SA03240136B1 - Bostone deacetylase - Google Patents

Abstract

Abstract: The invention relates to a compound of formula (I): where ring A is a heterocyclic ring, m is zero to 4, each R1 is a group like hydroxy, halo, trifluoromethyl and cyano, and ring B is a ring like thienyl and thiadiazolyl, pyrimidyl pyrimidyl, pyrazinyl, pyridazinyl, pyridyl, 2R is a halo, n is zero to 2, each R4 is a group like hydroxy, halo, trifluoromethyl, and cyano, and P is zero to 4, and R 3 are amino or hydroxy or pharmaceutically acceptable salts or ester or amide thereof subject to hydrolysis in vivo, and processes for their preparation and pharmaceutical formulations containing them and their use in the treatment of diseases or medical conditions caused by the enzyme histone deacetylase.

Description

B Y _ hostone deacetylase inhibitors Full description BACKGROUND The invention relates to benzamide amide derivatives; Pharmaceutical acceptable salts, esters, or amides thereof that are hydrolyzable in the organism for these benzamide derivatives. cancer (Marks et al, Nature Reviews, 1, 194 — 202, (2001)) and cystic fibrosis qu—Sll «(Li, 5. et al, J.

Biol.

Chem., 274, 7803 -7815, (1999)) and Huntingdon's chorea (Steffan, J.

S. et al, Nature, 413, 739 — 743 , (2001)) chorea and sickle cell anemia Blood, 95, 3555-3561, (2000)) sickle cell anemia,. et accordingly 0 are considered useful in methods of treating warm-blooded animals such as humans The invention relates to processes for the manufacture of the aforementioned benzamide derivatives; ) in a free-blooded animal such as a human. In a eukaryotic cell, the DNA is combined to prevent access to a transcription factor, and when this cell is activated, the combined DNA becomes available for proteins to bind with DNA, and in this way allows research 1 Inheritance copy:

trampled

(Beato, M., J.

Med.

Chem., 74, 711-724 (1996); wolffe, A.P., Nature, 387, 16-17 (19997) DNA combines with histones to form a complex known as chromatin. The cores of histones are known as <H2A and H2B 5 113 and © 114 enclosed in 1576 base pairs of DNA The basic unit of chromatin; nucleosome The ends of the 17-ends of the cores of histones contain lysines and are sites for the insertion of an acetyl group After transcription, the introduction of the acetyl group is equivalent to the side chain potential to form a positive charge on the lysines chain.

lateral It is believed to affect the structure of chromatin.

zine are zinc-containing enzymes Histone Deacetylases Histone deacetylases enzymes 0 of the amino building blocks of lysine from acetyl-amino ends catalyze the removal of acetyl groups histones CUS jal amino terminus gathered near The amino endings 5 5¢Y and HDAC) are divided into two classes, the first being HDACs in nucleosomes. Enzymes can be divided into 4, Mo1, and La (HDAC) and the second is Rpd3, and they are represented by yeast-like proteins (A and oF).

vo© and 01) represented by the yeast-like proteins Hladal is the reverse process that introduces dda catalyse acetyl groups in clonal adaptation and in cell cycle progression. HDAC maladjustment has been associated with many cancers and HDAC inhibitors such as trichostatin A (a natural product isolated from Streptomyces hygroscopicus) have been shown to exhibit significant antitumor effects and cell growth inhibition:

0. Meinke, P.T., Current Medicinal Chemistry, 8, 211-235 (2001).

_ $ — Yoshida et al., Exper. Cell Res., 177, 122-131 (1988) that Trichostatin A causes arrest of mouse fibroblasts at stages 61 and G2 of 5550 cells; In doing so, it engages HDAC enzymes in cell cycle adaptation. Furthermore, tricostatin A has been shown to induce terminal variegation and to inhibit cell growth; and prevents tumor formation in rats: (Finnin et al., Nature, 401, 188-193 (1999)) 5 To date, few HDAC inhibitors are known in the art. Thus, there is a need to identify more HDAC enzyme inhibitors General description of the invention Accordingly, the present invention provides a compound of formula (1): (RY), (RY), 0

H

R3 @ 0 where : ring A is a heterocyclic ring; Whereas, if the ring contains a -1113- moiety, then this nitrogen atom is optionally replaced by a group chosen from 0 RY that is substituted on the carbon atom and is chosen from:

Halo, nitro, cyano, hydroxy, oxo, trifluoromethyl, trifluoromethoxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl, C,′alkyl, C,′alkenyl, Cs.′alkynyl, C,′alkoxy, Ci.salkanoyl, C;galkanoyloxy, N-(C,.salkyl)amino, N,N-(Cj.salkyl),amino, Ci.ealkanoylamino, N-(C,salkyl)carbamoyl, N,N-( C.galkyl),carbamoyl, C,.¢alkylS(O), oo where 8 from zero - 7; or : Cjealkoxycarbonyl, N-(Ci.salkyl)sulphamoyl, N,N-(C;¢alkyl),sulphamoyl, aryl, 2, aryloxy, or a heterocyclic group + or Cg alkyl ( heterocyclic group ” or (D-E-) group ; where it does not include a (D-E-) group and can have an optional substitution on the carbon atom by one 0 or more than 7, and since if the aforementioned heterocyclic group contains a –NH- moiety, that nitrogen atom can optionally be replaced by a group chosen from J: halo ¢ or nitro or cyano; or hydroxy ¢ or Sc oxo 0 trifluoromethyl or trifluoromethoxy ¢ or amino “carboxy ¢ or carbamoyl carbamoyl ¢ or mercapto or sulphamoyl (bgalsl) i.e. alkyl mc of alkenyl Cy of 0 alkynyl or Cie bitter alkanoyl or alkanoyloxy Ci « or N-(Cj.¢alkyl)amino ¢ 0 N,N-(C,_galkyl);amino « or rang «alkanoylamino or N-(C.¢alkyl)carbamoyl » or N,N-(Cy.¢alkyl),carbamoyl 0 « or CialkylS(0), where ia wa -? \ A

- =

Lauda malo-Ren or N-(Cjsalkyl)sulphamoyl” or “N,N-(C,_galkyl),sulphamoy]l or aryl” aryl or aryloxy ” or carylCrealkyl or cyclic group heterocyclic group " or ie sana) heterocyclic heterocyclic group ( m" alkyl group (DAE) where an optional substitution occurs in ; including the (D-E-) group on an atom

carbon by one or more of the 17 ; Where 7 and 7 are selected separately from halo; or nitro or cyano + or hydroxy; or 0X0¢ oxo or trifluoromethyl ¢ or trifluoromethoxy or amino “carboxy” or carbamoyl or mercapto or sulphamoyl » or alkyl Ci ¢ or alkanoyloxy C. ¢ or “alkanoyl” or “alkoxy” or “alkynyl” or “alkenyl mon ye” or “calkanoylamino Cis sl” N,N -(Cyalkyl)amino § «amino ( alkyl C14) Nf from a where CpealkylS(O), which is (alolah) -a or daa (1 olah). 0) - sea or or N-(C.galkyl)sulphamoyl or « Cj.salkoxycarbonyl Clap - ? Or Al-Amtastam Lud (Al-Waldo.R0)- Ara ;

¢ alkynyl Cas of “alkenyl Cag of “alkyl L” and K1, each separately from 5G. Vo or carbamoyl “C,.galkoxycarbonyl” or Basmata? And oxy-benzyl “NN-(Cygalkyl)carbamoyl” meaning “N-(Cygalkyl)carbamoyl si “carbamoyl” or “phenylsulphonyl” and phenylsulfonyl benzoyl or “benzoyl 0” benzyloxycarbonyl carbonyl ‎( heterocyclic group heterocyclic Ala or (carylCrgalkyl group of » aryl

- "a

of alkyl » where an optional substitution may occur in K 5d 5G on the carbon atom

by one or more ©;

Whereas, if the heterocyclic group contains a ligand Ld NH - the nitrogen atom

These nitrogen may be optionally substituted by a group chosen from a hydrogen or a mer alkyl ;

© is halo or nitro ¢ or cyano or hydroxy ¢ or oxo

« trifluoromethoxy or trifluoromethoxy « trifluoromethyl or trifluoromethyl » oxo

or an amino “carboxy ¢ or carbamoyl ¢ or mercapto” or

m-sulphamoyl “alkyl Cre” or alkenyl hand + or alkynyl Ca “or V-her “alkoxy” or m-alkanoyl “or alkanoyloxy ¢ or adsorbent) Student Ren)-Ed 0

N,N-(C,.¢alkyl),amino” or from “alkanoylamino” or “alkanoylamino” or

Absorption: D(A-ClD-Rn)-Ara or CealkylS(O), where 8 is Fo or

« N,N-(C_alkyl),sulphamoyl or « , N-(Cisalkyl)sulphamoyl or ¢« Cyisalkoxycarbonyl

or aryl or aryloxy; or carylCralkyl or heterocyclic group 0 » or Ac gana) heterocyclic group ( from “ alkyl or

set (DE) where an optional substitution occurs in ©; Including the group (15-"0) on an atom

carbon by one or more Z's

5D '0 is selected; and JSD" separately from alkyl C16;" 4 hand of 0” alkenyl between alkynyl

Csseycloalkyl of 0 “i.e. CygoycloalkylCysalkyl” or “aryl” or carylCigalkyl or 0 heterocyclic group; or (a heterocyclic group

-

heterocyclic group ( bitter alkyl where an optional substitution may occur in ©; and D" 5D" on the carbon atom by one or more than 7 and where if said heterocyclic group contains a -—NH moiety This nitrogen atom may be optionally substituted by a group chosen from K;

5B 5E 187 are each selected separately from - 1189 - or - 0 = $ “—C(0)0 - R - Ruvo § - C0) =” R = NERHC(0) tr = ~NRHCONR®) sf tumor) and gaar nar khalarmum-r “—S(O)r sle—C(O)N(R?) rahatomoi rr- ,218950; where *8 and 8 are selected separately from hydrogen or alkyl Cog having optionally substituted by one or more than 1 and where + from zero = 7 ;

0 and 7 are selected separately from halo; or nitro; or cyano or hydroxy; or “oxo” or “ok J” trifluoromethyl fluoromethoxy ¢ or amino-0 + carboxy; or carbamoyl + or “mercapto” or “sulphamoyl” 4-alkyl ¢ or Cag alkenyl or alkynyl cities or “alkoxy” or “alkanoyl” or alkanoyloxy bitter «or

, or calkanoylamino or bitter “N,N-(C,_¢alkyl),amino” or “N-(Cy.galkylamino Vo a) where CealkylS(0), or + N,N=(Cysalkyl),carbamoyl si » N-(Cy.salkyl)carbamoyl or 'N-(C,-salkyl)sulphamoyl' or ¢' Cj.alkoxycarbonyl saqr -? or . give Leo (the Wallaren)- oh.”; or ;; and where the values of !18 are the same or different; JY JO is zero; or

0 episode 3 to be selected from

1,2 ya 7 Cy

A J or \ 7 Y 3 Y 4 5 where x! and xX? are selected from “CH” or “N” and a is selected; and “7, 7, and YH of CH or LOAN to be one of Ala, and SY Y 57 is ¢N m R* is halo” an zero ; or ) 0 or 7; and where is R? af are the same or different; rR' is amino or hydroxy ¢ R* is halo or nitro; or cyano¢ or 1-hydroxy or oxo + or trifluoromethyl or trifluoromethoxy 0 or amino; carboxy 0 or carbamoyl ; or mercapto or sulphamoyl Jaselél i.e. alkyl Cig or alkenyl Cag ¢ or mi alkynyl or m-calkoxy or alkanoyl Ci. or alkanoyloxy mer or resorbed (Allah 0)-a or N,N-(C,.¢alkyl),amino “or bitter calkanoylamino or N-(C,.galkyl)carbamoyl” or Alkanoylamino “¢ or dua CrealkylS(0), p from zero - ¥ ¢ or Cjsalkoxycarbonyl « or , -N,N-(Cj.salkyl),sulphamoyl 0 « N-(Cjsalkyhsulphamoyl eo J in

1. - - P is zero; or 1 or ? ; and where RY af is the same or different; Or a pharmaceutically acceptable salt or ester 88168 or an amide of it that is hydrolyzable in the organism. In this specification, Jody defines the JS term “alkyl” from straight-chain and branched-chain alkyl groups. For example, the alkyl Cg 5a alkyl groups include methyl Jie , ethyl , propyl , isopropyl , pentyl , and axyl hexyl and butyl « heptyl -©. However, reference to discrete alkyl groups such as propyl + is for the straight-chain species only; reference to branched-chain alkyl groups is considered to be « ie isopropyl" is for the branched-chain type only. The term “halo” refers to fluoro, chloro chloro, bromo 0 0 and i0do when facultative substituents are chosen from “one or more groups” It should be understood that this definition includes all substituents chosen from one of the specified groups or substituents chosen from one or more of the specified groups. Saturated containing of SF 11" ve an atom of which at least one atom is chosen of nitrogen » or sulfur » or oxygen ; which may be, unless otherwise indicated, attached to a carbon atom or a nitrogen atom ¢ and where the sulfur atom of the ring may optionally be oxidized to form oxides -5. The 'heterocyclic group' is preferably saturated; or Lis saturated or unsaturated; having a single ring containing © or + atoms of which at least one atom is selected from 0 nitrogen, i.e. 0 sulfur or oxygen unless otherwise stated; OS Add

_ 1 \ —

Attached to a carbon atom or a nitrogen atom 6 and where the cyclic sulfur atom may optionally be oxidized to form S- oxides. Examples and appropriate values for the term "a group of heterogeneous rings".

They are: thiazolidinyl, pyrrolidinyl, 1,3-benzodioxolyl, 1,2,4-oxadiazolyl, 2- azabicyclo[2.2.1]heptyl, morpholinoyl, tetrahydrofuranyl, furanyl, tetrahydropyranyl, ° piperidinyl, piperazinyl, thiomorpholinyl , 1,3-dioxolanyl, homopiperazinyl, thienyl, pyrrolyl, pyrazolyl, oxadiazolyl, tetrazolyl, oxazolyl, thienopyrimidinyl, thienopyridinyl, thieno[3,2d]pyrimidinyl, 1,3,5-triazinyl, purinyl, 1,2 ,3,4-tetrahydroquinolinyl, 1°,2°,3°,6'-tetrahydropyridinyl, tetrahydropyridinyl, benzimidazolyl, benzthiazolyl, benzoxazolyl, benzothienyl, benzofuranyl, indazolyl, quinazolinyl, cinnolinyl, 01 phthalazinyl, quinoxalinyl, napthyridinyl, benzotriazolyl, pyrrolothienyl, imidazothienyl, isoxazolyl, imidazolyl, thiadiazolyl, isothiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, pyranyl, indolyl, pyrimidinyl, thiazolyl, pyrazinyl, pyridazinyl, py ridel, quinolyl, quinazolinyl, and 1-isoquinolonyl. The "heterocyclic group" is saturated, partially saturated, or unsaturated; monocyclic or dicyclic containing a © - VY atom of which at least one atom is chosen from nitrogen; or sulfur + or oxygen “ which is attached to a carbon atom or a nitrogen atom Le nitrogen not otherwise indicated where the CH group, can optionally be substituted by (0)©; and where (Se) optionally substitutes a sulfur atom for the ring to form oxides 58. Preferably, the “heterocyclic group” consists of one saturated, partially saturated, or unsaturated ring containing of 0 - + atoms of which one atom on The least is chosen from “nitrogen” or “sulfur” or “oxygen” or “dicyclic” containing 4 or 01 atoms that are attached to a carbon atom 0 a nitrogen atom unless otherwise specified; and where Optionally CH, ic sana can be replaced by C(O) ¢ and where optionally a sulfur atom can be oxidized

_ 1 Y -— Examples and appropriate values for the term 'heterocyclic group'. 58- The oxides of the ring to be: are: "heterocyclic group pyrrolidinyl, 2-pyrrolidonyl 2,5-dioxopyrrolidinyl, 2,4-dioxoimidazolidinyl, 2- oxo-1,3,4- triazolinyl, oxazolidinyl, 2-oxazolidonyl, 5,6-dihydro-uracilyl, 1,3-benzodioxolyl, 1,2,4- oxadiazolyl, 2-azabicyclo[2,2.1]heptyl, morpholinyl, 2-oxotetrahydrofuranyl, °tetrahydrofuranyl, furanyl, tetrahydropyranyl, piperidinyl, piperazinyl, thiomorpholinyl, 1,1-dioxothiomorpholinyl, 1,3-dioxolanyl, homopiperazinyl, thiophenyl, thienopyridinyl, thienopyrimidinyl, thieno[3,2d]pyrimidinyl, 1,3,5 -triazinyl, purinyl, quinolinyl, isoquinolinyl, 1,2,3,4-tetrahydroquinolinyl, 1°,2°,3”,6'-tetrahydropyridinyl, tetrahydropyridinyl, tetrahydroisoquinolinyl, imidazolyl, benzimidazolyl, benzothiazolyl, Ve benzoxazolyl, benzothiophenyl, benzofuran yl, indazolyl, quinazolinyl, cinnolinyl, phthalazinyl, quinoxalinyl, napthyridinyl, oxazolyl, isoxazolyl, pyrrolyl, tetrazolyl, thiadiazolyl, isothiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, pyranyl, indolyl, phthalamido, isoin dolyl, pyrimidinyl, Thiazolyl, pyrazolyl, 3-pyrrolinyl, pyrazinyl, pyridazinyl, pyridinyl, pyridonyl, quinolonyl, pyrimidonyl and 1-isoquinolinyl.

Vo or ¢indenyl; or indenyl phenyl for example phenyl "aryl" being an "aryl" group; Or Fluorenyl tetrahydronaphthyl or tetrahydronaphthyl + naphthyl or Navel « indanyl . phenyl and preferably the vinyl group ¢ fluorenyl "i hd" includes the acetoxy group "alkanoyloxy" as an example for the "Cl 4dalkoxycarbonyl" and "Cj.ealkoxycarbonyl" and "C)galkoxycarbonyl 0" groups carbonethyl ethoxy; And ethoxy methoxycarbonyl carbutyl methoxy methoxy Judi) Sle gene alkynyl Jai. n and t butoxycarbonyl «<ethoxycarbonyl and © methoxy dc gana "alkoxy Cg" include 0.2-propynyl and thienyl be "butoxy include ¢ propoxy and propoxy ¢ ethoxy and acetamide ¢ formamido formamide groups 'alkanoylamino' and 'bitter' alkanoylamino yo

_ 1 7 —_ from a where CealkylS(0), examples include . propionylamine; And propynyl amino acetamido: zero — 7 groups

Ci.salkylsulphonyl, C;.;alkylS(O),, methylthio, ethylthio, methylsulphinyl, ethylsulphinyl, mesyl and ethylsulphonyl; and alkanoyl propionyl ©: The 'alkanoyl Cig' and ¢" alkanoyl Cig groups include 0 (alkyl C13) - N" 5" N-(Cyalkyl)amino" examples include 0. acetyl And acetyl propionyl ¢ amino ethyl sisal and ethyl “amino” and “methylamine” methylamine groups “amino amino butyl” and butyl amino “amino propyl” and “propyl amino”

N-(Cj.salkyl)amino” and N-(C;.3alkyl)amino include methylamino, ethylamino, propylamino and butylamino -(C,.;alkyl),amino include di-N-methylamino, di-(N-ethyl)amino, di-(N-butyl)amino and N-ethyl-N-methylamino Examples: “Cz. salkenyl” and “C,.¢alkenyl” are Cs.;alkenyl and include vinyl, allyl and 1-propenyl. “N-(Cy. ¢alkyl)sulphamoyl” are N-(C. 3alkyl)sulphamoyl, N-(methyl)sulphamoy! and

N-(ethyl)sulphamoyl.

— \ ¢ — : umbrella “N-(C\.salkyl)carbamoyl” and “N-(C,.calkyl)carbamoyl” are N-(C;.4alkyl)carbamoyl,

N-(Cjsalkyl)carbamoyl, methylaminocarbonyl and ethylaminocarbonyl. They are “NN-(Cyealkyl),carbamoyl” groups: Examples: N,N-(Cj.qalkyl)carbamoyl, N,N-(C,.,alkyl),carbamoyl, dimethylaminocarbonyl and ° methylethylaminocarbonyl.: 'alkyl Ci ( heterocyclic group dc gana)' groups' examples include piperidin-1-ylmethyl, piperidin-1-ylethyl, piperdin-1-ylpropyl, pyridylmethyl, 3-morpholinopropyl, 2-morpholinoethyl and 2-pyrimid-2-ylethyl. Examples of “(heterocyclic group)C.salkoxy” include (heterocyclic group)methoxy, (heterocyclic \ group)ethoxy and (heterocyclic group)propoxy. : "arylChealkyl" groups include: Examples include benzyl, 2-phenylethyl, 2-phenylpropyl and 3-phenylpropyl "Csscycloalkyl' Jad 3 phenoxy and naphthyloxy acids: "aryloxy" "ahd" groups include. cyclohexyl and cyclopropyl cyclopropyl groups Vo and methoxycarbonylamino methoxycarbonylamine groups ' C\.¢alkoxycarbonylamino . t-butoxycarbonyl

- and 1 - In this specification compound terms are used to describe groups that include more than one functional group arylCralkyl Jie These terms are to be interpreted as understood by a person skilled in the art. For example, arylCrealkyl includes an alkyl group©. which is substituted by an aryl group. This group includes 1 benzyl benzyl, 2-phenylethyl “ and

3-phenylpropyl ¢«2-phenylpropyl ° . A suitable pharmaceutically acceptable salt of the compound of the invention is for example the acidifying salt of the compound of the invention which is sufficiently basic as the acidifying salt with; For example. inorganic acid or organic acid; such as acetic or hydrochloric acid; or hydrobromic ¢ or sulfuric sulfuric;

0 or phosphoric or trifluoroacetic or citric or maleic. In addition, the appropriate, pharmaceutically acceptable salt for the compound of the invention that is acidic to a sufficient extent is the salt of an alkali metal “Je” the salt of sodium or potassium “or the salt of an earth alkali metal such as the salt of calcium or magnesium” ¢ or an ammonium salt “or a salt with an organic base giving physiologically acceptable cation 081100

0 as salt with methylamine » or dimethylamine + or piperidine trimethylamine (pa uu df « trimethylamine » morpholine » or

,. tris- (2 hydroxyethyl)amine hydrolyzes in the organism into esters Compounds of formula (1) can be given in the form of esters (1) hydrolyze in the organism of the compound of the formula amide or in the form of amide

Add

1 = — —_ ester that hydrolyzes in the organism of compound 53 (formula (I) and contains a carboxy group or a hydroxy group; it is an acceptable ester because it hydrolyzes Like in the human or animal body to produce parent acid or alcohol (alcohol) It includes esters (318) suitable pharmacologists that have the group: esters ° Al-Gataas “” Muallem. Jie rang : Jie methoxymethyl, C;.salkanoyloxymethyl esters : pivaloyloxymethyl, phthalidyl esters, Cs.cycloalkoxycarbonyloxyC i-salkyl esters for example 1-cyclohexylcarbonyloxyethyl; 1,3-dioxolen-2-onylmethyl esters for example 5-methyl-1,3-dioxolen-2-onylmethyl; and C,.¢alkoxycarbonyloxyethyl esters 0 as (Says 1-methoxycarbonyloxyethyl) formed with any carboxy ic gana in the compounds of this invention. The esters include the compound of formula (1) that hydrolyzes in The al organism contains a group of inorganic hydrolysable ester Jie phosphate esters, acyloxyalkyl ethers and related compounds, which are broken as a result of hydrolysis in the living organism 1 to give a hydroxy group. parent hydroxy Examples include: of a-acyloxyalkyl ethers include acetoxymethoxy and 2,2-dimethylpropionyloxy- methoxy

