ES2370472T3 - PROCEDURE FOR THE PREPARATION OF USEFUL COMPOUNDS AS INTERMEDIATES FOR THE PREPARATION OF MODULATORS OF THE ACTIVITY OF THE CHEMIOCIN RECEIVER. - Google Patents

Abstract

A process for preparing a compound having the formula (X) comprising the steps of: hydrolyzing an ester moiety of the compound of formula V with a hydrolysis agent to form the acid of compound VI at temperatures from about -5 to about 5 ° C : reacting a compound of formula VIa, HO-Z-OH, with a compound of formula IV (optionally in situ) in the presence of an acid catalyst, to give a compound of formula VII having a carboxylic acid moiety: transforming the moiety ketal carboxylic acid of formula VII in a corresponding isocyanate of formula VIII: contacting the isocyanate of formula VIII with a compound of formula R10COW in the presence of a corresponding acid anhydride, (R10CO) 2O, to form the amide of formula IX which it has a ketal moiety: hydrolyze the ketal moiety of the amide of formula IX to form the compound of formula X, in which: R1 and R2 are, independently, hydrogen or a amine protecting group; R4 and R10 are independently C1-6 alkyl or optionally substituted benzyl; R8 and R9 are, independently, hydrogen or C1-6 alkyl; W is OH or C1-6 alkyl; Z is - (CT1T2) 2-, - (CT1T2) 3-, o and T1, T2 and T3, each time they appear they are independently selected from hydrogen, C1-4 alkyl, C2-4 alkenyl, halogen, hydroxy, cyano , nitro, CF3, C1-4alkyl, OCF3 and C (= O) C1-4alkyl.

Description

Process for preparing compounds useful as intermediates for the preparation of modulators of chemokine receptor activity.

Field of the Invention

The present invention provides N - ((1R, 2S, 5R) –5– (tert-butylamino) –2 - ((S) –2 – oxo – 3– (6– (trifluoromethyl) quinazolin-4-ylamino) pyrrolidine -1-yl) cyclohexyl) acetamide or a pharmaceutically acceptable salt, solvate or prodrug thereof, which has an unexpected combination of desirable pharmacological characteristics. The crystalline forms of the present invention are also provided. Pharmaceutical compositions containing the same and methods of use thereof as agents

10 for the treatment of inflammatory, allergic, autoimmune, metabolic, cancer and / or cardiovascular diseases are also an object of the present invention. The present invention also provides a process for preparing compounds of Formula (I), including N - ((1R, 2S, 5R) -5- (tert-butylamino) -2 - ((S) -2-oxo-3- ( 6– (trifluoromethyl) quinazolin-4-ylamino) pyrrolidin-1-yl) cyclohexyl) acetamide:

in which R1, R8, R9, R10, and

They are as described in this document. Compounds that are useful intermediates of the process are also provided herein.

20 Summary of the invention

The present invention provides a novel antagonist or partial agonist / partial antagonist of the activity of the MCP-1 receptor: N - ((1R, 2S, SR) -5- (tert-butylamino) -2 - ((S) 2-oxo-3– (6– (trifluoromethyl) quinazolin-4– ylamino) pirlidino-1-yl) cyclohexyl) acetamide or a pharmaceutically acceptable salt, solvate or prodrug thereof, which has an unexpected combination of desirable pharmacological characteristics . The crystalline forms 25 of the present invention are also provided. Pharmaceutical compositions containing the same and methods of use or the same as agents for the treatment of inflammatory, allergic, autoimmune, metabolic, cancerous and / or cardiovascular diseases are also an object of the present invention. The present disclosure also provides a process for the preparation of compounds of Formula (I), including N - ((1R, 2S, SR) –5– (tert-butylamino) -2 - ((S) –2 – oxo – 3 - (6-trifluoromethyl) quinazolin-4-ylamino) pyrrolidin-1–

30 il) cyclohexil) acetamide:

in which R1, R8, R9, R10, and

5 are as described herein. Compounds that are useful intermediates of the process are also provided herein.

The present invention provides the use of N - ((1R, 2S, SR) –5– (tert-butylamino) –2 - ((S) –2 – oxo – 3– (6– (trifluoromethyl) quinazolin-4-ylamino ) pirlidino-1-yl) cyclohexyl) acetamide or a pharmaceutically acceptable salt, solvate or prodrug thereof for the manufacture of a medicament for the treatment of

10 inflammatory, allergic, autoimmune, metabolic, cancerous and / or cardiovascular diseases.

Detailed description

The present invention provides a new antagonist or partial agonist / partial antagonist of the activity of the MCP-1 receptor: N - ((1R, 2S, SR) -5- (tert-butylamino) -2 - ((S) - 2 – oxo – 3– (6 – trifluoromethyl) quinazolin – 4–

15-ylamino) pyrrolidin-1-yl) cyclohexyl) acetamide or a pharmaceutically acceptable salt, solvate or prodrug thereof, which has an unexpected combination of desirable pharmacological characteristics. The crystalline forms of the present invention are also provided.

The pharmaceutical compositions containing the same and methods of use thereof as agents for the treatment of inflammatory, allergic, autoimmune, metabolic, cancerous and / or diseases

20 cardiovascular diseases are also an objective of the present invention.

The present invention also provides a process for preparing compounds of Formula (I), including N- ((1R, 2S, SR) -5- (tert-butylamino) -2 - ((S) -2-oxo-3- ( 6-trifluoromethyl) quinazolin-4-ylamino) pyrrolidin-1-yl) cyclohexyl) acetamide:

E10001989 10-25-2011

in which R1, R8, R9, R10, and

they are as described herein. Compounds that are useful intermediates of the process are also provided herein.

N - ((1R, 2S, SR) –5– (tert-butylamino) –2 - ((S) –2 – oxo – 3– (6-trifluoromethyl) quinazolin – 4-ylamino) pyrrolidin – 1– il) cyclohexil) acetamide, unexpectedly demonstrates a desirable combination of pharmacological characteristics including a surprisingly high degree of oral bioavailability in combination with indications that it is highly effective and has excellent safety criteria.

Known modulators of CCR2 receptors, such as those described in WO2005021500 published on March 10, 2005 (US Patent No. 7,163,937, issued on January 16, 2007, assigned to this Applicant) which demonstrate an adequate degree of membrane permeability (a critical factor for oral bioavailability), are not sufficiently effective, as measured by its ability to bind CCR2 (a measure of efficacy) and / or its lack of adequate safety criteria as indicated by ion channel selectivity as measured by hERG and Na + ion channel studies.

On the contrary, as illustrated by the data presented herein in the section called "Comparative Pharmacological Characteristics", subsequently, the relatively polar molecule, N- ((1R, 2S, SR) -5- (tert-butylamino) –2 - ((S) –2 – oxo – 3– (6-trifluoromethyl) quinazolin-4-ylamino) pyrrolidin-1-yl) cyclohexyl) acetamide demonstrates a surprisingly high degree of membrane permeability and yet still maintains the powerful ability to bind CCR2 together with the excellent selectivity of ion channels.

Accordingly, the present invention provides a new chemokine modulator that has improved pharmacological characteristics and is expected to be useful in the treatment of inflammatory, allergic, autoimmune, metabolic, cancerous and cardiovascular diseases.

Realizations

In one embodiment, the disclosure relates to N - ((1R, 2S, SR) -5- (tert-butylamino) -2 - ((S) -2-oxo-3- (6- trifluoromethyl) quinazolin-4– ylamino) pyrrolidin-1-yl) cyclohexyl) acetamide and pharmaceutically acceptable salts thereof.

Another embodiment is a crystalline form of N - ((1R, 2S, SR) –5– (tert-butylamino) –2 - ((S) –2 – oxo – 3– (6– trifluoromethyl) quinazolin-4-ylamino) pyrrolidin-1-yl) cyclohexyl) acetamide, free base.

Another embodiment is a crystalline form of N - ((1R, 2S, SR) –5– (tert-butylamino) –2 - ((S) –2 – oxo – 3– (6– trifluoromethyl) quinazolin-4-ylamino) pyrrolidin-1-yl) cyclohexyl) acetamide, free base, in which the crystalline form comprises Form N-2.

Procedure Performances

The present disclosure also provides a new process for manufacturing compounds of formula I: including N - ((1R, 2S, 5R) -5- (tert-butylamino) -2 - ((S) -2-, oxo-3- ( 6- (trifluoromethyl) quinazolin-4-ylamino) pyrrolidin-1yl) cyclohexyl) acetamide, or a pharmaceutically acceptable salt thereof.

In a 1st embodiment, the present disclosure provides a new process for preparing a compound of formula IV, wherein the process comprises:

coupling an amino acid derivative of structure III, or a salt thereof, with a cyclohexanone of formula II, or a salt thereof (see preparation in WO2005021500), to give a compound of structure IV, or a salt thereof, which has a substituted amide side chain

10 in which: Ra and Rb are independently C1-6 alkoxy;

or Ra and Rb together with the carbon atom to which they are attached combine to form a carbonyl, a

thiocarbonyl, a cyclic acetal or cyclic thioacetal, in which the cyclic acetal or cyclic thioacetal is selected from -Z-O- and -S-ZS-, Z is - (CT1T2) 2, - (CT1T2) 3, or

and T1, T2 and T3, each time, are independently selected from hydrogen, C1-4 alkyl, C2-4 alkenyl, halogen, hydroxy, cyano, nitro, CF3, C1-4alkyl, OCF3 and C (= O) C1-4 alkyl (preferably T1, T2 and T3 are each hydrogen);

R1, R2 and R3 are independently hydrogen or an amino protecting group;

R4 is lower C1-6 alkyl or optionally substituted benzyl; 5

45 E10001989 10-25-2011

Y is halogen, SMe, S (Me) + R12, or OSO2R13;

V is OH, halogen or OSO2R13;

R12 is hydrogen, C1-6 alkyl, - (CH2) C (O) O C1-6 alkyl, or - (CH2) C (O) O C1-6 alkyl; Y

R13 is increasingly C1-6 alkyl.

Preferred amine protecting groups are groups that can be removed by hydrolysis or hydrogenolysis under standard conditions. Such groups include, without limitation, a carbobenzyloxy (Cbz) group, a tert-butyloxycarbonyl (BOC) group, a fluorenylmethyloxycarbonyl (FMOC) group, a benzyl (Bn) group or a p-methoxybenzyl (PMB) group. More preferred are the Cbz, BOC, or Bn groups (especially Cbz and Bn).

In a 2nd embodiment, the present disclosure provides a new procedure in which:

Ra and Rb together with the carbon atom to which they are attached combine to form a carbonyl or a 1,3-dioxolane group (especially a 1,2-dioxolane group);

R1 is hydrogen;

R2 is Cbz;

R3 is hydrogen;

R4 is C1-6 alkyl;

Y is S (Me); Y

V is OH.

In a third embodiment, in which Y is -Sme, the disclosure provides a method that further comprises renting the compound of formula IV with an R12X group, in which x is halogen, to form a sulfonium salt thereof. The alkylating agent is preferably methyl iodide.

In a 4th embodiment, the disclosure provides a process in which the cyclohexanone of formula IV is a toluenesulfonate salt.

In a 5th embodiment, the disclosure provides a process in which the compound of formula IV is a sulphonium salt.

In a 6th embodiment, the disclosure provides a process in which the coupling is performed in an inert atmosphere, such as nitrogen, argon (preferably nitrogen) in an aprotic solvent, such as propionitrile, isopropyl acetate, n-butyl acetate, tert-butyl acetate or acetonitrile (especially acetonitrile and / or ethyl acetate).

In a 7th embodiment, the disclosure provides a method in which the coupling can be performed by contacting a compound of formula II with a resignation coupling reagent in the presence of an activator and a tertiary amine base. The dimide coupling reagent includes reagents such as, for example EDAC. Examples of activators include HOBt ((this term includes hydrates thereof) and N ', N’-4-dimethylamino-pyridine. A tertiary amine base includes, for example, triethylamine, N-N-diisopropyl-N-ethylamine and trin-propylamine.

In an 8th embodiment, the disclosure provides a process in which the resignation coupling reagent is EDAC, the activator is HOBt (said term includes hydrates thereof (and the tertiary amine base is triethylamine.

In a 9th embodiment, the disclosure provides a process in which the molar proportions of a compound of formula II and the coupling reagent with the activator and with the tertiary amine is from about one to about 0.090-1.50 to about 0, 95-1.50 to about 2.00 to 3.00, respectively. Said molar proportions are preferably from one to about 0.095-1.05 to about 0.095-1.10 and at about 2.10 to 2.20, respectively.

In a 10th embodiment, the present disclosure provides a new process for preparing a compound of formula V, which has an ester moiety

The procedure includes:

cycling the side chain of the amino acid derivative of a compound of formula IV, or a salt thereof, to give a compound of formula V having an ester moiety.

In an 11th embodiment, in which Ra and Rb are independently C1-C6 alkoxy, or Ra and Rb together with the carbon to which they are attached combine to form a thiocarbonyl, a cyclic acetal or cyclic thioacetal, the The disclosure provides a method that optionally further comprises the step of hydrolyzing the Ra and Rb groups so that the combination of Ra and Rb together with the carbon to which they are attached form a carbonyl. Hydrolyzing can be performed in a solvent such as acetone, butanone, acetonitrile and isopropanol, or aqueous solutions of

10 the same, and, preferably, canned in aqueous acetone. Preferably, the hydrolysis stage follows the cyclization stage.

In a 12th embodiment, the disclosure provides a process in which the cyclization is performed by combining a compound of formula IV, or a salt thereof, with a base in the presence of a solvent. Said bases may be, for example, without limitations, cesium carbonate, cesium bicarbonate, potassium carbonate, tert-butylate

Sodium, sodium hexamethyldisilazide and, preferably, cesium carbonate.

In a 13th embodiment, the disclosure provides a process in which the cyclization is performed in an inert atmosphere, such as nitrogen, argon (preferably nitrogen) in a solvent included, for example, without limitations, DMSO, DMF, DMA, N- methylpyrrolidone, sulfolane (especially DMSO and / or DMF).

In a 14th embodiment, the disclosure provides a process for preparing a compound of formula VI:

The procedure includes:

Hydrolyze the ester moiety of the compound of formula V with a hydrolysis agent to form the acid of compound VI at temperatures of about -5 to about 5 ° C. Ester hydrolysis agents are well known to those skilled in the art and include alkali metal hydroxides, MOH, in

Those of which M is Li, Na or K, preferably the hydrolysis agent is aqueous NaOH. Preferably, the hydrolysis step is performed under two-phase conditions with an organic solvent that is partially miscible in water. Preferred organic solvents are acyclic or cyclic ethers include THF, 2-methyl-THF, 1,2 dimethoxyethane, 1,4-dioxane, especially THF.

Alternatively, in a 15th embodiment, when Ra and Rb together with the atom to which they are attached combine to form a carbonyl, the disclosure provides a process for preparing a compound of formula VII:

The procedure includes:

reacting a compound of formula VIa, HO-Z-OH, with a compound of formula IV (optionally in situ) in the presence of an acid catalyst, to give a compound of formula VII, wherein Z is - (CT1T2) 2 , - (CT1T2) 3-, or

Y

T1, T2 and T3, each time, are independently selected from hydrogen, C1-4 alkyl, C2-4 alkenyl, halogen, hydroxy, cyano, nitro, CF3, O (C1-4 alkyl, OCF3 and C (= O ) C1-4 alkyl (preferably, T1, T2 and T3 are each hydrogen.

Preferably, the compound of formula VIa is ethylene glycol and the acid catalyst is ptoluenesulfonic acid or a hydrate thereof.

In a 16th embodiment, the disclosure provides a process for preparing a compound of formula VIII:

The method comprises: transforming the ketal of formula VII into a corresponding isocyanate of formula VIII. Preferably, the transformation is performed by reordering Curtius. In a 17th embodiment, the disclosure provides a method in which the transformation step is performed by Curtius rearrangement, which comprises the steps of: a) mixing a substantially anhydrous solution of formula VII with a base (the base is, by example, without limitations, an alkylamine, especially a tertiary amine, preferably triethylamine); b) adding a haloformate (e.g., a chloroformate, preferably i-BuO2CCI) to the solution at a temperature of about -10 ° C to about 0 ° C, to form a mixed acid anhydride of formula VII;

c) treating the mixed anhydride with an azide reagent (preferably NaN3) in the presence of a phase transfer catalyst (preferably a tetraalkylammonium salt, such as tetrabutylammonium bromide at about 5 mol%) at a temperature of about -10 ° C at approximately 0 ° C, to form the acid azide of formula VIIa:

Y

d) heating a substantially anhydrous solution of the acyl azide of formula VIIa, to form the corresponding isocyanate of formula VIII. Preferably, the substantially anhydrous solution of the acyl azide is dried over molecular sieves.

In one embodiment, the disclosure provides a process for preparing a compound of formula IX having a ketal moiety:

The process comprises: contacting the isocyanate of formula VIII (optionally in situ) with a compound of formula R10COW (e.g., acetic acid) in the presence of a corresponding acid anhydride, (i.e., R10CO) 2O, for forming the amide of formula IX, wherein: R 10 is C 1-6 alkyl (R 10 is preferably methyl): and W is OH or C 1-6 alkyl;

In a 19th embodiment, the disclosure provides a process for preparing a compound of formula X: ketal hydrolysis reagents are well known to those skilled in the art. Preferably, the hydrolysis is performed by heating a solution of compound IX having a ketal moiety in an organic solvent (e.g., acetone) and hydrochloric acid (about 1N) at about 45 ° C to about 55 ° C for about 2-4 hours .

In a 20th embodiment, the disclosure provides a process for preparing a compound of formula XI:

The procedure includes:

reductive amination of the compound of formula X with an amine of formula HNR8R9 in the presence of a Lewis acid, followed by a reducing agent to form a compound of formula XI having a pyrrilidylamine residue.

In a 21st embodiment, the disclosure provides a method in which reductive tuning comprises the steps of:

a) adding a Lewis acid (preferably a titanium reagent, which includes, without limitation, TiCl2 (O-isopropyl) 2) to a solution of compound X and the amine having the formula HNR8R9 in an aprotic solvent 15 to form a imine-enamine of formula XA:

Y

b) treating the imine-enamine of formula Xa with a reducing agent (preferably dimethylborane sulfide),

20 to give the compound of formula XI having a pyrrolidonylamine moiety. In the above steps, the aprotic solvent can be, for example, without limitations, dichloromethane, acetonitrile, DMSO, DMF and N-methyl-pyrrolidinone (preferably dichloromethane).

