WO1999001423A1 - Glucagon antagonists/inverse agonists - Google Patents

Glucagon antagonists/inverse agonists Download PDF

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Publication number
WO1999001423A1
WO1999001423A1 PCT/DK1998/000287 DK9800287W WO9901423A1 WO 1999001423 A1 WO1999001423 A1 WO 1999001423A1 DK 9800287 W DK9800287 W DK 9800287W WO 9901423 A1 WO9901423 A1 WO 9901423A1
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WO
WIPO (PCT)
Prior art keywords
lower alkyl
γçö
aryl
hydrogen
compound according
Prior art date
Application number
PCT/DK1998/000287
Other languages
French (fr)
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WO1999001423A8 (en
Inventor
Anthony Ling
Vlad Gregor
Javier Gonzales
Yufeng Hong
Dan Kiel
Atsuo Kuki
Shenghua Shi
Lars Naerum
Peter Madsen
Christian Sams
Jesper Lau
Michael Bruno Plewe
Jun Feng
Min Teng
Michael David Johnson
Kimberly Ann Teston
Ulla Grove Sidelmann
Lotte Bjerre Knudsen
Original Assignee
Novo Nordisk A/S
Agouron Pharmaceuticals, Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
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Publication date
Application filed by Novo Nordisk A/S, Agouron Pharmaceuticals, Inc. filed Critical Novo Nordisk A/S
Priority to JP50616099A priority Critical patent/JP2003514508A/en
Priority to AU79083/98A priority patent/AU749271B2/en
Priority to CA002294046A priority patent/CA2294046A1/en
Priority to BR9810378-4A priority patent/BR9810378A/en
Priority to IL13337798A priority patent/IL133377A0/en
Priority to HU0002373A priority patent/HUP0002373A3/en
Priority to EP98929244A priority patent/EP0994848A1/en
Publication of WO1999001423A1 publication Critical patent/WO1999001423A1/en
Publication of WO1999001423A8 publication Critical patent/WO1999001423A8/en
Priority to NO996550A priority patent/NO996550L/en

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    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
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Definitions

  • the present invention relates to agents that act to antagonize the action of the giucagon peptide hormone. It relates particularly to non-peptide giucagon antagonists or inverse agonists.
  • Giucagon is a key hormonal agent that, in cooperation with insulin, mediates homeostatic regulation of the amount of glucose in the blood. Giucagon primarily acts by stimulating certain cells (mostly liver cells) to release glucose when blood glucose levels fall. The action of giucagon is opposed by insulin which stimulates cells to take up and store glucose whenever blood glucose levels rise. Both giucagon and insulin are peptide hormones.
  • Giucagon is produced in the alpha islet cells and insulin in the beta islet cells of the pancreas.
  • Diabetes mellitus the common disorder of glucose metabolism, is characterized by hypergly- cemia, and can present as type I, insulin-dependent, or type II, a form that is non-insulin- dependent in character.
  • Subjects with type I diabetes are hyperglycemic and hypoinsulinemic, and the conventional treatment for this form of the disease is to provide insulin.
  • absolute or relative elevated giucagon levels have been shown to contribute to the hyperglycemic state.
  • giucagon can be suppressed by providing an antagonist or an inverse agonist, substances that inhibit or prevent giucagon induced response.
  • the antagonist can be peptide or non-peptide in nature.
  • Native giucagon is a 29 amino acid- containing peptide having the sequence: His-Ser-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Tyr-Ser-Lys-Tyr-Leu-Asp-Ser-Arg-Arg-Ala-Gln-Asp- Phe-Val-Gln-Trp-Leu-Met-Asn-Thr-NH 2 .
  • Giucagon exerts its action by binding to and activating its receptor, which is part of the Glu- cagon-Secretin branch of the 7-transmembrane G-protein coupled receptor family (Jelinek et al. Science 259, 1614, (1993)).
  • the receptor functions by activation of the adenylyl cyclase second messenger system and the result is an increase in cA P levels.
  • Peptide antagonists of peptide hormones are often quite potent; however, they are defective as drugs because of degradation by physiological enzymes, and poor biodistribution. Therefore, non-peptide antagonists of the peptide hormones are preferred.
  • non-peptide glu- cagon antagonists a quinoxaline derivative, (2-styryl-3-[3-(dimethylamino)propylmethyl- amino]-6,7-dichloroquinoxaline was found to displace giucagon from the rat liver receptor (Collins, J.L. et al. (1992) Bioorganic and Medicinal Chemistry Letters 2(9):915-918). West, R.R.- et al.
  • WO 94/14426 discloses use of skyrin, a natural product comprising a pair of linked 9,10-anthracenedione groups, and its synthetic analogues, as giucagon antagonists.
  • Anderson, P.L., U.S. Patent No. 4,359,474 discloses the giucagon antagonistic properties of 1- phenyl pyrazole derivatives.
  • Barcza, S., U.S. Patent No. 4,374,130 discloses substituted disi- lacyclohexanes as giucagon antagonists.
  • WO 98/04528 (Bayer Corporation) discloses substituted pyridines and biphenyls as giucagon antagonists.
  • WO 97/16442 discloses substituted pyridyl pyrroles as giucagon antagonists
  • WO 98/21957 discloses 2,4-diaryl-5-pyridylimidazoles as giucagon antagonists. These giucagon antagonists differ structurally from the present compounds. Description of the invention
  • Halogen designates an atom selected from the group consisting of F, Cl, Br or I.
  • alkyl in the present context designates a hydrocarbon chain or a ring that is either saturated or unsaturated (containing one or more double or triple bonds where feasible) of from 1 to 10 carbon atoms in either a linear or branched or cyclic configuration.
  • alkyl includes for example n-octyl, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, allyl, propargyl, 2- hexynyl, cyclopropyl, cyclopropylmethyl, cyclopentyl, cyclohexyl, cyclooctyl, 4-cyclohexylbutyl, and the like.
  • non-limiting examples are sec-butyl, n-pentyl, isopentyl, neopentyl, te/ ⁇ -pentyl, n- hexyl, isohexyl, n-heptyl, n-nonyl, n-decyl, vinyl, 1-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-methyl-1-propenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 3-met.hyl-2-but.enyl, 1- hexenyl, 3-hexenyl, 2,4-hexadienyl, 5-hexenyl, 1-heptenyl, 2,4-heptadienyl, 1-octenyl, 2,4- octadienyi, ethynyl, 1-propynyl, 1-butynyl, 2-butyn
  • lower alkyl designates a hydrocarbon moiety specified above, of from 1 to 6 carbon atoms.
  • Aryl means an aromatic ring moiety, for example: phenyl, naphthyl, furyl, thienyl, pyrrolyl, pyridyl, pyrimidinyl, pyrazolyl, imidazolyl, pyrazinyl, pyridazinyl, 1 ,2,3-triazinyl, 1 ,2,4-triazinyl, oxazolyl, isoxazolyl, 1 ,2,3-oxadiazolyl, 1 ,2,4-oxadiazolyl, 1 ,3,4-oxadiazolyl, 1 ,2,3-thiadiazolyl, 1 ,2,4-thiadiazolyl, 1 ,3,4-thiadiazolyl, thiazolyl, isothiazolyl, tetrazolyl, 1-H-tetrazol-5-yl, indolyl, quinolyl, quinazolinyl, benzofuryl, be
  • Non-limiting examples are biphenyl, anthracenyl, phenanthrenyl, fluorenyl, indenyl, 1 ,2,3,4-tetrahydronaphthyl, 2,3-dihydrobenzofuryl, triazolyl, pyranyl, thiadiazinyl, isoindolyl, in- dazolyl, 1 ,2,5-oxadiazolyl, 1 ,2,5-thiadiazolyl, benzothienyl, benzimidazolyl, benzthiazolyl, ben- maiothiazolyl, benzoxazolyl, benzisoxazolyl, purinyl, quinolizinyl, isoquinolyl, quinoxalinyl, naphthyridinyl, pteridinyl, carbazolyl, acridinyl, pyrrolinyl, pyrazolinyl, indolinyl, pyrrolidinyl
  • the aryl moieties are optionally substituted by one or more substituents, for example selected from the group consisting of F, Cl, I, and Br; lower alkyl; lower alkanoyl such as formyl, acetyl, propionyl, butyryl, valeryl, hexanoyl and the like; -OH; -NO 2 ; -CN; -CO 2 H; -O-lower alkyl; aryl; aryl-lower alkyl; -CO 2 CH 3 ; -CONH 2 ; -OCH 2 CONH 2 ; -NH 2 ; -N(CH 3 ) 2 ; -SO 2 NH 2 ; -OCHF 2 ; -CF 3 ; -OCF 3 and the like.
  • Such aryl moieties may also be substituted by two substituents forming a bridge, for example -OCH 2 O-.
  • Aryl-lower alkyl means a lower alkyl as defined above, substituted by an aryl, for example:
  • the aryl group is optionally substituted as described above.
  • the present invention is based on the unexpected observation that compounds having a selected nitrogen-bearing central motif and the general structural features disclosed below antagonize the action of giucagon. Accordingly, the invention is concerned with compounds of the general formula
  • R 1 and R 2 independently are hydrogen or lower alkyl or together form a valence bond
  • R 3 and R 4 independently are hydrogen or lower alkyl
  • n 0, 1, 2 or 3;
  • n 0 or 1 ;
  • R 5 is hydrogen, lower alkyl, aryl-lower alkyl or -OR 6 ;
  • R 6 is hydrogen, lower alkyl, aryl or aryl-lower alkyl
  • R 7 is hydrogen, halogen, -CN, -CF 3 , -OCF 3 , -OCH 2 CF 3 , -NO 2 , -OR 11 , -NR 11 R 12 , lower alkyl, aryl, aryl-lower alkyl, -SCF 3 , -SO 2 NR 11 R 12 , -SR 11 , -CHF 2 , -OCHF 2 , -OSO 2 R 11 , -CONR 11 R 12 , -OCH 2 CONR 11 R 12 , -CH 2 OR 11 , -CH 2 NR 11 R 12 , -OCOR 11 , -CO 2 R 13 or -OSO 2 CF 3 ;
  • R 8 and R 9 independently are hydrogen, halogen, -CN, -CF 3 , -OCF 3 , -OCH 2 CF 3 , -NO 2 , -OR 11 , -NR 11 R 12 , lower alkyl, aryl, -SCF 3 , -SR 11 , -CHF 2 , -OCHF 2 , -OSO 2 R 11 , -CONR 11 R 12 , -CH 2 OR 11 , -CH 2 NR 11 R 12 , -OCOR 11 , -CO 2 R 13 or -OSO 2 CF 3 , or R 8 and R 9 together form a bridge -OCH 2 O- or -OCH 2 CH 2 O-;
  • R 11 and R 12 independently are hydrogen, -COR 13 , -SO 2 R 13 , lower alkyl or aryl;
  • R 13 is hydrogen, lower alkyl, aryl-lower alkyl or aryl
  • R 10 is hydrogen, lower alkyl, aryl-lower alkyl or aryl;
  • R 14 and R 15 independently are hydrogen, halogen, -CN, -CF 3 , -OCF 3> -O(CH 2 ) ! CF 3 , -NO 2 , -OR 16 , -NR 16 R 17 , lower alkyl, aryl, aryl-lower alkyl, -SCF 3 , -SR 16 , -CHF 2 , -OCHF 2 , -OCF 2 CHF 2 , -OSO 2 CF 3 , -CONR 16 R 17 , -(CH 2 ),CONR 16 R 17 , -O(CH 2 ),CONR 16 R 17 , -(CH 2 ),COR 16 , -(CH 2 ),COR 16 , -(CH 2 ),COR 16 , -(CH 2 ),OR 16 , -O(CH 2 ),OR 16 , -(CH 2 ),NR 16 R 17 , -O(CH 2 ),NR 16 R 17 ,
  • I is 1 , 2, 3 or 4;
  • R 16 and R 17 independently are hydrogen, -COR 18 , -SO 2 R 18 , lower alkyl, aryl, or R 16 and R 17 together form a cyclic alkyl bridge containing from 2 to 7 carbon atoms;
  • R 18 is hydrogen, lower alkyl, aryl or aryl-lower alkyl
  • Q is -NR 23 -, -O- or -S-;
  • R 19 , R 20 , R 21 and R 22 independently are hydrogen, halogen, -CN, -CF 3 , -OCF 3 , -OCH 2 CF 3 , -NO 2 , -OR 24 , -NR 24 R 25 , lower alkyl, aryl, aryl-lower alkyl, -SCF 3 , -SR 24 , -CHF 2 , -OCHF 2 , -OCF 2 CHF 2 , -OSO 2 CF 3 , -CONR 24 R 25 , -CH 2 CONR 24 R 25 , -OCH 2 CONR 24 R 25 , -CH 2 OR 24 , -CH 2 NR 4 R 25 , -OCOR 24 or -CO 2 R 24 , or R 19 and R 20 , R 20 and R 21 , or R 21 and R 22 together form a bridge -OCH 2 O-; wherein R 24 and R 25 independently are hydrogen, -COR 26 , -SO
  • R 26 is hydrogen, lower alkyl, aryl or aryl-lower alkyl
  • R 23 is hydrogen, lower alkyl, aryl or aryl-lower alkyl
  • R 3a , R 3b , R 4a and R 4b independently are hydrogen, halogen, -CN, -CF 3 , -OCF 3 , -OCH 2 CF 3 , -NO 2 , -OR 24a , -NR 24a R 25a , lower alkyl, aryl, aryl-lower alkyl, -SCF 3 , -SR 24a , -CHF 2 , -OCHF 2 , -OCF 2 CHF 2, -OSO 2 CF 3 , -CONR 24a R 25a , -CH 2 CONR 24a R 25a , -OCH 2 CONR 24a R 5a , -CH 2 OR 24a , -CH 2 NR 24a R 25a , -OCOR 24a or -CO 2 R 24a ;
  • R 24a and R 25a independently are hydrogen, -COR 26a , -SO 2 R 26a , lower alkyl, aryl or aryl-lower alkyl;
  • R 26a is hydrogen, lower alkyl, aryl or aryl-lower alkyl
  • R 3a and R 3b , R 4a and R 4b , or R 3a and R 4b together form a bridge -(CH 2 ) r ;
  • i is 1 , 2, 3 or 4;
  • a, b, c and d independently are 0, 1 , 2, 3 or 4; e, f and p independently are 0 or 1 ;
  • q 0, 1 or 2;
  • R 5a and R 5b independently are hydrogen, lower alkyl, -OH, -(CH 2 ) k -OR 6a , -COR 6a , -(CH 2 ) k -CH(OR 6a ) 2 , -(CH 2 ) k -CN, -(CH 2 ) k -NR 6a R 6b , aryl, aryl-lower alkyl, -(CH 2 ) g -COOR 43 or (CH 2 ) g -CF 3 ;
  • k is 1 , 2, 3 or 4;
  • R 6a and R 6b independently are hydrogen, lower alkyl, aryl or aryl-lower alkyl
  • g 0, 1 , 2, 3 or 4;
  • R 43 is hydrogen or lower alkyl
  • G" is -OCH 2 CO-, -CH 2 CO-, -CO- or a valence bond
  • F' is >CR 38 - or >N-;
  • Q' is -NR 36 -, -O- or -S-;
  • R 27 , R 28 , R 32 , R 33 , R ⁇ and R 35 independently are hydrogen, halogen, -CN, -CF 3 , -O(CH 2 ) y CF 3 , -(CH 2 ) y NHCOCF 3 , -NO 2 , lower alkyl, aryl, aryl-lower alkyl, -SCF 3 , -SR 29 , -CHF 2 , -OCHF 2 , -OCF 2 CHF 2 , -OSO 2 R 29 , -OSO 2 CF 3 , -(CH 2 ) y CONR 29 R 30 , -O(CH 2 ) y CONR 29 R 30 , -(CH 2 ) y OR 29 , -(CH 2 ) y NR 29 R 30 , -OCOR 29 , -COR 29 or -CO 2 R 29 ;
  • R 27 and R 28 , R 32 and R 33 , R 33 and R 34 , or R 34 and R 35 together form a bridge -O(CH 2 ) y O-;
  • y is 0, 1 , 2, 3 or 4;
  • R 29 and R 30 independently are hydrogen, -COR 31 , -CO 2 R 31 , -SO 2 R 31 , lower alkyl, aryl or aryl-lower alkyl; wherein R 31 is hydrogen, lower alkyl, aryl or aryl-lower alkyl;
  • R 36 and R 39 independently are hydrogen, lower alkyl, aryl or aryl-lower alkyl
  • R 38 is hydrogen, -OR 40 , -NR 40 R 41 , lower alkyl, aryl, aryl-lower alkyl, -SCF 3 , -SR 40 , -CHF 2 , -OCHF 2 , -OCF 2 CHF 2 , -CONR 40 R 41 , -(CH 2 ) X CONR 40 R 41 , -O(CH 2 ) X CONR 40 R 41 , -(CH 2 ) x OR 40 , -(CH 2 ) X NR 40 R 41 , -OCOR 40 or -C0 2 R 40 ;
  • x is 1 , 2, 3 or 4;
  • R 40 and R 41 independently are hydrogen, -COR 42 , -SO 2 R 42 , lower alkyl, aryl or aryl-lower alkyl;
  • R 42 is hydrogen, lower alkyl, aryl or aryl-lower alkyl
  • R 19 , R 20 , R 21 , R 22 and R 23 may alternatively be re- placed by R 14 or R 1S , respectively.
  • R 32 , R 33 , R 34 , R 35 , R 36 , R 38 and R 39 may alternatively be replaced by R 27 or R 28 , respectively.
  • R 3 is preferably hydrogen.
  • R 4 is preferably hydrogen.
  • A is preferably selected from the group consisting of:
  • R 7 , R 8 , R 9 and R 10 are as defined for formula I.
  • A is more preferably
  • R 7 , R 8 and R are as defined for formula I.
  • R 7 is preferably halogen, lower alkyl, -OH, -NO 2 , -CN, -CO 2 H, -O-lower alkyl, aryl, aryl-lower alkyl, -CO 2 CH 3 , -CONH 2 , -OCH 2 CONH 2 , -NH 2 , -N(CH 3 ) 2 , -SO 2 NH 2 , -OCHF 2 , -CF 3 or -OCF 3 .
  • R 8 and R 9 are independently hydrogen, halogen, -OH, -NO 2 , -NH 2 , -CN, -OCF 3 , -SCF 3 , -CF 3 , -OCH 2 CF 3 , -O-lower alkyl such as methoxy and ethoxy, lower alkyl such as methyl and ethyl, or phenyl, and R 10 is hydrogen, lower alkyl or phenyl.
  • R 8 and R 9 are independently selected from hydrogen, halogen such as -F and -Cl, -O-lower alkyl such as methoxy and ethoxy, -NH 2 , -CNor -NO 2 , and R 10 is hydrogen.
  • R 8 and R 9 independently are hydrogen, halogen, -OH, -NO 2 , -NH 2 , -CN, -OCF 3 , -SCF 3 , -CF 3 , -OCH 2 CF 3 , -O-lower alkyl such as methoxy and ethoxy, lower alkyl such as methyl and ethyl, or phenyl, preferably hydrogen, halogen such as -F and -Cl, -O-lower alkyl such as methoxy and ethoxy, -NH 2 , -CNor -NO 2 .
  • R 8 is hydrogen, halogen such as -F or -Cl, -O-lower alkyl such as -OCH 3 or -OC 2 H 5 , -NH 2 , -CN or -NO 2 ; and R 9 is hydrogen or halogen such as -F or -Cl.
  • R 8 is halogen and R 9 is hydrogen.
  • R 4 , B, K, D and m are as defined for formula I and R 8 and R 9 are as defined for formula I and preferably as defined for the preferred embodiments of A above.
  • B is preferably:
  • V, W, Z, Y and Q are as defined for formula I;
  • R 14 and R 15 independently are hydrogen, halogen, -CF 3 ⁇ -OCF 3 , -OR 16 , -NR 16 R 17 , lower alkyl, aryl, aryl-lower alkyl, -OSO 2 CF 3 , -CONR 16 R 17 , -CH 2 OR 16 , -CH 2 NR 6 R 17 , -OCOR 16 or -CO 2 R 18 ; or R 14 and R 15 together form a bridge -OCH 2 O- or -(CH 2 ) r ;
  • Q is preferably -O- or -NH-.
  • V, W, Z, Y and Q are as defined for formula I;
  • R 14 and R 15 independently are hydrogen, halogen, -CF 3, -OCF 3 , -OR 16 , -NR 16 R 17 , lower alkyl, aryl, aryl-lower alkyl, -OS0 2 CF 3 , -CONR 16 R 17 , -CH 2 OR 16 , -CH 2 NR 6 R 17 , -OCOR 16 or -CO 2 R 18 ; or R 14 and R 15 together form a bridge -OCH 2 O- or -(CH 2 ) r ;
  • R 14 and R 15 independently are hydrogen, halogen, -CF 3, -OCF 3 , -OR 16 , -NR 16 R 17 , lower alkyl, aryl, aryl-lower alkyl, -OSO 2 CF 3 , -CONR 16 R 17 , -CH 2 OR 16 , -CH 2 NR 16 R 17 , -OCOR 16 or -CO 2 R 18 ; or R 14 and R 15 together form a bridge -OCH 2 O- or -(CH 2 ) r ;
  • I, R 6 , R 17 and R 18 are as defined for formula I; K, D and m are as defined for formula I; and
  • R 8 and R 9 are as defined for formula I and preferably as defined for the preferred embodiments of A above.
  • R 14 and R 15 are preferably independently hydrogen, halogen, lower alkyl, aryl such as phenyl, or -O-lower alkyl such as methoxy.
  • K is preferably bound in para-position and in the above formulae Villa and Vlllb, K is preferably bound at the nitrogen atom of the indole group.
  • K is preferably selected from the group consisting of:
  • R 3a , R 3 , R 4a , R 4b , R 5a , R 5b , a, b, c, d, p and q are as defined for formula I.
  • K is selected from the group consisting of:
  • R 3a , R 3b , R 4a , R 4b , R 5a , R 5b , a, b, c, d, p and q are as defined for formula I.
  • R 3a , R 3b , R 4a , R 4b , R 5a , R 5b , b, c, d, p and q are as defined for formula I.
  • R 5a and R 5 are preferably independently hydrogen, lower alkyl, -OH, -(CH 2 ) k OR 6a , aryl, aryl-lower alkyl, -CH 2 CF 3> -(CH 2 ) g -COOR 43 , -COOR 43 , -(CH 2 ) k - CN or -(CH 2 ) k -NR 6a R 6b wherein g, k, R 43 , R 6a and R 6 are as defined for formula I.
  • g and k are independently 1 , 2 or 3
  • R 6a and R 6b are independently hydrogen, lower alkyl such as methyl or ethyl, or aryl such as phenyl,
  • R 3a and R 3b are preferably independently hydrogen, halogen, -OH, -O-iower alkyl, -COO-lower alkyl, lower alkyl or aryl-lower alkyl.
  • R a and R b are preferably independently hydrogen, -CN, -CONH 2 , -(CH 2 )-N(CH 3 ) 2 , -O-lower alkyl, -CH 2 OH, -CH 2 O-aryl, -N(CH 3 ) 2 , -OH, -CO 2 -lower alkyl or lower alkyl.
  • D is preferably hydrogen
  • D is hydrogen
  • D is more preferably hydrogen
  • E and E' independently are >CHR 38 , >NR 39 or -O-;
  • F' is >CR 38 - or >N-; and
  • s, r, R 27 , R 28 , R 38 , R 39 , V, Y', Z', Q' and W * are as defined for formula I.
  • R 27 and R 28 are preferably independently hydrogen; halogen such as -Cl, -Br or -F; -CF 3 ; -OCF 3; -OCHF 2 ; -OCH 2 CF 3 ; -(CH 2 ) y NHCOCF 3 ; -NHCOCF 3 ; -CN; -NO 2 ; -COR 29 , -COOR 29 , -(CH 2 ) y OR 29 or -OR 29 wherein R 29 is hydrogen, aryl or lower alkyl and y is 1 , 2, 3 or 4; lower alkyl such as methyl, ethyl, 2-propenyl, isopropyl, tert-butyl or cyclohexyl; lower alkylthio; -SCF 3 ; aryl such as phenyl; -(CH 2 ) y NR 29 R 30 or -NR 29 R 30 wherein R 29 and R 30 independently are hydrogen, -COO-
  • R 1 and R 2 independently are hydrogen or lower alkyl or together form a valence bond
  • R 3 and R 4 independently are hydrogen or lower alkyl
  • n 0, 1 , 2 or 3;
  • n 0 or 1 ;
  • R 5 is hydrogen, lower alkyl, aryl-lower alkyl, or -OR 6 ;
  • R 6 is hydrogen, lower alkyl, aryl or aryl-lower alkyl
  • R 7 is hydrogen, halogen, -CN, -CF 3 , -OCF 3 , -OCH 2 CF 3 , -NO 2 , -OR 11 , -NR 11 R 12 , lower alkyl, aryl, -SCF 3 , -SR 11 , -CHF 2 , -OCHF 2 , -OSO 2 R 11 , -CONR 11 R 12 , -CH 2 OR 11 , -CH 2 NR 1 R 12 , -OCOR 11 , -CO 2 R 13 , -OSO 2 CF 3 .
  • R 8 and R 9 independently are hydrogen, halogen, -CN, -CF 3 , -OCF 3 , -OCH 2 CF 3 , -NO 2 , -OR 11 , -NR 11 R 12 , lower alkyl, aryl, -SCF 3 , -SR 11 , -CHF 2 , -OCHF 2 , -OSO 2 R 11 , -CONR 11 R 12 , -CH 2 OR 11 , -CH 2 NR 1 R 12 , -OCOR 11 , -CO 2 R 13 , -OSO 2 CF 3 , or R 8 and R 9 together form a bridge -OCH 2 O-;
  • R 1 and R 12 independently are hydrogen, -COR 13 , -SO 2 R 13 , lower alkyl or aryl;
  • R 13 is hydrogen, lower alkyl, aryl-lower alkyl or aryl;
  • R 10 is hydrogen, lower alkyl, aryl-lower alkyl or aryl;
  • R 14 and R 15 independently are hydrogen, halogen, -CN, -CF 3 , -OCF 3 , -O(CH 2 )
  • R 14 and R 5 preferably independently representing hydrogen, halogen, -CF 3, -OCF 3 , -OR 16 , -NR 16 R 17 , lower alkyl, aryl, aryl-lower alkyl, -OSO 2 CF 3 , -CONR 16 R 17 , -CH 2 OR 16 , -CH 2 NR 16 R 17 , -OCOR 16 or -CO 2 R 18 ; or together forming a bridge -OCH 2 O-;
  • I is 1 , 2, 3 or 4;
  • R 16 and R 17 independently are hydrogen, -COR 18 , -SO 2 R 18 , lower alkyl, aryl, or R 16 and R 17 together form a cyclic alkyl bridge containing from 2 to 7 carbon atoms;
  • R 18 is hydrogen, lower alkyl, aryl or aryl-lower alkyl
  • Q is -NR 23 -, -O- or -S-;
  • R 19 , R 20 , R 2 and R 22 independently are hydrogen, halogen, -CN, -CF 3 , -OCF 3 , -OCH 2 CF 3 , -NO 2 , -OR 24 , -NR 24 R 25 , lower alkyl, aryl, aryl-lower alkyl, SCF 3 , -SR 24 , -CHF 2 , -OCHF 2 , OCF 2 CHF 2 , -OSO 2 CF 3 , -CONR 24 R 25 , -CH 2 CONR 24 R 25 , -OCH 2 CONR 24 R 2 VCH 2 OR 24 , - CH 2 NR 24 R 25 , -OCOR 24 or -CO 2 R 24 , or R 19 and R 20 , R 20 and R 21 or R 21 and R 22 together form a bridge -OCH 2 O-;
  • R 24 and R 25 independently are hydrogen, -COR 26 , -SO 2 R 26 , lower alkyl, aryl or aryl-lower alkyl;
  • R 26 is hydrogen, lower alkyl, aryl or aryl-lower alkyl
  • R 23 is hydrogen, lower alkyl, aryl or aryl-lower alkyl
  • R 3a , R 3b , R 4a and R 4b independently are hydrogen, halogen, -CN, -CF 3 , -OCF 3 , -OCH 2 CF 3 , -NO 2 , -OR 24a , -NR 24a R 25a , lower alkyl, aryl, aryl-lower alkyl, SCF 3 , -SR 24a , -CHF 2 2 ,, -O v_/Cv_#H ⁇ ⁇ F 22 ,, -CONR 24a R 25a , -CH 2 CONR 24a R 25a , -OCH 22 CCOONNRR 44aa RR 2255aa ,, --CCHH 22 OORR 2244aa ,, --CCHH 22 IN,R ⁇ 24a ,R ⁇ 25a ,, --OCO.RX 24a U o,r -- W CO 22 .RX 24a - , wherein R 2 a and R 25a independently are hydrogen
  • R 26a is hydrogen, lower alkyl, aryl or aryl-lower alkyl
  • R 3a and R 3b , R 4a and R 4b or R 3a and R 4b together form a bridge -(CH 2 ) r , wherein
  • i 1 , 2, 3 or 4;
  • a, b, c and d independently are 0, 1 , 2, 3 or 4;
  • e, f, p and q independently are 0 or 1 ;
  • R 5a and R 5b independently are hydrogen, lower alkyl, -(CH 2 ) k -OH, -(CH 2 ) k - NR 6a R 6b , aryl or aryl-lower alkyl;
  • k is 2, 3 or 4;
  • R 6a and R 6b independently are hydrogen, lower alkyl or aryl-lower alkyl
  • K preferably representing — (CH 2 ) b -0— (CH 2 ) d , (CH2 j_ CH - CH _ (CH2)d
  • r and s independently are 1 or 2;
  • Q' is -NR 36 -, -O- or -S-;
  • R 27 , R 28 , R 32 , R 33 , R 34 and R 35 are independently hydrogen, halogen, -CN, -CF 3 , -OCF 3> _O(CH 2 ) y CF 3 , -NO 2 , -OR 29 , -NR 29 R 30 , lower alkyl, aryl, aryl-lower alkyl, -SCF 3 , -SR 29 , -CHF 2 , -OCHF 2 , -OCF 2 CHF 2> -OSO 2 R 29 , -OSO 2 CF 3 , -CONR 29 R 30 , -(CH 2 ) y CONR 29 R 30 , -O(CH 2 ) y CONR 29 R 30 , -(CH 2 ) y OR 29 , -(CH 2 ) y NR 29 R 30 , -OCOR 29 , -CO 2 R 29; or R 27 and R 28 , R 32 and R 33 ,
  • R 27 and R 28 preferably independently representing hydrogen, halogen,-CF 3 , -OCF 3 , -OCH 2 CF 3 , -OR 29 , lower alkyl, aryl or aryl-lower alkyl, or together forming a bridge -OCH 2 O-;
  • y is 1 , 2, 3 or 4;
  • R 29 and R 30 independently are hydrogen, -COR 31 , -SO 2 R 31 , lower alkyl, aryl or aryl-lower alkyl;
  • R 31 is hydrogen, lower alkyl, aryl or aryl-lower alkyl
  • R 36 and R 39 independently are hydrogen, lower alkyl, aryl or aryl-lower alkyl
  • R 38 is hydrogen, -OR 40 , -NR 40 R 41 , lower alkyl, aryl, aryl-lower alkyl, -SCF 3 , -SR 40 , -CHF 2 , - OCHF 2 , -OCF 2 CHF 2 , -CONR 40 R 41 , -(CH 2 ) X CONR 40 R 41 , -O(CH 2 ) X CONR 40 R 41 , -(CH 2 ) x OR 40 , -(CH 2 ) X NR 40 R 41 , -OCOR 40 or -CO 2 R 40 ; x is 1 , 2, 3 or 4;
  • R 40 and R 41 independently are hydrogen, -COR 42 , -SO 2 R 42 , lower alkyl, aryl or aryl-lower alkyl;
  • R 42 is hydrogen, lower alkyl, aryl or aryl-lower alkyl.
  • R 1 and R 2 independently are hydrogen or lower alkyl or together form a valence bond
  • R 3 and R 4 independently are hydrogen or lower alkyl
  • n 0, 1 , 2 or 3;
  • n 0 or 1 ;
  • R 5 is hydrogen, lower alkyl, aryl-lower alkyl or -OR 6 ;
  • R 6 is hydrogen, lower alkyl, aryl or aryl-lower alkyl
  • R 7 is hydrogen, halogen, -CN, -CF 3 , -OCF 3 , -OCH 2 CF 3 , -NO 2 , -OR 11 , -NR 11 R 12 , lower alkyl, aryl, -SCF 3 , -SR 11 , -CHF 2 , -OCHF 2 , -OSO 2 R 11 , -CONR 11 R 12 , -CH 2 OR 11 , -CH 2 NR 11 R 12 ,
  • R 8 and R 9 independently are hydrogen, halogen, -CN, -CF 3 , -OCF 3 , -OCH 2 CF 3> -NO 2 , -OR 11 , -NR 11 R 12 , lower alkyl, aryl, -SCF 3 , -SR 11 , -CHF 2) -OCHF 2 , -OSO 2 R 11 , -CONR 1 R 12 , -CH 2 OR 11 , -CH 2 NR 11 R 12 , -OCOR 11 , -CO 2 R 13 or -OSO 2 CF 3> or R 8 and R 9 together form a bridge -OCH 2 O- or - OCH 2 CH 2 O-;
  • R 11 and R 12 independently are hydrogen, -COR 13 , -SO 2 R 13 , lower alkyl or aryl;
  • R 13 is hydrogen, lower alkyl, aryl-lower alkyl or aryl
  • R 10 is hydrogen, lower alkyl, aryl-lower alkyl or aryl;
  • R 14 and R 15 independently are hydrogen, halogen, -CN, -CF 3 , -OCF 3 , -O(CH 2 ),CF 3 , -NO 2 , -OR 16 , -NR 16 R 17 , lower alkyl, aryl, aryl-lower alkyl, -SCF 3 , -SR 16 , -CHF 2 , -OCHF 2 , -OCF 2 CHF 2 , -OSO 2 CF 3 , -CONR 16 R 17 , -(CH 2 ),CONR 16 R 17 , -O(CH 2 ),CONR 16 R 17 , -(CH 2 ),COR 16 , -(CH 2 ),COR 16 , -(CH 2 ),COR 16 , -(CH 2 ),OR 16 , -O(CH 2 ),OR 16 , -(CH 2 ),NR 16 R 17 , -0(CH 2 ),NR 16 R 17 , -
  • R 14 andR 15 preferably independently representing hydrogen, halogen, -CF 3 , -OCF 3 , -OR 16 , -NR 16 R 17 , lower alkyl, aryl, aryl-lower alkyl, -OSO 2 CF 3 , -CONR 6 R 17 , -CH 2 OR 16 , -CH 2 NR 16 R 17 , -OCOR 16 or -CO 2 R 18 ; or together forming a bridge -OCH 2 O-;
  • I is 1 , 2, 3 or 4;
  • R 16 and R 17 independently are hydrogen, -COR 18 , -SO 2 R 18 , lower alkyl, aryl, or R 16 and R 17 together form a cyclic alkyl bridge containing from 2 to 7 carbon atoms;
  • R 18 is hydrogen, lower alkyl, aryl or aryl-lower alkyl
  • Q is -NR 23 -, -O- or -S-;
  • R 19 , R 20 , R 21 and R 22 independently are hydrogen, halogen, -CN, -CF 3 , -OCF 3 , -OCH 2 CF 3 , -NO 2 , -OR 24 , -NR 24 R 25 , lower alkyl, aryl, aryl-lower alkyl, SCF 3 , -SR 24 , -CHF 2 , -OCHF 2 , -OCF 2 CHF 2 , -OSO 2 CF 3 , -CONR 24 R 25 , -CH 2 CONR 24 R 25 , -OCH 2 CONR 24 R 25 , -CH 2 OR 24 , -CH 2 NR 24 R 25 , -OCOR 24 or -CO 2 R 24 , or R 19 and R 20 , R 20 and R 21 or R 21 and R 22 together form a bridge -OCH 2 O-;
  • R 24 and R 25 independently are hydrogen, -COR 26 , -SO 2 R 26 , lower alkyl, aryl or aryl-lower alkyl;
  • R 26 is hydrogen, lower alkyl, aryl or aryl-lower alkyl
  • R 23 is hydrogen, lower alkyl, aryl or aryl-lower alkyl
  • R 3a , R 3 , R 4a and R 4b independently are hydrogen, halogen, -CN, -CF 3 , -OCF 3 , -OCH 2 CF 3 , -NO 2 , -OR 24a , -NR 24a R 25a , lower alkyl, aryl, aryl-lower alkyl, SCF 3 , -SR 24a , -CHF 2 , -OCHF 2 , -OCF 2 CHF 2, -OSO 2 CF 3 , -CONR 24a R 25a , -CH 2 CONR 24a R 25a , -OCH 2 CONR 24a R 25a , -CH 2 OR 24a , -CH 2 NR 24a R 25a , -OCOR 24a or -CO 2 R 24a ; wherein R 24a and R 25a independently are hydrogen, -COR 26a , -SO 2 R 26a , lower alkyl, aryl or ary
  • R 6a is hydrogen, lower alkyl, aryl or aryl-lower alkyl
  • R 3a and R 3b , R 4a and R 4b or R 3a and R 4b together form a bridge -(CH 2 ) r ;
  • i is 1 , 2, 3 or 4;
  • a, b, c and d independently are 0, 1 , 2, 3 or 4;
  • e, f and p independently are 0 or 1 ;
  • q 0,1 or 2;
  • R 5a and R 5b independently are hydrogen, lower alkyl, -(CH 2 ) k -OH, -(CH 2 ) k - NR 6a R 6 , aryl or aryl-lower alkyl;
  • k is 2, 3 or 4;
  • R 6a and R 6b independently are hydrogen, lower alkyl or aryl-lower alkyl
  • K preferably representing -(CH 2 )- -N- -O— (CH 2 ) 2 -N— (CH H 2' ⁇
  • r and s independently are 0, 1 or 2;
  • F' is >CR 38 - or >N
  • Q' is -NR 36 -, -O- or -S-;
  • R 27 , R 28 ,R 32 , R 33 , R 34 and R 35 are independently hydrogen, halogen, -CN, -CF 3 , -OCF 3 , -O(CH 2 ) y CF 3 , -NO 2 , -OR 29 , -NR 29 R 30 , lower alkyl, aryl, aryl-lower alkyl, -SCF 3 , -SR 29 , -CHF 2 , -OCHF 2 , -OCF 2 CHF 2 , -OSO 2 R 29 , -OSO 2 CF 3 , -CONR 29 R 30 , -(CH 2 ) y CONR 29 R 30 , -O(CH 2 ) y CONR 29 R 30 , -(CH 2 ) y OR 29 , -(CH 2 ) y NR 9 R 30 , -OCOR 29 or -CO 2 R 29 ;
  • R 27 and R 28 , R 3 and R 33 , R 33 and R M or R ⁇ and R 35 together form a bridge -OCH 2 O-;
  • R 27 and R 28 preferably independently representing hydrogen; halogen such as -Cl or -F; -CF 3 ; -OCF 3 . -OCHF 2 ; -OCH 2 CF 3 ; -OR 29 wherein R 29 is hydrogen or lower alkyl; lower alkyl such as methyl, isopropyl or tert-butyl; lower alkylthio; -SCF 3 ; -CH 2 OH; -COO-lower alkyl; aryl or -CONH 2 ; or together forming a bridge -OCH 2 O-;
  • y is 1 , 2, 3 or 4;
  • R 29 and R 30 independently are hydrogen, -COR 31 , -SO 2 R 31 , lower alkyl, aryl or aryl-lower alkyl;
  • R 31 is hydrogen, lower alkyl, aryl or aryl-lower alkyl
  • R 36 and R 39 independently are hydrogen, lower alkyl, aryl or aryl-lower alkyl
  • R 38 is hydrogen, -OR 40 , -NR 40 R 41 , lower alkyl, aryl, aryl-lower alkyl, -SCF 3 , -SR 40 , -CHF 2 , -OCHF 2 , -OCF 2 CHF 2 , -CONR 40 R 41 , -(CH 2 ) X CONR 40 R 41 , -O(CH 2 ) X CONR 40 R 41 , -(CH 2 ) x OR 40 , -(CH 2 ) X NR 40 R 41 , -OCOR 40 or -CO 2 R 40 ; wherein x is 1 , 2, 3 or 4;
  • R 40 and R 41 independently are hydrogen, -COR 42 , -SO 2 R 42 , lower alkyl, aryl or aryl-lower alkyl;
  • R 42 is hydrogen, lower alkyl, aryl or aryl-lower alkyl.
  • Preferred specific compounds represented by the formulae VI and VII are the following:
  • Especially preferred according to the present invention are the following compounds which show a particularly high affinity to the human giucagon receptor:
  • the compounds of the present invention may have one or more asymmetric centres and it is intended that any optical isomers, as separated, pure or partially purified optical isomers or racemic mixtures thereof are included in the scope of the invention.
  • one or more carbon-carbon or carbon-nitrogen double bonds may be present in the compounds which brings about geometric isomers. It is intended that any geometric isomers, as separated, pure or partially purified geometric isomers or mixtures thereof are included in the scope of the invention.
  • the compounds of the present invention may exist in different tautomeric forms, eg the following tautomeric forms:
  • any tautomeric forms which the compounds are able to form are included in the scope of the present invention. Owing to their efficacy in antagonizing the giucagon receptor the present compounds may be suitable for the treatment and/or prevention of any glucagon-mediated conditions and diseases.
  • the present compounds may be applicable for the treatment of hyperglycemia associated with diabetes of any cause or associated with other diseases and conditions, eg impaired glucose tolerance, insulin resistance syndromes, syndrome X, type I diabetes, type II diabetes, hyperlipidemia, dyslipidemia, hypertriglyceridemia, glucagonomas, acute pancreatitis, cardiovascular diseases, cardiac hypertrophy, gastrointestinal disorders, diabetes as a consequence of obesity etc.
  • diseases and conditions eg impaired glucose tolerance, insulin resistance syndromes, syndrome X, type I diabetes, type II diabetes, hyperlipidemia, dyslipidemia, hypertriglyceridemia, glucagonomas, acute pancreatitis, cardiovascular diseases, cardiac hypertrophy, gastrointestinal disorders, diabetes as a consequence of obesity etc.
  • the present invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising, as an active ingredient, at least one compound according to the present invention together with one or more pharmaceutically acceptable carriers or excipients.
  • the present invention furthermore relates to methods of treating type I or type II diabetes or hyperglycemia which methods comprise administering to a subject in need thereof an effective amount of a compound according to the invention.
  • the present invention relates to a method of lowering blood glucose in a mammal, comprising administering to said mammal an effective amount of a compound according to the invention.
  • the present invention is also concerned with the use of a compound according to the invention for the manufacture of a medicament for treating type I or type II diabetes or hyperglycemia, or for lowering blood glucose in a mammal.
  • Pharmaceutical formulations and administration methods are also concerned with the use of a compound according to the invention for the manufacture of a medicament for treating type I or type II diabetes or hyperglycemia, or for lowering blood glucose in a mammal.
  • the compounds according to the invention may be administered for therapy by any suitable route including oral, rectal, nasal, pul- monal, topical (including buccal and sublingual), transdermal, vaginal and parenteral (including subcutaneous, intramuscular, intravenous and intradermal), the oral route being preferred. It will be appreciated that the preferred route will vary with the condition and age of the recipient, the nature of the condition to be treated, and the chosen active ingredient.
  • a typical dosage is in the range of from 0.05 to about 1000 mg, preferably of from about 0.1 to about 500 mg, such as of from about 0.5 mg to about 250 mg for administration one or more times per day such as 1 to 3 times per day. It should be understood that the exact dosage will depend upon the frequency and mode of administration, the sex, age, weight and general condition of the subject treated, the nature and severity of the condition treated and any concomitant diseases to be treated as well as other factors evident to those skilled in the art.
  • formulations may conveniently be presented in unit dosage form by methods known to those skilled in the art.
  • parenteral routes such as intravenous, intrathecal, intramuscular and similar administration
  • typically doses are on the order of about 1/2 the dose employed for oral administration.
  • the compounds of this invention are generally utilized as the free substance or as a pharmaceutically acceptable salt thereof.
  • One example is an acid addition salt of a compound having the utility of a free base.
  • a compound of formula I contains a free base such salts are prepared in a conventional manner by treating a solution or suspension of a free base of formula I with a chemical equivalent of a pharmaceutically acceptable acid, for example, inorganic and organic acids, for example: maleic, fumaric, benzoic, ascorbic, pamoic, succinic, bis- methylene salicylic, methanesulfonic, ethanedisulfonic, acetic, oxalic, propionic, tartaric, sali- cylic, citric, pyruvic, gluconic, lactic, malic, mandelic, cinnamic, citraconic, aspartic, stearic, palmitic, EDTA, glycolic, p-aminobenzoic, glutamic, benz
  • the compounds of the invention may be administered alone or in combination with pharma- ceutically acceptable carriers, in either single or multiple doses.
  • solutions of the novel compounds of formula I in sterile aqueous solution, aqueous propylene glycol or sesame or peanut oil may be employed.
  • aqueous solutions should be suitable buffered if necessary and the liquid diluent first rendered isotonic with sufficient saline or glucose.
  • the aqueous solutions are particularly suitable for intravenous, intramuscular, subcutaneous and intraperitoneal administration.
  • the sterile aqueous media employed are all readily available by standard techniques known to those skilled in the art.
  • Suitable pharmaceutical carriers include inert solid diluents or fillers, sterile aqueous solution and various organic solvents.
  • solid carriers are lactose, terra alba, sucrose, cy- clodextrin, talc, gelatin, agar, pectin, acacia, magnesium stearate, stearic acid or lower alkyl ethers of cellulose.
  • liquid carriers are syrup, peanut oil, olive oil, phospholipids, fatty acids, fatty acid amines, polyoxyethylene or water.
  • the carrier or diluent may include any sustained release material known in the art, such as glyceryl monostearate or glyceryl distearate, alone or mixed with a wax.
  • the pharmaceutical compositions formed by combining the novel compounds of formula I and the pharmaceutically acceptable carriers are then readily administered in a variety of dosage forms suitable for the disclosed routes of administration.
  • the formulations may conveniently be presented in unit dosage form by methods known in the art of pharmacy.
  • Formulations of the present invention suitable for oral administration may be presented as discrete units such as capsules or tablets, each containing a predetermined amount of the active ingredient, and which may include a suitable excipient. These formulations may be in the form of powder or granules, as a solution or suspension in an aqueous or non-aqueous liquid, or as an oil-in-water or water-in-oii liquid emulsion.
  • the preparation may be tabletted, placed in a hard gelatin capsule in powder or pellet form or it can be in the form of a troche or lozenge.
  • the amount of solid carrier will vary widely but will usually be from about 25 mg to about 1 g.
  • the preparation may be in the form of a syrup, emulsion, soft gelatin capsule or sterile injectable liquid such as an aqueous or non-aqueous liquid suspension or solution.
  • a typical tablet which may be prepared by conventional tabletting techniques may contain:
  • Active compound (as free compound or salt 100 mg thereof)
  • the preparation may contain a compound of formula I dissolved or suspended in a liquid carrier, in particular an aqueous carrier, for aerosol application.
  • a liquid carrier in particular an aqueous carrier
  • the carrier may contain additives such as solubilizing agents, e.g. propylene glycol, surfactants, absorption enhancers such as lecithin (phosphatidylcholine) or cyclodextrin, or preservatives such as parabenes.
  • the pharmaceutical composition of the invention may comprise a compound of formula I combined with one or more other pharmacologically active compounds, e.g. an an- tidiabetic or other pharmacologically active material, including compounds for the treatment and/or prophylaxis of insulin resistance and diseases wherein insulin resistance is the pato- physiological mechanism.
  • Suitable antidiabetics comprise insulin, GLP-1 derivatives such as those disclosed in WO 98/08871 (Novo Nordisk A S) which is incorporated herein by refer- ence as well as orally active hypoglycaemic agents such as sulphonylureas, e.g. glibencla- mide and glipizide; biguanides, e.g.
  • metformin metformin
  • benzoic acid derivatives e.g. repaglinide
  • thiazolidinediones e.g. troglitazone and ciglitazone, as well as PPAR and RXR agonists.
  • Giucagon Binding Assay (I) Binding of compounds to the giucagon receptor was determined in a competition binding assay using the cloned human giucagon receptor.
  • antagonism was determined as the ability of the compounds to inhibit the amount of cAMP formed in the presence of 5 nM giucagon.
  • antagonism was determined in a functional assay, measured as the ability of the compounds to right-shift the giucagon dose-response curve. Using at least 3 different antagonist concentrations, the K, was calculated from a Schild plot. Receptor binding was assayed using cloned human receptor (Lok et al, Gene 140, 203-209 (1994)). The receptor inserted in the pLJ6' expression vector using EcoRI/SSt1 restriction sites (Lok et al) was expressed in a baby hamster kidney cell line (A3 BHK 570-25). Clones were selected in the presence of 0.5 mg/ml G-418 and were shown to be stable for more than 40 passages. The « ⁇ , was shown to be 0.1 nM.
  • Plasma membranes were prepared by growing cells to confluence, detaching them from the surface and resuspending the cells in cold buffer (10 mM tris/HCI), pH 7.4 containing 30 mM NaCl, 1 mM dithiothreitol, 5 mg/l leupeptin (Sigma), 5 mg/l pepstatin (Sigma), 100 mg/l baci- tracin (Sigma) and 15 mg/l recombinant aprotinin (Novo Nordisk)), homogenization by two 10-s bursts using a Polytron PT 10-35 homogenizer (Kinematica), and centrifugation upon a layer of 41 w/v% sucrose at 95.000 * g for 75 min. The white band located between the two layers was diluted in buffer and centrifuged at 40.000 * g for 45 min. The precipitate containing the plasma membranes was suspended in buffer and stored at -80°C until required.
  • Giucagon was iodinated according to the chloramine T method (Hunter and Greenwood, Na- ture 194, 495 (1962)) and purified using anion exchange chromatography (J ⁇ rgensen et al, Hormone and Metab. Res. 4, 223-224 (1972). The specific activity was 460 ⁇ Ci/ ⁇ g on day of iodination. Tracer was stored at -18°C in aliquots and were used immediately after thawing.
  • Binding assays were carried out in triplicate in filter microtiter plates (MADV N65, Millipore).
  • the buffer used in this assay was 25 mM HEPES pH 7.4 containing 0.1% human serum albumin (Sigma, grade V).
  • Giucagon was dissolved in 0.05 M HCI, added equal amounts(w/w) of HSA and freeze-dried. On the day of use, it was dissolved in water and diluted in buffer to the desired concentrations. 175 ⁇ l of sample (giucagon or test compounds) was added to each well. Tracer (50.000 cpm) was diluted in buffer and 15 ⁇ l was added to each well. 0.5 ⁇ g freshly thawed plasma membrane protein diluted in buffer was then added in 15 ⁇ l to each well.
  • the functional assay was carried out in 96 well microtiter plates (tissue culture plates, Nunc).
  • the resulting buffer concentrations in the assay were 50 mM tris/HCI, 1 mM EGTA, 1.5 mM MgSO 4 , 1.7 mM ATP, 20 ⁇ M GTP, 2 mM IBMX, 0.02% tween-20 and 0.1% HSA.
  • pH was 7.4 Giucagon and proposed antagonist were added in 35 ⁇ l diluted in 50 mM tris/HCI, 1 mM EGTA, 1.85 mM MgSO 4 , 0.0222 % tween-20 and 0.111 % HSA, pH 7.4.
  • the total assay volume was 140 ⁇ l.
  • the assay was incubated for 2 hours at 37°C with continuous shaking. Reaction was terminated by addition of 25 ⁇ l 0.5 N HCI.
  • cAMP was measured by the use of a scintillation proximity kit (Amersham).
  • Giucagon Binding Assay (lh Receptor binding was assayed using the cloned human receptor (Lok et al, Gene 140, 203- 209 (1994)). The receptor inserted in the pLJ6' expression vector using EcoRI/SSt1 restriction sites (Lok et al) was expressed in a baby hamster kidney cell line (A3 BHK 570-25). Clones were selected in the presence of 0.5 mg/ml G-418 and were shown to be stable for more than 40 passages. The Kd was shown to be 0.1 nM.
  • Plasma membranes were prepared by growing cells to confluence, detaching them from the surface and resuspending the cells in cold buffer (10 mM tris/HCI), pH 7.4 containing 30 mM NaCl, 1 mM dithiothreitol, 5 mg/l leupeptin Sigma), 5 mg/l pepstatin (Sigma), 100 mg/l baci- tracin (Sigma) and 15 mg/l recombinant aprotinin (Novo Nordisk)), homogenization by two 10-s bursts using a Polytron PT 10-35 homogenizer (Kinematica), and centrifugation. The ho- mogenate was resuspended and centrifuged again. The final precipitate containing the plasma membranes was suspended in buffer and stored at -80 C C until required.
  • cold buffer 10 mM tris/HCI
  • pH 7.4 containing 30 mM NaCl, 1 mM dithiothreitol, 5 mg/l le
  • Binding assays were carried out in duplicate in polypropylene tubes or microtiter plates.
  • the buffer used in this assay was 25 mM HEPES pH 7.4 containing 0.1 % bovine serum albumin
  • the functional assay determined the ability of the compounds to antagonize glucagon- stimulated formation of cAMP in a whole-cell assay.
  • the assay was carried out in borosilicate glass 12 x 75 tubes.
  • the buffer concentrations in the assay were 10 mM HEPES, 1 mM EGTA, 1.4 mM MgCI 2t 0.1 mM IBMX, 30 mM NaCl, 4.7 mM KCI, 2.5 mM NaH 2 PO 4 , 3mM glucose and 0.2% BSA.
  • the pH was 7.4. Loose whole cells (0.5 ml, 10 6 /ml) were pretreated with various concentrations of compounds for 10 min at 37°C, then challenged with giucagon for 20 min.
  • the compounds of general formula I may be prepared according to one embodiment of the invention, the alkylidene hydrazides of general formula II, as indicated in Scheme I, that is, by converting an ester of a carboxylic acid, for example, an aromatic acid to a hydrazide derivative and further reacting that product compound with a substituted aldehyde or ketone to yield a substituted alkylidene hydrazide.
  • HN-N r— (CH 2 ) n — B-(K)— D
  • A, B, K, D, m, n and R 4 are as defined for formula I and R a is lower alkyl.
  • the reactions are performed between 0°C to 130°C, preferably between 20°C to 100°C, most preferably at or about the reflux temperature of the solvent.
  • the reactions are preferably con- ducted under an inert atmosphere such as N 2 or Ar.
  • the solvent may be removed by concentration at atmospheric or reduced pressure.
  • the product can be further purified by either recrystallization from a solvent such as ethyl alcohol, methyl alcohol, isopropyl alcohol, toluene, xylene, hexane, tetrahydrofuran, diethyl ether, dibutyl ether, water or a mixture of two or more of the above.
  • the product can be purified by column chromatography using dichloromethane/methanol or chloroform/methanol or isopropyl alcohol as eluent.
  • the corresponding fractions are concentrated either at atmospheric pressure or in vacuo to provide the pure aroyl hydrazide.
  • aromatic acid hydrazides The methyl or ethyl ester of the corresponding aromatic acid, such as for example a substituted benzoic acid ester, is dissolved in ethanol and hydrazine (5 eq) is added. The reaction is refluxed overnight under nitrogen. Upon cooling the substituted hydrazide derivative usually precipitates. After filtration the product is usually recrystallized from hot methanol, ethanol or isopropyl alcohol. In cases where the hydrazide does not precipitate, the reaction is concen- trated under vacuo and chromatographed over silica gel using dichloromethane/methanol as the eluent. Specific examples illustrating the preparation of aromatic hydrazides are provided below.
  • step D Preparation of 2.3-Dichloro-4-hydroxybenzoic acid hydrazide and 2.5-dichloro-4- hydroxybenzoic acid hydrazide
  • 2,5-dichloro-4-hydroxybenzoic acid hydrazide was prepared in a similar way starting from 2,5-dichloro-4-hydroxybenzoate.
  • the product was purified via silica gel column chromatography using CH2Cl2/MeOH ( 95/5 to 80/20) to afford the title compound.
  • Methyl-4-hydroxybenzoate (35.5 g, 0.233 mol) was dissolved in 200 mL of warm (65 °C) acetic acid. A solution of iodine monochloride (37.8 g, 0.233 mol) in 50 mL of acetic acid was added slowly (40 minutes) to the methyl-4-hydroxybenzoate solution, while maintaining a temperature of 65 °C and vigorous stirring. The product crystallizes from solution upon cooling to room temperature and standing overnight. The crystals were collected on a filter, washed with water, then dried under vacuum. Methyl-4-hydroxy-3-iodobenzoate was obtained as white crystals (28.6 g, 44%).
  • Methyl-4-hydroxy-3-iodobenzoate (2.00 g, 7.2 mmol) was dissolved into 5 mL of dry DMF. Copper(l) cyanide (0.72 g, 8.0 mmol) and a small crystal of sodium cyanide was added. The mixture was flushed with nitrogen, placed in an oil heating bath (100-110 °C), and stirred overnight. TLC indicated nearly complete reaction. The mixture was cooled and the solids removed by filtration. The solids were extracted with DMF (3 mL). The filtrate and washings were taken up in 100 mL of ethyl acetate, then washed with 3 portions of saturated sodium chloride solution.
  • Methyl-3-cyano-4-hydroxybenzoate (2.71 g, 15.3 mmol) was dissolved in 50 mL of THF. The solution was chilled in an ice bath, and 2.0M potassium hydroxide (17 mL, 34 mmol) was added dropwise. The resulting mixture was stirred at room temperature overnight. TLC indicated complete reaction. The THF was removed by rotary evaporation. The aqueous re- sidue was acidified with aqueous trifluoroacetic acid and purified by reverse-phase HPLC (C- 18, 0.1 % TFA in water and acetonitrile). 3-Cyano-4-hydroxybenzoic acid was obtained as a white powder (2.1g, 84%) after lyophilization.
  • Step E The Boc-hydrazide (1.8g, 6.5 mmol) was suspended in 50 mL of chloroform and cooled in an ice-bath. Trifluoroacetic acid was added with stirring, and the resulting solution stood for 4 hours at 0 °C. TLC indicated complete reaction. Solvent and excess TFA were removed by rotary evaporation. The remaining oil was purified by reverse-phase liquid chromatography (Aquasil C-18 column, water/acetonitrile/0.1 % TFA). The title compound was obtained as a white solid (0.24 g, 13%).
  • Step A Silver nitrate (17 g, 0.1 mol) was dissolved in water (10 mL) and treated with 1 N NaOH (300 mL, 0.3 mol). The brown precipitate which was formed was stirred for 30 minutes and the supernatant was decanted. The brown silver oxide was washed with additional volumes of water (3x). To the silver oxide above was added 1N NaOH (150 mL) and 4-hydroxynaphthaldehyde (1 g, 6 mmol)). The mixture was heated to 70 °C for 10 minutes after which additional amounts of 4-hydroxynaphthaldehyde (5.5 g, 32 mmol) was added in portions. The mixture was kept at 80 °C for 16 hours. TLC analysis indicated incomplete conversion.
  • the ether-linked aldehydes may be prepared by 0-alkylation of the corresponding phenolic compounds using various electrophilic alkylating agents that introduce the -(K) m -D moiety as defined above in a reaction generally known as Williamson ether synthesis (H. Feuer, J. Hooz in The Chemistry of the Ether Linkage, S. Patai Ed., Wiley, New York 1967, p. 446-460).
  • Lx is a leaving group such as -Cl, -Br, -I, -OSO 2 CH 3 , -OSO 2 p-tolyl or -OSO 2 CF 3 ;
  • an ether-substituted aryl-aldehyde can be prepared by stirring hy- droxybenzaldehydes or hydroxynaphthaldehydes in an organic solvent such as acetone, meth- ylethyl ketone, dimethylformamide, dioxane, tetrahydrofuran, toluene, ethylene glycol dimethyl ether, sulfolane, diethylether, water or a compatible mixture of two or more of the above solvents with an equimolar amount of an alkyl halide or an aryl-lower alkyl halide and in the pres- ence of 1 to 15 equivalents (preferably 1 to 5 equivalents) of a base such as sodium hydride, potassium hydride, sodium or potassium methoxide, ethoxide or tej -butoxide, sodium, potassium or cesium carbonate, potassium or cesium fluoride, sodium or potassium hydroxide or organic bases
  • the reaction can be performed at 0°C to 150°C, preferably at 20°C to 100°C and preferably in an inert atmosphere of N 2 or Ar.
  • the reaction is complete the mixture is filtered, concentrated in vacuo and the resulting product optionally purified by column chromatography on silica gel using ethyl acetate/hexane as eluent.
  • the compound can also (when appropriate) be purified by recrystallization from a suitable solvent such as ethyl alcohol, ethyl acetate, isopropyl alcohol, water, hexane, toluene or their compatible mixture. Specific examples illustrating the preparation of ether-substituted aryl-aldehydes are provided below.
  • the crude syrup was heated neat in an oil bath at 200 °C for 6 h.
  • the crude material was dissolved in chloroform and filtered through a pack of silica gel.
  • the crude product (yield 72%) was used as is in the next step for O-alkylation.
  • a small portion was purified using prep-TLC to give a pure sample of 3-allyl-4-hydroxy-5-methoxy-benzaldehyde.
  • step D This type of aldehydes can be coupled to hydrazides using the methodology as described in step D to give a compound of formula IXa.
  • these compounds can undergo rearrangement by treatment with base as described below (step C), followed by coupling to a hydrazide (step D) to give a compound of formula IXb.
  • the resulting carbonyl compounds are treated with the corresponding acylhydrazide in a solvent.
  • the solvent may be one of the following: ethyl alcohol, methyl alcohol, isopropyl alcohol, tert-butyl alcohol, dioxane, tetrahydrofuran, toluene, chlorobenzene, anisole, benzene, chloroform, dichloromethane, DMSO, acetic acid, water or a compatible mixture of two or more of the above solvents.
  • a catalyst such as acetic acid can be added.
  • a dehydrating reagent such as triethylorthoformate can also be added to the reaction mixture.
  • the reaction is performed by stirring the reaction mixture preferably under an inert atmosphere of N 2 or Ar at temperatures between 0°C to 140°C, preferably between 10°C to 80°C.
  • the product simply crystallizes out when the reaction is completed and is isolated by suction filtration. It can be further recrystallized if necessary from a solvent such as the above described reaction sol- vents.
  • the product can also be isolated by concentration of the reaction mixture in vacuo, followed by column chromatography on silica gel using a solvent system such as chloroform/methanol or dichloromethane/methanol or chloroform/ethyl acetate to give a compound of formula IXb.
  • the acylhydrazides are treated with the corresponding carbonyl compounds, such as aldehydes or ketones, in a solvent.
  • the solvent may be one of the following: ethyl alcohol, methyl alcohol, isopropyl alcohol, te/ ⁇ f-butyl alcohol, dioxane, tetrahydrofuran, toluene, chlorobenzene, anisole, benzene, chloroform, dichloromethane, DMSO, acetic acid, water or a compatible mixture of two or more of the above solvents.
  • the reaction is performed by stirring the reaction mixture preferably under an inert atmosphere of N 2 or Ar at temperatures between 0°C to 140°C, preferably between 10°C to 80°C.
  • the product simply crystallizes out when the reaction is completed and is isolated by suction filtration. It can be further recrystal- lized if necessary from a solvent such as the above described reaction solvents.
  • the product can also be isolated by concentration of the reaction mixture in vacuo. followed by column chromatography on silica gel using a solvent system such as chloroform/-methanol or dichloromethane/methanol or chloroform/ethyl acetate. The product is isolated by concentration in vacuo of the appropriate fractions. Specific examples illustrating the preparation of compounds according to the invention are provided below. EXAMPLE 6:

Abstract

Non-peptide compounds comprising a central hydrazide motif and methods for the synthesis thereof. The compounds act to antagonize the action of the glucagon peptide hormone.

Description

GLUCAGON ANTAGONISTS/INVERSE AGONISTS
Field of the invention
The present invention relates to agents that act to antagonize the action of the giucagon peptide hormone. It relates particularly to non-peptide giucagon antagonists or inverse agonists.
Background of the invention
Giucagon is a key hormonal agent that, in cooperation with insulin, mediates homeostatic regulation of the amount of glucose in the blood. Giucagon primarily acts by stimulating certain cells (mostly liver cells) to release glucose when blood glucose levels fall. The action of giucagon is opposed by insulin which stimulates cells to take up and store glucose whenever blood glucose levels rise. Both giucagon and insulin are peptide hormones.
Giucagon is produced in the alpha islet cells and insulin in the beta islet cells of the pancreas. Diabetes mellitus, the common disorder of glucose metabolism, is characterized by hypergly- cemia, and can present as type I, insulin-dependent, or type II, a form that is non-insulin- dependent in character. Subjects with type I diabetes are hyperglycemic and hypoinsulinemic, and the conventional treatment for this form of the disease is to provide insulin. However, in some patients with type I or II diabetes, absolute or relative elevated giucagon levels have been shown to contribute to the hyperglycemic state. Both in healthy animals as well as in animal models of type I and II, removal of circulating giucagon with selective and specific antibodies has resulted in reduction of the glycemic level (Brand et al. Diabetologia 37, 985 (1994); Diabetes 43, [suppi 1], 172A (1994); Am J Physiol 269, E469-E477 (1995); Diabetes 44 [suppi 1], 134A (1995); Diabetes 45, 1076 (1996)). These studies suggest that giucagon suppression or an action antagonistic to giucagon could be a useful adjunct to conventional antihypergly- cemia treatment of diabetes. The action of giucagon can be suppressed by providing an antagonist or an inverse agonist, substances that inhibit or prevent giucagon induced response. The antagonist can be peptide or non-peptide in nature. Native giucagon is a 29 amino acid- containing peptide having the sequence: His-Ser-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Tyr-Ser-Lys-Tyr-Leu-Asp-Ser-Arg-Arg-Ala-Gln-Asp- Phe-Val-Gln-Trp-Leu-Met-Asn-Thr-NH2.
