CZ20001717A3 - Benzothiazole inhibitors of protein-tyrosine kinase - Google Patents

Abstract

The new benzothiazoles of formula I and their salts, pharmaceutical compositions comprising such compounds a methods of using such compounds for treating a disease associated with protein-tyrosine kinases such as e.g. immunological diseases.

Description

Benzothiazole protein-tyrosine kinase inhibitors

Technical field

The present invention relates to benzothiazoles and salts thereof, methods of using such compounds for the treatment of diseases related to protein tyrosine kinases, such as immunological diseases, and pharmaceutical compositions containing such compounds.

BACKGROUND OF THE INVENTION

Protein-tyrosine kinases (PKS) are enzymes that - using ATP as a substrate - phosphorylate tyrosine residues in peptides and proteins. These enzymes are key elements in the regulation of cell signaling, including cell proliferation and differentiation. ΡΤΚ include, but are not limited to, receptor tyrosine kinases (RPTKs), including members of the epidermal growth factor (e.g. HER1 and HER2) kinase family, platelet-derived growth factor (PDGF), and angiogenesis-relevant kinases (Tie-2 and KDR); and other non-receptor tyrosine kinases, including members of the Syk, JAK and Src (e.g., src, fyn, Lek, and blk) families (see Bolen, JB, Rowley, RB, Spana, C. and Tsygankov, AY). in hemopoietic signal transduction FASEB J., 6: 3403-3409 (1992), Ullrich, A. and Schlessinger, J., Transduction signal by receptors with tyrosine kinase activity, Cell 61: 203-212 (1990) and Ihle, JN , The Janus protein tyrosine kinases in hematopoietic cytokine signaling, Sem. Immunol. 7: 247-254 (1995)).

Increased PTK activity is anticipated in many malignant and non-malignant proliferative diseases. In addition, PTKs play a central role in the regulation of immune system cells. PTK inhibitors may therefore affect a wide variety of cancer and immunological diseases. Such diseases can be alleviated by the selective inhibition of some receptor or non-receptor

PTKs, such as Lck, or inhibition by multiple PTK inhibitors, which is possible due to homology between classes of PTKs.

A particularly important PTK is Lck, which has been shown in T cells where it participates in the phosphorylation of key protein substrates. It is required for receptor signaling after antigen binding and cell activation. In the absence of Lck activity, the zeta chain of the T cell receptor (TCR) is not phosphorylated, the ZAP-70 kinase is not activated and Ca ² * mobilization is essential for T cell activation (see Weiss, A. and Littman, DR, Tranduction signal by lymphocyte antigen receptors, Cell, 76: 263-274 (1994); Iwashima, R., Irving, BA, van Oers, NSC, Khan, AC, and Weiss, A., Sequential interactions of the TCR with two distinct cytoplasmic tyrosine kinases, Science, 263: 1136-1139 (1994) and Khan, AC, Dalton, M., Johnson, R., Kong, G., Wang,

T., Thoma, R. and Kurosaki, T., Activation of ZAP-70 kinase activity by tyrosine 493 phosphorylation is required for lymphocyte antigen receptor function, EMBO J., 14: 2499-2508 (1995)). Lk inhibitors are therefore useful for the treatment of T-cell mediated diseases such as chronic diseases with a significant T-cell component, such as rheumatoid arthritis, multiple sclerosis and lupus, as well as for the treatment of acute diseases in which a significant role of T cells, such as for example, acute transplant rejection and delayed hypersensitivity (DTH).

SUMMARY OF THE INVENTION

The present invention includes the benzthiazole compounds of formula I and salts thereof, which are used as inhibitors

p is e, 1, 2 or 3;

and X ₂ are both hydrogen, or taken together are = O or = S; each R is independently selected from the group consisting of:

(1) hydrogen or R, wherein R _e is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, aryl, aralkyl, heterocycle or heterocycloalkyl, each of which may be unsubstituted or substituted with Z Z ₂ and one or more (preferably one or two) Z ₃ groups;

(2) -OH or -0R _g;

(3) -SH or -SR ₆ ;

(4) -C (O) H, -C (O) R or -O-C (O) R, wherein q is 1 or 2;

(5) -SO H or -S (O) R;

C 6 (6) halogen;

(7) cyano;

(8) nitro;

(9) -Z-NR R;

* 7 e '(10) -Z -N (R) -Z -NR R';

4 '9 * 5 * 1, Q 1 (11) -Z -N (R) -Z R';

(12) -P (O) (OR ₆ ) ₂ ;

(13) any two R _x groups may be together an alkylene or alkenylene complementing a 3- to 8-membered saturated or unsaturated ring formed with the carbon atoms to which they are attached, which ring may be unsubstituted; or * (14) (1) (2) (1) (2) (3) (4) substituted with _{χ χ} , Z ₂ and Z ₃ ;

any two R _x groups may form, with the carbon atoms to which they are attached, a heterocyclic group which is unsubstituted or substituted by _{χ χ} , Z ₂ and Z ₃ ; are each independently selected from:

hydrogen or _Rg;

-Z -R; or

6 '(2) (3)

R and R

5 (1) (2) are each independently hydrogen or R _g ;

may, together with the nitrogen atom to which they are attached, complement a 3- to 8-membered heterocyclic ring, which ring may be unsubstituted or substituted by _{χ χ} , Z ₂ and Z ₃ , wherein said ring may optionally be fused to a benzene ring which is itself unsubstituted or substituted by Ζ _χ , Z ₂ and Z ₃ ;

R, R, R and R: they are each independently hydrogen or _Rg;

R ^ and _Rg may together be alkylene or alkenylene additional 3- to 8-membered saturated or unsaturated ring formed with the nitrogen to which they are attached, which ring may be unsubstituted or substituted _Ζ χ, Z ₂ and Z;

any two of R _g , R _xo and R may together be an alkylene or alkenylene supplementing a 3- to 8-membered saturated or unsaturated ring formed with the nitrogen atoms to which they are attached, which ring may be unsubstituted or substituted Ζ _χ , Z ₂ and Z ₃ ;

cyan;

nitro;

-NH;

-NHOalkyl;

• (S) -OH;

(6) -NHaryl;

(7) -NHCOOalkyl;

(8) -NHCOOaryl;

(9) -NHSO ₂ alkyl;

(10) -NHSO ₂ aryl;

(11) aryl;

(12) heteroaryl;

(13) -Oalkyl; or (14) -Oaryl;

R is:

(1) -NO ₂ ;

(2) -COOalkyl; or (3) -COOaryl;

Z, Z ₂ and Z ₃ are each independently:

(1) hydrogen or _Z, where Z _g is (i) alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, aryl, aralkyl, alkylaryl, cycloalkylaryl, heterocyclo, or heterocycloalkyl; (ii) a group (i) that is substituted by one or more of the same or different groups (i); or (iii) a group of (i) or (ii) which is substituted with one or more of the following groups (2) to (16), definitions Ζ _χ , Z ₂ and Z ₃ ;

(2) -OH or -OZ;

Fe (3) -SH or -sa _e;

(4) -C (O) H, -C (O) Z, or -O-C (O) Z;

<3 <36 6 <3 fe (5) -SO H or -S (O) Z;

<3 fe (6) halogen;

(7) cyano;

(8) nitro;

(9) -Z-ZZ;

(10) -Z -N (Z) -Z -NZ Z;

(11) -Z -N (Z) -Z Z;

'IO 5 6' • 0

(12) ₄ -Ζ -Ν _(Ζ ιθ) -Z _with -H;

(13) oxo;

(14) -OC (O) -Z _g ;

(15) any two of Ζ _χ , Z ₂ and Z ₃ may together be alkylene or alkenylene complementing a 3- to 8-membered saturated or unsaturated ring formed with the atoms to which they are attached; or (15) any two of _{χ χ} , Z ₂ and Z ₃ can be taken together -O- (CH) -O-;

<3

Z ₄ and Z _s are each independently:

(1) single bond;

(2) -Z 2 -SiO 2 -Z 2;

(3) -Z _xx -C (O) -Z _i2;

(4) -Z _xx -C (S) -Z _x2;

(7) _-Ζ χχ -0-0 (0) _-Ζ χ2; or (8) -Z _xx -C (O) -O- _{χ 2} ;

(1) are each independently hydrogen or _Zg ;

(2) Z ₇ and Ζθ or Z _g and Z may together be an alkylene or alkenylene supplementing a 3- to 8-membered saturated or unsaturated ring formed with the atoms to which they are attached, which ring may be unsubstituted or substituted by Z, Z and OF ;

i '2 3' (3) Z ₇ or Ζθ, together with _{Ζ χθ} may be together alkylene or alkenylene supplementing a 3- to 8-membered saturated or unsaturated ring formed with the nitrogen atoms to which they are attached, where this ring may be unsubstituted or substituted Ζ _χ , Z ₂ and Z ₃ ;

_{Ζ χχ} and _{Ζ χ2} are each independently:

(1) single bond;

(2) alkylene;

• • • •

(3) alkenylene; or (4) alkynylene; Yippee: (1) single bond; (2) -Z -S (O) -Z; (3) -Z -C (O) -Z; XX X2 (4) -Z-C (S) -Z; (5) -Z-O-Z; (6) -Z -S-Z; XX X2 ' (7) -Z-O-C (O) -Z XX X2 (8) -Ζ _χι -Ο (Ο) -Ο- _{Ζ ι 2} ; Italy (9) -C (NR ₁₃ ) -; (10) - (CHR ₁₄ ) -; or Italy (11) -C (C (R)) -. 14 2

The following definitions of terms are used in the present invention. The definitions used for the groups or terms set forth herein apply to the groups or terms set forth in the present invention, alone or as part of other groups, unless otherwise indicated.

The term alk or alkyl refers to a straight or branched chain hydrocarbon having 1 to 12 carbon atoms, preferably 1 to 8 carbon atoms. The term lower alkyl refers to an alkyl group having 1 to 4 carbon atoms.

The term alkenyl refers to a straight or branched chain hydrocarbon having 2 to 10, preferably 2 to 4, carbon atoms containing at least one double bond. When an alkenyl group is attached to a nitrogen atom, it is preferred that the group is not attached directly to the carbon atom that forms the double bond.

The term alkynyl refers to a straight or branched chain hydrocarbon having 2 to 10, preferably 2 to 4, carbon atoms containing at least one triple bond. If the alkynyl group is attached to a nitrogen atom, it is preferred that the alkynyl group is not attached directly to the carbon atom which forms the triple bond.

The term alkylene refers to a straight chain bridge of 1 to 5 carbon atoms linked by single bonds (for example - (CH) where x is 1 to 5), which may be substituted with 1 to 3 lower alkyl groups.

The term alkenylene refers to a straight chain bridge of 2 to 5 carbon atoms containing one or two double bonds in which the other carbon atoms are bonded by single bonds and which may be substituted by 1 to 3 lower alkyl groups. Examples of alkenylene groups are -CH = CH-CH = CH-,

-CH-CH = CH-, -CH-CH = CH-CH-; -C (CH) CH = CH- and -CH (C H) -CH = CH-.

The term alkynylene refers to a straight chain bridge of 2 to 5 carbon atoms containing a triple bond in which other carbon atoms are bonded by single bonds and which may be substituted with 1 to 3 lower alkyl groups. Examples of alkynylene groups are -CH = C-,

-CH-C = C-, -C (CH) C-C- and -C -CC-CH (C H) CH.

The term ar or aryl refers to phenyl, naphthyl and biphenyl.

The terms cycloalkyl and cycloalkynel refer to a cyclic hydrocarbon group of 3 to 12 carbon atoms.

The terms halogen and halo refer to fluorine, chlorine, bromine and iodine.

The term unsaturated ring includes partially unsaturated and aromatic rings.

The term heterocycle, heterocyclic and heterocyclo denote fully saturated or unsaturated, including aromatic (heteroaryl) or non-aromatic cyclic groups, for example 4 to 7-membered monocyclic, 7 to 11-membered bicyclic or 10 to 15-membered tricyclic ring systems containing at least one heteroatom in the ring containing at least one carbon atom. Each ring of the heteroatom-containing heterocyclic group may contain 1, 2, 3 or 4 heteroatoms selected from nitrogen, oxygen and / or sulfur atoms, wherein the nitrogen and sulfur heteroatoms may be optionally oxidized and the nitrogen heteroatom may optionally be quaternized. The heterocyclic group may be attached at any heteroatom or carbon atom of the ring or ring system.

Examples of monocyclic heterocyclic groups are pyrrolidine, pyrrolyl, pyrazolyl, oxetanyl, pyrazolinyl, imidazolyl, imidazolinyl, imidazolidinyl, oxazolyl, oxazolidinyl, isoxazolinyl, isoxazolyl, thiazolyl, thiazolidinyl, thiazolidinyl, isothiazolyl, isothiazolidinyl, isothiazolidinyl, isothiazolidinyl, isothiazolidinyl, isothiazolidinyl, , 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, 2-oxoazepinyl, azepinyl, 4-piperidonyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, tetrahydropyranyl, morpholinyl, thiamorpholinyl, thiamorpholinylsulfoxide, thiamorpholinylsulphone, thiamorpholinylsulphone , 1-dioxothienyl and the like.

Examples of bicyclic heterocyclic groups are indolyl, benzothiazolyl, benzoxazolyl, benzodioxolyl, benzothienyl, quinuclidinyl, quinolyl, tetrahydroisoquinolyl, isoquinolinyl, benzimidazolyl, benzopyranyl, indolizinyl, benzofuryl, chromonyl, coumarinyl, indino, quinolinyl, benzopyranyl, benzopyranyl, benzopyranyl, benzopyranyl; Pyrrolopyridyl, furopyridinyl (such as furo [3,2-c] pyridinyl, furo [3,2-b] pyridinyl or furo [2,3-b] pyridinyl), dihydroisoindolyl, dihydroquinazolinyl (such as

3,4-dihydro-4-oxo-quinazolinyl), tetrahydroquinolinyl and the like.

Examples of tricyclic heterocyclic groups are carbazolyl, benzidolyl, phenanthrolinyl, acridinyl, phenanthidinyl, xanthenyl and the like.

When q is 1 or 2, -C (O) -411 denotes -C (O) -H or -C (O) -OH; -C (O) R or -C (O) Z denote, respectively

G? 6 order, -C (O) -R or -C (O) -OR or -C (O) -Z or -C (O) -OZ; -O-C (O) R or -O-C (O) Z denote, respectively

CJ € cj € “* order, -0-C (0) -R _g or -OC (O) -OR _g or -OC (O) -Z _g or

-O-C (O) -OZ; and -S (O) R or -S (O) Z denote, respectively β β β order, -SO-R or -SO-R or -SO-Z or -SO -Z.

The compounds of formula I may in some cases form salts which are also within the scope of the present invention. The term compound of formula I is meant to include salts of said compound, unless otherwise indicated. The term salts as used herein refers to acidic and / or alkaline salts formed with inorganic and / or organic acids and bases. Bivalent (internal or internal) salts are included in the term salts as used herein (and may be formed, for example, when the R substituents contain an acid group such as a carboxyl group). The term salts also includes quaternary ammonium salts such as alkylammonium salts. Preferred are pharmaceutically acceptable (i.e., non-toxic, physiologically acceptable) salts, although other salts are useful, for example, in isolation and purification. Salts of compounds of formula I may be prepared, for example, by reacting a compound of formula I with a certain amount of acid or base, such as an equivalent salt.

amount, in a medium in which the salt precipitates or in an aqueous medium, and then freeze-dried.

Examples of acid addition salts are acetates (for example those formed with acetic acid or trihaloacetic acid, for example trifluoroacetic acid), adipates, alginates, ascorbates, aspartates, benzoates, benzenesulfonates, sulfites, borates, butyrates, citrates, camforates, camphorsulfanates, cyclopentane sulfonates, cyclopentane sulfonates, , digluconates, dodecyl sulfates, ethanesulfonates, fumarates, glucoheptanoates, glycerophosphates, hemisulfates, heptanoates, hexanoates, hydrochlorides, hydrobromides, hydroiodides, 2-hydroxyethanesulfonates, lactates, maleicates, methanesulfonates, 2-naphthalenesulfonates, p-naphthalenesulfonates, p-naphthalenesulfonates, -phenylpropionates, phosphates, picrates, pivlatates, propionates, salicylates, succinates, sulfates (including sulfates formed with sulfuric acid), sulfonates (such as those disclosed herein), tartrates, thiocyanates, toluenesulfonates such as tosylates, undecanoates and the like .

Examples of basic salts (formed, for example, when the R substituent contains an acidic group such as a carboxyl group) include ammonium salts, alkali metal salts such as sodium, lithium and potassium salts, alkaline earth metal salts such as calcium salts and magnesium, psole formed with organic bases (e.g. organic amines) such as benzathines, dicyclohexylamines, hydrabamines, N-methyl-D-glucamines, N-methyl-D-glucamides, t-butylamines and salts with amino acids such as arginine, lysine etc. The nitrogen-containing basic groups can be quaternized using reagents such as lower alkyl halides (e.g. methyl, ethyl, propyl and butyl chlorides, bromides and iodides), diacyl sulfates (e.g. dimethyl, diethyl, dibutyl and diamyl sulfates), long halides Chain (e.g., decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides), aralkyl halides (e.g., beznyl and phenethyl bromides) and the like.

Prodrugs and solvates of the compounds of the present invention are also within the scope of the present invention. The term prodrug, as used herein, refers to a compound that upon administration to an individual undergoes chemical conversion by metabolic or chemical processes that results in the formation of a compound of Formula I or a salt and / or solvate thereof. The solvates of the compounds of formula I are preferably hydrates.

All stereoisomers of the compounds of the present invention, such as those formed by asymmetric carbon on the R substituents of the compound of formula I, including enantiomers and diastereomeric forms, are within the scope of the present invention. The individual stereoisomers of the compounds of the present invention may be, for example, free of other isomers, or may be in admixture, for example, as racemic mixtures or mixtures of all stereoisomers or otherwise selected stereoisomers. The chiral centers of the compounds of the present invention may have the S or R configuration as defined in IUPAC 1974 Recommendations.

In the present invention, the groups and their substituents are selected so as to obtain stable groups and compounds.

Preferred compounds

Compounds of formula I and salts thereof wherein one or more, preferably all, of ρ, _Χ χ, X _2, R _x, R _z, R _3, R ₄ and R _s are selected from the following definitions, are preferred compounds of the present invention:

p is 0 or 1;

each R is independently selected from the group consisting of hydrogen, halogen, alkyl or alkoxy;

Χ _χ and X ₂ together form = 0 or = S;

R ₂ is hydrogen;

3 ^R 3 ^e is selected from the group consisting of hydrogen, alkyl, -Z ₄ -Z -R _g or NR R;

V β '

R is hydrogen; and

_R is selected from aryl groups which are substituted _Ζ χ, Z ₂ and one or more (for example one or two) groups Z _3rd

Particularly preferred are those compounds wherein the -C (X) (X) -N (R) (R) group in Formula I is attached at the 6-position

X 2 4 S of benzothiazole skeleton.

Methods of preparation

Compounds of formula I may be prepared by the methods outlined in Reaction Schemes A to C and I to X. Solvents, temperatures, pressures and other reaction conditions may be readily selected by one skilled in the art. All cited documents are hereby incorporated by reference in their entirety. Starting materials are commercially available or can be readily prepared by one skilled in the art.

A person skilled in the art is able to prepare the compounds of the present invention after studying the present invention and the documents cited herein.

• ft ftftftft ftft • ftft ftftft

Scheme A shows a general process for the preparation of compound Ia, which is compound I, wherein X and X ₂ together form = 0. As shown in Scheme A, 2-amino-substituted benzothiazolecarboxylate ϋ can be prepared by reacting a suitably substituted aminobenzoate with sodium or potassium thiocyanate and bromine in an acidic solvent such as acetic acid (see US Patent No. 5496816). R 'is a protecting group for a carboxyl group such as alkyl or arylalkyl.

Compound 1a, where R ₂ and R ₃ are hydrogen, can be prepared by saponification ii, followed by reaction with amine iy, which is this 4 The process is carried out in a manner well known in the art. Alternatively, it may be reacted with R ₂ L, where L is a leaving group such as halogen (e.g. in an equimolar amount), followed by optionally reacting with R ₃ L (e.g. in an equimolar amount) to form iii. Compound iii can then be saponified and reacted with amine iv to give 1a where R ₂ and / or R ₃ are other than hydrogen.

Methods for preparing preferred substituents in compounds I are set forth in Schemes I through X below.

Scheme B shows a general process for preparing Compound 1b, which is Compound I, wherein X and X ₂ together form = S. As shown in Scheme B, the compound of Formula Ia obtained in Scheme A can be converted to the corresponding thioamide 1b using reagents such as Lawesson's reagent (2,4-bis (4-methoxyphenyl) -1,3-dithia-2,4 diphosphetane-2,4-disulfide (see Bull. Soc. Chim. Belg. 87: 223 (1978)).

Methods for preparing preferred substituents in compounds I are set forth in Schemes I through X below.

Ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft

Scheme C shows a general process for preparing Compound 1c, which is Compound I, wherein both Χ _χ and X _{2 are} hydrogen. As shown in Scheme C, the compound of Formula Ib obtained in Scheme B can be converted to the corresponding amine IC by reduction, for example, by reaction with Raney nickel.

Methods for preparing preferred substituents in compounds I are set forth in Schemes I through X below.

• «· ·

Scheme I

(A) p synthesize peptide bonds, i.e. kontakts _f q

OR (B) synthesis via acid chloride, i.

(1) thionyl chloride or oxalic chloride ⁽²⁾ JU nhČiy

R5

Xd

R 5 = COOR 6 X 1, Xa = O 2: R 2 = alkyl, arylalkyl, or C 1-6 alkylalkyl of 13 * R 2 -R 1

As shown in Scheme I, the carboxylate ii can be reacted with chloroform or dicarbonate of the ring 1. Compound 1 can be reacted with a base such as sodium hydride, sodium / potassium hexamethyldisilazide or lithium diisopropylamide (LDA) and an alkylating agent R 1 X where X is halogen and R ₂ is preferably alkyl, arylalkyl, or cycloalkyl, and then can be saponified with an aqueous base such as potassium hydroxide to give 2. Alternatively, compound 1 can be simply saponified with an aqueous base such as potassium hydroxide to form a potassium hydroxide. where R ₂ is hydrogen.

Acid 2 can be reacted with amine iv using reaction conditions well known in the art for peptide bond synthesis (see, for example, Bodanszky and Bodanszky, The Practice of Peptide Chemistry, Springer-Verlag, 1984; Bodanszky, Principles of Peptide Synthesis, Springer-Verlag). , 1984), to obtain compound Id, which is a compound of formula I, wherein X and X ₂ together form = O

R ₃ is COOR _g and, since 2 is the starting material, R ₂ is preferably alkyl, arylalkyl or cycloalkylalkyl. For example, agents that activate carboxyl group 2 for reaction with amine iv include bis- (2-oxo-3-oxazolidinyl) -phosphine chloride (BOP chloride), benzotriazol-1-yloxy-tris (dimethylamino) phosphonium hexafluorophosphate (BOP) reagent), [0- (7-azabenzotriazol-1-yl) -1,1,3,3-tetramethyluronium] hexafluorophosphate (HATU) and carbodiimides such as dicyclohexylcarbodiimide (DCC) or 3-ethyl-3 '- (dimethylamino) propylcarbodiimide (EDCI), either alone or in combination with hydroxybenzotriazole. Alternatively, the activated ester intermediate may be isolated and then reacted with a suitable amine iv in an aprotic solvent such as tetrahydrofuran (THF) or dimethylformamide (DMF) in the presence of a base such as an organic base such as sodium / potassium hexamethyldisilazide, triethylamine, diisopropylethylamine or 1. 8-diazabicyclo [5.4.0] undec-7-ene (DBU), or in the presence of an inorganic base such as sodium, potassium or cesium carbonate or sodium or potassium hydride. Alternatively, the acid halide 2 can be prepared, for example by reaction with thionyl chloride or oxalyl chloride, followed by further reaction with amine iv to give compound Id.

Similar reactions to those used to convert 2 to 1d can be used to convert 3 to 1d where R ₂ is hydrogen.

• · · ·

X 1, X ₂ = H 2> R 3 * H

As shown in Scheme II, acid 4 wherein R ₂ and R ₃ are other than hydrogen and are selected such that the nitrogen to which they are attached is non-basic is reduced to the aldehyde 5 by methods well known in the art (see March, Advanced Organic Chemistry, Wiley, 1985). For example, acid 4 can be converted to the corresponding ester and then reduced with diisobutylaluminum hydride. Alternatively, acid 4 may be reduced to the corresponding primary alcohol, for example by reaction with borane / THF, LiAlH 4, or by reduction of mixed anhydrides followed by oxidation to aldehyde 5 using Cr (IV) (e.g. pyridinium chlorochroman, PCC) or using Swern or Moffatt conditions (e.g., (COCl ₂ / dimethylsilfoxid). the starting acid 4 may be obtained, for example, saponification of iii.

Reductive amination (see Hudlicky, Reductions in Organic

Chemistry, Wiley, 1984) of aldehyde 5 with an amine iv in the presence of a reducing agent such as NaBH ₃ CN, NaBH (OAc) ₃ (Ac = acetyl) or hydrogen and a palladium catalyst yields the amine compound Ie which is a compound of formula I wherein X ₁ and X ₂ are both

Scheme III

X _n , X ₂ = H

As shown in Scheme III, reduction of acid 4 to a primary alcohol (e.g., by reaction with borane / tetrahydrofuran, LiAlH 4 or mixed anhydride reduction) followed by conversion using methods well known in the art (see March, Advanced Organic Chemistry, Wiley, 1985) yields compound 6 which contains a leaving group such as halide, tosylate (OTs), mesylate (OMs) or triflate (OTf). The groups R ₂ and R ₃ are selected such that the resulting nitrogen to which they are attached is non-basic. Compound 6 can then be converted to compound If, by substitution with an amine iv, preferably such that the amine iv is used in excess.

Scheme IV

_R2 = any group as defined _R3 = acyl or thioacyl

Amide / thioamide

Λ ^z

R _and OH

-3- »

Λ ^a

R _and X (X = halogen)

λ ²

ReO Cl or

IQ

Urea / thiourea

[χ ,, χ, .η]

Scheme IV illustrates methods that can be used to prepare compounds of Formula I (ie, Ih, Ii, Ij, Ik and II), wherein R ₂ is any of the groups defined above, and R ₃ is acyl

or thioacyl, _{χ χ} and X ₂ are other than hydrogen and R _x is not a primary or secondary amine. The starting compound Ig can be prepared by the methods described herein.

Amide Ih can be prepared by reacting the amine compound Ig with carboxylic acid 7 in the presence of a reagent that activates the carboxyl group for the reaction as described above, for example BOP reagent, HATU and carbodiimides such as DCC or EDCI either alone or in combination with hydroxybenztriazole . Alternatively, the acid halide 8 can be reacted with an amine compound Ig in the presence of an acid acceptor such as diisopropylethylamine. The corresponding thioamide 1i can be prepared by reacting the amide Ih (where Χ _χ , Χ ₂ 3 ^SOU other than 0) with Lawesson's reagent as described above.

Carbamate 1j can be prepared by reacting the amine compound Ig with chloroformate 9 or dicarbonate 10 in the presence of an acid acceptor such as diisopropylethylamine.

The urea Ik may be prepared by reacting the amine compound Ig either with: 1) chloroformate 9, such as phenyl chloroformate, followed by reaction with amine 11; 2) carbamoyl chloride 12 in the presence of an acid acceptor such as diisopropylethylamine; or 3) reaction with isocyanate 13a (where R _c in Ik = H). The corresponding thiourea II can be prepared by reacting the amine compound Ig with thioisocyanate 13b.

R _a is selected from the groups defined for R _g , such that the group

-C (= A) -R _a is an acyl or thioacyl group as defined in R ₃ . R and R _c are selected from those groups defined for R ₇ and _Rg such that the group -C (= A) -N (R) (R _c) is an acyl or thioacyl group corresponding definitions of R _3rd

Scheme V

R _z = any group of defined groups except acyl R ₃ = alkyl, cycloalkyl, cycloalkylalkyl, cycloalkenylalkyl, aralkyl or saturated heterocycle

O

->

reductive amination of t-butylnitrite / CuX et al

NaNO ₂ / H ⁺ / CuX X = halogen

- >>

base

Scheme V illustrates a method that can be used to prepare In, which is a compound of formula I, wherein R ₂ is any group of defined groups except acyl which is selected such that the nitrogen to which it is attached is basic, R ₃ is alkyl, cycloalkyl, cycloalkylalkyl, cycloalkenylalkyl, aralkyl or a saturated heterocycle and Χ _χ and X ₂ together are oxygen. Starting compounds • ·

Im and Io can be prepared by the methods described herein.

As shown in Scheme V, the amine compound Im is reacted with an aldehyde or ketone 14 under reductive amination conditions as described above to yield the amine In. Compound In can also be prepared by reacting an aminobenzothiazole Io, where R ₂ and R ₃ are hydrogen, with T-butyl nitrite or sodium nitrite in the presence of a copper (I) halide to give a halogen substituted benzothiazole 15 and then amine substitution in the presence of a base such as hydride sodium or potassium or the like (see Lee et al., J. Heterocyclic Chemistry, 22: 1621 (1985)).

and R _e are independently selected from the group consisting of hydrogen, alkyl, aryl, cycloalkyl or cycloalkenyl, or together form an alkylene or alkenylene complementing a 3- to 8-membered saturated or unsaturated ring such that the -CH 2 R 6 group (R _e ) is a group corresponding to the definition of R _3rd

Scheme VI

_R2 = any group defined groups except acyl _R3 = aryl, heteroaryl,

As shown in Scheme VI, where R ₂ is any group of defined groups except acyl which is selected such that the nitrogen to which it is attached is basic, R _a is aryl or heteroaryl and Χ _χ and X ₂ are other than hydrogen, the amine compound Ip can be reacted with a halophenyl or a halo heteroaromatic group 17 in the presence of a palladium (0) catalyst (see J. Am. Chem. Soc., 118, 7215 (1996)) to obtain an amine Iq which is a compound of formula I which contains the substituents shown in this scheme. The starting compound Ip can be prepared by the methods described herein.

Scheme VII

_R2 = any group defined groups

Heteroaryl _and R =

As shown in Scheme VII, wherein R ₂ is any of the defined groups and R ₃ is heteroaryl, the amine compound Ir can be reacted with a 2-halo-substituted heteroaromatic compound 17 in which Q, together with the atoms to which it is attached, forms 5 a 6-membered monocyclic or 10- to 12-membered bicyclic heteroaromatic group (for example, 2-chloropyridine or 2-chloropyrimidine) to give amine Is, which is a compound of formula I which contains the substituents shown in this scheme. The starting compound Ir can be prepared by the methods described herein.

• 0

,Ι, Χζ * Η]

As shown in Scheme VIII, the thiourea compound II (where _{χ χ} and X ₂ are other than hydrogen) can be reacted with a suitable amine in the presence of bis- (2-oxo-3-oxazolidinyl) -phosphine chloride (BOP chloride), benzotriazole-1. -yloxy-tris- (dimethylamino) phosphonium hexafluorophosphate (BOP reagents), [0- (7-azabenzotriazol-1-yl) -1,1,3,3-tetramethyluronium] hexafluorophosphate (HATU) and carbodiimide such as dicyclohexylcarbodiimide (DCC) ) or 3-ethyl-3 '- (dimethylamino) propylcarbodiimide (EDCI) or diisopropylcarbodiimide (DIC) in the presence of an organic base such as triethylamine, diisopropylethylamine or dimethylaminopyridine, in solvents such as dimethylformamide, dichloromethane or tetrahydrofuran, to give compound It.

Alternatively, compound II can be reacted with a suitable amine in the presence of a mercuric salt, such as mercuric chloride, to obtain It, or other methods known in the literature can be used.

R _{X is} -CO ₂ alkyl, CN, CO 2 aryl

HN

Ip

Rs

IX1 X ₂ H]

As shown in Scheme IX, the amine Ip (where _{χ χ} and X ₂ are other than hydrogen) can react with diphenylcyanecarbonimidate, either alone or in the presence of a base such as sodium hydride, sodium hexamethyldisilazide or dimethylaminopyridine, in acetonitrile or tetrahydrofuran or dimethylformamide. , at ambient temperature or at elevated temperature, to yield intermediate Iu, which can be reacted with an amine (R _in R _e NH) to give compound It (where R = cyanide).

• · ·

[* ₂ * Η]

As shown in Scheme X, the amine Ip (where X and X ₂ are other than hydrogen) can be reacted with compound 17 or 18, either alone or in the presence of a base such as sodium hydride, sodium hexamethyldisilazide or dimethylaminopyridine, in dimethylformamide or tetrahydrofuran, at ambient temperature or at elevated temperature, to obtain compounds IV or Iw, respectively, that can be reacted with an amine (R ₇ R _with NH) at ambient temperature or higher to give compounds Ix or Iy, respectively.

Use

The compounds of the present invention inhibit protein tyrosine kinases, particularly Lκ, and various degrees of Src family kinase such as Fyn, Lyn, Src, Yes, Hek, Fgr, and Blk. Therefore, they are useful for the treatment, including prophylactic and therapeutic treatment, of diseases associated with protein-tyrosine kinase, such as immunological and oncological diseases. The term protein-tyrosine kinase-associated diseases refers to those diseases that arise from improper protein-tyrosine kinase activity and / or which are alleviated by inhibition of one or more of these enzymes. For example, Lck inhibitors are important for the treatment of many such diseases (for example, for the treatment of autoimmune diseases) because inhibition of Lck blocks T cell activation.

The compounds of the present invention block T cell activation. The treatment of T cell mediated diseases, including inhibition of T cell activation and proliferation, is a particularly preferred embodiment of the present invention. Compounds that selectively inhibit T cell activation and proliferation are preferred compounds. Compounds of the present invention that block PTK activation of endothelial cells by oxidative stress, thereby limiting surface expression of adhesion molecules that induce neutrophil binding, and that inhibit PTKs required for neutrophil activation, are useful, for example, for the treatment of ischemia and reperfusion injury.

Accordingly, the present invention provides a method for treating diseases associated with protein-tyrosine kinases, wherein an individual is administered an effective amount of at least one compound of Formula I. Other therapeutic agents, such as those described below, may be used in conjunction with the compounds of the present invention. In the methods of the present invention, such therapeutic agents may be administered before, concurrently with, or after administration of the compounds of the present invention.

The use of the compounds of the present invention in the treatment of diseases associated with protein-tyrosine kinase is exemplified by their use, for example: for the treatment of transplant rejections (e.g., organ transplant, acute transplant or heterotransplant or homotransplant (such as burns)); for the prevention of ischemic or reperfusion injury following organ transplantation, myocardial infarction, stroke or other conditions; for inducing graft tolerance; for the treatment of arthritis (such as rheumatoid arthritis, psoriatic arthritis or osteoarthritis); multiple sclerosis; inflammatory bowel diseases such as ulcerative colitis and Crohn's disease; for the treatment of lupus (e.g. systemic lupus erythematosus); for treating graft versus host disease; for the treatment of T-cell mediated hypersensitivity, including contact hypersensitivity, delayed type hypersensitivity, and gluten enteropathy (celiac disease); psoriasis; contact dermatitis (including ivy allergy); Hashimoto's thyroiditis; Sjogren's syndrome; autoimmune hyperthyroidism such as Graves disease; Adison's disease (adrenal autoimmune disease); autoimmune polyglandular disease (also known as autoimmune polyglandular syndrome); autoimmune alopecia; pernicious anemia; vitiliga; autoimmune hypopituitarism; Guiilain_barre syndrome; other autoimmune diseases; further, for the treatment of tumors in which the Lek kinases or other Src-family kinases such as colorectal cancer and thymoma are activated or overexpressed, or for the treatment of tumors in which the Src family kinase facilitates tumor growth and survival; for the treatment of glomerulonephritis, serum disease; urticarie; allergic diseases such as respiratory allergies (asthma, hay fever, allergic rhinitis) or skin allergies; scleracierma; mycosis

31:

fungoides; acute inflammatory reactions (such as acute respiratory distress syndrome and ischemic / reperfusion injury); dermatomyositis; alopecia areata; chronic actinic dermatitis; ekzemu; Behcet's disease; pustulosis pamoplantaris; pyoderma gangrenosum; Sezary's syndrome; atopic dermatitis; systemophé sclerosis and morphea. The present invention also includes a method for treating the above diseases, such as atopic dermatitis, by administering any compound that inhibits protein tyrosine kinases.

Non-Lk Src family kinases, such as Hek and Fgr, are important in the Fc gamma receptor-induced respiratory burst of neutrophils, as well as in the Fc gamma receptor-induced monocyte and macrophage response. The compounds of the present invention inhibit Fc gamma receptor-induced respiratory burst of neutrophils. The ability to inhibit the responses of neutrophils and potentially other cells induced by the Fc gamma receptor may result in further anti-inflammatory activity of the compounds of the present invention, in addition to their effects on T cells. Activity against T-cells and potentially other cells is particularly important, for example, in the treatment of inflammatory diseases such as arthritis or inflammatory bowel diseases. In particular, the compounds of the present invention are important for the treatment of autoimmune glomerulonephritis and, and in cases of glomerulonephritis, induced by immunocomplex deposition in the kidney, which triggers an Fc receptor response that leads to renal damage.

In addition, non-Lk Src family kinases such as Lyn and Src are important in Fc epsilon receptor-induced mast cell and basophil degranulation, which plays a major role in asthma, allergic rhinitis and other allergic diseases. Fc-epsilon receptors are stimulated by IgE-antigen complexes. The compounds of the present invention inhibit degranulation induced by this to this to this to this to this to this to

Fc-epsilon receptor, even in the basophil cell line RBL, which does not express Lck. The ability to inhibit the response of basophils and mast cells to Fc-epsilon receptor activation may result in additional anti-inflammatory activity of the compounds of the present invention in addition to their T cell effects. The activity of the compounds against T cells suggests that they may be useful for the treatment of asthma, allergic rhinitis and other allergic diseases. The activity of the compounds of the present invention against mast cells and basophils may be potentially beneficial in the treatment of such diseases.

The activity of the compounds of the present invention against T cells is of importance in the treatment of any of the above diseases.

Further, the potential of combined activity against T cells, neutrophils and other cells may be of additional importance in the treatment of any of the above diseases.

In a particular embodiment, the compounds of the present invention are useful for the treatment of the aforementioned diseases regardless of their etiology, for example, for the treatment of transplant rejection, rheumatoid arthritis, multiple sclerosis, inflammatory bowel disease, lupus, graft versus host disease, T-cell mediated hyersensitivity, psoriasis Hashimoto's thyroiditis, Guiilain-Barre syndrome, tumors, contact dermatitis, allergic diseases such as allergic rhinitis, asthma, ischemic or reperfusion injury, or atopic dermatitis, whether or not associated with PTK.

The present invention also comprises pharmaceutical compositions comprising at least one of the compounds of Formula I capable of treating a protein-tyrosine kinase-associated disease in an amount effective for said treatment, and a pharmaceutically acceptable vehicle or diluent. The compositions of the present invention may contain other therapeutic agents as described below, and may be prepared, for example, using conventional solid or liquid vehicles or diluents, as well as pharmaceutical auxiliaries which are suitable for the selected method. administration (e.g., additives, swelling agents, preservatives, stabilizing agents, flavoring agents and the like), using techniques well known in the art of preparing pharmaceutical compositions.

The compounds of formula I may be administered by any suitable route, for example orally, for example in the form of tablets, capsules or granules or powders; sublingually; buccally; parenterally, for example by subcutaneous, intravenous, intramuscular or intrasternal injection or infusion (for example, in the form of a sterile injectable aqueous or non-aqueous solution or suspension); nasally, for example in an inhalation spray; topically, for example in the form of a cream or ointment; or rectally, for example in the form of suppositories; in compositions comprising a dosage unit and non-toxic, pharmaceutically acceptable carriers or diluents. The compounds of the present invention may be administered in a form suitable for immediate release or in a form suitable for sustained release. Immediate or sustained release may be achieved using suitable pharmaceutical compositions containing the compounds of the present invention, or, in particular, in the case of sustained release compositions, using subcutaneous implants or osmotic pumps. The compounds of the present invention may also be administered in liposomal form.

Examples of compositions for oral administration are suspensions which may contain, for example, microcrystalline cellulose to achieve a certain volume of the composition, alginic acid or sodium alginate as a suspending agent, methylcellulose as a viscosity enhancing agent, and sweeteners or flavoring agents known in the art; immediate-release tablets, as well as immediate release tablets.

Which may contain, for example, microcrystalline cellulose, calcium dicalcium phosphate, starch, magnesium stearate, and the like. and / or lactose and / or other additives, binders, bulking agents, disintegrants, diluents and glidants as known in the art. The compounds of the present invention may be administered into the oral cavity by sublingual and / or buccal administration. Cast tablets, compressed tablets or lyophilized tablets are examples of forms that can be used. Exemplary compositions are those compositions comprising a compound of the present invention with a rapidly soluble diluent, such as mannitol, lactose, sucrose, and / or cyclodextrins. Such compositions may also contain high molecular weight additives such as celluloses (avicel) or polyethylene glycols (PEG). Such compositions may also include mucosal adhesion promoters such as hydroxypropylcellulose (HPC), hydroxypropylmethylcellulose (HPMC), sodium carboxymethylcellulose (SCMC), maleic anhydride copolymer (e.g. Gantrez) and release rate control agents such as polyacrylate copolymer ( for example, Carbopol 934). Moisturizing agents, glidants, flavoring agents, coloring agents and stabilizing agents may also be used to facilitate manufacture and use.

Examples of compositions for nasal aerosol or inhalation administration include saline solutions which may contain, for example, benzyl alcohol or other suitable preservatives, absorption enhancers to increase bioavailability, and / or other suitable solubilizing or dispersing agents known in the art.

Examples of compositions for parenteral administration are injectable solutions or suspensions, which may contain, for example, suitable non-toxic, parenterally acceptable diluents or solvents, such as 3 ', 3 &apos;. · · · · · · · · · · · · · · · ·

Such as mannitol, 1,3-butanediol, water, Ringr's solution, istonic sodium chloride solution, or other suitable dispersing or wetting and suspending agents, including synthetic mono- or diglycerides, and fatty acids, including oleic acid.

Examples of formulations for rectal administration are suppositories which may contain, for example, suitable non-irritating ingredients such as cocoa butter, esters of synthetic glycerides or polyethylene glycols which are solid at ambient temperature but which melt and / or dissolve in the rectum and thereby they release the drug.

Examples of topical formulations are carriers for topical formulations, such as Plastibase (polyethylene gelatinized mineral oil).

An effective amount of a compound of the present invention can be determined by one of ordinary skill in the art, and is an adult dose ranging from about 0.1 to 100 mg / kg body weight of active compound per day, which can be administered in single or divided doses. , for example, 1 to 4 times a day. It will be appreciated that the particular dosages and frequency of dosing to any particular subject depend on many factors, including the activity of the particular compound used, its metabolic activity and its duration, species, age, body weight, general health, sex and dietary habits of the individual. and the mode and time of administration, rate of excretion, drug combinations, and severity of the condition being treated. Preferred subjects for treatment are animals, more preferably mammals, such as humans, and pets, such as dogs, cats, and the like, which suffer from a protein-tyrosine kinase-related disease.

The compounds of the present invention may be used alone or in combination with each other and with other suitable therapeutic agents suitable for the treatment of diseases associated with protein-tyrosine kinase, such as PTK inhibitors other than those of the present invention, anti-inflammatory agents , antiproliferative agents, chemotherapeutic agents, and immunosuppressants.

