Hydroxyethylamine derivatives for the treatment of alzheimer`s disease

DESCRIPTION

HYDROXYETHYLAMINE DERIVATIVES FOR THE TREATMENT OF

ALZHEIMER'S DISEASE

The present invention relates to novel Asp2 (β-secretase, BACE1 or Memapsin) inhibiting activity hydroxyethylamine compounds, processes for their preparation, compositions containing them and their use in the treatment of diseases characterized by elevated levels. β-amyloid deposits or β-amyloid deposits, particularly in Alzheimer's disease.

Alzheimer's disease is a degenerative brain disorder in which extracellular deposition of Ab in the form of senile plaques represents a key pathological feature of the disease (Selkoe, DJ (2001) Physiological Reviews 81: 741-766). The presence of senile plaques is accompanied by a prominent inflammatory response and neuronal loss. Bamyloids (Ab) exist in soluble and insoluble forms, fibrillar forms, and a specific fibrillar form has been identified as the predominant neurotoxic species (Vassar, R. and Citron, M. (2000) Neuron 27: 419-422). Furthermore, it has been found that dementia is more closely related to soluble amyloid levels than to plaque burden (Naslund, J. et al. (2000) J. Am. Med. Assoe. 12: 1571-1577; Younkin , S. (2001) Nat. Med. 1: 8-19). It is known

ΡΕ1567488 Αβ is produced by cleaving the beta-amyloid precursor protein (also known as APP) by an aspartyl protease enzyme known as Asp2 (also known as β-secretase, BACEl or Memapsin) (De Strooper, B. and Konig, G (1999) Nature 402: 471-472).

Thus, it was proposed that inhibition of the Asp2 enzyme would reduce the level of APP processing and consequently reduce the levels of Αβ peptides found in the brain. Thus, inhibition of the enzyme Asp2 is also thought to be an effective therapeutic target in the treatment of Alzheimer's disease.

APP is cleaved by various proteolytic enzymes (De Strooper, B. and Konig, G. (1999) Nature 402: 471-472). Key enzymes in the amyloidogenic pathway are Α3ρ2 (βsecretase) and γ-secretase, both aspartic proteinases and the cleavage of APP by these enzymes generates Αβ. The non-amyloidogenic pathway, α-secretase, which prevents formaçãoβ formation has been shown to be catalyzed by several proteinases, the best candidate being ADAM10, a disintegrin and metalloproteinase. Aspl has been reported to exhibit both α- and β-secretase activity in vitro. Aspl and Asp2 expression patterns are quite different, Asp2 is expressed higher in the pancreas and brain while Aspl expression occurs in many other peripheral tissues. The mouse with deleted Asp2 indicates that the lack of Asp2 abolished Αβ production and also shows that in this endogenous Aspl animal model it cannot replace

61567488 Asp2 deficiency (Luo, Y. et al. (2001) Nat Neurosci. 4: 231-232; Cai, H. et al. (2001) Nat Neurosci. 4: 233-234;

Roberds, SL et al. (2001) Hum. Mol. Genet. 10: 13171324).

For an agent to be therapeutically useful in the treatment of Alzheimer's disease it is preferred that said agent be a potent Asp2 enzyme inhibitor, but should ideally also be Asp2 selective over other aspartyl proteinase enzymes, eg Cathepsin D (Connor , GE (1998) Cathepsin D in Handbook of Proteolytic Enzymes, Barrett, AJ, Rawlings, ND, & Woesner, JF (Eds) Academic Press London.

828-836).

WO 01/70672, WO 02/02512, WO 02/02505, WO 02/02506 and WO 03/040096 (Elan Pharmaceuticals Inc.) describe a series of hydroxyethylamine compounds with β-secretase activity that are considered useful in the treatment of Alzheimer's disease.

We have found a new series of compounds that are potent inhibitors of the Asp2 enzyme, thereby indicating the potential for these compounds to be effective in treating Alzheimer's disease.

Thus, according to a first aspect of the present invention, we provide a compound of formula (I):

ΡΕ1567488

air

H OH H (I) where

R¹ represents C₂-₆ alkyl, C₂-6 alkenyl halogen C₂6th alkoxy, amino, cyano, hydroxy, aryl, heteroaryl or heterocyclyl;

R^2nd represents hydrogen, C1-3 alkyl C1-3 alkoxy or halogen;

m and n independently represent 0, 1 or 2;

X represents CO, SO or SO₂;

p represents an integer from 1 to 3;

R^2b represents hydrogen,₆ C alkyl₂-₆ alkenyl, halogen, C1-4₆ alkoxy, amino, cyano, hydroxy, aryl, heteroaryl or heterocyclyl;

R³ represents halogen, C₂_6 C alkyl₂- 6 alkenyl, aryl, heteroaryl, heterocyclyl, -C1-₆ alkylaryl, -C1-₆alkyl heteroaryl, -C 1-6 alkyl heterocyclyl, -C₂-6 alkenyl aryl, -C₂Alkenyl heteroaryl, -C₂_6 alkenyl-heteΡΕ1567488 rocylyl, C₃-8 cycloalkyl, -Cg-₆ C-alkyl₃-8 cycloalkyl, cyano, azido, nitro, -NR⁷R⁸, -NR⁹COLOR¹⁰, -NR^noSO2R¹², -0R¹³, -SO2R¹⁴, -SR¹⁵, -C = CR¹⁶-C1-6 alkyl- (CF₂)_whatCF₃, -CONR¹⁷R¹⁸,

COOR¹⁹, -Cg-g alkyl-NR²⁰R²¹ or -Cg-₆ N-alkyl₃ or R³ and R^2btogether with the phenyl group to which they are attached form a benzofused naphthyl or heterocyclic ring or heteroryl optionally substituted by one or two C1-6 alkyl groups;

R⁴ represents -C₂-6 alkynyl, -Cg_₆ alkylaryl, -Cg-₆alkyl heteroaryl or -C6-6 alkyl heterocyclyl;

R⁵ represents hydrogen, -Cg_10 alkyl -C3_10 cycloalkyl, -C3_g0 cycloalkenyl, aryl, heteroaryl, heterocyclyl, -Cg_6 alkyl-C3_g and cycloalkyl, -C3_g cycloalkyl-Cg_6 alkyl-aryl, -C3_gyl-cycloalkyl -aryl heteroaryl, -C (R^TheR^B) CONH-C1-6 alkyl -C (R^çR^d) -CONH-C 3-10 cycloalkyl-C 1-6 alkyl-S-C 1-6 alkyl, -C 6₆ alkyl-NR^andR^f, -Cg_₆ alkyl aryl,

C6-6 alkyl heteroaryl, -C6₆ C1-6 alkyl heterocyclyl₆ C 6 -C 6 alkyl alkoxy aryl, C 6 -C 6 alkyl C 6 -C 6 alkoxy heteroaryl or C 6 -C 6 alkylC 6 alkoxyheterocyclyl;

R⁷, R⁸, R⁹, R¹⁰, R¹³, R¹⁴, R¹⁵, R¹⁶, R¹⁷, R¹⁸, R¹⁹, R²⁰ and R²¹independently represent hydrogen,₆ alkyl, C₂-₆alkenyl, C₃-₈ cycloalkyl, aryl, heteroaryl, heterocyclyl, -C 6 -C 6 alkyl₃-8 cycloalkyl-, Cg-₆ alkyl aryl, -C 6 -C 6 alkyl heteroaryl, -C 6 -C 6 alkyl heterocyclyl or -C 0 -C 6 alkyl;

ΡΕ1567488

R¹¹, R¹², R^The, R^ç, R^and and R^f independently represent hydrogen,₆ alkyl or C₃_₈ cycloalkyl;

R^B and R^d independently represent hydrogen,₆alkyl, O3₈ cycloalkyl or -C 1-6 alkyl-SO 2 -C 1-6 alkyl;

q represents 1 to 3;

wherein said alkyl groups may be optionally substituted by one or more (eg, 1, 2 or 3) halogen, C1-6 alkyl, C1-6 alkoxy, C1-6 alkenoxy, C3 groups₈ cycloalkyl, amino, cyano or hydroxyl;

and wherein said cycloalkyl, aryl, heteroaryl or heterocyclyl groups may be optionally substituted by one or more (eg, 1, 2 or 3) C1-4.₆ alkyl, C 2-6 alkenyl, C 2-6 alkynyl, halogen, haloC 1-6 alkyl, -OCF 3, oxo, C 1-6 alkoxy, -C 1-6 alkoxy-CN, amino, cyano, nitro, -NR²²COLOR²³, -CONR²²R²³, -COOR²², -SO₂R²², -CÇ-g alkylpp pq ρ ppq

NR is R (wherein R and R independently represent hydrogen or C1-6 alkyl), C1-6 alkyl-C1-6 alkoxy, C1-6 alkanol or hydroxy groups;

or a pharmaceutically acceptable salt or solvate thereof.

In a particular aspect of the present invention there is provided a compound of formula (I) as defined above wherein:

ΡΕ1567488

X represents CO or SO₂; and

R^2nd represents hydrogen, C1-₃ alkyl or halogen; and

R³ and R^2b together with the phenyl group to which they are attached form an unsubstituted benzofused heterocyclic ring or heteroaryl; and

R⁴ represents -C₂_₆ alkyl aryl, -C₂_₆ alkyl heteroaryl or -C 1-6 alkyl heterocyclyl; and

R⁵ represents hydrogen, -C 1-10 alkyl C 3-8 cycloalkyl, -C 3-8 cycloalkenyl, aryl, heteroaryl, heterocyclyl, -C 1-6 alkyl C 3-8 cycloalkyl, -C 2-6 alkyl aryl heteroaryl, -C (R^TheR^B) -CONH-C1- and alkyl, -C (R^çR^d) -CONH-C3_₈cycloalkyl, -C₂_₆ alkyl-S-C1₆ alkyl, -C₂_₆ alkyl-NR^andR^f-C1-6 alkylaryl, -C1-6 alkylheteroaryl, -C1-6 alkylheterocyclyl -C1-6 alkyl₆ alkoxy aryl, -C 1₆ C1-alkyl₆alkoxy heteroaryl or -C 1₆ C1-alkyl₆ alkoxyheterocyclyl;

and said alkyl groups may be optionally substituted by one or more (eg, 1, 2 or 3) halogen groups, C1-4.₆ alkoxy, amino, cyano or hydroxy; and wherein said aryl, heteroaryl or heterocyclyl groups may be optionally substituted by one or more (eg, 1, 2 or 3) C1-4 groups.₆ alkyl, halogen,

ΡΕ1567488 ο ο 2 3

-OCF₃, oxo, C1-6 alkoxy, amino, cyano, nitro, -NR COR, -C1₆alkyl-NR R (wherein R and R independently represent hydrogen or C1-4).₆ alkyl), -C1₆ C1-alkyl₆ alkoxy, C1-6 alkanol or hydroxyl.

References to alkyl include references to both straight chain aliphatic isomers and branched chain alpha isomers of the corresponding alkyl. It should be understood that references to alkenyl and alkenoxy should be interpreted similarly. It should also be understood that when an alkenyl or alkenoxy group is bonded to an atom of 0, N or S the double bond is not in the alpha position with respect to said atom of 0, N or S.

References to cycloalkyl include references to all alicyclic (including branched) isomers of the corresponding alkyl. When a cycloalkyl group is substituted by one or two C 1-6 alkyl groups, said cycloalkyl groups together with any two alkyl groups may form a bridged cycloalkyl group which includes bicycloheptyl, adamantyl, bicyclooctyl and the like.

References to aryl include references to monocyclic carbocyclic aromatic rings (eg, phenyl) and bicyclic carbocyclic aromatic rings (eg, naphthyl) or benzofused carbocyclic rings (eg C₃_₈ cycloalkyl fused to a phenyl ring, such as dihydroindenyl or tetrahydronaphthalenyl).

ΡΕ1567488

References to heteroaryl include references to mono- and bicyclic heterocyclic aromatic rings containing 1-4 heteroatoms selected from nitrogen, oxygen and sulfur. Examples of monocyclic heterocyclic aromatic rings include eg, thienyl, furyl, pyrrolyl, triazolyl, imidazolyl, oxazolyl, thiazolyl, oxadiazolyl, isothiazolyl, isoxazolyl, thiadiazolyl, pyrimidyl, pyridazinyl, pyrazinyl, pyridyl and the like. Examples of bicyclic heterocyclic aromatic rings include eg, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, cinolinyl, naphthyridinyl, indolyl, indazolyl, pyrrolopyridinyl, benzofuranyl, benzothienyl, benzimidazolyl, benzisoxazolyl, benzothiazol, benzothiazol, benzothiazol, benzothiazole

References to heterocycle include references to 5- to 7-membered non-aromatic monocyclic rings selected from nitrogen, sulfur or oxygen. Examples of heterocyclic nonaromatic rings include eg, morpholinyl, piperidinyl, piperazinyl, thiomorpholinyl, oxathianyl, dithianyl, dioxane, pyrrolidinyl, dioxolanyl, oxathiolanyl, imidazolidinyl, pyrazolidinyl and the like.

References to benzofused heteroaryl or heterocyclic ring include quinolinyl, isoquinolinyl, indolyl, indazolyl, dihydroindolyl, benzofuranyl, benzothiazyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, benzothiazolidinyl, benzothiazolidinyl, benzoxydiazol, benzoyl dihydroxybenzothiazole .

Preferably m is 0 or 1, preferably 0. When m represents 1, R¹ is preferably aryl (eg phenyl).

Preferably n is 0 or 1, more preferably 1.

When n represents 1, R^2nd is preferably C 1-3 alkoxy (eg methoxy) or halogen (eg fluorine), more preferably halogen (eg fluorine).

When n represents 1, R^2nd is preferably in the ortho position of the phenyl ring.

When X represents SO₂p is preferably 2 or 3, more preferably 2 and when X represents CO, p is preferably 1 or 2, more preferably 1.

Preferably R^2b is:

hydrogen;

halogen (eg chlorine or fluorine);

ΡΕ1567488

C1-6 alkyl (eg methyl);

(7-6 alkoxy (eg methoxy); or heterocyclyl (eg pyrrolidinyl) optionally substituted by an oxo group (eg 2-oxopyrrolidin-1-yl).

More preferably, R^2b is hydrogen or halogen (eg fluorine), more preferably hydrogen.

Preferably R³ represents:

Ci_₆ alkyl (eg methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl or t-butyl), optionally substituted by one or more (eg 1, 2 or 3) hydroxyl, halo groups (eg fluorine) or Ci_₆ alkoxy (eg methoxy or ethoxy);

Ç₂Alkenyl (eg propenyl);

C 3-8 cycloalkyl (eg cyclopentyl or cyclohexyl);

cyan;

heterocyclyl (eg piperidinyl, pyrrolidinyl or isothiazolidinyl) optionally substituted by one or two oxo groups;

-NR⁷R⁸;

ΡΕ1567488

-OR¹³;

-SR¹⁵; or

-CONR¹⁷R¹⁸.

Also preferably R³ and R^2b together with the phenyl group to which they are attached, represent indolyl, indazolyl, dihydroindolyl, benzofuranyl, dihydrocromenyl, benzotriazolyl, benzimidazolyl or tetrahydroquinoxalinyl, optionally substituted by one or two C1-4 groups.₆ alkyl (eg methyl, ethyl, n-propyl, ipropyl, n-butyl, i-butyl, sec-butyl, t-butyl or pentyl). More preferably R and R together with the phenyl group to which they are attached represent benzimidazolyl or indolyl substituted by a group Ο₃_₆alkyl (eg ethyl).

More preferably, R³ represents:

C1-6 alkyl (eg n-propyl);

-NR⁷R⁸ ;

Ç₃_₈ cycloalkyl (eg cyclopentyl or cyclohexyl);

-OR¹³; or

ΡΕ1567488

-concr¹⁷r¹⁸ .

Preferably R⁷ and R⁸ independently represent:

hydrogen;

C1-6 alkyl (eg methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl, t-butyl, pentyl, ipropyl, i-butyl, -CH₂C (CH₃)₃, -CH (CH₂CH₃) CH₂CH₃ or (CH₂)₂CH (CH₃)₂) ;

Ç₃cycloalkyl (eg cyclopentyl or cyclohexyl);

aryl (eg phenyl);

-C 1-6 alkyl-C₃_₈ cycloalkyl (eg -CH₂-cyclopropyl);

-C 1-6 alkyl aryl (eg-CH₂-phenyl or - (CH₂) ₂-phenyl);

or

-CO-C1-6 alkyl (eg -COCH₃) .

More preferably, R⁷ represents hydrogen and R⁸ represents Ci_₆ alkyl (particularly ethyl or isopropyl, especially ethyl).

Preferably R¹³ represents C₂-6 alkyl (eg methyl, ethyl, n-propyl, i-propyl, n-butyl, butyl, sec-butyl or t-butyl or pentyl) optionally substituted by hydroxy or C1-6 alkoxy (eg methoxy) plus preferably R¹³ represents ethyl or ipropyl.

Preferably R¹⁵ represents C₂- 6 alkyl (eg methyl or ethyl).

Preferably R¹⁷ and R¹⁸ both represent C1-6 alkyl (eg both represent propyl or one represents propyl and the other represents methyl).

Preferably R⁴ represents -Ci_₆ alkylaryl (eg benzyl) or -C1₆ alkyl heteroaryl (eg -CH₂pyridinyl, -CH₂-thiazolyl, -CH₂-furanyl, -CH₂-thienyl or CH₂pyrazolyl) optionally substituted by one or two halogen atoms (eg chlorine or fluorine). More preferably, R⁴ represents -C 1-6 alkylaryl (eg benzyl) optionally substituted by one or two halogen atoms (eg chlorine or fluorine), more preferably R⁴represents unsubstituted benzyl.

Preferably R⁵ represents

-C 1-10 alkyl (eg methyl, ethyl, n-propyl, n-butyl, n-pentyl or n-hexyl) optionally substituted by one or more C 1-10 groups.₆ alkyl (eg methyl),₆ alkoxy (eg methoxy or -OCH₂CH (CH₃) ₂) or C₂_₆ alkenoxy (eg OCH₂C (CH₃) = CH₂) ;

ΡΕ1567488

-C3-10 cycloalkyl (eg cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, bicycloheptyl, adamantyl or bicyclooctyl) optionally substituted by one or more C1-6 alkyl groups (eg methyl, ethyl or propyl) or halogen (eg fluorine);

-C 1-6 alkyl-C₃-io cycloalkyl (eg -CH₂-cyclohexyl or -CH 2 -cyclopropyl);

-aryl (eg phenyl, dihydroindenyl or tetrahydronaphthalenyl) optionally substituted by one or more hydroxyl or C 1-4 groups.₆ alkoxy (eg methoxy);

-C 1-6 alkyl aryl (eg benzyl, -ethyl-phenyl, -ethylnaphthyl, -propyl-phenyl, -C (H) (Me) -phenyl, -C (H) (Et) -phenylC (Me) (Me) - benzyl or -C (Me) (Me) -phenyl) optionally substituted by one or more halogen (eg chlorine, bromine or fluorine), hydroxyl, -OCF groups₃haloCi_₆ alkyl (eg -CH₂CF₃ or -CF₃), Ci_₆ alkyl (eg methyl, ethyl, npropyl, i-propyl, n-butyl, i-butyl, sec-butyl or t-butyl), C₂-₆ alkenyl (eg ethenyl), C₂-₆ alkynyl,₆alkoxy (eg methoxy, ethoxy, propoxy, isopropoxy or methylethoxy), cyano, nitro, -COOR²² (eg COOH or COOMe), SO2R²² (eg -SO2Me), - NR²²COLOR²³ (eg NHCOCH3), -C1-6 alkylNR²²R²³ (eg -CH2N (CH₃) ₂), - Ci_₆ C1-alkyl₆ alkoxy (eg CH₂OC (CH₃)₃), -C 1-6 alkanol (eg -CH₂OH) or -Ci-₆ CN-alkoxy (eg OCH₂CN);

ΡΕ1567488

-C 1-6 alkylheteroaryl (eg -CH₂-furanyl, -CH₂quinolinyl, -CH₂-thiophenyl, -CH₂-indolyl, -CH₂benzoimidazolyl, -CH₂-imidazolyl, -CH₂-benzofuranyl, CH₂-thiazolyl, -CH₂-pyridinyl, -CH₂-benzothiazolyl, -CH₂pyrazolyl, -CH₂-isoxazolyl, -CH₂-oxazolyl, -CH₂pyrrolyl, -CH₂-dihydrobenzofuranyl, -CH₂-dihydrobenzodioxinyl or -CH₂-dihydrocromenyl) optionally substituted by one or more C1-6 alkyl groups (eg methyl, ethyl, n-propyl, i-propyl, n-butyl, ibutyl, sec-butyl or t-butyl), C₂_₆ alkenyl (eg ethenyl or propenyl), C₂Alkynyl, halogen (eg bromine or chlorine), halogenC 1-6 alkyl (eg fluoroethyl or pp o trifluoroethyl), cyano, C 1-6₆ alkoxy (eg methoxy), -CONR R (eg -CONHMe) or -COOR²² (eg -COOMe);

heterocyclyl (eg tetrahydropyranyl or tetrahydrothiopyranyl);

-C 1-6 alkylheterocyclyl (eg -CH₂tetrahydropyranyl;

-C 3-10 cycloC 1-10 alkylalkyl (eg -cyclobutylisopropyl, -cyclobutyl-ethyl, -cyclobutyl-propyl, cyclopropyl-ethyl, -cyclopropyl-propyl, -cyclopropyl-isopropyl, -cyclopropyl-t-butyl, -cyclopropyl-CH₂CH (CH₃) ₂, -cyclopropyl- (CH₂) ₂CH (CH₃) ₂, -cyclopropyl- (CH₂) ₂CH (CH₃) ₂ or cyclopropyl- (CH₂) ₃CH (CH₃) ₂) ;

-Ç₃_io cycloalkyl-C1_₆ alkylaryl (eg cyclopropylΡΕ1567488

CH₂phenyl) optionally substituted by one or more halogen atoms (eg chlorine;

-Ç₃_cycloalkylaryl (eg -cyclopropyl-phenyl) optionally substituted by one or more halogen (eg chloro, bromo or fluoro), hydroxy, -OCF₃halogen₆alkyl {eg -CH₂CF₃ or -CF₃), Ci_₆ alkyl (eg methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl or t-butyl), C₂_₆ alkenyl (eg ethenyl), C₂_₆ alkynyl, C₂_ ₆ alkoxy (eg methoxy, ethoxy, propoxy, isopropoxy or methylethoxy), cyano, nitro, -COOR²² (eg COOH or COOMe), SO2R²² (eg -SO2Me), -NR²²COLOR²³ (eg NHCOCH3), -C1-6 alkylNr²²r23 (e_g_ -CH₂N (CH₃) ₂), - Ci_₆ C1-alkyl₆ alkoxy {eg CH₂OC (CH₃) ₃), -C 1-6 alkanol (eg -CH₂OH) or -Ci_₆ CN-alkoxy {eg OCH₂CN);

-C (R^TheR^B) -CONH-C1-6 alkyl {eg -C (R^TheR^B) -CONH-tributyl);

-C (R^çR^d) -CONH-C₃_₁₀ cycloalkyl {eg C (R^çR^d) -CONH-cyclohexyl);

-C 1-6 alkyl-S-C 1-6 alkyl (eg -propyl-S-methyl or dimethylethyl-S-isobutyl); or

-C 1-6 alkyl-NR^andR^f {eg -dimethylpropyl-NR^andR^f) .

More preferably R⁵ represents:

ΡΕ1567488

-C 3-10 cycloalkyl (eg cyclohexyl);

-C 1-6 alkylaryl (eg benzyl) optionally substituted by one or more halogen groups (eg chlorine, bromine or fluorine), -OCF₃ or halogen₆ alkyl (eg -CF₃);

- Ci_₆ alkyl heteroaryl (eg -CH₂-thienyl, -CH₂pyrazolyl or -CH₂-isoxazolyl) optionally substituted by one or more C₂Alkyl (eg methyl, ethyl, isopropyl, propyl or butyl) or haloC1₆ alkyl (eg CH₂CF₃); or

heterocyclyl (eg tetrahydropyranyl).

Preferably q represents 1 or 2.

Preferably R^The represents hydrogen or C₂_ ₆ alkyl (methyl).

Preferably R^B and R^d independently represent Ci_₆ alkyl (eg methyl, ethyl, propyl or butyl) or -C 1-6 alkyl-SO₂-C 1-6 alkyl (eg CH₂CH₂ONLY₂CH₃) optionally substituted by one or more hydroxyl groups.

Preferably R^ç represents hydrogen or C1- ₆ alkyl (methyl).

Preferably R^and and R^f they both represent C1-6 alkyl (eg methyl).

ΡΕ1567488

Preferred compounds according to the invention include examples E1-E744 as shown below, or a pharmaceutically acceptable salt thereof.

More preferred compounds according to the invention include:

Formic-5-cyclopentyl-3- (1,1-dioxide-tetrahydro-2H-1,2-thiazin-2-yl) -N - [(1S, 2R) -3 - {[(1-ethyl-1H-pyrazole -4yl) methyl] amino} -2-hydroxy-1- (phenylmethyl) propyl] -2-fluorobenzamide (1: 1);

Formic-3- (1,1-dioxide-tetrahydro-2H-1,2-thiazin-2-yl) -2-fluoro-N - [(IS, 2R) -2-hydroxy-1- (phenylmethyl) -acetic acid 3 ({[3- (trifluoromethyl) phenyl] methyl} amino) propyl] -5 - [(1-methylethyl) amino] benzamide (1: 1);

Formic-3- (1,1-dioxide-tetrahydro-2H-1,2-thiazin2-yl) -N - [(1S, 2R) -3 - {[(1-ethyl-1H-pyrazol-4-yl acid) ) methyl] amino} 2-hydroxy-1- (phenylmethyl) propyl] -2-fluoro-5 - [(1-methylethyl) amino] benzamide (1: 1);

Formic-3- (1,1-dioxide-tetrahydro-2 H -1,2-thiazin-2-yl) -2-fluoro-N- (IS, 2R) -2-hydroxy-1- (phenylmethyl) -3- [acid] ({3 [(trifluoromethyl) oxy] phenyl] methyl) amino] propyl} -5 - [(1-methylethyl) amino] benzamide (1: 1);

N - ((IS, 2R) -1-Benzyl-3 - {[4-fluoro-3- (tri-1567488 fluoromethyl) benzyl] amino} -2-hydroxypropyl) -3- (1,1-dioxide1,2-thiazinan acid) -2-yl) -5- (ethylamino) -2-fluorobenzamide (1: 1);

- (1,1-dioxide-tetrahydro-2 H -1,2-thiazin-2-yl) -5 (ethylamino) -2-fluoro-N - [(IS, 2R) -2-hydroxy-1- ( phenylmethyl) -3 ({[3- (trifluoromethyl) phenyl] methyl} amino) propyl] benzamide;

Formic-3- (1,1-dioxide-tetrahydro-2h-1,2-thiazin2-yl) -5- (ethylamino) -N - [(1S, 2R) -3 - {[(5-ethyl-3 -thienyl) methyl] amino} -2-hydroxy-1- (phenylmethyl) propyl] benzamide (1: 1); and

Formic-3- (1,1-dioxide-tetrahydro-2h-1,2-thiazin2-yl) -5- (ethylamino) -2-fluoro-N - {(IS, 2R) -2-hydroxy-1-acid (phenylmethyl) -3 - [({3 - [(trifluoromethyl) oxy] phenyl} methyl) amino] propyl} benzamide (1: 1) or a pharmaceutically acceptable salt thereof.

The compounds of formula (I) have the ability to form their acid addition salts. It will be understood that for use in drugs the salts of the compounds of formula (I) must be pharmaceutically acceptable. Suitable pharmaceutically acceptable salts will be apparent to those skilled in the art and include those described in J. Pharm. Sci., 1977, 66, 1-19, as acid addition salts formed with inorganic or organic acids eg, hydrochlorides, hydrobromides, sulfates, phosphates, acetates, benzoates, citrates, nitrates, succinates, lactates, tartrates, fumarates, maleates , 1ΡΕ1567488 hydroxy-2-naphthoates, palmoates, methanesulfonates, ptoluenesulfonates, naphthalenesulfonates, formates or trifluoroacetates. The present invention includes within its scope all possible stoichiometric and non-stoichiometric forms.

The present invention also includes within its scope prodrugs of the compounds of formula (I). As used herein, the term prodrug means a compound that is converted within the body, eg, by hydrolysis in the blood, to its active form that has medical effects. Pharmaceutically acceptable prodrugs are described in T. Higuchi and V. Stella, Prodrugs as Novel Delivery Systems, Vol. 14 of ACS Symposium Series, Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, and in D. Fleisher, S. Ramon and H. Barbra Improved oral drug delivery: solubility limitations overcome by the use of prodrugs, Advanced Drug Delivery Reviews (1996) 19 (2) 115-130. The esters may be active on their own and / or hydrolyzable under conditions in vivo in the human body. Pharmaceutically acceptable in vivo hydrolysable ester groups include those which readily degrade in the human body to leave the mother acid or salt thereof.

The compounds of formula (I) may be prepared in crystalline or non-crystalline form, and, if in crystalline form may optionally be solvate, eg as

61567488 hydrate. This invention includes within its scope stoichiometric solvates (eg hydrates) as well as compounds containing varying amounts of solvent (eg water).

Certain compounds of formula (I) are apt to exist in stereoisomeric forms (eg diastereomers and enantiomers) and the invention encompasses each such stereoisomeric form and mixtures thereof including racemates. The different stereoisomeric forms may be separated from each other by standard methods, or a given isomer may be obtained by stereospecific or asymmetric synthesis. The invention also encompasses any tautomeric forms and mixtures thereof. Preferably, the compounds of formula (I) are in the form of a single enantiomer of formula (Ia):

<img file="PT1567488E_D0001.tif" />

w

The compounds of formula (I) and their salts and solvates may be prepared by the methodology described hereinafter, which constitutes a further aspect of this invention.

A process according to the invention for preparing a compound of formula (I) comprising:

61567488 (a) reacting a compound of formula (II)

<img file="PT1567488E_D0002.tif" />

or an activated and optionally protected derivative thereof

A 2a 2b 3 wherein R, m, X, p, R, n, R and R are as defined above with a compound of formula (III)

<img file="PT1567488E_D0003.tif" />

where R⁴ and R⁵ are as defined above; or (b) preparing a compound of formula (I) comprising reductive amination of a compound of formula (IV)

R1567488 where R¹, m, X, p, R^2nd, n, R^2b, R³ and R⁴ are as defined above with an appropriate aldehyde or ketone; or (c) deprotecting a compound of formula (I) which is protected; and optionally in sequence (d) interconversion of compounds of formula (I) into other compounds of formula (I).

process (a) typically comprises the use of water-soluble carbodiimide, HOBT and a suitable base such as tertiary aquylamine or pyridine in a suitable solvent such as DMF and at a suitable temperature, eg between

0 ° C and room temperature.

Process (b) typically comprises the use of sodium borohydride triacetate in the presence of a suitable solvent such as ethanol and dichloromethane and at a suitable temperature, eg between 0 ° C and room temperature.

In process (c), examples of protecting groups and means for their removal can be found in TW Greene and PGM Wuts Protective Groups in Organic Synthesis (J. Wiley and Sons, 3).^rd Ed. 1999). Suitable amine protecting groups include aryl sulfonyl (eg tosyl), acyl (eg acetyl), carbamoyl (eg benzyloxy (carbonyl or t-butoxycarbonyl)) and arylalkyl (eg benzyl), which may be removed by hydrolysis or hydrogenolysis as appropriate. Other suitable amino protecting groups include trifluoroacetyl (-COCF₃) which can be removed by catalyzed hydrolysis. Suitable hydroxyl protecting groups would be silyl based groups such as t-butyldimethylsilyl, which may be removed using standard methods, for example the use of an acid such as trifluoroacetic acid or hydrochloric acid or a fluoride source such as tetra n-butylammonium fluoride.

process (d) may be performed using traditional interconversion procedures such as epimerisation, oxidation, reduction, alkylation, aromatic substitution, ester hydrolysis, amide bond formation or removal and sulfonylation. An example of such an interconversion reaction may include the interconversion of a compound of formula (I) wherein R³ represents a group containing C 2-6 alkenyl for a corresponding compound of formula (I) wherein R³ represents a group containing C 2-6 alkyl using standard hydrogenation or reduction conditions. Another example of such an interconversion reaction may include the interconversion of a compound of formula (I) wherein R³ represents -C 2-6 alkyl-N 3 in a compound of formula (I) wherein R³ represents -C 1-6 alkylNH₂using hydrogenation or standard reduction conditions. Still another example of such an interconversion reaction may include the interconversion of a compound

ΡΕ1567488 of formula (I) wherein R³ represents a nitro group in a corresponding compound of formula (I) wherein R³ represents NH₂using standard hydrogenation or reduction conditions.

Compounds of formula (II) or their activated and optionally protected derivatives may be prepared according to the following process:

<img file="PT1567488E_D0004.tif" />

<img file="PT1567488E_D0005.tif" />

where R^2nd, above and L¹ and L²suitable output chlorine or bromine).

n, R^2b, R³, p, x, r¹ and are as defined independently represent a group of as a halogen atom (eg, iodine, step (i) typically comprises the use of

61567488 of a suitable solvent such as dichloromethane and a suitable base such as triethylamine.

Step (ii) comprises the use of sodium hydride in the presence of a suitable solvent such as tetrahydrofuran under nitrogen.

The compounds of formula (II) or their activated and optionally protected derivatives may also be prepared according to the following process:

<img file="PT1567488E_D0006.tif" />

where R^2nd, n, R^2b, R³, ρ, X, R¹ in are as defined above and L³ represents a suitable leaving group such as a halogen atom (eg iodine, chlorine or bromine).

step (i) typically comprises the use of cesium carbonate, 4,5-bis (diphenylphosphino) -9,9dimethylxanthene and a suitable catalyst such as tris (dibenzylidenoacetone) dipaladium (0) under suitable conditions as reflux under argon in the presence of a solvent suitable as dioxane.

ΡΕ1567488

The compounds of formula (III) may be prepared according to the following process:

<img file="PT1567488E_D0007.tif" />

where R⁴ and R^B are as defined above and P¹ represents a suitable amino protecting group such as t-butoxycarbonyl.

step (i) typically comprises reacting a compound of formula (IX) with a compound of formula NH₂R⁵ in the presence of a suitable solvent, eg ethanol at a suitable temperature, eg reflux temperature.

step (ii) typically comprises the use of suitable deprotection reactions as described above for process (c), eg when P¹ represents butoxycarbonyl, deprotection typically comprises the use of trifluoroacetic acid in the presence of a suitable solvent, such as dichloromethane at a suitable temperature, eg, between 0 ° C and room temperature.

The compounds of formula (IV) may be prepared according to the following process:

ΡΕ1567488

<img file="PT1567488E_D0008.tif" />

Pass (ii)

<img file="PT1567488E_D0009.tif" />

<img file="PT1567488E_D0010.tif" />

<img file="PT1567488E_D0011.tif" />

<img file="PT1567488E_D0012.tif" />

where R¹, defined above other than P¹, m, X, p, R^2nd, n, R^2b, R³, and P² represents a group like -COOCH₂-phenyl.

R⁴ and P¹ As a protective amine step (i) typically comprises reacting a compound of formula (IX) in aqueous ammonia in the presence of a suitable solvent, eg, ethanol at a suitable temperature, eg, reflux temperature.

When P² represents -COOCH₂-phenyl, step (ii) typically comprises the use of ClCOOCH₂phenyl in the presence of a suitable base, eg triethylamine, a suitable solvent, eg dimethylformamide at a suitable temperature, eg, between 0 ° C and room temperature.

ΡΕ1567488

Step (iii) typically comprises the use of suitable deprotection reactions as described above for process (c), eg when P¹ represents t-butoxycarbonyl, deprotection typically comprises the use of trifluoroacetic acid in the presence of a suitable solvent such as dichloromethane at a suitable temperature, eg between 0 ° C and room temperature.

Step (iv) typically comprises reacting a compound of formula (XII) with a compound of formula (II) in the presence of water-soluble carbodiimide and HOBT.

Step (iv) typically comprises the use of suitable deprotection reactions as described above for process (c), eg when P² represents -COOCH₂phenyl, deprotection typically comprises the use of a suitable catalyst, eg palladium in the presence of a suitable solvent, eg water and ethanol and in the presence of a suitable hydrogen source, eg ammonium formate and a suitable temperature, eg, 60 ° C.

The compounds of formula (V) are commercially available or may be prepared by interconversion of commercially available compounds of formula (V).

The compounds of formulas (VI), (VIII) and (IX) are known or may be prepared according to known procedures.

ΡΕ1567488

In another aspect of the invention there is provided a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof for use as a drug, particularly in the treatment of patients with diseases characterized by elevated β-amyloid levels or β-amyloid deposits.

According to another aspect of the invention there is provided the use of a compound of formula (I) or a physiologically acceptable salt or solvate thereof for the manufacture of a medicament for the treatment of patients with diseases characterized by elevated β-amyloid levels. or β-amyloid deposits.

In another or an alternative aspect there is provided a method for treating a human or animal with diseases characterized by high β-amyloid levels or β-amyloid deposits, which method comprises administering to said human or animal an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof.

As another aspect of the invention there is provided a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof for use in the treatment of diseases characterized by elevated β-amyloid levels or βamyloid deposits.

ΡΕ1567488

It will be understood by those skilled in the art that reference herein to treatment encompasses prophylaxis as well as the treatment of diseases characterized by elevated β-amyloid levels or β-amyloid deposits.

The compounds according to the invention may be formulated for administration in any convenient form, and the invention therefore includes within its scope pharmaceutical compositions for use in the treatment of diseases characterized by elevated β-amyloid levels or β-amyloid deposits, comprising a compound. of formula (I) or a physiologically acceptable salt or solvate thereof, if desired, with one or more physiologically acceptable diluents or carriers.

It should be understood that diseases characterized by elevated β-amyloid levels or βamyloid deposits include Alzheimer's disease, moderate cognitive deficit, Down's syndrome, Dutch-type β-amyloidosis hereditary cerebral hemorrhage, βamyloid cerebral agiopathy and various types of degenerative dementias, such as those associated with Parkinson's disease, progressive supranuclear palsy, cortical basal degeneration, and diffuse Lewis body type of Alzheimer's disease.

More preferably, the disease characterized by high β-amyloid levels or β-amyloid deposits is Alzheimer's disease.

ΡΕ1567488

Also provided is a process for preparing this pharmaceutical formulation comprising mixing the agents.

The compounds of formula (I) may be used in combination with other therapeutic agents. Suitable examples of other therapeutic agents may be acetylcholine esterase inhibitors (such as tetrahydroaminoacridine, donepezil hydrochloride and rivastigmine), gamma secretase inhibitors, anti-inflammatory agents (such as cyclooxygenase 11 inhibitors), antioxidants (such as Vitamin E and gincolidesor) , statins or pglycoprotein (P-gp) inhibitors (such as cyclosporin A, verapamil, tamoxifen, quinidine, Vitamin E-TGPS, ritonavir, megestrol acetate, progesterone, rapamycin, 10,11-methanodibenzosuberane, phenothiazines, acridine derivatives as

GF120918, FK506, VX-710, LY335979, PSC-833, GF-102 and 918).

When the compounds are used in combination with other therapeutic agents, the compounds may be administered sequentially or simultaneously by any convenient route.

The compounds according to the invention may, for example, be formulated for oral, inhaled, intranasal, buccal, enteral, parenteral, topical, sublingual, intrathecal or rectal administration, preferably for oral administration.

ΡΕ1567488

Tablets and capsules for oral administration may contain conventional excipients as binding agents, for example syrup, acacia, gelatin, sorbitol, tragacanth, starch mucilage, cellulose or polyvinyl pyrrolidone; fillers, for example lactose, microcrystalline cellulose, sugar, cornstarch, calcium phosphate or sorbitol; lubricants, for example magnesium stearate, stearic acid, talc, polyethylene glycol or silica; disintegrants, for example potato starch, sodium croscamelose or sodium starch glycolate; or wetting agents such as sodium lauryl sulfate. The tablets may be coated according to methods well known in the art. Oral liquid preparations may be in the form of, for example, aqueous or oily suspensions, solutions, emulsions, syrups or elixirs, or may be presented as a dry product for constitution with water or any other suitable vehicle before use. These liquid preparations may contain conventional additives such as suspending agents, for example sorbitol syrup, methylcellulose, glucose / sugar syrup, gelatin, hydroxymethylcellulose, carboxymethylcellulose, aluminum stearate gel or hydrogenated edible fats; emulsifying agents, for example lecithin, sorbitan monooleate or acacia; non-aqueous vehicles (which may include edible oils), for example almond oil, fractionated coconut oil, oily esters, propylene glycol or ethyl alcohol; or preservatives, for example methyl or propyl p-hydroxybenzoates or acid

61567488 sorbic. The preparations may also contain buffering, flavoring, coloring and / or sweetening salts.

<td colspan="2">(eg mannitol)</td><td colspan="3">as appropriate.</td>

<td></td><td>For</td><td>administration</td><td>oral the compositions</td><td>may</td>

<td>to take</td><td>the shape</td><td>of pills</td><td colspan="2">or lozenges formulated</td>

<td>form</td><td colspan="2">conventional.</td><td></td><td></td>

<td></td><td colspan="2">The compounds may</td><td>also be formulated</td><td>how</td>

suppositories, eg, containing conventional suppository bases such as cocoa butter or other glycerides.

The compounds according to the invention may also be formulated for parenteral administration by bolus injection or continuous infusion and may be presented in unit dosage form, for example ampoules, vials, small volume infusions or pre-filled syringes, or in vials. multi-dose with added preservative. The compositions may take the form of solutions, suspensions, or emulsions in aqueous or non-aqueous vehicles, and may contain formulatory agents such as antioxidants, buffers, antimicrobial agents and / or tonicity adjusting agents. Alternatively, the active agent may be in powder form for constitution with a suitable carrier, eg sterile pyrogen-free water, before use. The dried solid presentation may be prepared by aseptically filling a sterile powder into individual sterile packs or by aseptically filling a sterile solution in each pack and lyophilizing.

ΡΕ1567488

When the compounds of the invention are administered topically they may be presented as a cream, ointment or dressing.

The composition may contain from 0.1% to 99% by weight, preferably from 10 to 60% by weight of active material, depending on the method of administration.

The dose of the compound used in the treatment of the above conditions will vary in the usual manner according to the severity of the conditions, the patient's weight, and other similar factors. However, as a general indicator, unit doses may be 0.05 mg to 3000 mg; and these unit doses may be administered more than once a day, for example, two, three or four times a day (preferably once or twice); and this therapy may extend over several weeks, months or years.

Examples

Intermediate Preparation

Description 1

3-Amino-5-nitro-benzoic acid methyl ester (D1)

To a 3-amino-5-nitro-benzoic acid solution

61567488 (65 g, 357 mmol, 1 equiv.) In MeOH (650 mL) at 0 ° C added SOCl 2 (39 mL, 536 mmol, 1.5 equiv). The resulting solution was allowed to warm to room temperature and stirred for 16 hours. An additional portion of SOC1 was added dropwise.₂ NaCl (10 mL, 137 mmol, 0.4 equiv.) And the solution was stirred at room temperature for 5 hours, at 50 ° C for 2 hours and then cooled to room temperature and concentrated in vacuo. The residue was dissolved in EtOAc and the organic phase was washed with saturated aqueous NaHCO3 solution, dried over MgSO4 and concentrated in vacuo. The solid residue was triturated with EtOAc / isohexane to give 3-amino-5-nitro-benzoic acid methyl ester (D1) (55 g, 78%) as a pale yellow solid.

Description 2

3- (4-Chloro-butanoylamino) -5-nitro-benzoic acid methyl ester (D2)

To a solution of 3-amino5-nitro-benzoic acid (D1) methyl ester (38 g, 194 mmol, 1 equiv.) In CH₂C1₂(350 mL) NEt was added dropwise₃ (32 mL, 230 mmol,

1.2 equiv.) Followed by 4-chlorobutyryl chloride (24.7 mL, 220 mmol, 1.13 equiv.) For 20 minutes. The resulting mixture was allowed to warm to room temperature and stirred for 30 minutes. The organic phase was then washed with 2 N aqueous HCl solution, dried over concentrated MgSO 4 in vacuo. The residue was triturated with iso-1567488 hexane and Et 2 O to give 3- (4-chlorobutanoylamino) -5-nitro-benzoic acid methyl ester D2 (56 g, 96%) as a brown solid.

Description 3

3- (5-Chloro-pentanoylamino) -5-nitro-benzoic acid methyl ester (D3)

5-Chlorovaleryl chloride (2.64 g, 17 mmol, 1.1 equiv) in CH₂CL₂ (5 mL) for 2 minutes to a stirring solution of 3-amino-5-nitro-benzoic acid (D1) methyl ester (3 g, 15.3 mmol, 1 equiv.) And NEt₃ (2.6 mL, 18 mmol, 1.2 equiv.) In CH₂C1₂ (30 mL). The resulting mixture was stirred for 1 hour at room temperature and then washed with 2 N aqueous HCl solution, dried over MgSO4.₄ and concentrated in vacuo. The residue was triturated with CH 2 Cl 2 to give 3- (5-chloropentanoylamino) -5-nitro-benzoic acid methyl ester D3 (6 g, 112%) as a brown oil.

Description 4a

3-Amino-5- (2-oxo-pyrrolidin-lil) -benzoic acid methyl ester (D4a)

A flask was charged with acid methyl ester.

3-nitro-5- (2-oxo-pyrrolidin-1-yl) -benzoic (B27) (5 g, 19 mmol, 1 equiv.), 10% palladium on charcoal (50% wet,

ΡΕ1567488

750 mg, 7.5% w / w), NH 4 COOH (11.9 g, 190 mmol, 10 equiv.) H₂O (30 mL) and MeOH (60 mL). The resulting mixture was stirred at 50 ° C for 1.5 hours, cooled to room temperature and the catalyst was filtered off through a pad of celite. Most of

MeOH was removed in vacuo and the residue was diluted with saturated aqueous NaHCO 3.₃. The aqueous phase was extracted twice with EtOAc. The combined organic phases were dried over MgSO4 and concentrated in vacuo to give an off-white solid, the catalyst was then washed three times with DMF and the combined organic phases were concentrated in vacuo. The residue was combined with previously obtained material and was triturated with Et₂To give amino-5- (2-oxo-pyrrolidin-yl) -benzoic acid methyl ester (D 4a) (3.9 g, 88%) as a white solid which was used in the next step without further purification.

Description 4a (Alternative Procedure)

3-Amino-5- (2-oxo-pyrrolidin-lil) -benzoic acid methyl ester (D4a)

To a solution of 3-amino-5- (2-oxopyrrolidin-1-yl) benzoic acid (D6) (2.2 g, 10 mmol, 1 equiv) in MeOH / Et₂(1: 1, 20 mL) was added 1- (3-dimethylaminopropyl) -3-ethyl carbodiimide hydrochloride (2.3 g, 12 mmol,

1.2 equiv.), DMAP (112 mg, 1 mmol, 0.1 equiv.) And the resulting mixture was stirred at room temperature for 16 hours and then diluted with EtOAc. The organic phase

61567488 was washed with saturated aqueous NaHCO3 solution, dried over MgSO4 and concentrated in vacuo. The residue was triturated with Et₂O to give 3-amino-5- (2-oxo-pyrrolidin-1-yl) -benzoic acid methyl ester (D4a) (1.6 g, 68%) as a white solid.

Description 4b

3-Amino-5- (2-oxo-piperidin-lil) -benzoic acid methyl ester (D4b)

Description 4b was prepared of formula analogous to that of Description 4a from 3nitro-5- (2-oxo-piperidin-1-yl) -benzoic acid methyl ester (B82).

Description 5

3-Bromo-5-nitro-benzoic acid (D5)

To a solution of 3-amino-5-nitro-benzoic acid (17.6 g, 96.6 mmol, 1 equiv.) In 48% aqueous HBr solution (180 mL) at 0 ° C was added portionwise. NaNC (8.67 g, 126 mmol, 1.3 equiv.) For 20 minutes. The temperature was kept below 8 ° C during this addition. The resulting mixture was then added to a suspension of CuBr (9.7 g, 67.6 mmol, 0.7 equiv.) In 48% aqueous HBr solution (50 mL) at 65 ° C for 40 minutes. The temperature was maintained above 60 ° C during the addition. The resulting mixture was stirred at 70 ° C for 45 minutes, was

ΡΕ1567488 cooled to room temperature and was diluted with IL of water. The aqueous phase was extracted three times with Et₂O. The combined organic layers were washed twice with H₂0, were dried over MgSO4₄ and concentrated in vacuo to give 3-bromo-5-nitro-benzoic acid (D5) (21 g, 88%) as a brown solid. [MH] _ = 245.7, RT = 2.82 minutes

Description 6

3-Amino-5- (2-oxo-pyrrolidin-1-yl) -benzoic acid (D6)

To a solution of 3-nitro-5- (2-oxo-pyrrolidin-1-yl) -benzoic acid (A27) (4 g, 16 mmol, 1 equiv.) In

MeOH / H₂O (9: 1, 40 mL) was added 10% palladium on charcoal (50% wet, 800 mg, 0.1 equiv. W / w). The resulting mixture was stirred for 6 hours at atmospheric pressure under a hydrogen atmosphere. The catalyst was removed by filtration through a pad of celite and the solvent was removed in vacuo. The residue was dried at 60 ° C in vacuo for 16 hours to give 3-amino-5- (2-oxopyrrolidin-1-yl) benzoic acid (D6) (3.34 g, 15.2 mmol, 95%) as a light brown solid. [MH] = 218.8, R T = 1.86 minutes

Description 7

3-Bromo-5-iodo-benzoic acid (D7)

Description 7 is commercially available from

Avocado Research Chemicals Ltd.

ΡΕ1567488

Description 8a

3-Bromo-5-iodo-benzoic acid methyl ester (D8a)

To a solution of 3-bromo-5-iodo-benzoic acid (D7) (14.6 g, 44.7 mmol, 1 equiv) in MeOH (150 mL) at 0 ° C was added SOCl 2 (3.9 mL, 53.6 mmol, 1.2 equiv.). The resulting solution was heated at reflux for 2 hours, cooled to room temperature and concentrated in vacuo. The residue was diluted with EtOAc and was washed twice with 2 N aqueous NaOH solution and then with brine, dried over MgSO4.₄ and concentrated in vacuo to give 3-bromo-5-iodo-benzoic acid methyl ester (D8a) (14.8 g, 97%) as a light brown solid.