Giucagon exerts its action by binding to and activating its receptor, which is part of the Glu- cagon-Secretin branch of the 7-transmembrane G-protein coupled receptor family (Jelinek et al. Science 259, 1614, (1993)). The receptor functions by activation of the adenylyl cyclase second messenger system and the result is an increase in cA P levels.
Several publications disclose peptide antagonists. Probably, the most thoroughly characterized antagonist is DesHis1[Glu9]-glucagon amide (Unson et al., Peptides 10, 1171 (1989); Post et al., Proc. Natl. Acad. Sci. USA 90, 1662 (1993)). Other antagonists are eg DesHis\Phe6[Glu9]-glucagon amide (Azizh et al., Bioorganic & Medicinal Chem. Lett. 16, 1849 (1995)) or NLeu9,Ala11'16-glucagon amide (Unson et al., J. Biol. Chem. 269(17), 12548 (1994)).
Peptide antagonists of peptide hormones are often quite potent; however, they are defective as drugs because of degradation by physiological enzymes, and poor biodistribution. Therefore, non-peptide antagonists of the peptide hormones are preferred. Among the non-peptide glu- cagon antagonists, a quinoxaline derivative, (2-styryl-3-[3-(dimethylamino)propylmethyl- amino]-6,7-dichloroquinoxaline was found to displace giucagon from the rat liver receptor (Collins, J.L. et al. (1992) Bioorganic and Medicinal Chemistry Letters 2(9):915-918). West, R.R.- et al. (1994), WO 94/14426 discloses use of skyrin, a natural product comprising a pair of linked 9,10-anthracenedione groups, and its synthetic analogues, as giucagon antagonists. Anderson, P.L., U.S. Patent No. 4,359,474 discloses the giucagon antagonistic properties of 1- phenyl pyrazole derivatives. Barcza, S., U.S. Patent No. 4,374,130, discloses substituted disi- lacyclohexanes as giucagon antagonists. WO 98/04528 (Bayer Corporation) discloses substituted pyridines and biphenyls as giucagon antagonists. Furthermore, WO 97/16442 (Merck & Co., Inc.) discloses substituted pyridyl pyrroles as giucagon antagonists and WO 98/21957 (Merck & Co., Inc.) discloses 2,4-diaryl-5-pyridylimidazoles as giucagon antagonists. These giucagon antagonists differ structurally from the present compounds. Description of the invention
Definitions
The following is a detailed definition of the terms used to describe the compounds of the invention:
"Halogen" designates an atom selected from the group consisting of F, Cl, Br or I.
The term "alkyl" in the present context designates a hydrocarbon chain or a ring that is either saturated or unsaturated (containing one or more double or triple bonds where feasible) of from 1 to 10 carbon atoms in either a linear or branched or cyclic configuration. Thus, alkyl includes for example n-octyl, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, allyl, propargyl, 2- hexynyl, cyclopropyl, cyclopropylmethyl, cyclopentyl, cyclohexyl, cyclooctyl, 4-cyclohexylbutyl, and the like.
Further non-limiting examples are sec-butyl, n-pentyl, isopentyl, neopentyl, te/τ-pentyl, n- hexyl, isohexyl, n-heptyl, n-nonyl, n-decyl, vinyl, 1-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-methyl-1-propenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 3-met.hyl-2-but.enyl, 1- hexenyl, 3-hexenyl, 2,4-hexadienyl, 5-hexenyl, 1-heptenyl, 2,4-heptadienyl, 1-octenyl, 2,4- octadienyi, ethynyl, 1-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1 -pentynyl, 2-pentynyl, 3- pentynyl, 4-pentynyl, 1-hexynyl, 3-hexynyl, 2,4-hexadiynyl, 5-hexynyl, 1-hepynyl, 1-octynyl, 2-decynyl, cyclobutyl, cyclopentyl, 1-cyclopentenyl, 2-cyclopentenyl, 3-cyclopentenyl, 1- cyclohexenyl, 2-cyclohexenyl, 3-cyclohexenyl, 2-cyclopropylethyl, cyclobutylmethyl, 2- cyclobutylethyl, cyclohexenyimethyl, 4-cyclohexyl-2-butenyl, 4-(1-cyclohexenyl)-vinyl and the like.
The term "lower alkyl" designates a hydrocarbon moiety specified above, of from 1 to 6 carbon atoms.
"Aryl" means an aromatic ring moiety, for example: phenyl, naphthyl, furyl, thienyl, pyrrolyl, pyridyl, pyrimidinyl, pyrazolyl, imidazolyl, pyrazinyl, pyridazinyl, 1 ,2,3-triazinyl, 1 ,2,4-triazinyl, oxazolyl, isoxazolyl, 1 ,2,3-oxadiazolyl, 1 ,2,4-oxadiazolyl, 1 ,3,4-oxadiazolyl, 1 ,2,3-thiadiazolyl, 1 ,2,4-thiadiazolyl, 1 ,3,4-thiadiazolyl, thiazolyl, isothiazolyl, tetrazolyl, 1-H-tetrazol-5-yl, indolyl, quinolyl, quinazolinyl, benzofuryl, benzothiophenyl (thianaphthenyl) and the like.
Further non-limiting examples are biphenyl, anthracenyl, phenanthrenyl, fluorenyl, indenyl, 1 ,2,3,4-tetrahydronaphthyl, 2,3-dihydrobenzofuryl, triazolyl, pyranyl, thiadiazinyl, isoindolyl, in- dazolyl, 1 ,2,5-oxadiazolyl, 1 ,2,5-thiadiazolyl, benzothienyl, benzimidazolyl, benzthiazolyl, ben- zisothiazolyl, benzoxazolyl, benzisoxazolyl, purinyl, quinolizinyl, isoquinolyl, quinoxalinyl, naphthyridinyl, pteridinyl, carbazolyl, acridinyl, pyrrolinyl, pyrazolinyl, indolinyl, pyrrolidinyl, piperidinyl and the like.
The aryl moieties are optionally substituted by one or more substituents, for example selected from the group consisting of F, Cl, I, and Br; lower alkyl; lower alkanoyl such as formyl, acetyl, propionyl, butyryl, valeryl, hexanoyl and the like; -OH; -NO2; -CN; -CO2H; -O-lower alkyl; aryl; aryl-lower alkyl; -CO2CH3; -CONH2; -OCH2CONH2; -NH2; -N(CH3)2; -SO2NH2; -OCHF2; -CF3; -OCF3 and the like. A further non-limiting example is -NH-(C=S)-NH2.
Such aryl moieties may also be substituted by two substituents forming a bridge, for example -OCH2O-.
"Aryl-lower alkyl" means a lower alkyl as defined above, substituted by an aryl, for example:
Figure imgf000006_0001
The aryl group is optionally substituted as described above.
Description of the invention
The present invention is based on the unexpected observation that compounds having a selected nitrogen-bearing central motif and the general structural features disclosed below antagonize the action of giucagon. Accordingly, the invention is concerned with compounds of the general formula
"
Figure imgf000007_0001
wherein:
R1 and R2 independently are hydrogen or lower alkyl or together form a valence bond;
R3 and R4 independently are hydrogen or lower alkyl;
n is 0, 1, 2 or 3;
m is 0 or 1 ;
X is >C=O, >C=S, >C=NR5 or >SO2;
wherein R5 is hydrogen, lower alkyl, aryl-lower alkyl or -OR6;
wherein R6 is hydrogen, lower alkyl, aryl or aryl-lower alkyl;
A is
Figure imgf000008_0001
Figure imgf000008_0002
wherein: R7 is hydrogen, halogen, -CN, -CF3, -OCF3, -OCH2CF3, -NO2, -OR11, -NR11R12, lower alkyl, aryl, aryl-lower alkyl, -SCF3, -SO2NR11R12, -SR11, -CHF2, -OCHF2, -OSO2R11, -CONR11R12, -OCH2CONR11R12, -CH2OR11, -CH2NR11R12, -OCOR11, -CO2R13 or -OSO2CF3;
R8 and R9 independently are hydrogen, halogen, -CN, -CF3, -OCF3, -OCH2CF3, -NO2, -OR11, -NR11R12, lower alkyl, aryl, -SCF3, -SR11, -CHF2, -OCHF2, -OSO2R11, -CONR11R12, -CH2OR11, -CH2NR11R12, -OCOR11, -CO2R13or -OSO2CF3, or R8 and R9 together form a bridge -OCH2O- or -OCH2CH2O-;
wherein R11 and R12 independently are hydrogen, -COR13, -SO2R13, lower alkyl or aryl;
wherein R13 is hydrogen, lower alkyl, aryl-lower alkyl or aryl; and
R10is hydrogen, lower alkyl, aryl-lower alkyl or aryl;
B is
Figure imgf000009_0001
or a valence bond; wherein:
R14and R15 independently are hydrogen, halogen, -CN, -CF3, -OCF3> -O(CH2)!CF3, -NO2, -OR16, -NR16R17, lower alkyl, aryl, aryl-lower alkyl, -SCF3, -SR16, -CHF2, -OCHF2, -OCF2CHF2, -OSO2CF3, -CONR16R17, -(CH2),CONR16R17, -O(CH2),CONR16R17, -(CH2),COR16, -(CH2),COR16, -(CH2),OR16, -O(CH2),OR16, -(CH2),NR16R17, -O(CH2),NR16R17, -OCOR16, -CO2R18 , -O(CH2),CO2R18, -O(CH2),CN, -O(CH2),CI, or R14and R15 together form a bridge -O(CH2),O- or -(CH2)r;
wherein I is 1 , 2, 3 or 4;
R16 and R17 independently are hydrogen, -COR18, -SO2R18, lower alkyl, aryl, or R16 and R17 together form a cyclic alkyl bridge containing from 2 to 7 carbon atoms;
wherein R18 is hydrogen, lower alkyl, aryl or aryl-lower alkyl;
W is -N= or -CR19=;
Y is -N= or -CR20=;
Z is -N= or -CR21=;
V is -N= or -CR22=; and
Q is -NR23-, -O- or -S-;
wherein:
R19, R20, R21 and R22 independently are hydrogen, halogen, -CN, -CF3, -OCF3, -OCH2CF3, -NO2, -OR24, -NR24R25, lower alkyl, aryl, aryl-lower alkyl, -SCF3, -SR24, -CHF2, -OCHF2, -OCF2CHF2, -OSO2CF3, -CONR24R25, -CH2CONR24R25, -OCH2CONR24R25, -CH2OR24, -CH2NR 4R25, -OCOR24 or -CO2R24, or R19and R20, R20 and R21, or R21 and R22 together form a bridge -OCH2O-; wherein R24 and R25 independently are hydrogen, -COR26, -SO2R26, lower alkyl, aryl or aryl- lower alkyl;
wherein R26 is hydrogen, lower alkyl, aryl or aryl-lower alkyl; and
R23 is hydrogen, lower alkyl, aryl or aryl-lower alkyl;
K is
Figure imgf000011_0001
wherein:
R3a, R3b, R4a and R4b independently are hydrogen, halogen, -CN, -CF3, -OCF3, -OCH2CF3, -NO2, -OR24a, -NR24aR25a, lower alkyl, aryl, aryl-lower alkyl, -SCF3, -SR24a, -CHF2, -OCHF2, -OCF2CHF2,-OSO2CF3, -CONR24aR25a, -CH2CONR24aR25a, -OCH2CONR24aR 5a, -CH2OR24a, -CH2NR24aR25a, -OCOR24a or -CO2R24a;
wherein R24a and R25a independently are hydrogen, -COR26a, -SO2R26a, lower alkyl, aryl or aryl-lower alkyl;
wherein R26a is hydrogen, lower alkyl, aryl or aryl-lower alkyl;
or
R3aand R3b, R4a and R4b, or R3a and R4b together form a bridge -(CH2)r;
wherein i is 1 , 2, 3 or 4;
a, b, c and d independently are 0, 1 , 2, 3 or 4; e, f and p independently are 0 or 1 ;
q is 0, 1 or 2; and
L and M independently are
-O-, -S-, -CH=CH-, -C=C-, -NR5\ -CH2NR5a-, -CO-, -OCO-, -COO-, -CONR5a-, -CONR5b-, -NR5aCO-, -SO-, -SO2-, -OSO2-, -SO2NR5a-, -NR5aSO2-, -NR5aCONR5b-, -CONR5aNR5b-, -NR5aCSNR5\ -OCONR5"-, -CH2CONR5b-, -OCH2CONR5 -,
-P(O)(OR5a)O-, -NR5aC(O)O- or
Figure imgf000012_0001
;
wherein R5aand R5b independently are hydrogen, lower alkyl, -OH, -(CH2)k-OR6a, -COR6a, -(CH2)k-CH(OR6a)2, -(CH2)k-CN, -(CH2)k-NR6aR6b, aryl, aryl-lower alkyl, -(CH2)g-COOR43 or (CH2)g-CF3;
wherein k is 1 , 2, 3 or 4;
R6a and R6b independently are hydrogen, lower alkyl, aryl or aryl-lower alkyl;
g is 0, 1 , 2, 3 or 4;
R43 is hydrogen or lower alkyl;
G" is -OCH2CO-, -CH2CO-, -CO- or a valence bond; and
E" is -CH2-, -CH2CH2-, -CH=CH-, -CH2NH- or -CH2CH2NH-;
D is hydrogen,
Figure imgf000013_0001
wherein:
r is 0 or 1; s is 0, 1 , 2 or 3;
E, E", F, G and G* independently are -CHR38-, >C=O, >NR39, -O- or -S-;
F' is >CR38- or >N-;
Y' is -N= or -CR32=;
Z' is -N= or -CR33=;
V is -N= or -CR34^
W' is -N= or -CR35=; and
Q' is -NR36-, -O- or -S-;
wherein:
R27, R28, R32, R33, R^and R35 independently are hydrogen, halogen, -CN, -CF3, -O(CH2)yCF3, -(CH2)yNHCOCF3, -NO2, lower alkyl, aryl, aryl-lower alkyl, -SCF3, -SR29, -CHF2, -OCHF2, -OCF2CHF2, -OSO2R29, -OSO2CF3, -(CH2)yCONR29R30, -O(CH2)yCONR29R30, -(CH2)yOR29, -(CH2)yNR29R30, -OCOR29, -COR29 or -CO2R29;
or
R27and R28, R32and R33, R33and R34, or R34 and R35 together form a bridge -O(CH2)yO-;
wherein y is 0, 1 , 2, 3 or 4; and
R29 and R30 independently are hydrogen, -COR31, -CO2R31, -SO2R31, lower alkyl, aryl or aryl-lower alkyl; wherein R31 is hydrogen, lower alkyl, aryl or aryl-lower alkyl;
R36 and R39 independently are hydrogen, lower alkyl, aryl or aryl-lower alkyl; and
R38 is hydrogen, -OR40, -NR40R41, lower alkyl, aryl, aryl-lower alkyl, -SCF3, -SR40, -CHF2, -OCHF2, -OCF2CHF2, -CONR40R41, -(CH2)XCONR40R41, -O(CH2)XCONR40R41, -(CH2)xOR40, -(CH2)XNR40R41, -OCOR40 or -C02R40;
wherein x is 1 , 2, 3 or 4;
R40 and R41 independently are hydrogen, -COR42, -SO2R42, lower alkyl, aryl or aryl-lower alkyl;
wherein R42is hydrogen, lower alkyl, aryl or aryl-lower alkyl;
as well as any optical or geometric isomer or tautomeric form thereof including mixtures of these or a pharmaceutically acceptable salt thereof.
Where the formulae for B make it possible, R19, R20, R21, R22 and R23 may alternatively be re- placed by R14 or R1S, respectively. In such case eg W may be selected from -N=, -CR19- and -CR14-.
Similarly, where the formulae for D make it possible, R32, R33, R34, R35, R36, R38 and R39 may alternatively be replaced by R27 or R28, respectively. In such case eg E may be selected from -CHR38-, >C=O, >NR39, -O-, -S-, -CHR27- and >NR27.
In a preferred embodiment the invention relates to compounds of the following general formula
Figure imgf000015_0001
wherein A, B, K, D, R3, R4, n and m are as defined for formula In another preferred embodiment the invention relates to compounds of the following general formula III:
Figure imgf000016_0001
wherein A, B, K, D, R3, R4, n and m are as defined for formula I.
In still another preferred embodiment the invention relates to compounds of the following formula IV:
Figure imgf000016_0002
wherein A, B, K, D, R3, R4, n and m are as defined for formula I.
In the compounds of the above formulae I to IV the following substituents are preferred:
R3 is preferably hydrogen.
R4 is preferably hydrogen.
A is preferably selected from the group consisting of:
Figure imgf000016_0003
wherein R7, R8, R9 and R10 are as defined for formula I.
A is more preferably
Figure imgf000017_0001
wherein R7, R8 and R are as defined for formula I.
In the above embodiments of A, R7 is preferably halogen, lower alkyl, -OH, -NO2, -CN, -CO2H, -O-lower alkyl, aryl, aryl-lower alkyl, -CO2CH3, -CONH2, -OCH2CONH2, -NH2, -N(CH3)2, -SO2NH2, -OCHF2, -CF3 or -OCF3.
Preferably, R8and R9 are independently hydrogen, halogen, -OH, -NO2, -NH2, -CN, -OCF3, -SCF3, -CF3, -OCH2CF3, -O-lower alkyl such as methoxy and ethoxy, lower alkyl such as methyl and ethyl, or phenyl, and R10 is hydrogen, lower alkyl or phenyl.
More preferably, R8 and R9 are independently selected from hydrogen, halogen such as -F and -Cl, -O-lower alkyl such as methoxy and ethoxy, -NH2, -CNor -NO2, and R10 is hydrogen.
In a particularly preferred embodiment A is
Figure imgf000017_0002
wherein R8 and R9 independently are hydrogen, halogen, -OH, -NO2, -NH2, -CN, -OCF3, -SCF3, -CF3, -OCH2CF3, -O-lower alkyl such as methoxy and ethoxy, lower alkyl such as methyl and ethyl, or phenyl, preferably hydrogen, halogen such as -F and -Cl, -O-lower alkyl such as methoxy and ethoxy, -NH2, -CNor -NO2.
In a further particularly preferred embodiment A is
Figure imgf000018_0001
wherein R8 is hydrogen, halogen such as -F or -Cl, -O-lower alkyl such as -OCH3 or -OC2H5, -NH2, -CN or -NO2; and R9 is hydrogen or halogen such as -F or -Cl.
In a preferred embodiment R8 is halogen and R9 is hydrogen.
In still a preferred embodiment the invention relates to compounds of the following formula V:
Figure imgf000018_0002
wherein R4, B, K, D and m are as defined for formula I and R8and R9are as defined for formula I and preferably as defined for the preferred embodiments of A above.
B is preferably:
Figure imgf000018_0003
wherein V, W, Z, Y and Q are as defined for formula I; and
R14and R15 independently are hydrogen, halogen, -CF3ι -OCF3, -OR16, -NR16R17, lower alkyl, aryl, aryl-lower alkyl, -OSO2CF3, -CONR16R17, -CH2OR16, -CH2NR 6R17, -OCOR16or -CO2R18; or R14 and R15 together form a bridge -OCH2O- or -(CH2)r;
wherein I, R16, R17 and R18 are as defined for formula I.
Q is preferably -O- or -NH-.
Particularly preferred compounds are those in which B is
Figure imgf000019_0001
wherein V, W, Z, Y and Q are as defined for formula I; and
R14and R15 independently are hydrogen, halogen, -CF3, -OCF3, -OR16, -NR16R17, lower alkyl, aryl, aryl-lower alkyl, -OS02CF3, -CONR16R17, -CH2OR16, -CH2NR 6R17, -OCOR16or -CO2R18; or R14and R15 together form a bridge -OCH2O- or -(CH2)r;
wherein I, R16, R17 and R18 are as defined for formula I.
Still more preferred are compounds of the following formula VI:
Figure imgf000020_0001
as well as compounds of the following formula VII:
Figure imgf000020_0002
as well as compounds of the general formulae Villa or Vlllb:
(Villa) or
Figure imgf000020_0003
(Vlllb)
Figure imgf000020_0004
wherein R14and R15 independently are hydrogen, halogen, -CF3, -OCF3, -OR16, -NR16R17, lower alkyl, aryl, aryl-lower alkyl, -OSO2CF3, -CONR16R17, -CH2OR16, -CH2NR16R17, -OCOR16 or -CO2R18; or R14 and R15 together form a bridge -OCH2O- or -(CH2)r;
wherein I, R 6, R17 and R18 are as defined for formula I; K, D and m are as defined for formula I; and
R8 and R9 are as defined for formula I and preferably as defined for the preferred embodiments of A above.
In the above formulae VI, VII and VIII, R14and R15 are preferably independently hydrogen, halogen, lower alkyl, aryl such as phenyl, or -O-lower alkyl such as methoxy.
In the above formulae VI and VII, K is preferably bound in para-position and in the above formulae Villa and Vlllb, K is preferably bound at the nitrogen atom of the indole group.
K is preferably selected from the group consisting of:
-(CH2)b-0— (CH2)d- (CH-Jg-S— (CH.)d— (CHΛ— CH=CH-(CH2)d
"(CH, 2)',b -(CH,)d -(CH2)b-N— (CH,)d- -(CH, -0-(CH,)d-
^5a
Figure imgf000022_0001
Figure imgf000022_0002
-(CH2 -O— (CH2)b-N— (CH2)d
Figure imgf000022_0003
-O— (CH2)b— CHR≥-(CH2)-N (CH2)d— , —o-fCH,),-^ -(CH2
-.5a
-O-tCHjJs-N-JJ— (CH2)g-
Figure imgf000022_0004
Figure imgf000022_0005
-0-(CH2)b O— (CH2)d— , —
Figure imgf000022_0006
Figure imgf000022_0007
Figure imgf000023_0001
, —CHj-U-N-tCHj),— O— (CH,),
Figure imgf000024_0001
(CH2)d—
Figure imgf000024_0002
Figure imgf000024_0003
wherein R3a, R3 , R4a, R4b, R5a, R5b, a, b, c, d, p and q are as defined for formula I.
More preferably, K is selected from the group consisting of:
-(CH2)b-0— (CH2)d (CH2)b-N-(CH2)d- O— (CH2)b-N— (CH 2. 'd
R53
-O— (CH - -CHR^CH, -N- -(CH2 2)>,d -0-(CH2)- "(CH2)d—
R5a
O O -0-(CH2)b-jLo_(CH2)d— , _0-(CH2)b-ii (CH2)d-
O O
-0-S-(CH2)d— , — (CH2)d — , _0-(CH2)b O-U-N— (CH2)d—
O R=°
O -0-(CH2)b-CHR3a— , _(CH2)_O— L(CH2)d_ _ _{CH2)b_S-(CH2)d-
Figure imgf000025_0001
-o— cHj-J - Ay—
Figure imgf000026_0002
Figure imgf000026_0001
Figure imgf000026_0003
— O— CH2— u— N N-(CHA- -CH„- -(CH2)b—
Figure imgf000026_0004
-0-(CH2)b— 0-(CH2)d-
-CH2-U- -(CH2)b-N-(CH2)d
Figure imgf000027_0001
H. "(CH2),
Figure imgf000027_0002
Figure imgf000027_0003
and — CH2— U— N-(CH2)b— O — (CH '22)',d
wherein R3a, R3b, R4a, R4b, R5a, R5b, a, b, c, d, p and q are as defined for formula I.
In a further preferred embodiment K is selected from the group consisting of:
— (CH2)— θ-(CH2)d— ■ — (CH^N- CH^- , — 0-(CH2) N— (CH2)d~ ,
R53 R53
0-CH2 CHR?3 CH2 ,
Figure imgf000028_0001
-0-CH2— LO- (CH2)2— , —(c^Jg-S-tCH,),-
O II — O-S — , a valence bond O— (CH,fe-
II ■ l z'2
O
O O
II
-O— (CH2)b- -CHR— -CH,- -O— CH,
Figure imgf000028_0002
(CH - -N-CHR— Ch -CHj-SO-CR^R—
,
Figure imgf000028_0003
-CH2 , _CH_M— U— C ,4"a" -R,4' b
Figure imgf000029_0001
-O— CHj-JJ— N N-(CH '2,'b -CH,- N-(CHA-
-O— CH,- r~yκ (CH2)b-N-(CHA- -U-N -(CH2)b-
Figure imgf000029_0002
— O— CH, -N— (CH2)b— S-(CH2)d- -O- (CH2)b— 0-(CHA—
Figure imgf000030_0001
wherein R3a, R3b, R4a, R4b, R5a, R5b, b, c, d, p and q are as defined for formula I.
In the above embodiments of K, R5a and R5 are preferably independently hydrogen, lower alkyl, -OH, -(CH2)kOR6a, aryl, aryl-lower alkyl, -CH2CF3> -(CH2)g-COOR43, -COOR43, -(CH2)k- CN or -(CH2)k-NR6aR6b wherein g, k, R43, R6a and R6 are as defined for formula I.
Preferably, g and k are independently 1 , 2 or 3, and R6a and R6b are independently hydrogen, lower alkyl such as methyl or ethyl, or aryl such as phenyl,
In the above embodiments of K, R3a and R3b are preferably independently hydrogen, halogen, -OH, -O-iower alkyl, -COO-lower alkyl, lower alkyl or aryl-lower alkyl. In the above embodiments of K, R a and R b are preferably independently hydrogen, -CN, -CONH2, -(CH2)-N(CH3)2, -O-lower alkyl, -CH2OH, -CH2O-aryl, -N(CH3)2, -OH, -CO2-lower alkyl or lower alkyl.
D is preferably hydrogen,
Figure imgf000031_0001
wherein s, r, R27, R28, V, Y', Q', Z', W\ E, E', F, F', G and G' are as defined for formula I.
In still a further preferred embodiment D is hydrogen,
Figure imgf000032_0001
Figure imgf000032_0002
wherein s, r, R27, R28, V, Y', Z', Q\ Z', W, E, E', F, F, G and G' are as defined for formula I.
D is more preferably hydrogen,
Figure imgf000033_0001
Figure imgf000033_0002
Figure imgf000033_0003
Figure imgf000033_0004
wherein E and E' independently are >CHR38, >NR39 or -O-; F, G and G' independently are >CHR38, >C=O or >NR39; F' is >CR38- or >N-; and s, r, R27, R28, R38, R39, V, Y', Z', Q' and W* are as defined for formula I.
R27 and R28 are preferably independently hydrogen; halogen such as -Cl, -Br or -F; -CF3; -OCF3; -OCHF2; -OCH2CF3; -(CH2)yNHCOCF3; -NHCOCF3; -CN; -NO2; -COR29, -COOR29, -(CH2)yOR29 or -OR29 wherein R29 is hydrogen, aryl or lower alkyl and y is 1 , 2, 3 or 4; lower alkyl such as methyl, ethyl, 2-propenyl, isopropyl, tert-butyl or cyclohexyl; lower alkylthio; -SCF3; aryl such as phenyl; -(CH2)yNR29R30 or -NR29R30 wherein R29 and R30 independently are hydrogen, -COO-lower alkyl or lower alkyl and y is 1 , 2, 3 or 4; or -CONH2; or R27and R28 together form a bridge -OCH2O-; R38 is hydrogen; -OCHF2; -OR40 wherein R40 is hydrogen or lower alkyl; lower alkyl such as methyl, isopropyl or tert-butyl; lower alkylthio; -SCF3; -CH2OH; -COO-lower alkyl or -CONH2; and R39 is hydrogen, lower alkyl, aryl or aryl-lower alkyl.
In a further embodiment the invention relates to the compounds of the formula I wherein:
R1 and R2 independently are hydrogen or lower alkyl or together form a valence bond;
R3 and R4 independently are hydrogen or lower alkyl;
X is >C=O, >C=S, >C=NR5 or >SO2;
n is 0, 1 , 2 or 3;
m is 0 or 1 ;
R5 is hydrogen, lower alkyl, aryl-lower alkyl, or -OR6;
wherein R6 is hydrogen, lower alkyl, aryl or aryl-lower alkyl;
A is
Figure imgf000036_0001
Figure imgf000036_0002
wherein R7 is hydrogen, halogen, -CN, -CF3, -OCF3, -OCH2CF3, -NO2, -OR11, -NR11R12, lower alkyl, aryl, -SCF3, -SR11, -CHF2, -OCHF2, -OSO2R11, -CONR11R12, -CH2OR11, -CH2NR 1R12, -OCOR11, -CO2R13, -OSO2CF3.
R8 and R9 independently are hydrogen, halogen, -CN, -CF3, -OCF3, -OCH2CF3, -NO2, -OR11, -NR11R12, lower alkyl, aryl, -SCF3, -SR11, -CHF2, -OCHF2, -OSO2R11, -CONR11R12, -CH2OR11, -CH2NR1 R12, -OCOR11, -CO2R13, -OSO2CF3, or R8 and R9 together form a bridge -OCH2O-;
R 1 and R12 independently are hydrogen, -COR13, -SO2R13, lower alkyl or aryl;
R13 is hydrogen, lower alkyl, aryl-lower alkyl or aryl;
R10 is hydrogen, lower alkyl, aryl-lower alkyl or aryl;
B is
Figure imgf000037_0001
or a valence bond; preferably
Figure imgf000038_0001
R14and R15 independently are hydrogen, halogen, -CN, -CF3, -OCF3, -O(CH2)|CF3, -NO2, -OR16, -NR16R17, lower alkyl, aryl, -SCF3, -SR16, -CHF2, -OCHF2, -OCF2CHF2, -OSO2CF3, -CONR16R17, -(CH2),CONR16R17, -O(CH2),CONR1βR17, -(CH2),COR16, -O(CH2),COR16, -(CH2),OR16, -O(CH2),OR16, -(CH2),NR16R17, -O(CH2),NR16R17, -OCOR16, -CO2R18 , -O(CH2),CN, -O(CH2),CI, or R 4and R15 together form a bridge -O-CH2-O-;
R14and R 5 preferably independently representing hydrogen, halogen, -CF3, -OCF3, -OR16, -NR16R17, lower alkyl, aryl, aryl-lower alkyl, -OSO2CF3, -CONR16R17, -CH2OR16, -CH2NR16R17, -OCOR16 or -CO2R18; or together forming a bridge -OCH2O-;
I is 1 , 2, 3 or 4;
R16 and R17 independently are hydrogen, -COR18, -SO2R18, lower alkyl, aryl, or R16 and R17 together form a cyclic alkyl bridge containing from 2 to 7 carbon atoms;
R18is hydrogen, lower alkyl, aryl or aryl-lower alkyl;
W is -N= or -CR19=;
Y is -N= or -CR20=; Z is -N= or -CR21=;
V is -N= or -CR22=;
Q is -NR23-, -O- or -S-;
wherein:
R19, R20, R2 and R22 independently are hydrogen, halogen, -CN, -CF3, -OCF3, -OCH2CF3, -NO2, -OR24, -NR24R25, lower alkyl, aryl, aryl-lower alkyl, SCF3, -SR24, -CHF2, -OCHF2, OCF2CHF2, -OSO2CF3, -CONR24R25, -CH2CONR24R25, -OCH2CONR24R2VCH2OR24, - CH2NR24R25, -OCOR24 or -CO2R24, or R19and R20, R20 and R21or R21 and R22 together form a bridge -OCH2O-;
R24 and R25 independently are hydrogen, -COR26, -SO2R26, lower alkyl, aryl or aryl-lower alkyl;
R26 is hydrogen, lower alkyl, aryl or aryl-lower alkyl;
R23 is hydrogen, lower alkyl, aryl or aryl-lower alkyl;
K is
Figure imgf000039_0001
wherein:
R3a, R3b, R4a and R4b independently are hydrogen, halogen, -CN, -CF3, -OCF3, -OCH2CF3, -NO2, -OR24a, -NR24aR25a, lower alkyl, aryl, aryl-lower alkyl, SCF3, -SR24a, -CHF2 2,, -O v_/Cv_#Hι πF22,,
Figure imgf000039_0002
-CONR24aR25a, -CH2CONR24aR25a, -OCH 22CCOONNRR 44aaRR2255aa,, --CCHH22OORR2244aa,, --CCHH22IN,RΛ24a ,RΛ25a ,, --OCO.RX24a U o,r --WCO22.RX24a- , wherein R2 a and R25a independently are hydrogen, -COR26a, -SO2R26a, lower alkyl, aryl or aryl-lower alkyl;
R26a is hydrogen, lower alkyl, aryl or aryl-lower alkyl; or
R3aand R3b, R4a and R4b or R3a and R4b together form a bridge -(CH2)r, wherein
i is 1 , 2, 3 or 4;
a, b, c and d independently are 0, 1 , 2, 3 or 4;
e, f, p and q independently are 0 or 1 ;
L and M independently are
-O-, -S-, -CH=CH-, -C=C-, -NR5a-, -COO-, -CONR5a-, -NR5aCO-, -SO-, -SO2-, -OSO2-, -SO2-NR5a-, -NR5aSO2-, -NR5aCONR5b-, -NR5aCSNR5b-, -OCONR5b- or -NR5aC(O)O-
wherein R5aand R5b independently are hydrogen, lower alkyl, -(CH2)k-OH, -(CH2)k- NR6aR6b, aryl or aryl-lower alkyl;
wherein k is 2, 3 or 4;
R6a and R6b independently are hydrogen, lower alkyl or aryl-lower alkyl;
K preferably representing — (CH2)b-0— (CH2)d , (CH2j_CH-CH_(CH2)d
"(CH - -(CH2)d -(CH2)b-N— (CH2)d-
,5a
O
II
-(CHΛ-O- -(CH2 -s- -(CH2)d- O— (CH2)b-N— (CH2)d-
II o
-0-(CH2)b— CHR*-(CH2)-N (CH2)d— 9
-0-{CH2)ζ-U-N— (CH2)d—
R53 ' R5a
-0-(CH2)-^(CH2)d- , _0_{CH2)_1_C^(CH2)_
R
Figure imgf000041_0001
D is hydrogen or
Figure imgf000042_0001
preferably hydrogen,
Figure imgf000042_0002
wherein:
r and s independently are 1 or 2;
E, F and G independently are -CHR38-, >C=O, >NR39, -O- or -S-;
Y' is -N= or -CR32=; Z' is -N= or -CR33=;
V is -N= or -CR34^
W* is -N= or -CR3 =;
Q' is -NR36-, -O- or -S-;
wherein
R27, R28, R32, R33, R34and R35 are independently hydrogen, halogen, -CN, -CF3, -OCF3> _O(CH2)yCF3, -NO2, -OR29, -NR29R30, lower alkyl, aryl, aryl-lower alkyl, -SCF3, -SR29, -CHF2, -OCHF2, -OCF2CHF2> -OSO2R29, -OSO2CF3, -CONR29R30, -(CH2)yCONR29R30, -O(CH2)yCONR29R30, -(CH2)yOR29, -(CH2)yNR29R30, -OCOR29, -CO2R29; or R27and R28, R32and R33, R33and R^or R^and R35 together form a bridge -OCH2O-;
R27and R28 preferably independently representing hydrogen, halogen,-CF3, -OCF3, -OCH2CF3, -OR29, lower alkyl, aryl or aryl-lower alkyl, or together forming a bridge -OCH2O-;
y is 1 , 2, 3 or 4;
R29 and R30 independently are hydrogen, -COR31, -SO2R31, lower alkyl, aryl or aryl-lower alkyl;
R31is hydrogen, lower alkyl, aryl or aryl-lower alkyl;
R36 and R39 independently are hydrogen, lower alkyl, aryl or aryl-lower alkyl;
R38 is hydrogen, -OR40, -NR40R41, lower alkyl, aryl, aryl-lower alkyl, -SCF3, -SR40, -CHF2, - OCHF2, -OCF2CHF2, -CONR40R41, -(CH2)XCONR40R41, -O(CH2)XCONR40R41, -(CH2)xOR40, -(CH2)XNR40R41, -OCOR40 or -CO2R40; x is 1 , 2, 3 or 4;
R40 and R41 independently are hydrogen, -COR42, -SO2R42, lower alkyl, aryl or aryl-lower alkyl; and
R42is hydrogen, lower alkyl, aryl or aryl-lower alkyl.
In a further embodiment the invention relates to the compounds of the formula I wherein:
R1 and R2 independently are hydrogen or lower alkyl or together form a valence bond;
R3 and R4 independently are hydrogen or lower alkyl;
n is 0, 1 , 2 or 3;
m is 0 or 1 ;
X is >C=O, >C=S, >C=NR5 or >SO2;
wherein R5 is hydrogen, lower alkyl, aryl-lower alkyl or -OR6;
wherein R6 is hydrogen, lower alkyl, aryl or aryl-lower alkyl;
A is
Figure imgf000045_0001
Figure imgf000045_0002
wherein: R7 is hydrogen, halogen, -CN, -CF3, -OCF3, -OCH2CF3, -NO2, -OR11, -NR11R12, lower alkyl, aryl, -SCF3, -SR11, -CHF2, -OCHF2, -OSO2R11, -CONR11R12, -CH2OR11, -CH2NR11R12,
-OCOR11, -CO,R13or -OSO )22CCFF33;
R8 and R9 independently are hydrogen, halogen, -CN, -CF3, -OCF3, -OCH2CF3> -NO2, -OR11, -NR11R12, lower alkyl, aryl, -SCF3, -SR11, -CHF2) -OCHF2, -OSO2R11, -CONR1 R12, -CH2OR11, -CH2NR11R12, -OCOR11, -CO2R13or -OSO2CF3> or R8 and R9 together form a bridge -OCH2O- or - OCH2CH2O-;
wherein R11 and R12 independently are hydrogen, -COR13, -SO2R13, lower alkyl or aryl;
wherein R13 is hydrogen, lower alkyl, aryl-lower alkyl or aryl; and
R10 is hydrogen, lower alkyl, aryl-lower alkyl or aryl;
B is
Figure imgf000046_0001
or a valence bond; preferably
Figure imgf000047_0001
wherein:
R14and R15 independently are hydrogen, halogen, -CN, -CF3, -OCF3, -O(CH2),CF3, -NO2, -OR16, -NR16R17, lower alkyl, aryl, aryl-lower alkyl, -SCF3, -SR16, -CHF2, -OCHF2, -OCF2CHF2, -OSO2CF3, -CONR16R17, -(CH2),CONR16R17, -O(CH2),CONR16R17, -(CH2),COR16, -(CH2),COR16, -(CH2),OR16, -O(CH2),OR16, -(CH2),NR16R17, -0(CH2),NR16R17, -OCOR16, -CO2R18 , -O(CH2),CO2R18, -O(CH2),CN, -O(CH2),CI, or R14and R15 together form a bridge -OCH2O-;
R14 andR15 preferably independently representing hydrogen, halogen, -CF3, -OCF3, -OR16, -NR16R17, lower alkyl, aryl, aryl-lower alkyl, -OSO2CF3, -CONR 6R17, -CH2OR16, -CH2NR16R17, -OCOR16or -CO2R18; or together forming a bridge -OCH2O-;
wherein I is 1 , 2, 3 or 4;
R16 and R17 independently are hydrogen, -COR18, -SO2R18, lower alkyl, aryl, or R16 and R17 together form a cyclic alkyl bridge containing from 2 to 7 carbon atoms;
wherein R18is hydrogen, lower alkyl, aryl or aryl-lower alkyl;
W is -N= or -CR19=;
Y is -N= or -CR20=; Z is -N= or -CR21=;
V is -N= or -CR22=; and
Q is -NR23-, -O- or -S-;
wherein:
R19, R20, R21 and R22 independently are hydrogen, halogen, -CN, -CF3, -OCF3, -OCH2CF3, -NO2, -OR24, -NR24R25, lower alkyl, aryl, aryl-lower alkyl, SCF3, -SR24, -CHF2, -OCHF2, -OCF2CHF2, -OSO2CF3, -CONR24R25, -CH2CONR24R25, -OCH2CONR24R25, -CH2OR24, -CH2NR24R25, -OCOR24 or -CO2R24, or R19and R20, R20 and R21or R21 and R22 together form a bridge -OCH2O-;
wherein R24 and R25 independently are hydrogen, -COR26, -SO2R26, lower alkyl, aryl or aryl-lower alkyl;
wherein R26 is hydrogen, lower alkyl, aryl or aryl-lower alkyl; and
R23 is hydrogen, lower alkyl, aryl or aryl-lower alkyl;
K is
Figure imgf000048_0001
wherein:
R3a, R3 , R4a and R4b independently are hydrogen, halogen, -CN, -CF3, -OCF3, -OCH2CF3, -NO2, -OR24a, -NR24aR25a, lower alkyl, aryl, aryl-lower alkyl, SCF3, -SR24a, -CHF2, -OCHF2, -OCF2CHF2,-OSO2CF3, -CONR24aR25a, -CH2CONR24aR25a, -OCH2CONR24aR25a, -CH2OR24a, -CH2NR24aR25a, -OCOR24a or -CO2R24a; wherein R24a and R25a independently are hydrogen, -COR26a, -SO2R26a, lower alkyl, aryl or aryl-lower alkyl;
wherein R 6ais hydrogen, lower alkyl, aryl or aryl-lower alkyl;
or
R3aand R3b, R4a and R4b or R3a and R4b together form a bridge -(CH2)r;
wherein i is 1 , 2, 3 or 4;
a, b, c and d independently are 0, 1 , 2, 3 or 4;
e, f and p independently are 0 or 1 ;
q is 0,1 or 2; and
L and M independently are
-O-, -S-, -CH=CH-, -C≡C-, -NR5a-, -CO-, -OCO-, -COO-, -CONR5a-, -NR5aCO-, -SO-, -SO2-, -OSO2-, -SO2-NR5\ -NR5aSO2-, -NR5aCONR5b-, -NR5aCSNR5b-, -OCONR5b- or -NR5aC(O)O-;
wherein R5aand R5b independently are hydrogen, lower alkyl, -(CH2)k-OH, -(CH2)k- NR6aR6 , aryl or aryl-lower alkyl;
wherein k is 2, 3 or 4; and
R6a and R6b independently are hydrogen, lower alkyl or aryl-lower alkyl;
K preferably representing -(CH2)- -N- -O— (CH2)2-N— (CH H 2'ύ
O-CH -CHR -CH,- -N— CH,- — O- -CH,- - Ni¬ -(CH H 2 '2. 'd l s.
-CH2 U-0 — (CH2 2)/22 — -O— CH,-
-o-s- a valence bond 0-(CH '22)/.2 -N-
II H o
3a
-O — CHR — O-U-CH,-
Figure imgf000050_0001
D is hydrogen,
Figure imgf000051_0001
Figure imgf000051_0002
Figure imgf000051_0004
Figure imgf000051_0003
Figure imgf000051_0005
preferably hydrogen,
Figure imgf000052_0001
Figure imgf000052_0002
Figure imgf000052_0003
Figure imgf000052_0004
Figure imgf000052_0005
wherein:
r and s independently are 0, 1 or 2;
E, F and G independently are -CHR38-, >C=O, >NR39, -O- or -S
F' is >CR38- or >N
Y' is -N= or -CR32=;
Z is -N= or -CR33=;
V is -N= or -CR34^ W is -N= or -CR35=; and
Q' is -NR36-, -O- or -S-;
wherein:
R27, R28,R32, R33, R34and R35 are independently hydrogen, halogen, -CN, -CF3, -OCF3, -O(CH2)yCF3, -NO2, -OR29, -NR29R30, lower alkyl, aryl, aryl-lower alkyl, -SCF3, -SR29, -CHF2, -OCHF2, -OCF2CHF2, -OSO2R29, -OSO2CF3, -CONR29R30, -(CH2)yCONR29R30, -O(CH2)yCONR29R30, -(CH2)yOR29, -(CH2)yNR 9R30, -OCOR29 or -CO2R29;
or
R27and R28, R3 and R33, R33and RMor R^ and R35 together form a bridge -OCH2O-;
R27 and R28 preferably independently representing hydrogen; halogen such as -Cl or -F; -CF3; -OCF3. -OCHF2; -OCH2CF3; -OR29 wherein R29 is hydrogen or lower alkyl; lower alkyl such as methyl, isopropyl or tert-butyl; lower alkylthio; -SCF3; -CH2OH; -COO-lower alkyl; aryl or -CONH2; or together forming a bridge -OCH2O-;
wherein y is 1 , 2, 3 or 4; and
R29 and R30 independently are hydrogen, -COR31, -SO2R31, lower alkyl, aryl or aryl-lower alkyl;
wherein R31 is hydrogen, lower alkyl, aryl or aryl-lower alkyl;
R36 and R39 independently are hydrogen, lower alkyl, aryl or aryl-lower alkyl; and
R38 is hydrogen, -OR40, -NR40R41, lower alkyl, aryl, aryl-lower alkyl, -SCF3, -SR40, -CHF2, -OCHF2, -OCF2CHF2, -CONR40R41, -(CH2)XCONR40R41, -O(CH2)XCONR40R41, -(CH2)xOR40, -(CH2)XNR40R41, -OCOR40 or -CO2R40; wherein x is 1 , 2, 3 or 4;
R40 and R41 independently are hydrogen, -COR42, -SO2R42, lower alkyl, aryl or aryl-lower alkyl; and
wherein R42 is hydrogen, lower alkyl, aryl or aryl-lower alkyl.
Examples of specific compounds represented by the above general formula V are the following:
Figure imgf000055_0001
3-Chloro-4-hydroxybenzoic acid [5-chloro-2- 3-Chloro-4-hydroxybenzoic acid [3,5-dichloro- methoxy-4-(4-isopropy!benzyloxy)- 4-(4-isopropylbenzyloxy)benzylidene]hydrazide benzylidene]hydrazide
Figure imgf000055_0002
3-Chloro-4-hydroxybenzoic acid 3-Chloro-4-hydroxybenzoic acid [2,3-dichloro- [2,3-dimethoxy-4-(4-isopropylbenzyloxy)- 4-(4-isopropylbenzyloxy)benzylidene]hydrazide benzylidene]hydrazide
Figure imgf000055_0003
3-Chloro-4-hydroxybenzoic acid 3-Chloro-4-hydroxybenzoic acid [3-isopropyl-4-
[2,3-dimethyl-4-(4-isopropylbenzyloxy)- (4-isopropylbenzyloxy)-5- benzylidene]hydrazide methoxybenzylidene]hydrazide
Figure imgf000056_0001
3-Chloro-4-hydroxybenzoic acid [3-isopropyl- 3-Chloro-4-hydroxybenzoic acid
4-(4-isopropylbenzyloxy)-5- {3-[2-(1-pyrrolidino)ethoxy)]-4-(4- methylbenzylidene]hydrazide isopropylbenzyloxy)-5- methoxybenzylidene}hydrazide
Figure imgf000056_0002
3-Chloro-4-hydroxybenzoic acid 3-Chloro-4-hydroxybenzoic acid
[3-(2-diethylaminoethoxy)-4-(4-isopropyl- [3-(2-diethylaminoethyl)-4-(4- benzyloxy)-5-methoxybenzylidene]hydrazide isopropylbenzyloxy)-5- methoxybenzylidenejhydrazide
Figure imgf000056_0003
3-Chloro-4-hydroxybenzoic acid 5-[(3-Chloro-4-hydroxybenzoyl)hydrazono-
[3-diethylaminomethyl-4-(4-isopropylbenzyl- methylj-3-methoxy-2-(4-isopropylbenzyloxy)- oxy)-5-methoxybenzylidene]hydrazide phenoxyacetic acid
Figure imgf000057_0001
3-Chloro-4-hydroxybenzoic acid 3-Chloro-4-hydroxybenzoic acid [3-(2-hydroxyethoxy)-4-(4-isopropyl- [3,5-bis-(2-hydroxyethoxy)-4-(4- benzyloxy)-5-methoxybenzylidene]hydrazide isopropylbenzyloxy)benzylidene]hydrazide
Figure imgf000057_0002
3-Chloro-4-hydroxybenzoic acid 3-Chloro-4-hydroxybenzoic acid
[2,3,5-trimethoxy-4-(4-isopropylbenzyloxy)- [3,5-dimethoxy-4-(4-n-propylbenzyloxy)- benzylidene]hydrazide benzylidenejhydrazide
Figure imgf000057_0003
3-Chloro-4-hydroxybenzoic acid 3-Fluoro-4-hydroxybenzoic acid
[3,5-dimethoxy-4-(4-ethoxybenzyloxy)- [3,5-dimethoxy-4-(4-isopropylbenzyloxy)- benzylidene]hydrazide benzylidene]hydrazide
Figure imgf000058_0001
3-Nitro-4-hydroxybenzoic acid 3-Carboxy-4-hydroxybenzoic acid
[3,5-dimethoxy-4-(4-isopropylbenzyloxy)- [3,5-dimethoxy-4-(4-isopropylbenzyloxy)- ben- benzylidene]hydrazide zylidenejhydrazide
Figure imgf000058_0002
3-Carbamoyl-4-hydroxybenzoic acid 3-Cyano-4-hydroxybenzoic acid
[3,5-dimethoxy-4-(4-isopropylbenzyloxy)- [3,5-dimethoxy-4-(4-isopropylbenzyloxy)- benzylidene]hydrazide benzylidene]hydrazide
Figure imgf000058_0003
3-Chloro-4-hydroxybenzoic acid 3-Chloro-4-hydroxybenzoic acid
{3,5-dimethoxy-4-[4-(2,2,2-trifiuoroethoxy)- [3,5-dimethoxy-4-(3-chloro-4- benzyioxy]-benzylidene}hydrazide trifluoromethoxybenzyloxy)benzylid- ene]hydrazide
Figure imgf000059_0001
3-Chloro-4-hydroxybenzoic acid [3,5- 3-Chloro-4-hydroxybenzoic acid [3,5- dimethoxy-4-(4-chlorophenoxy) benzylid- dimethoxy-4-(4-isopropylphenoxy) benzylid- ene]hydrazide enejhydrazide
Figure imgf000059_0002
3-Chloro-4-hydroxybenzoic acid [3,5- 3-Chloro-4-hydroxybenzoic acid [3,5- dimethoxy-4-(4-trifluoromethyl-2- dimethoxy-4-(6-methylheptyloxy) benzylid- pyhdylmethoxy)- benzylidene]hydrazide ene]hydrazide
Figure imgf000059_0003
3-Chloro-4-hydroxybenzoic acid [3,5- 3-Chloro-4-hydroxybenzoic acid [3,5- dimethoxy-4-(5-hexenyloxy) benzylid- dimethoxy-4-(5,5-dimethyl-3-hexynyloxy) ene]hydrazide benzylidene]hydrazide
Figure imgf000060_0001
3-Chloro-4-hydroxybenzoic acid [4-(4- 3-Chloro-4-hydroxybenzoic acid [4-(4- trifluoromethoxyphenoxy)-1 - isopropylphenoxy)-1 - naphthylmethylene]hydrazide naphthylmethylene]hydrazide
Figure imgf000060_0002
3-Chloro-4-hydroxybenzoic acid {3,5- 3-Chloro-4-hydroxybenzoic acid {3,5-di- dimethoxy-4-[2-(4-E-trifluoromethylphenyl)- methoxy-4-[(4-isopropylphenyl)- ethenyl]benzylidene}hydrazide ethynyl]benzylidene}hydrazide
Figure imgf000060_0003
3-Chloro-4-hydroxybenzoic acid [3,5- 3-Chloro-4-hydroxybenzoic acid [3-(2- dimethoxy-4- methoxy-4-methyiphenyl)ethynyl-5-
(cyclohexylethynyl)benzylidene]hydrazide methoxybenzylidene]hydrazide
3-Chloro-4-hydroxybenzoic acid (4-hydroxy-1- 3-chloro-4-hydroxybenzoic acid [4-(3,5-bis- naphthylmethylene)hydrazide trifluoromethylbenzyloxy)-1 - naphthylmethylene]hydrazide
Figure imgf000061_0002
3-chloro-4-hydroxybenzoic acid [4-(2- 4-Hydroxy-3-methoxybenzoic acid (2- chloroethoxy)-1-naphthylmethylene]hydrazide naphthylmethylene)hydrazide
Figure imgf000061_0003
4-Hydroxy-3-methoxybenzoic acid (4- 4-Hydroxy-3-methoxybenzoic acid (4-tert- methoxy-1-naphthylmethylene)hydrazide butylbenzyiidene)hydrazide
Figure imgf000061_0004
4-Hydroxy-3-methoxybenzoic acid (4- 4-Hydroxy-3-methoxybenzoic acid (4- isopropylbenzylidene)hydrazide thfluoromethoxybenzylidene)hydrazide
Figure imgf000062_0001
4-Hydroxy-3-methoxybenzoic acid (1 H-indol-3- 4-Hydroxy-3-methoxybenzoic acid (4- ylmethylene)hydrazide dimethylamino-1 - naphthylmethylene)hydrazide
Figure imgf000062_0002
4-Hydroxy-3-methoxybenzoic acid (4- 4-Hydroxybenzoic acid (1- phenylbenzylidene)hydrazide naphthylmethylene)hydrazide
Figure imgf000062_0003
4-Hydroxybenzoic acid (4-methoxy-1 ■ 3,4-Dihydroxybenzoic acid (1- naphthylmethylene)hydrazide naphthylmethylene)hydrazide
Figure imgf000062_0004
4-Hydroxy-3-methoxy benzoic acid (1- 4-Hydroxy-3-methoxybenzoic acid [3-(3-tri- naphthyimethyiene)hydrazide fluoromethylphenoxy)benzylidene]hydrazide
Figure imgf000063_0001
4-Hydroxy-3-methoxybenzoic acid (4- 4-Hydroxybenzoic acid [3-(1 ,1 ,2,2- quinolinylmethylene)hydrazide tetrafluoroethoxy)benzylidene]hydrazide
Figure imgf000063_0002
4-Hydroxybenzoic acid [3-(4-tert-butylphenyl)- 4-Hydroxy-3-methoxybenzoic acid (4- E-but-2-enylidene]hydrazide hydroxy-1-naphthylmethyiene)hydrazide
Figure imgf000063_0003
4-Hydroxybenzoic acid (benzylidene)hydrazide 4-Hydroxybenzoic acid (1- naphthylmethyiene)hydrazide
Figure imgf000063_0004
3-Amino-4-hydroxybenzoic acid (1- naphthyl- 3-Amino-4-hydroxybenzoic acid (4-hydroxy- methylene)hydrazide 1- naphthylmethylene)hydrazide
Figure imgf000064_0001
4-Hydroxybenzoic acid [3-(3-trifluoro- 3-Chloro-4-hydroxybenzoic acid (1- methylbenzyloxy)benzylidene]hydrazide naphthylmethylene)hydrazide
Figure imgf000064_0002
3-Chloro-4-hydroxybenzoic acid (4-hydroxy-1- 4-Hydroxybenzoic acid (4-hydroxy-1- naphthylmethylene)hydrazide naphthylmethylene)hydrazide
Figure imgf000064_0003
4-Hydroxybenzoic acid [4-(3- 4-Hydroxybenzoic acid (5-phenyl-3- trifluoromethylphenoxy)benzylidene]hydrazide pyrazolylmethylene)hydrazide
Figure imgf000064_0004
2,4-Dihydroxybenzoic acid (4-hydroxy-1- 4-Hydroxy-3-nitrobenzoic acid (1- naphthylmethyiene)hydrazide naphthylmethylene)hydrazide
Figure imgf000065_0001
4-Hydroxy-3-nitrobenzoic acid (4-hydroxy-1- 3,4-Dihydroxybenzoic acid (4-hydroxy-1- naphthylmethylene)hydrazide naphthylmethylene)hydrazide
Figure imgf000065_0002
4-Hydroxybenzoic acid (6-methoxy-2- 3,5-Dichloro-4-hydroxybenzoic acid (4- naphthylmethylene)hydrazide hydroxy-1-naphthylmethylene)hydrazide
Figure imgf000065_0003
4-Hydroxy-3-methoxybenzoic acid (9-ethyl-9H- 4-Hydroxy-3-methoxybenzoic acid [5-(3- 3-carbazolylmethylene)hydrazide chlorophenyl)-2-furanylmethylene]hydrazide
Figure imgf000065_0004
3-Chloro-4-hydroxybenzoic acid (3-phenyl-E- 3-Chloro-4-hydroxybenzoic acid (4-allyloxy-1- allylidene)hydrazide naphtylmethylene)hydrazide
Figure imgf000066_0001
3-Chloro-4-hydroxybenzoic acid (4- 3-Chloro-4-hydroxybenzoic acid (4- ethynylmethoxy-1- benzyloxy-1-naphthylmethylene)hydrazide naphthylmethylene)hydrazide
Figure imgf000066_0002
2-(4-[(3-Chloro-4-hydroxyben zoyl)hydra- zo- 3-Chloro-4-hydroxybenzoic acid (4-methyl-1- nomethyl]-1-naphthyloxy)acetamide naphthylmethylene)hydrazide
Figure imgf000066_0003
3-Chloro-4-hydroxybenzoic acid (2-hydroxy-1- 3-Chloro-4-hydroxybenzoic acid (4-methoxy- naphthylmethylene)hydrazide 1 -naphthylmethylene)hydrazide
Figure imgf000066_0004
N-(2-[(3-Chloro-4- 3-Chloro-4-hydroxybenzoic acid (1-hydroxy- hydroxybenzoyl)hydrazono]ethyl)-2,2- 2-naphthylmethylene)hydrazide diphenylacetamide
Figure imgf000067_0001
3-Chloro-4-hydroxybenzoic acid (2,2- 3-Chloro-4-hydroxybenzoic acid (4- diphenylethylidene)hydrazide benzyloxy-3,5- dimethoxybenzylidene)hydrazide
Figure imgf000067_0002
3-Chloro-4-hydroxybenzoic acid [3-(4-tert- 3-Chloro-4-hydroxybenzoic acid (4-methyl-1- butylphenoxy)benzylidene]hydrazide naphthyimethylene)hydrazide
Figure imgf000067_0003
3-Chloro-4-hydroxybenzoic acid (3-bromo-4- Acetic acid 4-[(3-Chloro-4- hydroxy-1-naphthylmethylene)hydrazide hydroxybenzoyl)hydrazonomethyl]-1 -naphthyl ester
Figure imgf000067_0004
3-Chloro-4-hydroxybenzoic acid (4- 3-Chloro-4-hydroxybenzoic acid (2-hydroxy- cyanomethoxy-1- 1 -naphthylmethylene)hydrazide naphthylmethylene)hydrazide
Figure imgf000068_0001
3-Chloro-4-hydroxybenzoic acid (2,3- 3-Chloro-4-hydroxybenzoic acid [3-(4- methyienedioxybenzylidene)hydrazide methoxyphenoxy)benzylidene]hydrazide
Figure imgf000068_0002
3-Chloro-4-hydroxybenzoic acid (9- 3-Chloro-4-hydroxybenzoic acid [4-(2- phenanthrenylmethylene)hydrazide hydroxyethoxy)-1- naphthylmethylene]hydrazide
Figure imgf000068_0003
3-Bromo-4-hydroxybenzoic acid (4-hydroxy-1- Nicotinic acid 4-[(3-chloro-4- naphthylmethylene)hydrazide hydroxybenzoyl)hydrazonomethyl]-1 -naphthyl ester
Figure imgf000068_0004
3-Chloro-4-hydroxybenzoic acid [4-(1 ,3-dioxo- 3-Chloro-4-hydroxybenzoic acid [4- 1 ,3-dihydroisoindol-2-ylmethoxy)-1 -naphthyl- (cyciohexylmethoxy)-l - methylene]hydrazide naphthylmethylene]hydrazide
Figure imgf000069_0001
3-Chloro-4-hydroxybenzoic acid [4- 3-Chloro-4-hydroxybenzoic acid [4-(3-
(tetrahydro-2-pyranylmethoxy)-1-naphthyl- pyridylmethoxy)-1- methylenejhydrazide naphthylmethylene]hydrazide
Figure imgf000069_0002
4-[(3-Chloro-4- 3-Chloro-4-hydroxybenzoic acid (3- hydroxybenzoyl)hydrazonomethyl]-1- nitrobenzylidene)hydrazide naphthyloxy)acetic acid ethyl ester
Figure imgf000069_0003
3-Chloro-4-hydroxybenzoic acid (2,4- 3-Chloro-4-hydroxybenzoic acid (4-fluoro-1- dichlorobenzylidene)hydrazide naphthylmethylene)hydrazide
Figure imgf000070_0001
3-Fluoro-4-hydroxybenzoic acid (4-hydroxy-1- 3-Chloro-4-hydroxybenzoic acid [4-(2,4- naphthylmethylene)hydrazide difluorobenzyloxy)-1 - naphthylmethylene]hydrazide
Figure imgf000070_0002
3-Fluoro-4-hydroxybenzoic acid (1- 3-Chloro-4-hydroxybenzoic acid [4-(3- naphthylmethylene)hydrazide methoxybenzyloxy)-1 - naphthylmethylene]hydrazide
Figure imgf000070_0003
3-Chloro-4-hydroxybenzoic acid [4-(4- 3-Chloro-4-hydroxybenzoic acid [4-(2- fluorobenzyloxy)-1- tetrahydrofuranylmethoxy)-1 - naphthylmethyiene]hydrazide naphthylmethylene]hydrazide
Figure imgf000071_0001
3-Chloro- 4-hydroxybenzoic acid (3-bromo-4- 3-Chloro-4-hydroxybenzoic acid [4- (3- methoxy- 1 -naphthylmethylene)hydrazide tetrahydrofuranylmethoxy)-1 - naphthylmethylene]hydrazide
Figure imgf000071_0002
4-(4-[3-Chloro-4- 3-Chloro-4-hydroxybenzoic acid [3,5- hydroxybenzoyl)hydrazonomethyl]-1- dimethoxy-4-(4-trifluoromethoxybenzyloxy)- naphthyloxymethyl)benzoic acid methyl ester benzylidene]hydrazide
Figure imgf000071_0003
3-Chloro-4-hydroxybenzoic acid [4-(4- 3-Chloro-4-hydroxybenzoic acid [4-(2- trifluoromethoxybenzyloxy)-1 - methoxybenzyloxy)-1- naphthylmethylenejhydrazide naphthylmethylene]hydrazide
Figure imgf000072_0001
3-Chloro-4-hydroxybenzoic acid [4-(2- 3-Chloro-4-hydroxybenzoic acid [4-(2,6- fluorobenzyloxy)-1- difluorobenzyloxy)-1 - naphthylmethylene]hydrazide naphthylmethylene]hydrazide
Figure imgf000072_0002
Figure imgf000073_0001
Figure imgf000074_0001
The most preferred specific compounds represented by the above general formula III are the following:
Figure imgf000074_0002
The most preferred specific compounds represented by the above general formula IV are the following:
Figure imgf000075_0001
Preferred specific compounds represented by the formulae VI and VII are the following:
Figure imgf000075_0002
Figure imgf000076_0001
Figure imgf000077_0001
Figure imgf000078_0001
Figure imgf000079_0001
Figure imgf000079_0002
Figure imgf000080_0001
Figure imgf000080_0002
Figure imgf000081_0001
co
Figure imgf000081_0002
Figure imgf000082_0001
Figure imgf000083_0001
oo
Figure imgf000083_0002
Figure imgf000084_0001
Figure imgf000085_0001
Figure imgf000085_0002
The most preferred specific compounds of formula I wherein A is a heterocyclic and/or bicyclic moiety are the following:
Figure imgf000086_0001
lndole-5-carboxylic acid [4-(4- lndazole-5-carboxylic acid [4-(4- trifluoromethylbenzyloxy)-1 - trifluoromethylbenzyloxy)-1 - naphthylmethylenejhydrazide naphthylmethylene]hydrazide
Figure imgf000086_0002
Pyrazole-3-carboxylic acid [4-(4- 3-Hydroxyisoxazole-5-carboxylic acid[4-(4- trifluoromethylbenzyloxy)-1 - trifluoromethylbenzyloxy)-1 - naphthylmethylene]hydrazide naphthylmethylene]hydrazide
Figure imgf000087_0001
Especially preferred according to the present invention are the following compounds which show a particularly high affinity to the human giucagon receptor:
Figure imgf000088_0001
Figure imgf000089_0001
Figure imgf000090_0001
Figure imgf000091_0001
Figure imgf000092_0001
Figure imgf000093_0001
Figure imgf000094_0001
Figure imgf000095_0001
Figure imgf000096_0001
Figure imgf000097_0001
Figure imgf000098_0001
Figure imgf000099_0001
Figure imgf000100_0001
Figure imgf000101_0001
Figure imgf000102_0001
Figure imgf000103_0001
Figure imgf000104_0001
Figure imgf000105_0001
Figure imgf000106_0001
Figure imgf000107_0001
Figure imgf000108_0001
Figure imgf000109_0001
Figure imgf000110_0001
Figure imgf000111_0001
Figure imgf000112_0001
Figure imgf000113_0001
Figure imgf000114_0001
Figure imgf000115_0001
Figure imgf000116_0001
Figure imgf000117_0001
Figure imgf000118_0001
Figure imgf000119_0001
The compounds of the present invention may have one or more asymmetric centres and it is intended that any optical isomers, as separated, pure or partially purified optical isomers or racemic mixtures thereof are included in the scope of the invention.
Furthermore, one or more carbon-carbon or carbon-nitrogen double bonds may be present in the compounds which brings about geometric isomers. It is intended that any geometric isomers, as separated, pure or partially purified geometric isomers or mixtures thereof are included in the scope of the invention.
Furthermore, the compounds of the present invention may exist in different tautomeric forms, eg the following tautomeric forms:
Figure imgf000119_0002
It is intended that any tautomeric forms which the compounds are able to form are included in the scope of the present invention. Owing to their efficacy in antagonizing the giucagon receptor the present compounds may be suitable for the treatment and/or prevention of any glucagon-mediated conditions and diseases.
Accordingly, the present compounds may be applicable for the treatment of hyperglycemia associated with diabetes of any cause or associated with other diseases and conditions, eg impaired glucose tolerance, insulin resistance syndromes, syndrome X, type I diabetes, type II diabetes, hyperlipidemia, dyslipidemia, hypertriglyceridemia, glucagonomas, acute pancreatitis, cardiovascular diseases, cardiac hypertrophy, gastrointestinal disorders, diabetes as a consequence of obesity etc. Furthermore, they may be applicable as diagnostic agents for identifying patients having a defect in the giucagon receptor, as a therapy to increase gastric acid secretions, to reverse intestinal hypomobility due to giucagon administration, to reverse catabolism and nitrogen loss in states of negative nitrogen balance and protein wasting including all causes of type I and type II diabetes, fasting, AIDS, cancer, anorexia, aging and other conditions, for the treatment of any of the above conditions or diseases post-operative or during surgery and for decreasing saitety and increasing energy intake. Thus, in a further aspect the present invention relates to a pharmaceutical composition comprising, as an active ingredient, at least one compound according to the present invention together with one or more pharmaceutically acceptable carriers or excipients.
