WO2006060225A2

WO2006060225A2 - Process for asymmetric synthesis of hexahydropyrimido[1,2-a] azepine-2-carboxamides and related compounds

Info

Publication number: WO2006060225A2
Application number: PCT/US2005/042211
Authority: WO
Inventors: Yong-Li Zhong; Shane W. Krska; Jaemoon Lee
Original assignee: Merck & Co., Inc.
Priority date: 2004-11-23
Filing date: 2005-11-18
Publication date: 2006-06-08
Also published as: WO2006060225A3

Abstract

Processes for asymmetric synthesis of 1O(S)-amino-3-hydroxy-4-oxo-4,6,7,8,9,10hexahydropyrimido[1,2-a]azepine-2-carboxamides and related compounds are disclosed. The enantiomerically enriched carboxamides are useful as HIV integrase inhibitors and thus are useful for treating HIV infection and AIDS.

Description

TITLE OF TBDE INVENTION

PROCESS FOR ASYMMETRIC SYNTHESIS OF BEXAHYDROPYRIMIDO[1, 2-a]AZEPINE-2-

CARBOXAMIDES AND RELATED COMPOUNDS

FIELD OF THE INVENTION

The present invention is directed to processes for asymmetric synthesis of 10(S)-amino- 3-hydroxy-4-oxo-4,6,7,8,9,10-hexahydropyrimido[l,2-a]azepine-2-carboxamides and related compounds. These enantiomerically enriched hexahydropyrimidoazepine carboxamides and related compounds are useful as intermediates in the preparation of pharmacologically active compounds.

BACKGROUND OF THE INVENTION

A class of hexahydropyrimido[l,2-a]azepine-2-carboxamides and related compounds are inhibitors of the HTV integrase enzyme. The compounds of Formulas VIL VIE and DC as defined and described below are representative of this class. These compounds and pharmaceutically acceptable salts thereof are useful for preventing or treating infection by BQV and for treating or delaying the onset of AIDS. One approach to making these enantiomerically pure compounds is to prepare a racemic mixture of the intermediates, then separate the racemic mixture of the intermediates into the desired single enantiomer by optical resolution, and obtain the end products. The following Scheme A for preparing a hexahydropyrimido[l,2-α]azepine carboxamide illustrates this approach, wherein the racemic PIl is undergone classical resolution to yield (S)-enantiomer of PIl before the desired end product (S)-P12 is obtained.

Scheme A

The following Scheme B illustrates a resolution/racemization process for preparing chiral amine (SVPIl. wherein (S)-P18 is treated with a base to give (S)-PIl and DTTA is di-p-toluoyl-D-tartaric acid. Scheme B

The overall yield for making P12 from Pl following Schemes A and B is about 7% without recycle and about 10% after two recycles. Accordingly, there is a need for an alternative more efficient and/or higher yielding synthesis of the enaαtiomerically pure hexahydropyrimido[l,2-a]azepine-2-carboxamide intermediates.

The following publications describe asymmetric hydrogenation of enamines/imines to chiral amines: a) Hsiao, Y., et al. J. Am. Chem. Soc. 2004, 126, p. 9918; b) Cobley, CJ.; Henschke, J.P. Adv. Synth. Catal 2003, 345, p. 195; c) Cobley, C.J., et al. Tetrahedron : Asymm. 2003, 14, p. 3431; d) Abdur-Rashid, K., et al. Organometallics 2001, 20, p. 1047; e) Abe, H., et al. Org. Lett. 2001, 3, p. 313; f) Ringwald, M., et al. J. Am. Chem. Soc. 1999, 121, p. 1524; g) Mao, J.; Baker, D.C. Org. Lett. 1999, 1, p. 841; g) Tararov, V.I., et al. Tetrahedron: Asymm. 1999, 10, p. 4009; and h) Ohkuma, T.; Kitamura, M.; Noyori, R. in Catalytic Asymmetric Synthesis, 2^nd ed.; Ojima, I., Ed.; Wiley-VCH: New York, 2000, pp. 83-95.

SUMMARY OF THE INVENTION

The present invention relates to processes for asymmetric synthesis of 10(S)-amino-3- hydroxy-4-oxo-4,6,7,8,9,10-hexahydropyrimido[l,2-a]azepine-2-carboxamides and derivatives thereof. More particularly, the present invention includes a process for preparing a compound of Formula VII:

comprising:

(E) contacting a compound of Formula V:

or a compound of Formula VI:

with a hydrogen source in the presence of a rhodium metal precursor complexed to a chiral mono-or bisphosphine ligand; wherein:

L is a hydroxy protecting group;

Rl is:

(D H,

(2) Ci-6 alkyl,

(3) Ci_6 alkyl substituted with O-Ci_6 alkyl, C3-8 cycloalkyl, or aryl, wherein the cycloalkyl is optionally substituted with from 1 to 3 Ci_6 alkyl groups and the aryl is optionally substituted with from 1 to 5 substituents each of which is independently C\.β alkyl, O-Ci-6 alkyl, CF3, OCF3, halo, CN, orNO2, or

(4) aryl which is optionally substituted with from 1 to 5 substituents each of which is independently Cl -6 alkyl, O-Ci-6 alkyl, CF3, OCF3, halo, CN, or NO2;

R.2, R3, each R4, each R^, and R6 are independently:

(1) H,

(2) Ci-6 alkyl, or

(3) C i_6 alkyl substituted with O-Ci_6 alkyl, C3.8 cycloalkyl, or aryl, wherein the cycloalkyl is optionally substituted with from 1 to 3 Ci_g alkyl groups and the aryl is optionally substituted with from 1 to 5 substituents each of which is independently Ci_6 alkyl, O-Ci_6 alkyl, CF3, OCF3, halo, CN, orNO2;

each aryl is independently phenyl or naphthyl;

n is an integer equal to zero, 1, 2 or 3;

TJl, TJ2 and Tj3 are each independently selected from the group consisting of H, halo, C\.β alkyl, O-Ci-6 alkyl, C\-6 fluoroalkyl, SO2-Ci_6 alkyl, C(=O)-NH(-Ci_6 alkyl), C(=O)-N(-Ci_6 alkyl)₂, and HetA; Vl is H, halo, Cμg alkyl, or C\.β fluoroalkyl; and

each HetA is independently a 5- or 6-membered heteroaromatic ring containing from 1 to 4 heteroatoms independently selected from N, O and S, wherein the heteroaromatic ring is optionally substituted with 1 or 2 C i_6 alkyl groups.

The processes of the present invention eliminate the resolution step of racemates and provide optically pure compounds of Formula VII in a higher yield than the process described in the Background, which involves two recycles of resolution. Accordingly, the present processes are useful for large-scale preparation of enantiomerically enriched (or even enantiomerically pure) compounds.

The present invention also includes a process for preparing an N-halo compound comprising contacting an N-H compound with (R^C-OZ generated in situ wherein each R7 is independently C^-Cj2 alkyl and Z is halo.

The present invention also includes a class of substituted hydroxypyrimidinone carboxamides that can be employed as reactants in the process set forth above. Additional classes of compounds encompassed by this invention are described below.

Various embodiments, aspects and features of the present invention are either described in or will be apparent from the ensuing description, example, and appended claims.

DETAILED DESCRIPTION OF THE INVENTION

The present invention includes the process set forth above in the Summary of the Invention, in which a compound of Formula VII is prepared from a compound of Formula V and/or a compound of Formula VI. A compound of Formula VII is alternatively referred to herein more simply as "Compound VII". Similarly, compounds of Formula V and VI are alternatively and respectively referred to as "Compound V" and "Compound VI". Analogous nomenclature is employed for other compounds described below.

The process set forth above in the Summary of the Invention relates to a method for preparing chiral amine Formula VII in an efficient enantioselective fashion via rhodium metal-catalyzed asymmetric hydrogenation of a prochiral enamine of Formula V and/or a prochiral imine of Formula VI. The present method circumvents the need for protecting the amino group in the enamine for the asymmetric hydrogenation reaction and proceeds with excellent reactivity and enantioselectivity.

The complex of the rhodium metal precursor and the chiral phosphine ligand useful in Step E may be either (a) generated in situ by the sequential or contemporaneous addition of the rhodium metal precursor and chiral phosphine ligand to the reaction mixture or (b) pre-formed with or without isolation and then added to the reaction complex is represented by the formula:

where X represents a non-coordinating anion, such as trifluoromethanesulfonate, tetrafluoroborate, and hexafluorophosphate, and L' is a neutral ligand such as an olefin (or chelating di-olefin such as 1,5- cyclooctadiene or norbornadiene) or a solvent molecule (such as MeOH and TFE). ha the case where olefin is arene, the complex is

The pre-formed complex useful in is represented by the formula:

One embodiment of the process of the invention is the process as originally described, wherein the rhodium metal precursor is [Rh(monoolefm)2Cl]2, [Rh(diolefin)Cl]2, [Rh(monoolefin)2acetylacetonate];, [Rh(diolefin)acetylacetonate], [Rh(monoolefin)4]X, or [Rh(diolefϊn)2]X; wherein X is a non-coordinating anion selected from the group consisting of methanesulfonate, trifluoromethanesulfonate (Tf), tetrafluoroborate (BF4), hexafluorophosphate (PFg), and hexafluoroantimonate (SbFg); and all other variables are as originally defined (i.e., as defined in the

Summary of the Invention), hi an aspect of the preceding embodiment, the rhodium metal precursor is [Rh(cod)Cl]2, [Rh(norbornadiene)Cl]2, [Rh(cod)2]X, or [Rh(norbornadiene)2]X. hi another aspect of the preceding embodiment, the rhodium metal precursor is [Rh(cod)Cl]2 or [(COD^RhJBF^

Another embodiment of the process of the invention is the process as originally described, wherein the chiral phosphine ligand is (R)-l-[(S)-2-di-2-furylphosphmo]ferrocenyl]-ethyldi- tert-butylphosphine (Josiphos J212-1); 2,2'-bis(diphenylphosphino)-l,l'-binaphthyl (BINAP); (HaS)- dibenzo[d,f][l,3]dioxepm-l,l l-diylbis[diphenylphosphine] (C₁ TunaPhos); [(12aS)-6,7- dmydrodibenzo[e,g][l,4]dioxocin-l,12-diyl]bis[diphenylphosphine] (C2 TunaPhos); (R)-(-)-l,13- bis(diphenylphosphino)-7,8-dihydro-6H-dibenzo[f,h][l,5]dioxonin (C₃ TunaPhos); [(14aS)-6,7,8,9- tetrahydrodibenzo[b,d][l,6]dioxecin-l,14-diyl]bis[diphenylphosphine] (C4 TunaPhos); [(15aS)-7,8,9,10- tetrahydro-βH-dibenzotb^jfl_jόldioxacycloundecin-ljlS-diylJbisfdiphenylphosphine] (C5 TunaPhos);

[(16a8)-6,7,8,9,10,l l -hexahydrodibenzo [b,d] [ 1 ,6] dioxacyclododecin- 1 , 16-diyl]bis [diphenylphosphine] (Cg TunaPhos); (S)-(-)-2,2',6,6^l-tetramethoxy-4,4'-bis(diphenylphosphino)-3,3'-bipyridme (CTH-P-Phos);

(R)-(+)-2,2'-bis[di(3,5-xylyl)phosphino]-l,r-binaphthyl (xylBINAP); (S)-(-)-2,2',6₅6'-tetramethoxy-4,4'- bis(di(3,5-xylyl)phosphino)-3,3'-bipyridine (xyl-P-Phos); (S)-N-dicyclohexylphosphino-N-methyl-[(R)- 2-(diphenylphosphino)ferrocenyl]ethylamine (Pcyco-BoPhoz); (-)- 1 , l'-bis((2S,4S)-2,4- diethylphophotano)ferrocene (Et-FerroTANE); (-)- 1 , 1 '-bis((2S,4S)-2,4-di-i-propylphophotano)ferrocene (iPrFerroTANE); (R)-(-)-l-[(S)-2-(di-2-furylphosphino)ferrocenyl]ethyl-di-3,5-xylylphosphine [Josiphos (2-fiuyl)₂P-F-C-P(3,5-Me₂Ph)₂]; (R)-(-)-l-[(S)-2-(di-2-ftιrylphosphino)ferrocenyl]ethyl-di-2- tolylphosphine [Josiphos (2-furyl)₂P-F-C-P(o-tolyl)₂]; (R)-(-)-l-[(S)-2-(bis(3,5-dimethyl-4- methoxyphenyl)phosphino)ferrocenyl]ethyl-di-t-butylphosphine [Josiphos (3,5-Me2-4-MeOPh)₂P-F-C-

PtBu₂]; (R)-(-)-l-[(S)-2-(dicyclohexylphosphino)ferrocenyl]ethyl-dicyclohexylphosphine [Josiphos (cyHex)₂P-F-C-P(cyHex)2]; (R)-(-)-l-[(S)-2-(di-2-tolylphosphino)ferrocenyl]ethyl-di-2-tolylphosphme

[Josiphos (o-tolyl)2P-F-C-P(o-tolyl)2]; (R)-(-)-l-[(S)-2-(bis(4-fluorophenyl)phosphino)ferrocenyl]ethyl- di-t-butylphosphine [Josiphos (p-FPh)₂P-F-C-PtBu₂] ; (R)-(-)- 1 -[(S)-2-(diphenylphosphino) ferrocenyl]ethyl-di-t-butylphosphine (Josiphos Ph₂P-F-C-PtBu₂); (3S,3'S,4S,4'S,1 IbS₅I l'bS)-(+)-4,4'-di- t-butyl-4,4',5,5'-tetrahydro-3,3'-bi-3H-dinaphtho[2,l-c: l',2'-e]phosphepin (binapine); or (R)-(+)-l,l'- bis(diphenylphosphino)-2,2'-bis(N,N-di-i-propylamido)ferrocene (CTH- JAF APhos); and all other variables are as originally defined. Jj₁ an aspect of the preceding embodiment, the chiral phosphine ligand is (R)-l-[(S)-2-di-

2-furylphosphino]ferrocenyl]-ethyldi-tert-butylphosphine (Josiphos J212-1).