Description 8b

3-Bromo-5-iodo-benzoic acid tert-butyl ester (D8b)

To a solution of 3-bromo-5-iodo-benzoic acid (D7) (50 g, 153 mmol, 1 equiv) in CH 2 Cl 2 (500 mL) was added 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (30.8 g, 160 mmol, 1.05 equiv.), DMAP (14 g, 114 mmol, 0.75 equiv) and tert-butanol (90 mL, 917 mmol, 6 equiv.). The resulting mixture was stirred at room temperature for 48 hours. Then DMAP (4.67 g,

61567488 mmol, 0.25 equiv) and the solution was stirred for a further 24 hours and then concentrated in vacuo. The residue was dissolved in AcOEt and washed sequentially with 2N HCl aqueous solution, 1 N NaOH aqueous solution and brine, dried over MgSO 4 and concentrated in vacuo to give 3-bromo acid tert-butyl ester. 5-Iodo-benzoic (D8b) (50.6 g, 86%) as a brown solid.

Description 8b (Alternative Procedure)

3-Bromo-5-iodo-benzoic acid tert-butyl ester (D8b)

To a solution of 3-bromo-5-iodo-benzoic acid (D7) (50 g, 153 mmol, 1 equiv.) In CH₂C1₂ (500 mL) 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (30.8 g, 160 mmol, 1.05 equiv), DMAP (14 g, 114 mmol, 0.75 equiv) and tert-butanol (90 mL, 917 mmol, 6 equiv.). The resulting mixture was stirred at room temperature for 38 hours and then DMAP (4.67 g, 38 mmol, 0.25 equiv) was added, and the solution was stirred for a further 24 hours and then concentrated in vacuo. . The residue was diluted with EtOAc and washed sequentially with 2N HCl aqueous solution, NaOH aqueous solution and brine, dried over MgSO 4 and concentrated in vacuo to give 3-bromo-5 tert-butyl ester. -iodo-benzoic (D8b) (50.6 g, 86%) as a brown solid.

ΡΕ1567488

Description 9a

3-Bromo-5- (2-oxo-pyrrolidin-lil) -benzoic acid methyl ester D9a

A flask under nitrogen was charged with 3-bromo-5-iodo-benzoic acid methyl ester (D8a) (14.8 g, 43.4 mmol, equiv.), Cs.₂CO₃ (21 g, 65 mmol, 1.5 equiv.), Tris (dibenzylidenoacetone) dipaladium (0) (794 mg, 0.87 mmol, 0.02 equiv.), Xantphos (1.5 g, 2.6 mmol, 0.06 equiv) and dioxane (150 mL). Pyrrolidin-2-one (5 mL, 5.54 mmol, 1.5 equiv.) Was then added with a syringe and the resulting mixture was stirred at 55 ° C for 5 days and then cooled to room temperature. was concentrated in vacuo. The residue was partitioned between H₂O and EtOAc and the aqueous phase was reextracted with EtOAc. The combined organic solutions were dried over MgSO4.₄ and concentrated in vacuo to give a solid residue. Purification of the residue by silica gel flash chromatography (isohexane / AcOEt: 4/1 to 1/1) gave 3bromo-5- (2-oxo-pyrrolidin-1-yl) -benzoic acid methyl ester (D9a) ( 6.4 g, 50%) as a white solid. [M + H]⁺ = 299.9, TR = 2.95 minutes

Description 9a (Alternative Procedure)

3-Bromo-5- (2-oxo-pyrrolidin-lil) -benzoic acid methyl ester (D9a)

To a solution of 3-bromo acid methyl esterΡΕ1567488

5- (4-Chloro-butanoylamino) -benzoic acid (D13) (530 mg, 1.6 mmol, 1 equiv) in THF (5 mL) at room temperature was added NaH (60% in mineral oil, 64 mg, 1.7 mmol, 1.1 equiv.) And the resulting mixture was stirred at room temperature for 2 hours. H was then added₂The resulting mixture was diluted with EtOAc. The two layers were separated and the organic phase was dried over MgSO4 and concentrated in vacuo to give 3bromo-5- (2-oxo-pyrrolidin-1-yl) -benzoic acid methyl ester (D9a) (361 mg, 76%) as a yellow solid. [M-Hf = 296.3, RT = 2.49.

Description 9b

3-Bromo-5- (2-oxopyrrolidin-1-yl) -benzoic acid tert-butyl ester (D9b)

A flask under nitrogen was charged with bromo-5-iodo-benzoic acid tert-butyl ester (D8b) (11.5 g, 30 mmol, 1 equiv.), Cs.₂CO₃ (13.7 g, 42 mmol, 1.5 equiv.), Tris (dibenzylidenoacetone) dipaladium (0) (549 mg, 0.6 mmol, 0.02 equiv.), Xantphos (1.04 g, 1.8 mmol, 0.06 equiv.) and dioxane (100 mL). Pyrrolidin-2-one (2.5 mL, 33 mmol, 1.1 equiv) was then added via syringe and the resulting mixture was stirred at 60 ° C for 60 hours and then cooled to room temperature. and was concentrated in vacuo. The residue was partitioned between H₂O and EtOAc and the aqueous phase was reextracted with EtOAc. The combined organic solutions were dried over MgSO4 and concentrated in vacuo to give a solid residue which was

ΡΕ1567488

6th crushed with Et₂To give 3bromo-5- (2-oxo-pyrrolidin-1-yl) -benzoic acid tert-butyl ester (D9b) (6.63 g, 65%) as an off-white solid. The filtrate was concentrated in vacuo. Purification of the residue by silica gel flash chromatography (isohexane / AcOEt: 4/1 to 1/1) gave an additional 1.46 g (14%) of 3-bromo5- (2-2C) tert-butyl ester. oxo-pyrrolidin-1-yl) -benzoic (D9b) as a white solid. [M + H-tBu)]⁺ = 285.9, RT = 3.46 minutes

Description 10

3-Bromo-5- (2-oxo-piperidin-1-yl) -benzoic acid tert-butyl ester (D10)

A flask under nitrogen was charged with 3-bromo-5-iodo-benzoic acid tert-butyl ester (D8b) (6.42 g, 16.7 mmol, 1 equiv.), Cs.₂CO₃ (7.6 g, 23.4 mmol, 1.4 equiv.), Tris (dibenzylidenoacetone) dipaladio (0) (307 mg, 0.33 mmol, 0.02 equiv.), Xantphos (578 mg, 1 mmol, 0.06 equiv) and dioxane (120 ml). 8Valerolactane (1.9 mL, 20 mmol, 1.2 equiv) was then added via syringe and the resulting mixture was stirred at 60 ° C for 40 hours and then cooled to room temperature and concentrated to vacuum. The residue was partitioned between H₂O and EtOAc and the aqueous phase was reextracted with EtOAc. The combined organic solutions were dried over MgSO4.₄ and were concentrated in vacuo. Purification by silica gel flash chromatography (isohexane / AcOEt: 3/1 to 1/1) gave tert-butyl ester of the

61567488 3-Bromo-5- (2-oxo-piperidin-1-yl) -benzoic acid (D10) (4 g, 68%) as a white solid. RT = 2.88 minutes

Description 11

3-Bromo-5-nitro-benzoic acid methyl ester

To a solution of 3-bromo-5-nitro-benzoic acid (D5) (22.3 g, 90.6 mmol, 1 equiv.) In MeOH (300 mL) at 0 ° C was added dropwise SOC1.₂ (7.9 mL, 108 mmol, 1.2 equiv.). The resulting solution was stirred at reflux for 4 hours and then cooled to room temperature and concentrated in vacuo. The residue was diluted with EtOAc, washed twice with 2 N aqueous NaOH solution and once with brine, dried over MgSO4.₄ and concentrated in vacuo to give 3-bromo-5-nitro-benzoic acid methyl ester (D11) (22.1 g, 94%) as a light brown solid. RT = 3.18 minutes

Description 11 (Alternative Procedure)

3-Bromo-5-nitro-benzoic acid methyl ester (Dll)

To a chilled ice solution of 3bromo-5-nitro-benzoic acid (D5) (2.5 g, 10 mmol, 1 equiv.) In MeOH (25 mL) was added dropwise SOC1.₂ (1 mL, 15 mmol,

1.5 equiv.). The resulting solution was allowed to warm to room temperature and then stirred at 60 ° C for 3 hours, cooled to room temperature and

ΡΕ1567488 concentrated in vacuo. The residue was dissolved in EtOAc and the organic layer was washed with saturated aqueous NaHCO 3.₃, dried over MgSO 4 and concentrated in vacuo to give 3-bromo-5-nitro-benzoic acid methyl ester (D11) (2.6 g, 100%) as a yellow solid. RT = 3.22 minutes

Description 12

3-Amino-5-bromo-benzoic acid methyl ester (D12)

To a solution of 3-bromo5-nitro-benzoic acid (D11) methyl ester (12.1 g, 46.5 mmol, 1 equiv) in MeOH (200 mL) was added SnCl₂ (44 g, 233 mmol, 5 equiv.). The resulting mixture was stirred at reflux temperature for 4 hours, cooled to room temperature and concentrated in vacuo. The residue was partitioned between ice-cold AcOEt and H₂The aqueous phase was basified with 2N aqueous NaOH solution until a white precipitate appeared, then with 12.5 N aqueous NaOH solution until this precipitate disappeared. The temperature was kept below 10 ° C during this addition. The two layers were separated and the aqueous phase was extracted with EtOAc. The combined organic layers were washed with brine, dried over MgSO4.₄ and concentrated in vacuo to give 3-amino-5-bromo-benzoic acid methyl ester (D12) (9.9 g,

93%) as a brown solid.

ΡΕ1567488

Description 13

3-Bromo-5- (4-chlorobutanoylamino) benzoic acid methyl ester (D13)

To a solution of 3-amino5-bromo-benzoic acid (D12) methyl ester (460 mg, 2.0 mmol, 1 equiv.) In

CH 2 Cl 2 (10 mL) at room temperature was added NEt 3 (306 pL, 2.2 mmol, 1.1 equiv) then 4-chlorobutyryl chloride (247, pL, 2.2 mmol, 1.1 equiv). The resulting mixture was stirred at room temperature for 16 hours and then diluted with EtOAc. The organic phase was washed with 2N aqueous HCl solution, dried over MgSO4 and concentrated in vacuo to give 3bromo-5- (4-chloro-butanoylamino) -benzoic acid methyl ester (D13) (530 mg, 79C).

%) as a light yellow oil. RT = 2.88 s

Description 14

3- (3-Chloro-propane-1-sulfonylamino) -5-nitro-benzoic acid methyl ester (D14)

To a solution of 3-amino5-nitro-benzoic acid (D1) methyl ester (45 g, 229 mmol, 1 equiv.) In CH₂C1₂(450 mL) were added pyridine (18.5 mL, 229 mmol, 1 equiv.), DMAP (100 mg, 0.8 mmol, catalytic) and

3-chloropropanesulfonyl (28 mL, 230 mmol, 1 equiv). The resulting mixture was stirred for 40 hours and then diluted with EtOAc. The organic phase was diluted.

15467488 with 2N aqueous HCl solution. The resulting solid was filtered to give 3- (3-chloropropan-1-sulfonylamino) -5-nitro-benzoic acid methyl ester (23 g, 32%). The filtrate was separated and the organic phase was washed with saturated aqueous NaHCO 3 solution.₃, dried over MgSO₄ and concentrated in vacuo. The residue was triturated with EtOAc and isohexane to give an additional 50 g (65%) of 3- (3-chloro-propane-1-sulfonylamino) -5-nitro-benzoic acid methyl ester (D14) as a brown solid clear. [MH] = = 334.9, RT = 3.11 minutes

Description 15

3- (1,1-Dioxo-1 / methyl acid ester)⁶-isothiazolidin-2-yl) -5-nitro-benzoic (D15)

To a solution of 3- (3-chloro-propane-1-sulfonylamino) -5-nitro-benzoic acid methyl ester (D14) (73 g, 217 mmol, 1 equiv) in EtOH (600 mL) was added. Et₃N (60 mL, 430 mmol, 2 equiv.) And the resulting mixture was refluxed for 3 hours, cooled to room temperature and concentrated in vacuo. The residue was dissolved in AcOEt, washed with 2N aqueous HCl solution, dried over MgSO4.₄ and concentrated in vacuo. The residue was triturated with isohexane and AcOEt to give 3- (1,1-dioxo-1 / methyl acid ester).⁶-isothiazolidin-2-yl) -5-nitro-benzoic (D15) (58 g, 88%) as a light brown solid. [M + H + NH₃]⁺= 318.0, TR = 2.78 minutes

ΡΕ1567488

Description 15 (Alternative Procedure)

3- (1,1-Dioxo-1 / methyl acid ester)⁶-isothiazolidin-2-yl) -5-nitro-benzoic (D15)

A 50 mL flask was charged under nitrogen with 3-bromo-5-nitro-benzoic acid (D11) methyl ester (1 g, 3.8 mmol, 1 equiv.), CS 2 CO 3 (536 mg, 4.4 mmol, 1.2 equiv.) Tris (dibenzylidenoacetone) dipaladium (0) (5 mg,

0.0055 mmol, 0.0154 equiv), Xantphos (10 mg, 0.014 mmol, 0.04 equiv) and toluene (15 mL). Isothiazolidine 1,1-dioxide (D 22a) (536 mg, 4.4 mmol, 1.1 equiv) was then added and the resulting mixture was stirred at 90 ° C for

<td>16 hours and on</td><td>followed</td><td>was</td><td>cooled</td><td>up until</td><td colspan="2">the temperature</td>

<td>environment and it was</td><td>diluted</td><td>with</td><td>H₂O and AcOEt,</td><td>. At</td><td>layers</td><td>were</td>

<td colspan="2">separated, the aqueous phase</td><td>was</td><td>diluted with</td><td>an</td><td>solution</td><td>watery</td>

NaHCO₃ and was extracted with AcOEt. The combined organic phases were dried over MgSO4 and concentrated in vacuo to give 3- (1,1-dioxo-1/1-methyl acid ester).⁶isothiazolidin-2-yl) -5-nitro-benzoic (D15) (187 mg, 16%) as a yellow solid. [M + H + NH 3]⁺ = 318.0, TR = 2.81 minutes

Description 16

3-Amino-5- (1,1-dioxo-1 / methyl) ester⁶isothiazolidin-2-yl) benzoic (D16)

A flask was charged with methyl ester of the

61567488 3- (1,1-dioxo-1 /⁶-isothiazolidin-2-yl) -5-nitro-benzoic (D15) (25 g, 83 mmol, 1 equiv.) and 10% palladium (0) on charcoal (50% wet, 5 g, 10% w / w ) and EtOH (500 mL). The resulting suspension was stirred under a hydrogen atmosphere (atmospheric pressure) for 4 hours and the catalyst was filtered off through a pad of celite. The catalyst was washed three times with

DMF and the combined organic layers were concentrated in vacuo. The residue was dissolved in EtOAc and filtered again through celite to remove residual catalyst. The organic phase was concentrated in vacuo. The residue was triturated Et₂O to give acid methyl ester

3-amino-5- (1,1-dioxo-1 H)⁶(16-isothiazolidin-2-yl) -benzoic acid (18 g, 80%) as a light brown solid. [M + H]⁺ = 271.0, TR = 2.16 minutes

Description 17

3-Bromo-5- (1,1-dioxo-1 / tert-butyl ester)⁶isothiazolidin-2-yl) benzoic (D17)

A flask under nitrogen was charged with 3-bromo-5-iodo-benzoic acid tert-butyl ester D8b (1 g, 2.6 mmol, 1 equiv.), Cs.₂TLC> 3 (1.26 g, 3.9 mmol, 1.5 equiv.), Tris (dibenzylidenoacetone) dipaladium (0) (12 mg, 0.013 mmol,

0.005 equiv.), Xantphos (22 mg, 0.038 mmol, 0.015 equiv.) And toluene (20 mL). Isothiazolidine 1,1-dioxide (D22a) (350 mg, 2.9 mmol, 1.1 equiv) was then added and the resulting mixture was stirred at 100 ° C for 16 hours and

61567488 was then cooled to room temperature and was diluted with AcOEt. The organic phase was washed with saturated aqueous NaHCO 3 solution.₃, dried over MgSO₄ and was concentrated in vacuo. The residue was triturated with Et₂O to give 3-bromo-5- (1,1-dioxo-1 / t-butyl ester)⁶(D17) isothiazolidin-2-yl) benzoic acid (350 mg 38%) as a white solid.

Description 18

3-Bromo-5- (1,1-dioxo-1 / tert-butyl ester)⁶[1,2] thiazinan-2-yl) benzoic acid (D18)

Description 18 was prepared analogously to Description 17b from acid tert-butyl ester.

3-bromo-5-iodo-benzoic (D8b) (5.2 g, 13.6 mmol) and [1,2] thiazinane 1,1-dioxide (D22b) which gave the title compound (D18) (1.8 g, 34%) as a light yellow solid.

[M + H-tert-Bu]⁺ = 335.9, RT = 3.26 minutes

Description 19

3-Bromo-5- (3-chloro-propane-isulfonylamino) -benzoic acid methyl ester (D19)

To a solution of 3-amino5-bromo-benzoic acid (D12) methyl ester (2.3 g, 10 mmol, 1 equiv) in CH 2 Cl 2 (30 mL) was added dropwise pyridine (1.6 mL, 20 mmol, 2 equiv), DMAP (320 mg, 2.5 mmol, 2.5 equiv) and

ΡΕ1567488

3-chlorosulfonyl (1.46 mL, 12 mmol, 1.2 equiv). The resulting mixture was stirred at room temperature for 16 hours and then concentrated in vacuo. The residue was dissolved in EtOAc and the organic phase was washed sequentially with 2N aqueous HCl, saturated aqueous NaHCO3 and brine, dried over MgSO4.₄ and concentrated in vacuo to give 3-bromo-5- (3-chloro-propane-sulfonylamino) -benzoic acid methyl ester (D19) (3.36 g, 91%) as a red solid. [MH] = 369.9, R T = 3.25 minutes

Description 20

4-Chloro-1-butanesulfonyl chloride (D20)

To a mixture of [1,2] oxatiano (D23) 2,2-dioxide (50 g, 367 mmol, 1 equiv.) And SOC1₂ (29 mL, 401 mmol, 1.1 equiv) DMF (4 mL, 51.6 mmol, 0.14 equiv) was added. The resulting mixture was stirred under nitrogen at 70 ° C for 3 days. A second portion of SOC1 was added₂ (10 mL, 137 mmol, 0.37 equiv.). The mixture was stirred at 70 ° C for a further 3 days and then cooled to room temperature and concentrated in vacuo. The residue was diluted with toluene and then concentrated in vacuo. This procedure was repeated and the residue was dried under vacuum for 16 hours to give crude 4-chloro-butanesulfonyl chloride (D20) (63 g, 90%).

ΡΕ1567488

Description 21a

3-Chloro-1-propanesulfonamide (D21a)

To an ice-cold solution of 3-chloro-1-propanesulfonyl chloride (Chem. Pharm. Buli, 40 (1), 7584, 1999) (30 mL, 250 mmol, 1 equiv) in CH 2 Cl 2 (150 mL) was added. slowly aqueous ammonia solution (32%, 30 mL). The resulting mixture was stirred at room temperature for 16 hours and H₂O (20 mL). The layers were separated and the organic layer was dried over MgSO4.₄ θ is concentrated in vacuo to give crude 3-chloro-1-propanesulfonamide (D21a) (27 g, 69%) as a white solid. Chem. Pharm. Bull, 40 (1), 75-84, 1999].

Description 21b

3-Chloro-1-butanesulfonamide (D21 b)

To an ice-cooled solution of 4-chloro-1-butanesulfonyl chloride (D20) (43 g, 225 mmol, 1 equiv.) In CH₂C1₂ (350 mL) was slowly added aqueous ammonia solution (25%, 140 mL). The resulting mixture was stirred at room temperature for 16 hours and then concentrated in vacuo. The residue was diluted with EtOAc and washed with brine. The organic phase was dried over MgSO4.₄ and concentrated in vacuo to give crude 3-chloro-1-butanesulfonamide (D21b) (31g, 88%).

ΡΕ1567488

Description 22a

Isothiazolidine 1,1-dioxide (D22a)

<td>THE</td><td>a solution of 3-chloro-1-propanesulfonamide</td>

<td>(D21a) (27</td><td>170 mmol, 1 equiv) in EtOH (250 mL) at</td>

<td>temperature</td><td>NaOEt (11.7 g, 170 mmol,</td>

<td>1 equiv.).</td><td>The resulting mixture was heated to reflux.</td>

<td>for 5</td><td>hours and then cooled to</td>

<td>temperature</td><td>ambient and was concentrated in vacuo. 0 solid</td>

The residual residue was extracted with CH 2 Cl 2 and the extracts were concentrated in vacuo to give isothiazolidine 1,1-dioxide (D22a) (20 g, 100%).

Description 22b

[1,2] thiazinane 1,1-dioxide (D22b)

<td>THE</td><td>a solution of 3-chloro-1-butanesulfonamide</td>

<td>(D21b) (31</td><td>200 mmol, 1 equiv) in EtOH (500 mL) at</td>

<td>temperature</td><td>NaOEt (14.9 g, 220 mmol,</td>

<td>1.1 equiv.)</td><td>. The resulting mixture was heated to reflux.</td>

<td>for 5</td><td>hours and then cooled to</td>

<td>temperature</td><td>ambient and was concentrated in vacuo. 0 solid</td>

residual was extracted with CH₂C1₂ and the extracts were concentrated in vacuo. The residual solid was triturated with

Et₂O to give [1,2] thiazinane (D22b) 1,1-dioxide (18.7 g, 69%) as a light brown solid.

ΡΕ1567488

Description 23

4-Chloro-3,5-dinitrobenzoic acid (D23)

Description 23 is commercially available from Sigma-Aldrich Company.

Description 24

4-Methoxy-3,5-dinitro benzoic acid (D24)

To a solution of KOH (1.12 g, 20 mmol, 1 equiv.) In MeOH (20 mL) at 0 ° C was added portionwise 4-chloro-3,5-dinitrobenzoic acid (D23) (4.93 g, 20 mmol, 1 equiv.). The resulting mixture was heated at reflux for 1 hour and then cooled to room temperature. A second portion of KOH (1.12 g, 20 mmol, 1 equiv) was added and the mixture was heated at reflux for 90 minutes, cooled to room temperature and diluted with H₂The aqueous phase was acidified to pH 1 and extracted with EtOAc. The organic phase was dried over MgSO4.₄ and was concentrated in vacuo to give crude 4-methoxy-3,5-dinitro-benzoic acid (D24) (4.49 g, 93%) as a light brown solid.

Description 25

4-Methoxy-3,5-dinitro benzoic acid methyl ester (D25)

ΡΕ1567488

To a solution of crude 4-methoxy-3,5-dinitrobenzoic acid (D24) (4.43 g, 17.3 mmol, 1 equiv.) In MeOH (60 mL) was added H₂ONLY₄ concentrate (4 mL). The resulting mixture was refluxed for 3 hours, cooled to room temperature and concentrated in vacuo. The residue was partitioned between H₂O and AcOEt. The two layers were separated and the organic phase was washed with saturated aqueous NaHCO3 solution, dried over MgSO4.₄ and concentrated in vacuo. Purification by silica gel flash chromatography (isohexane / AcOEt: 85/15) gave 4-methoxy-3,5-dinitro-benzoic acid methyl ester (D25) (2.84 g, 65%) as a off-white solid.

The following descriptions were prepared analogously to Description 25 from commercially available starting materials:

<td>description</td><td>Material of match</td>

<td>4-Chloro-3,5-acid methyl ester</td><td>D24a</td>

<td>dinitro-benzoic</td><td></td>

<td>3-Amino-4-chloroacetic acid methyl ester</td><td>D26</td>

<td>benzoic (D27c)</td><td></td>

Description 27a

3,5-Diamino-4-chloro-benzoic acid methyl ester (D27a)

ΡΕ1567488

A mixture of 4-chloro3,5-dinitro-benzoic acid methyl ester (D25a) (2.6 g, 10 mmol, 1 equiv.) And SnCl₂ HCl (18.95 g, 100 mmol, 10 equiv.) In MeOH (80 mL) was heated at reflux for 1 hour, cooled to room temperature and concentrated in vacuo. The residue was partitioned between AcOEt 2 N aqueous NaOH solution. The organic phase was dried over MgSO4.₄ and was concentrated in vacuo. The residue was triturated with 1: 1 Et₂Isohexane to give 3,5-diamino-4-chlorobenzoic acid methyl ester (D27a) (1.56 g, 78%) as a light orange solid.

The following Description was prepared in a similar manner to Description 27a (using 5 equivalents SnCl₂ nitroaryl and 10 equivalents for bis nitroaryl) from the starting material given in the table below:

<td>description</td><td>Material of match</td>

<td>3,5-Diamino-4- acid methyl ester</td><td>D25b</td>

<td>methoxy benzoic (D27b)</td><td></td>

Description 28c

4-Chloro-3- (4-chlorobutanoylamino) benzoic acid methyl ester (D28c)

4-Chlorobutyryl chloride (2.82 g,

61567488 mmol, 2.0 equiv) in CH 2 Cl 2 (5 mL) for 2 minutes to a stirred solution of 3 amino-4-chloro benzoic acid methyl ester (D27c) (1.66 g, 10 mmol, 1 equiv. ) and NEt₃ (2.22 g, 22 mmol, 2.2 equiv.) In CH₂C1₂ (40 mL). The resulting mixture was stirred for 1 hour at room temperature and then washed with 2 N aqueous HCl solution, dried over MgSO4.₄ and concentrated in vacuo. The residue was triturated CH₂C1₂ to give 4-chloro-3- (4-chloro-butanoylamino) -benzoic acid methyl ester (D28c) (1.81 g, 48%) as a light pink solid.

The following Descriptions were prepared analogously to the process described in D28c from the starting material given in the table below:

<td>description</td><td>Precursor</td>

<td>4- (Chloro-3,5-bis- (4-</td><td>D27a</td>

<td>chloro-butanoylamino) benzoic (D28a)</td><td></td>

<td>3,5-Bis- (4-Chloroacetic acid methyl ester</td><td>D27b</td>

<td>butanoylamino) -4-methoxybenzoic (D28b)</td><td></td>

Description 30

(Benzyl-ethyl-amino) - (2oxo-pyrrolidin-1-yl) -benzoic acid tert-butyl ester (D30)

A flask under nitrogen was charged with 3-bromo-5- (2-oxo-pyrrolidin-1-yl) benzoic acid tert-butyl ester (D9b) (4.6 g, 13 mmol, 1 equiv), tert-butoxide in

Δ1567488 sodium (1.9 g, 19.5 mmol, 1.5 equiv.), Tris (dibenzylidenoacetone) dipaladium (0) (395 mg, 0.65 mmol, 0.05 equiv.), 2 (dicyclohexylphosphine) biphenyl (341 mg, 0.97 mmol, 0.075 equiv.) and toluene (100 mL). Netylbenzylamine (2.9 mL, 19.5 mmol, 1.5 equiv) was then added via syringe and the resulting mixture was stirred at 90 ° C for 2 hours and then cooled to room temperature. diluted with H₂O and AcOEt. The layers were separated, the aqueous phase was diluted with saturated aqueous NaHCO 3 solution.₃ and extracted with AcOEt. The combined organic phases were dried over MgSO4 and concentrated in vacuo. Purification of the residue by silica gel flash chromatography (isohexane / AcOEt: 1/2) gave (benzyl-ethyl-amino) (2-oxo-pyrrolidin-1-yl) -benzoic acid tert-butyl ester ( D30) (3 g, 60%) as a white solid. [M + H]⁺ = 395.0, TR = 3.70 minutes

Descriptions 31-35 (D31-D35)

Descriptions 31-35 were prepared analogously to D30 from aryl bromide and amine starting materials listed in the table below:

<td>description</td><td>Bromide of aryl</td><td>The mine</td><td>[M + H]⁺</td><td>RT (min)</td>

<td>Tert-Butyl ester of acid</td><td>D9b</td><td>jK THE,</td><td> 381, 1</td><td> 3, 59</td>

<td>(benzyl methyl amino) - (2-</td><td></td><td>u</td><td></td><td></td>

<td>oxo-pyrrolidin-1-yl) ben-</td><td></td><td></td><td></td><td></td>

<td>zoic (D31)</td><td></td><td></td><td></td><td></td>

ΡΕ1567488 (continued)

<td>description</td><td>Bromide of aryl</td><td>The mine</td><td>[M + H]⁺</td><td>RT (min)</td>

<td>(Benzyl-methyl-amino) tert-butyl ester - (2- oxo-piperidin-1-yl) benzoic (D32)</td><td>D10</td><td></td><td> 395, 2</td><td> 3, 51</td>

<td>(Benzyl-ethyl-amino) tert-butyl ester - (2- oxo-piperidin-1-yl) benzoic (D33)</td><td>D10</td><td>H r'x 0</td><td></td><td></td>

<td>(Benzyl-methyl-amino) - tert-butyl ester (1,1-dioxo-1 /⁶-isothiazole- din-2-yl) benzoic (D34)</td><td>D17</td><td>Λ</td><td> 417, 1</td><td> 3, 51</td>

<td>(Benzyl-ethyl-amino) - tert-butyl ester (1,1-dioxo-1 /⁶- [1,2] thiazide nan-2-yl) benzoic (D35)</td><td>D18</td><td>O</td><td> 445, 2</td><td> 3, 82</td>

Description 36

3-Hydroxy-5- (2-oxo-pyrrolidin-1-yl) -benzoic acid (D36)

To a solution of 3-amino-5- (2-oxo-pyrrolidin-1-yl) -benzoic acid (D6) (280 mg, 1.25 mmol, 1 equiv.) In a mixture of 2 N aqueous HCl solution ( 2.5 mL) and MeOH (5 mL) at 0 ° C were added portionwise.₃ (190 mg, 2.75

61567488 mmol, 2.2 equiv.) For 20 minutes. H 2 O (5 mL) was added and the resulting mixture was heated at 90 ° C for 1 hour and then cooled to room temperature and diluted with EtOAc. The two layers were separated and the aqueous phase was extracted twice with EtOAc (20 mL). The combined organic layers were washed with brine (20 mL), dried over MgSO4.₄ and concentrated in vacuo to give a crude product which was triturated with Et₂O / MeOH to give 3-hydroxy-5- (2-oxo-pyrrolidin-1-yl) -benzoic acid (D36) (110 mg, 40%) as a light brownish solid.

Description 37

3-Hydroxy-5- (2-oxo-pyrrolidin-1-yl) -benzoic acid methyl ester (D37)

3-Hydroxy-5- (2-oxo-pyrrolidin-yl) -benzoic acid (D36) (400 mg, 1.72 mmol, 1 equiv) was heated to reflux temperature in a mixture of MeOH (20 mL) and H₂ONLY₄concentrate (4 drops) for 7 hours. The solution was then cooled to room temperature and concentrated in vacuo to give 3-hydroxy-5- (2-oxopyrrolidin-1-yl) benzoic acid methyl ester (D37) (300 mg, 74%) as a brown solid clear.

Description 37 (Alternative Procedure)

3-Hydroxy-5- (2-oxo-pyrrolidin-1-yl) -benzoic acid methyl ester (D37)

ΡΕ1567488

4

3-Amino-5- (2-oxo-pyrrolidin-1-yl) -benzoic acid methyl ester (D4a) (1.50 g, 6.4 mmol, 1 equiv) was dissolved in a mixture of aqueous HCl solution 2 N (25 mL) and MeOH (50 mL) at 0 ° C and treated with portions of NaN₃ (950 mg, 13.8 mmol, 2.2 equiv.) For 20 minutes. H added₂O (50 mL) and the resulting mixture was heated to 90 ° C for 45 minutes and then cooled to room temperature and diluted with Et₂O (300 mL). The two layers were separated and the organic phase was dried over MgSO4 and concentrated in vacuo to give 3-hydroxy-5- (2-oxo-pyrrolidin-1-yl) -benzoic acid methyl ester (D37) (1.0 g 67%) as a brownish solid.

Description 38

3- (3-Benzyloxy-propoxy) -5- (2oxo-pyrrolidin-1-yl) -benzoic acid methyl ester (D38)

A solution of 3-hydroxy 5- (2-oxopyrrolidin-1-yl) benzoic acid methyl ester (D37) (300 mg, 1.28 mmol, equiv), 3-benzyloxypropan-1-ol (0.28 mL) 1.79 mmol, 1.4 equiv.) And triphenyl phosphine (470 mg, 1.79 mmol, 1.4 equiv.) In THF (10 mL) at room temperature were treated with DEAD drops (0.282 mL, 1 mL). , 79 mmol, 1.4 equiv.). The mixture was stirred for 16 hours at room temperature and then concentrated in vacuo. Purification by silica gel flash chromatography (ethyl acetate / isohexane: 1/4 to 1/1) gave 3-1567488 (3-benzyloxy-propoxy) -5- (2-oxo-pyrrolidin-1) methyl ester (yl) benzoic (D38).

Description 39

Description 39 was prepared analogously to Description 38 from Description 37 using the appropriate alcohol indicated in the table below:

<td>description</td><td>Alcohol</td>

<td>3- (2-Benzyloxy-ethoxy) -5- (2-</td><td></td>

<td>oxo-pyrrolidin-1-yl) benzoic (D39)</td><td></td>

Description 40

3- (2-Benzyloxy-ethoxy) -5- (2-oxopyrrolidin-1-yl) benzoic acid (D40)

Description 40 was prepared by saponification of Description 39 according to known procedures.

Description 41

3- (1,1-Dioxo-1 / methyl acid ester⁶-isothiazolidin-2-yl) -5-hydroxybenzoic acid (D41)

1- [3-Amino-5- (1,1-dioxo-1 /⁶(isothiazolidin-2-yl) phenyl] propan-1-one (D16) (1.0 g, 3.7 mmol, 1 equiv.) dissolved in a mixture of 2 N aqueous HCl solution (15

15467488 mL) and MeOH (30 mL) were stirred at 0 ° C and treated with portions of sodium nitrite (550 mg, 8.0 mmol, 2.2 equiv) for 20 minutes. H added₂O (50 mL) and the resulting mixture was heated at 90 ° C for 45 minutes, cooled, and diluted with Et₂O (300 mL). The two layers were separated and the organic phase was dried over MgSO4.₄ and concentrated in vacuo to give 3- (1,1-dioxo-1 / acid methyl ester).⁶isothiazolindin-2-yl) -5-hydroxybenzoic acid (D41) (800 mg, 80%) as a brown oil.

Description 41 (Alternative Procedure)

3- (1,1-Dioxo-1 / methyl acid ester⁶-isothiazolidin-2-yl) -5-hydroxybenzoic acid (D41)

A mixture of 3benzyloxy-5- (1,1-dioxo-116-isothiazolidin-2-yl) -benzoic acid methyl ester (D54) (4.5 g, 12.5 mmol, 1 equiv), NH 4 COOH (7 , 7 g, 125 mmol, 10 equiv.) And 10% Pd on charcoal (50% wet, 1.0 g, 11% w / w) in MeOH (150 mL) and H₂O (10 mL) was heated to

50 ° C for 2 hours. The cooled reaction mixture was filtered through a pad of celite and was concentrated in vacuo. H added₂O (100 mL) to the filtrate which was then extracted with EtOAc (150 mL). The organic solution was dried over MgSO4.₄ and concentrated in vacuo. The residue was crystallized from Et₂O to give 3- (1,1-dioxo-1 / methyl acid ester)⁶-isothiazolidin-2-yl) -5-hydroxybenzoic acid (D41) (2.6 g, 77%) as a white solid.

ΡΕ1567488

Description 42

5-Hydroxyisophthalic acid dimethyl ester (D42)

Description 42 is commercially available from Sigma-Aldrich Company.

Description 43

5-Ethoxy-isophthalic acid dimethyl ester (D43)

K was added₂CO₃ (31.6 g, 223 mmol, 2.23 equiv.) And iodoethane (17.8 mL, 230 mmol, 2.3 equiv.) To a solution of 5-hydroxyisophthalic acid dimethyl ester (D42) (21 g, 100 mmol, 1 equiv) in acetone (500 mL) at room temperature. The resulting solution was heated at reflux for 16 hours then cooled to room temperature and concentrated in vacuo. The residue was partitioned between H₂O and AcOEt. The aqueous phase was extracted with EtOAc and the combined organic layers were washed with 2 N aqueous NaOH solution, brine, dried over MgSO4.₄ and concentrated in vacuo to give 5ethoxyisophthalic acid dimethyl ester (D43) (23 g, 96%) as a white solid. RT = 3.13 minutes

Description 44

5-Benzyloxy-isophthalic acid dimethyl ester (D44)

ΡΕ1567488

K 2 CO 3 (21 g, 153 mmol, 2 equiv.) And benzyl bromide (11 mL, 92 mmol, 1.2 equiv) were added to a solution of 5-hydroxyisophthalic acid (D42) dimethyl ester (16.1 g, 76.7 mmol, 1 equiv) in acetone (400 mL) at room temperature. The resulting solution was heated at reflux for 18 hours, cooled to room temperature and concentrated in vacuo. The residue was shared between H₂O and AcOEt. The aqueous phase was extracted with EtOAc and the combined organic layers were washed with 2 N aqueous NaOH solution and brine, dried over MgSO 4 and concentrated in vacuo to give 5-benzyloxyisophthalic acid dimethyl ester (D44 ) (24.2 g, 105%) as a white solid. [M + H]⁺ = 301.0, TR = 3.50 minutes

Description 45

5-Ethoxyisophthalic acid monomethyl ester (D45)

To a solution of 5-ethoxyisophthalic acid (D43) dimethyl ester (22 g, 92.4 mmol, 1 equiv.) In MeOH (440 mL) was added 1 N aqueous NaOH solution (87.8 mL, 87%). 8 mmol, 0.95 equiv.) And the resulting solution was stirred at room temperature for 17 hours. Most of the MeOH was removed in vacuo and the residue was partitioned between AcOEt and 1 aquosa aqueous NaOH solution. The aqueous layer was extracted with EtOAc, acidified to pH 1 and re-extracted with EtOAc. The second organic extract was dried over MgSO 4 and concentrated in vacuo to give acid monomethyl ester.

ΡΕ1567488

5-ethoxyisophthalic (D45) (17 g, 82%) as a white solid.

[M + H + NH 3]⁺ = 242.0, TR = 2.79 minutes

Description 46

5-Benzyloxy-isophthalic acid monomethyl ester (D46)

To a solution of 5benzyloxyisophthalic acid (D44) dimethyl ester (24 g, 80 mmol, 1 equiv) in MeOH (300 mL) was added 1 N aqueous NaOH solution (76 mL, 76 mmol, 0.95). equiv.) and the resulting solution was stirred at room temperature for 17 hours. A second portion of 1 N NaOH aqueous solution (15 mL, 15 mmol, 0.2 equiv) was added and the solution was stirred for a further 6 hours. Most of the MeOH was removed in vacuo and the residue was partitioned between EtOAc and 1 N aqueous NaOH solution. The aqueous layer was extracted with EtOAc, acidified to pH 1 and re-extracted with EtOAc. The second organic extract was dried over MgSO4.₄ and concentrated in vacuo. The residue was triturated with Et 2 O to give 5-benzyloxyisophthalic acid monomethyl ester (D46) (15.5 g, 68%) as a white solid. [M + H]⁺ = 2.86.0, TR = 3.32 minutes

Description 47

3-Benzyloxycarbonylamino-5ethoxy-benzoic acid methyl ester (D47)

ΡΕ1567488

Added NEt₃ (14.2 mL, 102 mmol, 1.3 equiv.) And diphenylphosphoryl azide (22 mL, 102 mmol, 1.3 equiv.) To a suspension of 5-ethoxyisophthalic acid monomethyl ester (D45) (17.6 g 78.6 mmol, 1 equiv.) In toluene (250 mL) and the mixture was heated at 80 ° C for 3 hours. Benzyl alcohol (12 mL, 118 mmol, 1.5 equiv) was added and the resulting mixture was heated at reflux for 4 hours, cooled to room temperature and concentrated in vacuo. The residue was dissolved in EtOAc (300 mL) and the resulting solution was washed with 2 N aqueous HCl (100 mL) followed by saturated aqueous NaHCO 3.₃ (100 mL), dried over MgSO4₄ and concentrated in vacuo. The residue was triturated with Et₂To give 3benzyloxycarbonylamino-5-ethoxy benzoic acid methyl ester (D47) (15 g, 62%) as a white solid. [MH] = 328.1, RT = 3.46 minutes

Description 48

3-Benzyloxy-5- (2-trimethylsilanyl-ethoxycarbonylamino) -benzoic acid methyl ester (D48)

Added NEt₃ (8.2 g, 81 mmol, 1.5 equiv.) And diphenylphosphoryl azide (22.3 g, 81 mmol, 1.5 equiv.) To a suspension of 5-benzyloxyisophthalic acid monomethyl ester (D46) (15, 5 g, 54.2 mmol, 1 equiv) in toluene (120 mL) and the resulting mixture was heated at 80 ° C for 3 hours. 2-Trimethylsilylethanol (12.7 g, 108 mmol, 2 equiv) was added and the resulting mixture was heated at reflux for 4 hours, cooled to room temperature.

61567488 ambient and concentrated in vacuo. The residue was dissolved in EtOAc (300 mL) and the resulting solution was washed with 2 N aqueous HCl (100 mL) followed by saturated aqueous NaHCO 3.₃ (100 mL), dried over MgSO4₄ and concentrated in vacuo. The residue was triturated with Et₂O isohexane to give 3-benzyloxy-5- (2-trimethylsilanyl-ethoxycarbonylamino) -benzoic acid methyl ester (D48) (8.5 g, 40%) as a white solid.

Description 49

3-Amino-5-ethoxy-benzoic acid methyl ester (D49)

A mixture of 3benzyloxycarbonylamino-5-ethoxy benzoic acid methyl ester (D47) (15 g, 45.5 mmol, 1 equiv), 10% palladium on carbon (50% wet,

1.5 g, 5% w / w) and NH₄COOH (15 g, 455 mmol, 10 equiv.) H₂The (50 mL) and MeOH (200 mL) was stirred at 50 ° C for 2 hours. The mixture was cooled to room temperature and the catalyst was filtered off through a pad of celite. Most of the MeOH was removed in vacuo and the residue was partitioned between saturated aqueous NaHCO 3 solution.₃ and AcOEt. The aqueous phase was reextracted with EtOAc. The combined organic phases were dried over MgSO4.₄ and concentrated in vacuo to give 3-amino-5-ethoxy-benzoic acid methyl ester (D49) (8.8 g, 99%) as a light green solid which was used in the next step without further purification. [M + H]⁺ = 196.1, RT = 2.49 minutes

ΡΕ1567488

Description 50

3-Amino-5benzyloxy-benzoic acid methyl ester hydrochloride (D50)

3-Benzyloxy-5- (2-trimethylsilanyl-ethoxycarbonylamino) -benzoic acid methyl ester (D48) (8.5 g,

21.2 mmol, 1 equiv.) In THF (40 mL) was treated with 1 M tetrabutyl ammonium fluoride in THF (40 mL, 40 mmol, 1.9 equiv.) And the resulting solution was stirred at room temperature for 16 hours. hours and then concentrated in vacuo. The residue was dissolved in EtOAc (200 mL) and washed with H₂The (20 OmL) was then dried over MgSO4.₄ and concentrated in vacuo. The residue was redissolved in Et₂O / EtOAc and treated with 2 N HCl in Et₂O to give, after filtration, acid methyl ester hydrochloride

3-Amino-5-benzyloxy-benzoic (D50) (5.0 g, 80%) as a white solid.

Description 51

3- (4-Chloro-butanoylamino) -5ethoxy-benzoic acid methyl ester (D51)

3-Amino-5-ethoxy-benzoic acid methyl ester (D49) (4.0 g, 20.5 mmol, 1 equiv.) Was suspended in CH₂C1₂NaCl (40 mL) and was treated at room temperature with NEt3 (2.32 g, 23mmol, 1.1 equiv.). The resulting solution was cooled to 0 ° C and 4ΡΕ1567488 chlorobutyryl chloride (3.1 g, 22 mmol, 1.1 equiv) was added dropwise. The resulting mixture was stirred at 0 ° C for 3 hours and then allowed to warm to room temperature. The solution was then washed with 2 N aqueous HCl solution, dried over MgSO4.₄ and concentrated in vacuo to give 3- (4-chloro-butanoylamino) -5-ethoxy-benzoic acid methyl ester (D51) (7.0 g, 115%) as a brown oil.

Description 52

3-Benzyloxy-5- (3-chloro-propane-1-sulfonylamino) -benzoic acid methyl ester (D52)

A suspension of 3-amino-5-benzyloxy-benzoic acid methyl ester hydrochloride (D50) (5.0 g, 17 mmol, 1 equiv.) In CH₂C1₂ (100 mL) was treated with DMAP (400 mg, 3.2 mmol) and pyridine (3.5 g, 44 mmol, 2.6 equiv) followed by 3-chloropropanesulfonyl chloride (3.54 g, 20 mmol, 1.2 equiv.) Dropwise at room temperature. The resulting mixture was stirred for 16 hours and then concentrated in vacuo. The residue was dissolved in EtOAc (200 mL) and the resulting solution was washed with 2 N aqueous HCl (100 mL) followed by saturated aqueous NaHCO 3.₃ (100 mL), dried over MgSO4₄ and concentrated in vacuo to give 3-benzyloxy-5- (3-chloro-propane-1-sulfonylamino) -benzoic acid methyl ester (D52) (6.0 g, 97%) as a light pink solid. [M + H]⁺ = 366.1, RT = 2.34 minutes

ΡΕ1567488

Description 53

3- (3-Chloro-propane-1-sulfonylamino) -5-ethoxy-benzoic acid methyl ester (D53)

A suspension of 3-amino5-ethoxy-benzoic acid methyl ester (D49) (4.0 g, 20.5 mmol, 1 equiv.) In

CH 2 Cl 2 (100 mL) was treated dropwise with DMAP (400 mg,

3.2 mmol) and pyridine (1.74 g, 22 mmol, 1.1 equiv.) Followed by 3-chloropropanesulfonyl chloride (3.89 g, 22 mmol, 1.1 equiv). The resulting mixture was stirred for 16 hours and then concentrated in vacuo. The residue was dissolved in EtOAc (200 mL) and the resulting solution was washed with 2 N aqueous HCl solution (100 mL) followed by aqueous NaHCO3 solution (100 mL), then dried over MgSO4.₄ and concentrated in vacuo to give 3- (3-chloro-propane-1-sulfonylamino) -5-ethoxybenzoic acid methyl ester (D53) (6.7 g, 98%) as a light orange solid.

Description 54

3-Benzyloxy-5- (1,1-dioxo-1 H) methyl ester⁶isothiazolidin-2-yl) benzoic (D54)

A solution of 3benzyloxy-5- (3-chloro-propane-1-sulfonylamino) -benzoic acid methyl ester (D52) (6.0 g, 17 mmol, 1 equiv) in EtOH (80 mL) was treated with NEt.₃ (3.4 g, 34 mmol, 2 equiv.). The mix

The resulting solid is refluxed for 6 h, cooled to room temperature and light pink solid isothiazolidin-2-yl) -benzoic acid methyl ester.

concentrated in vacuo to give

3-benzyloxy-5- (1,1-dioxo-1 /⁶(D54) (4.5 g, 74%) as a

Description 55

5-Dimethylthiocarbamoyloxyisophthalic acid dimethyl ester (D55)

To a solution of 5hydroxyisoffalic acid (D42) dimethyl ester (21 g, 100 mmol, 1 equiv) in DMF (300 mL) at room temperature was added DABCO (14.6 g, 130 mmol, 1.3 equiv.) followed by dimethylthiocarbamoyl chloride (14.8 g, 120 mmol, 1.2 equiv.). The resulting mixture was stirred at room temperature for 16 hours and at 60 ° C for 2 hours, then cooled to room temperature and concentrated in vacuo. The residue was partitioned between AcOEt and H₂The aqueous phase was reextracted with EtOAc. The combined organic solution was washed sequentially with 5% aqueous citric acid solution, 2 N aqueous NaOH solution and brine, then dried over MgSO4.₄ and concentrated in vacuo to give 5-dimethylthiocarbamoyloxyisoffalic acid dimethyl ester (D55) (23.5 g, 79%) as a light yellow solid. [M + H]⁺ = 298.0, TR = 3.06 minutes

ΡΕ1567488

Description 56

5-Dimethylcarbamoylsulfanylisophthalic acid dimethyl ester (D56)

5-Dimethylthiocarbamoyloxyisophthalic acid dimethyl ester (D55) (15.5 g, 52.2 mmol, 1 equiv.) Was stirred at 200 ° C for 24 hours under nitrogen and then cooled to room temperature. Purification by silica gel flash chromatography (isohexane / AcOEt: 4/1 then 3/1) gave 5-dimethylcarbamoylsulfanyl isophthalic acid dimethyl ester (D56) (7.0 g, 45%) and recovered 5-dimethyl acid ester. -dimethylthiocarb-

<td>moiloxy isophthalic (D55)</td><td> (2,</td><td>77g,</td><td>18%), both</td><td>as solids</td>

<td>white. [M + H]⁺ = 298,0,</td><td>TR =</td><td> = 2,92</td><td>minutes</td><td></td>

<td>Description 57</td><td></td><td></td><td></td><td></td>

<td>Monomethyl ester</td><td>of</td><td>acid</td><td colspan="2">5-dimethylcarbamoyl sulphate</td>

<td>isophthalic (D57)</td><td></td><td></td><td></td><td></td>

<td>The one solution</td><td>in</td><td>ester</td><td>dimethyl</td><td>of acid 5-</td>

dimethylcarbamoylsulfanyl isophthalic (D56) (6 g, 20.2 mmol, 1 equiv) in THF (100 mL) at room temperature was added 2 N aqueous NaOH (9.6 mL, 19.2 mmol, 0.95). equiv.). The resulting mixture was stirred for 11 hours and then partitioned between AcOEt and H₂The two layers were separated and the aqueous phase was extracted with EtOAc. After acidification to pH 1, the aqueous phase was

ΡΕ1567488 extracted twice with AcOEt. The organic solution was dried over MgSO4.₄ It was then concentrated in vacuo to give 5-dimethylcarbamoylsulfanylisophthalic acid monomethyl ester (D57) (4.54 g, 79%) as a white solid.

