NZ617628B2 - 4-aryl-n-phenyl-1,3,5-triazin-2-amines containing a sulfoximine group - Google Patents

4-aryl-n-phenyl-1,3,5-triazin-2-amines containing a sulfoximine group Download PDF

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NZ617628B2
NZ617628B2 NZ617628A NZ61762812A NZ617628B2 NZ 617628 B2 NZ617628 B2 NZ 617628B2 NZ 617628 A NZ617628 A NZ 617628A NZ 61762812 A NZ61762812 A NZ 61762812A NZ 617628 B2 NZ617628 B2 NZ 617628B2
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group
phenyl
methyl
rac
triazin
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NZ617628A
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NZ617628A (en
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Rolf Bohlmann
Ulf Bomer
Mark Jean Gnoth
Dirk Kosemund
Philip Lienau
Ulrich Lucking
Gerd Ruhter
Arne Scholz
Carsten Schultzfademrecht
Gerhard Siemeister
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Bayer Intellectual Property Gmbh
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Priority claimed from EP11167317A external-priority patent/EP2527332A1/en
Application filed by Bayer Intellectual Property Gmbh filed Critical Bayer Intellectual Property Gmbh
Priority claimed from PCT/EP2012/059399 external-priority patent/WO2012160034A1/en
Publication of NZ617628A publication Critical patent/NZ617628A/en
Publication of NZ617628B2 publication Critical patent/NZ617628B2/en

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Abstract

Disclosed are 4-aryl-N-phenyl-1,3,5-triazin-2-amines containing a sulfoximine group of general formula (I) where the substituents are as described and defined herein for example 4-(4-Fluoro-2-methoxyphenyl)-N-{3-[(S-methylsulfonimidoyl)methyl]phenyl}-1,3,5-triazin-2-amine. Also disclosed are methods for their preparation and their use in the treatment and/or prophylaxis of disorders, in particular of hyper-proliferative disorders and/or virally induced infectious diseases and/or of cardiovascular diseases. The invention further relates to intermediate compounds useful in the preparation of said compounds of general formula (I). for their preparation and their use in the treatment and/or prophylaxis of disorders, in particular of hyper-proliferative disorders and/or virally induced infectious diseases and/or of cardiovascular diseases. The invention further relates to intermediate compounds useful in the preparation of said compounds of general formula (I).

Description

-N-phcnyl-1 ,3,5-triazinamines containing a sulfoximino group The t invention relates to 4—aryle—phenyl-l,3,5—triazin—2—amines ning a sulfoximine group of general formula (I) or (Ia) as described and defined herein, and methods for their preparation, their use for the ent and/or prophylaxis of disorders, in particular ofhyper-proliferative disorders and/or virally induced ious diseases and/or of cardiovascular diseases. The invention r relates to intermediate compounds useful in the preparation of said compounds of general a (I) or (Ia).
The family of —dependent kinase (CDK) proteins consists ofmembers that are key regulators of the cell division cycle (cell cycle CDK's), that are involved in regulation of gene transcription (transcriptional CDK‘s), and of members with other functions. CDKs require for activation the ation with a regulatory cyclin subunit. The cell cycle CDKs CDKI/cyclin B, CDKZ/cyclin A, CDK2/eyclinE, yciinD, and CDK6/cycliuD get activated in a sequential order to drive a cell into and through the cell on cycle. The transcriptional CDKs yclin T and CDK7/eyclin H regulate the activity of RNApolymerase ii via orylation of the carboxy—terminal domain (CTD).
Positive transcription factor b (P—TEFb) is a heterodimcr ofCDK9 and one of four cyclin partners, cyclin T] T22: or TZb. , eyelin K, eyelin Whereas CDK9 (NCBI GenBank Gene ID 1025) is exclusively involved in transcriptional regulation, CDK? in addition participates in cell cycle regulation as CDK-aetivating kinase (CAK).
Transcription of genes by RNA polymerase I] is initiated by assembly of the pro-initiation complex at the promoter region and phosphorylation of Set 5 and Ser 7 of the CTD by CDK'i/cyclin H. For a major fraction of genes RNA polymerase 11 stops itiRNA transcription after it moved 20-40 nucleotides along the DNA template. This promoter-proximal pausing of RNA polymerase ll is mediated by negative elongation factors and is recognized as a major control ism to regulate expression of rapidly induced genes in response to a variety of stimuli (Cho et al., Cell Cycle 2010, 9, 1697). P-TEFb is crucially involved in overcoming promoter-proximal pausing of RNA polymerase II and transition into a productive elongation state by phosphoryiation of Ser 2 of the CTD as well as by phosphorylatien and inactivation of negative elongation factors.
Activity of P-TEFb itself is regulated by several mechanisms. About half of cellular P-TEFb exists in an inactive complex with 78K small nuclear RNA (78K snRNA), La—relatcd protein 7 (LARP7/PIP7S) and hexamethylene bis-acetamide inducible proteins 1/2 (HEXlMl/Q, He ct al., Mol. Cell 2008, 29, 588).
The remaining half of P-TEFb exists in an active complex containing the bromodomain n Brd4 (Yang et al., Mol. Cell 2005, 19, 535). Brd4 recruits P-TEFb h interaction with acetylated ies to chromatin areas primed for gene transcription. Through alternately interacting with its positive and negative regulators, P-TEFb is maintained in a functional equilibrium: P-TEFb bound to the 78K snRNA complex represents a reservoir from which active P-TEFb can be released on demand of cellular transcription and cell proliferation (Zhou & Yik, Microbiol. Mol. Biol. Rev. 2006. 70, 646).
Furthermore, the activity of P-TEFb is regulated by posttranslational modifications including phosphorylation/dc-phosphorylation, ubiquitination, and acteylation (reviewed in Cho et al., Cell Cycle 2010, 9, 1697).
Deregulated activity of CDK9 kinase activity of the P-TEFb heterodimer is associated with a variety of human pathological gs such as hyper-proliferativc diseases (eg. cancer), virally induced infectious diseases or cardiovascular diseases.
Cancer is regarded as a ltyper-prolit‘erative disorder ed by a disbalance ofproliferation and cell l0 death (apoptosis). High levels of anti-apoptotic Bola-Family proteins are found in various human tumors and account for prolonged survival of tumor cells and therapy resistance. Inhibition of P—TEFb kinase activity was shOWn to reduce riptional activity of RNA polymerase 11 leading to a decline of short- lived anti-apoptotic proteins, especially Mel-l and XlAP, reinstalling the ability of tumor cells to undergo ap optosis. A number of other proteins associated with the transformed tumor ype (such as Mye, NF-kB responsive gene transcripts, mitotic kinases) are either short-lived proteins or are encoded by short-lived transcripts which are sensitive to reduced RNA polymerase II activity mediated by P- TEFb tion (reviewed in Wang & Fischer, Trends Pharmacol. Sci. 2008, 29, 302).
Many viruses rely on the transcriptional ery of the host cell For the transcription of their own within the viral genome. In case of HIV-1 RNA polymerase II gets recruited to the promoter region LTR‘s. The viral transcription activator (Tat) n binds to nascent viral transcripts and overcomes promoter—proximal RNA rase II pausing by recruitment of P-TEFb which in turn promotes transcriptional elongation. Furthermore, the Tat protein increases the fraction of active P-TEFb by ement of the P—TEFb inhibitory proteins HEXlMl/Z within the 73K snRNA complex. Recent data have shown that inhibition of the kinase activity of P-TEFb is sufficient to block HIV-1 replicticn at kinase inhibitor concentrations that. are not cytotoxic to the host cells (reviewed in Wang & Fischer, Trends Pharmacol. Sci. 2008, 29, 302). Similarly, recruitment of P-TEFb by viral ns has been reported for other viruses such as B-ccll cancer—associated Epstein-Barr virus, where the nuclear n EBNAZ protein interacts with P-TEFb (Bark-Jones ct al., Oncogene 2006. 25. 1775). and the human T» lymphotropic virus type 1 (HTLV—l), where the transcriptional activator Tax recruits P-TEFb (Zhou et al., J. Virol. 2006, 80, 4781).
Cardiac hypertrophy, the heart’s adaptive se to mechanical overload and pressure ynautic stress e.g. hypertension, myocardial infarction), can lead, on a long term, to heart failure and death. c hypertrophy was shown to be associated with increased transcriptional activity and RNA polymerase II CTD phosphorylation in cardiac muscle cells. P-TEFb was found to be activated by dissociation from the inactive 78K HEXlMl/Z complex. These s suggest cological inhibition of P-TEFb kinase activity as a therapeutic approach to treat cardiac hypertmphy (reviewed in Dey et al., Cell Cycle 2007, 6, 1356). in summary, multiple lines of evidence suggest that selective inhibition of the CDK9 kinase activity of the P-TEFb helerodimer (= CDK9 and one of four cyclin partners, cyclin T1, cyclin K, cyclin T2a or TZb) represents an innovative approach for the treatment of diseases such as cancer, viral diseases, and/or diseases of the heart. CDK9 s to a family of at least 13 closely related kinases ofwhich the subgroup of the cell cycle CDK's fulfills multiple roles in regulation of cell proliferation. Thus, co- inhibition of cell cycle CDK's (cg. yclin B, CDKZ/cyclin A, CDK2/cyclinE, CDK4/cyclinD, CDKG/cyclinD) and of CDK9 is expected to impact normal proliferating tissues such as intestinal mucosa, lymphatic and hematopoietic organs, and reproductive organs. To maximize the eutic margin of CDK9 kinase inhibitors, molecules with high selectivity towards CDK9 are therefore required.
CDK inhibitors in general as well as CDK9 inhibitors are described in a number ofdifferent publications: W02008129070 and W02008l290'7l both be 2‘4 disubstituted aminopytimidines as CDK inhibitors in general. It is also asserted that some of these compounds may act as selective CDK9 inhibitors (WOZOOSIZWHO) and as CDKS inhibitors 081290”), respectively, but no specific CDK‘) ICSO (Vt/02008129070) or CDKS IC50(W02008I2971) data is presented.
W02008129080 discloses 4,6 disubstitutcd aminopyrimidincs and demonstrates that these nds show an inhibitory effect on the protein kinase activity of various protein kinases. such as CDK], CDKZ, CDK4, CDKS, CDK6 and CDK9, with a preference for CDK9 inhibition (example 80). 5P1218360 Bl bes triazin derivatives as kinase tors, but does not disclose potent or ive CDK9 inhibitors.
W02008079933 discloses aminopyridine and aminopyrimidine derivatives and their use as CDKI, CDK2, CDKB, CDKtt. CDKS, CDK6, CDK7, CDK8 or CDK9 tors.
W02011012661 describes aminopyridine derivatives useful as CDK inhibitors.
Wang et a1. stry & Biology 2010, 17, 1111-11.21) desan'be 2-anilino(tltiazol—S-yl)pyrimidine transcriptional CDK inhibitors, which show anticancer activity in animal models.
W020040095 62 discloses substituted tn'azine kinase inhibitors. For selected compounds CDK1 and CDK 4 test data, but no CDK9 data is presented.
W02004072063 describes heteroaryl (pyrimidine, triazine) tuted pyrroles as inhibitors of protein kinascs such as ERK2, GSK3, PKA or CDK2.
W02010009155 discloses ne and pyrimidine derivatives as inhibitors of histone deacetylase and/or cyclin dependent kinases (CDKS). For selected compounds CDK2 test data is described.
WO200303 7346 (corresponding to US761896882, US729161682, USZOO8064700A1, U82003153570A1) relates to aryl triazines and uses thereof, including to inhibit lySOphOSphatidic acid acyltransferase beta (LPAAT—beta) activity and/or proliferation of cells such as tumor cells.
W02008025556 describes carbamoyl imides having a pyrimidine core, which are useful as kinase inhibitors. No CDK9 data is presented.
W02002066481 describes dine derivatives as cyclin ent kinase inhibitors CDK9 is not mentioned and no CDK9 data is presented.
W02008l09943 concerns phenyl aminopyri(mi)dine compounds and their use as kinase inhibitors, in particular as JAKZ kinase inhibitors. The specific es focus on compounds having a pyrimidine core.
W0200903286l describes substituted pyrimidinyl amines as JN'K kinase inhibitors. The specific es focus on compounds having a dine core.
WOZO] l046970 ns amino-pyrimidine compounds as inhibitors ofTBKL and/or IKK epsilon. The specific examples focus on compounds having a pyrimidine core.
Despite the fact that various inhibitors of CDK’S are known, there remains a need for selective CDK9 inhibitors to be used for the treatment of diseases such as hyper-proliferative diseases, viral diseases, and/or diseases of the heart, which offer one or more advantages over the compounds known from prior art, such as: ed activity and/or efficacy, beneficial kinase selectivity profile according to the respective eutic need, improved side effect , such as fewer undesired side effects, lower intensity of side effects, or reduced (cyto)toxicity, improved physicochemical properties, such as solubility in water and body 3S fluids, 5937934_1 (GHMallers) P95387.NZ KARENM 12/11/14 improved pharmacokinetic properties, allowing e.g. for dose reduction or an easier dosing scheme.
A particular aim of the invention is to provide CDK9 kinase inhibitors which, compared to the compounds known from prior art, show an increased solubility in water.
A particular aim of the invention is to provide CDK9 kinase inhibitors which, ed to the compounds known from prior art, show an increased ivity for CDK9/Cyclin Tl as ed to yc1in E.
Another aim of the invention is to provide CDK9 kinase inhibitors which show an increased potency to inhibit CDK9 activity (demonstrated by a lower IC50 value for CDK9/Cyc T 1) compared to the compounds known from prior art.
Another aim of the invention is to provide CDK9 kinase inhibitors, which show an improved anti-proliferative activity in one or more of certain tumor cell lines such as for example HeLa or DUl45 compared to the compounds known from prior art.
Another aim of the ion is to provide CDK9 kinase inhibitors, which show an improved side effect e such as a reduced carbonic anhydrase-l and —2 inhibition compared to the compounds known from prior art.
Further, it is also an aim of the present invention to provide CDK9 kinase tors, which, compared to the compounds known from prior art, show an increased solubility in water and/or which are highly selective for CDK9/Cyclin Tl as compared to CDKZ/Cyclin E, and/or which show an increased potency to inhibit CDK9 activity (demonstrated by a lower iCSO value for CDK9/Cyc TI) and/or which Show an improved anti-proiiferative activity in one or more of certain tumor cell lines such as HeLa or DU145. 3O The above aims of the invention are to be read disjunctively with the aim of at least ing the public with a useful alternative.
The present invention relates to compounds of general formula (I) 5937934_1 (GHMauers) P95387iNZ KARENM 12111114 R‘L- N\\ //0 A Nl N R1/s {TIANAR2 or of general formula (Ia) RLN\\ I; j:§N RV I?! N/ R2 (Ia) wherein represents a group selected from alkyl-, C3-C7-cycloalkyl-, heterocyclyl~, phenyl, aryl, pheriyl-Ci-Cyalkyl- or heteroaryl-Cl-Cg—alkyl, wherein said group is optionally substituted with one or two or three substituents, identically or differently, selected from the group consisting of hydroxy, cyano, halogen, halo-Cl-Cg-alkyl-, C1-C6-aikoxy~, Cng- fluoroalkoxy-, amino, alkylamino-, dialkylamino—, acetylamino-, N-methyl-N- acetylamino-, cyclic amines; represents a group selected from 5937934_1 lers) P95387.NZ KARENM 12/11/14 8 8 8 8 /R /R ,R /R \ N \ \ R6 R6 R6 I R6 R7 R7 R7 R7 fi aF o 0 R6 R6 R6 R6 R7 R7 R7 7 0 '\ o o R6 R6 R6 R7 R7 R7 R“. R4 represent, independently from each other, a group selected from a hydrogen atom, fluoro atom, chloro atom, cyano, Cr~Ca-alkyl-, Cr-Ca-alkoxy-, halo-Ct'Ca—atkylg Ctvca—fluoroalkoxyg R5 represents a group selected fi'om a hydrogen atom, cyzmo, -C(O)R9, -C(O)OR°, -S(O)3R9, - C(O)NR1°R”, C1-C5-all<yl-, C3—C7-cycloalkyl-, heteroeycyl-, l, heteroaryl wherein said C1-Cs-alkyl, C3—Cy-cyclualkyl—, heteroeyeyl-, phenyl or heteroaryl group is ally substituted with one, two or three tuents, identically or differently, selected fl‘om halogen, hydroxy, cyano, C1~C3-all<yl-, CI-Cg-alkoxy-, amino, alkylamino-, diallcylamino-, acctylamino~, N—mcthyI-N-aectylamino-, cyclic amines, halo-C l-Cg—alkyl-, C 1—C3—fluoroail<oxy-; R6 R’ represent, independently from each other, a group selected from a hydrogen atom, tluoro atom, chloro atom, cyano, alkyl—, alkoxy-, halo-Cr-Cg-alkyL, fluoroalkoxy—; R3 represents a group selected from a) a Cr-C o-alkyl group, which is optionally substituted with one or two or three substituents, identically or differently, selected from the group consisting of halogen, ltydroxy,amino, atl<ylamino-, lamino-, acctylamino-, N-inetliyl-i\'-acetylamino-, cyclic amines, cyano, Cl-Cg-alkyl-, halo-Ct-Cg-alkyl-, Ci-Ca—fluoroalkoxy—, C1-C3-alkoxy~, Cg—Cg-alkcnyl-, C3-C3-alky1‘lyi-, C3-C7-cycloalkyl-, heterocycyl-, phenyl, ltctcroaryl, wherein said C3-C7-cycloalkyl-, heterocycyl-,plic11yl or heteroaryl group is optionally substituted with one, two or three substitoents, identically or differently, selected from halogen, liydroxy. cyano, C;-C;—alkyl~, C.~Cz-alkoxy-,amino, alkylamino—, dialkylamino-, acetylamino-, N~methyl—N—ncetylamino~, cyclic amines, r—Cs-alkyl-, "fluoronlkoxy—; b) a C3~C7-cycioalkyl- group, which is optionally substituted with one or two or three substituents, identically or differently. selected from the group consisting gen. hydroxy, amino, alkylamino-, dialkylainino-, acetylamino—, N—methyl-N—acetylamino-, cyclic amines, cyano, C1-C3-alkyl-, Ci-Cs-alkyl-, Cl-Cs-fiuoroalkoxy-, C1-C3-alkoxy-, alicenyl-, C2-C3-alkynyl-; e) a heteroeyclyl-group, which is optionally substituted with one or two or three substituems, identicaliy or ently, ed from the group consisting of halogen, hydroxy, amino, alkylamino-, dialkylamino-, acetylamino-, N-methyl-N—acetylamino-, cyclic amines, cyano. Ci~C3-all<yI-. halo-Ci—C3-allcyl-. C1-Cg-fluoroalkoxy-, C1-Cs-alkoxy-, C2-C3-alkcnyl-, C2-C3—alkynyl-; cl) a phenyi group, which is optionally substituted with one or two or three substituents, identically or dift‘erentiy, selected from the group consisting of halogen, hydroxy, amino, alkylamino-, diulkylamino—, amino-, N-methyl-N-acety1amino-, cyclic amines, cyano, C1-C3—alkyt-, halo-Cr-Ca-alkyL, C1—C3-fluoroa1koxy-, C1-Cg-alkoxy«; c) a heteroaryl group, which is optionally substituted with one or two or three substitucnts, identically or differently, selected from the group consisting ofhalogen, hydroxy,amino, alkylamino-, dialkylamino-, acetylamino-, N-methyl-N-acetyIamino-. cyclic amines, cyano, C1—C3-alkyl-, halo-Ci—Cg—alkyI—, Cr-Ca—fluoroamoxy—, Ci-Cg-alkoxy—; t) a -Ca-Ci-allq'l— group, which is optionally substituted with one or two or three tuents, identically or differently, selected from the group consisting ofhalogen, hydroxy, amino, alkylamino-, dialkylamino—, acetylamino-, N-methyl—N~acetyla1nino-, cyclic amines, cyano, Ci-Cg-alkyl-, Ct-C3~all<yl—, fluoroalkoxy—, C1»C3-all<oxy-; g) a lieteroaryl—Ct-C3~alkyl- group, which is Optionally substituted with one or two or three substituents, identically or differently, ed from the group consisting of halogen, hydroxy, amino, alkyiamino-, dialkylamino-, acetylamino—, N-methyI—N-acetylamino-, cyclic amines, cyano, Cl—Ca-alkyl—, halo-Cl-Cg-alkyl-, C1-C3-fluoroalkoxyg C1-C3-alkoxy—; R9 ents a group selected from Ci-Cs—alkyl—, C3-C7-cycloalkyl-, heterocycyl-, phenyl, benzyl or heteroaryl wherein said group is optionally substituted with one, two or three substituents, cally or difi‘crently, selected from halogen, hydroxy, Cl-Cg-alkyl-, CI‘CS" -, amino, alkylamino-, dialkylamino-, acetylamino-, N-methyl-N—acetylamino-, cyclic , ha Io-Cl-Cg-alkyL, C1—C3—fluoroa lkoxy—; R”, R” represent. independently fi'om each other. a group selected from hydrogen, C1-Cfi-a1kyl-, C1- Cv-cycloalkyh, heterocycyl-, phenyl or heteroaryl wherein said Ci—Cs-alkyl, C3-C7- cycloalkyl—, heterocycyl-, phenyl or heteroaryl group is optionally substituted with One, two or three substituents, identically or ently, selected from halogen, hydroxy, C1-C3-all<yl—. C1-C3-alkoxy-,amino, alkylarnino-, dialkylamino-. acetylamino—, N—methyl-N— acetylamino-, cyclic amines , halo-CrCi—alkyl—, Ci-Cs-fluoroamoxy~; or their salts, solvates or salts of solvates.
Compounds according to the invention are the compounds of the formula (I) or (In) or ([b) and the salts, solvates and solvates of the salts thereof, the compounds of the hereinafter recited formula which are encompassed by formula (I) or (Ia) or (lb) and the salts, solvatcs and solvates of the salts thereof, and the compounds which are encompassed by formula (I) or (Ia) or (Ib) and which are ned hereinafter as exemplary embodiments and the salts, solvates and solvates ofthe salts thereof, where the compounds which are encompassed by formula (I) or (In) or (lb) and are mentioned hereinafter are not already salts, solvates and solvates ofthe salts.
The compounds according to the invention may, depending on their structure, exist in stereoiSOmeric forms (enantiomers, diastereomers). The invention therefore relates to the enantiomers or diastereorners and respective mixtures f. The isomerically pure constituents can be isolated in a known manner from such mixtures ntiomers and/or diastcreomcrs.
If the compounds according to the invention can be in tautomeric forms, the present invention encompasses all tautomeric forms.
Further, the compounds of the present ion can exist in free form, eg. as a free base, or as a free acid, or as a zwitterlon, or can exist in the form of a salt. Said salt may be any salt, either an organic or inorganic on salt, ularly any logically acceptable organic or nic addition salt, customarily used in pharmacy.
Salts which are preferred for the purposes of the present invention are physiologically acceptable salts of the compounds according to the invention. However, salts which are not suitable for pharmaceutical applications per se, but which, for example, can be used for the isolation or purification of the compounds according to the invention, are also comprised.
The term “physiologically acceptable salt" refers to a relatively non-toxic, inorganic or organic acid addition salt of a compound of the t invention, for example, see 5. M. Berge, et a1. aceutical Salts,“ J. Pharm. Sci. 1977, 66, l-l9.
Physiologically acceptable salts of the nds according to the invention encompass acid addition salts of mineral acids, ylic acids and sulfonie acids, for e salts of hydrochloric acid, hydrobromic acid, hydroiodic, sulfuric acid. bisulfuric acid, phosphoric acid, nitric acid or with an organic acid, such as , acetic, cetic, pyruvic, trifluoroacctic, propionic, butyric, hexanoic, heptanoic, undecanoic, lauric, benzoie, salicylic, 2-(4-hydroxybenzoyl)-benzoie, eamphoric, cinnamie, cyclopentanepropionic, digluconie, 3-hydroxynaphthoic, nicotinic, pamoie, pectinic, persulfuric, 3- phenylpropionic, picric, pivalic, 2-hydroxycthanesulfonate, itaconic, sulfamic, trifluorotnethanesulfonic, dodecylsulfuric, ethansulfonic, benzenesulfonic, para-toluenesulfonic, methansulfonic, 2- naphthalenesulfonic, naphthalinedisulfonic, rsulfonic acid, citric, ic, stearic, lactic, oxalic, malonic, ic, malic, adipic, o, maieic, finnaric, D-gluconic, inandelic, ascorbic, glucoheptanoic, glycerophosphoric, aspartic, alicylie, hemisulfiurie, or thiocyanic acid, for e.
Physiologically acceptable salts of the compounds according to the invention also comprise salts of conventional bases, such as, by way of example and by preference, alkali metal salts (for example sodium and potassium salts), alkaline earth metal salts (for example calcium and magnesium salts) and ammonium salts derived from ammonia or organic amines with l to 16 C atoms, such as, by way of example and by preference, cthylamine, diethylamine, triethylamine, ethyldiisopropylamine, monocthanolaminc, diethanolaminc, anolamine, dicyclohcxylamine, dimcthylaminoethanol, procaine, ylaminc, N-mcthylmorpholine, arginine, lysine, ethylenediamine, N-methylpiperidine, N—methylglucamine, dimethylglucamine, ethylglueamine, 1,6-hcxadiamine, glueosamiue, ine, l, Iris(hydroxymethyl)aminomethane, aminopropanediol, Sovak base, and I-amino-2,3,4’ butanelriol. Additionally, basic nitrogen containing, groups may be quaternised with such agents as lower alkylhalides such as methyh -, propyl—, and butylchlorides, -bromides and -ioditles ; (lialkylsulfates like diinethyl-, dietliy1-, dibutyl- and diamylsulfates, long chain halides such as deey1-, lauryl—, myristyl- and stcarylchloridcs, -bromides and —iodidcs, aralkylhalidcs like benzyl- and phonethylbromidcs and others.
The present ion includes all possible salts of the compounds of the present invention as single salts, or as any mixture of said salts, in any ratio.
Solvates is the term used for the purposes of the invention for these forms of the compounds according to the invention which form a complex with solvent molecules by coordination in the solid or liquid state.
Hydrates are a special form of sch/ates in which the coordination takes place with water. Hydrates are preferred as solvates within the scope of the present invention.
The invention also includes all suitable isotopic variations of a compound of the invention. An isotopic variation of a compound of the invention is defined as one in which at least one atom is ed by an atom having the same atomic number but an atomic mass ent from the atomic mass usually or predominantly found in nature. Examples of' isotopes that can be incorporated into a nd of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, bromine and iodine, such as 2H (deuterium), 3H (tritium), 13c, l“c, lsN, I70, ”‘0, 329,331), 333, 3“s, ”s. 36S, mF, mCl, ”Br, ”31, ’“I, 12"I and ”'1, respectively. Certain isotopic variations of a nd of the invention, for example, those in which one or more radioactive isotopes such as 3H or l4C are incorporated. are useful in drug and/or substrate tissue distribution studies. 'I‘n'tiated and carbon-l4. i.c., :‘C, isotopes are particularly preferred for their case of preparation and detectability. Further, substitution with isotopes such as deuterium may afford certain eutic ages resulting from greater metabolic stability, for example, sed in vivo half-life or reduced dosage requirements and hence of the invention may be preferred in some circumstances. Isotopic variations of a compound can lly be prepared by conventional procedures known by a person skilled in the art such as by the l5 illustrative methods or by the preparations described in the examples ter using appropriate isotopic variations of suitable reagents.
In addition, the present invention also encompasses prodrugs of the compounds according to the invention. The term “prodi'ugs” encompasses compounds which themselves may be biologically active or inactive, but are converted (for example by metabolism or hydrolysis) to compounds according to the invention during their residence time in the body.
For the purposes of the present invention, the substitucnts have the ing meaning, unless otherwise The term “halogen”, “halogen atom” or “halo” represents fluorine, chlorine, bromine and iodine, particularly chlorine or fluorine, ably fluorine atoms.
The term “alkyl” represents a linear or branched alkyl radical having the number of carbon atoms specifically indicated, c.g. Ci-Cio one, two, three, four, five, six, seven, eight, nine or ten carbon atoms, cg methyl, ethyl, n-propyl, isopropyl, l, isobutyl, sec-butyl, tert—butyl, pentyl, tyl, hexyl, heptyl, octyl, nonyl-, decyl-, 2-methylbutyl, l-methylbutyl, l-ethylpropyl, methylpropyl, neo— pentyl, 1,1-dimethylpropyl, 4—mothylpentyl, 3—methylpentyl, 2-methylpentyl, l—mcthylpcntyl, 2- ethylbutyl, I—ethylbutyl, 3,3—dimethylbutyl, 2,2-dirnethylbutyl, 1,1-dimethylbutyl, 2,3-dimethylbutyl, l,3-dimethylbutyl, or methylbutyl. If the number of carbon atoms is not specifically indicated the term “alkyl” represents a linear or branched alkyl radical having, as a rule, 1 to 9, particularly 1 to 6, preferably 1 to 4 carbon atoms. Particularly. the alkyl group has 1, 2, 3, 4, 5 or 6 carbon alums (“CerG— alkyi”), e.g. methyl, ethyl, n-propyl-, isopropyl, n-butyl, tert-butyi, pentyl, isopentyl, hexyl, 2— methylbutyl, l-ntcthylbutyl, l-ctliylpropyl, 1,2—dimetliylpropyl, ntyl, 1,1-dimethylpropyl, 4- pentyl, 3-methylpentyl, 2-mcthylpenty1, l—methylpentyl, ylbutyl, l-ethylbutyl, 3,3- dimethylbutyl” 2,2-diinethylbutyl, 1,1-dimethylbutyl, 2,3-dimethylbutyl, 1,3-di1nethylbutyl, or 1,2- dimethylbutyl. Preferably, the alkyl group has 1, 2 or 3 carbon atoms ("Ci-Ca-alkyl”), methyl, ethyl, n» propyl or isopropyl.
The term -alkenyl" is to be tood as preferably meaning a linear or branched, monovalent hydrocarbon group, which contains one double bond, and which has 2 or 3 carbon atoms (“C2—C3- aikenyl”). Said l group is, for example. a vinyl, aliyl, (E)—2-methyivinyi, (Z)-2—methylvinyl or isopropeuyl group.
The term “Cz-Cg—alkynyl” is to be understood as preferably meaning a linear, monovaient hydrocarbon group which contains one triple bond, and which contains 2 or 3 carbon atoms. Said C2-C3-alkynyl group is, for example, ethynyl, prop-l-ynyl or prova-ynyl group.
The term “C3-C7-cycloalkyl” is to be understood as ably meaning a saturated, monovalcnt, monocyclic hydrocarbon ring which contains 3, 4, 5, 6 or 7 carbon atoms. Said C3-C1-cycloalkyl group is for example, a inonocyclic arbon ring, c.g. a cyclopropyl, oyclobutyl, cy010pcntyl, cyclohcxyl or cycloheptyl group. Said cycloalkyl ring can optionally contain one or more double bonds cg. cycloalkenyl, such as a cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl or cycloheptenyl group, wherein the bond n said ring with the rest of the molecule may be to any carbon atom said ring, be it saturated or unsaturated. Preferably the “C3-C7-Cycloalkyl” is a cyclopropyl group.
The term “heterocyclyi” is to be understood as meaning a saturated or partially unsaturated, monovalent, mono- or bicyclic hydrocarbon ring which contains 3, 4, 5, 6, 7, 8 or 9 carbon atoms and further ning 1, 2 or 3 heteroatom-containing groups selected From oxygen, sulfur, nitrogen. Particularly, the term “heterocyclyl” is to be understood as meaning a “4- to lO-membered heterocyclic ring“.
The term a “4- to lO—membered heterocyclic ring" is to be understood as meaning a saturated or partially unsaturated, munovalem, mono- or bicyclic hydrocarbon ring which contains 3, 4, 5, 6. 7, 8 or 9 carbon atoms, and further containing 1, 2 or 3 heteroatorn—eoutaining groups selected from oxygen, sulfiir1 nitrogen. Said heterocyclic ring is for example, a monocyclic heterocyclie ring such as an oxatanyl, czctidinyl, ydrofuranyl, idinyl, oxolanyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, l,4-dioxanyl, pyrrolinyl, tetrahydropyranyl, pipcridinyl, morpholinyl, 1,3-dithianyl, thiomorpholinyl, piperazinyl, or chinuclidinyl group. Optionally, said heterocyclclie ring can contain one or more double bonds, e.g. 4H-pyranyl, 2H-pyranyl, 2,5-dihydro-ll-l-pyrrolyl, oxolyl, 4H—],3,4- azinyl. 2,5-dihydrofi1ranyl, 2,3—dihydrofuranyl, 2,5-dihydrothienyl, hydrothienyl, 4,5— ooxazolyl, 4,5-dihydrcisoxazolyl, or 4H-l,4-thiazinyl group, or. it may be benzo fused.
Particularly, the term “heterocyclyl” is to be tood as being a heterocyclic ring which contains 3, 4 or 5 carbon atoms, and i, 2 or 3 of the above-mentioned heteroatom-containing groups (a “4- to 7- 1ne1nbercd heterocyclic ring“), more ulariy said ring can contain 4 or 5 carbon atoms, and 1, 2 or 3 of the above—mentioned heteroatom-containing groups (a “5 to 7-membered cyclic ring"), more particularly said heterocyclic ring is a “6-membcred heterocyclic ring", which is to be understood as containing 4 carbon atoms and 2 of the above-mentioned heteroatom-eontaining groups or 5 carbon atoms and one of the above-mentioned atom-containing groups, preferably 4 carbon atoms and 2 of the above—mentioned heteroatom-containing groups.
The term “Ci-Ca-alkoxy-“ is to be tood as preferably meaning a linear or branched, saturated, monovalent, hydrocarbon group of formula ~0—alkyl, in which the term “alkyl” is defined supra, eg. a methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, iso-butoxy, tert—butoxy, sec—butcxy, pentyloxy, iso— pentyloxy, n—hexyloxy group, or an isomer thereof. Particularly, the “Ci-Ca-alkony’ group is a “Cl-C4- alkoxy—”, a “C1-C3-alkoxy-”, a methoxy, ethoxy, or propoxy group, preferably a Inethoxy, ethoxy or propoxy group.
The term ,,Cl-C3-fluoroalkoxy-“ is to be understood as preferably meaning a linear or branched, saturated, monovalent, C i-Cg—alkoxy- group, as defined supra, in which one or more of the hydrogen atoms is replaced, identically or differently, by one or more fluoro atoms. Said C1-Ca-fluoroalkoxy- is, for example a l,1-dilluoromethoxy—, a l,1,l-trifluoromethoxy-, a 2—fluoroethoxy-, a 3- group fluoropropoxy-, a 2,2,2-nifluoroethoxy—, a 3,3,3-trifluoropropoxy- particularly a “Ci—C2~fluoroalkoxy-" group.
The term ,,alkylamino-“ is to be tood as preferably meaning an alkylamino group with a linear or branched alkyl group as defined supra. )~alkylamino- for example means a kylamino group with I, 2 oder 3 carbon atoms, (C1-Ce)-alkylamino- with l, 2, 3, 4, S or 6 carbon atoms. The term “alkylaininow” comprises for example methylamino-, cthylamino-, n-propylamiuo-, isopropylamiuo-, butylamino-, n-pentylamino- or lamlno~.
The term ,,dialkylamino-“ is to erstood as preferably meaning an alkylemino group having two linear or branched alkyl groups as defined supra, which are independent from each other. (Ci—Cs)- lamino— for e represents a dialkylamino group with Mo alkyl groups each of them having 1 to 3 carbon atoms per alkyl group. The term “diall<ylan1ino~” comprises for example: N,N— Dimethylamino-, N thylaniinog N—EthyI—N—mcthylamino-, yl-N-n-propylamino—, N- Isopropyl-N-n—propylamino-, N-t-Butyl—N-methylamino-, N—Elhyl-N-n-pentylamino- und N~n~Hexyl-N- methylamino-.
The term “cyclic amine” is to be understood as ably meaning a cyclic amine group. Suitable cyclic amines are (specially azetidine, pyrrolidine, piperidine, piperazine, l-methylpiperazlne, morpholine, thiomorpholine, which could be optionally substituted by one or two methyl groups.
The term “halo-Cl—Ca-aikyl‘” is to be understood as preferably meaning a linear or branched, saturated, monovalent hydrocarbon grOUp in which the term “C i-C3—alkyl” is defined supra, and in which one or more en atoms is replaced by a n atom, identically or differently, i.e. one halogen atom being independent from another. Particularly, said halogen atom is fluorine. Preferred is fluoro—Cr-C-g— alkyl such as for example-C133, ~CHF2, -CH2F, -CF2CF3, or -CH2CF3. Said lialo-Ct-Cg-alkyl- group is, for example, a halo-Cl—Cz-alkyl- group, —CF3, -Cl-lF2, -Cl-l2F, -CF2CF3, or -CH2CF3, preferably it is —CF3.
The term “phenyl-Cl-Cg-alkyI-“ is to be understood as preferably meaning a phenyl group, in which one of the hydrogen atoms is replaced by a C1-C3-alkyl group, as defined supra, that links the pllcnyl-Cng- alkyl- group to the molecule. Particularly, the “plienyl-C1-C:.-a.lkyl-" is a phenyl~Ct~C2-alkyl—, ably a benzyl- group.
The term “heteroaryi” is to be understood as preferably meaning a rnonovalent. aromatic, mono— or bicyclie aromatic ring system having 5, 6, ’7, 8, 9, 10, ll, 12, 13 or 14 ring atoms (a “5- to l4-membered heteroaryl” group), particularly 5 (a “5»membered heteroaryl”) or 6 (a “6-1nemberedheteroaryl”) or 9 (a “9'membcred aryl”) or 10 ring atoms (a “10~membcrcd oaryl”), and which contains at least one heteroatom which may be identical or different, said heteroatom being such as , en or sulfur, and can be monocyclic, bicyclie, or lic, and in addition in each case can be benze- condensed. Particularly, heteroaryl is selected fiom thicnyl, furanyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, tetrazolyl etc., and benzo derivatives thereof, such as, for example, benzofuranyi, benzothienyl, benzoxazolyl, benzisoxazolyl, benzimidazolyl, benzotriazolyl, indazolyl, indolyl. isoindoiyl. etc.; or pyridyl, pyridazinyl, pyrimidinyl, pyraziuyl, lriazinyl, etc, and benzo tives thereof, such as, for example, quinolinyl, quinazolinyl, isoquinolinyl, etc.; or azocinyl, indolizinyl, purinyl, etc., and benzo derivatives thereof; or cinnolinyl, phtlialazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, ptcridinyl, olyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, xanthcnyl, or oxepinyl, nzodioxanyl etc.
Preferably, hctcroaryl is selected from monocyclie ltcteroaryl, 5- ed heteroaryl or 6- nicmbcrcd heteroaryl.
The term “5-membered heteroaryl” is understood as preferably meaning a Inonovalent, aromatic, mono- aromatic ring system having 5 ring atoms and which contains at least one hetero-atom which may be identical or ent, said heteroalom being such as , nitrogen or sulfiir. Particularly, “S meinbered heteroaryl” is selected from l, furanyl, pyrrolyl, yl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, tetrazolyl.
The term “6—membered heteroaryl” is understood as preferably meaning a monovalent, aromatic, mono- aromatic ring system having 6 ring atoms and which contains at least one heteroatom which may be identical or different, said heteroalom being such as oxygen, en or sulfur. Particularly, “6 membered heteroaryl” is selected from l, pyridazinyl, pyrimidinyl, nyl, triazinyl.
The term oaryl-C-_-C3—alkyl-" is to be understood as preferably meaning a heleroaryl, a 5- membered heteroaryl or a 6~ membercd heteroaryl group, each as defined supra in which one of the hydrogen atoms is ed by a C1—C3-alkyl group, as defined supra, that links the heteroaryl-Ci-Ca- alkyl- group to the molecule. ularly, the "heteroaryl-C1-C3-alkyl-“ is a heteroaryl—Cl—Cz—amyh, a pyridinyl~C]-C3-alkyl-, a pyridinylniethyl-, a pyridinyletliyl—, a pyridinylpropyl—, —a pyriinidinyl-Cl-Cg— a1kyl-, a pyrimidinylmethyi-, a pyrimidinylethyl-, a pyrintidinylpropyl-, preferably a pyridinylrnethyl- or a pyridinyiethyl- or a dinylethyl— or a pyrimidinyipropyl- group.
The term 0”, as used throughout this text, e.g. in the context of the ion of “C1-C1o—alkyl” is to be understood as meaning an alkyl group having a finite number of carbon atoms of l to 10, i.e. l, 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms. It is to be understood further that said term “C1-C1o” is to be interpreted as any sub-range comprised therein, cg. C1~Cm, C1-C9, C1-C3 , C1-C7 , C1-C5 C1-C5. C1-C4, C1-C3, C1-C2, C2-Cto, C2-C9, C2-C3, C2-C7, C2-C5, C2-C5, C2-C4, C2-C3, C3—Cte, C3-C9, C3-C8, C3-C7, C3- C6, C3-C5, C3-C4, C4-Clo, C4-C9, C4-C3, C4-C1, C4-C0, C4-C5, CS'CIO, C5-C9, C5-C3, C5-C7, C5-C6, C6-Cm, C6‘C9. C6“CS, C5-C7, C7-Cto, C7-C9. C7-C8, . C8-C9. C9-Cio.
Similarly, as used herein, the term “Ct-Ca”, as used throughout this text, cg. in the context of the definition of “C1-CG-alkyl”, “Cl-Cg-alkoxy” is to be understood as meaning an alkyl group having a finite number of carbon atoms of l to 6, i.e. l, 2, 3, 4, 5 or 6 carbon atoms. It is to be understood further that said term “C 1-Cr1” is to be interpreted as any sub-range comprised therein, 6. g. C1-C6 Cr-C<, C1-C4, C1-C2, C1-C2, C2-C6, C2-C5, C2-C4, C2-C3, C3-C6, C3-C5, C3-C4, C4-C6, C4-C5, CS'Cé.
Similarly, as used herein, the term “C1-C3", as used throughout this text, eg. in the context of the definition of “C1-C3-alkyl”, “C1~C3—ali<oxy” or “C1-C3-tluoroaikoxY’ is to be understood as meaning an alkyl group having a finite number of carbon atoms of 1 to 3, Le. l, 2 or 3 carbon atoms. It is to be understood further that said term “C1—C3” is to be interpreted as any nge comprised therein, e.g. C1~ C3, Cl-Cz, C2-C3.
Further, as used herein, the term “Cg-Cr”, as used throughout this text, eg. in the context of the definition of “C3—C7-cyeloalkyl”, is to be tood as meaning a cycloalkyl group having a finite number of carbon atoms of 3 to 7, La. 3, 4, 5, 6 or 7 carbon atoms, particularly 3, 4, 5 or 6 carbon atoms. It is to be understood further that said term “C3-C7" is to be interpreted as any sub—range comprised therein, 6. g. C3- C7 , C3-C6 , C3-C5 , C3-C4 , C4—C7 , C4-C6 , C4-C5, C5-C7, C5-C5, C6-C7.
A symbol / at a bond s the linkage site in the molecule.
As used herein, the term “one or more , e.g. in the definition of the tuents of the compounds of the general formulae of the present invention, is understood as meaning one, two, three, four or five times, particularly one, two, three or four times, more particularly one, two or three times, even more particularly one or two times.
Where the plural form of the word nds, salts, hydrates, solvates and the like, is used herein, this is taken to mean also a single compound, salt, isomer, hydrate, solvate or the like.
The t ion relates to nds of general formula (I) or (Ia), wherein R1 represents a group selected from C1-C0-alkyl-, C3-C7-cycloalkyl- or heterocyclyl-; R2 represents a group selected from 0 fl R" R6 R8 R7 R7 7 R6 R6 R7 R7 113.11“ represent, independently from each other, a group selected from a hydrogen atom. fluoro atom, chloro atom or C1—C3-alkyl-; R5 represents a group selected from a hydrogen atom, cyano, -C(O)R9, ~C(O)OR9, -S(O)2R9, -C(O)NR"’R”, alkyl—g R6 R7 represent, independently from each other. a group selected from a hydrogen atom, fluoro atom, chloro atom; to Rs represents a group selected from a) a Cr—C_o-alkyl group, which is optionally substituted with one or two or three substituents, selected from the grorlp consisting of halogen, hydroxy, Cz-Ca-alkenyl-, C2~C3-alkynyl-, C3-C7—cycloalkyl-, heterocycylw, phenyl, heteroaryl, wherein said C3—C7-cycloalkyl—. heterocycyl-, phenyl or heterouryl group is optionally substituted with one, two or three substituenrs, identically or differently, selected from halogen, cynno, CI—Cx-alkyI-, halo-C;-C3-alkyl-; b) a phenyl group; c) a phenyl-Ci-Cz-alkyl- group, which phenyl group is optionally substituted with one or two or three tuents, identically or differently, selected from the group consisting of halogen, cyano, Cl~Cz-all\'yl—. halo-Cl-Cz-alkyl-; d) a heteroaryl—Cth—alkyl- group, which heteroaiyl group is ally substituted with one substituent selected from the group consisting of halogen; R9 represents a C1-C5~alkyl group; R”, R“ represent, independently from each other, a group selected from hydrogen or Ct-Ce-alkyl-; or their salts, solvatcs or salts of cs.
In a preferred embodiment the present invention s to compounds of general formula (I) or (Ia), wherein R‘ represents a Cr-Co-alkyh or C3—C7-cycloalkyl- group; R2 represents a group selected from / o/fi R6 R8 R6 R7 R7 R7 R3, R“ represent, independently from each other, a group selected from a hydrogen atom, fluoro atom, chloro atom, C1-C3-alkyl-; R5 represents a group selected from a hydrogen atom, cyano, -C(O)R9, -C(O)OR9, -C(O)NR1°R“; R“, R7 represent, independently from each other, a hydrogen atom or fluoro atom; R’1 represents a group selected from a) a Ct'C.0-81kyi group, which is ally substituted with one or two substituents. ed from the group consisting ofhydroxy, Cg-Cg-alkcnyl-, alkynyl-, C3-C7-cycloalltyl~, phenyl, heteroatyl, wherein said C3-C7-cycloalkyl-, phenyl or heteroaryl group is optionally tuted with one. two or three substituents, identically or differently, selected from halogen, cyano, halo-Cl-Cs-alkyl-; b) a phenyl-C t-Ca-alkyl- group, which phenyl group is optionally substituted with one or two or three substituents, identically or difi‘erently, selected from the group consisting of halogen, cyano, halo-C 1—C3~alkyl-; c) a heteroaiyl-Cl—Cg-allq'l- group, which aryl group is optionally substituted with one substituent selected from the group consisting of halogen; R9 represents a C1-Cs-alkyl group; R‘“, R” represent, ndently from each other, a group selected from hydrogen or Cr-Co-aIkyL; or their salts, solvatcs or salts of solvntes.
In another preferred embodiment the present invention relates to compounds of general formula (I) or (Ia), wherein R' represents a C1-C6-alkyl- group; l 2 represents a group selected from o’R8 R7 .
R3 represents a hydrogen atom; R“ ents a hydrogen atom; R5 represents a group selected from a en atom, cyano group or -C(O)NR'°R‘ 1; R“, R7 represent, independently from each other, a hydrogen atom or fiuoro atom; R2] represents a group selected item a) a C1-C.u-alkyl group, which is optionally substituted with one substitueut selected from the group consisting of C2-C3-alkyny1; R“), R“ represent, independently from each other, a hydrogen atom or a Ct-Ca-alkyl- group; or their salts, solvates or salts ates. hi another preferred embodiment the present ion relates to compounds of general formula (Ib) R4 /\ R8 RLN o N \N o’ 1/8 JL / (1b), wherein represents a Cr-Cr.~alkyl- group; represents a hydrogen or fluoro or ehloro atom; represents a hydrogen or fluore atom: represents a group selected from a hydrogen atom, cyano, 9, -C(O)OR9,- C(0)NR“’R”; represents a group selected from a) a C1—C.o-a1kyl group, which is optionally substituted with one or two substitu ents, selected from the group consisting 3-alkenyI-, Cg-Cg-alkynyl-, phenyl, lieteroaryl, n said phenyl or heteroaryl group is optionally substituted with one. two or three substituents, identically or ently, selected from halogen, cyano, halo-Cl-Cz-alkyh; b) a phenyl group; c) a phenyl—Crcralkyl- group, which phenyl group is optionally substituted with one or two or three substitueuts, identically or differently, selected from the group consisting of halogen, cyano. halo-Cl-Cg-alkyl-; d) a heteroaryl—Ci-Cs-alkyl» group, which heteroaryl group is optionally substituted with one substituent selected flow the group consisting ofhalogen; R9 represents a Ct-Cs-alkyl group; Rm,R” represent, independently {rem each other, a group selected from hydrogen or C1-C6-alkyl-; or their salts, solvates or salts of solvates.
The t invention relates to compounds of l formula (I) or (Ia), wherein R1 represents a group selected from C4-C5-alky1— or heterocyclyl-; R2 represents a group selected from 0/ O 0/} R6 R5 R8 R7 R7 R7 3 1 ’ O O R6 R6 R7 R7 R3, R“ represent, independently fi-om each other, a group selected from a hydrogen atom, fluoro atom, chloro atom; R5 represents a group selected from a hydrogen atom, cyano, ~C(O)R9, -C(O)OR9, -S(O)3Rg, -C(O)NR'°R”, C1—Ce-alkylfi R“, R7 represent, independently from each other, a group selected flour a hydrogen atom, fluoro atom, chloro atom; Rs represents a group selected frorn a) a C1-C;o—alkyl group, which is ally substituted with one substituent, selected from the group consisting of C3‘C7'CYC1031kyl'3 heteroeycyl-, , wherein said C3-C 7- cycloalkyl-, heterocycyl— or phenyl group is optionally substituted with one. or two subsrituents, identically or difi‘erently, Selected from halogen; b) a phenyl group; c) a phenyI—Ct-Cg-alkyl- group, which is optionally substituted with one or two substituents, cally or ently, selected from the group consisting of halogen; R9 represents a C1-C5-alkyl group; R'", R” represent, ndently from each other. a group selected front hydrogen or C1-Ca-a1kyl-; or their salts, solvatw or salts of solvates.
The present invention relates to compounds of general formula (I) or (Ia), wherein RI represents a C1-C6-alkyl- group; R.- represents a group selected from ,R5 0/\ R7 R7 R I 3 Y R3, Rd represent, independently from each other, a group ed from a hydrogen atom, fluoro atom, chloro atom; represents a group selected from a hydrogen atom, cyano, ~C(O)R9, -C(O)OR9, -S(O)2Rg, -C(O)NRI0R“; represent, independently from each other, a group selected from a hydrogen atom, fluoro atom; represents a group selected from a) a C1-C,o-all<yl group, which is optionally substituted with one substitucnt selected from the group consisting of -cycloalkyl-, phenyl, wherein said C3—C7-cycloalkyl- or phenyl group is optionally substituted with one halogen atom; b) a phenyl-Ct—Cg-alkyl- group, which is optionally substituted with one halogen atom; R9 represents a Ct—Ca-alkyl group; thl’ R.” represent, independently from each other, a group selected from hydrogen, C1-C6-aikyE-; or their salts, solvatcs or salts ofsolvntcs.
The t invention relates to compounds ofgcneral formula (l) or (In), n R1 ents a Ct-CG-alkyl- group; 1 R; represents a group selected from R3, R4 represent, independentty from each other, a group selected from a hydrogen atom, fluoro atom, ehloro atom; represents a group selected from a hydrogen atom, cyano, —C(O)R9, -C(O)OR9, -C(O)NR‘°R”; represent. independently from each other, a group selected from a hydrogen atom. fluoro atom; represents a group selected fi'om a) a C1-C ;o-alky1 group, which is optionally substituted with one phenyl group, n said phenyl group is optionally substituted with one halogen atom; b) a phenyi-Ct-Cg-aikyl- group, which is optionally substituted with one halogen atom; R9 represents a C1-C5-alkyl group; R10, R11 represent, independently from each other, a group selected from hydrogen, C1-C6-alkyl—; or their salts, solvates or salts of solvates.
The present invention relates to compounds of general formula (I) or (In), n R] represents a Cit—Co-alkyl- group; R2 represents a group selected from R‘3 R6 R7 R7 .
R3, R4 represent ahydrogen atom; R5 represents a group selected fiom a hydrogen atom or -C(O)NR‘°R“; R“, R7 represent, independently from each other, a hydrogen or a fluoro atom; R8 represents a C1-Cm-alkyl group; R'“, R” represent, independently from each other, a en atom or C1-C5-a1kyl- group ; or their salts, solvares or salts of as The present invention relates to compounds of general formula (I) or (Ia), n R1 represents a Cr-Co-alkyl-group; R2 represents a group selected from 0/ fl R6 R6 R6 R7 R7 R7 R3, R4 represent a hydrogen atom; R5 represents a group selected from a hydrogen atom or -C(O)NR loR1 l; R“, R7 represent, independently from each other, a hydrogen atom or a fluoro atom; R8 ents a Cr-Cro-allwl group; R10, R” represent, ndently from each other, a group selected from hydrogen, C1—C6-nlkyl—; or their salts, solvates or salts of solvates.
In another embodiment the present invention concerns compounds of general fonnulu (I) or (Ia), wherein R‘ represents alkyl-, R' represents a group selected frorn R‘, R" represent a hydrogen atom; R5 represents a group ed from a hydrogen atom or -C(O)OR9; R“, R7 represent, independently from each other, a group selected from a hydrogen atom or a fluoro atom; R‘ represents a group selected from a) a C1-Clo-alkyl- group or b) a phenyl-Cl-Cg-alkyl— group; R9 represents a C1-Ce-alkyl- group; or their salts, solvates or salts of solvates.
The present invention relates to compounds of general formula (I) or (Ia), wherein RI represents a group selected from methyl, ethyl, cyclopropyl, tetrahydro-2H-pyranyl; R‘ ents a group selected from 0/ 0 fl R“ R6 R6 R7 R7 7 R6 R6 R7 R7 R3, R4 represent, independently from each other, a group selected from a en atom, fluoro atom, chloro atom or methyl; R5 represents a group selected from a hydrogen atom, cyano, -C(0)R9, R9, -S(O)3R9, -C(O)NR”R” or cl-c6.att<yt—; R6, R7 represent, independently from each other, a group selected from a hydrogen atom, tluoro atom, chloro atom: R8 represents a group ed from a) a methyl, ethyl propyl or butyl group, which group is optionally substituted with one or two or three tuents, selected from the group consisting of halogen , hydroxy, ethenyi, yl, ethynyl, propynyl, cyclopentyl, cyclohexyl, tetrahydro—ZH-pyranyl, phony], pyridinyl, thiazolyl, oxazolyl, wherein said phenyl or pyridinyl group is optionally substituted with one, two or three tucnts, identically or differently, selected from a fluoro or chtoro atom, cyano, methyl, or trifluoromethyl; £5 b) a (21-lz)methyl group substituted with a (2H5)phcnyl group; c) a phenyi group; (1) a benzyl group, which phenyl ring is optionally substituted with one or two or three substituents, identically or difl‘erently, selected from the group consisting of a fluoro atom, chloro atom, oyano, methyl or trifluoromcthyl-; e) 21 pyridin-Z-ylmethyl- group, which pyridine is optionally substituted with one fluoro atom; f) a pyridinyhncthyl- group, which pyridine is optionally substituted with one fluoro atom; g) a pyridinylmethyl- group, which pyridine is optionally substituted with one fluoro atom; h) a thiazolylmcthyl- group; i) an oxazolylmethyl- group R9 represents a methyl or ethyl group; R10, R11 represent, independently from each other, a gram selected fiom hydrogen, methyl; or their salts, solvates or salts of solvates.
The present invention relates to compounds of general formula (I) or (Ia), wherein R1 represents a group ed from methyl, tetrahydro-ZH-pyranyl; R- represents a group selected from /R /\l l l é—Rel I ;R6 R6 R7 R7 7 R7 R7 R3, R4 ent, independently from each other, a group selected from a hydrogen atom, fluoro atom, ehloro atom; represents a group selected from a hydrogen atom. cyano, «C(OJRg, -C(O)OR9, -S(O)2R9, —C(0)NR‘°R“, ; represent, ndently from each other, a group selected from a hydrogen atom, fluoro atom, chloro atom; represents a group selected fi'om a) a methyl group, which is optionally substituted with one substituent, selected from the group consisting ofcyclohexyl, tetrahydro-ZH—pyranyl, phenyl, wherein said phenyl group is optionally substituted with one, or two tncnts, identically or ently, selected from a fluoro or ehloro atom; b) a (2H2)methyl group substituted with a (2H5)Phenyl group; c) an ethyl group, which group is ally substituted with one substituent selected from the group consisting of tetrahydro-2H-pymnyl, cyclopentyl; d) a phenyl group; 0) a phenyl-Ct-Cs-alkyl— group, which is optionally substituted with one or two substitucnts, identically or differently, selected from a fluoro or ehloro atom; R9 represents a methyl or ethyl group; RIO, RH represent, ndently from each other, a group ed from hydrogen, methyl; or their salts, es or salts of solvates.
The present invention relates to compounds of general formula (I) or (Ia). wherein represents a methyl or ethyl or cyclopropyl group; represents a group ed from ’ o/fi o R7 R7 R7 represents a group selected from a hydrogen atom, fluoro atom, chloro atom or methyl; represents a group selected from a hydrogen atom or fluoro atom represents a group selected from a hydrogen atom, cyano, -C(O)R9, -C(O)OR9, —C(O)NR1°R”; represent, independently from each other, a group selected from a hydrogen atom or fluoro atom; represents a group selected from methyl, ethyl, -en-l -yl, 2-methy1propen-lyl, 2-(hydroxyrnethyl)propen- l -yl, (ZZ)-but-2—en- 1—yl, prop-Z-yn» l yl, but-Z-yn—l yl, eyelohexyhnethyl, benzyl, 3—eyanohenzyl, 3-finorobenzyl, 3-chlorohcnzyl, 4-fluorobenzyl, 4~ehlorobcnzyl, 3—fluoro(trifluoromethyl)benzyl, 3-ehlorofluorobenzyl, pyridin—4-yl. opyridin—4—yL- 2,3,5-u'il‘luorobenzy1, lrifluorobenzyl; R9 represents a methyl or ethyl group: R'", R” represent, independently from each other, a group selected from hydrogen, C1-C5-alkyl~; or their salts, solvates or salts of solvates.
The present invention relates to compounds of general a (I) or (Ia), wherein R’ represents a group selected from methyl; R2 represents a group selected from R7 .
R3 represents a hydrogen atom; R‘1 represents a hydrogen atom; R5 represents a hydrogen atom, a cyano group or -C(O)NR1°R“; R6, R7 represent, independently from each other, a hydrogen atom or fluoro atom; R“ represents a group selected from a) a methyl group‘ which is optionally substituted with one substituent selected from the group consisting of l, propynyl; b) an ethyl group; RIn represents a hydrogen atom; R“ represents a methyl group; or their salls, es or salts of sob/ates.
The t invention relates to compounds of general formula (I) or (Ia), wherein R‘ represents a methyl group; R2 ents a group selected from / o/fi O R6 R6 R“ R7 R7 R7 R3, R" represent, independently from each other, a hydrogen, fluore or chloro atom; R5 represents a group selected from £1 hydrogen atom, cyano, -C-(O)R9, -C(O)OR9, -S(O)2R9, R1°R“; R‘, R7 represent, independently from each other, a group selected from a hydrogen atom, fluoro atom; Ra represents a group selected from a) methyl group, which is optionally substituted with one substituent, selected from the group consisting ofcyclohcxyl and phenyl, n said phenyl group is optional iy substituted with one fluoro atom; b) a benzyl group, which is optionally substituted with one t‘luoro atom; R9 represents a methyl or ethyl group; R”, R“ represent, independently from each other, a group selected from hydrogen or methyl; or their salts, es or salts ofsolvates.
The present invention relates to compounds of general formula (I) or (Ia), wherein RI represents a, methyl group; R2 represents a group selected from o’ o/fi R6 R3 R6 R7 R7 R7 1 t I R‘, R4 reP resent, inde Jeudentlt Y from each other, ahydroven, fluoro or chloro atom;b R’ represents a group selected from a hydrogen atom. cyano, -C(O)R9, -C(O)OR9, -C(O)NR'°R”; R", R7 represent, independently from each other, a group selected from a hydrogen atom, fluoro atom; R8 represents a group selected from a) a methyl group, which is optionally substituted with one phenyl group, wherein said phenyl group is optionally substituted with one fluoro atom; b) a benzyl group, which is optionally substituted with one fluoro atom; R9 represents a methyl or ethyl group; R”, R” represent, independently from each other, a group ed from hydrogen or methyl; or their salts, solvates or salts of solvates.
The present invention relates to compounds of general formula (I) or (Ia), wherein R1 represents a methyl group; R2 represents a group selected from /R O/fi R6 R‘5 R6 R7 R7 R7 R3, R" each represent a hydrogen atom; R5 represents a group selected from a hydrogen atom, R'°R”; R6, R7 represent, independently from each other, a hydrogen or a fluoro atom; R8 represents a methyl group; R”, R” represent, ndently from each other, a group selected from hydrogen, methyl; or their salts, solvates or salts of es.
The present invention s to compounds of general formula (I) or (Ia), wherein R1 represents a methyl group; R2 represents a group selected from R6 R6 R7 R7 .
R3 . R4 represent a hydrogen atom; R5 ents a hydrogen atom or a -C(O)NR"’Rll group; R6, R7 represent, independentty from each other, a hydrogen or a tluoro atom; RS represents 2L methyl group; R”, R” represent, independently from each other, a hydrogen atom or a methyl group; or their salts, solvates or salts ofsolvatw.
In another embodiment the present invention concerns nds of l formula (1) or (Ia), wherein R' represents methyl, R2 represents a group selected from R‘A‘, R" represent a hydrogen atom; R5 represents a group ed from a hydrogen atom or -C(O)OR9; R6, R7 represent, independently from each other, a group selected from a hydrogen atom or fluoro atom; Rs represents a group selected from methyl or benzyl; R9 represents ethyl; or their salts, solvates or salts of soivates.
