CA2271116A1 - Benzothiazo and related heterocyclic group-containing cysteine and serine protease inhibitors - Google Patents

Abstract

The present invention is directed to novel benzothiazo and related heterocyclic group-containing inhibitors of cysteine or serine proteases.
Methods for using the same are also described.

Description

Benzothiazo and Related Heter~ocyclic Group-Containing Cysteine and Serine Protease Inhibitors Cross Reference To Related Applications This application is claims benefit of U.S.
Provisional Application Serial No. 60/030,526, filed November 13, l996, and U.S. Application entitled "Benzothiazo and Related Heterocyclic Group-Containing Cysteine and Serine Protease Inhibitors" filed in the names of Ron Bihovsky, Gregory J. Wells, and Ming Tao on November 12, 1997, the disclosures of which are hereby incorporated herein by reference in their entirety.
Field of the Lnvention Novel benzothiazo and related heterocyclic group-containing inhibitors of cysteine or serine proteases, methods for making these novel compounds, and methods for using the same are disclosed.
Background of then Invention Numerous cysteine and serine proteases have been identified in human tissues. A "protease" is an enzyme which degrades proteins into smaller components (peptides).
The terms "cysteine protease" and "serine protease" refer to proteases which are distinguished by the presence therein of a cysteine or serine residue which plays a critical role in the catalytic process. Mammalian systems, including humans, normally degrade and process proteins via a variety of enzymes including cysteine and se:rine proteases. However, when present at elevated levels o:r when abnormally activated, cysteine and serine proteases may be involved in pathophysiological processes.
For example, calcium-activated neutral proteases ("calpains") comprise a family of intracellular cysteine proteases which are ubiquitously expressed in mammalian tissues. Two major calpains have been identified; calpain I
and calpain II. While calpain II is the predominant form in many tissues, calpain I is thought to be the predominant form in pathological conditions of nerve tissues. The calpain family of cysteine proteases has been implicated in many diseases and disorders, including neurodegeneration, stroke, Alzheimer's, amyotrophy, motor neuron damage, acute central nervous system injury, muscular dystrophy, bone resorption, platelet aggregation, cataracts and inflammation. Calpain I has been implicated in excitatory amino-acid induced neurotoxicity disorders including ischemia, hypoglycemia, Huntington's Disease, and epilepsy.
The lysosomal cysteine protease cathepsin B has been implicated in the following disorders: arthritis, inflammation, myocardial infarction, tumor metastasis, and muscular dystrophy. Other lysosomal cysteine proteases include cathepsins C, H, L and S. Interleukin-li3 converting enzyme ("ICE") is a cysteine protease which catalyzes the formation of interleukin-1f3. Interleukin-li3 is an immunoregulatory protein implicated in the following disorders: inflammation, diabetes, septic shock, rheumatoid arthritis, and Alzheimer's disease. ICE has also been linked to apoptotic cell death of neurons, which is implicated in a variety of neurodegenerative disorders including Parkinson's disease, ischemia, and amyotrophic lateral sclerosis (ALS).
Cysteine proteases are also produced by various pathogens. The cysteine protease clostripain is produced by Clostridium histolyticum. Other proteases are produced by Trypanosoma cruzi, malaria parasites Plasmodium falciparum and P.vinckei and Streptococcus. Hepatitis A viral protease HAV C3 is a cysteine protease essential for processing of picornavirus structural proteins and enzymes.

Exemplary serine proteases implicated in degenerative disorders include thrombin, human leukocyte elastase, pancreatic elastase, chymase and cathepsin G.
Specifically, thrombin is produced in the blood coagulation cascade, cleaves fibrinogen to form fibrin and activates Factor VIII; thrombin is implicated in thrombophlebitis, thrombosis and asthma. Human leukocyte elastase is implicated in tissue degenerative disorders such as rheumatoid arthritis, osteoarthritis, atherosclerosis, bronchitis, cystic fibrosis, and emphysema. Pancreatic elastase is implicated in pancreatitis. Chymase, an enzyme important in angiotensin synthesis, is implicated in hypertension, myocardial infarction, and coronary heart disease. Cathepsin G is implicated in abnormal connective tissue degradation, particularly in the lung.
Given the link between cysteine and serine proteases and various debilitating disorders, compounds which inhibit these proteases would be useful and would provide an advance in both research and clinical medicine.
The present invention is directed to these, as well as other, important ends.
SUMMARY OF THE INVENTION
The present invention is directed to novel cysteine and serine protease inhibitors which contain a benzoheterocyclic group. Exemplary compounds are represented by the following Formula I:

R6 ~ p'~B~~ Q
N
/ ~Y H
R~ ~ Z
RA
wherein:

A-B represents one, two, or three carbon atoms or nitrogen atoms, optionally connected by single bonds or one double bond, optionally substituted with one or more groups selected from R3, R4, OR3, OR4, R4a, and OR4a, with the proviso that the number of nitrogen atoms is 0, 1 or 2;
Rl and RZ are each independently hydrogen, alkyl having from one to about 14 carbons, cycloalkyl having from 3 to about 10 carbons, aryl having from about 6 to about 14 carbons, heteroaryl having from about 6 to about 14 ring atoms, aralkyl having from about 7 to about 15 carbons, heteroaralkyl, or an optionally protected natural or unnatural side chain of an amino acid, said alkyl, cycloalkyl, aryl, and heteroaryl groups being optionally substituted with one or more K groups;
R3, R4 and R4a are each independently hydrogen, lower alkyl, or a natural or unnatural side chain of an optionally protected amino acid, said alkyl groups being optionally substituted with an aryl or heteroaryl group;
R5, R6, R' and Re are each independently hydrogen, alkyl having from one to about 14 carbons wherein said alkyl groups are optionally substituted with one or more K groups, alkoxy having from one to about 10 carbons, halogen, alkoxycarbonyl, carboxyl, hydroxyl, heterocyclic, or amino optionally substituted with 1 to 3 aryl or lower alkyl groups;
or any two adjacent R5, R~, R' and RB groups taken together with any intervening atoms of the benzene ring to which they are attached form an alicyclic, aromatic, heterocyclic, or heteroaryl ring having 5 to 8 ring atoms;
K is halogen, lower alkyl, lower alkenyl, aryl, heterocyclic, guanidino, nitro, alkoxycarbonyl, alkoxy, hydroxyl, carboxyl, arylaminosulfonyl, heteroarylaminosulfonyl, alkylaminosulfonyl, or amino optionally substituted with an alkylsulfonyl, arylsulfonyl, or heteroarylsulfonyl group, or with 1 to 3 aryl or lower alkyl groups, said alkyl, aryl, and heteroaryl groups being optionally substituted with one or more G groups;

G is the same as K;
Y i s O , NH , NR9 or CHRy ;
Z is S (=O) 2, S (=O) , S, or C (=O) ;
j is 0, 1 or 2;
Q is hydrogen, C (=O) NHR9, C (=O) OR9, CH=N2, or CH2R1°;
R9 is hydrogen, alkyl having from one to about 10 carbons, said alkyl groups being optionally substituted with one or more K groups, aryl having from about 6 to about 14 carbons, or aralkyl having from about 7 to about 15 carbons;
R1° is aryloxy, heteroaryloxy, L, halogen, or has the formula O-M, wherein M has the structure:
\N/~~N
I
D
W-E F
wherein:
R is N or CRll;
W is a double bond or a single bond;
D is C=O or a single bond;
E and F are independently Rlz, R13, or J;
or E and F taken together comprise a joined moiety, said joined moiety being an aliphatic carbocyclic ring optionally substituted with J and having from 5 to 7 carbons, an aromatic carbocyclic :ring optionally substituted with J and having from 5 to 7 carbons, an aliphatic heterocyclic ring optionally subsvtituted with J and having from 5 to 7 atoms, or an aromatic heterocyclic ring optionally substituted with J and having from 5 to 7 atoms, said aliphatic heterocyclic ring or said aromatic heterocyclic ring each having from 1 to 4 heteroatoms;
Riz, R12, and R13 are independently H, alkyl having from 1 to 10 carbons, heteroaryl having from 1 to 10 carbons, alkanoyl having from 1 to 10 carbons, or aroyl, wherein said alkyl, heteroaryl, alkanoyl and aroyl groups are optionally substituted with J;
J is halogen, C (=O) OR14, R140C (=0) , R140C (=O) NH, OH, CN, NO-~ , NRl4Rls , N=C ( R14 ) Rls , N=C ( NRl4Rls ) 2 , SR14 , ORl4 , phenyl , napthyl, heteroaryl, or a cycloalkyl group having from 3 to 8 carbons;
R14 and R15 are independently H, alkyl having from 1 to carbons, aryl, or heteroaryl, wherein said alkyl, aryl and heteroaryl groups are optionally substituted with K;
10 L is a phosphorus-containing enzyme reactive group having the formula:
-~/(~)rri R16 ( )b wherein:
m, n, and b are each independently 0 or 1;
1S R16 and R1' are each independently hydrogen, lower alkyl optionally substituted with K, aryl optionally substituted with K, or heteroaryl optionally substituted with K;
or Rl~ and R1' taken together with - (O) n-P (=O) - (O) m-can form a 5-8 membered ring containing up to 3 hetero atoms;
or R16 and R1' taken together with - (0) n-P (=O) - (O) m-can form a 5-8 membered ring optionally substituted with K;
or a pharmaceutically acceptable salt or bisulfate addition product thereof.
The compounds of the invention are useful for the inhibition of cysteine and serine proteases. Beneficially, the compounds find utility in a variety of settings. For example, in a research arena, the claimed compounds can be used, for example, as standards to screen for natural and synthetic cysteine protease and serine protease inhibitors which have the same or similar functional characteristics as the disclosed compounds. In a clinical arena, the compounds of the present invention can be used to alleviate, mediate, reduce and/or prevent disorders which are associated with abnormal and/or aberrant activity of cysteine proteases and/or serine proteases. Accordingly, methods for using the subject compounds, such as methods for inhibiting serine proteases or cysteine proteases comprising contacting said proteases with an inhibitory amount of a compound of the invention are disclosed. Methodologies for making the benzothiazine group-containing inhibitors are also disclosed. These and other features of the compounds of the subject invention are set forth in more detail below.
Detailed Description Novel cysteine and serine protease inhibitors have been discovered which are represented by the general Formula I:

R6 .~ AwBW Q
N
R~ ~ Z
Rg I
wherein:
A-B represents one, two, or three carbon atoms or nitrogen atoms, optionally connected by single bonds or one double bond, optionally substituted with one or more groups selected from R', R4, OR3, OR4, R4a, and OR4a, with the proviso that the number of nitrogen atoms is 0, 1 or 2;
R1 and RZ are each independently hydrogen, alkyl having from one to about 14 carbons, cycloalkyl having from 3 to about 10 carbons, aryl having from about 6 to about 14 carbons, heteroaryl having from about 6 to about 14 ring atoms, aralkyl having from about 7 to about 15 carbons, WO 98/21186 PCTI(.TS97/20782 _ g _ heteroaralkyl, or an optionally protected natural or unnatural side chain of an amino acid, said alkyl, cycloalkyl, aryl, and heteroaryl groups being optionally substituted with one or more K groups;
R3, R4 and R4a are each independently hydrogen, lower alkyl, or a natural or unnatural side chain of an optionally protected amino acid, said alkyl groups being optionally substituted with an aryl or heteroaryl group;
R5, R6, R' and RB are each independently hydrogen, alkyl having from one to about 14 carbons wherein said alkyl groups are optionally substituted with one or more K groups, alkoxy having from one to about 10 carbons, halogen, alkoxycarbonyl, carboxyl, hydroxyl, heterocyclic, or amino optionally substituted with 1 to 3 aryl or lower alkyl groups;
or any two adjacent RS, R6, R' and RB groups taken together with any intervening atoms of the benzene ring to which they are attached form an alicyclic, aromatic, heterocyclic, or heteroaryl ring having 5 to 8 ring atoms;
K is halogen, lower alkyl, lower alkenyl, aryl, heterocyclic, guanidino, nitro, alkoxycarbonyl, alkoxy, hydroxyl, carboxyl, arylaminosulfonyl, heteroarylaminosulfonyl, alkylaminosulfonyl, or amino optionally substituted with an alkylsulfonyl, arylsulfonyl, or heteroarylsulfonyl group, or with 1 to 3 aryl or lower alkyl groups, said alkyl, aryl, and heteroaryl groups being optionally substituted with one or more G groups;
G is the same as K;
Y is O, NH, NR9 or CHR9;
Z is S (=0) 2, S (=O) , S, or C (=O) ;
j is 0, 1 or 2;
Q i s hydrogen, C ( =O ) NHR9 , C ( =O ) OR9 , CH=NZ , or CHzRlo ;
R9 is hydrogen, alkyl having from one to about 10 carbons, said alkyl groups being optionally substituted with one or more K groups, aryl having from about 6 to about 14 carbons, or aralkyl having from about 7 to about 15 carbons;

_ g _ R'° is aryloxy, heteroaz-yloxy, L, halogen, or has the formula O-M, wherein M has the structure:
\N/~N

D
W-E F
wherein:
R is N or CR";
W is a double bond or a single bond;
D is C=O or a single bond;
E and F are independently R'z, R'3, or J;
or E and F taken together comprise a joined moiety, said joined moiety being an aliphatic carbocyclic ring optionally substituted with J and having from 5 to 7 carbons, an aromatic carbocyclic ring optionally substituted with J and having from 5 to 7 carbons, an aliphatic heterocyclic ring optionally substituted with J and having from 5 to 7 atoms, or an aromatic heterocyclic ring optionally substituted with J and having from 5 to 7 atoms, said aliphatic heterocyclic ring or said aromatic heterocyclic ring each having from 1 to 4 heteroatoms;
R", R'z, and R'3 are independently H, alkyl having from 1 to 10 carbons, heteroaryl having from 1 to 10 carbons, alkanoyl having from 1 to 10 carbons, or aroyl, wherein said alkyl, heteroaryl, alkanoyl and aroyl groups are optionally substituted with J;
J is halogen, C (=O) OR", R'4OC (=O) , R'90C (=O) NH, OH, CN, NOZ , NR'4R'S ( N=C ( R'9 ) R15 , N=C ( NF:'4R'S ) 2 , SR'4 , OR'q , phenyl , naphthyl, heteroaryl, or a cycloalkyl group having from 3 to 8 carbons;
R'4 and R'S are independently H, alkyl having from 1 to 10 carbons, aryl, or heteroaryl, wherein said alkyl, aryl and heteroaryl groups are optionally substituted with K;

L is a phosphorus-containing enzyme reactive group having the formula:
-O/(~)rri R16 )b wherein:
m, n, and b are each independently 0 or 1;
R16 and R1' are each independently hydrogen, lower alkyl optionally substituted with K, aryl optionally substituted with K, or heteroaryl optionally substituted with K;
or Rl~ and R1' taken together with - (O) "-P (=O) -(O)m- can form a 5-8 membered ring containing up to 3 hetero atoms;
or R16 and R1' taken together with - (O) n-P (=O) - (O) m-can form a 5-8 membered ring optionally substituted with K;
or a pharmaceutically acceptable salt or bisulfate addition product thereof.
It is recognized that various stereoisomeric forms of the compounds of Formula I may exist. All such racemates, diastereomers, individual enantiomers, and mixtures thereof form part of the present invention. In some preferred embodiments of the compounds of the invention where RZ is H, it is preferred that the carbon to which the substituent R1 is attached have the L-configuration.
In some preferred embodiments of the compounds of Formula I, A-B is - [CH (R4) ] ~-C (R3) -, -C (R4) =C-, -CH(OR4)-C(R3)-, -C(OR4)=C-, -N(R9)-C(R3)-, -N=C-, -C (R4a) =C (R9) -C (R3) -, or -CH (R4a) -C (Rq) =C- where j is 0, 1, or 2 . In more preferred embodiments A-B is - [CH (R') ] ~-C (R3) -where j is 1, -C (Rq) =C-, -N (R') -C (R3) -, or -N=C-, preferably where R3 and R4 are each H.

In some preferred embodiments of the compounds of Formula I, Z is SOz or C(=O), with SO? being preferred.
In further preferred embodiments of the compounds of Formula I, R2, RS and RB are each H. In still further preferred embodiments R1 is alkyl or aralkyl, preferably i-butyl or benzyl.
In preferred embodiments of the compounds of formula I, R6 and R' are independently H, alkoxy, halogen, or heterocyclic, or R6 and R' taken together form -O-CHz-CH2-O-. In more preferred embodiments R6 and R' are independently H, -OCH" F, Cl, or morpholin-4-yl, or R6 and R' taken together form -O-CHZ-CHZ-O- .
In some preferred embodiments of the compounds of Formula I, Q is H, C (=O) NHR9, or ~~ (=O) OR9, where R~ is alkyl or alkyl substituted with K. In further preferred embodiments of the compounds of formula I, Y is O, NH, NR9 or CHR9, where R9 is alkyl or aral_kyl. Preferably, Y is NR9 or CHR9, where R~ is methyl ethyl, i-propyl, i-butyl or benzyl.
In particularly preferred embodiments of the compounds of Formula I, A-B is - [CH (R4) ] ~-C (R3) - with -CH~-CH- being preferred, -C (R4) =C-, -1V (R4) -C (R3) -, or -N=C-; Z is SOz or C (=O) with SOZ being preferred; R2, RS and R8 are each H; R1 is alkyl or aralkyl, with i-butyl or benzyl being preferred; R6 and R' are independently H, alkoxy, halogen, or heterocyclic, or R6 and R' taken together form -O-CHZ-CHZ-O-; Q is H, C (=O) NHR9, or C (=O) OR'', where R9 is alkyl or alkyl substituted with K; and Y is O, NH, NR9 or CHR9, where R9 is alkyl or aralkyl. In these preferred embodiments R6 and R' are preferably independent:Ly H, -OCH3, F, C1, or morpholin-4-yl, or R6 and R' taken together form -O-CH2-CHZ-O-, and Y is preferably NR9 or CHR9, where R9 is methyl ethyl, i-propyl, i-butyl or benzyl.
In some preferred embodiments of the compounds of Formula I, A-B is -CHZ-CH-; Z is :3O2; R2, RS and Rg are each H; and R1 is alkyl, alkyl substituted with K, or aralkyl, with i-butyl, benzyl, or alkyl substituted with phenylsulfonyl-amino being preferred;
R6 and R' are independently H, alkoxy, halogen, or heterocyclic, with H, OCH3, F, Cl, or morpholin-~-yl being preferred, or preferably R6 and R' taken together form -O-CHz-CHZ-O-;
Q is H, C (=0) NHR9, or C (=O) OR9, where R9 is alkyl, preferably methyl, ethyl, or butyl; and Y is 0, NH or NR9 where R9 is alkyl or aralkyl, with methyl, ethyl, propyl, butyl or benzyl being preferred.
In especially preferred embodiments, A-B is -CHz-CH- ; Z i s SO, ; R2 , RS and R$ are each H ; and R1, R6 , R' , Y and Q have the values shown in Table II, infra.
In further preferred embodiments of the compounds of Formula I, A-B is -CHZ-CH-; Z is SOz; R2, RS and Rs are each H; R6 and R' taken together form -O-CHZ-CH2-O-; Rl is benzyl; Y is N-H or N-ethyl; and Q is C(=0)NHR~ where R9 is alkyl or alkyl substituted with K, preferably CONHEt, CONHBu , CONHCHzCHzOCH3 , CONHCH ( CH3 } 2 , CONH ( CHZ ) 9 CH3 , CONHCH?Ph, CONHCH~CH2Ph, CONHCHZCH=CH2, CONH (CHZ) 3- (imidazol-1-yl) , CONH(CHz}3-{2-ketopyrrolidin-1-yl), CONH(CHz)3(morpholin-4-yl), CONHCHZ(pyridin-2-yl), CONHCH2-cyclopropane, CONHCHZCH2NHSOZCH3, CONHCHZCHZNHS02 (4-NOz-Ph) , CONH (CH2) 3NHS02 (4-NOz-Ph) , CONHCHzCHzNHSO., {3, 4-C12-Ph) , CONH (CHz) 3NHS0z (3, 4-C12-Ph) , CONHCHzCH2NHS02Ph, CONHCHzCHzNHSOZ ( 5- ( 2 -pyridinyl ) -thiophen-2 -yl ) , CONH (CHZ) 3NHS02 (~-F-Ph) , CONH (CHZ) 3NHSOzPh, CONHCHZ- (pyridin-4-yl) , or CONHCHzCH2NHS02 (4-F-Ph) .
In especially preferred embodiments, A-B is -CH2-CH-; Z is SO2; RZ, RS and R6 are each H; R6 and R' taken together form -O-CHZ-CH2-O-; Rl is benzyl; and Y and Q have the values shown in Table III, infra.
In further preferred embodiments of the compounds of Formula I, A-B is -C (R4) =C-; Z is SO2; R2, R' and R8 are each H; R1 is benzyl; R6 and R' are independently H or halogen, or R6 and R' taken together form -O-CHz-CHZ-O-; R4 is H, alkoxy with methoxy being preferred, or hydroxy; Y is NR9 wherein R9 is alkyl with methyl and ethyl being preferred;
and Q is H or C(=O)NHR9 where R9 is alkyl, preferably butyl.
In especially preferred embodiments, A-B is -. C (R4) =C-; Z is SO?; R2, RS and R8 a.re each H; and R1 , R6, R', R4, Y and Q have the values shown in Table IV, infra.
. In further preferred err~bodiments of the compounds of Formula I, A-B is -N(R4) -CH- where R4 is preferably H, propyl, or benzyl; Z is SOZ; R2, F:5 and R~ are each H;
Rl is benzyl; R6 and R' are each H; Y is N-R9 where Ry is alkyl, preferably methyl or ethyl; and Q is H or C(=O)NHR9 where R9 is alkyl, preferably but~~l.
In especially preferred embodiments, A-B is -N ( R4 ) -CH- ; Z is SOZ ; RZ , RS and RB are each H; Rl is benzyl ;
R6 and R' are each H; Y is N-R9; a:nd R~, R9 and Q have the values shown in Table V, infra.
In further preferred embodiments of the compounds of Formula I, A-B is -N=C-; Z is S02; Y is NH; R2, RS and Rg are each H; R1 is benzyl and R' and R' are each H, or R~ and R' taken together form -O-CHZ-CHZ-O-; and Q is H or C (=O) NHR9 where R9 is alkyl, preferably butyl.
In especially preferred embodiments, A-B is -N=C-;
Z is SOz; Y is NH; RZ, RS and R8 are each H; R1 is benzyl and R6 , R' and Q have the values shown in Table VI , infra .
In further preferred embodiments of the compounds of Formula I, A-B is -CH2-CH-; Z is C (=0) ; R2, RS and R8 are each H; Rl is benzyl; R6 and R' are each H; Q is H; Y is N-R9 where R9 is H or alkyl, preferably methyl.
In some preferred embodiments, compounds of the invention have the formula:

WO 98l21186 PCT/US97/20782 RS R4 R3 O R2 Rl R~ ~ Q
L J~~ N
H

Rg wherein the constituent variables are as defined above.
When Q is hydrogen, the invention includes the bisulfite addition products of the aldehydes of Formula I, as exemplified in Example 187, infra.
As used herein, the term "alkyl" is meant to include straight-chain, branched and cyclic hydrocarbon groups such as, for example, ethyl, isopropyl and cyclopropyl groups. Preferred alkyl groups have 1 to about 10 carbon atoms. "Cycloalkyl" groups are cyclic alkyl groups. "Aryl" groups are aromatic cyclic compounds including but not limited to phenyl, naphthyl, anthracyl, phenanthryl, and pyrenyl. Also included within the definition of "aryl" are ring systems having two aromatic rings connected by a bond, such as biphenyl. Preferred aryl groups include phenyl and naphthyl. The term "carbocyclic", as used herein, refers to cyclic groups in which the ring portion is composed solely of carbon atoms. The term "hetero" denotes the presence of one or more noncarbon atoms. Thus, the term "heterocyclic" refers to cyclic groups in which the ring portion includes at least one heteroatom such as O, N or S. "Heteroalkyl" groups are heterocycles containing solely single bonds within their ring portions, i.e. saturated heteroatomic ring systems.
The term "lower alkyl" refers to alkyl groups of 1-4 carbon atoms. The term "halogen" refers to F, Cl, Br, and I atoms.
The term "aralkyl" denotes alkyl groups which bear aryl groups, for example, benzyl groups. The term "heteroaryl" denotes aryl groups having one or more heteroatoms (e. g., O, N, or S) contained within an aromatic WO 98/21186 PCTlUS97/20782 ring. "Heteroaralkyl" groups are aralkyl groups which have one or more heteroatoms in their aromatic ring portion.
Also included within the definition of "heteroaryl" are ring systems having two aromatic ring~~ connected by a bond, where at least one of the rings contains a hetero atom.
As used herein, "alkoxy" groups are alkyl groups linked through an oxygen atom. Examples of alkoxy groups include methoxy ( -OCH, ) and ethoxy ( -OCHzCH3 ) groups .
Alkoxycarbonyl groups are carbonyl groups which contain an alkoxy substituent, i.e., groups of general formula -C(=O}-O-R, where R is alkyl. As used herein the term "alkanoyl" denotes an alkyl group attached through a carbonyl group, i.e., -C(=O)-R where R is alkyl. The term "aroyl" analogously denotes an aryl group attached through a carbonyl group.
As used herein, the term "alkenyl" is intended to include straight-chain or branched hydrocarbon chains having at least one carbon-carbon double bond. Examples of alkenyl groups include ethenyl groups and propenyl groups.
As used herein, the term "amino acid" denotes a molecule containing both an amino group and a carboxyl group. As used herein the term "L-amino acid" denotes an a-amino acid having the L configuration around the a-carbon, that is, a carboxylic acid of general formula CH(COOH)(NHZ)-(sidechain), having the L-configuration.
Sidechains of L-amino acids include naturally occurring and non-naturally occurring moieties. Nonnaturally occurring amino acid sidechains are moieties that are used in place of naturally occurring amino acid sidechains in, for example, amino acid analogs. See, for example, Lehninger, Biochemistry, Second Edition, Worth Publishers, Inc, 1975, pages 73-75. Representative a-amino acid sidechains are shown below in Table 1.