Description 58

Methyl-butoxycarbonylaminodimethylcarbamoylsulfanyl benzoic acid methyl ester (D58)

To a solution of crude 5-dimethylcarbamoylsulfanyl isophthalic acid monomethyl ester (D57) (4.56 g,

16.1 mmol, 1 equiv.) In toluene (100 mL) was added triethylamine (6.7 mL, 48 mmol, 3 equiv.) And diphenylphosphoryl azide (5.2 mL, 24 mmol, 1.5 equiv.) . The resulting mixture was stirred under nitrogen at 80 ° C for 3 hours and then tert-butanol (4.6 mL, 48 mmol, 3 equiv) was added. The solution was stirred at 80 ° C for a further 16 hours and then cooled to room temperature and concentrated in vacuo. The crude product was dissolved in EtOAc and the resulting solution was washed sequentially with 2 N aqueous NaOH solution, 2 N aqueous HCl solution and brine, dried over MgSO4.₄ and concentrated in vacuo. Purification by silica gel flash chromatography (isohexane / AcOEt: 3/1 to 6/4) gave tert-butoxycarbonylamino-dimethylcarbamoylsulfanyl-benzoic acid methyl ester (D58) (2.24 g,

40%) as a white solid.

ΡΕ1567488

Description 59

3-tert-Butoxycarbonylamino-5-mercapto benzoic acid (D59)

To a solution of tert-butoxycarbonylamino-dimethylcarbamoylsulfanyl-benzoic acid methyl ester (D58) (2.24 g, 6.3 mmol, 1 equiv) in MeOH (30 mL) and H₂O (23 mL) was added 2 N aqueous NaOH solution (7 mL, 14 mmol, 2.2 equiv.). The resulting mixture was heated at reflux for 3 hours and then cooled to room temperature and concentrated in vacuo. The residue was partitioned between EtOAc and 1 N aqueous NaOH solution. The aqueous phase was acidified to pH 1 and extracted twice with EtOAc. The combined organic solutions were dried over MgSO 4 and then concentrated in vacuo to give 3-tert-butoxycarbonylamino-5-mercapto benzoic acid (D59) (1.54 g, 90%) as a white solid.

Description 60

3-tert-Butoxycarbonylamino-5-methylsulfanyl-benzoic acid methyl ester (D60)

To a solution of 3-tert-butoxycarbonylamino-5-mercapto-benzoic acid (D59) (0.68 g, 2.52 mmol, 1 equiv) in acetone (15 mL) was added K₂CO₃ (3.5 g, 25.3 mmol, 10 equiv.) And iodomethane (473 µL, 7.59 mmol, 3 equiv.). The resulting mixture was stirred at 50 ° C for 2

61567488 hours, cooled to room temperature and concentrated in vacuo. The residue was partitioned between AcOEt and H₂0 The organic layer was washed with H₂0 and brine, dried over MgSO4₄ and concentrated in vacuo. Purification by silica gel flash chromatography (isohexane / AcOEt: 85/15) gave 3-tert-butoxycarbonylamino-5methylsulfanyl benzoic acid methyl ester (D60) (0.47 g, 63%) as a white solid . [MH] = 296.1, R T = 3.51 minutes

Description 61

3-tert-Butoxycarbonylamino-5-ethylsulfanyl-benzoic acid ethyl ester (D61)

Description 61 was obtained from 0.68 g (2.53 mmol) of 3-tert-butoxycarbonylamino-5-methylsulfanyl-benzoic acid methyl ester (D59) and iodoethane using the procedure used in Description 60, which gave the Title compound (D61) (0.58 g, 71%) as a white solid. [MH] = = 324.2, RT = 3.79 minutes

Description 62

3-Amino-5-methylsulfanyl-benzoic acid methyl ester hydrochloride (D62)

3-tert-Butoxycarbonylamino-5-methylsulfanyl-benzoic acid methyl ester (D60) (0.54 g, 1.82 mmol,

61567488 equiv.) Was dissolved in dioxane (2 mL) and 4 M HCl in dioxane (16 mmol, 4 mL, 8.8 equiv) was added. The solution was stirred at room temperature for 2 hours allowing the amine hydrochloride salt to precipitate. This precipitate was filtered off, washed with Et 2 O and dried giving 3-amino-5-methylsulfanyl-benzoic acid methyl ester hydrochloride (D62) (0.224 g, 52%). [M + H]⁺ = 198.1, RT = 2.68 minutes

Description 63

3-Amino-5-ethylsulfanyl-benzoic acid ethyl ester hydrochloride (D63)

Description 63 was prepared from 0.57 g (1.75 mmol) of 3-tert-butoxycarbonylamino-5-ethylsulfanyl benzoic acid ethyl ester (D61) in a manner analogous to that described in Description 62 which gave 0.335 g (73%) 3-Amino-5-ethylsulfanyl benzoic acid ethyl ester hydrochloride (D63) as a white solid. [M + H]⁺ = 226.1, TR = 3.13 minutes

Description 64

3- (4-Chloro-butanoylamino) -5-methylsulfanyl-benzoic acid methyl ester (D64)

To a methyl ester hydrochloride solution of

ΡΕ1567488 3-amino-5-methylsulfanyl benzoic acid (D62) (0.13 g, 0.556 mmol, 1 equiv) in dry CH 2 Cl 2 (2 mL) at 0 ° C was added NEt₃ (193 mL, 1.39 mmol, 2.5 equiv.) And then 4-chlorobutyryl chloride (69 mL, 0.612 mmol, 1.1 equiv.) Was added dropwise over 2 minutes. The resulting solution was stirred at 0 ° C for 15 minutes and then at room temperature for 30 minutes. The solution was then diluted with EtOAc, washed sequentially with 2 N aqueous HCl, saturated aqueous NaHCO 3 solution.₃ and brine, dried over Na₂SOA and concentrated in vacuo to give 3- (4-chloro-butanoylamino) -5-methylsulfanyl-benzoic acid methyl ester (D64) (173 mg, 103%) as light yellow crystals. [M + H]⁺= 302.0, TR = 3.20 minutes

Description 65

3- (4-Chloro-butanoylamino) -5-ethylsulfanyl-benzoic acid ethyl ester (D65)

Description 65 was prepared from 140 mg (0.535 mmol) of 3-amino-5-ethylsulfanylbenzoic acid ethyl ester hydrochloride (D63) in a manner analogous to that described in Description 64 which gave 182 mg (103%) of ester. 3- (4-Chloro-butanoylamino) -5-ethylsulfanylbenzoic acid (D65) ethyl acetate as light yellow crystals. [M + H]⁺ = 330.0, TR = 3.51 minutes

ΡΕ1567488

Description 66

3- (3-Chloro-propane-1-sulfonylamino) -5-methylsulfanyl-benzoic acid methyl ester (D66)

To a solution of 3-amino-5-methylsulfanyl benzoic acid methyl ester hydrochloride (D62) (130 mg, 0.556 mmol, 1 equiv) in CH 2 Cl 2 (2 mL) was added pyridine (142 mL, 1.75 mmol, 3 equiv.), DMAP (6.8 mg, 0.056 mmol, 0.1 equiv.) and then 3-chloropropanesulfonyl chloride (71 pL, 0.584 mmol, 1.05 equiv.) dropwise. drop for 2 minutes. The resulting mixture was stirred at room temperature for 2 hours, diluted with AcOEt, washed sequentially with 2 N aqueous HCl solution, saturated aqueous NaHCO 3 solution and saturated aqueous sodium chloride solution, dried over Na₂ONLY₄ and concentrated in vacuo to give 3- (3-chloro-propane-isulfonylamino) -5-methylsulfanyl-benzoic acid methyl ester (D66) (196 mg,

104%) as light brown crystals. [MH] _ = 336.0 TR =

3.20 minutes

Description 67

3- (3-Chloro-propane-1-sulfonylamino) -5-ethylsulfanyl-benzoic acid ethyl ester (D67)

Description 67 was prepared from 140 mg (0.6 mmol) of 3-amino acid ethyl ester hydrochloride1567488

5-ethylsulfanyl benzoic acid (D63) in a manner analogous to that described in Description 66 which gave 200 mg (102%) of 3- (3-chloro-propane-1-sulfonylamino) -5ethylsulfanyl benzoic acid ethyl ester (D67) like light brown crystals. [MH] = 364.0, R T = 3.49 minutes

Description 68

3- (2-Oxo-piperidin-1-yl) 5- (E / Z) -propenyl-benzoic acid tert-butyl ester (D68)

To a solution of 3bromo-5- (2-oxo-piperidin-1-yl) -benzoic acid tert-butyl ester (D10) (500 mg, 1.4 mmol, 1 equiv) in DME (14 mL) and H₂(4 mL) was added tetrakis (triphenylphosphine) palladium (0) (81 mg, 0.07 mmol,

0.05 equiv.), And the suspension was stirred for 10 minutes. 2,4,6-Tripropenylcyclotriboroxanopyridin complex (394 mg, 1.4 mmol, 1 equiv.) And K₂CO₃ (193 mg, 1.4 mmol, 1 equiv.) And the resulting mixture was stirred at 90 ° C for 1 hour, cooled to room temperature and diluted with EtOAc. The organic phases were washed with H₂O, dried over MgSO₄ and concentrated in vacuo. Purification by silica gel flash chromatography (isohexane / AcOEt: 4/1) gave 3- (2-oxo-piperidin-1-yl) -5- (E / Z) -propenyl acid tert-butyl ester. benzoic (D68) (480 mg, 100%) of adduct as a light yellow solid. [M + H]⁺ = 316.2, RT = 3.41 minutes

ΡΕ1567488

Descriptions 69-72

Descriptions 69-72 were prepared in a manner analogous to that described for Description 68 from the appropriate aryl bromide starting material indicated in the table below using the appropriate 2,4,6-trialcenylcyclotriboroxane-pyridine complex as described by F. Kerins and DFO'Shea in J. Org. Chem, 2002, 67, 4968-4971:

<td>description</td><td>Bromide of aryl</td><td>[M + H]⁺</td><td>RT (min)</td>

<td>3- Acid tert-butyl ester (1,1-dioxo-1 /⁶- [1,2] thiazinan-2- yl) -5- (E / Z) -propenyl-benzoic (D69)</td><td>D18</td><td>(t-Bu) 296.1</td><td> 3,61</td>

<td>3- (2—- Acid methyl ester oxo-pyrrolidin-1-yl) -5-vinyl benzoic (D70)</td><td>D9a</td><td></td><td></td>

<td>3- Acid methyl ester isopropenyl-5- (2-oxo-pyrrolidin-2-one 1-yl) benzoic (D71)</td><td>D9a</td><td> 260, 0</td><td> 2, 96</td>

<td>3- (2—- Acid methyl ester oxo-pyrrolidin-1-yl) —5— (E / Z) - propenyl benzoic (D72)</td><td>D9a</td><td> 260, 0</td><td> 2,97</td>

Description 73

3-Cyclopent-2-enyl-5- (2-oxopyrrolidin-1-yl) -benzoic acid methyl ester;

ΡΕ1567488

3-Cyclopent-3-enyl-5- (2-oxopyrrolidin-1-yl) -benzoic acid methyl ester; and

3-Cyclopent-1-enyl-5- (2-oxopyrrolidin-1-yl) -benzoic acid methyl ester (D73)

To a solution of 3-bromo5- (2-oxo-pyrrolidin-1-yl) -benzoic acid methyl ester (D9a) (686 mg, 2.3 mmol, equiv.) In DMF (3 mL) was added cyclopentene (409 μΐ,

4.6 mmol, 2 equiv.), Palladium (II) acetate (26 mg, 0.12 mmol, 0.05 equiv.), Tri (o-tolyl) phosphine (71 mg, 0.23 mmol, 0, 1 equiv.) And triethylamine (969 μΐ, 7 mmol, 3 equiv.). The resulting mixture was stirred at 125 ° C for 16 hours and then cooled to room temperature and partitioned between H₂O and Et₂O. The two layers were separated and the organic phase was dried over Na₂ONLY₄ and concentrated in vacuo to give a mixture of 3-cyclopent-2-enyl-5- (2-oxo-pyrrolidin-1-yl) benzoic acid methyl ester, 3-cyclopent-3-enyl-5-methyl ester (2oxo-pyrrolidin-1-yl) -benzoic acid and 3-cyclopent-1-enyl-5- (2-oxo-pyrrolidin-1-yl) -benzoic acid methyl ester (D73) (562 mg, 85%) as an oil brown.

Description 74

3-Cyclohex-2-enyl-5- (2-oxopyrrolidin-1-yl) -benzoic acid methyl ester;

ΡΕ1567488

3-Cyclohex-3-enyl-5- (2-oxopyrrolidin-1-yl) -benzoic acid methyl ester; and

3-Cyclohex-1-enyl-5- (2-oxopyrrolidin-1-yl) -benzoic acid methyl ester (D74)

Description 74 was prepared in a manner analogous to that described for Description 73 from 686 mg (mmol) of 3-bromo-5- (2-oxo-pyrrolidin-1-yl) benzoic acid methyl ester (D9a) and cyclohexene which gave 207 mg (30%) of 3-cyclohex-2-enyl-5- (2-oxo-pyrrolidin-yl) -benzoic acid methyl ester, 3-Cyclohex-3-enyl-5- (2-oxo-pyrrolidin-1-yl) -benzoic acid methyl ester and 3-cyclohex-1-enyl-5- (2-oxo-methyl) ester pyrrolidin-1-yl) benzoic (D74) after purification by silica gel flash chromatography (isohexane / EtOAc: 5/1)

Description 75

3- (1,1-Dioxo-1 / tert -butyl acid ester⁶-isothiazolidin-2-yl) -5- (3-hydroxy-3-methyl-but-1-ynyl) -benzoic acid (D75)

To a solution of 3bromo-5- (1,1-dioxo-1 / tert -butyl ester)⁶(17) -isothiazolidin-2-yl) -benzoic acid (376 mg, 1 mmol, 1 equiv) in DME (5 mL) and H₂O (5 mL) was added K₂CO₃ (345 mg, 2.5 mmol, 2.5 equiv.), Cul (8 mg, 0.04 mmol, 0.04 equiv.), Triphenyl phosphine (21 mg, 0.08

61567488 mmol, 0.08 equiv), 10% palladium on charcoal (21 mg, 0.02 mmol, 0.02 equiv) and the solution was stirred at room temperature for 15 minutes. 2-Methyl-3-butine2-ol (254 µL, 2.5 mmol, 2.5 equiv) was added and the resulting mixture was stirred at 80 ° C for 16 hours and then cooled to room temperature. The catalyst was removed by filtration through a pad of celite and the filtrate was diluted with EtOAc. The organic phase was washed with 2 N aqueous HCl solution, saturated aqueous NaHCO 3 solution.₃, dried over MgSO₄ and concentrated in vacuo. Purification by silica gel flash chromatography (isohexane / AcOEt: 4/1 to 2/1) gave acid tert-butyl ester

3- (1,1-dioxo-1 /⁶-isothiazolidin-2-yl) -5- (3-hydroxy-3-methylbut-1-ynyl) -benzoic acid (D75) (142 mg, 37%) as a colorless oil which solidified on standing.

Description 76

3- (3-Hydroxy-3-methyl-but-1-ynyl) -5- (2-oxo-pyrrolidin-1-yl) -benzoic acid tert-butyl ester (D76)

Description 76 was prepared using a procedure analogous to that described for Description 5 from 390 mg of 3-bromo-5- (2-oxopyrrolidin-1-yl) -benzoic acid tert-butyl ester (D9b) which gave 300 3- (3-Hydroxy-3-methyl-butyl-linyl) -5- (2-oxo-pyrrolidin-1-yl) -benzoic acid tert-butyl ester (D76) mg (76%) as a white foam .

ΡΕ1567488

Description 77

5-Nitro-isophthalic acid monomethyl ester (D77)

Description 77 is commercially available from Sigma-Aldrich Company.

Description 78

1-tert-Butyl ester 5-nitro-isophthalic acid 3-methyl ester (D78)

A mixture of 5-nitro-isophthalic acid (D77) monomethyl ester (5.0 g, 22.2 mmol, 1 equiv.), TertBuOH (8.2 g, 111 mmol, 5 equiv), EDAC. HCl (4.8 g, 25 mmol, 1.1 equiv.) And DMAP (205 mg, 1.68 mmol, 0.07 equiv.) Dissolved in CH 2 Cl 2 (50 mL) were stirred for 1 hour at room temperature. The mixture was then diluted with CH₂C1₂ NaHCO3 (50 mL), washed with 2 N aqueous HCl (50 mL) and saturated aqueous NaHCCb (50 mL), dried over MgSO4 and concentrated in vacuo to give 1-tert-butyl ester. nitro-isophthalic (D78) (5.3 g,

85%) as a light yellow oil.

Description 79

1-tert-Butyl ester 5-amino-isophthalic acid 3-methyl ester (D79)

ΡΕ1567488

A mixture of 5-nitro-isophthalic acid 1-tert-butyl ester 3-methyl ester (D78) (5.3 g, 19 mmol, equiv), NH 4 COOH (11.9 g, 190 mmol, 10 equiv) and 10% palladium on carbon (50% wet, 0.75 g, 7% w / w) in EtOH (50 mL) and H₂The (25 mL) was heated at 50 ° C for 30 minutes. MeOH (20 mL) was added and the resulting solution was heated at 50 ° C for an additional hour and then cooled to room temperature, filtered through a pad of celite and concentrated in vacuo. The residue was diluted with saturated aqueous NaHCO 3 solution (100 mL) and the aqueous phase was extracted with EtOAc (150 mL). The organic phase was dried over MgSO4.₄ and concentrated in vacuo. The residue was triturated with isohexane to give 1-tert-butyl ester 5-amino-isophthalic acid (D79) 3-methyl ester (3.4 g, 71%) as a white solid.

Description 80

1-tert-Butyl ester 5- (4-Chloro-butanoylamino) -isophthalic acid 3-methyl ester (D80)

A suspension of 5-amino-isophthalic acid 1-tert-butyl ester (D79) 3-methyl ester (3.4 g, 13.5 mmol, 1 equiv.) In CH₂C1₂ NaHCO 3 (25 mL) was treated with NEt 3 (2.32 g, 23 mmol, 1.1 equiv.) And was cooled to 0 ° C. 4-Chlorobutyryl chloride (1.6 g, 15.7 mmol, 1.1 equiv) was added dropwise and the resulting solution was stirred at 0 ° C for 3 hours and then allowed to warm to

61567488 at room temperature and was washed with 2N aqueous HCl solution, dried over MgSO4.₄ and concentrated in vacuo. The residue was triturated with isohexane and Et₂To give 1-tert-butyl ester 5- (4-chlorobutanoylamino) -isophthalic acid 3-methyl ester (D80) (4.5 g, 94%) as a white solid.

Description 81

1-tert-Butyl ester 5- (3-Chloro-propane-1-sulfonylamino) -isophthalic acid 3-methyl ester (D81)

To a solution of 1-tert-butyl ester 5-amino-isophthalic acid (D79) 3-methyl ester (5.0 g, 20 mmol, 1 equiv.), DMAP (0.3 g, 2.46 mmol, 0, 12 equiv.) And pyridine (1.64 g, 20 mmol, 1 equiv.) In CH₂C1₂ (80 mL) was added 3-chloropropanesulfonyl chloride (2.4 mL, 20 mmol, 1 equiv.) Dropwise. The resulting mixture was stirred for 16 hours and then was diluted with EtOAc (150 mL). The organic phase was washed with 2 N aqueous HCl solution and saturated aqueous NaHCO 3 solution.₃, dried over MgSO₄ and concentrated in vacuo to give 1-tert-butyl ester 5- (3-chloro-propane-1-sulfonylamino) isophthalic acid (D81) 3-methyl ester (7.8 g, 99%) as a pink solid. -light orange.

Description 82

1-tert-Butyl ester 5- (1,1-dioxo-1/3-methyl acid ester⁶-isothiazolidin-2-yl) -isophthalic (D82)

ΡΕ1567488

A mixture of 5- (3-chloro-propane-1-sulfonylamino) isophthalic acid 1-tert-butyl ester (D81) 3-methyl ester (7.8 g, 20 mmol, 1 equiv.) And NEt₃ HCl (4.0 g, 40 mmol, 2 equiv) in EtOH (100 mL) was heated at reflux for 3 hours, cooled to room temperature and concentrated in vacuo. The residue was diluted with EtOAc and the organic phase was washed with 2N aqueous HCl solution and saturated aqueous NaHCO 3 solution.₃, dried over MgSO₄ and concentrated in vacuo to give 1-tert-butyl ester 5- (1,1-dioxo-1 H-acid / 3-methyl ester⁶-isothiazolidin-2-yl) isophthalic (D82) (4.4 g, 62%) as a white solid.

Description 83

5- (1,1-Dioxo-1 / monomethyl acid ester⁶-isothiazolidin-2-yl) -isophthalic (D83)

A suspension of 5- (1,1-dioxo-1-tert-butyl ester 3-methyl ester)⁶(isothiazolidin-2-yl) isophthalic (D82) (4.4 g, 12.4 mmol, 1 equiv.) in CH₂C1₂ (10 mL) was treated with TFA (10 mL) and the resulting mixture was stirred for 2 hours at room temperature. Toluene (10 mL) was added and the resulting mixture was concentrated in vacuo. The residue was triturated with Et₂O to give 5- (1,1-dioxo-1 / monomethyl acid ester⁶-isothiazolidin-2-yl) isophthalic (D83) (3.6 g, 97%) as a white solid.

ΡΕ1567488

Description 84

3- (1,1-Dioxo-1 / methyl acid ester)⁶-isothiazolidin-2-yl) -5-hydroxymethylbenzoic acid (D84)

A solution of 5- (1,1-dioxo-1/1-acid monomethyl ester)⁶-isothiazolidin-2-yl) -isophthalic (D83) (500 mg,

1.67 mmol, 1 equiv.) In THF (30 mL) was treated with BH₃Me₂S (2 M solution in THF, 1.0 mL, 2 mmol, 1.2 equiv.) And the mixture was heated at reflux for 30 minutes and then cooled to room temperature. MeOH (5 mL) was added dropwise and the resulting mixture was concentrated in vacuo. The residue was diluted with EtOAc (100 mL), and the resulting solution was washed with 2 N aqueous HCl (100 mL) and saturated NaHCO 3 solution.₃, dried over MgSO₄ and concentrated in vacuo to give 3- (1,1-dioxo-1 /⁶isothiazolidin-2-yl) -5-hydroxymethylbenzoic acid (D84) (450 mg,

95%) as a clear colorless oil.

Description 85

3- (1,1-Dioxo-1 / methyl acid ester)⁶-isothiazolidin-2-yl) -5-methanesulfonyloxymethylbenzoic acid (D85)

A solution of 3- (1,1-dioxo-1 /⁶isothiazolindin-2-yl) -5-ethoxymethylbenzoic acid (D84) (400 mg, 1.4 mmol, 1 equiv.) in CH₂C1₂ (20 mL) was treated with NEt₃(303 mg, 3.0 mmol, 2.1 equiv.) And methanesulfonic anhydride

61567488 (261 mg, 1.5 mmol, 1.1 equiv.) And was stirred for 30 minutes at room temperature. The solution was then washed with aqueous HCl (30 mL) and saturated aqueous NaHCO 3.₃ (30 mL), dried over MgSO4₄ and concentrated in vacuo. The residue was ground in Et₂O to give 3- (1,1-dioxo-1/2-methyl acid ester⁶-isothiazolidin-2-yl) -5-methanesulfonyloxymethylbenzoic acid (D85) (390 mg, 77%) as a white solid.

Description 86

3- (1,1-Dioxo-1 / methyl acid ester)⁶-isothiazolidin-2-yl) -5-formylbenzoic acid (D86)

A solution of 3- (1,1dioxo-1/3) acid methyl ester⁶-isothiazolidin-2-yl) -5-hydroxymethylbenzoic acid (D84)

<td> (500</td><td>mg, 1,</td><td colspan="2">8 mmol, 1 equiv.) In</td><td>CH₂C1</td><td> 2 (20</td><td>mL) was</td><td>treated</td>

<td>with</td><td>Mon0₂</td><td> (763</td><td>mg, 8.8 mmol,</td><td> 4, 9</td><td>equiv,</td><td>.) and the</td><td>mixture</td>

<td colspan="2">resulting</td><td>was</td><td>stirred during</td><td> 3</td><td>hours</td><td colspan="2">the temperature</td>

environment. A second portion of MnO was added.₂ (500 mg, 5.8 mmol, 3.2 equiv.) And the mixture was stirred for 3 hours and then a third portion of MnO was added.₂(300 mg, 3.5 mmol, 1.9 equiv.). The mixture was stirred for 2 hours and then filtered through a pad of celite. The filtrate was concentrated in vacuo to give 3- (1,1-dioxo-1 H-methyl acid ester).⁶-isothiazolidin2-yl) -5-formylbenzoic acid (D86) (450 mg, 88%) as a waxy yellow solid.

ΡΕ1567488

Description 87

5-Nitro-N, N-Dipropyl-Isophthalamic Acid Methyl Ester (D87)

A suspension of 5-nitro-isophthalic acid monomethyl ester (D77) (1.0 g, 4.44 mmol, 1 equiv.) In

CH 2 Cl 2 (40 mL) was treated with (COCl) 2 (655 mg, 5.2 mmol,

1.2 equiv.) Followed by a few drops of DMF. The resulting mixture was stirred for 1 hour at room temperature and then dipropylamine (1.65 g, 15 mmol, 3.4 equiv) was added and the resulting solution was stirred for a further 30 minutes. The solution was then washed with 2N aqueous HCl (50 mL), saturated aqueous NaHCO3 (50 mL), dried over MgSO4.₄ and concentrated in vacuo to give 5-nitro-N, N-dipropylisophthalamic acid methyl ester (D87) (1.5 g, 110%) as a light yellow oil.

Description 88

5-Amino-N, N-dipropyl isophthalamic acid methyl ester (D88)

A mixture of 5-nitroN, N-dipropyl isophthalamic acid methyl ester (D87) (1.5 g, 4.9 mmol, 1 equiv.), NH₄COOH (3.0 g, 49 mmol, 10 equiv), 10% palladium on carbon (50% wet, 250 mg, 0.082 wt / wt), EtOH

61567488 (20 mL) and H 2 O (10 mL) was heated at 50 ° C for 90 minutes. The mixture was cooled to room temperature, filtered through a pad of celite and concentrated in vacuo. The residue was dissolved in EtOAc (200 mL) and the resulting solution was washed with saturated aqueous NaHCO 3.₃ (100 mL), dried over MgSO4₄ and concentrated in vacuo to give 5 amino-N, N-dipropyl isophthalamic acid methyl ester (D88) (1.2 g, 88%) as a waxy white solid.

Description 89

5- (4-Chloro-butanoylamino) -N, Ndipropyl-isophthalamic acid methyl ester (D89)

A solution of 5-aminoN, N-dipropyl isophthalamic acid methyl ester (D88) (1.2 g, 4.3 mmol, 1 equiv.) In CH 2 Cl 2 (10 mL) was treated with NEt.₃ (525 mg, 5.2 mmol,

1.2 equiv.). The solution was cooled to 0 ° C and 4-chlorobutyryl chloride (733 mg, 5.0 mmol, 1.2 equiv) was added dropwise. The reaction mixture was then allowed to warm to room temperature with stirring for 1 hour. The solution was washed with 2 N aqueous HCl (20 mL), dried over MgSO4.₄ and concentrated in vacuo to give 5- (4-chloro-butanoylamino) -NN-propyl isophthalamic acid methyl ester (D89) (1.7 g, 104%) as a colorless oil.

ΡΕ1567488

Description 90

5- (5-Chloro-pentanoylamino) N, N-dipropyl-isophthalamic acid methyl ester (D90)

Description 90 was prepared analogously to Description 89 from 5 amino-N methyl ester, N-dipropyl isophthalamic acid (D88) and 5-chlorovaleryl chloride.

Description 91

5- (3-Chloro-propane-isulfonylamino) -N, N-dipropyl-isophthalamic acid methyl ester (D91)

A solution of 5-aminoN, N-dipropyl isophthalamic acid methyl ester (D88) (1.4 g, 5.0 mmol, 1 equiv.), DMAP (100 mg) and pyridine (392 mg, 5.0 mmol) , 1.1 equiv.) In CH₂C1₂ (20 mL) was treated dropwise with 3-chloropropane-1-sulfonyl chloride (946 mg, 5.3 mmol, 1.1 equiv.). The resulting mixture was stirred for 16 hours at room temperature and then diluted with EtOAc (100 mL). The resulting solution was washed with 2 N aqueous HCl solution (50 mL) followed by saturated aqueous NaHCO 3 solution.₃ (50 mL), dried over MgSO4₄ and concentrated in vacuo. The residue was triturated with Et₂O to give 5- (3-chloro-propane-1-sulfonylamino) -N, Ndipropyl-isophthalamic acid methyl ester (D91) (1.8 g, 86%) as a pink solid.

ΡΕ1567488

Description 92

5- (4-Chloro-butan-1-sulfonylamino) -N, N-dipropyl-isophthalamic acid methyl ester (D92)

Description 92 was prepared analogously to Description 91 from 5 amino-W methyl ester, N-dipropyl isophthalamic acid (D88) and 4-chlorobutane-1-sulfonyl chloride.

Description 93

(2S, 3R) -3-Hydroxy-2 - ((S) -2-hydroxy-1-phenyl-ethylamino) -hexanoic acid methyl ester (D93)

Description 93 was obtained according to Alker, D .; Hamblett, G .; Harwood, LM; Robertson, SM; David, J .; Williams, CE Tetrahedron, 54 (22), 1998, 6089-6098.

Description 94

(2S, 3R) -2-tert-Butoxycarbonylamino-3-hydroxyhexanoic acid methyl ester (D94)

(2S, 3R) -3-Hydroxy-2 - ((S) 2-hydroxy-1-phenyl-ethylamino) -hexanoic acid methyl ester (D93) (2.88 g, 10.25 mmol, 1 equiv.) 10% palladium on charcoal (50% wet, 2 g, 35% w / w), HCOOH (5 mL, excess) in MeOH (50 mL) were

61567488 stirred at 60 ° C for 1 hour. The mixture was then cooled to room temperature, filtered through a pad of celite and then concentrated in vacuo. The residue was dissolved in dioxane / water (1/1, 50 mL) and NaHCO was added.₃ (10 g, excess) di-tert-butyl dicarbonate (3.37 g, 15 mmol, 1.5 equiv). The resulting mixture was stirred at room temperature for 2 hours then concentrated in vacuo. The residue was dissolved in EtOAc and the organic phase was washed successively with aqueous HCl solution and saturated aqueous NaHCO 3 solution.₃, dried over MgSO₄ and concentrated in vacuo. Purification by silica gel flash chromatography (CH₂Cl₂(MeOH: 99/1) gave (2S, 3R) -2-tert-Butoxycarbonylamino-3-hydroxyhexanoic acid methyl ester (D94) (1.88 g, 70%) as a colorless gum.

Description 95

(S) -2-tert-Butoxycarbonylamino-4-methylsulfanylbutyric acid (D95)

Description 95 is commercially available from Sigma-Aldrich Company.

Description 96

((S) -1-Isobutylcarbamoyl3-methylsulfanyl-propyl) -carbamic acid tert-butyl ester (D96)

ΡΕ1567488

(S) -2-tert-Butoxycarbonylamino-4-methylsulfanyl-butyric acid (D95) (2.0 g, 8.0 mmol, 1 equiv.), EDAC. HCl (1.84 g, 9.6 mmol, 1.2 equiv.), HOBT (1.47 g, 9.6 mmol, 1.2 equiv.), 4-ethylmorpholine (1.76 g, 16 mmol, 2 equiv.) And isobutylamine (952 mL, 9.6 mmol, 1.2 equiv.) In CH 2 Cl 2 (10 mL) were stirred at room temperature for 16 hours. The solution was concentrated in vacuo and the residue was dissolved in EtOAc. The organic phase was washed with 2 N aqueous HCl solution, saturated aqueous NaHCO3 solution and brine, dried over MgSO4.₄ and concentrated in vacuo to give ((S) -1-isobutylcarbamoyl-3-methylsulfanyl-propyl) carbamic acid tert-butyl ester (D96) (2.38 g, 98%) as a colorless oil.

Description 97

(3-Methoxy-phenyl) -acetic acid ethyl ester (D97)

Description 97 is commercially available from Sigma-Aldrich Company.

Description 98

2- (3-Methoxy-phenyl) -2-methylpropionic acid ethyl ester (D98)

To a solution of (3-methoxy-phenyl) -acetic acid (D97) ethyl ester (19.72 g, 0.101 m, 1 equiv.) In

THF (200 mL) was added NaH (8.8 g, 0.222 mol, 2.2

ΡΕ1567488

100 equiv.) then iodomethane (26 mL, 0.4 mol, 4 equiv.). The resulting mixture was stirred at room temperature for 16 hours and then partitioned between EtOAc and saturated aqueous NaHCO 3.₃. The two layers were separated and the organic phase was washed with brine, dried over MgSO4.₄ and concentrated in vacuo to give 2- (3-methoxyphenyl) -2-methyl-propionic acid ethyl ester (D98) (20.85 g, 98%) as an orange oil.

Description 99

2- (3-Methoxy-phenyl) -2-methyl-propionic acid (D99)

To a solution of 2- (3-methoxy-phenyl) -2-methyl-propionic acid (D98) ethyl ester (20.95 g, 94 mmol, 1 equiv) in EtOH (200 mL) was added aqueous solution. 2 N NaOH (90 mL, 180 mmol, 1.9 equiv.) and the resulting mixture was stirred at 70 ° C for 16 hours and then cooled to room temperature. Most of the

EtOH was removed in vacuo and the residue was extracted with

AcOEt then was acidified to pH 1. The aqueous phase was then extracted with AcOEt and then acidified to pH 1. The aqueous phase was then extracted with AcOEt and the organic phase was dried over MgSO4.₄ and concentrated in vacuo to give 2- (3-methoxy-phenyl) -2-methyl-propionic acid (D99) (15 g, 82%) as a yellow oil.

ΡΕ1567488

101

Description 100

[1- (3-Methoxy-phenyl) -1-methylethyl] -carbamic acid benzyl ester (D100)

To a solution of 2- (3-methoxy-phenyl) -2-methyl-propionic acid (D99) (1 g, 5.15 mmol, 1 equiv.) In toluene (20 mL) at room temperature was added NEt.₃ (1.07 mL, 7.72 mmol, 1.5 equiv) and then diphenylphosphoryl azide (2.2 mL, 10.3 mmol, 2 equiv). The resulting mixture was then heated at 80 ° C for 2 hours and then benzyl alcohol (1.61 mL, 15.45 mmol, 3 equiv.) Was added and the solution was heated for a further 2 hours, cooled to between EtOAc and saturated aqueous NaHCO₃ aqueous solution. The two layers were separated and the aqueous phase was dried over MgSO4.₄ and concentrated in vacuo. Purification of the residue by silica gel flash chromatography (isohexane / AcOEt: 9/1) gave [1- (3-methoxy-phenyl) -1-methylethyl] -carbamic acid benzyl ester (D100) (lg, 65% ) as a yellow gum.

Description 101

((S) - (S) -1-Oxiranyl-2-phenyl-ethyl) -carbamic acid tert-butyl ester (D101)

Description 101 is commercially available from Chirex (ref 1819W94, lot # 9924382).

ΡΕ1567488

102

Description 102

((IS, 2R) -3-Amino-lbenzyl-2-hydroxy-propyl) -carbamic acid tert-butyl ester (D102)

To a solution of ((S) - (S) -1-oxiranyl-2-phenyl-ethyl) -carbamic acid tert-butyl ester (D101) (25 g,

95.1 mmol, 1 equiv.)) In MeOH (350 mL) was added aqueous ammonia (32% w / w, 180 mL, 3.2 mol, 3.3 equiv.). The resulting mixture was stirred at room temperature for 16 hours and then concentrated in vacuo to give ((IS, 2R) -3-amino-1-benzyl-2-hydroxypropyl) -carbamic acid tert-butyl ester (D102) (25.2 g, 95%) as a white solid.

Description 103

((2R, 3S) -3-tert-Butoxycarbonylamino-2-hydroxy-4-phenyl-butyl) -carbamic acid benzyl ester (D103)

((IS, 2R) -3-Amino-1-benzyl-2-hydroxy-propyl) -carbamic acid tert-butyl ester solution (D102) (25.6 g, 91.4 mmol, 1 equiv.) in DMF (250 mL) at 0 ° C was treated with NEt₃ HCl (15 mL, 108 mmol, 1.2 equiv.) And then dropwise with benzyl chloroformate (14 mL, 98 mmol, 1.1 equiv.) In DMF (50 mL). The resulting solution was stirred at 0 ° C for 1 hour and at room temperature for 16 hours and then concentrated in vacuo. O

ΡΕ1567488

103 The residue was partitioned between AcOEt and saturated aqueous NaHCO 3 solution. The resulting precipitate was diluted with H₂The e was filtered to give ((2R, 3S) -3-tert-butoxycarbonylamino-2-hydroxy-4-phenylbutyl) -carbamic acid benzyl ester (D103) (31.5 g, 83%) as a white solid.

Description 104

((2R, 3S) -3-Amino-2-hydroxy-4-phenyl-butyl) -carbamic acid benzyl ester (D104)

A solution of ((2R, 3S) 3-tert-Butoxycarbonylamino-2-hydroxy-4-phenyl-butyl) -carbamic acid benzyl ester (D103) (31.5 g, 76.1 mmol, 1 equiv) in THF (300 mL) was treated with 4 N HCl solution in dioxane (40 mL, 160 mmol, 2.1 equiv.). The resulting solution was stirred at room temperature for 2 hours and then concentrated in vacuo. The residue was triturated with Et₂O (isohexane to give ((2R, 3S) -3-amino-2-hydroxy-4-phenyl-butyl) -carbamic acid benzyl ester hydrochloride (D104) (22.1 g, 83%) as a white solid .

Description 105

[(2R, 3S) -2-Hydroxy-3 - {(1- [3- (2-oxo-pyrrolidin-1-yl) -5-pentyloxy-phenyl] -methanol} -amino) 4-phenyl acid benzyl ester -butyl] -carbamic (D105)

To a suspension of 3- (2-oxo-pyrrolidin-1ΡΕ1567488

104 (5-mg, 1.82 mmol, 1 equiv) in CH 2 Cl 2 (20 mL) was added HOBT (300 mg, 2.2 mmol, 1.2 equiv) and EDAC.HCl (420 mg, 2.2 mmol, 1.2 equiv.). After stirring for 5 minutes 3- (2-oxo-pyrrolidin-1-yl) -5-pentyloxybenzoic acid hydrochloride (D104) (570 mg, 1.82 mmol, 1 equiv) was added and the resulting mixture was added. stirred at room temperature for 16 h. The reaction mixture was then diluted with CH₂C1₂ (20 mL) washed with saturated aqueous NaHCO₃, dried over MgSO 4 and concentrated in vacuo to give [(2R, 3S) -2-hydroxy-3 - ({1- [3- (2-oxo-pyrrolidin-1-yl) 5-pentyloxy-phenyl] acid benzyl ester ] -methanoyl} -amino) -4-phenyl-butyl] carbamic (D105) (510 mg, 48%) as a white solid.

Description 106

[(2R, 3S) -3 - ({1- [3-Ethylamino5- (2-oxo-pyrrolidin-1-yl) -phenyl] -methanoyl} -amino) -2-hydroxy-4-phenyl-butyl acid ester ] -carbamic (D106)

Description 106 was prepared analogously to Description 105 from 3- (2-oxopyrrolidin-1-yl) -5-pentyloxy-benzoic acid hydrochloride (D104) and 3-ethylamino-5- ( 2-oxopyrrolidin-1-yl) benzoic acid (A31).

Description 107

[(2R, 3S) -3 - ({1- [3-Isopropylamino-5- (2-oxo-pyrrolidin-1-yl) -phenyl] -methanoyl} -amino) -2-hydroxy-4-phenyl acid benzyl ester butyl] -carbamic (D107)

ΡΕ1567488

105

Description 107 was prepared analogously to Description 105 from 3- (2-oxopyrrolidin-1-yl) -5-isopropylamino-benzoic acid hydrochloride (A44) and benzyl acid ester ((2R, 3S) -3-Amino-2-hydroxy-4-phenyl-butyl) -carbamic (D104).

Description 108-119

The following compounds (D108-D119) were prepared from Description 104 in a manner analogous to the process described for Description 105 using the appropriate acid.

<td>description</td><td>Acid</td>

<td>[(2R, 3S) -3 - ({[3- (1,1-dioxide-tetrahydro-2H-1,2- thiazin-2-yl) -5- (ethylamino) phenyl] carbonyl} amino) -2- phenylmethyl hydroxy-4-phenylbutyl] carbamate (D108)</td><td>A73</td>

<td>[(2R, 3S) -3 - ({[3- (1,1-dioxide-tetrahydro-2A-1,2- thiazin-2-yl) -5- (ethylamino) -2-fluorophenyl] carbonyl} - amino) -2-hydroxy-4-phenylbutyl] carbamate of phenylmethyl (D109)</td><td>A119</td>

<td>[(2R, 3S) -3 - ({[3-cyclopentyl-5- (2-oxo-1-pyrrolidinyl nyl) phenyl] carbonyl} amino) -2-hydroxy-4-phenylbutyl] - phenylmethyl carbamate (D110)</td><td>AIO 7</td>

<td>[(2R, 3S) -2-hydroxy-3 - ({[3 - [(1-methylethyl) oxy] -5- (2- oxo-1-pyrrolidinyl) phenyl] carbonyl} amino) -4- phenylmethyl phenyl butyl carbamate (D11l)</td><td>A12</td>

ΡΕ1567488

106 (continuation)

<td>description</td><td>Acid</td>

<td>{(2A, 3S) - 3 - [({3- (1,1-dioxide-tetrahydro-2H-1,2-thiadiazole)</td><td>A168</td>

<td>zin-2-yl) -5 - [(1-methylethyl) oxy] phenyl} carbonyl) amino] -</td><td></td>

<td>Phenylmethyl 2-hydroxy-4-phenylbutyl} carbamate</td><td></td>

<td>(DI12)</td><td></td>

<td>[2R, 3S) -3 - ({[3-cyclopentyl-5- (1,1-dioxide</td><td>A126</td>

<td>hydro-2H-1,2-thiazin-2-yl) phenyl] carbonyljamino) -2-</td><td></td>

<td>phenylmethyl hydroxy-4-phenylbutyl] carbamate (D113)</td><td></td>

<td>[2R, 3S) -3 - ({[3- (ethyloxy) -5- (2-oxo-1-pyrrodinyl) te-</td><td>All</td>

<td>nyl] carbonyl} amino) -2-hydroxy-4-phenylbutyl] carbamate</td><td></td>

<td>of phenylmethyl (D114)</td><td></td>

<td>[2A, 3S) -3 - ({[3- (1,1-dioxide-2-isothiazolidinyl) -5-</td><td>A18</td>

<td>(ethyloxy) phenyl] carbonyljamino) -2-hydroxy-4-</td><td></td>

<td>phenylbutyl] phenylmethyl carbamate (D115)</td><td></td>

<td>{(2R, 3S) -3 - [({3- (1,1-dioxide-2-isothiazolidinyl) -5-</td><td>A19</td>

<td>[(1-methylethyl) oxy] phenyl} carbonyl) amino] -2-hydroxy-4</td><td></td>

<td>phenylbutyl} phenylmethyl carbamate (D116)</td><td></td>

<td>[2R, 3S) -3 - ({3-cyclopentyl-5- (1,1-dioxide-2-</td><td>A169</td>

<td>isothiazolidinyl) phenyl] carbonyl} amino) -2-hydroxy-4-</td><td></td>

<td>phenylbutyl] phenylmethyl carbamate (D117)</td><td></td>

<td>[2R, 3S) —3 - ({[3- (1,1-dioxide-2-isothiazolidinyl) -5-</td><td>A70</td>

<td>(ethylamino) phenyl] carbonyl} amino) -2-hydroxy-4-</td><td></td>

<td>phenylbutyl] phenylmethyl carbamate (D118)</td><td></td>

<td>[2A, 3S) -3 - ({[3- (1,1-dioxide-tetrahydro-2 H -1,2-</td><td>A170</td>

<td>thiazin-2-yl) -5- (ethyloxy) phenyl] carbonyljamino) -2-</td><td></td>

<td>phenylmethyl hydroxy-4-phenylbutyl] carbamate (D119)</td><td></td>

ΡΕ1567488

107

Description 120-131

The following compounds (D120-D131) were prepared analogously to the procedure described for Example 182 using the appropriate precursor:

<td>description</td><td>Precursor</td>

<td>N - [(IS, 2R) -3-Amino-2-hydroxy-1- (phenylmethyl) propyl</td><td>D108</td>

<td>pil] -3- (1,1-dioxide-tetrahydro-2 H -1,2-thiazin-2-one</td><td></td>

<td>yl) -5- (ethylamino) benzamide (D20)</td><td></td>

<td>N - [(IS, 2R) -3-Amino-2-hydroxy-1- (phenylmethyl) propyl</td><td>D109</td>

<td>pil] -3- (1,1-dioxide tetrahydro-2H-1,2-thiazin-2-one</td><td></td>

<td>yl) -5- (ethylamino) -2-fluorobenzamide (D21)</td><td></td>

<td>N - [(IS, 2R] -3-Amino-2-hydroxy-1- (phenylmethyl) propyl</td><td>D110</td>

<td>pil] -3-cyclopentyl-5- (2-oxo-1-pyrrolidinyl) benzenyl</td><td></td>

<td>zamide (D122)</td><td></td>

<td>N - [(IS, 2R] -3-Amino-2-hydroxy-1- (phenylmethyl) propyl</td><td>Dlll</td>

<td>pil] -3 - [(1-methylethyl) oxy] -5- (2-oxo-1-pyrrolyl)</td><td></td>

<td>dinyl) benzamide (D123)</td><td></td>

<td>N - [(IS, 2R] -3-Amino-2-hydroxy-1- (phenylmethyl) propyl</td><td>D112</td>

<td>pil] -3 - [(1,1-dioxide-tetrahydro-2A-1,2-thiazin-2-one</td><td></td>

<td>yl) -5 - [(1-methylethyl) oxy] benzamide (D124)</td><td></td>

<td>N - [(IS, 2R] -3-Amino-2-hydroxy-1- (phenylmethyl) propyl</td><td>D113</td>

<td>pil] -3-cyclopentyl-5- (1,1-dioxide thihydro-2H-</td><td></td>

<td>1,2-thiazin-2-yl) benzamide (D125)</td><td></td>

<td>N - [(IS, 2R] -3-Amino-2-hydroxy-1- (phenylmethyl) propyl</td><td>D114</td>

<td>pil] -3- (ethyloxy) -5- (2-oxo-1-pyrrolidinyl) benzenyl</td><td></td>

<td>zamide (D126)</td><td></td>

ΡΕ1567488

108 (continuation)

<td>description</td><td>Precursor</td>

<td>N - [(IS, 2R] -3-Amino-2-hydroxy-1- (phenylmethyl) propyl</td><td>D115</td>

<td>pil] -3- (1,1-dioxide-2-isothiazolidinyl) -5-</td><td></td>

<td>(ethyloxy) benzamide (D127)</td><td></td>

<td>N - [(IS, 2R] -3-Amino-2-hydroxy-1- (phenylmethyl) propyl</td><td>D116</td>

<td>pil] -3- (1,1-dioxide-2-isothiazolidinyl) -5 - [(1-</td><td></td>

<td>methylethyl) oxy] benzamide (D128)</td><td></td>

<td>N - [(IS, 2R] -3-Amino-2-hydroxy-1- (phenylmethyl) propyl</td><td>D117</td>

<td>pil] -3-cyclopentyl-5- (1,1-dioxide-2-</td><td></td>

<td>isothiazolidinyl) benzamide (129)</td><td></td>

<td>N - [(IS, 2R] -3-Amino-2-hydroxy-1- (phenylmethyl) propyl</td><td>D118</td>

<td>pil] -3- (1,1-dioxide-2-isothiazolidinyl) -5-</td><td></td>

<td>(ethylamino) benzamide (D130)</td><td></td>

<td>N - [(IS, 2R] -3-Amino-2-hydroxy-1- (phenylmethyl) propyl</td><td>D119</td>

<td>pil] -3- (1,1-dioxide tetrahydro-2H-1,2-thiazin-2-one</td><td></td>

<td>yl) -5- (ethyloxy) benzamide (D131)</td><td></td>

Description 132

Methyl 3-nitro-5 - [(1E / Z) -1-propen-1-yl] benzoate (D132)

Methyl 3-nitro-5- [1E / Z) -1-propen-1-yl] benzoate (D132) was prepared from methyl 3-bromo-5-nitrobenzoate (D11) in a manner analogous to that described for The

Description 68 (D68). No molecular ion. RT = 3.42 minutes

ΡΕ1567488

109

Description 133

Methyl 3-amino-5-propylbenzoate (D133)

Methyl 3-amino-5-propylbenzoate (D133) was prepared from methyl 3-nitro-5 - [(1E / Z) -1-propen-1-yl] benzoate (D132) in a similar manner to that described for Ester 116 (Bl16).