In a 22nd embodiment, the disclosure provides a process in which the amine of formula HN (R8) (R9) is preferably tert-butylamine.

In a 23rd embodiment, the disclosure provides a process for preparing a compound of formula XII: the process comprises:

deprotecting pyrrolidonylamine of formula XI to form a compound of formula XII.

In a 24th embodiment, the disclosure provides a method in which the deprotection stage is carried out.

5 carried out by hydrogenation of a solution of the compound of formula XII in the presence of a catalyst such as palladium. Preferably, hydrogenation is carried out at about 20 to about 40 psig in a solvent, including, without limitation, methanol, over 5% of the Pd / C catalyst at about 25 ° C for about two to about six hours.

In a 25th embodiment, the disclosure provides a process for preparing a compound of formula I which comprises coupling the compound of formula XII with a compound of formula

to give a compound of formula I, in which:

HET is a 3-14-membered heteroaryl ring having one to four heteroatoms selected from N, O or S (preferably one to three heteroatoms, especially one to two nitrogen atoms) in at least one of the rings ( HET is preferably a 6-substituted quinazolin-4-yl, more preferably 6-trifluoromethyl-quinazolin-4-yl); Y

LG is a leaving group selected from halogen or OSO2R16, wherein R16 is phenyl, a heteroaryl of 5 to

20 7 members having one or more atoms selected from N, S or O, C 1-6 alkyl or a 3- to 7-membered cycloalkyl, all optionally substituted with one to three groups selected from halogen, CF 3 and C 1-6 alkyl (preferably, LG is a halogen, especially chlorine).

A leaving group, as used herein, includes, without limitation, groups such as halogens, mesylate, nonaphthalates, sulfonates, tosylates and triflates. A preferred leaving group is halogen or OSO2R16, wherein R16 is phenyl, a 5- to 7-membered heteroaryl having one or more atoms selected from N, S or O, C1-6 alkyl

or a 3 to 7 membered cycloalkyl, all optionally substituted with one to three groups selected from halogen, CF3 and C1-6 alkyl. In the most preferred embodiment, LG is a halogen, especially chlorine.

In a 26th embodiment, the disclosure provides a process for preparing a compound of formula X:

comprising the steps of: hydrolyzing an ester moiety of the compound of formula V with a hydrolysis agent to form the acid of compound VI at temperatures from about -5 to about 5 ° C:

reacting a compound of formula VIa, HO-Z-OH, with a compound of formula IV (optionally in situ) in the presence of an acid catalyst, to give a compound of formula VII having a carboxylic acid moiety:

reacting a compound of formula VIa, HO-Z-OH (preferably alkylene glycol, especially ethylene glycol), with a compound of formula IV (optionally in situ) in the presence of an acid catalyst (preferably p-toluenesulfonic acid or a hydrate thereof) , to give a compound of formula VII having a carboxylic acid moiety:

Transforming the carboxylic acid moiety of the ketal of formula VII into a corresponding intermediate isocyanate of formula VIII:

contacting the isocyanate of formula VIII (optionally in situ) with a compound of formula R10COW (e.g., acetic acid) in the presence of a corresponding acid anhydride, (i.e., R10CO) 2O, to form the amide of formula IX, which has a ketal rest:

Hydrolyze the ketal moiety of the amide of formula IX to form the compound of formula X:

wherein: R1 and R2 are independently hydrogen or an amine protecting group; R4 and R10 are independently C1-6 alkyl or optionally substituted benzyl; R8 and R9 are, independently, hydrogen or C1-6 alkyl; W is OH or C1-6 alkyl; Z is - (CT1T2) 2-, - (CT1T2) 3-, or

and T1, T2 and T3, each time they appear they are independently selected from hydrogen, C1-4 alkyl, C2-4 alkenyl, halogen, hydroxy, cyano, nitro, CF3, C1-4alkyl, OCF3 and C (= O ) C1-4-alkyl In a 27th embodiment, the disclosure provides a process for preparing a compound of formula XI, in which:

the compound of formula VII is (7R, 8S) -8 - ((3S) -3 - (((benzyloxy) carbonyl) amino) -2-oxo-1-pyrrolidinyl) -1,4-dioxaspiro [4.5] decane-7 -carboxylic, or a salt thereof; the compound of formula VIIa is ((3S) -1 - ((7R, 8S) -7- (azidocarbonyl) -1,4-dioxaspiro [4.5] dec-8-yl) -2-oxo-3

benzyl pyrrolidinyl) carbamate, or a salt thereof;

The compound of formula VIII is ((3S) -1 - ((7R, 8S) -7-isocyanate-1,4-dioxaspiro [4.5] dec-8-yl) -2-oxo-3-pyrrolidinyl) benzyl carbamate, or a salt thereof; the compound of formula IX is ((3S) -1 - ((7R, 8S) -7-acetamido-1,4-dioxaspiro [4.5] dec-8-yl) -2-oxo-3

benzyl pyrrolidinyl) carbamate, or a salt thereof; the compound of formula X is ((3S) -1 - ((1S, 2R) -2-acetamido-4-oxocyclohexyl) -2-oxo-3-pyrrolidinyl) benzyl carbamate, or a salt thereof; the compound of formula XI is ((3S) -1 - ((1S, 2R, 4R) -2-acetamido-4- (tert-butylamino) cyclohexyl) -2-oxo-3-pyrrolidinyl) benzyl carbamate, or a salt of same; In a 28th embodiment, the disclosure provides a process for preparing a compound of formula I:

The procedure includes:

hydrolyze the ester moiety of the compound of formula V with a hydrolysis agent (preferably an alkali hydroxide, especially sodium hydroxide), to form a compound of formula VI; reacting a compound of formula Va, HO-Z-OH, with a compound of formula VI, optionally in

5 situ, in the presence of an acid catalyst (preferably p-toluenesulfonic acid or a hydrate thereof),

to give a compound of formula VII having a carboxylic acid moiety; transform the carboxylic acid moiety of the ketal of formula VII to form a corresponding isocyanate intermediate of formula VIII;

contacting the isocyanate of formula VIII (optionally in situ) with a compound of formula 10 R10COW (preferably acetic acid) in the presence of a corresponding acid anhydride, R10CO) 2O, (preferably acetic anhydride) to form the amide of formula IX , which has a ketal rest;

hydrolyze the ketal moiety of the amide of formula IX to form the compound of formula X; and reductive amination of the compound of formula X with an amine of formula HNR8R9 (preferably tert-butylamine) in the presence of a Lewis acid (preferably a titanium reagent, such as TiCl2 (O-iso

Propyl) 2), to form a compound of formula XI having a pyrrolidonylamine moiety; deprotecting pyrrolidonylamine of formula XI to form a compound of formula XII. and coupling the compound of formula XII with a compound of formula

to give a compound of formula I; wherein: R1 and R2 are independently hydrogen or an amine protecting group;

R4 and R10 are, independently, C1-6 alkyl or optionally substituted benzyl; R8 and R9 are, independently, hydrogen or C1-6 alkyl; W is OH or C1-6 alkyl; Z is - (CT1T2) 2-, - (CT1T2) 3-, or

T1, T2 and T3, each time they appear, are independently selected from hydrogen, C1-4 alkyl, C2-4 alkenyl, halogen, hydroxy, cyano, nitro, CF3, C1-4alkyl, OCF3 and C (= O) C1-4 alkyl (preferably Z is - (CH2) 2-);

HET is a 3-14 membered heteroaryl ring having one to four heteroatoms selected from N, O or S (preferably one to three heteroatoms, especially one to two nitrogen atoms) in at least one

Of the rings (HET is preferably a 6-substituted quinazolin-4-yl, more preferably 6-trifluoromethylquinazolin-4-yl); Y

LG is a leaving group selected from halogen or OSO2R16, wherein R16 is phenyl, a 5- to 7-membered heteroaryl having one or more atoms selected from N, S or O, C1-6 alkyl or a 3 to 7 cycloalkyl members, all optionally substituted with one to three groups selected from halogen, CF3 and C1-6 alkyl

40 (preferably, LG is a halogen, especially chlorine).

In a 29th embodiment, the disclosure provides a compound of formula VI or a salt thereof:

in which:

R1 and R2 are independently selected from hydrogen and an amine protecting group selected from BOC, Cbz and benzyl (preferably R1 is hydrogen and R2 is Cbz); Z is - (CT1T2) 2-, - (CT1T2) 3-, or

10 and T1, T2 and T3, each time they appear they are independently selected from hydrogen, C1-4 alkyl,

C2-4 alkenyl, halogen, hydroxy, cyano, nitro, CF3, C1-4alkyl, OCF3 and C (= O) C1-4 alkyl (preferably Z is - (CH2) 2-); A preferred compound of formula VI is (1R, 2S) -2 - ((S) -3- (benzyloxycarbonylamino) -2-oxopyrrolidin-1-yl)

5-oxocyclohexanecarboxylic acid, or a salt thereof. In a 30th embodiment, the disclosure provides a compound of formula VI which is (1R, 2S) -2 - ((S) -3 (benzyloxycarbonylamino) -2-oxopyrrolidin-1-yl) -5-oxocyclohexanecarboxylic acid, or a salt of the same.

In a 31st embodiment, the disclosure provides a new compound of formula VII or a salt thereof:

in which:

R1 and R2 are independently selected from hydrogen and an amine protecting group selected from BOC, Cbz and benzyl (preferably R1 is hydrogen and R2 is Cbz); Z is - (CT1T2) 2-, - (CT1T2) 3-, or

and T1, T2 and T3, each time, are independently selected from hydrogen, C1-4 alkyl, C2-4 alkenyl, halogen, hydroxy, cyano, nitro, CF3, C1-4alkyl, OCF3 and C (= O ) C1-4 alkyl (preferably Z is - (CH2) 2-); the compound of formula VII is (7R, 8S) -8 - ((3S) -3 - (((benzyloxy) carbonyl) amino) -2-oxo-1-pyrrolidinyl) -1,4-dioxaspiro [4.5] decane-7 -carboxylic. In a 32nd embodiment, the disclosure provides a compound of formula VII is (7R, 8S) -8 - ((3S) -3 ((((benzyloxy) carbonyl) amino) -2-oxo-1-pyrrolidinyl) -1, 4-dioxaspiro [4.5] decane-7-carboxylic acid, or a salt thereof. In a 33rd embodiment, the disclosure provides new compounds of formula VIIa or a salt thereof:

in which:

R1 and R2 are independently selected from hydrogen and an amine protecting group selected from BOC, Cbz and benzyl (preferably R1 is hydrogen and R2 is Cbz); Z is - (CT1T2) 2-, - (CT1T2) 3-, or

20 and T1, T2 and T3, each time they appear they are independently selected from hydrogen, C1-4 alkyl,

C2-4 alkenyl, halogen, hydroxy, cyano, nitro, CF3, C1-4alkyl, OCF3 and C (= O) C1-4 alkyl (preferably Z is - (CH2) 2-); A preferred compound of formula VIIa is ((3S) -1 - ((7R, 8S) -7- (azidocarbonyl) -1,4-dioxaspiro [4.5] dec-8-yl) -2

benzyl oxo3-pyrrolidinyl) carbamate. In a 34th embodiment, the disclosure provides a compound of formula VIIa is ((3S) -1 - ((7R, 8S) 7 (azidocarbonyl) -1,4-dioxaspiro [4.5] dec-8-yl) -2-oxo -3-pyrrolidinyl) benzyl carbamate, or a salt thereof.

In a 35th embodiment, the disclosure provides a compound of formula VIII or a salt thereof: in which:

R1 and R2 are independently selected from hydrogen and an amine protecting group selected from BOC, Cbz or benzyl (preferably R1 is hydrogen and R2 is Cbz); Z is - (CT1T2) 2-, - (CT1T2) 3-, or

10 and

T1, T2 and T3, each time they appear, are independently selected from hydrogen, C1-4 alkyl, C2-4 alkenyl, halogen, hydroxy, cyano, nitro, CF3, C1-4alkyl, OCF3 and C (= O) C1-4 alkyl (preferably Z is - (CH2) 2-);

A preferred compound of formula VIII is ((3S) -1 - ((7R, 8S) -7-isocyanate-1,4-dioxaspiro [4.5] dec-8-yl) -2-oxo315 pyrrolidinyl) benzyl carbamate.

In a 36th embodiment, the disclosure provides a compound of formula VIII which is ((3S) -1 - ((7R, 8S) -7isocyanate-1,4-dioxaspiro [4.5] dec-8-yl) -2-oxo- Benzyl 3-pyrrolidinyl) carbamate, or a salt thereof.

In a 37th embodiment, the disclosure provides a compound of formula IX or a salt thereof:

wherein: R1 and R2 are independently selected from hydrogen and an amine protecting group selected from BOC, Cbz or benzyl (preferably R1 is hydrogen and R2 is Cbz); 25 Z is - (CT1T2) 2-, - (CT1T2) 3-, or

T1, T2 and T3, each time they appear, are independently selected from hydrogen, C1-4 alkyl, C2-4 alkenyl, halogen, hydroxy, cyano, nitro, CF3, C1-4alkyl, OCF3 and C (= O) C1-4 alkyl (preferably Z 5 is - (CH2) 2-); Y

R10 is C1-6 alkyl (preferably, methyl).

A preferred compound of formula IX is ((3S) -1 - ((7R, 8S) -7-acetamido-1,4-dioxaspiro [4.5] dec-8-yl) -2-oxo3pyrrolidinyl) benzyl carbamate.

In a 38th embodiment, the disclosure provides a compound of formula IX which is ((3S) -1 - ((7R, 8S) -710 acetamido-1,4-dioxaspiro [4.5] dec-8-yl) -2-oxo -3-pyrrolidinyl) benzyl carbamate, or a salt thereof.

In a 39th embodiment, the disclosure provides a compound of formula X or a salt thereof:

15 in which:

R1 and R2 are independently hydrogen or an amine protecting group selected from BOC, Cbz and benzyl; Y

R10 is C1-6 alkyl.

Preferably, R1 is hydrogen, R2 is Cbz and R10 is methyl. A preferred compound of formula X is ((3S) 20 1 - ((1S, 2R) -2-acetamido-4-oxocyclohexyl) -2-oxo-3-pyrrolidinyl) benzyl carbamate

In a 40th embodiment, the disclosure provides a compound of formula X which is ((3S) -1-1 - ((7R, 8S) -2acetamido-4-oxocyclohexyl-2-oxo-3-pyrrolidinyl) benzyl carbamate, or A salt of it.

In a 40th embodiment, the disclosure provides a compound of formula XI or a salt thereof:

in which:

35 E10001989 10-25-2011

R1 and R2 are independently hydrogen or an amine protecting group selected from BOC, Cbz and benzyl;

R8 and R9 are, independently, hydrogen or C1-6 alkyl; Y

R10 is C1-6 alkyl.

Preferably, R1 is hydrogen, R2 is Cbz, R8 is hydrogen, R9 is tert-butyl and R10 is methyl. A preferred compound of formula XI is ((3S) -1 - ((1S, 2R, 4R) -2-acetamido-4- (tert-butylamino) cyclohexyl) -2-oxo-3-pyrrolidinyl) benzyl carbamate.

In a 41st embodiment, the disclosure provides a compound of formula XI which is ((3S) -1 - ((1S, 2R, 4R) -2acetamido-4- (tert-butylamino) cyclohexyl) -2-oxo-3-pyrrolidinyl ) benzyl carbamate, or a salt thereof.

In a 42nd embodiment, the disclosure provides a compound of formula XII or a salt thereof:

wherein: R1 is hydrogen or an amine protecting group selected from BOC, Cbz and benzyl; R8 and R9 are, independently, hydrogen or C1-6 alkyl; and R10 is C1-6 alkyl. Preferably, R1 is hydrogen, R8 is hydrogen, R9 is tert-butyl and R10 is methyl. A preferred compound of formula XII is N - ((1R, 2S, 5R) -2 - ((3S) -3-amino-2-oxo-1-pyrrolidinyl) -5- (tert-butylamino) cyclohexyl) acetamide.

In a 43rd embodiment, the disclosure provides a compound of formula XII which is N - ((1R, 2S, 5R) -2 - ((3S) -3-amino-2-oxo-1-pyrrolidinyl) -5- (tert-butylamino ) cyclohexyl) acetamide, or a salt thereof.

In a 44th embodiment, the disclosure provides a compound selected from: (7R, 8S) -8 - ((3S) -3 - ((((benzyloxy) carbonyl) amino) -2-oxo-1-pyrrolidinyl) -1, 4-dioxaspiro [4.5] decane-7 carboxylic acid, or a salt thereof;

((3S) -1 - ((7R, 8S) -7- (azidocarbonyl) -1,4-dioxaspiro [4.5] dec-8-yl) -2-oxo-3-pyrrolidinyl) benzyl carbamate, or a

get out of it; ((3S) -1 - ((7R, 8S) -7-Isocyanate-1,4-dioxaspiro [4.5] dec-8-yl) -2-oxo-3-pyrrolidinyl) benzyl carbamate, or a salt of the same;

((3S) -1 - ((7R, 8S) -7-acetamido-1,4-dioxaspiro [4.5] dec-8-yl) -2-oxo-3-pyrrolidinyl) benzyl carbamate, or a salt of the same;

((3S) -1 - ((1S, 2R) -2-acetamido-4-oxocyclohexyl) -2-oxo-3-pyrrolidinyl) benzyl carbamate, or a salt thereof; ((3S) -1 - ((1S, 2R, 4R) -2-acetamido-4- (tert-butylamino) cyclohexyl) -2-oxo-3-pyrrolidinyl) benzyl carbamate, or a salt thereof

In a 45th embodiment, the disclosure provides a process in which: a compound of formula VII is (7R, 8S) -8 - ((3S) -3 - ((((benzyloxy) carbonyl) amino) -2-oxo- 1-pyrrolidinyl) -1.4

50 E10001989 10-25-2011

dioxaspiro [4.5] decane-7-carboxylic acid, or a salt thereof;

a compound of formula VIIa is ((3S) -1 - ((7R, 8S) -7- (azidocarbonyl) -1,4-dioxaspiro [4.5] dec-8-yl) -2-oxo-3-pyrrolidinyl) benzyl carbamate , or a salt thereof;

a compound of formula VIII is ((3S) -1 - ((7R, 8S) -7-isocyanate-1,4-dioxaspiro [4.5] dec-8-yl) -2-oxo-3-pyrrolidinyl) benzyl carbamate, or a salt thereof;

a compound of formula IX is ((3S) -1 - ((7R, 8S) -7-acetamido-1,4-dioxaspiro [4.5] dec-8-yl) -2-oxo-3-pyrrolidinyl) benzyl carbamate, or a salt thereof;

a compound of formula X is ((3S) -1 - ((1S, 2R) -2-acetamido-4-oxocyclohexyl) -2-oxo-3-pyrrolidinyl) benzyl carbamate, or a salt thereof;

a compound of formula XI is ((3S) -1 - ((1S, 2R, 4R) -2-acetamido-4- (tert-butylamino) cyclohexyl) -2-oxo-3-pyrrolidinyl) benzyl carbamate, or a salt of same;

In one embodiment # 46, the disclosure provides a process in which a compound of formula I is - ((1R, 2S, 5R) -5- (tert-butylamino) -2 - ((S) -2-oxo-3 - (6-trifluoromethyl) quinazolin-4-ylamino) pyrrolidin-1-yl) cyclohexyl) acetamide or a salt thereof.