Another embodiment of the process of the invention is the process as originally described, wherein the complex formed by a rhodium metal precursor and a chiral phosphine ligand is employed in a catalytic amount in Step E; and all other variables are as originally defined. In an aspect of the preceding embodiment, the ratio of rhodium metal precursor to substrate (e.g., Compound V and/or VI) is about 0.01 mol % to about 10 mol %. In another aspect of the preceding embodiment, the ratio of the rhodium metal precursor to the substrate is about 0.05 mol % to about 0.5 mol %.

Other suitable chiral phosphine ligands useful for Step E include those of the following structural formulae:

m is 1, 2, or 3; R.8 is Ci-g alkyl or C6-10 aryl; and R9 is aryl or a ferrocenyl phospholane radical;

HetAr — p_Ri4a_Ri4b

HetAr — p_Ri5a_Ri5b

t = 1-6 wherein Ar is phenyl or naphthyl unsubstituted or substituted with one to four substituents independently selected from Cl -4 alkyl, Ci_4 alkoxy, chloro, and fluoro; or two adjacent substituents on Ar together with the carbon atoms to which they are attached form a five-membered methylenedioxy ring; HetAr is pyridyl or thienyl each of which is unsubstituted or substituted with one to four substituents independently selected from Ci_4 alkyl, C 1.4 alkoxy, chloro, and fluoro; or two adjacent substituents on

HetAr together with the carbon atoms to which they are attached form a five-membered methylenedioxy ring;

Rl4a_; Rl4b₃ Rl5a_; and Rl5b are each independently C1.4 alkyl, aryl, or C3_6 cycloalkyl wherein aryl and cycloalkyl are unsubstituted or substituted with one to four substituents independently selected from C 1-4 alkyl and C 1.4 alkoxy; or or Rl 4a and Rl 4b when taken together or Rl5a and Rl5b when taken together can form a 4- to 7- membered cyclic aliphatic ring unsubstituted or substituted with two to four substituents independently selected from the group consisting of C 1.4 alkyl, Ci_4 alkoxy, hydroxymethyl, C 1.4 alkoxymethyl, aryl, and C3-6 cycloalkyl and said cyclic aliphatic ring being optionally fused with one or two aryl groups;

wherein r is 1, 2, or 3; and Rl 9 is C 1.4 alkyl or aryl; or the corresponding enantiomers thereof;

- 8 -

wherein R^e is hydrogen or methyl; Rc and Rd are each independently hydrogen, C 1.4 alkyl, benzyl, or α- methylbenzyl; or R^c and Rd together with the nitrogen atom to which they are attached form a pyrrolidine or piperidine ring; or

wherein R20 is C 1.4 alkyl or aryl; and R21 and R22 are each independently C 1-6 alkyl, C542 cycloalkyl, or aryl; wherein aryl in formula (l)-(3) and (5) is independently phenyl or naphthyl, wherein aryl is unsubstituted or substituted with one to five substituents independently selected from phenyl, halogen, hydroxy, amino, carboxy, C 1.4 alkyl, Cl .4 alkoxy, C 1.4 alkylthio, C 1.4 alkylsulfonyl, and C 1.4 alkyloxycarbonyl, wherein the alkyl moiety of each is unsubstituted or substituted with one to five fluorines.

Other suitable chiral bisphosphine ligands encompass those disclosed in U.S. Patents 5,874,629 and

6,043,387, the contents of both are incorporated herein by reference in their entirety. Another embodiment of the process of the invention is the process as originally described, wherein the hydrogen source is H2 (gas); and all other variables are as originally defined. The hydrogenation reaction of Step E may be performed at a hydrogen pressure range of about 0 psig to about 1500 psig. A typical hydrogen pressure range is about 80 psig to about 200 psig.

The asymmetric hydrogenation reaction of Step E may be carried out in a solvent E. Suitable solvents that may be used as solvent E include alcohols, such as methanol, ethanol, and isopropyl alcohol; halogenated alcohols, such as 2,2,2-trifluoroethanol (TFE) and hexafluoroisopropyl alcohol; phenol; halogenated phenols, such as fluorinated phenols; polyhydroxylated benezenes, such as 1,2,3-trihydroxybenzene (pyrogallol) and 1,2,3,4-tetrahydroxybenzene; ethers, such as tetrahydrofuran and methyl t-butyl ether; halogenated alkanes, such as dichloromethane; aromatic and alkylated aromatic hydrocarbons, such as toluene; esters such as ethyl acetate; and mixtures thereof. Step E may also be carried out in the presence of an acid, wherein the role of the acid is to protonate or partially protonate the product secondary amine (i.e., Compound VII), thus preventing it from binding to the rhodium complex and slowing down the reaction. Examples of such suitable acid include carboxylic acids such as trifluoroacetic acid (TFA), acetic acid, propionic acid, butyric acid, and chloroacetic acid; sulfonic acids, such as methanesulfonic acid, camphorsulfonic acid, and trifluoromethanesulfonic acid (triflic acid); and HBF4.

Compounds V, VI and VII each contain one L group, wherein L is a hydroxy protecting group which, as described below, can be formed by treatment of the corresponding OH-containing precursors with a hydroxy protecting agent. As used herein, the term "hydroxy protecting agent" is a chemical reagent (e.g., a sulfonyl halide, a phosphinyl halide, etc.) that will form a protected hydroxy group (e.g., sulfonate, phosphinate, etc.). Hydroxy protective groups are known in the art and are described, for example, in Protective Groups in Organic Chemistry, edited by J.F.W. McOmie, Plenum Press, New York, 1973; and in T. W. Greene and P.G.M. Wuts, Protective Groups in Organic Synthesis. 3^rd edition, John Wiley, New York, 1999, the disclosures of which are herein incorporated by reference. An embodiment of the process of the invention is the process as set forth above wherein

L is a sulfonate or a phosphinate; and all other variables are as originally defined.

Another embodiment of the process of the invention is the process as originally described above, wherein L is hydrocarbylsulfonyl, dihydrocarbylphosphinyl, or dihydrocarbyloxyphosphinyl; and all other variables are as originally defined. Another embodiment of the process of the invention is the process as originally described, wherein L is:

(1) SO₂Rl₅

(2) P(O)(RJ)₂, or

(3) P(O)(ORK)₂; wherein

RI is (i) C i_6 alkyl, (ii) Ci -6 haloalkyl, (iii) C\.6 alkyl substituted with aryl, (iv) aryl, or (v) camphoryl; each RJ is independently (i) Cl -6 alkyl, (ii) C\.β haloalkyl, (iii) Cl -6 alkyl substituted with aryl, or (iv) aryl; and each RK is independently (i) Ci -6 alkyl or (ii) C 1-6 alkyl substituted with aryl; and wherein any aryl defined in Rl, RJ, and RK is optionally substituted with from 1 to 5 substituents each of which is independently halogen, -Ci -4 alkyl, -O-Ci-4 alkyl, OCF3, CN, or nitro; and all other variables are as originally defined.

Another embodiment of the process of the invention is the process as originally described, wherein L is SO2RI, wherein Rl is C 1.3 alkyl, CH2CF3, CH2-aryl, aryl, or 10-camphoryl; wherein the aryl is optionally substituted with from 1 to 3 substituents each of which is independently F₃ Cl, Br, -Ci_4 alkyl, -O-C1.4 alkyl, OCF3, or nitro; and all other variables are as originally defined.

In an aspect of the preceding embodiment, L is p-toluenesulfonyl, benzenesulfonyl, methanesulfonyl, p-nitrobenzenesulfonyl, naphthalenesulfonyl, or 10-camphorsulfonyl. In another aspect of the preceding embodiment L is methanesulfonyl.

Another embodiment of the process of the invention is the process as originally described, wherein R2, R3_; each R4, each R5, and R6 are independently H or Cl .4 alkyl; and all other variables are as originally defined or as defined in any of the foregoing embodiments.

Another embodiment of the process of the invention is the process as originally described, wherein R2, R3, each R4, each R^, and R6 are all H; and all other variables are as originally defined or as defined in any of the foregoing embodiments. Another embodiment of the process of the invention is the process as originally described, wherein n is an integer equal to 1 or 2; and all other variables are as originally defined or as defined in any of the foregoing embodiments. In an aspect of this embodiment, n is 1. In another aspect, n is 2.

Another embodiment of the process of the invention is the process as originally

U^ are each independently H, halo, Ci_g alkyl or C _j_g fiuoroalkyl, and all other variables are as originally defined or as defined in any of the foregoing embodiments. In an aspect of this embodiment, U^, Tj2 and U^ are each independently H or halo.

It is understood that the definition of any one of L, W, Y, Rl, R2, R3_; R4, R5, R6, Rl₅ RJ, RK, T and n as originally set forth or as defined in any of the foregoing embodiments of the process, or aspects thereof, can be combined with the definition of any one or more of the others of L, W, Y, Rl, R2, R3, R4_S R5_S R6₌ Rl₅ RJ₅ RK₅ T and n as originally set forth or as defined in one of the foregoing embodiments or aspects thereof. Each such possible combination not expressly described above can be incorporated into the process of the invention, and each represents an additional embodiment of the process of the present invention.

The contacting in Step E of Compound V or VI with the hydrogen source can be conducted at any temperature at which the reaction (asymmetric hydrogenation) forming Compound VII can be detected. The reaction can suitably be conducted at a temperature in a range of from about -10 ⁰C to about 90 °C, and is typically conducted at a temperature in a range of from about 15 ⁰C to about 65 ⁰C. In one embodiment, the reaction of Step E is conducted at about room temperature.

The contacting in Step E of Compound V or VI with the hydrogen source can be conducted till the reaction is complete or the desired degree of conversion of the reactants is achieved. The reaction time can vary widely depending upon, inter alia, the reaction temperature and the choice and relative amounts of reactant and catalyst (i.e., the rhodium metal precursor and the chiral phosphine ligand), but the reaction time for complete or near complete conversion is typically in a range of from about 1 to about 36 hours (e.g., from about 10 to about 30 hours). Compound VII can subsequently be isolated (alternatively referred to as recovered) from the reaction mixture using conventional procedures, such as crystallization from a suitable organic solvent or chromatography, or used directed for the subsequent steps. The process of Step E of the present invention provides compounds of Formula VII with high optical purity, typically in excess of 50% ee. In one embodiment, compounds of Formula VII are obtained with an optical purity in excess of 70% ee. Ia a class of this embodiment, compounds of Formula VII are obtained with an optical purity in excess of 80% ee. In a subclass of this class, compounds of Formula VII are obtained with an optical purity in excess of 90% ee.

In a particularly suitable embodiment of Step E, the contacting is conducted in a halogenated alcohol (e.g., TFE), the hydrogen source is H2, the rhodium metal precursor is [Rh(cod)Cl]2 or [(COD)2Rh]BF4, the chiral phosphine ligand is Josiphos J212-1, and the rhodium metal precursor is employed in an amount of at least about 0.1 equivalent (e.g., from about 0.1 to about 0.2 equivalents) per equivalent of Compound V and/or VI, at about room temperature at hydrogen pressure of about 100 psig.

The present invention includes a process for preparing a compound of Formula VII which comprises Step E as described above; and which further comprises:

(D) treating a compound of Formula IV:

with a base to form a compound of Formula V, a compound of Formula VI or a mixture thereof, wherein

Z is halo.