Description 134

Methyl 3 - [(3-buten-1-ylsulfonyl) amino] -5-propylbenzoate (D134)

To a solution of methyl 3-amino-5-propylbenzoate (D133) (2.49 g, 12.9 mmol, 1 equiv.) In CH₂C1₂ (25 mL) were added pyridine (1.13 mL, 14 mmol, 1.1 equiv.), 2-propene-1-sulfonyl chloride (2 g, 12.9 mmol, 1 equiv.) And DMAP (350 mL). mg, 2.9 mmol, 0.2 equiv) and the resulting mixture was stirred at room temperature for 4 days. The solution was diluted with EtOAc and the organic phase was washed with H₂O, dried over MgSO₄ and concentrated in vacuo. Purification of the residue by silica gel flash chromatography (4: 1 isohexane / EtOAc: 4: 1) gave methyl 3 - [(3-buten-1-ylsulfonyl) amino] -5-propylbenzoate (D134) (1.3 g, 32%) as a colorless oil. [MH] “= 310.0, RT = 3.39 minutes

ΡΕ1567488

110

Description 135

Methyl 3 - [(3-buten-1-ylsulfonyl) (2-propen-1-yl) amino] -5propylbenzoate (D135)

To a solution of methyl 3 - [(3-buten-1-ylsulfonyl) amino] 5-propylbenzoate (D134) (1.3 g, 4.2 mmol, 1 equiv), 2-propen-1-ol ( 280 µL, 4.2 mmol, 1 equiv.) And triphenylphosphine (1.28 g, 4.9 mmol, 1.15 equiv.) In toluene (20 mL) at room temperature was slowly added disopropyl azodicarboxylate (964 mL). , 4.9 mmol, 1.15 equiv.). The resulting solution was stirred at this temperature for 30 minutes and then concentrated in vacuo. Purification of the residue by silica gel flash chromatography (Isohexane / AcOEt: 4: 1) gave methyl 3 - [(3-butenylsulfonyl) (2-propen-1-yl) amino] -5-propylbenzoate (D135) (1.1 g, 75%) as a yellow oil. [M + H]⁺ = 352, 1,

RT = 3.63 minutes

Description 136

2-Fluoro-3,5-dinitrobenzoic acid (D136)

An aqueous solution of

HNO₃ 70% (80 mL) was added to H₂ONLY₄ (160 mL). The temperature was kept below 10 ° C using an ice bath. 2-Fluoro benzoic acid (14 g, 0.1 mol, 1 equiv.) Was added portionwise over 5 minutes and then the colorless suspension was slowly warmed to 90 ° C and was

ΡΕ1567488

111 Stirred at this temperature for 1 hour and then at 100 ° C for 3 hours. The solution was then cooled to room temperature and carefully poured into ice (1 L) diluted with H₂0 (1.5 L). The aqueous phase was extracted 3 times with EtOAc and the combined organic layers were dried over MgSO4.₄ and concentrated in vacuo. The residue was triturated with EttaO to give 2-fluoro-3,5-dinitrobenzoic acid (D136) (13.6 g, 59%) as a pale yellow solid which was used in the next step without further purification. Without molecular ion, RT = 2.06 minutes.

Description 137

Methyl 2-fluoro-3,5-dinitrobenzoate (D137)

Methyl 2-fluoro-3,5-dinitrobenzoate (D137) was prepared analogously to Description 25 (D25) from 2-fluoro-3,5-dinitrobenzoic acid (D136).

Description 138

Methyl 3-amino-2-fluoro-5-nitrobenzoate (D138)

To a solution of methyl 2-fluoro-3,5-dinitrobenzoate (D137) (24.4 g, 0.1 mol, 1 equiv) in AcOH (1 L) was added iron (27.5 g, 0 0.5 mol, 5 equiv.) And the resulting suspension was stirred vigorously for 1 hour. The temperature was kept below 35 ° C by small amount of cooling using a water bath.

ΡΕ1567488

112 ice during this time. Toluene (200 mL) was added and the suspension was filtered through a pad of celite. The remaining solution was concentrated in vacuo and the residue was partitioned between AcOEt and a saturated aqueous NaHCO solution.₃. The two layers were separated and the aqueous phase was extracted twice with EtOAc. The combined organic phases were dried over MgSO4.₄ and concentrated in vacuo to give methyl 3-amino-2-fluoro-5-nitrobenzoate (D138) (17 g, 79%) as a yellow solid which was used for the next step without further purification. [MH] = 212.9, R T = 2.68 minutes

Description 139

Methyl 3 - [(4-chlorobutanoyl) amino] -2-fluoro-5-nitrobenzoate (D139)

To a solution of methyl 3-amino-2-fluoro-5-nitrobenzoate (D138) (12 g, 56 mmol, 1 equiv.) In ΟΗ₂Ο1₂ (150 mL) at room temperature was added NEt₃ (11.7 mL, 84 mmol, 1.5 equiv.) And 4-chlorobutanoyl chloride (6.9 mL,

61.6 mmol, 1.1 equiv.) And the resulting mixture was stirred for 2 hours and then washed with 2 N aqueous HCl solution and saturated aqueous NaHCO 3 solution.₃, dried over MgSO₄ and concentrated in vacuo. Purification of the residue by silica gel flash chromatography (isohexane / AcOEt: 4/1) gave methyl 3 - [(4-chlorobutanoyl) amino] -2-fluoro5-nitrobenzoate (D139) (16.2 g, 91% ) as a yellow solid. [M + H]⁺= 319.1, TR = 3.12 minutes

ΡΕ1567488

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Description 140

Methyl 2-fluoro-5-nitro-3- (2-oxo-1-pyrrolidinyl) benzoate (D140)

To a solution of methyl 3 - [(4-chlorobutanoyl) amino] -2-fluoro-5-nitrobenzoate (D139) (8.5 g, 26.7 mmol, equiv) in THF (100 mL) was added NaH ( 60% dispersion in mineral oil, 1.17 g, 29.4 mmol, 1.1 equiv) and the resulting mixture was stirred at room temperature for 1.5 hours and then diluted with EtOAc. The organic phase was washed with H₂O, dried over MgSO₄ and concentrated in vacuo. Purification of the residue by flash silica gel chromatography (Isohexane / AcOEt: 2/1) gave methyl 2-fluoro-5-nitro-3- (2-oxo-1-pyrrolidinyl) benzoate (D140) (3.3 g, 43%) as a yellow solid. [M + H]⁺ = 283.1, TR = 2.53 minutes

Description 141

Methyl 3- {bis [(3-chloropropyl) sulfonyl] amino} -2-fluoro-5-nitrobenzoate (D141)

To a solution of methyl 3-amino-2-fluoro-5-nitrobenzoate (D138) (500 mg, 2.34 mmol, 1 equiv.) In CH₂C1₂ (50 mL) was added NEt₃ (840 pL, 6.0 mmol, 2.6 equiv.) Then 3-chloro-1-propanesulfonyl chloride (624 pL, 5.0 mmol, 2.1 equiv.) And the resulting mixture was stirred

ΡΕ1567488

114 for 1 hour. The organic phase was then washed with 2 N aqueous HCl solution, dried over MgSO4.₄ and concentrated in vacuo to give methyl 3- {bis [(3-chloropropyl) sulfonyl] amino} -2-fluoro-5-nitrobenzoate (D141) (900 mg, 78%) as a brown foam which was used in the next step without further ado. purification. No molecular ion, RT = 3.51 minutes

Description 142

Methyl 3- {bis [(4-chlorobutyl) sulfonyl] amino} -2-fluoro-5-nitrobenzoate (D42)

Methyl 3- {bis [(4-chlorobutyl) sulfonyl] amino} -2-fluoro-5-nitrobenzoate (D142) was obtained from methyl 3-amino-2-fluoro-5-nitrobenzoate (D138) in a manner analogous to that described for methyl 3- {bis [(3-chloropropyl) sulfonyl] amino} -2-fluoro-5-nitrobenzoate (D141) using 4-chloro-1-butanesulfonyl chloride (D20) instead of 3-chloro- 1-propanesulfonyl. [M + H + NH 3]⁴ =

540.1, RT = 3.62 minutes

Description 143

3 - {([(3-chloropropyl) sulfonyl] amino) -2-fluoro-5-nitrobenzoic acid (D143)

To a solution of crude methyl 3- {bis [(3-chloropropyl) sulfonyl] amino} -2-fluoro-5-nitrobenzoate (D141) (900 mg, 1.81 mmol, 1 equiv) in MeOH (25 mL). mL) was added

ΡΕ1567488

115 an aqueous 2 N NaOH solution (15 mL, 30 mmol, excess) and the resulting mixture was stirred for 1 hour. Most MeOH was removed in vacuo and the residue was partitioned between EtOAc and 2 N aqueous HCl solution. The two layers were separated and the aqueous phase was dried over MgSO4.₄ and concentrated in vacuo. The residue was triturated with Et₂O / isohexane to give 3 - {[(3-chloropropyl) sulfonyl] amino} -2-fluoro-5-nitrobenzoic acid (D143) (600 mg, 97%) as a light brownish solid which was used in step following without further purification. Without molecular ion, RT = 3.05 minutes

Description 144

3- {1- (4-Chlorobutyl) sulfonyl] amino} -2-fluoro-5-nitrobenzoic acid (D144)

3- {[(4-Chlorobutyl) sulfonyl] amino} -2-fluoro5-nitrobenzoic acid (D144) was obtained from methyl 3- {bis [(4-chlorobutyl) sulfonyl] amino} -2-fluoro-5-nitrobenzoate (D142) analogously to the process described for 3 - {[(3-chloropropyl) sulfonyl] amino} -2-fluoro-5-nitrobenzoic acid (D143).

Description 145

Methyl 3- {1- (3-chloropropyl) sulfonyl] amino} -2-fluoro-5-nitrobenzoate (D45)

3 - {[(3-chloropropyl) sulfonyl] amino} -2-fluoro-5β1567488

116 Methyl nitrobenzoate (D145) was prepared in a manner analogous to that of Description 25 from 3 - {[(3-chloropropyl) sulfonyl] amino} -2-fluoro-5-nitrobenzoic acid (D143). [MH] = 353.0, R T = 3.05 minutes

Description 146

Methyl 3- {1- (4-chlorobutyl) sulfonyl] amino} -2-fluoro-5-nitrobenzoate (D146)

Methyl 3- {[(4-chlorobutyl) sulfonyl] amino} -2-fluoro-5-nitrobenzoate (D146) was prepared in a manner analogous to that of Description 25 from 3 - {[(4-chlorobutyl) sulfonyl] amino acid } -2-fluoro-5-nitrobenzoic (D144). [M + H + NH 3]⁺ = 386.1, TR = 3.13 minutes

Description 147

Methyl 3- (1,1-dioxide-2-isothiazolidinyl) -2-fluoro-5-nitrobenzoate (D147)

To a solution of methyl 3 - {[(3-chloropropyl) sulfonyl] amino} -2-fluoro-5-nitrobenzoate (D145) (300 mg, 0.85 mmol, 1 equiv.). in EtOH (30 mL) was added NEt₃(280 µl, 2 mmol, 2.3 equiv.) And the resulting solution was heated at reflux for 1.5 hours and then cooled to room temperature and concentrated in vacuo. The residue was dissolved in EtOAc and the organic phase was washed with 2N aqueous HCl solution, dried over

ΡΕ1567488

117

MgSO₄ and concentrated in vacuo. The residue was triturated with EtOAc / Et 2 O to give methyl 3- (1,1-dioxide-2-isothiazolidinyl) -2-fluoro-5-nitrobenzoate (D147) (150 mg, 55%) as a light brownish solid which was used in next step without further purification. [M + H + NH 3]⁺ = 336.3, RT = 2.50 min.

Description 148

Methyl 3- (1,1-dioxide-tetrahydro-2H-1,2-thiazin-2-yl) -2-fluoro-5-nitrobenzoate (D148)

Methyl 3- (1,1-dioxide-tetrahydro-2H-1,2-thiazin-2-yl) -2-fluoro-5-nitrobenzoate (D148) was prepared analogously to the process for 3- (1,1-yl) methyl dioxy-2-isothiazolidinyl) -2-fluoro-5-nitrobenzoate (D147) from methyl 3 - {[(4-chlorobutyl) sulfonyl] amino} -2-fluoro-5-nitrobenzoate (D146). [M + H + NH 3]⁺ = 350.1, TR =

2.79 minutes

Description 149

Methyl 3- (1,1-dioxide-tetrahydro-2H-1,2-thiazin-2-yl) -2 (methyloxy) -5-nitrobenzoate (D149)

To a solution of methyl 3- {[(4-chlorobutyl) sulfonyl] amino} -2-fluoro-5-nitrobenzoate (D146) (1.5 g, 4.1 mmol, 1 equiv) in MeOH (30 mL) NEt was added₃ (1.2 mL,

8.6 mmol, 2.1 equiv.) And the resulting solution was heated to

ΡΕ1567488

118 reflux for 15 hours and then cooled to room temperature and concentrated in vacuo. The residue was dissolved in EtOAc and the organic phase was washed with 2 N aqueous HCl solution, dried over MgSO4.₄ and concentrated in vacuo. The residue was triturated with EtOAc / Et 2 O to give methyl 3- (1,1-dioxide tetrahydro-2H-1,2-thiazin-2-yl) -2- (methyloxy) 5-nitrobenzoate (D149) (1, 2 g, 55%) as a light brown solid which was used in the next step without further purification. [M + H]⁺ = 345.1, RT = 2.80 minutes

Description 150

Methyl 5-amino-2-fluoro-3- (2-oxo-1-pyrrolidinyl) benzoate (D150)

To a solution of methyl 2-fluoro-5-nitro-3- (2-oxo-lpyrrolidinyl) benzoate (D140) (3.3 g, 11.7 mmol, 1 equiv) in EtOH (100 mL) and H₂O (10 mL) was added NH₄COOH (7.4 g, 117 mmol, 10 equiv.) And 10% palladium on charcoal (50% wet, 660 mg, 10% w / w) and the resulting mixture was refluxed for 2 hours and then cooled to room temperature. The catalyst was removed by filtration through a pad of celite and most of the solvent was removed in vacuo. The residue was shared between AcOEt and H₂O and the two layers were separated. The organic phase was dried over MgSO4.₄ and concentrated in vacuo to give methyl 5-amino-2-fluoro-3- (2-oxo-1-pyrrolidinyl) benzoate (D150) (1.85 g, 63%) as a pale yellow solid which was used in the next step without more purification. [M + H]⁺ = 253.0, TR = 2.12 minutes

ΡΕ1567488

119

Descriptions 151-153 (D151-153)

The following compounds were prepared from the appropriate precursor in a manner analogous to the process described for methyl 5-amino-2-fluoro-3- (2-oxo-1-pyrrolidinyl) benzoate (D150).

<td>description</td><td>Precursor</td><td>[M + H]⁺</td><td>RT (min)</td>

<td>5-amino-3- (1,1-dioxide-2-isothiazole) lidinyl) -2-fluorobenzoate of methyl (D151)</td><td>D147</td><td> 289,1</td><td> 2,12</td>

<td>5-amino-3- (1,1-dioxide tetrahydro- Methyl 2H-1,2-thiazin-2-yl) -2-fluorobenzoate (D152)</td><td>D148</td><td> 303,1</td><td> 2,33</td>

<td>5-amino-3- (1,1-dioxide tetrahydro- 2H-1,2-thiazin-2-yl) -2- (methyloxy) - methyl benzoate (D153)</td><td>D149</td><td> 315,1</td><td> 2,18</td>

Description 154

Methyl 2-fluoro-5 - ({[4- (methyloxy) phenyl] methyl} amino) -3- (2-oxo-1-pyrrolidinyl) benzoate (D154)

Methyl 2-fluoro-5 - ({[4- (methyloxy) phenyl] methyl} amino) -3- (2-oxo-1-pyrrolidinyl) benzoate (D154) was prepared from 5-amino-2-fluoro Methyl 3- (2-oxo-1-pyrrolidinyl) benzoate (D150) in a manner analogous to that of

ΡΕ1567488

120 process described for Ester 35 (B35) using 4- (methyloxy) benzaldehyde instead of propionaldehyde. [M + H]⁺ =

373.4, RT = 2.85 minutes

Description 155

Methyl 5- (ethyl {[4- (methyloxy) phenyl] methyl} amino) -2-fluoro-3- (2oxo-1-pyrrolidinyl) benzoate (D155)

Methyl 5- (ethyl {[4- (methyloxy) phenyl] methyl} amino) -2-fluoro3- (2-oxo-1-pyrrolidinyl) benzoate (D155) was prepared from 2-fluoro-5 - ({ Methyl [4-methyloxy) phenyl] methyl} amino) -3- (2-oxo-1-pyrrolidinyl) benzoate (D154) in a manner analogous to the procedure described for Ester 35 (B35) using acetaldehyde instead of propionaldehyde. [M + H]⁺ = 401.4, TR = 3.11 minutes

Description 156

Methyl 5-bromo-2-fluoro-3- (2-oxo-1-pyrrolidinyl) benzoate (D156)

To a solution of methyl 5-amino-2-fluoro-3- (2-oxo-lpyrrolidinyl) benzoate (D150) (650 mg, 2.6 mmol, 1 equiv) in a 48% aqueous solution of HBr at 0 ° C. ° C added in portions NaNO₂ and the resulting mixture was stirred at 0 ° C for 30 minutes. CuBr (260 mg, 1.82 mmol, 0.7 equiv.) In a 48% aqueous Hbr solution (1 mL) was added and the resulting mixture was stirred at 90 ° C for 1 hour and in

ΡΕ1567488

121 It was then cooled to room temperature and partitioned between H₂0 and AcOEt. The two layers were separated and the organic phase was dried over MgSO4.₄ and concentrated in vacuo. Purification of the residue by silica gel flash chromatography (isohexane / AcOEt: 2/1) gave methyl 5bromo-2-fluoro-3- (2-oxo-1-pyrrolidinyl) benzoate (D156) (145 mg, 18%) as a white solid. [M + H]⁺ = 318.1, TR = 2.51 minutes

Descriptions 157-158 (D157-158)

The following compounds were prepared analogously to the process described for Description 156 (D156) from the appropriate aniline:

<td>description</td><td>Precursor</td><td>RT (min)</td>

<td>5-bromo-3- (1,1-dioxide-2-isothiazolidinyl) methyl) -2-fluorobenzoate (D157)</td><td>D151</td><td> 2,55</td>

<td>5-bromo-3- (1,1-dioxotetrahydro-2H-1,2- methyl thiazin-2-yl) -2-fluorobenzoate (D158)</td><td>D152</td><td></td>

Descriptions 159-161 (D159-161)

The following compounds were prepared analogously to the process described for Description 68 (D68) from the appropriate aryl bromide indicated in the table below:

ΡΕ1567488

122

<td>description</td><td>Precursor</td><td>[M + H]⁺</td><td>RT (min)</td>

<td>2-fluoro-3- (2-oxo-1-pyrrolidinyl) - 5 - [(1E / Z] -1-propen-1-yl] benzoate methyl (D159)</td><td>D156</td><td> 278, 4</td><td> 2,60</td>

<td>3- (1,1-dioxide-2-isothiazolidinyl) - 2-fluoro-5 - [(1E / Z] -1-propen-1- yl] methyl benzoate (D160)</td><td>D157</td><td> 314, 2</td><td> 2,67</td>

<td>3- (1,1-dioxide tetrahydro-2H-1,2- thiazin-2-yl) -2-fluoro-5 - [(1E / Z] -1- methyl propen-1-yl] benzoate (61)</td><td>D158</td><td></td><td></td>

Description 162

Methyl 4-methyl-3,5-dinitrobenzoate (D162)

Methyl 4-methyl-3,5-dinitrobenzoate (D162) was prepared in a manner analogous to that of Description 25 from commercially available 4-methyl-3,5-dinitrobenzoic acid. [M + H]⁺ = 240.2, RT = 3.07 minutes

Description 163

Methyl 3-amino-4- (methyloxy) -5-nitrobenzoate (D163)

To a solution of methyl 4- (methyloxy) -3,5-dinitrobenzoate (D25) (5.0 g, 19.5 mmol, 1 equiv) in AcOH (150 mL) at room temperature was added iron powder. (9.0 g,

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123

161 mmol, 8.2 equiv.) in portions and the resulting mixture was stirred for 3 hours. Toluene (500 mL) was added and the organic phase was filtered through a pad of celite and then concentrated in vacuo. The residue was dissolved in EtOAc and the organic phase was washed with a saturated aqueous NaHCO 3 solution.₃, dried over MgSO₄ and concentrated in vacuo. Trituration of the residue with Et₂Isohexane gave methyl 3-amino-4- (methyloxy) -5-nitrobenzoate (D163) (3.65 g, 83%) as a yellow solid which was used for the next step without further purification. [M + H]⁺ = 226.9, RT = 2.76 min.

Description 164

Methyl 3-amino-4-methyl-5-nitrobenzoate (DL64)

Methyl 3-amino-4-methyl-5-nitrobenzoate (D164) was obtained from methyl 4-methyl-3,5-dinitrobenzoate (D162) in a manner analogous to the procedure described for 3-amino-4- ( methyl methyloxy) -5-nitrobenzoate (D163). [M + H]⁺ = 211.0, TR = 2.81 minutes

Description 165

Methyl 3-iodo-4- (methyloxy) -5-nitrobenzoate (D165)

To a solution of methyl 3-amino-4- (methyloxy) -5-nitrobenzoate (D163) (370 mg, 1.64 mmol, 1 equiv) in toluene (20 mL at 0 ° C) was added iodine (218 mg, 0.86 mmol, 0.5 equiv), then 1,1-dimethylethyl nitrite (200 mg,

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124

1.75 mmol, 1.1 equiv.) And the resulting mixture was stirred at room temperature for 15 hours and then partitioned between EtOAc and brine. The two layers were separated and the organic phase was dried over MgSO4.₄ and concentrated in vacuo. Purification of the residue by silica gel flash chromatography gave methyl 3-iodo-4- (methyloxy) -5-nitrobenzoate (D165) (280 mg, 51%) as a light brown solid. No molecular ion. RT = 3.33 minutes.

Description 166

Methyl 4- (methyloxy) -3-nitro-5 - [(1E / Z) -1-propen-1-yl] benzoate (D166)

Methyl 4- (methyloxy) -3-nitro-5 - [(1E / Z) -1-propen-1-yl] benzoate (D166) was prepared from 3-iodo-4- (methyloxy) -5-nitrobenzoate methyl (D165) in a similar manner to the process described for Description 68 (D68). No molecular ion. RT = 3.46 minutes

Description 167

Methyl 3-amino-4- (methyloxy) -5 - [(1E / Z) -1-propen-1-yl] benzoate (D167)

To a solution of methyl 4- (methyloxy) -3-nitro-5 - [(1E / Z) 1-propen-1-yl] benzoate (D166) (1.0 g, 4.0 mmol, 1 equiv. ) in AcOH (150 mL) at room temperature was added iron powder (1.4 g, 25 mmol, 6.25 equiv) in portions and

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125 The resulting mixture was stirred for 3 hours at room temperature. Iron powder (1 g, 17.9 mmol, 4.2 equiv) was added and the mixture was stirred for a further 1 hour. Iron powder (1 g, 17.9 mmol,

4.2 equiv.) And the mixture was stirred at 45 ° C for 3 hours and then cooled to room temperature and stirred at this temperature for 14 hours. Toluene (200 mL) was added and the organic phase was filtered through a pad of celite and then concentrated in vacuo. The residue was dissolved in EtOAc and the organic phase was washed with a saturated aqueous NaHCO 3 solution.₃, dried over MgSO₄ and concentrated in vacuo to give methyl 3-amino-4- (methyloxy) -5 - [(1E / Z) -1-propen-1-yl] benzoate (D167) (800 mg, 90%) as a brown oil which was used for the next step without further purification. [M + H] + =

222.1, TR = 2.99 minutes

Description 168

Methyl 3- {bis [(4-chlorobutyl) sulfonyl] amino} -4- (methyloxy) -5 [(1E / Z) -1-propen-1-yl] benzoate (D168)

To a solution of methyl 3-amino-4- (methyloxy) -5 - [(1E / Z) 1-propen-1-yl] benzoate (D167) (800 mg, 3.6 mmol, 1 equiv.) In CH 2 Cl 2 (50 mL) was added NEt₃ (1.5 mL, 10.8 mmol, 3.0 equiv.) Then 4-chloro-butanesulfonyl chloride (D20) (2 g, 10.8 mmol, 3.0 equiv) and the resulting mixture was stirred for 1 hour. The organic phase was then washed with a 2N aqueous HCl solution and a saturated aqueous NaHCO 3 solution.₃, dried over MgSO₄ and

ΡΕ1567488

126 concentrated in vacuo. Purification of the residue by silica gel flash chromatography (isohexane / AcOEt: 9/1 to 3/1) gave 3- {bis [(4-chlorobutyl) sulfonyl] amino} -4 (methyloxy) -5- [ Methyl (1E / Z) -1-propen-1-yl] benzoate (D168) (1.0 g, 52%) as a light yellow oil.

Description 169

3 - {[(4-Chlorobutyl) sulfonyl] amino} -4- (methyloxy) 5 - [(1S / Z) -1-propen-1-yl] benzoic acid (D169)

To a solution of methyl 3- {bis [(4-chlorobutyl) sulfonyl] amino} -4- (methyloxy) -5 - [(1E / Z) -1-propen-1-yl] benzoate (D168) (1 0.1 g, 1.88 mmol, 1 equiv) in MeOH (20 mL) was added 2 N aqueous NaOH (10 mL, 20 mmol, excess) and the resulting mixture was stirred for 1 hour. Most of the MeOH was removed in vacuo and the residue was partitioned between EtOAc and 2N aqueous HCl solution. The two layers were separated and the aqueous phase was dried over MgSO4.₄ and concentrated in vacuo. The residue was triturated with Et₂O / isohexane to give 3 - {[(4-chlorobutyl) sulfonyl] amino} -4- (methyloxy) -5 - [(1E / Z) -1-propenyl-yl] benzoic acid (D169) (470 mg , 69%) as a light cream solid which was used in the next step without further purification. [MH] _ = 360.0, RT = 3.19 minutes

Description 170

Methyl 3 - {[(4-chlorobutyl) sulfonyl] amino} -4- (methyloxy) -5 [(1S / Z) -1-propen-1-yl] benzoate (D170)

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127

Methyl 3 - {[(4-chlorobutyl) sulfonyl] amino} -4- (methyloxy) -5 [(1E / Z) -1-propen-1-yl] benzoate (D170) was prepared from 3-acid {[(4-chlorobutyl) sulfonyl] amino} -4 (methyloxy) -5 - [(1E / Z) -1-propen-1-yl] benzoic (D169) in a similar manner to that of Description 25 (D25).

Descriptions 171-172 (D171-172)

The following compounds were obtained from their corresponding precursors in a manner analogous to the process described for Description 2 (D2):

<td>description</td><td>Precursor</td><td>[M + H]⁺</td><td>RT (min)</td>

<td>3 - [(4-chlorobutanoyl) amino] -4- (methyloxy) -5-nitrobenzoate of methyl (D171)</td><td>D163</td><td> 331,0</td><td> 3,13</td>

<td>3 - [(4-chlorobutanoyl) amino] -4-methoxy methyl til-5-nitrobenzoate (D172)</td><td>D164</td><td> 315,1</td><td> 3, 02</td>

Descriptions 173-174 (D173-174)

The following compounds were obtained from their corresponding precursors in a manner analogous to the process described for Description 14 (D14):

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128

<td>description</td><td>Precursor</td><td>[M + H]⁺</td><td>RT (min)</td>

<td>3 - {[(3-chloropropyl) sulfonyl] amino} -4-methyloxy) -5-nitrobenzoate methyl (D173)</td><td>D163</td><td> 364, 9</td><td> 3,10</td>

<td>3 - {[(3-chloropropyl) sulfonyl] amino} -4-methyl-5-nitrobenzoate methyl (D174)</td><td>D164</td><td> 349, 0</td><td> 3,12</td>

Descriptions 175-176 (D175-176)

The following compounds were obtained from their corresponding precursors in a manner analogous to the process described for Description 14 (D14) using 4-chloro-1-butanesulfonyl chloride (D20) instead of 3-chloro-1-propanesulfonyl chloride. :

<td>description</td><td>Precursor</td><td>[Μ- Η] '</td><td>RT (min)</td>

<td>3- {[(4-chlorobutyl) sulfonyl] amino} - 4- (methyloxy) -5-nitrobenzoate of methyl (D175)</td><td>D163</td><td></td><td></td>

<td>3- {[(4-chlorobutyl) sulfonyl] amino} - Methyl 4-methyl-5-nitrobenzoate (D176)</td><td>D164</td><td> 362, 8</td><td> 3,21</td>

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129

Descriptions 177-178 (D177-178)

The following compounds were obtained from their corresponding precursors in a manner analogous to the process described for Ester 27 (B27):

<td>description</td><td>Precursor</td><td>[Μ- Η]</td><td>RT (min)</td>

<td>4- (methyloxy) -3-nitro-5- (2-oxo-1- pyrrolidinyl) methyl benzoate (D177)</td><td>D171</td><td> 295,1</td><td> 2,61</td>

<td>4-methyl-3-nitro-5- (2-oxo-1-pyrrho methyl lidinyl) benzoate (D178)</td><td>D172</td><td> 279, 0</td><td> 2,60</td>

Descriptions 179-182 (D179-182)

The following compounds were obtained from their corresponding precursors in a manner analogous to the process described for Description 15 (D15):

<td>description</td><td>Precursor</td><td>[Μ- Η]</td><td>RT (min)</td>

<td>3- (1,1-dioxide-2-isothiazolidinyl) - 4- (methyloxy) -5-nitrobenzoate of methyl (D179)</td><td>D173</td><td> 331, 0</td><td> 2, 78</td>

<td>3- (1,1-dioxide-2-isothiazolidinyl) - Methyl 4-methyl-5-nitrobenzoate (Dl 80)</td><td>D174</td><td></td><td></td>

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130 (continuation)

<td>description</td><td>Precursor</td><td>[Μ- Η]</td><td>RT (min)</td>

<td>3- (1,1-dioxide-tetrahydro-2 H -1,2- thiazin-2-yl) -4- (methyloxy) -5- methyl nitrobenzoate (D181)</td><td>D175</td><td> 345, 0</td><td> 2,90</td>

<td>3- (1,1-dioxide-tetrahydro-2/1-1,2-yl thiazin-2-yl) -4-methyl-5-nitroben- zoato (D182)</td><td>D176</td><td> 329, 0</td><td> 2, 93</td>

Descriptions 183-188 (D183-188)

The following compounds were obtained from their corresponding precursors in a manner analogous to the process described for the synthesis of Description 16 (D16) using the precursor indicated in the table below:

<td>description</td><td>Precursor</td><td>[Μ- Η]</td><td>RT (min)</td>

<td>3-amino-4- (methyloxy) -5- (2-oxo-1- pyrrolidinyl) methyl benzoate (D183)</td><td>D177</td><td> 265,1</td><td> 2,18</td>

<td>3-amino-4-methyl-5- (2-oxo-1-pyrrophenyl) lidinyl) methyl benzoate (D184)</td><td>D178</td><td> 249,1</td><td> 2,16</td>

<td>3-amino-5- (1,1-dioxide-2-isothiazole) lidinyl) -4- (methyloxy) benzoate of methyl (D185)</td><td>D179</td><td> 301,0</td><td> 2,25</td>

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131 (continuation)

<td>description</td><td>Precursor</td><td>[Μ- Η]</td><td>RT (min)</td>

<td>3-amino-5- (1,1-dioxide-2-isothiazole) methyl lidinyl) -4-methylbenzoate (Dl 86)</td><td>D180</td><td> 285,0</td><td> 2,22</td>

<td>3-amino-5- (1,1-dioxide tetrahydro- 2H-1,2-thiazin-2-yl) -4- (methyloxy) - methyl benzoate (D187)</td><td>D181</td><td> 315,1</td><td> 2,40</td>

<td>3-amino-5- (1,1-dioxide tetrahydro- 2H-1,2-thiazin-2-yl) -4-methylbenzene methyl zoate (D188)</td><td>D182</td><td> 299,0</td><td> 2,42</td>

Description 189

4 - ((Z / E) -But-2-enylamino) -3,5diodo-benzoic acid ethyl ester (D189)

To a solution of 4-amino3,5-diiodo-benzoic acid ethyl ester (commercially available from Maybridge) (72.6 g, 0.17 mmol, 1 equiv.) In DMF (450 mL) at 0 ° C under nitrogen NaH (60% in mineral oil, 7.3 g, 0.18 mmol, 1.05 equiv) was added portionwise over 2 minutes. After 10 minutes crotyl bromide (21.5 mL, 0.21 mmol, 1.2 equiv) in DMF (50 mL) was added via cannula over 5 minutes and the resulting mixture was allowed to warm to room temperature. for 30 minutes. EtOH (5 mL) was added and the mixture was concentrated in vacuo. The residue was dissolved in AcOEt and the organic phase.

ΡΕ1567488

132 was washed with H₂0 The aqueous phase was extracted with EtOAc and the combined organic phases were washed with brine, dried over MgSO 4 and concentrated in vacuo to give 4 ((Z / E) -but-2-enylamino) ethyl ester. -3,5-diiodo benzoic (D189) (82 g, 100%) as a pink solid which was used in the next step without further purification. [M + H]⁺ = 472.0, TR = 4.93 minutes

Description 190

3-Ethyl-7-iodo-1H-indole-5-carboxylic acid ethyl ester (D190)

To a solution of 4 - ((Z / E) but-2-enylamino) -3,5-diiodo-benzoic acid ethyl ester (D189) (15 g, 31.8 mmol, 1 equiv) in DMF (150 at room temperature under nitrogen was added Pd (OAc)₂ (357 mg, 1.6 mmol, 0.05 equiv.), NaCOOH (6.5 g, 95.6 mmol, 3 equiv.), Na₂CO₃ (8.4 g, 79.6 mmol, 2.5 equiv.) And NBu₄C1 (8.0 g, 35.0 mmol, 1.1 equiv.). The resulting suspension was stirred under nitrogen at 80 ° C for 30 minutes and then cooled to room temperature and concentrated in vacuo. The residue was partitioned between AcOEt and H₂O and the two phases were separated. The organic phase was dried over MgSO4.₄ and concentrated in vacuo. Purification of the residue by silica gel flash chromatography (isohexane / AcOEt: 9/1) gave 3-ethyl-7-iodo-1B-indole-5-carboxylic acid ethyl ester (D190) (6.3 g , 58%) as a white solid. [M + H]⁺ = 344.0 TR = 3.86 minutes

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133

Description 191

3-bromo-5- (2-oxo-5-phenyl-1-piperidinyl) benzoate from

1,1-dimethylethyl (D191)

A flask under nitrogen was charged with 3-bromo-5-iodo-benzoic acid methyl ester (D8b) (840 mg, 2.2 mmol, 1.1 eguiv.), Cs.₂CO₃ (900 mg, 2.8 mmol, 1.4 eguiv.), Tris (dibenzylidenoacetone) dipaladium (0) (92 mg, 0.1 mmol, 0.05 eguiv.), Xantphos (120 mg, 0.2 mmol, 0.1 eguiv.) And toluene (40 mL). 5-Phenyl-2-piperidinone (Koelsch, J. Am. Chem. Soc. 1943, (65), 2093, 350 mg, 2 mmol, 1 eiv.) Was then added and the resulting mixture was stirred at 100 ° C. for 2.5 hours and then cooled to room temperature and concentrated in vacuo. The residue was partitioned between AcOEt and a saturated NaHCO solution.₃. The layers were separated and the organic phase was dried over MgSO4.₄ and concentrated in vacuo to give a solid residue. Purification of the residue by silica gel flash chromatography (isohexane / AcOEt: 4/1 to 1/1) gave 1,1-3-bromo-5- (2οχο-5-phenyl-1-piperidinyl) benzoate dimethylethyl (D191) (480 mg, 51%) as a white solid. [M + H]⁺ = 432,2,

RT = 3.82 minutes

Description 192

1,1-dimethylethyl 3- (2-oxo-5-phenyl-1-piperidinyl) -5 - [(1E / Z) -1-propenyl] benzoate (D192)

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134

1,1-Dimethylethyl 3- (2-oxo-5-phenyl-1-piperidinyl) -5 - [(1E / Z) -1-propen-1-yl] benzoate (D192) was prepared in a similar manner to from the process described for Description 68 (D68) from 1,1-dimethylethyl 3-bromo-5- (2-oxo-5-phenyl-1-piperidinyl) benzoate (D191). [M + H]⁺ = 392.3, TR = 3.83 minutes

Description 193

Methyl 3- (1,1-dioxide-tetrahydro-2H-1,2-thiazin-2-yl) -5-nitrobenzoate (D133)

Methyl 3- (1,1-dioxide-tetrahydro-2H-1,2-thiazin-2-yl) -5-nitrobenzoate (D193) was obtained from methyl 3-bromo-5-nitrobenzoate (D11) in a similar manner to of the process described for Description 15 (D15) (alternative procedure) using tetrahydro2H-1,2-thiazine 1,1-dioxide (D22b) instead of isothiazolidine 1,1-dioxide (D22a). [M + H + NH 3]⁴ = 332.2, RT = 2.75 minutes

Description 194

Methyl 3-amino-5- (1,1-dioxide-tetrahydro-2H-1,2-thiazin-2yl) benzoate (D194)

Methyl 3-amino-5- (1,1-dioxide-tetrahydro-2H-1,2-thiazin-2-yl) benzoate (D194) was obtained from 3- (1,1-dioxide-tetrahydro-2H-1, 2-thiazin-2-yl) -5-nitrobenzoate

ΡΕ1567488

135 methyl (D193) in a similar manner to the process described for Description 2 (D2). [M + H]⁺ = 285.1, TR = 2.12 minutes

Description 195

Methyl 3 - [(4-chlorobutanoyl) amino] -5- (1,1-dioxide-2isothiazolidinyl) benzoate (D195)

Methyl 3 - [(4-chlorobutanoyl) amino] -5- (1,1-dioxide-2isothiazolidinyl) benzoate (D195) was obtained from 3-amino-5- (1,1-dioxide-2-isothiazolidinyl) methyl benzoate (D16) in a similar manner to the process described for Description 13 (D13).

Description 196

Methyl 3-amino-4-methyl-5-nitrobenzoate (D196)

To a solution of methyl 4-methyl-3,5-dinitrobenzoate (D162) (30 g, 0.125 mmol, 1 equiv.) In MeOH (150 mL) and cyclohexene (300 mL) was added 10% palladium. over carbon (50% wet, 3 g, 5% w / w) and the resulting suspension was refluxed for 7 hours and then cooled to room temperature. The catalyst was filtered off through a pad of celite and most of the solvent was removed in vacuo. The formed precipitate was filtered off to give methyl 3-amino-4-methyl-5-nitrobenzoate (D196) (22 g, 84%).

ΡΕ1567488

136 as a yellow solid which was used in the next step without further purification. [M + H]⁺ = 211.0, TR = 2.81 minutes

Description 197

Methyl 4-nitro-1H-indazole-6-carboxylate (Dl97)

To a suspension of methyl 3-amino-4-methyl-5-nitrobenzoate (D196) (3.5 g, 16.7 mmol, 1 equiv.) In H₂O (100 mL) at 0 ° C was added 36% aqueous HCl (15 mL) and the resulting suspension was treated with NaNO₂ (1.35 g,

19.6 mmol, 1.2 equiv.) Was then warmed to room temperature and stirred for 1.5 hours. Insoluble material was removed by filtration and small amounts of urea were added to the mother liquor. The resulting solution was diluted with H₂O (500 mL) is treated with H₂ONLY₄NaHCO3 (17.5 mL) and then warmed to 50 ° C for 15 minutes, cooled to room temperature and extracted with EtOAc. The organic phase was dried over MgSO4.₄ and then concentrated in vacuo. The residue was triturated with MeOH to give methyl 4-nitro-1H-indazole-6carboxylate (D197) (0.8 g, 22%) as a cream solid which was used in the next step without further purification. [M + H]⁺ = 222.1, TR = 2.84 minutes

Description 198 Methyl 1-ethyl-4-nitro-1H-indazole-6-carboxylate (D198)

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137

To a solution of methyl 4-nitro-1H-indazole-6-carboxylate (D197) (500 mg, 2.3 mmol, 1 equiv) in DMF (10 mL) at room temperature was added K₂CO₃ (346 mg,

2.5 mmol, 1.1 equiv.) Then ethyl iodide (200 μΐ,

2.5 mmol, 1.1 equiv.). The resulting suspension was stirred at room temperature for 15 minutes and then at 40 ° C for 30 minutes, cooled to room temperature and partitioned between EtOAc and 2 N aqueous HCl. The two layers were separated and the organic phase was separated. dried over MgSO₄ and concentrated in vacuo. Purification of the residue by silica gel flash chromatography (isohexane / AcOEt: 2/1) gave methyl 1-ethyl-4-nitro-1H-indazole-6-carboxylate (D198) (200 mg, 35%) as a light yellow solid. [M + H]⁺ = 250.1, TR = 3.11 minutes

Description 199

Methyl 4-amino-1-ethyl-1H-indazole-6-carboxylate (D199)

To a solution of methyl 1-ethyl-4-nitro-1H-indazole-6-carboxylate (D198) (2.2 g, 8.8 mmol, 1 equiv.) In

MeOH (100 mL) and H₂O (10 mL) was added 10% palladium on charcoal (50% wet, 700 mg, 16% w / w) and the resulting mixture was stirred at 60 ° C for 30 minutes and then cooled to room temperature. . The catalyst was removed by filtration through a pad of celite and most of the solvent was removed.

ΡΕ1567488

138 in vacuum. The residue was partitioned between EtOAc and a saturated aqueous NaHCO 3 solution.₃ and the two layers were separated. The organic phase was dried over MgSO4.₄ and concentrated in vacuo. The residue was triturated with isohexane to give methyl 4-amino-1-ethyl-1A-indazole-6-carboxylate (D199) (1.55 g, 80%) which was used for the next step without further purification. [M + H]⁺ = 220.1, RT = 3.31 minutes

Description 200

Methyl 4 - [(E) -2- (dimethylamino) ethenyl] -3,5-dinitrobenzoate (D200)

To a solution of methyl 4-methyl-3,5-dinitrobenzoate (D162) (20 g, 83.3 mmol, 1 equiv.) In DMF (30 mL) was added N, W-dimethylformamide dimethylacetal (35 mL, excess) and the resulting solution was stirred at 45 ° C for 30 minutes and then cooled to room temperature and concentrated in vacuo. Trituration of the residue with Et 2 O / isohexane gave methyl 4 - [(E) -2- (dimethylamino) ethenyl] -3,5-dithitrobenzoate (D200) (20 g, 81%) as a dark red solid which was used in next step without further purification.

Description 201

Methyl 4-amino-1H-indole-6-carboxylate (D201)

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139

To a solution of methyl 4 - [(E) -2- (dimethylamino) ethenyl] 3,5-dinitrobenzoate (D200) (10 g, 34 mmol, 1 equiv) in MeOH (250 mL) was added palladium on. 10% on charcoal (50% wet, 1.0 g, 5% w / w) and the resulting mixture was stirred under a hydrogen atmosphere for 7 hours. The catalyst was removed by filtration through a pad of celite and the solution was concentrated in vacuo. The residue was triturated with EtOAc / isohexane to give methyl 4-amino-1H-indole-6-carboxylate (D201) (5 g, 77%) as a dark pink solid. [M + H]⁺ = 191.0, TR = 1.20 minutes

Description 202

Methyl 4-amino-1-ethyl-1H-indole-6-carboxylate (D202)

To a solution of methyl 4-amino-1H-indole-6-carboxylate (D201) (900 mg, 4.74 mmol, 1 equiv) in DMF (25 mL) at room temperature was added NaH (dispersion at 60 ° C). % in mineral oil, 200 mg, 5 mmol, 1.05 equiv) and after 5 minutes ethyl iodide (400 µL, 5 mmol, 1.05 equiv). The resulting mixture was stirred for 30 minutes and then most of the solvent was removed in vacuo. The residue was diluted with EtOAc and the organic phase washed with 2N aqueous HCl solution, dried over MgSO4.₄ and concentrated in vacuo. Purification of the residue by silica gel flash chromatography (isohexane / AcOEt: 1/1) gave an oil which was diluted with Et₂O is treated with a

ΡΕ1567488

140 4 N HCl solution in Et₂The precipitate obtained was filtered off to give methyl 4-aminol-ethyl-1H-indole-6-carboxylate hydrochloride salt (D202) (800 mg,

66%) as a white solid. [M + H]⁺ = 219.0, TR = 2.50 minutes

Description 203

Methyl 4-amino-3,5-dinitrobenzoate (D203)

Methyl 4-amino-3,5-dinitrobenzoate (D203) was prepared in a manner analogous to that of Description 25 from commercially available 4-amino-3,5-dinitrobenzoic acid. [MH] _ = 240.1, RT = 2.42 minutes

Description 204

Methyl 3,4-diamino-5-nitrobenzoate (D204)

To a solution of methyl 4-amino-3,5-dinitrobenzoate (D203) (3.0 g, 12.4 mmol, 1 equiv.) In MeOH (40 mL) and cyclohexane (80 mL) was added 10% palladium on charcoal (50% wet, 2.0 g, 33% w / w) and the resulting mixture was refluxed for 30 minutes and then cooled to room temperature. The catalyst was filtered off through a pad of celite and washed with DMF. The combined organic phases were concentrated in vacuo and the residue was triturated with

Et₂O / isohexane to give 3,4-diamino-5-nitrobenzoate of

ΡΕ1567488

141 methyl (D204) (2.1 g, 80%) as a red solid which was used in the next step without further purification. [M + H]⁺ =

212.2, R T = 2.46 minutes

Description 205

Methyl 4-amino-3- (ethylamino) -5-nitrobenzoate (D205)

To a solution of methyl 3,4-diamino-5-nitrobenzoate (D204) (1.5 g, 7.1 mmol, 1 equiv.) In DMF (30 mL) at room temperature was added K₂CO₃ (2.2 g, 16.0 mmol, 2.25 equiv.) Then ethyl iodide (1.28 mL, 16.0 mmol, 2.25 equiv). The resulting suspension was stirred at 60 ° C for 2 hours and then ethyl iodide (1 mL, 12.5 mmol, 1.8 equiv) was added and the resulting mixture was stirred for a further 6 hours and then added. cooled to room temperature and partitioned between AcOEt and a saturated aqueous NaHCO₃. The two layers were separated and the organic phase was washed with H₂O, dried over MgSO₄ and concentrated in vacuo. The residue was triturated with Et₂O to give methyl 4-amino-3- (ethylamino) -5-nitrobenzoate (D205) (0.85 g, 50%) as a red solid which was used in the next step without further purification. [M + H]⁺ = 240.2, RT = 2.95 minutes

Description 206 Methyl 1-ethyl-4-nitro-1H-benzimidazole-6-carboxylate (D206)

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142

Methyl 4-amino-3- (ethylamino) -5-nitrobenzoate (D205) (850 mg, 3.55 mmol, 1 equiv.) Was dissolved in formic acid (20 mL) and the resulting solution was stirred at 100 ° C. for 45 minutes and then cooled to room temperature and diluted with EtOAc (200 mL. The organic phase was washed with a 2N aqueous NaOH solution, dried over MgSO 4 and concentrated in vacuo to give methyl 1-ethyl-4-nitro-1A-benzimidazole-6-carboxylate (D206) (700 mg, 79%) as a brownish solid which was used in the next step without further purification. [M + H]⁺ = 250.1, TR = 2.41 minutes

Description 207

Methyl 4-amino-1-ethyl-1H-benzimidazole-6-carboxylate (D207)

To a solution of methyl 1-ethyl-4-nitro-1H-benzimidazole6-carboxylate (D206) (700 mg, 2.81 mmol, 1 equiv.) In MeOH (50 mL) and H₂O (5 mL) was added 10% palladium on charcoal (50% wet, 400 mg, 28% w / w) and NH₄COOH (1.77 g, 28.1 mmol, 10 equiv.) And the resulting mixture was stirred at 70 ° C for 30 minutes and then cooled to room temperature. The catalyst was filtered off through a pad of celite and most of the MeOH was removed in vacuo. The residue was diluted with EtOAc and the organic layer was washed with a saturated aqueous NaHCO 3 solution.₃, dried over MgSO₄ and

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143 It is concentrated in vacuo to give methyl 4-amino-1-ethyl-1H-benzimidazole-6-carboxylate (D207) (500 mg, 81%) as a white solid which was used in the next step without further purification. [M + H]⁺ = 220.2, RT = 2.17 minutes

Description 208

Methyl 4 - [(2-chloroethyl) amino] -3,5-dinitrobenzoate (D208)

To a solution of methyl 4-chloro-3,5-dinitrobenzoate (D25a) (5.0 g, 19.2 mmol, 1 equiv.) In MeOH (300 mL) was added 2-chloroethylamine hydrochloride (4, 64 mg, 40 mmol, 2.1 equiv.) And NEt₃ (5.5 mL, 40 mmol, 2.1 equiv.) And the resulting mixture was refluxed for 5 minutes and then cooled to room temperature. Most of the solvent was evaporated in vacuo and the residue was filtered off to give methyl 4 - [(2-chloroethyl) amino] 3,5-dinitrobenzoate (D208) (9 g, 156%) as a yellow solid. was used for the next step without further purification. [M + H]⁺ = 304.1, TR = 3.06 minutes

Description 209

Methyl 8-nitro-1,2,3,4-tetrahydro-6-quinoxalinecarboxylate (D209)

To a solution of crude methyl 4 - [(2-chloroethyl) amino] -3,5-dinitrobenzoate (D208) (9 g, 19.2 mmol, 1

ΡΕ1567488

144 equiv.) in MeOH (75 mL and cyclohexene (150 mL) was added 10% palladium on charcoal (50% wet, 4.5 g, 25% w / w) and the resulting mixture was heated at reflux for 3 hours and then cooled to room temperature The catalyst was filtered off through a pad of celite and most of the solvent was removed in vacuo.The residue was partitioned between EtOAc and 2 N aqueous HCl solution. the two layers were separated. The aqueous phase was extracted twice with EtOAc and the combined organic layers were washed with saturated aqueous NaHCO 3 solution.₃, dried over MgSO₄ and concentrated in vacuo. Purification of the residue by silica gel flash chromatography (isohexane / AcOEt: 1/1) gave methyl 8-nitro-1,2,3,4-tetrahydro-6-quinoxalinecarboxylate (D209) (1, 5 g, 34%) as a red solid. [MH] = = 236.2, RT = 2.65 minutes

Description 210

Methyl 4-ethyl-8-nitro-1,2,3,4-tetrahydro-6-quinoxalinecarboxylate (D210)

Methyl 4-ethyl-8-nitro-1,2,3,4-tetrahydro-6-quinoxalinecarboxylate (D210) was prepared from 8-nitro-1,2,3,4-tetrahydro-6-quinoxalinecarboxylate (D209) in a manner analogous to the process described for Ester 35 (B35) using acetaldehyde instead of propionaldeldo. [M + H]⁺ = 266.3, RT = 3.07 minutes

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Description 211

Methyl 8-amino-4-ethyl-1,2,3,4-tetrahydro-6-quinoxalinecarboxylate (D211)

Methyl 8-amino-4-ethyl-1,2,3,4-tetrahydro-6-quinoxalinecarboxylate (D211) was prepared from 4-ethyl-8nitro-1,2,3,4-tetrahydro Methyl-6-quinoxalinecarboxylate (D210) in a similar manner to the process described for Description 207 (D207). [M + H]⁺ = 236.2, TR = 2.23 minutes

Description 212

Ethyl 4-amino-3-nitrobenzoate (D212)

Ethyl 4-amino-3-nitrobenzoate (D212) was prepared in a manner analogous to that of Description 25 from commercially available 4-amino-3-nitrobenzoic acid using EtOH as solvent instead of MeOH.