Table 1 CH3 - HS - CHz -HO-CH2- HOZC-CH (NHZ) -CHZ-S-S-CHZ-C6H5 - CHZ - CH3 - CHz _ CH3-CHZ-S-CH2-CHz-HO ~ ~ CH2- HO-CHZ-CHz-HQ CH3-CH (OH) -H02C-CHz-NHC (=O) -CHZ-N
H HO2 C - CHz - CHz -NH2C (=O) -CH,-CHz-(CH3) 2-CH-(CH3) 2-CH-CHz_ H2N-C (=NH) -NH-CHz-CHZ-CHZ-H2N-C (=O) -NH-CHz-CH2-CHZ-CH3 - CHZ - CH ( CH3 ) -cHz- CH3 - CHz - CH2 - CH2 -CHZ
O O O O HZN - CH2 - CHZ - CHz - CHZ -Functional groups present on the compounds of Formula I may contain blocking groups. Blocking groups are known per se as chemical functional groups that can be selectively appended to functionalities, such as hydroxyl groups, amino groups, thio groups and carboxyl groups.
Protecting groups are blocking groups that can be readily removed from functionalities. These groups are present in a chemical compound to render such functionality inert to chemical reaction conditions to which the compound is exposed. Any of a variety of protecting groups may be employed with the present invention. One such protecting WO 98I21186 PCT/US97l20782 group is the benzyloxycarbonyl (Cbz; Z) group. Other protecting groups include toluenesulfonyl, t-butoxycarbonyl, methyl ester and benzyl ether groups. Other preferred - protecting groups according to the invention may be found in Greene, T.W. and Wuts, P.G.M., ".Protective Groups in Organic Synthesis" 2d. Ed.) Wiley & Sons, 199l, which is incorporated herein by reference. Further blocking groups useful in the compounds of the p,_esent invention include the phthalimido group, arylcarbonyls,, alkylcarbonyls, alkoxycarbonyls, aryloxycarbonyls, aralkyloxycarbonyls, alkyl- and aralkylsulfonyls, and arylsulfonyl groups such as those which have the following formulas:
SOZ ~ ~ OCH3 -Spz MTR MTS
-:iO2 PMC TOS
Because the benzothiazo and related heterocyclic group-containing components of the invention inhibit cysteine proteases and serine proteases, they can be used in both research and therapeutic settings.
In a research environment, preferred compounds having defined attributes can be used to screen for natural and synthetic compounds which evidence similar characteristics in inhibiting protease activity. The compounds can also be used in the refinement of in vitro and in vivo models for determining the effects of inhibition of particular proteases on particular cell types or biological conditions. In a therapeutic setting, given the connection i i between cysteine proteases and certain defined disorders, and serine proteases and certain defined disorders, compounds of the invention can be utilized to alleviate, mediate, reduce and/or prevent disorders which are associated with abnormal and/or aberrant activity of cysteine proteases and/or serine proteases.
In preferred embodiments, compositions are provided for inhibiting a serine protease or a cysteine protease comprising a compound of the invention. In other preferred embodiments, methods are provided for inhibiting serine proteases or cysteine proteases comprising contacting a protease selected from the group consisting of serine proteases and cysteine proteases with an inhibitory amount of a compound of the invention.
The disclosed compounds of the invention are useful for the inhibition of cysteine proteases and serine proteases. As used herein, the terms "inhibit" and "inhibition" mean having an adverse effect on enzymatic activity. An inhibitory amount is an amount of a compound of the invention effective to inhibit a cysteine and/or serine protease.
Pharmaceutically acceptable salts of the cysteine and serine protease inhibitors also fall within the scope of the compounds as disclosed herein. The term "pharmaceutically acceptable salts" as used herein means an inorganic acid addition salt such as hydrochloride, sulfate, and phosphate, or an organic acid addition salt such as acetate, maleate, fumarate, tartrate, and citrate. Examples of pharmaceutically acceptable metal salts are alkali metal salts such as sodium salt and potassium salt, alkaline earth metal salts such as magnesium salt and calcium salt, aluminum salt, and zinc salt. Examples of pharmaceutically acceptable organic amine addition salts are salts with morpholine and piperidine. Examples of pharmaceutically acceptable amino acid addition salts are salts with lysine, glycine, and phenylalanine.
Compounds provided herein can be formulated into pharmaceutical compositions by admixture with pharmaceutically acceptable nontc>xic excipients and carriers. As noted above, such compositions may be prepared for use in parenteral administration, particularly in the form of liquid solutions or suspensions; or oral administration, particularly in the form of tablets or capsules; or intranasally, particularly in the form of powders, nasal drops, or aerosols; or dermally, via, for example, transdermal patches; or prepared in other suitable fashions for these and other forms of administration as will be apparent to those skilled in the art.
The composition may conveniently be administered in unit dosage form and may be prepared by any of the methods well known in the pharmaceutical art, for example, as described in Remingtor2's Pharrr,~aceutical Sciences (Mack Pub. Co., Easton, PA, 1980). Formulations for parenteral administration may contain as common excipients sterile water or saline, polyalkylene glycols such as polyethylene glycol, oils and vegetable origin, hydrogenated naphthalenes and the like. In particular, biocompatible, biodegradable lactide polymer, lactide/glycolide copolymer, or polyoxyethylene-polyoxypropylene copolymers may be useful excipients to control the release of the active compounds.
Other potentially useful parenteral delivery systems for these active compounds include ethylene-vinyl acetate copolymer particles, osmotic pumps, implantable infusion systems, and liposomes. Formulations for inhalation administration contain as excipients, for example, lactose, or may be aqueous solutions containing, for example, polyoxyethylene-9-lauryl ether, glycocholate and deoxycholate, or oily solutions for administration in the form of nasal drops) or as a gel to be applied intranasally.
Formulations for parenteral administration may also include glycocholate for buccal administration, a salicylate for rectal administration, or citric acid for vaginal administration. Formulations far transdermal patches are preferably lipophilic emulsions.

The materials for this invention can be employed as the sole active agent in a pharmaceutical or can be used in combination with other active ingredients which could facilitate inhibition of cysteine and serine proteases in diseases or disorders.
The concentrations of the compounds described herein in a therapeutic composition will vary depending upon a number of factors, including the dosage of the drug to be administered, the chemical characteristics (e. g., hydrophobicity) of the compounds employed, and the route of administration. In general terms, the compounds of this invention may be provided in effective inhibitory amounts in an aqueous physiological buffer solution containing about 0.1 to loo w/v compound for parenteral administration.
Typical dose ranges are from about l~,g/kg to about 1 g/kg of body weight per day; a preferred dose range is from about 0.01 mg/kg to 100 mg/kg of body weight per day. Such formulations typically provide inhibitory amounts of the compound of the invention. The preferred dosage of drug to be administered is likely, however, to depend on such variables as the type or extent of progression of the disease or disorder, the overall health status of the particular patient, the relative biological efficacy of the compound selected, and formulation of the compound excipient, and its route of administration.
As used herein, the term "contacting" means directly or indirectly causing at least two moieties to come into physical association with each other. Contacting thus includes physical acts such as placing the moieties together in a container, or administering moieties to a patient.
Thus, for example administering a compound of the invention to a human patient evidencing a disease or disorder associated with abnormal and/or aberrant activity of such proteases falls within the scope of the definition of the term "contacting".
The invention is further illustrated by way of the following examples which are intended to elucidate the invention. These examples are not intended, nar are they to be construed, as limiting the scope of the disclosure.
Examples Compounds of the invention were prepared according to the following procedures.
The synthesis of these compounds are summarized in Schemes 1-7:

! I

A

1 ) NaNO
z R6 N~ HCI, R6 CN !) H2SO4, H20 20-i00 oC
R6 COzH
~ I i i refl ~ I
O

w I CI 2) N

CN R7 ux .
.

R
S

_ O..O

I CuCl2, KCI

NaOAc acetone H20 CISOgH

CHCt3 or neat 0-i00 oC

R6 CONHZ ~ R6/~'\~CONH2 l T
I

~ ~ ~ Cl H20 or dioxane~S
H
N
R~
J
~

R reflux, 1-2 .
SOZCI hours O'~
' O

6N NaOH or H ZSOq RBr or RI reflux D ~2 KZC03, DMF

E F

R6 ~ CONIL~ R6 ~

w R~ S Y I
,NH
R~
S

.
o..o o..o 6N NaOH RI (2 equiv.), K 2C03 or HzSO
q reflux DMF, 60-?0 oC

R6 ~ COZH 4-6N NaOH R6 i R~ \ S'.Y or4NHCl ~
~
I
1' O..O R
,5~
O..O

Scheme 1 ~I
R7 \ S'~
O' O
3; Y=O

7; Y=NH
R; Y=NR

~OEt G \ ~N~CONHR HZN z Hz N ~C OH OH
OEt HOBt, BOP, NMM
DMF, 0-20 oC R t or ~OH
HZN

R6 ~ CONH~OEt OH

OEt y ~ I y Q
R7 S. R7 S.
O O () H I
p-TsOH-H z0 (1 equiv.) Dess-Martin (2-4 equiv.) MeOH CHZCI~, 0-20 oC, I-24 hrs.

~ ~Q
R6 , CONI-I l i 'Y O
R~ S.
O'~O
12; Q=H
13; Q = CO 2 CHI HOBt, BOP, NMM R 1 RNH~
14; Q=CONHR .~ 8 + H2N~CONHR
nO
Scheme 1 (cont. ) f I ' ' WO 98I21186 PCT/US97l20782 HO COyH HO C02CH~ Cbz-OSuTHF-Dioxane HO CO C
i I SOCIZ McOH i I ~ 2 w Ntl2 > 95% I-10 ~ ~~CI' 90°/ HO w I NHCbz HO
l5 16 I
Dibromoethane O , C02CH3 C1503HCHC13 0°C CO , CO=CI it lOeq.K2C03Acetone CO ~ I NHCbz EI3NDMAPCHCI3 ~ p ~ I ~S'~
O. .O
70°l O COiCH3 O COZH
EtI K2C03 i 2N NaOH
DMF ~O ~ I ,S ~t MeOH CO ~ I ,S :fit 0' 'O O' 'O
20 8s Scheme 2 R6 ~ COZR NBS PO R6 ~COZR t) CH~INeOH OH
I ~(H ) i I w H208tOH R6 , ~ COzR
R7 ~ g~Y CCIq,CH2CF2 ' R7 ~ S.Y E ~ I ,NH
O R7 %~'~~
O O 2) CFh I KiC03 p' ' O
21 Acetone SN NaOH
MeOH, 20-50 oC

R6 ~COiH
i R7~i.Y
O'~O

Z ~OEt G ~CONHR R1 ~C N ~
H N OEt HOBt, BOP, NMM ~ OH or H2N' v OH
DMF, 0-20oC

OEt R6 ~ \ CONH OH
R6 ~ \ CONI1~
OEt ~ I Y Q
R7 ~ g-Y R7 S. ~ 22 O..O O..O

H I
Dess-Martin (2-4 cquiv.) p-TsOH-H20(1 equiv.) MeOH CH2C>2, 0-20 oC, I-24 hrs.
RI

R6 ~ \ COhIFI~
\ I ,Y O
R7 S, O'~O
26; Q = H
27; Q = CONHBu Scheme 3 i i i 6 H BH3-NMe3 R ~ ~z RCHO R6 N R HOAc 60 oC R6 NHg4 R7 \ S02NHZ MeOH R7 ~ S'NH R~
SOzNHz O'~O

(CH30)zCHCOZCH3 R4 Hz0 R6 N COzH ~ KzC03 R6 N CO R
i I ~ ~ ~ I ~ z R7 ~ S~NH DMF 60-70 oC R7 ~ S'N~R
O..O O..O
3t 32 2M NeOH, EtOH R4 R6 ~ N"C02H
~I
R7' v _S'y O' O

RI Rl H N' vOli ~N~CONHR
IIz G O
HOBt, BOP, NMM
DMF, 0-20nC IBCF, NMM
DMF, 0-20oC
I

R4 Dess-Martin R4 R6 ~ N~CONH~OH CHzCIz-CH3CN R6 / N~CONH~Q
R7 \ I S'Y Q -~ \ I Y O
R7 S' O' O O'~O

Scheme 4 1) CISO zNCO, EINt?i I1 R~ NI-h -40-0 oC R6 N O HCI R6 _s, ~ I ~ -~. ~ I z R7 ~ S .'~1 R7 \ SOzNH2 2) AICh 110oC O' O

CICOC Et C02 Et R6 NH-~ NaOEt, EtOH
Et3N,TfR: ~ ~ I O R6 ~ NY C02 Et --i R7 \ SOzNHz R7 w I S~NH
O'~O