Step D can be conducted in a solvent D. Suitable solvents for use as solvent D in Step D include those selected from the group consisting of halogenated alkanes, aromatic hydrocarbons, alkylated aromatic hydrocarbons, alcohols, ethers, esters, tertiary amines, tertiary amides, N- alkylpyrrolidones, pyridines, sulfoxides, and nitriles. A class of solvents suitable for use as solvent H in Step H consists of the solvents selected from the group consisting of Cj-io linear and branched halogenated alkanes, C\.β alkyl alcohols, C5.7 cycloalkyl alcohols, dialkyl ethers wherein each alkyl is independently a Cl -6 alkyl, C\.β linear and branched alkanes substituted with two -O-Ci_6 alkyl groups (which are the same or different), C4-C8 cyclic ethers and diethers, phenyl C 1.4 alkyl ethers, diethylene glycol di(Ci-4 alkyl) ethers, C\.β alkyl esters of C\.β alkylcarboxylic acids, tri-(Ci_6 alkyl)amines, N,N-di-(Ci_6 alkyl)-Ci_6 alkylamides, N-(C i_6 alkyl)pyrrolidones, pyridine, (mono- and di- and tri-Ci_6 alkyl)pyridines, di-(Ci_6 alkyl)sulfoxides, and C₂-Cg aliphatic nitriles.

Representative examples of solvents suitable for use in Step D include carbon tetrachloride, chloroform, methylene chloride, 1,2-dichloroethane, 1,1,2-trichloroethane, 1,1,2,2- tetrachloroethane, toluene, xylene, methanol, ethanol, isopropanol, 77-butanol, t-butyl alcohol, cyclohexanol, cyclopentanol, dimethyl ether, ethyl ether, MTBE, THF, dioxane, 1,2-dimethoxyethane, anisole, phenetole, diglyme, methyl acetate, ethyl acetate, isopropyl acetate, triethylamine, tri-n- propylamine, diethylisopropylamine, diisopropylethylamine, DMF, DMAC, N-methylpyrrolidone, N- ethylpyrrolidone, pyridine, 2- or 3- or 4-picoline, 2,4,6-collidine, DMSO, acetonitrile, and propionitrile. The contacting in Step D is conducted in the presence of a base. Suitable bases include those selected from the group consisting of tertiary alkyl amines, tertiary cyclic amines, diazabicycloalkenes, amidine, alkoxides of alkali and alkaline earth metals, alkali metal and alkaline earth metal phosphates, alkali metal and alkaline earth metal carbonates, alkali metal and alkaline earth metal hydroxides, and tetraalkyl ammonium hydroxide [(alkyl)₄NOH].

Exemplary bases suitable for use in Step D include TEA, DIPEA, DBU (1,8- diazabicyclo[5.4.0]undec-7-ene), DBN (l,5-diazabicyclo[4.3.0]non-5-ene), DABCO, tri-n-propylamine, tri-isopropylamme, tri-n-butylamine, tri-t-butylamine, 1,1,3,3-tetramethylguanidine, K3PO4, Na3PO4,

CS3PO4, K₂CO₃, Na₂CO₃, Cs₂CO₃, LiOH, NaOH, KOH, Mg(OH)₂, Ca(OH)₂, Ba(OH)₂, lithium methoxide, sodium methoxide, potassium methoxide, lithium ethoxide, sodium ethoxide, potassium ethoxide, magnesium dimethoxide, magnesium diethoxide, Et₄NOH, and Pr₄NOH.

The base may be employed in Step D in any proportion with respect to Compound IV which will result in the formation of at least some of Compound V and/or VI but it is typically employed in an amount that can optimize conversion of Compound IV and formation of Compounds V and/or VI. The base may be suitably employed in Step D in an amount of at least about 0.5 equivalent (e.g., from about 0.5 to 3 equivalents) per equivalent of Compound IV. In one embodiment, the base is employed in an amount in a range of from about 0.8 to about 1.5 equivalents per equivalent of Compound IV. The base is typically employed in an amount of at about 1 equivalent per equivalent of Compound IV. The contacting in Step D of Compound IV with the base may be conducted at any temperature at which the reaction forming Compounds V and/or VI can be detected. The reaction can suitably be conducted at a temperature in a range of from about -50 to about 9O⁰C. In one embodiment, the temperature is in a range of from about -30 to about 60⁰C (e.g., from about -2O⁰C to about 25°C). In a suitable embodiment of Step D, the contacting is conducted in an ester solvent (e.g.,

BPAC), the base is an diazabicycloalkene (e.g., DBU), the temperature is in a range of from about -10 to about 20⁰C (e.g., from about -5 to about 0 ⁰C), and the base is employed in an amount of about 1 equivalent (e.g., from about 1.0 to about 1.5 equivalents) per equivalent of Compound IV.

The reaction of Step D may be conducted by forming a mixture (typically a solution) of Compound IV in a suitable organic solvent at a temperature below the desired reaction temperature, charging the base thereto, and then bringing the resulting mixture to reaction temperature and maintaining the mixture at reaction temperature (optionally with agitation such as stirring) until the reaction is complete or the desired degree of conversion of the reactants is achieved. The reaction time can vary widely depending upon, inter alia, the reaction temperature and the choice and relative amounts of reactant and base, but the reaction time for complete conversion is typically in a range of from about 0.1 to about 10 hours (e.g., from about 0.1 to about 2 hours). Compound V and/or VI may subsequently be isolated (alternatively referred to as recovered) from the reaction mixture using conventional procedures, such as crystallization from a suitable organic solvent or chromatography.

The present invention also includes a process for preparing a compound of Formula VII which comprises Steps D and E as described above; and which further comprises:

(C) contacting a compound of Formula IH:

with a halogenating agent to form a compound of Formula IV.

Step C relates to the conversion of an amine group in Compound DI to a halamine group (i.e., conversion of an N-H bond in Compound IH to an N-halo bond) by a halogenating agent. Suitable halogenating agents for Step C include Ν-halosuccinimide, alkali metal and alkaline earth metal hypohalite, and (R^C-OZ either generated in situ or pre-formed wherein each R7 is independently C^-

Ci2 alkyl and Z is halo (e.g., tert-butylhypohalite).

The halogenating agent (R^C-OZ (e.g., tert-butylhypohalite) may be generated in situ under biphasic conditions by dropwise addition of alkali metal and alkaline earth metal hypochlorite (e.g., sodium hypochlorite) to tert-alcohol (e.g., tert-bvAanol) in the presence of an acid. Suitable alkali metal and alkaline earth metal hypochlorites, tert-alcdhols and acids useful for generating the halogenating agent (R^C-OZ in situ for Step C also include those described below for the process of preparing an N-halo compound from an N-H compound. In one embodiment, organic solutions of Compound DI are treated with an aqueous solution of alkali metal or alkaline earth metal hypohalite in the presence of tert-butanol and an acid (e.g., aliphatic carboxylic acid such as acetic acid). Typically, the acid is employed in 1 equiv.

Exemplary halogenating agents suitable for use in Step C include tert-butylhypochlorite, NaOCl (including aq.), NaOBr (including aq.), Ca(OCl)2 (including aq.), Ca(OBr)2 (including aq.), ΝCS (Ν-chlorosuccinimide), and ΝBS (Ν-bromosuccinimide).

Step C can be conducted in a solvent C. Suitable solvents for use as solvent C in Step C include those selected from the group consisting of halogenated alkanes, aromatic hydrocarbons, alkylated aromatic hydrocarbons, ethers, and esters. The halogenated alkanes, aromatic hydrocarbons, alkylated aromatic hydrocarbons, ethers, and esters described above as suitable for use as solvent D in Step D are also suitable for use as solvents in Step C, and accordingly the earlier description of those solvent classes is incorporated herein.

Exemplary solvents suitable for use in Step C include EtOAc, EPAc, D? Ac/water, dichloromethane, chloroform, 1,2-dichloroethane, toluene, MTBE, and diethyl ether.

The halogenating agent may be employed in Step C in any proportion with respect to Compound DI which will result in the formation of at least some of Compound IV, but it is typically employed in an amount that can optimize conversion to Compound IV. The halogenating agent is suitably employed in an amount of at least about 0.5 equivalent per equivalent of Compound HI, and is typically employed in an amount from about 0.5 to about 1.5 equivalents) per equivalent of Compound m. The reaction of Step C may be conducted at any temperature at which formation of

Compound IV can be detected. The temperature is suitably in a range of from about -45 to about 65°C, and is typically in a range of from about -10 to about 25°C (e.g., from about 0 to about 15⁰C).

The reaction of Step C may be conducted till the reaction is complete or the desired degree of conversion of Compound IV is achieved. The reaction time can vary widely depending upon, inter αliα, the reaction temperature and the choice and relative amounts of reactant and the halogenating agent, but the reaction time for complete conversion is typically in a range of from about 0.1 to about 24 hours (e.g., from about 0.1 to about 2 hours). Compound IV may subsequently be isolated (alternatively referred to as recovered) from the reaction mixture using conventional procedures and then redissolved for use in Step D, or alternatively the reaction mixture containing Compound IV can be concentrated and solvent switched for use in Step D without isolation.

The present invention includes a process for preparing a compound of Formula Vn which comprises Steps C, D and E as described above; and which further comprises:

(B) treating a compound of Formula II:

with an amine deprotecting agent to remove group W and obtain a compound of Formula in.

The group W in Compound II is an amine protective group. The amine protective group W can be any amine protective group that is stable with respect to the reaction conditions employed in generating precursors to Compound π and any subsequent processing to a desired derivative and labile enough to be removed (cleaved) via contact with a suitable amine deprotecting agent to give the free amine with little or no degradation of any other functional groups present in the compound. Amine protective groups are known in the art and are described, for example, in Protective Groups in Organic Chemistry, edited by J.F.W. McOmie, Plenum Press, New York, 1973, pp. 43-74; and in T.W. Greene and P.G.M. Wuts, Protective Groups in Organic Synthesis. 3^rd edition, John Wiley, New York, 1999, the disclosures of which are herein incorporated by reference.

Another embodiment of the process of the invention is the process as originally described, wherein the group formed by the / moiety in Compound II is a carbamate, an amide, or a tertiary amine; and all other variables are as originally defined or as defined in any one of the preceding embodiments. The term "carbamate" here refers to a group of formula /" ^cv °' , the term "amide" refers to a group of formula / '^" ' , and the term "tertiary amine" refers to / , wherein in each case R' independently represents an organic group which is chemically stable under reaction conditions employed in generating precursors of Compound π and which can be easily cleaved selectively to afford the unprotected amine. Another embodiment of the process of the invention is the process as originally described, wherein W is an amine protective group selected from the group consisting of:

(1) C i-6 alkyl substituted with aryl, where the aryl is optionally substituted with from 1 to 5 substituents each of which is independently halo, -NO2, -C 1.4 alkyl, or -O-Ci_4 alkyl, (2) C(=O)-Ci_4 haloalkyl,

(3) C(=O)-Ci_4 alkylene-aryl, where the aryl is optionally substituted with from 1 to 5 substituents each of which is independently halo, -NO2, -C 1.4 alkyl, or -OCi -4 alkyl, (4) C(=O)-O-(CH2)0-l-CH=CH2, and

(5) C(=0)-0-Ci-4 alkylene-aryl, where the aryl is optionally substituted with from 1 to 5 substituents each of which is independently halo, -NO2, -C 1.4 alkyl, or -OC I-4 alkyl; and all other variables are as originally defined or as defined in any of the foregoing embodiments. Still another embodiment of the process of the invention is the process as originally described, wherein W is an amine protective group selected from the group consisting of:

(1) -CH2-phenyl, where the phenyl is optionally substituted with from 1 to 3 substituents each of which is independently halo, -NO2, -Ci .4 alkyl, or -O-C1-.4 alkyl, (2) -C(=O)-CF₃,

(3) -CC=O)-CCl₃,

(4) -C(=0)-CH2-phenyl, where the phenyl is optionally substituted with from 1 to 3 substituents each of which is independently halo, -NO2, -Ci .4 alkyl, or -O-C1-4 alkyl, (5) -C(=O)-O-CH2-CH=CH2, and

(6) -C(=0)-0-CH2-phenyl, where the phenyl is optionally substituted with from 1 to 3 substituents each of which is independently halo, -NO2, -Ci .4 alkyl, or -O-C1-4 alkyl; and all other variables are as originally defined or as defined in any of the foregoing embodiments. In an aspect of the preceding embodiment, W is t-butyloxycarbonyl (i.e., Boc), benzyloxycarbonyl (Cbz), allyloxycarbonyl (Alloc), p-nitrobenzyloxycarbonyl, p-methoxybenzyloxycarbonyl, p-bromobenzyloxycarbonyl, p-chlorobenzyloxycarbonyl, or 2,4-dichloroben2yloxycarbonyl. In another aspect of the preceding embodiment, W is Boc.