In r embodiment the present invention concerns compounds of general formula (I) or ([3), wherein R‘ represents methyl; R2 represents [1 group selected from R7 .
R‘ represents a fluoro atom; R‘1 represents a hydrogen atorn; R5 represents a group selected from a hydrogen atom or cyano; R“. R7 represent. independently from each other, a group selected from a hydrogen atom or tluoro atom; R3 represents a group ed from methyl or benzyl; or their salts, solvates or salts of solvates.
The present invention relates to compounds of general a (la) R /\ RLN o N \ N R1/ I}! N R2 ('3) , wherein R1 represents a methyl group; R2 represents a group selected from 2—methoxyphenyl-, 4-fluoromethoxyphenyl-, S-fluoro-Z-methoxyphenyI-, 2-(benzyloxy)~4-fluoropheny1—, 4,5-difluoremethoxyphenyl—, 4-chloro-Z-methoxyphenyl, 2-[(4-fluorobenzyl)oxy]phenyl—. lohexylmethoxy)-4— fluorophenyl-, 4-fluoro[(4-fluorobenzy1)oxy]phenyl-; 2-[(3,4-dichlorobenzy1)oxy]phenyi-, 2-(1-cyclopcntylethoxy)fluorophcnyl—, 3-chloromethoxyphenyl-, oxyphenyl-; R“ represents a group selected from a hydrogen atom, fluoro atom, chloro atom; R4 re )rcsents al gronP selected from a hydrogen atom or ehloro atom; R5 represents a group selected from a hydrogen atom, -C(O)R9. -C(O)OR9, methyl; R5’ represents methyl or ethyl; or their salts, solvatcs or salts of solvatos.
The present invention relates to compounds of l formula (Ia) R /\ R5--N o N \ N 1 A A/ / R N N R2 ('3) , wherein R‘ represents a methyl group; R3 represents a group selected From 2-methoxyphcnyl-, o-Z-methoxyphenyl-, -fluoro—2-methoxyphenyl—, 2-(benzyloxy)fluorophcnyl-, 4,5-difluoro-2—Inethoxypheuy1-, 4-chlore-Z-methoxyphenyl—, 2-[(4-fluorobenzyl)oxyjphenyl-. 2-(cyclohexylmethoxy) fluorophcnyl-, ro—2-[(4-fluorobenzyl)oxy]phenyl-; 2-[(3,4-clichlorobenzyl)oxy)phenyl-, 2-(1 —cyclopentylethoxy)—4-fluorophenyl-; R3 represents a group selected from a hydrogen atom, fluoro atom, chloro atom; R4 represents a group selected from a hydrogen atom, chloro atom; R5 represents a hydrogen atom; or their salts, solvates or salts of solvates.
The present invention relates to compounds of general a ([3) A R—‘N O N N \\ // RVS A N N/ R2 (la) wherein R1 represents a methyl group; R2 represents a group selected from 2-methoxyphenyl-, 4—fluoro-Z-methoxyphenyl-, 2-(bcnzyl)oxyfluorophcnyl~, 4,5—difluoro~2-mcthoxyphcnyl-, 2—[(4—fluorobcnzyl)oxy]phcnyl-, lohexylmcthoxyy4~fluorophcnyl—, 4-fluoro-2—[(4-fluorobcnzyl)oxy]phenyl—; R3 represents a group selected from a hydrogen atom, fluoro atom, chloro atom; R“ represents a group selected from a hydrogen atom, chloro atom; R5 represents a group selected from a hydrogen atom; or their salts, solvatcs or salts of solvatcs.
The present invention relates to compounds ofgeneral formula (Ia) R4 /\ R‘L—N o N \ N JL / Rl/ [El N R2 (13) , wherein R] represents a group selected from methyl; R“ represents a group selected from 4-fluoro—Z—methoxyphenyl—, 2-(benzyloxy)-4~f1uorophenyl-, 4,5-difluore-2—1nethoxyphcnyl-, 2-[(4-fluorobcnzyl)exy]phcnyl—, 4-fluoro[(4~fluorobenzyl)uxy]phenyl-; R3 represents a group selected from a hydrogen atom, fluoro atom, chloro atom; R“ represents a group ed from a hydrogen atom, ehloro atom; R” represents a group selected from a hydrogen atom, -C(O)R9, -C(O)OR9; R9 represents methyl or ethyl; or their salts, solvates or salts of solvates.
The t invention relates to compounds of general formula (Ia) R /\ R5—N o N “ N R1/ [:1 N R2 ('3) wherein R' represents a group selected from ; R2 represents a group selected from 4-fiuoro-2~methoxypheny1-, 5—fluoro-2~methoxyphenyl-, 4,5-difluoro-2»methoxyphenyl—; R3, R4 ent, independently from each other, a hydrogen atom; R5 ents a hydrogen atom; or their salts, solvates or salts of solvates.
The present invention s to compounds of general formula (Ia) R4 /\ R5—N \ N o N JL / Rt/ {:1 N R2 ('3) wherein R’ represents a group selected from methyl; R2 represents a group selected from 4—fluoro-2—methoxyphenyl-, 4,5-difluoro1nethoxyphenyl-; R3, R“ represent, independently from each other, a hydrogen atom; R5 represents a hydrogen atom; or their salts, solvatcs or salts of solvates.
In another preferred embodiment the present invention relates to compounds of general formula (11)) 4 8 Rs—N 0R A ’R N N O \\ // RVs J|\ N N/ (11)), wherein R‘ represents a methyl group; R3 represents a group selected from a hydrogen atom or fluoro atom or chloro atom; R“ ents a group selected From a hydrogen atom or fluoro atom; R5 represents a group selected from a hydrogen atom, cyano, —C(O)CH3 -C(O)OCH2CH3-; -C(O)NHCH3; R2‘ represents a group selected from methyl, ethyl, prop—Z-en- l-yl, 2-methylprop-2«en—lyl, (ZZ)—buten-l-yl, -yn-lyl, but-Z—yn-lyl, roxymcthyl)propcn-I~yl, , benzyl. 3-cyanobenzyl, 3-fluorobenzyl. 3-chlorobenzyl, 4-fluorobenzyl, 4—ehlorobenzyl, o—5-(trifluoromethyl)benzyl, 3~chlorofluorobenzyl, pyridin—4-yl, Z-fluoropyridin-tt-yl, 2,3.5-trifluorobenzyl, tt'ifluorobenzyl; or their salts, sch/ates or salts of solvates.
In another embodiment the invention relates to compounds of formula (I) or (.121) or (1b), in which R1 represents a C1-Cs-alkyl-, a C3~C5-cycloalkyl— or a heterocyctyl group.
In another embodiment the invention relates to compounds of formula (I) or (In) or (lb), in which R1 represents a C1-C3-alky1- or a heterocyclyl group.
In another embodiment the invention relates to compounds of formula (1) or (la) or (lb), in which R1 represents a Cr-Ct-alkyl- group.
In another embodiment the invention relates to compounds of a (I) or (18.) or (ID), in which R1 represents a methyl group.
In a preferred embodiment the invention s to compounds of formula (I) or (Ia) or ([b), in which R1 represents a methyl group. ln another ment the invention relates to compounds of formula (1) or (la) or (lb), in which R1 represents a. C3-C5—cycloalkyl-group, preferably a cycopropyl group.
In another embodiment the invention s to compounds of formula (I) or (In), in which R2 ents R6 R° R6 R7 R7 R7 In another embodiment the invention relates to compounds of formula (I) or (la), in which R2 represents In a preferred embodiment the invention relates to compounds of formula (I) or (Ia). in which R2 represents In another preferred embodiment the invention relates to compounds of a (I) or (Ia), in which R2 represents In another embodiment the ion relates to compounds of formula (I) or (la), in which R2 represents a group selected from 2-metlioxyphenyl-, 4-fluoro-2—mcthoxyphenyl-, S-fluoro-Z-methoxyphenyl-, 2~(benzyloxy)fiuorophenyl-, 4,5-difluoro—Z-methoxyphenyl-, 4-ehloro—2-methoxyphenyl-, fluorobenzyl)oxy}phenyl—, 2-(cyclohexylmethoxy)—4-fluorophenyl~, 4-fluoro—2-[(4-fluorobenzyl)oxy]plienyl~, 2-[(3,4—dichlorobenzyl)oxy]phenyl-, 2-(1-cyclopentyletltoxy)~ 4—fluorophenyl-, 3-chloro-Z-methoxyphenyl—, 2-phenoxyphenyl—. in a preferred embodiment the invention relates to nds of formula (1) or (la), in which R2 represents a group selected from 4-fluoro—2-methoxyphenyln 4-fluoro[(4-fluorobenzyl)oxy]phenyl-; 4~fluoro[(2-fluoropyridiny1)methoxy]phenyl-, 2-(butyn-i-yloxy)fluorophenyl-, 4-fluoro—2— (prop-Z-yn-l -yl oxy)phenyl-.
In another. particularly preferred ment the invention relates to compounds of formula (I) or (Ia), in which R2 represents a group selected from 4-fluoro-Z-methoxyphenyI-, o‘2-[(4- fluorobenzyl)oxy]phenyl-; oro-2~[(2-fluoropyridinyl)methoxy]phenyl-, 4-fluoro(prop—2-yn-l- onxy)phenyl—.
In another, ularly preferred embodiment the invention relates to compounds of formula (I) or (Ia), in which R2 represents a group selected from 4-fluoromethoxyphenyl-.
In another embodiment the invention relates to compounds of formula (I) or (In) or (11)), in which R3 represents a group selected from a hydrogen atom, fluoro atom, chloro atom, cyano, Ct-Cz-alkyL, Cl-Cz- alkoxy—, ltalo-Ct—Cz-alkyl-, Ct-Cg-fluoroalkoxy—.
In r embodiment the invention relates to compounds of formula (l) or (In) Or (lb), in which R3 ents a hydrogen atom or a fluoro atom or a chloro atom.
In another embodiment the invention s to compounds of formula (I) or (Ia) or {1b), in which R3 represents a hydrogen atom or a fluoro atorn In a preferred embodiment the invention relates to compounds of formula (I) or (In) or (lb), in which R3 represents a hydrogen atom.
In another preferred embodiment the invention relates to compounds of formula (I) or (Ia) or (Ib), in which R3 represents a fluoro atom. in another embodiment the invention relates to compounds offormula (I) or (la), in which R3 represents a fluoro atom and in which R3 is in meta position of the N—phenyl suhstituent in 2-positimi of the l, 3, 5- triazine core.
In another embodiment the invention relates to compounds of formula (I) or (Ia), in which R3 ents a fluoro atom and in which R3 is in meta position of the N-phenyl substituent in 2-position of the l, 3, 5- triazine core, and in which R4 represents a hydrogen atom.
In another embodiment the invention relates to nds of formula (1), in which R3 represents a fluoro atom and in which R3 is in para position of the yl substituent in 2-position of the l, 3, 5- ne core.
In another embodiment the invention s to compounds of formula (I), in which R3 represents a fluoro atom and in which R3 is in para position of the N-phenyl substituent in 2-position of the 1. 3, 5- triazine core. and in which R4 represents a hydrogen atom.
In another embodiment the invention relates to compounds of formula (I) or (Ia) or (Ib), in which R4 represents a group selected from a hydrogen atom, fluoro atom, chloro atom, cyano, Cr-Cg-alkyl-, C1-C2- v, halo-Ci-Cz-alkyl-, C1-C2-fluoroalkoxy-.
In another embodiment the invention relates to compounds of formula (I) or (In) or (lb), in which R4 represents a group ed from a hydrogen, a fluoro or a chloro atom.
In another embodiment the invention relates to nds of formula (I) or (Ia) or (lb), in which R4 represents a group selected from a hydrogen atom or fluoro atom.
In another embodiment. the invention relates to nds of formula (I) or (Ia) or (lb), in which R4 represents a hydrogen atom.
In another embodiment the invention relates to compounds of formula (I) or (In) or (ID), in which R4 represents a chloro atom In a preferred embodiment the invention relates to compounds of formula (In) or (111), in which R3 represents a fluoro atom and R" represents a en atom.
In another embodiment the invention relates to compounds of formula (In) or (ID). in which R3 represents a hydrogen atom and R4 ents a fluoro atom.
In another preferred ment the invention relates to compounds of formula (In) or (lb), in which R3 ents a hydrogen atom and R4 represents a hydrogen atom.
In another embodiment the invention s to compounds of formula (I) or (Ia) or (lb), in which R5 represents a group selected from a hydrogen atom, cyano, —C(O)R9, -C(O)OR9, -S(O)2R9, -C(O)NR1°R”, -a1kyl-, C-s-Cv-cycloalkyl-, heterocycyl, phenyl, heteroaryl, wherein said Cl-Ca-alkyl, C1—C7- cyeloalkyl-, heterocycyl, phenyl or helcroaryl group is optionally substituted with one, two or three substituents, identically or differently, selected from halogen, hydroxy, cyano, Cr-Ca-alkyl—, C1-C3— alkoxy-, amino, alkylamino-, dialkylamino—, acctylamino-, N-mcthyl~N—acctylamino-, cyclic amines, halo-Ct -C2-a]ky1-, CI-Ct-fluoroalkoxy-.
In another embodiment the invention relates to compounds of formula (I) or (Ia) or (11)), in which R5 represents a group selected from a hydrogen atom, cyano. -C(O)R9, -C(O)OR9, -S(O)3R9, -C(O)\lRwR”, . in another ment the ion s to compounds of formula (I) or (Ia) or (113), in which R5 represents a group selected from cyano, —C(O)R9, -C(O)OR9, -S(O)2R°, -C(0)NR‘“R”, methyl.
In another embodiment the invention relates to compounds of formula (I) or (In) or ([b), in which R5 represents a group selected from a hydrogen atom, eyztno, R”, C(O)NR‘°R”.
In another embodiment the invention relates to compounds of formula (I) or (la) or (11)), in which R5 represents a group selected from cyano, -C(O)OR9, C(O)NR'°R”.
In another embodiment the invention relates to compounds of formula (I) or (Ia) or (lb), in which R5 represents a group selected from a hydrogen atom, cyano or ~C(O)OR".
In another embodiment the invention relates to compounds of formula (I) or (Ia) or (lb). in which R5 represents a group ed from cyano or -C(O)OR9.
In a red embodiment the invention relates to compounds of formula (I) or (la) or (ID), in which R5 ents a group ed from a hydrogen atom or a cyano group. 1n another embodiment the invention relates to compounds of formula (I) or (Ia) or (Ih), in which R5 represents a group selected fi'om cyano, —S(O)2R”, R“’R". in another embodiment the invention relates to compounds of formula (I) or (In) or (lb), in which R5 represents a group selected from a hydrogen atom or -C(O)OR”.
In another embodiment the ion relates to compounds of formula (I) or (Ia) or (11)), in which R5 represents a hydrogen atom.
In another embodiment the invention relates to compounds of formula (I) or (Ia) or (lb), in which R5 represents ~C(O)OR9.
In r embodiment the invention relates to compounds of formuia (I) or (Ia) or (11)), in which R5 represents —C(O)NR1°Rl '.
In another embodiment the invention relates to compounds of formula (I) or (Ia) or (Ib), in which R5 represents —S(O)2R9.
In another preferred embodiment the ion relates to compounds of formula (I) or (Ia) or (lb), in which R5 represents a cyano group.
In another preferred embodiment the invention relates to compounds of formula (I) or (In) or (lb). in which R5 represents a hydrogen atom.
In another embodiment the invention relates to compounds of formuta (I) or (Ia), in which R6 represents a group selected from a hydrogen atom, fluoro atom, chloro atom, cyano, C1-C2—alkyl—, C1-C2—alkoxy—, halo-C: -C2-alkyl-, fluoroalkoxyv. in another embodiment the invention relates to compounds of formula (I) or (In), in which R6 represents a group selected from a hydrogen atom or fluoro atom or chloro atom.
In another embodiment the invention relates to compounds of formuia (I) or (Ia), in which R6 represents a group ed from a hydrogen atom or fluoro atom.
In another embodiment the ion relates to compounds of formula (I) or (In), in which R6 represents a hydrogen atom.
In another preferred embodiment the invention relates to nds of formula (I) or (In). in which R6 is in para position of the phenyl substituent in 4-position of the I, 3, 5- triazine core and represents a fluoro atom.
In another preferred embodiment the ion relates to compounds of formula (I) or (Ia), in which R6 is in para position of the phenyl substitucnt in 4-position of the 1, 3, 5— triazine core and represents a fluoro atom; R7 represents a hydrogen atom.
In another embodiment the invention relates to compounds of a (I) or (In), in which R1 represents a group selected from a hydrogen atom, fluoro atom, chloro atom, cyane, Ci-Ca-alky1-, C:-C;-a]koxy~, l-C2~a1kyI—, fluoroalkoxy-.
In another embodiment the invention relates to nds ula (I) or (Ia), in which R” represents a group selected from a hydrogen atom or fluoro or chloro atom.
In another embodiment the invention relates to compounds of formula (I) or (Ia), in which R7 represents a group selected from a hydrogen atom or fluoro atom.
In another embodiment the invention relates to compounds u to (I) or (la), in which R7 ents a fluoro atom.
In another embodiment the invention s to compounds offermuia (I) or (Ia), in which R1 represents a chloro atom.
In r embodiment the invention relates to compounds of formula (I) or (Ia), in which R7 is a hydrogen atom.
In another embodiment the invention relates to compounds of formula (I) or (Ia), in which R6 is in para on of the phenyl substituent in 4-position of the l, 3, 5- triazine core and R6 represents a fluoro atom and in which R7 ents a group selected from a hydrogen atom, fluoro atom, chloro atom, Ci- Cg-alkyl-, Ct-Cg-alkoxy-, halo-Ct-Cz-alkyh, C1—Cz-fluoroalkoxy», In r embodiment the invention relates to compounds of formula (I) or (Ia), in which R6 is in para on of the phony} substituent in tion ofthe l, 3, 5- triazinc core and R5 ents a fluoro atom and in which R7 represents a group selected from a en atom or fluoro atom. ln another embodiment the invention relates to compounds of formula (1) or (la), in which R6 is in para position of the phenyl substituent in 4-position of the l, 3, 5- triazine core and R6 represents a fluoro atom and in which R7 rcDresents a h drooen atom.
In a preferred embodiment the invention relates to compounds of formula (I) or (In). in which R6 is in para position of the phenyl substituent in 4—position of the 1, 3, 5- triazine core and R6 represents a fluoro atom and in which R7 represents a en atom.
In another embodiment the invention relates to compounds of formula (I) or (In) or (lb), in which R8 represents a C1-C2-alkyl group, which is optionally substituted with one substituent, selected from the group consisting of C3—C7-cycloalkyl-, heterocycyI-, phenyl, wherein said C3—Cv-eycloalkyla, heterocycyl- or phenyl group is optionally substituted with one, or two substiments, identically or differently, selected From halogen.
In r embodiment the invention relates to compounds of formula (I) or (Ia) or (In), in which R8 represents a methyl group, which is optionally substituted with one substitucnt selected from the group eonsisring ofphenyl, wherein said phenyl group is optionally substituted with one or two substituents, identically or differently, selected from a fluoro or chloro atom.
In another embodiment the invention s to compounds of formula (I) or (Ia) or (1b), in which R8 represents a methyi group, which is optionally substituted with one substituent selected from the group consisting of heteroaryl, wherein said heteroaryl group is optionally substituted with one or two substituents. identically or differently, selected from a fluoro or chloro atom In a preferred embodiment the invention relates to compounds offormula (I) or (la) or (lb), in which R5 represents a methyl group.
In r embodiment the invention relates to compounds of formula (I) or (Ia) or (Ib), in which R8 represents a group selected from —CH2—CH20F3, -CH2CH2CF2CF3.
In another embodiment the ion relates to nds of a (I) or (Ia) or (lb), in which R3 represents a methyl or a (3H3)methyl group.
In another embodiment the ion relates to compounds of formula (I) or (In) or (Ib), in which R8 represents a phenyl group, which is optionally substituted with one or two or three tuents, identically or difl’erently, selected from the group consisting of halogen, hydroxy, amino, alkylamino-, dialkylamino-, acetylamino-, N-methyl-N-acetylamino-, cyclic amines, cyano, Cl-Cg-alkyl-, lialo-Cl-Cg- , C1-C2—fluoroalkoxy-, Ci-Cz-alkoxy-.
In another embodiment the invention relates to nds of formula (I) or (Ia) or (lb), in which R8 represents a heteroaryl group, which is optionally substituted with one or two or three substimcnts, cally or differently, selected from the group consisting of halogen, y, amino, alkylamino-, dialkylamino-. aeetylamino-, N-methyl-N-acetylamino«, cyclic amines, cyano, Ct-Cz-alkyl-, halo~Ct-Cz- alkyl~, Ct-Cz-fluoroalkoxy—, C1-C2-alkoxy~. in another embodiment the invention relates to compounds of formula (I) or (Ia) or (11)), in which R2 represents a phenyl—Ct- 3-alkyl- group, which is ally substituted with one or two or three substituents, identically or ently, selected from the group consisting of fluoro atom, chloro atom, cyano, methyl-, trifluorornethylx In r embodiment the invention s to compounds of formula (I) or (Ia) or (lb), in which R8 represents a phenyl-Ct-Cg-alkyl— group, which is optionally substituted with one or two substituents, identically or differently, selected from the group consisting of halogen.
In another embodiment the invention relates to compounds of formula (I) or (Ia) or (Ib), in which R8 represents a benzyl group, which is optionally substituted with one or two or three substituents, identically or differently, selected from the group consisting of fluoro atom1 chloro atom, eyano, methyl—, trifluoromethylw.
In r embodiment the invention relates to compounds of formula (I) or (Ia) or (lb), in which R8 represents a benzyl group, which is optionally substituted with one or two substituents, identically or differently, selected from the group consisting of a fluoro or chloro atom In another ment the invention relates to compounds of formula (I) or (In) or (11)), in which R8 represents a benzyl group, which is optionally substituted with one fluoro atom.
In another embodiment the invention relates to compounds of formula (I) or (In) or ([39), in which R8 represents a heteroarthr-C2—alkyl-, which is optionally substituted with one or two or three substituents, identically or differently, selected from the group consisting of halogen, lialo—Cr-Cz-alkyl- and Ct-Cz- alkoxy~.
In another ment the invention relates to compounds of formula (I) or (Ia) or (lb), in which R8 represents a pyridyl-Ct-Cg-alkyl- group, wherein said pyridyl is optionally substituted with one or two or three substituents, identically or diii‘erently, selected from the group consisting of halogen, hydroxy, NHg, alkylamino-, lamino-, acetylamino-, N—methyl-N-acctylamino-, cyclic amines, cyano, C1-C2-alkyl—, halo-Cl-Cg-alkyl-, C1-C2-fluoroalkoxy-, C1-Cz-alltoxy-. in another embodiment the invention relates to compounds of formula (I) or (In) or (lb), in which R8 ents a pyridyl-Ct-Cz-alkyl- group, wherein said pyridyl is optionally substituted with one or two or three substituents, cally or differently, selected from the group consisting of halogen, halo-Cr-Cz— alkyl- and alkoxy-.
In another embodiment the invention relates to compounds of formula (I) or (Ia) or (ID). in which R8 represents a oxazolyl-Ct-C2~all<yl- or thiazoiyl-Ct-Cz-alkyl- group, wherein said oxazolyi or thiazolyl group is optionally tuted with one or two or three substituents, identically or differently, selected from the group consisting of halogen, hydroxy, NHz, alkylamino-, dialkylamino-, acetylamino-, N—methyl- N-acetylamino-, cyclic amines, cyano, Cr-Cz-alkyl-, halo-Ci-Cz-aikyl-, Ct-Cz—fluoroalkoxy-, C1-C2- alkoxy-.
In another ment the invention relates to compounds of formula (I) or (Ia) or (1b), in which R8 represents a oxazolyl-C1~Cg-alkyl- or thiazolyl-Ct-Cz-alhyl- group. wherein said yl orthiazolyl group is ally substituted with one or two or three substituents, identically or differently, selected from the group ting of halogen, halo-Ct—Cg-alkyI-, Cl~C2-alkoxy~.
In another embodiment the invention relates to compounds of formula (I) or (Ia) or (1b), in which R3 represents a group selected from methyl, ethyl, prop—2-cnyl-, 2-mothyIpropen-lyl-, 2- (hydroxymethyl)prop-Z-en-l—yl—, (ZZ)-huten-l-yl», propyn-1yl-, but-Z-yn-lyl—t cyclohexylmethyl-, benzyl-. 3~eyanobenzyl-. 4—cyanobenzyt-. 3—fluorobenzyl-. 3-chlorobenzy1—, 4-fluorobenzyl-, 4- benzyl-, 3-fluoro—S-(trifluoromethyl)benzy1—, 3-chlorofluorobenzyl-, pyridinyl~, 2- tiuoropyridin-4—yI—, 2,3,5-trifluorobenzyl-, 3,4,5-lrit‘luorobenzyl-.
In a preferred embodiment the ion relates to nds of a (I) or (Ia) or (lb), in which R8 represents a group selected from methyl, ethyl, prop-2~en~l-y]-, 2-methylpropen-1yl-, 2- (hydroxymethyl)prop~2-en-I-yI-, (2Z)-but—2-enyl~, propyn-1y1-, but-Z-yn-l yl-, phenyl, 3— cyanobcnzyl-, 3-fluorobenzyl-, 3-cIiIorobenzyl-, 4-fluorobenzyl—, 4-chlorobenzyl-, 3—fluoro (trifluoromethyl)benzyl-, 3~chlorov5-fluorobenzyl-, pyridin—4-yl-, 2-fluoropyridin—4-yl-, 2,3,5— trifluorobenzyl—, 3,4,5—trifluorobenzyl-. in another ment the invention relates to compounds of formula (I) or (in) or (lb), in which R8 represents a group selected from Ci—Ca—alkyl or benzyl.
In another embodiment the invention s to compounds of formula (I) or (In) or (1b), in which R8 ents a group selected from methyl or benzyi. in a red embodiment the invention relates to nds of formula (I) or (Ia) or (113), in which R8 represents methyl. in another embodiment the invention relates to compounds of formula (I) or (Ia) or (lb), in which R8 represents henzyl.
In another embodiment the invention relates to compounds of formula (I) or (Ia) or ([b), in which R9 ents a C|~C6-all<yl-g1'oup.
In another embodiment the invention relates to compounds of formula (I) or (Ia) or (1b), in which Rlo represents a group selected from a hydrogen atom or Ci-Cs-alkyl-.
In another embodiment the invention relates to compounds of formula (I) or (Ia) or (lb), in which R[0 represents a hydrogen atom.
In another embodiment the invention relates to compounds of formula (I) or (Ia) or (lb), in which R” represents a group selected flour a hydrogen atom or C1-Cs-alkyl-.
In r embodiment the invention relates to compounds of formula (I) or (Ia) or (lb), in which R” represents methyl.
It is to be understood that the present invention relates to any subcombination Within any embodiment ofthe present invention of compounds of formula (I) or (la) or (lb), supra.
More particularly still, the t invention covers nds of a (I) or (1a) or (Ib) which are disclosed in the Example section ofthis text, infra.
Very specially preferred are combinations of two or more of the abovementioned preferred ranges. in ular, r preferred subjects of the present invention are the compounds selected from: Ethyl [(3— 1. [4-(4-fluoro~2-1nethoxyphenyl)-1,3,5-triazinyl]amino}benzyl)(methy[)oxide-X‘— sulfanyiidenekarbamate, (rac)(4-FIuom—Z-methoxyphenyl)-N- {3-[(S-mcthylsulf‘onimidoyl)mcthyUphenyl} -l ,3,5-triazin-2« amme, 4-(4-Fluor0111ct110xyphcnyl)-N-{3-[(S-methylsulfonimidoy1)mcthyl]pheuy1}~I ,3,S—triaziu—Z—amiuc; enantiomer l . 4—(4-Fluoro-Z-mcthoxyphcnyD-N- {3-[(S-melhylsu1fonimidoy1)methyl]pheny1} -I ,3,5-triazin-2—amine; cnzmtiomcr 2, (rac)—Bthyl {[3 -( {4-[2-(bcnzyloxy)—4-fluorophcnyl]—I ,3,5-triazin—2-y1}amino)benzy1](methyl)oxido-7L(’- sult’anylidcnc} carbamatc, 4-[2-(B enzyloxy)f1uorophenyl]-N- {3 —[(S-methylsuIfonimidoy!)melhyl]phenyl}-1,3,5-triazin amine, 4-[2-(Bcnzyloxy)fluorophcnyl]~N-{3-[(S—mcthylsulfonimidoyl)mcthyl]phcnyl}-1,3,5-triazin amine; cnantiomcr 1, 4-[2-(Bcnzyloxy)41-quoruphenyl]»N- {3-[(S-methylsulfonimidoyl)melhy[]phenyl} -1.3,5- triazin~2 ~ amine; enanriomer 2, (rad-Ethyl [(3- {[4-(4,5-difluoro-Z-mcthoxyphcnyl)—1,3,5-n‘iazin—2—y1]amino}bcnzlemcthynoxido-kfi— sulfanylidcnc]carbamate, (rac)- 4- (4,5-Difluoro-Z-mcthoxyphcnyD-N— {3 -[( S-mcthylsulfonimidoyi)mcthyl]phenyl} - 1,3,5 -tr1'azin- Z—amine, (rac)—Ethy1 [(3- {[4-(4-ch10ro-Z-methoxyphenyl)-1 n‘azinyl]amino} benzy1)(mcthy])oxido-7K6- sulfany1idene]carbamate, (rac) 4-(4-Chloro-2~methoxyphcnyl)-N— {3-[(S~mcthylsulfonim idoyl)mcthyl}phcnyl} -l ,3,5-triazin amine. 4-(4-Chloromelhoxypheny1)-N— {3—[(S-mcihylsuIfonimidoyl)melh_vl]phenyl} ~1,3,5-triazinamine; omcr 1, 4—(4-Chloro-Z-methoxyphe11y1)-N-{3-[(S-methylsulfonimidoyl)methyl]phenyl} -1,3,5-triazin-2—amine; cnantiomcr 2, (rac)[(3 - {[4-(4- F[uoro-Z—methoxyphenyl)-1,3,5-triazin-2~yl]amino}benzyl)(methyl)oxido-7»6- suifanylidene]—3-methy1urea, 1~[(_3 - {{4-(4 -Fiuoro~2-methoxyphenyl)- l ,3, S-triazin-Z-yllamino} )(methyl)oxido—M— sulfanylidene]—3-methylurea; cnamiomer 1, 1—[(3— {[4-(4—I-‘1uoro-2~methoxyphenyl)- 1,3,5-triazinyl]amino} benzyl)(mcthyl)oxido—?\6- sulfanylidene]—3-methylu1'ea; enantiomer 2 (rad-Ethyl [(3— {[4-(2,2-difluoro-I.,3-benzodioxolyl)-1,3,5~triazin-2—yl]amino}benzy])(methyl)oxido— XG-sulfanylidcnc]carbamatc, (rac)—4—(2,2-Difluoro~1 ,3 -benzodioxolyl)—N— {3-[(S-1ncthylsulfonimidoyl)mcthy1]phenyl}-1 .3 ,5 - n-Z—aminc, (rad-Ethyl 4-(5-fluoromethoxyphcnyl}?,3,5-triazin~2-yl]amino}bcnzyl)(mct11yl)oxitic-7‘6- suifanylidene]carbamate, (rac)-4—(5-FluoromelhoxyphenyD-N-{3-[(S-methylsulfonimidoyl)methyl]phenyI}-1,3,5-tria2in amine, 4-(5-Fluoro~2—mcthoxyphcnyl)—N~ {3-[(S-mcthylsulfonimidoyl)mcthyl]phcny] } -1 ,3,5-triazinaminc; cnantiomcr 1, 4-(5-F1uoromethoxyphenyl)-N- {3-[(S-methylsulfonimidoyl)methyl]phenyl} -I ,3,5-triazin—2-amine; cnantiomcr 2, (rac)—N-[(3 - { [4-(4-fluoromethoxyphenyl)-I ,3 ,S-tfiazin-Z-yHamino} benzyl)(methyi)oxido—?»Gv ylidcnc]acctamido, (rac)—EthyI [(3-{[4-(2-methoxyphenyl)~1 ,3,5-tn'a2iuyl]amino} benzinmcthyl)oxide-KG- sulfidnylidenekarbamale, (rac)—4-(2—MethoxyphcnyD-N— {3 -[(S-mcthylsulfonimidoyl)methyl]pheny1} -1 ,3 , 5-triazin—2-amine, 4-(2-Methoxyphenyl)-N— {3-[(S-methylsulfonimidoyI)methy]]phenyl} ~1 ,3,5-triaziuamine; cnantiomcr l, 4-(2-Methoxyphcnyl)-N- ~1nethylsulfonimidoyl)1nethyl]pheuyl} «1 ,3,5-triazina1nine; enantiomcr 2, (rac)-Bthyl [(3- { [4 —(3 ,4~dihydro-2H—chromcnyl)- l ,3,5-triazin—2-yl]amino}benzy1)[methyl)oxido—?»‘- sulfanylidenekarbanmte, (rac)~4~(3,4—Dihydro—ZI-I-chromcnyI)«N- {‘3 - [(S—mcthylsulfonimidoyUmcthyljphcnyl} - 1.3 ,5-triazin—2- amine, 4-(3,4-Dihydro~2H-chromcn-8—yl)-N- {3-[(S-mcthylsulfonimidoy1)methy1]phenyl}-l ,3 ,5—triazin~2- amine; enantiomer 1, 4-(3,4-Dibydro—ZH—chromen-8—y1)-N- {3~[(S-methylsulfonimidoyl)me1hy1]phenyl}-1 ,3 ,S-triazin—Z— amine; cnantiomer 2, thyl [(3- {[4—(2,3-dihy(lro- l —benzo Fumnyl)- 1 riazi11yi]amino} benzyl)(methyi)ox idol“- sulfanylidene]carbamate, (rac)-4—(2,3-Dihydro-l-bcnzofuran—7-yl)-N- {3~[(S-melhylsulfonimidoyl)methy[}phenyl} -1,3,5-triazin—2- amine, 4-(2,3—Dihydro-I-benzofuran—7-y1)—N—{3—[(S-methylsulfonimidoyl)mcthyl]phenyl}-1,3,5-triazin amino; cnamiomcr 1, -Di hydro-l —beuzofi,1ran—7-y1)—N— {3- [( S-methylsulfonimidoy1)methyl]phcnyl } -1 ,3 ,5-triazin amine; cuantiomcr 2, Ethyl [(3-{[4—(2,3-dihydro-1,4-bcnzodioxinyl)—l ,3,5-triazinyl]aminc}benzlemethyDOXido- lfi-sulfany1idcne]carbumate, (rac)(2,3-Dihydro-l,4-bcnzodioxin—5~yl)-N- {3~[(S-melhylsulfonimidoyl)methyl]phcnyl} -1,3,5v n~2-aminc, 4—(2,3-Dihydro-],4-bcnzodioxin—S-yl)-N—{3-[(S-mctl1ylsulfonimidoyl)methyl}phenyl}-1,3,5-triazin amine; cnantiomcr I, 4—(2,3-Dihydro—1,4-benzodioxin—5—yl)-N-{3 -[(S-methylsulfonimidoyl)methy1}phenyl}-I,3,5-triazin amine; cnantiomcr 2, (rac)—N— {3{(N,S-Dimcthylsulfonimidoyl)mcthyl]phcnyl} (4«fluoro-Z-mcthoxyphcnyi)-I ,3,5-m’azin-Z- amine, (rac)-Ethyl [ {3 - [(4- {2-[(4—fluorobenzyl)oxy}phenyl} ~ 1 ,3,5-tria2inyl)amino] benzyl} (methy1)oxido-K“- sulfanylidenekarbamate, (rac) {2- [(4-Fluorobcnzy1)oxy]p hcnyl}-N-{3-[(S—mcthylsulfonimidoyl)mcthyl]phcnyl}-1,3,S-triazin— Z-amine, N-[(3 - { [4-(4-Fluoromcthoxyphcuy|)- l ,3,5-triazinyl]amino } bcnzlemcthyl)oxide-2.6- sulfanylidene]methanesu1fonamide, (rac)-Ethyl [(3 ~ {{4-(3 -c1110romethoxyphcnyE)-1,3,5-t1'iazi11yl]amino}benzy1)(mcthyl)oxido~k5- sulfanylidenekarbamate, (ra c)—Ethyl {[3 5-fluoro-2—(fctrahydro-2H-pymn—4-yImcthoxy)phcnyl]-1,3,S-triazin-‘2- yl} amino)benzyl](methyl)oxido-?»G-sulfanylidene§ carbamatc, (rad-Ethyl [melhy1(oxido)(3 -{[4-(2—phenoxyphenyl)-1,3,5-lfiazin—2-yl]amino}benzyl)-)J'~ sulfanylidcnc]carbamate, (rac)-[(3~ { [4—(4-fluoro-Z—methoxyphenyl)- 1 ,3,5—Iriazinyl] amino} benzyl)(methyl)oxido-?»“— sulfanylidcnckyanamidc, [(3 — { [4 -(4-fluoromethoxyphenyl)-1 ,3,S-triazin-Z-yl]amino}benzyl)(111ct11y1)oxido-A‘- sulfanyIidemkyanamidc; enautiomer 1, [(3- {[4 —(4-fluoro-2—methoxyphenyl)—1,3,S-tfiazin-Z—y1]amino}benzyl)(methyk)oxido—A°— sulfnnylidene]cyanamide; enantiomer 2, (rac)-b‘thy1 [(3—flu 01‘0-5— -fluoro~2~methoxyphenyl)— 1 ,3,S—triazin yl]amino}benzy])(mcthyl)oxido-7»6—sulfanylidenekarbamate, (rac)(4-Fluoro~2~mcthoxyphcnyl)-N- {Ts-fluoro-S-[(S -methylsulfonimidoyl)methyl]phenyl}-1,3,5 - triazin-Z-ami nc, 4-(4-F1uoru—2-methoxyphenyl)—N-{3-fluoro-5—[(S—methylsulfonimidoyi)methy1]pheny]}-1,3,5-triazin—2— amine, cnantiomcr 1, luoro-Z-mcthoxyphcnyD—N— {S-fluoro-S-[{S-mcthylsulfonimidoyl)mcthyl]phenyl} -1 ,3,5—Triazin~2- , cnantiomcr 2, (rac)-4~ [2~(CycIohcxyhnetl1oxy)fluorophenyl]-N— {3-[(S-methylsulfonimidoyl)mcthy1]phenyl} —J ,3 , 5- Iriazin—Z—umine, (mo) oro-2 - [(4- fluorobenzyl)oxy]p11enyl} ~N~ {3-[(S-mcthylsulfonimidoyi)methyl}phenyl} - l,3,5-triazin-2—aminc, (rac)-4— {4-FIuoro—2-{2-(tctrahydro-ZH-pyran—4—yI)cthoxy]phcnyl} «N— {3—[(S-mcthylsulfonimidoyl)- methyl]phenyl} -triazinamine, (rac)(4-F Iuoro-Z-mcthoxyphenyl)-N-(3- {[S-(tetrahydro-2H-pyran-4—yi)sulfonimidoyl] methyl} ~ phcnyD-1,3,5-tn’azinaufine, (ra c)-N- {4—Chloro- 3- [(S-mcthylsu lfonimidoyl)mcthyl]phenyl} (4-fiuoro~2-mcthoxyphcnyl)-l ,3, 5- triazin-Z-amine, (rac)—Ethyl [{3 2-[(3,4-dichlowbenzyl)0xy]pheny1}-1,3.S-Iriazin-2~yl)aminu]ben2yl} (methyl)- oxido-?.6-su1fanylidcne]carbamate, (rac) {2-[(3,4-Dicl1lorobenzyl)oxy]pheny1} -N- {3-[(S-methylsu1fonimidoyl)1nethyl]phenyl}-1 ,3,5- triazin—Z-aminc, (rac)(4-Fluoro—2- { [(2H5)pheny1(2Hz)1nethyI]oxy} phenyl)-N- {3 -[(S-methylsulfonimidoyl)methyl] - pl1cny_l}-] ,3 ,5-triazinamine, 4-[2-(1 ~cyclopentylethoxy)fluorophenyl]-Nv {3-[(Smethylsulfonimidoyl)methy1]phenyl}-I ,3,5- triazin-Z-nminc, (rac)-N— {3-Chloro-S-[(S-methylsulfonimidoyl)mcthyl}phenyl}~4-(4—fluoro—2-methoxyphcnyl)- l ,3,5- triazin—Zamine, (ruc)-4—[4-Fluoro-2*(3,3 ,3 -triflu0ropropoxy)phcny1}-N- {3 -{(S—mcthyisulfonimidoyDmcthyIIphcnyl} - triazin-2—amine, (rac)[4—Fluoro—2-{pyri di n«3-yl y)pheny1] -N— {3-[(S-mcthylsulfonimidoyl) methyl ]pheny1} - 1,3,5-Triazinaminc, (rac)-4~{4-Fluoro-2—(pyridiny1mclhoxy)pheuyl]—N— {3-[(S-methylsulfonimicloyl)mcthyl]phcny1} - l,3,5-triazin~2—amine, (rac) [4-F1uoro(pyridin—4-y]methoxy)p henyl] -N— {3—[(S-me1hylsulfonimidoyl)methy l]phenyl} - 1,3,5-triazin—2-amine, 4-{4-Fluoro~2—[1-(4-fluorophenyl)ethoxy}pheny]}-N-{3-[(S—methylsulfonimidoyl)1ncthyl]phcny1}—1,3,5— triazin-Z-aminc, mixture of 4 stcrcoisomcrs, (rac)-[(3 -F1uoro { [4—(4-fluoromethoxyphenyl)-1 ,3, S—triazin-Z-y11amino} benzyl)(methyI-?.6- sulfauylidenekyanamidc, uoro~5— { [4-(4-fluoro-2~mcthoxyphcnyl)-1,3,5-triazin—2-yl]amino}bcnzyl)(mcthyl—?.6~ sulfauylidcncjcyanamidc; cnantiomcr I, {(fi3—Fluoro 5. [4-(4-fluoro—2-methoxyphenyl)- I ,3.5-triazinyl]amino } benzyl)(methyl-16— sulfianyiidcne]cyanamide; enamiomer 2, (rac)[2—(But—2—yn~1 -yloxy)f1uorophenyl]N {3— [(S-methylsulfonimidoyl)methyl]pheny1} -1 ,3 , 5- triazin—Z-aminc, 4-[2-(But-2—ynyloxy)—4-fluorophcny1]~N—{3-[(S—mcthylsulfonimidoyl)mcthyl]phcnyl}-1,3,5vtriazin- Z-aminc; enantiomer 1. 4—[2-(Butyn-E -yloxy)-4—fluorophcnyl]~N~ {3 -[(S-111ethylsu1f‘ouimidoyl)methyl}phcnyl} -l ,3 ,5-triazin- Z—amine; enantiomer 2, (rac)-4—[2-(2-Cyclopropylcthoxy)~4-fluoropheny1] -N- { 3 «[(S-methylsulfonimidoyl)mcfhyl] phenyl} - 1,3,5-triazinamine, (rac)[4-Fluoro-Z-(prop—Z—yn—1-yloxy)phenyl]-N-{3-[(S-methylsulfonimiduyl)methyl]phenyl}-1,3,5- triazin-Z-amine, 4-[4-Fluoro(prop-Z-yn-l-yloxy)phenyl]-N- {3-[(S-methylsulfonimidoyl)methyl]pheny1} —1,3,5-tria2in- Z-aminc; cnantiomcr l, 4-[4-F1u0ro(prop-2—yn—l ~yloxy)phenyl]-N»{3-[(S-1nethylsu1foni111idoyl)1nethyl]phenyl} -1 ,3,5-triazin- Z-amine; omcr 2, (rac)-4— {2- [(3 ,4 robenzy1)oxy] rophenyl} -N- {3-[(Smethylsu1fonimidoy1)methyl]phenyi} - 1,3,5—triazinamine, 4-[4-Fluoro-2~( l ,3 ~111iazolylmethoxy)phenyl]-N- {3 - [(Sumcthylsulfonimidoyl)mcthyl]phcnyl} - 1,3,5-triazinaminc, (rac)~4- {4-Fluoro—2-[(2-fluoropyridin~4-yE)methoxy]phcnyI}—N- -methylsulfonimidoyl)methyl]- phenyl} -] ,3,5-Iriazinamine, 4- {4-Fluoro—Z-[(2-fluoropyridinyl)mcthoxy}phcnyl} -N- {3~[(S-methylsulfouimidoyl)mcthyi]phenyl} - l,3,5—triazin-2~aminc; cnantiomer 1, 4- {4~Fluoro{(2- fluoropyridinyl)mcihoxflphenyl} -N- {3v[(S~mcthy]sulfon im icloyl) methyl]phcnyl} - 1,3,5-triazinamine; enantiomer 2, (rac)~4«[4-Fluoro-Z-(prop-Q-en-l ~yloxy)phcnyl]—N— {3 -[(S-methylsulfonimidoyl)methy1]pheny1} —1 ,3,5— triazin~2~1minc, (rac)-4—(4-Fluoro—2- {[4-(trifluoromcthyl)bcnzyl] oxy} phenyl)-N- {3 {($- méthyisulfonimidoyl)mcthyl]phcnyl}—1,3,5-triazin—2-aminc, (rac)-4— {2- [(4-Ch10robenzy1)oxy] fluorophenyl}-N- {3-[(S—melhylsulfonimidoyl)methprhenyl} - 1,3,5-triazinamine, (rac)(2—EthoxyfluorophcnyD—N— -mcthylsu1fonimidoy])mcthyl]phcnyl}-1 =3 ,S-triazin-z- amino, ' (rac)(4~F]uoro {{3 -fiuoro-S-(triflu01'0111et11yl)benzyl]oxy}phenyl)—N- {3-[(S-methylsulfonimidoyl)- methyi]phenyl} -1,3,5-1‘riazin—2-amine, (rac)‘4~ {4~Fluoro [(3 -fluorobcnzyl)oxy]phenyl} -N- -methylsulfonimidoybmethyl]phenyl] - I,3,5-triazin~2-aminc, (rac)(4-Fluoro-Z-propoxyphcnyl)-N- { 3-[(S-methylsulfonimidoyl)mcthy1]phenyl} —] ,3 , 5-triazin amine, (rac) {2~[(3-Chlorob enzyl)oxy] fluorophenyl} —N- {3-[(S-mcthylsulfonimidoyl)methy1]plmnyl} - l, 3, S-triazin-Z-amine, (rac)—4-[4 -F1uoro(l ,2-oxazo1-3 -ylmcthoxy)phcny1]-N—{3 -[(S—melhylsu lfonimicloy])mcthyl]phenyl} - 1,3,5 ~triazin—2-amine, (rac) {2-[(3—Chloro-S-fluorobenzyl)0xy]-4~ fluorophen'yl} -N- {3-[(S-melhylsulfonimidoyl)melhyl]- phenyi} -1 ,3 ,5-triazin—2-aminc, 4-[2-(2,2-Difluoroe1hoxy)fluorophenyl]-N— {3-[(S-methylsulfonimidoylhnethyl}phenyl}-1,3,5— triazin-l— amine, (rac) {4-Fluoro—2-[(4- fluoromethylbenzyi)oxy]phenyl} -N- {3 -{(S-methylsulfonimidoyI)1nefl1y1]- phcny1}-] ,3,5-1riazin-2—amine, 4~{2- [(3vChlorofluorobenzyl)oxy]—4~fluorophenyl} -N- {3- [(S-methylsulfonimidoyl)methyl]~ phenyl}-1,3,5-rriazin-2‘amine, (rac)-3 -( {S-Fluoro-Z- [4—( {3-[(S-mcthylsulfouimidoyl)mcthyl]phenyl} amino)- 1 ,3 ,S-triazin—Z—yl} y} 111cthyl)beuzonitri1c, (rac)-4—{4-Fluoro[(Z-rnethylprop-Z-cn-l-y1)0xy]pheny1}—N—{3—{(S-mcthylsulfonimidoyl)mcthyl]- } ~] ,3,5-triazin—2-amine, 4-[4-Fluoro—2—(4,4,4-trifluorobutoxy)phcnyl]—N- {3-[(S-mcthylsulfonimidoyl)methyl]phcnyl} - 1,3 ,S-triazin-Z-aminc, (rac)—4- {4-Fluoro [(2,3.5~1rifluorobeuzyl)oxy]phcuyl } -N- {3-[(S-mcthylsulfonimidoyl)mcthyl] - phenyl} -J ,3,5-1riazinamine, (rac)-4— {2~[(2Z)—Buten~ i -onxy]-4—fluorophenyl} ~N- -melhylsulfonimidoyl)methyl]phcnyi} “ 1,3,5-triazin-2—aminc, (rac) {4-F1uoro{(2,4,5-trifluorobenzyl)oxy]phonyl} -N- {3 -[(S-methylsulfonimidoyl)methyl} - phenyl} ~l ,3,5—triazin-2—aminc, 4- {4-Fluoro{(3 ,4,5-trifluorobenzyl)oxy]phcnyl} -N— {3{(8-methylsulfonirnidoyl)melhyl] - pltcnyl} — l ,3,5-triazin—2—amine, (rac)—[(2,3-Difluoro-S- { [4-(4-fiuoromcthoxyphcnyl)-I ,3,5-triazinyl]amino } bcnzyl)(mcthyi) oxido. lea-so lfanyl idcnc] cyanamidc, 1' rac)-N- {3,4—Difluoro[(S-methylsulfonimidoyl)methyl]pheny1}(4—fluoromethoxyphenyll- 1.3.5- triazinamine, (mo)-[Ethyl(3- {[4—(4-fluoromethoxyphenyl)—l ,3,5-triazin~2-yl]amino}benzyl)oxido-?»G- sulfanylidcno]cyanamidc, (rac)-N-{3—[(S-ethylsulfonimidoyl)mcthyl]phony]} (4-fluoro~2«methoxyphcnyh-1,3,5 in—2-aminc N- {3-[(S-ethylsulfonimidoyl)methyl]phenyl}(4-fluoromethoxyphenyl)-1 ,3 .S-triazin-Z-amine; chantiomer 1 , N- {3~[(8-ethylsulfonimidoyl)methyl]phenyl}(4-fluoro-Z-methoxyphenyl)—l ,3,S-triazinamine; cna ntiomcr 2, (rac)-L(3 - l L4-(4-F1uoro-2~methoxyphenyl)- I ,3,5-triaziny1Jamino} methylbenzyl)(methyl)oxido—X°— sulfanylidenekyanamide, (rac)({S-Fluoro-Z-[4—({3-[(S-mothylsulfonimidoyl)methyl}phcnyl}amino)— 1 ,3,5-triazin yl]phenoxy}methyl)propenoI, (rac)-[Cyclopropy1(3- {{4-(4-fluoro-Z-methoxyphenyl)-1 ,3,5-triazinyl]amino} bcnzyl)oxido ylidenc]cyanamide, or their salts, solvatcs or salts ofsolvates.
The mentioned definitions of ls which have been detailed in general terms or in red ranges also apply to the end products ofthe formula (I) or (la) or (lb) and, analogously, to the starting materials or intermediates required in each case for the preparation.
Scheme 1: The invention furthermore relates to a process for the preparation of the compounds of a (I) or (Ia) or (1b) according to the invention, in which N-unprotcctcd sulfoximines of formula (6) are reacted to give Nv functionalized sulfoxmines of formula (I) or (Ia) or (ID). 3 3 R4 R R4 R A A N \N HN o N \N __m.___. R” N o a / i / RV N N R2 RV N N R2 H H formula _6 la (I). R5 = H) (I) The present invention therefore relate: to a method for the preparation of the compounds of a (I) or (la) or (lb), in which R5 is not a hydrogen atom, according to the invention, in which method the nitrogen of the sult‘oximine group of a compound of formula (6) HN\\ ”0 ANARZNi“ N R1 /8 N in which R', R2. R‘ and R‘1 are as defined for the nd of general formula (I) or (Ia) or (11)) according to the invention, is functionalized according to methods known in the art, thus providing a compound of general formula (I) or (In) or (ID) according to the invention, in which R5 is not hydrogen, and the resulting compounds are optionally, if appropriate, d with the corresponding (i) solvents and/or (ii) bases or acids to the solvates, salts and’or solvates of the salts thereof.
There are multiple methods for the ation of N—functionalized sulfoximines by fimetionalization of the nitrogen of the sulfoximine group: - Alkylation: see for example: a) U. Liicking ct al, US 2007/0232632; b) CR. Johnson, J. Org. Chem. 1993, 58, 1922; c) C. Bolm et al, Synthesis 2009, 10, 1601.
- Acylation: see for example: a) C. Bolm et al, Chem. Europ. J. 2004. 10, 2942; b) C. Bolm et 9.1, Synthesis 2002, 7, 879; c) C. Bolm et al, Chem. Europ. J. 200], 7, 1118.
~ Aryletion: sec for example: a) C. Bolm et al, 'I‘et. Lett. 1998, 39, 5731; b) C. Bohn et 211., J. Org. Chem. 2000, 65, 169; c) C. Bolm et al, Synthesis 2000, 7, 911; d) C. Bolm et al, J. Org. Chem. 2005, 70, 2346; e) U. Liicking ct al, W02007/71455.
- Reaction with isocyanales: see for example: a) V.J. Bauer et al, J. Org. Chem. 1966, 31, 3440; b) C. R.
Johnson et al, J. Am. Chem. Soc. 1970, 92, 6594; c) S. ark et al, Acta Chem. Scand. Ser. B 1983, 325; d) U. Liicking et a1, U82007/0'l91393.
- Reaction with snlfonylchlorides: see for example: a) D.J. Cram et al, J. Am. Chem. Soc. 1970, 92, 7369; b) (LR. Johnson et al, J. Org. Chem. 1978, 43, 4136; 0) AC. Barnes. J. Med. Chem. 1979, 22, 418; d) D. Craig et a1, Tet. 1995, 51, 607]; e) U. Liicking et al, /19l393.
- Reaction with formiates: see for example: a) RB. Kirby et at, DE2129678; b) DJ. Cram et al. J. Am.
Chem. Soc. I974, 96, 2183; c) P. Stoss ct. nl, Chem. Ber. I978, ill, 1453; d) U. Liieking ct. al, W02005/37800.
N-unprotected sulfoximines of' formula (6) can be prepared by depretection ol’N-protected sulfoximines of formula (5). Preferred it the use of sodium ethanolate in ethanol at 60°C (see for example: U. Liicking et at, W02005/37800). > R3 R4 4 R3 o R NIAN M /\ No/P HNo/P NI \N Res ) NAN/AR: H H (formula (I), R5 = C(O)0Et) 6 (formula (I), R5 = H) The invention therefore rmore relates to a method for the preparation of the compounds of formula (1) or (la) or (lb) according to the t invention, in which R5 is a hydrogen atom (identical to the N- unprotected sulfoximines of formula (6) shown above), according to the invention, in which method the -C(O)O-Ethyl group of an N-protectcd compound of formula (5) o R4 Moo\ / Ni“ O S A A R)" 2 in which R‘, RLR3 and R”1 are as defined for the compound of general formula (I) or (Ia) or (ID), is deprotected according to methods known in the art, thus providing a compound ofgeneral formula (I) or (Ia) or (1b) according to the invention, in which R5 is a hydrogen atom, and the resulting compounds (the oteeted sultbximines of formula (6) shown above) are optionally, if appropriate, reacted with the corresponding (i) solvents and/or (ii) bases or acids lo the soivales, salts and/or solvates ofthe salts thereof.
The invention furthermore relates to a method for the preparation of the compounds of formula (I) or (In) or (1b) according to the t invention, in which R5 is ~C(O)O-Ethyl (identical to the N-protected sulfoximines of formula (5) shown , in which method an intermediate compound of formula (3), > R3 0 R4 O S H/ RV N N CI in which R', R3 and R4 are as defined for the compound of general formula (I) or (la) or (lb), is reacted with a compound of formula (4) R—O\ in which R2 is as defined for the compound of general formula (I) or (Ia) or (Ib),and R represent, independently from each other, a hydrogen atom, or a Ci-Cm-alkyl group or, atively, both R together form a R-R group, which is —C(CH3)2—C(CH3)2—, thus providing a compound of general formula (I) or (Ia) or (11)) according to the invention. in which R5 is —C(O)O-Ethyl, and the resulting compounds (see N—proteeted sulfoximines of formula (5) shown above) are optionally, if appropriate, reacted with the corresponding (i) solvents and/or (ii) bases or acids to the solvates, salts and/or solvates of the salts thereof.
Compounds of general formula (4) can be prepared ously to known processes (review: D.G. Hall, Boronic Acids, 2005 WILEY—VCH Verlag GmbH & Co. KGaA, Weinheim, ISBN 330991—8 and references cited herein). Further, a wide y of compounds of general formula (4) are commercially available.
The coupling reaction of compounds of formula (3) with compounds of formula (4) is catalyzed by Pd catalysts, e.g. by Pd(0) catalysts or by Pd(H) catalysts. Examples for I’d(0) sts are tetrakis(triphenylphosphine)palladium(0) ha)4] or tris(dibenzylideneac-etone)di—palladium(0) [Pd2(dba)3], examples for Pd(II) catalysts dichlorobisfiriphenylphosphine)—palladium(II) [Pd(PPh3)2C12], palladiumfll) acetate and ti‘iphcnylphosphine or [1, l‘-bis(diphenylphosphino)ferrocene]palladium dichloride {Pd(dppf)C12] (review: 110. Hall, Boronic Acids, 2005 VCH Verlag Gmbl-l & Co. KGaA, Weinheim. lSBN 30991 -8 and references cited therein).
This reaction is preferably carried out in aproiie or protic solvents, preferably in a e of c and protic solvents, more preferably in solvents like, for example, l,2-dimethoxyethane, dioxane, dimethlyformatuid, ydrofuran, or isopropanol with water (review: D.G. Hall, Eoronic Acids, 2005 WILEY-VCI-I Verlag GmbH & Co. KGaA, Weinheim, ISBN 3—5278 and references cited therein).
Preferably the reaction is carried out in the ce of a suitable base, such as for example aqueous potassium carbonate, aqueous sodium onate or aqueous potassium phosphate (review: D.G. Hall, Boronic Acids 2005 WILEY-VCl-l Verlag Gmbl-i & Co. KGaA, Weinlteim, ISBN 3—5278 and references cited therein).
The reaction is performed at temperatures ranging from room temperature (=20°C) to the boiling point of the solvent. Further on, the reaction can be med at temperatures above the boiling point using pressure tubes and a microwave oven. w: D.G. Hall, Boronic Acids, 2005 WILEY-VCH Verlag Gmbl-l & Co. KGaA, Weinheim, lSBN 330991-8 and references cited therein).
The on is preferably completed after 1 to 36 hours of reaction time.
Compounds of general formula (3) can be obtained as follows: o R 0}”ng > % Rt/ R4 R NH; O gt r o / )‘s’ i , c: N Cl if N 0' chloro-l,3,5-rriazinc (I), which is known [GAS-Registry Number: 283l5] or can be prepared analogously to known processes, is reacted with suitable anilincs of formula (2) to give the corresponding 4—chloro-N-phenyl-1,3,5-triazin-2—amines offormula (3).
This reaction can be d out with one equivalent of the aniline of formula (2) in an inert solvent like, for example, l,Z-ditnethoxyethane, dioxane, dimcthlyfonnamid, tetrahydrofiiran, or an alcohol like, for example, isopropanol, or mixtures of such ts. Preferably, the reaction is carried out at a temperature below 0°C in such a way that the reaction mixture is kept homogenous. red conditions use an additional base like for example tricthylaminc or N,N-diisopropylethylaminc. The reaction is ably completed after 1 to 6 hours.
Anilines of formula (2) can be prepared by the following processes: Reaction of suitable benzylchlorides or bromides of formula (7) with suitable thiois of a (8) under basic conditions yields the corresponding thioethcrs of formula (9) (sec for example: Sammond et a1, Bioorg. Med. Chem. Lett. 2005, 15, 3519).
R4 R R1/S\H R4 R . ——-————> S +- 7 6‘ 9 0" LG = Cl. Br Oxidation of hers of formula (9) gives the corresponding sulfoxides of formula (10). The oxidation can be performed analogously to known processes (see for example: (a) M.H. Ali et al, Synthesis 1997, 764; (b) M.C. o, Chem. Rev. 1995, 95, 1717; (e) l. Patel et al, Org. Proc. Res. Dev. 2002, o, 225; (d) N. Khiar et a1, Chem. Rev. 2003, 103, 365]). Peferred is the herein described use of periodic acid und iron(111)chloride.
R3 R4 R R1/Sso —_—.—-—.--—> s +._() N-HO R1/ “ll 9 cl)" 10 o" Rhodium-catalyzed imi'nalion of the sulfoxides of formula (10) followed by deprotection gives the corresponding N—unprotected sulfoximines offormula (1 1) (see for example: Bolin et al, Org. Lett. 2004, 6, 1305).
R3 R3 R4 R4 RVs N+-.o Hum» RVs MO 1o (5* 11 (5 Introduction of a. le protecting group leads to N-protected sulfoximines of a (12) (see for example: Liicking ct al, ).
R3 > R3 R4 0 R“ HNxV/O 0%NoSI/O R1/3 1 / .0 NW” .0 R N+ 11 a; 12 ('3 Reduction of the nitro group finally gives the desired anilincs of formula (2). The reduction can be prepared analogously to known processes (sec for example: (a) d et a]; Bioorg. Med. Chem.
Len. 2005, 15. 3519; (b) R.C. Larock, Comprehensive Organic Transformations, VCH, New York, 1989, 411—415). 4 R3 2 3 o>—N :2) R4 R \\ // >—-N\ ,0 O 1/8 ' +30 0 \S/ R I‘lfi R1/ NH2 O 2 The preparation of the compounds of general formula (I) or (In) or (lb) according to the ion can be illustrated by fine following synthesis schcmc (Scheme 1): O> R3 >—N o \\// > 3 0 8 4 R R1/ O R NH /\ m 2 W CI/kNACIl / / s/ 11 (j N C' 1 3 > R-O\ ,B—R R3 R—O > 3 O R R A 4 O R4 N O N N A J|\ / -—-—-———-—-—-> N O N N \\// O 1/5 0 $30 JL / Q N ‘3' RV N N R2 (formula (l), R5 = C(O)0Et} H H (formula (I). R5 = C(O)0Et) 6 (formula (I), R5 = H) 3 3 R R4 R “0:111 *—*R4 A A \ \ N R 0:115_ N R1/ N/ ” R2 R1/ m N R2 formula ‘6 (formula (I), R5 = H) (I) Compounds of general formula (Ia), (1b), (2a), (3a), (5a), (6a) can be prepared analogously.
Scheme 2: The invention furthermore s to a method for the preparation of the compounds of formula (I) or (Ia) or (lb) according to the present invention, in which R5 is a hydrogen atom (identical to the N- unprotccted sulfoximines of female (6) shown above), in which method a compound ot‘fonnula (l 5) o N \ N 3 JL A Rt/ N N R2 in which R‘, R2,R3 and R‘1 are as defined for the compound of formula (I) or (Ta) or (lb) according to the present invention, is reacted with sodium azide in the presence of an acid thus providing a compound of general formula (I) or (Ia) or (11)) according to the invention, in which R5 is a hydrogen atom, and, the resulting compounds (the N—unprotected sulfoximines 'of formula (6) shown above) are optionally, if appropriate, reacted with the corresponding (i) solvents and/or (ii) bases or acids to the solvates, salts and/or solvates of the salts thereof.
This reaction is preferably d out in the presence of sulfuric acid or polyphosphoric acid. It is preferably carried out in oromethane in the presence of sulfuric acid and at temperatures ranging from 40°C to 50°C, preferably from 43°C to 47°C, most red at about 45°C. This on is preferably completed afier l2 hours to no hours ol’ reaction time (see for example: a) H. R. Bentley et al’ J. Chem. Soc. 1952, 1572; b) C. R Johnson et at, J. Am. Chem Soc. 1970, 92, 6594; c) Satzinger et al, Angew. Chem. 1971, S3, 83).
In another embodiment of the present invention the method of the present ion is performed with sodium azide in polyphosphoric acid at temperatures ranging from 40°C to 70°C, ably from 55°C to 65°C. most preferred at about 60°C (see for example: a) MD. Sindkhedkar et a1, ).
The preparation of compounds of general formula (15) is described below in context of the description of synthesis Scheme 2. Compounds of general formula (la) or (lb) can be ed analogously.
Scheme 3 The invention furthermore relates to a method for the preparation of the compounds of formula (I) or (Ia) 01' (11)) according to the t ion, in which R5 is a cyano group (identical to the N- ulfoximines of formula (20)), R4 3 N R \\ // Rt/S J\NARZ| in which method a compound of formula (19) R4 3 N\ R \\i‘l Nl/stN RVs NAN/AR. in which R'. R2, R1 and R‘1 are as defined for the compound of formula (I) or (Ia) or (Ib) according to the present invention, is oxidized ing to methods known in the an, thus providing a compound of general formula (I) or (Ia) or (ID) according to the invention, in which R5 is a cyano group. and the resulting nds (the N-cyanosulfoximines of formula (20) as shown above) are ally, if appropriate. reacted with the corresponding (i) solvents and/or (ii) bases or acids to the solvates, salts and/or solvatcs of the salts thereof.
There are multiple s for the oxidation of osulfiliminos of formula ([9) to N— cyanosulfoximines of formula (20): a) C. Bolm ct a1, Org. Lctt. 2007, 9, 3809 b) I.E.G. Kemp et a1, Tet. Lett. 1979, 39, 3785 0) MR. Loso et al, US patent publication /0203l9].
The preparation of compounds of general formula (19) is described below in context of the description of synthesis Scheme 3. Compounds of general formula (In) or (lb) can be prepared analogously.
The invention furthermore relates to a method for the preparation of the compounds of formula (I) or (Ia) or (11)), in which Rs is a hydrogen atom (identical to the sulfoximines of formula (6)), R4 R S 11/ Rt/ g N R2 6 (formula (I), R5 = H) in which method the N-eyano group ofthe compound of formula (20) R 3 N R \V/ 1 S / RV NANARZ in which R', R333 and R4 are as defined for the compound of formula (I) or (Ia) or (11)), is converted Upon ent with TFAA to the corresponding N-trifluoroacctylsulfoximine, which N— trifluoroacetylsulfoximine is converted by methanolysis into the nd of general formula (I) or (Ia) or (Ib) according to the invention, in which R5 is a hydrogen group, and the resulting compounds (compounds of general formula (6)) are optionally‘ if appropriate. reacted with the corrCSponding (i) solvents and/or (ii) bases or acids to the solvates, salts and/or solva’tes of the salts thereof.
The preparation of compounds of general formula (6) from compounds of general formula (20) is bed in more detail below in context of the description of synthesis Scheme 3.
Scheme 4: The invention furthermore relates to a method for the ation of the compounds of formula (I) or (Ia) or (lb) ing to the present invention, in which R5 is a hydrogen atom ical to the N- unprotected sulfoximines of formula (6) shown above). in which method a compound of formula (22) 4 R3 O R >—N o NAN F o “s” )L / Rt/ ti N 22 R7 in which R‘, R3, R4, R6 and R7 are as defined for the compound of general formula (i) or (Ia) or (lb) according to the invention, is solubilized in an alcohol RB—OH, in which R5‘ is as defined for the compounds of general formula (I) or (Ia) or (Ib)aecording lo the invention and is reacted With at least two equivalents of alkali hydride. thus providing a compound of general formula (I) or (Ia) or (1b) according to the inventiOn, in which R5 is a hydrogen atom, and the resulting compounds (the N-unprotected imines of formula (6)) are ally, if appropriate, reacted with the corraponding (i) solvents and/or (ii) bases er acids to the solvates, salts and/or solvates of the salts thereof.
The on can be med with potassium hydride or sodium hydride. Preferably, it is performed with sodium hydride. The reaction is performed at temperatures ranging from 40°C to the boiling point of the alcohol Rs-Ol-l, preferably at 50°C to 70°C. The reaction is preferably ted after IO to 100 hours ufreaction time.
The preparation of compounds ofgeneral formula (22) is described below in context of the description of synthesis Scheme 4. Compounds of general fonnula (1a) and (1b) can be prepared analogously.
In another embodiment the present invention concerns ediate compounds of general formula (3) 4 R3 O R O S H/ R" N N e: 3 or of general formula (3:1) > as O R4 >—N\ IO\ / O [+41\ RV n N on 3a ,wherein R’, R3 and R4 are as defined for the compound of general formula (I) or (Ia) or (1b) ing to the invention.
In another embodiment the present invention ns compounds of general formula (5) O R Mp\I tit/w O S nANARZ/ R1/ >/—N /\ o N/ N O 1/\\Sll \ J\ fl] N R 53 ,wherein R‘, R3, R3 and R‘ are as defined for the compound of general formula (I) or (Ia) or (Ib) ing to the invention.
In another embodiment the present invention concerns compounds of general formula (2) o> R3 H0 \\l/ O S R NH2 or of general formula (221) > as O R4 o “no RV NH2 , wherein R’, R3 and R4 are as d for the compound of general formula (I) or (Ia) or (1b) according to the invention.
In another embodiment the present invention cancerns compounds of general a (11) “V 0 R1/ N+‘- 11 g,- or of general formula (11a) R1/ +« .0 1 1 a O” , wherein R‘, R3 and R" are as defined fortho compound of general a (I) or (in) or (lb) according to the invention.
In another ment the present invention concems compounds ofgeneral formula (12) :N—R\\// R1/s O 12 (5* or of general formula (12a) 3 R3 :2 R4 \\ f/O R1/S liq-v.0 12a 0 l0 R‘, R3 and R4 are as defined for the compound of general formula (I) or (Ia) or (lb) according to the invention.
In another embodiment the present invention concerns compounds of general formula (20) R4 3 N R \\ // A| S / R1/ N N/I\R2 or of general formula (20a) N 3 \\ 4 R /\ \ I S 11/ R‘l/ l?! N R2 :]. wherein R’, R3, R3 and R4 are as defined for the compound ofgeneral formula (I) or (Ia) or (11)) according to the invention.
The compounds according to the invention show a valuable pharmacological and pharmacokinetic spectrum of action which could not have been ted.
They are therefore suitable for use as medicaments for the treatment and/or prophylaxis of disorders in humans and animals.
Within the scope of the t invention, the term “treatment” includes prophylaxis.
The pharmaceutical ty of the compounds according to the invention can be explained by their action as tors of CDK9. Thus. the nds according to the general formula (I) or (Ia) or ([11) as well as pharmaceutically acceptable salts thereof are used as tors for CDK9.
Furthermore, the nds according to the invention show a particularly high potency (demonstrated by a low 1cm value in the CDK9/Cych assay) for inhibiting CDK9 activity, in context of the present inVention, the ICso value with respect to CDK‘) can be determined by the methods described in the method section below. Preferably, it is determined according to Method 1.
(“CDK9/Cych kinase assay") described in the Materials and Method section below.
Surprisingly it turned out that the compounds according to the general a (I) or (Ia) or (lb) as well as pharmaceutically acceptable salts thereof selectively inhibit CDK9 in comparison to other cyclin- dependent protein kinases, preferably in comparison to CDKZ. Thus, the compounds according to the general a (I) or (12) or (Ib) as well as pharmaceutically acceptable salts thereof are preferably used as selective inhibitors for CDK9.
Compounds of the present invention according to general formula (1) or (la) or ([b) show a significantly stronger CDK9 than CDK2 inhibition. Preferred compounds of the present invention show a CDKZ leo / CDK9 ICso ratio of more than 40, ably of more than 55 and even more preferably of more than 70. The CDK9 ICsn is determined according to Method 1.. the CDKZ ICso according to Method 2, both described in more detail in the als and Method section below. in context of the present invention, the ICso value with respect to CDK2 can be determined by the methods described in the method section below. Preferably, it is ined ing to Method 2.
/Cch kinase assay”) described in the Materials and Method section below.
Further, compounds of the present invention according to formula (I) or (la) or (lb) mediate a surprisingly strong anti-proliferative activity in tumor cell lines such as HeLa and/or DUl45. In context of the present invention, the ICso values of the compounds with respect to these cell lines is ably determined according to Method 3. (“Proliferation Assay”) described in the Materials and Method section below.
Further, preferred compounds ofthe present invention according to formula (I) or (Ia) or (Ib) surprisingly show an increased solubility in water at pH 6.5 compared to the compounds described in the prior art.
In context ofthe present ion the solubility in water at pH 6.5 is preferably determined according to Method 4. (“Equilibrium Shake Flask lity Assay") bed in the Materials and Method section below.
Further, compounds of the t invention according to formula (I) or (Ia) or (Ib) show no significant inhibition of carbonic anhydrase—l or «2 (ICSO values of more than 10 MA) and therefore show an improved side effect profile as compared to those CDK tors described in the prior art containing a sulfonamide group, which inhibit carbonic anhydrase-l or -2. in context of the present invention, the carbonic anhydrase-l and -2 inihibtion is preferably ined according to Method 5. (“Carbonic anhydrasc Assay”) described in the Materials and Method section below.
A fiirther subjecl matter of the present invention is the use of the compounds of general formula (I) or (Ia) or (Ib) according to the invention for the treatment and/or prophylaxis of disorders, preferably of disorders relating to or mediated by CDK9 activity, in particular of hyper—proliferative disorders, virally induced infectious diseases and/or ofcardiovascular diseases, more preferably of hyper-proliferative disorders.
The nds of the present invention may be used to inhibit the activity or expression of CD10. ore, the compounds of formula (I) or (In) or (Ib) are cd to be valuable as therapeutic agents.
Accordingly, in r embodiment, the present inventioa provides a method of treating disorders relating to or mediated by CDKQ activity in a patient in need of such treatment, comprising administering .to the patient an effective amount of a compound of formula (I) or (Ia) or (lb) as defined above. in certain embodiments, the ers relating to CDK9 activity are hyper—proliferativc disorders, virally induced infectious diseases and/or of cardiovascular diseases, more preferably hyper-proliferative disorders, particularly .
The term "treating" or "treatment" as stated throughout this document is used conventionally, e.g., the management or care of a subject for the purpose of combating, alleviating, reducing, relieving, improving the condition of a disease or disorder. such as a carcinoma.
The term "subject" or "patient" includes organisms which are capable of suffering from a cell proliferative disorder or a disorder associated with reduced or insufficient programmed cell death osis) or who could otherwise benefit from the administration of a compound of the invention, such as human and man animals. Preferred humans include human patients ing from or prone to suffering from a cell proliferative disorder or associated state, as described herein. The term "non-human animals" es vertebrates, e.g., mammals, such as man primates, sheep, cow, dog, cat and s, e.g., mice, and non-mammais, such as chickens, amphibians, es, etc.
The term "disorders relating to or mediated by CDK9" shall e diseases associated with or implicating CDK9 activity, for example the hyperactivity of CDK9, and conditions that accompany with these diseases. Examples of "disorders relating to or mediated by CD149" include disorders resulting from increased CDK9 activity due to mutations in genes regulating CDK9 ty auch as LARP7, HEXIMi/Z or 7sk snRNA, or disorders resulting from sed CDK‘) activity due to activation of the CDK9/cyelinT/RNApolymerase ll complex by viral proteins such as HIV~TAT or HTLV-TAX or disorders resulting from increased CDK9 ty due to activation of mitogenic signaling pathways.
The term "hyperactivity of CDK9" refers to sed enzymatic activity of CDK9 as compared to normal non-diseased cells, or it refers to increased CDK9 activity leading to unwanted cell proliferation, or to reduced or insufficient programmed cell death osis), or mutations leading to constitutive activation of CDK9.
The term “hyper—proliferative disorder” includes disorders involving the undesired or uncontrolled eration of a cell and it includes disorders ing reduced or insufficient programmed cell death (apoptesis). The compounds of the present invention can be utilized to t, inhibit, block, reduce, decrease, control, etc., cell proliferation and/or cell division, and/or produce apoptosis. This method comprises administering to a subject in need thereof. including a mammal, including a human, an amount of a compound of this invention, or a pharmaceutically acceptable salt, hydrate or solvate thereof which is effective to’ treat or prevent the disorder.
Hyper-proliferative disorders in'the context of this invention e, but are not limited to, e.g., psoriasis, keloids and other hyperplasias affecting the skin, endometriosis, skeletal disorders, angiogenic or blood vessel proliferative disorders, ary hypertension, fibrotic disorders, mesangial cell proliferativo disorders, colonic polyps, stic kidney disease, benign prostate hyperplasia (BPH), and solid tumors, such as cancers of the breast, respiratory tract, brain, reproductive organs, digestive tract, urinary tract, eye, liver, skin, head and neck, thyroid, parathyroid, and their distant metastases.
Those disorders also e lymphomas, sarcomas and leukemias. es of breast cancer include, but are not limited to invasive ductal oma, invasive lobular carcinoma, ductal carcinoma in situ, and lcbular carcinoma in situ. Canine or feline mammary carcinoma.
Examples of cancers of the respiratory tract include, but are not limited to small-cell and non-small-ccll lung carcinoma, as well as ial adenoma, pleuropulmonary blastoma, and mesothelioma.
Examples of brain cancers include, but are not limited to brain stem and liypOphtalmic glioma, cerebellar and cerebral astrocytoma, glioblastoma, medulloblastoma, ependymoma, as well as ueurocctodermal and pineal tumor.
Tumors of the male reproductive organs include, but are not d to prostate and testicular cancer.
Tumors of the female reproductive organs include, but are not d to endometrial, cervical, ovarian, vaginal and vulvar cancer, as well as sarcoma of the .
Tutnors of the digestive tract include, but are not limited to anal, colon, colorectal, esophageal, gallbladder, c, pancreatic, rectal, small-intestine, and salivary gland cancers. Anal gland adenocarcinomas, mast cell tumors.
Tumors of the urinary tract include, but are not limited to bladder, penile, kidney, renal pelvis, ureter, urethral, and hereditary and sporadic papillary renal cancers.
Bye cancers e, but are not limited to intraocular melanoma and retinoblastoma.
Examples of liver cancers include, but are not limited to hepatocellular carcinoma (liver cell carcinomas with or without fibrol‘dmellar variant), giocarcinoma heputic bile duct carcinoma), and mixed hepatocellular cholangiocarcinoma.
Skin cancers include, but are not limited to squamous cell carcinoma, 's sarcoma, malignant melanoma, Mcrkcl cell skin cancer, and non-melanoma skin cancer. Mast cell tumors.
Head-and—neck cancers include, but are not limited to laryngeal, hypopharyngeal, nasophatyngeal, oropharyngeal cancer, lip and oral cavity , and squamous cell cancer. Oral melanoma.
Lymphomas include, but are not limited to AIDS-related lymphoma, dgkin's ma, cutaneous T~ccll lymphoma, Burkitt lymphoma, Hodgkin's disease, and lymphoma of the central nervous system.
Sarcomas include, but are not limited to sarcoma of the soft tissue, osteosarcoma. malignant fibrous histiocytoma, lymphosarcoma, and rhabdomyosarcoma. Malignant cytosis, fibrcsarcoma, hemangiosarcorna, hemangiopericytorna, leiomyosarcoma.
Leukemias e, but are not limited to acute mycloid leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, chronic myelogenous leukemia, and hairy cell leukemia.
Fibrotic proliferative disorders, Le. the abnormal fomtation of extracellular matrices, that may be treated with the compounds and methods of the t invention include lung fibrosis, atherosclerosis, rcstenosis, hepatic cirrhosis, and mesangial cell proliferalivc disorders, including renal diseases such as ulonephritis, diabetic nephmpatliy, malignant nephrosclcrosis, thrombotic microangiopathy syn- dromes, transplant rejection, and glomerulopathies.
Other conditions in humans or other mammals that. may be treated by administering a compound of the present invention include tumor growth, retinopathy, including diabetic retinopathy, ischemic retinal- vein ion, retinopathy of prematurity and age—related macular degeneration, rheumatoid arthritis, sis, and s disorders ated with subepidermal blister formation, including bullous pernphigoid, erythema multiforme and dermatitis herpetifomiis.
The compounds of the present invention may also be used to prevent and treat diseases of the airways and the lung, es of the gastrointestinal tract as well as diseases ot‘the bladder and bile duct. .15 The ers mentioned above have been well characterized in humans, but also exist with a similar etiology in other s, including mammals, and can be treated by administering pharmaceutical compositions of the present invention.
In a further aspect of the present invention, the nds according to the invention are used in a method for preventing and/or treating infectious diseases, in particular virally induced infectious es. The vitally induced infectious diseases, including opportunistic diseases, are caused by retroviruses hepadnaviruses, herpesviruses, flaviviridae, and/or adenoviruses. In a further preferred embodiment of this method, the retroviruses are selected from lentivituses or encoretroviruscs, n the irus is Selected from the group comprising: HIV-l, HIV-2, FIV, BIV, SIVs, SHIV, CAEV, VMV or EIAV, preferably HIV-l or HIV-2 and wherein the onccrctrovirus is selected from the group ting of: I-ITLV—I, HTLV-ll or BLV. In a further preferred embodiment of this method, the hepadnavirus is selected from HBV, GSHV or WHV, preferably HBV, the herpcsivirus is selected from the group comprising: HSV I, I-lSV II, EBV, VZV, HCMV or HHV 8, ably HCMV and the flaviviridae is selected from HCV, West mile or Yellow Fever.
The compounds according to general formula (I) or (Ia) or (11)) are also useful for prophylaxis and/or treatment of cardiovascular diseases such as cardiac hypertrophy. adult congenital heart disease. aneurysm, stable angina, unstable angina, angina pectoris, angioneurotic edema, aortic valve stenosis, aortic aneurysm, arrhythmia, arrhythmogenic right ventricular dysplasia, arteriosclerosis, arteriovenous malformations, atrial fibrillation, Behcet syndrome, ardia, cardiac tamponade, cardiomegaly, congestive niyopathy, hypertrophic cardiomyopathy, restrictive cardiomyopathy, cardiovascular e prevention, carotid stenosis, cerebral hemorrhage, Churg-Strauss syndrome, diabetes, Ebstein's Anomaly. Eisenmenger complex, cholesterol embolism, bacterial rditis. fibromuscular dysplasia, congenital heart defects, heart diseases, tive heart failure, heart valve es, heart attack, epidural hematoma, henratoina, subdural, Hippel-Lindau disease, hyperemia, hypertension, pulmonary hypertension, hypertrophic growth, left ventricular hypertrophy, right ventricular hypertrophy, hypoplastic left heart syndrome, hypotension, ittent clandication, ischemie heart disease, [Clippel- Trcnaunay-Webcr me, lateral medullary syndrome, long QT syndrome milral valve prolapse, moyamoya disease, muoncutaneous lymph node syndrome, myocardial infarction, myocardial isahemia, myocarditis, perioarditis, peripheral vascular diseases, phlebitis, polyartcritis nodosa, pulmouary atrcsia, Raynaud e, restenosis, Sneddon syndrome, stenosis, superior vena cava syndrome, syndrome X, tachycardia, su's arteritis, hereditary hagic telangiectasia, telangieetasis, temporal afleritis, tetralogy of fallot, thrornboangiitis obliterans, osis, thromboembolism, tricuspid atresia, varicose veins, vascular diseases, vasculitis, vasospasm, cular fibrillation, Williams syndrome, peripheral vascular disease, varicose veins and leg ulcers, deep vein thrombosis, Wolff-Parkinson—White syndrome.
Preferred are cardiac hypertrophy, adult congenital heart disease, aneurysms, angina, angina pectoris, arrhythmias, cardiovascular disease prevention, cardiomyopathies, congestive heart failure, myocardial infarction, pulmonary hypertension, hypertrophic growth, restenosis, stenosis, thrombosis and arteriosclerosis.
A further subject matter of the present invention is the use of the compounds of general formula (I) or (Ia) or (lb) according to the invention for the treatment and/or prophylaxis of disorders, in particular of the disorders mentioned above.
A further subject matter ofthe present invention are the compounds according to the invention for use in a method for the ent and/or prophylaxis of the disorders ned above.
A further subject matter of the present invention is the use of the compounds according to the invention in the manufacture of a medicament for the treatment. and/or prophylaxis of ers, in particular the ers mentioned above.
A further subject matter of the t ion is a method for the treatment and/or prophylaxis of disorders, in particular the disorders mentioned above, using an ive amount of the nds ing to the invention.
Another aspect of the present invention relates to pharmaceutical ations comprising a compound of general formula (I) or (In) or (Ib) according to the invention in nation with at least one or more further active ingredients.
As used herein the term “pharmaceutical cembination” refers to a combination of at least one compound of general formula (I) or (Ia) or (11)) according to the invention as active ingredient together with at least one other active ingredient with or without further ingredients, carrier, diluents and/or solvents.
Another aspect of the present invention relates to pharmaceutical compositions comprising a compound of general formula (1) or (In) or (lb) according to the invention in ation with an inert, ic, pharmaceutically suitable adjuvant.
As used herein the term “pharmaceutical composition” refers to a galenic formulation of at least one pharmaceuticaily active agent together with at least one further ingredient, r, diluent and/or solvent.
Another aspect of the present invention relates to the use of the ceutical ations and/or the pharmaceutical compositions according to the invention for the treatment and/or prophylaxis of disorders, in particular of the disorders mentioned above.
Compounds of formula (I) or (13) Or (lb) may be administered as the sole pharmaceutical agent or in ation with one or more onal therapeutic agents where the combination causes no unacceptable adverse effects. This pharmaceutical combination includes administration of a single pharmaceutical dosage ation which contains a compound of formula (I) or (Ia) or (ID) and one or more onal therapeutic agents, as well as administration of the compound of a (I) or (Ia) or (lb) and each additional therapeutic agent in its own separate pharmaceutical dosage formulation. For example, a compound of formula (I) or (Ia) or ([b) and a therapeutic agent may be administered to the patient together in a single oral dosage composition such as a tablet or capsule, or each agent may be administered in separate dosage formulations.
Where te dosage formulations are used. the compound of formula (T) or (Ia) or (lb) and one or more onal therapeutic agents may be administered at essentially the same time (e.g., concurrently) or at separately red times (e.g., sequentially). in particular, the compounds of the present invention may be used in fixed or te combination with other anti—tumor agents such as alkylating , anti-metabolites, plant-derived anti-tumor agents, hormonal therapy agents. omcrasc inhibitors, camptothecin derivatives, kinasc inhibitors. targeted drugs, antibodies, interferons and/or biological response modifiers, anti-augiogenic compounds, and other umor drugs. In this , the following is a non—limiting list of examples of secondary agents that may be used in combination with the compounds of the present invention: 0 ting agents include, but are not limited to, nitrogen mustard N-oxide, cyclophosphamide, ifosfamidc, thiotepa. ranimustine, nimustine, temozolomidc, altretaminc, apaziquone, brostallicin, bendamustine, carmnstinc, cstramustinc, fotcmustinc, glut‘osfamidc, mafosfamidc, bendamustin, and mitolactol; platinum-coordinated ting compounds include, but are not limited to, cisplatin, carboplatin, eptaplatin, lobaplatin, nedaplatin, oxaliplatin, and satraplatin; o Anti-metabolites include, but are not limited to, methotrexate, 6-mercaptopurine riboside, mercaptopurine, 5-fluorouracil alone or in combination with lcucovorin, tegafur, doxifluridine, cannofur, cytarabine, cytarabine oefosfate, cnocitabine, gemcitabine, fludarabin, S-azacitidine, capeeitabine. cladn'bine, clofarabine, dccitabine. ellornilhine. ethynylcytidine, cytosine arabinoside. hydroxyurea, melphalan, nelarabine, nolatrexcd, ocfosfite, disodium premetrexed, pentostatin, pelitrexol, raltitrexed, triapine, trimetrexate, vidarabine, vineristine, and lbine; Hormonal therapy agents e, but are not limited to, exemestane, , amutrozole, doxercaleiferol. fadrozole. formeslane. 11-beta hydroxysteroid dehydrogenase 1 inhibitors. 17-alpha hydroxylase/l7,20 lyase inhibitors such as abiraterone acetate, S-alpha reductase inhibitors such as finasteride and epristcride, anti—estrogens such as tamoxifen citrate and fulvestrant, Trclstar, toremifene, raloxifene, xifene, letrozole, anti-androgens such as bicalutamide, flutamide, mifepristonc, nilutamide, Casodex, and anti-progesteroncs and combinations thereof; Plant—derived anti-tumor substances include, e.g., those selected from mitotic inhibitors, for example epothilones such as sagopilone, ixabepilone and lone B, vinblastine, ine, docetaxel, and axel; Cytotoxic topoisomerase inhibiting agents include, but are not limited to, aclarubicin, doxorubiein, amonafide, belotecan, eamptothecin, 10~hydroxycamptotheein, 9-aminocamptotheein. diflomoteean, irinoteean, topoteean, edoteearin, epimbiein, etoposide, exateean, gimatecan, lurtotecan, mitoxantrone, pirambicin, pixantrone, rubitecan, sobuzoxane, tafluposide, and combinations thereof; Immunologicals include interferons such as interferon alpha, interferon alpha-2a, interferon alpha- 2b, interferon beta, interferon gamma-l a and interferon gamma—n1 , and other immune enhancing agents such as L} 9-1L2 and other 1L2 derivatives, filgrastim, lentinan, sizofilan, TheraCys, ubenimex, aldesleukin, alemtuzumab, RAM-002, dacarbazine, daclizumab, denileukin, gemtuzumab. ozogamiein, ibritumomab, imiquimod, lcnograstim, lentinan, melanoma vaccine (Corixa), molgramostim, mostim, tasonermin, tecleukin, thymalasin, tositumomab, Vimlizin, epratuzumab, mitumomab, omab, pemtumomab, and Provenge; Merial melanoma vaccine Biological response modifiers are agents that modify defense isms of living organisms or biological responses such as survival, growth or differentiation of tissue cells to direct them to have anti-tumor activity; such agents include. e.g., n, lentinan, sizofiran. nil, PruMune, and ubenimex; ngiogenie cempounds include, but are not d to, aeitrctin, aflibcrcept, tatin, aplidine, r, axitinib, recentin, bevaeizumab, brivanib alaninat, ciIengtide. eombretastatin, DAST, endostatin, inide, halofuginone, pazopanib, ranibizumab, rebimastat, removab, revlimid, scrafenib, vatalanib, squalamine, sunitinib, telatinib, thalidomide, ukrain, and vitaxin; Antibodies e, but are not limited to, trastuzumab, mab, zumab, rituximab, ticilimurnab, ipilimumab, lumitiximab, catumaxomab, atacieept, orcgovomab, and alemtuzumab; VEGF inhibitors such as, e.g., sorafenib, DAST, bevacizumab, suniiinib, recentin, axitinib, afli- t, telatinib, brivanib alaninate, vaialanib, pazopanib, and ranibizumnb; Palladia EGFR (HERi) inhibitors such as, e.g., cetuximab, panitumumab, vectibix, gefitinib, erlotinib, and I-IERZ inhibitors such as, e.g., lapatinib, tratuzumab, and pcrtnzuinab; mTOR inhibitors such as, e.g.. temsiroiirnus, sirolimus/Rapamycin, and everulimus; c-Mct inhibitom; PBK and AKT inhibitors; CDK inhibitors such as roscoviiinc and flavopiridol; Spindle assembly checkpoints inhibitors and ed anti-mitotic agents such as [’LK inhibitors, Aurora inhibitors (ag. Hesperadin), checkpoint kinase inhibitors, and KS? inhibitors; HDAC inhibitors such as, e.g., panobinostat, vorinosiat, 348275, bclinostat, and LBH589; HSP90 and I-ISP70 inhibitors; Proteasome inhibitors such as bortuzomib and cariilzomib; Scrine/thrconino kinasc tors including MEK inhibitors (such as e.g. RDEA ] 19) and Raf inhibitors such as sorafenib; Famesyi lransferasc inhibitors such as, e.g., tipifamib; Tyrosine kinase tors including, e.g., nib, nilotibib, DAST, bosutinib, sorafenib, bcvaciznmab, sunitinib, A7.D2171, axitinib, aflibcrccpt, relatinib, imatinib mcsyiatc, brivanib ate. pazopanib, ranibizumab. vatalanib, cetuxinmb, panirumumab, vectibix, gefitinib, erlotinib, lapalinib, umab, pertuzumab, and c—Kit inhibitors; Pailadia, nib Vitamin D receptor agonists; Bel-2 protein'inhibitors such as lax, oblimerscn sodium, and gossypol; r of differentiation 20 receptor antagonists such as, e.g., rituximab; Ribonucleotidc rcductasc inhibitors such as, e.g., gcmcimbinc; 0 Tumor necrosis apoptosis inducing ligand receptor I agonists such as, e.g., mapatnrnunmb; c 5-Hydroxytryptaminc receptor antagonists such as, e.g., 1'EV598, xaliprodc, paleriosctron hydro- chloride, granisetron, Zindol, and AB-lOOl; o Integt'in inhibitors including alphas—beta] intcgrin inhibitors such as, e.g., E7820, JSM 6425, volociximab, and endostatin; I Androgen receptor antagonists including, e.g., nandroione decanoate, fluoxymesterone, Android, Frost—aid. andrornustine, bicaiutamide, flutamide, apo-cyproterone, apo-flutamide, chlormadinone acetate, Androcur, Tabi, cyproterone acetate, and niintamide; o Aromatasc inhibitors such as, e.g., ozolc, letrozole, testolactonc, cxcmcstane, amino- himide, and formestane; 0 Matrix metailoprotcinase inhibitors; - Other anti—cancer agents including, e.g., alitretinoin, ampligen, atrasentan bexarotene, bonezomib, bosentan, calcitriol, ind, ‘fotemustine, onic acid, osine, mitoxantrone, I- asparaginasc, procarbazinc, azinc, ycarbamidc, pegaspargasc, pontostatin, tazarotcn, velcade, gallium nitrate, canfosfamide, darinaparsin, and tretinoin.
The compounds of the present ion may also be employed in cancer treatment in conjunction with radiation therapy and/or surgical intervention.
In a further embodiment of the present invention the compounds of the present invention may be used in fixed or separate combination with one or more other active ingredients such as: IBII-chTNT, abarelix, 21biratcrone, aclarubicin, aidesleukin, alcmtuzumnb, alitrctinoin, altretamine, aminoglutethimidc, amrnbicin, amsacrine, anastrozole, arglabin, c trioxide, asparaginase, azacitidinc, basiliximab, BAY 80-6946, BAY 1000394, BAY 86-9766 (RDEA 119), can, bendamustine, zumab, bexarotene, bicalutamide, bisantrene, bleornycin, omib, buserelin, busulfan, cabazitaxel, m folinate, calcium levofolinate, capecitabine, carbOplatin, carmofur, tinc, catumaxomab, cciccoxib, ccimolcukin, cctuximab, cltlcrambucil, chlormadinonc, chlorrnethine, cisplatin, cladribine, clodronic acid, rabine, crisuntaspase, cyclophosphamide, cyproterone, cytarabinc, dacarbazine, dactinomycin, darbepoetin alfa, dasatinib, ubicin, dccitabinc, dcgarelix, clenileukin diftitox, dcnosumab, deslorclin, dibrospidium chloride, xoi, doxifluridine, bicin,doxorubicin + cstrone, eculizumab, edrecolomab, clIiptinium acetate, clrrombopag, endostatin, cnocitabine, epirubicin, stanol, cpoetin alfa, n beta, eptaplatin, cribulin. crlotinib, estradiol, cstramustinc, ctoposide, cvcrolimus, cxcmcstanc, fndrozolc, filgrastim, fiudarabine, fluorouracil, fiutamide, formestane, fotemustine, fulvestrant, gallium nitrate, ganirelix, gefitinib,- gemcitabine, gemtuzumab, glutoxim, goserelin, histamine dihydrochloride, histrelin, hydroxycarbamide, 1-125 seeds, ibandronic acid, ibritumomab tiuxetan, idarubicin, ifosfamide, iniatinib, imiquimod, ulfan, interferon alfa, interferon beta, interferon gamma, ipiiimumab, irinotecan, ixabcpilonc, lanrcotidc, lapatinib, lcnalidomidc, Icnograslim, lentinan, letrozolc, rclin, levamisolc, lisuride, lobapiatin, lomustine, mine, masoprocol, medroxyprogestercne, niegestrol, melphalan, mepitiostanc, meroaptopurinc, metliotrexatc, methoxsalen, Methyl aminolevulinatc, methyltcstosteronc, mifamurtide,miltefosinqmiriplatin, onitol, mitoguazone, mitolactol, mitomycin, mitotane, mitoxantrone, nedaplatin, neiarabine, nilotinib, nilutamide, nimotuzumab, nimustinc, nitracrine, ofatumumab; zolc. oprclvekin, oxaliplatin, p53 gene therapy, paclitaxcl. palifcrmin, pailadium~ 103 seed, paniidronie acid, panitumumab, pazopanib, pegaspargase, PEG-epoetin beta xy PEG— epoetin beta), pegfilgrastim, peginterferon alfa-Zb, pernetrexed, pentazocine, pentostatin, peplomycin, perfosfamidc, picibanil, pirarubicin, plerixafor, plicamyein, poliglusam, polyestradiol ate, polysaccharidc-K, porf‘tmer sodium, pralatrcxatc, prcdnimnstinc, bazinc, quinagolidc, radium-223 de.) raloxifene, raltitrexed, ranimustine, razoxane, regorafenib, onic acid, rituximab, romidepsin, romiplostim, sargramostim,sipuieucel-T, sizofiran, sobuzoxane, sodium glycididazolc, sorafenib, streptozocin, sunitint’b, talaporfin, tamibarotene, tamoxifen, rmin, teceleukin, tegafilr, tegafur + gimeracil + oteracil, temoporfin, temozolomide, temsirolimus, teniposide, testosterone, tetrofosmin, thalidomide, thiotepa. thymalfasin, tioguanine, tocilizumab, topotecan, fene. tositumomab, trabectedin, trastuzumab, treosulfan, tretinoin, trilostane, triptorelin, trotbsfamide, tryptophan, ubenimex, valrubicin, vandetanib, vaprcotide, vcmurafenib, vinblastine, vincristine, vindesine,vinflunine,vinorelbine,vorinostat,vorozole,yttrium.90 glass microspherm, zinostatin, atin amcr, zolcdronic acid, cin.
Generally, the use of cytotoxic and]or cytostatic agents in combination with a compound or composition of the present invention will serve to: ( I) yield better efficacy in reducing the growth of a tumor or even eliminate the tumor as compared to stration of either agent alone, (2) provide for the administration of lesser amounts of the administered chemotherapeutic , (3) provide for a chemotherapeutic treatment that is well tolerated in the patient with fewer deleterious pharmacological cations than observed with single agent chemotherapies and certain other combined therapies, (4) provide for ng a broader spectrum of different cancer types in mammals, especially humans, (5) e for a higher response rate among treated patients, (6) provide for a longer survival time among treated patients compared to standard herapy treatments, (7) provide a longer time for tumor progression, and/or (8) yield efficacy and tolerability s at least as good as those of the agents used alone, compared to known instances where other cancer agent combinations produce antagonistic effects.
Furthermore, the compounds of formula (I) or (Ia) or (Eb) may be utilized, as such or in compositions, in research and diagnostics, or as analytical reference standards, and the like, which are well known in the art.
The compounds according to the invention can act systemically and/or locally. For this purpose, they can be administered in a suitable way, such as, for example, by the oral, parenteral, pulmonal, nasal, sublingual, lingual, buccal, rectal, dermal, transdermal, conjunctiva! or otic route, or as an implant or stout.
For these administratioa routes, it is possible to administer the cempounds according to the invention in suitable application forms.
Suitable for oral administration are administration forms which work as described in the prior art and deliver the compounds according to the invention rapidly and/or in modified form, which comprise the compounds according to the invention in crystalline and/or amorphous and/or dissolved form, such as, for e, s d or uncoatcd, for example tablets provided with enteric coatings or coatings whose dissolution is delayed or which are ble and which control the e of the compound according to the invention), tablets which rapidly decompose in the oral cavity, or films/wafers, films/lyophilizates, capsules (for example hard or soft gelatin capsules), sugar-coated tablets, granules, pellets, s, emulsions, suspensions, aerosols or solutions.
Parenteral administration can take place with avoidance of an absorption step (for example intravenously, intraarterially1 intracardially, intraspinally or intralumbally) or with inclusion of absorption (for e intramuscularly, subcutaneously, intracutaneously, percutaneously or intraperitoneally). Administration forms suitable for parenteral administration are, inter alia, preparations for injection and infusion in the form of solutions, suspensions, emulsions, lyophilizatcs or e powders.
Examples suitable for the other administration routes are pharmaceutical forms for inhalation (inter alia powder inhalers, nebulizers), nasal drops/solutions/Sprays; tablets to be administered lingually, sublingually or ly, films/wafers or capsules, suppositories, preparations for the eyes or cars, vaginal capsules, s suspensions (lotions, shaking mixtures), lipophilic suspensions, ointments, creams, transdermal therapeutic systems (such as plasters, for example), milk, pastes, foams, dusting powders, implants or .
The compounds according to the invention can be converted into the stated administration forms. This can take place in a manner known per so by mixing with inert, nontoxic, ceutically suitable adjuvants. These adjuvants include, inter alia, carriers (for example microcrystalline cellulose, lactose, ol), solvents (for example liquid polyethylene glycols), emulsifiers and dispersants or wetting agents (for example sodium dodecyl sulphate, polyoxysorbitan oleate), binders (for example polyvinylpyrrolidone), synthetic and natural polymers (for example albumin), izers (for example antioxidants, such as, for example, ascorbic acid), nts (for e inorganic pigments, such as, for example, iron oxides) and flavour— and/or odour-masking agents.
Tire present invention furthermore provides medicaments comprising at least one compound according to the invention, usually together with one or more inert, nontoxic, pharmaceutically suitable adjuvants, and their use for the es mentioned above.
When the compouuds of the present invention are administered as pharmaceuticals, to humans or animals, they can be given per se or as a pharmaceutical composition containing, for example, 0.1% to 99,5% (more preferably 0.5% to 90%) of active ingredient in ation with one or more inert, nontoxic, pharmaceutically suitable adjuvants.
Regardless ofthe route of administration selected, the nds of the invention of general formula (I) or (la) and/or the pharmaceutical composition of the present invention are ated into pharmaceutically able dosage forms by conventional methods known to those of skill in the art.
Actual dosage levels and time course of administration of the active ingredients in the pharmaceutical compositions of the invention may be varied so as to obtain an amount of the active ient which is effective to achieve the desired therapeutic response for a particular patient without being toxic to the patient.
Materials and Methods: The percentage data in the following tests and examples are tages by weight unless otherwise indicated; parts are parts by weight. Solvent ratios, dilution ratios and tration data of liquid/liquid solutions are in each case based on volume.
Examples were tested in selected biological assays one or more times. When tested more than Once, data are reported as either average values or as median values, wherein 'the average value, also referred to as the arithmetic mean value, represents the sum of the values obtained divided by the number of times tested, and 'the median value represents the middle number of the group ofvalucs when ranked in ascending or descending order. If the number of values in the data set is odd, the median is the middle value. If the number of values in the data set is even, the median is the arithmetic mean of the two middle values.
Examples were synthesized one or more times. When synthesized more than once, data from biological assays represent average values or median values calculated utilizing data sets obtained from testing of one or more synthetic batch.
The in vitro cological and physico-chcmical properties of the compounds can be determined according to the following assays and methods. 1. CDK9/Cych kinase assay: CDK9/Cych -inhibitory activity of compounds of the present invention was quantified employing the CDK9/CyeTl “PR-FRET assay as described in the ing paragraphs: Recombinant fiill-lcngth His-tagged human CDK9 and Cych, expressed in insect cells and purified by Ni—NTA affinity chromatography, were purchased from lnvitrogcn (Cat. No PV4131). As substrate for the kinase reaction biolinylated e biotin—thls-YISPLKSPYKISEG (Cderminus in amid form) was used which can be sed cg. form the company JERINl Peptide Technologies n, Germany).
For the assay 50 ml of a l00fold concentrated solution of the test compound in DMSO was pipetted into a black low volume 384well microtiter plate (Greiner Bio~0ne, Frickenhausen, Germany), 2 ul of a on of CDK9/Cych in aqueous assay buffer [50 mM Tris/BC] pH 8.0, 10 mM MgClz, 1.0 mM dithiothrcitol. 0.] 111M sodium ortho-vanadate, 0.01% (v/v) t-P40 fl were added and the mixture was incubated for 15 min at 22°C to allow pro-binding of the test compounds to the enzyme before the start of the kinase reactions Then the kinase reaction was started by the addition of 3 pl of a solution of adcnosinc-tri-phosphatc (ATP, 16.7 pM => final cone. in the 5 ul assay volume is 10 MW) and substrate (1.67 [1M =" final cone. in the 5 ul assay volume is 1 uM) in assay buffer and the resulting mixture was incubated for a reaction time of 25 min at 22°C. The concentration of CDK9/Cych was adjusted ing of the activity of the enzyme lot and was chosen appropriate to have the assay in the linear range. typical concentrations were in the range of l pg/mL. The reaction was stopped by the addition of 5 pl of a on of ”FR-FRET detection reagents (0.2 uM streptavidine-XL665 [Cisbio Bioassays, Codolet, France} and 1 nM anti-RB(pSer807/pSer81l)-antibody from BD Pharmingen [# 558389] and 1.2 nM LANCE EU—W1024 labeled anti-mouse IgG antibody [Perkin-Elmer, product no.
AD0077]) in an aqueous EDTA-solution (IOO mM EDTA, 0.2 % (w/v) bovine serum n in 100 mM /NaOH pH 7.0).
The resulting mixture was incubated l h at 22°C to allow the formation of complex n the phosphorylated biotinylated peptide and the detection ts. Subsequently the amount of phosphorylated substrate was evaluated by measurement of the resonance energy transfer from the Eu- e to the streptavidine—XL. Therefore, the fluorescence emissions at 620 nm and 665 nm after excitation at 350 nm was measured in a HTRF reader, eg. a Rubystar (BMG Labtechnologies, Offenburg, Germany) or a Viewlux (Perkin-Elmer). The ratio of the emissions at 665 nm and at 622 nm was taken as the measure for the amount of phosphorylated substrate. The data were normalised (enzyme reaction t inhibitor = 0 % inhibition, all other assay components but no enzyme = 100 % inhibition). Usually the test compounds were tested on the same mierotiterplate in 1] different concentrations in the range of 20 uM to 0.] 11M {20 ttM, 5.9 M4, 1.7 uM, 0.51 uM, 0.]5 uM, 44 nM, 13 nM, 3.8 nM, 1.] nM, 0.33 nM and 0.1 nM, the dilution series prepared separately before the assay 0n the level of the iOOl‘oid concentrated solutions in DMSO by serial 123.4 dilutions) in duplicate values for each tration and ICSO values were calculated by a 4 parameter fit. 2. CDK2/Cycli kinase assay: CDK2/Cch vinhibitory activity of compounds of the present invention was quantified ing the CDKZ/CyeE TR-FRET assay as described in the following aphs: Recombinant fusion proteins of GST and human CD10. and of GST and human CyeE, eXpressed in insect cells (819) and purified by Glutathion—Sepharosc y chromatography, were purchased from ProQinase GmbH (Freiburg, Germany). As substrate for the kinasc reaction ylated peptide biotin- Ttds-YISPLKSPYKISEG (C-temiinus in amid form) was used which can be purchased e.g. form the company IERINI Peptide Technologies (Berlin, y).
For the assay 50 iii ot‘a 100fold concentrated solution of the test compound in DMSO was pipetted into a black low volume l microtitcr plate (Greiner Bio-One, Friokenhausen, Germany), 2 ul of a solution of CDKZ/Cch in aqueous assay buffer [50 mM Tris/HCi pH 8.0, 10 mM MgClg, 1.0 mM dithiothreitol, 0.1 mM sodium ortho-vanadate, 0.01% (v/v) Nonidct-P40 (Sigmafl were added and the mixture was ted for 15 min at 22°C to allow pro-binding of the test compounds to the enzyme before the start of the kinase reaction. Then the kinase reaction was started by the addition of 3 pl of a solution of adenosinc—tri-phosphatc (ATP, 16.7 uM => final cone. in the 5 ul assay volume is 10 uM) and substrate (1.25 uM =\ final cone. in the 5 pl assay volume is 0.75 uM) in assay buffer and the resulting mixture was incubated for a reaction time of 25 min at 22°C. The concentration of CDKZ/Cch was adjusted depending of the activity of the enzyme lot and was chosen appropriate to have the assay the linear range, typical concentrations were in the range of 130 rig/mi... The reaction was stopped by the addition of 5 pl of a solution of TR-FRET detection ts (0.2 uM streptavidine-XL665 [Cisbio Bioassays, Codolet, France) and inM anti-RB(pSer807/pSer811)—antibody from BD Pharmingen [# 558389] and 1.2 nM LANCE EU'WlO24 d anti-mouse IgG dy [Perkin-Elmer, t no.
AD0077]) in an aqueous EDTA-solution (100 mM EDTA, 0.2 % (w/v) bovine serum albumin in 100 mM HEPES/NaOl—i pH 7.0).
The resulting mixture was incubated 1 h at 22°C to allow the formation of complex betwaen the oryiated biotinyiated peptide and the detection reagents. uently the amount of orylated substrate was evaluated by measurement of the resonance energy transfer from the Eu~ ehclato to the streptavidine-XL. Therefore, the fluorescence emissions at 620 nm and 665 nm after excitation at 350 nm was measured in a TR-FRET reader, eg. a Rubystar (BMG hnologies, Offenburg, Germany) or a Viewlux (Perkin-Elmer). The ratio of the emissions at 665 nm and at 622 run was taken as the measure for the amount ot’phosphorylatcd substrate. The data were normalised (enzyme reaction without inhibitor = 0 % inhibition, all other assay components but no enzyme = 100 % inhibition). Usually the test compounds were tested on the same microtiterplate in ll different concentrations in the range of 20 uM to 0.1 nM (20 [.tM, 5.9 uM, 1.7 nM, 0.51 [AM 0.15 “M, 44 nM, 13 nM, 3.8 nM, 1.1 nM, 0.33 nM and 0.l nM, the dilution series ed separately before the assay on the level ofthe d concentrated solutions in DMSO by serial 1:3.4 dilutions) in duplicate values for each concentration and ICSO values were calculated by a 4 ter fit. 3. Proliferation Assay: Cultivated tumour cells (NCl-H460, human non~small cell lung carcinoma cells, ATCC HTB-l77; DU145, hormone-independent human prostate carcinoma cells, ATCC HTB—Sl; HeLa~MaTu, human cervical carcinoma cells, BPO-Gmbl—l, Berlin; HeLa-Ma’l‘u—ADR, multidrug-resistant human cervical carcinoma cells, EPO-GmbH, Berlin; HeLa human cervical tumour cells, ATCC COL-2; Cece-2 human colorectal carcinoma, ATCC HTB-S'i; B16F10 mouse melanoma cells, ATCC CRL-6475) were plated at a density of 5000 cells/well (DUMS, l-leLa-lvlaTu-ADR), 3000 cells/well (NCI—l-l460, HeLa—MaTu, HeLa), 1500 cells/well (Cece-2), or 1000 cells/well (Bl 6F10) in a 96-well multititer plate in 200 uL of their respective growth medium supplemented 10% fetal calfserum. After 24 hours, the cells of one plate (zero-point plate) were stained with crystal violet (see below), while the medium of the othcr plates was replaced by fresh culture medium (200 [.lL), to which the test substances were added in various concentrations (0 uM, as well as in the range of 0 pM; the final concentration of the solvent dimethyl sulfoxide was 0.5%). The cells were incubated for 4 days in the presence of test. substances.
Cell proliferation was determined by staining the cells with crystal violet: the cells were fixed by adding asuring point of an 1 l% ic aldehyde solution for 15 minutes at room temperature. After three washing cycles of the fixed cells with water, the plates were dried at room temperature. The cells were stained by adding 100 uL/measuring point of a 0.1% crystal violet solution (pH 3.0). After three washing cycles of the stained cells with water, the plates were dried at room temperature. The dye Was dissolved by adding 100 uL/ineasuring point of a 10% acetic acid solution. The absorbence was ined by photometry at. a wavelength of 595 nm. The change of cell number, in percent, was ated by normalization of the measured values to the absorbanec values of the zero-point plate (=0%) ,and the absurbanee of the ted (0 uM) cells (=100%). The lCSO values were ined by means of a 4 parameter fit. 4. Equilibrium Shake Flask Solubility Assay: The thermodynamic solubility of compounds in water was determined by an equilibrium shake flask method (see for example: EH. Kcms, L. Di: Diugilike Properties: Concepts, Structure Design and Methods, 276-286, Burlington, MA, Academic Press, 2008). A ted solution of the drug was prepared and the solution was mixed for 24 h to ensure that equilibrium was reached. The solution was centrifuged to remove the insoluble fraction and the concentration of the compound in solution was determined using a standard calibration curve.
To prepare the sample. 2 mg solid compound was weighed in a 4 mL glass vial. 1 mL phosphate buffer pH 6.5 was added. The suspension was stirred for 24 hrs at room temperature. The solution was centrifuged afterwards. To prepare the sample for the standard ation, 2 mg solid sample was dissolved in 30 mL aeetonitrile. After sonificalion the solution was diluted with water to 50 mL.. Sample and standards were quantified by HPLC with UV-detection. For each sample two injection volumes (5 and 50 1.11) in triplicates were made. Three injection s (5 pl, 10 pl and 20 pl) were made for the standard.
Cln‘onialographic conditions: HPLC column: Xterra MS Cl 8 2.5 pm 4.6 x 30 mm Injection : Sample: 3X5ttl and 3x50p| Standard: Sill, 10m, 20m Flow: 1.5mL/min Mobile phase: acidic gradient: A: Water/ 0.01% TFA B: itrile 1' 0.01% TFA 0 min -> 95%A 5%B 0-3 min -> 35%A 65%B, linear gradient 3-5 min —> 35%A 65%B, isocratic —6 min —> 95%A 5%B, isocratic UV detector: wavelength near the absorption m (between 200 and 400nm) The areas ofsamplc- and standard ions as well as the ation of the solubility value (in mg/l) were determined by using HPLC soflware (Waters Empower 2 FR).
. Carbonic anhydrase Assay The principle of the assay is based on the hydrolysis of 4-nitrophenyl acetate by carbonic anhydrases (Packer & Stone, Biochemistry, 1967, 6, 668), with subsequent photometric determination of the dye product 4-nitrophenolate at 400 mn by means of a 96—channcl spectral photometer. 2 microL of the test nds, dissolved in DMSO (lOO-fold final tration), in a concentration range of 0.03- l 0 ol/L (final), was pipettcd as quadruplieatcs into the wells of a e mierotiter plate. Wells that contained the solvent t test compounds were used as reference values (1. Wells without carbonic anhydrase for correction of the non-enzymatic hydrolysis of the substrate, and 2. Wells with carbortic anhydrasc for ining the activity of the non-inhibited enzyme). l0 188 microL of assay buffer (10 millimol/L /HCI, pH 7.4, 80 millimol/L ofNaCl), with or without 3 units/well of carbonic anhydrase-I [= human carbonic anhydrase—I (Sigma, #C4396)] in order to determine carbonic anhydrase—l inhibition or 3 units/well of carbonic anhydrase-Z [= human carbonic anhydrase-Z (Sigma, #C6165)] for ing carbonic anhydrasc—Z inhibition, was pipetted into the wells of the microtiter plate. The enzymatic reaction was d by the addition of 10 microL of the substrate solution (1 millitnoI/L of 4-nitrophcnyl acetate (Fluka #4602), dissolved in anhydrous acetonitrile (final substrate concentration: 50 mieromol/L). The plate was incubated at room temperature for 15 minutes. Absorption was measured by photometry at a wavelength of 400 nm. The enzyme inhibition was calculated after the measured values were normalized to the absorption of the ons in the wells without enzyme (=100% inhibition) and to the absorption of reactions in the wells with non- inhibited enzyme (=0% inhibition). ICSO values were determined by means of a 4 parameter lit.
Preparative Examples Syntheses ofcompounds The syntheses of the inventive disubstituted triazines according to the present invention is preferably carried out according to one of the general synthetic sequences, shown in s 1, 2, 3 or 4 below: Schcmcl: > a 0 R4 2 N\\//0 > 4 R3 0 RV8 O R /\ 2 A N \N 2 MW" 1 i CHAN/k0!I O S / / 1/ R g N CI 1 3 > R-O\ 2 3 ,B—R R R—O > 3 O R4 4 R NAN 4 O R >—N O A o JL A *—’ ”I R” 0 R1/8 N N c: NXNA 2 R H H 3 5 (formula (I), R5 = C(0)0Et) > 3 3 O R4 R R4 R W /\ /\ M —-—-- 953iM O S / S / RV N N R2 R"’ N N R2 H H la 6 (formula (I), R5 = H) (I), R5 = C(O)0Et) 3 3 R4 R R4 R /\ /\ HNV/O\ Nl \N _.....__. RLN\\//(') NXNARZ S JNL\N R1/s / R1/ N N R2 H H formula 6 (formula (I), R5 = H) (I) Scheme 1 In the first step 2,4-dichloro-1,3,5~triazine (l) is reacted with le anilines (2) to give the corresponding ro-N-phenyl-l,3,5-triazin—2—amines (3). The reaction is carried out with one lent of the aniline (2) in an inert solvent like DMF, THF, DME, e or an alcohol like isopropanol,. or mixtures of such solvents. Preferably, the reaction is carried out at a temperature below 0°C in such a way that the reaction mixture is kept homogcnous. Preferred ioris use an additional base like trietllylamine or N,N-diisopropyletltylamine.
In the second step the intermediate 4-chloro-N—phenyl-i,3,5-triazin-2~amine (3) is reacted with a boronic acid derivative RQ-B(OR)3 (4) to give compounds of formula (5). The boronic acid derivative (4) may be l0 a c acid (R = —l-l) or an ester of the boronic acid, eg. its isopropyl ester (R a «CH(CH3)2), preferably an ester derived from pinacol in which the boronic acid intermediate forms a 2-aryl-4,4,5,5- ethyl—1,3.2-dioxaborolane (R—R = —C(CHz)z-C(CH3)2—).
The coupling reaction is catalyzed by Pd catalysts, e.g. by Pd(0) catalysts like tetrakis(tripltenylphusphine)palladium(0) [P(l(PPl13)4], tris(dibenzylideneacetone)di-palladium(0) [Pd2(dba)3], or by Pd(II) catalysts like dichlorobis(triphenylphosphine)-palladium(ll) [Pd(PPhg)2C12], palladiumfll) acetate and triphenylphosphine or by [1,1'-bis(diphenylphosphino)ferroccnc]palladium dichloride [Pd(dppl)C12].
The reaction is preferably carried out in a mixture of a t like 1,2-dimethoxyetltane, dioxane, DMF, DME, THF or isopropanol with water and in the presence of a base like aqueous potassium carbonate, aqueous sodium bicarbonate or potassium phosphate.
Deprotection of nds of formula (5) gives the corresponding N-unprotected sulfoximines of formula (6). The deprotection is preferably carried out with sodium ethanolate in ethanol at 60°C. otectcd sulfoximincs of formula (6) may be reacted to to give N—functionalized derivatives of formula.([).
Scheme 2 Another synthesis route to N—unprotected sulfoximines of formula (6) is shown in Scheme 2. if 3 4 R R1/ R NH2 /\ A O N \N N N 13 orN/ R/1 1°! )L / n N Cl C] c1 1 14 ‘B—R2 R3 R—o’ R4 4 R3 NAN 4 R O /\ R N \N |! ————~—~> RVs A N N/ C. RVs JL A2 H H N 14 15 R3 R3 R4 R4 o NAN _.____... HN o NAN 3 JL I 1 / / R1/ N N R2 R" N N R2 H H 6 (formula (I), R5 = H) Scheme2 In the first step 2,4-dichloro—l,3.5-triazine (1) is reacted with suitable es of formula (13) to give the corresponding 4-chloro—N-phenyl-1,3,5-triazin-2—amines of fomtula (14). The reaction is carried out with one equivalent of the aniline (13) in an inert solvent like DMF, THF, DME, dioxane or an alcohol like isopropanol, or mixtures of such solvents. Preferably, the reaction is carried out at a temperature below 0°C in such a way that the reaction mixture is kept homogcnous. Preferred conditions use an additional base like triethylamine or N,N~diisopropytethylamine.
In the Second step the intermediate 4-chloro-N-phenyl-l,3,5—triazin-2~amine of formula (14) is reacted with a borom‘c acid derivative RZ-B(OR)2 (4) to give compounds of a (I S). The c acid derivative (4) may be a boronic acid (R = 4-1) or an ester of the boronic acid, eg. its isopropyl ester (R = 3)2). ably an ester derived from pinacol in which the boronic acid ediate forms a Z— aryl-4,4,5,5-tetramcthy1-l,3,2-dioxaborolane (R—R = ‘C(CH1)2-C(CH3)z—).
The coup ling reaction is catalyzed by Pd catalysts, e.g. by Pd(0) catalysts like tetrakis(triphenylphosphine)palladium(0) [Pd(PPhg)4], tris(diben2ylideneacetone)di-palladium(0) {Pd2(dba)z], or by Pd(II) catalysts likc dichlorobisGriphenylpliOSphinc)-palladium(ll) [Pd(PPhfit)2Cl'l], iumm) acetate and tripltcnylphosphinc or by [1,1'—bis(diphenylphosphino)fcrrocene]pttlladium dichloride {Pd(dppf)Clz].
The reaction is preferably carried out in a mixture of a t like 1,2-dimethoxycthanc, dioxanc, DMF, DME, THE, or isopropanol with water and in the presence of a base like aqueous potassium carbonate, aqueous sodium bicarbonate or potassium ate.
Finally, the compound of a (15) is reacted with sodium azide in trichlorometlmne and sulfuric acid at 45°C to give the N-unprotectcd sulfoximine of formula (6) (see for example: a) H. R. Bentley ct al, J.
Chem. Soc. 1952, 1572; b) C. R. n et al, J. Am. Chem. Soc. 1970, 92, 6594; c) Satzinger et a1, Angew. Chem. 1971, 83, 83).
Scheme 3 Another synthesis route to N-cyanosukfoximines of formula (20), which can also be converted to unprotected sulfoximines of formula (6), is shown in Scheme 3.
R4 R S R4 R R1/ NH W 2 CIANACII S n/ RV H N C' 1 17 R3 R—0’ R'1 R3 A 4 R4 i i ——-——a~ S w RV N N/ c] 1/8 A A 2 R N R H m 17 18 4 R3 N\\ R3 R1/ \ NAN/kw»./ S / R1/ N N R2 H H 18 19 N\ R3 R4 s \\N R NAN N\\ /\ ll JL mm... NMo N \N R1/S N N/ R2 1/S i A 2 R N H £211 R 19 20 (formula (I), R5 = CN) 4 4 R R3 R R3 N\\\ A A 1 A ---—~ w 1 ,1 RV N N R2 R" N N R2 H H (formuIa (l), R5 = CN) 6 (formula (I), R5 = H) SchemeS In the first step 2,4-dichloro-l,3,5-triazinc (1) is reacted with suitable es of formula (16) to give the corrcspondiug 4-chloro—N-phcnyE-1,3,5~triazin-2—amincs of formula (17). The reaction is carried out with one equivalent of the aniline of fonnula (2) in an inert solvent like DMF, THF, DME, di0xane or an alcohol like isopropanol, or mixtures of such solvents. Preferably, the reaction is carried out at a temperature below 0°C in such a way that the reaction mixture is kept homogenous. Preferred conditions use an additional base like tricthylamine or N,N-diisopropyletbylaminc.