Groups in which an ester is selected include SLA hydrolyses in the organism to hydroxy groups + alkanoyl and benzoyl groups; and 0-phenylacetyl and benzoyl; They have phenylacetyl and alkoxycarbonyl substituted (to give alkyl carbonate esters ("and © dialkylcarbamoyl") and N-(N,N-dialkylaminoethyl)-N-alkylcarbamoyl (To give carbamates: and “N,N-dialkylaminoacetyl” and carboxyacetyl. Examples of substituents in benzoyl morpholino and piperazino are connected from a nitrogen atom to the ring by means of a group Methylene at the position “- or ;- of the benzoyl ring 0. Suitable examples of a compound amide of the formula ( ) that is hydrolyzable in the organism and contains a carboxy group are, for example: amide such as N-methyl, N-ethyl, N-propyl, a N-Cj.alkyl or N,N-dimethyl, N-ethyl-N-methyl or N,N-diethyl amide 15 of some compounds of formula (I) have chiral centers and/or geometric isomeric centers (Z, 2 and 5 isomers) and it must be understood that the invention includes all isomers optical isomers and diisomers; and engineering. Which has inhibitory activity of the HDAC enzyme

Other examples for loop A are loop 8, y, y, perhaps, RY, and “; and « as follows. These examples may be used where appropriate by any of the instructions; or safeguards; or the forms defined in this application earlier or later. Its ring is pyridyl » or: 0 in concave form pyridyl, quinolyl, indolyl, pyrimidinyl, morpholinyl, piperidinyl, piperazinyl, pyrazinyl, thiazolyl, thienyl, thienopyrimidinyl, thienopyridinyl, purinyl, 1°,2',3° ,6'- tetrahydropyridinyl, triazinyl, oxazolyl, pyrazolyl, or furanyl Cua If the .me ring contains an “NH” moiety, that nitrogen atom may be optionally substituted by a group chosen from G. 0 - The M ring is: pyridin-4-yl, pyridin-3-yl, pyridin-2-yl, quinolin-8-yl, pyrimidin-6-yl, pyrimidin-5-yl, pyrimidin- 4-yl, morpholin-4-yl, piperidin-4-yl, piperidin-3-yl, piperdin-2-yl, piperazin-4-yl, pyridazin-5-yl, pyrazin-6-yl, thiazol- 2-yl, thien-2-yl, thieno[3,2d]pyrimidinyl, thieno[3,2b]pyrimidinyl, thieno[3,2b]pyridinyl, purin-6-yl, 1°,2°,3' ,6'-tetrahydropyridin- 4-yl or triazin-6-yl Vo (13) Where the A ring contained a -NH moiety, this nitrogen atom can be replaced by the ring:

— \ a — pyridin-4-yl, pyridin-3-yl, pyridin-2-yl, morpholin-4-yl, piperidin-4-yl, piperidin-3-yl, piperdin-2-yl, piperazin-4- yl, thiazol-2-yl, thien-2-yl, furan-3-yl, pyrrolidin-1-yl, piperidin-1-yl, triazol-1-yl or 1°,2°,3°,6'- tetrahydropyridin-4-yl that can be replaced by nitrogen, the nitrogen atom —NH - on the A moiety and where the 13) ring contained

G is given by a group chosen from: or “pyridyl” is the pyridyl A ring pyrimidyl, morpholinyl, piperidinyl, piperazinyl, pyridazinyl, thienyl, pyrazinyl, thiazolyl, 1,2,4-triazolyl or furanyl. pyridin-4-yl, pyridin-3-yl, pyridin-2-yl or 1,2-4-triazolyl. : he A ring : ring 5 is -0 thienyl, thiadiazolyl, thiazolyl, pyrimidyl, pyrazinyl, pyridazinyl or pyridyl. Ring 5 is thienyl, thiazolyl, pyrimidyl, pyrazinyl, pyridazinyl or pyridyl . pyridyl Or pyridyl thienyl Jud ring 13 is thienyl where both phenyls are pyridyl or pyridyl thienyl ring 5 is: thinyl 1 pyridyl thienyl from the thienyl ring Y= to the M ring in the pyridyl position Walperidel

-Y. - The compound of formula (1) at the —0 position of the thienyl amide ring and with a pyridyl amide group. .jalkanoyloxy, N-(Ci.;alkyl)amino,

N,N-(C.;alkyl);amino, C;_jalkanoylamino, N-(C,.zalkyl)carbamoyl, °

N,N-(C,salkyl),carbamoyl. .alkoxy or from “alkyl Cig” or “amino or halo” is Halo R! . methoxy or methoxy « methyl or methyl + amino sud ; or halo is halo R! : It is chosen from carbon H is substituted on the carbon atom halo, nitro, cyano, hydroxy, oxo, trifluoromethyl, trifluoromethoxy, amino, carboxy, 01 carbamoyl, mercapto, sulphamoyl, C,.salkyl, C;.¢alkenyl , C,.salkynyl, C.salkoxy,

Ci.salkanoyl, Calkanoyloxy, N-(C,¢alkyl)amino, N,N-(C;.salkyl),amino,

Ci.salkanoylamino, N-(C,_alkyl)carbamoyl, N,N-(C,_alkyl) carbamoyl, C,.¢alkylS(O), wherein a is 0 to 2, C.¢alkoxycarbonyl, N-(C ,_¢alkyl)sulphamoyl,

N,N-(C,.salkyl);sulphamoyl, aryl, aryloxy, arylC, .salkyl, Vo or (or “heterocyclic group dc gana” or “(D-E-) include the R! group, where (D-E-) ic sana or “alkyl C4 ( heterocyclic group) by one or more carbons and can have an optional substitution on the carbon atom

— 1? 7 Whereas, if said heterocyclic group contains an NH moiety, that nitrogen atom can optionally be replaced by a group chosen from [ . They are: halo, nitro, cyano, hydroxy, oxo, trifluoromethyl, trifluoromethoxy, or amino carboxy amino ¢ or carbamoyl or mercapto or sulphamoyl ¢ or alkyl ¢ or alkenyl Cy ¢ or alkynyl ¢ or Cis alkoxy or Cy. alkylase or N-(C,.¢alkyl)amino 0 « alkanoyloxy ¢ or N,N-(C,.¢alkyl),amino » or <alkanoylamino C, or N-(C.¢alkyl)carbamoyl” or or f (5)0 atolehi© Cus from fer - 7 i.e. C alkoxycarbonyl© or z N-(Cj.¢alkyl)sulphamoyl + or «<N,N-(C,.alkyl),sulphamoyl or “aryl Jd” or “aryl oxy” i.e. arylCrgalkyl “or heterocyclic group” or “heterocyclic group (m© alkyl” or ¢ group (D-E"-) where an optional substitution occurs in ; including the (D-E-) group on the carbon atom carbon Vo by one or more of the 17 ; where 17 and 2 are selected separately from the halo halo, ligand nitro, cyano, hydroxy, oxo, trifluoromethyl, trifluoromethoxy +, or carboxy amino or carbamoyl ¢ or mercapto; or alkyl Cig of sulphamoyl ¢ + or Cas d alkenyl or alkynyl Cy ¢ or alkoxy bitter or from alkanoyl ¢ or alkanoyloxy Ci « or

Al-absorbed (abol. rn)-a0 or assimilated (lo-0)-arla or from calkanoylamino or N-(C.¢alkyl)carbamoyl” or N,N-(C,.galkyl),carbamoyl ¢ or f(5)0 the where a from saqr - ¥ ¢ Cy.galkoxycarbonyl of ¢ i.e. N=(C,4alkylsulphamoyl ” or N,N-(C,.¢alkyl),sulphamoyl ¢ oo 6”, J and JSK are selected separately from alkynyl Cog 3 “ alkenyl Cag of “ alkyl Cig ¢

Or the alkanoyl mel – or the alkanoyl alkanoyl 0 “or the meaning “> carbamoyl 0 0 carbamoyl” ¢ or N,N-(C.galkyl)carbamoy! “N-(C.salkyl)carbamoyl “benzyloxycarbonyl” or benzoyl and phenylsulphonyl “or aryl” i.e. ¢arylCpealkyl or (heterocyclic group ( m

calkyl 0 where an optional substitution may occur in 6; and 5d 16 on the carbon atom by one or more of ; Whereas, if the heterocyclic group contains an NH segment, that hydrogen atom 000 may be optionally replaced by a group chosen from hydrogen or alkyl Cy.;

0© is halo tweezers » or nitro or 0 cyano or hydroxy ¢ or 0 oxo or trifluoromethyl ; trifluoromethoxy, amino, carboxy, carbamoyl, or mercapto; or s_of sulphamoyl ¢ or of an alkyl ; or alkenyl Cy “or mon alkynyl ¢ or Cis “alkoxy” or m-alkanoyl “or alkanoyloxy” or mutasam (alkyl-Rn) or

00 Absorbosazoazollah (Ren)- colostrum or myrrh “alkanoylamino” or “N-(C_salkyl)carbamoyl” and or

- Secret

N,N-(C,.¢alkyl),carbamoyl ¢ or) 0.1115 where 8 is notched sor - ? or

Cy.galkoxycarbonyl « or N-(Cpgalkyl)sulphamoyl « or N,N-(Cy_galkyl);sulphamoyl ¢ or

aryl anon or aryl oxy; , anylCrealkyl or a heterocyclic group

heterocyclic group ” or (heterocyclic group ( of ” alkyl or

© set (DE) where an optional substitution occurs in ©; Including the group (DME) on an atom

carbon by one or more Z's

alkynyl or b ¢ alkenyl Cag or ¢ alkyl Crg separately from JSD" 54D 5D is selected

0 i.e. Cgcycloalkyl “i.e. lolmi 10 and lolmaarno0” (aryl J) or arylCrgalkyl or

heterocyclic group” or heterocyclic group “alkyl © + ( heterocyclic group 0) where an optional substitution may occur in 5D 5D” 1 on

carbon atom «00:e» by one or more oF and where if the cyclic group contains not

mentioned congener on the = =NH moiety, this nitrogen atom may be optionally substituted

by a group chosen from K ;

E, 57, and 287 are each selected separately from -NRY - or -0 - or m w § - rq a stop a = “NRHC(0) a - J NRHC(ONR® ).

-R0)0 fire Je—C(OIN(R?) J—OC(OIN(R?)):5 R

—SONRY- or 24089507; Whereby RP 18 is selected separately from hydrogen

eT _has optionally substituted by one or more of the 7 and where alkyl Cis or hydrogen

zero - ?; “F” and “7” are selected separately from nitro 550 halo ¢ or cyano Jv. hydroxy + or oxo or trifluoromethyl ; or (sh

trifluoromethoxy ¢ amino ¢ carboxy ¢ or carbamoyl “or mercapto” or sulphamoyl + or alkyl Cig “or Cas alkenyl” 0 mon alkynyl “or from “alkoxy” or from “alkanoyl” or “alkanoyloxy bitter” or “N-(C,.salkyl)amino” or “N,N-(Ci.salkyl);amino” or from “alkanoylamino or N-(Cysalkyl)carbamoyl © ¢ or N,N-(Cy.salkyl);carbamoyl ” or CgalkylS(0), where a is from

oy — ha or N-(C,.salkyl)sulphamoyl 0 « Calkoxycarbonyl » or N,N-(C,.salkyl);sulphamoyl . RY is a substituent on a carbon atom selected from a cyano, hydroxy ¢, alkyl Cig” or (D-E-) group where a selective substitution can occur in RY

0 - including group (D-E-) on one or more dad carbons of 7; an optional substitution in V including the (-01) group on the carbon atom by one 0 more than ba ; W and 7 are selected separately from cyano », m alkyl » or ‘alkoxy Cig’

1 6 and SK are selected separately from alkyl Cig” or “alkenyl Cog +” or “alkynyl Min” or “alkyl Cre aryl Ju” or (alkyl Cy) heterocyclic group ; and where an optional substitution can occur in 6 and K on the carbon atom by one or more © ;

_ Y mug —

Cas 3 “alkyl cig that” 0x0 sa S4 5 ¢ hydroxy; or hydroxy cyano is cyano© alkenyl » or from alkoxy or alkanoyloxy Ci. « alkanoyl Ci « or J¢ Cpealkoxycarbonyl or > N,N~(Cy.ealkyl);carbamoyl sl « N-(Cy.salkyl)carbamoyl (D7-E7) or a group » aryloxy or aryl 1e; or aryl oxy “Cpalkoxycarbonylamino” on the carbon atom (DEY); where an optional substitution in © including group 0 “slow”_ can occur by one or more of the 7 ; © is selected; and '©; and JSD" separately from carylCrgalkyl of ¢ aryl Jaf or group (D"- E"); where an optional substitution can occur in D" 5D 5D on the carbon atom by one or more From 7 and since 13 the heterocyclic group yo. ©, 857 and SSE” are selected separately from -© = or - C(0)0 -. or - CO) -. or -NRY)C(O) =« or -CONGR?) =« or -S(O) = where 8 hydrogen or alkyl Cr 43 is optionally substituted by one or over oF : from 0 \o - 7 ; oF and JSF are selected separately from nitro; or hydroxy ¢ or alkyl Cy. « « N,N-(Calkyl)amino » N-(Ci.alkyl)amino © alkanoyl Cr. “alkoxy Ci of C. alkoxycarbonyl or “alkanoylamino” or bitter 111 is zero ¢ or \ ¢ or Y ¢ or 7 6 or 3 ¢ and where C values are equal or different 3

a am zero; or oY J and where af !© is equal or different; 1 is zero; or 1 is zero; 8 is .1 ° is halo . R? is a fluoro or chloro ¢ R? is a fluoro. it is zero; or YJ) and where the values of 82 are equal or different; is zero; or 1,200 is zero; is 1 rR? is an amino or hydroxy . 3c is an amino. rR? is a hydroxy acid. Add

R* is halo; or nitro ¢ or cyano slaw; or hydroxy “trifluoromethyl” or trifluoromethoxy “trifluoromethoxy” or “carboxy” or carbamoyl; R* is halo; Or cyano + or trifluoromethyl or trifluoromethoxy. R* is halo “P is zero ¢ or 1 or ;” and where values of rR? are equal or different P is zero ¢ or 1 . AP zero P yo is A so in another form of the invention a compound of formula (1( LS) was described before); where: ring A is pyridyl ¢ or indolyl 1000171; or pyrimidyl or morpholinyl or piperidinyl; or piperazinyl; or pyridazinyl of « pyridazinyl 0 thienyl ; or to pyrazethyl chloride; or thiadiazolyl “or oxazolyl ¢ or 1,2,4-triazolyl ¢ or isoxazolyl” or 0-thiadiazolyl or 0-pyrazolyl or furanyl;

Ring 8 is thienyl Jud + or thiadiazolyl » or thiadiazolyl » or pyrimidyl « epyrazinyl or pyridazinyl » or pyridyl ¢ a halo amino amino » or m »alkyl or alkanoyloxy Ci; 4 salkoxy

0 “or N-(Cjsalkyl)amino” or sf “N-(C,alkyl)carbamoyl sf “ N-(C,alkyl)carbamoyl . m is zero < or 1 4 or Y ' or Y m or $ ' and where values of rR? are equal or different ¢ R? is fluoro or 5.5 chloro ¢ 1 is zero 3 or 3 0 ¥ and where values of R? are equal or different ¢

¢ hydroxy or hydroxy amino treatment is amino 00 or thaladene » hydroxy ; or hydroxy cyano or cyano ¢ nitro; or halo is an R* amino or an equal or different amino » trifluoromethoxy or trifluoromethyl fluoromethoxy « carbamoyl or carbamoyl » carboxy or carboxy; R* or l and where oy is zero 3 or P and

1 . or a pharmaceutically acceptable salt. Or ester or amide _ of it is hydrolyzable in the living organism. Therefore, in another form of the invention, a compound of formula (1) (as previously described) is provided where: ring A is: pyridin-4-yl, pyridin-3-yl, pyridin-2-yl or 1,2 ,4-triazolyl

Ring 8 is thienyl Jud or pyridyl ¢ R! is halo; or amino ¢, sulfuric acid, or methoxy ‘m is zero’, 3, or y and where p-values are equal or different; R* is fluoro ¢ N ° is ya ¢ or 3 rR' is amino ¢ R* is halo ¢ and P is 0 ' or 3 or oY and where the values of 4c equal to 0 are different; or a pharmaceutically acceptable salt; Or an ester or an amide thereof that is hydrolyzable in the organism. 0 Therefore in another embodiment of the invention a compound of formula (WS(1) has been previously described) is provided where: ring A is pyridyl “or quinolyl” or indolyl 1000171; or pyrimidinyl or morpholinyl or piperidinyl; or piperazinyl + or pyridazinyl ¢ or pyrazinyl or thiadiazolyl or thienyl ¢ or thienopyrimidinyl ¢ or thienopyridine 0 or purinyl -tetrahydropyridinyl 1°,2°,3°,6 or triazinyl + or oxazolyl or pyrazolyl; or furanyl furanyl; and where

— But if the m ring contains a -1411- moiety, then that nitrogen atom may optionally be substituted by a group chosen from 6; The B ring is thienyl or thiadiazolyl or thiadiazolyl or pyrimidyl or 7m pyrazinyl or pyridazingl or pyridyl they are pyridyl R! It is a substituent on an aus carbon atom of choice of halo, nitro, cyano, or hydroxy; or oxo or trifluoromethyl or trifluoromethoxy + or amino ¢ carboxy or carbamoyl + or mercapto or sulfamoyl + or alkyl Crs 0 “or alkenyl Cos + or of alkynyl” that of “alkoxy or alkanoyl  or alkanoyloxy bitter” or absorbents (amyldiron)-A or N,N -(C,.¢alkyl);amino ¢ or Cis “alkanoylamino” or absorbent (Aboldir 0)-a; or Alkanoylamino “or C.6alkylS(0O), where 8 is ssfar-¢Y or Cr.¢alkoxycarbonyl “¢ or N-(C;.alkyl)sulphamoyl” or Mos1( 2801 lm.©)-1,27” or aryl 1h” or aryloxy “ie olme 0 label 101 or heterocyclic group + or de sand) heterocyclic group ( m© “alkyl group ¢(D-E-) where R’ includes a group ¢(D-E-) and can have an optionally substituted on the carbon atom by one or more (V Whereas, if the aforementioned heterocyclic group contains the -1117- moiety, then this nitrogen atom can optionally be replaced by a group chosen from J

— vy =

V is halo ; or nitro ¢ or cyano or hydroxy + or oxo

0e + or ob trifluoromethyl + or trifluoromethoxy ¢

or amino + carboxy; or carbamoyl; or mercapto “or s_for sulphamoyl ¢ or from alkyl” or alkenyl cities “or alkynyl madun; or Cis

0 “N-(Cj.galkyl)amino” or “alkanoyloxy” or “alkanoyl” or “alkoxy eo” or “N-(C.¢alkyl)carbamoyl” or “<alkanoylamino Cj. or “N,N-(C,.¢alkyl),amino.”

Alkanoylamino “or f(1715)0ld.”), where 8 of ssfar - ¥ ¢ or Cy.galkoxycarbonyl “or N+ (Cj.salkyl)sulphamoyl” i.e. (NN-(Cyalkyl)psulphamoyl or aryl aryl or aryl oxy with the arylCigalkyl of «or heterocyclic group»

«((D-E-) or « alkyl group © ( heterocyclic group or (heterocyclic group) 0 group Lest; including carbon where an optional substitution can occur in 7 on the carbon atom

,. 177 by one or more (DE)

Where 177 and 7 are selected separately from Halo; nitro, cyano, hydroxy, or oxo-0; Or trifluoromethyl or thaladene

1-trifluoromethoxy ¢ or amino© carboxy + or carbamoyl ¢ or mercapto ¢ or sulphamoyl » or alkyl Cig » or Cas

alkenyl “or alkynyl cities” ¢ or from “alkoxy” or alkanoyl bitter “or alkanoyloxy Cj” or absorbents (N-ol)-A or N,N-(Cy.salkyl);amino Or from calkanoylamino or N-(Cy.¢alkyl)carbamoyl or N,N-(Cy.salkyl),carbamoyl or 11 0 ld. where a from

a a TY -?; or Cy.galkoxycarbonyl; Or N-(Cy.salkyl)sulphamoyl + or 1 atm1(2901,0)-11,11. . 5G selected 1; and JSK separately from alkyl Cig; or

the alkynyl Cys 0 ¢ alkenyl “or M0 alkanoyl” or Cygalkylsulphonyl – or L or carbamoyl; or N-(C,_salkyl)carbamoyl the Cy.) - N alkyl s ) carbamoyl ; and benzyloxycarbonyl + or benzoyl and phenyl “phenylsulphonyl Js salu ¢arylCrealkyl” aryl or ic gana)© heterocyclic Cua “alkyl Cre ( heterocyclic group) selective substitution may occur in 6; and K 5d on the carbon atom by one or more than ©, and where if the aforementioned heterocyclic group contains a moiety - NH - then that nitrogen atom Cpa sill may have an optional substitution by a group They are selected from hydrogen or alkyl Cy 0 0. They are halo, nitro, cyano, hydroxy, oxo, or trifluoromethyl Jie "or trifluoromethoxy" or amino "carboxy" or carbamoyl "or mercapto" or sulphamoyl sell ws ¢ or alkyl Cy ¢ or min alkenyl “¢ or alkynyl ¢ cities or cis “alkoxy” or from alkanoyl “or from alkanoyloxy” or N-(Cy.¢alkyl)amino” or N,N-( C_alkyl),amino \o « or calkanoylamino cities or N-(C,.¢alkyl)carbamoyl ' or N,N<(C)galkyl)carbamoyl « or JeY oi a sadn a CrealkylS( 0). aryloxy; or carylCrealkyl or heterocyclic group + or Ac sana) alkyl C16 heterocyclic ( heterocyclic group © or Y. group (-"2-"0); Cus occurs Optional substitution in © including the (DE) group on the carbon atom by one or more Z add

vy — 5D '©,; and JSD' separately from alkynyl Cag 5 ¢ alkenyl Cag sf + alkyl Cig ' or anoldmau win; or CsgcycloalkylC) alkyl ¢ or arylCjealkyl 0 heterocyclic group group” or “alkyl Cig + ( heterocyclic group) where an optional substitution may occur in ©; and 5D” 0 on 0 carbon atoms by one or more than 7 and where 13 contained the cyclic group said heterocyclic on the -071<- moiety, that nitrogen atom may optionally be substituted by a group to be chosen from 16; E, “5, and SSE” are each chosen separately from =N(R) ) or = 4-0 or - 0(0)©- or “0CO)- 4 (with “ J - WHY SIGN A - J NRICONRD 0 -0(0)0CONE? )—OCONR?Tr«Rm(R-Alawiyy R-110050) where 8 and 1" are selected separately from the alkyl arne hydrogens having an optionally substituted by one or more than 7 and where (Y = 0 Ger F and JSF are selected separately from halo ¢ , nitro , cyano ; hydroxy ¢ , oxo , or trifluoromethyl trifluoromethyl + or No trifluoromethoxy ; or 0 amino sual carboxy + or carbamoyl ¢ or mercapto or sulphamoyl or 0 alkyl Cig or Cas alkenyl or alkynyl or “alkoxy Cj 0 bitter alkanoyl; or alkanoyloxy Ci. or N-(C,.g¢alkyl)amino or sublimated (Alta0)-ara or alkanoylamine or abrasive (Alola.Ren)1 or N,N -(C,alkyl),carbamoyl « or CyelakylS(O), where a from