The present invention furthermore relates to methods of treating type I or type II diabetes or hyperglycemia which methods comprise administering to a subject in need thereof an effective amount of a compound according to the invention.
Moreover, the present invention relates to a method of lowering blood glucose in a mammal, comprising administering to said mammal an effective amount of a compound according to the invention.
The present invention is also concerned with the use of a compound according to the invention for the manufacture of a medicament for treating type I or type II diabetes or hyperglycemia, or for lowering blood glucose in a mammal. Pharmaceutical formulations and administration methods
The compounds according to the invention, which may also be referred to as an active ingredient, may be administered for therapy by any suitable route including oral, rectal, nasal, pul- monal, topical (including buccal and sublingual), transdermal, vaginal and parenteral (including subcutaneous, intramuscular, intravenous and intradermal), the oral route being preferred. It will be appreciated that the preferred route will vary with the condition and age of the recipient, the nature of the condition to be treated, and the chosen active ingredient.
The compounds of the invention are effective over a wide dosage range. A typical dosage is in the range of from 0.05 to about 1000 mg, preferably of from about 0.1 to about 500 mg, such as of from about 0.5 mg to about 250 mg for administration one or more times per day such as 1 to 3 times per day. It should be understood that the exact dosage will depend upon the frequency and mode of administration, the sex, age, weight and general condition of the subject treated, the nature and severity of the condition treated and any concomitant diseases to be treated as well as other factors evident to those skilled in the art.
The formulations may conveniently be presented in unit dosage form by methods known to those skilled in the art.
For parenteral routes, such as intravenous, intrathecal, intramuscular and similar administration, typically doses are on the order of about 1/2 the dose employed for oral administration.
The compounds of this invention are generally utilized as the free substance or as a pharmaceutically acceptable salt thereof. One example is an acid addition salt of a compound having the utility of a free base. When a compound of formula I contains a free base such salts are prepared in a conventional manner by treating a solution or suspension of a free base of formula I with a chemical equivalent of a pharmaceutically acceptable acid, for example, inorganic and organic acids, for example: maleic, fumaric, benzoic, ascorbic, pamoic, succinic, bis- methylene salicylic, methanesulfonic, ethanedisulfonic, acetic, oxalic, propionic, tartaric, sali- cylic, citric, pyruvic, gluconic, lactic, malic, mandelic, cinnamic, citraconic, aspartic, stearic, palmitic, EDTA, glycolic, p-aminobenzoic, glutamic, benzenesulfonic, p-toluensulfonic, hydrochloric, hydrobromic, sulfuric, phosphoric or nitric acids. Physiologically acceptable salts of a compound with a hydroxy group include the anion of said compound in combination with a suitable cation such as sodium or ammonium ion.
The compounds of the invention may be administered alone or in combination with pharma- ceutically acceptable carriers, in either single or multiple doses.
For parenteral administration, solutions of the novel compounds of formula I in sterile aqueous solution, aqueous propylene glycol or sesame or peanut oil may be employed. Such aqueous solutions should be suitable buffered if necessary and the liquid diluent first rendered isotonic with sufficient saline or glucose. The aqueous solutions are particularly suitable for intravenous, intramuscular, subcutaneous and intraperitoneal administration. The sterile aqueous media employed are all readily available by standard techniques known to those skilled in the art. Suitable pharmaceutical carriers include inert solid diluents or fillers, sterile aqueous solution and various organic solvents. Examples of solid carriers are lactose, terra alba, sucrose, cy- clodextrin, talc, gelatin, agar, pectin, acacia, magnesium stearate, stearic acid or lower alkyl ethers of cellulose. Examples of liquid carriers are syrup, peanut oil, olive oil, phospholipids, fatty acids, fatty acid amines, polyoxyethylene or water. Similarly, the carrier or diluent may include any sustained release material known in the art, such as glyceryl monostearate or glyceryl distearate, alone or mixed with a wax. The pharmaceutical compositions formed by combining the novel compounds of formula I and the pharmaceutically acceptable carriers are then readily administered in a variety of dosage forms suitable for the disclosed routes of administration. The formulations may conveniently be presented in unit dosage form by methods known in the art of pharmacy.
Formulations of the present invention suitable for oral administration may be presented as discrete units such as capsules or tablets, each containing a predetermined amount of the active ingredient, and which may include a suitable excipient. These formulations may be in the form of powder or granules, as a solution or suspension in an aqueous or non-aqueous liquid, or as an oil-in-water or water-in-oii liquid emulsion.
If a solid carrier is used for oral administration, the preparation may be tabletted, placed in a hard gelatin capsule in powder or pellet form or it can be in the form of a troche or lozenge. The amount of solid carrier will vary widely but will usually be from about 25 mg to about 1 g. If a liquid carrier is used, the preparation may be in the form of a syrup, emulsion, soft gelatin capsule or sterile injectable liquid such as an aqueous or non-aqueous liquid suspension or solution.
A typical tablet which may be prepared by conventional tabletting techniques may contain:
Core:
Active compound (as free compound or salt 100 mg thereof)
Colloidal silicon dioxide (Aerosil) 1.5 mg
Cellulose, microcryst. (Avicel) 70 mg
Modified cellulose gum (Ac-Di-Sol) 7.5 mg
Magnesium stearate
Coating:
HPMC approx. 9 mg
*Mywacett 9-40 T approx. 0.9 mg
*Acylated monoglyceride used as plasticizer for film coating.
For nasal administration, the preparation may contain a compound of formula I dissolved or suspended in a liquid carrier, in particular an aqueous carrier, for aerosol application. The carrier may contain additives such as solubilizing agents, e.g. propylene glycol, surfactants, absorption enhancers such as lecithin (phosphatidylcholine) or cyclodextrin, or preservatives such as parabenes.
Optionally, the pharmaceutical composition of the invention may comprise a compound of formula I combined with one or more other pharmacologically active compounds, e.g. an an- tidiabetic or other pharmacologically active material, including compounds for the treatment and/or prophylaxis of insulin resistance and diseases wherein insulin resistance is the pato- physiological mechanism. Suitable antidiabetics comprise insulin, GLP-1 derivatives such as those disclosed in WO 98/08871 (Novo Nordisk A S) which is incorporated herein by refer- ence as well as orally active hypoglycaemic agents such as sulphonylureas, e.g. glibencla- mide and glipizide; biguanides, e.g. metformin; benzoic acid derivatives, e.g. repaglinide; and thiazolidinediones, e.g. troglitazone and ciglitazone, as well as PPAR and RXR agonists.
EXPERIMENTAL
Giucagon binding:
In the following section binding assays as well as functional assays useful for evaluating the efficacy of the compounds of the invention are described.
Giucagon Binding Assay (I) Binding of compounds to the giucagon receptor was determined in a competition binding assay using the cloned human giucagon receptor.
In the screening setup, antagonism was determined as the ability of the compounds to inhibit the amount of cAMP formed in the presence of 5 nM giucagon.
For full characterization, antagonism was determined in a functional assay, measured as the ability of the compounds to right-shift the giucagon dose-response curve. Using at least 3 different antagonist concentrations, the K, was calculated from a Schild plot. Receptor binding was assayed using cloned human receptor (Lok et al, Gene 140, 203-209 (1994)). The receptor inserted in the pLJ6' expression vector using EcoRI/SSt1 restriction sites (Lok et al) was expressed in a baby hamster kidney cell line (A3 BHK 570-25). Clones were selected in the presence of 0.5 mg/ml G-418 and were shown to be stable for more than 40 passages. The «<, was shown to be 0.1 nM.
Plasma membranes were prepared by growing cells to confluence, detaching them from the surface and resuspending the cells in cold buffer (10 mM tris/HCI), pH 7.4 containing 30 mM NaCl, 1 mM dithiothreitol, 5 mg/l leupeptin (Sigma), 5 mg/l pepstatin (Sigma), 100 mg/l baci- tracin (Sigma) and 15 mg/l recombinant aprotinin (Novo Nordisk)), homogenization by two 10-s bursts using a Polytron PT 10-35 homogenizer (Kinematica), and centrifugation upon a layer of 41 w/v% sucrose at 95.000 * g for 75 min. The white band located between the two layers was diluted in buffer and centrifuged at 40.000 * g for 45 min. The precipitate containing the plasma membranes was suspended in buffer and stored at -80°C until required.
Giucagon was iodinated according to the chloramine T method (Hunter and Greenwood, Na- ture 194, 495 (1962)) and purified using anion exchange chromatography (Jørgensen et al, Hormone and Metab. Res. 4, 223-224 (1972). The specific activity was 460 μCi/μg on day of iodination. Tracer was stored at -18°C in aliquots and were used immediately after thawing.
Binding assays were carried out in triplicate in filter microtiter plates (MADV N65, Millipore). The buffer used in this assay was 25 mM HEPES pH 7.4 containing 0.1% human serum albumin (Sigma, grade V). Giucagon was dissolved in 0.05 M HCI, added equal amounts(w/w) of HSA and freeze-dried. On the day of use, it was dissolved in water and diluted in buffer to the desired concentrations. 175 μl of sample (giucagon or test compounds) was added to each well. Tracer (50.000 cpm) was diluted in buffer and 15 μl was added to each well. 0.5 μg freshly thawed plasma membrane protein diluted in buffer was then added in 15 μl to each well. Plates were incubated at 25°C for 2 hours. Non specific binding was determined with 10"6 M giucagon. Bound and unbound tracer were then separated by vacuum filtration (Millipore vacuum manifold). The plates were washed once with 150 μl buffer/ well. The plates were air dried for a couple of hours, whereafter filters were separated from the plates using a Millipore Puncher. The filters were counted in a γ counter.
Functional Assay (I)
The functional assay was carried out in 96 well microtiter plates (tissue culture plates, Nunc). The resulting buffer concentrations in the assay were 50 mM tris/HCI, 1 mM EGTA, 1.5 mM MgSO4, 1.7 mM ATP, 20 μM GTP, 2 mM IBMX, 0.02% tween-20 and 0.1% HSA. pH was 7.4 Giucagon and proposed antagonist were added in 35 μl diluted in 50 mM tris/HCI, 1 mM EGTA, 1.85 mM MgSO4, 0.0222 % tween-20 and 0.111 % HSA, pH 7.4. 20 μl of 50 mM tris/HCI, 1 mM EGTA, 1.5 mM MgSO4, 11.8 mM ATP, 0.14 mM GTP, 14 mM iso-buthyl-methyl- xanthine (IBMX) and 0.1% HSA, pH 7.4 was added. GTP was dissolved immediately before the assay. 50 μl containing 5 μg plasma membrane protein was added in a tris/HCI, EGTA, MgSO4, HSA buffer (the actual concentrations were dependent upon the concentration of protein in the stored plasma membranes).
The total assay volume was 140 μl. The assay was incubated for 2 hours at 37°C with continuous shaking. Reaction was terminated by addition of 25 μl 0.5 N HCI. cAMP was measured by the use of a scintillation proximity kit (Amersham).
Giucagon Binding Assay (lh Receptor binding was assayed using the cloned human receptor (Lok et al, Gene 140, 203- 209 (1994)). The receptor inserted in the pLJ6' expression vector using EcoRI/SSt1 restriction sites (Lok et al) was expressed in a baby hamster kidney cell line (A3 BHK 570-25). Clones were selected in the presence of 0.5 mg/ml G-418 and were shown to be stable for more than 40 passages. The Kd was shown to be 0.1 nM.
Plasma membranes were prepared by growing cells to confluence, detaching them from the surface and resuspending the cells in cold buffer (10 mM tris/HCI), pH 7.4 containing 30 mM NaCl, 1 mM dithiothreitol, 5 mg/l leupeptin Sigma), 5 mg/l pepstatin (Sigma), 100 mg/l baci- tracin (Sigma) and 15 mg/l recombinant aprotinin (Novo Nordisk)), homogenization by two 10-s bursts using a Polytron PT 10-35 homogenizer (Kinematica), and centrifugation. The ho- mogenate was resuspended and centrifuged again. The final precipitate containing the plasma membranes was suspended in buffer and stored at -80CC until required.
Binding assays were carried out in duplicate in polypropylene tubes or microtiter plates. The buffer used in this assay was 25 mM HEPES pH 7.4 containing 0.1 % bovine serum albumin
(Sigma, fraction V). Sample (giucagon (Bachem CA) or test compounds) was added to each tube or well. Tracer (~ 25000 cpm) was diluted in buffer and was added to each tube or well.
0.5 μg freshly thawed plasma membrane protein diluted in buffer was then added in aliquots to each tube or well. Tubes or plates were incubated at 37°C for 1 hour. Non specific binding was determined with 10"7 M giucagon. Bound and unbound tracer were then separated by vacuum filtration (Brandel). The tubes or wells were washed twice with buffer. The filters or plates were counted in a gamma counter. Functional Assay (II)
The functional assay determined the ability of the compounds to antagonize glucagon- stimulated formation of cAMP in a whole-cell assay. The assay was carried out in borosilicate glass 12 x 75 tubes. The buffer concentrations in the assay were 10 mM HEPES, 1 mM EGTA, 1.4 mM MgCI2t 0.1 mM IBMX, 30 mM NaCl, 4.7 mM KCI, 2.5 mM NaH2PO4, 3mM glucose and 0.2% BSA. The pH was 7.4. Loose whole cells (0.5 ml, 106/ml) were pretreated with various concentrations of compounds for 10 min at 37°C, then challenged with giucagon for 20 min. Some aliquots (500 μL) of cells were treated with test compounds (55 uL) alone to test for agonist activity. The reactions were terminated by centrifugation, followed by cell lysis with the addition of 500 μl 0.1% HCI. Cellular debris was pelleted and the supernatant containing cAMP evaporated to dryness. cAMP was measured by the use of an RIA kit (NEN, NEK-033). Some assays were carried out utilizing the adenylate cyclase FlashPlate system from NEN.
Synthesis methods
The following synthesis protocols refer to intermediate compounds and final products identified in the specification and in the synthetic schemes. The preparation of the compounds of the present invention is described in detail using the following examples, but the chemical reactions described are disclosed in terms of their general applicability to the preparation of the giucagon antagonists of the invention. Occasionally, the reaction may not be applicable as described to each compound included within the disclosed scope of the invention. The compounds for which this occurs will be readily recognized by those skilled in the art. In all such cases, either the reactions can be successfully performed by conventional modifica- tions known to those skilled in the art, that is, by appropriate protection of interfering groups, by changing to other conventional reagents, or by routine modification of reaction conditions. Alternatively, other reactions disclosed herein or otherwise conventional will be applicable to the preparation of the corresponding compounds of the invention. In all preparative methods, all starting materials are known or readily preparable from known starting materials. All temperatures are set forth in degrees Celsius and unless otherwise indicated, all parts and percentages are by weight when referring to yields and all parts are by volume when referring to solvents and eluents.
General procedures for the preparation of alkylidene hydrazides: The compounds of general formula I may be prepared according to one embodiment of the invention, the alkylidene hydrazides of general formula II, as indicated in Scheme I, that is, by converting an ester of a carboxylic acid, for example, an aromatic acid to a hydrazide derivative and further reacting that product compound with a substituted aldehyde or ketone to yield a substituted alkylidene hydrazide.
SCHEME I
0-Ra NHNH? solvent '
A~ \^ + NH2NH2 *■ A
O reflux Q'
Figure imgf000129_0001
HN-N=r— (CH2)n— B-(K)— D
solvent, reflux H κ4
wherein A, B, K, D, m, n and R4 are as defined for formula I and Ra is lower alkyl.
General procedure for the synthesis of precursor hydrazides A-(C=O NHNH2:
The reaction is known (Org. Syn., Coll. Vol. II, A.H.BIatt, ed., John Wiley & Sons, New York, 1943, p. 85; Org. Syn., Coll. Vol. IV, N. Rabjohn, ed., John Wiley & Sons, New York, 1963, p. 819) and is generally performed by stirring the corresponding ester (either methyl, ethyl or other lower alkyl ester) with 2-10 molar excess of hydrazine in the presence of a solvent such as ethyl alcohol, methyl alcohol, isopropyl or tert-butyl alcohol or tetrahydrofuran, dioxane, DMSO, ethylene glycol, ethylene glycol dimethyl ester, benzene, toluene or a mixture of the above solvents or, in the absence of a solvent where excess of hydrazine acts as a solvent. The reactions are performed between 0°C to 130°C, preferably between 20°C to 100°C, most preferably at or about the reflux temperature of the solvent. The reactions are preferably con- ducted under an inert atmosphere such as N2 or Ar. When the reaction is complete as judged by disappearance of the starting ester by TLC or HPLC, the solvent may be removed by concentration at atmospheric or reduced pressure. The product can be further purified by either recrystallization from a solvent such as ethyl alcohol, methyl alcohol, isopropyl alcohol, toluene, xylene, hexane, tetrahydrofuran, diethyl ether, dibutyl ether, water or a mixture of two or more of the above. Alternatively, the product can be purified by column chromatography using dichloromethane/methanol or chloroform/methanol or isopropyl alcohol as eluent. The corresponding fractions are concentrated either at atmospheric pressure or in vacuo to provide the pure aroyl hydrazide.
Preparation of aromatic acid hydrazides: The methyl or ethyl ester of the corresponding aromatic acid, such as for example a substituted benzoic acid ester, is dissolved in ethanol and hydrazine (5 eq) is added. The reaction is refluxed overnight under nitrogen. Upon cooling the substituted hydrazide derivative usually precipitates. After filtration the product is usually recrystallized from hot methanol, ethanol or isopropyl alcohol. In cases where the hydrazide does not precipitate, the reaction is concen- trated under vacuo and chromatographed over silica gel using dichloromethane/methanol as the eluent. Specific examples illustrating the preparation of aromatic hydrazides are provided below.
Preparation of 5-hvdroxyindole-2-carboxylic acid hydrazide: To a sample of ethyl 5-hydroxyindole-2-carboxylate (5g, 24 mmol), dissolved in ethanol (250 mL) was added hydrazine (4 mL, 121 mmol). The reaction was refluxed overnight under nitrogen. Upon cooling the reaction vessel, the desired product crystallized. The white solid was isolated by filtration. Recrystallization from hot ethanol gave the 5-hydroxyindole-3- carboxylic acid hydrazide in 85% yield.
Figure imgf000130_0001
1H NMR (DMSO-d6): δ 4.38 (s, 2H); 6.62 (dd, 1 H); 6.76 (dd, 2H); 7.13 (d, 1H); 8.70 (s, 1H); 9.57 (s, 1 H); 11.21 (s, 1 H); MS (FAB): m/z 192 (M+H)+. Preparation of 3-chloro-4-hvdroxybenzoic acid hydrazide:
To a sample of methyl 3-chloro-4-hydroxybenzoate (2 g) dissolved in ethanol (50 mL) was added hydrazine (1.8 mL). The reaction was refluxed overnight under nitrogen. Upon cooling the reaction vessel, the desired product crystallized out of solution. The white solid was isolated by filtration. Recrystallization from hot ethanol gave the 3-chloro-4-hydroxybenzoic acid hydrazide in 60% yield.
Figure imgf000131_0001
1 H NMR (DMSO-d6): δ 4.49 (broad s, 2H), 7.05 (dd, 1 H), 7.71 (dd, 1 H), 7.89 (d, 1 H), 9.669 (s, 1 H), 10.72 (broad s, 1 H).
By use of the above methodology, other hydrazides useful as intermediates in preparing the compounds of the invention are prepared, for example:
Figure imgf000131_0002
3-Bromo-4-hydroxybenzoic acid hydrazide
1 H NMR (DMSO-d6): δ 9.95 (s, 1 H), 9.65 (d, 1 H), 9.61 (broad s, 1 H), 6.95 (d, 1 H), 4.40 (broad s, 2H); MS m/z 233.1.
Figure imgf000131_0003
3-Nitro-4-hydroxybenzoic acid hydrazide
1 H NMR (DMSO-d6): δ 9.28 (broad s,1 H), 8.28 (s, 1 H), 7.52 (d, 1 H), 6.41 (d, 1 H). MS m/z
198.
Figure imgf000132_0001
3-Fluoro-4-hydroxybenzoic acid hydrazide
1 H NMR (DMSO-d6): δ 9.45 (broad s, 1 H), 7.5 (d, 1 H), 7.43 (d, 1 H), 6.85 (t, 1 H), 5.55 (broad s, 3H).
Preparation of 2-chloro-4-hydroxybenzoic acid hydrazide, 2,3-dichloro-4- hydroxybenzoic acid hydrazide and 2,5-dichloro-4-hydroxybenzoic acid hydrazide.
Figure imgf000132_0003
Preparation of 2-chloro-4-hydroxybenzoic acid hydrazide:
Step A:
4-amino-2-chlorobenzoic acid (10 g, 58 mmol) was dissolved in H2SO4 (12 N, 120 mL) with heating. After cooling the solution in an ice-bath aqueous NaNO2 (2.5 M, 25 mL) was added dropwise such that the internal temperature remained at 5 °C. Urea was added to the mixture for after stirring for 15 minutes to destroy excess NaNO2 (monitored by starch iodine test). CuSO4 (100-200 mg) was added and the mixture was heated to 90 °C until evolution of gas stopped. After cooling, the mixture was extracted with ethyl ether (3x). The combined organic fractions were extracted with 3N NaOH (3x). The combined aqueous layer was acidified with cone. HCI and the product was extracted with ethyl ether (3x). The organic fractions were washed with water, brine, and dried over MgSO4. The crude product was introduced into a silica gel column and eluted with ethyl acetate/hexane (1/1) to afford 2-chloro-4- hydroxybenzoic acid.
H NMR (DMSO-D6): δ 6.97 (dd, 1 H), 7.05 (d, 1 H), 7.95 (d, 1 H), 10.90 (brd s, 1 H).
Step B:
To a solution 2-chloro-4-hydroxybenzoic acid in anhydrous methanol was added thionyl chloride (1.5 eq). After stirring the solution at room temperature for 16 hours, the solvent was evaporated. The residue was taken up in ethyl acetate and washed with saturated aqueous sodium bicarbonate, water, brine, and dried over MgSO4 and concentrated in vacuo to give methyl 2-chloro-4-hydroxybenzoate.
Step C:
To a solution of methyl 2-chloro-4-hydroxybenzoate (13.6 g, 73.1 mmol) in acetic acid (300 mL) was added N-chlorosuccinimide (9.8 g, 73.7 mmol). The solution was refluxed for 24 h and the solvent was evaporated under vacuo. The residue was taken up in chloroform, washed with water, brine, dried over magnesium sulfate, filtered and concentrated. Methyl 2,3-dichloro-4-hydroxybenzoate precipitated out of ethyl acetate. Chromatography of the residue using ethyl acetate/hexane (1/9 to 3/7) afforded methyl 2,5-dichloro-4- hydroxybenzoate (1.4 g, 60%) as well as an additional batch of methyl 2,3-dichloro-4- hydroxybenzoate isomer (total of 8.4 g, 10%).
Methyl 2,3-dichloro-4-hydroxybenzoate:
1H NMR (DMSO-D6) δ 3.81 (s, 3H), 7.02 (d, 1 H), 7.70 (d 1 H), 11.52 (s, 1 H); MS (APCI): 221 , 223.
Methyl 2,5-dichloro-4-hydroxybenzoate: 1H NMR (CDCI3): δ 3.90 (s, 3H), 6.00 (s, 1H), 7.14 (s, 1H), 7.27 (s, 1H), 7.96 (s, 1H); MS (APCI): 221.9.
Step D:
The title compound was prepared according to the general procedure for the synthesis of precursor hydrazides A-(C=O)-NHNH2.
Η NMR (DMSO-D6): δ 6.82 (dd, 1 H), 6.90 (d, 1 H), 7.79 (d, 1 H, 10.68 (brd s, 1 H).
Preparation of 2.3-Dichloro-4-hydroxybenzoic acid hydrazide and 2.5-dichloro-4- hydroxybenzoic acid hydrazide (step D):
The 2,3-dichloro-4-hydroxybeπzoic acid hydrazide was prepared from the methyl 2,3- dichloro-4-hydroxybenzoate above according to the general procedure for the synthesis of precursor hydrazides A-(C=O)-NHNH2 with the exception that pentanol was the solvent of choice. The product was purified via silica gel column chromatography using CH2Cl2/MeOH ( 95/5 to 80/20), yield = 50%.
2,5-dichloro-4-hydroxybenzoic acid hydrazide was prepared in a similar way starting from 2,5-dichloro-4-hydroxybenzoate.
2.3-Dichloro-4-hydroxybenzoic acid hydrazide:
Η NMR (DMSO-D6) δ 4.41 (brd s, 2H), 6.99 (1 , 1 H), 7.37 (s, 1 H), 9.46 (s, 1 H), 11.04 (s, 1 H).
2.5-Dichloro-4-hydroxybenzoic acid hydrazide:
Η NMR (DMSO-D6) δ 4.48 (brd s, 3H), 6.92 (d, 2H), 7.18 (d, 2H), 9.45 (brd s, 1 H).
Preparation of 2.3-difluoro-4-hydroxybenzoic acid hydrazide:
Figure imgf000135_0001
Step A:
A mixture of 2,3-difluoro-4-cyanophenol (1 g, 6.45 mmol) in water (8 mL), H2SO4 (8 mL), and acetic acid (8 mL) was refluxed for 48 hours. The solvents were removed by rotary evaporation to give a slurry which was poured onto ice. The product precipitated out of solution and filtered. The solid was washed with water and dried to give 2,3-difluoro-4- hydroxybeπzoic acid (800 mg, 71%).
1H NMR (DMSO-D6): δ 6.87 (t, 1 H), 7.60 (t, 1 H), 11.28 (s, 1 H), 12.53 (brd s, 1 H).
Step B:
To the 2,3-difluoro-4-hydroxybenzoic acid (800 mg, 5.1 mmol) dissolved in anhydrous methanol (50 mL) was added thionyl chloride (0.55 mL, 7.3 mmol). After stirring the solution at room temperature for 16 hours, the solvent was evaporated. The residue was taken up in ethyl acetate and washed with saturated aqueous sodium bicarbonate, water, brine, and dried over MgSO4 to give methyl 2,3-difluoro-4-hydroxybenzoate (540 mg, 62%).
Η NMR (CDCI3): δ 3.92 (s, 3H), 6.34 (brd s, 1 H), 6.82 (dt, 1 H), 7.68 (dt, 1 H).
Step C:
The 2,3-difluoro-4-hydroxybenzoic acid hydrazide was prepared from the methyl 2,3-difluoro- 4-hydroxybenzoate above according to the general procedure for the synthesis of precursor hydrazides A-(C=O)-NHNH2. The product was purified via silica gel column chromatography using CH2Cl2/MeOH ( 95/5 to 80/20) to afford the title compound.
Η NMR (DMSO-D6): δ 4.48 (s, 2H), 6.80 (m, 1 H), 7.22 (m, 1 H), 9.36 (s, 1 H), 10.89 (s, 1 H); MS (APCI): 189. Preparation of 3-cyano-4-hydroxybenzoic acid hydrazide. trifluoroacetate:
Figure imgf000136_0001
Step A:
Methyl-4-hydroxybenzoate (35.5 g, 0.233 mol) was dissolved in 200 mL of warm (65 °C) acetic acid. A solution of iodine monochloride (37.8 g, 0.233 mol) in 50 mL of acetic acid was added slowly (40 minutes) to the methyl-4-hydroxybenzoate solution, while maintaining a temperature of 65 °C and vigorous stirring. The product crystallizes from solution upon cooling to room temperature and standing overnight. The crystals were collected on a filter, washed with water, then dried under vacuum. Methyl-4-hydroxy-3-iodobenzoate was obtained as white crystals (28.6 g, 44%).
Η NMR (DMSO-D6): δ 3.79 (s, 3H), 6.95 (d, J = 8.3, 1 H), 7.81 (dd, J = 8.3, 2.2, 1 H), 8.22 (d, J = 2.2, 1H); 13C NMR (DMSO- Dβ) δ 52.8, 85.2, 115.5, 123.0, 132.0, 141.0, 161.9, 165.6.; MS (APCI, neg): 277.
Step B:
Methyl-4-hydroxy-3-iodobenzoate (2.00 g, 7.2 mmol) was dissolved into 5 mL of dry DMF. Copper(l) cyanide (0.72 g, 8.0 mmol) and a small crystal of sodium cyanide was added. The mixture was flushed with nitrogen, placed in an oil heating bath (100-110 °C), and stirred overnight. TLC indicated nearly complete reaction. The mixture was cooled and the solids removed by filtration. The solids were extracted with DMF (3 mL). The filtrate and washings were taken up in 100 mL of ethyl acetate, then washed with 3 portions of saturated sodium chloride solution. The solids and aqueous washings were combined, and shaken with a mixture of 50 mL of ethyl acetate and a ferric chloride solution (4 g of hydrated ferric chloride in 7 mL of cone, hydrochloric acid). The ethyl acetate layers were combined, washed with brine containing sodium metabisulfite, dried over sodium sulfate, filtered, and the solvent removed in vacuo. The resulting solids were purified by flash chromatography on silica gel (20% ethyl acetate/ hexane) to afford methyl-3-cyano-4-hydroxybenzoate, 0.93g (73%).
Η NMR (DMSO- Dβ): δ 3.79 (s, 3H), 7.07 (d, J = 8.7, 1H), 8.02 (dd, J = 8.7, 1.9, 1H), 8.10 (d, J = 1.9, 1 H).
Step C:
Methyl-3-cyano-4-hydroxybenzoate (2.71 g, 15.3 mmol) was dissolved in 50 mL of THF. The solution was chilled in an ice bath, and 2.0M potassium hydroxide (17 mL, 34 mmol) was added dropwise. The resulting mixture was stirred at room temperature overnight. TLC indicated complete reaction. The THF was removed by rotary evaporation. The aqueous re- sidue was acidified with aqueous trifluoroacetic acid and purified by reverse-phase HPLC (C- 18, 0.1 % TFA in water and acetonitrile). 3-Cyano-4-hydroxybenzoic acid was obtained as a white powder (2.1g, 84%) after lyophilization.
Η NMR (DMSO- D6): δ 7.09 (d, J = 9.0, 1 H), 8.00 (dd, J = 9.0, 2.3, 1 H), 8.07 (d, J = 2.3, 1 H) 12.50 (br s, 2H); MS (APCI, neg): 162. IR: 2252 cm"1, CN.
Step D:
3-Cyano-4-hydroxybenzoic acid (1.88g, 11.5 mmol) was dissolved in 20 mL of methylene chloride/DMF (1/1 ) and chilled in an ice-bath. Diisopropylethylamine (12 mL, 69 mmol), t- butyl carbazate (1.76g, 13.3 mmol), and PyBroP (bromo-tris-pyrrolidino-phosphonium he- xafluorophosphate, 6g, 12.9 mmol) were added, and the mixture was stirred to form a clear solution. The solution stood in the refrigerator overnight. TLC indicated that the reaction was not complete, so additional diisopropylethylamine (22 mL, 127 mmol), t-butyl carbazate (0.85g, 6.4 mmol) and PyBroP (3.0g, 6.4 mmol) were added. After 8 more hours at 0 °C, the reaction was worked up as follows. The solution was reduced by rotary evaporation. The remaining DMF solution was diluted with 100 mL of ethyl acetate, and washed with several portions of 0.1 M HCI (until the wash remained acidic to litmus paper). The ethyl acetate layer was further washed with 3 portions of brine, dried over magnesium sulfate, filtered, and O 99/01423
136
reduced to an oil in vacuo. The oil was purified by chromatography on silica gel (6:4 hexa- ne:ethyl acetate) to afford tert-butyloxycarbonyl (3-cyano-4-hydroxy)benzoic acid hydrazide as a white solid (1.8g, 56%).
1H NMR (DMSO- D6): δ 1.42 (s, 9H), 7.09 (d, J = 8.7, 1 H), 7.98 (m, 1 H), 8.11 (br s, 1 H), 8.92 (s, 1 H), 10.15 (s, 1H), 11.73 (br s, 1 H); MS (APCI, neg): 276; IR: 2232 cm"1, CN.
Step E: The Boc-hydrazide (1.8g, 6.5 mmol) was suspended in 50 mL of chloroform and cooled in an ice-bath. Trifluoroacetic acid was added with stirring, and the resulting solution stood for 4 hours at 0 °C. TLC indicated complete reaction. Solvent and excess TFA were removed by rotary evaporation. The remaining oil was purified by reverse-phase liquid chromatography (Aquasil C-18 column, water/acetonitrile/0.1 % TFA). The title compound was obtained as a white solid (0.24 g, 13%).
Η NMR (DMSO- Dβ): δ 7.16 (d, J = 9.0, 1H), 8.00 (dd, J = 1.5, 9.0, 1H), 8.14 (d, J = 1.5, 1 H), 10.47 (br s, 5H); MS (APCI, neg): 176.
Preparation of 4-hydroxynaphthoic acid hydrazide:
Figure imgf000138_0001
Step A: Silver nitrate (17 g, 0.1 mol) was dissolved in water (10 mL) and treated with 1 N NaOH (300 mL, 0.3 mol). The brown precipitate which was formed was stirred for 30 minutes and the supernatant was decanted. The brown silver oxide was washed with additional volumes of water (3x). To the silver oxide above was added 1N NaOH (150 mL) and 4-hydroxynaphthaldehyde (1 g, 6 mmol)). The mixture was heated to 70 °C for 10 minutes after which additional amounts of 4-hydroxynaphthaldehyde (5.5 g, 32 mmol) was added in portions. The mixture was kept at 80 °C for 16 hours. TLC analysis indicated incomplete conversion. An additional portion of silver oxide was prepared as above and added to the reaction mixture. After heating the mixture for an additional 6 hours, the mixture was cooled and acidified with 1N HCI. The aqueous layer was extracted with ethyl acetate (3x) and upon concentration 4- hydroxynaphthoic acid precipitated (3.7 g, 60%) out of solution.
1H NMR (DMSO-D6): δ 6.69 (d, 1H), 7.28 (t, 1H), 7.39 (t, 1 H), 7.93 (d, 1H), 8.03 (d, 1H), 8.82 (d, 1H), 10.82 (s, 1H), 12.29 (s, 1H).
Step B:
To a solution 4-hydroxynaphthoic acid in anhydrous methanol at 0 °C was added thionyl chloride (1.5 eq). After stirring the solution at room temperature for 16 hours, the solvent was evaporated. The residue was taken up in ethyl acetate and washed with saturated aqueous sodium bicarbonate, water, brine, and dried over MgSO4 to give methyl 4- hydroxynaphthoate.
Η NMR (DMSO-D6): δ 3.87 (s, 3H), 6.92 (d, 1 H), 7.53 (t, 1 H), 7.65 (t, 1 H), 8.13 (d, 1 H), 8.26 (d, 1 H), 8.93 (d, 1 H), 11.16 (s, 1H).
Step C:
The title compound was prepared from methyl 4-hydroxynaphthoate according to the proce- dure for the synthesis of precursor hydrazides A-(C=O)-NHNH2.
Η NMR (DMSO-D6): δ 6.60 (d, 1H), 7.28 (m, 3H), 7.95 (d, 1H), 8.07 (d, 1H), 9.25 (brd s, 1H).
Moreover, by use of the above methodology, the following hydrazides useful as intermediates in preparing the compounds of the invention may be prepared:
Figure imgf000140_0001
Figure imgf000140_0002
Figure imgf000140_0003
Figure imgf000140_0004
Figure imgf000141_0001
Figure imgf000141_0002
Figure imgf000141_0003
General procedure for the synthesis of ether-substituted aryl-aldehydes: The ether-linked aldehydes may be prepared by 0-alkylation of the corresponding phenolic compounds using various electrophilic alkylating agents that introduce the -(K)m-D moiety as defined above in a reaction generally known as Williamson ether synthesis (H. Feuer, J. Hooz in The Chemistry of the Ether Linkage, S. Patai Ed., Wiley, New York 1967, p. 446-460). SCHEME
Figure imgf000142_0001
wherein Lx is a leaving group such as -Cl, -Br, -I, -OSO2CH3, -OSO2p-tolyl or -OSO2CF3; and
R3a _ R3bι R4a _ R4b_ a_ _ Cι d j f) PJ qj D] Mι R14 and R15 ^Q gs defjned for formU|a |.
According to Scheme II an ether-substituted aryl-aldehyde can be prepared by stirring hy- droxybenzaldehydes or hydroxynaphthaldehydes in an organic solvent such as acetone, meth- ylethyl ketone, dimethylformamide, dioxane, tetrahydrofuran, toluene, ethylene glycol dimethyl ether, sulfolane, diethylether, water or a compatible mixture of two or more of the above solvents with an equimolar amount of an alkyl halide or an aryl-lower alkyl halide and in the pres- ence of 1 to 15 equivalents (preferably 1 to 5 equivalents) of a base such as sodium hydride, potassium hydride, sodium or potassium methoxide, ethoxide or tej -butoxide, sodium, potassium or cesium carbonate, potassium or cesium fluoride, sodium or potassium hydroxide or organic bases such as diisopropylethylamine, 2,4,6-collidine or benzyldimethyl- ammonium methoxide or hydroxide. The reaction can be performed at 0°C to 150°C, preferably at 20°C to 100°C and preferably in an inert atmosphere of N2 or Ar. When the reaction is complete the mixture is filtered, concentrated in vacuo and the resulting product optionally purified by column chromatography on silica gel using ethyl acetate/hexane as eluent. The compound can also (when appropriate) be purified by recrystallization from a suitable solvent such as ethyl alcohol, ethyl acetate, isopropyl alcohol, water, hexane, toluene or their compatible mixture. Specific examples illustrating the preparation of ether-substituted aryl-aldehydes are provided below.
Preparation of 4-(2-tetrahvdropyranylmethoxy)-1 -naphthaldehyde:
A mixture of 4-hydroxynaphthaldehyde (1 g, 5.8 mmol), 2-bromomethyl tetrahydropyran (1 g, 5.8 mmol) and powdered K2CO3 (1.2 g, 8.7 mmol) in dimethyl formamide was stirred at 60°C overnight. The mixture was taken up in water and ethyl acetate. The organic layer was separated and washed with water, brine, dried over MgSO4, filtered, and concentrated. The product was purified by silica gel column chromatography using ethyl acetate/hexane.
Figure imgf000143_0001
1H NMR (DMSO-d6): δ 1.48 (m, 4H), 1.74 (d, 1H), 1.84 (m, 1 H), 3.44 (m, 1 H), 3.78 (m, 1H), 3.92 (d, 1 H), 4.23 (m, 2H), 7.17 (d, 1H), 7.64 (t, 1 H), 7.74 (t, 1 H), 8.11 (d, 1H), 8.27 (d, 1H), 9.22 (d, 1H), 10.17 (s,1H).
Preparation of 4-[(3.5-bis-trifluoromethyl)benzyloxy]-1 -naphthaldehyde:
A mixture of 4-hydroxynaphthaldehyde (1 g, 5.8 mmol), 3,5-bis-trifluoromethylbenzylbromide (1.8 g, 5.8 mmol), and powdered K2CO3 (1.2 g, 8.7 mmol) was stirred in acetone (40 mL) overnight. The mixture was poured onto 200 mL of ice-chips and stirred until the ice melted. The yellow precipitate, 4-((3,5-bis-trifluoromethyl)benzyloxy)-1 -naphthaldehyde, was collected and dried.
Figure imgf000144_0001
H NMR (DMSO-d6): δ 5.58 (s, 2H), 7.07 (d, 1H), 7.22 (d, 1H), 7.63 (t, 1 H), 7.69 (t, 1 H), 7.79 (d, 1H), 7.86 (d, 1 H), 7.99 (s, 1 H), 8.14 (s, 1 H), 8.30 (s, 3H), 8.94 (s, 1 H), 8.97 (d, 1H), 11.0 (broad s, 1 H), 11.69 (s,1 H); MS (ESI) m/z 675.2 (M+H)+.
Preparation of 4-( 2-chloroethoxy)-1 -naphthaldehyde:
To a solution of 4-hydroxy-1 -naphthaldehyde (8.6 g, 50 mmoles) and potassium carbonate (13.8 g, 100 mmoles) in N,N-dimethylformamide (DMF)(40 mL) was added 1-bromo-2- chloroethane (7.4 g, 50 mmoles). The mixture was heated at 60°C overnight. The solution was diluted with ethyl acetate (500 mL), extracted with water and brine. The organic layer was dried over magnesium sulfate and the solvent was evaporated to obtain 12.1 g product (52 % yield).
Figure imgf000144_0002
MS (Cl): 403, 405, 407. Η NMR (CDCI3): δ 10.2 (s, 1 H), 9.3 (d, 1 H) 8.35 (d, 1 H), 7.85 (d, 1 H), 7.65 (m, 1 H), 7.5 (m, 1H), 7.1 (d, 1 H), 4.35 (t, 2H), 4.15 (t, 2H).
The products were used as such in further transformations. By application of the above methodology the following substituted aldehyde intermediates were synthesized:
Figure imgf000145_0001
4-carbomethoxymethoxy-1 -naphthaldehyde 4-benzyloxy-1 -naphthaldehyde m.p.: 115-116°C
Figure imgf000145_0002
4-(4-chlorobenzyloxy)-1 -naphthaldehyde 4-allyloxy-1 -naphthaldehyde
Figure imgf000145_0003
4-(4-trifluoromethoxybenzyloxy)-1-
4-propargyloxy-1 -naphthaldehyde naphthaldehyde
Figure imgf000145_0004
4-(4-trifluoromethylbenzyloxy)-1- 2-[(4-carboxaldehydo)-1 - naphthaldehyde naphthyloxy]acetamide m.p. 174-175°C
Figure imgf000146_0001
4-(3-trifluoromethylbenzyloxy)-1-
Figure imgf000146_0002
naphthaldehyde
4-(2-(4-trifluoromethoxyphenyl)-2-oxo- ethoxy)-1 -naphthaldehyde m.p. 112-114°C
Figure imgf000146_0003
4-(4-trifluoromethoxybenzyloxy)-3,5- Nicotinic acid 4-formyl-1 -naphthyl ester dimethoxybenzaldehyde m.p. 142-143°C
-2-
Figure imgf000146_0004
Figure imgf000146_0005
4-(4-isopropylbenzyloxy)-1 -naphthaldehyde
4-(tetrahydro-2-pyranylmethoxy)-1- naphthaldehyde
Figure imgf000147_0001
4-(3,5-difluorobenzyloxy)-1-naphthaldehyde m.p. 100-101°C
Preparation of 3-Allyl-4-hvdroxy-5-methoxy-benzaldehyde:
Figure imgf000147_0002
To a solution of vanillin (1.0 g, 6.57 mmol) in acetone (30 mL) was added potassium carbonate (4.50 g, 32.8 mmol) and allyl bromide (0.62 mL, 7.3 mmol). The mixture was heated under reflux for 6 h. TLC showed appearance of a new spot. Potassium salts were removed by filtration and the filtrate was concentrated to a syrup. A small sample was purified using prep
TLC using hexane/ethyl acetate 7:3 as developing solvent. 1 H NMR (CDCI3) δ = 3.94 (s, 3H), 4.67 - 4.83 (m, 2H), 5.30 - 5.55 (m, 2H), 6.01 - 6.21 (m, 1 H), 6.98 (d, J = 9 Hz, 1 H), 7.40 - 7.56 (m, 2H), 9.85 (s, 1 H); MS (APCI): 193.6
The crude syrup was heated neat in an oil bath at 200 °C for 6 h. The crude material was dissolved in chloroform and filtered through a pack of silica gel. The crude product (yield 72%) was used as is in the next step for O-alkylation. A small portion was purified using prep-TLC to give a pure sample of 3-allyl-4-hydroxy-5-methoxy-benzaldehyde. 1 H NMR (CDCI3) δ = 3.46 (d, J = 6 Hz, 2 H), 3.96 (s, 3H), 5.02 - 5.22 (m, 2H), 5.94 - 6.11 (m, 1 H), 6.30 (s, 1 H), 7.45 (s, 2H), 9.80 (s, 1 H); MS (APCI): 193.3. Preparation of 3-Allyl-4-(4-isopropylbenzyloxy)-5-methoxybenzaldehyde:
The crude 3-allyl-4-hydroxy-5-methoxy-benzaldehyde was taken up in acetone and treated with 4-isopropylbenzyl chloride in the presence of potassium carbonate to give the desired product.
Figure imgf000148_0001
1 H NMR (CDCI3) δ = 1.26 (d, J = 7 Hz, 6 H), 2.92 (m, 1 H), 3.38 (d, J = 7 Hz, 2H), 3.95 (s, 3H), 4.98 - 5.12 (m, 4H), 5.93 - 5.75 (m, 1H), 7.20 - 7.43 (m, 6H), 9.87 (s, 1H).
General procedure for the synthesis of compounds of formulae IXa and IXb:
Figure imgf000149_0001
In the above formulae B, D, R8 and R have the same meanings as defined for formula I.
Step A:
To a solution of aniline (or an aniline derivative) (1 eq.) in THF was added dropwise chloroacetyl chloride (1.2 eq.). After stirring at room temperature overnight, 100 mL water was added, and the mixture was extracted with ethyl acetate. The organic phase was washed twice with dilute hydrochloric acid, twice with water, dried over MgSO4 and then concentrated to give pure product.
Step B:
To a solution of chloroacetanilide (or a derivative thereof) (1.2 eq.) and 2-methoxy-4- hydroxy benzaldehyde (or another aromatic aldehyde substituted with a hydroxy group) (1 eq.) in DMSO was added potassium carbonate (1.5 eq.). After stirring overnight at room temperature, 100 ml water was added. The mixture was extracted with ethyl acetate, the organic extracts were washed twice with a satd. sodium bicarbonate solution, twice with water, and dried over MgS04. After concentration in vacuo. the product was obtained. The following two aldehydes were prepared as examples of compounds that can be prepared using this methodology:
N-(4-Chlorophenyl)-2-(4-formyl-3-methoxyphenoxy)acetamide:
Figure imgf000150_0001
Η NMR (CDCI3 ): δ 4.28 (s, 3H), 5.01 (s, 2H), 6.90 (d, J = 2.2 Hz, 1H), 6.97 ( dd, J = 8.6, 2.1 Hz, 1 H), 7.67 ( d, J = 8.9Hz , 2H), 7.89 (d, J = 8.8 Hz, 2H), 8.20 (d, J = 8.6Hz, 1 H), 8.51 (s, 1 H), 10.66 ( s, 1 H); MS ( APCI ): 319.9 .
N-(4-isopropylphenylV2-(4-formyl-3-methoxyphenoxy)acetamide:
Figure imgf000150_0002
1H NMR ( DMSO-D6): δ 2.07 (d, J = 6.9 Hz , 6H), 2.70 (m, J = 6.9 Hz, 1 H), 3.77 (s, 3H), 4.68 (s, 2H), 6.56 (dd, J = 8.7, 2.1 Hz, 1 H), 6.66 ( d, J = 2.1 Hz, 1 H), 7.06 (d, J = 8.5Hz, 2H), 7.39 ( d, J = 8.50 Hz, 2H), 7.55 (d, J = 8.7 Hz, 1 H), 9.93 (s, 1 H), 10.05 (s, 1 H); MS (APCI ): 328.
This type of aldehydes can be coupled to hydrazides using the methodology as described in step D to give a compound of formula IXa. Alternatively these compounds can undergo rearrangement by treatment with base as described below (step C), followed by coupling to a hydrazide (step D) to give a compound of formula IXb. Step C:
The mixture of aldehyde (1 eq.) and potassium carbonate (1.5 eq.) in acetonitrile was refluxed. The reaction was monitored by TLC (hexane : ethyl acetate = 2:1). When TLC showed almost complete conversion (about 48 h), 100 mi water was added. The mixture was extracted with ethyl acetate, the organic extracts were dried over MgSO4, and concentrated to give the desired product which can be further purified by column chromatography, or used directly for the next step.
The following two aldehydes were prepared as examples of compounds that can be prepared using this methodology:
4-(4-Chlorophenylamino)-2-methoxybenzaldehyde:
Prepared from N-(4-chlorophenyl)-2-(4-formyl-3-methoxyphenoxy)acetamide using the pro- cedure described in step C above.
Figure imgf000152_0001
1H NMR (CDCI3 ): δ 3.84 (s, 3 H), 6.14 (s, 1 H), 6.45 (d, J = 2.0 Hz, 1 H), 6.54 ( dd, J = 8.4, 1.8Hz, 1 H), 7.14 (d, J = 8.7Hz, 2H), 7.33 (d, J = 8.7 Hz, 2H), 7.74 (d, J = 8.5Hz, 1 H), 10.22 (s, 1 H); MS (APCI ): 261.9.
4-( -lsopropylphenylaminoV2-methoxybenzaldehyde:
Prepared from N-(4-isopropylphenyl)-2-(4-formyl-3-methoxyphenoxy)acetamide using the procedure described in step C above.
Figure imgf000152_0002
1H NMR (CDCI3) δ 1.26 (d, J = 6.9Hz, 6H), 2.88 (m, J = 6.9Hz, 1 H), 3.84 (s, 3H), 6.50 (d, J = 1.9Hz, 1 H), 6.55 (dd, J = 8.6, 1.8Hz, 1 H), 6.96 (s, 1 H), 7.15 (d, 2H, J = 8.5Hz, 2H), 7.22 (d, J = 8.5Hz, 2H), 7.69 (d, J = 8.5Hz, 1 H), 10.18 (s, 1 H); MS (APCI ): 269.
Step D:
The resulting carbonyl compounds are treated with the corresponding acylhydrazide in a solvent. The solvent may be one of the following: ethyl alcohol, methyl alcohol, isopropyl alcohol, tert-butyl alcohol, dioxane, tetrahydrofuran, toluene, chlorobenzene, anisole, benzene, chloroform, dichloromethane, DMSO, acetic acid, water or a compatible mixture of two or more of the above solvents. A catalyst such as acetic acid can be added. A dehydrating reagent such as triethylorthoformate can also be added to the reaction mixture. The reaction is performed by stirring the reaction mixture preferably under an inert atmosphere of N2 or Ar at temperatures between 0°C to 140°C, preferably between 10°C to 80°C. In many cases the product simply crystallizes out when the reaction is completed and is isolated by suction filtration. It can be further recrystallized if necessary from a solvent such as the above described reaction sol- vents. The product can also be isolated by concentration of the reaction mixture in vacuo, followed by column chromatography on silica gel using a solvent system such as chloroform/methanol or dichloromethane/methanol or chloroform/ethyl acetate to give a compound of formula IXb.
The following compounds of formulae IXa or IXb according to the invention were prepared as examples of compounds that can be prepared using this methodology:
EXAMPLE 1 : 3-Chloro-4-hydroxybenzoic acid [4-(4-chlorophenylaminoV2-methoxybenzylidene]hydra-zide
Figure imgf000153_0001
Η NMR ( DMSO-D6 ): δ 3.81 (s, 3H), 6.72-6.67 (m, 2H), 7.04 (d, J = 8.5Hz, 1 H), 7.17 ( d, J = 8.7Hz, 2H) 7.31 (d, J = 8.7Hz, 2H), 7.77- 7.70 (m, 2H), 7.96 (d, J = 1.6Hz, 1 H), 8.65 (s, 1 H), 8.70 (s, 1 H), 10.87 (s, 1 H), 11.51 (s, 1 H); MS (APCI ): 430.
EXAMPLE 2:
3-Chloro-4-hydroxybenzoic acid [4-(4-isopropylphenylamino)-2-methoxybenzylidene]hy- drazide
Figure imgf000153_0002
1 H NMR (DMSO-D6): δ 1.18 (2s, 6H), 2.86 (m, 1 H), 3.79 (s, 3H), 6.65 (m, 2H), 7.03 (d, 1 H), 7.11 (d, 2H), 7.19 (d, 2H), 7.70 (d, 1 H), 7.75 (dd, 1 H), 7.97 (s, 1 H), 8.49 (s, 1 H), 8.64 (s, 1 H), 10.88 (s, 1 H), 11.48 (s, 1H); MS (FAB): 438.16. EXAMPLE 3: 2-{4-[(3-Chloro-4-hydroxybenzov0hydrazonomethyl]-3-methoxyphenoxy}-N-(4- chlorophenyhacetamide
Figure imgf000154_0001
H NMR (DMSO-D6): δ 3.66 (s, 3H), 4.57 (s, 2H), 6.48 (d, 1H), 6.55 (s, 1H), 6.83 (d, 1H), 7.20 (d, 2H), 7.48 (d, 2H), 7.56 (dd, 1H), 7.58 (d, 1H), 7.77 (d, 1H), 8.48 (s, 1H), 10.05 (s, 1H), 10.72 (brd s, 1H), 11.40 (s, 1H); MS (APCI): 487.8.
EXAMPLE 4:
2-{4-[(3-Chloro-4-hvdroxybenzoy0hydrazonomethyl]-3-methoxyphenoxy}-N-(4- isopropylphenyl)acetamide
Figure imgf000154_0002
1H NMR (DMSO-Dβ): δ 1.17 (2 s, 6H), 2.85 (m, 1H), 3.87 (s, 3H), 4.76 (s, 2H), 6.70 (d, 1H), 6.76 (d, 1H), 7.05 (d, 1H), 7.20 (d, 2H), 7.55 (d, 2H), 7.77 (dd, 1H), 7.80 (d, 1H), 7.98 (s, 1H), 8.70 (s, 1H), 10.03 (s, 1H), 10.92 (s, 1H), 11.62 (s, 1H); MS (FAB): 496.16. EXAMPLE 5:
2-{4-[(3-Chloro-4-hydroxybenzoyl)hydrazonomethyl]-3-methoxyphenoxy}-N-(3.5- dichlorophenyhacetamide
Figure imgf000155_0001
1 H NMR (DMSO-D6): δ 4.06 (s, 3H), 4.94 (s, 2H), 6.8 (d, 1H), 6.88 (s, 1H), 7.20 (d, 1H), 7.45 (s, 1 H), 7.90 (m, 3H), 8.10 (s, 1 H), 8.82 (s, 1 H), 10.62 (s, 1 H), 11.07 (brd s, 1 H), 11.75 (s, 1H); MS (APCI): 524.8.
General procedure for the synthesis of alkylidene hydrazides of formula II according to the invention:
The acylhydrazides are treated with the corresponding carbonyl compounds, such as aldehydes or ketones, in a solvent. The solvent may be one of the following: ethyl alcohol, methyl alcohol, isopropyl alcohol, te/τf-butyl alcohol, dioxane, tetrahydrofuran, toluene, chlorobenzene, anisole, benzene, chloroform, dichloromethane, DMSO, acetic acid, water or a compatible mixture of two or more of the above solvents. The reaction is performed by stirring the reaction mixture preferably under an inert atmosphere of N2 or Ar at temperatures between 0°C to 140°C, preferably between 10°C to 80°C. In many cases the product simply crystallizes out when the reaction is completed and is isolated by suction filtration. It can be further recrystal- lized if necessary from a solvent such as the above described reaction solvents. The product can also be isolated by concentration of the reaction mixture in vacuo. followed by column chromatography on silica gel using a solvent system such as chloroform/-methanol or dichloromethane/methanol or chloroform/ethyl acetate. The product is isolated by concentration in vacuo of the appropriate fractions. Specific examples illustrating the preparation of compounds according to the invention are provided below. EXAMPLE 6:
3-Chloro-4-hydroxybenzoic acid (4-hydroxy-1 -naphthylmethylene hydrazide
Figure imgf000156_0001
To a solution of 3-chloro-4-hydroxybenzoic acid hydrazide (200 mg, 1.1 mmol) in DMSO (2 ml) was added 4-hydroxynaphthaldehyde and a catalytic amount of glacial acetic acid (5 drops). The reaction was stirred overnight under nitrogen and diluted with ethyl acetate. The solution was washed with saturated sodium bicarbonate, water, brine, and dried over MgSO4. The organic volume was concentrated in vacuo to give the crude product. The product was purified by silica gel column chromatography using CH2CI2/MeOH as the mobile phase.
Η NMR (DMSO-d6): δ 6.89 (d, 2H), 7.02 (d, 1H), 7.47 (t, 1H), 7.58 (t, 1H), 7.66 (d, 1H), 7.73 (d, 1H), 7.93 (s, 1 H), 8.17 (d, 1H), 8.84 (s, 1 H), 8.88 (d, 1H), 10.73 (s, 1 H), 10.88 (s, 1H), 11.54 (s, 1 H); MS (ESI): m/z 341.04 (M+H)+.
EXAMPLE 7: 3-chloro-4-hydroxybenzoic acid [4-(3.5-bis-trifluoromethylbenzyloxy 1-naphthylmethylene]- hydrazide
Figure imgf000156_0002
To a solution of 3-chloro-4-hydroxybenzoic acid hydrazide (200 mg, 1.1 mmol) in DMSO (2 mL) was added 4-(3,5-bis-trifluoromethylbenzyloxy)-1-naphthaldehyde (440 mg, 1.1 mmol) and a catalytic amount of glacial acetic acid (5 drops). The reaction was stirred overnight under nitrogen and diluted with ethyl acetate. The solution was washed with saturated sodium bicarbonate, water, brine, and dried over MgSO4. The organic volume was concentrated under vacuo to give the crude product. The product was purified by silica gel column chromatography using CH2CI2/MeOH as the mobile phase.
Η NMR (DMSO-d6): δ 3.77 (s, 6H), 4.91 (s, 2H), 6.95 (s, 2H), 6.99 (d, 1H), 7.30 (d, 2H), 7.52 (d, 2H), 7.68 (m, 1H). 7.89 (s, 1H), 8.29 (s, 1H), 10.90 (broad s, 1H), 11.69 (s, 1H); MS (ESI): m/z 525.37 (M+H)\
EXAMPLE 8:
3-chloro-4-hydroxybenzoic acid [4-(2-chloroethoxy)-1 -naphthylmethylenejhydrazide
Figure imgf000157_0001
A solution of 1-(4-chloroethoxy)naphthaldehyde (2.35 g, 10 mmoles), 3-chloro-4-hydroxy benzoic acid hydrazide (1.87g, 10 mmoles), glacial acetic acid (0.2 mL) and dimethylsulfoxide (DMSO)(15 mL) was stirred at room temperature overnight. Ethyl acetate (100 mL) was added. The solution was extracted with water and brine which induced precipitation. The product (3.1 g, 77% yield) was obtained by suction filtration. The product was purified by recrystallization from ethyl acetate.
MS (Cl): 235. 1H NMR (DMSO-d6): δ 11.5 (s, 1 H), 10.7 (s, 1 H), 8.7 (bs, 2H), 8.1 (m, 1 H), 7.8 (s, 1 H), 7.6-7.3 (m, 2H), 7.0 (m, 2H), 4.3 (t, 2H), 3.7 (t, 2H).
By application of the above methodology the following compounds of the invention are synthesized employing the following general procedure:
To a solution of 1 mmol of an arylcarboxylic acid hydrazide in 2 ml of anhydrous DMSO was added 1 mmol of the carbonyl compound (an aldehyde or ketone), followed by a catalytic amount of glacial acetic acid. The reaction was stirred overnight under nitrogen and diluted with ethyl acetate. The organic layer was washed with saturated sodium bicarbonate, water, brine, and dried over MgSO4. Upon partial concentration of the solvent in vacuo. the alkylene hydrazides usually precipitated. The alkylene hydrazides were further purified by recrystallization from
hot ethanol or ethyl acetate, or chromatographed using CH2CI2/MeOH as an eluent.
EXAMPLE 9:
4-Hvdroxy-3-methoxybenzoic acid (2-naphthylmethylene)hydrazide
Figure imgf000158_0001
Η NMR (DMSO-d6) δ 3.66 (s, 3 H), 6.67 (d, J = 8.2 Hz, 1 H), 7.32 - 7.47 (m, 5 H), 7.74 (d, J = 7.2 Hz, 1 H), 7.79 (d, J = 8.2 Hz, 2 H), 8.60 (d, J = 8.2 Hz, 1 H), 9.11 (s, 1 H), 11.80 (s, 1 H). APCI m/z: 321
EXAMPLE 10:
4-Hydroxy-3-methoxybenzoic acid (4-methoxy-1 -naphthylmethylene)hydrazide
Figure imgf000158_0002
1 H NMR (CDCI3): δ 4.80 (s, 3 H), 3.86 (s, 3 H), 6.00 (s, 1 H), 6.59 (d, 1 H), 6.83 (d, 1 H), 7.39 (m, 3 H), 7.52 (s, 1 H), 7.73 (s, 1 H), 8.18 (d, 1 H), 8.58 (d, 1 H), 8.88 (s, 1 H), 9.95 (s,1 H). MS (APCI): 351. EXAMPLE 11 :
4-Hydroxy-3-methoxybenzoic acid (4-tert-butylbenzylidene^hydrazide
Figure imgf000159_0001
1H NMR (CDCI3): δ 1.30 (s, 9 H), 3.91 (s, 3 H), 6.16 (s, 1 H), 6.88 (d, 1 H), 7.23 - 7.78 (m, 6 H), 8.28 (s, 1 H), 9.58 (s, 1 H). MS (APCI): 327.
EXAMPLE 12:
4-Hydroxy-3-methoxybenzoic acid (4-isopropylbenzylidene hvdrazide
Figure imgf000159_0002
1 H NMR (CDCI3) δ 1.29 (d, 6 H), 2.94 (q, 1 H), 3.98 (s, 3 H), 6.13 (s, 1 H), 6.97 (d, 1 H), 7.20 - 7.80 (m, 6 H), 8.29 (s, 1 H), 9.38 (s, 1 H). MS (APCI): 313
EXAMPLE 13:
4-Hydroxy-3-methoxybenzoic acid (4-trifluoromethoxybenzylidene)hydrazide
Figure imgf000160_0001
1 H NMR (DMSO-d6): δ 4.01 (s, 3 H), 7.04 (d, J = 8.1 Hz, 1 H), 7.60 - 7.65 (m, 4 H), 8.01 (d, J = 8.4 Hz, 2 H), 8.63 (s, 1 H), 9.92 (s, 1 H), 11.89 (s, 1 H). MS (APCI): 355, 313, 222, 205.
EXAMPLE 14: 4-Hydroxy-3-methoxy benzoic acid (1 H-indol-3-ylmethylene^hydrazide
Figure imgf000160_0002
1 H NMR (DMSO-d6) δ 3.79 (s, 3 H), 6.80 (d, J = 8.2 Hz, 1 H), 7.11 (m, 2 H), 7.38 (m, 3 H), 7.73 (d, J = 2.0 Hz, 1 H), 8.53 (d, J = 7.5 Hz, 1 H), 8.53 (s, 1 H), 9.58 (s, 1 H), 11.23 (s, 1 H), 11.49 (s, 1 H). MS (APCI): 310. EXAMPLE 15:
4-Hydroxy-3-methoxybenzoic acid (4-dimethylamino-1 -naphthylmethylene)hydrazide
Figure imgf000161_0001
1 H NMR (DMSO-d6): δ 3.05 (s, 6 H), 4.03 (s, 3 H), 7.06 (d, J = 8.1 Hz, 1 H), 7.33 (d, J = 8.0 Hz, 1 H), 7.63 - 7.80 (m, 4 H), 7.97 (d, J = 8.0 Hz, 1 H), 8.38 (d, J = 7.9 Hz, 1 H), 9.10 (d, J = 8.4 Hz, 1 H), 9.15 (s, 1 H), 9.90 (s, 1 H), 11.73 (s, 1 H). MS (APCI): 364.
EXAMPLE 16: 4-Hydroxy-3-methoxybenzoic acid (4-phenylbenzylidene)hydrazide
Figure imgf000161_0002
1 H NMR (DMSO-d6): δ 4.02 (s, 3 H), 7.04 (d, J = 8.2 Hz, 1 H), 7.63 - 7.68 (m, 5 H), 7.88 7.96 (m, 6 H), 8.64 (s, 1 H), 9.91 (s, 1 H), 11.83 (s, 1 H). MS (APCI): 347.
EXAMPLE 17:
4-Hydroxybenzoic acid (l-naphthylmethylene)hydrazide
Figure imgf000162_0001
1 H NMR (DMSO-d6): δ 6.82 (d, J = 8.2 Hz, 2 H), 7.48 - 7.68 (m, 3 H), 7.72 - 7.88 (m, 3 H), 7.95 (d, J = 8.2 Hz, 2 H), 8.80 (d, 1 H), 9.04 (s, 1 H), 10.14 (s, 1 H). MS (APCI): 291.
EXAMPLE 18: 4-Hydroxybenzoic acid (4-methoxy-1-naphthylmethylene)hydrazide
Figure imgf000162_0002
1H NMR (DMSO-d6): δ 3.97 (s, 3 H), 6.82 (d, J = 8.6 Hz, 2 H), 7.04 (d, J = 8.2 Hz, 1 H), 7.52 (dd, J = 7.3, 7.7 Hz, 1 H), 7.62 (dd, J = 6.8, 7.7 Hz, 1 H), 7.77 (d, J = 8.5 Hz, 3 H), 8.19 (d, J = 8.2 Hz, 1 H), 8.89 (m, 2 H), 10.06 (s, 1 H). MS (APCI): 321.
EXAMPLE 19:
3.4-Dihydroxybenzoic acid (l-naphthylmethylene hydrazide
Figure imgf000163_0001
1H NMR (DMSO-d6): δ 6.64 (d, J = 8.6 Hz, 1 H), 7.13 (d, J = 8.2 Hz, 1 H), 7.19 (d, J = 2.0 Hz, 1 H), 7.36 - 7.42 (m, 3 H), 7.68 (d, J = 8.2 Hz, 1 H), 7.80 (d, J = 8.2 Hz, 2 H), 8.65 (d, J 8.2 Hz, 1 H), 8.88 (s, 1 H), 9.07 (s, 1 H), 9.46 (s, 1 H), 11.45 (s, 1 H). MS (APCI): 307.
EXAMPLE 20: 4-Hydroxy-3-methoxybenzoic acid (l-naphthylmethylene)hydrazide
Figure imgf000163_0002
1 H NMR (DMSO-d6) δ 3.94 (s, 3H), 6.74 (d, 1H), 7.37-7.52 (m, 6H), 7.77 (d, 1H), 7.89 (d, 2H), 8.67 (d, 1 H), 9.93 (s, 1 H), 10.90 (s, 1 H). MS (APCI): 321.