In most instances the W group can be removed by treatment with acids including mineral acids, Lewis acids, and organic acids. Suitable mineral acids include hydrogen halides (HCl, HBr, and HF, as a gas or in aqueous solution), sulfuric acid, and nitric acid. Suitable organic acids include carboxylic acids, alkylsulfonic acids and arylsulfonic acids. Exemplary organic acids include trifluoroacetic acid (TFA), toluenesulfonic acid, benzenesulfonic acid, methanesulfonic acid, and trifluoromethanesulfonic acid. Suitable Lewis acids include BF₃-Et2θ, SnCl4, ZnBr2, Me₃SiI, Me3SiCl, Me3 SiOTf, and AICI3. Cleavage conditions (e.g., temperature, choice and concentration of acid) can vary from mild to harsh depending upon the lability of the amino protective group. In one embodiment the temperature is in a range of from about -40⁰C to about 100⁰C, and the acid (e.g., anhydride hydrogen chloride in ethyl acetate) is present in an amount of at least about 1 equivalent per equivalent of Compound H Although acid treatment is typically effective, other means can often be employed. Removal of CBZ or ALLOC, for example, is typically accomplished via hydrogenolysis (e.g., hydrogenation with a Pd catalyst). Further description of amine deprotecting agents and deprotection treatments suitable for use in Step B can be found in Protective Groups in Organic Chemistry, edited by J.F.W. McOmie, Plenum Press, New York, 1973, pp. 43-74; and in T. W. Greene and P.G.M. Wuts, Protective Groups in Organic Synthesis. 3^rd edition, John Wiley, New York, 1999, pp. 520-525. After removal of the protective group, Compound HI can be isolated using conventional techniques.

It is noted that under the deprotecting conditions described above, Compound IH may exist in a salt form, in which case Compound in may need to undergo a de-salting step before Step C may be performed. Suitable de-salting conditions include treating the salt form of Compound HI with a base. Examples of suitable base include alkali metal and alkaline earth metal hydroxide (e.g., LiOH,

NaOH, KOH, Mg(OH)₂, and Ca(OH)₂), alkali metal and alkaline earth metal phosphates (e.g., 3PO₄,

K3PO4, and Li3PO4), alkali metal and alkaline earth metal carbonates and bicarbonates (e.g., Li2CO3, K2CO3, Na2CO3, NaHCθ3, and CS2CO3), tertiary amines (e.g., triethylamine, tributylamine, tri-n- propylamine, and tri-isopropylamine), and diazabicycloalkenes (e.g., DBU and DABCO). Such de- salting treatment may also be conducted in a solvent. Suitable solvents include water/IP Ac, water/EtOAc, water/MTBE and water/THF.

The present invention includes a process for preparing a compound of Formula VII which comprises Steps B, C, D and E as described above; and which further comprises:

(A) treating a compound of Formula I:

with a hydroxy protecting agent to foπn a product which is a compound of Formula H

Suitable hydroxy protecting agents for use in Step A include those selected from the group consisting of sulfonylating agents and phosphinating agents, wherein the resulting O-L group in Compound II is respectively a sulfonate or a phosphinate. Treatment with a sulfonylating agent or a phosphinating agent is typically conducted in the presence of a base. A class of suitable protecting agents includes agents of formula L-Y, wherein L is hydrocarbylsulfonyl, dihydrocarbylphosphinyl, or dihydrocarbyloxyphosphinyl, and Y is halogen. A sub-class of the preceding class of suitable protecting agents includes agents of formula L-Y, wherein L is RISO2, (R^J)2P(O), or (R^KO)2P(O); Y is halogen; and RI, each RJ, and each RK are each as defined above in the description of Step E. Another sub-class of suitable agents includes agents of formula RΪSO2Y wherein Y is halogen, and Rl is as defined above in the description of Step E. Still another sub-class of suitable agents includes consists of p-toluenesulfonyl halides, benzenesulfonyl halides, methanesulfonyl halides, p-nitrobenκenesulfonyl halides, naphthalenesulfonyl halides, and 10-camphorsulfonyl halides. Another class of suitable protecting agents include anhydrides. Representative examples of such suitable hydroxy protecting agents include methanesulfonic anhydride.

Representative examples of suitable hydroxy protecting agents of formula L-Y are p-toluenesulfonyl chloride, benzenesulfonyl chloride, methanesulfonyl chloride, methanesulfonyl fluoride, p-nitrobenzenesulfonyl chloride, naphthalenesulfonyl chloride, 10-camphorsulfonyl chloride, methanesulfonyl bromide, and p-toluenesulfonyl bromide. Other suitable hydroxy protective groups are known in the art and are described, for example, in Protective Groups in Organic Chemistry, edited by J.F.W. McOmie, Plenum Press, New York, 1973; and in T.W. Greene and P.G.M. Wuts, Protective Groups in Organic Synthesis, 3^rd edition, John Wiley, New York, 1999.

The treatment of Compound I in Step A can be conducted in a solvent A which is virtually any solvent compatible with the protecting reagent and which won't compete with reagents in subsequent reaction conditions (e.g., the carboxylic acid or the amine in the coupling). Suitable solvents include those selected from the group consisting of alkanes, cycloalkanes, halogenated alkanes, halogenated cycloalkanes, aromatic hydrocarbons, alkylated and halogenated aromatic hydrocarbons, ethers, esters, tertiary amides, N-alkylpyrrolidones, sulfoxides, and nitriles. A class of solvents suitable for use as solvent A in Step A consists of the solvents selected from the group consisting of Ci- 10 linear and branched alkanes, Ci_lθ linear and branched halogenated alkanes, C5-I0 cycloalkanes, halogenated C5-10 cycloalkanes, benzene, naphthalene, mono- and di- and tri-Ci-6 alkyl substituted benzenes, halogenated benzenes, halogenated mono- and di- and tri-Ci_6 alkyl substituted benzenes, dialkyl ethers wherein each alkyl is independently a Ci-6 alkyl, Cμg linear and branched alkanes substituted with two -O-Ci-6 alkyl groups (which are the same or different), C4-C8 cyclic ethers and diethers, phenyl C 1.4 alkyl ethers, diethylene glycol di(Ci_4 alkyl) ethers, Ci -6 alkyl esters of Ci -6 alkylcarboxylic acids, N,N-di-(Ci_6 alkyl)-Ci_6 alkylamides, di-(Ci_6 alkyl)sulfoxides, and C2-C6 aliphatic nitriles. Representative examples of solvents suitable for use in Step A include carbon tetrachloride, chloroform, methylene chloride, 1,2-dichloroethane, 1,1,2-trichloroethane, 1,1,2,2- tetrachloroethane, ethyl ether, MTBE, THF, tetrahydropyran, dioxane, 1,2-dimethoxyethane, anisole, phenetole, diglyme, methyl acetate, ethyl acetate, isopropyl acetate, DMF₅ DMAC, DMSO, acetonitrile, propionitrile, pentane (individual isomers and mixtures thereof), hexane (individual isomers and mixtures thereof), heptane (individual isomers and mixtures thereof), cyclopentane, cyclohexane, cycloheptane, chlorocyclopentane, chlorocyclohexane, NMP, benzene, toluene, o- and m- and p-xylene, xylene mixtures, ethylbenzene, chlorobenzene, bromobenzene, o-chlorotoluene, 2,4-dichlorotoluene, and 2,4,6-trichlorotoluene.

The treatment in Step A can be conducted in the presence of a base, wherein the role of the base is to neutralize the acid by-product (e.g., HY such as HCl) caused by the derivatization (e.g., sulfonylation or phosphination with an L-Y agent as described above) of the OH group. Suitable bases included those selected from the group consisting of tertiary alkyl amines, tertiary cyclic amines, and diazabicycloalkenes. Representative examples of suitable bases include TEA, DIPEA, NMM, NMP, DBU (l,8-diazabicyclo[5.4.0]undec-7-ene), DBN (l,5-diazabicyclo[4.3.0]non-5-ene), DABCO, tri-n- propylamine, tri-isopropylamine, or tri-n-butylamine.

In a suitable embodiment, Step A is conducted in a solvent as described above and in the presence of a base as described above.

The hydroxy protecting agent can be employed in Step A in any proportion with respect to Compound I which will result in the formation of at least some of Compound π, but it is typically employed in an amount that can optimize conversion to Compound H The hydroxy protecting agent is suitably employed in an amount of at least about 0.5 equivalent per equivalent of Compound I, and is typically employed in an amount of at least about 1 equivalent (e.g., from about 1 to about 20 equivalents) per equivalent of Compound I. The hydroxy protecting agent is more typically employed in an amount in a range of from about 1 to about 5 equivalents (e.g., from about 1 to about 1.5 equivalents) per equivalent of Compound I.

The treatment in Step A can be conducted at any temperature at which the reaction to form Compound II can be detected. The temperature is suitably in a range of from about -45 to about

200⁰C, and is typically in a range of from about -30 to about 100⁰C (e.g., from about -15 to about 50⁰C), and is more typically in a range of from about -5 to about 30 ⁰C.

When base is employed in Step A, it is suitably employed in an amount of at least one equivalent per equivalent of hydroxy protecting agent, is typically employed in an amount of from about 1 to about 2 equivalents per equivalent of hydroxy protecting agent, and is more typically employed in a ratio of about 1 equivalent per equivalent of hydroxy protecting agent.

The treatment in Step A can be conducted by charging Compound I and a suitable solvent to a suitable reaction vessel, followed by the slow addition of the hydroxy protecting agent and base (if employed), bringing the resulting mixture to reaction temperature, and maintaining the mixture at reaction temperature (optionally with agitation such as stirring) until the reaction is complete or the desired degree of conversion to Compound II is achieved. The reaction time can vary widely depending upon, inter alia, the reaction temperature and the choice and relative amounts of reactant, protecting agent, and base, but the reaction time for complete conversion is typically in a range of from about 0.5 to about 24 hours (e.g., from about 1 to about 5 hours). The Step A product can be isolated using conventional procedures such as chromatography or crystallization from solvent, and redissolved in a suitable solvent B, or the product can be concentrated and solvent switched from a solvent A to a solvent B without isolation, followed by subsequent transformations.

The compounds of Formula I employed in Step A above may be prepared in accordance with procedures set forth in International patent application PCT/US/ (attorney docket No.

21595Y, titled "Process for Preparing Hexahydropyrimido[l,2-a]azepine-2-carboxylates and Related Compounds"), the content of which is incorporated herein by reference in their entirety.

The present invention also includes a process for preparing a compound of Formula DC:

which comprises conducting Step E as recited in claim 1; and which further comprises:

(F) either (i) reacting the compound of Formula VII with (i) (RMRN)N-C(=O)-C(=O)-OC(=O)-O-CI_6 alkyl, or (ii) reacting the compound of Formula VII with

RFO-C(=O)-C(=O)-K and then with (RMRN)NH₅ to obtain Compound VDI:

(G) removing the L group from Compound VIE to obtain a compound of Formula

IX; wherein: RM and RN are each independently C 1-6 alkyl or Cj_6 alkyl substituted with aryl, or alternatively RM and RN together with the N to which both are attached form C4.7 azacycloalkyl;

RF is C 1-6 alkyl; and

K is halo or OH.

Step F concerns with the coupling of Compound VII with (i) formula (RMRN)N-C(=0)-C(=0)-0C(=0)-0-CI_6 alkyl or (ii) formula RFO-C(=O)-C(=O)-K and then with

(RMRN)NH, to obtain Compound VIH The coupling reaction is suitably conducted in a solvent F at a temperature in the range of from about -50 to about 200⁰C, and is typically conducted at a temperature in the range of from about 50 to about 16O⁰C. Solvents suitable for use in Step F include those selected from the group consisting of halogenated alkanes, halogenated cycloalkanes, ethers, and nitriles. Further description of these solvent classes is set forth above in the discussion of solvents suitable for use in the other steps. These earlier descriptions are applicable here, and are incorporated herein. Examples of suitable solvent F include THF, DME, dioxane, dichloromethane, chloroform, 1,2-dichloroethane, DMF, and NMP. The coupling reaction of Step F is also suitably conducted in the presence of a base. Examples of such suitable base include 4-NMM, triethylamine, tripropylamine, and tributylamine.