Description 213

Ethyl 4-amino-3-bromo-5-nitrobenzoate (D213)

To a solution of ethyl 4-amino-3-nitrobenzoate (D212) (21.0 g, 100 mmol, 1 equiv.) In ΟΗ₂Ο1₂ (500 mL) at room temperature was added bromine (6.7 mL, 130 mmol,

1.3 equiv.) And the resulting mixture was refluxed for 4 hours and then bromine (2 mL, 40 mL) was added.

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146 mmol, 0.4 equiv.) and the resulting mixture was refluxed for a further 3 hours and then cooled to room temperature. The organic phase was washed twice with an aqueous Na₂s₂O₃ 10% and twice with H₂O, dried over MgSO 4 and concentrated in vacuo to give

Ethyl 4-amino-3-bromo-5-nitrobenzoate (D213) (27.1 g, 94%) as a yellow solid which was used in the next step without further purification.

Description 214

Ethyl 3-bromo-5-nitro-4 - [(trifluoroacetyl) amino] benzoate (D214)

To a solution of ethyl 4-amino-3-bromo-5-nitrobenzoate (D213) (27.1 g, 93.1 mmol, 1 equiv.) In CH₂C1₂ N, N-diisopropylethylamine (22 mL, 130 mmol, 1.4 equiv) and trifluoroacetic acid anhydride (15.8 mL, 111.7 mmol, 1.2 equiv) were added at room temperature. The resulting mixture was stirred for 2 hours. N, N-Diisopropylethylamine (22 mL, 130 mmol, 1.4 equiv) and trifluoroacetic acid anhydride (15.8 mL, 111.7 mmol, 1.2 equiv) were added and the resulting mixture was stirred for a further 2 hours H added₂O and the two layers were separated. The organic phase was washed twice with 2 N aqueous HCl solution.₂O, dried over MgSO₄ and concentrated in vacuo. Purification of the residue by silica gel flash chromatography (isohexane / AcOEt: 9/1 to 3/1) gave ethyl 3-bromo5-nitro-4 - [(trifluoroacetyl) amino] benzoate (D214) (29, 4 g, 82%) as a yellow solid.

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Description 215

Ethyl 3-bromo-4 - [(3-methyl-2-buten-1-yl) (trifluoroacetyl) amino] -5-nitrobenzoate (D215)

To a solution of ethyl 3-bromo-5-nitro-4 - [(trifluoroacetyl) amino] benzoate (D214) (12.0 g, 31.3 mmol, 1 equiv.) In CH₃CN (100 mL) was added K₂CO₃ (5.6 g, 40 mmol, 1.3 equiv) and 1-bromo-3-methyl-2-butene (5.1 mL, 43.8 mmol, 1.4 equiv) and the resulting mixture was heated at reflux for 1 hour and then cooled to room temperature. The formed precipitate was filtered off through a pad of celite and was washed with CH₃CN. The combined organic layers were concentrated in vacuo and the residue was diluted with EtOAc. The organic layer was washed with brine, dried over MgSO4.₄ and concentrated in vacuo. Purification of the residue by silica gel flash chromatography (isohexane / AcOEt: 9/1 to 4/1) gave 3-bromo-4 - [(3methyl-2-buten-1-yl) (trifluoroacetyl) amino] Ethyl 5-nitrobenzoate (D215) (12.9 g, 91%) as an orange oil.

Descriptions 216-217 (D216-217)

The following compounds were obtained from ethyl 3-bromo-5-nitro-4 - [(trifluoroacetyl) amino] benzoate (D214) in an analogous manner using the appropriate allyl bromide:

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<td>description</td><td>Bromide allyl</td>

<td>Ethyl 3-bromo-4 - [(2E / Z] -2-buten-1-yl- (trifluoroacetyl) amino] -5-nitrobenzoate (D216)</td><td></td>

<td>Ethyl 3-bromo-5-nitro-4- [2-propen-1-yl (trifluoroacetyl) amino] benzoate</td><td></td>

Description 218

Ethyl 3- (1-methylethyl) -7-nitro-1H-indole-5-carboxylate (D218)

To a solution of ethyl 3-bromo-4 - [(3-methyl-2-butenyl) (trifluoroacetyl) amino] -5-nitrobenzoate (D215) (12.9 g, 28.5 mmol, 1 equiv. ) in DMF (130 mL) was added

HCOONa (1.94 g, 28.5 mmol, 1 equiv.), Na₂CO₃ (7.54 g, 71.2 mmol, 2.5 equiv.), Bu₄NCl (8.7 g, 31.3 mmol, 1.1 equiv.) And palladium (II) acetate (320 mg, 1.42 mmol, 0.05 equiv.) And the resulting mixture was stirred under nitrogen for 1 h. It was then cooled to room temperature and concentrated in vacuo. The residue was partitioned between AcOEt and H₂O and the two layers were separated. The insoluble material in the aqueous phase was filtered off through a pad of celite and the aqueous layer was extracted twice with EtOAc. The combined organic layers were washed with saturated aqueous sodium chloride solution,

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149 dried over MgSO4 and concentrated in vacuo to give methyl 3- (1-methylethyl) -7-nitro-1H-indole-5-carboxylate (D218) (10.1 g, 128%) as a black solid which was used in next step without further purification.

Descriptions 219-220 (D219-220)

The following compounds were obtained analogously using the appropriate precursor:

<td>description</td><td>Precursor</td>

<td>Ethyl 3-ethyl-7-nitro-1H-indole-5-carboxylate</td><td>D216</td>

<td>(D219)</td><td></td>

<td>Ethyl 3-methyl-7-nitro-1H-indole-5-carboxylate</td><td>D217</td>

<td>(D220)</td><td></td>

Description 221

Ethyl 7-amino-3- (1-methylethyl) -1H-indole-5-carboxylate (D221)

To a solution of crude ethyl 3- (1-methylethyl) -7-nitro-1-indole-5-carboxylate (D218) (10.1 g, 28.5 mmol, 1 equiv) in MeOH (250 mL) and H₂O (25 mL) was added 10% palladium on charcoal (50% wet, 1.5 g, 8% w / w) and NH 4 COOH (17 g, 280 mmol, 10 equiv) and the resulting mixture was stirred at room temperature. 70 ° C for 3 hours and then cooled to room temperature. The catalyst was

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150 filtered off through a pad of celite most of the MeOH was removed in vacuo. The residue was diluted with EtOAc and the organic layer was washed with a saturated aqueous NaHCO 3 solution.₃, dried over MgSO₄ and concentrated in vacuo. Purification of the residue by silica gel flash chromatography (isohexane / AcOEt: 3/1 to 1/1) gave methyl 7-amino-3- (1-methylethyl) -1H-indole-5-carboxylate (D221 ) (1.47 g, 21%) as a white solid.

Descriptions 222-223 (D222-223)

The following compounds were obtained in a manner analogous to the process described for Description 221 using the appropriate precursor:

<td>description</td><td>Precursor</td>

<td>Ethyl 7-amino-3-ethyl-1H-indole-5-carboxylate</td><td>D216</td>

<td>(D222)</td><td></td>

<td>Ethyl 7-amino-3-methyl-1H-indole-5-carboxylate</td><td>D217</td>

<td>(D223)</td><td></td>

Descriptions 224-230 (D224-230)

The following compounds were obtained from their corresponding precursors in a manner analogous to the process described for Description 2 (D2):

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<td>description</td><td>Precursor</td><td>[M + H]⁺</td><td>RT (min)</td>

<td>7 - [(4-chlorobutanoyl) amino] -3-methoxy til-1H-indole-5-carboxylate from ethyl (D224)</td><td>D223</td><td></td><td></td>

<td>7 - [(4-chlorobutanoyl) amino] -3-ethyl ethyl 1H-indole-5-carboxylate (D225)</td><td>D222</td><td></td><td></td>

<td>7 - [(4-chlorobutanoyl) amino] -3- (1- methylethyl) -1H-indole-5-carboxylate of ethyl (D226)</td><td>D221</td><td></td><td></td>

<td>4 - [(4-chlorobutanoyl) amino] -1-ethyl 1H-benzimidazole-6-carboxylate methyl (D227)</td><td>D207</td><td></td><td></td>

<td>4 - [(4-chlorobutanoyl) amino] -1H- methyl indole-6-carboxylate (D228)</td><td>D201</td><td> 295, 0</td><td> 2, 63</td>

<td>4 - [(4-chlorobutanoyl) amino] -1-ethyl 1H-indazole-6-carboxylate from methyl (D229)</td><td>D199</td><td> 324,3</td><td> 2, 70</td>

<td>8 - [(4-chlorobutanoyl) amino] -4-ethyl 1,2,3,4-tetrahydro-6-quinoxali methyl nocarboxylate (D230)</td><td>D211</td><td> 340,2</td><td> 2, 73</td>

Description 231

Methyl 4- (1,1-dioxide-tetrahydro-2H-1,2-thiazin-2-yl) -1H-indole-6-carboxylate (D231)

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Methyl 4- (1,1-dioxide-tetrahydro-2H-1,2-thiazin-2-yl) -1H-indole-6-carboxylate (D231) was obtained from 4- (1,1-dioxide-tetrahydro acid -2H-1,2-thiazin-2-yl) -1H-indole-6-carboxylic acid (A155) in a similar manner to that of Description 25 (D25).

Description 232

1- (1,1-Dimethylethyl) 6-methyl 4- (1,1-dioxide-tetrahydro-2H-1,2-thiazin-2-yl) -1H-indole-1,6-dicarboxylate (D232)

To a solution of methyl 4- (1,1-dioxide-tetrahydro-2H1,2-thiazin-2-yl) -1H-indole-6-carboxylate (D231) (308 mg, 1.0 mmol, 1 equiv. ) in CH₂C1₂ (10 mL) was added NEt 3 (166 µL, 1.2 mmol, 1.2 equiv), bis (1,1-dimethylethyl) dicarbonate (251 mg, 1.15 mmol, 1.15 equiv) and DMAP (12 mg, 0.1 mmol, 0.1 equiv.) And the resulting mixture was stirred at room temperature for 30 minutes. The organic phase was washed with 2 N aqueous HCl solution and saturated aqueous NaHCO 3 solution.₃, dried over MgSO₄ and concentrated in vacuo. The crunch in Et₂0 / isohexane gave

1- (1,1-Dimethylethyl) 6-methyl 4- (1,1-dimethyl tetrahydro-2A-1,2-thiazin-2-yl) -1H-indol-6-dicarboxylate (D232) (150 mg , 37%) as a white solid which was used in the next step without further purification. [M + H + NH 3]⁺ = 426.2, RT = 3.38 minutes

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Description 233

1- (1,1-Dimethylethyl) 6methyl 4- (1,1-dioxide-tetrahydro-2H-1,2-thiazin-2-yl) -2,3-dihydro-1H-indole-1,6-dicarboxylate (D233)

1- (1,1-Dimethylethyl) 6- (1,1-dihydro tetrahydro-2B-1,2-thiazin-2-yl) 2,3-dihydro-1B-indole-1,6-dicarboxylate 6- methyl (D233) was obtained from 1- (1,1-dimethylethyl) 6-methyl 4- (1,1-dioxo-tetrahydro-2B-1,2-thiazin-2-yl) -1H-indole-1,6-dicarboxylate (D232) in a similar manner to the process described for Ester 116 (B116). Without molecular ion, R T = 3.23 minutes

Description 234

Methyl 4- (1,1-dioxide-tetrahydro-2H-1,2-thiazin-2-yl) -2,3-dihydro-1H-indole-6-carboxylate hydrochloride salt (D234)

1- (1,1-Dimethylethyl) 4- (1,1-dimethyl tetrahydro-2B-1,2-thiazin-2-yl) 2,3-dihydro-1B-indole-1,6-dicarboxylate 6-methyl (D233) (500 mg, 1.2 mmol, 1 equiv.) Was dissolved in 4 N HCl solution in Et₂O (10 mL, 40 mmol, excess) and the resulting solution was stirred at room temperature for 1 hour and then concentrated in vacuo. Trituration of the residue with Et₂Methyl 4- (1,1-dioxide-tetrahydro-2B-1,2-thiazin-2-yl) -2,3-dihydro-1B-indole-6-carboxylate hydrochloride salt (D234) (430 mg ,

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100%) as a white solid which was used in the next step without further purification. [M + H]⁺ = 311.0, TR = 2.16 minutes

Description 235 Methyl 1-acetyl-4- (1,1-dioxide-tetrahydro-2H-1,2-thiazin-2yl) -2,3-dihydro-1H-indole-6-carboxylate (D235)

To a solution of methyl 4- (1,1-dioxo-tetrahydro-2H-1,2-thiazin-2-yl) -2,3-dihydro-1H-indole-6-carboxylate hydrochloride salt (D234) (350 mg 1.0 mmol, 1 equiv.) In AcOEt (5 mL) was added NEt₃ (140 mL, 1.0 mmol, 1 equiv) and acetic anhydride (0.5 mL, 5.6 mmol, 5.6 equiv) and the resulting mixture was stirred at 50 ° C for 30 minutes and then cooled to room temperature and washed with 2N aqueous HCl followed by saturated aqueous NaHCO 3.₃then dried over MgSO₄ and concentrated in vacuo to give methyl 1-acetyl-4- (1,1-dioxide-tetrahydro-2 H -1,2-thiazin-2-yl) -2,3-dihydrol A-indole-6-carboxylate (D235) as a white solid which was used in the next step without further purification. [M + H]⁺ = 353.2, RT = 2.24 minutes

Description 236

Methyl 4- {bis [(3-chloropropyl) sulfonyl] amino} -1-ethyl-1H-indole-6-carboxylate (D236)

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To a solution of methyl 4-amino-letyl-1 H -indole-6-carboxylate hydrochloride salt (D202) (1.7 g, 6.68 mmol, 1 equiv) in CH 2 Cl 2 (50 mL) was added. if NEt₃ (4.2 mL, 30 mmol, 4.5 equiv.) And then 3-chloro-lpropanesulfonyl chloride (1.8 mL, 15.0 mmol, 2.2 equiv.) And the resulting mixture was stirred for 2 hours. The organic phase was washed with 2 N aqueous HCl solution and saturated aqueous NaHCO 3 solution.₃, dried over MgSO₄ and concentrated in vacuo. Purification of the residue by flash silica gel chromatography (EtOAc / isohexane: 1/1) gave methyl 4- {bis [(3-chloropropyl) sulfonyl] amino} -1-ethyl-1-indole-6-carboxylate ( D236) (1.85 g, 55%) as a light brownish solid. [MH] = 498.1, R T = 3.51 minutes

Description 237

Methyl 4- {bis [(3-chloropropyl) sulfonyl] amino} -1-ethyl-1H-indazole-6-carboxylate (D237)

Methyl 4- {bis [(3-chloropropyl) sulfonyl] amino] -1-ethyl-1-indazole-6-carboxylate (D237) was obtained from methyl 4-amino-1-ethyl-1H-indazole-6-carboxylate of a form analogous to the process described for methyl 4- {bis [(3-chloropropyl) sulfonyl] amino} -1-ethyl-1H-indole-6-carboxylate (D236). [M + H]⁺ = 500.1, TR = 3.50 minutes

Description 238

Methyl 8- {bis [(3-chloropropyl) sulfonyl] amino} -4-ethyl-1,2,3,4tetrahydro-6-quinoxalinecarboxylate (D238)

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Methyl 8- {bis [(3-chloropropyl) sulfonyl] amino} -4-ethyl1,2,3,4-tetrahydro-6-quinoxalinecarboxylate (D238) was obtained from 8-amino-4-ethyl Methyl 1,2,3,4-tetrahydro-6-quinoxalinecarboxylate (D211) in a similar manner to the procedure described for 4- {bis [(3-chloropropyl) sulfonyl] amino] -1-ethyl-1H-indole-6-one methyl carboxylate (D236). [M + H]⁺ = 517.2, TR = 3.32 minutes

Description 239

Methyl 4- {bis [(3-chloropropyl) sulfonyl] amino} -1-ethyl-1H-benzimidazole-6-carboxylate (D239)

- {{[[(3-chloropropyl) sulfonyl] amino} -1-ethyl-1 H -benzimidazole-6-carboxylate (D239) was obtained from 4-amino-1-ethyl-1H-benzimidazole-6-one methyl carboxylate (D207) in a manner analogous to the process described for methyl 4- {bis [(3-chloropropyl) sulfonyl] amino) -1-ethyl-1H-indole-6-carboxylate (D236). [M + H]⁺ = 500.3, TR =

3.20 minutes

Description 240

4- {1- (3-Chloropropyl) sulfonyl] amino} -1-ethyl-1H-indole-6-carboxylic acid (D240)

To a solution of methyl 4- {bis [(3-chloropropyl) sulfonylamino} -1-ethyl-1H-indole-6-carboxylate (D236) (1.8

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157 g, 3.6 mmol, 1 equiv) in MeOH (100 mL) was added an aqueous 2 N NaOH solution (20 mL, 40 mmol, excess) and the resulting mixture was stirred for 1 h. Most MeOH was removed in vacuo and the residue was partitioned between EtOAc and 2 N aqueous HCl solution. The two layers were separated and the aqueous phase was dried over MgSO4.₄ and concentrated in vacuo to give 4 - {[(3-chloropropyl) sulfonyl] amino} -1-ethyl-1A-indole-6-carboxylic acid (D240) (930 mg, 75%) as a brown oil which was used in next step without further purification.

Description 241

Methyl 4- {[(3-chloropropyl) sulfonyl] amino} -1-ethyl-1H-indole-6-carboxylate (D241)

Methyl 4- {[(3-chloropropyl) sulfonyl] amino} -1-ethyl-1H-indole-6-carboxylate (D241) was obtained from 4- {[(3-chloropropyl) sulfonyl] amino] -1- ethyl -1H-indole-6-carboxylic acid (D240) in a similar manner to that of Description 25 (D25). [M + H]⁺ = 359.2, RT = 3.12 minutes

Description 242

Ethyl 7 - {[((4-chlorobutyl) sulfonyl] amino} -3-ethyl-1H-indole-5carboxylate (D242)

To a solution of ethyl 7-amino-3-ethyl-1A-indole-5-carboxylate (D222) (150 mg, 0.65 mmol, 1 equiv.)

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158 In CH 2 Cl 2 (10 mL) at room temperature was added pyridine (115 µL, 1.42 mmol, 2.2 equiv), 4-chloro-1-butanesulfonyl chloride (D20) (259 mg, 1.36 mmol, 2, 1 equiv.) And DMAP (8 mg, 0.065 mmol, 0.1 equiv.) And the resulting mixture was stirred for 1 hour and then diluted with EtOAc and washed with 2N aqueous HCl and saturated aqueous chloride. sodium then dried over MgSO₄ and concentrated in vacuo to give ethyl 7 - {[(4-chlorobutyl) sulfonyl] amino} -3-ethyl-1H-indole-5-carboxylate (D242) (230 mg, 92%) as a purple oil which was used in the next step without further purification. [M + H]⁺ =

387.3, R T = 3.35 minutes

Description 243

Ethyl 7 - {[(3-chloropropyl) sulfonyl] amino} -3-ethyl-1H-indole-5carboxylate (D243)

Ethyl 7- {[(3-chloropropyl) sulfonyl] amino} -3-ethyl-1H-indole-5-carboxylate (D243) was obtained from

Ethyl 7-amino-3-ethyl-1H-indole-5-carboxylate (D222) in a similar manner to the procedure described for Description 242 (D242) using 3-chloro-1-propanesulfonyl chloride instead of 4-chloro-1-butanesulfonyl (D20). [M + H]⁺ = 373.0, RT = 3.49 minutes

Description 244

3,4-Diamino-5-nitrobenzoic acid (D244)

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To a solution of 4-amino-3,5-dinitrobenzoic acid (10 g, 44 mmol, 1 equiv.) In DME (100 mL) and CHCl 3 (10 mL under nitrogen) was added 10% palladium on carbon (50% 1 g, 5% w / w) and the resulting suspension was stirred under an atmosphere of nitrogen (35 psi) for 15 h. 10% Palladium on carbon (50% wet, 1 g, 5% w) was added. (p) and the resulting suspension was stirred under a hydrogen atmosphere (35 psi) for a further 15 hours. The catalyst was filtered off through a pad of celite and the solution was concentrated in vacuo to give 3,4-diamino-5-nitrobenzoic acid (D244) (9.85 g, 113%) as a red solid which was used. in the next step without further purification. [MH] = 196.1, R T = 2.15 minutes

Description 245

Methyl 3,4-diamino-5-nitrobenzoate (D245)

Methyl 3,4-diamino-5-nitrobenzoate (D245) was prepared in a manner analogous to that of Description 25 from 3,4-diamino-5-nitrobenzoic acid (D244). [M + H]⁺ =

212.2, R T = 2.40 minutes

Description 246

Methyl 4-nitro-1H-1,2,3-benzotriazole-6-carboxylate (D246)

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To a solution of methyl 3,4-diamino-5-nitrobenzoate (D245) (2.5 g, 12 mmol, 1 equiv.) In AcOH (10 mL) at room temperature was added NaNO.₂ (900 mg, 13 mmol, 1.1 equiv.) And the resulting mixture was stirred at 60 ° C for 1 hour, cooled to room temperature and concentrated in vacuo. The residue was partitioned between EtOAc and 5% citric acid solution and the layers separated. The organic phase was washed with brine, dried over MgSO4.₄ and concentrated in vacuo. The trituration of the residue in Et₂Isohexane gave methyl 4-nitro-1H-1,2,3-benzotriazole-6-carboxylate (D2 46) (2.08 g, 78%) as an orange solid as it was used. in the next step without further purification. [M + H]⁺ =

223.3, R T = 2.31 minutes

Description 247

Methyl 4-amino-1H-1,2,3-benzotriazolo-6-carboxylate (D247)

Methyl 4-amino-1H-1,2,3-benzotriazolo-6-carboxylate (D247) was obtained from methyl 4-nitro-1H-1,2,3benzotriazolo-6-carboxylate (D246) in a similar manner. analogous to the process described for methyl 5-amino-2-fluoro-3- (2oxo-1-pyrrolidinyl) benzoate (D150). [M + H]⁺ =

193.3, R T = 2.01 minutes

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Description 248

Methyl 4 - [(4-chlorobutanoyl) amino] -1H-1,2,3-benzotriazolo-6carboxylate (D248)

Methyl 4 - [(4-chlorobutanoyl) amino] -1H-1,2,3-benzotriazolo-6-carboxylate (D248) was obtained from 4-amino-1 H -1,2,3-benzotriazolo-6-carboxylate of methyl (D247) in a similar manner to the process described for Description 2 (D2). Without molecular ion, RT = 3.19 minutes

Description 249

Methyl 4- (2-oxo-1-pyrrolidinyl) -1H-1,2,3-benzotriazole-6carboxylate (D249)

Methyl 4- (2-oxo-1-pyrrolidinyl) -1H-1,2,3-benzotriazolo6-carboxylate (D249) was obtained from 4 [(4-chlorobutanoyl) amino] 2,3-benzotriazolo-6-one methyl carboxylate (D248) in a manner analogous to the process described for Ester 27 (B27). [M + H]⁺ = 261.2, RT = 2.25 minutes

Description 250

Methyl 4-nitro-1H-benzimidazole-6-carboxylate (D250)

A 3,4-diamino-5-nitrobenzoate solution of

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162 Methyl (D245) (1.3 g, 6.16 mmol, 1 equiv.) in HCOOH (20 mL) was stirred at 100 ° C for 1 hour and then cooled to room temperature and concentrated in vacuo. The residue was partitioned between EtOAc and 2 N aqueous NaOH solution and the layers separated. The organic phase was dried over MgSO4.₄ and concentrated in vacuo to give methyl 4-nitro-1H-benzimidazole-6-carboxylate (D250) (1.5 g, 110%) as a light brown solid which was used in the next step without further purification. [M + H]⁺ =

222.3, R T = 2.29 minutes

Description 251

Methyl 4-amino-1H-benzimidazole-6-carboxylate (D251)

Methyl 4-amino-1H-benzimidazole-6-carboxylate (D251) was obtained from methyl 4-nitro-1H-benzimidazole-6carboxylate (D250) in a similar manner to the procedure described for 5-amino-2- methyl fluoro-3- (2-oxo-1-pyrrolidinyl) benzoate (D150). [M + H]⁺ = 192.3, RT = 1.55 minutes

Description 252

Methyl 4 - {[(4-chlorobutyl) sulfonyl] amino} -1H-benzimidazole-6carboxylate (D252)

To a solution of 4-amino-1H-benzimidazole-6-carΡΕ1567488

163 methyl boxylate (D251) (1.1 g, 5.76 mmol, 1 equiv.) in

At room temperature CH 2 Cl 2 (80 mL) was added pyridine (1.02 mL, 12.67 mmol, 2.2 equiv), 4-chloro-butanesulfonyl chloride (D20) (2.31 g, 12.1 mmol , 2.1 equiv.) And

DMAP (704 mg, 5.76 mmol, 1 equiv.) And the resulting mixture was stirred for 1 hour and then concentrated in vacuo. The residue was diluted with EtOAc and the organic phase was washed with 2 N aqueous HCl solution and brine, then dried over MgSO4.₄ and concentrated in vacuo. Purification of the residue by silica gel flash chromatography (EtOAc / isohexane: 2/3) gave methyl 4 - {[(4-chlorobutyl) sulfonyl] amino} -1H-benzimidazole-6-carboxylate (D252) ( 1 g, 50%) as a colorless oil. [M + H]⁺ = 346.1, RT = 2.97 minutes

Description 253

Methyl 4- (1,1-dioxide-tetrahydro-2H-1,2-thiazin-2-yl) -1H-benzimidazole-6-carboxylate (D253)

To a solution of methyl 4- {[(4-chlorobutyl) sulfonyl] amino} -1H-benzimidazole-6-carboxylate (D252) (1 g, 3.23 mmol, 1 equiv) in EtOH (50 mL) was added NEt₃HCl (2 mL, excess) and the resulting solution was stirred at 70 ° C for 2 days and then cooled to room temperature and concentrated in vacuo. The residue was dissolved in EtOAc and the organic phase was washed with a 5% aqueous citric acid solution. The aqueous phase was saturated with NaCl and extracted twice with EtOAc. The phases

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164 Organic extracts were dried over MgSO4.₄ and concentrated in vacuo. Purification of the residue by silica gel flash chromatography (CH₂Cl₂(MeOH: 96/4 to 90/10) gave methyl 4- (1,1-dioxide-tetrahydro-2H-1,2-thiazin-2-yl) -1H-benzimidazole-6-carboxylate (D253) (250 mg, 25%) as a light yellow solid. [M + H]⁺ = 310.3, RT = 2.11 minutes

Description 254

Methyl 4-hydroxy-3,5-diiodobenzoate (D254)

Methyl 4-hydroxy-3,5-diiodobenzoate (D254) was prepared in a manner analogous to that of Description 25 (D25) from commercially available 4-hydroxy-3,5-diiodobenzoic acid.

Description 255

Methyl 4 - [(2E / Z) -2-buten-1-yloxy] -3,5-diiodobenzoate (D255)

To a solution of methyl 4-hydroxy-3,5-diiodobenzoate (D254) (26.9 g, 66.7 mmol, 1 equiv) in acetone (250 mL) at room temperature was added K₂CO 3 (13.8 g, 100 mmol, 1.5 equiv) and 1-bromo-2-butene (8.25 mL, 80 mmol, 1.2 equiv) and the resulting suspension was stirred at 55 ° C for 15 hours and then cooled to room temperature and concentrated in vacuo. The residue was partitioned between AcOEt and H₂O and the two layers were separated. THE

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165 The organic phase was washed with 2 N aqueous NaOH solution and brine, dried over MgSO4.₄ and concentrated in vacuo to give methyl 4 - [(2E / Z) -2-buten-liloxy] -3,5-diiodobenzoate (D255) (28.6 g, 94%) as a white solid which was used in step following without further purification.

Description 256

Methyl 3,5-diiodo-4- (2-propen-1-yloxy) benzoate (D256)

Methyl 3,5-diiodo-4- (2-propen-1-yloxy) benzoate (D256) was obtained from methyl 4-hydroxy-3,5-diiodobenzoate (D254) in a similar manner to the procedure described. 255 (D255) using 3-bromo-lpropene instead of 1-bromo-2-butene.

Description 257

Methyl 4- (3-buten-1-yloxy) -3,5-diiodobenzoate (D257)

Methyl 4- (3-buten-1-yloxy) -3,5-diiodobenzoate (D257) was obtained from methyl 4-hydroxy-3,5-diiodobenzoate (D254) in a similar manner to the process described for Description 255 (D255) using 4-bromo-lbutene instead of 1-bromo-2-butene. [M + H]⁺ = 458.8, TR = 4.05 minutes

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Description 258

Methyl 4 - [(2E / Z) -2-buten-1-yloxy] -3-iodo-5- (2-oxo-1-pyrrolidinyl) benzoate (D258)

To a solution of methyl 4 - [(2E / Z) -2-buten-1-yloxy] -3,5diiodobenzoate (D255) (5 g, 11 mmol, 1 equiv) in toluene (50 mL) was added 2-pyrrolidinone (1.08 g, 13 mmol, 1.2 equiv.), K₃POWDER₄ (4.46 g, 21 mmol, 2 equiv.), Cul (105 mg, 0.55 mmol, 0.05 equiv.) And dimethyl ethylene diamine (117 µL, 1.1 mmol, 0.1 equiv.) And The resulting mixture was stirred at 100 ° C for 15 hours and then cooled to room temperature and concentrated in vacuo. The residue was partitioned between AcOEt and H₂O and the layers were separated. The organic phase was dried over MgSO4.₄ and concentrated in vacuo. Purification of the residue by silica gel flash chromatography (EtOAc / isohexane: 1/1) gave 4 - [(2E / Z) -2-buten-1-yloxy] -3-iodo-5- (2- methyl oxo-pyrrolidinyl) benzoate (D258) (1.4 g, 31%) as a colorless oil. [M + H]⁺ = 415.9, TR = 3.27 minutes

Description 259

Methyl 3-iodo-5- (2-oxo-1-pyrrolidinyl) -4- (2-propen-1-yloxy) benzoate (D259)

Methyl 3-iodo-5- (2-oxo-1-pyrrolidinyl) -4- (2-propenyloxy) benzoate (D259) was obtained from 3,5ΡΕ1567488

167 methyl diiodo-4- (2-propen-1-yloxy) benzoate (D256) in a similar manner to the procedure described for Description 258 (D258).

Description 260

Methyl 4- (3-buten-1-yloxy) -3-iodo-5- (2-oxo-1-pyrrolidinyl) benzoate (D260)

Methyl 4- (3-buten-1-yloxy) -3-iodo-5- (2-oxo-1-pyrrolidinyl) benzoate (D260) was obtained from 4- (3-buten-1-yloxy) - Methyl 3,5-diiodobenzoate (D257) in a similar manner to the process described for Description 258 (D258). [M + H]⁺ = 416.0, TR = 3.02 minutes

Description 261

Methyl 4-methyl-8- (2-oxo-1-pyrrolidinyl) -2H-chromene-6-carboxylate and 4- (ethyloxy) -3- [ethyl (propanoyl) amino] -5- (1-methylethenyl) benzoate methyl (D261)

Methyl 4-methyl-8- (2-oxo-1-pyrrolidinyl) -2H-chromene-6carboxylate and methyl 4- (ethyloxy) -3- [ethyl (propanoyl) amino] -5- (1-methylethenyl) benzoate (D261) were obtained from methyl 4- (3-buten-1-yloxy) -3-iodo-5- (2-oxo-1-pyrrolidinyl) benzoate (D260) in a similar manner to the procedure described for 3- methyl-7- (2-oxo-1-pyrrolidinyl) -1-benzofuran-5-carboxylate (B163). [M + H]⁺ = 288.1, TR = minutes

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Description 262

Methyl 3-bromo-5- (1,1-dioxide-2-isothiazolidinyl) benzoate (D262)

Methyl 3-bromo-5- (1,1-dioxide-2-isothiazolidinyl) benzoate (D262) was obtained from methyl 3-bromo-5iodobenzoate (D8a) in a similar manner to the procedure described for Description 17. (D17) using D8a instead of D8b as a starting material.

Description 263

Methyl 3-bromo-5- (1,1-dioxide-tetrahydro-2H-1,2-thiazin-2yl) benzoate (D263)

Methyl 3-bromo-5- (1,1-dioxide-tetrahydro-27-1,2-thiazin2-yl) benzoate (D263) was obtained from methyl 3-bromo-5-iodobenzoate (D8a) in an analogous manner that of the process described for Description 18 (D18) using D8a instead of D8b as a starting material.

Description 264

Methyl 3- (3-cyclopenten-1-yl) -5- (1,1-dioxide-2-isothiazolidinyl) benzoate;

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Methyl 3- (2-cyclopenten-1-yl) -5- (1,1-dioxide-2-isothiazolidinyl) benzoate;

Methyl 3- (1-cyclopenten-1-yl) -5- (1,1-dioxide-2-isothiazolidinyl) benzoate (D264)

Methyl 3- (3-cyclopenten-1-yl) -5- (1,1-dioxide-2-isothiazolidinyl) benzoate, 3- (2-cyclopenten-1-yl) -5- (1,1-dioxide-2- methyl isothiazolidinyl) benzoate and methyl 3- (Ιοί c lopen-en-1-1) -5- (1,1-dioxide-2-isothiazolidinyl) benzoate (D264) were obtained from 3-bromo-5 - (methyl (1,1-dioxide-2-isothiazolidinyl) benzoate (D262) in a similar manner to the process described for Description 73 (D73)

Description 265

Methyl 3- (1-cyclopenten-1-yl) -5- (1,1) -dioxidotetrahydro-2H1,2-thiazin-2-yl) benzoate;

Methyl 3- (2-cyclopenten-1-yl) -5- (1,1) -dioxidotetrahydro-2H1,2-thiazin-2-yl) benzoate;

Methyl 3- (3-cyclopenten-1-yl) -5- (1,1) -dioxydetetrahydro-2H1,2-thiazin-2-yl) benzoate (265)

Methyl 3- (1-cyclopenten-1-yl) -5- (1,1) -dioxydetetrahydro-2 H -1,2-thiazin-2-yl) benzoate, 3- (2-cyclopenten-1-yl) 5- (1,1) -dioxydetetrahydro-2H-1,2-thiazin-2β1567488

170 yl) methyl benzoate and methyl 3- (3-cyclopenten-1-yl) -5- (1,1) dioxide tetrahydro-2 H -1,2-thiazin-2-yl) benzoate (265) were obtained from from methyl 3-bromo-5- (1,1-dioxide-tetrahydro-2H-1,2-thiazin-2-yl) benzoate (D263) in a similar manner to the procedure described for Description 73 (D73).

Description 266

Methyl 3- (1,1-dioxide-tetrahydro-2H-1,2-thiazin-2-yl) -5-nitrobenzoate (D266)

Methyl 3- (1,1-dioxide-tetrahydro-2H-1,2-thiazin-2-yl) -5-nitrobenzoate (D266) was obtained from 3-bromo-5-nitrobenzoate (D11) in a manner analogous to the procedure described. to Description 15 (D15) using the

Description 22b (D22b) instead of Description D22a (D22a).

Description 267

Methyl 3-amino-5- (1,1-dioxide-tetrahydro-2H-1,2-thiazin-2yl) benzoate (D267)

Methyl 3-amino-5- (1,1-dioxide-tetrahydro-2 H -1,2-thiazin-2-yl) benzoate (D267) was obtained from 3- (1,1-dioxide-tetrahydro-2H-1, Methyl 2-thiazin-2-yl) -5-nitrobenzoate (D266) in a similar manner to the process described for Description 16 (D16).

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Description 268

Methyl 3- (1,1-dioxide-tetrahydro-2H-1,2-thiazin-2-yl) -5-hydroxybenzoate (D268)

To a solution of methyl 3-amino-5- (1,1-dioxide tetrahydro-2H-1,2-thiazin-2-yl) benzoate (D267) (7.5 g,

26.4 mol, 1 equiv) in 2N aqueous HCl (75 mL) and MeOH (75 mL) at 0 ° C was added NaNO₂ (4.0 g, 58.1 mmol, 2.2 equiv.) In portions over 20 minutes. MeOH (50 mL) and H₂O (200 mL) and the resulting mixture was stirred at 95 ° C for 1 hour and then cooled to room temperature. Most of the MeOH was removed in vacuo and the resulting aqueous phase was extracted with EtOAc. Insoluble material was filtered off to give methyl 3- (1,1-dioxide-tetrahydro-2H-1,2-thiazin-2-yl) -5-hydroxybenzoate (0.63 g, 8%). The organic phase was washed with brine, dried over MgSO4.₄ and concentrated in vacuo to give a brown residue which was redissolved in EtOAc. The organic phase was extracted with a saturated aqueous Na₂CO 3 and the aqueous phase was extracted three times with Et₂The then was acidified to pH 1 and reextracted three times with EtOAc. The combined organic phases were washed with brine, dried over MgSO4.₄ and concentrated in vacuo to give methyl 3- (1,1-dioxide-tetrahydro-2H-1,2-thiazin-2-yl) -5-hydroxybenzoate (D268) (2.2 g, 30%).

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Description 269

Methyl 5- (1-cyclopenten-1-yl) -3- (1,1-dioxide-tetrahydro-2H1,2-thiazin-2-yl) -2-fluorobenzoate; Methyl 5- (2-cyclopenten-1-yl) -3- (1,1-dioxide-tetrahydro-2H-1,2-thiazin-2-yl) -2-fluorobenzoate; Methyl 5- (3-cyclopenten-1-yl) -3 (1,1-dioxide-tetrahydro-2H-1,2-thiazin-2-yl) -2-fluorobenzoate (D269)

Methyl 5- (1-cyclopenten-1-yl) -3- (1,1-dioxide-tetrahydro-2H-1,2-thiazin-2-yl) -2-fluorobenzoate; Methyl 5- (2-cyclopenten-1-yl) -3- (1,1-dioxide-tetrahydro-2 H -1,2-thiazin-2-yl) -2-fluorobenzoate; Methyl 5- (3-cyclopenten-1-yl) -3- (1,1-dioxide-tetrahydro-2 H -1,2-thiazin-2-yl) -2-fluorobenzoate (D269) was obtained from of Description 158 (D158) in a manner analogous to the process described for Description 73 (D73)

Description 270

Ethyl 2-methyl-2- [3- (trifluoromethyl) phenyl] propanoate (D270)

Ethyl 2-methyl-2- [3- (trifluoromethyl) phenyl] propanoate (D270) was obtained from ethyl [3- (trifluoromethyl) phenyl] acetate in a manner similar to the procedure described for Description 98 (D98). ).

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Description 271

2-Methyl-2- [3- (trifluoromethyl) phenyl] propanoic acid (D271)

2-Methyl-2- [3- (trifluoromethyl) phenyl] propanoic acid (D271) was obtained from ethyl 2-methyl-2- [3- (trifluoromethyl) phenyl] propanoate (D270) in a similar manner to that of described for Description 99 (D99).

Description 272 phenylmethyl {1-methyl-1- [3- (trifluoromethyl) phenyl] ethyl} carbamate (D272) phenylmethyl {1-methyl-1- [3- (trifluoromethyl) phenyl] ethyl] carbamate (D272) was obtained from 2-methyl-2- [3- (trifluoromethyl) phenyl] propanoic acid (D271) in a similar manner to the process described for Description 100 (D100).

Description 273

2 - ({[(1,1-Dimethylethyl) oxylcarbonyl} amino) -2-methylpropyl methanesulfonate (D273)

To a solution of 1,1-dimethylethyl (2-hydroxy-1,1-dimethylethyl) carbamate (5.1 g, 27 mmol, 1 equiv.) In CH₂C1₂ (100 mL) at room temperature was added NEt₃

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174 (11.3 mL, 81mmol, 3 equiv.) And methanesulfonyl chloride (28.3 mmol, 2.2 mL, 1.05 equiv.) And the resulting solution was stirred for 2 hours and then partitioned between EtOAc and a saturated aqueous NaHCO solution₃. The two layers were separated and the organic phase dried over MgSO4.₄and concentrated in vacuo to give 2 - ({[(1,1-dimethylethyl) oxy] carbonyljamino) -2-methylpropyl methanesulfonate (D273) (7.8 g, 108%) as a yellow oil which was used in the next step without more purification.

Description 274 1,1-Dimethylethyl [1,1-dimethyl-2- (phenyloxy) ethyl] carbamate (D274)

To a solution of phenol (2.1 g, 22.4 mmol, 3 equiv.) In DMF (10 mL) at room temperature was added NaH (60% dispersion in mineral oil, 360 mg, 9.0 mmol, 1.2 equiv.) And after 10 min 2 - ({[(1,1-dimethylethyl) oxy] carbonyl} amino) -2-methylpropyl methanesulfonate (D273) (2 g,

7.5 mmol, 1 equiv.) And the resulting solution was stirred at 50 ° C for 2 hours and then cooled to room temperature and concentrated in vacuo. Purification of the residue by silica gel flash chromatography (isohexane / AcOEt: 9/1 to 6/1) gave 1,1-dimethylethyl [1,1-dimethyl-2- (phenyloxy) ethyl] carbamate (D274 ) (180 mg, 9%) as a yellow oil.

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Description 275 1,1-dimethylethyl 1,1-dimethyl-2 - [(phenylmethyl) oxyethyl} carbamate (D275) {1,1-dimethyl-2 - [(phenylmethyl) oxyethyl} carbamate

1,1-Dimethylethyl (D2 75) was prepared from 2 - ({[(1,1-dimethylethyl) oxy] carbonyl} amino) -2-methylpropyl methanesulfonate (D273) in a similar manner to [1,1-dimethylethyl] 1,1-dimethylethyl dimethyl 2- (phenyloxy) ethyl] carbamate (D274) using phenylmethanol instead of phenol.

Description 276 {1,1-dimethyl-2 - [(2-methylpropyl) thiolethyl} carbamate

1,1-dimethylethyl 1,1-dimethyl (1,1-dimethyl-2 - [(2-methylpropyl) thiolethyl} carbamate (D276) was prepared from 2 - ({[(1, 1-dimethylethyl) oxy] carbonyl} amino) 2-methylpropyl (D273) in a similar manner to 1,1-dimethylethyl [1,1-dimethyl-2- (phenyloxy) ethyl] carbamate (D274) using 2-methyl -1-propanethiol instead of phenol.

Description 277 1,1-Dimethylethyl (4,4-difluorocyclohexyl) carbamate (D277)

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To a solution of (4-oxocyclohexyl) carbamate of

1,1-Dimethylethyl (1 g, 4.69 mmol, 1 equiv.) In CH 2 Cl 2 (15 mL) was added DAST (1.05 mL, 7.98 mmol, 1.7 equiv) and the resulting mixture was stirred for 15 hours. A saturated aqueous NaHCO solution was added.₃ and the resulting biphasic mixture was stirred vigorously for 1 hour. The two layers were separated and the aqueous phase was extracted with CH₂C1₂. The combined organic phases were dried over MgSO4 and concentrated in vacuo to give 1,1-dimethylethyl (4,4difluorocyclohexyl) carbamate (D277) (1.03 g, 93%) as a beige solid which was used in the next step. without further purification.

Descriptions 278-281 (D278-281)

The following acids were obtained by alkylation of cyclobutanecarboxylic acid as described in: K. Tani, A. Naganawa, A. Ishida, K. Sagawa, H. Harada, M. Ogawa, T Maruyama, S. Ohuchida, H. Nakai, K Kondo, M. All Βίο. Med. Chem. 2002, 10, 1093-1106:

description

1-Texycyclobutanecarboxylic acid (D278)

1-Propylcyclobutanecarboxylic acid (D279)

1- (1-Methylethyl) cyclobutanecarboxylic acid (D280)

1 - [(3-chlorophenyl) methyl] cyclobutanecarboxylic acid (D281)

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Descriptions 282-285 (D282-285)

The following compounds were obtained from their precursors in a manner analogous to the process described for Description 100 (D100):

<td>description</td><td>Precursor</td>

<td>Phenylmethyl (1-ethylcyclobutyl) carbamate (D2 82)</td><td>D278</td>

<td>Phenylmethyl (1-propylcyclobutyl) carbamate (D283)</td><td>D279</td>

<td>[1- (1-methylethyl) cyclobutyl] carbamate phenylmethyl (D284)</td><td>D280</td>

<td>{1 - [(3-chlorophenyl) methyl] cyclobutyl} carbamate phenylmethyl (D285)</td><td>D281</td>

Descriptions 286-293 (D286-293)

The following amides were obtained by a Ritter reaction as described in: M. Mousseron Buli. Soc. Chim. Fr. 1957, 596 .:

<td>description</td><td>Precursor</td>

<td>N- (1-Methylcyclohexyl) acetamide (D286)</td><td></td>

<td>N- (1-Ethylcyclohexyl) acetamide (D287)</td><td>no HS -</td>

<td>N- (1-Methylcyclopentyl) acetamide (D288)</td><td></td>

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<td>description</td><td>Precursor</td>

<td>N- (1-Propylcyclopentyl) acetamide (D289)</td><td></td>

<td>N- (1-Propylcyclohexyl) acetamide (D290)</td><td></td>

<td>N- (1,1-Dimethyl-hexyl) acetamide (D291)</td><td></td>

<td>N- [2- (3-Chlorophenyl) -1,1-dimethylethyl] acetamide (D292)</td><td></td>

<td>N- {1,1-Dimethyl-2- [3- (methyloxy) phenyl] ethyl} - acetamide (D293)</td><td></td>

4,4-Dimethylcyclohexanone (D294) was obtained from 4,4-dimethyl-2-cyclohexen-1-one in a similar manner to the procedure described for Ester 116 (B116).

Description 295

3,3-Dimethylcyclopentanone (D2 95)

3,3-Dimethylcyclopentanone (D295) was obtained from 4,4-dimethyl-2-cyclopenten-1-one in a similar manner to the procedure described for 4,4-dimethylcyclohexanone (D294).

Description 296

4,4-Dimethylcyclohexanone oxime (D296)

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To a solution of 4,4-dimethylcyclohexanone (D294) (9.2 g, 73 mmol, 1 equiv.) In EtOH (50 mL) and H₂O (50 mL) was added NH₂OH.HCl (6.6 g, 94.5 mmol, 1.3 equiv.) And Na₂CO₃ (10.06 g, 94.5 mmol, 1.3 equiv.) And the resulting cloudy solution was heated at reflux for 2 hours and then cooled to room temperature. Most of the EtOH was removed in vacuo and the aqueous phase was extracted twice with EtOAc. The combined organic phases were dried over MgSO4.₄ and concentrated in vacuo to give 4,4-dimethylcyclohexanone oxime (D296) (10 g, 97%) as a colorless solid which was used in the next step without purification.

Descriptions 297-298 (D297-298)

The following oximes were obtained from their precursors in a manner analogous to the process described for Description (D296).

<td>description</td><td>Precursor</td>

<td>(1E / Z) -2,2-Dimethylcyclohexanone oxime (D297)</td><td>D294</td>

<td>(1E / Z) -3,3-Dimethylcyclohexanone oxime (D298)</td><td>D295</td>

Descriptions 299-311 (D299-311)

The following compounds were obtained from (25) -2- (1-methylethyl) -3,6-bis (methyloxy) -2,5-dihydropyrazine according to the general procedure described in: P. dalla Croce, C. la Rosa, E. Pizzatti Tetrahedron: Asymmetry 2000, 11, 2635-2642:

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<td>description</td>

<td>3,5-Difluoro-L-phenylalaninate (D299)</td>

<td>3-Fluoro-L-phenylalaninate (D300)</td>

<td>3,4-Difluoro-L-phenylalaninate (D301)</td>

<td>2-Chloro-L-phenylalaninate (D302)</td>

<td>Methyl 3-chloro-L-phenylalaninate (D303)</td>

<td>Methyl 4-chloro-L-phenylalaninate (D304)</td>

<td>Methyl 3- (2-thienyl) -L-alaninate (D305)</td>

<td>Methyl 3- (3-thienyl) -L-alaninate (D306)</td>

<td>Methyl 3- (2-furanyl) -L-alaninate (D307)</td>

<td>Methyl 3- (2-pyridinyl) -L-alaninate (D308)</td>

<td>Methyl 3- (1,3-thiazol-2-yl) -L-alaninate (D309)</td>

<td>Methyl 3- (1H-pyrazol-1-yl) -L-alaninate (D310)</td>

<td>Methyl 3- (3-pyridinyl) -L-alaninate (D311)</td>

Descriptions 312-313 (D312-313)

Descriptions 312-313 were prepared analogously to Example 1 from the appropriate acid and amines as indicated in the table below:

<td>description</td><td>Acid</td><td>The mine</td><td>[M + H]⁺</td><td>RT (min)</td>

<td>3- (1,1-dioxide-6,7-dihydro-1,2- thiazepin-2 (3Η) -1) -N - [(IS, 2R) -2- hydroxy-1- (phenylmethyl) -3 - ({[3- (trifluoromethyl) phenyl] methyl} - amino) propyl] -5-propylbenzamide (D312)</td><td>A117</td><td>C16</td><td> 630, 4</td><td> 2, 89</td>

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<td>description</td><td>Acid</td><td>The mine</td><td>[M + H]⁺</td><td>RT (min)</td>

<td>3- (1,1-dioxide-6,7-dihydro-1,2- thiazepin-2 (3H) -yl) -N - [(IS, 2R) -2- hydroxy-3 - ({[3- (methyloxy) phenyl] - methyl) amino) -1- (phenylmethyl) pro- pil] -5-propylbenzamide (D313)</td><td>A117</td><td> 04</td><td> 592, 4</td><td> 2, 75</td>

Description 314

1- [3- (Methyloxy) phenyl] cyclohexanol (D314)

To a solution of 3-methoxyphenyl magnesium bromide (1 M in THF, 61 mL, 61 mmol, 1 equiv) at 0 ° C was slowly added cyclohexanone (6 g, 61 mmol, 1 equiv) in Et₂O (30 mL). The resulting mixture was stirred at room temperature for 4 hours and then poured into H₂O at 0 ° C. The two layers were separated and the aqueous phase was extracted three times with Et₂The combined organic phases were washed with brine, dried over MgSO4.₄ and concentrated in vacuo to give 1- [3- (methyloxy) phenyl] cyclohexanol (D314) (12.4 g, 100%) as a light yellow oil which was used in the next step without further purification.