_— p Tv _ a 8 -- ? or C.salkoxycarbonyl « or N-(C,salkyl)sulphamoyl « or N,N-(C,.salkyl);sulphamoyl ; m is zero’, 1, yell, neither, or of and where the values of R! are the same or different; R* is fluoro or chloro ¢ m AN zero or 1 or oY and where RY a8 is the same or different; 3c is amino or hydroxy ¢ R* is halo or nitro or cyano; or hydroxy; or trifluoromethyl ¢ or trifluoromethoxy » or amino sue or carboxy ¢ carbamoyl » A and P are zero ' 0 3 or 31 and where the values of R* Equal or different, a pharmaceutically acceptable salt, an ester, or an amide 4a that is hydrolyzable in the organism. Therefore in another form of the invention a compound of formula (1) (as previously described) is provided where: ring A is: pyridin-4-yl, pyridin-3-yl, pyridin-2-yl, morpholin-4 -yl, piperidin-4-yl, piperidin-3-yl, piperidin-2-yl, piperazin-4-yl, thiazol-2-yl, thien-2-yl, furan-3-yl, pyrrolidin-1 -yl, Vo piperidin-1-yl, triazol-1-yl

o — b — or 17,27,3°,6'-tetrahydropyridin-4-yl ¢ where if the A ring contains an -NH moiety then that nitrogen atom may be optionally substituted by group to be selected from 6 ep 8 thienyl Jif « or thiadiazolyl » or pyrimidyl ; or pyrazinyl or pyridazinyl or pyridyl; R! 2 is a substituent on a carbon atom that is selected from a cyano ¢, hydroxy », or alkyl C16 or Cua (DE) group selective substitution can occur in R' La has the (D-E-) group on the carbon atom carbon by one or more of 7 ; V is cyano; or hydroxychloroquine 0:7; or group (DUE) where an optional substitution V2 including group (D-E-) can occur on the carbon atom by one or more yo. 17 ¢ a choice b and 7 each Separately from cyano ¢ or alkyl Cis 6 or “alkoxy Cis 6 and ISK are separately selected from alkyl Cp.g; or min alkenyl; or Min alkynyl ¢ or arylC alkyl « or (Cus ¢ alkyl Cp ) heterocyclic group The selective substitution in © and K on the carbon atom is carried out by one or more Q ; Vo 0 is cyano¢ or hydroxy “or oxo 0X0¢ 0mer alkyl” or alkenyl cities or “alkoxy Ci or alkanoyl Ci.; or alkanoyloxy Ci « 0 ,N-(C_galkyl)carbamoyl » or C,.¢alkoxycarbonyl of « N,N-(C,.¢alkyl),carbamoyl ‘ or succinate: “causative”. © « or aryl or aryloxy » or the ¢(D"-E") group

Where an optional substitution can occur in © including the group ‎(DUE) on the carbon atom «Htah»_ by one or more of the Z PX select 39 3 D "9 D' each separately with an aryl tooth aryl ' or arylCj.salkyl ¢ or ic sana (DE) where an optional substitution in ©, “© and D7 can occur on one or more adal sr carbon 7” Whereas, if the heterocyclic group contains a -NH moiety, that nitrogen atom may optionally be substituted by a group chosen from K; E, '8; and KE' are selected separately from - 0 = or - COO = or - (0). 8 of hydrogen 0 or alkyl Cig optionally substituted by one or more of 7 and gar zero 17 - ; oF and 77 are selected separately from nitro ¢ or hydroxy ¢ or from alkoxy or from “alkoxy” or from “alkanoyl” or from “N-(C,.salkyl)amino” or assimilated (anol 0 )- abaca or from “<alkanoylamino” or from the a m 11 is zero 6 or 1 º or Y ¢ and where values of R! are equal or different ¢ R* is fluoro; N is zero ' or 3 rR' is amino © Yvys

Sala 8 is halo ¢ P 5 is zero; or 1 or oY and where the values of R* are equal or different; or an acceptable salt (Liana or an ester or an amide thereof that is hydrolyzable in the organism. In another form of the invention, the preferred compounds of the invention are any one of the examples or a pharmaceutically acceptable salt of 0; or an ester ester or an amide thereof that is hydrolysable in living organism. In another embodiment of the invention a compound of formula (1) or a pharmaceutically acceptable die salt (where the cA ring and the “B” ring and nagel and “ +, 3c, (RR, 02, © and © as then previously defined in formula (1) unless otherwise indicated.) In another form of the invention, the preferred compounds of the invention are any one of the examples or a salt of 01 Pharmaceutically acceptable form of the invention Another form of the invention provides a process for preparing a compound of formula (1) or a pharmaceutically acceptable salt; or an ester thereof that is hydrolyzable in vivo; and includes such a process (where the oA ring and the 5B ring are li and a, p, a, “, and sam © as defined in formula (1) unless otherwise indicated): vo (a) is a complex reaction of formula (I)

and 80 0 7 2< N H an b where X is a group reactant with the compound of formula (I) RYH, p00 J 12 gL! Cua 1 associative groups; © (b) A complex reaction of formula (IV) (R%), L! 0 \ N (Iv) R3 Cua a and 1 bonding groups with a compound of formula FV)

(RH, X (V) where 76 is the reactant group; or (c) the reaction in the presence of: 4-(4,6-dimethoxy-1,3,5-triazinyl-2-yl) -4-methylmorpholinium chloride » compound of God of formula (171): 1 HN PN H,N (RY, (VD) with a compound of formula (VII) RY, 82: (VII) and thereafter, if necessary:

M. (V) conversion of a compound of formula (A) to another compound of formula (1) and/or (Y) removal of any protecting groups;

operations can be performed (a); or (b); or (c) in the presence of a rule. appropriate rule of operations (a); or (b); or (c) is for example a base of a Jie organic amine pyridine ¢ or 2,6-lutidine, collidine ¢ or 4-dimethylaminopyridine s-amino or triethylamine triethylamine “or morpholine ¢ ie N-methylmorpholine” or diazabicyclo[5,4.0]undec-7-ene ” or for example a carbonate or hydroxide of an alkali metal or of an alkali metal; such as sodium carbonate; Or potassium carbonate »or calcium carbonate« or sodium hydroxide 0 + or potassium hydroxide J potassium hydroxide for example alkali metal hydride such as sodium hydride ¢ or alkoxide metal as ethoxide

Sodium ethoxide ¢ The appropriate reactant X group is for example halogeno sia sla or calkoxy or aryloxy + or sulfonyloxy 50101007107 such as 1 chloro 1 chloro group or bromo or methoxy + or phenoxy or methanesulphonyloxy or trifluoromethanesulphonyloxy + or toluene 4-sulphonyloxy. The reactions are suitably carried out in the presence of a suitable inert solvent or sabe suitable diluent; Such as alkanol or ester such as methanol or ethanol or isopropanol or vy. ethyl acetate ¢ or a halogenated solvent such as methylene chloride » or

chloroform or carbon tetrachloride ¢ any ether

such as tetrahydrofuran “or 1,2-dimethoxyethane ¢ or 1,4-dioxan” or

an aromatic solvent such as toluene; or a dipolar aprotic solvent

Proton donor N,N-dimethylformamide Jia » or N N-dimethylacetamide _ + or

M «<N-methylpyrrolidin-2-one or dimethylsulphoxide.

The reaction is carried out appropriately at a temperature ranging from 0 - 0 to a You, preferably between 0 - 6 A You

Suitable examples of bonding groups include .1 and 12 on the boron atom, for example

For example, hydroxy bonding groups in calkoxy or from alkoxy less than 0 hydroxy bonding groups » or methoxy + or ethoxy » or

propoxy ; or isoPropoxy; or butoxy; or mechthel

methyl + or “ethyl Ji” or “propyl” or butyl. Alternatively you may call

The bonding groups LY and 1 together with the boron atom attached to them to form a ring. May be

lea 2 SL! zlau-adhaboaad(j0)-”<: e group such as oxyethyleneoxy or oxytrimethyleneoxy so that they are with an atom

Boron to which they are attached is a cyclic boronic acid ester ¢

Operations (a) or (b) can be performed in the presence of a catalyst. Suitable triggers for operations include ( ) or

(Ibb); For example; metallic catalysts such as:

— $ Y — : as a palladium(0), palladium(II), nickel(0) or nickel(II) tetrakis(triphenylphosphine)palladium(0), palladium(II) chloride, palladium(Il) bromide, bis (triphenylphosphine)palladium(Il) chloride, tetrakis(triphenylphosphine)nickel(0), nickel(Il) chloride, nickel(IT) bromide or bis(triphenylphosphine)nickel(II) chloride as azo azo compound fe plus To this a free radical initiator “azo(bisisobutyronitrile) may be added. It will be estimated that some of the various ring substituents in the compounds of the present invention may be introduced by standard aromatic substitution reactions or generated by modifications of conventional functional groups either prior to operations. mentioned immediately before or after it, and in this way the invention is made. These interactions and modifications include; For example; Entry Adee embed in 0 aromatic substitution; reduction of substitutes; and all substitutes; The oxidation of the Jeli is substituted by the substitutes. The reactants and reaction conditions for these procedures are well known in the art of chemistry. Using nitro acid Specific examples of aromatic substitution reactions include the introduction of a nitro acyl halide using eg; concentrated acyl halide; And the introduction of an acyl group under (aluminium trichloride Jie) Lewis acid and Lewis acid Vo

Lewis and alkyl alla Lewis acid using an alkyl and introducing a group ¢ Friedel Crafts conditions “Friedel Crafts” under the condition of (aluminium trichloride Jia) acid Specific examples of modifications include the reduction of the nitro group. halogeno and introducing a halogeno group, for example, by catalytic hydrogenation using a nickel or amino catalyst to a nitro amino group

C treatment by iron in the presence of hydrochloric acid with heating; Or the oxidation of an alkylthio to an alkylsulphinyl or an alkylsulphonyl . It will also be estimated that in some of the reactions mentioned in this application it may be necessary | It is desirable to protect any sensitive groups in vehicles. The cases in which protection 0 is necessary or desirable and the appropriate methods of protection are known to those skilled in the art. Conventional protective groups may be used according to the standard method (for clarification see T.W.

Green, Protective Groups in Organic Sythesis, John Wiley and Sons, 1991). or hydroxy. It may be desirable to protect the group in some of the 0 reactions mentioned in this order. A suitable protecting group for an amino group or an amino alkyl sud group is, for example, an acyl group such as an alkanoyl group such as an acetyl group an alkoxycarbonyl group such as a methoxycarbonyl group or an ethoxycarbonyl group Or t-butoxycarbonyl group ¢ or ic sama 0 aryl methoxycarbonyl Jie aryl methoxycarbonyl benzyl oxycarbonyl group a dc sana aroyl as benzoyl group. The conditions for deprotection of the aforementioned protecting groups necessarily differ according to the selected protecting group. Etc. (JB an acyl group Jie an alkanoyl group ¢ or an alkoxy carbonyl group; or an aroyl group can be removed by AW hydrolysis) by a suitable base Jie 0 | hydroxide an alkali metal; Such as lithium hydroxide or sodium

.sodium is an alternative to that, an acyl group such as the 1-butoxycarbonyl group can be removed, for example, by treatment with a suitable acid such as hydrochloric acid or sulfuric acid; or phosphoric acid; Or trifluoroacetic acid ¢ The aryl methoxycarbonyl group Jie arylmethoxycarbonyl 0 benzyloxyearbonyl group can be removed for example by hydrogenation over a catalyst such as palladium on carbon or by treatment with Lewis acid acid such as boron tris(trifluoroacetate) A suitable substitute protecting group for a primary amine group is for example a phthaloyl Just group which can be removed by treatment with an alkyl amine

such as dimethylaminopropylamine »or by hydrazine.

0 The protective group suitable for a hydroxy group is, for example, an acyl group, Jie, an alkanoyl group, such as an acetyl group, or an aroyl group, such as benzoyl, or an aryl-methyl group, such as Jie arylmethyl. benzyl The conditions for deprotection of the aforementioned protecting groups will necessarily vary according to the selected protecting group. Thus for example an acyl group such as an alkanoy group or an Orwell group can be removed

aroyl 0, for example, by hydrolysis by a suitable base such as the alkali metal hydroxide Ja, lithium hydroxide, or sodium hydroxide. Alternatively, the arylmethyl group can be removed as a benzyl group. For example Jha by hydrogenation over Jie catalyst with palladium on carbon. A suitable protecting group for a carboxy group is eg de gene esterification

0 ._such as a methyl group or an ethyl group, which can be removed, for example, by hydrolysis

Add

Sia _— by a base such as sodium hydroxide ¢ or for example an As t-butyl group Sia can be removed by treatment with an acid such as an organic acid such as trifluoroacetic acid or for example a benzyl group benzyl, which can be removed, for example, by hydrogenation over a palladium-carbon Jie catalyst. 0 Protecting groups may be removed at any suitable stage in the synthesis using conventional methods well known in the art of chemistry. Biological tests: The following tests can be used to measure the effects of the compounds of the present invention as inhibitors of the enzyme (HDAC) as in vitro inhibitors of histone acetylases enzyme aggregated aged 0 nuclear extracts prepared from the strain of any human neck cancer cell Hela and as in vitro inhibitors of the enzyme HDAC-1 produced in insect cells “His” and as in vitro inducers of the insertion of an acetyl group 21 into histones 113 in whole cells. HDAC versus histone deacetylases enzymes Histone Vo 5 collected from nuclear extracts of ADL human cervical cancer cell HeLa m3 deacetylases experiments were performed in a reaction volume foo jade μl. 3.8 µg of diluted nuclear extracts were mixed in 1 µL of reaction buffer yo) mM Tris HCL (pH (A - [pH]) and

PE

8) with either MgCly 1 mM and KCl 7.7 mM NaCl 17 µL) of buffer alone; or with (0 μL) buffer solution containing micromolar YO min at room temperature. Then the Te complex was added for 1 0 μL of a solution diluted in fluor—de-lys substrate (Biomol) enzyme subject matter (Biomol) 1 h at room temperature. 1 regulator was suspended to the reaction mixture and incubated for fluor de lys developer from the reaction developer tly by adding an equal volume (40 μM at ? μm). The reaction was left to continue for 1 day Trichostatin A containing (Biomol) ) (a minute fluorescence at room temperature, after which the fluorescence was measured at “0 nm and an emission wavelength of” fluorescence 710) at an excitation wavelength estimated by making HDAC-response curves for ICsp enzyme inhibitors 5 yo values of 7500 per dose were determined from the separate compounds and the concentration of the inhibitor that produced a decrease of the maximum signal was determined (the comparison sample in which there was no inhibitor). (B) _ Laboratory enzyme test for human enzyme recombinant HDAC 1 vs. HDAC enzyme Enzyme inhibitors were tested at (Flag) The enzyme was cloned by Hi 5 gene tag Produced in insect cells — Jala “agarose” -terminus of the gene and the fusion was purified using agarose (A2220) SIGMA 2E of 0 in a reaction volume of Deacetylases. µL of 11 µg of nuclear extracts were performed. Diluted in v0 μl. F (A = [pH] (pH Tris HCl mM Yo) buffer solution 1 was mixed

0) Ld with MgCl, mM 1 mM !© and Y,V NaCl 117 mM) of buffer alone; or with (© μl) buffer solution containing micromolar YO min at room temperature. Then the Ve compound was added for 1 0 μL solution diluted in fluor—de-lys substrate (Biomol) enzyme subject matter (Biomol) 1 hour at room temperature. Then 1 regulator was suspended to the reaction mixture and the incubation took place for 1 ° (Biomol) fluor-de-lys reaction by adding an equal volume (+ § μl) of Ye min profile at ? micromolar. The reaction was allowed to continue for Trichostatin A containing at room temperature after which fluorescence was measured at nm wavelength and an emission wavelength of £70 nm. 01 for excitability was determined by making dose-response curves; of HDACs for ICs enzyme inhibitors, ye values from the discrete 7250 maximum signal and determine the concentration of the inhibitor that results in a decrease of the comparator in which there is no inhibitor (ie)

Pad (C) Laboratory enzymatic experiment to determine the activity of the enzyme histone D. Whole cells: 3 histones Deacetylases in whole cells 113 histones in acetyl histones The introduction of an acetyl group has been identified \o -Cellomics have been cultured histological and analysis using a de lial format scan using cell/eye chemistry; It was left to stick 1” 10 in dishes containing 976 eyes, with an average of AS49 cells, and it was treated with inhibitors for a period of time; 7 hours and then fixed in oJ solution for an hour. Cells were made 1 for (TBS) formaldehyde in Tris buffered saline 78 and after ice-cooled TBS for ¾ minutes; It was rinsed in methanol permeated with Ye methanol

A — $ — that was plugged in TBS 77 low fat milk powder for 90 minutes. The cells were then incubated with polyclonal antibodies specific for histones 113 to which an acetyl group (Upstate # 06-599) was introduced (44 acetyl group) diluted 1:50600 in TBS with milk 77 for 1 Cells were rinsed 3 times and then incubated with fluorescein-conjugated secondary antibodies (Molecular Probes # A 11008) and 1 (μg/m) (Molecular Probes # A 3570) Hoechst 333542 (Ja) in TBS with 71 bovine serum albumin (6917 3#) (Sigma) for 1 hour. Unbound antibodies were removed by ¥ rinses with TBS and after the last rinse 100 μl TBS was added to Cells were sealed, dishes were sealed, and analyzed using a Cellomics format scan yo. ECsp values for HDAC inhibitors were determined by making dose-response curves of the isolated compounds and determining the concentration of the inhibitor that produced 72506 of the maximum signal (comparator reference compound — Trichostatin A ((Sigma) A yo. In structural form, the activity of compounds of formula (1) at the following concentrations or doses can generally be demonstrated by one or more of the preceding tests (i), (b), and (c): - Test A: - 10, for example, in the range of > 50.0 micromolar; Test (b): - 10, for example, is within > 0.¥ micromolar;

q _ $ ̊ test (c): - The Se ECsp is in the range of > 9.6 micromolar ¢ According to another version of the invention, a pharmaceutical composition has been provided that includes a compound of formula (1); or a pharmaceutically acceptable salt, ester, or amide 4a hydrolyzable in vivo; As defined in this application before with a pharmaceutically acceptable diluent or carrier.

0 The formulation may be in a form suitable for oral administration; for example as a tablet or capsule; or for injection other than by an intravenous route (including intravenously; subcutaneously; intramuscularly; intravascularly; or by intravenous sutures) as a sterile solution; or a sterile suspension; or a sterile emulsion; or for topical administration as an ointment; or cream; Or for rectal administration as a suppository. The aforementioned formulations can generally be prepared in a conventional manner using conventional excipients.

0 A compound of formula ( 1 ) will normally be administered to warm-blooded animals in a dose unit of ~ 5 mg/Fa squared of animal body area' or Yor — ov) mg/kg approximately 6 and provides This dose unit is a therapeutically effective dose. The unit dose image of Jie will usually contain a tablet or capsule of YOu - 1 mg of the active ingredient. Preferably, the daily dose used ranges from 1-00 mg/kg. However, it is necessary to vary the daily dose (aie).

vo on the intended host (candle) and the specified route of administration; The severity of the disease being treated. According to another form of the present invention a compound of formula (1) is provided; or a pharmaceutically acceptable salt; or an ester or amide of it is hydrolyzable in the organism; They were also previously defined for use in a manner of treating the body of a human or an animal with this remedy.

Con The inventors have found that the compounds defined in the present invention; or pharmaceutically acceptable salt; or of it that is hydrolyzable in the organism; They are effective amide or amide ester inhibitors whose properties are lam inhibitors of the cell cycle (anti-cell proliferation agents); It is believed that this property, and the inventors also believe that the compounds of the current invention are responsible for inhibiting the formation of HDAC of the vascular enzyme; and activation of cell death and differentiation. Accordingly, it is expected that the compounds of the present invention 0 ie (HDAC) can be useful in treating diseases or conditions mediated partially or alone by enzymes in a warm-blooded animal in need of such treatment. HDAC The use of compounds to produce an enzyme-inhibiting effect Thus, the compounds of the present invention provide a method for treating malignant cell proliferation that is characterized by inhibiting enzymes, that is, the compounds can be used to produce an effect that is partially mediated by anti-proliferation or (HDAC).

HDACs alone activate enzymes > 0 A compound of formula (1) was provided; or a pharmaceutically acceptable salt; or Mall of one of the forms of the invention, EY, is hydrolyzable in a living organism; They were also defined by aie amide or amide ester ester for use in a method of treating a human or animal body with this treatment. Thus according to another form of the invention a compound of the formula ([); or an acceptable salt thereof that is hydrolyzable in the organism; They were also defined as amide or amide ester pharmacologically; Or ester 1 in a warm-blooded animal HDAC before manufacturing a drug for use in producing an enzyme inhibitory effect like humans.

HDAC According to another feature of this form of the invention, a method was provided to produce an inhibitory effect on a human enzyme in need of this treatment, and this method includes giving the animal Jie la in an animal with blood

— 0 \ _

Said effective quantity of a compound of formula (1); Or a pharmaceutically acceptable salt or an amide ester

amide 43a is hydrolyzable in vivo as defined previously.

According to another version of the invention, the use of a compound of formula (1) was provided; or acceptable salt

pharmaceutically, an ester or an amide thereof that is biodegradable like in a living organism; They have also been defined before in the manufacture of a drug used to produce a cell cycle inhibitory effect (anti-cell proliferation) in

A warm-blooded animal like a human.

Adal For another feature in this version of the invention a method is provided to produce an inhibitory effect of the lai cycle

(anti-proliferative) in an animal with blood, such as a human, in need of this treatment and these include

The method is to give the aforementioned animal a therapeutically effective amount of a compound of the formula (oT) or an acceptable salt (0 pharmacologists) or ester fd or amide 430 that is hydrolyzable in the living organism; as they are defined

before.

According to another aspect of this form of the invention, a method of treating cancer in an animal was provided

Those with blood, like a human being, need this treatment, and this method includes giving the aforementioned animal

An effective amount of a compound of formula ( ] ); or a salt of 1 L thereof is hydrolyzable in the organism; as they were defined before.

According to another feature of the invention a compound of formula (1) is used; or a pharmaceutically acceptable salt; or

An ester or an amide thereof is hydrolyzable in the organism; As they were defined before; in

Manufacture of a drug used in the treatment of cancer.

to

lai For another feature of this form of the invention a compound of formula (1) is provided; or acceptable salt

pharmaceutically or an ester or amide thereof (ALS) for hydrolysis in vivo; as they are defined

before; For use in the treatment of cancer

In another form of the present invention a compound of formula (1) is provided; or a pharmaceutically acceptable salt or an ester or amide hydrolyzable in vivo; As they were defined before;

For use in the treatment of lung cancer; And colorectal cancer

rectum and breast cancer; And prostate cancer » and cancer

Adenium - Lymphoma and leukemia.

In another form of the present invention, a method for the treatment of lung cancer is provided

0 colorectal cancer + or breast cancer ¢ or prostate cancer “or lymphoma” or leukemia “in an animal with cla blood like a human in A need for this treatment. This method includes giving the aforementioned animal an effective amount of a compound of formula (1); or a pharmaceutically acceptable salt; or a Jester amide aie amide hydrolyzable in vivo; as they were defined before.

1 The cancers treatable by the present invention are oesophageal cancer; and myeloma; hepatocellular cancer, pancreatic cancer, and cervical cancer; and Ewing's tumor; neuroblastoma and kaposis sarcoma; ovarian cancer, breast cancer sal, and colorectal cancer

and the rectum”; And prostate cancer ¢ and bladder cancer «and the tumor

oy — — black melanoma + lung cancer [cancer includes non-small cell lung cancer (Ua jus (NSCLC) small cell lung (5010))]” and stomach cancer 0 gastric cancer and head and neck cancer; brain cancer ¢ and renal cancer; Lymphoma and leukemia. It is also expected that the compound of the present invention will have efficacy against a wide range of pathological conditions other than cell proliferation diseases. These groups include types of leukemia; AA fibroproliferative and differentiative disorders 0 and psoriasis psoriasis ¢ rheumatoid arthritis « Kaposi's tumor

Kaposi's sarcoma 0 "haemangioma" and acute and chronic nephropathies; and atheroma; atherosclerosis and arterial restenosis; and autoimmune diseases, acute and chronic inflammation, and bone diseases 5 p. 01; And ocular diseases with retinal vessel proliferation.

amide or amide ester iu) A compound of formula (1) has also been presented; a pharmaceutically acceptable salt or 1 hydrolyzable in vivo; As they were defined before; for use in the treatment of die inflammatory diseases; autoimmune diseases; and allergic/atopic diseases. An amide or ester amide in particular a compound of formula (1) is supplied; or a pharmaceutically acceptable salt; or an ester thereof that is hydrolyzable in the organism; They have also been defined before for use in the method of treatment

© Arthritis (especially rheumatoid arthritis).