2MNaOH,EtOH R6 NYCOzH
-~ i R7 w I S,~NH
O'~O

~CONHR
HZN~OH HZN
G
IIOBt, BOP, NMM
DMF, 0-20nC IBCF, NMM
DMF, 0-20oC

Dess-Martin R6 , N CONH~ OH CHZ Ct~ - CHI CN R6 / N CONH~ Q
R7 \ I S,Y Q ~ R7 \ I SY O
O..O O..O

Scheme 5 I I ! I

COZH phCOCI NaOH ~ COzH KMn04 C02H
NH w I N~Ph w I H1v'~ Ph IO COzH ll O

Reflux 18h , COyH I) Ag 20, CHI) DMF / COzH
NII 2) NaOH, MeOH ~ N
~~~'~ CHI
O O

~OH
HZ N
HOBt) BOP) NMM
DMF, 0-20oC

Dess-Martin CONH~OH CH~C)z_CH~CN ~ CONH~H
I
Y \ I Y O
O O
48; Y=NH 50 49; Y=NCH3 Scheme 6 o NI-1 cod ~--~ ~, ~N ~ coNrlz 5',NC~ Pyridine w ~ NCI-13 O O 80 oC 10 days S .
O'~O
6k 6z RI Bu-NC TiCb RI O
R4 ~Ij CHzC~ R
R6 , CONH II ~ R6 , ~CONH~NHBu mss-Martin O \ ~ . ' ~~, OH _~ 14 R7 S . K R2~'S'.
O'~O O'~O
12 1:l 26 2:i Scheme 7 Example 1 General.Procedure A: Condensation of Anilines with Acrylonitrile Synthesis of Intermediate 2a (R6 - R' - OCH3) 2-Chloro-3-(3,4-dimethoxyphenyl)propanenitrile The synthesis of intermediate 2a was performed according to the procedure of W. Popel et al., Pharmazie, 1980, 35, 266-278, which is herein incorporated by reference.
To a vigorously stirred solution of 4-aminoveratrole (17.8 g, 1l6 mmol) in water (150 ml) and 12N HCl (29 ml, 349 mmol) chilled in an ice-water bath was added dropwise a solution of sodium nitrite (9.2 c~, l33 mmol) in water (15 ml) over 10-15 minutes. The mixture was stirred for an additional 15 minutes at the same temperature. This solution was added dropwise over 20 minutes to a vigorously stirred solution of acrylonitrile (18.6 g, 23 ml, 349 mmol), CuCl2-2H20 (3 g, 17.4 mmol) , KC1 (10 g, 134 mmol) and NaOAc (l3.1 g, 160 mmol) in water (l50 ml) and acetone (350 ml) chilled in an ice-water bath. The resulting mixture was allowed to stir while slowly warming to ambient temperature over 24-48 hours or until evolution of nitrogen gas had ceased. The acetone was removed on a rotary evaporator and the residue was extracted with ethyl acetate (2 x 250 ml).
The combined organic phase was washed with water and brine, dried over anhydrous magnesium sulfate, filtered and concentrated. The dark residue was purified by flash chromatography (silica gel, dichloromethane) to give 6.0 g (23%) of the title compound as a pale yellow mobile oil.
NMR (CDC13) b 3 .25 (2H, d, J = 7 Hz) , 3 .88 (3H, s) , 3 .89 (3H, s), 4.53 (1H, t, J = 7 Hz), 6.79 {1H, s), 6.85 (2H, s);
Anal . Calc' d for C11H12C1N0z : C, 58 . 54 ; H, 5 . 37 ; N, 5 . 21 ; Cl, 15.71; Found: C, 58.67; H, 5.42; N, 6.52; Cl, 15.98.
Example 2 Synthesis of Intermediate 2k (R6 - F; R' - H) 2-Chloro-3-(3-fluorophenyl)propanenitrile This compound was prepared according to General Procedure A. From 3-fluoroaniline (25 g, 0.23 mol) crude title compound (42 g) was obtained which was purified by flash chromatography on silica gel {10% CH2C12:hexanes) followed by further purification by distillation on a Kugelrohr apparatus (oven T = 12S°C, 0.3mm Hg) to give 22 g (53a); NMR (CDC13) b 3.30 (m, 2H), 4.56 (t, J = 7 Hz, 1H), 7. 04 (m, 3H) , 7. 35 (m, 1H) .
Example 3 Synthesis of Intermediate 21 (R6 - R' - Cl) 2-Chloro-3-(3,4-dichlorophenyl)propanenitrile This compound was prepared according to General Procedure A. From 3,4-dichloroaniline (35 g, 0.22 mol) crude title compound (41 g) was obtained which was purified by triple distillation on a Kugelrohr apparatus (oven T =
160°C, 0.5mm Hg) followed by treatment with decolorizing carbon in refluxing methanol to give 17.3 g (340) of a WO 98I21186 PCTlUS97/20782 yellow-orange mobile oil after filtration and concentration to constant weight; NMR (CDC13) b 3.26 (m, 2H), 4.S6 (t, J =
7 Hz, 1H) , 7.13 (m, 1H) , 7.40 (m, 2H) .
Example 4 Synthesis of Intermediate 2n (R6 - Cl; R' - H) 2-Chloro-3-(3-chlorophenyl)propanenitrile This compound was prepared .according to General Procedure A. From 3-chloroaniline (25 g, l96 mmol) a crude product (19.6 g) was obtained which was further purified by distillation on a Kugelrohr apparatus (oven temp. 140°C, 0.2 mm Hg) to afford 17.1 g (440) of the title compound as a yellow mobile oil; NMR (CDC13) 8 3.28 (2H, m), 4.57 (1H, t, J = 7 Hz}, 7.20 (1H, m), 7.28-7.33 (3H, m}.
Example 5 Synthesis of Intermediate 2r iR6 + R' - OCH2CH?O) 2-Chloro-3-(3,4-ethylenedioxyphenyl)propanenitrile This compound was prepared <~ccording to General Procedure A. From 1,4-benzodioxa.n-6-amine (25 g, l65 mmol) the title compound (9.8 g, 260) was obtained as a yellow solid; NMR (CDC13) b 3.2 (2H, d, J = 7 Hz), 4.25 (4H, s), 4.50 (1H, t, J = 7 Hz), 6.73-6.86 (3H, m).
Example 6 Synthesis of Intermediate 2,3-Dihydrobenzothiazole 1,1-dioxide Derivatives 2,3-Dihydrobenzothiazole 1,:L-dioxide derivatives (compounds of Formula I, where A-B = CR3) can be prepared from 2,3-dihydrobenzothiazole-3-carboxylates according to the methods specified in Scheme I and General Procedures G -J. These intermediates can be formed by reduction of 3-hydroxy-2,3-dihydrobenzothiazole-3-carboxylates, described by J. Wrobel and A. Dietrich [He~terocycles 1994, 38, 1823 -1838, incorporated by reference herein in its entirety] with reagents including sodium cyanoborohydride, sodium borohydride, zinc - acetic acid, or catalytic hydrogenation WO 98l21186 PCT/US97/20782 by methods known to those skilled in the art.
Alternatively, 2,3-dihydrobenzothiazole-3-carboxylates may be prepared by treating N-alkylbenzenesulfonamides with a strong base such as butyllithium followed by glyoxylic ester by a modification of the method of Wrobel and Dietrich, supra .
Example 7 Synthesis of Intermediate 4,5-Dihydrobenzothiazepine 1,1-dioxide Derivatives 4,5-Dihydrobenzothiazepine 1,1-dioxide derivatives (compounds of Formula I, where A-B = CHR4a-CR3) can be prepared from 4,5-dihydrobenzothiazepine-3-carboxylates according to the methods specified in Scheme I and General Procedures G - J. These intermediates can be synthesized by modification of previously reported methods. For example, 3-(m-chlorophenyl)propionaldehyde (prepared according to the method of H. Hashizume et al., Chem. Pharm. Bull. 1994, 42, 5l2 - 520, incorporated by reference herein in its entirety), can be transformed into m-chlorohomophenylalanine by reaction with sodium cyanide and ammonium carbonate followed by hydrolysis. Treatment of m-chlorohomophenylalanine with chlorosulfonic acid by a modification of the procedure described by H. Zenno and T.
Mizutani (Japanese patent application No. 7004990, l956;
Chem. Abstr. 72, 111525, incorporated by reference herein in its entirety) affords 7-chloro-4,5-dihydrobenzothiazepine-3-carboxylate. Alternatively, 2-(aminosulfonyl)phenyl-propanoic acid, described by P. Catsoulacos and C. Camoutsis (J. Heterocycl. Chem. 1976, I3, 1309 - 1314, incorporated by reference herein in its entirety), may be reduced to the corresponding aldehyde, treated with cyanide, hydrolyzed with acid or base, and cyclized by the procedure of Catsoulacos and Camoutsis to give 4,5-dihydrobenzothiazepine-3-carboxylate.

Example S
Synthesis of Intermediate 3a (R6 - R' - OCH3) 3,4-Dihydro-6,7-dimethoxy-2,1-benzoxathiin-3-carboxylic acid To a flask containing 1.0g (4.4 mmol) of compound 2a was added 1 ml of 98% HZSO~ with :stirring. The viscous dark mixture was stirred overnight at ambient temperature, diluted with water (5 ml) and wa:~ held at reflux for four hours. The mixture was cooled to ambient temperature, water (25 ml) was added, and stirring was continued for an additional 15 minutes. The resulting precipitate was filtered and washed to neutrality with water before being allowed to air dry. The dark crude product was purified by recrystallization from 1,4-dioxane (activated carbon) to give 290 mg (220) of the title cc>mpound as a tan powder, mp 273-275°C (dec.); NMR (CDC13-DMSO--d6) b 3.16-3.29 (2H, m), 3.8l (6H, s), 5.34 (1H, dd, J = 9 Hz, 12 Hz), 6.63 (1H, s), 7 . 11 ( 1H, s ) ; MS : 311 m/z (M+Na) +; Anal . Calc' d for C11H1zO,S
C, 45.83; H, 4.20; S, l1.10; Found: C, 45.26; H, 4.04; S, 1l.98.
Example 9 General Procedure B: Aromatic Chlorosulfonylation Synthesis of Intermediate 4c (R6 - R' - OCH3) 2-Chloro-3-(2-chlorosulfonyl-4,5-dimethoxyphenyl)propanamide To a solution of compound 2.a (4.07 g, 18.0 mmol) in anhydrous chloroform (50 ml) chilled in an ice-water bath was added chlorosulfonic acid (4.2 g, 2.4 ml, 36.0 mmol) dropwise over 10-15 minutes. The: mixture was stirred at this temperature for 5 hours and poured into a separatory funnel containing chloroform (50 ml) and water (50 ml). The organic phase was washed further with water and brine, dried (MgS04), filtered and concentrated. The brown sticky residue (2.8 g) was slurried with benzene: (5 ml) for fifteen minutes, decanted and dried in-va.cuo to constant weight to give 2.5 g (410) of the title compound as a red-brown solid.
The intermediate was used without. further purification; MS:
342 m/z (M+H)', CIz pattern.

Example 10 Synthesis of Intermediate 41 (R6 - R' - Cl) 2-Chloro-3-(2-chlorosulfonyl-4,5-dichlorophenyl)propanamide This compound was prepared according to General Procedure B. From 21 (2.5 g, 10.7 mmol) in neat chlorosulfonic acid (-10 ml) at 150°C for 1.5 hours, 3.3 g (890) of the title compound was obtained as a yellow powder which was isolated by dropwise addition of the dark reaction mixture (cooled to ambient temperature) to a vigorously stirred slurry of ice-water 0100 g), suction filtration of the precipitate and washing with cold water and drying to constant weight in vacuo to give analytically pure material;
Anal. Calc'd for C9H.,C14N03S: C, 30.80; H, 2.01; N, 3.99; S, 9.12; Found: C, 30.47; H, 1.92; N, 3.38; S, 9.29.
Example 11 Synthesis of Intermediate 4n (R6 - C1; R' - H) 2-Chloro-3-(2-chlorosulfonyl-5-chlorophenyl)propanamide This compound was prepared according to General Procedure B. To a dry flask equipped with a magnetic stirrer, rubber septum and drying tube was added compound 2n (5.0 g, 25.0 mmol). Chlorosulfonic acid (17 ml) was added with stirring over 5-10 minutes at ambient temperature. An appreciable exotherm was observed along with gas evolution (HC1) that persisted for 10-15 minutes following completion of the addition. After being allowed to stir for an additional one hour, the mixture was heated to 100°C for one hour, cooled to ambient temperature, and added dropwise with vigorous stirring to an ice-water slurry (500g). The resulting precipitate was collected by suction filtration, washed with water several times, and dried in-vacuo to constant weight to afford 8.9 g of crude title compound as a pale yellow solid; NMR analysis suggested the presence of the desired product as well as an unidentified regioisomer:
NMR (DMSO-d6) b 3.37 (1H, ABq), 3.60 (1H, ABq), (J = 7 Hz, 14 Hz), 4.59 & 4.80 (1H, 2t, J = 7 Hz), 7.18-7.26 (2H, m), 7.65-7.80 (1H, m). The product was used without further purification.
Example 12 Synthesis of Intermediate 4r (R6 + R' - OCHzCHzO) 2-Chloro-3-(2-chlorosulfonyl-4,5--ethylenedioxyphenyl)propanamide This compound was prepared according to General Procedure B. From compound 2r (3.0 g, l3.4 mmol) the title compound (2.4 g, 51%) was obtained as a tan powder, which was used without further purification.
Example 13 General Procedure C: Reaction of Sulfonyl Chloride with Ammonia Synthesis of Intermediate 5c (R6 = R., = OCH3) 3,4-Dihydro-6,7-dimethoxy-2H-1,2--benzothiazine-3-carboxamide l,l-dioxide To a flask containing a solution of NH3 in 1,4-dioxane (0.5M, 30 ml) was added compound 4c (1.0 g, 2.9 mmol). The mixture was held at reflux for 2 hours, cooled to room temperature and concentrated in-vacuo. The residue was slurried in water and the solid voas collected by vacuum filtration, washed to neutrality with water and dried in-vacuo to constant weight to give 0.31 g (37%) of the title compound as an off-white powder; MS: 287 m/z (M+H)', 309 m/z (M+Na)'.
Example 14 Synthesis of Intermediate 5r (R6 + R' - OCHZCH20) 3,4-Dihydro-6,7-ethylenedioxy-2H--1,2-benzothiazine-3-carboxamide l,l-dioxide This compound was prepared according to General Procedure C. However, the reaction was performed using concentrated aqueous ammonium hydroxide. From compound 4r (2.4 g, 7.1 mmol) and conc. NH40H (50 ml) the title compound (0.87 g, 44%) was obtained following flash chromatography on silica gel (25% ethyl acetate/hexane to ethyl acetate); MS:

283 (M-H)-.
Example 15 General Procedure D: Reaction of Sulfonyl Chlorides with Primary Amines Synthesis of Intermediate 6e (R6 - R' - OCH3; Y = NCH3) 3,4-Dihydro-6,7-dimethoxy-2-methyl-2H-1,2-benzothiazine-3-carboxamide 1,1-dioxide A mixture of compound 4c (1.1 g, 3.2 mmol) in 400 aqueous methylamine (10 ml) was stirred while being warmed to reflux. Small amounts of water (1-2 ml) were added after 30 and 45 minutes to facilitate stirring. After a total reflux period of 1.5 hours, the mixture was cooled in an ice-water bath and the solid was collected by suction filtration and washed to neutrality with water before being dried to constant weight in-vacuo. The title compound (0.57 g, 590) was obtained as an off-white powder; mp 215-222°C;
NMR (DMSO-d6) b 2.58 (3H, s) , 2. 97-3.28 (2H, m) , 4.51 (3H, s), 4,S2 (3H, s), 4.53 (1H, dd, J = 5 Hz, 12 Hz), 7.02 (1H, s), 7.l2 (1H, s), 7.44 (1H, br; absent in DZO), 7.64 (1H, br;
absent in D20); MS: 30l m/z (M+H)+, 323 m/z (M+Na)+; Anal.
Calc'd for ClzH,6N20.,S: C, 47.99; H, 5.38; N, 9.42; S, l0.66;
Found: C, 48.22; H, 5.37; N, 9.25; S, 10.93.
Example 16 General Procedure E: Alkylation of Sulfonamides Synthesis of Intermediate 6g (R6 - R' - OCH3; Y = NBn) 3,4-Dihydro-6,7-dimethoxy-2-benzyl-2H-1,2-benzothiazine-3-carboxamide 1,1-dioxide A mixture of compound 5c (250 mg, 0.87 mmol) and anhydrous potassium carbonate (300 mg, 2.2 mmol) in DMF (3 ml) was treated with benzyl bromide (0.11 ml, 0.96 mmol).
The mixture was stirred while being warmed to 95-100°C.
After five hours an additional 0.05 ml of benzyl bromide was added and the mixture was allowed to stir overnight at 95-100°C. The mixture was cooled to ambient temperature, the 3S solvent was evaporated in-vacuo and the residue was partitioned between ethyl acetate and 5o aqueous citric acid solution. The organic phase was washed further with saturated aqueous sodium bicarbonate solution, brine, dried over anhydrous magnesium sulfate, filtered and concentrated to afford 310 mg (940) of the title compound as a pale yellow solid which was used without further purification;
MS: 377 m/z (M+H)', 399 m/z (M+Na;l+.
Example 17 Synthesis of Intermediate 6k (R6 -- F; R' - H; Y = NCH3) 3,4-Dihydro-6-fluoro-2-methyl-2H-1,2-benzothiazine-3 carboxamide 1,1-dioxide This compound was prepared according to General Procedure D. From 4k (l4.1 g, 52.6 mmol) the title compound (7.2 g, 530) was obtained following flash chromatography on silica gel (30% to 80% ethyl acetate/hexanes); NMR {CDC13) b 2.59 (s, 3H), 3.08-3.2l (m, 2H), 4.49-4.55 (m, 1H), 7.27-7.40 (m, 2H), 7.47 (br, 1H, CONH), 7.68 (br, 1H, CONH), 7.77-7.81 (m, 1H); MS: 259 m/z (M+H)'; Anal. Calc'd for C1oH11FN2O3S: C, 46.5l; H, 4.30; N, 10.85; S, 12.39; F, 7.36;
Found: C, 47.11; H, 4.49; N, l0.91; S, 12.02; F, 7.19.
Example 18 Synthesis of Intermediate 61 (R6 -- R' - Cl; Y = NCH3) 3,4-Dihydro-6,7-dichloro-2-methyl-2H-1,2-benzothiazine-3-carboxamide 1,1-dioxide This compound was prepared according to General Procedure D. From 41 (3.0 g, 8.5 mmol) the title compound (0.94 g, 36%) was obtained following flash chromatography on silica gel (25% ethyl acetate/hexanes); MS: 307, 309, 311 m/z (M+H) * (C12 pattern) .
Example 19 Synthesis of Intermediate 6p (R6 -- C1; R' - H; Y = NCH3) 3,4-Dihydro-5-chloro-2-methyl-2H-1,2-benzothiazine-3-carboxamide 1,1-dioxide This compound was prepared according to General Procedure D. From compound 4n (8.0 g, 25.3 mmol) the title compound (3.4 g, 490) was obtained following flash chromatography on silica gel (25% ethyl acetate/hexane to ethyl acetate); NMR (DMSO-d6) b 2.60 (3H, s), 3.l1-3.19 (2H, m), 4.48 (1H, dd, J = 6 Hz), 7.47-7.74 (5H, m; 3Ar + 2NHz);
MS: 275, 277 m/z, chloride isotope pattern.
Example 20 Synthesis of Intermediate 6r (R6 + R' - OCHZCH20; Y = NCH3) 3,4-Dihydro-6,7-ethylenedioxy-2-methyl-2H-1,2-benzothiazine-3-carboxamide 1,1-dioxide This compound was prepared according to General Procedure D. From compound 4r (1.0 g, 2.9 mmol) the title compound (0.77 g, 880) was obtained as an off-white solid;
NMR (DMSO-d6) b 2.56 (3H, s) , 2.95-3.04 (2H, m) , 4.25 & 4 .26 (4H, 2s), 4.40-4.46 (1H, ABq, J = 6 Hz), 6.95 (1H, s), 7.l2 (1H, s), 7.43 (1H, br; absent in D~O), 7.63 (1H, br; absent in D20) .
Example 21 Synthesis of Intermediate 6z (R6 - 4-morpholino; R' - H; Y =
2 0 NCH3 ) 3,4-Dihydro-6-(4-morpholino)-2-methyl-2H-1,2-benzothiazine-3-carboxamide 1,1-dioxide A solution of 6k (2.0 g, 7.75 mmol) in pyridine i30 ml) was treated with morpholine (6.75 g, 77.5 mmol) and warmed to 80-85°C with stirring. After 10 days the mixture was concentrated in vacuo and the residue was partitioned between ethyl acetate and water. The organic phase was washed twice more with water and then brine) dried over anhydrous magnesium sulfate, filtered and concentrated to give 2.6 g of the crude product which was further purified by recrystallization (ethyl acetate/hexanes) to afford 1.7 g (710) of the title compound as an off-white solid; NMR
(DMSO-d6) b 2.70 (s, 3H), 3.l8-3.33 (m, 6H), 3.82-3.8S (m, 4H), 4.12-4.18 (m, 1H), 6.75 (s, 1H), 6.84 (dd, J = 2 Hz, 8 Hz, 1H), 7.65 (d, J = 8 Hz, 1H); MS: 326 m/z (M+H)'.

Example 22 General Procedure F: Amide Hydrolysis - Alkaline Conditions Synthesis of Intermediate 7c (R6 - R' - OCH3 ) 3,4-Dihydro-6,7-dimethoxy-2H-1,2--benzothiazine-3-carboxylic acid 1,1-dioxide A slurry of compound 5c (300 mg, 1.05 mmol) in 6N NaOH
(7 ml) was heated to reflux. After about 10 minutes the mixture became homogeneous. Reflux was continued for an additional 30-40 minutes at which time tlc analysis revealed complete consumption of starting material. The mixture was cooled to room temperature, a small amount of water was added to dissolve precipitated solids, and the pH was adjusted to -.3 with 6N HCl. The resulting precipitate was collected by suction filtration, washed to neutrality with water, and dried to constant weight in-vacuo to give 250 mg (84a) of the title compound as a white solid; NMR (DMSO-d6) b 2.97-3.18 (2H, m), 3.76 (6H, 2s), 4.33 (1H, m; dd in D~O), 7.10 (1H, s), 7.57 (1H, s), 7.58 (1H, d, J = 11 Hz; absent in D20) ; MS : 286 m/z (M-H) -; Anal .. Calc' d for C;,H13N06S : C, 45.99; H, 4.57; N, 4.88; S, I1.19:; Found: C, 46.l6; H, 4.52; N, 4.86; S, l0.85.
Example 23 Synthesis of Intermediate 7r (R6 + R' - OCHZCHzO) 3,4-Dihydro-6,7-ethylenedioxy-2H-1,2-benzothiazine-3-carboxylic acid 1,1-dioxide This compound was prepared .according to General Procedure F (alkaline conditions). From compound 5r (250 mg, 0.88 mmol) the title compound (228 mg, 91%) was obtained as a tan solid; NMR (DMSO-d6) b 2.86-3.08 (2H, m), 4.25-4.33 (5H, m + s), 6.90 (1H, s), 7.08 (1H, s), 7.60 (1H, d, J = 11 Hz; NH, absent in D20) ; MS: 284 (M-H)-.

Example 24 Synthesis of Intermediate 8e (R6 - R' - OCH3; Y = NCH3) 3,4-Dihydro-6,7-dimethoxy-2-methyl-2H-1,2-benzothiazine-3-carboxylic acid 1,1-dioxide This compound was prepared according to General Procedure F (alkaline conditions). From compound 6e (500 mg, 1.7 mmol) the title compound (480 mg, 960) was obtained as a buff white solid; mp 196-200°C; MS: 300 m/z (M-H)-.
Example 25 Synthesis of Intermediate 8g (R6 - R' - OCH3; Y = NBn) 3,4-Dihydro-6,7-dimethoxy-2-benzyl-2H-1,2-benzothiazine-3-carboxylic acid 1,1-dioxide This compound was prepared according to General Procedure F (alkaline conditions). From compound 6g (290 mg, 0.77 mmol) the title compound (183 mg, 63%) was obtained as a white solid; NMR (DMSO-d6) b 3.l3-3.27 (2H, m), 3.78 (6H, s), 4.19 (2H, ABq, J = 16 Hz, 41 Hz), 4.54-4.59 (1H, dd, J = 6 Hz), 7.04 (1H, s), 7.l4 (1H, s), 7.18-7.33 (5H, m), 13.2 (1H, br; absent in D20); MS: 378 m/z (M+H)", 400 m/z (M+Na)~.
Example 26 Synthesis of Intermediate 8i (R6 - H; R' - H; Y = NCH3) 3,4-Dihydro-2-methyl-2H-1,2-benzothiazine-3-carboxylic acid 1,1-dlOXlde A solution of 8p (550 mg, 2.0 mmol) in ethanol (25 ml) was shaken on a Paar apparatus with Raney nickel (~1 g, 500 aqueous, pH 9) under 50psi hydrogen at room temperature for 18 hours. The mixture was filtered through a bed of Celite°
filter aid and the filtrate was concentrated on a rotary evaporator. The residue was dissolved in water (10 ml), acidified to pH 3, and extracted with ethyl acetate. The organic phase was washed with brine, dried over magnesium sulfate, filtered and concentrated to give 378 mg (790) of the title compound as a white solid; NMR (CDC13) b 2.63 (s, 3H), 3.01-3.35 (m, 2H), 4.70-4.76 (m, 1H), 7.42-7.71 (m, 4H) ; MS : 240 m/z (M-H) -; Anal . Calc' d for C1~H11NOqS : C, 49 . 79 ;
H, 4.6l; N, S.81; S, 13.27; Found: C, 49.51; H, 4.62; N, 5.65; S, 13.05.
Example 27 Synthesis of Intermediate 8k (R6 .- F; R' - H; Y = NCH3) 3,4-Dihydro-6-fluoro-2-methyl-2H-1,2-benzothiazine-3-carboxylic acid 1,1-dioxide This compound was prepared according to General Procedure F using acidic conditions (refluxing 4 N aqueous HC1 in 1,4-dioxane) rather than basic conditions. From 6k (1.0 g, 3.87 mmol) the title compound (0.43 g, 43%) was obtained following recrystallization (ether/hexanes); MS:
258 m/z (M-H)-; Anal. Calc'd for CloHIOFNOqS: C, 47.57; H, 4.55; N, S.04; S, 1l.52; F, 6.84; Found: C, 47.8l; H, 4.28;
N, 5.36; S, 11.62; F, 7.29.
Example 28 Synthesis of Intermediate 81 (R6 -- R' - Cl; Y = NCH3) 3,4-Dihydro-6,7-dichloro-2-methyl-2H-1,2-benzothiazine-3-carboxylic acid 1,1-dioxide This compound was prepared according to General Procedure F (acidic conditions using refluxing 4N aqueous HCl in 1,4-dioxane). From 61 (200 mg, 0.65 mmol) the title compound (200 mg, 1000) was obtained following lyophillization of the reaction mixture; NMR (DMSO-d6) b 2.64 (s, 3H), 3.I3-3.37 (m, 2H), 4.72-4.77 (m, 1H), 7.87 {s, 1H), 7.98 (s, 1H). MS: 308, 310, 312 m/z (M+H)' (C12 pattern).
Example 29 Synthesis of Intermediate 8n (R6 -- Cl; R' - H; Y = N-i-Bu) 3,4-Dihydro-6-chloro-2-isobutyl-2H-1,2-benzothiazine-3-carboxylic acid 1,1-dioxide A solution of compound 9n (175 mg, 0.47 mmol) in 1,4-dioxane (7 ml) was treated with 4N HC1 (10 ml) and refluxed for 1.5 hours. Upon cooling to ambient temperature a white precipitate formed. The 1,4-dioxane was removed on the rotary evaporator, the solid was collected by suction filtration, washed with water and air-dried to constant weight to give 148 mg (100a) of the title compound; MS: 316, 318 m/z (M-H)- (chloride isotope pattern).