The reagent (RMRN)N-C(=O)-C(=O)-OC(=O)-O-CI_6 alkyl or RFθ-C(=0)-C(0)-K is either available commercially or can be prepared by methods known in the art. The reagent (RMRN)N-C(=O)-C(=O)-OC(=O)-O-C 1 _6 alkyl or RFO-C(=O)-C(=O)-K may be employed in Step F in any proportion which will result in the formation of at least some of Compound VIE. Typically, however, the reagent (RMRN)N-C(=O)-C(=O)-OC(=O)-O-CI_6 alkyl or RFθ-C(=O)-C(=O)-K is employed in a stoichiometric or excess amount (i.e., an amount greater than about 1 equivalent per equivalent of Compound VII) in order to optimize the conversion of Compound VII. The reagent is typically employed in an amount of at least about 1.05 equivalents per equivalent of Compound VII, and is more typically employed in an amount in a range of from about 1.1 to about 10 equivalents per equivalent of Compound VII. The reaction of Step F may be suitably conducted by adding the reagent (RMRN)N-C(=O)-C(=O)-OC(=O)-O-CI_6 alkyl or RFOC(=0)-C(=0)-K to a solution or suspension of

Compound VII in the selected solvent or by adding Compound VII (either as a solid or in solution) to a solution or suspension of the reagent (RMRN)N-C(=O)-C(=O)-OC(=O)-O-C 1 _6 alkyl or

RFO-C(=O)-C(=O)-K, and then heating the mixture to reaction temperature and maintaining at reaction temperature until the reaction is complete or the desired degree of conversion of the reactants is achieved. The subsequent reaction in (ii) with the amine of formula (RMRN)NH is typically conducted by adding the amine to the reaction mixture containing acylated VII, bringing the mixture to the desired reaction temperature and aging the mixture at the reaction temperature until the amidation is complete. Isolation of Compound VIH can be accomplished by using conventional procedures.

In Step G, the L protecting group is removed from -O-L in the carboxamide of Formula Viπ to give a carboxamide of Formula IX. Such agents for removing the L group are well known in the art. Generally speaking, a chemical treatment can be employed in Step B which is suitable for the removal of group W (e.g., hydrogenolysis or acid hydrolysis as described above) is also suitable for the removal of residual L. Step G may be conducted in one-pot as Step F. Exemplary agents that may be used for the removal of group L include dimethylamine.

Embodiments of the process for preparing Compound IX include the process as described above and further comprising one or more of the pre-steps described above for preparing

Compound VH. Thus, embodiments of the process include the process comprising Steps E, F and G; and (1) further comprising Step D, or (2) further comprising Steps C and D, or (3) further comprising Steps B, C, D, or (4) further comprising Steps A, B, C, and D.

The present invention also relates to a process for preparing an N-halo compound comprising contacting an N-H compound with a halogenating agent (R^ C-OZ generated in situ, wherein each R7 is independently C \ -C\ 2 alkyl and Z is hao. This process represents a practical and efficient synthesis for the preparation of N-halo compounds via the in situ generation of (R^C-OZ. A class of the N-H compound that may be N-halogenated using the present process includes a primary amine, a secondary amine, a primary amide, a secondary amide, a primary sulfonamide, a secondary sulfonamide, a primary carbamate and a secondary carbamate.

N-HaIo compounds are versatile reagents and have been employed as potentially reactive intermediates that are widely used in organic synthesis. Several methods utilizing an electrophilic halogen source have been reported to achieve the N-halogenation of N-H compounds (see e.g., a) Zakrzewski, J. Synth. Commun. 1988, 18, p. 2135; b) Uskokovc, M.; Henderson, T.; Reese, C; Gutzwiller, J.; Lee, H. L.; Grethe, G.; Gutzwiller, J. J. Am. Chem. Soc. 1978, 100, p. 571; c) Poisel, H.; Schmidt, U. Chem. Ber. 1975, 108, p. 2547; d) Schneider, W.; Pomorin, D. K. Chem. Ber. 1972, 105, p.1553; e) Quick, J. Oterson, R. Synthesis 1976, p. 745; f) Coleman, G. H.; Nichols, G.; Martens, T. F. Org. Synth 1945, 25, p. 14; g) Gassman, P. G.; Dygos, D. K.; Trent, J. E. J. Am. Chem. Soc. 1970, 92, p. 2048; h) Favreau, S.; Lizzanicuvelier, L.; Loiseau, M.; Dunach, E.; Fellous, R. Tetrahedron Lett. 2000, 41, p. 9787; i) Claxton, G. P.; Allen, L.; Grisar, J. M. Org. Synth 1988, VI, p. 968; and j) Durham, T. B.; Miller, M. J. J. Org. Chem. 2003, 68, p. 27). Sodium hypohalites (e.g., bleach and NaOBr), fert-butyl hypochlorite, and N-halo succinimides (ΝCS and ΝBS) are the most common reagents used to perform this N-H to N-halo oxidation. However, these reagents have several limitations which curtail their use. NCS and NBS are widely used as N-halogenating reagents, but removal of the succinimide by-product is often difficult. Sodium hypochlorite is a safe, inexpensive commodity chemical, although secondary amine (/ ) oxidations typically suffer from prolonged reaction times with modest yields. N- halogenation with tert-butyl hypochlorite generally provides good to excellent yields; however, tert-butyl hypochlorite is an expensive, hazardous reagent that is best suited for small scale research applications (see, e.g., Curini, M.; Epifano, F.; MarcotuUio, M. C; Rosati, O.; Tsadjout, A. Synlett 2000, pp. 813-814; and Paquette, L. A. Encyclopedia of Reagents for Organic Synthesis; New York; John Wiley and Sons, 1995, Vol. 2, pp 890).

In the present process, the halogenating agent is (R^C-OZ which is generated in situ under biphasic conditions in the presence of an acid, wherein each R' is independently Cj-C^ alkyl and Z is halo. In one embodiment, organic solutions of the N-H compounds (e.g., amines or amides) are treated with an aqueous solution of alkali metal or alkaline earth metal hypohalite in the presence oϊtert- alcohol and an acid (e.g., aliphatic carboxylic acid such as acetic acid), wherein the role of the acid is to neutralize the alkali metal or alkaline earth metal hydroxides generated from the formation of (R '^C-

OZ. Under these biphasic conditions, (R^C-OZ (e.g., fe/t-butylhypohalite) is slowly generated in situ with the dropwise addition of the oxidant (i.e., hypohalites). The N-H compound in an organic solvent reacts with the organic soluble (R^C-OZ (e.g., te/t-butylhypohalite) to give the desired N-halo product in high yield (e.g., 90-100%). The N-H oxidation usually occurs rapidly, especially with amines, and the resulting exotherm is controlled in the present halogenation process by the slow addition of the oxidant (e.g., sodium hypohalite) to avoid the large buildup of (R^C-OZ (e.g., tert-bxAy\ hypohalite). This feature makes the present halogenation process particularly attractive for industrial scale processing given the low concentration of (R^C-OZ (e.g., tert-butyl hypohalite) at any given time.

In one embodiment, each R^ is independently C \ -C \Q alkyl. In an aspect of the preceding embodiment, each R^ is independently (4-C3 alkyl.

Exemplary alkali metal and alkaline earth metal hypohalites include sodium hypohalites (e.g., aqueous NaOCl and NaOBr) and calcium hypohalites (e.g., Ca(OCl)2 and Ca(OBr)2). Exemplary tert-alcohol include tert-bvAscnol; fert-amyl alcohol;2,3-dimethyl-2-butanol; 2-methyl-2-pentanol; 3- methyl-3-pentanol; 3-ethyl-3-pentanol; 2,3-dimethyl-3-pentanol; 3-ethyl-2,2-dimethyl-3-pentanol; 2- methyl-2-hexanol; 3,-7-dimethyl-3-octanol; and 2,4-dimethyl-2,4-pentanediol. Exemplary neutralizing acid includes an organic acid and a mineral acid. Suitable mineral acids include sulfuric acid, the hydrohalic acids (i.e., HCl, HBr, HI, and HF), nitric acid, phosphoric acid, and sulfuric acid. Suitable organic acids include carboxylic acids, such as C\. ft alkylcarboxylic acids and C\.β haloalkylcarboxylic acids. Representative examples of organic acids suitable for use in the present halogenating process include acetic acid, propionic acid, butyric acid, trifluoroacetic acid (TFA) and trichloroacetic acid. Organic solvents suitable for the present halogenation process include aromatic hydrocarbons, alkylated aromatic hydrocarbons, ethers, esters, and halogenated alkanes. Examples of such suitable organic solvents include methyl acetate, EtOAc, EPAc, diethyl ether, MTBE, THF, methylene chloride, benzene, toluene, o-, m-, and p-xylene and xylene mixtures. The present halogenation process may be conducted at any temperature at which tert-buty\ hypohalite is generated and the N-halo compound can be detected. The halogenation process is typically conducted at a temperature in a range of from about -80 to about 120⁰C, and is more typically conducted at a temperature in a range of from about -20 to about 6O⁰C (e.g., from about 0 to 25°C).

The contacting of an N-H compound with the halogenating agent (R^C-OZ (e.g., tert- butyl hypohalite) can be conducted till the reaction is complete or the desired degree of conversion of the reactant is achieved. The reaction time can vary widely depending upon, inter alia, the reaction temperature and the choice and relative amounts of reactants, but the reaction time for complete or near complete conversion is typically in a range of from about 0.1 to about 5 hours (e.g., from about 15 minutes to about 2 hours). The present invention also includes a compound of Formula IV:

wherein all variables are as originally defined above or as defined in any of the preceding embodiments (see, e.g., the embodiments defined in the description of Step E).

An embodiment is a compound of Formula IV, wherein Rl is C\S alkyl or Ci_g alkyl substituted with aryl wherein the aryl is optionally substituted with from 1 to 3 substituents each of which is independently Ci_4 alkyl, O-Ci-4 alkyl, CF3, OCF3, halo, CN, or NO2;

R2, R3₅ each R.4, each R^, and R6 are all H;

Z is chloro;

L is (1) SO2R¹, (2) P(O)(RJ)2, or (3) P(O)(ORK)₂; wherein Rl is (i) Ci-6 alkyl, (ii) Ci- β haloalkyl, (iii) C\-β alkyl substituted with aryl, (iv) aryl, or (v) camphoryl; each RJ is independently (i) Ci_6 alkyl, (ii) Cl -6 haloalkyl, (iii) Cl -6 alkyl substituted with aryl, or (iv) aryl; and each RK is independently (i) Q _6 alkyl or (ii) Ci_6 alkyl substituted with aryl; and wherein any aryl defined in Rl,

R^j, and RK is optionally substituted with from 1 to 5 substituents each of which is independently halogen, -Ci_4 alkyl, -O-C1.4 alkyl, CF3, OCF3, CN, or nitro; and T is

U^ are each independently H or halo. hi an aspect of the preceding embodiment, the compound of Formula IV is compound

The present invention also includes a compound of Formula V:

The present invention also includes a compound of Formula VI:

An embodiment is a compound of Formula V or VI, wherein Rl is C\.β alkyl or Cχ_6 alkyl substituted with aryl wherein the aryl is optionally substituted with from 1 to 3 substituents each of which is independently Ci_4 alkyl, O-Ci-4 alkyl, CF3, OCF3, halo, CN, or NO2;

R2, R3, each R4, each R5, and R6 are all H;

L is (1) SO2R¹, (2) P(0)(RJ)2, or (3) P(O)(ORK)₂; wherein Rl is (i) Ci-6 alkyl, (ii) Ci- 6 haloalkyl, (iii) C\.β alkyl substituted with aryl, (iv) aryl, or (v) camphoryl; each RJ is independently (i) C 1-6 alkyl, (ii) Ci_6 haloalkyl, (iii) C 1-6 alkyl substituted with aryl, or (iv) aryl; and each RK is independently (i) Q_6 alkyl or (ii) C 1-6 alkyl substituted with aryl; and wherein any aryl defined in Rl,

R^j, and RK is optionally substituted with from 1 to 5 substituents each of which is independently halogen, -Ci_4 alkyl, -O-Ci-4 alkyl, CF3, OCF3, CN, or nitro; and

are each independently H or halo. hi an aspect of the preceding embodiment, the compound of Formula V is 5a or the compound of Formula VI is compound 5b:

Other embodiments of the present invention include any and all of the processes as originally defined and described above and any embodiments or aspects thereof as heretofore defined, further comprising isolating (which may be alternatively referred to as recovering) the compound of interest (including but not limited to any of the compounds of Formula II to EK or any of the compounds 2, 3, 4, 4a, 5a, 5b, 6, or 9 as described in the examples) from the reaction medium. The progress of any reaction step set forth herein can be followed by monitoring the disappearance of a reactant (e.g., Compound V and/or VI in Step E) and/or the appearance of the desired product (e.g., Compound VII in Step E) using such analytical techniques as TLC, HPLC, IR, NMR or GC.

