alkyl)-, (C₁- C₆alkyl)carboxyl-, d-diCarboxyamidoalkyl-, or O₂N-.

Ηeterocycle" or "heterocyclyl-" refers to 3-10-membered monocyclic, fused bicyclic, and bridged bicyclic groups containing at least one heteroatom, e.g. 1 to 4 heteroatoms, selected from oxygen, sulfur and nitrogen. A heterocycle may be saturated or partially saturated. Exemplary d-Cgheterocyclyl- groups include but are not limited to aziridine, oxirane, oxirene, thiirane, pyrroline, pyrrolidine, dihydrofuran, tetrahydrofuran, dihydrothiophene, tetrahydrothiophene, dithiolane, piperidine, 1 ,2,3,6-tetrahydropyridine-1-yl, tetrahydropyran, pyran, thiane, thiine, piperazine, oxazine, 5,6-dihydro-4H-1 ,3-oxazine, azetidine, 1 ,4-dioxane, hexahydroazepine, piperazine, morpholine, thiomorpholine, dihydrobenzimidazole, dihydrobenzofurane, dihydrobenzothiene, dihydrobenzoxazole, dihydroimidazole, dihydroindole, dihydroisooxazole, dihydroisothiazole, dihydrooxadiazole, dihydrooxazole, dihydropyrrazine, dihydropyrazole, dihydropyridine, dihydropyrimidine, dihydropyrrole, dihydroquinoline, dihydrotetrazole, dihydrothiadiazole, dihydrothiazole, dihydrotriazole, dihydroazetidine, dihydro-1 ,4-dioxine, tetrahydroquinoline, and tetrahydroisoquinoline, 2,5-diazabicyclo[2.2.1]heptane, 2,5- diazabicyclo[2.2.2]octane, 3,6-diazabicyclo[3.1.1]heptane, 3,8- diazabicyclo[3.2.1]octane, 6-oxa-3,8-diazabicyclo[3.2.1]octane, 7-oxa-2,5- diazabicyclo[2.2.2]octane, 2,7-dioxa-5-azabicyclo[2.2.2]octane, 2-oxa-5- azabicyclo[2.2.1]heptane-5-yl, 2-oxa-5-azabicyclo[2.2.2]octane, 3,6-dioxa-8- azabicyclo[3.2.1]octane, 3-oxa-6-azabicyclo[3.1.1]heptane, 3-oxa-8- azabicyclo[3.2.1]octan-8-yl, 5,7-dioxa-2-azabicyclo[2.2.2]octane, 6,8-dioxa-3- azabicyclo[3.2.1]octane, 6-oxa-3-azabicyclo[3.1.1]heptane, 8-oxa-3- azabicyclo[3.2.1]octan-3-yl, 2-methyl-2,5-diazabicyclo[2.2.1]heptane-5-yl, 1 ,3,3- trimethyl-6-azabicyclo[3.2.1]oct-6-yl, S-hydroxy-δ-azabicycloβ^.iloctan-δ-yl-, 7- methyl-3-oxa-7,9-diazabicyclo[3.3.1]nonan-9-yl, 9-oxa-3-azabicyclo[3.3.1]nonan-3-yl, 3-oxa-9-azabicyclo[3.3.1]nonan-9-yl, 3,7-dioxa-9-azabicyclo[3.3.1]nonan-9-yl, 4- methyl-3,4-dihydro-2H-1 ,4-benzoxazin-7-yl, thiazine, dithiane, and dioxane. The contemplated heterocycle rings or ring systems have a minimum of 3 members. Therefore, for example, C₁ heterocyclyl- radicals would include but are not limited to oxaziranyl, diaziridinyl, and diazirinyl, C₂heterocyclyl- radicals include but are not limited to aziridinyl, oxiranyl, and diazetidinyl, C₆heterocyclyl- radicals include but are not limited to azepanyl, 3-azabicyclo[3.2.0]heptanyl, and 3-azabicyclo[3.1.0]hexanyl, Cgheterocyclyl- radicals include but are not limited to azecanyl, tetrahydroquinolinyl, and perhydroisoquinolinyl.