Examples of such other therapeutic agents include the following: cyclosporins (e.g., cyclosporin A), CTLA-4Ig, antibodies such as anti-ICAM-3, anti-IL-2 receptor (Anti-Tac), anti-CD45RB, anti-CD2, anti-CD3 (OKT-3), anti-CD4, anti-CD80, anti-CD86, monoclonal antibody OKT3), agents blocking the interaction between CD40 and gp39, such as antibodies specific for CD40 and / or gp39 (e.g. CD154), fusion proteins prepared from CD40 and gp39 (CD40Ig and CD8gp39), inhibitors such as nuclear translocation inhibitors, NF-kappa function such as deoxypergualin (DSG), non-steroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen, steroids such as for example, prednisone or dexamethasone, gold compounds, antiproliferative agents such as methotrexate, FK506 (tacrolimus, Prograf), mycophenolate mofetil, cytotoxic drugs such as azathiprine and cyclophosphamide, TN inhibitors Fa, such as tenidap, anti-TNFα antibodies or a soluble TNF receptor, and rapamycin (sirolimus or Rapamune) or derivatives thereof, and PKT inhibitors described in the following U.S. Pat. and U.S. patent applications, which are incorporated herein by reference in their entirety: Serial No. 09/097338, filed June 15, 1998 and Serial No. 09/094797, filed June 15, 1998. See the following documents and references cited therein: Hollenbaugh, D., Douthwright, J., McDonald, V. and Aruffo, A., Cleavable CD40Ig fusion proteins and the binding to sgp39, J. Immunol. Methods (Netherlands), 188 (1), pp. 1-7 (15.12.1995); Hollenbaugh, D., Grosmaire, L.S., Kullas, C.D., Chalupny, N.J., Breasch-Andersen, S., Noelle, R.J., Sramenkovic.

I., Ledbetter, JA, and Aruffo, A., The human T cell antigen gp39, a member of the TNF gene family, is a ligand for the CD40 receptor: an expression of a soluble form of gp39 with B cell co-stimulatory activity EMBO J. (England), 11 (12), pp. 4313-4321 (12/1992); and Moreland, L.W. et al., Treatment of Rheumatoid Arthritis with a Recombinant Human Tumor Necrosis Factor Receptor (p75) -Fc Fusion Protein, New England J. of Medicine, 337 (3), pp. 141-147 (1997).

The above therapeutic agents can be used, for example, at the dosages listed in the Physicians' Desk Reference (PDR), or at dosages otherwise determined by one skilled in the art when co-administered with the compounds of the present invention.

The following assays can be used to determine the activity of the compound (test compound) as PTK inhibitors. The compounds described in the following examples were tested by one or more of these assays and showed activity in them.

Enzyme assay using Lek, Fyn, Lyn, Hek, Fgr or Src

The following assay was performed using protein-tyrosine kinases Lek, Fyn, Lyn, Hek, Fgr and Src.

The selected protein-tyrosine kinase is incubated in kinase buffer (20 mM MOPS, pH7, 10 mM MgCl ₂ ) in the presence of the test compound. The reaction is initiated by the addition of substrates to a final concentration of 1 μΜ ATP, 3.3 µCi / ml ( ³³ P) -gamma-ATP, and 0.1 mg / ml acid denatured enolase (prepared as described in Cooper, JA, Esch, FS, Taylor). , SS and Hunter, T., Phosphorylation Sites in Enolase and Lactate Dehydrogenase utilized by tyrosine protein kinases in vivo and in vitro, J. Biol. Chem., 259: 7835-7841 (1984)). The reaction ends after 10 minutes.

minutes by adding 10% trichloroacetic acid, 100 mM sodium pyrophosphate and then bovine serum albumin at a concentration of 2 mg / ml. The labeled enolase protein substrate is precipitated at 4 ° C, harvested using Packard Unifilter plates and evaluated on a Topcount scintillation counter to determine the inhibitory activity of the test compound for protein-tyrosine kinase (activity is inversely proportional to the amount of labeled enolase protein recovered). The exact concentration of reagents and probe amount may vary, depending on the need.

This assay is advantageous because it uses an exogenous substrate (enolase) for more accurate enzyme kinetics and can be performed in a 96-well format that can be easily automated. In addition, His-tagged protein-tyrosine kinases (as described below) allow higher assay yield and higher purity compared to the GST-protein-tyrosine kinase fusion protein.

The protein tyrosine kinase may be obtained from commercial sources or may be obtained recombinantly as described herein. For the preparation of recombinant Lck, human Lck was prepared as a His-terminal fusion protein using Life Technologies (Gibco) baculovirus vector pFastBac Hta (commercially available) in insect cells. The cDNA encoding human Lck isolated by PCR (polymerase chain reaction) was inserted into the vector and the protein was expressed according to the manufacturer's instructions. The drug was purified by affinity chromatography. For a method of producing Lck in insect cells using a baculovirus, see Spana, C., C. O'Rourke, EC, Bolen, JB, and Fargnoli, J. Analysis of the tyrosine kinase p561ck expressed as glutathione S-transferase protein in Spodoptera frugiperda cells, Protein expression and purification, Vol. 4, pp. 390-397 (1993). Similar techniques can be used for recombinant production of other Src-family kinases.

• • • •

Cellular Assays (1) Cellular tyrosine phosphorylation

Jurkat T cells are incubated with the test compound and then stimulated by the addition of anti-CD3 antibody (monoclonal antibody G19-4). After 4 minutes or at another appropriate time, the cells are lysed by adding a lysis buffer containing NP-40 detergent. Protein phosphorylation is detected by anti-phosphotyrosine immunotransmission. Detection of phosphorylation of specific proteins such as ZAP-70 is detected by immunoprecipitation with an anti-ZAP-70 antibody followed by an anti-phosphotyrosine immuno-transfer. Such procedures are described in Schieven, GL, Mittler, RS, Nadler, SG, Kirihara, JM, Bolen, JB, Kanner, SB, and Ledbetter, JA, ZAP-70 tyrosine kinase, CD45 and T cell receptor involved in UV and H ₂ 0 ₂ induced T cell signal transduction, J. Biol. Chem., 269: 20718-20726 (1994) and references cited therein. Lek inhibitors inhibit the tyrosine phosphorylation of cellular proteins induced by anti-CD3 antibodies.

For the preparation of G19-4 see Hansen, J.A., Martin, P.J., Beatty, P.G., Clark, E.A. and Ledbetter, JA, Human T lymphocyte cell surface molecules defined by the monoclonal antibody workshop, in Leukocyte Typing I, A. Bernard, J. Boumsell, J. Dausett, C. Milstein, and S. Schlossman, ed., (New York, Springer Verlag, pp. 195-212 (1984); and Ledbetter, J.A., June, C.H., Rabinovitch, P.S., Grossman, A., Tsu, T.T., and Imboden, J.B., Transduction signal through CD4 receptors: stimulators vs. Inhibitors of activity is regulated by CD4 proximity to the CD3 / T cell receptor, Eur. J. Immunol., 18: 525 (1988).

(2) Calcium test

Drug inhibitors block calcium mobilization in T-cells stimulated with anti-CD3 antibodies. Cells are placed on the Indo-1 color calcium indicator, treated with an anti-CD3 antibody such as monoclonal antibody G19-4, and calcium mobilization is measured by flow cytometry by recording blue / violet changes for Indo-1 as described in Schieven, GL,

Mittler, RS, Nadler, SG, Kirihara, JM, Bolen, JB, Kanner, SB, and Ledbetter, JA, ZAP-70 tyrosine kinase, CD45 and T cell receptor involved in UV and H ₂ 0 ₂ induced T cell signal transduction, J. Biol. Chem., 269: 20718-20726 (1994) and references cited therein.

(3) Proliferation assays

Drug inhibitors inhibit the proliferation of normal human peripheral blood T cells stimulated with anti-CD3 and anti-CD28 antibodies. A 96-well plate is coated with a monoclonal antibody to CD3 (such as G19-4), the antibody is allowed to bind, and the plate is then rinsed. Platelet-bound antibody serves to stimulate cells. Normal human peripheral blood T cells are added to the wells along with the test compound and the anti-CD28 antibody that co-stimulates growth. After the required time (e.g., 3 days), the cells are added with ( ³ H) -thymidine and after incubation allowing incorporation of the labeling reagent into the newly synthesized DNA, the cells are harvested and scintillation counted to determine cell proliferation.

The following examples illustrate embodiments of the present invention and do not limit the scope of the appended claims. The abbreviations used in the examples are defined below.

of the examples are identified by example and degree;

The compounds are prepared (for example, IA denotes the title compound of Step A of Example 1), or only by example if the compound is the title compound of the example (for example, 2 denotes the title compound of Example 2).

DETAILED DESCRIPTION OF THE INVENTION

Abbreviations aq. = aqueous conc. = concentrated

DMSO = dimethylsulfoxide

EtOAc = ethyl acetate

Et 2 O = diethyl ether h = hour

HATU = N- [dimethylamino-1H-1,2,3-triazolo- [4,5-b] pyridin-1-ylmethylene] -N-methyl-methaminium hexafluorophosphate N-oxide

MeOH = methanol

MOPS = 4-morpholine-propanesulfonic acid

MS = mass spectrometry

Lip. time = retention time sat. = saturated

TFA = trifluoroacetic acid

THF = tetrahydrofuran

Example 1: Preparation of [6 - [(2,4,6-trimethylphenyl) aminocarbonyl] -2-benzothiazolyl] carbamic acid 1,1-dimethylethyl ester

A. Ethyl 2-amino-benzothiazole-6-carboxylate

•

A solution of ethyl 4-aminobenzoate (35 g, 212 mmol) in glacial acetic acid (300 mL) was added to a stirred solution of sodium thiocyanate (69 g, 848 mmol) in acetic acid (150 mL). The mixture was cooled in an ice / water bath and bromine (12 mL, 233 mmol) in acetic acid (60 mL) was added dropwise via addition funnel. The reaction mixture was stirred at 0 ° C to ambient temperature for 4 hours and then added to water (1.5 L). Saturated sodium carbonate solution was added to neutralize the solution. The precipitated solid was filtered off, washed with water and EtOAc and dried in vacuo to give the title compound (31.65 g, yield 67.2%).

B. Ethyl 2-tert-butoxycarbonyloxyamino-benzothiazole-6-carboxylate

A suspension of 1A (10 g, 45 mmol), di-t-butyl dicarbonate (11.78 g, mmol) and 4-dimethylaminopyridine (549 mg, 4.5 mmol) in dichloromethane (330 mL) was stirred at ambient temperature overnight. Additional di-t-butyl dicarbonate (3 g, 13.75 mmol) was added. After 20 hours, the mixture was concentrated under reduced pressure, and the residue was diluted with a 1: 1 mixture of EtOAc and Et 2 O (200 mL). The solid material was filtered off and dried under vacuum to give the title compound (10.5 g, yield 72.4%).

C. 2-tert-Butoxycarbonyloxyamino-benzothiazole-6-carboxylic acid

A 1 N solution of sodium hydroxide in water (931 mL) was added to a suspension of compound IB (10 g, 31.05 mmol) in methanol (170 mL). The mixture was stirred at ambient temperature overnight, cooled to 0 ° C and acidified with aqueous HCl. The precipitated solid material was filtered off, washed with water and dried under reduced pressure. The solid material was suspended in tetrahydrofuran and concentrated under reduced pressure. The obtained material was further diluted with toluene and concentrated under reduced pressure to remove water. The solid material was collected and dried under vacuum over phosphorus pentoxide

yield of the title acid (8.32 g, yield 91%).

D. [6 - [(2,4,6-Trimethylphenyl) aminocarbonyl] -2-benzothiazolyl] carbamic acid 1,1-dimethylethyl ester

Diisopropylethylamine (1.83 mL, 10.48 mmol) was added to a stirred solution of 1C (2.57 g, 8.73 mmol),

2,4,6-trimethylaniline (1.47 mL, 10.48 mmol) and HATU (3.98 g,

10.48 mmol) in dimethylformamide (77.1 mL). The solution was stirred at ambient temperature overnight and then diluted with EtOAc (70 mL). The reaction mixture was washed with 2N aqueous HCl (80 mL). The aqueous layer was extracted with EtOAc (25 mL). Combine the EtOAc extracts, wash with 2N aqueous HCl (60 mL), brine, dry (Na ₂ SO ₄ ) and concentrate. The crude residue was triturated with 4: 1 ether: EtOAc (100 mL). The solid material was collected and dried under vacuum to give the title compound (2.88 g, yield 80.1%).

MS = 412.2 (M + H).

Example 2: Preparation of 2-amino-N- (2,4,6-trimethylphenyl) -6trifluoracetatové salt (1: 1) CH _3! L ^ r * ^CH3

A solution of 1D (77.8 mg, 0.19 mmol) in trifluoroacetic acid (5.3 mL) was stirred at ambient temperature for 1.5 hours. The solution was concentrated under reduced pressure and the residue was evaporated with ether. Trituration with ether-hexanes gave the title compound (62 mg, 72% yield) as an off-white solid.

MS = 311.9 (M + H).

-benzothiazolecarboxamide,

CF3COOH · H ₂ N—

• * · · · · ·

Example 3: Preparation of 2- (acetylamino) -N- (2,4,6-trimethylphenyl) -6-benzothiazolecarboxamide

A. Ethyl 2-acetamido-benzothiazole-6-carboxylate

A suspension of 1A (150 mg, 0.67 mmol) and acetic anhydride (0.18 mL, 1.86 mmol) in dichloromethane (19 mL) and pyridine (3.7 mL) was stirred at ambient temperature. After 2 hours, additional pyridine (3 mL) and 4-dimethylaminopyridine (8.2 g, 0.067 mmol) were added. The mixture was stirred for 16 hours, diluted with dichloromethane (20 mL) and washed with 2N aqueous HCl (20 mL, 3x), saturated aqueous KHCO ₃ (20 mL, 2x), and brine. The dichloromethane extract was dried (Na 2 SO 4), filtered and concentrated. The residue was triturated with ether-hexanes to give the title compound (130 mg, 73% yield).

B. 2-Acetamido-benzothiazole-6-carboxylic acid

A 2M aqueous solution of potassium hydroxide (5.7 mL) and ethanol (8 mL) were added to a solution of compound 3A (100 mg, 0.38 mmol) in THF (5 mL). The homogeneous solution was stirred at ambient temperature overnight, cooled to 0 ° C and acidified with 6M aqueous HCl. Most of the ethanol and THF were removed by distillation under reduced pressure. The precipitated solid was filtered off, washed with water and dried in vacuo to give the title compound (64 mg, 72% yield) as a white solid.

C. 2- (acetylamino) -N- (2,4,6-trimethylphenyl) -6-benzothiazolecarboxamide

In analogy to the method used to prepare 1D, except for using 3B, the title compound of this example was obtained as a yellow solid (21.5%).

MS = 354 (M + H).

Example 4: Preparation of 2- (benzoylamino) -N- (2,4,6-trimethylphenyl) -6-benzothiazolecarboxamide

A solution of 2 in the free base form (100 mg, 0.32 mmol), obtained by reacting a solution of the trifluoroacetate salt of 2 in dichloromethane with aqueous sodium bicarbonate) and benzoic anhydride (200 mg, 0.89 mmol) in THF (8.9 ml) and pyridine (1.8 ml) were stirred at ambient temperature overnight. Additional benzoic anhydride (200 mg, 0.89 mmol) and 4-dimethylaminopyridine (3.9 mg, 0.032 mmol) were added and the solution was stirred for 2 days. Additional 4-dimethylaminopyridine (3.9 mg, 0.032 mmol) was added and the solution stirred for an additional 1 hour. The mixture was diluted with dichloromethane (40 mL), washed with 1N aqueous HCl (15 mL), dried (Na 2 SO 4), filtered and concentrated. The residue was triturated with ether to give a white solid, which was suspended in dichloromethane and washed with saturated aqueous KHCO ₃ (3x). The dichloromethane extract was dried (Na 2 SO 4), filtered and concentrated. The residue was triturated with EtOAc (15 mL) to afford the title compound (49 mg, 37% yield) as a white solid.

MS = 416.1 (M + H).

· * * Ř ř ř ř ř · • • • · · · · · · · · · · · · · · · · · · · · ··· ······· «·« ·· ,,

Example 5: Preparation of 2 - [(1-oxopropyl) amino] -N- (2,4,6-trimethylphenyl) -6-benzothiazolecarboxamide

In analogy to the method used for the preparation of compound 4, except for the use of propionic anhydride, the title compound 5 is obtained as a white solid. MS = 367 (M + H).

Example 6: Preparation of 2 - [(1-oxobutyl) amino] -N- (2,4,6-trimethylphenyl) -6-benzothiazolecarboxamide

In analogy to the method used to prepare Compound 4, except for butyric anhydride, the title compound 6 is obtained as a white solid. MS = 382 (M + H).

Example 7: Preparation of 2 - [[[(1,1-dimethylethyl) amino] carbonyl] amino] -N- (2,4,6-trimethylphenyl) -6-benzothiazolecarboxamide

Η Hz ^H 3 ^C CH ₃ 0

► · * »

A. 2 - [[[phenoxy] carbonyl] amino] -N- (2,4,6-trimethylphenyl) -6-benzothiazolecarboxamide

Phenylchloroformate (470 mg, 3 mmol) was added dropwise to a stirred solution of Compound 2 free base (311 mg, 1 mmol) in THF (20 mL) and saturated aqueous KHCO ₃ (20 mL) at 0-5 ° C. The biphasic mixture was stirred for 3 hours. The THF layer was separated and the aqueous layer was extracted with dichloromethane (30 mL, 2x). The organic extracts were combined, dried (MgSO ₄ ), filtered and concentrated. The crude material was diluted with EtOAc (25 mL) and the solid was filtered off, washed with EtOAc (8 mL, 4x) and dried in vacuo to afford the title compound as a white solid (269 mg, 62%).

B. 2 - [[[(1,1-dimethylethyl) amino] carbonyl] amino] -N- (2,4,6-trimethylphenyl) -6-benzothiazolecarboxamide

Tert -butylamine (73 mg, 1 mmol) was added to a stirred solution of compound 7A (22 mg, 0.05 mmol) in THF (5 mL). The solution was stirred at ambient temperature for 16 hours, diluted with dichloromethane (30 mL) and washed with 2N aqueous HCl (10 mL, 2X) and 0.5 N in NaOH (10 mL, 2X). The dichloromethane extract was dried (MgSO 4), filtered and concentrated to give the title compound (17 mg, 80%) as a white solid.

MS = 411.1 (M + H).

Example 8: Preparation of 2 - [[[bis (1-methylethyl) amino] carbonyl] amino] -N- (2,4,6-trimethylphenyl) -6-benzothiazolecarboxamide

In analogy to the method used to prepare 7B, except for diisopropylamine, the title compound 8 was obtained as an off-white solid MS = 439.2 (Μ * + H).

Example 9: Preparation of [6-bromo-4 - [[(2,4,6-trimethylphenyl) amino] carbonyl] -2-benzothiazolyl] carbamic acid 1,1-dimethyl ester

In analogy to the method used to prepare Compound 1, except for using methyl 2-amino-6-bromobenzothiazole-4-carboxylate (U.S. Patent No. 5496816) instead of Compound IA, the title compound 9 was obtained as a white solid.

MS = 491.8 (M + H).

Example 10: Preparation of [4 - [[(2,4,6-trimethylphenyl) amino] carbonyl] -2-benzothiazolyl] carbamic acid 1,1-dimethyl ester

• · · · · · · · · · · · ·

Palladium hydroxide (40 mg) was added to a stirred suspension of compound 9 (50 mg, 0.1 mmol) in absolute ethanol (60 mL). The reaction vessel is equipped with a balloon filled with hydrogen using a three way cock. The air in the reaction vessel is evacuated under reduced pressure, and the vessel is then filled with hydrogen from the balloon. This process is repeated (3x). Hydrogenolysis is continued overnight. The reaction mixture was filtered through a pad of anhydrous MgSO ₄ . The residual solid was washed with ethanol (10 mL, 3x). The filtrate was concentrated and the crude residue was chromatographed on a silica gel column. Elution with 5% EtOAc in hexanes followed by 10% and 20% EtOAc in hexanes gave the title compound 10 (37 mg, 88%) as a white solid.

MS = 412.1 (M + H).

Example 11: Preparation of [6-bromo-7 - [[(2,4,6-trimethylphenyl) amino] carbonyl] -2-benzothiazolyl] carbamic acid 1,1-dimethyl ester

A. Methyl 3-amino-6-bromo-benzoate

Stannous chloride dihydrate (22.56 g, 100 mmol) was added to a stirred solution of methyl 2-bromo-5-nitrobenzoate (9 g, 34.61 mmol) in methanol (250 mL) and concentrated HCl (25 mL). The solution was stirred at ambient temperature for 8 hours and then treated with a saturated aqueous KHCO ₃ solution (600 mL). Additional KHCO ₃ in solid form (50 mg) was added. The mixture was extracted with EtOAc (200 mL, 5x). The EtOAc extracts were combined, dried (MgSO _4), filter and concentrate to. The residue was diluted with EtOAc (250 mL) and washed with brine (50 mL,

2x), dried (MgSO ₄ ), filtered and concentrated to give the title compound (7.45 g, 94%) as a brown oil.

B. Methyl 2-amino-6-bromo-benzothiazole-7-carboxylate (UBa) and methyl 2-amino-6-bromo-benzothiazole-5-carboxylate (HBb)

A method analogous to that used for the preparation of IA is used except for the use of compound 9A in place of ethyl 4-aminobenzoate as the starting aniline. Trituration of the crude residue with EtOAc gave pure UBa (43%). The filtrate was concentrated and the residue was chromatographed on a silica gel column. Elution with 10% EtOAc in hexanes followed by 20%, 30% and 50% EtOAc in hexanes gave a 1: 1 mixture of UBa and HBb (13%) as a white solid.

C. [6-Bromo-7 - [[(2,4,6-trimethylphenyl) amino] carbonyl] -2-benzothiazolyl] carbamic acid 1,1-dimethyl ester

Use a method analogous to that used for the preparation of ID, except for the use of compound UBa instead of compound IA, to give the title compound as a white solid.

MS = 491.9 (M + H).

Example 12: Preparation of 1,1-dimethylethyl [7 - [[(2,4,6-trimethylphenyl) amino] carbonyl] -2-benzothiazolyl] carbamic h ₃ i

ch ₃ • ·

Use a method analogous to that used for the preparation of compound 10, except using compound 11C instead of compound 9, to afford the title compound 12 (89%) as a white solid.

MS = 412.1 (M + H).

Example 13: Preparation of [6-bromo-5 - [[(2,4,6-trimethylphenyl) amino] carbonyl] -2-benzothiazolyl] carbamic acid 1,1-dimethyl ester

O

A method analogous to that used to prepare Compound ID is used, except for the use of a 1: 1 mixture of UBa and 11Ba as the starting benzothiazole in place of Compound IA. The crude material obtained was diluted with EtOAc and allowed to stand at ambient temperature for 2 hours. The precipitated solid was filtered off, washed with EtOAc and dried in vacuo to afford the title compound 13 as a white solid.

MS = 492.0 (M + H).

Example 14: Preparation of (5 - [[(2,4,6-trimethylphenyl) amino] carbonyl] -2-benzothiazolyl] carbamic acid 1,1-dimethyl ester

O

Use a method analogous to that used to prepare Compound 10, except for using Compound 13 in place of Compound

9, to afford the title compound 14 (63%) as a white solid.

MS = 412.1 (M + H).

Example 15: Preparation of 2 - [[[phenylamino] carbonyl] amino] -N- (2,4,6-trimethylphenyl) -6-benzothiazolecarboxamide. · ···· · · ··· ··· «

A solution of the free base of compound 2 (100 mg, 0.32 mmol), phenyl isocyanate (119 mg, 1 mmol) and 4-dimethylaminopyridine (10 g) in THF (2 mL) and pyridine (2 mL) was stirred at room temperature overnight . The mixture was diluted with dichloromethane (30 mL) and washed with 2N aqueous HCl (20 mL, 2x). Dichloromethane extract was diluted with methanol (10 mL), dried (MgSO ₄ ), filtered and concentrated. The crude material was diluted with EtOAc (25 mL) and the solid material was filtered and washed with EtOAc (5 mL, 3x). The white solid was suspended in dichloromethane (30 mL) and methanol (2 mL) and stirred for 20 minutes and filtered. The residual solid was washed with dichloromethane (5 mL, 3x) and dried in vacuo to afford the title compound 15 (88 mg, 64%).

MS = 431.1 (M + H).

Example 16: Preparation of 2 - [[[(phenylmethyl) amino] carbonyl] amino] -N- (2,4,6-trimethylphenyl) -6-benzothiazolecarboxamide σ-τκ

O

HaC

Use a method analogous to that used for the preparation of compound 15, except for the use of benzyl isocyanate, to afford the title compound 16 as a white solid.

MS = 445 (M + H).

Example 17: Preparation of 2 - [[[ethylamino] carbonyl] amino] -N- (2,4,6-trimethylphenyl) -6-benzothiazolecarboxamide

Use a method analogous to that used for the preparation of compound 15, except for the use of ethyl isocyanate, to afford the title compound 17 as a white solid.

MS = 383 (M + H).

Example 18: Preparation of 2 - [[butylamino) carbonyl] amino] -N- (2,4,6-trimethylphenyl) -6-benzothiazolecarboxamide

Use a method analogous to that used for the preparation of compound 15, except using n-butyl isocyanate, to afford the title compound 18 as a white solid.

MS = 411 (M + H).

Examples 19 to 58

General procedure

Compounds 19-58 were prepared as follows.

The appropriate amine (0.08 mmol) was added to a solution of compound 7A (20 mg, 0.054 mmol) in THF (3 mL). The solution is stirred at ambient temperature for 18 to 40 hours. The reaction mixture was diluted with dichloromethane (5 mL) and washed with 1N aqueous HCl (1.5 mL, 2X) and 1N aqueous NaOH (1.5 mL, 2X). The organic extract was dried (MgSO ₄ ), filtered and concentrated in vacuo to give the compounds of these examples, which are described in Table 1, below.

In Table 1, HPLC Ret time is the HPLC retention time obtained under the following conditions: YMC S5 ODS 4.6 x 50 mm Ballastic Column, min. gradient from 100% solvent A (10% MeOH, 90% H ₂ O, 0.2% H ₃ POJ to 100% solvent B (90% MeOH, 10% H ₂ O, 0.2% H ₃ P0J, flow 4 ml / min, lambda = 220 nM for compounds 19 to 56. The following conditions were used for compound 57: Zorbax SB-C18

4.5 mm x 7.5 cm short column, 8 min. gradient from 100% solvent A (10% MeOH, 90% H ₂ O, 0.2% H ₃ PO ₄ ) to 100% solvent B (90% MeOH, 10% H ₂ O, 0.2% H ₃ PO ₄₎ ), flow rate 2.5 ml / min., lambda = 217 nM.

Table 1

• · »<<.. <<

·· ··· «

20 May ^{HAC _N} ^ Q K> ^K * 78f ^H HgCl CH (R) -2 - [[[[(3,3-Dimethylcyclohexyl) - J methyl] amino] carbonyl] amino] - N- (2,4,6-trimethylphenyl) -1-6-benzothiazolecarboxamide 4.81 21 = Η / Λ = ςχ _Α 2 - [[[(4-methylcyclohexyl) amino] carbonyl] amino] -N- (2,4,6-? -trimethylphenyl) - -6-benzothiazolecarboxamide 4.52 22nd 2 - [[[(cyclohexylmethyl) amino] - carbonyl] amino] -N- (2,4,6- -trimethylphenyl) - -6-benzothiazolecarboxamide 4.53 23 ck,  4m 2 - [[[(2,3-dihydro-1H-indene-1- -yl) amino] carbonyl] amino] -N- (2,4,6-Trimethylphenyl) - -6-benzothiazolecaboxamide 4.40 24 - ° '^ VA-p 2 - [[[(1-Naphthalenomethyl) amino] carbonyl] amino] -N- (2,4,6-trimethylphenyl) -6-benzothiazolecarboxamide 4.53 25 CH, ₀ CH, o '\ = / H JI S ^ N ^ N ^ · O · N ^J 2 - [[[[2- (1H-imidazol-4-yl) ethyl] amino] carbonyl] amino] -N- (2,4,6- ^l- trimethylphenyl) -6-benzothiazolecarboxamide 3.19 26 CH, CH, 0 ^ W JI JI ^ε><Ν><Ν'^Ύ2> 2 - [[[(tetrahydro-2- (fluoroyl) methyl> amino] carbonyl] - amino] -N- (2,4,6-trimethylphenyl) -6- -benzothiazolecarboxamide 4.14 27 Mar: CH, HjC ^ AN — 2 - [[[2- (5-methoxy-1H-indol-3-one)] -yl) ethyl] amino] carbonyl] amino] - N- (2,4,6-trimethylphenyl) -6- -berisothiazolecarboxes ^ 4.19

· Ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft ft · · ······· ftft * ·· ·

28 2 - [[[2- (4-morpholinyl) ethyl] - amino] carbonyl] anuno] -N- (2,4,6- -trimethylphenyl) -6- -benzothiazolkaiboxamide 3.08 29 O 2 - [[[2- (2-pyridinyl) ethyl] amino] - carbonyl] amino] -N- (2,4,6- -trimethylphenyl) -6- -benzothiazolecarboxamide 3.17 30 ^ ^{οΚ =} % χΛχ · 2 - [[[(1,1,3,3-tetramethylbutyl) - amino] kaibonyl] amino] -N- (2,4,6- -trimethylphenyl) -6- -benzothiazolkaiboxamide 4.64 31 CH - ^ \ _N yy _"r CH 2 - [[[(1,1-dimethylpropyl) - amino] carbonyl] amino] -N- (2,4,6- -trimethylphenyl) -6- -benzothiazolecarboxamide . ... I 4.32 32 \ fí \ / “ ^N 0 CH- CH- 2 - [[[(1,5-dimethylhexyl) amino] - kaibonyl] amino] -N- (2,4,6- -trimethylphenyl) -6- -benzothiazolecarboxamide 4.74 33 --Q-y ^ /> 2 - [[(cyclopentylamino) kaibonyl] - amino] -N- (2,4,6-trimethylphenyl) -6- -benzothiazolkaiboxamide 4.28 34 CH, 0 y CHj 2 - [[[(1,1-dimethyl-2- -hydroxyethyl) amino] carbonyl] - amino] -N- (2,4,6-trimethylphenyl) -6- -benzothiazolecarboxamide 3.90

* ·

35 4 {Υ, _o <*. ⁰ o X JI OUT ^ ►y 2 - [[[[(3-methoxyphenyl) xethyl] -1] - amino] carbonyl] amino] -N- (2,4,6- -trimethylphenyl) -6- -benzothiazolecarboxamide 4.19 36 -4w> VYV ^ CH, 2 - [[[[(3-methylphenyl) methyl] - amino] kaibonyl] amino] -N- (2,4,6- -trimethylphenyl) -6- -benzothiazolecarboxamide 4.34 37 ° * 3θ \ = <li II 2 - [[[[(4-chlorophenyl) methyl] - amino] carbonyl] amino] -N- (2,4,6- (trimethylphenyl) -6- 1-benzothiazolkaiboxamide 4.37 38 CH3 4x-o Φ H, m / z 2 - [[[2- (4-methoxyphenyl) ethyl] - amino] kaibonyl] amino] -N- (2,4,6- -trimethylphenyl) -6- i -benzothiazolecarboxamide 4.30 39 y - = CH N CH ₃ <W 2 - [[(2-propylamino) carbonyl] amino] -N- (2,4,6-trimethylphenyl) -6- -benzothiazolecarboxamide 4.66 40 4o o 2 - [[(2-propenylamino) carbonyl] - amino] -N- (2,4,6-trimethylphenyl) -6- -benzothiazolecarboxamide 3.94 41 4ο o "O" "Gl x." 2 - [[[(3-phenylpropyl) amino] carbonyl] amino] -N- (2,4,6-. -trimethylphenyl) -6- -benzothiazolecarboxamide 4.45

42 CH, 1 2 - [[[[1- (hydroxymethyl)] - j cyclopentyl] amino] carbonyl] amino] -N- (2,4,6-trimethylphenyl) -6- * benzothiazolecarboxamide 4.07 43 -you you ^ ^{he =} UA 2 - [[[4- (1,1-dimethylethyl) - cyclohexyl] amino] carbonyl] - amino] -N- (2,4,6-trimethylphenyl) -6- -benzothiazolecarboxamide 4.87 44 H, c - / y - n W> ^ = <HA-> / XH, 2 - [[[(l-propylbutyl) amiiK>] carbonyl] amino] -N- ^(2,4,6-1 -trimeth.ylfenyl) -6- -benzothiazolkarboxamid 4.54 45 y 2 - [[[(l, 3-dimethylpentyl) amino] - carbonyl] amino] -N- (2,4 ₅ 6 -trimethylfenyl) -O- -benzothiazolkarboxamid 4.57 46 ch, 0 Án ^ / ^ ch, 2 - [[[[3- (methylthio) propyl] amino] - carbonyl] amino] -N- (2,4,6- -trimethylphenyl) -6- -benzothiazolecarboxamide 4.08 47 CH, H, C — Z? N? K> ^ THaaA, CH, 2 - [[[[1- (methoxymethyl) propyl] amino] carbonyl] amino] -N- (2,4,6-trimethylphenyl) -6-benzothiazolecarboxamide 4.05 48 ^ν ~ ^ ΓΉ> ° ΟΗ, ς / \ = / Η II 2 - [[[[2- (thienyl) ethyl] amino] - carbonyl] amino] -N- (2,4,6- -trimethylphenyl) -6- -benzothiazolecarboxamide 4.24 49 ^ HA- 0 1 CH, 2 - [[[[(2,6-dimethoxyphenyl) methyl] - ₍ amino) carbonyl] amino] -N- (2,4,6-trimethylphenyl) -6-benzothiazolecarboxamide 4.31 50 .CH, t— 'Hm,' Ό OH (R) -2 - [[[[1- (Hydroxymethyl) -2-phenylethyl] amino] carbonyl] amino] -N- (2,4,6-trimethylphenyl) -6-benzothiazolecarboxamide 4.13

• · · ·

51 CH, ° ', ο I JL HER (R) -2 - [[[(1-Phenylethyl) amino] carbonyl] amino] -N- (2,4,6- ^l- trimethylphenyl) -6-benzothiazolecarboxamide 4.28 52 h, ⁰ y_y — n _ ^ οΚ / ° 2 - [[(1-adamantylanuno) carbonyl] - amino] -N- (2,4,6-trimethylphenyl) -6- -benzothiazolecarboxamide 4.74 53 CH, 'φ F 2 - [[[2- (4-fluorophenyl) -1,1- dimethylethyl] amino] carbonyl] - amino] -N- (2,4,6-trimethylphenyl) -6- -benzothiazolecarboxamide 4.54 54 2 - [[[2- (2-pyridinyloxy) ethyl] - amino] carbonyl] -andno] -N- (2,4,6- -trimethylphenyl) -6- -benzothiazolecarboxamide 3.97 55 .CH, Μ> \ λ 2 - [[[(1-methyl-1-phenylethyl) anrino] carbonyl] amino] -N- (2,4,6] trimethylphenyl) -6- -benzothiazolecarboxamide 4.36 56 cn, * vVy χΜ = Η s ( ^R ) -2 - [[[] 1- (4-Methylphenyl) ethyl] amino] carbonyl] amino] -N- (2,4,6-trimethylphenyl) -6-benzothiazolecarboxamide 4.44 57 0 ie \\ -G / - CH, H.C 2 - [[[(1-methylheptyl) amino] -, carbonyl] amino] -N- (2,4,6-trimethylphenyl) -6-benzothiazolecarboxamide 9.75 58 - H, C o! í-% 2 - [[[[(4-methoxyphenyl) methyl] - amino] carbonyl] amino] -N- (2,4,6- -trimethylphenyl) -6- -benzothiazolecarboxamide 8.38

• ·

Examples 59 to 95

General procedure

Compounds 59 to 95 were prepared as follows.

The appropriate arylamine (0.08 mmol) was added to a solution of compound 7A (20 mg, 0.054 mmol) in THF (3 mL). The solution is heated at 45 ° C for 24-72 hours. The reaction mixture was diluted with dichloromethane (5 mL) and washed with 1N aqueous HCl (3 mL, 2X) and 1N aqueous NaOH (3 mL, 2X). The organic extract was dried (MgSO ₄ ), filtered, and concentrated in vacuo to give the compounds of these examples, which were purified by HPLC under the following conditions: YMC ODS 200 x 100 mm column, 10 min. gradient from 30% solvent B (90% MeOH, 10% H ₂ O, 0.2% H ₃ PO ₄ ) and 70% solvent A (10% MeOH, 90% H ₂ O, 0.2% H ₃ POJ to 100% solvent B, flow rate 20 ml / min, lambda = 220 nM The compounds of these examples are shown in Table 2.

In Table 2, the HPLC Ret time is the HPLC retention time obtained under the following conditions: YMC S5 ODS 4.6 x 50 mm Ballastic Column, min. gradient from 100% solvent A (10% MeOH, 90% H ₂ O, 0.2% H ₃ PO ₄ ) to 100% solvent B (90% MeOH, 10% H ₂ O, 0.2% H ₃ PO ₄ ), flow rate 4 ml / min., lambda = 220 nM.

Table 2

Ex. C. Formula compound - Name of compound F R - IPLC Time (mii 59 2 - [[[(4-Cyclohexylphenyl) amino] - carbonyl] amino] -N- (2,4,6- -trimethylphenyl) -6- -benzothiazolecarboxamide 4.99

• · · · · · ·

60 2) 2 - [[[(5,6,7,8-tetrahydro-1-naphthalenyl) amino] carbonyl] - ' amino] -N- (2,4,6-trimethylphenyl) -6-benzothiazolecarboxamide 4.64 61 2 - [[[(2,3-dihydro-1H-indene-5- -yl) amino] carbonyl] amino] -N- - (2,4,6-Trimethylphenyl) - -6-benzothiazolecarboxamide 3.94 62 .ch, ο-Λθ "-IN 2 - [[(1,3-benzodioxol-5-ylamino)] - carbonyl] amino] -N- (2,4,6- -trimethylphenyl) -6- -benzothiazolecarboxamide 4.20 63 CH, 'Aíyrx X) VSr ^ o ; 2 - [[(2-pyridinylamino) 'carbibonyl] amino] -N- (2,4,6] -timethylphenyl) -6- -benzothiazolecarboxaxnid 3.95 64 ch, '’Όχν X) 2 - [[[(3-methyl-2-pyridinyl) amino] -, carbonyl] amino] -N- (2,4,6-trimethylphenyl) -6-benzothiazolecarboxamide 3.75 65 CH, ^at ~ 0;> - q ^ XX 2 - [[[(4-methyl-2-pyridinyl) amino] - carbonyl] amino] -N- (2,4,6- -trimethylphenyl) -6- -benzothiazolecarboxamide 3.89 66 CH, 2 - [[[(2-chloro-5-methylphenyl) - amino] carbonyl] amino] -N- (2,4,6- -trimethylphenyl) -6- -benzothiazolecarboxamide 4.62 67 .ch, -Qvq, Xi · ° · = <λ, Αο " 2 - [[[(2,6-dichloro-phenyl) - ' amino] carbonyl] amino] -N- (2,4,6-trimethylphenyl) -6-benzothiazolecaboxamide 5.03 68 CH, CH, X) -AA 2 - [[[(2-methoxyphenyl) amino] - carbonyl] amino] -N- (2,4,6- (trimethylphenyl) -6- -benzothiazolecarboxamide 4.37

• · · · · · · · · · · · · ·

• · · · · · · · · · · · · · ·

69 2 - [[([1,1'-biphenyl] -2-ylamino) cartonyl] amino] -N- (2,4,6-trimethylphenyl) -6-benzothiazolecarboxamide 4.57 70 CH 'and ^c vU 2 - [[[(2-benzoylphenyl) amino] carbonyl] amino] -N- (2,4,6,4-trimethylphenyl) -6- -benzothiazolecarboxamide 3.53 71 CH, X) '' KA 2 - [[[(2-methylphenyl) amino] kaibonyl] amino] -N- (2 ₅ 4 _with 6'-trimethylphenyl) -6-benzothiazolecarboxamide 4.30 72 <SA or N- (2,4,6-trimethylphenyl) -2 - [[[(2,4,6-trimethylphenyl) amino] -1] - carbonyl] amino] -6- -benzothiazolecarboxamide 4.35 73 CH, CH, 1 : 2 - [[[[2-methyl-6- (1-methylethyl) -1: phenyl] amino] carbonyl] amino] -N- (2,4,6-trimethylphenyl) -6-benzothiazolecarboxamide 4.42 74 Xx. 2 - [[[(3,5-difluorophenyl) amino] -; , carbonyl] amino] -N- (2,4,6-trimethylphenyl) -6-benzothiazolecarboxamide 4.23 75 rc 70 _{s 3} ° C Xa 24 [[(3-methoxyphenyl) amino] -carbonyl] amino] -N- (2,4,6-trimethylphenyl) -6-benzothiazolecarboxamide 4.25 76 CH, CH, and) “‘ 'HAA 2 - [[[(3-methylphenyl) amino] -, carbonyl] amino] -N- (2,4,6-trimethylphenyl) -6-benzothiazolecarboxamide 4.38

* ············································ · · · ·········· · · · ··

77 ό II N 2 - [[[(4-cyanophenyl) amino] - carbonyl] amino] -N- _herein - (2,4,6-trimethylphenyl) -6-benzothiazolkarboxamid 4.10 78 ^ ^tn VA 2 - [[[(4-fluorophenyl) amino] - carbonyl] amino] -N-. - (2,4,6-trimethylphenyl) -6-benzothiazolecarboxamide 4.27 79 CHj jy 2 - [[[(4-chlorophenyl) amino] - [ carbonyl] amino] -N- - (2,4,6-trimethylphenyl) -6-benzothiazolecarboxamide 4.47 80 ΐζ 4 - [[[[6 - [[(2,4,6-trimethylphenyl) amino] carbonyl] -2-benzothiazolyl] amino] carbonyl] amino] benzoic acid ethyl ester 4.50 81 ₀ -ch »K> y ^ y" Λ '"· 2 - [[[(3,4,5-trimethoxyphenyl) - amino] -carbonyl] amino] -N- - (2,4,6-trimethylphenyl) -6- -benzothiazolecarboxamide 4.16 82 σ ' ⁰ “ ³ ΧΓ ^ -. λ 2 - [[[(3,4-dimethoxyphenyl) amino] -. , carbonyl] amino] -N- (2,4,6-trimethylphenyl) -6-benzothiazolecarboxamide 4.10 83 F Τ ’ - <Η 2 - [[[2,6-bis (1-methylethyl) - phenyl] amino] carbonyl] amino] -N- - (2,4,6-trimethylphenyl) -6- -benzothiazolecarboxamide 5.03 84 CKj 2 - [[[(2-propylphenyl) amino] carbonyl] amino] -N- (2,4,6-trimethylphenyl) -6-benzothiazolecarboxamide ¹ ------- 4.52

• · · · · · · · · · · · · · ·

G4 • · · · · ·········

85 AAA, ”· 2 - [[[(3-bromo-2,4,6- -trimethylphenyl) amino] kaibonyl] -1'-amino] -N- (2,4,6-trimethylphenyl) -6- t -benzothiazolecarboxamide 4.59 86 CH, fX ’^ Χγ, X . ^^ = <AAo 2 - [[[[2- (4-morpholinyl) phenyl] amino] carbonyl] amino] -N- (2,4,6-trimethylphenyl) -6-benzothiazolecarboxamide 4.70 87 HAyzy _N 'XX 2 - [[[(3-Bromo-2-methylphenyl) - amino] carbonyl] amino] -N- - (2,4,6-trimethylphenyl) -6- -benzothiazolecarboxamide 4.59 88 CH, ^ Η, ννο- X 2 - [[[(2,6-dimethoxyphenyl) amino] - kaibonyl] amino] -N- - (2,4,6-trimethylphenyl) -6- -benzothiazolkaiboxaxnid 3.91 89 2 - [[[(2-Bromo-5-methoxyphenyl) - amino] carbonyl] amino] -N- - (2,4,6-trimethylphenyl) -6- -benzothiazolecarboxamide 4.61 90 PH, CH, I %Η%, X 2 - [[[(2-methoxy-6-methylphenyl) - amino] carbonylJamino] -N-, - (2,4,6-trimethylphenyl) -6-benzothiazolecarboxamide 4.10 91 ^ ζ ^ κζ-γ jCcx ^ ^c ^ ^oH XxX / X 2 - [[[(2,3-dimethyl-1H-indole-5-)] yl) amino] carbonyl] amino] -N- - (2,4,6-trimethylphenyl) -6- -benzothiazolecarboxamide 4.28 92 , ^{ν =} = \ CHα Τ ^{<η =} ΑΑ 2 - [[[[3- (1,3,4-oxadiazol-2-yl)] -. phenyl] airuno] carbonyl] amino] -N- (2,4,6-trimethylphenyl) -6-benzothiazolecarboxamide 3.76 93 H, C / —f ⁰ ” ³ ο ν — χχ ν Χ \ <$ aa X X> H α HP 2 - [[[(2-chloro-6-methylphenyl) - amino] carbonyl] amino] -N- - (2,4,6-trimethylphenyl) -6- -benzothiazolecarboxamide 4.08

· E e e e e e e e e e e e e e e e e e e e e e e e e e e e · · ·· ··

94 HjC 2 - [[[[3- (methylthio) phenyl] amino] ^-1- carbonyl] amino] -N (2,4,6-trimethylphenyl) -6-benzothiazolecarboxamide 4.48 95 CH, ď ' 2 - [[[(4-Methoxy-2-methylphenyl) - amino] carbonyl] amino] -N- - (2,4,6-Trimethylphenyl) -6- -benzothiazolecarboxamide 4.59

Examples 96-140

General procedure

Compounds 96-140 were prepared as follows.