As is clear from the foregoing description, compounds embraced by Formula VII and precursors thereof are useful as intermediates in the preparation of compounds of Formula EX, which are FHV integrase inhibitors useful, inter alia, in treating FDV infection. More particularly, carboxamide compounds representative of the compounds embraced by Formulas VII and FX (e.g., Compound 9) have exhibited activity in an assay described in WO 02/30930 for inhibition of strand transfer in HTV integrase. Representative compounds have also exhibited activity in an assay (disclosed in Vacca et al., Proc. Natl. Acad. Sci. USA 1994, 9Jj 4096) for inhibition of acute HEV infection of T-lymphoid cells. The teπn "hydrocarbyl" as used herein refers to a group (e.g., a Ci -20 hydrocarbyl group) consisting of carbon and hydrogen atoms and having a carbon atom directly attached to the rest of the molecule. Examples of hydrocarbyl groups include alkyl, alkenyl, alicyclic, saturated bicyclic, alkyl substituted alicyclic, aromatic, and alkyl substituted aromatic. The hydrocarbyl group is optionally substituted with one or more non-hydrocarbon substituents (e.g., oxo, halo, nitro, cyano, and alkoxy) and also optionally has one or more of its carbon atoms replaced with a heteroatom (e.g., N, O, or S) provided that the substituted hydrocarbyl group is not chemically reactive under the reaction/treatment conditions employed and do not interfere with subsequent reaction steps.

The term "alkyl" refers to any linear or branched chain alkyl group having a number of carbon atoms in the specified range. Thus, for example, "Ci-6 alkyl" (or "Ci-Cβ alkyl") refers to all of the hexyl alkyl and pentyl alkyl isomers as well as n-, iso-, sec- and t-butyl, n- and isopropyl, ethyl and methyl. As another example, "C 1.4 alkyl" refers to n-, iso-, sec- and t-butyl, n- and isopropyl, ethyl and methyl.

The term "halogen" (or "halo") refers to fluorine, chlorine, bromine and iodine (alternatively referred to as fluoro, chloro, bromo, and iodo).

The term "haloalkyl" refers to an alkyl group as defined above in which one or more of the hydrogen atoms has been replaced with a halogen (i.e., F, Cl, Br and/or T). Thus, for example, "Ci_6 haloalkyl" (or "Ci-Cβ haloalkyl") refers to a Cl to C6 linear or branched alkyl group as defined above with one or more halogen substituents. The term "fluoroalkyl" has an analogous meaning except that the halogen substituents are restricted to fluoro. Suitable fluoroalkyls include the series (CH2)θ-4CF3 (i.e., trifiuoromethyl, 2,2,2-trifluoroethyl, 3,3,3-trifluoro-n-propyl, etc.). The term "-alkylene-" refers to any linear or branched chain alkylene (or alternatively

"alkanediyl") having a number of carbon atoms in the specified range. Thus, for example, "-C1-4 alkylene-" refers to the Cl to C4 linear or branched alkylenes. A class of alkylenes of particular interest with respect to the invention is -(CH2)l-4-, and sub-classes of particular interest include -(CH2)l-4-, -(CH2)l-3-, -(CH2)l-2-, and -CH2-. Also of interest is the alkylene -CH(CH3)-. The term "cycloalkyl" refers to any cyclic ring of an alkane having a number of carbon atoms in the specified range. Thus, for example, "C3.8 cycloalkyl" (or "C3-C8 cycloalkyl") refers to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.

The term "C4-7 azacycloalkyl" (or "C4-C7 azacycloalkyl") means a saturated cyclic ring consisting of one nitrogen and from four to seven carbon atoms (i.e., pyrrolidinyl, piperidinyl, azepanyl, or octahydroazocinyl).

Unless expressly stated to the contrary, all ranges cited herein (i.e., process ranges such as a temperature range and ranges defined in the compounds set forth herein) are inclusive; i.e., the range includes the values for the upper and lower limits of the range as well as all values in between. Thus, for example, a heterocyclic ring described as containing from "1 to 4 heteroatoms" means the ring can contain I₅ 2, 3 or 4 heteroatoms. It is also to be understood that any range (e.g., a temperature range) cited herein includes within its scope all of the sub-ranges within that range.

When any variable (e.g., R4 and R5) occurs more than one time in any constituent or in Formula I or in any other formula depicting and describing compounds employed or included in the invention, its definition on each occurrence is independent of its definition at every other occurrence. Also, combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.

The term "substituted" (e.g., as in "the aryl is optionally substituted with from 1 to 5 substituents ...") includes mono- and poly-substitution by a named substituent to the extent such single and multiple substitution (including multiple substitution at the same site) is chemically allowed. Unless expressly stated to the contrary, substitution by a named substituent is permitted on any atom in a ring provided such ring substitution is chemically allowed and results in a stable compound.

Any heterocyclic ring substituent defined herein (e.g., HetA) can be attached to the rest of the compound via either a ring carbon atom or a ring heteroatom, provided such attachment is chemically allowed and results in a stable compound.

The term "solvent" in reference to any of the solvents employed in a reaction or treatment step set forth herein (e.g., solvent E in Step E) refers to any substance which under the reaction conditions employed in the step of interest is in the liquid phase, is chemically inert, and will dissolve, suspend, and/or disperse the reactants and any reagents so as to bring the reactants and reagents into contact and to permit the reaction to proceed.

The term "aging" and variants thereof (e.g., "aged") mean allowing the reactants in a given reaction or treatment step to stay in contact for a time and under conditions effective for achieving the desired degree of conversion. The terms "aging" and variants thereof (e.g., "aged" are used herein interchangeably with the expression "maintaining at reaction temperature until the desired degree of conversion is achieved" and variants thereof (e.g., "maintained ...")

The "squiggly" line in a structure (i.e., " ΛAΛ, " ) refers to a bond that attaches a group to a double bond and further denotes that that group is either in a cis configuration or a trans configuration with a group attached to the other end of the double bond. It is to be understood that a structural formula of a compound containing " ^ " bonds encompasses all isomeric forms of the compounds, singly and in mixtures.

An asterisk ("*") in front of an open bond in the structural formula of a group marks the point of attachment of the group to the rest of the molecule.

10-camphorsulfonyl is

wherein the asterisk (*) indicates the point of attachment.

The term "% enantiomeric excess" (abbreviated "ee") means the % major enantiomer less the % minor enantiomer. Thus, a 70% enantiomeric excess corresponds to formation of 85% of one enantiomer and 15% of the other. The term "enantioselective" shall mean a reaction in which one enantiomer is produced (or destroyed) more rapidly than the other, resulting in the predominance of the favored enantiomer in the mixture of products.

The term "catalytic amount" refers herein to any amount that allows the reaction of interest (e.g., hydrogenation in Step E) to proceed under less extreme conditions and/or in a shorter reaction time compared to the reaction conditions and/or reaction time in the absence of the catalyst. A catalytic amount of a reagent can suitably be a substoichiometric amount of the reagent relative to the reactant substrate, such as an amount in a range of from about 0.01% to less than 10% equivalent per equivalent of the substrate.

Abbreviations used in the instant specification include the following: Ac = acetyl

Alloc or ALLOC = allyloxycarbonyl Bn = benzyl Bz = benzoyl

Boc or BOC = t-butyloxycarbonyl t-Bu = tertiary butyl

Cbz or CBZ = carbobenzoxy (alternatively, benzyloxycarbonyl) DMAC = N,N-dimethylacetamide DMF = N,N-dimethylformamide EtOAc = ethyl acetate EtOH = ethanol h = hour(s)

IPA = isopropyl alcohol IPAc = isopropyl acetate KF = Karl Fisher titration for water Me = methyl Ms = mesyl (methanesulfonyl) MTBE = methyl tert-butyl ether NMM = N-methylmorpholine NMR = nuclear magnetic resonance TEA = triethylamine

THF = tetrahydrofiiran

The following example serves only to illustrate the invention and its practice. The example is not to be construed as limitations on the scope or spirit of the invention.

EXAMPLE 1 Step 1: Preparation of (9-Mesylated Bicvclic Pyrimidone 2

To a solution of bicyclic pyrimidone 1 (36.84 g, 1.0 eq.) in acetonitrile (200 mL) was added TEA (12.3 mL, 8.91 g, 1.1 eq.) at room temperature. The resulting slurry was cooled to 0-5 ⁰C. To the slurry was slowly added methanesulfonyl chloride (6.5 mL, 9.62 g, 1.1 eq.) at 0-15 °C. The resulting slurry was aged at 5-15 ⁰C for 2 h (the reaction was monitored by HPLC). To the reaction mixture was slowly added water (450 mL). The resulting slurry was aged at 0 ⁰C for 2 h. The crystalline solid was filtered off, washed with water (200 mL), then haptane (100 mL), and dried under vacuum with nitrogen sweep to afford desired O-Mesylated Bicyclic Pyrimidone 2 (42.09 g, 98%). ¹H NMR (CD₃CN, 400 MHz) δ: 7.91 (br s, 0.3 H, rotamer), 7.64 (br s, 0.7 H, rotamer), 7.30 (br t, J= 8.5 Hz, 2 H), 7.04 (t, J= 8.5 Hz, 2 H), 5.40-5.15 (m, 1.7 H), 5.03 ( m, 0.3 H), 4.65-4.46 (m, 2 H), 3.55 (s, 3 H), 3.50-3.33 (m, 1 H), 2.84 (s, 3 H), 2.23-2.05 (m, 3 H), 1.85 (m, 1 H), 1.73 (m, 1 H), 1.43 (m, IH), 1.30 (s, 9 H). HPLC conditions: Column: Zorbax, Rx C8 250 x 4.6 mm; Temperature: 30 ⁰C; Detection at 210 nm; Mobile Phase: 0.1% aq H₃PO₄ (A)MeCN (B); Gradient: 90:10 (A)/(B) to 10:90 over 15 min, 10:90 hold for 5 min, 10:90 to 90:10 (A)/(B) over 10 seconds; Flow Rate: 1 mL/min. Retention time for the (9-Mesylated Bicyclic Pyrimidone 2: 14.769 min. Step_2L Preparation of O-Mesylated Bicvclic Pyrimidone Amine Hydrochloride Salt 3

Vigorous stirring was recommended for this step. To a 1 L round bottom flask was charged ethyl acetate (160 mL). To the solution of ethyl acetate was bubbled HCl gas (33.44 g, 10 eq.), at -30 to -20 ⁰C. O-Mesylated bicyclic pyrimidone 2 (crystalline solid, 49.34 g, 1.0 eq.) was slowly charged to the HCl-EtOAc solution at -30 to -20 ⁰C. The resulting solution was aged at -30 to -20 ⁰C for

1 h, and slowly warmed to 0 °C over 2.5 h, then aged from 0 ⁰C to rt over 2 h (100% conversion by HPLC). To the reaction mixture was diluted with EtOAc (188 mL), and slowly added heptane (376 mL) over 1 h. The resulting slurry was aged at rt for 1-2 h. The crystalline solid was filtered off, washed with heptane (100 mL), dried under vacuum with nitrogen sweep to afford desired product 3 (43.2 g, 99% isolated yield). ¹HNMR (CD₃CN, 400 MHz) δ: 7.91 (br s, 0.3 H, rotamer), 7.64 (br s, 0.7 H, rotamer), 7.30 (br t, J= 8.5 Hz, 2 H), 7.04 (t, J= 8.5 Hz, 2 H), 5.40-5.15 (m, 1.7 H), 5.03 ( m, 0.3 H), 4.65-4.46 (m,

2 H), 3.55 (s, 3 H), 3.50-3.33 (m, 1 H), 2.84 (s, 3 H), 2.23-2.05 (m, 3 H), 1.85 (m, 1 H), 1.73 (m, 1 H), 1.43 (m, IH), 1.30 (s, 9 H). HPLC conditions: Column: Zorbax, Rx C8 250 x 4.6 mm; Temperature: 30 ⁰C; Detection at 210 nm;

Mobile Phase: 0.1% aq H₃PO₄ (A)MeCN (B); Gradient: 90:10 (A)/(B) to 10:90 over 15 min, 10:90 hold for 5 min, 10:90 to 90:10 (A)/(B) over 10 seconds; Flow Rate: 1 mL/min. Retention time for compound 3: 8.015 min.

Step 3: Preparation of O-mesylated N-chloro Compound 4a

Vigorous stirring was required for this step. To a solution of amine-HCl salt 3 (34.77 g, 1.0 eq.) in IPAc/water (400mL/120 mL) was slowly added 2.5 Ν of NaOH (29.3 mL, 1.0 eq.) at 10-15 ⁰C. The resulting slurry was aged at 10-15 ⁰C for 0.5 h. The resulting mixture was directly used in the next step. To the solution of crude free amine 4 (0.07321 moles) in IP Ac/water solution was added (3.50 mL, 0.5 eq.). To the resulting solution was dropwise added acetic acid (4.23 mL, 1.0 eq.) and 0.75 M of aq. sodium hypochlorite (97.6 mL, 1.0 eq.) at the same time at -5-0 ⁰C over 0.5 h, and aged at 0 ⁰C for another 0.5 h. After phase cut, the organic layer was washed with brine (50 mL) at 0-5 °C. The organic solution was used in the next step.