The present invention may be contained in other specific forms without departing from the spirit or essential attributes thereof. Therefore, the above embodiments should not be construed as limiting. It is understood that any and all embodiments of the present invention may be taken together with any other embodiment or embodiments to describe additional embodiments. Each individual element (including preferred aspects) of the embodiments is its own independent realization. In addition, this covers all combinations of different embodiments, parts of embodiments, definitions, descriptions and examples of the invention indicated herein.

Definitions

The following are definitions of terms used in this specification and in the appended claims. The initial definition provided for a group or term in this specification applies to that group or term through the specification and claims, individually or as part of another group, unless otherwise specified.

The term "alkyl" refers to straight or branched chain hydrocarbon groups having 1 to 12 carbon atoms, preferably 1 to 6 carbon atoms. When the numbers appear in a subscript after the symbol "C", the subscript defines more specifically the number of carbon atoms that a particular group can contain. For example, "C1-C6 alkyl" refers to straight and branched chain hydrocarbon groups having 1 to 6 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, n- pentyl and so on. The subscript "0" refers to a link. Thus, the term hydroxyalkyl (C0-2) includes hydroxy, hydroxymethyl and hydroxyethyl. The alkyl groups may be substituted with one to three groups selected from (C1-6) alkyl, (C2-6) alkenyl, hydroxy, halogen, cyano, nitro, CF3, O (C1-6 alkyl), OCF3, C ( = O) H, C (= O) (C1-6 alkyl), CO2H, CO2 (C1-6 alkyl), NHCO2 (C1-6 alkyl), -S (C1-6 alkyl), NH2, NH (C1 alkyl -6), N (C1-6 alkyl) 2, N (CH3) 3+, SO2 (C1-6 alkyl), C (= O) (C1-4 alkylene) NH2, C (= O) (C1- alkylene 4) NH (alkyl), C (= O) (C1-4 alkylene) N (C1-4 alkyl) 2, C3-7 cycloalkyl, phenyl, benzyl, phenylethyl, phenyloxy, benzyloxy, naphthyl, a four to seven heterocycle members and / or a heteroaryl of five to six members. When a substituted alkyl is substituted with an aryl, heterocycle, cycloalkyl or heteroaryl group, said ring systems are as defined below and, therefore, may have zero, one, two or three substituents, also as defined below.

When the term "alkyl" is used together with another group, such as in "arylalkyl," this set defines more specifically at least one of the substituents that the substituted alkyl will contain. For example, "arylalkyl" refers to a substituted alkyl group as defined above, in which at least one of the substituents is an aryl, such as benzyl. Thus, the term aryl (C0-4 alkyl) includes a substituted minor alkyl having at least one aryl substituent and also includes an aryl attached directly to another group, that is aryl (C0 alkyl).

The term "alkenyl" refers to straight or branched chain hydrocarbon groups having 2 to 12 carbon atoms and at least one double bond. Alkenyl groups of 2 to 6 carbon atoms and having a double bond are the most preferred. Alkenyl groups may be substituted as described above for alkyl groups.

The term "alkynyl" refers to straight or branched chain hydrocarbon groups having 2 to 12 carbon atoms and at least one triple bond. Alkynyl groups of 2 to 6 carbon atoms and having a triple bond

50 E10001989 10-25-2011

They are the most preferred. The alkyl groups may be substituted as described above for the alkyl groups.

The term "alkylene" refers to bivalent straight or branched chain hydrocarbon groups having 1 to 12 carbon atoms, preferably 1 to 8 carbon atoms, for example {-CH2-} n, where n is of 1 to 12, preferably 1-8. The smaller alkylene groups, that is to say the alkylene groups of 1 to 2 carbon atoms, are the most preferred. The terms "alkenylene" and "alkynylene" refer to bivalent radicals of alkenyl and alkynyl groups, respectively, as defined above. Alkenylene groups may be substituted as described above for all alkyl groups.

The term "alkoxy" refers to an oxygen atom substituted by alkyl, as defined herein. For example, the term "alkoxy" or includes the group -O-C1-6 alkyl.

When a subscript is used in reference to an alkoxy, thioalkyl or aminoalkyl, the subscript refers to the number of carbon atoms that the group may contain in addition to the heteroatoms.

It should be understood that selections for all groups, including, for example, alkoxy, thioalkyl and aminoalkyl, will be made by one skilled in the art to provide stable compounds.

The term "carbonyl" refers to a bivalent carbonyl group -C (= O) -.

The term "acyl" refers to a carbonyl group attached to an organic radical, more particularly the C (= O) Re group, as well as the bivalent C (= O) Re- group, which are attached to organic radicals. The Re group may be selected from alkyl, alkenyl, alkynyl, cycloalkyl, heterocycle, aryl or heteroaryl, as defined herein, or, where appropriate, the corresponding bivalent group, for example alkylene.

The term "cycloalkyl" refers to fully saturated and partially unsaturated hydrocarbon rings (and therefore includes "cycloalkylene rings") from 3 to 9, preferably from 3 to 7, carbon atoms. The term "cycloalkyl" includes rings having zero, two or three substituents selected from (C1-4) alkyl, alkenyl (C2-4), halogen, hydroxy, cyano, nitro, CF3, O (C1-4 alkyl), OCF3 , C (= O) H, C (= O) (C1-4 alkyl), CO2H, CO2 (C1-4 alkyl), NHCO2 (C1-4 alkyl), -S (C1-4 alkyl), NH2, NH (C1-4 alkyl), N (C1-4 alkyl) 2, N (C1-4 alkyl) 3+, SO2 (C1-4 alkyl), C (= O) (C1-4 alkylene) NH2, C (= O) (C1-4 alkylene) NH (alkyl), and / or C (= O) (C1-4 alkylene) N (C1-4 alkyl) 2. The term "cycloalkyl" also includes rings that have a second ring fused thereto (eg, that include benzo, heterocycle or heteroaryl rings) or that have a carbon-carbon bridge of 3 to 4 carbon atoms.

The term "halo" or "halogen" refers to fluorine, chlorine, bromine and iodine.

The term "haloalkyl" means a substituted alkyl having one or more halo substituents. For example, "haloalkyl" includes mono, bi and trifluoromethyl.

The term "haloalkoxy" means an alkoxy group having one or more halo substituents. For example, "haloalkoxy" includes OCF3.

The term "heteroatom" It should include oxygen, sulfur and nitrogen.

The term "aryl" refers to phenyl, biphenyl, fluorine, 1-naphthyl and 2-naphthyl. The term "aryl" includes rings having zero, one, two or three substituents selected from (C1-4) alkyl, alkenyl (C2-4), halogen, hydroxy, cyano, nitro, CF3, O (C1-4 alkyl) , OCF3, C (= O) H, C (= O) (C1-4 alkyl), CO2H, CO2 (C1-4 alkyl),

NHCO2 (C1-4 alkyl), -S (C1-4 alkyl), NH2, NH (C14 alkyl), N (C1-4 alkyl) 2, N (C1-4 alkyl) 3+, SO2 (C1-4 alkyl ), C (= O)

(C1-4 alkylene) NH2, C (= O) (C1-4 alkylene)) NH (alkyl), and / or C = O) (C1-4 alkylene)) N (C1-4 alkyl) 2.

The terms "heterocycle" or "heterocyclic" refers to unsubstituted and non-aromatic substituted (which may be partially or completely saturated) rings of 3 to 15 members having one to four heteroatoms. Such rings may be monocyclic groups of 3 to 7 members, bicyclic groups of 7 to 11 members and tricyclic groups of 10 to 15 members. Each ring of the heterocycle group containing a heteroatom may contain one

or two oxygen or sulfur atoms and / p of one to four nitrogen atoms, provided that the total number of heteroatoms in each ring is four or less and also provided that the ring contains at least one carbon atom. The condensed rings that complete the bicyclic and tricyclic groups may contain only carbon atoms and may be saturated, partially saturated or unsaturated. The nitrogen and sulfur atoms can be optionally oxidized and the nitrogen atoms can optionally be quaternized. The heterocycle group may be attached to any available nitrogen or carbon atom. The heterocycle ring may contain zero, one, two or three substituents selected from (C1-4) alkyl, (C2-4) alkenyl, halogen, hydroxy, cyano, nitro, CF3, O (C1-4 alkyl), OCF3, C (= O) H, C (= O) (C1-4 alkyl), CO2H, CO2 (C1-4 alkyl), NHCO2 (C1-4 alkyl), S (C1-4 alkyl), NH2, NH (C1 alkyl -4), N (C1-4 alkyl) 2, N (C1-4 alkyl) 3+, SO2 (C1-4 alkyl), C (= O) (C1-4 alkylene) NH2,

55 E10001989 10-25-2011

C (= O) (C1-4 alkylene) NH (alkyl), and / or C (= O) (C1-4 alkylene) N (C1-4 alkyl) 2. Examples of heterocyclic groups include azetidinyl, pyrrolidinyl, oxetanyl, imidazolinyl, oxazolidinyl, isoxazolinyl, thiazolidinyl, isothiazolidinyl, tetrahydrofuranyl, piperidyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidyl, 2-oxopyrrolodinyl, 2-oxoazepinyl, azepinyl, 4-piperidonyl, tetrahydropyranyl , morpholinyl, thiamorpholinyl, thiamorpholinyl sulfoxide, thiamorpholinyl sulfone, 1,3-dioxolane, quinuclidinyl and tetrahydro-1,1-dioxothienyl and the like.

The term "heteroaryl" refers to substituted and unsubstituted aromatic rings of 3 to 14 members having one to four heteroatoms selected from O, S or N in at least one of the rings. Said rings may be monocyclic groups of 5 or 6 members, bicyclic groups of 9 or 10 members and tricyclic groups of 11 to 14 members. Each ring of the heteroaryl group containing a heteroatom may contain one or two oxygen or sulfur atoms and / p of one to four nitrogen atoms, provided that the total number of heteroatoms in each ring is four or less and each ring has At least one carbon atom. The condensed rings that complete the bicyclic and tricyclic groups may contain only carbon atoms and may be saturated, partially saturated or unsaturated. The nitrogen and sulfur atoms can be optionally oxidized and the nitrogen atoms can optionally be quaternized. Heteroaryl groups that are bicyclic or tricyclic must include at least one completely aromatic ring, but the other fused ring or rings may be aromatic or non-aromatic. The heteroaryl group may be attached to any available nitrogen or carbon atom of any ring. The heteroaryl ring system may contain zero, one, two or three substituents selected from (C1-4) alkyl, (C2-4) alkenyl, halogen, hydroxy, cyano, nitro, CF3, O (C1-4 alkyl), OCF3 , C (= O) H, C (= O) (C1-4 alkyl), CO2H, CO2 (C1-4 alkyl), NHCO2 (C1-4 alkyl), -S (C1-4 alkyl), NH2, NH (C1-4 alkyl), N (C1-4 alkyl) 2, N (C1-4 alkyl) 3+, SO2 (C1-4 alkyl), C (= O) (C1-4 alkylene) NH2, C (= O) (C1-4 alkylene) NH2, C (= O) (C14 alkylene) NH (alkyl), and / or C (= O) (C1-4 alkylene) N (C1-4 alkyl) 2.

Examples of the heteroaryl group include pirrolilopirazolilo, pyrazolinyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, thiadiazolyl, isothiazolyl, furanyl, thienyl, oxadiazolyl pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, indolyl, benzothiazolyl, benzodioxolyl, benzoxazolyl, benzothienyl, quinolinyl, tetrahydroisoquinolinyl, isoquinolinyl, benzimidazolyl, benzopyranyl, indolizinyl, benzofuranyl, chromonyl, coumarinyl, benzopyranyl, cinnolinyl, quinoxalinyl, indazolyl, pyrrolopyridyl, furopyridyl, dihydroisoindolyl, tetrahydroquinolinyl and the like. Concrete heteroaryl groups include, for example, 6-substituted quinazolin-4-yl and 6-trifluoromethyl-quinazolin-4-yl.

When a group is called "optionally substituted" in this document the term is defined as including a group both substituted and unsubstituted.

The compounds described herein may have asymmetric centers. The compounds of the present invention that contain an asymmetrically substituted atom can be isolated in optically active or racemic forms. It is well known in the art how to prepare forms optically, such as by resolution of racemic forms or by synthesis from optically active starting materials. Many geometric isomers of olefins, C = N double bonds and the like may also be present in the compounds described herein and all these stable isomers are contemplated in the present invention. Cis and trans geometric isomers of the compounds of the present invention have been described and can be isolated as a mixture of isomers or as different isomeric forms. All chiral, diastereomeric, racemic and all geometric isomeric forms of a structure are intended, unless the specific stereochemical or isomeric form is specifically indicated.

An enantiomer of the compounds disclosed herein may show superior activity compared to the other. Therefore, all stereochemistry is considered a part of the present invention. When necessary, separation of racemic material can be achieved by HPLC using a chiral column or by resolution using a resolution agent such as canfonic chloride, as in Steven

D. Young, et al., Antimicrobial Agents and Chemotherapy, 1995, 2602-2605.

The term "pharmaceutically acceptable" is used herein to refer to those compounds, materials, compositions and / or pharmaceutical forms that are, within the scope of good medical judgment, suitable for use in contact with the tissues of the Humans and animals without excessive toxicity, irritation, allergic response or other problems or complications, corresponding to a reasonable percentage of benefit / risk.

As used herein, "pharmaceutically acceptable salts" refers to derivatives of the described compounds in which the parent compound is modified by the preparation of acidic or basic salts thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkaline salts or organic salts of acidic residues such as carboxylic acids; and the like Pharmaceutically acceptable salts include conventional non-toxic salts or quaternary ammonium salts of the parental compound formed, for example, from inorganic or organic non-toxic acids. For example, such conventional non-toxic salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and

55 E10001989 10-25-2011

Similar; and the prepared salts of organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroximaleic, phenylacetic, glutamic, benzoic, salicylic, sulphanilic, 2-acetoxybenzoic, fumaric , toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic, and the like.

The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound containing a basic or acidic moiety by conventional chemical procedures. Generally, such salts can be prepared by reacting the free acidic or basic forms of these compounds with a stoichiometric amount of the appropriate base or the acid in water or an inorganic solvent or in a mixture of the two; Generally, a non-aqueous medium such as ether, ethyl acetate, ethanol, isopropanol or acetonitrile are preferred. The lists of suitable salts are found in Remington’s Pharmaceutical Sciences, ed. 17th, Mack Publishing Company, Easton, PA, 1985, p. 1418, the description of which is incorporated herein by reference.

Since prodrugs are known to potentiate numerous desirable qualities of pharmaceutical products (eg, solubility, bioavailability, manufacture, etc.) the compounds of the present invention can be supplied in the form of a prodrug. In this way, the present invention is intended to cover the currently claimed compounds, methods for delivering them, and compositions containing them. It is thought that the "prodrugs" include any covalently bound vehicle that releases an active parental drug of the present invention in vivo when said prodrug is administered to a mammalian subject. The prodrugs of the present invention are prepared by means of the modification of functional groups present in the compound, such that the modifications are cleaved, either by routine manipulation or in vivo, to the parent compound. Prodrugs include compounds of the present invention in which a hydroxy, amino or sulfhydryl group is attached to any group that, when the prodrug of the present invention is administered to a mammalian subject, cleaves to form a free, free amino, hydroxyl group. or free sulfhydryl, respectively. Examples of prodrugs include, but are not limited to, acetate, format and benzoate derivatives of alcohol and functional amino groups in the compounds of the present invention.

"Stable compound" and "stable structure" are intended to indicate a compound that is sufficiently resistant to survive isolation to a useful degree of purity of a reaction mixture and to the formulation in an effective therapeutic agent. The present invention is intended to contain stable compounds.

"Therapeutically effective amount" is intended to include an amount of a compound of the present invention alone or an amount of the combination of claimed compounds or an amount of a compound of the present invention in combination with other active ingredients effective to inhibit MCP-1 or effective to treat or prevent disorders.

As used herein, "treating" or "treatment" covers a treatment of a disease state in a mammal, particularly in a human being and includes: (a) the prevention of the disease state from occurring in a mammal, in particular, when said mammal is predisposed to the disease state but has not yet been diagnosed as having it; (b) the inhibition of the disease state, that is, the arrest of its development and / or (c) the relief of the disease state, that is, producing the regression of the disease state.

The names used herein to refer to a specific form, for example, "N-2", should not be considered limiting with respect to any other substance that has similar or identical physical and chemical characteristics, but rather should be understood that these denominations are mere identifiers that must be interpreted according to the characterization of the information also presented in this document.

The present invention provides, at least in part, crystalline forms of the free base of N - ((1R, 2S, 5R) –5– (tert-butylamino) –2 - ((S) –2 – oxo – 3– ( 6– (trifluoromethyl) quinazolin-4-ylamino) pyrrolidin-1-yl) cyclohexyl) acetamide, as a new material, in particular, in a pharmaceutically acceptable form. In certain preferred embodiments, the crystalline forms of the free base are in substantially pure form. Preferred embodiments of the crystalline forms of the free base are described in Example 2 as Forms E-1, HAC-1, IPA-1, N-2, RPG-3, H0.5-4, and H1.75 -5.

As used herein, "polymorph" refers to crystalline forms that have the same chemical composition but different spatial configurations of the molecules, atoms and / or ions that form the crystal.

As used herein, "solvate" refers to a crystalline form of a molecule, atom and / or ions that also contain molecules of a solvent or solvents incorporated in the crystalline structure. Solvent molecules may be present in the solvate in a regular configuration and / or in an unordered configuration. The solvate may comprise a stoichiometric or non-stoichiometric amount of the molecules of

55 E10001989 10-25-2011

solvent For example, a solvate with a non-stoichiometric amount of solvent molecules may be the result of the partial loss of solvent from the solvate.