Example 30 Synthesis of Intermediate 8p (R6 - Cl; R' - H; Y = NCH3) 3,4-Dihydro-6-chloro-2-methyl-2H-1,2-benzothiazine-3-carboxylic acid 1,1-dioxide A slurry of compound 6p (500 mg, 1.8 mmol) in 6N
sulfuric acid (15 ml) was heated to reflux and stirred for 1.5 hours. The mixture was cooled to ambient temperature, extracted with ethyl acetate (50 ml) and the organic phase was washed twice with water, brine, dried over anhydrous magnesium sulfate, filtered and concentrated to afford 430 mg (860) of the title compound; MS: 274, 276 m/z (M+H)', chlorine isotope pattern.
Example 31 Synthesis of Intermediate 8r (R6 + R' - OCH2CHz0; Y = NCH3) 3,4-Dihydro-6,7-ethylenedioxy-2-methyl-2H-1,2-benzothiazine-3-carboxylic acid 1,1-dioxide This compound was prepared according to General Procedure F (alkaline conditions). From compound 6r (600 mg, 2.0 mmol) the title compound (550 mg, 920) was obtained as a pale yellow solid; NMR {DMSO-d6) b 2.59 (3H, s), 3.01-3.24 (2H, m), 4.25, 4.26 (4H, 2s), 4.64-4.70 (1H, ABq, J = 6 Hz), 6.95 ( 1H, s), 7.11 (1H, s), 13.40 (1H, br; absent in D20) ; MS : 298 m/z (M-H) - .
Example 32 Synthesis of Intermediate 8s (R6 + R' - OCH2CH20; Y = NEt) 2-Ethyl-3,4-dihydro-6,7-ethylenedioxy-2H-1,2-benzothiazine-3-carboxylic acid 1,1-dioxide A mixture of compound 9s (200 mg, 0.59 mmol) in ethanol (1.5 ml) and 4N NaOH (3 ml) was stirred at room temperature for two hours. A small amount of solid separated from the initially homogeneous solution, ,and the mixture was warmed to ~50°C to reestablish homogeneity. This process was repeated over the next four hours, whereupon the mixture was acidified to pH 2 (4N HC1), and the resulting oily precipitate was extracted into ethyl acetate. The organic phase was washed with water and brine, dried over anhydrous magnesium sulfate, filtered and concentrated to afford 153 mg (830) of the title compound a;~ a white solid which was used without further purification; NMR (CDC13) b 0.99 (3H, t, J = 7 Hz), 2.95-3.09 (4H, m), 4.25 (4H, br), 4.47 (1H, t, J

- 8 Hz), 6.97 (1H, s), 7.10 (1H, s); MS: 312 m/z (M-H)-.
Example 33 Synthesis of Intermediate 8s (RE' + R' - OCHZCH?O; Y = NEt) 2-Ethyl-3,4-Dihydro-6,7-ethylenedioxy-2H-1,2-benzothiazine-3-carboxylic acid 1,1-dioxide To a mixture of 272 mg (0.83 mmol) of compound 20 in 1.0 ml of MeOH and 3 ml of H20 was added 1.25 ml (3.0 eq) of 2N NaOH at 0 °C with stirring. After 5 min, the ice bath was removed and the mixture was stirred at room temperature for 2 hours. The mixture was diluted with 5 ml of H20 and the solvent was evaporated. The aqueous solution was extracted with ether) acidified to pH~3 with HCl, and extracted with CHZCl? . The combined extracts were dried and evaporated to afford 250 mg (96%) of a white solid; NMR (CDC13) b 1.09 (t, 3H, J = 7.1 Hz), 3.01 {m, 1H) 3.26 (m, 3H), 4.l4 (dd, 1H, J
- 7 Hz) , 4.28 (s, 4H) , 6.82 (s, 7_H) , 7.34 (s, 1H) . MS: 314 m/z (M+H)'. Condensation with L-phenylalaninol (General Procedure G) revealed that this ~~ample of 8s consists of a 2 : 1 mixture of enantiomers . Ana7_ . Calc' d for C13H1sNOs ~ S
Calc'd: C, 49.83; H, 4.73; N, 4.47; Found: C, 49.73; H, 4.69; N, 4.4l.
Example 34 Synthesis of Intermediate 8u (R6 + R' - OCHZCHZO; Y = N-i-Pr) 3,4-Dihydro-6,7-ethylenedioxy-2-isopropyl-2H-1,2-benzothiazine-3-carboxylic acid 7_,1-dioxide A solution of 9u (l65 mg, 0.4S mmol) in ethanol (3 ml) was treated with 6N NaOH, refluxed for five hours and allowed to cool to ambient temperature while being stirred overnight. The mixture was acidified to pH 3 with HCl and extracted with ethyl acetate. The organic phase was washed with water and brine, dried over anhydrous magnesium sulfate, filtered and concentrated to give 126 mg (86%) of the title compound as a white solid; NMR (CDC13) b 0.58 (d, J
- 7 Hz, 3H), 1.17 (d, J = 7 Hz, 3H), 3.29 (m, 2H), 4.05 (m, 1H), 4.30 (s+m, 5H), 6.84 (s, 1H), 7.35 (s, 1H); MS: 326 m/z (M-H)-. Anal. Calc'd for C14H1.,N06S: C, 51.37; H, 5.25; N, 4.28; S, 9.78; Found: C, 50.92; H, 5.06; N, 4.18; S, 9.94.
Example 35 Synthesis of Intermediate 91 (R~ - R' - C1; Y = NCH; R = CH3) Methyl 3,4-Dihydro-6,7-dichloro-2-methyl-2H-1,2-benzothiazine-3-carboxylate 1,1-dioxide To a solution of 81 (500 mg, 1.6l mmol) in THF (10 ml) and MeOH (5 ml) was added dropwise over five minutes a solution of {trimethylsilyl)diazomethane (2M in hexanes).
After being stirred for one hour at ambient temperature the mixture was quenched with glacial acetic acid (0.5 ml) and extracted with ethyl acetate. The organic phase was washed with saturated sodium bicarbonate, water, brine, dried over anhydrous magnesium sulfate, filtered and concentrated to give the crude product which was recrystallized (ethyl acetate/hexanes) to afford 347 mg (660) of the title compound as a tan solid; NMR (CDC13) b 2.8l (s, 3H), 3.15-3.42 (m, 2H), 3.86 {s, 3H), 4.68-4.74 (m, 1H), 7.43 (s, 1H), 7.9l (s, 1H) ; Anal. Calc'd for C11H11C12NOQS: C, 40.76; H, 3.43; N, 4.32; S, 9.87; Found: C, 41.31; H, 3.47; N, 4.48;
S, 9.76.
Example 36 Synthesis of Intermediate 9n (R6 - C1; R' - H; Y = N-i-Bu; R
- i-Bu) Isobutyl 3,4-Dihydro-6-chloro-2-isobutyl-2H-1,2-benzothiazine-3-carboxylate 1,1-dioxide A mixture of 7n (540 mg, 2.06 mmol), potassium carbonate (1.4 g, 10.3 mmol) and isobutyl bromide (0.71 g, 0.56 ml, 5.16 mmol) in DMF (10 ml) was stirred at 70°C.
After 18 hours the solvent was evaporated in vacuo and the residue was partitioned between ethyl acetate and water.
The organic phase was washed with water and brine, dried over anhydrous magnesium sulfate, filtered and concentrated.
The crude product was purified by flash chromatography on silica gel (30% ether/hexanes) to give 270 mg (35a) of the title compound as a white solid; NMR (CDC13) b 0.82 (d, J = 7 Hz, 6H), 0.96 (s, J = 7H, 6H), 2.71 (m, 2H), 2.90 (m, 2H), 3.16 (m, 2H), 3.48 (m, 2H), 4.38 (m, 1H), 7.37 (m, 2H), 7.73 (t, J = 8 Hz, 1H}; MS: 373, 375 m/z (M+H)' (chloride isotope pattern).
Example 37 Synthesis of Intermediate 9s (R6 + R' - OCHZCHzO; R = Et; Y =
NEt) Ethyl 2-Ethyl-3,4-dihydro-6,7-ethylenedioxy-2H-1,2-benzothiazine-3-carboxylate 1,I-dioxide A stirred mixture of compound 7r (220 mg, 0.42 mmol) and anhydrous potassium carbonate (293 mg, 2.12 mmol) in DMF
was treated with ethyl iodide (0.07 ml, 0.87 mmol) and warmed to 65 °C. After three hours an additional aliquot of ethyl iodide (0.07 ml) was added and stirring was continued for a further three hours. The mixture was filtered, the DMF
was stripped in-vacuo, and the residue was partitioned between ethyl acetate and water. The organic phase was washed with saturated aqueous sodium bicarbonate and brine, dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was further purified by flash chromatography on silica gel (dic:hloromethane) to afford 200 mg (760) of the title compound; NMR (CDC13) b 1.16 (3H, t, J
- 7 Hz), 1.32 (3H, t, J = 7 Hz), 3.08-3.29 (4H, m), 4.24-4.31 (6H, m), 4.45 (1H, dd, J = 6 Hz), 6.76 (1H, s), 7.32 (1H, s); MS: 342 m/z (M+H)', 364 m/z (M+Na)'.

Example 38 Synthesis of Intermediate 9u (R6 + R' - OCHZCH20; Y = N-i-Pr;
R = i-Pr) Isopropyl 3,4-Dihydro-6,7-ethylenedioxy-2-isopropyl-2H-1,2-benzothiazine-3-carboxylate 1,1-dioxide This compound was prepared using the procedure described for 9n. From 7r (200 mg, 0.70 mmol) the title compound (167 mg, 650) was obtained as a white solid following preparative tlc on silica gel (CHZC12); NMR (CDC13) b 0.66 (d, J = 7 Hz, 3H) , 1.l5 (d, J = 7 Hz, 3H) , 1.28 (d, J
- 6 Hz, 6H), 3.1l-3.39 (m, 2H), 3.93-3.99 (m, 1H), 4.18-4.27 (s+m, 5H), 5.07-5.11 (m, 1H), 6.77 (s, 1H), 7.30 (s, 1H);
MS: 370 m/z (M+H)+.
Example 39 General Procedure G: Amide Formation Synthesis of Intermediate l0a (R6 - R' - OCH3; R1 - i-Bu; Y =
O) N-(3,4-Dihydro-6,7-dimethoxy-2,1-benzoxathiin-3-carbonyl)-L-leucinal 1,1-dioxide diethyl acetal A solution of compound 3a (180 mg, 0.63 mmol), HOBt (93 mg, 0.69 mmol) and N-methylmorpholine (NMM) (202 mg, 2.0 mmol) in DMF (2 ml) was cooled in an ice-water bath and treated with BOP (304 mg, 0.69 mmol). After being stirred an additional 15 minutes the mixture was treated with a solution of (L)-leucinal diethyl acetal (130 mg, 0.69 mmol) in DMF (1 ml). The resulting mixture was allowed to stir overnight while slowly warming to ambient temperature. The DMF was removed under reduced pressure and the residue was partitioned between ethyl acetate and 5o aqueous citric acid. The organic phase was washed with saturated aqueous sodium bicarbonate, water and brine, dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was further purified by flash chromatography on silica gel (25-50o ethyl acetate/hexane) to afford 126 mg (44%) of the title compound as an amorphous solid; MS: 482 m/z (M+Na)~;
Anal. Calc'd for CzlH3aNO8S: C, 54.88; H, 7.25; N, 3.05;
Found: C, 55.05; H, 7.25; N, 3.26.

Example 40 Synthesis of Intermediate 10v (R6 + R' - OCHZCH20; R' - i-Bu;
Y = NEt) N-(3,4-Dihydro-6,7-ethylenedioxy-2-ethyl-2H-1,2-benzothiazine-3-carbonyl)-L-leucinal 1,1-dioxide diethyl acetal This compound was prepared according to General Procedure G. From 8v (350 mg, 1.12 mmol) and (L)-leucinal diethyl acetal (275 mg, 1.45 mmol) crude title compound (574 mg) was obtained. Separation of diastereomers was achieved by flash chromatography on silica gel (50o ethyl acetate/hexanes):
Isomer 1: l62 mg (300); MS:: 507 m/z (M+Na)';
Isomer 2: 160 mg (29%); MS:: 507 m/z (M+Na)'.
Example 41 Synthesis of Intermediate 11b (R6 - R' - OCH3; R1 - Bn; Y = O;
Q = H) N-(3,4-Dihydro-6,7-dimethoxy-2,1-benzoxathiin-3-carbonyl)-L-phenylalaninol 1,1-dioxide This compound was prepared according to General Procedure G. From compound 3a (61 mg, 0.21 mmol} and L-phenylalaninol (42 mg, 0.28 mmol) the title compound (64 mg, 72a) was obtained as a mixture of diastereomers; MS: 422 m/z (M+H)', 444 m/z (M+H)'.
Example 42 Synthesis of Intermediate llc (R6 - R' - OCH3; R1 - Bn; Y =
13H; Q = H) N-(3,4-Dihydro-6,7-dimethoxy-2H-1,2-benzothiazine-3-carbonyl)-L-phenylalaninol 1,1-dioxide This compound was prepared according to General Procedure G. From compound 7c (100 mg, 0.35 mmol) the crude title compound (l76 mg) was obtained as a mixture of diastereomers which were separated by flash chromatography on silica gel (EtOAc:hexane, 1:1 to 3:1).
Isomer 1: 40 mg (270); MS: 42I m/z (M+H)';

Isomer 2: 54 mg (370); MS: 421 m/z (M+H)~.
Intermediate fractions gave a small amount of the product as a mixture of diasteromers. Anal. Calc'd for C20H24N2~6S~0.5Hz0: C, 55. 93; H, 5.88; N, 6.52; S, 7.45; Found:
C, 55.55; H, 5.83; N, 6.32; S, 7.76.
Example 43 Synthesis of Intermediate 11e (R6 - R' - OCH3; R1 - Bn; Y =
NCH3 ; Q = H ) N-(3,4-Dihydro-6,7-dimethoxy-2-methyl-2H-1,2-benzothiazine-3-carbonyl)-L-phenylalaninol 1,1-dioxide This compound was prepared according to General Procedure G. From compound 8e (250 mg, 0.83 mmol) the crude title compound (343 mg) was obtained as a mixture of diastereomers which were separated by flash chromatography on silica gel (EtOAc:hexane, 1:3 to 1:1).
Isomer 1 : l23 mg (34 0 ) ; MS : 435 m/z (M+H) ';
Isomer 2: l18 mg (33 0) ; MS: 435 m/z (M+H) ~.
Example 44 Synthesis of Intermediate 11g (R6 - R' - OCH3; R1 - Bn; Y =
NBn; Q = H) N-(2-Benzyl-3,4-dihydro-6,7-dimethoxy-2H-1,2-benzothiazine-3-carbonyl)-L-phenylalaninol 1,1-dioxide This compound was prepared according to General Procedure G. From compound 8g (155 mg, 0.41 mmol) the crude title compound (220 mg) was obtained as a mixture of diastereomers, partial separation being achieved by flash chromatography on silica gel tether to loo ethyl acetate/ether):
Isomer 1: 27 mg (130); MS: S11 m/z (M+H)', 533 m/z (M+Na)';
Isomer 2: 30 mg (140); MS: 511 m/z (M+H)', 533 m/z (M+Na) ';
Intermediate fractions gave an additional 105 mg (500) of the diastereomeric mixture.

Example 45 Synthesis of Intermediate 11i (Rf' - H; R' - H; R1 - Bn; Y =
NCH3 ; Q = H ) N-(3,4-Dihydro-2-methyl-2H-1,2-bf~nzothiazine-3-carbonyl)-L-phenylalaninol 1,1-dioxide This compound was prepared according to General Procedure G. From 8i (200 mg, 0..83) the crude title compound was obtained as a mixture of diastereomers which were separated by preparative thin layer chromatography on silica gel using ethyl acetate as eluent:
Isomer 1 (Rf 0.6) : 120 mg (39%) ; MS: 375 m/z (M+H) ';
Isomer 2 (Rf 0.7) : 81 mg (26a) ; MS: 375 m/z (M+H)'.
Example 46 Synthesis of Intermediate 11k (R6 - F; R' - H; R1 - Bn; Y =
NCH3; Q = H) N-(3,4-Dihydro-2-methyl-6-fluoro--2H-1,2-benzothiazine-3-carbonyl)-L-phenylalaninol 1,1-dioxide This compound was prepared according to General Procedure G. From 8k (200 mg, 0.83) the crude title compound was obtained as a mixture of diastereomers.
Attempted separation of these isomers by preparative tlc on silica gel (10o methanol/CHZC12) cave only one characterizable isomer of Rf 0.7; 78 mg (26%); MS: 393 m/z ( M+H ) ' .
Example 47 Synthesis of Intermediate 11-1 (F:6 - R' - Cl; R1 - Bn; Y =
NCH3; Q = H) N-(3,4-Dihydro-6,7-dichloro-2-methyl-2H-1,2-benzothiazine-3-carbonyl)-L-phenylalaninol 1,1-dioxide This compound was prepared according to General Procedure G. From 81 (200 mg, 0.65 mmol) the crude title compound was obtained as a mixture of diastereomers which were separated by flash chromatography on silica gel using ethyl acetate as eluent:
Isomer 1: 60 mg (21%); MS: 465, 467, 469 m/z (M+H)' (C12 pattern) ;
Isomer 2: 100 mg (350); MS: 465, 467, 469 m/z (M+H)' (C12 pattern) .
Example 48 Synthesis of Intermediate 11n (R6 - C1; R' - H; R1 - Bn; Y =
N-i-Bu; Q = H) N-(3,4-Dihydro-6-chloro-2-isobutyl-2H-1,2-benzothiazine-3-carbonyl)-L-phenylalaninol 1,1-dioxide This compound was prepared according to General Procedure G. From 8n (146 mg, 0.46 mmol) the crude title compound was obtained as a mixture of diastereomers which were separated by preparative tlc on silica gel using 500 ethyl acetate/hexanes as eluent:
Isomer 1 (Rf = 0.5) : 76 mg (370) ; MS: 450, 452 m/z (M+H)' (C1z pattern);
Isomer 2 (Rf = 0.6): 81 mg (39%); MS: 450, 452 m/z (M+H)' (C12 pattern).
Example 49 Synthesis of Intermediate 11p (R6- Cl; R' - H; R1 - Bn; Y =
NCH3; Q = H) N-(6-Chloro-3,4-dihydro-2-methyl-2H-1,2-benzothiazine-3-carbonyl)-L-phenylalaninol 1,1-dioxide This compound was prepared according to General Procedure G. From compound 8p (420 mg, 1.52 mmol) crude product (690 mg) was obtained as a mixture of diastereomers.
Separation was achieved by flash chromatography on silica gel (30o ethyl acetate/hexane to 50o ethyl acetate/hexane) to give two isomers of the title compound:
Isomer 1: 78 mg (130); MS: 409, 411 m/z (M+H)', 431, 433 m/z (M+Na)';
Isomer 2: 71 mg (110); MS: 409, 411 m/z (M+H)', 43l, 433 m/z (M+Na)+.

Example 50 Synthesis of Intermediate llr (R6 + R' - OCH2CHz0; R1 = Bn; Y =
NCH3; Q = H) N-(3,4-Dihydro-&,7-ethylenedioxy--2-methyl-2H-1,2-benzothiazine-3-carbonyl)-L-phen~rlalaninol 1,1-dioxide This compound was prepared .according to General Procedure G. From compound 8r (9:04 mg, 1.35 mmol) the title compound (475 mg, 810) was obtained as a mixture of diastereomers following purification on silica gel (300 ethyl acetate/hexane). This product was used in the subsequent step without further purification; MS: 433 m/z (M+H)', 455 m/z (M+Na)+.
Example 51 Synthesis of Intermediate lls (R6 + R' - OCHZCH70; R1 = Bn; Y =
NEt; Q = H) N-(3,4-Dihydro-6,7-ethylenedioxy-2-ethyl-2H-1,2-benzothiazine-3-carbonyl)-L-phenylalaninol 1,1-dioxide This compound was prepared according to General Procedure G. From compound 8s (l34 mg, 0.43 mmol) crude product (203 mg) was obtained as a mixture of diastereomers.
Separation was achieved by flash chromatography on silica gel (50o ethyl acetate/hexane) to give two isomers of the title compound:
Isomer 1: 75 mg (39%); MS: 447 m/z (M+H)', 469 m/z (M+Na)';
Isomer 2: 82 mg (43%); MS: 447 m/z (M+H)', 469 m/z (M+Na)' Example 52 Synthesis of Intermediate 11u (R6 + R' - OCH2CH20; R1 - Bn; Y
- N-i-Pr; Q = H) N-(3,4-Dihydro-6,7-ethylenedioxy-2-isopropyl-2H-1,2-benzothiazine-3-carbonyl)-L-phenylalaninol 1,1-dioxide This compound was prepared according to General Procedure G. From 8u (120 mg, 0.37) crude title compound (l83 mg) was obtained. Attempted. separation of diastereomers on silica geI (either flash chromatography or preparative t1c using 3o MeOH/CHzClz) was unsuccessful, giving 85 mg of the diastereomeric mixture; MS: 461 m/z ( M+H ) ' .
Example 53 Synthesis of Intermediate 11x (R6 + R' - OCH2CH20; R1 -(CHZ) QNHSOzPh; Y = NEt; Q = H) Na-(3,4-Dihydro-6,7-ethylenedioxy-2-methyl-2H-1,2-benzothiazine-3-carbonyl)-L-N,-(benzenesulfonyl)lysinof 1,1-dioxide This compound was prepared according to General Procedure G. From 8s (70 mg, 0.23 mmol) and L-Nf-(benzenesulfonyl)lysinol trifluoroacetic acid salt (117 mg, 0.30 mmol) crude product (l44 mg) was obtained as a mixture of diastereomers. Separation was effected by preparative tlc on silica gel (5o MeOH/CH2C12) Isomer 1: 31 mg (250); MS: 554 m/z (M+H)+;
Isomer 2: 31 mg (25%); MS: 554 m/z (M+H)+.
Example 54 Synthesis of Intermediate llz (R6 + R' - OCHZCH20; R1 - Bn; Y
- NCH3 ; Q = H ) N-(3,4-Dihydro-6-(4-morpholino)-2-methyl-2H-1,2-benzothiazine-3-carbonyl)-L-phenylalaninol 1,1-dioxide This compound was prepared according to General Procedure G. From 8z (200 mg, 0.6l mmol) crude product (357 mg) was obtained as a mixture of diastereomers which were separated by flash chromatography on silica gel (75o ethyl acetate/hexanes):
Isomer 1: 116 mg (410) ; MS: 460 m/z (M+H)';
Isomer 2: 113 mg (400) ; MS: 460 m/z (M+H)'.
Example 55 Synthesis of Intermediate 11A (R6 - C1; R' = H; R1 - Bn; Y =
NCH3 ; Q = CONHEt ) N-Ethyl-3-(6-chloro-3,4-dihydro-2-methyl-2H-1,2-benzothiazine-3-carboxamido)-2-(R, S)-hydroxy-3-(S)-benzylpropanamide 1,1-dioxide This compound was prepared according to General Procedure G. From compound 8p (.L10 mg, 0.40 mmol) and N-ethyl-2-(R,S)-hydroxy-3-(S)-benzyl-3-aminopropanamide, trifluoroacetic acid salt (167 mg, 0.50 mmol) (Harbeson, S.
L., et al.; J. Med. Chem., 1994, 37, 2918-2929, incorporated by reference herein in its entirety) the title compound (60 mg, 31%) was obtained following purification by preparative tlc on silica gel (CHZC12:CH30H:cc>nc. NH90H; 90:9:1; Rf 0.5) ;
MS: 480 m/z (M+H)'; 502 m/z (M+Na)'.
Example 56 General Procedure K: Reaction of Aldehydes with Butyl Isocyanide Synthesis of Intermediate 11B (R6 + R' - OCHZCH20; R1 - i-Bu;
Y = NEt; Q = CONHBu) 3-((3,4-Dihydro-6,7-ethylenedioxy-2-ethyl-2H-1,2-benzothiazine-3-carbonyl)amino)-a-(S)-isobutyl-2-(R,S)-hydroxy-N-butylpropanamide 1,1-dioxide A solution of butyl isocyanide (22 mg, 0.27 mmol) in dichloromethane (3 ml) was cooled in an ice-water bath and treated with TiCl4 (0.28 ml, 1M in CHzCl2). The mixture was stirred for three hours, cooled to -78°C and treated with a solution of 12v (114 mg, 0.26 mmol) in CHzCl2 (2 ml). The mixture was allowed to slowly warm to ambient temperature while being stirred overnight. The mixture was stirred with 1N HCl (5 ml) for 30 minutes, ethyl acetate (35 ml) was added and 1N NaOH was added to pH 9. The organic phase was washed with water and brine, dried over anhydrous sodium sulfate, filtered and concentrated to give 125 mg crude product which was triturated with ether to give 38 mg of the title compound as a white solid; MS: 512 m/z (M+H)*.

Example 57 Synthesis of Intermediate 11C (R6 + R' - OCH2CH20; R1 - i-Bu;
Y = NEt; Q = CONHBu) 3-((3,4-Dihydro-6,7-ethylenedioxy-2-ethyl-2H-1,2-benzothiazine-3-carbonyl)amino)-3-(S)-isobutyl-2-(R,S)-hydroxy-N-butylpropanamide 1,1-dioxide This compound was prepared according to General Procedure K. From 12w (116 mg, 0.26 mmol) the title compound (76 mg) was obtained as a white solid; MS: 512 m/z (M+H) " .
Example 58 Synthesis of Intermediate 11E (R6 + R' - OCHZCH20; R1 - Bn; Y
- NEt; Q = CONHBu) 3-((3,4-Dihydro-6,7-ethylenedioxy-2-ethyl-2H-1,2-benzothiazine-3-carbonyl)amino)-3-(S)-benzyl-2-(R,S)-hydroxy-N-butylpropanamide 1,1-dioxide This compound was prepared according to General Procedure K. From 12s (250 mg, 0.56 mmol) the title compound (200 mg, 65o yield) was obtained as a white solid;
MS: 5I2 m/z (M+H)'; MS: 546 m/z (M+H)'; Anal. Calc'd for CZ-,H35N3O.,S~0.5H20: C, 58.46; H, 6.56; S, 5.77; Found: C, 58.73; H, 6.42; S, 5.83.
Example 59 Synthesis of Intermediate 11F (R6 + R' - OCHZCHZO; R1 - Bn; Y
- NEt; Q = CONHBu) 3-((3,4-Dihydro-6,7-ethylenedioxy-2-ethyl-2H-1,2-benzothiazine-3-carbonyl)amino)-3-(S)-benzyl-2-(R,S)-hydroxy-N-butylpropanamide 1,1-dioxide This compound was prepared according to General Procedure K. From 12t (250 mg, 0.56 mmol) crude title compound (200 mg) was obtained as a yellow oil which could not be made to crystallize from ether. Purification was effected by flash chromatography on silica gel (50o ethyl acetate/hexanes) to give 68 mg (220) of the pure product;
MS: 546 m/z (M+H)'.

Example 60 Synthesis of Intermediate 11S (R6 + R' - OCHZCH20; R1 - Bn; Y
- NEt ; Q = CONHCHzCHZNHS02CH3 ) N-(2-(Methanesulfonylamino)ethyl)-3-(3,4-Dihydro-6,7-ethylenedioxy-2H-1,2-benzothiazir..~e-3-carboxamido)-2-(R,S)-hydroxy-3-(S)-benzylpropanamide 1.,1-dioxide This compound was prepared according to General Procedure G. From compound 8s (31.0 mg, 0.1 mmol, prepared from L-DOPA) and N- (2- (methanesul.fonylamino) ethyl) -2- (R, S) -hydroxy-3-(S)-benzyl-3-aminopropa.namide, HC1 salt (42 mg, 1.20 eq) the title compound (45.0 mg, 740) was obtained; MS:
61l (M+H)'.
N- (2- (methanesulfonylamino) a=_thyl) -2- (R, S) -hydroxy-3-(S)-benzyl-3-aminopropanamide, Hf1 salt was prepared by coupling of N-(methanesulfonyl)arninoethyleneamine to N-3-(t-butoxycarbonyl)amino-2-(R,S)-hydroxy-3-(S)-benzylpropionic acid according to Harbeson's procedure (J. Med. Chem., 1994, 37, 2918-2929). N-(methanesulfon.yl)aminoethanamine was prepared from (N-(t-butoxycarbonyl)amino)ethanamine and methanesulfonyl chloride according to the procudure of Essien, H. et al., J. Med. Chem., l988, 31, 898-90l, incorporated by reference herein in its entirety.
Example 61 Synthesis of Intermediate 11T (R6 + R' - OCHZCHzO; R1 - Bn; Y
2 5 - NEt ; Q = CONHCHZ CH2NHSO2 ( 4 -NOz - PlZ ) ) 3-((3,4-Dihydro-6,7-ethylenedioxy-2-ethyl-2H-1,2-benzothiazine-3-carbonyl)amino)-3-(S)-benzyl-2-(R,S)-hydroxy-N-(2-(4-nitrobenzenesulfonylamino)ethyl) propanamide 1,1-dioxide This compound was prepared according to General Procedure G. From 8s (prepared from L-DOPA, 30 mg, 0.10 mmol) and 3-amino-3-(S)-benzyl-2-(R,S)-hydroxy-N-(2-(4-nitrobenzenesulfonylamino)ethyl)propanamide hydrochloride (57 mg, 0.l2 mmol) the title compound (52 mg, 910) was obtained following flash chromatography on silica gel (750 ethyl acetate/hexanes); MS: 718 rri/z (M+H)'.