For free amine 4: ¹HNMR (CD₃CN, 400 MHz) 5: 8.41 (br s, 1 H), 7.38 (dd, J= 8.6, 5.6 Hz, 2 H), 7.09 (t, J= 8.6 Hz, 2 H), 4.92 (dd, J= 14.2, 4.8 Hz, 1 H), 4.57-4.47 (m, 2 H), 3.90 (br d, J= 10.9 Hz, 1 H), 3.83 (d, J= 9.5 Hz, 1 H), 3.44 (s, 3 H), 2.36 (s, 3 H), 2.20-2.12 (m, 1 H), 1.88-1.79 (m, 3 H), 1.65-1.50 (m, 2 H).

HPLC conditions: Column: Zorbax, Rx C8 250 x 4.6 mm; Temperature: 30 ⁰C; Detection at 210 nm; Mobile Phase: 0.1% aq H₃PO₄ (A)ZMeCN (B); Gradient: 90:10 (A)/(B) to 10:90 over 15 min, 10:90 hold for 5 min, 10:90 to 90:10 (A)/(B) over 10 seconds; Flow Rate: 1 mL/min. Retention time for compound 4a: 14.183 min.

Preparation of O-Mesylated Imines/Enamine (5a/5b)

To the organic solution of N-chloro compound 4a (34.62 g, 1.0 eq.) in IPAc was slowly added DBU (11.0 mL, 1.0 equiv) at -5-0 ⁰C over 10 min. The resulting slurry was aged at 0 ⁰C for 1 h (>99A% conversion). To the reaction mixture was added water (100 mL). After a phase cut, the organic layer was washed with 5% Na₂SO₃ (50 mL), water (2 x 50 mL), and brine (50 mL). The organic layer was concentrated to 130 mL (total volume). Then, MTBE (100 mL), and heptane (120 mL) were slowly added over 0.5 h, respectively. The resulting slurry was aged at 15-20 ⁰C for 1 h. The yellow crystalline solid was filtered off, washed with IPAc/MTBE/heptane (1:1:2, 50 mL), dried under vacuum with nitrogen sweep to give desired product 5a and 5b (24.00 g, 75% isolated yield from 3). ¹H NMR (CDCl₃, 400 MHz) δ: 7.93 (br t, J= 6.2 Hz, 0.27 H), 7.73 (br t, J= 6.2 Hz, 0.73 H), 7.33-7.27 (m, 2 H), 7.04-6.98 (m, 2 H), 4.95 (t, J= 7.2 Hz, 0.73 H), 4.57 (d, J= 6.2 Hz, 1.46 H), 4.54 (d, J= 6.2 Hz, 0.54 H), 4.19-4.15 (m, 2 H), 4.03 (br s, 0.73 H), 3.57 (s, 2.19 H), 3.54 (s, 0.81 H), 3.39 (s, 0.81 H), 2.70 (s, 2.19 H), 2.56- 2.53 (m, 0.73 H), 2.20-2.06 (m, 1.81H), 1.96-1.90 (m, 1 H), 1.84-1.77 (m, 1 H). HPLC conditions: Column: Zorbax, Rx C8 250 x 4.6 mm; Temperature: 30 ⁰C; Detection at 210 nm; Mobile Phase: 0.1% aq H₃PO₄ (A)MeCN (B); Gradient: 90:10 (A)/(B) to 10:90 over 15 min, 10:90 hold for 5 min, 10:90 to 90:10 (A)/(B) over 10 seconds; Flow Rate: 1 mL/min. Retention time for enamine/imines (5a/5b): from 10.939 to 12.049 min. (broad)

Preparation of Chiral Free Amine 6 via Asymmetric hvdrogenation

Trifiuoroethanol (Acros, 99.8%) was degassed by sparging with N₂ and dried over molecular sieves overnight. A degassed solution OfCF₃CO₂H (1.96 g, 17.15 mmol; Fisher, peptide synthesis grade) was prepared in trifiuoroethanol (18.65 mL) and dried overnight over molecular sieves (total solution volume of 20 mL). The catalyst solution was prepared by dissolving (chloro(l,5- cyclooctadiene)rhodium(I) dimer (0.022 g, 0.195 mole%), and Josiphos J212-1 (0.050 g, 0.42 mole%; purchased from Solvias AG, Basel, Switzerland) in trifiuoroethanol (3.0 mL) and aging at room temperature for 2 h. The enamine/imine (5a/5b, 10.0 g, 1.0 eq.) was dissolved in trifiuoroethanol (20 mL) and transferred to the glass hydrogenation vessel along with a trifiuoroethanol rinse (10 mL). The catalyst solution was transferred to the same vessel along with trifiuoroethanol rinse (5 mL). A portion of the CF₃CO₂H solution (12.0 mL) was also added to the reaction mixture. The resulting mixture was hydrogenated for 20.5 h at 90 psi in a thermostated 25 ⁰C oil bath (98.4A% conversion). The assay yield of O-mesylated free amine was 92% with 91.4% ee. Work up procedure: The chiral amine/amine^»TFA salt in trifloroethanol solution was concentrated to a total volume (15 mL) at 15 ⁰C to 25 ⁰C, and solvent-switched by IPAc ( about 3 x 50 mL) at the temperature until the concentration of trifloroethanol is less than 1 equiv of chiral amine 6. The IPAc solution was adjusted to a total volume (115 mL), and cooled to 0-5 ⁰C. Water (25 mL) was added and aged for 0.5 h at the same temperature. To the resulting solution was added dropwise 2.5 N sodium hydroxide solution (4.12 mL, 0.45 eq.) at 0-5 ⁰C, and aged for 1 h at the same temperature. After phase cut, the aqueous solution was extracted by IPAc (25 mL). The combined organic layer was washed with water (2 x 25 mL) and brine (25 mL). The organic solution was treated with activated carbon DARCO G-60 (5 g, 50wt%) at room temperature for 1 h. The DARCO was filtered off by pass a short Solka flock (5 g, 50wt%) and washed with IPAc (25 mL). The combined organic solution was concentrated to a total volume (20 mL) at 15-25°C, and solvent-switched by THF (about 20 volume) at the same temperature, then concentrated to a total volume (20 mL). At this point, the concentration of

PAc is less than 10 mole% compared to the chiral amine, and KF <320 ppm. The chiral amine 6 in the

IPAc solution was assayed to be 8.66 g.

HPLC conditions: Column: Zorbax, Rx C8 250 x 4.6 mm ; Temperature: 30 ⁰C; Detection at 210 nm;

Mobile Phase: 0.1% aq H₃PO₄ (A)/MeCN (B); Gradient: 90:10 (A)/(B) to 10:90 over 15 min, 10:90 hold for 5 min, 10:90 to 90:10 (A)/(B) over 10 seconds; Flow Rate: 1 mL/min.

Retention time for enamine/imines (5a/5b): from 10.939 to 12.049 minutes (broad). Retention time for product amine 6: 8.015 min. Retention time for des-OMs impurity: 7.686 min. Retention time for hydroxy impurity: 11.271 min.

Chiral SFC conditions: Column: Chiralpak AD-H 250 x 4.6 mm; Temperature: 35 ⁰C; Detection at 215 nm; Mobile Phase: 200 bar CO₂ (A)/25 mM /BuTMH₂ in MeOH (B); Isocratic 25% B; Flow Rate: 1.5 mL/min.

Retention time for undesired enantiomer: 4.33 min. Retention time for desired enantiomer (6): 5.79 min.

Step 6: Preparation of 9

To a solution of acid 7 (2.95 g, 1.3 eq.) in THF (57 mL) was added ethyl chloroformate (2.23 mL, 1.2 eq.) at 0-5 ⁰C. Then, 4-NMM (2.60 mL, 1.22 eq.) was slowly added to the reaction mixture at 0-5 °C. The reaction mixture was aged at the same temperature for 2 h. The chiral free amine 6 (8.50 g, 1.0 eq.) in THF (20 mL, KF <320 ppm) solution was slowly added to the mixed-anhydride solution at - 5 to 0 °C over 20 min., and aged at the same temperature for 10 min. To the reaction mixture was slowly added 4-NMM (2.56 mL, 1.2 eq.) at 0-5 ⁰C, and aged for 1 h, and then warmed to room temperature (100A% conversion by HPLC). Dimethylamine anhydrous (gas, 7.0 g, 8 eq.) was added to the reaction mixture, and aged at 50 ⁰C for 3-5 h (100 A% conversion by HPLC). The reaction mixture was acidified by 5 N HCl to adjust pH = 2-4 at 5-15 ⁰C. EtOAc (75 mL) was added. After a phase cut, the aqueous layer was extracted by EtOAc (36 mL). The combined organic layer was washed with 1 N HCl (20 mL), water (36 mL), brine (36 mL). The organic layer was concentrated at 20-25 ⁰C. About 10 volume of additional EtOAc was used for the azeotrope (KF <250 ppm). The final volume of EtOAc solution was adjusted to 27 mL, and was seeded with 20 mg of 9. The resulting slurry was aged at room temperature for 0.5 h. n-Heptane (65 ml) was slowly added to the slurry over 0.5 h. The slurry was aged at room temperature for 1 h. The crystalline solid was filtered off, washed with EtOAc/n-heptane (1: 3, 30 mL), dried under vacuum with nitrogen sweep to give crude compound 9 (8.5 g, 96%). The crude compound 9 was recrystallized from methanol/water to give pure compound 9 (7.31 g, 86%). [α]_D -86.3 (c 1.8, DMSO). ¹HNMR (CDCl₃, 400 MHz) δ: 12.13 (s, 1 H), 9.41 (br s, 1 H), 7.38 (dd, J= 8.5, 5.4 Hz, 2 H), 7.00 (t, J= 8.5 Hz, 2 H), 5.40 (br s, 1 H), 5.29 (dd, J= 14.5, 6.0 Hz, 1 H), 4.60 (dd, J= 14.5, 6.6 Hz, 1 H), 4.52 (dd, J= 14.5, 6.3 Hz, 1 H), 3.35 (dd, J= 14.5, 11.6 Hz, 1 H), 3.04 (s, 3 H), 3.01 (s, 3 H), 2.98 (s, 3 H), 2.23-2.12 (m, 3 H), 1.95-1.81 (m, 2 H), 1.58-1.49 (m, 1 H).

HPLC conditions: Column: Zorbax, Rx C8 250 x 4.6 mm; Temperature: 30 ⁰C; Detection at 210 nm; Mobile Phase: 0.1% aq H₃PO₄ (A)/MeCN (B); Gradient: 90:10 (A)/(B) to 10:90 over 15 min, 10:90 hold for 5 min, 10:90 to 90:10 (A)/(B) over 10 seconds; Flow Rate: 1 mL/min. Retention time for title compound 9: 12.191 min.

EXAMPLE 2 General procedure for preparation of N-halo compounds:

To a solution of amine/amide (5.0 mmole), tert-hutanol (0.25-1 equiv.) in MTBE solution was slowly added acetic acid (1-1.5 equiv.) and sodium hypohalite (1-1.5 equiv) at -5 to 0 ⁰C at the same time. The resulting solution was aged at the same temperature for 15 min to 2 h. The organic layer was separated and washed with water, and then brine. The organic solution was concentrated to give desired N-halo compound in 90-100% yield. Representative N-halo compounds prepared by this method are shown in Table 1 below. All of the resulting N-halo compounds gave satisfactory analytical and spectral data in accordance to their structures. Compound 2-4: ¹H ΝMR (400 MHz, CDCl₃) δ: 7.44-7.34 (m, 5 H), 5.27 (s, 2 H), 4.53

(dd, J= 5.9, 2.7 Hz, 1 H), 3.40 (dd, J= 13.6, 5.9 Hz, 1 H), 3.21 (dd, J= 13.6, 2.7 Hz, 1 H); ¹³C ΝMR (100 MHz, CDCl₃) δ: 168.1, 164.8, 134.7, 128.9 (2C), 128,8, 128.5 (2 C), 68.0, 57.4, 43.4.

Compound 2-5: ¹HNMR (400 MHz, CDCl₃) δ: 7.40-7.30 (m, 5 H), 5.21 (s, 2 H), 4.27 (dd, J= 5.9, 2.7 Hz, 1 H), 3.46 (dd, J= 13.3, 5.9 Hz, 1 H), 3.29 (dd, J= 13.3, 2.7 Hz, 1 H); ¹³C NMR (100 MHz, CDCl₃) δ: 168.5, 166.0, 134.7, 128.7 (2 C), 128.5, 127.0.