EXAMPLE 21 :
4-Hydroxy-3-methoxybenzoic acid [3-(3-trifluoromethylphenoxy^benzylidene]hydrazide
Figure imgf000164_0001
1 H NMR (DMSO-d6) δ 3.83 (s, 3H), 6.85 (d, 1 H), 7.16 (dd, 1 H), 7.36 (m, 5H), 7.44 (m, 3H), 7.61 (t, 1 H), 8.43 (s, 1 H), 1.75 (s, 1H), 1 1.69 (s, 1 H). MS (APCI): 431.
EXAMPLE 22:
4-Hydroxy-3-methoxybenzoic acid (4-quinolinylmethylene^hvdrazide
Figure imgf000164_0002
1H NMR (DMSO-d6): δ 3.58 (s, 3 H), 6.52 (d, J = 8.0 Hz, 1 H), 7.28 (d, J = 7.8 Hz, 2 H), 7.47 (dd, J = J* = 8.1 Hz, 1 H), 7.59 (m, 2 H), 7.86 (d, J = 8.4 Hz, 1 H), 8.50 (d, J = 8.4 Hz, 1 H), 8.73 (d, J = 4.5 Hz, 1 H), 8.94 (s, 1 H). MS (APCI): 322. EXAMPLE 23:
4-Hydroxybenzoic acid [3-(1.1.2.2-tetrafluoroethoxy^benzylidenelhydrazide
Figure imgf000165_0001
1H NMR (DMSO-d6) δ 6.49-6.78 (m, 3H), 7.10 (d, 1H), 7.32 (t, 1H), 7.41 (m, 2H), 7.57 (d, 2H), 8.23 (s, 1 H), 10.01 (s, 1 H), 11.59 (s, 1 H). MS (APCI): 357.
EXAMPLE 24:
4-Hvdroxybenzoic acid [3-(4-tert-butylphenyl)but-2-enylidene]hydrazide
Figure imgf000165_0002
1 H NMR (DMSO-d6) δ 1.15 (s, 9H), 1.99 (s, 3H), 6.64 (s, 1 H), 6.17 (d, 2H), 7.29 (s, 4H), 7.64 (d, 2H), 8.06 (s, 1 H), 9.98 (s, 1 H), 11.36 (s, 1 H). MS (APCI): 337.
EXAMPLE 25:
4-Hydroxy-3-methoxybenzoic acid (4-hydroxy-1 -naphthylmethylene^hydrazide
Figure imgf000166_0001
1 H NMR (DMSO-d6): δ 3.90 (s, 3 H), 6.89 (d, 1 H), 6.99 (d, 1 H), 7.19 (d, 1 H), 7.45 - 7.80 (m, 5 H), 8.22 (d, 1 H), 8.90 (s, 2 H), 9.62 (s, 1 H), 10.68 (s, 1 H). MS (APCI): 337.
EXAMPLE 26:
Figure imgf000166_0002
1 H NMR (DMSO-d6): δ 6.86 (d, 2 H), 7.41 - 7.52 (m, 3 H), 7.72 (m, 2 H), 7.82 (d, 2 H), 8.41 (s, 1 H), 10.14 (s, 1 H). MS (APCI): 241.
EXAMPLE 27:
3-Amino-4-hydroxybenzoic acid (l-naphthylmethylene)hydrazide
Figure imgf000167_0001
1 H NMR (DMSO-d6): δ 4.71 (bs, 2 H), 6.68 (d, J = 8.1 Hz, 1 H), 7.01 (dd, J = 2.0, 8.2 Hz, 1 H), 7.17 (d, J = 2.0 Hz, 1 H), 7.51 - 7.62 (m, 3 H), 7.84 (d, J = 7.2 Hz, 1 H), 7.94 (d, J = 8.0 Hz, 2 H), 8.75 (d, J = 7.6 Hz, 1 H), 9.01 (s, 1 H), 9.70 (s, 1 H), 11.54 (s, 1 H). MS (APCI): 306.
EXAMPLE 28:
3-Amino-4-hydroxybenzoic acid (4-hydroxy-1 -naphthylmethylene^hydrazide
Figure imgf000167_0002
1 H NMR (DMSO-d6): δ 4.68 (bs, 2 H), 6.67 (d, J = 8.2 Hz, 1 H), 6.91 (d, J = 7.3 Hz, 1 H), 7.03 (d, J = 8.2 Hz, 1 H), 7.15 (s, 1 H), 7.43 - 7.65 (m, 3 H), 8.16 (d, J = 8.2 Hz, 1 H), 8.83 (m, 2 H), 10.71 (s, 1 H), 11.34 (s, 1 H). MS (APCI): 322. EXAMPLE 29:
4-Hydroxybenzoic acid [3-(3-trifluoromethylbenzyloxy)benzylidene]hydrazide
Figure imgf000168_0001
1H NMR (DMSO-d6): δ 5.28 (s, 2 H), 6.88 (d, 2 H), 7.12 (m, 1 H), 7.24 - 7.50 (m, 3 H), 7.55 - 7.92 (m, 6 H), 8.41 (s, 1 H), 10.16 (s, 1 H), 10.86 (s, 1 H). MS (APCI): 415.
EXAMPLE 30:
3-Chloro-4-hydroxybenzoic acid (l-naphthylmethylene)hydrazide
Figure imgf000168_0002
1 H NMR (DMSO-d6): δ 7.03 (d, J = 8.2 Hz, 1 H), 7.52 - 7.62 (m, 3 H), 7.74 (d, J = 8.2 Hz, 1 H), 7.86 (d, J =7.0 Hz, 1 H), 7.96 (m, 3 H), 8.79 (d, J = 8.2 Hz, 1 H), 9.01 (s, 1 H), 10.94 (s, 1 H), 11.76 (s, 1 H). MS (APCI): 325.
EXAMPLE 31 :
3-Chloro-4-hydroxybenzoic acid (4-hydroxy-1 -naphthylmethylene)hydrazide
Figure imgf000169_0001
H NMR (DMSO-d6): δ 6.90 (d, J = 8.0 Hz, 1 H), 7.02 (d, J = 8.5 Hz, 1 H), 7.50 (dd, J = J' = 7.8 Hz, 1 H), 7.58 (dd, J = 7.1 , 8.0 Hz, 1 H), 7.65 (d, J = 8.0 Hz, 1 H), 7.72 (d, J = 8.5 Hz, 1 H), 7.93 (s, 1 H), 8.17 (d, J = 8.2 Hz, 1 H), 8.83 (s, 1 H), 8.88 (d, J =8.5 Hz, 1 H), 10.73 (s, 1 H), 10.88 (s, 1 H), 11.54 (s, 1 H). MS (APCI): 343, 341.
EXAMPLE 32:
4-Hydroxybenzoic acid C4-hydroxy-1-naphthylmethylene)hydrazide
Figure imgf000169_0002
1 H NMR (DMSO-d6): δ 6.88 (d, 2 H), 6.98 (d, 1 H), 7.55 (dd, 1 H), 7.64 (dd, 1 H), 7.71 (d, 1 H), 7.82 (d, 2 H), 8.22 (d, 1 H), 8.94 (m, 2 H), 10.11 (s, 1 H), 10.77 (s, 1 H). MS (APCI): 307. EXAMPLE 33:
4-Hydroxybenzoic acid [4-(3-trifluoromethylphenoxy)benzylidene]hydrazide
Figure imgf000170_0001
1 H NMR (DMSO-d6): δ 6.81 (d, 2 H), 6.98 (d, 1 H), 7.13 (dd, 1 H), 7.30 - 7.48 (m, 3 H), 7.48 - 7.60 (m, 3 H), 7.68 (dd, 1 H), 7.81 (d, 2 H), 8.41 (s, 1 H). MS (APCI): 401.
EXAMPLE 34: 4-Hydroxy benzoic acid (5-phenyl-3-pyrazolylmethylene^hydrazide
Figure imgf000170_0002
1 H NMR (DMSO-d6): δ 6.81 (d, 2 H), 7.40 - 7.62 (m, 5 H), 7.78 (d, 2 H), 8.09 (s, 1 H), 8.50 (s, 1 H). MS (APCI): 307.
EXAMPLE 35:
2.4-Dihydroxybenzoic acid (4-hydroxy-1 -naphthylmethylene)hydrazide
Figure imgf000170_0003
1 H NMR (DMSO-d6): 6.35 (s, 1 H), 6.39 (d, 1 H), 6.99 (d, 1 H), 7.51 (dd, 1 H), 7.65 (dd, 1 H), 7.73 (d, 1 H), 7.82 (d, 1 H), 8.26 (d, 1 H), 8.88 (s, 1 H), 8.98 (d, 1 H), 10.0 - 11.0 (m, 4 H). MS (APCI): 323. EXAMPLE 36:
4-Hydroxy-3-nitrobenzoic acid (l-naphthylmethylene)hydrazide
Figure imgf000171_0001
1 H NMR (DMSO-d6): δ 6.15 (d, J = 9.3 Hz, 1 H), 7.37 - 7.48 (m, 4 H), 6.70 (d, J = 7.1 Hz, 1 H), 7.78 - 7.82 (m, 2 H), 8.29 (s, 1 H), 8.43 (d, J = 8.5 Hz, 1 H), 8.85 (s, 1 H).
EXAMPLE 37: 4-Hydroxy-3-nitrobenzoic acid (4-hydroxy-1 -naphthylmethylene)hydrazide
Figure imgf000171_0002
1 H NMR (DMSO-d6): δ 6.24 (d, J = 9.3 Hz, 1 H), 6.83 (d, J = 8.0 Hz, 1 H), 7.37 -7.52 (m, 3 H), 7.57 (d, J = 8.0 Hz, 1 H), 8.10 (d, J = 8.0 Hz, 1 H), 8.34 (s, 1 H), 8.76 (s, 1 H), 8.79 (s, 1 H), 10.57 (s, 1 H), 11.17 (m, 1 H).
EXAMPLE 38:
3.4-Dihydroxybenzoic acid (4-hydroxy-1 -naphthylmethylene)hydrazide
Figure imgf000172_0001
1 H NMR (DMSO-d6): δ 6.86 (d, 1 H), 6.98 (d, 1 H), 7.32 (d, 1 H), 7.42 (s, 1 H), 7.56 (dd, 1 H), 7.63 (dd, 1 H), 7.71 (d, 1 H), 8.24 (d, 1 H), 8.88 (s, 1 H), 8.92 (m, 2 H), 9.26 (s, 1 H), 9.54 (s, 1 H), 10.75 (s, 1 H). MS (APCI): 323.
EXAMPLE 39: 4-Hydroxybenzoic acid (6-methoxy-2-naphthylmethylene)hydrazide
Figure imgf000172_0002
1 H NMR (DMSO-d6): δ 3.89 (s, 3 H), 6.86 (d, J = 8.6 Hz, 2 H), 7.22 (dd, J = 2.3, 8.9 Hz, 1 H), 7.37 (d, J = 2.3 Hz, 1 H), 7.80 - 7.93 (m, 6 H), 8.04 (s, 1 H), 8.53 (s, 1 H), 11.67 (s, 1 H). MS (APCI): 321.
EXAMPLE 40:
3.5-Dichloro-4-hydroxybenzoic acid (4-hydroxy-1 -naphthylmethylene)hydrazide
Figure imgf000173_0001
1H NMR (DMSO-d6): δ 6.98 (d, 1 H), 7.58 (dd, 1 H), 7.68 (dd, 1 H), 7.78 (d, 1 H), 8.02 (s, 2 H), 8.27 (d, 1 H), 8.90 (s, 1 H), 8.96 (d, 1 H), 10.81 (s, 1 H), 10.98 (s, 1 H), 11.67 (s, 1 H). MS (APCI): 375, 377.
EXAMPLE 41: 6-Hydroxy-2-naphthoic acid (4-hydroxy-1 -naphthylmethylene^hydrazide
Figure imgf000173_0002
1H NMR (DMSO-d6): δ 6.04 (d, 2 H), 6.33 (m, 1 H), 6.62 (dd, 2 H), 6.79 (dd, 2 H), 7.06 (d, 2 H), 7.44 (d, 2 H), 8.27 (d, 2 H), 8.39 (s, 2 H).
EXAMPLE 42:
4-Hydroxy-3-methoxybenzoic acid (9-ethyl-9H-3-carbazolylmethylene)hydrazide
Figure imgf000173_0003
Η NMR (DMSO-d6) δ 1.34 (t, J = 7.0 Hz, 3 H), 3.88 (s, 3 H), 4.47 (q, J = 7.0 Hz, 2 H), 6.90 (d, J = 8.0 Hz, 1 H), 7.25 (t, J = 7.5 Hz, 1 H), 7.47 - 7.54 (m, 3 H), 7.64 (d, J = 8.2 Hz, 1 H), 7.69 (d, J = 8.5 Hz, 1 H), 7.89 (d, J = 8.5 Hz, 1 H), 8.24 (d, J = 7.7 Hz, 1 H), 8.45 (s, 1 H), 8.62 (s, 1 H) 9.62 (s, 1 H), 11.51 (s, 1H). MS (APCI): 388.
EXAMPLE 43:
4-Hydroxy-3-methoxybenzoic acid [5-(3-chlorophenyl)-2-furanylmethylene]hvdrazide
Figure imgf000174_0001
1H NMR (DMSO-d6): δ 3.93 (s, 3 H), 6.97 (d, J = 8.2 Hz, 1 H), 7.14 (d, J = 3.5 Hz, 1 H), 7.37 (d, J = 3.5 Hz, 1 H), 7.48 - 7.63 (m, 4 H), 7.84 (d, J = 8.0 Hz, 1 H), 7.93 (s, 1 H), 8.47 (s, 1 H), 9.85 (s, 1 H), 11.75 (s, 1 H). MS (APCI): 371.
EXAMPLE 44:
3-Chloro-4-hydroxybenzoic acid (3-phenylallylidene)hydrazide
Figure imgf000174_0002
1 H NMR (DMSO-d6): δ 7.00 (m, 3 H), 7.22 - 7.40 (m, 3 H), 7.57 (d, 2 H), 7.69 (d, 1 H), 7.89 (s, 1 H), 8.12 (d, 1 H), 11.0 (s, 1 H), 12.0 (s, 1 H). MS (APCI): 301.
EXAMPLE 45:
3-Chloro-4-hydroxybenzoic acid (4-allyloxy-1 -naphtylmethylene hydrazide
Figure imgf000175_0001
1 H NMR (DMSO-d6): δ 4.68 (m, 2 H), 5.21 (d, 1 H), 5.38 (d, 1 H), 5.90 -6.10 (m, 1 H), 6.86 (dd, 2 H), 7.42 (dd, 1 H), 7.53 (dd, 1 H), 7.67 (dd, 2 H), 7.86 (s, 1 H), 8.18 (d, 1 H), 8.78 (s, 1 H), 8.82 (d, 1 H), 10.9 (s, 1 H), 12.0 (s, 1 H). MS (APCI): 381.
EXAMPLE 46:
3-Chloro-4-hydroxybenzoic acid (4-ethynylmethoxy-1 -naphthylmethylene)hydrazide
Figure imgf000175_0002
1 H NMR (DMSO-d6): δ 3.60 (s, 1 H), 5.06 (s, 2 H), 6.99 (d, 1 H), 7.12 (d, 1 H), 7.55 (t, 1 H), 7.66 (t, 1 H), 7.73 (t, 1 H), 7.93 (s, 1 H), 8.02 (d, 1 H), 8.16 (t, 1 H), 8.86 (d, 1 H), 9.27 (d, 1 H), 10.90 (s, 1 H), 11.62 (s, 1 H). MS (APCI): 378.
EXAMPLE 47:
3-Chloro-4-hydroxybenzoic acid (4-benzyloxy-1 -naphthylmethylene^hydrazide
Figure imgf000175_0003
1H NMR (DMSO-d6): δ 5.40 (s, 2 H), 7.08 (d, 1 H), 7.08 (s, 1 H), 7.39 (d, 1 H), 7.43 (m, 3 H), 7.70 (m, 5 H), 8.00 (s, 1 H), 8.01 (d, 1 H), 8.33 (t, 1 H), 8.94 (d, 1 H), 9.35 (d, 1 H), 10.98 (s, 1 H), 11.69 (s, 1 H). MS (APCI): 431 , 433.
EXAMPLE 48:
2-("4-[f3-Chloro-4-hvdroxybenzoyπhydrazonomethyl]-1-naphthyloxy)acetamide
Figure imgf000176_0001
1H NMR (DMSO-d6): δ 4.68 (d, 2 H), 6.94 (d, 1 H), 6.98 (dd, 1H), 7.40 - 7.86 (m, 5 H), 8.00 (m, 1 H), 8.48 (dd, 1 H), 8.93 (m, 1 H), 9.38 (m, 1 H). MS (APCI): 398.
EXAMPLE 49:
3-Chloro-4-hydroxybenzoic acid (4-methyl-1 -naphthylmethylene^hydrazide
Figure imgf000176_0002
1 H NMR (DMSO-d6): δ 2.70 (s, 3 H), 7.10 (d, 1 H), 7.49 (d, 1 H), 7.67 (m, 2 H), 7.81 (m, 2 H), 8.00 (s, 1 H), 8.11 (d, 1 H), 8.88 (d, 1 H), 9.07 (s, 1 H), 11.0 (s, 1 H). MS (APCI): 339, 341.
EXAMPLE 50:
3-Chloro-4-hydroxybenzoic acid (2-hydroxy-1 -naphthylmethylene)hydrazide
Figure imgf000177_0001
1H NMR (DMSO-d6): δ 6.98 (d, 1 H), 7.98 (d, 1 H), 7.29 (dd, 1 H), 7.48 (dd, 1 H), 7.69 (d, 1 H), 7.78 (dd, 2 H), 7.90 (s, 1 H), 8.06 (d, 1 H), 9.32 (s, 1 H), 11.00 (s, 1 H). MS (APCI): 341.
EXAMPLE 51 :
3-Chloro-4-hydroxybenzoic acid (4-methoxy-1 -naphthylmethylene)hydrazide
Figure imgf000177_0002
1H NMR (DMSO-d6): δ 4.05 (s, 3 H), 7.06 (m, 2 H), 7.59 (dd, 1 H), 7.70 (dd, 1 H), 7.81 (d, 1 H), 7.86 (d, 1 H), 8.00 (s, 1 H), 8.27 (d, 1 H), 8.93 (s, 1 H), 8.99 (d, 1 H), 11.00 (s, 1 H). MS (APCI): 341 , 339.
EXAMPLE 52: N-(2-[(3-Chloro-4-hydroxybenzoyl)hydrazono]ethyl)-2.2-diphenylacetamide
Figure imgf000177_0003
1 H NMR (DMSO-d6) δ 3.85 (t, 2 H), 4.93 (s, 2 H), 7.16 - 7.25 (m, 10 H), 7.26 (m, 1 H), 7.62 (d, 1 H), 7.82 (s, 1 H), 8.69 (t, 1 H), 10.85 (s, 1 H), 11.39 (s, 1 H). MS (APCI): 422
EXAMPLE 53: 3-Chloro-4-hydroxybenzoic acid (1 -hydroxy-2-naphthylmethylene)hydrazide
Figure imgf000178_0001
1 H NMR (DMSO-d6): δ 6.99 (d, 1 H), 7.22 (d, 1 H), 7.37 -7.56 (m, 4 H), 7.68 (dd, 1 H), 7.77 (d, 1 H), 7.90 (s, 1 H), 8.19 (d, 1 H), 8.58 (s, 1 H), 11.00 (s, 1 H). MS (APCI): 341.
EXAMPLE 54:
3-Chloro-4-hydroxybenzoic acid (2.2-diphenylethylidene)hydrazide
Figure imgf000178_0002
1 H NMR (DMSO-d6): δ 4.94 (d, 1 H), 6.98 (d, 1 H), 7.11 - 7.22 (m, 5 H), 7.22 -7.34 (m, 4 H), 7.68 (d, 1 H), 7.82 (s, 1 H), 8.19 (d, 1 H), 11.00 (s, 1 H). MS (APCI): 365, 367.
EXAMPLE 55: 3-Chloro-4-hydroxybenzoic acid (4-benzyloxy-3.5-dimethoxybenzylidene^hydrazide
Figure imgf000179_0001
1 H NMR (DMSO-d6): δ 3.86 (s, 6 H), 4.98 (s, 2 H), 7.03 (s, 2 H), 7.09 (d, 1 H), 7.25 - 7.33 (m, 3 H), 7.48 (m, 2 H), 7.89 (dd, 1 H), 7.99 (s, 1 H), 8.32 (s, 1 H), 11.00 (s, 1 H). MS (APCI): 441.
EXAMPLE 56:
3-Chloro-4-hydroxybenzioc acid [3-(4-tert-butylphenoxy)benzylidene]hydrazide
Figure imgf000179_0002
1 H NMR (DMSO-d6): δ 1.05 (s, 9 H), 6.90 (m, 3 H), 7.09 (d, 1 H), 7.30 (t, 1 H), 7.40 (m, 3 H), 7.69 (m, 2 H), 7.88 (s, 1 H), 8.44 (s, 1 H), 10.60 (s, 1 H), 11.55 (s, 1 H). MS (APCI): 423.
EXAMPLE 57:
3-Chloro-4-hydroxybenzoic acid (4-methyl-1 -naphthylmethylene)hydrazide
Figure imgf000179_0003
1 H NMR (DMSO-d6): δ 2.64 (s, 3 H), 7.03 (d, J = 8.5 Hz, 1 H), 7.41 (d, J = 7.4 Hz, 1 H), 7.58 (m, 2 H), 7.78 (m, 2 H), 7.95 (d, J = 2.0 Hz, 1 H), 8.06 (dd, J = 2.0, 8.0 Hz, 1 H), 8.82 (d, J = 8.0 Hz, 1 H), 9.07 (s, 1 H), 10.93 (s, 1 H), 11.71 (s, 1 H). MS (APCI): 337. 339.
EXAMPLE 58:
3-Chloro-4-hvdroxybenzoic acid (3-bromo-4-hydroxy-1 -naphthylmethylene)hydrazide
Figure imgf000180_0001
1 H NMR (CDCI3): δ 7.02 (d, J = 8.5 Hz, 1 H), 7.51 - 7.62 (m, 4 H), 7.80 (dd, J = 2.0, 8.5 Hz, 1 H), 8.00 (d, J = 2.0 Hz, 1 H), 8.21 (s, 1 H), 8.59 (d, J = 8.5 Hz, 1 H), 8.91 (s, 1 H). MS (APCI): 421 , 423.
EXAMPLE 59: Acetic acid 4-[(3-Chloro-4-hvdroxybenzoyπhydrazonomethyl]-1 -naphthyl ester
Figure imgf000180_0002
1 H NMR (DMSO-d6): δ 2.63 (s, 3 H), 7.03 (d, J = 8.5 Hz, 1 H), 7.36 (d, J = 8.0 Hz, 1 H), 7.60 (dd, J = 7.0, 7.5 Hz, 1 H), 7.68 (dd, J = 7.0, 8.0 Hz, 1 H), 7.75 (dd, J = 1.4, 8.0 Hz, 1 H), 7.89 (d, J = 8.0 Hz, 1 H), 7.97 (d, J = 8.0 Hz, 2 H), 8.85 (d, J = 8.5 Hz, 1 H), 9.08 (s, 1 H), 11.0 (s, 1 H), 11.78 (s, 1 H). MS (APCI): 383. EXAMPLE 60:
3-Chloro-4-hydroxybenzoic acid (4-cyanomethoxy-1 -naphthylmethylene)hvdrazide
Figure imgf000181_0001
1H NMR (DMSO-d6): δ 5.40 (s, 2 H), 7.00 (d, 1 H), 7.21 (d, 1 H), 7.58 - 7.80 (m, 3 H), 7.82 (d, 1 H), 7.96 (s, 1 H), 8.18 (d, 1 H), 8.90 (s, 2 H), 9.28 (s, 1 H), 11.62 (s, 1 H). MS (APCI): 380, 382.
EXAMPLE 61 :
3-Chloro-4-hydroxybenzoic acid (2-hydroxy-1 -naphthylmethylene^hydrazide
Figure imgf000181_0002
1H NMR (DMSO-d6): δ 7.18 (d, 1 H), 7.30 (d, 1 H), 7.50 (dd, 1H), 7.68 (dd, 1 H), 7.88 (d, 1 H), 7.95 (m, 2 H), 8.08 (s, 1 H), 8.29 (d, 1 H), 9.51 (s, 1 H), 11.12 (s, 1 H), 12.12 (s, 1 H). MS (APCI): 341 , 343.
EXAMPLE 62:
3-Chloro-4-hydroxybenzoic acid (2.3-methylenedioxybenzylidene^hvdrazide
Figure imgf000181_0003
1 H NMR (DMSO-d6): δ 6.06 (s, 2 H), 6.86 (dd, 1 H), 6.90 (dd, 1 H), 7.01 (d, 1 H), 7.25 (d, 1 H), 7.71 (dd, 1 H), 7.92 (s, 1 H), 8.49 (s, 1 H), 10.93 (s, 1 H), 11.70 (s, 1 H). MS (APCI): 319, 321.
EXAMPLE 63:
3-Chloro-4-hydroxybenzoic acid [3-(4-methoxyphenoxy benzylidene]hydrazide
Figure imgf000182_0001
1 H NMR (DMSO-d6): δ 3.98 (s, 3 H), 7.38 (m, 6 H), 7.48 (s, 1 H), 7.72 (m, 2 H), 7.97 (d, 1 H), 8.19 (s, 1 H), 8.64 (s, 1 H), 11.93 (s, 1 H). MS (APCI): 397, 399.
EXAMPLE 64:
3-Chloro-4-hydroxybenzoic acid (9-phenanthrenylmethylene)hydrazide
Figure imgf000182_0002
1H NMR (DMSO-d6): δ 7.02 (d, 1 H), 7.52 - 7.83 (m, 5 H), 7.99 (d, 1 H), 8.08 (d, 1 H), 8.21 (s, 1 H), 8.82 (d, 1 H), 8.89 (dd, 1 H), 8.96 (dd, 1 H), 9.06 (s, 1 H), 10.96 (s, 1 H), 11.82 (s, 1 H). MS (APCI): 375, 377.
EXAMPLE 65:
3-Chloro-4-hydroxybenzoic acid [4-(2-hydroxyethoxy)-1 -naphthylmethylene]hydrazide
Figure imgf000183_0001
1H NMR (DMSO-d6): δ 3.81 (t, J = 4.8 Hz, 2 H), 4.16 (t, J = 4.8 Hz, 2 H), 6.46 (d, J = 8.5 Hz, 1 H), 7.01 (d, J = 8.5 Hz, 1 H), 7.51 - 7.61 (m, 3 H), 7.72 (d, J = 8.2 Hz, 1 H), 7.82 (d, J = 2.1 Hz, 1 H), 8.30 (d, J = 8.2 Hz, 1 H), 8.85 (s, 1 H), 8.87 (d, J = 8.5 Hz, 1 H), 11.38 (s, 1 H). MS (APCI): 385, 387.
EXAMPLE 66:
3-Bromo-4-hydroxybenzoic acid (4-hydroxy-1 -naphthylmethylene^hydrazide
Figure imgf000183_0002
1 H NMR (DMSO-d6): δ 6.90 (d, J = 8.0 Hz, 1 H), 7.00 (d, J = 8.0 Hz, 1 H), 7.47 (dd, J = J' = 8.0 Hz, 1 H), 7.58 (dd, J = J " = 8.0 Hz, 1 H), 7.66 (d, J = 8.0 Hz, 1 H), 7.77 (dd, J = 2.0, 8.0 Hz, 1 H), 8.08 (d, J = 2.0 Hz, 1 H), 8.17 (d, J = 8.0 Hz, 1 H), 8.83 (s, 1 H), 8.88 (d, J = 8.0 Hz, 1 H), 10.73 (s, 1 H), 11.53 (s, 1 H). MS (APCI): 385, 387.
EXAMPLE 67:
Nicotinic acid 4-[(3-chloro-4-hydroxybenzoyl)hydrazonomethyl]-1 -naphthyl ester
Figure imgf000183_0003
1 H NMR (DMSO-d6): δ 7.04 (d, J = 8.5 Hz, 1 H), 7.58 (d, J = 8.0 Hz, 1 H), 7.64 - 7.69 (m, 4 H), 7.74 - 8.02 (m, 3 H), 8.56 (dd, J = 2.0, 8.0 Hz, 1 H), 8.91 (m, 2 H), 9.05 (s, 1 H), 8.35 (d, J = 1.8 Hz, 1 H), 10.96 (s, 1 H), 11.84 (s, 1 H). MS (APCI): 446, 448.
EXAMPLE 68:
3-Chloro-4-hydroxybenzoic acid [4-(1.3-dioxo-1.3-dihydroisoindol-2-ylmethoxyV1-naphthyl- methylenejhydrazide
Figure imgf000184_0001
1 H NMR (DMSO-d6): δ 5.78 (s, 2 H), 7.03 (d, J = 8.5 Hz, 1 H), 7.37 (d, J = 8.2 Hz, 1 H), 7.48 (m, 1 H), 7.61 (m, 1 H), 7.73 - 7.81 (m, 8 H), 8.90 (m, 2 H), 10.91 (s, 1 H), 11.67 (s, 1 H). MS (APCI): 500, 502.
EXAMPLE 69:
3-Chloro-4-hydroxybenzoic acid [4-(cyclohexylmethoxy)-1 -naphthylmethylenelhydrazide
Figure imgf000184_0002
1 H NMR (DMSO-d6): δ 1.08 - 1.19 (m, 4 H), 1.66 - 1.72 (m, 3 H), 1.83 - 1.92 (m, 3 H), 3.21 (m, 1 H), 3.95 (m, 2 H), 6.99 (d, J = 8.1 Hz, 1 H), 7.03 (d, J = 8.5 Hz, 1 H), 7.53 (dd, J = J' = 7.4 Hz, 1 H), 7.62 (dd, J = J ' = 7.5 Hz, 1 H), 7.72 -7.93 (m, 2 H), 7.94 (d, J = 2.1 Hz, 1 H), 8.22 (d, J = 8.0 Hz, 1 H), 8.87 (s, 1 H), 8.90 (d, J = 8.5 Hz, 1 H), 10.94 (s, 1 H), 11.60 (s, 1 H). MS (APCI): 437, 439.
EXAMPLE 70:
3-Chloro-4-hydroxybenzoic acid [4-(tetrahydro-2-pyranylmethoxy -1 -naphthylmethylene]- hydrazide
Figure imgf000185_0001
1 H NMR (DMSO-d6): δ 1.35 (m, 3 H), 1.60 - 1.71 (m, 2 H), 3.15 - 3.38 (m, 2 H), 3.64 (m, 1 H), 3.78 (m, 1 H), 4.02 (m, 2 H), 6.94 (d, J = 8.5 Hz, 2 H), 7.46 (dd, J = J' = 7.4 Hz, 1 H), 7.54 (dd, J = J ' = 8.2 Hz, 1 H), 7.66 (m, 2 H), 7.86 (d, J = 2.1 Hz, 1 H), 8.13 (d, J = 8.0 Hz, 1 H), 8.78 (s, 1 H), 8.83 (d, J = 8.5 Hz, 1 H), 10.83 (s, 1 H), 11.52 (s, 1 H). MS (APCI): 439, 441.
EXAMPLE 71 :
3-Chloro-4-hydroxybenzoic acid [4-(3-pyridylmethoxy)-1 -naphthylmethylene]hydrazide
Figure imgf000185_0002
1 H NMR (DMSO-d6): δ 5.28 (m, 2 H), 6.94 (d, J = 8.5 Hz, 1 H), 7.10 (d, J = 8.5 Hz, 1 H), 7.34 (dd, J = 4.8, 7.8 Hz, 1 H), 7.45 (dd, J = J' = 7.6 Hz, 1 H), 7.54 (dd, J = J ' = 7.5 Hz, 1 H), 7.66 (d, J = 8.5 Hz, 1 H), 7.70 (d, J = 8.2 Hz, 1 H), 7.86 (m, 2 H), 8.15 (d, J = 8.0 Hz, 1 H), 8.45 (dd, J =1.5, 4.8 Hz, 1 H), 8.65 (s, 1 H), 8.81 (m, 2 H), 10.90 (s, 1 H), 11.56 (s, 1 H). MS (APCI): 432, 434.
EXAMPLE 72: 4-[(3-Chloro-4-hydroxybenzoyl)hydrazonomethyl]-1-naphthyloxy acetic acid ethyl ester
Figure imgf000186_0001
1 H NMR (DMSO-d6): δ 1.25 (t, J = 7.0 Hz, 3 H), 4.25 (q, J = 7.0 Hz, 2 H), 5.11 (s, 2 H), 7.06 (d, J = 8.2 Hz, 1 H), 7.13 (d, J = 8.5 Hz, 1 H), 7.64 -7.70 (m, 2 H), 7.76 (d, J = 8.2 Hz, 2 H), 8.04 (d, J = 2.1 Hz, 1 H), 8.36 (d, J = 8.2 Hz, 1 H), 8.97 (s, 1 H), 9.02 (d, J = 8.5 Hz, 1 H), 11.01 (s, 1 H), 11.74 (s, 1 H). MS (APCI): 427, 429.
EXAMPLE 73:
3-Chloro-4-hydroxybenzoic acid (3-nitrobenzylidene)hydrazide
Figure imgf000186_0002
1 H NMR (DMSO-d6): δ 7.13 (d, J = 8.5 Hz, 1 H), 7.79 -7.86 (m, 2 H), 8.03 (d, J = 2.1 Hz, 1 H), 8.18 (d, J = 7.5 Hz, 1 H), 8.30 (d, J = 8.0 Hz, 1 H), 8.58 (s, 2 H), 11.08 (s, 1 H), 12.05 (s, 1 H). MS (APCI): 320, 322.
EXAMPLE 74:
3-Chloro-4-hydroxybeπzoic acid (2.4-dichlorobenzylidene)hydrazide
Figure imgf000187_0001
1 H NMR (DMSO-d6): δ 7.02 (d, J = 8.5 Hz, 1 H), 7.46 (d, J = 8.2 Hz, 1 H), 7.66 (s, 1 H), 7.73 (d, J = 8.2 Hz, 1 H), 7.95 (m, 2 H), 8.71 (s, 1 H), 11.97 (s, 1 H), 11.94 (s, 1 H). MS (APCI): 345.
EXAMPLE 75:
3-Chloro-4-hydroxybenzoic acid (4-fluoro-1 -naphthylmethylene)hydrazide
Figure imgf000187_0002
1 H NMR (DMSO-d6): δ 7.00 (d, J = 8.5 Hz, 1 H), 7.33 (dd, J = 8.2, 10.3 Hz, 1 H), 7.62 - 7.72 (m, 3 H), 7.82 (m, 1 H), 7.91 (d, J = 1.9 Hz, 1 H), 8.04 (d, J = 8.1 Hz, 1 H), 8.09 (m, 1 H), 8.91 (s, 1 H), 10.81 (s, 1 H), 11.67 (s, 1 H). MS (APCI): 343.
EXAMPLE 76:
3-Fluoro-4-hydroxybenzoic acid (4-hydroxy-1 -naphthylmethylene)hydrazide
Figure imgf000187_0003
1 H NMR (DMSO-d6): δ 6.90 (d, J = 8.0 Hz, 1 H), 7.00 (t, J = 8.6 Hz, 1 H), 7.44 - 7.72 (m, 6 H), 8.17 (d, J = 8.6 Hz, 1 H), 8.84 (s, 1 H), 8.89 (d, J = 8.5 Hz, 1 H), 10.60 (s, 1 H), 11.50 (s, 1 H). MS (APCI): 325.
EXAMPLE 77:
3-Chloro-4-hydroxybenzoic acid [4-(2.4-difluorobenzyloxy)-1 -naphthylmethylene]hvdrazide
Figure imgf000188_0001
1 H NMR (DMSO-d6): δ 5.33 (s, 2 H), 7.03 (d, J = 8.5 Hz, 1 H), 7.12 (m, 1 H), 7.21 (d, J = 8.2 Hz, 1 H), 7.31 (m, 1 H), 7.52 (m, 1 H), 7.54 (m, 1 H), 7.69 - 7.80 (m, 3 H), 7.94 (s, 1 H), 8.16 (d, J = 8.2 Hz, 1 H), 8.90 (m, 2 H), 10.91 (s, 1 H), 11.63 (s, 1 H). MS (APCI): 467, 469.
EXAMPLE 78:
3-Fluoro-4-hydroxybenzoic acid (l-naphthylmethylene)hydrazide
Figure imgf000188_0002
MS (APCI): 309.
EXAMPLE 79:
3-Chloro-4-hydroxybenzoic acid [4-f3-methoxybenzyloxy)-1 -naphthylmethylene]hydrazide
Figure imgf000189_0001
1 H NMR (DMSO-d6): δ 3.71 (s, 3 H), 5.29 (s, 2 H), 6.87 (d, J = 8.5 Hz, 1 H), 7.00 - 7.14 (m, 4 H), 7.29 (t, J = 8.0 Hz, 1 H), 7.55 (m, 1 H), 7.68 (m, 1 H), 7.75 (m, 2 H), 7.94 (d, J = 2.0 Hz, 1 H), 8.25 (d, J = 8.0 Hz, 1 H), 8.87 (s, 1 H), 8.92 (d, J = 8.5 Hz, 1 H), 11.00 (s, 1 H), 11.62 (s, 1 H). MS (APCI): 461.
EXAMPLE 80:
3-Chloro-4-hydroxybenzoic acid [4-(4-fluorobenzyloxy)-1 -naphthylmethylenejhydrazide
Figure imgf000189_0002
1 H NMR (DMSO-d6): δ 5.30 (s, 2 H), 7.02 (d, J = 8.5 Hz, 1 H), 7.13 - 7.25 (m, 3 H), 7.53 - 7.60 (m, 4 H), 7.79 (m, 2 H), 7.94 (d, J = 2.0 Hz, 1 H), 8.23 (d, J = 8.0 Hz, 1 H), 8.88 (s, 1 H), 8.92 (d, J = 8.5 Hz, 1 H), 10.93 (s, 1 H), 11.63 (s, 1 H). MS (APCI): 449, 451.
EXAMPLE 81 :
3-Chloro-4-hydroxybenzoic acid [4-(2-tetrahydrofuranylmethoxy)-1 -naphthylmethylene]- hvdrazide
Figure imgf000189_0003
1 H NMR (DMSO-d6): δ 1.77 - 2.04 (m, 4 H), 3.68 (m, 1 H), 3.78 (m, 1 H), 4.12 - 4.16 (m, 2 H), 4.26 (m, 1 H), 7.02 (d, J = 8.5 Hz, 1 H), 7.04 (d, J = 8.2 Hz, 1 H), 7.53 (m, 1 H), 7.62 (m, 1 H), 7.74 (m, 2 H), 7.94 (d, J = 2.0 Hz, 1 H), 8.20 (d, J = 8.2 Hz, 1 H), 8.87 (s, 1 H), 8.90 (d, J = 8.5 Hz, 1 H), 10.93 (s, 1 H), 11.61 (s, 1 H). MS (APCI): 425, 427.
EXAMPLE 82:
3-Chloro-4-hydroxybenzoic acid (3-bromo-4-methoxy-1 -naphthylmethylene hydrazide
Figure imgf000190_0001
1 H NMR (DMSO-d6): δ 3.91 (s, 3 H), 7.03 (d, J = 8.5 Hz, 1 H), 7.65 - 7.76 (m, 3 H), 7.94 (d, J = 2.0 Hz, 1 H), 8.02 (s, 1 H), 8.12 (d, J = 8.0 Hz, 1 H), 8.71 (d, J = 8.0 Hz, 1 H), 8.95 (s, 1 H), 10.96 (s, 1 H), 11.85 (s, 1 H). MS (APCI): 433, 435.
EXAMPLE 83: 3-Chloro-4-hydroxybenzoic acid [4-(3-tetrahydrofuranylmethoxyV1 -naphthylmethylene]- hydrazide
Figure imgf000190_0002
1 H NMR (DMSO-d6): δ 1.92 (m, 1 H), 2.10 (m, 1 H), 2.77 (m, 1 H), 3.28 - 3.88 (m, 4 H), 4.12 (m, 2 H), 7.03 (d, J = 8.5 Hz, 1 H), 7.04 (d, J = 8.2 Hz, 1 H), 7.55 (m, 1 H), 7.62 (m, 1 H), 7.74 (d, J = 8.5 Hz, 1 H), 7.76 (d, J = 8.0 Hz, 1 H), 7.94 (d, J = 2.0 Hz, 1 H), 8.20 (d, J = 8.0 Hz, 1 H), 8.88 (s, 1 H), 8.90 (d, J = 8.5 Hz, 1 H), 10.91 (s, 1 H), 1 1.63 (s, 1 H). MS (APCI): 425, 427. EXAMPLE 84:
4-(4-[3-Chloro-4-hydroxybenzoyl)hydrazonomethyπ-1-naphthyloxymethyhbenzoic acid methyl ester
Figure imgf000191_0001
1 H NMR (DMSO-d6): δ 3.80 (s, 3 H), 5.43 (s, 2 H), 7.03 (d, J = 8.5 Hz, 1 H), 7.12 (d, J = 8.2 Hz, 1 H), 7.54 (m, 1 H), 7.57 (d, J = 8.0 Hz, 4 H), 7.93 - 7.99 (m, 3 H), 8.30 (d, J = 8.0 Hz, 1 H), 8.87 (s, 1 H), 8.93 (d, J = 8.5 Hz, 1 H), 10.91 (s, 1 H), 11.63 (s, 1 H). MS (APCI): 489, 491.
EXAMPLE 85:
3-Chloro-4-hydroxybenzoic acid [3.5-dimethoxy-4-(4-trifluoromethoxybenzyloxy)benzyli- dene]hydrazide
Figure imgf000191_0002
1 H NMR (DMSO-d6): δ 3.76 (s, 6 H), 4.91 (s, 2 H), 6.95 - 7.00 (m, 3 H), 7.30 (d, J = 8.2 Hz, 2 H), 7.52 (d, J = 8.5 Hz, 2 H), 7.68 (d, J = 2.0, 8.5 Hz, 1 H), 7.88 (s, 1 H), 8.29 (s, 1 H), 10.91 (s, 1 H), 11.69 (s, 1 H). MS (APCI): 525, 527.
EXAMPLE 86:
3-Chloro-4-hydroxybenzoic acid [4-(4-trifluoromethoxybenzyloxyV1 -naphthylmethylene]- hydrazide
Figure imgf000192_0001
1 H NMR (DMSO-d6): δ 5.36 (s, 2 H), 7.02 (d, J = 8.4 Hz, 1 H), 7.14 (d, J = 8.2 Hz, 1 H), 7.39 (d, J = 8.2 Hz, 2 H), 7.56 (m, 1 H), 7.62 (m, 3 H), 7.76 (m, 2 H), 7.94 (d, J = 2.0 Hz, 1 H), 8.26 (d, J = 8.3 Hz, 1 H), 8.88 (s, 1 H), 8.93 (d, J = 8.5 Hz, 1 H), 10.91 (s, 1 H), 11.63 (s, 1 H). MS (APCI): 515, 517.
EXAMPLE 87:
3-Chloro-4-hydroxybenzoic acid [4-(2-methoxybenzyloxy)-1 -naphthylmethylene]hydrazide
Figure imgf000192_0002
1 H NMR (DMSO-d6): δ 3.79 (s, 3 H), 5.27 (s, 2 H), 6.95 (m, 1 H), 7.03 (d, J = 8.5 Hz, 1 H), 7.04 (d, J = 8.2 Hz, 1 H), 7.13 (d, J = 8.5 Hz, 1 H), 7.31 (m, 1 H), 7.46 - 7.53 (m, 2 H), 7.61 (m, 1 H), 7.76 (m, 2 H), 7.94 (d, J = 2.0 Hz, 1 H), 8.22 (d, J = 8.3 Hz, 1 H), 8.88 (s, 1 H), 8.92 (d, J = 8.5 Hz, 1 H), 10.90 (s, 1 H), 11.62 (s, 1 H). MS (APCI): 461 , 463.
EXAMPLE 88:
3-Chloro-4-hydroxybenzoic acid [4-(2-fluorobenzyloxy)-1 -naphthylmethylenejhydrazide
Figure imgf000192_0003
1 H NMR (DMSO-d6): δ 5.36 (s, 2 H), 7.03 (d, J = 8.5 Hz, 1 H), 7.19 - 7.28 (m, 3 H), 7.39 (m, 1 H), 7.53 (m, 1 H), 7.63 (m, 2 H), 7.72 - 7.80 (m, 2 H), 7.94 (d, J = 2.1 Hz, 1 H), 8.19 (d, J = 8.3 Hz, 1 H), 8.88 (s, 1 H), 8.92 (d, J = 8.5 Hz, 1 H), 10.90 (s, 1 H), 11.64 (s, 1 H). MS (APCI): 449, 451.
EXAMPLE 89:
3-Chloro-4-hvdroxybenzoic acid r4-(2.6 lifluorobenzyloxy 1 -naphthylmethy|enelhvdra7i-
Figure imgf000193_0001
1 H NMR (DMSO-d6): δ 5.34 (s, 2 H), 7.03 (d, J = 8.5 Hz, 1 H), 7.16 (d, J = 8.2 Hz, 1 H), 7.18 (d, J = 8.0 Hz, 1 H), 7.27 (d, J = 8.2 Hz, 1 H), 7.51 (m, 2 H), 7.72 (m, 1 H), 7.74 (d, J = 8.0 Hz, 1 H), 7.78 (d, J = 8.0 Hz, 1 H), 7.94 (d, J = 2.1 Hz, 1 H), 8.03 (d, J = 8.3 Hz, 1 H), 8.89 (s, 1 H), 8.91 (d, J = 8.5 Hz, 1 H), 10.97 (s, 1 H), 11.65 (s, 1 H). MS (APCI): 467, 469.
EXAMPLE 90:
4-Hvdroxy-3-methoxybenzoic acid [3.5-dimethoxy-4-(5.5.8.8-tetramethyl-5.6.7.8-tetrahydro- naphth-1-ylmethoxy)benzylidene]hydrazide
Figure imgf000193_0002
1 H NMR (DMSO-d6): δ 1.2 (s, 12H), 1.63 (s, 4H), 3.82 (s, 6H), 3.85 (s, 3H), 4.90 (s, 2H), 6.88 (d, 1 H), 7.01 (s, 2H), 7.18 (d, 1 H), 7.29 (d, 1 H), 7.38 (s, 1 H), 7.44 (d, 1 H), 7.48 (s, 1 H), 8.40 (brd s, 1H), 11.62 (s 1 H); MS (APCI): 547.1. EXAMPLE 91:
3-Fluoro-4-hydroxybenzoic acid [4-(4-isopropylbenzyloxy)-3.5-dimethoxybenzylidene]hy- drazide
Figure imgf000194_0001
1H NMR (DMSO-d6): δ 1.05 (d, 6H), 2.67 (m, 1H), 3.61 (s, 6H), 4.69 (s, 2H), 6.79 (s, 2H), 6.86 (t, 1H), 7.01 (d, 2H), 7.24 (d, 1H), 7.44 (dd, 1H), 7.51 (d, 1H), 8.10 (brd s, 1H), 10.32 (s, 1H), 11.41 (s, 1H); MS (APCI): 467.19.
EXAMPLE 92:
3-Chloro-4-hydroxybenzoic acid [4-(4-tert-butylbenzyloxy)-3.5-dimethylbenzylidene]hy- drazide
Figure imgf000194_0002
1H NMR (DMSO-d6): δ 1.06 (s, 9H), 1.99 (s, 6H), 4.55 (s, 2H), 6.83 (d, 1H), 7.19 (s, 6H), 7.52 (d, 1H), 7.73 (s, 1H), 8.09 (s, 1H), 10.74 (brd s, 1H), 11.44 (s, 1H); MS (FAB): 465.6.
EXAMPLE 93:
3-Chloro-4-hydroxybenzoic acid [3-bromo-5-rnethoxy-4-(4-trifluoromethoxybenzyl- oxytoenzylidene]hydrazide
Figure imgf000195_0001
1H NMR (DMSO-d6): δ 3.92 (s, 3H), 5.07 (s, 2H), 7.07 (d, 1 H), 7.40 (m, 3H), 7.52 (s, 1H), 7.63 (d, 2H), 7.77 (dd, 1 H), 7.97 (d, 1H), 8.35 (s, 1 H), 11.00 (brd s, 1 H), 11.86 (s, 1 H); MS (FAB): 575.0
EXAMPLE 94:
4-Hydroxybenzoic acid [4-(4-isopropylbenzyloxyV3.5-dimethoxybenzylidene]hydrazide
Figure imgf000195_0002
"Η NMR (DMSO-d6): δ 1.05 (d, 6H), 2.71 (m, 1 H), 3.67 (s, 6H), 4.75 (s, 2H), 6.70 (d, 2H), 6.85 (s, 2H), 7.14 (d, 2H), 7.21 (d, 2H), 7.64 (d, 2H), 8.21 (brd s, 1 H), 9.97 (brd s, 1 H), 11.47 (s, 1 H); MS (APCI): 448.9.
EXAMPLE 95: 2-Chloro-4-hydroxybenzoic acid [4-(4-isopropylbenzyloxy)-3.5-dimethoxybenzylidene]hy- drazide:
Figure imgf000195_0003
Η NMR (DMSO-D6): d 1.18 (d, 6H), 2.87 (septet, 1H), [3.68 (s, 1H) + 3.81 (s, 5H), 6H], [4.83 (s, 0.5H) + 4.90 (s, 1.5H), 2H], [6.76 (s, 0.5H) + 7.01 (s, 1.5 H), 2H], [6.80 (dd, 1H) + 6.88 (d, 1H), 2H], 7.23 (d, 2H), 7.35 (d, 2H), 7.38 (m, 1H), [7.91 (s, 0.3H) + 8.18 (s, 0.7H), 2H], 10.17 (s, 0.7H) + 11.73 (s, 0.3H), 1H]; MS (APCI): 483.0.
EXAMPLE 96:
3-Chloro-4-hydroxybenzoic acid [3-(4-isopropylbenzyloxy)-4.5-dimethoxybenzylidene]hy- drazide
Figure imgf000196_0001
1H NMR (DMSO-d6): δ 1.05 (d, 6H), 2.70 (m, 1H), 3.54 (s, 3H), 3.66 (s, 3H), 4.94 (s, 2H), 6.87 (m, 3H), 7.08 (d, 2H), 7.20 (d, 2H), 7.56 (dd, 1H), 7.77 (s, 1H), 8.15 (s, 1H), 10.76 (s, 1H), 11.52 (s, 1H); MS (APCI): 483.7.
EXAMPLE 97:
3-Chloro-4-hydroxybenzoic acid [3-( -isopropylbenzyloxy)-2.4-dimethoxybenzylide- nelhvdrazide
Figure imgf000196_0002
1H NMR (DMSO-d6): δ 1.20 (d, 6H), 2.89 (m, 1H), 3.85 (s, 6H), 4.95 (s, 2H), 6.95 (d, 1H), 7.07 (d, 1H), 7.22 (d, 2H), 7.40 (d, 2H), 7.64 (d, 1H), 7.78 (dd, 1H), 7.97 (d, 1H), 8.62 (s, 1H), 11.68 (s, 1H); MS (APCI): 483.8.
EXAMPLE 98: 3-Chloro-4-hydroxybenzoic acid [4-(3-trifluoromethoxybenzyloxy)naphth-1 ■ ylmethylenejhydrazide
Figure imgf000197_0001
1 H NMR (DMSO-d6): δ 5.46 (s, 2H), 7.10 (d, 1 H), 7.20 (d, 1 H), 7.37 (d, 1 H), 7.65 (m, 5H), 7.82 (m, 2H), 8.01 (s, 1 H), 8.32 (d, 1 H), 8.97 (m, 2H), 11.70 (s, 1 H); MS (APCI): 514.8
EXAMPLE 99:
3-Chloro-4-hydroxy-benzoic acid [4-(4-isopropylbenzyloxy)-8-methoxynaphthalen-1 - ylmethylene]-hydrazide
Figure imgf000197_0002
4-hydroxy-8-methoxynaphthalene-1-carbaldehyde (2 g, 9.9 mmol) was dissolved in DMF (25 mL). To this mixture potassium carbonate (6.8 g, 50 mmol) and 4-isopropylbenzylchloride (1.8 g, 10.4 mmol) were added and the resulting mixture was stirred at room temperature for 16 hours. Water (100 mL) was added and the resulting mixture was extracted with diethyl ether (3 x 100 mL). The combined organic extracts were washed with saturated sodium chloride (100 mL), dried (MgSO4) and evaporated in vacuo to afford 3.0 g crude product. This was purified using column chromatography on silica gel (300 mL) eluting with a mixture of ethyl acetate and heptane (1 :4). This afforded 2.57 g (81%) of 4-isopropylbenzyloxy-8- methoxynaphthalene-1-carbaldehyde.
Calculated for C^H^O.,:
C, 79.02%; H, 6.63%. Found: C, 79.10%, H, 6.69%, C, 79.17%, H, 6.69%.
3-Chloro-4-hydroxybenzoic acid hydrazide (205 mg, 1.1 mmol) was dissolved in DMSO (2 mL) and the above 4-isopropylbenzyloxy-8-methoxynaphthalene-1-carbaldehyde (365 mg, 1.1 mmol) and glacial acetic acid (5 drops) were added and the resulting mixture was stirred at room temperature for 20 minutes. More DMSO (2 mL) was added and the mixture was stirred at room temperature for 16 hours. The solid was collected by filtration and washed successively with DMSO and ethyl acetate to afford 330 mg (66%) of the title compound.
M.p.: > 250 °C.
EXAMPLE 100:
Figure imgf000198_0001
1H NMR ( DMSO-d6 ) δ 1.13 (d, 6H), 2.82 (sept, 1H), 3.77 (s, 6H), 4.8 (s, 2H), 7.15 (s, 1H), 7.18 (s, 2H), 7.30 (d, 2H), 8.00 (dd, 1 H), 8.30 (s, 1 H), 8.44 (s, 1 H), 11.84 (s, 1 H);. MS (APCI): 494.0
EXAMPLE 101:
Figure imgf000198_0002
Η NMR ( DMSO-d6 ) δ 5.38 (s, 2H), 6.95 (d, 1 H), 7.06 (d, 1 H), 7.49 (t, 1 H), 7.56 (t, 1 H), 7.65-7.71 (m, 6H), 7.87 (d, 1H), 8.22 (d, 1 H), 8.80 (s, 1H), 8.86 (d, 1H), 10.82 (s, 1H), 11.55 (s, 1 H); MS (FAB): 499 EXAMPLE 102:
Figure imgf000199_0001
Η NMR ( DMSO-d6 ) δ 5.85 (s, 2H), 7.05 (t, 2H), 7.52-7.63 (m, 4H), 7.73 (m, 2H), 7.95 (s, 1 H), 8.16 (d, 2H), 8.33 (d, 1 H), 8.90 (s, 1 H), 893 (s, 1 H), 10.90 (brd s, 1 H), 11.63 (s, 1 H); MS (FAB): 543
EXAMPLE 103: 3-Chloro-4-hydroxybenzoic acid {4-[2-f4-bromophenoxy)ethoxy]-3.5-dimethoxybenzylide- ne}hydrazide
Figure imgf000199_0002
1 H NMR (DMSO-d6): δ 3.78 (s, 6H), 4.21 (m, 4H), 6.87 (d, 2H), 7.00 (s, 2H), 7.05 (d, 1H), 7.44 (d, 2H), 7.75 (dd, 1H), 7.96 (s, 1H), 8.36 (s, 1H), 10.95 (brd s, 1 H), 11.66 (s, 1H); MS(APCI): 548.8.
EXAMPLE 104:
3-Chloro-4-hydroxybenzoic acid [4-( 3-methoxy-3-(4-methylphenyl)-propyloxy)naphth-1 - ylmethylene]hydrazide
Figure imgf000200_0001
MS (APCI): 502.9
EXAMPLE 105:
(2-Ethylphenyl)carbamic acid 2-{4-[f3-chloro-4-hydroxybenzoyl)hydrazonomethyl]-naphth-1- yloxy}ethyl ester
Figure imgf000200_0002
1 H NMR (CDCI3): δ 1.12 (t, 3H), 2.50 (qt, 2H), 3.69 (t, 2H), 4.39 (t, 2H), 5.20 (t, 1 H), 6.57 (t, 1 H), 6.74 (d, 1H), 6.97 (d, 1 H), 7.08 (m, 3H), 7.57 (t, 1 H), 7.67 (t, 1 H), 7.81 (t, 2H), 8.01 (s, 1 H), 8.35 (d, 1 H), 8.95 (m, 2H), 11.67 (s, 1 H).
EXAMPLE 106:
3-Chloro-4-hydroxybenzoic acid [3-allyl-4-(4-isopropylbenzyloxy 5- methoxybenzylidenejhydrazide
Figure imgf000200_0003
1H NMR (DMSO-d6) : δ 1.13 (d, 6H), 2.80 (m, 1H), 3.20 (m, 2H), 3.85 (s, 3H), 4.82 (s, 2H), 5.00 (d, 2H), 5.70 (m, 1H), 6.96 (s, 1H), 7.05 (s, 1H), 7.20 (d, 2H), 7.30 (d, 2H), 7.70 (d, 1H), 7.89 (s, 1H), 8.28 (s, 1H), 10.80 (brd s, 1H), 11.61 (s, 1H); MS (APCI): 493.1.
Similarly, the following compounds were made:
EXAMPLE 107:
Figure imgf000202_0001
1H NMR (DMSO-D6): δ 0.99 (d, 6H), 2.68 (septet, 1H), 4.89 (s, 2H), 6.84 (d, 2H), 7.06 (m, 2H), 7.16 (m, 3H), 7.55 (d, 1H), 7.75 (s, 1H), 8.18 (s, 1H), 10.75 (s, 1H), 11.52 (s, 1H); MS (APCI): 423.7, 425.6.
Figure imgf000202_0002
1H NMR (DMSO-D6): δ 1.18 (d, 1H), 2.88 (septet, 1H), 5.20 (s, 2H), 7.04 (d, 1H), 7.28 (t, 2H), 7.30 (s, 1H), 7.38 (d, 2H), 7.62 (d, 1H), 7.73 (dd, 1H), 7.79 (s, 1H), 7.94 (d, 1H), 8.32 (s, 1H), 11.94(s, 1H), 11.72(s, 1H); MS (APCI): 457.4, 459.1.
EXAMPLE 109:
Figure imgf000202_0003
Η NMR (DMSO-D6): δ 1.1 (d, 6H), 2.2 (s, 6H), 2.8 (septet, 1H), 4.7 (s, 2H), 7.0 (d, 1H), 7.2 (d, 2H), 7.4 (d, 4H), 7.7 (d, 1H), 7.9 (s, 1H), 8.2 (s, 1H), 10.9 (s, 1H), 11.6 (s, 1H); MS (APCI): 451.6,453.3. EXAMPLE 110:
Figure imgf000203_0001
1H NMR (DMSO-D6): δ 1.1 (d, 6H), 2.8 (septet, 1H), 3.3 (d, 1H), 5.0 (d, 1H), 5.1 (d, 1H), 5.2 (s, 2H), 5.9 (m, 1H), 7.0 (d, 1H), 7.1 (d, 1H), 7.2 (d, 2H), 7.3 (d, 2H), 7.4 (d, 1H), 7.5 (s, 1H), 7.7 (dd, 1H), 7.9 (d, 1H), 8.3 (s, 1H), 10.9 (brd s, 1H), 11.5 (s, 1H); MS (APCI): 463.5, 465.1.
EXAMPLE 111:
Figure imgf000203_0002
Η NMR (DMSO-D6): δ 4.47 (t, 2H), 4.54 (t, 2H), 7.01 (d, 2H), 7.07 (d, 1H), 7.14 (d, 1H), 7.45 (d, 2H), 7.53 (t, 1H), 7.27 (d, 1H), 7.79 (m, 2H), 7.96 (d, 1H), 8.17 (d, 1H), 8.91 (s, 1H), 8.94 (d, 1H), 10.92 (s, 1H), 11.64 (s, 1H), MS (APCI): 539.3, 541.1, 543.1.
EXAMPLE 112:
Figure imgf000203_0003
Η NMR (DMSO-D6): δ 1.18 (d, 6H), 2.87 (septet, 1H), [3.67 (s, 1.5H) + 3.81 (s, 4.5H), 6H], [4.83 (s, 0.5H) + 4.90 (s, 1.5H), 2H], 6.73 (s, 0.5H) + [7.02 (m, 2.5H), + 7.27 (m, 2.5H) +
7.37 (m, 2.5H), 8H], [7.92 (s, 0.3H) + 8.17 (s, 0.7H), 1H], [10.96 (s, 0.3H) + 11.12 (s, 0.7H), 1H], [11.82 (s, 0.7H) + 11.95 (s, 0.3H), 1H]; MS (APCI): 517.6, 519.2. EXAMPLE 113:
Figure imgf000204_0001
1H NMR (DMSO-D6): δ 1.19 (d, 6H), 2.89 (septet, 1 H), [3.68 (s, 1.5H) + 3.82 (s, 4.5H), 6H], [4.84 (s, 0.5H) + 4.89 (s, 1.5H), 2H], [6.76 (s, 0.5H) + 7.02 (m, 2.5H), 3H], 7.20 (m, 2H), 7.34 (m, 2H), [7.50 (s, 0.3H) + 7.62 (s, 0.7H), 1 H], 7.92 (s, 0.3H) + 8.18 (s, 0.7H), 1 H], 11.17 (brd s, 1 H), 11.81 (s, 0.7H) + 11.96 (s, 0.3H), 1 H]; MS (APCI): 517.7, 519.2.
EXAMPLE 114:
Figure imgf000204_0002
1H NMR (DMSO-D6): δ 1.20 (d, 6H), 2.87 (septet, 1 H), 3.82 (s, 6H), 4.89 (s, 2H), 6.69 (d, 1 H), 6.98 (m, 3H), 7.21 (m, 3H), 7.36 (d, 2H), 8.32 (s, 1 H), 9.8 (brd s, 1 H), 11.50 (s, 1 H); MS (APCI): 464.7.
EXAMPLE 115:
Figure imgf000204_0003
Η NMR (DMSO-D6): δ 1.19 (d, 6H), 2.30 (septet, 1 H), [3.71 (s) + 3.82 (s), 6H], 4.90 (s, 2H), [6.81 (m, 1.5H) + 6.88 (s, 1.5H), 3H], [7.24 (s, 0.2H) + 8.24 (s, 0.8H), 1 H], 11.05 (brd, 1 H), 11.69 (s, 0.75H) + 11.94 (s, 0.25H), 1 H]; MS (APCI): 485.5, 486.3. EXAMPLE 116:
Figure imgf000205_0001
1H NMR (DMSO-D6): δ 1.19 (d, 6H), 2.88 (septet, 1 H), 3.83 (s, 6H), 4.90 (s, 2H), 6.87 (d, 1 H), 7.03 (s, 2H), 7.23 (d, 2H), 7.36 (d, 2H), 7.53 (m, 3h), 8.26 (m, 3H), 10.73 (s, 1 H), 11.82 (s, 1 H); MS (APCI): 499.8.
EXAMPLE 117:
Figure imgf000205_0002
1H NMR (DMSO-D6): δ 1.20 (d, J = 6.9, 6H), 2.89 (sept, J = 6.9, 1 H), 3.84 (s, 6H), 4.91 (s, 2H), 7.03 (br s, 2H), 7.12 (d, J = 8.8, 1 H), 7.23 (d, J = 8.0, 2H), 7.37 (d, J = 8.0, 2H), 8.04 (dd, J = 2.2, 8.8, 1 H), 8.21 (br s, 1 H), 8.35 (br s, 1 H), 11.78 (s, 1 H), 11.89 (br s, 1 H); MS (APCI, neg): 472.
Preparation of acyl-hydrazones of 4-(2-hydroxyethyl)-1 -naphthaldehyde:
General procedure for synthesis of compounds of the general formula X:
Figure imgf000205_0003
formula X wherein b is 1 , 2, 3 or 4
Preparation of 4-(2-hydroxyethyl)-1 -naphthaldehyde:
Figure imgf000206_0001
1-Bromo-4-(2-hydroxyethy0naphthalene:
To a solution of methyl 4-bromo naphthalene acetate (2.0 g, 7.16 mmol) in anhydrous THF (15 mL) was added drop wise at 0°C 1 M lithium aluminum hydride in THF (4 mL). The mixture was stirred at room temperature for 16 h, diluted with water (5 ml), acidified with cone, hydrochloric acid, and extracted with ethyl acetate (3 x 20 mL). The combined organic extracts were dried (MgSO4), and concentrated to provide a 1.71 g (95%) colorless oil (1.71 g, 95%). A similar synthetic reference is described in A. A. Kiprianov, A. A. Shulezhko. Zh. Org. Khim. 2 (1966), 1852, English translation: J. Org. Chem. (USSR) 2 (1966) 1820].
1H NMR (CDCI3) δ = 2.36 (s, 1H), 3.33 (t, J = 6.7 Hz, 2H), 3.99 (t, J = 6.7 Hz, 2H), 7.24 (d, J = 7.3 Hz, 1H), 7.58 - 7.63 (m, 2H), 7.73 (d, J = 7.6 Hz, 1H), 7.61 (m, 1H), 8.31 (dd, J = 1.1 , 8.0 Hz, 1 H). GCMS (pos.) 250, 252.
1-Bromo-4-(2-tetrahvdropyranyloxyethyπnaphthalene:
To a solution of 1-bromo-4-(2-hydroxyethyl)naphthalene (1.71 g, 6.8 mmol) in dichloromethane (20 mL) was added 3,4-dihydro-2H-pyrane (1 mL, 0.92 g, 11.0 mmol) and p- toluene sulfonic acid (80 mg). The mixture was stirred at room temperature for 90 min, diluted with dichloromethane (20 mL), washed with satd. NaHCO3 sol. (20 mL), dried (MgSO4), and concentrated. Flash chromatography using hexane/ethyl acetate 9:1 as eluent provided 1.69 g (75%) of a colorless oil.