Ηeterocyclyl(alkyl)-" refers to an alkyl group, as defined above, wherein one or more of the alkyl group's hydrogen atoms have been replaced with a heterocycle group as defined above. Examples of heterocyclyl(Ci-C₆alkyl)- moieties include 1- piperazinylethyl, 4-morpholinylpropyl, 6-piperazinylhexyl, and the like. A heterocyclyl(alkyl) group can be unsubstituted or substituted with one or more of the following groups: halogen, H₂N-, (d-C₆alkyl)amino-, di(Ci-C₆alkyl)amino-, (d- C₆alkyl)C(O)N(Ci-C₃alkyl)-, (Ci-C₆alkyl)carboxyamido-, HC(O)NH-, H₂NC(O)-, (d- C₆alkyl)NHC(O)-, di(C_rC₆alkyl)NC(O)-, NC-, hydroxyl, C_rC₆alkoxy-, C_rC₆alkyl-, HO₂C-, (Ci-C₆alkoxy)carbonyl-, (d-C₆alkyl)C(O)-, 4- to 7-membered monocyclic heterocycle, C₆-Ci₄aryl-, d-Cgheteroaryl-, or C₃-C₈cycloalkyl-.

As used herein, the terms "optionally substituted" or "substituted or unsubstituted" are intended to refer to the optional replacement of up to four hydrogen atoms with up to four independently selected substituent groups as defined herein. Unless otherwise specified, suitable substituent groups independently include hydroxyl, nitro, amino, imino, cyano, halo, thio, sulfonyl, aminocarbonyl, carbonylamino, carbonyl, oxo, guanidine, carboxyl, formyl, d-C₆alkyl, perfluoroalkyl, alkyamino, dialkylamino, C₁-C₆BIkOXy, alkoxyalkyl, alkylcarbonyl, arylcarbonyl, alkylthio, C₆-Ci₄aryl, C₄-C₉heteroaryl, a heterocyclic ring, cycloalkyl, hydroxyalkyl, carboxyalkyl, haloalkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₇-Ci₆arylalkyl, aryloxy, heteroaryloxy, heteroarylalkyl, and the like. Substituent groups that have one or more available hydrogen atoms can in turn optionally bear further independently selected substituents, to a maximum of three levels of substitutions. For example, the term "optionally substituted d-C₆alkyl" is intended to mean an d-C₆alkyl group that can optionally have up to four of its hydrogen atoms replaced with substituent groups as defined above (i.e., a first level of substitution), wherein each of the substituent groups attached to the d-C₆alkyl group can optionally have up to four of its hydrogen atoms replaced by substituent groups as defined above (i.e., a second level of substitution), and each of the substituent groups of the second level of substitution can optionally have up to four of its hydrogen atoms replaced by substituent groups as defined above (i.e., a third level of substitution).

Unless indicated otherwise, the nomenclature of substituents that are not explicitly defined herein are arrived at by naming from left to right the terminal portion of the functionality followed by the adjacent functionality toward the point of attachment. For example, the substituent "arylalkyloxycabonyl" refers to the group

(C6-Ci₄arylHCi-C₆alkyl)-O-C(O)-.

It is understood that the above definitions are not intended to include impermissible substitution patterns (e.g., methyl substituted with 5 fluoro groups). Such impermissible substitution patterns are well known to the skilled artisan.