Meh

osteoarthritis and gout (gout and inflammation of the gastro-intestinal tract (ala) inflammation of the gastro-intestinal tract) “gastritis and inflammation of the skin (especially psoriasis © ¢ and eczema; dermatitis and multiple sclerosis; atherosclerosis” and “spondyloarthropathies” ankylosing spondylitis ¢ psoriatic arthritis ¢ arthritis connected to ulcerative colitis AIDS-related neuropathies 0 ; systemic lupus erythematosus systemic lupus erythematosus ¢ and asthma al yal 5 ¢ asthma Chronic obstructive lung diseases “bronchitis” and pleuritis; adult respiratory distress syndrome; sepsis poisoning; Wl) acute and chronic hepatitis either viral, bacterial, or toxic 1 A compound of formula (1) or a pharmaceutically acceptable salt or ester was also presented ester or an amide thereof that is hydrolyzable in the organism; as defined before; for use in a method for treating inflammatory diseases; Ag immune diseases; allergic diseases [allergic atopy]

Hot as a human. In particular, provide a compound of formula (I) or a pharmaceutically acceptable salt; or an ester or amide ae © that is hydrolyzable in the organism; They are also defined by the use in the method of treatment

so = arthritis (especially rheumatoid arthritis) and osteoarthritis; and scurvy); gastrointestinal tract inflammation (especially inflammatory bowel disease; ulcerative colitis; gastritis); inflammation of the skin (especially psoriasis; eczema and dermatitis); coastal and atherosclerosis; osteoarthritis of the vertebrae and ankylosing spondylitis0 and arthritis due to psoriasis; arthritis associated with ulcerative colitis); glomerulonephritis due to AIDS; systemic lupus erythematosus; asthma and chronic obstructive pulmonary disease; bronchitis; pleurisy and respiratory distress syndrome in adults; poisoning; and acute and chronic hepatitis (either viral, bacterial, or toxic). The use of a compound of formula (1) is also provided; or a pharmaceutically acceptable salt or ester of ALS 430 amide 0 for hydrolysis in vivo; As they were defined before; in the manufacture of a drug used in the treatment of inflammatory diseases; autoimmune diseases; and allergic/atopic diseases in a warm-blooded animal such as a human. As mentioned before, the size of the dose required for the treatment or prophylaxis of a particular cytoproliferative disease will necessarily vary depending on the host being treated; the way of giving; Severity 1 of the disease being treated. For example a dose range of 100-1 mg/kg can be envisioned; Preferably 1 - 50 mg/kg. The HDAC inhibitory activity previously defined may be used as a monotherapy or may include in addition to the compound of the invention one or more substances and/or other therapies. This combination therapy can be achieved by administering at the same time; or respectively; or separate for separate components © treatment. In the field of medical treatment of tumors, the use of a combination of different forms of treatment to treat

1E - Every patient suffers from cancer in a normal manner. In the medical treatment of tumors other components of this combination therapy may be in addition to the previously defined cell cycle inhibition therapy: surgery; or radiation therapy; or chemotherapy. Chemotherapy may include one or more of the following classes of antitumor agents: (V)° Other cell cycle inhibitory agents acting by mechanisms similar or different from those previously defined; such as cyclin-dependent kinase (CDK) inhibitors, especially 00122 inhibitors; (Y) factors that stop gail cells and inhibit their proliferation Jie antiestrogens (eg tamoxifen; toremifene ys ¢ and droloxifene; and iodoxifen (iodoxyfen) progestogens (such as megestrol acetate and aromatase inhibitors (such as anastrozole, letrazole, vorazole, exemestane)); Antiprogestogens 0 Vo and antiandrogens (such as flutamide + and nilutamide » and bicalutamide + cyproterone acetate and LHRH antagonists and cofactors (such as acetate goserelin acetate; luprolide); So-dihydroreductase inhibitors of testosterone (such as finasteride and anti-invasive agents Jia) 7 metalloproteinase inhibitors such as Marimstat

A241 and inhibitors of urokinase plasminogen receptor function and inhibitors of growth factor function (growth factors include eg endothelial cell growth factor; epithelial growth factor; platelet-derived growth factor; hepatocyte growth factor These include ° Inhibitors Growth factor antibodies; growth factor receptor antibodies; ctyrosine 100888 tyrosine kinase inhibitors and serine/threonine kinase inhibitors Antiproliferative/antitumor drugs and terminator combinations as used in therapy (Y) Anti-folates such as Je) oncological pathology; such as anti-metabolites 5-fluorouracil (ie fluoropyrimidines) methotrexate, Ve-fluoropyrimidines, cytosine + adenosine analogues, adenosine purine and 0-purine analogues; and antibiotics Antineoplastic compounds (such as cytosine arabinoside, doxorubicin, e.g. doxorubicin, anthracyclines, anthracyclines, mitomycin-C, epirubicin, daunomycin, platinum derivatives, mithramycin, and mither Amycin ¢ dactinomyein and dactinomycin Vo

LX; and agents (carboplatin and carboplatin “cisplatin Jie) platinum” melphalan and melphalan ¢ nitrogen mustard (as nitrogen restorer); ifosfamide, cyclophosphamide, thiotepa, nitrosoureas and Je vinca alkaloids (eg antimitotic agents

A — 0 — vincrisitine and taxoids such as taxol ¢ and taxotere ¢ (taxotere and le) topoisomerase inhibitors eg Jie epipodophyllotoxins etoposide teniposide ¢, amsacrine, topotecan ° (£) and antiangiogenic agents act by mechanisms different from those previously identified (eg Jie tyrosine kinases 2 and Sl tats function of cintegrin avp3, angiostatin, razoxin, thalidomide, including vascular targeting agents, Ve (9) contrast agents, retinoic acid, and vitamin A. d) According to this image of J to invent and then provide a fishing product because it includes CLS ya of formula (1) and its pharmaceutically acceptable salts or esters or amides of them ALE for hydrolysis in the organism; They are also useful as pharmacological tools in developing and standardizing in vitro and in vivo test regimens for evaluating the effects of cell cycle inhibitors in experimental animals such as cats; ve and dogs; rabbits; monkeys; eof mally and rats as part of the search for new therapeutic agents. Detailed Cha gl) The invention will now be illustrated by the following examples in which it will generally be: 1) The processes will be carried out at room temperature i.e. in the range of alg 5 Yo -1 atmosphere of the inert gas Jie argon argon unless otherwise noted;

uh-

(vii) the evaporation is performed by a vacuum rotary evaporator and the treatment procedure is carried out after the residual solids have been removed by filtration;

(V) Column chromatography (by flash procedure) and medium pressure liquid chromatography (MPLC) were performed on silica

Merck Kieselgel (Art. 9385) ° or reverse-phase silica Lichroprep RP-18 (Art. 9303) obtained from Merck, Darmstadt Germany 5. Or HPLC High Phase Reverse Phase (HPLC) on Silica 018; For example, on a reversed-phase preparatory column of type Dynamax C-1860A°;

“0” (the outputs when they exist are not necessarily the maximum that can be obtained;

(0) The final product compositions of formula (1) were generally confirmed by nuclear magnetic resonance (NMR) and/or mass spectrometry techniques; fast atom bombardment (FAB) mass spectrometry data were obtained using a computer spectrometer ; and done

Positive ions or ions data as appropriate either collect ions data vo

negative The NMR chemical displacement values were measured on a delta scale

[The NMR spectrum of protons was determined using the Chall scale

Jeol INM EX 0 operating at a field strength of 4080MHz; and scale

Spectrum 2000 Varian Gemini operating at a field strength of 060 MHz or

a Burker AM 300 spectrophotometer operating at a field strength of 0000 mfm

The following abbreviations have been used: 5 means singular; and l means binary; and + means qs cal means quad; m stands for multiple and br stands for wide.

1) Intermediate compounds are not usually fully characterized and purity is evaluated by analysis

5 ff thin layer chromatography using HPLC and/or infrared (IR) ° and/or nuclear electromagnetic spectrometry.

(7) The melting points were not corrected and were determined using a Mettler Sp62 automated melting point apparatus or an apparatus with an oil bath; the melting points were determined for the final products of formula (I) after crystallization from a conventional organic solvent Jie ethanol or methanol or acetone or ether or hexane alone or

01 in a mixture. 0 The following abbreviations were used: - DMF means: N,N-dimethylformamide ad DMSO: dimethylsulphoxide. 7 means: tetrahydrofuran \o Example No. (1). N2-(2-Aminophenyl)-5-(pyridin-3-yl)thiophene-2-carboxamide Then stir N2 -(2-t-Butoxycarbonylaminophenyl)-5-(pyridin-3-yl)thiophene-2-carboxamide (Method 0 70 mM IVY pla + mmol) and Ld-dioxane (0,197 mM =( and solved

of hydrochloric acid at a concentration; molar in dioxane (/29 mM (A) at ambient temperature for YA 0 h) and the resulting dl was collected by filtration, washing with Ju)AUD diethyl ether and drying in vacuum to produce dihydrochloride (£4 mg); (ZY mentioned in oo gall with the resonance spectrum. NMR oo

NMR Spectrum; (DMSO-dg) 7.36 (m, 2H); 7.49 (d, 1H), 7.63 (d, 1H), 7.84 (m, 1H), 7.91 (d, 1H), 8.42 (d, 1H), 8.56 (d, 1H), 8.73 (d, 1H), 9.20 (s, 1H), 10.85 (s, 1H); mass

Spectrum: M+H" 296. Example No. (Y):

N2-(2-Aminophenyl)-5-(pyridin-4-yl)thiophene-2-carboxamide

N2-(2-t-Butoxycarbonylaminophenyl)-5-(pyridin-4-yl)thiophene-2-carboxamide (0 mL) and Ld-dioxane (V,V) (mmol) and + YA solution were stirred al a mM VIA 7 (method 011) dioxane at a concentration of 4 M in hydrochloric acid dioxane of hydrochloric acid produced by filtration rd hour. YA ml liter was collected at ambient temperature for a period Vacuum drying to produce diethyl ether (Ju) and washing with the dihydrochloride mentioned in the title; resonance spectrum (Vo al ya m AY) dihydrochloride 1 NMR (m). , 2H), 7.45 (m, 1H), 7.60 (m, 1H), 8.25 (d, 1H), 7.32 (and 101/150-0) NMR Spectrum: (d, 2H), 8.50 (d, 1H), 8.87 (d, 2H), 10.92 (s, 1H); Mass Spectrum: M+H" 296. 8.30

Example No. (f): N3-(2-Aminophenyl)-6-(pyridin-4-yl)nicotinamide Hlall) N3-(2-t-Butoxycarbonylaminophenyl)-6-(pyridin-4-yDnicotinamide) has been stirred 43 ¢ 8 mM 1.11 ola (1.11 mmol) and 1 ¥ (14-mM 14-dioxane) and a solution of hydrochloric acid in mM (1Y+,) dioxane (A) at 0 °C at room temperature for one hour.The resulting precipitate was collected by filtration and washing using iso-hexane.The resulting solid was dissolved in aqueous sodium hydroxide solution (Y) 01 mL The solution was extracted using aqueous acetate J. The combined organic extracts were dried over magnesium sulfate and evaporated to produce the compound mentioned in heading Yo) mg; (70) NMR Spectrum 0 (br s, 2H), 6.86 (m, 1H), 7.13 (m, 1H), 7.45 (m, 1H), 7.65 3.92 (YL0020) NMR Spectrum Mass Spectrum: M +H" 291. Example (4): N3-(2-Aminophenyl)-6-(1H-1,2,4-triazol-1-yl)nicotinamide Vo solution of 1-(N-t) added add

S 6-(1H-1,2,4-triazol-1-yl)nicotinic acid, (CAS 281232-20-0) (5 9 mg; 0.5 mmol) followed by the addition of: 4-(4,6-dimethoxy-1,3,5-triazinyl-2-yl)-4-methylmorpholinium chloride (method 18 CY mg; 15 mmol) and the reaction mixture was stirred at ambient temperature 0 a for fA hours. The solvent was extracted in vacuo and the resulting residue was divided between ethyl acetate and water. The organic phase was separated, washed with water, then with brine, and dried on sodium sulfate. The organic extracts were concentrated to the middle and a solution of hydrochloric acid was added at a concentration of ; Molar of 1,4-dioxane (1 milliliter). The reaction mixture was stirred at ambient temperature VE for another hour. The product 0 was purified using preparative HPLC; and sequentially increasing acetonitrile in water (containing 0.1 7 (v/v) trifluoroacetic acid) to produce the title compound as its trifluoroacetate (? mM (YE cal a NMR Spectrum (DMSO-dg) 6.71 (t, 1H), 6.87 (d, 1H), 7.06 (t, 1H), 7.23 (d, 1H), 8.02 (d, 1H). ), 8.38 (s, 1H), 8.61 (dd, 1H), 9.11 (s, 1H), 9.49 (s, 1H), 9.99 (s, 1H); Mass Veo Spectrum: 11711 281.

Example No. (*): N2-(2-Aminopheny!)-5-(pyridin-2-yl)thiophene-2-carboxamide Deprotected: N2-(2-t-Butoxycarbonylaminophenyl)-5-( pyridin-2-yl)thiophene-2-carboxamide (method YAT A mg; EY mmol) like Example No. (1) to produce the title compound You (° 6 741 mg) » NMR Spectrum (DMSO-dg): 7.39 (m, 4H), 7.52 (d, 1H), 7.64 (d, 1H), 7.90 (m, 2H), (d, 1H) , 8.34 (d, 1H), 8.58 (d, 1H), 10.77 (s, 1H); Mass Spectrum: M+H" 296. 8.03 Example No. (1): N-(2-Aminophenyl)-3, 3'-bipyridine-6-carboxamide 0 N-(2-t-Butoxycarbonylaminophenyl)-3,3"-bipyridine-6-carboxamide was stirred (Method A B mg 6 1 mmol) and 1) 1,4-mM dioxane (=) and a solution of hydrochloric acid with a concentration of 1mM in (1) 14-dioxane mM (A) at ambient temperature for YA for an hour. The resulting precipitate was collected by filtration Washing with diethyl ether and vacuum drying to produce trishydrochloride 1 _ mentioned in the title) 1 mEv cal a 10 with nuclear magnetic resonance spectrum.

— M4b NMR Spectrum (DMSO-dg): 7.36 (m, 2H), 7.47 (d, 1H), 7.66 (d, 1H), 7.96 (t, 1H), 8.31 (d, 1H), 8.54 (d, 1H), 8.73 (d, 1H), 8.88 (d, 1H), 9.21 (s, 1H), 9.32 (s, 1H), 10.75 (s, 1H); Mass Spectrum: M+H 291. Example No.: (V) N-(2-Aminophenyl)-2,3'-bipyridine-5-carboxamide °N-(2-t-Butoxycarbonylaminophenyl)-2,3' was stirred -bipyridine-5-carboxamide (method YEO 0 mM cal a 0.71 mmol); and Bacillus*1,4-4:0 (¥ mM) a and a solution of hydrochloric acid at concentration; Molar in 1,4-dioxane (¥ mM) at da ambient temperature YA sad h. The resulting precipitate was collected by filtration and washing using 0-Jul diethyl ether. Then the solid was dissolved in water and made basic to 01 pH using ammonium hydroxide 0.LY A — ammonium hydroxide and the resulting precipitate was filtered, washed with water and dried in vacuum to produce the title compound (vv (mg; 79 7) NMR Spectrum: (DMSO-d): 5.00 (s, 2H), 6.61 (1, 1H), 6.81 (d, 1H), 7.00 (t, 1H), 2 m (d) , 1H), 7.58 (m, 1H), 8.24 (d, 1H), 8.45 (d, 1H), 8.52 (d, 1H), 8.69 (d, 1H), 9.26 (s, IH), (s , 1H), 9.85 (s, 1H); Mass Spectrum: 11+11 291. 9.36

Example No. (8): N-(2-Aminophenyl)-6-(3-furyl)nicotinamide N-(2-t-Butoxycarbonylaminophenyl)-6-(3-furyl)nicotinamide “= Ai ( milliliter) and a solution of hydrochloric acid with a concentration of; Molar in 14-dioxane© (; milliliters) at ambient temperature 18 Bad h. The resulting precipitate was collected by filtration and washing with diethyl ether. Then the solid was dissolved in water and made basic to pH 01 using 0 778 A ammonium hydroxide and the resulting precipitate was filtered, washed with water and dried in vacuum to produce the title compound (AV) mg; (TY NMR Spectrum. NMR Spectrum: (DMSO-dg): 6.85 (t, 1H), 7.01 (d, 1H), 7.15 (m, 2H), 7.32 (d, 1H), 7.83 00 (s, 1H), 7.90 (d, 1H), 8.39 (d, 1H), 8.48 (s, 1H), 9.16 (s, 1H), 10.08 (s, 1H); Mass Spectrum: M+ H" 280. Example No. (): N-(2-Aminophenyl)-6-(morpholin-4-yl)nicotinamide 0 (N-methylmorpholine 0.4 mmol) added and (YET) 2,4-dimethoxy-6-chlorotriazine | milligram” 0.4 mmol) to a solution of YO) 6-(4-morpholino)nicotinic acid mM VY pl js mMs. ) and 1-(N-t-butyloxycarbonylamino)-2-aminobenzene (Method You milligram; 11 milligram my —

mol) in dimethylformamide (©mL). The resulting mixture was stirred

at ambient temperature for 11 hours. The mixture was poured into ele and extracted three times using ethyl acetate. The combined organic extracts were dried on magnesium sulfate and evaporated. The remainder was purified by flash chromatography and filtered

0 sequentially with methanol/dichloromethane (0 - © 0) and the obtained product was dissolved in p0*1.4-010 (7.5 mL) and the solution was treated with a solution of 3S 5 hydrochloric acid acid in 1.4-010 * 806 (7.4 ml) and the mixture was stirred for two hours.The solid was collected by filtration and washed using diethyl ether and re-dissolved in sodium hydroxide solution at a concentration of ?

0 molar. The solution was extracted three times with ethyl acetate J) and the combined organics were dried over magnesium sulfate and evaporated to produce the crude product. This was purified by flash chromatography and eluting with methanol/dichloromethane (0 = 771) to yield title compound 118 (mg; 777);

Magnetic nuclear resonance spectrum.

NMR Spectrum: (DMSO-d) 3.59 (m, 4H), 3.70 (m, 4H), 4.87 (s, 2H), 6.60 (t, 1H), 6.78 Vo (d, 1H), 6.91 (d, 1H) ), 6.96 (t, 1H), 7.16 (d, 1H), 8.11 (d, 1H), 8.76 (s, 1H), 9.45 (s, 1H);

Mass Spectrum: M+H" 299.

Example No. (Yo ): N-(2-Aminophenyl)-1',2',3',6'-tetrahydro-2,4'-bipyridine-5-carboxamide t-Butyl 5-[ was stirred ((2-[(t-butoxycarbonyl)amino]phenyl}amino)carbonyl]-3',6'-dihydro- 4-bipyridine-1'(2'H)-carboxylate 2 (OY method 1 ,14 g; § mmol) and 1,4-dioxane© (£4 mL) and a solution of hydrochloric acid with a concentration of ¢m in 1,4-dioxane (40 mL) at ambient temperature for YA hours. The resulting precipitate was collected by filtration, washed with Jl diethyl ether, and dried in vacuum (zy) the title compound in its trishydrochloride form (0 g; \ (ZA NMR Spectrum . NMR Spectrum: (DMSO-de) 2.85 (m, 2H), 3.32 (m, 2H), 3.82 (m, 2H), 6.92 (s, 1H), Ve (t, 1H), 7.42 (t, 1H), 7.52 (d, 1H), 7.64 (d, 1H), 7.83 (d, 1H), 8.54 (d, 1H), 9.25 (s, 7.37 1H ), 9.40 (s, 2H), 10.80 (s, 1H); ,2',3",6'-tetrahydro-2,4'-bipyridine-5-carboxamide vo triethylamine (; 17 mL; Y00 mmol) was added to the suspension of the salt of N-(2-aminophenyl)-1',2",3',6'-tetrahydro-2,4'-bipyridine-5-carboxamide trishydrochloride (ex. 1001 mg; +70 mmol ) in NN-dimethylformamide (© ml) As, the solution was stirred at a temperature of Ad all for 10 minutes, and benzyl bromide 9 mM was added to form (Yo mmol) and iodide Potassium iodide

AT) milligram; 5 mmol) and the resulting solution was stirred at 0 9° die VA for 1 hour. The cooled solution was purified using a SCX-2 column with an epoxy filter using ammonia solution in methanol at a concentration of ? Molar. The resulting residue was further purified by flash chromatography and eluting with (Jia) methanol/dichloromethane - (Hyo/) to yield the title compound (71 mg; YY 10 NMR spectroscopy. NMR Spectrum: (DMSO-ds) 2.60 (m, 2H), 2.65 (m, 2H), 3.12 (s, 2H), 3.60 (s, 2H), 4.94 (s, 2H), 6.58 (t, 1H), 6.73 (d, 1H), 6.81 (s, 1H), 6.96 (t, 1H), 7.14 (d, 1H), 7.25 (m, 1H), (m, 4H), 7.63 (d, 1H), 8.24 (d, 1H), 9.03 (s, 1H), 9.69 (s, 1H); Mass Spectrum: 7.33 M+H" 385. 01 Example No. (11): Using a method similar to that mentioned in Example No. (VY), the reaction of the N-(2-Aminophenyl)-1 salt was carried out. ',2',3',6'-tetrahydro-2,4'-bipyridine-5-carboxamide trishydrochloride salt (Example No. (01) using a suitable starting material for the production of the compounds mentioned in Table No. (1): ‏

Table No. (1) No. NH, ~~ 7 H hI N Starting material | Mass spectrum Spectrum of the nuclear magnetic field 1 mlad “(DMSO-dg): 2.52 (m, 2H) , | MH" 415 o 2.60 (s, 2H), 2.77 (t, 2H), NTA 10.85 (1, 2H), 4.14 (¢, 2H), (s, 2H), 6.58 (t , 1H), 4.93 (d, 1H), 6.84 (s, 1H), 6.75 (m, 4H), 7.16 (d, 1H), 6.96 (t, 2H), 7.66 (d, 1H ), 7.26 (d, 1H), 9.05 (s, 1H), 8.25 (s, 1H 9.70 Y (DMSO-dg): 1.90 (t, 2), M+H" 468 | Method 39 (m, 2H), 2.70 (m, 2H), 2.60 5 NT 12.79 (m.2H), 3.30 (m, 2H), (s, 2H), 3.77 (m, 2H), 3.49 and 24 (s, 2H), 6.60 (t, 1H), 4.95 (d, 1H), 6.83 (s, 1H), 6.79 (t, 1H), 7.10 (d, 1H), 6.99 (m, 3H), 7.62 (m, 1H), 7.20 (d, 1H), 8.28 (d, 1H), 7.68 (s, 1H), 9.73 (s, 1H) 9.08 M+ H" 402.5 + 8 J N J M +H" 377.5 ¢ ~~ IF 0 0

_ 7 1 _ "1 fit . 8 | CC or a 0 M+H" 443.5 0 AA 9 0 M+H"460.5 | CAS 13288-06-7 0 N 0 vy ? + M+ H" 452.5 ~~ 0 J.N

M+H 437.5 yy 9 itches i) ' 0 ا 0 مـــ | A A A Boredom

Cage or ® 9 M+H" 5

VY a MAH 472.5 oy J 0

V4 9M+H" 4

So

M+H" 438.5

Y 0 5 ~ N St

OR

Y) M+H" 466.5 | CAS 114561-16-9 26

Y — 7 b_ 0 y M+H" 457.5 vO ess or y : J N { b 0 Yo ~~ M+H" 415.5 0 M+H 463.4 | CAS 38798-68-4 0 1 º | | | z roll ON M+H" 409.5 M+H" 459.5 | CAS 66619-92-9 © ve Q TN 0 M+H" 44 3 . 4 "~~ b 7 wv 0 i 0 NS Ng 0 0

—_7 0 _ "8"

N=

Cla Bn vy Kappa M+H" 465.5

J 0 s" or b" 0 ِ 12 Oo M+H" 443.5 0 tr M+H" 367.3 — ِ َ ْ َ 0 1 | »>

M+H" 484.5 ¢Y Z N M Z . M MLHm A _ 0 0 3 M+H" 407.5 ~~ 0 Tazerjar 5 we ee 7 > 11+11 473.5 | CAS 56850-91-0 “0 0 \ immediately or 0

Z a to a 0 a o.