H NMR (CDCI3) δ = 1.51 -1.60 m (6H), 3.37 (t , J = 7.2 Hz, 2H), 3.39 - 3.47 (m, 1H), 3.74 (t, J = 7.2 Hz, 2H), 4.08 (dd, J = 2.4, 7.5 Hz, 1 H), 4.60 (m, 1 H), 7.25 (d, J = 7.3 Hz, 1 H), 7.56 - 7.61 (m, 2H), 7.72 (d, J = 7.6 Hz, 1 H), 8.09 - 8.12 (m, 1 H), 8.29 (dd, J = 2.5, 7.1 Hz, 1 H). GCMS (pos), 334, 336.
1-Formyl-4-(2-tetrahvdropyranyloxyethy0naphthalene: A solution of 1-bromo-4-(2-tetrahydropyranyloxyethyl)naphthalene in anhydrous THF (15 mL) under nitrogen was cooled to -78°C. n-Butyl lithium (1.4 mL of a 2.5 M solution in hexane) was added via syringe, and the mixture was stirred at the same temperature for 30 min. DMF (1.1 mL) was added, and the mixture was allowed to reach room temperature. It was diluted with satd. NH4CI solution (10 mL), extracted with ether (3 x 10 ml), dried (MgSO4) and concentrated. Flash chromatography using hexane/ethyl acetate 5:1 as eluent provided 408 mg (54%) of a colorless oil.
1H NMR (CDCI3) δ = 1.48 -1.69 m (6H), 3.45 - 3.50 (m, 3H), 3.69 - 3.85 (m, 2H), 4.07 - 4.17 (m, 1 H), 4.61 (m, 1 H), 7.58 (d, J = 7.3 Hz, 1 H), 7.62 -7.73 (m, 2H), 7.92 (d, J = 7.3 Hz, 1 H), 8.20 (d, J = 1.0, 8.1 Hz, 1H), 10.36 (s, 1 H). GCMS: 284
1-Formyl-4-(2-hydroxyethyl)naphthalene:
1-Formyl-4-(2-tetrahydropyranyloxyethyl)naphthalene (400 mg, 1.40 mmol) was dissolved in methanol (15 mL), and p-toluene sulfonic acid (45 mg) was added. The mixture was stirred at room temperature for 16 h, and concentrated. The residue was dissolved in ethyl acetate (3 x 10 mL), washed with satd. NaHCO3 (20 mL), dried (MgSO4) and concentrated. Purification by flash chromatography using hexane/ethyl acetate 3:1 as eluent provided 182 mg (65%) of a colorless oil .
1H NMR (CDCI3) δ = 2.09 (s, 1H), 3.40 (t, J = 6.6 Hz, 2H), 4.02 (t, J = 6.6 Hz, 2H), 7.54 (d, J = 7.3 Hz, 1 H), 7.61- 7.71 (m, 2H), 7.88 (d, J =7.3 Hz, 1 H), 8.13 (dd, J = 1.3, 8.0 Hz, 1 H), 9.29 (dd, J = 1.3, 8.0 Hz, 1 H), 10.28 (s, 1 H). GCMS: 200
The following compounds were prepared according to the general procedure for the synthe- sis of alkylidene hydrazones from the condensation of 1-formyl-4-(2-hydroxyethyl) naphthalene (from step D) with 4-hydroxy benzoic acid hydrazides. EXAMPLE 118:
Figure imgf000208_0001
H NMR (DMSO-D6) δ = 3.25 (t, J = 6.5 Hz, 2H), 3.73 (dt, J =J'=6.5 Hz, 2H), 4.84 (t, J = 6.5 Hz, 1 H), 7.08 (d, J = 8.5 Hz, 1 H), 7.49 (d, J = 7.4 Hz, 1 H), 7.60 - 7.68 (m, 2H), 7.80 (dd, J = 1.8, 7.4 Hz, 1H), 7.84 (d, J = 7.3 Hz, 1 H), 8.00 (d, J = 1.8 Hz, 1 H), 9.19 (d, J = 6.7 Hz, 1 H), 8.85 (d, J = 7.7 Hz, 1H), 9.05 (s, 1H), 10.98 (s, 1H), 11.76 (s, 1H); MS (APCI, pos.): 369.4, 371.2.
EXAMPLE 119:
Figure imgf000208_0002
H NMR (DMSO-D6) δ = 3.18 (t, J = 7.0 Hz, 1 H), 3.25 (t, J = 7.0 Hz, 1 H), 3.65 (dd, J = 7.0 Hz, 1 H), 3.74 (dd, J = 5.3, 7.0 Hz, 1H), 4.74 (t, J = 5.3 Hz, 0.5H), 4.79 (t, J = 5.3 Hz, 0.5H), 7.04 (d, J = 8.3 Hz, 0.5H), 7.05 (d, J = 8.3 Hz, 0.5H), 7.25 (d, J = 8.3 Hz, 0.5H), 7.28 (d, J = 8.3 Hz, 0.5H), 7.38 (d, J = 7.4 Hz, 0.5H), 7.43 (d, J = 8.4 Hz, 0.5H), 7.47 - 7.57 (m, 1.5H), 7.61-7.72 (m, 1 H), 7.82 (d, J = 7.2 Hz, 0.5H), 8.10 (d, J = 8.6 Hz, 0.5H), 8.19 (dd, J = 2.2, 7.2 Hz, 0.5H), 8.45 (d, J = 8.6 Hz, 0.5H), 8.48 (s, 0.5H), 8.85 (s, 0.5H), 8.87 (dd, J = 2.2, 6.5 Hz, 0.5H), 11.00 (s, 0.5H), 11.15 (s, 0.5H), 11.86 (s, 0.5H), 11.92 (s, 0.5H); MS (APCI, pos.): 403.4, 405.2, 406.1. Preparation of acylhydrazones of 4-hydroxymethyinaphthaldehyde:
Figure imgf000209_0001
Step A:
The 1 ,4-Naphthalenedicarboxylic acid (25 g, 116 mmol) was dripped into a mixture of Lithium Aluminum Hydride (15 g, 395 mmol) in 600 mL of anhydrous THF and refluxed for two days. The mixture was cooled in an ice bath and excess LAH was decomposed by the slow addition of methanol followed by ice chips. THF was removed under vacuum and the residue was acidified with 1 N HCI. The product was extracted with ethyl acetate (3x), washed with aqueous sodium bicarbonate (3x), water, brine, and dried over magnesium sulfate. 1 ,4- Bishydroxymethylnaphthalene (70%) was obtained as a solid after evaporation of the solvent and can be used in the subsequent oxidation step without further purification. A portion of the material was purified by column chromatography using hexane/ethyl acetate (80/20 to 75/25) for characterization purposes.
1H NMR (DMSO-D6): δ 5.19 (s, 4H), 7.77 (m, 4H), 8.32 (m, 2H).
Step B:
To a solution of 1 ,4-bishydroxymethylnaphthalene (12 g, 65 mmol) in ethyl acetate (300 ml) was added manganese dioxide ( 28 g, 325 mmol). After stirring for 45 minutes most of the starting material had disappeared and two new spots (mono aldehyde and dialdehyde) were seen on TLC. The upper spot corresponds to the dialdehyde. The mixture was passed through a bed of Celite and eluted with additional volumes of ethyl acetate. The solvent was evaporated and 4-hydroxymethylnaphthaldehyde was purified by column chromatography using hexane/ethyl acetate (80/20 to 75/25) in 50% yield.
H NMR (DMSO-D6): δ 5.19 (s, 2H), 5.71 (brd s, 1 H), 7.73 (t, 1 H), 7.78 (t, 1 H), 7.95 (d, 1 H),
8.26 (m, 2H), 9.34 (d, 1 H), 10.46 (s, 1 H). Examples of products employing the above aldehyde:
EXAMPLE 120:
Figure imgf000210_0001
The above compound was prepared according to the general procedure for the synthesis of alkylidene hydrazones from the condensation of the above aldehyde with 3-cyano-4- hydroxybenzoic acid hydrazide.
1H NMR (DMSO-D6): δ 5.02 (s, 2H), 5.44 (s, 1H), 7.14 (d, 1H), 7.69 (m, 3H), 7.91 (d, 1H), 8.10 (d, 1H), 8.14 (d, 1H), 8.27 (s, 1H), 8.87 (d, 1H), 9.06 (s, 1H), 11.84 (brd s, 2H); MS (ACPI): 346.3, 347.2.
EXAMPLE 121:
Figure imgf000210_0002
The above compound was prepared according to the general procedure for the synthesis of alkylidene hydrazones from the condensation of the above aldehyde with 3-chloro-4- hydroxybenzoic acid hydrazide.
Η NMR (DMSO-D6): δ 5.02 (s, 2H), 5.43 (t, 1H), 7.10 (d, 1H), 7.66 (m, 3H), 7.80 (d, 1H), 7.90 (d, 1H), 8.02 (s, 1H), 8.15 (d, 1H), 8.87 (d, 1H), 9.08 (s, 1H), 10.98 (s, 1H), 11.79 (s, 1H); MS (APCI): 355.5 EXAMPLE 122:
Figure imgf000211_0001
The above compound was prepared according to the general procedure for the synthesis of alkylidene hydrazones from the condensation of the above aldehyde with 3-fluoro-4- hydroxy benzoic acid hydrazide.
Η NMR (DMSO-D6): d4.84 (s, 2H), 6.91 (t, 1H), 7.43-7.53 (m, 4H), 7.62 (d, 1 H), 7.72 (d, 1H), 7.96 (d, 1 H), 8.68 (d, 1 H), 8.98 (s, 1 H), 11.71 (brd s, 1 H); MS (APCI): 339.4, 340.3.
The compounds of formula II can also be prepared by parallel synthesis using the protocol mentioned above in a combinatorial approach. Thousands of compounds of formula II can thus be prepared by this combinatorial approach which can be semi- or fully automated. The automation of this protocol can be performed using solution phase combinatorial chemistry in e.g. a 96 well setup using an automated synthesizer device. In the first step of the synthesis the aldehydes or ketones may be prepared according to Scheme II by a combination of a selected number of aldehydes or ketones with a selected number of alkylating reagents. In the second step the formed aldehydes/ketones can be combined with a selected number of the hydrazides (which may be synthesized according to Scheme I) thereby generating a predetermined very large number of compounds as single entities.
The synthesized compounds mentioned above are examples of such compounds that can be prepared using this combinatorial methodology.
By application of the above methodology, the following compounds may also be synthesized:
Figure imgf000212_0001
EXAMPLE 124:
Figure imgf000212_0002
Figure imgf000212_0003
Figure imgf000213_0001
Figure imgf000213_0002
EXAMPLE 130:
Figure imgf000213_0003
EXAMPLE 131:
Figure imgf000213_0004
Figure imgf000214_0001
EXAMPLE 134:
Figure imgf000214_0002
EXAMPLE 135:
Figure imgf000214_0003
EXAMPLE 136:
Figure imgf000214_0004
EXAMPLE 137:
Figure imgf000215_0001
EXAMPLE 138:
Figure imgf000215_0002
EXAMPLE 139
Figure imgf000215_0003
Figure imgf000215_0004
EXAMPLE 142:
Figure imgf000216_0001
General procedure for the synthesis of further derivatized hydrazides of formula II: The compounds of general formula I may be prepared according to one embodiment of the invention, the alkylidene hydrazides of general formula II, as indicated in Scheme III, that is, by converting an alkylidene hydrazide (prepared according to the general method shown in Scheme I, and more specifically as in example 8) into a further derivatized alkylidene hydrazide. Thus, by reacting an amine with an alkylidene hydrazide that contains a leaving group XL (Scheme III) a new alkylidene hydrazide containing an amine in the group K of formula II can be formed.
SCHEME
Figure imgf000216_0002
solvent, base
Figure imgf000216_0003
wherein A, B, D, n, R4 , R3aa, b and d are as defined for formula I and R5a is lower alkyl. Specific examples illustrating the preparation of further derivatized hydrazides of formula II are provided below:
EXAMPLE 143: 3-Chloro-4-hydroxybenzoic acid {4-[2-[N'-(2-N.N-diethylaminoethyl)-N'-(4-trifluoromethoxy- benzylamino)]]ethoxy -1 -naphthylmethylene}hydrazide
Figure imgf000217_0001
N,N-diethyl-N'-(4-trifluoromethoxybenzyl)ethylenediamine:
Figure imgf000217_0002
A solution of (4-trifluoromethoxy)benzaldehyde (1.9 g, 10 mmoles), N,N-diethylethylene- diamine (1.16 g, 10 mmoles), zinc chloride (1.36 g, 10 mmoles) and sodium cyanoborohy- dride (1.26 g, 20 mmoles) in methanol (10 mL) in a dry 100 mL round- bottom flask was stirred at room temperature for 8 hours. Water (20 mL) was then added and most of the methanol was removed in vacuo. The residue was distributed between ethyl acetate and 1 N HCI. The acidic aqueous phase was basified with excess of sodium hydroxide. Crude N,N- diethyl-N'-(4-trifluoromethoxybenzyl)ethylenediamine was obtained. The crude product was used in the following reaction without further purification.
MS (Cl): 291. 1H NMR (CDCI3): δ 7.4 (m, 2H), 7.2 (m, 2H), 3.9 (bs, 2H), 3.1-2.6 (m, 9H), 1.4- 1.1 (t, 6H).
To a flask containing N,N-diethyl-N'-(4-trifluoromethoxybenzyl)ethylenediamine (0.29 g, 1 mmole) in DMF (5 mL) was added [1-(4-chloroethoxy)naphthyl](3-chloro-4-hydroxy)benzoic acid hydrazide (0.41 g, 1 mmole) and triethylamine (0.1 g, 1 mmole). The resulting solution was heated at 80°C overnight. Removal of most of the solvent in vacuo followed by flash chromatography (10:1 CHCI3/MeOH) on silica gel provided the title compound as a brown solid. 1HNMR (DMSO-d6): δ 11.7 (1H), 9.0 bs, 2H), 8.4-7.0 (m, 12 H), 4.75 (bs, 1 H), 4.65 (bs, 1 H), 4.55 (t, 1 H), 4.35 (t, 1H), 4.15 (t, 1 H), 3.9 (bs, 1 H), 3.5 (q, 4H), 3.05 (t, 1 H), 1.3 (t, 3H), 0.95 (t, 3H). M.p.: 134-136°C. MS (Cl): 657, 659.
EXAMPLE 144:
3-Chloro-4-hydroxybenzoic acid {4-[2-(4-trifluoromethoxy)benzylaminoethoxy]-1-naphthyl- methylene}hydrazide
Figure imgf000218_0001
To a flask containing 4-trifluoromethoxybenzylamine (0.29 g, 1 mmole) in DMF (5 mL) was added 3-chloro-4-hydroxybenzoic acid [4-(2-chloroethoxy)-1-naphthylmethylene]hydrazide (0.403g, 1 mmole) and triethylamine (0.1 g, 1 mmole). The resulting solution was heated at 80°C for 16 hours. Removal of most of the solvent in vacuo, followed by flash chromatography (10:1 CHCIa/MeOH) oh silica gel provided the title compound as a brown solid.
ΗNMR (DMSO-d6): δ 11.6 (s, 1 H), 9.0 (m 2H), 8.3 (m 1 H), 8.0 (m,1 H), 7.8 (s, 2H), 7.7 (m,1 H), 7.6 (m, 1 H), 7.5 (m, 3H), 7.3 (m, 2H), 7.1 (m, 2H), 4.3 (t, 2H), 3.9 (s, 2H), 3.0 (t, 2H). MS (Cl): 557, 559.
By application of the above methodology the following compounds of the invention were synthesized:
EXAMPLE 145: 3-Chloro-4-hydroxybenzoic acid {3.5-dimethoxy-4-[2-(4-trifluoromethoxybenzylamino)- ethoxy]benzylidene}hydrazide
Figure imgf000219_0001
1 H NMR (CD3OD): δ 2.90 (brd t, 2H), 3.75 (s, 6H), 3.89 (s, 2H), 4.08 (brd t, 2H), 6.87 (d, 1 H), 7.10 (s, 2H), 7.20 (d, 2H), 7.43 (d, 2H), 7.65 (m, 1 H), 7.82 (m, 1 H), 8.11 (brd s, 1 H); MS (APCI): 567.9.
EXAMPLE 146:
3-Chloro-4-hydroxybenzoic acid {4-[2-(2-piperidin-1-yl-ethylamino)ethoxy]naphth-1- ylmethylene}hydrazide
Figure imgf000219_0002
1 H NMR (DMSO-d6): δ 1.53 (m, 2H), 1.74 (m, 4H), 3.12 (m, 2H), 3.40 (m, 2H), 3.54 (m, 2H), 3.63 (m, 4H), 4.52 (s, 2H), 7.10 (d,1 H), 7.14 (d, 1 H), 7.60 (t, 1 H), 7.71 (m,1 H), 7.80 (dd, 1 H), 7.83 (d, 1 H), 8.00 (d,1 H), 8.51 (d, 1 H), 8.95 (d, 1 H), 8.98 (s, 1 H), 11.69 (s,1H); MS (APCI): 495.0
EXAMPLE 147:
3-Chloro-4-hydroxybenzoic acid {4-[2-(3-diethylaminopropylamino)ethoxy]naphth-1 ■ ylmethylene}hydrazide
Figure imgf000220_0001
1 H NMR (DMSO-d6): δ 1.21 (t, 6H), 2.10 (m, 2H), 3.14 (m, 10H), 4.52 (t, 2H), 7.10 (d, 1 H), 7.14 (d, 1 H), 7.63 (t, 1 H), 7.73 (m, 1 H), 7.80 (dd, 1 H), 7.84 (d, 1 H), 8.00 (d, 1H), 8.46 (d,1 H), 8.93 (s,1 H), 8.98 (m, 1 H), 9.20 (m, 2H), 9.69 (m, 1 H), 11.00 (s, 1 H), 11.69 (s, 1 H); MS (APCI): 497.0.
EXAMPLE 148:
1-(2-{4-[(3-Chloro-4-hydroxybenzoyl)hydrazonomethyl]naphth-1-yloxy}ethyl)-4- phenylaminopiperidine-4-carboxylic acid amide
Figure imgf000220_0002
1 H NMR (DMSO-d6): δ 1.16 (m, 2 H), 1.88 (m, 2H), 2.03 (m, 2H), 2.80 (m, 2H), 2.92 (m, 2H), 4.37 (m, 2 H), 4.40 (brd s, 2H), 4.44 (s, 1 H), 6.55 - 6.62 (m, 3 H), 6.96 (s,1 H), 7.03- 7.16 (m, 5H), 7.61 (dd, 1 H), 7.68 (dd,1 H), 8.00 (d, 1 H), 8.27 (d, 1 H), 8.94 (s,1 H), 8.97 (s, 1H), 11.63 (s, 1H); MS (APCI): 586.4
EXAMPLE 149:
4-(2-{4-[(3-Chloro-4-hydroxybenzoyl)hydrazonomethyl]naphth-1-yloxy}ethylamino)piperidine- 1 -carboxylic acid ethyl ester
Figure imgf000221_0001
1H NMR (DMSO-d6): δ 1,10 (t, 3H), 1.15 - 1.23 (m, 2H), 1.86 (m, 2H), 2.79 (m, 3H), 3.30 (m, 2H), 3.87 (m, 2H), 3.94 (q, 2H), 4.28 (m, 2H), 7.03 (d,1H), 7.05 (m, 1H), 7.51 - 7.63 (m, 3H), 7.13 (d, 1H), 7.75 (m,1 H), 7.93 (d, 1H), 8.29 (d,1 H), 8.87 (m,2 H), 11.55 (s, 1H); MS (APCI): 539.1, 541.0.
EXAMPLE 150:
3-Chloro-4-hydroxybenzoic acid {4-[2-(1.2.3.4-tetrahydronaphth-1-ylaminotethoxy]-naphth-1- ylmethylene}hydrazide
Figure imgf000221_0002
1H NMR (DMSO-d6): δ 1.76 (m, 1H), 2.04 (m, 1H), 2.17 (m, 2H), 2.75 - 2.94 (m, 2H), 3.61 (m, 2H), 4.55 (m,2H), 4.71(s, 1H), 7.11 (d, 1H), 7.13 (d, 1H), 7.23 - 7.35 (m, 3H), 7.61 (d, 1H), 7.67 (d,1H), 7.71 (dd, 1H), 7.81 (dd, 1H), 7.86 (d, 1H), 8.01 (d, 1H), 8.48 (d, 1H), 8.94 (m, 1H), 8.99 (m, 1H), 9.22 (m, 2H), 11.00 (s,1 H), 11.64 (s,1H); MS (APCI): 514.0, 516.0
EXAMPLE 151:
1-(2-{4-[(3-Chloro-4-hvdroxybenzoyπhydrazonomethyl]naphth-1-yloxy}ethyπpiperidine-4- carboxylic acid amide
Figure imgf000222_0001
MS (APCI): 495.0
EXAMPLE 152:
3-Chloro-4-hydroxybenzoic acid {4-[2-(2-trifluoromethoxybenzylamino)-ethoxy]-1 -naphthyl- methylene}hydrazide
Figure imgf000222_0002
EXAMPLE 153:
3-Chloro-4-hydroxybenzoic acid {4-[2-(4-morpholinylethylaminotethoxy]-1 -naphthylmethylene}- hydrazide
Figure imgf000222_0003
By application of the above methodology the following compounds may also be synthezised:
EXAMPLE 154:
Figure imgf000222_0004
EXAMPLE 155:
Figure imgf000223_0001
EXAMPLE 156:
Figure imgf000223_0002
EXAMPLE 157:
Figure imgf000223_0003
EXAMPLE 158:
Figure imgf000223_0004
EXAMPLE 159:
Figure imgf000224_0001
EXAMPLE 160:
Figure imgf000224_0002
General procedures for the preparation of alkylidene arylsulfonyl hydrazides according to the invention
The compounds of general formula I are prepared according to one embodiment of the invention, the alkylidene arylsulfonyl hydrazides of general formula III, that is, by converting an arylsulfonyl halide, for example chloride or bromide to the corresponding hydrazide derivative and further reacting the product arylsulfonyl hydrazide compound with a substituted aldehydes or ketones to yield alkylidene arylsulfonyl hydrazide derivatives as illustrated in Scheme IV.
SCHEME IV
Figure imgf000225_0001
wherein A, B, K, D, m, n and R4 are as defined for formula I.
The synthesis of the arylsulfonylhydrazide precursors is performed by application of general methodology, for example as described by Friedman, L.; Litle, R.L; Reichle, W. R. in Org. Synth. Coll. Vol. V, 1973, 1055-1057, by slowly adding the arylsulfonyl chloride either neat, or in a solution in an inert solvent such as tetrahydrofuran, dimethyl ether, dioxane or diethyl ether to an excess of hydrazine, either neat or in solution in the one of the above solvents or a mix- ture of these at -20°C to 100°C, preferably between 0°C to 60°C. When the reaction is judged to be completed, the excess of solvent and volatile reagents is removed by distillation either at atmospheric pressure or in vacuo. The residual product can be further purified by recrystallization from a solvent such as methyl alcohol, ethyl alcohol, isopropyl alcohol, water, toluene, acetic acid, dioxane, tetrahydrofuran or a mixture of two or more of the above solvents when compatible.
Alternatively, the product can be purified by column chromatography using dichloromethane/- methanol or chloroform/methanol or isopropyl alcohol as eluent. The corresponding fractions are concentrated either at atmospheric pressure or in vacuo to provide the pure arylsulfonyl hydrazide.
By use of the above methodology the following compounds can be prepared:
EXAMPLE 161 : 3-Chloro-4-hydroxybenzenesulfonic acid (benzylidene^hydrazide
Figure imgf000226_0001
3-Chloro-4-hydroxybenzenesulfonyl hydrazide:
A solution of 4.82 g (21.2 mmol) 3-chloro-4-hydroxy-benzenesulfonyl chloride, (prepared according to the procedure described by Popoff, I. C; Frank, J. R.; Whitaker R. L.; Miller H. J., Demaree K. D. J. Agr. Food Chem. 1969, 17, 810.) in 15 ml THF was added dropwise with stirring to 3.4 ml 50% hydrazine hydrate (54.4 mmol, 2.5 eq.) at such a rate that the temperature is maintained below 10°C. A precipitate formed after the addition was completed. The mixture was stirred for an additional 30 min, and cooled to 0 °C. The solid was collected in a Buchner funnel, washed several times with distilled water, and air dried. Recrystallization from methanol provided 1.20 g 3-chloro-4-hydroxybenzenesulfonyl hydrazide as a white solid.
H NMR (DMSO-d6): δ 4.78 (bs, 4 H), 6.72 (d, J = 8.6 Hz, 1 H), 7.35 (dd, J = 2.3, 8.6 Hz, 1 H), 5.55 ( J = 2.2 Hz, 1 H); MS(CI): m/z 223, 221.
To a solution of 105 mg (0.48 mmol) of the above 3-chloro-4-hydroxybenzenesulfonyl hydrazide in 5 ml methanol was added 0.05 ml (52 mg, 0.49 mmol) benzaldehyde and one drop of acetic acid. After 30 min the mixture was concentrated. Flash chromatography (silica gel, 2:1 hexane/ethylacetate) provided 67 mg (45%) of the title compound as a solid.
1 H (DMSO-d6): δ 7.10 (d, J = 8.6 Hz, 1 H), 7.38 (m, 3 H), 7.55 (dd, J = 2.3, 6.0 Hz, 2 H), 7.66 (d, J = 2.2, 8.6 Hz, 1 H), 7.76 (d, J = 2.2 Hz, 1 H), 7.90 (s, 1 H), 11.3 (m, 2 H). MS(CI): m/z 311.
EXAMPLE 162: 3-Chloro-4-hydroxy-benzenesulfonic acid [4-(4-trifluoromethoxybenzyloxy)-1 - naphthylmethylene]hydrazide
Figure imgf000227_0001
To a solution of 3-chloro-4-hydroxy-benzene sulfonyl hydrazide (105 mg, 0.48 mmol) in 5 ml methanol was added 4-trifluoromethoxybenzyloxy-1 -naphthaldehyde (163 mg, 0.49 mmol) and a catalytical amount of glacial acetic acid (5 drops). The reaction mixture was stirred overnight, and filtered. The filtrate was concentrated under vacuo to give the crude product. Flash chromatography (silica gel, 1 :1 hexane/ethylacetate) provided 145 mg (56%) of the title compound as a solid.
Η NMR (DMSO-d6) δ 5.27 (s, 2 H), 6.06 (s, 1 H), 6.83 (d, J = 8.1 Hz, 1 H), 7.10 (d, J = 8.1 Hz, 1 H), 7.26 (d, J = 7.3 Hz, 2 H), 7.50 - 7.60 (m, 5 H), 7.80 (s, 1 H), 7.85 (dd, J = 3.0, 8.2 Hz, 1 H), 8.08 (d, J = 2.1 Hz, 1 H), 8.26 (s, 1 H), 8.36 (d, J = 7.76 Hz, 1 H), 8.67 (d, J = 8.5 Hz, 1 H). CIMS m/z: 551 , 553.
By using the above methodology, the following compounds may be prepared:
EXAMPLE 163:
Figure imgf000227_0002
EXAMPLE 164:
Figure imgf000227_0003
EXAMPLE 165:
Figure imgf000228_0001
EXAMPLE 166:
Figure imgf000228_0002
Synthesis of alkylhydrazides according to the invention:
The alkylidene hydrazide derivatives given above can be reduced to the dihydroderivatives by the method given in Scheme V:
SCHEME V
Figure imgf000228_0003
where A, R4, B, K, D, m and n are as defined for formula I.
The alkylhydrazide derivatives can be prepared by reduction (i.e. Lane, C.F.(1975), Synthesis, p.135) of the corresponding alkylidene hydrazides using a metal hydride, such as sodium bo- rohydride or sodium cyanoborohydride. The alkylidene hydrazide derivative is treated with between 1-10 equivalents, preferentially 1-3 equivalents, of sodium cyanoborohydride in a solvent such as methyl alcohol, ethyl alcohol, isopropyl alcohol, tetrahydrofuran, dioxane, water or a compatible mixture of two or more solvents. Optionally a small amount of an acid is used as a catalyst such as hydrochloric acid, trifluoroacetic acid, acetic acid, or sulfuric acid. The reactions are performed at 0°C to 60°C, preferably at 10°C to 30°C. When the reaction is complete as judged by HPLC or TLC (silica gel, 1 % methanol in dichloromethane as eluent) the solvents) are removed and the residue is chromatographed on a silica gel column using 1% methanol in dichloromethane or chloroform as an eluent. The corresponding fractions are con- centrated to give the desired product. Specific examples illustrating the preparation of alkylhy- drazides according to the invention are provided below.
EXAMPLE 167:
4-hydroxybenzoic acid (1-naphthylmethyπhydrazide
Figure imgf000229_0001
4-Hydroxybenzoic acid (l-naphthylmethylene)hydrazide (100 mg, 0.34 mmol) was dissolved in methanol (10 mL) and treated with sodium cyanoborohydride (236 mg, 4.1 mmol) followed by two drops of trifluoroacetic acid. After stirring the reaction solution for three hours at room temperature, the solvent was evaporated in vacuo. The residue was introduced into a silica gel column and eluted with dichloromethane/methanol (99/1 ). Evaporation of the corresponding fractions in vacuo gave the title compound in 30% yield. MS (ESI) m/z 293 (M+H)+.
Using the same methodology as described above the following compound was prepared:
EXAMPLE 168:
3-Chloro-4-hydroxybenzoic acid N-[4-(4-isopropylbenzyloxyV3.5-dimethoxybenzyl]hydra-zide
Figure imgf000230_0001
1H NMR (DMSO-d6): δ 1.18 (d, 6H), 2.87 (m, 1H), 3.75 (s, 6H), 3.90 (m, 2H), 4.80 (s, 2H), 5.43 (brd s, 1H), 6.68 (s, 2H), 6.98 (d, 1H), 7.20 (d, 2H), 7.34 (d, 2H), 7.64 (dd, 1H), 7.87 (d, 1H), 9.89 (brd s, 1H), 10.80 (s, 1H); MS (APCI): 485.2.
Furthermore, the following compounds may also be prepared:
EXAMPLE 169:
Figure imgf000230_0002
EXAMPLE 170:
Figure imgf000230_0003
EXAMPLE 171:
Figure imgf000230_0004
EXAMPLE 172:
Figure imgf000231_0001
EXAMPLE 173:
Figure imgf000231_0002
General procedure for synthesis of compounds of the general formula XI:
Figure imgf000231_0003
Figure imgf000231_0004
formula XI
A and B are as defined for formula I and -NR5cR5d is
Figure imgf000231_0005
where RJ* R4a_ R4bι c> Q) d and D are as defined for for- mula I or
-D' where -D' is defined as a subset of -D that contains a primary or secondary amine that can react as a nucleophile. Step A: The reaction is known and is generally performed by stirring hydroxy benzaldehyde, hydroxy naphthaldehyde or the like together with a bromo acetic acid ester (either methyl, ethyl or other lower alkyl ester) in the presence of a base such as lithium, sodium, potassium or cesium carbonate in a solvent such as acetone, 2-methyl-3-pentanone, tetrahydrofuran, dioxane, DMSO, DMF, ethylene glycol, benzene, toluene or a mixture of the above solvents. The reactions are performed between 0°C to 130°C, preferably between 20°C to 100°C, most preferably at or about the reflux temperature of the solvent. The reactions are preferably conducted under an inert atmosphere such as N2 or Ar. When the reaction is complete as judged by disappearance of the starting ester by TLC or HPLC, the solvent may be removed by concentra- tion at atmospheric or reduced pressure. The product can be further purified by either recrystallization from a solvent such as ethyl alcohol, methyl alcohol, isopropyl alcohol, toluene, xylene, hexane, tetrahydrofuran, diethyl ether, dibutyl ether, water or a mixture of two or more of the above. Alternatively, the product can be purified by column chromatography using dichloromethane/methanol or chloroform/methanol or isopropyl alcohol as eluent.
Step B: The resulting derivative of acetic ester is then saponified using methods well-known to those skilled in the art such as dissolving the compound in an appropriate solvent such as a lower alcohol (e.g methanol, ethanol or isopropanol), DMF, dioxane or DMSO and adding an aqueous base like lithium, sodium or potassium hydroxide. The reactions are performed be- tween 0°C to 130°C, preferably between 20°C to 100°C. When the reaction is complete as judged by disappearance of the staring ester by TLC or HPLC, the solvent may be removed by concentration at atmospheric or reduced pressure. The product can then be isolated by pouring the residue into water or cooled water and acidifying the mixture using an inorganic acid such as hydrochloric acid or sulfuric acid. The product can then be isolated either by filtration or by extraction using a solvent such as ethyl acetate, toluene, dichloromethane or diethylether and the solvent may then be removed by concentration at atmospheric or reduced pressure. The product can be further purified by either recrystallization from a solvent such as ethyl alcohol, methyl alcohol, isopropyl alcohol, toluene, xylene, hexane, tetrahydrofuran, diethyl ether, dibutyl ether, water or a mixture of two or more of the above. Alternatively, the product can be purified by column chromatography using dichloromethane/methanol or chloroform/methanol or isopropyl alcohol as eluent . Step C: The resulting carbonyl compounds are treated with an acylhydrazide in a solvent. The solvent may be one of the following: ethyl alcohol, methyl alcohol, isopropyl alcohol, tert-butyl alcohol, dioxane, tetrahydrofuran, toluene, chlorobenzene, anisole, benzene, chloroform, dichloromethane, DMSO, acetic acid, water or a compatible mixture of two or more of the above solvents. A catalyst such as acetic acid can be added. A dehydrating reagent such as triethy- lorthoformate can also be added to the reaction mixture. The reaction is performed by stirring the reaction mixture preferably under an inert atmosphere of N2 or Ar at temperatures between 0°C to 140°C, preferably between 10°C to 80°C. In many cases the product simply crystallizes out when the reaction is completed and is isolated by suction filtration. It can be further re- crystallized if necessary from a solvent such as the above described reaction solvents. The product can also be isolated by concentration of the reaction mixture in vacuo. followed by column chromatography on silica gel using a solvent system such as chloroform/methanol or dichloromethane/methanol or chloroform/ethyl acetate.
Step D: The resulting acid is then coupled to a primary or secondary amine using one of the methods well-known to those skilled in the art. This coupling can be performed using one of the standard amide or peptide synthesis procedures such as by generating an active ester, an anhydride or an acid halide that can then react with the amine to give a compound of formula XI. Step D can also be done combinatorially with a selected number of amines. The product can then be isolated either by filtration or by extraction using a solvent such as ethyl acetate, toluene, dichloromethane or diethylether and the solvent may then be removed by concentration at atmospheric or reduced pressure. The product can be further purified by either recrystallization from a solvent such as ethyl alcohol, methyl alcohol, isopropyl alcohol, toluene, xylene, hexane, tetrahydrofuran, diethyl ether, dibutyl ether, water or a mixture of two or more of the above. Alternatively, the product can be purified by column chromatography using dichloromethane/methanol or chloroform/methanol or isopropyl alcohol as eluent giving a compound of formula XI.
Specific examples illustrating the preparation of compounds of the general formula XI ac- cording to the invention are provided below. EXAMPLE 174:
2-{4-[(3-Chloro-4-hvdroxy-benzovπhydrazonomethyl]naphthyl-1-yloxy}-N-(4-chloro- phenyhacetamide
Figure imgf000234_0001
Step A: Hydroxynaphthaldehyde (10 g, 58 mmol), potassium carbonate (16 g, 110 mmol), and methyl bromoacetate (16 g, 100 mmol) were refluxed in acetone (120 mL) overnight. The reaction mixture was poured into an Erlenmeyer flask containing approximately 500 mL of ice chips. The mixture was stirred until all of the ice was melted. (4-Formylnaphth-1-yloxy) acetic acid methyl ester (13 g, 50 mmol) was filtered and dried in vacuo overnight.
1 H NMR (CDCI3): δ 3.86 (s, 3H), 4.93 (s, 2H), 6.80 (d, 1 H), 7.61 (t, 1 H), 7.72 (t, 1 H), 7.90 (d, 1 H), 8.42 (d, 1 H), 9.29 (d, 1 H), 10.22 (s, 1 H).
Step B: The above ester (13 g, 50 mmol) was dissolved in methanol (100 mL) and 2 M
NaOH (40 mL) was added. The reaction solution was stirred overnight and concentrated to approximately 100 mL under vacuo. The residue was poured into approximately 500 mL of ice chips and the mixture was acidified (by pH paper) with the addition of 3N HCI. The mixture was stirred until all of the ice was melted. (4-Formylnaphth-1-yloxy) acetic acid was filtered and washed with water.
Step C: To a solution of 3-chloro-4-hydroxybenzoic acid hydrazide (2g, 10.7 mmol) in DMSO (20 mL) was added the above (4-formylnaphth-1-yloxy) acetic acid (3g, 13 mmol) and a catalytic amount of acetic acid (10 drops). The solution was stirred overnight and diluted with ethyl acetate. The solution was washed with water (3x), brine, and dried over MgSO4. The volume was reduced to approximately 100 mL and placed in an ice-bath. The resulting solid was filtered and washed with cold ethyl acetate to afford {4-[(3-chloro-4-hydroxy- benzoyl)hydrazonomethyl]naphth-1-yloxy} acetic acid. 1 H NMR (DMSO-d6): δ 4.91 (s, 2H), 6.95 (d, 1H), 7.02 (d, 1 H), 7.55 (t, 1 H), 7.64 (t, 1 H), 7.74 (d, 1 H), 7.92 (d, 1 H), 8.27 (d, 1 H), 8.90 (m, 2H), 10.92 (brd s, 1 H), 11.63 (s, 1 H), 13.14 (brd s, 1 H).
Step D: To a solution of the hydrazone-carboxylic acid (50 mmol) in anhydrous DMSO was added a solution of carbonyldiimidazole (55 mmol) in anhydrous DMSO. After the evolution of gases ceased (approximately 3-4 minutes), the amine was added and the reaction mixture was stirred for 3 hours. The mixture was diluted with ethyl acetate and washed with water, brine, and dried over magnesium sulfate. Evaporation of the solvent afforded the crude material, which was purified by reverse phase HPLC chromatography to give the title compound.
1 H NMR (DMSO-d6): δ 4.99 (s, 2H), 7.04 (m, 2H), 7.36 (d, 2H), 7.65 (m, 4H), 7.79 (t, 2H), 7.99 (s, 1H), 8.40 (d, 1 H), 8.72 (s, 1 H), 8.92 (d, 1 H), 10.42 (s, 1 H), 10.96 (s, 1H), 11.69 (s, 1 H); MS (APCI): 507.9.
By using the same methodology, the following compounds were prepared:
EXAMPLE 175:
N-(1-Benzylpyrrolidin-3-yl)-2-{4-[(3-chloro-4-hydroxy-benzoyl)hydrazonomethyl]naphth-1- vloxvϊacetamide
Figure imgf000235_0001
H NMR (DMSO-d6): δ 1.96 (m, 2H), 2.32 (m, 5H), 4.58 (s, 2H), 6.78 (d, 1H), 6.92 (d, 1H), 7.15 (m, 5H), 7.47 (t, 1H), 7.52 (t, 1H), 7.62 (d, 2H), 7.82 (d, 1H), 8.18 (m, 2H), 8.78 (d, 2H), 10.75 (brd s, 1H), 11.52 (s, 1H); MS (APCI): 556.9.
EXAMPLE 176:
2-{4-[(3-Chloro-4-hydroxybenzoyl)hydrazonomethyl]naphth-1-yloxy}-N-indan-1-yl-acetamide
Figure imgf000236_0001
1H NMR (DMSO-d6): δ 1.94 (m, 1H), 2.40 (m, 1H), 2.80-3.07 (m, 3H), 4.87 (s, 2H), 7.04 (d, 1H), 7.10 (d, 1H), 7.21 (m, 4H), 7.61 (t, 1H), 7.69 (t, 1H), 7.80 (t, 2H), 8.10 (s, 1H), 8.42 (d, 1H), 8.64 (d, 1H), 8.98 (m, 2H), 11.00 (brd s, 1H), 11.68 (s, 1H); MS (APCI): 514, 516.
EXAMPLE 177:
2-{4-[(3-Chloro-4-hydroxybenzoyπhydrazonomethyl]naphth-1-yloxy}-N-(1.2.3.4-tetrahydro- naphthalen-1 -yOacetamide
Figure imgf000236_0002
1H NMR (DMSO-d6): δ 1.75 (m, 2H), 1.92 (m, 2H), 2.74 (m, 2H), 4.87 (m, 2H), 5.12 (m, 1H), 7.12 (m, 6H), 7.61 (t, 1H), 7.74 (t, 1H), 7.84 (m, 2H), 8.01 (s, 1H), 8.40 (d, 1H), 8.62 (d, 1H), 8.97 (m, 2H), 11.72 (s, 1H); MS (APCI): 528, 530. EXAMPLE 178:
2-f4-[(3-Chloro-4-hvdroxybenzoyπhydrazonomethyl]naphth-1-yloxy}-N-[2-(4-chloro- phenyOethyl]acetamide
Figure imgf000237_0001
1H NMR (DMSO-d6): δ 2.40 (t, 2H), 2.79 (t, 2H), 4.74 (s, 2H), 6.96 (d, 1H), 7.10 (d, 1 H), 7.63 (t, 1 H), 7.69 (t, 1H), 7.72 (m, 2H), 7.81 (s, 1 H), 8.01 (m, 2H), 8.23 (t, 1 H), 8.40 (d, 1 H), 8.95 (s, 1 H), 9.01 (d, 1 H), 10.98 (brd s, 1 H), 11.70 (s, 1 H); MS (APCI) 538.8, 537.8.
EXAMPLE 179:
2-{4-[(3-Chloro-4-hydroxybenzoyπhydrazonomethyl]naphth-1-yloxy}-N-[3-(4-methylpiperazin- 1 -yhpropyljacetamide
Figure imgf000237_0002
1 H NMR (DMSO-d6): δ 1.50 (m, 2H), 2.26 (m, 2H), 2.48 (m, 5H), 3.01 (m, 8H), 4.53 (s, 2H), 6.78 (d, 1H), 6.89 (d, 1H), 7.38 (t, 1H), 7.47 (t, 1H), 7.5 (t, 2H), 7.76 (d, 1 H), 8.01 (t, 1H), 8.22 (d, 1 H), 8.68 (d, 1 H), 8.74 (s, 1 H), 10.74 (brd s, 1 H), 11.45 (s, 1 H); MS (APCI): 538.0.
EXAMPLE 180:
3-Chloro-4-hydroxybenzoic acid {4-[2-(1.2.3.4-tetrahydroisoquinolin-2-yl)-2-oxoethoxy]- naphth-1 -ylmethylene}hydrazide
Figure imgf000238_0001
1 H NMR (DMSO-d6): δ 2.90 (d, 2H), 2.75 (m, 2H), 4.70 (d, 2H), 5.24 (s, 2H), 6.90 (t, 2H), 7.10 (m, 4H), 7.66 (m, 4H), 8.01 (s, 1H), 8.34 (t, 1H), 8.95 (m, 2H), 10.97 (brd s, 1H), 11.68 (brd s, 1 H); MS (APCI): 514.2.
EXAMPLE 181 :
2-{4-[(3-Chloro-4-hydroxy-benzoyl)hydrazonomethyl]naphth-1-yloxy}-N-(3- trifluoromethoxybenzyπacetamide
Figure imgf000238_0002
1 H NMR (DMSO-d6): δ 4.49 (d, 2H), 4.90 (s, 2H), 7.13 (m, 2H), 7.42 (m, 4H), 7.59 (dd, 1 H), 7.68 (dd, 1 H), 7.78 (m, 2H), 8.03 (s, 1 H), 8.51 (d, 1 H), 8.79 (t, 1 H), 9.0 (m, 2H), 10.85 (brd s, 1H), 11.72 (s, 1H); MS (APCI): 572.1.
EXAMPLE 182:
3-Chloro-4-hydroxybenzoic acid (4-{2-[4-(4-bromophenyπ-4-hydroxypiperidin-1 -yl]-2- oxoethoxy}naphth-1-ylmethylene)hydrazide
Figure imgf000238_0003
MS (APCI): 636, 638.
EXAMPLE 183:
2-{4-[(3-Chloro-4-hydroxybenzoyπhydrazonomethyl]naphth-1-yloxy}-N-(4- trifluoromethylsulfanylbenzyOacetamide
Figure imgf000239_0001
1 H NMR (DMSO-d6): δ 4.48 (d, 2H), 4.88 (s, 2H), 7.08 (m, 2H), 7.45 (d, 2H), 7.68 (m, 4H), 7.82 (m, 2H), 8.01 (d, 1H), 8.52 (d, 1H), 8.87 (t, 1 H), 8.96 (s, 1H), 9.01 (d, 1H), 10.98 (brd s, 1 H), 11.72 (s, 1 H); MS (APCI): 588.2
EXAMPLE 184:
2-{4-[(3-Chloro-4-hydroxy-benzoyπhydrazonomethyl]naphth-1-yloxy}-N-(3.4- dichlorobenzyl)acetamide
Figure imgf000240_0001
1H NMR (DMSO-d6):δ 4.42 (d, 2H), 4.91 (s, 2H), 7.08 (d, 1H), 7.11 (d, 1H), 7.22 (d, 1H), 7.48 - 7.76 (m, 4H), 7.82 (d, 2H), 8.04 (d, 1 H), 8.51 (dd, 1 H), 8.83 (m, 1 H), 8.91 (s, 1 H), 10.02 (d, 1H), 11.00 (brd s, 1H), 11.73 (s, 1H); MS (APCI): 556.0
EXAMPLE 185:
Figure imgf000240_0002
1H NMR (DMSO-D6): δ 0.97 (d, 6H), 2.42 (m, 2H), 2.50 (m, 2H), 2.68 (septet, 1H), 3.49 (m, 4H), 5.12 (s, 2H), 7.03 (d, 1H), 7.08 (d, 1H), 7.60 (t, 1H), 7.68 (t, 1H), 7.80 (d, 2H), 8.01 (d, 1H), 8.33 (d, 1H), 8.94 (s, 1H), 9.00 (d, 1H), 11.68 (s, 1H); MS (APCI, neg.): 507.1, 509.1.
EXAMPLE 186:
Figure imgf000240_0003
Η NMR (DMSO-D6): δ 1.75 (m, 2H), 2.25 (m, 2H), 2.24 (d, 3H), 2.39 (quintet, 1 H), 3.26 (m, 2H), [2.84 (s, 1.5H) + 3.04 (s, 1.5H), 3H], 5.16 (d, 2H), 6.72 (t, 1H), 7.07 (d, 1H), 7.62 (t, 1H), 7.68 (t, 1H), 7.78 (dd, 2H), 8.00 (d, 1H), 8.34 (m, 1H), 8.94 (s, 1H), 9.00 (d, 1H), 11.65 (brd s, H); MS (APCI): 495.2, 497.2.
EXAMPLE 187:
Figure imgf000241_0001
Η NMR (DMSO-D6): δ 0.86 (s, 3H), 1.48 (m, 4H), 2.38 (t, 1H), 2.72 (m, 1H), 3.09 (t, 1H), 3.84 (t, 1H), 4.18 (t, 1H), 5.09 (m, 2H), 7.03 (d, 1H), 7.11 (d, 1H), 7.59 (t, 1H), 7.64 (t, 1H), 7.82 (d, 2H), 8.01 (s, 1H), 8.33 (d, 1H), 8.94 (s, 1H), 9.00 (d, 1H), 11.0 (brd, 1H), 11.69 (brd s, 1H); MS (APCI): 480.1, 482.1.
EXAMPLE 188:
Figure imgf000241_0002
1H NMR (DMSO-D6): δ 2.88 (s, 1.5H) + (s, 1.5H), 3H], 2.95 (t, 1H), 3.01 (s, 1.5H), 3.10 (s, 1.5H), 3.10 (t, 1H), 3.69 (t, 1H), 3.81 (t, 1H), 5.05 (d, 2H), [6.66 + 6.95 (d), 1H], 7.10 (d, 1H), [7.20 + 7.38 (d), 1H], 7.29 (d, 1H), 7.67 (m, 5H), 8.01 (s, 1H), 8.30 (t, 1H), 8.53 (dd, 1H), 8.97 (m, 2H), 11.67 (brd s, 1H); MS (APCI): 517.3, 519.2.
EXAMPLE 189:
Figure imgf000241_0003
Η NMR (DMSO-D6): δ 3.88 (s, 6H), 4.75 (s, 2H), 6.93 (d, 1H), 7.08 (m, 3H), 7.34 (dd, 1H), 7.74 (dd, 1H), 7.79 (d, 1H), 7.95 (s, 1H), 8.37 (s, 1H), 9.74 (s, 1H), 10.03 (m, 1H), 10.96 (brd s, 1H), 11.76 (brd s, 1H); MS (APCI): 534.4, 536.2.
EXAMPLE 190:
Figure imgf000242_0001
Η NMR (DMSO-D6): δ 1.18 (d, 6H), 2.85 (m, 1H), 3.87 (s, 3H), 4.76 (s, 2H), 6.71 (d, 1H), 6.78 (d, 1H), 7.06 (d, 1H), 7.20 (d, 2H), 7.58 (d, 2H), 7.78 (dd, 1H), 7.82 (d, 1H), 7.99 (d, 1H), 8.70 (s, 1H), 10.04 (s, 1H), 10.92 (brd s, 1H), 11.62 (brd s, 1H); MS (APCI): 496.5, 498.2.
EXAMPLE 191:
Figure imgf000242_0002
Η NMR (DMSO-D6): δ 4.88 (s, 2H), 6.93 (t, 2H), 7.23 (d, 2H), 7.47 - 7.70 (m, 6H), 7.86 (d, 1H), 8.30 (d, 1H), 8.80 (s, 1H), 8.87 (d, 1H), 10.34 (s, 1H), 10.82 (brd s, 1H), 11.55 (brd s, 1H); MS (APCI): 558.5, 560.0. EXAMPLE 192:
Figure imgf000243_0001
1H NMR (DMSO-D6): δ 4.06 (s, 3H), 4.94 (s, 2H), 6.81 (d, 1H), 6.89 (s, 1H), 7.19 (d, 1H), 7.45 (s, 1H), 7.90 (m, 3H), 8.10 (s, 1H), 8.82 (s, 1H), 10.62 (s, 1H), 11.07 (brd s, 1H), 11.75 (s, 1H); MS (APCI): 523.3, 524.8, 526.6.
EXAMPLE 193:
Figure imgf000243_0002
1H NMR (DMSO-D6): δ 1.68 (m, 2H), 2.01 (m, 2H), 3.05 (m, 2H), 3.35 (m, 2H), 3.86 (m, 1H), 4.26 (s, 2h), 4.81 (s, 2H), 6.95 (d, 1H), 7.09 (d, 1H), 7.46 (s, 5H), 7.59 (m, 1H), 7.66 (t, 1H), 7.77 (d, 1H), 7.98 (d, 1H), 8.34 (d, 1H), 8.41 (d, 1H), 8.92 (m, 2H), 9.65 (brd s, 1H), 11.02 (brd s, 1H), 11.80 (brd s, 1H); MS (APCI): 571.3, 572.3, 573.3.
EXAMPLE 194:
Figure imgf000243_0003
Η NMR (DMSO-D6): δ 2.79 (t, 2H), 3.43 (qt, 2H), 4.71 (s, 2H), 6.95 (d, 1H), 7.08 (d, 1H), 7.17 (m, 1H), 7.26 - 7.30 (m, 3H), 7.61 (t, 1H), 7.67 (t, 1H), 7.76 (m, 2H), 7.99 (d, 1H), 8.24 (t, 1H), 8.38 (d, 1H), 8.91 (s, 1H), 8.98 (d, 1H), 10.94 (s, 1H), 11.67 (s, 1H); MS (APCI): 536.3, 538.2, 539.1.
EXAMPLE 195:
Figure imgf000244_0001
1H NMR (DMSO-D6): δ 4.42 (d, 2H), 4.87 (s, 2H), 7.06 (m, 2H), 7.38 (d, 2H), 7.60 (t, 1 H), 7.63 (m, 1 H), 7.80 (t, 1 H), 7.99 (d, 1H), 8.49 (d, 1 H), 8.79 (t, 1 HJ), 8.93 (s, 1 H), 8.98 (d, 1 H), 10.95 (s, 1H), 11.68 (s, 1H); MS (APCI): 558.2, 560.1.
EXAMPLE 196:
4-(4-bromophenyl-3.4-dihvdropiperadinylacetamideoxy)naphth-1-yl methylene-3-chloro-4- hvdroxybenzoic acid hydrazone
Figure imgf000244_0002
Reaction scheme:
Figure imgf000245_0001
4-(4-bromophenyπ-4-piperidinol chloroacetamide (step A):
To a solution of 4-(4-bromophenyl)-4-piperidinol (5 g, 19.5 mmol) and diisopropylethylamine (2.8 g, 21.5 mmol) in DMF (30 mL) was added dropwise chloroacetylchloride ( 2.2 g, 21.5 mmol). After stirring the mixture for one hour, the mixture was diluted with ethyl acetate and washed with aqueous sodium bicarbonate (2x), 1 N HCI (3x), water, brine, and dried over MgSO The solution was concentrated and chromatographed over silica gel with ethyl acetate to give the product as a brown solid (4 g, 62 %).
1H NMR (DMSO-D6): δ 1.21 (d, 2H), 1.71 (t. 1 H), 1.96 (t, 1 H), 2.71 (t, 1 H), 3.37 (t, 1 H), 3.70 (d, 1 H), 4.27 (d, 1 H), 4.54 (s, 2H), 5.26 (s, 1H), 7.42 (d, 2H), 7.51 (d, 2H).
4-(4-bromophenyπ-3.4-dihvdropiperidine chloroacetamide (step B):
To a solution of 4-(4-bromophenyl)-4-piperidinol chloroacetamide (4 g, 12 mmol) and diisopropylethylamine (4.6 mL, 26 mmol) in THF (40 mL) cooled in an ice-bath was added methanesulfonyl chloride (2 mL, 26 mmol) and the mixture was refluxed for 16 hours under a nitrogen blanket. The reaction mixture was diluted with ethyl acetate and washed with 1 N HCI (2x), aqueous NaHCO3 (2x), brine (2x), and dried over MgSO4. The solvent was evaporated and the product was chromotographed over silica gel with ethyl acetate/hexane (4/6). The product was obtained as a yellow solid (1.5 g, 32%). Η NMR (DMSO-D6): δ 2.44 (t, 2H), 3.62 (m, 2H), 4.14 (dd, 2H), 4.42 (d, 2H), 6.21 (s, 1 H), 7.36 (m, 2H), 7.51 (d, 2H).
4(-4-bromophenyl-3.4-dihydropiperadinylacetamideoxy)naphthaldehvde (step C):
A mixture of 4-(4-bromophenyl)-3,4-dihydropiperidine chloroacetamide (1.5 g, 4.8 mmol). 4- hydroxynapthaldehyde (1.2 g , 7 mmol), and powdered potassium carbonate (1 g, 7.2 mmol) in acetonitrile (50 mL) was refluxed for 16 hours. The mixture was diluted with ethyl acetate and washed with brine (3x), dried over MgSO4, and concentrated. Silica gel chromatography with ethyl acetate/hexane (1/1 ) provided the product (1.4 g, 65%).
1H NMR (DMSO-D6): δ 2.27-2.32 (m, 2H), 3.49-3.55 (m, 2H), 3.94 (brd s, 1 H), 4.06 (brd s, 1 H), 5.08 (s, 1 H), 5.13 (s, 1H), 6.05 (s, 1 H), 6.97 (t, 1 H), 7.20 (t, 1 H), 7.34 (d, 2H), 7.42-7.47 (m, 1 H), 7.52-7.57 (m, 1 H), 7.92 (d, 1 H), 8.16 (d, 1 H), 9.01 (d, 1 H), 9.97 (s, 1 H).
4(-4-bromophenyl-3,4-dihydropiperadinylacetamideoxy)naphth-1-yl methylene-3-chloro-4- hydroxybenzoic acid hydrazone (step D):
The title compound was prepared according to the general procedure for the synthesis of alkylidene hydrazides from the condensation of 3-chloro-4-hydroxybenzoic acid hydrazide and 4-(4-bromophenyl-3,4-dihydropiperadinylacetamideoxy)naphthaldehyde:
1H NMR (DMSO-D6): δ 2.47-2.58 (m, 2H), 3.72 (br s, 2H), 4.13 (s, 1 H), 4.26 (s, 1 H), 5.14 (s, 1 H), 5.18 (s, 1 H), 6.23 (s, 1 H), 6.50-6.53 (m, 1 H), 7.03-7.06 (m, 1 H), 7.35-7.38 (m, 2H), 7.52 (d, 2H), 7.58 (d, 2H), 7.59-7.67 (m, 1H), 7.75 (d, 1 H), 7.84 (s, 1 H), 8.32 (d, 1 H), 8.89 (s, 1 H), 8.92 (s, 1 H), 11.41 (s, 1 H); MS (APCI): 618.1 , 620.1 , 621.1 , 622.1 EXAMPLE 197: EXAMPLE 202:
Figure imgf000247_0001
20
EXAMPLE 198:
EXAMPLE 2
Figure imgf000247_0002
EXAMPLE 199:
EXAMPLE 204:
Figure imgf000247_0003
EXAMPLE 205:
Figure imgf000247_0004
30
EXAMPLE 201 : EXAMPLE 206:
Figure imgf000247_0005
EXAMPLE 207: 15 EXAMPLE 212:
Figure imgf000248_0001
EXAMPLE 208: EXAMPLE 213:
Figure imgf000248_0002
20
EXAMPLE 209: EXAMPLE 214:
Figure imgf000248_0003
EXAMPLE 210: EXAMPLE 215:
Figure imgf000248_0004
EXAMPLE 211 :
EXAMPLE 216:
Figure imgf000248_0005
Figure imgf000248_0006
EXAMPLE 217: EXAMPLE 222:
Figure imgf000249_0001
20
EXAMPLE 218:
EXAMPLE 223:
Figure imgf000249_0002
EXAMPLE 224:
EXAMPLE 219:
Figure imgf000249_0003
EXAMPLE 220: EXAMPLE 225:
Figure imgf000249_0004
30
EXAMPLE 221 : EXAMPLE 226:
Figure imgf000249_0005
EXAMPLE 227: EXAMPLE 232:
Figure imgf000250_0001
EXAMPLE 233:
Figure imgf000250_0002
EXAMPLE 234:
Figure imgf000250_0003
25
EXAMPLE 235:
EXAMPLE 230:
Figure imgf000250_0004
EXAMPLE 236:
EXAMPLE 231 :
Figure imgf000250_0005
EXAMPLE 237: EXAMPLE 242:
Figure imgf000251_0001
20 EXAMPLE 243:
EXAMPLE 238:
Figure imgf000251_0002
EXAMPLE 244:
EXAMPLE 239:
Figure imgf000251_0003
25
EXAMPLE 245:
Figure imgf000251_0004
EXAMPLE 246:
Figure imgf000251_0005
EXAMPLE 247: 15 EXAMPLE 252:
Figure imgf000252_0001
EXAMPLE 248: EXAMPLE 253:
Figure imgf000252_0002
20
EXAMPLE 249: EXAMPLE 254:
Figure imgf000252_0003
EXAMPLE 250:
EXAMPLE 255:
Figure imgf000252_0004
25
EXAMPLE 251 :
EXAMPLE 256:
Figure imgf000252_0005
EXAMPLE 257: 15 EXAMPLE 262:
Figure imgf000253_0001
EXAMPLE 258: EXAMPLE 263:
Figure imgf000253_0002
20
EXAMPLE 259: EXAMPLE 264:
Figure imgf000253_0003
EXAMPLE 265: EXAMPLE 260:
Figure imgf000253_0004
EXAMPLE 261 : EXAMPLE: 266
Figure imgf000253_0005
EXAMPLE 267: EXAMPLE 272:
Figure imgf000254_0001
EXAMPLE 268:
20 EXAMPLE 273:
Figure imgf000254_0002
EXAMPLE 269: EXAMPLE 274:
Figure imgf000254_0003
25
EXAMPLE 270: EXAMPLE 275:
Figure imgf000254_0004
EXAMPLE 276:
EXAMPLE 271 :
Figure imgf000254_0005
EXAMPLE 277: EXAMPLE 282:
Figure imgf000255_0001
20 EXAMPLE 278: EXAMPLE 283:
Figure imgf000255_0002
EXAMPLE 284:
EXAMPLE
Figure imgf000255_0003
EXAMPLE 285:
Figure imgf000255_0004
EXAMPLE 287: EXAMPLE 291 :
Figure imgf000256_0001
EXAMPLE 288: 15 EXAMPLE 292:
Figure imgf000256_0002
EXAMPLE 293:
EXAMPLE 289:
Figure imgf000256_0003
EXAMPLE 294: EXAMPLE 290:
Figure imgf000256_0004
EXAMPLE 295: EXAMPLE 299:
Figure imgf000257_0001
15
EXAMPLE 296: EXAMPLE 300:
Figure imgf000257_0002
EXAMPLE 297:
EXAMPLE 301 :
Figure imgf000257_0003
20 EXAMPLE 298:
Figure imgf000257_0004
EXAMPLE 302: 15 EXAMPLE 307:
Figure imgf000258_0001
EXAMPLE 303: EXAMPLE 308:
Figure imgf000258_0002
20
EXAMPLE 304: EXAMPLE 309:
Figure imgf000258_0003
EXAMPLE 305:
EXAMPLE 310:
Figure imgf000258_0004
25
EXAMPLE 306:
EXAMPLE 311 :
Figure imgf000258_0005
EXAMPLE 312: 15 EXAMPLE 317:
Figure imgf000259_0001
EXAMPLE 318:
EXAMPLE 313:
Figure imgf000259_0002
20
EXAMPLE 319:
EXAMPLE 314:
Figure imgf000259_0003
EXAMPLE 315: EXAMPLE 320:
Figure imgf000259_0004
EXAMPLE 321 :
EXAMPLE 316:
Figure imgf000259_0005
EXAMPLE 322: 15 EXAMPLE 327:
Figure imgf000260_0001
EXAMPLE 323: EXAMPLE 328:
Figure imgf000260_0002
EXAMPLE 329:
EXAMPLE 324:
Figure imgf000260_0003
EXAMPLE 325: 25 EXAMPLE 330:
Figure imgf000260_0004
EXAMPLE 326:
EXAMPLE 331 :
Figure imgf000260_0005
30 EXAMPLE 332: EXAMPLE 337:
Figure imgf000261_0001
EXAMPLE 333: 20 EXAMPLE 338:
Figure imgf000261_0002
EXAMPLE 339:
EXAMPLE 334:
Figure imgf000261_0003
25 EXAMPLE 340:
Figure imgf000261_0004
EXAMPLE 342:
Figure imgf000262_0001
General procedure for synthesis of compounds of the general formula XII:
Figure imgf000263_0001
Figure imgf000263_0002
formula XII
A and B are as defined for formula I and -NR5cR5d is
Figure imgf000263_0003
where R5a, R4a, R , c, q, d and D are as defined for formula I or
-D' where -D' is defined as a subset of -D that contains a primary or secondary amine that can react as a nucleophile.
Step A: The carbonyl compounds are treated with an acylhydrazide in a solvent. The solvent may be one of the following: ethyl alcohol, methyl alcohol, isopropyl alcohol, tert-butyl alcohol, dioxane, tetrahydrofuran, toluene, chlorobenzene, anisole, benzene, chloroform, dichloromethane, DMSO, acetic acid, water or a compatible mixture of two or more of the above sol- vents. A catalyst such as acetic acid can be added. A dehydrating reagent such as triethylort- hoformate can also be added to the reaction mixture. The reaction is performed by stirring the reaction mixture preferably under an inert atmosphere of N2 or Ar at temperatures between 0°C to 140°C, preferably between 10°C to 80°C. In many cases the product simply crystallizes out when the reaction is completed and is isolated by suction filtration. It can be further recrystalli- zed if necessary from a solvent such as the above described reaction solvents. The product can also be isolated by concentration of the reaction mixture in vacuo. followed by column chromatography on silica gel using a solvent system such as chloroform/methanol or dichloromethane/methanol or chloroform/ethyl acetate. Step B: The resulting acid is then coupled to a primary or secondary amine using one of the methods well-known to those skilled in the art. This coupling can be performed using one of the standard amide or peptide synthesis procedures such as by generating an active ester, an an- hydride or an acid halide that can then react with the amine to give a compound of formula XII. Step B was also done combinatorially with a preactivated acid and a selection of amines. The product can then be isolated either by filtration or by extraction using a solvent such as ethyl acetate, toluene, dichloromethane or diethylether and the solvent may then be removed by concentration at atmospheric or reduced pressure. The product can be further purified by either recrystallization from a solvent such as ethyl alcohol, methyl alcohol, isopropyl alcohol, toluene, xylene, hexane, tetrahydrofuran, diethyl ether, dibutyl ether, water or a mixture of two or more of the above. Alternatively, the product can be purified by column chromatography using dichloromethane/methanol or chloroform/methanol or isopropyl alcohol as eluent giving a compound of formula XII.
Specific examples illustrating the preparation of compounds of the general formula XII according to the invention are provided below.
Preparation of 4-formyl-1-naphthylacetic acid:
This compound was prepared from the reduction of 4-cyano-1-naphthylacetic acid in the presence of 85% formic acid and Raney alloy as described in the literature. References : 1 ) A.A. Shulezhko and A.I. Kiprianov, J. org. Chem., (USSR) English translation, 4, 1968, p.1052. 2) Zh. Org. Khim., 4, 1968, p. 1089.
Preparation of 4-[3-Chloro-4-hydroxybenzoyl)-hydrazonomethyl]-1-naphthylacetic acid (step A):
This compound was prepared according to the general procedure for the synthesis of alkyli- dene hydrazides from the condensation of 4-formyl-1-naphthylacetic acid above and 3- chloro-4-hydroxybenzoic acid hydrazide. 1H NMR (DMSO-D6): δ 4.1 (s, 2H), 7.1 (d, 1H), 7.5 (d, 1H), 7.7 (qt, 2H), 7.8 (d, 1H), 7.9 (d, 1 H), 8.0 (s, 1 H), 8.1 (d, 1 H), 8.8 (d, 1H), 9.1 (s, 1 H), 11.0 (brd s, 1 H), 11.8 (s, 1H), 12.2 (brd s, 1 H); MS (APCI): 383.4, 385.2.