The synthetic methods of the present invention are described in Schemes 1 and 2 and are illustrated in the examples. Reasonable variations of the described procedures are intended to be within the scope of the present invention:

Scheme 1

Cyanuric Chloride (1)

Scheme 1 outlines the synthesis of 1-(4-(4-(dimethylamino)piperidine-1- carbonyl)phenyl)-3-(4-(4,6-dimorpholino-1 ,3,5-triazin-2-yl)phenyl)urea (9). Scheme 2

II III

VII when R⁵ is (C₁-C₆alkoxy)carbonyl-C₆-C₁₄aryl- or (C₁-C₆alkoxy)carbonyl-C₁-C₉heteroaryl-

IX

VII I

Scheme 2 outlines a synthesis of X, using a carboxyl-activating agent to effect condensation of acid IX with amine R^aR^bNH. Formula VII is equivalent to formula I because R² is Ce-Cuaryl-NH-COR³, Ci-Cgheteroaryl-N H-COR³, -CH=CH- (C₆-Ci₄aryl)-NH-COR³ or -CH=CH-(Ci-C₉heteroaryl)-NH-COR³ and R³ is NHR⁵. EXAMPLES

The following abbreviations are used herein and have the indicated definitions: DIPEA or Hunig's Base is diisopropylethylamine, DME is 1 ,2- dimethoxyethane, HPLC is high-pressure liquid chromatography, KF means Karl Fischer a method used for water determination, LSI refers to largest single impurity, MeOH is methanol, MS is mass spectrometry, mTOR is Mammalian Target of Rapamycin (a protein), NMP is N-methylpyrrolidinone or 1-methyl-2-pyrrolidinone. PI3K is phosphoinositide 3-kinase (an enzyme), TFA is trifluoroacetic acid, and THF is tetrahydrofuran.

Synthetic Methods

The following methods outline the synthesis of the Examples of the present invention.

Synthesis of 1-(4-(4-(dimethylamino) piperidine-1-carbonyl)phenyl-3-(4-(4,6- dimorpholino-1 ,3,5-triazine-2-yl)phenyl) urea (9)

2-chloro-4,6-dimorpholin-4-yl-[1 ,3,5]triazine (2):

To the suspension of cyanuric chloride (1 , 100 g, 0.54 mol, Aldrich) in acetone (600 ml ) and ice (1.1 kg) was added triethylamine (100 ml, 0.7 mol) , followed by addition by drops of the mixture of triethylamine (100 ml, 0.7 mol) and morpholine (93.3 ml, 1.08 mol, Aldrich) maintaining the temperature below -5 ⁰C with ice cooling. The reaction mixture was stirred for 16 hours at ambient temperature. To the reaction mix was added water (400 ml) and the solids were filtered and washed thoroughly with water. The cake was rinsed with ether (2x150 ml) and air dried to give white solids (100 g, 0.35 mol). Yield 64 %; Mass: 286.7 (M+H)⁺.

2 5h, reflux

4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl) aniline (4)

The mixture of 2-chloro-4,6-dimorpholin-4-yl-[1 ,3,5]triazine (2, 30 g, 0.105 mol) 4-aminophenylboronic acid pinacol ester (3, 25.7 g, 0.117 mol, Boron Molecular), sodium carbonate (23 g , 0.21 mol) and tetrakistriphenylphosphine palladium (1 g, O.δwt % Aldrich) in water (150 ml) and dimethoxyethane (DME, 450 ml) was heated at reflux for 5 hours. The reaction mix was cooled to the room temperature and filtered through paper filter. The layers of the filtrate were separated, the organic layer was washed with brine and concentrated. The residue was dissolved in methylene chloride, washed with brine, dried over sodium sulfate and concentrated. The solids were triturated with diethyl ether, filtered, and air dried to give the beige solids (31.5 g, 0.092 mol). Yield 88%; Mass: 343.1 (M+H)⁺.

methyl 4-(3-(4-(4,6-dimorpholino-1 ,3,5-triazine-2-yl)ureido)benzoate (6)

The mixture of 4-(4,6-dimorpholin-4-yl-1 ,3,5-triazin-2-yl) aniline (4, 49 g, 0.14 mol) and methyl-4-isocyanato benzoate (5, 27.5 g, 0.15 mol) in dichloromethane (700 ml) was stirred at room temperature for 5 hours. To the reaction mixture was added ethyl ether (200 ml) and the solids were filtered. The cake was washed with 1 :1 dichloromethane/ether (200 ml) and ether. Methyl 4-(3-(4-(4,6-dimorpholino-1 ,3,5- triazine-2-yl)ureido)benzoate was obtained as beige solids in 90 % yield (66 g, 0.12 mol); HPLC: 97 % product and 3 % of 4-(4,6-dimorpholin-4-yl-1 ,3,5-triazin-2-yl) aniline.