Add diisopropylamine (50 μΐ, 0.288 mmol) to the free base mixture of compound 2 (30 mg, 0.096 mmol), the appropriate carboxylic acid (0.115 mmol), 1-hydroxy-7-azabenzotriazole (17 mg,

0.125 mmol) and ethyl 3- (3-dimethylamino) -propylcarbodiimide hydrochloride (24 mg, 0.125 mmol) in THF (1 mL). The mixture was heated at 45 ° C for 18 to 72 hours. The reaction mixture was diluted with dichloromethane (5 mL) and washed with 1N aqueous HCl (2X) and 1N aqueous NaOH (2X). The organic extract was dried (MgSO ₄ ), filtered and concentrated in vacuo. The crude compounds were purified by either trituration with dichloromethane-ether or automatic preparative HPLC (conditions: YMC ODS A 20 x 100 mm column, 10 min gradient from 30% solvent B (90% MeOH, 10%

H ₂ O, 0.2% H ₃ PO ₄ ) and 70% solvent A (10% MeOH, 90% H ₂ O, 0.2% H ₃ PO ₄ ) to 100% solvent B, flow rate 20 ml / min. , lambda = 220 nM) to give the compounds of these examples, which are shown in Table 3, below.

In Table 3, HPLC Ret time is the HPLC retention time obtained for 9 9 9 4 94444 4. t · tl of the following conditions: YMC S5 ODS 4.6 x 50 mm Ballastic Column, min. gradient from 100% solvent A (10% MeOH, 90% H ₂ O, 0.2% H _with PO ₄ ) to 100% solvent B (90% MeOH, 10% H ₂ O, 0.2% H ₃ PO ₄ ), flow rate 4 ml / min., lambda = 220 nM, for compounds 99 to 140. The following conditions were used for compound 98: Zorbax SB-C18

4.5 mm x 7.5 cm short column, 8 min. gradient from 100% solvent A (10% MeOH, 90% H ₂ O, 0.2% H ₃ PO ₄ ) to 100% solvent B (90% MeOH, 10% H_0, 0.2% H ₃ POJ, flow 2 , 5 ml / min, lambda = 217 nM The following conditions were used for compound 96: YMC S5 ODS 4.6 x 50 mm Ballastic Column, min gradient from 100% solvent A (10% MeOH, 90% H ₂ O) 0.2% H ₃ PO 4 to 100% solvent B (90% MeOH, 10% H ₂ O, 0.2% H ₃ POJ, flow rate 3 ml / min., Lambda = 220 nM. For compound 97, the following were used. conditions: YMC S5 ODS 4.6 x 50 mm Ballastic Column, min gradient from 100% solvent A (10% MeOH, 90% H ₂ O, 0.2% H ₃ PO ₄ ) to 100% solvent B (90% MeOH, 10% H ₂ O, 0.2% H ₃ PO ₄ ), flow rate 3 ml / min., Lambda = 220 nM.

Table 3

1 Ex. C. Formula compound Name of the compound F - -TPLC flight time (min 96 2 - [[(4-methoxycyclohexyl) - kaibonyl] amino] -N- - (2,4,6-trimethylphenyl) -6- -benzothiazolecarboxamide 4.73 97 2 - [(2,2-Dimethyl-1-oxopropyl) - amino] -N- (2,4,6-trimethylphenyl) -6- -benzothiazolecarboxamide 8.62 98 • - - 1 XT 2 - [(2-thienylacetyl) amino] -N- (2,4,6-trimethylphenyl) -6- -benzothiazolecarboxamide 8.58 99 N 2 - [(Cyclopropyl] aa-bonyl) anuno] - N- (2,4,6-Trimethylphenyl) -6- (benzothiazolkartx) xamide 3.93

Α * β

100 ALIGN! Yeah Μ WITH-/ Α, Ν κ Ο 2 - [(cyclobutylcarbonyl) amino] -N (2,4,6-trimethylphenyl) -6- -benzothiazolecarboxamide 4.00 101 CX Ν S-1I Α Α γΎ 2 - [(cyclopentylcarbonyl) amino] - N- (2,4,6-trimethylphenyl) -6- -benzothiazolecarboxamide 3.97 ífl ν Ο 102 X 4.52 κ 2 - [(3-Cyclopentyl-1-oxopropyl) - amino] -N- (2,4,6-trimethylphenyl) -6- -benzothiazolecarboxamide 103 ΟΑ Α - ^Ν γΎ 2 - [(3-Cyclopenten-1-ylcarbonyl) - amino] -N- (2,4,6-trimethylphenyl) -6- -benzothiazolecarboxamide 4.27 ΙιΊ »0 104 Ν 0 = / 2 - [(cyclohexyacetyl) amino] -N- - (2,4,6-trimethylphenyl) -6- -benzothiazolecarboxamide 4.51 V _with >>> αΑ 105 4 ^ 4 Α> γΎ 2 - [(1-oxo-2-phenylpropyl) amino] -N- - (2,4,6-trimethylphenyl) -6- -benzothiazolecarboxamide 4.20 ιίπ .ψυ s ο

• • ο ο

106 -X 2 - [(2-Methyl-1-oxopropyl) -amino] - -N- (2,4,6-trimethylphenyl) -6- -benzothiazolecarboxamide 3.89 107 ED O = < N s-K 2 - [(1-oxo-3-phenoxypropyl) amino] -> - -N- (2,4,6-trimethylphenyl) -6- -benzothiazolecarboxamide 4.34 108 °>> 0 2 - [(1-oxo-3-phenylpropyl) amino] - -N- (2,4,6-trimethylphenyl) -6- -benzothiazolecarboxamide 4.22 109 h-s 0 0 ' 2 - [[3- (2-methoxyphenyl) -1- -oxopropyl) amino] - -N- (2,4,6-trimethylphenyl) -6- -benzothiazolecarboxamide 4.25 110 N CH o o ' 1 2 - [[3- (2,3,4-trimethoxyphenyl) -1- -oxopropyl) amino] - -N- (2,4,6-trimethylphenyl) -6- -benzothiazolecarboxamide 4.15 111 2 - [(1,4-dioxypentyl) amino] - -N- (2,4,6-trimethylphenyl) -6- -benzothiazolecarboxamide 3.98

·

112 nn n AZ ro 2 - [(2-Naphthalenylacetyl) amino] - -N- (2,4,6-trimethylphenyl) -6- -benzothiazolecarboxamide 4.42 113 0 <b _N Cl s - ^ ZN u 2 - [[(2-chloro-6- -fluorophenyl) acetyl] amino] - -N- (2,4,6-trimethylphenyl) -6- -benzothiazolecarboxamide 4.21 114 N J? 2 - [[(2-methylphenyl) acetyl] amino] - -N- (2,4,6-trimethylphenyl) -6- -benzothiazolecarboxamide 4.31 115 N s- ^ 2 N Γϊί 2 - [[(2-methoxyphenyl) acetyl] amino] -N- (2,4,6-trimethylphenyl) -6- -benzothiazolecarboxamide 4.07 AJi 116 N s4 JL M 2 - [[(4-chlorophenyl) acetyl] amino] - -N- (2,4,6-trimethylphenyl) -6- -benzothiazolkaiboxamide 4.30 jČc ¹ ^ 117 2 - [(1-oxo-4-pentynyl) amino] - -N- (2,4,6-trimethylphenyl) -6- -benzothiazolecarboxamide 3.76

• · · · · ·

118 0 o / ¹ Ο-β 0 0 5-Oxo-5 - [[6 - [[(2,4,6-trimethylphenyl) amino] carbonyl] -2-benzothiazolyl] amino] pentanoic acid methyl ester 3.96 119 ° 0> s 0 3- 2 - [(1-oxohexyl) anuno] - -N- (2,4,6-trimethylphenyl) -6- -benzothiazolecarboxamide 4.36 120 ° Í> o hr ^ 44 <Z \ zZ \ ^ 2 - [(1-oxoheptyl) amino] - -N- (2,4,6-trimethylphenyl) -6- -benzothiazolkaiboxamide 4.49 121 N * sX ^ ^N 2 - [[1-oxo-4- (2- -thienyl) butyl] amino] - -N- (2,4,6-trimethylphenyl) -6- -benzoethiazolecarboxamide 4.42 122 GX 2 - [(3-thienylcarbonyl) amino] - -N- (2,4,6-trimethylphenyl) -6- -benzothiazolecarboxamide 4.06 123 ο = τ ^ · £ N 2 - [[(4-nitrophenyl) acetyl] amino] - -N- (2,4,6-trimethylphenyl) -6- -benzothiazolecarboxamide 4.17

AND. * 4 4 4 4 4 4 4 4

124 ^F 2 - [[3,5-bis (trifluoromethyl) phenyl] -, acetyl] amino] -N- (2,4,6-trimethylphenyl) -6-benzothiazolecarboxamide 4.65 125 2 - [[2- [4- (2-methylpropyl) phenyl] -1- -oxopropyl) amino] - -N- (2,4,6-trimethylphenyl) -6- -benzothiazolecarboxamide 4.80 126 2 N S ~ 6 2 - [[(3-Cyclohexen-1-yl) carbonyl] - amino] -N- (2,4,6-trimethylphenyl) -6- -benzothiazolecarboxamide 4.20 127 ^ -3 0 2 - [[3- (3-methoxyphenyl) -1- -oxopropyl) amino] - -N- (2,4,6-trimethylphenyl) -6- -benzothiazolecarboxamide 4.22 128 x ~ P N ^Cl CI 2 - [[(2,3,6-trichlorophenyl] -1-acetyl) amino] -N- (2,4,6-trimethylphenyl) -6-benzothiazolecarboxamide 4.50 129 N 2 - [[(1,3-benzodioxol-5-yl) acetyl] amino] -N- (2,4,6-trimethylphenyl) -6-benzothiazolecarboxamide 4.04

i · · »* a a

9 · · 9 · · «« *

130 b- · » 2 - [[[2- (phenylmethoxy) phenyl] -a acetyl] amino] -N- (2,4,6-trimethylphenyl) -6-benzothiazolecaboxamide 4.35 131 N 0 'sX ^' ' 2 - [[(3,5-dimethoxyphenyl) acetyl] -> amino] -N- (2,4,6-trimethylphenyl) -6-benzothiazolecarboxamide 4.09 132 ° Í> s o 2 - [[3- (1H-benzodioxol-5-yl) -1] - -oxopropyl] amino] -N- (2,4,6- -trimethylphenyl) -6- -benzothiazolecarboxamide 4.18 133 cw 0 N 2 - [[(tetrahydro-2-furanyl) - carbonyl] amino] -N- (2,4,6- -trimethylphenyl) -6- -benzothiazolecarboxamide 3.93 134 N ° ^ e 0 Α, Αγγγ ⁰ 2 - [[2- (acetylamino) -1- oxopropyl] amino] -N- (2,4,6- -trimethylphenyl) -6- -benzothiazolecarboxamide 3.63 135 O HL N ' with-/ 2 - [[2- (acetylamino) -1- -oxohexyl] amino] -N- (2,4,6- -tximethylphenyl) -6- -benzothiazolecarboxamide 3.97

• · ♦ ♦ ♦ 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 · · · »· ·

136 Xi / 2 '- 2 - [(cyclopropylacetyl) amino] -N- (2 _with 4,6-trimethylphenyl) -6-benzothiazolecarboxamide 3.92 137 o, 0 ¹ N, N-dimethyl-N '- [6 - [[(2,4 _T ^' -trimethylfenyl) amino] carbonyl] -2-benzothiazolyl] butanediamine 3.66 138 H. N 2 - [(1-adamantylcarbonyl) amino] - -N- (2,4,6-trimethylphenyl) -6- -benzothiazolecarboxamide <. · 4.59 139 2 - [[(4-methylcyclohexyl) ^-1- carbonyl] amino] -N- (2,4,6-trimethylphenyl) -6-benzothiazolecarboxamide 4.42 140 2 - [(3-methoxy-1- oxopropyl) amino] -N- (2,4,6- -trimethylphenyl) -6- -benzothiazolecarboxamide 3.34

Examples 141-163

Compounds 141-163 were prepared by the following methods, which are described below.

A. 2-tert-Butoxycarbonyloxyamino-benzothiazole-6-carboxylic acid chloride

A 2M solution of oxalyl chloride in dichloromethane (6.8 mL, 13.59 mmol) was added to a suspension of compound IC (2 g, 6.79 mmol) in dichloromethane (25 mL) at 0 ° C. Dimethylformamide was added dropwise (3 drops). Remove the water bath and stir the suspension at ambient temperature for 3 hours and then heat at 32 ° C for an additional 3 hours. The mixture was diluted with ether (25 mL) and the solid material was collected by filtration. The solid material was washed several times with ether and dried in vacuo to give the title compound of this step (1.75 g, 82%). Another portion of the title acid chloride was obtained by trituration of the filtrate after concentration with ether (250 mg, 12%).

B. Compounds 141-163

Add diisopropylamine (23 μΐ, 0.288 mmol) to a mixture of 2-tert-butoxycarbonyloxyamino-benzothiazole-6-carboxylic acid chloride (34.41 mg, 0.11 mmol) and the appropriate aniline (0.12 mmol) in THF (1 mL) ). The mixture was stirred at ambient temperature for 22 hours. The reaction mixture was diluted with dichloromethane (4 mL) and washed with 1 N aqueous HCl (2x), dried (Na ₂ SO ₄ ), filtered, and concentrated in vacuo. The crude compounds were purified by either trituration with dichloromethane-ether (1: 1) or silica gel chromatography (eluting: 2-5% MeOH in dichloromethane) and the obtained compounds are shown in Table 4 below.

In Table 4, the HPLC Ret time is the HPLC retention time obtained under the following conditions: YMC S5 ODS 4.6 x 50 mm Ballastic Column, min. gradient from 100% solvent A (10% MeOH, 90% H ₂ O, 0.2% H ₃ PO ₄ ) to 100% solvent B (90% MeOH, 10% H ₂ O, 0.2% H ₃ PO ₄ ), flow rate 4 ml / min., lambda = 220 nM.

• to • •• to «· ·

Table 4

Ex. C. Formula compound Name of the compound HPLC Ret time (min) 141 O, '' In ZoU [6 - [[(2,3-Dihydro-1H-inden-5-yl) amino] carbonyl] -2-benzothiazolyl] carbamic acid 1,1-dimethylethyl ester 4.44 142 in # Q o ⁰ Y Acid 1,1-dimethylethyl ester [6 - [(2-naphthylenylamino) carbonyl] - -2-benzothiazolyl] carbamic 4.46 143 M, ^0N [6 - [[(3-hydroxy-2-naphthalenyl) amino] carbonyl] -2-benzothiazolyl] carbamic acid 1,1-dimethylethyl ester 4.46 144 Q- » [6 - [[(2-fluoro-5-methylphenyl) amino] carbonyl] -2-benzothiazolyl] carbamic acid 1,1-dimethylethyl ester 4.21 145 A / <y _with p. [6 - [[(2-Chloro-6-methylphenyl) amino] carbonyl] -2-benzothiazolyl] kaibamic acid 1,1-dimethylethyl ester 1 4.05 146 [6 - [[(2,6-dimethylphenyl) amino] carbonyl] -2-benzothiazolyl] kaibamic acid 1,1-dimethylethyl ester 1 4.07 L

• · ·)))))))

147 Ά [6 - [[(4-Bromo-2-methyl-phenyl) -amino] -carbonyl] -2-benzothiazolyl] -carbamic acid 1,1-dimethylethyl ester 4.34 148 Az [6 - [[(3-Bromo-2,4,6-trimethyl-phenyl) -amino] -carbonyl] -benzothiazolyl] -carbamic acid 1,1-dimethyl-ethyl ester 4.45 149 6 - [[[2,6-dimethyl-3- (1-methylethyl) phenyl] amino] carbonyl] -2-benzothiazolyl] carbamic acid 1,1-dimethylethyl ester 4.44 150 X [6 - [[(2-Bromo-4,6-dimethyl-phenyl) -amino] -a-carbonyl] -2-benzothiazolyl] -carbamic acid 1,1-dimethyl-ethyl ester 4.22 151 / Xy, o [6 - [[(2-methyl-6-quinolinyl) amino] carbonyl] -2-benzothiazolyl] carbamic acid 1,1-dimethylethyl ester 3.41 152 CX <Vs 0, VaaA 6 - [[(4-methoxy-2-naphthalenyl) imino] carbonyl] -1-benzothiazolyl] carbamic acid, 1-dimethylethyl ester 4.58 153 Y-XX-1> 1 -dimethylethylester acids 3-26 \ _ / \ / F [6 - [[(6-methyl-5-quinolinyl) - ^w * ~ \ amino] carbonyl] -2- _(V wy benzothiazolyljkarbamové -, |

• · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · »

154 0-, ». [6 - [[[2- (2-hydroxy-ethyl) -6-methyl-phenyl] -amino] -carbonyl] -2-benzothiazolyl] -carbamic acid 1,1-dimethylethyl ester 3.85 155 ° ^iN- Ct ^> - λν / EN 0 I [6-t [(2,6-Dimethyl-3-nitrophenylamino) -carbonyl] -2-benzothiazolyl] -carbamic acid 1,1-dimethylethyl ester AND 4.03 156 TO ΧΑΛΛ, [6 - [[(2-Bromo-3,4,6-trimethyl-phenyl) -amino] -carbonyl] -benzothiazolyl] -calabamic acid 1,1-dimethylethyl ester 4.32 157 Q-. Xď [6 - [[(2-acetyl-6-hydroxyphenyl) amino] carbonyl] -2-benzothiazolyl] carbamic acid 1,1-dimethylethyl ester 4.26 158 ° -H- · · J_ ΆαΛοΑ [6 - [[[4 - [[(1,1-dimethylethoxy) carbonyl] amino] -2,3,5,6-tetramethylphenyl] amino] kaibonyl] -2-benzothiazolyl] kattamic acid 1,1-dimethylethyl ester 4.31 159 -¾. [6 - [[(4-bromo-2,6-dimethyl-phenyl) -amino] -carbonyl] -2-benzothiazolyl] -carbamic acid 1,1-dimethylethyl ester - —X - 5.13 160 ,,. βς o n-AA ch, Ύ * 0 [6- (1- (3-Acetylamino) -4,6-dimethylphenyl] amino] carbonyl] -2-benzothiazolyl] carbamic acid 1,1-dimethylethyl ester 4.27

161 ? [6 - [[(2,6-Dimethoxyphenyl) amino] carbonyl] -2-benzothiazolyl] carbamic acid 1,1-dimethylethyl ester , 3.73 162 Αλλ [6 - [[(2-methyl-1-naphthalenyl) amino] carbonyl] -2-benzothiazolyl] carbamic acid 1,1-dimethylethyl ester 4.18 163 YV ťV 4.09 3 - [[[2 - [[(1,1-dimethylethoxy) carbonyl] amino] -6-benzothiazolyl] carbonyl] amino] -4-methyl-2-thiophenecarbonyl

Example 164: Preparation of [6 - [[(2,4,6-trimethylphenyl) amino] carbonyl] -2-benzothiazolyl] carbamic acid methyl ester

Methyl chloroformate (250 μΐ) was added dropwise to a stirred solution of the free base of compound 2 (62 mg, 0.2 mmol) in THF (10 mL) and a 10% aqueous KHCO ₃ solution (15 mL) at 0-5 ° C.

The biphasic mixture was stirred for 2 hours and then diluted with dichloromethane (25 mL) and water (20 mL). The organic extracts were dried (MgSO ₄ ), filtered and concentrated. The crude residue was chromatographed on a silica gel column eluting with 30% EtOAc in hexanes followed by 50% and 70% EtOAc in hexanes and 10% MeOH in dichloromethane to give the title compound (42 mg, 57%) as a white solid.

• · · · · ·

MS = 370 (. + -.).

Example 165: Preparation of 2 - [[(acetylamino) acetyl] amino] -4- (2,4,6-trimethylphenyl) -6-benzothiazolecarboxamide

Add diisopropylamine (400 μϊ, 2.3 mmol) to the free base mixture of compound 2 (50 mg, 0.16 mmol), N-acetylglycine (42 mg,

0.36 mmol), 1-hydroxy-7-azabenzotriazole (49 mg, 0.36 mmol) and ethyl 3- (3-dimethylamino) -propylcarbodiimide hydrochloride (72 mg, 0.36 mmol) in THF (6 mL) ). The mixture was heated at 50 ° C overnight, cooled to ambient temperature, diluted with dichloromethane (60 mL) and washed with 2N aqueous HCl (20 mL) and saturated NaHCO ₃ (15 mL, 2x). Dichloromethane extract was dried (MgSO ₄ ), filtered and concentrated. The residue was diluted with dichloromethane-methanol (20 mL, 4: 1) and EtOAc (5 mL) was added. The precipitated solid was filtered, washed with EtOAc (5 mL, 3x) and dried in vacuo to give the title compound (15 mg,

22.8%).

MS = 411.1 (M + H).

Example 166: Preparation of N- (2-chloro-6-methylphenyl) -2 - [[[(1,1-dimethylethyl) amino] carbonyl] amino] -6-benzothiazolecarboxamide

• ·

A. Ethyl 2 - [[(phenoxy) carbonyl] amino] benzothiazole-6-carboxylate

Phenylchloroformate (14.25 mL, 113.6 mmol) was added dropwise to a stirred solution of compound IA (8.6 g, 37.86 mmol) in THF (300 mL) and saturated aqueous KHCO ₃ (300 mL) at temperature 0-5 ° C. The biphasic mixture was stirred for 3.5 hours. The THF layer was separated and the aqueous layer was extracted with dichloromethane (150 mL,

2x). The yellow solid which precipitates during the reaction is recovered by filtration, washed with dichloromethane, water and ether. Combine the organic extracts, dry (Na ₂ SO ₄ ), filter and concentrate to give a yellow solid. Combine the crude solid, dilute with ether (100 mL), filter, and dry in vacuo to afford the title compound of this step as a yellow solid (11.24 g, 85%).

B. Ethyl 2 - [[[(1,1-dimethylethyl) amino] carbonyl] amino] benzothiazole-6-carboxylate

Tert-Butylamine (6.66 mL, 63.4 mmol) was added to a stirred suspension of compound 166A (11.23 g, 32.33 mmol) in THF (163 mL). The suspension was stirred at ambient temperature for 16 hours and the yellow solid was filtered off, washed with THF, 2N aqueous HCl, 0.1 N aqueous NaOH, water and ether. The filtrate was diluted with dichloromethane and washed with 2N aqueous HCl (2x) and 0.1N aqueous NaOH (2x) and brine. The dichloromethane extract was dried (Na ₂ SO ₄ ), filtered, and concentrated to give a yellow solid. The solids were combined, suspended in ether, filtered, washed several times with ether and dried in vacuo to afford the title compound of this step (10.41 g, 100%).

C. 2 - [[[(1,1-Dimethylethyl) amino] carbonyl] amino] -benzothiazole-6-carboxylic acid

A 2N aqueous potassium hydroxide solution (405 mL) was added to a suspension of 166B (10.41 g, 32.4 mmol) in THF (90 mL) and ethanol (135 mL). Warm the mixture to 60 ° C, cool to 0 ° C and concentrate. The residue was cooled to 0 ° C and acidified to pH 1.0 with conc. HCl. The precipitated solid was filtered, washed with water and ether. The solid material was suspended in toluene (2x) and concentrated under reduced pressure. This procedure was repeated with ether (2x). The solid material was collected and dried under vacuum over phosphorus pentoxide to give the title compound of this step (10 g, 100% yield).

D. 2 - [[[(1,1-Dimethylethyl) amino] carbonyl] amino] benzothiazole-6-carboxylic acid 7-aza-benzotriazole ester (HOAT ester)

Add diisopropylethylamine (958 μΐ, 6.84 mmol) to a solution of 166C (500 mg, 1.71 mmol) and HATU (778 mg, 2.05 mmol) in dimethylformamide (10 mL). The solution was stirred at ambient temperature overnight, diluted with dichloromethane and washed with 1N aqueous HCl and water. The dichloromethane extract was separated, dried (MgSO ₄₎ and concentrated. The crude solid was triturated with methanol (2x) to give the title compound of this step (380 mg, 54.3%). A second crop of the title compound (152 mg, 21.7%) was obtained after trituration of the residual filtrate.

Ε. N- (2-chloro-6-methylphenyl) -2 - [[[(1,1-dimethylethyl) amino] carbonyl] amino] -6-benzothiazolecarboxamide

A 1M solution of sodium bis-trimethylsilylamide (366 μΐ, 0.37 mmol) was added to a stirred solution of 2-chloro-6-methyaniline (33.1 μΐ, 0.268 mmol) in THF (2 mL). The mixture was stirred at ambient temperature for 10 minutes and compound 166D (100 mg, 0.244 mmol) was added. Dimethylformamide (2 mL) was added to dissolve the precipitate formed during the reaction. The mixture was stirred at ambient temperature overnight, diluted with dichloromethane and washed with 1N aqueous HCl (30 mL, 3x), 5% aqueous KHCO ₃ (20 mL, 2x). The organic extract was dried (MgSO ₄ ), filtered, and concentrated. The crude residue was purified by automatic preparative HPLC (conditions: YMC ODS A 20 x 100 mm column, 10 min gradient from 30% solvent B (90%).

MeOH, 10% H ₂ O, 0.1% TFA) and 70% solvent A (10% MeOH, 90%

H ₂ O, 0.1% TFA) to 100% solvent B, flow rate 20 mL / min, lambda = 220 nM) to give the title compound of this example (19.5 g,

19%).

MS = 417 (M + H).

Alternative method

A (alt.). [6 - [[(2-chloro-6-methylphenyl) amino] carbonyl] -2-benzothiazolyl] carbamic acid 1,1-dimethylethyl ester

Diisopropylethylamine (1.67 mL, 6.02 mmol) was added to a stirred suspension of compound 141A (2-tert-butoxycarbonyloxyamino-benzothiazole-6-carboxylic acid chloride) (1.88 g,

6.02 mmol), 2-chloro-6-methylaniline (960 μΐ, 7.83 mmol) in THF (40 mL). The mixture was stirred at ambient temperature overnight and then diluted with dichloromethane (100 mL). The reaction mixture was washed with 1N aqueous HCl (2X), 1N aqueous NaOH and brine.

The organic layer was dried (Na ₂ SO ₄ ), filtered, and concentrated. The residue was diluted with EtOAc (10 mL). Stir for 20 minutes and add diethyl ether (5 mL). After 5 minutes, the solid material was filtered off and dried in vacuo to give the title compound of this step (940 mg, 37%).

B (alt.). 2-Amino-N- (2-chloro-6-methylphenyl) -6-benzothiazolecarboxamide

A solution of 166A (alt) (940 mg, 2.25 mmol) in trifluoroacetic acid (5 mL) and dichloromethane (2 mL) was stirred at ambient temperature overnight. The mixture was concentrated, diluted with dichloromethane (100 mL) and washed with saturated sodium bicarbonate solution (2x), water and brine. The dichloromethane extract was dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo to give the title compound of this step (750 mg, 98%).

C (alt.). [6 - [[(2-chloro-6-methylphenyl) amino] carbonyl] -2-benzothiazolyl] -6-carbamic acid phenyl ester

Use a method analogous to that used for the preparation of 7A, except for the use of 1666B (alt) instead of the free base of 2, to give the title compound of this step (92%), obtained after trituration with diethyl ether / EtOAc (1: 1). ).

D (alt). N- (2-chloro-6-methylphenyl) -2 - [[[(1,1-dimethylethyl) amino] carbonyl] amino] -6-benzothiazolecarboxamide

A solution of 166C (alt) (680 mg, 1.57 mmol) and tert-butylamine (196 µL, 1.87 mmol) in THF (50 mL) was stirred for 7 hours. The mixture was diluted with dichloromethane (200 mL) and washed with 1 N aqueous HCl (50 mL), 1 N aqueous NaOH (50 mL, 2x). The organic extract was dried (Na ₂ SO ₄ ), filtered and concentrated. The residue was triturated with diethyl ether to give the title compound of this example (488 mg, 75%).

Example 167: Preparation of N- (2,6-dichlorophenyl) -2 - [[[(1,1-dimethylethyl) amino] carbonyl] amino] -6-benzothiazolecarboxamide

• ·

Use a method analogous to that used for the preparation of 166E, except using 2,6-dichloroaniline, to give the title compound of this example (17%), which was obtained after purification by automatic preparative HPLC (conditions: YMC ODS A 20 x 100 mm) column, 10 min gradient from 30% solvent B (90% MeOH, 10% H ₂ O, 0.1% TFA) and 70% solvent A (10% MeOH, 90% H _from O, 0.1% TFA) to 100% solvent B, flow rate 20 ml / min, lambda = 220 nM).

MS = 438 (M + H).

Example 168: Preparation of N- (4-bromo-2,6-dimethylphenyl) -2 - [[[(1,1-dimethylethyl) amino] carbonyl] amino] -6-benzothiazolecarboxamide

Use a method analogous to that used for the preparation of compound 166E, except using 4-bromo-2,6-dimethylaniline, to afford the title compound (19%), which was obtained after purification by automatic preparative HPLC (conditions: same as Example 167) ).

MS = 477 (M + H).

Example 169: Preparation of N- (4-carbomethoxy-2,6-dimethylphenyl) -2 - [[(1,1-dimethylethoxy) carbonyl] amino] -6-benzothiazolecarboxamide

C (O) -OCH ₃ o

• · · · ·

A method analogous to that used for the preparation of the compounds listed in Table 4 is used, except for use

4-carbomethoxy-2,6-dimethylaniline, affording the title compound of this example (53%).

MS = 428.1 (M + H).

Example 170: Preparation of N- (4-hydroxymethyl-2,6-dimethylphenyl) -2 - [[(1,1-dimethylethoxy) carbonyl] amino] -6-benzothiazolecarboxamide

Use a method analogous to that used for the preparation of compounds 141 to 163, except using 4-hydroxymethyl-2,6-dimethylaniline, to give the title compound of this example (71%).

MS = 456.1 (M + H).

Example 171. Preparation of [4-methyl-6 - [[(2,4,6-trimethylphenyl) amino] carbonyl] -2-benzothiazolyl] carbamic acid 1,1-dimethylethyl ester

A. Methyl 2-amino-4-methylbenzothiazole-6-carboxylate

Use a method analogous to that used for the preparation of compound IA, except using methyl 4-amino-3-methylbenzoate, to afford the title compound of this step.

B. Methyl 2,2-bis-tert-butoxycarbonyloxyamino-4-methyl-benzothiazole-6-carboxylate

A suspension of Compound 171A (1.16 g, 5.2 mmol, 85% pure), di-tert-butyl carbonate (2.37 g, 10.87 mmol) and 4-dimethylaminopyridine (93 mg, 0.76 mmol) in THF (80 mL) was heated at 60 ° C for 3.5 h. The mixture was cooled, washed with 1N aqueous HCl (50 mL, 2X) and water. The organic extract was dried (MgSO ₄ ), filtered and concentrated to give the title compound of this step (693 mg, 31.5%).

C. 2-tert-Butoxycarbonyloxyamino-4-methylbenzothiazole-6-carboxylic acid

Use a method analogous to that used for the preparation of compound IC, except for the use of compound 171B, to obtain (95%) the title compound of this step as a white solid.

D. [4-Methyl-6 - [[(2,4,6-trimethylphenyl) amino] carbonyl] -2-benzothiazolyl] carbamic acid 1,1-dimethylethyl ester

Add diisopropylethylamine (65 μΐ, 0.51 mmol) to a stirred solution of Compound 171C (50 mg, 0.17 mmol),

2,4,6-trimethylaniline (28.4 μΐ, 0.203 mmol) and benzotriazolo-1-yloxytris (dimethylamino) phosphonium hexafluorophosphate (Castro reagent, 89.6 mg, 0.203 mmol) in dimethylformamide (2 mL). The solution was stirred at ambient temperature for 40 hours and then diluted with dichloromethane (50 mL). The mixture was washed with 1N aqueous HCl (25 mL, 2x) and water, dried (MgSO 4), filtered and concentrated. The crude residue was triturated with ether / EtOAc. The solid material was collected and dried under vacuum to give the title compound of this example (43 mg, 62%).

Example 172: Preparation of 2-amino-4-methyl-N- (2,4,6-trimethylphenyl) -6-benzothiazolecarboxamide, trifuloroacetate (1: 1)

Use a method analogous to that used to prepare Compound 2, except for Compound 171D, to afford the title compound of this example (74%).

MS = 326 (M + H)

Example 173. Preparation of 4-methoxy- [6 - [[(2,4,6-trimethylphenyl) amino] carbonyl] -2-benzothiazolyl] carbamic acid 1,1-dimethylethyl ester

Use a method analogous to that used for the preparation of Compound 171D, except using methyl 4-amino-3-methoxybenzoate, to give the title compound of this example.

MS = 442 (M + H).

• · · »

Example 174: Preparation of 2-Amino-4-methoxy-N- (2,4,6-trimethylphenyl) -6-benzothiazolecarboxamide, trifuloroacetate (1: 1).

Use a method analogous to that used for the preparation of Compound 2, except using Compound 173, to give the title compound of this example (82%) as a white solid.

MS = 342 (M + H).

Example 175. Preparation of 2 - [[(methylamino) carbonyl] amino] -N- (2,4,6-trimethylphenyl) -6-benzothiazolecarboxamide

Use a method analogous to that used for the preparation of compound 15, except using methyl isocyanate, to give the title compound of this example (71%) as a white solid.

MS = 369 (M + H).

Example 176. Preparation of 2 - [[(methylamino) carbonyl] amino] -4-methoxy-N- (2,4,6-trimethylphenyl) -6-benzothiazolecarboxamide

A method analogous to compound 175 was used except for using the title compound of this example material.

MS = 399 (M + H).

of the method used to prepare Compound 174 to give (39%) as a white solid

Example 177. Preparation of 1,1-dimethylethyl 5-methoxy [6 - [[(2,4,6-trimethylphenyl) amino] carbonyl] -2-benzothiazolyl] carbamic _CH3 about

ΆΛΑ ^H3 ° H '.OCH ₃ ^H 3 ^C.

Use a method analogous to that used for the preparation of Compound 171D, except using methyl 4-amino-2-methoxybenzoate, to give the title compound of this example.

MS = 442 (M + H).

Example 178: Preparation of 2-amino-N- (4-N, N-dimethylamino-2,3,5,6-tetramethyl) -6-benzothiazolkarboxamidu, trifluoroacetate (1: 1) CF ₃ COOH · «·« · · · · · · · * * * *

Use a method analogous to that used for the preparation of the compounds listed in Table 4, except for the use of _{χ χ} , Ν, 2,3,5,6-hexamethyl-1,4-phenylenediamine dihydrochloride, to give the title compound of this example, obtained after Purification by automatic preparative HPLC (conditions: same as Example 167).

MS = 369.2 (M + H).

Examples 179 and 180: Preparation of 1,1-dimethylethyl acid ester

5-chloro- [6 - [[(2,4,6-trimethylphenyl) amino] carbonyl] -2-benzothiazolyl] carbamic acid (179)

and preparation of 7-chloro- [6 - [[(2,4,6-trimethylphenyl) amino] carbonyl] -2-benzothiazolyl] carbamic acid 1,1-dimethylethyl ester (180)

A. Methyl 2-amino-5-chloro-benzothiazole-6-carboxylate (179A) and methyl 2-amino-7-chloro-benzothiazole-6-carboxylate (180A)

Use a method analogous to that used for the preparation of compound IA, except using methyl 2-amino-4-chlorobenzoate, to give a 2: 1 mixture of the title compounds of this example (71%).

• 4

Β. Methyl 2-tert-butoxycarbonyloxyamino-5-chlorobenzothiazole-6-carboxylate (179B) and methyl 2-tert-butoxycarbonyloxyamino-7-chlorobenzothiazole-6-carboxylate (180B)

Use a method analogous to that used for the preparation of compound IB, except using compounds 179A and 180A, to obtain a 2: 1 mixture of the title compounds of this example as a yellow solid (63%).

C. 2-tert-Butoxycarbonyloxyamino-5-chlorobenzothiazole-6-carboxylic acid (179C) and 2-tert-butoxycarbonyloxyamino-7-chlorobenzothiazole-6-carboxylic acid (180C)

A solution of a mixture of Compounds 179B and 180B (3.75 g, 10.9 mmol) in ethanol (50 mL) and 2N aqueous sodium hydroxide solution (27.5 mL, mmol) was stirred at ambient temperature for 18 hours. Most of the ethanol was removed in vacuo and the residue was cooled to 0 ° C and acidified to pH 1-2 using a saturated aqueous solution of potassium hydrogen sulfate. The precipitate was filtered off, washed with water and dried in vacuo to give a mixture of the title acids 179C and 180C (4.3 g, 100%, 2: 1 ratio) as a yellow solid.

D. 5-Chloro- [6 - [[(2,4,6-trimethylphenyl) amino] carbonyl] -2-benzothiazolyl] carbamic acid 1,1-dimethylethyl ester (179D) and 7-chloro- [6 - [[(2,4,6-trimethylphenyl) amino] carbonyl] -2-benzothiazolyl] carbamate (180D)

Add diisopropylamine (400 μΐ, 2.2 mmol) to a mixed suspension of Compounds 179C and 180C (328 mg, 1 mmol), 2,4,6-trimethylaniline (170 μΐ, 1.1 mmol) and benzotriazol-1-yloxytris ( dimethylamino) phosphonium hexafluorophosphate (Castro reagent, 485 mg, 1.1 mmol) in dichloromethane (5 mL). The solution was stirred at ambient temperature for 18 hours, filtered and dried to give benzotriazole esters (400 mg), which was dissolved in dimethylformamide (5 mL) and 2,4,6-trimethylaniline was added. (560 μΐ, 4 mmol). The solution was heated at 50 ° C for 72 hours, cooled and diluted with EtOAc (100 mL) and water (100 mL). Separate the EtOAc layer, wash with 1N aqueous HCl (100 mL, 3x), brine (50 mL), dry (MgSO ₄ ), filter and concentrate. The orange-yellow solid was dissolved in dimethylsulfoxide (1 mL) and diluted with methanol (5 mL) and then water (5 mL). The solution is allowed to stand at ambient temperature for several hours. The precipitated solid was filtered, washed with water (20 mL), dried, and then recrystallized from DMSO-MeOH-H ₂ O to give pure title compound 179D (45 mg, 10%).

MS = 447 (M + H).

Additional solid material was obtained from the original liquid material from which it was filtered and dried under vacuum to give the title compound 180D (44 mg, 10%).

MS = 447 (M + H).

Example 181. Preparation of 2-amino-5-hydroxy-N- (2,4,6-trimethylphenyl) -6-benzothiazolecarboxamide

Add boron tribromide (300 μΐ, 3 mmol) to a solution of Compound 177 (441 mg, 1 mmol) in dichloromethane (7 mL) at -78 ° C. The solution was stirred at -78 ° C for 1 hour and at ambient temperature for 1 hour, diluted with a saturated aqueous NaHCO 3 solution and concentrated in vacuo. The residue was diluted with water and filtered. The white solid was washed thoroughly with water, ether and dried

under vacuum to give the title compound of this example (260 mg, 80%).

MS = 328 (M + H).

Example 182. Preparation of 5-tert-butoxycarbonyloxy- [6 - [[(2,4,6-trimethylphenyl) amino] carbonyl] -2-benzothiazolyl] carbamic acid 1,1-dimethylethyl ester

Use a method analogous to that used for the preparation of compound IB except for the use of compound 181 to afford the title compound 182 (25%), which was obtained after purification by silica gel chromatography eluting with a gradient of dichloromethane-5% MeOH in dichloromethane with 1% addition. MeOH.

MS = 428 (M + H).

Example 176. Preparation of 2 - [[[(1,1-dimethylethyl) amino] carbonyl] amino] -N- (2,6-dimethylphenyl) -6-benzothiazolecarboxamide

Use a method analogous to that used for the preparation of compound 166E, except using 2,6-dimethylaniline, to afford the title compound of this example (19%), which was obtained after purification by automatic preparative HPLC (conditions: same as in Example 167).

MS = 397 (M + +).

Alternative method

A (alt.). [6 - [[(2,6-dimethylphenyl) amino] carbonyl] -2-benzothiazolyl] carbamic acid 1,1-dimethylethyl ester

Add diisopropylethylamine (1.17 mL, 6.42 mmol) to a stirred suspension of Compound 141A (2-tert-butoxycarbonyloxyamino-benzothiazole-6-carboxylic acid chloride) (1.0 g, 3.21 mmol), 2.6- dimethylaniline (473 μϊ, 3.84 mmol) in THF (25 mL).

The mixture was stirred at ambient temperature overnight and then diluted with dichloromethane (70 mL). The reaction mixture was washed with 1N aqueous HCl solution (30 mL, 2x), water and brine. The organic layer was dried (Na ₂ SO ₄ ), filtered, and concentrated. The residue was triturated with diethyl ether / EtOAc (1: 1), filtered and dried in vacuo to afford the title compound of this step (475 mg, 37%).

B (alt.). 2-amino-N- (2,6-dimethylphenyl) -6-benzothiazolecarboxamide

A solution of 183A (alt) (1 g, 2.5 mmol) in trifluoroacetic acid (6 mL) and dichloromethane (5 mL) was stirred at ambient temperature for 2.5 hours. The mixture was concentrated, diluted with dichloromethane and washed with saturated sodium bicarbonate solution (25 mL, 2x), water and brine. The dichloromethane extract was dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo. The residue was triturated with ether to give the title compound of this step (570 mg, 76%).

C (alt.). [6 - [[(2,6-dimethylphenyl) amino] carbonyl] -2-benzothiazolyl] -6-carbamic acid phenyl ester

Use a method analogous to that used for the preparation of compound 7A, except using compound 183B (alt) instead of the free base of compound 2, to obtain the title compound of this step (98%), obtained after trituration with diethyl ether / EtOAc (10: 1). ).

D (alt). 2 - [[[(1,1-dimethylethyl) amino] carbonyl] amino] -N- (2,6-dimethylphenyl) -6-benzothiazolecarboxamide

A solution of compound 183C (alto) (46 mg, 0.11 mmol) and tert-butylamine (14 μί, 0.13 mmol) in THF (4 mL) was stirred at ambient temperature overnight. The mixture was diluted with dichloromethane (50 mL) and washed with 1N aqueous HCl (30 mL), 1N aqueous NaOH (25 mL, 2X) and water. The organic extract was dried (Na ₂ SO ₄ ), filtered and concentrated. The residue was triturated with diethyl ether to give the title compound of this example (23 mg, 66%).

Examples 184-204

General procedure

The appropriate amine (0.086 mmol) was added to a solution of compound 183C (alt) (30 mg, 0.072 mmol) in THF (3 mL). In the case of aliphatic amines, the solution is stirred at ambient temperature for 48-72 hours. In the case of anilines, the solution is heated at 60 ° C for 72 hours. The reaction mixture was diluted with dichloromethane (5 mL) and washed with 1N aqueous HCl (2X) and 1N aqueous NaOH (2X). The organic extract was dried (MgSO ₄ ), filtered and concentrated in vacuo to give the title compounds of these examples. Some of the title compounds of these examples must be purified by automatic preparative HPLC under the following conditions: YMC ODS A 20 x 100 mm column, 10 min. gradient from 70% solvent A (10% MeOH, 90% H ₂ O, 0.2% H ₃ PO ₃ and 30% solvent

B to 100% solvent B (90% MeOH, 10% H ₂ O, 0.2% H ₃ PO 4, flow rate ml / min, lambda = 220 nM).