As used herein, "amorphous" refers to a solid form of a molecule, atom and / or ions that is not crystalline. An amorphous solid does not have a definitive X-ray diffraction pattern.

As used herein, "substantially pure", when used in reference to a crystalline form, means a compound having a purity greater than 90% by weight, including greater than 90, 91, 92, 93, 94, 95, 96, 97, 98 and 99% by weight, and also includes about 100% by weight of the compound, based on the weight of the compound. The remaining material comprises another form (s) of the compound and / or the impurities of the reaction and / or the impurities of the processing that arise from its preparation. For example, a crystalline form of N - ((1R, 2S, 5R) –5– (tert-butylamino) –2 - ((S) –2 – oxo – 3– (6– (trifluoromethyl) quinazolin – 4 – ylamino ) pyrrolidin-1-yl) cyclohexyl) acetamide, can be considered substantially pure in that it has a purity greater than 90% by weight, as measured by means that are known at this time and are generally accepted in the art, in which less of the remaining 10% of material by weight comprises another form (s) of N - ((1R, 2S, 5R) –5– (tert-butylamino) –2– ((S) –2 – oxo – 3– (6 - (trifluoromethyl) quinazolin-4-ylamino) pyrrolidin-1-yl) cyclohexyl) acetamide, and / or reaction impurities and / or processing impurities.

Samples of the crystalline forms may be provided with substantially pure phase homogeneity, indicating the presence of a dominant amount of a single crystalline form and optionally smaller amounts of one or more other crystalline forms. The presence of more than one crystalline form in a sample can be determined by techniques such as powder X-ray diffraction (PXRD) or solid-state nuclear magnetic resonance spectroscopy (SSNMR). For example, the presence of extra peaks in comparison with an experimentally measured PXRD pattern with a stimulated PXRD pattern may indicate more than one crystalline form in the sample. The stimulated PXRD can be calculated from a single X-ray data per crystal. See Smith, D. K., “A FORTRAN Program for Calculating X – Ray Powder Diffraction Patterns”, Lawrence Radiation Laboratory, Livermore, California, UCRL – 7196 (April 1963).

Preferably, the crystalline form has a substantially pure phase homogeneity as indicated by less than 10%, preferably less than 5% and more preferably less than 2% of the total peak area in the experimentally measured PXRD pattern arising from the peaks. extras that are absent in the stimulated PXRD pattern. More preferably it is a crystalline form that has a substantially pure phase homogeneity with less than 1% of the total peak area in the experimentally measured PXRD pattern that arises from the extra peaks that are absent in the stimulated PXRD pattern.

Procedures for the preparation of crystalline forms are known in the art. Crystalline forms can be prepared by a variety of procedures, including for example, crystallization or recrystallization of a suitable solvent, sublimation, development from a molten material, transformation to the solid state from another phase, crystallization. of a supercritical fluid and jet spray. Techniques for crystallization or recrystallization of crystalline forms from a solvent mixture include, for example, evaporation of the solvent, decrease of the temperature of the solvent mixture, placement of the supersaturated solvent mixture of the molecule and / or salt in seminal crystals, freeze drying of the solvent mixture and the addition of anti-solvents (counter-solvents) to the solvent mixture.

The shapes can be characterized and distinguished using a single X-ray diffraction by crystals, which is based on single-cell unit cell measurements of a shape at a set analytical temperature. A detailed description of the unit cells is provided in Stout & Jensen, X – Ray Structure Determination: A Practical Guide, Macmillan Co., New York (1968), Chapter 3, which is incorporated herein by reference. Alternatively, the only configuration of atoms in the spatial relationship within the crystalline network can be characterized according to the observed fractional atomic coordinates. See reference Stout & Jensen for the experimental determination of fractional coordinates for structural analysis. Other means of characterizing the crystalline structure are by analyzing the powder X-ray diffraction in which the experimental or observed diffraction profile is compared with a stimulated profile representing the pure powder material, both at the same analytical temperature and the measures for the subject form characterized as series of values of 28 and intensities.

The expression "insignificant weight loss", as used herein, as characterized by TGA indicates the presence of a pure (non-solvated) crystal form.

The expression "% insignificant water uptake", as used herein, as characterized by the moisture sorption isotherm indicates that the tested form is not hygroscopic.

In one embodiment of the invention, a crystalline form of N - ((1R, 2S, 5R) –5– (tert-butylamino) –2 - ((S) –2 – oxo – 3– (6– (trifluoromethyl) quinazolin -4-ylamino) pyrrolidin-1-yl) cyclohexyl) acetamide is provided in a form

55 E10001989 10-25-2011

substantially pure. This crystalline form can be used in pharmaceutical compositions that may optionally include one or more other components selected, for example, from the group consisting of excipients, vehicles and one of other pharmaceutically active ingredients or active chemical entities of different molecular structures.

Preferably, the crystalline form has a substantially pure phase homogeneity as indicated by less than 10%, preferably less than 5%, and more preferably less than 2% of the total peak area in the experimentally measured PXRD pattern arising from the extra peaks that are absent in the stimulated PXRD pattern. More preferably it is a crystalline form that has a substantially pure phase homogeneity with less than 1% of the total peak area in the experimentally measured PXRD pattern that arises from the extra peaks that are absent in the stimulated PXRD pattern.

In another embodiment, a composition is provided which is essentially constituted of the crystalline forms of N - ((1R, 2S, 5R) -5- (tert-butylamino) -2 - ((S) -2-oxo-3- ( 6– (trifluoromethyl) quinazolin-4-ylamino) pyrrolidin-1-yl) cyclohexyl) acetamide. The composition of this embodiment may comprise at least 90% by weight of the form, which is based on its weight in the composition.

The presence of reaction impurities and / or processing impurities can be determined by analytical techniques known in the art, such as, for example, chromatography, nuclear magnetic resonance spectroscopy, mass spectroscopy or infrared spectroscopy.

The crystalline forms can be prepared by a variety of procedures, including for example, crystallization or recrystallization from a suitable solvent, sublimation, development from a molten material, transformation to the solid state from another phase, crystallization from a supercritical fluid and jet spraying. Techniques for crystallization or recrystallization of crystalline forms from a solvent mixture include, for example, evaporation of the solvent, lowering the temperature of the solvent mixture, placing a supersaturated solvent mixture of the molecule and / or salt in seminal crystals, freeze drying of the solvent mixture and the addition of anti-solvents (counter-solvents) to the solvent mixture. High performance crystallization techniques can be used to prepare crystalline forms including polymorphs.

Drug crystals, including polymorphs, preparation procedures and characterization of drug crystals are analyzed in Solid-State Chemistry of Drugs, S. R. Byrn. R. R. Pfeiffer and J. G. Stowell, 2nd Edition, SSCI, West Lafayette, Indiana (1999).

For crystallization techniques employing solvents, the choice of solvent or solvents typically depends on one or more factors, such as the solubility of the compounds, the crystallization technique and the vapor pressure of the solvent. Solvent combinations can be used; for example, the compound can be solubilized in a first solvent to provide a solution, followed by the addition of an anti-solvent to decrease the solubility of the compound in the solution and to provide crystal formation. An "anti-solvent" is a solvent in which the compound has low solubility. Suitable solvents for preparing crystals include polar and non-polar solvents.

In a process for preparing crystals, N - ((1R, 2S, 5R) –5– (tert-butylamino) –2 - ((S) –2 – oxo – 3 - ((- (trifluoromethyl) quinazolin-4-ylamino ) pyrrolidin-1-yl) cyclohexyl) acetamide, is suspended and / or stirred in a suitable solvent to provide a suspension, which can be heated to promote dissolution The term "suspension", as used herein, means a saturated solution of the free base, which may also contain an additional amount of the compound to provide a heterogeneous mixture of the compound and a solvent at a given temperature. Suitable solvents in this regard include, for example, aprotic polar solvents and polar solvents Prosthetics and mixtures of two or more of these, as described herein.

The seminal crystals can be added to any crystallization mixture to promote crystallization. As will be apparent to the person skilled in the art, seeding is used as a means of controlling the growth of a particular crystalline form or as a means of controlling the particle size distribution of the crystalline product. Therefore, the calculation of the quantity of seeds needed depends on the size of available seed and the desired size of an average product particle as described, for example, in "Programmed cooling of batch crystallizes", J.W. Mullin and J. Nyvlt, Chemical Engineering Science 1971, 26: 369 -

377. In general, small-sized seeds are needed to effectively control the growth of crystals in the batch. Small seeds can be generated by sieving, grinding or micronizing larger crystals or by microcrystallizing solutions. Care must be taken that grinding or micronizing crystals does not result in any change in the crystallinity of the desired crystalline form (i.e., change to amorphous or other polymorph).

55 E10001989 10-25-2011

A cooled mixture can be filtered under vacuum, and the isolated solids can be washed with a suitable solvent, such as cold recrystallization solvent, and dried in a nitrogen purge to provide the desired crystalline form. The solids isolated can be analyzed with a suitable spectroscopic or analytical technique, such as SSNMR, DSC, PXRD or the like, to ensure the formation of the preferred crystalline form of the product. The resulting crystalline form is typically produced in an amount of more than about 70% by weight of isolated yield, but preferably more than 90% by weight based on the weight of N - ((1R, 2S, 5R) –5– ( tert-butylamino) –2 - ((S) –2 – oxo-3– (6– (trifluoromethyl) quinazolin-4-ylamino) pyrrolidin-1-yl) cyclohexyl) acetamide, originally used in the crystallization process. The product can be co-milled or passed through a mesh sieve to deagglomerate the product, if necessary.

Crystalline forms can be prepared directly from the reaction medium of the final process step to prepare N - ((1R, 2S, 5R) -5- (tert-butylamino) -2 - ((S) -2-oxo-3 - (6– (trifluoromethyl) quinazolin-4-ylamino) pyrrolidin-1-yl) cyclohexyl) acetamide. This can be achieved, for example, by using a solvent in the final process stage

or solvent mixture from which the free base can crystallize. Alternatively, the crystalline forms can be obtained by distillation or solvent addition techniques. Suitable solvents for this purpose include any of the solvents described herein, including polar protic solvents, such as alcohols, and polar aprotic solvents, such as ketones.

As a general guideline, the reaction mixture can be filtered to remove any unwanted impurity, inorganic salts, and the like, followed by washing with a reaction solvent or crystallization. The resulting solution can be concentrated to remove excess solvent or gaseous constituents. If distillation is used, the last amount of distillate collected may vary, depending on process factors including, for example, vessel size, stirring capacity, and the like. As a general guideline, the reaction solution can be distilled at approximately 1/10 of the original volume before solvent replacement is performed. Samples of the reaction can be taken and tested to determine the degree of reaction and the weight% of product according to conventional processing techniques. If desired, a reaction solvent can be added or removed to optimize the concentration of the reaction. Preferably, the final concentration is adjusted to about 50% by weight, at which point a suspension is typically formed.

It may be preferable to add solvents directly to the reaction vessel without distilling the reaction mixture. Preferred solvents for this purpose are those that ultimately participate in the crystalline lattice structure, as discussed above with respect to solvent exchange. Although the final concentration may vary depending on the desired purity, recovery and the like, the final concentration of the free base in solution is preferably from about 4% to about 7%. The reaction mixture may be stirred followed by solvent addition and simultaneous heating. By way of illustration, the reaction mixture can be stirred for about 1 hour while heating to about 70˚C. The reaction is preferably filtered while remaining hot and washed with the reaction solvent, the added solvent or a combination thereof. Seminal crystals can be added to any crystallization solution to initiate crystallization.

The various forms described herein can be distinguished from each other through the use of various analytical techniques known to a person skilled in the art. Such techniques include, but are not limited to, X-ray powder diffraction (PXRD), and / or thermogravimetric analysis (TGA). Specifically, the shapes can be characterized and distinguished using single crystal X-ray diffraction, which is based on single cell measurements of a single crystal in a given way at a fixed analytical temperature. A detailed description of unit cells is provided in Stout & Jensen, X – Ray Structure Determination: A Practical Guide, Macmillan Co., New York (1968), Chapter 3, which is incorporated herein by reference. As an alternative, the unique arrangement of atoms in spatial relationship within the crystalline lattice structure can be characterized according to the observed fractional atomic coordinates. Another means to characterize the crystalline structure is by powder X-ray diffraction analysis in which the diffraction profile is compared with a simulated profile representing the pure powder material, both are developed at the same analytical temperature, and measurements for The object form is characterized as a series of values 28 (usually four or more).

Another means can be used to characterize the shape, such as solid-state nuclear magnetic resonance spectroscopy (SSNMR), differential scanning calorimetry (DSC), thermography and gross recognition of crystalline or amorphous morphology. These parameters can also be used in combination to characterize the object form.

One skilled in the art will appreciate that an X-ray diffraction pattern can be obtained with a measurement error that depends on the measurement conditions employed. In particular, it is generally known that the intensities in an X-ray diffraction pattern may fluctuate depending on the measurement conditions employed and the shape and morphology of the crystal. It should also be understood that the relative intensities may also vary depending on the experimental conditions and, therefore, the

30 E10001989 10-25-2011

exact order of intensity. Additionally, a diffraction angle measurement error for a conventional X-ray diffraction pattern is typically about 0.2˚ or less, preferably about 0.1˚ (as discussed hereinafter) , and said degree of measurement error must be taken into account as concerning the diffraction angles mentioned above. Accordingly, it should be understood that the crystal forms of the present invention are not limited to the crystal forms that provide X-ray diffraction patterns completely identical to the X-ray diffraction patterns depicted in the attached Figures described herein. . Any crystal form that provides X-ray diffraction patterns substantially identical to those described in the accompanying figures is within the scope of the present invention. The ability to determine substantial identities of X-ray diffraction patterns is within the scope of a person skilled in the art.

Synthesis

Scheme 1

Hydrolysis of ketoester V to keto acid VI

Ketoester V is hydrolyzed to its corresponding keto acid VI by suspending V in an organic solvent partially miscible with water, such as cyclic or acyclic ethers including THF, 2-methyl THF, 1,2-dimethoxyethane, 1,4-dioxane, with preferred THF, and adding an aqueous base such as aqueous solutions of MOH alkali metal hydroxides, in which M is Li, Na or K, with 1N NaOH being the preferred base, from -5˚C to + 5˚C. The biphasic mixture is then stirred at: 5 ° C for at least one hour. The low temperature for the addition and reaction of the base is important to minimize the epimerization in the carbon adjacent to the ester group. Then a solvent not miscible with water is added, preferably methyl tert-butyl ether and the phases are separated. The product is then transferred from the aqueous solution back to the organic solvent, preferably dichloromethane, by adjusting the pH with acid, preferably 3N HCl, and VI is used in solution for the next step.

Scheme 2

Ketalization of keto acid VI to ketal acid VII

The VI solution, preferably in dichloromethane, is exchanged through distillation in a higher, non-hygroscopic boiling solvent, such as toluene, trifluorotoluene, xylenes, higher boiling esters such as n-butyl acetate or isobutyl acetate, preferably Toluene. A glycol of the formula HO-Z-OH is then added, (in which Z is as defined supra), preferably ethylene glycol (1.2 eq), followed by a catalytic amount (0.5-2 M%) of an acid, preferably p-toulenesulfonic acid, and the mixture is distilled at atmospheric pressure until the formation of compound VII is complete. Product VII crystallizes after the addition of ethyl acetate after cooling to approximately 70 ° C. After further cooling to room temperature, VII is isolated by filtration and subsequent drying in approximately 70% yield (for HO (CH2) 2OH, R1 = H, R2 = CBz).

Scheme 3

Transformation of acid ketal VII to non-isolated isocyanate ketal VIII and then to ketal amide IX through acid activation / azidation, Curtius rearrangement and acylation

Ketoacid VII is first activated by its transformation to its mixed anhydride using tertiary amines, preferably triethylamine, and haloformates, preferably isobutyl chloroformate in dry solvents, such as toluene, trifluorotoluene, 1,2-dichloroethane, 1-chlorobutane, xylenes, preferably dry toluene, by adding a haloformate to a pre-cooled solution of VII and trialkylamine. The preferred temperature for mixed anhydrous formation is from –10˚C to 0˚C. After about 30 minutes, an aqueous solution of alkali metal azide, preferably ~ 30% by weight sodium azide and a phase transfer catalyst, such as tetralkylammonium salts, preferably tetrabutylammonium bromide (5 mol%) ) and the biphasic mixture is stirred vigorously for approximately 1h from –10˚C to 0˚C. Then the organic phase is separated and the acyl azide solution is dried, 4 Å molecular sieves being preferred as drying agent. Concomitant transposition and entrapment of isocyanate VIII in situ with a carboxylic acid to form a ketal amide IX is carried out by first adding a carboxylic acid, preferably acetic acid and its corresponding anhydride, until a dry solution of the acyl azide is obtained, and after

20 by heating the mixture from 80˚ to 90˚C for 1 to 4 hours. The use of an anhydride together with carboxylic acid is critical to minimize the formation of impurities. After partially removing the solvent and carboxylic acid by distillation, the product crystallizes after cooling to room temperature. IX is isolated by filtration and dried in 65% -78% yield (for Z = - (CH2) 2–, R1 = H, R2 = CBz, R10 = Me).

Scheme 4

25 Hydrolysis of ketal amide IX to ketoamide X

The ketal hydrolysis of compound IX to ketoamide X is carried out by heating a solution of IX in organic solvent, water miscible, preferably acetone and an aqueous solution of strong acid, preferably 1N HCl, for 2-4 hours. The preferred temperature for hydrolysis is 45˚C - 55˚C. After removing the acetone, the product is extracted to dichloromethane, which is exchanged to ethyl acetate by distillation. Product X crystallizes from ethyl acetate after cooling to room temperature, and is isolated by filtration and drying in yield.

85% - 90% (for HO (CH2) 2OH, R1 = H, R2 = CBz, R10 = Me).

Scheme 5 Reduction amination of ketoamide X to amino acid XI

To a dry solution of X, preferably in dichloromethane, a primary or secondary amine is added, preferably tert-butylamine (5 eq), followed by a Lewis acid, preferably TiCl2 (OPr-i) 2 (1.2 eq), from –20˚C to 0˚C. The resulting imine mixture is heated to 10˚C-20˚C and borane (1.1-1.2 eq) is added as a complex with dimethyl sulphide or THF, preferably dimethyl sulphide. The reaction mixture is stirred for 4-6 hours and then ethyl acetate saturated with water is added. Titanium salts are removed by

10 filtration and product XI is extracted from the organic filtrate to water in the form of its salt with an aqueous acid, preferably 1N HCl. Dichloromethane and aqueous base, preferably concentrated ammonium hydroxide, are then added to the concentrated biphasic mixture until the pH is adjusted to 8.0-8.5. The product-rich dichloromethane phase is then separated and washed twice with aqueous ammonium chloride solution to remove the unwanted trans isomer of XI, and finally with water. The dichloromethane is exchanged in ethyl acetate for

Distillation and XI crystallizes from ethyl acetate after cooling and addition of heptane. XI is isolated by filtration and dried in 65% -70% yield (for R1 = H, R2 = CBz, R8 = H, R9 = tert-Bu, R10 = Me).