4-(3-(4-(4,6-dimorpholino-1 ,3,5-triazine-2-yl)phenyl)ureido) benzoic acid (7)

The solution of methyl 4-(3-(4-(4,6-dimorpholino-1 ,3,5-triazine-2- yl)ureido)benzoate (6, 65.8 g, 0.12 mol) and lithium hydroxide monohydrate 12 g, 0.28 mol) in THF/methanol/water (ml, 360/150/150) was heated at gentle reflux (64 ⁰C) for 2 hours. To the reaction mixture cooled to 10 ⁰C was added 2N aqueous hydrochloric acid (144 ml, pH -6.5) and stirred for 30 min. The reaction mixture was filtered, the cake was washed with water and with acetone, and dried in a vacuum oven at 75 ⁰C until constant weight to give 4-(3-(4-(4,6-dimorpholino-1 ,3,5-triazine-2- yl)phenyl)ureido) benzoic acid. White solids (58.5 g, 0.115 mol) in 92 % yield. KF: 0.5 mol water. HPLC: 98 % pure, 1.3% LSI is 4-(4,6-dimorpholin-4-yl-1 ,3,5-triazin-2-yl) aniline.

Preparation of 1-(4-(4-(dimethylamino) piperidine-1-carbonyl)phenyl-3-(4-(4,6- dimorpholino-1 ,3,5-triazine-2-yl)phenyl) urea (9)

To a slurry of 4-(3-(4-(4,6-dimorpholino-1 ,3,5-triazine-2- yl)phenyl)ureido)benzoic acid (7, 45.5 g, 0.09 mol) in dry THF (1.6 L) heated to 50 ⁰C was added N,N'-carbonyl diimidazole (28 g, 0.17 mol). The reaction mixture was heated for 2 hours and followed by dimethylaminopiperidine (8, 23.5 g, 0.18 mol) and stirred at 53 ⁰C for 16 hours. The reaction mixture was cooled to the room temperature and filtered. The cake was washed with 2-propanol and air-dried to give 97 % pure white powder in 88% yield (49.2 g, 0.08 mol). To the solids stirred in dimethyl acetamide (DMAC, 165 ml) at 70° C for 1 hour was added 2-propanol (640 ml) and the mixture was stirred at 65 ⁰C for additional 1 hour. The solids were filtered, washed with 2-propanol and dried in a vacuum oven at 70⁰C for 16 hour to give crystalline white powder (45 g) with >99% purity. The above-mentioned work up process and crystallization procedure gave a Pd residue of 20 ppm. Alternate procedures for the formation of 1-(4-(4-(dimethylamino) piperidine-1 - carbonyl)phenyl-3-(4-(4,6-dimorpholino-1 ,3,5-triazine-2-yl)phenyl) urea (9)

To the solution of 4-(4,6-dimorpholin-4-yl-1 ,3,5-triazin-2-yl) aniline (4, 18 g, 0.052 mol) in dichloromethane (300 ml) was added methyl 4-isocyanato benzoate (5, 10.5 g, 0.061 mol) and the reaction mixture was stirred for 5 hours. The separated solids were filtered, washed with ether and air dried to give beige solids (21 g, 0.04 mol). Yield 77%. 90 % pure by HPLC; Mass: 520.1 (M+H). Preparation of 4-(3-(4-(4,6-dimorpholino-1 ,3,5-triazine-2-yl)phenyl)ureido) benzoic acid (7)