Compound 2-15: ¹H NMR (400 MHz, CDCl₃) δ: 6.58 (s, 2 H), 4.19 (q, J= 6.6 Hz, 1 H), 3.85 (s, 6 H), 3.63 (m, 1 H), 3.38 (m, 1 H), 3.00-2.89 (m, 2 H), 1.56 (d, J= 6.6 Hz, 3 H); ¹³C NMR (IOO MHz, CDCl₃) δ: 148.0, 147.7, 129.7, 124.5, 111.1, 109.7, 65.3, 56.1, 55.9, 55.3, 27.1, 21.6. Compound 2-16: ¹HNMR (400 MHz, CDCl₃) δ: 7.39-7.19 (m, 3 H), 7.12 (br. d, J= 7.0 HZ, 2 H), 4.62 (d, J= 9.2 Hz, 1 H), 4.20 (q, J= 7.2 Hz, 2 H), 3.89 (td, J= 9.2, 6.8 Hz, 1 H), 3.04 (d, J= 6.8 Hz, 2 H), 1.22 (t, J= 7.2 Hz, 3 H); ¹³C NMR (100 MHz, CDCl₃) δ: 171.9, 135.8, 129.2 (2 C), 128.6 (2 C), 127.1, 68.4, 61.5, 37.9, 14.1.

While the foregoing specification teaches the principles of the present invention, with an example provided for the purpose of illustration, the practice of the invention encompasses all of the usual variations, adaptations and/or modifications that come within the scope of the following claims.

Table 1. Synthesis of N-HaIo Compound

Entry Substrate Product NaOX (equiv f f-BuOH (equiv ) AcOH (equiv ) Solvent reaction time (h) Yield (%)'

1 1 1 1 toluene 2 100

8 1 1 — MTBE 025 100

9

1 1 — MTBE 0 5 90

^ ,CONH₂ _/-_V^CONH₂

13 14 2-13 X = Cl 1 1 1 EtOAc 0 5

2-14 X = Br 1 1 1 EtOAc 1 90 90

NH₂. HCI ^CKNH

16 ^Ph^CO₂Et ^Ph^CO₂E* 1 0 5 — MTBE 1 96 2-16

^a 0.75 M of sodium hypochlorite solution and 0.5 M of sodium hypobromide was used. ^b Isolated yields were obtained via evaporation of solvents to give desired products which were determined to be >95% pure by ¹HNMR.

Claims

WHAT IS CLAIMED IS:

1. A process for preparing a compound of Formula VII:

comprising:

(E) contacting a compound of Formula V:

or a compound of Formula VI:

L is a hydroxy protecting group;

Rl is:

(D H₅

(2) Ci-6 alkyl,

(3) Ci-6 alkyl substituted with O-Ci_6 alkyl, C3.8 cycloalkyl, or aryl, wherein the cycloalkyl is optionally substituted with from 1 to 3 C\-β alkyl groups and the aryl is optionally substituted with from 1 to 5 substituents each of which is independently Cχ-6 alkyl, O-Ci_β alkyl, CF3, OCF3, halo, CN, or NO2, or (4) aryl which is optionally substituted with from 1 to 5 substituents each of which is independently C\-β alkyl, O-Ci_6 alkyl, CF3, OCF3, halo, CN, or NO2;

R2, R3, each R.4, each R^, and R6 are independently: (1) H,

(2) Ci_6 alkyl, or

(3) Ci_6 alkyl substituted with O-Cχ-6 alkyl, C3_8 cycloalkyl, or aryl, wherein the cycloalkyl is optionally substituted with from 1 to 3 Ci_6 alkyl groups and the aryl is optionally substituted with from 1 to 5 substituents each of which is independently C\.β alkyl, O-Cl-6 alkyl, CF3, OCF3, halo, CN, or NO2;

each aryl is independently phenyl or naphthyl;

n is an integer equal to zero, 1, 2 or 3;

TJl, Tj2 and U^ are each independently selected from the group consisting of H, halo, Cl -6 alkyl, O-Cl-6 alkyl, Ci_6 fluoroalkyl, SO2-C1.6 alkyl, C(=O)-NH(-Ci_6 alkyl), C(=O)-N(-Ci_6 alkyl)2, and HetA;

Vl is H, halo, Ci -6 alkyl, or Ci -6 fluoroalkyl; and

2. The process of claim 1 , wherein said rhodium metal precursor is

[Rh(monoolefin)2Cl]2, [Rh(diolefm)Cl]2, [Rh(monoolefin)2acetylacetonate], [Rh(diolefin)acetylacetonate], [Rh(monoolefin)4]X, or [Rh(diolefin)2]X; wherein X is a non- coordinating anion selected from the group consisting of methanesulfonate, trifluoromethanesulfonate (Tf), tetrafluoroborate (BF4), hexafluorophosphate (PF β), and hexafluoroantimonate (SbFg).

3. The process of claim 2, wherein said rhodium metal precursor is [Rh(COD)Cl]2 or [(COD)₂Rh]BF₄.

4. The process of claim 1, wherein said chiral phosphine ligand is Josiphos J212-1,

BINAP, C₁ to C₆-TunaPhos, CTH-P-Phos, xylBJJSLAP, xyl-P-Phos, Pcyco-BoPhoz, Et-FerroTANE, iPrFerroTANE, Josiphos (2-furyl)₂P-F-C-P(3, 5-Me₂Ph)₂, Josiphos (2-furyl)₂P-F-C-P(o-tolyl)₂, Josiphos (3,5-Me2-4-MeOPh)₂P-F-C-PtBu₂, Josiphos (cyHex)₂P-F-C-P(cyHex)₂, Josiphos (o-tolyl)₂P-F-C-P(o- tolyl)2, Josiphos (p-FPh)₂P-F-C-PtBu₂, Josiphos Ph₂P-F-C-PtBu₂, Binapine, CTH-JAFAPhos.

5. The process of claim 4, wherein said chiral phosphine ligand is (R)-l-[(S)-2-di- 2-furylphosphino]ferrocenyl]-ethyldi-tert-butylphosphine (Josiphos J212-1).

6. The process of claim 1, wherein the hydrogen source is H₂ gas.

7. The process according to claim 1, wherein L is a sulfonate or a phosphinate.

8. The process according to claim 7, wherein L is: (1) SO₂Rl, (2) P(O)(RJ)₂, or

wherein

Rl is (i) Ci_6 alkyl, (ii) C\.β haloalkyl, (iii) C\s alkyl substituted with aryl, (iv) aryl, or (v) camphoryl; each RJ is independently (i) C\.β alkyl, (ii) C 1-6 haloalkyl, (iii) C\.β alkyl substituted with aryl, or (iv) aryl; and each RK is independently (i) C\. β alkyl or (ii) C\.β alkyl substituted with aryl; and wherein any aryl defined in Rl, RJ, and RK is optionally substituted with from 1 to 5 substituents each of which is independently halogen, -Ci .4 alkyl,

-O-Cl-4 alkyl, OCF3, CN, or nitro.

9. The process of claim 1, wherein R2, R3, each R4, each R^, and R6 are all H.

10. The process of claim 1, wherein T is U¹

U³ , wherein TJl, TJ2 and XJ3 are each independently selected from the group consisting of H, halo, C 1-6 alkyl, and C\.ζ fluoroalkyl.

11. The process of claim 1 , wherein said rhodium metal precursor is employed in a catalytic amount; and Step E is conducted at a temperature in a range of from about -10 to about 90 ⁰C.

12. The process of claim 1, wherein the contacting is conducted in a solvent E selected from the group consisting of alcohols, halogenated alcohols, phenol, halogenated phenols, polyhydroxylated benezenes, ethers, halogenated alkanes, aromatic and alkylated aromatic hydrocarbons, and esters.

13. The process of claim 1 , further comprising: (D) treating a compound of Formula IV:

with a base to form a compound of Formula V, a compound of Formula VI or a mixture thereof, wherein Z is halo.

14. The process of claim 13, wherein said base is tertiary alkyl amines, tertiary cyclic amines, diazabicycloalkenes, amidine, alkoxides of alkali and alkaline earth metals, alkali metal and alkaline earth metal phosphates, alkali metal and alkaline earth metal carbonates, alkali metal and alkaline earth metal hydroxides, and tetraalkyl ammonium hydroxide [(alkyl^NOH].

15. The process of claim 13 , further comprising: (C) contacting a compound of Formula HI:

with a halogenating agent to form a compound of Foπnula IV.

16. The process of claim 15, wherein said halogenating agent is t-butylhypohalite either generated in situ or pre-formed.

17. The process of claim 15 , further comprising: (B) treating a compound of Formula II:

with an amine deprotecting agent to remove group W and obtain a compound of Formula EOL

18. The process of claim 17, further comprising: (A) treating a compound of Formula I:

with a hydroxy protecting agent to form a product which is a compound of Formula π.

19. A process for preparing a compound of Formula IX:

(F) either (i) reacting the compound of Formula VII with (i) (RMRN)N-C(=O)-C(=O)-OC(=O)-O~CI_6 alkyl, or (ii) reacting the compound of Formula VII with

RFO-C(=O)-C(=O)-K and then with (RMRN)NH, to obtain Compound VIE:

(G) removing the L group from Compound VIE to obtain a compound of Formula

IX; wherein:

RM and RN are each independently C\-β alkyl or C\.β alkyl substituted with aryl, or alternatively RM and RN together with the N to which both are attached form C4.-7 azacycloalkyl;

RF is C 1-6 alkyl; and

K is halo or OH.

20. A process for preparing an N-halo compound comprising contacting an N-H compound with (R^C-OZ generated in situ, wherein each R^ is independently Cj-C^ alkyl and Z is halo.

21. The process of claim 20, wherein (R^C-OZ is generated in situ by contacting alkali metal or alkaline earth metal hypohalite with tert-alcohol in the presence of an acid.

22. The process of claim 21, wherein tert-alcohol is selected from the group consisting of tert-butanόl; tert-amy\ alcohol; 2,3-dimethyl-2-butanol; 2-methyl-2-pentanol; 3-methyl-3- pentanol; 3--ethyl-3-pentanol; 2,3-dimethyl-3-pentanol; 3-ethyl-2,2-dimethyl-3-pentanol; 2-methyl-2- hexanol; 3,-7-dimethyl-3-octanol; and 2,4-dimethyl-2,4-pentanediol.

23. The process of claim 21 , wherein (R^ C-OZ is t-butylhypohalite .

24. The process of claim 21, wherein the acid is a carboxylic acid.

25. The process of claim 20, wherein the N-H compound is selected from the group consisting of a primary amine, a secondary amine, a primary amide, a secondary amide, a primary sulfonamide, a secondary sulfonamide, a primary carbamate and a secondary carbamate.

26. The process of claim 20, wherein the contacting is conducted in an organic solvent selected from the group consisting of esters, ethers, aromatic hydrocarbons, alkylated aromatic hydrocarbons, and halogenated alkanes.

27. A compound of Formula IV, Formula V, or Formula VI:

L is a hydroxy protecting group; Rl is:

(1) H,

(2) Ci_6 alkyl,

(3) C 1-6 alkyl substituted with O-Ci-6 alkyl, C3-8 cycloalkyl, or aryl, wherein the cycloalkyl is optionally substituted with from 1 to 3 Ci_6 alkyl groups and the aryl is optionally substituted with from 1 to 5 substituents each of which is independently C 1-6 alkyl, O-Ci_6 alkyl, CF3, OCF3, halo, CN, orNO2, or

(4) aryl which is optionally substituted with from 1 to 5 substituents each of which is independently C\s alkyl, O-Ci-6 alkyl, CF3, OCF3, halo, CN₅ or NO2;

R2, R3, each R4, each R5, and Rfi are independently:

(D H,

(2) Ci-6 alkyl, or

(3) Ci_6 alkyl substituted with O-Ci_6 alkyl, C3-8 cycloalkyl, or aryl, wherein the cycloalkyl is optionally substituted with from 1 to 3 Ci_6 alkyl groups and the aryl is optionally substituted with from 1 to 5 substituents each of which is independently Cl -6 alkyl, O-Ci-6 alkyl, CF3, OCF3, halo, CN, or NO2;

each aryl is independently phenyl or naphthyl;

n is an integer equal to zero, 1, 2 or 3;

TJl, TJ2 and Ij3 are each independently selected from the group consisting of H, halo, Ci_6 alkyl, O-Ci-6 alkyl, fluoroalkyl, SO2-C1-6 alkyl, C(=O)-NH(-Ci_6 alkyl), C(=0)-N(-Ci_6 alkyl)2, and HetA;

Vl is H, halo, Ci_6 alkyl, or Ci-6 fluoroalkyl; each HetA is independently a 5- or 6-membered heteroaromatic ring containing from 1 to 4 heteroatoms independently selected from N, O and S, wherein the heteroaromatic ring is optionally substituted with 1 or 2 Ci_6 alkyl groups; and

Z is halo.

28. The compound according to claim 27, which is Compound 4a, Compound 5a or

Compound 5b: