Untitled record

Cyclic protein tyrosine kinase inhibitors wi

-Ό

<img file="HU0202708A2_D0001.tif" />

cyclic protein tyrosine kinase inhibitors of the general formula - with certain limitations

Q is optionally one or more R's¹ a five or six membered heteroaromatic or aromatic ring substituted with a group;

Z is a single bond, -R¹⁵C = CH or - (CH 2&gt;_m- a group wherein m is 1 or 2;

2

X and X are hydrogen or together are oxo or dioxo;

R is hydrogen or R, wherein R is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, aryl, aralkyl, heterocyclyl or heterocyclyl12.

-alkyl, each optionally -2 e-sx 3

A-gy-gyh-b · —— e-SOporbbs sub-g, 6 titers; hydroxy or -OR; a mercapto or -SR group; carboxy, -C (O) q R⁵ or -OC (O) q R⁶ a group wherein q is 1 or 2; sulfo or -S (O)_qR⁶ group; halogen;

. . 4 7 fi 4, Q 5 ΊΠΊΊ 4 cyano-; nitro; -Z -NR R; -Z-N (R) -Z-NR R; -Z -N (R¹²) -Z⁵-R⁶; -P (O) (OR⁶)₂ group;

R² and R³ hydrogen or R⁶; -Z⁴-R⁶; or -Z¹³NR⁷R⁸ group;

R⁴ and R⁵ hydrogen or R⁶; -Z⁴-N (R⁹) -Z⁵NR¹⁰R¹¹; -N (R⁹) Z⁴R⁶; together with the nitrogen atom form an optionally substituted hetero331 cyclic ring;

R⁷, R⁸, R⁹, R¹⁰, R¹¹ and R¹² hydrogen or R⁶;

8

R and R together are alkylene, alkenylene or heteroalkyl; or 910-11

Two of R, R and R are alkylene or alkenyl;

cyano; nitro; amino; alkoxyamino; hydroxy; (Aryloxy) alkylamino; (Alkoxycarbonyl) amino; [(aryloxy) carbonyl] amino; (Alkylsulfonyl) amino; (Arylsulfonyl) amino; aryl; heteroaryl; alkoxy; aryloxy group; nitro; alkoxycarbonyl; [(Aryloxy) carbonyl] alkyl; hydrogen; alkyl; aryl; aralkyl; cycloalkyl;

—And 7? hydrogen or - Z⁶-; - where Z⁷ ü) —alkyl = r — in the case of alkene · - -cycloalkyl, -e-tk 1 oa 1 ka 1 - a 1 ki 1 -g cyclic og l′ke ríTT-, cyclo 1 ke nyl ^ a-lki 1 - , -Aryl = 7-aralkyl-alkyl-cycloaltyl-arch, -7-ore-alkyl or -hehe rp / rfk1-yl-alkyl;

(± i ~) —- substituted with one ~ or more (i) groups · '2._ __ 1 7 - *. (t _) - group -; - or (L11) one or more 7r ~, 2r and kidney-por-aü-s-zubs ^ otTttraTE (T) or - (- ü) -esc

-or-QZ⁶ group; mercapto - va.gf-y - eseport.; -C (0)_qH, or -0-C (0) _qZ⁶ - Souife, ----- S-fO-bgZ - or - (0) q = ~

M_csoport; ---- ni L ι ocs oport

7 fiction

-ZZ-NZZ;

- Z⁴-N (Z ⁹) .aklütplp-o - z⁴-N (Z ¹-^t^ - = - tl-4ÍtZ¹⁰) -zlut; ere — r — é — C (0) —Z⁶ group;

3

Z -, - Z, and - Z - hand-sitting - - two ..... alkylene - ^ - or alkenyl groups - a-lkc -; -....... Z¹, Z² and Z³ Two közíil - Θ - (0¾) _r~ Q -—group_alk, ____ where..x is equal to — 4- or — 5y

Z⁴ and Z⁵ single bond; -Zⁿ-S (0) _q-Z¹²-; -Zⁿ-C (O) -Z¹²-; -Z¹¹-C (S) -Z¹²-; -Z¹¹-ROE¹²-; -Zⁿ-S¹²-;

-0-Z¹²- a group;

-Z^U-OC (O) -Z¹²73 196 / BE

332

Z⁷, Z⁸, Z⁹ and Z¹⁰ hydrogen or Z⁶;

Z⁷ and Z⁸, or Z⁶ and Z¹⁰ together form an alkylene or alkenylene group; obsession

Z⁷ or Z⁸ and Z⁹ together form an alkylene or alkenylene group;

Z¹¹ and Z¹² single bond; alkylene; -alkenylene; alkynylene;

Z¹³ single bond; -Z^U-S (0) _q-Z¹²-; -Zⁿ-C (O) -Z¹²-; -Zⁿ-C (S) -Z¹²-;

-Z¹⁷-ROE¹²-; -Z ^ -s¹²-; -Z¹¹-OC (O) -Z¹²-; -Z¹¹-C (O) -O-Z¹²-;

-C (NR¹³) -; -C (CHR¹⁴) -; or -C [C (R¹⁴)₂] - and their use as pharmaceuticals and for their use in the treatment of disorders related to protein tyrosine kinase.

<img file="HU0202708A2_D0002.tif" />

73 196 / BE

&amp; SBG's.

Patent Attorney's Office H-1062 Budapest, Andrássy út 113, Phone: 461-1000, Fax: 461-1099 ,, ζ -, -, - ιγ-'γΛτγ: I Difi PlAhlY KOZ-hL-C! L_L.Í i L-UUi uw 1

73 196 / BE

P020270 8

Cyclic protein tyrosine kinase inhibitors _fe ^h ' ^{1 1} '¹ 'Xv&gt;' ·. t υΦοα ..... c W.aM s olkJu / ö

The present invention relates to cyclic compounds and their salts, to methods of treating protein tyrosine kinase-related disorders, such as immunological and oncological disorders, and to pharmaceutical compositions containing such compounds.

Protein tyrosine kinases (PTKs) are enzymes that, together with ATP as a substrate, phosphorylate tyrosine groups in peptides and proteins. These enzymes play a key role in the regulation of cellogenesis, including cell proliferation and cellular differentiation. Protein tyrosine kinases include, but are not limited to, receptor tyrosine kinases (RPTKs), including members of the epidermal growth factor kinase family (e.g., HER1 and HER2), platelet-derived growth factor (PDGF), and other components involved in angiogenesis. kinases (Tie-2 and KDR); and non-receptor tyrosine kinases, including the Syk, JAK, and Src (e.g., Src, Fyn, Lyn, Lek, and Blk) families [see Bolen, JB, Rowley, R. B., Spana, C., and Tsygankov, AY, FASEB J., 6, 3403-3409 (1992); Ullrich, A. and Schlessinger, J., Cell, 61, 203-212 (1990); and Ihle, JN, Sem. Immunol., 1995, 247-254].

Increased PTK activity is associated with a variety of malignant and non-malignant proliferative diseases. In addition, PTKs play a central role in cellular regulation of the immune system. Thus, PTK inhibitors are capable of acting on a wide range of oncological and immunological disorders. Selective inhibition of certain receptor or non-receptor PTKs, such as Lck, by an inhibitor of γ, or inhibition of more than one PTK due to homology between the PTK classes, can advantageously influence these disorders.

One particularly important PTK is the Lek in T cells, where Lek is found in key phosphorylating protein substrates. Lck is required for productive antigen receptor signaling and cell activation. Without Lek activity, the T cell receptor (TCR) zeta chain is not phosphorylated, ZAP-70 kinase is not activated, and Ca mobilization of 2+ Z z is essential for T cell activation [see Weiss, THE. and Littman, DR, Cell, 76, 263-274 (1934); Iwashima, M., Irving, BA, van Oers,

NSC, Chan, AC, and Weiss, A., Science 263: 1136-1139 (1994);

and Chan, A.C., Dalton, M., Johnson, R., Kong, G., Wang, T.,

Thoma, R., and Kurosaki, T., EMBO J., 14, 2499-2508 (1995). Thus, Lek inhibitors can be used to treat T-cell-mediated diseases such as chronic diseases containing certain significant T-cell components, such as rheumatoid arthritis, multiple sclerosis and lupus, and acute diseases in which T-cells are well known to be essential. such as acute graft rejection and delayed-type hypersensitivity (DTH) reactions.

The present invention is for use as protein tyrosine kinase inhibitors

<img file="HU0202708A2_D0003.tif" />

cyclic compounds of the general formula: wherein

73 196 / BE

Q is a (1) five-membered heteroaromatic ring optionally substituted with one or more R's;

(2) a six-membered heteroaromatic ring; or (3) an aromatic ring;

Z is (1) a single bond;

(2) -R¹⁵C = CH; or (3) - (CH 2)_m- a group of the formula wherein m is 1 or 2;

X¹ and X² each is hydrogen or taken together to form oxo or dioxo;

R¹ is (1) hydrogen or R⁶, where

R⁶ is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, aryl, aralkyl, heterocyclyl or heterocyclylalkyl, each of which is optionally Z, Z and one or substituted (preferably by one or two) Z groups;

(2) hydroxy or -O R^S a group of the general formula;

(3) a mercapto group or -SR⁶ a group of the general formula;

(4) carboxy, -C (O)_qR⁶ or -OC (O)_qR⁶ wherein q is 1 or 2;

(5) sulfo or -S (O)_qR⁶ a group of the general formula;

(6) halogen;

(7) cyano;

(8) nitro;

9 · ~ Ι Ο (9) -Ζ -NR R;

(10) -Ζ⁴-Ν (R⁹) -Z⁵NR¹⁰R¹¹ a group of the general formula;

(11) - Ζ⁴-N (R¹²) -Z⁵-R⁶ a group of the general formula;

(12) -P (O) {OR⁶) A group of formula 2;

R² and R³ each independently represents (1) hydrogen or R⁶;

(2) -Z⁴-R⁶ a group of the general formula; or (3) -Z¹³NR⁷R⁸ a group of the general formula;

R⁴ and R⁵ each independently represents (1) hydrogen or R⁶;

(2) -Z⁴-N (R⁹) -Z⁵NR¹⁰R¹¹ a group of the general formula;

(3) -N (R⁹) Z⁴R⁶ a group of the general formula; or (4) together with the nitrogen atom to which it is attached forms a 3-8 membered saturated or unsaturated heterocyclic ring optionally substituted with Z, Z and Z, the heterocyclic ring being optionally fused to a benzene ring, the benzene ring being optionally independently Substituted with Z, Z and Z;

R⁷, R⁸, R⁹, R¹⁰, R¹¹ and R¹² (1) each independently is hydrogen or R⁶;

(2) R⁷ and R⁸ together form an alkylene, alkenylene or heteroalkyl group which, when taken together with the nitrogen atom to which it is attached, represents a 3 to 8 membered saturated or unsaturated ring optionally substituted with Z, Z and Z; obsession

73.196 / BE • · · · (3) R⁹, R¹⁰ and R¹¹ any two of which form an alkylene or alkenylene moiety which, on the attached nitrogen atoms, forms a 3- to 8-membered saturated or unsaturated ring optionally substituted with Z, Z and Z;

<td colspan="2">meaning</td>

<td> (1)</td><td>CN;</td>

<td> (2)</td><td>nitro;</td>

<td> (3)</td><td>amino;</td>

<td> (4)</td><td>alkoxyamino;</td>

<td> (5)</td><td>OH;</td>

<td> (6)</td><td>(Aryloxy) alkylamino;</td>

<td> (7)</td><td>(Alkoxycarbonyl) amino;</td>

<td> (8)</td><td>[(Aryloxy) carbonyl] amino</td>

<td> (9)</td><td>(alkylsulfonyl) amino;</td>

<td> (10)</td><td>(Arylsulfonyl) amino;</td>

<td> (11)</td><td>aryl;</td>

<td> (12)</td><td>heteroaryl;</td>

<td> (13)</td><td>group; obsession</td>

<td> (14)</td><td>aryloxy group;</td>

<td colspan="2">meaning</td>

<td> (1)</td><td>nitro;</td>

<td> (2)</td><td>alkoxycarbonyl group; obsession</td>

<td> (3)</td><td>[(Aryloxy) carbonyl] alkyl;</td>

<td colspan="2">meaning</td>

<td> (1)</td><td>hydrogen;</td>

<td> (2)</td><td>a1kilesöpört;</td>

73.196 / BE • · · · · · · · ····································································· (· (3) aryl group;

(4) aralkyl; or (5) cycloalkyl;

Z¹, Z² and Z³ each independently represents (1) hydrogen or Z⁶; where

Z⁶ is (i) alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, aryl, aralkyl, alkylaryl, cycloalkylaryl, heterocyclyl or heterocyclyl-alkyl; (ii) a single group (i) substituted by one or more identical or different groups (i); or (iii) a group (i) or (ii) substituted with one or more groups as defined in Z, Z and Z below in (2) to (16);

(2) hydroxy or -OZ⁶ a group of the general formula;

(3) a mercapto group or -S⁶ a group of the general formula;

(4) -C (O) q H, -C (O) q Z^S or -OC (O) q Z⁶ a group of the general formula;

(5) sulfo group, -S (O)_qZ⁶ or -S (0) _qN (Z⁹) Z⁶ a group of the general formula;

(6) halogen;

(7) cyano;

(8) nitro;

(9) -Z -NZ Z;

(10) -Z⁴-N (Z⁹) -Z⁵-NZ⁷Z⁸ a group of the general formula;

(11) -Z⁴-N (Z¹⁰) -Z⁵-Z⁶ a group of the general formula;

(12) -Z⁴-N (Z¹⁰) -Z⁵-H;

73.196 / BE • * · · · · ·

<img file="HU0202708A2_D0004.tif" />

(13) oxo;

(14) -OC (O) -Z⁶ a group of the general formula;

(15) Z¹, Z² and Z³ any two of them together form an alkylene or alkenylene group which, taken together with the atoms to which they are attached, forms a 3- to 8-membered saturated or unsaturated ring; or (16) Z¹, Z² and Z³ any two of them together is -0- (CH2) _r- forms a group of the general formula wherein r is 1, 2,

3, 4 or 5, which together with the atoms to which they are attached form a 4-8 membered saturated or unsaturated ring;

Z⁴ and Z⁵ each independently represents (1) a single bond;

(2) -Z^{1 L}-S (O) q Z¹²- a group of the general formula;

(3) -Z¹¹-C (0) -Z¹²- a group of the general formula;

(4) —Z¹¹—C (S) -Z¹²- a group of the general formula;

(5) ~ Z¹¹-ROE¹²- a group of the general formula;

(6) -Z⁴¹-S¹²- a group of the general formula;

(7) -Z-O-C (O) -Z - general group; or (8) -Z¹¹-C (O) -O-Z¹²- a group of the general formula;

Z⁷, Z⁸, Z⁹ and Z¹⁰ (1) each independently represents hydrogen or Z⁶;

(2) Z⁷ and Z⁸, or Z⁶ and Z¹⁰ together form an alkylene or alkenylene group which, taken together with the atoms to which they are attached, forms a 3-8 membered saturated or unsaturated ring z 1 2 3, which ring is optionally substituted with Z, Z and Z; obsession

73.196 / BE • *, 11, 13 and (3) Z⁷ or Z⁸ and Z⁹ together form an alkylene or alkenylene group which, taken together with the nitrogen atoms to which it is attached, forms a 3-8 membered saturated or unsaturated ring z 1 2 3, which ring is optionally substituted with Z, Z and Z;

and Z are each independently (1) a single bond;

(2) alkylene;

(3) alkenylene; or (4) alkynylene; and j is (1) a single bond;

(2) -Z¹¹-S (0) Gz¹²- a group of the general formula;

(3) -Z^{1 L}-C (Ο) -Z¹²- a group of the general formula;

(4) —Z '^L^L—C (S) -Z¹²- a group of the general formula;

(5) -Z¹¹ -0-Z¹²- a group of the general formula;

(6) -Z¹¹-S¹²- a group of the general formula;

(7) -Z¹¹-OC (Ο) -Z¹²- a group of the general formula;

(8) -Z^{1 L}-C (O) -O-Z¹²- a group of the general formula;

(9) -C (NR¹³) - a group of the general formula;

(10) -C (CHR) - general group; or (11) -C [C (R¹⁴) 2] ~ refers to their salts.

Compounds of formula I include:

<img file="HU0202708A2_D0005.tif" />

Compounds of the formula: wherein n is 1 or 2;

A is carbon or nitrogen;

B is N, O or S;

X is oxygen or sulfur; as well as

R¹, R², R³, R⁴ and R⁵ is as defined above - and salts thereof.

The meanings of some of the terms used herein are described below. Unless otherwise indicated, the meaning of a particular group or term refers to the entire description; the group may be independent or part of another group.

The term "alk or" alkyl refers to straight or branched chain hydrocarbon radicals having from 1 to 12 carbon atoms, preferably from 1 to 8 carbon atoms. The term "lower alkyl" refers to C1-C4 alkyl groups.

The term "alkenyl" refers to straight or branched chain hydrocarbon radicals having from 2 to 10 carbon atoms, preferably from 2 to 4 carbon atoms, having at least one double bond. Where an alkenyl group is attached to a nitrogen atom, the alkenyl group is preferably not directly attached to the nitrogen atom through a carbon atom having a double bond.

The term "alkynyl" refers to straight or branched chain hydrocarbon radicals having from 2 to 10 carbon atoms, preferably from 2 to 4 carbon atoms, having at least one triple bond. Where an alkynyl group is attached to a nitrogen atom, the alkenyl group is preferably not directly on a carbon having a triple bond.

<td rowspan="2">¹</td><td rowspan="2"> 10</td><td colspan="2">·· ·· »·· &lt;· ···· · the · · ·</td>

<td> • ··· · • · · ♦ • · · · ·· ·</td><td> • · «·· ·· · · · • · · ·</td>

<td>reszta</td><td>is bound to the nitrogen atom.</td><td></td><td></td>

<td>The</td><td>The term "alkylene group" is as defined in claims 1-5</td><td>-C,</td><td>straight</td>

<td>chain,</td><td colspan="2">denotes a bond attached to certain bonds</td><td>[e.g.</td>

<td>- (CH₂)_x-</td><td>• a group of the general formula in which</td><td>x is 1,</td><td> 2, 3, 4</td>

or 5] which may be optionally substituted with 1-3 lower alkyl groups.

The term "alkenylene" refers to a C2-C5 straight-chain, single or double-bonded, hydroxy-linked hydroxy group which may be optionally substituted with 1-3 lower alkyl groups. Examples of alkenylene groups are -CH = CH-CH = CH-, -CH₂-CII = CII-, -CH₂-CH = CH-CH₂-, -C (CH₃)₂CH = CH- and -CH (C₂H₅) -CH = CH-.

The term "alkynylene" refers to a C2-C5 straight chain triple bonded single bond, which may be optionally substituted with 1 to 3 lower alkyl groups. Examples of alkynylene groups are -C = C-, -CH₂-CsC-, -CH (CH₃) -OC- and -C = c-CH (C₂H₅) CH₂group.

The term "ar or" aryl refers to aromatic cyclic groups of 6 to 14 carbon atoms (e.g., 6-membered monocyclic, 10-membered bicyclic or 14-membered tricyclic ring systems). Examples of aryl include phenyl, naphthyl, biphenyl and anthryl.

The terms "cycloalkyl" and "cycloalkenyl" refer to a C 3 -C 12 cyclic hydrocarbon group.

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

73.196 / BE ···· • · ·

The term "unsaturated ring" includes partially unsaturated and aromatic rings.

The term "heterocyclic" refers to fully saturated or unsaturated, including aromatic cyclic ("heteroaryl") groups, such as 4-7 membered monocyclic, 7-11 membered bicyclic or 10-15 membered tricyclic ring systems containing at least one ring member containing at least one carbon atom. they have a heteroatom. Each ring of the heteroatom-containing heterocyclic group may contain 1, 2, 3, or nitrogen and / or oxygen and / or sulfur atoms, wherein the heteroatom is nitrogen and the sulfur atom is optionally oxidized or the heteroatom nitrogen is optionally quaternized. Heterocyclic groups may be attached via any heteroatom or carbon atom in the ring or ring system.

Monocyclic heterocyclic groups include, but are not limited to, the following: pyrrolidinyl, pyrrolyl, pyrazolyl, oxetanyl, pyrazolinyl, imidazolyl, imidazolinyl, imidazolidinyl, oxazolyl, oxazolidinyl, isoxazolinyl, isoxazolyl, thiazolyl, thiadiazolyl, isothiazolidinyl, , furyl, tetrahydrofuryl, thienyl, oxadiazolyl, piperidyl, piperazinyl, 2-oxo-piperazinyl, 2-oxo-piperidyl, 2-oxo-pyrrolidinyl, 2-oxo-azepinyl, azepinyl, 4-piperidonyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, tetrahydropyranyl, morpholinyl ·, thiomorpholinyl, thiomorpholinylsulfoxide, thiomorpholinylsulfone, 1,3-dioxa-cyclopentyl (1,3-dioxolanyl) and tetrahydro-1,1-dioxothienyl, triazolyl, triazinyl and the like.

Bicyclic heterocyclic groups - among others -

73.196 / BE ·· ·· ···· ·

...........

for example: indolyl ·, benzothiazolyl, benzoxazolyl, benzodioxolyl, benzothienyl, quinuclidinyl, quinyl, tetrahydroisoquinolyl, isoquinolyl, benzimidazolyl, benzopyranyl, indolizinyl, benzofuryl, chrominyl, coumarinyl -, quinoxalinyl, indazolyl, pyrrolopyridyl, furopyridyl (e.g. furo [2,3-c] pyridyl, furo [3,2-b] pyridyl or furo [2,3-b] pyridyl), dihydroisoindolyl , dihydroquinazolinyl (e.g. 3,4-dihydro-4-oxoquinazolinyl), tetrahydroquinolyl and the like.

Tricyclic heterocyclic groups include carbazolyl, benzindolyl, phenanthrolinyl, acridinyl, phenanthridinyl, xanthenyl and the like.

The term "heteroaryl" refers to aromatic heterocyclic groups.

Heteroaryl groups include, but are not limited to, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, thiazolyl, thiadiazolyl, isothiazolyl, furyl, thienyl, oxadiazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazolyl, triazinyl and the like.

Where q is 1 or 2, the ,, - C (O)_qH represents a formyl or carboxy group; ,, - C (O)_qR⁵ or, - C (O) q Z⁶ is -C (O) -R 0 or -C (O) -OR⁶and -C (O) -Z⁶ or -C (O) -OZ⁶ a group of the general formula; ,, - OC (O) q R⁶ or, - OC (O) q Z⁶ is -OC (O) -R⁶ or -OC (O) -OR⁶and -OC (O) -Z⁶ or -O-C (O) -OZ⁶ a group of the general formula; and, - S (O) q R⁶ or ,, - S (O)_qZ⁶ is -SO-R⁶ or -SO 2 -R⁶and -SO-Z⁰ or -SO 2 -Z⁶ a group of the general formula.

73.196 / BE • · · · ····

<img file="HU0202708A2_D0006.tif" />

In some cases, the compounds of formula I may form salts which are also within the scope of the invention. Unless otherwise indicated, the term "compound of formula (I) as used herein includes salts of the compound. As used herein, the term salt (s) refers to acidic and / or basic salts of inorganic and / or organic acids and bases. The term "salt (s)" as used herein also includes zwitterions (inner salts) (which may be formed when, for example, the R substituent contains an acidic group, such as a carboxy group). The salts also include quaternary ammonium salts, such as alkyl ammonium salts. Pharmaceutically acceptable (i.e., non-toxic, physiologically acceptable) salts are preferred, but other salts may be used, for example, in the isolation or purification steps used in the preparation process. For example, salts of the compounds of formula (I) may be prepared by reacting a compound of formula (I) with an appropriate amount of an acid or base, for example, in a medium in which the salt is precipitated or in an aqueous medium, and performed.

Acid addition salts include, but are not limited to, the following: acetates (e.g., acetates with acetic acid or trihaloacetic acid, such as trifluoroacetic acid), adipates, alginates, ascorbates, aspartates, benzoates, benzenesulfonates, hydrogen sulfates, borates, butyrates, cifrates, camphoric acids, , ethanesulfonates, fumarates, glucoheptanoates, glycerophosphates, hemisulfates, heptanoates, hexanoates, hydrochloride73.196 / BE «* * · • · · *

<img file="HU0202708A2_D0007.tif" />

d, hydrobromides, hydroiodides, 2-hydroxyethane sulfonates, lactates, maleates, methanesulfonates, 2-naphthalenesulfonates, nicotinate, nitrates, oxalates, pectinates, persulfates, 3-phenylpropionates, phthalates, phosphates, sulfates (e.g. sulfates with sulfuric acid), sulfonates (e.g. the sulfonates mentioned above), tartrates, thiocyanates, toluenesulfonates, undecanoates and the like.

Basic salts (for example, the basic salts formed when R contains an acidic group such as a carboxy group) include, but are not limited to, the following: ammonium salts, alkali metal salts such as sodium, lithium and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, and organic bases (such as organic amines) such as benzathine, dicyclohexylamine, hydrabamine, IV-methyl-D-glucamine Salts with D-glucamide, tert-butylamine, and salts with amino acids such as arginine, lysine, and the like. Basic nitrogen-containing groups include suitable reagents, such as lower alkyl halides (e.g., metal, ethyl, propyl and butyl chloride, bromide and iodide), dialkyl sulfates (e.g., dimethyl, diethyl, dibutyl and diamyl). sulfate), long-chain halides (e.g. decyl, lauryl, myristyl and stearyl chloride, bromide and iodide), aralkyl halides (e.g. benzyl and phenethyl bromide) and the like. quarternized.

Prodrugs and solvates of the compounds of the invention are also included within the scope of the invention. As used herein, the term "prodrug" refers to compounds that are a

73.196 / BE • · · ·

...........

after administration to a subject, it undergoes a chemical transformation by metabolic or chemical processes which results in a compound of formula (I) or a salt and / or solvate of a compound of formula (I). Solvates of the compounds of formula I are preferably hydrates.

All stereoisomers, including all enantiomeric and diastereomeric forms, are possible within the scope of the invention due to asymmetric carbon atoms in the R substituents of the compounds of formula (I). For example, the individual stereoisomers of the compounds of the invention may be substantially free of other isomers or may be in mixed forms, such as racemates, or may be in the form of mixtures with any other or other selected stereoisomers. The chiral centers in the compounds of the invention may have the S or R configuration as defined by IUPAC 1974 Recommendations.

The groups and substituents are selected to provide stable moieties and compounds.

Preferred compounds of the present invention are those compounds of formula I wherein Q is a thiazole ring and wherein Z, X¹, X², R¹, R², R³, R⁴ and R⁵ one or more of these, and particularly preferably all of them, have the meanings given below:

Z is a single bond;

R¹ is hydrogen, halogen, alkyl, aryl, alkoxy, alkoxycarbonyl or (aryloxy) carbonyl, and more preferably is hydrogen;

73.196 / BE ·· ·· «· · ♦ ·· ··· *« ·· · * * *

X¹ and X² together form an oxo or thioxo group, more preferably an oxo group;

R² is hydrogen;

R³ is -Z⁴-R⁶ or -Z¹³NR⁷R⁸ more preferably -Z-R, wherein

Z⁴ is a single bond, and R⁶ represents an aryl or hetero12 aryl group optionally substituted with Z, Z and one or more (preferably one or two) Z groups;

R⁴ is hydrogen; and

R⁵ is an aryl or heteroaryl group optionally substituted with Z, Z and one or more (preferably one or two) Z groups.

Examples of compounds of formula I include [A] - [E] and I-XI. the reaction scheme. One skilled in the art will have no difficulty in selecting suitable solvents, temperatures and pressures, and other reaction conditions. The starting compounds are commercial products or are readily prepared by one of ordinary skill in the art. The components of the compounds are as defined herein or as individually defined in the reaction schemes.

The procedures with the starting compounds and / or reagents may be carried out in solution or, where possible, alternatively, with one or more starting compounds or reagents fixed to a solid support. 555-600 (1996); (2) Terrett, N.K., Gardner, M., Gordon, D.W., Kobylecki, R.J., Steele, J., Tetrahedron, 51, 8135-8173 (1995); (3)

73.19S / BE * · «··· · ·« · «·· ·

Gallop, MA, Barrett, RW, Dower, WJ, Fodor, SPA, Gordon, EM, Journal of Medicinal Chemistry, 37, 1233-1251 (1994);

(4) Gordon, EM, Barrett, RW, Dower, WJ, Fodor, SP

A., Gallop, MA, Journal of Medicinal Chemistry, 37, 1385-1401 (1994); (5) Balkenhohl, F., von dem Bussche-Hunnefeld, Lansky,

A., Zechel, C., Angewandte Chemie International Edition, 35,

2288-2337 (1996); (6) Balkenhohl, F., von dem Bussche Hunnefeld,

Lansky, A., Zechel, C., Angewandte Chemie, 108, 2436-2487 (1996);

and (7) Sofia, MJ, Drugs Discovery Today, 1996, L, 27-34.

Scheme [A]

<img file="HU0202708A2_D0008.tif" />

(Ia)

X1, X2 = Ο

73.196 / BE ·· ···· ····] _θ. ··· ·· · ♦ * ·

Scheme [A] illustrates a general procedure for the preparation of compounds of formula (Ia), that is, compounds of formula (I) wherein X and X together form an oxo group. As shown in Scheme [A], a compound of formula (Ia) wherein R and R are hydrogen may be prepared by reacting a compound of formula (I) (R * is a carboxy protecting group such as alkyl or aralkyl). ) by saponification and reaction with an amine of formula (iii) according to methods known in the art. Alternatively, compound (2) of formula (i) is reacted (e.g., in equimolar amounts) with a compound of formula RL wherein L is a leaving group, such as halogen, and optionally (e.g., equimolar) with a compound of general formula RL. a compound of formula (ii). In another alternative, the compound of formula (i) is converted to the compound of formula (ii) by reductive amination using the appropriate aldehyde or ketone. Subsequently, the compound of formula (ii) is saponified under conditions known to those skilled in the art and then reacted with an amine of formula (iii) to give a compound of formula (Ia) wherein R and / or R³ is other than hydrogen.

Processes for the preparation of preferred substituents on compounds of formula I are described in Sections I-XI.

are shown in the following Schemes.

73.196 / BE ···· [B] Reaction Scheme

<img file="HU0202708A2_D0009.tif" />

RONO / CuX2 _or_

NaNO2 / hP / CuX2 X = halogen (ia)

<img file="HU0202708A2_D0010.tif" />

COOR *

First reduction

Second oxidation

<img file="HU0202708A2_D0011.tif" />

<img file="HU0202708A2_D0012.tif" />

<img file="HU0202708A2_D0013.tif" />

Scheme [B] illustrates a general procedure for the preparation of compounds of formula Ib, that is, compounds of formula I wherein Z is a vinylene group (-CH = CH-) and X¹· And X together form an oxo group. As shown in Scheme [B], a 2-halo compound of formula (vi) can be prepared by reacting a 2-amino compound of formula (ia) with a microsphere. in an aprotic solvent, such as acetonitrile, with copper (II) halide and an alkyl nitrite, such as tert-butyl nitrite, to give the 2-halo compound (iv). Chem., 22, 1621 (1985). The compound of formula (iv) may be reduced to an alcohol with a reducing agent, such as ethanol or aqueous tetrahydrofuran (1-), and then oxidized with an oxidizing agent, such as pyridinium chlorochromate or pyridinium dichromate, to give (v). can be oxidized to an aldehyde of formula. The compound of formula (v) is then reacted with alkyl triphenylphosphorylidene acetate to form a carboxylate of formula (vi). The compound of formula (vi) is saponified using methods known to those skilled in the art and then reacted with an amine of formula (iii) to give the compound of formula (vii). Reaction of the compound of formula (vii) with an amine of formula R'R'NH gives a compound of formula (Ib) in which 1 '2

Z is X and X together form an oxo group. Alternatively, compounds of formula (Ib) wherein R and R are hydrogen may be prepared by reacting a compound of formula (vii) with an appropriately substituted benzylamine, such as (4-methoxybenzyl) amine, and The compound of formula (ix) thus obtained is hydrogenated or acidified, for example, in the presence of anisole, by reaction with trifluoromethanesulfonic acid and trifluoroacetic acid to form a compound of formula Ib wherein R and R are hydrogen.

73.196 / BE • ·· · ··

Schemes for the preparation of preferred substituents on compounds of formula I are illustrated in Schemes I to XI.

<img file="HU0202708A2_D0014.tif" />

R1

<img file="HU0202708A2_D0015.tif" />

COOR *

First saponification

Second R15 | _í

R6O

<img file="HU0202708A2_D0016.tif" />

First Ph3P = CHCOOR *

-&gt;.

Second deprotection

<img file="HU0202708A2_D0017.tif" />

<img file="HU0202708A2_D0018.tif" />

<img file="HU0202708A2_D0019.tif" />

(xiii) when R2 and / or R3 is H

Scheme [C] illustrates a general procedure for (Ic)

For the preparation of compounds of formula I, wherein Z is -R¹⁵C = CH- and X¹ and X² together form an oxo group. As shown in Scheme [C], a 2-amino compound of formula (ia) is reacted with a chloroformate or dicarbonate to produce a compound of formula (x), which is then saponified and then reacted with an organolithium reagent. can be converted to a compound of formula (xi). The compound of formula (xi) is converted to the compound of formula (xii) by reaction with an alkyl (triphenylphosphorylidene) acetate and subsequent removal of the carbamate protecting groups. Alternatively, the compounds of formula (Ic) wherein R and R are hydrogen may be prepared by saponification of a compound of formula (xii) followed by the reaction of a compound of formula (I) known to those skilled in the art.⁴R⁵Reaction with an amine of formula NH. Alternatively, the compound of formula (xii) is reacted (e.g., in equimolar amounts) with a compound of formula PuL wherein L is a leaving group, such as halogen, and optionally (e.g., equimolar) with a compound of formula RL. The compound of formula (xiii) thus obtained is then saponified and then, by methods known to those skilled in the art,⁴R⁵Reaction with an amine of formula NH gives a compound of formula Ia wherein R and / or R is other than hydrogen.

73.196 / BE • ·

Processes for the preparation of preferred substituents on compounds of formula I are described in Sections I-XI.

are shown in the following Schemes.

Scheme [D]

<img file="HU0202708A2_D0020.tif" />

Scheme [D] illustrates a general procedure for the preparation of compounds of formula (Id), that is, compounds of formula (I) which have X and X taken together to form a dioxo group. Compounds of formula (Ia) obtained in Scheme [A] can be converted to the corresponding thioamides of formula (Id), such as the Lawesson reagent, i.e. 2,4-bis (4-methoxyphenyl) -1 , 3-Dithia-2,4-diphosphetane-2,4-disulfide [see Bull. Soc.

Chim. Belg., 87, 223 (1978)].

Processes for the preparation of preferred substituents on compounds of formula I are described in Sections I-XI.

are shown in the following Schemes.

Scheme [E]

<img file="HU0202708A2_D0021.tif" />

73.196 / BE • · · ·

Scheme [E] illustrates a general procedure for the preparation of compounds of formula (le), i.e. compounds of formula (I) wherein X and X are each hydrogen. As shown in Scheme [E], the compounds of formula (Id) obtained in Scheme [D] can be converted to the corresponding amines of formula (Le) by reduction, for example in the presence of Raney nickel.

Processes for the preparation of preferred substituents on compounds of formula I are described in Sections I-XI.

are shown in the following Schemes.

73.196 / BE • *

i. Scheme

<img file="HU0202708A2_D0022.tif" />

COOR *

COOH (A) peptide bond synthesis, i

N

Synthesis of H (III) or (B) via acid chloride, i.e. (1) sulfinyl chloride or oxalyl dichloride

<img file="HU0202708A2_D0023.tif" />

(If)

R3 = C00R6 X1, X2 = O starting from (2);

R2 = alkyl, arylalkyl or cycloalkylalkyl starting from (3); R2 = H

73.196 / BE »· · ·

As shown in Scheme I, a carboxylate of formula (i) can be reacted with a chloroformate or a dicarbonate to produce a compound of formula (I). The compound of formula (1) is treated with a base such as sodium hydride, sodium / potassium hexamethyldisilazide or lithium diisopropylamide (LDA) and an R²Reaction with an alkylating agent X (X is halogen, and R is preferably alkyl, aralkyl or cycloalkylalkyl) and then saponified with an aqueous base such as aqueous potassium hydroxide to give 2. Alternatively, reductive amination of the compound of formula (1) with the appropriate aldehyde or ketone followed by saponification with an aqueous base, such as an aqueous potassium hydroxide solution, affords the compound of formula (2). Alternatively, simple saponification of the compound of formula (1) with an aqueous base, such as aqueous potassium hydroxide, yields a compound of formula (3) wherein R is hydrogen.

The acid of Formula 2 is well known in the art of peptide bond synthesis (see, e.g., Bodanszky and Bodansky, The Practice of Peptide Chemistry, Springer-Verlag (1984); Reaction of Bodanszky, Principles of Peptide Synthesis, Springer-Verlag (1984)] with an amine of formula (iii) to give a compound of formula (Id), wherein X and X together form an oxo group , R³ represents -COOR⁶ and since a compound of general formula (2) is a starting material, R is preferably an alkyl, aralkyl or cycloalkylalkyl group. For the reaction with the amine of formula (arc), the carboxy group of the compound of formula (2) 73.19S / BE ··· · · · ··· · ··· is activated, among other things, by the following reagents: bis (2-oxo-3-oxazolidinyl) phosphinic acid chloride (BOP chloride), [(1-benzotriazolyloxy) tris (dimethylamino) phosphonium] hexafluorophosphate (BOP reagent), [ O- (7-aza-1-benzotriazolyl) -1,1,3,3-tetramethyluronium] - hexafluorophosphate (HATU) as well as carbodiimides such as 1,3-dicyclohexylcarbodiimide or 1- [3 - (dimethylamino) propyl] -3-ethylcarbodiimide hydrochloride (EDCI), alone or in combination with 1-hydroxybenzotriazole. Alternatively, the activated ester intermediate may be isolated and then in a non-protic solvent such as tetrahydrofuran or N, N-dimethylformamide, a base such as an organic base such as sodium / potassium (hexamethyldisilazide), triethylamine, N, W. diisopropylethylamine or 1,8-diazabicyclo [5.4.0] undec-7-ene, or an inorganic base such as sodium, potassium or cesium carbonate, or in the presence of sodium or potassium hydride, with the corresponding amine of formula (iv). Alternatively, the acid chloride of the compound of formula (2) may be prepared, for example, by reacting the starting compound with sulfinyl chloride or oxalyl dichloride. The acid chloride is then reacted with an amine of formula (iii) to give a compound of formula (If), i.e. a compound of formula (I) wherein R is -COOR, X and X together form an oxo group, and R² is alkyl, aralkyl or cycloalkylalkyl.