In the second step the intermediate 4-chloro-N—phenyl-l,3,5~triazinamine of formula (1 7) is reacted with a boronic acid derivative Rg-B(OR)3 (4) to give compounds of formula (18). The boronic acid derivative (4) may be a c acid (R = —H) or an ester of the boronic acid, e. g. its isopropyl ester (R = —CH(CH3)2), preferably an ester derived fi'om pinaeol in which the boronic acid intermediate forms a 2— aryl-4,4,5,5-tetramethyl—l ,3,2-dioxaborolane (R-R = —C(CH3)2—C(CH3)2-).
The coupling reaction is catalyzed by Pd catalysts, eg. by Pd(0) catalysts like tetrakis(triphenylphosphine)pa1ladium(0) [Pd(PPh3)4], iben2ylideneacetone)di~palladium(0) [Pd2(<iba)3], or by Pdfll) catalysts like robis(triphenylphosphine)-palladium(li) [Pd(PPhg)3Clz], palladium(II) acetate and nylphosphine or by [1,1‘—bis(diphenylphosphino)ferrocene]palladium dichloride [Pd(dppf)Clz].
The reaction is preferably carried out in a mixture of a solvent like 1,2-dimethoxyethane, dioxane, DMF, DME, THF, or isoprOpanol with water and in the presence of a base like aqueous potassium carbonate. aqueous sodium bicarbonate or potassium phosphate.
In the next step, the sulfide of formula (18) is reacted with cyanogen amine as a nitrogen source to give the corresponding osulfilimine of a (1 9). Preferably, the reaction is carried out using NBS and potassium utoxide in methanol at room temperature (see for example: a) C. Bolm et al, Org.
Lett. 2007, 9, 3809). Even more preferred is the use of iodobenzenediacetate in DCM at room temperature (see for example: a) 1M. Babcock, US 023782).
Finally, N-cyanosulfilimine of a (19) is oxidized to the corresponding N-cyanosulfoximinc of formula (20). The reaction is prefably carried out using tnCPBA and potassium carbonate in l at room temperature (see for example: a) C. Bolm et a1, Org. Lett. 2007. 9, 3809). Even more preferred is the use of potassium permanganate in e at 50°C (see for example: a) C. Bolm ct a1, Adv. Synth.
Catal. 2010, 352, 309), The N—cyano group of nd (20) is cleaved upon treatment with TFAA affording the corresponding luoroacetylsulfoximine which is converted into the NH—free sulfoximine of formula (6) by methanolysis of the trifluoroacetyl moiety (see for example: C. Bolm et al, Org. Lett. 2007, 9(19), 3809).
Scheme 4: Another sis route to N-unprotected sulfoximines of formula (6) is shown in Scheme 4.
N N H H R6 3 22 o> R3 RL-OH R3 Rt R4 R8 >_N 23 o NAN F HN o NAN o’ o “s” )L / _" “s” )L / R” N N R" N N 6 6 H R H R 22 R7 6 (formula (I). R5 = H) R7 Scheme4 In the first stop the intermediate ro—N—phcnyl-l,3,5-triazin—2-amine (3) is reacted with a suitable ortho-fluorine boronic acid tive of formula (21) to give a compound of formula (22). The boronic acid derivative of formula (21) may be a boronic acid (R = -H) or an ester of the boronic acid, e.g. its iSOpl'Opyl ester (R = —CH(CH1)2), or an ester d from pinacol in which the borOnic acid intermediate forms a 2-aryl-4,4,5,5-tetramethyl-l ,3,2-dioxaborolane (R-R = —C(CH3)2-C(CH3)2—).
The coupling react ion is catalyzed by Pd catalysts, e.g. by Pd(0) catalysts like tctrakis(triphenylphosphine)palladium(0) [PdtPPhah], tris(dibenzylideneacctonc)di-palladium(0) [Pdg(dba)3}, or by Pd(ll) catalysts like dichlorobis(triphenylphosphine)~palladiumfll) [Pd(PPl13)2Clg], palladiumOI) e and triphenylphosphine or by [l,‘1'-bis(diphenylphosphino)ferrocene]palladium dichloride pf)Clz].
The reaction is preferably d out in a mixture of a solvent like 1,2-dimethoxyethane, dioxane, DMF, DME, THE, or isopropanol with water and in the presence of a base like aqueous potassium carbonate, aqueous sodium bicarbonate or potassium phosphate.
In the second step the ortho-flourine of the substituent in 4-positiun of the compound of formula (22) is replaced by a suitable alkoxy group-0R8. The reaction is prefably carried out by adding at least two equivalents of sodium e to a solution of compound (22) in alkohol (23) to give the desired N— unprotected sulfoxhnines of formula (6). The reactions are run at a temperature of 60°C or in the temperature range between 50°C and 70°C .
Preparation of compounds: Abbreviations used in the description of the chemistrv and in the Examnles that foliow are: CDC]; (deuterated chloroform); cHex (cyclohexane); DCM (dichloromethane); DIPEA (di-iso- propylethylamine); DME (1,2-dimethoxyethane ), DMF (dimethylformamide); DMSO (dimethyl ide); eq (equivalent); ES (electrospray); EtOAc (ethyl acetate); EtOl—I (ethanol); iPrOH (iso— propanol); mCPBA (meta-ch]oroperoxybcuzoic acid), MeOI-l (methanol); MS (mass spectrometry); NBS (N-bromosuccinimide), NMR (nuclear magnetic resonance); Pd(dppt)Clz ([I,1’— bis(diphenylphosphino)fen'ocene]dichloro palladiumfll) complex with dichloromethane); iPrOH (ism propanol); RT (room temperature); sat. aq. (saturated aqueous); Si02 (silica gel); TFA (trifluoroacctic acid); TFAA (trifluoroacetic ide), THF hydrofuran).
The HIPAC names of the examples were ted using the program 'ACD/Name batch version 12.0l from ACD LABS. (rac)~E th y l 1(3-{[4-(4-fluoro—2-methoxyphenyl)-1.3.S-triazinyl]amino}benzyl)(methyl)oxido-}»°- snlfauylidene]carbamate >—N o NAN 0/ ”o 5 / JL/ a or: F Preparation of Intermediate 1.1: 1-[(Methyisulfanyl)methyll-S-nitrobenzene °~N‘©\/S\ Sodium ethiolate (13.5 g; i92 mmol) was added in two portions to a stirred solution of l-(chloro- methyl)—3—nitrobenzene (30.0 g; 175 mmol; h) in ethanol (360 mL) at 45°C. The cold bath was removed and the batch was stirred at room temperature for 3 hours. The batch was diluted with brine and extracted with ethyl acetate (2x). The combined organic phases were washed with water, dlied (sodium sulfate), filtered and concentrated to give the desired t (32.2 g) that was used withour further purification.
"H NMR (400MHz, CDCla, 300K) 5 = 8.18 (m, 1H), 8.11 (m,1H), 7.66 (m, 1H), 7.50 (m, 1H), 3.75 (s, 2H), 2.01 (s. 3H).
Preparation of Intermediate 1.2: (rac)—141(Methylsulfinyl)methyl]-3~nitrobenzene O‘N+CUS\ Iron(]ll)chloride (0.55 g; 3.4 mmol) was added to a solution of l-[(methylsulfanyl)methy1}~3- nitrobenzene (21.6 g; 117.9 mmol) in itrile (280 mL) and the batch was stirred at room temperature for 10 minutes. Periodic acid (28.8 g; 126.1 mmol) was added under stirring in one portion and the temperature was kept below 30°C by cooling. The batch was stin'ed at room temperature for 90 s before it was added to a stirred solution of sodium lfatepentahydrate (163 g; 660 mmol) in ice water (1500 mL). The batch was ted with solid sodium chioridc and extracted with THF (2x).
The combined organic phases were washed with brine, dried m sulfate), filtered and concentrated.
The residue was purified by chromatography (DCM / ethanol 95:5) to give the desired product (16.6 g; 33.1 inmol). 2HNMR (400MHz, CDCls, 300K) 5 = 8.21 (m, 1H). 8.17 (m, 11-1), 7.67 (m, 1H), 7.58 (m, 1H), 4.10 (d, 1H). 3.97 (d. 1H), 2.53 (s. 3H).
Preparation ot'Intermediate 1.3: (rac)-2,2,2-Trifluoro—N-[methyl(3-nitrobenzyl)oxido-xs-sulfanylidene]acetamide F\‘/F /\\ 1* OWN ‘0‘\ 0. 1:” "'1 NV \\;5? \\/,S .\ To a sion of {reel} -[(methylsulfiny1)methy1]-3 -nitrobenzene (16. 6 g: 83.1 mmol). trifluoroacetamide (18.8 g; 166.] mmol), magnesium oxide (13.4 g; 332.3 11111101) and t110dium(II)-acetat dimer (1.7 g; 8.3 mmol) in DCM (2290 mL) was added iodobenzene diacetate (40,] g; 124.6 mmol) at room temperature. The batch was stirred for 16 hours at room temperature. filtered and concentrated. The residue was purified by chromatography (DCM / ethanol 97:3) to give the desired product (25.6 g; 82.4 11111101).
"H NMR (400MHz, CD C13, 300K) 8 = 8.36 (m, 11-1), 8.31 (m, 1H), 7.80 (m, 1H), 7.69 (m, 1H), 4.91 (d, 1H), 4.79 (d, 1H), 3.28 (s, 3H).
Preparation of Intermediate 1.4: 1-[(S-lVIethylsulfonimidoyl)methyl]—3-nitrobenzene /’ \\ 0.1.14“ _ j: “1 Potassium carbonate (56.9 g; 41 1.8 mmol) was added to a solution of (rac)-2,2,2—trifluoro~N—[methyl(3— nitrobenzyl)oxido-lf—sult’anylidenelacetamide (25.6 g; 82.4 1nmol) in methanol (1768 mL) at room temperature. The batch was stirred for 1 hour at room temperature before it was diluted with ethyl acetate and brine. After extraction with ethyl acetate (2x) the combined organic phases were dried m e); filtered and concentrated to give the desired product (13.9 g; 65.1 mrnol). 5H NMR (400MHz, 000;, 300K) 5 = 8.29 (m, 2H), 7.79 (m, 1H), 7.63 (m, 1H), 4.47 (d, 1H), 4.34 (d, 1H), 2.99 (s, 3H), 2.66 (br, 1H).
Preparation of Intermediate 1.5: (rac)-Ethy1 [methyl(3-nitrobenzyl)oxido-h‘-sull‘anylidene]carbamate Ethyl chloroearbonate (8.] mL; 84.6 mtnol) was added dropwise to a stirred solution of (rac)-l-[(S- methylsulfonimidoyl)methy|]~3-nitrobenzene 03.9 g; 65.l mmol) in pyridine (615 mL) at 0°C. The batch was slowly warmed to room temperature. After 24 hours the batch was concentrated and the residue was ved in ethyl acetate and washed with brine. The organic phase was filtered using a Whatman filter and concentrated to give the desired product (19.7 g) that was used without further purification.
‘H NMR (400MHz, d5- CDCls, 300K) 5 = 8.30 (m, 2H). 7.8] (m, 1H), 7.64 (m, 1H), 4.88 (d, 1H), 4.79 (d, ll-i), 4.18 (q, 21-1), 3.07 (5, 31-1), 1.31 (tr, 3H).
Prenaration of Intermediate 1.6: (mo-Ethyl [(3-aminobenzyl)(methyI)oxido-l‘-sulfanylidcnclcarbnmate ‘3” 0 HZN \ Titanium(]]l)chloride solution (about 15% in about 10% hydrochloric acid, 118 1111.; Merck Schuchardt Ol-lG) was added to a stirred solution of (rac)-cthyl [methyl(3-nitrobenzyl)oxido~3\6- sulfanylidene]carbamate (5.0 g; 17.5 mmol) in THF (220 mL) at room ature. The batch was stirred for 18 hours. By adding 2N sodium hydroxide solution the pH value of the reaction mixture, that was cooled with an ice bath, was raised to 8. The batch was ted with solid sodium chloride and extracted with ethyl acetate (3x). The combined organic phases were washed with brine, dried m sulfate), filtered and concentrated to give the desired product (4.2 g) that was used t further purification.
"H NMR (400MHz, (la-DMSO, 300K) 8 = 7.00 (m, 1H), 6.53 (in, 3H), 5.18 (br, 2H), 4.62 (s, 2H), 3.95 (m, 2H); 3.08 (s. 3H). 1.13 (tr, 3H).
Preparation of Intermediate 1.7: (rac)—Ethyl [{3-[(4-chlore-1,3,5-triazin~2~yi)aminoIbenzyl}(methyl)oxido—?f’~sulfanylidene|- carbamate : DIPEA (3.1 mL; 17.8 mmol) was added to a d solution of2,4-dichloro—1,3,5-triazine (1.34 g; 8.9 mine 1) in T H F / i-PrOI—l (1:1; 18 mL) at 40°C. Then a solution of (rad-ethyl [(3— aminobenzyl)(methyl)oxide-lfi-sulfanylidenekarbarnate (2.29 g; 8.9 mmol) in THF i’ i-PrOH (1:1; 9 mL) was added at this ature. Under stirring the ature of the reaction mixture was slowly raised over 3 hours to 0°C. The batch was concentrated to giVe the crude product (4.9 g) that was used without further purification.
System: Waters Acquity UPLC-MS: Binary Solvent Manager, Sample Manager/Organizer, Column Mana-er. PDA, ELSD. SOD 3001 Acquity UPLC BEH 0181.7 50x2.1mm A1 = H20 + 0.1% HCOOH -Bi = Acetonitrile 0-1.6 min 1-99% B, 1.8-2.0 min 99% B 60°C DAD scan ran-e 0 nm -> Peaktable Method: MS ESH. ESI- Switch A1 + Bi = C:\MassL nxiMass 160 1000.fl Retention: 0.88 min Preparation of end product: A batch with crude (rac)-cthyl [{3-{(4-chloro-1,3,5—triazinyl)amino}benzyl}(methyl)oxido-XG- sulfanylidene]carbamate (400 mg), (4—fluoromethoxyphenyl)boronic acid (276 mg; 1.62 mmol; Aldrich) and t.etrakis(triphenylphosphin)palladium(0) (187 mg; 0.16 mmol) in 1,2-dimethoxyethane (5.0 mL) and 2M solution of potassium carbonate (1 .1 mL) was degassed using argon. The batch was stirred under argon for 80 minutes at 100°C. After g the batch was d with ethyl acetate and washed with brine. The organic phase was filtered using a Whatman filter and concentrated. The residue was purified by chromatography (DCM / ethanol 95:5) to give the desired product (178 mg; 0.39 mmol).
'H NMR (400MHz, CDCla, 300K) 5 = 8.82 (s, 1H), 7.94 (m, 1H), 7.84 (s, 1H), 7.74 (br, 1H), 7.53 (s, 1H). 7.42 (m, 1H), 7.16 (m, 1H), 6.77 (m, 2H), 4.74 (in, 2H), 4.17 (q, 2H). 3.93 (s, 3H), 3.00 (s, 3H), 1.30 (tr, 3H).
Examgle 2: (rac)—4-(4-Fluoro-Z—methoxyphenyl)-N-{3-[(S-methylsulfonimidoyl) methyl]phenyl}~l,3,5—triazin~2~ amine A freshly prepared LSM solution of sodium ethanolate in ethanol (2.9 mL; 4.35 mmol) was added under argon to a solution of (rac)—ethyl [(3-{[4a(4-fluoron1elhoxyphenyl)-l,3,5-triazinyl]amino}- benzyl)(methyl)oxide-XG-sulfanylidenelcarbamate (500 mg; 1.09 mmol) in ethanol (18.5 mL). The batch was stirred at 60°C for 2 hours. Further 1.5M solution of sodium ethanolate in ethanol (2.9 mL; 4.35 mmol) was added and the batch was stirred for additional 5 hours at 60°C. After cooling the batch was diluted with brine and ted with ethyl acetate (3x). The combined organic phases were filtered using a Whatman filter and concentrated. The residue was purified by tography (DCM / ethanol 9:1) to give the desired product (378 mg; 0.98 mmol).
'H NMR (400MHz, CDCIa, 300K) 5 = 8.80 (s, 1H), 7.95 (m, 1H), 7.77 (m, 2H), 7.55 (s, 1H), 7.40 (m, 1H), 7.15 (m, 1H), 6.75 (m, 2H), 4.39 (d, 1H), 4.26 (d, 1H), 3.92 (s, 3H), 2.96 (s, 3H), 2.71 (s, 1H).
Alternative preparation of Example 2 ((rac)(4-Flu0r0melhoxyphenyl)-N-{3-[(S-methyl- sulfonimidoyl)methyllphenyl}-1,3,S-triazinamine ): Preparation of Intermediate 2.1: (rac)—4-Chloro-N-{3-[(methylsulfinyl)methyl]phenyl}-l,3,5—triazin-2~ /SUQHN N/ Cl - H amine Intermediate 2.1 was prepared under similar conditions as bed in the preparation oflntermediate 1.7 using (rac)~3-[(methylsulfinyl)methyl]aniline (UkrOrSynthesis Ltd).
-Wm"Column Manaer, PDA. ELSD. SQD 3001 Aequity UPLC BEH 0181.7 50x2.1mm A2 = H20 + 0.2% NH: —B1 = Acetonitrite 04.6 min 1-99% B, 0 min 99% B 0.8 mL/min 60°C 2.0 w ion: DAD scan ran-e 210—400 nm -> Peaktable —ELSD Mm“: A2 + 81 = C:\ MassL nx\NH3 Mass 100 1000.0I Column Mama-er, PDA, ELSD. SQD 3001 Preparation of Intermediate 2.2: (rac)—4-.(4-Fluoro-Z-methoxyphenyl)~N-{3-[(methylsulfinyl)methyl]phenyl}-l,3,S-triazinamine 4 / /5Q NXNAQH I F Intermediate 2.2 was prepared under similar conditions as described in the preparation of Example 42 using crude 4-chloro-N~{3—[(methylsulfinyl)rnethyl]phenyl}-l.3,5-triazinamine and (4-fluoro methoxyphenyl)boronic acid (Aldrich Chemical Company Inc). The batch was purified by column chromatography (DCM 7’ EtOH 95:5) to give the desired product. 2H NMR z, CD013, 300K) 6 = 8.82 (s, 1H). 7.95 (br, 1H), 7.74 (br, 18’), 7.65 (s, 1H), 7.40 (m, 2H), 7.05 (m, 1H), 6.77011, 2H), 4.07 (d, 11-1), 3.95 (m, 4H), 2.49 (s, 31]).
Preparation of end product Concentrated sulfuric acid (2.5 ml.) was added dropwise to a stirred batch of sodium azide (0.61 g; 9.4 mmol) and (4-fluoro—2-methoxyphenyl)-N-{3—[(inethylsulfinyl)methyl}phenyl}~l,3,5-triazin amine (1.75 g; 4.7 mmol) in trichloromcthanc (8.0 mL) at 0°C. The batch was stirred for 18 hours at 45°C. While cooling in an ice bath the batch was cautiously diluted with ice water. The batch was further diluted with saturated sodium chloride solutiori and THF before solid sodium bicarbonate was added under stirring to neutralize the acid. The batch was extracted with THF (3x). The ed organic phases were washed with saturated sodium chloride solution, dried (Nags Oi), filtered and trated to give the desired product (1.79 g; 4.6 mmol).
HNMR (400MHz, CDCl:, 300K) 5 = 8.80 (s, 1H), 7.95 (m, 1H), 7.77 (m, 2H), 7.55 (s, 1H), 7.40 (m, 11—1), 7.15 (m, 11-1), 6.75 (m, 2H), 4.39 (d, 11-1), 4.26 (d, 11-1), 3.92 (s, 3H), 2.96 (s, 3H), 2.71 (s, 1H).
Example 3 and 4: (-)(4-Fluoromethoxyphenyl)-N-{3-1(S-mcthylsulfonimidoyl)methyl]phenyi}~1,3,5—triazin amine (enantiomer 1) and (+)(4-fluormZ-methoxyphenyin-{3-[(S-methylsulfonimidoyl)- methyl]phenyl}-1,3,5—triazinamine (enantiomer 2) (rac)—4»(4-FIuore-2~111ethoxyphenyl)-N-{3—[(S-methylsul’tbnimidoyi)methyl}pheuyl}-l ,3,5-triazin amine see exam le 2 was se e aratcd into the enantiomcrs b rearativc HPLC.
: Pump P 580, Gilson: Liquid Handler 215, Knauer: UV-Detektor K-2501 Chiralpak IC 551m 250x20 mm Hexane I Ethanol 60:40 + 0.1% lamine ———Opttcat rotation tnctex Example 3 134 ~ 156 ~5.2° +/~ 031° (c =1.0000 g/ 100 mL CHCIa) 1 20°C Enantiomer 17.9° +l- 048° (C = 1.0000 g/ 100 mL DMSO) °C Example 4 15.6—17.8 23° +/- 006" (e = 1.0000 9/100 mL CHCla) Enamiomer 2 20°C -14.0° +/-- 0.40" (c = 1.0000 9/100 mL DMSO) °C Enantiomer 1: l1-1 NMR (400MHz, CDCls, 300K) 5 = 8.80 (S, 111), 7.95 (111, 11-1), 7.77 (m, 2H), 7.55 (5, EH), 7.40 (m, 1H), 7.15 (m, 1H), 6.75 (m, 2H), 4.39 (d, 1H), 4.26 (d, 1H), 3.92 (s, 3H), 2.96 (s, 3H), 2.71 (s, 1H).
Enantiorner 2: 1H NMR (400MHz, CDCls, 300K) 8 = 8.80 (s, 1H), 7.95 (m, 1H), 7.77 (111, 21-1), 7.55 (s, 1H), 7.40 (m. 1H), 7.15 (In, 1H), 6.75 (m, 2H), 4.39 (d, 1H), 4.26 (d, 1H), 3.92 (s, 3H), 2.96 (s, 3H), 2.71 (s, 1H)...
Due to its negative optical rotation index in chloroform Enantiomcr 1 is also referred to as (-)(4- Fluo1'0meilioxyphcnyl)-N- {3—{(S—1ncthylsulfonimidoyl)mcthy1]phenyl}—1 ,3 ,5-t1‘iazinaiuinc.
Enantiomcr 2 is also ed to as (+)—4~(4«Fluoromethoxyphenyl)-N—{3-[(S-methylsulfonimidoyl)- phcnyl} - l ,3,5-triazin—2-aminc.
Examnle 5: (rac)-Ethyl {[3-({4-[2-(benzyloxy)-4—fluorophenyII-l,3,5-triazinyl}amino)benzyl](methyl)0xido- AG—sulfanylidene}carbamate M03 “IA“ ”I: /-o S / NANAQH F Example 5 was prepared under similar conditions as described in the preparation ofExample 1 using crude eiliy1[ {3-[(4-chloro- 1 .3.5-triazin—2~yl)amino]benzyl}(nictliy1)oxido-k6- sulfanylidmickarbamato and [2-(bcnzyloxy)fluorophcnyl]boronic acid (ABCR GmbH & Co. KG).
The batch was urificd bv rc arativo HPLC.
Waters Autopurificationsystem: Pump 2545, Sample Manager 2767. CFO, DAD 2996. ELSD 2424, SQD 3001 XBrigde C18 5pm 100x30 mm A = H20 + 0.1% HCOOH _B=Acetonitriie 0~1 min 1% B, 1-8 min 1-99% B, 8-10 min 99% B Max. 250 m. lmax. 2.5 mL DMSO 0. ow DAD scan range 210400 nm —MSESH, ESl-, scan range 160—1000 m/z ‘HNMR (400MHz, CDCla, 300K) 8 = 8.82 (s, 1H), 7.94 (m, 1H), 7.82 (5, 11-1), 7.65 (m, 1H), 7.44 (m, 3H), 7.31 (m, 4H), 7.12 (m, 11-1), 6.80 (m, 21-1)‘ 5.20 (3, 21-1), 4.66 (s, 2H), 4.16 (q, 2H), 2.96 (s, 3H), 1.30 (tr, 3H).
Examgle 6: (rac)-4~[2-(Benzyloxy)fluorophenyll-N-{3-[(S-methylsulfonimidoyl}methyllphenyl}-1,3,5-triazin- Z-amine Example 6 was prepared under similar conditions as bed in the preparation of Example 2 using (rad—ethyl { [3-( {4-[2-(bcnzyloxy)-4—fluorophcnyl]~l ,3,5-triazinyl} amino)bcnzyl}(:netl1yl)ox i 6- sulfanylidcne}carbamatc. The batch was d by column chromatography (DCM / EtOl-l 95:5).
‘H NMR (400MHz, CDClz, 300K) 6 = 8.82 (s, 1H), 7.95 (m, 1H), 7.70 (m, 2H). 7.50 (s, lH}, 7.44011, 2H), 7.32 (m, 4H), 7.12 (m, 1H), 6.79 (m, 2H), 5.20 (s, 2H), 4.33 (d, 1H), 4.21 (d, 1H), 2.92 (s, 3H), 2.69 (s, 1H).
Example 7 and 8: (-)[2-(Benzyloxy)fluorophenyl]-N-{3-[(S~methylsull‘onimidoyl) methyllphenyl}-1,3,5-lriazin~2— amine (enantiomer 1) and (+)l2-(benzyloxy)fluorophenyII-N-{3—[(S-metllylsulfonimidoyl)- methyl]phenyl}-1,3,5-triazin—2-amine (enantiomer 2) (rac) [2-(Bcnzyloxy)~4-fluorophcnyl]’N- {3 —[(Swmcthylsu lfonimidoy1)mctl1yl]phcnyl} -l ,3 ,5miazin-2— amine was sepeparated into the enantiomers by preparative HPLC.
Dionex: Pump P 580, Gilson: Liquid r 215, Knauer: UV—Detektor K-2501 Chiralpak IC 5pm 250x30 mm Hexane / Ethanol 50:50 + 0.1% Diethylamine __—_ (c =1.0000 9/100 ml. CHCIa) mer 1 20°C ExampleB 13.5 - 15.3 98.2 3.5" +/- 0.08“ (c = 1.0000 9/100 mL CHCla) °C Enantiomcr 2 Enantiomer I: 1H NMR (400MHz, CDCls, 300K) 3 = 8.82 (s, 1H). 7.95 (m, 1H), 7.70 (m, 2H), 7.50 (s, 1H), 7.44 (111, 21-1), 7.32 (m, 4H), 7.12 (m, 1H), 6.79 (m, 2H), 5.20 (s, 2H), 4.33 (d, lH), 4.21 (d, 1H), 2.92 (s, 3H), 2.69 (s, 1H).
Enamiomer 2: lE-I NMR (400MHz, CDClg, 300K) 8 = 8.82 (s, 1H), 7.95 (m, 1H), 7.70 (m, 2H), 7.50 (s, ”-1), 7.44 (m, 2H), 7.32 (m, 4H), 7.12 (m, 1H), 6.79 (m, 2H), 5.20 (s, 2H), 4.33 (d, 1H), 4.2'] (d, 1H), 2.92 (s, 3H), 2.69 (s, 1H).
Example 9: (racy-Ethyl [(34 {4~(4,5-difluoromethoxyphenyl)-1,3,5-triazin~2~yl]amino 5 benzyl)(methyl)oxido~ ins-sulfanylidenekarbamate Mug 1‘“/\ 0’ /_O /S N, Example 9 was prepared under similar conditions as described in the preparation of Example 1 using crude (rad—ethyl [{3~[(4-chloro-l ,3,5—triazin—2-yl)amino]benzyl} (methyl)oxido~?l°—sulfanylidene]carb- amale and (4,5-difluur0—2~Inethoxyphenyl)boronic acid (Aldrich). The batch was purified by column chromatography (DCM / BtOH 95:5).
*H NMR (400MHz, 0130;, 300K) 8 = 8.82 (s, ll—I). 7.82 (m, 3H), 7.46 (m, 2H), 7.18 (m, 1H), 6.87 (m, 11-1), 4.74 (m, 21—1), 4.17 ((1, 21-1), 3.92 (s, 31-1), 3.01 (s, 3H), 1.31 (tr, 3H).
Example If]: (rac)(4,5-Difluoro—2-methoxyphenyl)-N—{3-[(S—mcthylsulfonimidoyi)mothyl]phenyl}-l,3,5- triazin—Z-amine Example 10 was ed under similar conditions as described in the ation of Example 2 using ethyl [(3- { [Al-(4,5-difluoro-Zwmetlmxyphenyl)—l ,3,5-triazinyl]amino}benzyl)(mefl1yl)oxido-lf- sulfan lidene carbamate. The batch was ourified b re arative HPLC.
System Waters Autopurlficallonsystem: Pump 254, Sample Manager 2767. CFO, ' DAD 2996, ELSD 2424, SOD 3001 e C18 5pm 100x30 mm A = H20 + 0.2% NHa —B=Acetonitrile 0—1 min15% B. 1-8 min 15-60% B so mL/min Solution: 48 m- / 2 mL DMSO lnjektion: DAD scan ranoe 210—400 nm —MSESI+, scan ran-e 160-1000 mlz 7.57 — 8.00 min ‘H NMR (400MHz, CDCIz, 300K) 6 = 8.81 (s, 1H), 7.78 (m, 3H), 7.54 (s, 1H), 7.42 (m, 1H), 7.17 (m, 1H). 6.86 (m. 1H), 4.40 (d, 1H), 4.27 (d, 1H), 3.91 (s, 3H), 2.96 (s, 3H). 2.72 (S. 1H).
Example 11: (rac)—E tl1 yl I(3-{[4-(4-chlor0methoxyphenyl)-l,3,5—triazinyl]amino}henzyl)(methyl)oxido—k6— sulfanylidenelearbamate ”IA“ °’ ”0M103/S N H“W;C! Example 11 was ed under similar conditions as described in the preparation of Example 1 using crude '(raCJ-cthyl [{3-[(4-chloro-l,3,5-triazinyl)amino]bcnzyl}(methyl)oxido-Kfi-sulfanylidene]- alc and (4-chloro—Z-methoxyphcnyl)boronic acid (ABCR GmbE-I & Co. KG). The batch was d by preparative HPLC.
System: Waters Autopurifioationsystem: Pump 2545. Sample Manager 2767. CFO.
DAD 2996. ELSD 2424. SQD 3001 Column: XBrigde C18 5pm 100x30 mm A = H20 + 0.1% HCOOH _B = itrile 0—1 min 1% B, 1-8 min 1-99% B, 340 min 99% B 50 mL/min Max. 250 mg / max. 2.5 mL DMSO 0. DMF Injektion: 1 x 2.5 mL DAD scan ran-e 210—400 nm —MSESl+, ESI-, scan range 160-1000 m/z 214 NMR(400MH2,CDC13, 300K) 5 = 8.82 (s, 1H), 7.85 (m, 2H), 7.75 (br, 1H), 7.57 (m, 1H), 7.42 (m, 1H), 7.17 (m, 1H), 7.04 (m, 2H), 4.73 (m. 2H), 4.16 (q. 2H). 3.93 (s. 3H), 2.99 (s. 3H), 1.30 (tr, 3H).
Example 12: (rac)—4-(4-Chloremetlloxyphenyl)-N-{3-[(S-metllylsul‘t’onimidoyl)metllyllphenyl}-1,3,5-triazin /\ \ N HN o N o’ AL , / N N amine 0‘ Example 12 was prepared under similar conditions as described in the preparation of Example 2 using (rac)-ethyl[( 3— { [4—(4-ehloro-2—methoxyphenyl)-l ,3,S-triazin-Z-yllamino} benzyl)(methyl)oxido-ls- sulfanylidcne]carbamatc. The batch was purified by preparative I-IPLC.
DAD 2996, ELSD 2424, SQD 3001 _B:Acelcnitriie 0—1 min 1% B, 1-8 min 1—99% B, 8-10 min 99% B ‘HNMR (400MHz, CDCIs, 300K) 5 = 8.80 (s, 1H), 7.80 (m, 4H), 7.39 (m, 1H), 7.15 (m, 1H), 7.03 (m, 2H), 4.39 (d, 1H), 4.26 (d, 1H), 3.92 (s, 3H), 2.96 (s, 3H). 2.39 (br, 1H).
Example 13 and 14: omers of 4-(4—Chloromethoxyphenyl)-N-{3-[(S-methylsulfonimidoyl)methyl}phcnyl}- l,3,S-triazinamine (Iac)(4—Chloro—2—mcthoxyphcnyl)-N- {3~[(S-metbylsulfonimidoyi)methyi]phcnyl} -I ,3,5-triazin—2- amine was separated into the enantiomcrs by preparative HPLC.
A-ilent: Prep 1200, 2 x Prep Pump. DLA, MWD, Prep FC Chiralpak [C 5pm 250x20 mm Ethanol / ol 65 35 +0 1% DEA 13...... 13 “ Enantiomer 1 Example 14 >95 % Eua'ntiOmer 2 Enantiomcr 1: 1H NMR (400MHz, CDCh, 300K) 8 = 8.80 (s, 1H), 7.80 (m, 4H), 7.39 (m, 1H), 7. is (m, 1H), 7.03 (m, 2H), 4.39 (d, 1H), 4.26 (d, 1H), 3.92 (s, 3H), 2.96 (s, 3H). 2.39 (br, 1H).
Enantiomer 2: 1H NMR (400MHz, CDClz, 300K) 8 = 8.80 (s, 1H), 7.80 (m, 4H), 7.39 (In, 1H), 7.15 (In, 1H), 7.03 (m, 2H), 4.39 (d, 1H), 4.26 (d, 1H), 3.92 (s, 3H), 2.96 (s, 3H). 2.39 (br, 1H).
Example 15: (racH -[(3-{ [4-(4-Flnoromethoxyphenyl)—l,3,5-triazin~2~yl]amino}benzyl)(methyl)oxido-l‘. sulfanylideneI-S-methylurea >\-—N..i/Q NIAN O/ Isocyanatomethane (7.6 ul; 0.13 mmol) was added to a solution of (rac)(4-fluoro-Z—methoxyphenyl)— N—{3-[(S-mcthylsulfonimidoyl)methyl]phcnyl}-l.3.5-tn'azinaminc (50 mg; 0.13 mmol) in DMF (2.0 ml) and methyiamine (18.0 p]; 0.13 mmol) at room temperature. The batch was stirred for 5 hours before further isocyanatomethane (3.8 11.1; 0.07 mmol) was added. After 72 hours the batch was diluted with sodium bicarbonate and extracted with ethyl acetate (2x). The combined organic phases were filtered using a Wliatman filter and concentrated. The residue was purified by preparative HPLC to give the desired product (34 mg; 0.08 mmol) System: Waters Autopurificationsystem: Pump 2545, Sample Manager 2767. CFO.
DAD 2996, ELSD 2424, 808 3001 XBrigde C18 5pm 100x30 mm A = H20 + 0.1% HCOOH -B = Acetonitriie 0—1 min 1% 8.1-8 min 1-99% 8.8-10 min 99% B Max. 250 mo I max. 2.5 mL DMSO 0. DMF Injektion: DAD scan range 210—400 nm —MSES|+. ESl-, scan range 160-1000 m/z "H NNIR (400MHz. CDCls. 300K) 5 = 8.81 (s, 1H). 7.80 (m. 4H), 7.4] (m, 1H), 7.17 (m, 1H), 6.78 (In. 2H), 5.04 (br, 1H), 4.83 (d, 1H), 4.64 (d. 1H), 3.94 (s, 3H), 3.00 (s, 3H), 2.78 (d, 3H).
Example 16 and 17: [(3-{ [4-(4-Fluoromethoxyphenyl)-l ,3,5-triazin—2—yljamino} )(methyl)oxido-k“- sulfanylidenelmethy1urea (enantiomer l) and (+)[(3-{I4-(4~Fluoromethoxyphenyl)-l,3,S— triazin-Z— no benzyl)(methvl)oxido-}.°-sulfanylidene]~3-methylureab omer 2) 1-[(3-{[4-(4--F1uoro—2-methoxyphenyl)—l,3,5-triazinyl]amino}benzyl)(metlryl)oxido-kG-sulfanyl— idenc]-3—methylurea was separated into the enantiomers by preparative HPLC.
Dionex: Pump P 580, Gilson: Liquid Handler 215, Knauer: UV-Detektor K-2501 --_— Example 16 27.5 —— 35.5 98.9 -25.1° +/— 019° Enantiomcr 1 (C = 1.0000 g I 100 mL CHCla) °C Example 17 99.2 18.7“ +/- 010° Bnantiomer 2 (c = 1.0000 g l 100 mL CHCla) °C Enantiomer 1: lH NMR (400MHz, CD013, 300K) 5 = 8.81 (s, 1H), 7.80 (m, 4H), 7.41 (m. 1H), 7.17 (m, 1H), 6.78 (m, 2H), 5.04 (br, 1H), 4.83 (d, 1H), 4.64 (d, 1H), 3.94 (s, 3H), 3.00 (s, 3H). 2.78 ((1, 31-1).
Enantiomer 2: 1H NMR (400MHz, CDC13, 300K) 6 = 8.81 (s, 18), 7.80 (m, 4H), 7.41 (m, 1H), 7.17 (m, 1H), 6.78 (m, 21-1). 5.04 (br, 11-1), 4.83 (d, 1H). 4.64 (d. 1H). 3.94 (s. 3H). 3.00 (3. 31-1). 2.78 ((1,3H).
Example 18: (rac)-Ethyl [(3-{[4~(2,2-difiuoro-1,3-benzodioxolyl)-1 riazin~2-yl]amino}benzy1)(methyl)- l‘s-s ulfanylidenekarhamate O F >L03 1““ “SF ”‘3 ’5 n31? e 18 was prepared under similar conditions as described in the preparation of Example 1 using crude (rac )-ethyl [{3-[(4—ch[oro- I ,3,S-triazin-Z-yl)amino]bcnzyl} (methyl)oxido-7&°—sulfanylidcnc] carb- amate and (2,2—difiuoro-1,3-benzodioxol—4~yl)boronic acid (Combi Blocks 1110.). The batch was purified by preparative I-IPLC.
Waters Autopurlficationsystem: Pump 2545. Sample Manager 2767, CFO, DAD 2996, ELSD 2424. SQD 3001 XBri-de (318 5pm 100x30 mm A: H20+ 0.1% HCOOH —B=Acetonllrile 0-1 min 1% B, 1-8 min 1-99% B, 8-10 min 99% 8 Max. 250 mg / max. 2.5 mL DMSO 0. DMF lnjektr‘on: DAD scan range 210—400 nm +, ES[—, scan range 160-1000 m/z ‘H‘ NMR (400MHz, CDCis, 300K) 5 = 8.86 (s, 1H), 8.12011, 1H), 7.82 (m, 1H), 7.48 (m, 3H), 7.24 (m, 3H), 4.76 (m, 2H), 4.17 (q, 2H), 3.02 (s, 3H), 1.31 (Ir, 3H).
Example 19: (rac)(2,2-Di'lluoro-I,3~benzodioxolyl)-N-{3-l(S-methylsulfonimidoyhmethyll plrenyl}-1,3,5- triaziunmine Hmfl 1 ,NA orF / n N Example 19 was prepared under similar conditions as described in the preparation oFExamplc 2 using cthyl [(3 - {[4-(2,2—diflu oro-l ,3-benzodioxol-4—yl)— I ,3 ,5-triazinyl]amino}benzyl)(methy1) oxide- KG-sulfanylidcnc]carbamatc. The batch was purified by column chromatography (DCM / EtOH 95:5).
'H NMR (400MHz, @303, 300K) 8 = 8.84 (s, 1H), 8.13 (m, 1H), 7.87 (m, 2H), 7.52 (br, 1H), 7.45 (m, 1H), 7.22 (m, 3H), 4.44 (d, 1H), 4.29 (d, 1H), 2.97 (s, 3H), 2.70 (s, 1H).
Example 20: (rad-Ethyl [(3-{{4—(5—fluoro-2~methoxyphenyl)~l,3,5-triazin-2~yl]amino}benzyl)(methy1)oxido sulfanylidene]carbamate ©\ flu 0/ \ I / O S / / n N Example 20 was prepared under similar conditions as bed in the preparation of Example 1 using crude (ram—ethyl [{3-[(4-chloro-1,3,5—triaziny1)amino]bcnzyl}(metliyl)oxido-?k°—sulfauylidcnc]carb— ammo and (S-fluoro-Z-methoxyphcnyl)boronic acid (Aldrich Chemical Company Inc.) The batch was purified by preparative HPLC.
System: Waters Autopurificationsystem: Pump 2545, Sample Manager 2767, CFO, DAD 2996, ELSD 2424. SOD 3001 : XBri-de C18 5pm 100x30 mm Solvent: A = H20 + 0.1% HCOOH B = itrile nt: 0—1 min 1% B, 1-8 min 1—99% B. 8-10 min 99% B How: remperarure: swunon: mjekuon: Deiection: DAD scan range 210-400 nm MS ESE+. ESl—. scan range 160—1000 m/z H NMR (400MHz, CDCla, 300K) 5 = 8.84 (s, 1H), 7.84 (m, 1H), 7.73 (br, 1H), 7.60 (m, 1H), 7.51 (s, 1H), 7.43 (m, 1H), 7.19 (m, 2H), 7.00 (m, 1H), 4.74 (m, 211), 4.13 (q, 2H), 3.91 (s, 3H), 3,00 (s. 3H), 1.30 (tr, 3H).
Examgle 21: (rac)—4-(5-Fluoromethoxyphenyl)—N-{3-[(S-methylsulfonimidoyl) methyllphenyl}-l ,3,5-triazi 11 amine HN“ ”(i/Q N: \N 0/ /3 NAN/ Example 21 was prepared under similar conditions as described in the preparation of Example 2 using (rac)-ethyl [(3- {[4-(5-fluoro-Z-methoxyphenyl)- l ,3,5—triazin—2—yi]amino}benzy1)(melhyl)oxido—7§— sulfanylidcnckarbnmatc. The batch was purified by column chromatography (DCM .’ EtOH 95:5).
'H NMR (400MHz, CDCls, 300K) 8 = 8.84 (s, 1H), 7.73 (m, 2H), 7.63 (m, 1H), 7.43 (m, 2H), 7.19 (m, 2H), 7.02 (m, 1H), 4.38 (d, 1H), 4.28 (d, 1H), 3.91 (s, 3H), 2.95 (s, 3H), 2.70 (br, 1H).
Example 22 and 23: Enantio mers of 4-(5-fluor0meth0xyphenyl)-N-{3-I(S-mEthylsuiibnimidoyl)methylIphenyl}-l,3,5- trinzin-Z-amine {rac)—4-(5-F1uoro-Z-mcthoxyphenyl)-N- {3-[(S-methylsulfonimidoyl)rnethy1]phcny1} - l ,3,5-triazin~2— amino was ted into the cnamiomcrs by preparative HPLC: System: Agilent: Prep 1200, 2 x Prep Pump, DLA, MWD, Prep FC Column: cel OJ-H 50m 250x20 mm /7t: Ethanol I methanol 50:50 +01% DEA Flow: 16 mL/mrn Example 22 6.1 - 7.2 >99 % Enantiomer 1 Example 23 8,5 — 10,2 >99 % Enamiomer 2 Enantiomer 1: 1H NMR (400MHz, CDCls, 300K) 5 = 8.84 (s, 1H), 7.73 (m, 2H), 7.63 (m, 1H), 7.43 (m, 2H), 7.19 (m 2H), 7.02 (m, 1H), 4.38 ((1, 11-1), 4.28 (d, 1H), 3.91 (s, 3H), 2.95 (s, 3H), 2.70 (br, 11—1).
Enantiomer 2: 'H NMR (400MHz, CDCls, 300K) 6 = 8.84 (s, 1H), 7.73 (111,211), 7.63 (m, 1H), 7.43 (m, 2H), 7.11) (m, 2H), 7.02 (m, 1H), 4.38 (d, 1H), 4.23 (d, 1H), 3.91 (s, 3H), 2.95 (s, 3H), 2.70 (br, 1H).
Example 24: (rac)~N-[(3-{_[4-(4-fluoromethoxyphenyl}-l,3,5-triaziny]]amino}benzyl)(methyl)oxido-).6- sulfanylidenelacetarrfide N O NAN o/ ”‘s,’ / JL / N N Acctyl chloride (10.1 pl; 0.14 mmol) was added to a solution of (rac)(4-fluoro-Z-mcthoxyphcnyl)-N~ {3-[(S-methytsulfonimidoyl)methyl]phenyl}—1,3,5—triazinamine (50 mg; 0.13 mmol) in DCM (1.5 ml) and tricthylamine (45.0 pi; 0.32 mol) at 0°C. The ice bath was removed and the batch was stirred for 23 hours before further acetyl chloride (4.0 p]; 0.06 mmol) was added. After 24 hours additional acetyl chloride (5.0 ul; 0.07 mmol) was added and the batch was aimed for 3 heurs before it was dituted with water and ted with ethyl acetate (2x). The combined organic phases were filtered using a Whatman filter and concentrated. The residue was purified by preparative HPLC to give the desired product (35 mg; 0.08 11111301).
DAD 2996. ELSD 2424. SQD 3001 1 X 2-5 ml- DAD scan range 210—400 nm —MSESH. ES]~, scan range 160-1000 m/z "H NMR (400MHz, CDCls, 300K) 8 = 8.82 (s, 1H), 7.95 (m, 1H), 7.78 (m, 2H), 7.56 (m, 1H), 7.42 (m, 1H), 7.16 (m, 1H), 6.79 (m, 2H), 4.78 (d, 1H), 4.65 (d, 1H), 3.94 (s, 3H), 3.03 (s, 3H). 2.12 (s, 3H).
Exalee 25: (rac)-Ethyl [(3-{[4-(2-methoxypl1enyl)~l,3,5~triazin~2~yl|amino}benzyl)(methyl)oxi(lo-7.6- sulfanylideneicarbamate nyIO NIA N 0/ /_O /s NAN/ Example 25 was prepared under similar ions as described in the preparation of Example 1 using crude (rac)-ethyl [{3-[(4-chloro— l,3,S-triazinyl)amino]benzyl} l)oxido-lé-sulfanylidene]carb- amatc and (2-methoxyphenyl)boronic acid (Aldrich Chemical Company 1110.). The batch was purified by preparative HPLC.
DAD 2996, ELSD 2424. 800 3001 XBrigde 018 5pm 100x30 mm A = H20 + 0.1% HCOOH _B=Acetonitrile 0—1 min 1% B. 1-8 min 1-99% B. 8-10 min 99% B 50 mL/min "H NMR (400MHz, CDCls, 300K) 8 = 8.82 (s, 1H), 7.85 (m, 2H), 7.71 (m, 1H), 7.56 (s, 1H), 7.48 (m, 1H), 7.42 (m, 1H), 7.17 (m, 1H), 7.07 (m, 2H), 4.73 (s, 2H), 4.17 (q, 2H), 3.93 (s, 3H). 2.98 (s, 3H), 1.30 (Ir, 3H).
Example 26: 4—(2-Methoxyphenyl)-N~{3-[(S-methylsulibnimidoyl)methyl]phenyl}-l,3,5~triazin-2—amine fiN\I(:/©\ flu 0/ \ I S / Example 26 was prepared under similar condiiions as described in the ation of Example 2 using (rac)-etfiyl[(3— { [4~(2—methoxyphenyl)-I ,3 ,5-tria2inyl]amiuo} benzyl)(methy1)oxido-kb-suifanylidcne]- carbamate. After aqueous work up no further ation was necessary.
‘H NMR (400MHz, CDCIs, 300K) 5 = 8.83 (s, 1H), 7.86 (m, 1H), 7.75 (m, 2H), 7.54 (s, 1H), 7.49 (m, 1H), 7.41 (m, 1H), 7.16 (m, 1H), 7.05 (m, 2H), 4.38 (d, 1H), 4.26 (cl. 1H), 3.93 (s, 3H), 2.94 (s, 3H). 2.70 (s, 1H).
Example 27 and 28: Enantiomers of 4—(2-Methoxyphenyl)—N-{3—[(S-methylsulfonimidoyl)mcthyl]phenyl}-I,3,5~trinzin- 2-3mine(rac)(2-Methoxypheny1)-N— {3-[(S-methylsulfonimidoyl)methyl]pheny1} —1 ,3,5-triazin—2— amine was separated into me enamiomers by preparative HPLC: Chiralcel OJ-H 5pm 250x20 mm Ethanol / methanol 50:50 +01% DEA Example 27 11.7 -12.2 >99 % Enamiomer 1 Example 28 Enantiomer 2 Enamiomer 1: 'H NMR (400MHz, CDCls, 300K) 5 -— 8.83 (s. 1H), 7.86 (m, 1H), 7.75 (111, 21-1), 7.54 (5. 1H), 7.49 (m, 1H), 7.41 (m, 1H), 7.16 (m, 1H), 7.05 (m, 2H), 4.38 (d, 1H), 4.26 (d, 1H), 3.93 (s, 3H), 2.94 (s, 3H). 2.70 (s, 1H).
Enantiomer 2: ‘11 NMR(4OOM1—lz, CDClg, 300K) 5 = 8.83 (s, 111), 7.86 (m, 111), 7.75 (m, 211), 7.54 (s, 1H), 7.49 (m, 1H), 7.41 (m, 1H), 7.16 (m, 1H), 7.05 (m, 2H), 4.38 (d, 1H), 4.26 (d. 1H), 3.93 (s, 3H), 2.94 (s, 3H). 2.70 (s, 1H).
Example 29: (rac)—Ethyl. {(3-{[4~(3,4—dihydro-2H-chromen-S—yD-l,3,5—triazin—2-yl]amino}benzyl)(mcthyl)0xido~ )flsulfanylidene]carbamate N\ ,o ill/W /#0 /S NAN/ Example 29 was prepared under similar conditions as described in the preparation of Example 1 using crude (rac)-cthyl [{3-[(4—chloro-l,3,S~1fiazinyl)amino]bcnzyl}(mothyl)oxido-?k°—sulfa11ylidcnc]carb— amate and 3,4-dihydro-ZH-chromen-S-ylboronic acid ay Scientific LLC). The batch was purified by preparative HPLC.
: Waters Autopurificationsystem: Pump 2545, Sample Manager 2767, CFO.
DAD 2996. ELSD 2424. SOD 3001 XBrigde C18 5pm 100x30 mm A = H20 + 0.1% HCOOH -B=Acetonitriie 0—1 mm 1% B, 1-8 min 1-99% B, 8-10 min 99% B Max. 250 mg I max. 2.5 mL DMSO 0. DMF 1 x 2.5 mL DAD scan range 210—400 nm _MSESl+, ESI-, scan range 160—1000 11112 ‘H NMR (400MHz, CDCls, 300K) 6 = 8.84 (s, 1H), 7.85 (m, 1H), 7.74 (br, 1H), 7.65 (m, 1H), 7.42 (m, 2H), 7.19 (m, 2H), 6.94 (m, 1H), 4.73 (s, 2H), 4.30 ('0', 2H], 4.17 (q, 2H), 2.98 (s, 3H), 2.89 (tr, 2H), 2.10 (m, 2H), 1.31 (tr, 3H).
Example 38: (rac)(3,4—Dihydro-2H4:hromen-8~yl)~N~{3-[(S-methyls ulfonimidoyl)methyl} phenyl}-l,3,5— triazin-Z-amine mini/Q /\ JNL \N o /S N N/ Example 30 was prepared under similar conditions as described in the ation of Example 2 using (rac)-othyl[(3— {[4-(3,4-dihydro-2H-chromenyl)-1,3,5-lriazinyl]amino}benzyl)(methyl)oxidu—7x“~ sulfanylidenekarbamate. Aficr aqueous work up no further purificatiOn was necessary. 3H NMR(400M1-iz, 0003, 300K] 8 a 8.83 (s, 1H), 7.74 (m, 3H), 7.49 (br, 15), 7.40 (m, 1H), 7.17 (m, 2H), 6.94 (111, 11-1), 4.30 (m, 4H), 2.94 (s, 3H), 2.88 (0,211), 2.69 (s, 1H), 2.10 (m, 2H).
Example 31 and 32: Enantiomers of 4-(3,4-dihydro-2H-chromen-S-yl)~N-{3~[(S-mcthylsulfonimidoyl)mcthyllphcnyl}- 1,3,5-triazin—2-amine(rac)(3,4-Dihydro-ZH—chromen—S-yl)-N-{3-{(S— methylsulfonimiduyl)methyl]phenyl}~1,3,5—triazinamine was separated into the cnantiomers by re . amiivc HPLC.
Agilent: Prep 1200, 2 x Prep Pump, DLA, MWD, Prep FC Chiralcel OJ-H Sum 250x20 mm Solvent: l I methanol 50:50 +01% DEA Flow: 16 mL/mln Example 3| 7.0 - 8.1 >99 % Enamiomer 1 Example 32 10.0 — 11.3 Enamiomcr 2 omcr 1: 1H NMR (400MHz, CDCla, 300K) 8 = 8.83 (s, 1H), 7.74 (m, 3H), 7.49 (br, 1H), 7.40 (m, 1H), 7.17 (m, 2H), 6.94011, 1H), 4.30 (m, 4H), 2.94 (s, 3H), 2.88 (tr, 2H), 2.69 (s, 1H), 2.10011, 2H).
Enantiomcr 2: lH NMR (400MHz, CDClg, 300K) 5 = 8.83 (s, 1H), 7.74 (m, 3H), 7.49 (br, 1H), 7.40 (m, 1H), 7.17 (m, 21-1), 6.94 (In, 1H), 4.30011, 4H), 2.94 (s, 3H), 2.88 (tr, 2H), 2.69 (s, 1H), 2.10 (m, 2H).
Example 33: (rac)-Ethyl [(3-{ [4-(2,3-dihydro-l -benzofuran—7~yl)-1,3,S-triazin-2—yl] amino}benzyl)(methyl)oxido- XG-sulfanylidenelcarbamate / OM‘SCQ 1W / n N” Example 33 was prepared under similar ions as described in the preparation of Example 1 using crude (rac)—ethyl [{3-[(4-chloro-1,3,5-ln'azinw2—yl)amino]benzyl}(methy1)oxido-?»6-sulfanylidenc]carb- amate and (2,3«dihyclro~1~benzofuran—7-yl)boronic acid (ChemBridge ation). The batch was d by preparative HPLC.
System: Waters Autopurificationsystem: Pump 2545, Sample Manager 2767. CFO.
DAD 2996, ELSD 2424. SQD 3001 XBrigde C18 5pm 100x30 mm A = H20 + 0.1% HCOOH -B=Acetonitrile 04 min 1% B, 1-8 min 1—99% 8, 8-10 min 99% B 50 ml-fmin Max. 250 mg / max. 2.5 mL DMSO 0. DMF Injektion: 1 x 2.5 mL DAD scan range 210—400 nm —MSESI+, ESL, scan range 00 m/z 1H NIVIR (400MHz, CDCls. 300K) 5 = 8.85 (5, 1H), 3J0 (m. 1H), 7.96 (S, 1H), 7.75 (m. 1H), 7.42 (m, 3H), 7.18 (In, 1H), 6.98 (m. 1H), 4.80 (tr, 2H), 4.76 (8, 2H), 4.17 (q, 2H), 3.29 (tr, 2H), 3.01 (S, 3H), 1.3} (11', 3H).
Example 34: (rac)~4~(2,3-Dihydro-l-benzofuranyl)-N-{3-[(Samethylsulfonimidoyl)methyl]phenyl}-1,3,5- triazin-Z-amine Example 34 was prepared under similar ions as described in the preparation of Example 2 using (rac)-ethyl[(3- { [4-(2,3-dihydro— l —benzofi1ranyl)-1 .3,5-lriazin~2—yl]amino} benzyl)(melhyl)oxide-K‘— sulfanylidenc]carbamate. After aqueous work up no fiirther purification was necessary. ‘11 NMR (400MHz, CDCls, 300105 a 8.85 (s, 111), 8.11 (m, 1H), 7.87 (5, 11—1), 7.76 (br, 111), 7.44011, 2H), 7.39 (m, 11-1), 7.17 (m, 11-1), 6.98 (m, 11-1), 4.81 (tr, 2H), 4.40 (d, 1H), 4.30 (d, 1H), 3.29 (tr, 2H), 2.95 (s, 3H), 2.72 (s, 1H).
Example 35 and 36: Enantiomers of 4-(2,3—dihydrobenzofuranyl)-N-i3-[(S-methylsulfonimidoyl)methyl}pl1enyl}- 1,3,S-triazinamine (rac)(2,3—Dihydrobcnzofuranyl)~N-{3-[(S—mcthylsulfonimiduyl)mclhyl]phcnyl}—l ,3,5—lriazin—2- amine was separated into the enamiomers by ative HPLC.
Ethanol I Methanol 50:50 +0.1% DEA 74 mg l 0.9 mL DMSO Example 35 9,1 — 10,5 Buantiomer 1 Example 36 10,8 “ 15.8 Enamiomcr 2 Enantiomer I: 1H NMR (400MHz, CDC13, 300K) 6 = 8.85 (s. 1H). 8.11 (m, 1H). 7.87 (s. 1H), 7.76 (br, 11-1), 7.44 (m, 2H), 7.39 (111, 11-1), 7.17 (m, 1H), (7.98 (m, 11-1), 4.31 (tr, 2H), 4.40 (d, 1H), 4.30 (d, 1H), 3.29 (tr, 2H), 2.95 (s, 3H), 2.72 (s, 1H). omer 2: [H NMR (400MHz, c1303, 300K) 5 = 8.85 (5, 11-1), 8. El (m, 1H), 7.87 (s, 1H), 7.76 (br, 1H), 7.44 (m, 2H), 7.39 (m, 1H), 7.17 (m, 1H), 6.98 (m, m), 4.31 (tr, 2H), 4.40 (d, 1H), 4.30 (d, 1H), 3.29 (tr, 2H), 2.95 (s, 3H), 2.72 (s, 1H).
Example 37: (rac)-Ethyl [(3-{[4-(2,3-dihydro—l,4-benzodi0xinyl)-1,3,S—triazin—2-yllamino}benzyl)(methyl)- oxido-XG-sulfanylidenelcarbamate N‘O O’\ /—O /S’\/©\ JLN/A : .0 N Example 37 wés prepared under r conditions as described in the preparation of Example 1 using crudc cthyl [{3~[(4~chloro-1,3,S—tria2inyl)amino}benzyl}(methyl)oxido-?L6-sulfanylidcnc]carb- amatc and ihydro-l ,4—bcnzodioxin-S-ylboronic acid (Combi Blocks lnc.). The batch was d by column chromatography (DCM / 6101-] 95:5).
"H NMR (400MHz, CDCls, 300K) 3 = 8.85 (s, 1H), 7.87 (s, 1H), 7.71 (m. 1H), 7.48 (In, 2H), 7.42 (m, 1H), 7.17 (m, 1H), 7.04 (m, 1H), 6.95 (m, 1H), 4.74 (m, 2H), 4.37 (m, 4H), 4.17 (<1, 2H), 3.00 (s, 3H), 1.31 (1r, 3H).
Example 38: (rac)(2,3-Dihydro-1,4-benzodioxin-S-yl)—N—{3-[(S—methylsulfonimidoyl)methyllphenyl}-I,3,5- triazin-Z-amine ””MLQ JL/\N \N m/S N/ 0 Example 38 was prepared under similar conditions as described in the preparation of Example 2 using (rac)-cthyl[(3— { [4-(2,3 -dihydro-1,4-bcnzodioxinyl)-1,3,5-triazinyl]amino}bcnzyl)(mcthyl)oxido—k6— sulfanylidenekarbamate. After aqueous workup no further purification was necessary.
"H NMR (400MHz, CDCls, 300K) 6 = 8.84 (s, 1H), 7.75 (m, 2H), 7.56 (s, 1H), 7.49 (in, 1H), 7.40 (in, 11-1), 7.15 (m, 1H), 7.04 (m, 1H), 6.94 (m, 1H), 4.38 (in, 51-1), 4.26 (d, 1H), 2.95 (s, 3H), 2.72 (s, 1H).
Example 39 and 40: Ennntiomcrs of 4-(2,3—r¥ihydro-l,4-beumdioxin-S-yl)~N-{3~1(S-mcthylsulfonimidoyl)methyl]- phenyl}-1,3,S—trlazin—Z-amine(rac)-4—(Z,3-Dihydro-1 ,4-benzodioxinyl)—N— {3 -[(S- methylsulfonimidoyl)methyl]phenyl}~l,3,5-triazinarnine was separated into the enantiomers by preparative HPLC.
Chiralcel OJ-H 5pm 250x20 mm Solvent: Ethanol / methanol 50:50 +01% DEA Example 39 7.5 -— 9,0 >99 % Enantiomcr 1 Example 40 9,4 ~11.3 >98 % Enantiomer 2 omer l: ‘H 0M1—lz, CDCla, 300K) 8 = 8.84 (3, 11-1), 7.75 (1n,21i), 7.56 (s, 1H), 7.49 (m, 1H), 7.40 (m, 1H), 7.15 (m, lH), 7.04 (m, 1H), 6.94 (m, 1H), 4.38 (m, 5H), 4.26 (d, 1H), 2.95 (s, 3H), 2.72 (s, 1H).
Bnantiomer 2: 'H NMR (400MHz, CDCls, 300K) 5 = 8.84 (s, 1H), 7.75 (m, 2H), 7.56 (s, 1H), 7.49 (m, 1H), 7.40 (m, 1H), 7.15 (m, 1H), 7.04 (m, 1H), 6.94 (m, 1H), 4.38 (m, 5H), 4.26 (d, 1H), 2.95 (s, 3H), 2.72 (s, 1H).
Example 4 I: (rac)—N~{3~[(N,S-Dimethylsulfonimidoyl)methyllphenyl}(4-fluoro—2-methoxyphenyl)-1,3,5- triazin-Zm mine Formaldehyde (17.9 pl; 0.65 mmol) was added to a solution of (rac)—4-(4~fluoro-2—methoxyphcnyl)-N- {3-[(S-methylsulfonimidoyi)metltyl]phenyl}-I,3,5-triazinamine (50 mg; 0.13 mmol) in formic acid (1.0 mI)'at room temperature. The batch was stirred at 80°C for 24 hours. After cooling the batch was diluted with aqueous sodium bicarbonate solution and extracted with ethyl acetate (2x). The combined c phases were filtered using a Whatman filter and concentrated. The residue was purified by preparative HPLC to give the desired product (5 mg; 0.0] mmol).