Scheme 6

Deprotection of pyrrolidonyl amine XI

The removal of the amine protection group R2, in which R2 is CO2CH2Ph or CH2Ph, is carried out by hydrogenating a solution of XI in an alcohol, preferably methanol, in the presence of Pd catalyst, preferably Pd / C 5% by weight for several hours. The catalyst is then removed by filtration, and the methanol is exchanged in ethyl acetate by distillation. Product XII, which crystallizes from ethyl acetate after cooling and the addition of heptane, is isolated by filtration and dried in 90% -95% yield (for

R1 = H, R2 = CBz, R8 = H, R9 = tert-Bu, R10 = Me).

Scheme 7

Amine XII coupling with heterocycle that supports a HET-LG leaving group

40 E10001989 10-25-2011

The synthesis of compound I is carried out by coupling pyrrolidonylamine XII and a heterocycle that supports a leaving group in the presence of a tertiary amine, preferably triethylamine, in a compatible solvent, such as dichloromethane, isopropanol or acetonitrile, dichloromethane being preferred . Therefore, all components are combined and the solution is reacted for 24-48 hours at room temperature. A previously prepared crude heterocyclic component solution can also be used. After completion of the reaction, the dichloromethane is washed with dilute acid, preferably 5% by weight aqueous acetic acid, the aqueous phase is separated and the dichloromethane is then exchanged in ethyl acetate by distillation. The product I, which crystallizes from ethyl acetate after cooling and the addition of heptane, is isolated by filtration and dried in 75% -80% yield (for R1 = H, R8 = H, R9 = tert-Bu , R10 = Me, H ET = 6– (trifluoromethyl) quinazolin-4-yl).

For the process of the present invention, the starting materials are commercially available or can easily be prepared by a person skilled in the art. Solvents, temperatures, pressures, starting materials having the desired groups, and other reaction conditions, can easily be selected as appropriate by a person skilled in the art. The process can be extended in order to prepare larger amounts of the compound of formula I, such as in a commercial production facility.

Examples

The following Examples illustrate embodiments of the compounds and starting materials of the invention, and are not intended to limit the scope of the claims.

Where appropriate, the reactions were performed in an atmosphere of dry nitrogen (or argon). For the anhydrous reactions, EM Dri-Solv solvents were used. For other reactions, reactive quality or HPLC quality solvents were used. Unless stated otherwise, all reagents obtained on the market were used as received.

The LC / MS measurements were obtained using a Shimadzu HPLC / Waters ZQ hybrid single quadrupole mass spectrometer system. The data for the peak of interest are indicated from electrospray ionization in positive mode. NMR (nuclear magnetic resonance) spectra were typically obtained on 400 MHz and 500 MHz Bruker or JEOL instruments in the indicated solvents. All chemical shifts are indicated in ppm from tetramethylsilane with solvent resonance as internal standard. 1H NMR spectral data is typically indicated as follows: chemical shift, multiplicity (s = singlet, sa = wide singlet, d = doublet, dd = doublet doublet, t = triplet, c = quadruplet, sept. = Septuplete, m = multiplet, ap. = apparent), coupling constants (Hz) and integration.

A person skilled in the art will recognize the conventional abbreviations used herein, through the specification. For ease of reference, the abbreviations include, but are not necessarily limited to: saturated = saturated, HPLC = high performance liquid chromatography, PA = percentage of area, KF = Karl-Fischer, TA = room temperature, mmol = millimoles, EMAR = high resolution mass spectroscopy. TBTU = O-benzotriazol-2-yl-N, N, N ', N'-tetramethyluronium tetrafluoroborate, MTBE = TBME = tert-butyl methyl ether, EDAC = N- (3-dimethylaminopropyl) hydrochloride-N'-ethylcarbodiimide , EDC = N– (3-dimethylaminopropyl) - N'-ethylcarbodiimide, TEA = triethylamine, DPPA = diphenyl phosphoryl azide, IPA = isopropyl alcohol, TFA = trifluoroacetic acid, DCM = dichloromethane, THF = tetrahydrofuran, DMF = N, N– dimethylformamide, BOP = (benzotriazol-1-yloxy) tris (dimethylamino) phosphonium hexafluorophosphate, EtOAc = ethyl acetate, DMSO = dimethylsulfoxide. ˚C = degrees Celsius, eq. = equivalent or equivalent, g = gram or grams, mg = milligram or milligrams, ml = milliliter or milliliters, h = hour or hours, M = molar, N = normal, min = minute or minutes, MHz = megahertz, tlc = chromatography thin layer and v / v = volume to volume ratio, and approximately =

45 E10001989 10-25-2011

approximately. "A", "w", "R" and "S" are stereochemical designations familiar to those skilled in the art.

Example 1

N - ((1R, 2S, 5R) –5– (tert-butylamino) –2 - ((S) –2 – oxo – 3– (6– (trifluoromethyl) quinazolin – 4-ylamino) pyrrolidin – 1– il) cyclohexyl) acetamide

Example 1, Stage 1: 2-Benzyloxycarbonylamino-7-oxo-6-aza-bicyclo [3.2.1] octane-6-carboxylate (1R, 2S, 5R) -terc-butyl (89.6 g, 0 , 24 mol, see: PH Carter, et al. PCT application WO 2005/021500) in ethyl acetate (1.5 L) and the resulting solution was washed with saturated NaHCO3 (2 x 0.45 L) and saturated NaCl ( 1 x 0.45 l). The solution was dried (Na2SO4) and then filtered directly into a 3 l round bottom 3-neck flask. The solution was purged with a direct nitrogen injection before being charged with 10% Pd / C (13.65 g) under a nitrogen atmosphere. The flask was evacuated and recharged with hydrogen; This was repeated two more times. Hydrogen was bubbled through the solution for 30 min and then the reaction was stirred under an H2 atmosphere for 18 h. The flask was evacuated, recharged with nitrogen and charged with fresh catalyst (6 g of 10% Pd / C). Hydrogen was bubbled through the solution for 30 min and then the reaction was stirred under an H2 atmosphere for 18 h. The flask was evacuated and recharged with nitrogen. The mixture was filtered through Celite; then, the filter layer was washed with ethyl acetate. The filtrate (volume of ~ 1.6 L of EtOAc) was diluted with acetonitrile (0.3 L) and loaded sequentially with L-N-Cbz-methionine (68 g, 0.24 mol), TBTU (77 g, 0.24 mol) and N, N-diisopropylethylamine (42 ml, 0.24 mol). The reaction was stirred at room temperature for 4 h, during which time it changed from a suspension to a clear solution. The reaction was quenched with the addition of saturated NH4Cl (0.75 L) and water (0.15 L); The mixture was further diluted with EtOAc (0.75 L). The phases were mixed and separated and the organic phase was washed with saturated Na2CO3 (2 x 0.9 L) and saturated NaCl. (1 x 0.75 l). The solution was dried (Na2SO4), filtered and concentrated in vacuo, giving 2 - ((S) -2- (benzyloxycarbonylamino) -4- (methylthio) butanamide) -7-oxo-6-aza-bicyclo [3.2. 1] octane-6-carboxylate of (1R, 2S, 5R) -terc-butyl in the form of an oil, which was collected in the next step without further purification. LC / MS for the main peak: [M – Boc + H] + = 406.3; [M + Na] + = 528.3. 1H NMR (400 MHz, d4 – MeOH): • 7.36 (m, 5H), 5.11 (s, 2H), 4.32 (m, 1H), 4.2 (m, 1H), 4, 0 (m, 1H), 2.5-2.7 (m, 3H), 2.25 (m, 1H), 2.11 (s, 3H), 2.05 (m, 4H), 1.9 (m, 1H), 1.7 (m, 2H), 1.54 (s, 9H). EtOAc [1.26 (t), 2.03 (s), 4.12 (c)] and N, N, N, N-tetramethylurea [2.83 (s)] are also present.

Example 1, Stage 2: A sample of 2 - ((S) –2– (benzyloxycarbonylamino) –4– (methylthio) butanamide) –7 – oxo – 6 – aza– bicyclo [3.2.1] octane – 6 – carboxylate (1R, 2S, 5R) -terc-butyl (0.24 mol course; see previous procedure) was dissolved in iodomethane (1,250 g) and stirred for 48 h at room temperature. The reaction was concentrated in vacuo. The residue was dissolved in dichloromethane and concentrated in vacuo. This was repeated two more times. The resulting sludge was dissolved in dichloromethane (0.4 L) and poured into a solution with rapid stirring of MTBE (4.0 L). The resulting yellow solids were collected by suction filtration and dried under high vacuum to provide the sulphonium salt (179 g). This material was collected in the next step without further purification. LC / MS for the main peak: [M – Me2S + H] + = 458.4; [M] + = 520.4. 1H NMR (400 MHz, d4 – MeOH): � 7.35 (m, 5H), 5.09 (s, 2H), 4.33 (m, 1H), 4.28 (m, 1H), 3, 98 (m, 1H), 3.3-3.45 (m, 2H), 2.97 (s, 3H), 2.94 (s, 3H), 2.78 (m, 1H), 2.0 - 2.3 (m, 4H), 1.7 (m, 2H), 1.52 (s, 9H). MTBE [1.18 (s), 3.2 (s)] and indications of N, N, N, N-tetramethylurea [2.81 (s)] are also present.

Example 1, Step 3: All the sulfonium salt of the previous stage (0.24 mol assumed) was dissolved in DMSO (2.0 L). The resulting solution was stirred under a nitrogen atmosphere at room temperature and charged portionwise with cesium carbonate (216 g). The suspension was stirred at room temperature for 3 h and then filtered to remove solids. The solution was divided into portions of ~ 0.22 l and treated as follows: the reaction mixture (~ 0.22 l) was diluted with ethyl acetate (1.5 l) and washed successively with water (3 x 0 , 5 l) and brine (1 x 0.3 l). The organic phase was dried (Na2SO4), filtered and concentrated in vacuo. The 2 - ((S) –3– (benzyloxycarbonylamino) –2 – oxopyrrolidin– 1-yl) –7 – oxo – 6 – azabicyclo [3.2.1] octane – 6 – carboxylate of (1R, 2S, 5R) –terc -Butyl desired (90.8 g, 83%) was obtained in the form of a microcrystalline foam, free of tetramethylurea impurities. LC / MS for the main peak: [M– Boc + H] + = 358.4; [M + Na] + = 480.4. 1H NMR (400 MHz, d4 – MeOH): 5 7.35 (m, 5H). 5.12 (s, 2H), 4.35 (m, 2H), 4.2

55 E10001989 10-25-2011

(m, 1H), 3.6 (m, 1H), 3.3 (m, 1H), 2.64 (m, 1H), 2.28-2.42 (m, 2H), 2.15 ( m, 1H), 1.7-2.0 (m, 5H), 1.55 (s, 9H). If desired, this material can be isolated as a solid by dissolving in MTBE (1 volume), adding to heptane (3.3 volumes) and collecting the resulting precipitate.

Example 1, Step 4: A stirring solution of 2 - ((S) –3– (benzyloxycarbonylamino) –2 – oxopyrrolidin – 1-yl) –7 – oxo– 6 – azabicyclo [3.2.1] octane-6-carboxylate of (1R, 2S, 5R) -terc-butyl (108 g, 0.236 mol) in THF (1 L) was charged with lithium hydroxide monohydrate (21.74 g, 0.519 mol). Water (0.3 L) was added slowly, so that the temperature did not exceed 20 ° C. The reaction was stirred at room temperature overnight and the volatiles were removed in vacuo. The pH was adjusted to ~ 4 by the addition of 1 N HCl (450 ml) and NaH2PO4. The resulting white precipitates were collected by filtration and washed with water (2 x 1 L). The solid was dissolved in dichloromethane (1.5 L) and water (1 L). The organic phase was dried (Na2SO4), filtered and concentrated in vacuo. The residue was dissolved in EtOAc (0.7 L) and the resulting solution was heated at reflux for 1 h. After cooling to RT, the solids were separated and collected by filtration. These solids were purified by recrystallization from isopropanol, providing the desired (1R, 2S, 5R) -2 - ((S) -3- (benzyloxycarbonylamino) -2-oxopyrrolidin-1-yl) -5- (tert-butoxycarbonylamino) cyclohexanecarboxylic acid in form of a white solid (104.5 g, 93% yield). LC / MS for the main peak: [M – tBu + H] + = 420.2; [M – Boc + H] + = 376.2; [M + H] + = 476.2. 1H NMR (400 MHz, d4 – MeOH): � 7.35 (m, 5H), 5.11 (s, 2H), 4.35 (m, 2H), 3.71 (m, 1H), 3, 45-3.6 (m, 2H), 2.99 (m, 1H), 2.41 (m, 1H), 2.15 (m, 1H), 2.0 (m, 2H), 1.6 -1.9 (m, 4H), 1.46 (s, 9H).

Example 1, Step 5: A 3 l round bottom flask was charged with acid (1R, 2S, 5R) -2 - ((S) -3- (benzyloxycarbonylamino) -2-oxopyrrolidin-1-yl) -5– (tert-butoxycarbonylamino) cyclohexanecarboxylic acid (75.5 g, 0.158 mol), EDC • HCl (33.5 g, 0.175 mol), 1-hydroxybenzotriazole (23.6 g, 0.175 mol) and dichloromethane (1 L). The reaction was stirred at room temperature for 2 h, during which time it changed from a white suspension to a clear solution. Ammonia (gas) was bubbled through the solution until the pH was strongly basic (paper) and the reaction was stirred for 10 min; This ammonia addition was repeated and the reaction was stirred for a further 10 minutes. Water was added. Before concentrating in vacuo, the organic phase was washed with saturated NaHCO3, NaH2PO4 and brine. The residue was suspended with acetonitrile (0.5 L) and then concentrated, giving (1R, 2S, 5R) -2 - ((S) -3- (benzyloxycarbonylamino) -2-oxopyrrolidin-1-yl) -5- (tert-butoxycarbonylamino) cyclohexanecarboxamide in the form of a white solid (75.9 g, ~ 100%), which was used in the next step without further purification. LC / MS for the main peak: [M – Boc + H] + = 375.3; [M + H] + = 475.4. [M – tBu + H] + = 419.3, 1H NMR (400 MHz, d4 – MeOH): ,3 7.35 (m, 5H), 5.11 (s, 2H), 4.25 (m, 2H ), 3.70 (m, 1H), 3.6 (m, 1H), 3.45 (m, 1H), 2.91 (m, 1H), 2.38 (m, 1H), 2.12 (m, 1H), 1.9

- 2.05 (m, 2H), 1.65 - 1.9 (m, 4H), 1.46 (s, 9H).

Example 1, Step 6: The reaction was performed in three equal portions and combined for aqueous treatment. A round bottom flask with 3 mouths of 5 l was charged with (1R, 2S, 5R) –2 - ((S) –3– (benzyloxycarbonylamino) –2– oxopyrrolidin – 1-yl) –5– (tert-butoxycarbonylamino ) cyclohexanecarboxamide (25.3 g, 53 mmol), acetonitrile (1.9 l) and 2.6 l of water / ice. The mixture was stirred and cooled to 0 ° C. Iodobenzene diacetate (25.77 g, 80 mmol) was added and the reaction was stirred for 2 h; another 0.5 eq. of iodobenzene diacetate. The reaction was stirred for 9 h (reaction temperature <10˚C). The mixture was loaded with 8 eq. of N, N-diisopropylethylamine and 2 equiv. of acetic anhydride. During the next thirty minutes, 4 eq. of N, N-diisopropylethylamine and 2 eq. of acetic anhydride every ten minutes until the reaction is complete (HPLC). The acetonitrile was removed in vacuo; Some liquid was separated from the residue and this was collected by filtration. The remaining residue was extracted with dichloromethane (3 L, then 1 L). The organic phase was washed sequentially with water, saturated NaHCO3 and brine. The collected solids were added to the organic phase, together with activated carbon (15 g). The mixture was stirred for 30 minutes at 40˚C before filtering and concentrating in vacuo. The residue was dissolved in EtOAc (1 L) and the resulting solution was stirred at 75 ° C for 1 h before being allowed to cool to room temperature. A solid was separated and collected by filtration. This solid was further purified by recrystallization: it was first dissolved in 0.5 L of CH2CI2, then concentrated in vacuo and then recrystallized from 1 L of EtOAc; This was repeated three times. The solids obtained from the mother liquors from before were recrystallized three times using the same procedure. The combined solids were recrystallized twice more in acetonitrile (0.7 L), providing 66 g (84%) of (1R, 3R, 4S) -3-acetamido-4 - ((S) -3- (benzyloxycarbonylamino) - Tert-Butyl 2-oxopyrrolidin-1-yl) cyclohexylcarbamate (with a purity of> 99.5% by HPLC). LC / MS for the main peak: [M + H] + = 489.4; [M – tBu + H] + = 433.3. 1H NMR (400 MHz, d4 – MeOH): � 7.3-7.4 (m, 5H), 5.11 (s, 2H), 4.35 (m, 1H), 4.15 (m, 1H ), 4.04 (m, 1H), 3.8 (m, 1H), 3.6 (m, 2H), 2.44 (m, 1H), 2.12 (m, 1H), 1.87 - 2.05 (m, 4H), 1.87 (s, 3H), 1.55 - 1.7 (m, 2H), 1.46 (s, 9H). The stereochemical fidelity of the Hofmann transposition was confirmed through the analysis of the X-ray crystal structure of this compound, as shown in Figure 1.

Example 1, Step 7: To a solution of (1R, 3R, 4S) -3-acetamido-4 - ((S) -3- (benzyloxycarbonylamino) -2-oxopyrrolidin-1-yl) cyclohexylcarbamate of tert-butyl (100 g, 0.205 mol) in dichloromethane (400 ml) TFA (400 ml) was added at -20˚C. The reaction solution was stirred for 2 h at room temperature. The solvent and most of the TFA were removed under reduced pressure, and the residue was diluted with dichloromethane (2 L) and aqueous K2CO3 solution (2 L). The pH was adjusted to 10 with 1N HCl. The aqueous phase was extracted with dichloromethane (3 x 1 L). The combined organic phase was dried over Na2SO4, and concentrated to provide (S) -1 - ((1S, 2R, 4R) -2-acetamido-4-

55 E10001989 10-25-2011

Aminocyclohexyl) -2-benzyl oxopyrrolidin-3-ylcarbamate in the form of an oil (81 g, 100% yield). This amine was used directly in the next step without further purification.