Similar to the reactions used to convert compounds of formula (2) to compounds of formula (If), compounds of formula (3) can be prepared from compounds of formula (3) wherein R is -COOR, X and XO are oxo. 196 / BE «• • · n n n n n n n ez ez ez ez ez ez ez ez ez kép ez ez ez kép ez ez ez kép kép kép ez kép ez ez ez ezez ez^z is hydrogen.

Scheme II

<img file="HU0202708A2_D0024.tif" />

COOH reduction

<img file="HU0202708A2_D0025.tif" />

CHO (5)

<img file="HU0202708A2_D0026.tif" />

X | X₂ = H R2, r3 h

II. in Scheme 4, an acid of Formula 4 wherein R and R are hydrogen and nitrogen to which R and R are attached are of a non-basic nature by methods well known in the art. See, e.g., March, Advanced Organic Chemistry, Wiley. (1985)] is reduced to an aldehyde of formula (5). For example, the acid of formula (4) is converted to the corresponding ester and the ester is reduced with diisobutylaluminum hydride. Alternatively, the acid of Formula 4 is reduced to the corresponding primary alcohol by, for example, borane / tetrahydrofuran complex, lithium aluminum hydride or mixed anhydride reduction, and then the primary alcohol is Cr (VI) [e.g., pyridinium chlorochromate (PCC) ], in the Swern or Moffatt conditions (e.g., oxalyl dichloride / dimethyl sulfoxide) as described in general formula (5). is oxidized to the aldehyde of formula. The starting acids of formula (4) may be prepared, for example, by saponification of the compounds of formula (ii).

The aldehyde (5) may be combined with an amine (iii) in the presence of a reducing agent such as sodium cyano trihydroborate (1-), sodium triacetoxyborohydroborate (1-) or palladium catalyst and hydrogen. reductive amination [see Hudlicky, Reductions in Organic Chemistry, Wiley (1984)] gives a compound of formula (Ig), that is, a compound of general formula (I) wherein X and X 2 3 are each hydrogen and R and R are each other than hydrogen.

ni. Scheme

<img file="HU0202708A2_D0027.tif" />

Rö (Ih)

X1, X2 = H R2, R3 / H

In III. the acid of formula (4)

For example, borane / tetrahydrofuran complex, lithium aluminum hydride or mixed anhydride reduction is reduced to a primary alcohol and then the primary alcohol is well known in the art. March, Advanced Organic Chemistry, Wiley (1985)] is converted to a compound of Formula 6 which contains a leaving group such as a halogen atom, a tosyloxy (OTs), a mesyloxy (OMs) or a triflate group. (OTf) The groups R and R are chosen so that the nitrogen atom to which R and R are attached is non-basic. The compound of formula (6) can then be converted into a compound of formula (Ih), i.e., a compound of formula (I) having X and X in the form of a compound of general formula (I) by substitution reaction with a preferred excess of amine (III). each is hydrogen and R and R are each other than hydrogen.

arc. Scheme

R2 = any given group

R3 = acyl or thioacyl

Amides / Thioamides

<img file="HU0202708A2_D0028.tif" />

<img file="HU0202708A2_D0029.tif" />

(X = halogen) χ1 Y2

<img file="HU0202708A2_D0030.tif" />

R4 (1j) A = O (p.) A = S

73 196 / BE

.... · ···· • ·· ····

<img file="HU0202708A2_D0031.tif" />

X (Χ2

X

L Ν R5

<img file="HU0202708A2_D0032.tif" />

Χ {Χ2 / R⁴

Ζ Ν

Urea / Thiourea

<img file="HU0202708A2_D0033.tif" />

<img file="HU0202708A2_D0034.tif" />

RbNCS (13b) [X1, X2 ^ H]

The IV. Scheme I illustrates methods which can be used to prepare compounds of formula (Ij), (Ik), (II), (1m) and (In). Derivatives of formula (Ij), (Ik), (II), (lm) and (In) are compounds of formula (I) wherein R is as defined above, R is acyl or thioacyl, X and X are other than hydrogen, and R¹ denotes a primary or secondary amine. Further individual substituents for the compounds of formula (Ij), (Ik), (II), (lm) and (In) are outlined in the Scheme and described below. The starting compounds of formula (II) may be prepared by any of the appropriate methods described in Schemes [A] to [D].

The amides of formula (Ij) may be prepared by:

An amine of formula Ii as described above, which activates the carboxy group for amide formation, such as BOP reagent, HATU, carbodiimides such as DCC or optionally.

In the presence of EDCI combined with 1-hydroxybenzotriazole, it is reacted with an acid of formula (Ί). Alternatively, in the presence of an acid acceptor such as N, N-diisopropylethylamine, an acid halide of formula (8) is reacted with an amine of formula (II). The corresponding thioamides of formula (Ik) may be prepared by reacting an amide of formula (Ij) (wherein X and X do not form an oxo group) with Lawesson's reagent as described above.

The carbamates of formula (II) may be prepared by reacting an amine of formula (II) with an acid acceptor such as N, 2N-diisopropylethylamine with chloroformate (9) or a dicarbonate (10). with.

The ureas of formula (1m) may be prepared by reacting an amine of formula (II) with: (1) a chloroformate of formula (9), such as phenyl chloroformate, and then a compound of formula (11): reacting with an amine; 2) reacting with an acid acceptor such as N, N-diisopropylethylamine with a carbamoyl chloride 12; or 3) reacting with an isocyanate of formula 13a [R^c is hydrogen). The corresponding thioureas of formula (In) may be prepared by reacting an amine of formula (II) with an isothiocyanate of formula (13b).

6

The R substituent is selected from the group consisting of R, for example, -C (= A) -R^the is a compound of formula R³ an acyl or thioacyl group as defined in b. R and R

8 the substituent is selected from the group consisting of R and R, for example 3 -C (= A) -N (R) (R) is an acyl or thioacyl group in the meaning of R.

Scheme V

R2 = any specified group other than acyl

R3 = alkyl, cycloalkyl, cycloalkylalkyl, cycloalkenylalkyl, aralkyl or saturated heterocycle

<img file="HU0202708A2_D0035.tif" />

<img file="HU0202708A2_D0036.tif" />

<img file="HU0202708A2_D0037.tif" />

χ1 χ2

X

ZN R5

Or RONO / CUX2

NaNO2 / H® / CuX2 X = halogen

Λ / Λ ^Χ1 ^χ2 (15)

Rd R 2) -N (16)

Re H

<img file="HU0202708A2_D0038.tif" />

[χ1, ​​χ2 AH] base

The V. Scheme II illustrates a process for the preparation of compounds of formula (Ip) wherein R is a substituent of 2 acyl as defined above and R the nitrogen atom to which it is attached is chosen to be basic, R is alkyl, cycloalkyl, cycloalkylalkyl, cycloalkenylalkyl, aralkyl or a saturated heterocyclic group, and X and X are hydrogen. The starting compounds of formula (Io) and (Iq) may be prepared by any of the appropriate methods described in Schemes [A] and [DJ].

In Scheme V, an amine of formula Io is reacted with an aldehyde or ketone of formula 14 under the reductive amination reaction conditions described above to produce an amine of formula Ip. The compounds of formula (Ip) may also be prepared by reacting an amine of formula (Iq) in which R and R are hydrogen with tert-butyl nitrite or sodium nitrite in the presence of a copper (II) halide. The halogen-substituted compound of formula (15) thus obtained is a base such as sodium or potassium hydride and the like. See Lee et al., J. Heterocyclic Chemistry, 22, 1621 (1985)] with an amine of formula (16).

R^d and R^e each independently is hydrogen, alkyl, aryl, cycloalkyl or cycloalkenyl, or R^d and R^e together form a 3 to 8 membered alkylene or alkenylene moiety resulting in a saturated or unsaturated ring; for example, -CH (R^d) (R^e) is one of the groups represented by R.

73.196 / BE • · ·

VI. Scheme

R2 = any specified group other than acyl R3 = alkyl, heteroaryl

<img file="HU0202708A2_D0039.tif" />

Ar-X (17)

Pd (X = Br)

-&gt;

<img file="HU0202708A2_D0040.tif" />

z 2 '

As shown in VI. wherein R is other than acyl as defined above and R is selected so that the nitrogen atom to which it is attached is basic, R is aryl or heteroaryl, and X is¹ and X² is an amine of formula (I) other than hydrogen in the presence of a palladium (0) catalyst (see J. Am. Chem. Soc., 118, 7215 (1996)) with an aryl halide of formula (17) or heteroaryl. by reacting with a halide to form a compound of formula (I), i.e., a compound of formula (I) having the specific substituents shown in the scheme.

The starting compounds of the formula (Irish) may be prepared by any of the appropriate methods described in Scheme [A] and [D].

73.196 / BE · »* ·« * · '··

VII. Scheme

R2 = any given group

R3 = heteroaryl

<img file="HU0202708A2_D0041.tif" />

ZZ 2

As shown in FIG. where R is any given group, and R is heteroaryl, an amine of formula (I) may be optionally substituted in the presence of a base with a 2-halo-heteroaromatic compound of formula (17)¹ together with the attached atoms to form a 5 or 6 membered monocyclic or 10-12 membered bicyclic heteroaromatic ring (e.g. 2-chloropyridine or 2-chloropyrimidine) - reacting an amine of formula Iu, i.e. A compound of formula (I) may be prepared which has the individual substituents indicated in the scheme. The starting compounds of formula (I) may be prepared by any of the appropriate methods described in Scheme [A] and [D].

73.196 / BE ····································································

<img file="HU0202708A2_D0042.tif" />

Vili. Scheme

R13NH2

<img file="HU0202708A2_D0043.tif" />

(In) (arc) [X1, X2 £ H]

As shown in FIG. schematically illustrates a thiourea having the general formula (In) wherein X and X are other than hydrogen in solvents such as N, N-dimethylformamide, methylene chloride or tetrahydrofuran, an organic base such as triethylamine, N, N-diisopropyl; ethylamine or 4- (dimethylamino) pyridine and bis (2-oxo-3-oxazolidinyl) phosphinic acid chloride (BOP chloride), [(1-benzotriazolyloxy) tris (dimethylamino) ) -phosphonium] - hexafluorophosphate (BOP reagent), [O- (7-Aza-1-benzotriazolyl) -1,1,3,3-tetramethyluronium] - (hexafluorophosphate) (HATU) and a carbodiimide such as 1,3-dicyclohexylcarbodiimide (DCC) or 1 - in the presence of [3- (dimethylamino) propyl] -3-ethylcarbodiimide (EDCI) or 1,3-diisopropylcarbodiimide (DIC) by reaction with the corresponding amine to form a compound of formula (I): ) having the substituents indicated in the scheme.

Alternatively, the compounds of formula (I) may be reacted with the appropriate amine in the presence of a mercury (II) salt, such as mercury (II) chloride, or by other methods known in the art. to produce the desired compounds of formula (arc).

73 196 / BE

IX. reaction scheme ···· »« ·

<img file="HU0202708A2_D0044.tif" />

Rx = -CO2-alkyl, CN, -CO2-aryl

<img file="HU0202708A2_D0045.tif" />

[χ1, ​​χ2 £ H]

IX. Scheme 1 shows an amine of formula (I) in 1 2 (wherein X and X are hydrogen) in acetonitrile, tetrahydrofuran or TV, N-dimethylformamide, at room temperature or higher, optionally with a base such as sodium hydride, sodium ( in the presence of hexamethyldisilazide) or 4- (dimethylamino) pyridine to form an intermediate of formula (Iw) with diphenyl cyanocarbonimidate. The compound of formula (Iw) can be reacted with an amine of formula R OH to produce a compound of formula (I), i.e., a compound of formula (I) having the substituents shown in the scheme.

73 196 / BE

Scheme X. · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ·

<img file="HU0202708A2_D0046.tif" />

(taste) (taste *) [X1, X2 £ h]

In Scheme X, an amine of the formula (wherein X and X are hydrogen) is in N, N-dimethylformamide or tetrahydrofuran at room temperature or higher, optionally with a base such as sodium hydride, sodium (hexamethyl) -disilazide) or 4- (dimethylamino) pyridine can be reacted with a compound of formula (18) or (19) to produce a compound of formula (Ix) or a compound of formula (Iy). Reaction of the compound of formula (Ix) or the compound of formula (Iy) at room temperature or higher with an amine of formula RR NH gives a compound of the formula (taste) and (taste *) respectively. A compound of the formula (Taste) is a compound of the formula (I) having the substituents indicated in the scheme. The compound of the formula (taste *) is a compound of the formula (I) having the substituents indicated in the scheme.

XI. Scheme

R2 = aryl, heteroaryl, bicyclic heteroaryl,

R3 = H, alkyl, aryl, heteroaryl, bicyclic heteroaryl

<img file="HU0202708A2_D0047.tif" />

As shown in FIG. Compounds of formula (I) may also be prepared by reacting a compound of formula (I) with an amine in the presence of an acid catalyst [see, e.g., Gunzenhauser

Chim. Acta, 71, 33 (1988)].

general image (15) general defined et al., Helv.

Application

The compounds of the invention inhibit protein tyrosine kinases, in particular Src family kinases such as Lek, A Fyn, Lyn, Src, Yes, Hck, Fgr and Blk, and thus the compounds. they can be used for the treatment, including prevention and treatment, of disorders related to protein tyrosine kinase, in particular immunological and oncological disorders. The compounds also inhibit receptor tyrosine kinases, such as HER1 and HER2, and are useful in the treatment of proliferative disorders such as psoriasis.

73 196 / BE

<img file="HU0202708A2_D0048.tif" />

»··· and cancer treatment. The ability of the compounds to inhibit HER1 and other receptor kinases provides an opportunity to use the compounds as anti-angiogenic agents in the treatment of disorders such as cancer and diabetic retinopathy. Protein tyrosine kinase-related disorders are disorders that are caused by abnormal tyrosine kinase activity and / or that can be advantageously affected by inhibiting one or more of said enzymes. For example, Lek inhibitors are effective in treating many of these disorders (e.g., autoimmune diseases) because Lek inhibition blocks cell activation. One particularly preferred embodiment of the invention relates to the treatment of T cell-mediated diseases, including inhibition of T cell activation and proliferation. Particularly preferred are compounds which selectively inhibit T cell activation and proliferation. Compounds of the invention that block oxidative stress-induced endothelial cell PTK activation, thereby limiting surface expression of adhesion molecules that cause neutrophil binding, and which inhibit PTK required for neutrophil activation, can be used, for example, to treat ischemia and reperfusion. .

Accordingly, one aspect of the invention relates to methods for treating disorders associated with protein tyrosine kinase comprising administering to a subject in need thereof an effective amount of at least one compound of formula (I). Other therapeutic agents may be used in the methods of the invention together with the compounds of the invention,

73.196 / BE, such as those described below. In the methods of the invention, the one or more other therapeutic agents may be administered before, after or simultaneously with the administration of one or more compounds of the invention.

For the treatment of disorders related to protein tyrosine kinase, the compounds of the present invention may be used, for example, to treat the following disorders: transplantation (e.g., organ transplantation, acute transplantation, or heterograft or homograft (e.g., in the treatment of burns)); protection against ischemic or reperfusion injury, such as organ transplantation, myocardial infarction, stroke or other causes due to stroke or other causes; transplant tolerance induction; arthritis (e.g. rheumatoid arthritis, psoriatic arthritis or osteoarthritis); multiple sclerosis; chronic obstructive pulmonary disease (COPD), such as emphysema; inflammatory bowel disease, including ulcerative colitis and Crohn's disease; lupus (systemic lupus erythematosis); graft versus hero disease; T-cell-mediated hypersensitivity disorders including contact hypersensitivity, delayed-type hypersensitivity, and gluten-sensitive enteropathy (coeliac disease); psoriasis; contact dermatitis (including contact dermatitis caused by poisonous poison); Hashimoto's thyroiditis; Sjogren's syndrome; autoimmune hyperchyroidism such as Graves' disease; Addison's disease (an autoimmune disease of the adrenal gland); autoimmune polyglandular disease (also known as autoimmune polyglandular syndrome); autoimmune alopecia; perniciosus anemia;

73.196 / BE • · · · vitiligo; autoimmune hypopituitarism; Guillain-Barre syndrome; other autoimmune diseases; cancers, including those in which Lek or other Src family kinases, such as Src activated or overexpressed, such as colon carcinoma and thymoma, and cancers in which Src family kinase activity promotes tumor growth; glomerulonephritis; serum sickness; uticaria; allergic diseases such as respiratory allergies (asthma, hay fever, allergic rhinitis) or skin allergies; scleracierma; myeosis fungoides; acute inflammatory responses (e.g., acute respiratory distress syndrome and / or ischemia / reperfusion injury); dermatomyositis; alopecia areata; chronic actinic dermatitis; eczema; Behcet's disease;

pustulosis palmoplanteris; pyoderma gangrenum; Sezary's syndrome; atopic dermatitis; systemic celerosis; and morphea. The invention further provides a method of treating the above-mentioned disorders, such as atopic dermatitis, comprising administering any compound capable of inhibiting protein tyrosine kinase.

Kinases of the Src family other than Lck, such as

Hck and Fgr, play important roles in the Fc-gamma receptor responses of monocytes and macrophages. The compounds of the invention inhibit TNF-alpha Fc-gamma-dependent production of THP-1 monocyte cell line, which does not express Lck. In addition to its effects on T cells, the ability to inhibit Fc-gamma receptor-dependent monocyte and macrophage responses provides the compounds of the invention with additional anti-inflammatory activity. This activity is particularly significant, for example, in the case of such an inflammation.

..........

in the treatment of inflammatory diseases such as arthritis and inflammatory bowel disease. In particular, the compounds of the invention are particularly useful in the treatment of autoimmune glomerulonephritis and other cases of glomerulonephritis induced by the deposition of immune complexes in the kidneys that elicit Fc-gamma receptor responses leading to renal impairment.

In addition, kinases other than Lck of the Src family, such as Lyn and Src, play important roles in mast cell (mastocytes) and basophils degranulation induced by the Fc-epilone receptor, which in turn plays an important role in asthma, allergic rhinitis and other allergic diseases. Fc-epsilon receptors are stimulated by IgE-antigen complexes. The compounds of the invention inhibit Fc-epsilon-induced degranulation responses in the RBL basophil cell line that does not express Lck. The ability to inhibit Fc-epsilon receptor-dependent mast cell and basophilic responses in addition to its effects on T cells provides the compounds of the invention with additional anti-inflammatory activity. This activity of the compounds of the invention is particularly significant in the treatment of, for example, asthma, allergic rhinitis and other examples of allergic diseases.

The combined activity of the compounds of the invention on monocytes, macrophages, T cells is very advantageous in the treatment of the abovementioned disorders.

In one embodiment of the invention, the compounds of the present invention, regardless of their etiology, may be used in the treatment of the disorders exemplified above.

such as treating the following disorders, whether or not they are related to PTK: graft rheumatoid arthritis, rheumatoid arthritis, multiple sclerosis, chronic obstructive pulmonary disease, inflammatory bowel disease, lupus, graft versus febrile disease, T cell-mediated hypersensitivity disease, psoriasis, Hashimoto's thyroiditis, rheumatoid dermatitis, Guillain's dermatitis, for example allergic rhinitis, asthma, ischemic or reperfusion injury, or atopic dermatitis.

Due to their ability to inhibit HER1 and HER2 kinase, the compounds of the invention may also be used in the treatment of proliferative diseases including psoriasis and cancer.

HER1 receptor kinase has previously been shown to be expressed and activated in a number of solid tumors, including non-small cell lung cancer, colorectal cancer and breast cancer. Similarly, HER2 receptor kinase was found to be overexpressed in breast, ovarian, lung and gastric cancer. Monoclonal antibodies that downregulate excess HER2 receptor or inhibit HER1 receptor signaling have been shown to have potent antitumor activity in preclinical and clinical studies. Based on this, it is expected that inhibitors of HER1 and HER2 kinase will be effective in treating tumors that are dependent on the signaling of one of the two receptors. The compounds are expected to be used alone or in combination with other chemotherapeutic agents such as paclitaxel (Taxol), doxorubicin hydrochloride (adriamycin) and cisplatin (Platinol).

73.196 / BE a * · · ···· »w» - • · · · *. ·: ♦ ·,. · ···. ...........

will be effective [see, for example, the following documents and references therein: Cobleigh, MA, Vogel, CL,

Tripathy, D., Róbert, N.J., Scholl, S., Fehrenbacher, L., Wolter, J.M., Paton, V., Shak, S., Lieberman, G., and Slamon, D.

J., J. of Clin. Oncol., 17 (9): 2639-2648 (1999); Baselga, J.,

Pfister, D., Cooper, MR, Cohen, R., Burtness, B., Bős, M.,

D'Andrea, G., Seidman, A., Norton, L., Gunnett, K., Falcey, J.,

Anderson, V., Waksal, H., and Mendelsohn, J., J. Clin. Oncol., 18 (4), 904-914 (2000)].

The present invention also provides pharmaceutical compositions comprising a pharmaceutically acceptable carrier or diluent and an effective amount of at least one compound of formula (I) for the treatment of protein tyrosine kinase disorders. The compositions of the invention may also contain other therapeutic agents, such as those described below. The pharmaceutical compositions of the invention may be formulated according to methods well known in the art of formulation, for example, using conventional solid or liquid vehicles or diluents, and pharmaceutical additives (e.g., carriers, excipients, preservatives, stabilizers, flavors, etc.) suitable for the desired mode of administration.

The compounds of formula (I) in non-toxic pharmaceutically acceptable carriers or diluents may be administered by any suitable route, such as tablets, capsules, granules or powders; sublingually; buccal; parenterally, for example, by subcutaneous, intravenous, intramuscular or intrastar injection or infusion (e.g., in the form of sterile injectable aqueous or non-aqueous solutions or suspensions); nasally, for example in the form of an inhalation spray; topically, for example in the form of creams or ointments; or rectally, for example in the form of suppositories. The compounds of the invention may also be administered in forms suitable for immediate or sustained release. Immediate or sustained release can be achieved by the use of suitable pharmaceutical compositions containing the compounds of the invention, or, in particular, by the use of devices such as subcutaneous implants or osmotic pumps for sustained release. The compounds of the invention may also be administered liposomal.

Examples of compositions for oral administration include suspensions which may contain, for example, microcrystalline cellulose for weight formulation, alginic or sodium alginate suspending agents, methylcellulose for viscosity enhancers, and sweetening and flavoring agents known in the art; and immediate release tablets, which may contain, for example, microcrystalline cellulose, dicalcium phosphate, starch, magnesium stearate and / or lactose and / or other excipients, binders, extenders, disintegrants, diluents and lubricants known in the art. The compounds of the invention may also be administered via the oral cavity by sublingual and / or buccal administration. For this purpose, for example, fused

Tablets, compressed tablets or freeze-dried (lyophilized) tablets may be used. Examples of compositions include formulations containing the compound (s) of the invention formulated with rapidly dissolving diluents such as mannitol, lactose, sucrose and / or cyclodextrins. The compositions may also contain high molecular weight carriers such as celluloses (avicel) or polyethylene glycols (PEG). The formulations also include mucoadhesive carriers, such as hydroxypropylcellulose (HPC), hydroxypropylmethylcellulose (HPMC), sodium carboxymethylcellulose, maleic anhydride copolymer (e.g. ) and controlled release agents, such as polyacrylic copolymers (e.g. Carbopol 934). Lubricants, glidants, flavors, colorants and stabilizers may also be added to the compositions for ease of preparation and use.

Compositions suitable for nasal aerosol or inhalation administration include, for example, saline solutions containing, for example, benzyl alcohol or other preservatives, absorption enhancers to enhance bioavailability, and / or solubilizing or dispersing agents known in the art.

Formulations suitable for parenteral administration include, for example, injectable solutions or suspensions, for example, in the form of suitable non-toxic parenterally acceptable diluents or solvents, such as mannitol, 1,3-butanediol, water, Ringer's solution, isotonic sodium chloride solution or other suitable dispersions. 196 / BE may contain gelling or wetting or suspending agents, including synthetic mono- or diglycerides, and fatty acids, including oleic acid.

Examples of compositions for rectal administration include suppositories that may contain, for example, non-irritating excipients, such as cocoa butter, synthetic glycerides, or polyethylene glycols, which are solid at ambient temperature but will liquid or dissolve in the rectal cavity to release the active ingredient.

Compositions for topical application contain a topical carrier such as Plastibase (a mineral oil gelled with polyethylene).

One skilled in the art can determine the effective amount of a compound of the invention. For example, an effective dosage amount of the active ingredient in an adult human is about 0.1 to about 100 mg / kg body weight, which may be administered in a single dose or in divided doses, for example, 1 to 4 times daily. It will be appreciated that the individual dose amount and the frequency of administration may be varied for individual subjects, since their values ​​are affected by various factors such as, for example: activity of the particular active ingredient used, metabolic stability and duration of action of the compound, species, age, weight, general health, sex and nutrition of the subject, mode and time of administration, rate of excipient combination composition and severity of the particular condition . For the treatment of disorders related to protein tyrosine kinase

Animal subjects, preferably mammalian species such as man, and domesticated animals such as dogs, cats, etc. are preferred subjects.

The compounds of the present invention may be used alone or in combination and / or in combination with other suitable therapeutic agents useful in the treatment of protein tyrosine kinase-related disorders such as, for example, other PTK inhibitors other than the compounds of the invention, anti-inflammatory agents. , antiproliferative agents, chemotherapeutic agents, immunosuppressants, anticancer agents and cytotoxic agents.

Examples of such other therapeutic agents include, but are not limited to, cyclosporins (e.g., cyclosporin A), CTLA4-Ig, antibodies such as anti-ICAM-3, anti-IL-2 receptor (Anti-Tac), anti-CD45R. , B, anti-CD2, anti-CD3 (OKT-3), anti-CD4, anti-CD80, anti-CD86, OKT3 monoclonal antibody, a

Agents that block the interaction between CD40 and gp39, e.g.

CD40 and / or gp39 specific antibodies (e.g., CD154), fusion proteins constructed from CD40 and gp39 (CD40Ig and CD8gp39);

inhibitors of NF-kappa B function such as nuclear translocation inhibitors such as deoxyspergualin (DSG), non-steroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen, steroids such as prednisone or dexamethasone, gold compounds, antiproliferative drugs such as methotrexate , Prograf), mycophenolate mofetil, cytotoxic agents such as azatiprine and cyclophosphamide, TNF-α inhibitors such as

Tenidap, anti-TNF antibodies or soluble TNF receptors such as etanercept (Enbrel), rapamycin (sirolimus or Rapamune), leflunimide (Arava), and cyclooxygenase-2 (COX-2) inhibitors such as celecoxib ( Celebrex) and rofecoxib (Vioxx) and their derivatives and the PTK inhibitors disclosed in the following U.S. Patents: U.S. Pat.

Serial No. 60 / 056,770 filed August 25, Serial No. 60 / 069,159 filed December 9, 1997, June 1998

Serial No. 09 / 097,338, filed May 15, Serial No. 60 / 056,797, filed August 25, 1997, Serial No. 09 / 094,797, filed June 15, 1998, Serial No. 60 / 065,042, filed November 10, 1997, October 1998 U.S. Patent Application Serial Nos 09 / 173,413, filed March 15, U.S. Patent Application Serial No. 60,076,789, filed March 4, 1998, and Serial No. 09,262,525, filed March 4, 1999. See also Hollenbaugh,

D., Douthwright, J., McDonald, V., and Aruffo, A., J. Immunol.

Methods (Netherlands), 188 (1), 1-7 (1995); Hollenbaugh, D.,

Grosmaire, LS, Kullas, CD, Chalupny, NJ, Braesch-Andersen,

S., Noelle, RJ, Stamenkovic, L., Ledbetter, JA, and Aruffo,

A., EMBO J. (England), 11 (12), 4313-4321 (1992); and Moreland, L.

W. et al., New England J. of Medicine, 337 (3), 141-147 (1997).

Examples of anticancer and cytotoxic agents include, but are not limited to, alkylating agents, such as nitrogen mustards, alkyl sulfonates, nitrosoureas, ethyleneimines, and triazenes; antimetabolites such as folate antagonists, purine analogs and pyrimidine analogs; antibiotics such as antra73.196 / BE • cyclins, bleomycins, mitomycin, dactinomycin and plicamycin;

enzymes such as L-asparaginase; farnesyl protein transferase inhibitors; hormonal agents such as glucocorticoids, estrogens / antiestrogens, androgens / antiandrogens, progestins, and luteinising hormone releasing hormone antagonists, octreotide acetate; microtubule disruptors, such as ecteinascidins or their analogs and derivatives; microtubule stabilizers such as paclitaxel (Taxol), docetaxel (Taxotere), and epothilones AF or their analogs and derivatives; plant products such as vinca alkaloids, epipodophyllotoxins, taxanes; and topoisomerase inhibitors; prenyl protein transferase inhibitors; and various agents such as hydroxyurea, procarbazine, mitotane, hexamethylmelamine, platinum coordination complexes such as cisplatin and carboplatin; and other agents used as anticancer and cytotoxic agents, such as biological response modifiers, growth factors; immunomodulators and monoclonal antibodies. The compounds of the invention may also be used in combination with radiotherapy.

Representative examples of anticancer and cytotoxic agents include, but are not limited to: mechlorethamine hydrochloride, cyclophosphamide, chlorambucil, melphalan, ifosfamide, busulfan, carmustine, lomustine, semustine, streptozocin, thiotepa, dacarbazine, methotrexate, thioguanine, mercaptopurine, fludarabine, pentastatin, cladribin, cladribin in, bleomycin - sulfate, mitomycin C, actinomycin D, safracins, saframycins, quinocarcinols, discodermolides, vincristine, vinblastine,

73.196 / BE ··· · vinorelbine-tartrate, etoposide, teniposide, paclitaxel, tamoxifen, estramustine, estramustine-phosphate sodium, flutamide, buserelin, leuprolide, pteridines, diineses, interleukin, aflakone, afla filgrastim, sargramostim, rituximab, BCG, tretinoin, irinotecan hydrochloride, betamethasone, gemcitabine hydrochloride, altretamine and topoteca, and analogues and derivatives thereof.

Preferred members of the above classes include, but are not limited to, the following: paclitaxel, cisplatin, carboplatin, doxorubicin, carminomycin, daunorubicin, aminopterin, methotrexate, metopterin, mitomycin C, ecteinascidin 743, porphyromycin, 5 -purin, gemcitabine, cytosine arabinoside, podophyllotoxin or podophyllotoxin derivatives such as etoposide, etoposide phosphate or teniposide, melphalan, vinblastine, vincristine, leurosidine, vindesine and leurosin.

Examples of anticancer and cytotoxic agents include, but are not limited to, the epothilone derivatives disclosed in U.S. Patent Application Serial No. 09 / 506,481 filed February 17, 2000; Federal Republic of Germany Patent No. 4138042.8

<td colspan="2">Dalmatian description</td><td rowspan="2">; WO WO</td><td colspan="3">&gt; 97/19086, WO 98/22461,</td><td rowspan="2">WO WO</td><td colspan="2">98/25929, WO</td><td rowspan="2"> 98/38192, 99/07692,</td>

<td>WO</td><td> 99/01124,</td><td> 99/02224,</td><td>WO</td><td> 99/02514,</td><td> 99/03848</td><td>, WO</td>

<td>WO</td><td> 99/27890,</td><td>WO</td><td> 99/28324,</td><td>WO</td><td> 99/43653,</td><td>WO</td><td> 99/54330</td><td>, WO</td><td> 99/54318,</td>

<td>WO</td><td> 99/54319,</td><td>WO</td><td> 99/65913,</td><td>WO</td><td colspan="3">99/67252, WO 99/67253,</td><td>and WO</td><td> 00/00485</td>

International Patent Application Publication Nos. cyclin-dependent kinase inhibitors disclosed in WO 99/24416; and WO 97/30992 and WO 98/54966

Prenyl protein transferase inhibitors disclosed in International Patent Application Publication No. 73.196 / BE · · ···.

When used in combination with the compounds of the present invention, the aforesaid compounds may be administered in amounts indicated, for example, in the Physicians' Desk Reference (PDR) or otherwise as determined by one skilled in the art.

The following assays determine the extent to which a compound ("test compound") acts as a PTK inhibitor. The compounds described in the Preparation Examples were tested in one or more assays where they exhibited PTK inhibitory activity.

Enzyme assay using Lek, Fyn, Lyn, Hck, Fgr, Src, Blk or Yes

The following assay was performed using the Lek, Fyn, Lyn, Hck, Fgr, Src, Blk, and Yes protein tyrosine kinases.

The given protein tyrosine kinase was incubated in the presence of the test compound in kinase buffer (20 mM MOPS, pH 7, 10 mM MgCl 2). The reaction was performed with substrates of 1 μΜ, 3.3 gCi / ml [ ³³P] gamma-ATP and 0.1 mg / ml acid denatured enolase [see Cooper, J.

A., Esch, FS, Taylor, SS, and Hunter, T., J. Biol. Chem.,

259, 7835-7841 (1984)] to the final concentration. Ten minutes later, the reaction was quenched by the addition of 10% trifluoroacetic acid, 100 mM sodium pyrophosphate, followed by 2 mg / ml bovine serum albumin. The labeled enolase protein substrate precipitates at 4 ° C on Packard Unifilter plates.

73.196 / BE • · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · kinase inhibitory activity was determined by counting on a Topcount scintillation counter (activity inversely proportional to the amount of labeled enolase protein recovered). The exact concentration of reagents and the amount indicated may be varied as desired.

The assay is advantageous because, on the one hand, it uses an exogenous substrate (enolase) that results in more accurate enzyme kinetics, and, on the other hand, it can be carried out in easily automated 96-well forms.

In addition, His-tagged protein tyrosine kinases (described below) provide significantly higher yields and purity than the GST protein tyrosine kinase fusion protein.

Protein tyrosine kinase may be obtained from commercial sources or may be prepared by recombinant methods as described below. Life is used to produce recombinant Lek

By using Technologies (Gibco) pFastBac Hta baculovirus vector (commercial product) in human cells, His L-fusion protein was produced as His-tagged fusion protein. A human

The cDNA isolated by PCR (polymerase chain reaction) encoding Lck was inserted into the vector and expressed using the methods described by the manufacturer. Lck was purified by affinity chromatography. For more information on producing Lek using baculovirus in insect cells, see, for example:

Spana, C., O'Rourke, EC, Bolén, J.B., and Fargnoli, J., Protein Expression and Purification, Vol. 4, 390-397 (1993). Similar methods may be used to recombinantly produce other Src family kinases.

73.196 / BE · »··

Enzyme assay using HER1 or HER2

The compounds were tested in a kinase buffer containing 20 mM Tris-HCl, pH 7.5, 10 mM MnCl 2, 0.5 mM dithiothreitol, 0.1 mg / ml bovine serum albumin, 0.1 mg / ml poly ( glu / tyr, 4: 1), 1 μΜ ATP, and 4 μΟί / πιΙ [gamma-³³P] -ATP. Poly (glu / tyr, 4: 1), available from Sigma Chemicals, is a synthetic polymer that functions as a phosphoryl acceptor. The kinase reaction is initiated by the addition of the enzyme and the reaction mixture is incubated for one hour at 26 ° C. The reaction is stopped by the addition of EDTA to a concentration of 50 mM and the proteins precipitated by the addition of trifluoroacetic acid to a concentration of 5%. The precipitated proteins were filtered on Packard Unifilter plates and the amount of radioactivity incorporated was measured with a Topcount scintillation counter.

To produce recombinant HER1, the cytoplasmic sequence of the receptor was expressed in insect cells as a GST fusion protein, and the GST fusion protein was purified by affinity chromatography as described above for Lek. The cytoplasmic sequence of HER2 was subcloned into the baculovirus expression vector pBlueBac4 (Invitrogen) and expressed as an unlabeled protein in insect cells. The recombinant protein was partially purified by ion exchange chromatography.

Cell assay (1) Cellular tyrosine phosphorylation

Jurkat T cells are incubated with the test compound and the cells are stimulated with CD3 antibody (monoclonal antibody G19-4). Cells are lysed by addition of lysis buffer containing NP-40 detergent for 4 minutes at a later time or other desired time. Protein phosphorylation is detected by anti-phosphotyrosine immunoblotting. Phosphorylation of particular proteins such as ZAP-70 is detected by immunoprecipitation with anti-ZAP-70 antibody followed by anti-phosphotyrosine immunoblotting. Such procedures are described, for example, in Schieven, GL,

Mittler, RS, Nadler, SG, Kirihara, JM, Bolen, JB,

Kanner, SB, and Ledbetter, JA, J. Biol. Chem., 269, 2071820726 (1994). Lek inhibitors inhibit tyrosine phosphorylation of cellular proteins induced by anti-CD-3 antibodies.

For example, the preparation of G19-4 monoclonal antibody is described in Hansen, JA, Martin, PJ, Beatty, P.

G., Clark, EA, and Ledbetter, JA, Leukocyte Typing I, A.

Bemard, J. Boumsell, J. Dausett, C. Milstein, and S. Sklossman, eds. (New York: Springer Verlag), 195-212 (1984); and Ledbetter, JA, June, CH, Rabinovitch, PS, Grossman, A., Tsu, T.

T., and Imboden, JB, Eur. J. Immunol., 18, 525 (1988).

(2) Calcium test

Lek inhibitors block calcium mobilization in T cells stimulated with anti-CD3 antibodies. Cells are loaded with indo-1 calcium indicator dye, reacted with anti-CD3 antibody, such as monoclonal antibody G19-4, and monitored by flow cytometry for changes in blue / violet indo-1 ratio according to known methods [Schieven, GL, Mittler, RS .

Nadler, SG, Kirihara, JM, Bólén, JB, Kanner, SB, and

Ledbetter, JA, J. Biol. Chem., 269, 20718-20726 (1994)]

73.196 / BE • · · ···· calcium mobilization.

(3) Proliferation assay

Lek inhibitors inhibit the proliferation of normal human peripheral blood T cells for growth stimulated with anti-CD3 + anti-CD28 antibody. A 96-well plate is covered with a CD3 monoclonal antibody (e.g., G19-4 monoclonal antibody), the antibody is allowed to bind, and the plate is washed. The plate-bound antibody stimulates the cells. Normal human peripheral blood T cells are added to the wells with the test compound and anti-CD28 antibody to ensure co-stimulation. After the desired time (e.g., 3 days), [H] -thymidine is added to the cells, and after further incubation to allow incorporation of the label into the newly synthesized DNA, the cells are harvested and counted in a scintillation counter to measure cell proliferation.

The following examples serve to illustrate the present invention. The examples do not limit the scope or scope of the invention. Below is the meaning of the abbreviations used in the examples. The compounds of the Examples are identified by the Example and the step by which the compounds are prepared (e.g., "Compound 1A is Example 1A. or where the compound is the title compound of that example, the compound is identified only by the number of the example (e.g., "Compound 2 is the title compound of Example 2).

Abbreviations used in this description

DMSO = dimethyl sulfoxide

EtOAc = ethyl acetate

Et2O = diethyl ether

73 196 / BE

HATU = [0- (7-aza-1-benzotriazolyl) -1,1,3,3-tetramethyluronium] - (hexafluorophosphate)

MeOH = methanol

MOPS = 3-morpholinopropanesulfonic acid

MS = mass spectrometry

Rt = retention time

TFA = trifluoroacetic acid

THF = tetrahydrofuran

DMF = N, N-dimethylformamide

First example

Preparation of O-tert-Butyl N- [5 - {[(2,4,6-trimethylphenyl) amino] carbonyl} -4-methyl-2-thiazolyl] carbamate

<img file="HU0202708A2_D0049.tif" />

A. Ethyl 2 - {[(tert-butoxycarbonyl) oxy] amino} -4-methyl-5-thiazolecarboxylate

18.6 g (100 mmol) of ethyl 2-amino-4-methyl-5-thiazolecarboxylate, 26.2 g (120 mmol) of dl-tert-butyl dicarbonate, 800 mg (6.55 mmol)

A suspension of 4- (dimethylamino) pyridine and 300 ml of anhydrous tetrahydrofuran was stirred under nitrogen for 18 hours. The solvent was evaporated in vacuo and the residue was suspended in CH 2 Cl 2 and filtered through a pad of Celite. The filtrate was washed twice with 300 ml of 1 M hydrochloric acid solution, followed by water and a saturated aqueous sodium chloride solution.

Dry over magnesium sulfate and concentrate in vacuo. The residue was triturated with hexane, and the solid was filtered off and dried in vacuo. The title compound was obtained as a tan solid (20 g, 72%).

B. 2 - {[(tert-Butoxycarbonyl) oxy] amino] -4-methyl-5-thiazolecarboxylic acid g (34.95 mmol) ethyl 2 - {[(tert-butoxycarbonyl) oxy] To a solution of -amino} -4-methyl-5-thiazolecarboxylate in 250 ml of a 2: 3 mixture of tetrahydrofuran / ethanol was added 250 ml of 6 M aqueous potassium hydroxide solution with stirring. The reaction mixture was heated at 55 ° C overnight, then the solution was cooled to 0 ° C and acidified to pH 1 with concentrated hydrochloric acid. The solvent was evaporated in vacuo and the residue was washed with water and diethyl ether and dried in vacuo over anhydrous phosphorus (V) oxide. The title compound was obtained in 89% yield as a white solid.

C. {[2 - {[(tert-Butoxycarbonyl) oxy] amino] -4-methyl-5-thiazolyl] carbonyl} chloride g (38.72 mmol) 2 - {[{tert-butoxy -carbonyl) oxy] amino} -4-methyl-5-thiazolecarboxylic acid, a suspension of 150 ml of methylene chloride and 150 μ, of N, N-dimethylformamide was cooled to 0 ° C with stirring and 22.5 ml of (45 mmol) in 2M oxalyl chloride in CH 2 Cl 2. Upon completion of the addition, the suspension gradually became a homogeneous solution. The reaction mixture was allowed to warm to room temperature and stirred for 1.5 hours at room temperature. The solvent was evaporated in vacuo and the residue re-evaporated with toluene (2 x 300 mL).

73.196 / BE and then vacuum dried. 10.7 g of the title compound are obtained in the form of a tan solid in 99% yield.

D. O-tert-Butyl ΛΓ- [5 - {[(2,4,6-trimethylphenyl) amino] carbonyl} -4-methyl-2-thiazolyl] carbamate

10.7 g (38, 66 min) of {[2 - {[(tert-butoxycarbonyl) oxy] amino} -4-methyl-5-thiazolyl] carbonyl} chloride were prepared in 150 ml of dichloromethane and To the solution cooled to 0 ° C, 2,4,6-trimethylaniline (6.3 mL, 38.66 mmol) was added dropwise with stirring. Twenty minutes later, N, N-diisopropylethylamine (8.8 mL, 44.88 mmol) was added dropwise to the mixture, and the solution was warmed to room temperature and stirred for a further 2 hours. The solvent was evaporated in vacuo and the residue was suspended in ethyl acetate (700 mL), washed with 1M hydrochloric acid (2 x 300 mL), water and brine, dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was triturated with diethyl ether to give the title compound as a tan solid (12.5 g, 86%).

Example 2

2-Amino-4-methyl-N- (2,4,6-trimethylphenyl) -5-thiazolecarboxamide

<img file="HU0202708A2_D0050.tif" />

G (26.63 iranol) O-tert-butyl-N- [5 - {[(2,4,6-trimethylphenyl) amino] carbonyl} -4-methyl-2 -thiazolyl] -carbamate in 100 ml of trifluoroacetic acid was stirred at room temperature for 3 hours. The reaction mixture was then concentrated under reduced pressure, diluted with ethyl acetate (700 mL) and washed with 5% aqueous potassium bicarbonate solution (2 x 400 mL), water, and saturated aqueous sodium chloride. dried over anhydrous magnesium sulfate, filtered and the filtrate was concentrated. The rest

200 After washing with diethyl ether (100 ml) and acetonitrile (100 ml), the title compound was obtained as a white solid (6.7 g, 91%).

Third example

Preparation of O-tert-Butyl-N- [5 - {[(2,4,6-trimethylphenyl) amino] carbonyl} -4- (trifluoromethyl) -2-thiazolyl] carbamate

<img file="HU0202708A2_D0051.tif" />

A. Ethyl 2 - {[(tert-butoxycarbonyl) oxy] amino} -4-trifluoromethyl-5-thiazolecarboxylate

Ethyl 2-amino-4- (trifluoromethyl) -5-thiazolecarboxylate (5.05 g, 21.02 mmol), di-tert-butyl dicarbonate (4.82 g, 22.07 mmol), 260 mg ( A suspension of 4-dimethylamino-pyridine (2.1 mmol) in dichloromethane (209 mL) was stirred for 1.5 h under nitrogen. The solvent was evaporated in vacuo and the residue chromatographed on a silica gel column eluting with ethyl acetate / hexane (5:95, then 15:85, v / v). 6.57 g (92%) of the title compound were obtained as a white solid.

B. 2 - {[(tert-Butoxycarbonyl) oxy] amino} -4- (trifluoromethyl) -5-thiazolecarboxylic acid

To a solution of 6.5 g (19.1 mmol) of ethyl 2 - {[(tert-butoxycarbonyl) oxy] amino} -4-trifluoromethyl-5-thiazolecarboxylate in 100 mL of methanol was added 573 with stirring. ml of 1 M aqueous sodium hydroxide solution. After stirring overnight at room temperature, the reaction mixture was cooled to 0 ° C and then acidified to pH 1 with 6M hydrochloric acid. The mixture was extracted with chloroform (6 x 150 mL), the chloroform solutions were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and in vacuo. 5.75 g (96%) of the title compound are obtained in the form of a white solid.

C. O-tert-Butyl N- [5 - {[(2,4,6-trimethylphenyl) amino] carbonyl} -4- (trifluoromethyl) -2-thiazolyl] carbamate

100 mg (0.32 mmol) of 2 - {[(tert-butoxycarbonyl) oxy] amino} -4- (trifluoromethyl) -5-thiazolecarboxylic acid, 45 μΐ (0.32 mmol) 2.4,6 trimethylaniline, 380 mg (0.4 mmol) [(1-benzotriazolyloxy) tris (dimethylamino) phosphonium] hexafluorophosphate (BOP reagent) and 2 mL of N, N-dimethyl- 4-methylmorpholine (40 μΐ, 0.39 mmol) was added to the formamide mixture. The solution was stirred at room temperature for 72 hours, then diluted with dichloromethane, then with 0.25 M aqueous potassium hydrogen sulfate solution and then with saturated aqueous potassium bicarbonate. solution. The methylene chloride layer was separated, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was chromatographed on a silica gel column eluting with ethyl acetate / hexane (5:95, then 10:90, v / v). 90 mg (65%) of the title compound were obtained as a white solid.

4th example

Preparation of 2-Amino-N- (2,4,6-trimethylphenyl) -4- (trifluoromethyl) -5-thiazolecarboxamide trifluoroacetate (1: 1)

<img file="HU0202708A2_D0052.tif" />

120 O-tert-butyl 2-N- [5 - {[(2,4,6-trimethylphenyl) amino] carbonyl} -4- (trifluoromethyl) -2-thiazolyl (mg) (0.28 mmol) -carbamate and ml of trifluoroacetic acid solution were stirred for 1 hour at 0 ° C and the reaction mixture was concentrated under reduced pressure. The residue was re-evaporated with diethyl ether and the resulting yellow solid was triturated with hexane. The title compound (96 mg, 76%) was obtained as a light yellow solid.

73.196 / BE »· · · •» ♦ ♦ · »··· · • · · ·

5th example

Preparation of O-tert-Butyl N- [5 - {[(2,4,6-trimethylphenyl) amino] carbonyl} -4-phenyl-2-thiazolyl] carbamate

<img file="HU0202708A2_D0053.tif" />

A. Ethyl 2 - {[(trans-c-butoxycarbonyl) oxy] amino} -4-phenyl-5-thiazolecarboxylate

5A. 3A. with the exception that ethyl 2-amino-4-phenyl-5-thiazolecarboxylate was used. Obtained as a white solid in 90.5% yield. title.

B. 2 - {[(tert-Butoxycarbonyl) oxy] amino} -4-phenyl-5-thiazolecarboxylic acid

5B. 3B. of Example 5A except that in this case the compound of Example 5A was prepared.

compound was used. Obtained as a white solid in 99% yield. title.

C. {[2 - {[(tert-Butoxycarbonyl) oxy] amino} -4-phenyl-5-thiazolyl] carbonyl} chloride

5C. Compound IC. except that in this case the compound of Example 5B was prepared.

compound was used. Obtained as a white solid in 90% yield. title.

73 196 / BE

D. O-tert-Butyl N- [5 - {[(2,4,6-trimethylphenyl) amino] carbonyl} -4-phenyl-2-thiazolyl] carbamate

5D. 1D. Compound 5C, except that in this case the compound of formula 5C. compound was used. Obtained as a light yellow solid in 93% yield. title.

6th example

Preparation of 2-Amino-N- (2,4,6-trimethylphenyl) -4-phenyl-5-thiazolecarboxamide - trifluoroacetate (1: 1)

<img file="HU0202708A2_D0054.tif" />

Compound 6 was prepared by a procedure analogous to Compound 4 except that in this case 5D. compound was used. The title compound (6) was obtained as a white solid in 68% yield.

7th example

O-tert-Butyl-N- [5- (anilinocarbonyl) -4-methyl-2-thiazolyl] -

<img file="HU0202708A2_D0055.tif" />

73 196 / BE

<img file="HU0202708A2_D0056.tif" />

Compound 7 is shown in Figure 1D. with the exception of aniline instead of 2,4,6-trimethylaniline and triethylamine instead of N, N-diisopropylethylamine. The title compound was obtained in the form of an off-white solid (76%).

8th example

Preparation of 2-Amino-N-phenyl-4-diethyl-5-thiazolecarboxamide trifluoroacetate (1: 1)

<img file="HU0202708A2_D0057.tif" />

H₃C

Compound 8 was prepared by a procedure analogous to Compound 4 except that Compound 7 was used in this case. The title compound was obtained as a white solid in 68% yield.

9th example

Preparation of O-tert-Butyl N- [5 - {[(2,4-dichlorophenyl) amino] carbonyl} -4-methyl-2-thiazolyl] carbamate

<img file="HU0202708A2_D0058.tif" />

Compound 9 is depicted in Figure 1D. with the exception that in this case 2,4-di73.196 / BE ··· »*« · chloroaniline was used. The title compound was obtained in the form of a white solid (28%).

10th example

2-Amino-N- (2,4-dichlorophenyl) -4-methyl-5-thiazolecarboxamide -

<img file="HU0202708A2_D0059.tif" />

Compound 10 was prepared in a manner analogous to Compound 4 except that Compound 9 was used in this case. The title compound was obtained in the form of a white solid (100% yield).

11th example

Preparation of O-tert-Butyl N-5 - {[(2,4,6-trimethylphenyl) amino] carbonyl} -2-thiazolyl] carbamate

<img file="HU0202708A2_D0060.tif" />

A. Ethyl 2 - {[(tert-butoxycarbonyl) oxy] amino} -5-thiazolecarboxylate

11A. 3A. with the exception that ethyl 2-amino-5-thiazolecarboxylate was used. Obtained as a white solid in 79.5% yield. title.

73.196 / BE «·

Β. 2 - {[(tert-Butoxycarbonyl) oxy] amino} -5-thiazolecarboxylic acid

11B. 3B. with the exception that in this case the compound of Example 11A was prepared. compound was used. Obtained as a white solid in 95.5% yield. title.

C. {[2 - {[(tert-Butoxycarbonyl) oxy] amino] -5-thiazolyl] carbonyl} chloride

11C. Compound IC. with the exception that in this case the compound of Example 11B was prepared.

compound was used.

D. O-tert-Butyl N- [5 - {[(2,4,6-trimethylphenyl) amino] carbonyl} -2-thiazolyl] carbamate

Ά 11D. 1D. with the exception that in this case the compound of formula 11C.

compound was used. Obtained as an off-white solid in 70% yield with 11D. title.

12th example

2-Amino-N- (2,4,6-trimethylphenyl) -4-phenyl-5-thiazolecarboxamide—

<img file="HU0202708A2_D0061.tif" />

Compound 12 was prepared by a procedure analogous to Compound 4 except that in this case, Compound 11D was prepared. compound was used. The title compound was obtained as a light yellow solid in 88% yield.

73.196 / BE »· · *

13-53. example

General procedure

Ά 13-53. compounds were prepared according to the procedure described below. 100 mg (0.36 mmol) IC. To a suspension of compound (3) and methylene chloride (3 mL) was added 0.40 mmol of the appropriate amine and 70 μΐ (0.40 mmol) of N, N-diisopropylethylamine. The solution was stirred in a sealed tube with a mechanical stirrer for 16 hours at room temperature. The reaction mixture was then diluted with 200 μΐ of methanol and the solution was applied to a Varian SCX ion exchange column (2 g / 6 mL) which had been pre-treated with 1: 1 methanol / dichloromethane and then 8 mL dichloromethane. Screening on the SCX column was performed using a Gilson robot unit. The column was treated sequentially with 9 mL of dichloromethane, 9 mL of 4: 1 dichloromethane / methanol, 9 mL of 1: 1 dichloromethane / methanol, mL of methanol, 9 mL of 0.01 M ammonium hydroxide in methanol. and 9 ml of 0.05 M ammonium hydroxide in methanol. The robot separated the eluates and then concentrated the solutions under high-speed vacuum. The product-containing fractions were combined.

"HPLC Rt is the HPLC retention time measured under the following conditions: YMC S5 ODS 4.6 χ 50 mm Ballastic column, 4 minute gradient from 100% solvent A (10% methanol, 90% water, 0.2 volume) % phosphoric acid) to 100% solvent B (90 volumes; methanol, 10% water, 0.2% phosphoric acid), flow rate 4 ral / min, λ = 220 nm.

73 196 / BE

<td>Example number</td><td>Compound structure</td><td>Compound name</td><td>HPLC (minute)</td>

<td> 13.</td><td>HC Λ ' gb-b </td><td>0-tert-butyl-N- [5 - {[(2- methoxy-6-methylphenyl) - amino] carbonyl} -4 methyl-2-thiazolyl] - carbamate</td><td> 3,79</td>

<td> 14.</td><td>Hac ^^ - N ch₃</td><td>0-tert-butyl-N- [4-methyl -5 - {[(3-methyl-4- isopropyl-phenyl) amino] - carbonyl} -2-thiazolyl] - carbamate</td><td> 4,51</td>

<td> 15.</td><td>'XT 'NO O., 3 ° CH₃</td><td>0-tert-butyl-N- [5 - {[(4- bromo-2,6-dimethylphenyl) - amino] carbonyl} -4 methyl-2-thiazolyl] - carbamate</td><td> 4,24</td>

<td> 16.</td><td>DEFEND⁰”³K ^CH= HgC CH₃ ο Ca ° ^ 3 ch₃</td><td>0-tert-butyl-N- [4-methyl -5 - {[(2-methyl-6- isopropyl-phenyl) amino] - carbonyl} -2-thiazolyl] - carbamate</td><td> 4, 17</td>

<td> 17 .</td><td>prl "⁵'·' ja :,</td><td>O-tert-butyl-N- [5 - {[(2,4- dimethylphenyl) amino] - carbonyl} -4-methyl-2- thiazolyl] carbamate</td><td> 4, 05</td>

73 196 / BE

<td> 18.</td><td>σ;</td><td>0-tert-butyl-N- [4-methyl 5 - {[(2-methylphenyl) - amino] carbonyl} -2- thiazolyl] carbamate</td><td> 3,87</td>

<td> 19.</td><td>h₃c f ~ y -&gt; &lt;A / ffT ™ · CHG the</td><td>0-tert-butyl-N- [5 - {[(2- chloro-6-methylphenyl) - amino] carbonyl} -4 methyl-2-thiazolyl] - carbamate</td><td> 3,86</td>

<td> 20.</td><td>H cf "³^{Η3 &lt;λ}/ -ο CH-j ° y ~ S HgCJp / tíHa Η, θ o &lt;X_CT3</td><td>0-tert-butyl-N- [5— {[(2 - tert-butyl 4-methyl phenyl) amino] carbonyl} - -4-methyl-2-thiazolyl] - carbamate</td><td> 4,30</td>

<td> 21.</td><td>the CH3 CH3</td><td>0-tert-butyl-N- {5- - [(furfurylamino) - carbonyl] -4-methyl-2- thiazolyl} carbamate</td><td> 3,54</td>

<td> 22.</td><td>K, CP *³«3 °&gt; ~ N⁰ TVV-A^FH3C 0 LJ ^FH3C '⁰</td><td>0-tert-butyl-N- {5 - [{[3- methoxy-5- (trifluoromethyl methyl) phenyl] amino} - carbonyl] -4-methyl-2- thiazolyl} carbamate</td><td> 4,43</td>

<td> 23.</td><td>H, C /IRISH·</td><td>0-tert-butyl-N- [5 - {[(4- cyclohexyl-phenyl) - -amino] -carbonyl} - 4- methyl-2-thiazolyl] - carbamate</td><td> 4,78</td>

73.196 / BE ···

<td> 24.</td><td></td><td>0-tert-butyl-N- [5- - {[(cyclohexylmethyl) - amino] carbonyl} -4 methyl-2-thiazolyl] - carbamate</td><td> 4,21</td>

<td> 25.</td><td>h,_{v Ν} 1¾³³&lt;Xr^N</td><td>O-tert-butyl-77- [5 - {[(2,3- dihydro-lK-5-indenyl) - amino] carbonyl} -4 methyl-2-thiazolyl] - carbamate</td><td> 4,30</td>

<td> 26.</td><td>* CH₃^υ CH₃</td><td>O-tert-butyl-N- {5 - [(2, 5- dihydro-lH-l-pyrrolyl) - carbonyl] -4-methyl-2- thiazolyl} carbamate</td><td> 3,56</td>

<td> 27 .</td><td>ch₃^w ch₃</td><td>0-tert-butyl-N- {5 - [(2,5- dihydro-2,5-dimethyl-lH- -1-pyrrolyl) carbonyl] -4- -methyl-2-yl} - carbamate</td><td> 3,86</td>

<td> 28.</td><td>ÍAbsz.J &lt;XI °</td><td>1 - [{2 - [(tert-butoxy carbonyl) amino] -4- methyl-5-thiazolyl} - carbonyl] -L-prolinamide</td><td> 2,96</td>

<td> 29.</td><td>'' ÁTxw CH₃(&gt; X - N /) 0</td><td>0-tert-butyl-N- {5 - [(4- -formyl-1-piperazinyl) - carbonyl] -4-methyl-2- thiazolyl} carbamate</td><td> 2,90</td>

<td> 30.</td><td>Q 7&gt; ο να j? l^h= o sr ^_NTHE₀^ CH₃ch₃</td><td>0-tert-butyl-N- {5 - [(1,4- dioxa-8-aza- -spiro [4.5] decan-8-yl) - carbonyl] -4-methyl-2- thiazolyl} carbamate</td><td> 3, 54</td>

73.196 / BE · «» · «

&lt; «4

<td> 31.</td><td>HAC C&gt; H, C Kx j? Γ ' os ^_nA ^ -ch₃ch₃</td><td>O-tert-butyl-77- {5 - [{3- - [(diethylamino) carbonyl] -1-piperidinyl} - carbonyl] -4-methyl-2- thiazolyl} carbamate</td><td> 3,66</td>

<td> 32.</td><td>HaCCHa</td><td>O-tert-butyl-N- {4-methyl- -5- [(octahydro-1- quinolinyl) carbonyl] -2- thiazolyl} carbamate</td><td> 4,37</td>

<td> 33 .</td><td>n₃c h₃c-4 ^^CH3v °</td><td>2 - [(tert-butoxy carbonyl) amino] -4- methyl-5-tiazolkarbonsav- -2- (tert-butoxy-carbo- phenyl) hydrazide</td><td> 3,50</td>

<td> 34.</td><td></td><td>0-tert-butyl-N- [5 - {[(4- methoxyphenyl) amino] - carbonyl} -4-methyl-2- thiazolyl] carbamate</td><td> 3, 83</td>

<td> 35.</td><td></td><td>0-tert-butyl-N- [4-methyl 5 - {[(4-methylphenyl) - amino] carbonyl} -2- thiazolyl] carbamate</td><td> 4,07</td>

<td> 36.</td><td>ch₃ &lt;RT ~ CH₃ch₃</td><td>0-tert-butyl-N- [5 - {[(1,2- N-propyl) amino] - carbonyl} -4-methyl-2- thiazolyl] carbamate</td><td> 3,87</td>

73.196 / BE · * · * ♦ · *

<td> 37.</td><td>h₃c, ch₃RCH₃ch₃ ° CH₃</td><td>O-tert-butyl-N- [5 - {[(2,2 - dimethylpropyl) amino] - carbonyl! 1} -4-methyl-2- thiazolyl] carbamate</td><td> 3, 97</td>

<td> 38.</td><td>ch₃^ CH, Ofe_- ° HAC</td><td>O-tert-butyl-N- [4-methyl -5 - ([(2-propynyl) amino] - carbonyl} -2-thiazolyl] - carbamate</td><td> 3,22</td>

<td> 39.</td><td></td><td>O-tert-butyl-N- {4-methyl- -5 - [(allylamino) - carbonyl] -2-thiazolyl} - carbamate</td><td> 3,41</td>

<td> 40 .</td><td>G ^ '</td><td>O-tert-butyl-N- {4-methyl- -5 - [(N-methylanilino) - carbonyl] -2-thiazolyl} - carbamate</td><td> 3,75</td>

<td> 41.</td><td> « _N Λ '' If C '⁰</td><td>O-tert-butyl-N- [4-methyl -5 - {[(3,4,5-trimethoxy- phenyl) amino] carbonyl} - -2-thiazolyl] carbamate</td><td> 3,84</td>

<td> 42.</td><td>HC AV ' VvJ '°^x°^H3H3C. Chiyo ^ S guard^Nch₃</td><td>O-tert-butyl-N- [5 - {[(2,6- diisopropyl-phenyl) - amino] carbonyl} -4 methyl-2-thiazolyl] - carbamate</td><td> 4,40</td>

73.196 / ΒΕ ··· * «« *

Ί6

<td> 43.</td><td>^H= CH₃HSC Kq &lt;A O ^ⁿ</td><td>\ = N</td><td>O-tert-butyl-N- {5 - [{[3- - (1 H-1-imidazolyl) - propyl] amino} - carbonyl] -4-methyl-2- thiazolyl} carbamate</td><td> 2,45</td>

<td> 44.</td><td>h₃Q ch₃HSC ^ o THE,</td><td></td><td>O-tert-butyl-N- [5 - {[(3,4- difluoro-benzyl) amino] - · carbonyl} -4-methyl-2-</td><td> 3,97</td>

<td></td><td>THE &lt;5</td><td>rOF N ^ = ( F</td><td>thiazolyl] carbamate</td><td></td>

<td> 45.</td><td colspan="2">_Fh₃ Θ _____ &lt; oh Xxh₃^{HIC N} Oh ™, h₃c ch₃</td><td>N - [{2 - [(tert-butoxy carbonyl) amino] -4- methyl-5-thiazolyl} - carbonyl] -L-leucine methyl ester</td><td> 3,99</td>

<td> 46.</td><td>* Vch₃Ox &lt;r^N</td><td>P⁰'³</td><td>methyl-5 - {[{2 - [(tert-Bu methoxy-carbonyl) amino] -4- -meti1-5-yl} - -carbonyl] -amino. -4-oxo- pentanoate</td><td> 3,27</td>

<td> 47.</td><td></td><td>hac ^</td><td>O-tert-butyl-N- [5 - {[2-</td><td> 3, 75</td>

<td></td><td></td><td></td><td>- (ethylthio) ethyl] - carbamoyl} -4-methyl-2-</td><td></td>

<td></td><td>ch₃ °</td><td>X " ch₃</td><td>thiazolyl] carbamate</td><td></td>

73.196 / BE ···· • * ·. · F ··· «* ·

<td> 48.</td><td>CH₃^H3^C'^_CH3</td><td>O-tert-butyl-N- {5- [W, N- bis (3-methylbutyl) - carbamoyl] -4-methyl-2- thiazolyl} carbamate</td><td> 4, 67</td>

<td> 49.</td><td>ΎΆ o ch₃</td><td>O-tert-butyl-77- [5- (N- ethyl-N-isopropyl- carbamoyl) -4-methyl-2- thiazolyl] carbamate</td><td> 3,84</td>

<td> 50 .</td><td>h₃c ch₃If &lt;r% She</td><td>2 - [(tert-butoxy carbonyl) amino] -4- methyl-5-tiazolkarbonsav- -2 - {[(3,5-dichlorophenyl) - amino] thiocarbonyl} - hydrazide</td><td> 4,66</td>

<td> 51.</td><td>_rCH₃HAC</td><td>O-tert-butyl-N- {5- [N, N- bis (2-ethoxy-etí1) - carbamoyl] -4-methyl-2- thiazolyl} carbamate</td><td> 3,83</td>

<td> 52.</td><td>H, C &lt;p^oeTHE_N"Xrvb</td><td>0-tert-butyl-TV- {4-methyl- -5- [{3 - [(trifluoro- acetyl) amino] -1- pyrrolidinyl} carbonyl] - -2-thiazolyl} carbamate</td><td> 3,47</td>

<td> 53.</td><td>u C «(V *¹VP °^c* ch₃ T ^theof ch₃</td><td>0-tert-butyl-N- {5 - [(2,6- dimethyl-phenyl) - carbamoyl] -4-methyl-2- thiazolyl} carbamate</td><td> 3,87</td>

73.196 / BE · * ·· · • · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ·

54-129. example

General Procedure, pp. 54-129. compounds were prepared according to the procedure described below. 30 mg (0.11 mmol) of Compound 2 (amine), 0.13 mmol of the corresponding carboxylic acid, 19.5 mg (0.14 mmol) of 1-hydroxy-7-aza-benzotriazole, 26.8 mg (0.14 mmol) To a mixture of? 7-ethyl-7? - [3- (dimethylamino) propyl] carbodiimide hydrochloride and 0.4 mL of tetrahydrofuran was added 60 μΐ (0.34 mmol) of N, N-diisopropylethyl- once. The reaction mixture was heated in a sealed tube under argon for 24 hours at 45 ° C, then diluted with 4 mL of dichloromethane and washed three times with 2 mL of 2M hydrochloric acid. The methylene chloride solution was passed through a Varian SCX cation exchange column (2 g, 6 mL) on a Gilson robot. The column was eluted sequentially with 10 mL of 4: 1 acetonitrile / methanol, 3 mL of 4: 1 methanol / 2M methanolic ammonia, and 4 x 3 mL of 2M methanolic ammonia. Using the Gilson robot, we collected the fractions separately.

54-127. for compounds "HPLC R_T refers to HPLC retention time measured under the following conditions: YMC S5 ODS 4.6 x mm Ballastic column, 4 minute gradient, from 100% solvent A (10 volumes of methanol, 90 volumes of water, 0.2 volumes of phosphoric acid) to 100% solvent B. (90 volumes of methanol, 10 volumes of water, 0.2% phosphoric acid), flow rate 4 ml / min, λ = 220 nm. For Compounds 128 and 129, the following HPLC conditions were used: Zorbax S8-C18 4.5 mm x 7.5 cm short column, 8 minute gradient, 100% A. solvent (10 vol. methanol, 90 vol

73.196 / BE ·· · »

Volume water, 0.2 volume% phosphoric acid) to 100% solvent B (90 volume% methanol, 10 volume% water, 0.2% phosphoric acid), flow rate 2. , 5 ml / min, λ = 217 nm.

<td>Example number</td><td colspan="5">Compound structure</td><td>Compound name</td><td>HPLC rj (minute)</td>

<td> 54.</td><td></td><td> //»</td><td>ch₃</td><td>CH₃</td><td></td><td>2 - {[(2,2-dichloro-1-methyl-</td><td> 4,22</td>

<td></td><td></td><td></td><td></td><td>THE T Π</td><td></td><td>cyclopropyl) carbonyl] -</td><td></td>

<td></td><td>to CJ</td><td></td><td></td><td>K</td><td>'CH₃</td><td>-amino} -4-methyl-N- (2,4,6- -trimethylphenyl) -5- thiazolecarboxamide</td><td></td>

<td> 55.</td><td>Q = CF *</td><td>lg</td><td>_zCH₃Ύ °</td><td> 9^3</td><td></td><td>2 - [(cyclohexylacetyl) - amino] -4-methyl-N- (2,4,6- trimethylphenyl) -5- thiazolecarboxamide</td><td> 4,47</td>

<td></td><td></td><td></td><td> .7</td><td colspan="2"></td><td></td><td></td>

<td> 56.</td><td>F F</td><td></td><td>_ZCH₃</td><td>CH₃ 0</td><td>'ch₃</td><td>2 - [(2,5-difluorobenzoyl) - -amino] -4-methyl-N- (2,4,6) -trimethylphenyl) -5- thiazolecarboxamide</td><td> 4, 15</td>

<td> 57.</td><td>cl &amp;</td><td>-'b;</td><td>.CH₃\ c</td><td> 9^h3</td><td></td><td>2 - [(5-bromo-2-chloro- benzoyl) amino] -4-methyl- -N- (2,4,6-trimethyl-</td><td> 4,37</td>

<td></td><td></td><td></td><td> %</td><td>Λ</td><td></td><td>) -5-</td><td></td>

<td></td><td></td><td></td><td>H3C</td><td>LA</td><td>ch₃</td><td>thiazolecarboxamide</td><td></td>

<td></td><td></td><td></td><td></td><td></td><td> 1</td><td>2 - [(3-cyanobenzoyl) - -amino] -4-methyl-N- (2,4,6- -trimethylphenyl) -5-</td><td> 4,06</td>

<td></td><td></td><td></td><td></td><td></td><td></td><td>Iazolkarboxamid</td><td></td>

<td> 59.</td><td>R *³^CH3o ^ V ^ⁿ4r</td><td>2 - {[4- (acetylamino) - benzoyl] amino} -4-methyl- -N- (2,4,6-trimethyl- ) -5- thiazolecarboxamide</td><td> 4, 60</td>

<td> 60.</td><td>Ny^CHI oh QC ^ Wx HaC CH₃</td><td>4-methyl-2 - {[3- (trifluoro methyl) benzoyl] amino} - -N- (2,4,6-trimethyl- ) -5- thiazolecarboxamide</td><td> 4,45</td>

<td> 61.</td><td>ch₃£ p =^{N s 1H}y}^CH3HAC</td><td>4-methyl-2 - {[2- (2-phenyl- ethyl) benzoyl] amino} -N- - (2,4,6-trimethylphenyl) - -5thiazolecarboxamide</td><td> 4, 64</td>

<td> 62.</td><td>CH_the</td><td>2 - [(3,5-dimethyl-benzoyl) - -amino] -4-methyl-N- (2,4,6) trimethylphenyl) -5- thiazolecarboxamide</td><td> 4,49</td>

<td> 63 .</td><td>.. 'CHj °% ΑΚ ».</td><td>2 - [(4-vinylbenzoyl) - amino] -4-methyl-N- (2,4,6- trimethylphenyl) -5- thiazolecarboxamide</td><td></td>

<td> 64 .</td><td>^ -y^CWhenh₃c ^ V ch₃^c% ^ Qn X,</td><td>2 - [(4-butyl-benzoyl) - -amino] -4-methyl-N- (2,4,6- trimethylphenyl) -5- thiazolecarboxamide</td><td> 4,58</td>

73.196 / BE t ·

<td> 65.</td><td>Η3 &lt;5 ^ ~</td><td>ch₃Λ-N HjC^b M 0 =³</td><td>N^kN bt</td><td colspan="2">Ά ch₃</td><td>4-methyl-2 - [(4-pentyl benzoyl) amino] -IV- - (2,4,6-trimethylphenyl) - -5thiazolecarboxamide</td><td> 4,76</td>

<td> 66.</td><td>If</td><td>N- ^</td><td>_Z^CH3 3L °</td><td>ch₃</td><td></td><td>4-methyl-2 - [(2-methyl- -caproyl) -amino] -IV-</td><td> 4,41</td>

<td></td><td></td><td>J Ό</td><td></td><td></td><td></td><td>- (2,4,6-trimethylphenyl) -</td><td></td>

<td></td><td>H 3 C-⁷</td><td></td><td>H3C</td><td></td><td>'ch₃</td><td>-5thiazolecarboxamide</td><td></td>

<td> 67 .</td><td>Q</td><td>N-</td><td>xH₃c</td><td>&lt;? H₃</td><td></td><td>4-methyl-2 - [(3-phenoxy -propionyl) -amino] -IV-</td><td> 4,21</td>

<td></td><td>She-</td><td></td><td>S</td><td>-S</td><td></td><td>- (2,4,6-trimethylphenyl) -</td><td></td>

<td></td><td></td><td></td><td>hac ^</td><td></td><td>'ch₃</td><td>-5thiazolecarboxamide</td><td></td>

<td> 68.</td><td></td><td>rt</td><td> &gt;^CH3 Co</td><td>ch₃</td><td></td><td>4-methyl-2 - [(3-phenyl- -propionyl) -amino] -IV-</td><td> 4,26</td>

<td></td><td rowspan="2">the-</td><td>Z \&gt;</td><td> &lt;</td><td>X</td><td></td><td>- (2,4,6-trimethylphenyl) -</td><td></td>

<td></td><td></td><td>hac ^</td><td>sA</td><td>'ch₃</td><td>-5thiazolecarboxamide</td><td></td>

<td> 69.</td><td></td><td colspan="2">nx^ch’</td><td>&lt;? H₃</td><td></td><td>2 - [[3- (2-methoxyphenyl) - -propionyl) amino] -4-</td><td> 4,31</td>

<td></td><td>ΓΥ-</td><td>J 0</td><td>Sf</td><td>X.</td><td></td><td>-methyl-IV- (2,4,6-trimethyl-</td><td></td>

<td></td><td>P h₃c</td><td></td><td>h₃?</td><td></td><td>'ch₃</td><td>) -5- thiazolecarboxamide</td><td></td>

<td> 70.</td><td>(S</td><td>THE vZ N—</td><td>&gt; ch₃</td><td></td><td></td><td>4-methyl-2 - {[(2-naphthyl) - -acetyl] -amino} -IV- (2,4,6- trimethylphenyl) -5-</td><td> 4,43</td>

<td></td><td></td><td>"V</td><td>ίγΟ</td><td>QH₃</td><td></td><td>thiazolecarboxamide</td><td></td>

<td></td><td></td><td></td><td> 1)</td><td></td><td></td><td></td><td></td>

<td></td><td></td><td></td><td>II</td><td></td><td>ch₃</td><td></td><td></td>

73.196 / BE «· · ·

<td> 71.</td><td>'VO ., oh ch₃</td><td>2 - [(diphenyl-acetyl) - -amino] -4-methyl-N- (2,4,6 - trimethylphenyl) -5- thiazolecarboxamide</td><td> 4,13</td>

<td> 72 .</td><td>" .THE,</td><td>2 - {[(2-chloro-6-fluoro- -phenyl) -acetyl] -amino} - 4- methyl-N- (2,4,6-trimethyl- ) -5- thiazolecarboxamide</td><td> 4,17</td>

<td> 73.</td><td>ch₃zz Ά- THE</td><td>4-methyl-2 - {[(2-methyl- phenyl) acetyl] amino} -N- - (2,4,6-trimethylphenyl) - -5thiazolecarboxamide</td><td> 3, 95</td>

<td> 74 .</td><td>,&gt; X</td><td>2 - {[(3-methoxyphenyl) - acetyl] amino} -4-methyl- -N- (2,4,6-trimethyl- ) -5- thiazolecarboxamide</td><td> 4,11</td>

<td> 75.</td><td>ch₃THE The LP if the</td><td>2 - {[(3,4-dimethoxyphenyl) - acetyl] amino} -4-methyl- -N- (2,4,6-trimethyl- ) -5- thiazolecarboxamide</td><td> 3,90</td>

<td> 76.</td><td>aa h₃CAAX_CH3</td><td>2 - {[(4-chlorophenyl) - acetyl] amino) -4-methyl- -N- (2,4,6-trimethyl- ) -5- thiazolecarboxamide</td><td> 4,34</td>

73.196 / BE • ·

<td rowspan="3"> 77.</td><td colspan="5"></td><td rowspan="3">2 - [([1,1'-Biphenyl] -4- -yl) amino] -4- -methyl-N- (2,4,6-trimethyl- ) -5- thiazolecarboxamide</td><td rowspan="3"> 4, 60</td>

<td rowspan="2">M</td><td rowspan="2">'M ·</td><td colspan="2">.ch₃v T f^H3 Μ,</td><td rowspan="2">'ch₃</td>

<td>Foam</td><td></td>

<td> 78.</td><td></td><td></td><td>U /^CHS</td><td></td><td></td><td>4-methyl-2 - [(4-phenyl</td><td> 4,40</td>

<td></td><td></td><td></td><td>J \ zo</td><td>CH</td><td></td><td>butanoyl) amino] -N-</td><td></td>

<td></td><td></td><td>Ό</td><td> %</td><td></td><td></td><td>- (2,4,6-trimethylphenyl) -</td><td></td>

<td></td><td></td><td></td><td>IF</td><td>THE</td><td>'ch₃</td><td>-5thiazolecarboxamide</td><td></td>

<td> 79.</td><td></td><td>Yeah</td><td>s *</td><td>Λ</td><td></td><td>4-methyl-2- (octanoyl -amino) -N- (2,4,6- trimethylphenyl) -5-</td><td> 4,65</td>

<td></td><td></td><td></td><td>hac ^</td><td></td><td>ch₃</td><td>thiazolecarboxamide</td><td></td>

<td> 80.</td><td></td><td></td><td>&gt; CH₃i</td><td></td><td></td><td>2 - [(2-hydroxy-2-phenyl-</td><td> 4,13</td>

<td></td><td>&lt;M</td><td></td><td>R ^ O</td><td>CH&gt;</td><td></td><td>-propionyl) amino] -4-</td><td></td>

<td></td><td>MONTH</td><td> %</td><td>V</td><td>ζ</td><td></td><td>-methyl-N- (2,4,6-trimethyl-</td><td></td>

<td></td><td></td><td></td><td>Ύ</td><td>THE</td><td></td><td>) -5-</td><td></td>

<td></td><td></td><td></td><td>hac ^</td><td></td><td>ch₃</td><td>thiazolecarboxamide</td><td></td>

<td> 81.</td><td></td><td>"Z</td><td>VkZ^CH3</td><td></td><td></td><td>2 - [(2-hydroxy-caproyl) -</td><td> 4,14</td>

<td></td><td></td><td></td><td>JMj.0</td><td></td><td></td><td>amino] -4-methyl-N- (2,4,6-</td><td></td>

<td></td><td></td><td>Ό</td><td>N</td><td></td><td></td><td>trimethylphenyl) -5-</td><td></td>

<td></td><td>THE</td><td></td><td>II H3C</td><td>Ί K</td><td>ch₃</td><td>thiazolecarboxamide</td><td></td>

<td> 82.</td><td></td><td></td><td>CH</td><td></td><td></td><td>4-methyl-2 - {[4- (2-thienyl) -</td><td> 4,32</td>

<td></td><td colspan="2">V?</td><td>ΛγΟ % r</td><td> £</td><td></td><td>butyl] amino} -N- - (2,4,6-trimethylphenyl) -</td><td></td>

<td></td><td></td><td></td><td>H3Í</td><td>THE</td><td>ch₃</td><td>-5thiazolecarboxamide</td><td></td>

73.196 / BE • · · · ϊ *

<td rowspan="2"> 83.</td><td rowspan="2">ch₃HTLiL Oh, Ό HJC</td><td colspan="2">ΠΗ.</td><td rowspan="2">4-methyl-2 - [(3-thenoyl) - amino] -N- (2,4,6- trimethylphenyl) -5- thiazolecarboxamide</td><td rowspan="2"> 4,04</td>

<td>&gt; Λ</td><td>ch₃</td>

<td> 84 .</td><td rowspan="2">^ CH 0-0 °% c ·</td><td>&lt;? H₃</td><td></td><td>2 - {[(2-benzofuranyl) -</td><td> 4,37</td>

<td rowspan="3"></td><td rowspan="3">«Σ-Α. XJL</td><td rowspan="3">'ch₃</td><td rowspan="3">-carbonyl] -amino} -4- -methyl-AZ- (2,4,6-trimethyl- ) -5- thiazolecarboxamide</td><td rowspan="3"></td>

<td></td>

<td></td>

<td> 85.</td><td rowspan="2">= CH₃'-cV'c</td><td> 9^*3</td><td></td><td>N- [4-methyl-5 - {[(2,4,6-</td><td> 3,50</td>

<td rowspan="2"></td><td rowspan="2"> 6</td><td rowspan="2">'ch₃</td><td rowspan="2">trimethylphenyl) amino] - -carbonyl} -2-thiazolyl] -4-pyridinecarboxamide N-oxide</td><td rowspan="2"></td>

<td></td>

<td> 86.</td><td>J.CH3 jr &lt;XK</td><td>ch₃</td><td></td><td>6-chloro-N- [4-methyl-5-</td><td> 4,08</td>

<td></td><td></td><td>T n</td><td></td><td>- {[(2,4,6-trimethyl-</td><td></td>

<td></td><td>O'mb / ^xo 0 fv h₃c</td><td></td><td>'ch₃</td><td>phenyl) amino] carbonyl} - -2-thiazolyl] -3- -piridinkarboxamid</td><td></td>

<td> 87 .</td><td rowspan="2">IW^CHSn 4X.n_</td><td>CH₃</td><td></td><td>N- [4-methyl-5 - {[(2,4,6-</td><td> 3,56</td>

<td></td><td>π</td><td></td><td>trimethylphenyl) amino] -</td><td></td>

<td></td><td>oo j. N-⁷ H₃C</td><td></td><td>ch₃</td><td>carbonyl} -2-thiazolyl] -3-</td><td></td>

<td></td><td></td><td></td><td></td><td>-piridinkarboxamid</td><td></td>

<td> 88.</td><td>m /^CH3</td><td>CH₃</td><td></td><td>N- [4-methyl-5 - {[(2,4,6-</td><td> 4,11</td>

<td></td><td>N '\, JJl hL^sli</td><td>T ti</td><td></td><td>trimethylphenyl) amino] -</td><td></td>

<td></td><td>/ \ - = / oo. Π3^C</td><td></td><td>ch₃</td><td>carbonyl} -2-thiazolyl] -3-</td><td></td>

<td></td><td></td><td></td><td></td><td>-kinolinkarboxamid</td><td></td>

<td> 89.</td><td>0 'OK</td><td></td><td></td><td>4-methyl-2 - {[(4-nitro-</td><td> 4,08</td>

<td></td><td></td><td></td><td></td><td>phenyl) acetyl] amino} -N- - (2,4,6-trimethylphenyl) -</td><td></td>

<td></td><td>^νΛ I</td><td>δ.</td><td></td><td>-5thiazolecarboxamide</td><td></td>

<td></td><td>K3C^X</td><td></td><td>ch₃</td><td></td><td></td>

73.196 / BE • · • ·

<td> 90.</td><td rowspan="2">the</td><td>_zch₃</td><td>&lt;? H₃</td><td>4-methyl-2 - [(2,4,6)</td><td> 4,45</td>

<td rowspan="3"></td><td rowspan="3">^ x'N'vxí^ΟΗ3 &lt;/ ^</td><td rowspan="3">J1 '= CH ₃</td><td rowspan="3">trichloro-benzoyl) amino] - -N- (2,4,6-trimethyl- ) -5- thiazolecarboxamide</td><td rowspan="3"></td>

<td></td>

<td></td>

<td> 91.</td><td>Λ? j</td><td>ch₃fis &lt;r</td><td>ch₃ch₃</td><td>4-methyl-2 - {[2 - {[3- - (trifluoromethyl) phenyl] - amino} benzoyl] amino} - -N- (2,4,6-trimethyl- ) -5- thiazolecarboxamide</td><td> 4,86</td>

<td> 92.</td><td>.P ^ ON</td><td>CH₃</td><td></td><td>4-methyl-2 - {[4- (4-nitro-</td><td> 4,28</td>

<td></td><td>Ö Γ-4 \ _y o</td><td> 5^&lt;·⁰THE</td><td>CH³X</td><td>phenyl) butyl] amino} - N- (2,4,6-trímeti1- ) -5- thiazolecarboxamide</td><td></td>

<td> 93.</td><td></td><td></td><td>ch₃</td><td>4-methyl-2 - {[4- (methyl</td><td> 3,79</td>

<td></td><td></td><td colspan="2">Ck J. ^ 3</td><td>sulfonyl) benzoyl] - amino} -N- (2,4,6-</td><td></td>

<td></td><td></td><td>Γ</td><td></td><td>-trimethylphenyl) -5-</td><td></td>

<td></td><td colspan="3"> #^ΛHSC '^ q</td><td>thiazolecarboxamide</td><td></td>

<td> 94 .</td><td>^ .Ch, Η, οΦΎ VaJ ^ N CH_theN</td><td>"THE</td><td>ch₃</td><td>2 - [(4-heptylbenzoyl) - amino] -4-methyl-N- (2,4,6- trimethylphenyl) -5- thiazolecarboxamide</td><td></td>

73.196 / BE • · ··· ·

<td rowspan="2"> 95.</td><td colspan="2"></td><td rowspan="2">_zch₃N X h₃c ^</td><td rowspan="2">&lt;? H₃• Z ^ cWhen</td><td rowspan="2">2 - {[(2,4-difluorophenyl) - acetyl] amino} -4-methyl- -N- (2,4,6-trimethyl- ) -5- thiazolecarboxamide</td><td rowspan="2"> 4,15</td>

<td>vz F</td><td> /^3 0</td>

<td> 96.</td><td>c</td><td> 3</td><td></td><td>(Abs.)</td><td>(S) -2 - [[2- (dipropylamino amino) -propionyl] -</td><td> 3,20</td>

<td></td><td colspan="2"></td><td>^ ch₃Co</td><td rowspan="2">&lt;&gt; 3 s</td><td>amino} -4-methyl-N- (2,4,6- trimethylphenyl) -5-</td><td></td>

<td></td><td></td><td></td><td></td><td>thiazolecarboxamide</td><td></td>

<td></td><td></td><td></td><td>H₃cClean</td><td> '^&lt;##= CH₃</td><td></td><td></td>

<td> 97 .</td><td></td><td>CH</td><td>h₃c³ JU \</td><td></td><td>2 - {[(2-biphenylenyl) -</td><td> 4,64</td>

<td></td><td>ο</td><td>N ^&amp;</td><td>oH₃C</td><td>y-CH₃</td><td>carbonyl] amino} -4- -methyl-N- (2,4,6-trimethyl-</td><td></td>

<td></td><td>Γ 3</td><td></td><td></td><td></td><td>) -5- thiazolecarboxamide</td><td></td>

<td> 98.</td><td></td><td></td><td rowspan="2">HLZ^CH3 Ρψ^Nx</td><td></td><td>2 - {[3- (3-methoxyphenyl) -</td><td> 4,26</td>

<td></td><td></td><td> _/ '0</td><td>3 QH₃IL</td><td>propyl] amino} -4- -methyl-N- (2,4,6-trimethyl-</td><td></td>

<td></td><td>h₃co</td><td></td><td>h₃c^x</td><td></td><td>) -5-</td><td></td>

<td></td><td></td><td></td><td></td><td></td><td>thiazolecarboxamide</td><td></td>

<td> 99.</td><td>hac ^</td><td></td><td></td><td></td><td>4-methyl-N- (2,4,6-</td><td> 4,52</td>

<td></td><td>CZ</td><td>CH₃</td><td></td><td></td><td>trimethylphenyl) -2-</td><td></td>

<td></td><td>H3C.</td><td></td><td>ch₃</td><td></td><td>- {[(2,4,6-trimethyl-</td><td></td>

<td></td><td></td><td>"Ci</td><td>tj</td><td>z H₃</td><td>phenyl) acetyl] amino} -5- thiazolecarboxamide</td><td></td>

<td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td></td><td></td><td colspan="2">hac ^</td><td>Z ^ cWhen</td><td></td><td></td>

<td> 100.</td><td></td><td>N-</td><td>ch₃Co</td><td>? h₃</td><td>4-methyl-2 - {[(5-hexen-l- -yl) -carbonyl] -amino} -27-</td><td> 4,47</td>

<td></td><td>z</td><td> ^0</td><td> %</td><td>X</td><td>- (2,4,6-trimethylphenyl) -</td><td></td>

<td></td><td>H2C</td><td></td><td>h₃c</td><td>^ ch₃</td><td>-5thiazolecarboxamide</td><td></td>

73.196 / BE • · · · ·

<td rowspan="3"> 101.</td><td colspan="2"></td><td colspan="2" rowspan="2">m /^CH3 OCO</td><td rowspan="3">2 - {[(1,3-benzodioxol-5- yl) acetyl] amino} -4- methyl-N- (2,4,6-trimethyl- ) -5- thiazolecarboxamide</td><td rowspan="3"> 4,07</td>

<td rowspan="2"></td><td rowspan="2">/ Λ o</td>

<td>Γ £ * 3</td><td>ch₃</td>

<td> 102.</td><td>d</td><td>R</td><td></td><td>ch₃</td><td>4-methyl-2 - [{[2- (phenyl- methoxy) phenyl] acetylamino} - -amino] -N- (2,4,6 trimethylphenyl) -5- thiazolecarboxamide</td><td> 4,46</td>

<td> 103.</td><td></td><td>Ό</td><td>ru /^CH' The &lt;Slo T CH₃ Lake</td><td>'CH₃</td><td>4-methyl-2 - {[(3-phenoxy phenyl) acetyl] amino} -N- - (2,4,6-trimethylphenyl) - -5thiazolecarboxamide</td><td> 4,56</td>

<td> 104.</td><td>When &lt;i 0</td><td colspan="2">O-CH₃</td><td>'CH₃</td><td>2 - {[(3,5-dimethoxy-phenyl) - acetyl] amino} -4-methyl- -N- (2,4,6-trimethyl- ) -5- thiazolecarboxamide</td><td> 4,13</td>

<td> 105.</td><td></td><td></td><td>ΗΧθ -^s ch₃• “d</td><td>'ch₃</td><td>2 - {[4- {4- [bis (2-chloro- ethyl) amino] phenyl} - butyl] amino} -4-methyl- -N- (2,4,6-trimethyl- ) -5- thiazolecarboxamide</td><td> 4,75</td>

<td> 106.</td><td></td><td>q Γ</td><td colspan="2">.ch₃ΧΛ&gt;^Η&gt;</td><td>Metallic-3 - [{4 - [{4-meti1-5- - [(2,4,6-trimethylphenyl) - carbamoyl] -2-thiazolyl} - carbamoyl] phenyl} - carbamoyl] propionate</td><td> 4,03</td>

<td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td></td><td>P ~ h₃c</td><td>She</td><td></td><td></td><td></td><td></td>

73.196 / BE • · «· · ·

<td> 107.</td><td>'CH I Pb Λ</td><td>4-methyl-2 - {[(phenyl- sulfonyl) acetyl] - -amino} -77- (2,4,6- trimethylphenyl) -5- thiazolecarboxamide</td><td> 3,77</td>

<td> 108.</td><td>° sA. "&gt;^c 11 Hac '^' ^ CWhen</td><td>2 - {[2- (acetylamino) - -kaproil] amino} -4-methyl- -N- (2,4,6-trimethyl- ) -5- thiazolecarboxamide</td><td> 3, 99</td>

<td> 109.</td><td>Vsy ^ -N Pb N f B / CH₃r¹HJC</td><td>2 - {[4- (dipropylamino sulfamoyl) benzoyl] - -amino} - 4-methyl 1-77- (2,4, 6- trimethylphenyl) -5- thiazolecarboxamide</td><td> 4,51</td>

<td> 110.</td><td>ch₃yn ^H3</td><td>2 - [(4-cyclohexyl) benzoyl) amino] -4-methyl- -N- (2,4,6-trimethyl- ) -5- thiazolecarboxamide</td><td> 4,94</td>

<td> 111.</td><td>»- &lt;l μ Γ³^s\ Xk, h₃c</td><td>2 - [(4-bromo-3-methyl- benzoyl) amino] -4-methyl- -N- (2,4,6-trimethyl- ) -5- thiazolecarboxamide</td><td> 4,80</td>

73 196 / ΒΕ

<img file="HU0202708A2_D0062.tif" />

<td> 112.</td><td></td><td colspan="2">ZQf ,,</td><td>'ch₃</td><td>2 - {[(2,3-difluorophenyl) - acetyl] amino} -4-methyl- -N- (2,4,6-trimethyl- ) -5- thiazolecarboxamide</td><td> 4,14</td>

<td> 113.</td><td>, CH₃h₃c \</td><td></td><td></td><td></td><td>4-methyl-2 - {[(4-isopropyl-</td><td> 4,56</td>

<td></td><td></td><td></td><td></td><td></td><td>phenyl) acetyl] amino} -N-</td><td></td>

<td></td><td>M</td><td></td><td></td><td></td><td>- (2,4,6-trimethylphenyl) -</td><td></td>

<td></td><td></td><td>H</td><td>ch₃</td><td></td><td>-5thiazolecarboxamide</td><td></td>

<td></td><td> 0^</td><td>'* Λ</td><td>Co CH3</td><td></td><td></td><td></td>

<td></td><td></td><td></td><td> %</td><td></td><td></td><td></td>

<td></td><td></td><td></td><td>HSC ^</td><td>'ch₃</td><td></td><td></td>

<td> 114.</td><td></td><td></td><td colspan="2">CH₃</td><td>2 - {[(4-tert-butyl</td><td> 4,85</td>

<td></td><td></td><td></td><td>WHO IS HE</td><td>ch₃</td><td>cyclohexyl) carbonyl] - amino} -4-methyl-N- (2,4,6-</td><td></td>

<td></td><td></td><td></td><td>THE</td><td></td><td>trimethylphenyl) -5-</td><td></td>

<td></td><td></td><td>Λ</td><td></td><td></td><td>thiazolecarboxamide</td><td></td>

<td></td><td></td><td>J</td><td></td><td></td><td></td><td></td>

<td></td><td>H3C^THEch₃</td><td></td><td></td><td></td><td></td><td></td>

<td> 115.</td><td></td><td>H?</td><td>yCH₃</td><td></td><td>N, N-dimethyl-N '- [4-methyl-</td><td> 3,50</td>

<td></td><td></td><td>Ο</td><td>• equidistant »,</td><td></td><td>-5- {[(2,4,6-trimethyl-</td><td></td>

<td></td><td></td><td>ο</td><td>V</td><td></td><td>phenyl) amino] carbonyl} -</td><td></td>

<td></td><td>HAC-fi ch₃</td><td></td><td>H3C ^^</td><td>ch₃</td><td>-2-thiazolyl] -butándiamid</td><td></td>

<td> 116.</td><td>r</td><td colspan="2"></td><td></td><td>2 - [(5-acetylvaleryl) - -amino] -4-methyl 1-77- (2,4, 6-</td><td> 4,40</td>

<td></td><td>K₃C</td><td>ο</td><td>vg</td><td></td><td>trimethylphenyl) -5-</td><td></td>

<td></td><td>Irish She</td><td></td><td>Η₃0 → λ</td><td>'ch₃</td><td>thiazolecarboxamide</td><td></td>

<td> 117.</td><td></td><td rowspan="2">u-Λ \ ^S</td><td>= CH₃CH3</td><td></td><td>2 - {[(benzo [E]] thiophene-2-</td><td> 4,53</td>

<td></td><td></td><td>JT ll</td><td></td><td>yl) carbonyl] amino} -4-</td><td></td>

<td></td><td></td><td> 0</td><td>0 Jk</td><td>'ch₃</td><td>-methyl-77- (2,4,6-trimethyl-</td><td></td>

<td></td><td></td><td></td><td></td><td></td><td>) -5-</td><td></td>

<td></td><td></td><td></td><td></td><td></td><td>thiazolecarboxamide</td><td></td>

73.196 / BE ···· · · β · · · · · · · · · · · ·

<td> 118.</td><td>Η, A</td><td>CH₃vn ch₃She</td><td> &lt;1</td><td>0 / * World Cup¹⁴Rao</td><td>2 - {[(1-adamantyl) - carbonyl] amino} -4- methyl-N- (2,4,6-trimethyl- ) -5- thiazolecarboxamide</td><td> 4,66</td>

<td> 119.</td><td></td><td></td><td></td><td>CH₃</td><td>4-methyl-2 - {[(4-methyl-</td><td> 4, 48</td>

<td></td><td></td><td></td><td colspan="2">y</td><td>cyclohexyl) carbonyl] - amino} -N- (2,4,6- trimethylphenyl) -5-</td><td></td>

<td></td><td></td><td>THE</td><td colspan="2"></td><td>thiazolecarboxamide</td><td></td>

<td></td><td>Hac '</td><td></td><td></td><td></td><td></td><td></td>

<td> 120.</td><td></td><td colspan="2"></td><td>&lt;? H₃</td><td>2 - [(6-acetyl-caproyl) - amino] -4-methyl-N- (2,4,6-</td><td> 3, 88</td>

<td></td><td>r</td><td> &lt; 0</td><td>Ί</td><td>rS</td><td>trimethylphenyl) -5-</td><td></td>

<td></td><td>U ch₃</td><td></td><td>HaCT</td><td>CH₃</td><td>thiazolecarboxamide</td><td></td>

<td> 121.</td><td>vv</td><td></td><td>/ CH₃</td><td></td><td>2 - {[2- (acetylamino) -4-</td><td> 3, 93</td>

<td></td><td>HsC /</td><td>Ατ-ς</td><td>X /_She</td><td></td><td>- (ethylthio) butyl] -</td><td></td>

<td></td><td> &gt; ^S&gt;</td><td></td><td>r Ύ</td><td>ch₃d</td><td>-amino} -4-methyl-N- (2,4,6- trimethylphenyl) -5-</td><td></td>

<td></td><td>H3C</td><td></td><td>HaCT *</td><td></td><td>thiazolecarboxamide</td><td></td>

<td> 122 .</td><td></td><td></td><td>.CH₃</td><td>ch₃</td><td>1,5-Dimethyl-N- [4-methyl-5-</td><td> 3, 91</td>

<td></td><td>✓N-LI K3C</td><td> 0</td><td>W</td><td>ch₃</td><td>- {[(2,4,6-trimethyl- phenyl) amino] carbonyl} - -2-thiazolyl] -1-3- -pirazolkarboxamid</td><td></td>

<td> 123.</td><td></td><td>THE</td><td>_zch₃T ° '</td><td rowspan="2">h₃c</td><td>2 - [{[4-methyl-5 - {[(2,4,6) trimethylphenyl) amino] -</td><td> 3,70</td>

<td></td><td>K</td><td>THE</td><td>"THE</td><td>carbonyl} -2-thiazolyl] - amino} carbonyl] - benzoic acid</td><td></td>

73.196 / BE ·· · · »» ♦

<td rowspan="2"> 124.</td><td rowspan="2"></td><td colspan="2">, CH₃</td><td rowspan="2">ch₃</td><td rowspan="2">N- [4-methyl-5 - {[(2,4,6- trimethylphenyl) amino] - -carbonyl} -2-thiazolyl] -6- -benzotiazolkarboxamid</td><td rowspan="2"> 4,</td><td rowspan="2"> 18</td>

<td>N ⁵</td><td>5 K₃C</td>

<td> 125.</td><td>ch₃</td><td></td><td>xH₃</td><td>CH₃</td><td>1-Ethyl-4-methyl-N- [4-</td><td> 4,</td><td> 09</td>

<td></td><td>lV</td><td>N \</td><td></td><td>π</td><td>methyl-5 - {[(2,4,6-</td><td></td><td></td>

<td></td><td>ch₃</td><td>'She</td><td>'Κσ⁵</td><td>II</td><td>trimethylphenyl) amino] - carbonyl} -2-thiazolyl] - -ΙΗ-3-pyrazolecarboxamide</td><td></td><td></td>

<td> 126.</td><td></td><td>* MZ ' &lt; ^S‘</td><td colspan="2">.ch₃/ f^Ifπ T | J</td><td>4-methyl-2 - {[3 - {[(3H- -1,2,3-triazolo [4,5-</td><td> 4,</td><td> 15</td>

<td></td><td>r</td><td>νθ</td><td colspan="2">° h₃c '^z^^5íxKch₃</td><td>- (-&gt;] pyridin-3-yl) oxy] -</td><td></td><td></td>

<td></td><td>p</td><td></td><td></td><td></td><td>methyl} benzoyl] amino} -</td><td></td><td></td>

<td></td><td>RV</td><td></td><td></td><td></td><td>-N- (2,4,6-trimethyl-</td><td></td><td></td>

<td></td><td>Ό</td><td></td><td></td><td></td><td>) -5- thiazolecarboxamide</td><td></td><td></td>

<td> 127.</td><td colspan="2">Ν '/ l ΟΛ </td><td>, CH₃° H3 &lt;r ^</td><td>? H₃L | ^ ch₃</td><td>2 - [(2-Furoyl) amino] -4- -methyl-TV- (2,4,6-trimethyl- ) -5- thiazolecarboxamide</td><td> 4,</td><td> 45</td>

<td> 128.</td><td colspan="2">crOC- /</td><td colspan="2">, .CH₃X ^ NPV?^s TT u</td><td>2 - [(4-chlorobenzoyl) - amino] -4-methyl-N- (2,4,6-</td><td> 8,</td><td> 85</td>

<td></td><td></td><td></td><td>OAH₃cr</td><td></td><td>trimethylphenyl) -5-</td><td></td><td></td>

<td></td><td></td><td></td><td></td><td></td><td>thiazolecarboxamide</td><td></td><td></td>

<td> 129.</td><td>\ / P</td><td></td><td>ch₃</td><td>h₃</td><td>2 - [(2,2-dimethyl- -propionyl) amino] -4-</td><td> 8,</td><td> 30</td>

<td></td><td></td><td></td><td>° h₃c ^</td><td>11 ^ CHG</td><td>methyl-N- (2,4,6-trimethyl- ) -5- thiazolecarboxamide</td><td></td><td></td>

73.196 / BE • »· · ♦ ··

130th example

Preparation of O-tert-Butyl-N- [4-methyl-5 - {[(2-nitrophenyl) amino] carbonyl} -2-thiazolyl] carbamate

<img file="HU0202708A2_D0063.tif" />

100 mg (0.36 mmol) of {[2 - {[(tert-butoxycarbonyl) oxy] amino) -4-methyl-5-thiazolyl] carbonyl} chloride (Compound IC) in 3 mL of dichloromethane To this solution of 2-nitroaniline (55 mg, 0.4 mmol) and N, N-diisopropylethylamine (70 μΐ, 0.4 mmol) was added dropwise. The reaction mixture was stirred at room temperature for 16 hours at which time 4- (dimethylamino) pyridine (22 mg, 0.18 mmol) was added and stirring continued for 3.5 hours. The solvent was evaporated in vacuo and the residue was chromatographed on a silica gel column eluting with ethyl acetate / hexane (5:95, then 20:80, v / v). 15 mg of the title compound were isolated as a yellow solid (11%).

131st example

O-Benzyl-N- [4-methyl-5 - {[(2,4,6-trimethyl-phenyl) -amino] -carbonyl} -

<img file="HU0202708A2_D0064.tif" />

73.196 / BE ·· · · · · · · · · · · · · · · · · · ··· ·

A. Ethyl 2 - [{[(benzyloxy) carbonyl] oxy} amino] -4-methyl-5-thiazolecarboxylate

372 To a solution of ethyl 2-amino-4-methylthiazolecarboxylate (2 mg, 2 mg) in THF (20 mL) cooled to 0-5 ° C was added 3 M sodium bicarbonate (10 mL, 30 mmol) with stirring. To the resulting mixture was added 500 μΐ, and two hours later an additional 500 μΐ benzyl chloroformate. The biphasic system was stirred for an additional two hours at 0-5 ° C and then diluted with dichloromethane (50 mL) and water (30 mL). The organic layer was separated, dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was chromatographed on a silica gel column eluting with ethyl acetate / hexane (10:90, then 20:80 and then 30:70, v / v). The title compound was isolated as a white solid (310 mg, 48%).

B. 2 - [{[(Benzyloxy) carbonyl] oxy} amino] -4-methyl-5-thiazolecarboxylic acid

131B. 3B. with the exception that in this case

131A. compound was used. Yield: 77B as a white powder, 77B. title.

C. O-Benzyl-N- [4-methyl-5 - {[(2,4,6-trimethylphenyl) amino] carbonyl} -2-thiazolyl] carbamate

100 mg (0.34 mmol) 131B. Compound, 60 μΐ (0.41 mmol) 2,4,6-trimethylaniline and 160 mg (0.41 mmol) [O- (7-aza-1-benzotriazolyl) -1,1,3,3-tetramethyl] -uronium] - (hexafluorophosphate) (HATU) was added 70 μΐ (0.41 mmol) of N, N-diisopropylethyl73.196 / BE ···················································································· ··

amine. The reaction mixture was stirred at room temperature for 24 hours, then diluted with methylene chloride (20 mL), washed three times with 2M hydrochloric acid and brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was triturated with 40 ml of diethyl ether to give the title compound as an off-white solid (100 mg, 77%).

132nd example

Preparation of O-tert-Butyl-N-methyl-N- [4-methyl-5 - {[(2,4,6-trimethylphenyl) amino] carbonyl} -2-thiazolyl] carbamate

<img file="HU0202708A2_D0065.tif" />

CH₃

The title compound 132 was prepared in a manner analogous to that of Compound 1, except that in this case ethyl 2 - {[N- (tert-butoxycarbonyl) oxy] -N-methylamino} -4-methyl -5-Thiazolecarboxylate was used. The title compound was obtained as a tan solid (132).

133rd example

Preparation of 4-Methyl-2- (methylamino) -N- (2,4,6-trimethylphenyl) -5-thiazolecarboxamide trifluoroacetate (1: 1)

<img file="HU0202708A2_D0066.tif" />

73.196 / BE • · • · • · ·

The title compound was prepared in a manner analogous to that of Compound 4, except that Compound 132 was used in this case. The title compound was obtained as a white solid (91%).

134th example

Preparation of O-tert-Butyl N- [4-methyl-5 - {[N-methyl-N- (2,4,6-trimethylphenyl) amino] carbonyl} -2-thiazolyl] carbamate

<img file="HU0202708A2_D0067.tif" />

CH₃

The title compound was prepared in a manner analogous to that of Compound 1, except that N-methyl-2,4,6-trimethylaniline was used. The title compound was obtained in 60% yield as a white solid.

135th example

2-Amino-N, 4-dimethyl-N- (2,4,6-trimethylphenyl) -5-thiazolecarboxamide—

-trifluoroacetate (1: 1)

<img file="HU0202708A2_D0068.tif" />

The title compound 135 was prepared by a procedure analogous to that of compound 4, except that compound 134 was used in this case. The title compound was obtained as a white solid in 97% yield.

73 196 / BE

<img file="HU0202708A2_D0069.tif" />

• · · · ·

136th example

Preparation of O-Methyl-N- [4-methyl-5 - {[(2,4,6-trimethylphenyl) amino] carbonyl} -2-thiazolyl] carbamate ^c

<img file="HU0202708A2_D0070.tif" />

100 A mixture of 2 mg (0.36 mmol) of Compound 2, 87 μΐ (1.08 mmol) of pyridine, 111 μΐ (1.44 mmol) of methyl chloroformate and 3 mL of dichloromethane was stirred at room temperature for 1.5 hours. The reaction mixture was diluted with dichloromethane, washed twice with 20 ml of saturated aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was triturated with diethyl ether to give the title compound as a white solid (88 mg, 82%).

137th example

Preparation of O-tert-Butyl N- [4-ethyl-5 - {[(2,4,6-trimethylphenyl) amino] carbonyl} -2-thiazolyl] carbamate

<img file="HU0202708A2_D0071.tif" />

CH₃

The title compound was prepared in a manner analogous to that of Compound 1, except that methyl 2-amino-4-ethyl-5-thiazolecarboxylate was used. The title compound (137) was obtained as a white solid (70% yield) as a white solid.

138th example

2-Amino-4-ethyl-N- (2,4,6-trimethylphenyl) -5-thiazolecarboxamide-

<img file="HU0202708A2_D0072.tif" />

The title compound 138 was prepared by a procedure analogous to that of Compound 4 except that Compound 137 was used in this case. The title compound was obtained as a white solid in 89% yield.

139th example

Preparation of O-tert-Butyl N- [5 - {[(2,6-dichlorophenyl) amino] carbonyl) -4-methyl-2-thiazolyl] carbamate

<img file="HU0202708A2_D0073.tif" />

To a solution of 13.4 mg (0.08 mmol) of 2,6-dichloroaniline in 1 mL of tetrahydrofuran was added 290 μΐ (0.29 mmol)

M sodium bis (trimethylsilyl) amide solution. Thirty minutes later, the mixture was cooled to 0 ° C and IC (30 mg, 0.11 mmol) was added all at once. compound. The reaction mixture was warmed to room temperature and stirred for 16 hours. The solution was diluted with dichloromethane and washed three times with 2 ml of 2M hydrochloric acid solution, dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was subjected to silica gel column chromatography (eluent: ethyl acetate / hexane = 30:70, v / v). The title compound was isolated as a light yellow solid (20 mg, 45%).

140th example

2-Amino-A^TPreparation of (2,6-dimethylphenyl) -4-methyl-5-thiazolecarboxamide-trifluoroacetate (1: 1)

<img file="HU0202708A2_D0074.tif" />

The title compound 140 was prepared by a procedure analogous to that of Compound 4 except that Compound 53 was used in this case. The title compound was obtained as a light tan solid in 100% yield.

141st example

- Preparation of amino-N- (2-methoxy-6-methylphenyl) -4-methyl-5-thiazolecarboxamide trifluoroacetate (1: 1)

H2

<img file="HU0202708A2_D0075.tif" />

73.196 / BE • · · ·

The title compound 141 was prepared in a manner analogous to that of Compound 4 except that Compound 13 was used in this case. The title compound was obtained as an off-white solid in 100% yield.

Example 142

Preparation of 2-Amino-AZ- (2-methylphenyl) -4-methyl-5-thiazolecarboxamide-trifluoroacetate (1: 1)

<img file="HU0202708A2_D0076.tif" />

The title compound 142 was prepared by a procedure analogous to that of Compound 4, except that in this case, Compound 18 was synthesized.

compound was used. The title compound was obtained as a light tan solid in 90% yield.

143rd example

2-Amino-AZ- (2,6-dimethyl-4-bromophenyl) -4-methyl-5-thiazolecarboxamide—

<img file="HU0202708A2_D0077.tif" />

The title compound 143 was prepared by a procedure analogous to that of Compound 4 except that Compound 15 was used in this case. The title compound was obtained as a light tan solid (70% yield).

73.196 / BE • · «

100

144th example

Preparation of 2-Amino-27- (2-chloro-6-methylphenyl) -4-methyl-5-thiazolecarboxamide - trifluoroacetate (1: 1)

<img file="HU0202708A2_D0078.tif" />

The title compound 144 was prepared by a procedure analogous to that of Compound 4 except that Compound 19 was used in this case. The title compound was obtained as a light tan solid in 81% yield.

145th example

Preparation of 2-Amino-N- (2,4-dimethylphenyl) -4-methyl-5-thiazolecarboxamide-trifluoroacetate (1: 1)

<img file="HU0202708A2_D0079.tif" />

CH₃

The title compound 145 was prepared by a procedure analogous to that of Compound 4, except that in this case the compound of Example 17 was prepared. compound was used. The title compound was obtained as a light tan solid in 68% yield.

146th example

Preparation of 2-Amino-27- (2-methyl-6-isopropylphenyl) -4-methyl-5-thiazolecarboxamide trifluoroacetate (1: 1)

73.196 / BE • · · ·

101 • ·

Η2Ν

<img file="HU0202708A2_D0080.tif" />

The title compound 146 was prepared by a procedure analogous to that of compound 4, except that in this case, compound 16 was prepared.

compound was used. The title compound was obtained as a light tan solid in 100% yield.

147th example

2- (Acetylamino) -4-methyl-N- (2,4,6-trimethylphenyl) -5-

<img file="HU0202708A2_D0081.tif" />

A mixture of 2 mg (0.2 mmol) of Compound 2, 22 μΐ (0.23 mmol) of acetic anhydride, 3 mg of 4-dimethylamino-pyridine and 4.5 ml of dichloromethane was stirred at room temperature for 4.5 hours. diluted with methylene chloride (65 mL). 20 ml of solution 1

It was washed with M hydrochloric acid and water, dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was chromatographed on a silica gel column eluting with ethyl acetate / hexane (35:65, v / v). The title compound was isolated as a white solid (43 mg, 69%).

73 196 / BE

102 • · · · · · • »·» · · · ·»· • · ·· ··«· · ··· ·· » · ···

148th example

2- (Benzoylamino) -4-methyl-N- (2,4,6-trimethylphenyl) -5-

<img file="HU0202708A2_D0082.tif" />

100 A solution of Compound 2 (22 mg, 0.36 mmol) and benzoic anhydride (226 mg, 1 mmol) in methylene chloride (10 mL) and pyridine (2 mL) was stirred overnight at room temperature. The reaction mixture was diluted with dichloromethane (50 mL), washed with 2M hydrochloric acid (2 x 15 mL) and 10% aqueous sodium bicarbonate (2 x 20 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated. The residue was chromatographed on a silica gel column eluting with ethyl acetate / hexane (30:70, then 50:50, v / v). The title compound, which was contaminated with benzoic acid as a solid, was dissolved in ethyl acetate (40 mL), washed with saturated aqueous potassium bicarbonate (4 x 15 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated. The title compound was obtained as a white solid (110 mg, 80%).

149th example

Preparation of 4-Methyl-2- (propionylamino) -N- (2,4,6-trimethylphenyl) -5-thiazolecarboxamide

73.196 / BE • * · · • · · »

103 ··· · ··

H₃C

<img file="HU0202708A2_D0083.tif" />

ch₃

100 A solution of compound 2 mg (0.36 mmol) in propionic anhydride (332 μ 33, 2.58 mmol) in methylene chloride (10 mL) and pyridine (4 mL) was stirred at room temperature for 3 hours.

Then, 4-dimethylamino-pyridine (122 mg, 1 mmol) was added to the reaction mixture and stirring was continued for an additional 1.5 hours. The reaction mixture was diluted with dichloromethane and washed with 1M hydrochloric acid (3 x 25 mL), saturated aqueous sodium bicarbonate (2 x 20 mL), water (20 mL) and brine, dried over anhydrous magnesium sulfate. , filtered and concentrated. The residue was subjected to silica gel column chromatography (eluent: ethyl acetate / hexane = 20:80, v / v). The title compound was isolated as a white solid (81 mg, 68%).

150th example

Preparation of 4-Methyl-2- (butyrylamino) -N- (2,4,6-trimethylphenyl) -5-thiazolecarboxamide

H₃c

<img file="HU0202708A2_D0084.tif" />

The title compound 150 was obtained in a manner analogous to compound 149

73.196 / BE ·· «• · ·

104 with the exception that butyric anhydride was used in this case. The title compound was obtained as a white solid in 76% yield.

151st example

Preparation of 4-Methyl-2- (valerylamino) -N- (2,4,6-trimethylphenyl) -5-thiazolecarboxamide

Ο N

<img file="HU0202708A2_D0085.tif" />

<img file="HU0202708A2_D0086.tif" />

The title compound 151 was prepared in a manner analogous to compound 149 except that valeric anhydride was used. The title compound was obtained as a white solid in 77% yield.

152nd example

Preparation of 4-Methyl-2- (caproylamino) -N- (2,4,6-trimethylphenyl) -5-thiazolecarboxamide

<img file="HU0202708A2_D0087.tif" />

The title compound 152 was prepared in an analogous manner to compound 149 except that caproic anhydride was used. The title compound (152) was obtained as a white solid in 75% yield.

73.196 / BE • «· ·

105 • · · · • ·· · »· · • · ··*·

153rd example

Preparation of 4-Methyl-2 - [(phenylacetyl) amino] -N- (2,4,6-trimethylphenyl) -5-thiazolecarboxamide

<img file="HU0202708A2_D0088.tif" />

CH₃ mg (0.18 mmol) of compound 2 (amine), 101 μΐ (0.58 mmol) of N, N-diisopropylethylamine, 27.2 mg (0.20 mmol) of phenylacetic acid, 29.4 mg (0.22 mmol) of 1-hydroxy-7-aza-benzotriazole and 42.2 mg (0.22 mmol) of N-ethyl-N '- [3- (dimethylamino) propyl] carbodiimide hydrochloride, A solution of 62 ml of dichloromethane was mechanically stirred in a sealed tube for 16 hours. The reaction mixture was then loaded onto a Varian SCX ion exchange column (2 g / 6 mL), eluted first with 10 mL of 4: 1 acetonitrile / methanol and then with 9 mL of 2M ammonia in methanol. The product-containing fractions were combined and concentrated. The residue was dissolved in dichloromethane and the solution was washed three times with 2M hydrochloric acid, dried over anhydrous sodium sulfate, filtered and concentrated. The title compound was isolated as a tan solid (39 mg, 55%).

154th example

Preparation of 2 - {[(Acetylamino) acetyl] amino} -4-methyl-N- (2,4,6-trimethylphenyl) -6-thiazolecarboxamide

73 196 / BE

106

<img file="HU0202708A2_D0089.tif" />

mg (0.18 mmol) Compound 2 (amine), 400 μΐ (2.3 mmol) Ν, N-diisopropylethylamine, 42 mg (0.36 mmol) N-acetylglycine, 49 mg (0 , 36 mmol) of 1-hydroxy-7-aza-benzotriazole and 72 mg (0.36 mmol) of N-ethyl-N '- [3- (dimethylamino) propyl] carbodiimide hydrochloride in 6 ml of tetrahydrofuran overnight at 50 ° C. The reaction mixture was cooled, diluted with dichloromethane (60 mL), washed with 2M hydrochloric acid (20 mL) and saturated aqueous potassium bicarbonate solution (20 mL), dried over anhydrous magnesium sulfate, filtered and concentrated. The crude solid was triturated with diethyl ether (10 mL), filtered and washed with diethyl ether (3 x 5 mL). The title compound was obtained in the form of an off-white solid (40 mg, 59%).

155th example

2-Amino-4-methyl-N- (2,4,6-trimethylphenyl) -5-thiazolethiocarboxamide

<img file="HU0202708A2_D0090.tif" />

(0.23 ml of toluene)

Lawesson hours ke73.196 / BE

107 · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · An additional 44 mg (0.11 mmol) of Lawesson's reagent was added and heating continued for another 3.5 hours. The crude reaction mixture was chromatographed on a silica gel column eluting with ethyl acetate / hexane (50:50, then 70:30, v / v). The yellow solid thus isolated was triturated with hexane (6 mL) to give the title compound as a yellow solid (11 mg, 21%).

156-170. example

General procedure

156-170. compounds were prepared according to the procedure described below. 30 mg (0.11 mmol) of compound 2 (amine), 0.13 mmol of the corresponding carboxylic acid, 19.5 mg (0.14 mmol) of 1-hydroxy-7-aza-benzotriazole, 26.8 mg (0.14 mmol) N, N-diisopropylethylamine (60 μ am, 0.34 mmol) was added to a mixture of N-ethyl N- [3- (dimethylamino) propyl] carbodiimide hydrochloride (1 mmol) and tetrahydrofuran (1 mL). The reaction mixture was heated in a sealed tube under argon for 24 hours at 45 ° C, then diluted with 4 mL of dichloromethane and then 3 times with 2 mL of 2

It was washed with M hydrochloric acid, dried over anhydrous sodium sulfate and concentrated under high vacuum. The crude product was purified by trituration with 5 ml of a 1: 1 mixture of dichloromethane / diethyl ether or chromatography on silica gel eluting with 50:50 ethyl acetate / hexane / ethyl acetate.

73 196 / BE

108 ··· · ··

"HPLC Rt is the HPLC retention time measured under the following conditions: YMC S5 ODS 4.6 χ 50 mm Ballastic column, 4 minute gradient from 100% solvent A (10 volumes of methanol, 90 volumes of water, 0.2 volumes of phosphoric acid) To 100% solvent B (90 volumes of methanol, 10 volumes of water, 0.2% phosphoric acid), flow rate 4 ml / min, λ = 220 nm.

<td>Example number</td><td>Compound structure</td><td>Compound name</td><td>HPLC Ltd. (minute)</td>

<td> 156.</td><td>_ Ch₃</td><td>2 - [(4-bromo-benzoyl) - amino] -4-methyl-N- (2,4,6- trimethylphenyl) -5- thiazolecarboxamide</td><td> 5,03</td>

<td> 157.</td><td>_zch₃ 0</td><td>4-methyl-2 - [(4-nitro- benzoyl) amino] -N- - (2,4,6-trimethylphenyl) - -5thiazolecarboxamide</td><td> 4,87</td>

<td> 158.</td><td>_zch₃í? rY?^H3</td><td>2 - [(4-cyanobenzoyl) - -amino] -4-methyl-N- (2,4,6- trimethylphenyl) -5- thiazolecarboxamide</td><td> 4,70</td>

<td> 159.</td><td>ch₃Q NZ CH₃/ X-WSS_SHEV ° ftc-dcH, She</td><td>4-methyl-2 - {[(5-nitro-2- furanyl) carbonyl] amino) - -N- (2,4,6-trimethyl- ) -5- thiazolecarboxamide</td><td> 4,63</td>

<td> 160.</td><td>_ Ch₃ \ ^s ^ C ^^ CWhen</td><td>4-methyl-2 - [(2-thenoyl) - amino] -N- (2,4,6- trimethylphenyl) -5- thiazolecarboxamide</td><td> 4, 60</td>

73.196 / BE • ·

109

<td> 161.</td><td colspan="2">OL JUJ h₃c ' She</td><td>.ch₃OUN. % C '</td><td>ch₃^ A_Ch₃</td><td>methyl 4 - {[4-methyl-5- - {[(2,4,6-trimethyl- -phenyl) -amino] -carbonyl} - -2-thiazolyl] carbamoyl} - benzoate</td><td> 4,99</td>

<td> 162.</td><td></td><td>ff il</td><td>, CH₃</td><td> -^h3</td><td>2 - {[(5-isoxazolyl) -</td><td> 4,87</td>

<td></td><td>\\ T ^N</td><td>H l | s</td><td>X ||</td><td></td><td>carbonyl] amino} -4-</td><td></td>

<td></td><td>WOMAN</td><td></td><td>ft &lt;A</td><td>^ CWhen</td><td>methyl-N- (2,4,6-trimethyl-</td><td></td>

<td></td><td></td><td></td><td></td><td></td><td>) -5-</td><td></td>

<td></td><td></td><td></td><td></td><td></td><td>thiazolecarboxamide</td><td></td>

<td> 163.</td><td></td><td>w-a</td><td>_zch₃</td><td> «3</td><td>2 - [(3-Furoyl) amino] -4-</td><td> 4,54</td>

<td></td><td>/ y^N'</td><td>Jl H s</td><td>Η Π</td><td></td><td>methyl-N- (2,4,6-trimethyl-</td><td></td>

<td></td><td>\ ff</td><td></td><td> 8₃&lt;A</td><td>^ ch₃</td><td>) -5-</td><td></td>

<td></td><td></td><td></td><td></td><td></td><td>thiazolecarboxamide</td><td></td>

<td> 164.</td><td>^K3 &lt;? j?</td><td rowspan="2">JL</td><td>.ch₃if</td><td>? h₃</td><td>2 - {[(2,4-dimethyl-5-</td><td> 4,74</td>

<td></td><td rowspan="2">Ά¹HAC</td><td>il ||</td><td>Ί</td><td>thiazolyl) carbonyl] -</td><td></td>

<td rowspan="2"></td><td rowspan="2"></td><td rowspan="2"></td><td rowspan="2">^ Xh₃</td><td rowspan="2">-amino} -4-methyl-AZ- (2,4,6- trimethylphenyl) -5- thiazolecarboxamide</td><td rowspan="2"></td>

<td></td>

<td> 165.</td><td>H3C-O νίΓ</td><td>Λ</td><td>&gt; ch₃jf * lf η</td><td>3 &lt;? Ί</td><td>2 - [(4-methoxy-3-thenoyl) - -amino] -4-methyl-AZ- (2,4,6</td><td> 4,75</td>

<td></td><td></td><td></td><td>rA</td><td></td><td>trimethylphenyl) -5-</td><td></td>

<td></td><td></td><td></td><td></td><td></td><td>thiazolecarboxamide</td><td></td>

<td> 166.</td><td>w /</td><td>Λ</td><td>ch₃Ύν</td><td>&lt;? H₃yl</td><td>4-methyl-2 - [(5-nitro-3- -tenoyl) -amino] -N- (2,4,6)</td><td> 4,78</td>

<td></td><td>0M</td><td></td><td>RIC</td><td>^ xh₃</td><td>trimethylphenyl) -5-</td><td></td>

<td></td><td></td><td></td><td></td><td></td><td>thiazolecarboxamide</td><td></td>

<td> 167.</td><td>XX. k</td><td colspan="2">ch₃JUöCk</td><td>&lt;? H₃</td><td>2 - [{4 - [(4-chlorophenyl) - thio] -3-thenoyl} amino] -4-</td><td> 5, 27</td>

<td></td><td>V</td><td></td><td>fiction₃c</td><td>v ^ 3</td><td>methyl-N- (2,4,6-trimethyl- ) -5- thiazolecarboxamide</td><td></td>

73 196 / BE

110

<td> 168.</td><td>H3C-0 Ο N</td><td>ch₃THE ftc '</td><td>ch₃</td><td>2 - [(5-chloro-4-methoxy-3- -tenoil) amino] -4-methyl- -N- (2,4,6-trimethyl- ) -5- thiazolecarboxamide</td><td> 169.</td>

<td> 169.</td><td></td><td>.ch₃</td><td>CH3</td><td>2 - {[2- (4,5-dihydro-4,4-</td><td> 5,13</td>

<td></td><td>THE</td><td>I μ</td><td></td><td></td><td></td>

<td></td><td>THE/ ^N</td><td>Π II</td><td>Ί</td><td>dimethyl-2-oxazolyl) -3-</td><td></td>

<td></td><td></td><td> 8₃&lt;A</td><td>Ach₃</td><td>-tenoil] amino] -4-methyl-</td><td></td>

<td></td><td>ch₃</td><td> 3</td><td></td><td>-N- (2,4,6-trimethyl-</td><td></td>

<td></td><td></td><td></td><td></td><td>) -5-</td><td></td>

<td></td><td></td><td></td><td></td><td>thiazolecarboxamide</td><td></td>

<td> 170.</td><td>ff II</td><td>.CH₃You</td><td>&lt;? H₃</td><td>2 - [(2-acetyl-3-tenoyl)</td><td> 4,54</td>

<td></td><td>II</td><td>II M u if</td><td></td><td>amino] -4-methyl-N- (2,4,6-</td><td></td>

<td></td><td></td><td></td><td>= CH₃</td><td>trimethylphenyl) -5-</td><td></td>

<td></td><td>SHE</td><td></td><td></td><td>thiazolecarboxamide</td><td></td>

171-180. example

General procedure

171-180. compounds were prepared according to the procedure described below.

A mixture of 2 mg (0.28 mmol) of Compound 2 (amine), 0.87 mmol of the corresponding isocyanate, 2 ml of pyridine and 3.5 ml of tetrahydrofuran was stirred overnight at room temperature. In some cases, the reaction mixture was heated at 60-70 ° C for 5 hours. Some reactions were carried out overnight at room temperature but in the presence of a catalytic amount of 4- (dimethylamino) pyridine. The reaction mixture was diluted with dichloromethane, washed three times with 1 M hydrochloric acid, once with water and brine, dried over anhydrous magnesium sulfate, filtered and concentrated.

111 • · · • · «« • · · «« * »* needles. The crude product was purified by either trituration with diethyl ether or diethyl ether / hexane or silica gel column chromatography eluting with 20:80/40:60 ethyl acetate / hexane. The title compound was prepared by trituration of the product isolated by chromatography or

Purified on a Varian cation exchange SCX cartridge, eluting successively with 5 mL of methanol, 5 mL of dichloromethane, 10 mL of 4: 1 acetonitrile / methanol and 10 mL of 4: 1 methanol / 2M methanolic ammonia.

For compounds 171, 172, 175 and 177, "HPLC Rt is the HPLC retention time measured under the following conditions:

Zorbax S8-C18 4.5 mm χ 7.5 cm short column, 30 min gradient from 100% solvent A (10% methanol, 90% water,

0.2% phosphoric acid) to 100% solvent B (90% methanol, 10% water, 0.2% phosphoric acid), flow rate

2.5 ml / min, λ = 217 nm.

For the other compounds, the following HPLC conditions were used: Zorbax S8-C18 4.5 mm χ 7.5 cm short column, 8 minute gradient from 100% solvent A (10% methanol, 90% water, 0.2 volume) % phosphoric acid) to 100% solvent B (90% by volume methanol, 10% by volume water, 0.2% phosphoric acid), flow rate 2.5 ml / min, λ = 217 nm.

73.196 / BE * ·

112 • · · • · ·· • · • · · * ·· . » ·♦· • ««·« * • · ··♦

<td>Example number</td><td>Compound structure</td><td>Compound name</td><td>HPLC Rqj (minute)</td>

<td> 171.</td><td>CH₃ HGC fl₃c</td><td>4-methyl-2 - [(methyl carbamoyl) amino] -N- - (2,4,6-trimethylphenyl) - -5thiazolecarboxamide</td><td> 24,48</td>

<td> 172.</td><td>HAC CHG ^^</td><td>4-methyl-2 - [(anilino carbonyl) amino] -N- - (2,4,6-trimethylphenyl) - -5thiazolecarboxamide</td><td> 30, 45</td>

<td> 173.</td><td>'• ^ -o- zC-bL " HAC</td><td>4-methyl-2 - {[(4-methyl- phenyl) carbamoyl] - amino} -N- (2,4,6- trimethylphenyl) -5- thiazolecarboxamide</td><td> 8,81</td>

<td> 174.</td><td>h₃c</td><td>4-methyl-2 - [(benzyl- carbamoyl) amino] -N- - (2,4,6-trimethylphenyl) - -5thiazolecarboxamide</td><td> 8,52</td>

<td> 175.</td><td></td><td>2 - [(butylcarbamoyl) - -amino] -4-methyl-N- (2,4,6) trimethylphenyl) -5- thiazolecarboxamide</td><td> 30, 49</td>

<td> 176.</td><td>h₃c h₃c</td><td>4-methyl-2 - [(propyl carbamoyl) amino] -N- - (2,4,6-trimethylphenyl) - -5thiazolecarboxamide</td><td> 7,41</td>

<td> 177 .</td><td>^ ch₃ h₃c HAC</td><td>2- [(cyclohexyl- carbamoyl) amino] -4- -methyl-N- (2,4,6-trimethyl- ) -5- thiazolecarboxamide</td><td> 27, 21</td>

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113

<td> 178.</td><td>H3C</td><td>2 - [{[(2-chlorophenyl) - amino] carbonyl} amino] - -4-methyl-N- (2,4,6) trimethylphenyl) -5- thiazolecarboxamide</td><td> 8, 99</td>

<td> 179.</td><td> ^^CH3 H₃C HAC</td><td>2 - [{[(3-fluorophenyl) - amino] carbonyl} amino] - -4-methyl-N- (2,4,6- trimethylphenyl) -5- thiazolecarboxamide</td><td> 8,87</td>

<td> 180.</td><td>z^CH3 m_Z^{CH3 h}3? \ = &lt;NNSH CH₃ tyjC</td><td>2 - {[(2,6-dimethylphenyl) - carbamoyl] amino} -4- methyl-N- (2,4,6-trimethyl- ) -5- thiazolecarboxamide</td><td> 8,92</td>

181st example

O-Phenyl 1-AT- {5 - [(2,4,6-trimethyl-phenyl) -carbamoyl] -4-methyl-2-

<img file="HU0202708A2_D0091.tif" />

To a solution of compound 2 (1.02 g, 3.7 mmol) in tetrahydrofuran (130 mL) was added a solution of potassium bicarbonate (10% w / w, 170 mL) in water, and 1.39 mL (11 mL) was added dropwise to the resulting mixture. (1 mmol) phenyl chloroformate. The biphasic mixture was stirred overnight at room temperature, then diluted with 200 mL of dichloromethane, then twice with 50 mL of water and sat.

114

<img file="HU0202708A2_D0092.tif" />

The solution was washed with sodium chloride solution. The organic layer was separated, dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was subjected to silica gel column chromatography (eluent: ethyl acetate / hexane = 10:90, v / v). The title compound (980 mg, 69%) was obtained as a solid.

182-236. example

General procedure

A 182-236. compounds were prepared according to the following procedure.

A solution of 181-phenylcarbamate (18 mg) (0.054 mmol) and 0.08 mmol of the corresponding amine in 3 ml of a 1: 1 mixture of tetrahydrofuran / acetonitrile was stirred at room temperature overnight. Some reactions required heating at 60 ° C for 4 hours to overnight. The reaction mixture was diluted with dichloromethane (4 mL), and the solution was washed twice with 1.5 mL of 1 M hydrochloric acid and twice with 1.5 mL of 1 M aqueous sodium hydroxide. The methylene chloride solution was separated, dried over anhydrous magnesium sulfate, filtered and concentrated to give the desired product.

A 182-192. for compounds, "HPLC Rt is the HPLC retention time measured under the following conditions: Zorbax S8-C18 4.5mm x 7.5cm short column, 8 min gradient from 100% solvent A (10% methanol, 90% v / v) water, 0.2% by volume phosphoric acid) to 100% solvent B (90% by volume methanol, 10% v / v).

115 * · ············································································································· · 5 ml / min, λ =

217 nm.

A 193-236. The following HPLC conditions were used for the compounds: YMC S5 ODS 4.6 χ 50 mm Ballastic column, 4 min gradient from 100% solvent A (10% methanol, 90% *}; water, 0.2% phosphoric acid) 100 To solvent B (90 volumes *}; methanol, 10 volumes water, 0.2% phosphoric acid), flow rate 4 ml / min, λ = 220 nm.

<td>Example number</td><td>Compound structure</td><td>Compound name</td><td>HPLC R * p (minute)</td>

<td> 182.</td><td>H3C</td><td>4-methyl-2 - {[(2-phenyl- ethyl) carbamoyl] amino) - -N- (2,4,6-trimethyl- ) -5- thiazolecarboxamide</td><td> 8,83</td>

<td> 183.</td><td>H3C</td><td>2 - [(hexylcarbamoyl) - -amino] -4-methyl-N- (2,4,6- trimethylphenyl) -5- thiazolecarboxamide</td><td> 9, 01</td>

<td> 184.</td><td>^H=^cNrZ'^syyy_CH3H3C</td><td>2 - [(fcerc-butyl carbamoyl) amino] -4- methyl-N- (2,4,6-trimethyl- ) -5- -trázolkarboxamid</td><td> 8,48</td>

<td> 185.</td><td>HJC bow [^SN^THEN '^ S'nr'^N^ λ--, H3C H3C F</td><td>2 - {[(3-fluoro-4-methyl- phenyl) carbamoyl] - -amino} -4-methyl-N - (2,4,6- -trimethylphenyl) -5- thiazolecarboxamide</td><td> 8,92</td>

73 196 / BE

116 • · · • · ·· ····· • · · · ·

<td> 186.</td><td></td><td>2 - {[(4-methoxyphenyl) - carbamoyl] amino} -4- methyl-N- (2,4,6-trimethyl- ) -5- thiazolecarboxamide</td><td> 8,57</td>

<td> 187.</td><td>ch₃ »^c</td><td>2 - [(diethylcarbamoyl) - amino] -4-methyl-N- (2,4,6- trimethylphenyl) -5- thiazolecarboxamide</td><td> 8, 19</td>

<td> 188.</td><td>^ CHs *^C</td><td>2 - [(diisopropyl carbamoyl) amino] -4- methyl-N- (2,4,6-trimethyl- ) -5- thiazolecarboxamide</td><td> 8,90</td>

<td> 189.</td><td>ΟΫ-ΑΆ CH₃ HSC</td><td>4-methyl-2 - [(N-benzyl-N- -methyl-carbamoyl) -amino] - -N- (2,4,6-trimethyl- ) -5- thiazolecarboxamide</td><td> 8,56</td>

<td> 190.</td><td>yCH₃ ΗβΟ Ak-OVzX 10 0H3 CH₃ H3C</td><td>4-methyl-2 - {[(N-phenyl-N- -methyl-carbamoyl) amino] - -N- (2,4,6-trimethyl- ) -5- thiazolecarboxamide</td><td> 8,39</td>

<td> 191.</td><td>n &lt;^{CH3 H3 &lt;}L 5LA^ch3 CH₃ H3C</td><td>2 - [(N-cyclohexyl-N-methyl- carbamoyl) amino] -4- -methyl-N- (2,4,6-trimethyl- ) -5- thiazolecarboxamide</td><td> 8,84</td>

<td> 192.</td><td>K₃C</td><td>4-methyl-2 - {[(1-phenyl- ethyl) carbamoyl] amino} - -N- (2,4,6-trimethyl- ) -5- thiazolecarboxamide</td><td> 8,47</td>

73.196 / BE • ·

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<td> 193.</td><td>In Figure 1 -p Λ.</td><td>2 - {[N- (cyclopropylmethyl) -N-propyl carbamoyl] amino} -4- -methyl-N- (2,4,6-trimethyl- ) -5- thiazolecarboxamide</td><td> 4,36</td>

<td> 194.</td><td>Q^CH3Λ Hac '^^ CWhen</td><td>4-methyl-2 - {[(2-methyl- cyclohexyl) carbamoyl] - amino} -N- (2,4,6- trimethylphenyl) -5- thiazolecarboxamide</td><td> 4,42</td>

<td> 195.</td><td>h₃c. 0 o = Z i * - /³¹' ;, Φ .dk,</td><td>4-methyl-2 - {[(4-methyl- cyclohexyl) carbamoyl] - -amino} -N- (2,4,6- -trimethylphenyl) -5- thiazolecarboxamide</td><td> 4,49</td>

<td> 196.</td><td>ry = il</td><td>2 - {[(cyclohexylmethyl) - carbamoyl] amino} -4- -methyl-TV- (2,4,6-trimethyl- ) -5- thiazolecarboxamide</td><td> 4,49</td>

<td> 197 .</td><td>O ^ See^CHS^N^ ° f », Λ.</td><td>2 - {[(2,3-dihydro-lH-l- indenyl) carbamoyl] - amino} -4-methyl-N- (2,4,6- trimethylphenyl) -5- thiazolecarboxamide</td><td> 4,35</td>

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118

<td> 198.</td><td>Shoot..</td><td>4-methyl-2 - [{[(1-naphthyl) - methyl] -carbamoyl} - amino] -N- (2,4,6- trimethylphenyl) -5- thiazolecarboxamide</td><td> 4,43</td>

<td> 199.</td><td>HAC - '^^ CWhen</td><td>2 - [(dibenzylamino-carbamoyl) - -amino] - 4-methyl-TV- (2,4,6- trimethylphenyl) -5- thiazolecarboxamide</td><td> 4, 66</td>

<td> 200.</td><td>ch₃She H₃cx_iX- '_N'^IL'fii'S OK3C ch₃</td><td>2,6-dimethyl-N- {4-methyl-5- - [(2,4,6-trimethylphenyl) - carbamoyl] -2-thiazolyl} - -4-morpholinecarboxamide</td><td> 3, 97</td>

<td> 201.</td><td>ch₃SHE? ' ch₃</td><td>2-ethyl-N- {4-methyl-5- - [(2,4,6-trimethylphenyl) - carbamoyl] -2-thiazolyl} - -1-piperidinecarboxamide</td><td> 4,29</td>

<td> 202 .</td><td>, CH₃t xS-Ok X ^ 'hr'N ^s n— / ch₃h₃c_SheTHE_She= CH₃</td><td>ethyl 1 - {[4-methyl-5- - [(2,4,6-trimethylphenyl) - carbamoyl] -2-thiazolyl} - carbamoyl] -3- piperidinecarboxylate</td><td> 4,10</td>

<td> 203.</td><td>H3C CH₃0 trC H3C ch₃</td><td>3,3-dimethyl-TV- {4-methyl-5- - [(2,4,6-trimethylphenyl) - carbamoyl] -2-thiazolyl} - -1-piperidinecarboxamide</td><td> 4,32</td>

73 196 / BE

<img file="HU0202708A2_D0093.tif" />

• · · ·

119

<td> 204.</td><td>CH₃° Ί ch₃</td><td>ethyl 1 - {[4-5- met.il - [(2,4,6-trimethylphenyl) - carbamoyl] -2-thiazolyl} - carbamoyl] -4 piperidinecarboxylate</td><td> 4,06</td>

<td> 205.</td><td>CW 1ώ "</td><td>4-methyl-2 - {[(3-methyl-2- pyridyl) carbamoyl] - -amino} -W- (2,4,6- trimethylphenyl) -5- thiazolecarboxamide</td><td> 3,51</td>

<td> 206.</td><td>Λ.,</td><td>4-methyl-2 - {[(l-benzyl-4- piperidyl) carbamoyl] - amino} -N- (2,4,6- trimethylphenyl) -5- thiazolecarboxamide</td><td> 3, 28</td>

<td> 207.</td><td>PH₃Z ^ ian^s n-O-CH₃AA HaC</td><td>octahydro-TV- {4-methyl-5- - [(2,4,6-trimethylphenyl) - carbamoyl] -2-thiazolyl} - -1 (2H) -kinolinkarboxamid</td><td> 4,55</td>

<td> 208.</td><td>G^H3 Η, ^ Ο \ -n · CC ^ " '</td><td>3,4-Dihydro-7H- {4-methyl-5- - [(2,4,6-trimethylphenyl) - carbamoyl] -2-thiazolyl} - -2 (1H) - -isoquinolinecarboxamide</td><td> 4, 35</td>

<td> 209.</td><td>h₀ ®t ° r · "Z ch₃</td><td>2 - {[(1,5-dimethyl-hexyl) - carbamoyl] amino} -4- -methyl-N- (2,4,6-trimethyl- ) -5- thiazolecarboxamide</td><td> 4,72</td>

73.196 / BE • · *

120

<td> 210.</td><td>N?^ch3 rT ^ A H3C</td><td>4-methyl-2 - {[(1-methylheptyl) carbamoyl] - -amino} -TV- (2,4,6- -1-trimethylphenyl) -5- thiazolecarboxamide</td><td> 4,74</td>

<td> 211.</td><td>&lt;AA^F H₃c '^^^&lt;CH3</td><td>2 - {[(2-fluorobenzyl) - carbamoyl] amino} -4- -methyl-TV- (2,4,6-trimethyl- ) -5- thiazolecarboxamide</td><td> 4,17</td>

<td> 212.</td><td>r ^^CH3</td><td>2 - {[(2-methoxybenzyl) - carbamoyl] amino} -4- -methyl TV- (2,4,6-trimethyl- ) -5- thiazolecarboxamide</td><td> 4,22</td>

<td> 213.</td><td>CH₃ = CH_S</td><td>2 - {[(2-ethoxy-benzyl) - carbamoyl] amino} -4- -methyl TV- (2,4,6-trimethyl- ) -5- thiazolecarboxamide</td><td> 4,36</td>

<td> 214.</td><td>c. HAC ^^ CWhen</td><td>2 - {[(3-methoxybenzyl) - carbamoyl] amino} -4- -methyl TV- (2,4,6-trimethyl- ) -5- thiazolecarboxamide</td><td> 4,13</td>

<td> 215.</td><td>fH, • θ '° A HjtA ^ CWhen</td><td>2 - {[(4-chlorobenzyl) - carbamoyl] amino} -4- -methyl TV- (2,4,6-trimethyl- ) -5- thiazolecarboxamide</td><td> 4,36</td>

73 196 / ΒΕ

121 • · · ·

<td> 216.</td><td>_H3C '^J'''^&lt;II’^kCH₃</td><td>2 - {[(4-methoxybenzyl) - carbamoyl] amino} -4- methyl-N- (2,4,6-trimethyl- ) -5- thiazolecarboxamide</td><td> 4,12</td>

<td> 217.</td><td>»/ * 3 \ = &lt;T ph₃ &lt;5</td><td>2 - {[(2,2-diphenylethyl) - -carbamoyl] -amino} -4- methyl-N- (2,4,6-trimethyl- ) -5- thiazolecarboxamide</td><td> 4,57</td>

<td> 218.</td><td>^HZN Xjl h₃c '^ *^z^ ch₃</td><td>2 - {[N- (2-aminoethyl) -N- phenylcarbamoyl] amino} - -4-methyl-N- (2,4,6 trimethylphenyl) -5- thiazolecarboxamide</td><td> 3,70</td>

<td> 219.</td><td> 0-^ch3 Ν_ζθΗ₃SHE "Λ H₃C '^^&lt;CH₃</td><td>2 - {[2- (3-methoxyphenyl) - ethyl] carbamoyl] amino} - -4-methyl-N- (2,4,6- -trimethylphenyl) -5- thiazolecarboxamide</td><td> 4,26</td>

<td> 220.</td><td>ch₃Oh .O-CHa N ^^CH3 "Λ HGC ^^ CWhen</td><td>2 - [{[2- (3,4-dimethoxy) phenyl) ethyl] carbamoyl} - amino] -4-methyl-N- (2,4,6- trimethylphenyl) -5- thiazolecarboxamide</td><td> 4,05</td>

<td> 221.</td><td>Λ,</td><td>2 is {[2- (4-methoxyphenyl) - ethyl] carbamoyl} amino] - -4-methyl-N-2,4,6- trimethylphenyl) -5- thiazolecarboxamide</td><td> 4,25</td>

73 196 / BE

122

<td> 222.</td><td>Ο</td><td>⁰</td><td>.I₃T ° f «3 »· Ρ".</td><td>4-methyl-2 - {[(3-phenyl- propyl) carbamoyl] - amino} -N- (2,4,6- trimethylphenyl) -5- thiazolecarboxamide</td><td> 4,40</td>

<td> 223.</td><td>Q</td><td></td><td>_ZCH₃P ° CH, Pn</td><td>2 - [{[2- (cyclohex-l-en-1- yl) ethyl] carbamoyl} - amino] -4-methyl-N- (2,4,6-</td><td> 4,11</td>

<td></td><td></td><td></td><td></td><td>trimethylphenyl) -5- thiazolecarboxamide</td><td></td>

<td> 224.</td><td>HGC</td><td>CT3</td><td></td><td>2 - {[(4-tert-butyl-</td><td> 4,85</td>

<td></td><td>H3C</td><td>Q</td><td>ch₃T ° C t^If</td><td>cyclohexyl) carbamoyl] - amino} -4-methyl-N- (2,4,6- -trimethylphenyl) -5- thiazolecarboxamide</td><td></td>

<td></td><td></td><td colspan="2">H3 C ^^ CHa</td><td></td><td></td>

<td> 225.</td><td></td><td></td><td>pc</td><td>2 - {[(3-butoxypropyl) - carbamoyl] amino} -4-</td><td> 4,33</td>

<td></td><td colspan="2"></td><td></td><td>methyl-N- (2,4,6-trimethyl- ) -5-</td><td></td>

<td></td><td></td><td></td><td></td><td>thiazolecarboxamide</td><td></td>

<td> 226.</td><td></td><td rowspan="2"></td><td>ch₃</td><td>2 - [{[2- (2-methoxyphenyl) -</td><td> 4,46</td>

<td></td><td></td><td>T QH₃</td><td>ethyl] carbamoyl} amino] -</td><td></td>

<td></td><td> /</td><td></td><td></td><td>-4-methyl-N- (2,4,6</td><td></td>

<td></td><td></td><td>^% Κ₃</td><td> 4₃σ ^^ ΟΗ₃</td><td>trimethylphenyl) -5- thiazolecarboxamide</td><td></td>

<td> 227.</td><td></td><td rowspan="2">N-</td><td>, CH₃</td><td>2 - {[(2-chloro-4-fluoro-</td><td> 4,39</td>

<td></td><td></td><td>T CHq</td><td>benzyl) -carbamoyl] -</td><td></td>

<td></td><td colspan="2">⁰the</td><td>Yu,</td><td>amino} -4-methyl-N- (2,4,6- trimethylphenyl) -5-</td><td></td>

<td></td><td></td><td></td><td></td><td>thiazolecarboxamide</td><td></td>

73.196 / BE • ·

123

<td> 228.</td><td></td><td>2 - [(IV-methyl-IV-hexyl carbamoyl) amino] -4- -methyl-IV- (2,4,6-trimethyl- ) -5- thiazolecarboxamide</td><td> 4, 65</td>

<td> 229.</td><td>Oz = °</td><td>2 - [{[1- (4-chlorophenyl) - -ethyl] -carbamoyl } -amino] - -4-methyl-IV- (2,4,6- trimethylphenyl) -5- thiazolecarboxamide</td><td> 4,42</td>

<td> 230.</td><td>HGC '^^ CWhen</td><td>2 - [{[2- (3-chlorophenyl) - ethyl] carbamoyl} amino] - -4-methyl-N- (2,4,6- trimethylphenyl) -5- thiazolecarboxamide</td><td> 4,44</td>

<td> 231.</td><td>1ώ "</td><td>4-methyl-2 - [{[(2- (2- thienyl) ethyl] - carbamoyl} amino] -N- - (2,4,6-trimethylphenyl) - -5thiazolecarboxamide</td><td> 4,18</td>

<td> 232.</td><td>Q MO \ ° fH, 'Λ,</td><td>2 - [{[2- (2-fluorophenyl) - ethyl] carbamoyl} amino] - -4-methyl-IV- (2,4,6) -trimethylphenyl) -5- thiazolecarboxamide</td><td> 5,85</td>

<td> 233.</td><td>N ^ /^CH3 / ° ZC , Ή · T? Hs σ · iá „,</td><td>4-methyl-2 - {[{2 - [(2- pyridyl) oxy] ethyl} - carbamoyl] amino) -N- - (2,4,6-trimethylphenyl) - -5thiazolecarboxamide</td><td> 4,28</td>

73 196 / BE

124

<td> 234.</td><td>U · x^Br H₃cX x CH₃</td><td>2 - {[Ν- (2-bromo-4,5- dimethoxy-benzyl) -Ν- -methyl.carbamoyl] -amino} - -4-methyl-N- (2,4,6) trimethylphenyl) -5- thiazolecarboxamide</td><td> 3,87</td>

<td> 235.</td><td>XX, HjC- \ ch₃</td><td>(E) -2 - {[(3,7-dimethyl-2,6- -oktadienil) carbamoyl] - amino} -4-methyl-N- (2,4,6- trimethylphenyl) -5- thiazolecarboxamide</td><td> 4, 34</td>

<td> 236.</td><td>Xy * · ΑΧ</td><td>2 - [{[(2,3-dihydro-1,4- benzodioxin-2-yl) - methyl] -carbamoyl} - amino] -4-methyl-N- (2,4,6- trimethylphenyl) -5- thiazolecarboxamide</td><td> 4,27</td>

237-285, Example

General procedure

A 237-285. compounds were prepared according to the following procedure.

A solution of 181-phenylcarbamate (18 mg) (0.054 mmol) and 0.08 mmol of the corresponding amine in 3 ml of a 1: 1 mixture of tetrahydrofuran / acetonitrile was stirred at room temperature overnight. The reaction mixture was diluted with dichloromethane (4 mL), and the solution was washed twice with 1.5 mL of 1 M hydrochloric acid and twice with 1.5 mL of 1 M aqueous sodium hydroxide. The methylene chloride solution was separated, dried over anhydrous magnesium sulfate, filtered and concentrated to give the desired product.

73 196 / BE

125 • ·· · • ··

Ά 237-278. for compounds "HPLC R_T refers to HPLC retention time measured under the following conditions: YMC S5 ODS 4.6 * 50 mm Ballastic column, 4 minute gradient from 100% solvent A (10% methanol, 90% water, 0.2% phosphoric acid) 100 To solvent B (90% methanol, 10% water, 0.2% phosphoric acid), flow rate 4 ml / min, λ = 220 nm.

A 279-285. The following HPLC conditions were used for the compounds: Zorbax S8-C18 4.5 mm * 7.5 cm short column, 8 minute gradient from 100% solvent A (10% methanol, 90% water, 0.2% phosphoric acid) ) To 100% solvent B (90% methanol, 10% water, 0.2% phosphoric acid), flow rate 2.5 ml / min, λ = 217 nm.

<td>Example number</td><td colspan="3">Compound structure</td><td>Compound name</td><td>HPLC Ltd. (minute)</td>

<td> 237 .</td><td></td><td></td><td></td><td>2 - [{[3-methoxy-5- - (trifluoromethyl) phenyl] - carbamoyl} amino] -4-</td><td> 5,36</td>

<td></td><td></td><td>S</td><td>ch₃THE</td><td>-methyl-N- (2,4,6-trimethyl- ) -5- thiazolecarboxamide</td><td></td>

<td></td><td></td><td></td><td>^^ CWhen</td><td></td><td></td>

<td> 238.</td><td>THE</td><td></td><td></td><td>2 - {[(4-cyclohexyl-phenyl) - carbamoyl] amino} -4-</td><td> 4,73</td>

<td></td><td>M</td><td></td><td></td><td>methyl-N- (2,4,6-trimethyl-</td><td></td>

<td></td><td rowspan="2"></td><td>.CH₃</td><td></td><td>) -5-</td><td></td>

<td></td><td>V</td><td>PH₃</td><td>thiazolecarboxamide</td><td></td>

<td></td><td></td><td></td><td>^ ch₃</td><td></td><td></td>

73.196 / BE • ·

126 ·· · · • · · · · · • ···· · « · ··

<td> 239.</td><td>-¾. THE.</td><td>4-methyl-2 - {[(5,6,7,8- tetrahydro-l-naphthyl) - carbamoyl] amino} -N- - (2,4,6-trimethylphenyl) - -5thiazolecarboxamide</td><td> 5,38</td>

<td> 240.</td><td>λΑ^0,3y / "^CWhenHGC</td><td>2 - {[(1-anthryl) - carbamoyl] amino} -4- methyl-N- (2,4,6-trimethyl- ) -5- thiazolecarboxamide</td><td> 4,82</td>

<td> 241.</td><td>% THE.,</td><td>2 - {[(4-chloro-l-naphthyl) - carbamoyl] amino} -4- -methyl-N- (2,4,6-trimethyl- ) -5- thiazolecarboxamide</td><td> 4,76</td>

<td> 242 .</td><td>The M_Z^CH3 "Ά.</td><td>4-methyl-2 - {[(2-naphthyl) - carbamoyl] amino} -N- - (2,4,6-trimethylphenyl) - -5thiazolecarboxamide</td><td> 5,28</td>

<td> 243.</td><td>AJA&gt; She H₃C JP ». ^ - η ° ° HAC</td><td>2- {[(ΙΗ-5-indolyl) - carbamoyl] amino} -4- methyl-N- (2,4,6-trimethyl- ) -5- thiazolecarboxamide</td><td> 5, 00</td>

73 196 / BE

127 *« ·· ···· · ··*· • · · · · · • ··· · ·· ··· • · *· *··· · ·«·· ·· · « ·»·

<td rowspan="3"> 244.</td><td colspan="4"></td><td rowspan="3">2 - {[(1,3-benzodioxol-5- -yl) carbamoyl] amino} -4- -methyl-N- (2,4,6-trimethyl- ) -5- thiazolecarboxamide</td><td rowspan="3"> 4,76</td>

<td rowspan="2"></td><td colspan="2">.ch₃V ° fHa Ά</td><td rowspan="2">ch₃</td>

<td></td><td></td>

<td> 245.</td><td>q N</td><td></td><td></td><td></td><td>4-methyl-2 - {[(2- pyrazinyl) carbamoyl] -</td><td> 3,84</td>

<td></td><td>Ox ^N"V"^C</td><td>fl₃r °?</td><td>H3</td><td></td><td>-amino} -N- (2,4,6- -trimethylphenyl) -5-</td><td></td>

<td></td><td></td><td>M</td><td></td><td></td><td>thiazolecarboxamide</td><td></td>

<td></td><td colspan="4">HaC ^^ CH₃</td><td></td><td></td>

<td> 246.</td><td></td><td></td><td></td><td></td><td>2 - {[(5-chloro-2-pyridyl) -</td><td> 4,38</td>

<td></td><td>Q</td><td></td><td></td><td></td><td>carbamoyl] amino} -4-</td><td></td>

<td></td><td></td><td>ch₃</td><td></td><td></td><td>methyl-N- (2,4,6-trimethyl- ) -5-</td><td></td>

<td></td><td></td><td colspan="2">I ch₃</td><td></td><td>thiazolecarboxamide</td><td></td>

<td></td><td colspan="2">η, Α</td><td colspan="2">^ ch₃</td><td></td><td></td>

<td> 247.</td><td>• A7 &lt;&lt;]</td><td>&gt; ch₃L ^ o</td><td>PH₃</td><td></td><td>4-methyl-2 - {[(6-methyl-2- pyridyl) carbamoyl] - amino} -N- (2,4,6- trimethylphenyl) -5-</td><td> 4,44</td>

<td></td><td></td><td></td><td>s</td><td></td><td>thiazolecarboxamide</td><td></td>

<td></td><td></td><td>HGC</td><td>• ^ ia</td><td>ch₃</td><td></td><td></td>

<td> 248.</td><td></td><td></td><td></td><td></td><td>4-methyl-2 - {[(2-methyl-4-</td><td> 5,23</td>

<td></td><td>H3^cAlc</td><td></td><td></td><td></td><td>quinolinyl) carbamoyl] -</td><td></td>

<td></td><td></td><td>/ CH₃</td><td>PH₃</td><td></td><td>-amino} -N- (2,4,6- trimethylphenyl) -5- thiazolecarboxamide</td><td></td>

<td></td><td></td><td>Ύ</td><td>s</td><td></td><td></td><td></td>

<td></td><td></td><td>hfeC</td><td>• XI? The</td><td>'ch₃</td><td></td><td></td>

73 196 / BE

128 • · · · ··

<td rowspan="2"> 249.</td><td colspan="2">Whoa₃</td><td rowspan="2">2 - {[(2,3-dihydro-4- benzodioxan-6-yl) - carbamoyl] amino} -4- -methyl-N- (2,4,6-trimethyl- ) -5- thiazolecarboxamide</td><td rowspan="2"> 4,72</td>

<td>η₃&lt;/</td><td>^^ CWhen</td>

<td> 250.</td><td>ao</td><td></td><td>2 - {[(2-biphenylyl) -</td><td> 5,29</td>

<td></td><td></td><td></td><td>carbamoyl] amino} -4-</td><td></td>

<td></td><td> -7^N h ^^CH3Άτς. J</td><td>&lt;? H₃</td><td>methyl-N- (2,4,6-trimethyl- ) -5- thiazolecarboxamide</td><td></td>

<td></td><td>Η, ίΛ</td><td>^ ch₃</td><td></td><td></td>

<td> 251.</td><td>^ EC) #V^CH3</td><td></td><td>2 - {[(4-methoxy-2-methyl- phenyl) carbamoyl] -</td><td> 4,80</td>

<td></td><td colspan="2">/ m, CH.</td><td>amino} -4-methyl-N- (2,4,6-</td><td></td>

<td></td><td></td><td>SHE</td><td>trimethylphenyl) -5-</td><td></td>

<td></td><td>Γ N '</td><td>ch₃</td><td>thiazolecarboxamide</td><td></td>

<td></td><td>H3C</td><td>Í ^ CWhen</td><td></td><td></td>

<td> 252.</td><td>Haq / = \ ™</td><td></td><td>4-methyl-N- (2,4,6-</td><td> 5, 06</td>

<td></td><td>M</td><td></td><td>trimethylphenyl) -2-</td><td></td>

<td></td><td></td><td>ch₃</td><td>- {[(2,4,6-1remimeth1- phenyl) carbamoyl] - amino} -5-</td><td></td>

<td></td><td>i¹</td><td>X = CH,</td><td>thiazolecarboxamide</td><td></td>

<td> 253.</td><td>qa " /^N »Ch₃-MX.</td><td>ch₃</td><td>2 - [{[2- (2-hydroxyethyl) - phenyl] carbamoyl} - -amino] -4-methyl-N- (2,4,6- trimethylphenyl) -5-</td><td> 4,02</td>

<td></td><td>Ύ</td><td>s</td><td>thiazolecarboxamide</td><td></td>

<td></td><td></td><td>^ ch₃</td><td></td><td></td>

73.196 / BE • »c ·

129

<td rowspan="2"> 254.</td><td colspan="3"></td><td rowspan="2">2 - {[(3-methoxyphenyl) - carbamoyl] amino} -4- methyl-N- (2,4,6-trimethyl- ) -5- thiazolecarboxamide</td><td rowspan="2"> 4,86</td>

<td>OK N-</td><td></td><td>pb I ^ ch₃</td>

<td> 255.</td><td></td><td>H₃&lt;?</td><td rowspan="2"></td><td>2 - {[(4-methoxy-3-</td><td> 4,81</td>

<td></td><td>Hap</td><td></td><td>biphenylyl) carbamoyl] -</td><td></td>

<td></td><td rowspan="2">cH₃^cyA ch₃</td><td>rtrto</td><td></td><td>amino} -4-methyl-N- (2,4,6- trimethylphenyl) -5-</td><td></td>

<td></td><td></td><td></td><td>thiazolecarboxamide</td><td></td>

<td> 256.</td><td>VQ C ·</td><td>rv '</td><td></td><td>2 - {[(3-acetylphenyl) - carbamoyl] amino} -4- -methyl-N- (2,4,6-trimethyl-</td><td> 4,12</td>

<td></td><td></td><td>'' Y</td><td>pb</td><td>) -5-</td><td></td>

<td></td><td></td><td></td><td>s</td><td>thiazolecarboxamide</td><td></td>

<td></td><td></td><td>η, Λ</td><td>^ 0Η₃</td><td></td><td></td>

<td> 257.</td><td colspan="2">.ch₃aAó-</td><td></td><td>2 - {[(4-cyanophenyl) - carbamoyl] amino} -4-</td><td> 4,15</td>

<td></td><td></td><td></td><td>CH ₃</td><td>-methyl-77- (2,4,6-trimethyl-</td><td></td>

<td></td><td></td><td>h₃c</td><td></td><td>) -5-</td><td></td>

<td></td><td>II N</td><td></td><td></td><td>thiazolecarboxamide</td><td></td>

<td> 258.</td><td rowspan="2">Wrote'</td><td>/ CH₃</td><td></td><td>2 - [{[4-fluoro-2- - (trifluoromethyl) phenyl] - carbamoyl} amino] -4-</td><td> 4,99</td>

<td></td><td>Co</td><td></td><td>-methyl-N- (2,4,6-trimethyl-</td><td></td>

<td></td><td></td><td>Irish</td><td></td><td>) -5-</td><td></td>

<td></td><td></td><td></td><td>^ CWhen</td><td>thiazolecarboxamide</td><td></td>

73.196 / BE ····

130 »·· * ·· t · ····

<td> 259.</td><td>^Η3 &lt;Λ. h</td><td>2 - [{[4- (hexyloxy) - phenyl] carbamoyl} - amino] -4-methyl-N- (2,4,6- trimethylphenyl) -5- thiazolecarboxamide</td><td> 4,42</td>

<td> 260.</td><td>M</td><td>ethyl 4 - {[{4-methyl-5- - [(2,4,6-trimethylphenyl) - carbamoyl] -2-thiazolyl} - carbamoyl] amino} - benzoate</td><td> 4,26</td>

<td> 261.</td><td> ^¾.</td><td>2 - {[(4-decyl-phenyl) - carbamoyl] amino} -4- -methyl-N- (2,4,6-trimethyl- ) -5- thiazolecarboxamide</td><td></td>

<td> 262 .</td><td> 1 9^H3</td><td>4-methyl-2 - {[(4-propyl phenyl) carbamoyl] - amino} -N- (2,4,6- trimethylphenyl) -5- thiazolecarboxamide</td><td> 4,71</td>

<td> 263.</td><td>&lt;F "\ o-CH₃⁵ Ύ &lt;? H₃xc,</td><td>4-methyl-2 - {[(3,4,5- trimethoxy-phenyl) - carbamoyl] amino} -N- - (2,4,6-trimethylphenyl) - -5thiazolecarboxamide</td><td> 4,67</td>

73 196 / BE

131 ···' • * ·« ··· · · • · · · · · « ·♦· · · · ··· • · « · ···· » •••4 ·· · · ···

<td> 264.</td><td>Q /^N n ^ ch.</td><td>4-methyl-2 - {[{4 - [(5-methyl- -3-isoxazolyl) - sulfamoyl] -phenyl} - carbamoyl] amino} -N- - (2,4,6-trimethylphenyl) - -5thiazolecarboxamide</td><td> 4,27</td>

<td> 265.</td><td>AQ /^N O / CH₃THE</td><td>-butyl 4 - {[{4-methyl-5- - [(2,4,6-trimethylphenyl) - carbamoyl] -2-thiazolyl} - carbamoyl] amino} - benzoate</td><td> 4,75</td>

<td> 266.</td><td>N pt.^S T CHa κ, ΑΧ,</td><td>2 - {[(1-isoquinolyl) - carbamoyl] amino} -4- methyl-N- (2,4,6-trimethyl- ) -5- thiazolecarboxamide</td><td> 3,81</td>

<td> 267.</td><td>-O ^ AAA? »3 &lt;ϊ ^ · ζ2^Ν r^CH'Q</td><td>4-methyl-2 - [{[2- (benzyl- thio) phenyl] carbamoyl} - amino] -N- (2,4,6- trimethylphenyl) -5- thiazolecarboxamide</td><td> 4,42</td>

<td> 268.</td><td>Q H3 &lt;AA_CH3</td><td>4-methyl-2 - {[{4 - [(5- phenoxy-pentyl) oxy] - phenyl} carbamoyl] - -amino} -N- (2,4,6- trimethylphenyl) -5- thiazolecarboxamide</td><td> 4,96</td>

73.196 / BE ·· ···· · ····

132

<td rowspan="2"> 269.</td><td colspan="2"> «3?</td><td rowspan="2">2 - [{[5- (1,1-dimethyl- propyl) -2-methoxy-phenyl] - carbamoyl} amino] -4- methyl-N- (2,4,6-trimethyl- ) -5- thiazolecarboxamide</td><td rowspan="2"> 5,76</td>

<td>&lt;? "THE</td><td>Wv^CHSh₃c Ό</td>

<td> 270.</td><td colspan="2">«• vt-v * · ^ 5^-CH' H3C</td><td>2 - {[(1,2-dihydro-5- -acenaftenil) carbamoyl] - amino} -4-methyl-N- (2,4,6- trimethylphenyl) -5- thiazolecarboxamide</td><td> 4,70</td>

<td> 271.</td><td colspan="2">° A, A,</td><td>4-methyl-2 - {[(3-phenoxy phenyl) carbamoyl] - amino} -N- (2,4,6- trimethylphenyl) -5- thiazolecarboxamide</td><td> 4,70</td>

<td> 272.</td><td>GG ° aq</td><td> £</td><td>4-methyl-2 - {[(2-morpholino- phenyl) carbamoyl] - amino} -N- (2,4,6- trimethylphenyl) -5- thiazolecarboxamide</td><td> 5, 01</td>

<td></td><td>THE</td><td>ah₃</td><td></td><td></td>

<td> 273.</td><td>QO s</td><td>PHA</td><td>4-methyl-2 - [{[2- (1- piperidinyl) phenyl] - carbamoyl} amino] -N- - (2,4,6-trimethylphenyl) - -5thiazolecarboxamide</td><td> 5, 55</td>

<td></td><td>H₃C</td><td>1 ^ CWhen</td><td></td><td></td>

33.196 / BE • ·

133

<td> 274 .</td><td>Ο - "= HGC</td><td>2 - {[(1-acetyl-2,3- dihydro-lH-6-yl) - carbamoyl] amino} -4- TV-methyl (2,4,6-trimethyl- ) -5- thiazolecarboxamide</td><td> 4,08</td>

<td> 275.</td><td> /^Ν M = Z^CH3 H₃C '^^#^ 'CH₃</td><td>2 - {[(2-bromo-5-methoxy- phenyl) carbamoyl] - -amino} -4-methyl-2V- (2,4,6) -trimethylphenyl) -5- thiazolecarboxamide</td><td> 4,55</td>

<td> 276.</td><td>ΛΑΑ ' V ^Ν CH₃ό V / L^0,3yy "^CH3 HAC</td><td>2 - {[(2,3-dimethyl-yl-5-) indolyl) carbamoyl] - -amino} -4-methyl-TV- (2,4,6) trimethylphenyl) -5- thiazolecarboxamide</td><td> 4, 30</td>

<td> 277 .</td><td>λΛ Λν ο- ^ ΐ , Hch * « HaQ Λ-ί ³0 = H3C</td><td>4-methyl-2 - [{[2- - (isopropylcarbamoyl) - phenyl] carbamoyl} - amino] -N- (2,4,6- trimethylphenyl) -5- thiazolecarboxamide</td><td> 4,82</td>

<td> 278 .</td><td>Λ&gt; λ. 1 ch₃6- Hayat ^0,35- £ «» hfeC</td><td>2 - {[(3-bromo-2-methyl- phenyl) carbamoyl] - -amino} -4-methyl-TV- (2,4,6) -trimethylphenyl) -5- thiazolecarboxamide</td><td> 4, 60</td>

73 196 / BE

134

<td> 279.</td><td>^ CH, n, C</td><td>2 - {[(4-methoxy-butyl) - carbamoyl] amino} -4- methyl-N- (2,4,6-trimethyl- ) -5- thiazolecarboxamide</td><td> 7,62</td>

<td> 280.</td><td>ch₃ 0 pX ™³H3C</td><td>2 - {[(3,3-dimethylbutyl) - carbamoyl] amino} -4- -methyl-N- (2,4,6-trimethyl- ) -5- thiazolecarboxamide</td><td> 9,13</td>

<td> 281.</td><td>j ^ CH 5 H 3 C —FA ιΧ &lt;1ΓΆΧ1 U ° η, Α ^ </td><td>4-methyl-2 - {[(2-methyl- butyl) carbamoyl] - -amino} -N- (2,4,6- trimethylphenyl) -5- thiazolecarboxamide</td><td> 8, 90</td>

<td> 282.</td><td>h₃c</td><td>4-methyl-2 - {[(3-methyl- butyl) carbamoyl] - -amino} -N- (2,4,6- trimethylphenyl) -5- thiazolecarboxamide</td><td> 8,98</td>

<td> 283.</td><td>.c "3 h₃c</td><td>2 - {[(2-methoxyethyl) - carbamoyl] amino} -4- -methyl-N- (2,4,6-trimethyl- ) -5- thiazolecarboxamide</td><td> 7,30</td>

<td> 284.</td><td>* S 9 J * 'H, c HJC</td><td>2 - [{[2- (dimethylamino) - ethyl] carbamoyl} amino] - -4-methyl-N- (2,4,6 trimethylphenyl) -5- thiazolecarboxamide</td><td> 5,73</td>

<td> 285.</td><td>ch₃^Hs^c'^S'' '' ~ '' Ά CH₃h₃c</td><td>4-methyl-2 - [{[2- (methyl- thio) ethyl] carbamoyl} - amino] -N- (2,4,6- trimethylphenyl) -5- thiazolecarboxamide</td><td> 8,19</td>

73.196 / BE • ·

135 , ··· · · ···· · ···· ·· · · ···

286-311. example

General procedure

With the exception of compound 307, the compounds 286-311. compounds were prepared according to the following procedure.

of a solution of {[2 - {[(butylamino) carbonyl] amino} -4-methyl-5-thiazolyl] carbonyl} chloride (0.11 mmol) and 0.12 mmol of the corresponding amine in 1 mL of tetrahydrofuran N, N-diisopropylethylamine (22.6 μiz, 0.13 mmol) was added. The reaction mixture was purged with argon, then mechanically stirred in a sealed vial for 22 hours and then diluted with 4 mL of dichloromethane. The solution was washed three times with 2M hydrochloric acid solution, the organic phase was separated, dried over anhydrous sodium sulfate, filtered and concentrated. The crude products were purified by trituration with a 1: 1 mixture of dichloromethane / diethyl ether or silica gel column chromatography eluting with ethyl acetate / hexane (80:20 v / v) followed by HPLC. performed [conditions: YMC S5 ODS A 20 * 100 mm column, 10 min gradient at 30% v / v A]. a mixture of solvent (90% methanol, 10% water, 0.1% trifluoroacetic acid) and 70% solvent B (10% methanol, 90% water, 0.1% trifluoroacetic acid) 100 Up to 20 ml / min, λ = 220 nm)].

Compound 307 was prepared according to the following procedure. 100 mg (0.36 mmol) of 2 - {[(butylamino) carbonyl] amino} -4-methyl-5-thiazolecarboxylic acid, 170 mg (0.44 mmol) of HATU and 3 mL of N, N-dimethyl73. 196 / BE

136 N, N-diisopropylethylamine (62 μΐ, 0.44 mmol) was added to a suspension of ethyl formamide. The reaction mixture was heated at 60 ° C for 2 hours, then cooled, diluted with 12 mL of dichloromethane, then 3 x 6 mL of 2 M hydrochloric acid and 3 x 6 mL of 5% aqueous potassium bicarbonate. solution, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was triturated with ethyl acetate / diethyl ether to give 102 mg (74%) of the mixed anhydride intermediate as a white solid. To a solution of 19.4 mg (0.12 mmol) of 2,6-dichloroaniline in 1 mL of tetrahydrofuran was added dropwise 170 mL (0.17 mmol) of

M solution of sodium bis (trimethylsilyl) amide in tetrahydrofuran.

Fifteen minutes later, mixed anhydride intermediate (41.3 mg, 0.11 mmol) was added once. A few drops of N, N-dimethylformamide were added to the reaction mixture and the solution was stirred for 16 hours. An additional 110 μΐ sodium bis (trimethylsilyl) amide solution was added and stirring was continued for another two hours. The reaction mixture was diluted with dichloromethane (ml), washed with 2M hydrochloric acid (3 x 2 ml) and saturated aqueous potassium bicarbonate (3 x saturated), dried over anhydrous sodium sulfate, filtered and concentrated. The solid was washed twice with hexane, and the residue was chromatographed on a silica gel column eluting with ethyl acetate / hexane (80:20 v / v) followed by ethyl acetate. It is a light tan solid (12 mg)

73 196 / BE

137 The title compound was obtained (27% yield).

"HPLC Rt is the HPLC retention time measured under the following conditions: YMC S5 ODS 4.6 χ 50 mm Ballastic column, 4 minute gradient from 100% solvent A (10% methanol, 90% water, 0.2 volume) % phosphoric acid) to 100% solvent B (90% methanol, 10% water, 0.2% phosphoric acid), flow rate 4 ml / min, λ = 220 nm.

<td>Example number</td><td>Compound structure</td><td>Compound name</td><td>HPLC rj (minute)</td>

<td> 286.</td><td>while Z-ch₃ctr</td><td>2 - [(Butylcarbamoyl) - amino] -N- (2,3-dihydro- -1-phenyl-5-indenyl) -4-methyl-5- thiazolecarboxamide</td><td> 4,20</td>

<td> 287.</td><td>ccr</td><td>2 - [(Butylcarbamoyl) - -amino] -N- (2-naphthyl) -4- methyl-5-thiazolecarboxamide</td><td> 4,20</td>

<td> 288.</td><td></td><td>2 - [(Butylcarbamoyl) - amino] -N- (3-hydroxy-2- naphthyl) -4-methyl-5- thiazolecarboxamide</td><td> 4,24</td>

<td> 289.</td><td>H3C Qn _CH?F</td><td>2 - [(butylcarbamoyl) - amino] -N- (2-fluoro-5- methyl-phenyl) -4-methyl-5- thiazolecarboxamide</td><td> 3,95</td>

73 196 / BE

138

<td> 290.</td><td></td><td>2 - [(Butylcarbamoyl) - -amino] -N- (2,6-dimethyl- phenyl) -4-methyl-5- thiazolecarboxamide</td><td> 3,78</td>

<td> 291.</td><td>VY Z- ^ O 'hH, HaC- ^</td><td>N- (4-bromo-2-methylphenyl) - -2- [(butylcarbamoyl) - amino] -4-methyl-5- thiazolecarboxamide</td><td> 4,12</td>

<td> 292.</td><td>HAC &gt; N ° y ~ s ch₃H »^c % &lt;Α&gt; λ_εΗ3</td><td>N- (3-bromo-2,4,6-trimethyl- -phenyl) -2- [(butyl- carbamoyl) amino] -4- methyl-5-thiazolecarboxamide</td><td> 4,28</td>

<td> 293.</td><td>CH₃ CH ^ T ^S</td><td>2 - [(butylcarbamoyl) - -amino] -N- (2,6-dimethyl-3- isopropyl-phenyl) -4- methyl-5-thiazolecarboxamide</td><td> 4,28</td>

<td> 294.</td><td>Br</td><td>N- (2-bromo-4,6-dimethyl- phenyl) -2 - [(butyl carbamoyl) amino] -4- methyl-5-thiazolecarboxamide</td><td> 4,00</td>

<td> 295.</td><td>HAC &gt; ~ N ° y ~ s coocHs HaC O / X /^SH3C</td><td>methyl 3 - {[{2 - [(butyl carbamoyl) amino] -4- methyl-5-thiazolyl} - carbonyl] amino} -4- methyl-2-thiophenecarboxylate</td><td> 3,83</td>

<td> 296.</td><td>O / -CH1 · PCR "W</td><td>2 - [(butylcarbamoyl) - -amino] -4-methyl-IV- (2- -methyl-6-quinolyl) -5- thiazolecarboxamide</td><td> 2,98</td>

73 196 / BE

139

<td> 297.</td><td>ch₃</td><td>2 - [(Butylcarbamoyl) - amino] -N- (2,6-dimethoxy- phenyl) -4-methyl-5- thiazolecarboxamide</td><td> 3,39</td>

<td> 298.</td><td>CGR H3C⁰</td><td>2 - [(Butylcarbamoyl) - amino] -N- (4-methoxy-2- naphthyl) -4-methyl-5- thiazolecarboxamide</td><td> 4,31</td>

<td> 299.</td><td>«-Vh Cc-X » 4&gt; ch₃°</td><td>2 - [(butylcarbamoyl) - amino] -N- (2-methyl-l- naphthyl) -4-methyl-5- thiazolecarboxamide</td><td> 3, 92</td>

<td> 300.</td><td>ch₃ ch₃DSB H 3 C- / ^u</td><td>2 - [(butylcarbamoyl) - amino] -N- [4- (dimethyl- amino) -2,3,5,6- N'-phenyl] -4- methyl-5-thiazolecarboxamide</td><td> 3,14</td>

<td> 301.</td><td>X is&gt; CH₃°</td><td>2 - [(Butylcarbamoyl) - amino] -N- (6-methyl-5- quinolinyl) -4-methyl-5- thiazolecarboxamide</td><td> 3, 13</td>

<td> 302.</td><td>Ϊ ec</td><td>2 - [(butylcarbamoyl) - amino] -N- [2- (2-hydroxy- ethyl) -6-methylphenyl] -4- methyl-5-thiazolecarboxamide</td><td> 3,50</td>

73.196 / BE • · · ·

140 • · · • · · · · · • · ·· · * · · · ·

<td rowspan="2"> 303.</td><td rowspan="2">H3 &lt;^</td><td colspan="2">° CHg p-</td><td rowspan="2">2 - [(butylcarbamoyl) - -amino] -N- (2,6-dimethyl-3- nitro-phenyl) -4-methyl-5- thiazolecarboxamide</td><td rowspan="2"> 3,75</td>

<td>HGC</td><td>* No «°</td>

<td> 304.</td><td></td><td>Kai</td><td rowspan="3">ch₃</td><td>N- (2-Bromo-3,4,6-trimethyl-</td><td> 4,12</td>

<td></td><td>HjC- ^</td><td></td><td>-phenyl) -2- [(butyl-</td><td></td>

<td rowspan="2"></td><td rowspan="2">&gt; H3C</td><td rowspan="2">Br</td><td rowspan="2">carbamoyl) amino] -4- methyl-5-thiazolecarboxamide</td><td rowspan="2"></td>

<td></td>

<td> 305.</td><td></td><td></td><td rowspan="2">Ι-Χ * -N</td><td>N- (2-acetyl-6-hydroxy)</td><td> 3,75</td>

<td></td><td> &lt;</td><td> 05-</td><td>phenyl) -2 - [(butyl</td><td></td>

<td></td><td>P^H</td><td>Ύ ^s</td><td></td><td>carbamoyl) amino] -4-</td><td></td>

<td></td><td>γΊ</td><td>_ N Γ</td><td></td><td>methyl-5-thiazolecarboxamide</td><td></td>

<td></td><td></td><td>1, CH₃</td><td></td><td></td><td></td>

<td></td><td></td><td> 0</td><td></td><td></td><td></td>

<td> 306.</td><td></td><td></td><td>h ^ c^h» r ~ cH₃QyO H, C ^ \ n T II</td><td>O-tert-Butyl-N- [4 - {[{2 - - [(butylcarbamoyl) - amino] -4-methyl-5-</td><td> 4,10</td>

<td></td><td></td><td></td><td>- Γ ch₃</td><td>thiazolyl} carbonyl] -</td><td></td>

<td></td><td></td><td rowspan="2"></td><td>1ϊ ⁰</td><td>-amino} -2,3,5,6-</td><td></td>

<td></td><td>HjC- /</td><td>^ ch₃</td><td>N'-phenyl] -</td><td></td>

<td></td><td></td><td></td><td></td><td>carbamate</td><td></td>

<td> 307.</td><td></td><td>She</td><td>_.ch₃</td><td>2 - [(butylcarbamoyl) -</td><td> 4,42</td>

<td></td><td></td><td colspan="2"></td><td>amino] -N- (2,6-dichloro-</td><td></td>

<td></td><td></td><td></td><td>Ci ° ^</td><td>phenyl) -4-methyl-5-</td><td></td>

<td></td><td></td><td></td><td></td><td>thiazolecarboxamide</td><td></td>

<td> 308 .</td><td>HSC "^</td><td></td><td>1-yl⁰”^{3 H}'f III</td><td>N- (4-amino-2,3,5,6- -tetramethylphenyl) -2-</td><td> 3, 15</td>

<td></td><td></td><td></td><td>HgC'g^JIXNH₂ch₃</td><td>- [(butylcarbamoyl) -</td><td></td>

<td></td><td></td><td></td><td></td><td>amino] -4-methyl-5-</td><td></td>

<td></td><td></td><td></td><td></td><td>thiazolecarboxamide</td><td></td>

73 196 / BE

141 • · ··· • · · · · • · · ·

<td> 309.</td><td></td><td>^ N HAc 0</td><td>N- [5- (acetylamino) -2,4 dimethyl-phenyl] -2- - [(butylcarbamoyl) - amino] -4-methyl-5- thiazolecarboxamide</td><td> 3,52</td>

<td> 310.</td><td></td><td></td><td>N- (4-bromo-2,6-dimethyl- phenyl) -2 - [(butyl carbamoyl) amino] -4- methyl-5-thiazolecarboxamide</td><td> 4,51</td>

<td> 311.</td><td>hac ^</td><td>Λ JOC'nJL</td><td>2 - [(Butylcarbamoyl) - amino] -N- (2-chloro-6- methyl-phenyl) -4-methyl-5- thiazolecarboxamide</td><td> 4,51</td>

312th example

4-Methyl-2 - [(methylsulfonyl) amino] -N- (2,4,6-trimethylphenyl) -5-

<img file="HU0202708A2_D0094.tif" />

A. Ethyl 2 - [(methylsulfonyl) amino] -4-methyl-5-thiazolecarboxylate

558 To a solution of ethyl 2-amino-4-methyl-5-thiazolecarboxylate (3 mg) in methylene chloride (15 mL) and pyridine (5 mL) was added methanesulfonyl chloride (687 mg, 6 mmol). The reaction mixture was stirred at room temperature for 6 hours, then diluted with dichloromethane (50 ml), washed with 2M hydrochloric acid (3 x 15 ml), dried over anhydrous magnesium sulfate, filtered and concentrated. The crude residue was diluted with 25 mL of diethyl ether and the solid filtered off.

142 The mixture was washed three times with 10 ml of a 1: 1 mixture of diethyl ether and hexane and dried in vacuo. 687 mg (87%) of the title compound are obtained in the form of an off-white solid.

B. 2 - [(Methylsulfonyl) amino] -4-methyl-5-thiazolecarboxylic acid

300 To a solution of ethyl 2 - [(methylsulfonyl) amino] -4-methyl-5-thiazolecarboxylate (1.14 mmol) in methanol (9 mL) was added 1 M aqueous sodium (28.4 mL, 28.4 mmol) with stirring. hydroxide solution. The reaction mixture was stirred at room temperature overnight, then the solution was discarded to 0 ° C and then acidified to pH 1 with 6M hydrochloric acid. The solution was extracted with a dichloromethane / chloroform solvent mixture. The organic solution was dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. 148 mg (55%) of the title compound are obtained.

C. 4-Methyl-2 - [(methylsulfonyl) amino] -N- (2,4,6-trimethylphenyl) -5-thiazolecarboxamide mg (0.42 mmol) 312B. compound, 68 μΐ (0.5 mmol) 2,4,6-trimethylaniline and 191 mg (0.5 mmol) [O- (7-aza-1-benzotriazolyl) -1,1,3,3-tetramethyl] -uronium] hexafluorophosphate (HATU) in 3 ml of N, N-dimethylformamide was added 87 μΐ (0.5 mmol) of N, N-diisopropylethylamine. The reaction mixture was stirred overnight at room temperature, then diluted with ethyl acetate followed by 15 mL of 0.5 M hydrochloric acid, three times 25 mL of 10% aqueous lithium chloride solution, twice with 930 mL of water and saturated aqueous sodium chloride. solution, dried over anhydrous magnesium sulfate, filtered

73 196 / BE

143 and concentrated. The residue was chromatographed on a silica gel column eluting with 50:50 ethyl acetate / hexane (75:25 v / v) and methanol / ethyl acetate 2:98 (v / v). The title compound was isolated as a white solid (19 mg, 13%).

313th example

Preparation of 4-Methyl-2 - [(anilino-thiocarbamoyl) -amino] -N- (2,4,6-trimethyl-phenyl) -5-thiazolecarboxamide

<img file="HU0202708A2_D0095.tif" />

A solution of 2 mg (0.16 mmol) of compound 2 and 43 mg (0.32 mmol) of phenyl isothiocyanate in 2 ml of pyridine was heated at 80 ° C for 20 hours. The reaction mixture was cooled, diluted with 80 mL of a 3: 1 mixture of dichloromethane / tetrahydrofuran and washed twice with 15 mL of 2M hydrochloric acid. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was diluted with ethyl acetate (20 mL) and the solid was filtered, washed with diethyl ether (3 x 10 mL) and dried in vacuo.

The title compound was obtained as an off-white solid (35 mg, 52%).

73.196 / BE • · * ·

144

Example 314

Preparation of 2 - [(Ethylcarbamoyl) amino] -4-methyl-N- (2,4,6-trimethylphenyl) -5-thiazolecarboxamide₃c ch₃

<img file="HU0202708A2_D0096.tif" />

ch₃

314-180. with the exception that ethyl isocyanate was used in this case. The title compound was obtained as a white solid in 65% yield.

315th example

N- (2-Chloro-6-methylphenyl) -2 - [(cyclopropylcarbonyl) amino] -5-

<img file="HU0202708A2_D0097.tif" />

A. Ethyl 2 - {[(tert-butoxycarbonyl) oxy] amino) -4-methyl-5-thiazolecarboxylate

972 mg (6 mmol) of ethyl 2-amino-5-thiazolecarbonylate [B. Plouvler, C. Bailly, R. Houssin, JP. Henlchart, Heterocycles, 32 (4), 693-701 (1991); and HJ Becker, J. de Jonge, Rec. Trav. Chim., 61,

463 (1942)], a suspension of di-tert-butyl dicarbonate (1.94 g, 9 mmol) and 4- (dimethylamino) pyridine (73 mg, 0.6 mmol) in dry tetrahydrofuran (75 mL) was stirred under nitrogen for 24 hours. . Subsequently, the solvent was evaporated in vacuo

145 ··· «·· roltuk. The residue was suspended in diethyl ether (50 mL) and the solid was washed with diethyl ether (3 x 10 mL) and dried in vacuo. As a result, 1.1 g of the title compound were obtained in 70% yield.

B. 2 - {[(tert-Butoxycarbonyl) oxy] amino} -4-methyl-5-thiazolecarboxylic acid

Mixing with a solution of ethyl 2 - {[(tert-butoxycarbonyl) oxy] amino} -4-methyl-5-thiazolecarboxylate (1.1 g, 4.2 mmol) in 80 mL of a 1: 1 mixture of tetrahydrofuran / methanol aqueous sodium hydroxide solution (20 mL, 120 mmol) was added. After stirring for 24 hours at room temperature, most of the tetrahydrofuran and methanol were removed by distillation under reduced pressure and the aqueous residue was acidified with 22 ml of 6M hydrochloric acid. The precipitated solid was filtered off, washed with water and diethyl ether and then dried in air and then in vacuo. Obtained as an off-white solid (940 mg, 96%).

C. O-tert-Butyl N- {5 - [(2-chloro-6-methylphenyl) carbamoyl] -2-thiazolyl} carbamate

234 To a solution of 2 - {[(tert-butoxycarbonyl) oxy] amino) -4-methyl-5-thiazolecarboxylic acid (1 mg) in a mixture of 10 ml of tetrahydrofuran and a few drops of N, N-dimethylformamide was added dropwise with stirring. 1 ml (2 mmol) of 2 M oxalyl chloride in dichloromethane. The solution was stirred at room temperature for 4 hours, then the solvent was evaporated under reduced pressure and finally in vacuo to give

73.196 / BE • · · · ···

146 the crude acid chloride was obtained.

A solution of crude {[2 - {[(tert-butoxycarbonyl) oxy] amino} -5-thiazolyl] carbonyl} chloride in methylene chloride (10 mL) was added dropwise with stirring to 212 2-chloro-6-methylaniline (mg, 1.5 mmol). To the resulting mixture was added N, N-diisopropylethylamine (516 mg, 4 mmol), and the reaction mixture was warmed to room temperature, stirred for 24 hours, and diluted with dichloromethane (60 mL). The solution was washed with 15 ml of 2M hydrochloric acid, and the organic phase was dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was diluted with 25 mL of ethyl acetate: diethyl ether (1: 4). The solid was filtered off, washed with diethyl ether (4 x 5 mL) and dried in vacuo. The title compound was obtained as a tan solid (175 mg, 48%).

D. 2-Amino-N- (2-chloro-6-methylphenyl) -5-thiazolecarboxamide

A 315D. Compound 315C was prepared in an analogous manner to Compound 2 except that in this case 315C.

compound was used. Yield 315D as a tan solid. title.

E. N- (2-Chloro-6-methylphenyl) -2 - [(cyclopropylcarbonyl) amino] -5-thiazolecarboxamide

50.6 mg (0.19 mmol) 315D. and cyclopropanecarboxylic anhydride (302 mg, 1.96 mmol) in dioxane (2 mL) was heated at 93 ° C overnight. The reaction mixture was concentrated in vacuo, diluted with ethyl acetate, and the solution was saturated aqueous potassium hydroxide.

147 Washed twice with a solution of rogen carbonate twice. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated. The residue was triturated with diethyl ether to give the title compound as a white solid (11 mg, 17%).

316th example

Preparation of 2 - ([tert-Butylcarbamoyl) amino] -N- (2-chloro-6-methylphenyl) -5-thiazolecarboxamide

<img file="HU0202708A2_D0098.tif" />

H₃C ch₃

48.3 mg (0.18 mmol) of 315D. Sodium hydride (19.2 mg, 0.8 mmol) was added to a solution of compound (4) and tert-butyl isocyanate (41 μΐ, 0.36 mmol) in tetrahydrofuran (5 mL) cooled to 0 ° C. One hour later, the reaction mixture was diluted with ethyl acetate and washed with cold saturated aqueous ammonium chloride solution. The aqueous layer was separated and extracted with ethyl acetate. The ethyl acetate solutions were combined, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by automatic preparative HPLC [conditions: YMC S5 ODS A 20 χ 100 mm column, 10 min gradient of 10% v / v solvent A (90% v / v methanol, 10% v / v water, 0.1% v / v trifluoroacetic acid). and 90% v / v B.

solvent (10% methanol, 90% water, 0.1% trifluoroacetic acid) to 100% solvent B, flow rate 73-196 / BE

148 20 ml / min (λ = 220 nm)]. The title compound was obtained as an off-white solid (18 mg, 28%).

317th Example 2 Preparation of {2 - [(tert-Butoxycarbonyl) amino] -4-methyl-5-thiazolyl} -N- (2,4,6-trimethylphenyl) acetamide

CH₃

<img file="HU0202708A2_D0099.tif" />

Compound 317 was prepared in a manner analogous to Compound 1 except that methyl (2-amino-4-methyl-5-thiazolyl) acetate was used. The title compound was obtained as an off-white solid.

318th Example 2 (2-Amino-4-methyl-5-thiazolyl) -N- (2,4,6-trimethylphenyl) acetamide

<img file="HU0202708A2_D0100.tif" />

CH₃

Compound 318 was prepared by a procedure analogous to Compound 2 except that Compound 317 was used in this case. The title compound was obtained as a light brown solid.

73 196 / 3E

149

<img file="HU0202708A2_D0101.tif" />

319th example

N- (2-Chloro-6-methyl-phenyl) -2 - [(4,6-dimethyl-2-pyridyl) -amino] -5-

<img file="HU0202708A2_D0102.tif" />

A. 2-Bromo-N- (2-chloro-6-methylphenyl) -5-thiazolecarboxamide

A solution of copper (II) bromide (2.68 g, 12 mmol) in acetonitrile (50 mL) was purged with nitrogen and cooled to 0 ° C. To the solution was added 2 ml (15 mmol) of tert-butyl nitrite and 2m68 g of 315D was added to the resulting mixture. of acetonitrile in 50 mL of acetonitrile. The reaction mixture was stirred overnight at room temperature and then concentrated in vacuo. The residue was dissolved in ethyl acetate, washed with a saturated aqueous sodium bicarbonate solution, and the precipitate was filtered off. The organic solution was dried over anhydrous sodium sulfate, filtered and concentrated. The residue was crystallized from ethyl acetate / diethyl ether / hexane to give the title compound as a yellow solid (1.68 g, 51%).

B. N- (2-Chloro-6-methylphenyl) -2 - [(4,6-dimethyl-2-pyridyl) amino] -5-thiazolecarboxamide mg (0.075 mmol) 319A. To a mixture of 2-amino-4,6-dimethylpyridine (37 mg, 0.302 mmol) and tetrahydrofuran (1 mL) was added 15 mg of 95% sodium hydride. The reaction mixture was heated at 60 ° C overnight, then at room temperature

150 It was cooled to room temperature and diluted with saturated aqueous ammonium chloride solution. The mixture was extracted twice with ethyl acetate, the organic solutions were combined, washed with water, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was triturated with diethyl ether to give the title compound as a tan solid (17.5 mg, 63%).

320th example

Preparation of N- (2-Chloro-6-methylphenyl) -2 - [(4-ethyl-2-pyridyl) amino] -5-thiazolecarboxamide

<img file="HU0202708A2_D0103.tif" />

Compound 320 is shown in Example 319B. except that 2-amino-4-ethylpyridine was used in the synthesis of the title compound in this case.

321st example

N- (2-Chloro-6-methylphenyl) -2 - [(2,6-dimethyl-4-pyrimidinyl) amino] -

<img file="HU0202708A2_D0104.tif" />

Compound 321 is described in Example 319B. by analogous procedure to p.73.196 / BE

151 except that 4-amino-2,6-dimethylpyrimidine was used in the synthesis of the title compound 321 in this case.

322nd example

N- (2-Chloro-6-methylphenyl) -2 - [(3-pyridazinyl) amino] -5-

<img file="HU0202708A2_D0105.tif" />

Compound 322 is described in Example 319B. except that 3-aminopyridazine was used for the synthesis of the title compound 322 in this case.

323-335. example

General procedure

A 323-335. compounds were prepared according to the following procedure. Compound 144 (amine) (31 mg, 0.11 mmol), appropriate carboxylic acid (0.13 mmol), 1-hydroxy-7-aza-benzotriazole (19.5 mg, 0.14 mmol), 26.8 mg (0, To a mixture of N-ethyl-N '- [3- (dimethylamino) propyl] carbodiimide hydrochloride (14 mmol) and tetrahydrofuran (0.4 mL) was added N, N-diisopropylethylamine (60 μ 60, 0.34 mmol). .

The reaction mixture was heated in a sealed tube under argon for 24 hours at 50 ° C, then diluted with 4 mL of dichloromethane and then washed with 1M hydrochloric acid. The methylene chloride solution was pre-washed with methanol and 4: 1

73 196 / BE

152 The column was loaded on a Varian Mega Bond Elite SCX cation exchange column equilibrated with acetonitrile / methanol and then eluted with 4: 1 acetonitrile / methanol and 4: 1 methanol / 2M ammonia in methanol. The product-containing fractions were combined and concentrated in vacuo.

A HPLC R_T refers to HPLC retention time measured under the following conditions: YMC S5 ODS 4.6 χ 50 mm Ballastic column, 4 min gradient from 100% solvent A (10% methanol, 90% water, 0.2% phosphoric acid) 100 To solvent B (90% methanol, 10% water, 0.2% phosphoric acid), flow rate 4 ml / min, λ = 220 nm.

<td>Example number</td><td>Compound structure</td><td>Compound name</td><td>HPLC (minute)</td>

<td> 323.</td><td>ch₃ „</td><td>N- (2-chloro-6-methylphenyl) - -4-methyl-2 - [(2-thenoyl) - amino] -5- thiazolecarboxamide</td><td> 3, 70</td>

<td> 324.</td><td>_N_.CH₃ p</td><td>N- (2-chloro-6-methylphenyl) - -2- [(cyclopropyl) carbonyl) amino] -4- methyl-5-thiazolecarboxamide</td><td> 3,41</td>

<td> 325.</td><td>_ CH₃ p vZc »f?₃&lt;N</td><td>N- (2-chloro-6-methylphenyl) - -4-methyl-2 - [(2-furoyl) - amino] -5- thiazolecarboxamide</td><td> 3,49</td>

73.196 / BE • *

153

<td> 326.</td><td></td><td>N- (2-chloro-6-methylphenyl) - -4-methyl-2 - [(3-thenoyl) - amino] -5- thiazolecarboxamide</td><td> 3,71</td>

<td> 327.</td><td></td><td>N- (2-chloro-6-methylphenyl) - -4-methyl-2 - [(3-furoyl) - amino] -5- thiazolecarboxamide</td><td> 3,57</td>

<td> 328.</td><td></td><td>trans-N- (2-chloro-6-methyl- phenyl) -4-methyl-2 - {[(2- phenyl-cyclopropyl) - carbonyl] amino} -5- thiazolecarboxamide</td><td> 4,09</td>

<td> 329.</td><td> -^¼½</td><td>N- (2-chloro-6-methylphenyl) - -4-methyl-2 - {[(2-methyl- cyclopropyl) carbonyl] - amino} -5- thiazolecarboxamide</td><td> 3, 65</td>

<td> 330.</td><td> 1/¼½</td><td>N- (2-chloro-6-methylphenyl) - -2 - [(cyclobutyl carbonyl) amino] -4- methyl-5-thiazolecarboxamide</td><td> 3,63</td>

<td> 331.</td><td>THE "_/^CH3 cl í?₃cX ^</td><td>N- (2-chloro-6-methylphenyl) -2 - [(cyclopentyl) carbonyl) amino] -4- methyl-5-thiazolecarboxamide</td><td> 3,82</td>

<td> 332.</td><td>z^CH3 cl</td><td>N- (2-chloro-6-methylphenyl) - -2 - [(2-methyl-propionyl) - amino] -5- thiazolecarboxamide</td><td> 3, 50</td>

<td> 333.</td><td>fijjC</td><td>N- (2-chloro-6-methylphenyl) - -2- (pentanoyl) amino-5- thiazolecarboxamide</td><td> 3,79</td>

73 196 / BE

154 • · · ♦ • · · • · · · • · · ··· · ··

<img file="HU0202708A2_D0106.tif" />

<td> 334.</td><td></td><td>N- (2-chloro-6-methylphenyl) - -2 - [(2-methyl-valeryl) - amino] -5- thiazolecarboxamide</td><td> 3,90</td>

<td> 335.</td><td>_, CH₃ c.</td><td>2- (benzoylamino) -N- (2-</td><td> 3,79</td>

<td></td><td></td><td>chloro-6-methylphenyl) -4-</td><td></td>

<td></td><td></td><td>methyl-5-thiazolecarboxamide</td><td></td>

336-362. example

General procedure

A 336-362. 323-335. with the exception that in these cases, 315D was replaced with compound 144 instead of compound 144. compound was used. A 336-362. crude products were purified by automatic preparative HPLC [conditions: YMC S5 ODS A 20 x 100 mm column, 10 min gradient of 10% (v / v) methanol, 10% (v / v) water, 0.1% (v / v) trifluoro acetic acid) and 90% v / v B. solvent (10% methanol, 90% water, 0.1% trifluoroacetic acid) to 100% solvent B, flow rate 20 mL / min, λ = 220 nm).

A HPLC R_T refers to HPLC retention time measured under the following conditions: YMC S5 ODS 4.6 χ 50 mm Ballastic column, 4 minute gradient from 100% solvent A (10% methanol, 90% v / v), 0.2% phosphoric acid ) To 100% solvent B (90 volumes of methanol, 10 volumes of water, 0.2% phosphoric acid), flow rate 4 ml / min, λ = 220 nm.

73.196 / BE • · · ·

155 ··· · ··

<td>Example number</td><td>Compound structure</td><td>Compound name</td><td>HPLC R »p (minute)</td>

<td> 336.</td><td></td><td>N- (2-chloro-6-methylphenyl) - -2- (propionylamino) -5- thiazolecarboxamide</td><td> 3, 53</td>

<td> 337.</td><td></td><td>N- (2-chloro-6-methylphenyl) - -2- (butyrylamino) -5- thiazolecarboxamide</td><td> 3, 61</td>

<td> 338.</td><td></td><td>N- (2-chloro-6-methylphenyl) - -2 - [(2-ethylbutyryl) - amino] -5- thiazolecarboxamide</td><td> 3,54</td>

<td> 339.</td><td></td><td>N- (2-chloro-6-methylphenyl) - -2- {[(1-phenyl- cyclopropyl) carbonyl] - amino} -5- thiazolecarboxamide</td><td> 3, 86</td>

<td> 340.</td><td></td><td>N- (2-chloro-6-methylphenyl) - -2 - {[(1-methyl- cyclopropyl) carbonyl] - amino} -5- thiazolecarboxamide</td><td> 3, 53</td>

<td> 341.</td><td></td><td>N- (2-chloro-6-methylphenyl) - -2 - {[(2,2-dichloro-1-methyl- cyclopropyl) carbonyl] - amino} -5- thiazolecarboxamide</td><td> 3, 53</td>

73.196 / BE • ·

156

<td> 342.</td><td></td><td>N- (2-chloro-6-methylphenyl) - -2 - {[(2-methyl- cyclopropyl) carbonyl] - amino} -5- thiazolecarboxamide</td><td> 3, 53</td>

<td> 343.</td><td></td><td>N- (2-chloro-6-methylphenyl) - -2- {[(1-hydroxy- cyclopropyl) carbonyl] - -amino} -5- thiazolecarboxamide</td><td> 3,58</td>

<td> 344 .</td><td>Me Me</td><td>N- (2-chloro-6-methylphenyl) - -2 - {[(2,2,3,3-tetramethyl- cyclopropyl) carbonyl] - amino} -5- thiazolecarboxamide</td><td> 3, 69</td>

<td> 345.</td><td>vd-M</td><td>N- (2-chloro-6-methylphenyl) - -2- {[(1-cyano- cyclopropyl) carbonyl] - amino} -5- thiazolecarboxamide</td><td> 3, 53</td>

<td> 346.</td><td></td><td>N- (2-chloro-6-methylphenyl) - -2- [(cyclobutyl- carbonyl) amino] -5- thiazolecarboxamide</td><td> 3, 52</td>

<td> 347.</td><td>cd ^</td><td>N- (2-chloro-6-methylphenyl) - -2- [(cyclopentyl- carbonyl) amino] -5- thiazolecarboxamide</td><td> 3, 59</td>

<td> 348.</td><td></td><td>N- (2-chloro-6-methylphenyl) - -2- ((cyclohexyl- carbonyl) amino] -5- thiazolecarboxamide</td><td> 3,78</td>

73.196 / BE • · · · ♦ ·· ··

157

<img file="HU0202708A2_D0107.tif" />

<td> 349.</td><td></td><td>N- (2-chloro-6-methylphenyl) - -2 - [(phenylacetyl) - amino] -5- thiazolecarboxamide</td><td> 3,62</td>

<td> 350.</td><td>OUUVi</td><td>N- (2-chloro-6-methylphenyl) - -2- [(cyclohexylacetyl) - amino] -5- thiazolecarboxamide</td><td> 4,07</td>

<td> 351.</td><td>CuoíWj</td><td>N- (2-chloro-6-methylphenyl) - -2 - [(4-pyridyl-α-acetyl) - amino] -5- thiazolecarboxamide</td><td> 3, 75</td>

<td> 352.</td><td>A &lt; 'Me</td><td>N- (2-chloro-6-methylphenyl) - -2 - {[(2,5-dimethyl-l # -3- pyrrolyl) carbonyl] - amino} -5- thiazolecarboxamide</td><td> 3,17</td>

<td> 353.</td><td></td><td>N- (2-chloro-6-methylphenyl) - -2 - {[(2-pyridyl) - carbonyl] amino} -5- thiazolecarboxamide</td><td> 3,07</td>

<td> 354 .</td><td>THE</td><td>N- (2-chloro-6-methylphenyl) - -2 - {[(3-pyridyl) - -carbonyl] -amino} -5- thiazolecarboxamide</td><td> 3,07</td>

<td> 355.</td><td>CT ^^{, f}^ \ Aⁱ</td><td>N- (2-chloro-6-methylphenyl) - -2 - {[(4-pyridyl) - carbonyl] amino} -5- thiazolecarboxamide</td><td> 3,61</td>

<td> 356.</td><td>&lt;/ Ά5</td><td>N- (2-chloro-6-methylphenyl) - -2 - [(3-thenoyl) amino] -5- thiazolecarboxamide</td><td> 3, 60</td>

73 196 / BE

158

<td> 357.</td><td>n m__, Cl</td><td>N- (2-chloro-6-methylphenyl) - -2- [(2-tenoyl) -amino] -5- thiazolecarboxamide</td><td> 3,61</td>

<td> 358.</td><td></td><td>N- (2-chloro-6-methylphenyl) - -2 - [(2-furoyl) amino] -5- thiazolecarboxamide</td><td> 3, 61</td>

<td> 359.</td><td></td><td>N- (2-chloro-6-methylphenyl) - -2- [(3-furoyl) amino] -5- thiazolecarboxamide</td><td> 3, 69</td>

<td> 360.</td><td></td><td>trans-N- (2-chloro-6-methyl- phenyl) -2 - {[(2-phenyl- cyclopropyl) carbonyl] - amino} -5- thiazolecarboxamide</td><td> 3,98</td>

<td> 361.</td><td></td><td>N- (2-chloro-6-methylphenyl) - -2 - [(2-methyl-valeryl) - amino] -5- thiazolecarboxamide</td><td> 3,90</td>

<td> 362.</td><td></td><td>2- (benzoylamino) -N- (2- chloro-6-methylphenyl) -5- thiazolecarboxamide</td><td> 3, 61</td>

363rd example

2 - [(cyclopropylcarbonyl) amino] -N- (2,6-dimethylphenyl) -5-

<img file="HU0202708A2_D0108.tif" />

Compound 363 was prepared by a procedure analogous to Compound 315 except that 2,6-dimethylaniline was used in this case to produce the title compound 363.

73.196 / BE ·· ·· «· · ····

159 • * ··· ···· · • ···

364th example

2 - [(Cyclopropylcarbonyl) amino] -6- (2,4,6-trimethylphenyl) -5-

<img file="HU0202708A2_D0109.tif" />

Compound 364 was prepared by a procedure analogous to that of Compound 315 except that 2,4,6-trimethylaniline was used in this case to provide the title compound.

365th example

N- (2-Chloro-4,6-dimethylphenyl) -2 - [(cyclopropylcarbonyl) amino] -5-

<img file="HU0202708A2_D0110.tif" />

Compound 365 was prepared by a procedure analogous to compound 315 except that 2-chloro-4,6-dimethylaniline was used in this case to produce the title compound 365.

366th example

O-tert-Butyl-N- [4 - {[(2,4,6-trimethyl-phenyl) -carbamoyl] -methyl} -2-

<img file="HU0202708A2_D0111.tif" />

h₃c ch₃

73.196 / BE · * ···· · · * · «

160 • · · · · · • ·· · · · ··· • · · · ···· · ···· ·· · « ···

Compound 366 was prepared in a manner analogous to Compound 1 except that [2 - {[(tert-butoxycarbonyl) oxy] amino} -4-thiazolyl] acetic acid was used. The title compound was obtained as a white solid.

367th Example 2 (2-Amino-4-thiazolyl) -N- (2,4,6-trimethylphenyl) acetamide

<img file="HU0202708A2_D0112.tif" />

CH₃

Compound 367 was prepared by a procedure analogous to Compound 4, except that in this case, Compound 365 was prepared.

compound was used. The title compound was obtained as a white solid.

368th example

Preparation of 2-Methyl-5-nitro-N- (2,4,6-trimethylphenyl) -benzamide

<img file="HU0202708A2_D0113.tif" />

Compound 368 was prepared in a manner analogous to Compound 3 except that 2-methyl-5-nitrobenzoic acid was used. The title compound was obtained as a white solid.

73.196 / BE r

161 • 4

369th example

Preparation of 5-Amino-2-methyl-N- (2,4,6-trimethylphenyl) -benzamide

<img file="HU0202708A2_D0114.tif" />

149 To a solution of 368 mg (0.5 mmol) of Compound 368 in 50 ml of ethyl acetate was added 30 mg of 10% palladium on carbon catalyst with stirring. A flask filled with hydrogen was connected to the flask through a three-pin stopper. The air in the flask was evacuated under reduced pressure and the flask was filled with hydrogen from the balloon. Four hours later, the catalyst was filtered off and washed with ethyl acetate (5 x 5 mL). The filtrate was concentrated to give the title compound as a white solid (133 mg, 99%).

370th example

Preparation of 2-Amino-5-chloro-1- (2,4,6-trimethylphenyl) -4-pyrimidinecarboxamide

<img file="HU0202708A2_D0115.tif" />

Compound 370 was prepared in a manner analogous to Compound 3 except that 2-amino-5-chloro-4-pyrimidine carboxylic acid was used. The title compound 370 was obtained as a white solid.

73 196 / BE

162

371st example

Preparation of O-tert-Butyl-N- {4-methyl-5 - [(2,4,6-trimethylphenyl) carbamoyl] -2-oxazolyl} carbamate₃

<img file="HU0202708A2_D0116.tif" />

ch₃

-THE ^N

HscY TV h

CH₃ Ο N

Compound 371 was prepared in a manner analogous to Compound 1 except that 2 - {[(tert-butoxycarbonyl) oxy] amino} -4-methyl-5-oxazolecarboxylic acid was used. Yield 371 as a pale yellow foam.

title.

372nd example

2-Amino-4-methyl-N- (2,4,6-trimethylphenyl) -5-oxazolecarboxamide trifluoroacetate. (1: 1)

<img file="HU0202708A2_D0117.tif" />

ch₃

Compound 372 was prepared by a procedure analogous to Compound 4, except that in this case, Compound 369 was prepared.

compound was used. The title compound was obtained as a white solid.

373rd example

Preparation of 2-Amino-N- (2,4,6-trimethylphenyl) -5-pyridinecarboxamide

73.196 / BE • ·

163

<img file="HU0202708A2_D0118.tif" />

Compound 373 was prepared by a procedure analogous to that of Compound 3 except that 6-amino-nicotinic acid was used. The title compound was obtained as a white solid.

374th example

Preparation of 3-Amino-N- (2,4,6-trimethylphenyl) -4-pyridinecarboxamide

<img file="HU0202708A2_D0119.tif" />

Compound 374 was prepared in a manner analogous to Compound 3, except that 3-amino-4-pyridinecarboxylic acid was used. The title compound (374) was obtained as a white solid.

375th example

2-Amino-4-methyl-N- (2,4,6-trimethyl-phenyl) -5-pyrimidinecarboxamide

<img file="HU0202708A2_D0120.tif" />

CH₃

Compound 375 was prepared by a procedure analogous to Compound 3, except that in this case 2-amino73.196 / BE

164

-4-Methyl-5-pyrimidinecarboxylic acid was obtained as a material, m.p.

the title compound was used.

White, solid

376th example

Preparation of N- (2-Chloro-6-methylphenyl) -2 - [(4-methyl-2-pyridyl) amino] -5-thiazolecarboxamide

<img file="HU0202708A2_D0121.tif" />

Compound 376 is described in 319B. except that 2-amino-4-methylpyridine was used. The title compound was obtained as an off-white solid.

377th example

Preparation of 2 - [(6-Amino-2-pyridyl) amino] -N- (2-chloro-6-methylphenyl) -5-thiazolecarboxamide

<img file="HU0202708A2_D0122.tif" />

Compound 377 is described in 319B. except that 2,6-diaminopyridine was used in this case. The title compound was obtained as a light brown solid.

73.196 / BE etc

165

378th example

Preparation of N- (2-Chloro-6-methylphenyl) -2 - [(6-propyl-2-pyridyl) amino] -5-thiazolecarboxamide

<img file="HU0202708A2_D0123.tif" />

<img file="HU0202708A2_D0124.tif" />

with the exception that in this case 2-amino-6-propylpyridine was used. The title compound was obtained as an off-white solid.

379th example

Preparation of N- (2-Chloro-6-methylphenyl) -2 - [(6-ethyl-4-pyrimidinyl) amino] -5-thiazolecarboxamide

<img file="HU0202708A2_D0125.tif" />

Compound 379 is prepared as described in 319B. with the exception that in this case 4-amino-6-ethylpyrimidine was used. The title compound (379) was obtained as a white solid.

380-409, Example

General procedure

380-409. 319B. was prepared by an analogous procedure. A 380-527. for compounds "HPLC R_T the

73 196 / BE

166 • · * refers to HPLC retention time measured under the following conditions: YMC S5 ODS 4.6 x 50 mm Ballastic column, 4 minute gradient, 100%

From solvent A (10% methanol, 90% water, 0.2% phosphoric acid) to 100% solvent B (90% methanol, 10% water, 0.2% phosphoric acid), flow rate 4 ml / min , λ = 220 nm. Where HPLC R_T The 'B' is used, giving the HPLC retention time measured under the following conditions: YMC S5 ODS 4.6 x 33 mm Turbo column, 2 minute gradient from 100% solvent A (10% methanol, 90% water, 0%). , 1% v / v trifluoroacetic acid) to 100% solvent B (90% v / v methanol, 10 v / v water, 0.1% trifluoroacetic acid), flow rate 4 ml / min, λ = 220 nm.

<td>Example number</td><td>Compound structure</td><td>Compound name</td><td>HPLC Ltd. (minute)</td>

<td> 380.</td><td>° H, C</td><td>N- (2-chloro-6-methylphenyl) - -2- (2-pyridyl) -5- thiazolecarboxamide</td><td> 3,337</td>

<td> 381.</td><td></td><td>N- (2-chloro-6-methylphenyl) - -2 - [(6-methyl-2-pyridyl) - amino] -5- thiazolecarboxamide;</td><td> 3,61</td>

<td> 382.</td><td></td><td>N- (2-chloro-6-methylphenyl) - -2 - [(5-methyl-2-pyridyl) - amino] -5- thiazolecarboxamide</td><td> 3,487</td>

<td> 383.</td><td>° H, C</td><td>N- (2-chloro-6-methylphenyl) - -2 - [(4-methyl-2-pyridyl) - amino] -5- thiazolecarboxamide</td><td> 3,293</td>

73 196 / BE

167

<td> 384.</td><td>^N</td><td>N- (2-chloro-6-methylphenyl) - -2 - [(3-methyl-2-pyridyl) - amino] -5- thiazolecarboxamide</td><td> 3,243</td>

<td> 385.</td><td></td><td>2 - [(5-bromo-3-methyl-2- pyridyl) amino] -N- (2- chloro-6-methylphenyl) -5- thiazolecarboxamide</td><td> 4,17</td>

<td> 386.</td><td>nA Λ.λΑ c%</td><td>2 - [(6-amino-2-pyridyl) - amino] -N- (2-chloro-6- -methylphenyl) -5- thiazolecarboxamide</td><td> 2,817</td>

<td> 387.</td><td>c%</td><td>2 - [(5-bromo-2-pyridyl) - amino] -N- (2-chloro-6- methyl-phenyl) -5- thiazolecarboxamide</td><td> 4,023</td>

<td> 388.</td><td></td><td>N- (2-chloro-6-methylphenyl) - 2 - {[3- (phenylmethoxy) -2- pyridinyl] amino] -5- thiazolecarboxamide</td><td> 4,143</td>

<td> 389.</td><td>V-IU-i '</td><td>N- (2-chloro-6-methylphenyl) -2 - [(5-chloro-2-pyridyl) - amino] -5- thiazolecarboxamide</td><td> 3,957</td>

<td> 390.</td><td>'' -Τ-οΤ) ° H, C</td><td>N- (2-chloro-6-methylphenyl) - -2 - [(6-ethyl-2-pyridyl) - amino] -5- thiazolecarboxamide</td><td> 3,867</td>

<td> 391.</td><td></td><td>N- (2-chloro-6-methylphenyl) - -2 - [(6-propyl-2-pyridyl) - amino] -5- thiazolecarboxamide</td><td> 4,083</td>

73.196 / BE • · ·

168

<td> 392.</td><td>h, c.</td><td>2 - [(3-Bromo-5-methyl-2- pyridyl) amino] -N- (2- -chloro-6-methylphenyl) -5- thiazolecarboxamide</td><td> 4,077</td>

<td> 393.</td><td></td><td>2 - [(2-amino-3-pyridyl) - amino] -N- (2-chloro-6- -methylphenyl) -5- thiazolecarboxamide</td><td> 2,343</td>

<td> 394.</td><td></td><td>2 - [(3-amino-2-pyridyl) - -amino] -N- (2-chloro-6- methyl-phenyl) -5- thiazolecarboxamide</td><td> 2,777</td>

<td> 395.</td><td></td><td>N- (2-chloro-6-methylphenyl) - -2 - [(4-pyridyl) amino] -5- thiazolecarboxamide</td><td> 2,493</td>

<td> 396.</td><td>Ο A / -A</td><td>N- (2-chloro-6-methylphenyl) - -2 - [(3-pyridyl) amino] -5- thiazolecarboxamide</td><td> 2,47</td>

<td> 397.</td><td>Ί, Α ^ .c</td><td>N- (2-chloro-6-methylphenyl) - -2 - [(6-chloro-3-pyridyl) - amino] -5- thiazolecarboxamide</td><td> 3,75</td>

<td> 398.</td><td>% χ J ~ V /^NvS</td><td>N- (2-chloro-6-methylphenyl) - -2 - [(2-chloro-3-pyridyl) - amino] -5- thiazolecarboxamide</td><td> 3, 443</td>

<td> 399.</td><td>kp °</td><td>N- (2-chloro-6-methylphenyl) - -2 - [(6-methoxy-3-pyridyl) - amino] -5- thiazolecarboxamide</td><td> 3, 517</td>

73.196 / BE :. u.

169

<td> 400.</td><td></td><td>N- (2-chloro-6-methylphenyl) - -2 - [(3,5-dimethyl-2-) pyrazinyl) amino] -5- thiazolecarboxamide</td><td> 3,583</td>

<td> 401.</td><td></td><td>N- (2-chloro-6-methylphenyl) - 2-anilino-5- thiazolecarboxamide</td><td> 3,697</td>

<td> 402.</td><td>^SHEH, C</td><td>N- (2-chloro-6-methylphenyl) - -2 - [(3-ethylphenyl) - amino] -5- thiazolecarboxamide</td><td> 4,107</td>

<td> 403.</td><td>Λ% ΑΛγ £ J ^, 0</td><td>N- (2-chloro-6-methylphenyl) - -2 - [(3,5-dimethylphenyl) - amino] -5- thiazolecarboxamide</td><td> 3, 98</td>

<td> 404.</td><td>~ A- &lt;n</td><td>N- (2-chloro-6-methylphenyl) - -2 - [(4,6-dimethyl-2- pyrimidinyl) amino] -5- thiazolecarboxamide</td><td> 3,51</td>

<td> 405.</td><td>% Λ&gt;</td><td>N- (2-chloro-6-methylphenyl) - -2 - [(6-ethyl-4- pyrimidinyl) amino] -5- thiazolecarboxamide</td><td> 2,943</td>

<td> 406.</td><td>, VjL. Ϊ / - {if 13 w yu cl</td><td>N- (2-chloro-6-methylphenyl) - -2 - [(6-chloro-2-pyrazinyl) - amino] -5- thiazolecarboxamide</td><td> 3,763</td>

<td> 407 .</td><td>&gt; vAA 7 / ~ ν /ⁿv ^ * AAi y ......</td><td>2 - [(3-aminophenyl) - amino] -N- (2-chloro-6- methyl-phenyl) -5- thiazolecarboxamide</td><td> 2,633</td>

73.19S / BE

...,.

170

<td> 408.</td><td>**&gt; Ά \</td><td>N- (2-chloro-6-methylphenyl) - -2 - [(3-hydroxyphenyl) - amino] -5- thiazolecarboxamide</td><td> 3,337</td>

<td> 409.</td><td>° Kc</td><td>2 - [(3-bromophenyl) amino] - -N- (2-chloro-6-methyl- ) -5- thiazolecarboxamide</td><td> 4,12</td>

410th example

N- (2,6-Dimethyl-phenyl) -2-anilino-5-thiazolecarboxamide

<img file="HU0202708A2_D0126.tif" />

A. O-tert-Butyl N- {5 - [(2,6-dimethylphenyl) carbamoyl] -2-thiazolyl} carbamate

410A. 315C. with the exception that 2,6-dimethylaniline was used in this case.

B. 2-Amino-N- (2,6-dimethylphenyl) -5-thiazolecarboxamide

A 410B. 315D. Compound 410A was prepared in an analogous manner to that of Example 410A. compound was used.

C. N- (2,6-Dimethylphenyl) -2-anilino-5-thiazolecarboxamide

319B. with the exception that in this case 410B. compound and aniline were used. HPLC rt = 3.69 min.

73.196 / BE · * ··· * *

171

411-427. example

General procedure

A 411-427. 319B. was prepared by an analogous procedure.

<td>Example number</td><td>Compound structure</td><td>Compound name</td><td>HPLC rj (minute)</td>

<td> 411.</td><td>she's Có</td><td>N- (2,6-dimethylphenyl) -2- - (N-methylanilino) -5- thiazolecarboxamide</td><td> 3,667</td>

<td> 412.</td><td>° k, c</td><td>N- (2,6-dimethylphenyl) -2- - [(2-pyridyl) amino] -5- thiazolecarboxamide</td><td> 3,297</td>

<td> 413.</td><td></td><td>N- (2,6-dimethylphenyl) -2- - [(6-methyl-2-pyridyl) - amino] -5- thiazolecarboxamide</td><td> 3,587</td>

<td> 414.</td><td></td><td>N- (2,6-dimethylphenyl) -2- - [(4-methyl-2-pyridyl) - amino] -5- thiazolecarboxamide</td><td> 3,222</td>

<td> 415.</td><td></td><td>N- (2,6-dimethylphenyl) -2- - [(4-ethyl-2-pyridyl) - amino] -5- thiazolecarboxamide</td><td> 3, 54</td>

<td> 416.</td><td> χ J * \ C</td><td>N- (2,6-dimethylphenyl) -2- - [(4,6-dimethyl-2- pyridyl) amino] -5- thiazolecarboxamide</td><td> 3, 543</td>

73 196 / BE

172

<td> 417.</td><td>° η £</td><td>2 - [(6-amino-2-pyridyl) - -amino] -N- (2,6-dimethyl- ) -5- thiazolecarboxamide</td><td> 2,807</td>

<td> 418.</td><td>° H, C</td><td>N- (2,6-dimethylphenyl) -2- - [(6-ethyl-2-pyridyl) - amino] -5- thiazolecarboxamide</td><td> 3,847</td>

<td> 419.</td><td>'' '• TL'VŐ ° K, C</td><td>N- (2,6-dimethylphenyl) -2- - [(6-propyl-2-pyridyl) - amino] -5- -fiazolkarboxamid</td><td> 4,057</td>

<td> 420.</td><td></td><td>2 - [(2-amino-3-pyridyl) - amino] -N- (2,6-dimethyl- ) -5- thiazolecarboxamide</td><td> 2,337</td>

<td> 421.</td><td></td><td>2 - [(3-amino-2-pyridyl) - -amino] -N- (2,6-dimethyl- ) -5- thiazolecarboxamide</td><td> 2,737</td>

<td> 422.</td><td>r ΗΓ</td><td>2 - [(6-amino-2-methyl-4- pyrimidinyl) amino] -N- - (2,6-dimethylphenyl) -5- thiazolecarboxamide</td><td> 2,71</td>

<td> 423.</td><td></td><td>N- (2,6-dimethylphenyl) -2- - [(6-morpholino-3- -pyridazinylmethyl) amino] -5- thiazolecarboxamide</td><td> 2,727</td>

<td> 424.</td><td>^cketc., / c%</td><td>2 - [(6-chloro-3- -pyridazinylmethyl) amino] -N- - (2,6-dimethylphenyl) -5- thiazolecarboxamide</td><td> 3,46</td>

73.196 / BE • · ·

173 ··· ·

<td> 425.</td><td></td><td>N- (2,6-dimethylphenyl) -2- - [(3-pyridazinyl) amino] - -5thiazolecarboxamide</td><td> 2,973</td>

<td> 426.</td><td>H ° c</td><td>2 - [(3-aminophenyl) - amino] -N- (2,6-dimethyl- ) -5- thiazolecarboxamide</td><td> 2,63</td>

<td> 427.</td><td>c%</td><td>2 - [(3-bromophenyl) amino] - -N- (2,6-dimethylphenyl) -5- thiazolecarboxamide</td><td> 4,143</td>

Example 428

2 - [(2-Pyridyl) amino] -N- (2,4,6-trimethylphenyl) -5-

<img file="HU0202708A2_D0127.tif" />

A. O-tert-Butyl N- {5 - [(2,4,6-trimethylphenyl) carbamoyl] -2-thiazolyl} carbamate

428A. 315C. except that 2,4,6-trimethylaniline was used in this case.

B. 2-Amino-N- (2,4,6-dimethylphenyl) -5-thiazolecarboxamide

428B. 315D. Compound 428A was prepared in an analogous manner to that of Example 428A.

compound was used.

C. 2 - [(2-Pyridyl) amino] -N- (2,4,6-trimethylphenyl) -5-thiazolecarboxamide

73 196 / BE

174

319B. except that in this case, 428B. and 2-aminopyridine were used. HPLC rt = 3.66 min.

429-443. example

General procedure

A 429-443. 319B. was prepared by an analogous procedure.

<td>Example number</td><td>Compound structure</td><td>Compound name</td><td>HPLC (minute)</td>

<td> 429.</td><td></td><td>2 - [(6-methyl-2-pyridyl) - amino] -N- (2,4,6- trimethylphenyl) -5- thiazolecarboxamide</td><td> 3,903</td>

<td> 430.</td><td>HC ii X c</td><td>2 - [(5-methyl-2-pyridyl) - amino] -N- (2,4,6- -trimethylphenyl) -5- thiazolecarboxamide</td><td> 3, 8</td>

<td> 431.</td><td></td><td>2 - [(4-methyl-2-pyridyl) - amino] -N- (2.4,6- -trimethylphenyl) -5- thiazolecarboxamide</td><td> 3,603</td>

<td> 432.</td><td></td><td>2 - [(3-methyl-2-pyridyl) - amino] -N- (2,4,6- -trimethylphenyl) -5- thiazolecarboxamide</td><td> 3,56</td>

<td> 433.</td><td>Br.</td><td>2 - [(5-bromo-2-pyridyl) - -amino] -N- (2,4,6 -trimethylphenyl) -5- thiazolecarboxamide</td><td> 4,263</td>

73.196 / BE • · ·

175 • · • ·· ·

<td> 434.</td><td></td><td>2 - [(5-chloro-2-pyridyl) - amino] -N- (2,4,6- trimethylphenyl) -5- thiazolecarboxamide</td><td> 4,203</td>

<td> 435.</td><td></td><td>2 - [(6-methoxy-3-pyridyl) - amino] -N- (2,4,6- trimethylphenyl) -5- thiazolecarboxamide</td><td> 3, 8</td>

<td> 436.</td><td></td><td>2 - [(4-ethyl-2-pyridyl) - amino] -N- (2,4,6- trimethylphenyl) -5- thiazolecarboxamide</td><td> 3,86</td>

<td> 437.</td><td></td><td>2 - [(6-ethyl-2-pyridyl) - amino] -N- (2,4,6- trimethylphenyl) -5- thiazolecarboxamide</td><td> 4,127</td>

<td> 438.</td><td></td><td>2 - [(6-chloro-3-pyridyl) - amino] -N- (2,4,6- trimethylphenyl) -5- thiazolecarboxamide</td><td> 4,017</td>

<td> 439.</td><td>CL ·</td><td>2 - [(2,6-dimethyl-4- pyrimidinyl) amino] -N- - (2,4,6-trimethylphenyl) - -5thiazolecarboxamide</td><td> 2,943</td>

<td> 440.</td><td>Λ _M Ύ SX.JfX / 'The</td><td>2 - [(4-methyl-2- pyrimidinyl) amino] -N- - (2,4,6-trimethylphenyl) - -5thiazolecarboxamide</td><td> 3,723</td>

<td> 441.</td><td></td><td>2 - [(2-pyrazinyl) amino] - -N- (2,4,6-trimethyl- ) -5- thiazolecarboxamide</td><td> 3,65</td>

73 196 / BE

176

<td> 442.</td><td>^s »</td><td>2 - [(6-chloro-2-pyrazinyl) - -amino] -N- (2,4,6 trimethylphenyl) -5- thiazolecarboxamide</td><td> 4,05</td>

<td> 443.</td><td>^H3^CSJS |</td><td>2 - [(3,5-dimethyl-2- pyrazinyl) amino] -N- - (2,4,6-trimethylphenyl) - -5thiazolecarboxamide</td><td> 3,877</td>

444th example

Preparation of N- (2-Chloro-6-methylphenyl) -2 - [{2-methyl-6 - [(2-morpholinoethyl) amino] -4-pyrimidinyl] amino] -5-thiazolecarboxamide

<img file="HU0202708A2_D0128.tif" />

148 To a suspension of sodium hydride (20 mg, 6.17 mmol) in tetrahydrofuran (20 mL) was added 315D (551 mg, 2.06 mmol).

A solution of compound (10) in tetrahydrofuran (10 mL) was added. The mixture was stirred at room temperature for 30 minutes and a solution of 4,6-dichloro-2-methylpyrimidine (671.6 mg, 4.12 mmol) in tetrahydrofuran (10 mL) was added. Reaction mixture overnight73.196 / BE • ·

177 After stirring at room temperature for 1 h, the reaction was quenched with acetic acid and the solvent removed in vacuo. Water and a saturated aqueous sodium bicarbonate solution were added to the residue, and the aqueous mixture was extracted with dichloromethane. The organic phase was concentrated in vacuo and the crude product was purified by column chromatography (494 mg, 444A). compound was obtained.

B. N- (2-Chloro-6-methyl-phenyl) -2 - [{2-methyl-6 - [(2-morpholino-ethyl) -amino] -4-pyrimidinyl} -amino] -5-thiazolecarboxamide mg 444A. of compound N- (2-aminoethyl) morpholine (300 μg). The reaction mixture was heated at 80 ° C for 2 hours, water was added and the product filtered. HPLC rt = 2.377 min.

445-461, Example

A 445-461. 444B. except that the appropriate amines were used in these cases.

<td>Example number</td><td colspan="2">Compound structure</td><td>Compound name</td><td>HPLC Ltd. (minute)</td>

<td> 445.</td><td>Ο N—</td><td>k Hl Ϊ⁵ T ϊί Ή \ // o JU CHI</td><td>TV- (2-Chloro-6-methyl-phenyl) - 2 - [{2-methyl-6 - [(3- morpholino-propyl) - -amino] -4-pyrimidinyl} - amino] -5- thiazolecarboxamide</td><td> 2,253</td>

73 196 / BE

178

<td> 446.</td><td>CH</td><td>N- (2-chloro-6-methylphenyl) - -2 - {[2-methyl-6- {AZ-methyl- -N- [3- (methylamino) - propyl] amino} -4- pyrimidinyl] amino} -5- thiazolecarboxamide</td><td> 2,493</td>

<td> 447.</td><td>CH</td><td>N- (2-chloro-6-methylphenyl) - 2 - {[2-methyl-6 - {[2- - (tetrahydro-2-oxo-1H-1- imidazolyl) ethyl] - amino} -4-pyrimidinyl] - amino} -5- thiazolecarboxamide</td><td> 2,71</td>

<td> 448.</td><td>Ύ</td><td>N- (2-chloro-6-methylphenyl) - 2 - {[2-methyl-6 - {[(2- (ltf- -4-imidazolyl) ethyl] - amino} -4-pyrimidinyl] - amino} -5- thiazolecarboxamide</td><td> 2,303</td>

<td> 449.</td><td>n AT OM-X ^s ϊVj</td><td>N- (2-chloro-6-methyl-1-phenyl) - -2 - [(2-methyl-6-morpholino- -4-pyrimidinyl) amino] -5- thiazolecarboxamide</td><td> 3, 337</td>

<td> 450.</td><td>Al, &lt;? ' chiral WM H, C CM,</td><td>N- (2-chloro-6-methylphenyl) - -2 - {[6 - [{[(2R) -1-ethyl-2- -pyrrolidinyl] -ethyl} - amino] -2-methyl-4- pyrimidinyl} amino] -5- thiazolecarboxamide</td><td> 2,703</td>

73 196 / BE

179

<td> 451.</td><td>HW H_theC 'CH,</td><td>N- (2-chloro-6-methylphenyl) - -2 - {[6 - [{[(2S) -l-ethyl-2- pyrrolidinyl] methyl} - amino] -2-methyl-4- pyrimidinyl} amino] -5- thiazolecarboxamide</td><td> 2,717</td>

<td> 452.</td><td>w *</td><td>2- [6 - [(2S) -2-Carbamoyl] -1-pyrrolidinyl] -2-methyl- -4-pyrimidinyl} amino] -N- - (2-chloro-6-methylphenyl) - -5thiazolecarboxamide</td><td> 2, 81</td>

<td> 453.</td><td>cf. CH</td><td>N- (2-chloro-6-methylphenyl) - -2 - [{6 - [(2-hydroxyethyl) - amino] -2-methyl-4- pyrimidinyl} amino] -5- thiazolecarboxamide</td><td> 2,677</td>

<td> 454 .</td><td>vxXcó CH</td><td>N- (2-chloro-6-methylphenyl) - -2 - [{6- [4- (hydroxy methyl) -1-piperidinyl] -2-methyl-4-pyrimidinyl} - amino] -5- thiazolecarboxamide</td><td> 3,05</td>

<td> 455 .</td><td></td><td>N- (2-chloro-6-methylphenyl) - -2 - [{6- [4- (2-hydroxy- -ethyl) -1-piperazinyl] - 2- methyl-4-pyrimidinyl} - amino] -5- thiazolecarboxamide</td><td> 2,717</td>

<td> 456.</td><td>xxfXó CH</td><td>1- {6 - [{5 - [(2-chloro-6- methylphenyl) carbamoyl] - -2-thiazolyl} amino] -2- -methyl-4-pyrimidinyl} - 4- -piperidinkarboxamid</td><td> 2,863</td>

73.196 / BE ····

180 «·· «

• * «

<td> 457.</td><td>CM,</td><td>N- (2-chloro-6-methylphenyl) - 2 - [{2-methyl-6 - [(3S) -3- methyl-l-piperazinyl] -4- pyrimidinyl] amino] -5- thiazolecarboxamide</td><td> 2,823</td>

<td> 458.</td><td>HI &lt;1</td><td>2 - [{6- [3- (acetylamino) - -1-pyrrolidinyl] -2-methyl- -4-pyrimidinyl} amino] -N- - (2-chloro-6-methylphenyl) - -5thiazolecarboxamide</td><td> 2,78</td>

<td> 459.</td><td>VhZ ° h, &lt;AA CH</td><td>N- (2-chloro-6-methylphenyl) - -2 - {[6 - {[2- (l-methyl-2- pyrrolidinyl) ethyl] - amino} -2-meti1-4- pyrimidinyl] amino} -5- thiazolecarboxamide</td><td> 2,383</td>

<td> 460.</td><td>^N-&gt; a axPAK ' CH</td><td>N- (2-chloro-6-methylphenyl) - 2 - {[2-methyl-6 - {[(5- methyl-2-pyrazinyl) - -methyl] -amino} - 4- pyrimidinyl] amino} -5- thiazolecarboxamide</td><td> 3,027</td>

<td> 461.</td><td></td><td>N- (2-chloro-6-methylphenyl) - 2 - {[2-methyl-6 - {[2- (lH- -1,2,3-triazol-l-yl) - -ethyl] -amino} -4- pyrimidinyl] amino} -5- thiazolecarboxamide</td><td> 2,78</td>

462nd example

Preparation of α- (2-Chloro-6-methylphenyl) -2 - [{6 - [(2-morpholinoethyl) amino] -4-pyrimidinyl} amino] -5-thiazolecarboxamide

73 196 / BE

181 ·* "* ···· • · " * " ··* " • · * * the··" **. * ·· »·

<img file="HU0202708A2_D0129.tif" />

Ά 462Α. 444A. except that in this case 4,6-dichloropyrimidine was used.

B. N- (2-Chloro-6-methylphenyl) -2 - [{6 - [(2-morpholinoethyl) amino] -4-pyrimidinyl} amino] -5-thiazolecarboxamide

444B. with the exception that 444A. instead of compound 462A. compound was used. HPLC R_T = 2.553 min.

463-472. example

General procedure

A 463-472. 444B. except that the appropriate amines were used in these cases. HPLC Rt 'B' is the HPLC retention time measured under the following conditions: YMC S5 ODS 4.6^x 33 mm Turbo column, 2 minute gradient from 100% solvent A (10% methanol, 90% water, 0.1% trifluoroacetic acid) to 100% solvent B (90% methanol, 10% water, 0.1% trifluoroacetic acid), flow rate 4 ml / min, λ = 220 nm.

73 196 / BE

182 ··» · ·♦·· • · · • · « ··· • ···* · » · *··

<td>Example number</td><td>Compound structure</td><td>Compound name</td><td>HPLC Ltd. (minute)</td>

<td> 463.</td><td></td><td>N- (2-chloro-6-methylphenyl) - -2 - {[6 - {[2- (dimethyl- amino) ethyl] amino} -4 pyrimidinyl] amino} -5- thiazolecarboxamide</td><td> 2,527</td>

<td> 464.</td><td></td><td>N- (2-chloro-6-methylphenyl) - -2- {[6 - {[2- (tetrahydro-2-) # -1-oxo-l-yl) - -ethyl] -amino} - 4- pyrimidinyl] amino} -5- thiazolecarboxamide</td><td> 2,797</td>

<td> 465.</td><td>S ~ /</td><td>N- (2-chloro-6-methylphenyl) - -2 - {[6- {N-methyl-N- [2- - (methylamino) ethyl] - amino} -4-pyrimidinyl] - amino} -5- thiazolecarboxamide</td><td>1,137 B</td>

<td> 466.</td><td>&lt;* · &lt;AW</td><td>N- (2-chloro-6-methylphenyl) - -2 - {[6 - {[2- (l-methyl-2- pyrrolidinyl) ethyl] - amino] -4-pyrimidinyl] - amino} -5- thiazolecarboxamide</td><td>1,113 B</td>

<td> 467.</td><td>cr ^ om A-na cb</td><td>N- (2-chloro-6-methylphenyl) - -2- {[6- {[2- (l- pyrrolidinyl) ethyl] - amino} -4-pyrimidinyl] - amino} -5- thiazolecarboxamide</td><td>1,150 B</td>

73 196 / BE

183 • · • * ···· «··· ··« .

···

<td> 468.</td><td>X</td><td>RV</td><td> 4-«</td><td>N- (2-chloro-6-methylphenyl) - -2- {[6 - {[(1-ethyl-2- pyrrolidinyl) methyl] - amino} -4-pyrimidinyl] - amino} -5- thiazolecarboxamide</td><td>1.237 B</td>

<td> 469.</td><td rowspan="2">X</td><td>Λ X</td><td></td><td>N- (2-chloro-6-methylphenyl) -</td><td> 1,160</td>

<td rowspan="2"></td><td rowspan="2"></td><td rowspan="2">She</td><td rowspan="2">-2 - {[6 - {[(4-piperidyl) - methyl] amino} -4-</td><td rowspan="2">B</td>

<td></td>

<td></td><td></td><td></td><td></td><td>pyrimidinyl] amino} -5- thiazolecarboxamide</td><td></td>

<td> 470.</td><td></td><td>W</td><td>Λ H ^cloy-1 H, C ^ 2</td><td>2 - {[6 - {[2- (acetylamino) - ethyl] amino} -4 pyrimidinyl] amino} -N- - (2-chloro-6-methylphenyl) - -5thiazolecarboxamide</td><td>2.457 B</td>

<td> 471.</td><td></td><td></td><td>SHE i — Η Q</td><td>N- (2-chloro-6-methylphenyl) - -2- {[6- {[2- (177-1,2,3-</td><td> 2,897</td>

<td></td><td></td><td></td><td>Defend-/ H, C</td><td>triazol-l-yl) ethyl] - amino} -4-pyrimidinyl] - amino} -5- thiazolecarboxamide</td><td></td>

<td> 472.</td><td></td><td>X</td><td rowspan="2"></td><td>N- (2-chloro-6-methylphenyl) -</td><td> 3,437</td>

<td></td><td colspan="2"></td><td>-2 - [(6-morpholino-4- pyrimidinyl) amino] -5-</td><td></td>

<td></td><td></td><td></td><td></td><td>thiazolecarboxamide</td><td></td>

473rd example

Preparation of N- (2-Chloro-6-methylphenyl) -2 - [{6 - [(2-morpholinoethyl) amino] -2-pyridyl} amino] -5-thiazolecarboxamide

73 196 / BE

184

<img file="HU0202708A2_D0130.tif" />

To a suspension of sodium hydride (2.83 g, 118 mmol) in N, N-dimethylformamide (350 mL) cooled to 0 ° C was added 319A (93.5 mmol). compound. The mixture was stirred at 0 ° C for 45 minutes before adding (tetrabutylammonium) iodide (6.9 g, 18.7 mmol) followed by (4-methoxybenzyl) (18 g, 115 mmol). chloride. The reaction mixture was warmed to room temperature, stirred overnight at room temperature, then quenched by slow addition of acetic acid and the solvent removed in vacuo. Water was added to the residue, and the mixture was neutralized with saturated aqueous sodium bicarbonate. The aqueous mixture was extracted three times with ethyl acetate, and the organic solutions were combined, washed with water and saturated brine, and the ethyl acetate layer was concentrated in vacuo. The residue was purified by column chromatography to give 35 g of 473A. compound was obtained.

73 196 / BE

185 • . . · » ··· . · · · ···· ·

...........

Β.

<img file="HU0202708A2_D0131.tif" />

0.5 g (1.1 mmol) of 473A. Dissolve compound (50 mL) in tetrahydrofuran (50 mL) and add sodium hydride (0.13 g, 5.5 mmol) and 6-amino-2-bromopyridine (0.76 g, 4.4 mmol) slowly. The reaction mixture was refluxed for 2 hours, cooled to room temperature, and quenched with acetic acid. The solvent was removed in vacuo and water and hexane were added to the residue. The mixture was stirred at room temperature, then the solid precipitate was filtered off and washed with water and diethyl ether. 0.48 g 473B. compound was obtained.

C.

<img file="HU0202708A2_D0132.tif" />

0.48 g 473B. compound (5) was dissolved in trifluoroacetic acid (5 mL), followed by the addition of 2 mL of anisole followed by 1 mL of trifluoromethanesulfonic acid. The reaction mixture was stirred at room temperature for 3 hours and then ice, saturated aqueous sodium bicarbonate solution was added slowly,

73 196 / BE

186 • · * for a vigorously stirred mixture of diethyl ether and dichloromethane. The resulting mixture was stirred cold for one hour, after which the solid precipitate was filtered off and washed with water and diethyl ether / dichloromethane. 0.344 g 473C. compound was obtained. HPLC R_T - 3.85 minutes.

D. N- (2-Chloro-6-methylphenyl) -2 - [{6 - [(2-morpholinoethyl) amino] -2-pyridyl} amino] -5-thiazolecarboxamide

444B. with the exception that in this case, 444A. instead of compound 473C. compound was used. HPLC rt = 2.80 min.

474-480, Example

General procedure

A 474-480. 473D. except that the appropriate amines were used in these cases.

<td>Example number</td><td>Compound structure</td><td>Compound name</td><td>HPLC (minute)</td>

<td> 474 .</td><td></td><td>N- (2-chloro-6-methylphenyl) - -2 - [{6 - [(3-morpholino propyl) amino] -2- pyridinyl} amino] -5- thiazolecarboxamide</td><td> 2,867</td>

<td> 475.</td><td>cl HjC N — v Π I „RO vU</td><td>N- (2-chloro-6-methylphenyl) - -2 - {[6- {N-methyl-W- [3- - (methylamino) propyl] amino} -2-pyridyl] - amino} -5- thiazolecarboxamide</td><td> 3,067</td>

73 196 / BE

187 • · · • · · · ··· · ··

<td> 476.</td><td>(R, _r, chiral WVO</td><td>N- (2-chloro-6-methylphenyl) - -2 - [{6 - [(3S) -3-methyl-l- piperazinyl] -2-pyridinyl} - amino] -5- thiazolecarboxamide</td><td> 2,827</td>

<td> 477.</td><td></td><td>N- (2-chloro-6-methylphenyl) - -2- {[6- {[3- (177-1- imidazolyl) propyl] - amino} -2-pyridyl] - amino} -5- thiazolecarboxamide</td><td> 2,83</td>

<td> 478.</td><td></td><td>N- (2-chloro-6-methylphenyl) - -2 - [{6 - [(2-hydroxyethyl) - amino] -2-pyridinyl} - amino] -5- thiazolecarboxamide</td><td> 3,077</td>

<td> 479.</td><td></td><td>N- (2-chloro-6-methylphenyl) - -2- {[6- {[2- (177-1- imidazolyl) ethyl] - amino} -2-pyridyl] - amino} -5- thiazolecarboxamide</td><td> 2,903</td>

<td> 480.</td><td></td><td>N- (2-chloro-6-methylphenyl) - -2 - [(6-morpholino-2- pyridyl) amino] -5- thiazolecarboxamide</td><td> 3,727</td>

481st example

Preparation of N- (2-Chloro-6-methylphenyl) -2 - [{6 - [(2-morpholinoethyl) amino] -2-pyrazinyl} amino] -5-thiazolecarboxamide

73 196 / BE

188 • ·

<img file="HU0202708A2_D0133.tif" />

481A. 473B. except that 6-amino-2-chloropyrazine was used instead of 6-amino-2-bromopyridine.

B. (Alternative Synthesis of Compound 406)

<img file="HU0202708A2_D0134.tif" />

Compound 406 is prepared as described in 473C. with the exception that 473B. instead of compound 481A. compound was used.

C. N- (2-Chloro-6-methylphenyl) -2 - [{6 - [(2-morpholinoethyl) amino] -2-pyrazinyl} amino] -5-thiazolecarboxamide

444B. except that 444B. Compound 406 was used instead of Compound. HPLC rt = 2.69 min.

73 196 / BE

189 • ·

482-486. example

General procedure

A 482-486. 481C. except that the appropriate amines were used in these cases.

<td>Example number</td><td>Compound structure</td><td>Compound name</td><td>HPLC (minute)</td>

<td> 482.</td><td>ΤΆ Λϊΐ a</td><td>N- (2-chloro-6-methylphenyl) - -2 - [{6 - [(3-morpholino propyl) amino] -2-pyrazinyl} amino] -5- thiazolecarboxamide</td><td> 2,783</td>

<td> 483.</td><td>_N_Ajl 2 '</td><td>N- (2-chloro-6-methylphenyl) - -2 - [(6-morpholino-2- pyrazinyl) amino] -5- thiazolecarboxamide</td><td> 3,57</td>

<td> 484 .</td><td></td><td>N- (2-chloro-6-methylphenyl ·) - —2 - [{6 - [(3S) -3-methyl-1- piperazinyl] -2- pyrazinyl} amino] -5- thiazolecarboxamide</td><td> 2,743</td>

<td> 485.</td><td></td><td>N- (2-chloro-6-methylphenyl) - -2 - {[6- (3-hydroxy-l- pyrrolidinyl) -2-pyrazinyl] amino} -5- thiazolecarboxamide</td><td> 3,327</td>

<td> 486.</td><td>r c-fPP</td><td>N- (2-chloro-6-methylphenyl) - -2- {[6- (1H-1-imidazolyl) - -2-pyrazinyl] -amino} - 5- thiazolecarboxamide</td><td> 2,68</td>

73 196 / BE

190

487th example

Preparation of N- (2-Chloro-6-methylphenyl) -2 - {[6- (3-hydroxy-1-pyrrolidinyl) -3-pyridazinyl] amino} -5-thiazolecarboxamide

<img file="HU0202708A2_D0135.tif" />

THE.

<img file="HU0202708A2_D0136.tif" />

487A. 473B. with the exception that in this case 5-amino-3-chloropyridazine was used instead of 6-amino-2-bromopyridine.

B

<img file="HU0202708A2_D0137.tif" />

487B. 473C. with a compound analogous to a compound

73 196 / BE

191 It was prepared with the exception that in this case 473B.

instead of compound 487A. compound was used.

C. N- (2-Chloro-6-methylphenyl) -2 - {[6- (3-hydroxy-1-pyrrolidinyl) -3-pyridazinyl] amino} -5-thiazolecarboxamide

444B. with the exception that in this case, 444A.

487B. and 3-hydroxypyrrolidine was used in place of N- (2-aminoethyl) morpholine. HPLC R_T = 2.493 min.

488th example

Preparation of N- (2-Chloro-6-methylphenyl) -2 - {[6- (1H-1-imidazolyl) -3-pyridazinyl-3-amino} -5-thiazolecarboxamide

<img file="HU0202708A2_D0138.tif" />

Compound 488 is prepared according to 487C. except that imidazole was used in place of 3-hydroxypyrrolidine. HPLC R_T = 2.61 min.

489th example

Preparation of N- (2-Chloro-6-methylphenyl) -2 - {[3- (methyl-amino) -2-pyrazinyl] amino) -5-thiazolecarboxamide

73.196 / BE • ·

<img file="HU0202708A2_D0139.tif" />

489A. 473B. with the exception of 3-amino-2-chloropyrazine instead of 6-amino-2-bromopyridine.

<img file="HU0202708A2_D0140.tif" />

489B. 473C. with the exception that in this case 473B. instead of compound 489A. compound was used.

C. N- (2-Chloro-6-methylphenyl) -2 - {[3- (methylamino) -2-pyrazinyl] amino} -5-thiazolecarboxamide

444B. with the exception that in this case, 444A. 489B. and methylamine was substituted for 77- (2-aminoethyl) -morpholine. HPLC R_T = 2.81 min.

73.196 / BE »· · ·

193

490-494. example

General procedure

A 490-494. 489C. except that the appropriate amines were used in these cases.

<td>Example number</td><td>Compound structure</td><td>Compound name</td><td>HPLC Ltd. (minute)</td>

<td> 490.</td><td>w VJ</td><td>TV- (2-Chloro-6-methyl-phenyl) - 2 - {[3- (3-hydroxy-l- pyrrolidinyl) -2- pyrazinyl] amino} -5- thiazolecarboxamide</td><td> 2,82</td>

<td> 491.</td><td>w yu</td><td>TV- (2-Chloro-6-methyl-phenyl) -2 - {[3- (cyclopropyl) amino) -2-pyrazinyl] - amino} -5- thiazolecarboxamide</td><td> 2,94</td>

<td> 492.</td><td>oh yeah</td><td>TV- (2-Chloro-6-methyl-phenyl) - -2 - [(3-morpholino-2- pyrazinyl) amino] -5- thiazolecarboxamide</td><td> 3, 643</td>

<td> 493.</td><td>She*</td><td>TV- (2-Chloro-6-methyl-phenyl) - 2 - [{3 - [(2-morpholino ethyl) amino] -2- pyrazinyl} amino] -5- thiazolecarboxamide</td><td> 2,72</td>

<td> 494.</td><td>p w</td><td>2 - {[3 - {[2- (acetylamino) - ethyl] amino} -2- pyrazinyl] amino} -N- (2- chloro-6-methylphenyl) -5- thiazolecarboxamide</td><td> 2,933</td>

73.196 / BE • · «· ·

194 ···« « » · · ·· · · • · · ·

495th example

N- (2-Chloro-6-methylphenyl) -2- (cyclohexylamino) -5-thiazolecarboxamide

<img file="HU0202708A2_D0141.tif" />

Compound 495 is described in 444B. Compound 444A was prepared in an analogous manner to that of Example 319A. with cyclohexylamine instead of N- (2-aminoethyl) morpholine. HPLC rt = 3.547 min.

496-500. example

General procedure

A 496-500. compounds were prepared by a procedure analogous to that of compound 495 except that in these cases the corresponding amines were used.

<td>Example number</td><td colspan="2">Compound structure</td><td> *</td><td>Compound name</td><td>HPLC Ltd. (minute)</td>

<td> 496.</td><td></td><td>h₃ct</td><td> 5</td><td>N- (2-chloro-6-methylphenyl) - -2- (methylamino) -5- thiazolecarboxamide</td><td> 2,357</td>

<td> 497 .</td><td></td><td> /—\</td><td>cl She</td><td>N- (2-chloro-6-methylphenyl) - -2- (cyclopropylamino) -5- thiazolecarboxamide</td><td> 2,887</td>

73.196 / BE ·· · · ·

195

<td rowspan="2"> 498.</td><td colspan="2" rowspan="2"></td><td colspan="2">cl</td><td rowspan="2">N- (2-chloro-6-methylphenyl) - -2- (benzylamino) -5- thiazolecarboxamide</td><td rowspan="2"> 3,500</td>

<td>Hy °</td><td>ú</td>

<td> 499.</td><td></td><td rowspan="2">i'ü</td><td></td><td>cl</td><td>2 - {[2- (acetylamino) -</td><td> 2,483</td>

<td></td><td rowspan="2">V</td><td></td><td>yS</td><td>ethyl] amino} -N- (2-chloro-</td><td></td>

<td></td><td></td><td rowspan="2">0 HJC</td><td></td><td>-6-methylphenyl) -5-</td><td></td>

<td></td><td>HJC</td><td></td><td></td><td>thiazolecarboxamide</td><td></td>

<td> 500.</td><td>MONTH</td><td>-Λ</td><td>ct</td><td>chiral</td><td>N- (2-chloro-6-methylphenyl) -</td><td> 3,407</td>

<td></td><td></td><td> ( ^s* [R</td><td>yS</td><td></td><td>-2 - {[(IR) -1- (hydroxymethyl</td><td></td>

<td></td><td rowspan="2">HC</td><td></td><td></td><td></td><td>methyl) -3-methyl-butyl] -</td><td></td>

<td></td><td>V</td><td></td><td></td><td>amino} -5-</td><td></td>

<td></td><td></td><td></td><td></td><td></td><td>thiazolecarboxamide</td><td></td>

/

Five hundred and first example

Preparation of N- (2-Chloro-6-methylphenyl) -2 - {[6- (methoxymethyl) -4-pyrimidinyl] amino} -5-thiazolecarboxamide

<img file="HU0202708A2_D0142.tif" />

H₃cc / 'Y^:r^0H

To a mixture of 14.6 g (0.1 mol) of 4-methoxyacetoacetate, 16.1 g (0.2 mol) of formamidine hydrochloride and 70 ml of anhydrous methanol was added 70 ml (0.3 mol) of 25% w / w methanol in portions. A white precipitate formed immediately, and the reaction mixture was stirred at room temperature for 1 hour, followed by the addition of acetic acid (28.6 mL, 0.5 mol) and

73.196 / BE ·· · »• · ·

196 It was concentrated in vacuo. Water was added to the residue, after which the mixture was supersaturated with sodium chloride and extracted five times with ethyl acetate. The organic solutions were combined, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. 8.11 g of 501A as a yellow solid. compound was obtained.

B

H₃CO

<img file="HU0202708A2_D0143.tif" />

N, N

cl

5.3 g (37.8 mmol) of 501A. A mixture of Compound II and 40 ml of phosphoryl (V) chloride (POCl 3) was refluxed for 2.0 hours, then concentrated in vacuo and the residue poured into a mixture of ice and dichloromethane. The pH was adjusted to 6.5-7 with concentrated ammonium hydroxide and the mixture was extracted three times with dichloromethane. The organic solutions were combined, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was flash chromatographed on silica gel eluting with methylene chloride / ethyl acetate 9: 1 (v / v). 5.33 g of 501B as a pale yellow oil. compound was obtained.

C.

NH2

N, N

3.2 g (20 mmol) of 501B. A mixture of compound (50) and 50 ml of ammonium hydroxide was heated in a pressure tube for 3 hours at 85 ° C. The reaction mixture was then cooled to room temperature,

73 196 / BE

197 then concentrated in vacuo. The residue was triturated with diethyl ether as 2.81 g of 501C as a pale yellow solid. compound was obtained.

D.

<img file="HU0202708A2_D0144.tif" />

501D. 501C. 473B. was prepared by an analogous procedure.

E. N- (2-Chloro-6-methylphenyl) -2 - {[6- (methoxymethyl) -4-pyrimidinyl]

amino} -5-thiazolecarboxamide

The title compound is described in 501D. 473C. was prepared by an analogous procedure. HPLC rt = 3.25 min.

502nd example

Preparation of N- (2-Chloro-6-methylphenyl) -2 - {[6- (hydroxymethyl) -4-pyrimidinyl] amino} -5-thiazolecarboxamide

<img file="HU0202708A2_D0145.tif" />

To a solution of 501 mg (0.144 mmol) in CH 2 Cl 2 (3.0 mL) and cooled to 0 ° C was added

0.054 mL (0.574 mmol) of pure boron tribromide. The reaction mixture

73.196 / BE ·· »*

198 After stirring for 1 hour at ambient temperature, methanol was added slowly to the reaction mixture at 0 ° C. The resulting mixture was concentrated in vacuo, water was added to the residue, and the pH was adjusted to 7 with saturated aqueous sodium bicarbonate. The white precipitate was filtered off, washed with water and diethyl ether and dried under high vacuum. 52 mg (50 mg) of the title compound were obtained as an off-white solid. HPLC rt = 2.84 min.

503rd example

N- (2-Chloro-6-methylphenyl) -2 - {[6- (morpholinomethyl) -4-pyrimidinyl] -

<img file="HU0202708A2_D0146.tif" />

To a suspension of compound 502 (44.2 mg, 0.118 mmol) in dichloromethane (0.5 mL) was added sulfinyl chloride (0.086 mL, 1.18 mmol). The reaction mixture was stirred for 5.0 hours and then concentrated in vacuo. Methylene chloride was added to the residue followed by azeotropic distillation. 563 mg of 503A as a yellow solid. compound was obtained.

B. N- (2-Chloro-6-methylphenyl) -2 - {[6- (morpholinomethyl) -4-pyrimidinyl] amino) -5-thiazolecarboxamide

73 196 / BE

199 mg 503A. A mixture of 0.014 ml of morpholine, 0.09 ml of N, N-diisopropylethylamine and 0.5 ml of anhydrous dioxane was heated at 85 ° C for 4.0 hours, and then the reaction mixture was concentrated in vacuo. The residue was flash chromatographed on silica gel eluting with 95: 5: 0.5 v / v methylene chloride / methanol / ammonium hydroxide. 15 mg of the title compound are obtained as an off-white solid. HPLC rt = 2.52 min.

504-503. example

General procedure

504-513. 503A. Compound 503 was prepared analogously to the procedure used for the synthesis of Compound 503. 504-513. The structure of the compounds is shown in the following table.

<td>Example number</td><td>Compound structure</td><td>Compound name</td><td>HPLC R «j&gt; (minute)</td>

<td> 504.</td><td>«Α'νγγ'Μ</td><td>N- (2-chloro-6-methylphenyl) - -2 - [{6- [{[2- (dimethyl) amino) ethyl] amino} - methyl] -4-pyrimidinyl} - amino] -5- thiazolecarboxamide</td><td> 2,083</td>

<td> 505.</td><td></td><td>N- (2-chloro-6-methylphenyl) - -2 - {[6 - {[(2-morpholino ethyl) amino] methyl} -4- pyrimidinyl] amino} -5- thiazolecarboxamide</td><td> 2,593</td>

73.196 / BE: ··

200

<td> 506.</td><td>ex</td><td></td><td>'She O ^ V Η, £ θ)</td><td>N- (2-chloro-6-methylphenyl) - -2 - {[6 - {[(3-morpholinopropyl) amino] methyl} -4- pyrimidinyl] amino} -5- thiazolecarboxamide</td><td> 2,163</td>

<td> 507.</td><td></td><td></td><td>She</td><td>N- (2-chloro-6-methylphenyl) - -2 - [{6 - [{[3- (2-oxo-l-</td><td> 2,693</td>

<td></td><td></td><td></td><td>cl o \ ~ J ^ xz</td><td>pyrrolidinyl) propyl] - amino] methyl} -4- pyrimidinyl} amino] -5- thiazolecarboxamide</td><td></td>

<td> 508.</td><td></td><td></td><td>&lt;r \ - {iTYk</td><td>N- (2-chloro-6-methylphenyl) - -2- [{6- [{[2- (17 / -4- imidazolyl) ethyl] -</td><td> 2,143</td>

<td></td><td></td><td></td><td></td><td>amino] methyl] -4- pyrimidinyl} amino] -5- thiazolecarboxamide</td><td></td>

<td> 509.</td><td></td><td></td><td>A n α</td><td>N- (2-chloro-6-methylphenyl) - -2- [{6- [{[(3- (17 / -1-</td><td>1,103 B</td>

<td></td><td></td><td></td><td>o '\ —1 VQ</td><td>imidazolyl) propyl] - amino] methyl} -4-</td><td></td>

<td></td><td></td><td></td><td></td><td>pyrimidinyl} amino] -5-</td><td></td>

<td></td><td></td><td></td><td></td><td>thiazolecarboxamide</td><td></td>

<td> 510.</td><td colspan="3"></td><td>N- (2-chloro-6-methylphenyl) - -2 - [{6 - [{[2- (2-pyridyl) -</td><td>1,113 B</td>

<td></td><td></td><td></td><td>/-" the</td><td>ethyl] amino} methyl] -4- pyrimidinyl} amino] -5- thiazolecarboxamide</td><td></td>

<td> 511.</td><td>Oh</td><td>* vyv '</td><td></td><td>77- (2-chloro-6-methylphenyl) -</td><td> 1,117</td>

<td></td><td></td><td>II T ►R&gt;^N</td><td>C?</td><td>-2 - [{6 - [{[2- (3-pyridyl) -</td><td>B</td>

<td></td><td></td><td></td><td> 05'</td><td>ethyl] amino} methyl] -4- pyrimidinyl} amino] -5- thiazolecarboxamide</td><td></td>

73 196 / BE

201 ···

<td> 512.</td><td> °</td><td>1 - [{6 - [{5— [(2-chloro-6- methylphenyl) carbamoyl] - -2-thiazolyl} amino] -4- pyrimidinyl] methyl} -4- -piperidinkarboxamid</td><td>1,207 B</td>

<td> 513.</td><td>° ZQ</td><td>2 - [{6 - [{[2- (acetyl amino) ethyl] amino} - methyl] -4-pyrimidinyl} - amino] -N- (2-chloro-6- methyl-phenyl) -5- thiazolecarboxamide</td><td>1,193 B</td>

514th example

N- (2-Chloro-6-methyl-phenyl) -2 - [(2-naphthyl) -amino] -5-thiazolecarboxamide

<img file="HU0202708A2_D0147.tif" />

<img file="HU0202708A2_D0148.tif" />

514A. 473A. 473B. of compound

73 196 / BE

202 except that instead of 6-amino-2-bromoaniline, 2-aminonaphthalene was used.

B. N- (2-Chloro-6-methylphenyl) -2 - [(2-naphthyl) amino] -5-thiazolecarboxamide

473C. with the exception that in this case 473B. instead of compound 514A. compound was used. HPLC R_T = 4.11 min.

515th example

N- (2-Chloro-6-methylphenyl) -2 - [(2-quinolyl) amino] -5-

<img file="HU0202708A2_D0149.tif" />

SHE

<img file="HU0202708A2_D0150.tif" />

515A. 473A. 473B. of compound

73.196 / BE · ♦ · ♦ · «*

203 except that 6-amino-2-bromoaniline was used in this case instead of 2-aminoquinoline.

B. N- (2-Chloro-6-methylphenyl) -2 - [(2-quinolyl) amino] -5-thiazolecarboxamide

473C. with the exception that in this case 473B. instead of compound 515A. compound was used. HPLC rt = 3.94 min.

516th example

Preparation of N- (2-Chloro-6-methylphenyl) -2 - [(3-isoquinolyl) amino] -5-thiazolecarboxamide

<img file="HU0202708A2_D0151.tif" />

516A. 473A. 473B. with the exception that instead of 6-amino-2-bromoaniline, in this case 2-aminoisoquino73.196 / BE · «·

204 linen was used.

B. N- (2-Chloro-6-methylphenyl) -2 - [(3-isoquinolyl) amino] -5-thiazolecarboxamide

473C. with the exception that in this case 473B. instead of compound 516A. compound was used. HPLC rt = 3.94 min.