The mixture of methyl 4-(3-(4-(4,6-dimorpholino-1 ,3,5-triazine-2- yl)ureido)benzoate (6, 21 g, 0.04mol) and lithium hydroxide monohydrate (3.8 g, 0.09 mol) in THF (120 ml), MeOH (60 ml), and water (60 ml) was heated at 80 ⁰C for 3 hours. The dark brown solution was cooled to room temperature and made acidic with concentrated HCI. The solids were filtered, washed with water, washed with acetone , washed with ether, and dried in a vacuum oven at 60 ⁰C for 48 hours to give off white solids of 4-(3-(4-(4,6-dimorpholino-1 ,3,5-triazine-2-yl)phenyl)ureido) benzoic acid (19.2 g, 0.038 mol). Mass: 506.3 (M+H)⁺; Yield.94%. 1 -(4-(4-(dimethylamino) piperidine-1 -carbonyl)phenyl-3-(4-(4,6-dimorpholino-

1 ,3,5-triazine-2-yl)phenyl) urea (9)

The suspension of 4-(3-(4-(4,6-dimorpholino-1 ,3,5-triazine-2-yl)phenyl)ureido) benzoic acid (7, 17 g, 33.66 mmol) and N-(3-dimethylaminopropyl)ethyl carbodiimide hydrochloride (9.5 g, 49.5 mmol) in THF (200 ml) and acetonitrile (50 ml) was stirred for 10 min and followed by addition of 1-hydroxybenzotriazole hydrate (6.4 g, 47.88 mmol). The reaction mixture was stirred for 30 min and 4-dimethylaminopiperidine (8, 8.86 g, 69.2 mmol) was added by drops. After being stirred for additional 16 hours, the reaction mixture was concentrated to min. The solids were filtered and washed thoroughly with water (very fine suspension). The cake was slurred in hot ethanol, filtered and dried in a vacuum oven at 68 ⁰C for 16 hours to give off white solids (10.3 g, 16.77 mmol). M. p. 238-240 ⁰C. 99 % pure. Mass: 616.3 (M+H)⁺; Yield 50 %.

The XRD, shown in FIG. 1 , of the amorphous material made in Example 76, page 99 of US Patent Application 12/470,521 exhibits only a broad background signal establishing that it is not crystalline.

By contrast, as shown in FIG. 2, the 1-(4-(4-(dimethylamino) piperidine-1- carbonyl)phenyl-3-(4-(4,6-dimorpholino-1 ,3,5-triazine-2-yl)phenyl) urea (9) made above by either N,N'-carbonyl diimidazole or N-(3-dimethylaminopropyl)ethyl carbodiimide hydrochloride induced coupling shows the series of sharp peaks characteristic of a crystalline material.

Claims

What is claimed is:

1. A method of making a compound of formula VII:

VII wherein: R¹ is

R⁶, R⁷, R⁸, R⁹ are each independently selected from the group consisting of a hydrogen atom, and a Ci-C₆alkyl optionally substituted with C₂-C₆alkenyl, C₄- C₆alkadienyl, C₂-C₆alkynyl or C₄-C₆alkadiynyl; or R⁶ and R⁹ and/or R⁷ and R⁸ independently are attached by a (CH₂)_y or (CH₂-X-CH₂) linking group wherein one hydrogen atom in the linking group may be replaced by an OH; y is 2 or 3;

X is O, S(O)_n, or NR¹⁰; n is O, 1 or 2;

R¹⁰ is selected from the group consisting of H, d-C₆alkyl-, (d-C₆alkyl)SO₂-, (Ci-C₆alkoxy)carbonyl-, (C_rC₆alkyl)amido-, and R¹¹NHSO₂-;

R¹¹ is selected from the group consisting of H, d-C₆alkyl-, d-C₆heterocyclyl, C₆-C₁₄aryl, and d-Cgheteroaryl; or either R⁶ and R⁸ or R⁷ and R⁹ are attached by (CH₂)_Z or (CH₂-X-CH₂) linking group; z is 1 , 2 or 3; or one of R⁶ and R⁷ or R⁸ and R⁹, together with the carbon atoms to which they are attached form an optionally substituted 5-8 membered saturated or unsaturated ring containing 0, 1 or 2 atoms independently selected from O, N and S;