Example 1, Step 8: A solution of (S) –1 - ((1S, 2R, 4R) –2 – acetamido – 4 – aminocyclohexyl) –2 – oxopyrrolidin – 3– benzylcarbonate (13.3 g, 34 mmol ) and 3,5-di-tert-butylcyclohexa-3,5-diene-1,2-dione (7.54 g, 34 mmol) in methanol (160 ml) was stirred at room temperature for 2 h. The solution was concentrated and diluted with acetone (132 ml) and water (33 ml), followed by the addition of Dowex-50WX8-200 (33 g). The reaction was stirred at room temperature for 2 h. Dowex – 50WX8–200 was filtered off and washed with dichloromethane (300 ml). The filtrate was concentrated in vacuo to remove most of the acetone. The residue was diluted with dichloromethane (200 ml) and washed with aqueous NaHCO3 solution (200 ml) and brine (200 ml). The combined aqueous phases were extracted with dichloromethane (2 x 100 ml). The combined organic extracts were dried over Na2SO4 and concentrated. The product (S) –1 - ((1S, 2R) –2 – acetamido – 4 – oxocyclohexyl) –2 – oxopyrrolidin-3-ylcarbamate of benzyl was obtained as a solid (12 g, 90% yield) by crystallization in EtOAc (100 ml) and Hexane (200 ml). 1H NMR (500 MHz, DMSO – d6) � ppm 7.99 (d, J = 9.35 Hz, IH), 7.44 (d, J = 8.80 Hz, 1 H), 7.28 - 7 , 39 (m, 5 H), 5.03 (s, 2 H), 4.50 (s, 1 H), 4.31 (d, J = 12.10 Hz, 1 H), 4.18 ( c, J = 8.98 Hz, 1 H), 3.27 (m, 2 H), 2.82 (dd, J = 15.12, 5.22 Hz, 1 H), 2.52 - 2, 65 (m, 1 H), 2.40 (dd, J = 12.92, 4.67 Hz, 1 H), 2.15 - 2.31 (m, 2 H), 2.09 (d, J = 15.40 Hz, 1 H), 1.90 (m, 1 H), 1.81 (s, 3 H), 1.68 (m, 1 H), m / z: 388.46 [M + H].

Example 1, Step 9: To a solution of TiCl4 (1M in dichloromethane, 36 ml, 36 mmol) in dichloromethane (30 ml) at 0˚C Ti (OiPr) 4 (10.8 ml, 36 mmol) was added. The mixture was then stirred at room temperature for 10 min. To a solution of (S) –1 - ((1S, 2R) –2 – acetamido – 4 – oxocyclohexyl) –2 – oxopyrrolidin-3-ylcarbamate benzyl (23.25 g, 60 mmol) in dichloromethane (600 ml) tert-butylamine (30 ml, 300 mmol) was added at room temperature, followed by the addition of the TiCl 4 / Ti (OiPr) 4 solution at –50 ° C. The reaction was allowed to slowly warm to room temperature. The reaction was terminated after 2 h (The reaction was monitored in HPLC by means of the inactivation of an HPLC sample with NaBH4 in methanol). The solution was cooled to 10 ° C and BH3 • SMe2 (1M in dichloromethane, 66 ml, 66 mmol) was added. The mixture was stirred at room temperature for 5 h then quenched with aqueous Na2CO3 solution (300 ml). The precipitate was filtered. The two phases were separated and the aqueous phase was extracted with dichloromethane (600 ml). The combined dichloromethane phases were extracted with 1N HCl twice (150 ml and 15 ml). (The product and the unwanted trans isomer were both in the acidic aqueous phase.) The combined acidic aqueous phases were neutralized with 12M NH4OH aqueous solution (12 ml) at pH ~ 8 and extracted with dichloromethane twice (600 ml, 450 ml) (The product was in the inorganic phase, while the trans isomer was still in the aqueous phase.) The combined organic phases were washed with aqueous NH4Cl solution 3 times (3 x 200 ml) until no trans isomer was left in the organic phase The organic phase was dried over Na2SO4 and concentrated. The residue was purified by crystallization from EtOAc / Hexane (200 ml / 800 ml) to provide the desired (S) –1 - ((1S, 2R, 4R) –2 – acetamido – 4– (tert-butylamino) cyclohexyl) –2 Desired benzyl-oxopyrrolidin-3-ylcarbamate (20.80 g, 78% yield) as a white solid with 99.5% purity. 1H NMR (500 MHz, DMSO – d6) � ppm 8.76 (s, 1H), 7.27-7.46 (m, 6 H), 5.03 (m, 2 H), 4.14 (m , IH), 4.07 (q, J = 8.80 Hz, 1H), 3.83 (m, 1H), 3.36 (m, 2H), 2.91 (s, 1H), 2.18 (m, 1H), 2.04 (m, 1H), 1.78 (s, 3H), 1.41 - 1.74 (m, 7H), 1.04 (s, 9H), m / z: 445.54 [M + H].

Example 1, Step 10: To a solution of (S) –1 - ((1S, 2R, 4R) –2 – acetamido – 4– (tert-butylamino) –cyclohexyl) –2– oxopyrrolidin – 3-ylcarbamate of benzyl ( 43.3 g, 98 mmol) in methanol (400 ml) was added 10% wet Pd / C (4.34 g). The mixture was evacuated and re-filtered with hydrogen with a hydrogen balloon. The mixture was stirred at room temperature for 5 h. The mixture was filtered and washed with methanol (500 ml) and concentrated in vacuo until dried. The crude product obtained was distilled with IPA (2 x 100 ml) under reduced pressure to provide the product N - ((1R, 2S, SR) -2 - ((S) -3-amino-2-oxopyrrolidin-1-yl) –5– (tert-butylamino) cyclohexyl) acetamide in the form of an oil (30 g, 98% yield). This amine was used in the next step without further purification.

Example 1, Step 11: To a solution of N - ((1R, 2S, SR) -2 - ((S) –3 – amino – 2 – oxopyrrolidin – 1 – yl) –5– (tert-butylamino) cyclohexyl) Acetamide (30 g, 97 mmol) in IPA (400 ml) was added TEA (27 ml, 195 mmol) and 4-chloro-6– (trifluoromethyl) quinazoline (25 g, 107 mmol); see: P. H. Carter et al., PCT application WO 2005/021500). The mixture was stirred at room temperature overnight at 70 ° C for 1 hour. The resulting solution was concentrated under reduced pressure until it dried. The residue was dissolved in dichloromethane (1 L) and extracted with acetic acid solution I (prepared by combining 700 ml of water and 22.6 ml of glacial acetic acid) twice (500 ml, 200 ml). The acidic aqueous phase (pH 4-5) was extracted with dichloromethane (2 x 300 ml). The dichloromethane phase was extracted with acetic acid solution II (300 ml; prepared by combining 300 ml of water with 4 ml of glacial acetic acid). The combined acetic acid phases were basified with 1M NaOH at pH> 12 and extracted with dichloromethane (3 x 700 ml). The combined organic phases were dried and concentrated to give the crude product as a solid (45.6 g, 93% yield). The crude product was purified by recrystallization from EtOAc (400 ml) / Hexane (900 ml) to provide 42.86 g (88%) of N - ((1R, 2S, 5R) -5- (tert-butylamino) - 2 - ((S) –2 – oxo – 3– (6– (trifluoromethyl) quinazolin-4-ylamino) pyrrolidin-1-yl) cyclohexyl) acetamide with 99.7% purity. 1H NMR (500 MHz, DMSO – d6) � ppm 9.71 (1 H, s, s.), 9.02 (1 H, s), 8.71 (1 H, d, J = 7.97 Hz ), 8.59 (1 H, s), 8.04 (1 H, dd, J = 8.66, 1.79 Hz), 7.88 (1 H, d, J = 8.52 Hz), 4.91 - 5.13 (1 H, m), 4.30 - 4.57 (1 H, m), 3.86 (1 H, dt, J = 11.89, 3.71, 3.64 Hz), 3.43

55 E10001989 10-25-2011

- 3.57 (1 H, m), 3.35 - 3.45 (1 H, m), 3.04 (1 H, t, J = 3.85 Hz), 2.23 - 2.40 ( 1 H, m), 2.05 - 2.22 (1 H, m), 1.90 - 1.98 (1 H, m), 1.86 - 1.93 (3 H, m), 1, 50 - 1.78 (5 H, m), 0.98 - 1.15 (9 H, m), 13 C NMR (126 MHz, DMSO – d6) 5 ppm 171.23, 169.35, 159.54, 156.87, 151.17, 128.97, 128.20, 125.76 (1 C, c, J = 30.52 Hz), 121.55 (1 C, s, s,), 124.04 ( 1 C, c, J = 272.11 Hz), 114.31, 53.26, 52.39, 50.81, 47.56, 45.70, 42.77, 34.52, 32.17, 29 , 14 (3 C, s), 26.49, 23.29, 20.30, 19F NMR (471 MHz, DMSO – d6) 5 ppm –60.34 (s), m / z: 507.0 [M + H], Anal, Calculated for C25H33N6O2F3: C, 59.27; H, 6.56; N, 16.59; F, 11.25 Found: C, 59.44; H, 6.64; N, 16.74; F, 10.99,

Alternative preparation of Example 1

Example 1, Alternative Preparation, Stage 1: An oven-dried 3-round round bottom flask was equipped with a dry stir bar, a dry reflux condenser and two partitions. After cooling under N2, the flask was sequentially charged with acid (1R, 2S, 5R) -2- ((S) -3- (benzyloxycarbonylamino) -2-oxopyrrolidin-1-yl) -5- (tert-butoxycarbonylamino) cyclohexanecarboxylic acid (60 g, 126 mmol; See Example 1, Step 4), acetonitrile (800 ml), N-methylmorpholine (27.7 ml, 252 mmol), and diphenylphosphoryl azide (29.9 ml, 139 mmol). The reaction was stirred at RT for 1 h and 40 min, at which time 2-trimethylsilyletanol (90 ml, 631 mmol) was added. The reaction was allowed to warm, and reached reflux 30 minutes later. It was allowed to reflux for 1 h, at which time it was allowed to cool to 50 ° C gradually and then cooled to 15 ° C with external cooling. The reaction was quenched with the addition of acetic acid (1,734 ml, 30.3 mmol). The reaction was concentrated in vacuo and then dissolved in EtOAc (1.2 L). It was washed sequentially with water (1 x 0.3 L), saturated NaHCO3 (2 x 0.3 L), 1N HCl (1 x 0.3 L), and brine (2 x 0.3 L). The organic phase was dried (Na2SO4), filtered and concentrated in vacuo. A solid appeared very early in the concentration process. After volatile compounds were removed, 800 ml of 10% EtOAc / Hexanes was added, and the mixture was stirred overnight. The solid was collected and dried to provide (1R, 3R, 4S) -4- ((S) -3-benzyloxycarbonylamino-2-oxopyrrolidin-1-yl) -3- ((2-trimethylsilyl) ethoxycarbonylamino) cyclohexylcarbamate of tert -Butyl (60.5 g, 102 mmol, 81% yield). HPLC showed that the material was 72% pure, with two 12% impurities. This material was taken in the next stage without purification. The filtrate was concentrated later to provide another 4.38 g of product. Total yield = 64.9 g (87%).

Example 1, Alternative Preparation, Step 2: A dry 500 ml round bottom flask was equipped with a stir bar and charged sequentially with (1R, 3R, 4S) - 4 - ((S) - 3 - benzyloxycarbonylamino - 2 - oxopyrrolidin - 1 - yl) - 3 - ((2 - trimethylsilyl) ethoxycarbonylamino) tert-butyl cyclohexylcarbamate (60.5 g), CH2Cl2 (180 ml), and a solution of para-toluenesulfonic acid monohydrate (19.48 g, 102 mmol) in CH2Cl2 (120 ml) and methanol (30 ml). The mixture was placed in a rotary evaporator and the bulk of CH2Cl2 (bath temperature approximately 20 ° C) was removed. When the mixture began to foam, the vacuum was released, and the bath temperature increased to 46˚C (the temperature varied between 44˚C and 51˚C; it was controlled with the addition of external ice). The mixture was rotated at this temperature for exactly one hour (gas evolution was visible everywhere) and then diluted with EtOAc (1 L). The organic phase was washed with 0.5 N NH4OH (2 x 250 ml). The aqueous washes were combined and separated. The organic phase was washed with saturated NH4Cl (1 x 250 ml) and saturated NaCl (1 x 250 ml); These aqueous washes were discarded. The combined NH4OH washings were reextracted with EtOAc (1 x 250 ml), and this organic extract was washed with saturated NH4C (1 x 60 ml) and saturated NaCl (1 x 60 ml). All organic extracts were combined, dried (Na2SO4), filtered, and concentrated. The residue was purified by elution through a bed of SiO2 (13 cm wide x 7.5 cm high). The first eluent was pure EtOAc (approximately 4 L). The second eluent was 1: 9 (10% NH4OH in MeOH) / CH2Cl2 (approximately 5 L). The fractions containing the desired product were pooled together and evaporated to provide the 2– (trimethylsilyl) ethyl (1R, 2S, 5R) -5-amino-2 - ((S) -3-benzyloxycarbonylamino-2-oxopyrrolidine- 1-yl) desired cyclohexylcarbamate (31.6 g, 64.4 mmol, 63% yield).

Example 1, Alternative Preparation, Step 3: A stirring solution of (1R, 2S, 5R) -5-amino-2 - ((S) -3- benzi) oxicarbonylamino-2-oxopyrrolidin-1-yl) cyclohexylcarbamate of 2 - (trimethylsilyl) ethyl (400 mg, 0.82 mmol) in acetonitrile (3 ml) was loaded sequentially with charged sequentially with diisopropylethylamine (315.8 mg, 3 eq.) And bromoacetonitrile (109.5 mg, 1.1 eq.). The mixture was stirred at 40 ° C for 30 h. The solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel, using 1.5% methanol in dichloromethane as eluent. The desired (1R, 2S, 5R) –2 - ((S) –3-benzyloxycarbonylamino – 2-oxopyrrolidin – 1-yl) –5– (cyanomethylamino) cyclohexylcarbamate of 2– (trimethylsilyl) ethyl was obtained as a solid white (400 mg, 93%). LC / MS found [M + H] + = 530.

Example 1, Alternative Preparation, Step 4: A stirring solution of 2– (trimethylsilyl) ethyl (1R, 2S, SR) -2 - ((S) - 3-benzyloxycarbonylamino – 2 – oxopyrrolidin – 1-yl) –5– (cyanomethylamino) cyclohexylcarbamate (400 mg, 0.76 mmol) in dichloromethane (5 ml), cooled to 0˚C and charged with m-CPBA (372.6 mg, 2.2 eq) in portions. The mixture was stirred at room temperature for 1.5 h. Saturated Na2S2O3 solution (3 ml) and saturated NaHCO3 solution (3 ml) were added and the mixture was stirred at room temperature for 0.5 h. The mixture was diluted with dichloromethane (80 ml), washed with saturated NaHCO3 (20 ml) and brine (20 ml). The solution was dried over anhydrous Na2SOa, filtered and concentrated in vacuo. The obtained residue was dissolved in methanol (5 ml) and the solution was charged with NH2OH-HCl (262.7 mg, 5 eq). The mixture was stirred at 60 ° C for 2.5 h. After cooling to room temperature, the mixture was diluted

45 E10001989 10-25-2011

with dichloromethane (80 ml) and filtered through a bed of celite. The filtrate was washed with saturated NaHCO3 (2 x 20 ml). The aqueous washings were extracted with dichloromethane (30 ml). The dichloromethane phases were combined and washed with brine (30 ml). The solution was dried over anhydrous Na2SO4, filtered and concentrated in vacuo to provide 2– (trimethylsilyl) ethyl (1R, 2S, 5R) -2 - ((S) –3-benzyloxycarbonylamino-2-oxopyrrolidin-1-yl) - 5– (hydroxyaminolcyclohexylcarbamate (350 mg, 91%). LC / MS found [M + H] + = 507.

Example 1, Alternative Preparation, Step 5: A solution of (1R, 2S, 5R) -2 - ((S) -3-benzyloxycarbonylamino-2-oxopyrrolidin-1-yl) -5- (hydroxyamino) cyclohexylcarbamate of 2– ( Trimethylsilyl) ethyl (350 mg, 0.69 mmol) in acetone (5 ml) was stirred at room temperature for 16 h. The mixture was concentrated in vacuo. The residue was dissolved in anhydrous THF (7 ml) and cooled to 0 ° C. A solution of MeMgBr (1.1 ml, 3M in diethyl ether, 5 eq) was added dropwise. The mixture was stirred at room temperature for 1.5 h. The reaction was quenched with water (5 ml) at 0˚C. The mixture was diluted with ethyl acetate (100 ml) and filtered through a bed of celite. The filtrate was washed with brine (30 ml). The solution was dried over anhydrous MgSO4, filtered and concentrated in vacuo. The residue was dissolved in 2 ml of acetonitrile and 1 ml of CS2 was added. The mixture was stirred at room temperature for 1 hour. The solvent was removed and the crude product was purified by column chromatography on silica gel, using 1.5% methanol in dichloromethane as eluent, to provide (1R, 2S, 5R) -2 - ((S) -3-benzyloxycarbonylamino-2-oxopyrrolidin-1-yl) -5- (tert-butylamino) cyclohexylcarbamate of 2- (trimethylsilyl) ethyl desired (160 mg, 42%). LC / MS found [M + H] + = 547.

Example 1, Alternative Preparation, Step 6: A stirring solution of (1R, 2S, 5R) -2 - ((S) -3- benzyloxycarbonylamino-2-oxopyrrolidin-1-yl) -5- (tert-butylamino) cyclohexylcarbamate 2– (trimethylsilyl) ethyl (100 mg, 0.183 mmol) in dichloromethane (3 ml) was charged with trifluoroacetic acid (2 ml). The reaction was stirred for 2 h at room temperature and concentrated in vacuo. The residue was dissolved in dichloromethane (50 ml) and washed with saturated NaHCO3 (20 ml). The aqueous phase was extracted with dichloromethane (3 x 30 ml). The dichloromethane phases were combined and dried over saturated Na2SO4, filtered, and concentrated in vacuo to provide (S) -1 ((1S, 2R, 4R) -2-amino-4- (tert-butylamino) cyclohexyl) -2 -Oxypyrrolidin-3-benzyl ilcarbamate (66 mg, 90%). LC / MS found [M + H] + = 403.