HPLC Ret time HPLC retention time obtained under the following conditions: YMC S5 ODS 4.6 x 50 mm Ballastic Column, 4 min. gradient from 100% solvent A (10% MeOH, 90% H ₂ O, 0.2% H ₃ PO ₄ ) to 100% solvent B (90% MeOH, 10% H ₂ O, 0.2% H ₃ POJ, flow rate 4 ml / min., lambda = 220 nM.

Ex. C. Formula compound - _r Name of compound] I HPLC I et time (min) 184 2 - [[(cyclopropylamino) - -carbonyl] amino] -N- (2,6- -dimethylphenyl) -6- -benzothiazolecarboxamide 3.62 185 ⁰ 'VA 2 - [[(cyclopentylamino) - -carbonyl] amino] -N- (2,6- -dimethylphenyl) -6- -benzothiazolecarboxamide 4.04 186 ° 'va * 2 - [[[[1- (ethynyl) cyclohexyl] amino] carbonyl] amino] -N- (2,6-dimethylphenyl) -6-benzothiazolecarboxamide 4.13 187 ⁰ ^ = <AAo 2 - [[[(4-methylcyclohexyl) amino] - carbonyl] amino] -N- (2,6- -dimethylphenyl) -6- -benzothiazolecarboxamide 4.39 188 2 - [[[(2,3-dihydro-1H-indene-1- -yl) amino] carbonyl] axno] - N- (2,6-dimethylphenyl) -6- -benzothiazolecarboxamide 4.25 189 ά 2 - [[[2- (1H-imidazole-4- -yl) ethyl] amino] carbonyl] amino] - N- (2,6-dimethylphenyl) -6- -benzothiazolkaiboxamide 2.84

* «· ·

190 ^ ΑιιΊ - '' γ-x 2 - [[[(tetrahydro-2- furanyl) methyl] amino] carbonyl] - amino] -N- (2,6-dimethylphenyl) -6- -benzothiazolecarboxamide 3.68 191 '-χ Μ ~ / / Ν 0 2 - [[[2- (5-methoxy-1H-indol-3-one)] -yl) ethyl] amino] carbonyl] amino] - N- (2,6-dimethylphenyl) -6- -benzothiazolecarboxamide 3.99 192 V— ^ ΟΗ ° ^ \ Χ _Ν Χ _Ν > Υ ' 2 - [[[(1,1-dimethyl-2- -hydroxyethyl) amino] carbonyl] - amino] -N- (2,6-dimethylphenyl) -6- -benzothiazolecarboxamide 4.07 193 Αυο ~ «ο < 2 - [[[(1,1-dimethyl- -propyl) amino] carbonyl] amino] - -N- (2,6-dimethylphenyl) -6- -benzothiazolecarboxamide 414 194 2 - [[[[(3-methoxyphenyl) methyl] amino] carbonyl] amino] -N- (2,6-dimethylphenyl) -6-benzothiazolecarboxamide 4.02 195 2 - [[[[(4-methoxyphenyl) methyl] - amino] kaibonyl] amino] -N- (2,6- dimethylphenyl) -6- -benzothiazolecarboxamide 4.00 196 or in ^ jC ^ CV ⁰ 2 - [[(2-propynylamino) carbonyl] _-1'- amino] -N- (2,6-dimethylphenyl) -6-benzothiazolecarboxamide 4.06 197 ^ VQ-h ο 2 - [[(2-propenylamino) carbonyl] - amino] -N- (2,6-dimethylphenyl) -6- -benzothiazolecarboxamide 3.69 198 2 - [[[(3-phenylpropyl) amino] -a carbonyl] amino] -N- (2,6-dimethylphenyl) -6-benzothiazolecarboxamide 4.29

• · · · ·

199 2 - [[[1- (hydroxymethyl) - cyclopentyl] amino] carbonyl] - amino] -N- (2,6-dimethylphenyl) -6- -benzothiazolecarboxamide 3.90 200 2 - [[[[1- (methoxymethyl) propyl] - _; amino] carbonyl] amino] -N- (2,6-dimethylphenyl) -6-benzothiazolecarboxamide 3.86 201 1 H-o. O, (R) -2 - [[[(1-Phenylethylamino] carbonyl] amino] -N- (2,6-dimethylphenyl) -6-benzothiazolecarboxamide 4.12 202 2 - [[[(3,4,5-trimethoxyphenyl) -, amino] carbonyl] amino] -N- (2,6- dimethylphenyl) -6- -benzothiazolecarboxamide 4.15 203 2 - [[(1,3-benzodioxole-5- -ylamino] carbonyl] amino] -N- (2,6- dimethylphenyl) -6- -benzothiazolecarboxamide 4.02 204 Ά ' 2 - [[[(4-fluorophenyl) - amino] carbonyl] amino] -N- (2,6- dimethylphenyl) -6- -benzothiazolecarboxamide 4.05

• ·

Examples 205 to 226

General procedure

Compounds 205 to 226 were prepared as follows.

The appropriate amine (0.086 mmol) was added to a solution of 166C (alt) (30 mg, 0.072 mmol) in THF (3 mL). In the case of aliphatic amines, the solution is stirred at ambient temperature for 48-72 hours. In the case of anilines, the solution is heated at 60 ° C for 72 hours. The reaction mixture was diluted with dichloromethane (5 mL) and washed with 1N aqueous HCl (2X) and 1N aqueous NaOH (2X). The organic extract was dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo to afford the title compounds of these examples. Some of the title compounds of these examples must be purified by automatic preparative HPLC under the following conditions: YMC ODS A 20 x 100 mm column, 10 min. gradient from 70% solvent A (10% MeOH, 90% H ₂ O, 0.2% H ₃ PO ₄ ) and 30% solvent B to 100% solvent B (90% MeOH, 10% H _from 0, 0.2 % H ₃ PO ₄ ), flow rate 20 ml / min., Lambda = 220 nM.

HPLC Ret time HPLC retention time obtained under the following conditions: YMC S5 ODS 4.6 x 50 mm Ballastic Column, 4 min.

gradient from 100% solvent A (10% MeOH, 90% H ₂ O, 0.2% H ₃ PO ₄ ) to 100% solvent B (90% MeOH, 10% H ₂ O, 0.2% H ₃ PO ₄ ), flow ml / min, lambda = 220 nM.

• • • •

100 ALIGN!

Ex. C. Formula compound Name of the HPLC compound Ret time (min) 205 whose X y-Ο- ,, O 2 - [[(cyclopropylamino) carbonyl] - amino] -N- (2-chloro-6-methylphenyl) - -6-benzothiazolecarboxamide 4.15 206 of ’ΧΑΛ. 2 - [[(cyclopentylamino) kaibonyl] - amino] -N- (2-chloro-6-methylphenyl) - -6-benzothiazolecarboxamide 4.08 207 Xuy. / 2 - [[[[1- (ethynyl) cyclohexyl] - amino] carbonyl] amino] -N- (2- -chloro-6-methylphenyl) -6- -benzothiazolecarboxamide 4.17 206 Cl Xq, A ^ sA | Ao 2 - [[[(4-methylcyclohexyl) amino] - carbonyl] anuno] -N- (2-chloro-6- -methylphenyl) -6- -benzothiazolecarboxamide 4.37 1

• · • ·

101

209 Φ ^ -. 53, 2 - [[[(2,3-dihydro-1H-indene-1- -yl) amino] carbonyl] amino] - N- (2-chloro-6-methylphenyl) -6- -benzotibiazolecarboxamide 4.23 210 α S ^ N ^ N ^ j ό ^Ν 2 - [[[[2- (1H-imidazol-4-yl) ethyl] amino] carbonyl] araino] N- (2-chloro-6-methylphenyl) -6-benzothiazolecaboxamide 2.87 211 Cl ^{χ χ} ° 2 - [[[(tetrahydro-2- furanyl) methyl] amino] carbonyl] - amino] -N- (2-chloro-6-methylphenyl) - -6-benzothiazolecarboxamide 4.00 212 CI '\ ν χ ~ /' • Ν ^0/0 ~ 5 ^ ⁿ 2 - [[[2- (5-methoxy-1H-indol-3-one)] -yl) ethyl] aminojecarbonyl] amino] - N- (2-chloro-6-methylphenyl) -6- -benzothiazolecarboxamide 3.97 213 CI Q ~ Y <y _N o ^{on =} W 2 - [[[(1,1-dimethyl-2-hydroxyethyl) amino] carbonyl] amino] -N- (2-chloro-6-methylphenyl) -6-benzothiazolecarboxamide 4.29 214 Cl 0 ~-Η 0 _r '' ^ λλΛ 2 - [[[(1,1-Dimethyl-propyl) -amino] -methyl] -amino] -1 -N- (2-chloro-6-methyl-phenyl) -6- -benzothiazolecarboxamide 4.12 215 Cl 'χ ff / NO NO O J ^{Sn Sn} XQ 2 - [[[[(3-methoxyphenyl) methyl] - amino] carbonyl] amino] -N- (2- -chloro-6-methylphenyl) -6- -benzothiazolecarboxamide 4.01 216 ^ oK> 0 2 - [[[[(4-methoxyphenyl) methyl] -,, andno] kaibonyl] amino] -N- (2-chloro-6-methylphenyl) -6-benzothiazolecaboxamide 3.98

102

217 2 - [[(2-propynylamino) carbonyl] -, amino] -N- (2-chloro-6-methylphenyl) -6-benzothiazolecarboxamide! 4.37 218 4- ^ν X Κ> 0 0 2 - [[(2-propenylamino) carbonyl] - amino] -N- (2-chloro-6-methylphenyl) - -6-benzothiazolecarboxamide 3.67 219 α 'οΗ = 4ΐ X 2 - [[[(3-phenylpropyl) amino] carbonyl] amino] -N- (2-chloro-6- ¹ -methylphenyl) -6-benzothiazolecarboxamide 4.27 221) >> Q .. X ^O ^ S ^ N ^ O 2 - [[[[1- (hydroxymethyl) ₃ cyclopentyl] amino] carbonyl] amino] -N- (2-chloro-6-methylphenyl)]. -6-benzothiazolecarboxamide 4.28 221 α \ y <"x ο /’ ^ ΑΧχ 2 - [[[[1- (methoxymethyl) propyl] - amino] carbonyl] amino] -N- (2- -chloro-6-methylphenyl) -6- -benzothiazolecarboxamide 3.84 999 α (R) -2 - [[[(1-Phenylethylamino] carbonyl] amino] -N- (2-chloro-6-methylphenyl) -6-benzothiazolecarboxamide 4.10 223 WHOSE 2 - [[[(2,3-dimethyl-1H-indol-5- ₍ -yl) amino] carbonyl] amino] -N- (2-chloro-6-methylphenyl) -6-benzothiazolecarboxamide 4.32 224 CI ο ^χ Χκ>. SΛ ° °ΗΗ I S S S S. S S 2 - [[[(3A, 5-trimethoxyphenyl) amino] carbonyl] amino] -N; (2- ³ -chloro-6-methylphenyl) -6-benzothiazolecarboxamide 4.03

• · ···· · · · · · · ·

103:

9 9 9 9 9

225 , ^CI Xa 2 - [[(1,3-benzodioxole-5- -ylamino] carbonyl] amino] -N- -chloro-6-methylphenyl) -6- -benzothiazolecarboxamide 4.01 226 2 - [[[(4-fluorophenyl) amino] carbonyl] amino] -N- (2-chloro-6-methylphenyl) -6-benzothiazolecarboxamide 4.37

Example 227. Preparation of 2 - [[[[(1-methoxycarbonyl) cyclopropyl] amino] carbonyl] amino] -N- (2,4,6-trimethylphenyl) -6-benzothiazolecarboxamide

Use a method analogous to that used for the preparation of the compounds in Table 1, using 1-methoxycarbonyl-cyclopropylamine, to give the title compound of this example (6%), which was obtained after automatic preparative HPLC purification under the following conditions: YMC ODS 20 x 100 mm column, 10 min. gradient from 70% solvent A (10% MeOH, 90% H _and O, 0.2% H ₃ PO ₄ ) and 30% solvent B to 100% solvent B (90% MeOH, 10% H ₂ O, 0.2 % H ₃ PO ₄ ), flow rate 20 ml / min., Lambda = 220 nM.

MS = 453 (M + H) +.

Example 228: Preparation of [6 - [[[(2,6-dimethyl-4-phenyl) phenyl] amino] carbonyl] -2-benzothiazolyl] carbamic acid 1,1-dimethylethyl ester

• • • •

104 • · · ·· ·

A method analogous to that used to prepare the compounds listed in Table 4 is used, using

2,6-dimethyl-4-phenylaniline, to give the title compound of this example (45%), which was obtained after purification by silica gel chromatography eluting with 1-5% methanol in chloroform.

MS = 474.1 (t + H) +.

Example 229: Preparation of [6 - [[[(2,6-dimethyl-4- (2-N, N-dimethylethoxy) phenyl] amino] carbonyl] -2-benzothiazolyl] carbamic acid 1,1-dimethylethyl ester

Use a method analogous to that used for the preparation of the compounds in Table 4, using 2,6-dimethyl-4- (2-N, N-dimethylethoxy) aniline, to give the title compound of this example (45%), which was obtained Purification by silica gel chromatography eluting with 1-5% methanol in chloroform and chloroform: methanol: triethylamine (95: 4: 1).

MS = 485.1 (t + H) +.

Example 230: Preparation of [6 - [[[(2,6-dimethyl-4- (2-morpholinoethoxy) phenyl] amino] carbonyl] -2-benzothiazolyl] carbamic acid 1,1-dimethylethyl ester

You— * * · ······ · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ·

105 • 99 · 9 9 ··

Use a method analogous to that used for the preparation of the compounds in Table 4, using 2,6-dimethyl-4- (2-morpholinoethoxy) aniline, to give the title compound of this example (18%), which was obtained after purification by chromatography on Silica gel, eluting with chloroform: methanol: triethylamine (95: 4: 1).

MS = 527.7 (t + H) +.

Example 231. Preparation of 2 - [(cyclopropylcarbonyl) amino] -N- (2-chloro-6-methylphenyl) -6-benzothiazolecarboxamide

Use a method analogous to that used for the preparation of compound 99 in Table 3, except using compound 166B (alt) to give the title compound of this example.

MS = 386 (M + H).

Example 232. Preparation of 2 - [(2-methyl-cyclopropylcarbonyl) amino] -N- (2-chloro-6-methylphenyl) -6-benzothiazolecarboxamide

Cl

The title compound of this example was obtained in a manner analogous to that used to prepare Compound 231, except for the use of 2-methyl-cyclopropanecarboxylic acid. MS = 400 (t + H) +.

• · · ft · ·

106 ftft ftft

Example 233. Preparation of 2 - [(2,2-dichloro-1-methyl-cyclopropylcarbonyl) amino] -N- (2-chloro-6-methylphenyl) -6-benzothiazolecarboxamide

The title compound of this example was obtained in a manner analogous to that used to prepare Compound 231, except using 2,2-dichloro-1-methyl-cyclopropanecarboxylic acid.

MS = 469 (M + H) +.

Example 234. Preparation of 2 - [(1-hydroxy-cyclopropylcarbonyl) amino] -N- (2-chloro-6-methylphenyl) -6-benzothiazolecarboxamide

The title compound of this example was obtained in a manner analogous to that used to prepare Compound 231, except for the use of 1-hydroxy-cyclopropanecarboxylic acid. MS = 402 (t + H) +.

Examples 235 to 282 and 467 to 478

General procedure

Compounds 235-282 and 467 and 478 were prepared as follows

107 «* · 4 * ··» · · 4 · 4 4 c c 4 4 4 4 4 4 4 4 4 4 4 · «» «« <

way.

Diisopropylethylamine (50 µL, 0.288 mmol) was added to a mixture of 166B (alt) (30 mg, 0.096 mmol), carboxylic acid (0.115 mmol), 1-hydroxy-7-azabenzotriazole (17 mg, 0.125 mmol) and ethyl-3. - (3-dimethylamino) -propylcarbodiimide hydrochloride (24 mg, 0.125 mmol) in THF (1 mL). The mixture was heated at 45 ° C for 18-72 hours. The reaction mixture was diluted with dichloromethane (5 mL) and washed with 1N aqueous HCl (2X) and 1N aqueous NaOH (2X). The organic extract was dried (MgSO ₄ ), filtered and concentrated in speedvac. The crude materials were purified by either trituration with dichloromethane-ether or automatic preparative HPLC under the following conditions: YMC ODS 20 x 100 mm column, 10 min. gradient from 70% solvent A (10% MeOH, 90% H _from O, 0.2% H ₃ PO ₄ ) and 30% solvent B to 100% solvent B (90% MeOH, 10% H ₂ O, 0.2 % H ₃ PO ₄ ), flow rate 20 ml / min., Lambda = 220 nM.

HPLC Ret time HPLC retention time obtained under the following conditions: YMC S5 ODS 4.6 x 50 mm Ballastic Column, 4 min. gradient from 100% solvent A (10% MeOH, 90% H ₂ O, 0.2% H ₃ PO ₄ ) to 100% solvent B (90% MeOH, 10% H ₂ O, 0.2% H ₃ PO ₄ ) with 2 min hold, flow 4 ml / min, lambda = 220 nM for compounds 235-271 and for compounds 467-478, and Phenomenex-Prime S5, 4.6 x 50 mm column, 2 min. gradient from 100% solvent A (10% MeOH, 90% H ₂ O, 0.2% H ₃ PO ₄ ) to 100% solvent B (90% MeOH, 10% H ₂ O, 0.2% H ₃ PO ₄ 1), maintaining a flow rate of 5 ml / min, lambda = 220 nM for compounds 272-282.

108 • ► ί »» »» ».

»· · · · · · · · ·

Ex. C. Formula compound Name of the compound HPLC Ret time (n iin) 235 07 / X N- (2-chloro-6-methylphenyl) - -2 - [(cyclobutylcarbonyl) amino] - -6-benzothiazolecarboxamide 3.84 236 AND Cl N Q-; ° N- (2-chloro-6-methylphenyl) - -2 - [(cyclopentylcarbonyl) amino] -6-benzothiazolecarboxamide 4.00 237 Cl \ N- (2-chloro-6-methylphenyl) - -2 - [(cyclohexalacetyl) amino] - -6-benzothiazolecaboxamide 4.32 238 θ ^-0 »cA N- (2-chloro-6-methylphenyl) - -2 - [(methoxyacetyl) amino] - -6-benzothiazolecarboxamide 3.39

• · · · · · · · · · · · · ·

109,

239 Ν X 1 = Cl 0 N- (2-chloro-6-methylphenyl) - -2 - [(1-oxo-2-phenylpropyl) amino] - -6-benzothiazolecarboxamide 4.1 240 0 = ^ N r ^ y ^ • ^ 'and ⁰ N- (2-chloro-6-methylphenyl) - -2 - [(1-oxo-2-methylpropyl) amino ' -6-benzothiazolecarboxamide 1 and and 4.06 - 241 CA ^- ca N H2-chloro-6-methylphenyl) - -2 - [(1-oxo-3-phenylpropyl) amino] - -6-benzothiazolecarboxamide 4.11 242 r4 O N- (2-chloro-6-methylphenyl) -2 - [[3- (2-methoxyphenyl) -1-oxopropyl] amino] -6-benzothiazolecarboxamide 4.16 243 α n <>. o r N- (2-chloro-6-methylphenyl) - -2 - [[1-oxo-3- (2,3,4- -trimethoxyphenyl) propyl] amino] - -6-benzothiazolecarboxamide 4.03

• · · ·

244 R α ν .....- -'- ¹ - -1 N- (2-chloro-6-methylphenyl) - 2 - [(l, 4-dioxopentyl) amino] - 6-B benzothiazolkarboxamid 3.37 245 R ”R. N- (2-chloro-6-methylphenyl) - -2 - [(2,2-dimethyl-1- oxobutyl) amino] - -6-benzothiazolecarboxamide % 4.04 246 R Cl N 0 = / Οχχη F 2 - [[(2-chloro-6-fluorophenyl) acetyl] amino] -N- (2-chloro-6-methylphenyl) -6-benzothiazolecarboxamide 4.05 ) - 247 fjA O N- (2-chloro-6-methylphenyl) - -2 - [[(2-methylphenyl) acetyl] amino -6-benzothiazolecarboxamide 4.06 ] - 248 -X -jó XX ⁰ Cl N- (2-chloro-6-methylphenyl) - -2 - [[(3-methoxyphenyl) acetyl] - amino] -6-benzothiazolecarboxam 3 3.94 id

• • • •

111

249 aX ~ G ~ ^C ' N- (2-chloro-6-methylphenyl) - -2 - [[(4-chlorophenyl) acetyl] amino] - -6-benzothiazolecarboxamide * ] S 4.19 250 R c \ ^ N N- (2-chloro-6-methylphenyl) - -2 - [(1-oxo-4-pentynyl) amino] -6-benzothiazolecarboxamide AND and 3.58 251 0 ^- o ° = C <y. oo 5 - [[6 - [[(2-Chloro-6-methyl-phenyl) -amino] -a-bonyl] -2-benzothiazolyl] -amino] -5-oxopentanoic acid methyl ester 3.63 252 R Cl _N ⁰ <> s 0 N- (2-chloro-6-methylphenyl) - -2 - [(1-oxohexyl) amino] - -6-benzothiazolecarboxamide 4.17 253 O ^- c / o N- (2-chloro-6-methylphenyl) - -2 - [[3- (3-methoxyphenyl) -1- oxopropyljamino] - -6-benzothiazolecarboxamide 4.!

• · • · ii2.

254 2 - [[(1,3-benzodioxol-5-yl) - acetyl] amino] -N- (2-chloro-6- methylphenyl) -6- -benzothiazolecarboxamide W1AUV > 3.89 255 X X. · ^A øx> 2 - [[3- (1,3-benzodioxol-5-yl)] - -1-oxopropyl] amino] -N- (2-chloro- ( methylphenyl) -6- -benzothiazolecarboxamide • »» ft. - - - l 4.08 256 O — CH. N 0 H ^ C &; X N- (2-chloro-6-methylphenyl) - -2 - [[(3,5-dimethoxyphenyl) acetyl] amino] -6-benzothiazolecarboxane r - 1 .3.95 - limb 257 ⁰¹ N Xz N- (2-chloro-6-methylphenyl) - -2 - [(Cydopropylacetyl) amino] - -6-benzothiazolecarboxamide AND X 3.76 258 a. ^0/7-Ά> S / ^N 'x / ⁼ \ N- (2-chloro-6-methylphenyl) - X- // -2 - [[(methylcyldopropyl) ⁰ / carbonyl] amino] -6- ³ -benzothiazolecarboxamide 3.82 _

• · * ·

113

259 Ν Ν - H ₃ C / to H ₃ C ^CH 3 O α up 1 N- (2-chloro-6-methylphenyl) - -2 - [[[2- (trimethylsilyl) - Cydopropyl] carbonyl] amino] -6- -benzothiazolecarboxamide T _; 4.55 X * < '/of 260 ρ N- νΛΧΧ O α N- (2-chloro-6-methylphenyl) - 4.41 • ^ χ · ^Ν \ χ As -2 - [[[1- (4-methoxyphenyl) - Ϊ A cyclopropyl] carbonyl] amino] -6- ° h ₃ c ^X -benzothiazolecarboxamide 0 HjC 261 0 N- α Trans-N- (2-chloro-6-methylphenyl) 4.37 W As -2 - [[(2-Phenylcyclopropyl) - v ^{N s} τ -I carbonyl] amino] -6- of o A “A -benzothiazolecarboxamide 0 I-ZIZ · ...... ] 262 H, Ck Ά, 4.51 ⁰ H N- (2-chloro-6-methylphenyl) - ^s > X 2 - [[[1- (4-Methylphenyl) - aJ Cl cyclopropyl) carbonyl] amino] -6- 4-Benzothiazolecarboxamide ï l / μρ 263 ΠΑ AND 3 N- (2-chloro-6-methylphenyl) - -2 - [[[1- (4-chlorophenyl) - 4.49 and/ Ύ cyclopropyl) carbonyl] amino] -6- % J -benzothiazolecarboxamide Γ Cl

114. :

264 ° γ-Ν 0 HjC CH, ---- -. * Λ | [1 - [[6 - [[(2-chloro-6-methylphenyl) amino] carbonyl] -2-benzothiazolyl] - amino] carbonyl] cyclopropyl] - kaibamové 3.96 265 HaC (1S-trans) -N- (2-Chloro-6- methylphenyl) -2 - [[[2,2-dimethyl] - (2-Methyl-1-propenyl) - cyclopropyl] carbonyl] amino] -6- -benzothiazolecarboxamide 7 4.52 3- 266 qhjg ^ ^«0 Hj -l ^ ³ / ^N_ C H = C (1S-cis) -N- (2-chloro-6- -methylphenyl) -2 - [[[2,2-dimethyl- - (2-Methyl-1-propenyl) - cyclopropyl] carbonyl] amino] -6- -benzothiazolecarboxamide <T .......... 1 3 e 4.48 3- 267 ο ^ ύΆ, yl N - (A A ^{α α} °) N- (2-chloro-6-methylphenyl) -2 - [[(1 phenylcyldopropylcarbonyl] amino 6-Benzothiazolecarboxamide 4.30 268 0 ^H 3 ^C x A ^ _ν υυυ3 '> 0 ° o = / Αν ^α J N- (2-chloro-6-methylphenyl) -2 - [[( formylcyclopropylcarbonyl] amino -6-benzothiazolecarboxamide 4.28 2- 10]

• · · · · · · · · · ·

13-5 • ·

269 s ^, N-A o = 6 ^N ch ₃ 0 H, Cl Π Cl ¹ - 2 - [[[6 - [[(2-chloro-6-methylphenyl) amino] carbonyl] -2-benzothiazolyl] amino] carbonyl] cyclopropanecarboxylic acid ethyl ester | 4.04 270 S- ^, ⁿ ~ 40 = 6 N ^ ° ú> 0 H.C. O '' Ά Cl 2 - [[[6 - [[(2-chloro-6-methylphenyl) amino carbonyl] -2-benzothiazolyl] aminocarbonyl] methyl ester - cyclopropanecarboxylic S - 3 3.95 1- 3.98 0 CH, 'CH, 271 , ^N A 0 = 6 N 0 H, C. AND Cl N- (2-chloro-6-methylphenyl) - 2 - [[[2- (phenylmethyl) - ^r CT klopropyl) carbonyl] amino-6- -benzothiazolkarboxamid 4.36 272 CQ, ^N tT o "N" c _r 0 H, C- α ώ N- [6 - [[(2-chloro-6-methylphenyl) - amino] carbonyl] -2- benzothiazolyl] -2- -quinoline carboxamide 2.39 273 Ovxl α N- (2-chloro-6-methylphenyl) - 2.14 -2 - [(2-pyridinylcarbonyl) amino] - 6-Benzothiazolecarboxamide 0 ^{s # ø} > r ' ^N ' s ό ⁰ / Η, < and _ 1

4 · · · ·

US. ’

274 H ₃ o 4 ^Ν κ i O. '0- V o X . N- (2-chloro-6-methylphenyl) II -2 - [(2-pyridinylcarbonyl) amino] - 2.02 / 6 ! -benzothiazolkaiboxamide, 1-oxide ,and ~ N C 275 n— # j ý X and ΪΛ H ₃ R WHOSE χ Trans-N- (2-chloro-6-methylphenyl) -2 - [[[2- (dimethylamino) methyl] cyclopropyl] carbonyl] amino] -6- -benzothiazolecarboxamide 1.66 ) - 276 rXj __ / zdf CH3 Ϊ J HgC α N- (2-chloro-6-methylphenyl) -2 - [[(1-methyl-1H-pyrrol-2-yl) acetyl] amino] -6-benzothiazolecarboxamide 2.07 277 dX CH, SzA 0> K, C α ό N- (2-chloro-6-methylphenyl) - -2 - [[5- (dimethylamino) -1- -oxopentyl] amino] -6- -benzothiazolecarboxamide 1.65 278 / xX h _3C - ⁿ '^^ X ₎ ¹⁰ d α ό N- (2-chloro-6-methylphenyl) - -2 - [[4- (dimethylamino) -1- -oxobutyl] amino] -6- -benzothiazolecarboxamide 1.58

• · · ·

279 G ~ - 1 Trans-N- (2-chloro-6-methylphenyl) -1-2 - [[[2- (1-pyrrolidinomethyl) cyclopropyl] kaibonyl] amino] -6-benzothiazolecarboxamide Ί 1 1.67 O 0, H, C- 280 N— <JI r n o O Ύ in Cl 4 Trans-N- (2-chloro-6-methylphenyl) -2 - [[[2- (1-piperidinylmethyl) cyclopropyl] carbonyl] amino] -6-benzothiazolecarboxamide - 1.70 281 ι, ^ jQ / ΎζΧ ^s 0 O Ί N- (2-chloro-6-methylphenyl) - -2 - [[(dimethylamino) acetyl] - amino] -6-benzothiazolecarboxamide 1 1.49 282 M— / Ύ YM ^Λ A 0 α ώ N- (2-chloro-6-methylphenyl) - -2 - [[3- (2-Methyl-4-methyl-1H) - -imidazol-1-yl) -1-oxopropyl] - amino] -6-benzothiazolecarboxamides d 1.91 467 ^ XC O / Cl O Trans-N- (2-chloro-6-methylphenyl) -2 - [[[2- [4- (1,1-dimethylethyl) phenyl] cyclopropyl] carbonyl] amine -6-benzothiazolecarboxamide ^T '3 >] 4.87

• φ · · · »

ΦΦΦ ·

Χ18 ·

Φ φ · φ φ · · • • φ φ φ φ φ

468 Φ r ° Ο X ρι Trans-N- (2-chloro-6-methylphenyl) -2- [[[2- (4-ethoxyphenyl)]] | cyclopropyl] carbonyl] amino] -6- ; 4.51 -benzothiazolecarboxamide) Ο- Ι 469 φ F ό _χ ό Trans-N- (2-chloro-6-methylphenyl-2 - [[[2- (4-fluorophenyl) cyclopropyl] carbonyl] amino] -6-benzothiazolecaboxamide ) - 4.39 470 / Λζ ο ο / WHOSE ό Trans-N- (2-chloro-6-methylphenyl-2 - [[[2- [4- (1-methylethyl) phenyl] cyclopropyl] carbonyl] aino] -6-benzothiazolecarboxamide * 1) -: 4.77 471 r-A-Il-H- ' ό cXt 0 _χ NO. 1 ώ Trans-N- (2-chloro-6-methylphenyl-2 - [[[2- [4- (trifluoromethyl) phenyl] cyclopropyl] carbonyl] amino] -6-benzothiazolecarboxamide * · ** / - And W - - · D- 4.57 IN CF, and 472 , / / ^χ φ νο ₂ Q 0 Trans-N- (2-chloro-6-methylphenyl) -2 - [[[2- (4-nitrophenyl) - cyclopropyl] carbonyl] amino] -6- -benzothiazolecarboxamide ) - 4.36 473 ό Ο 0 _χ ό and Trans-N- (2-chloro-6-methylphenyl) -2 - [[[2- (4-cyanophenyl)] | cyclopropyl] carboethyl] amino] -6-benzothiazolecarboxamide .4.20 IN CN AND

• · · · ·

119 «· · · · · · · · · · · · · ·

474 ΥΥ WHOSE Α. Trans-2 - [[(2- [1,1'-biphenyl] -4-yl- cyclopropyl) carbonyl] amino] -N- - (2-chloro-6-methylphenyl) -6- -benzothiazolecarboxamide 1 1 * 4.80 475 χχ £ Q 0γΑ 0 / α ό Trans-2-f [[2- (1,3-benzodioxole-4- -yl) cyclopropyl) carbonyl] amino] - -N- (2-chloro-6-methylphenyl) -6- -benzothiazolecarboxamide L 4.37 476 0 Ν- δ χ X ΟγΆ Ο / whose ό Trans-N- (2-chloro-6-methylphenyl) -2 - [[[2- (3-chlorophenyl) - cyclopropyl] carbonyl] amino] -6- -benzothiazolecarboxamide 4.59 477 0 Ν- δ] ι ξ-χ'Ίίν X) οχ ⁰ S WHOSE ό Trans-N- (2-chloro-6-methylphenyl) -2 - [[[2- (3-cyanophenyl) - Cydopropyl] carbonyl] amino] -6- -benzothiazolecarboxamide 'l 4.21 478 0 Ν- Χ-Α ό Tans-N- (2-chloro-6-methylphenyl) - -2 - [[[2- (3-nitrophenyl) - cyclopropyl] carbonyl] amino] -6- -benzothiazolecarboxamide - - -čí.— 4.37

• · i »

I · »»

12CC

Examples 283 to 322

General procedure

Compounds 283 to 322 were prepared as follows. Diisopropylethylamine (50g, 0.288 mmol) was added to a mixture of compound 183B (alt) (30 mg, 0.096 mmol), carboxylic acid (0.115 mmol), 1-hydroxy-7-azabenzotriazole (17 mg, 0.125 mmol) and ethyl-3. - (3-dimethylamino) -propylcarbodiimide hydrochloride (24 mg, 0.125 mmol) in THF (1 mL). The mixture was heated at 45 ° C for 18-72 hours. The reaction mixture was diluted with dichloromethane (5 mL) and washed with 1N aqueous HCl (2X) and 1N aqueous NaOH (2X). The organic extract was dried (MgSO ₄ ), filtered and concentrated in speedvac. The crude materials were purified by either trituration with dichloromethane-ether or automatic preparative HPLC under the following conditions: YMC ODS 20 x 100 mm column, 10 min. gradient from 70% solvent A (10% MeOH, 90% H ₂ O, 0.2% H ₃ PO ₄ ) and 30% solvent B to 100% solvent B (90% MeOH, 10% H ₂ O, 0.2 % H ₃ PO ₄ ), flow rate 20 ml / min., Lambda = 220 nM.

HPLC Ret time HPLC retention time obtained under the following conditions: YMC S5 ODS 4.6 x 50 mm Ballastic Column, 4 min. gradient from 100% solvent A (10% MeOH, 90% H ₂ O, 0.2% H ₃ PO ₄ ) to 100% solvent B (90% MeOH, 10% H ₂ O, 0.2% H ₃ PO _{4 s} ) hold for 2 min, flow 4 ml / min, lambda = 220 nM.

• ·

121

• · · ·

122:

288 <O ^"CH 3 ^H 3 ^C \ N- (2,6-dimethylphenyl) -2 - [(1-oxo-3-phenylpropyl) amino] -6-benzothiazolecarboxamide 3 4.11 289 C> ^ch · • ^c N and 0-S 0 0 ^ UAX N- (2,6-dimethylphenyl) -2 - [[3- (2- aethoxyphenyl) -1-oxopropyl] - mino] -6-benzothiazolecarboxamic 4.15 290 O ~ ^CH3 N- h / ~ \ (2, 0 = 7 OX per. Be OS 0 o ™)? CH3 (2,6-Dimethylphenyl) -2 - [[3- 3,4-trimethoxyphenyl) -1- propyl] amino] -6- nzothiazolkaiboxamide 4.00 291 C / H ^CH 3 l · KsC \. ^C 4L en ° ch ₃ 4- (2,6-dimethylphenyl) -2 - [(1,4- (oxopentyl) amino] -6- > enzothiazolkaiboxamide J 3.37 292 CS ^CHi iv. . ^{N <} ^ ^N ' ^X S <^ ^CH 3 h ₃ c ch ₃ 2 - [(2,2-dimethyl-1- -oxobutyl) amino] -N- - (2,6-dimethylphenyl) -6- -benzothiazolecarboxamide 4.05

123 · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ·

293 <ΓΎ- ° ^Η 3 HC \ ^H 3 ^c Ν X ~. . N- (2,6-dimethylphenyl) -2- [(methoxyacetyl) amino] -6- benzothiazolecarboxamide X 3.39 294 X X \ / 0 S 0 CH. O N-dimethyl-N '- [6 - [[(2,6- imethylphenyl) amino] carbonyl] - , -benzotbiazolyl] butanediamide T OU. 3.34 295 ^H 3 ^{C 0} I? “X / ch ₃ h ₃ c ^with 1- (2,6-dimethylphenyl) -2 - [[(1-methylcyclopropyl) carbonyl] unino-6-benzothiazolecarboxamic 3..83 296 NP N x S X ch ₃ ° 2 - [[(2-chloro-6-fluorophenyl) acetyl] amino] -N- (2,6-dimethylphenyl) -6- aenzothiazolecarboxamide t r 4.03 297 ζ> -3 ^H 3 ^C \ X? N- (2,6-dimethylphenyl) -2 - [[(2- -methylphenyl) acetyl] amino] -6- benzothiazolecarboxamide 4.07

· * * · * * * * * * * *

124:. ::. ·.: :::

* · ·····················

296 0 — CH, N and A Wah ₃ ⁰ N- (2,6-dimethylphenyl) -2 - [[(3- -methoxyphenyl) acetyl] amino] -6- benzothiazolkaiboxamide 3.94 299 α R-CX N α \ ₃ ° 2 - [[(4-chlorophenyl) acetyl] amino] -> - (2,6-dimethylphenyl) -6- -benzothiazolecarboxamide 4.19 AND- 300 OC _r - oArv v N- (2,6-dimethylphenyl) -2 - [(1-oxo-) 4-Pentynyl) amino] -6- -benzothiazolecarboxamide L 3.58 301 O “^ «3 ° \ Kl " N- (2,6-dimethylphenyl) -2 - [(1- -oxohexyl) amino] -6- -benzothiazolecarboxamide 4.18 302 O- ° \ £ S -> N- (2,6-dimethylphenyl) -2 - [[3- (3-methoxyphenyl) -1-oxopropyl] amino] -6-benzothiazolecarboxane 4.11

125:

303 Q- ^ch ' ^Η Α ν Q.. 2 - [[3- (1,3-benzodioxol-5-yl) -1- -oxopropyl] amino] -N- - (2,6-dimethylphenyl) -6- -benzothiazolkaiboxamide 4.09 304 N AT ^> όη ₃ ^ο 2 - [[(1,3-benzodioxol-5-yl) - -acetyl] amino] -N- - (2,6-dimethylphenyl) -6- -benzothiazolecarboxamide 3.91 305 O — CH, / A NO H 2 AA ¹ L ^ ch ₃ ⁰ 2 - [[(3,5-dimethoxyphenyl) - -acetyl] amino] -N- - (2,6-dimethylphenyl) -6- -benzothiazolecarboxamide 3.97 306 Q - ^H 3 ^C \ n ^ n ^ o ; 2 - [(cyclopropylacetyl) amino] -N- (2,6-dimethylphenyl) -6-benzothiazolecarboxamide 1 * ··· - 3.79 307 R> Q H3C N — J oa n- ^ n- ^ o N- (2,6-dimethylphenyl) -2 - [[2- - (phenylmethyl) cyclopropyl] - kaibonyl] amino] -6- -benzothiazolecarboxamide __ and 4.48

• »

126

308 0 Ν - ^H 3 ^C jk h ₃ cY ch ₃ O ch ₃ M JL 1 N- (2,6-dimethylphenyl) -2 - [[2- - (trimethylsilyl) cyclopropyl] - kaibonyl] amino] -6- -benzothiazolkaiboxamide f 4.58 SA HjC Ί sZ 309 0 Ν — r χΖ ^ SZ ' ₃ n ₃ cr CH3 Ί OF 2 - [(cyclopropylcarbonyl) amino] - -N- (2,6-dimethylphenyl) -6- -benzothiazolecarboxamide 3.82 310 ο ν — r ch ₃ 8 Λ H ₃ C 2 CH ₃ Ί Z N- (2,6-dimethylphenyl) -2- [[(methylcyclopropyl) - carbonyl] amino] -6- -benzothiazolecarboxamide 4.02 311 ρ Ν- ό O T J ch ₃ A xZ Trans-N- (2,6-dimethylphenyl) -2- [[(2-phenylcyclopropyl) - carbonyl] amino] -6- -benzothiazolecarboxamide - 4.38 312 / Ve · Hp \ _f OF X Γ N- (2,6-dimethylphenyl) -2 - [[[1- - (4-Methylphenyl) cyclopropyl] - kaibonyl] amino] -6- -benzothiazolecarboxamide C 4.50 313 «Α C \ ^nZ ^ ^p > AND Z ° 2 - [[[1- (4-chlorophenyl) - -cyclopropyl] carbonyl] amino] -h - (2,6-dimethylphenyl) -6- -benzothiazolecarboxamide l 4.47 Cl

127

314 / Υ- », [1 - [[[i - [[(2,6-dimethylphenyl) amino] - carbonyl] -2-benzothiazolyl] - amino] carbonyl] cyclopropyl] - carbamové ³ · ⁹⁷ 315 0- = ,. «OCn— / <y _with o \ Α _Ν ϋΐΗχ- ^ ΟΗ, Λ (1S-cis) -2 - [[[2,2-dimethyl-3- (2- -methyl-1-propenyl) - -cyclopropyl] carbonyl] amino] -N- - (2,6-dimethylphenyl) -6- -benzothiazolecarboxamide 4.50 316 CH, Qup N- (2,6-dimethylphenyl) -2 - [[[1- (4-methoxyphenyl)] - -cyclopropyl] carbonyl] amino] -6- -benzothiazolecarboxamide 4.36 317 H, C „Χ „ψ N- (2,6-dimethylphenyl) -2 - [[(1- phenylcyclopropyl] carbonyl] amino 6-Benzothiazolecarboxamide 4.32 E 318 Qc h ₃ cn - QxO n - ^ n ^ o N- (2,6-dimethylphenyl) -2 - [[(2- -formylcyldopropyl] carbonyl] - amino] -6-benzothiazolecaboxam 4.29 and d 319 And i AC ethyl 2 - [[[6- - [[(2,6-dimethylphenyl) amino] - carbonyl] -2-benzothiazolyl] - amino] carbonyl] - cyclopropanecarboxylic 4.03

»Φ φ φ φ φ φ φ φ φ φ φ φ φ

128 • φ φ φ φ · · · · φ φ φ φ φ

320 h ₃ c JX == / 0 ^H 3 ^C II N • '' ............. ---- 1 2 - [[(2-cyancyclopropyl) carbonyl amino] -N- (2,6-dimethylphenyl) -6- -benzothiazolecarboxamide 2.5 1- 321 Qa h / W ch ^ w 2 - [[[6 - [[(2,6-Dimethylphenyl) amino] carbonyl] -2-benzothiazolyl] amino] carbonyl] -1-methylcyclopropaneboxylic acid methyl ester 3.97 4.00 322 0-, ° (1S-trans) -2 - [[[2,2-dimethyl-3- (: -methyl-1-propenyl) -cyclopropyl] carbonyl] amino] -N- (2,6-dimethylphenyl) -6-benzothiazolecarboxamide _? 4.53

Examples 323 to 337

General procedure

Compounds 323-337 were prepared as follows. Diisopropylethylamine (50 g, 0.288 mmol) was added to a mixture of the free base of compound 2 (30 mg, 0.096 mmol), carboxylic acid (0.115 mmol), 1-hydroxy-7-azabenzotriazole (17 mg, 0.125 mmol) and ethyl-3- (3-dimethylamino) -propylcarbodiimide hydrochloride (24 mg, 0.125 mmol) in THF (1 mL). The mixture was heated at 45 ° C for 18-72 hours. The reaction mixture was diluted with dichloromethane (5 mL) and washed with 1N aqueous HCl (2X) and 1N aqueous NaOH (2X). The organic extract was dried (MgSO4, filtered).

129I and concentrated in speedvac. The crude materials were purified by either trituration with dichloromethane-ether or automatic preparative HPLC under the following conditions: YMC ODS 20 x 100 mm column, 10 min. gradient from 70% solvent A (10% MeOH, 90%

H ₂ O, 0.2% H ₃ PO ₄ ) and 30% solvent B to 100% solvent B (90% MeOH, 10% H ₂ O, 0.2% H ₃ PO ₄ ), flow rate 20 ml / min. , lambda =

220 nM.