Example 62 Synthesis of Intermediate 11U (R6 + R' - OCHZCH20; R1 - Bn; Y
- NEt ; Q = CONH ( CHZ ) 3NHSO2 ( 4 -NOZ - Ph ) ) 3-((3,4-Dihydro-6,7-ethylenedioxy-2-ethyl-2H-1,2-benzothiazine-3-carbonyl)amino)-3-(S)-benzyl-2-(R,S)-hydroxy-N-{3-(4-nitrobenzenesulfonylamino)propyl)propanamide 1,1-dioxide This compound was prepared according to General Procedure G. From 8s (prepared from L-DOPA, 30 mg, 0.l0 mmol) and 3-amino-3-(S)-benzyl-2-(R,S)-hydroxy-N-(3-(4-nitrobenzenesulfonylamino)propyl)propanamide hydrochloride (59 mg, 0.12 mmol) the title compound (32 mg, 55%) was obtained following flash chromatography on silica gel (750 ethyl acetate/hexanes); MS: 732 m/z (M+H)'.
Example 63 Synthesis of Intermediate 11V (R6 + R' - OCHZCH20; R1 - Bn; Y
- NEt; Q = CONHCHZCHZNHSOZ ( 3 , 4-C12-Ph) ) 3-((3,4-Dihydro-6,7-ethylenedioxy-2-ethyl-2H-1,2-benzothiazine-3-carbonyl)amino)-3-(S)-benzyl-2-(R,S)-hydroxy-N-(2-(3,4-dichlorobenzenesulfonylamino)ethyl)propan-amide 1,1-dioxide This compound was prepared according to General Procedure G. From 8s (prepared from L-DOPA, 30 mg, 0.l0 mmol) and 3-amino-3-(S)-benzyl-2-(R, S)-hydroxy-N-(2-(3,4-dichlorobenzenesulfonylamino)ethyl)propanamide hydrochloride (60 mg, 0.12 mmol) the title compound (58 mg, 970) was obtained following flash chromatography on silica gel (750 ethyl acetate/hexanes); MS: 741, 743, 745 m/z (M+H)'.
Example 64 3 0 Synthesis of Intermediate 11W (R6 + R' - OCHZCHZO; R1 - Bn; Y
- NEt; Q = CONH(CHZ)3NHS02(3,4-C12-Ph) ) 3-((3,4-Dihydro-6,7-ethylenedioxy-2-ethyl-2H-1,2-benzothiazine-3-carbonyl)amino)-3-(S)-benzyl-2-(R,S)-hydroxy-N-(3-(3,4-dichlorobenzenesulfonylamino)propyl)propanamide l,l-dioxide This compound was prepared according to General Procedure G. From 8s (prepared from L-DOPA, 30 mg, 0.10 mmol) and 3-amino-3-(S)-benzyl-2-(R, S)-hydroxy-N-(3-(3,4-dichlorobenzenesulfonyl)propyl)p:ropanamide hydrochloride (62 mg, 0.12 mmol) the title compound (58 mg, 970) was obtained following flash chromatography o:n silica gel (75% ethyl acetate/hexanes); MS: 755, 757, 759 m/z (M+H)'.
Example 65 Synthesis of Intermediate 11X (R'' + R' - OCHzCH20; R1 - Bn; Y
- NEt; Q = CONHCHzCHzNHSOzPh) 3-((3,4-Dihydro-6,7-ethylenedioxy-2-ethyl-2H-1,2-benzothiazine-3-carbonyl)amino)-:3-(S)-benzyl-2-(R,S)-hydroxy-N-(2-(benzenesulfonylamino)ethyl) propanamide 1,1-dioxide This compound was prepared according to General Procedure G. From 8s (prepared :From L-DOPA, 35 mg, 0.11 mmol) and 3-amino-3-(S)-benzyl-2-(R,S)-hydroxy-N-(2-(benzenesulfonylamino)ethyl)propanamide hydrochloride (60 mg, 0.25 mmol) the title compound (62 mg, 830) was obtained following trituration with ether; MS: 673 m/z (M+H)'.
Example 66 Synthesis of Intermediate 11Y (R'' + R' - OCH2CH2O; R1 - Bn; Y
- NEt ; Q = CONHCH2CH2SOz ( 5 - ( 2 -pyr~~~dinyl ) thiophen- 2 -yl ) ) N-(2-((5-(Pyridin-2-yl)thiophen-2-yl)sulfonylamino)ethyl)-3-(3,4-Dihydro-6,7-ethylenedioxy-2~Y-1,2-benzothiazine-3-carboxamido)-2-(R,S)-hydroxy-3-(:3)-benzylpropanamide 1,1-dioxide This compound was prepared according to the procedure used to synthesize 11s. From compound 8s (62.U mg, 0.2 mmol, prepared from L-DOPA) and N- (2- ( (5- (pyridin-2-yl)thiophen-2-yl)sulfonylamino)ei~hyl)-2-(R,S)-hydroxy-3-(S)-benzyl-3-aminopropanamide, HC1 s<~lt (100 mg, 1.20 eq) the title compound (81.0 mg, 540) was obtained; MS: 756 (M+H)'.

Example 67 Synthesis of Intermediate 11Z (R6 + R' - OCH2CHZ0; R1 = Bn; Y
- NEt ; Q = CONH ( CHZ ) 3NHSO2 ( 4 -F- Ph ) ) 3-((3,4-Dihydro-6,7-ethylenedioxy-2-ethyl-2H-1,2-benzothiazine-3-carbonyl)amino)-3-(S)-benzyl-2-(R,S)-hydroxy-N-(3-(4-fluorobenzenesulfonylamino)propyl) propanamide 1,1-dioxide This compound was prepared according to General Procedure G. From 8s (prepared from L-DOPA, 30 mg, 0.10 mmol) and 3-amino-3-(S)-benzyl-2-(R,S)-hydroxy-N-(3-(4-fluorobenzenesulfonylamino)propyl)propanamide hydrochloride (43 mg, 0.12 mmol) the title compound (40 mg, 590) was obtained following preparative tlc on silica gel (ethyl acetate); MS: 705 m/z (M+H)'.
Example 68 Synthesis of Intermediate 11AA (R6 + R' - OCH2CHZ0; R1 - Bn; Y
- NEt ; Q = CONH ( CHZ ) 3NHSO?Ph) 3-((3,4-Dihydro-6,7-ethylenedioxy-2-ethyl-2H-1,2-benzothiazine-3-carbonyl)amino)-3-(S)-benzyl-2-(R,S)-hydroxy-N-(3-(benzenesulfonylamino)propyl) propanamide 1,1-dioxide This compound was prepared according to General Procedure G. From 8s (prepared from L-DOPA, 30 mg, 0.l0 mmol) and 3-amino-3-(S)-benzyl-2-(R,S)-hydroxy-N-(3-(benzenesulfonylamino)propyl)propanamide hydrochloride (41 mg, 0.12 mmol) the title compound (38 mg, 58%) was obtained following preparative tlc on silica gel (ethyl acetate); MS:
687 m/z (M+H)'.
Example 69 3 0 Synthesis of Intermediate 11AC (R6 + R' - OCHZCH20; R1 - Bn; Y
- NEt; Q = CONHCHzCH2NHS0z (4-F-Ph) ) 3-((3,4-Dihydro-6,7-ethylenedioxy-2-ethyl-2H-1,2-benzothiazine-3-carbonyl)amino)-3-(S)-benzyl-2-(R,S)-hydroxy-N-(2-(4-fluorobenzenesulfonylamino)ethyl)propanamide l,l-dioxide This compound was prepared according to General Procedure G. From 8s (prepared from L-DOPA, 30 mg, 0.10 mmol) and 3-amino-3-(S)-benzyl-2-(R,S)-hydroxy-N-(2-(4-fluorobenzenesulfonylamino)ethyl)propanamide hydrochloride (54 mg, 0.12 mmol) the title compound (48 mg, 770) was obtained following preparative tlc on silica gel (ethyl acetate); MS: 691 m/z (M+H)'.
Example 70 Synthesis of Intermediate 11AD (R6 + R' - OCH2CH20; R1 - Bn; Y
- NH; Q = CONHBu) N-Butyl-3-(3,4-Dihydro-6,7-ethylenedioxy-2H-1,2-benzothiazine-3-carboxamido)-2-(R.,S)-hydroxy-3-(S)-benzylpropanamide 1,1-dioxide Compound 7r was prepared from compound 19 according to the procedure described for synthesis of 8s. Compound 11AD
was prepared according to General Procedure G. From compound 7r (22 mg, 0.077 mmol) and N-butyl 2-(R, S)-hydroxy-3-(S)-benzyl-3-aminopropanamide, HC1 salt (27.6 mg, 1.25 eq) (Harbeson, S. L., et al.; J. Med. Chem., l994, 37, 2918-2929) the title compound (20.0 mg, 50%) was obtained; MS:
5l8 (M+H)'.
Example 71 Synthesis of Intermediate 11AE (R6 + R' - OCHZCH20; R1 - Bn;
Y = NH; Q = CONHCHZCH2NHSOzPh) N-(2-(Benzenesulfonylamino)ethyl)-3-(3,4-Dihydro-6,7-ethylenedioxy-2H-1,2-benzothiazine-3-carboxamido)-2-(R,S)-hydroxy-3-(S)-benzylpropanamide 1,1-dioxide Compound 11AE was prepared according to the procedure used to synthesize 11S. From compound 7r (28.5 mg, 0.1 mmol) and N- (2- (benzenesulfonylamino) ethyl) -2- (R, S) -hydroxy-3-(S)-benzyl-3-aminopropanamide, HC1 salt (51.68 mg, 1.25 eq) the title compound (47.0 mg, 730) was obtained; MS: 645 (M+H)'.

Example 72 General Procedure H: Acetal Hydrol,sis Synthesis of Aldehyde 12a (R6 - R' - OCH3; R1 - i-Bu; Y = O; Q
- H) N-(3,4-Dihydro-6,7-dimethoxy-2,1-benzoxathiin-3-carbonyl)-L-leucinal 1,1-dioxide A solution of compound 10a (16 mg, 0.03S mmol) in a mixture of acetone/water (0.5 m1/0.75 ml) was treated with p-TsOH-H,O (7 mg, 0.037 mmol). After being stirred overnight at ambient temperature the mixture was brought to reflux for one hour, cooled to ambient temperature and extracted into ethyl acetate. The organic phase was washed with saturated aqueous sodium bicarbonate, water, brine, dried (MgSO~), filtered and concentrated to afford 10 mg (770) of the title compound as a mixture of diastereomers; MS: 386 m/z (M+H)+, 408 m/z (M+Na)'.
Example 73 General Procedure I: Dess-Martin Oxidation Synthesis of Aldehyde 12b (R6 - R' - OCH3; R1 - Bn; Y = O; Q =
H) N-{3,4-Dihydro-6,7-dimethoxy-2,1-benzoxathiin-3-carbonyl)-L-phenylalaninal 1,1-dioxide A solution of compound 11b (30 mg, 0.071 mmol) in dichloromethane (10 ml) chilled in an ice-water bath was treated with 1,1,1-triacetoxy-1,1-dihydro-1,2-benziodoxol-3(1H)-one (Dens-Martin periodinane, DMP; 60 mg, 0.14 mmol).
After one hour tlc analysis indicated complete consumption of starting material. The mixture was stirred for five minutes with loo aqueous sodium thiosulfate solution and poured into a separatory funnel. The organic phase was washed once more with 10% sodium thiosulfate followed by saturated aqueous sodium bicarbonate (2x), water, brine, dried (MgS04), filtered and concentrated to afford 30 mg (990) of the title compound as an off-white amorphous solid;
MS: 420 m/z (M+H)'.

Example 74 Synthesis of Aldehyde 12c (R6 - R:' - OCH3; R1 - Bn; Y = NH; Q
- H) N-(3,4-Dihydro-6,7-dimethoxy-2H-1,2-benzothiazine-3-carbonyl)-L-phenylalaninal 1,1-d_Loxide This compound was prepared according to General Procedure I. From compound llc (~_somer 1; 20 mg, 0.048 mmol) the title compound (18 mg, 900) was obtained as a pale yellow solid; MS: 4l7 m/z (M-H)-.
Example 75 Synthesis of Aldehyde 12d (R6 - R' - OCH3; R1 - Bn; Y = NH; Q
- H) N-(3,4-Dihydro-6,7-dimethoxy-ZH-7L,2-benzothiazine-3-carbonyl)-L-phenylalaninal 1,1-dioxide This compound was prepared according to General Procedure I. From compound 11c (isomer 2; 35 mg, 0.083 mmol) the title compound (32 mg, 910) was obtained as a pale yellow solid; MS: 417 m/z (M-H)-.
Example 76 Synthesis of Aldehyde 12e (R6 - R' - OCH3; R1 - Bn; Y = NCH3;
Q = H) N-(3,4-Dihydro-6,7-dimethoxy-2-methyl-2H-1,2-benzothiazine-3-carbonyl)-L-phenylalaninal 1,1--dioxide This compound was prepared according to General Procedure I. From compound 11e (isomer 1; 50 mg, 0.12 mmol) the title compound (48 mg, 960) vuas obtained as a white solid; MS: 433 m/z (M+H)', 455 m/z (M+Na)+.
Example 77 Synthesis of Aldehyde 12f (R6 = R.~ = OCH3; R1 = Bn; Y = NCH3;
Q = H) N-(3,4-Dihydro-6,7-dimethaxy-2-mEahyl-2H-1,2-benzothiazine-3-carbonyl)-L-phenylalaninal 1,1--dioxide This compound was prepared according to General Procedure I. From compound 11e (isomer 2; 50 mg, 0.12 mmol) the title compound (47 mg, 94%) was obtained as a white solid; MS: 433 m/z (M+H)', 455 m/z (M+Na)+.
Example 78 Synthesis of Aldehyde 12g (R6 - R' - OCH3; Rl - Bn; Y = NBn; Q
- H) N-(2-Benzyl-3,4-dihydro-6,7-dimethoxy-2H-1,2-benzothiazine-3-carbonyl)-L-phenylalaninal 1,1-dioxide This compound was prepared according to General Procedure I. From compound 11g (isomer 1; 25 mg, 0.05 mmol) the title compound (23 mg, 82%) was obtained; MS: 509 m/z (M+H)', 531 m/z (M+Na)'.
Example 79 Synthesis of Aldehyde 12h (R6 - R' - OCH3; R1 - Bn; Y = NBn; Q
- H) N-(2-Benzyl-3,4-dihydro-6,7-dimethoxy-2H-1,2-benzothiazine-3-carbonyl)-L-phenylalaninal 1,1-dioxide This compound was prepared according to General Procedure I. From compound 11g (isomer 2; 28 mg, 0.06 mmol) the title compound (20 mg, 71o) was obtained; MS: 509 m/z (M+H) *, 531 m/z (M+Na)'.
Example 80 Synthesis of Aldehyde 12i (R6 - H; R' - H; R1 - Bn; Y = NCH3;
Q = H) N-(3,4-Dihydro-2-methyl-2H-1,2-benzothiazine-3-carbonyl)-L-phenylalaninal 1,1-dioxide This compound was prepared according to General Procedure I. From lli (isomer 1; 107 mg, 0.29 mmol) the title compound (84 mg, 790) was obtained; MS: 373 m/z (M+H)*.
Example 81 Synthesis of Aldehyde 12j (R6 - H; R' - H; R1 - Bn; Y = NCH3;
Q = H) N-(3,4-Dihydro-2-methyl-2H-1,2-benzothiazine-3-carbonyl)-L-phenylalaninal 1,1-dioxide This compound was prepared according to General Procedure I. From 11i (isomer 2,; 76 mg, 0.20 mmol) the title compound (64 mg, 840) was obtained; MS: 373 m/z (M+H)+.
Example 82 Synthesis of Aldehyde 12k (R6 - F'; R' - H; R1 - Bn; Y = NCH3;
Q = H) N-(3,4-Dihydro-2-methyl-6-fluoro--2H-1,2-benzothiazine-3-carbonyl)-L-phenylalaninal 1,1-dioxide This compound was prepared according to General Procedure I. From 11k (41 mg, 0.10 mmol) the title compound (33 mg, 830) was obtained as a white solid; MS: 39l m/z ( M+H ) ' .
Example 83 Synthesis of Aldehyde 12-1 (R6 - R' - C1; R1 - Bn; Y = NCH3; Q
- H) N-(3,4-Dihydro-6,7-dichloro-2-methyl-2H-1,2-benzothiazine-3-carbonyl)-L-phenylalaninal 1,1-dioxide This compound was prepared .according to General Procedure I. From 11-1 (isomer 1.; 32 mg, 0.07 mmol) the title compound (27 mg, 840) was obtained; MS: 441, 443, 445 m/z (M+H) + (C12 pattern) .
Example 84 Synthesis of Aldehyde 12m (R6 - R' - C1; R1 - Bn; Y = NCH3; Q
- H) N-(3,4-Dihydro-6,7-dichloro-2-methyl-2H-1,2-benzothiazine-3-carbonyl)-L-phenylalaninal 1,1-dioxide This compound was prepared according to General Procedure I. From 11-1 (isomer 2; 50 mg, 0.11 mmol) the title compound (45 mg; 900) was obtained; MS: 441, 443, 445 m/z (M+H)' (ClZ pattern).

Example 85 Synthesis of Aldehyde 12n (R6 - C1; R' - H; R1 - Bn; Y = N-i-Bu; Q = H) N-(3,4-Dihydro-6-chloro-2-isobutyl-2H-1,2-benzothiazine-3-carbonyl)-L-phenylalaninal 1,1-dioxide This compound was prepared according to General Procedure I. From 11n (isomer l; 41 mg, 0.09 mmol) the title compound (35 mg; 880) was obtained; MS: 449, 451 m/z (M+H)' (chloride isotope pattern).
Example 86 Synthesis of Aldehyde 12o (R6 - Cl; R' - H; R1 - Bn; Y = N-i-Bu; Q = H) N-(3,4-Dihydro-6-chloro-2-isobutyl-2H-1,2-benzothiazine-3-carbonyl)-L-phenylalaninal l,l-dioxide This compound was prepared according to General Procedure I. From lln (isomer 2; 41 mg, 0.09 mmol) the title compound (37 mg, 900) was obtained; MS: 449, 451 m/z (M+H)' (chloride isotope pattern).
Example 87 Synthesis of Aldehyde 12p (R6 - Cl; R' - H; R1 - Bn; Y = NCH3;
Q = H) N-(6-Chloro-3,4-dihydro-2-methyl-2H-1,2-benzothiazine-3-carbonyl)-L-phenylalaninal 1,1-dioxide This compound was prepared according to General Procedure I. From compound llp (isomer 1; 25 mg, 0.06 mmol) the title compound (21 mg, 84%) was obtained as an off-white solid; MS: 405, 407 m/z (M+H)+.
Example 88 Synthesis of Aldehyde 12q (R6 - C1; R' - H; R1 - Bn; Y = NCH3;
Q = H) N-(6-Chloro-3,4-dihydro-2-methyl-2H-1,2-benzothiazine-3-carbonyl)-L-phenylalaninal 1,1-dioxide This compound was prepared according to General Procedure I. From compound llp (isomer 2; 25 mg, 0.06 mmol) the title compound (19 mg, 760) was obtained as an off-white solid; MS: 405, 407 m/z (M+H)+.
Example 89 Synthesis of Aldehyde 12r (R6 + R.' - OCH2CH2O; R1 - Bn; Y =
NCH3 ; Q = H ) N-(3,4-Dihydro-6,7-ethylenedioxy--2-methyl-2H-1,2-benzothiazine-3-carbonyl)-L-phenylalaninal 1,1-dioxide This compound was prepared according to General Procedure I. From compound 10r g100 mg, 0.23 mmol) the title compound (67 mg, 67%) was obtained as a buff-white solid; MS: 431 m/z (M+H)', 453 m/z (M+Na)'.
Exampl 90 Synthesis of Aldehyde 12s (R6 + R' - OCHzCHzO; R1 - Bn; Y =
NEt; Q = H) N-(3,4-Dihydro-6,7-ethylenedioxy--2-ethyl-2H-1,2-benzothiazine-3-carbonyl)-L-phenylalaninal 1,1-dioxide This compound was prepared according to General Procedure I. From compound 11s (i-sourer 1; 30 mg, 0.07 mmol) the title compound (25 mg, 830) was obtained as a white amorphous solid; MS : 445 m/z (M+F~i) ', 467 m/z (M+Na) ' .
Example 91 Synthesis of Aldehyde 12t (R6 + R' - OCHZCHZO; R1 - Bn; Y =
NEt; Q = H) N-(3,4-Dihydro-6,7-ethylenedioxy--2-ethyl-2H-1,2-benzothiazine-3-carbonyl)-L-phenylalaninal 1,1-dioxide This compound was prepared according to General Procedure I. From compound lls (isomer 2; 30 mg, 0.07 mmol) the title compound (27 mg, 90%) was obtained as a white amorphous solid; MS: 445 m/z (M+H)', 467 m/z (M+Na)+.
Example 92 Synthesis of Aldehyde 12u (R6 + R' - OCHZCHZO; R1 - Bn; Y = N-i-Pr; Q = H) N-(3,4-Dihydro-6,7-ethylenedioxy--2-isopropyl-2H-1,2-benzothiazine-3-carbonyl)-L-phenylalaninal 1,1-dioxide This compound was prepared according to General Procedure I. From 11u (78 mg, 0.17 mmol) the title compound (63 mg, 81%) was obtained as a white solid; MS: 459 m/z (M+H)'.
Example 93 Synthesis of Aldehyde 12v (R6 + R' - OCH7CH20; R1 - i-Bu; Y =
NEt; Q = H) N-(3,4-Dihydro-6,7-ethylenedioxy-2-ethyl-2H-1,2 benzothiazine-3-carbonyl)-L-leucinal 1,1-dioxide This compound was prepared according to General Procedure H. From lOv (isomer l; 158 mg, b.32 mmol) the title compound (119 mg, 890) was obtained as a white solid;
NMR (CDC13) b 0.96 (t, J = 7 Hz, 6H), 1.07 (t, J = 7 Hz, 3H), 1.22 (m, 1H), 1.74 (m, 2H), 2.95 (m, 1H), 3.25-3.35 (m, 3H), 3.95 (m, 1H), 4.29 (br, 4H), 4.46 (m, 1H), 6.83 (s, 1H), 7.25 (br, 1H), 7.34 (s, 1H), 9.55 (s, 1H); MS: 41l m/z (M+H)'.
Example 94 Synthesis of Aldehyde 12w (R6 + R' - OCHZCHZO; R1 - i-Bu; Y =
NEt; Q = H) N-(3,4-Dihydro-6,7-ethylenedioxy-2-ethyl-2H-1,2 benzothiazine-3-carbonyl)-L-leucinal 1,1-dioxide This compound was prepared according to General Procedure H. From 10v (isomer 2; l55 mg, 0.32 mmol) the title compound (118 mg, 890) was obtained as a white solid;
NMR {CDC13) b 0.95 (t, J = 7 Hz, 6H), 1.07 (t, J = 7 Hz, 3H), 1.20 (m, 1H), 1.73 (m, 2H), 2.99 (m, 1H), 3.16-3.45 (m, 3H), 3.83 (m, 1H), 4.29 (br, 4H), 4.57 (m, 1H}, 6.83 (s, 1H), 7.25 (br, 1H), 7.34 (s, 1H), 9.57 (s, 1H); MS: 41l m/z (M+H)'.
Example 95 Synthesis of Aldehyde 12x (R6 + R' - OCHZCHZO; R1 -(CH,) 9NHSOZPh; Y = NEt; Q = H) Na-(3,4-Dihydro-6,7-ethylenedioxy-2-methyl-2H-1,2-benzothiazine-3-carbonyl)-L-NE-(benzenesulfonyl.)lysinal 1,1-dioxide This compound was prepared according to General Procedure I. From 11x (isomer 1; 30 mg, 0.05 mmol) the title compound (27 mg, 900) was obtained as a white solid;
MS: 552 m/z (M+H)'.
Example 96 Synthesis of Aldehyde 12y (R6 + R'.' - OCH?CH?O; R1 -(CHZ)4NHSOZPh; Y = NEt; Q = H) Na-(3,4-Dihydro-6,7-ethylenedioxy-2-methyl-2H-1,2-benzothiazine-3-carbonyl)-L-NE-(benzenesulfonyl)lysinal 1,1-dioxide This compound was prepared according to General Procedure I. From 11x {isomer 1; 30 mg, 0.05 mmol) the title compound (28 mg, 93%) was obtained as a white solid;
MS: 552 m/z (M+H)~.
Example 97 Synthesis of Aldehyde 12z (R6 + R' - OCHZCH20; R1 - Bn; Y =
NCH3; Q = H) N-(3,4-Dihydro-6-(4-morpholino)-2-methyl-2H-1,2-benzothiazine-3-carbonyl)-L-phenylalaninal 1,1-dioxide This compound was prepared according to General Procedure I. From 11z (isomer l; 63 mg, 0.14 mmol) the title compound (56 mg, 890) was obtained; MS: 4S8 m/z (M+H)+.
Example 98 Synthesis of Aldehyde l2aa (R6 + R' - OCHzCHzO; R1 - Bn; Y =
NCH3 ; Q = H ) N-(3,4-Dihydro-6-(4-morpholino)-2-methyl-2H-1,2-benzothiazine-3-carbonyl)-L-phenylalaninal 1,1-dioxide This compound was prepared according to General Procedure I. From 11z (isomer 2; 102 mg, 0.22 mmol) the title compound (91 mg, 89%) was obtained; MS: 458 m/z (M+H)".

Example 99 Synthesis of Ester 13 (R6 + R' - OCHZCH?O; R1 - Bn; Y = NEt; Q
- COzMe ) Methyl 3-(3,4-Dihydro-6,7-ethylenedioxy-2-ethyl-2H-1,2-benzothiazine-3-carboxamido)-2-oxo-3-(S)-benzylpropionic acid 1,1-dioxide To a solution of 283 mg (0.9 mmol) of compound 8s (from L-DOPA) in l0.0 ml of DMF at 0 °C was added 298 ul (3.0 eq) of NMM, 277.5 mg (l.25 eq) of methyl 2-(R, S)-hydro-3-(S)-benzyl-3-aminopropionic acid hydrochloride salt, 122.1 mg (1.0 eq) of HOBt and 399.l mg (1.2 eq) of BOP. After 5 min, the ice bath was removed and the reaction was stirred at room temperature for 3 hours. The DMF was removed under reduced pressure and the residue was diluted with CH2Clz (40 ml). The CHzCl2 solution was washed with water, 30 of citric acid, 50 of NaHC03, brine and dried. Purification by flash chromatography (20o hexane in EtOAc) gave 428 mg (94%) of methyl 3-(3,4-Dihydro-6,7-ethylenedioxy-2-ethyl-2H-1,2-benzothiazine-3-carboxamido)-2(R,S)-hydroxy-3-(S)-benzylpropionic acid 1, 1-dioxide (11; R6 + R' - OCH~CH20; R1 -Bn; Y = NEt; Q = COzMe): MS: 505 m/z {M+H)'.
To a solution of 428 mg (0.85 mmol) of this intermediate in 40 ml of CHZC12 at 0°C was added 720 mg (1.7 mmol) of 1,1,1-triacetoxy-1,1-dihydro-1,2-benziodoxol-3(1H)-one (Dess-Martin reagent). After 5 min, the ice-bath was removed and the reaction was stirred at room temperature for 2 hours. More CHzCl? (30 ml) was added to the reaction, and the product was washed with l00 of sodium thiosulfate (3x20 ml), water, brine and dried. Evaporation gave 404 mg (950) of the product; MS: 40S m/z (M+H)'.
Example 100 Synthesis of Ketoamide 14A (R6 - Cl; R' - H; R1 - Bn; Y =
NCH3 ; Q = CONHEt ) N-Ethyl-3-(6-chloro-3,4-dihydro-2-methyl-2H-1,2-benzothiazine-3-carboxamido)-2-oxo-3-(S)-benzylpropanamide 1,1-dioxide This compound was prepared according to General Procedure I. From compound 11A (Q = CONHEt) (58 mg, 0.12 mmol) the title compound (35 mg, 610) was obtained as a mixture of diastereomers; MS: 478 m/z (M+H)'; 500 m/z (M+Na)'.
Example 101 Synthesis of Ketoamide 14B (R6 + R' - OCH2CH2O; R1 - i-Bu; Y =
NEt; Q = CONHBu) 3-((3,4-Dihydro-6,7-ethylenedioxY-2-ethyl-2H-1,2-benzothiazine-3-carbonyl)amino)-:3-(S)-isobutyl-2-oxo-N-butylpropanamide 1,1-dioxide This compound was prepared according to General Procedure I. From 11B (R6 + R' - OCHZCH20; R1 - i-Bu; Y = NEt; Q =
CONHBu; 38 mg, 0.07 mmol) the tii~le compound (26 mg, 68%) was obtained; MS: 510 m/z {M+H)'.
Example 102 Synthesis of Ketoamide 14C (R6 + R' - OCHZCHZO; R1 - i-Bu; Y =
NEt; Q = CONHBu) 3-((3,4-Dihydro-6,7-ethylenediox~~-2-ethyl-2H-1,2-benzothiazine-3-carbonyl)amino)-3-(S)-isobutyl-2-oxo-N-butylpropanamide 1,1-dioxide This compound was prepared according to General Procedure I . From 11C ( R6 + R' - OCH2CHz0; R1 - i -Bu ; Y = NEt ; Q =
CONHBu; 76 mg, 0.15 mmol) the tit=le compound (56 mg, 740) was obtained; MS: 510 m/z (M+H)'.
Example 103 Synthesis of Ketoamide 14D (R6 + R' - OCHZCHZO; R1 - Bn; Y =
NEt; Q = CONHEt) N-Ethyl-3-(3,4-Dihydro-6,7-ethylc~nedioxy-2H-1,2-benzothiazine-3-carboxamido)-2-o:KO-3-(S)-benzylpropanamide 1,1-dioxide This compound was prepared according to General Procedure G. From 8s (31.3 mg, 0.1 mmol, prepared from L-DOPA) and N-ethyl-2-oxo-3-(S)-benzyl-3-aminopropanamide, HC1 salt (31.94 mg, 1.25 eq) the title compound (5.0 mg, l0a) was obtained;

MS: 5l6 (M+H)'. N-Ethyl-2-oxo-3-(S)-benzyl-3-aminopropanamide, HC1 salt was prepared according to Rich's procedure (Ocain, T. D.; Rich, D. H. J. Med. Chem. 1992, 35, 451-456, incorporated by reference herein in its entirety).
However, oxidation to the Boc ketoamide was accomplished with Dess-Martin periodinane (General Procedure I).
Example l04 Synthesis of Ketoamide 14E (R6 + R' - OCHZCH20; R1 - Bn; Y =
NEt; Q = CONHBu) 3-((3,4-Dihydro-6,7-ethylenedioxy-2-ethyl-2H-1,2-benzothiazine-3-carbonyl)amino)-3-{S)-benzyl-2-oxo-N-butylpropanamide 1,1-dioxide This compound was prepared according to General Procedure I. From 11E (R6 + R' - OCH2CHZ0; R1 - Bn; Y = NEt; Q =
CONHBu; 50 mg, 0.09 mmol) the title compound (49 mg, 98a) was obtained; MS: 544 m/z (M+H)'.
Example 105 Synthesis of Ketoamide 14F (R6 + R' - OCHZCH20; R1 - Bn; Y =
NEt; Q = CONHBu) 3-((3,4-Dihydro-6,7-ethylenedioxy-2-ethyl-2H-1,2-benzothiazine-3-carbonyl)amino)-3-(S)-benzyi-2-oxo-N-butylpropanamide 1,1-dioxide This compound was prepared according to General Procedure I. From 11F (R6 + R' - OCHzCH20; R~ - Bn; Y = NEt; Q =
CONHBu; 65 mg, 0.12 mmol) the title compound (52 mg, 800) was obtained; MS: 544 m/z (M+H}'.
Example 106 General Procedure J: Synthesis of a-Ketoamides from a-Ketoesters Synthesis of Ketoamide 1.4G (R6 + R' - OCHZCHZO; R1 - Bn; Y =