Example 1, Alternative Preparation, Step 7: A solution of (S) -1 - ((S, 2R, 4R) -2-amino-4- (tert-butylamino) cyclohexyl) -2-oxopyrrolidin-3-ylcarbamate of benzyl (22 mg, 0.055 mmol) in dichloromethane (2 ml) was sequentially charged with triethylamine (11.1 mg, 2 eq) and acetic anhydride (6.1 mg, 1.1 eq). The reaction was stirred for 1.5 h at room temperature, diluted with dichloromethane (50 ml) and washed with saturated NaHCO3 (20 ml). The organic phase was dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to afford (S) -1 - ((1S, 2R, 4R) -2- acetamido-4- (tert-butylamino) cyclohexyl) -2-oxopyrrolidine –3 – Benzyl ilcarbamate (22 mg, 90%). LC / MS found [M + H] + = 445.

Example 1, Alternative Preparation, Step 8: To a solution of (S) –1 - ((1S, 2R, 4R) –2 – acetamido – 4– (tert-butylamino) cyclohexyl) –2 – oxopyrrolidin – 3-ylcarbamate of Benzyl (22 mg, 0.05 mmol) in methanol (2 ml) was added Pd (OH) 2 (20 mg of 50% wet catalyst). The flask was evacuated and refilled with hydrogen from a hydrogen balloon. The mixture was stirred at room temperature for 1 h and the catalyst was removed by filtration. The filtrate was concentrated in vacuo to provide N - ((1R, 2S, 5R) -2 - ((S) -3-amino-2-oxopyrrolidin-1-yl) -5- (tert-butylamino) cyclohexyl) acetamide (13 mg, 85%). LC / MS found [M + H] + = 311.

Example 1, Alternative Preparation, Step 9: To a solution of N - ((1R, 2S, 5R) –2 - ((S) –3-amino – 2-oxopyrrolidin– 1-yl) –5– (tert-butylamino ) cyclohexyl) acetamide (70 mg, 0.225 mmol) in isopropanol (3 ml) 4-chloro-6- (trifluoromethyl) quinazoline (63 mg, 1.2 eq.) and triethylamine (56.9 mg, 2.5 eq.). The mixture was stirred at room temperature for 1.5 h. The solvent was removed under reduced pressure. The residue was purified with preparative HPLC to provide the title compound as its bis-TFA salt (110 mg, 67%). LC / MS found [M + H] + =

507

Second alternative preparation of example 1

Example 1, Second alternative preparation, Step 1a: 4-toluenesulfonate salt of (7R, 8S) -8 - ((S) -1-phenyl-ethylamino) -1,4-dioxa-spiro [4.5] decane – 7 – ethyl carboxylate 1A (1417 g, 2.8 mol, 10

see: WO2004098516, prepared analogously to US Patent 6,835,841), ethanol (200 test, 11.4 L) and 10% Pd / C catalyst (50% humidity, 284 g). The mixture was made inert with nitrogen, then pressurized with hydrogen gas (45 psig) and stirred vigorously at approx. 40 ° C until the starting material was consumed (HPLC). The suspension was cooled, purged with nitrogen gas and the catalyst was filtered off while inert. The spent catalyst was washed with ethanol (4.3 L). The filtrate and washings were combined and concentrated in vacuo to a volume of 2-3 L, while maintaining the batch between 40 ° C - 60 ° C. Isopropyl acetate (5 L) was charged and the mixture was concentrated to a volume of ~ 2 L until most of the ethanol was removed (<0.5%) and the residual moisture content was <1,000 ppm. The batch volume was adjusted to ~ 7.5 L by the addition of isopropyl acetate. The mixture was heated at 80 ° C until it became clear and then cooled to 65 ° C - 70 ° C. 1 (5 g) seminal crystals were added and the batch was cooled at 50 ° C for 2 hours, then cooled to 20 ° C for a further 4 hours and held for ~ 10 hours. The resulting suspension was filtered and the cake was washed with isopropyl acetate (2 L). The product was dried under vacuum at ~ 35 ° C until volatile compounds were reduced below ~ 1% (LOD). 4-Toluenesulfonate salt of (7R, 8S) -8- amino-1,4-dioxa-spiro [4.5] decane-7-ethyl carboxylate 1 was obtained as a white crystalline solid (936 g, yield of 83%, HPLC purity: 99.8%). 1H NMR: (300 MHz, CDCl3) 8.14-7.89 (sa, 3H), 7.75 (d, J 9.0 Hz, 2H), 7.15 (d, J 8.0 Hz, 2H ), 4.22-4.04 (m, 2H), 4.01-3.77 (m, 4H), 3.55-3.43 (m, 1H), 3.20-3.13 (m , 1H), 2.40-2.27 (m, 4H), 2.21-1.94 (m, 2H), 1.81-1.51 (m, 3H), 1.23 (t, J 7.0 Hz, 3H); HPLC: Waters Xterra EM C18 4.6 mm x 150 mm di, particle size 3.5 µm, 0.05% NH4OH (5% ACN, 95% H2O, solvent A), at 0 NH4OH , 05% (95% ACN, 5% H2O, solvent B), from 5% B to 20% B in 10 minutes, changed to 95% B at 25 minutes and then changed to 5% B at 1 minute; 11.1 minutes (amino ester 1).

Example 1, Second alternative preparation, Step 1b: 4-Toluenesulfonate salt (7R, 8S) -8-amino-1,4-dioxospiro [4.5] decane-7-ethyl carboxylate 1 (450.1 g) was combined; the reductive deprotection product of a known compound, see R. J. Cherney, WO2004 / 098516 and G. V. Delucca &amp; SS Ko, WO2004 / 110993) with 1-ethyl-3– (3-dimethyl-amino-propyl) carbodiimide hydrochloride (236.3 g), 1-hydroxy benzotriazole hydrate (171.9 g), N-carbobenzyloxy– L-methionine (333.4 g) and acetonitrile (3.1 l). To the stirred mixture was added triethylamine (249.5 g) below 30 ° C. After the reaction was completed (HPLC), the mixture was diluted with ethyl acetate (8.2 L) and washed with 5% aqueous potassium bicarbonate solution (2 x 4.5 L) followed by water (4 , 5 l). The organic phase was separated and concentrated under reduced pressure, obtaining a solution of (7R, 8S) -8- ((S) -2-benzyloxycarbonylamino-4-methylsulfanyl-butyrylamino) -1,4-dioxapiro [4.5] dean- 7-ethyl carboxylate 2 (1.4 L). Methyl iodide (2.39 kg) was added, the vessel was protected from light and the mixture was kept under slow stirring for approx. 24 h To the thick yellow precipitate, tert-butyl methyl ether (2.7 L) was added and the mixture was maintained for approx. 1 hour. The product was isolated by filtration and the cake was washed with tert-butyl methyl ether (2 x 1.4 L) and then dried under vacuum, yielding [(S) -3-benzyloxy-carbonylamino-3 - (( 7R, 8S) -7-ethoxycarbonyl-1,4-dioxa-spiro [4.5] dec-8-ylcarbamoyl) -propyl] -dimethylsulfonium 3 (671.4g, ~ 94% yield) as a colored solid off-white (99.9% purity by HPLC).

Wash the sulfonium salt 3 (619.4 g), cesium carbonate (416.8 g) and anhydrous dimethylsulfoxide (6.2 L) to neutralize volatile sulphides. It was kept under vigorous stirring until complete conversion (HPLC) was obtained. Ethyl acetate (12.4 L) was added, followed by 20% brine (3 L). The organic phase was separated, washed twice with brine (2 x 3 L) and evaporated, obtaining a solution of (7R, 8S) -8 - ((S) -3-benzyloxycarbonylamino-2-oxo-pyrrolidin-1 –Il) –1,4 – dioxa – spiro [4.5] decane – 7 – ethyl carboxylate 4 in ethyl acetate (~ 0.8 l). Acetone (2.55 L) was added followed by 0.5 M aqueous hydrochloric acid solution (2.3 L). With good mixing, the solution was heated from 50 ° C to 60 ° C until the conversion of 4 to (1R, 2S) -2 - ((S) -3-benzyloxycarbonylamino-2-oxo-pyrrolidin-1-yl) -5 was completed –Oxo – ethyl cyclohexanecarboxylate 5 (HPLC). The mixture was concentrated under reduced pressure while remaining below 40 ° C, cooled to ~ 30 ° C and water (4.1 L) was added. The resulting suspension was cooled from 5 to 10 ° C and stirred for ~ 1 hour. The product was filtered and the cake was washed with water (2 x 2.5 L). After distillation, the cake was dried at a constant weight below 40 ° C in a vacuum oven. Cyclohexanone 5 (272 g, 70% yield) (98.7% purity by HPLC) was obtained.

Example 1, Second alternative preparation, Step 3: Cyclohexanone 5 (100 g) was suspended in THF (500 ml) and cooled to 0 ° C. 1N NaOH (271 g) was added at 0˚C-5˚C and the biphasic mixture was stirred at: 5˚C for at least one hour. MTBE (500 ml) was added and the phases were separated. The aqueous bottom phase was washed again with MTBE (500 ml) and the phases were separated. Dichloromethane (500 ml) was charged to the aqueous phase rich in product, and the mixture was cooled to 0 ° C. 3N HCl (156 g) was charged maintaining: 85˚C. After stirring for at least 10 min, the mixture was heated to 20˚C - 25˚C, and the phases were separated. The aqueous phase was extracted with dichloromethane (100 ml). The organic phases were combined and the solvent was exchanged in toluene through distillation. The volume of the toluene solution was adjusted to approximately 1 L, and p-toluenesulfonic acid monohydrate (0.24 g) was added. Ethylene glycol (16.22 g) was added, and the mixture was distilled at atmospheric pressure until the formation of compound 7 was completed and the volume of the vessel was approximately 500 ml - 700 ml. The solution was cooled to approximately 70 ° C, and ethyl acetate (500 ml) was added maintaining approximately 70 ° C. The mixture was cooled and filtered to provide 73 g (70% yield) of compound 7, acid (7R, 8S) -8- ((3S) -3- ((((benzyloxy) carbonyl) amino) -2-oxo- 1-pyrrolidinyl) -1,4-dioxaspiro [4.5] decane-7-carboxylic.

Example 1, Second alternative preparation, Step 4: To a suspension of compound 7 (147 g) in dry toluene (370 ml), triethylamine (32.7 g) was charged at 15˚C-25˚C. After the suspension became a solution after stirring for 10-15 minutes at 25˚C, the flask was cooled to –10˚C and isobutyl chloroformate (44.1g) was charged to –10˚– 0˚C . The mixture was stirred at –10˚– 0˚C for approximately 30 min. A solution of sodium azide (42 g) and tetrabutylammonium bromide (5.2 g) in water (130 ml) was added at –10˚– 0˚C. The biphasic suspension was vigorously stirred for at least one hour and toluene (1750 ml) was added followed by water (300 ml). The two phases were stirred for at least 10 min and the upper organic phase was separated and dried with 4Å molecular sieves. Acetic anhydride (76 ml) and acetic acid (28 ml) were added and the solution was heated at 80˚C - 90˚C for 1-4 hours, until <2 AP of intermediate 9 was detected by HPLC. The solvent was partially distilled at approximately two thirds of the initial volume under atmospheric pressure, the solution was cooled to room temperature and the resulting suspension was stirred for 16 hours. Heptane (350 ml) was added slowly and the suspension was stirred for 1 hour. The solids were filtered, washed with 4: 1 toluene / heptane (300 ml), and dried to give 109 g (78% yield) of compound 10, ((3S) -1 - ((7R, 8S) -7 –Acetamido – 1,4– dioxaspiro [4.5] dec – 8-yl) –2 – oxo-3-pyrrolidinyl) benzyl carbamate.

Example 1, Second alternative preparation, Step 5: A 1N HCl (760 ml) was charged to a solution of compound 10 (109 g) in acetone (760 ml). The mixture was heated at 50 ° C for 2.5 hours. The acetone was distilled under reduced pressure and the product was extracted with dichloromethane twice 1 x 1 L and 1 x 0.5 L. The dichloromethane phases were combined and the dichloromethane was exchanged in ethyl acetate by distillation until the boiling point in the vessel reached 78˚C and the final volume was approximately 10 ml / g of the inlet of compound 10. The suspension of Ethyl acetate was cooled to room temperature, stirred for 16 hours and the solids filtered and washed with ethyl acetate (400 ml). The solid was dried to provide 84 g (87% yield) of compound 11, ((3S) -1 - ((1S, 2R) -2-acetamido-4-oxocyclohexyl) -2-oxo-3-pyrrolidinyl) carbamate benzyl

Example 1, Second alternative preparation, Step 6: TiCl2 reagent (OPri) 2 was pre-formed by adding Ti (OiPr) 4 (11.5 ml) to a solution of 1M TiCl4 in dichloromethane (39 ml) at 5˚C - 10˚C and subsequent stirring at room temperature for 15 min. Compound 11 (25 g) was dissolved in dichloromethane (500 ml) and t-butylamine (34 ml) was added at room temperature. After 10 min the solution was cooled to -25 ° C to -20 ° C and the preformed titanium reagent solution was added at a temperature below -20 ° C. The mixture was allowed to warm to room temperature and stirred for 1 h. A sample was taken to confirm the complete formation of imine by mini-inactivation with sodium borohydride in methanol (the absence of alcohols indicated the complete consumption of the starting ketone 11). Then borane dimethyl sulfide (7.0 ml) at 0 atC-5 --C was added and the reaction mixture was heated to room temperature and stirred for at least 5 hours. The dichloromethane was partially evaporated (about half) under reduced pressure and wet ethyl acetate (300 ml, preformed by stirring ethyl acetate with water) was added in 30-60 min. The resulting suspension was stirred for at least 4 h, the solids were filtered and washed several times with dichloromethane until no more than 5% M of the product was retained in the cake. The filtrate and the washings were combined, 1N HCl (200 ml) was added and the biphasic mixture was stirred for at least 30 min (gas evolution ceased after ~ 20 min). The product rich aqueous phase (upper phase) was separated and dichloromethane (500 ml) was added. Concentrated ammonium hydroxide was added to the concentrated biphasic mixture until the pH was adjusted to 8-8.5 (~ 15 ml). The organic phase was separated and washed 2 x 100 ml with 14% by weight ammonium chloride, to remove the unwanted trans isomer of compound 12, and finally with water (25 ml). The dichloromethane was exchanged in ethyl acetate by distillation under normal pressure until the boiling point of the vessel reached 78 ° C and the final volume was approximately 5 ml / g of the inlet of compound 11 (~ 140 ml). The solution was cooled to room temperature. Heptane (250 ml) was added slowly at 40˚C - 50˚C and compound 12 began to crystallize. The suspension was stirred at room temperature for 3 hours and the solids filtered, washed with heptane (100 ml) and dried to provide 20.1 g (70% yield) of compound 12, ((3S) -1- ( (1S, 2R, 4R) –2 – acetamido – 4– (tert-butylamino) cyclohexyl) –2 – oxo– 3-pyrrolidinyl) benzyl carbamate, in the form of white spongy crystals.

Example 1, Second alternative preparation, Step 7: Compound 12 (20 g) was dissolved in methanol (400 ml) and 5% Pd / C catalyst (1.8 g, 9% by weight) was added. The mixture was hydrogenated at 25˚C and 25 psig for 3 hours. The catalyst was removed by filtration, and the methanol was exchanged in ethyl acetate by continuous distillation. The product crystallized from ethyl acetate (160 ml) after cooling. Heptane (160 ml) was added at 25 ° C, the suspension was stirred for 1 hour and the product was filtered, washed with heptane and dried to provide 12.8 g (94% yield) of compound 13, N- ( (1R, 2S, 5R) –2 - ((3S) –3-amino-2-oxo-1-pyrrolidinyl) –5– (tert-butylamino) cyclohexyl) acetamide.

Example 1, Second alternative preparation, Step 8: 6– (trifluoromethyl) -4-quinazolinol, 14 (5 g; see P. H. Carter, et al. PCT application WO 2005/021500) was suspended in dichloromethane (100 ml). N, N-diisopropylethylamine (4.2 ml, 1.05 eq) and DMF (0.4 ml, 0.2 eq) were added. Oxalyl chloride (3.0 ml, 1.5 eq) was then added to the stirred suspension at 20˚C-25˚C under cooling (exothermic addition). The orange suspension was stirred at 30 ° C - 35 ° C for 2 hours. Constant gas evolution was observed for ~ 1.5 hours, at which time

15 that the suspension became an orange solution. After cooling to 20 ° C, the reaction solution was added dropwise to 20% aqueous K2HPO4 (50 ml) under vigorous stirring and gas evolution. The lower organic phase was separated and washed once more with 20% aqueous K2HPO4 (50 ml). The organic solution was used as it is for the next stage in 16h.

Example 1, Second alternative preparation, Step 8: To a solution of 15 in dichloromethane (22 ml, 5.5 mmol), solid 13 (1.55 g, 5 mmol) was added and the mixture was stirred at room temperature until solids dissolved. Triethylamine (1.4 ml, 11 mmol) was added and the mixture was stirred for 24 hours at room temperature. Water (10 ml) was added, the two phases were stirred for 10 min and the organic phase was separated. Dichloromethane in ethyl acetate was exchanged by continuous distillation until the boiling point of the vessel reached

78 ° C and the final volume was approximately 10 ml / g of the inlet of compound 13 (~ 15 ml). The suspension was cooled to room temperature, heptane (15 ml) was added slowly and the suspension was stirred for 16 h. The solids were filtered, washed with 1: 1 heptane / ethyl acetate (5 ml) and dried to provide 1.83 g (72% yield) of beige crystals (N-2 form by XRD) of N– ((1R, 2S, 5R) –5– (tert-butylamino) –2– ((S) –2 – oxo – 3– (6– (trifluoromethyl) quinazolin – 4-ylamino) pyrrolidin – 1-yl) cyclohexyl) Acetamide, Example 1.

30 Example 2

Crystal forms of N - ((1R, 2S, 5R) –5– (tert-butylamino) –2 - ((S) –2 – oxo – 3– (6– (trifluoromethyl) quinazolin – 4– ylamino) pyrrolidin – 1 –Il) cyclohexyl) acetamide

50 E10001989 10-25-2011

Various crystal forms of N - ((1R, 2S, 5R) –5– (tert-butylamino) –2 - ((S) –2 – oxo – 3– (6– (trifluoromethyl) quinazolin – 4– ylamino) pyrrolidine -1-yl) cyclohexyl) acetamide, free base, were prepared and characterized as described below.