Description 315

1- (1-Azidocyclohexyl) -3- (methyloxy) benzene (D315)

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To a solution of 1- [3- (methyloxy) phenyl] cyclohexanol (2.93 g, 14.22 mmol, 1 eguiv.) In CH₂C1₂ (25 mL) under nitrogen at 0 ° C was added sodium azide (1.85 g, 28.44 mmol, 2 eguiv.) Then TFA (4.4 mL, 56.89 mmol, 4 eguiv.) Slowly. . 40 ml CH₂C1₂ and the resulting suspension was stirred at room temperature for 16 hours and then partitioned between Et₂O and H₂O. The two layers were separated and the organic phase was washed with H₂O is an aqueous 1 N NaOH solution and then dried over MgSO4.₄ and concentrated in vacuo to give 1- (1-azidocyclohexyl) -3- (methyloxy) benzene (D315) (2.78 g, 85%) as a clear oil which was used in the next step without further purification.

Description 316 (1E / Z) -Propanal oxime (D316) (1E / Z) -Propanal oxime was obtained from propanal in a similar manner to the procedure described for Description 296 (D296).

Description 317

1,1-dimethylethyl 2-propyn-1-ylcarbamate (D317)

To a solution of 2-propyn-1-amine (2 g, 36.4 mmol, 1 eguiv.) In CH₂C1₂ (20 mL) was added NEt₃ (5.3 mL,

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38.18 mmol, 1.05 equiv.) And bis (1,1-dimethylethyl) dicarbonate (8.32 g, 38.18 mmol, 1.05 equiv.). The resulting mixture was stirred at room temperature for 3 hours and then poured into 2N aqueous HCl solution. The two layers were separated and the organic phase was washed with a saturated aqueous NaHCO3 solution and then dried over MgSO4.₄ and concentrated in vacuo to give 1,1-dimethylethyl 2-propin-1-yl carbamate (D317) (4.05 g, 72%) as a colorless crystal.

Description G33

((IS, 2R) -2-Hydroxy-lysobutylcarbamoyl-pentyl) -carbamic acid tert-butyl ester (G33)

(2S, 3R) -2-tert-Butoxycarbonylamino-3-hydroxyhexanoic acid methyl ester (D94) (1.57 g, 6.02 mmol, 1 equiv) was refluxed in iso-butylamine (10 mL) The solution was concentrated in vacuo and the residue was purified by silica gel flash chromatography to give ((IS, 2R) -2-hydroxy-lisobutylcarbamoyl-pentyl) -carbamic acid tert-butyl ester (G33) ( 1.52g, 84%) as a white solid.

The following compounds were obtained in a manner analogous to Description 96a using the appropriate commercially available acid and amine:

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Name

[(S) -1-Cyclohexylcarbamoyl-3-methylsulfanyl-propyl) -carbamic acid tert-butyl ester (G6)

[(S) -1- (3,3-Dimethylbutylcarbamoyl) ethyl] carbamic acid tert-butyl ester (G36)

Description G38

((S) -1-Isobutylcarbamoyl3-methanesulfonyl-propyl) -carbamic acid tert-butyl ester (G38)

((S) -1-Isobutylcarbamoyl-3-methylsulfanyl-propyl) -carbamic acid tert-butyl ester (D96) (1.19 g,

3.9 mmol, 1 equiv.) In CH₂C1₂ (25 mL) at 0 ° C was added m-chloroperbenzoic acid (50-55%, 4.0 g, 11.6 mmol, 3 equiv) in portions. The resulting mixture was stirred for 2 hours at 0 ° C and then diluted with AcOEt and washed with saturated aqueous NaHCO 3 solution, dried over MgSO 4 and concentrated in vacuo to give ((S) -1- isobutylcarbamoyl-3-methanesulfonyl-propyl) -carbamic (G38) (1.06 g, 81%) as a colorless solid.

Description G157 1,1-Dimethylethyl [(3-ethyl-5-isoxazolyl) methyl] carbamate (G157)

To a solution of (1E / Z) -propanal oxime (D316) (4 g, 54.8 mmol, 1 equiv.) In CH₂C1₂ (200 mL) at room temperature

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185 N-chloro succinamide (7.44 g, 55.8 mmol, 1.02 equiv) was added to the environment and the resulting solution was stirred at this temperature for 2.5 hours and then NEt was added.₃ HCl (20 mL, excess) and the resulting mixture was stirred for 2 hours. DIPEA (9.52 mmol, 55.8 mmol, 1.02 equiv) and 1,1-dimethylethyl 2-propyn-1-yl carbamate (D317) (1.34 g, 8.76 mmol, 0.16 equiv.) And the solution was stirred for 48 hours and then poured into 1 M aqueous HCl solution. The two layers were separated and the organic phase was washed with a saturated aqueous NaHCO solution.₃ and then dried over MgSO₄ and concentrated in vacuo. Purification of the residue by silica gel flash chromatography (isohexane / AcOEt: 4/1 to 3/1) gave 1,1-dimethylethyl [(3-ethyl-5-isoxazolyl) methyl] carbamate (G157) ( 1.28 g, 63%).

Description F5

1,1,5-Trimethylhexylamine (F5)

Description F5 was obtained according to SS Berg and DT Cowling, J. Chem. Soc. (C) 1971, 1653-1658.

Description F33

(2S, 3R) -2-Amino-3-hydroxyhexanoic acid hydrochloride salt (F33)

(2S, 3R) -2-tert-Butoxycarbonic acid ester1567488

186 bonylamino-3-hydroxyhexanoic (G33) (235 mg, 0.86 mmol, 1 eguiv.) was dissolved in 4 M HCl in dioxane (4 mL) and the solution was stirred for 1 hour at room temperature and then stirred. concentrated in vacuo. The residue was triturated with Et₂O to give (2S, 3R) -2amino-3-hydroxyhexanoic acid hydrochloride salt (F33) (176 mg, 95%) as a white solid.

The following compounds (as well as their hydrochloride salts) were obtained from the appropriate precursors as indicated in the table below in a manner analogous to that described for Description F33:

<td>Name</td><td>Precursor</td>

<td>(S) -2-Amino-N-cyclohexyl propionamide (F6)</td><td>G6</td>

<td>(S) -2-Aminohexanoic acid isobutyl amide</td><td>G36</td>

<td>(F36)</td><td></td>

Description F15

1- (3-Methoxy-phenyl) -1-methyl-ethylamine (F15)

A flask was charged with [1- (3-methoxy-phenyl) -1-methyl-ethyl] -carbamic acid benzyl ester (D100) (1 g, 3.34 mmol, 1 eiv.), 10% palladium over charcoal (50% wet, 100 mg, 10% w / w), NH₄COOH (2.1 g, 33 mmol, 10 eguiv.), EtOH (40 mL) and H₂O (8 mL). The resulting mixture was stirred at 80 ° C for 2 hours, cooled to room temperature and the catalyst was separated by

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187 filtration using a layer of celite. Most of the

EtOH was removed in vacuo and the residue was diluted with 1 N aqueous HCl solution. The aqueous phase was extracted with EtOAc and then basified to pH 13 and extracted twice with EtOAc. These combined organic layers were dried over MgSO4.₄ and concentrated in vacuo to give 1- (3-methoxy-phenyl) -1-methyl-ethylamine (F15) (290 mg, 53%) as a yellow gum.

Description F40

2- [3- (Trifluoromethyl) phenyl] -2-propanamine (F40)

2- [3- (Trifluoromethyl) phenyl] -2-propanamine (F40) was obtained from phenylmethyl {1-methyl-1- [3- (trifluoromethyl) phenyl] ethyl} carbamate (D272) in a similar manner to of the process described for Description F15 (F15).

Description F41 {1- [3- (Methyloxy) phenyl] cyclohexyl] amine (F41)

To a solution of 1- (1-azidocyclohexyl) -3 (methyloxy) benzene (D315) (2.78 g, 12.0 mmol, 1 equiv.) In

THF (20 mL) at room temperature was added LiAlH₄ (1 M in THF, 36 mL, 36 mmol, 3 equiv.) And the resulting mixture was stirred at this temperature for 4 hours. The mixture was then carefully quenched with 1 N aqueous NaOH solution (6 mL, 60 mmol, 1 equiv.) And then H₂O.

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188 The mixture was filtered through a pad of celite and then acidified with 2 N aqueous HCl (50 mL). The two layers were separated and the pH of the aqueous phase was adjusted to 9 using an aqueous 2 N NaOH solution. The aqueous phase was extracted three times with Et₂The combined organic phases were dried over MgSO4.₄ and then concentrated in vacuo to give {1- [3- (methyloxy) phenyl] cyclohexyl} amine (F41) (1.55 g, 63%) as a clear oil which was used for the next step without further purification. . [M + H]⁺ = 189.0, RT = 1.90 minutes.

Descriptions F48, F61, F81 and F110-114

The following amines were obtained from their corresponding amides in a manner analogous to the process described for Description F5 (F5):

<td>description</td><td>Precursor</td>

<td>2-Methyl-2-heptanamine (F48)</td><td>D291</td>

<td>2-Methyl-1- [3- (methyloxy) phenyl] -2-propanamine (F61)</td><td>D293</td>

<td>1-Methylcyclohexanamine (F81)</td><td>D286</td>

<td>1-Methylcyclohexanamine (F110)</td><td>D287</td>

<td>1-Methylcyclopentanamine (Flll)</td><td>D288</td>

<td>1-Propylcyclopentanamine (F112)</td><td>D289</td>

<td>1-Propylcyclohexanamine (F113)</td><td>D290</td>

<td>1- (3-Chlorophenyl) -2-methyl-2-propanamine (F114)</td><td>D292</td>

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Description F52

7- (Methyloxy) -1,2,3,4-tetrahydro-1-naphthalenamine (F52)

7- (Methyloxy) -1,2,3,4-tetrahydro-1-naphthalenamine (F52) was obtained from 7- (methyloxy) -3,4-dihydro1 (2H) -naphthalenone in a similar manner. analogous to the process described in US 4,121,737.

Descriptions F54-56 and F155

The following amines were prepared from their precursor in a manner analogous to the process described for Amine 1 (Cl):

<td>description</td><td>Precursor</td>

<td>2-Methyl-1 - [(2-methylpropyl)] thio] -2- hydrochloride propanamide (F54)</td><td>D276</td>

<td>2-Methyl-1- (phenyloxy) -2-propanamide Hydrochloride (F55)</td><td>D274</td>

<td>2-Methyl-1 - [(phenylmethyl) oxy] -2- hydrochloride propanamide (F56)</td><td>D275</td>

<td>4,4-Difluorocyclohexanamine hydrochloride (F155)</td><td>D277</td>

Descriptions F63, F73-75 and F77-80

The following amines were prepared from their corresponding nitriles according to the general method.

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190 described in: P. Bertus, J. Szvmoniak Chem. Comm. 2001,

1792:

<td>1- [3- (methyloxy) phenyl] cyclopropanamine (F63)</td><td></td>

<td>1- (4-methylpentyl) cyclopropanamine (F73)</td><td></td>

<td>1-ethylcyclopropanamine (F74)</td><td>'V</td>

<td>1- (1-methylethyl) cyclopropanamine (F75)</td><td></td>

<td>1-propylcyclopropanamine (F77)</td><td></td>

<td>1- (3-methylbutyl) cyclopropanamine (F78)</td><td></td>

<td>1- (2-methylpropyl) cyclopropanamine (F79)</td><td></td>

<td>1 - [(3-chlorophenyl) methyl] cyclopropanamine (F80)</td><td></td>

F69 and F148-150 Descriptions

The following compounds were obtained from their precursors in a manner analogous to the process described for Description F15 (F15):

<td>description</td><td>Precursor</td>

<td>1-Ethylcyclobutanamine (F69)</td><td>D282</td>

<td>1-Propylcyclobutanamine (F148)</td><td>D283</td>

<td>1-1-Methylethyl) cyclobutanamine (F149)</td><td>D284</td>

<td>1 - [(3-Chlorophenyl) methyl] cyclobutanamine (F150)</td><td>D285</td>

Description F70

2-Methyl-1 - [(2-methylpropyl) oxy] -2-propanamine (F70)

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191

2-Methyl-1 - [(2-methylpropyl) oxy] -2-propanamine (F70) was obtained from 2-Methyl-1 - [(2-methyl-2-propen1-yl) oxy] -2-propanamine (F71) in a manner analogous to the process described for Ester 166 (B116).

Description F71

2-Methyl-1 - [(2-methyl-2-propen-1-yl) oxy] -2-propanamine (F71)

To a solution of NaH (60% dispersion in mineral oil, 2.0 g, 50 mmol, 1 equiv.) In DMF at 0 ° C was added 2-amino-2-methyl-1-propanol (4.8 mL, 50 mmol, 1 equiv.) And after 1 hour 3-bromo-2-methyl-1-propene (5.5 mL, 55 mmol, 1.1 equiv.). The resulting solution was stirred at room temperature for 15 hours and then partitioned between AcOEt and H2O. The two layers were separated and the organic phase was washed with H₂O and brine, dried over MgSO4₄ and distilled (45 ° C, P = 150 mbar) to give 2-methyl-1 - [(2-methyl-2-propen-1-yl) oxy] 2-propanamine (F71) as a pink solid clear.

Description F83

4,4-Dimethylcyclohexanamine (F83)

4,4-Dimethylcyclohexanone oxime (D296) (10 g,

71 mmol, 1 equiv.) In EtOH (100 mL) was stirred with Ni of

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Raney (1 g, 10% w / w) under an atmosphere of H₂ (50 psi) for 4 days. The catalyst was filtered off through a pad of celite and HCl (1 M in Et 2 O, 100 mL, 100 mmol, 1.4 equiv) was added. The formed precipitate was filtered off and dissolved in water. The aqueous phase was washed with Et₂O is made strongly basic with KOH pellets and then extracted twice with CH₂C1₂. The combined organic phases were dried over MgSO4.₄ and concentrated in vacuo to give 4,4-dimethylcyclohexanamine (F83) (8 g, 89%) as a clear oil which was used in the next step without further purification.

F86 and F92 Descriptions

The following amines were obtained from their precursor in a manner analogous to the process described for

4,4-dimethylcyclohexanamine (F83):

<td>The mine</td><td>Precursor</td>

<td>2,2-Dimethyl cyclohexanamine (F86)</td><td>D297</td>

<td>3,3-Dimethyl cyclohexanamine (F92)</td><td>D298</td>

Description F157 [(3-Ethyl-5-isoxazolyl) methyl] amine (F157) [(3-Ethyl-5-isoxazolyl) methyl] amine (F157) was obtained from [(3-ethyl-5-isoxazolyl) methyl ] 1,1-dimethylethyl carbamate (G157) in a similar manner to the process described in Description F33 (F33).

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Ester Preparation

Ester 1

3-Methylsulfanyl-5- (2-oxopyrrolidin-1-yl) -benzoic acid methyl ester (B1)

To a solution of crude 3- (4-chloro-butanoylamino) -5-methylsulfanyl-benzoic acid methyl ester (D64) (0.17 g, 0.56 mmol, 1 eguiv.) In THF (2 mL) a At 0 ° C portions of NaH (60% in mineral oil, 24.6 mg, 0.616 mmol, 1.1 eguiv.) Were added over 2 minutes. The resulting mixture was stirred at room temperature for 40 minutes and a drop of MeOH was added to destroy remaining NaH. The resulting mixture was then diluted with EtOAc, then washed with 2 N aqueous HCl solution, saturated aqueous NaHCO 3 solution.₃ and saturated aqueous sodium chloride solution, dried over Na₂ONLY₄ and concentrated in vacuo. Purification by silica gel flash chromatography (isohexane / AcOEt: 1/1) gave 3- (4-chloro-butanoylamino) -5-methylsulfanyl-benzoic acid methyl ester (Bl) (122 mg, 82%) as a white solid. [M + H]⁺ = 266.0, RT = 2.86 min

Esther 2

3-Ethylsulfanyl-5- (2-oxopyrrolidin-1-yl) -benzoic acid ethyl ester (B2)

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194

Ester 2 was prepared from 177 mg (0.54 mmol) of 3- (4-chloro-butanoylamino) 5-ethylsulfanyl benzoic acid ethyl ester (D65) in a manner analogous to that described for Ester 1 which gave 129 mg. (82%) 3-ethylsulfanyl-5- (2-oxo-pyrrolidin-1-yl) -benzoic acid ethyl ester (B2) as a clear colorless gum after purification by silica gel flash chromatography (isohexane / AcOEt: 60/40). [M + H]⁺ = 294.1, RT = 3.23 minutes

Ester 3

3- (1,1-Dioxo-1 / methyl acid ester⁶-isothiazolidin-2-yl) -5-methylsulfanyl benzoic (B3)

To a solution of 3- (3-chloro-propane-1-sulfonylamino) -5-methylsulfanyl-benzoic acid methyl ester (D66) (183 mg, 0.54 mmol, 1 equiv) in MeOH (3 mL) was added NEt₃ (150 µl, 1.08 mmol, 2 equiv.). The resulting mixture was stirred at 70 ° C for 2 hours and then allowed to cool to room temperature overnight. A further portion of NEt was added₃ (75 µL, 0.54 mmol, 1 equiv.) And the mixture was stirred at 80 ° C for 3 hours and then another portion of NEt was added.₃ (75 µl, 0.54 mmol, 1 equiv.). After a further 2 hours at 80 ° C, the solution was cooled to room temperature and concentrated in vacuo. The residue was partitioned between AcOEt and 2N aqueous HCl solution. The organic layer was washed with brine, dried over Na₂ONLY₄ and

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195 concentrated in vacuo. Purification by flash chromatography on silica gel (isohexane / AcOEt: 60/40) gave 3- (1,1-dioxo-1/1-metric acid ester).⁶-isothiazolidin-2yl) -5-methylsulfanyl benzoic (B3) (150 mg, 92%). [M + H]⁺ =

302.0 TR = 2.89 minutes

Ester 4

3- (1,1-Dioxo-1 / acid ethyl ester⁶-isothiazolidin2-yl) -5-ethylsulfanyl benzoic (B4)

Ester 4 was prepared from 190 mg (0.52 mmol) of 3- (3-chloro-propane-isulfonylamino) -5-ethylsulfanyl-benzoic acid ethyl ester (D67) in a similar manner to that described for Ester 3 which gave 154 mg (90%) of 3- (1,1-dioxo-1/2-ethyl ester⁶-isothiazolidin-2yl) -5-ethylsulfanyl benzoic acid (B4) after purification by silica gel flash chromatography (isohexane / AcOEt: 60/40). [M + H]⁺ = 330.0, RT = 3.24 minutes

Ester 11

3-Ethoxy-5- (2-oxo-pyrrolidin-lil) -benzoic acid methyl ester (B11)

To 3-hydroxy-5- (2-oxopyrrolidin-1-yl) -benzoic acid methyl ester (D37) (0.80 g, 3.4 mmol, 1 equiv.) Dissolved in DMF (10 mL) was added K 2 CO 3 (0.94 g, 6.8 mmol, 2 equiv.) And ethyl iodide (1.1 g, 6.8 mmol,

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196 equiv.). The resulting mixture was heated at 50 ° C for 4 h, cooled to room temperature, diluted with 2 N aqueous HCl (50 mL) and extracted with Et₂O (50 mL). The organic phase was then washed with water (50 mL), dried over MgSO4.₄ and concentrated in vacuo to give 3-ethoxy-5- (2-oxo-pyrrolidin-1-yl) benzoic acid methyl ester (B11) (0.85 g, 95%) as a brown oil which slowly solidified to a solid. brownish.

Ester 11 (Alternative Procedure)

3-Ethoxy-5- (2-oxo-pyrrolidin-yl) -benzoic acid methyl ester (B11):

3- (4-Chloro-butanoylamino) -5-ethoxy-benzoic acid methyl ester (D51) (7 g, 20 mmol, 1 equiv) in THF (50 mL) was treated with portions of NaH (60% in oil (0.88 g, 22 mmol, 1.1 equiv.) for 15 minutes at room temperature. The resulting mixture was stirred for 30 minutes and then diluted with EtOAc (300 mL). The resulting solution was washed with 2 N aqueous HCl solution (200 mL), dried over MgSO4.₄ and concentrated in vacuo. Recrystallization of the residue from Et₂Hexane gave 3-ethoxy-5- (2-oxo-pyrrolidin-1-yl) benzoic acid methyl ester (B11) (3.5 g, 66%) as a white solid.

The following esters were prepared analogously to ester 11 from D37 using an appropriate commercially available reagent:

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Ester

3-Methoxy-5- (2-oxo-pyrrolidin-1-yl) benzoic acid methyl ester (B9)

3- (2-Oxo-pyrrolidin-1-yl) -5propoxy-benzoic acid methyl ester (B10)

3-Isopropoxy-5- (2-oxo-pyrrolidin-yl) -benzoic acid methyl ester (B12)

3- (2-Oxo-pyrrolidin-1-yl) -5-pentyloxy-benzoic acid methyl ester (B13)

Ester 14 The following ester was prepared in a manner analogous to Description 38 from Description 37 using the appropriate alcohol as indicated in the table below:

<td>Ester</td><td>Alcohol</td>

<td>3- (2-Methoxy-ethoxy) -5- (2-</td><td></td>

<td>oxo-pyrrolidin-1-yl) benzoic (B14)</td><td></td>

Ester 15

3- (3-Hydroxy-propoxy) -5- (2oxo-pyrrolidin-1-yl) -benzoic acid methyl ester (B15)

3- (3-Benzyloxy-propoxy) 5- (2-oxo-pyrrolidin-1-yl) -benzoic acid methyl ester (D38) MeOH (15 mL) was

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198 initially hydrogenated with 10% Pd on charcoal (50% wet, 0.25 g, 0.25 equiv. w / w) at atmospheric pressure for 24 hours and then an additional 0.25 g of 10% Pd on charcoal and The mixture was hydrogenolysed at 50 psi for a further 48 hours. The mixture was filtered through celite and was concentrated in vacuo. Purification by silica gel flash chromatography (EtOAc / isohexane: 1/1) gave 3- (3-hydroxy-propoxy) -5- (2-oxo-pyrrolidin-1-yl) -benzoic acid methyl ester ( B15) (260 mg, 69% in 2 steps). [M + H]⁺ = 294,0

Ester 17

3- (3-Methoxy-propoxy) -5- (2-oxopyrrolidin-1-yl) -benzoic acid methyl ester (B17)

3- (3-Hydroxy-propoxy) -5- (2-oxo-pyrrolidin-1-yl) -benzoic acid methyl ester (B15) (127 mg, 0.43 mmol, 1 equiv.) In CH 2 Cl 2 (2 mL) was treated with Proton Sponge (279 mg, 1.30 mmol, 3 equiv) and trimethyloxonium tetrafluoroborate (192 mg, 1.30 mmol, 3 equiv). After 3 hours, more Proton Sponge (93 mg, 0.43 mmol, 1 equiv) and trimethyloxonium tetrafluoroborate (65 mg, 0.43 mmol, 1 equiv) were added and stirring was continued for a further 2 hours. The mixture was then partitioned between EtOAc and 2N aqueous HCl solution. The two layers were separated and the aqueous phase extracted with EtOAc. The combined organic layers were washed with saturated aqueous NaHCO 3 solution.₃, 2 N aqueous HCl and saturated aqueous sodium chloride solution, and then

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199 drought on Na₂ONLY₄ and concentrated in vacuo. Purification by silica gel flash chromatography (ethyl acetate / isohexane: 1/4 to 1/3) gave 3- (3-methoxy-propoxy) -5- (2-oxo-pyrrolidin-1) methyl ester (yl) -benzoic (B17) (76 mg, 58%). [M + H]⁺ = 308,1

Ester 18

3- (1,1-Dioxo-1 / methyl acid ester⁶-isothiazolidin-2-yl) -5-ethoxybenzoic acid (B18)

3- (1,1-Dioxo-1 / acid methyl ester)⁶isothiazolidin-2-yl) -5-hydroxybenzoic acid (D41) (0.80 g, 3.0 mmol, 1 eguiv.) dissolved in DMF (10 mL) was added K₂TLC> 3 (0.94 g, 6.8 mmol, 2 equiv) and ethyl iodide (1.1 g, 6.8 mmol, 2 equiv) and the resulting mixture was heated at 50 ° C for 4 h It was then cooled to room temperature and diluted with 2 N aqueous HCl solution (50 mL). The aqueous phase was extracted with Et₂O (50 mL). The organic phase was washed with H₂O (50mL), dried over MgSO4₄ and concentrated in vacuo. Purification by silica gel flash chromatography (EtOAc / isohexane: 1/1) gave 3- (1,1-dioxo-1/1-methyl acid ester).⁶-isothiazolidin-2-yl) -5-ethoxybenzoic acid (B18) (220 mg, 25%) as a light yellow oil.

Ester 18 (Alternative Procedure)

3- (1,1-Dioxo-1 / methyl acid ester)⁶-isothiazolidin-2-yl) -5-ethoxybenzoic acid (B18)

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200

A solution of 3- (3-chloro-propane-1-sulfonylamino) -5-ethoxy-benzoic acid methyl ester (D53) (6.7 g, 20 mmol, 1 equiv) in EtOH (100 mL) was treated with NEt₃(4.0 g, 40 mmol, 2 equiv.). The resulting mixture was heated at reflux for 4 hours, cooled to room temperature and concentrated in vacuo. The residue was dissolved in EtOAc (200 mL) and the resulting solution was washed with 2 N aqueous HCl (100 mL) followed by saturated aqueous NaHCO 3.₃ (100 mL) and then dried over MgSO4₄ and concentrated in vacuo to give a brown oil. Crystallization from Et 2 O / hexane gave 3- (1,1-dioxo-1 / methyl acid ester).⁶-isothiazolidin-2-yl) -5ethoxybenzoic acid (B18) (4.7 g, 78%) as a light brownish solid.

Ester 19

3- (1,1-Dioxo-1 / methyl acid ester)⁶-isothiazolidin-2-yl) -5-isopropoxy-benzoic (B19)

3- (1,1-Dioxo-1 / methyl acid methyl ester)⁶(D41) -isothiazolidin-2-yl) -5-hydroxybenzoic acid (0.30 g, 1.1 mmol, 1 equiv.) dissolved in DMF (5 mL) was added K₂CO₃(0.306 g, 2.2 mmol, 2 equiv.) And 2-iodopropane (374 mg, 2.2 mmol, 2 equiv.) And the mixture was heated at 50 ° C for 4 hours and then cooled to room temperature. diluted with 2 N aqueous HCl (50 mL). The aqueous phase was extracted with Et₂O (50 mL) and the organic phase

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201 was washed with H₂O (50 mL), dried over MgSO4₄ and concentrated in vacuo to give 3- (1,1-dioxo-1 / acid methyl ester).⁶isothiazolidin-2-yl) -5-isopropoxy-benzoic (B19) (290 mg, 88%) as a light yellow oil.

The following esters were prepared from Description 41 in a manner analogous to the process described for Ester 19 using the appropriate commercially available reagents:

Ester

3- (1,1-Dioxo-1 / methyl acid ester)⁶-isothiazolidin-2yl) -5-methoxy-benzoic (B20)

3- (1,1-Dioxo-1 / methyl acid ester)⁶-isothiazolidin-2yl) -5-propoxy-benzoic (B21)

3- (1,1-Dioxo-1 / methyl acid ester)⁶-isothiazolidin-2yl) -5-pentyloxy-benzoic (B22)

The following esters were prepared analogously to the process described in Description 30 from the aryl bromide and appropriate amine starting materials listed in the table below:

<td>Ester</td><td>Bromide of aryl</td><td>The mine</td><td>[M + H]⁺</td><td>RT (min)</td>

<td>3- Acid methyl ester (2-oxo-pyrrolidin-1-yl) -5- pyrrolidin-1-yl-benzoic (Bl13)</td><td>D9a</td><td>O</td><td> 289,1</td><td> 3, 03</td>

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202 (continuation)

<td>Ester</td><td>Bromide of aryl</td><td>The mine</td><td>[M + H]⁺</td><td>RT (min)</td>

<td>3- Acid methyl ester morpholin-4-yl-5- (2-oxo-pyrrophenyl) rolidin-1-yl) benzoic (B29)</td><td>D9a</td><td>w Q</td><td> 305, 0</td><td> 2,59</td>

<td>3- Acid methyl ester (4-methyl-piperazin-1-yl) -5- (2-oxo-pyrrolidin-1-yl) - benzoic (B115)</td><td>D9a</td><td>jl T</td><td> 318,1</td><td> 1, 91</td>

<td>3- Acid methyl ester (2-oxo-pyrrolidin-1-yl) -5- piperidin-1-yl-benzoic (B28)</td><td>D9a</td><td>5+ u</td><td> 303,1</td><td> 2, 93</td>

<td>Tert-Butyl acid ester 3- (2-oxo-piperidin-1-yl) -5- pyrrolidin-1-yl-benzoic (B54)</td><td>D10</td><td> «</td><td> 345,2</td><td> 3,35</td>

<td>Tert-Butyl acid ester 3-morpholin-4-yl-5- (2-oxo-piper) peridin-1-yl) benzoic acid (B56)</td><td>D10</td><td>O</td><td> 361,2</td><td> 2, 95</td>

<td>Tert-Butyl acid ester 3- (2-oxo-piperidin-1-yl) -5- piperidin-1-yl-benzoic (B55)</td><td>D10</td><td>H 0</td><td> 359,2</td><td> 3,35</td>

<td>Tert-Butyl acid ester 3- (1,1-dioxo-1 /⁶-isothiazole- din-2-yl) -5-pyrrolidin-1-yl benzoic (B114)</td><td>D17</td><td>O</td><td> 67,1</td><td> 3, 43</td>

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203 (continuation)

<td>Ester</td><td>Bromide of aryl</td><td>The mine</td><td>[M + H]⁺</td><td>RT (min)</td>

<td>Tert-Butyl acid ester</td><td>D17</td><td>,, N, Q</td><td> 383,1</td><td> 3, 04</td>

<td>3- (1,1-dioxo-1 /⁶-isothiazole-</td><td></td><td></td><td></td><td></td>

<td>din-2-yl) -5-morpholin-4-yl-</td><td></td><td></td><td></td><td></td>

<td>benzoic (B61)</td><td></td><td></td><td></td><td></td>

Ester 24

3,5-Bis- (2-oxo-pyrrolidin-lil) benzoic acid methyl ester (B24)

To a solution of 3-bromo5-iodobenzoic acid methyl ester (D8a) (588 mg, 1.72 mmol, 1.5 equiv) in dioxane (10 mL) was added pyrrolidin-2-one (120 µl, 1 , 14 mmol, 1 equiv.), CS 2 CO 3 (720 mg, 2.21 mmol, 2 equiv.), Xantphos (51 mg, 0.09 mmol, 0.08 equiv.) And tris (dibenzylidenoacetone) dipaladium (0) ( 28 mg, 0.03 mmol, 0.026 equiv.). The reaction mixture was stirred at 100 ° C for 16 hours and then cooled to room temperature and filtered through a pad of celite and concentrated in vacuo. Purification by silica gel column chromatography (EtOAc) gave acid methyl ester

3,5-bis- (2-oxo-pyrrolidin-1-yl) benzoic (B24) (411 mg, 79%) as a light yellow solid. [M + H]⁺ = 303,2

The following esters were prepared analogously to Ester 23 from the appropriate starting materials given in the table below:

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<td>Ester</td><td>Precursor</td>

<td>4-Chloro-3,5-bis- (2-oxo-acid) methyl ester</td><td>D28a</td>

<td>pyrrolidin-1-yl) benzoic (B28a)</td><td></td>

<td>4-Methoxy-3,5-bis- (2-oxo-acid) methyl ester</td><td>D28b</td>

<td>pyrrolidin-1-yl) benzoic (B26)</td><td></td>

Ester 27

3-Nitro-5- (2-oxo-pyrrolidin-lil) -benzoic acid methyl ester (B27)

To a solution of 3- (4-chloro-butanoylamino) -5-nitro-benzoic acid (D2) methyl ester (56 g, 186 mmol, equiv) in THF (500 mL) under nitrogen was added portionwise. (60% w / w in mineral oil, 8 g, 200 mmol, 1.07 equiv.) For 10 minutes. The resulting mixture was stirred at room temperature for 1 hour and then cooled to 0 ° C and MeOH was added dropwise until the mixture no longer bubbled. The solution was concentrated in vacuo and the residue was diluted with EtOAc. The organic phase was washed with H₂O, dried over MgSO₄ and concentrated in vacuo. The residue was triturated with isohexane to give 3-nitro-5- (2-oxo-pyrrolidin-1-yl) benzoic acid methyl ester (B27) (38.5 g, 78%) as a light brownish solid.

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Ester 30

3- (2-Oxo-pyrrolidin-1-yl) -5-phenylamino-benzoic acid methyl ester (B30)

A flask under nitrogen was charged with 3-bromo-5- (2-oxo-pyrrolidin-1-yl) -benzoic acid methyl ester (D9a) (298 mg, 1 mmol, 1 equiv), CS2CO3 (488 mg 1.5 mmol, 1.5 equiv.), Tris (dibenzylidenoacetone) dipaladium (0) (18.3 mg,

0.02 mmol, 0.02 equiv.), 2- (di-tert-butylphosphino) biphenyl (18 mg, 0.06 mmol, 0.06 equiv.) And DME (8 mL). Aniline (136 µL, 1.5 mmol, 1.5 equiv) was then added with a syringe and the resulting mixture was stirred at 100 ° C for 16 h and then cooled to room temperature, diluted with H₂O and AcOEt. The layers were separated and the aqueous phase was extracted with EtOAc. The combined organic phases were dried over MgSO4.₄ and concentrated in vacuo. Purification of the residue by silica gel flash chromatography (isohexane / AcOEt: 3/1 to 1/1) gave 3- (2-oxo-pyrrolidin-1-yl) -5-phenylamino benzoic acid methyl ester ( B30) (100 mg, 32%) as a white solid. [M + H]⁺ = 311.0, TR = 3.14 minutes

Ester 31

3-Ethylamino-5- (2-oxopyrrolidin-1-yl) benzoic acid tert-butyl ester (B31)

A flask was charged with (benzyl-ethyl-amino) - (2-oxopyrrolidin-1-yl) -benzoic acid tert-butyl ester (D30) (3 g, 7.6 mmol, 1 equiv.), 10% Pd on coal (50%

ΡΕ1567488

206 600 mg, 10% w / w), Na 4 COOH (4.8 g, 76 mmol, 10 equiv), MeOH (30 mL) and H₂O (50 mL). The resulting mixture was stirred at 50 ° C for 16 hours, cooled to room temperature and the catalyst was filtered off using a celite pad. Most of the MeOH was removed in vacuo and the residue was diluted with saturated aqueous NaHCO 3.₃. The aqueous phase was extracted twice with EtOAc. The combined organic phases were dried over MgSO 4 and concentrated in vacuo to give 3-ethylamino-5- (2-oxopyrrolidin-1-yl) -benzoic acid tert-butyl ester (B31) (2.2 g, 95%) as a yellow solid. [M + H]⁺ = 305.2, TR = 3.11 minutes

<td>Ester</td><td>Precursor</td><td>[M + H]⁺</td><td>RT (min)</td>

<td>3- Acid tert-butyl ester methylamino-5- (2-oxo-pyrrolidinyl) 1-yl) benzoic (B32)</td><td>D31</td><td> 291,1</td><td> 2, 96</td>

<td>3- Acid tert-butyl ester methylamino-5- (2-oxo-piperidin-1-one yl) benzoic (B57)</td><td>D32</td><td>249.1 (-tBu)</td><td> 2,91</td>

<td>3- Acid tert-butyl ester ethylamino-5- (2-oxo-piperidin-1-one yl) benzoic (B59)</td><td>D33</td><td> 319,2</td><td> 3,10</td>

<td>3- Acid tert-butyl ester (1,1-dioxo-1 /⁶-isothiazolidin-2- yl) -5-methylamino benzoic (B62)</td><td>D34</td><td></td><td></td>

<td>3- Acid tert-butyl ester (1,1-dioxo-1 /⁶- [1,2] thiazinan-2- yl) -5-ethylamino benzoic (B73)</td><td>D35</td><td> 355,2</td><td> 3, 32</td>

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Ester 33

Diethylamino- (2-oxo-pyrrolidin-1-yl) -benzoic acid methyl ester (B33)

To a solution of 3-amino5- (2-oxo-pyrrolidin-1-yl) -benzoic acid methyl ester (D4a) (100 mg, 0.43 mmol, 1 equiv.) In (CH₂C1₂)₂ (1.5 mL) were added acetaldehyde (0.072 mL, 1.29 mmol, 3 equiv.) And sodium triacetoxyborohydride (273 mg, 1.29 mmol, 3 equiv.). The resulting solution was stirred at room temperature for 1 hour, diluted with EtOAc (20 mL), washed with 2 N aqueous NaOH solution (20 mL), dried over MgSO4.₄ and concentrated in vacuo to give diethylamino- (2-oxopyrrolidin-1-yl) -benzoic acid methyl ester (B33) (110 mg, 98%) as a light yellow oil.

The following esters were prepared analogously to the process described in Ester 33 (B33) using the appropriate aldehyde and appropriate aniline as indicated in the table below:

<td>Ester</td><td>Aniline</td><td>[M + H]⁺</td><td>RT (min)</td>

<td>Dimethylamino acid methyl ester</td><td>D4a</td><td> 263, 0</td><td> 2, 63</td>

<td>n- (2-oxo-pyrrolidin-1-yl) benzoic</td><td></td><td></td><td></td>

<td>(B34)</td><td></td><td></td><td></td>

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208 (continuation)

<td>Ester</td><td>Aniline</td><td>[M + H]⁺</td><td>RT (min)</td>

<td>Diethylamine methyl ester no- (1,1-dioxo-1 /⁶-isothiazolidin-2- yl) benzoic (B63)</td><td>D16</td><td> 327, 0</td><td> 2, 96</td>

<td>Dimethylamino acid methyl ester n- (2-oxo-piperidin-1-yl) benzoic (B60)</td><td>D4b</td><td></td><td></td>

Ester 35

3- (2-Oxo-pyrrolidin-1-yl) -5propylamino-benzoic acid methyl ester (B35)

To a solution of 3-amino5- (2-oxo-pyrrolidin-1-yl) -benzoic acid methyl ester (D4a) (500 mg, 2.14 mmol, 1 eiviv) in (CH₂(C 2) 2 (10 mL) was added sodium triacetoxyborohydride (640 mg, 3.02 mmol, 1.4 eguiv.), Propionaldehyde (0.156 mL, 2.14 mmol, 1 eguiv.) And CH₃COOH (0.125 mL, 2.18 mmol, 1.02 eguiv.). The resulting mixture was stirred at room temperature for 2 hours, diluted with CH₂C1₂ NaHCO 3 (20 mL), washed with saturated aqueous NaHCO 3 solution.₃ (20 mL), dried over MgSO4₄ and concentrated in vacuo. Purification of the residue by silica gel flash chromatography (isohexane / AcOEt: 3/2) gave 3- (2-oxo-pyrrolidin-1-yl) -5-propylaminobenzoic acid methyl ester (B35) (250 mg , 42%) as a colorless oil.

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The following esters were obtained analogously to the process described in Ester 35 (B35) using the appropriate aldehyde and appropriate aniline given in the table below:

<td>Ester</td><td>Aniline</td><td>[M + H]⁺</td><td>RT (min)</td>

<td>3-Benzylamino acid methyl ester no-5- (1,1-dioxo-1 /⁶-isothiazolidin-2- yl) benzoic (B64)</td><td>D16</td><td></td><td></td>

<td>3-Butylaminic acid methyl ester no-5- (1,1-dioxo-1 /⁶-isothiazolidin-2- yl) benzoic (B65)</td><td>D16</td><td> 327, 0</td><td> 3,10</td>

<td>3- (1,1-Acid) methyl ester dioxo-1 /⁶-isothiazolidin-2-yl) -5- (3- methyl butylamino) benzoic (B66)</td><td>D16</td><td> 341,1</td><td> 3,26</td>

<td>3- (1,1-Acid) methyl ester dioxo-1 /⁶-isothiazolidin-2-yl) -5- phenethylamino benzoic (B67)</td><td>D16</td><td> 375, 0</td><td> 3,23</td>

<td>3- (1,1-Acid) methyl ester dioxo-1 /⁶-isothiazolidin-2-yl) -5- pentylamino benzoic (B68)</td><td>D16</td><td> 341,1</td><td> 3,29</td>

<td>3- (1,1-Acid) methyl ester dioxo-1 /⁶-isothiazolidin-2-yl) -5- propylamino benzoic (B69)</td><td>D16</td><td> 313, 0</td><td> 2, 90</td>

<td>3- (1,1-Acid) methyl ester dioxo-1 /⁶-isothiazolidin-2-yl) -5- ethylamino benzoic (B70)</td><td>D16</td><td> 299, 0</td><td> 2,91</td>

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210 (continuation)

<td>Ester</td><td>Aniline</td><td>[M + H]⁺</td><td>RT (min)</td>

<td>3- (Cyclopropyl) methyl ester pilmethylamino) -5- (1,1-dioxo-1 /⁶- isothiazolidin-2-yl) benzoic (B71)</td><td>D16</td><td> 325, 0</td><td> 2, 91</td>

<td>3- acid methyl ester isobutylamino-5- (2-oxo-pyrrolidin-1- yl) benzoic (B36)</td><td>D4a</td><td> 291, 1</td><td> 3, 03</td>

<td>3-Benzylamino acid methyl ester no-5- (2-oxo-pyrrolidin-1-yl) - benzoic (B37)</td><td>D4a</td><td></td><td></td>

<td>3- (3-Methyl-Acid) methyl ester butylamino) -5- (2-oxo-pyrrolidin-1- yl) benzoic (B38)</td><td>D4a</td><td></td><td></td>

<td>3- (2-Oxoacetic acid methyl ester pyrrolidin-1-yl) -5-pentylamino- benzoic (B39)</td><td>D4a</td><td></td><td></td>

<td>3- acid methyl ester butylamino-5- (2-oxo-pyrrolidin-1- yl) benzoic (B40)</td><td>D4a</td><td></td><td></td>

<td>3- (2,2-Acid) methyl ester dimethyl propylamino) -5- (2-oxo pyrrolidin-1-yl) benzoic (B41)</td><td>D4a</td><td> 305, 0</td><td> 3,22</td>

<td>3- acid methyl ester (cyclopropylmethyl-amino) -5- (2-oxo pyrrolidin-1-yl) benzoic (B42)</td><td>D4a</td><td></td><td></td>

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211 (continuation)

<td>Ester</td><td>Aniline</td><td>[M + H]⁺</td><td>RT (min)</td>

<td>3- (2-Oxoacetic acid methyl ester</td><td>D4b</td><td></td><td></td>

<td>piperidin-1-yl) -5-propylamino-</td><td></td><td></td><td></td>

<td>benzoic (B58)</td><td></td><td></td><td></td>

Ester 43

3- (Ethyl-propylamino) -5- (2-oxopyrrolidin-1-yl) -benzoic acid methyl ester (B43)

To a solution of 3-amino5- (2-oxo-pyrrolidin-1-yl) -benzoic acid methyl ester (D4a) (200 mg, 0.87 mmol, 1 equiv.) In (CtbCl2 A (5 mL) sodium triacetoxyborohydride (1.536 g, 5.22 mmol, 6 equiv), 3-pentanone (0.546 mL, 5.22 mmol, 6 equiv) and AcOH (0.050 mL, 0.87 mmol, 1 mL) were added. The resulting mixture was stirred at room temperature for 48 hours, diluted with (CH 2 Cl 2) (20 mL), washed with saturated aqueous NaHCO 3.₃ (20 mL), dried over MgSO4₄ and concentrated in vacuo. Purification of the residue by silica gel flash chromatography (isohexane / AcOH: 3/2) gave 3- (1-ethyl-propylamino) -5- (2-oxo-pyrrolidin-1-yl) methyl ester -benzoic acid (B43) (106 mg, 40%) as a colorless oil. [M + H]⁺ = 305.0 TR = 3.19

The following esters were obtained analogously to Ester 43 (B43) using the appropriate ketone and appropriate aniline as indicated in the table below.

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<td>Ester</td><td>Aniline</td><td>[M + H]</td><td>RT (min)</td>

<td>3- (1,1- dioxo-1 /⁶-isothiazolidin-2-yl) -5- isopropylamino benzoic (B72)</td><td>D16</td><td> 313, 0</td><td> 2, 82</td>

<td>3-Isopropyl acid methyl ester amino-5- (2-oxo-pyrrolidin-1-yl) - benzoic (B44)</td><td>D4a</td><td> 227, 0</td><td> 2, 75</td>

<td>3- Acid methyl ester cyclopentylamino-5- (2-oxo- pyrrolidin-1-yl) benzoic (B45)</td><td>D4a</td><td></td><td></td>

<td>3-Cyclic acid methyl ester hexylamino-5- (2-oxo-pyrrolidin-1- yl) benzoic (B46)</td><td>D4a</td><td></td><td></td>

Ester 47

(Acetyl-methyl-amino) (ethyl-propionyl-amino) -benzoic acid tert-butyl ester (B47)

To a solution of 3-methylamino-5- (2-oxo-pyrrolidin-1-yl) -benzoic acid tert-butyl ester (B32) (200 mg, 0.69 mmol, 1 eguiv.) In CH 2 Cl 2 (5 mL) was added NEt₃(278 pL, 2 mmol, 2.9 eguiv.) And acetic anhydride (195 pL, 2 mmol, 2.9 eguiv.). The resulting mixture was stirred at room temperature for 16h, diluted with CH 2 Cl 2, washed with saturated aqueous NaHCO 3 solution.₂, dried over MgSO₄ and concentrated in vacuo to give tert-butyl ester

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213 (acetyl methyl amino) - (ethyl propionyl amino) benzoic acid (B47) (203 mg, 89%) as a light yellow solid which was used in the next step without further purification. [M + H] + = 333.1, RT = 2.76 minutes

The following esters were prepared analogously to the process described in Ester 47 from the appropriate amine starting materials:

<td>Ester</td><td>The mine</td>

<td>(Acetyl-propyl-amino) -2-oxo-methyl ester</td><td>B35</td>

<td>pyrrolidin-1-yl) benzoic (B48)</td><td></td>

<td>(Acetyl-isopropyl-amino) -2-</td><td>B44</td>

<td>oxo-pyrrolidin-1-yl) -benzoic acid (B49)</td><td></td>

Ester 50

3-Acetylamino-5- (2-oxo-pyrrolidin-1-yl) -benzoic acid methyl ester (B50)

To a solution of 3-amino5- (2-oxo-pyrrolidin-1-yl) benzoic acid methyl ester (D4a) (80 mg, 0.34 mmol, equiv.) In CH₂C1₂ (10 mL) was added NEt₃ (0.142 mL, 1.02 mmol, 2 equiv.) And acetic anhydride (0.078 mL, 0.82 mmol, 2.4 equiv.). The resulting mixture was stirred at room temperature for 16 hours. The reaction was then diluted with EtOAc (20 mL), washed with aqueous HCl solution.

N (20 mL), dried over MgSO4₄ and concentrated in vacuo to give 3-acetylamino-5- (2-oxoΡΕ1567488 acid methyl ester

214 pyrrolidin-1-yl) benzoic (B50) (67 mg, 71%) as a light yellow foam.

Ester 51

(Methanesulfonyl-methylamino) - (2-oxo-pyrrolidin-1-yl) -benzoic acid tert-butyl ester (B51)

To a solution of 3-methylamino-5- (2-oxo-pyrrolidin-1-yl) -benzoic acid tert-butyl ester (B32) (200 mg, 0.69 mmol, 1 equiv) in CH 2 Cl 2 (5 mL) was added NEt 3 (278 pL, 2 mmol, 2.9 equiv) and methanesulfonyl chloride (162 pL, 2 mmol, 2.9 equiv). The resulting mixture was stirred at room temperature for 16 hours, diluted with CH₂C1₂, washed with saturated NaHCO solution₃, dried over MgSO4 and concentrated in vacuo to give (methanesulfonyl-methyl-amino) - (2-oxopyrrolidin-1-yl) -benzoic acid tert-butyl ester (B51) (203 mg, 89%) as a pale yellow oil. [M + H]⁺= 313.0, TR = 2.95 minutes

Ester 52

(Methanesulfonyl-propylamino) - (2-oxo-pyrrolidin-1-yl) -benzoic acid methyl ester (B52)

Ester 52 was prepared from 3- (2-oxo-pyrrolidin-1-yl) -5-propylaminobenzoic acid methyl ester (B35) in a similar manner to that described for Ester (B51)

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Ester 53

3-Methanesulfonylamino-5- (2oxo-pyrrolidin-1-yl) -benzoic acid methyl ester (B53)

To a solution of 3-amino5- (2-oxo-pyrrolidin-1-yl) -benzoic acid methyl ester (D4a) (200 mg, 0.85 mmol, 1 equiv) in CH 2 Cl 2 (5 mL) and DMF ( 5 mL) NEt was added₃ (0.181 mL, 1.3 mmol, 1.5 equiv.) And methanesulfonyl chloride (0.071 mL, 1 mmol, 1.2 equiv). The resulting mixture was stirred at room temperature for 1 h, diluted with EtOAc (30 mL), washed with 2 N aqueous HCl (30 mL), dried over MgSO4.₄ and concentrated in vacuo. The residue was triturated with Et₂The was then filtered to give 3-methanesulfonylamino-5- (2-oxopyrrolidin-1-yl) benzoic acid methyl ester (B53) as a light yellow solid (100 mg, 38%).