NEt; Q = CONHBu) N-Butyl-3-(3,4-Dihydro-6,7-ethylenedioxy-2-ethyl-2H-1,2-benzothiazine-3-carboxamido)-2-oxo-3-benzylpropanamide 1,1-dioxide Compound 13 (23 mg, 0.04& mmol) and 0.2 ml of butylamine were stirred neat at room temper2~ture overnight. LC-MS
analysis indicated completion of the reaction. The reaction was diluted with EtOAc (20 ml) arid cooled to 0 °C as 5.0 ml of 2N HC1 was added to decompose the imine product formed in the reaction. The aqueous mixture was stirred for 30 min and extracted with EtOAc (3 X 10 mI). The combined organic layers were washed with water, 50 of NaHC03, brine and dried.
Filtration and evaporation afforded 20.5 mg (82 0) of the product; MS: 6l5 m/z (M+H)+.
Example 107 Synthesis of Ketoamide 14H (R6 + :R' - OCH2CH20; R1 - Bn; Y =
NEt ; Q = CONHCHZCHZOCH3 ) N-(2-Methoxyethyl)-3-(3,4-Dihydro-6,7-ethylenedioxy-2-ethyl-2H-1,2-benzothiazine-3-carboxamido)-2-oxo-3-benzylpropanamide 1,1-dioxide This compound was prepared according to General Procedure J from 2-methoxyethylamine; 84o yield; MS: 546 m/z (M+H)'.
Example 108 Synthesis of Ketoamide 14I (R6 + :R' - OCH2CH20; R1 - Bn; Y =
NEt; Q = CONH-iPr) N-Isopropyl-3-(3,4-Dihydro-6,7-et.hylenedioxy-2-ethyl-2H-1,2-benzothiazine-3-carboxamido)-2-oxo-3-benzylpropanamide 1,1-dioxide This compound was prepared according to General Procedure J from isopropylamine; 85% yield; MS: 592 m/z (M+H)~.
Example109 Synthesis of Ketoamide 14J (R6 + :R' - OCH2CH20; R1 - Bn; Y =
NEt ; Q = CONH ( CH2 ) q CH3 ) N-Pentyl-3-(3,4-Dihydro-6,7-ethyl.enedioxy-2-ethyl-2H-1,2-benzothiazine-3-carboxamido)-2-ox:o-3-benzylpropanamide 1,1-dioxide This compound was prepared according to General Procedure J from pentylamine; 93 o yield; M~~ : 558 m/z (M+H) i .

Example 110 Synthesis of Ketoamide 14K (R6 + R' - OCH2CH20; R1 - Bn; Y =
NEt; Q = CONHCH2Ph) N-Benzyl-3-(3,4-Dihydro-6,7-ethylenedioxy-2-ethyl-2H-1,2-benzothiazine-3-carboxamido)-2-oxo-3-benzylpropanamide 1,1-dioxide This compound was prepared according to General Procedure J from benzylamine; 80o yield; MS: 578 mjz (M+H)'.
Example 111 Synthesis of Ketoamide 14L (R6 + R' - OCHZCH20; R1 - Bn; Y =
NEt; Q = CONHCHzCH2Ph) N-Phenethyl-3-(3,4-Dihydro-6,7-ethylenedioxy-2-ethyl-2H-1,2-benzothiazine-3-carboxamido)-2-oxo-3-benzylpropanamide 1,1-dioxide This compound was prepared according to General Procedure J from phenethylamine; 85o yield; MS: 592 m/z (M+H)'.
Example 112 Synthesis of Ketoamide 14M (R6 + R' - OCHZCH20; R' - Bn; Y =
NEt ; Q = CONHCHzCH= CHz ) N-(2-Propenyl)-3-(3,4-Dihydro-6,7-ethylenedioxy-2-ethyl-2H-1,2-benzothiazine-3-carboxamido)-2-oxo-3-benzylpropanamide 1,1-dioxide This compound was prepared according to General Procedure J from allylamine; 91o yield; MS: 551 m/z (M+H)'.
Example 113 Synthesis of Ketoamide 14N (R6 + R' - OCHzCH20; Rl = Bn; Y =
NEt; Q = CONHCHzCHzCHz- (imidazol-1-yl) ) N-(3-(Imidazol-1-yl)propyl)-3-(3,4-Dihydro-6,7-ethylenedioxy-2-ethyl-2H-1,2-benzothiazine-3-carboxamido)-2-oxo-3-benzylpropanamide 1,1-dioxide This compound was prepared according to General Procedure J from 3-imidazolylpropylamine; llo yield; MS: 596 m/z (M+H) ' .

Example 114 Synthesis of Ketoamide 14-O (R6 + R' - OCHZCHzO; R1 - Bn; Y =
NEt; Q = CONHCHzCHzCHz-(2-ketopyrrolidin-1-yl)) N-(3-(2-Ketopyrrolidin-1-yl)propyl)-3-(3,4-Dihydro-6,7-ethylenedioxy-2-ethyl-2H-1,2-ben~:othiazine-3-carboxamido)-2-oxo-3-benzylpropanamide 1,1-dioxide This compound was prepared according to General Procedure J from 3-(2-ketopyrrolidin-1-yl)propylamine; 68% yield; MS:
613 m/z (M+H)'.
Example 115 Synthesis of Ketoamide 14P (R6 + R' - OCH2CHz0; R1 - Bn; Y =
NEt; Q = CONHCHzCHzCH2(morpholin-4-yl)) N- (3- (Morpholin-4-yl)propyl) -3- (3;,4-Dihydro-6, 7-ethylenedioxy-2-ethyl-2H-1,2-ben2;othiazine-3-carboxamido)-2-oxo-3-benzylpropanamide 1,1-dioxide This compound was prepared according to General Procedure J from 3-(morpholin-4-yl)propylamine; 84 o yield; MS: MS:
6l5 m/z (M+H)'.
Example l16 Synthesis of Ketoamide 14Q (R6 + :R' - OCH2CHz0; R1 - Bn; Y =
NEt; Q = CONHCHZ(pyridin-2-yl)) N-(Pyridin-2-ylmethyl)-3-(3,4-Dihydro-6,7-ethylenedioxy-2-ethyl-2H-1,2-benzothiazine-3-carboxamido)-2-oxo-3-benzylpropanamide 1,1-dioxide This compound was prepared according to General Procedure J from 2-(aminomethyl)pyridine; 82.5o yield; MS: 579 m/z ( M+H ) ' .
Example 117 3 0 Synthesis of Ketoamide 14R (R6 + :R' - OCHZCH2O; Rl - Bn; Y =
NEt; Q = CONHCHzcyclopropyl) N-(Cyclopropylmethyl)-3-(3,4-Dihydro-6,7-ethylenedioxy-2-ethyl-2H-1,2-benzothiazine-3-cart>oxamido)-2-oxo-3-benzylpropanamide 1,1-dioxide This compound was prepared according to General Procedure J from aminomethylcyclopropane; 96.6o yield; MS: 542 m/z (M+H)'.
Example 118 Synthesis of Ketoamide 14S (R6 + R' - OCHzCHzO; R1 - Bn; Y =
NEt ; Q = CONHCHzCH2NHSO2CH3 ) N-(2-(Methanesulfonylamino)ethyl)-3-(3,4-Dihydro-6,7-ethylenedioxy-2H-1,2-benzothiazine-3-carboxamido)-2-oxo-3-(S)-benzylpropanamide 1,1-dioxide This compound was prepared according to General Procedure I. From compound 11S (45.0 mg, 0.074 mmol) the title compound (34.0 mg, 750) was obtained; MS: 609 (M+H)'.
Example 1l9 Synthesis of Ketoamide 14T (R6 + R' - OCHZCH20; R1 - Bn; Y =
NEt; Q = CONHCH?CHZNHSO2 (4-NOZ-Ph) ) 3-((3,4-Dihydro-6,7-ethylenedioxy-2-ethyl-2H-1,2-benzothiazine-3-carbonyl)amino)-3-(S)-benzyl-2-oxo-N-(2-(4-nitrobenzenesulfonylamino)ethyl)propanamide 1,1-dioxide This compound was prepared according to General Procedure I . From 11T (R6 + R' - OCHZCHzO; R1 - Bn; Y = NEt ; Q =
CONHCHzCH2NHS02{4-NOZ-Ph); 50 mg, 0.07 mmol) the title compound (31 mg, 620) was obtained as a pale yellow solid;
MS: 716 m/z (M+H)'.
Example 120 Synthesis of Ketoamide 14U (R6 + R' - OCHZCHzO; Rl - Bn; Y =
2 5 NEt ; Q = CONH ( CH2 ) 3NHSO2 ( 4 -NOZ - Ph ) ) 3-((3,4-Dihydro-6,7-ethylenedioxy-2-ethyl-2H-1,2-benzothiazine-3-carbonyl)amino)-3-(S)-benzyl-2-oxo-N-(3-(4-nitrobenzenesulfonylamino)propyl)propanamide 1,1-dioxide This compound was prepared according to General Procedure 3 0 I . From 11U ( R6 + R' - OCH2CH20 ; Rl - Bn ; Y = NEt ; Q =
CONH (CHZ) 3NHS02 (4-NOz-Ph) , 30 mg, 0 . 04 mmol) the title compound was obtained (24 mg, SOo) as a pale yellow solid;
MS: 730 m/z (M+H)'.

Example 121 Synthesis of Ketoamide 14V (R6 + R' - OCHzCHzO; R1 - Bn; Y =
NEt; Q = CONHCHZCHzNHS02 (3, 4-Clz-Ph) ) 3-((3,4-Dihydro-6,7-ethylenedioxy-2-ethyl-2H-1,2-benzothiazine-3-carbonyl)amino)-3-(S)-benzyl-2--oxo-N-(2-(3,4-dichlorobenzenesulfonylamino)ethyl)propanamide 1,1-dioxide This compound was prepared according to General Procedure I. From 11V (R6 + R' - OCHZCHZO; R1 - Bn; Y = NEt; Q =
CONHCH2CHZNHS02(3,4-C12-Ph); 58 mg, 0.08 mmol) the title compound (44 mg, 76%) was obtained as a pale yellow solid;
MS: 7l6 m/z (M+H)'.
Example 122 Synthesis of Ketoamide 14W (R6 + R' - OCH2CH20; R1 - Bn; Y =
NE t ; Q = CONH ( CH2 ) 3NHS0z ( 3 , 4 - C 12 - P.h ) ) 3-((3,4-Dihydro-6,7-ethylenedioxy-2-ethyl-2H-1,2-benzothiazine-3-carbonyl)amino)-3-(S)-benzyl-2-oxo-N-{3-(3,4-dichlorobenzenesulfonylamino)propyl)propanamide 1,1-dioxide This compound was prepared according to General Procedure I. From 11W (R6 + R' - OCHZCHZO; :R1 - Bn; Y = NEt; Q =
CONH (CHz) 3NHS02 (3, 4-C12-Ph) ; 56 mg, 0 . 07 mmol) the title compound (40 mg, 71%) was obtained as a pale yellow solid;
MS: 753 m/z (M+H)'.
Example l23 Synthesis of Ketoamide 14X (R6 + R' - OCHzCHzO; R1 - Bn; Y =
NEt ; Q = CONHCHzCHzNHSO2Ph) 3-({3,4-Dihydro-6,7-ethylenedioxy-2-ethyl-2H-1,2-benzothiazine-3-carbonyl)amino)-3-(S)-benzyl-2-oxo-N-(2-(benzenesulfonylamino)ethyl)propanamide 1,1-dioxide This compound was prepared according to General Procedure I. From 11X (R6 + R' - OCHZCH20; R1 - Bn; Y = NEt; Q =
CONHCHzCH2NHSOZPh; 33 mg, 0.05 mmol) the title compound (28 mg, 850) was obtained as a pale yellow solid; MS: 671 m/z (M+H) +.

Example 124 Synthesis of Ketoamide 14Y (R6 + R' - OCH2CHz0; R1 - Bn; Y =
NEt; Q = CONHCH2CH,S02(5-(2-pyridinyl)thiophen-2-yl)) N-(2-((5-(Pyridin-2-yl)thiophen-2-yl)sulfonylamino)ethyl)-3-(3,4-Dihydro-6,7-ethylenedioxy-2H-1,2-benzothiazine-3-carboxamido)-2-oxo-3-(S)-benzylpropanamide 1,1-dioxide This compound was prepared according to General Procedure I. From compound 11Y (75.5 mg, 0.1 mmol} the title compound (80 mg, 93%) was obtained; MS: 754 (M+H)'.
Example l25 Synthesis of Ketoamide 14Z (R6 + R' - OCHZCH?O; R1 - Bn; Y =
NEt; Q = CONH (CH2) 3NHSO2 (4-F-Ph) ) 3-((3,4-Dihydro-6,7-ethylenedioxy-2-ethyl-2H-1,2-benzothiazine-3-carbonyl)amino)-3-(S)-benzyl-2-oxo-N-(3-(4-fluorobenzenesulfonylamino)propyl)propanamide 1,1-dioxide This compound was prepared according to General Procedure I. From 11Z;(35 mg, 0.05 mmol) the title compound (28 mg, 800) was obtained as a pale yellow solid; MS: 703 m/z (M+H)'.
Example 126 Synthesis of Ketoamide 14AA (R6 + R' - OCH2CH20; R1 - Bn; Y =
NEt ; Q = CONH ( CHZ ) 3NHSOZPh) 3-((3,4-Dihydro-6,7-ethylenedioxy-2-ethyl-2H-1,2-benzothiazine-3-carbonyl)amino)-3-(S)-benzyl-2-oxo-N-(3-(benzenesulfonylamino)propyl)propanamide 1,1-dioxide This compound was prepared according to General Procedure I. From 11AA;(34 mg, 0.05 mmol) the title compound (30 mg, 880) was obtained as a pale yellow solid; MS: 685 m/z (M+H)' Example l27 Synthesis of Ketoamide 14AB (R6 + R' - OCH2CH20; R1 - Bn; Y =
NEt; Q = CONHCH2-(pyridin-4-yl)) N-(Pyridin-4-ylmethyl)-3-(3,4-Dihydro-6,7-ethylenedioxy-2-ethyl-2H-1,2-benzothiazine-3-carboxamido)-2-oxo-3-benzylpropanamide 1,1-dioxide This compound was prepared according to General Procedure _ 77 _ J from 4-pyridylmethylamine; 32o yield; MS: 579 m/z (M+H)' Example 128 Synthesis of Ketoamide 14AC (R6 + R' - OCHzCH20; R1 - Bn; Y =
NEt; Q = CONHCHzCH2NHSOz (4-F-Ph) ) 3-((3,4-Dihydro-6,7-ethylenedioxy-2-ethyl-2H-1,2-benzothiazine-3-carbonyl) amino) -3- (S) -benzyl-2-~oxo-N- (2- (4-fluorobenzenesulfonylamino)ethyl)propanamide 1,1-dioxide This compound was prepared according to General Procedure I. From 11AC;(45 mg, 0.07 mmol) the title compound (30 mg, 670) was obtained as a pale yellow solid; MS: 689 m/z (M+H)' Example 129 Synthesis of Ketoamide 14AD (R6 + R' - OCHzCH20; R1 - Bn; Y =
NH; Q = CONHBu) N-Butyl-3-{3,4-Dihydro-6,7-ethylenedioxy-2H-1,2-benzothiazine-3-carboxamido)-2-0~:o-3-(S)-benzylpropanamide 1,1-dioxide This compound was prepared according to General Procedure I. From compound IlAD (20.0 mg, 0.037 mmol) the title compound (16.0 mg, 840) was obtained; MS: 516 (M+H)~.
Example 130 Synthesis of Ketoamide 14AE (R6 + R' - OCHZCHZO; R1 - Bn; Y =
NH; Q = CONHCHZCH2NHSO2Ph) N-(2-(Benzenesulfonylamino)ethyl)-3-(3,4-Dihydro-6,7-ethylenedioxy-2H-1,2-benzothiazine-3-carboxamido)-2-oxo-3-(S)-benzylpropanamide 1,1-dioxide:
This compound was prepared according to General Procedure I. From compound 11AE (47.0 mg, 0.073 mmol) the title compound (16.0 mg, 340) was obtained; MS: 643 (M+H)'.
Example l31 Synthesis of Intermediate 16.
3-(3,4-Dihydroxyphenyl)-L-alanine methyl ester hydrochloride A solution of 1.97g (10 mmol) of L-DOPA 15 in 100 ml of MeOH at 0 °C was added 6.57 ml (90 mmol) of thionyl chloride _ 78 -via addition funnel. The mixture was stirred overnight while the temperature was slowly warmed to room temperature.
The solvent was evaporated and the thick oil was treated with toluene (3 x 15 ml) and evaporated. The yield of white solid was 3.26 g (1000); NMR (DMSO-d6) b 2.90 (m, 2H), 3.38 (bs, 2H), 3.6I (s, 3H), 4.08 (m, 1H), 6.40 (d, 1H, J = 7 Hz), 6.59 (s) 1H), 6.65(d, 2H, J = 7 Hz). 8.59 (bs, 1H), 8.90 (d, 1H, J = 10 Hz). MS: 212 m/z (M+H)'.
Example 132 Synthesis of Intermediate 17.
N-(Benzyloxycarbonyl)-3-(3,4-dihydroxyphenyl)-L-alanine methyl ester A suspension of 4.94 g (20 mmol) of compound 16 and 4.4 ml {2.0 eq) of N-methyl morpholine in 8 ml of THF and 1 ml of water was stirred at room temperature as 4.98 g (20 mmol) of benzyloxycarbonyloxy-succinimide in 8 ml of 1,4-dioxane was added dropwise. The reaction mixture was stirred overnight.
The solvent was evaporated and the residue was diluted with ethyl acetate (100 ml). The ethyl acetate solution was washed with water (20 ml), 50 of NaHCO~ (20 ml), 30 of citric acid (20 ml), brine (20 ml) and dried over MgS04. Filtration and concentration afforded 5.36 g (78 0) of a white solid;
NMR (CDC13) b 2.99 (m, 2H), 3.65 (s, 3H), 4.59 (m, 1H), 5.04 (s, 2H) , 5.39 (m, 1H) , 6.38 (bs, 2H) , 6.42 (d, 1H, J = 7 Hz), 6.60 (s, 1H), 6.67 (d, 1H, J = 7 Hz), 7.30 (m, 5H).
MS: 346 m/z (M+H)'.
Example 133 Synthesis of Intermediate 18.
N-(Benzyloxycarbonyl)-3-(3,4-ethylenedioxyphenyl)-L-alanine methyl ester A suspension of 13.40 g (38.8 mmol) of compound 17 and 53 . 6 6 g ( 3 8 8 mmol ) of KzC03 in 2 0 0 ml of acetone was ref luxed under N2 for 30 minutes. Dibromoethane (13.37 ml, 77.6 mmol) was added in one portion. The suspension was refluxed for 40 hours, the solid was filtered, and the filtrate was - 79 _ evaporated. The residue after evaporation was diluted with 150 ml of water and extracted with CHzCl2 (3x70 ml) . The CH2C12 extracts were washed with brine and dried over MgS09 and concentrated. The crude product was washed with small amount of ether to give 12.26 g (85%) of white solid; NMR
(CDC13) & 3.01 (d, 2H, J = 5.2 Hz), 3.73 (s, 3H), 4.22 (s, 4H), 6.52 (d, 1H, J = 7 Hz), 6.6G (s, 1H), 6.75 (d, 1H, J =
7 Hz), 7.34 (m, 5H). MS: 372 m/z (M+H)'. Anal. Calc'd for CZOH21N06 0 . 2H20 : Calc' d: C, 64 . 00 ; H, 5 . 80 ; N, 3 . 73 ; Found C, 63.83; H, 5.70; N, 3.63.
Example 134 Synthesis of Intermediate 19.
Methyl 3,4-Dihydro-6,7-ethylenedioxy-2H-1,2-benzothiazine-3-carboxylate 1,1-dioxide A solution of 14.82 g (40 mmol) of compound 18 in 150 ml of dried CHC13 was stirred with mechanic stirrer at 0 °C as 13.32 ml (5.0 eq) of chlorosulfonic acid in 100 ml of CHC13 was added dropwise via addition funnel over ~ 1.0 hour. The solution was first turned to yellow, then some thick oil formed and became suspended in the solution. After addition, the reaction mixture was stirred at room temperature and LC-MS was used to follow the reaction. At 3 hours, no starting material was left in the reaction. The reaction was cooled to ~ 5 °C and 43 ml (10 eq) of Et3N, 733 mg (0.3 eq) of DMAP in CHC13 (50 rnl) was added. The mixture was stirred overnight (-- l4hr) while the temperature was warmed to room temperature and then the reaction mixture was refluxed for 3 hours. After that, the reaction mixture was poured into 500 ml of ice-water and separated. The aqueous layer was extracted with CHZC12 (3x100 ml). The combined organic layers were washed with water, 3o HC1, 5% of NaHC03, brine and dried. The crude product was dissolved in CH2C12 and filtered through a short silica column eluted with 80 of EtOAc in hexane to remove remaining Et3N-HCl salt.
Evaporation solvent afforded 3.0 g (250) of a white solid;
NMR (CDC13) b 3.20 (abd, 2H, J = 5.1 Hz, 16 Hz), 3.82 (s, 3H), 4.33 (s, 4H), 4.60 (m, 1H), 4.99 (d, 1H, J = 8 Hz), 6.77 (s, 1H), 7.39 (s, 1H). MS: 300 m/z (M+H)+. Anal.
Calc'd for C12H13N06 S: Calc'd: C, 48.16; H, 4.38; N, 4.68;
Found: C, 48.09; H, 4.66; N, 5.l0.
Example 135 Synthesis of Intermediate 20_ Methyl 3,4-Dihydro-6,7-ethylenedioxy-2-ethyl-2H-1,2-benzothiazine-3-carboxylate 1,1-dioxide A solution of 317 mg (1.06 mmol) of compound 19 and 513 mg (3.5 eq) of K?C03 in 2.0 ml of DMF was stirred under N2 as 339 ul (4.0 eq) of EtI was added at room temperature. After 14 hours (overnight) at room temperature, the mixture was diluted with CHZC12 (20 ml). The solid was filtered and washed with CHzCl?. The filtrates were washed with water, 30 citric acid, 50 of NaHC03, brine and dried. Evaporation of the solvent afforded 313 mg (90 % yield) of a pure white solid; NMR (CDC13) b l.09 (t, 3H, J = 7.1 Hz), 3.01-3.4 (m, 6H), 3.79 (s, 3H), 4.25 (s, 4H), 4.15 (1H, dd, J = & Hz, 11 Hz), 6.74 (s, 1H), 7.28 (s, 1H). MS: 328 m/z (M+H)'. Anal.
Calc' d for C14H1.,N06~S : Calc' d: C, 51 . 37; H, 5 . 23 ; N, 4 . 28 ;
Found: C, 51.26; H, 5.08; N, 4.30.
Example 136 Synthesis of Intermediate 21a (R' = H; R6 = R' - C1; Y = NCH3;
R = CH3) Methyl 6,7-dichloro-2-methyl-2H-1,2-benzothiazine-3-carboxylate 1,1-dioxide To a solution 91 (256 mg, 0.79 mmol) in CC14-CHZC12 (25 ml-5 ml) was added NBS (155 mg, 0.87 mmol) and dibenzoylperoxide (38 mg, 0.16 mmol). The mixture was refluxed in the dark for one hour, at which time tlc analysis showed complete consumption of starting material.
After being cooled to ambient temperature, dichloromethane was added and the mixture was washed with l0a sodium thiosulfate, water, brine, dried over anhydrous magnesium sulfate, filtered and concentrated to give 250 mg of the title compound, subsequently used without further purification; NMR (CDC13) b 3.18 (s, 3H), 3.87 (s, 3H), 7.43 (s, 1H) , 7.59 (s, 1H) , 7.87 (s, :LH) .
Example 137 Synthesis of Intermediate 21b (RE' + R' - OCH2CH20; R1 - H; Y =
NMe ; R = CH3 ) Methyl 6,7-ethylenedioxy-2-methyl-2H-1,2-benzothiazine-3-carboxylate 1,1-dioxide This compound was prepared according the procedure above for 21a. From 9r (R = CH3; 150 m.g, 0.48 mmol) the title compound (l00 mg, 660) was obtained following flash chromatography on silica gel (30'> ethyl acetate/hexanes);
MS : 312 ( M+H ) ' .
Example 138 Synthesis of Intermediate 21d (R = Me; R4 - OMe; R6 - R' - H;
Y = NMe) Methyl 2-methyl-4-methoxy-2H-1,2--benzothiazine-3-carboxylate This compound was prepared according to Zinnes et. al., J.
Med. Chem., l973, 16, 44-48. Thus, a solution of methyl 2 methyl-4-hydroxy-2H-1,2-benzothiazine-3-carboxylate (500 mg, 1.86 mmol) (Lombardino, et. al., J. Med. Chem., 197l, 14, 1l71-l177, incorporated by reference herein in its entirety) in acetone (10 ml) was treated with anhydrous potassium carbonate (2.6 g, 18.6 mmol) and iodomethane (1.32 g, 9.29 mmol) and refluxed for 40 hours. The mixture was filtered and concentrated and the residue was partitioned between ethyl acetate and water. The organic phase was washed with saturated aqueous sodium bicarbonate and brine, dried over anhydrous magnesium sulfate, filtered and concentrated to afford 285 mg (54%) of the title compound as a yellow viscous oil, used subsequently w_~thout need for further purification; NMR (CDC13) b 3.03 (s, 3H), 3.83 (s, 3H), 3.91 (s, 3H), 7.67-7.72 (m, 2H), 7.8l--7.88 (m, 2H); MS: 284 m/z ( M+H ) ' .

Example 139 Synthesis of Intermediate 23a (R' - H; R6 - R' - Cl; Y = NCH3) 6,7-Dichloro-2-methyl-2H-1,2-benzothiazine-3-carboxylic acid l,l-dioxide To a solution of 21a (250 mg, 0.77 mmol) in MeOH (10 ml) and DMF (3 ml, to aid solubility) was added 5N NaOH (25 ml).
The mixture was warmed to ~50°C while being stirred for 20 minutes, at which time tlc analysis showed complete consumption of starting material. The mixture was cooled to ambient temperature, the MeOH was stripped on the rotary evaporator, the residue was diluted with water (25 ml) and clarified by filtration. Adjustment to pH 2 gave a precipitate which was collected by suction filtration, washed with water and allowed to air-dried overnight to afford 128 mg (540 overall from 9a) of the title compound;
MS: 306, 308, 310 m/z (M-H)-, C12 pattern.
Example 140 Synthesis of Intermediate 23d (R' - OMe; R6 = R' - H; Y = NMe) 2-Methyl-4-methoxy-2H-1,2-benzothiazine-3-carboxylic acid 1,1-dioxide A solution of 21d (159 mg, 0.56 mmol) in methanol (3 ml) was treated with 5N NaOH (2 ml) and stirred at room temperature for 20 minutes, at which time tlc analysis showed complete consumption of starting material. The methanol was removed on the rotary evaporator and the aqueous residue was adjusted to pH 3 with 4N HCl. The precipate so formed was collected by suction filtration, washed with water and allowed to air-dry to constant weight to give 94 mg (620) of the title compound as a white solid;
MS: 292 m/z (M+Na)'; Anal. Calc'd for C11H11N05S: C, 49.07; H, 4.13; N, 5.20; S, 11.89; Found: C, 48.84; H, 3.85; N, 4.98;
S, 11.78.
Example 141 Synthesis of Intermediate 25a (R4 - H; R6 - R' - C1; R1 - Bn;
Y=NCH3; Q=H) N-(6,7-Dichloro-2-methyl-2H-1,2-benzothiazine-3-carbonyl)-L-phenylalaninol 1,1-dioxide This compound was prepared according to General Procedure G. From 23a (l00 mg, 0.32 mmol) the title compound (137 mg) was obtained following flash chromatography on silica gel (50% ethyl acetate/hexanes); MS: 441, 443, 445 m/z (M+H)', C12 pattern.
Example 142 Synthesis of Intermediate 25b (R'' - H; R6 + R' - OCHZCH20; R1 -Bn ; Y = NCH3 ; Q = H ) N-(6,7-Ethylenedioxy-2-methyl-2H-1,2-benzothiazine-3-carbonyl)-L-phenylalaninol 1,1-dioxide This compound was prepared according to General Procedure G. From 23b (80 mg, 0.27 mmol) the title compound (96 mg, 830) was obtained following flash chromatography on silica gel (50% ethyl acetate/hexanes); MS: 431 m/z (M+H)'.
Example l43 Synthesis of Intermediate 25c (R' - H; R6 + R' - OCHZCHZO; R1 -Bn; Y = NEt; Q = H) N-(6,7-Ethylenedioxy-2-ethyl-2H-1,2-benzothiazine-3-carbonyl)-L-phenylalaninol l,l-dioxide This compound was prepared according to General Procedure G. From 23c (100 mg, 0.32 mmol) the title compound (136 mg, 950) was obtained following flash chromatography on silica gel (50o ethyl acetate/hexanes); MS: 445 m/z (M+H)'.
Example l44 Synthesis of Intermediate 25d (R' - OMe; R6 - R' - H; R1 - Bn;
Y=NMe; Q=H) N-(2-Methyl-4-methoxy-2H-1,2-ben:~othiazine-3-carbonyl)-L-phenylalaninol 1,1-dioxide This compound was prepared according to General Procedure G. From 23d (22 mg, 0.08 mmol) t=he title compound (32 mg, 990) was obtained; MS: 403 m/z (M+H)a.

Example l45 Synthesis of Intermediate 25e (R4 - H; R6 + R' - OCHzCH20; R1 -Bn; Y = NMe; Q = CONHBu) 3-((6,7-Ethylenedioxy-2-methyl-2H-1,2-benzothiazine-3-carbonyl)amino)-3-{S)-benzyl-2-(R,S)-hydroxy-N-butylpropanamide 1,1-dioxide This compound was prepared according to General Procedure K. From 26b (55 mg, 0.13 mmol) the title compound (22 mg, 320) was obtained following flash chromatography on silica gel (ethyl acetate); MS: 530 m/z (M+H)+.
Example 146 Synthesis of Intermediate 25f {R4 - H; R6 + R' - OCH?CH20; R1 -Bn; Y = NEt; Q = CONHBu) 3-({6,7-Ethylenedioxy-2-methyl-2H-1,2-benzothiazine-3-carbonyl)amino)-3-(S)-benzyl-2-(R,S)-hydroxy-N-butylpropanamide 1,1-dioxide This compound was prepared according to General Procedure K. From 26c (80 mg, 0.18 mmol) the title compound (30 mg, 310) was obtained following preparative tlc on silica gel (ethyl acetate); MS: 542 m/z (M-H)-.
Example 147 Synthesis of Intermediate 25g (R' - OMe; R6 - R' - H; R1 - Bn;
Y = NMe; Q = CONHBu) 3-((4-Methoxy-2-methyl-2H-1,2-benzothiazine-3-carbonyl)amino)-3-(S)-benzyl-2-(R,S)-hydroxy-N-butylpropanamide 1,1-dioxide This compound was prepared according to General Procedure G. From 23d (50 mg, 0.18 mmol) the title compound (80 mg, 830) was obtained following flash chromatography on silica gel (65o ethyl acetate/hexanes); MS: 502 m/z (M+H)+