Ar¹ is C₆-Ci₄aryl or d-Cgheteroaryl; wherein any C₆-Ci₄aryl or d- Cgheteroaryl is optionally substituted with 1 or 2 moieties selected from the group consisting of: a) Ci-C₆alkyl- optionally substituted with di(Ci-C₆alkyl)amino-, or d- Cgheterocyclyl; b) halogen; c) O₂N-; d) H₂NSO₂-; e) HOOC-; f) (d-C₆alkoxy)carbonyl- ; g) (Ci-C₆alkyl)amido-; h) di(d-C₆alkyl)amino-; i) R^aR^bNC(O)-, wherein R^a is H or d- C₆alkyl, and R^b is H, d-C₆alkyl, C₃-C₆cycloalkyl, d-Cgheterocyclyl, or di(d- C₆alkyl)amino-(CH₂)_a- wherein a is 2, 3 or 4; or R^a and R^b, when taken together with the nitrogen to which they are attached, form a 3- to 7- membered heterocycle wherein up to two of the carbon atoms of the heterocycle are optionally replaced with -N(d-C₆alkyl)-, -N(C₃- Cβcycloalkyl)-, -N(C₆-d₄aryl)-, -N(d-C₉heteroaryl)-, -S-, -SO-, -S(O)₂-, or -O- and wherein any carbon atom of the heterocycle is optionally substituted with from 1 or 2 substituents independently selected from d-C₆alkyl-, H₂N-, (d-C₆alkyl)amino-, CIi(C₁- C₆alkyl)amino-, and d-Cgheterocyclyl-; j) Q-Z-, wherein Z is O, NHSO₂, SO₂NH, NHCONH, S(0)_q, or is absent, q is O, 1 or 2, and Q is selected from C₆-C₁₄aryl, d-Cgheteroaryl, d-Cgheterocyclyl, C₃- docycloalkyl, d-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, (d-C₆alkyl)amino-(CH₂)_x- wherein x is 1 , 2, 3 or 4, di(d-C₆alkyl)amino-(CH₂)_x-, (C₆-d₄aryl)alkyl-, (d- Cgheteroaryl)alkyl-, and heterocyclyl(d-C₆alkyl)-; and k) R^CC(O)- wherein R^c is H, d- C₆alkyl, C₃-C₆cycloalkyl, or d-Cgheterocyclyl,

R⁵ is C₆-Ci₄aryl or d-Cgheteroaryl wherein the C₆-d₄aryl or d-Cgheteroaryl is optionally substituted with 1 or 2 moieties selected from the group consisting of:

O₂N-, H₂NSO₂-, HOOC-, (C_rC₆alkoxy)carbonyl-, (d-C₆alkyl)amido-, di(d- C₆alkyl)amino-, R^aR^bNC(0)-, and Q-Z-;

R⁴ is selected from the group consisting of: a) d-Cgheterocyclyl- attached to the triazine moiety through a carbon or nitrogen atom and optionally substituted with:

NR¹¹R¹¹ or d-Cβheterocyclyl, with the proviso that 3 membered d- C₆heterocyclyl is saturated and attached to the triazine moiety through a nitrogen atom, and the 5 membered d-C₆heterocyclyl is saturated; b)

wherein Z is CH₂, O, S(O)_n or NR¹⁰ ; c)

wherein a and b are each independently -CH₂-, O, S, or NR , and z is 1-3;

d)

e)

and f) R¹²R¹³N-; wherein R¹² and R¹³ are each independently selected from H, d-C₈alkyl, C₃- C₈alkenyl, and C₃-C₈alkynyl, the Ci-C₈alkyl, C₃-C₈alkenyl, and C₃-C₈alkynyl optionally substituted from the group selected from NR¹¹R¹¹ and Ci-C₆heterocyclyl, provided that an NR¹¹R¹¹ is not directly bonded to a carbon atom that is double- or triple- bonded to another carbon atom; or R¹² and R¹³ taken together with the nitrogen atom to which they are attached form a 3 to 8 membered ring system optionally substituted with d-C₆alkyl, which ring system is saturated or unsaturated and has, in addition to said nitrogen atom, 0 to 2 heteroatom ring members selected from O, S(O)_n and NR¹⁰; comprising reacting compound Vl:

Vl with R⁵-N=C=O to give compound VII:

VII or a pharmaceutically acceptable salt thereof, if desired converting a compound of formula VII obtained to a different compound of formula VII.