HPLC Ret time HPLC retention time obtained under the following conditions: For Compounds 327-334 YMC S5 ODS 4.6 x 50 mm Ballastic Column, 4 min. gradient from 100% solvent A (10% MeOH, 90%

H ₂ O, 0.2% H ₃ PO ₄ ) into 100% solvent B (90% MeOH, 10% H ₂ O, 0.2% H ₃ PO ₄ ) with a 2 min hold, flow rate 4 mL / min. .lambda. = 220 nM.

For compounds 323-326 and 335-337 YMC S5 ODS 4.6 x 50 mm Ballastic Column, 4 min. gradient from 100% solvent A (10% MeOH, 90%

H ₂ O, 0.1% TFA) to 100% solvent B (10% MeOH, 90% H ₂ O, 0.1% H ₃ PO ₄ ) with 2 min hold, flow rate 4 mL / min, lambda = 220 nM.

• · · ·

130 ► ► · · · · · · · · · · · · · ·

325 and? ^N —fy 9¾ i “kc-AA ^ 0 Trans-2 - [[(2-phenylcyclopropyl) - carbonyl] amino] -N- - (2,4,6-Trimethylphenyl) -O- -benzothiazolecarboxaxnid 4.54 326 Ν Ν-CH «4 ° θ '? h ₃ c 4.32 Ethyl 2 - [[[6- - [[(2,4,6-trimethylphenyl) amino] - kaxbonyl] -2-benzothiazolyl] - aminojkaibonyl] - cyclopropankaiboxyl 327 ΗΛ fVcH, Ζν ο [1 - [[[ - [[(2,4,6-trimethylphenyl) amino] - carbonyl] -2-benzothiazolyl] - amino] carbonyl] cyclopropyl] - carbamové ... 4.15 328 H, C, C, W, O, 0 V ^X CH 2 (1S-trans) -2 - [[[2,2-dimethyl-3-C -methyl-1-propenyl) - -cyclopropyl] carbonyl] amino] -N - (2,4,6-trimethylphenyl) -6- -benzothiazolecarboxamide 4.65 > _ 329 H, C CWral H-ch, V k- / <y _s o H x d, (1S-cis) -2 - [[[2,2-dimethyl-3- (2- -methyl-1-propenyl) - -cyclopropyl] carbonyl] amino] -N- - (2,4,6-trimethylphenyl) -6- -benzothiazolecarboxamide l 4.63

• · · · · · · · · · · · · · · · · · · · · · · · ·

131 • · ··

330 H-C . 2 - [[(1-Phenylcyclopropyl) - carbonyl] amino] -N- - (2,4,6-trimethylphenyl) -6- -benzothiazolecarboxamide 4.45 HaC Άα P 331 h ₃ c 4.43 y “Λ 2 - [[(2-formylcyclopropyl) - Ych ₃ carbonyl] amino] -N- > - (2,4,6-trimethylphenyl) -6- H ₃ C on -benzothiazolecarboxamide fy s A ° % 332 h ₃ c 2 - [[(2-cyancyclopropyl) - 4.42 y carbonyl] amino] -N- Y-ch ₃ - (2,4,6-trimethylphenyl) -6- N - \ 7-. 5 " = z -benzothiazolecarboxamide JI \ = / 'b ^ N- ^ S A-7 II N 333 H-C 4.14 \ - 2 - [[[6- F Λ-CH, - [[(2,4,6-trimethylphenyl) amino] \ = = λ o carbonyl] -2-benzothiazolyl] - / H-C aminocarbonyl] - y ^ Wi / o methylcyldopropanecarboxylic acid O-s Whatever ^π --Λ. λ. n- ^ n ^x IN - 334 H-C 4.48 y 2 - [[[2- (phenylmethyl) - Λ-CH -cyclopropyl] carbonyl] amino] -N- in = / 0 O - (2,4,6-trimethylphenyl) -6- / HgC \ -7 -benzothiazolecarboxamide <y s' ’‘ '1 .__ 3 Aa, X)

· · · »· 9

4 44 4444

43 4 9 9 9 9

132

335 ⁰ N-CH RX. CH, --- 2 - [[[1- (4-methylphenyl) -cyclopropyl] carbonyl] amino] -1- (2,4,6-trimethylphenyl) -6-benzothiazolecarboxamide ] 1 4.73 AND- 336 ⁰ N RX CH XXQyR Cl 2 - [[[1- (4-chlorophenyl) -cyldopropyl] carbonyl] amino] -N- (2,4,6-trimethylphenyl) -6-benzothiazolecarboxamide l 4.68 337 About N-RX CH, ARVYU. ° H ₃ C ' ^Z X ^? CH 3 O 3 H 3 C 2 - [[[1- (4-Methoxyphenyl) -cyclopropyl] kaibonyl] amino] -N- (2,4,6-trimethylphenyl) -6-benzothiazolecaboxamide 4.59

Examples 338 to 466

General procedure

Compounds 338-466 were prepared as follows. The appropriate amine (0.086 mmol) was added to a solution of compound 166A (30 mg, 0.072 mmol) in THF (3 mL). The solution was stirred at 57 ° C for 48-72 hours. The reaction mixture was diluted with dichloromethane (5 mL) and washed with 1N aqueous HCl (2X) and 1N aqueous NaOH (2X). The organic extract was dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo to afford the title compounds of these examples. Some of the title compounds of these examples must be purified by automatic preparative HPLC under the following conditions: YMC ODS A 20 x 100 mm column, 10 min. gradient from 70% solvent A (10% MeOH, 90% H ₂ O, 0.2% H ₃ PO ₄ ) and 30% solvent B to 100% solvent B (90% MeOH, 10% H ₂ O, 0.2 % H ₃ PO ₄ ), flow rate 20 ml / min., Lambda = 220 nM.

* * * * * * * * *

133 · · · · «· · t t t t t t t t

HPLC Ret time HPLC retention time obtained under the following conditions: Phenomenex-Prime S5 C18, 4.6 x 30 mm column, 2 min. gradient from 100% solvent A (10% MeOH, 90% H ₂ O, 0.2% H ₃ PO ₄ ) to 100% solvent B (90% MeOH, 10% H ₂ O, 0.2% H ₃ PO ₄ ) with holding for 1 min., flow rate 5 ml / min., lambda = 220 nM, for compounds 387-388; 390-405; 422; 426-428; 431-466;

Phenomenex-Luna S5 C18, 4.6 x 30 mm column, 2 min. gradient from 100% solvent A (10% MeOH, 90% H ₂ O, 0.1% TFA) to 100% solvent B (90% MeOH, 10% H ₂ O, 0.1% TFA) holding for 1 min. flow rate 5 ml / min, lambda = 220 nM, for compounds 338-340; 344-345; 347-386; 389; 406-421; 423-425; 429-430; and YMC S5 ODS

4.6 x 50 mm Ballastic Column, 4 min. gradient from 100% solvent A (10% MeOH, 90% H ₂ O, 0.2% H ₃ PO ₄ ) to 100% solvent B (90% MeOH, 10% H ₂ O, 0.2% H ₃ PO ₄ ), flow rate 4 ml / min, lambda = 220 nM, for compounds 341-343; and 346.

134 * ·· ··· · · · · · · ftft

340 ρ o ^δ ^ ιΓ ^Ν Ύ | Ι N- (2-chloro-6-methylphenyl) -2- [[[[(2-fluorophenyl) methyl] amino] - kaibonyl] amino] -6- -benzothiazolecarboxamide h 1 2.23 341 ° 1 N- (2-chloro-6-methylphenyl) -2 - [[[(. phenoxyethyl) amino] - kaibonyl] amino] -6- -benzothiazolecarboxamide 4.16 2- 342 4 ° ÁsJ * HgCT 1 2 - [[[(Benzo [b] thiophen-3- ylmethyl) amino] carbonyl] amino <N- (2-chloro-6-methyphenyl) -6- -benzothiazolkarboxamid ₄ · * ft \ YFT 4.31 >] - 343 Chiral 0YXCLn jl θ ⁰ ο X) '3.82 (R) -N- (2-chloro-6-methylphenyl) -2- [[[(2-hydroxy-fenylethvl) amino] - carbonyl] amino] -6- -benzothiazolkarboxamid ^{n 1} 1 i. I 344 CH, '' ^ 'Υ'Ίι ^^ ⁿ ySjOi ^σ N- (2-chloro-6-methylphenyl) -2- - [[[[4- (dimethylamino) phenyl] - methyl] amino] carbonyl] amino] - -benzothiazolkarboxanud 1 OF_____ 1.81 6- 345 χ <\ ^{Chiral σ Xqh} 0) (S) -N- (2-chloro-6-methylphenyl) -2 - [[[(2-hydroxy-1-phenylethyl) amine carbonyl] amino] -6-benzothiazolecaboxamide r AND 2.13 0] -

• ·

346 O 0 ^ V ^Nx 0. and O N- (2-chloro-6-methylphenyl) -2- - [[[[(4-nitrophenyl) methyl] amino] - carbonyl] amino] -6- -benzothiazolecarboxamide Ř r 3.96 347 1.73 ., K, Λ <^ ^ΥΧ Ζ Ϊ Cl N- (2-chloro-6-methylphenyl) -2- \ J o ^{s> x} - ríi - [[[[2- (1-pyrrolidinyl) ethyl] - o p AT amino] -carbonyl] amino] -6- HjC -benzothiazolecarboxamide 348 Ηχχ _ν ^ 2.38 cl. 0 N- (2-chloro-6-methylphenyl) -2- rS - [[[[4- (trifluoromethoxy) phenyl] - 0 «Α methyl] amino] carbonyl] amino] -O- -benzothiazolecarboxamide 349 'Η, ο _χ 1.61 0 íL N- (2-chloro-6-methylphenyl) -2- O-N- / X HLn Cl - [[[[2- (2-pyridinyl) ethyl] amino] kaibonyl] amino] -6- -benzothiazolecarboxamide 350 N — 4 AND- 0 * ^ 9 and N- (2-chloro-6-methylphenyl) -2- - [[[(2-pyridinylmethyl) amino] - carbonyl] amino] -6- -benzothiazolecarboxamide 1.62 351 cH N- (2-chloro-6-methylphenyl) -2- 1.59 3-3 ah - [[[(3-pyridinylmethyl) amino] - χΛλ CH ⁰ ji ^N Cl carbonyl] amino] -6- -benzothiazolecarboxamide

«· ·· · · · · · · β3β ·. ::. ·.: :::

• ··· ···· · · ·

352 S-X. / ¼ Λ 0 O Op Cl and 1 - *. 1 'N- (2-chloro-6-methylphenyl) -2 - [[[(4-pyridinylmethyl) amino] carbonyl] amino] -6-benzothiazolecarboxamide 1.58 353 α Ι _/"IN 2.27 /. Λ — Ν ^ A. N- (2-chloro-6-methylphenyl) -2- • - [[[[(3-chlorophenyl) methyl] amino] - ch ₃ □ A Ά kaibonyl] amino] -6- -benzothiazolecarboxamide 1 354 Cl 2.35 Aa, N- (2-chloro-6-methylphenyl) -2- OP - [[[[(2,3-dichlorophenyl) methyl] - Y HjC amino] kaibonyl] amino] -6- Y> from ^N- O -benzothiazolecarboxamide v7 ~ O w 355 AND □ A rQ- . N- (2-chloro-6-methylphenyl) -2 - [[[[(3,4-difluorophenyl) methyl] - 2.22 0 F amino] carbonyl] amino] -6- Ex -benzothiazolecarboxamide J 356 _η Άχ N- (2-chloro-6-methylphenyl) -2- 2.24 O Ω Η, Ο , ^N —4 —Z tr p AA - [[[[(2,6-dimethoxyphenyl) methyl] - / = (.N Cl amino] carbonyl] amino] -6- Φ in 0 -benzothiazolecarboxamide 0 H, C 357 o HA 2.29 Γ O Xj N- (2-chloro-6-methylphenyl) -2- 5 N— £ p - [[[[(2-ethoxyphenyl) methyl] - α amino] carbonyl] amino] -6- -benzothiazolecarboxamide CL _

• · · · ···· · · · ·

137 .: :::

• ··· ···· · · · ···

358 o ”A Γ » 9 α - .. ¹ ---- ^{1 1} - '' r N- (2-chloro-6-methylphenyl) -2 - [[[[(2,3-dihydro-1,4-benzodioxin-2-yl) methyl] amino] kaibonyl] amino] -6-benzothiazolecarboxamide ►% · z z \ \ \]]] 2.25 n- 359 "» ¥ < 2.23 O-CH, X} N- (2-chloro-6-methylphenyl) -2- n - [[[[2- (3-methoxyphenyl) ethyl] - A ¹¹ Cl amino] carbonyl] amino] -6- -benzothiazolecarboxamide i. - AND 3Θ0 CH, o ^ S AA 2.22 0 D N- (2-chloro-6-methylphenyl) -2- O / A O Cl - [[[[2- (4-methoxyphenyl) ethyl] - Y_ / n_ ^ tr- amino] kaibonyl] amino] -6- '-' 0 -benzothiazolecarboxamide 361 o ^ S AY N- (2-chloro-6-methylphenyl) -2- 2.24 S-x. - [[[[(2-methylphenyl) methyl] - • CH, N- ^4N O α amino] kaibonyl] amino] -6- -benzothiazolecarboxamide 3G2 YY (N- (2-chloro-6-methylphenyl) -2-) 2.25 / A Υ = \ / Ά ^N ' ^{ji nX} ΑίΑ -frr [(3-methylphenyl) methyl] - Cl amino] kaibonyl] amino] -6: -benzothiazolecarboxamide l Λ

• ·

1 * 38:

363 Ν - <\ 1 ------ _r N- (2-Chloro-6-methylphenyl) -2 - [[[[(5-methyl-2-furanyl) methyl] amino] kaitolinyl] amino] -6-benzothiazolecaboxamide 2.14 364 _of H CLX ^ "rCCtí \" Χ ° ^H / O 13 (S) -N- (2-chloro-6-methylphenyl) -2 - [[[[1- (hydroxymethyl) -2-phenylethyl] amino] carbonyl] amino] -6-benzothiazolecarboxamide ¹ '' and 365 ₀ - _n mX kT, K Qt ° N- (2-chloro-6-methylphenyl) -2- - [[[[2- (phenylamino) ethyl] - amino] carbonyl] amino] -6- -benzothiazolecarboxamide 1.96 366 oHAsy · - '' ^ / ¼ A J α N- (2-chloro-6-methylphenyl) -2- - [[[(2-thienylmethyl) - amino] carbonyl] amino] -6- -benzothiazolecarboxamide 2.11 367 nAJ _ν αύΊι ^nX i> -r 0 N- (2-chloro-6-methylphenyl) -2 - [[[[2- (1H-indol-3-yl) ethyl] amino] carbonyl] amino] -6-benzothiazolecarboxamide 2.19 368 o ^ V ^ i ^ -O- ⁷ ° 2 - [[[[(4-aminophenyl) methyl] - amino] kaibonyl] amino] -N- (2- -chloro-6-methylphenyl) -6- -benzothiazolecarboxamide Π l XI____ 1.69

• 4 · I

139:

369 0 / xXjj / Ν— Cl -F N- (2-chloro-6-methylphenyl) -2- - [[[(diphenylmethyl) amino] - carbonyl] amino] -6- -benzothiazolecarboxamide 2.34 AND Ο 370 Η ^H 3 ^C / ^{o <} Yy _s % Chiral in (1R-exo) -2- [[(bicyclo [2.2.1]] heptane-2- -ylamino) carbonyl] amino] -N- (2- -chloro-6-methylphenyl) -6- -benzothiazolecarboxamide · ’- · ......... 2.29 371 , -λΠ Η ” σ ^α N- (2-chloro-6-methylphenyl) -2- - [[[[(4-chlorophenyl) methyl] - amino] carbonyl] amino] -6- -benzothiazolecarboxamide AND 2.26 ° χ α ^Ν Qach, 372 ^α γ \ You ⁰¹ »TV> = \ 0 Ν -— / \ Hjc N-0 o N- (2-chloro-6-methylphenyl) -2 - [[[[1- (4-chlorophenyl) ethyl] amino] carbonyl] amino] -6-benzothiazolecarboxamide 1 «» ».1 ____ v__ 2.31 373 Ο * vXXji and 2.30 (R) -N- (2-Chloro-6-methylphenyl) -2- - [[[[1- (4-methylphenyl) ethyl] - amino] carbonyl] amino] -6- -benzothiazolecarboxamide and

• * *: f4C £

374 (S) -N- (2-chloro-6-methylphenyl) - [[[[1- (4-methylphenyl) ethyl] - amino] kaibonyl] amino] -6- -benzothiazolecarboxamide ****** J WWUA -2- 2.30 375 XYY r ⁰ α ^N Qhch N- (2-chloro-6-methylphenyl) -2- - [[[[(4-fluorophenyl) methyl] - amino] carbonyl] amino] -6- -benzothiazolecarboxamide 2.17 376 YA H- ^O ' ⁰ ' N- (2-chloro-6-methylphenyl) -2 - [[[[1- (4-fluorophenyl) ethyl] amino] carbonyl] amino] -6-benzothiazolecaboxamide · ¹ ---- 1 ---- 2.22 377 Ο ^ -γΆ, E > N- (2-chloro-6-methylphenyl) -2- - [[[(2-furanylmethyl) - amino] carbonyl] an ± io] -6- -benzothiazolecarboxamide 2.05 378 ^ν- Χ ~ ^ ^: ^ Γ ^ζ ^ ^ν ^ ^χ '«-7 ^α rCX> N- (2-chloro-6-methylphenyl) -2 - [[[[1- (4-methoxyphenyl) ethyl] amino] catbonyl] amino] -6-benzothiazolecarboxamide 2.20

• 4 · ···: ι * 40:

• this this • this • this to • tt

379 H, C, > 5-Chiral i jl '' Ύ ' 1 (S) -N- (2-chloro-6-methylphenyl) -2 - [[[(1-Phenylmethyl) - amino] carbonyl} amino] -6- -benzothiazolecarboxamide 2.20 380 , ^N - <\ aO Ethyl a - [[[[6 - [[2- -chloro-6-methylphenyl) amino] - carbonyl] -2-benzothiazolyl] - amino] carbonyl] amino] - benzene acetic '.....' 1 2.22 381 H, C / ^N_4 p ^ Y> ^a N- (2-chloro-6-methylphenyl) -2 - [[[[2- (4-methylphenyl) -phenylethylamino] carbonyl] amino] -6- ^; -benzothiazolecarboxamide Γ 2.44 O 382 / ⁿ ~ 4 L. O0 HC •AND (R) -N- (2-Chloro-6-methyl-phenyl) - - [[[(1-Phenylpropyl) - amino] carbonyl] amino] -6- -benzothiazolecarboxamide 2.27 383 Άγ, · o ^p XX? Aaa ⁰ H, C N- (2-chloro-6-methylphenyl) -2 - [[[[(4-methylphenyl) methyl] amino] carbonyl] amino] -6-benzothiazolecarboxamide; ₍ 2.30 384 0 ’ CH, O Chiral τΓ ^ ° νύ (R) -N- (2-chloro-6-methylphenyl) -. - [[[[1- (4-nitrophenyl) ethyl] - amino] carbonyl] amino] -6- -benzothiazolecarboxamide XXV J VCU M VXXJ XJ CULXXXXXV J ”V T _____ Λ 4 · Ί. . Λ ____ ₂ - 2.26

· Ϊ ϊ ϊ ϊ ϊ ϊ ϊ ϊ ϊ ϊ ϊ ϊ ϊ ϊ ϊ ϊ ϊ ϊ ϊ ϊ ϊ ϊ ϊ ϊ ϊ ϊ ϊ ϊ

385 ^σ ΎΊ ϊ ° Hj <AA N- (2-chloro-6-methylphenyl) -2- - [[[[(4-chlorophenyl) phenylmethyl] - amino] carbonyl] amino] -6- -benzothiazolecarboxamide l AND____ 1 2.49 386 Ο ^ ε ^ ^Ν γ ΖΎΧ 7 ° H, cA> X N- (2-chloro-6-methylphenyl) -2- - [[[[2- (phenylthio) ethyl] - amino] carbonyl] amino] -6- -benzothiazolecarboxamide 2.33 387 Br 0 vV 2 - [[[[(2-bromophenyl) methyl]] amino] carbonyl] amino] -N- (2-chloro-6-methylphenyl) -6-  -benzothiazolecarboxamide  ~ ”- · / ------- ' 2.26 388 F ® AJ ^F H, C N- (2-chloro-6-methylphenyl) -2- - [[[[2- (3-fluorophenyl) ethyl] - amino] carbonyl] amino] -6- -benzothiazolecarboxamide AND 1 1 2.23 389 '' Z ^Y O θ-cn, N- (2-chloro-6-methylphenyl) -2- - [[[[- (trifluoromethylphenyl) - methyl] -aminocarbonyl] amino] - -benzothiazolecarboxamide 2.28 6-

• · • ·

143

390 Br ο ^ γ ^Ν Ύ | - 2 - [[[[(3-bromophenyl) methyl] amino] carbonyl] amino] -N- (2-chloro-6-methylphenyl) -6-benzothiazolecarboxamide 2.28 391 | f ο ^δ ^ ^< ^ ΐΓ ^Ν Ύ ^: | 1 2 - [[[(4-chloro-2-fluorophenyl) - methyl] amino] carbonyl] amino] - N- (2-chloro-6-methylphenyl) -6- -benzothiazolecarboxamide 2.28 392 Χγχχνχ ° XJ 2 - [[[(2-amino-2-oxo-1-phenylethyl); amino] kaibonyl] amino] -N- (2- chloro-6-methylphenyl) -6- -benzothiazolecarboxamide _n 2.36 W) 393 Ν = ξ 4 ^Ν 7ζ-χζ- ^Ν γ ^Ν 4ν> α ν0 N- (2-chloro-6-methylphenyl) -2- - [[[[3- (1H-imidazol-1-yl) propyl] amino] carbonyl] amino] -6- -benzothiazolecarboxamide - · »· --Ί ____. 1 1.61 1- 391 ° ^ χΧ ^Ν γ ^Ν 4ΧΧ? , Ο Η I ο p • 2.19 N- (2-chloro-6-methylphenyl) -2 - [[[[(2,4-dimethoxyphenyl) methyl] amino] carbonyl] amino] -6-benzothiazolecarboxamide ------- ------ --1 '1 395 ο ^s ^ ir ^N in \ N- (2-chloro-6-methylphenyl) -2- - [[[(3-chloro-4- -methylphenyl) methyl] - amino] carbonyl] annno] -6- -benzothiazolecarboxamide 2.34

• · · · ·

• ·

144

396 0 O \ - ' ^N ' - 0, *> C σ O  - - ť—- 2 - [[[[(3-chloro-4-fluorophenyl) methyl] axino] carbonyl] amino] -N- (2-chloro-6-methylphenyl) -6-benzothiazolecarboxamide 2.27 397 2.22 οο yO> 0 ^sec Cl 2 - [[[(2-chloro-6-fluorophenyl) - AND Cl methyl] amino] carbonyl] amino] -N- o / O - (2-chloro-6-methylphenyl) -6- HiC -benzothiazolecarboxamide 396 2.28 XX n Cl 2 - [[[(2-chloro-4-fluorophenyl) - 1 Cl n y 0 ^X X ^N '· methyl] amino] carbonyl] amino] -N- o _ in - (2-chloro-6-methylphenyl) -6- "AND -benzothiazolecarboxamide 399 F 1 - 2.20 _ťjL U ^N ‘N- (2-chloro-6-methylphenyl) -2- yx ΎΧ O Cl ^[[[[(3, 5-difluorophenyl) methyl] - 0 ^sec X-z-N 1 rii amino] carbonyl] amino] -6- o _ H, d Also -benzothiazolecarboxamide 1 - - 400 '2.18 AND N- (2-chloro-6-methylphenyl) -2- Okay Cl - [[[[(2,5-dimethoxyphenyl) methyl] - O amino] carbonyl] amino] -6- A ° 0 ώ -benzothiazolecarboxamide H.C ' • xx

• · · ·

145 • • • •

401 CH. Λ -, 0 α ΆΛ • ---— = - N- (2-chloro-6-methylphenyl) -2- - [[[[(3,5-Dimethylphenyl) methyl] - amino] carbonyl] amino] -6- -benzothiazolkaiboxamide , 2.32 402 «Λ 2.04 ° jfjL „ _Ν γ N- (2-chloro-6-methylphenyl) -2- Ca α - [[1 [(3,4-dimethoxyphenyl) methyl] - CH, O AND amino] carbonyl] amino] -6- 0. H, C -benzothiazolecarboxamide 403 , CH, 2.15 ϊ N- (2-chloro-6-methylphenyl) -2- 14 Μ U ^Ν ^ ^χ - [[[[(3,5-dimethoxyphenyl) methyl] - amino] carbonyl] amino] -6- 1 II ς · * ^ CHj 0 ^{59 se!} t < ^N '' AND -benzothiazolecarboxamide 0> AND HjC 404 CH, 2.38 tP Ν Vx / VY Fri ct N- (2-chloro-6-methylphenyl) -2- Η S-- 0 'yíPS - [[[[4- (1-methylethyl) phenyl] - 0 IN methyl] amino] carbonyl-3-amino] -6- H, C ' -benzothiazolecarboxamide • 405 ν = ν 2.10 N- (2-chloro-6-methylphenyl) -2- Cl α - [[[[4- (1,2,3-thiadiazol-4-yl)] - 0 AND phenyl] -methyl-amino] -carbonyl] - 0 HjC Αχ amino] -6-benzothiazolecarboxamide Γ

• »· ·

146 * · ··· ···

406 € Υ "c _Ο FVS 1 N- (2-chloro-6-methylphenyl) -2- - [[[2- (2-chlorophenyl) ethyl] - amino] carbonyl] amino] -6- -benzothiazolkaiboxamide and 2.29 407 jC CH, N- (2-chloro-6-methylphenyl) -2- - [[[(1-methyl-1-phenylethyl) - [amino] carbonyl] amino] -6- -benzothiazolecarboxamide 2.24 406 Cl N- (2-chloro-6-methylphenyl) -2- - [[[[(2,5-dichlorophenyl) methyl] - amino] kaibonyl] amino] -6- -benzothiazolecarboxamide 2.34 409 o », / = </ ⁿ N- (2-chloro-6-methylphenyl) -2- - [[[[(2,4-dimethylphenyl) methyl] - amino] carbonyl] amino] -6- -benzothiazolecarboxamide Ί Λ 2.32 410 Sx ^ SXx-XxXxX N — 4 \ Y i / = V / K VrV N- (2-chloro-6-methylphenyl) -2 - [[[[1- (1-naphthalenyl) ethyl] amino] carbonyl] amino] -6-benzothiazolecarboxamide 2.34

• · · · ·

147

411 «Ci μχΛχ H, c-O N- (2-chloro-6-methylphenyl) -2- - [[[[(3,4,5- -trimethoxyphenyl) methyl] - amino] kaibonyl] amino] -6- -benzothiazolecarboxamide 1 * * • ί 2.06 412 H.C xpX ° 0 H, C N- (2-chloro-6-methylphenyl) -2- - [[[[(2,4,6- -trimethoxyphenyl) methyl] - amino] carbonyl] amino] -6- -benzothiazolecarboxamide 1 2.22 413 ff / = <'Y tL 2 - [[[(4-bromophenyl) - methyl] amino] carbonyl] amino; - (2-chloro-6-methylphenyl) -6- -benzothiazolecarboxamide ' 1 2.29 -Ν- 414 HC Chiral V _o H t tF 2.19 Ethyl ester of [1R- - (endo, endo)] - 3 - [[[[6 - [[(2-chloro-6-methylphenyl) amino] carbonyl] -2-benzothiazolyl] amino] carbonyl] amino] bicyclo [2.2.1] hept-5-ene-2-carboxylic acid 1 t_____ and 415 KjC Oltal Ethyl ester of [1S- - (exo, exo)] - 3 - [[[[6 - [[(2-chloro-1-chloro-2-chloro-propyl) -cyclohexyl]] -methylphenyl) amino] carbonyl] - -benzothiazolyl] amino] kaibone; amino] bicyclo [2.2. l] heptane-2- -carboxylic «Ϊ́. .i? 2.25 • 2- fl] -

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148

416 HjC Chiral Η X ⁰ _α Ethyl ester of [1R- - (exo, exo)] - 3 - [[[[6 - [[(2-chloro-6- -methylphenyl) amino] carbonyl] -2 -benzothiazolyl] amino] carbonyl amino] bicyclo [2.2. 1] hept-5-en-2 -carboxylic 222 ] 417 CKiral X ^H 3 ^C [1R- (endo, endo)] - N- (2-chloro-6- -methylphenyl) -2 - [[[[3- (hydroxymethyl) bicyclo [2.2.1] h -5-en-2-yl] amino] carbonyl] amine -6-benzothiazolecarboxamide 2.07 spt 0] -. 418 Chiral X ^H 3 ^C [1S- (endo, endo)] - N- (2-chloro-6-methylphenyl) -2 - [[[[3 (hydroxymethyl) bicyclo [2.2.1] heptan-2-yl] amino] carbonyl] amino] -6- benzothiazolkaiboxam ) 2.11 people- 419 θ-- ^{01 chirai} i ». [1R- (exo, exo)] - N- (2-chloro-6-methylphenyl) -2 - [[[[3 (hydroxymethyl) bicyclo [2.2.1] heptan-2-yl] amino] carbonyl] amino] -6-benzothiazolecarboxane * ) L 2.14 people ί 420 / ° yzv _N (γ-Ν ^{ΛΑ =} % Λ _Ν * ^CH * cAiR ^ y ^F N- (2-chloro-6-methylphenyl) -2- - [[[[(3-fluorophenyl) methyl] - amino] carbonyl] amino] -6- -benzothiazolkaiboxamide 1 2.17

149 *

421 N- (2-chloro-6-methylphenyl) -2- - [[[[(2-methoxyphenyl) methyl] - amino] kaibonyl] amino] -6- 4v'n7nthia7nllcarhnvamid i 2.19 422 X π * ⁰ J CX / Xn Μ ^η Ν \ Η-, Ν-'η ^Η 0 (exo, exo) - [[[3- - (aminocarbonyl) bicyclo [2.2.1] heptan-2-yl] amino] carbonyl] amino] -N- (2-chloro-6-methylphenyl) 6-benzothiazolecarboxamide 2.07 D- 423 Chiral χχΛ * VKh / (S) -N- (2-Chloro-6-methylphenyl) -2 - [[[[1- (1-naphthalenyl) ethyl] • amino] carbonyl] amino] -6 '- benzothiazolecarboxamide 2.34 424 / ° Wy _Ν (χ χ · ^s ΧχχχΧ N- (2-chloro-6-methylphenyl) -2- - [[[[3- (trifluoromethyl) phenyl] - methyl] amino] catonyl] amino] -t -benzothiazolecarboxamide 3 2.27 425 χΧΟ Ν-ςΥΊ) ^νΧ ι ° N- (2-chloro-6-methylphenyl) -2- - [[[(phenylmethyl) - amino] kaibonyl] amino] -6- -benzothiazolecarboxamide .2.15 J

150 • · · ···

426 cr  2.06 (endo, endo) - [[[[3- (aminocarbonyl) bicyclo [2.2.1] heptan-2-yl] amino] carbonyl] amino] -N- (2-chloro-6-methylphenyl) - H, C O < n L ^h 6-Benzothiazolecaboxamide 1 N 0, Ν-Υ ^h 0 427 HA 2.05 from ^N— 4. O N- (2-chloro-6-methylphenyl) -2- XX ^N O - [[[[1- (4-hydroxyphenyl) ethyl] - <X? amino] carbonyl] amino] -6- -benzothiazolecarboxamide in • 428 O ^ S X N- (2-chloro-6-methylphenyl) -2- 2.22 ^N X [[[[(2,6-difluorophenyl) methyl] - rí at Cl amino] carbonyl] amino] -6- -benzothiazolecarboxamide Q F -> 0 3 429 0 ^ ]: 2.30 LJ - N- (2-chloro-6-methylphenyl) -2- H.C CH, N— IN O - [[[[(2,3-dimethylphenyl) methyl]] amino] carbonyl] amino] -6- // -Benzothiazolecarboxamide AND • 439 HC .. Chiral <? ň ί 2.34 N— X <AJ II T (R) -N- (2-Chloro-6-methyl-phenyl) -2- / sss \ ^{Α 1 α} - [[[[1- (1-Naphthalenyl) ethyl] - O? K ⁰ amino] carbonyl] amino] -6- w CH, -benzothiazolecarboxamide ]

151 • 4 • 4

431 CH, 0 ⁵ O 0. H, C ^X Cl O N- (2-chloro-6-methylphenyl) -2- - [[[[2- (dimethylainino) ethyl] - amino] carbonyl] amino] -6- -benzothiazolecarboxamide ; 1.70 432 α Cl N- (2-chloro-6-methylphenyl) -2- 1.71 ί / Hj CHj 0 ώ - [[[[1,1-dimethyl-2-] «/ - (dimethylamino) ethyl] - amino] carbonyl] amino] -6- -benzothiazolecarboxamide • 433 _h , _w N ~. 1.62 O Cl N- (2-chloro-6-methylphenyl) -2- θ * ή - [[[1- (phenylmethyl) -4- H, C ^Z piperidinyl] amino] cartxinyl] amino] 6-Benzothiazolecaboxamide * ΙΓ 434 1.70 Whose S < ^N x α N- (2-chloro-6-methylphenyl) -2- ^ N ^ xCH, O Λ - [[[3- (2-methyl-1- 0. Η, Ο AC -piperidinyl) propyl] amino] - kaibonyl] amino] -6- -benzothiazolecarboxamide 435 1.65 ΤΆΎΧ O Cl N- (2-chloro-6-methylphenyl) -2- * ⁿ ^ ch, ⁰ Til ¹ - [[[2- (1-methyl-2-pyrrolidinyl) - 0 H, C AC • ethyl] anuno] carbonyl] amino] -6-3-benzothiazazolecarboxamide 1

• · · · ·

152

436 0 ° Α. _Νχ ο> Κ, Α ct O ^F- «.! 1. !! . - N- (2-chloro-6-methylphenyl) -2 - [[[[3- (4-morpholinyl) propyl] amino] carbonyl] amino] -6-benzothiazolecarboxamide 1 j 1.60 437 - * «*. * - - 1.81 <ΎΥΧί Cl N- (2-chloro-6-methylphenyl) -2 - [[[[1- (phenylmethyl) -3- / O -pyrrolidinyl) ethyl] - HjC X / amino] carbonyl] amino] -6- υ -benzothiazolecarboxamide 438 ΑΥΧΙ 1.65 AND Cl N- (2-chloro-6-methylphenyl) -2- Α ⁰ CHs CHj rii - [[[[3- (diethylamino) - ο. HjC AND -propyl] amino] carbonyl] amino] -6- -benzothiazolecarboxamide 439 XY-y 0 ° AND Cl Άϊ N- (2-chloro-6-methylphenyl) -2- 1.51 O in - [[[3- (4-methyl-1-piperazinyl) - HgC -propyl] amino] carbonyl] amino] -6- CHj -benzothiazolecarboxamide 440 ι. .. Ν * 1.46 ΠΑΗ Ν ^ χΙ 0 AND· O Ά, N- (2-chloro-6-methylphenyl) -2- O Xj - [[[[3- (1-piperazinyl) - HgC -ethyl] amino] carbonyl] amino] -6- -benzothiazolecarboxamide 441 ι. .. Ν- 1.58 ° Ν ο ^p AND- α rS N- (2-chloro-6-methylphenyl) -2- - [[[[3- (4-morpholinyl) - 0 HaC ΆΧ -ethyl] amino] carbonyl] amino] -6- -benzothiazolecarboxamide 1

153

442 ^{Ν Α 0} H, C CH, X Cl Μ .Μ 1 : N- (2-chloro-6-methylphenyl) -2 - [[[(2,2,6,6-tetramethyl-4-piperidinyl) amino] carbonyl] amino] -6-benzothiazolecarboxamide 1.77 Ο HjC υ 443 Chiral 1.80 <γγχθ α (R) -N- (2-Chloro-6-methylphenyl) -2- 0 Χχ ) - [[[1- (phenylmethyl) -3- η HjC -pyrrolidinyl] amino] carbonyl] - Μ amino] -6-benzothiazolecarboxamide nid 444 Chiral 1.80 0Α0 Ν— ^J 0 ⁵ (xs α  (S) -N- (2-Chloro-6-methylphenyl) -2- 0 ) - [[[1- (phenylmethyl) -3- η H, C -pyrrolidinyl] aimno] carbonyl] - Μ amino] -6-benzothiazolecarboxai mid 445 ΥΥΧΑ Ν. Π α N- (2-chloro-6-methylphenyl) -2 - [[[[3- (1-piperidinyl) - 1.65 Ο Ο -propyl] amino] carbonyl] amino] -6- HjC -benzothiazolecarboxamide 446 1.62 „ΧίΑ In '* ¹ '' α ; N- (2-chloro-6-methylphenyl) -2- 0 ⁰ rii ¹ - [[[3- (1-pyrrolidinyl) - Ο Μ -propyl] amino] carbonyl] amino] -O- HjC : -benzothiazolecarboxamide 1. - » 447 Q ν ^ ζ N- (2-chloro-6-methylphenyl) -2- 1.70 ΥννχΊ α - [[[1- (2-pyridinyl) - 1 Feb CH, 0 ^& -ethyl] amino] carbonyl] amino] -6- 0 IN -hfinznthiazolcarboxamide HjC 11 »! ^ XX

• «· · · ·

154 this · to · this · to · to · this

448 CH, O ^S N- (2-chloro-6-methylphenyl) -2 - [[[[1- (3-pyridinyl) - -ethyl] amino] carbonyl] amino] -6-i-benzothiazolecarboxamide j 1.65 ⁰ in HjC α ό 449 γ ^ ^Ν γ ^Ν γγ α N- (2-chloro-6-methylphenyl) -2- - [[[3- (2-oxo-1-pyrrolidinyl) - 1.91 n O -propyl] amino] carbonyl] amino] -6- ^H and ^c -benzothiazolecarboxamide 450 'N 'ΊίΎ α 2.12 0 ^s 0 ΛΛλ Κί 4 - [[[[6 - [[(2- 0 JU chloro-6-methylphenyl) amino] - Η, Ο carbonyl] -2-benzothiazolyl] - amino] kaibonyl] amino] -1- piperidinecarboxylové | 451 X) yy «-f σ (S) -2 - [[[[1- (4-Bromophenyl) - 2.34 ΟΙ ethyl] amino] carbonyl] amino] -N CH, O ŤS - (2-chloro-6-methylphenyl) -6- 0. IN -benzothiazolecarboxamide and 452 ΗΛ n Chiral 2.02 (1S-cis) -2 - [[[[2- (Armocarbonyl) - rV yYCO σ cycohexyl] amino] carbonyl] amino] - LJ S Y ^'N' with ^-cis N- (2-chloro-6-methylphenyl) -6- ο -Ύ J -benzothiazolecarboxamide 433 • 2 - [[[[3- (1H-azepin-1-yl) propyl] amino] carbonyl] amino] -N- 1.70 cyyx w α Yň 0 IN Also - (2-chloro-6-methylphenyl) -6- -benzothiazolecarboxamide

• · · · ·

155 • · · ·

454 ? «. γΎΎ € 0 HaC Cl rJl Ύα - ¹¹ - N- (2-chloro-6-methylphenyl) -2 - [[[[2,2-dimethyl-3- (dimethylamino) -propyl] amino] carbonyl] amino] -6, -benzothiazolecarboxamide T ----- χϊ .. · '' - 1.65 H, C ^X zk O » C ^ 455 Ν, N P — ť. '' M Cl N- (2-chloro-6-methylphenyl) -2- 1.54 IN - [[(3-pyrrolidinylamino) carbonyl] - 0 ^sec AND amino] -6-benzothiazolecarboxamide ⁰ J H ₃ C in XI 456 p Λ 2.02 α Acid 4 - [[[[6 - [[(2-chloro-6-)] 0 1Ά methylphenyl) amino] carbonyl] -2 0 X) benzothiazolyl] amino] carbonyl] - HgC amino] methyl] benzoic 457 N ^ x- Υγ 4 ^s O Cl N- (2-chloro-6-methylphenyl) -2- 1.74 N - [[(3-Pyridinylamino) carbonyl] - O '—N 0 Z Η < at amino] -6-benzothiazolecarboxar nid • 458 z ^- xc 'Ύ Cl N- (2-chloro-6-methylphenyl) -2- 1.73 N AND - [[(4-pyridinylamino) carbonyl] O N — z 0 0 HjCr M amino] -6-benzothiazolecarboxai mid 459 N-. N— sí r O X ^ zN ··. α Λ N- (2-chloro-6-methylphenyl) -2- 1.75 / X ~ O. IN Ky - [[[[2- (1H-Rynol-3-yl) -ethyl] - amino] carbonyl] amino] -6- -benzothiazolecarboxamide AND

• ·· ·· ···· · · · · · · · · · · · · · · · ·

156

460 / _ ^Ν_ / ^{Ν Χ S} ό 'Χ, SsíA- s / ^N \ X O α N- (2-chloro-6-methylphenyl) -2- - [[(2-pyridinylamino)] - carbonyl] amino] -6- -benzothiazolecarboxamide 2.06 461 ^- ^ χ / ^Ν “Ο / Χ ^with Ν = <Ο Ο X, 5 1 Cl X • <£ d N- (2-chloro-6-methylphenyl) -2- - [[(2-pyrimidinylamino) - carbonyl] amino] -6- -benzothiazolecarboxamide 2.03 462 Ν ^ ζ , Ά'1 κ, ο-ο R \ A> o S HjC α O 4 - [[[[[6 - [[2- chloro-6-methylphenyl) amino] - carbonyl] -2-benzothiazolyl] - aminocarbonyl] - amino] methyl] benzoic 1 L 2.14 463 N-Χ Ο-R ^ν ΤΙ 0 ^ ch, C α AND N- (2-chloro-6-methylphenyl) -2- - [[[2- (1-ethyl-2-pyrrolidinyl) - methyl] amino] carbonyl] amino] -e -benzothiazolecarboxamide 1.63 464 Ν ^ χ ΗΪ, ^Ν Λ 0 '““ Ν 0. H, C α O N- (2-chloro-6-methylphenyl) -2- • [[[[2 - [(5-nitro-2-pyridinyl)]] amino] ethyl] amino] carbonyl] - amino] -6- -benzothiazolecarboxamide 2.07 465 Ογύχι ° / X ) N- (2-chloro-6-methylphenyl) -2- - [[[(1-ethyl-3-piperidinyl) - amino] carbonyl] amino] -6- -benzothiazolkaiboxamide J 1.65

«« · ·

157 9 8 9 9 9 9 9 9 9 9 9

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158:

JPettontovéé n a x? o 3c y

Claims (2)