M+H"395.5 ! a 0 : ~ M+H"393.4 ) 0 N=— / N ov ° M+H"381.3 ~ — 0 ov M+H" 441.5 0 of M+H" 409.3 ~ 0a k7 Example No. (1) : N-(2-Aminophenyl)-6-(4-benzylpiperazin-1-yl)nicotinamide N- was stirred (2-t-Butoxycarbonylaminophenyl)-6-(4-benzylpiperazin-1-yl)nicotinamide ° (method Ye mg al + mmol) with a solution of 1 3S 54 hydrochloric acid molar in 14-dioxane (; ml) for YE 1 h. The resulting precipitate was filtered, washed with ether, and dissolved in water. The solution was made alkaline to pH 01 using aqueous ammonium hydroxide 0 8 and the resulting precipitate was filtered and washed with water to yield the title compound (Ye mg; 0” “0 oo with oda 0 - NMR.

_7 o —

NMR Spectrum: (DMSO-dg) 2.43 (m, 4H), 3.52 (s, 2H), 3.62 (s, 4H), 4.84 (s, 2H), 6.60 (t, 1H), 6.76 (d, 1H), 6.87 (d, 1H), 6.95 (t, 1H), 7.12 (d, 1H), 7.31 (m, 4H), 7.42 (m, 1H), 8.09 (d, 1H), 8.72 (s, 1H), 9.40 (s, 1H); Mass Spectrum: M+H" 388. : ( \¢ ) Example No

N-(2-Aminophenyl)-6-(piperazin-1-yl)nicotinamide ° (method N-(2-t-Butoxycarbonylaminopheny!)-6-(piperazin-1-ylnicotinamide) hydrochloric acid was stirred in millimeter mol) with a solution of HCl 1.45 mg; YY 7 ml) for 2 hours. The resulting precipitate was filtered and washed (A) 1,4-010 * 806 with a concentration of ? Molar in a concentration of ? sodium hydroxide and made alkaline using ether sodium hydroxide solution, and the organic substances were washed, ethyl acetate Ju Molar, in water. The product was extracted into Ne acetate and evaporated to produce magnesium sulfate using brine and dried on Mg.

NMR Spectrum: (DMSO-dg) 2.79 (t, 4H), 3.55 (t, 4H), 4.88 (s, 2H), 6.58 (t, 1H), 6.78 (d, 1H), 6.85 (d, 1H), 6.95 (t, 1H), 7.16 (d, 1H), 8.05 (d, 1H), 8.71 (s, 1H), 9.40 (s, 1H);

Mass Spectrum: M+H"-Boc 298. Vo (Vo) Example No

N-(2-Aminophenyl)-5-(piperazin-1-yl)pyrazine-2-carboxamide in concentration; Molar of hydrochloric acid <b 4S 0 a A solution of acid : mL) was added to a suspension of ¥) 1,4-dioxane

AAR

- D- ‎t-Butyl-4-{5-[({2-[(t-butoxycarbonyl)amino]phenyl }amino)carbonyl] pyrazin-2- yl} piperazine-1-carboxylate (method 1159 Vo mM ala 0.74 mmol) in 1,4-dioxane (¥ mL). The reaction mixture was allowed to stir at ambient temperature s.d. 76 hours before it was diluted with Su© ether and the solid was collected by suction filtration. This solid was dissolved in water and made basic by adding ammonium hydroxide solution, Si.

YA ammonium hydroxide Extraction of the resulting suspension using ethyl acetate. The combined organic extracts were washed with brine, dried over magnesium sulfate, filtered, and evaporated to yield the compound mentioned in heading (AY) mg; 76 Twu magnetic resonance imaging. (m, 4H), 3.63 (m, 4H), 4.81 (s, 2H), 6.63 (t, 1H), 6.81 / 2.82 (m01150-0) NMR Spectrum: (d, 1H), 6.92 (t, 1H), 7.46 (d, 1H), 8.32 (s, 1H), 8.70 (s, 1H), 9.58 (s, 1H); Mass Spectrum: 11 + 11 299. Example No. (1): N-(2-Aminophenyl)-5-(4-benzylpiperazin-1-yl)pyrazine-2-carboxamide 1 was added A solution of hydrochloric acid with a concentration of Molar in 1,4-dioxane (7 mM) to a solution of: t-butyl [2-({[5-(4-benzylpiperazin-1-yl) pyrazin-2-yl[carbonyl}amino)phenyl] carbamate (method VA VT mg; 0 )+ mmol) in Y (1d-dioxane mL). The reaction mixture was allowed to stir at ambient temperature for 7 hours before it was diluted with Juve diethyl ether, the solid was collected by suction filtration, and dried under an air stream. And it was thawed

This solid was dissolved in water (7 milliliters) and made basic to a pH of 01 pH by adding an aqueous amino hydroxide solution (YA) (0 ° points) and the resulting precipitate was collected by filtration and dried under vacuum at 01 degrees C for two hours to produce the compound mentioned in the title in its free base form (21 mg; 0” (ZV Y NMR).

NMR Spectrum: (DMSO-dg) 2.52 (m, 4H), 3.55 (s, 2H), 3.74 (m, 4H), 4.83 (s, 2H), 4 (t, 1H), 6.82 (d, 1H), 6.94 (t, 1H), 7.27 (m, 1H), 7.35 (m, 4H), 7.48 (d, 1H), 8.34 (s, 1H), 8.71 (s, 1H), 9.58 (s, 1H); Mass Spectrum: M+H" 389. (VV) Example No

N-(2-Aminophenyl)-2-piperazin-1-ylpyrimidine-5-carboxamide : in concentration; Molar of hydrochloric acid A solution of hydrochloric acid was added 0 t-Butyl-4-{5-[({2-[(t-butoxycarbonyl)amino]phenyl }amino)carbonyl] pyrimidin-2- yl} piperazine-1 -carboxylate milliliters). (Y) 1,4-dioxane in (Use 194 mg; 7950 VA) method The reaction mixture was allowed to stir at ambient temperature for 7 hours before it was diluted with diethyl and collected The solid was filtered by sucking and dried under air current. The precipitate 0) 77/8 Sl ammonium hydroxide ammonium hydroxide solution °C for two hours to produce the aforementioned compound 1 produced by filtration and drying under vacuum at

YA - - in the title as its free base (y) 01 mg; >10 NMR spectrum. NMR Spectrum: (DMSO-d) 2.75 (m, 4H), 3.77 (m, 4H), 4.91 (s, 2H), 6.58 (1, 1H), 7 (d, 1H), 6.96 (t, 1H), 7.14 (d, 1H), 8.88 (s, 2H), 9.45 (s, 1H); Mass Spectrum: M-H 297.0 Example No. YA ( : N-(2-Aminophenyl)-3-piperazin-1-ylpyrazine-2-carboxamide trishydrochloride A solution of hydrochloric acid was added at a concentration of molar T+ (mL) to a suspension of: t- t-Butyl-4-{ 5-[({2-[(t-butoxycarbonyl)amino]phenyl ( amino)carbonyl] pyrazin-2- yl}piperazine-1-carboxylate \(Method 1.71 0 g; Y, EF mmol) in Yo)14-dioxane mL). The Jeli mixture was allowed to stir at ambient temperature for ¥ hours before it was diluted with diethyl ether, the solid was collected by suction filtration, and dried in vacuum at Te °C to produce the compound mentioned in the title (cf AY cal a 7) NMR Spectrum 1 (m, 4H), 4.01 (m, 4H), 7.24 (m, 2H), 7.32 (m, 1H), 3.24 (and 01150-0) NMR Spectrum : (d, 1H), 8.45 (s, 1H), 8.79 (s, 1H), 9.40 (s, 1H), 10.24 (s, 1H). 7.58 lv

Example No. (V4): N-(2-Aminophenyl)-2-[4-(3-anilino-3-oxopropyl)piperazin-1-yl]pyrazine-5-carboxamide A mixture of N was heated -(2-Aminophenyl)-5-piperazin-1-ylpyrazine-2-carboxamide (ex. OF VA 08 cal a mmol) 5 3-chloro-N-phenylpropanamide (4 7 mg; 0 19 mmol) potassium iodide (mg) 6.77 mmol) and triethylamine (YOu) Mec Roller; 1.74 mmol) in NN- dimethylformamide (¥ mM) A to 0 °C for VT 1 h. The reaction mixture was then allowed to cool before being poured into water. The precipitate was collected by suction filtration to produce the compound mentioned in the title in the form of its DMF addition product (01 mM (ZV) pla. NMR cada of 01

NMR Spectrum: (DMSO-dg) 2.52 (m, 2H), 2.56 (m, 4H), 3.29 (m, 2H), 3.90 (m, 4H), 4.83 (s, 2H), 6.64 (t, 1H), 6.82 (d, 1H), 6.94 (t, 1H), 7.03 (t, 1H), 7.29 (t, 2H), 7.47 (d, 1H), 7.59 (d, 2H), 8.37 (s, 1H), 8.71 (s, 1H), 9.59 (s, 1H), 10.00 (s, 1H); Mass Spectrum:

M+H" 446. : ( Yo ) Example No. 11 : The reaction (V9) was carried out using a method similar to that mentioned in Example No.

Jal) N-(2-aminophenyl)-5-piperazin-1-ylpyrazine-2-carboxamide trishydrochloride with the appropriate alkylating agent at the indicated temperature and residence time to produce the compounds (VA No. (7) listed in Table No. ,

—- A — (Y) Table No

Ri

NT

LUNN >

Tog Psalm AN 0 1 Note R Adverbs | The nuclear spectrum spectrum | sald magnetic mass dela | prefix 1 and 01150-0) 1.91 (qn, M+H"472 | + .2H method), 2.59 (m, 4H), 2.73 ve (t, 2H), 3.40 (s, 2H) ), 0 degree 3.69 (m, 4H), 3.74 (t, l" | bd 2H), 4.83 (s, 2H), 6.64 se

C0) (t, 1H), 6.82 (d, 1H), 8 6.94 (t, LH), 7.09 (t, 1H), 7.18 (m, 2H), 7.48 hours (d, 1H), 7.58 ( m, 1H), 8.34 (s, 1H), 8.71 (s, 1H), 9.59 (s, 1H)

Y (DMSO-dg) 1.62 (qn, | M+H 426 | 4, 2H), 2.33 (m, 8H), 2.52 (m, 4H), 3.57 (m, 4H), 3.72 degrees (m, 4H), 4.83 (s, Co 2H), 6.64 (t, 1H), 6.82 thunderous (d, 1H), 6.94 ) 1H), 8 7.48 (d, 1H), 8.35 (s, (NNR 1H) , 8.71 (s, 1H), 9.59 h s, IH for (s, 1H) v (DMSO-dg) 2.64 (m, M+H 419 | + 4H), 2.78 (t, 2H), 3.75 (m, 4H), 4.13 (t, 2H), 4.83 degrees (s, 2H), 6.64 (t, oo

OU | 1H), 6.82 (d, 1H), 6.94 Tremendous (m, 4H), 7.29 ) 2H), 8 7.48 (d, 1H), 8.37 (s, 1H), 8.71 (s, 1H), 9.60 hour (s, 1H

Example No. (YY) N-(2-Aminophenyl)-2-[4-(2-phenoxyethyl)piperazin-1-yl]pyrimidine-5-carboxamide YE CAS 589-10-6[added] ( B-bromophenetole milligram; 10097 mmol) and triamine J “lg Sa YY +) triethylamine (1.0 mmol) and potassium iodide €A) potassium iodide mg; 1749 mmol) to a solution of N-(2-aminophenyl)-2- piperazin-1-ylpyrimidine-5-carboxamide 0 (Example No. AY 45 mM ala 119 mmol) in N,N-dimethylformamide (7 ml). The reaction mixture was heated to Ay °C and stirred for VT 1 hour before it was allowed to cool and decanted in Yo (ele mL). The resulting precipitate was collected by suction filtration, washed with water and diethyl ether, and dried to yield the compound mentioned in the title (1 mg; No, with nuclear magnetic resonance spectroscopy. (m, 4H), 2.77 (t, 2H), 3.86 (m, 4H), 4.13 (t, 2H), 4.92 / 2.58 (and 01150-0) NMR Spectrum: (s, 2H), 6.58 (1, 1H), 6.77 (d, 1H), 6.95 (m, 4H), 7.14 (d, 1H), 7.29 (t, 2H), 8.89 (s, 2H), (s, 1H); Mass Spectrum: M+H" 419. 9.47 Example No. (YY): N-(2-Aminophenyl)-5-(pyrrolidin-1-yl)thiophene-2-carboxamide stirred: N-( 2-t-Butoxycarbonylaminophenyl)-5-(pyrrolidin-1-yl)thiophene-2-carboxamide Vo (Method TY 71 mg » 02160 mmol) and 1,4-dioxane (+1 mL) and a solution of hydrochloric acid with a concentration of 1,4-dioxane molar (+1 ml)

at ambient temperature for YA hours. The resulting precipitate was collected by filtration and washed with J diethyl ether. The resulting solid solution in water was made basic to VE pH using sodium hydroxide solution with a concentration of ¥ M, and the product was extracted using ethyl acetate Ju, and the extracts were washed © combined organics using brine, dried over sodium sulfate ag ga, filtered, and evaporated to produce the compound mentioned in heading FY) mg; (Ve NMR spectrum. (m, 4H), 3.34 (m, 4H), 3.92 (s, 2H), 5.72 (d, 1H), 6.82 2.08 (O© 00 ) NMR Spectrum: (m, 2H), 7.05 (m, 1H), 7.29 (m, 2H), 7.36 (d, 1H); Mass Spectrum: M+H" 288.0 Example No. (YY) N-(2-Aminophenyl)-5-(piperidin-1-yl)thiophene-2-carboxamide Stirred: N-(2-t-Butoxycarbonylaminophenyl)-5-(piperidin-1-yl)thiophene-2 -carboxamide (method 10" (VE mg » YOY + mmol) and Y,+) L4-dioxane mM) and a solution of Su hydrochloric acid ¢ M at 1.4 -dioxane (+,¥ mCr) yo at ambient temperature for 1 h. Then the resulting precipitate was collected by filtration and washed with diethyl ether. The suspension of the resulting solid in Ye water (mL) was made basic to a pH of VE pH using slasodium hydroxide solution at a concentration of 1 M, and the product was extracted using ethyl acetate Ju, and Ju Organic extracts

United using brine, dried on sodium sulfate, filtered and evaporated. The resulting residue was purified by flash chromatography and eluting using methanol/dichloromethane 7/7 to produce the compound mentioned in heading (VY) 6 mg NMR spectroscopy. NMR Spectrum: (CDCl3) 1.62 (m, 2H), 1.73 (m, 4H), 3.26 (m, 4H), 3.91 (s, 2H), 6.00 ° (d, 1H), 6.82 (m, 2H) ), 7.06 (m, 1H), 7.29 (m, 1H), 7.36 (m, 2H); Mass Spectrum: M+H" 302 Example No. (Y¢): N-(2-Aminophenyl)-5-piperidin-4-ylthiophene-2-carboxamide yo. Stirred: t-Butyl 4-(5-{[(2-t-butoxycarbonylaminophenyl)amino]carbonyl}-2-thienyl)piperidine- 1-carboxylate (Method 171 (YY mg” 0.776 mmol) and dissolved in V , +) 1d-dioxane mM = (a solution of hydrochloric acid was added with a concentration of 1,4 molar at -1,4 yo) dioxane yo mL 664 mmol). The reaction mixture was stirred at ambient temperature (18) The resulting sediment was collected by filtration to produce hydrochloride, and it was dissolved in water and extracted using ethyl acetate, washing the organic layer with brine, drying it on magnesium sulfate, filtering and evaporating it to produce the compound mentioned in the title ( Yes, 11 milligram NMR spectrum

NMR Spectrum: (DMSO-dg) 1.51 (m, 2H), 1.87 (m, 2H), 2.59 (m, 2H), 2.96 (m, 3H), 4.87 (s, 2H), 6.59 (m, 1H), 6.78 (d, 1H), 6.96 (m, 2H), 7.12 (d, 1H), 7.81 (d, 1H), 9.56 (s, 1H); Mass Spectrum: M+H" 302. Example No.: (Yo).

N-(2-Aminophenyl)-5-(1,2,3 ,6-tetrahydropyridin-4-yl)thiophene-2-carboxamide : ° t-Butyl 4-(5-{[(2-t) was stirred -butoxycarbonylaminophenyl)amino]carbonyl}-2-thienyl)-3,6- dihydropyridine-1(2 H)-carboxylate l mmol) and add (1,4,4-dioxane 5 mmol) and dissolve it in Y ol \ yr YA (method MV,0) 1,4-dioxane at a concentration of 4 M in hydrochloric acid solution, hour. YE was done and the reaction mixture was stirred at ambient temperature for 0 mmol) 0 Ay. ethyl acetate The precipitate obtained by filtration was collected, dissolved in water, extracted using ethyl acetate at a concentration of 778, then extracted with ammonia, and the aqueous solution was made alkaline using aqueous ammonia solution. The organic extracts were washed using brine, dried acetate Ji, filtered, and evaporated to produce the aforementioned compound in magnesium sulfate over magnesium sulfate. NMR Spectrophotometer » (7 000 mg AN) title yo

NMR Spectrum: (DMSO-de) 2.34 (d, 2H), 2.90 (t, 2H), 3.36 (d, 2H ), 4.88 (s, 2H), 6.31 (s, 1H), 6.60 (t, 1H), 6.78 (d, 1H), 6.98 (t, 1H), 7.13 (d, 2H), 7.86 (d, 1H), 9.61 (s, 1H);

Mass Spectrum: M+H" 300.

A o — _ Example No. (5): N-(2-Aminophenyl)-5-(1-benzylpiperidin-4-yl)thiophene-2-carboxamide added triethylamine (9+ mM) to see Use 0.4 mL and stirred solution at room temperature for 11 minutes to a suspension of: N-(2-Aminophenyl)-5-piperidin-4-ylthiophene-2-carboxamide (Example No. (YE 56 mg 0 g; 0.154 mmol) in N,N-dimethylformamide (¥ mM) A. Benzyl bromide (No. ? mg; 1176) was added mmol) and potassium iodide (Y 9 mg + mmol) and the resulting solution was stirred at ambient temperature for YA h for 1 h. The solution was evaporated. The resulting residue was purified by flash chromatography with elutriation using methanol/dichloromethane (0 - 771) to produce a solid residue.0 This residue was dissolved in dichloromethane, washed ela, and evaporated to produce the Spall mentioned in heading A) milliol a 5 0 “” NMR spectrum. NMR Spectrum: (DMSO-d) 1.82 (m, 2H), 2.20 (m, 2H), 3.12 (m, 2H), 3.50 (m, 3H), (s, 2H), 4.91 (s, 2H) ) 6.21 (t, 1H), 6.80 (d, LH), 6.98 (m, 2H), 7.14 (d, 1H), 7.50 (m, 4.35 SH), 7.86 (s, 1H), 9.61 (s, 1H); Mass Spectrum: M+H" 392 vo Example No. (YY) t-Butyl {3-[4-(5-{[(2-aminophenyl)amino]carbonyl}-2-thienyl)-3 ,6-dihydropyridin- 1(2H)-yl]propyl} carbamate

3-(t-butoxycarbonylamino)propy!l bromide (No. 01 mg 1.67 mmol) and 1-triethylamine (1 mL VT mmol) were added to a solution of: N-(2-Aminophenyl)-5-(1,2,3 ,6-tetrahydropyridin-4-yl)thiophene-2-carboxamide (Ex. No. VTA (VO mg; +07 mmol) in N 0, N-dimethylacetamide (©mL) and stirred the resulting solution at 0©C for ; hours. The cooled solution was evaporated and the remainder purified by flash chromatography and eluting with methanol/dichloromethane (0 - ©27) to yield the compound mentioned in heading Yo) mg; 779); with nuclear magnetic resonance spectroscopy. NMR Spectrum: (MeOH-ds) 1.34 (s, 9H), 1.69 (t, 2H), 2.59 (s, 4H), 2.86 (s, 2H), 3.02 (t, 2H), 3.28 (s, 2H), 6.18 (s, 1H), 6.65 (t, 1H), 6.79 (d, 1H), 6.97 (t, 1H), 7.05 (m, 3H), 1 (s, 1H); Mass Spectrum: M+H" 457. 7.65 Example No. (YA): A method similar to the method mentioned in Example No. (77) was done using a reaction: N-(2-aminophenyl)-5-(piperidin-4-yl thiophene-2-carboxamide (Example No. (YE eo) was the appropriate alkylation agent at the appropriate temperature. The crude products were purified using column 2 with eluting using ammonia solution in 3S 4 methanol "m The resulting residue was also purified by flash chromatography and eluting using methanol/dichloromethane (zero — Yo 0) to produce the compounds mentioned in Table No. (7): RA

_ AY —_ (¥) Table No

NH

RI—N / H ’ 9 N 0 : nuclear resonance spectrum | caudal material score: R for you "Al-Mughni Notes 1 Eddabla sal 3 3 \ (DMSO-dg): 1.15 (m, | M+H"™ | Method | Ambient 2H), 1.55 (m , 2H), 1.91 | 475 39 (m, 4H), 2.20 (m, 2H),

LL 2.73 (m, 2H), 2.85 (m,

O | 2H), 3.40 (m, 1H), 3.72 : (m, 2H), 4.85 (s, 2H), 6.58 (t, 1H), 6.76 (d, 1H), 6.96 (m, 2H), 7.06 (m, 2H), 7.14 (m, 2H), 7.57 (m, 1H), 7.78 (4, 1H), 9.55 (s, 1H). 0 )01150-40: 1.65 (m, | M+H" set 2H), 1.94 (m, 2H), 2.21 | 422 ' ls (m.2H), 2.75 (m, 3H), Specifically | 3.02 (m, 2H), 4.08 (s, 2H), 4.86 (s, 2H), 6.56 (t, 1H), 6.76 (d, 1H), 6.96 (m, SH), 7.10 (d, 1H) ), 7.25 (m, 2H), 7.78 (s, 1H), 9.54 (s, 1H).v (DMSO-dg): 1.68 (m, | M+H" 0 2H degree), 2.02 (m, 2H), 2.18 | 449 (m, 2H), 2.72 (m, 2H), recess 2.78 (s, 1H), 2.90 (m,

N 2H), 3.05 (m, 2H), 4.94

TO (s, 2H), 6.65 (t, 1H), 6.82 (d, 1H), 7.05 (m, 3H), 7.15 (d, 1H), 7.35 (m, 2H), 7.64 (m, 2H), 7.90 (s, 1H), 9.64 (s, 1H), 10.10 (s, 1H). +H" ; ¢ + Nos deg 0 4) fie

-AN—

M+H" degree 2 419.6 Celsius +1 da ya 6 1 M 471.6 - M 0"

M+H" degree 2 4477 °C M+H" ;

A grade 0 / most important 4015 2 — 0 residual M+H" | CAS dau 8 1 m 4796 | 56850 | 0-91°C 0 0 1 0 M+ H" deg ¢ 0 W 490.7 ~ 0 C " Labla [CAS deg A 0 —( 400.6 | 75726- — 0 96-4 4 sie 1 Y M+H" CAS deg ¢ 0 0 4977 |20854- 61-9 °C 0 Vy M+H" deg 0 375.5 / °C d 1 11m day 0 373.5 0

VT

Ami A 12 degrees \o NS M+H" 399.5 r she 2 + 0 degrees MAH | CAS ~ o 493.7 | 105589 sie 4 0- 66- for 0 $ M+H CAS degree of 7 1 -66619 | 465.6 ° v ee 0 VA MH degree" 447.6 semen 1 2 degree va M+H" 398.5 1 she 2 0 CAS 2 | trax 0 Y. da yd 8 a 469.6 | 38798 | 7 celsius 684 5 CAS | ay sg, | 1017 mm 1 -3351 | 4977 celsius 60-8 (

84.0 - Example No. (19) N-(2-Aminophenyl)-5-piperazin-1-ylthiophene-2-carboxamide then flip t-Butyl 4-{5-[({2-[(t-butoxycarbonyl) (amino]phenyl }amino)carbonyl]thien-2- yl}piperazine-1-carboxylate (method 74 yo mg; .01 mmol) and 1,4-(1,45) dioxane©mL) and a solution of hydrochloric acid with a concentration of ¢m in 1,4-dioxane (+£0,000mL) at ambient temperature for VA h. The resulting precipitate was collected by filtration, washed with Ju) diethyl ether, and dried in vacuum to produce dihydrochloride, the title compound. This solid was suspended in dichloromethane (©mM)A and the resulting suspension was treated with 0 Fram 1,1,3,3-60 (00 μl) to produce a clear solution. This solution was purified by flash chromatography and eluting with methanol/dichloromethane (AY. -© (to produce the compound mentioned in heading AT) mM (TAY alga) NMR Spectrum: (DMSO) -dg) 3.03 (m, 4H), 3.27 (m, 4H), 4.85 (s, 2H), 6.23 (d, 1H), 6.57 (t, 1H), 6.77 (d, 1H), 6.93 (t , 1H), 7.10 (d, 1H), 7.75 (d, 1H), 9.39 (s, 1H); Mass Vo & Spectrum: M+H" 303. Mal No. (+7) N-(2- Aminophenyl)-5-(4-benzylpiperazin-1-yl)thiophene-2-carboxamide A mixture of N-(2-aminophenyl)-5-(piperazin-1-yl)thiophene-2-carboxamide was allowed to be left. (Example No. 749 80.0 mg” YT mmol); Benzyl bromide £0,Y)

ay - - milligram; 1.77 mM (Use and triethylamine (0.0 mg » 8.87 mmol) and (Y, +) N,N-dimethylformamide mL) at ambient temperature for VA hour. The mixture was evaporated and the remainder was purified by flash chromatography and eluting with (Fo =, ©) methanol/dichloromethane to produce the compound mentioned in heading YA) 0 mM AYA NMR Spectrum. : (DMSO-dg) 2.49 (m, 4H), 3.19 (m, 4H), 3.53 (s, 2H), 4.81 (s, 2H), 7 (d, 1H), 6.56 (t, 1H), 6.74 (d, 1H), 6.92 (t, 1H), 7.10 (d, 1H), 7.26 (m, 1H), 7.33 (m, 4H), (d, 1H), 9.28 (s, 1H); Mass Spectrum: M+H" 393. 7.68 dia No. (71) N-(2-aminophenyl)-2-(4-methylpiperazin-1-yl)-1,3-thiazole-5-carboxamide 0 was then added 1 ( Nickel (IT) acetate mg » 0.74 mmol) to a volatile suspension of N-(2-nitrophenyl)-2-(4-methylpiperazin-1-yl)-1,3 -thiazole-5-carboxamide (method YY © mg; 1.14 mM (Use) in methanol (4 mM (A) at 0°C and sodium borohydride added ©F) sodium hydride (mg; 0.4 mmol) over 11 minutes and the resulting mixture was stirred at ambient temperature for ½ hours.ye The mixture was filtered, the solvent was evaporated, and the remainder purified by flash chromatography and eluting using methanol/dichloromethane (zero — Yo 7) to yield the compound mentioned in heading Yo) milligrams” (Z0V NMR spectroscopy).

NMR Spectrum: (DMSO-d) 2.24 (s, 3H), 2.43 (s, 4H), 3.49 (t, 4H), 4.76 (s, 2H), 6.56 (t, 1H), 6.75 (d, 1H), 6.96 (t, 1H), 7.11 (d, 1H), 8.01 (s, 1H), 9.43 (s, 1H); Mass Spectrum: 11+11 5 Ex. (YY) N-(2-Aminophenyl)-2-(4-benzylpiperazin-1-yl)-1,3-thiazole-5-carboxamide oo AY) potassium iodide mg added; 149 mmol), benzyl bromide (77 mg; 177 mmol) and triethylamine 1473 (mL , 7 mmol) to a solution of: N-(2 -aminophenyl)-2-piperazin-1-yl-1,3-thiazole-5-carboxamide (Method 001 VE mg; YY mmol) in N,N-dimethylformamide (5 mL) 0 and stir the solution 0 > product at ambient temperature for 4; hour. The product was isolated using a SCX-2 column with an epoxy filter using ammonia solution in methanol at a concentration of ? Molar. The resulting residue was purified with preparative reverse-phase Hple eluting with Lyte/NH; 70.1 (© - £90) in water to produce the compound mentioned in the heading (IF) mRIPEN «£9 (7) NMR Spectrum: (DMSO-de): 2.50 (s) , 4H), 3.50 (s, 4H), 3.55 (s, 2H), 4.85 (s, 2H), 6.58 Vo (t, 1H), 6.76 (d, 1H), 6.95 (t, 1H), 7.10 (d, 1H), 7.28 (m, 1H), 7.34 (s, 4H), 8.01 (s, 1H), (s, 1H); Mass Spectrum: M+H" 394, 9.42 add

:) 9) Example: The (YY) reaction was carried out using a method similar to that in Example (method ¢ 0 with N-(2-aminophenyl)-2-piperazin-1-yl-1 , 3-thiazole-5-carboxamide The appropriate alkylation agent at the temperature and residence time indicated for the production of the compounds mentioned in: ¢ (Table No. 2) (4) Table No. 1 / R NH

RI-N Psalm | H 2 s N 0 : 1 Note R nuclear resonance spectrum | call) conditions | Damla magnetic mass interaction! asl \ (DMSO-dg): 1.90 M+H" method | 1 hour 8 (m, 2H), 2.60 (s, 477 ct 4H), 2.72 (t, 2H), at v4 3.41 (s, 2H), 3.45 (s, Cu 4H), 3.73 (t, 2H), for heat 4.86 (s, 2H), 6.58 (, specification 1H), 6.76 (d, 1H), 1 6.95 (t, 111(), 7.09 (m, 2H), 7.17 (m, 2H), 7.57 (m, 1H), 8.01 (s, 1H), 9.42 (s, 1H).

Y (DMSO-de): 2.63 (s, | M+H" h EA for 411,278 (t, 2H), 4 kH 13.49 (s, 4H), 4.10 (4, at 2H ), 4.84 )8, } 6.56 (t, 1H), 6.75 (d, temperature 1H), 6.93 (m, 4H), ambient then 7.08 (d, 1H), 7.27 Pa) 1 2H ), 8.00 (s, 1H), 1 hour 9.40 (s, 1H).JU v (CDCly): 2.55 (t, M+H" hour SA 2H), 2.69 (s, 4H), | 451 2.78 (t, 2H), 3.64 (s, at

N 4H), 3.89 (s, 2H),

TT 6.79 (d, 2H), 7.07 Temp (m, 2H), 7.27 (m, ambient then 3H), 7.49 (d, 2H), 7.73 (s, 2H), 10.12 08 h ( s, 1H). Av at °C ot M+H clave | CaS 481.5 57011- Enemies; 2

N is destructive > thunderous degree m h Ye 450.5 0 0 at dew point ee 5 > M+H h $ 7 CAS o 482.5 56850-$v stubborn 91-0 degree of residual text + v M+H ;? An hour is 4244 0 at degrees Celsius

A M+H watch Ye

N495.5

W 60 at °C 9 M+H h Ye 376.4 0 560 at / 0 °C

— Mg 8 — Ye 01 hr © M+H" 482.3 at $e 0 P da ;? 1 hr 7 M+H' 493.5 B at N $e deg Celsius M+H" 4 ;? YY hour 440.4 pain at 46 degrees sie 0 ;? VY M+H' hour 4.4 at 80 7 Ss / °C 7 + 7 M+H dela 413.4 at 560 N= °C ;? yo M+H" clock 408.5 at $e asie degree + CAS; VY ST M+H" -66619 468.5 0 92-9 at 46 0°C ; +;? VA M+H hour 452.4 at 060 - lee 0 degrees sie 0 2

+; 11 ye re at 60°C;? Y watch.

M+H" 494.5 5 at 1 560 degress +1 V¢ h a 452.4 a OH 0 deg; ?' x M+H" o 452.4 h at 6 deg Celsius 0 9; hour for 0 at 56 N= deg; Y¢ hens clock at 6° Asie Ye yo clock M+H' 432.4 0 at 560 0 degrees / Y¢ CAS M+H clock 7 -3245 466.5 55-4 at 66 © residual degree in Y¢ h M+H in o 1 474.5 at 0 - 6 Ax C [

; YA Me h d 0 °C "> y ¢ h Yq Pp JU. at £4 °C Y h vu = M+H" 4115 s" at +0 $ y y degree Asie 1 Ny ps elu Yt at 56 °C + Ye h vy es at £4 °C / Yi h M+H 0 b o 452.5 at NN $e °C + ; 7 h Ys = a pa 66.5 5 at 6 {Ashe degree _ Vi an hour Yo pe at 260 °C + Y§ h v1 M-+H 386.5 at 66 / °C rv MH YE 422.4 560 Hours at Recurring Degree

YA M+H ieluye| CAS 496.5 105589 0 0 at | -66-0 0 ve MH 0 ve MH" VE 7 412.5 560 hr at denaturing degree Preparation of starting materials: Either the starting materials for the previous examples are commercially available, or they are easily prepared by standard methods. The following reactions are illustrative but not exclusive of +0 known substances, eg for the preparation of some of the starting materials used in the above reactions.

N2-(2-t-Butoxycarbonylaminophenyl)-5-(pyridin-3-yl)thiophene-2-carboxamide

N2-(2-t-Butoxycarboylaminophenyl)-5-bromothiophene-2-carboxamide Stir 1 mg; 1 4 (pyridine-3-boronic acid mmol) and 1900 mg; 001 oF (Method mg; 8.005 mM©) tetrakis(triphenylphosphine) palladium mMol) and 0 1600 and a saturated aqueous solution of sodium bicarbonate (A mM¥) 1,2-dimethoxyethane and (Js argon) Residual point in argon atmosphere Ay at (A mM ¥) sodium hydrogen carbonate

J gall and water. The ethyl acetate was washed for an hour. The cooled mixture was divided among VY ethyl acetate for a period

Gu - organic using brine, dried on magnesium sulfate and evaporated. The resulting residue was purified by flash chromatography and eluting with methanol/dichloromethane (77) to yield the compound in heading A) mg; 75) with a nuclear magnetic resonance spectrum. (s, 9H), 7.16 (m, 2H), 7.55 (m, 3H), 7.73 (d, 1H), 7.92 0 1.43 (and 01150-0) NMR Spectrum: (d, 1H), 8.13 (m, 1H), 8.55 (d, 1H), 8.63 (br, 1H), 8.95 (s, 1H), 9.86 (s, 1H); Mass Spectrum: 11111 396. Method No. (?): N2-(2-t-Butoxycarbonylaminophenyl)-5-(pyridin-4-yl)-thiophene-2-carboxamide N2-(2) was stirred -t-Butoxycarboylaminophenyl)-5-bromothiophene-2-carboxamide 0001 (FALL) 0 mg” 1.90 mg” (Je and 1/4( pyridine-4-boronic acid) mg ae mmol), tetrakis(triphenylphosphine) palladium (© mg » 0.006 mmol), 1,2-dimethoxyethane (? ml) and a saturated Se solution of sodium hydrogen carbonate (?) mA at 860 degrees held in argon atmosphere for 1 hour. The cooled mixture was divided between ethyl acetate and water. The organic matter 1 was washed with brine and dried. The resulting residue was purified by flash chromatography and eluted with methanol/dichloromethane (77) to produce the compound mentioned in heading VY (mg; 4) with NMR spectroscopy.

“Na. =

NMR Spectrum: (DMSO-d) 1.42 (s, 9H), 7.16 (m, 2H), 7.52 (m, 2H), 7.70 (d, 2H), 7.87 (d, 1H), 7.94 (d, 1H), 8.60 (d, 2H), 8.65 (br, 1H), 9.90 (br, 1H); Mass Spectrum: M+H" 396. :)©( Method no

N2-(2-t-Butoxycarboylaminophenyl)-5-bromothiophene-2-carboxamide 5-Bromothiophene-2-carboxylic acid (1.50 g, 7.25 mmol) and 1-(N-t-m) mmol were stirred together in V ,4V g; 16 a (method butoxycarbonylamino)-2-aminobenzene minutes; 01 was required to harden (for Lov) 7 NN-dimethylacetamide (method 4-(4,6-dimethoxy-1) ,3,5-triazinyl-2-yl)-4-methylmorpholinium chloride h.m.Y mmol was obtained and the mixture was stirred at ambient temperature for 8.70 grams; and water, ethyl acetate, evaporation of the solvent, division of the remainder between ethyl acetate 0, evaporation, and then purification of the resulting organic magnesium sulfate residue on dichloromethane magnesium sulfate by flash chromatography and elutriation with dichloromethane with nuclear resonance spectrometry (o) WY to produce the compound mentioned in the title (?17, gram; magnetic. NMR Spectrum: ,(m103150-0) 1.44 (s, 9H), 7.16 (m, 2H), 7.35 (d, 1H) , 7.42 (d, 1H), 7.55 0 (d, 1H), 7.72 (d, 1H), 8.60 (br, 1H), 9.81 (br, 1H); Mass Spectrum: (M+H" -Boc ) 299.

1.1 - Method No. (4): N3-(2-t-Butoxycarbonylaminophenyl)-6-(pyridin-4-yl)nicotinamide N3-(2-t-Butoxycarbonylaminophenyl)-6- was stirred bromonicotinamide (method 0' 001 mg; 177 mmol) and 2610 YA)pyridine-4-boronic (0.71 mmol); 01(tetrakis(triphenylphosphine) palladium © mg) and a saturated sodium carbonate solution (7 mL) and mM Y) dimethoxyethane (A) at 880 °C for 48 hours in argon atmosphere argon, the mixture was poured into saline solution 01 (ml) and extracted using ethyl acetate Ji and the combined organic extracts were dried on magnesium sulfate and evaporated.The resulting residue was purified by a flash column chromatography with Lysate with methanol/ethyl acetate (yellow - ) to produce the compound in heading To) mg; (NE NMR Spectrum. NMR Spectrum: (CDCl3) 1.52 (s, 9H), 7.19 (m, 2H), 7.43 (m, 1H), 7.61 (m, 1H), 7.83 (m , 2H), 7.94 (d, 2H), 8.37 (dd, 1H), 8.75 (d, 2H), 9.31 (d, 1H), 9.79 (brs, 1H); Mass Spectrum: M+H" 391. yo Method No. (9) N3-(2-t-Butoxycarbonylaminophenyl)-6-bromonicotinamide dissolved 6-Bromonicotinic acid (g; Oo, mmol) and (1-(N-t- butoxycarbonylamino)-2-aminobenzene (method 0.1 : 1 g; 9.0 mmol) 0 in 01 (DMF) and added:

11.7 — - 4-(4,6-dimethoxy-1,3,5-triazinyl-2-yl)-4-methylmorpholinium chloride (method per gram; Te mmol) and then stir the solution output for YA hours at ambient temperature. The solution was decanted in ¥ (1 ml) water and extracted with ethyl acetate Ju (¥ * 0 ml). The combined organic extracts were dried over magnesium sulfate© and evaporated. The remainder was purified by trituration with A diethyl ether AJ Yo (mL) and the resulting solid was collected by filtration. The solid was washed with (mL) Ju (Diethyl ether) and vacuum dried to produce the compound mentioned in heading Gl ja (797/7); with nuclear magnetic resonance spectroscopy. NMR Spectrum: (CDCl5) 1.45 (s, 9H), 7.12 (t, 1H), 7.20 (t, 1H), 7.47 (d, 1H), 7.61 (d, 1H), 7.83 (d, 1H) , 8.21 (d, 1H), 8.63 (s, 1H), 8.91 (s, 1H), 9.97 (s, 1H); Mass Spectrum: \ M-H 390 and 392. Method No. (1) 1-(N-t-Butoxycarbonylamino)-2-aminobenzene The compound mentioned in the title was prepared according to the method mentioned in the references mentioned in: Seto, C, T Mathias, J.

P.; Whitesides, G.

M.; J.

Am.

Chem.

Soc., 1993, 115, 1321- Vo.1329

— Method No. (7): 4-(4,6-Dimethoxy-1,3,5-triazinyl-2-yl)-4-methylmorpholinium chloride 4-(4,6-Dimethoxy-1, 3,5-triazinyl-2-yl)-4-methylmorpholinium chloride according to the referenced method mentioned in: Kunishima, M., Kawachi, C., Morita, J., Terao, K., Iwasaki, F., Tani , S., Tetrahedron, ° .13159-13170 , 55 , 1999 Method No. (A): N2-(2-t-Butoxycarbonylaminophenyl)-5-(pyridin-2-yl)thiophene-2-carboxamide Yo 0) 5-(Pyridin-2-yl)thiophene-2-carboxylic acid mg was stirred; 01 mmol) and 1-(N-t-butoxycarbonylamino)-2-aminobenzene | 0 (Method A ?? mg; 1.1 mmol) together in N N-dimethylacetamide (©) mM (La) for 10 minutes; 4-(4,6-dimethoxy-1,3,5-triazinyl-2-yl)-4-methylmorpholinium chloride was added, (Method Vv 7 ?? mg; 1.1 mmol ) and stirred the mixture at ambient temperature for an hour. The solvent was evaporated and the remainder was divided between ethyl acetate and water. The organic extracts 10 were dried on magnesium sulfate, filtered, evaporated, and the resulting dal was purified by flash chromatography and eluted using zero-0 methanol dichloromethane to produce the compound mentioned in Title 198. milligram; 4) with nuclear magnetic resonance spectroscopy. I'm sorry

- 1.60

NMR Spectrum: (WH-01180) 1.44 (s, 9H), 7.16 (m, 2H), 7.34 (m, 1H), 7.52 (m, 2H), 7.88 (m, 3H), 8.00 (d, 1H) ), 8.57 (d, 1H), 8.65 (s, 1H), 9.83 (s, 1H); Mass Spectrum: ( M+H" -Boc ) 296. (4): Method No

N-(2-t-Butoxycarbonylaminophenyl)-3,3'-bipyridine-6-carboxamide ° t+ solution (method 2-(N-t-Butoxycarbonylamino)phenyl-5-bromopicolinamide heated mmol) and 1.77 ala 4 ( 3-pyridine boronic acid mmol) and 119 mg; 6.607 mmol) and 0 (mM T) tetrakis(triphenylphosphine) palladium carbonate ethanol (0.0014 mmol) and sodium carbonate 001) minutes in a microwave oven. The cooled mixture was concentrated at 01°C for 1590 grams) into 00 water. The organic materials were washed with ethyl acetate Ju, divided among acetates, and evaporated. The resulting residue magnesium sulfate was purified and dried on magnesium sulfate/ethyl acetate by flash chromatography eluting with ethyl acetate (700 to yield the compound mentioned in the title) £0 mg (VO - YO) iso -hexane Mass Spectrum: 11 + 11 Mass Spectrum: .391 ve: (01) Method No.

N-(2-t-Butoxycarbonylaminophenyl)-2,3'-bipyridine-5-carboxamide 6 077 (Method N-(2-t-Butoxycarbonylaminophenyl)-6-chloronicotinamide stirred mg; YY 01 (method 3-pyridine boronic acid trimer mmol) and 1.75 ala mg mg; 0.075 mg VE ( tetrakis(triphenylphosphine) palladium y mmol) 17 0 add

d QO \_mol) and Y) 1,2-dimethoxyethane mM (A) and a saturated aqueous solution of sodium carbonate (?mL) at Ar °C in an atmosphere of argon Y, 0 50d argon h.The cooled mixture was diluted with ethyl acetate and water, then the AL layer was removed by passing through a column containing diatomaceous earth.The organic matter was evaporated and the resulting residue was purified by chromatography and lyophilized with eluting with methanol J ste | dichloromethane (zero = + (ZY) to produce the oS all mentioned in the title (1 5 mg; 10 01 mass spectrum: Mass Spectrum : 11 + 11 391 Method No. (1): 3-Pyridine Boronic acid trimer 3-Pyridine Boronic acid trimer was prepared according to the method: J.

Org.

Chem. 2002, 67, 5394. Malacca W. Method No. (VY) N-(2-t-Butoxycarbonylaminophenyl)-6-(3-furyl)nicotinamide 0 stirred N- (2-t-Butoxycarbonylaminophenyl)-6-chloronicotinamide (Method 4 1176 1 mg » 1.8 mmol) and 3-furan boronic acid )07 mm = pl 8.58 mmol ) 04 ) tetrakis(triphenylphosphine) palladium mg; ) at 80 °C in an argon atmosphere

- 1.1 and a half hours. The cooled mixture was concentrated and stirred vigorously using 30d argon acetate and water, then the aqueous layer was removed by passing through a column containing ethyl acetate soil, and the organic materials were evaporated to produce the compound mentioned in the title. diatomaceous earth that has been used without scrubbing; mass spectrum.

Mass Spectrum: M+H" 380. ° (VY) Method No. t-Butyl 5-[({2-[(t-butoxycarbonyl)amino]phenyl}amino)carbonyl]-3',6'-dihydro- 2,4'- bipyridine-1'(2'H)-carboxylate 176 064 (method N-(2-t-Butoxycarbonylaminophenyl)-6-chloronicotinamide stirred mmol) and 15 mg; ye m Yoo (YA (method N-(t-butoxycarbonyl-3,4-dehydropiperidinyl)-4-pinacolatoboron 0.095 al a m Ye £) tetrakis(triphenylphosphine) palladium 5 mmol) 16 g mL) and a saturated aqueous solution of 7,*(1,2-dimethoxyethane mmol) bicarbonate at °C in an atmosphere of Av mL) at ,*( sodium hydrogen sodium carbonate (ethyl acetate Ju) for 771 hours. The vigorously cooled mixture was stirred in argon acetate 1 and water. The aqueous layer was removed by passing through a column containing diatomaceous earth, the organics were evaporated, and purified. Residue produced by chromatography diatomaceous earth 71 (iso-hexane [ethyl acetate J) scintillation with elution with milligram acetate; 778 (resonance spectrum WY) to produce the compound mentioned in title) 2725 - The magnetic nuclear.‎ _ ©

Vay —

NMR Spectrum: (DMSO-dg) 1.44 (s, 18H), 2.62 (m, 2H), 3.58 (t, 2H), 4.10 (m, 2H), 6.86 (m, 1H), 7.11 (t, 1H), 7.20 ( 1H), 7.51 (d, 1H), 7.59 (d, 1H), 7.71 (d, 1H), 8.27 (d, 1H), 8.61 (s, 1H), 9.07 (s, 1H), 9.90 (s , 1H); 495 Mass Spectrum: M+H. 1,3,5-triazine g" 17.7 mmol) in Monseh"1]00Lt6"N-21,4L (© + Je) L) and cooling to 0 °C. N- was added TA) methylmorpholine 17.7 mmol) slowly to keep the temperature below 0° Aggie and a solution of al ja V, +) 6-chloronicotinic acid 4 was added;; 47 mM (method 9.7 g 1-(N-t-butyloxycarbonylamino)-2-aminobenzene mol) and 0 mL) through a microtube to keep NN-dimethylformamide (011 mmol) in The temperature is less than 10 ° C. The mixture was stirred at 0 - 0 ° C for 2 hours. The mixture was then concentrated and the residue pulverized with ether Ju and filtered. The resulting solution was concentrated to obtain the compound mentioned in the title ( ZY ve ala VAY) NMR Spectrum 1. NMR Spectrum: (DMSO-dg) 1.45 (s, 9H), 7.12 (t, 1H), 7.21 (t, 1H), 7.50 (d, 1H) ), 7.62 (d, 1H), 7.72 (d, 1H), 8.33 (d, 1H), 8.63 (s, 1H), 8.95 (s, 1H), 9.96 (s, 1H); Mass Spectrum: M+H"-t-Bu 292. Add

- M111 - Method No. (Vo): t-Butyl 4-{5-[({2-[(t-butoxycarbonyl)amino]pheny!} amino)carbonyl]pyrazin-2- yl} piperazine -1-carboxylate A solution of: N-(2-t-Butoxycarbonylaminophenyl)-5-chloropyrazine-2-carboxamide |0 was heated (Method 17 197 mg; 1.91 mmol) and 0 ) t-butyl-1-piperazinecarboxylate mg; 4 mmol) in N,N-dimethylacetamide (? ml) to Av °C for 2 hours. The reaction mixture was then allowed to cool before it was poured onto V0 (ele mL). The resulting precipitate was collected by suction filtration, washed with ele and 0 diethyl ether, and dried in vacuum to produce the compound mentioned in heading “You (mg” 178); NMR spectroscopy. NMR Spectrum: (DMSO-dg) 1.43 (s, 9H), 1.49 (s, 9H), 3.49 (m, 4H), 3.78 (m, 4H), 7.15 (t, 1H), 7.24 (m, 2H), 7.95 (d, 1H), 8.25 (s, 1H), 8.74 (s, 1H), 8.99 (s, 1H), 9.98 (s, 1H); Mass Spectrum: 11+11 -Boc 399. vo Method No. (V1) t-Butyl [2-({[5-(4-benzylpiperazin-1-yl)pyrazin-2-yl]carbonyl}amino)phenyl|carbamate then heating a solution of :

- 1.8!

AY (Method N-(2-t-Butoxycarbonylaminophenyl)-5-chloropyrazine-2-carboxamide mmol) +,0A 001 µL (1-benzylpiperazine mg; 0.77 mmol) and Vo in N,N-dimethylacetamide (¥ ml) to Av s.d. 2 hours. The reaction mixture was then allowed to cool and water was then added. The resulting precipitate was collected by suction filtration© and washed with ela and isohexane Alb | iso-hexane diethyl ether and dried it under air current to produce the compound mentioned in the title (Vo) m (ZV pla) NMR Spectrum: (DMSO-dg) 1.49 (s, 9H ), 7.23 (m, 2H), 7.34 (d, 1H), 7.86 (d, 1H), 8.86 (s, 1H), 9.10 (S, 1H), 9.13 (s, 1H), 10.32 (s, 1H); Mass Spectrum: M+H" -Boc 249.0 Method No. (VV)

N-(2-t-Butoxycarbonylaminophenyl)-5-chloropyrazine-2-carboxamide (V+) (N,N-dimethylformamide points) and thiotyl thionyl chloride (0.0 mL 75.4 mmol) were added to suspension of (Y,+) 5-hydroxypyrazine-2-carboxylic acid g; VEY (mmol) in dichloromethane (0 (mL) dichloromethane). The reaction mixture 1 was heated to reflux for three and a half hours before it was allowed to cool and evaporated to dryness. The residue was azeotropic 40 distilled with toluene and dried in vacuum. The resulting solid (sale) was then dissolved in dichloromethane (0 mM) and treated with di-isopropylethylamine (V,0 mL (£7 mmol) ). The reaction mixture was stirred for five minutes before adding a solution of Ag hall) 1-(N-t-butyloxycarbonylamino)-2-aminobenzene 0 7.19 g 1 mm

— . \ \ _— mol) in dichloromethane (© milliliters) and continued stirring at ambient temperature for 11 hours. Many carefully poured the reaction mixture onto a saturated aqueous solution of sodium hydrogen carbonate (VY) mL). The organic layer was separated, washed with water and brine, dried over magnesium sulfate©, and evaporated to dryness. The resulting residue was pulverized using oy Jul A diethyl ether and the solid was collected by filtration and dried in an air stream to produce the compound mentioned in the heading (10) (al a Y,00) with nuclear magnetic resonance spectrum. NMR Spectrum: (DMSO- dg) 1.44 (s, 9H), 1.45 (s, 9H), 3.44 (m, 4H), 3.85 (m, 4H), 7.12 (t, 1H), 7.20 (t, 1H), 7.48 (d, 1H), 7.61 (d, 1H), 8.54 (s, 1H), 8.90 (s, 2H), 9.70 (s, 1H); Mass Spectrum: M-O'Bu 423.1 Method A) \ ( : t-Butyl-4-{5-[({2-[(t-butoxycarbonyl)amino]phenyl ( amino)carbonyl]pyrimidin-2- yl} piperazine-1-carboxylate solution was heated From : N-(2-t-Butoxycarbonylaminophenyl)-2-(methylsulfonyl)pyrimidine-5-carboxamide Vo (Method 8 406 mg; 0.17 mmol) and £Vo)r-butyl-1 -piperazinecarboxylate mg; The reaction mixture was then allowed to cool and the solvent was extracted in broilers. The resulting residue was purified by an F-column chromatogram and filtered on silica with sequential filtering.

111 - - using ethyl acetate J | isohexane ve - Yo ) isohexane in percent) to yield the compound mentioned in heading YAY) mg; (oY Cada NMR NMR Spectrum: (DMSO-dg) 1.46 (s, 9H), 3.49 (s, 3H), 7.14 (t, 1H), 7.25 (t, 1H), 7.52 (d, 1H), 7.72 (d, 1H), 8.71 (s, 1H), 9.50 (s, 2H), 10.24 (s, 1H); Mass Spectrum: M+H"-t- Bu 337 ° Method No. (V4) N-(2-t-Butoxycarbonylaminophenyl)-2-(methylsulfonyl)pyrimidine-5-carboxamide added 11 ZV +) NN-dimethylformamide g » £0.0 m od) (Use a cooled (0°C) solution of : N-(2-t-Butoxycarbonylaminophenyl)-2-(methylthio)pyrimidine-5-carboxamide \ (Method VER 71 mM +A ala) ¥ mmol) in N,N-dimethylformamide (+© mL). The reaction mixture was allowed to warm to room temperature and stirred under 0 argon for 16 h. The DAT portion of meta-JY (JY) was then added chloroperbenzoic acid 0 mg; +, Y0 sodium metabisulfite M. The organic phase was separated, washed using water, then brine, dried over magnesium sulfate, filtered, and evaporated to dryness. The residue was raised in dichloromethane and all insoluble matter was removed by filtration. The filtrate was evaporated and re-dissolved in an acetate-add mixture

ethyl acetate (Ju) and methanol, and washed. The solution was washed using a saturated aqueous solution of sodium hydrogen carbonate, then with water, then with a saline solution before drying on magnesium sulfate, filtration and evaporation to produce the compound mentioned in title (5 05). Milli (ZY alga NMR Spectrum. NMR Spectrum: (DMSO-dg) 1.45 (s, 9H), 2.60 (s, 3H), 7.13 (t, 1H), 7.22 0 0 (d, TH), 7.66 (d, 1H), 8.64 (s, 1H), 9.10 (s, 2H), 9.96 (s, 1H); Mass Spectrum: M+H" 361. Method No. (01): N-(2-t-Butoxycarbonylaminophenyl)-2-(methylthio)pyrimidine-5-carboxamide 0 A mixture of 0 (2-methylsulfanylpyrimidine-5-carboxylic acid) g; 8.88 mL is allowed (Use and 1-(N-t-butoxycarbonylamino)-2-aminobenzene (method C = al), YY (0.4 mmol) and 4-(4,6-dimethoxy-1,3,5-triazinyl- 2-yl)-4-methylmorpholinium chloride (Method A 7.7 g; 7.55 mmol) in NN-dimethylformamide (+¥ mm =) by stirring at room temperature for ; hours before being partitioned between the acetates J ethyl acetate 0 _ and water. The organic layer was separated, washed with water, then with brine, dried over magnesium sulfate, filtered, and evaporated to dryness. The residue was purified by flash column chromatography on silica eluting with ethyl acetate Ji in (Lv© — Yo) isohexane; To produce the compound mentioned in the title (1.19 grams; (ZA) with NMR spectrum.

11” - - NMR Spectrum: (CDCl3) 1.53 (s, 9H), 2.07 (m, 4H), 3.38 (m, 4H), 5.72 (d, 111(, 6.92 (s, 1H), 7.15 (m, 2H), 7.34 (m, 1H), 7.40 (d, 1H), 7.64 (m, 1H), 8.33 (m, 1H); Mass Spectrum: 11 + 11 388. Method number ( YY) N-(2-t-Butoxycarbonylaminophenyl)-5-(pyrrolidin-1-yl)thiophene-2-carboxamide M 4-(4,6-Dimethoxy-1,3,5-triazinyl) added -2-yl)-4-methylmorpholinium chloride (Method A TAY mM 0.78 Gala mmol) to a solution of L: 5-pyrrolidin-1-ylthiophene-2-carboxylic acid Ly (Method 770771 milligrams; Liter). The reaction mixture was stirred at 0 ambient temperature under nitrogen for twenty hours. The solvent was evaporated and the remaining sald) was divided between ethyl acetate Ji and water. The organic extracts were dried on sodium sulfate and filtered by Ad snc ag.

La pans the remainder all by flash chromatography eluting with ethyl acetate/isohexane 0. — 01 iso-hexane 7 followed by SLE | ethyl acetate dichloromethane 001 (£0) to produce the compound mentioned in the title (10 mg; NMR V0). Spectrum: (DMSO-ds) 1.99 (m, 4H), 3.26 (m, 4H), 5.78 (d, 1H), 7.41 (d, 1H); Mass Spectrum: M+H" 198.

1116 - - Method No. (YY) 5-(pyrrolidin-1-yl)thiophene-2-carboxylic acid an aqueous lithium hydroxide was added with a concentration of #1 molar (0% mL) 0 mmol) to a solution of ethyl S-pyrrolidin-1-ylthiophene-2-carboxylate (Method 770 0©; mg; Voor mmol) in 11 methanol (1 mL methanol) and stir the reaction mixture At Av degree Lda under nitrogen for a period of YE one hour. The methanol was evaporated [00A6_, the Al solution was washed with ether, and the aqueous solution was acidified to a pH © using methanol. The ethyl acetate extracts were dried on sodium sulfate and evaporated to produce the compound mentioned in (0 heading (YAY) mloa 700) with nuclear magnetic resonance spectrum. Method No. (YY) Ethyl -5-(pyrrolidin-1-yl)thiophene-2-carboxylate cesium carbonate (4¢,) g added; 5.95 mmol), tris(dibenzylideneacetone)dipalladium(0) ( 84 mg; 8.71" mmol), and racemic-2,2'-bis(diphenylphosphino)-1,1-binaphthyl 00 (1 4 mg; 21773 mmol) to £,Y0 «ola 001( ethyl 5-bromothiophene-2-carboxylate mmol) followed by (€Y)toluene (A) and pyrrolidine (¥ mL 8.01 mmol).The reaction mixture was gas extracted and stirred under nitrogen at Av ° C for YA h. The cooled mixture was divided between ethyl acetate and water. The organic materials were washed with 0% brine, dried over sodium sulfate and evaporated.The remainder was purified.

o — \ \ _ produced by flash chromatography and eluting using SH dichloromethane to produce the compound mentioned in the title (ANY) m ala 797)"; with nuclear magnetic resonance spectroscopy. NMR Spectrum: (CDCly) 1.34 (t, 3H), 2.07 (m, 4H), 3.32 (m, 4H), 4.28 (q, 2H), 5.73 (d, 1H), 7.58 (d, 1H) ; Mass Spectrum: M+H" 226 ° Method No. (AR): N-(2-t-Butoxycarbonylaminophenyl)-5-(piperidin-1-yl)thiophene-2-carboxamide was done using a homogeneous method. For what is mentioned in Method No. (YY) Reacting S-piperidin-1-ylthiophene-2-carboxylic acid (Methase (Yo) with 1-(N-t-butyloxycarbonylamino)-2-aminobenzene to produce the compound mentioned in Title 0 (7277); (d, 1H), 6.88 (s, 1H), 7.15 (m, 2H), 7.32 (m 1H), 7.40 (d, 1H), 7.66 (m, 1H), 8.46 (s, 1H) ; Mass Spectrum: M+H" 402. Method No. (Yo) The reaction of ethyl-5-(piperidin-1-yl)thiophene-2 was carried out using a method similar to that mentioned in method No. (YY). -carboxylate (method (V1) with lithium hydroxide to produce the compound mentioned in Title (777) with NMR spectrum 1.

11151 - - NMR Spectrum: (DMSO-d) 1.58 (m, 6H), 3.20 (m, 4H), 6.12 (d, 1H), 7.40 (d, 1H); Mass Spectrum: M+H 212. Method No.: (1) Ethyl-5-(piperidin-1-yl)thiophene-2-carboxylate 0 Cesium carbonate (1.4 ¢) added; 0.90 mmol) and rris(dibenzylideneacetone)dipalladium (zero) ) 4 mg; YVY + mmol) and racemic-2,2'-bis(diphenylphosphino)-1,1-binaphthyl ) 17 mg; 37+ mM (Use to €,Y0 «al ja V+ +) ethyl S-bromothiophene-2-carboxylate mmol) followed by Y') toluene ;? mL) and piperidine (+,0Y) piperidine mL 1.5 mmol). The gas was extracted from the reaction mixture and stirred under nitrogen at 800 °C for YA hours. The cooled mixture was divided between ethyl acetate and water. The organic materials were washed with brine, dried over sodium sulfate, and evaporated. The resulting residue was purified by flash chromatography and eluting with [ethyl acetate Ji isohexane (Yo — +) isohexane %) followed by dichloromethane to yield 1 mg EAA ; (LEA NMR Spectrum. NMR Spectrum: (CDCl3) 1.34 (t, 3H), 1.63 (m, 2H), 1.72 (m, 4H), 3.26 (m, 4H), 4.28 (gq , 2H), 5.99 (d, 1H), 7.54 (d, 1H); Mass Spectrum: M+H" 240.

- 117 -

(YY) Method No. t-Butyl 4-(5-{[(2-t-butoxycarbonylaminophenyl)amino]carbonyl}-2-thienyl)piperidine-1- carboxylate

0 palladium was added on charcoal (0,17 ZY mg) to a solution of t-butyl4-(5-{[(2-t-butoxycarbonylaminophenyl)amino]carbonyl ( -2-thienyl) -3,6- dihydropyridine-1(2H)-carboxylate (Method 17 (YA mg; 177 mmol) in 1 mL pure YO ethanol) and the mixture was stirred in atmosphere of hydrogen for a period of Y¢ 0 hour, then the mixture was filtered and evaporated zy \ the compound mentioned in the title (0 mg « 1 7) 0 with a nuclear resonance spectrum

,. Magnetic NMR Spectrum: (WL000) 1.48 (s, 9H), 1.53 (s, 9H), 1.66 (m, 2H), 2.00 (m, 2H), 2.84 (m, 2H), 2.98 (m , 1H), 4.20 (m, 2H), 6.74 (s, 1H), 6.82 (d, 1H), 7.20 (m, 2H), 7.56 (m, 3H), 8.99 (s, 1H); Mass Spectrum: M+H" - BOC 402.

(YA) Method No. vo t-Butyl 4-(5-{[(2-t-butoxycarbonylaminophenyl)amino]carbonyl}-2-thienyl)-3,6- dihydropyridine-1(2H)-carboxylate

M11 - A saturated solution of sodium hydrogen carbonate (¥ mL) was added to a volatile solution of: N-(2-t-butoxycarbonylaminophenyl)-5-bromothiophene-2-carboxamide (Metrisa ¥ 1" mg; 171 mmol) in 1,2-dimethoxyethane (¥ mL). N-(t-Butoxycarbonyl-3,4-dehydropiperidinyl)-4-pinacolatoboron 0 () was added Method YA 156 mM TY Gla (mmol) followed by €A) rerrakistriphenylphosphine palladium (mg; 4,150 mmol) and stirred the mixture at 0 °C for 1 hour. The cooled mixture was divided between ethyl acetate (Ji) and water. The organic phase was separated, washed with water, dried over magnesium sulfate 0, filtered and evaporated. The resulting residue was purified by flash column chromatography with eluting using methanol / dichloromethane (0-601) to produce the compound mentioned in the title (1.7 mg; AT NMR Spectrum NMR Spectrum: (CDCls) 1.49 (s, or), 1.53 (s, 9H), 2.53 (s, 2H), 3.64 (t, 2H), 4.08 (s, 2H), 6.19 (s, 1H), 6.84 (s, 1H), 6.97 (d, 1H) , 7.17 (m, 2H), 7.54 (m, 3H), 9.18 (s, 1H); Mass Spectrum: M+H"-Boc 400. \o Method #: (Y4) t-Butyl -4-{5-[({2-[(t-butoxycarbonyl)amino]phenyl }amino)carbonyl]thien-2- yl } piperazine-1-carboxylate A volatile solution of 5-[4- was treated (t-butoxycarbonyl)piperazin-1-yl]thiophene-2- carboxylic acid Ye (method YY oF mg; 0001 mmol) in ALD is chloromethane

(-119- μl) (©) N,N-dimethylformamide containing (A mM Y,0) dichloromethane and the mixture was stirred at (Use 01 mM; AY) oxalyl chloride oxalyl chloride at ambient temperature for one hour. To this was added in one batch a solution of 0.01 mg;17 (method 1-(N-t-butyloxycarbonylamino)-2-aminobenzene mL 7.776 mmol) in chloro + YA ) triethylamine and triethylamine (seo 1 hour and evaporation thereafter ad ml). The mixture (Y) dichloromethane (lus) was stirred to dryness. The resulting dark green gum was purified by flash chromatography with dichloromethane eluting in sequential dichloromethane ethyl acetate J using an acetate spectral gradient (AF) milligrams. 0 (for the production of the compound mentioned in the title (01 - Lia)

Mass Spectrum: 11 + 11 503. Mass 0 (Fe) Method No. 5-[4-(t-Butoxycarbonyl)piperazin-1-yl]thiophene-2-carboxylic acid: A solution of ,

Aor al a 0.21 (TY (method t-butyl 4-(5-formylthien-2-yl)piperazine-1-carboxylate g; V+, +) silver (I) nitrate mL) into solution A2) ethanol mmol) in ethanol (V mmol) 1713 cal a £,AY) sodium hydroxide mmol) and sodium hydroxide 0/4 h. YY mL). This mixture was stirred and heated at 715°C for A) in water and the mixture was cooled by adding ice and then filtered to remove silver salts. The filtrate was carefully evaporated and the resulting aqueous solution was filtered again through a piece of ethanol to remove the ethanol and glass wool to remove the tar. The filtrate was then diluted with water by volume

1776 — a total of 50 860 mL and then acidified to pH 11 ºC© with acetic acid and the precipitate was filtered, washed with water and dried in a vacuum oven at £0°C to produce the compound mentioned in heading (VAN) gram; (VY NMR Spectrum. ° NMR Spectrum: (DMSO-d) 1.41 (s, 9H), 3.18 (m, 4H), 3.45 (m, 4H), 6.20 (d, 1H), 7.43 (d, 1H); Mass Spectrum: M+H" 313. Method No. (FY) t-Butyl 4-(5-formylthien-2-yl)piperazine-1-carboxylate 0 is stirred hla from (YAY) S-bromothiophene-2-carboxaldehyde g"; 0.1 mmol) and 77.1 cal a 1 ) t-butyl piperazine-1-carboxylate mmol) and diisopropyl 10 ethylamine (10 mM diisopropylethylamine to read 40.060 mmol) and 1-dimethyl sulfoxide (©, 100621010086 mL) at 01 °C in nitrogen for VA for 1 h. The cooled mixture was divided between clay ethyl acetate Ji and the organic Spd 1 was washed with water then brine then dried over magnesium sulfate and evaporated.The resulting solid was purified by flash chromatography and eluting with dichloromethane followed by Ji ethyl acetate | dichloromethane (719) to produce the compound mentioned in heading (7,; (VY ala) with NMR spectrum.

1171 - = NMR Spectrum: (DMSO-dg) 1.41 (s, 9H), 3.34 (m, 4H), 3.47 (m, 4H), 6.36 (d, 1H), 7.70 (d, 1H) , 9.49 (s, 1H); Mass Spectrum: M+H" 297. Method No. (YY) N-(2-Nitrophenyl)-2-(4-methylpiperazin-1-yl)-1,3-thiazole-5-carboxamide 0 A solution of 1.1 M concentration of n-butyllithium in mM (+,V)hexane (1 mmol) was added to a tiie solution of 1-(5-bromo-1, 3-thiazol-2-yl)-4-methylpiperazine (method YAY (VT) mg; After 15 minutes a solution of V1¢ (2-nitrophenylisocyanate mg; 001 mmol) in diethyl ether (©mL) was added and the mixture was heated to ye The ambient temperature is more than hours.A saturated Sle ammonium chloride solution (©mL) was added and the solution was extracted using acetate, Ju 266 Rat©.The combined organic extracts were washed using saline and dried on magnesium sulfate magnesium sulfate was purified, filtered, and evaporated.The resulting residue was purified by flash chromatography and eluted with methanol/dichloromethane 0 (0-701) to yield the compound mentioned in heading VAY) mg; ((Z0V) NMR Spectrum. NMR Spectrum: (CDCl3) 2.37 (s, 3H), 2.55 (t, 4H), 3.64 ( ) 4H, 7.17 (t, 1H), 7.66 (t, 1H), 7.89 (s, 1H), 8.26 (d, 1H), 8.86 (d, 1H), 11.03 (s, 1H); Mass Spectrum: M+H" 348.5 Lumens

1177 - - Method No. (FY) 1-(5-bromo-1,3-thiazol-2-yl)-4-methylpiperazine (V+) 2,5-dibromothiazole g”; 4,1 mmol) and 2,5-dibromothiazole (1,¢ mL €),Y mmol) and 4-(N,N-dimethylamino)pyridine ('amino )£ 4 mg; 1.40 0 mmol) at the reflux point (ls) in 10) mM n-butanol (A) for two hours. Methanol/dichloromethane (zero - 701) to produce the compound mentioned in title ( 0 7/4 mg;>61 10 NMR Spectrum (s, 3H), 2.50 (t, 4H), 3.45 ( ) 4H), 7.06 (s, 1H); Mass 2.34 ( 2i) NMR Spectrum: “Spectrum: M-+H” 264.01 Method No. (¢ (r). N-(2-Aminophenyl)-2-piperazin-1-yl-1,3-thiazole -5-carboxamide was stirred: t-Butyl 4-(5-{[(2-aminophenyl)amino]carbonyl }-1,3-thiazol-2-yl)piperazine-1- carboxylate \ o (method (Yo 7795 mg; + 0 4 mmol) and Y 7) 1,4-dioxane mM) and a solution of concentration ;molar of hydrochloric acid in Y,¥) 1 ,4-dioxane = mM at ambient temperature for 7 hours. Then the resulting precipitate was filtered and washed using SD (diethyl ether). The solid was dissolved in (10 ml) ele and make it basic

1177 - - using NaOH ¥ N and extracted using ethyl acetate .cthyl acetate and the ethyl acetate extracts were washed using brine and dried on magnesium sulfate, filtered and evaporated to produce the compound mentioned in Title 118( mg of 7a NMR Spectrum: (DMSO-ds) 2.79 (t, 4H), 3.40 (t, 4H), 4.85 (s, 2H), 6.58 (t, 1H) , 6.76° (d, 1H), 6.95 (t, 1H), 7.10 (d, 1H), 8.01 (s, 1H), 9.40 (s, 1H); No. (Yo) t-Butyl 4-(5-{[(2-aminophenyl)amino]carbonyl}-1,3-thiazol-2-yl)piperazine-1- carboxylate Ve 2 added ,0 €) Nickel (ID) acetate g; 1.7 mmol) to a volatile suspension of: t-butyl 4-(5-{[(2-nitrophenyl)amino]carbonyl}-1,3- thiazol-2-yl)piperazine-1-carboxylate (Method 7 7.14 g; 6.1 mmol) in yoo (mL methanol) at 0 °C. Sodium borohydride was added ,71 (Sodium borohydride g; 11 eo mmol) over 11 minutes and the resulting mixture was stirred at ambient temperature for 2 hours. The mixture was filtered, the solvent evaporated, and the residue purified by flash chromatography and eluted with methanol/dichloromethane (0-770) to produce the compound mentioned in heading VAY) g; ; 7 with a nuclear magnetic resonance spectrum. Add

NMR Spectrum: (J0020) 1.49 (s, 9H), 3.56 (s, 8H), 3.85 (s, 2H), 6.82 (m, 2H), 7.09 (t, 1H), 7.28 (m, 1H), 7.35 (s, 1H), 7.68 (s, 1H); Mass Spectrum: M+H" 404. (91:) -carboxylate

A 0,¥ M solution of n-butyllithium in mL (V,Y)hexane was added

0 7 mmol) to a volatile solution of:

cal Ja 0,77 1 (method t-butyl 4-(5-bromo-1,3-thiazol-2-yl)piperazine-1-carboxylate

4 mmol) in (mM (Yo) diethyl ether) at -YA °C. And done

After 15 minutes add a solution of 137 (2-nitrophenylisocyanate g; 7.79 mmol) in

01 (mL diethyl ether) and warm the mixture to ambient temperature during ;

yy hours. Ala ammonium chloride (saturated YO) (mL) was added and the solution was extracted using ethyl acetate J). The organic matter extract was washed with brine, dried over magnesium sulfate, filtered, and evaporated. The resulting residue was purified by flash chromatography and eluted with ethyl acetate | iso-hexane (Zero - 777) to produce the aforementioned compound

,. Sh NMR spectrum (% YA mg; 01) in title ye

NMR Spectrum: (CDCl) 1.49 (s, 9H), 3.60 (s, 8H), 7.17 (t, 1H), 7.66 (t, 1H), 7.88 (s,

1H), 8.26 (d, 1H), 8.86 (d, 1H), 11.04 (s, 1H); Mass Spectrum: M+H" 434.