Ester 74

1-tert-Butyl ester 5- (2-oxo-pyrrolidin-1-yl) -isophthalic acid 3-methyl ester (B74)

A solution of 1-tert-butyl ester 3 methyl ester (D80) (4.5 g, 12.7 mmol, 1 equiv) in THF (60 mL) was treated with portions of NaH (60% suspension in mineral oil). , 560 mg, 14 mmol, 1.1 equiv) for 5 minutes at room temperature. The resulting mixture was stirred.

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216 for 1 hour, then MeOH (5 mL) was added and the mixture was concentrated in vacuo. The residue was diluted with EtOAc (200 mL) and the organic phase was washed with H₂O (100 mL), dried over MgSO4₄ and concentrated in vacuo to give 1-tert-butyl ester 5- (2-oxopyrrolidin-1-yl) isophthalic acid 3-methyl ester (B74) (3.9 g, 97%) as a white solid.

Ester 76

3-Hydroxymethyl-5- (2-oxopyrrolidin-1-yl) -benzoic acid methyl ester (B76)

A suspension of 5- (2-oxo-pyrrolidin-1-yl) -isophthalic acid monomethyl ester (A75) (200 mg, 0.76 mmol, 1 equiv) in THF (20 mL) was cooled to 0 ° C and was treated with BH₃-Me₂S (2 M solution in THF, 0.64 mL, 1.28 mmol, 1.3 equiv.). The resulting mixture was heated at reflux for 1 hour and then cooled to room temperature. MeOH (5 mL) was added and the resulting mixture was concentrated in vacuo. The residue was diluted with EtOAc (50 mL) and the resulting solution was washed with saturated aqueous NaHCO 3.₃ HCl (30 mL) and 2 N aqueous HCl (30 mL), dried over MgSO4₄ and concentrated in vacuo to give 3-hydroxymethyl-5- (2-oxopyrrolidin-1-yl) -benzoic acid methyl ester (B76) (70 mg, 37%) as a light yellow oil.

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Ester 77

5- (2-Oxo-pyrrolidin-1-yl) -Npropyl-isophthalamic acid methyl ester (B77)

A suspension of 5- (2-oxo-pyrrolidin-1-yl) -isophthalic acid (A75) monomethyl ester (200 mg, 76 mmol, eguiv.) In CH 2 Cl 2 (20 mL) at room temperature was treated with a few drops of DMF. followed by (COC1)₂ (100 mg, 0.8 mmol, 1.1 eguiv.). The resulting mixture was stirred for 1 hour and then propylamine (140 mg, 2.4 mmol, 3.3 eguiv) was added and the resulting solution was stirred for 30 minutes. The solution was then washed with 2 N aqueous HCl solution (30 mL), saturated aqueous NaHCO 3 solution (30 mL), dried over MgSO 4 and concentrated in vacuo to give 5- (2-oxopyrrolidin-1-methyl acid ester). yl) -N-propyl isophthalamic (B77) (127 mg, 55%) as a waxy cream solid.

The following compounds were prepared in a manner analogous to that described for Ester 77 from 5- (2-oxo-pyrrolidin-1-yl) -isophthalic acid monomethyl ester (A75) and the appropriate amine:

Ester

N, N-Dimethyl-5- (2-oxo-pyrrolidin-lil) -isophthalamic acid methyl ester (B78)

N-Methyl-5- (2-oxo-pyrrolidin-1-yl) isophthalamic acid methyl ester (B79)

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218

Ester 80

5- (2-Oxo-pyrrolidin-1-yl) -N, Ndipropyl-isophthalamic acid methyl ester (B80)

A solution of 5- (4-chloro-butanoylamino) -N, N-dipropyl-isophthalamic acid methyl ester (D89) (1.7 g, 4.4 mmol, 1 equiv.) THF (20 mL) was treated with NaH portions (60% dispersion in mineral oil, 180 mg, 4.5 mmol, 1.1 equiv.) and the resulting mixture was stirred for 1 hour and then diluted with EtOAc (100 mL). The resulting solution was washed with 2 N aqueous HCl solution (50 mL), dried over MgSO4.₄ and concentrated in vacuo to give 5- (2-oxo-pyrrolidin-1-yl) -N, Ndipropyl-isophthalamic acid methyl ester (B80) (1.38 g, 91%) as a colorless oil.

Ester 81

5- (2-Oxo-piperidin-1-yl) -N, Ndipropyl-isophthalamic acid methyl ester (B81)

Ester 81 was prepared analogously to Ester 80 from 5- (5-chloropentanoylamino) -N, N-dipropyl isophthalamic acid methyl ester (D90).

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Ester 82

3-Nitro-5- (2-oxo-piperidin-lil) -benzoic acid methyl ester (B82)

NaH (60% w / w in mineral oil, 680 mg, 17 mmol, 0.9 equiv) was added portionwise to a 3- (5-chloro-pentanoylamino) -5-nitrobenzoic acid methyl ester solution ( D3) (6 g, 19 mmol, 1 equiv.) In THF (40 mL) under nitrogen. The resulting mixture was stirred at room temperature for 1 hour and then MeOH was added dropwise. The solution was concentrated in vacuo and the residue was diluted with EtOAc. The organic phase was washed with H₂O, dried over MgSO₄ and concentrated in vacuo. Purification by silica gel flash chromatography (EtOAc / isohexane: 1/2) gave 3-nitro-5- (2-oxopiperidin-1-yl) benzoic acid methyl ester (B82) (2.8 g , 53%) as a light orange solid.

Ester 83

3- (1,1-Dioxo-1 / methyl acid ester)⁶-isothiazolidin-2-yl) -5-fluoromethylbenzoic acid (B83)

A solution of 3- (1,1dioxo-1/3) acid methyl ester⁶-isothiazolidin-2-yl) -5-hydroxymethylbenzoic acid (D84) (400 mg, 1.4 mmol, 1 equiv.) in CH₂C1₂ (40 mL) at 0 ° C was treated with (diethylamino) sulfur trifluoride (240 mg,

1.5 mmol, 1.1 equiv.). The mixture was stirred at 0 ° C for

ΡΕ1567488

220 hour and then allowed to warm to room temperature. The solution was washed with 2 N aqueous HCl (40 mL), dried over MgSO4.₄ and concentrated in vacuo to give 3- (1,1-dioxo-1 H-methyl acid ester).⁶-isothiazolidin-2yl) -5-fluoromethylbenzoic acid (B83) (250 mg, 62%) as a white solid.

Ester 84

3-Dimethylaminomethyl-5- (dioxol / acid) methyl ester⁶-isothiazolidin-2-yl) -benzoic acid (B84)

A solution of 3- (1,1dioxo-1/3) acid methyl ester⁶-isothiazolidin-2-yl) -5-methanesulfonyloxymethylbenzoic acid (D85) (200 mg, 0.55 mmol, 1 equiv.) in EtOH (3 mL) was treated with dimethylamine (33% in EtOH, 3 mL, excess). The resulting mixture was stirred for 15 minutes and then concentrated in vacuo and re-evaporated with toluene (5 mL). The residue was dissolved in EtOAc (50 mL) and the resulting solution was washed with saturated aqueous NaHCO 3.₃ (50 mL), dried over MgSO4₄ and concentrated in vacuo to give 3-dimethylaminomethyl-5 (dioxo-1 H) methyl ester.⁶-isothiazolidin-2-yl) -benzoic acid (B84) (170 mg, 99%) as a waxy yellow solid.

Ester 85

3-Azidomethyl-5- (1,1-dioxo-1 H) methyl ester⁶isothiazolidin-2-yl) benzoic (B85)

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A solution of 3- (1,1dioxo-1 /⁶-isothiazolidin-2-yl) -5-methanesulfonyloxymethylbenzoic acid (D85) (200 mg, 0.55 mmol, 1 equiv) in DMF (2 mL) was treated with NaN₃ HCl (39 mg, 0.6 mmol, 1.1 equiv) and the resulting mixture was stirred for 1 hour at room temperature and then diluted with EtOAc (50 mL). The resulting solution was washed sequentially with 2 N aqueous HCl (30 mL), saturated aqueous NaHCO 3.₃(30 mL) and H₂O (50 mL), dried over MgSO4₄ and concentrated in vacuo to give 3-azidomethyl-5- (1,1-dioxide-1/1) methyl ester⁶-isothiazolidin-2-yl) -benzoic acid (B85) as a white solid (129 mg, 76%).

Ester 89

3- (1,1-Dioxo-1 / methyl acid ester⁶-isothiazolidin-2-yl) -5- (Z) -propenyl-benzoic acid (B89)

A suspension of (ethyl) triphenylphosphonium bromide (371 mg, 1.0 mmol, 1.4 equiv) in THF (20 mL) was treated with KCÓBu (112 mg, 1.0 mmol, 1.4 equiv) and The resulting mixture was stirred for 15 minutes at room temperature. A solution of 3- (1,1-dioxo-1 H-acid methyl ester) was added.⁶-isothiazolidin-2-yl) -5-formylbenzoic acid (D86) (200 mg, 0.7 mmol, 1 equiv) in THF (10 mL) and the resulting mixture was stirred for 1 hour at room temperature and then diluted. with AcOEt

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222 (100ml). The resulting solution was washed with 2 N aqueous HCl (100 mL), dried over MgSO4.₄ and concentrated in vacuo. Purification by silica gel flash chromatography (EtOAc / isohexane: 1/1) gave 3- (1,1-dioxo-1 / methyl acid ester).⁶-isothiazolidin-2-yl) -5- (E / Z) -propenylbenzoic acid (B89) (135 mg, 65%) as a colorless oil.

The following compounds were prepared in a manner analogous to the process described for Ester 89 from 3- (1,1-dioxo-1 H-methyl ester).⁶-isothiazolidin2-yl) -5-formylbenzoic acid (D86) and appropriate commercially available starting material:

Ester

3- (1,1-Dioxo-1 / methyl acid ester)⁶-isothiazolidin-2yl) -5-vinyl benzoic acid (B88)

(Z / E) -But-1-enyl- (ethanesulfonylethyl-amino) -benzoic acid methyl ester (B90)

3- (1,1-Dioxo-1-isothiazolidin-2-yl) 5- (2-methyl-propenyl) -benzoic acid methyl ester (B91)

Ester 92

5- (1,1-Dioxo-1 / methyl acid ester)⁶-isothiazolidin-2-yl) -isophthalamic (B92)

A suspension of 5- (1,1-dioxo-1/1-acid monomethyl ester)⁶-isothiazolidin-2-yl) -isophthalic (D83) (750

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223 mg, 2.5 mmol, 1 equiv) in CH 2 Cl 2 (30 mL) was treated with 2 M (COCl) 2 in CH₂C1₂ (1.5 mL, 3.0 mmol, 1.2 equiv.) Followed by a few drops of DMF. The resulting mixture was stirred for 30 minutes and then 32% aqueous ammonia was added. The resulting mixture was stirred for 15 minutes and then diluted with CH₂C1₂ NaHCO 3 (50 mL) and was washed with 2 N aqueous HCl (50 mL). The resulting white precipitate was filtered to give 5- (1,1-dioxo-1/1-methyl acid ester).⁶-isothiazolidin-2-yl) -isophthalamic B92 (650 mg, 87%) as a white solid.

Ester 93

3-Cyano-5- (1,1-dioxo-1 / methyl ester)⁶isothiazolidin-2-yl) benzoic (B93)

A suspension of 5- (1,1dioxo-1 /⁶-isothiazolidin-2-yl) -isophthalamic (B92) (500 mg, 1.68 mmol, 1 equiv.) in CH₂C1₂ (100 mL) was treated with NEt₃(404 mg, 4.0 mmol, 2.4 equiv.) And trifluoroacetic anhydride (378 mg, 1.8 mmol, 1.1 equiv). The resulting mixture was stirred for 1 hour at room temperature and then treated with further portions of NEt.₃ (404 mg, 4.0 mmol, 2.4 equiv) and trifluoroacetic anhydride (378 mg, 1.8 mmol, 1.1 equiv) and stirred for a further 45 minutes. The resulting solution was washed with 2 N aqueous HCl solution (50 mL), saturated aqueous NaHCO 3 solution.₃ NaHCO3 (50 mL), dried over MgSO4 and concentrated in vacuo. The residue was triturated with

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Et₂O to give 3-cyano-5- (1,1-dioxol / acid) methyl ester⁶(B93) -isothiazolidin-2-yl) benzoic acid (350 mg, 75% as a white solid.

Ester 94

5- (1,1-Dioxo-1 / methyl acid ester)⁶-isothiazolidin-2-yl) -N, N-dipropyl isophthalamic (B94)

A solution of 5- (3-chloro-propane-1-sulfonylamino) -N, N-dipropyl-isophthalamic acid methyl ester (D91) (1.7 g, 4.0 mmol, 1 equiv) in EtOH (20 mL) was treated with NEt₃ (799 mg, 7.9 mmol, 2 equiv.) And the mixture was heated at reflux for 3 hours and then cooled to room temperature and concentrated in vacuo. The residue was dissolved in EtOAc (100 mL) and the organic phase was washed with 2 N aqueous HCl solution (50 mL), dried over MgSO4.₄ and concentrated in vacuo. The residue was triturated with Et₂O to give 5- (1,1dioxo-l / acid) methyl ester⁶-isothiazolidin-2-yl) -N, N-dipropyl isophthalamic (B94) (1.2 g, 78%) as a white solid.

Ester 95

5- (1,1-Dioxo-1 / acid methyl ester⁶- [1,2] thiazinan-2-yl) -N, N-dipropyl isophthalamic (B95)

Ester 95 was prepared in a similar manner to

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225 of Ester 94 from 5- (4-chlorobutane-1-sulfonylamino) -N, N-dipropyl isophthalamic acid methyl ester (D92).

Ester 100

Fluoro- (2-oxo-pyrrolidin-lil) -trifluoromethyl-benzoic acid methyl ester (B100)

3-Bromo-2-fluoro-5-trifluoromethylbenzoic acid methyl ester (D29a) (500 mg, 1.95mmol, 1 eguiv.),

CS2CO3 (950 mg, 2.92 mmol, 1.5 equiv), pyrrolidin-2-one (248 mg, 2.92 mmol, 1.5 equiv), Xantphos (68 mg, 0.117 mmol, 0.06 equiv) .) and tris (dibenzylidenoacetone) dipaladium (0) (36 mg, 0.039 mmol, 0.02 equiv.) were heated at reflux under argon in dioxane (7 mL) for 18 hours. After cooling, the mixture was filtered and evaporated in vacuo. Purification by silica gel flash chromatography (EtOAc / isohexane: 1/4 to 1/2) gave fluoro (2-oxo-pyrrolidin-1-yl) trifluoromethyl benzoic acid methyl ester (B100) ( 195 mg, 32%). [M + H]⁺ 306,2.

The following compounds (Esters 101-102) were prepared in a manner analogous to that described for Description 68 from the appropriate aryl bromide starting material as indicated in the table below using the appropriate 2,4,6-trialcenylcyclotriboroxane-pyridine complex as described by F. Kerins and DF O'Shea in J. Org. Chem, 2002, 67, 4968-4971:

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<td>description</td><td>Bromide of aryl</td><td>[M + H]⁺</td><td>RT (min)</td>

<td>3- (2—- Acid methyl ester methyl propenyl) -5- (2-oxo pyrrolidin-1-yl) benzoic (B101)</td><td>D9a</td><td> 2, 74</td><td> 3,14</td>

<td>3- (2-Oxoacetic acid methyl ester pyrrolidin-1-yl) -5 - ((E-styryl) - benzoic (B102)</td><td>D91</td><td></td><td></td>

The following compounds were prepared in a manner analogous to the process described for 3- (2-oxo-piperidin-1-yl) -5-propyl-benzoic acid tert-butyl ester (B116):

<td>Ester</td><td>Alken</td><td>[M + H]⁺</td><td>RT (min)</td>

<td>3-Isopropyl acid methyl ester 5- (2-oxo-pyrrolidin-1-yl) -benzoic (Bl04)</td><td>D71</td><td> 248,1</td><td> 2,77</td>

<td>3- (2-Oxoacetic acid methyl ester pyrrolidin-1-yl) -5-propylbenzoic (Bl06)</td><td>D72</td><td> 262,1</td><td> 3,04</td>

<td>3-Cyclopentric acid methyl ester til-5- (2-oxo-pyrrolidin-1-yl) - benzoic (B107)</td><td>D74</td><td> 288,1</td><td> 3,26</td>

<td>3-Cyclic acid methyl ester hexyl-5- (2-oxopyrrolidin-1-yl) - benzoic (B108)</td><td>D74</td><td></td><td></td>

<td>3- (1,1-Acid-tert-butyl ester) dioxo-1 /⁶- [1,2] thiazin-2-yl) -5-propyl benzoic (B112)</td><td>D6 9</td><td></td><td></td>

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Ester 109

3-Ethinyl-5- (2-oxo-pyrrolidin-1-yl) -benzoic acid tert-butyl ester (B109)

Ester 109 was prepared analogously to the process described for Ester 111 from 300 mg (mmol) of 3- (3-hydroxy-3-methyl-but-1-ynyl) -5- ( 2-oxo-pyrrolidin-1-yl) -benzoic acid (D76) which gave 220 mg (88%) of 3etinyl-5- (2-oxo-pyrrolidin-1-yl) -benzoic acid tert-butyl ester (B109) ) as an off-white solid.

Ester 111

3- (1,1-Dioxo-1 / tert-butyl ester)⁶isothiazolidin-2-yl) -5-ethynylbenzoic acid (B11l)

To a solution of tert-butyl ester of 3- (1,1-dioxo-1 /⁶-isothiazolidin-2-yl) -5- (3-hydroxy-3-methylbut-1-ynyl) -benzoic acid (D75) (142 mg, 0.37 mmol, 1 equiv) in toluene (20 mL) was added NaH (60% dispersion in mineral oil, 4 mg, 0.1 mmol, 0.3 equiv.). The resulting mixture was stirred at 110 ° C for 30 min, cooled to room temperature and diluted with EtOAc. The organic phase was washed with saturated aqueous NaHCO 3 solution.₃, dried over MgSO₄ and concentrated in vacuo to give 3- (1,1-dioxo-1 / tert-butyl ester).⁶-isothiazolidin-2-yl) -5etinylbenzoic acid (B11l) (142 mg, 118%) as a light yellow oil.

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Ester 116

3- (2-Oxo-piperidin-1-yl) 5-propyl-benzoic acid tert-butyl ester (B116)

To a solution of 3- (2-oxo-piperidin-1-yl) -5- (E / Z) -propenyl-benzoic acid tert-butyl ester (D68) (485 mg, 1.5 mmol, 1 equiv.) in EtOH (10 mL) and H₂O (2 mL) was added 10% palladium on charcoal (50% wet, 485 mg, 5% w / w) and NH₄COOH (945 mg, 15 mmol, 10 equiv.). The resulting mixture was stirred at 65 ° C for 1 hour and then cooled to room temperature. Most of the EtOH was removed in vacuo and the residue was dissolved in EtOAc. The organic phase was washed with H₂O, dried over MgSO₄ and concentrated in vacuo to give 3- (2-oxo-piperidin-1-yl) -5-propylbenzoic acid tert-butyl ester (B116) (300 mg, 70%) as a colorless oil.

Ester 117

Methyl 3- (1,1-dioxide-6,7-dihydro-1,2-thiazepin-2 (3H) -yl) -5propylbenzoate (B117)

To a solution of methyl (D135) 3 - [(3-buten-1-ylsulfonyl) (2propen-1-yl) amino] -5-propylbenzoate (1 g, 2.8 mmol, 1 equiv.)₂C1₂ (200 mL) bis (tricyclohexylphosphino) benzylidene ruthenium (IV) dihydrochloride (117 mg, 0.14 mmol, 0.05 equiv) was added and the resulting solution was stirred at room temperature for 48 h

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229 and then concentrated in vacuo. Purification of the residue by silica gel flash chromatography (9: 1 isohexane / AcOEt: 9) gave 3- (1,1-dioxide-6,7-dihydro-1,2-thiazepin-2 (3H) -yl) - Methyl 5-propylbenzoate (B117) (700 mg, 76%) as a light purple oil. [M + H]⁺ = 324.4, RT = 3.10 minutes.

Ester 118

Methyl 5- (ethylamino) -2-fluoro-3- (2-oxo-1-pyrrolidinyl) benzoate (B118)

To a solution of methyl 5- (ethyl {[4- (methyloxy) phenyl] methylamino) -2-fluoro-3- (2-oxo-1-pyrrolidinyl) benzoate (D155) (7 g, 17.5 mmol, 1 equiv.) In EtOH (150 mL) was added 10% palladium on charcoal (50% wet, 1.4 g, 10% w / w) and the resulting mixture was stirred under a hydrogen atmosphere (1 atm) for 3 hours. The catalyst was filtered off through a pad of celite and the solution was concentrated in vacuo. The residue was triturated with AcOEt / isohexane to give methyl 5- (ethylamino) -2-fluoro-3- (2-oxo-1-pyrrolidinyl) benzoate (B118) (4.8 g, 98%) as a solid green that was used in the next step without further purification. [M + H]⁺ = 281.2, RT = 2.35 minutes

The following esters were obtained from the appropriate precursor in a manner analogous to the procedure described for Ester 35 (B35) using acetaldehyde instead of propionaldehyde.

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<td>Ester</td><td>Precursor</td><td>[M + H]⁺</td><td>RT (min)</td>

<td>3- (1,1-dioxide tetrahydro-2H-1,2- thiazin-2-yl) -5- (ethylamino) -2- methyl fluorobenzoate (B119)</td><td>D152</td><td> 331,2</td><td> 2, 80</td>

<td>3- (1,1-dioxide-2-isothiazolidinyl) - 5- (ethylamino) -2-fluorobenzoate methyl (B122)</td><td>D151</td><td> 317,1</td><td> 2,64</td>

<td>3- (1,1-dioxide tetrahydro-2H-1,2- thiazin-2-yl) -5- (ethylamino) -2- methyl (methyloxy) benzoate</td><td>D153</td><td> 343,2</td><td> 2,64</td>

The following compounds were prepared analogously to the process described for 3- (2-oxo-piperidin-1-yl) -5-propyl-benzoic acid tert-butyl ester (B116) from their appropriate precursor:

<td>Ester</td><td>Precursor</td><td>[M + H]⁺</td><td>RT (min)</td>

<td>2-fluoro-3- (2-oxo-1-pyrrolidinyl) - Methyl 5-propylbenzoate (B120)</td><td>D159</td><td> 280,2</td><td> 2, 73</td>

<td>3- (1,1-dioxide-tetrahydro-2/1-1,2-yl thiazin-2-yl) -2-fluoro-5-propyl methyl benzoate (B173)</td><td>D161</td><td> 330,2</td><td> 2,91</td>

<td>3- (1,1-dioxide-2-isothiazolidinyl) - 2-fluoro-5-propylbenzoate of methyl (B174)</td><td>D160</td><td></td><td> 2, 74</td>

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Ester 121

1,1-Dimethylethyl 3- (2-oxo-5-phenyl-1-piperidinyl) -5-propylbenzoate (B121)

1,1-Dimethylethyl 3- (2-oxo-5-phenyl-1-piperidinyl) -5-propylbenzoate (B121) was prepared from 3- (2- οχο-5-phenyl-1-piperidinyl) -5 1,1-dimethylethyl [[(1E / Z) -1-propen-1-yl] benzoate (D192) in a manner analogous to the process described for 3- (2-oxo-piperidin-3-yl) tert-butyl ester 1-yl) -5-propylbenzoic acid (B116). [M + H]⁺ =

394.3, R T = 3.88 min.

Ester 123

Methyl 3- (1,1-dioxide-4-phenylthetrahydro-2H-1,2-thiazin-2-yl) 5-nitrobenzoate (B123)

A flask under nitrogen was charged with methyl 3-bromo-5-nitrobenzoate (D11) (136 mg, 0.52 mmol, 1.1 equiv), CS2CO3 (216 mg, 0.66 mmol, 1.4 equiv.) tris (dibenzylidoneacetone) dipaladium (0) (22 mg, 0.023 mmol,

0.05 equiv.), Xantphos (27 mg, 0.047 mmol, 0.1 equiv.) And toluene (10 mL). Then 4-phenylthetrahydro-2H-1,2-thiazine 1,1-dioxide (J. Morris, DG Wishka J. Org. Chem. 1991, 56, 3549-3556, 100 mg, 0.47 mmol, 1 equiv.) and the resulting mixture was stirred at 120 ° C for 5 hours and then cooled to

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232 ambient and concentrated in vacuo. The residue was partitioned between H₂0 and EtOAc and the aqueous phase was back extracted with EtOAc. The combined organic solutions were dried over MgSO4.₄ and concentrated in vacuo. Purification of the residue by silica gel flash chromatography (isohexane / AcOEt: 7/3) gave 3- (1,1-dioxide-4-phenylthetrahydro-2H-1,2-thiazin-2yl) -5 methyl nitrobenzoate (B123) (110 mg, 60%) as a yellow oil. [M + H + NH 3]⁺ = 408.3, RT = 3.24 minutes

Ester 124

Methyl 3-amino-5- (1,1-dioxide-4-phenylthetrahydro-2H-1,2-thiazin-2-yl) benzoate (B124)

Methyl 3-amino-5- (1,1-dioxide-4-phenylthetrahydro-2B-1,2-thiazin-2-yl) benzoate (B124) was obtained from 3- (1,1-dioxide-4) -phenyl tetrahydro-2H-1,2-thiazin-2-yl) methyl 5-nitrobenzoate (B123) in a similar manner to the process described for Description 16 (D16). [M + H]⁺ =

361.3, RT = 2.91 minutes

Ester 125

Methyl 3- (1,1-dioxide-4-phenylthetrahydro-2H-1,2-thiazin-2-yl) 5- (ethylamino) benzoate (B125)

Methyl 3- (1,1-dioxide-4-phenylthetrahydro-2H-1,2-thiazin2-yl) -5- (ethylamino) benzoate (B125) was obtained from 3-amino-5- (1 methyl 1-dioxide-4-phenylthetrahydro-2H-1,2-thiazin-2-yl) benzoate (B124) in a similar manner

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233 to the process described for Ester 35 (B35) using acetaldehyde instead of propionaldehyde. [M + H]⁺ = 389.4, TR =

3.23 minutes

Ester 126

Methyl 3-cyclopentyl-5- (1,1-dioxide-tetrahydro-2H-1,2-thiazin2-yl) benzoate (B126)

Methyl 3-cyclopentyl-5- (1,1-dioxide-tetrahydro-2H-1,2-thiazin-2-yl) benzoate (B126) was obtained from 3- (1-cyclopenten-1-yl) -5- Methyl (1,1-dioxide-tetrahydro-2 H -1,2-thiazin-2-yl) benzoate, 3- (2-cyclopenten-1-yl) -5 (1,1-dioxotetrahydro-2 H) methyl-1,2-thiazin-2-yl) benzoate and methyl 3- (3-cyclopenten-1-yl) -5- (1,1-dioxide-tetrahydro-2 H -1,2-thiazin-2-yl) benzoate methyl (D265) in a similar manner to the procedure described for Ester 107 (B107).

Ester 127

Methyl 3- (1,1-dioxide-tetrahydro-2H-1,2-thiazin-2-yl) -5 [(methylethyl) amino] benzoate (B127)

Methyl 3- (1,1-dioxide-tetrahydro-2 H -1,2-thiazin-2-yl) -5 [(methylethyl) amino] benzoate (B127) was obtained from 3-amino-5- Methyl (1,1-dioxide-tetrahydro-2 H -1,2-thiazin-2-yl) benzoate (D194) in a similar manner to the procedure described for Ester 35 (B35) using acetone instead of propionaldehyde. [M + H]⁺ = 327.2, RT = 2.82 minutes

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Ester 128

1,1-dimethylethyl 3- [ethyl (methyl) amino] -5- (2-oxo-1-pyrrolidinyl) benzoate (B128)

1,1-Dimethylethyl 3- [ethyl (methyl) amino] -5- (2-oxo-1-pyrrolidinyl) benzoate (B128) was obtained from 3- [ethyl (methyl) amino] -5- (2- 1,1-dimethylethyl oxo-1-pyrrolidinyl) benzoate (B32) analogously to the process described in Ester 35 (B35) using acetaldehyde instead of propionaldehyde. [M + H]⁺ = 319.4, TR = 3.17 minutes

The following compounds were obtained from their corresponding precursors in a manner analogous to the process described for Ester 35 (B35) using acetaldehyde instead of propionaldehyde and the appropriate precursor indicated in the table below.

<td>Ester</td><td>Precursor</td><td>[M + H]⁺</td><td>RT (min)</td>

<td>3- (ethylamino) -4-methyl-5- (2-oxo-1- pyrrolidinyl) methyl benzoate (B129)</td><td>D184</td><td> 277, 1</td><td> 2, 63</td>

<td>3- (1,1-dioxide-2-isothiazolidinyl) - 5- (ethylamino) -4-methylbenzoate of methyl (B130)</td><td>D186</td><td> 313,1</td><td> 2, 79</td>

<td>3- (1,1-dioxide tetrahydro-2B-1,2- thiazin-2-yl) -5- (ethylamino) -4- methyl methyl benzoate (B131)</td><td>D188</td><td> 327,1</td><td> 2, 93</td>

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235 (continuation)

<td>Ester</td><td>Precursor</td><td>[M + H]⁺</td><td>RT (min)</td>

<td>3- (1,1-dioxide tetrahydro-2H-1,2- thiazin-2-yl) -5- (ethylamino) -4- (methoxy) methyl benzoate (B132)</td><td>D187</td><td> 343,1</td><td> 2, 90</td>

<td>3- (ethylamino) -4- (methyloxy) -5- (2- oxo-1-pyrrolidinyl) benzoate from methyl (B133)</td><td>D183</td><td> 293,1</td><td> 2,64</td>

<td>3- (1,1-dioxide-2-isothiazolidinyl) - 5- (ethylamino) -4- (methyloxy) benzoate methyl (B134)</td><td>D185</td><td> 329,1</td><td> 2, 79</td>

Ester 135

Methyl 3- (diethylamino) -5- (1,1-dioxide-tetrahydro-2H-1,2-thiazin-2-yl) -4-methylbenzoate (B135)

Methyl 3- (diethylamino) -5- (1,1-dioxide-tetrahydro-2H-1,2-thiazin-2-yl) -4-methylbenzoate (B135) was obtained as a by-product during the synthesis of 3- (1, Methyl 1-hydroxy-tetrahydro-2H-1,2-thiazin-2-yl) -5- (ethylamino) -4-methylbenzoate (B131) from 3-amino-5- (1,1-hydroxy-tetrahydro-2H-1,2) methyl thiazin-2-yl) -4-methylbenzoate (D188). [M + H]⁺ = 355.1, TR = 2.95 minutes

Ester 136

3- (1,1-dioxide-tetrahydro-2H-1,2-thiazin-2-yl) -4- (methyloxy) -5 - [(1E / Z) -1-propen-1-yl] benzoate methyl (B136)

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To a solution of methyl 3- {[(4-chlorobutyl) sulfonyl] amino} -4- (methyloxy) -5 - [(1E / Z) -1-propen-1-yl] benzoate (D170) (650 mg 1.72 mmol, 1 equiv) in EtOH (50 mL) was added NEt₃ (500 µL, 3.6 mmol, 2.1 equiv.) And the resulting solution was heated at reflux for 6 hours and then cooled to room temperature and concentrated in vacuo. The residue was dissolved in EtOAc and the organic phase was washed with 2 N aqueous HCl solution and saturated aqueous NaHCO 3 solution.₃, dried over MgSO₄ and concentrated in vacuo. Purification of the residue by silica gel flash chromatography (isohexane / AcOEt: 3/1) gave 3- (1,1-dioxide-tetrahydro-2H-1,2-thiazin-2-yl) -4 (methyloxy). Methyl) -5 - [(1E / Z) -1-propen-1-yl] benzoate (B136) (450 mg, 77%) as a light yellow oil. [M + H]⁺ =

340.0, R T = 3.14 minutes

Ester 138

Methyl 3- (1,1-dioxide-2-isothiazolidinyl) -5- (2-oxo-1-pyrrolidinyl) benzoate (B138)

Methyl 3- (1,1-dioxide-2-isothiazolidinyl) -5- (2-oxo-1-pyrrolidinyl) benzoate (B138) was obtained from 3 - [(4-chlorobutanoyl) amino] -5- (1, Methyl 1-dioxide-2-isothiazolidinyl) benzoate (D195) in a manner analogous to the process described for Ester 27 (B27). [M + H]⁺ = 339.0, TR = 2.41 minutes

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Methyl 140-1-ethyl-4- (2-oxo-1-pyrrolidinyl) -1H-indole-6-carboxylate ester (B140)

To a solution of methyl 4- (2-oxo-1-pyrrolidinyl) -1H-indole-6-carboxylate (B154) (500 mg, 1.94 mmol, 1 eiv.) In DMF (10 mL) was added at room temperature. NaH (60% dispersion in mineral oil, 84 mg, 2.1 mmol, 1.1 eguiv.) and the resulting mixture was stirred for 15 minutes. Ethyl iodide (200 µl, 2.5 mmol,

1.3 eguiv.) And the resulting solution was stirred for 30 minutes and then concentrated in vacuo. The residue was dissolved in EtOAc and the organic phase was washed with 2 N aqueous HCl solution, dried over MgSO 4 and concentrated in vacuo. Purification of the residue by silica gel flash chromatography (EtOAc / isohexane: 1/4 to 1/1) gave 1-ethyl-4- (2-oxo-1-pyrrolidinyl) -1H-indole-6-carboxylate (B140) (400 mg, 72%) as an off-white solid. [M + H]⁺ = 287.0, RT = 2.73 min.

The following compounds were obtained from their corresponding precursors in a manner analogous to the process described for Description 2 (D2):

<td>Ester</td><td>Precursor</td><td>[M + H]⁺</td><td>RT (min)</td>

<td>3-Ethyl-7- (2-oxo-1-pyrrolidinyl) -</td><td>D225</td><td></td><td></td>

<td>ethyl 1H-indole-5-carboxylate</td><td></td><td></td><td></td>

<td>(BI 41)</td><td></td><td></td><td></td>

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238 (continuation)

<td>Ester</td><td>Precursor</td><td>[M + H]⁺</td><td>RT (min)</td>

<td>1-Ethyl-4- (2-oxo-1-pyrrolidinyl) - 1H-benzimidazole-6-carboxylate methyl (B149)</td><td>D227</td><td></td><td></td>

<td>1-Ethyl-4- (2-oxo-1-pyrrolidinyl) - 1H-indazole-6-carboxylate from methyl (B152)</td><td>D229</td><td> 288, 4</td><td> 2,20</td>

<td>4- (2-oxo-1-pyrrolidinyl) -1H- methyl indole-6-carboxylate (B154)</td><td>D228</td><td> 259, 0</td><td> 2,22</td>

<td>3-Methyl-7- (2-oxo-1-pyrrolidinyl) - ethyl 1H-indole-5-carboxylate (Bl6 0)</td><td>D224</td><td></td><td></td>

<td>3- (1-Methylethyl) -7- (2-oxo-1- pyrrolidinyl) -1H-indole-5- ethyl carboxylate (B161)</td><td>D226</td><td></td><td></td>

<td>4-Ethyl-8- (2-oxo-1-pyrrolidinyl) - 1,2,3,4-tetrahydro-6-quinoline methyl carboxylate (B171)</td><td>D230</td><td> 304,3</td><td> 2,52</td>

Ester 142

Ethyl 3-ethyl-1-methyl-7- (2-oxo-1-pyrrolidinyl) -1H-indole-5-carboxylate (B142)

To a solution of ethyl 3-ethyl-7- (2-oxo-1-pyrrolidinyl) 1H-indole-5-carboxylate (B141) (658 mg, 2.3 mmol,

ΡΕ1567488

239 equiv.) in DMF (10 mL) at room temperature was added NaH (60% dispersion in mineral oil, 120 mg, 3.0 mmol,

1.3 equiv.) And the resulting mixture was stirred for 15 minutes at this temperature. Ethyl iodide (187 µl, 3.0 mmol, 1.3 equiv) was added and the resulting solution was stirred for 30 minutes and then concentrated in vacuo. The residue was dissolved in EtOAc and the organic phase was washed with H₂O, dried over MgSO₄ and concentrated in vacuo. The residue was triturated with isohexane to give ethyl 3-ethyl-1-methyl-7- (2-oxo-1-pyrrolidinyl) -1H-indole-5-carboxylate (620 mg, 90%) as a yellow solid which was used in the next step without further purification.

Ester 143

Methyl 4- (1,1-dioxide-2-isothiazolidinyl) -1-ethyl-1H-indole-6-carboxylate (B143)

To a solution of methyl 4 - {[(3-chloropropyl) sulfonyl] amino} -1-ethyl-1H-indole-6-carboxylate (D241) (900 mg, 2.5 mmol, 1 equiv) in EtOH ( 100 mL) NEt was added₃HCl (1 mL, 7.3 mmol, 3 equiv.) And the resulting solution was heated at reflux for 1.5 hours and then cooled to room temperature and concentrated in vacuo. The residue was dissolved in EtOAc and the organic phase was washed with 2N aqueous HCl solution, dried over MgSO4.₄and concentrated in vacuo to give methyl 4- (1,1-dioxide-2isothiazolidinyl) -1-ethyl-1H-indole-6-carboxylate (B143) (386 mg, 48%) as a brown oil which was used in step following without further purification.

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Ester 144

Ethyl 7- (1,1-dioxide-2-isothiazolidinyl) -3-ethyl-1H-indole-5-carboxylate (B144)

Ethyl 7- (1,1-dioxide-2-isothiazolidinyl) -3-ethyl-1H-indole-5-carboxylate (B144) was obtained from 7 {[(3-chloropropyl) sulfonyl] amino} -3- ethyl ethyl 1H-indole-5-carboxylate (D243) in a manner analogous to the procedure described for methyl 4- (1,1-dioxide-2-isothiazolidinyl) -1-ethyl-1H-indole-6-carboxylate (B143) . [M + H]⁺ = 337.1, TR =

3.23 minutes

Ester 145

Methyl 4- (1,1-dioxide-tetrahydro-2H-1,2-thiazin-2-yl) -1-ethyl2,3-dihydro-1H-indole-6-carboxylate

To a solution of methyl 1-acetyl-4- (1,1-dioxide-tetrahydro-2H-1,2-thiazin-2-yl) -2,3-dihydro-1H-indole carboxylate (D235) (300 mg 0.85 mmol, 1 equiv) in THF (20 mL) at room temperature was added BH₃ (1.5 M in THF, 2 mL, 3 mmol, 3.5 equiv) and the resulting mixture was stirred at room temperature for 15 hours. EtOH (5 mL) was added and the resulting mixture was concentrated in vacuo after 5 minutes. The residue was partitioned between 2 N aqueous HCl (20 mL) and CH 2 Cl 2 (20 mL) and the biphasic mixture was stirred vigorously for 3 hours.

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The two layers were separated and the organic phase was dried over MgSO4 and concentrated in vacuo. Purification of the residue by silica gel flash chromatography (EtOAc / isohexane: 1/2) gave 4- (1,1-dioxide-tetrahydro-2H1.2-thiazin-2-yl) -1-ethyl-2 Methyl 3-dihydro-1H-indole carboxylate (B145) (200 mg, 70%) as a very light yellow solid. [M + H]⁺ = 339.2, RT = 2.92 minutes

Ester 146

Ethyl 7- (1,1-dioxide-2-isothiazolidinyl) -3-ethyl-1-methyl-1H-indole-5-carboxylate (B146)

Ethyl 7- (1,1-dioxide-2-isothiazolidinyl) -3-ethyl-1-methylH-indole-5-carboxylate (B146) was prepared from 7- (1,1-dioxide-2-isothiazolidinyl) Ethyl -3-ethyl-1H-indole-5-carboxylate (B144) in a similar manner to the procedure described for Ester 142 (B142).

Ester 147

Methyl 4- (1,1-dioxide-tetrahydro-2H-1,2-thiazin-2-yl) -1-ethyl-indole-6-carboxylate (B147)

To a solution of methyl 4- (1,1-dioxide-tetrahydro-2β-1,2-thiazin-2-yl) -1H-indole-6-carboxylate (D231) (180 mg, 0.58 mmol, 1 mL). equiv.) in DMF (3 mL) at room temperature was added NaH (60% dispersion in mineral oil, 24 mg, 0.6 mmol, 1 equiv.) and the resulting mixture was

ΡΕ1567488

242 stirred for 15 minutes at this temperature. Ethyl iodide (64 µl, 0.8 mmol, 1.4 equiv) was added and the resulting solution was stirred for 1 hour and then concentrated in vacuo. The residue was dissolved in EtOAc and the organic phase was washed with 2 N aqueous HCl solution, dried over MgSO4.₄ and concentrated in vacuo. Purification of the residue by silica gel flash chromatography gave methyl 4- (1,1-dioxide-tetrahydro-2 H -1,2-thiazin-2-yl) -1-ethyl-1H-indole-6-carboxylate (B147 ) (110 mg, 51%) as a yellow solid which was used for the next step without further purification. [M + H]⁺ = 337.0, TR = 2.82 minutes

Ester 148

Ethyl 7- (1,1-dioxide-tetrahydro-2H-1,2-thiazin-2-yl) -3-ethyl-indole-5-carboxylate (B148)

To a solution of ethyl 7- {[(4-chlorobutyl) sulfonyl] amino} -3-ethyl-1H-indole-5-carboxylate (D242) (230 mg,

0.59 mmol, 1 equiv.) In EtOH (10 mL) was added NEt₃ (249 µL, 1.78 mmol, 3 equiv.) And the resulting solution was stirred at 70 ° C for 3 hours. Added NEt₃ HCl (1 mL, excess) and the solution was stirred at the same temperature for 15 hours and then cooled to room temperature and concentrated in vacuo. The residue was dissolved in EtOAc and the organic phase was washed with 2 N aqueous HCl solution, dried over MgSO4.₄ and concentrated in vacuo. Purification of the residue by silica gel flash chromatography (EtOAc / isohexane: 3/7) gave 7- (1,1-dioxide tetrahydro-2HΡΕ1567488

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Ethyl 1,2-thiazin-2-yl) -3-ethyl-1H-indole-5-carboxylate (B148) (150 mg, 72%) as a colorless oil. [MH] _ = 349.3, RT = 3.10 minutes

Ester 150

Methyl 4- (1,1-dioxide-2-isothiazolidinyl) -1-ethyl-1H-benzimidazole-6-carboxylate (B150)

Methyl 4- (1,1-dioxide-2-isothiazolidinyl) -1-ethyl-1H-benzimidazole-6-carboxylate (B150) was obtained from 4- {bis [(3-chloropropyl) sulfonyl] amino} - Methyl 1-ethyl-1H-benzimidazole-6-carboxylate (D239) in a manner analogous to the procedure described for methyl 4- (1,1-dioxide-2-isothiazolidinyl) -1-ethyl-1H-indazole-6-carboxylate methyl (B153) [M + H]⁺ = 324.5, TR = 2.10 minutes

Ester 151

Methyl 4- (1,1-dioxide-tetrahydro-2H-1,2-thiazin-2-yl) -1-ethyl-benzimidazole-6-carboxylate (B151)

To a solution of methyl 4- (1,1-dioxide-tetrahydro-2H1,2-thiazin-2-yl) -1H-benzimidazole-6-carboxylate (D253) (230 mg, 0.74 mmol, 1 equiv. ) in DMF (10mL) at room temperature was added NaH (60% dispersion in mineral oil, 33 mg, 0.82 mmol, 1.1 equiv) and the resulting mixture was stirred for 5 minutes at this temperature. Ethyl iodide (66 µL, 0.82 mmol, 1.1

ΡΕ1567488

244 equiv.) and the resulting solution was stirred for 30 minutes at 60 ° C and then cooled to room temperature and concentrated in vacuo. The residue was partitioned between EtOAc and a 5% aqueous citric acid solution. The two layers were separated and the aqueous phase was saturated with NaCl and extracted twice with EtOAc. The combined organic phases were dried over MgSO4.₄ and concentrated in vacuo to give methyl 4- (1,1-dioxide-tetrahydro-2 H -1,2-thiazin-2-yl) -1-ethyl-1H-benzimidazole-6-carboxylate (B151) (400 mg, 160% ) as a viscous light yellow oil which was used in the next step without further purification. [M + H]⁺ = 338.1, RT = 2.43 minutes

Ester 153

Methyl 4- (1,1-dioxide-2-isothiazolidinyl) -1-ethyl-1H-indazole-6-carboxylate (B153)

To a solution of methyl 4- {bis [(3-chloropropyl) sulfonyl] amino} -1-ethyl-1H-indazole-6-carboxylate (D237) (1.5 g, 3 mmol, 1 equiv) in EtOH (20 mL) was added Net₃(920 µl, 6.6 mmol, 2.2 equiv.) And the resulting solution was heated at reflux for 3 hours and then cooled to room temperature and concentrated in vacuo. The residue was dissolved in EtOAc and the organic phase was washed with 2 N aqueous HCl solution, dried over MgSO4.₄ and concentrated in vacuo. The residue was triturated with EtOAc / isohexane to give methyl 4- (1,1-dioxide-2-isothiazolidinyl) -1-ethyl-1H-indazole-6-carboxylate (B153) as

ΡΕ1567488

245 a light brown solid which was used in the next step without further purification. [M + H]⁺ = 324.5, RT = 2.35 min.

The following compounds were obtained from Ester 154 (B154) in a manner analogous to the process described for Ester 140 (B140) using the appropriate alkylating reagent:

<td>Ester</td><td>Reagent alkylating</td><td>[M + H]⁺</td><td>RT (min)</td>

<td>1-Methyl-4- (2-oxo-1-pyrrolidinyl) nyl) -1H-indole-6-carboxylate methyl (B156)</td><td>_x--^!</td><td> 273,0</td><td> 2,52</td>

<td>1-Butyl-4- (2-oxo-1-pyrrolidinyl) nyl) -1,7-indole-6-carboxylate methyl (B157)</td><td></td><td> 315,1</td><td> 3,10</td>

<td>4- (2-Oxo-1-pyrrolidinyl) -1- pentyl-1H-indole-6-carboxylate of methyl</td><td>... ··· X / k</td><td></td><td></td>

Ethyl 162-1-methyl-3- (1-methylethyl) -7- (2-oxo-1-pyrrolidinyl) -1H-indole-5-carboxylate (B162) 1-methyl-3- (1-methylethyl) -7- Ethyl (2-oxo-1-pyrrolidinyl) -1H-indole-5-carboxylate (B162) was obtained from 3- (1-methylethyl) -7- (2-oxo-1-pyrrolidinyl) -1H-indole Ethyl 5-carboxylate (B161) using a procedure

ΡΕ1567488

246 analogous to the process described for ethyl 3-ethyl-1-methyl-7- (2-oxol-pyrrolidinyl) -1H-indole-5-carboxylate (B142).

Ester 163

Methyl 3-ethyl-7- (2-oxo-1-pyrrolidinyl) -1-benzofuran-5carboxylate (B163)

To a solution of methyl 4 - [(2E / Z) -2-buten-1-yloxy] -3iodo-5- (2-oxo-1-pyrrolidinyl) benzoate (D258) (1.4 g, 3.37 mmol, 1 eguiv.) in DMF (20 mL) at room temperature under nitrogen was added Pd (OAc)₂ (38 mg, 0.17 mmol, 0.05 eguiv.), NaCOOH (688 mg, 10.1 mmol, 3 eguiv.), Na₂CO₃(893 mg, 8.4 mmol, 2.5 eguiv.) And NBU4 Cl (845 mg, 3.71 mmol, 1.1 eguiv.). The resulting suspension was stirred under nitrogen at 120 ° C for 1 hour and then cooled to room temperature and concentrated in vacuo. The residue was shared between AcOEt and H₂O and the two phases were separated. The organic phase was washed with saturated aqueous sodium chloride solution, dried over MgSO4.₄ and concentrated in vacuo. Purification of the residue by silica gel flash chromatography (isohexane / AcOEt: 1/1) gave methyl 3-ethyl-7- (2-oxo-1-pyrrolidinyl) -1-benzofuran-5carboxylate (B163) ( 250 mg, 26%) as a white solid. [M + H]⁺ = 288.1, TR = 3.02 minutes

Ester 164

Methyl 4- (ethyloxy) -3- [ethyl (propanoyl) amino] -5- (1-methylethyl) benzoate (B164)

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Methyl 4- (ethyloxy) -3- [ethyl (propanoyl) amino] -5- (1-methylethyl) benzoate (B164) was obtained from 4-methyl-8- (2-oxo-1-pyrrolidinyl) -2H- methyl chromene-6-carboxylate and ethyl 4- (ethyloxy) -3- [ethyl (propanoyl) amino] -5- (1-methylethenyl) benzoate (D261) in a manner analogous to the procedure described for tert-butyl ester of 3- (2-Oxo-piperidin-1-yl) -5-propyl-benzoic acid (B116).

Ester 165

Ethyl 3-ethyl-7- (2-oxo-1-piperidinyl) -1H-indole-5-carboxylate (B165)

To a solution of ethyl 3-ethyl-7-iodo-1A-indole-5-carboxylate (D190) (1 g, 2.91 mmol, 1 equiv) in toluene (10 mL) was added 2-piperidinone (346 mg, 3 50 mmol, 1.2 equiv.), K 3 PO 4 (1.24 g, 5.83 mmol, 2 equiv.), Cul (56 mg, 0.29 mmol, 0.1 equiv.) And dimethyl ethylene diamine (62 µL, 0.58 mmol, 0.2 equiv.) And the resulting mixture was stirred at 100 ° C for 15 hours and then cooled to room temperature and concentrated in vacuo. The residue was partitioned between AcOEt and H₂O and the layers were separated. The organic phase was dried over MgSO4.₄and concentrated in vacuo. Purification of the residue by silica gel flash chromatography (EtOAc / isohexane: 1/0) gave ethyl 3-ethyl-7- (2-oxo-1-piperidinyl) -hl-indole-5-carboxylate (B165) ( 250 mg, 27%) as an off-white solid. [M + H]⁺ = 315.4, TR = 2.98 minutes

ΡΕ1567488

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Ester 166

Ethyl 3-ethyl-7- (2-oxo-4-phenyl-1-pyrrolidinyl) -1H-indole-5-carboxylate (B166)

Ethyl 3-ethyl-7- (2-oxo-4-phenyl-1-pyrrolidinyl) -1H-indole-5-carboxylate (B166) was obtained from 3-ethyl-7-iodo-1H-indole-5-carboxylate (D166) in an analogous manner to the procedure described for 1,1-dimethylethyl 3-bromo-5- (2-oxo-5-phenyl-1-piperidinyl) benzoate (D190) using 4-phenyl-2-pyrrolidinone (Koelsch J. Am. Chem Soc. 1943, (65), p 2093) instead of 5-phenyl-2-piperidinone.