[6 - [[[(2,6-dimethyl-4- (2-morpholinoethoxy) phenyl] amino] carbonyl] -2-benzothiazolyl] carbamic acid 1,1-dimethylethyl ester; 2 - [(cyclopropylcarbonyl) amino] -N- (2-chloro-6-methylphenyl) -6-benzothiazolecarboxamide; 2 - [(2-methyl-cyclopropylcarbonyl) amino] -N- (2-chloro-6-methylphenyl) -6-benzothiazolecarboxamide; 2 - [(2,2-dichloro-1-methyl-cyclopropylcarbonyl) amino] -N- (2-chloro-6-methylphenyl) -6-benzothiazolecarboxamide; and [6 - [[[(2,6-dimethyl-4- (2-N, N-dimethylethoxy) phenyl] amino] carbonyl] -2-benzothiazolyl] carbamic acid 1,1-dimethylethyl ester; [6 - [[[(2,6-dimethyl-4-phenyl) phenyl] amino] carbonyl] -2-benzothiazolyl] carbamic acid 1,1-dimethylethyl ester; 5-tert-butoxycarbonyloxy- [6 - [[(2,4,6-trimethylphenyl) amino] carbonyl] -2-benzothiazolyl] carbamic acid 1,1-dimethylethyl ester; 2 - [[[(1,1-dimethylethyl) amino] carbonyl] amino] -N- (2,6-dimethylphenyl) -6-benzothiazolecarboxamide; 2 - [[(cyclopropylamino) carbonyl] amino] -N- (2,6-dimethylphenyl) -6-benzothiazolecarboxamide; 2 - [[(cyclopentylamino) carbonyl] amino] -N- (2,6-dimethylphenyl) -6-benzothiazolecarboxamide; 2 - [[[[1- (ethynyl) cyclohexyl] amino] carbonyl] amino] -N- (2,6-dimethylphenyl) -6-benzothiazolecarboxamide; 2-t [[(4-methylcyclohexyl) amino] carbonyl] amino] -N- (2,6-dimethylphenyl) -6-benzothiazolecarboxamide; 2 - [[[(2,3-dihydro-1H-inden-1-yl) amino] carbonyl] amino] -N- (2,6-dimethylphenyl) -6-benzothiazolecarboxamide; • · · · · · · · · · · · · · · · · · · · 213 2 - [[[[2- (1H-imidazol-4-yl) ethyl] amino] carbonyl] amino] -N- (2,6-dimethylphenyl) -6-benzothiazolecarboxamide; 2 - [[[[(tetrahydro-2-furanyl) methyl] amino] carbonyl] amino] -N- (2,6-dimethylphenyl) -6-benzothiazolecarboxamide; 2 - [[[[2- (5-methoxy-1H-indol-3-yl) ethyl] amino] carbonyl] amino] -N- (2,6-dimethylphenyl) -6-benzothiazolecarboxamide; 2 - [[[(1,1-dimethyl-2-hydroxyethyl) amino] carbonyl] amino] -N- (2,6-dimethylphenyl) -6-benzothiazolecarboxamide; 2 - [[[(1,1-dimethylpropyl) amino] carbonyl] amino] -N- (2,6-dimethylphenyl) -6-benzothiazolecarboxamide; 2 - [[[[(3-methoxyphenyl) methyl] amino] carbonyl] amino] -N- (2,6-dimethylphenyl) -6-benzothiazolecarboxamide; 2 - [[[[(4-methoxyphenyl) methyl] amino] carbonyl] amino] -N- (2,6-dimethylphenyl) -6-benzothiazolecarboxamide; 2 - [[(2-propynylamino) carbonyl] amino] -N- (2,6-dimethylphenyl) -6-benzothiazolecarboxamide; 2 - [[(2-propenylamino) carbonyl] amino] -N- (2,6-dimethylphenyl) -6-benzothiazolecarboxamide; 2 - [[[(3-phenylpropyl) amino] carbonyl] amino] -N- (2,6-dimethylphenyl) -6-benzothiazolecarboxamide; 2 - [[[[1- (hydroxymethyl) cyclopentyl] amino] carbonyl] amino] -N- (2,6-dimethylphenyl) -6-benzothiazolecarboxamide; 2 - [[[[1- (methoxymethyl) propyl] amino] carbonyl] amino] -N- (2,6-dimethylphenyl) -6-benzothiazolecarboxamide; (R) -2 - [[[(1-phenylethyl) amino] carbonyl] amino] -N- (2,6-dimethylphenyl) -6-benzothiazolecarboxamide; 2 - [[[(3,4,5-trimethoxyphenyl) amino] carbonyl] amino] -N- (2,6-dimethylphenyl) -6-benzothiazolecarboxamide; 2 - [[(1,3-benzodioxol-5-ylamino) carbonyl] amino] -N- (2,6-dimethylphenyl) -6-benzothiazolecarboxamide; 2 - [[[(4-fluorophenyl) amino] carbonyl] amino] -N- (2,6-dimethylphenyl) -6-benzothiazolecarboxamide; 2 - [[(cyclopropylamino) carbonyl] amino] -N- (2-chloro-6-methylphenyl) -6-benzothiazolecarboxamide; • · ♦ · · · 214 2 - [[(cyclopentylamino) carbonyl] amino] -N- (2-chloro-6-methylphenyl) -6-benzothiazolecarboxamide; 2 - [[[[1- (ethynyl) cyclohexyl] amino] carbonyl] amino] -N- (2-chloro-6-methylphenyl) -6-benzothiazolecarboxamide; 2 - [[[(4-methylcyclohexyl) amino] carbonyl] amino] -N- (2-chloro-6-methylphenyl) -6-benzothiazolecarboxamide; 2 - [[[(2,3-dihydro-1H-inden-1-yl) amino] carbonyl] amino] -N- (2-chloro-6-methylphenyl) -6-benzothiazolecarboxamide; 2 - [[[[2- (1H-imidazol-4-yl) ethyl] amino] carbonyl] amino] -N- (2-chloro-6-methylphenyl) -6-benzothiazolecarboxamide; 2 - [[[[(tetrahydro-2-furanyl) methyl] amino] carbonyl] amino] - N - (2-chloro-6-methylphenyl) -6-benzothiazolecarboxamide; 2 - [[[[2- (5-methoxy-1 H -indol-3-yl) ethyl] amino] carbonyl] amino] -N- (2-chloro-6-methylphenyl) -6-benzothiazolecarboxamide; 2 - [[[(1,1-dimethyl-2-hydroxyethyl) amino] carbonyl] amino] -N- (2-chloro-6-methylphenyl) -6-benzothiazolecarboxamide; 2 - [[[(1,1-dimethylpropyl) amino] carbonyl] amino] -N- (2-chloro-6-methylphenyl) -6-benzothiazolecarboxamide; 2 - [[[[(3-methoxyphenyl) methyl] amino] carbonyl] amino] -N- (2-chloro-6-methylphenyl) -6-benzothiazolecarboxamide; 2 - [[[[(4-methoxyphenyl) methyl] amino] carbonyl] amino] -N- (2-chloro-6-methylphenyl) -6-benzothiazolecarboxamide; 2 - [[(2-propynylamino) carbonyl] amino] -N- (2-chloro-6-methylphenyl) -6-benzothiazolecarboxamide; 2 - [[(2-propenylamino) carbonyl] amino] -N- (2-chloro-6-methylphenyl) -6-benzothiazolecarboxamide; 2 - [[[(3-phenylpropyl) amino] carbonyl] amino] -N- (2-chloro-6-methylphenyl) -6-benzothiazolecarboxamide; 2 - [[[[1- (hydroxymethyl) cyclopentyl] amino] carbonyl] amino] -N- (2-chloro-6-methylphenyl) -6-benzothiazolecarboxamide; 2 - [[[[1- (methoxymethyl) propyl] amino] carbonyl] amino] -N- (2-chloro-6-methylphenyl) -6-benzothiazolecarboxamide; ·· · 215 (R) -2 - [[[(1-phenylethyl) amino] carbonyl] amino] -N- (2-chloro-6-methylphenyl) -6-benzothiazolecarboxamide; 2 - [[[(2,3-dimethyl-1H-indol-5-yl) amino] carbonyl] amino] -N- (2-chloro-6-methylphenyl) -6-benzothiazolecarboxamide; 2 - [[[(3,4,5-trimethoxyphenyl) amino] carbonyl] amino] -N- (2-chloro-6-methylphenyl) -6-benzothiazolecarboxamide; 2 - [[(1,3-benzodioxol-5-ylamino) carbonyl] amino] -N- (2-chloro-6-methylphenyl) -6-benzothiazolecarboxamide; 2 - [[[(4-fluorophenyl) amino] carbonyl] amino] -N- (2-chloro-6-methylphenyl) -6-benzothiazolecarboxamide; 2 - [[[[(1-methoxycarbonyl) cyclopropyl] amino] carbonyl] amino] -N- (2,4,6-trimethylphenyl) -6-benzothiazolecarboxamide; 7-Chloro- [6 - [[(2,4,6-trimethylphenyl) amino] carbonyl] -2-benzothiazolyl] carbamic acid 1,1-dimethylethyl ester; 2-amino-5-hydroxy-N- (2,4,6-trimethylphenyl) -6-benzothiazolecarboxamide; 5-chloro- [6 - [[(2,4,6-trimethylphenyl) amino] carbonyl] -2-benzothiazolyl] carbamic acid 1,1-dimethylethyl ester; 5-methoxy- [6 - [[(2,4,6-trimethylphenyl) amino] carbonyl] -2-benzothiazolyl] carbamic acid 1,1-dimethylethyl ester; 2-amino-N- (4-N, N-dimethylamino-2,3,5,6-tetramethylphenyl) -6-benzothiazolecarboxamide, trifluoroacetate (1: 1); 4-methoxy- [6 - [[(2,4,6-trimethoxyphenyl) amino] carbonyl] -2-benzothiazolyl] carbamic acid 1,1-dimethylethyl ester; 2-amino-4-methoxy-N- (2,4,6-trimethylphenyl) -6-benzothiazolecarboxamide, trifluoroacetate (1: 1); 2 - [[(methylamino) carbonyl] amino] -N- (2,4,6-trimethylphenyl) -6-benzothiazolecarboxamide; 2 - [[(methylamino) carbonyl] amino] -4-methoxy-N- (2,4,6-trimethylphenyl) -6-benzothiazolecarboxamide; [4-methyl-6 - [[(2,4,6-trimethylphenyl) amino] carbonyl] -2-benzothiazolyl] carbamic acid 1,1-dimethylethyl ester; 2-amino-4-methyl-N- (2,4,6-trimethylphenyl) -6-benzothiazolecarboxamide, trifluoroacetate (1: 1); • · · · 212 [6 - [[(2-methyl-1-naphthalenyl) amino] carbonyl] -2-benzothiazolyl] carbamic acid 1,1-dimethylethyl ester; 3 - [[[2 - [[(1,1-dimethylethoxy) carbonyl] amino] -6-benzothiazolyl] carbonyl] amino] -4-methyl-2-thiophenecarboxylic acid methyl ethyl ester; [6 - [[(2,4,6-trimethylphenyl) amino] carbonyl] -2-benzothiazolyl] carbamic acid methyl ethyl ester; 2 - [[(acetylamino) acetyl] amino] -N- (2,4,6-trimethylphenyl) -6-benzothiazolecarboxamide; N- (2-chloro-6-methylphenyl) -2 - [[[(1,1-dimethylethyl) amino] carbonyl] amino] -6-benzothiazolecarboxamide; N- (2,6-dichlorophenyl) -2 - [[[(1,1-dimethylethyl) amino] carbonyl] amino] -6-benzothiazolecarboxamide; N- (4-bromo-2,6-dimethylphenyl) -2 - [[[(1,1-dimethylethyl) amino] carbonyl] amino] -6-benzothiazolecarboxamide; N- (4-carbomethoxy-2,6-dimethylphenyl) -2 - [[[(1,1-dimethylethoxy) amino] carbonyl] amino] -6-benzothiazolecarboxamide; N- (4-hydroxymethyl-2,6-dimethylphenyl) -2 - [[[(1,1-dimethylethoxy) amino] carbonyl] amino] -6-benzothiazolecarboxamide; [6 - [[(2,6-dimethoxyphenyl) amino] carbonyl] -2-benzothiazolyl] carbamic acid 1,1-dimethylethyl ester; [6 - [[(3-acetylamino) -4,6-dimethylphenyl] amino] carbonyl] -2-benzothiazolyl] carbamic acid 1,1-dimethylethyl ester; [6 - [[(4-bromo-2,6-dimethyl-phenyl) -amino] -carbonyl] -2-benzothiazolyl] -carbamic acid 1,1-dimethylethyl ester; [6 - [[[4 - [[(1,1-dimethyloxy) carbonyl] amino] -2,3,5,6-tetramethylphenyl] amino] carbonyl] -2-benzothiazolyl] carbamic acid 1,1-dimethylethyl ester; [6 - [[(2-acetyl-6-hydroxyphenyl) -amino] carbonyl] -2-benzothiazolyl] carbamic acid 1,1-dimethylethyl ester; • • • 211 [6 - [[(2-bromo-3,4,6-trimethyl-phenyl) -amino] -carbonyl] -2-benzothiazolyl] -carbamic acid 1,1-dimethylethyl ester; [6 - [[(2,6-Dimethyl-3-nitrophenyl) amino] carbonyl] -2-benzothiazolyl] carbamic acid 1,1-dimethylethyl ester; [6 - [[[2- (2-hydroxyethyl) -6-methylphenyl] amino] carbonyl] -2-benzothiazolyl] carbamic acid 1,1-dimethylethyl ester; [6 - [[(6-methyl-5-quinolinyl) amino] carbonyl] -2-benzothiazolyl] carbamic acid 1,1-dimethylethyl ester; [6 - [[(6-methoxy-2-naphthalenyl) amino] carbonyl] -2-benzothiazolyl] carbamic acid 1,1-dimethylethyl ester; [6 - [[(2-methyl-6-quinolinyl) amino] carbonyl] -2-benzothiazolyl] carbamic acid 1,1-dimethylethyl ester; [6 - [[(2-bromo-4,6-dimethylphenyl) amino] carbonyl] -2-benzothiazolyl] carbamic acid 1,1-dimethylethyl ester; [6 - [[[2,6-dimethyl-3- (1-methylethyl) phenyl] amino] carbonyl] -2-benzothiazolyl] carbamic acid 1,1-dimethylethyl ester; [6 - [[(3-bromo-2,4,6-trimethyl-phenyl) -amino] -carbonyl] -2-benzothiazolyl] -carbamic acid 1,1-dimethylethyl ester; [6 - [[(4-bromo-2-methylphenyl) amino] carbonyl] -2-benzothiazolyl] carbamic acid 1,1-dimethylethyl ester; [6 - [[(2,6-dimethylphenyl) amino] carbonyl] -2-benzothiazolyl] carbamic acid 1,1-dimethylethyl ester; [6 - [[(2-chloro-6-methylphenyl) amino] carbonyl] -2-benzothiazolyl] carbamic acid 1,1-dimethylethyl ester; [6 - [[(2-fluoro-5-methylphenyl) amino] carbonyl] -2-benzothiazolyl] carbamic acid 1,1-dimethylethyl ester; [6 - [[(3-hydroxy-2-naphthalenyl) amino] carbonyl] -2-benzothiazolyl] carbamic acid 1,1-dimethylethyl ester; [6 - [(2-naphthylenylamino) carbonyl] -2-benzothiazolyl] carbamic acid 1,1-dimethylethyl ester; [6 - [[(2,3-dihydro-1H-inden-5-yl) amino] carbonyl] -2-benzothiazolyl] carbamic acid 1,1-dimethylethyl ester; • • • 210 [5 - [[(2,4,6-trimethylphenyl) amino] carbonyl] -2-benzothiazolyl] carbamic acid 1,1-dimethylethyl ester; 2 - [[[phenylamino] carbonyl] amino] -N- (2,4,6-trimethylphenyl) -6-benzothiazolecarboxamide; 2 - [[[(phenylmethyl) amino] carbonyl] amino] -N- (2,4,6-trimethylphenyl) -6-benzothiazolecarboxamide; 2 - [[[ethylamino] carbonyl] amino] -N- (2,4,6-trimethylphenyl) -6-benzothiazolecarboxamide; 2 - [[(butylamino) carbonyl] amino] -N- (2,4,6-trimethylphenyl) -6-benzothiazolecarboxamide; 2 - [[(cyclopropylamino) carbonyl] amino] -N- (2,4,6-trimethylphenyl) -6-benzothiazolecarboxamide; (R) -2 - [[[[(3,3-dimethylcyclohexyl) methyl] amino] carbonyl] amino] -N- (2,4,6-trimethylphenyl) -6-benzothiazolecarboxamide; 2 - [[[(4-methylcyclohexyl) amino] carbonyl] amino] -N- (2,4,6-trimethylphenyl) -6-benzothiazolecarboxamide; 2 - [[[(cyclohexylmethyl) amino] carbonyl] amino] -N- (2,4,6-trimethylphenyl) -6-benzothiazolecarboxamide; 2 - [[[(2,3-dihydro-1H-inden-1-yl) amino] carbonyl] amino] -N- (2,4,6-trimethylphenyl) -6-benzothiazolecarboxamide; 2 - [[[(1-naphthalenylmethyl) amino] carbonyl] amino] -N- (2,4,6-trimethylphenyl) -6-benzothiazolecarboxamide; 2 - [[[[2- (1H-imidazol-4-yl) ethyl] amino] carbonyl] amino] -N- (2,4,6-trimethylphenyl) -6-benzothiazolecarboxamide; 2 - [[[[(tetrahydro-2-furanyl) methyl] amino] carbonyl] amino] -N- (2,4,6-trimethylphenyl) -6-benzothiazolecarboxamide; 2 - [[[[2- (5-methoxy-1H-indol-3-yl) ethyl] amino] carbonyl] amino] -N- (2,4,6-trimethylphenyl) -6-benzothiazolecarboxamide; 2 - [[[[2- (4-morpholinyl) ethyl] amino] carbonyl] amino] -N- (2,4,6-trimethylphenyl) -6-benzothiazolecarboxamide; 2 - [[[[2- (2-pyridinyl) ethyl] amino] carbonyl] amino] -N- (2,4,6-trimethylphenyl) -6-benzothiazolecarboxamide; 4 4 203 . 9 4 4 4 4 4444995 9 4 4 2 - [[[(1,1,3,3-tetramethylbutyl) amino] carbonyl] amino] N- (2,4,6-trimethylphenyl) -6-benzothiazolecarboxamide; 2 - [[[(1,1-dimethylpropyl) amino] carbonyl] amino] N- (2,4,6-trimethylphenyl) -6-benzothiazolecarboxamide; 2 - [[[(1,5-dimethylhexyl) amino] carbonyl] amino] N- (2,4,6-trimethylphenyl) -6-benzothiazolecarboxamide; 2 - [[(cyclopentylamino) carbonyl] amino] -N- (2,4,6 trimethylphenyl) -6-benzothiazolecarboxamide; 2 - [[[(1,1-dimethyl-2-hydroxyethyl) amino] carbonyl] amino] N- (2,4,6-trimethylphenyl) -6-benzothiazolecarboxamide; 2 - [[[[(3-methoxyphenyl) methyl] amino] carbonyl] amino] -N- (2,4,6-trimethylphenyl) -6-benzothiazolecarboxamide; 2 - [[[[(3-methylphenyl) methyl] amino] carbonyl] amino] -N- (2,4,6-trimethylphenyl) -6-benzothiazolecarboxamide; 2 - [[[[(4-chlorophenyl) methyl] amino] carbonyl] amino] -N- (2,4,6-trimethylphenyl) -6-benzothiazolecarboxamide; 2 - [[[[2- (4-methoxyphenyl) ethyl] amino] carbonyl] amino] -N- (2,4,6-trimethylphenyl) -6-benzothiazolecarboxamide; 2 - [[(2-propynylamino) carbonyl] amino] -N- (2,4,6-trimethylphenyl) -6-benzothiazolecarboxamide; 2 - [[(2-propenylamino) carbonyl] amino] -N- (2,4,6-trimethylphenyl) -6-benzothiazolecarboxamide; 2 - [[[(3-phenylpropyl) amino] carbonyl] amino] -N- (2,4,6-trimethylphenyl) -6-benzothiazolecarboxamide; 2 - [[[[1- (hydroxymethyl) cyclopentyl] amino] carbonyl] amino] -N- (2,4,6-trimethylphenyl) -6-benzothiazolecarboxamide; 2 - [[[[4- (1,1-dimethylethyl) cyclohexyl] amino] carbonyl] amino] -N- (2,4,6-trimethylphenyl) -6-benzothiazolecarboxamide; 2 - [[[[(1-propylbutyl) amino] carbonyl] amino] -N- (2,4,6-trimethylphenyl) -6-benzothiazolecarboxamide; 2 - [[[[(1,3-dimethylpentyl) amino] carbonyl] amino] -N- (2,4,6-trimethylphenyl) -6-benzothiazolecarboxamide; • · 204 · · · · · a · a · a · a · a · a · a · a · a · a · ·· · · 2 - [[[[3- (methylthio) propyl] amino] carbonyl] amino] -N- (2,4,6-trimethylphenyl) -6-benzothiazolecarboxamide; 2 - [[[[1- (methoxymethyl) propyl] amino] carbonyl] amino] -N- (2,4,6-trimethylphenyl) -6-benzothiazolecarboxamide; 2 - [[[[2- (2-thienyl) ethyl] amino] carbonyl] amino] -N- (2,4,6-trimethylphenyl) -6-benzothiazolecarboxamide; 2 - [[[[(2,6-dimethoxyphenyl) methyl] amino] carbonyl] amino] -N- (2,4,6-trimethylphenyl) -6-benzothiazolecarboxamide; (R) -2 - [[[[1- (hydroxymethyl) -2-phenylethyl] amino] carbonyl] amino] -N- (2,4,6-trimethylphenyl) -6-benzothiazolecarboxamide; (R) -2 - [[[(1-phenylethyl) amino] carbonyl] amino] -N- (2,4,6-trimethylphenyl) -6-benzothiazolecarboxamide; 2 - [[(1-adamantylamino) carbonyl] amino] -N- (2,4,6-trimethylphenyl) -6-benzothiazolecarboxamide; 2 - [[[[2- (4-fluorophenyl) -1,1-dimethylethyl] amino] carbonyl] amino] -N- (2,4,6-trimethylphenyl) -6-benzothiazolecarboxamide; 2 - [[[[2- (2-pyridinyloxy) ethyl] amino] carbonyl] amino] -N- (2,4,6-trimethylphenyl) -6-benzothiazolecarboxamide; 2 - [[[(1-methyl-1-phenylethyl] amino] carbonyl] amino] -N- (2,4,6-trimethylphenyl) -6-benzothiazolecarboxamide; (R) -2 - [[[[1- (4-methylphenyl) ethyl] amino] carbonyl] amino] -N- (2,4,6-trimethylphenyl) -6-benzothiazolecarboxamide; 2 - [[[(1-methylheptyl) amino] carbonyl] amino] -N- (2,4,6-trimethylphenyl) -6-benzothiazolecarboxamide; 2 - [[[[(4-methoxyphenyl) methyl] amino] carbonyl] amino] -N- (2,4,6-trimethylphenyl) -6-benzothiazolecarboxamide; 2 - [[[(4-cyclohexylphenyl) amino] carbonyl] amino] -N- (2,4,6-trimethylphenyl) -6-benzothiazolecarboxamide; 2 - [[[(5,6,7,8-tetrahydro-1-naphthalenyl) amino] carbonyl] amino] -N- (2,4,6-trimethylphenyl) -6-benzothiazolecarboxamide; 2 - [[[(2,3-dihydro-1H-inden-5-yl) amino] carbonyl] amino] -N- (2,4,6-trimethylphenyl) -6-benzothiazolecarboxamide; 205 «ft · t ft ft ft ft ft ft ft ft t t t t t t t t t t t t t t «« «« Ftft »·· · · 2 - [[(1,3-benzodioxol-5-ylamino) carbonyl] amino] -N- (2,4,6-trimethylphenyl) -6-benzothiazolecarboxamide; 2 - [[(2-pyridinylamino) carbonyl] amino] -N- (2,4,6-trimethylphenyl) -6-benzothiazolecarboxamide; 2 - [[[(3-methyl-2-pyridinyl) amino] carbonyl] amino] -N- (2,4,6-trimethylphenyl) -6-benzothiazolecarboxamide; 2 - [[[(4-methyl-2-pyridinyl) amino] carbonyl] amino] -N- (2,4,6-trimethylphenyl) -6-benzothiazolecarboxamide; 2 - [[[(2-chloro-5-methylphenyl) amino] carbonyl] amino] -N- (2,4,6-trimethylphenyl) -6-benzothiazolecarboxamide; 2 - [[[(2,6-dichlorophenyl) amino] carbonyl] amino] -N- (2,4,6-trimethylphenyl) -6-benzothiazolecarboxamide; 2 - [[[(2-methoxyphenyl) amino] carbonyl] amino] -N- (2,4,6-1-dimethylphenyl) -6-benzothiazolecarboxamide; 2 - [[([1,1'-biphenyl] -2-ylamino) carbonyl] amino] -N- (2,4,6-trimethylphenyl) -6-benzothiazolecarboxamide; 2 - [[[(2-benzoylphenyl) amino] carbonyl] amino] -N- (2,4,6-1-dimethylphenyl) -6-benzothiazolecarboxamide; 2 - [[[(2-methylphenyl) amino] carbonyl] amino] -N- (2,4,6-trimethylphenyl) -6-benzothiazolecarboxamide; N- (2,4,6-trimethylphenyl) -2 - [[[(2,4,6-trimethylphenyl) amino] carbonyl] amino] -6-benzothiazolecarboxamide; 2 - [[[[2-methyl-6- (1-methylethyl) phenyl] amino] carbonyl] amino] -N- (2,4,6-trimethylphenyl) -6-benzothiazolecarboxamide; 2 - [[[(3,5-difluorophenyl) amino] carbonyl] amino] -N- (2,4,6-trimethylphenyl) -6-benzothiazolecarboxamide; 2 - [[[(3-methoxyphenyl) amino] carbonyl] amino] -N- (2,4,6-trimethylphenyl) -6-benzothiazolecarboxamide; 2 - [[[(3-methylphenyl) amino] carbonyl] amino] -N- (2,4,6-trimethylphenyl) -6-benzothiazolecarboxamide; 2 - [[[(4-cyanophenyl) amino] carbonyl] amino] -N- (2,4,6-trimethylphenyl) -6-benzothiazolecarboxamide; • · · · 206 2 - [[[(4-fluorophenyl) amino] carbonyl] amino] -N- (2,4,6-trimethylphenyl) -6-benzothiazolecarboxamide; 2 - [[[(4-chlorophenyl) amino] carbonyl] amino] -N- (2,4,6-trimethylphenyl) -6-benzothiazolecarboxamide; 4 - [[[[- 6 - [[(2,4,6-trimethylphenyl) amino] carbonyl] -2-benzothiazolyl] amino] carbonyl] amino] benzoic acid ethyl ester; 2 - [[[(3,4,5-trimethoxyphenyl) amino] carbonyl] amino] -N- (2,4,6-trimethylphenyl) -6-benzothiazolecarboxamide; 2 - [[[(3,4-dimethoxyphenyl) amino] carbonyl] amino] -N- (2,4,6-trimethylphenyl) -6-benzothiazolecarboxamide; 2 - [[[[2,6-bis (1-methylethyl) phenyl] amino] carbonyl] amino] -N- (2,4,6-trimethylphenyl) -6-benzothiazolecarboxamide; 2 - [[[(2-propylphenyl) amino] carbonyl] amino] -N- (2,4,6-trimethylphenyl) -6-benzothiazolecarboxamide; 2 - [[[(3-bromo-2,4,6-trimethylphenyl) amino] carbonyl] amino] -N- (2,4,6-trimethylphenyl) -6-benzothiazolecarboxamide; 2 - [[[[2- (4-morpholinyl) phenyl] amino] carbonyl] amino] -N- (2,4,6-trimethylphenyl) -6-benzothiazolecarboxamide; 2 - [[[(3-bromo-2-methylphenyl) amino] carbonyl] amino] -N- (2,4,6-trimethylphenyl) -6-benzothiazolecarboxamide; 2 - [[[(2,6-dimethoxyphenyl) amino] carbonyl] amino] -N- (2,4,6-trimethylphenyl) -6-benzothiazolecarboxamide; 2 - [[[(2-bromo-5-methoxyphenyl) amino] carbonyl] amino] -N- (2,4,6-trimethylphenyl) -6-benzothiazolecarboxamide; 2 - [[[(2-methoxy-6-methylphenyl) amino] carbonyl] amino] -N- (2,4,6-trimethylphenyl) -6-benzothiazolecarboxamide; 2 - [[[(2,3-dimethyl-1H-indol-5-yl) amino] carbonyl] amino] -N- (2,4,6-trimethylphenyl) -6-benzothiazolecarboxamide; 2 - [[[[3- (1,3,4-oxadiazol-2-yl) phenyl] amino] carbonyl] amino] -N - (2,4,6-trimethylphenyl) -6-benzothiazolecarboxamide; 2 - [[[(2-chloro-6-methylphenyl) amino] carbonyl] amino] -N- (2,4,6-trimethylphenyl) -6-benzothiazolecarboxamide; 207 2 - [[[[3- (methylthio) phenyl] amino] carbonyl] amino] -N- (2,4,6-trimethylphenyl) -6-benzothiazolecarboxamide; 2 - [[[(4-methoxy-2-methylphenyl) amino] carbonyl] amino] -N- (2,4,6-trimethylphenyl) -6-benzothiazolecarboxamide; 2 - [[(4-methoxycyclohexyl) carbonyl] amino] -N- (2,4,6-trimethylphenyl) -6-benzothiazolecarboxamide; 2 - [(2,2-dimethyl-1-oxopropyl) amino] -N- (2,4,6-trimethylphenyl) -6-benzothiazolecarboxamide; 2 - [(2-thienylacetyl) amino] -N- (2,4,6-trimethylphenyl) -6-benzothiazolecarboxamide; 2 - [(cyclopropylcarbonyl) amino] -N- (2,4,6-trimethylphenyl) -6-benzothiazolecarboxamide; 2 - [(cyclobutylcarbonyl) amino] -N- (2,4,6-trimethylphenyl) -6-benzothiazolecarboxamide; 2 - [(cyclopentylcarbonyl) amino] -N- (2,4,6-trimethylphenyl) -6-benzothiazolecarboxamide; 2 - [(3-cyclopentyl-1-oxopropyl) amino] -N- (2,4,6-trimethylphenyl) -6-benzothiazolecarboxamide; 2 - [(1-cyclopenten-1-ylcarbonyl) amino] -N- (2,4,6-trimethylphenyl) -6-benzothiazolecarboxamide; 2 - [(cyclohexylacetyl) amino] -N- (2,4,6-trimethylphenyl) -6-benzothiazolecarboxamide; 2 - [(1-oxo-2-phenylpropyl) amino] -N- (2,4,6-trimethylphenyl) -6-benzothiazolecarboxamide; 2 - [(2-methyl-1-oxopropyl) amino] -N- (2,4,6-trimethylphenyl) -6-benzothiazolecarboxamide; 2 - [(1-oxo-3-phenoxypropyl) amino] -N- (2,4,6-trimethylphenyl) -6-benzothiazolecarboxamide; 2 - [(1-oxo-3-phenylpropyl) amino] -N- (2,4,6-trimethylphenyl) -6-benzothiazolecarboxamide; 2 - [[3- (2-methoxyphenyl) -1-oxopropyl) amino] -N- (2,4,6-trimethylphenyl) -6-benzothiazolecarboxamide; • · · · · · 208 2 - [[3- (2,3,4-trimethoxyphenyl) -1-oxopropyl) amino] -N- (2,4,6-trimethylphenyl) -6-benzothiazolecarboxamide; 2 - [(1,4-dioxopentyl) amino] -N- (2,4,6-trimethylphenyl) -6-benzothiazolecarboxamide; 2 - [(2-naphthalenylacetyl) amino] -N- (2,4,6-trimethylphenyl) -6-benzothiazolecarboxamide; 2 - [[(2-chloro-6-fluorophenyl) acetyl] amino] -N- (2,4,6-trimethylphenyl) -6-benzothiazolecarboxamide; 2 - [[(2-methylphenyl) acetyl] amino] -N- (2,4,6-trimethylphenyl) -6-benzothiazolecarboxamide; 2 - [[(3-methoxyphenyl) acetyl] amino] -N- (2,4,6-trimethylphenyl) -6-benzothiazolecarboxamide; 2 - [[(4-chlorophenyl) acetyl] amino] -N- (2,4,6-trimethylphenyl) -6-benzothiazolecarboxamide; 2 - [(1-oxo-4-pentynyl) amino] -N- (2,4,6-trimethylphenyl) -6-benzothiazolecarboxamide; 5-Oxo-5 - [[6 - [[(2,4,6-trimethylphenyl) amino] carbonyl] -2-benzothiazolyl] amino] pentanoic acid methyl ethyl ester; 2 - [(1-oxohexyl) amino] -N- (2,4,6-trimethylphenyl) -6-benzothiazolecarboxamide; 2 - [(1-oxoheptyl) amino] -N- (2,4,6-trimethylphenyl) -6-benzothiazolecarboxamide; 2 - [[1-oxo-4- (2-thienyl) butyl] amino] -N- (2,4,6-trimethylphenyl) -6-benzothiazolecarboxamide; 2 - [(3-thienylcarbonyl) butyl] amino] -N- (2,4,6-trimethylphenyl) -6-benzothiazolecarboxamide; 2 - [[(4-nitrophenyl) acetyl]] amino] -N- (2,4,6-trimethylphenyl) -6-benzothiazolecarboxamide; 2 - [[[3,5-bis (trifluoromethyl) phenyl] acetyl] amino] -N- (2,4,6-trimethylphenyl) -6-benzothiazolecarboxamide; 2 - [[2- [4- (2-methylpropyl) phenyl] 1-oxopropyl] amino] -N- (2,4,6-trimethylphenyl) -6-benzothiazolecarboxamide; • · ·· ·· 209 2 - [[(3-Cyclohexen-1-yl) carbonyl] amino] -N- (2,4,6-trimethylphenyl) -6-benzothiazolecarboxamide; 2 - [[3- (3-methoxyphenyl) -1-oxopropyl] amino] -N- (2,4,6-trimethylphenyl) -6-benzothiazolecarboxamide; 2 - [[(2,3,6-trichlorophenyl) acetyl] amino] -N- (2,4,6-trimethylphenyl) -6-benzothiazolecarboxamide; 2 - [[(1,3-benzodioxol-5-yl) acetyl] amino] -N- (2,4,6-trimethylphenyl) -6-benzothiazolecarboxamide; 2 - [[[2- (phenylmethoxy) phenyl] acetyl] amino] -N- (2,4,6-trimethylphenyl) -6-benzothiazolecarboxamide; 2 - [[(3,5-dimethoxyphenyl) acetyl] amino] -N- (2,4,6-trimethylphenyl) -6-benzothiazolecarboxamide; 2 - [[3- (1,3-benzodioxol-5-yl) -1-oxopropyl] amino] -N- (2,4,6-trimethylphenyl) -6-benzothiazolecarboxamide; 2 - [[(tetrahydro-2-furanyl) carbonyl] amino] -N- (2,4,6-trimethylphenyl) -6-benzothiazolecarboxamide; 2 - [[2- (acetylamino) -1-oxopropyl] amino] -N- (2,4,6-trimethylphenyl) -6-benzothiazolecarboxamide; 2 - [[2- (acetylamino) -1-oxohexyl] amino] -N- (2,4,6-trimethylphenyl) -6-benzothiazolecarboxamide; 2 - [(cyclopropylacetyl) amino] -N- (2,4,6-trimethylphenyl) -6-benzothiazolecarboxamide; N, N-dimethyl-N '- [6 - [[(2,4,6-trimethylphenyl) amino] carbonyl] -2-benzothiazolyl] butanediamide; 2 - [(1-adamantocarbonyl) amino] -N- (2,4,6-trimethylphenyl) -6-benzothiazolecarboxamide; 2 - [[(4-methylcyclohexyl) carbonyl] amino] -N- (2,4,6-trimethylphenyl) -6-benzothiazolecarboxamide; 2 - [(3-methoxy-1-oxopropyl) amino] -N- (2,4,6-trimethylphenyl) -6-benzothiazolecarboxamide; [6-bromo-5 - [[(2,4,6-trimethylphenyl) amino] carbonyl] -2-benzothiazolyl] carbamic acid 1,1-dimethylethyl ester; • · · · · · · · · · 202 • · · · · ·········· [7 - [[(2,4,6-trimethylphenyl) amino] carbonyl] -2-benzothiazolyl] carbamic acid 1,1-dimethylethyl ester; [6-bromo-7 - [[(2,4,6-trimethylphenyl) amino] carbonyl] -2-benzothiazolyl] carbamic acid 1,1-dimethylethyl ester; [4 - [[(2,4,6-trimethylphenyl) amino] carbonyl] -2-benzothiazolyl] carbamic acid 1,1-dimethylethyl ester; [6-bromo-4 - [[(2,4,6-trimethylphenyl) amino] carbonyl] -2-benzothiazolyl] carbamic acid 1,1-dimethylethyl ester; [6 - [(2,4,6-trimethylphenyl) amino] carbonyl] -2-benzothiazolyl] carbamic acid 1,1-dimethylethyl ester; 2-amino-N- (2,4,6-trimethylphenyl) -6-benzothiazolecarboxamide, trifluoroacetate (1: 1); 2- (acetylamino) -N- (2,4,6-trimethylphenyl) -6-benzothiazolecarboxamide; 2- (benzoylamino) -N- (2,4,6-trimethylphenyl) -6-benzothiazolecarboxamide; 2 - [(1-oxopropyl) amino] -N- (2,4,6-trimethylphenyl) -6-benzothiazolecarboxamide; 2 - [(1-oxobutyl) amino] -N- (2,4,6-trimethylphenyl) -6-benzothiazolecarboxamide; 2 - [[[(1,1-dimethylethyl) amino] carbonyl] amino] -N- (2,4,6-trimethylphenyl) -6-benzothiazolecarboxamide; 2 - [[[bis (1-methylethyl) amino] carbonyl] amino] -N- (2,4,6-trimethylphenyl) -6-benzothiazolecarboxamide; [1 - [[[6 - [[(2,4,6-trimethylphenyl) amino] carbonyl] -2-benzthiazolyl] amino] carbonyl] cyclopropyl] carbamic acid 1,1-dimethylethyl ester; (1S-trans) -2 - [[[2,2-dimethyl-3- (2-methyl-1-propenyl) cyclopropyl] carbonyl] amino] -N- (2,4,6-trimethylphenyl) -6-benzothiazolecarboxamide ; (1S-cis) -2 - [[[2,2-Dimethyl-3- (2-methyl-1-propenyl) cyclopropyl] carbonyl] amino] -N- (2,4,6-trimethylphenyl) -6-benzothiazolecarboxamide ; 2 - [[(1-phenylcyclopropyl) carbonyl] amino] -N- (2,4,6-trimethylphenyl) -6-benzothiazolecarboxamide; 2 - [[(2-formylcyclopropyl) carbonyl] amino] -N- (2,4,6-trimethylphenyl) -6-benzothiazolecarboxamide; 2 - [[(2-cyancyclopropyl) carbonyl] amino] -N- (2,4,6-trimethylphenyl) -6-benzothiazolecarboxamide; 2 - [[[6 - [[(2,4,6-trimethylphenyl) amino] carbonyl] -2-benzthiazolyl] amino] carbonyl] -1-methylcyclopropanecarboxylic acid methyl ester; 2 - [[[2- (phenylmethyl) cyclopropyl] carbonyl] amino] -N- (2,4,6-trimethylphenyl) -6-benzothiazolecarboxamide; 2 - [[[1- (4-methylphenyl) cyclopropyl] carbonyl] amino] -N- (2,4,6-trimethylphenyl) -6-benzothiazolecarboxamide; * · 192 2 - [[[1- (4-chlorophenyl) cyclopropyl] carbonyl] amino] -N- (2,4,6-trimethylphenyl) -6-benzothiazolecarboxamide; 2 - [[[1- (4-methoxyphenyl) cyclopropyl] carbonyl] amino] -N- (2,4,6-trimethylphenyl) -6-benzothiazolecarboxamide; N- (2-chloro-6-methylphenyl) -2 - [[[[2- (1-piperidinyl) ethyl] amino] carbonyl] amino] -6-benzothiazolecarboxamide; N- (2-chloro-6-methylphenyl) -2 - [[[[(2-chlorophenyl) methyl] amino] carbonyl] amino] -6-benzothiazolecarboxamide; N- (2-chloro-6-methylphenyl) -2 - [[[[(2-fluorophenyl) methyl] amino] carbonyl] amino] -6-benzothiazolecarboxamide; N- (2-chloro-6-methylphenyl) -2 - [[[(2-phenoxyethyl) amino] carbonyl] amino] -6-benzothiazolecarboxamide; 2-t [[(benzo [b] thiophen-3-ylmethyl) amino] carbonyl] amino] -N- (2-chloro-6-methylphenyl) -6-benzothiazolecarboxamide; (R) -N- (2-chloro-6-methylphenyl) - [[[(2-phenoxyethyl) amino] carbonyl] amino] -6-benzothiazolecarboxamide; N- (2-chloro-6-methylphenyl) -2 - [[[[[4- (dimethylamino) phenyl] methyl] amino] carbonyl] amino] -6-benzothiazolecarboxamide; (S) -N- (2-chloro-6-methylphenyl) -2 - [[[(2-hydroxy-1-phenylethyl) amino] carbonyl] amino] -6-benzothiazolecarboxamide; N- (2-chloro-6-methylphenyl) -2 - [[[[(4-nitrophenyl) methyl] amino] carbonyl] amino] -6-benzothiazolecarboxamide; N- (2-chloro-6-methylphenyl) -2 - [[[[2- (1-pyrrolidinyl) ethyl] amino] carbonyl] amino] -6-benzothiazolecarboxamide; N- (2-chloro-6-methylphenyl) -2 - [[[[[4- (trifluoromethoxy) phenyl] methyl] amino] carbonyl] amino] -6-benzothiazolecarboxamide; N- (2-chloro-6-methylphenyl) -2 - [[[[2- (2-pyridinyl) ethyl] amino] carbonyl] amino] -6-benzothiazolecarboxamide; N- (2-chloro-6-methylphenyl) -2 - [[[(3-pyridinylmethyl) amino] carbonyl] amino] -6-benzothiazolecarboxamide; N- (2-chloro-6-methylphenyl) -2 - [[[(4-pyridinylmethyl) amino] carbonyl] amino] -6-benzothiazolecarboxamide; • · · · · · 193 N- (2-chloro-6-methylphenyl) -2 - [[[[(3-chlorophenyl) methyl] amino] carbonyl] amino] -6-benzothiazolecarboxamide; N- (2-chloro-6-methylphenyl) -2 - [[[[(2,3-dichlorophenyl) methyl] amino] carbonyl] amino] -6-benzothiazolecarboxamide; N- (2-chloro-6-methylphenyl) -2 - [[[[(3,4-difluorophenyl) methyl] amino] carbonyl] amino] -6-benzothiazolecarboxamide; N- (2-chloro-6-methylphenyl) -2 - [[[[(2,6-dimethoxyphenyl) methyl] amino] carbonyl] amino] -6-benzothiazolecarboxamide; N- (2-chloro-6-methylphenyl) -2 - [[[[(2-ethoxyphenyl) methyl] amino] carbonyl] amino] -6-benzothiazolecarboxamide; N- (2-chloro-6-methylphenyl) -2 - [[[[(2,3-dihydro-1,4-benzodioxin-2-yl) methyl] amino] carbonyl] amino] -6-benzothiazolecarboxamide; N- (2-chloro-6-methylphenyl) -2 - [[[[2- (3-methoxyphenyl) ethyl] amino] carbonyl] amino] -6-benzothiazolecarboxamide; N- (2-chloro-6-methylphenyl) -2 - [[[[2- (4-methoxyphenyl) ethyl] amino] carbonyl] amino] -6-benzothiazolecarboxamide; N- (2-chloro-6-methylphenyl) -2 - [[[[(2-methylphenyl) methyl] amino] carbonyl] amino] -6-benzothiazolecarboxamide; N- (2-chloro-6-methylphenyl) -2 - [[[[(3-methylphenyl) methyl] amino] carbonyl] amino] -6-benzothiazolecarboxamide; N- (2-chloro-6-methylphenyl) -2 - [[[[(5-methyl-2-furanyl) methyl] amino] carbonyl] amino] -6-benzothiazolecarboxamide; (S) -N- (2-chloro-6-methylphenyl) -2 - [[[[1- (hydroxymethyl) -2-phenylethyl] amino] carbonyl] amino] -6-benzothiazolecarboxamide; N- (2-chloro-6-methylphenyl) -2 - [[[[(2-phenylamino) ethyl] amino] carbonyl] amino] -6-benzothiazolecarboxamide; N- (2-chloro-6-methylphenyl) -2 - [[[(2-thienylmethyl) amino] carbonyl] amino] -6-benzothiazolecarboxamide; N- (2-chloro-6-methylphenyl) -2 - [[[[2- (1H-indol-3-yl) ethyl] amino] carbonyl] amino] -6-benzothiazolecarboxamide; 2 - [[[[(4-aminophenyl) methyl] amino] carbonyl] amino] -N- (2-chloro-6-methylphenyl) -6-benzothiazolecarboxamide; • · 194 Ν- (2-chloro-6-methylphenyl) -2 - [[[(diphenylmethyl) amino] carbonyl] amino] -6-benzothiazolecarboxamide; (1R-Exo) -2 - [[(bicyclo [2.2.1] heptan-2-ylamino] carbonyl] amino] -N- (2-chloro-6-methylphenyl) -6-benzothiazolecarboxamide; N- (2-chloro-6-methylphenyl) -2 - [[[[(4-chlorophenyl) methyl] amino] carbonyl] amino] -6-benzothiazolecarboxamide; N- (2-chloro-6-methylphenyl) -2 - [[[[1- (4-chlorophenyl) ethyl] amino] carbonyl] amino] -6-benzothiazolecarboxamide; (R) -N- (2-chloro-6-methylphenyl) -2 - [[[[1- (4-methylphenyl) ethyl] amino] carbonyl] amino] -6-benzothiazolecarboxamide; (S) -N- (2-chloro-6-methylphenyl) -2 - [[[[1- (4-methylphenyl) ethyl] amino] carbonyl] amino] -6-benzothiazolecarboxamide; N- (2-chloro-6-methylphenyl) -2 - [[[[(4-fluorophenyl) methyl] amino] carbonyl] amino] -6-benzothiazolecarboxamide; N- (2-chloro-6-methylphenyl) -2 - [[[[1- (4-fluorophenyl) ethyl] amino] carbonyl] amino] -6-benzothiazolecarboxamide; N- (2-chloro-6-methylphenyl) -2 - [[[(2-furanylmethyl) amino] carbonyl] amino] -6-benzothiazolecarboxamide; N- (2-chloro-6-methylphenyl) -2 - [[[[1- (4-methoxyphenyl) ethyl] amino] carbonyl] amino] -6-benzothiazolecarboxamide; (S) -N- (2-chloro-6-methylphenyl) -2 - [[[(1-phenylethyl) amino] carbonyl] amino] -6-benzothiazolecarboxamide; Α - [[[[6 - [[(2-chloro-6-methylphenyl) amino] carbonyl] -2-benzothiazolyl] amino] carbonyl] amino] benzeneacetic acid ethyl ester; N- (2-chloro-6-methylphenyl) -2 - [[[[2- (4-methylphenyl) -1-phenylethyl] amino] carbonyl] amino] -6-benzothiazolecarboxamide; (R) -N- (2-chloro-6-methylphenyl) -2 - [[[(1-phenylpropyl) amino] carbonyl] amino] -6-benzothiazolecarboxamide; N- (2-chloro-6-methylphenyl) -2 - [[[[2- (4-methylphenyl) methyl] amino] carbonyl] amino] -6-benzothiazolecarboxamide; (R) -N- (2-chloro-6-methylphenyl) -2 - [[[[1- (4-nitrophenyl) ethyl] amino] carbonyl] amino] -6-benzothiazolecarboxamide; • • • • 195 N- (2-chloro-6-methylphenyl) -2 - [[[[(4-chlorophenyl) phenylmethyl] amino] carbonyl] amino] -6-benzothiazolecarboxamide; N- (2-chloro-6-methylphenyl) -2 - [[[[2- (phenylthio) ethyl] amino] carbonyl] amino] -6-benzothiazolecarboxamide; 2 - [[[[(2-bromophenyl) methyl] amino] carbonyl] amino] -N- (2-chloro-6-methylphenyl) -6-benzothiazolecarboxamide; N- (2-chloro-6-methylphenyl) -2 - [[[[2- (3-fluorophenyl) ethyl] amino] carbonyl] amino] -6-benzothiazolecarboxamide; N- (2-chloro-6-methylphenyl) -2 - [[[[[4- (trifluoromethyl) phenyl] ethyl] amino] carbonyl] amino] -6-benzothiazolecarboxamide; 2 - [[[[(3-bromophenyl) methyl] amino] carbonyl] amino] -N- (2-chloro-6-methylphenyl) -6-benzothiazolecarboxamide; 2 - [[[[(4-chloro-2-fluorophenyl) methyl] amino] carbonyl] amino] -N- (2-chloro-6-methylphenyl) -6-benzothiazolecarboxamide; 2 - [[[(2-amino-2-oxo-1-phenylethyl) amino] carbonyl] amino] -N- (2-chloro-6-methylphenyl) -6-benzothiazolecarboxamide; N- (2-chloro-6-methylphenyl) -2 - [[[[3- (1-H-imidazol-1-yl) propyl] amino] carbonyl] amino] -6-benzothiazolecarboxamide; N- (2-chloro-6-methylphenyl) -2 - [[[[(2,4-dimethoxyphenyl) methyl] amino] carbonyl] amino] -6-benzothiazolecarboxamide; N- (2-chloro-6-methylphenyl) -2 - [[[[(3-chloro-4-methylphenyl) methyl] amino] carbonyl] amino] -6-benzothiazolecarboxamide; 2 - [[[[(3-chloro-4-fluorophenyl) methyl] amino] carbonyl] amino] -N- (2-chloro-6-methylphenyl) -6-benzothiazolecarboxamide; 2 - [[[[(2-chloro-6-fluorophenyl) methyl] amino] carbonyl] amino] -N- (2-chloro-6-methylphenyl) -6-benzothiazolecarboxamide; 2 - [[[[(2-chloro-4-fluorophenyl) methyl] amino] carbonyl] amino] -N- (2-chloro-6-methylphenyl) -6-benzothiazolecarboxamide; N- (2-chloro-6-methylphenyl) -2 - [[[[(3,5-difluorophenyl) methyl] amino] carbonyl] amino] -6-benzothiazolecarboxamide; N- (2-chloro-6-methylphenyl) -2 - [[[[(2,5-dimethoxyphenyl) methyl] amino] carbonyl] amino] -6-benzothiazolecarboxamide; • · 196 · · · * * * * * * * * * * N- (2-chloro-6-methylphenyl) -2 - [[[[(2,3-dimethylphenyl) methyl] amino] carbonyl] amino] -6-benzothiazolecarboxamide; N- (2-chloro-6-methylphenyl) -2 - [[[[(3,4-dimethoxyphenyl) methyl] amino] carbonyl] amino] -6-benzothiazolecarboxamide; N- (2-chloro-6-methylphenyl) -2 - [[[[(3,5-dimethoxyphenyl) methyl] amino] carbonyl] amino] -6-benzothiazolecarboxamide; N- (2-chloro-6-methylphenyl) -2 - [[[[[4- (1-methylethyl) phenyl] methyl] amino] carbonyl] amino] -6-benzothiazolecarboxamide; N- (2-chloro-6-methylphenyl) -2 - [[[[[4- (1,2,3-thiadiazol-4-yl) phenyl] methyl] amino] carbonyl] amino] -6-benzothiazolecarboxamide; N- (2-chloro-6-methylphenyl) -2 - [[[[2- (2-chlorophenyl) ethyl] amino] carbonyl] amino] -6-benzothiazolecarboxamide; N- (2-chloro-6-methylphenyl) -2 - [[[(1-methyl-1-phenylethyl) amino] carbonyl] amino] -6-benzothiazolecarboxamide; N- (2-chloro-6-methylphenyl) -2 - [[[[(2,5-dichlorophenyl) methyl] amino] carbonyl] amino] -6-benzothiazolecarboxamide; N- (2-chloro-6-methylphenyl) -2 - [[[[(2,4-dimethylphenyl) methyl] amino] carbonyl] amino] -6-benzothiazolecarboxamide; N- (2-chloro-6-methylphenyl) -2 - [[[[1- (1-naphthalenyl) ethyl] amino] carbonyl] amino] -6-benzothiazolecarboxamide; N- (2-chloro-6-methylphenyl) -2 - [[[[(3,4,5-trimethoxyphenyl) methyl] amino] carbonyl] amino] -6-benzothiazolecarboxamide; N- (2-chloro-6-methylphenyl) -2 - [[[[(2,4,6-trimethoxyphenyl) methyl] amino] carbonyl] amino] -6-benzothiazolecarboxamide; 2 - [[[[(4-bromophenyl) methyl] amino] carbonyl] amino] -N- (2-chloro-6-methylphenyl) -6-benzothiazolecarboxamide; [IR- (endo, endo)] - 3 - [[[[6 - [[(2-chloro-6-methylphenyl) amino] carbonyl] -2-benzothiazolyl] amino] carbonyl] amino] bicyclo [2.2.1] ethyl ester hept-5-ene-2-carboxylic acid; [1S- (exo, exo)] - 3 - [[[[6 - [[(2-chloro-6-methylphenyl) amino] carbonyl] -2-benzothiazolyl] amino] carbonyl] amino] bicyclo [2.2.1] ethyl ester heptane-2-carboxylic acid; 197 [IR- (exo, exo)] - 3 - [[[[6 - [[(2-chloro-6-methylphenyl) amino] carbonyl] -2-benzothiazolyl] amino] carbonyl] amino] bicyclo [2.2.1] ethyl ester hept-5-ene-2-carboxylic acid; [IR- (endo, endo)] - N- (2-chloro-6-methylphenyl) -2 - [[[[(3-hydroxymethyl) bicyclo [2.2.1] hept-5-en-2-yl] amino] carbonyl] amino] -6-benzothiazolecarboxamide; [IS - (endo, endo)] - N- (2-chloro-6-methylphenyl) -2 - [[[[(3-hydroxymethyl) bicyclo [2.2.1] heptan-2-yl] amino] carbonyl] amino 6-Benzothiazolecarboxamide; [IR- (exo, exo)] - N- (2-chloro-6-methylphenyl) -2 - [[[[(3-hydroxymethyl) bicyclo [2.2.1] heptan-2-yl] amino] carbonyl] amino 6-Benzothiazolecarboxamide; N- (2-chloro-6-methylphenyl) -2 - [[[[(3-fluorophenyl) methyl] amino] carbonyl] amino] -6-benzothiazolecarboxamide; N- (2-chloro-6-methylphenyl) -2 - [[[[(2-methoxyphenyl) methyl] amino] carbonyl] amino] -6-benzothiazolecarboxamide; (exo, exo)] - 2 - [[[[3- (aminocarbonyl) bicyclo [2.2.1] hept-5-en-2-yl] amino] carbonyl] amino] -N- (2-chloro-6- methylphenyl) -6-benzothiazolecarboxamide; (S) -N- (2-chloro-6-methylphenyl) -2 - [[[[1- (1-naphthalenyl) ethyl] amino] carbonyl] amino] -6-benzothiazolecarboxamide; N- (2-chloro-6-methylphenyl) -2 - [[[[[3- (trifluoromethyl) phenyl] methyl] amino] carbonyl] amino] -6-benzothiazolecarboxamide; N- (2-chloro-6-methylphenyl) -2 - [[[(phenylmethyl) amino] carbonyl] amino] -6-benzothiazolecarboxamide; (endo, endo)] - 2 - [[[[3- (aminocarbonyl) bicyclo [2.2.1] hept-5-en-2-yl] amino] carbonyl] amino] -N- (2-chloro-6- methylphenyl) -6-benzothiazolecarboxamide; N- (2-chloro-6-methylphenyl) -2 - [[[[1- (4-hydroxyphenyl) ethyl] amino] carbonyl] amino] -6-benzothiazolecarboxamide; N- (2-chloro-6-methylphenyl) -2 - [[[[(2,6-difluorophenyl) methyl] amino] carbonyl] amino] -6-benzothiazolecarboxamide; • · · · · 198 N- (2-chloro-6-methylphenyl) -2 - [[[[(2,3-dimethylphenyl) methyl] amino] carbonyl] amino] -6-benzothiazolecarboxamide; (R) -N- (2-chloro-6-methylphenyl) -2 - [[[[1- (1-naphthalenyl) ethyl] amino] carbonyl] amino] -6-benzothiazolecarboxamide; N- (2-chloro-6-methylphenyl) -2 - [[[[2- (dimethylamino) ethyl] amino] carbonyl] amino] -6-benzothiazolecarboxamide; N- (2-chloro-6-methylphenyl) -2 - [[[[1,1-dimethyl-2- (dimethylamino) ethyl] amino] carbonyl] amino] -6-benzothiazolecarboxamide; N- (2-chloro-6-methylphenyl) -2 - [[[[1- (phenylmethyl) -4-piperidinyl] amino] carbonyl] amino] -6-benzothiazolecarboxamide; N- (2-chloro-6-methylphenyl) -2 - [[[[3- (2-methyl-1-piperidinyl) propyl] amino] carbonyl] amino] -6-benzothiazolecarboxamide; N- (2-chloro-6-methylphenyl) -2 - [[[[2- (1-methyl-2-pyrrolidinyl) ethyl] amino] carbonyl] amino] -6-benzothiazolecarboxamide; N- (2-chloro-6-methylphenyl) -2 - [[[[3- (4-morpholinyl) propyl] amino] carbonyl] amino] -6-benzothiazolecarboxamide; N- (2-chloro-6-methylphenyl) -2 - [[[[1- (phenylmethyl) -3-pyrrolidinyl] amino] carbonyl] amino] -6-benzothiazolecarboxamide; N- (2-chloro-6-methylphenyl) -2 - [[[[3- (diethylamino) propyl] amino] carbonyl] amino] -6-benzothiazolecarboxamide; N- (2-chloro-6-methylphenyl) -2 - [[[[3- (4-methyl-1-piperazinyl) propyl] amino] carbonyl] amino] -6-benzothiazolecarboxamide; N- (2-chloro-6-methylphenyl) -2 - [[[[2- (1-piperazinyl) ethyl] amino] carbonyl] amino] -6-benzothiazolecarboxamide; N- (2-chloro-6-methylphenyl) -2 - [[[[2- (4-morpholinyl) ethyl] amino] carbonyl] amino] -6-benzothiazolecarboxamide; N- (2-chloro-6-methylphenyl) -2 - [[[(2,2,6,6, -tetramethyl-4-piperidinyl) amino] carbonyl] amino] -6-benzothiazolecarboxamide; (R) -N- (2-chloro-6-methylphenyl) -2 - [[[[1- (phenylmethyl) -3-pyrrolidinyl] amino] carbonyl] amino] -6-benzothiazolecarboxamide; (S) -N- (2-chloro-6-methylphenyl) -2 - [[[[1- (phenylmethyl) -3-pyrrolidinyl] amino] carbonyl] amino] -6-benzothiazolecarboxamide; 199 Ν - (2-chloro-6-methylphenyl) -2 - [[[[3- (1-piperidinyl) propyl] amino] carbonyl] amino] -6-benzothiazolecarboxamide; N- (2-chloro-6-methylphenyl) -2 - [[[[3- (1-pyrrolidinyl) propyl] amino] carbonyl] amino] -6-benzothiazolecarboxamide; N- (2-chloro-6-methylphenyl) -2 - [[[[1- (2-pyridinyl) ethyl] amino] carbonyl] amino] -6-benzothiazolecarboxamide; N- (2-chloro-6-methylphenyl) -2 - [[[[1- (3-pyridinyl) ethyl] amino] carbonyl] amino] -6-benzothiazolecarboxamide; N- (2-chloro-6-methylphenyl) -2 - [[[[3- (2-oxo-1-pyrrolidinyl) propyl] amino] carbonyl] amino] -6-benzothiazolecarboxamide; 4 - [[[[[6 - [[(2-chloro-6-methylphenyl) amino] carbonyl] -2-benzothiazolyl] amino] carbonyl] amino] -1-piperidinecarboxylic acid ethyl ester; 2 - [[[[1- (4-bromophenyl) ethyl] amino] carbonyl] amino] -N- (2-chloro-6-methylphenyl) -6-benzothiazolecarboxamide; (1S-cis) -2 - [[[[2- (aminocarbonyl) cyclohexyl] amino] carbonyl] amino] -N- (2-chloro-6-methylphenyl) -6-benzothiazolecarboxamide; 2 - [[[[3- (1H-azepin-1-yl) propyl] amino] carbonyl] amino] -N- (2-chloro-6-methylphenyl) -6-benzothiazolecarboxamide; N- (2-chloro-6-methylphenyl) -2 - [[[[2,2-dimethyl-3- (dimethylamino) propyl] amino] carbonyl] amino] -6-benzothiazolecarboxamide; N- (2-chloro-6-methylphenyl) -2 - [[(3-pyrrolidinylamino) carbonyl] amino] -6-benzothiazolecarboxamide; 4 - [[[[[6 - [[(2-chloro-6-methylphenyl) amino] carbonyl] -2-benzothiazolyl] amino] carbonyl] amino] methyl] benzoic acid; N- (2-chloro-6-methylphenyl) -2 - [[(3-pyridinylamino) carbonyl] amino] -6-benzothiazolecarboxamide; N- (2-chloro-6-methylphenyl) -2 - [[(4-pyridinylamino) carbonyl] amino] -6-benzothiazolecarboxamide; N- (2-chloro-6-methylphenyl) -2 - [[[[2- (1H-pyrrol-3-yl) ethyl] amino] carbonyl] amino] -6-benzothiazolecarboxamide; N- (2-chloro-6-methylphenyl) -2 - [[(2-pyridinylamino) carbonyl] amino] -6-benzothiazolecarboxamide; 200 to toto toto toto toto toto toto toto toto toto toto N- (2-chloro-6-methylphenyl) -2 - [[(2-pyrimidinylamino) carbonyl] amino] -6-benzothiazolecarboxamide; 4 - [[[[[[6 - [[(2-chloro-6-methylphenyl) amino] carbonyl] -2-benzothiazolyl] amino] carbonyl] amino] methyl] benzoic acid methyl ester; N- (2-chloro-6-methylphenyl) -2 - [[[[(1-ethyl-2-pyrrolidinyl) methyl] amino] carbonyl] amino] -6-benzothiazolecarboxamide; N- (2-chloro-6-methylphenyl) -2 - [[[[2 - [(5-nitro-2-pyridinyl) amino] ethyl] amino] carbonyl] amino] -6-benzothiazolecarboxamide; N- (2-chloro-6-methylphenyl) -2 - [[[(1-ethyl-3-piperidinyl) amino] carbonyl] amino] -6-benzothiazolecarboxamide; N- (2-chloro-6-methylphenyl) -2 - [[[[2- (6-fluoro-1H-indol-2-yl) ethyl] amino] carbonyl] amino] -6-benzothiazolecarboxamide; Trans-N- (2-chloro-6-methylphenyl) -2 - [[[2- [4- (1,1-dimethylethyl) phenyl] cyclopropyl] carbonyl] amino] -6-benzothiazolecarboxamide; Trans-N- (2-chloro-6-methylphenyl) -2 - [[[2- (4-ethoxyphenyl) cyclopropyl] carbonyl] amino] -6-benzothiazolecarboxamide; Trans-N- (2-chloro-6-methylphenyl) -2 - [[[2- (4-fluorophenyl) cyclopropyl] carbonyl] amino] -6-benzothiazolecarboxamide; Trans-N- (2-chloro-6-methylphenyl) -2 - [[[2- [4- (1-methylethyl) phenyl] cyclopropyl] carbonyl] amino] -6-benzothiazolecarboxamide; Trans-N- (2-chloro-6-methylphenyl) -2 - [[[2- [4- (trifluoromethyl) phenyl] cyclopropyl] carbonyl] amino] -6-benzothiazolecarboxamide; Trans-N- (2-chloro-6-methylphenyl) -2 - [[[2- (4-nitrophenyl) cyclopropyl] carbonyl] amino] -6-benzothiazolecarboxamide; Trans-N- (2-chloro-6-methylphenyl) -2 - [[[2- (4-cyanophenyl) cyclopropyl] carbonyl] amino] -6-benzothiazolecarboxamide; Trans-2 - [[(2- [1,1-biphenyl] -4-ylcyclopropyl) carbonyl] amino] -N- (2-chloro-6-methylphenyl) -6-benzothiazolecarboxamide; Trans-2 - [[[2- (1,3-benzodioxol-4-yl) cyclopropyl] carbonyl] amino] -N- (2-chloro-6-methylphenyl) -6-benzothiazolecarboxamide; Trans-N- (2-chloro-6-methylphenyl) -2 - [[[2- (3-chlorophenyl) cyclopropyl] carbonyl] amino] -6-benzothiazolecarboxamide; 201 Trans-4- (2-chloro-6-methylphenyl) -2 - [[[2- (3-cyanophenyl) cyclopropyl] carbonyl] amino] -6-benzothiazolecarboxamide; and Trans-N- (2-chloro-6-methylphenyl) -2 - [[[2- (3-nitrophenyl) cyclopropyl] carbonyl] amino] -6-benzothiazolecarboxamide. The compound of claim 41 which is a compound of Formula I or a salt of a compound of Formula 1 selected from the group consisting of: [1 - [[[6 - [[(2,6-dimethylphenyl] amino] carbonyl] -2-benzothiazolyl] amino] carbonyl] cyclopropyl] carbamic acid 1,1-dimethylethyl ester; (1S-cis) -2 - [[[2,2-dimethyl-3- (2-methyl-1-propenyl) cyclopropyl] carbonyl] amino] -N- (2,6-dimethylphenyl) -6-benzothiazolecarboxamide; N- (2,6-dimethylphenyl) -2 - [[[1- (4-methoxyphenyl) cyclopropyl] carbonyl] amino] -6-benzothiazolecarboxamide; N- (2,6-dimethylphenyl) -2 - [[(1-phenylcyclopropyl) carbonyl] amino] -6-benzothiazolecarboxamide; N- (2,6-dimethylphenyl) -2 - [[(2-formylcyclopropyl) carbonyl] amino] -6-benzothiazolecarboxamide; 2 - [[[6 - [[(2,6-dimethylphenyl) amino] carbonyl] -2-benzthiazolyl] amino] carbonyl] cyclopropanecarboxylic acid ethyl ester; 2 - [[(2-cyancyclopropyl) carbonyl] amino] -N- (2,6-dimethylphenyl) -6-benzothiazolecarboxamide; 2 - [[[6 - [[(2,6-dimethylphenyl) amino] carbonyl] -2-benzothiazolyl] amino] carbonyl] -1-methylcyclopropanecarboxylic acid methyl ester; • ⁹ • ⁹ • ⁹ 19X '' (IS-trans) -2 - [[[2,2-dimethyl-3- (2-methyl-1-propenyl) cyclopropyl] carbonyl] amino] -N- (2,6-dimethylphenyl) -6-benzothiazolecarboxamide; N- (2,4,6-trimethylphenyl) -2 - [[[2- (trimethylsilyl) cyclopropyl] carbonyl] amino] -6-benzothiazolecarboxamide; 2 - [[(2-methylcyclopropyl) carbonyl] amino] -N- (2,4,6-trimethylphenyl) -6-benzothiazolecarboxamide; Trans-2 - [[(2-phenylcyclopropyl) carbonyl] amino] -N- (2,4,6-trimethylphenyl) -6-benzothiazolecarboxamide; 2 - [[[6 - [[(2,4,6-trimethylphenyl) amino] carbonyl] -2-benzothiazolyl] amino] carbonyl] cyclopropanecarboxylic acid ethyl ester; [1 - [[[6 - [[(2-chloro-6-methylphenyl) amino] carbonyl] -2-benzothiazolyl] amino] carbonyl] cyclopropyl] carbamic acid 1,1-dimethylethyl ester; (1S-trans) - N - (2-Chloro-6-methylphenyl) -2 - [[[2,2-dimethyl-3- (2-methyl-1-propenyl) cyclopropyl] carbonyl] amino] -6-benzothiazolecarboxamide ; (1S-cis) -N- (2-chloro-6-methylphenyl) -2 - [[[2,2-dimethyl-3- (2-methyl-1-propenyl) cyclopropyl] carbonyl] amino] -6-benzothiazolecarboxamide ; N- (2-chloro-6-methylphenyl) -2 - [[(1-phenylcyclopropyl) carbonyl] amino] -6-benzothiazolecarboxamide; N- (2-chloro-6-methylphenyl) -2 - [[(1-formylcyclopropyl) carbonyl] amino] -6-benzothiazolecarboxamide; 2 - [[[6 - [((2-chloro-6-methylphenyl) amino] carbonyl] -2-benzothiazolyl] amino] carbonyl] cyclopropanecarboxylic acid ethyl ester; 2 - [[[6 - [[(2-chloro-6-methylphenyl) amino] carbonyl] -2-benzothiazolyl] amino] carbonyl] -1-methylcyclopropanecarboxylic acid methyl ester; N- (2-chloro-6-methylphenyl) -2 - [[[2- (2-phenylmethyl) cyclopropyl] carbonyl] amino] -6-benzothiazolecarboxamide; N- (2-chloro-6-methylphenyl) -2 - [(2-pyridinylcarbonyl) amino] -6-benzothiazolecarboxamide; «· · Β * 188 • 9 • · · · ······· Ν- (2-chloro-6-methylphenyl) -2 - [(2-pyridinylcarbonyl) amino] -6-benzothiazolecarboxamide, 1-oxide; Trans-N- (2-chloro-6-methylphenyl) -2 - [[[2 - [(dimethylamino) methyl] cyclopropyl] carbonyl) amino] -6-benzothiazolecarboxamide; N- (2-chloro-6-methylphenyl) -2 - [[(1-methyl-1H-pyrrol-2-yl) acetyl] amino] -6-benzothiazolecarboxamide; N- (2-chloro-6-methylphenyl) -2 - [[5- (dimethylamino) -1-oxopentyl] amino] -6-benzothiazolecarboxamide; N- (2-chloro-6-methylphenyl) -2 - [[4- (dimethylamino) -1-oxobutyl] amino] -6-benzothiazolecarboxamide; Trans-N- (2-chloro-6-methylphenyl) -2 - [[[2- (1-pyrrolidinylmethyl) cyclopropyl] carbonyl) amino] -6-benzothiazolecarboxamide; Trans-N- (2-chloro-6-methylphenyl) -2 - [[[2- (1-piperidinylmethyl) cyclopropyl] carbonyl) amino] -6-benzothiazolecarboxamide; N- (2-chloro-6-methylphenyl) -2 - [[(dimethylamino) acetyl] amino] -6-benzothiazolecarboxamide; N- (2-chloro-6-methylphenyl) -2 - [[3- (2-methyl-4-nitro-1H-imidazol-1-yl) -1-oxopropyl] amino] -6-benzothiazolecarboxamide; 2 - [(cyclobutylcarbonyl) amino] -N- (2,6-dimethylphenyl) -6-benzothiazolecarboxamide; 2 - [(cyclohexylacetyl) amino] -N- (2,6-dimethylphenyl) -6-benzothiazolecarboxamide; N- (2,6-dimethylphenyl) -2 - [(1-oxo-2-phenylpropyl) amino] -6-benzothiazolecarboxamide; N- (2,6-dimethylphenyl) -2 - [(2-methyl-1-oxopropyl) amino] -6-benzothiazolecarboxamide; N- (2,6-dimethylphenyl) -2 - [(1-oxo-3-phenylpropyl) amino] -6-benzothiazolecarboxamide; N- (2,6-dimethylphenyl) -2 - [[3- (2-methoxyphenyl) -1-oxopropyl] amino] -6-benzothiazolecarboxamide; N- (2,6-dimethylphenyl) -2 - [[3- (2,3,4-trimethoxyphenyl) -1-oxopropyl] amino] -6-benzothiazolecarboxamide; • · · · 18 * 3 N- (2,6-dimethylphenyl) -2 - [(1,4-dioxypentyl) amino] -6-benzothiazolecarboxamide; 2 - [(2,2-dimethyl-1-oxobutyl) amino] -N- (2,6-dimethylphenyl) -6-benzothiazolecarboxamide; N- (2,6-dimethylphenyl) -2 - [(methoxyacetyl) amino] -6-benzothiazolecarboxamide; N, N-dimethyl-N '- [6 - [[(2,6-dimethylphenyl) amino] carbonyl] -2-benzthiazolyl] butanediamine; N- (2,6-dimethylphenyl) -2 - [[(1-methylcyclopropyl) carbonyl] amino] -6-benzothiazolecarboxamide; 2 - [[(2-chloro-6-fluorophenyl) acetyl] amino] -N- (2,6-dimethylphenyl) -6-benzothiazolecarboxamide; N- (2,6-dimethylphenyl) -2 - [[(2-methylphenyl) acetyl] amino] -6-benzothiazolecarboxamide; N- (2,6-dimethylphenyl) -2 - [[(3-methoxyphenyl) acetyl] amino] -6-benzothiazolecarboxamide; 2 - [[(4-chlorophenyl) acetyl] amino] -N- (2,6-dimethylphenyl) -6-benzothiazolecarboxamide; N- (2,6-dimethylphenyl) -2 - [(1-oxo-4-pentynyl) amino] -6-benzothiazolecarboxamide; N- (2,6-dimethylphenyl) -2 - [(1-oxohexyl) amino] -6-benzothiazolecarboxamide; N- (2,6-dimethylphenyl) -2 - [[3- (3-methoxyphenyl) -1-oxopropyl] amino] -6-benzothiazolecarboxamide; 2 - [[3- (1,3-benzodioxol-5-yl) -1-oxopropyl] amino] -N- (2,6-dimethylphenyl) -6-benzothiazolecarboxamide; 2 - [[(1,3-benzodioxol-5-yl) acetyl] amino] -N- (2,6-dimethylphenyl) -6-benzothiazolecarboxamide; 2 - [[(3,5-dimethoxyphenyl) acetyl] amino] -N- (2,6-dimethylphenyl) -6-benzothiazolecarboxamide; 2 - [(cyclopropylacetyl) amino] -N- (2,6-dimethylphenyl) -6-benzothiazolecarboxamide; • · N- (2,6-dimethylphenyl) -2 - [[[2- (phenylmethyl) cyclopropyl] carbonyl] amino] -6-benzothiazolecarboxamide; N- (2,6-dimethylphenyl) -2 - [[[2- (trimethylsilyl) cyclopropyl] carbonyl] amino] -6-benzothiazolecarboxamide; 2 - [(cyclopropylcarbonyl) amino] -N- (2,6-dimethylphenyl) -6-benzothiazolecarboxamide; N- (2,6-dimethylphenyl) -2 - [[(2-methylcyclopropyl) carbonyl] amino] -6-benzothiazolecarboxamide; Trans-N- (2,6-dimethylphenyl) -2 - [[(2-phenylcyclopropyl) carbonyl] amino] -6-benzothiazolecarboxamide; N- (2,6-dimethylphenyl) -2 - [[[1- (4-methylphenyl) cyclopropyl] carbonyl] amino] -6-benzothiazolecarboxamide; 2 - [[[1- (4-chlorophenyl) cyclopropyl] carbonyl] amino] -N- (2,6-dimethylphenyl) -6-benzothiazolecarboxamide; [6 - [[[(2,6-dimethyl-4- (2-morpholinoethoxy) phenyl] amino] carbonyl] -2-benzothiazolyl] carbamic acid 1,1-dimethylethyl ester; 2 - [(cyclopropylcarbonyl) amino] -N- (2-chloro-6-methylphenyl) -6-benzothiazolecarboxamide; 2 - [(2-methyl-cyclopropylcarbonyl) amino] -N- (2-chloro-6-methylphenyl) -6-benzothiazolecarboxamide; 2 - [(2,2-dichloro-1-methyl-cyclopropylcarbonyl) amino] -N- (2-chloro-6-methylphenyl) -6-benzothiazolecarboxamide; 2 - [(1-hydroxy-cyclopropylcarbonyl) amino] -N- (2-chloro-6-methylphenyl) -6-benzothiazolecarboxamide; N- (2-chloro-6-methylphenyl) -2 - [(cyclobutylcarbonyl) amino] -6-benzothiazolecarboxamide; N- (2-chloro-6-methylphenyl) -2 - [(cyclopentylcarbonyl) amino] -6-benzothiazolecarboxamide; N- (2-chloro-6-methylphenyl) -2 - [(cyclohexylacetyl) amino] -6-benzothiazolecarboxamide; N- (2-chloro-6-methylphenyl) -2 - [(methoxyacetyl) amino] -6-benzothiazolecarboxamide; N- (2-chloro-6-methylphenyl) -2 - [(1-oxo-2-phenylpropyl) amino] -6-benzothiazolecarboxamide; N- (2-chloro-6-methylphenyl) -2 - [(1-oxo-2-methylpropyl) amino] -6-benzothiazolecarboxamide; N- (2-chloro-6-methylphenyl) -2 - [(1-oxo-3-phenylpropyl) amino] -6-benzothiazolecarboxamide; · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · * ** 186 N- (2-chloro-6-methylphenyl) -2 - [[3- (2-methoxyphenyl) -1-oxopropyl) amino] -6-benzothiazolecarboxamide; N- (2-chloro-6-methylphenyl) -2 - [[1-oxo-3- (2,3,4-trimethoxyphenyl) propyl] amino] -6-benzothiazolecarboxamide; N- (2-chloro-6-methylphenyl) -2 - [(1,4-dioxypentyl) amino] -6-benzothiazolecarboxamide; N- (2-chloro-6-methylphenyl) -2 - [(2,2-dimethyl-1-oxobutyl) amino] -6-benzothiazolecarboxamide; 2 - [[(2-chloro-6-fluorophenyl) acetyl] amino] -N- (2-chloro-6-methylphenyl) -6-benzothiazolecarboxamide; N- (2-chloro-6-methylphenyl) -2 - [[(2-methylphenyl) acetyl] amino] -6-benzothiazolecarboxamide; N- (2-chloro-6-methylphenyl) -2 - [[(3-methoxyphenyl) acetyl] amino] -6-benzothiazolecarboxamide; N- (2-chloro-6-methylphenyl) -2 - [[(4-chlorophenyl) acetyl] amino] -6-benzothiazolecarboxamide; N- (2-chloro-6-methylphenyl) -2 - [(1-oxo-4-pentynylamino) -6-benzothiazolecarboxamide; 5 - [[6 - [[(2-chloro-6-methylphenyl) amino] carbonyl] -2-benzothiazolyl] amino] -5-oxopentanoic acid methyl ethyl ester; N- (2-chloro-6-methylphenyl) -2 - [(1-oxohexyl) -6-benzothiazolecarboxamide; N- (2-chloro-6-methylphenyl) -2 - [[3- (3-methoxyphenyl) -1-oxopropyl] amino] -6-benzothiazolecarboxamide; 2 - [[(1,3-benzodioxol-5-yl) acetyl] amino] -N- (2-chloro-6-methylphenyl) -6-benzothiazolecarboxamide; 2 - [[3- (1,3-benzodioxol-5-yl) -1-oxopropyl] amino] -N- (2-chloro-6-methylphenyl) -6-benzothiazolecarboxamide; N- (2-chloro-6-methylphenyl) -2 - [[(3,5-dimethoxyphenyl) acetyl] amino] -6-benzothiazolecarboxamide; N- (2-chloro-6-methylphenyl) -2 - [(cyclopropylacetyl] amino] -6-benzothiazolecarboxamide; N- (2-chloro-6-methylphenyl) -2 - [[(1-methylcyclopropyl) carbonyl] 187 6-amino] -6-benzothiazolecarboxamide; N- (2-chloro-6-methylphenyl) -2 - [[[2- (trimethylsilyl) cyclopropyl] carbonyl] amino] -6-benzothiazolecarboxamide; N- (2-chloro-6-methylphenyl) -2 - [[[1- (4-methoxyphenyl) cyclopropyl] carbonyl] amino] -6-benzothiazolecarboxamide; Trans-N- (2-chloro-6-methylphenyl) -2 - [[(phenylcyclopropyl) carbonyl] amino] -6-benzothiazolecarboxamide; N- (2-chloro-6-methylphenyl) -2 - [[[1- (4-methylphenyl) cyclopropyl] carbonyl] amino] -6-benzothiazolecarboxamide; N- (2-chloro-6-methylphenyl) -2 - [[[1- (4-chlorophenyl) cyclopropyl] carbonyl] amino] -6-benzothiazolecarboxamide; [6 - [[[(2,6-dimethyl-4- (2-N, N-dimethylethoxy) phenyl] amino] carbonyl] -2-benzothiazolyl] carbamic acid 1,1-dimethylethyl ester; [6 - [[[(2,6-dimethyl-4-phenyl) phenyl] amino] carbonyl] -2-benzothiazolyl] carbamic acid 1,1-dimethylethyl ester; 5-tert-butoxycarbonyloxy- [6 - [[(2,4,6-trimethylphenyl) amino] carbonyl] -2-benzothiazolyl] carbamic acid 1,1-dimethylethyl ester; 2 - [[[(1,1-dimethylethyl) amino] carbonyl] amino] -N- (2,6-dimethylphenyl) -6-benzothiazolecarboxamide; 2 - [[(cyclopropylamino) carbonyl] amino] -N- (2,6-dimethylphenyl) -6-benzothiazolecarboxamide; 2 - [[(cyclopentylamino) carbonyl] amino] -N- (2,6-dimethylphenyl) -6-benzothiazolecarboxamide; 2 - [[(cyclopentylamino) carbonyl] amino] -N- (2,6-dimethylphenyl) -6-benzothiazolecarboxamide; 2 - [[[[1- (ethynyl) cyclohexyl] amino] carbonyl] amino] -N- (2,6-dimethylphenyl) -6-benzothiazolecarboxamide; 2 - [[[(4-methylcyclohexyl) amino] carbonyl] amino] -N- (2,6-dimethylphenyl) -6-benzothiazolecarboxamide; 2 - [[[(2,3-dihydro-1H-inden-1-yl) amino] carbonyl] amino] -N- (2,6-dimethylphenyl) -6-benzothiazolecarboxamide; 2- [1 - [[2- (1H-imidazol-4-yl) ethyl] amino] carbonyl] amino] -N- (2,6-dimethylphenyl) -6-benzothiazolecarboxamide; 2 - [[[[(tetrahydro-2-furanyl) methyl] amino] carbonyl] amino] -N- (2,6-dimethylphenyl) -6-benzothiazolecarboxamide; 2 - [[[[2- (5-methoxy-1H-indol-3-yl) ethyl] amino] carbonyl] amino] -N- (2,6-dimethylphenyl) -6-benzothiazolecarboxamide; 2 - [[[(1,1-dimethyl-2-hydroxyethyl) amino] carbonyl] amino] -N- (2,6-dimethylphenyl) -6-benzothiazolecarboxamide; • · 183 2 - [[[(1,1-dimethylpropyl) amino] carbonyl] amino] N- (2,6-dimethylphenyl) -6-benzothiazolecarboxamide; 2 - [[[[(3-methoxyphenyl) methyl] amino] carbonyl] amino] N- (2,6-dimethylphenyl) -6-benzothiazolecarboxamide; 2 - [[(2-propynylamino) carbonyl] amino] -N- (2,6-dimethylphenyl) - 6-benzothiazolecarboxamide; 2 - [[(2-propenylamino) carbonyl] amino] -N- (2,6-dimethylphenyl) - 6-benzothiazolecarboxamide; 2 - [[[(3-phenylpropyl) amino] carbonyl] amino] -N- (2,6-dimethylphenyl) -6-benzothiazolecarboxamide; 2 - [[[[1- (hydroxymethyl) cyclopentyl] amino] carbonyl] amino] -N- (2,6-dimethylphenyl) -6-benzothiazolecarboxamide; 2 - [[[[1- (methoxymethyl) propyl] amino] carbonyl] amino] -N (2,6-dimethylphenyl) -6-benzothiazolecarboxamide; (R) -2 - [[[(1-phenylethyl) amino] carbonyl] amino] -N- (2,6-dimethylphenyl) -6-benzothiazolecarboxamide; 2 - [[[(3,4,5-trimethoxyphenyl) amino] carbonyl] amino] -N- (2,6-dimethylphenyl) -6-benzothiazolecarboxamide; 2 - [[(1,3-benzodioxol-5-ylamino) carbonyl] amino] -N- (2,6-dimethylphenyl) -6-benzothiazolecarboxamide; 2 - [[[(4-fluorophenyl) amino] carbonyl] amino] -N- (2,6-dimethylphenyl) -6-benzothiazolecarboxamide; 2 - [[(cyclopropylamino) carbonyl] amino] -N- (2-chloro-6-methylphenyl) -6-benzothiazolecarboxamide; 2 - [[(cyclopentylamino) carbonyl] amino] -N- (2-chloro-6-methylphenyl) -6-benzothiazolecarboxamide; 2 - [[[[1- (ethynyl) cyclohexyl] amino] carbonyl] amino] -N- (2-chloro-6-methylphenyl) -6-benzothiazolecarboxamide; 2 - [[[(4-methylcyclohexyl) amino] carbonyl] amino] -N- (2-chloro-6-methylphenyl) -6-benzothiazolecarboxamide; 2 - [[[(2,3-dihydro-1H-inden-1-yl) amino] carbonyl] amino] -N- (2-chloro-6-methylphenyl) -6-benzothiazolecarboxamide; • · 184 2 - [[[[2- (1H-imidazol-4-yl) ethyl] amino] carbonyl] amino] -N- (2-chloro-6-methylphenyl) -6-benzothiazolecarboxamide; 2 - [[[[(tetrahydro-2-furanyl) methyl] amino] carbonyl] amino] -N- (2-chloro-6-methylphenyl) -6-benzothiazolecarboxamide; 2 - [[[[2- (5-methoxy-1 H -indol-3-yl) ethyl] amino] carbonyl] amino] -N- (2-chloro-6-methylphenyl) -6-benzothiazolecarboxamide; 2 - [[[(1,1-dimethyl-2-hydroxyethyl) amino] carbonyl] amino] -N- (2-chloro-6-methylphenyl) -6-benzothiazolecarboxamide; 2 - [[[(1,1-dimethylpropyl) amino] carbonyl] amino] -N- (2-chloro-6-methylphenyl) -6-benzothiazolecarboxamide; 2 - [[[[(3-methoxyphenyl) methyl] amino] carbonyl] amino] -N- (2-chloro-6-methylphenyl) -6-benzothiazolecarboxamide; 2 - [[[[(4-methoxyphenyl) methyl] amino] carbonyl] amino] -N- (2-chloro-6-methylphenyl) -6-benzothiazolecarboxamide; 2 - [[(2-propynylamino) carbonyl] amino] -N- (2-chloro-6-methylphenyl) -6-benzothiazolecarboxamide; 2 - [[(2-propenylamino) carbonyl] amino] -N- (2-chloro-6-methylphenyl) -6-benzothiazolecarboxamide; 2 - [[[(3-phenylpropyl) amino] carbonyl] amino] -N- (2-chloro-6-methylphenyl) -6-benzothiazolecarboxamide; 2 - [[[[1- (hydroxymethyl) cyclopentyl] amino] carbonyl] amino] -N- (2-chloro-6-methylphenyl) -6-benzothiazolecarboxamide; 2 - [[[[1- (methoxymethyl) propyl] amino] carbonyl] amino] -N- (2-chloro-6-methylphenyl) -6-benzothiazolecarboxamide; (R) -2 - [[[(1-Phenylethyl) amino] carbonyl] amino] -N- (2-chloro-6-methylphenyl) -6-benzothiazolecarboxamide; 2 - [[[(2,3-dimethyl-1H-indol-5-yl) amino] carbonyl] amino] -N- (2-chloro-6-methylphenyl) -6-benzothiazolecarboxamide; 2 - [[[(3,4,5-trimethoxyphenyl) amino] carbonyl] amino] -N- (2-chloro-6-methylphenyl) -6-benzothiazolecarboxamide; 2 - [[(1,3-benzodioxol-5-ylamino) carbonyl] amino] -N- (2-chloro-6-methylphenyl) -6-benzothiazolecarboxamide; • · · · 185 2 - [[[(4-fluorophenyl) amino] carbonyl] amino] -N- (2-chloro-6-methylphenyl) -6-benzothiazolecarboxamide; 2 - [[[[(1-methoxycarbonyl) cyclopropyl] amino] carbonyl] amino] -N- (2,4,6-trimethylphenyl) -6-benzothiazolecarboxamide; 7-Chloro- [6 - [[(2,4,6-trimethylphenyl) amino] carbonyl] -2-benzothiazolyl] carbamic acid 1,1-dimethylethyl ester; 2-amino-5-hydroxy-N- (2,4,6-trimethylphenyl) -6-benzothiazolecarboxamide; 5-chloro- [6 - [[(2,4,6-trimethylphenyl) amino] carbonyl] -2-benzothiazolyl] carbamic acid 1,1-dimethylethyl ester; 5-methoxy- [6 - [[(2,4,6-trimethylphenyl) amino] carbonyl] -2-benzothiazolyl] carbamic acid 1,1-dimethylethyl ester; • · · · · 182 2-amino-N- (4-N, N-dimethylamino-2,3,5,6-tetramethylphenyl) -6-benzothiazolecarboxamide, trifluoroacetate (1: 1); 4-methoxy- [6 - [[(2,4,6-trimethoxyphenyl) amino] carbonyl] -2-benzothiazolyl] carbamic acid 1,1-dimethylethyl ester; 2-amino-4-methoxy-N- (2,4,6-trimethylphenyl) -6-benzothiazolecarboxamide, trifluoroacetate (1: 1); 2 - [[(methylamino) carbonyl] amino] -N- (2,4,6-trimethylphenyl) -6-benzothiazolecarboxamide; 2 - [[(methylamino) carbonyl] amino] -4-methoxy-N- (2,4,6-trimethylphenyl) -6-benzothiazolecarboxamide; [4-methyl-6 - [[(2,4,6-trimethylphenyl) amino] carbonyl] -2-benzothiazolyl] carbamic acid 1,1-dimethylethyl ester; 2-amino-4-methyl-N- (2,4,6-trimethylphenyl) -6-benzothiazolecarboxamide, trifluoroacetate (1: 1); [6 - [[(2-methyl-1-naphthalenyl) amino] carbonyl] -2-benzothiazolyl] carbamic acid 1,1-dimethylethyl ester; 3 - [[[2 - [[(1,1-dimethylethoxy) carbonyl] amino] -6-benzothiazolyl] carbonyl] amino] -4-methyl-2-thiophenecarboxylic acid methyl ethyl ester; [6 - [[(2,4,6-trimethylphenyl) amino] carbonyl] -2-benzothiazolyl] carbamic acid methyl ethyl ester; 2 - [[(acetylamino) acetyl] amino] -N- (2,4,6-trimethylphenyl) -6-benzothiazolecarboxamide; N- (2-chloro-6-methylphenyl) -2 - [[[(1,1-dimethylethyl) amino] carbonyl] amino] -6-benzothiazolecarboxamide; N- (2,6-dichlorophenyl) -2 - [[[(1,1-dimethylethyl) amino] carbonyl] amino] -6-benzothiazolecarboxamide; N- (4-bromo-2,6-dimethylphenyl) -2 - [[[(1,1-dimethylethyl) amino] carbonyl] amino] -6-benzothiazolecarboxamide; N- (4-carbomethoxy-2,6-dimethylphenyl) -2 - [[[(1,1-dimethylethoxy) amino] carbonyl] amino] -6-benzothiazolecarboxamide; N- (4-hydroxymethyl-2,6-dimethylphenyl) -2 - [[[(1,1-dimethylethoxy) amino] carbonyl] amino] -6-benzothiazolecarboxamide; [6 - [[(2,6-dimethoxyphenyl) amino] carbonyl] -2-benzothiazolyl] carbamic acid 