DAD 2996. ELSD 2424. SOD 3001 0—1 min 15% B. 1-8 min 15-50% B. 8-8.1 min (SO-100% B. 81—10 min 100% B DAD scan range 210—400 nm —MS581+, ES|-, scan range 00 m/z _ELSD as 5.8 min 'H NMR (400MHz, CDCls. 300K) 5 = 8.81 (5. 1H), 7.94 (in, 1H),7.71 (m, 2H). 7.58 (m. 1H). 7.40 (In. 1H), 7.13 (1111 11-1), 6.75 (in, 2H), 4.33 (5, 2H), 3.93 (s, 3H), 2.86 (s, 3H), 2.74 (s, 3H).
Examgle 42: (rac)—Ethyl [{3-{(4-{2-[(4-fluorobenzy1)oxy]pheny1}-l,3,S-triazinyl)aminoibenzyl}(methyl)oxido- 16-su11‘any1idenelcarbamate hit/PVC) A ANwFN, N o /—_O /S N A batch with cru de (rac)~etliy1 i{3-{(4-chloro-1,3,5-triazin-Z-y1)amino]benzyl} (methyl)oxid0-7LG- sulfanylidcnekarbamatc (400 mg), {2-[(4-fluorobcnzyl)oxy]phcny1}boronic acid (266 mg; 1.08 mmol; Aldrich Chemical y Inc.) and {1,1‘-bis(_c1iphcnylphosphino)ferroccncipalladiumdichloride (132 mg; 0.16 01) in 1,2-di1nethoxycthane (2.5 uiL) and 2M solution of potassium carbonate (1.1 mL) was degassed using argon. The batch was stirred under argon for 90 minutes at 100°C. After cooling the batch was d with DCM. The organic phase was fi1tcred using a Whatman filter and concentrated.
The residue was purified by chromatography (DCM / ethanol 95:5) to give the desired product (134 mg; 0.25 mmoi).
HNMR (400MHz, CDCI3, 300K) 5 = 8.84 (s, 1H), 7.86 (m, 2H), 7.62 (m, 1H), 7.42 (111, 51-1), 7.12 (m, 3H), 7.09 (m, 2H), 5.16 (s, 2H), 4.67 (s, 2H), 4.16 (q, 2H), 2.95 (s, 3H), 1.30 (tr, 3H).
Example 43: (rac){2-[(4-Fluorobenzyl)oxylphenyl}-N-{3-[(S—methylsulfonimidoyl)methyllphenyl}-l,3,5— n-Z-amine “No? o /k /”I \N /S n N F e 43 was prepared under similar conditions as described in the preparation of Example 2 using (rac)—ethyl{ {3 - [(4 - {2—[(4-fluorobenzyl)oxy}phenyl} -1 ,3,5—Hiazin—2-yl)amino]benzyl}(methyl)oxido-k6- sulfanylidenekarbamate. After s work up no further purification was necessary.
'H NMR (400MHz, CDCls. 300K) 8 = 8.83 (s, 1H). 7.87 (m, 1H), 7.76 (s, 1H), 7.68 (in, 1H), 7.42011, 5H), 7.04 (m, 5H), 5.16 (s, 2H), 4.34 (d, 1H), 4.22 (d, 1H), 2.92 (s, 3H), 2.70 (s, 1H).
Example 44: (rac)-N-[(3-{[4-(4-Fluoro—Z—methoxyphenyi)-1,3,5-triazinyl}amine}benzyl)(methyl)oxido—2f— sulfanylidenelmcthanesulfonamide H / o\ /§ ‘S—NO / ”\Q | ,3 NAN/ Mcthanesulfonyl chloride (£20 pl; 0.16 mmol) was added to a solution of (rac)(4-fluoro methoxyphenyl)-N-{3-{(S-melhylsulfonimidoyl)melhyl]phonyl}—l,3,5-tria7.inaminc (50.0 mg; 0.13 mmol), triethylamine (21.6 pl; 0.16 mmol) and 4-dimethylaminopyridine (1.6 mg; 0.0] mmol) in DCM (2.0 ml) at room temperature. The batch was stirred for 23 hours before additional methanesulfonyl de (8.0 pl; 0.10 mmol) was added, After 23 hours additional merhanesulfonyl chloride (8.0 ul; 0.10 mmol) was added. After 24 hours additional methanesulf‘onyl chloride (12.0 1,11; 0.16 mmol) was added.
Finally, after 48 hours additional csulfonyl chloride (20.0 til; 0.26 mmol) was added and the batch was stirred for 2 additionai hours. The batch was diluted with aqueous water and extracted with DCM (2x). The combined organic phases were filtered using a Whatman filter and concentrated. The residue was purified by ative HPLC to give the desired product (21 mg; 0.05 mmol).
DAD 2996. ELSD 2424. SOD 3001 Max. 250 mg / max. 2.5 mL DMSO 0. DMF Injektion: 1 x 2.5 mi.
DAD scan range 210—400 nm —MSESl+, ESl-. scan range 160-1000 m/z ;H NMR (400MHz, CDCl:, 300K) 5 = 8.82 (S, 1H), 7.94 (m, 1H), 7.82011, 3H), 7.43 (m, 1H), 7.21 (m, 1H). 6.76 (m, 2H), 4.74 (s, 2H), 3.92 (5, 3H), 3.14 (s, 3H), 3.06 (S, 3H).
Example 45: (racy-Ethyl [(3-{[4-(3—chloro—2-meth0xyphenyl)-1.3.5-triazlnyl}amino}benzy])(methyl)oxido~l~.6- sulfanylidenelcarbamate NMO N. ‘N o’ /—O /S N/kN/ CI Example 45 was prepared under similar conditions as described in the ation of e 42 using crude (raw-ethyl [{3-{(4-chluro—l,3,S—triazin-Z-yl)amino]bcnzyl}(methyl)oxido-A6-sulfanylidenclcarb- ammo and (3-chloro-Z-mcthoxyphcnyl)boronic acid (Aalcn Chemical Co., Ltd.) The batch was purified by preparative HPLC.
DAD 2996. ELSD 2424, SQD 3001 XBrigde C18 5pm 100x30 mm A = H20 + 0.1% HCOOH —B=Acetonltrlle 0—1 min 1% B, «a min 1-99% B, 8-10 min 99% B Injektr‘on: ion: DAD scan range 210—400 nm -MSES|+, ESl-. scan range 160-1000 m/z in NMR (400MHz, CDCls, 300K) 5 = 8.85 (s, 1H), 7.97 (s, 11-1), 7.81 (In, 1H), 7.58 (m, 3H), 7.43 (in, 11-1), 7.18 (m, 21-1), 4.75 (m, 2H), 4.17 (q, 217), 3.87 (s, 3H), 3.02 (s, 3H), 1.30 (tr, 3H).
Example 46: (racyEthyl { [3-({4-[S-fluoro-Z-(tetraliydro-ZH-pyranylmethoxy)phenyII-l,3,5-triazinyl}- amino)benzyl](metl1yl)oxido~k‘~sulfanylidene}carbamate yva“A“ o /"_o /3 ”inf/\fij/U Example 46 was prepared under similar conditions as described in the preparation of Example 42 using cmde (rac)~ethyl [{3 -[(4-chloro-1,3,5—triazinyl)amino]benzyl}(methyl)0xid0-}»°—suifauylidene} ate and [5~f1uoro(1etmhydro-2H-pyranylmethoxy)pheny1]boronie acid (FCH Group Company). The batch was purified by preparative HPLC.
System: Waters Autopurificationsystem: Pump 2545, Sample Manager 2767. CFO, DAD 2996. ELSD 2424. SOD 3001 XBrigde 018 5pm 100x30 mm A = H20 + 0.1% HCOOH _B=Aeetonitriie 0‘1 min 1% a. 1-8 min 1-99% B, 8-10 min 99% B 50 mL/min Solution: Max. 250 mg I max. 2.5 mL DMSO 0. DMF ion: DAD scan range 210—400 nm _MSES!+, ESl-, scan range 160-1000 m/z ‘H NMR z, CDCls, 300K) 3 = 8.83 (s, 111), 7.89 (br, 11—1), 7.70 (111, 31-1), 7.43 (m, 1H), 7.15 (m, 2H), 6.93 (m, 11-1), 4.74 (m, 2H), 4.18 ((1, 21-1), 3.96 (m, 4H), 3.41 (m, 2H), 3.01 (s, 3H), 2.02 (br, 1H), 1.64 (m, 4H). 1.31 (tr, 3H).
Example 47: (rac)-Ethyl[methyl(oxi(lo)(3-{[4-(2~phenoxyphenyl)~l,3,S-triazinyi]amino}benzyle— sulfanylidenelcarbamate NU’:/©\ JNL\N /\ O /—O /s N Nab ExampIe 47 was prepared under similar conditions as described in the preparation ofExarnpie 42 using c ru (1 e (ra c )-cthyl [{3-[(4—ehloro-l ,3,5-triazinyl)amino]benzyl} (methyl)oxido-ké~sulfanylidenc]- carbamate and enoxyplienyl)boronic acid (ABCR GmbH & CO. 1(0). The batch was purified by preparative HPLC.
System Waters Autopurificationsystem: Pump 2545, Sample Manager 2767, CFO, DAD 2996, ELSD 2424, SQD 3001 XBride 018 5pm 100x30 mm A =’ H20 + 0.1% HCOOH _B = Acetonitrile 0-1 min 1% B, 1-8 min 1—99% B, 8-10 min 99% B Max. 250 m / max. 2.5 mL DMSO 0. DMF Injektion. 1 x 2.5 mL DAD scan range 210-400 nm ’r. ESI-. scan range 160-1000 rn/z 'H NMR (400MHz, dc-DMSO, 300K) 3 = 10.35 (S, 1H), 8.72 (S, 1H), 7.89 (In, 2H), 7.55 (br, 1H), 7.52 (In, 1H), 7.26 (m, 4H), 7.03 (m, 3H), 6.89 (m, 2H). 4.78 (5, 2H), 3.93 (q. 2H), 3.12 (5, 3H), 1.09 (tr, 3H).
Examnle 48: (me)-[(3-{[4-(4-F1uor0methoxyphenyl)-l,3,5-triazin—2-yl]amino}benzyl)(methyl)oxido-Ns- ylidenelcyanamide NE“ N\'i/Q NI“ N 0/ /s )\Néfi Pregaration of Intermediate 48.1: 4-Cliloro-N-{3-l(Inethylsulfanyl)methyl]phenyl}-1,3,5-triazinamine Q“A“ | ,s NANACI Intermediate 48.1 was prepared under similar conditions as described in the preparation of Intermediate l.7 using 3—{(mcthyisuifanyl)mcthyi]ani1inc (UkrOrgSynthcsis Ltd).
System: Waters Acquity UPLC-MS: Binary SOIVent Manager. Sample ManagerlOrganizer, Column Manaoer, PDA, ELSD. SOD 3001 Column: Acquity UPLC BEH C18 1.? 50x2.1mm A2 = H20 + 0.2% NH3 _81 = Acetonitrile 04.6 min 1-99% B, 1.6-2.0 min 99% B 0.8 mL/min Injeklion: 2.0 pl DAD scan ran-e 210-400 nm -> Peaktable _ELSD Method: MS ES|+, ESI- Switch A2 + B1 = C:\MassL anlass 160 1000 eport.flp Waters Acquily UPLC—MS: Binary Solvent Manager. Sample Manager/Organizer.
Column Mama-er, PDA, ELSD, SQD 3001 MS(ES~): m/z = 268 [M+H] Preparation of Intermediate 48.2: 4-(4-Fluoromethoxyphenyl)-N-{3~I(methylsulfanyl)methyl]phenyl}-1,3,5-trlazin-2~amine S / Intermediate 48.2 was prepared under similar conditions as described in the preparation of Example 1 using crude ro-N—{3-{(rnethyisull‘anyl)me1hyl]phenyl}-I,3,5-iriazinamine and (4-fluoro yphenyl)boronic acid (Aldrich Chemical Company Inc). The batch was purified by column tography (DCM / EtOH 95:5) to give the desired product.
'H NMR (400MHz, CDCls, 300K) 6 — 8.80 (s, 1H), 7.97 (br, 11-1). 7.83 (In, 2H), 7.50 (s, 1H), 7.3] (m, 1H), 7.07 (m. 1H), 6.77 (in, 2H), 3.93 (s, 3H), 3.69 (s, 2H), 2.02 (s, 3H).
Preparation of Intermediate 48.3: (rac)~[Ci-{[4-(4-fluoro~2-methoxyphenyl)-l,3,5-triazinyl]amino}benzyl)(methyl)—x"' sulfanytideneleyanamide ”'2 W 0/ (DJ3 / ~)\N’J\CLH F Z-Bromo-lH—isoindole—I,3(2H)-dionc (150 mg; 0.84 11111101) was added to a solution of 4-(4-fluoro—2— methoxthenyl)—N-{3-[(111cthylsulfanyl)methyl]phenyl}«1,3,5-triazinaminc (200 mg; 0.56 mmol), cyanamide (31 mg; 0.73 mmol) and potassium 2-methylpropanolate (76 mg; 0.67 mmol) in ol (3.0 ml) at room temperature. The batch was stirred for 2 hours before it was diluted with aqueous sodium lfate on and extracted with DCM (2x). The combined organic phases were filtered using a Whatman filter and concentrated. The residue was purified by ative HPLC to give the desired product.
DAD 2996. ELSD 2424. SQD 3001 0—1 min 1% B, 1—8 min 1-99% B, 8-10 min 99% B Max. 250 m / max. 2.5 mL DMSO 0. DMF DAD scan ran-e 210—400 nm —MSESH, ESl-, scan range 160—1000 W: ‘H NMR (400MHz, CDClrt, 300K) 3 = 8.82 (s, 1H), 7.94 (m, 2H), 7.76 (m, 2H), 7.40 (In, 1H), 7.08 (m, 1H), 6.77 (m, 2H), 4.41 (d, 1H), 4.20 (<1, 1H), 3.92 (s, 3H), 2.74 (s, 3H).
Preparation of end product: Potassium carbonate (84 mg; 0.61 mmol) and 3»chlorobenzenecarboperoxoic acid (75 mg; 0.30 mmol) were added to a stirred solution of (rae)-[(3-{[4-(4-fluoro-Z-methoxyphcnyl)-I riazin-Z- yl]amino}benzy1)(mcthyl)-?k6-sulf'anyiidcnc]cyanamide (80 mg; 0.20 mmol) in ethanol (2.0 ml) at 0°C.
The ice bath was removed and the batch was slowly warmed to room temperature. The batch was stirred for 22 hours at room temperature. The batch was diluted with aqueous sodium chloride solution and extracted with ethyl acetate (2x) and DCM (1 x). The combined organic phases were filtered using a Whatman filter and concentrated. The residue was purified by preparative HPLC to give the desired t (10 mg; 0.03 mmol).
Dionex: Pump P 580, : Liquid Handler 215, Knauer: UV-Detektor K-2501 Chiralpak IA 50m 250x30 mm ol + 0.1% diethylamine 55 m 72 mL DMSOlMeOH1:1 lnjektion: s o — 10.3 mm "H NMR (400MHz, CDC13, 300K) 6 = 8.84 (s, 1H), 7.93 (m, 2H), 7.76 (In, 1H), 7.48 (m, 2H), 7.19 (In, 1H), 6.79 (m, 2H), 4.63 (In, 2H), 3.94 (s. 3H), 3.04 (s, 3H). e 49 and 50: Enantiomers of [(3-{ [4-(4~fluoro—2-methoxyphenyl)-l,3,5-triazinyllamino}benzyl)(methyl)oxido- fanylidene]cyanamide (ruc)-[(3- {[4-(4- fluoro-Z-mclhoxyphcnyl)-1,3,5-triazinyl]amino}bcnzyl)(mcthyl)0xidu‘lfi- sulfanylidene]cyanamide was separated into the enantiomers by preparative HPLC: Dionex: Pump P 580, Gilson: Liquid Handler 215, Knauer: UV-Detektor K-2501 Example 49 >99 Enantiomer 1-- Example 50 >99 Enantiomcr 2 Enantiomer 1: ]H NMR (400MHz, CDCEg, 300K) 6 = 8.84 (s, 1H), 7.93 (m, 2H), 7.76 (m, 1H), 7.48 (m, 214), 7.1901}, 1H), 6.79 (111, 21-1), 4.63 (m, 2H), 3.94 (s, 3H), 3.04 (s, 3H).
Enantiomer 2: ‘H NMR (400MHz, 0003, 300K) 3 = 8.84 (s, 1H), 7.93 (m, 2H), 7.76 (m, 1H), 7.48 (m, 2H), 7.19 (m, 1H), 6.79 (m, 2H), 4.63 (m, 2H), 3.94 (s, 3H), 3.04 (s, 3H).
Example 51: (rad-Ethyl [(3-fluoro-S-{[4-(4~fluoro—2—methoxyphenyl)—l,3,5-triaziny}]amino}benzyl)(methyl)— oxido-lfi-sulfanylidenekarbama te >—NO NAN 0/ O \‘S’/ JL/ Preparntion of Intermediate 51.]: I-Fiuoro-3—flmethylsulfanyl)methyll-S-nitrobenzene Intermediate 5].] was prepared under r conditions as described in the ation of Intermediate 1.! using l-(chloromethyl)fluoro—S-nitrobcnzcne (Hausa Fine Chemicals (3111be).
:H NMR (400MHz, CDCIs, 300K) 6 = 8.00 (m, 1H), 7.82 (m, 1H), 7.44 (m, 1H), 3.74 (s, 2H), 2.03 (s, 3H). ation of Intermediate 51.2: (rac)~i -Fluoro-3~[(methyisulfinyl)methyH-S-nitrobenzene O\N.(>9)S\ Intermediate 51.2 was prepared under similar conditions as bed in the preparation of Intermediate [.2 using 1~fluoro[(methy]sulthnyl)mcthyl]—S’nitrobcnzene. "i—I NMR (400MHz, Lia-DMSO, 300K) 6 = 8.06 (m, 2H), 7.63 (111, 11-1), 4.32 (d, 1H), 4.08 (d, 1H), 2.45 (s, 3H).
Prenaration of Intermediate 51.3: (rac)-2,2,2-trifluoro~N~[(3-fluoronitrobenzy])(methyl)oxido-k5-sulfanylidenelacetamide Intermediate 51.3 was prepared under similar conditions as described in the preparation of Intermediate 1.3 using (rac)- i -fluoro—3-[(mcthylsulfinyl)mcthyl]-5—nitrobcnzcne.
‘H NMR (400MHz, CDC13, 300K) 5 = 8.13 (m, 1H) 8.07 (m, 1H), 7.56 (m, 1H), 4.92 (d, 1H), 4.76 (d, 1H), 3.33 (s, 3H). ation of Intermediate 51.4: (rac)-] -Fluoro«3— [(S-methylsulfonimidoyl)methyll~5-nitrobenzene J’i‘ 0 NH 0:“1‘ ‘xyf' \V/\SI\~ Intermediate 51.4 was prepared under similar conditions as described in the preparation of Intermediate 1.4 using (racj—Z,2,2-trifluoro—N—[(3-fiuoro~5-nitrobcnzyl)(mcthyl)oxido-7t6-sulf‘anylidone]acctamidc.
[H NMR (400MHz, CDCls, 300108 e 8.19 (m, 1H), 8.08 (m, 1H), 7,76 (m, 1H), 4.60 (d, 1H), 4.49 (d, 1H), 3.85 (s, 1H), 2.79 (s, 3H).
Preparation of Intermediate 51.5: (rac)-Ethy1 [(3-flu0ro-Sunitrobeuzyl)(metityl)oxid0->~6-sulfanylidenelcarbamate F OJ o.Ni s\ ediate 51.5 was prepared under r conditions as described in the preparation of Intermediate 1.5 using (rac)fiuoro-3—{(S-methyisulfonimidoyl)methyl]nitrobcnzene.
'H NMR (400MHz, CDClg, 300K) 8 = 8.11 (in, 1H), 8.02 (m, 1H), 7.57 (m, 1H), 4.90 (cl, 1H), 4.759 (d, 1H), 4.18 (q, 2H), 3.12 (s, 3H), 1.31 (11', 3H).
Preparation of Intermediate 51.6: (rac)-Ethy] [(3-3mino-S-fluorobenzyl)(methyI)oxido—L6-sult’anylidenelcarbamate Intermediate 51.6 was prepared under similar conditions as described in the preparation of Intermediate 1.6 using ethyl [(3-fluoro-5—nitrobenzyi)(methyi)oxide—ZG-suifanyiidene]carbamate.
"H NMR (400MHz, CDCls, 300K) 6 = 6.49 (m, 3H), 4.58 (m, 2H), 4.17 (q, 2H), 3.91 (s, 2H), 3.00 (s, 3H). 1.31 (tr. 3H).
Pre nation of Intermediate 51.7: (rad-Ethyl l{3-[(4-chloro-1,3,S-triaziny])amino]~S~fluorobenzyl}(methyl)oxido—?.‘~ sulfanylidenelcarbamate LO F O \‘ ’I i /S ”ANkaI Intermediate 51.7 was prepared under similar conditions as described in the preparation of Intermediate 1.7 using (rac)-ethyl [(3-aminofluorobenzyl)(methyl)oxido—‘Aé—sulfanylidene]carbamate.
Column Mama-er. PDA, ELSD, SQD 3001 : Acquity UPLC BEH C18 1.7 50x2.1mm A1 = H20 + 0.1% HCOOH -B1 = itrile 0~1.6 min 1-99% B. 1.6-2.0 min 99% B 60°C 2.0 ul DAD scan range 210-400 nm ~> Peaktable Method: MS ESI+, ESI- Switch A1 + B1 = C:\ MassL nx\NH3 Mass 000.olp MS(ES+).‘ m/z = 388 [M+H} Preparation of end product: Example 5} was prepared under similar conditions as described in the preparation of e 42 using crude (rac)—ethy1 [{3-[(4-ehloro—1.3,5-triaziny1)amino]~5-fluorobenzyl}(methyl)oxide—9.6—sulfanyl- idene]ca;rbamate and (4-fluoro—2-methoxyphcnyl)boronic acid (Aldrich Chemical Company Inc). The batch was purified by preparative HPLC.
DAD 2996, ELSD 2424. SQD 3001 DAD scan range 210—400 nm —MSESH. ESl-, scan range 160-1000 mlz _ELSD 1.12 mm "H NMR (400MHz, 66-00480, 300K.) 5 = 10.65 (s, 1H), 8.86 (5, 11-1). 8.32 (br, 1H), 8.00 (br, 11-1), 7.48 (br, 1H), 7.12 (m, 11-1), 6.98 (m, 1H), 6.92 (m, 1H), 4.87 (m, 2H), 3.98 (m, 2H), 3.92 (s, 3H), 3.22 (s, 3H), 1.15 (tr, 3H).
Example 52: (rac)(4-Fluoro-Z-methoxyphenyl)-N-{3-flu0ro~5—[(S-methylsulfonimidoyl)methyl]phenyl}-I,3,5- triazin-Z-amine HH‘S’i/QJL//\N\NO// N N Example 52 was prepared under similar conditions as bed in the preparation of Example 2 using (rac)~ethyl{(3~fluoro{[4-(4-fluoro-Z-mcthoxyphc:1yl)-1,3,5-triazin—2-yl]amino}benzy1)(_methyl)oxido- Kfi—sulfanylidcne]carbamate.
'H NMR(4OOMHz,CDC13, 300K) 6 = 8.79 (s, 1H), 8.10 (br.21~l), 7.92 (br, 1H), 7.20 (hr, 1H), 6.85 (m, 1H), 6.76 (m, 2H), 4.36 (d, 1H), 4.22 (s, 1H), 3.95 (s, 3H), 3.01 (s, 3H).
Example 53 and S4: Enantiomers of 4-(4-Fluoro~2~methoxyphenyl)-N-{3-11uoro-S-[(S-methylsulfonlmldoyl)methyl]- phenyl}—1.3,5-triazinamine (rac)(4-FIuoromethoxyphenyl)-N—{3-fluoro[(S-methylsulfonimidoyl)methy1]phenyl}-].3.5- triaziu—Z—amine was ted into the cuantiomcrs by preparative HPLC: Dionex: Pump P 580, : Liquid Handler 215, Knauer: UV-Detektor K-2501 Example 53 13.7 — 15.4 Enantiomer 1 Example 54 15.4 — 17-2 Enantiomcr 2 Enantiomer 1: lH NMR (400MHz, CDCla, 300K) 3 = 8.79 (s, 1H), 8.10 (br, 2H), 7.92 (br, 1H), 7.20 (br, 1H), 6.85 (m, 1H), 6.76 (m, 2H), 4.36 (d, 1H), 4.22 (s, 1H), 3.95 (s, 3H), 3.0] (s, 3H).
Enantiomcr 2: 1H NMR (400MHz, CDCla, 300K) 6 = 8.79 (s, 1H), 8.10 (bf, 2H). 7.92 (br, 1H), 7.20 (br, 1H), 6.85 (m, 1H), 6.76 (m, 2H), 4.36 (d, 1H), 4.22 (s, 1H), 3.95 (s, 3H), 3.01 (5, 3H).
Example 55: (rac)—4~12-(Cyclohexylmethoxy)-4—fluorophenyll-N-{3-[(SumethyISulfonimidomeethyl]phenyl}- 1,3,5-triazinamine Preparation: of Intermediate 55.]: (rac)—Ethyl [(34 {4-(2,4-dif1uorophenyi)—1,3,5-triazin—2-yllamino}benzyl)(methyl)oxido-l‘- ylidenelcarbamate j Nuifl NIAN F /_O /3 ”*NfiF Intermediate 55.1 was prepared under similar conditions as described in the preparation of Example 42 using crude (rac)-cthyl 4-chloro-l,3,5—triazin—2—yl)amino}-5—fluorobenzyl}(methyI)oxido-7L°- sulfanyiidene]carbamate and (2,4-difluorophenyl)bor0nic acid ch Chemical Company Inc.). The batch was purified by column chromatography (DCM / EIOH 95:5).
‘H NMR(400MHZ,CDC1~.. 300K) 6 = 8.82 (s, 1H). 8.31 (m. 1H). 8.05 (br. 1H). 7.61 (m, 1H). 7.45 (m, 2H), 7.21 (m, 1H), 7.00 (m, 2H), 4.76 (dd, 2H), 4.17 (q, 2H), 3.02 (s, 3H), 1.31 (tr, 3H).
Preparation of end t: Sodium hydride (60%; 3.2 mg; 0.08 mmoi) was added under stirring to a solution of' (rac)-cthy1 [(3-{[4- (2,4-difluorophenyl)—1,3,5—triaziny11amino}benzyl)(methy'i)oxido-?t“-sulfanylidenek arbamate (3 0. 0 mg; 0.07 mmoi) in cyclohcxylmcthanol (0.5 ml) at room temperature. The batch was stined under argon at. 50°C for 2 hours before additional sodium hydride (60%; 2.7 mg; 0.07 mmol) was added. After 20 hours additional sodium hydride (60%; 2.7 mg; 0.07 mmol) was added and the batch was stirred for further 5 hours. After cooling. the batch was diluted with ethyl e and diluted sodium chloride solution. The organic phase was filtered using a Wliatman filter and concentrated. The desired product (10 mg; 0.02 mmol) was isolated by preparative HPLC.
DAD 2996. ELSD 2424, SOD 3001 A = H20 + 0.1% HCOOH _MSESI+, ES|-, scan range 160-1000 m/z 1H NMR (400MHz, CDCls, 300K) 5 = 8.83 (s, 1H), 7.88 (in, 1H), 7.84 (br, 1H), 7.72 (br, 1H), 7.44 (m, 1H), 7.36 (s, 1H), 7.19 (m, 1H), 6.77 (m, 2H), 4.43 (d, 1H), 4.28 (d, 1H), 3.85 (d, 2H), 2.98 (s, 3H), 2.73 (br, 1H)1 1.78 (In, 6H), 1.15 (In, 5H).
Examgle 56: (rac)—4-{4-FIuoro[(4-fluorobenzyl)oxy]phenyl}-N~{3-[(S-methylsulfonimidoyl)methyl]phenyl}- 1,3,5-tria7jnamine Exampie.56. was prepared under similar conditions as described in the preparation of Example 55 using (rad-ethyl [(3- i[4-(2,4-difluorophcnyl)-1,3,5—triazin—2-y1]amino}bcnzyl)(mothyl)oxido-ZG-sulfanyl- idenc]carbama1c and (4-fluorophcnyl)methanol.
DAD 2996. ELSD 2424, SQD 3001 e C18 5pm 100x30 mm A = H20 + 0.1% HCOOH —B=Methanol 0—1 min 50% B, 1-8 min 50-90% B. 8-8.1 min 90-10070 B, 3.1-10 min 100% B 620mg /4.5mL DMSO Injektion.ll AD scan range 210—400 nm —MS ESI+, ESE—. scan range 160-1000 m/z £0 =11 NMR (400MHz, CDCls, 300K) 21 = 8.81 (5, 11-1), 7.95 (m, 1H), 7.75 (br, 1H), 1, 1H), 7.38 (m, 4H), 7.13 (m, 1H), 7.01 (m, 2H), 6.80 (m, 2H), 5.15 (s, 2H), 4.36 (d, 1H), 4.22 (d, 1H), 2.93 (s, 3H), 2.68 (br, 1H).
Example 56.2 and 56.b: Enantiomers of 4-{4-fluoro-Z-[(4-11uorobenzyl)oxy]phenyl}~N-{3~1(S-methylsullbnimidoyl) methyl]- plrenylpl ,3,S-triazinamine(rac)~4~ {4-Fluoro-2—[(4~fluorobcnzyl)oxy]phenyl} ~.N- { 3—[(S- sulfonimidoyl)mcthyl]phenyl}—1,3,5—triazin—2-aminc was separated into the cnantiomcrs by preparative Hl’LC: Dionex: Pump P 580. Gilson: Liquid Handler 215, Knauer: UV-Detektor K-2501 Example 56.21 17.2 —23‘5 Enantiomcr 1 Example 56.!) 35.8—52.5 Enantiomcr 2 Enuntiomcr 1: 1H NMR (400MHz, CDCls, 300K) 5 = 8.81 (3, 1H), 7.95 (m, 11-1), 7.75 (br, 1H), 7.68 (m, 1H), 7.38 (m, 4H), 7.13 (m, 1H), 7.01 (m, 2H), 6.80 (m, 2H), 5.15 (s, 2H), 4.36 (d, 1H), 4.22 (d, 1H), 2.93 (s, 3H), 2.68 (br, 1H).
Enantiomcr 2: 1H NMR (400MHz, CDCls, 300K) 6 = 8.81 (s, 1H), 7.95 (In, 1H), 7.75 (br, 1H), 7.68 (m, 1H), 7.38 (m, 4H), 7.13 (m, 1H), 7.01 (m, 2H), 6.80 (m, 2H), 5.15 (s, 2H), 4.36 (d, 1H), 4.22 (d, 1H), 2.93 (s. 3H), 2.68 (br, 1H).
Example 57: (rac){4-Fluoro-2—[2-(tetrahydro-2H-pyranyl)eth0xy]phenyl}—N—{3—[(S-methylsulfonimidoyl)- methyl}phenyl}-1,3,S-triazin’2-amine Example 57. was preparcd under r conditions as dcscxibcd in the preparation of Example 55 using (rad—ethyl [(3- { [4~(2,4~difluorophenyl)- l riazin—2—yl]amino}benzyl)(mcthyl)oxiclo-ls-SIIlfanyl— idcnc]carbam ate and 2-(tctrahydro-2H—pymnyl)cthanol.
DAD 2996. ELSD 2424, SOD 3001 04 min 50% B, 1-8 min 50-90% B, 8-8.1 min % B, 8.1-10 min 100% B —MsESI+. 1231-. scan range 160-1000 m/z 2 min 1H NMR (400MHz, CDClg, 300K) 5 = 8.80 (s, 1H), 7.78 (m, 3H), 7.49 (s, 1H), 7.42 (m, 111), 7.16 (m, 111), 6.76 (m, 211), 4.39 ((1, 11-1), 4.26 ((1, 11—1), 4.10 (tr, 21-1), 3.91 (m, 2H), 3.32 (m, 2H), 2.95 (s, 311), 2.71 (br, 1H), 1.75 (m, 31-1), 1.33 (m, 41-1).
Examglc 58: (rac)(4-Fluoro-2—methoxyphenyl)-N-(3-{[S—(tetrahydro-ZH-pyran-4—yl)sulfonlmldoyl] methyl}- phenyl)-1,3,5-triazinamine 1°03 ”1“” °’ 8 fiAN/ F Pre aration of Intermediate 58.1: (rac)Chioro-N~{3-[(tetrahydro-2H~pyranylsulfmyl)methyl]phenyl}—l,3,5-triazinamine RC) “1““ Intermediate 58.1 was prepared under similar conditions as described in the preparafion of lntcnncdiatc 1.7 using (rac)[(tetrahydro~2H-pyranylsulfinyl)mcthyl]aniline (UkrOrgSynthc-sis Ltd).
Column Mana-er, PDA, ELSD. SOD 3001 2.0 m DAD scan range 210-400 nm ~> Peaktable —ELso Melhod: MS ESl+. ESI- Switch A2 + B1 = C:\ MassLynx\NH3 Mass 100 1000.0]p Retgniion 0.81 min MS(ES-): m/z = 351 [M—HI Pre aration of Intermediate 58.2: (rac)4-(4-Fluoromethoxyphenyl)-N-{3-[(tetrahydro-2H~pyran-4~ylsulfinyl)methyl]phenyl}- 1,3,5-triazinamine lnteruicdiate 58.2 was prepared under similar ions as described in the preparation of Example 42 using crudc (rac)-4—chloro-N-{3-[(tctrahydro-ZH-pyrau-Ll-ylsulfiny1)mctliyl]phenyl}-1,3,5—triazin—2— amino and (4—fluoromcthoxyphcnyl)boronic acid (Aldrich Chemical Company Inc). The baich was purified by column chromatography (DCM / EtOH 95:5) 10 give the desired product.
'H NMR (400MHz, CDCIa, 300K) 8 = 8.81 (s, 1H), 7.96 (m, 1H), 7.70 (m, 2H), 7.40 (m, 2H), 7.06 (m, 1H), 6.78 (m, 2H), 4.03 (m, 7H), 3.39 (m, 2H), 2.73 (m, 1H), 1.83 (m, 4H).
Preuaration and end Qroduct Example 58 was prepared under similar conditions as described in the alternative preparation of e 2 u sing 4- (4-fluoro-Z—mcthoxyphcnyl)-l\‘ - ctral1ydIo-2H-pyranylsulfiuy l)methyl] phenyl} - l,3,5~triazin—2-aminc, sodium azidc, sulfixric acid and lrichloromcthanc.
DAD 2996, ELSD 2424. SOD 3001 Solvent: 0—1 min 10% B, 1-8 min 10-45% B 6.5 — 6.9 min 111 OMHz,CDC13, 300K) 5 = 8.81 (s, 111), 7.97 (hr, 111), 7.76 (111, 21-1), 7.53 (s, 1H), 7.41 (m, 1H), 7.16 (m, 11-1), 6.77 (m, 2H), 4.31 (d, 1H), 4.09 (m, 3H), 3.93 (s, 3H), 3.36 (m, 2H), 3.15 (m, 1H), 2.61 (s, 1H), 2.01 (111,411).
Examnle 59: (rac)-N-{4-Chloro[(S-methylsuifonimidoyl)methyl]phenyl}(4-flu0ro~2-methoxyphenyl)—l,3,5~ triazin-Z-amine Pregaration of Intermediate 59.1: (rac)—4~Chloro-N-{4—chloro—3~[(methylsulfinyl)methyl]phenyl}-},3,5~trinzin~2~aminc 1531 1“" s , NAN/AC1 H Intermediate 591 was prepared under similar conditions as described in the preparation of Intermediate [.7 using (rac)ohloro[(mcthyisulfinyl)methyl]aniline (UkrOrgSynthesis Ltd.).
System: Column r, PDA, ELSD, SOD 3001 Column: Soxvenr: Gradient.‘ 04.6 min 1-99% B, 1.6-2.0 min 99% B How: Temperaruer Injekuon: Detecfion: DAD scan ran-e 210-400 nm -> Peaktable ELSD Method: MS ES|+, ESI— Switch A2 + Bl = C:\ MassL nx\NH3 Mass 1001000.olp System: Waters Acquity UPLC-MS: Binary Solvent r, Sample Manager/Organizer.
Column Mana-er, PDA, ELSD. SQD 3001 Retention 0.85 min MS(ES-): mlz= 317 [M+H] ation of Intermediate 59.2: (rac)-N-{4-Chloro[(methylsulfinyl)methyl}phenyl}(4-fluoro-Z-methoxyphenyl)—1,3,5-triazin amine Intermediate 59.2 was prepared under r conditions as described in the preparation of Example 42 using crude (rac)—4-chloro—N— {4-chloro[(metl1ylsuIfinyl)methyl]phenyl}-l,3,5-triazinamlne and (4- fluoro-2~methoxyphenyl)boronic acid ch Chemical Company Inc). The batch was purified by column chromatography (DCM / EIOH 95:5) to give the desired product.
"H NMR (400MHz, CDCla, 300K) 5 = 8.80 (s, 1H), 7.85 (m, 3H), 7.64 (m, 1H), 7.39 (m, l H), 6.76 (m, 2H), 4.19 (d, 1H), 4.13 (d, 1H). 3.93 (s, 3H), 2.57 (s, 3H), Preparation of end product Example 59 was prepared under similar conditions as described in the alternative preparation of Example 2 using ((rac)—N-{4-chloro[(mefl1ylsulfiny1)methyl]phenyl}(4- fiuoro—Z-mcthoxyphcnyl)—l ,3.S-triazin—2-aminc, sodium azido, sulfuric acid and trichloromctlmnc.
DAD 2996. ELSD 2424, SQD 3100 1H NMR (400MHz, CDCEs. 300K) 3 x 8.80 (s, 1H), 7.87 (m, 3H), 7.57 (5, 11-1). 7.42 (111. 11-1), 6.78 (in, 2H), 4.60 (d, 1H), 4.51 (d, 1H), 3.93 (s, 3H), 2.97 (s, 3H), 2.84 (s, IH).
Example 59.21 and 59.1): Enantiomers of N-{4-CMoro[(S-methylsulfonlmidoyl)methyuphenyl}~4-(4-fluoromethoxy- phenyl)-1,3.5-triazin-2~amine(rac)-N~{4-Chloro[(S-methylsulfonimidoy})methy1]phenyl}(_4- fluoro-Z-mclhoxyphcnyl)-1,3.5-triazin-2—aminc was separated into the cnantiomcrs by preparative HPLC: : Pump P 580, Gilson: Liquid Handler 215, Knauer: UV-Detektor K-2501 Example 5.3 98.7 S9.a Euantiomér' 1 Example .9.b omer 2 Enantiomer I: lH NMR (400MHz, CDCIg, 300K) 5 = 8.80 (s, 1H), 7.87 (m, 31-1), 7.57 (s, 1H), 7.42 (In, 11-1), 6.78 (m, 2H), 4.60 (d, 1H), 4.53 (d, 1H), 3.93 (s, 3H), 2.97 (s, 3H), 2.84 (s, 1H).
Enamiomer 2: 'H NMR (400MHz, CD013, 300K) 5 —- 8.80 (s. 1H). 7.87 (m. 3H). 7.57 (s, 1H), 7.42 (m, 1H), 6.78 (111,2H), 4.60 (d, 1H), 4.51 (d, 1H), 3.93 (s, 33), 2.97 (s, 3H), 2.84 (s, 1H).
Example 60: Ethyl {{3~[(4-{2-[(3,4-dichlorobenzyl)oxy]phenyl}-l,3,S-triazin-Z-yl)amino]benzyl}(methyl)- oxido-LG- sulfunylidenelcarbamate O S / / / E NJ\© CI Example 60 was prepared under similar conditions as described in the preparation of Example 42 using crude ethyl [{3-[(4-chloro- ! ,3,5-triazinyl)amino]benzyi} (methyl)oxido-x‘-sulfanylidene]carb- amatc and {2-[(3,4-dichl0r0benzyl)0xy]phcnyl}boronic acid (Combi Blocks Inc.). The batch was purified by preparative HPLC.
Agiient: Prep 1200, 2 x Prep Pump, DLA. MWD. ELSD, Prep FC XBrigde C18 5pm 100x30 mm A = H20 +02% NHa _B=Acetonitrile 047,5 min 40-80% 8; 17,5-20 min 80-100% B as mum ‘H NMR (400MHz, CDCb, 300K) 5 = 8.87 (s, 1H), 7.9] (m, 1H), 7.85 (s, 1H), 7.66 (m, 2H), 7.46 (m, 2H), 7.38 (m, 2H), 7.22 (m, 1H), 7.15 (m, 2H), 7.06 (m, 1H), 5.15 (s, 2H), 4.70 (s, 2H), 4.16 (q, 2H), 2.97 (s, 3H). 1.30 (tr, 3H).
Example 61: (rac){2-[(3,4-Dichlorobenzyl)oxy]phenyl}-N—{3-[(S-methylsultbnimidoyl)methyl]phenyl}-l,3,5- triazin-Z-amine < O NAN Cl HN 0 JL / K m N Cl Example 61 was ed under similar conditions as described in the preparation of Example 2 using (rac)—ethyl[{3-[(4- {2-[(3,4-dichlorobenzyl)oxy]phenyl} -] riazin-2—yl)amino]benzyl}(methyl)oxido— kfi-sull‘anylidcne]carbamatc. Aficr aqueous work up no further purification was necwsary.
:H NMR (400MHz, CDCia, 300K) 5 = 8.87 (s, 1H). 7.93 (in, 1H), 7.78 (s, 1H), 7.70 (m, 2H), 7.48 (m, IH), 7.36 (in, 3H), 7.24 (m, 1H), 7.34 (111,21-1), 7.06 (m, 1H), 5.15 (s, 2H), 4.37 (d, 1H), 4.25 (d, 1H), 2.93 (s, 3H), 2.68 (s, 1H), Example 62: (rnc)(4-Fluoro~2«{[(2Hs)phenleHz)methylloxy}phcnyl)-N-{3-{(S-methylsulfonimidoyl)methyl]- phenyl}—l,3,5-triazinamine D D D D ”him JNLW/\ 0 DD 8 / Example 62 was ed under similar conditions as bed in the preparation ofExample 55 using (rad-ethyl [(3-{[4-(2,4-difluorophenyl)-1,3.5-triazin—2—yl]amino}benzyi)(methyl)oxido-l‘S-sulfanyl— idene]carbamate and (2H5)pheny1(2H2)methanol (Aldrich Chemical Company Inc). The batch was purified by preparative HPLC.
System‘ DAD 2996, ELSD 2424, SQD 3001 Column: XBrI-de C18 5pm 100x30 mm Solvent: A = H20 + 0.1% HCOOH B = Acetonitrile Gradient: 0—1 min 1% B, 1-8 min 1-99% B, 8'10 min 99% 8 Flow: 50 mL/min Temperature: Solution: Injektion: ion: ‘H NMR (400MHz, CDCla, 300K) 8 = 8.81 (S, 1H), 7.94 (m, 11-3), 7.68 (m, 3H), 7.32 (br, 1H). 7.11 (m, l H), 6.79 (m, 2H), 4.33 (d, 1H), 4.21 (d, 1H), 2.92 (s, 3H).
Examgie 63: 4-{2-(1-Cyc10pentylethoxy)fluorophenyl}-N-{3-{(S-methylsulfonimidoyl)methyllphenyl}-1,3,S- triazin-Z-amine, mixture of 2114 stereoisomers HN“”:0 ”EA“ 0% /s N/lxN/J\©\H Example 63. was prepared under similar conditions as described in the preparation of Exampie 55 using (rac)—ethy1 [(3 -{ [4 -(2,4-dif1uorophcnyl)- 1 ,3,5-triaziny1]amino} )(1nethyl)oxido-XG-sulfanyl— idcnc]carbamatc and (rac)cycIopemylcthanol (ChemSampCo, Inc.).
System: Waters Autopurificationsystem: Pump 2545. Sample r 2767. CFO, DAD 2996. ELSD 2424. 800 3001 XBrigde C18 5pm 100x30 mm Solvent: A = H20 + 0.1% HCOOH B = Acetonitrile 0—1 min 1% B. 1~8 min 1-99% 8. 8-10 min 99% B so mLImin Solyfion: Max. 250 mg I max. 2.5 mL DMSO 0. DMF Injektion: 1 x 2.5 mL DAD scan range 210—400 nm —MSES|+, ESl-. scan range 160—1000 m/z E1-1 NMR (400MHz, CDCls, 300K) 6 = 8.78 (s, 1H), 7.75 (m, 3H), 7.54 (s, 1H), 7.40 (m, 1H), 7.15 (m, 1H), 6.72 (m, 2H), 4.39 (d, 1H), 4.24 (In, 2H), 2.95 (5, 3H), 2.70 (br, 1H), 2.09 (m, 1H), 1.47 (m, 11H).
Exam 1e 64: (rac)—N-{3-Cllloro-S-[(S-methy!sulfonimidoyl)methyl]phenyl}(4-flu0ro1uetl10xyphenyl)-1,3,5- triazin—2-amine HN o NAN 0/ / A / N N Preparation of Intermediate 64.1: 1~Chloro'[(methylsquanyl)methyl|~5~nitrobenzene A suspension of 3—bromomethyl-I-chloronitrobenzene (10.0 g) in l (200 mi.) at -20°C was treated with sodiummethanethioiate (3.3 g) in 3 portions, during 3 hours the temperature was increased from -20°C to room temperature. Then brine was added, extracted with ethyl acetate (3 x), the ed organic phases were washed with water to neutrality, dried with sodium sulfate, filtered and concentrated. The title compound (8.6 g) was thus obtained and used without fizrther purification.
Preparation ot'Intermediate 64.2: l-Cltloro[(inethylsulfinyl)methyl]nitrobenzene 8 .0 / N" (I)- To a solution of l—chloro[(methyisuifanylhnethyi}S-nitrobenzene (4.3 g) in methanol (340 ml.) water ( i 8.7 mL) and sodium pcriodat (4.4 g) was added and stirred for 24 hours at room temperature. Then the reaction mixture was trated under reduced pressure to 30% of the volume, diluted with water, extracted with ethyl acetate (3x), washed with disodium sulfurothioate and brine, dried with sodium sulfate, filtered and concentrated. The title compound (4.5 g) was thus obtained and used without r ation.
‘H—NMR (600MHz, CDCia): 5 L'.‘== 8.23 (t, 1H), 8.08 (t, 1H), 7.67 (t, 1H), 4.07 (d‘ 1H), 3.92 (d, 1H), 2.57 (s, 3H).
Preparation ot’lntermediate 64.3: ro-S-[(methylsulfinyl)methyl]aniline /(“)fi8 NH 2 A solution of ro-3~[(methylsulfinyl)methyl]nitrobenzene (4.4 g) in methanol (40 mL) and water (11.6 mL) was treated with ammoniumchloridc (5.1 g), cooled to 0°C, treated with portions of zinc powder (6,2 g) and stirred for 5 hours at room temperature. The reaction mixture was filtered ever cellite, washed with THE / ethyl acetate, washed with brine, dried with sodium sulfate and condensed to dryness.
Crystallization of the crude product (4.9 g) from l ether furnished the pure title compound (3.4 g). l1101le(600MHz, CDC13)EI: 6 a 6.63 (m, 2H), 6.49 (in, 1H), 3.90 (6, 11-1), 3.80 (m, 3H), 2.48 (5, 31-1).
Preparation rmediale 64.4: 4-Chloro—N-{3-ehloro[(methylsulfinyl)methyllphenyl}-l,3,5—triazinamine A solution of 2,4-dichloro-triazine (250 mg) in TI-IF (2.2 niL) and 2-propanol (2.2 mL) at -40°C was treated with N,N-diisopropylethylamine (0.55 mL) and 3-chloro-5—{(methylsulfinylhnethyl]aniline (322.6 mg) an then stirred and gradually warmed from -40°C to 0°C for 3 hours. The reaction mixture was then concentrated in vacuo to give the crude title compound (934 mg) which was used without further purification.
Preparation of Intermediate 64.5: hloro[(methylsull‘inyl)methyl]pl:enyl}(4-fluoro—2-methoxyphenyl)-1,3,5-triazin amine A solution of ro~N~{3-chloro[(methylsulfinyl)methyl]pheny1}-l,3,5-triaziu-2—amine (934 mg) in methoxycthanc (5.2 ml.) and a 2 M solution of sodium carbonate (1.6 mL) is treated with 4- fluoro~2-methoxyphenylboronic acid (269 mg) and Pd(dppf)Ch (129 mg) and then heated for 3 hours at 100°C. The on mixture was then allowed to cool to room temperature, taken up in ethyl acetate (l00 mL) and water (50 mL), washed with saturated brine, dried over sodium sulfate, and condensed in vacuo to give the crude product that was purified by flash column chromatography on SiOz with DCM/ acetone (5% — 60%) to give analytically pure product (340 mg).
'H-NMR (500MHz, CDC];): 8 = 8.83 (s, 1H), 8.18 (br. 5., 1H), 7.99 (br. 5., 1H), 7.33 (br. s., 1H), 7.64 (s. 1H). 7.02 (s, 1H), 6.78 (m, 2H), 3.96 (m, 5H), 2.53 (5, 31-1).
Preparation of end QroductzTo a solution of N—{3-ehloro[(methylsulfinylhnethylJphenyl}-4a(4~ 8U0ro—2—methoxypheny1)—l,3,5wtriazinamine (75 mg) in chloroform (0.8 mL) sodiumazide (48.4 mg) was added and treated at 0°C dropwisc with cone. sulfuric acid (0.35 mL) and stirred for 48 hours in a scaled tube. Then the reaction mixture was poured into ice water, alkalized with sodium bicarbonate, extracted with ethyl acetate / THF (9:1), washed, dried over sodium sulfate and evaporated to dryness.
The crude product was purified by flash column chromatography on SiOz with DCM / ethanol (0% - 5%) to give the desired product (42 mg).
'H—NMR (600MHz, CDC13): 6 = 8.81 (s, 1H), 7.99 (m, 3H), 7.41 (br, 1H), 7.10 (m, 1H), 6.76 (m, 2H), 4.35 (d, ‘i H), 4.20 (d, 1H), 3.94 (s, 3H), 3.01 (s, 3H).
Example 65: (rac)—4-l4-Fiuoro-2—(3,3,3-trifluoropropoxy)phenyl]—N~{3-[(S-methylsulfonimidoyl)methyl]phenyl}~ 1,3,5-triazinamine /'i‘\ HN\ IQ \‘q TIQN 0L; 6V fix" \ / x 3” .4" , N N 1/ \[1 V “F Sodium hydride (60%; 26.8 mg; 0.67 mmol) was added under stirring to a solution of (mc)-ethyl[(3- {[4- (2,4—diflliorophcnyl)-l ,3,S-triazin-Z-yl]amino} bcnzyl)(mcthyl)oxido-hG-suif‘anylidcnc]carbamate (75.0 mg; 0.17 mmoi) in 3,3,3-trifluoropropan—1—ol (0.5 ml; ABCR GmbH & CO. KG) at room temperature.
The batch was stirred under argon at 70°C for 19 hours. After UPLC MS cheek. additional sodium hydride (60%; 13.4 mg; 0.34 mmoi) was added and the batch was stirred for onal 22 hours at 70°C.
After g, the batch was diluted with ethyl acetate and saturated aqueous sodium de solution.
The organic phase was filtered using a Whatrnan filter and concentrated. The desired product (12 mg; 0.03 mmol) was isolated by preparative HPLC.
: Waters Autopurificatlonsystem Pump 254. Sample Manager 2767, CFO, DAD 2996. ELSE) 2424 SQD 3100 =—Graifieni: ‘ 2H NMR (400MHz, CDCls, 300K) 3 = 8.78 (s, 1H). 7.88 (m. 1H), 7.71 (m, 3H). 7.39 (m, 18), 7.15 (m, 1H), 6.82 (In, 1H), 6.73 (m, 1H), 4.39 (d, 1H), 4.25 (m, 3H), 2.96 (s, 3H), 2.60 (m, 3H), Example 66: (rad[4-Fluoro(pyridin~3~ylmethoxy)phenyl]-N—{3-|(S-methylsulfonimidomeethyl]phenyl}- 1,3,5-triazinamine Example 66 was prepared under similar conditions as described in the preparation of Example 65 using (rac)—ethyl [(3- { [4-(2,4-difluorophenyl)- l ,3,5-1riazin—2—yl]amino} benzyl)(methyl)oxido-lf-sulfanyl- idc11c]carbamatc and pyridin-3—ylmcthanol (Aldrich Chemical Company inc). The desired product was isolated by preparative HPLC.
DAD 2996. ELSD 2424, SQD 3100 Column: XBrigde 018 5pm 100x30 mm Solvent: A = H20 + 0.2% Vol. NH: (32%) B = Methanol 0-1 min 30% B, 1-8 min 30.70% B so mUmin Tempefgture: RT Solution: 233 mg I 2.3 mi. eOH 1:1 ion.‘ 3 x 0.75 mL DAD scan ran-e 210—400 nm —MSESl+, ES|-, scan range 160~1 000 m/z ELSD Retention? 6.3 - 6.7 min 1H NMR (400MHz, CDCls, 300K) 3 = 8.82 (s, 1H), 8.76 (br, 1H), 8.55 (m, ll-l), 7.98 (m, 1H), 7.77 (m, 2H), 7.69 (m, 1H), 7.39 (m, 2H), 7.28 (m, 1H), 7.14 (m, 1H), 6.82 (m, 2H), 5.20 (s, 2H), 4.37 (d, lH), 4.23 (d, 1H), 2.94 (s, 3H), 2.70 (br, 1H).
Example 67: (rad-4—[4-Fluor0(pyridin-Z-ylmethoxy)phenyl]—N—{3-[(S-methylsull‘onimidoyhmethyl}phony”- triazinamine mini/Q 1‘”/\8 / / 0’15/ N N Example 67. was prepared under similar conditions as described in the preparation of Example 65 using (rac)—ethy1 [(3 - {[4-(2,4-(lifluorophenyl)- l ,3,5- triazimZ-yllamino} benzyl)(methyl) oxido-lfi-sulf'anylidenc ]carbamale and n—Z-ylmcthanol ch Chemical Company Inc.). The desired product was isolated by preparative HPLC.
System: DAD 2996. ELSD 2424. SQD 3100 Column: Solvent: Gcaaienz: How: arure: mjekuon: Detection: Retention: ‘H NMR (400MHz, CDC13,300K) 6 = 8.85 (s, 1H), 8.59 (m, 1H), 8.00 (m, 1H), 7.75 (m, 2H), 7.63 (m, 2H), 7.51 (br, m), 7.36 (m, 1H), 7.21 (m, 1H), 7.13 (m, 1H), 6.81 (m, 2H), 5.32 (s, 2H), 4.37 (d, 1H), 4.23 (d, 1H), 2.95 (s, 3H), 2.68 (s, 1H).
Example 68: (rac)[4-Fluoro-Z-(pyridin—4~ylmethoxy)phenle-N-{3-[(S-methyls ull‘onimidomeethyl] phenyl}- IO 1,3,5-triazinamine Example 68. was prepared under similar conditions as described in the preparation of Example 65 using cthyl [(3- { [4—(2,4-difluorophenyl)- 1 ,3,5-triazinyl]amino} benzyl)(methyl) oxido-Qflsulfanyl- idene]carbamatc and pyridin—4—ylmelhanol (Aldrich Chemical Company Inc.). The desired t was isolated by preparative HPLC.
System: Waters Autopurificationsystem: Pump 254, Sample Manager 2767, CFO, DAD 2996. ELSD 2424, SQD 3100 XBride C18 5pm 100x30 mm A = H20 + 0.2% Vol. NH3 (32%) -B=Methanol 0—1 min 30% B, 1-8 min 30~7o% B so mUmin 3H NMR (400MHz, cock, 300K) 6 = 8.85 (s, 1H), 8.57 (br, 2H), 8.01 (111, 11-1), 7.77 (br, 1H), 7.70 (hr, 111), 7.36 (m, 41-1), 7.13 (m, 111), 6.85 (m, 114), 6.75 (m, 111), 5.20 (s, 211), 4.37 (d, 11-1), 4.22 (d, 111), 2.94 (s, 3H), br, 1H).
Example 69: 4-{4-Fluoro-2—[1-(4—fluorophenyl)ethoxy}phenyl}-N-{3-[(S-methylsulfOnlmidoyDmetllyl}phanyl}- [,3,5—triazin—2—amine, mixture of 4 stereoisomers ”5£1 9”?” $01 N N/ F F Example 69 was prepared under similar conditions as described in the preparation of Example 65 using (rac)-et11yl [(3- { [4-(2,4~difluorophenyl)- 1 ,3,5-triaziuyl]amino} benzyl)(methyl) la-sulfanyl- idenc]cnrbamatc and -(4-fluorophenyl)etl1anol (Aldrich Chemical Company me). The desired product was isolated by preparative HPLC.
System: Waters Autopurificationsystem: Pump 254, Sample Manager 2767. CFO.
DAD 2996. ELSD 2424, SQD 3001 XBrigde C18 511m 100x30 mm A = H20 + 0.2% NH3 8 = Acetonitrile Gradient.' 0—1 min 30% B, 1-8 min 30-70% B. 8-8.1 min 70-100% B, 8.1—10 min 100% B “-11 NMR (400MHz, CD013, 300K] 8 = 8.83 (s, 111), 7.78 (m, 311), 7.48 (br, 1H), 7.34 (m, 3H), 7.15 (m, m), 6.99 (m, 2H), 6.73 (m, 1H), 6.58 (m, 1H), 5.32 (q, 1H), 4.38 (d, 1H), 4.25 (:1, 1H), 2.95 (s, 3H), 1.59 (d, 3H).
Examgle 70: (rac)—[(3-Flu_oro-S-{ [4-(4~fluoromethoxyphenyl)-1,3,S-triazinyI]amino}benzyl)(methyl)oxido- ks-sulfanylidene]cyanamide A / — N \N O “‘ ”8'on / JL , N N F Preparation ofIntermediate 70.1: 3-Fluoro[(methylsulfnnyl)methyl}aniline Intermediate 70.1 was prepared under similar conditions as described in the preparation of Intermediate 1.6 using 1-fluoro[(methylsulfanyl)methyl]nitrobenzene.
!H NMR (400MHz, CDCla, 300K) 5 = 6.42 (m, 2H), 6.26 (m, 1H), 3.74 (br, 2H), 3.55 (s, 2H), 2.01 (s, 3H).
Prenaration 01‘ Intermediate 70.2: 4-Chloro-N-{3-fluoro-S-Kmethylsulfanyl) methyl]phenyl}-l,3,5-iriazin-Z-amine Intermediate 70.2 was prepared under similar conditions as described in the preparation of Intermediate 1.7 using 3-fluoro[(methylsulfanyl)methyl]anilinc.
System: Column Mana-er, PDA, ELSD, SOD 3001 Column: Acquity UPLC BEH 0181.7 50x2.1mm Solvent: A2 = H20 + 0.2% NH3 B1 = ltrile Gradient: 0-1.6 9% B, 1.6-2.0 min 99% B Flow: 0.8 mL/min Temperatuen 60°C ion: 2.0 ul Detection: DAD scan range 210-400 nm -> Peaktable ELSD Method: MS ESI+, ESI- Switch A2 + B1 = C:\MassL nx\Mass 100 1000 BasicReo-ort.fl " ‘ ' V!Retentio 1.20 mln MS(ES- .' m/z = 285 [M+H] Preparation of Intermediate 70.3: 4-(4-Fluerometlioxyphenyl)-N-{3-fluoro—S-[(methylsulfanyl)methyliphenylkl,3,5-triazin-2~ amine NIAN 0/ S / / \/©\NAN/vH Intermediate 70.3 was prepared under similar conditions as described in the preparation of Example 42 using crude 4-chloro-N—{3~fluoro[(methylsulfanyl)methyl]phenyl}-l,3,5-triazin-2—a1nine and (4- Z—mcthoxyphenyl)boronic acid (Aldrich Chemical Company inc). The batch was purified by chromatography (hexane / ethyl acetate 6:4) and finally recrystallized from ethyl acetate to give the desired product.
"H NMR (400MHz, O, 300K) 5 = 10.47 (s, 1H), 8.81 (s, 1H), 7.95 (br, 2H), 7.38 (br, 1H), 7.09 (m, 1H), 6.89 (m, 1H), 6.81 (m, 1H), 3.87 (s, 3H). 3.64 (s, 2H), 1.94 (s, 3H).
Preparation of ediate 70.4: (rac)-[(3-Fluoro—S-{[4~(4-fluoro—2-methoxyphenyl)-l,3,5-triazinyl]amino}benzyl)(methyl-7f- sulfanylideneky anamide S / A mixture of 4-(4-fluoro1nethoxyphenyl)-N-{3-fluoro[(methylsulfanyl)methyl]phenyl}-l,3,5- triazin-Z-amine (500 mg; 1.33 mmol), cyanamide (112 mg; 2.67 mmol) and bis(acetyloxy)(phenyl)-}~3— iodane (473 mg; 1.47 mmol) in DCM (7.5 ml) was stirred at a temperature between 0-5cC for 3 hours.The batch was concentrated and the residue was d by chromatography (DCM / EtOH 92:8) to give the desired product (494 mg; 1.19 mmol). 51-1 NMR(400MHZ,CDC13, 300K) 5 = 8.84 (3, 11-1), 8.06 (br, 2H), 7.79 (s, 1H), 7.24 (m, 1H), 6.80 (m, 3H), 4.40 (d, 1H), 4.15 (d, 111), 3.98 (s, 3H), 2.80 (s, 3H).
Preparation of end t: At room temperature sodium metaperiodate (380 mg; 1.774 mmol) was dissolved in water (4.5 ml).