Preparation of (3-formylindolyl)acetic acid:
Ethyl (3-formylindolyl)acetate:
3-Formylindole (10.0 g, 69 mmoles) was dissolved in DMF (100 ml). Under N2 was a 60% suspension of NaH in mineral oil (3.0 g) added in portions with cooling (temp < 15 °C). At < 15 °C was a solution of ethyl bromoacetate (8.4 ml) in DMF (15 ml) added drop wise over 30 minutes. The resulting mixture was stirred at room temperature for 16 hours and evaporated in vacuo. The residue was added water (300 ml) and extracted with ethyl acetate (2 x 150 ml), the combined organic extracts were washed with satd. NH4CI, dried (MgS04) and concentrated to afford 15.9 g ethyl (3-formylindolyl)acetate.
1H NMR ( CDCI 3 ) δ 1.26 (t, 3H), 4.22 (q, 2H), 4.90 (s, 2H), 7.21 - 7.35 (m, 3H), 7.72 (s, 1 H), 8.30 (d, 1 H), 10.0 (s, 1 H).
(3-formylindolyl)acetic acid: Ethyl (3-formylindolyl)acetate (15.9 g) was dissolved in 1 ,4-dioxane (100 ml) and added 36% aq. NaOH (10 ml). The resulting mixture was stirred at room temperature for 4 days. Water (500 ml) was added and the mixture was washed with diethyl ether (150 ml). The aqueous phase was made acidic with 5N HCI and extracted with ethyl acetate (250 + 150 ml). The combined organic extracts were dried (MgSO4) and evaporated in vacuo to afford 10.3 g (73 % over two steps) of (3-formylindolyl)acetic acid.
1H NMR ( DMSO-d6 ) δ 4.94 (s, 2H), 7.27 - 7.36 (m, 3H), 7.98 (s, 1 H), 8.25 (d, 1H), 10.0 (s, 1 H), 12.5 (bs, 1 H).
Preparation of (4-Formylindolyl)acetic acid:
4-Formylindole: This compound was synthesized according to F. Yamada, M. Somei, Heterocycles 26 (1987) 1173.
1H NMR ( CDCI 3 ) δ 7.28 - 7.36 (m, 2H), 7.41 (t, J = 3.0 Hz, 1 H), 7.60 - 7.70 (m, 2H), 8.62 (brd s, 1 H), 10.20 (s, 1 H). GC-MS (pos.): 146
Ethyl (4-formylindolyl)acetate:
This compound was synthesized according to the general procedure for N-alkylation of in- doles.
Η NMR (CDCI 3) δ 1.13 (t, J = 6.9 Hz, 3H), 4.15 (q, J = 7.2 Hz, 2H), 4.86 (s, 2H), 7.22 - 7.35 (m, 3H), 7.49 (d, J = 8.6 Hz, 1 H), 7.60 (d, J = 7.3 Hz, 1 H), 10.20 (s, 1 H).
(4-Formylindolyl)acetic acid: This compound was synthesized according to the general procedure for saponification of esters.
1H NMR ( DMSO-dβ ) δ 5.15 (s, 2H), 7.12 (d, J = 3.0 Hz, 1 H), 7.36 (d, J = 7.9 Hz, 1H), 7.61 (d, J = 3.1 Hz, 1 H), 7.71 (d, J = 7.3 Hz, 1 H), 7.82 (d, J = 8.2 Hz, 1 H), 10.20 (s, 1 H), 12.94 (brd s, 1 H).
Preparation of (5-formylindolyl)acetic acid:
5-Cyano-N-tosylindole: In a 100 mL round-bottom flask was placed NaH (0.4 g, 60% dipersion in mineral oil, 10 mmol) and anhydrous THF (10 mL) was added. To the suspension was added a solution of 5-cyanoindole (1.0 g, 7 mmol) in anhydrous THF (10 mL) by syringe at 0°C. The mixture was stirred for 10 min, and tosyl chloride (1.6 g, 8.4 mmol) was added. After stirring at room temperature for 2 h, water (100 mL) was added. The mixture was extracted with ethyl ace- tate (3x50 mL), dried (MgSO4), and concentrated. The residue was purified by column chromatography using hexane: ethyl acetate = 2:1 as eluent to yield 1.86 g (92%) of the desired product. Η NMR ( CDCI 3) δ 2:32 (s, 3H), 6.65 (d, J = 3.6 Hz, 1 H), 7.19 (d, J = 7.9 Hz, 2H ), 7.41 (d, J = 8.6 Hz, 1 H), 7.57 (d, J = 3.6 Hz, 1 H), 7.63 (s, 1 H), 7.75 ( d, J = 8.3 Hz, 1 H), 7.99 (d, J = 8.6 Hz, 1 H).
5-Formyl-N-tosyliπdole:
To a solution of 5-cyano-N-tosylindole (0.66 g, 2.2 mmol) in anhydrous THF (20 mL), was added 1 M DIBAL in hexane (4 mL, 4 mmol) via syringe at 0°C. The mixture was stirred at room temperature for 16 h, poured into ice-cooled 1 N hydrochloric acid (50 mL), extracted with ethyl acetate (3 x 80 mL). The combined organic extracts were dried (MgSO4), and concentrated to give an oil. After a short column chromatography using hexane/ethyl acetate 2: 1 as eluent 0.62 g (95%) pure 5-formyl-N-tosylindole was obtained.
Η NMR (CDCI3) δ 2.29 (s, 3H), 6.74 (d, J = 3.7 Hz, 1 H), 7.21 (d, J = 8.3 Hz, 2H), 7.65 (d, J = 3.7 Hz, 1 H), 7.77 (d, J = 8.4 Hz, 2H), 7.82 (dd, J = 1.4, 8.6 Hz, 1 H), 8.02 (d, J = 1.1 Hz, 1 H), 8.09 (d, J = 8.6 Hz, 1 H ), 9.99 (s, 1 H).
5-Formylindole:
5-formyl-N-tosylindole (0.5 g, 1.7 mmol) was dissolved in a mixture of methanol (10 mL) containing 5% aqueous KOH solution (5 mL). The mixture was refluxed for 3_h, neutralized with 1 N hydrochloric acid, and extracted with ethyl acetate (3x50 mL). The combined organic extracts were dried (MgSO4), and concentrated. The residue was purified by short column chromatography to provide 240 mg (97%) of the desired product.
Η NMR (CDCI3) δ 6.70 (t, J = 2.1 Hz, 1 H), 7.32 (t, J = 2.3 Hz, 1 H), 7.49 (d, J = 8.4 Hz, 1 H), 7.78 ( dd, J = 1.5, 8.6 Hz, 1 H), 8.19 (s, 1 H), 9.45 (b, 1 H), 10.15 (s, 1 H). GC-MS (pos.): 146.
Ethyl (5-formylindolyl)acetate:
This compound was synthesized according to the general procedure for N-alkylation of in- doles. Η NMR (CDC ) δ 1.27 (t, J = 6.8 Hz, 3H), 4.22 (q, J = 7.2 Hz, 2H), 4.87 (s, 2H), 6.70 (d, J = 3.4 Hz, 1 H), 7.18 (d, J = 3.0 Hz, 1 H), 7.36 (d, J = 8.7 Hz, 1 H), 7.78 (d, J = 8.3 Hz, 1 H), 8.14 (s, 1 H), 10.01 (s, 1 H).
(5-Formyiindolyl)acetic acid: this compound was synthesized according to the general procedure for saponification of esters.
Η NMR (DMSO-dβ) δ 5.10 (s, 2H), 6.66 (d, J = 3.0 Hz, 1 H), 7.48 (d, J = 3.0 Hz, 1H), 7.56 (d, J = 8.7 Hz, 1 H), 7.66 (d, J = 8.3 Hz, 1 H), 8.17 (s, 1 H), 9.97 (s, 1 H), 12.9 (brd s, 1 H).
General procedure for preparation of [(3-chloro-4-hydroxybenzoyl)hydrazonomethyl]indolyl acetic acids:
These compounds were prepared according to the general procedure for the synthesis of alkylidene hydrazones by condensation of the various formylindolylacetic acids with 3-chloro- 4-hydroxy benzoic acid hydrazide.
3-[(3-chloro-4-hydroxybenzoyl)hydrazonomethyl]indolyl acetic acid:
Η NMR (DMSO-Ds): δ 2.81 (t, J = 6.5, 2H), 4.43 (t, J = 6.5, 2H), 7.06 (d, J = 8.5, 1 H), 7.15- 7.28 (m, 2H), 7.56 (d, J = 8.1 , 1 H), 7.75 (d, J = 8.5, 1 H), 7.83 (s, 1 H), 7.95 (s, 1H), 8.27 (d, J = 7.65, 1 H), 8.54 (s, 1 H), 10.88 (br s, 1 H), 11.41 (s, 1 H). LRMS calcd for C19 H1β Cl, N3 O4 (M - H) 384, found 384.0.
4-[(3-chloro-4-hydroxybenzoyl)hydrazonomethyl]indolyl acetic acid:
Η NMR ( DMSO-d6 ) δ 5.09 (s, 2H), 7.09 (d, J = 8.6 Hz, 1 H), 7.16 - 7.25 (m, 2H), 7.32 (d, J = 7.2 Hz, 1 H), 7.45 - 7.55 (m, 2H), 7.81 (d, J = 8.2 Hz, 1 H), 8.01 (d, J = 1.8 Hz, 1 H), 8.68 (s, 1 H), 10.96 (s, 1 H), 11.71 (s, 1 H), 12.90 (b, 1 H). MS ( APCI, neg.): 370.
5-[(3-Chloro-4-hydroxybenzoyl)hydrazonomethyl]indolyi acetic acid: Η NMR (DMSO-d6) δ 5.09 (s, 2H), 6.35 (d, J = 2.9 Hz, 1 H), 7.06 (d, J = 8.6 Hz, 1 H), 7.39 (d, J = 3.1 Hz, 1 H), 7.47 (d, J = 8.6 Hz, 1 H), 7.61 (d, J = 8.6 Hz, 1 H), 7.76 (d, J = 8.5 Hz, 1 H), 7.83 (s, 1 H), 7.97 (s, 1 H), 8.48 (s, 1 H), 10.93 (s, 1 H), 11.58 (s, 1 H), 12.90 (brd s, 1 H). MS (APCI, neg. ): 370.
4-[3-Chloro-4-hydroxybenzoyl)-hydrazonomethyll-1-naphthylacetamides and the various indolacetamides (step B):
General library production procedures :
To solutions of 4-[(3-chloro-4-hydroxybenzoyl)-hydrazonomethyl]naphthylacetic acid and the various indolylacetic acids in DMSO was added carbonyldiimidazole (1.2 eq). The solution was agitated for 5 minutes and diluted with DMSO to a concentration of 50 mM. The soluti- on was then dispensed into 88 deep well plates containing solutions of amines in DMSO (50 mM). The plates were covered and agitated for 16 hours. The products were purified by HPLC.
Examples of compounds of the formula XII:
EXAMPLE 343:
Figure imgf000269_0001
H NMR (DMSO-D6): δ 1.06 (t, 3H), 1.17 (t, 3H), 3.31 (qt, 2H), 3.50 (qt, 2H), 4.19 (s, 2H), 7.10 (d, 1 H), 7.45 (d, 1 H), 7.64 (quintet, 2H), 7.83 (d, 1 H), 7.88 (d, 1 H), 7.98 (m, 2H), 8.87 (d, 1 H), 9.09 (s, 1 H), 10.99 (brd s, 1 H), 11.80 (brd s, 1 H); ms (APCI); 438.1 , 440.1. EXAMPLE 344:
Figure imgf000270_0001
Η NMR (DMSO-D6): δ 0.98 (d, 4H), 2.76 (t, 2H), 3.02 (quintet, 1H), 3.59 (t, 2H), 4.40 (s, 2H), 7.10 (d, 1H), 7.48 (d, 1H), 7.48 (d, 1H), 7.59 (qt, 1H), 7.67 (t, 1H), 7.81 (d, 1H), 7.89 (d, 1H), 7.97 (d, 1H), 8.02 (s, 1H), 8.84 (d, 1H), 9.09 (s, 1H), 10.99 (brd s, 1H) 11.80 (brd s, 1H); MS (APCI, neg.): 473.1, 475.1.
EXAMPLE 345:
1H NMR (DMSO-D6): δ 2.50 (2H), 2.68 (t, 2H), 4.00 (s, 2H), 7.10 (d, 1H), 7.53 (d, 1H), 7.65 (tt, 2H), 7.80 (dd, 1H), 7.90 (d, 1H), 8.02 (d, 1H), 8.14 (d, 1H), 8.62 (t, 1H), 8.84 (d, 1H), 9.09 (s, 1H), 11.0 (brd s, 1H) 11.80 (s, 1H); MS (APCI): 433.1, 435.1
EXAMPLE 346:
Figure imgf000270_0003
1H NMR (DMSO-D6): δ 1.08 (m, 4H), 1.54 (m, 6H), 2.70 (t, 2H), 3.45 (t, 2H), 3.76 (m, 1H), 4.30 (s, 2H), 7.06 (d, 1H), 7.49 (d, 1H), 7.64 (m, 2H), 7.80 (d, 1H), 7.88 (d, 1H), 8.01 (s, 1H), 8.07 (d, 1H), 8.83 (d, 1H), 9.09 (s, 1H), 10.5 (brd d, 1H), 11.78 (brd s, 1H); MS (APCI, neg.): 515.2. EXAMPLE 347:
Figure imgf000271_0001
1H NMR (DMSO-D6): δ 1.26 (m, 2H), 1.37 (m, 4H), 1.67 (m, 2H), 2.43 (m, 4H), 2.62 (m, 3H), 3.10 (t, 2H), 3.90 (d, 1H), 4.32 (s, 2H), 4.48 (d, 1H), 7.10 (d, 1H), 7.31 (d, 1H), 7.48 (m, 2H), 7.81 (d, 1H), 7.88 (d, 1H), 8.03 (m, 2H), 8.85 (d, 1H), 9.08 (brd s, 1H), 11.76 (brd s, 1H): MS (APCI): 533.2.
EXAMPLE 348:
Figure imgf000271_0002
Η NMR (DMSO-D6): δ 3.03 (m, 4H), 3.68 (t, 2H), 3.79 (t, 2H), 4.30 (s, 2H), 7.14 (m, 5H), 7.47 (d, 1 H), 7.66 (quintet, 2H), 7.82 (d, 1 H), 7.88 (d, 1 H), 8.02 (d, 1 H), 8.07 (d, 1 H), 8.87 (d, 1 H), 9.10 (s, 1 H), 10.99 (s, 1 H), 11.80 (s, 1 H); MS (ACPI): 545.6.
EXAMPLE 349:
Figure imgf000271_0003
1H NMR (DMSO-D3): δ 3.10 (d, 4H), 3.67 (d, 4H), 4.30 (s, 2H), 7.00 (m, 2H), 7.09 (m, 3H), 7.47 (d, 1H), 7.62 (quintet, 2H), 7.82 (d, 1H), 7.88 (d, 1H), 8.03 (s, 1H), 8.06 (d, 1H), 8.85 (d, 1H), 9.10 (s, 1H), 10.99 (s, 1H), 11.80 (s, 1H); MS (ACPI): 544.5, 545.3.
EXAMPLE 350:
Figure imgf000272_0001
1H NMR (DMSO-D6): δ 2.15 (s, 6H), 2.39 (m, 8H), 3.51 (d, 4H), 4.22 (s, 2H), 7.03 (d, 1H), 7.43 (d, 1H), 7.64 (quintet, 2H), 7.77 (d, 1H), 7.87 (d, 1H), 7.99 (s, 1H), 8.02 (d, 1H), 8.83 (d, 1 H), 9.08 (s, 1 H), 11.80 (brd s, 1 H); MS (APCI): 522.2.
EXAMPLE 351:
Figure imgf000272_0002
1H NMR (DMSO-D6): δ 3.93 (d, 2H), 4.10 (d, 2H), 4.23 (s, 2H), 5.20 (m, 4H), 5.79 (m, 1H), 5.94 (m, 1H), 7.10 (d, 1H), 7.78 (d, 1H), 7.63 (m, 2H), 7.80 (d, 1H), 7.83 (d, 1H), 7.95 (d, 1H), 8.02 (d, 1H), 8.85 (d, 1H), 9.10 (s, 1H), 11 (brd s, 1H), 11.80 (brd s, 1H); MS (ACPI): 462.2 EXAMPLE 352:
Figure imgf000273_0001
Η NMR (DMSO-D6): δ 0.9 (t, 3H), 1.30 (sextet, 2H), 1.54 (sextet, 2H), 3.56 (t, 2H), 4.31 (s, 2H), 4.39 (s, 2H), 7.06 (d, 1H) 7.48 (d, 1H), 7.65 (quintet, 2H), 7.79 (dd, 1H), 7.87 (d, 1H), 7.97 (d, 1H), 8.01 (d, 1H), 8.85 (d, 1H), 9.09 (s, 1H), 11.79 (s, 1H); MS (APCI): 477.01, 479.2.
EXAMPLE 353:
Figure imgf000273_0002
Η NMR (DMSO-D6): δ 1.17 (m, 4H), 1.54 (m, 4H), 2.68 (m, 1H), 3.77 (d, 1H), 4.18 (s, 2H), 4.33 (m, 1H), 4.76 (brd, 1H), 7.10 (d, 1H), 7.43 (m, 1H), 7.65 (quintet, 2H), 7.81 (d, 1H), 7.88 (d, 1H), 8.02 (s, 1H), 8.04 (d, 1H), 8.84 (d, 1H), 9.09 (s, 1H), 11.79 (s, 1H); MS (APCI): 464.1,466.2.
EXAMPLE 354:
Figure imgf000273_0003
1H NMR (DMSO-D6): δ 0.85 (qt, 3H), 1.53 (m, 2H), 3.00 (dt, 2H), 3.29 (quintet, 2H), 3.77 (dt, 2H), 4.13 (d, 2H), 7.05 (d, 1H), 7.26 (m, 2H), 7.36 (d, 1H), 7.52 (qt, 1H), 7.69 (m, 2H), 7.87 (m, 2H), 7.95 (d, 1H), 8.00 (s, 1H), 7.87 (dd, 1H), 8.84 (t, 1H), 9.07 (brd, 1H), 11.76 (brd s, 1H); MS (APCI): 529.2, 529.7, 531.2.
EXAMPLE 355:
Figure imgf000274_0001
1H NMR (DMSO-Dβ): δ 0.85 (qt, 3H), 1.33 (m, 1H), 1.65 (m, 7H), 2.60 (t, 0.5H), 3.10 (t, 0.5H) 3.80 (m, 1H), 4.21 (s, 2H), 4.24 (m, 1H), 7.11 (d, 1H), 7.45 (t, 1H), 7.65 (m, 2H), 7.75 (d, 1H), 7.89 (d, 1H), 8.01 (d, 1H), 8.05 (d, 1H), 8.83 (d, 1H), 9.09 (s, 1H), 11.80 (s, 1H); MS (APCI): 478.4, 480.3.
EXAMPLE 356:
Figure imgf000274_0002
1H NMR (DMSO-Dβ): δ 2.36 (m, 4H), 2.97 (d, 2H), 3.50 (m, 2H), 3.60 (m, 2H), 4.23 (s, 2H), 5.17 (t, 2H), 5.86 (m, 1H), 7.08 (d, 1H), 7.43 (d, 1H), 7.64 (quintet, 2H), 7.79 (dd, 1H), 7.87 (d, 1H), 8.01 (s, 1H), 8.04 (d, 1H), 8.83 (d, 1H), 9.09 (d, 1H), 11.79 (brd s, 1H); MS (APCI): 4.91.2,493.2. EXAMPLE 357:
Figure imgf000275_0001
1H NMR (DMSO-D6): δ 1.50 (m, 1H), 1.90 (m, 2H), 1.95 (m, 1H), 2.72 (t, 1H), 2.95 (t, 1H), 3.30 (m, 1H), 3.55 (m, 1H), 3.65 (t, 2H), 3.75 (m, 1H),3.92(t, 1H),4.12(t, 1H) 4.35 (d, 2H), 7.11 (d, 1H), 7.48 (m, 1H), 7.65 (t, 1H), 7.68 (t, 1H), 7.8 (dd, 1H), 7.87 (d, 1H), 8.00 (d, 1H), 8.03 (d, 1H), 8.83 (d, 1H), 9.10 (s, 1H), 11.80 (brd s, 1H); MS (APCI): 519.5, 521.2, 522.2.
EXAMPLE 358:
Figure imgf000275_0002
1H NMR (DMSO-D6): δ 2.19 (s, 3H), 2.30 (m, 4 H), 3.50 (T, 2H), 3.58 (T, 2H), 4.22 (S, 2H), 7.03 (D, 1H), 7.43 (D, 1H), 7.64 (quint, 2H) 7.77 (dd, 1H), 7.87 (d, 1H), 7.99 (d, 1H), 8.04 (s, 1H), 8.83 (d, 1H), 9.09 (s, 1H), 11.80 (brd s, 1H); MS (APCI): 465.2, 467.3.
EXAMPLE 359:
Figure imgf000275_0003
Η NMR (DMSO-D6): δ 2.38 (m, 4H), 3.51 (s, 4H), 3.61 (t, 2H), 4.22 (s, 2H), 7.08 (d, 1H), 7.31 (m, 5H), 7.43 (d, 1H), 7.61 (quintet, 2H), 7.82 (dd, 1H), 7.88 (d, 1H), 8.00 (s, 1H), 8.02 (d, 1H), 8.85 (d, 1H), 9.10 (s, 1H), 11.80 (brd s, 1H); MS (APCI): 541.4, 543.1. EXAMPLE 360:
Figure imgf000276_0001
1H NMR (DMSO-D6): δ 1.33 (dd, 3H), 2.76 (s, 1.5H), 2.96 (s, 1.5H), 3.61 (d, 1H), 4.14 (quintet, 1H), 4.65 (m, 2H), 7.10 (m, 2H), 7.33 (s, 3H), 7.42 (m, 3H), 7.54 (m, 2H), 8.02 (t, 1H), 8.80 (m, 1H), 9.07 (brd, 1H), 11.80 (brd s, 1H); MS (APCI): 530.2, 532.2.
EXAMPLE 361:
Figure imgf000276_0002
Η NMR (DMSO-Ds): δ[2.94 (s, 1.5H) + 3.10 (s, 1.5H), 3H], 3.54 (m, 2H), 4.00 (d, 1H), 4.28 (d, 1H), 4.81 (t, 1H), 4.96 (t, 1H), 7.09 (d, 1H), 7.35 (m, 3H), 7.43 (m, 3H), 7.61 (m, 2H), 7.83 (m, 3H), 8.04 (s, 1H), 8.85 (t, 1H), 9.11 (d, 1H), 11.80 (brd s, 1H); MS (APCI): 516.3, 518.2.
EXAMPLE 362:
Figure imgf000276_0003
Η NMR (DMSO-D6): δ 2.75 (t, 1H), 2.95 (t, 1H), 3.59 (t, 1H), 3.80 (t, 1H), 4.38 (brd s, 3H), 4.61 (s, 1H), 4.84 (s, 1H), 6.40 (d, 1H), 6.53 (d, 1H), 7.05 (d, 1H), 7.45 (t, 1H), 7.58 (m, 3H), 7.81 (m, 3H), 8.00 (brd, 2H), 8.83 (d, 1H), 9.10 (s, 1H), 11.78 (brd s, 1H); MS (APCI, neg.): 513.3,514.2. EXAMPLE 363:
Figure imgf000277_0001
H NMR (DMSO-Dβ): δ 1.50 (m, 2H), 1.68, (d, 2H), 2.28 (t, 1H), 2.59 (t, 1H), 3.05 (t, 1H), 3.96 (d, 1H), 4.16 (s, 2H), 4.32 (d, 1H), 6.74 (brd s, 1H), 6.95 (d, 1H), 7.22 (brd s, 1H), 7.36 (d, 1H), 7.57 (quintet, 2H), 7.71 (dd, 1H), 7.79 (d, 1H), 7.92 (dd, 1H), 7.96 (d, 1H), 8.76 (d, 1H), 9.01 (s, 1H), 11.80 (brd s, 1H); MS (ACPI): 493.1, 495.2.
EXAMPLE 364:
Figure imgf000277_0002
1H NMR (DMSO-Dβ): δ 2.10 (s, 3H), 2.15 (s, 3H), 2.29 (t, 1H), 2.40 (t, 1H), 2.80 (s, 1H), 3.05 (s, 2H), 3.36 (t, 1H), 3.46 (t, 1H), 4.16 (d, 2H), 7.01 (d, 1H), 7.38 (t, 1H), 7.56 (m, 2H), 7.72 (dd, 1 H), 7.79 (d, 1 H), 7.94 (m, 2H), 8.77 (d, 1 H), 9.02 (s, 1 H), 11.71 (brd s, 1 H); MS (ACPI): 467.3,469.1.
EXAMPLE 365:
Figure imgf000277_0003
1H NMR (DMSO-Dβ): δ 2.11 (s, 3H), 2.14 (s, 3H), 2.33 (t, 1H), 2.39 (t, 1H), 3.37 (t, 1H), 3.46 (t, 1H), 4.14 (s, 1H), 4.32 (s, 1H), 4.55 (s, 1H), 4.74 (s, 1H), 7.05 (d, 1H), 7.23 (d, 1H), 7.29 (m, 3H), 7.38 (t, 1H), 7.43 (d, 1H), 7.57 (m, 2H), 7.81 (m, 2H), 7.97 (s, 1H), 8.06 (d, 1H), 8.79 (t, 1H), 9.05 (s, 1H), 11.75 (brd s, 1H); MS (APCI): 543.2, 545.2.
EXAMPLE 366: EXAMPLE 371:
Figure imgf000279_0001
EXAMPLE 367: EXAMPLE 372:
Figure imgf000279_0002
EXAMPLE 368:
15 EXAMPLE 373:
Figure imgf000279_0003
EXAMPLE 369:
Figure imgf000279_0004
EXAMPLE 374:
Figure imgf000279_0005
EXAMPLE 370:
Figure imgf000279_0006
EXAMPLE 375:
Figure imgf000279_0007
20
Figure imgf000279_0008
EXAMPLE 376: EXAMPLE 381 :
Figure imgf000280_0001
EXAMPLE 382:
EXAMPLE 377: CH, i 3
Figure imgf000280_0002
EXAMPLE 386: EXAMPLE 390:
Figure imgf000281_0001
EXAMPLE 387:
H3Css EXAMPLE 391:
Figure imgf000281_0002
EXAMPLE 389:
Figure imgf000281_0003
EXAMPLE 394: EXAMPLE 398:
Figure imgf000282_0001
15
EXAMPLE 395: EXAMPLE 399:
Figure imgf000282_0002
EXAMPLE 396:
EXAMPLE 400:
II
Figure imgf000282_0003
20 EXAMPLE 397:
EXAMPLE 401 :
Figure imgf000282_0004
EXAMPLE 402: EXAMPLE 406:
Figure imgf000283_0001
15
EXAMPLE 403: EXAMPLE 407:
Figure imgf000283_0002
EXAMPLE 404: EXAMPLE 408:
Figure imgf000283_0003
EXAMPLE 405: EXAMPLE 409:
Figure imgf000283_0004
EXAMPLE 410: 15 EXAMPLE 415:
Figure imgf000284_0001
EXAMPLE 416:
EXAMPLE 411 :
Figure imgf000284_0002
20
EXAMPLE 412: EXAMPLE 417:
Figure imgf000284_0003
EXAMPLE 413:
EXAMPLE 418:
Figure imgf000284_0004
EXAMPLE 414:
EXAMPLE 419:
Figure imgf000284_0005
Figure imgf000284_0006
EXAMPLE 420: EXAMPLE 425:
Figure imgf000285_0001
EXAMPLE 421 : EXAMPLE 426:
Figure imgf000285_0002
EXAMPLE 422: EXAMPLE 427:
Figure imgf000285_0003
EXAMPLE 423: 25 EXAMPLE 428:
Figure imgf000285_0004
EXAMPLE 424: EXAMPLE 429:
Figure imgf000285_0005
EXAMPLE 430:
Figure imgf000286_0001
EXAMPLE 431 :
20 EXAMPLE 435:
Figure imgf000286_0002
Figure imgf000286_0003
EXAMPLE 432:
EXAMPLE 436:
Figure imgf000286_0004
25 EXAMPLE 433: EXAMPLE 437:
Figure imgf000286_0005
EXAMPLE 438:
EXAMPLE 434:
Figure imgf000286_0006
Figure imgf000286_0007
EXAMPLE 439: EXAMPLE 444:
Figure imgf000287_0001
EXAMPLE 445:
Figure imgf000287_0002
EXAMPLE 446:
Figure imgf000287_0003
25 EXAMPLE 447:
Figure imgf000287_0004
EXAMPLE 448:
Figure imgf000287_0005
EXAMPLE 449: EXAMPLE 452:
Figure imgf000288_0001
EXAMPLE 450:
EXAMPLE 453:
Figure imgf000288_0002
EXAMPLE 451 :
EXAMPLE 454:
Figure imgf000288_0003
General procedure for synthesis of compounds of the general formula XIII:
Figure imgf000289_0001
formula XIII
A and B are as defined for formula I and -NR5cR5d is
Figure imgf000289_0002
where RS* R43I R4b> Cι qι d and D are as defined for for¬ mula I or -D' where -D' is defined as a subset of -D that contains a primary or secondary amine that can react as a nucleophile.
Step A: The carbonyl compounds are treated with an acylhydrazide in a solvent. The solvent may be one of the following: ethyl alcohol, methyl alcohol, isopropyl alcohol, terf-butyl alcohol, dioxane, tetrahydrofuran, toluene, chlorobenzene, anisole, benzene, chloroform, dichloromethane, DMSO, acetic acid, water or a compatible mixture of two or more of the above solvents. A catalyst such as acetic acid can be added. A dehydrating reagent such as triethylort- hoformate can also be added to the reaction mixture. The reaction is performed by stirring the reaction mixture preferably under an inert atmosphere of N2 or Ar at temperatures between 0°C to 140°C, preferably between 10°C to 80°C. In many cases the product simply crystallizes out when the reaction is completed and is isolated by suction filtration. It can be further recrystalli- zed if necessary from a solvent such as the above described reaction solvents. The product can also be isolated by concentration of the reaction mixture in vacuo, followed by column chromatography on silica gel using a solvent system such as chloroform/methanol or dichloromethane/methanol or chloroform/ethyl acetate. Step B: The resulting acid is then coupled to a primary or secondary amine using one of the methods well-known to those skilled in the art. This coupling can be performed using one of the standard amide or peptide synthesis procedures such as by generating an active ester, an anhydride or an acid halide that can then react with the amine to give a compound of formula XIII. The product can then be isolated either by filtration or by extraction using a solvent such as ethyl acetate, toluene, dichloromethane or diethylether and the solvent may then be removed by concentration at atmospheric or reduced pressure. The product can be further purified by either recrystallization from a solvent such as ethyl alcohol, methyl alcohol, isopropyl alcohol, toluene, xylene, hexane, tetrahydrofuran, diethyl ether, dibutyl ether, water or a mixture of two or more of the above. Alternatively, the product can be purified by column chromatography using dichloromethane/methanol or chloroform/methanol or isopropyl alcohol as eluent giving a compound of formula XIII.
Specific examples illustrating the preparation of compounds of the general formula XIII according to the invention are provided below.
Preparation of 4-formylnaphthoic acid is depicted below:
Figure imgf000290_0001
4-Bromomethyinaphthoic acid:
A mixture of 4-methylnaphthoic acid (10 g, 54 mmol), N-bromosuccinimide (10 g, 56 mmol) and AIBN (100 mg) in CCI4 (250 mL) was refluxed for 3 hr. The reaction mixture was con- centrated and dissolved in ethyl acetate. The organic layer was washed with water, brine and dried over MgSO4. Evaporation of the solvent gave the desired product (16 g, 80%).
Η NMR (DMSO-D6): δ 5.24 (s, 2H), 7.73 (m, 3H), 8.03 (d, 1H), 8.28 (d, 1 H), 8.86 (d, 1H), 13.29 (brd s, 1 H).
4-Hydroxymethylnaphthoic acid:
4-Bromomethylnaphthoic acid (16 g, 60 mmol) in an aqueous solution of K2CO3 (10%, 100 mL) was stirred at 70 °C for 30 minutes. The reaction mixture was cooled and made acidic with cone. HCI. The resulting precipitate was filtered and dried to give the desired product as a yellow solid in quantitative yield.
H NMR (DMSO-Dβ) ", δ 5.01 (s, 2H), 5.96 (s, 1 H), 7.70 (m, 3H), 8.10 (m, 2H), 8.90 (d, 1 H).
Methyl 4-hydroxymethylnaphthoate:
A mixture of 4-hydroxymethylnaphthoic acid (10 g, 50 mmol), methanol (300 mL), and cone. H2SO4 (2 mL) was refluxed overnight. The insolubles were filtered off and the filtrate was concentrated. The residue was taken up in ethyl acetate and washed with aqueous NaHCO3 (2x), brine, dried over MgSO4, and concentrated to give a yellow oil. Silica gel column chromatography using ethyl acetate/hexane (1/3) gave the desired product as a yellow oil (3.3 g, 35%).
1H NMR (CDCI3): δ 2.05 (t, 1 H), 4.01 (s, 3H), 5.22 (s, 2H), 7.66 (m, 3H), 8.09 (d, 1 H), 8.16 (d, 1 H), 8.96 (d, 1 H).
Methyl 4-formylnaphthoate:
To a solution of methyl 4-hydroxymethylnaphthoate above (3.3 g, 15.3 mmol) in dichloromethane (20 mL) was added MnO2 (6.6 g, 76 mmol). After stirring the dark mixture for 16 hours, the insolubles were filtered through a bed of Celite. Evaporation of the solvent gave the desired product as a white solid in quantitative yield. Η NMR (CDCI3): δ 4.06 (S, 3H), 7.75 (m, 2H), 8.03 (d, 1H), 8.20 (d, 1 H), 8.80 (d, 1H), 9.27 (d,1H), 10.50 (s, 1 H).
4-Formylnaphthoic acid:
A mixture of the methyl 4-formylnaphthoate above (2.3 g, 1 mmol) and Na2CO3 (1.25 g, 12 mmol) in water (30 mL) was heated in a water bath for approximately 2 hr until a clear solution was obtained. The solution was cooled and filtered. The filtrate was acidified with cone. HCI to give a yellow precipitate. The solids were collected and dried over night to give the desired product (1.86 g, 87%).
1H NMR (DMSO-D6): δ 7.76 (m, 2H), 8.22 (m, 2H), 8.71 (d, 1 H), 9.20 (d, 1 H), 10.49 (s, 1 H).
4-[(3-Chloro-4-hydroxybenzoyl)hydrazonomethyl]naphthoic acid (step A): To a solution of 3-chloro-4-hydroxybenzoic acid hydrazide (1.53 g, 8.23 mmol) in DMSO (20 mL) was added a solution of 4-formylnaphthoic acid (1.65 g, 8.23 mmol) in DMSO (2 mL). After stirring the solution for 16 hr, the reaction was diluted with ethyl acetate (30 mL) and water (30 mL). A precipitate formed. The precipitate was collected,, washed with hexane and dried to give the product as a white solid in quantitative yield.
1H NMR (DMSO-Dβ): δ 4.70 (d, 1 H), 7.70 (m, 2H), 7.83 (d, 1 H), 8.03 (m, 2H), 8.18 (d, 1 H), 8.72 (s, 1 H), 8.90 (d, 1 H), 9.17 (s, 1 H), 11.0 (brd s, 1 H), 11.94 (s, 1 H), 13.4 (brd s, 1 H); MS (APCI, neg): 368.5, 370.2).
General procedure Derivatives of 4-[(3-Chloro-4-hydroxybenzovhhydrazonomethyl]naphthamides (step B):
To a solution of a derivative of4-[(4-hydroxybenzoyl)-hydrazonomethyl]naphthoic acid in DMSO was added carbonyldiimidazole (1.2 eq). The solution was agitated for 5 minutes and diluted with DMSO to a concentration of 50 mM. The solution was then dispensed into 88 deep well plates containing solutions of amines in DMSO (50 mM). The plates were covered and agitated for 16 hours. The products were purified by HPLC.
The following compounds of formula XIII were prepared: EXAMPLE 455:
Figure imgf000293_0001
1H NMR (DMSO-Dβ): δ 2.91 (t, 2H), 3.67 (t, 2H), 7.12 (d, 1H), 7.38 (qt, 4H), 7.58 (t, 2H), 7.70 (t, 1H), 7.50 (d, 1H), 7.95 (d, 2H), 8.03 (s, 1H), 8.69 (brd t.1H), 8.81 (d.1H), 9.12 (s, 1H), 11.02 (s, 1H), 11.89 (s, 1H); MS (APCI): 507.3, 508.5.
EXAMPLE 456:
Figure imgf000293_0002
Η NMR (DMSO-D6): δ 2.20 (brd m, 1H), 2.30 (brd m, 1H), 2.55 (m, 2H), 3.10 (brd m, 2H), 3.50 (s, 2H), 3.72 (brd m, 1H), 3.85 (brd m, 1H), 7.10 (d, 1H), 7.36 (qt, 4H), 7.53 (d, 1H), 7.70 (m, 2H), 7.82 (m, 2H), 7.95 (d, 1H), 8.03 (s, 1H), 8.88 (d, 1H), 9.11 (s, 1H), 11.00 (brd s, 1H), 11.89 (s, 1H); MS (APCI, neg.): 559.2, 561.2.
EXAMPLE 457: 15 EXAMPLE 462:
Figure imgf000294_0001
EXAMPLE 458: EXAMPLE 463:
Figure imgf000294_0002
20
EXAMPLE 459: EXAMPLE 464:
Figure imgf000294_0003
EXAMPLE 460: EXAMPLE 465:
Figure imgf000294_0004
EXAMPLE 461 : EXAMPLE 466:
Figure imgf000294_0005
EXAMPLE 467: EXAMPLE 472:
Figure imgf000295_0001
EXAMPLE 468: EXAMPLE 473:
Figure imgf000295_0002
EXAMPLE 469: EXAMPLE 474:
Figure imgf000295_0003
EXAMPLE 470: 25 EXAMPLE 475:
Figure imgf000295_0004
EXAMPLE 471 : EXAMPLE 476:
Figure imgf000295_0005
30 EXAMPLE 477: EXAMPLE 482:
Figure imgf000296_0001
EXAMPLE 478: EXAMPLE 483:
Figure imgf000296_0002
EXAMPLE 484:
EXAMPLE 479:
Figure imgf000296_0003
Figure imgf000296_0004
25 EXAMPLE 485:
Figure imgf000296_0005
EXAMPLE 486:
Figure imgf000296_0006
EXAMPLE 487: EXAMPLE 492:
Figure imgf000297_0001
EXAMPLE 488: EXAMPLE 493:
Figure imgf000297_0002
EXAMPLE 494:
EXAMPLE 489:
Figure imgf000297_0003
25 EXAMPLE 495: EXAMPLE 490:
Figure imgf000297_0004
EXAMPLE 496:
EXAMPLE 491 :
Figure imgf000297_0005
30 EXAMPLE 497: EXAMPLE 502:
Figure imgf000298_0001
EXAMPLE 498:
EXAMPLE 503:
Figure imgf000298_0002
20
Figure imgf000298_0003
EXAMPLE 499:
EXAMPLE 504:
Figure imgf000298_0004
Figure imgf000298_0005
EXAMPLE 500:
25 EXAMPLE 505:
Figure imgf000298_0006
Figure imgf000298_0007
EXAMPLE 501 :
Figure imgf000298_0008
EXAMPLE 507:
Figure imgf000299_0001
General procedure for synthesis of compounds of the general formula XIV:
Figure imgf000299_0002
formula XIV
A and B are as defined for formula I and -NR5cR5d is
Figure imgf000299_0003
where R5a, R4a, R4 , c, q, d and D are as defined for formula I or
-D' where -D' is defined as a subset of -D that contains a primary or secondary amine that can react as a nucleophile.
Step A: The acid is coupled to a primary or secondary amine using one of the methods well- known to those skilled in the art. This coupling can be performed using one of the standard amide or peptide synthesis procedures such as by generating an active ester, an anhydride or an acid halide that can then react with the amine to give a compound of formula XIV. The product can then be isolated either by filtration or by extraction using a solvent such as ethyl acetate, toluene, dichloromethane or diethylether and the solvent may then be removed by concentration at atmospheric or reduced pressure. The product can be further purified by either recrystallization from a solvent such as ethyl alcohol, methyl alcohol, isopropyl alcohol, toluene, xylene, hexane, tetrahydrofuran, diethyl ether, dibutyl ether, water or a mixture of two or more of the above. Alternatively, the product can be purified by column chromatography using dichloromethane/methanol or chloroform/methanol or isopropyl alcohol as eluent giving a compound of formula XIV.
Step B: The carbonyl compounds are then treated with an acylhydrazide in a solvent. The solvent may be one of the following: ethyl alcohol, methyl alcohol, isopropyl alcohol, tert-butyl alcohol, dioxane, tetrahydrofuran, toluene, chlorobenzene, anisole, benzene, chloroform, dichloromethane, DMSO, acetic acid, water or a compatible mixture of two or more of the above solvents. A catalyst such as acetic acid can be added. A dehydrating reagent such as triethy- lorthoformate can also be added to the reaction mixture. The reaction is performed by stirring the reaction mixture preferably under an inert atmosphere of N2 or Ar at temperatures between 0°C to 140°C, preferably between 10°C to 80°C. In many cases the product simply crystallizes out when the reaction is completed and is isolated by suction filtration. It can be further recry- stallized if necessary from a solvent such as the above described reaction solvents. The product can also be isolated by concentration of the reaction mixture in vacuo. followed by column chromatography on silica gel using a solvent system such as chloroform/methanol or dichloromethane/methanol or chloroform/ethyl acetate.
Specific examples illustrating the preparation of compounds of the general formula XIV according to the invention are provided below.
The preparation of 3-(4-formylnaphthalene)propanoic acid is depicted below:
Figure imgf000301_0001
4-Trifluoromethylsulfonyloxy naphthaldehyde:
To a solution of 4-hydroxy naphthaldehyde (34.4 g, 0.20 mol) in dichloromethane (200 mL) and pyridine (19 mL, 18.58 g, 0.23 mol) was added dropwise at 0°C trifluoromethane sulfonic anhydride (46.75 g, 0.16 mol). The mixture was stirred at 0°C for 2 hr and at room temperature for 16 hr. It was poured into water (200 mL), and extracted with ether (3 x 100 mL). The combined organic extracts were washed with water (100 mL), 0.1 N hydrochloric acid (2 x 100 mL), water (100 mL), brine (100 mL), dried (MgSO4), and concentrated.
1H NMR (CDCI3) δ 7.89 - 7.97 (m, 3H), 8.09 (dd, J = 2.8, 6.5 Hz, 1 H), 8.33 (d, J = 8.0 Hz, 1 H), 9.24 (dd, J = 2.8, 6.5 Hz, 1 H), 10.45 (s, 1 H).
2-(4-Trifluoromethylsulfonyloxy naphthyl) dioxolane:
A solution of 4-trifluoromethyisulfonyloxy naphthaldehyde (4.09 g, 13.4 mmol), ethylene glycol (1.5 mL, 1.67 g, 26.9 mmol), and p-toluene sulfonic acid (250 mg) in toluene (250 mL) was refluxed for 16 hr using a Dean -Stark trap. The solution was allowed to reach room temperature, was washed with satd. NaHCO3-sol. (2x 80 mL), brine (80 mL), dried (MgSO4), and concentrated to give a yellow oil (4.79 g, quant).
1H NMR (CDCI3) δ 4.19 (m, 4H), 6.47 (s, 1 H), 7.47 (d, J = 8.0 Hz, 1 H), 7.66- 7.70 (m, 2H), 7.81 (d, J = 8.0 Hz, 1 H), 8.13 (dd, J = 3.3, 6.3 Hz, 1 H), 8.30 (dd, J = 3.3, 6.3 Hz, 1 H). GCMS: 348.
2-[4-(2-ethoxycarbonyivinyl)naphthyl]dioxolane:
Nitrogen was passed through a solution of 2-(4-trifluoromethylsulfonyloxynaphthyl) dioxolane (2.46 g, 7.06 mmol), ethyl acrylate (2.3 mL, 2.1 g, 21.2 mmol), triethylamine (4.3 g, 42.3 mmol) in DMF (6 mL) for 15 min, and bis(triphenylphosphine)palladium dichloride was added. The well stirred solution was heated at 90°C for 8 hr, and concentrated. The residue was dissolved in ethyl acetate (50 mL), washed with brine (2x 50 mL), dried (Na2SO4), and concentrated. Purification by flash chromatography using hexane /ethyl acetate 9:1 as elu- ent provided a yellow solid (1.13 g, 53%).
1H NMR (CDCI3) δ 1.38 (t, J = 7.0 Hz, 3H), 3.74 - 4.22 (m, 4H), 8.65 (q, J = 7.0 Hz, 2H), 6.50 (s, 1 H), 6.53 (d, J = 15.7 Hz, 1 H), 7.58-7.62 (m, 2H), 7.74 (d, J = 7.5 Hz, 1 H), 7.80 (d, J = 7.5 Hz, 1 H), 8.21-8.28 (m, 2H), 8.52 (d, J = 15.2 Hz, 1 H).
2-[4-(2-ethoxycarbonylethyl)naphthyl]dioxolane:
To a solution of 2-[4-(2-ethoxycarbonylvinyl)naphthyl]dioxolane (701 mg, 2.35 mmol) in ethyl acetate (15 mL) was added palladium (5% on BaCO3, 51 mg). The mixture was stirred under a hydrogen atmosphere for 16 hr, filtered by suction through Celite and concentrated to pro- vide 689 mg (98%) of a coloriess oil.
1H NMR (CDCI3) δ 1.25 (t, J = 7.0 Hz, 3H), 2.75 (t, J = 8.0 Hz, 2H), 3.43 (t, J = 8.0 Hz, 2H), 4.12- 4.22 (m, 6H), 6.46 (s, 1H), 7.37 (d, J = 7.3 Hz, 1 H), 7.54 - 7.70 (m, 2H), 7.70 (d, J = 7.3 Hz, 1 H), 8.07 (dd, J = 3.3, 6.5 Hz, 1 H), 8.26 (dd, J = 3.3, 6.5 Hz, 1 H).
Ethyl 3-(4-formylnaphthalene)propanoic acid:
To a solution of 2-[4-(2-ethoxycarbonylethyl)naphthyl]dioxolane (689 mg, 2.29 mmol) in THF (15 mL) was added 6N hydrochloric acid (2 mL). The mixture was stirred for 16 hr at room temperature, diluted with ethyl acetate (20 mL), washed with satd. NaHC03 solution (20 mL), dried (MgSO4), and concentrated to give the product as a colorless oil (407 mg, 68%) that crystallized upon sitting. 3-(4-formylnaphthalene)propanoic acid:
Ethyl 3-(4-formylnaphthalene)propanoic acid (310 mg, 1.2 mmol) was suspended in water (10 mL), and Na2CO3 (130 mg, 1.2 mmol) was added. The mixture was refluxed for 5 hr, and allowed to cool to room temperature. After acidification with cone, hydrochloric acid, a preci- pitate was formed. The precipitate was collected by suction, and dried at 80°C in vacuum for 16 hr to give a white solid (300 mg, 73%).
1H NMR (DMSO-Dβ) δ 2.69 (t, J = 7.0 Hz, 2H), 3.39 (t, J = 7.0 Hz, 2H), 7.66-7.77 (m, 2H), 8.10 (d, J = 7.3 Hz, 1 H), 8.23 (dd, J = 1.1 , 8.0 Hz, 1 H), 9.22 (dd, J = 1.1 , 9.0 Hz, 1 H), 10.33 (s, 1 H), 12.30 (br s, 1H).
General procedure (Step A):
Preparation of 3-(4-formylnaphthalene)propanamides:
To a solution of 3-(4-formylnaphthalene)propanoic acid (100 mg, 0.437 mmol) in DMF (3 mL) was added carbonyl diimidazole (140 mg, 0.863 mmol). The mixture was stirred at room temperature for 1 hr, and amine (1.3 equivalents) was added. After stirring at room temperature for 16 hr, the mixture was diluted with ethylacetate (5 mL), extracted with water (5 mL), 1 N hydrochloric acid (5 mL), and water (3 x 5 mL), dried (MgSO4) and concentrated. After flash chromatography using hexane/ethylacetate 1 : 1 pure amide was isolated.
Examples of amides:
Figure imgf000303_0001
H NMR (CDCI3) δ 1.06 (t, J = 7.0 Hz, 3H),1.12 (t, J = 7.0 Hz, 3H), 2.79 (t, J = 8.0 Hz, 2H), 3.50 (t, J = 8.0 Hz, 2H), 4.12 (q, J = 7.1 Hz, 2H), 7.54 (d, J = 7.3 Hz, 1 H), 7.64 - 7.71 (m, 2H), 7.92 (d, J = 7.3 Hz, 1 H), 8.18 (dd, J = 1.3, 8.0 Hz, 1 H), 9.34 (dd, J = 1.3, 8.0 Hz, 1 H), 10.34 (s, 1 H). MS (APCI, pos.) 284.1
Figure imgf000304_0001
1H NMR (CDCI3) δ 0.77 (t, J = 7.0 Hz, 3 H), 0.86 (t, J = 7.0 Hz, 3 H), 1.15 -1.82 (m, 8 H), 2.58 (dt, 0.5 H), 2.65 - 2.88 (m, 2H), 2.92 (dt, 0.5H), 3.39 - 3.60 (m, 2.5H), 3.62- 3.73 (m, 0.5H), 4.58 (dd, 0.5H), 4.73 (m, 0.5H), 7.56 (d, J = 7.3 Hz, 1 H), 7.91 (d, J = 7.3 Hz, 1 H), 7.61 - 7.72 (m, 2H), 8.16 (d, J = 8.3 Hz, 1 H), 9.33 (d, J = 8.0 Hz, 1 H), 10.34 (s, 1 H). MS (APCI, pos.) 325.2
Derivatives of 4-[(4-hydroxybenzoyl)hydrazonomethyl]naphthylpropanamides (step B):
These compounds were prepared according to the general procedure for the synthesis of alkylidene hydrazones from the condensation of 4-formyl-1 -naphthyl propanamides (from step A) and 4-hydroxybenzoic acid hydrazide derivatives.
EXAMPLE 508:
Figure imgf000304_0002
1H NMR (DMSO-D6) δ 0.95 - 1.02 (m, 6H), 2.69 (t, J = 7.3 Hz, 2H), 3.19 (q, J = 7.0 Hz, 2H), 3.25 (q, J = 7.0 Hz, 2H), 3.33 (t, J = 7.3 Hz, 2H), 7.08 (d, J = 8.5 Hz, 1 H), 7.49 (d, J = 7.5 Hz, 1 H), 7.65 (m, 2H), 7.81 (m, 2H), 8.00 (d, J = 2.0 Hz, 1 H), 9.17 (dd, J = 2.4, 6.5 Hz, 1 H), 8.87 (d, J = 7.6 Hz, 1 H), 9.05 (s. 1 H), 11.00 (s, 1 H), 11.77 (s, 1 H). MS (APCI, pos. ): 452.2, 454.2 EXAMPLE 509:
Figure imgf000305_0001
H NMR (DMSO-D6) δ 0.68 (t, J = 7.5 Hz, 3H), 0.75 (t, J = 7.5 Hz, 3H), 0.76 (dd, 0.5 H), 0.90 (dd, 0.5 H), 1.02 - 1.68 (m, 8H), 2.49 (m. 0.5H), 2.75 (m, 2H), 2.90 (t, J = 14.0 Hz, 0.5H), 3.33 (m, 2H), 3.61 (d, J = 12.0, Hz, 0.5H), 3.75 (m, 0.5H), 4.36 (d, J = 12.0 Hz, 0.5H), 4.53 (m, 0.5H), 7.08 (d, J = 8.5 Hz, 1 H), 7.50 (d, J = 7.5 Hz, 1 H), 7.64 - 7.66 (m, 2H), 7.80 (dd, J = 1.9, 8.5 Hz, 1 ), 7.83 (d, J =7.5 Hz, 1 H), 8.00 (d, J = 1.9, Hz, 1 H), 8.17 (m, 1 H), 8.88 (d, J 0 = 7.5 Hz, H), 7.25 (s, 1H), 11.0 (s, 1 H), 11.76 (s, 1 H). MS (APCI, pos.): 492.1 , 494.1
EXAMPLE 510:
Ethyl 4-[(3-Chloro-4-hydroxybenzoy0 hydrazonomethyl] naphthyl propanate 5
Figure imgf000305_0002
The compound was prepared according to the general procedure for the synthesis of alkylidene hydrazones from the condensation of ethyl 4-formyl-1-naphthylpropanate (from step E) o and 3-chloro-4-hydroxy benzoic acid hydrazide.
H NMR (DMSO-D6) δ 1.14 (t, J = 7.0 Hz, 3H), 2.73 (t, J = 7.5 Hz, 2H), 3.35 (t, J = 7.5 Hz, 2H), 4.02 (q, J = 7.0 Hz, 2H), 7.08 (d, J = 8.6 Hz, 1 H), 7.66 (m, 2H), 7.79 (dd, J = 1.8, 8.6 Hz, 1 H), 7.86 (d, J = 7.5 Hz, 1 H), 8.85 (d, J = 7.7 Hz, 1 H), 9.05 (s, 1 H), 11.0 (brd s, 1 H), 5 11.78 (s, 1 H). MS (APCI, pos.): 425.5, 427.3 EXAMPLE 511 :
3-Chloro-4-hydroxy benzoic acid (4-trifluoromethylsulfonyloxy naphthylidene) hydrazide
Figure imgf000306_0001
The compound was prepared according to the general procedure for the synthesis of alkyli- dene hydrazones from the condensation of 4-trifluoromethylsulfonyloxy naphthaldehyde 3- chloro-4-hydroxy benzoic acid hydrazide.
1H NMR (DMSO-Dβ) δ 7.09 (d, J = 8.7 Hz, 1 H), 7.68 - 7.95 (m, 4H), 8.00 - 8.10 (m, 3H), 8.90
(s, 1 H), 9.10 (s, 1 H), 11.02 (s, 1 H), 11.96 (s, 1 H). MS (APCI, pos.): 473.2, 475.1
General procedure for synthesis of compounds of the general formula XV:
Figure imgf000307_0001
NHRScRSd step B
A
Figure imgf000307_0002
formula XV
A and B are as defined for formula I and -NR5cR5d is
Figure imgf000307_0003
where R5a, R4a, R4b, c, q, d and D are as defined for formula I or -D' where -D' is defined as a subset of -D that contains a primary or secondary amine that can react as a nucleophile.
Step A: The carbonyl compounds are treated with an acylhydrazide in a solvent. The solvent may be one of the following: ethyl alcohol, methyl alcohol, isopropyl alcohol, tert-butyl alcohol, dioxane, tetrahydrofuran, toluene, chlorobenzene, anisole, benzene, chloroform, dichloromethane, DMSO, acetic acid, water or a compatible mixture of two or more of the above solvents. A catalyst such as acetic acid can be added. A dehydrating reagent such as triethylort- hoformate can also be added to the reaction mixture. The reaction is performed by stirring the reaction mixture preferably under an inert atmosphere of N2 or Ar at temperatures between 0°C to 140°C, preferably between 10°C to 80°C. In many cases the product simply crystallizes out when the reaction is completed and is isolated by suction filtration. It can be further recrystalli- zed if necessary from a solvent such as the above described reaction solvents. The product can also be isolated by concentration of the reaction mixture in vacuo. followed by column chromatography on silica gel using a solvent system such as chloroform/methanol or dichloromethane/methanol or chloroform/ethyl acetate.
Step B: The epoxide is then ring opened by a primary or secondary amine using one of the methods well-known to those skilled in the art to give a compound of formula XV. The solvent may be one of the following: ethyl alcohol, methyl alcohol, isopropyl alcohol, tert-butyl alcohol, dioxane, tetrahydrofuran, toluene, chlorobenzene, anisole, benzene, chloroform, dichloromethane, DMSO, DMF, NMP, water or a compatible mixture of two or more of the above solvents. The product can then be isolated either by filtration or by extraction using a solvent such as ethyl acetate, toluene, dichloromethane or diethylether and the solvent may then be removed by concentration at atmospheric or reduced pressure. The product can be further purified by either recrystallization from a solvent such as ethyl alcohol, methyl alcohol, isopropyl alcohol, toluene, xylene, hexane, tetrahydrofuran, diethyl ether, dibutyl ether, water or a mixture of two or more of the above. Alternatively, the product can be purified by column chromatography using dichloromethane/methanol or chloroform/methanol or isopropyl alcohol as eluent giving a compound of formula XV.
Specific examples illustrating the preparation of compounds of the general formula XV accor- ding to the invention are provided below.
The preparation of 4-(2,3-epoxypropanoxy)-1 -naphthaldehyde is depicted below:
Figure imgf000308_0001
4-(2,3-epoxypropanoxy)-1 -naphthaldehyde:
To a solution of 4-hydroxy-1 -naphthaldehyde (1 g, 5.8 mmol) in DMSO (20 mL) was added K2CO3 (1 g, 7.2 mmol ). The mixture was stirred at room temperature for 30 min, and then 2,3-epoxypropyl bromide (0.96 g, 7 mmol) was added. After stirring for 24 hr, water (100 mL) was added. The mixture was extracted with ethyl acetate (3x80 mL), dried (MgSO4), and concentrated to give a brown solid (1.23 g, 93%).
Η NMR (CDCI3) δ 2.88 (dd, J = 2.6, 4.8 Hz, 1 H), 3.02 (dd, J = 4.0, 4.6 Hz, 1H), 3.51 - 3.57 (m, 1 H), 4.22 (dd, J = 5.8, 11.1 Hz, 1 H), 4.55 (dd, J = 2.8, 11.1 Hz, 1 H), 6.94 (d, J = 8.1 Hz, 1 H), 7.60 (t, J = 7.2 Hz, 1 H), 7.71 (t, J = 7.7 Hz, 1 H), 7.92 (d, J = 8.0 Hz, 1 H), 8.89 (d, J = 8.4 Hz, 1 H), 9.31 (d, J = 8.6 Hz, 1H), 10.22 (s, 1 H).
General Procedure: 4-hydroxybenzoic acid 4-(2,3-epoxypropanoxy)-1-naphthylidene hydrazide derivatives (step A):
The compound was prepared according to the general procedure for the synthesis of alkylidene hydrazones from the condensation of the above epoxy-aldehyde with 4-hydroxy benzoic acid hydrazide derivatives.
Η NMR (DMSO-dβ) δ 2.84 (dd, J = 2.2, 4.9 Hz, 1 H), 2.92 (dd, J = 4.5, 4.5 Hz, 1 H), 3.45 - 3.57 (m, 1 H), 4.11 (dd, J = 6.4, 11.3 Hz, 1 H), 4.60 (d, J = 11.3 Hz, 1 H), 7.02 - 7.18 (m, 2H), 7.55 - 7.90 (m, 4H), 7.99 (d, J = 1.9 Hz, 1H), 8.29 (d, J = 8.3 Hz, 1 H), 8.90 - 9.05 (d, 2H), 10.94 (s, 1 H), 11.66 (s, 1 H). MS ( APCI, negative ): 395.
General procedure for epoxide ring opening (step B):
A mixture of epoxide (0.2 mmol) and amine (0.3 mmol) in 10 mL ethanol was refluxed for 4 hr. A red oil was obtained after concentration. Products were purified by preparatory HPLC.
Examples of compounds of formula XV:
EXAMPLE 512:
Figure imgf000309_0001
H NMR (DMSO-d6) δ 0.95 (t, J = 6.9 Hz, 6H),' l .90 (s, 3H), 2.50, 2.62 (2q, J = 6.6 Hz, 4H), 2.70 (dd, J = 6.6, 13.0 Hz, 1 H), 2.88 (dd, J = 7.0, 14.2 Hz, 1 H), 3.95 - 4.35 (m, 3H), 7.02 (d, J = 8.7 Hz, 1 H), 7.06 (d, J = 8.3 Hz, 1 H), 7.55 - 7.85 (m, 4H), 7.96 (d, J = 1.9 Hz, 1 H), 8.36 (d, J = 8.3 Hz, 1 H), 8.85 - 9.05 (d, 2H), 11.60 (s, 1 H); MS (APCI, pos.): 470.
EXAMPLE 513:
Figure imgf000310_0001
Η NMR (DMSO-d6) δ 1.67 (brd s, 4H), 1.88 (s, 3H), 2.50 - 2.85 (m, 6H), 4.0 - 4.3 (m, 3H), 7.00 - 7.12 (t, 2H), 7.55 - 7.85 (m, 4H), 7.97 (s, 1 H), 8.36 (d, J = 8.3 Hz, 1 H), 8.85 - 9.05 (d, 2H), 11.63 (s, 1 H); MS ( APCI, pos.): 468.
EXAMPLE 514:
Figure imgf000310_0002
1H NMR (DMSO-dβ) δ 1.30 -1.55 (m, 6H), 1.88 (s, 3H), 2.35 -2.60 (m, 6H), 4.05 - 4.30 (m, 3H), 7.04 (d, J = 8.5 Hz, 1H), 7.12 (d, J = 8.3 Hz, 1H), 7.55 - 7.85 (m, 4H), 7.97 (d, J = 2.1 Hz, 1 H), 8.36 (d, J = 8.2 Hz, 1 H), 8.85 - 9.05 (d, 2H), 11.62 (s, 1 H); MS (APCI, pos.): 470.
EXAMPLE 515:
Figure imgf000310_0003
Η NMR (DMSO-dβ) δ 1.25 -1.82 (m, 8H), 1.88 (s, 3H), 2.68 -2.90 (m, 2H), 3.08 ( m, 1 H), 4.0 - 4.25 (m, 3H), 7.03 (d, J = 8.6 Hz, 1 H), 7.07 (d, J = 8.3 Hz, 1 H), 7.52 - 7.85 (m, 4H), 7.97 (d, J = 1.4 Hz, 1 H), 8.34 (d, J = 8.4 Hz, 1 H), 8.85 - 9.0 (d, 2H), 11.61 (s, 1 H); MS (APCI, pos.): 482.
EXAMPLE 516:
Figure imgf000311_0001
1H NMR (DMSO-d6) δ 0.95 -1.80 ( m, 10H ), 1.88 (s, 3H ), 2.45 (m, 1 H ), 2.70 -2.90 (m, 2H ), 3.98-4.30 (m, 3H), 7.02 (d, J = 8.52 Hz, 1 H), 7.07 (d, J = 8.2 Hz, H ), 7.52 -- 7.75 (m, 4H), 7.97 (d, J = 2.05 Hz, 1 H), 8.34 (d, J = 8.33 Hz, 1 H), 8.87 - 9.00 (m, 2H), 11.61 (s, 1 H); MS ( APCI, pos.): 496.
EXAMPLE 517: 3-Chloro-4-hydroxybenzoic acid 4-(3-hydroxypropyl)naphthylmethylene hydrazide
Figure imgf000311_0002
2-[4-(3-Hydroxypropyl)naphthyi]dioxolane (step A): To a solution of 2-[4-(2-ethoxycarbonylethyl)naphthyl]dioxoiane (210 mg, 0.70 mmol) in anhydrous THF (5 mL) was added at 0°C 1 M lithium aluminum hydride in THF (0.5 mL). THF (5 mL) was added and the mixture was stirred at room temperature for 16 hr, diluted with water (10 mL), acidified with cone, hydrochloric acid, and extracted with ether (3x 10 mL). The combined organic extracts were dried (MgSO4), and concentrated. The residue was pu- rified by flash chromatography using hexane/ethyl acetate 2:1 as eluent to provide 67 mg (37 %) of a coloriess oil. Η NMR (CDCI3) δ 1.51 (brd s, 1H), 1.99 - 2.04 (m, 2H), 3.19 (t, J = 7.4 Hz, 2H), 3.75 (t, J =
6.3 Hz, 2H), 4.16 - 4.22 (m, 4H), 6.47 (s, 1 H), 7.35 (d, J = 7.3 Hz, 1 H), 7.52 - 7.70 (m, 2H), 7.70 (d, J = 7.3 Hz, 1 H), 8.11 (d, J = 9.8 Hz, 1 H), 8.25 (d, J = 9.8 Hz, 1 H). GCMS: 258
1-Formyl-4-(3-hydroxypropyl)naphthalene (step B):
To a solution of 2-[4-(3-hydroxypropyl)naphthyl]dioxolane (67 mg, 0.26 mmol) in anhydrous THF (5 mL) was added 1 N hydrochloric acid (1 mL). The mixture was stirred at room temperature for 48 hr, diluted with ethyl ether (20 mL), washed with satd. NaHCO3 solution (2x 10 mL), dried (MgSO4), concentrated and coevaporated with CHCI3 (3 x 10 mL) to yield 40 mg (72%) of a colorless oil.
Η NMR (CDCI3) δ 1.56 (brd s, 1 H), 2.02 - 2.08 (m, 2H), 3.27 (t, J = 7.5 Hz, 2H), 3.78 (t, J =
6.4 Hz, 2H), 7.53 (d, J = 7.3 Hz, H), 7.62 -7.70 (m, 2H), 7.92 (d, J = 7.3 Hz, 1 H), 9.17 (d, J = 8.3 Hz, 1 H), 9.34 (d, J = 8.6 Hz, 1 H), 10.34 (s, 1 H).
3-Chloro-4-hydroxybenzoic acid 4-(3-hydroxypropyl)naphthylmethylene hydrazide (step C): This compound was prepared according to the general procedure for the synthesis of alkylidene hydrazones by condensation of 1-formyl-4-(3-hydroxypropyl) naphthalene from step B and 3-chloro-4-hydroxy benzoic acid hydrazide.
Η NMR DMSO-D6) δ 1.83 (m, 2H), 3.12 (t, J = 7.5 Hz, 2H), 3.51 (dt, J = 4.9, 7.0 Hz, 2H), 7.09 (d, J = 8.5 Hz, 1 H), 7.47 (d, J = 7.5 Hz, 1 H), 7.65 (m, 2H), 7.80 (dd, J = 2.0, 8.5 Hz, 1 H), 7.86 (d, J = 7.5 Hz, 1 H), 8.00 (d, J = 2.0 Hz, 1 H),8.19 (dd, J = 2.5, 7.0 Hz, 1 H), 8.84 (d, J = 8.4 Hz, 1H), 9.05 (s, 1H), 10.98 (s, 1 H), 11.76 (s, 1H). MS (APCI, pos.): 383.1 , 385.1.