Shape characterization procedures

Data of a single crystal

Data were collected on a Bruker – Nonius diffractomer (BRUKER AXS, Inc., 5465 East Cheryl Parkway Madison. Document Wl 53711 United States) of CAD4 series. The unit cell parameters were obtained through least-squares analysis of the experimental diffractrometer settings of 25 high-angle reflections. Intensities were measured using Cu Ka radiation (A = 1.5418 Å) at a constant temperature with the variable scanning technique of � – 2� and corrected only for Lorentz polarization factors. Background counts were collected at the ends of the scan for half the time of the scan. Alternatively, data from a single crystal was collected in a Bruker-Nonius Kappa CCD 2000 system using Cu K • radiation (A = 1.5418 Å). The indexing and processing of the measured intensity data were performed with the HKL2000 software package (Otwinowski, Z. & amp. Minor. W. (1997) in Macromolecular Crystallography, eds. Carter, WC Jr & Sweet, RM (Academic New York), Vol. 276, p. 307-326) in the Collect program suite. (Collect Data collection and processing user interface: Collect: Data collection software, R. Hooft, Nonius B.V., 1998,). Alternatively, data from a single crystal was collected in a Bruker-AXS APEX2 CCD system using Cu Ka radiation (� = 1.5418 Å). The indexing and processing of the measured intensity data were performed with the software package / set of programs APEX2 (APEX2 Data collection and processing user interface: APEX2 User Manual, v1.27; BRUKER AXS, Inc., 5465 East Cheryl Parkway Madison, Wl 5371 United States).

When indicated, the crystals were cooled in the cold stream of an Oxford cryo system (Oxford Cryosystems Cry - ostream cooler: J. Cosier and AM Glazer, J. Appl. Cryst., 1986, 19, 105) during data collection .

The structures were dissolved by direct procedures and refined based on the reflections observed using the SDP software package (SDP, Structure Determination Package, Enraf-Nonius, Bohemia NY 11716, Dispersion factors, including f 'and f' ', in The SDP program was taken “InternationalTablasforCrystallography”, Kynoch Press, Birmingham, England, 1974; Vol. IV, Tables 2,2A and 2,3,1) with small local modifications or MAXUS crystallographic packages (maXus solution and refinement package software: S. Mackay, CJ Gilmore, C. Edwards, M. Tremayne, N. Stewart, K. Shankland.maXus: a computer program for the solution and refinement of crystal structures from diffraction data or SHELXTL4. Atomic bypass (coordination and temperature factors) were refined through a complete least squares matrix.The minimized function in refinements was Lw (| FO | - | FC |) 2 R was defined as L || FO | - | FC || / L | FO | while Rw = [Lw (| FO | - | FC |) 2 / Lw | FO | 2] 1/2 in which w is an appropriate weighting function based on the observed intensity errors. Different maps were examined at all stages of refinement. Hydrogens were introduced at ideal positions with isotropic temperature factors, but the hydrogen parameters were not varied.

X-ray powder diffraction data (PXRD)

PXRD data was obtained using a Bruker C2 GADDS. The radiation was Cu Ka (40 KV, 50 mA). The distance between the sample and the detector was 15 cm. The powder samples were placed in sealed glass capillaries of 1 mm or less in diameter; The capillary was rotated during data collection. Data were collected for 3:

2 8: 35º with a sample exposure time of at least 2000 seconds. The resulting two-dimensional diffraction arcs were integrated to create a one-dimensional PXRD pattern with a stage size of 0.02 degrees 2� in the range of 3 to 35 degrees 28.

Differential Scanning Calorimetry (DSC)

The DSC experiments were performed on an InstrumentsTM TA model Q1000 or 2920. The sample (approximately 2-6 mg) was weighed in an aluminum container and recorded with an accuracy of one hundredth of a milligram and transferred to the DSC. The instrument was purged with nitrogen gas at 50 ml / min. The data was collected between room temperature and 300 ° C at a heating rate of 10 ° C / min. The representation was made with the endothermic peaks oriented downwards.

Thermogravimetric analysis (ATG)

The ATG experiments were performed on an InstrumentsTM TA model Q500 or 2950. The sample (approximately 10-30 mg) was placed in a previously tared platinum container. The sample weight was measured accurately and recorded up to thousandths of a milligram with the instrument. The oven was purged with nitrogen gas at 100 ml / min. The data was collected between room temperature and 300 ° C at a heating rate of 10 ° C / min.

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Preparation and analysis of forms

The unit cell data and other properties of these examples are presented in Table 1. The unit cell parameters were obtained from X-ray crystallographic analysis of a single crystal. A detailed explanation of unit cells can be found in Chapter 3 of Stout &amp; Jensen, X – Ray Structure Determination: a Practical Guide, (MacMillian, 1968).

The fractional atomic coordinates for Examples 2a, b, c, d, e, f and g, and the conditions under which they are measured are presented in Tables 2-9.

In addition, the characteristic positions of the powder X-ray diffraction peaks (grades 28 ± 0.1) at RT for Examples 2a, b, d, and f are presented in Table 9, all of which are based on patterns of High quality collected with a diffractrometer (CuKa) with a centrifuge capillary with 28 calibration with NIST of another suitable standard.

Finally, Figures 1, 2, 3, 4, 5 and 6 present PXRD patterns for Examples 2a, b, c, d, e and f. Figures 8, 10, 13, 15, 17 and 19 describe the ATG of Examples 2a, b, c, d, e and f, respectively. Figures 7, 9, 12, 14, 16 and 18 describe the DSC of Examples 2a, b, c, d, e and f, respectively. Figure 11 describes the Moisture Absorption Isotherm of Example 2b.

Form preparation, characterization by DSC and ATG

Example 2a, Form H0.5-4: 150 mg of N - ((1R, 2S, 5R) –5– (tert-butylamino) –2 - ((S) –2 – oxo – 3– (6– (trifluoromethyl ) quinazolin-4-ylamino) pyrrolidin-1-yl) cyclohexyl) acetamide, free base was dissolved in warm n-butyl acetate saturated with water. Heptane was added until a persistent cloud was observed. The suspension was allowed to cool to room temperature. Form H0.5–4 was characterized by 0.5 moles of water per mole of N– ((1R, 2S, 5R) –5– (tert-butylamino) –2 - ((S) –2 – oxo – 3 - (6– (trifluoromethyl) quinazolin-4-ylamino) pyrrolidin-1-yl) cyclohexyl) acetamide, free base. Form H0.5-4 was characterized by a DSC thermogram that had a broad onset of endothermia typically in the range between about TA and about 67˚C according to the ATG curve; at higher temperatures, other circumstances may result. Form H0.5-4 was characterized by an ATG thermal curve that typically has a weight loss of 0.6% to about 1.4% to about 100˚C. The theoretical weight loss for Form H0.5–4 is 1.7%, however, it is normal for unstable hydrates to partially dehydrate after drying.

Example 2b, Form N – 2: 1 g of N - ((1R, 2S, 5R) –5– (tert-butylamino) –2 - ((S) –2 – oxo – 3– (6– (trifluoromethyl) quinazolin - 4-ylamino) pyrrolidin-1-yl) cyclohexyl) acetamide, free base was dissolved in 10 ml of water-free EtOAc at 77˚C. The solution was cooled to 70˚C. 10 mg of N-2 seeds were added. To the suspension was added 18 ml of n-heptane for 1 with a syringe pump. The suspension was cooled from 70˚C to 20˚C for 1 hour, and stirred at 20˚C overnight. The solid was isolated by filtration, washed with 3 ml of n-heptane, dried at 50 ° C in a vacuum oven overnight. Form N – 2 is N - ((1R, 2S, 5R) –5– (tert-butylamino) –2 - ((S) –2 – oxo – 3– (6– (trifluoromethyl) quinazolin – 4 – ylamino) pyrrolidin-1-yl) cyclohexyl) acetamide, free base, a pure form (without additional molecules of water or solvent). Form N-2 was characterized by DSC thermogram that had an onset of endothermia typically between about 230˚C and about 232˚C in the form of a single fusion without additional transformations. The N – 2 form was characterized by an ATG curve that had negligible weight loss up to approximately 200 yC and according to the structure of the monocrystalline.

Example 2c, Form H1.75-5: A 50 mg suspension of N - ((1R, 2S, 5R) –5– (tert-butylamino) –2 - ((S) –2 – oxo – 3– (6 - (trifluoromethyl) quinazolin-4-ylamino) pyrrolidin-1-yl) cyclohexyl) acetamide, free base was vigorously stirred in 1 ml of water for more than 16 hours. Form H1.75–5 is characterized by 1.75 moles of water per one mole of N– ((1R, 2S, 5R) –5– (tert-butylamino) –2 - ((S) –2 – oxo– 3– (6– (trifluoromethyl) quinazolin-4-ylamino) pyrrolidin-1-yl) cyclohexyl) acetamide, free base. Form H1.75-5 was characterized by a DSC thermogram that had an onset of endothermia typically between about TA and about 70˚C according to the ATG curve; at higher temperatures, other circumstances may result. Form H1.75-5 was characterized by an ATG curve that had weight loss of approximately 4.3% to approximately 5.3%, at temperatures up to approximately 100˚C. The theoretical weight loss is approximately 5.9%, however, it is normal for unstable hydrates to partially dehydrate after drying.

Example 2d, HAC – 1: 100 mg of N - ((1R, 2S, 5R) –5– (tert-butylamino) –2 - ((S) –2 – oxo – 3– (6– (trifluoromethyl) quinazolin– 4-ylamino) pyrrolidin-1-yl) cyclohexyl) acetamide, free base, was dissolved in 0.1 ml of HOAc at 80˚C. To this, 0.2 ml of t-BuOAc was added and the solution was cooled to 20 ° C. The solution was evaporated until it dried. The resulting solid was stirred in heptane at 50 ° C for 15 hours, followed by cooling at 20 ° C. HAC-1 was filtered and dried at 25 ° C under vacuum overnight. Form HAC – 1 is characterized by 1 mole of acetic acid per one mole of N– ((1R, 2S, 5R) –5– (tert-butylamino) –2 - ((S)) - 2 – oxo – 3– (6– (trifluoromethyl) quinazolin-4-ylamino) pyrrolidin-1-yl) cyclohexyl) acetamide, free base. Form HAC – 1 was characterized by a DSC thermogram that had a beginning

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of endothermia typically between about 100˚C according to the ATG curve; at higher temperatures, other circumstances may result. The HAC – 1 Form was also characterized by an ATG curve that has approximately 15.3% weight loss to approximately 200˚C. The theoretical weight loss is approximately 10.5%, however it is normal for smaller amounts of solvents with a high boiling point to remain associated with the solid. In cases like this, PXRD is diagnostic of the Form but is not sensitive to small amounts of adventitious solvent.

Example 2e, Form E – 1: 50 mg of N - ((1R, 2S, 5R) –5– (tert-butylamino) –2 - ((S) –2 – oxo – 3– (6– (trifluoromethyl) quinazolin -4-ylamino) pyrrolidin-1-yl) cycloolyexyl) acetamide, free base was dissolved in <1ml of boiling ethanol. The solution was cooled to RT and allowed to evaporate slowly. Form E – 1 is characterized by 1 mole of ethanol per one mole of Ng ((1R, 2S, 5R) –5– (tert-butylamino) –2 - ((S) –2 – oxo – 3– (6– (trifluoromethyl) quinazolin-4-ylamino) pyrrolidin-1-yl) cyclohexyl) acetamide, free base. Form E – 1 was characterized by a DSC thermogram that had an onset of endothermia typically at approximately 100˚C according to the ATG curve; at higher temperatures, other circumstances may result. Form E – 1 was characterized by an ATG thermal curve that has a weight loss of approximately 7.1% to approximately 7.6% to approximately 150˚C. The theoretical weight loss is approximately 8.3%, however, it is normal for unstable hydrates to partially dissolve after drying.

Example 2f, RPG – 3: From 30 to 40 mg of N - ((1R, 2S, SR) –5– (tert-butylamino) –2 - ((S) –2 – oxo – 3– (6– (trifluoromethyl ) Quinazolin-4-ylamino) pyrrolidin-1-yl) cyclohexyl) acetamide, free base, was dissolved in 2 ml of racemic propylene glycol. Water was added until a cloud was observed. The solvent was allowed to evaporate slowly until it dried. The RPG-3 Form is characterized by 1 molecule of R-propylene glycol per one molecule of N– ((1R, 2S, 5R) –5– (tert-5-butylamino) –2 - ((S) –2 – oxo– 3– (6– (trifluorometi) quinazolin-4-ylamino) pyrrolidin -) - 1– yl) cyclohexyl) acetamide, free base. The RPG-3 Form was characterized by a DSC thermogram that had an onset of endothermia typically at about 70 ° C according to the ATG curve, at higher temperatures, other circumstances may result. The RPG-3 Form was characterized by an ATG curve that has a weight loss of about 16.4% to about 110˚C. The theoretical weight loss is approximately 13.1%, however it is normal for smaller amounts of solvents with a high boiling point to remain associated with the solid. In cases like this, PXRD is diagnostic of the Form but is not sensitive to small amounts of adventitious solvent.

Example 2g, Form IPA – 1: 40 mg of N - ((1R, 2S, 5R) –5– (tert-butylamino) –2 - ((S) –2 – oxo – 3– (6– (trifluoromethyl) quinazolin -4-ylamino) pyrrolidin-1-yl) cyclohexyl) acetamide, free base was suspended in <1ml of isopropyl alcohol. The suspension was gently heated to dissolve the remaining solid. The solution was cooled to RT and allowed to evaporate slowly until crystals were observed. Form IPA – 1 is characterized by 1 mole of isopropyl alcohol per one mole of N - ((1R, 2S, 5R) –5– (tert-butylamino) –2 - ((S) –2 – oxo – 3– ( 6– (trifluoromethyl) quinazolin-4– ylamino) pyrrolidin-1-yl) cyclohexyl) acetamide, free base.

Claims (4)

1. A process for preparing a compound having the formula (X) which comprises the stages of: Hydrolyze an ester moiety of the compound of formula V with a hydrolysis agent to form the acid of compound VI at temperatures of about -5 to about 5 ° C: reacting a compound of formula VIa, HO-Z-OH, with a compound of formula IV (optionally in situ) 10 in the presence of an acid catalyst, to give a compound of formula VII having a carboxylic acid moiety: Transforming the carboxylic acid moiety of the ketal of formula VII into a corresponding isocyanate of formula VIII: contacting the isocyanate of formula VIII with a compound of formula R10COW in the presence of a corresponding acid anhydride, (R10CO) 2O, to form the amide of formula IX having a ketal moiety: 5 hydrolyze the ketal moiety of the amide of formula IX to form the compound of formula X, in which: R1 and R2 are independently hydrogen or an amine protecting group; R4 and R10 are independently C1-6 alkyl or optionally substituted benzyl; R8 and R9 are independently hydrogen or C1-6 alkyl; W is OH or C1-6 alkyl; Z is - (CT1T2) 2-, - (CT1T2) 3-, or and 15 T1, T2 and T3, each time they appear they are independently selected from hydrogen, C1-4 alkyl, C2-4 alkenyl, 30 E10001989 10-25-2011 halogen, hydroxy, cyano, nitro, CF3, C1-4alkyl, OCF3 and C (= O) C1-4alkyl. 2. The method according to claim 1, wherein the step of reductive tuning comprises: a) adding a Lewis acid to a solution of compound X and the amine having the formula HNR8R9, in an aprotic solvent, to form an imine-enamine of formula Xa; Y b) treating the imine-enamine of formula Xa with a reducing agent, to give the compound of formula X having a pyrrolidonylamine moiety. 3. The method of claims 1-2, wherein: the compound of formula VII is (7R, 8S) -8 - ((3S) -3 - (((benzyloxy) carbonyl) amino) -2-oxo-1-pyrrolidinyl) -1,4-dioxaspiro [4.5] decane-7 -carboxylic, or a salt thereof; the compound of formula VIIa is ((3S) -1 - ((7R, 8S) -7- (azidocarbonyl) -1,4-dioxaspiro [4.5] dec-8-yl) -2-oxo-3-pyrrolidinyl) benzyl carbamate , or a salt thereof; the compound of formula VIII is ((3S) -1 - ((7R, 8S) -7-isocyanate-1,4-dioxaspiro [4.5] dec-8-yl) -2-oxo-3-pyrrolidinyl) benzyl carbamate, or a salt thereof; the compound of formula IX is ((3S) -1 - ((7R, 8S) -7-acetamido-1,4-dioxaspiro [4.5] dec-8-yl) -2-oxo-3-pyrrolidinyl) benzyl carbamate, or a salt thereof; the compound of formula X is ((3S) -1 - ((1S, 2R) -2-acetamido-4-oxocyclohexyl) -2-oxo-3-pyrrolidinyl) benzyl carbamate, or a salt thereof; The compound of formula XI is ((3S) -1 - ((1S, 2R) -2-acetamido-4-oxocyclohexyl) -2-oxo-3-pyrrolidinyl) benzyl carbamate, or a salt thereof. 4. A compound selected from: (7R, 8S) -8 - ((3S) -3 - ((((benzyloxy) carbonyl) amino) -2-oxo-1-pyrrolidinyl) -1,4-dioxaspiro [4.5] decane-7-carboxylic acid, or a salt thereof; ((3S) -1 - ((7R, 8S) -7- (azidocarbonyl) -1,4-dioxaspiro [4.5] dec-8-yl) -2-oxo-3-pyrrolidinyl) benzyl carbamate, or a salt of the same; ((3S) -1 - ((7R, 8S) -7-Isocyanate-1,4-dioxaspiro [4.5] dec-8-yl) -2-oxo-3-pyrrolidinyl) benzyl carbamate, or a salt of same; ((3S) -1 - ((7R, 8S) -7-acetamido-1,4-dioxaspiro [4.5] dec-8-yl) -2-oxo-3-pyrrolidinyl) benzyl carbamate, or a salt of same; ((3S) -1 - ((1S, 2R) -2-acetamido-4-oxocyclohexyl) -2-oxo-3-pyrrolidinyl) benzyl carbamate, or a salt thereof; ((3S) -1 - ((1S, 2R, 4R) -2-acetamido-4- (tert-butylamino) cyclohexyl) -2-oxo-3-pyrrolidinyl) benzyl carbamate, or a salt of the same.