DCM (6.0 mi) and ruthenium(111)chloride (2 mg; 0.009 mmol) were added under stirring. A suspension of (rac)-[(3-fluoro { [4~('4—f1uoro—2—methoxyphenyl)-1 riazinyl]amino} benzyl)('methyl-X’— sulfanylidene]cyanamide (490 mg; 1.183 mmol) in DCM (8.0 ml) was added dropwise and the batch was stirred at room temperature. After 18 hours additional ruthenium(III)ch101ide (2 mg; 0.009 mmol) was added and the batch was stirred for 5 hours. y, further ruthenium(lll)chloridc (2 mg; 0.009 mmoi) was added and the batch was stirred overnight. The batch was filtered and the fitrate was extracted with DCM (3x). The combined organic phases Were filtered using a Whatman filter and concentrated. The residue was purified by chromatography (DCM / EtOl—l 9:1) to give the d product (146 mg; 0.340 mmol). iH NMR (400MHz, tie-DMSO, 300K) 8 = 10.66 (s, 1H), 8.83 (s, 1H), 8.27 (br, 1H), 7.93 (br, 1H), 7.47 (br, 1H), 7.09 (m, 1H), 6.97 (m, 1H), 6.89 (m, 1H), 4.99011, 2H), 3.87 (s, 3H), 3.38 (s, 3H).
Example 71 and 72: Enantiomers of (mic)-[(3-fluor0{[4-(4—11uoromethoxyphenyl)-1,3.5-triazinyl]amino}benzyl)- (metliyl)oxido-kfi-sulfauylideue]cyanamide [(3 -Fluoro-S- {{4-(4-fluoro-Z-mcthoxyphcnyl)-l ,3, zin~2—yl}amino}benzy1)(methyl)oxido-7t6- sulfanylidcnckyanamidc was separated into the cnantinmcrs by preparative H'PLC.
Dionex: Pump P 580, Gilson: Liquid Handler 215, Knauer; UV-Detektor K-2501 Chiralpak IA 5pm 250x30 mm Ethanol I methanol 50:50 (WV) 143 mg I 3.3 mL EtOHlMeOH/DMSO 1.5:1.5:o.3 11.8 _15'2 Exampie 71 Enamiomer 1 Example 72 Enantiomer 2-“ Enantiomer 1: 1{-1 NMR (400MHz, O, 300K) 8 = 10.66 (s, 1H), 8.83 (s, 1H), 8.27 (br, 1H), 7.93 (br, 1H), 7.47 (br, 1H). 7.09 (m, 1H), 6.97 (m, 1H), 6.89 (m, 1H), 4.99 (m, 2H), 3.87 (s, 3H), 3.38 (s, 3H).
Enantiomer 2: I1-1 NMR (400MHz, dsvDMSO, 300K) 5 = 10.66 (s, 1H), 8.83 (5, 11-1), 8.27 (br, 1H), 7.93 (br, 1H), 7.47 (br, 1H), 7.09 (m, 1H), 6.97 (m, 1H), 6.89 (m, 1H), 4.99 (m, 2H), 3.87 (s, 3H), 3.38 (s, 3H).
Example 73:" (rac)[2-(But-Z-yn~1~yloxy)fiu0rophenyH-N-{3-[(S-methy15uifonimidoyl)methy1]phenyl}~1,3,5- triazinamine HN)‘S’VQNJLNA‘9o NAN o \ Example 73 was prepared under similar conditions as described in the ation of Example 65 using (rad—ethyl [(3 - { [4-(2,4~cliflu oropimnyl)-I ,3,5-m'azin—2-yi]amino} bcnzyl)(1ucthyi)oxido-kG-sulfanyl- idenc]carbamatc and butyn-l-ol (Aldrich al Company Inc.). The compound was purified by chromatography (DCM I EtOH 97:3).
‘H NMR (400MHz, CDCla, 300K) 6 = 8.79 (s, 1H), 7.96 (m, 1H), 7.30011, 2H), 7.60 (m, 1H), 7.41 (m, 1H), 7.15 (m, 1H), 6.96 (m, 1H), 6.80 (m, 1H), 4.79 (d, 2H), 4.42 (d, 1H), 4.29 (d, 1H), 2.95 (s, 3H), 2.72 (br, 1H), 1.85 (tr, 3H).
Example 74 and 75: E na 11 tiomers of 4-[2-(1)utyn-l-yloxy)-4~fluoropheny]l-N-{3-[(S-methylsulfouimidoyl)methyl]- phenyl}-l,3,5-triazinamine (rac)[2-(Butyn-l -yloxy)—4—fluorophcnyl]-N- {3-{(S-mcthylsulfonimidoyl)mcthyl] } -1 ,3 ,5- Iriazin—Z-aminc was separated into the omcrs by preparative HPLC.
Dionex: Pump P 580, Gilson: Liquid Handler 215, Knauer: UV~Detektor K-2501 360 mg l 6 mL ElOH/MeOH/DCM . U _Retention timein min purity in% '4 _ 23 8 Example 74 Enantiomcr 1 24'1 — 28'1 Example 75 Enantiomcr 2 3121111101116: 1: lH NMR (400MHz, CDC13, 300K) 5 = 8.79 (s, 1H), 7.96 (m, 1H), 7.80 (m, 2H), 7.60 (111, 11-1), 7.41 (m, 1H), 7.15 (m, 1H), 6.96 (m, 1H), 6.80 (111, 11-1), 4.79 (d, 2H), 4.42 (d, 1H), 4.29 (d, 11-1), 2.95 (s, 3H), 2.72 (br, IH), [.85 (tr, 3H).
Enamiomcr 2: 1H NMR (400MHz, CDClz, 300K) 5 = 8.79 (s, 1H), 7.96 (m, 1H), 7.80 (m, 2H), 7.60 (m, 1H), 7.41 (In, 11-1), 7.15 (m, 1H), 6.96 (m, 1H), 6.80 (m, 1H), 4.79 (d, 2H), 4.42 (d, 1H), 4.29 (d, 1H), 2.95 (s, 3H), 2.72 (br, 1H), 1.85 (tr, 3H). e 76: (rac)[2-(2-Cyclopropylethoxy)fluorop11enyl]—N-{3—[(S~methylsulfonimidoyl)methyl] plxeny1}- 1,3,5-triazinamine Example 76. was prepared under r conditions as described in lhe preparalion of Example 65 using (rac)-ethyl {(3-{[4-(2,4-difluorophenyl)-l,3,5-triazin~2—yl]amino}benzyl)(metl1yl)oxide-7.6-sulfanyl- idcchcarbamatc and 2-cyclopropylcthanol (ABCR 01an & CO. KG). The desired product was isolated by preparative I-IPLC.
System: Waters Autopurificationsystem: Pump 254. Sampie Manager 2767. CFO, DAD 2996. ELSD 2424, $00 3100 XBrigde C18 5pm 100x30 mm Solvent: A = H20 '1 0.2% NH3 _B=Acetonitrile _Gradient 0-8 min 30 -70% B so mUmin :11 NMR z, 0001;, 300K) 3 = 8.79 (s, 1H), 7.35 (m, 1H), 7.73 (111,217), 7.50 (hr, 111), 7.40 (m, 1H), 7.16 (m, 1H), 6.75 (111,211), 4.39 ((1, 1H), 4.25 (d, 1H), 4.11 (Tr, 2H), 2.95 (5,311), 2.71 (s, 1H), 1.67 (m, 2H), 0.79 (m, 11-1), 0.43 (m, 2H), 0.07 (m, 2H).
Examgle 77: (rac)[4-F!uoro~2—(prop-Z-yn-l-onxy)phenyl]—N~{3-[(S-methyisultbnimidoyl)methyllphenyl}- 1,3,5-triazinamine WK) 1A” °\/8 N/Jfi Example 77. was prepared under similar conditions as described in lhe prepamlion of Example 65 using (rac)-cthy1 [(3- { [ti-(2,4-difloorophenyl)-1 ,3,5-1riazin—2—yl]amino} benzyl) (methyl) oxide—ls-sul fanyl- idcnc]carbamatc and prop-Z-yn-l-ol (Aldrich al Company lnc.). The compound was purified by chromatography (DCM 1’ EtOI‘I 97:3).
‘H NMR (400MHz, CDCls, 300K) 6 = 8.80 (s, 1H), 7.98 (m, 1H), 7.76 (m, 2H), 7.62 (br, 1H), 7.42 (m, 1H), 7.15 (m, ”-1), 6.93 (m, 1H), 6.64 (m, 1H), 4.82 (d, 2H), 4.42 (d, 1H), 4.28 (d, 1H), 2.96 (s, 3H), 2.72 (s, 1H), 2.60 (br, 1H).
Example 78 and 79: omers of 4-[4-flu01‘o(propyn-l»yloxy)phenyl]~N~{3~[(Sqnethylsulfonimidoyl)methyl]- phenyl}-l,3,5-triazinamine (rac)[4-Fluoro-Z-(prop—Zwyn- l —yloxy)phcnyl]-N— {3-[(S-methylsulfonimidoyl)methyl]phcnyl } - I ,3 ,5 - tn'azin-Z-aminc was separated into the cnantiomcrs by preparative HPLC.
Dionex: Pump P 580, : Liquid Handler 215, Knauer: UV—Detektor K-2501 Chiralpak IC 5pm 250x30 mm Hexane / ethanol 70:30 (v/v) 228 mg / 3 mL ElOH/MeOH Retention time in min 19.1 — 22.9 98.7 e 78 Enamiomer 1 229 — 27.8 Emmple 79 Enantiomer 2 En'amiomer 1: 1H NMR (400MHz, CDClg, 300K) 8 = 8.80 (S, 1H), 7.98 (m, 1H), 7.76 (m, 2H), 7.62 (br, 11-1), 7.42 (m, 1H), 7.15 (In, 1H), 6.93 (m, 1H), 6.64011, 11—1), 4.82 (d, 2H), 4.42 (d, 1H), 4.28 (d, 11-1), 2.96 (s, 3H), 2.72 (s, 1H), 2.60 (br, 1H).
Enamiomcr 2: 'H NMR (400MHz, CDCls, 300K) 5 = 8.80 (s, 1H), 7.98 (m, 1H), 7.76 (m, 21-1), 7.62 (br, 1H), 7.42 (m, 1H), 7.15 (m, 1H), 6.93 (m, 1H), 6.64 (m, 1H), 4.82 (d, 2H), 4.42 ((1, 1H), 4.28 ((1, 1H), 2.96 (s, 3H), 2.72 (s, 1H), 2.60 (br, 1H).
Examgle 80: (rac){2-[(3,4-Difluorobenzyl)oxylfluorophenyl}-N-{3—[(S-metlxylsulfouimidoyl)methyl}- plnenyI}-l,3,5-triazin—2-amine Example 80 was prepared under r conditions as described in the preparation of Example 65 using .15 (rac)-elhyl [(3- {[4~(2,4~difluurophenyl}l ,3,5- lriazi11-2—yl]2unino} benzyl.)(methyl)oxidu-lfi-sull‘anyl- carbamate and (3,4—difluorophenyl)methanol (ABCR GmbI-I & CO. KG). The desired product was isolated by prepamtivc HPLC.
DAD 2996. ELSD 2424. SQD 3100 XBrigde 018 5pm 100x30 mm A = H20 + 01% Vol. HCOOH (99%) _B=Acetcnitrile 0-8 min 15-60% B 2(A) 3 mg I 3.9 ml. DMSO/MeOH 1:1 AD scan range 210—400 nm _S ESl+, ESL, scan range 160-1000 m/z 8.0 — 8.5 mm [H NMR z, (3001;, 300K) 6 = 8.80 (s, 1H), 7.96 (m. 1H), 7.69 (m, 3H), 7.33 (m, 2H], 7.09 (m, 3H), 6.83 (m, 2H), 5.25 (s. 2H), 4.37 (d, m), 4.23 (d, 1H), 2.95 (s, 3H), 2.70 (br, 1H), e 81: (rac)[4-Fluoro(],3—thiazoI-S-ylmethoxy)phenyl]-N-{3-[(S-methylsulibnimidoyl)methyl]- phenyl}-],3,5-triazin~2~amine Example 81 was prepared under similar conditions as described in the prepamlion of Example 65 using (rad-ethyl [(3-{ [4-(2,4-difluorophenyl)—1 ,3,5-triazin—2-y1]amino}bcnzyl)(methyi) oxide-7.6-sulfa11yl— carbamatc and 1,3-thiazoIylmcthanol (ABCR Gmbl-l & CO. KG). The desired product was isoiatcd by preparative HPLC.
System Waters Autopurificationsystem: Pump 254, Sample Manager 2767, CFO, DAD 2996. ELSE) 2424. SQD 3100 XBrIgde C18 Sum 100x30 mm A = H20 + 0.1% HCOOH —B=Acetonitrile 0~8 min 15 -60% B so mUmin 579 mg /3.5 mt. DMSO Injektion 7 x 0.5 mL DAD scan range 210-400 nm _2U) m9 + n19l Scan range 160-1000 m/z , , —ELSD .0 — 5.2 min ‘H NMR (400MHz, CDClz, 300K) 5 = 8.79 (m, 2H), 7.96 (m, 1H), 7.88 (m, 1H), 7.74 (br, 1H), 7.68 (m, 1H), 7.51 (br, 1H), 7.37 (m, 1H), 7.14 (m, 1H), 6.86011, 2H), 5.37 (s, 2H), 4.38 (d, 1H), 4.23 (d, 1H), 2.95 (s, 3H).
Exam le 82: (rac){4-Fluoro[(Z-i‘ltloropyridinyl)methoxy]phenyl}-N-{3-[(S-methylsulfonimidoyl)— methyl! phenyI}-1,3,5-triazinamine /3 fikN/J\©\ /N F Example 82 was prepared under similar ions as described in the preparation ofExamplc 65 using {rac)—ethyl [(3— { [Ll-(2,4-difluorophcnyl)-1,3,5-triazinyl]amino} benzyl)(mcthyl)oxido-lG-sulfanyl- idenc}carbamatc and (2-fluoropyridin—4-yl)methanol ate Scientific GmbH). The desired t was isolated by preparative HPLC.
DAD 2996. ELSD 2424. $00 3100 XBrigde C18 5pm 100x30 mm A = H20 + 0.1% HCOOH Gradient How: Temperaturev' Solution: Injekfion: 0939050”: Retention: I'H NMR z, CDCla, 300K) 5 = 8.85 (s, 1H), 8.17 (m, 1H), 8.04011, 1H), 7.76 (br, 1H), 7.70 (m, 1H), 7.61 (br, 1H), 7.36 (br, 11-1), 7.22 (m, 2H), 7.13 (m, 1H), 6.86 (m, 1H), 6.74013, 1H), 5.20 (5, 21-1), 4.37 (d, 1H), 4.24 (d, 1H), 2.95 (s, 3H), 2.73 (br, 1H).
Example 83 and 84: Enantlomers of 4-{4—fluoro-Z-i(2-fluor0pyridln~4~yl)methoxy]phenyi}-N-{3-[(S-methy}sulfon- imidoyl)methyllphenyl}-1,3,5-triazinamine 4- {4-Fluoro-Z-[(2-fluoropyridin—4-yl)meflaoxylphcnyl} -N- {3-[(S—mcthylsulfonimidoyl)mcthyl}- phenyl}-1,3,5-1riazinaminc was separated into the enantiomers by preparative l-iPLC.
Dionex: Pump P 580, Gilson: Liquid r 215, Knauer: UV-Detektor K-2501 _S°’*e"‘= 67 m / 4 mi. EtOH/MeOH lnjektion: 1 x 4.0 m1.
-Retention time an mm purity in % Example 83 Enantiomer 1 42.0 m 650 Example 84 Enamiomer 2 Enantiomcr .1: 1[-1 NMR (400MHz, CDClg, 300K) 8 = 8.85 (s, 1H), 8.17 (m, 1H), 8.04 (m, 1H), 7.76 (br, 1H), 7.70 (m, 1H), 7.61 (br, 1H), 7.36 (br, 1H), 7.22 (m, 2H), 7.13 (m, 1H), 6.86 (m, 1H), 6.74 (m, 1H), .20 (s, 2H). 4.37 (CI. 1H), 4.24 (d, 1H), 2.95 (s, 3H). 2.73 (br, 1H).
Enantiomcr 2: 1H NMR (400MHz, CDClz, 300K) 8 = 8.85 (s, 1H), 8.17 (m, 1H), 8.04 (m, 1H), 7.76 (br, 1H), 7.70011, 1H), 7.61 (br, 1H), 7.36 (br, 1H), 7.22 (m, 2H), 7.13 (m, 1H), 6.86 (m, 1H), 6.74011, 1H), .20 (s. 2H), 4.37 (d. 1H), 4.24 (cl, 1H), 2.95 (s, 3H). 2.73 (br, 1H).
Exalee 85: 4-{4-Flnoro(prop-Z-en-l-yloxy)phenyl]~N—{3-[(S-methylsulfonimidoyl)methyl]phenyl}- I,3,S-triazin-2~amine /5 kK/KQF Example 85 was prepared under similar ions as described in the preparation of Example 65 using (rad-ethyl [(3- { 4- difluorophcnyl)-1 ,3,5—triazin—2—yl]amino } benzyl)(methyl)oxido-7.‘-sulfanyl- idenc]carbamate and prop-Z—cn-l-ol (Aldrich Chemical Company Inc.) The desired product was isolated by preparative HPLC.
DAD 2996. ELSD 2424. SQD 3100 A = H20 + 0.1% HCOOH +. ES|-, so‘an range 160-1000 mlz —ELSD 3.2 - mm :H NMR (400MHz, CDCls, 300K) 5 = 8.81 (s, 1H), 7.92 (in, 1H), 7.75 (m, 2H), 7.49 (s, 1H), 7.40 (m, 1171), 7.16 (In, 1H), 6.76 (111, 21-1), 6.03 (in, 11-1), 5.46 (m, 1H), 5.28 (m, 1H), 4.85 (m, 2H), 4.39 (d, 1H), 4.26 (d, 1H), 2.94 (s, 3H), 2.70 (br, 1H).
Example 86: (rac)(4-Fluoro-2—{[4-(trifluoromethyl)benzyfloxy}phenyl)-N-{3-[(S—methylsulfonimidoyl)- methyllphenyi}-1,3,5~triazinamine Hing/Q in:/\ o 12 F F Exampie 86 was prepared under similar conditions as desaibed in the preparation of Example 65 using (rac)-cthyl [(3-{[4-(2,4~dif1uorophmy!)-1,3,5-triazin—2-y1]amino}bcnzyIchthyl)oxido-7."-sulfanyi- idcne]carbamate and [4-(trifluoromethyl)phenyl]methanol (ABCR GmbH & CO. KG). The desired t was isolated by ative HPLC.
System: Waters Autopurificalionsystem: Pump 254. Sampie Manager 2767, CFO.
DAD 2996. ELSD 2424, SOD 3100 Column: XBrigde C18 5pm 100x30 mm Solvent: A = H20 + 0.2% NHa -B=Acetonitrile 0-8 min 30 ~70% B so mUmin DAD scan rane 210—400 nm _MS581+, ESI-, scan range 160-1000 m/z ‘H NMR (400MHz, CDCl;, 300K) 8 —‘- 8.82 (s, 1H). 7.99 (m, 1H). 7.90 (br, 1H), 7,60 (in, 5H), 7.45 (m, 1H), 7.34 (m, 1H), 7.13 (m, 1H), 6.81 (m, 2H), 5.22 (s, 2H), 4.36 (d, 1H), 4.23 (d, 1E-I), 2.94 (s, 3H), 2.73 (br, 1H).
Exampie 87: (rac){2-[(4-Chlorobenzyl)oxy]fluorophenyl}-N-{3-{(S-methyisulfonimidoyl)methyl]phenyl}- trlazin-Z~amine “tag 1‘” or;/S /\ N N¢K© Cl F Example 87 was prepared under similar conditions as described in the preparation of Example 65 using {rac)-ethy1 [(3- { [4-(2,4-difluorophenyl)—1,3,5-triazin—2-yl]amino}benzyl)(methyl)oxido—ls-sulfanyl- idcnclcarbamatc and (4-el1loropl1enyl)methanol (Aldrich Chemical Company lnc). The desired product was isolated by preparative HPLC.
Waters Autopurifieationsystem: Pump 2545, Sample Manager 2767, CFO, DAD 2996. ELSD 2424. $00 3001 XBrigde C18 5pm 100x30 mm A = H20 + 0.1% HCOOH —B = Acetonitrile 0—1 min 1% 8.1-8 min 1-99% B. 8-10 min 99% B so mUmin Max. 250 mg / max. 2.5 mL DMSO 0. DMF Injektion: 1 x 2.5 mL DAD scan ran-e 0 nm _MSES|+, ESl-, scan range 160-1000 m/z i'H NMR (400MHz, CDCl3, 300K) 5 = 8.94 (5, 1H). 7.99 (m, 1H), 7.75 (m, 2H), 7.34 (m, 6H), 7.16 (m, 1H), 6.82 (m, 2H), 5.l 8 (S, 2H), 4.39 (d, 1H), 4.25 (d, 1H), 2.96 (5, 3H), 2.70 (br, 1H).
Example 88: (r304-(2-Ethoxyfluorophenyl)-N-{3-[(S-methylsulfonimidoyl)methyl]phenyl}-1,3,S-triazin amine HN O N N o’\ “3” JL/ / N Example 88 was prepared under similar conditions as described in the preparation of Example 65 using (rac)—ethyl [(3 - { [ti-(2,4-difluorophenyl)- 1 ,3,5-triazinyl]amino} )(methyl)oxide-1.6-sulfanyl- idene]carbamate and ethanol. The desired product was isolated by preparative HPLC.
System: DAD 2996. ELSD 2424. SQD 3100 Column.- Solvent: Gradient: How: Temperature: Injekuon: Detection: DAD scan ran-e 0 nm MS ESI+. ES|—, scan range 160-1000 m/z ELSD Retention: 5.8 — 6.2 min 3H NMR z, CDCls, 300K) 5 = 8.83 (s, 1H), 7.81 (111,3H), 7.53 (s, 1H), 7.43 (m, 1H), 7.18 (in, 11-1), 6.78 (m, 2H), 4.41 (d, 11-1), 4.28 (a, 114), 4.16 (q, 211), 2.97 (s, 3H), 2.73 (s, 111), 1.44 (tr, 311).
Examnle 89: (r ac)(4-Fluor0{ [3-fluoro—5-(trifluommcthyl)benzyl]oxy}phcnyl)~N-{3-[(S-methylsulfo n- imidoyl)methyl]phenyl}-l,3,5—triazin~2~amine HN‘SIZQ /\ N \N 0 /J‘\ / FF / 1 KCL Example 89 was prepared under similar conditions as described in the preparation of Example 65 using (rac)—ethyl [(3- {[4-(2,4~diflu0ropl1eny1)-l ,3,5-triazin-2—yl]amino} benzyl) (methyl)oxido-).6—sulfanyl- idcnc]ca'rbamatc and {3-fluoro-S-(trifluoromcthyUphcnylhncflianol (ABCR GmbH & CO. KG). The desired product was isolated by preparative HPLC.
DAD 2996. ELSD 2424. SQD 3001 XBrigde C18 511m 100x30 mm A = H20 + 0.1% HCOOH _B=Acetonitrile 0—1 min 1% B, 1-8 min 199% B. 8—10 min 99% B 50 mL/min Max. 250 mg / max. 2.5 mL DMSO 0. DMF ion: 1 x 2.5 mL DAD scan range 210—400 nm —MSES|+, ESL, scan range 160-1000 m/z ‘H NMR (400MHz, CDCIg, 300K) 5 m 8.84 (s, 1H), 8.04 (s, 1H), 7.77 (br, 1H), 7.67 (m, 2H), 7.42 (m, 3H), 7.26 (m, 1H), 7.15 (m, 1H), 6.83 (m, 2H), 5.21 (s, 2H), 4.38 (d, 1H), 4.25 (d, 1H), 2.95 (s, 3H).
Example 90: (1'ac)—4-{4—FluoroE(3-fluorobenzyl)oxylphenyl}-N-{3-[(S-methylsulfonimidoyl) methyllphenyik 1,3,S-triazinamine HN\'i/Q N!/§N QUE: /3 N HXM/KO Example 90 was prepared under r conditions as described in the preparation of Example 65 using (rac)-ethyl [(3—{ [4-(2,4-difluoroplienyI)—l ,3,5-tt'ia2inyl]amino}benzyl)(methyl)oxido-lé-sulfanyL idenc]carbamatc and (3-flu0rophenyl)methanol (ABCR Gmbl-i & CO. KG). The desired product was isolated by preparative HPLC.
Waters Autopurificationsystem: Pump 2545, Sample Manager 2767, CFO, DAD 2996. ELSE) 2424, SQD 3001 XBrigde 018 Sam 100x30 mm A = H20 + 0.1% HCOOH _B=Acetonitrile 0—1 min 1% 8.1-8 min 1-99% B. 8-10 min 99% B Max. 250 mg / max. 2.5 mL DMSO 0. DMF Injektion: DAD scan range 210—400 nm _MSESI+, ESL, scan range 160-1000 m/z 1H NMR z, CDClz, 300K) 8 = 8.86 (s, 1H), 8.02 (m, 1H), 7.75 (m, 2H), 7.54 (s, 1H), 7.35 (m, 3H), 7.18 (m, 2H), 7.01 (m, 1H), 6.82 (In, 2H), 5.21 (s. 2H), 4.39 (d, 1H), 4.26 (d. 1H), 2.96 (s, 3H). e 91: (rac)(4-Fluoro-2~propoxyphenyl)~N-{3-[(S-methylsulfonimidoyl)methyl]phenyl}-1,3,5-trinzin amine HN\"I:/©\ /\ Ni\N O/V Example 91 was prepared under similar conditions as described in the preparation of Example 65 using (rad-ethyl [(3- {[4-(2,4-difiu0rophenyl)— l .3,5—triazin-2—yl]amino}benzyl)(methyi)oxido-lé-sulfanylidenckarbamatc and propan-l '0!. The desired product was isolated by preparative HPLC.
Waters Autopurificationsystem: Pump 254, Sampie Manager 2767. CFO.
DAD 2996. ELSD 2424, 500 3100 XBri-de C18 5pm 100x30 mm A = H20 + 0.2% NHa -B = Acetonitrile 0-8 min 30 70% 13 Flow: 50 mUmin Temperature: 126 mg l 4 mL DMSO fnjeklion‘: DAD scan range 210—400 nm _MS581+. £31-, scan range 1001 000 mlz .5 — 6.9 min ‘H NMR (400MHz, CDC13, 300K) 5 = 8.80 (s, 1H), 7.85 (m, 1H), 7.75 (111, 211), 7.42 (111,21-1), 7.16 (m, 111), 8.74 (m, 21-1), 4.39 (d, 1H), 4.26 ((1, 11-1), 4.01 (tr, 21-1), 2.95 (s, 311), 2.70 (5, 11-1), 1.8] (m, 211), 1.00 (tr, 3H).
Exam le 92: (rac)—4-{2-[(3-Chlorobenzyl)oxy]fluorophenyl}~N-{3-[(S-methylsulionimldoyl)methyl] phenyl}- 1,3,S-triazin—2-amine HN 3/0 \\ II NIQN OUCA /S NANKQH F Example 92 was prepared under similar conditions as described in the ation of Example 65 using (rac)-cthy1 [(3-{[4-(2,4-difluorophcnyl)—1,3,5~1riazin-2—yl]amino}bcnzlemcthyl)oxido-if-sulf‘anyl- idene]carbamatc and (3-chIorophenyl)methanol (ABCR GmbI-I & CO. KG). The desired product was isolated by preparative HPLC.
Waters rificalionsystem: Pump 254. Sample Manager 2767. CFO.
' DAD 2996. ELSD 2424, SQD 3100 XBrigde C18 5pm 100x30 mm A = H20 + 0.2% NHa _B=Acetonitrile 0-6 min 30 -70% 8 Solution: 233 mg I 3 mL DMSO lnjekt/on: AD scan range 210—400 nm _S ESI+, ES|-. scan range 00 mlz ‘H NMR (400MHz, CDCls. 300K) 5 1..- 8.84 (s. 1H)1 8.00 (m, 1H), 7.68 (m, 3H), 7.53 (s, 1H), 7.35 (m, 1H), 7.20 (m, 3H), 7.14 (m, 1H), 6.81 (111,211), 5.16 (s, 2H), 4.36 (d, 1H), 4.23 (d, 1H), 2.94 (s, 3H), 2.70 (br, 1H).
Example 93: (rac)[4-Fluoro—2-(1,2~oxazoIylmethoxy)phenyl]-N~{3-[(S-methylsulibnimidomeethyll- phenylFI,3,5-triazinamine H’iupvQ NIAN 0%0/8 N)\N2\©\ \H Example 93 was prepared under similar cenditions as described in the preparation of e 65 using (rac)-elhyl [(3- ,4-dilluorophenyl)-1,3,5-lriazinyl]aminu}benzyl)(mclhyl)oxidoJf-sull‘dnyl— idenc]carbamate and 1,2—oxazoiylmethanol (UkrOrgSymhdsis Ltd). The desired product was isolated by preparative HPLC. t: Prep 1200, 2xPrep Pump. DLA, MWD, Prep FC.
XBrigde 018 5pm 100x30 mm A = H20 +0.1% TFA _B=Methanol 047,5 min 25~55% B, 17520 min 0 B 38 mL/min 29 mg / 0,8 mL DMSO Injektion 1 x 0.8 mL UV 210 nm 8.3 _ 10.2 min ‘H NMR (400MHz, da—DMSO, 300K) 5 = 10.41 (s, 1H), 8.80 (m, 211), 7.80 (m, 3H), 7.37 (m, 1H), 7.18 (m, 2H), 6.94 (m, 1H), 6.55 (br, 1H), 5.33 (s, 2H), 4.99 (m, 2H), 3.37 (s, 3H), Example 94: (rac){2-[(3-ChIorovS-fluorobenzylwxylfluorophenyl}~N-{3-{(S-methylsulfonimidoyl)methyl]- phenylH,3,5-triazinamine HN\ 'i/Q NIAN CI A WW Example 94 was prepared under similar conditions as described in the preparation of‘ Example 65 using (rac)~ethy1 [(3— { [4—(2,4-difluorophenyl)-l riazinyl]amino} benzylxmethyl)oxide—l“-sulfanyl— idene]carbamute and(3-chlorofluoropheny1)methanol (Apollo Scientific Ltd). The desired product was isolated by preparative HPLC.
DAD 2996. ELSD 2424, SQD 3001 021 min 1% B, 1—8 min 1—99% B. 8—10 min 99% 8 Max. 250 m / max. 2.5 mL DMSO 0. DMF lnjektion: 1 x 2.5 mL DAD scan range 210—400 nm —MSESI+, ESl—. scan range 160-1000 mlz ‘H NIVIR (400MHz, CDCia, 300K) 5 = 8.85 (S, 1H), 8.03 (m, 1H), 7.77 (S, 1H), 7.69 (m, 1H), 7.46 (In, 1H), 7.37 (m, 2H), 7.16 (m. 2H), 7.01 (m, 1H), 6.85 (m, 1H), 6.76 (m, 1H), 5.14 (5, 2H), 4.38 (d, 1H), 4.24 (d, 1H), 2.95 (s, 3H).
Example. 95: (rac)-4—[2-(2,2-Difluoroethoxy)fluorophenyl]—N-{3-[(S-methylsultbninfidoyi)methyllphenyl}- triazinamine F e 95 was prepared under similar conditions as described in the preparation of Example 65 using (rac)-ethy1 [(3—{[4-(2,4-difluorophenyl)-13,5-iriazinQ—yflamino}benzyl)(methyl)oxiclo-‘hfi-sulfanyl- idenc]carbamate and 2,2-difluoroethano} (ABCR GmbH & CO. KG). The desired product was isolated by preparative HPLC.
Waters Autopurifieationsystem: Pump 254, Sample Manager 2767, CFO, DAD 2996, ELSD 2424, SOD 3100 XBrigde C18 5pm 100x30 mm A = H20 + 0.2% NHs —B=Acetonitrile 0—8 min 15-50% B 50 mL/min O)8 mg I 3 mL DMSOIMeOH 1:1 Injektion: x 1 mL AD scan range 210—400 nm _8 ESI+, ESL, scan range 160-1000 m/z 6.18 - 6.54 min 5H NMR (400MH2,CDC13, 300K) 5 = 8.80 (s, 1H), 7.95 (m, 1H), 7.77 (br, ”-1), 7.69 (m, 1H), 7.43 (m, 1H), 7.34 (br, 1H), 7.18 (m, 1H), 6.88 (m, 1H), 6.76 (m, 1H), 6.05 (m, 1H), 4.40 (d, 1H), 4.27 (m, 3H), 2.95 (s, 3H), 2.63 (s, 1H).
Example 96: (rac)—4-{4-Fluoro[(4-fluoromethylbenzyl)oxy]phenyl}-N-{3-[(S-metlrylsulfonimidoyl)methyl]— phenyI}-1,3,5-triazinamine /3 N N//|\©\ F Example 96 was ed under similar cenditions as described in the preparation of Example 65 using (rac)~elhy1 [(3- {[4-(2,4-difluurophenyl)- l ,3,5- lriazin-Z-yl]amino} benzyl)(methyl)oxitlo—lfi-sullianyl- idene]carbamate and (4-fluoro—3-1nethylpl1eny1)methanol (ABCR GmbI-I & CO. KG). The desired product was isolated by preparative HPLC.
Waters Autopurifieationsystem: Pump 2545. Sample Manager 2767, CFO, DAD 2996. ELSD 2424, SQD 3001 XBrigde C18 5pm 100x30 mm A = H20 + 0.1% HCOOH _B=Acetonitrile 0-1 min 1% B, 1-8min1-99% B, 840 min 99% B 50 mUmi" Eex. 250 mg I max. 2.5 mL DMSO 0. DMF 1 x 2.5 mL DAD scan range 210—400 nm MS ESI+, ESl-, scan range 160-1000 m/z ‘I-I NMR (400MHz, CDClq, 300K) 8 = 8.81 (s, 1H), 7.94 (m, 1H), 7.70 (m, 2H), 7.51 (br, 1H), 7.32 (m, 2H), 7.20 (m. Il-l). 7.13 (m, 3H), 6.94 (m, 1H), 6.79 (m, 2H), 5.11 (s, 2H), 4.35 (d. 1H), 4.33 (d. 1H), 2.93 (s, 3H), 2.61 (s, lH), 2.23 (51 3H).
Example 97: 4-{2-[(3-Chlorofluorobenzyl)oxy]fluorophenyl}-N-{3-[(S-methyl3u]fonimidoyl)methyl}- l}-I ,3,5—trinzinamine S / / N/KQ F Example 97 was prepared under similar conditions as described in the preparation of e 65 using (rac)-ethyl [(3- { [4-(2,4-difluerophenyl)-1,3,5-triazin—2-yl]amino}benzyl)(methyl)oxide—l6—sulfanylidene ]carbamate and (3-ehIoro-4—fluoroplrenmeetlranol (ABCR GmbH & CO. KG). The desired product was isolated by preparative HPLC.
System: Waters Autopurificationsystem: Pump 2545, Sample Manager 2767. CFO.
DAD 2996. ELSD 2424. SOD 3001 XBrigde C18 511m 100x30 mm A = H20 + 0.1% HOOOH Injektion: 1 x 2.5 mi.
DAD scan range 210—400 nm —MS251+, ES|-, scan range 160-1000 m/z ‘H NMR (400MHz, C0013, 300105 = 8.84 (s, 1H), 8.00 (m, 1H), 7.76 (br, 1H), 7.69 (m, 2H), 7.48 (br, 1H), 7.36 (m, 1H), 7.27 (m, 1H), 7.11 (m, 2H), 6.79 (m, 2H), 5.12 (s, 2H), 4.37 (d, 1H), 4.24 (d, 1H), 2.95 (s, 3H), 2.71 (br, 1H).
Example 98: (rac)({5-FIuora-2—|4-({3-[(S-metIIyISulfonimidoyl)methyl]phenyl}amino)—1,3,5-triazinyl]- phenoxy}methyl)benzonitrile “4‘90 1 / °U/ /\ / N \ N / N N F Example 98 was ed under similar conditions as described in the preparation ofExamplc 65 using cthy1 {(3~ { [4-(2,4-difluor0phenyl)-1,3,5-triazi11yl]amino}benzyl)(methyl)oxido-7.6~sulfanyl— idene3carbamate and 3-(hydroxymcthyl)benzonitrilc (ABCR GmbH & CO. KG). The desired product was isolated by ative HPLC.
System: Waters Autopurificationsystem: Pump 254. Sampie Manager 2767. CFO, DAD 2996. ELSD 2424. SQD 3100 XBrigde C18 5pm 100x30 mm A = H20 + 0.2% NHs -B = Acetonitrile 0-8 min 30 70% B so mum -MSESH, ESL, scan range 160-1000 m/z _ELSD 4.7 — 4.9 min 1H NMR (400MHz, dc-DMSO, 300K) 5 = 10.35 (s, 1H), 8.83 (s, IH), 7.85 (m, 68), 7.53 (br, 1H), 7.28 (br. 1H), 7.16 (In, 1H), 7.11 (br, 18), 6.95 (m, 1H), 5.32 (s. 2H), 4.32 (br, 2H), 3.55 (s, 1H), 2.79 (s, 3H). e 99: (1-ac){4-Fluoro—2~[(2~methylprop-Z-en—l~yl)oxy]pheny!}-N-{3-{(S-methylsulfonimidoyl)methyl]- phenyl}-1,3,5~triazinamine W30 1‘“ OYS /\ / N H N)\© Example 99 was prepared under similar conditions as described in the preparation of Example 65 using (rac)-ethyl [(3-{{4-(2,4-difluorophenyl)-l,3,5—11'iazin—2—yl]amino}benzyl)(methyl)oxidoJF-sulfanyl- idcnc]carbamatc and 2-mothylpropcuol (Aldrich Chemical y inc}. The desired product was isolated by preparative HPLC.
Waters Autopurificationsystem: Pump 2545. Sample Manager 2767, CFO, DAD 2996. ELSD 2424, SQD 3001 XBrigde 018 Sam 100x30 mm A = H20 + 0.1% HCOOH —B = Acetonitrile 0—1 min 1% B, 1-8 min 1-99% B. 8-10 min 99% B so mUmin Max. 250 mg I max. 2.5 mL DMSO 0. DMF Injektion: 1 x 2.5 mL DAD scan ran-e 210—400 nm _MSESI+, ESI-, scan range 160-1000 rn/z il'l NMR (400MHz, CDCls, 300K) 5 = 8.83 (S, 1H). 7.94 (m. 1H), 7.76 (m, 2H), 7.55 (br, 1H), 7.42 (In, 1H), 7.18011. lH). 6.78 (m, 2H), 5.180.113 TH), 5.01 (br, ”'0. 4.55 (5, 2H), 4.41 (d. 1H). 4.28 ((1, 1H), 2.97 (s, 3H), 2.70 (br, 1H).1.82 (s, 3H).
Example 100: (rac)—4-[ti-Fluoro-Z-(4,4,4-trifluorobntoxy)phenyl]-N~{3~[(S—mcthylsulfonimidoyl) methyl]phcnyl}~ 1,3,5-triazinamine “ECG ii 3‘ 0W/ A F m N Example 100 was prepared under similar ions as described in the preparation of Example 65 using (rad-ethyl [(3» { 4-difluorophenyl)-l ,3,5-triazi n-Z-yl]amino } benzlemethyl)oxido—lé-sulfanyl- idene]carbamate and 4,4,4-lrifluorobutan—1-ol (ABCR GmbI-I & CO. KG). The d product was isolated by preparative HPLC.
' DAD 2996. ELSE) 2424, $00 3001 0—1 min 1% B, 1—8 min 1-99% B, 8—10 min 99% B Injektion: 1 x 2.5 mL DAD scan range 210400 nm -MSESH. ES|-, scan range 160-1000 m/z 'H NMR (400MHz, CDCla, 300K) 5 = 8.82 (8, 1H), 7.95 (m: 1H), 7.800313 1H), 7.70 (m, 1H), 7.46 (m, 2H), 7.19 (m, 1H), 6.82011, 1H), 6.73 (m, 1H), 4.42 (d, 1H), 4.29 (d, 1H), 4.12 (tr. 2H), 2.98 (S, 3H), 2.74 (br, 1H), 2.38 (m, 2H), 2.07 (m, 2H).
Exampie 10]: (rac)§4-Fluoro[(2,3,5-trifluombenzyl)oxy[phenyl}-N—{3-[(S-methylsulfonimidoyl)methyl]~ pllenyl}-l,3,5-triazinamine S / / 8 kCL Example 101 was ed under similar conditions as described in the preparation of e 65 using (rac)-cthyl [(3- {[4-(2,4—difluorophcnyl)~I ,3,5-triazinyl]amino}bcnzyl)(1ncthyl)oxido-ifisulfanyl— idene]carbamate and (2,3,5-Irifluor0phenyl)methanol (ABCR GmbH & CO. KG). The desired product was isolated by preparative HPLC.
DAD 2996. ELSD 2424, SOD 3001 XBrigde C18 5pm 100x30 mm A = H20 + 0.1% HCOOH _B=Acetonitrile Gradient: 0—1 min 1% B, 1-8 min 1-99% B, 8~10 min 99% B =11 NMR (400MHz, (313%, 300K) 3 = 8.87 (s, 1H), 8.07 (m, 1H), 7.80 (s, 1H), 7.72 (m, 11-1), 7.40 (m, 3H), 7.18 (m, 1H), 6.89 (m 3H), 5.26 (s, 2H), 4.42 (d, 1H), 4.28 (d. 1H), 2.98 (s, 3H), 2.71 (br, 1H).
Example 102: (rac){2-[(2Z)-But~2~en—l-yloxy]fluorophenyl}-N-{3-{(S-methylsultonimidoyl)methyl]phenyl}— 1,3,S-triazinamine Example 102 was prepared under r conditions as described in the preparation of Example 65 using (rac)-ethyl [(3— { [4-(2,4-difluorophenyl)-l ,3,5-triazi11-2—yl]amino} )(motl1yl)oxido—if—sul Fanyl- idene]carbamate and (ZZ)-buIen-l—ol ampCo, Inc.). The d product was isolated by preparative HPLC.
System: Waters Autopurificationsystem: Pump 2545. Sample Manager 2767, CFO.
DAD 2996. ELSD 2424, SOD 3001 XBrigde C18 5pm 100x30 mm A = H20 + 0.1% HCOOH —B=Acetonitrile _Gradient: 0—1 min 1% B, 1-8 min 1-99% B. 8-10 min 99% B Flow: Temperature: Max. 250 mg / max. 2.5 mL DMSO 0. DMF lnjektion: DAD scan range 210—400 nm _MSESI+, ESl-, scan range 160—1000 m/z “H NMR(400MI-I7.,CDC13, 300K) 6 = 8.80 (s, 1H), 7.89 (m: 1H), 7.76 (m, 21-1), 7.57 (br, 1H), 7.39 (m, ”-0, 7.15 (m, ll-l), 6.75 (m, 2H), 5.70 (m, 2H), 4.72 (m, 2H), 4.39 (d, 1H), 4.26 (d, 1H), 2.95 (s, 3H), 2.71 (br, 1H). 1.73 (d, 3H).
Example 103: (rac){4-Fluoro[(2,4,5—trifluorobenzyl)oxy[phenyl}-N—{fl—{($-methylsulfonimidoyl)metlryl]- phenyfl-l,3.5-triazinamine HN o N \N o \‘s’I )L / / n N F Example 103 was prepared under similar conditions as described in the preparation of Example 65 using {rad-ethyl [(3 - { [4-(2.4- difluorophenyl)— l ,3.5—triazinyllamino} bcnzyl)(methyl) oxido-lG-sulfanyl- idcne]carbamatc and (2,4,S-trifluorophenyl)mcthauol (ABCR GmbH & C0. KG). The d product was isolated by preparative HPLC.
- DAD 2996. ELSD 2424. SQD 3001 0—1 min 1% B, 1—8 min 1-99% 8, 8-10 min 99% 13 Max. 250 m- / max. 2.5 mL DMSO 0. DMF lnjektion: 1 x 2.5 ml.
DAD scan range 210-400 nm —MSESI+, ESl-, scan range 160-1000 m/z I'H NNIR (400MHz, CDCls, 300K) 5 = 8.84 (S, 1H), 8.03 (m, 1H), 7.770313 1H), 7.65 (m, 2H), 7.48 (br, 1H), 7.39011, 1H), 7.15011, 1H), 6.94 (m, 1H), 6.83 (m, 2H), 5.17 (S, 2H), 4.39 (d, 1H), 4.25 (d, 1H), 2.96 (S, 3H), 2.70 (br, 1H).
Exampje 104: (rac){4-Fluoro-2~[(3,4,5-trifluorobenzyl)oxy|phenyI}-N-{3-I(S~methylsultbnimidoyl)methyl]- piienyl}-1,3,S-triazin-Z-amine HN‘S’E/Q A JNL /N F / N N F F Example 104 was prepared under similar conditions as described in 1110 preparation ofExumplc 65 using clhy1 [(3— { [4-(2,4-(li f‘luorophcnyl)- i ,3,5-1riazin~2—yi}amino} benzyl)(methyl)oxiclo-if-sulfauyiidenc }carbamate and (3,4,5—trifluorophcnyl)methanol (ABCR GmbH & CO. KG). The desired product was isolated by preparative l-lL’LC.
Waters rificationsystem: Pump 254, Sample Manager 2767, CFO.
DAD 2996, ELSD 2424. SQD 3100 e C18 Sum 100x30 mm A = H20 + 0.1% HCOOH _a=Acetonirile 0-8 min 30 «70% B so mL/min 431 mg /4mL DMSO 3 x 0.5 mL DAD scan range 210—400 nm _MSES|+, ES|~. scan range 160-1000 m/z _F" 1““ CD 3H NMR (400MHz, CDCls, 300K) 8 = 8.84 (s, 1H), 8.02 (m, 1H), 7.77 (br, 1H), 7.69 (m, 1H), 7.39 (m, 2H), 7.17 (m, 3H), 6.85 (m, 1H), 6.74 (m, 1H), 5.10 (s, 2H), 4.39 (d, 1H), 4.25 (d, 1H), 2.95 (s, 3H).2.69 (br, 1H).
Examgle 105: (rac)~[(2,3-Difluoro—5~{ [4—(4-fluoromethoxyphenyl)-1,3,S-triazinyl]amino}benzyl)(methyl)- oxide-kfi-sulfanylidenelcyanamide \\ ’l /S NAN/Jfi Preparation of Intermediate 105.1: (2,3-Difluoro-S~nitrophenyi)methanol 0“ .f):OH Boraue—tetraliydrofiiran complex (1.0M solution in THE; 177 mL) was added under stirring to an ice- cold solution of 2,3-difluoronitrobenzoic acid (9.0 g; 44.3 mmol; Butt Park Ltd.) in THF (85 mL). The ice bath was removed and the batch was stirred for 18 hours at room temperature. The batch was cautiously diluted with methanol under stirring at 0°C. Ethyl acetate was added and the batch was washed with aqueous 1 M solution of sodium hydroxide and half-concentrated aqueous sodium ehoride solution. The c phase was dried 0:), filtered and concentrated. The residue was purified by chromatography (hexane/ ethyl acetate izl) to give the desired product (8.2 g; 43.3 mmol).
"H NMR (400MHz, CDCls, 300K) 8 = 8.26 (m, 1H), 8.03 (m, 1H), 4.89 (s, 2H), 2.13 (br, 1H).
Preparation ofIntermediate 105.2: ne-2,3-difluorophenyl)methanol 2 Intermediate 105.2 was ed under similar conditions as described in the ation of Intermediate 1.6 using. (2,3-difluuru-5—nilrophenyl)methanol.
LH NMR (400MHz, CDCls, 300K) 5 = 6.46 (m, 1H). 6.39 (m, 1H), 4.67 (s, 2H), 3.02 (br. 3H).
Preparation of Intermediate 105.3: 3—(Chloromethyl)-4,5-difluoroaniline (Ion Thionylchloride (7.7 g; 64.9 mmol) was added dropwise under stirring to a water-cooled solution of (S—ainino-2,3-difluorophenyl)methanol (4.1 g; 26.0 mmol) in DCM (78 ml) and l-methylpyrrolidin-Z- one (i 1 ml). The batch was stirred at room temperature for 18 hours before it was diiutcd with ice-water, aqueous sodium bicarbonate solution and brine, The batch was stirred for 2 hours at room temperature and finally it was extracted with ethyl e (2x). The combined c phases were filtered using a n filter and concentrated to give the crude product (6.5 g) that was used t further purification.
Preparation ofIntermediate 105.4: 3,4-Difl uoro-S-{(methylsulfanyl)methyijaniline HN \ Intermediate 105.4 was prepared under similar conditions as described in the preparation of Intermediate l.l using crude 3-(chloromcthyl)-4,S-difiuoroaniline. The batch was purified by chorniatography (hexane /' ethyl acetate 1 ‘. I).
"H NMR (400MHz. CDCla, 300K) 8 *- 635 (m, 2H), 3.62 (br, 4H), 2.99 (s, 3H).
Preparation of Intermediate 105.5: 4—Chloro-N-{3,4-difluorows—[(methylsulfanyl)methyl]phenyi}-l.3,5-trinzinamine Intermediate 105.5 was prepared under similar conditions as bed in the preparation of Intermediate 1.7 using 3,4—difluoro-S-[(mcthylsulfanyl)methyl]aniline.
System: Waters Acquity UPLC-MS: Binary Solvent Manager, Sample Manager/Organizer, Coiumn Mana-er, PDA, ELSD, SOD Acquity UPLC BEH 0181.7 50x2.1mm A1 = H20 '9‘ 0.1% Vol. HCOOH (99%) A2 = H20 4‘ 0.2% Vol. NH3 32% —m1 = Acetonitril |-1.6 min 1-99% B, 1.6-2.0 min 99% B Injektion: DAD scan ran-e 0 nm -> Peaktable Method: MS ESI+, ESI~ Switch A2 + B1 = sL nx\NH3Mass100 1000.011) Preparation of Intermediate 105.6: N»{3,4-Difluoro-S-[(methylsutfanyi)methyl]phenyl}(4-fluoro~2—methoxyphenyl)-l,3..5-triazin amine F O/ ”8\fi NIQN “AXE;H / Intermediate 105.6 was prepared under similar conditions as described in the preparation of Example 42 using crudc 4—chloro-N- {3,4-difluoro-S~[(1ncthylsulfanyl)mcthyl]phcnyl}-l ,3,5-triazinaminc and (4- fluoro-Z-mcthoxyphenyl)boronic acid (Aldrich Chemical Company Inc). The batch was purified by chromatography (hexane/ ethyl acetate 1:1) to give the dwired product. aH NMR (400MHz, CDCIq, 300K) 6 = 8.80 (s, 1H), 8.15 (br, 2H), 7.35 (m, 1H), 7.08 (br, 1H), 6.78 (m, 2H), 3.98 (s, 3H), 3.73 (s, 2H), 2.08 (s, 3H).
Preparation of Intermediate 105.7: (me)-[(2,3-Difluoro-S-{I4-(4—fluoromethoxyphenyD-l,3,S-triazinyl]amino}benzyl)(methyi)-}.4- sulfanylidenelcyanamide /) 0 \ d ctyloxy)(phenyl)-7€-iodanc (469 mg; 1.46 mmol) was added to a stirred solution of N-{3,4- difluoro-S-[(methylsulfanyl)methyl]pheny1}(4-fluoro-Z—metlioxyphenyl)-1,3,5-tr1azinamine (520 mg; 1.33 11111101) and cyanamidc (11 I mg; 2.65 11111101) in DCM (7.5 ml) at 0°C. The batch was stirred at this temperature for 4 hours.The batch was concentrated and the residue was purified by tography (DCM I' EtOl-l 8:2) to give the desired product (300 mg; 0.69 mmol).
‘H NMR (400MHz, CDCix, 300K) 8 = 8.81 (s, 1H), 8.49 (br. 1H), 8.06 (br, 1H), 7.87 (br, 1H), 7.22 (br, 11-1), 6.79 (in, 21-1), 4.34 (m, 2H), 3.96 (s, 3H), 2.86 (s, 3H).
Preparation of end product: Potassium permanganate (217 mg; 1.37 mmol) was added under stirring to a solution of (rac)-[(2,3- difluoro—S— {[4-(4-fluoremethoxyphenyl)—1,3,5-triazin—2-yl]amino}benzlemethyl)—k‘-sulfanylidene]- eyanamidc (297 mg; 0.69 mmol) in acetone (6.9 mL) at room temperature. The batch was stirred at 50°C IO for 1 hour. The batch was concentrated and the residue was purified by chromatography (DCM / EtOH 9:1) to give the desired product (153 mg; 0.34 mmol).
-H NMR (400MHz, ch—DMSO, 300K) 5 = 10.62 (s, 1H), 8.81 (s, 1H), 8.55 (br, 1H), 7.96 (br, 1H), 7.43 (hr, 11-1), 7.08 (m, 1H), 6.89 (m, 1H), 5.06 (m, 21-1), 3.87 (5, 31-1), 3.50 (3, 31-1). e 106: (rac)-N-{3,4-Difluoro-5—[(S—methylsulfonimidoyl)methyl]phenyl}(4-fluoro—2—methoxyphemy!)- l.3,S~triuzinamine HN\IO\:©\F Nl/sN o/ 2122*NfiF Trifluorna‘cetic anhydride (0.32 mL; 0.90 mmol) was added under stirring to an ice-cooled suspension of (rac)-[(2,3 -dit1uoro { fluoro-24nethoxyphenyl)-1 ,3 zinyl]amino } benzyl)(1nethyl)oxido- AG-sulfanylidcnc]eyanamide (134 mg; 0.30 mmol) in DCM (13 mL). The batch was stirred for 2 hours at room temperature before it was concentrated in vacuo. The residue was taken up in methanol (2.1 mL) and potassium carbonate (206 mg; 1.49 mmol) was added under stirring at room temperature. After 2 hours the batch was diluted with ethyl acetate and THF. The batch was washed with aqueous sodium chloride on. The organic phase was d using a Whatman filter and concentrated in vacuo. The e was purified by chromatography (DCM / EtOH 9:1) to give the desired product (68 mg; 0.16 mmol). 1H NMR (400MHz, CDCls1 300K) 5 =8.78 (3, 11-1), 8.49 (br, 1H), 8.08 (hr, 1H), 7.69 (br, 11-1), 7.18 (br, 1H), 6.78 (m1 2H), 4.46 (d, 1H), 4.38 (d, 1H), 3.94 (sI 3H), 3.03 (s, 3H).
Examnle 107: (rac)-[Ethy1(3-{ {4-(4-fluoro-2~methoxyphenyl)—1,3.S-triazin—2~yllamino} benzyl)oxido—L‘- sulfanylidenelcyanamide N 0/ \\lag ELAN Prenaration of Intermediate 107.1: l-[(EthylsuIfanyl)methyl]n!trobenzene Intermediate 107.1 was prepared under similar conditions as bed in the preparation of Intermediate 1.1 using 1-(chloromethyl)nitrobenzenc and sodium ethanethiolate.
‘H NMR (400MHz, CDClg, 300K) 6 = 8.19 (m, 1H), 8.11 (m, 1H), 7.67 (m, 1H), 7.49 (m, 1H), 3.80 (s, 2H), 2.45 ((1.2H). 1.25 (11'. 31-1).
Pregaration ofIntermediate 107.2: 3—[(Ethylsuli'anyl)methyllaniline Intermediate 107.2 was prepared under similar conditions as described in the preparation of Intermediate 1.6 using hylsulfanyl)methyl] -3—nitrobenzcne.
"H NMR (400MHz, CD013, 300K) 5 = 7.09 (In, lH), 6.68 (in, 2H), 6.57 (m, 1H), 3.63 (s, 2H), 3.42 (br, 2H), 2.45 (q, 2H), 1.23 (tr, 31-1).
Preparation of Intermediate 107.3: 4—Chlor0—N-{3-[(ethylsuifanyl)methyl]phenyl}-l,3,5-triazin-2—amine \/Sfl1“”/N N C! ediate 107.3 was prepared under similar conditions as described in the preparation ofIntermediate 1.7 using 3- [(cthyisulfanyl)mcthyl]anilinc.
System: Waters Acquity UPLC—MS: Binary Solvent Manager, Sample Manager/Organizer, Column Mana-er, PDA, ELSD. SQD Acquity UPLC BEH C181,? 50x2.1mm A1 = H20 + 0.1% Vol. HCOOH (99%) A2 = H20 + 0.2% Vol. NH3 32% —B1 = Acetonitrile 0-1.6 min 1-99% B, 1.6-2.0 min 99% B 0-8 mUmin 60°C lnjektion: 2.0 p! DAD scan range 210~400 nm -> Peaktable Method: MS ES]+, ESI— Switch A2 + B1 = C:\MassL nxiNH3HMass 100 1000.01p Preparation 01‘ Intermediate 107.4: N-{3-[(Ethyisulfanyl)methyl]plteuyl}(4-fluoro-Z-metlroxyplxenyl)—1,3,5-triazinamine N/§‘N 0/ \/8 ANéKQF Intermediate 107.4 was prepared under similar conditions as described in the preparation of e 42 using crude 4-cltloro—N— {3-[(etliyisulfanyl)mcthyi]phenyl}~1,3,5—triazinamine and (4-fluoro-Z- yphenyl)boronic acid (Aidrich Chemical Company 1110.). The batch was purified by column chromatography (hexane / ethyl acetate 1:1) to give the desired t.
EH NMR (900MHz, CDCls, 300K.) 5 = 8.80 (s, 1H), 7.98 (br, 1H), 7.62 (m, 2H), 7.46 (br, 1H), 7.31 (m, 1H), 7.08 (m, 1H), 6.76 (m, 21-1), 3.93 (s, 3H), 3.73 (5.21-1), 2.46 (q, 2H). 1.23 (tr, 31-1).
Preparation of Intermediate 107.5: [Ethyl(3—{[4-(4-fluoro—2-methoxyphcnylj-l,3,5—triazin—2-yl]amino}bcnzyl—A4-sulfanylidcnel- cyamlmide —'-;Z VS i”::F/ Intermediate 107.5 was prepared under similar conditions as described in the preparation of ediate 105.7 using N— {3 —[(ethylsulfanyl)methy1]phenyl} (4—fluoro-2—methoxyphenyl)-1,3,5-triazinamine.
‘H NMR (400MHz, CDCl:, 300K) 6 = 8.63 (s, 1H), 7.95 (m, 1H), 7.75 (m, 3H). 7.42 (m, 1H), 7.10 (m, 1H), 6.79 (m, 2H), 4.37 (d, 1H), 4.18 (d, 1H), 3.94 (s, 3H), 3.11 (m, 11-1), 2.89011, 1H), 1.43 (tr, 3H).
Preparation ofend product: Example 107 was prepared under r conditions as described in the preparation of Example 105 using (rac)-[elliyl(3— {[4-(4—fluoro-Z—mcthoxyphenyl)- l ,3,5-lTiazinyl]amino} bcnzyl-A4wsulfanylidene]— cyanamide.
"H NMR z, CDCls, 300K) 3 = 8.85 (s, 1H), 7.95 (m, 2H), 7.75 (br, 1H). 7.66 (m. 1H), 7.45 (m, 1H), 7.18 (m, 1H), 6.79 (m, 2H), 4.60 (m, 2H), 3.94 (s, 3H), 3.16 (q, 2H), 1.44 (tr, 3H).
Examgle 108: (rae)-N-{3—[(S—ethylsulfonimidoylmrethyl}phenyl}(4-fluoro—2-methoxyphenyD—l,3,5-triazin amine ~~ 3:1 1% 0, \‘ll e 108 was prepared under similar conditions as described in the preparalion of Example 106 using (rarc)-[ethyl(3- { [4-(4-fluoro-Z-methoxyphenyl)-1 ,3 .5-1riazin-2—y1]amino } benzyl)oxido-7.6-sulfany1- idcuechanamide.
;H NMR (400MHz, CDC13, 300K) 8 = 8.81 (s, 1H), 7.96 (m, 1H), 7.78 (in, 21-1), 7.41 (m, 2H), 7.16 (m, 1H), 6.78 (m, 2H), 4.33 ((1, EH), 4.18 (d, 1H), 3.94 (s, 3H), 3.04 (q, 2H), 1.43 (fr, 3H).
Example 109 and 110: Enantiomers of N-{3—[(Suethylsulfonimidoyl)methyl]phenyl}(4-fluoro-2~methoxyphenyl)-l,3,5- triazin-z-amine (rac)—N-{3-[(S-ethylsulfonimidoyl)methy1]p|1enyl}—4—(4-fluor0metlioxyphenyl)—1,3,5—1riazinamjne was separated into the enantiomers by preparative HPLC: Dionex: Pump P 580, Gilson: Liquid Handler 215, : ektor K-2501 205 mg / 4 9 mL DCM/MeOH 7 x 0.7 ml— -RetentiOn time in min purity in % 17.8 — 19.2 Example Enamiomcr 1 19.2 — 21.6 96.5 Exampie Enamiomer 2 Enautiomcr 1: [1H NMR (400MHz, CDClg, 300K) 6 = 8.8! (s, 1H), 7.96 (m, 1H), 7.78 (m, 2H), 7.41 (m, 2H), 7.16 (m, 1H), 6.78 (m, 2H), 4.33 (d, 1H), 4.13 (d, 1H), 3.94 (s, 3H), 3.04 (q, 28), 1.43 (tr, 3H).
Enamiomer 2: 1[-1 NMR (400MHz, CD013, 300K) 5 = 8.81 (s, 1H), 7.96 (m, 1H), 7.78 (m, 2H), 7.41 (m, 2H), 7.16 (m, 1H), 6.78 (m, 2H), 4.33 (d, 1H), 4.18 (d, 1H), 3.94 (s, 3H), 3.04 (q, 2H), 1.43 (tr, 3H).
Example 111: (rac)—[(3-{[4-(4-FIuoromethoxyphenyl)—I,3,S~lriazinyl]amino}-S~methy1benzyl)(methyl)oxido- Xs-sulfauylidene]cyanamide \\/I I S / / “W:H Preparation of Intermediate 111.1: 3—(ChioromethyI)-S-methylaniline 2 Thionyiehloride (15.3 g; 128.5 mmol) was added dropwise wider stirring to an ice-cooled solution of (3«amino—5~methylphenyl)methanoi (6.3 g; 42.8 mmol; GLSyntech, LLC) in DCM (140 ml). The batch was stirred at room temperature for 18 hours before it was trated in vacuo. The residue was taken up in DCM and concentrated once more in vacuc to give the crude product that was used without further purification.
Preparation of Intermediate 111.2: 3—MethyI—5-[(methylsulfanyl)methyllaniline HQN \ Intermediate 111.2 was prepared under r conditions as described in the preparation oflntcrmediate 1.1 using crude 3-(chloromethyl)1nethylaniline. The batch was purified by chormatography (hexane/ ethyl acetate 6:4). 1H NMR z, ds-DMSO, 300105 = 6.26 (m, 1H), 6.21 (m, 2H), 3.43 (s, 2H), 2.07 (s, 3H), 1.89 (s, 3H).
Preparation ofIntermediate 111.3: 4-Ch10ro-N-{3-methyl-S-[(methylsulfanyl)methyl]phenyl}-1,3,5-trlazInamlne ,3 Ni A intermediate 11 1.3 was prepared under similar conditions as described in the preparation of Intermediate 1.7 using yl{(methylsulfimyl)methyl]aniline. The crude pro du ct was purified by chromatography (hexane/ cetate 2:1) to give the desired product. 2H NMR (400MHz, da—DMSO, 300108 = 10.63 (s, 1H), 8.59 (br, IH). 7.37 (br, 1H), 7.30 (m, 1H), 6.87 (br, 1H), 3.60 (s, 2H), 2.25 (s, 3H), 1.95 (s, 3H).
Preparation of Intermediate 111.4: 4-(4-Flueromethoxyplienyl)-N—{3-methyl[(methylsulfanyl)methyl]phenyl}~1,3,5-triazin amine NAN 0’ /8 NJLN//K[:LH Intermediate 111.4 was prepared under similar conditions as described in the preparation of Example 42 using 4-ehloro-N- hyl-5—[(methylsulfanyl)methyl]phenyl}-l.3,S—triazin-2~amine and (4-fluoro methoxyphenyl)boronie acid (Aldrich Chemical Company Inc). The batch was purified by chromatography (hexane/ ethyi acetate 1:1) to give the desired product. 1H NMR z, ds-DMSO, 300K) 5 = 10.17 (s, 1H), 8.75 (s, 1H), 7.78 (br, 1H), 7.52 (111, 2H), 7.05 (m, 1H), 6.87 (m, 1H), 6.79 (m, 1H), 3.84 (5, 31—1), 3.59 (s, 2H), 2.25 (s, 3H), 1.93 (s, 3H). ation of Intermediate 111.5: (me)—[(3-{[4-(4-F]u0r0-2~methoxyphenyl)—l,3,S-triazinyl[amino}-5—methyibenzyl](methyl)—?J‘- sulfanylidenelcyanamidc Z Z (I) >=2; \ :2 Intermediate 111.5 was prepared under simiiar conditions as described in the preparation of Example [05.7 using 4-(4-fluoromcthoxyphenyl)-N-{3-mcrhyl[(mcthylsulfanyl)methy1]phenyl}«1,3,5- triazin-Z-aminc. The batch was purified by preparative H'PLC.
System. Waters Autopuriflcationsystem: Pump 2545, Sample r 2767, CFO, DAD 2996, ELSE) 2424, SQD 3001 XBrigde C18 5pm 100x30 mm A: H20 + 0.1% HCOOH _B=Acetonitrile 0—1 min 1% B. 1—8 min 1-99% B, 8-10 min 99% B 50 mL’min Max. 250 mg I max. 2.5 mL DMSO 0. DMF lnjekfion_ DAD scan range 210—400 nm —MSESI+, ESi-, scan range 1604000 m/z 1H NMR (400MHz, de-DMSO, 300K) 5 = 10.32 (s, 1H), 8.77 (s, 1H), 7.68 (m, 3H), 7.07 (m, 1H), 6.87 (m, 21-1), 4.39 (d, 1H), 4.20 (d, m), 3.34 (s, 3H), 2.31 (5, 31-1), 2.29 (s, 3H).
Preparation of end product: Example 111 was prepared under similar conditions as described in the preparation of e 105 using (rac)—[(3- {[4—(4-fiuoro—Z-mcthoxyphenyl)~1,3,5-triazin—2-yi]amino}—5-methy]benzy1)(methyl)-k‘- sulfanylidenekyanamide The batch was purified by preparative HPLC.
System Waters Autopurificationsystem: Pump 2545, Sample Manager 2767, CFO, DAD 2996, ELSD 2424, SQD 3001 XBride C18 5pm 100x30 mm A = H20 + 0.1% HCOOH _B=Acetonitrile 0—1 min 1% B, 1-8 min 1—99% B. 8-10 min 99% 8 Max. 250 m I max. 2.5 mL DMSO 0. DMF 1 x 2.5 m1.
DAD scan range 210—400 nm MS ESE+, ES|-. scan range 160-1000 m/z ”H NMR z, da-DMSO, 300K) 5 = 10.34 (8, 1H), 8.77 (S, 1H), 7.76 (br, 2H), 7.62 (m, 1H), 7.07 (m, 1H). 6.96 (m, 1H), 6.87 (In, 1H), 4.8901), 2H), 3.83 (8, 3H), 3.34 (s, 3H), 2.30 (S. 3H).
Example 112: 2-({5-Fluoro[4-({3-[(S-methylsulfonimidoyl)methyl]phenyl}amlno)-1.3,5-Iriazin yllphenoxy}methyl)propenol HN o NAN O / A / N N Example 112 was prepared under similar conditions as described in the preparation of Example 65 using (rac)-ethy1 [(3— { [4-(2,4-dif1uorophenyl)-1,3,5-triazin—2~yl]amino}benzyl)(meth_vi)oxido-Zfi—sulfanyl- idenelcarbamate and 2—methy1idenepropane-1,3~di01 (Aldrich Chemical Company Inc.).
System: Waters Autopurificationsystem: Pump 254. Sample Manager 2767, CFO, DAD 2996. ELSD 2424, SQD 3100 Column: XBrigde C18 5pm 100x80 mm Solvent: A = H20 + 02% Vol. NH: (32%) -B = Acetonitrile 0-8 min 20-30% B 40 mg I 1.5 mL DMSOlMeOH 1:1 Injektion: UAD scan range 210-400 nm —S ES|+, ESI-, scan range 160-1000 mlz _LSD "H NMR (400MHz, CDCLa, 300K) 6 = 8.77 (s, 1H), 8.53 (br, 1H), 8.36 (br, 1H), 7.81 (s, 1H), 7.64 (m, 11-1), 7.42 (m, 1H), 7.18 (m 1H), 6.83 (m, 1H), 6.76 (m, 1H), 5.29 (m, 2H), 4.78 (s, 2H), 4.40 (m, 3H), 4.28 (m, 1H), 2.97 (s, 3H).
Examnle 113: (rac)-{Cyclopropyl(3~{[4-(4-fluoromethoxyphenyl)-l,3,5-triazin-2~yl}amino}benzyl)oxido-?t6- sulfanylidenelcyanamide “Ii/Q A , N NI N o ,3 fixNKE: Pro n of Intermediate 113.1: l-[(Cyclopropylsulfanyl)methyllnitrobenzene I- \7 Sulfur (3.63 g; 25.0 mmol) was added nswise to a stirred 0.5 M solution of bromo(cyelopropylhnagnesium in THF (50.0 mi; 25.0 mmol). The batch was stirred at 50°C for 1 hour and then cooled to 0°C. Lithium tctrahydridoaluminatc(l-) (522 mg; 13.8 mmol) was cautiously added under stirring. The batch was stirred for 30 s at 50°C and cooled to 0°C again. Water (2 ml) was cautiously added under stirring. Finally, sulfuric acid (5%; 100 ml) was cautiously added and the batch was stilred for 10 minutes. The organic phase was separated and the aqueous phase was extracted with diethyl ether (2x). The combined c phases were washed with saturated aqueous ammonium chloride solution (2x), aqueous sodium bicarbonate solution (5%, 2x), water (2x) and ted aqueous sodium chloride solution (2x). The organic phase was dried (NazSOa) and filtered before it was slowly added to a stirred batch of 1—(_chloromethyl)—3-nitrobenzene (2.15 g; 12.5 mmol) and potassium carbonate (2.59 g; 18.8 nnnol) in DMF (40 ml). The batch was stirred at 85°C over night. After cooling, the batch was d over celite and concentrated in vacuo. The residue was taken up in ethyl acetate and washed with water (2x) and saturated aqueous sodium chloride solution (2x). The organic phase was dried (NHZSOA), filtered and concentrated. The residue was purified by chromatography (hexane / ethyl acetate 8:2) to give the desired product (2.38 g; 11.4 mmol).
‘H NMR (400MHz, (ls-DMSO, 300K) 6 = 8.16 (m, 1H), 8.06 (m, 1H), 7.75 (m, 1H), 7.56 (m, 1H), 3.90 (s, 2H), 1.72 (m, 1H), 0.77 (in, 2H), 0.39 (m, 2H).
Preparation of Intermediate 113.2: 3-[{Cyclopropylsulfanyl)methyl] aniline Hug/SW2 intermediate 1 13.2 was prepared under similar canditions as described in the preparation of intermediate 1.6 using 1—[(eyelopropylsu1fanyl)methyl]~3-nitrobcnzcnc. The batch was purified by chromatography. iH NMR (400MHz, da—DMSO, 300K) 8 = 6.89 (m, 1H), 6.49 (m, 1H), 6.38 (m, 2H), 4.96 (s, 2H), 3.56 (s, 2H), 1.75 (m, 1H), 0.78 (m, 2H), 0.42 (m, 2H).
Preparation 01‘ Intermediate 113.3: 4-Cliloro-N~{3-[(cyclopropylsulfanyl)methyl]phe11y]}—1,3,5—triazin-2—amine Intermediate 113.3 was prepared under similar conditions as bed in the preparation of intermediate [.7 using elopropylsulfanyl)methyl]aniiine. The crude product was d by chromatography (hexane / cetate 4:1) to give the desired product.
"H NMR (400MHz, da-DMSO, 300K) 5 = 10.69 (s, 1H), 8.59 (br, 1H), 7.59 (br, 1H), 7.48 (m, 1H), 7.27 (m, 1H), 7.05 (m. 1H), 3.72 (s, 21-1), 1.76 (m, 1H). 0.80 (m. 21-1), 0.44 (m. 2H).
Pre aration ofIntermediate 113.4: N-{3-[(Cyclopropylsulfanyl)methyl]phenyl}(4-fluoro-Z-mcthoxyphenyl)-l,3,5-triazin-2—aminc Intermediate 113.4 was prepared under similar conditions as described in the preparation of e 42 using 4-chloro-N-{3—[(eyeiopropylsulfanyl)melhyl]phenyl}—1,3,5-lr1a2in—2—amine a n d oro methoxyphenyl)boronic acid (Aldrich Chemical Company Inc). The batch was purified by chromatography (hexane/ ethyl acetate 2:1) to give the desired product.
‘-H NMR (400MHz, dé-DMSO, 300K) 3 = 10.24 (s, 1H), 8.75 (s, 1H), 7.75 (m, 3H), 7.25 (m, 1H), 7.07 (m, 1H), 6.99 (in, 1H), 6.86 (in, 1H), 3.84 (s, 3H), 3.72 (s, 2H), 1.74 (m, 1H), 0.75 (m, 2H), 0.42 (m, 2H).
Pregaration of ediate 113.5: (rac)~ [(34 [4-(4~Fluoromethoxyphenyl)-l,3,5-triazin-2~yllamino}methylbenzyl)(methyl)—7t4- sulfanylidenekyanamide ‘2l\/©\ NlAN 0/ :78 NJ\N/)\©\H F Intermediate 1 13.5 was prepared under similar conditions as described in the ation of Example 105.7 using N-{3-[(cyclopropylsulfanyl)methyl]phenyl}(4-fluoro-Z-1nethoxyphenyl)-1.3,5-triazin—2~ amine. The batch was purified by chromatography (ethyl acetate / methanol 9:1).
‘H NMR (400MHz, dg-DMSO, 300K) 5 = 10.38 (s, 1H), 8.78 (s, 1H), 7.63 (m, 3H), 7.37 (m, 1H), 7.14 (m, EH), 7.06 (m 1H), 6.88 (m, 1H), 4.53 (d, 1H), 4.38 (d, 11-1), 3.85 (s, 3H), 2.70 (m, 1H), 1.07 (m, 3H), 0.84 (m, 1H).
Preparation of end product: Example 1 13 was prepared under similar conditions as described in the preparation of Example 105 using (rad-[(3-{{4-(4-fluoromethoxyphenyl)-l,3,5-triazinyl]amino}methylbenzyl)(methyl)-?.“- sulfanylidenekyanamide The batch was purified by chromatography (gradient: ethyl acetate / hexanes 4 : 1 —> ethyl acetate).
‘H NMR z, (lo-DMSO, 300K) 8 = 10.44 (s, 1H), 8.8] (s, 11-1), 7.93 (m, 3H), 7.43 (m, 1H), 7.20 (m, 1H), 7.10 (m, 1H), 6.91 (m, 11-1), 5.01 (m, 2H), 3.88 (br, 3H), 2.97 (m, 1H), 1.18 (m, 3H), 0.90 (m, 1H).
The following Table 1 provides an overview on the nds of the invention: Table 1 Compound I (rac)-E1hyl [(3- { [4-(4-flu ore methoxyphenyl)—1 riazin~2~ no} benzyl)(methyl)0xido- R6- ylidene}carbamate (rac)—4-(4~Fluoromcthoxyphcnyl)- N— {3-[(S- methylsuIfonimidoyl)mcthyl]phcny1}— 1 ,3,5-triazin-2~amine (-)(4-Fluoro~2-mcthoxyphcnyl)-N- {3-[(S— methylsuifonimidoyl)methy1]phcnyl} ~ 1,3,5-u'iazinamine; enantiomer 1 (+)(4-Fluoro-Z-mcthoxyphcnyl)—N~ {3-[(5' methylsulfonimidoyl)mcthyl]phcnyl}~ 1,3,S-triazin-Z-aminc; enamiomcr 2 (rac)—Ethyi {[3—( {4—[2-(bcnzyloxy) fluoro;)hcny1}-} ,3 5 -triazin yi}amino)bcnzyl](1ncthyl)oxido-?vfi- suifhnylidcnckarbamatc (rac)-4—[2-(Bcnzyloxy)-4— fluorophenyl}-N— {3 -[(S~ methylsulfonimidoyl)mcthy1]phcny1}- 1,3,5—t1'iazin—2-aminc (-)[2-(Ben2yloxyj—4-fluorophenyl]- N- { 3-[(S- methylsulfonimidoylhnethyl]pheny]}— 1,3,5-triazinamine; enamiorner ] [2-(Bcnzyloxy)-4— fluorophcnyH-N- { 3 -[(S - methylsu lf‘om' midoyl )methyl]phcnyl} - 1.3,S-triazin-Z-aminc; cnantionmr 2 (rac)—Ethyl [(3- {[4-(4,5-difluoro mcthoxyphcnyIH ,3,5-rriazin yl] amino} benzyl) (methyl)0xid 0-7..“— sulf‘myiidene]ca1'bamaie l (rac)- 4-(4,5-Difluoro-2~ methoxyphenyl)-N— {3 - [(5- methylsulfouimidoyl)mcthyl]phony]} - 1,3,5—tria7in—2-aminc 11‘— (raw-Ethyl [(3~ vchloro mothoxyphcnyl)-1 ,3,5-triazin yl]arnino} benzyl)[methyDoxidoJf— sulfanyiidene]carbamate (rac) 4-(4-ChloroQ-mcthoxyphcnyU— 12 N« { 3-L(3- methylsulfonimidoyl)mcthyl]phcnyl} 1 1,3,5-triazin-2—amine 4-(4-Chloromethoxyphenyl)-N- {3- 13 {($- su1fonimidoyl)mcthyl]phenyl} 1,3,5—triazin-2uamine; enautiomer l I 4-(4-Chloro1nethoxyphenyl)-N~ {3- {(5- methykulfonimidoyl)methy1]pheny1} 1,3,5-triazinaminc; enantiomer 2 (rac)[(3- { [4-(4-Fluoro methoxyphenyl)-1 ,3,5—triazin~2 - yl] amino} bcnzyl)(mcthyi)oxide-M- sulfanylidcne]mcthylurea (-)[(3-{[4-(4-FIuoro methoxyphcnyl)-] ,3,5-triazin no}benzyl)(methyl)oxido—l6— sulfanylidenc]~3-methylurea; cnantiomcr 1 (+)—1-[(3- {[4-(4-F1uoro—2- methoxyphcnyi)-] ,3,5-triazin y1]amino}bcnzyl)(methyl)oxid0—2.6— ylidene]methylurea; cnantiomer 2 (rac)-Ethyl [(3-{[4-(2,2~difluoro-1,3— benzodioxolyl)v1,3,5-Iriazin—2- yl]amino}bcnzyl)(mcthyl)oxi(in—k“- ytidcnekarbamatc l (rac)-4—(2,2-Difluoro- 1 ,3- bcnzodioxolyl)—N— {3-[(S- methylsulfonimidoyl)mcthy1]phcnyl} - i ,3,5-triazin—2—amine (rac)-Ethyl [(3~{{4-(5-fluoro methoxyphenyl)-1‘3,5wtriazin—2- yl]amino} benzyl)(methyl)0xidu—9 ‘— sulfanylidenekarbamate (rac)—4—(5-FluoromethoxyphenyI)- 21 N- {3-[(S— methylsuIfonimidoyl)methyllphcnyl} - 1,3.5-triazin—2-aminc 4-(S-Fluuro~2—mclhoxyphenyl)-N— { 3- 22 {($- sulfonimidoyl)methyl]phenyl} - 1,3,5-triazinamine; enantiomer 1 4-(5-Fluoro~2-methoxyphenyl)-N— {3~ 23 [(S- sulf‘onimidoyl)mcthyl]phcnyl}- 1,3,5—triazinaminc; cnantiomcr 2 (ruc)-N-[(3- {[4—(4-fluoro-2— 24 yphenyl)-1,3,5—triazin—2- yl]amino}benzyl)(methyk)oxido-l‘t sulfanylidcnc]acctamidc thyl [(3- { [4-(2- methoxyphenyl)-1,3,5-triazin—2- yljamino} benzyl)(methyl)oxide-9.6— sulfanylidenekarbamate (rac)—4-(2-Methoxypheuyl)-N- {3 {($- 26 methylsulfonimidoyIJmethyl]phenyl} - 1 ,3,5-triazin—2~amine 4-(2-Mcthoxyphcnyl)—N— {3—{(S- 27 mcthylsulfonimidoyl)methyl]phcnyI} - 1,3,5-lriazinaminc; cnantiomer 1 4-(2-McthoxyplmnyD-N- {3 — [(S - 28 mothylsulfonimidoyl)mcthyl}phcnyl} ~ 1,3,5-triazinaminc; cnantiomer 2 (rac)-Ethyl [(3~ {[4—(3,4—dihydro-2H— 29 chromenyl)-l ,3 ,5—triazin—2— y1]amino} benzy1)(methyl)oxide-k"— suifidnylidcnc]carbamatc (rac)(3,4-Dihydro-2H-chromen yl)-N-{3-[(S- methylsulfonimidoyl)methyl]phcnyl} - 1,3,5-triazinaminc 4-(3,4-Dihydro-2H-chromenyI)-N— 3 {Ya-{(3- methylsulfonimidoyl)methyUphenyl}- 1,3,5-triazinamine; enantiomer I 4~(3,4-Dihydro-2H-chromcn-8—yl)—N— {3-[(S- 111ethylsulfouimidoy1)methyl}phcnyl} - 1,3.5-friazinaminc; enantiomer 2 (1'ac)-E1hyl [(3- {{4-(2,3—dihydro-] - benzufuranyl)-I,3,5-triazin—2- yi]amino}benzyl)(methyl)oxido-?f— suifanylidcnc]carbamatc (rac)(2,3 ~Dihydrobcnzo furan 34 y1)~N- {3-[(5- methylsulfonimidoyl)mcthyl]phcnyl}~ 1 ,3,5-triazinaminc 4-(2,3-Dihydro-l-bcnzofi1ranyl)- N-{3-[(S- sulfonimidomecthyl]pl1cuyl}- 1,3,5-triazinaminc; enantiomer 1 4-(2,3-Dihydmb enzofi1ran—7-yl)— 36 Nw {3—[(S— methyisu lfonimi duyl)mclhy[}phcnyl} — 1,3,5-triazinaminc; mer 2 (ruc)-Ethyl [(3- {[4-(2.3-dihydru-I ‘4- benzodioxin-S-yl)~1,3,5-triazin—2- yl]amino} bcnzyl)(methyl)oxido-?v°- sulfanyfidcnc]carbamatc (rac)(2,3 -Dihydro—l ,4- bcnzodioxin—S-yl)-N- {3 {(8- suIfonimidoyl)methyl]pheny1}- 1,3 ,S-lriazin-Z-amine 4-(2,3—Dihydro-l ,4-bcnzodioxin—5— yl)-N-{3-[(S- methylsulfonimidomecthyl1pheny}}— 1,3,5-triazin—2—amine; cnantiomer l -Dihydro~1,4-benzodioxin—5- YD-N- {3-E(S- sulfonimidoy1)methy1]phenyl} - 1,3,5-triazinamine; enautiomer 2 N-{3-[O‘I,S~ Dimethylsulfonimidoyl)methyl]pheny l}~4-(4-fluoro-2—me£hoxypheny1)- 1,3 ,S—triazin-Z—aminc l\To (rac)—Ethyl [{3—[(4-{2—[(4— fluorobenzyl)oxy]phenyl}—1,3,5— triazin-Z— yl)amino}benzyt} (methyl)oxido-?f— sulfanylidene]carbamatc (rac)-4— {2—[(4- 43 Fluorobcnzyl)oxy]phony! } -N- {Ii-[(3— lncthylsulfonimidoyl)mclhyl]phcnyl} - 1 ,3,5—triazinamine (rac)-N-[(3- {[4—(4-Fiuoro—2- mothexyphcnyD-l ,3,5—triazin yl]arnino}bcnzyl)(methyl)oxido—?~6- suifanylidenc]methancsulfonamide (rac)-Ethyl [(3- {{4-(3-chloro 45 Inctlloxyphenyl)—1 13,5—triazin yl]aminu}benzyl)(methyl)oxido-?.°— sulfanylidenelcarbamate (rac)-Bthyl {[3-( {4—[5-fluoro hydro-ZH-pyran y] meth()xy)phenyl}- 1 ,3,S-triazin yl} amino)bcnzyl] (mathyl) oxide—7f— sulfanylidene}carbamate (raw-Ethyl [methyl(0xido)(3- {[4-(2- 47 yphenyl)—1 ,3 azin yl] amino } barman-96‘— ylidcne]carbamate (rac)-{(3- {[4-(4~fluoro 48 methoxyphcnyl)-i ,3,5-triazin—2- yl]amino} benzy1)(methyl)0xido-?~d— yiidenekyanamide [(3- {[4-(4~fluoro—2~me hcny1)- 1,3,5-triazin yl]amino} benzyl)(methyl)oxido—?.°~ ‘ sulfanylidcnckyanamidc; cnantiomcr [(3-{[4-(4vfiuoro-2~methoxyphe11y})- 1.3,5-1‘1‘iaziu—2— yl]amino} benzyl)(methyl)oxidu- u“— sulfanylidene]cyanamidc; enantiomer (rac)-Ethy1 [(3-fluoro {[4-(4-fluor0- 51 2-methoxyphenyl)- 1.3.5—triazin—2— no} benzyl)(methyl)oxide-7f- sulfanylidenekarbumate (rac)(4—Fluoromethoxyphcnyi)- 52 N- {3-fluoro-5—[(S— methylsulfonimidoyihnethyl]phenyl} - 1,3,5—t1‘iazin—2-aminc 4-(4—F1uoro—2—mcthoxyphcnyD—N— {3 - 53 fluoro-S-[(S- methylsuIfonimidoyl)methyl}phenyl} - 1,3,5-triazin-2—aminc; enantiomer 1 4—(4-Fluoremcthoxyphcny1)-N~{3- fluoro-S-[(S- methylsuifonimidoyl)methyl]phenyl}- 1,3,5-triazin—2-amine; enamiomer 2 4-[2-(Cyclohexylmethoxy) fluorophenyl]-N— - methylsulfonimidoy1)methyl]phenyl} - 1 ,3 ,S-n‘iazin-Z-aminc (rac)—4— oro[(4- 56 fluorobenzyi)oxy]pheny1} ~N‘ {3418‘ methylsulfonimidoyl)mcthyljphcnyl}- 1.3,5-triazinaminc 4- {4-F‘Iuoro[(4- fluorobenzyl)oxy1phenyl} -N- {3-[(S- 56-a methylsulfonimidoyl)methyl]phenyl}- 1,3,5-triazin-2—aminc; cnantiomcr 1 4«{4-Fluor0[(4- fluorobenzy1)oxy]pheny1}-N- {3 - [(S » 56.1) methylsulfonimidomeethyl]phenyl}- 1,3,5-triazinamine: enantiomer 2 , (rac)—4—{4-Fluoro[2-(tctrahydro- 2H-pyrauyl)clhoxflphcnyl}-N-{3- 57 [(S- methylsuifonimidoyl)mcthyi]phenyl} — 1 ,3,5-triazinaminc (rac)(4-Fluoro—2~mcthoxyphcnyl)- N-(3 - { [S—(tctrahydro-2H-pyran—4- yl)sulfonimidoyl] methy! } phenyl} 1,3,5—triazin-2—amine (rac)-N— {4-Chlor0-3~{(S- 59 mothylsulfonimidoyl)mcthyUphcnyl}— 4-(4-f1uoromcthoxyphcnyl)- l ,3 ,5- triazin-Z-amine N- {4-Chlor0-3— [(S— methylsulfonimidoy1)mcthy1]phcny]} - 4—(4-fluom-2~metl1oxyphcnyl)— 1 ,3,5- n-Z-amiuc; cnantiomcr 1 hloro[(S- methylsulfonirnidoyl)mcthyl]phenyl}- 4-(4-fluoro—2~1nethoxyphenyl)-1 ,3,5- tn'azin-Z-amine; enantiomer 2 (rac)-Ethyl {{3-{(4 -{2’[(3,4- dichlorobenzyl)oxy]phenyl} -1,3,$- triazin-Z- yl)amino]benzyl} l)oxido-?~6- yiidenejcarbamatc (rac){2~[(3’4- Dichlorobenzyl)oxy]phenyI} -N- {3- [(S~ methylsu lfonimid oyl)mcfhyl]phenyl} - 1,3 ,S-triazin-Z—aminc (rac)(4-FEuoro {[(3H5]phenyl(3H2)methyl]oxy} pheny l)-N-{3-[(S- methylsuEfonimidoy1)mcthyl]phcnyl} — 1,3,5-triazin-2aminc 4-[2-(1vcyclopcntylcthoxyytt- flu orophenyII-N- {3-[(S- methylsuifonimidoyl)mct hyl] p henyl} - 1,3.5—triazinamine. mixture of all 4 stereoisomcrs (rac)—N - {3-Chloro[(S- mothylsulf‘onimidoyIJmclhyl]phcny]} - 4-(4—fluoro—2—1ncthoxyp henyl)~1 ,3 ,5- triazin-Z-aminc (rac)—4-[4—Fluoro(3,3,3~ 6S trifluoropropoxyh)henyl]—N— {IS-[(5- mcthylsu lfouimidomecthyl]phcnyl} ~ l,3,5-triazin~2-aminc (rac)[4-F1uor0—2—(pyridin 66 ylmethoxy)phenyl}-N- { 3-[(S- methyisulfoni1nidoyl)methyl]phenyl} - triazin—2—aminc (rac)[4—F1uoro(pyridin-Z- 6 7 ylmethoxy)phenyl]—N— {3-[(S- methylsu id oyl)mcthyl]pheny1}— 1,3,5-u'iazinaminc (rac){4-F1uoro(pyridin 68 ylmcthoxy)phcnyi]-N- {3-[(S- mcthylsulfbnimidoyl)mcthy1]pllcnyl} w 1,3,5—triazin—2-aminc 4-{4-Fluoro[1-(4— fluorophcnyDcthoxy]phcnyl} -N- {3 - (i9 KS“ methylsuifonimidoylhnct11yl]p 11cnyI} - 1.3,5-t1'iazinaminc. mixture of 4 stereoisomers [(3~Fluoro—5—{[4-(4-fiuoro 70 methoxyphenyl)-1 ,3 ,S-m'azin-Z- yl]amino} benzyl)(methyl-k°~ suI.fany1idcnc]cyanamidc {(3-Fluoro-S— { [4-(4- fluoro—Z— mcthoxyphcnyl)-1 ,3,5-tfiazin yl] amino} benzyl)(methyl-}»6- sulfanyiidene]cyanamide; enantiomer [(3—FIuor0—5- { fluoro methoxyphenyl)~l ,3 ,5- triazin-Q- yl]amino} benzyl) (methyl-N'- sulf‘anylidene]cyanamide; enantiomer (rac)-4~[2-(But—2—yn- l—yloxy)—4— 73 fluorophcnyI}-N— {3—315- methylsulfonimidoy})mcthyl}phcnyl} - I ,3,5«triazin—2—aminc But~2~yn-1~onxy) fluorophenyl]-N- {3-[('S- sulfonimidoyl)mcthyl]phcnyl} - 1,3,5—triazinaminc; cnantiomer l Butyn- 1-onxy) 75 fluorophenyl]—N- {IS-[($— methylsu1fonimidoy1)methyl]phenyl} - 1,3,5—triazinamine; enantiomer 2 4—[2-(2-Cyclopropylcthoxy) 76 fluorophcnle-N- {3~[(S— methylsulfonimidoyl)mcthyl]phenyl} — 1 ,3,5~triazin—2—aminc (ruc)—4—[4-Fluoro(prop—2—yn—lyioxy )phcnyl]-N- {3-[(S- methylsulfonimidoyl)mclhyl]phenyl}- 1 ,3,5-triazinaminc 4-[4-Fluoro(propyn-l - phenyI]-N- {ES-{($- methylsuIfonimidoyl)merhyl]phenyl} — 1,3,5-t1'iazinaminc; cnantiomcr 1 4-[4-F]uoro(propyn yloxy)phcnyl]-N- {3-[(S- mothylsulfonimidoyl)mcthyl]phenyl}- 1,3,5-t1‘iazinaminc; cnantiomer 2 n (rac) {2-[(3 ,4-Diflu orobcnzy1)oxy]- 4-fluorophcnyl}-N- {3-[(S- methylsulfonimidoyl)methyl}phenyl} - 1.3,5—triazin-2—amine (rac)[4~Fluoro—2—(1 ,3—thiazol ylmcthoxy)phcnyl]-N- {BE-[(8- methylsulfonimidoyt)methyl}phcny1}- 1,3,5-triazin—2-a1uine (rac)-4— {4-FIuor0-2—[(2- fluoropyridin- 4—y})methoxy]phenyl} -N~ {3-[(S— methylsuIfonimidoy1)methyl]phenyl}— 1,3,5-triazinamine 4~ {4~Fluoro{(Z-t‘iuoropyridin yl)methoxy]pher1y1} -N— {3-[(S- methylsu1f0ni111idoyl)mcthyl]p henyl} — 1,3,5-t1'iazin~2-aminc; enantimner l l 4- {4-Fluoro-2—[(2—fluoropyridin-4— yl)tnethoxyjphenyl} -N- {3»[(S— sulfonimidoyl)mcthyl}phcnyl}~ 1,3,5—triazin—2-amin0: cnantiomer 2 Structure Nomenclature (rac)-4—[4-F1uoro—2-(propen—l - 85 yloxy)phenyl]—N- {3- [(S- sulfonimidoyl)mcthyl]phcny1} - 1,3 ,S-triazin-LZ-aminc (rac)(4 —FIuoro { [4— (Irifluuromethyl)benzyl]oxy}phenyl)- N— {3-[CS- methylsu1fonimidoyl)methyl]phenyl} — 1 ,3,S-triazinaminc ( rac) {2-[(4~Chlorob enzyl)oxy] 87 fluorophenyl} -N— {3-[(S- methylsulfonimiduyl)mcthyl]phcnyl} - triazin—2—aminc (rac)~4—(2-Ethoxy—4—fluorophenyl)-N— {3-[(S- methylsu1fonimidoyl)methy[]pllcnyl} - 1,3,5-triazin~2-amine (rac)(4-Fluoro-2— {[3—fluoro (trifluoromethyi)bcnzyljoxy}phenyl)- N- {3—[(S~ methylsulfonimidoyIJmcthyI3phcny1}- 1,3,5-triazin-2—aminc 4—{4-FIuoro{(3- fluorobcuzy1)oxy]phcny[} -N- {3-[(S- methylsulf‘onimidoyl)mcthyl}p11eny1}- 1,3,5-triazin»2-amine (rac)(4-Fluoro~2-propoxyphcnyl)- 91 N- {3-[(S- methylsulfonimidoy1)mcthyl]phcny1}~ 1 ,3,5—triazin«2—aminc (rac)—4— {2-[(3-Chlorobenzyl)oxy]-4— 92 fluorophcnyI}-N- {3- [(S- methylsulfonimidoyl)mcthyi]phcnyl} - 1 ,3 azi11—2—aminc (rac)-4~[4—FEuoro(1,2-oxazol 93 ylmethoxy)pheny1}-N— {3-[(S - methylsulfonimidoyl)methyl]phenyl} — 1,3,5-triazinaminc (rac) {2-[(3-Chlor0 fluorobenzyl)oxy] flu nyl} - N- {34(8- methylsulfouimidoyl)methy1]pheny1}- 1,3,5-triazin-Z-amine (rac)[2-(2,2-Difluoroethoxy) ~4- 9S t1uorop11¢ny11-N-{3-[(S - methylsulfonimidoyIJmethy1]pheny}} - 1,3,5—triazin—2-amine (rac)—4—{4-Fluoro[(4-fluoro methylbenzyl)oxy]phenyl} —N- {3—[(S- mcthyIsulfonimidoyl)mcthyl]phcnyl}— 1,3.5-triazinaminc (rac)—4- {2-[(3-Ch]oro—4- fluorobenzyi)oxy]fiuuruphenyl} - N- {3-[(S- methyisulfonimidoyl)methyl]phenyl} - 1 ,3,5—triazinaminc (rac)({5-Fluoro—2-[4-({3-[(S- methylsulfonimidoyl)mcthy1]phonyl} amino)-1,3,5-triazin yl]phcnoxy} )bcnzonitri Ec (rac)—4—{4—Fluoro[(2-methyiprop~ Z-cnyl)oxy]phcnyl} ~N~ {3- [(S- mcthylsu lfonimidoyl)mcthyl]phonyl} - I,3,5vtriazinaminc (rac)[4~Fluoro-2—(4,4,4- trifluorobutoxymhcnyl]-Nv — methylsu idoylkncthyl]phcnyl} - l ,3,5-triazin—2-ami11c (rac)<4- {4-Fluom[(2,3,5- trifluorobenzyl)oxy]phenyl}-N- {3- [(S- mcthylsulfonimidoylfincthyl}p11eny1}- 1,3,5-lriazinaminc (rac) Z)-Buten-l -yloxy} fluorophenyl} ~N- {3—{(S- sulfonimidoy])mcthyl]phcny1}- 1,3,5-triazinaminc (rac)~4-{4-Flttor0-2~{(2,4,5- trifluorobenzyl)oxy]phenyl } -N- {3 - [(S- mcthylsuifonimidoy})mcthyl]phcnyl} - 1,3 ,5-triazin~2~aminc (rac)—4— {4-Fluoro[(3,4,5- trifluorobcnzykmxy]phenyl}-N—{3- [(S- methylsu1fonimidoyl)mcthyl]phcny1}- 1,3,5-triazinaminc (rac)«[(2,3-Difluoro { [4-(4-flu oro- 2~methoxyphenyl)-1 ,3,5-triazin yl]amino}benzy1)(methyl)oxido-9.‘- sulfanylidenekyanamide (rac)-N-{3.4-Difluoro‘5—[(S- 106 methylsulfonimidomeethyl]phenyl} — 4-(4—fluoro1nethoxyphenyl)—1 ,3.5~ triazin-Z-nmine (rac)-{Ethy1(3-{[4-(4~fluoro methoxyphenyl)-1 .3 ,S-Iriazin-Z- yl]amino}benzyl)oxido-?.°— sulfanyiidcnckyanamidc (rac)—N- {3 {(S- ethylsulfonimidoyl)1ncthyl]phcnyl} - 4-(4-fluoromcthoxyp -1 ,3,5— triazin-Z-aminc N - {3-[(S- 109 cthylsulfonimidoyl)mcthy[]phcnyl} - 4-(4-fluoromcthoxyphcnylj—1 ,3,5- n-Z-aminc; cnantiomcr l N- {3-[(_S- ethylsulfonimidoy1)methyi]phenyl}- 4 ~(4-fluoromethoxyphenyl)- 1 ,3,5- triazin-Z-amine; enantiomer 2 (rac)-[(3- {[4-(4-FIuoro—2— methoxyphenyl)- I ,3 ,5-triazin yl]amino}~5~ mothylbcnzlemmhyl)oxido-K6- sulfauylidcnc]cyanamidc 2—( {5—Pluoro—2—{4-( {3—[(S- sulfbnimidomecthy]]phcny]} amino)—1,3,5—triazin yl]phcnoxy} methyl)prop cn-] -ol (rac)-[Cyclopropyi(3- { [4-(4- Hume—2- methoxyphenyl)—] ,3,5-triazin yl] amino} benzyl)0xido-A6- sulfanylidenekyanamidc ReSults: Table 2: Inhibition of CDK9 and CDKZ of ceinpounds according to the present invention The ICso (inhibitory concentration at 50% of maximal effect) values arc indicated in nM or “M, “m." means that the compounds have not been tested in this assay.
(D: Compound Number 0): CDK9 CDK9/CyoT] kinase assay as bed under Method 1. of Materials and Methods (3): CDKZ CDKZ/Cch kinase assay as described under Method 2. of Materials and s 1 rac)-Ethyl [(3- {[4—(4—f1uoromethoxyphcnyi)- I ,3,S-triazin 16 nM 2200 nM ; l]amino}bcnzyl)(methyl)oxido~?.6~su]fattylidcncjcarbamate ’rac)-4—(4-Fluoromethoxyphcnyl)-N- {3-[(S- 25 nM 2100 nM methylsulfonimidoyIJnicthyl]phenyl } ~ I ,3,5-triazinaminc -)(4-Eluoro-Z—methoxyphenyl)-N- {3-[(S— methylsulfonimidoyl)methyl]phenyl} - I ,3 ,5-tn'azinaminc; 16 nM 1700 IN nantiomer 1 +)(4-F1uoromethoxyphenyl)-N-{3-[(S- mcthytsulf‘onimidoyl)mcthyl]phcnyI} -l ,3 ,S-triazin~2-aminc; 13nM nantiomer 2 Ethyl {[3-( {4-[2—(bcnzyloxy)fluorophcnle-l ,3,5-triazin L l}amino)benzy13(1netliyl)oxido- fanylidcne}carbamate enzyloxy)-4«fluorophenyl]-N- {3-[(S— nethylsu lfonimidoyl)mcthyl]phenyl } w1,3,5-1riazin—2-aminc rac)-Bthyl [(3- { [4~(4,5‘difluoromethoxyphenyl)-] ,3 ,5- triazitt—2-yl]amino } benzyl)(methyl)oxide-75’- uLf‘anvlidene ate nrac)» 4-(4,5-Difluoro—Q-methoxyphcnyl)-N- {3-[(S- 28nM cthylsulfonimidoyl)mcthyl]phenyl} -1,3,5-triazinamine nrac)-Ethyl [(3- { [4-(Al-chloro-Z-methoxyphenyl)—1,3,5-triazin- 2W -y1] amino} benzyl)(methyl)oxido-)f-sulfanylidene]carbamate rac) 4-(4-Ch1oro—2—methoxyphenyl)-N- {3- [(S- 74nM methylsulfonimidoyl)methy1]pheny1}-I,3,5-triazin~2-amine —(4—Chloro-Z-mcthoxyphcnyl)~N- {3-[(S- methylsulfonimidoyl)mcthy1]phcnyl} — 1 .3,5—triazinaminc; 93W nuntiomcr l -(4—Chloro-Z-methoxyphcnyl)~N- {3-[(S- metllylsulfonimidoyl)mclhyllphenyl} —1,3.5.lriazinamine; 16W nuntiomer 2 rac)[(3- 4‘1:luoro-Z-methoxyphenyl)—1,3,5-Iriazin—2- i l3amino} bcnzyl)(mcthyl)oxido—?.6-sulfanylidcnc] lature ® 1-[(3— { [4-(4-F1uoromethoxypheny1)~1 ,3 .S-Criazin-Z- 1]amino}benzyl)(rnethyl)oxidu-?.‘—sulfanylidene]-3~ 19 nM 1100 nM meth Iurea; enantiomer 1 1—[(3—{[4-(4-Fluoro-2—mcthoxyphenyl)—1,3,5-triazin-2— 1] amino} bcnzyl)(methyl)oxido—AG-sulfanylidenc] 14 nM 1200 nM methylurea; omer 2 rad-Ethyl [(3-{[4-(2,2-difluoro-1.3-benzodioxol-4—yl)-1,3,5- triazin—Z—yl]amino} benzyl)(mcthyl)oxido-k°— 33nM ‘ulfanvlidcnckarbamatc rac)(2,2-Difiuoro-1,3-benzodioxolyl)-N- {3-[(Sv 59nM ethylsu1fonimidoyl)mcthyl]phenyl}-1,3,5—1riazinamine rac)—E1hy1 [(3- {[4-(5-fluoro-2~mcthoxyphenyl)—1,3,5—m'azin—2- 2W 1]amino}bcnzyl)(mcthyl)oxi(Io-7.6-su1fanylidcnc]carbamatc rac)—4-(5~FIuoro—2-mcthoxyphcnyi)—N- {3-{(S- mm suifonimidoyl)methyl]plmnyl } ~I ,3,5-Iriazinaminc -(5-Fluoromcthoxyphcnyl)-N- {3-[(S- methylsulfonimidoyl)mcthyl]phenyl} -triazin—2—amine; 91 nM 2800 nM nantiomer I -(5-FJuoro-Z-methoxyphenyl)—N— {3—[(S- ethylsulfonimidoyl)methyl]phenyl} -1,3,5-triazin~2-amine; 110 nMM “nantiomcr 2 rac)-N- [(3- {[4-(4-fluoromethoxyphenyl)—1 ,3,5—Ifiazin 11nM ]]amino} benzyl)(methyl)oxido—l6-sulfanylidenc]acctamidc 1'ac)-E1hyl [(3- {[4-(2-mcthoxyphenyl)—1 ,3,5-Iriazin 28 nM I] ami no } bcnzyl)(mcthyl)ox.id0-).6-su Ifanylidcnc]carbamatc rac)(2’Mcthoxyphenyl)-N- {3 . [(5- 35 nM mothylsulfonimidoyl)mcthyl]phcnyl}—1,3,5-lriazinaminc -(2-Mcthoxyphcnyl)—N— {3-[(S- methylsu1fonimidoy)}methyl]phenyl}-1,3,5~triazinamine; 100 nM 7600 [WI nantiomer 1 thoxyphenyl)-N— {3-[(S— methylsulfonimidoyl)methyl]phenyl} -1,3,5-1riazina1nine; 5900 nM mer 2 rad-Ethyl [(3- { [4-(3,4-dihydro-2l-I-chromcnyl)- l ,3,5- triazin-Z-yljamino} bcnzyl)(mcthyl)oxido-7£6- 13 nM 1200 nM ulfan lidcnc carbamatc rac)—4-(3,4-Dihydro-2H-chromen-8—y1)—N— - 21 nM 940 nM ethylsulfonimidoyi)methyi]phenyl} -1,3,5-triazinamine ~(3,4-Dihydro»21—1~chromen—8-yi)—N-{3-[(S- ethylsulfonimidoyl)methyl]phenyl} —1,3,5—1riazin-2—amine; 22 nM 670 nM nantiomcr 1 —(3,4—Dihydro—2H-c11romcnyl)~N~{3-{LS- methyisulfonimi(loyl)mcthyl]phcnyl} -l ,3,5-triazin—2—amine; nantiumer 2 ruc)—Elhyl [(3— {[4—(2,3—dihydroben20furan~7~yl)-1,3,5— fiazin-Z-yl]amino}bcnzyl)(mcthy])oxfilo-k"— 21 nM 3100 RM ulfan lidene carbamaic rac)(2,3-Dihydro—1-benzofuranyl)-N~{3-[(S- 68 nM 2200 nM methylsuEfonimidoyl)methyljphcnyl} -1,3,5~1riaziuamiue Dihydro- I -bcnzofuranyl)—N— {3 — [(S- methylsuIfonimiduyl)mclhyl]phenyl}-1,3,5—lfiazinamine; 64 RM 3100 nM - nanuomer 1 I -(2,3-Dihydro— I —bcnzofi1ran—7-yI)—N- {3- [(S- methylsulfonimidoyl)methyl]phcny1} - l ,3,5—1n'azin—2-mninc; 50 nM 2900 nM - nannomcr 2 rac)-Ethyl [(3» {[4-(2.3—dihydro—] ,4-benzodioxinyl)- 1,3,5- triazin-2~yl] amino} benzyl)(methyl)oxido—7»‘— 9 nM 2300 nM lidenekarbamatc 38 ’rac)(2,3-Dihydro-1,4—benzodioxin-5—yI)-N- {3-{(S- ‘14 nM 1600 nM mcthylsulfonimidoyl)mc1hyi]phcnyl}~l ,3,5-Triazinaminc -(2,3-Dihydro—1,4-benzodioxin—5-yl)—N~ - methylsulfonimidoyl)mcthyl]phcnyl} -1 ,3,5-tfiazinaminc; 29 nM 1500 nM *nantiomcr I -(2,3-Dihydro-1,4-bcnzodioxin~5—yl)-N- {3~[(S- methylsulfonimidoyl)mcthyl]phenyl}-1,3,5-triazin-2»amine; 25 nM 1800 nM - nantmmer 2 rac)-N- {3-[(N,S-Dimcthylsulfonimidoyl)mcthyl]phcnyl } ~4-(4- 36 nM 2600 nM fluoro-Z-mcthoxyphenyl)-1,3,5-triazinaminc rac)-E1hyl [ {3 -[(4-{2-[(4-fluorobcnzyl)oxy]phenyI}-1,3,5- 'azi11y!)amino] } (methyl)oxide-76’- 5 nM 1600 nM ‘ulfan lidcnc]carbamatc rac)—4- {2-[(4-Fluorobenzyl) enyl} -N- {3-[(S- 9 nM 1900 nM methylsu1fonimidoy1)methyl]phenyl}-1,3,5 inamine rac)—N-{(3- {[4-(4-Fiuoromcthoxyphcnyl)—1 ,3,5-triazin-2~ 1] amino] benzyl)(methyl)oxido-?f— 20 {M 1800 nM ‘ulfanylidone]methanesulfonmnidc fl1yl [(3-{[4-(3-chloro-Z-mcthoxyphcnyl)-1,3,5-triazin- 820 nM 9000 nM -y1]amino}benzyl)(methyl)oxido-XG-suifanylidcne]carbarnatc rad-Ethyl {[3-( {4—[5-fluoro-Z—(tctrahydro-ZI-I-pyran 1mcthoxy)phenyl]-1.3,5-triazin 120 nM 11000 nM 1 amino)bcuz 1 math l)oxidu-7.6-sulfan lidene}carbamate rac)-E1hyl [methyl(oxido)(3- { [4—(2-phenoxyphenyl)—1 ,3,5— 35 nM 6500 nM Lriazin-Z—y11amino} benzyl)4&6-su1fanylidene]carbamate rac)-[(3- {[4 -(4-fluoro—2-mclhoxyphenyl)- 1 .3,5-lriazin 13 ”M 630 nM 1] amino} benzyl)(methyl)oxido-?.‘~sulfanylidene]cyanamide [(3 - [[4-(4~fluoro~2~methoxyphenyl)-1,3,5~triazin | Ramino}benzyl)(methyl)oxidOJf-sulfanylidene]cyanamide; 7’ nM 650 nM [(3— -fluoromcthoxyphcnyl)-1 ,3,5-triazin~2~ flan-lino}benzyl)(methyl)oxido-?.6-sulfanylidene]cyanamide; 7 nM 430 nM - nantiomer 2 rac)-E1hyl [(3-fluoro-5— {[4-(4—fluoro-Z—melhoxyphenyl)~1,3,5- fiazin-Z-y1}amino}bcnzyl)(mct’ny1)oxfilo-N"— 10 nM 430 nM ulfan lidenecarbamatc 52 rac)—4—(4-FluoromethoxyphcnyD-N - {3-fluoro[(S- nethyisulfonimidoyi)met11yl]phe11yij «1,3,5-iriazinan1ine (4-FluDro-Q-meihuxyphenyl)—N—{3~fluoro[(S- cli1yIsulfonimiduyl)methyl]phenyl}-1,3,5-11iazinamine; 16 IN 540 nM nantiomer l 4(4»Fiuoro-Z-mctiioxyphcnyi)-N-{3-fluoro-S-[(S- U14:» methylsulfoni1nidoyl)mcthyl]phenyl}—1,3,5-triazinaminc; 16 nM 850 nM nantiomer 2 1ac)[2 -(Cyclohcxy1111cthoxy)f1u010phc11yl]-N ~ {3 -[(S~ "M 2200 ”M nictliylsulfonimidomecthprhcuyl}—1,3,5-lriazi11—2—aminc rac)~4~ f4~Eluoro-2—[(4-fluorobenzyl)oxy]phenyl} —N- {3—[(S- 41 0 nM methylsuiibnimidoyl)methyl]phcnyl} -l ,3,5-triazina1nine {4-F1uoro[(4-fluorobenzyl)oxy]phenyl}~N—{3-[(S- methylsuli‘onimiduyl)melhyl]phenyl}-1,3,5-11iazin—2~amine; 4 nM 580 nM namiomer 1 ' {4-—Fluoro{(4fluorobcnzyiioxymhcnyl}-N—{3-[(S- methylsulfonimidoyi)mcthyl]phcnyl}--l ,35-triazin-Q--amine; 5 nM 560 nM nantiomer 2 mo)4— {4Fluorou.’7---{2(tetrahydro-ZH-pymn-li— oxy]phenyl}-N- {3 [(S— 370 nM 8300 nM methylsulfonimidoyIJmcth l] hen l ~1,3,5~triazin~2-aminc rac)—4--(4-F1uoron1ctl10xyphcnyl)-N-(3- {[S(totrahydro-2H- 1yl)su1fonimidoyl]mcthyl}phcnyl)- l,3,5~triazin-Z- 89 nM 5200 nM - {4-C11loro[(S~methylsulfonimidoyl)meihyl]phenyl} - 26 ”M 1400 "M -(4-fluoro-E-methoxyphcnyU-1,3,S-triazin-Z-amine |oro-3”[(Smethylsuifonimidoyi)mcthyi]phenyl} -4(4- 25 nM 2900 nM Z-111cii1oxypl1cnyl)- 1,3,5-tria7in-Z-aminc; cnantiomcr i I —{4-Chloro—3—[(Smethyisuifonimidomecthprhenyl}~4—(4- 1800 ”M fluo1ome1hoxypl1enyl)-1,3,5—triazinamine; enamiomer 2 rac)--Etl1yl [{3~[(4 {2[(3,4diciflorobcnzyl)oxy]phcnyl}~1,3,5- triazi11~’.Z-§r'l)an1ino]bcnzyl}(111(:i:l1yi)oxido 13 nM 3300 nM :ulfanylidcnclcarbamatc rac)4-{2 [(3,4-Diclilorobem'ljoxy]phenyl} -N-{3-[(S- nM 1200 nM sulfonimidoyl)1nethyl]phenyl}——1 ,,35-triazin-amine rac)-4—(4-Fluoro{[( Hs)phcr1yi( H2)mcthyl]0xy}phenyl)-N- {3- [(S -mcthylsulfonimidoyl)methyl]phenyl} « l riazin—2- 220 nM —[2~(] --cyclopcutylcthoxy)-—4—fluorophcnyl]—N-{ii—[(S- methylsulfonimi(oni)mclhyl]phcnyi}1,3.5-11'iazi11amine, mixture ofai14 stereoisomers rac)-N- {3-C11lo1fo[(S-methylsulfonimidoyl)methy1]phenyl} nM 250 nM -(4 —fluoro~2-methoxyphenyi)— ‘l ,3,5-triazin—2—amine rac)[4-Fluoro-Q-(3,3,3-trifluoropropoxy)phenyi]«N--‘3[(S~ 79 DM 6000 nM methyIsulfoni1nidoyi)methyl]phenyl} 1,3,5~11ia2in2-amine rac)—4—[4F1uoro~2~(pyridin-3~ylmcthoxy)phcnyl]-N {3[(S .4nM 1600 nM methylsulfonin1idoy1)mcthyl]phcnyl}—1,3,5—t1-iazinaminc Nomenclature rac)—4—[4-l"luoro(pyridin-Z-yimcthoxy)phcnyi]-N— {3-[(S- 97 FM 6900 nM methylsulfonimidoyl)mct11lep[161in } — l ,3 ,S-triazin-Z-amine rac)—4-[4-F1uoro—2-(pyridinyimcthoxy)phenyl]-N-{3-[(S- 14 nM 1500 nM methylsulfonimidoyl)methyl]phenyl} - l ,3 ,5—triazin—2-amine - {4-FIuoro-2—[l-(4-fluorophcnyl)ethoxy]phcny1}—N— — inctliylsulfonimidoyl)mcthyl]phcnyl} -1.3,5-triazina1nine. 22 nM 3500 nM mixture of 4 stereoisomors (3-F1uoro{[4-(4-fluoro-2—methoxyphcnyl)-1,3,5- triazin-Z-yl]amino}benzyl)(methyi)oxido-7\°- 6 nM 180 nM ulfan lidene c anamide {(S-Fluoro-S- { [4-(4-fluoro-Z—1nethoxyphenyl)-1,3,5-Lriazin l]amino}benzyi)(methyDOXido—lé-sulfanylidene]cyanamide; 6 nM 230 nM °nantiomer 1 {(B-Flu oro-5~{[4-(4-fluoro—Z—mcthoxyphcnyl)-1,3,5-triazin—2- ]] amino } benzyl)(methyl)oxido-7u6-sulfanylidenejcyanamidc; 5 NV! 240 nM “nautiomcr 2 rac)[2-(But-2—yn— l )fluoropheuyl]-N- {3- [(S- 8 nM 820 nM methylbuifonimidoyl)methyl]phenyl} - l ,3,5-triazin—2minim: -[2-(Butyn—1~yioxy)~4-flu0rophenyl}-N- {3 -[(S- methylsulfonimidoyl)methyl]phenyl} -1,3,5-n~iazinamine; 3 nM 590 nM nantiomcr 1 -[2-(But—2~yn-1~yioxy)flu01'ophcnyl}-N-{3 -[(S- Inctliyisulfonimidoyl)mctliyl]phenyl} - l ,3 azin-Z-aminc; 4 nM 450 nM mer 2 rac){2-(2-Cyclopropyiethoxy)fluorophenyl]-N- - 30 nM 3200 nM methylsulfonimidoyl)methyl]phenyl} - l ,3,5-Iriazinamine rac)[4—F1u0r0—2—(propyn-I-yloxy)phenyl]-N- {3-[(S~ 15 0M 1600 nM methylsulfonimidoy1)methyl]phenyl} - l ,3 ,5-triazin—2-amine -[4-F£uoro—2-(prop—2-yn- l -yloxy)phenyi]-N- {3-[(S- -[4-Finoro-Z-(prop—Z-yn- l ~yloxy)phcnyl]-N- {3-[(S- nctliylsulfoni midoyl) methyl] phcuyl} ~ 1 ,3 ,S-triaziu-Z-amine; nantiomer 2 rac)—4~ {2-[(3,4-Difluor0benzyl)oxy]-4—fluurophenyl} -N- {3- [(S—methylsulfonimidoyl)mcthyl]phenyl}-] ,3,5-triazin-2~amine 81 rac)-4—[4—F1uoro—2-( 1 ,3-lhiazolylmcthoxy)phcnyl]-N- {3- (S -methylsulfonimidoyl)methyl]phenyl} -] ,3 ,S-triazin-Z-amine - {4-Fluoro—2—[(2—fluoropyridin—4—yl)mcthoxy]phenyl} - N- {3-[(S~methylsu1f0nimidoyl)methy1}phenyl} -l,3,5-m'azin-2— 7 nM 360 nM '3 mmc - {4-13luoro[(Z-fluoropyridinyl)methoxyhnhcnyl} -N- {3- [(S—methylsuifonimidoyl)mclliyl]phcnyl}-1,3.5—triazin-2— . mine; an anti must I n- {4-F1uoro[(2-fluoropyridin~4~y1)melhoxy]phenyl} «N- {3— [(Swmcthylsulfonimidoyl)mcthyl]phenyl}~I ,3,5-triazin~2- mine; cnantiomer 2 “ Nomenclature rac)~4-{4-1"luoro(propen- l —yloxy)phcnyi]—N — {3-{(S- su1foni1nidoyl)methyljphcnylf - 1,3,5-1riazinamine rac)—4— {2-[(4—Cl1lorobenzyI)oxy]—4-fluorophenyl} —N- {3—{(S- methylsulfonimidoy])mcthyl]phcnyl}«1,3,5-triazinaminc 1'ac)-4—(4-Fluoro {[3—fluoro-5— Triflu oromcthyDbcnzyl] oxy}phcnyl)-N- {3 - [(S— 4 nM 280 nM rac)-4—{4-Fluoro[(3-fluorobenzyl)oxy]phcnyl}-N-{3—[(S- 2 NM 260 nM sulfonimid0yl)mcthyi]phcnyl} - l ,3,5-tn'azinan1iue rac)(4-FluoropropoxyphenyI)-N- {Ya-[(8- 29 ”M 2300 nM methylsu lfonimidomecthprhcnyl} -1 ,3,5-triazinamine m.c){2-[(3-Ch1orobcnzyl)oxy]fluorophcnyl} -N- {3-[(S- 4 MA 250 nM nethylsu[fonimidoyljmcthyl]phc'ny]}-1,3,5-triazinaminc rac){4-Flu oro( azoIylmcthoxy)phcny|]—N-{3- 7 “M 2000 nM [(S-1ncthylsulfonimidoykhncthyl]phony}}-l ,3 ,5~triazinaminc rac) {2-[(3-Chloro-S-fluorobenzyl)oxy] fluorophenyl} -N- S -methylsu]fonimidoyl)1nethyl]phenyi} -1,3 ,5-triazin-2— 3 nM 230 nM rac)~4-[2-(2,2-Difluorocthoxy)flu0rophcnyl]-N- {3-[(S- 21 ”M 1800 nM methylsulfonimidoyl)mcthyl]phcnyl} ~ 1 ,3 azian—amine rac)-4— {4-Fluoro[(4- fluoro-S-methylbenzyl)oxy]pheny1} -N- {3-[(S-methylsulfonimidoyl)methyl]phenyl}—1,3,5-triazin—2— 3 nM 350 nM rac)-4—{2-[(3~Chloro—4~fluorobenzyl)oxy]fluoropheny1} -N- {3 -[(_S -methylsulfonimidoyl)methy1]phenyl} — l .3 .S-triazin-Z- 3 nM 200 nM . mine 3 nM 180 nM 2 nM 250 nM rac)[4-Fluoro—2-(4,4,4-trifluorobutoxy)phenyl}—N— {3 -{(S— ”M 1300 “M methylsulfonimidoyl)mcthyl}phcnyl}~I,3,5—1riazin-2~aminc rac) {4-F1uoro[(2,3 ,S-Uifluorobenzyl)onyphenyl} —N— {3~ 4 nM 500 nM [(S—methylsulfonimidoyl)methyl]phenyl}-1,3,5-triazinamine rac)—4— {2-{(ZZ)-Buten-1 -yloxy]flu0ropheny] } -N- {3-[(S~ 7 nM 800 nM methyfsulfonimidomeethyl]phenyl}-I,3,5-triazinamine rac)-4— {4-Fluoro[(3,4,5-trifiuorobcnzyl)oxy]phcnyl} -N- { 3- l(S~metliylsulfonimidoyl)methy1]phenylE-] ,3 , zin-Z-amine rac)-[(2,3-Difluoro—5- {[4-(4-fluoro-Z-mcthoxyphcnyi)-1,3,5- triazin—Z-yl]amino} benzyl)(methyl)oxido—Kfi— lidene]cyanamide rae)-N- {3,4-Difluoro[(S- methylsulfonimidoyl)mcthyl]phcny1} fluoro methox henyl)-1,3,5-triazinamine rae)—N— {3-[(S«ethylsulfonimicloyl)methyl]phenyl} (4—fluoro— -metlioxyphenyl)- l riazinantine N~ {3 -[(S-ethylsu1fonimidoy1)methyl]phenyl} (4-flu oro-Z- methoxyphenyD-l ,3,5-triazinaminc; omer 1 — {3 - [(S-cthylsulfonimidoyl) methyl]phonyl} (4-fluoro methoxyphenyl)—l =3,S-triazin-l-amino; enam‘iomcr 2 rac)-[(3- { [4-(4-Fluoro-Z-methoxyphenyl)-l ,3 ,S-triazin-Z- l]amino} ~5-methylbenzyl)(methyl)oxido-kfi- rac)-2—( {S-Fluoro-Z-[4-( - methylsulfonimidoyl)mcthyl]phenyl} amino)—i ,3,5-triazin rac)—[Cyclopropyl(3- { [4-(4-f1uoromethoxyphenyl)-1,3,5- triazin-Z-yl]amino}benzyl)oxido—)L6-su1fanylidenc]cyanamidc Table 3: Inhibition of proliferation of HeLa, HeLa/MaTu/ADR, NON-1460, DU145, Caeo-2 and Bi 6F 10 cells by compounds according to the present ion. Determined as described above (Method 3. of Materials and Methods section). All leo (inhibitory concentration at 50% of maximal cf‘f‘oct) values are indicated in nM, “n.t.” means that the cornpounde have not been tested in this assay.
@: Compound Number Inhibition of HeLa cell eratiori Inhibition of HeLa/MaTu/ADR cell proliferation inhibition of NCI—H460 cell proiifcraiiou I0 @@@@@@ inhibition oi'DUl45 cell proliferation inhibition of Caco-2 cell proliferation Inhibition of B 16F l 0 cell proliferation —aalaa-® rac)—Ethyl [(3 {14-(4--t1u0ro-2111cthoxypheny1)- 1H35-triaziny1]amino}benzy1)(_mcthy1)oxid0n 1000 380 360 390 390 360 1 6-su1fanylidcnc]carbamatc (4-FluorOaZ-methnxyphenyl)-N-{3-[(S- nethylsuIfonimidoy1)1nct11y1]phcnyl}~1,3,5- I... riazin—Z-aminc )—4-(4-F1uoro—Z-melhoxyphenyl)-N—{3-[(S— : efl1ylsu1fonimidoyl)methy1]phenyl}-1,3,5- 1100 4001030 7401030 1000 riazin-Z-amine; enantiomer 1 +)(4-F1uoro111ethoxyp11eny1]-N- {3-[(S- IIIIIM netl1ylsu1fonimidoyl)methyl]phenyl}—1,3,5- 970 440 1200 670 1300 riazin-Z-aminc; c11antiomer 2 Ethyl {[3-({4—[2-(1)enzyioxy)—4-fluoropheny1]— 1,3,5-triazin-2~y1}amino)benzy1](mcthy1)oxido~ 270 210 260 250 270 °-sulfanvlidcnc carbamatc 4 c11zyloxy)fluorophcnyl}-N-{CB-[(8- 1et11ylsulfonimidoyl)1ncthyl]pheny1}-1,3,5- lriazin-Z-amine 1 cthoxyphenyl)—I,3,5-Iriazin . 1]amino}benzyl)(methy1)oxido-k‘- ulfanvlidcne carbamate rac)(4,5-Difluoromethoxyphenyl)-N- {3- r— c [(S-methylsulfonimidoylhnethyl]phenyl}-1,3,5- riazin—Z-amine MIIIII rac)[(3- {[4-[4-F1uoro-2~methoxyphcny1)- I ,3 ,S-triazin-Z-yIJamino} benzyIXmethyboxido- 6-sulfa11ylidcnc>]-3‘lncthylurca 1-[(3-{[4-(4-F1uoromcthoxyphenyl)—1,3,5- ’— ox riazil1y1]ami11o} benzyl)(methyl)oxido-k‘t Iulfany11dene]-3~111<3111ylu1'¢:a; cnantiomer 1 [(3—{[4-(4-F1uuro-Z»mcthoxyphcnyl)-1,3,5- hi \l riazi11y1]amino}benzy1)(methy1)oxido—71°— ‘ulfan lidene -3 -metl1 lurea; enantiomer 2 rac)—N— [(3 - -fluoromethoxypheny1)- 1,3,5-triazin-Z—y1]amino}bcnzy1)(mcthy1)oxido- 760 710 940 - 6-sulfa11 lidene acctamide rac)-Ethyl [(3- {[4—(2—methoxyphenyl)—] .3,5— NUs triazin—Z-y1]amino}benzyl)(methy1)oxido—7\.6- 1100 M. 11.1. m n.t. lidenekarbamate rac)-Ethyl [(3- { [4~(3,4-dihydro-QH-chromcn-S- N\9' | 1)—1,3,5—triazin—2- 510 760 720 540 760 960 1 flamino} benzylxn1ct11yl)oxido-}.°- cu] dcnclcarbamalc rac)~4-(3,4-Dihydro-2H—chromen—8-y1)—N— {3— '4) c thylsu1f0nimidoyl)metl1y1]phenyl}-1,3,5- riazin-Z-aminc rac)-Ethyl [(3- {[4-(2,3-dil1ydro-] ,4- b) \l enzodioxin-S-yI)-1,3,5-lriazin—2- 1]amino}benzy1)(methyl)oxid0-}.‘- ulfanylidenejcarbamate “I. _aanaln . . _ ,- .' _ _ _ ' 5_ r - a 1100 m. 11.1. ILL n.t. M.
“I... rac)—N- [(3- { [4-(4-F1uoromca‘hoxyphcnyl)— 1&3,5-friaziny]]amino}benzyl)(mcthyl)oxido- 1000 n.t. n.t, m. m. M. rac)-[(3——{ [4-(4- fluoro-2—methoxyphenyl)-I ,3,5— riazin-Z-yIJamino}bcnzyl)(mcthyl)oxido-h°- 330 400 410 280 420 320 lidendcyanamide [(3- { [4-(4~fluoromcthoxyphcnyl)-1,3,5- riazin-Z-yflamino}benzyl)(methyl)oxido~?»°- 260 I90 310 140 350 250 ulfan lidcne}cyanamidc; cnantiomcr 2 rd c)-Elhyl [(3 -fluoro { fluoro x ethoxypheuyl)-1,3,5-triazin 300 240 230 240 flamino}benzy1)(mcthy1)oxido-lfi 290 3‘40 ulfan lidene carbamatc rac)—4~(4-Fluorometh0xyphenyl)~N-{3- 410 I40 650 340 690 550 ethylsulfonimidomeethyljphenyl}—l,3,5— riazin-Z-amine rac)[2-(Cyclohexylmethoxy) fluorophcnyl]-N— {3-[(S— 850 980 890 ”'t' , cthylsuIfonimidoylhncihy1}phcnyl}-13,5- -Z—aminc rac)—4- {4-FIuoro-2—[(4- 56 fluorobcnzyl)oxy]phcnyl}-N- {3~[(S~ 370 780 350 370 860 .ncthylsulfonimidomecthyl]phenyl}—l,3,S- riazin—2~amiuc - {4-Fluoro«2-[(4~fluorobenzyl)oxy]phenyl}-N- 56.3 {3-[(S-methylsulfonimidoyl)methyl]phenyl}— 350 '70 340 340 4-30 1,3,5-triazin—2—amine; mer 1 — {4—Fiuoro«2-{(4-fluorobenzyl)oxy]pheuyl}~N- {3-[(S -methylsulfonimidoyl)methyl]phenyl} — 540 540 470 400 540 1,3,5-triazinaminc; enantiomer 2 . cthyisulfonimidoyi)mcthyi]phcnyl}(4-.
I -{4- Cl1loro{(S- uoro—2—methoxyphenyl)—1 ,3,5-triazinamine; nantiomer 1 ~{4-Chloro[(S— nethylsulfonimidoyI)methyl]phenyI}(4- 59.1) fluoro—2-methoxyphenyl)—] ,3,5-tn'azin—2-amine; mantiomar 2 rac)—N-{3-Chloro[(S- .cthylsulfonimidoyl)1ncthyl]phcnyl}(4- 400 280 360 290 350 320 fluor0mcth0xyphenle-1,3,5—triazinaminc ruc)—4-[4~Fluoro(pyridin 66 yImethoxy)phenyl]—N—{3—[(S- 1700 m. 11.1, m' n1. n.1, ahylsu1fonimidoyl)mcthyl]phenyl}-1,3,5- rmzm-Z-ammc rac)—4—[4 -F11101'0u2~(pyridin 00 ; lmethoxy)phenyl]-N— {3—{(S— . cl11ylsulfonimidoyI)mclhyl]phcnyl}4,3,5- riazin—Z-amine .30001100' 1300 rac)-[(3-Fluoro-S—{[4-(4—flu0r0—2— \le unethoxyp heny1)—1 ,3 , S-tn'azin-Z- ,.’9 l}amino}benzyl)(methy!-}.6- 150 120 230 170 130 ulfan lidene c anamide (3-PIuoro {[4-(4~fiuoromethoxyphenyl)— \IH 1.3,5-triazin-2—yl]amino}benzyl)(methyl—7L6- I20 120 130 110 ulfanylidcnckyanamidc; cnantiomcr I uoro {[4-(4-f1uoro-2‘mcthoxyphcnyl)~ ] ,3. 5-m'azin—2-yl]amino} bcnzylxmcthyl—kfi- 71 120160 110 190 160 ~u1fan iidcnc]cyanamidc; omcr 2 -[2-(BuIynyloxy)fluoropheny1]- I'll.- \1DJ -{3-[(S-methylsulf‘onimidoyl)mcthyl]phcnyl}- 240 280 260 200 300 150 triazinaminc -[2-(But-2 -ynyloxy)fluorophcnyl]-N- {3- [(S-methylsulfom'midoyl)methyl]phenyl}-1,3,5- 310 340 330 360 390 340 riazin—Z-amine; enantiomer I utyn-l-yloxy)fluorophcnyl]-N-{3- I... I \l(I! [(S-methylsulfonimidoyl)mcthyl]phcnyl}-l,3,5- 260 210 220 £70 310 240 riazin-Z-amine; enantiomer 2 rac)[2-(2~Cyclopr0pylethoxy) \l O\ fluorophenyl]~N~ {3-[(S- ”00 rm, 111. m' n.t. sulfonimidoyl)mcthyl]phenyl}—1,3,5— riazin-Z-aminc rac)—4—[4-Flu0ro—2—(propynyloxy)phenyl] E-{3-[(S~1nethylsulfonimidoyl)methylhflleuyl}- 470 630 560 480 300 520 1,3,5-triazin—2~amine -[4—Fluoro(prop~2nynyloxy)phenyl]-N- \lno {3-[(S-methylsuIfonimidoyl)methyl]phenyl}- 650 260 390 370 760 500 1,3,5—triazinaminc; enantiomcr I -[4—Fluoro—2-(prop—2-yn—1-yloxy)phenyl]-N- \l\O {3 -[(S-methylsu1fonimidoyl)methyl]pheny[} - 440 350 420 380 390 370 l.3,5~triazin~2~aminc: enantiomer 2 rac) {2-[(3,4-Difluorobcnzyl)oxy] fluorophcuyI}-N-{3-[(S- 730 n.t. n.t. III. 11.1 n.t. nethylsu1fonimidoy1)mcthyl]phcnyl}-1,3,5- triazin-2—aminc rac)-4—[4-Fluoro(1,3-thiazolvi- lmethOX' hylsufigmnfifioyihgethylmhenyl}-l,3,5-l]-N- 3w[(S- 860 "'t' 1‘" TL" M M riazin-Z-amine _mc)—4- {4-Fluoro—2—[(2—fluoropyridin-4— 'l)methoxy]phcnyl} -N~ - 190 180 130 180 150 nethylsulfonimidoyl)methyl]phenyl}~I,3.5- riazin-Z-amine - {4-Fluoro[(2-fluoropyridin—4- s l)methoxy]phenyl} —N— {3-[(S- “0 640 180 180 210 220 ulf‘onimidoyl)mcthyl]phcnyl}-1,3,5— riazin-Z-amiuc; cnantiomcr E - {4-Fluoro~2v{(2-fluoropyridin oxy]phenyl} -N- {3-[(S- 120 340 180 180 180 210 ethylsulfonimidoyl)methyl]phenyl}—I,3,5— riazin-Z-amine; enantiomer 2 rac)[4—F1u0ro(propcnyloxy)phcnyl]- N-{3-[(S—mcthy1sulfonimidoyl)methylmhenyl} - L3.5-triazinamine _rac)(4-Fluoro {[4- mcthylsulfonigfidoylfinc’thylfigbong}1,3[,5~(trifluorometh l)benzyl]oxy hen I)-N~ 3-[ S- “00 n.t. n't' nt‘ m' n.t. riazin-Z-aminc _rac)—4-{2-[(4-Chlorobcnzyl)oxy]—4- fluorophcnyI}-N- {3-[(S— 560 450 570 800 590 nethylsulfonimidoyl)mcthyl]phenyl}-1,3,5- riazin-Z-aminc rac)(2-Ethoxy—4-fluorophenyl)-N- {3-[(S- nethylsulfouimidoyl)mcthyl]phenyl}-1,3,5- 700 890 -Z-amine rac)(4-Fluoro { [3-fluoro—5- trifluoromethyl)benzyi]oxy} phenyI)-N- {3- [(S- 470 450 370 420 520 470 cthylsulfonimi(loyljmcthyflphcnyu-1,3,5- -Z—aminc rac){4-Fluoro—2~[(3- fluorobcnzyl)oxy]p hcnyl} -N- {3-[(S- 170 100 110 “0 nethylsulfonimidoyl)mcthyl]phcnyl}—1,3,5— riazin—Z-aminc rac)(4-Fluoro-2—propoxypheny1)—N— {3 —[(S— nethylsu lfonimidoyl)mcthyl]phenyl} —1 ,3,5- triazin-Z-aminc 92 rac)-4— {2—[(3-Chiorobcnzyl)ony—4— fluorophonyI}—N‘ {3-[(S~ 47° 36° 17° 33° 43° 39° clhylsulfonimidoyI)mcthyl]phcnyl}-1.3.5- riazin-Z-aminc rac)-4—[4-F1uoro(1,2-oxazol 93 lmethOX'ethylsulyfzalifimiydgylmictlggll]phenyl}-I,3,5-hen l—N— 3- S- 680 M ‘1" m" “- riazin-Z-aminc rac)-4— {2—[(3-Chloro—5-fluorobenzyl)oxy}~4— uorophenyl} ~N- {3- [(S— 180 . etlaylsulfonimidoyl)methy1}phenyl}4,3,5- riazian—amino I'll. fiuorophenyl]—N— {3-[(S- methylsu lfon imidoy])1ncfl1yl]phcnyl}-l ,3 ,5- triazin—Z—aminc 1'ac){4-Fluoro[(4-fluoro . ethylbenzyl)oxy]phenyl} —N— {Ti-[($- 1 ethylsulfonimidoyl}mcthyl]phenyl} «1 ,3 ,5- riazin-Z-amine r3041-{2-[(3-Chloro—4—fluorobeuzyl)oxy] 1uorophenyl}-N~{3-[(S~ methylsulfonimidoy]}melhyl]phenyl}—l.3,5— triazin-Z-amine rac)—3({5-Fluoro2[4-({3- [(S- . cthylsu lfon1m1doyl)mcthylphonyl}amino)- I40 260 120 120 150 130 ' moth lbcnzonitrilc 1ac)-”4-{4--Fluor0[(2~melhylprop——2-15:11-1— l)0xy}phenyl}-N- {3- {(S- 12° 18° ‘50 1 09 230 1 e1hylsulfonimidoyi)methyl]phenyl} 1 ,35- Wrac)4--[4--Fluoro(4,4,4~ rifluorobutoxy)phc11yl].N— {3[(S- 920 1 elhylsulfonimidoyl)methyl]phenyl}-1 3,5- rac)-4— {4-F—luoro—[(2,3,5- rifluorobenzyl)oxy]p'hcnyl}-N~{3-[(S- 330 350 360 340 240 340 methylsulfonfinidoyflmctE1yl]phcnyl}-l,3,5- riazin-Z-aminc rac)-4~{2-[(ZZ)-Butenyloxy]-4— heuyl}-N-{3-[(S—mcthylsulfonimidoyl) 340 140 150 I60 ] 1hen 1} -1,3,5-triazinaminc rac){4-Fluor0[(2,4,5- rifluorobcnzy1)0Xy]13116113’1}'N‘{3“KS" 1100 nt nt H 1 ethyisulfonimidoyl)meihy1]phenyl}'113’5" triazin-Z-amine rac)~4-{4-Fluoro—2—[(3,4,5~ r1fluorobcnzy1)oxy] phenyl} -N— {3 -[(S- 240 120 u idoyl)mcthyl]phenyl} «1,3,5- riazin-Zwaminc rac)-[(2,3—Difluoro {[4-(4-fluoro 1 cthoxyphcnylj—l,3,5-triazin 71 130 120 s 1] amino} bcnzyl)(methyl)oxido-7k‘- ulfan ]c anamidc 1ac)-[Ethyi(3- {[4—(4-1‘1uoromethoxyphcnyD- 1,3,S-Uiazin-Z-yUamino}benzyl)0xido-k6- 230 340 450 500 300 ulfanylidene]cyanamide rac)--N- {3- [(S- hen 1)-1,,35-triazi11amine mI rac)-[(3- {[4-(4-Fluoromethoxyphenyl}] ,3,5- riazin—Z-yflamino}—5—methylbenzyl) 170 270 110 220 math l)oxido-l6-sulfan lidenclc anamide - rac)( {S-Fluoro~2-[4—( {3-[CS- 112Inethylsulfoni1nidoyl)mcthyl]phenyl}amino)- 330 390 320 300 350 1,3,5-triazin~2-y1]phcnoxy}mothyl)prop~2—en*l- Table 4: Thennodynamic lity of compounds according to the present invention in water at pH 6.5 as determined by the equilibrium shake flask method described under Method 4. of Materials and Methods. 0): Compound Number @: Solubilt him-’1.
Nomenclature a -)-4—(4-Fluoro—Z-methoxyphenyl)-N- {3-[(S- methylsulfommtdomeethyl]phenyl} —1,3,5-triazin—2-amine; enantiomer l +)—4-(4~Fluorornethoxyphenyl)-N— {3-[(S- methylsulfonimidoyl)mcthyl]phenyl}—1,3,5-Ifiazin-2—amine; enamiomer 2 rac)- 4—(4,5—Dlfluoromethoxyphenyl)-N— {3-{(S- ethylsulfonimidoyl)methyI]phenyl}-1,3,5-triazinamine 1—[(3- { [4—(4-1?luoro-Z-methoxyphenyl)-] ,3 .5-triazin—2- l l]amino} benzyl)(methyl)oxido—?f—sulfanylidene]methylurea; 323 nantzomcr I ] -[(3-{[4-(4-1711!oro-Z-mcthoxyphcnyl)-l ,3 ,S-triazin L l]ami no} )(methyl)oxido-XG-sulfhnylidcne]mcthylurca; namiomer 2 InN -(5-Fluoro-Z-methoxyphenyl)—N— {3-{(S- methyisulfonimidoyl)methyl]phcnyl} - l ,3,5-triazinamine; enantiomer 1 -(5-Fluoro—Z-mclhoxyphenyl)-N-{3-[(S- methylsulfonimidoyl)methyl]phcnyl} -triazinamine; enantiumer 2 (A) H Dihydro—2H-chromen-8~yl)-N~ {3»[(S~ 1000 methylsulfonimidoyl)mcthyl]phcnyl}-I,3,5-Iriazin-2—aminc; cnantiumcr l b)N -(3,4-DiltydIo-ZH-clu'omcnyl)-N- {3-[(S- 1 000 cthylsulfonimidoyl)mcthyllphcnyl}—1.3.5-ln'azin-2—aminc; cnantiomcr 2 b) \G —(2,3-Diltydro—1,4-benzodioxin—5—yl)—N- {3-[(S— methylsulfonimidoyl)methyl]phcnyl} - I ,3,5-iriazin-2—amine; enantiomer l J-‘sQ Dihydro-1,4-bonzodioxinyl)—N-{3—[(S— methylsulfonimidoyl)mcthyl}phenyl}-1,3,5—tria2in—2—amine; enantiomer 2 [(3-{{4-(4-fluoro—2-mcfltoxyphcny1)-l,3,5-triazin-2— . l]amino}beuzyl)(methyl)oxido-9f‘-sulfanylidenc]cyanamicle; cnantimner 1 4-(4-fluoromcthoxyphcny1)-l ,3,5—triazin-2~ . i]amino} benzyl)(methyl)oxido-?.°—sulfanylidcnc]cyanamidc; cnantiomcr 2 U]A ~(4—F1uoro—Z—methoxyphenyl)-N— {3-fluoro-S- [(S— methylsulfoni1nidoyl)mcthyl]phenyl} - 1,3,5-triazinaminc; cnantiomcr 2 \l(A rac)-4~[2-(Butyn- I -yloxy)fluorophcnyl]~N— {3- [(S- ethylsulfonimidoyl)mcthyl]phenyl}-l,3,5-triazinamine Nomenclature rac)[4-t“luoro(prop-Z-yn-1—yloxy)phenyl]-N~{3—[(S- nethylsu lfonimidoyl)methyljplicnyl} - I fiazin-2—amine nrac)(2~Ethoxyfluorophenyl)-N— {3-[(S-Inethylsulfonimidoyi)metliyllphenyl} -1 ,3,5~ttiazin—2-an1ine rac)(4-Fluoropropoxyphenyl)-N~ {3 - [(S- methylsulfonimidoyi)methyl]phenyl} ~1,3,5-tfiazin-2~amine Table 5: Inhibition ofCarbonio onhydrase—l and Carbonic anhydruse-Z as determined by the Carbonic anhydrase Assay described above ED: Compound Number ’2): Inhibition of Carbonic anhydrase-l: the iCso (inhibitory concentration at 50% of maximal effect) values are ted in (mol/l) 6) Inhibition of ic anhydrase—Z: the leo (inhibitory concentration at 50% of maximal ) values are indicated in (incl/l) ‘ -(4-Fluoro—Z—mcthoxyphenyt)—N—{3-[(S— - methylsulfonimidoyl)metl1yl]phenyl} - 1,3,5- >1DEE riazin-Z-amine; enantiomer 1 -(4-F luoro-Z-mcthoxyphcnyi)-N- - methylsulfonimidoyl) inethyl}phenyl} - l ,3 ,5- >1.0E—05 >1.0E-05 triazin-Z-amine; enantiomer 2 205a In the claims which follow and in the preceding description of the ion, except where the context requires otherwise due to express language or necessary implication, the word “comprise” or variations such as “comprises” or “comprising” is used in an inclusive sense, i.e. to specify the presence of the stated features but not to de the presence or addition of further features in s embodiments of the invention. 5937934_1 (GHMallers) P95387.NZ KARENM 12/111141

Claims (7)

Patent claim 1‘ A compound of general formula (I) R5—N o N
1/8 JL ” 2 . wherein R1 represents a group selected from C1-Cg-alkyl-, C3-C7-cycloalkyl-, ltetcrocyclyl-, phenyl, heteroraryl. phenyI-Ct—Cg-alkyl- or heteroaryl-Cleyalkyly wherein said group is optionally substituted with One or two or three substitucnts, 10 identically or differently, selected from the group consisting of hydroxy, cyano, n, halo-Cl-Cs-alkyI-, C|~C5-alkoxy-, fluoroalkoxy-, amino, alkylamino-, dialkylamino-, acetylamino-, yl-N~acetylamino—, cyclic amines; R2 represents a group selected from 8 6 5 R 0,}? 01R \N \ \ R“ R5 R6 | R5 R7 R7 R’ 7&2' O O/\l F O O R6 R6 R6 R“ R7 R7 R7 0tF a; 01 R3 3 R4 ent, independently from each other, a group selected from a hydrogen atom, fluore atom, chioro atom, cyano, Ct~C3—all<yl-, Ct-Cs-alkoxy-, t-Cg-allt’ylg Ct-Cg-fluoroalkoxy-; represents a group selected from a hydrogen atom, cyano, -C(O)R9, -C(O)OR9, -S(O)2R”, - '°R ' ‘, C1-C5-alkyl-, C3-C7ueyeloalkqu heterocycyl-, phenyl, heteroatyl wherein said C lle- Cs-Cv-eycloalkyl-, heterocycyl—, phenyi or heteroaryl group is Optionally tuted with one, two or three substituents, identically or differently, selected from halogen, cyano, hydroxy, C1-C3-alltyl-, Ct—Cs-alkoxy-, amino, alkytamino-, dialkylamjno-, aeetylamino-, N-niethyl~N-aceryiamino—, 10 cyclic amines , halo—Ct-Cg-alkyl-. Ct-Cs-fluoroalkoxy-z R6, R7 represent, independently from each other, a group selected from a hydrogen atom, tluoro atom, chlono atom. cyano, Ct-Cs-alkyh C1-C3-aikoxy-, halo—Ct—Cs-alkyl-, C1-C3- fluoroalkoxy-; represents a group selected from 15 a) a C1-C,o-alkyl group, which is optionally substituted with one or two or three substituems, identically or differently, selected from the group consisting of halogen. hydroxy, amino, mino-, dialkylamino-, acetylamino-, N-methyl-N—acetylamino-, cyclic amines, cyano, Ct-Cs~aIkyI-. halo-Ct-Cs-alkyl-, C1-Cs-fluoroa1koxy-, Ct-Cs-alkoxyw, C2-C3-all<enyl-, Cng-alkynyl-, C3-Cy-cycloalkyl-, heteroeycyl-, phenyl, heteroaryl, 20 wherein said C3-C7-cycloalkyi-, heterocycyl—, phenyl or heteroaryl group is ally tuted with one, two or three substituents, identically or differently, selected item halogen, hydroxy, cyano, Ct-Ca-alkyl-, C1-C3-alkoxy-, amino, alkylamino—, dialkylamino~, acetylamino-, yl-N-acetylamino-, cyclic amines, halo-C t—Cg-alkyl-, C1-C3-fluor0alkoxy—; 25 b) a C3—C7-cyeloalkyl- group, which is optionally substituted with one or two or three substituents, identically or differently, selected from the group consisting of halogen, hydroxy, amino, alkylamino—, dialkylamino—, aeetylamino—, hyl-N-acetylamino—, cyclic amines, cyano, Ct-Cs-alkyl-, halo-C t-C3-alky1-, C1-C3-fluoroall<oxy-, C1-Ca-alkoxy-, C2-C3-alkenyl-, 1lltynyl-; 30 c) a heterocyclyl- group, which is optionally substituted with one or two or three substituenis, identically or differently, selected from the group consisting of halogen. hydroxy, amino, alkylamino-, dialkylamino-, acetylamino-, N-methyl-N-acetylamino-, cyclic amines cyano, all<yl—, halo-Ci-Cs-alkyl-, Ct-C3~tluoroall<oxy-, C1—Ca—rtlkoxy—, C2-C3-alkenyl-, Cszs-alkynyh; d) a phony! group, which is optionally substituted with one or two or three substituents, identically or ently, selected from the group consisting of halogen, y, amino, alkylamino-, dialkylamino-, amino-, N-methyl-N—acctylamino-, cyclic amines, cyano, C1-Cg—all<yl—. halo-Cl-Cg-alkyL, fluoroalkoxy-, CI-Cg-alkoxy-: e) a heteroaiyl group, which is optionally substituted with one or two or three substituents, identically or differently, ed fiom the group consisting of halogen, hydroxy. amino, all<ylamino-, dinlkylamino-, acetylamino-, N-methyl-N-acetylamino-, cyclic amines. cyano, Cl-Cg-alkyl-, halo-Cl-Cs-alkylg C1-C3—fluoroa1koxy-, CtvC3~alkoxy—; t) a phenyl-Ci-Cg-alkyl- group, which is optionally substituted with one or two or three 10 substitucnts, identically or difiercntly, selected from the group consisting of halogen, hydroxy, amino, a1kylamino-, dialkylamino—, acetylamino-, N-methyl-N-acetylaminc-, cyclic amines, cyano, CPCZPEHCYI'. halo-Ct-Cz-alkyl-, Ci-Cz-fluoroalkoxy-, C1-C3-alkoxy-; g) a heteroaryl-Ci-Cg-allql- group, which is optionally substituted with one or two or three substituents, identically or ently, selected from the group consisting of halogen, 15 hydroxy, amino, alkylatnino-, dialkylamino~, acetylatnino-, N~1uetltyl-N-acetylaniino-, cyclic , cyano, C1-C3—alkyl-, halo-Ci-Cg-alkyl-, C1-C3-fluoroall<oxy-, Ci-Cg- all<oxy-; represents a group selected from CrCs-alkyl-, C3-C7-cycloalkyi-, heterocycyl-, phony], beuzyl or lteteroaryl wherein said group is optionally substituted with one, two or three 20 tuents, identically or differently, selected {mm halogen, ltyrlroxy, C1-C3-alkyl-, C1-C3— allcoxy-, amino. alkylamino—. dialkylamino-. acetylamino-, N-methyl-N-acetylamino-, cyclic amines , halo-Ci-Cz-alkyl-, Ct-Cs-fluoroalkoxyv; R10 R11 represent, independently fi‘om each other, a group selected from en, C1~Cs—allcyl-, C3- Cy-cycloalkyl-, heterocycyl-, phenyl or heteroaryl wherein said C1-Ca-alkyl, C3-C7- 25 cycloa ikyl', heterocycyl—, phenyl or aryl group is optionally substituted with one, two or three substituents, identically or differently, selected from halogen, y, Ci—Ci-alkyl-, C1—Ci-alkoxy-, amino, alltylaminog dialkylamino-, acctylamino-, N—inethyl- N-acetylamino-, cyclic amines , halo-Cl-Cs-alkyl-, Ct—Cs-fluorcalkoxy-; or its salts, solvatcs or salts ofsolyatcs.
2. The compound ing to claim I, n Rl represents a group selected from Cu~Cavalkyl-, Ca—C7-cycloalkyl- or heterocyelyl-; R2 represents a group selected from 0’ o o/\ R6 R6 R{3 R7 R7 R7 R6 R° R7 R7 R3, R4 represent, independently from each other, a group selected from a hydrogen atom, fluoro atom, chloro atom or a Cng-alkyl-g R5 represents a group selected from a hydrogen atom, cyano, {(0)1297 .C(O)OR‘7’ -S(O)2R9, 5 'C(O)NRWRI '. Cr-Cn—all<yl-; R6, R7 represent, independently from each other, a group selected from a hydrogen atom, fluoro atom. chloro atom; R8 ents a. group selected from a) a -a1kyl group, which is Optionally tuted with one or two or three 10 substituents, selected from the group consisting of halogen, hydroxy, Cz-Cg-alkenyI-, C2-C3-alkynylg Cz—CT-cyeloallql-, heteroeyeyl-, phenyl. heteroaryl, wherein said C3-Cv-cycloalkyl—, heterocycyl-, phenyl or aryl group is optionally tuted with one, two or three tuents, identically or differently, selected from halogen, cyano, C1-C3-all<yl-, [tale-Ct-Cg-alkyl-; 15 b) a phenyl group; e) a phenyl-Ci-C3~all<yl- group, which phenyl group is optionally substituted with one or two or three substituents, identically or differently, selected from the group consisting of halogen, cyano, Cl-Cg-alkyl—, halo—Ct-Cs-alkyl-; d) ahcteroaryl-Ct-Cg-alkyl- group, which heteroaryl group is optionally substituted with 20 one substituent selected from the group consisting of halogen; R9 represents a Cl -C6-alkyl group; R10, RH. represent, independently from each other, a group selected from hydrogen or Ci-Ca-alkyl-; or its salts. solvates or salts of es.
3. The compound according to claim 1 or 2 of general formula (la) 5 A R—N O N N JL / R" I}: N R2 ('3) , wherein R! represents a C1-C6-alhyl- or C3~Cv-cycloalkyl- group; R2 represents a group selected from R R7 R7 2 a a R’, R‘ represent, independently from each other, a group selected from a hydrogen atom, fluoro 10 atom, chloro atom, Cr—Cz—alkyl-; R5 represents a group selected from a hydrogen atom, cyano, ‘C(O)R9, -C(O)OR”, -C(O)NR‘°R“; R6, R7 ent, independently from each other, a hydrogen atom or fluoro atom; R8 represents a group selected from 1 5 a) a Ci-C o—alkyl group, which is optionally substituted with one or two substituents, ed from the group consisting of hydroxy, C2-C3-alkenyl-, C2-C3-alkynyl-, C3-C7-cycloalkyl-, , heteroaryl, n said C3-C7-cycloalkyI-, phenyl or heteroaryl group is optionally substituted with one, two 01' three substituents, identically or differently. selected frOm halogen, cyano, halo-Ci—Cg-alkyl-z 20 b) a —Ci-Ca-alkyl- group, which phenyl group is optionally substituted with one or two or three substituents, identically or differently, selected from the group consisting of halogen, cyano, halo-Cl-Cg-alkyl-; c) aheteroaryvar—Ca-alkyl- group, which heteroaryl group is optionally substituted with one substituent selected from the group consisting of halogen; Rg represents a Cr-Cc-alkyl group; R“), R” ent, independently from each other, a group selected from hydrogen, C1—C5-a1kyl-; 5 or its salts, cs or salts of solvates.
4. The compound according to claim 1, 2 or 3 of general fomnrla (la) R /\ RL-N o N \ N JL / Rl/ l]! N R2 (la) , wherein R1 represents a group ed from methyl; 10 R2 represents a group selected from 4—fluoro—Z-melhoxypheny1-, 2-(benzyloxy) fluoropl1enyl-, 4,S-difluoro—Z-methoxyphenyl; 2~[(4-fluorobenzyl)oxy]phenyl-, 4-fluoro-Z-[(4—fluorobenzyl)oxy]phenyl ; R3 represents a group selected from a hydrogen atom, fluoro atom, chloro atom; R4 represents a group selected from a hydrogen atom, chloro atom; 15 R5 ents a group selected from a hydrogen atom, —C(0)R9, -C(O)OR9; R9 represents a group selected from methyl or ethyl; or its salts, solvates er salts ofsolvates.
5. The nd according to claim I, 2, 3 or 4 of general formula (la) (Ia) , wherein represents a group selected from methyl; represents a group selected item 4—fluoromethoxyphenyl— or 4,5—dit‘luoro-Z-methoxyphenyl-; represent, independently from each other, a hydrogen atom; represents a en atom; or its salts, solvates or salts ofsolvates.
6. The compound according to claim 1 or 2, wherein R1 represents a group ed from methyl, ethyl, cyclopropy}, tetrahydro—QI-I—pyranyl—; 10 R? represents a group selected from Re R6 R6 R7 R7 R7 o o R6 R6 R7 R7 s I R3, R‘l ent, independently from each other, a group selected from a hydrogen atom, fluoro atom, chloro atom or methyl; represents a group selected from a hydrogen atom, cyano, -C(O)R9, -C(O)OR9, R9, -C(O)NR'°R” or Cl-Cg-alkyl-; 15 R6, R7 represent, independently from each other, a group selected from a hydrogen atom, fluoro atom, chloro atom; represents a group selected from a) a methyl, ethyl propyl or butyl group, which group is optionally substituted with one or two or three substituents, selected from the group consisting ofhalogen , hydroxy, etlrenyl, 20 propenyl, ethynyl-, propynyl—, cyclopentyl-. cyclohexyl, ydre-ZH—pyranyl-, phenyl, pyridinyl-, thiazolyl-, yl, wherein said phenyl or pyridinyl- group is optionally substituted with one, two or three substituents, identically or ently, selected from a fluoro or chloro atom, cyano, methyl, or trifluoromcthyl; b) a (3H2)methyl group substituted with a (2H5)Phenyl group; 5 c) a phenyl group; (1) a benzyl group, which phenyl ring is optionally substituted with one or two or three substituents, identically or differently, selected from the group ting of a fluoro atom, chloro atom, cyano, methyl or trifluoromethyl-; c) a pyridin~2~ylmcthyl- group, which pyridin is optionally substituted with one fluoro 10 atom; t) a pyridin-fi-ylmethyl— group, which pyridin is optionally substituted with one fluoro atom; g) a pyridinylmethyl- group, which pyridin is optionally substituted with one fluoro atom; 15 11) a thiazolylmcthyl- group; i) an oxazolylmethyl- group R9 represents a methyl or ethyl group; 11101 R11 represent, independently from each other, a group selected from hydrogen, methyl; or its salts, solvates or salts of solvates.
7. The nd according to any one of claims 1, 2 or 3, wherein R] represents a methyl or ethyl or cyclopropyl group; R2 represents a group selected from R7 R7 R7 i I 3 R3 ents a group selected from a hydrogen atom, fluoro atom, chloro atom or methyl; R" represents a group selected from a hydrogen atom or fluoro atom R5 represents a group selected from a hydrogen atom, cyano, -C(O)R9, -C(O)0R9, -C(0)N'RwR”; R5, R7 represent, independently from each other, a group selected from a hydrogen atom or fluoro atom; RR represents a group ed frOm methyl, ethyl, propen—l-yl—, 2-methylpropen-ly1-, 2-(hydroxymethyl)propen-1~yl-, (ZZ)-buten-l~y1-, prop-Z-yn- lyl—, butyn—1y1—, exylmethyl-. benzyl-, 3-cyanobcnzy1~, 3—fluorobenzyl-, 3-ohlorobenzyl-, 4-fluorobenzy1-, 4-chlorobenzyl-, 10 3—fluoro—5—(trifluoromethyl)benzyI-, 3~chloro~5-fluorobcnzyl-, pyridin—4-y1~, 2-.fluoropyridin-4—yl—, 2,3,5-t1'ifiuorobenzyl-, 3,4,5—tr'ifluorobenzyl-. R" ents a methyl or ethyl group; R”, R” represent, independently from each other, a group selected from hydrogen, Ca-Ca-alkyL; or its salts, solvates or salts of solvates. The'compound according to claim 1, which is selected from Ethyl [(3- {[4~(4—fluoromethoxyphenyl)—1 ,3,S-triazin-2—yl}amino} benzyl)(methyl)oxide-K6- sulfanylidenekarbamatc, (rac)(4-Fluoromethoxyphenyl)-N- {3-[(S~mclhylsulfonimidoyl)methyflphenyl} —1 ,3.5-triazin—2— amine, 4-(4-Fluerornethoxypheny1)—N— {3 - [(S-1nethylsulfonimidoyl)methyl]phenyl} — 1 ,3,5-triazin—2-amine; enantiomer l, 4-(4-Flu0ro-2—1nethoxyphenyl)-N-{3-[(S-1nethylsultbnlmidoyl)1nethyllphenyl}-l,3,5-triazinamine; enantiomer 2, (rac)-E1hyl {[3—( {4-[2-(benzyloxy)—4—fluorophenyl]-1,3,5-tn'azinyl}amino)benzyl](methyl)0xido-?f— sulfanylidene} earbamatc, (rac)[2-(Benzyloxy)-4—fluorophenyl]-N—{3-[(S—methylsulfonimidoyl)methyl]phenyl}-1,3,5-triazin—2- amine, Benzyloxy)fluorophenylle- {3—{(S-methylsulfonimidoylhnethyl]phenyl} —] ,3,5-triazin~2- amine; enantiomer t, Benzyloxy)fluorophenyl] -N- {3-[(S—methy]sulfonimidoyihncthyl]phenyl} — I ,3,5—triazin amine; cnantiomcr 2. (rad-Ethyl [(3-{[4-(4,S-difluoru-Z-methoxypheny1)-1,3,5-1riaziny11amino}benzyl)(methy1)oxido-XG- sulfanylidcnc]carbamatc, (rac)- 4-(4,5-Difluoro—Z-mcthoxyphcnyl)-N- {3 —[(S-mct]1ylsulfonimidoyl)mcthyl]phcnyl} — 1 .3.S-triazin- 2-ami ne, (rac)-E1hy1 [(3 - {[4-(4—ch]oro-2~methoxyphenyl)- l riazinyl]amino}benzy1)(methyl)oxido—>f’— sulfanylidcnclcarbamatc, (rac) 4-(4—Chl012—nwthoxypl1cnyl')-N- {3-[(S-methylsulfonimidoyl)methy1]phenyl}-1 ,3,5-triazin-2— amine, 4-(4—Chloro-Z-mc’rhoxyphenyiJ-N- {3{(8-methylsulfonimidoyl)mcthyl]phenyl} ~] ,3 azin—2-amine; cnantion‘ler I 4-(4-Chloro-Z-mcthoxyphcnyD-N- {3‘[(S-mcthylsulfonimidoyl)methyl]phcny1} -J ,3,5-triazinaminc; enamiomer 2, (rac)[(3- {{4-(4-F1uoromelhoxyphenyl)-1.3,5—lria2in~2-yl]amino}benzlemclhyDOXido-kfi- ylidcnc] mcthy1urca, 1-[(3- { [4- (4-Flu oro—2-methoxypheny1)—I ,3 ,S-triazin-Z-yllamino} benzyl)(methy1)oxido-7xé— sulfanylidcnc]-3~mcthylurca; cnantiomcr l, 1-[(3- { [4 ~(4-1:luoromethoxyphenyll)-1 ,3,S-triazin-Z-yllamino}benzyl)(1nethyl)oxido-k‘- sulf'any lidene] mcthylurea; cnantiomcr 2, (rad-Ethyl [(3 - {[4-(2,2—difluoro-1,3—benzodioxolyI)-],3.5-triazin—2 -yl]amino} benzyl)(methyl)oxido- XG-sul Fanyh'dcn c] carbamatc, (rac)-4—(2,2-Difluoro-] ,3-benzodioxolyl)-N-{3-[(S-mcthylsuIfonimidoyl)methyl]phenyl}v1,3,5- triazin-Z— amine, (rac)-Ethy1 [(3- {[4—(S—fluoro-Z-methoxyphcnyl}1 riazin-2—yl]amino}bcnzyl)(mcthyl)oxido-?L°- sulfunylidcnekarbamate, (rac)-4—(5—F lu ore-2 -mcthoxyphcnyl)-N- —mcthylsuIfonimidoyi)mcthyl]phcnyl}-1,3,5-friazin amine, 4-(5—FEuOI'o-Z-Incthoxyphcny1)-N-{3-[(S-nmthylsulfmlimidoyl)mcthyl}phcuyl} -} ,3,5-lriazin-'2-aminc; enantiomer l. 4«(5-Fluoro—2—methoxyphenyl}N— {3-[(S-methylsulfonimidoyl)methyl]phenyl} -1,3,5-lriazinamine; cnamiomcr 2, (rac)-N - [(3- { [4-(4—fluoromethoxyphenyl)-1,3,5-triazin-2—yl}amino} benzyl)(methyl)oxido—l°— yiidcnc]acctamidc, (rac)—Ethy1 [(3- {[4-(2-methoxyphcnyl)-1 ,3,5-n'iazin—2-yl]amino}benzyl)(methy1)oxido-X"- sulfanyfidcnckarbamatc, (rac)(2-Methoxyphenyl)*N- {3 -[(S—methylsu lfonimidoyl)methyl]phenyl } - l ,3,S-triazin—Z—aminc, 4-(2—Mcthoxyphcnyl)—N—{3-[(S—methylsulfonimidomeethyl]phenyl}~1,3,5-triazin—2—aminc; enantiomer 4-(2-Methoxyphenyl)—N—{3-[(SmethylsuIfonimidoyl)methyl]phenyl}-1,3,5-triazin—2-amine; enantiomer Eihyl [(3 - {[4-8.4—dihydro—2H~chromen-S—yl)~ I ,3,5~triazin-2—yl]amino} benzyl)(methyl)oxido-K°— sulfanylidcnclcarbamatc, (rac)—4—(3 ,4-DilIydr0-2ki~chromcn-S-yi)-N- f3-[(_S-1ncthylsulfonimidoyl)methyl]phony}} «1,3,5-triazin amine, 4-(3 ,4—Dihydro-2H—chromen—8-yl)-N— {3—[(S-mcthylsulfom’midoyl)mcthyl]phcnyl } ~l ,3,5-triazin—Z- amine; enantiomer 1, 4~(3,4-Dihydro-ZH-chromcnyl)~N~ {3—[(S-mcthylsulfonimidoyl)mcthyl]phcnyl} — l,3,5-1riazin—Z- amine; cnantiomcr 2‘ (rac)-Blhyl [(3-{[4-(2,3-dihydru-}-benzo[‘urdny1)-l,3,S-lfiazin-Z-y]]amino}benzyl)(melhy1)oxido- k“- suifanylidenckarbamatc, (rac)(2,3-Dihydrobenzofi1ranyl)—N-{3-[(S-methylsulfonimidoyl)methyllphenyl}-I,3,5-triazin amine, 4-(2,3-Dihydrobeuzofuranyl)-N-{3-[(S—methylsulibnimidoyl)methyi]phenyl}-1,3,5-triazin amine: cuantiomcr 1. 4—(2,3 -Dihydro-1 -benzofi1ranyl)-N— {3-[(S-methylsulfonimidoyl)methyl]phenyl} -1 .3,5-triazin amine; enamiomer 2, (rac)—Ethy1 [(3— {[4-(2,3-dihydro-J .4-benzodioxin-5~yl)~l,3,5-1riazin»2—yl]amino] benzyl)(rnethy])oxido- 7x.°-sulf‘anylidene]carbamatc, 4-(2,3-Dihydru-] ,4-bcnzodioxin‘5-yi)»N S—methylsuifonimidoyi)methy11phcnyl}-1,3,5- n-Z-umine, 4—(2,3-Dihydro-l ,4-bcnzodioxinyl)-N- {3-[(S-mcthylsulfonimidoyl)mcthyl]phcnyl } -1 ,3 ,S-rriazin-Z- amine; cnantiomcr 1, 4-(2,3-Dihydro—l ,4-benzudioxin-S-yl)-N- {3-[(S-mcthylsulfonimidoyl)Inethyl]phcnyl} -] ,3 ,5-lriaziu—2- amine; enamiomer 2. (rac)-N- {3- [(N,S~DimethyIsulfonimidoyl)melhyl]phenyl} fluoro—Z-methoxyphcnyl)~1 ,3,5-triazin—2- amine, (rad-Ethyl [{3 —[(4-{2»[(4-fluorobcnzyl)oxy]phenyl}-1 ,3,5-t11'azinyl)amino]bcnzyl}(methy1)0xido-)\°~ sulfanylidcnckarbamalc. (rac) {2—[(4—F1uorobenzy1)oxy]phenyl}-N—{3 -{(S-methylsulfonimidoyl)methyl]pheny1}-1,3,5—Iriazin~ Z-amine, N—[(3- {[4-(4-Fluoro-Z-mcthoxyphenyl)-I ,3,5—triazinyl}amino}benzyl)(methy1)oxido-l6— sulfanyiidcnc}methancsulfonamidc, (racj—Eihyl {(3 - { [4-(3 -chloro-?.-methoxyphenyl)- I ,3 ,5-triazin—2-y1]amino} benzy1)(methyl)oxide-9.6- sukfanylidcnckarbamatc, (rac)-Ethyl {{3 -({4-[5-fluoro-Z—(telrahy(ho-ZH—pyran-tI-ylmethoxy)phenyl]-1 ,3,5-triaz'1n—2- yl} amino)b enzyl] (methyl)oxide-kG—sulfanylidenc} atc, (rac)-Ethy1 [mcthyt(oxido)(3- -phcnoxyphcnyl)-1 ,3,S—tri azin-Z-yl]amino } bcnzyl)—k"- 511 l fanylidcnckarbamatc, (rac)-[(_3~{[4-(4-fluo1'0methoxyphenyl)—1,3.S-triazin-2—yl]amino}benzyl)(mcthyl)oxido-l‘~ sulfany lidene}cyanamide, [(3- {[4 o romethoxyphenyl)-1,3,S-triazin-2~yl]amino} benzyl)(methyl)oxido-k6- sulfanylidcnckyanamidc; cnantiomcr 1, [(3~ { [4-(4~fluoro-2—mcthoxyphcnyl)- 1,3,5-h‘iazin—2-yl]amino} benzy])(mcthyl)oxido-7L6- sulfanyfidenc]cyanamide; mncr 2, (rad-Ethyl [(3 -f|uoro-5 - {[4-(4-fluoromcthoxyphenyl)- I ,3,5-triazinyl]amino } benzyl)(mcthyi)- oxido-}»G-sulfanylidene}oarbamate, (rac)-4~(4-Fluoromethoxyphcnyl)-N- {3-flu oro-S-[(S-mcfhylsulfonimidoyl)mcthy1]phenyl} - l ,3,5- triazin—Z -amine, 4-(4-FIu0rome1hoxypheny1)-N—{3-fluoro—S—[(S-melhylsulfonimidoy1)melhyl]phenyl}-1 .3,5-1riazin amine, omcr I , 4-(4-FluoromethoxyphenyI)-N-{3-fluoro-S-[(S~methylsulfonimidoyl)methyl]phenyl}-1,3,5-triazin amine, cnantiomcr 2, (rac)[2-(Cyclohexylmethoxy)fluor01)llenyI}-N- {3-[(S-methylsulfonimidoyl)methyl]phony]} - 1 ,3 ,5 - triazina1nine, (rac) {44Fluoro[(4—fluorobenzy1)oxy]pheny1} -N- { methylsu1fonimidoy1)methyl]phenyl} - 1,3,5—triazin—2—amine, (rac) {4—Fluoro -2—[2-(tetrahydro—2H—pyran—4-yl)cthoxy3phcnyl} —N- {3 —[(S- methylsulfonimidoylhnethyl]phenyl} - I ,3,5-triazinamine, (rac)-4—(4-F1uor0—2-mcthoxyphcnyl)-N-(3 - {[S-(1ctrahydro-2H-pyran~4- y1)sulfonimidoyl]methy1}phenyl)- l ,3 ,5-triazin-2—amine, N— {4-Chloro{(S-mcthylsuifonimidoyl)methyl]phenyl} (4-fluoromcthoxyphcnyi)— I ,3,5~ triazin-Z—amine, (rad—Ethyl [ {3 - [(4— {2- [(3 ,4—(1ichlorobenzyl)oxy]phcnyl}~1,3.5-triazin—2— yl)amino]benzy1} (methyl)oxido-K6— sulfanylidenekarbamate, (rac) {2-[(3,4-Dichlorobenzyl)oxy]phenyl] ~N- {3—[(S—methylsulfonimidoyDmethyl]phenyl} -1,3,5- triazin—Z-amine, (rac)—4-(4-FIuoro {[(2H5)phenyl(zl~12)methyl]oxy} phenyl)-N- {3 -[(s- methylsulfonimidoyl)mcthyl]phcnyl} ~ I riazin-2—aminc, 4—[2-(1 -cyclupentylethoxy)fluorophenyl]—N- {3-[(S-methylsu1funimidoyl)methy1]phenyl} - 1 ,3,5— triazin—Z-aminc, (rad-N-{3-Chloro-S-[(S-mcthylsulfonimidoyl)mcthyl]phcnyl}~4-(4-f‘luoromothoxyphcnyl)-1,3,5- triazin-Z-aminc, (rac)[4-F luoro(3,3‘3-trifluoropropoxy)pheny1]—N- {3—[(_S—methylsuifonimidoyI) methyl] pllcnyl } - 1,3,5-triazinamine, (rac)~4—[4-Fluoro—Z-(pyridin—3~y]methoxy)phcnyl}-N- -methylsu1fonimidoyl)methyl]phenyl} - l,3,5-triazin~2~aminc, (rac)-4—{4-Flu0ro—2~(pyridin-2—ylmcthoxy)pl1cny1]-N- {3-[(S-mcthylsulfonimidoyI)mcthy1}phcnyl} - 1,3 . 5-triazinamine, (rac)[4-Fluor0»2~(pyridinylmcthoxy)phcnyl] -N- {3-[(S-methylsulfonimidoy1)methyl]phenyl} - 1,3 ,S—triazin-Z-amine, 4- {4-FIuoro-2—[J -(4-fluorophcnyl)cthoxy]phenyl}—N~ { 3w[(S-mcthylsulfonimidoyl) methyl]phenyl} - l ,3 ,5 triazin-Z-amine, e of 4 stcrcoisomers, (rac)-[(3-FIuoro—5-{[4-(4-fluoromelhoxyphenyl)-I,3,5‘lriazinyl]amino}benzylxmelhyl-M- sulfanylidene]cyanamide, [(3-Fluoro {[4-(4~fluoromethoxypheny1)-1 ,3 ,5-triazinyi]amino}benzlemethyi—M- sulfanylidcnc]cyanamidc; cnantiomcr l, [(3-Fluoro—5- -fluoro-Z-methoxyphenyl)—1 ,3 ,5-triazin—2-yl]amino}benzlemethyl—lé- sulfanylidcne]cyanamide; omer 2, (rac)—4-[2—(But—2-yn— l )-fluor0phenyl]-N- {3-[(Smethylsulfonimidoyl)methyl]phenyi} - l ,3,5- triazin—Z-amine, 4-[2—(But—2-yn-l -yloxy)-4—fluorophcnyl] -N - {3—[(S-rnethylsulfonimidoyl)methyl]phenyl} - I ,3,5~triazin— 2-a1niue; cnantiomcr 1, 4-[2-(Butym l ~yloxy)fluorophcnyl] -N- {3-[(S-mcthylsuifonimidomeethyflphcny1}-I,3,5-triazin— Z-amine; enamiomer 2, (rac)—4-[29(2-Cyclopropylethoxy)—4-fluorophcnyl]-N- {3-[(S-methyisulfonimidoy1)methyl]phenyl} - 1,3,5—tTiazinamine, (rac)—4-[4-Fluoro—2-(prop-Z-yn—l ~yloxy)phenyl]-N— {3-[(S-metllylsulfonimidoy])mclhyl]pheny1}-1 ,3,5- triazin-Z-amine, 4-{4-Fluuru-2~(propyn~I wyloxy)phenyl}-N— {3—[(S—methylsulfonimidoyl)methy1]phenyl}-] riazin- 2-amine; enanfiomcr 1, 4—[4-Fluoro~2-(propyn—1-yloxy)pheny!]-N-{3-[(S-methylsulfoninfidoyl)methyl]phenyl} -1 =3 ,S-triazin- 2-aminc; omcr 2, 4— {2-[(3,4-Difluorobenzy1)oxy}—4-flu0rophenyl}-N- {3 - [(S-methylsuifonimidoyl)methyljpheny1} — 1,3.5-triazin-2—aminc, (rac)[4-Fluor0(1 ,3—thiazol—S-ylmcthoxy)phcnyl]-N- {3-[(S—mcthylsulfonimi doy1)mcthy1]phcny!}- 1,3,5-triazinaminc, (rac)-4~§4-Fluoro-Z—[(2-fluoropyridiny!)mcthoxy]phenyl} —N— - meifiylsulfonimidoyDmethyflphenyl} - l riazinamine, 4- {4-Fluoro—2—[(Z-fluoropyridiny1)methoxy]phenyl} ~N~ {3-[(S-methylsulfonimidoyI)mcthyl]phenyl} - l,3,5-triazin~2-aminc; cnantiomcr 1, 4- {4-Fluoro[ ropyridin—4-yi)mothoxy]phcnyl } -N— {3-[(S~mcthylsulfonimidoyl)mcthyl]phcnyi} - 1,3,5-triazinamine; enantiomer 2, (rac)[4-FIuoro—2-(prop-2—cnonxy)phcnyl]-N~{3-[(S-methyisu1fonimidoyl)methyl]pheny1}-] ,3,5- triazin-Z-amine, (ra c)(4-Fluoro {[4—(h‘if1uoromethyl)bcnzyl]oxy}phe‘nyl)-N-{3-[(S- met11ylsultbnimidoyifinethyljphenyl} - l ,3,5-triazinamine, (rac)—4- {2—[(4-Chlorob enzyl)oxy]fluurophenyl} -N- { 3 - [(S-methylsulfonimiduy l)methyl}pheny1} - I ,3,5—triazin-2~amine, (rac)(2-Ethoxy-4—fluorophenyI)-N- {3-[(S-methylsulfonimidomeethyl]phenyl} - 1,3,5-m'azin amine, (rac)(4-Fluoro {[3-fluoro~5—(trifluoron1cthyl)bcuzyl}oxy}phenyl)-N- { 3~ [(S- mcthylsulfonimidoylhncthy3}phenyl} — l ,3,5-t1‘iazinamine, (rao) {4-Fluoro-Z-[(3-fluorobenzyl)oxy}phcnyl} -N- {3—[(S-methylsulfonimidoyl)methyl]phenyl} - 1,3,5—triazinaminc, (rac)-4—(4-Fluoro—2-propoxyphenyl)~N - -mcthylsulfonimidoyl)methyl]phcnyl} - 1,3,5 —triazin-2— amine, (rac) {2-{(3-Chlorob cnzy])oxy]—4-fluorophcnyl} nN— {3 — [(S-methyIsu1fonimiduyl)mcthyl}phcnyl} - 1,3,5-triazin1mine, (rac)[4-Fluoro~2-(1 ,2-ox azolyimethoxy)phenyl]—N— { 3—[(S—metl1ylsulfonimidoyl)methyl]phenyl}~ 1,3,5-rriazin1mine, (rac) {2-[(3-Chlorofluorobenzyl)oxy]-4—fluoroplxenyl}-N- {3—[(S- methylsulfouimidoyl)methyl]phenyl} - l ,3.5-triazin—2—amine, 4-[2-(2,2-Difluoroethoxy)-4—fluorophcnyl] ~N— {3-[(S-mcthylsulf‘onimidoyl)methyl]phenyl} -1’3’5- triazin‘Z-aminc, (rac) {4-Flu oro[(4-fluoro-3 -methylbenzyl)oxy] } -N- {3-[(S— Incthylsulfonimidoyi)mcthy1]phcnyl} - l ,3,5—triazinaminc, (rac){2-[(3-Chloro—4—fluorobenzy1)oxy]flu0rophenyl}-N—{Ii-[($- mcthylsulfonimidoylhncthyl]phcnyl} - l ,3,5—triazin-2~aminc, (rac)—3—( { 5-Fluoro-2—[4-( {3-[(S-mcthyisulfonimi doyI)mcthyl]phcnyl } —1 ,3,5—triazin-Z- yl}pl1cnoxy} )bcnzonitrilc, (rac)-4~{4-Fluoro[(2—mcthylpropenyl)oxy]phenyl}-N- {3 - [(S— methylsulfonimiduy1)melhyl]phenyl}-1,3,5-triazinamine, 4- [4~Flu01'o~2«(4 .4,4 ~trifluorobutoxy)phenyl] »N— {3 ~ [(S-methylsulfonimidoyl)methy1}phenyl} - 1,3,5-triazinaminc, (rac)-4— {4-Flu0ro-2—[(2,3,5~trifluorobcnzyl)oxy]phcnyl} ~N- { 3-[(S— methylsulfonimidoyl)1nethyl]phenyI}-l.3,5—triazin-2—amine, (rac) {2-[(2Z)-Buten~ I -yloxy]fiuorophcnyl} «N- {3-[(S-mcthyIsulfonimidoylhnethylJphenyl}- 1,3,5-triazinamine, 4— {4-Fluoro-Z-[(2,4,S-triflu orobcnzyl)oxy]pheny}}~N- { 3-[(S- methylsulfonimidoyl)mcthyljphcnyl} - l ,3,5—triazinaminc, (rac) {4-F1uur0[(3,4,5-lrifluorobenzyl)uxy]phenyl} -N- {3-[(S- methylsulfonimidoyl)methyIJphenyl} — l ,3,5—triazin~2~aminc, (rac)-[(2,3-Difluoro{[4-(4-fluoromethoxyphenyl)-l,3,5-niazin—2-y1}amino}benzyl)(methyl)oxido- ké-sulfanyli dcnclcyanamidc, (rac)-N- {3 ,4-Difluoro-S-[(S-methylsulfouimidoylflneihyl]phenyi} (4-fluoromethoxypl'leny1)- 1 ,3,5— triaziu—Z-amine. (rac)r[Ethyl(3-1'[4-(4~fluoro—2-methoxyphenyl)— I ,3,5—triazinyl]amino } benzyl)oxido-?~‘- sulfa nyliclenc] cyana mid e, (rac)'N'- {3- [(S-ethylsulfonimidoyl)methyl]phenyl}—4-(4-f1u0romethoxyphcnyi)~l ,3 ,5-triazinaminc N- {3«[(S -cthylsu1foni1nidoyl)methyl]phcnyl} ~4-(4-flu0r0methoxyphenyl)-1 riazin—2 amine; omcr l , N-{3-[(S-ethylsulfonimidoyl)methy1]phenyl}(4-fluoromethoxyphenyl)—1,3,5-Iriazin—2-amine; enamiomcr 2, (rac)-[(3- {[4-(4~Fluoro—Z«methoxyphenyl)—I ,3 ,S-Iriazin—Z—yl]amino} -Svmethylbcnzyi) (methyl) oxide-7.6- sulfauylidene]cyanamide, (rac)—2-({5-Pluoro[4~({3-[(S-methylsulfonimidoy])methyl]phenyl}amino)—1,3,S-triazin yl]phenoxy} )prop~2-enol, (rac)—[Cyclopropy1(3 - {[4-(4—fluoro-Z-methoxyphenyl)—1,3,5—triazin-‘2-yl]amino}benzyl)oxido~?c6- ylidene]cyanamidc, or its salts, soivatcs or salts of solvatcs. 9. A compound of general formula (I) or (Ia) according to any one of claims 1 to 8 for the ent and/or prophylaxis ofhyper-proliferalive disorders, viraliy induced infectious diseases and/or of 5 cardiovascular diseases. 10. A phannaccutical combinatiori comprising a compound according to any one ofclaims 1 to 8 in combination with at least one or more further active ingredients. 10 11. A pharmaceutical composition comprising a compound according to any one of claims I to 8 in combination with an inert, nontoxic, pharmaceutically suitable adjuvant. 12. The pharmaceutical combination according to claim 10 for the treatment and/or prophylaxis of hyper-proliferative disorders, vitally induced ious diseases and/or of cardiovascular diseases. l3. The pharmaceutical ition according to claim 1 l for the treatment and/or prophylaxis of hyper- proiiferativc ers, vitally induced infectious disease; and/or ofcardiovascular diseases. [4. A compound of general a (3) > a 4 R O R N O N N 0
NZ617628A 2011-05-24 2012-05-21 4-aryl-n-phenyl-1,3,5-triazin-2-amines containing a sulfoximine group NZ617628B2 (en)

Applications Claiming Priority (7)

Application Number Priority Date Filing Date Title
EP11167317A EP2527332A1 (en) 2011-05-24 2011-05-24 4-Aryl-N-phenyl-1,3,5-triazin-2-amines containing a sulfoximine group as CDK9 inhibitors
EP11167317.4 2011-05-24
EP11180759 2011-09-09
EP11180759.0 2011-09-09
EP12158030 2012-03-05
EP12158030.2 2012-03-05
PCT/EP2012/059399 WO2012160034A1 (en) 2011-05-24 2012-05-21 4-aryl-n-phenyl-1,3,5-triazin-2-amines containing a sulfoximine group

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NZ617628B2 true NZ617628B2 (en) 2015-03-25

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