EXAMPLE 518:
4-[(3-Chloro-4-hydroxybenzoy0 hydrazonomethyl] naphthyl diethylacrylamide
Figure imgf000313_0001
Ethyl (4-hydroxy methyl) naphthalene acrylate (step A):
To a suspension of sodium hydride (160 mg, 60% dispersion in mineral oil, 4.00_mmol) in THF (10 mL) at 0°C was added triethylphosphonoacetate (0.77 mL, 670 mg, 3.88 mmol). The mixture was stirred at 0°C for 1 hr, and 4-hydroxymethyl naphthaldehyde (600 mg, 3.2 mmol) in THF (5 mL) was added at the same temperature. The mixture was stirred at room temperature for 16 hr, diluted with satd. NH4CI-solution (10 mL), and extracted with ethyl acetate (3x 10 mL). The combined organic extracts were dried (MgSO4), and concentrated, to provide 900 mg of a coloriess oil, which was used without further purification in the next step.
1H NMR (CDCI3) δ 1.37 (t, J = 7.1 Hz, 3H), 1.86 (brd s, 1 H), 4.32 (q, J = 7.1 Hz, 2H), 5.17 (s, 2H), 6.50 (d, J = 15.7 Hz, 1 H), 7.54 - 7.62 (m, 2H), 7.70 (d, J = 7.4 Hz, 1 H), 8.13 (dd, J = 2.8, 9.8 Hz, 1H), 8.21 (dd, J = 2.8, 9.8 Hz, 1 H), 8.49 (d, J = 15.7 Hz, 1 H).
Ethyl 4-formylnaphthalene acrylate (step B):
The crude material (900 mg) from step A was dissolved in chloroform (10 mL), and manganese dioxide (1.5 g, 17 mmol) was added. After stirring at room temperature for 16 h, the suspension was filtered by suction through Celite, and the filtrate was concentrated. Flash chromatography using hexane/ethyl acetate 5:1 provided 491 mg (60% over 2 steps) of a colorless oil.
Η NMR (CDCI3) δ 1.39 (t, J = 7.1 Hz, 3H), 1.86 (brd s, 1 H), 4.34 (q, J = 7.1 Hz, 2H), 6.60 (d, J = 15.7 Hz, 1 H), 7.68 - 7.75 (m, 2H), 7.85 (d, J = 7.4 Hz, 1 H), 8.00 (d, J = 7.4 Hz, 1 H), 8.25 (d, J = 8.1 Hz, 1H), 8.50 (d, J = 15.7 Hz, 1H), 9.31 (dd, J = 1.3, 8.1 Hz, 1H), 10.43 (s, 1 H). MS (APCI, neg.): 254.1 4-Formylnaphthaiene acrylic acid (step C):
A suspension of ethyl 4-formylnaphthalene acrylate (391 mg, 1.53 mmol), sodium carbonate (195 mg, 1.84 mmol) in water (10 mL) was refluxed for 16 hr. The cold solution was filtered, and the filtrate was acidified with cone, hydrochloric acid. The precipitate was collected by suction and dried for 48 hr in vacuum to give the product (325 mg, 94%) as a yellow solid.
H NMR (DMSO-D6) δ 6.72 (d, J = 15.7 Hz, 1 H), 7.71 - 7.75 (m, 2H), 8.12 (d, J = 7.45Hz, 1 H), 8.20 (d, J = 7.5 Hz, 1 H), 8.30 (d, J = 8.0 Hz, 1 H), 8.40 (d, J = 15.7 Hz, 1 H), 9.21 (d, J = 8.0 Hz, 1H), 10.43 (s,1 H).
4-Formylnaphthalene diethyl acrylamide (step D):
To a solution of 4-formylnaphthalene acrylic acid (210 mg, 0.92 mmol) in DMF (4 mL) was added carbonyl diimidazole (180 mg, 1.10 mmol). The mixture was stirred at room tempe- rature for 1 hr, and diethylamine (0.1 mL, 71 mg, 0.97 mmol) was added. After stirring at room temperature for 16 hr, the mixture was diluted with ethylacetate (5 mL), extracted with water (5 mL), 1 N hydrochloric acid (5 mL), and water (3 x 5 mL), dried (MgSO4) and concentrated. After flash chromatography using hexane/ethylacetate 1 : 1 , 115 mg (43%) of a yellow oil was obtained.
Η NMR (CDCI3) δ 1.25 (t, J = 7.1 Hz, 3H), 1.30 (t, J = 7.1 Hz, 3H), 3.55 (m, 4H), 6.97 (d, J = 15.7 Hz, 1H), 7.63 - 7.76 (m, 2 H), 7.80 (d, J = 7.4 Hz, 1H), 7.99 (d, J = 7.4 Hz, 1H), 8.29 (d, J = 8.3 Hz, 1 H), 8.51 (d, J = 15.7 Hz, 1 H), 9.30 (d, J = 8.3 Hz, 1 H), 10.43 (s, 1 H).
4-[(3-Chloro-4-hydroxybenzoyl) hydrazonomethyl] naphthyl diethylacrylamide (step E):
The compound was prepared according to the general procedure for the synthesis of alkylidene hydrazones from the condensation of 4-formyl-1 -naphthyl diethylacrylamide (from step D) and 3-chloro-4-hydroxy benzoic acid hydrazide.
1H NMR (DMSO-D6) δ 1.11 (t, J = 7.0 Hz, 3H), 1.18 (t, J = 7.0 Hz, 3H), 3.42 (q, J = 7.0 Hz, 1 H), 3.56 (q, J = 7.0 Hz, 2H), 7.10 (d, J = 8.5 Hz, 1 H), 7.22 (d, J = 15.1 Hz, 1 H), 7.67 - 7.72 (m, 2H), 7.81 (d, J = 8.3 Hz, 1 H), 7.96-8.03 (m, 2H), 8.06 (d, J = 7.7 Hz, 1 H), 8.26 (dd, J = 2.1 , 7.2 Hz, 1 H), 8.32 (d, J = 15.1 Hz, 1 H), 8.83 (d, J = 7.0 Hz, 1 H), 9.13 (s, 1 H), 11.00 (s, 1 H), 11.86 (s, 1 H). MS (APCI, pos.): 450.3
EXAMPLE 519: Ethyl 4-[(3-Chloro-4-hydroxybenzoyl) hydrazonomethyl] naphthyl acrylate
Figure imgf000315_0001
The compound was prepared according to the general procedure for the synthesis of alkyli- dene hydrazones from the condensation of ethyl 4-formyl-1 -naphthyl acrylate (from step B) and 3-chloro-4-hydroxy benzoic acid hydrazide.
1H NMR (DMSO-D6) δ 1.29 (t, J = 7.1 Hz, 3H), 4.25 (q, J = 7.1 Hz, 2H), 6.75 (d, J 15.7 Hz, 1 H), 7.10 (d, J = 8.5 Hz, 1H), 7.71 (m, 2H), 7.92 (d, J = 8.5 Hz, 1 H), 8.01 (m, 2H), 8.07 (d, J = 8.0 Hz, 1 H), 8.46 (d, J = 15.7 Hz, 1 H), 8.81 (d, J = 7.1 Hz, 1 H), 9.13 (s, 1 H), 11.00 (s, 1 H), 11.89 (s, 1 H). MS (APCI, pos.): 421.1 , 423.0
EXAMPLE 520:
4-|Y3-Chloro-4-hydroxybenzoyl') hydrazonomethyl] naphthyl acrylate
Figure imgf000315_0002
The compound was prepared according to the general procedure for the synthesis of alkylidene hydrazones from the condensation of 4-formyl -1 -naphthyl acrylate (from step C) and 3-chloro-4-hydroxy benzoic acid hydrazide. 1H NMR (DMSO-D6) δ 6.65 (d, J = 15.6 Hz, 1 H), 7.09 (d, J = 8.5 Hz, 1 H), 7.66 - 7.74 (m, 2H), 7.81 (d, J = 8.5 Hz, 1 H), 7.97 - 8.05 (m, 3H), 8.29 (dd, J = 2.2, 7.1 Hz, 1 H), 8.41 (d, J = 15.6 Hz, 1 H), 8.82 (d, J = 7.6 Hz, 1 H), 9.12 (s, 1 H), 10.92 (s, 1 H), 11.89 (s, 1 H), 12.62 (s, 1 H). MS (APCI, pos.): 394.1 , 395.3
General procedure for the synthesis of substituted piperazine-aryl-aldehydes followed by hy- drazone formation:
The substituted piperazine-aryl-aldehydes may be prepared by N-alkylation of the corresponding unsubstituted piperazine-aryl-aldehydes using various electrophilic alkylating agents that introduce the -(K)m-D moiety as defined above.
Figure imgf000317_0001
H N-NH,
0=^
Figure imgf000317_0002
wherein Lx is a leaving group such as -Cl, -Br, -I, -OSO2CH3, -OSO2p-tolyl or -OSO2CF3; and A, R3a , R3b, R4a , R b, a, b, c, d, f, p, q, D, M, R14 and R 5 are as defined for formula I.
According to the above scheme the substituted piperazine-aryl-aldehydes can be prepared by stirring piperazinylbenzaldehydes or piperazinylnaphthaldehydes in an organic solvent such as acetone, methylethyl ketone, dimethylformamide, DMSO, dioxane, tetrahydrofuran, toluene, ethylene glycol dimethyl ether, sulfolane, diethylether, water or a compatible mixture of two or more of the above solvents with an equimolar amount of an alkyl halide or an aryl-lower alkyl halide and in the presence of 1 to 15 equivalents (preferably 1 to 5 equivalents) of a base such as sodium hydride, potassium hydride, sodium or potassium methoxide, ethoxide or tert- butoxide, sodium, potassium or cesium carbonate, potassium or cesium fluoride, sodium or potassium hydroxide or organic bases such as diisopropylethylamine, 2,4,6-collidine or benzyl- dimethyl- ammonium methoxide or hydroxide. The reaction can be performed at 0°C to 150°C, preferably at 20°C to 100°C and preferably in an inert atmosphere of N2 or Ar. When the reaction is complete the mixture is filtered, concentrated in vacuo and the resulting product optionally purified by column chromatography on silica gel using ethyl acetate/hexane as eluent. The compound can also (when appropriate) be purified by recrystallization from a suitable solvent such as ethyl alcohol, ethyl acetate, isopropyl alcohol, water, hexane, toluene or their compatible mixture. Specific examples illustrating the preparation of unsubstituted piperazine- aryl-aldehydes are provided below.
The following step, the hydrazone formation is described above in general and below in detail.
Preparation of 4-piperazinyl-2.5-dimethylbenzaldehyde:
4-(2,5-dimethylphenyl)-1 -benzylpiperazine:
A solution of 2,5-dimethylphenylpiperazine (20 g, 105 mmol) was prepared in acetonitrile
(300 mL) and cooled to 0 °C. Benzyl bromide (19 g, 111 mmol) was added and the reaction mixture was stirred for 15 minutes before potassium carbonate (16 g, 116 mmol) was added. After stirring the mixture for two hours, the acetonitrile was evaporated and the residue taken up in water and ethyl acetate. The organic layer was separated and washed with brine and dried over magnesium sulfate. The benzylated product was purified by silica gel column chromatography using gradient hexane/ethyl acetate (10/0 to 8/2). The product (21 g, 71 %) was obtained as an oil.
1H NMR (CDCI3) δ 2.24 (s, 3H), 2.29 (s, 3H), 2.60 (brd s, 4H), 2.92 (brd s, 4H), 3.55 (s, 2H), 6.78 (m, 1 H), 6.84 (s, 1H), 7.04 (m, 1H), 7.30 (m, 5H).
4-(2,5-dimethyl-4-formylphenyl)-1 -benzylpiperazine:
The 4-(2,5-dimethylphenyl)-1 -benzylpiperazine (10 g, 36 mmol) was dissolved in anhydrous DMF (30 mL, 390 mmol) and cooled to 0 °C. Fresh POCI3 (70 mL, 750 mmol) was added drop wise with stirring. Once the addition was completed the dark mixture was warmed to 75 °C for five hours or until TLC analysis indicated the disappearance of the starting materi- al. The excess phosphorous oxychloride was distilled off and the entire mixture was diluted with ethyl acetate and added slowly to 500 mL of ice-chips. The solution was neutralized and made basic with concentrated NaOH. The neutralization and basification must be done at low temperatures to avoid creating by-products. The formylated product was extracted with ethyl acetate (5x). The organic layer was washed with water (2x), brine, dried over magnesium sulfate and purified by silica gel column chromatography using gradient hexane/ethyl acetate (10/0 to 8/2). The product (9 g, 81%) was obtained as an oil.
Η NMR (CDCI3) δ 2.29 (s, 3H), 2.28 (s + t, 7H), 3.03 (t, 4H), 3.59 (s, 2H), 6.75 (s, 1 H), 7.31 (m, 5H), 7.58 (s, 1 H), 10.12 (s, 1 H).
4-(2,5-dimethyl-4-formylphenyl)-1-(1-chloroethoxycarbonyl)piperazine: The 4-(2,5-dimethyl-4-formylphenyl)-1 -benzylpiperazine (9 g, 29 mmol) was dissolved in anhydrous 1 ,2-dichloroethane (100 mL) and 1-chloroethyl chloroformate (4.5 g, 31.5 mmol) was added. The solution was refluxed for 30 minutes or until TLC analysis indicated the disappearance of the starting material. The product was just slightly less polar than the starting material by TLC using hexane/EtOAc (3/1 ). Dichloroethane was evaporated and the residue was chromatographed using gradient hexane/EtOAc (10/0 to 8/2) to give the product (6 g, 64%) as an oil.
1H NMR (CDCI3) δ 1.84 (d, 3H), 2.32 (s, 3H), 2.61 (s, 3H), 2.99 (brd m, 4H), 3.70 (brd m, 4H), 6.62 (qt, 1 H), 6.76 (s, 1 H), 7.62 (s, 1 H), 10.14 (s, 1 H).
4-piperazinyl-2,5-dimethylbenzaldehyde: To a solution of the dimethylphenylpiperazinylcarbamate above (6 g, 18.5 mmol) in THF (50 mL) was added 1 N HCI (50 mL, 50 mmol). The mixture was warmed to approximately 80
°C until the evolution of CO2 stopped. Most of the THF was removed by rotary evaporation and the residue was lyophilized to give the product as the dihydrochloride salt (5.5 g, 99%).
1H NMR (DMSO-Dβ) δ 2.2 (s, 3H), 2.50 (s, 3H), 3.13 (brd s, 8H), 6.85 (s, 1 H), 7.54 (s, 1 H), 9.49 (brd s, 2H), 10.02 (s, 1H). 4-piperazinyl-2.3-dimethylbenzaldehyde:
4-Piperazinyl-2,3-dimethylbenzaldehyde was prepared in the same fashion as above. For- mylation of the N-benzyl-piperazinyl-2,3-dimethylbenzene was much slower and required overnight heating at 70 °C. All other steps were otherwise very similar and the yields were comparable.
1H NMR (DMSO-Dβ) δ 2.15 (s, 3H), 2.47 (s, 3H), 3.07 (brd m, 4H), 3.17 (brd m, 4H), 5.90 (brd s, 1 H, NH), 7.02 (d, 1 H), 7.50 (d, 1 H), 9.54 (brd s, 2H, NH2), 10.10 (s, 1 H).
4-piperazinyl-3.5-dimethylbenzaldehyde:
4-Piperazinyl-3,5-dimethylbenzaldehyde was prepared in the same manner as above.
General library procedure for N-alkylation and hydrazone formation:
To a solution of the unsubstituted piperazinyl-aryl-aldehyde in DMSO dispensed into 88 deep well plates were added solutions of desired alkylating agents (1 eq) in DMSO followed by diisopropylethylamine (5 eq). Solid potasssium carbonate (5 eq) may also be substituted. After stirring the solutions for 16 hours, a solution of 4-hydroxybenzoic acid hydrazide derivative (1 eq) in DMSO and a solution of acetic acid (catalytic) in DMSO were added into e- ach well. The reaction mixtures were agitated for 16 hours to give the crude products which were purified by HPLC.
Examples of products:
EXAMPLE 521 :
Figure imgf000321_0001
1H NMR (DMSO-Dβ): δ 2.26 (s, 3H), 2.38 (s, 3H), 2.65 (brd s, 4H), 2.73 (t, 2H), 2.89 (brd s, 4H), 4.07 (t, 2H), 6.03 (d, 2H), 6.84 (t, 2H), 7.02 (d, 1H), 7.13 (d, 1H), 7.72 (d, 1H), 7.82 (dd, 1 H), 8.01 (s, 1 H), 8.86 (brd s, 1 H), 11.68 (brd s, 1 H); MS (APCI): 480.7, 482.3.
EXAMPLE 522:
Figure imgf000321_0002
1H NMR (DMSO-D6): δ 2.49 (s, 6H), 2.68 (brd s 4H), 3.22 (brd s, 4H), 3.72 (s, 2H), 7.22 (d, 1H), 7.44 (m, 1H), 7.52 (m, 6H), 7.92 (dd, 1H), 8.13 (s, 1H), 8.46 (s, 1H), 11.12 (brd s, 1H), 11.80 (s, 1H); MS (APCI): 477.5, 479.2.
EXAMPLE 523:
Figure imgf000321_0003
Η NMR (DMSO-Dβ): δ 1.25 (s, 3H), 1.27 (s, 3H), 2.26 (s, 3H), 2.38 (s, 3H), 2.57 (brd s, 4H), 2.95 (brd s, 4H), 3.56 (s, 2H), 7.02 (d, 1H), 7.12 (d, 1H), 7.30 (qt, 4H), 7.72 (d, 1H), 7.82 (d, 1H), 8.01 (s, 1H), 8.83 (s, 1H), 11.0 (brd s, 1H), 11.1 (s, 1H); MS (APCI): 519.7, 521.5. EXAMPLE 524:
Figure imgf000322_0001
1H NMR (DMSO-D6): δ 2.22 (s, 3H), 2.33 (s, 3H), 3.17 (brd s, 4H), 3.23 (m, 2H), 3.36 (m, 2H), 4.41 (s, 2H), 6.98 (d, 1 H), 7.10 (d, 1 H), 7.48 (m, 3H), 7.68 (m, 3H), 7.71 (d, 1 H), 7.97 (s, 1 H), 8.83 (s, 1 H), 11.00 (s, 1 H), 11.02 (brd s, 1 H), 11.69 (s, 1 H); MS (APCI): 477.4, 479.2.
EXAMPLE 525:
Figure imgf000322_0002
Η NMR (DMSO-Dβ): δ 2.20 (s, 3H), 2.31 (s, 3H), 2.59 (s, 4H), 2.87 (s, 4H), 3.69 (s, 2H), 6.98 (d, 1 H), 7.02 (d, 1H), 7.64 (m, 2H), 7.75 (dd, 1 H), 7.82 (d, 1 H), 7.94 (d, 1 H), 8.12 (dd, 1 H), 8.19 (s, 1 H), 8.74 (s, 1 H), 10.94 (brd s, 1 H), 11.54 (s, 1 H); MS (APCI): 522.2, 524.3.
EXAMPLE 526:
Figure imgf000322_0003
1H NMR (DMSO-Dβ): δ 2.20 (s, 3H), 2.31 (s, 3H), 2.62 (brd s, 4H), 2.87 (brd s, 4H), 3.68 (s, 2H), 6.98 (d, 1 H), 7.04 (d, 1 H), 7.55 (d, 1 H), 7.61 (d, 1 H), 7.74 (dd, 1 H), 7.91 (s, 1 H), 7.92 (d, 1 H), 8.01 (d, 1H), 8.74 (s, 1H), 10.93 (brd s, 1H), 11.54 (s, 1 H); MS (APCI): 519.2, 521.3. EXAMPLE 527:
Figure imgf000323_0001
1H NMR (DMSO-D6): δ 2.21 (s, 3H), 2.37 (s, 3H), 2.66 (brd s, 4H), 2.91 (brd s, 4H), 3.76 (s, 2H), 6.83 (s, 1 H), 7.05 (d, 1 H), 7.62 (s, 1 H), 7.69 (s, 1 H), 7.75 (dd, 1 H), 7.86 (d, 2H), 7.94 (s, 1 H), 8.15 (d, 2H), 8.60 (s, 1 H), 10.92 (brd s, 1 H), 11.55 (s, 1 H); MS (APCI): 628.3, 630.2, 631.2.
General procedure for the synthesis of N-substituted indole aldehydes followed by hydrazone formation:
The N-substituted indole aldehydes may be prepared by N-alkylation of the corresponding unsubstituted indole aldehydes using various electrophilic alkylating agents that introduce the - (K)m-D moiety as defined above.
Figure imgf000324_0001
Figure imgf000324_0002
Base, solvent STEP A
Figure imgf000324_0003
wherein Lx is a leaving group such as -Cl, -Br, -I, -OSO2CH3, -OSO2p-tolyl or -OSO2CF3; and A, R3a , R3b, R a , R4b, a, b, c, d, f, p, q, D, M, R 4 and R15 are as defined for formula I.
According to the above scheme the N-substituted indole aldehydes can be prepared by stirring formylindoles in an organic solvent such as acetone, methylethyl ketone, dimethylformamide, DMSO, dioxane, tetrahydrofuran, toluene, ethylene glycol dimethyl ether, sulfolane, diethylether, water or a compatible mixture of two or more of the above solvents with an e- quimolar amount of an alkyl halide or an aryl-lower alkyl halide and in the presence of 1 to 15 equivalents (preferably 1 to 5 equivalents) of a base such as sodium hydride, potassium hydride, sodium or potassium methoxide, ethoxide or tert-butoxide, sodium, potassium or cesium carbonate, potassium or cesium fluoride, sodium or potassium hydroxide or organic bases such as diisopropylethylamine, 2,4,6-collidine or benzyldimethyl- ammonium methoxide or hy- droxide. The reaction can be performed at 0°C to 150°C, preferably at 20°C to 100°C and preferably in an inert atmosphere of N2 or Ar. When the reaction is complete the mixture is filtered, concentrated in vacuo and the resulting product optionally purified by column chromatography on silica gel using ethyl acetate/hexane as eluent. The compound can also (when appropriate) be purified by recrystallization from a suitable solvent such as ethyl alcohol, ethyl acetate, isopropyl alcohol, water, hexane, toluene or their compatible mixture.
The following step, the hydrazone formation is described above in general and below in detail.
Library Procedure for Indole Alkylation (Step A):
Preparation of the sodium salt of the indole: lndole-3-carboxaldehyde (1.45 g) was dissolved into 8.6 mL of dry DMF in a dried and cooled 3 100 mL 3-necked roundbottom flask.
Evolution of large amounts of hydrogen gas occurs during this step. Care should be taken to keep the flow of inert gas steady and maintain adequate venting to accommodate the hydrogen gas evolution.
While maintaining a steady flow of nitrogen or argon through the 3-necked round bottomed flask, 1.1 equivalent of sodium hydride (0.27 g of dry 95% reagent) was transferred to the indole solution. The mixture was stirred for 15 minutes, while maintaining flow of inert gas. Proceeded promptly to the next step.
Preparation of the alkyl halide solutions: Amber glass vials (for preparing stock solutions) were dried for at least four hours at 110 °C, then were allowed to cool under an argon atmosphere in a desiccator. Alkyl halides solutions (1.0 M) were prepared in anhydrous DMF in the dried vials. Each alkyl halide solution (100 μL) was added to its corresponding well of a deep-well plate (1 x 88 x 1 format). Alkylation of the indole sodium salt:
100 μL of the 1.0 M indole salt solution was quickly delivered to each alkyl halide in the deep-well plates. The plates were vortexed briefly to mix, then allowed to react for two hours.
Library Procedure for Hydrazone Formation (Step B):
Acyl Hydrazone formation:
3-Chloro-4-hydroxybenzoic acid hydrazide (1.86 g) was dissolved in 5 mL of dry DMSO, followed by trifluoroacetic acid (0.77mL). The resulting solution was diluted to a final volume of 10.0 mL. 100 μL of the 1.0 M acid hydrazide TFA salt solution was added to each well of the deep-well plate. The plate was vortexed for one minute to mix, then allowed to react for 30 minutes.
The products were purified by chromatography on silica gel with ethyl acetate/hexane eluent.
The following compounds were prepared:
Figure imgf000326_0001
Η NMR (DMSO-D6): δ 5.46 (s, 2H), 7.10 (d, J = 8.7, 2H), 7.20 (m, 2H), 7.28 (m, 5H), 7.51 (d, J = 7.53, 1 H), 7.79 (d, J = 7.9, 1 H), 7.99 (s, 1 H), 8.01 (s, 1 H) 8.33 (d, J = 6.96, 1 H), 8.62 (s, 1 H), 10.9 (s, 1 H), 11.5 (s, 1 H); LRMS calcd for C26 H24 Cl, N3 O2 (M - H) 402, found 402.1. EXAMPLE 529:
Figure imgf000327_0001
1H NMR (DMSO-D6): δ 1.14 (d, J = 6.8, 6H), 2.81 (sept, J = 6.9, 1H), 5.41 (s, 2H), 7.07 (d, J = 8.3, 1H), 7.20 (m, 6H), 7.54 (d, J = 7.6, 1H), 7.77 (d, J = 7.9, 1H), 7.97 (s, 1H), 8.01 (s, 1 H), 8.29 (d, J = 7.2, 1 H), 8.59 (s, 1 H), 10.88 (s, 1 H), 11.44 (s, 1 H). LRMS calcd for C26 H24 Cl, N3 O2 (M - H) 445, found 445.9
EXAMPLE 530:
Figure imgf000327_0002
1H NMR (DMSO-D6): δ 5.47 (s, 2H), 7.08, (d, J = 8.7, 1H), 7.13-7.25 (m, 5H), 7.18 (t, J = 74.2, 1H), 7.35 (d, J = 8.7, 1H), 7.54 (d, J = 7.9, 1H), 7.77 (dd, J = 8.7, 1.7, 1H), 7.97 (d, J = 1.7, 1H), 8.02 (s, 1H), 8.30 (d, J = 7.2, 1H), 8.59 (s, 1H), 10.89 (s, 1H), 11.45 (s, 1H). LRMS calcd for C24 H18 Cl, F2 N3 O3 (M - H) 468, found 468.1.
EXAMPLE 531:
Figure imgf000327_0003
Η NMR (DMSO-Dβ): δ 0.94 (d, J = 6.2, 6H), 1.54 (sept, J = 6.2, 1 H), 1.66-1.73 (m, 2H), 4.23 (t, J = 7.0, 2H), 7.08 (d, J = 8.7, 1H), 7.16-7.29 (m, 2H), 7.54 (d, J = 7.95, 1H), 7.77 (d, J = 8.7, 1 H), 7.88 (s, 1 H), 7.97 (s, 1 H), 8.29 (d, J = 7.5, 1 H), 8.57 (s, 1 H), 10.88 (s, 1 H). 11.42 (s, 1 H). LRMS calcd for C2, H^ Cl, N3 O2 (M + H) 384, found 384.2.
EXAMPLE 532:
Figure imgf000328_0001
1H NMR (DMSO-D6): δ 7.06 (d, J = 8.5, 1 H), 7.12-7.26 (m,3H), 7.46-7.49 (M,2H), 7.78 (d, J = 8.1 , 1 H), 7.99 (s, 1 H), 11.33 (s, 1 H), 11.65 (s, 1 H). LRMS calcd for C,6 H,2 Cl, N3 O2 (M - H) 312, found 312.0.
General procedure for the synthesis of alkyl/aryl-sulfonyloxy aryl-aldehvdes followed by hydrazone formation:
The alkyl/aryl-sulfonyloxy aryl-aldehydes may be prepared by 0-sulfonylation of the corre- sponding phenolic compounds using various electrophilic sulfonylating agents that introduce the -(K)m-D moiety as defined above.
Figure imgf000329_0001
Figure imgf000329_0002
Base, solvent
Figure imgf000329_0003
Figure imgf000329_0004
wherein Lx is a leaving group such as -Cl, -Br, -I, -OSO2CH3, -OSO2p-tolyl or -OSO2CF3; and A, R3a , R3b, R4a , R4b, a, b, c, d, f, p, q, D, M, R14 and R15 are as defined for formula I.
According to the above scheme an alkyl/aryl-sulfonyloxyaryl aldehyde can be prepared by stirring hydroxybenzaldehydes or hydroxynaphthaldehydes in an organic solvent such as acetone, methylethyl ketone, dimethylformamide, dioxane, tetrahydrofuran, toluene, ethylene glycol dimethyl ether, sulfolane, diethylether, water or a compatible mixture of two or more of the above solvents with an equimolar amount of an alkylsulfonylhalide, arylsulfonylhalide or an a- ryl-lower alkyl sulfonylhalide and in the presence of 1 to 15 equivalents (preferably 1 to 5 equivalents) of a base such as sodium hydride, potassium hydride, sodium or potassium methoxide, ethoxide or tert-butoxide. sodium, potassium or cesium carbonate, potassium or cesium fluoride, sodium or potassium hydroxide or organic bases such as diisopropylethylamine, 2,4,6- collidine or benzyldimethyl- ammonium methoxide or hydroxide. The reaction can be performed at 0°C to 150°C, preferably at 20°C to 100°C and preferably in an inert atmosphere of N2 or Ar. When the reaction is complete the mixture is filtered, concentrated in vacuo and the resulting product optionally purified by column chromatography on silica gel using ethyl acetate/hexane as eluent. The compound can also (when appropriate) be purified by recrystallization from a suitable solvent such as ethyl alcohol, ethyl acetate, isopropyl alcohol, water, hexane, toluene or their compatible mixture.
The following hydrazone formation step is described above in general.
Examples of compounds synthesized using the methodology described are given below:
EXAMPLE 533:
Figure imgf000330_0001
Η NMR (DMSO-Dβ): δ 7.03 (d, 1 H), 7.28 (d, 1 H), 7.39 (d, 1 H), 7.61 (t, 1 H), 7.67 (t, 1 H), 7.75 (m, 2H), 7.87 (d, 2H), 7.95 (s, 1 H), 8.75 (d, 1 H), 9.02 (s, 1 H), 11.00 (s, 1 H), 11.88 (s, 1 H); MS (APCI): 521.0, 523.0.
EXAMPLE 534:
Figure imgf000330_0002
1H NMR (DMSO-D6): δ 1.38 (d, 6H), 3.91 (septet, 1 H), 6.97 (d, 1 H), 7.46 (d, 1 H), 7.61 (m, 2H), 7.71 (d, 1H), 7.81 (d, 1H), 7.89 (s, 1 H), 8.01 (d, 1H), 8.69 (d, 1H), 9.11 (s, 1 H), 11.00 (brd s, 1 H), 11.98 (s, 1 H); MS (APCI, neg.): 445.0, 487.0, 339 - iprso2. General procedures for the preparation of alkylidene hydrazides according to the invention involving parallel synthesis on a solid support:
The compounds of Examples 535 to 614 were prepared according to the following equation
Resin [Building block 1] *-
Resin [Building block 1] [Building block 2] *~
Resin [Building block 1] [Building block 2] [Building block 3]
and were simultaneously deprotected and cleaved from the resin with 50% trifluoroacetic acid in dichloromethane to give the desired compounds as individual entities according to the following formula
[Building block 1] [Building block 2] [Building block 3].
The following 80 compounds were prepared as single entities by parallel synthesis on a solid support. Preparation of Resin-[Building block 1]-[Building block 2] was done manually, whereas the attachment of [Building block 3] and cleavage from the resin were performed on an Advanced ChemTech Model 384 HTS.
The starting resins, Resin-[Building block 1]-[Building block 2], were all prepared as described below.
The resin used was a polystyrene resin with a Wang linker and the substitution capacity was 0.9 mmol/g. All 80 compounds are based on attachment of [Building block 3] to Resin-[Building block 1]- [Building block 2] in a fully combinatorial way using a Heck reaction according to the following scheme:
Resin
Figure imgf000332_0001
Resin-[Building block IMBuilding block 21 _ , r_ ., ,. . , , A, ro .. .. . , , „ p_ ., .. . , , „
1 a i a J Resιn-[Buιldιng block 1]-[Buιldιng block 2]-[Buιldιng block 3]
where B-Lea is
Figure imgf000332_0002
wherein Lea is a leaving group and preferably is selected from bromo, iodo and trifluoromethanesulfonyloxy, and R14 and R15 are as defined for formula I.
The following resin, here depicted as Resin-[Building block 1] was used:
"Resin" is the
Figure imgf000332_0003
Where = Resin
Figure imgf000332_0004
The following building blocks were used: [Building block 2 . 3,4-dimethoxy-5-iodobenzaldehyde 3-Bromobenzaldehyde
Figure imgf000333_0001
Trifluoromethanesulfonic acid 4-formyl-1- 4-Bromobenzaldehyde
Figure imgf000333_0002
[Building block 3]:
1 -Ethynylcyclohexylamine 2-Amino-4-pentynoic acid
Figure imgf000334_0001
N-Methyi-N-propargylbenzylamine Propargylamine
^^ NH2
CH, H
N,N-Diethylpropargylamine Phenyl propargyl ether
Figure imgf000334_0002
3-Phenyl-1 -propyne Ethynyl p-tolyl sulfone
Figure imgf000334_0003
1 -Chloro-4-ethynylbenzene 3-Ethynylphenol
Figure imgf000335_0001
5-Phenyl-1 -pentyne 2-Ethynylpyridine
Figure imgf000335_0002
5-Phenyl-2-(2-propynylamino)-2-oxazolin-4- tert-Butyl propiolate
Figure imgf000335_0003
4-Pentynoic acid tert-Butyl 1-methyl-2-propynyl ether
Figure imgf000335_0004
5-Hexyn-3-ol
Figure imgf000336_0001
Figure imgf000336_0002
O-Trimethylsiiylpropargyl alcohol 3-(2,6-Dichlorophenoxy)prop-1-yne
Figure imgf000336_0003
By combination of these building blocks in a fully combinatorial way 1x4x20 = 80 compounds were prepared.
Preparation of [Building block 2]:
Preparation of 3,4-dimethoxy-5-iodobenzaldehyde: lodomethane (2.5 mL, 40 mmoles) was added to a mixture of 5-iodovanillin (10 g, 36 mmoles), potassium carbonate (25 g, 180 mmoles) in DMF (100 ml) and the resulting mixture was stirred at room temperature for 16 hours. The mixture was poured into water (0.5 L) and extracted with ethyl acetate (2 x 200 mL). The combined organic phases were washed with water (200 mL), dried over MgSO4 and evaporated in vacuo to afford 9.78 g (93%) of 3,4-dimethoxy-5-iodobenzaldehyde, m.p. 58-63 °C.
Preparation of trifluoromethanesulfonic acid 4-formyl-1 -naphthyl ester: 4-Hydroxy-1 -naphthaldehyde (10 g, 58 mmoles) was dissolved in pyridine (50 ml) and the mixture was cooled to 0 °C. Trifluoromethanesulfonic anhydride (11.7 mL, 70 mmoles) was added dropwise while maintaining the temperature below 5 °C. When the addition was com- pleted the mixture was stirred at room temperature for 30 minutes. Diethyl ether (200 mL) was added and the mixture was successively washed with water (2 x 250 mL), 3 N hydrochloric acid (200 mL), and saturated NaCl (200 mL). The organic phase was dried over MgSO4 and evaporated in vacuo. The residue was purified by column chromatography on silica gel (800 mL) eluting with a mixture of ethyl acetate and heptane (1 :4). Pure fractions eluting with Rf = 0.46 were pooled and evaporated in vacuo to afford 8.35 g (47 %) of trifluoromethanesulfonic acid 4-formyl-1 -naphthyl ester, m.p. 44-47 °C. The other [Building block 2]'s (3-Bromobenzaldehyde and 4-bromobenzaldehyde) are commercially available.
Preparation of Resin-[Building block 1]:
(Resin bound 3-chloro-4-hydroxybenzoic acid hydrazide)
Polystyrene resin (15 g) loaded with the Wang linker (0.92 mmoles/g), was successively washed with DMF (3 x 40 mL) and CH2CI2 (3 x 40 mL). The resin was suspended in CH2CI2 (80 mL) and diisopropylethylamine (60 mL) was added. The mixture was cooled to 0°C and methanesulfonyl chloride (5.8 mL) dissolved in CH2CI2 (30 mL) was added drop wise while maintaining the temperature below 5 °C. When addition was complete the mixture was stirred at 0 °C for 30 minutes and at room temperature for 30 minutes. The resin was successively washed with CH2CI2 (3 x 80 mL) and N-methylpyrrollidone (NMP) (3 x 80 mL). This resin and cesium carbonate (12.3 g) were added to ethyl 3-chloro-4-hydroxybenzoate (15 g) dissolved in NMP (200 mL) and the mixture was stirred at 80 °C for 4 hours. After cooling the resin was successively washed with NMP (3 x 80 mL) and methanol (3 x 80 mL).
The above resin was suspended in 1 ,4-dioxane (150 mL) and water (36 mL). Lithium hy- droxide (2.6 g) was added and the mixture was stirred at 60 °C under N2 for 16 hours. After cooling the resin was successively washed with DMF (3 x 80 mL), CH2CI2 (3 x 80 mL) and methanol (80 mL) and dried in vacuo at 50 °C for 3 days.
The above resin (3.0 g) was suspended in CH2CI2 (20 mL) and 1-hydroxybenzotriazole (0.6 9). N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide, hydrochloride (0.9 g) and DMF (10 mL) were added. The mixture was shaken at room temperature for 45 minutes, hydrazine hydrate (300 μL) was added, and the mixture was shaken overnight at room temperature. The resin was successively washed with DMF (3 x 20 mL) and CH2CI2 (3 x 20 mL) to afford resin bound 3-chloro-4-hydroxybenzoic acid hydrazide (Resin-[Building block 1]).
Preparation of Resin-[Buildinα block 1]-[Building block 2]:
Preparation of resin bound 3-chloro-4-hydroxybenzoic acid (3,4-dimethoxy-5-iodobenzyli- dene)hydrazide: The above resin (Resin-[Building block 1]) (4 g) was suspended in DMF (50 mL) and 3,4-dimethoxy-5-iodobenzaldehyde (5.8 g) and triethyl orthoformate (25 mL) were added and the mixture was shaken for 16 hours at room temperature. The resin was successively washed with DMF (4 x 40 mL) and CH2CI2 (6 x 40 mL), and dried in vacuo at 50 °C for 16 hours to afford resin bound 3-chloro-4-hydroxybenzoic acid (3,4-dimethoxy-5- iodobenzylidene)hydrazide.
Preparation of resin bound trifluoromethanesulfonic acid 4-[(3-chloro-4-hydroxybenzoyl)- hydrazonomethyl]naphthalen-1 -yl ester: Similarly as described above but using trifluoromethanesulfonic acid 4-formyl-1 -naphthyl ester instead of 3,4-dimethoxy-5-iodobenzaldehyde resin bound was trifluoromethanesulfonic acid 4-[(3-chloro-4-hydroxybenzoyl)hydrazonomethyl]naphthalen-1-yl ester obtained.
Preparation of resin bound 3-chloro-4-hydroxybenzoic acid (3-bromobenzylidene)hydrazide: Similarly as described above but using 3-bromobenzaldehyde instead of 3,4-dimethoxy-5- iodobenzaldehyde resin bound 3-chloro-4-hydroxybenzoic acid (3-bromobenzylidene)hydra- zide) was obtained.
Preparation of resin bound 3-chloro-4-hydroxybenzoic acid (4-bromobenzylidene)hydrazide: Similarly as described above but using 4-bromobenzaldehyde instead of 3,4-dimethoxy-5- iodobenzaldehyde resin bound 3-chloro-4-hydroxybenzoic acid (4-bromobenzylidene)- hydrazide) was obtained.
EXAMPLE 535:
Figure imgf000339_0001
3-Chloro-4-hydroxybenzoic acid [3-H -aminocvclohexylethyny0-4.5-dimethoxybenzylidene]- hydrazide
To the resin bound 3-chloro-4-hydroxybenzoic acid (3-bromobenzylidene)hydrazide (0.05 mmoles) was added copper (I) iodide (10 mg). Diisopropylethylamine (0.2 mL), a solution of triphenylphosphine in NMP (0.4 M, 0.5 mL), a solution of tetrabutylammonium chloride in water (0.66 M, 0.3 mL), a solution of palladium (II) acetate in NMP (0.16 M, 0.25 mL) and a solution of 1 -ethynylcyclohexylamine ([Building block 3]) in NMP (1 M, 0.5 mL) were added successively, and the mixture was shaken at 90 °C for 15 hours. The resin was repeatedly washed with NMP (1.5 mL, 3 times), 50% water in DMF (1.5 mL, 3 times), NMP (1.5 mL, 2 times), 1 % sodium diethylaminodithiocarbamate trihydrate (1.5 mL, 9 times), NMP (1.5 mL, 5 times), and CH2CI2 (1.5 mL, 6 times) for 2 minutes and filtered.
The compound was cleaved off the resin by shaking for 45 minutes at room temperature with a 50% solution of trifluoroacetic acid in CH2CI2 (1.5 mL). The mixture was filtered and the resin was extracted with CH2CI2 (0.5 mL). The combined CH2CI2 extracts were concentrated in vacuo. The residue was dissolved in a 1 :1 mixture of methanol and CH2CI2 (1 mL) and concentrated in vacuo to give the title compound.
The final product obtained was characterized by analytical RP-HPLC (retention time) and by LC-MS (molecular mass).
The RP-HPLC analysis was performed on a Waters HPLC system consisting of Waters™ 600S Controller, Waters™ 996 Photodiode Array Detector, Waters™ 717 Autosampler, Waters™ 616 Pump, Waters™ 3 mm x 150 mm 3.5 μ C-18 Symmetry column and Millenium QuickSet Control Ver. 2.15 using UV detection at 214 nm. A gradient of 5% to 90% acetoni- trile/0.1% trifluoroacetic acid/water during 15 minutes at 1 mlJminute.
The LC-MS analysis was performed on a PE Sciex API 100 LC/MS System using a Waters .TM 3 mm x 150 mm 3.5 μ C-18 Symmetry column and positive ionspray with a flow rate at 20 μUminute.
Examples 536 to 614:
A library of the following 79 compounds can be prepared in parallel as individual entities analogously to example 535 on an Advanced ChemTech Model 384 HTS using the following ChemFile to control the operation of the synthesizer. The 4 resins of type Resin-[Building block 1]-[Building block 2] are equally distributed in the 80 wells in the syntheziser prior to the initialization of the device.
ChemFile C:\ACT\90250004.CHM Page 1 1 Empty RB_Heating_AII_1 to36 for 2.000 minute(s)
2 REM Addition of DIPEA
3 Transfer 200μl from Monomers_1to36 [25] () to RB_Heating_AII_1to96 [1-80] using DCE
4 Mix for 1.00 minutes at 600 rpm(s)
5 REM Addition of Ph3P in NMP 6 Transfer 500μl from Monomers_1 to36 [21] () to RB Heating_AII_1to96 [1-80] using DCE
7 REM Addition of Bu4NCI in water
8 Transfer 300μl from Monomers_1to36 [22] () to RB Heating_AII_1to96 [1-80] using DCE
9 Mix for 1.00 minutes at 600 rpm(s)
10 REM Addition of Pd(OAc)2 in NMP 11 Transfer 250μl from Monomers_1to36 [22] () to RB_Heating_AII_1to96 [1-80] using DCE
12 Mix for 2.00 minutes at 600 rpm(s)
13 Dispense Sequence C:\ACT\ALKYNES.DSP with 500μl to RB_Heating_AII_1to96 rack
14 Set Temperature to 90.0 degrees Celsius
15 Mix for 15.00 minutes at 600 rpm(s) 16 Wait for 15.000 minute(s)
17 Repeat from step 15, 47 times
18 Turn Temperature Controller Off
19 Mix for 15.00 minutes at 600 rpm(s)
20 Wait for 15.000 minute(s) 21 Repeat from step 19, 7 times
22 Empty RB_Heating_AII_1to96 for 2.000 minute(s)
23 Dispense System Fluid NMP1 1500μl to RB_Cleavage_AII_1to96 [1-80]
24 Mix for 3.00 minutes at 600 rpm(s)
25 Empty RB_Heating_AII_1to96 for 2.000 minute(s) 26 Repeat from step 23, 2 times
27 REM Wash with 50% H2O/NMP 28 Transfer 1500μl from Reagent_3 [1] () to RB_Heating_AII_1 to96 [1-80] using NMP1
29 Mix for 3.00 minutes at 600 rpm(s)
30 Empty RB_Heating_AII_1to96 for 2.000 minute(s)
31 Repeat from step 28, 2 times 32 Dispense System Fluid NMP1 1500μi to RB_Cleavage_AII_1to96 [1-80]
33 Mix for 3.00 minutes at 600 rpm(s)
34 Empty RB_Heating_AII_1to96 for 2.000 minute(s)
35 Repeat from step 32, 1 times
36 REM Wash with Sodium diethylaminodithiocarbamate 37 Transfer 1500μl from Reagent_3 [1] () to RB_Heating_AII_1to96 [1-80] using NMP1
38 Mix for 3.00 minutes at 600 rpm(s)
39 Empty RB_Heating_AII_1to96 for 2.000 minute(s)
40 Repeat from step 37, 2 times
41 Transfer 1500μl from REAGENT_4 [1] () to RB_Heating_AII_1to96 [1-80] using NMP1 42 Mix for 3.00 minutes at 600 rpm(s)
43 Empty RB_Heating_AII_1to96 for 2.000 minute(s)
44 Repeat from step 41 , 2 times
45 Transfer 1500μl from REAGENT_5 [1] () to RB_Heating_AII_1to96 [1-80] using NMP1
46 Mix for 2.00 minutes at 600 rpm(s) 47 Empty RB_Heating_AII_1 to96 for 2.000 minute(s)
48 Repeat from step 45, 2 times
49 Dispense System Fluid NMP1 1500μl to RB_Cleavage_AII_1to96 [1-80]
50 Mix for 3.00 minutes at 600 rpm(s)
51 Empty RB_Heating_AII_1to96 for 2.000 minute(s) 52 Repeat from step 49, 4 times
53 Dispense System Fluid DCE1 1500μl to RB_Cleavage_AII_1to96 [1-80]
54 Mix for 3.00 minutes at 600 rpm(s)
55 Empty RB_Heating_AII_1to96 for 2.000 minute(s)
56 Repeat from step 53, 5 times 57 REM Cleavage from Resin
58 REM with 50% TFA/DCM
59 Transfer 1500μl from Reagent _3 [1] () to RB_Cleavage_AII_1to96 [1-80] using DCM1
60 Mix for 45.00 minutes at 600 rpm(s)
61 Empty RB_Cleavage_AII_1to96 for 1.000 minute(s) 62 Dispense System Fluid DCM1 500μl to RB_Cleavage_AII_1to96 [1-80]
63 Mix for 1.00 minutes at 300 rpm(s)
64 Empty RB_Cleavage_AII_1to96 for 1.000 minute(s) 65
66
Dispense Sequence C:\ACT\ALKYNES.DSP is a subroutine that controls the combinatorial addition of the solutions of the 20 alkynes of type [Building block 3] into the 80 wells in the synthesizer. The library containing the compounds listed below was synthesized. A subset of the library obtained was characterized by analytical RP-HPLC (retention time) and by LC-MS (molecular mass).
EXAMPLE 536: EXAMPLE 537: 2-Amino-5-{5-[(3-chloro-4- 3-Chloro-4-hydroxybenzoic acid [3-(3- hydroxybenzoyl)hydrazonomethyl]-2,3- diethylamino-1 -propynyl)-4,5- dimethoxyphenyl}-4-pentynoic acid dimethoxybenzylidene]hydrazide
Figure imgf000343_0001
EXAMPLE 538: EXAMPLE 539:
3-Chloro-4-hydroxybenzoic acid{3-[3- 3-Chloro-4-hydroxybenzoic acid [3,4- (benzylmethylamino)-1-propynyl]-4,5- dimethoxy-5-(3-phenyl-1 - dimethoxybenzylidene}hydrazide propynyl)benzylidene]hydrazide
Figure imgf000343_0002
EXAMPLE 540: EXAMPLE 541 :
3-Chloro-4-hydroxybenzoic acid [3-(3-amino-1- 3-Chloro-4-hydroxybenzoic acid [3,4- propynyl)-4,5-dimethoxybenzylidene]hydrazide dimethoxy-5-(3-phenoxy-1 - propynyl)benzylidene]hydrazide
Figure imgf000343_0003
EXAMPLE 542: EXAMPLE 543:
3-Chloro-4-hydroxybenzoic acid [3,4- 3-Chloro-4-hydroxybenzoic acid [3-(3- dimethoxy-5-(toluene-4-sulfonylethynyl> hydroxyphenylethynyl)-4,5- benzylidene]hydrazide dimethoxybenzylidene]hydrazide
Figure imgf000344_0001
EXAMPLE 544: EXAMPLE 545:
3-Chloro-4-hydroxybenzoic acid [3-(4- 3-Chloro-4-hydroxybenzoic acid [3,4- chlorophenylethynyl)-4,5- dimethoxy-5-(2-pyridylethynyl]- dimethoxybenzylidene]hydrazide benzylidene]hydrazide
Figure imgf000344_0002
EXAMPLE 546:
3-Chloro-4-hydroxybenzoic acid [3,4- dimethoxy-5-(5-phenyl-1 - pentynyl)benzylidene]hydrazide
Figure imgf000344_0003
EXAMPLE 547: EXAMPLE 548:
3-Chloro-4-hydroxybenzoic acid {3,4- {5-[(3-Chloro-4-hydroxybenzoyl)- dimethoxy-5-[3-(4-oxo-5-phenyl-4,5-dihydro- hyd razonomethy l]-2, 3-d i methoxy- 2-oxazolylamino)-1 -propynyl]- phenyljpropynoic acid benzylidene}hydrazide
Figure imgf000345_0001
EXAMPLE 549: EXAMPLE 550:
5-{5-[(3-Chloro-4-hydroxybenzoyl)- 3-Chloro-4-hydroxybenzoic acid [3-(3- hydrazonomethyl]-2,3-dimethoxyphenyl}-4- hydroxy-1-butynyl)-4,5-dimethoxy- pentynoic acid benzylidene]hydrazide
Figure imgf000345_0002
EXAMPLE 551 : EXAMPLE 552:
3-Chloro-4-hydroxybenzoic acid [3-(4- 3-Chloro-4-hydroxybenzoic acid [3-(4- hydroxy-1-butynyl)-4,5-dimethoxy- hydroxy-1-hexynyl)-4,5-dimethoxy- benzylidenejhydrazide benzylidenejhydrazide
Figure imgf000346_0001
EXAMPLE 553: EXAMPLE 554:
3-Chloro-4-hydroxybenzoic acid [3-(3- 3-Chloro-4-hydroxybenzoic acid {3-[3-(2,6- hydroxy-1-propynyl)-4,5-dimethoxy- dichlorophenoxy)-1-propynyl]-4,5- benzylidenejhydrazide dimethoxybenzylidene}hydrazide
Figure imgf000346_0002
EXAMPLE 555:
3-Chloro-4-hydroxybenzoic acid [4-(1- aminocyclohexylethynyl)-1 - naphthylmethylene]hydrazide
Figure imgf000346_0003
EXAMPLE 556: EXAMPLE 557:
3-Chloro-4-hydroxy benzoic acid [4-(3- 3-Chloro-4-hydroxybenzoic acid [4-(3-amino- benzylmethylamino-1 -propynyl)-1 - 1 -propynyl)-1 -naphthylmethylene]hydrazide naphthylmethylene] hydrazide
Figure imgf000347_0001
EXAMPLE 558: EXAMPLE 559:
2-Amino-5-{4-[(3-chloro-4-hydroxybenzoyl)- 3-Chloro-4-hydroxybenzoic acid[4-(3- hydrazonomethyl]-1-naphthyl}-4-pentynoic diethylamino-1 -propynyl)-1 -naphthyl- acid methylene]hydrazide
Figure imgf000347_0002
EXAMPLE 560: EXAMPLE 561 :
3-Chloro-4-hydroxybenzoic acid [4-(3-phenyl- 3-Chloro-4-hydroxybenzoic acid [4-(toluene-
1 -propynyl)-1 -naphthylmethylene]hydrazide 4-sulfonylethynyl)-1 - naphthylmethylene]hydrazide
Figure imgf000348_0001
EXAMPLE 562: EXAMPLE 563:
3-Chloro-4-hydroxybenzoic acid [4-(3- 3-Chloro-4-hydroxybenzoic acid [4-(4- phenoxy-1 -propynyl)-1 -naphthylmethylene]- chlorophenylethynyl)-1-naphthyl- hydrazide methylene]hydrazide
Figure imgf000348_0002
EXAMPLE 564: EXAMPLE 565:
3-Chloro-4-hydroxybenzoic acid [4-(5-phenyl- 3-Chloro-4-hydroxybenzoic acid {4-[3-(4-oxo- 1 -pentynyl)-1 -naphthylmethylene]hydrazide 5-phenyl-4,5-dihydro-(2-oxazolylamino)-1 - propynyl]-1-naphthylmethylene}hydrazide
Figure imgf000349_0001
EXAMPLE 566: EXAMPLE 567:
3-Chloro-4-hydroxybenzoic acid [4-(3- 5-{4-[(3-Chloro-4-hydroxybenzoyl)- hydroxyphenylethynyl)-1-naphthyl- hydrazonomethyl]-1-naphthyl}-4-pentoic acid methylene] hyd razide
Figure imgf000349_0002
EXAMPLE 568: EXAMPLE 569:
3-Chloro-4-hydroxybenzoic acid [4-(2- {4-[(3-Chloro-4-hydroxybenzoyl)- pyridyl)ethynyl-1-naphthylmethylene)- hydrazonomethyl]-1 -naphthyl}propynoic acid hydrazide
Figure imgf000350_0001
EXAMPLE 570: EXAMPLE 571 :
3-Chloro-4-hydroxybenzoic acid [4-(3- 3-Chloro-4-hydroxybenzoic acid [4-(3- hy- hydroxy-1 -butynyl)-1 -naphthylmethylene]- droxy-1 -propynyl)-1 -naphthylmethylene]- hydrazide hydrazide
Figure imgf000350_0002
EXAMPLE 572: EXAMPLE 573:
3-Chloro-4-hydroxybenzoic acid [4-(4- 3-Chloro-4-hydroxybenzoic acid [4-(4- hydroxy-1 -butynyl)-1 -naphthylmethylene]- hydroxy-1-hexynyl)-1-naphthylmethylene]- hydrazide hydrazide
Figure imgf000350_0003
EXAMPLE 574: EXAMPLE 575:
3-Chloro-4-hydroxybenzoic acid {4-[3-(2,6- 2-Amino-5-{3-[(3-chloro-4-hydroxy- dichlorophenoxy)-1 -propynyl]-1 - benzoyl)hydrazonomethyl]phenyl}-4- naphthylmethylene}hydrazide pentynoic acid
Figure imgf000351_0001
EXAMPLE 576: EXAMPLE 577:
3-Chloro-4-hydroxybenzoic acid [3-(1- 3-Chloro-4-hydroxybenzoic acid {3-[3- aminocyclohexylethynyl)benzylidene]- (benzylmethylamino)-l- hydrazide propynyl]benzylidene}hydrazide
Figure imgf000351_0002
EXAMPLE 578:
3-Chloro-4-hydroxybenzoic acid [3-(3-amino- 1-propynyl)benzylidene]hydrazide
Figure imgf000351_0003
EXAMPLE 579: EXAMPLE 580:
3-Chloro-4-hydroxybenzoic acid [3-(3- 3-Chloro-4-hydroxybenzoic acid [3-(toluene- diethylamino-1-propynyl)benzylidene]- 4-sulfonylethynyl)benzylidene]hydrazide hydrazide
Figure imgf000352_0001
EXAMPLE 581 : EXAMPLE 582:
3-Chloro-4-hydroxybenzoic acid [3-(3-phenyl- 3-Chloro-4-hydroxybenzoic acid [3-(4-
1-propynyl)benzylidene]hydrazide chlorophenylethynyl)benzylidene]hydrazide
Figure imgf000352_0002
EXAMPLE 583: EXAMPLE 584:
3-Chloro-4-hydroxybenzoic acid [3-(3- 3-Chloro-4-hydroxybenzoic acid [3-(5-phenyl- phenoxy-1-propynyl)benzylidene]hydrazide 1-pentynyl)benzylidene]hydrazide
Figure imgf000352_0003
EXAMPLE 585: EXAMPLE 586:
3-Chloro-4-hydroxybenzoic acid [3-(3- 5-{3-[(3-Chloro-4-hydroxybenzoyl)-hydrazo- hydroxyphenylethynyl)benzylidene]- nomethyl]phenyl}-4-pentynoic acid hydrazide
Figure imgf000353_0001
EXAMPLE 587: EXAMPLE 588:
3-Chloro-4-hydroxybenzoic acid [3-(2- {3-[(3-chloro-4-hydroxybenzoyl)- pyridylethynyl)benzylidene]hydrazide hydrazonomethyl]phenyl}propynoic acid
Figure imgf000353_0002
EXAMPLE 589: EXAMPLE 590:
3-Chloro-4-hydroxybenzoic acid {3-[3-(4-oxo- 3-Chloro-4-hydroxybenzoic acid [3-(3- 5-phenyl-4,5-dihydro-(2-oxazolylamino))-1- hydroxy-1-butynyl)benzylidene]hydrazide propynyl]benzylidene}hydrazide
Figure imgf000353_0003
EXAMPLE 591 : EXAMPLE 592:
3-Chloro-4-hydroxybenzoic acid [3-(4- 3-Chloro-4-hydroxybenzoic acid [3-(4- hydroxy-1-butynyl)benzylidene]hydrazide hydroxy-1-hexynyl)benzylidene]hydrazide
Figure imgf000354_0001
EXAMPLE 593: EXAMPLE 594:
3-Chloro-4-hydroxybenzoic acid [3-(3- 3-Chloro-4-hydroxybenzoic acid {3-[3-(2,6- hydroxy-1-propynyl)benzylidene]hydrazide dichlorophenoxy)-1-propynyl]benzylidene}- hydrazide
Figure imgf000354_0002
EXAMPLE 595: EXAMPLE 596:
3-Chloro-4-hydroxybenzoic acid [4-(1- 2-Amino-5-{4-[(3-chloro-4-hydroxybenzoyl)- aminocyclohexylethynyl)benzylidene]- hydrazonomethyl]phenyl}-4-pentynoic acid hydrazide
Figure imgf000354_0003
EXAMPLE 597: EXAMPLE 598:
3-Chloro-4-hydroxybenzoic acid {4-[3- 3-Chloro-4-hydroxybenzoic acid [4-(3-amino- (benzylmethylamino)-l-propynyl]- 1-propynyl)benzylidene]hydrazide benzylidenejhydrazide
Figure imgf000355_0001
EXAMPLE 599: EXAMPLE 600:
3-Chloro-4-hydroxybenzoic acid [4-(3- 3-Chloro-4-hydroxybenzoic acid [4-(3- diethylamino-1-propynyl)benzylidene]- phenoxy-1-propynyl]benzylidene]hydrazide hydrazide
Figure imgf000355_0002
EXAMPLE 601 : EXAMPLE 602:
3-Chloro-4-hydroxybenzoic acid [4-(3-phenyl- 3-Chloro-4-hydroxybenzoic acid [4-(toluene-
1-propynyl)benzylidene]hydrazide 4-sulfonylethynyl)benzylidene]hydrazide
Figure imgf000355_0003
EXAMPLE 603: EXAMPLE 604:
3-Chloro-4-hydroxybenzoic acid [4-(4- 3-Chloro-4-hydroxybenzoic acid [4-(3- chlorophenylethynyl)benzylidene]hydrazide hydroxyphenylethynyl)benzylidene]hydrazide
Figure imgf000356_0001
EXAMPLE 605: EXAMPLE 606:
3-Chloro-4-hydroxybenzoic acid [4-(5-phenyl- 3-Chloro-4-hydroxybenzoic acid [4-(2- 1-pentynyl)benzylidene]hydrazide pyridylethynyl)benzylidene]hydrazide
Figure imgf000356_0002
EXAMPLE 607: EXAMPLE 608:
3-Chloro-4-hydroxybenzoic acid {4-[3-(4-oxo- {4-[(3-Chloro-4-
5-phenyl-4,5-dihydro-(2-oxazolylamino)-1- hydroxybenzoyl)hydrazonomethyl]- propynyl]benzylidene}hydrazide phenyljpropynoic acid
Figure imgf000356_0003
EXAMPLE 609: EXAMPLE 610:
5-{4-[(3-Chloro-4-hydroxybenzoyl)- 3-Chloro-4-hydroxybenzoic acid [4-(3- hydrazonomethyl]phenyl}-4-pentynoic acid hydroxy-1-butynyl)benzylidene]hydrazide
Figure imgf000357_0001
EXAMPLE 611 : EXAMPLE 612:
3-Chloro-4-hydroxybenzoic acid [4-(4- -Chloro-4-hydroxybenzoic acid [4-(4- hydroxy-1-butynyl)benzylidene]hydrazide hydroxy-1-hexynyl)benzylidene]hydrazide
Figure imgf000357_0002
EXAMPLE 613: EXAMPLE 614:
3-Chloro-4-hydroxybenzoic acid [4-(3- 3-Chloro-4-hydroxy benzoic acid {4-[3-(2,6- hydroxy-1-propynyl)benzylidene]hydrazide dichlorophenoxy)-1-propynyl]benzylidene}- hydrazide
Figure imgf000357_0003
General procedure for the preparation of Examples 615 to 694:
The following 80 compounds were prepared as single entities by parallel synthesis on a solid support. The attachment of [Building block 3] and cleavage from the resin were performed on an Advanced ChemTech Model 384 HTS.
The compounds were prepared according to the following equation:
Resin [Building block 1] *-
Resin [Building block 1] [Building block 2]
Resin [Building block 1] [Building block 2] [Building block 3]
and were simultaneously cleaved (and deprotected when protected) from the resin with 50% trifluoroacetic acid in dichloromethane to give the desired compounds as individual entities according to the following formula:
[Building block 1] [Building block 2] [Building block 3].
The starting resins, Resin-[Buiiding block 1]-[Building block 2], were all prepared as described above.
The resin used was a polystyrene resin loaded with a Wang linker and the substitution ca- pacity was 0.9 mmol/g.
All 80 compounds are based on attachment of [Building block 3] to Resin-[Building block 1J- [Building block 2] in a fully combinatorial way using a Suzuki reaction according to the following scheme. -R [Building block 3]
Catec olborane
Figure imgf000359_0001
Pd catalyst
Resin-[Building block 1]-[Building block 2] Resin-[Building block 1]-[Building block 2]-[Building block 3]
where B-Lea is
Figure imgf000359_0002
wherein Lea is a leaving group and R14 and R15 are as defined for formula
The starting materials used were the same as those use in examples 535 to 614, i.e. Resin-[Building block 1], [Building block 2] and [Building block 3] were the same as those used in examples 535 to 614, the only difference being the products in examples 615 to 694 are having double bonds as compared to the products in examples 535 to 614 having triple bonds.
EXAMPLE 615:
3-Chloro-4-hydroxybenzoic acid {3-[2-H -aminocvclohexynvinyl]-4.5-dimethoxybenzylidene}- hydrazide
Figure imgf000360_0001
Preparation of a 1 ,4-dioxane/THF solution of 1-(2-Benzo[1 ,3,2]dioxaborol-2-ylvinyl)cyclo- hexylamine:
To a solution of 1 -ethynylcyclohexylamine ([Building block 3]) in 1 ,4-dioxane (1 M, 0.5 mL) was added a solution of catecholborane in THF (1 M, 0.5 mL) and the mixture was heated at
60 °C for 4 hours. The solution was cooled to room temperature and used directly in the
Suzuki coupling reaction.
To the resin bound 3-chloro-4-hydroxybenzoic acid (3-bromobenzylidene)hydrazide (0.05 mmoles) was added a solution of cesium carbonate in water (1.25 M, 0.2 mL), a solution of triphenylphosphine and tetrabutylammonium chloride in NMP (both 0.4 M, 0.5 mL), a solution of palladium (II) acetate in NMP (0.16 M, 0.25 mL), was mixed and the solution of 1-(2- benzo[1 ,3,2]dioxaborol-2-y!vinyl)cyclohexylamine in 1 ,4-dioxane/THF (prepared as described above) was added and the mixture was shaken at 70 °C for 15 hours. The resin was repeatedly washed with NMP (1.5 mL, 3 times), 50% water in DMF (1.5 mL, 3 times), NMP (1.5 mL, 2 times), 1% sodium diethylaminodithiocarbamate trihydrate (1.5 mL, 9 times), NMP (1.5 mL, 5 times) and CH2CI2 (1.5 mL, 6 times) for 2 minutes and filtered.
The compound was cleaved off the resin by shaking for 45 minutes at room temperature with a 50% solution of trifluoroacetic acid in CH2CI2 (1.5 mL). The mixture was filtered and the resin was extracted with CH2CI2 (0.5 mL). The combined CH2CI2 extracts were concentrated in vacuo. The residue was dissolved in a 1 :1 mixture of methanol and CH2CI2 (1 mL) and concentrated in vacuo to give the title compound.
The final product obtained was characterized by analytical RP-HPLC (retention time) and by LC-MS (molecular mass).
The RP-HPLC analysis was performed on a Waters HPLC system consisting of Waters™ 600S Controller, Waters™ 996 Photodiode Array Detector, Waters™ 717 Autosampler, Waters™ 616 Pump, Waters™ 3 mm x 150 mm 3.5 μ C-18 Symmetry column and Millenium QuickSet Control Ver. 2.15 using UV detection at 214 nm. A gradient of 5% to 90% acetoni- trile/0.1 % trifluoroacetic acid/water at 15 minutes at 1 mL/minute.
The LC-MS analysis was performed on a PE Sciex API 100 LC/MS System using a Waters™ 3 mm x 150 mm 3.5 μ C-18 Symmetry column and positive ionspray with a flow rate at 20 μUminute.
EXAMPLES 616 to 694:
A library of the following 79 compounds can be prepared in parallel as individual entities analogously to example 615 on an Advanced ChemTech Model 496 HTS using the following ChemFile to control the operation of the synthesizer. The 4 resins of type Resin-[Building block 1]-[Building block 2] are equally distributed in the 80 wells in the synthesizer prior to the initialization of device.