Example 148 Synthesis of Intermediate 25h (R' - OH; R6 - R' - H; R1 - Bn;
Y = NMe; Q = CONHBu) 3-((4-Hydroxy-2-methyl-2H-1,2-benzothiazine-3-carbonyl)amino)-3-(S)-benzyl-2-(R,S)-hydroxy-N-butylpropanamide 1,1-dioxide This compound was prepared according to the method of Lombardino et. al., J. Med. Chem., 1973, 16, 493-496, incorporated by reference herein in its entirety. Thus, a slurry of methyl 2-methyl-4-hydroxy-2H-1,2-benzothiazine-3-carboxylate (54 mg, 0.20 mmol) anal 3-amino-3-(S)-benzyl-2-(R,S)-hydroxy-N-butylpropanamide (50 mg, 0.20 mmol) in xylenes (5 ml) was refluxed for 18 hours. The mixture was concentrated on a vacuum line, th.e residue was partitioned between ethyl acetate and water, the organic phase was washed with 5o aqueous citric acid solution, water and brine, dried over anhydrous magnesium sulfate, filtered and concentrated to give 104 mg crude product, further purified by flash chromatography on silica gel (50o ethyl acetate/hexanes) to give 59 mg (600) of the title compound as an off-white solid; MS: 488 m/z (M+H)'.
Example 149 Synthesis of Aldehyde 26a (R4 - H; R6 - R' - Cl; R1 - Bn; Y =
2 0 NCH3 ; Q = H ) N-(6,7-Dichloro-2-methyl-2H-1,2-benzothiazine-3-carbonyl)-L-phenylalaninal l,l-dioxide This compound was prepared according to General Procedure I. From 25a (Q = H, 50 mg, 0.11 mmol) the title compound (942 mg, 84%) was obtained as an off-white solid; MS: 437, 439, 441 (M-H) -; C12 pattern.
Example 150 Synthesis of Aldehyde 26b (R' - H; R6 + R' - OCHzCH20; R1 - Bn;
Y = NCH3; Q = H) N-(6,7-Ethylenedioxy-2-methyl-2H-1,2-benzothiazine-3-carbonyl)-L-phenylalaninal 1,1-dioxide This compound was prepared according to General Procedure I. From 25b (Q = H, 52 mg, 0.12 mmol) the title compound (41 mg, 790) was obtained as a write solid; MS: 429 (M+H)~.

Example 151 Synthesis of Aldehyde 26c (R4 - H; R6 + R' - OCHZCH20; R1 - Bn;
Y = NEt ; Q = H) N-(6,7-Ethylenedioxy-2-ethyl-2H-1,2-benzothiazine-3-carbonyl)-L-phenylalaninal 1,1-dioxide This compound was prepared according to General Procedure I. From 25c (Q = H, 135 mg, 0.30 mmol) the title compound (109 mg, 81%) was obtained as a pale yellow solid; MS: 441 (M-H) - .
Example 152 Synthesis of Aldehyde 26d (R' - OMe; R6 = R' - H; Rl - Bn; Y =
NMe ; Q = H ) N-(2-Methyl-4-methoxy-2H-1,2-benzothiazine-3-carbonyl)-L-phenylalaninal 1,1-dioxide This compound was prepared according to General Procedure I. From 25d (Q = H, 32 mg, 0.08 mmol) the title compound (25 mg, 760) was obtained; MS: 40l m/z (M+H)+.
Example 153 Synthesis of Ketoamide 27e (R4 - H; R6 + R' - OCH2CHz0; R1 -Bn; Y = NMe; Q = CONHBu) 3-((6,7-Ethylenedioxy-2-methyl-2H-1,2-benzothiazine-3-carbonyl)amino)-3-(S)-benzyl-2-oxo-N-butylpropanamide 1,1-dioxide This compound was prepared according to General Procedure I. From 25e (Q = CONHBu, 20 mg, 0.04 mmol) the title compound (15 mg, 75%) was obtained as a white solid; MS: 528 m/z (M+H)+.
Example 154 Synthesis of Ketoamide 27f (R' - H; R6 + R' - OCHZCH20; R1 -Bn; Y = NEt; Q = CONHBu) 3-((6,7-Ethylenedioxy-2-methyl-2H-1,2-benzothiazine-3-carbonyl)amino)-3-(S)-benzyl-2-oxo-N-butylpropanamide 1,1-diaxide This compound was prepared according to General Procedure _ 87 -I. From 25f (Q = CONHBu, 24 mg, 0.04 mmol) the title compound (22 mg, 920} was obtained as a white solid; MS: 542 m/z (M+H) +.
Example 155 Synthesis of Ketoamide 27g (R4 - OMe; R6 - R' - H; R1 - Bn; Y
- NMe; Q = CONHBu) 3-((4-Methoxy-2-methyl-2H-1,2-benzothiazine-3-carbonyl)amino)-3-(S)-benzyl-2-ox;o-N-butylpropanamide 1,1-dioxide This compound was prepared according to General Procedure I. From 25g (Q = CONHBu, 60 mg, 0.l2 mmol) the title compound (49 mg, 820) was obtained as a white solid; MS: 500 m/z (M+H) ~.
Example 156 Synthesis of Ketoamide 27h (R' - OH; R6 - R' - H; R1 - Bn; Y =
NMe; Q = CONHBu) 3-((4-Hydroxy-2-methyl-2H-1,2-benzothiazine-3-carbonyl)amino)-3-{S)-benzyl-2-oxo-N-butylpropanamide 1,1-dioxide This compound was prepared according to General Procedure I. From 25h (Q = CONHBu, 42 mg, 0.09 mmol) the title compound (18 mg, 43%) was obtained following preparative tlc on silica gel (50% ethyl acetate/hexanes); MS: 486 m/z (M+H)'; Anal. Calc'd for C24HZ~N3O6~;: C, 59.36; H, 5.62; N, 8.66; S, 6.59; Found: C, 59.56; H, 5.76; N, 7.97; S, 6.71.
Example 157 Synthesis of Intermediate 31a (R' - Pr; R6 = R' - H) 3,4-Dihydro-4-propyl-2H-1,2,4-benzothiadiazine-3-carboxylic acid 1,1-dioxide This compound was prepared according to the method of Close et. al., J. Org. Chem., l961, 26, 3423-3433, incorporated by reference herein in its entirety. Thus, a solution of methyl dimethoxyacetate (3.6 g, 27.3 mmol) in water (50l) was refluxed for 2.5 hours. A stillhead was - 88 _ attached and the methanol so generated was allowed to distill off (a total of 10 ml of liquid was collected, of which 5 ml was replenished with water). To the hot solution was added 2-(propylamino)benzenesulfonamide (4.5 g, 21.0 mmol) (prepared according to the procedure of Biressi et.
al., Farmeco. Ed. Sci. (It.), l969, 24, 199-220, incorporated by reference herein in its entirety) and 1,4-dioxane (5 ml, to give a homogeneous solution) and reflux was continued for 1.5 hours. The mixture was adjusted to pH
3 (2N NaOH), extracted with ethyl acetate and the organic phase was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated to give 4.8 g crude product which was recrystallized (ethyl acetate/hexanes) to give 2.5 g (44%) of the title compound as a white solid; NMR
(DMSO-d6) b 0.85 (t, J = 7 Hz, 3H), 1.47-1.57 (m, 2H), 2.94-3 . 04 (m, 1H) , 3 .38 (br, 1H) , 3 .40-3 .46 (m, 1H) , 5.27 (d, J =
6 Hz, 1H), 6.70 (t, J = 7 Hz, 1H), 6.84 (d, J = 7 Hz, 1H), 7.36 (t, J = 7 Hz), 7.43 (d, J = 7 Hz, 1H), 8.44 (d, J = 7 Hz, 1H) , 13 . 04 (br, 1H) ; MS : 269 m/z (M-H) -; Anal . Calc' d for C1,H,QNz04S: C, 48.88; H, 5.23; N, l0.37; S, 1l.84; Found: C, 49.17; H, 5.21; N, 10.27; S, 11.54.
Example 158 Synthesis of Intermediate 34a (R4 - Pr; R6 - R' - H; R1 - Bn;
Y = NEt; Q = H) N-(3,4-Dihydro-2-ethyl-4-propyl-2H-1,2,4-benzothiadiazine-3-carbonyl)-L-phenylalaninol 1,1-dioxide This compound was prepared according to General Procedure G. From 33a (300 mg, 1.0 mmol) crude product (508 mg) was obtained as a mixture of diastereomers which were partially separated by flash chromatography on silica gel (50o ethyl acetate/hexanes):
Isomer 1: 95 mg (210); MS: 432 m/z (M+H)';
Isomer 2: 83 mg (200) ; MS: 432 m/z (M+H)'.
Also isolated was 118 mg (270) of a diastereomeric mixture.

_ 89 _ Example 159 Synthesis of Intermediate 34c (R' - Bn; R6 - R' - H; R1 - Bn;
Y = NEt; Q = H) N-(3,4-Dihydro-2-ethyl-4-benzyl-:?H-1,2,4-benzothiadiazine-3-carbonyl)-L-phenylalaninol 1,1-dioxide This compound was prepared according to General Procedure G. From 33c (65 mg, 0.19 mmol) crude product (100 mg) was obtained as a mixture of diastereomers which were separated by preparative tlc on silica gel (50% ethyl acetate/
l0 hexanes) Isomer 1: 24 mg (27%); MS: 480 m/z (M+H)';
Isomer 2: 40 mg (440) ; MS: 480 m/z (M+H)'.
Example 160 Synthesis of Aldehyde 35a (R' - Pr; R6 - R' - H; R1 - Bn; Y =
NEt; Q = H) N-(3,4-Dihydro-2-ethyl-4-propyl-2H-l,2,4-benzothiadiazine-3-carbonyl)-L-phenylalaninal 1,1-dioxide This compound was prepared according to General Procedure I. From 34a (isomer 1; 95 mg, 0.22 mol) the title compound (94 mg, 990) was obtained; MS: 430 m/z (M+H)'.
Example 161 Synthesis of Aldehyde 35b (R4 - Pr; R6 - R' - H; R~ - Bn; Y =
NEt; Q = H) N-(3,4-Dihydro-2-ethyl-4-propyl-~:H-1,2,4-benzothiadiazine-3-carbonyl)-L-phenylalaninal 1,1-dioxide This compound was prepared according to General Procedure I. From 34a (isomer 2; 83 mg, 0.19 mol) the title compound (42 mg, 510) was obtained; MS: 430 m/z (M+H)+.
Example 162 Synthesis of Aldehyde 35c (R' - Bn; R6 - R' - H; R1 - Bn; Y =
NEt; Q = H) N-(3,4-Dihydro-2-ethyl-4-benzyl-2H-1,2,4-benzothiadiazine-3-carbonyl)-L-phenylalaninal 1,1-dioxide This compound was prepared according to General Procedure I. From 34c (isomer 1; 22 mg, 0.05 mol) the title compound (21 mg, 95%) was obtained; MS: 478 m/z (M-H)-.
Example 163 Synthesis of Aldehyde 35d (R' - Bn; R6 - R' - H; R1 - Bn; Y =
NEt; Q = H) N-(3,4-Dihydro-2-ethyl-4-benzyl-2H-1,2,4-benzothiadiazine-3-carbonyl}-L-phenylalaninal 1,1-dioxide This compound was prepared according to General Procedure I. From 34c (isomer 2; 35 mg, 0.07 mot) the title compound (33 mg, 94a) was obtained; MS: 478 mjz (M+H)+; Anal. Calc'd for C26Hz~N3OqS.H20: C, 63.0l; H, 5.91; N, 8.48; S, 6.45;
Found: C, 63.03; H, 5.52; N, 7.86; S, 5.79.
Example 164 Synthesis of Ketoamide 35e (R4 - H; R6 - R' - H; Rl - Bn; Y =
NMe; Q = CONHBu) 3-((3,4-Dihydro-4H-2-methyl-2H-1,2,4-benzothiadiazine-3-carbonyl)amino)-3-(S)-benzyl-2-oxo-N-butylpropanamide 1,1-dioxide This compound was prepared according to General Procedure I in which isobutyl chloroformate was used in place of HOBt/BOP. From 33e (40 mg, 0.17 mmol) and 3-amino-3-(S)-benzyl-2-oxo-N-butylpropanamide hydrochloride (56 mg, 0.20 mmol) the title compound (46 mg, 97a) was obtained as a pale yellow solid; MS: 47l m/z (M-H)-.
Example 165 Synthesis of Intermediate 36b (R6 + R' - OCHzCHzO) 6,7-Ethylenedioxy-2H-1,2,4-benzothiadiazin-3-(4H)-one 1,1-dioxide This compound was prepared according to the method of Girard et. al., J. Chem. Soc., Perkin I; 1979, 1043-1047, incorporated by reference herein in its entirety. To a solution of chlorosulfonyl isocyanate (5.6 g, 40.0 mmol) in nitroethane (35 ml) at -40°C was added dropwise over five minutes a solution of 1,4-benzodioxan-6-amine (5.0 g, 33.1 mmol) in nitroethane (5 ml). The mixture was allowed to warm to 0°C and stirred for one hour at which time anhydrous aluminum chloride was added. The mixture was warmed to 110°C
and stirred for 30 minutes (copious HCl evolution) and allowed to cool to ambient temperature before being added dropwise to a vigorously stirred ice-water 0150 g) mixture.
The resulting precipitate was co:Llected by suction filtration, washed with water and air-dried to give 4.4 g (520) of the title compound as a light gray powder; MS: 255 m/z (M-H)-.
Example 166 Synthesis of Intermediate 37b (Re' + R' - OCHZCH20) 4,5-Ethylenedioxy-2-sulfanilamide hydrochloride A mixture of 36b (1.0 g, 3.0 mmol) in concentrated hydrochloric acid (40 ml) was stirred while being refluxed for 18 hours. The mixture was clarified by filtration and concentrated in vacuo. The residue was triturated with ether to give 1.0 g (96%) of the title compound as a tan solid; MS: 231 m/z (M+H-HCl)'.
Example 167 Synthesis of Intermediate 38a (R6 - R' - H) Ethyl 2-(Oxalylamino)benzenesulfonamide To a solution of o-sulfanilamide (10.5 g, 61 mmol) in THF
chilled in an ice-water bath was added triethylamine (8.9 ml, 64 mmol) followed by slow dropwise addition of ethyl oxalylchloride (7.2 ml, 64 mmol) over 5-10 minutes. The mixture was allowed to slowly warm to ambient temperature over five hours. The precipitatE: was removed by filtration and the concentrated filtrate wa~~ recrystallized (ethyl acetate) to give 9.0 g (540) of t:he title compound; MS: 273 m/z (M+H) ' ; Anal . Calc' d for CloHl;zN2 OSS : C, 44 . 12 ; H, 4 . 45 ;
N, 10.29; S, 11.75; Found: C, 44.21; H, 4.13; N, 10.08; S, 11.75.

Example 168 Synthesis of Intermediate 38b (R6 + R' - OCH2CH20) Ethyl 4,5-ethylenedioxy-2-(oxalylamino)benzenesulfonamide This compound was prepared using the procedure described for compound 38a. From compound 37b (1.0 g, 3.75 mmol) there was obtained 385 mg (31e) of the title compound following recrystallization (EtOAc); MS: 329 m/z (M-H)-.
Example 169 Synthesis of Intermediate 39a (R6 - R' - H) Ethyl 2H-1,2,4-benzothiadiazine-3-carboxylate 1,1-dioxide To a flask containing anhydrous ethanol (25 ml) was added NaH (60o suspension in mineral oil; 155 mg, 4.0 mmol). The mixture was stirred for 15 minutes and 38a (1.0 g, 3.7 mmol) was added in one portion. The mixture was stirred for two hours at which time tlc analysis showed complete consumption of starting material. Water (50 ml) was added, the pH was adjusted to 3-4 (4N HC1), and the ethanol was removed on the rotary evaporator. The precipitate was collected by suction filtration, washed with water and dried to constant weight to afford 0.66 g (710) of the title compound; MS: 273 m/z ( M+H ) ' Example 170 Synthesis of Intermediate 39b (R6 + R' - OCHZCHzO) Ethyl 2H-6,7-ethylenedioxy-1,2,4-benzothiadiazine-3-carboxylate 1,1-dioxide This compound was prepared using the procedure described for compound 39a. From compound 38b (330 mg, 1.0 mmol) there was obtained 173 mg (550) of the title compound as a tan powder; MS: 3l1 m/z (M-H) .
Example 171 Synthesis of Intermediate 40b (R6 + R' - OCHzCH20) 2H-6,7-Ethylenedioxy-1,2,4-benzothiadiazine-3-carboxylic acid l,l-dioxide This compound was prepared using the procedure described for compound 40a. From compound 39b (170 mg, 0.S4 mmol) there was obtained 100 mg (650) of the title compound as an off-white solid; MS: 283 m/z (M-H)-.
Example 172 Synthesis of Intermediate 41b (R'~ + R' - OCHzCHxO; R1 - Bn; Q
- H) N-(2H-6,7-Ethylenedioxy-1,2,4-be:nzothiadiazine-3-carbonyl)-L-phenylalaninol 1,1-dioxide This compound was prepared according to General Procedure G. From compound 40b (50 mg, 0.:18 mol) there was obtained 23 mg (320) of the title compound as a pale yellow solid;
MS: 440 m/z (M+Na)'.
Example 173 Synthesis of Aldehyde 42a (R6 - R' - H; R1 - Bn; Y = NH; Q =
H) N-(2H-1,2,4-Benzothiadiazine-3-carbonyl)-L-phenylalaninal 1,1-dioxide This compound was prepared (following hydrolysis of 39a) according to General Procedures C~ and I. From 41a (43 mg, 0.12 mol) the title compound (14 mg, 33%) was obtained; MS:
358 m/z (M+H)'.
Example 174 Synthesis of Aldehyde 42b f R6 + R' - OCHZCHzO; Rl - Bn; Y =
NH; Q = H) N-(2H-6,7-Ethylenedioxy-1,2,4-benzothiadiazine-3-carbonyl)-L-phenylalaninal 1,1-dioxide This compound was prepared according to General Procedure I. From compound 41b (23 mg, 0.06 mol) there was obtained 22 mg (960) of the title compound as an off-white solid;
MS: 415 m/z (M+H)'.
Example 175 Synthesis of Ketoamide 42c (R6 - R' - H; R1 - Bn; Y = NH; Q =
CONHBu) 3-((2H-1,2,4-Benzothiadiazine-3-carbonyl)amino)-3-(S)-benzyl-2-oxo-N-butylpropanamide 1,1-dioxide This compound was prepared according to General Procedure I (in this case, isobutyl chloroformate was used in place of HOBt/BOP). From compound 40a (25 mg, 0.11 mmol) and 3-amino-3-(S)-benzyl-2-oxo-N-butylpropanamide hydrochloride (35 mg, 0.12 mmol) the title compound (9 mg, 180) was obtained as an off-white solid following trituration of the crude (33 mg) product with ether; MS: 455 m/z (M-H)-.
Example l76 Synthesis of Ketoamide 42d (R6 + R' - OCH2CH20; R1 - Bn; Y =
NH; Q = CONHBu) 3-((2H-6,7-Ethylenedioxy-l,2,4-benzothiadiazine-3-carbonyl)amino)-3-(S)-benzyl-2-oxo-N-butylpropanamide 1,1-dioxide This compound was prepared according to General Procedure I (in which isobutyl chloroformate was used in place of HOBt/BOP. From compound 40b (40 mg, 0.l4 mmol) and 3-amino-3-(S)-benzyl-2-oxo-N-butylpropanamide hydrochloride (48 mg, 0.l7 mmol) the title compound (9 mg, 130) was obtained as an off-white solid following recrystallization (ethyl acetate/hexanes); MS: 5l3 m/z (M-H)-.
Example 177 Synthesis of Intermediate 44 (R6 - R' - H) N-Benzoyl-1,2,3,4-tetrahydro-3-isoquinolinecarboxylic acid This compound was prepared according to Hein et. al., J.
Amer. Chem. Soc.; 1962, 84, 4487-4494, incorporated by reference herein in its entirety. Thus, a slurry of 1,2,3,4-tetrahydro-3-isoquinolinecarboxylic acid hydrochloride (20.3 g, 95 mmol) in 2N NaOH (150 ml) was treated with benzoyl chloride (13.4 ml, 114 mmol) dropwise over 30 minutes. The mixture was stirred a further 1.5 hours, acidified to pH 2-3 (4N HCl), and extracted with ethyl acetate. The organic phase was washed with water and brine, dried over anhydrous magnesium sulfate, filtered and concentrated to afford 16.4 g (610) of the title compound following recrystallization (acetone/water); MS: 280 m/z (M-H)-.
Example 178 Synthesis of Intermediate 45 (R6 - R' - H) N-Benzoyl-2-carboxyphenylalanine This compound was prepared according to Maeda et. al., Chem. Pharm. Bull.; 1988, 36, l90-201, incorporated by reference herein in its entirety. A solution of compound 44 (1S.4 g, 54.7 mmol) and potassium carbonate (7.6 g, S4.7 mmol) in water (450 ml) was treated portionwise with potassium permanganate (17.3 g, 109.5 mmol) over 10 minutes.
The mixture was stirred for two ::ours, quenched with sodium bisulfate (6.5 g) and stirred fo:r 5-10 minutes, and filtered through a bed of Celite~. The filtrate was acidified to pH
2-3 and the resulting gummy precipitate was extracted with ethyl acetate. The organic phase was washed with water and brine, dried over anhydrous magna=_sium sulfate, filtered and concentrated to afford 10.0 g {58%) of the title compound as a white solid; MS: 312 m/z (M-H) .
Example 179 Synthesis of Intermediate 46 (R6 - R' - H) 1-Oxo-1,2,3,4-tetrahydroisoquino:line-3-carboxylic acid A slurry of compound 45 (6.4 g., 20.4 mmol) in 6N HCl (250 ml) was stirred while being refluxed for 18 hours. The resulting homogeneous solution w<~s allowed to cool to ambient temperature to give a precipitate which was collected by suction filtration, washed with water and air-dried to afford 3.05 (780) of the title compound; NMR (CDC13-CD30D) b 3.01-3.31 (m, 2H), 4.29 {m, 1H), 7.18-7.41 (m, 3H), 7.94 (t, J = 8 Hz, 1H); MS: 190 m/z (M-H)-.
Example 180 Synthesis of Intermediate 47 (R6 - R' - H) 2-Methyl-1-oxo-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid A solution of compound 46 (1.5 g, 7.8 mmol) in DMF (70 ml) was treated with iodomethane (9.7 ml, l57 mmol) and silver(I) oxide (5.5 g, 23.5 mmol) and stirred in the dark for seven days. The mixture was filtered through Celite", the DMF was removed in vacuo and the residue was partitioned between ethyl acetate and water. The organic phase was washed with loo aqueous sodium thiosulfate, water and brine, dried over anhydrous magnesium sulfate, filtered and concentrated to give 0.96 g (560) of methyl 2-methyl-1-oxo-1,2,3,4-tetrahydroisoquinoline-3-carboxylate following flash chromatography on silica gel (30% ethyl acetate/hexanes);
NMR (CDC13) b 3.17 (s, 3H), 3.23-3.50 (m, 2H), 3.6l (s, 3H), 4.2l (m, 1H), 7.l2 (d, J = 7 Hz, 1H), 7.32-7.38 (m, 2H), 8.06 (d, J = 7 Hz, 1H) .
This compound was saponified according to the procedure for 23a. From methyl 2-methyl-1-oxo-1,2,3,4-tetrahydroisoquinoline-3-carboxylate (0.95 g, 4.3 mmol) the title compound (0.66 g, 740) was obtained; MS: 204 m/z (M-H)-.
Example 181 Synthesis of Intermediate 48 (R6 - R' - H; R1 - Bn; Y = NH) N-(1-Oxo-1,2,3,4-tetrahydroisoquinoline-3-carbonyl)-L-phenylalaninol This compound was prepared according to General Procedure G. From compound 46 (200 mg, 1.05 mmol) crude product (353 mg) was obtained as a mixture of diastereomers which were partially separated by preparative tlc on silica gel (l00 MeOH/CHZC12) Isomer 1: 30 mg (90); MS: 325 m/z (M+H)'; 50:50 mix by HPLC
Isomer 2: 41 mg (13%}; MS: 325 m/z (M+H)'; 92:8 mix by HPLC
Example 182 Synthesis of Intermediate 49c (R6 - R' - H; R1 - Bn; Y = NCH3) N-(1-Oxo-2-methyl-1,2,3,4-tetrahydroisoquinoline-3-- 97 _ carbonyl)-L-phenylalaninol This compound was prepared according to General Procedure G. From compound 47 (250 mg, l.22 mmol) crude product (486 mg) was obtained as a mixture of diastereomers which were separated by preparative tlc on silica gel (5o MeOH/CHzCl2):
Isomer 1: 114 mg (28%); MS: 3:39 m/z (M+H)~;
Isomer 2: 107 mg {260) ; MS: 339 m/z (M+H) ~.
Example 183 Synthesis of Aldehyde 50a (R6 - R' - H; R1 - Bn; Y = NH) N-(1-Oxo-1,2,3,4-tetrahydroisoquinoline-3-carbonyl)-L
phenylalaninal This compound was prepared according to General Procedure I. From compound 48 (isomer 1; 28 mg, 0.09 mol) the title compound (13 mg, 460) was obtained; MS: 323 m/z (M+H)'.
Example 184 Synthesis of Aldehyde 50b (R6 - R' - H; R1 - Bn; Y = NH) N-(1-Oxo-1,2,3,4-tetrahydroisoquinoline-3-carbonyl)-L-phenylalaninal This compound was prepared according to General Procedure I. From compound 48 {isomer 2; 37 mg, 0.11 mol) the title compound (22 mg, 59%) was obtained; MS: 323 m/z (M+H)+.
Example l85 Synthesis of Aldehyde 50c (R6 - R'' - H; R1 - Bn; Y = NCH3) N-(1-Oxo-2-methyl-1,2,3,4-tetrahydroisoquinoline-3-carbonyl)-L-phenylalaninal This compound was prepared according to General Procedure I. From compound 49c (isomer 1; 43 mg, 0.13 mol) the title compound (22 mg, 510) was obtained; MS: 337 m/z (M+H)'.
Example 186 Synthesis of Aldehyde 50d (R6 - R'' - H; R1 - Bn; Y = NCH3) N-(1-Oxo-2-methyl-1,2,3,4-tetrahydroisoquinoline-3-carbonyl)-L-phenylalaninal This compound was prepared according to General Procedure I. From compound 49c (isomer 2; 39 mg, 0.12 mol) the title compound (30 mg, 77%) was obtained; MS: 337 m/z (M~-H)'.
Example 187 Synthesis of Bisulfate Addition Product of Aldehyde 12s N-(3,4-Dihydro-6,7-ethylenedioxy-2-ethyl-2H-1,2-benzothiazine-3-carbonyl)-L-phenylalaninal 1,1-dioxide, bisulfate addition compound To a solution of aldehyde 12s (Example 90) (200 mg, 0.45 mmol) in ethyl acetate (2 ml) was added water (1 ml) and sodium bisulfate (52 mg, 0.49 mmol). The mixture was stirred vigorously for 1.5 hours at ambient temperature.
The phases were separated and the organic phase was stirred for several minutes with water (1 ml). The combined aqueous phases were lyophilized to afford 214 mg (87%) of the title compound as a white solid; MS: 525 m/z (M-Na)-. ICSo (calpain), 8 nM.
Example 188 Inhibition of Cysteine Protease Activity To evaluate inhibitory activity, stock solutions (40 times concentrated) of each compound to be tested were prepared in 100% anhydrous DMSO and 5 mL of each inhibitor preparation were aliquoted into each of three wells of a 96-well plate.
Calpain I, prepared by a modification of the method of W. J.
Lee et al. (Biochem. Internatl. 22: 163-171 (1990), incorporated by reference herein in its entirety), was diluted into assay buffer (i.e., 50mM Tris, 50mM NaCl, 1mM
EDTA, 1mM EGTA, and 5mM-mercaptoethanol, pH 7.5 including 0.2mM Succ-Leu-Tyr-MNA (Enzyme Systems Products, Dublin, CA) and l75 mL aliquoted into the same wells containing the independent inhibitor stocks as well as to positive control wells containing 5 mL DMSO, but no compound. To start the reaction, 20 mL of 50 mM CaCl2 in assay buffer was added to each of the wells of the plate, excepting three, which were used as background signal baseline controls. Substrate hydrolysis was monitored every 5 minutes for a total of 30 - 99 _ minutes using a Fluoroskan II fluorescence plate reader.