1,1-dimethylethyl ester; 181 [6 - [[(3-acetylamino) -4,6-dimethylphenyl] amino] carbonyl] -2-benzothiazolyl] carbamic acid 1,1-dimethylethyl ester; [6 - [[(4-bromo-2,6-dimethyl-phenyl) -amino] -carbonyl] -2-benzothiazolyl] -carbamic acid 1,1-dimethylethyl ester; [6 - [[[[4 - [[(1,1-dimethyloxy) carbonyl] amino] -2,3,5,6-tetramethylphenyl] amino] carbonyl] -2-benzothiazolyl] carbamic acid 1,1-dimethylethyl ester; [6 - [[(2-acetyl-6-hydroxyphenyl) -amino] carbonyl] -2-benzothiazolyl] carbamic acid 1,1-dimethylethyl ester; [6 - [[(2-bromo-3,4,6-trimethyl-phenyl) -amino] -carbonyl] -2-benzothiazolyl] -carbamic acid 1,1-dimethylethyl ester; [6 - [[(2,6-Dimethyl-3-nitrophenyl) amino] carbonyl] -2-benzothiazolyl] carbamic acid 1,1-dimethylethyl ester; [6 - [[[2- (2-hydroxyethyl) -6-methylphenyl] amino] carbonyl] -2-benzothiazolyl] carbamic acid 1,1-dimethylethyl ester; [6 - [[(6-methyl-5-quinolinyl) amino] carbonyl] -2-benzothiazolyl] carbamic acid 1,1-dimethylethyl ester; [6 - [[(6-methoxy-2-naphthalenyl) amino] carbonyl] -2-benzothiazolyl] carbamic acid 1,1-dimethylethyl ester; [6 - [[(2-methyl-6-quinolinyl) amino] carbonyl] -2-benzothiazolyl] carbamic acid 1,1-dimethylethyl ester; [6 - [[(2-bromo-4,6-dimethylphenyl) amino] carbonyl] -2-benzothiazolyl] carbamic acid 1,1-dimethylethyl ester; [6 - [[[2,6-dimethyl-3- (1-methylethyl) phenyl] amino] carbonyl] -2-benzothiazolyl] carbamic acid 1,1-dimethylethyl ester; [6 - [[(3-bromo-2,4,6-trimethyl-phenyl) -amino] -carbonyl] -2-benzothiazolyl] -carbamic acid 1,1-dimethylethyl ester; [6 - [[(4-bromo-2-methylphenyl) amino] carbonyl] -2-benzothiazolyl] carbamic acid 1,1-dimethylethyl ester; [6 - [[(2,6-dimethylphenyl) amino] carbonyl] -2-benzothiazolyl] carbamic acid, 1,1-dimethylethyl ester; [6 - [[(2-chloro-6-methylphenyl) amino] carbonyl] -2-benzothiazolyl] carbamic acid 1,1-dimethylethyl ester; 180 [6 - [[(2-fluoro-5-methylphenyl) amino] carbonyl] -2-benzothiazolyl] carbamic acid 1,1-dimethylethyl ester; [6 - [[(3-hydroxy-2-naphthalenyl) amino] carbonyl] -2-benzothiazolyl] carbamic acid 1,1-dimethylethyl ester; [6 - [(2-naphthylenylamino) carbonyl] -2-benzothiazolyl] carbamic acid 1,1-dimethylethyl ester; [6 - [[(2,3-dihydro-1H-inden-5-yl) amino] carbonyl] -2-benzothiazolyl] carbamic acid 1,1-dimethylethyl ester; • · · · · · · · · · · · · · · · · · · · · · · · 17Q 2 - [[[(3,4-dimethoxyphenyl) amino] carbonyl] amino] -N- (2,4,6-trimethylphenyl) -6-benzothiazolecarboxamide; 2 - [[[[2,6-bis (1-methylethyl) phenyl] amino] carbonyl] amino] -N (2,4,6-trimethylphenyl) -6-benzothiazolecarboxamide; 2 - [[[(2-propylphenyl) amino] carbonyl] amino] -N (2,4,6-trimethylphenyl) -6-benzothiazolecarboxamide; 2 - [[[(3-bromo-2,4,6-trimethylphenyl) amino] carbonyl] amino] -N (2,4,6-trimethylphenyl) -6-benzothiazolecarboxamide; 2 - [[[[2- (4-morpholinyl) phenyl] amino] carbonyl] amino] -N (2,4,6-trimethylphenyl) -6-benzothiazolecarboxamide; 2 - [[[(3-bromo-2-methylphenyl) amino] carbonyl] amino] -N (2,4,6-trimethylphenyl) -6-benzothiazolecarboxamide; 2 - [[[(2,6-dimethoxyphenyl) amino] carbonyl] amino] -N (2,4,6-trimethylphenyl) -6-benzothiazolecarboxamide; 2 - [[[(2-bromo-5-methoxyphenyl) amino] carbonyl] amino] -N (2,4,6-trimethylphenyl) -6-benzothiazolecarboxamide; 2 - [[[(2-methoxy-6-methylphenyl) amino] carbonyl] amino] -N (2,4,6-trimethylphenyl) -6-benzothiazolecarboxamide; 2 - [[[(2,3-dimethyl-1H-indol-5-yl) amino] carbonyl] amino] -N (2,4,6-trimethylphenyl) -6-benzothiazolecarboxamide; 2 - [[[[3- (1,3,4-oxadiazol-2-yl) phenyl] amino] carbonyl] amino] -N (2,4,6-trimethylphenyl) -6-benzothiazolecarboxamide; 2 - [[[(2-chloro-6-methylphenyl) amino] carbonyl] amino] -N (2,4,6-trimethylphenyl) -6-benzothiazolecarboxamide; 2 - [[[[3- (methylthio) phenyl] amino] carbonyl] amino] -N- (2,4,6-trimethylphenyl) -6-benzothiazolecarboxamide; 2 - [[[(4-methoxy-2-methylphenyl) amino] carbonyl] amino] -N- (2,4,6-trimethylphenyl) -6-benzothiazolecarboxamide; 2 - [[(4-methoxycyclohexyl) carbonyl] amino] -N- (2,4,6-trimethylphenyl) -6-benzothiazolecarboxamide; 2 - [(2,2-dimethyl-1-oxopropyl) amino] -N- (2,4,6-trimethylphenyl) -6-benzothiazolecarboxamide; 177 * * ♦ <<<<<<<< 2 - [(2-thienylacetyl) amino] -N- (2,4,6-trimethylphenyl) -6-benzothiazolecarboxamide; 2 - [(cyclopropylcarbonyl) amino] -N- (2,4,6-trimethylphenyl) -6-benzothiazolecarboxamide; 2 - [(cyclobutylcarbonyl) amino] -N- (2,4,6-trimethylphenyl) -6-benzothiazolecarboxamide; 2 - [(cyclopentylcarbonyl) amino] -N- (2,4,6-trimethylphenyl) -6-benzothiazolecarboxamide; 2 - [(3-cyclopentyl-1-oxopropyl) amino] -N- (2,4,6-trimethylphenyl) • 6-benzothiazolecarboxamide; 2 - [(1-cyclopenten-1-ylcarbonyl) amino] -N- (2,4,6-trimethylphenyl) -6-benzothiazolecarboxamide; 2 - [(cyclohexylacetyl) amino] -N- (2,4,6-trimethylphenyl) -6-benzothiazolecarboxamide; 2 - [(1-oxo-2-phenylpropyl) amino] -N- (2,4,6-trimethylphenyl) -6-benzothiazolecarboxamide; 2 - [(2-methyl-1-oxopropyl) amino] -N- (2,4,6-trimethylphenyl) -6-benzothiazolecarboxamide; 2 - [(1-oxo-3-phenoxypropyl) amino] -N- (2,4,6-trimethylphenyl) -6-benzothiazolecarboxamide; 2 - [(1-oxo-3-phenylpropyl) amino] -N- (2,4,6-trimethylphenyl) -6-benzothiazolecarboxamide; 2 - [[3- (2-methoxyphenyl) -1-oxopropyl) amino] -N- (2,4,6-trimethylphenyl) -6-benzothiazolecarboxamide; 2 - [[3- (2,3,4-trimethoxyphenyl) -1-oxopropyl) amino] -N- (2,4,6-trimethylphenyl) -6-benzothiazolecarboxamide; 2 - [(1,4-dioxopentyl) amino] -N- (2,4,6-trimethylphenyl) -6-benzothiazolecarboxamide; 2 - [(2-naphthalenylacetyl) amino] -N- (2,4,6-trimethylphenyl) -6-benzothiazolecarboxamide; 2 - [[(2-chloro-6-fluorophenyl) acetyl] amino] -N- (2,4,6-trimethylphenyl) -6-benzothiazolecarboxamide; 178 2 - [[(2-methylphenyl) acetyl] amino] -N- (2,4,6-trimethylphenyl) -6-benzothiazolecarboxamide; 2 - [[(3-methoxyphenyl) acetyl] amino] -N- (2,4,6-trimethylphenyl) -6-benzothiazolecarboxamide; 2 - [[(4-chlorophenyl) acetyl] amino] -N- (2,4,6-trimethylphenyl) -6-benzothiazolecarboxamide; 2 - [(1-oxo-4-pentynyl) amino] -N- (2,4,6-trimethylphenyl) -6-benzothiazolecarboxamide; 5-Oxo-5 - [[6 - [[(2,4,6-trimethylphenyl) amino] carbonyl] -2-benzothiazolyl] amino] pentanoic acid methyl ethyl ester; 2 - [(1-oxohexyl) amino] -N- (2,4,6-trimethylphenyl) -6-benzothiazolecarboxamide; 2 - [(1-oxoheptyl) amino] -N- (2,4,6-trimethylphenyl) -6-benzothiazolecarboxamide; 2 - [[1-oxo-4- (2-thienyl) butyl] amino] -N- (2,4,6-trimethylphenyl) -6-benzothiazolecarboxamide; 2 - [(3-thienylcarbonyl) butyl] amino] -N- (2,4,6-trimethylphenyl) -6-benzothiazolecarboxamide; 2 - [[(4-nitrophenyl) acetyl]] amino] -N- (2,4,6-trimethylphenyl) -6-benzothiazolecarboxamide; 2 - [[[3,5-bis (trifluoromethyl) phenyl] acetyl] amino] -N- (2,4,6-trimethylphenyl) -6-benzothiazolecarboxamide; 2 - [[2- [4- (2-methylpropyl) phenyl] 1-oxopropyl] amino] -N- (2,4,6-trimethylphenyl) -6-benzothiazolecarboxamide; 2 - [[(3-cyclohexen-1-yl) carbonyl] amino] -N- (2,4,6-trimethylphenyl) -6-benzothiazolecarboxamide; 2 - [[3- (3-methoxyphenyl) -1-oxopropyl] amino] -N- (2,4,6-trimethylphenyl) -6-benzothiazolecarboxamide; 2 - [[(2,3,6-trichlorophenyl) acetyl] amino] -N- (2,4,6-trimethylphenyl) -6-benzothiazolecarboxamide; 2 - [[(1,3-benzodioxol-5-yl) acetyl] amino] -N- (2,4,6-trimethylphenyl) -6-benzothiazolecarboxamide; • · · · · · · · · · · 179 2 - [[[2- (phenylmethoxy) phenyl] acetyl] amino] -N- (2,4,6-trimethylphenyl) -6-benzothiazolecarboxamide; 2 - [[(3,5-dimethoxyphenyl) acetyl] amino] -N- (2,4,6-trimethylphenyl) -6-benzothiazolecarboxamide; 2 - [[3- (1,3-benzodioxol-5-yl) -1-oxopropyl] amino] -N- (2,4,6-trimethylphenyl) -6-benzothiazolecarboxamide; 2 - [[(tetrahydro-2-furanyl) carbonyl] amino] -N- (2,4,6-trimethylphenyl) -6-benzothiazolecarboxamide; 2 - [[2- (acetylamino) -1-oxopropyl] amino] -N- (2,4,6-trimethylphenyl) -6-benzothiazolecarboxamide; 2 - [[2- (acetylamino) -1-oxohexyl] amino] -N- (2,4,6-trimethylphenyl) -6-benzothiazolecarboxamide; 2 - [(cyclopropylacetyl) amino] -N- (2,4,6-trimethylphenyl) -6-benzothiazolecarboxamide; N, N-dimethyl-N '- [6 - [[(2,4,6-trimethylphenyl) amino] carbonyl] -2-benzothiazolyl] butanediamide; 2 - [(1-adamantocarbonyl) amino] -N- (2,4,6-trimethylphenyl) -6-benzothiazolecarboxamide; 2 - [[(4-methylcyclohexyl) carbonyl] amino] -N- (2,4,6-trimethylphenyl) -6-benzothiazolecarboxamide; 2 - [(3-methoxy-1-oxopropyl) amino] -N- (2,4,6-trimethylphenyl) -6-benzothiazolecarboxamide; [5 - [[(2,4,6-trimethylphenyl) amino] carbonyl] -2-benzothiazolyl] carbamic acid 1,1-dimethylethyl ester; 2 - [[[phenylamino] carbonyl] amino] -N- (2,4,6-trimethylphenyl) -6-benzothiazolecarboxamide; 17? • · 2 - [[[(phenylmethyl) amino] carbonyl] amino] -N- (2,4,6-trimethylphenyl) -6-benzothiazolecarboxamide; 2 - [[[ethylamino] carbonyl] amino] -N- (2,4,6-trimethylphenyl) -6-benzothiazolecarboxamide; 2 - [[(butylamino) carbonyl] amino] -N- (2,4,6-trimethylphenyl) -6-benzothiazolecarboxamide; 2 - [[(cyclopropylamino) carbonyl] amino] -N- (2,4,6-trimethylphenyl) -6-benzothiazolecarboxamide; (R) -2 - [[[[(3,3-dimethylcyclohexyl) methyl] amino] carbonyl] amino] N- (2,4,6-trimethylphenyl) -6-benzothiazolecarboxamide; 2 - [[[(4-methylcyclohexyl) amino] carbonyl] amino] -N- (2,4,6-trimethylphenyl) -6-benzothiazolecarboxamide; 2 - [[[(cyclohexylmethyl) amino] carbonyl] amino] -N- (2,4,6-trimethylphenyl) -6-benzothiazolecarboxamide; 2 - [[[(2,3-dihydro-1H-inden-1-yl) amino] carbonyl] amino] -N- (2,4,6 trimethylphenyl) -6-benzothiazolecarboxamide; 2 - [[[(1-naphthalenylmethyl) amino] carbonyl] amino] -N- (2,4,6-trimethylphenyl) -6-benzothiazolecarboxamide; 2 - [[[[2- (1H-imidazol-4-yl) ethyl] amino] carbonyl] amino] - N - (2,4,6-trimethylphenyl) -6-benzothiazolecarboxamide; 2 - [[[[(tetrahydro-2-furanyl) methyl] amino] carbonyl] amino] -N (2,4,6-trimethylphenyl) -6-benzothiazolecarboxamide; 2 - [[[[2- (5-methoxy-1H-indol-3-yl) ethyl] amino] carbonyl] amino] -N- (2,4,6-trimethylphenyl) -6-benzothiazolecarboxamide; 2 - [[[[2- (4-morpholinyl) ethyl] amino] carbonyl] amino] -N- (2,4,6-trimethylphenyl) -6-benzothiazolecarboxamide; 2 - [[[[2- (2-pyridyl) ethyl] amino] carbonyl] amino] -N- (2,4,6-trimethylphenyl) -6-benzothiazolecarboxamide; 2 - [[[(1,1,3,3-tetramethylbutyl) amino] carbonyl] amino] -N- (2,4,6-trimethylphenyl) -6-benzothiazolecarboxamide; 2 - [[[(1,1-dimethylpropyl) amino] carbonyl] amino] -N- (2,4,6-trimethylphenyl) -6-benzothiazolecarboxamide; 173 2 - [[[(1,5-dimethylhexyl) amino] carbonyl] amino] N- (2,4,6-trimethylphenyl) -6-benzothiazolecarboxamide; 2 - [[(cyclopentylamino) carbonyl] amino] -N- (2,4,6-trimethylphenyl) -6-benzothiazolecarboxamide; 2 - [[[(1,1-dimethyl-2-hydroxyethyl) amino] carbonyl] amino] N- (2,4,6-trimethylphenyl) -6-benzothiazolecarboxamide; 2 - [[[[(3-methoxyphenylmethyll] amino] carbonyl] amino] N- (2,4,6-trimethylphenyl) -6-benzothiazolecarboxamide; 2 - [[[[(3-methylphenyl) methyl] amino] carbonyl] amino] N- (2,4,6-trimethylphenyl) -6-benzothiazolecarboxamide; 2 - [[[[(4-chlorophenyl) methyl] amino] carbonyl] amino] N- (2,4,6-trimethylphenyl) -6-benzothiazolecarboxamide; 2 - [[[[2- (4-methoxyphenyl) ethyl] amino] carbonyl] amino] N- (2,4,6-trimethylphenyl) -6-benzothiazolecarboxamide; 2-t [(2-propynylamino) carbonyl] amino] -N- (2,4,6-trimethylphenyl) -6-benzothiazolecarboxamide; 2 - [[(2-propenylamino) carbonyl] amino] -N- (2,4,6-trimethylphenyl) -6-benzothiazolecarboxamide; 2 - [[[(3-phenylpropyl) amino] carbonyl] amino] -N- (2,4,6 trimethylphenyl) -6-benzothiazolecarboxamide; 2 - [[[(1- (hydroxymethyl) cyclopentyl] amino] carbonyl] amino] -N- (2,4,6-trimethylphenyl) -6-benzothiazolecarboxamide; 2 - [[[[4- (1,1-dimethylethyl) cyclohexyl] amino] carbonyl] amino] -N - (2,4,6-trimethylphenyl) -6-benzothiazolecarboxamide; 2 - [[t [3- (methylthio) propyl] amino] carbonyl] amino] -N- (2,4,6-trimethylphenyl) -6-benzothiazolecarboxamide; 2 - [[[[1- (methoxymethyl) propyl] amino] carbonyl] amino] -N- (2,4,6-trimethylphenyl) -6-benzothiazolecarboxamide; 2 - [[[[2- (2-thienyl) ethyl] amino] carbonyl] amino] -N- (2,4,6-trimethylphenyl) -6-benzothiazolecarboxamide; 2 - [[[[(2,6-dimethoxyphenyl) methyl] amino] carbonyl] amino] -N- (2,4,6-trimethylphenyl) -6-benzothiazolecarboxamide; • · · · · · · · · · · · · · 174. ::. ·.: ::: (R) -2 - [[[[1- (hydroxymethyl) -2-phenylethyl] amino] carbonyl] amino] - N- (2,4,6-trimethylphenyl) -6-benzothiazolecarboxamide; (R) -2 - [[[(1-phenylethyl) amino] carbonyl] amino] -N- (2,4,6-trimethylphenyl) -6-benzothiazolecarboxamide; 2 - [[(1-adamantylamino) carbonyl] amino] -N- (2,4,6-trimethylphenyl) -6-benzothiazolecarboxamide; 2 - [[[[2- (4-fluorophenyl) -1,1-dimethylethyl] amino] carbonyl] amino] -N- (2,4,6-trimethylphenyl) -6-benzothiazolecarboxamide; 2 - [[[[2- (2-pyridinyloxy) ethyl] amino] carbonyl] amino] -N- (2,4,6-trimethylphenyl) -6-benzothiazolecarboxamide; 2 - [[[(1-methyl-1-phenylethyl] amino] carbonyl] amino] -N- (2,4,6-trimethylphenyl) -6-benzothiazolecarboxamide; (R) -2 - [[[[1- (4-methylphenyl) ethyl] amino] carbonyl] amino] -N- (2,4,6-trimethylphenyl) -6-benzothiazolecarboxamide; 2 - [[[(1-methylheptyl) amino] carbonyl] amino] -N- (2,4,6-trimethylphenyl) -6-benzothiazolecarboxamide; 2 - [[[[(4-methoxyphenyl) methyl] amino] carbonyl] amino] -N- (2,4,6-trimethylphenyl) -6-benzothiazolecarboxamide; 2 - [[[(4-cyclohexylphenyl) amino] carbonyl] amino] -N- (2,4,6-trimethylphenyl) -6-benzothiazolecarboxamide; 2 - [[[(5,6,7,8-tetrahydro-1-naphthalenyl) amino] carbonyl] amino] -N- (2,4,6-trimethylphenyl) -6-benzothiazolecarboxamide; 2 - [[[(2,3-dihydro-1H-inden-5-yl) amino] carbonyl] amino] -N- (2,4,6-trimethylphenyl) -6-benzothiazolecarboxamide; 2 - [[(1,3-benzodioxol-5-ylamino) carbonyl] amino] -N- (2,4,6-trimethylphenyl) -6-benzothiazolecarboxamide; 2 - [[(2-pyridinylamino) carbonyl] amino] -N- (2,4,6-trimethylphenyl) -6-benzothiazolecarboxamide; 2 - [[[(3-methyl-2-pyridinyl) amino] carbonyl] amino] -N- (2,4,6-trimethylphenyl) -6-benzothiazolecarboxamide; 2 - [[[(4-methyl-2-pyridinyl) amino] carbonyl] amino] -N- (2,4,6-trimethylphenyl) -6-benzothiazolecarboxamide; 175 2 - [[[(2-chloro-5-methylphenyl) amino] carbonyl] amino] -N- (2,4,6-trimethylphenyl) -6-benzothiazolecarboxamide; 2 - [[[(2,6-dichlorophenyl) amino] carbonyl] amino] -N- (2,4,6-trimethylphenyl) -6-benzothiazolecarboxamide; 2 - [[[(2-methoxyphenyl) amino] carbonyl] amino] -N- (2,4,6-trimethylphenyl) -6-benzothiazolecarboxamide; 2 - [[([1,1 ¹ -biphenyl] -2-ylamino) carbonyl] amino] -N- (2,4,6-trimethylphenyl) -6-benzothiazolkarboxamid; 2 - [[[(2-benzoylphenyl) amino] carbonyl] amino] -N- (2,4,6-trimethylphenyl) -6-benzothiazolecarboxamide; 2 - [[[(2-methylphenyl) amino] carbonyl] amino] -N- (2,4,6-trimethylphenyl) -6-benzothiazolecarboxamide; N- (2,4,6-trimethylphenyl) -2 - [[[(2,4,6-trimethylphenyl) amino] carbonyl] amino] -6-benzothiazolecarboxamide; 2 - [[[[2-methyl-6- (1-methylethyl) phenyl] amino] carbonyl] amino] -N- (2,4,6-trimethylphenyl) -6-benzothiazolecarboxamide; 2 - [[[(3,5-difluorophenyl) amino] carbonyl] amino] -N- (2,4,6-trimethylphenyl) -6-benzothiazolecarboxamide; 2 - [[[(3-methoxyphenyl) amino] carbonyl] amino] -N- (2,4,6-trimethylphenyl) -6-benzothiazolecarboxamide; 2 - [[[(3-methylphenyl) amino] carbonyl] amino] -N- (2,4,6-trimethylphenyl) -6-benzothiazolecarboxamide; 2 - [[[(4-cyanophenyl) amino] carbonyl] amino] -N- (2,4,6-trimethylphenyl) -6-benzothiazolecarboxamide; 2 - [[[(4-fluorophenyl) amino] carbonyl] amino] -N- (2,4,6-trimethylphenyl) -6-benzothiazolecarboxamide; 2 - [[[(4-chlorophenyl) amino] carbonyl] amino] -N- (2,4,6-trimethylphenyl) -6-benzothiazolecarboxamide; 4 - [[[[- 6 - [[(2,4,6-trimethylphenyl) amino] carbonyl] -2-benzothiazolyl] amino] carbonyl] amino] benzoic acid ethyl ester; 2 - [[[(3,4,5-trimethoxyphenyl) amino] carbonyl] amino] -N- (2,4,6-trimethylphenyl) -6-benzothiazolecarboxamide; [6-bromo-5 - [[(2,4,6-trimethylphenyl) amino] carbonyl] -2-benzothiazolyl] carbamic acid 1,1-dimethylethyl ester; [7 - [[(2,4,6-trimethylphenyl) amino] carbonyl] -2-benzothiazolyl] carbamic acid 1,1-dimethylethyl ester; [6-bromo-7 - [[(2,4,6-trimethylphenyl) amino] carbonyl] -2-benzothiazolyl] carbamic acid 1,1-dimethylethyl ester; [4 - [[(2,4,6-trimethylphenyl) amino] carbonyl] -2-benzothiazolyl] carbamic acid 1,1-dimethylethyl ester; [6-bromo-4 - [[(2,4,6-trimethylphenyl) amino] carbonyl] -2-benzothiazolyl] carbamic acid 1,1-dimethylethyl ester; [6 - [(2,4,6-trimethylphenyl) amino] carbonyl] -2-benzothiazolyl] carbamic acid 1,1-dimethylethyl ester; 2-amino-N- (2,4,6-trimethylphenyl) -6-benzothiazolecarboxamide, trifluoroacetate (1: 1); 2- (acetylamino) -N- (2,4,6-trimethylphenyl) -6-benzothiazolecarboxamide; 2- (benzoylamino) -N- (2,4,6-trimethylphenyl) -6-benzothiazolecarboxamide; 2 - [(1-oxopropyl) amino] -N- (2,4,6-trimethylphenyl) -6-benzothiazolecarboxamide; 2 - [(1-oxobutyl) amino] -N- (2,4,6-trimethylphenyl) -6-benzothiazolecarboxamide; 2 - [[[(1,1-dimethylethyl) amino] carbonyl] amino] -N- (2,4,6-trimethylphenyl) -6-benzothiazolecarboxamide; 2 - [[[bis (1-methylethyl) amino] carbonyl] amino] -N- (2,4,6-trimethylphenyl) -6-benzothiazolecarboxamide; (1) single bond; (2) alkylene; (3) alkenylene; or (4) alkynylene; Z is: 13 ^J (1) j single bond; (2) -Z-S (O) -Z; (3) (4) (5) (6) - Z (7) - Z -SZ, 11 12 ¹ -O-C (O) -z or 12 ‘ 171 «* * 99 9 49 * ftft ftft ftftft ftftft ftftft ft ftft 4 9 (8 ) -Z _ix -C (O) -OZ _i2. The compound of claim 41, which is a compound of Formula I or a salt thereof selected from the group consisting of: (1) hydrogen or _Zg , wherein _Zg is (i) alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, aryl, aralkyl, alkylaryl, cycloalkylaryl, heterocycle or heterocycloalkyl; (ii) a group (i) that is substituted by one or more of the same or different groups (i); or (iii) a group of (i) or (ii) which is substituted with one or more of the following groups (2) to (16), definitions Ζ _χ , Z ₂ and Z ₃ ; (2) -OH or -Z _{2 g} ; (3) -SH or -sa _g; (4) -C (O) H, -C (O) Z, or -O-C (O) Z; <3 <€ 3 <3 β (5) -SO H or -S (O) Z; 3 < 30 (6) halogen; (7) cyano; (8) nitro; (9) -Z-ZZ; (10) -Z -N (Z) -Z -NZ Z; (11) -Z -N (Z) -Z Z; (12) -Z -N (Z) -Z-H; (13) oxo; (14) -OC (O) -Z ₆ ; (15) any two of Z, Z ₂ and Z ₃ may together be an alkylene or alkenylene complementing a 3- to 8-membered saturated or unsaturated ring formed with the atoms to which they are attached; or (16) any two of _{χ χ} , Z ₂ and Z ₃ can be taken together -O- (CH) -O-; 2 tg Z ₄ and Z _s are each independently: »· 170 * (1) is a single bond; (2) -Z-S (O) -Z; (3) -Z-C (O) -Z. (4) -Z. (5) -Z 12 -C (S) -z. -o-z (6) (7) -Z From -s-of 11 12 -OC (O) -z ,, 11 12 ¹ or (8) Z • Z -C (O) -O-Z 11 12 Z and Z: R 10 (1) are each independently hydrogen or Z ₆ ; (2) Z ₇ and Z _s or Z _s and _{Ζ ιθ} may together be an alkylene or alkenylene complementing a 3- to 8-membered saturated or unsaturated ring formed with the atoms to which they are attached, which ring may be unsubstituted or substituted (3) ) Z ₇ or Z ₈ , together with Z, may together be an alkylene or alkenylene supplementing a 3- to 8-membered saturated or unsaturated ring formed with the nitrogen atoms to which they are attached, which ring may be unsubstituted or substituted with Z, Z ₂ and Z ₃ ; and Z are each independently: (1) hydrogen or R; (2) (3) and R Z -R 4 6 ‘or -Z -NR R, X3 7 8 (1) are each independently hydrogen or _Rg; (2) may, together with the nitrogen atom to which they are attached, supplement a 3- to 8-membered heterocyclic ring, which ring may be unsubstituted or substituted by Z, Z ₂ and Z ₃ , wherein said ring may optionally be fused to a benzene ring which is itself unsubstituted or substituted by Z, Z ₂ and Z ₃ ; R and R XX X 2 (1) are each independently hydrogen or R _g ; (2) _R7 and _R together may be alkylene or alkenylene additional 3- to 8-membered saturated or unsaturated ring formed with the nitrogen to which they are attached, which ring may be unsubstituted or substituted _χ Z, Z ₂ and Z ; (3) any two of R, R and R may together be alkylene 169 or an alkenylene complementary 3- to 8-membered saturated or unsaturated ring formed with the nitrogen atoms to which they are attached, which ring may be unsubstituted or substituted with Z, Z ₂ and Z ₃ ; Ζ _χ , Z ₂ and Z ₃ are each independently: 1 2 3 and R ₃ are each independently selected from: (1) hydrogen or R, wherein R _g is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, aryl, aralkyl, heterocycle or heterocycloalkyl, each of which may be unsubstituted or substituted Ζ; _χ , Z ₂ and one or more Z ₃ groups; (2) -OH or -0R _s; (3) -SH or -SR _g ; (4) -C (O) H, -C (O) R or -O-C (O) R, wherein q is 1 or 2; (5) -SO H or -S (O) R; 3 < 3 o (6) halogen; (7) cyano; • · 168 * -Z -NR R. 4 V 8 -NR R, S X 0 XX ¹ (8) nitro; (9) (10) -Z ₄ -N _(R) -Z _£ (11) -Z, -N (R) -zr; (12) -P (O) (OR _e ) _a ; (13) any two R _x groups may together be an alkylene or alkenylene complementing a 3- to 8-membered saturated or unsaturated ring formed with the carbon atoms to which they are attached, which ring may be unsubstituted or substituted by _{χ χ} , Z__ and Z ₃ ; or (14) any two R groups may form, with the carbon atoms to which they are attached, a heterocyclic group which is unsubstituted or substituted with Z, Z and Z; (1) single bond; (2) -Z-S (O) -Z; (3) -Z 2 -C 10 -Z 2; (4) -Z 1 -C 1 S 3 -Z 2; • · 167 (6) - Z - S - Z: 11 12 (7) -Z-O-C (O) -Z; or (8) -Z -C (O) -O-Z. 38. A compound according to claim 1, wherein _Ζ χ3 is -C (NR _i3) -. A compound according to claim 1, -C (C (R ₁₄ ) ₂ ) -. where _{Ζ χ3} is -C (CHR _x J- or formula I or a salt thereof: (l) wherein p is 0, 1, 2 or 3; Χ _χ and X ₂ are both hydrogen, or taken together are = O or = S; each R _x is independently selected from the group consisting of: (1) single bond; (2) -Z-S (O) -Z; XX <3 X2 ' Z is -C (O) -Z XX 12 Z is -C (S) -Z XX X2 -O-Z; Z -S-Z; XX 12 ⁹ (3) (4) (5) -Z (6) or (7) -Z -O-C (0) -Z XX X 2 (8) -Z -C (O) -O-Z; Z, Z and Z: a 'and io (1) are each independently hydrogen or Z _g ; (2) Z ₇ and Z ₈ or Z _g and _{Ζ χθ} may together be an alkylene or alkenylene supplementing a 3- to 8-membered saturated or unsaturated ring formed with the atoms to which they are attached, which ring may be unsubstituted or substituted Z or Z 7 S together with _{Ζ χθ} may be together an alkylene or alkenylene supplementing a 3- to 8-membered saturated or unsaturated ring formed with the nitrogen atoms to which they are attached, which ring may be unsubstituted or substituted Ζ _χ , Z ₂ and Z ₃ ; (3) 162 Z and Z are each independently: 11 12 ^JJ (1) a single bond; (2) alkylene; (3) alkenylene; or (4) alkynylene; Z is: X3 ^J (1) single bond; (2) -Z-S (O) -Z; xx q x 2 '(3) -Z -C (O) -Z; XX X2 ^1- (4) -Z -C (S) -Z: (5) -Z-O-Z; (6) -Z-S-Z; (7) -Z-O-C (O) -Z; (8) -Z _ii, -C (O) -OZ _i2; (9) -C (NR _i3) -; (10) - (CHR ₁₄ ) -; or (11) -C (C (R ₁₄ ) ₂ ) The compound of claim 1, wherein p is 0 or 1 and each R ₁ is independently selected from the group consisting of hydrogen, halogen, alkyl or alkoxy. The compound of claim 1, wherein R ₂ is hydrogen. 4. A compound according to claim 1 wherein R ₃ is hydrogen, alkyl, -Z ₄ -Z _R or -NR R. X3 * 7 © The compound of claim 1, wherein R ₄ is hydrogen. 6. A compound according to claim 1, wherein _R is an aryl group which is substituted with Z, Z ₂ and one or more Z groups _third The compound of claim 1, wherein Χ _χ and X ₂ together form = O or = S. 163 8. A method of treating diseases associated with protein-tyrosine kinase comprising the step of administering an effective amount of at least one compound of claim 1 to an individual in need of such treatment. The method of claim 8, wherein said protein-tyrosine kinase-associated disease is transplant rejection. The method of claim 8, wherein said protein-tyrosine kinase-associated disease is rheumatoid arthritis. The method of claim 8, wherein said protein-tyrosine kinase-associated disease is multiple sclerosis. 12. The method of claim 8 wherein said protein-tyrosine kinase associated disease is an inflammatory bowel disease. The method of claim 8, wherein said protein-tyrosine kinase-associated disease is lupus. 14. The method of claim 8 wherein said protein-tyrosine kinase-associated disease is a graft versus host reaction. 15. The method of claim 8, wherein said protein-tyrosine kinase-associated disease is T cell-mediated hypersensitivity. • · 164 * ·· ·· · · · · · · · · · · · · · · · · · · · · · · · 16. The method of claim 1 wherein said protein-tyrosine kinase-associated disease is psoriasis. 17. The method of claim 8, wherein said protein-tyrosine kinase-associated disease is Hashimoto's thyroiditis. 18. The method of claim 8 wherein said protein-tyrosine kinase associated disease is Guillain-Barre syndrome. 19. The method of claim 8, wherein said protein-tyrosine kinase-associated disease is a cancer wherein the Src-family kinase is activated or overexpressed, or wherein the Src-family kinase activity facilitates tumor growth, or its survival. 20. The method of claim 8, wherein said protein-tyrosine kinase associated disease is contact dermatitis. 21. The method of claim 8 wherein said protein-tyrosine kinase-associated disease is an allergic disease. 22. The method of claim 1 wherein said protein-tyrosine kinase associated disease is asthma. 23. The method of claim 8, wherein said protein-tyrosine kinase-associated disease is. 165 ischemic or reperfusion injury. 24. The method of claim 8, wherein said protein-tyrosine kinase-associated disease is atopic dermatitis. 25. The method of claim 8, wherein said protein-tyrosine kinase-associated disease is allergic rhinitis. 26. The method of claim 8, wherein said protein-tyrosine kinase is Lck. 27. The method of claim 8, wherein said protein-tyrosine kinase is Fyn. 28. The method of claim 8 wherein said protein-tyrosine kinase is Lyn. 29. The method of claim 8 wherein said protein-tyrosine kinase is Hek. 30. The method of claim 8, wherein said protein-tyrosine kinase is Fgr. 31. The method of claim 8, wherein said protein-tyrosine kinase is Src. 32. The method of claim 8, wherein said compound of formula I or a salt thereof is administered simultaneously or sequentially with an anti-inflammatory, anti-proliferative, chemotherapeutic, immunosuppressive agent or inhibitor. PTK other than the compound of formula I or a salt thereof. 166 * The method of claim 32, wherein said compound of Formula I or a salt thereof is administered with one or more of the following agents: another PTK inhibitor; cyclosporin A; CTLA-4Ig; antibodies selected from anti-ICAM-3, anti-IL-2 receptor (Anti-Tac), anti-CD45RB, anti-CD2, anti-CD3 (OKT-3), anti-CD4, anti-CD80, anti-CD86, OKT3 monoclonal antibodies; agents blocking the interaction between CD40 and gp39; fusion proteins prepared from CD40 and gp39; inhibitors of NF-kappa B cell function; non-steroidal anti-inflammatory drugs (NSAIDs); steroids; gold compounds; antiproliferative agents; FK506 (tacrolimus, Prograf); mycophenolatmofetil; cytotoxic drugs; TNFα inhibitors; anti-TNFα antibodies or soluble TNF receptors; and rapamycin (sirolimus or Rapamune) or derivatives thereof. 34. A method of treating a T cell mediated disorder comprising the step of administering an effective amount of at least one compound of claim 1 to an individual in need of such treatment. 35. The method of claim 34, wherein T cell activation is inhibited. 36. A pharmaceutical composition for the treatment of protein kinase-associated diseases comprising a pharmaceutically acceptable vehicle or diluent and at least one compound of claim 1. The compound of claim 1, wherein _{Ζ χ3} is: (1) hydrogen or Z _g, where Z ₆ is (i) alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, aryl, aralkyl, alkylaryl, cycloalkylaryl, heterocyclo, or heterocycloalkyl; (ii) a group (i) that is substituted by one or more of the same or different groups (i); or (iii) a group of (i) or (ii) which is substituted by one or more of the following groups (2) to (16), the definition of _{χ χ} , Z ₂ and Z ₃ (2) -OH or -OZ ₆ ; (3) -SH or -SZ; o (4) -C (O) H, -C (O) Z 2, or -O-C (O) Z; C 6 -C 6 G [O (5) -SO H or -S (O) Z; (6) halogen; (7) cyano; (8) nitro; • · 161 (9) -Z ₄ -NZ _{7 Z;} (10) -Z ₄ -N (Z ₉ ) -Z _s -NZ ₇ Z _s ; (11) -Z -N (Z) -Z Z; 4 X O 5 6 (12) -Z -N (Z) -Z -H; (13) oxo; (14) -OC (O) -Z _g ; (15) any two of Ζ _χ , Z ₂ and Z ₃ may together be alkylene or alkenylene complementing a 3- to 8-membered saturated or unsaturated ring formed with the atoms to which they are attached; or (16) any two of the groups _{χ χ} , Z _, and Z ₃ can be taken together -O- (CH) -O-; 2 <g [ Z ₄ and Z _s are each independently: (1) -NO ₂ ; (2) -COOalkyl; or (3) -COOaryl; Ζ _χ , Z ₂ and Z ₃ are each independently: (1) hydrogen or R _g; (2) -Z-R; or (3) -Z (1) are each independently hydrogen or R _g ; (2) may, together with the nitrogen atom to which they are attached, supplement a 3- to 8-membered heterocyclic ring, which ring may be unsubstituted or substituted by _{χ χ} , Z ₂ and Z ₃ , wherein said ring may optionally be fused to a benzene a ring which is itself unsubstituted or substituted by Z. R and R 11 12 (1) (2) are each independently hydrogen or _{Rg; R7} and _Rg may together be alkylene or alkenylene additional 3- to 8-membered saturated or unsaturated ring formed with the nitrogen to which they are attached, which ring may be unsubstituted or substituted with Z, Z and Z _3; (3) any two of _Rg, R _io and R together may be alkylene or alkenylene additional 3- to 8-membered saturated or unsaturated ring formed with the nitrogen atoms to which they are attached, which ring may be unsubstituted or substituted with Z, Z ₌ and Z ₃ ; R ne: 13 ^J (1) cyano; • · 160 «(2) nitro; (3) -NH ₂ ; (4) -NHO alkyl; (S) -OH; (6) -NHaryl; (7) -NHCOOalkyl; (8) -NHCOOaryl; (9) -NHSO 4, alkyl; (10) -NHSO 4 aryl; (11) aryl; (12) heteroaryl; (13) -Oalkyl; or (14) -Oaryl; R is: (1) hydrogen or R, wherein R _g is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, aryl, aralkyl, heterocycle or heterocycloalkyl, each of which may be unsubstituted or substituted Ζ; _χ , Z ₂ and one or more Z ₃ groups; (2) -OH or -OR; (3) -SH or -SR _g ; (4) -C (O) H, -C (O) R or -O-C (O) R, wherein q is 1 or 2; (5) -SO H or -S (O) R: 3 G 6 6 (6) halogen; (7) cyano; (8) nitro; (9) -Z-NR R; (10) -Z-NR (R) -Z-NR; 4 S 5 10 11 '(11) -Z -N (R) -Z R; 4 12 5 6 '(12) -P (O) (OR _g ) ₂ ; (13) any two R groups may be together alkylene or 159 * alkenylene complementing a 3- to 8-membered saturated or unsaturated ring formed with the carbon atoms to which they are attached, which ring may be unsubstituted or substituted by _{χ χ} , Z ₂ and Z ₃ ; (14) any two R groups may form, with the carbon atoms to which they are attached, a heterocyclic group which is unsubstituted or substituted by _{χ χ} , Z ₂ and Z ₃ ; and R ₃ are each independently selected from: A benzothiazole compound of formula I or a salt thereof: wherein p is 0, 1, 2 or 3; Χ _χ and X ₂ are both hydrogen, or taken together are = O or = S; each R is independently selected from the group consisting of: 2 - [(1-hydroxy-cyclopropylcarbonyl) amino] -N- (2-chloro-6-methylphenyl) -6-benzothiazolecarboxamide.