[M + H]⁺ = 377.2, TR = 3.60 minutes

Methyl 167-1-ethyl-4- (2-oxo-1-pyrrolidinyl) -1H-1,2,3-benzotriazole-6-carboxylate ester (B167)

To a solution of methyl 4- (2-oxo-1-pyrrolidinyl) -1H1,2,3-benzotriazolo-6-carboxylate (D249) (400 mg, 1.54 mmol, 1 equiv) in DMF (10 NaH (60% dispersion in mineral oil, 68 mg, 1.69 mmol, 1.1 equiv) was added at room temperature and the resulting mixture was stirred for 5 minutes at this temperature. Ethyl iodide (135 µl, 1.69 mmol, 1.1 equiv) was added and the resulting solution was stirred for 2 hours and then concentrated in vacuo. The residue was dissolved in AcOEt and the

ΡΕ1567488

249 organic phase was washed with H₂O, dried over MgSO 4 and concentrated in vacuo. Purification of the residue by silica gel flash chromatography (EtOAc / isohexane: 100/0) gave 1-ethyl-4- (2-oxo-1-pyrrolidinyl) -1H-1,2,3-benzotriazole-6 methylcarboxylate (270 mg, 61%) as a light yellow oil. [M + H]⁺ = 289.3, TR = 2.47 minutes

Ester 168

Methyl 3- (1,1-dioxide-tetrahydro-2H-1,2-thiazin-2-yl) -5 (ethyloxy) benzoate (B168)

Methyl 3- (1,1-dioxide-tetrahydro-2H-1,2-thiazin-2-yl) -5 (ethyloxy) benzoate (B168) was obtained from 3- (1,1-dioxide-tetrahydro- Methyl 2A-1,2-thiazin-2-yl) -5-hydroxybenzoate (D268) in a manner analogous to the procedure described for Ester 18 (B18) of Description 41 (D41).

Ester 169

Methyl 3-cyclopentyl-5- (1,1-dioxide-2-isothiazolidinyl) benzoate (B169)

Methyl 3-cyclopentyl-5- (1,1-dioxide-2-isothiazolidinyl) benzoate (B169) was obtained from 3- (3-cyclopenten-1-yl) -5- (1,1-dioxide-2-isothiazolidinyl) ) methyl benzoate, methyl 3- (2-cyclopenten-1-yl) -5- (1,1-dioxide-2-isothiazolidinyl) benzoate and 3- (1-cyclopenten-1-yl) -5 (1, methyl 1-dioxide-2-isothiazolidinyl) benzoate (D264) from

ΡΕ1567488

250 analogous to the process described for Ester 107 (B107).

Ester 170

Methyl 3- (1,1-dioxide-tetrahydro-2H-1,2-thiazin-2-yl) -5 - [(1-methylethyl) oxy] benzoate

Methyl 3- (1,1-dioxide-tetrahydro-2B-1,2-thiazin-2-yl) -5 [(1-methylethyl) oxy] benzoate (B170) was obtained from 3- (1,1-yl). -Dioxide-tetrahydro-2B-1,2-thiazin-2-yl) -5-hydroxybenzoate (D268) in a manner analogous to the procedure described for Ester 18 (B18) of Description 41 (D41) using 2-iodopropane instead of iodoethane.

Ester 172

Methyl 8- (1,1-dioxide-2-isothiazolidinyl) -4-ethyl-1,2,3,4tetrahydro-6-quinoxalinecarboxylate (B172)

Methyl 8- (1,1-dioxide-2-isothiazolidinyl) -4-ethyl-1,2,3,4-tetrahydro-6-guinoxalinecarboxylate (B172) was obtained from 8- {bis [(3-chloropropyl methyl) sulfonyl] amino) -4-ethyl-1,2,3,4-tetrahydro-6-guinoxalinecarboxylate (D238) in a manner analogous to the procedure described for 4- (1,1-dioxide-2-isothiazolidinyl) -1 methyl-1B-indazole-6-carboxylate (B153). [M + H]⁺ = 340.2, TR = 3.32 minutes

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Ester 175

Methyl 3- (1,1-dioxide-tetrahydro-2H-1,2-thiazin-2-yl) -2-fluoro-5 - [(1-methylethyl) amino] benzoate (B175)

Methyl 3- (1,1-dioxide-tetrahydro-27-1,2-thiazin-2-yl) -2-fluoro-5 - [(1-methylethyl) amino] benzoate (B175) was obtained from Description 152 ( D152) in a manner analogous to the process described for Ester 43 (B43) using acetone instead of 3-pentanone.

Ester 176

Methyl 5-cyclopentyl-3- (1,1-dioxide-tetrahydro-2H-1,2-thiazin2-yl) -2-fluorobenzoate (B176)

Methyl 5-cyclopentyl-3- (1,1-dioxide-tetrahydro-2H-1,2-thiazin-2-yl) -2-fluorobenzoate (B176) was obtained from Description (D269) in a manner analogous to the procedure described. for ester B116 (B116).

Epoxide Preparation

1,1-Dimethylethyl {(IS) -2- (3,5-difluorophenyl) -1 - [(2S) -2-oxiranylethyl] carbamate (Kl) {(IS) -2- (3,5-epoxide) epoxide difluorophenyl) -1 - [(2S) -2-oxiranylethyl}

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252 1,1-dimethylethyl carbamate (K1) was obtained from

3,5-difluoro-L-phenylalaninate (D299) according to the procedure described in US Patent 2003/0004360 A1. The following epoxides were obtained in a manner analogous to the process described for epoxide K1 using the appropriate alaninate:

<td>Epoxide</td><td>Precursor</td>

<td>{(IS) -2- (3-fluorophenyl) -1 - [(2S) -2-oxiranyl] ethyl} 1,1-dimethylethyl carbamate (K2)</td><td>D300</td>

<td>1,1-dimethylethyl {(IS) -2- (3,4-difluorophenyl) -1 - [(2S) -2-oxiranyl] ethyl} carbamate (K3)</td><td>D301</td>

<td>{(1S) -2- (2-chlorophenyl) -1 - [(2S) -2-oxiranyl] ethyl} - 1,1-dimethylethyl carbamate (K4)</td><td>D302</td>

<td>{(1S) -2- (3-chlorophenyl) -1 - [(2S) -2-oxiranyl] ethyl} - 1,1-dimethylethyl carbamate (K5)</td><td>D303</td>

<td>{(1S) -2- (4-chlorophenyl) -1 - [(2S) -2-oxiranyl] ethyl} - 1,1-dimethylethyl carbamate (K6)</td><td>D304</td>

<td>[(1S) —1— [(2S) -2-oxiranyl] -2- (2-thienyl) ethyl] - 1,1-dimethylethyl carbamate (K7)</td><td>D305</td>

<td>[(1S) —1— [(2S) -2-oxiranyl] -2- (3-thienyl) ethyl] - 1,1-dimethylethyl carbamate (K8)</td><td>D306</td>

<td>{(1S) -2- (2-furanyl) -1 - [(2S) -2-oxiranyl] ethyl 1,1-dimethylethyl carbamate (K9)</td><td>D307</td>

<td>[(1S) —1— [(2S) -2-oxiranyl] -2- (2-pyridinyl) ethyl] - 1,1-dimethylethyl carbamate (K10)</td><td>D308</td>

ΡΕ1567488

253 (continuation)

<td>Epoxide</td><td>Precursor</td>

<td>[(1S) —1 - [(2S) -2-oxiranyl] -2- (1,3-thiazol-2-one) 1,1-dimethylethyl yl] ethyl] carbamate (K11)</td><td>D309</td>

<td>[(1S) —1 - [(2S) -2-oxiranyl] -2- (1H-pyrazol-1- 1,1-dimethylethyl yl] ethyl] carbamate (K12)</td><td>D310</td>

<td>[(1S) —1— [(2S) -2-oxiranyl] -2- (3-pyridinyl) ethyl] - 1,1-dimethylethyl carbamate (K13)</td><td>D311</td>

Preparation of BOC-protected amines

BOC-protected Amine 1 (Hl)

((IS, 2R) -1-Benzyl-3-cyclohexylamino-2-hydroxypropyl) -carbamic acid tert-butyl ester (H1)

((S) - (S) -1-Oxiranyl2-phenyl-ethyl) -carbamic acid tert-butyl ester (D101) (10 g, 38 mmol, 1 equiv.) [Chirex 1819W94 Lot # 9924382] was dissolved in EtOH (100 mL) and cyclohexylamine (13 mL, 114 mmol, 3 equiv.) Was added. The resulting mixture was heated under a nitrogen atmosphere for 12 hours at reflux temperature. The mixture was cooled and the solvent was removed by evaporation in vacuo. The resulting white solid was washed with H₂O and then with Et₂O before drying in vacuo to give ((1S, 2R) -1benzyl-3-cyclohexylamino-2-hydroxypropyl) -carbamic acid tert-butyl ester (Hl) (9.0 g, 66%) . [M + H]⁺ = 363,2

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BOC-protected amines H2-H20, H24-H33 and H36 were prepared in a manner similar to that described for BOC-protected amine H1, replacing cyclohexylamine with the amines indicated in the table below (unless when amines are commercially available). ):

<td>BOC-protected amine</td><td>Precursor</td>

<td>((1S, 2R) -1-Benzyl-acid-tert-butyl ester 3-cyclobutylamino-2-hydroxypropyl) carbamic (H2)</td><td></td>

<td>((IS, 2R) -1-Benzyl-acid tert-butyl ester 2-hydroxy-3-isobutylamino-propyl) -carbamic (H3)</td><td> -</td>

<td>((IS, 2R) -1-Benzyl-acid tert-butyl ester 2-hydroxy-3-propylamino-propyl) -carbamic (H4)</td><td> -</td>

<td>[(IS, 2R) -1-Benzyl-acid tert-butyl ester 2-hydroxy-3- (1,1,5-trimethylhexylamino) propyl] - carbamic (H5)</td><td>F5</td>

<td>[(IS, 2R) -1-Benzyl-acid tert-butyl ester 3- ((S) -1-cyclohexylcarbamoyl-ethylamino) -2- hydroxypropyl] carbamic (H6)</td><td>F6</td>

<td>{(IS, 2R) -1-Benzyl-acid tert-butyl ester 2-hydroxy-3 - [(R) -1- (3-methoxyphenyl) ethylamino] - propyl} -carbamic (H7)</td><td></td>

<td>[(IS, 2R) -1-Benzyl-acid tert-butyl ester 2-hydroxy-3- (1-methyl-1-phenyl-ethylamino) -propyl] - carbamic (H8)</td><td></td>

<td>[(IS, 2R) -1-Benzyl-acid tert-butyl ester 2-hydroxy-3- (3-methyl butylamino) propyl] - carbamic (H9)</td><td></td>

ΡΕ1567488

255 (continuation)

<td>BOC-protected amine</td><td>Precursor</td>

<td>((1S, 2R) -1-Benzyl-acid-tert-butyl ester 3-tert-Butylamino-2-hydroxypropyl) carbamic (H10)</td><td></td>

<td>[(IS, 2R) -1-Benzyl-acid tert-butyl ester 2-hydroxy-3- (3-trifluoromethoxy-benzylamino) - propyl] carbamic (Hll)</td><td></td>

<td>[(IS, 2R) -1-Benzyl-acid tert-butyl ester 2-hydroxy-3- (2,2,3,3,3-pentafluoro-propylamino) - propyl] carbamic (H12)</td><td></td>

<td>[(IS, 2R) -1-Benzyl-acid tert-butyl ester 3- (2,2,3,3,4,4,4-heptafluoro-butylamino) -2- hydroxypropyl] carbamic (H13)</td><td></td>

<td>[(IS, 2R) -1-Benzyl-acid tert-butyl ester 2-hydroxy-3- (3-methoxy-benzylamino) -propyl] carbamic (H14)</td><td></td>

<td>{(IS, 2R) -1-Benzyl-acid tert-butyl ester 2-hydroxy-3- [1- (3-methoxy-phenyl) -1-methyl-2-one ethylamino] propyl} carbamic (H15)</td><td>F15</td>

<td>[(IS, 2R) -1-Benzyl-acid tert-butyl ester 2-hydroxy-3- (3-trifluoromethyl benzylamino) - propyl] carbamic (H16)</td><td></td>

<td>{(IS, 2R) -1-Benzyl-acid tert-butyl ester 2-hydroxy-3 - [(S) -1- (3-methoxyphenyl) ethylamino] - propyl} -carbamic (H17)</td><td></td>

<td>{(IS, 2R) -1-Benzyl-acid tert-butyl ester 2-hydroxy-3 - [(S) -1- (3-methoxyphenyl) ethylamino] - propyl} -carbamic (H18)</td><td></td>

ΡΕ1567488

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<td>BOC-protected amine</td><td>Precursor</td>

<td>[(IS, 2R) -1-Benzyl-acid tert-butyl ester 2-hydroxy-3- (5-methylhexylamino) propyl] - carbamic (H19)</td><td></td>

<td>[(IS, 2R) -1-Benzyl-acid tert-butyl ester 3- (1,5-dimethylhexylamino) -2-hydroxypropyl] - carbamic (H20)</td><td></td>

<td>((IS, 2R) -1-Benzyl-acid tert-butyl ester 3-ethylamino-2-hydroxypropyl) carbamic (H24)</td><td> -</td>

<td>[(IS, 2R) -1-Benzyl-acid tert-butyl ester 3- (bis-trifluoromethyl-benzylamino) -2-hydroxy- propyl] carbamic (H25)</td><td></td>

<td>((IS, 2R) -1-Benzyl-acid tert-butyl ester 3-cyclopropylamino-2-hydroxypropyl) carbamic (H26)</td><td></td>

<td>[(IS, 2R) -1-Benzyl-acid tert-butyl ester 2-hydroxy-3- (4-methoxy-benzylamino) -propyl] - carbamic (H27)</td><td></td>

<td>((IS, 2R) -1-Benzyl-acid tert-butyl ester 2-hydroxy-3-isopropylamino-propyl) -carbamic (H28)</td><td></td>

<td>[(IS, 2R) -1-Benzyl-acid tert-butyl ester 2-hydroxy-3- (2-methoxy-benzylamino) -propyl] - carbamic (H29)</td><td></td>

<td>[(IS, 2R) -1-Benzyl-acid tert-butyl ester 2-hydroxy-3 - ((S) -1-phenylethylamino) propyl] - carbamic (H30)</td><td></td>

ΡΕ1567488

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<td>BOC-protected amine</td><td>Precursor</td>

<td>[(IS, 2R) -1-Benzyl-acid tert-butyl ester 2-hydroxy-3 - ((R) -1-phenylethylamino) propyl] - carbamic (H31)</td><td></td>

<td>[(IS, 2R) -1-Benzyl-acid tert-butyl ester 2-hydroxy-3- (4-methylpentylamino) propyl] - carbamic (H32)</td><td></td>

<td>[(IS, 2R) -1-Benzyl-acid tert-butyl ester 2-hydroxy-3 - ((R) -2-hydroxy-1-isobutylcarbamoyl) pentylamino) propyl] carbamic (H33)</td><td>F33</td>

<td>[(IS, 2R) -1-Benzyl-acid tert-butyl ester 2-hydroxy-3 - ((S) -1-isobutylcarbamoyl- pentylamino) propyl] carbamic (H36)</td><td>F36</td>

BOC-protected H40-H114 amines were prepared in a manner analogous to that described for BOC-protected H1 amine by replacing cyclohexylamine with the amines indicated in the table below (unless amines are commercially available):

<td>BOC-protected amine</td><td>Precursor</td>

<td>[(IS, 2R) -2-hydroxy-1- (phenylmethyl) -3 - ({[3- trifluoromethyl) phenyl] methyl] amino) - 1,1-dimethylethyl propyl] carbamate (H40)</td><td>F40</td>

<td>[(IS, 2R) -2-hydroxy-3 - ({1- [3- (methyloxy) phenyl] cyclo] chlohexylamino) -1- (phenylmethyl) propyl] carbamate 1,1-dimethylethyl (H41)</td><td>F41</td>

ΡΕ1567488

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<td>BOC-protected amine</td><td>Precursor</td>

<td>[(IS, 2R) -2-hydroxy-3 - {[(1-methyl-1H-pyrazol-4 yl) methyl] amino} -1- (phenylmethyl) propyl] carbamate 1,1-dimethylethyl (H42)</td><td></td>

<td>[(IS, 2R) -2-hydroxy-1- (phenylmethyl) -3- (tetrahydroxymethyl) hydroxy-27Î ± -pyran-4-ylamino) propyl] carbamate 1,1-dimethylethyl (H43)</td><td></td>

<td>[(IS, 2R) -3 - [(3,3-dimethylbutyl) amino] -2-hydroxy 1,1-1- (phenylmethyl) propyl] carbamate dimethylethyl (H44)</td><td></td>

<td>{(IS, 2R) -2-hydroxy-1- (phenylmethyl) -3 - [(1,1,3,3- 1,1-tetramethylbutyl) amino] propyl} carbamate dimethylethyl (H45)</td><td></td>

<td>[(1S, 2R) -3 - [(1,3-dimethylbutyl) amino] -2-hydroxy 1,1-1- (phenylmethyl) propyl] carbamate dimethylethyl (H46)</td><td></td>

<td>1,1-Dimethylethyl [(IS, 2R) -3 - ({[4-fluoro-3- (trifluoromethyl) phenyl] methyl} amino) -2-hydroxy-1- (phenylmethyl) propyl] carbamate (H47)</td><td></td>

<td>[(1S, 2R) -3 - [(1,1-dimethylhexyl) amino] -2-hydroxy 1,1-1- (phenylmethyl) propyl] carbamate dimethylethyl (H48)</td><td>F48</td>

<td>[(IS, 2R) -2-hydroxy-3 - ({[2-methyl-5- (trifluoromethyl) methyl) phenyl] methyl} amino) -1- (phenylmethyl) propyl] - 1,1-dimethylethyl carbamate (H49)</td><td></td>

<td>[(1S, 2R) -3 - [(1S) -2,3-dihydro-1 H -inden-1-one 1,1-dimethylethyl (H50) -1-hydroxy-1- (phenylmethyl) propyl] carbamate (H50)</td><td></td>

ΡΕ1567488

259 (continuation)

<td>BOC-protected amine</td><td>Precursor</td>

<td>[(IS, 2R) -2-hydroxy-3 - {[(IS, 2R) -2-hydroxy-2,3-di hydro-1A-inden-1-yl] amino} -1- (phenylmethyl) propyl 1,1-dimethylethyl pil] carbamate (H51)</td><td></td>

<td>[(1S, 2R) -2-hydroxy-3 - {[6- (methyloxy) -2,3-di- hydro-1A-inden-1-yl] amino} -1- (phenylmethyl) propyl 1,1-dimethylethyl pil] carbamate (H52)</td><td>F52</td>

<td>[(IS, 2R) -2-hydroxy-3 - {[(IR, 2S) -2-hydroxy-2,3-di hydro-1A-inden-1-yl] amino} -1- (phenylmethyl) propyl 1,1-dimethylethyl pil] carbamate (H53)</td><td></td>

<td>[(1S, 2R) —3 - ({1,1-dimethyl-2 - [(2-methylpropyl) thio] - ethyl} amino) -2-hydroxy-1- (phenylmethyl) propyl 1,1-dimethylethyl carbamate (H54)</td><td>F54</td>

<td>[(1S, 2R) -3 - {[1,1-dimethyl-2- (phenyloxy) ethyl] amino} -2-hydroxy-1- (phenylmethyl) propyl] carbamate 1,1-dimethylethyl (H55)</td><td>F55</td>

<td>[(1S, 2R) —3 - ({1,1-dimethyl-2 - [(phenylmethyl) oxy] - ethyl} amino) -2-hydroxy-1- (phenylmethyl) propyl] 1,1-dimethylethyl carbamate (H56)</td><td>F56</td>

<td>[(IS, 2R) -2-hydroxy-3 - {[3- (methyloxy) phenyl] amino) - 1,1-dimethylethyl 1- (phenylmethyl) propyl] carbamate (H57)</td><td></td>

<td>[(IS, 2R) -2-hydroxy-1- (phenylmethyl) -3 - ({2- [3- trifluoromethyl) phenyl] ethyl] amino) propyl] carbamate 1,1-dimethylethyl (H58)</td><td></td>

<td>[(1S, 2R) -3 - [(1,1-dimethyl-2-phenylethyl) amino] -2- 1,1-hydroxy-1- (phenylmethyl) propyl] carbamate dimethylethyl (H59)</td><td></td>

ΡΕ1567488

260 (continuation)

<td>BOC-protected amine</td><td>Precursor</td>

<td>[(IS, 2R) -2-hydroxy-3 - {[2- (1-naphthalenyl) ethyl] - amino} -1- (phenylmethyl) propyl] carbamate of 1,1- dimethylethyl (H60)</td><td></td>

<td>[(1S, 2R) —3 - ({1,1-dimethyl-2- [3- (methyloxy) phenyl] ethyl} amino) -2-hydroxy-1- (phenylmethyl) propyl] - 1,1-dimethylethyl carbamate (H61)</td><td>F61</td>

<td>1,1-Dimethylethyl [(IS, 2R) -2-hydroxy-3- (phenylamino) -1- (phenylmethyl) propyl] carbamate (H62)</td><td> -</td>

<td>[(IS, 2R) -2-hydroxy-3 - ({1- [3- (methyloxy) phenyl] - 1,1-dimethylethyl cyclopropyl} amino) -1- (phenylmethyl) propyl] carbamate (H63)</td><td>F63</td>

<td>[(1S, 2R) -3 - [(cyclohexylmethyl) amino] -2-hydroxy 1,1-dimethylethyl 1- (phenylmethyl) propyl] carbamate (H64)</td><td></td>

<td>{(IS, 2R) -2-hydroxy-1- (phenylmethyl) -3 - [(tetramethyl) hydro-2H-pyran-4-ylmethyl) amino] propyl} carbamate 1,1-dimethylethyl (H65)</td><td></td>

<td>[(IS, 2R) -2-hydroxy-1- (phenylmethyl) -3- (tetrahydroxymethyl) hydroxy-2H-thiopyran-4-ylamino) propyl] carbamate 1,1-dimethylethyl (H66)</td><td></td>

<td>[(IS, 2R) -2-hydroxy-3 - [(1-methylpropyl) amino] -1- 1,1-dimethylethyl phenylmethyl propyl] carbamate (H67)</td><td></td>

<td>[(IS, 2R) -3 - {[4- (1,1-dimethylethyl) cyclo hexyl] amino] -2-hydroxy-1- (phenylmethyl) propyl 1,1-dimethylethyl carbamate (H68)</td><td></td>

ΡΕ1567488

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<td>BOC-protected amine</td><td>Precursor</td>

<td>[(1S, 2R) -3 - [(1-ethylcyclobutyl) amino] -2-hydroxy 1,1-1-phenylmethyl) propyl] carbamate dimethylethyl (H69)</td><td>F69</td>

<td>[1S, 2R) -3 - ({1,1-dimethyl-2 - [(2-methylpropyl) oxy] - 1,1-dimethylethyl (H70) ethyl} amino) -2-hydroxy-1- (phenylmethyl) propyl] carbamate</td><td>F70</td>

<td>[(1S, 2R) —3 - ({1,1-dimethyl-2 - [(2-methyl-2-propen-1-one yl) oxy] ethyl} amino) -2-hydroxy-1- (phenylmethyl) - 1,1-dimethylethyl propyl] carbamate (H71)</td><td>F71</td>

<td>[(1S, 2R) -3 - [(1R) -2,3-dihydro-1A-inden-1-ylamino] -2-hydroxy-1- (phenylmethyl) propyl] carbamate 1,1-dimethylethyl (H72)</td><td></td>

<td>[(IS, 2R) -2-hydroxy-3 - {[1- (4-methylpentyl) cyclo propyl] amino} -1- (phenylmethyl) propyl] carbamate of 1,1-dimethylethyl (H73)</td><td>F73</td>

<td>[(1S, 2R) —3 - [(1-ethylcyclopropyl) amino] -2-hydroxy 1,1-1- (phenylmethyl) propyl] carbamate dimethylethyl (H74)</td><td>F74</td>

<td>[(IS, 2R) -2-hydroxy-3 - {[1- (1-methylethyl) cyclopropyl pil] amino} -1- (phenylmethyl) propyl] carbamate of 1,1-dimethylethyl (H75)</td><td>F75</td>

<td>1,1-Dimethylethyl [(IS, 2R) -3- (butylamino) -2-hydroxy-1- (phenylmethyl) propyl] carbamate (H76)</td><td> -</td>

<td>{(IS, 2R) -2-hydroxy-1- (phenylmethyl) -3 - [(1-propyl 1,1-cyclopropyl) amino] propyl carbamate dimethylethyl (H77)</td><td>F77</td>

ΡΕ1567488

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<td>BOC-protected amine</td><td>Precursor</td>

<td>[(IS, 2R) -2-hydroxy-3 - {[1- (3-methylbutyl) cyclo propyl] amino} -1- (phenylmethyl) propyl] carbamate of 1,1-dimethylethyl (H78)</td><td>F78</td>

<td>[(IS, 2R) -2-hydroxy-3 - {[1- (2-methylpropyl) cyclo propyl] amino} -1- (phenylmethyl) propyl] carbamate of 1,1-dimethylethyl (H79)</td><td>F79</td>

<td>[(1S, 2R) —3 - ({1 - [(3-chlorophenyl) methyl] cyclopropyl 1,1-dimethylethyl pil-amino) -2-hydroxy-1- (phenylmethyl) propyl] carbamate (H80)</td><td>F80</td>

<td>[(IS, 2R) -2-hydroxy-3 - [(1-methylcyclohexyl) - 1,1-amino] -1- (phenylmethyl) propyl] carbamate dimethylethyl (H81)</td><td>F81</td>

<td>[(1S, 2R) -3 - [(2S) -bicyclo [2.2.1] hept-2-ylamino] - 1,1-2-hydroxy-1- (phenylmethyl) propyl] carbamate dimethylethyl (H82)</td><td></td>

<td>[(1S, 2R) -3 - [(4,4-dimethylcyclohexyl) amino] -2- 1,1-hydroxy-1- (phenylmethyl) propyl] carbamate dimethylethyl (H83)</td><td>F83</td>

<td>((IS, 2R) -2-hydroxy-1- (phenylmethyl) -3 - {[(IR) - 1,2,2-trimethylpropyl] amino} propyl) carbamate of 1,1-dimethylethyl (H84)</td><td></td>

<td>((IS, 2R) -2-hydroxy-1- (phenylmethyl) -3 - {[(IS) - 1,2,2-trimethylpropyl] aminoIpropyl) carbamate 1,1-dimethylethyl (H85)</td><td></td>

<td>[(IS, 2R) -3 - [(2,2-dimethylcyclohexyl) amino] -2- 1,1-hydroxy-1- (phenylmethyl) propyl] carbamate dimethylethyl (H86)</td><td>F86</td>

ΡΕ1567488

263 (continuation)

<td>BOC-protected amine</td><td>Precursor</td>

<td>1,1-Dimethylethyl [(IS, 2R) -2-hydroxy-3- (pentylamino) -1- (phenylmethyl) propyl] carbamate (H87)</td><td> -</td>

<td>1,1-Dimethylethyl [(IS, 2R) -3- (hexylamino) -2-hydroxy-1- (phenylmethyl) propyl] carbamate (H88)</td><td> -</td>

<td>[(1S, 2R) -3 - [(3,3-dimethylbutyl) amino] -2-hydroxy 1,1-dimethylethyl 1- (phenylmethyl) propyl] carbamate (H89)</td><td></td>

<td>[(IS, 2R) -3 - [(1,1-dimethylpropyl) amino] -2-hydroxy 1,1-dimethyl 1- (phenylmethyl) propyl] carbamate tetraethyl (H90)</td><td></td>

<td>[(IS, 2R) -3 - [(cyclopropylmethyl) amino] -2-hydroxy 1,1-dimethylethyl 1- (phenylmethyl) propyl] carbamate (H91)</td><td></td>

<td>[(IS, 2R) -3 - [(3,3-dimethylcyclopentyl) amino] -2- 1,1-hydroxy-1- (phenylmethyl) propyl] carbamate dimethylethyl (H92)</td><td>F92</td>

<td>1,1-Dimethylethyl [(IS, 2R) -2-hydroxy-3- (methylamino) -1- (phenylmethyl) propyl] carbamate (H93)</td><td> -</td>

<td>[(IS, 2R) -2-hydroxy-1- (phenylmethyl) -3- (tricyclo [3.3.1.1³'⁷] dec-1-ylamino) propyl] carbamate of 1,1-dimethylethyl (H94)</td><td></td>

<td>[(IS, 2R) -2-hydroxy-1- (phenylmethyl) -3- (1,2,3,4- tetrahydro-1-naphthalenylamino) propyl] carbamate (H95)</td><td></td>

<td>[(IS, 2R) -2-hydroxy-3 - ({2- [3-methyloxy) phenyl] - ethyl} amino) -1- (phenylmethyl) propyl] carbamate of 1,1-dimethylethyl (H96)</td><td></td>

ΡΕ1567488

264 (continuation)

<td>BOC-protected amine</td><td>Precursor</td>

<td>[(IS, 2R) -2-hydroxy-3 - ({2- [4-methyloxy) phenyl] - ethyl} amino) -1- (phenylmethyl) propyl] carbamate of 1,1-dimethylethyl (H97)</td><td></td>

<td>[(IS, 2R) -2-hydroxy-3 - ({2- [2-methyloxy) phenyl] - ethyl} amino) -1- (phenylmethyl) propyl] carbamate of 1,1-dimethylethyl (H98)</td><td></td>

<td>[(1S, 2R) -3 - {[2- (2-chlorophenyl) ethyl] amino} -2- 1,1-hydroxy-1- (phenylmelyl) propyl] carbamate dimethylethyl (H99)</td><td></td>

<td>[(1S, 2R) -3 - {[2- (3-chlorophenyl) ethyl] amino} -2- 1,1-hydroxy-1- (phenylmethyl) propyl] carbamate dimethylethyl (H100)</td><td></td>

<td>[(1S, 2R) -3 - {[2- (4-chlorophenyl) ethyl] amino} -2- 1,1-hydroxy-1- (phenylmethyl) propyl] carbamate dimethylethyl (H101)</td><td></td>

<td>[(IS, 2R) -2-hydroxy-3 - {[2- (4-methylphenyl) ethyl] amino 1,1-N- (phenylmethyl) propyl] carbamate dimethylethyl (H102)</td><td></td>

<td>[(IS, 2R) -2-hydroxy-3 - {[2- (2-methylphenyl) ethyl] - 1,1-Amino} -1- (phenylmethyl) propyl] carbamate dimethylethyl (H103)</td><td></td>

<td>[(1S, 2R) -3 - {[2- (3,4-dichlorophenyl) ethyl] amino} -2- 1,1-hydroxy-1- (phenylmelyl) propyl] carbamate dimethylethyl (H104)</td><td></td>

<td>[(1S, 2R) -3 - {[2- (2,4-dichlorophenyl) ethyl] amino} -2- 1,1-hydroxy-1- (phenylmethyl) propyl] carbamate dimethylethyl (H105)</td><td></td>

ΡΕ1567488

265 (continuation)

<td>BOC-protected amine</td><td>Precursor</td>

<td>[(IS, 2R) -3 - ({2- [3,5-bis (methyloxy) phenyl] ethyl} -</td><td> -</td>

<td>amino) -2-hydroxy-1- (phenylmethyl) propyl] carbamate</td><td></td>

<td>1,1-dimethylethyl (H106)</td><td></td>

<td>[(1S, 2R) -3 - ({2- [2,3-bis (methyloxy) phenyl] ethyl} -</td><td> -</td>

<td>amino) -2-hydroxy-1- (phenylmethyl) propyl] carbamate</td><td></td>

<td>1,1-dimethylethyl (H107)</td><td></td>

<td>{(IS, 2R) -2-hydroxy-1- (phenylmethyl) -3- (phenylmethyl)</td><td> -</td>

<td>1,1-dimethylethyl] amino] propyl] carbamate</td><td></td>

<td>(H108)</td><td></td>

<td>[(IS, 2R) -2-hydroxy-3 - [(2-phenylethyl) amino] -1-</td><td> -</td>

<td>1,1-dimethylethyl (phenylmethyl) propyl] carbamate</td><td></td>

<td>(H109)</td><td></td>

<td>[(1S, 2R) -3 - [(1-ethylcyclohexyl) amino] -2-hydroxy</td><td>F110</td>

<td>1,1-1- (phenylmethyl) propyl] carbamate</td><td></td>

<td>dimethylethyl (H11 O)</td><td></td>

<td>[(IS, 2R) -2-hydroxy-3 - [(1-methylcyclopentyl) amino</td><td>Flll</td>

<td>1,1] -1- (phenylmethyl) propyl] carbamate</td><td></td>

<td>dimethylethyl (H11l)</td><td></td>

<td>{(IS, 2R) -2-hydroxy-1- (phenylmethyl) -3 - [(1-propyl</td><td>F112</td>

<td>1,1-cyclopentyl) amino] propyl} carbamate</td><td></td>

<td>dimethylethyl (H112)</td><td></td>

<td>{(IS, 2R) -2-hydroxy-1- (phenylmethyl) -3 - [(1-propyl</td><td>F113</td>

<td>1,1-cyclohexyl) amino] propyl] carbamate</td><td></td>

<td>dimethylethyl (H113)</td><td></td>

<td>[(1S, 2R) -3 - {[2- (3-chlorophenyl) -1,1-dimethylethyl] -</td><td>F114</td>

<td>amino} -2-hydroxy-1- (phenylmethyl) propyl] carbamate</td><td></td>

<td>1,1-dimethylethyl (H114)</td><td></td>

ΡΕ1567488

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The following BOC-protected H115-H147 amines were prepared in a manner analogous to that described for BOC-protected H1 amine using the appropriate epoxide and appropriate amine given in the tables below (only non-commercial amines are indicated):

<td>BOC-protected amine</td><td>Epoxide</td><td>The mine</td>

<td>[(IS, 2R) -2-hydroxy-3 - ({[3- (methyloxy) phenyl] 1,1-dimethylethyl-1- (3-pyridinylmethyl) propyl] carbamate (H115)</td><td>K13</td><td></td>

<td>[(IS, 2R) -2-hydroxy-3 - ({[3- (methyloxy) phenyl] methyl} amino) -1- (1,3-thiazol-2-ylmethyl) propyl 1,1-dimethylethyl pil] carbamate (H116)</td><td>Kll</td><td></td>

<td>[(IS, 2R) -3- (cyclohexylamino) -2-hydroxy-1-one (1,3-thiazol-2-ylmethyl) propyl] carbamate 1,1-dimethylethyl (H117)</td><td>Kll</td><td></td>

<td>[(1S, 2R) -3 - [(1,5-dimethylhexyl) amino] -2- 1,1-dimethylethyl hydroxy-1- (1,3-thiazol-2-ylmethyl) propyl] carbamate (H118)</td><td>Kll</td><td></td>

<td>[(IS, 2R) -1- (2-furanylmethyl) -2-hydroxy-3-one 1,1-Dimethylethyl ({[3-methyloxy) phenyl] methyl} amino) propyl] carbamate (H119)</td><td>K9</td><td></td>

<td>[(IS, 2R) -3- (cyclohexylamino) -1- (2-furanyl) 1,1-Methyl) -2-hydroxypropyl] carbamate dimethylethyl (H120)</td><td>K9</td><td></td>

<td>[(1S, 2R) -3 - [(1,5-dimethylhexyl) amino] -1- (2- furanylmethyl) -2-hydroxypropyl] carbamate 1,1-dimethylethyl (H121)</td><td>K9</td><td></td>

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267 (continuation)

<td>BOC-protected amine</td><td>Epoxide</td><td>The mine</td>

<td>{(IS, 2R) -1- (2-furanylmethyl) -2-hydroxy-3-one 1,1-dimethylethyl [(1,1,5-trimethylhexyl) amino] propyl} carbamate (H122)</td><td>K9</td><td>F5</td>

<td>[(IS, 2R) -2-hydroxy-3 - ({[3- (methyloxy) phenyl] - methyl} amino) -1- (2-pyridinylmethyl) propyl] - 1,1-dimethylethyl carbamate (H123)</td><td>K10</td><td></td>

<td>[(IS, 2R) -1 - [(4-chlorophenyl) methyl] -3- (cyclohexane) hexylamino) -2-hydroxypropyl] carbamate of 1,1-dimethylethyl (H124)</td><td>K6</td><td></td>

<td>[(1S, 2R) -1 - [(4-chlorophenyl) methyl] -2-hydroxy 3 - ({[3- (methyloxy) phenyl] methyl] amino) propyl] - 1,1-dimethylethyl carbamate (H125)</td><td>K6</td><td></td>

<td>[(1S, 2R) -1 - [(3,5-difluorophenyl) methyl] -2-hydroxy-3 - ({[3- (trifluoromethyl) phenyl] methyl} - 1,1-dimethylethyl amino propyl] carbamate (H126)</td><td>Kl</td><td></td>

<td>[(1S, 2R) -1 - [(3,5-difluorophenyl) methyl] -2-hydroxy-3 - ({[3- (methyloxy) phenyl] methyl] amino) - 1,1-dimethylethyl propyl] carbamate (H127)</td><td>Kl</td><td></td>

<td>{(1S, 2R) -1 - [(3,5-difluorophenyl) methyl] -3- 1,1-Dimethylethyl [(1,5-dimethylhexyl) amino] -2-hydroxypropyl} carbamate (H128)</td><td>Kl</td><td></td>

<td>{(IS, 2R) -3- (cyclohexylamino) -1 - [(3,5- difluorophenyl) methyl] -2-hydroxypropyl} - 1,1-dimethylethyl carbamate (H129)</td><td>Kl</td><td></td>

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268 (continuation)

<td>BOC-protected amine</td><td>Epoxide</td><td>The mine</td>

<td>{(1S, 2R) -1 - [(3,5-difluorophenyl) methyl] -2- 1,1-dimethylethyl hydroxy-3 - [(1,1,5-trimethylhexyl) amino] propyl] carbamate (H130)</td><td>Kl</td><td>F5</td>

<td>[(1S, 2R) -1 - [(3,4-difluorophenyl) methyl] -2-hydroxy-3 - ({[3- (methyloxy) phenyl] methyl] amino) - 1,1-dimethylethyl propyl] carbamate (H131)</td><td>K3</td><td></td>

<td>{(IS, 2R) -3- (cyclohexylamino) -1 - [(3,4 - 1,1-dimethylethyl difluorophenyl) methyl] -2-hydroxypropyl] carbamate (H132)</td><td>K3</td><td></td>

<td>{(1S, 2R) -1 - [(3,4-difluorophenyl) methyl] -2- hydroxy-3 - [(1,1,5-trimethylhexyl) amino] - 1,1-dimethylethyl propyl] carbamate (H133)</td><td>K3</td><td>F5</td>

<td>[(IS, 2R) -1 - [(3-chlorophenyl) methyl] -2-hydroxy 1,1-dimethylethyl 3 - ({[3- (methyloxy) phenyl] methyl] amino) propyl] carbamate (H134)</td><td>K5</td><td></td>

<td>[(1S, 2R) -1 - [(3-chlorophenyl) methyl] -3- (cyclohexane) hexylamino) -2-hydroxypropyl] carbamate of 1,1-dimethylethyl (H135)</td><td>K5</td><td></td>

<td>[(IS, 2R) -1 - [(2-chlorophenyl) methyl] -2-hydroxy 1,1-dimethylethyl 3 - ({[3- (methyloxy) phenyl] methyl] amino) propyl] carbamate (H136)</td><td>K4</td><td></td>

<td>[1S, 2R) -1 - [(2-chlorophenyl) methyl] -3- (cyclohexane) hexylamino) -2-hydroxypropyl] carbamate of 1,1-dimethylethyl (H137)</td><td>K4</td><td></td>

<td>{(1S, 2R) -1 - [(2-chlorophenyl) methyl] -3 - [(1,5- 1,1-dimethylethyl (dimethylhexyl) amino] -2-hydroxypropyl} carbamate (H138)</td><td>K4</td><td></td>

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269 (continuation)

<td>BOC-protected amine</td><td>Epoxide</td><td>The mine</td>

<td>{(IS, 2R) -1 - [(3-chlorophenyl) methyl] -3 - [(1,5- (dimethylhexyl) amino] -2-hydroxypropyl 1,1-dimethylethyl carbamate (H139)</td><td>K5</td><td></td>

<td>[(1S, 2R) -1 - [(3-fluorophenyl) methyl] -2-hydroxy 3 - ({[3- (methyloxy) phenyl] methyl} amino) - 1,1-dimethylethyl propyl] carbamate (H140)</td><td>K2</td><td></td>

<td>{(1S, 2R) -3 - [(1,5-dimethylhexyl) amino] -1- [(3-fluorophenyl) methyl] -2-hydroxypropyl} - 1,1-dimethylethyl carbamate (H141)</td><td>K2</td><td></td>

<td>[(IS, 2R) -2-hydroxy-3 - ({[3- (methyloxy) phenyl] - methyl} amino) -1- (2-thienylmethyl) propyl] - 1,1-dimethylethyl carbamate (H142)</td><td>K7</td><td></td>

<td>[(1S, 2R) -3 - [(1,5-dimethylhexyl) amino] -2-hydroxy] droxy-1- (2-thienylmethyl) propyl] carbamate 1,1-dimethylethyl (H143)</td><td>K7</td><td></td>

<td>[(IS, 2R) -2-hydroxy-3 - ({[3- (methyloxy) phenyl] - 1,1-dimethylethyl-1- (1H-pyrazol-1-ylmethyl) propyl] carbamate (H144)</td><td>K12</td><td></td>

<td>[(1S, 2R) -3 - [(1,5-dimethylhexyl) amino] -2- hydroxy-1- (1H-pyrazol-1-ylmethyl) propyl] - 1,1-dimethylethyl carbamate (H145)</td><td>K12</td><td></td>

<td>[(IS, 2R) -2-hydroxy-3 - ({[3- (methyloxy) phenyl] - methyljamino) -1- (3-thienylmethyl) propyl] - 1,1-dimethylethyl carbamate (H146)</td><td>K8</td><td></td>

<td>[(1S, 2R) -3 - [(1,5-dimethylhexyl) amino] -2- hydroxy-1- (3-thienylmethyl) propyl] carbamate of 1,1-dimethylethyl (H147)</td><td>K8</td><td></td>

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270

BOC-protected amines H148-H156 were prepared in a manner analogous to that described for BOC-protected amine H1, replacing cyclohexylamine with the amines listed in the table below (if amines are not commercially available):

<td>BOC-protected amine</td><td>Precursor</td>

<td>{(IS, 2R) -2-hydroxy-1- (phenylmethyl) -3 - [(1-propyl 1,1-di-cyclobutyl) amino] propyl} carbamate methylethyl (H148)</td><td>F148</td>

<td>[(IS, 2R) -2-hydroxy-3 - {[1- (1-methylethyl) cyclo butyl] amino} -1- (phenylmethyl) propyl] carbamate 1,1-dimethylethyl (H149)</td><td>F149</td>

<td>[(IS, 2R) -3 - ({1 - [(3-chlorophenyl) methyl] cyclobutyl] 1,1-dimethylethyl-2-hydroxy-1- (phenylmethyl) propyl] carbamate (H150)</td><td>F150</td>

<td>[(IS, 2R) -2-hydroxy-1- (phenylmethyl) -3- (tricyclo [3.3.1.1³'⁷] dec-2-ylamino) propyl] carbamate dimethylethyl (H151)</td><td></td>

<td>[(1S, 2R) -3 - [(1R, 4R) -bicyclo [2.2.1] hept-1-ylamino n] -2-hydroxy-1- (phenylmethyl) propyl] carbamate 1,1-dimethylethyl (H152)</td><td></td>

<td>[(1S, 2R) -3- (bicyclo [2.2.2] oct-1-ylamino) -2- 1,1-hydroxy-1- (phenylmethyl) propyl] carbamate dimethylethyl (H153)</td><td></td>

<td>[(1S, 2R) -3 - {[(1-ethyl-1H-pyrazol-4-yl) methyl] amino} -2-hydroxy-1- (phenylmethyl) propyl] carbamate 1,1-dimethylethyl (H154)</td><td></td>

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271 (continuation)

<td>BOC-protected amine</td><td>Precursor</td>

<td>[(1S, 2R) -3 - [(4,4-difluorocyclohexyl) amino] -2- 1,1-hydroxy-1- (phenylmethyl) propyl] carbamate dimethylethyl (H155)</td><td>F155</td>

<td>[(1S, 2R) —3 - ({(3,4-bis (methyloxy) phenyl] methyl] amino) -2-hydroxy-1- (phenylmethyl) propyl] carbamate 1,1-dimethylethyl (H156)</td><td></td>

BOC-protected amine H157 [(IS, 2r) -3 - {[(3-ethyl-5-isoxazolyl) methyl] amino} -2-hydroxy-1- (phenylmethyl) propyl] carbamate (H157) [ 1,1-Dimethylethyl (1S, 2R) -3 - {[(3-ethyl-5-isoxazolyl) methyl] amino} -2-hydroxy-1- (phenylmethyl) propyl] carbamate (H157) was prepared from Description F157 analogously to the process described for the BOC protected H1 amine.

Acid Preparation

Acid 1

3-Methylsulfanyl-5- (2-oxo-pyrrolidin-1-yl) -benzoic acid (Al)

To a solution of 3ΡΕ1567488 acid methyl ester

272 Methylsulfanyl-5- (2-oxo-pyrrolidin-1-yl) -benzoic acid (B1) (115 mg, 0.433 mmol, 1 eiv.) in MeOH (8 mL) was added 2 N aqueous NaOH (0 mL). 65 mL, 1.3 mmol, 3 eguiv.). The resulting mixture was stirred for 4 hours, 2 N aqueous NaOH solution (1 mL, mmol, eguiv.) Was added and the resulting solution was stirred for 16 hours and then concentrated in vacuo. The residue was diluted with H₂O is extracted with Et₂The aqueous layer was acidified using 2 N aqueous HCl solution and the white precipitate that formed was extracted twice with EtOAc. The combined organic solutions were dried over Na₂ONLY₄ and concentrated in vacuo to give 3-methylsulfanyl-5- (2oxo-pyrrolidin-1-yl) -benzoic acid (Al) (109 mg, 100%) as a white solid. [M + H]⁺ = 252.0, TR = 2.61 minutes

Acid 2

3-Ethylsulfanyl-5- (2-oxo-pyrrolidin-1-yl) -benzoic acid (A2)

Acid 2 was prepared from 125 mg (0.426mmol) of 3-methylsulfanyl-5- (2-oxo-pyrrolidin-1-yl) -benzoic acid methyl ester (B2) in a similar manner to that described for Acid 1 This gave 11 mg (98%) of 3-methylsulfanyl-5- (2-oxopyrrolidin-1-yl) -benzoic acid (A2) as a white solid. [M + H]⁺ = 266.1, TR = 2.82 minutes

ΡΕ1567488

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Acid 3

3- (1,1-dioxo-1 /⁶-isothiazolidin-2-yl) -5-methylsulfanyl benzoic (A3)

To a solution of 3- (1,1dioxo-1 /⁶(Isothiazolidin-2-yl) -5-methylsulfanyl-benzoic (B3) (144 mg, 0.48 mmol, 1 eguiv.) in MeOH (10 mL) was added 2 N aqueous NaOH solution (2.4 mL, 4.8 mmol, 10 eguiv.). The resulting mixture was stirred at room temperature for 3.5 hours and at 40 ° C for 1 hour, then cooled to room temperature and concentrated in vacuo. The residue was diluted with H₂O is extracted with Et₂The aqueous layer was acidified with 2 N aqueous HCl solution and the white precipitate that formed was extracted twice with EtOAc. The combined organic solutions were about Na₂ONLY₄ and concentrated in vacuo to afford 3- (1,1-dioxide-1 /⁶-isothiazolidin-2-yl) -5-methylsulfanyl benzoic (A3) (136 mg, 100%) as a white solid. [M + H]⁺ = 288.0, TR = 2.63 minutes

Acid 4

3- (1,1-dioxo-1 /⁶-isothiazolidin-2-yl) -5-ethylsulfanyl benzoic (A4)

To a solution of 3- (1,1dioxo-1 /⁶-isothiazolidin-2-yl) -5-ethylsulfanyl-benzoic (B4) (145 mg, 0.44 mmol, 1, eguiv.) in MeOH (5 mL) was added

ΡΕ1567488

274 2 N aqueous NaOH solution (2.2 mL, 4.4 mmol, 10 equiv.). The resulting mixture was stirred at room temperature for 3 hours and then concentrated in vacuo. The residue was diluted with H₂O is extracted with Et₂The aqueous layer was acidified with 2N aqueous HCl solution and the white precipitate that formed was extracted twice with EtOAc. The combined organic solutions were dried over Na₂ONLY₄ and concentrated in vacuo to afford 3- (1,1-dioxide-1 /⁶-isothiazolidin-2-yl) -5-ethylsulfanyl benzoic (A4) (133 mg, 100%) as a white solid. [M + H]⁺ = 302.0, TR = 2.83 minutes

Acid 5

3-Methanesulfonyl-5- (2-oxo-pyrrolidin-1-yl) -benzoic acid (A5)

To a solution of (Al) 3-methylsulfanyl-5- (2-oxopyrrolidin-1-yl) -benzoic acid (59 mg, 0.235 mmol, 1 equiv.) In MeOH / H₂O (3: 1, 24 mL) was added oxone (578 mg, 0.94 mol, 4 equiv.). The resulting mixture was stirred at room temperature for 50 minutes and then concentrated in vacuo. The residue was partitioned between AcOEt and H₂O and the layers were separated. The organic layer was washed with H₂O and saturated aqueous sodium chloride solution, dried over Na₂ONLY₄ and concentrated in vacuo to give a solid which was triturated with Et₂O to give 3-methanesulfonyl-5- (2-oxo-pyrrolidin-1-yl) -benzoic acid (A5) (57 mg, 86%) as a white solid. [M + H]⁺ = 284.0, TR = 2.05 minutes

ΡΕ1567488

275