1 Y o — — Method No. (FV) t-Butyl 4-(5-bromo-1,3-thiazol-2-yl)piperazine-1-carboxylate (0.1) (2, 5-Dibromothiazole (g; 5.17 mmol) and 1-t-butyloxycarbonylpiperazine (7 g) 01 mmol) and triethylamine (Y) triethylamine (°mL 41.7 mmol) at reflux condensation together in 0 (n-butanol o mL) sad 7 hours. The cooled solution was evaporated and the remainder purified by flash chromatography and eluting with sia) methanol/dichloromethane — (0) to yield the compound mentioned in heading NYY) g; 797); with nuclear magnetic resonance spectroscopy. (s, 9H), 3.60 (s, 8H), 7.17 (t, 1H), 7.66 ( 1H), 7.88 (s, 1.49 (and 002) NMR Spectrum: 1H), 8.26 (d, 1H) , 8.86 (d, 1H), 11.04 (s, 1H); Mass Spectrum: M+H" 434. Method No. (FA) N-(t-Butoxycarbonyl-3,4-dehydropiperidinyl)-4-pinacolatoboron (Tet Lett. 2000, 41, 3705). Addition of 17 ( 1,1-Bis(diphenylphosphino) ferrocenedichloropalladium (II) g; Vio 0 mmol) to a potassium acetate solution of 117 cal a VY, ¥) potassium acetate mmol) and al ja VY, A) bis-pinacolato diboron (£© mmol) in N,N-dimethylformamide (0 mL) was added (N-t-butoxycarbonyl-4-trifluoromethanesulfonyloxy-3,4-dehydropiperidinyl)- 4-pinacolatoboron [CAS 138647-49-1] + 0.10 g added 1 s

- 177 -

4 mmol) in 001 (<1.27-4106091001270106 mmol) slowly before heating the mixture to

0°C for VA 1 hour under argon. The cooled mixture was concentrated and divided between acetates

ethyl acetate Su and water. The organic materials were washed with brine, dried over magnesium sulfate, filtered, and evaporated. The remainder mentioned were nominated from

© through a piece of silica with elevation using ethyl acetate J (+70) / iso-hexane (+70) to produce the compound mentioned in the crude title (16.7 g;

00 NMR spectrum. NMR Spectrum: (DMSO-d) 1.21 (s, 12H), 1.40 (s, 9H), 2.10 (m, 2H), 3.34 6 (m, 2H), 6.39 (m, 1H). 0 Method No. (Fe).

1-Bromoacetyl-1,2,3 4-tetrahydroquinoline [CAS 63286-44-2]

(10) 1-Bromoacetyl-1,2,3,4-tetrahydroquinoline g; VO mmol) was dissolved in benzene (0mM£)A and cooled to 10°C. A solution of bromoacetyl bromide

VT) grams; Ar mmol) in benzene (£4 milliliters) drop by drop in one hour.

1 The organic layer was separated, washed with 100 m (A) water, dried over magnesium sulfate, filtered, and then evaporated to produce the crude compound. This was purified by distillation under reduced pressure followed by recrystallization from -60 Av. A petroleum ether for the production of the said compound

In heading 1",5 (737 grams), the analytical calculations for Cy HpONBr give 787.0 carbon, 8,7 hydrogen, 0,0 7# nitrogen, and 7714 bromine; and it is found:

1797 - 4 # carbon and TEA hydrogen ¢ and 78.3 nitrogen and 4 4,.¥ bromine Br Method No. (¢): 2-(N-t-butoxycarbonylamino)phenyl-5 _bromonicotinamide Then 4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride (method for TIA g; VY mmol) was then added to solution 7 1,(S-bromonicotinic acid g; 01 mmol) and 1,(1,7-(N-t-butyloxycarbonylamino)-2-aminobenzene g; 01 mmol) in Yo)NN-dimethylformamide Milli(A) and the mixture was stirred at ambient temperature for 4 hours. The mixture was concentrated and divided between water and ethyl acetate Jul. The organic layer 0 was separated, dried on magnesium sulfate and evaporated. The resulting solid residue was pulverized using Di-Jul diethyl ether and solid collection, filtering and vacuum drying to produce the compound mentioned in the heading (For) grams; 7776); Mass Spectrum: Mass Spectrum: M+H"-t-Bu 6 Method No. (41): N-(2-t-Butoxycarbonylaminophenyl)-6-(4-benzylpiperazin-1-yl)nicotinamide \o N-(2-t-Butoxycarbonylaminophenyl)-6-chloronicotinamide (Method 6 001 mg; 1749 mmol) was heated to Av °C with N-benzyl piperazine (0 ), + mL (AY, + mmol) in DMA (0 mL) for 1 hour. The cooled mixture was divided between ethyl acetate Ji and water. The organic materials were washed with brine and dried over sulfate.

1178 - Magnesium sulfate and its evaporation. The resulting residue was purified by flash chromatography and eluting with ethyl acetate/iso-hexane (Yo) — 6a7) to yield the compound in heading Ve) mg; 0 75); Mass Spectrum: “Mass Spectrum: M+H” 488 © Method No. (47): N-(2-t-Butoxycarbonylaminophenyl)-6-piperazin-1-ylnicotinamide N-(2-t) was heated -Butoxycarbonylaminophenyl)-6-chloronicotinamide (Method CT VA g; 5.117 mmol) to Av °C with cal ya 7.5 (N-boc-piperazine 12.0 mM mol) in DMA (001 mL) for VY h. The cooled mixture was divided between Jy ethyl acetate 0 and water. The organic layers were washed with brine, dried over magnesium sulfate, filtered, and evaporated. The resulting residue was purified by flash chromatography and eluting using [ethyl acetate Ju iso-hexane (ZV - Yo) to produce the compound mentioned in the heading (FEE ala VF) with mass spectrometry: Mass Spectrum: M+H 442. Plaited

Claims (1)

-78?1- claimant 1 ) = compound of formula (1): RY, 3: 0 M (RY) R3 0 "0 where The A ring is pyridyl » or quinolyl » or indolyl Ju sx » or pyrimidyl© » or morpholinyl » or piperidinyl 0 or Juju J »piperazinyl 1 pyridazinyl “or cpyrazinyl or thiadiazolyl Jus ks” + or thienyl ¢ or pyrimidinyl ¢ or thienopyrimidingl © A or purinyl “or tetrahydropytidnyl - 1,2,3,6 or ctriazinyl or 1-oxazolyl « or pyrazolyl + or furanyl Gs if 0 ring A contains an NH- moiety It optionally replaces the nitrogen atom by 11 groups chosen from 6; VY ring B is thienyl “or thiadiazolyl” or thiadiazolyl “or 1” pyrimidyl ¢ or pyrazinyl or pyridazingl “ or pyridyl Ve; 0 c is a substituent on a carbon atom and can be chosen from halo, nitro, 11-cyano, hydroxy, or trifluoromethyl » or trifluoromethoxy ¢ VV or amino sud or carboxy ¢ or carbamoyl VS z - .TB Cas or ¢ alkyl or from sulphamoyl or sulfamoyl mercapto or mercapto carbamoyl YA “alkanoyloxy” or “alkanoyl” or “alkoxy” or “alkynyl Cs” or “alkenyl” 8 is a where , (0)S alkyl Cis or » NN-(Cralkylpamino sf “N-(Cialkylamino) or 00 or » N-(C.¢alkyl)sulphamoyl or 9 0 Cisalkoxycarbonyl or ea 71 arylC alkyl ie ¢ aryloxy or aryl oxy caryl or aryl « NN-(Cpealkyl)osulphamoyl YY or (heterocyclic group » heterocyclic group or heterocyclic group) ¢ YY where an optional substitution may occur in ¢ (D-E) or an alkyl Cy + group ( heterocyclic group 74 and where oS is one or V by a carbon on the carbon atom (D-E) of which the group is Lo.L Yo Substitution of NH may occur if said heterocyclic group contains that Y moiety by a group chosen from [; optional pitrogen of the nitrogen atom YY YA for halo ¢, nitro, cyano, hydroxy, coxo YA, or trifluoromethyl; or trifluoromethoxy “0” or amino “or carboxy ¢ or carbamoyl” or mercapto J 1 sulfamoyl or alkenyl Cag so “ alkyl Cig + or from Cis 9 ¢ alkynyl alkoxy YY or m alkanoyl + or 0” alkanoyloxy bitter or N-(Calkyl)amino + or NN”(Cprealkylramino YY ” or amas a Or aryl or aryloxy » or arylCrsalkyl ; or heterocyclic group » or ( heterocyclic group ) c alkyl TV or (DEY) group Where an optional substitution may occur in 7 including the (DE) YA group on the carbon atom by one or more 17 YA and 157 and 7 are selected separately from halo; or we see nitro; or cyano or 0 hydroxy or oxo < or trifluoromethyl or - 1171 - 1- trifluoromethoxy or amino “or carboxy ¢ or carbamoyl 7” or mercapto or sulphamoyl or “© alkyl” or Cars alkenyl or m a Cus, (0)S alkyl is of Y= ji a 5 of “J wis Salkoxy ? « alkynyl- or alkenyl-magnet or alkyl Cig cities separately from SK and © and [ and EV or new 211»0:70:.:; or carbamoyl “Cy_salkylsulphonyl” or “0 alkanoyl” or “from £A” or “NN-(Csalkyl)carbamoyl” or “carbamoyl 4 phenylsulphonyl Jui sila” and phenyl benzoyl or “benzyloxycarbonyl oxy” carbonyl 0 ( heterocyclic group or (heterocyclic group) carylCrealkyl of » aryl bide on carbon on the carbon atom K; where an optional substitution may occur in one or more ©, 1, and alkyl Cg OF Sha and if it contains said heterocyclic group on Q by OY that optionally by a group selected nitrogen the nitrogen atom NH- of ; alkyl rm H of H0 can be substituted oT © is halo; or we nurse him; or cyano; or hydroxy” or “trifluoromethyl” or “trifluoromethoxy” or “amino©A” or “carboxy” or “carbamoyl” or “mercapto” or 4 sulphamoyl ¢ or from alkyl “or alkenyl cities” or alkynyl methyl “¢ or cis calkoxy -0 or alkanoyl bitter “or alkanoyloxy bitter” or adsorbent) for mole 0n ) at or N,N-(C.salkyl)oamino 1 « or from (0(5) alkyl 8 hemi soy = Y = or Cealkoxycarbonyl 7 «¢ or N-(Cy.ealkyl) sulphamoyl « or N,N-(C, .galkyl),sulphamoyl » or av aryl Jeary aryloxy ¢ or carylCrealkyl or de gana cyclic other than Sea - 1177 - heterocyclic group 4 « or Ac gana) alkyl Ci. ) heterocyclic group ¢ 0 or EV group - 07); where an optional substitution in © including group (DV-ET) IT may occur on the carbon atom by one or more 7s; 1, 0, “0, and JSD” are selected separately from alkyl ¢ ar alkenyl Cag “ab bin” alkyl Cr Caseycloalkyl sl “alkynyl 14” or “du aryl” or aryl 4 of a calkyl or heterocyclic group “ or (01) heterocyclic group ( mr Cua alkyl Optional substitution may occur in © ; and “0 VY and 0 on the carbon atom by one or more "7; and since the said heterocyclic VY group 13 contained an NH- moiety, the nitrogen atom VY optionally substitutes VY with a group chosen from 6); VE and 8, 8, and 87 are selected separately from —(NRY)- or -0- ; or -0(0) -C or -d -NRHC(0)- 5 “C(0)-AR -NRHC(ONRY-AR ~NRHC(0)O-AR COC(ONRY-AR -C(ONRY V1) or S(O); or NRHSO,—where “8 and 8 are selected separately from VV hydrogen or m© alkyl or an optional substitution occurs in one or more Falls alkyl Crp VA and : is zero Y = VA 7 and SSF are selected separately from halo; or “nitro or cyano-acne”; or Ae hydroxy “or trifluoromethyl” or tri trifluoromethoxy ~~ A) + or amino « or carboxy J « carboxy carbamoyl ¢ AY or mercapto + or sulfamoyl + or alkyl Ci » or alkenyl Cag ” or AY mon alkynyl ¢ or m “alkoxy or m alkanoyl ” or m alkanoyloxy “ or N)N-(Calkylamino “N-(Ciealkylamino ~~ Af” or (0)S alkyl Crs , where a is 6 mor N(C1alkyl)sulphamoyl § « Cealkoxycarbonyl 5 «Y= » or N,N-(C.ealkyl);sulphamoyl ~~ Al ¢ 1VY 4 am AY yellow; or JF JY JO ;; Where the values of !8 may be the same or different; ¢ chloro 55% or fluoro is fluoro R* AA an AS yellow; or J) 7; where the values of RY may be the same or different; ¢ hydroxy or hydroxy amino is amino 0 RY 10 is halo < or nitro ; or cyano, or hydroxy, or trifluoromethyl 7; or trifluoromethoxy “or amino 7 ¢ or carboxy” or carbamoyl ¢ aps 54 zero, 1, or "; where RY values may be the same or different; 58 and where: 57 The aryl group is a group that is selected from phenyl phenyl ; and cindenyl - and indanyl » and naphthyl ; tetrahydronaphthyl and fluorenyl 4 4 The heterocyclic group is a saturated monocyclic or dicyclic group; 0 or partially saturated; or unsaturated with *- 11 atoms of which at least one atom is selected from Ve) nitrogen or sulfur oxygen ¢ which unless otherwise stated; 17 be attached to a carbon or nitrogen atom; Whereas, the group CHy #0 can optionally be replaced by (0)0; Whereas, (Se) optionally oxidize the sulfur atom of the ring to be ¢s—oxide(s) 0 0 or a pharmaceutically acceptable salt thereof or an ester or amide of it Sts for hydrolysis in the alkythine Yen live. AA 174 - - 1 ?- a compound of formula (1) according to claim (1) where: ring H is: pyridin-4-yl, pyridin-3-yl, pyridin-2-yl, morpholin -4-yl, piperidin-4-yl, piperidin-3-yl, ¥ piperidin-2-yl, piperazin-4-yl, thiazol-2-yl, thien-2-yl, furan-3-yl, pyrrolidin-1-yl, ¢ piperidin-1-yl, triazol-1-yl or 1°,2°,3°,6° -tetrahydropyridin-4-yl ° 3 and where 13 the A ring contained a moiety This NH-nitrogen atom can optionally be replaced by a group chosen from ©; a pharmaceutically acceptable salt thereof or a Jester amide SUG 43 amide A for hydrolysis in the organism. =F) A compound having formula (1) according to claim (1) where: ARDY substituted on a carbon atom of choice of cyano, hydroxy “0” », ¢alkyl Ci, or a group ¢(D-E) where an optional substitution may occur in the © including df group (D-E) on the carbon atom by one or more V; V8 is a cyano; or a hydroxy or a group ¢(D-E) where an optional >1 substitution in La V in which group EY (-05) may occur on the carbon atom by 1 or more W; A W and 7 are selected separately from cyano or from alkyl or talkoxy bitter 9 6 and JSK are selected separately from alkynyl Cog of ¢ alkenyl Cag J “alkyl Cig” 4 0 aryl calkyl Cr aryl or ic gana) heterocyclic group ( bitter alkyl ¢ 11 where an optional substitution may occur in the 6 and K atom carbon by © one or more VY; OY© is cyano; or hydroxy » or oxo 0x0 » or from «alkyl or Cag alkenyl » or from “alkoxy or from alkanoyl ¢ or alkanoyloxy Ci. ¢ . 3 - and 1 - C.¢alkoxycarbonylamino (anol.0) or amstam (abolol.0)- ramat or Yo ((D" -E") or + aryloxy group or aryl or aryl 10 on carbon atom (D7 - EV) where an optional substitution may occur in © including the VY group “adjusted”_ by one or more 7s; VA atoll; or Crs aryl da) or caryl each on Sharpness of 5D 000 © is removed and 4 ; where an optional substitution may occur in 0 heterocyclic group Yo by one or more 7'; and where if carbon contains a carbon atom DY, ©, 71, an optional substitution may occur NH- heterocyclic group mentioned on that YY Ke moiety by a group selected nitrogen for the YY nitrogen atom - or :0C(0)- or « -C(0)0- each separately from -0- or 87 SE and 8 and VE are selected from RY hydrogen where SO) or -0897(©)©- or <NRHC(0)-) is selected 0) or Yo zero one or more AT and F optionally substituted by an alkyl or bitter hydrogen - 7 0-?; VV ©. Or alkyl Cis that “hydroxy separately from the nitro or hydroxy JSF and 7 and YA are chosen or <alkanoylamino” or from “N,N-(Cy.salkyl),amino” or « alkanoyl or of « alkoxy ¢ 95 thereof acceptable amide or amide ester or a pharmaceutically acceptable salt thereof or ester « Cralkoxycarbonyl 0 for hydrolysis in the organism. 1 Nam where (1) compound has formula (1) according to claim 4 -1 and 8 is zero fluoro where 182 is fluoro (1) a compound of formula (1) according to claim 1)0 or add . is an adsorbent sid where 183 is (1) for the claimant Gy (1) a compound of formula -> 1 1 7- A compound of formula (1) according to claim (1) where p is zero. =A) is a compound of formula (1) according to claim (1), where: pyridin-4-yl, pyridin-3-yl, pyridin-2-yl, morpholin-4-yl, piperidin-4-yl, Y ring piperidin-3-yl, piperdin-2-yl , piperazin-4-yl, thiazol-2-yl, thien-2-yl, furan-3-yl, 1 pyrrolidin-1-yl, piperidin-1-yl, triazol-1-yl or 1°,2', 3",6'-tetrahydropyridin-4-yl ¢ nitrogen The nitrogen atom can optionally be substituted NH- on the A moiety and wherein 19 contained that ring 1 5 by a combination chosen from 0;1 1 ring B is thienyl ; or thiadiazolyl “or thiadiazolyl” or A pyrimidyl ; or pyridazinyl edna “rum” or pyridazinyl “or pyridyl 8 ¢ R' 0 is a substituent on a carbon atom chosen from a cyano or an 11-hydroxy ; or © alkyl or combination (0-8); Cus an optional substitution may occur in 8 including the VY group (D-E) on the carbon atom by one or more Vs; VY cyano « or hydroxy or Cua group (DEY) An optional Vg substitution may occur in V including group (D'- EY) on the carbon atom by W one or more ve; Waal and 7 are each done separately from cyano; or from alkyl “¢ or from calkoxy an VY choose 6 and 16 separately from alkenyl Cos of » alkyl Cg » that alkynyl C5 + or VA aryl calkyl Crs aryl or Ae gana) is an alkyl Cy (heterocyclic group ¢ 1) where an optional substitution may occur at 6 and 16 on the carbon atom by a single Q 4 0 more; SQ 11 cyano; or hydroxy + oxo 0X0a of alkyl « or Cig alkenyl YY ; or from alkoxy or alkanoyl bitter “or alkanoyloxy bitter” or YY the absorbent (Abu 0)-/N or “N,N-(C,.¢alkyl),carbamoy]l or C,.salkoxycarbonylamino J Ye aryl caryl or aryl oxy aryloxy; or {(D" -E") de sane TO where an optional substitution in © including the (D7 - EV) group may occur on the carbon 7 atom "knapped"_ by one or more 7s; YY ©, “0, and JSD are selected separately from a caryl ayl or a Cig aryl atole + or YA heterocyclic group; where optional substitution may occur in 0; YA and DT 5D on the carbon atom by one or more 7 ; Whereas, if said heterocyclic group 0 contains an NH- moiety, an optional substitution of 1) for that nitrogen atom by a group chosen from 1 may occur; YY and 8 and SE" SE are selected separately from -0- » or -0(0)©- « or -(0©)0-. or ¥v -g(y)e or ¥v NR)C(0)- or -0(71087)©-; or SO) where RP is selected from hydrogen 4 or alkyl Cig having an optional substitution by one or more 7 and # : is zero ¢Y—Yo©_and 1 and 7 are chosen separately from the nitro or hydroxy “that” alkyl Cr or Ci. alkoxy ¢ VV or min alkanoyl ¢ or “N-(C).alkyl)amino or calkanoylamino Cj or Ciealkoxycarbonyl YA ¢ am YA zero or 1 or oY where the values of a may be the same or different; £o a 5.58 fluoro ¢ anf) zero or 1; ey 3 is amino sud ¢ 4 YA - - RY is halo ¢ Ps $< is zero, 1, or 1l where values of rR? may be the same or different £0, a pharmaceutically acceptable salt thereof, or an ester SUG ate amide is hydrolyzed in vivo. 1 4- A process for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof or an ester of SUS ae amide Y for hydrolysis in the organism according to claim (1); this process 1 includes :; )( reaction of a compound of formula (IT) (RY), 0 X O RY), an 8 1 where cr is a group reacting with a compound of formula (Ir) (RH), 7 © p—L (11D) / 12 A where SL 1 are two associative groups; 4(b) A complex reaction of formula (IV). _ 1 7 3 _ and 02 L! 0 \ {om / N 1 L? H (IV) R3 (V) are associative groups; With a compound of formula 1 SLT where yy RY, © VY V) is a reactant; de gana is X where VY or 4 04 -(4,6-dimethoxy-1,3,5- triazinyl-2-yl)-4-methylmorpholinium (c) reaction in and presence 0 (VI); A compound with the formula chloride V1 X HN A H,N ®, VD 1 app Sa 1 _ VA with a compound of formula (VII) 4 RY, RY), (VII) 0. | Then if necessary: YY and or (Y) vy remove any protecting groups. 01-1 A pharmaceutical composition comprising a compound of formula (I) or an acceptable salt Liana thereof or an ester Y or an amide SUG 430 for hydrolysis in vivo according to claims (A-1 - in combination with a pharmaceutically acceptable diluent or carrier. (A -1) as a drug. YY = use of a compound of formula (1); or a pharmaceutically acceptable salt thereof or a fester ie amide Y hydrolyzable in the organism according to claims (A - 1) In the manufacture of a drug ¥ used to produce an inhibitory effect of HDAC in a warm-blooded animal Jie human. 1-1 Use of a compound of formula oI) or a pharmaceutically acceptable salt thereof or Jester amide SUS ie amide 7 for in vivo hydrolysis according to claims (A-1) in the manufacture of a drug? It is used in the treatment of cancer. ly for protective elements -1 (4) in the treatment of 3 cancer.