2. The method of claim 1 further comprising, when R⁵ is -C₆-Ci₄aryl- carbonyl(Ci-C₆alkoxy) or -Ci-C₉heteroaryl-carbonyl(Ci-C₆alkoxy), saponifing the ester of formula VIII: )

VIII to give acid IX:

IX wherein the C₆-C₁₄aryl or d-Cgheteroaryl is optionally substituted with 1 or 2 moieties selected from the group consisting of:

O₂N-, H₂NSO₂-, HOOC-, (C_rC₆alkoxy)carbonyl-, (d-C₆alkyl)amido-, CIi(C₁- C₆alkyl)amino-, R^aR^bNC(O)-, and Q-Z-.

3. A method of claim 2 wherein the saponification is done with an alkali metal hydroxide.

4. A method of claim 3 wherein the alkali metal hydroxide is lithium hydroxide.

5. A method of any one of claims 2 to 4 further comprising condensing the acid of formula IX:

IX with amine R^aR NH -to give amide X:

X or a pharmaceutically acceptable salt thereof.

6. A method of claim 5 wherein the amide formation is done with a carboxyl-activating agent.

7. A method of claim 6 wherein the carboxyl-activating agent is N₁N'- carbonyldiimidazole or N-(3-dimethylaminopropyl)ethyl carbodiimide hydrochloride.

8. A method of any one of claims 1-7 wherein R¹ and/or R⁴ are:

or a pharmaceutically acceptable salt thereof.

9. A method of any one of claims 1-7 wherein R¹ and/or R⁴ are:

or a pharmaceutically acceptable salt thereof.

10. A method of any one of claims 1-7 wherein R¹ and/or R⁴ are:

or a pharmaceutically acceptable salt thereof.

11. A method of any one of claims 1-7 wherein R¹ and/or R⁴ are independently selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.

12. A method of any one of claims 1-1 1 wherein -Ar¹- is -C₆-C₁₄aryl-.

13. A method of claim 12 wherein -Ar¹- is -phenyl-.

14. A method of any one of claims 1-13 wherein R⁵ is phenyl is substituted with C(O)NR^aR^b.

15. A method of any one of claims 1-14 wherein the compound made of formula VII has the structure:

or a pharmaceutically acceptable salt thereof.

16. A method of making a compound of formula X comprising condensing the acid of formula IX:

IX with an amine R^aR^bNH- and a carboxyl-activating agent selected from N₁N'- carbonyldiimidazole and N-(3-dimethylaminopropyl)ethyl carbodiimide hydrochloride to give amide X:

X wherein Ar¹, R¹, R⁴, R^a, and R^b are defined in claim 1.

17. The method of claim 16 wherein the reaction is performed in THF or a mixture of THF and acetonitrile and the reaction is performed at a temperature from 15 to 50 ⁰C.

18. A crystalline form of 1-(4-(4-(dimethylamino)piperidine-1- carbonyl)phenyl-3-(4-(4,6-dimorpholino-1 ,3,5-triazine-2-yl)phenyl)urea.

19. The compound of claim 18 wherein the crystalline form has an X-ray diffraction pattern one or more characteristic peaks expressed in degrees 2Θ (2-th eta) at 7.9, 9.2, 14.1 , 15.7, 16.7, 17.2, 17.8, 18.7, 19.2, 21.2, 21.6, 22.0, 22.6, 23.0, 23.5, 24.3, 24.6, 26.4, 26.8, 28.2, 28.6, 29.5, 34.7, and 37.6 (±.0.2°).