Substrate hydrolysis in the absence of inhibitor was linear for up to 15 minutes.
Inhibition of calpain I activity was calculated as the percent decrease in the rate of ~;ubstrate hydrolysis in the presence of inhibitor relative to the rate in its absence.
Comparison between the inhibited and control rates was made within the linear range for substrate hydrolysis. For screening, compounds were tested at 10 mM. Compounds having 50o inhibition at 10 mM were considered active. The IC50s of inhibitors (concentration yielding 50°s inhibition) were determined from the percent decrease in the rates of substrate hydrolysis in the presence of five to seven different concentrations of the test compound. The results were plotted as percent inhibition versus log inhibitor concentration, and the IC50 was calculated from linear regression of the data. Results are presented in Tables II-VII and in Example 187.

Table II
Rl ~ Q
R6 , CONH- i t O
R7 \ S'.Y
O'~O
Cpd R6 R' R1 Y Q I CS
# 0 (nM) 12 OCH3 OCH3 I -Bu O H 13 0 a 12b OCH3 OCH~ Bn O H 51*

12c OCH3 OCH3 Bn NH H ~800a 12d OCH3 OCH~ Bn NH H ~700b 12 OCH3 OCH3 Bn NCH3 H 2 0 Oa a 12 OCH3 OCH3 Bn NCH3 H 3 8b f 12g OCH3 OCH3 Bn NBn H ~1000a 12h OCH3 OCH; Bn NBn H 150b l21 H H Bri NCH3 H 28a 12j H H Bn NCH3 H 110b 12k F H Bn NCH3 H 28a 121 C1 C1 Bri NCH3 H 21a 12m Cl Cl Bn NCH3 H 7b 12n C1 H Bn NiBu H ~200a 12o C1 H Bn NiBu H ~200'' 12p C1 H Bri NCH3 H 5a 12q C1 H Bn NCH3 H 15b 12r OCHZCHzO Bn NCH3 H 24*

12 OCHZCH20 Bri NEt H 7a S

12 OCHzCH20 Bn NEt H 3 3 b t 12u OCHzCH20 Bn NiPr H 30*

12V OCHZCHZO iBu NEt H ~300a 12w OCH2CH20 iBu NEt H 37b 12X OCHzCHzO ( CHZ ) 4NHSOzPhNCH3 H 3 6a 12y OCHZCH~O (CH2) QNHSO?PhNCH3 H 107b 12 Morpho H Bri NCH3 H ~ 5 0 Z lin-4- 0 a yl l2aa Morph H Bn NCH3 H 30b o-lin-4-WO 98/21 i86 PCT/US97/20782 - loi -13 OCHzCH20 Bn NEt COZCH3 ~1000 14A C1 H Bn NCH3 CONHEt ~1000 14B OCH~CH?O iBu NEt CONHBu ~1000a 14C OCHZCH20 iBu NEt CONHBu ~500F

* Mixture of diastereomers; a~h Si.ngle diastereomers Table I: I I
R~
~ Q
R6 ~ t:ONH- i I O
R7 \ S',Y
O'~O
R6 - R' - -OCHZCH20 Rl = Bn Cpd Y Q IC50 # (nM) 14D NEt CONHEt 340*

14E NEt CONHBu 50a 14F NEt CONHBu ~300h 14G NEt CONHBu 189*

14H NEt CONHCH~CH20CH3 ~2 0 14 I NEt CONHCH ( CH3 ) z 2 0 5 14J NEt CONH (CH2) QCH3 ~150*

14K NEt CONHCH2Ph 82*

14L NEt CONHCH?CHZPh 63 14M NEt CONHCHZCH=CHz ~200*

14N NEt CONH (CHZ) 3- (imidazol-1-yl) ~5000*

14O NEt CONH(CHZ)3-(2-ketopyrrolidin-1- ~500*
yl) 14P NEt CONH (CHZ) 3 (morpholin-4-yl) 195*

14Q NEt CONHCHZ(pyridin-2-yl) 170*

14R NEt CONHCH?-cyclopropane 286*

14S NEt CONHCH2CHZNHSOZCH3 89*

14T NEt CONHCHzCH2NHS0z (9:-N02-Ph) 47*

14U NEt CONH (CHz) 3NHS02 (9:-NO?-Ph) 50*

14V NEt CONHCHzCH2NHS02 (=~, 4-C12-Ph) 56*

14W NEt CONH (CH2) 3NHS02 (3, 4-C17-Ph) 56*

14X NEt CONHCHZCHzNHSO2Ph 40*

14 Y NEt CONHCH? CHZNHSO? { 5 - ( 2 - 2 0 pyridinyl)-thiophen-2-yl) 14 Z NE CONH { CHZ ) 3NHS02 ( 4 - F - 5 0 t Ph ) 14AA NEt CONH ( CHZ ) 3NHSOzPh 3 5 14AB NEt CONHCHZ- (pyridin-4-yl) 240*

14AC NEt CONHCHzCH?NHSOz (4-F-Ph) 29*

14AD NH CONHBu ~200*

14AE NH CONHCH~CHZNHSO~Ph 76*

* Mixture of diastereomers; ~~b Single diastereomers Table IV

R / \ CONH II
I O
R~ ~ S',Y
O'~O
Cpd R4 Rs R' R1 Y Q I C5 0 # (nM) 26a H Cl C1 Bn NCH3 H 15 26b H OCHzCH20 Bn NCH3 H 6 2 6 H OCH2CH~0 Bn NEt H 8 c 26d OCH, H H Bn NCH3 H 37 27e H OCHZCH20 Bn NCH3 CONHBu 2l0 2 7 H OCHZCH20 Bn NEt CONHBu 15 5 f 27g OCH3 H H Bn NCH CONHBu 900 27h OH H H Bn NCH3 CONHBu 10,000 Table V

R~

I Q
R6 / N\ /CONH
o R~ ~ O~S'O ~R9 Rl _ Bn; R6=H; R'-H
Cpd R9 R' Q IC50 # (nM) 35a Et Pr H ~1,OOOa 35b Et Pr H ~3 , 000'' 35c Et Bn H ~10~000 35d Et Bn H ~1, 000'' 35e CH3 H CONHBu ~2,000*

* Mixture of diastereorr~ers ;
a,b Single diastereomers Table 'JI

R6 N CO~ Q
'i ~ o R7 w S.NH
O' ' O
Rl - Bra Cpd R6 R' Q IC50 # (nM) 42a H H H 83 42b OCH2CH20 H 28 42c H H CONHBu 5,000 42d OCHZCH20 CONHBu ~10, 000 Table VII

Q

O
R7 ~ C~N~R9 I I
O
R1 - Bn; R6 - H; R' - H
Cpd R9 Q I C5 0 # (nM) 50a H H ~5000a 50b ~ H H ~5000b 50C CH3 H ~1000a 50d CH3 H 85b a,b Single diastereomers Example 189 Synthesis of 2,3-dihydrobenzothiazole Derivatives 2,3-Dihydrobenzothiazole derivatives (compounds of Formula I, where j - 0) Can be prepared from 2,3-dihydrobenzothiazole-3-carboxylates according to the methods specified in Scheme I and Examples 1-44. These intermediates can be formed by reduction of 3-hydroxy-2,3-dihydrobenzothiazole-3-carboxylates, described by J. Wrobel and A. Dietrich [Heterocycles 38, 1823 -1838 (1994), incorporated by reference herein in its entirety] with reagents including sodium cyanoborohydride, sodium borohydride, zinc-acetic acid, or catalytic hydrogenation by methods known to those skilled in the art. Alternatively, 2,3-dihydrobenzothiazole-3-carboxylates may be prepared by treating N-alkylbenzenesulfonamides with a strong base such as butyllithium followed by glyoxylic ester by a modification of the method of Wrobel and Dietrich.

Example 190 Synthesis of 4,5-dihydrobenzothiazepine Derivatives 4,5-Dihydrobenzothiazepine derivatives (compounds of Formula I, where j - 2) can be prepared from 4,5-dihydrobenzothiazepine-3-carboxy7_ates according to the methods specified in Scheme I and Examples 1-44. These intermediates can be synthesized by modification of previously reported methods. For example, 3-(m-chlorophenyl)propionaldehyde (prepared according to the method of H. Hashizume et al., Chem. Pharm. Bull. 42, 512 -520 (1994), incorporated by reference herein in its entirety), can be transformed into m-chlorohomophenylalanine by reaction with sodium cyanide and ammonium carbonate followed by hydrolysis. Treatment of m-chlorohomophenylalanine with chlorosulfonic acid by a modification of the procedure de:>cribed by H. Zenno and T.
Mizutani (Japanese patent application No. 7004990, 1966;
Chem. Abstr. 72, 111525, incorporated by reference herein in its entirety) affords 7-chloro-4,5-dihydrobenzothiazepine-3-carboxylate. Alternatively, 2-I;aminosulfonyl)phenyl-propanoic acid, described by P. C'atsoulacos and C. Camoutsis (J. Heterocycl. Chem. 13, 1309 - 1314 (1976), incorporated by reference herein in its entireay), may be reduced to the corresponding aldehyde, treated with cyanide, hydrolyzed with acid or base, and cyclized by the procedure of Catsoulacos and Camoutsis to give 4,5-dihydrobenzothiazepine -3-carboxylate.
It is intended that each of the patents, applications, printed publications, and other published documents mentioned or referred t:o in this specification be herein incorporated by reference in their entirety.
As those skilled in the art will appreciate, numerous changes and modifications may be made to the preferred embodiments of the invention without departing from the spirit of the invention. It is intended that all such variations fall within the :cope of the invention.

Claims (53)

WHAT IS CLAIMED IS:

1. A compound having the formula:
wherein:
A-B represents one, two, or three carbon atoms or nitrogen atoms, optionally connected by single bonds or one double bond, optionally substituted with one or more groups selected from the group consisting of R3, R4, OR3, OR4, R4a, and OR4a, with the proviso that the number of nitrogen atoms is 0, 1 or 2;
R1 and R2 are each independently hydrogen, alkyl having from one to about 14 carbons, cycloalkyl having from 3 to about 10 carbons, aryl, having from about 6 to about 14 carbons, heteroaryl having from about 6 to about 14 ring atoms, aralkyl having from about 7 to about 15 carbons, heteroaralkyl, or an optionally protected natural or unnatural side chain of an amino acid, said alkyl, cycloalkyl, aryl, and heteroaryl groups being optionally substituted with one or more K groups;
R3, R4 and R4a are each independently hydrogen, lower alkyl, or a natural or unnatural side chain of an optionally protected amino acid, said alkyl groups being optionally substituted with an aryl or heteroaryl group;
R5, R6, R7 and R8 are each independently hydrogen, alkyl having from one to about 14 carbons wherein said alkyl groups are optionally substituted with one or more K groups, alkoxy having from one to about 10 carbons, halogen, alkoxycarbonyl, carboxyl, hydroxyl, heterocyclic, or amino optionally substituted with 1 to 3 aryl or lower alkyl groups;
or any two adjacent R5, R6, R7 and R8 groups taken together with any intervening atoms of the benzene ring to which they are attached form an alicyclic, aromatic, heterocyclic, or heteroaryl ring having 5 to 8 ring atoms;
K is halogen, lower alkyl, lower alkenyl, aryl, heterocyclic, guanidino, nitro, alkoxycarbonyl, alkoxy, hydroxyl, carboxyl, arylaminosulfonyl, heteroarylaminosulfonyl, alkylaminosulfonyl, or amino optionally substituted with an alkylsulfonyl, arylsulfonyl, or heteroarylsulfonyl group, or with 1 to 3 aryl or lower alkyl groups, said alkyl, aryl, and heteroaryl groups being optionally substituted with one or more G groups;
G is the same as K;
Y is O, NH, NR9 or CHR9;
Z is S(=O)2, S(=O), S, or C(=O);
j is 0, 1 or 2;
Q is hydrogen, C(=O) NHR9, C(=O)OR9, CH=N2, or CH2R10;
R9 is hydrogen, alkyl having from one to about 10 carbons, said alkyl groups being optionally substituted with one or more K groups, aryl having from about 6 to about 14 carbons, or aralkyl having from about 7 to about 15 carbons;
R10 is aryloxy, heteroaryloxy, L, halogen, or has the formula O-M, wherein M has the structure:
wherein:
R is N or CR11;
W is a double bond or a single bond;
D is C=O or a single bond;
E and F are independently R12, R13, or J;

or E and F taken together comprise a joined moiety, said joined moiety being an aliphatic carbocyclic ring optionally substituted with J and having from 5 to 7 carbons, an aromatic carbocyclic ring optionally substituted with J and having from 5 to 7 carbons, an aliphatic heterocyclic ring optionally substituted with J and having from 5 to 7 atoms, or an aromatic heterocyclic ring optionally substituted with J and having from 5 to 7 atoms, said aliphatic heterocyclic ring or said aromatic heterocyclic ring each having from 1 to 4 heteroatoms;
R11, R12 and R13 are independently H, alkyl having from 1 to 10 carbons, heteroaryl having from 1 to 10 carbons, alkanoyl having from 1 to 10 carbons, or aroyl, wherein said alkyl, heteroaryl, alkanoyl and aroyl groups are optionally substituted with J;
J is halogen, C(=O)OR14, R14OC(=O) , R14OC(=O) NH, OH, CN, NO2, NR14R15, N=C(R14)R15, N=C(NR14R15)2, SR14, OR14, phenyl, napthyl, heteroaryl, or a cycloalkyl group having from 3 to 8 carbons;
R14 and R15 are independently H, alkyl having from 1 to carbons, aryl, or heteroaryl, wherein said alkyl, aryl and heteroaryl groups are optionally substituted with K;
L is a phosphorus-containing enzyme reactive group having the formula:
wherein:
m, n, and b are each independently 0 or 1;
R16 and R17 are each independently hydrogen, lower alkyl optionally substituted with K, aryl optionally substituted with K, or heteroaryl optionally substituted with K;
or R16 and R17 taken together with -(O)n-P(=O)-(O)m-can form a 5-8 membered ring containing up to 3 hetero atoms;
or R16 and R17 taken together with -(O)n-P(=O)-(O)m-ean form a 5-8 membered ring optionally substituted with K;
or a pharmaceutically acceptable salt or bisulfate addition product thereof.

2. The compound of claim 1 wherein A-B is -[CH(R4)]j-C(R3)-, -C(R4)=C-, -CH(OR4)-C(R3)-, -C(OR9)=C-, -N(R4)-C(R3)-, -N=C-, -C(R4a)=C(R4)-C(R3)-, or -CH(R4a)-C(R4)=C- where j is 0, 1, or 2.

3. The compound of claim 2 wherein A-B is -[CH(R4)]j-C(R3)- where j is 1, -C(R4)=C-, -N(R4)-C(R3)-, or -N=C-.

4. The compound of claim 3 wherein R3 and R4 are each H.

5. The compound of claim 1 wherein Z is SO2 or C(=O).

6. The compound of claim 5 wherein Z is SO2.

7. The compound of claim 1 wherein R2, R5 and R8 are each H.

8. The compound of claim 1 wherein R1 is alkyl or aralkyl.

9. The compound of claim 8 wherein R1 is i-butyl or benzyl.

10. The compound of claim 1 wherein R6 and R7 are independently H, alkoxy, halogen, or heterocyclic, or R6 and R7 taken together form -O-CH2-CH2-O-.

11. The compound of claim 10 wherein R6 and R7 are independently H, -OCH3, F, Cl, or morpholin-4-yl, or R6 and R7 taken together form -O-CH2-CH2-O-.

12. The compound of claim 1 wherein Q is H, C(=O)NHR9, or C(=O)OR9, where R9 is alkyl or alkyl substituted with K.

13. The compound of claim 1 wherein Y is O, NH, NR9 or CHR9, where R9 is alkyl or aralkyl.

14. The compound of claim 13 wherein Y is NR9 or CHR9, where R9 is methyl ethyl, propyl, i-butyl or benzyl.

15. The compound of claim 2 wherein A-B is -[CH(R4)]j-C(R3)-, -C(R4)=C-, -N(R4)-C(R3)-, or -N=C-; Z is SO2 or C(=O) ; R2, R5 and R8 are each H; R1 is alkyl or aralkyl; R6 and R7 are independently H, alkoxy, halogen, or heterocyclic, or R6 and R7 taken together form -O-CH2-CH2-O-;
Q is H, C(=O) NHR9, or C(=O) OR9, where R9 is alkyl or alkyl substituted with K; Y is O, NH, NR9 or CHR9, where R9 is alkyl or aralkyl.

16. The compound of claim 15 wherein Z is SO2.

17. The compound of claim 15 wherein R1 is i-butyl or benzyl.

18. The compound of claim 15 wherein R6 and R7 are independently H, -OCH3, F, Cl, or morpholin-4-yl, or R6 and R7 taken together form -O-CH2-CH2-O-.

19. The compound of claim 15 wherein Y is NR9 or CHR9, where R9 is methyl ethyl, propyl, i-butyl or benzyl.

20. The compound of claim 15 wherein A-B is -CH2-CH-.

21. The compound of claim 1 having the formula:
wherein:
R1 is alkyl, alkyl substituted with K, or aralkyl;
R6 and R7 are independently H, alkoxy, halogen, or heterocyclic, or R6 and R7 taken together form -O-CH2-CH2-O-;
Q is H, C(=O) NHR9, or C(=O)ORS, where R9 is alkyl;
and Y is O, NH or NR9 where R9 is alkyl or aralkyl.

22. The compound of claim 21 wherein R1 is i-butyl, benzyl, or alkyl substituted with phenylsulfonylamina.

23. The compound of claim 21 wherein R6 and R7 are independently H, OCH3, F, Cl, or morpholin-4-yl, or R6 and R7 taken together form -O-CH2-CH2-O-.

24. The compound of claim 21 wherein Q is C(=O)NHR9, or C(=O)OR9, where R9 is methyl, ethyl, or butyl.

25. The compound of claim 21 wherein Y is O, NH
or NR9, wherein R9 is methyl, ethyl, i-propyl, i-butyl or benzyl.

26. The compound of claim 21 wherein R1, R6, R7, Y and Q have the values shown in the horizontal rows of the following table:

OCH3 OCH3 i-Bu O H

OCH3 OCH3 Bn O H

OCH3 OCH3 Bn NH H

OCH3 OCH3 Bn NCH3 H

OCH3 OCH3 Bn NBn H

H H Bn NCH3 H

F H Bn NCH3 H

Cl Cl Bn NCH3 H

Cl H Bn NiBu H

Cl H Bn NCH3 H

OCH2CH2O Bn NCH3 H

OCH2CH2O Bn NEt H

OCH2CH2O Bn NiPr H

OCH2CH2O iBu NEt H

OCH2CH2O (CH2)4NHSO2Ph NCH3 H

Morpho- H Bn NCH3 H
lin-4-yl OCH2CH2O Bn NEt CO2CH3 Cl H Bn NCH3 CONHEt OCH2CH2O iBu NEt CONHBu

27. The compound of claim 1 having the formula:
wherein:
R1 is benzyl;
R6 and R7 taken together form -O-CH2-CH2-O-;
Y is N-H or NR9 wherein R9 is ethyl; and Q is C(=O)NHR9 where R9 is alkyl or alkyl substituted with K.

28. The compound of claim 27 wherein Q is CONHEt, CONHBu , CONHCH2CH2OCH3, CONHCH (CH3)2, CONH(CH2)4CH3, CONHCH2Ph, CONHCH2CH2Ph, CONHCH2CH=CH2, CONH (CH2)3-(imidazol-1-yl), CONH(CH2)3-(2-ketopyrrolidin-1-yl), CONH(CH2)3(morpholin-4-yl), CONHCH2 (pyridin-2-yl) , CONHCH2-cyclopropane, CONHCH2CH2NHSO2CH3, CONHCH2CH2NHSO2 (4-NO2-Ph) , CONH (CH2) 3NHSO2 (4-NO2-Ph), CONHCH2CH2NHSO2 (3,4-Cl2-Ph), CONH (CH2) 3NHSO2 (3,4-Cl2-Ph), CONHCH2CH2NHSO2Ph, CONHCH2CH2NHSO2(5-(2-pyridinyl)-thiophen-2-yl), CONH(CH2)3NHSO2(4-F-Ph), CONH (CH2) 3NHSO2Ph, CONHCH2- (pyridin-4-yl), or CONHCH2CH2NHSO2 (4-F-Ph).

29. The compound of claim 27 wherein Y and Q
have the values shown in the horizontal rows of the following table:
Y Q

NEt CONHEt NEt CONHBu NEt CONHCH2CH2OCH3 NEt CONHCH(CH3)2 NEt CONH(CH2) 4CH3 NEt CONHCH2Ph NEt CONHCH2CH2Ph NEt CONHCH2CH=CH2 NEt CONH(CH2)3-(imidazol-1-yl) NEt CONH (CH2)3- (2-ketopyrrolidin-1-yl) NEt CONH (CH2)3-(morpholin-4-yl) NEt CONHCH2(pyridin-2-yl) NEt CONHCH2-cyclopropane NEt CONHCH2CH2NHSO2CH3 NEt CONHCH2CH2NHSO2(4-NO2-Ph) NEt CONH (CH2) 3NHSO2 (4-NO2-Ph) NEt CONHCH2CH2NHSO2 (3,4-Cl2-Ph) NEt CONH(CH2)3NHSO2(3,4-Cl2-Ph) NEt CONHCH2CH2NHSO2Ph NEt CONHCH2CH2NHSO2(5-(2-pyridinyl)-thiophen-2-yl) NEt CONH (CH2) 3NHSO2(4-F-Ph) NEt CONH(CH2)3NHSO2Ph NEt CONHCH2-(pyridin-4-yl) NEt CONHCH2CH2NHSO2 (4-F-Ph) NH CONHBu NH CONHCH2CH2NHSO2Ph

30. The compound of claim 1 having the formula:
wherein:
R1 is benzyl;
R6 and R7 are independently H or halogen, or R6 and R7 taken together form -O-CH2-CH2-O-;
R4 is H, alkoxy, or hydroxy;
Y is NR9 wherein R9 is alkyl; and Q is H or C(=O)NHR9 where R9 is alkyl.

31. The compound of claim 30 wherein Q is H or CONHBu.

32. The compound of claim 30 wherein R6 and R7 are independently H or Cl, or R6 and R7 taken together form -O-CH2-CH2-O-.

33. The compound of claim 30 wherein R4 is H, methoxy, or hydroxy.

34. The compound of claim 30 wherein Y is NR9 wherein R9 is methyl or ethyl.

35. The compound of claim 30 wherein Y, Q, R1, R4, R6 and R7 have the values shown in the horizontal rows of the following table:

H Cl Cl Bn NCH3 H

H OCH2CH2O Bn NCH3 H

H OCH2CH2O Bn NEt H

OCH3 H H Bn NCH3 H

H OCH2CH2O Bn NCH3 CONHBu H OCH2CH2O Bn NEt CONHBu OCH3 H H Bn NCH3 CONHBu OH H H Bn NCH3 CONHBu

36. The compound of claim 1 having the formula:
wherein:
R1 is benzyl;
R6 and R7 are each H;
R4 is H, alkyl, or aralkyl;
R9 is alkyl; and Q is H or C (=O) NHR9 where R9 is alkyl .

37. The compound of claim 36 wherein R4 is H, propyl, or benzyl.

38. The compound of claim 36 wherein Q is H or CONHBu.

39. The compound of claim 36 wherein R9 is methyl or ethyl.

40. The compound of claim 36 wherein R9, R9 and Q
have the values shown in the horizontal rows of the following table:

Et Pr H

Et Bn H

CH3 H CONHBu

41. The compound of claim 1 having the formula:
wherein:
R1 is benzyl;
R6 and R7 are each H, or R6 and R7 taken together form -O-CH2-CH2-O-; and Q is H or C (=O) NHR9 where R9 is alkyl.

42. The compound of claim 41 wherein Q is H or CONHBu.

43. The compound of claim 41 wherein R6, R7 and Q
have the values shown in the horizontal rows of the following table:

H H H

H H CONHBu OCH2CH2O CONHBu

44. The compound of claim 1 having the formula:
wherein:
R1 is benzyl;
R6 and R7 are each H;
Q is H; and R9 is H or alkyl.

45. The compound of claim 44 wherein R9 is H or CH3.

46. The compound of claim 1 having the formula:
wherein:

R1 and R2 are each independently hydrogen, alkyl having from one to about 14 carbons, cycloalkyl having from 3 to about 10 carbons, aryl having from about 6 to about 14 carbons, heteroaryl having from about 6 to about 14 ring atoms, aralkyl having from about 7 to about 15 carbons, heteroaralkyl, or an optionally protected natural or unnatural side chain of an amino acid, said alkyl, cycloalkyl, aryl, and heteroaryl groups being optionally substituted with one or more K groups;
R3 and R4 are each independently hydrogen, lower alkyl, or a natural or unnatural side chain of an optionally protected amino acid, said alkyl groups being optionally substituted with an aryl or heteroaryl group;
R5, R6, R7 and R8 are each independently hydrogen, alkyl having from one to about 14 carbons wherein said alkyl groups are optionally substituted with one or more K groups, alkoxy having from one to about 10 carbons, halogen, alkoxycarbonyl, carboxyl, hydroxyl, or amino optionally substituted with 1 to 3 aryl or lower alkyl groups;
or any two adjacent R5, R6, R7 and R8 groups taken together with any intervening atoms of the benzene ring to which they are attached form an alicyclic, aromatic, heterocyclic, or heteroaryl ring having 5 to 8 ring atoms;
K is halogen, lower alkyl, aryl, heteroaryl, guanidino, alkoxycarbonyl, alkoxy, hydroxyl, carboxyl, or amino optionally substituted with 1 to 3 aryl or lower alkyl groups;
Y is O, NH, NHR9 or CHR9;
Z is S (=O) 2, S (=O) , S, or C(=O);
j is 0, 1 or 2;
Q i s H, C(=O) NHR9, C(=O) OR9, CH=N2, or CH2R10;
R9 is hydrogen, alkyl having from one to about 10 carbons, said alkyl groups being optionally substituted with one or more K groups, aryl having from about 6 to about 14 carbons, or aralkyl having from about 7 to about 15 carbons;
R10 is aryloxy, heteroaryloxy, L, halogen, or has the formula O-M, wherein M has the structure:

wherein:
R is N or CR11;
W is a double bond or a single bond;
D is C=O or a single bond;
E and F are independently R12, R13, or J;
or E and F taken together comprise a joined moiety, said joined moiety being an aliphatic carbocyclic ring optionally substituted with J and having from 5 to 7 carbons, an aromatic carbocyclic ring optionally substituted with J and having from 5 to 7 carbons, an aliphatic heterocyclic ring optionally substituted with J and having from 5 to 7 atoms, or an aromatic heterocyclic ring optionally substituted with J and having from 5 to 7 atoms, said aliphatic heterocyclic ring or said aromatic heterocyclic ring each having from 1 to 4 heteroatoms;
R11, R12, and R13 are independently H, alkyl having from 1 to 10 carbons, heteroaryl having from 1 to 10 carbons, alkanoyl having from 1 to 10 carbons, or aroyl, wherein said alkyl, heteroaryl, alkanoyl and aroyl groups are optionally substituted with J;
J is halogen, C (=O) OR14, R14OC (=O), R14OC (=O) NH, OH, CN , NO2, NR14R15, N=C (R14) R15, N=C (NR14R15)2, SR14 , OR14, phenyl, naphthyl, heteroaryl, or a cycloalkyl group having from 3 to 8 carbons;
R14 and R15 are independently H, alkyl having from 1 to 10 carbons, aryl, or heteroaryl, wherein said alkyl, aryl and heteroaryl groups are optionally substituted with K;
L is a phosphorus-containing enzyme reactive group having the formula:

wherein:
m, n, and b are each independently 0 or 1;
R16 and R17 are each independently hydrogen, lower alkyl optionally substituted with K, aryl optionally substituted with K, or heteroaryl optionally substituted with K;
or R16 and R17 taken together with - (O) n-P (=O) -(O)m- can form a 5-8 membered ring containing up to 3 hetero atoms;
or R16 and R17 taken together with - (O)n-P (=O) - (O) m-can form a 5-8 membered ring optionally substituted with K.

47. The compound of claim 1 wherein Z is SO.

48. The compound of claim 1 wherein Z is S.

49. The compound of claim 1 wherein Q is CH2R10.

50. The compound of claim 49 wherein R10 is -O-M.

51. The compound of claim 49 wherein R10 is -L.

52. The compound of claim 1 wherein Q is H.

53. The bisulfite addition product of the compound of claim 52.