ChemFile C:\ACT\90250003.CHM Page 1
I Empty RB_Heating_AII_1to96 for 2.000 minute(s) 2
3 REM Addition of Cs2C03 in water 4
5 Transfer 200μl from Monomers_1 to36 [25] () to RB_Heating_AII_lto96 [1-80] using DCE
6 Mix for 1.00 minutes at 600 rpm(s) 7
8 REM Addition of Ph3P + Bu4NCI in NMP
9
10 Transfer 500μl from Monomers_1to36 [21] () to RB_Heating_AII_1to96 [1-80] using DCE
I I Mix for 1.00 minutes at 600 rpm(s) 12
13 REM Addition of Pd(OAc)2 in NMP
14
15 Transfer 500μl from Monomers_1to36 [22] () to RB_Heating_AII_1to96 [1-80] using DCE Mix for 2.00 minutes at 600 rpm(s) Dispense Sequence C:\ACT\ALKYNES.DSP with 500μl to RB_Heating_AII_1to96 rack Set Temperature to 70.0 degrees Celsius Mix for 15.00 minutes at 600 rpm(s) Wait for 15.000 minute(s) Repeat from step 19, 29 times Turn Temperature Controller Off Mix for 15.00 minutes at 600 rpm(s) Wait for 15.000 minute(s) Repeat from step 23, 7 times Empty RB_Heating_AII 1to96 for 2.000 minute(s) Dispense System Fluid NMP1 1500μl to RB_Cleavage_AII_1to96 [1-80] Mix for 3.00 minutes at 600 rpm(s) Empty RB_Heating_AII_1to96 for 2.000 minute(s) Repeat from step 27, 2 times REM Wash with 50% H2O/NMP Transfer 1500μl from Reagent _3 [1] () to RB_Heating_AII_1to96 [1-80] using NMP1 Mix for 3.00 minutes at 600 rpm(s) Empty RB_Heating_AII_1to96 for 2.000 minute(s) Repeat from step 34, 2 times Dispense System Fluid NMP1 1500μl to RB_Cleavage_AII_1to96 [1-80] Mix for 3.00 minutes at 600 rpm(s) Empty RB_Heating_AII_1to96 for 2.000 minute(s) Repeat from step 38, 1 times REM Wash with Sodium diethylaminodithiocarbamate Transfer 1500μl from Reagent_3 [1] () to RB_Heating_AII_1to96 [1-80] using NMP1 Mix for 3.00 minutes at 600 rpm(s) Empty RB_Heating_AII_1to96 for 2.000 minute(s) Repeat from step 45, 2 times Transfer 1500μl from REAGENT_4 [1] () to RB_Heating_AII_1to96 [1-80] using NMP1 Mix for 3.00 minutes at 600 rpm(s) Empty RB_Heating_AII_1to96 for 2.000 minute(s) Repeat from step 49, 2 times Transfer 1500μl from REAGENT_5 [1] () to RB_Heating_AII_1to96[ 1-80] using NMP1 Mix for 2.00 minutes at 600 rpm(s) Empty RB_Heating_AII_1 to96 for 2.000 minute(s) Repeat from step 53, 2 times Dispense System Fluid NMP1 1500μl to RB_Cleavage_AII_1to96 [1-80] Mix for 3.00 minutes at 600 rpm(s) Empty RB_Heating_AII_1to96 for 2.000 minute(s) Repeat from step 57, 4 times Dispense System Fluid DCE1 1500μl to RB_Cleavage_AII_1to96 [1-80] Mix for 3.00 minutes at 600 rpm(s) Empty RB_Heating_AII_1to96 for 2.000 minute(s) Repeat from step 61 , 5 times 65
66 REM Cleavage from Resin
67 REM with 50% TFA/DCM 68 69 Transfer 1500μl from Reagent_3 [1] () to RB_Cleavage_AII_1to96 [1-80] using DCM1
70 Mix for 45.00 minutes at 600 rpm(s)
71 Empty RB_Cleavage_AII_1to96 for 1.000 minute(s)
72 Dispense System Fluid DCM1 500μl to RB_Cleavage_AII_1to96 [1-80]
73 Mix for 1.00 minutes at 300 rpm(s) 74 Empty RB_Cleavage_AII_1to96 for 1.000 minute(s) 75
Dispense Sequence C:\ACT\ALKYNES.DSP is a subroutine that controls the combinatorial addition of the solutions of the 20 2-vinyl-benzo[1 ,3,2]dioxaboroles of type [Building block 3] into the 80 wells in the synthesizer.
The library containing the compounds listed below was synthesized. A subset of the library obtained was characterized by analytical RP-HPLC (retention time) and by LC-MS (molecular mass).
EXAMPLE 616: EXAMPLE 617:
2-Amino-5-{5-[(3-chloro-4-hydroxybenzoyl)- 3-Chloro-4-hydroxybenzoic acid [3-(3- hydrazonomethyl]-2,3-dimethoxyphenyl}-4- amino-1-propenyl)-4,5-dimethoxy- pentenoic acid benzylidenejhydrazide
Figure imgf000364_0001
EXAMPLE 618:
3-Chloro-4-hydroxybenzoic acid {3-[3- (benzylmethylamino)propenyl]-4,5- dimethoxybenzylidene}hydrazide
Figure imgf000364_0002
EXAMPLE 619: EXAMPLE 620:
3-Chloro-4-hydroxybenzoic acid [3-(3- 3-Chloro-4-hydroxybenzoic acid [3,4- diethylamino-1 -propenyl)-4,5- dimethoxy-5-(3-phenoxy-1-propenyl)- dimethoxybenzylidene]hydrazide benzylidene]hydrazide
Figure imgf000365_0001
EXAMPLE 621 : EXAMPLE 622:
3-Chloro-4-hydroxybenzoic acid [3,4- 3-Chloro-4-hydroxybenzoic acid {3,4- dimethoxy-5-(3-phenyl-1-propenyl)- dimethoxy-5-[2-(toluene-4-sulfonyl)vinyl]- benzylidene]hydrazide benzylidenejhydrazide
Figure imgf000365_0002
EXAMPLE 623: EXAMPLE 624:
3-Chloro-4-hydroxybenzoic acid {3-[2-(4- 3-Chloro-4-hydroxybenzoic acid {3-[2-(3- chlorophenyl)vinyl]-4,5- hydroxyphenyl)vinyl]-4,5-dimethoxy- dimethoxybenzylidenejhydrazide benzylidenejhydrazide
Figure imgf000366_0001
EXAMPLE 625: EXAMPLE 626:
3-Chloro-4-hydroxybenzoic acid [3,4- 3-Chloro-4-hydroxybenzoic acid [3,4- dimethoxy-5-(5-phenyl-1-pentenyl)- dimethoxy-5-(2-(2-pyridyl)vinyl)- benzylidenejhydrazide benzylidene]hydrazide
Figure imgf000366_0002
EXAMPLE 627: EXAMPLE 628:
3-Chloro-4-hydroxybenzoic acid {3,4- 3-{5-[(3-Chloro-4-hydroxybenzoyl)- dimethoxy-5-[3-(4-oxo-5-phenyl-4,5-dihydro-2- hydrazonomethyl]-2,3-dimethoxyphenyl}- oxazolylamino)-1 -propenyl]- acrylic acid benzylidene}hydrazide
Figure imgf000367_0001
EXAMPLE 629: EXAMPLE 630:
5-{5-[(3-Chloro-4-hydroxybenzoyl)- 3-Chloro-4-hydroxy benzoic acid [3-(3- hydrazonomethyl]-2,3-dimethoxyphenyl}-4- hydroxy-1-butenyl)-4,5-dimethoxy- pentenoic acid benzylidenejhydrazide
Figure imgf000367_0002
EXAMPLE 631 : EXAMPLE 632:
3-Chloro-4-hydroxybenzoic acid [3-(4- 3-Chloro-4-hydroxybenzoic acid [3-(4- hydroxy-1-butenyl)-4,5-dimethoxy- hydroxy-1-hexenyl)-4,5-dimethoxy- benzylidene]hydrazide benzylidene]hydrazide
Figure imgf000368_0001
EXAMPLE 633: EXAMPLE 634:
3-Chloro-4-hydroxybenzoic acid [3-(3- 3-Chloro-4-hydroxybenzoic acid {3-[3-(2,6- hydroxy-1-propenyl)-4,5-dimethoxy- dichlorophenoxy)-1-propenyl]-4,5- benzylidene]hydrazide dimethoxybenzylidene}hydrazide
Figure imgf000368_0002
EXAMPLE 635: EXAMPLE 636:
3-chloro-4-hydroxybenzoic acid {4-[2-(1- 2-Amino-5-{4-[(3-chloro-4-hydroxybenzoyl)- aminocyclohexyl)vinyl]-1-naphthyl- hydrazonomethyl]-1-naphthyl}-4-pentenoic methylenejhydrazide acid
Figure imgf000369_0001
EXAMPLE 637: EXAMPLE 638:
3-Chloro-4-hydroxybenzoic acid {4-[3- 3-Chloro-4-hydroxybenzoic acid [4-(3-amino- (benzylmethylamino)propenyl]-1 - 1 -propenyl)-1 -naphthylmethylenejhydrazide naphthylmethylene}hydrazide
Figure imgf000369_0002
EXAMPLE 639: EXAMPLE 640:
3-Chloro-4-hydroxybenzoic acid[4-(3- 3-Chloro-4-hydroxybenzoic acid [4-(3- diethylamino-1 -propenyl)-1 -naphthylphenoxy-1 -propenyl)-1 -naphthylmethylenejhydrazide methylenejhydrazide
Figure imgf000369_0003
EXAMPLE 641 : EXAMPLE 642:
3-Chloro-4-hydroxybenzoic acid [4-(3-phenyl- 3-Chloro-4-hydroxybenzoic acid {4-[2-
1 -propenyl)-1 -naphthylmethylene]hydrazide (toluene-4-sulfonyl)vinyl]-1 - naphthyl- methylenejhydrazide
Figure imgf000370_0001
EXAMPLE 643: EXAMPLE 644:
3-Chloro-4-hydroxybenzoic acid {4-[2-(4- 3-Chloro-4-hydroxybenzoic acid {4-[2-(3- chlorophenyl)vinyl]-1-naphthylmethylene}- hydroxyphenyl)vinyl]-1-naphthyl- hydrazide methylene}hydrazide
Figure imgf000370_0002
EXAMPLE 645: EXAMPLE 646:
3-Chloro-4-hydroxybenzoic acid [4-(5-phenyl- 3-Chloro-4-hydroxy-benzoic acid [4-(2-(2-
1 -pentenyl)-1 -naphthylmethylenejhydrazide pyridyl)vinyl)-1 -naphthylmethylenejhydrazide
Figure imgf000370_0003
EXAMPLE 647: EXAMPLE 648:
3-Chloro-4-hydroxybenzoic acid {4-[3-(4-oxo- 3-{4-[(3-Chloro-4-hydroxybenzoyl)- 5-phenyl-4,5-dihydro-(2-oxazolylamino)-1- hydrazonomethyl]-1 -naphthyljacrylic acid propenyl]-1-naphthylmethylene}hydrazide
Figure imgf000371_0001
EXAMPLE 649: EXAMPLE 650:
5-{4-[(3-Chloro-4-hydroxybenzoyl)- 3-Chloro-4-hydroxybenzoic acid [4-(3- hydrazonomethyl]-1-naphthyl}-4-pentenoic hydroxy-1 -butenyl)-1 -naphthylmethylene]- acid hydrazide
Figure imgf000371_0002
EXAMPLE 651 : EXAMPLE 652:
3-Chloro-4-hydroxybenzoic acid [4-(4- 3-Chloro-4-hydroxybenzoic acid [4-(4- hydroxy-1 -butenyl)-1 -naphthylmethylene]- hydroxy-1 -hexenyl)-1 -naphthyl- hydrazide methylene] hydrazide
Figure imgf000371_0003
EXAMPLE 653: EXAMPLE 654:
3-Chloro-4-hydroxybenzoic acid [4-(3- 3-Chloro-4-hydroxybenzoic acid {4-[3-(2,6- hydroxy-1 -propenyl)-1 - dichlorophenoxy)-1 -propenyl]-1 - naphthylmethylene]hydrazide naphthylmethylenejhydrazide
Figure imgf000372_0001
EXAMPLE 655: EXAMPLE 656:
3-Chloro-4-hydroxybenzoic acid {3-[2-(1- 2-Amino-5-{3-[(3-chloro-4-hydroxy- aminocyclohexyl)vinyl]benzylidene}hydrazide benzoyl)hydrazonomethyl]phenyl}-4- pentenoic acid
Figure imgf000372_0002
EXAMPLE 657: EXAMPLE 658:
3-Chloro-4-hydroxybenzoic acid {3-[3- 3-Chloro-4-hydroxybenzoic acid [3-(3-amino- (benzylmethylamino)-l-propenyl]- 1-propenyl)benzylidene]hydrazide benzylidenejhydrazide
Figure imgf000373_0001
EXAMPLE 659: EXAMPLE 660:
3-Chloro-4-hydroxybenzoic acid [3-(3- 3-Chloro-4-hydroxybenzoic acid [3-(3- diethylamino-1-propenyl)benzylidene]- phenoxy-1-propenyl)benzylidene]hydrazide hydrazide
Figure imgf000373_0002
EXAMPLE 661 : EXAMPLE 662:
3-Chloro-4-hydroxybenzoic acid [3-(3-phenyl- 3-Chloro-4-hydroxybenzoic acid {3-[2- 1-propenyl)benzylidene]hydrazide (toluene-4-sulfonyl)vinyl]benzylidene}- hydrazide
Figure imgf000374_0001
EXAMPLE 663: EXAMPLE 664:
3-Chloro-4-hydroxybenzoic acid {3-[2-(4- 3-Chloro-4-hydroxybenzoic acid {3-[2-(3- chlorophenyl)vinyl]benzylidene}hydrazide hydroxyphenyl)vinyl]benzylidene}hydrazide
Figure imgf000374_0002
EXAMPLE 665: EXAMPLE 666:
3-Chloro-4-hydroxybenzoic acid [3-(5-phenyl- 3-Chloro-4-hydroxybenzoic acid [3-(2-(2- 1-pentenyl)benzylidene]hydrazide pyridyl)vinyl)benzylidene]hydrazide
Figure imgf000375_0001
EXAMPLE 667: EXAMPLE 668:
3-Chloro-4-hydroxybenzoic acid {3-[3-(4-oxo- 3-{3-[(3-Chloro-4-hydroxybenzoyl)- 5-phenyl-4,5-dihydro-(2-oxazoiylamino))-1- hydrazonomethyl]phenyl}acrylic acid propenyl]benzylidene}hydrazide
Figure imgf000375_0002
EXAMPLE 669: EXAMPLE 670:
5-{3-[(3-Chloro-4-hydroxybenzoyl)- 3-Chloro-4-hydroxybenzoic acid [3-(3- hydrazonomethyl]phenyl}-4-pentenoic acid hydroxy-1-butenyl)benzylidene]hydrazide
Figure imgf000376_0001
EXAMPLE 671 : EXAMPLE 672:
3-Chloro-4-hydroxybenzoic acid [3-(4- 3-Chloro-4-hydroxybenzoic acid [3-(4- hydroxy-1-butenyl)benzylidene]hydrazide hydroxy-1-hexenyl)benzylidene]hydrazide
Figure imgf000376_0002
EXAMPLE 673: EXAMPLE 674:
3-Chloro-4-hydroxy benzoic acid [3-(3- 3-Chloro-4-hydroxybenzoic acid {3-[3-(2,6- hydroxy-1-propenyl)benzylidene]hydrazide dichlorophenoxy)-1 -propenyl]- benzylidene}hydrazide
Figure imgf000377_0001
EXAMPLE 675: EXAMPLE 676:
3-Chloro-4-hydroxybenzoic acid {4-[2-(1- 2-Amino-5-{4-[(3-chloro-4-hydroxybenzoyl)- aminocyclohexyl)vinyl]benzylidene}hydrazide hydrazonomethyl]phenyl}-4-pentenoic acid
Figure imgf000377_0002
EXAMPLE 677: EXAMPLE 678:
3-Chloro-4-hydroxybenzoic acid {4-[3-( ben- 3-Chloro-4-hydroxybenzoic acid [4-(3-amino- zylmethylamino)-1 -propenyl]- 1-propenyl)benzylidene]hydrazide benzylidenejhydrazide
Figure imgf000377_0003
EXAMPLE 679: EXAMPLE 680:
3-Chloro-4-hydroxybenzoic acid [4-(3- 3-Chloro-4-hydroxybenzoic acid [4-(3- diethylaminopropenyl)benzylidene]hydrazide phenoxy-1-propenyl]benzylidene]hydrazide
Figure imgf000378_0001
EXAMPLE 681 : EXAMPLE 682:
3-Chloro-4-hydroxybenzoic acid [4-(3-phenyl- 3-Chloro-4-hydroxybenzoic acid {4-[2-
1-propenyl)benzylidene]hydrazide (toluene-4-sulfonyl)vinyl]benzylidene}- hydrazide
Figure imgf000378_0002
EXAMPLE 683: EXAMPLE 684:
3-Chioro-4-hydroxybenzoic acid {4-[2-(4- 3-Chloro-4-hydroxybenzoic acid {4-[2-(3- chlorophenyl)vinyl]benzylidene}hydrazide hydroxyphenyl)vinyl]benzylidene}hydrazide
Figure imgf000378_0003
EXAMPLE 685: EXAMPLE 686:
3-Chloro-4-hydroxybenzoic acid [4-(5-phenyl- 3-Chloro-4-hydroxybenzoic acid {4-[2-(2- 1-pentenyl)benzylidene]hydrazide pyridinyl)vinyl]benzylidene}hydrazide
Figure imgf000379_0001
EXAMPLE 687: EXAMPLE 688:
3-Chloro-4-hydroxybenzoic acid {4-[3-(4-oxo- {4-[(3-Chloro-4-hydroxybenzoyl)- 5-phenyl-4,5-dihydro-(2-oxazolylamino)-1- hydrazonomethyl]phenyl}acryiic acid propenyl]benzylidene}hydrazide
Figure imgf000379_0002
EXAMPLE 689: EXAMPLE 690:
5-{4-[(3-Chloro-4-hydroxybenzoyl)- 3-Chloro-4-hydroxybenzoic acid [4-(4- hydrazonomethyl]phenyl}-4-pentenoic acid hydroxy-1-hexenyl)benzylidene]hydrazide
Figure imgf000379_0003
EXAMPLE 691 : EXAMPLE 692:
3-Chloro-4-hydroxybenzoic acid [4-(4- 3-Chloro-4-hydroxybenzoic acid [4-(3- hydroxy-1-butenyl)benzylidene]hydrazide hydroxy-1-propenyl)benzylidene]hydrazide
Figure imgf000380_0001
EXAMPLE 693: EXAMPLE 694:
3-Chloro-4-hydroxybenzoic acid [4-(3- 3-Chloro-4-hydroxybenzoic acid {4-[3-(2,6- hydroxy-1-butenyl)benzylidene]hydrazide dichlorophenoxy)-1 -propenyl]- benzylidene}hydrazide
Figure imgf000380_0002
General Procedure for Examples 695 to 701 :
The compounds were prepared as single entities according to the following equation
Resin [Building block 1] *-
Resin [Building block 1] [Building block 2] *-
Resin [Building block 1] [Building block 2] [Building block 3]
and were simultaneously deprotected and cleaved from the resin with 50% trifluoroacetic acid in dichloromethane to give the desired compounds as individual entities according to the following formula
[Building block 1] [Building block 2] [Building block 3].
The following compounds were prepared as single entities by parallel synthesis on a solid support. Preparation of Resin-[Building block 1] was done manually, whereas the attachment of [Building block 2] and [Building block 3] and cleavage from the resin were performed on an Advanced ChemTech Model 384 HTS.
The starting resin, Resin-[Building block 1], was prepared as described above.
The resin used was a polystyrene resin with a Wang linker and the substitution capacity was 0.9 mmol/g.
All compounds are based on successive attachment of [Building block 2] and [Building block 3] to Resin-[Building block 1] in a combinatorial way using a nucleophilic substitution reaction according to the following formulae, which are included in the general formula II:
Figure imgf000382_0001
Resin-[Building block 1] [Building block 2]
Resin-[Building block 1]-[Building block 2]
Figure imgf000382_0002
[Building block 3]
Figure imgf000382_0003
[Building block 1]-[Building block 2]-[Building block 3] Resin-[Building block 1]-[Building block 2]-[Building block 3] and
Figure imgf000382_0004
Resin-[Building block 1] [Building block 2]
Resin-[Building block 1]-[Building block 2]
Figure imgf000382_0005
[Building block 1]-[Building block 2]-[Building block 3] Resin-[Building block 1]-[Building block 2]-[Building block 3]
wherein R14, R15 are as defined for formula I and -NR5cR5d is
Figure imgf000382_0006
where R5a, R4a, R4b, c, q, d, and D are as defined for formula I or -D' where -D' is defined as a subset of -D that contains a primary or secondary amine that can react as a nucleophile.
The following resin, here depicted as Resin-[Building block 1] was used:
where PS is polystyrene. In the following "Resin" is the polystyrene resin with the Wang linker:
Figure imgf000383_0001
= Resin
Figure imgf000383_0002
The following building blocks were used:
[Building block 2]:
Figure imgf000384_0001
Figure imgf000385_0001
[Building block 3]:
Figure imgf000386_0001
Figure imgf000387_0001
Figure imgf000388_0001
Preparation of resin-[Building block 1]:
This resin was prepared as described above.
Preparation of [Building block 2]:
Preparation of 4-(2-bromoethoxy)-2-methoxybenzaldehyde:
1 ,2-Dibromoethane (57 mL, 0.66 moles) was added to a mixture of 4-hydroxy-2- methoxybenzaldehyde (10 g, 66 mmoles) and potassium carbonate (45 g, 0.33 moles) in DMF (130 ml) and the resulting mixture was stirred vigorously at room temperature for 16 hours. The mixture was poured into water (0.8 L) and extracted with ethyl acetate (3 x 300 mL). The combined organic phases were washed with saturated sodium chloride (400 mL), dried over MgSO4 and evaporated in vacuo to afford 17.4 g (99%) of 4-(2-bromoethoxy)-2- methoxybenzaldehyde, M.p. 78 - 79 °C.
Preparation of 4-(2-bromoethoxy)-3-methoxybenzaldehyde:
1 ,2-Dibromoethane (57 mL, 0.66 moles) was added to a mixture of 4-hydroxy-3- methoxybenzaldehyde (10 g, 66 mmoles) and potassium carbonate (45 g, 0.33 moles) in DMF (130 ml) and the resulting mixture was stirred vigorously at room temperature for 16 hours. The mixture was poured into water (1.2 L) and extracted with ethyl acetate (500 + 4 x 300 mL). The combined organic phases were washed with saturated sodium chloride (500 mL), dried over MgSO4 and evaporated in vacuo to afford 16.3 g (95%) of 4-(2- bromoethoxy)-3-methoxybenzaldehyde. M.p. 61 - 64 °C.
Preparation of 4-(2-bromoethoxy)-3-chloro-5-methoxybenzaldehyde:
1 ,2-Dibromoethane (46 mL, 0.54 moles) was added to a mixture of 3-chloro-4-hydroxy-5- methoxybenzaldehyde (10 g, 54 mmoles) and potassium carbonate (37 g, 0.27 moles) in DMF (180 ml) and the resulting mixture was stirred vigorously at room temperature for 16 hours. The mixture was poured into water (100 mL) and extracted with ethyl acetate (2 x 100 mL). The combined organic phases were washed with saturated sodium chloride (150 mL), dried over MgSO4 and evaporated in vacuo to afford 9.33 g (59%) of 4-(2-bromoethoxy)-3- chloro-5-methoxybenzaldehyde. M.p. 52 - 54 °C.
Preparation of 4-(2-bromoethoxy)-3,5-dimethylbenzaldehyde:
1 ,2-Dibromoethane (26 mL, 0.3 moles) was added to a mixture of 3,5-dimethyl-4- hydroxybenzaldehyde (4.57 g, 30 mmoles) and potassium carbonate (21 g, 150 mmoles) in DMF (90 ml) and the resulting mixture was stirred vigorously at room temperature for 16 hours. The mixture was poured into water (0.3 L), added saturated sodium chloride (200 mL) and extracted with ethyl acetate (2 x 200 mL). The combined organic phases were washed with saturated sodium chloride (300 mL), dried over MgSO4 and evaporated in vacuo to afford 8.2 g (95%) of 4-(2-bromoethoxy)-3,5-dimethylbenzaldehyde as an oil.
Η-NMR (300 MHz, CDCI3): δ = 2.33 (6H, s), 3.83 (2H, t), 4.18 (2H, t), 7.60 (2H, s), 9.88 (1 H, s).
Preparation of 4-(2-bromoethoxy)-3,5-dibromobenzaldehyde:
1 ,2-Dibromoethane (62 mL, 0.72 moles) was added to a mixture of 3,5-dibromo-4- hydroxybenzaldehyde (10 g, 36 mmoles) and potassium carbonate (25 g, 180 mmoles) in DMF (100 ml) and the resulting mixture was stirred vigorously at 70 °C for 16 hours. After cooling, the mixture was poured into water (300 mL) and extracted with ethyl acetate (400 mL). Water (200 mL) was added to the aqueous phase and this was extracted with ethyl acetate (150 mL). The combined organic phases were washed with saturated sodium chlo- ride (3 x 150 mL), dried over MgSO4 and evaporated in vacuo. The residue was dissolved in refluxing 96% ethanol (60 mL). Water (15 mL) was added and after cooling, filtration, washing with 60% ethanol and drying 10.7 g (77%) of 4-(2-bromoethoxy)-3,5- dibromobenzaldehyde was isolated in two crops. M.p. 84 - 85 °C.
Preparation of 4-(2-bromoethoxy)-3-methoxy-5-phenylbenzaldehyde:
A mixture of 4-hydroxy-3-iodo-5-methoxybenzaldehyde (20 g, 72 mmoles), ethylene glycol (8.0 mL, 144 mmoles), and chlorotrimethylsilane 36.5 mL, 0.29 moles) in dichloromethane (300 mL) was heated at reflux for 16 hours. The mixture was cooled to room temperature and washed with saturated sodium hydrogencarbonate (3 x 200 mL). The combined aqueous phases were extracted with dichloromethane (3 x 150 mL). The combined organic extracts were washed with saturated sodium chloride (200 mL), dried over MgSO4 and evaporated in vacuo to afford 22.1 g (95%) of 4-[1 ,3]dioxolan-2-yl-2-iodo-6-methoxy-phenol. M.p. 120 - 121 °C.
Under N2, tetrakis-triphenylphosphinepalladium(O) was added to a mixture of the above dioxolane (10 g, 31 mmoles), benzeneboronic acid (4.5 g, 37 mmoles), toluene (67 mL), 2 M aqueous sodium carbonate (33 mL) and methanol (20 mL). The resulting mixture was heated at reflux under N2 for 16 hours. After cooling the mixture was diluted with water (150 mL) and washed with heptane (400 mL) . The aqueous phase was made acidic with 3N hydrochloric acid and extracted with ethyl acetate (3 x 300 mL). The combined organic extracts were dried over MgSO4 and evaporated in vacuo. The residue was purified by column chro- matography over silica gel (800 mL) eluting with a mixture of ethyl acetate and heptane (1 :2) to afford 5.49 g (77%) of 4-hydroxy-3-methoxy-5-phenylbenzaldehyde. M.p. 107 - 108 °C.
1 ,2-Dibromoethane (41 mL, 0.48 moles) was added to a mixture of the above 4-hydroxy-3- methoxy-5-phenylbenzaldehyde (5.49 g, 24 mmoles) and potassium carbonate (17 g, 123 mmoles) in DMF (80 ml) and the resulting mixture was stirred vigorously at room temperature for 16 hours. The mixture was poured into water (1 L) and extracted with ethyl acetate (3 x 300 mL). The combined organic phases were washed with saturated sodium chloride (200 mL), dried over MgSO4 and evaporated in vacuo to afford 8.1 g (100%) of 4-(2- bromoethoxy)-3-methoxy-5-phenylbenzaldehyde as an oil.
1H-NMR (300 MHz, DMSO-d6): δ = 3.50 (2H, t), 3.96 (3H, s), 4.19 (2H, t), 7.4-7.6 (11 H, m).
Preparation of 4-(2-bromoethoxy)-1 -naphthaldehyde:
1 ,2-Dibromoethane (30 mL, 0.35 moles) was added to a mixture of 4-hydroxy-1- naphthaldehyde (6 g, 35 mmoles) and potassium carbonate (24 g, 175 mmoles) in DMF (110 ml) and the resulting mixture was stirred vigorously at room temperature for 16 hours. The mixture was poured into water (0.5 L) and extracted with ethyl acetate (3 x 300 mL). The combined organic phases were washed with saturated sodium chloride (300 mL), dried over MgSO4 and evaporated in vacuo. The residue was purified by column chromatography on silica gel (800 mL) eluting with a mixture of ethyl acetate and heptane (1 :1) to afford 8.5 g (88%) of 4-(2-bromoethoxy)-1 -naphthaldehyde as a solid. M.p.: 83 - 84 °C.
Calculated for C^H^BrO;,: C, 55.94%; H, 3.97%. Found: C, 56.10%; H, 3.98%; C, 56.30%; H, 3.97%.
Preparation of 4-(2-bromoethoxy)-3,5-dimethoxybenzaldehyde: 1 ,2-Dibromoethane (47 mL, 0.55 moles) was added to a mixture of syringaldehyde (10 g, 55 mmoles) and potassium carbonate (38 g, 275 mmoles) in DMF (150 ml) and the resulting mixture was stirred vigorously at room temperature for 16 hours. The mixture was poured into water (0.5 L) and extracted with ethyl acetate (3 x 300 mL). The combined organic phases were washed with saturated sodium chloride (500 mL), dried over MgSO4 and evaporated in vacuo to afford 3.44 g (22%) of 4-(2-bromoethoxy)-3,5- dimethoxybenzaldehyde.
1H-NMR (300 MHz, DMSO-d6): δ = 3.70 (2H, t), 3.88 (3H, s), 4.27 (2H, t), 7.27 (2H, s).
Preparation of 3-(2-bromoethoxy)-4-methoxybenzaldehyde:
1 ,2-Dibromoethane (56 mL, 0.66 moles) was added to a mixture of 3-hydroxy-4- methoxybenzaldehyde (10 g, 66 mmoles) and potassium carbonate (45 g, 328 mmoles) in DMF (170 ml) and the resulting mixture was stirred vigorously at room temperature for 16 hours. The mixture was poured into water (0.5 L) and extracted with ethyl acetate (3 x 200 mL). The combined organic phases were washed with saturated sodium chloride (500 mL), dried over MgSO4 and evaporated in vacuo. The residue was purified by column chromatography on silica gel (800 mL) eluting with a mixture of ethyl acetate and heptane (1 :1 ) to af- ford 9.8 g (58%) of 3-(2-bromoethoxy)-4-methoxybenzaldehyde.
1H-NMR (300 MHz, DMSO-d6): δ = 3.82 (2H, t), 3.90 (3H, s), 4.40 (2H, t), 7.22 (1 H, d), 7.44 (1 H, d), 7.59 (1H, dd).
Preparation of 4-(2-bromoethoxy)-3-bromo-5-methoxybenzaldehyde:
1 ,2-Dibromoethane (37 mL, 0.43 moles) was added to a mixture of 5-bromovanillin (10 g, 43 mmoles) and potassium carbonate (30 g, 216 mmoles) in DMF (150 ml) and the resulting mixture was stirred vigorously at room temperature for 16 hours followed by vigorously stir- ring at 60 °C for 16 hours. The cooled mixture was poured into water (1 L) and extracted with ethyl acetate (3 x 250 mL). The combined organic phases were washed with saturated sodium chloride (300 mL), dried over MgSO4 and evaporated in vacuo to afford 13.7 g (94%) of 4-(2-bromoethoxy)-3-bromo-5-methoxybenzaldehyde. Η-NMR (300 MHz, DMSO-d6): δ = 3.79 (2H, t), 3.93 (3H, s), 4.40 (2H, t), 7.55 (1 H, d), 7.79 (1 H, d).
EXAMPLE 695:
Preparation of 3-Chloro-4-hydroxybenzoic acid {4-[2-(1.2.3.4-tetrahydroisoquinolin-2- yπethoxy]-2-methoxybenzylidene}hydrazide
Figure imgf000393_0001
The resin bound 3-chloro-4-hydroxybenzoic acid hydrazide (resin-[building blockl]) (3 g, ~3 mmoles) was swelled in DMF (35 mL) for 30 minutes. Then 4-(2-bromoethoxy)-2- methoxybenzaldehyde (2.33 g, 9 mmoles) and triethyl orthoformate (18 mL) were added and the mixture was shaken at room temperature for 16 hours. The resin was repeatedly swelled in DMF (35 ml, 4 times), CH2CI2 (35 mL, 6 times) and N-methyl-2-pyrrolidinone (NMP) (35 mL, 2 times) and filtered. The resin was swelled in NMP (40 mL) and 1 ,2,3,4- tetrahydroisoquinoline (3.75 mL, 30 mmoles) and potassium iodide (1.0 g, 6 mmoles) were added. The resin was shaken at room temperature for 16 hours and filtered. The resin was repeatedly swelled in DMF (40 ml, 5 times), CH2CI2 (40 mL, 10 times) and filtered. The com- pound was cleaved off the resin by shaking for 1 hour at room temperature with a 50% solution of trifluoroacetic acid in CH2CI2 (40 mL). The mixture was filtered and the resin was extracted with CH2CI2 (40 mL, 2 times). The combined CH2CI2 extracts were concentrated in vacuo. The residue was dissolved in CH2CI2 (40 mL) and concentrated in vacuo. The residue was dissolved in methanol (40 mL) and concentrated in vacuo. The residue was partitioned between ethyl acetate (50 mL) and saturated sodium hydrogencarbonate (50 mL). The aqueous phase was extracted with ethyl acetate (50 mL), and the combined organic extracts were dried over MgSO4 and concentrated in vacuo. The residue was purified by coloumn chromatography over silica gel (200 mL) eluting with a mixture of CH2CI2and methanol (9:1). This afforded 280 mg of the title compound. HPLC-MS (METHOD A): Rt = 8.44 min; m/z = 480 (M+1).
1H-NMR (300 MHz, DMSO-d6) δ = 2.80 (4H, m), 2.90 (2H, t), 3.69 (2H, s), 3.86 (3H, s), 4.25 (2H, t), 6.68 (2H, m), 7.04 (1H, d), 7.07-7.14 (5H, m), 7.75 (1H, dd), 7.80 (1 H, bs), 7.96 (1 H, d), 8.58 (1 H. s), 11.6 (1 H, s).
HR-MS: Calcd. for C26H26CIN3O4: 479.1611 ; Found: 479.1604.
EXAMPLE 696:
3-Chloro-4-hydroxybenzoic acid {2-methoxy-4-[2-(4-trifluoromethylbenzylaminotethoxy]- benzylidene}hydrazide
CH,
Figure imgf000394_0001
This compound was prepared analogously to the compound described in the previous example starting from resin bound 3-chloro-4-hydroxybenzoic acid hydrazide (resin-[building block 1]) (2 g, ~2 mmoles), 4-(2-bromoethoxy)-2-methoxybenzaldehyde ([building block 2]) (0.73 g, 1.5 equivs.), and 4-trifluoromethylbenzylamine ([building block 3]) (3.3 g, 10 equivs.). After cleavage with 50% trifluoroacetic acid, the residue (1 g) was purified by column chromatography on silica gel (20 g) eluting with a mixture of 25% aq. ammonia, ethanol and dichloromethane (1 :9:115). This afforded 130 mg of the title compound.
HPLC-MS (METHOD A): Rt = 9.4 min; m/z = 522 (M+1).
EXAMPLE 697:
3-Chloro-4-hydroxybenzoic acid {4-[2-( -benzylpiperazin-1 -yl)ethoxy]-2- methoxybenzylidene}hydrazide
Figure imgf000395_0001
This compound was prepared analogously to the compound described in the previous example starting from resin bound 3-chloro-4-hydroxybenzoic acid hydrazide (resin-[building block 1]) (2 g, ~2 mmoles), 4-(2-bromoethoxy)-2-methoxybenzaldehyde ([building block 2]) (0.73 g, 1.5 equivs.), and 1 -benzylpiperazine ([building block 3]) (3.3 g, 10 equivs.). After cleavage with 50% trifluoroacetic acid, the residue (1.4 g) was dissolved in 2-propanol (50 ml) and concentrated to 20 ml. The mixture was allowed to stand at 5 °C for 1 h and filtered. The mother liquor was concentrated in vacuo and the residue was purified by column chro- matography on silica gel (20 g) eluting with a mixture of methanol and dichloromethane (1 :9). This afforded 0.98 g of the title compound.
1H-NMR (400 MHz, DMSO-d6): δH = 2.4 (2H, bs), 2.55 (2H, bs), 2.62 (2H, bs), 3.50 (2H, bs), 3.85 (3H, s), 4.15 (2H, t), 6.62 (2H, m), 7.05 (1 H, d), 7.30 (5H, m), 7.75 (2H, t), 7.97 (1 H, s), 8.67 (1 H, s), 11 (1 H, bs), 11.5 (1 H, s).
HPLC-MS (METHOD A): Rt = 7.7 min; m/z = 523 (M+1).
EXAMPLE 698: 3-Chloro-4-hydroxybenzoic acid {2-methoxy-4-[2-(2-phenylpiperidin-1 - vBethoxy]benzylidene}hydrazide
Figure imgf000395_0002
This compound was prepared analogously to the compound described in the previous example starting from resin bound 3-chloro-4-hydroxybenzoic acid hydrazide (resin-[building block 1]) (2 g, ~2 mmoles), 4-(2-bromoethoxy)-2-methoxybenzaldehyde ([building block 2]) (0.73 g, 1.5 equivs.), and 2-phenylpiperidine ([building block 3]) (3.0 g, 10 equivs.). After cleavage with 50% trifluoroacetic acid, the residue (1.0 g) was purified by column chromatography on silica gel (28 g) eluting with a mixture of methanol and dichloromethane (1 :13). This afforded 0.24 g of the title compound.
1H-NMR (400 MHz, DMSO-d6): δH = 1.4 (2H, m), 1.65 (4H, m), 2.25 (2H, m), 2.75 (1 H, m), 3.16 (1 H, d), 3.25 (2H, d), 3.83 (3H, s), 4.0 (2H, m), 6.50 (1 H, d), 6.54 (1 H, s), 7.07 (1 H, d), 7.23 (1 H, t), 7.35 (4H, m), 7.73 (1 H, d), 7.77 (1 H, dd), 7.96 (1H, d), 8.65 (1H, s), 10.9 (1H, s), 11.6 (1 H, s).
HPLC-MS (METHOD A): Rt = 9.1 min; m/z = 508 (M+1).
EXAMPLE 699:
3-Chloro-4-hydroxybenzoic acid {3-chloro-4-[2-f 1.2.3.4-t.etrahvdro-isoquinolin-2-y0ethoxy]-5- methoxybenzylidene}hydrazide
Figure imgf000396_0001
This compound was prepared analogously to the compound described in the previous example starting from resin bound 3-chloro-4-hydroxybenzoic acid hydrazide (resin-[building block 1]) (2 g, ~2 mmoles), 4-(2-bromoethoxy)-3-chloro-5-methoxybenzaldehyde ([building block 2]) (0.81 g, 1.5 equivs.), and 1 ,2,3,4-tetrahydroisoquinoline ([building block 3]) (2.5 g, 10 equivs.). After cleavage with 50% trifluoroacetic acid, the residue (1.0 g) was dissolved in 15 ml of a mixture of 25% aq. ammonia, methanol and dichloromethane (1 :9:90) and purified by column chromatography on silica gel (25 g) eluting with a mixture of methanol and dichloromethane (1 :12). This afforded 0.11 g of the title compound. H-NMR (400 MHz, DMSO-d6): δH = 1.9 (1 H, p), 2.18 (1 H, t), 2.90 (2H, t), 3.70 (2H, s), 3.90 (3H, s), 4.19 (2H, t), 7.05 (5H, m), 7.37 (2H, s), 7.78 (1 H, d), 7.95 (1 H, s), 8.33 (1 H, s), 11 (1 H, bs), 11.8 (1 H, s).
HPLC-MS (METHOD A): Rt = 9.0 min; m/z = 514 (M+1 ).
EXAMPLE 700:
3-Chloro-4-hydroxybenzoic acid {6-[2-(1.2.3.4-tetrahydro-isoquinolin-2-yπethoxy]-5- methoxybiphenyl-3-ylmethylene}hydrazide
Figure imgf000397_0001
This compound was prepared analogously to the compound described in the previous ex- ample starting from resin bound 3-chloro-4-hydroxybenzoic acid hydrazide (resin-[building block 1]) (2 g, ~2 mmoles), 4-(2-bromoethoxy)-3-methoxy-5-phenylbenzaldehyde ([building block 2]) (0.93 g, 1.5 equivs.), and 1 ,2,3,4-tetrahydroisoquinoline ([building block 3]) (2.5 g, 10 equivs.). After cleavage with 50% trifluoroacetic acid, the residue was dissolved in 15 ml of a mixture of 25% aq. ammonia, methanol and dichloromethane (1 :9:90) and purified by column chromatography on silica gel (25 g) eluting with a mixture of methanol and dichloromethane (1 :12). This afforded 0.31 g of the title compound.
1H-NMR (400 MHz, DMSO-d6): δH = 2.60 (4H, m), 2.70 (2H, m), 3.48 (2H, s), 3.92 (3H, s), 3.96 (2H, t), 6.98 (1 H, m), 7.10 (4H, m), 7.22 (1 H, s), 7.40 (4H, m), 7.55 (2H, d), 7.78 (1 H, d), 8.00 (1 H, s), 8.40 (1 H, s), 11 (1 H, bs), 11.7 (1 H, s).
HPLC-MS (METHOD A): Rt = 9.6 min; m/z = 557 (M+1 ).
EXAMPLE 701 : 3-Chloro-4-hydroxybenzoic acid (3.5-dibromo-4-{2-[4-(4-chloropheriyl)piperazin-1 -yl]- ethoxy}benzylidene)hydrazide
Figure imgf000398_0001
A solution of 4-(2-bromoethoxy)-3,5-dibromobenzaldehyde ([building block 2]) in DMF (0.6 M, 1 mL) was added to the resin bound 3-chloro-4-hydroxybenzoic acid hydrazide (resin- [building block 1]) (0.05 mmoles) followed by addition of triethyl orthoformate (0.5 mL) and the mixture was shaken at room temperature for 15 hours. The resin was repeatedly swelled in DMF (1.5 mL, 3 times), CH2CI2 (1.5 mL, 2 times) and NMP (1.5 mL, 2 times) for 5 minutes and filtered. The resulting resin (resin-[building block 1]-[building block 2]) was added a solution of 1-(4-chlorophenyl)piperazine (0.4 M, 1 mL) and a solution of potassium iodide in NMP (0.08 M, 0.5 mL) were added and the mixture was shaken at room temperature for 16 hours. The resin was repeatedly swelled in DMF (1.5 mL, 3 times) and CH2CI2 (1.5 mL, 6 times) for 2 minutes and filtered.
The compound was cleaved off the resin by shaking for 1 hour at room temperature with a 50% solution of trifluoroacetic acid in CH2CI2 (1.5 mL). The mixture was filtered and the resin was extracted with CH2CI2 (0.5 mL). The combined CH2CI2 extracts were concentrated in vacuo. The residue was dissolved in methanol (1 mL) and concentrated in vacuo. The resi- due was dissolved in a 1 :1 mixture of methanol and CH2CI2 (1 mL) and concentrated in vacuo to give the title compound.
HPLC-MS (METHOD B): R, = 15.02 min; m/z = 671.
EXAMPLES 702 TO 791 :
The following 90 compounds were prepared in parallel as individual entities analogously to the previous example on an Advanced ChemTech Model 384 HTS using the following ChemFile to control the operation of the synthesizer. Further, a library of compounds of all the possible combinations of the above listed building blocks ([building block 1], [building block 2] and [building block 3]) was prepared in parallel as individual entities analogously to the previous example on an Advanced ChemTech Model 384 HTS using the following ChemFile to control the operation of the synthesizer. The compounds are all expected to be present in the respective wells.
The resin bound 3-chloro-4-hydroxybenzoic acid hydrazide (resin-[building block 1]) is equally distributed in the wells in the synthesizer prior to the initialization of the device.
ChemFile C:\ACT 1328\90250012.CHM:
1 REM Filtration of resin
2 Empty RB1_1to96 for 5.000 minute(s) 3 Empty RB2_1 to96 for 5.000 minute(s)
4 Empty RB3_ to96 for 5.000 minute(s)
5 Empty RB4_1to96 for 5.000 minute(s)
6 Pause 7 8 REM Washing of resin 9
10 Dispense System Fluid Disdu1_4* 1500ul to RB1_1to96[1-96]
11 Dispense System Fluid Disdu1_4* 1500ul to RB2_1to96[1-96]
12 Dispense System Fluid Disdu1_4* 1500ul to RB3_1to96[1-96] 13 Dispense System Fluid Disdu1_4* 1500ul to RB4_1to96[1-96]
14 Start mixing "RB1_1to96" for 5.00 minutes at 600 rpm(s) and continue.
15 Start mixing "RB2_1to96" for 5.00 minutes at 600 rpm(s) and continue.
16 Start mixing "RB3_1to96" for 5.00 minutes at 600 rpm(s) and continue. 17 Mix "RB4_1to96" for 5.00 minutes at 600 rpm(s) and wait. 18 Wait for 25.000 minute(s)
19 Repeat from step 14, 1000 times
20 Empty RB1_1to96 for 5.000 minute(s)
21 Empty RB2_1to96 for 5.000 minute(s)
22 Empty RB3_1to96 for 5.000 minute(s) 23 Empty RB4_1to96 for 5.000 minute(s)
24 Pause 25
26 REM Coupling with aldehydes 27 28 Dispense System Fluid Disdu2_3* 1500ul to RB1_1to96[1-96]
29 Dispense System Fluid Disdu2_3* 1500ul to RB2_1to96[1-96]
30 Dispense System Fluid Disdu2_3* 1500ul to RB3_1to96[1-96]
31 Dispense System Fluid Disdu2_3* 1500ul to RB4_1to96[1-96] Start mixing "RB1_1to96" for 5.00 minutes at 600 rpm(s) and continue. Start mixing "RB2_1to96" for 5.00 minutes at 600 rpm(s) and continue. Start mixing "RB3_1to96" for 5.00 minutes at 600 rpm(s) and continue. Mix "RB4_1to96" for 5.00 minutes at 600 rpm(s) and wait. Empty RB1_1to96 for 5.000 minute(s) Empty RB2_1to96 for 5.000 minute(s) Empty RB3_1to96 for 5.000 minute(s) Empty RB4_1to96 for 5.000 minute(s) Pause Dispense Sequence c:\ACT13_28\R2-A.DSP with 1000ul to RB1_1to96 rack using DMF Mix "RB1_1to96" for 2.00 minutes at 600 rpm(s) and wait. Dispense Sequence c:\ACT13_28\R2-B.DSP with 1000ul to RB2_1to96 rack using DMF Start mixing "RB1_1to96" for 2.00 minutes at 600 rpm(s) and continue. Mix "RB2_1to96" for 2.00 minutes at 600 rpm(s) and wait. Dispense Sequence c:\ACT13_28\R2-C.DSP with 1000ul to RB3_1to96 rack using DMF Start mixing "RB1_1to96" for 2.00 minutes at 600 rpm(s) and continue. Start mixing "RB2_1to96" for 2.00 minutes at 600 rpm(s) and continue. Mix "RB3_1to96" for 2.00 minutes at 600 rpm(s) and wait. Dispense Sequence c:\ACT13_28\R2-D.DSP with 1000ul to RB4_1to96 rack using DMF Start mixing "RB1_1to96" for 2.00 minutes at 600 rpm(s) and continue. Start mixing "RB2_1to96" for 2.00 minutes at 600 rpm(s) and continue. Start mixing "RB3_1to96" for 2.00 minutes at 600 rpm(s) and continue. Mix "RB4_1to96" for 2.00 minutes at 600 rpm(s) and wait. Pause REM Manual addition of CH(OC2H5)3 Start mixing "RB1_1to96" for 5.00 minutes at 600 rpm(s) and continue. Start mixing "RB2_1to96" for 5.00 minutes at 600 rpm(s) and continue. Start mixing "RB3_1to96" for 5.00 minutes at 600 rpm(s) and continue. Mix "RB4_1to96" for 5.00 minutes at 600 rpm(s) and wait. Wait for 25.000 minute(s) Repeat from step 59, 200 times Empty RB1_1to96 for 5.000 minute(s) Empty RB2_1to96 for 5.000 minute(s) Empty RB3_1to96 for 5.000 minute(s) Empty RB4_1to96 for 5.000 minute(s) Pause REM Wash after coupling with aldehydes Flush Arm1 with Flush Diluterl and Flush Diluter 2 , Arm2 with Flush Diluter Dispense System Fluid Disdu2_3* 1500ul to RB1_1to96[1-96] Dispense System Fluid Disdu2_3* 1500ul to RB2_1to96[1-96] Dispense System Fluid Disdu2_3* 1500ul to RB3_1 to96[1 -96] Dispense System Fluid Disdu2_3* 1500ul to RB4_1to96[1-96] Start mixing "RB1_1to96" for 5.00 minutes at 600 rpm(s) and continue. Start mixing "RB2_1to96" for 5.00 minutes at 600 rpm(s) and continue. Start mixing "RB3_1to96" for 5.00 minutes at 600 rpm(s) and continue. 81 Mix "RB4_1to96" for 5.00 minutes at 600 rpm(s) and wait.
82 Empty RB1_1to96 for 5.000 minute(s)
83 Empty RB2_1to96 for 5.000 minute(s)
84 Empty RB3_1to96 for 5.000 minute(s) 85 Empty RB4_1 to96 for 5.000 minute(s)
86 Repeat from step 74, 2 times
87 Pause
88 Dispense System Fluid Disdu1_4* 1500ul to RB1_1to96[1-96]
89 Dispense System Fluid Disdu1_4* 1500ul to RB2_1to96[1-96] 90 Dispense System Fluid Disdu1_4* 1500ul to RB3_1to96[1-96]
91 Dispense System Fluid Disdu1_4* 1500ul to RB4_1to96[1-96]
92 Start mixing "RB1_1to96" for 5.00 minutes at 600 rpm(s) and continue.
93 Start mixing "RB2_1to96" for 5.00 minutes at 600 rpm(s) and continue.
94 Start mixing "RB3_1to96" for 5.00 minutes at 600 rpm(s) and continue. 95 Mix "RB4_1to96" for 5.00 minutes at 600 rpm(s) and wait.
96 Empty RB1_1to96 for 5.000 minute(s)
97 Empty RB2_1to96 for 5.000 minute(s)
98 Empty RB3_1to96 for 5.000 minute(s)
99 Empty RB4_1to96 for 5.000 minute(s) 100 Repeat from step 88, 1 times
101 Dispense System Fluid Disdu2_3* 1500ul to RB1_1to96[1-96]
102 Dispense System Fluid Disdu2_3* 1500ul to RB2_1to96[1-96]
103 Dispense System Fluid Disdu2_3* 1500ul to RB3_1to96[1-96]
104 Dispense System Fluid Disdu2_3* 1500ul to RB4_1to96[1-96] 105 Start mixing "RB1_1to96" for 5.00 minutes at 600 rpm(s) and continue.
106 Start mixing "RB2_1to96" for 5.00 minutes at 600 rpm(s) and continue.
107 Start mixing "RB3_1to96" for 5.00 minutes at 600 rpm(s) and continue. 108 Mix "RB4_1to96" for 5.00 minutes at 600 rpm(s) and wait.
109 Wait for 25.000 minute(s) 110 Repeat from step 105, 1000 times
111 Pause
112 Empty RB1_1to96 for 5.000 minute(s)
113 Empty RB2_1to96 for 5.000 minute(s)
114 Empty RB3_1to96 for 5.000 minute(s) 115 Empty RB4_1 to96 for 5.000 minute(s)
116 Repeat from step 101 , 1 times 117
118 REM Coupling with amines
119 Flush Arm1 with Disdu2_3*, Arm2 with Disdu2_3* 120 Dispense Sequence c:\ACT13_28\R3-A.DSP with 1000ul to RB1_1to96 rack using NMP
121 Mix "RB1_1to96" for 2.00 minutes at 600 rpm(s) and wait.
122 Dispense Sequence c:\ACT13_28\R3-B.DSP with 1000ul to RB2_1to96 rack using NMP
123 Start mixing "RB1_1to96" for 2.00 minutes at 600 rpm(s) and continue. 124 Mix "RB2_1to96" for 2.00 minutes at 600 rpm(s) and wait. 125 Dispense Sequence c:\ACT13_28\R3-C.DSP with 1000ul to RB3_1to96 rack using NMP
126 Start mixing "RB1_1to96" for 2.00 minutes at 600 rpm(s) and continue.
127 Start mixing "RB2_1to96" for 2.00 minutes at 600 rpm(s) and continue. 128 Mix "RB3_1to96" for 2.00 minutes at 600 rpm(s) and wait.
129 Dispense Sequence c:\ACT13_28\R3-D.DSP with 1000ul to RB4_1to96 rack using NMP Start mixing "RB1_1to96" for 2.00 minutes at 600 rpm(s) and continue. Start mixing "RB2_1to96" for 2.00 minutes at 600 rpm(s) and continue. Start mixing "RB3_1to96" for 2.00 minutes at 600 rpm(s) and continue. Mix "RB4_1to96" for 2.00 minutes at 600 rpm(s) and wait. Pause Transfer 500ul from REAGENT_3[1]() to RB1_1to96[1-96] using NMP Mix "RB1_1to96" for 2.00 minutes at 600 rpm(s) and wait. Pause Transfer 500ul from REAGENT_3[1]() to RB2_1to96[1-96] using NMP Start mixing "RB1_1to96" for 2.00 minutes at 600 rpm(s) and continue. Mix "RB2_1to96" for 2.00 minutes at 600 rpm(s) and wait. Pause Transfer 500ul from REAGENT_3[1]() to RB3_1to96[1-96] using NMP Start mixing "RB1_1to96" for 2.00 minutes at 600 rpm(s) and continue. Start mixing "RB2_1to96" for 2.00 minutes at 600 rpm(s) and continue. Mix "RB3_1to96" for 2.00 minutes at 600 rpm(s) and wait. Pause Transfer 500ul from REAGENT_3[1]() to RB4_1to96[1-96] using NMP Start mixing "RB1_1to96" for 5.00 minutes at 600 rpm(s) and continue. Start mixing "RB2_1to96" for 5.00 minutes at 600 rpm(s) and continue. Start mixing "RB3_1to96" for 5.00 minutes at 600 rpm(s) and continue. Mix "RB4_1to96" for 5.00 minutes at 600 rpm(s) and wait. Wait for 25.000 minute(s) Repeat from step 148, 200 times Pause Empty RB1_1to96 for 5.000 minute(s) Empty RB2_1to96 for 5.000 minute(s) Empty RB3_1to96 for 5.000 minute(s) Empty RB4_1to96 for 5.000 minute(s)
REM Wash after coupling with amines Flush Arm1 with Flush Diluterl and Flush Diluter 2 , Arm2 with Flush Diluter Dispense System Fluid Disdu2_3* 1500ul to RB1_1to96[1-96] Dispense System Fluid Disdu2_3* 1500ul to RB2_1 to96[1 -96] Dispense System Fluid Disdu2_3* 1500ul to RB3_1to96[1-96] Dispense System Fluid Disdu2_3* 1500ul to RB4_1to96[1-96] Start mixing "RB1_1to96" for 5.00 minutes at 600 rpm(s) and continue. Start mixing "RB2_1to96" for 5.00 minutes at 600 rpm(s) and continue. Start mixing "RB3_1to96" for 5.00 minutes at 600 rpm(s) and continue. Mix "RB4_1to96" for 5.00 minutes at 600 rpm(s) and wait. Empty RB1_1to96 for 5.000 minute(s) Empty RB2_1to96 for 5.000 minute(s) Empty RB3_1to96 for 5.000 minute(s) Empty RB4_1to96 for 5.000 minute(s) Repeat from step 166, 2 times 179 Pause
180 Dispense System Fluid Disdu1_4* 1500ul to RB1_1to96[1-96]
181 Dispense System Fluid Disdu1_4* 1500ul to RB2_1to96[1-96]
182 Dispense System Fluid Disdu1_4* 1500ul to RB3_1to96[1-96] 183 Dispense System Fluid Disdu1_4* 1500ul to RB4_1to96[1-96]
184 Start mixing "RB1_1to96" for 5.00 minutes at 600 rpm(s) and continue.
185 Start mixing "RB2_1to96" for 5.00 minutes at 600 rpm(s) and continue.
186 Start mixing "RB3_1to96" for 5.00 minutes at 600 rpm(s) and continue. 187 Mix "RB4_1to96" for 5.00 minutes at 600 rpm(s) and wait. 188 Empty RB1_1to96 for 5.000 minute(s)
189 Empty RB2_1to96 for 5.000 minute(s)
190 Empty RB3_1to96 for 5.000 minute(s)
191 Empty RB4_1to96 for 5.000 minute(s) 192 193 Repeat from step 180, 5 times 194
195 Dispense System Fluid Disdu1_4* 1500ul to RB1_1to96[1-96]
196 Dispense System Fluid Disdu1_4* 1500ul to RB2_1to96[1-96]
197 Dispense System Fluid Disdu1_4* 1500ul to RB3_1to96[1-96] 198 Dispense System Fluid Disdu1_4* 1500ul to RB4_1 to96[1 -96]
199 Start mixing "RB1_1to96" for 5.00 minutes at 600 rpm(s) and continue.
200 Start mixing "RB2_1to96" for 5.00 minutes at 600 rpm(s) and continue.
201 Start mixing "RB3_1to96" for 5.00 minutes at 600 rpm(s) and continue. 202 Mix "RB4_1to96" for 5.00 minutes at 600 rpm(s) and wait. 203 Wait for 25.000 minute(s)
204 Repeat from step 199, 1000 times 205
206 Flush Arm1 with Flush Diluterl and Flush Diluter 2 , Arm2 with Flush Diluter 3
207 Empty RB4_1to96 for 5.000 minute(s) 208 Pause
209
210 REM Clevage (50%TFA/DCM manually added, one rack at a time)
211 Flush Arm1 with Flush Diluterl , Arm2 with Flush Diluter 4
212 Mix "RB1_1to96" for 5.00 minutes at 600 rpm(s) and wait. 213 Wait for 5.000 minute(s)
214 Repeat from step 7, 5 times
215 Empty RB1_1to96 for 1 second (s)
216 Wait for 4 second(s)
217 Repeat from step 10, 25 times 218 Empty RB1_1to96 for 5.000 minute(s) 219
220 Dispense System Fluid Disdu1_4* 500ul to RB1_1to96[1-96]
221 Wait for 1.000 minute(s)
222 Empty RB1_1to96 for 1 second (s) 223 Wait for 4 second(s)
224 Repeat from step 17, 25 times
225 Empty RB1_1to96 for 5.000 minute(s) 226 Dispense sequence files C:\ACT13_28\R3-A.DSP, C:\ACT13_28\R3-B.DSP, C:\ACT 13_28\R3-C.DSP and C:\ACT13_28\R3-D.DSP are subroutines that control the combinatorial addition of the amines into the 4 reaction blocks each containing 96 wells in the syn- theziser.
The library containing the following compounds was synthesized, and the products were characterised by HPLC-MS (molecular mass & retention time).
Figure imgf000405_0001
Figure imgf000406_0001
Figure imgf000407_0001
Figure imgf000408_0001
Figure imgf000409_0001
Figure imgf000410_0001
Figure imgf000411_0001
Figure imgf000412_0001
Figure imgf000413_0001
Figure imgf000414_0001
Figure imgf000415_0001
Figure imgf000416_0001
Figure imgf000417_0001
Figure imgf000418_0002
EXAMPLE 792:
3-Amino-4-hydroxybenzoic acid {4-[2-(1.2.3.4-tetrahydro-isoquinolin-2-vπethoxy]-2- methoxybenzylidene}hydrazide
Figure imgf000418_0001
The above 4-(2-bromoethoxy)-2-methoxybenzaldehyde (16.8 g, 65 mmol) ([building block 2]) was dissolved in acetone (300 ml) and potassium carbonate (44.9 g, 0.33 0 mol), potassium iodide (2 g) were added followed by addition of 1 ,2,3,4- tetrahydroisoquinoline (9.07 g, 72 mmol). The resulting mixture was stirred vigorously at reflux temperature for 16 hours. After cooling, the mixture was filtered and the inorganic precipitate was washed with acetone (100 ml). The combined acetone filtrates were concentrated in vacuo. The residue was dissolved in ethyl acetate (50 ml) and 5 washed with water (2 x 20 ml) saturated sodium chloride (20 ml), dried over MgSO4 and concentrated in vacuo. The residue (23 g) was purified by column chromatography on silica gel (400 g) eluting first with a mixture of ethyl acetate and heptane (1 :1 , 2 liters) then with a mixture of ethyl acetate and heptane (2:1 , 5 liters) to afford 12 g (60%) of 4- [2-(1 ,2,3,4-tetrahydroisoquinolin-2-yl)ethoxy]-2-methoxybenzaldehyde as a solid. M.p.: 0 69 - 71 °C.
Calculated for C19H21NO3.0.25H2O: C, 72.24%; H, 6.86%; N, 4.43%. Found: C, 72.79%; H, 6.86%; N, 4.46%; C, 72.65%; H, 6.88%; N, 4.47%.
Methyl 3-amino-4-hydroxybenzoate (5.0 g, 30 mmol) was dissolved in ethanol (50 ml) and hydrazine hydrate (4.4 ml, 90 mmol) was added and the resulting mixture was heated at re- flux temperature for 16 hours. After cooling the mixture was filtered and solid was washed with ethanol to afford after drying 1.4 g (28%) of 3-amino-4-hydroxybenzoic acid hydrazide as a solid. M.p.: 242 - 243 °C.
Calculated for C7H9N3O2: C, 50.30%; H, 5.43%; N, 25.14%. Found: C, 50.27%; H, 5.46%; N, 24.35%; C, 50.41%; H, 5.47%; N, 24.38%.
The above 3-amino-4-hydroxybenzoic acid hydrazide (50 mg, 0.3 mmol) and the above 4-[2- (1 ,2,3,4-tetrahydroisoquinolin-2-yl)ethoxy]-2-methoxybenzaldehyde (93 mg, 0.3 mmol) were dissolved in 2-propanol (4 ml) and the mixture was heated at reflux temperature for 16 hours. The cooled mixture was filtered and the precipitate was washed with 2-propanol (2 x 4 ml) and dried by suction to afford 66 mg (48%) of the title compound as a solid. M.p.: 162 - 164 °C.
HPLC -MS (METHOD B): Rt = 6.50 minutes, m/z = 461.
EXAMPLE 793:
3-Amino-4-hydroxybenzoic acid [4-(4-isopropylbenzyloxy)-3.5-dimethoxybenzylidene]- hvdrazide
Figure imgf000419_0001
Syringaldehyde (4-hydroxy-3,5-dimethoxybenzaldehyde) (10.2 g, 55 mmol) was dissolved in DMF (45 ml), and 4-isopropylbenzylchloride (9.7 g, 55 mmol) and potassium carbonate (11.5 g) were added successively. The resulting mixture was heated at 60 °C for 16 hours. After cooling, the mixture was partitioned between water (150 ml) and ethyl acetate (3 x 100 ml). The combined organic extracts were washed with water (100 ml), saturated NaCl (100 ml), dried (MgSO4), treated with activated carbon, filtered and concentrated in vacuo to afford 15 g (100%) of 4-(4-isopropylbenzyloxy)-3,5-dimethoxybenzaldehyde as an oil.
1H-NMR (400 MHz, DMSO-d6): δH = 1.20 (9H, d), 2.89 (1 H, h), 3.86 (6H, s), 4.98 (2H, s), 7.23 (2H, d), 7.27 (2H, s), 7.36 (2H, d).
The above 3-amino-4-hydroxybenzoic acid hydrazide (50 mg, 0.3 mmol) and the above 4-(4- isopropylbenzyloxy)-3,5-dimethoxybenzaldehyde(93 mg, 0.3 mmol) were dissolved in 2- propanol (4 ml) and the mixture was heated at reflux temperature for 16 hours. The cooled mixture was filtered and the precipitate was washed with 2-propanol (2 x 4 ml) and dried by suction to afford 144 mg (100%) of the title compound as a solid. M.p.: 174 - 175 °C.
HPLC-MS (METHOD B): R, = 10.40 minutes, m/z = 464.
EXAMPLE 794:
(RV2-{4-[(3-Amino-4-hydroxybenzovπhydrazonomethyl]-3-methoxyphenoxy}-N-(1- benzylpyrrolidin-3-yl)acetamide
Figure imgf000420_0001
(R)-(-)-1-Benzyl-3-aminopyrrolidine (5 g, 28 mmol) was dissolved in dichloromethane (10 ml). To this solution, a solution of bromoacetyl chloride (4.55 g, 28 mmol) in dichloromethane (5 ml) was added at room temperature. The mixture was stirred at room temperature for 16 hours. The mixture was filtered, washed with dichloromethane and dried in vacuo to afford 6.8 g (72%) of (3R)-N-(1-benzylpyrrolidin-3-yl)-2-bromoacetamide hydrochloride as a solid which was used directly in the next step.
4-Hydroxy-2-methoxybenzaldehyde (2.05 g, 13 mmol) was dissolved in DMF (7 ml) and potassium carbonate (6.2 g, 45 mmol) was added followed by a suspension of the above (3R)-N-(1-Benzylpyrrolidin-3-yl)-2-bromoacetamide hydrochloride (3.0 g, 9 mmol) in DMF (16 ml). The resulting mixture was stirred at room temperature for 16 hours. The mixture was then partitioned between water (100 ml) and ethyl acetate (30 ml). The aqueous phase was extracted with ethyl acetate (2 x 20 ml) and the combined organic extracts were washed with saturated sodium chloride (3 x 15 ml), dried (MgSO4) and concentrated in vacuo. The residue was crystallized from diethyl ether to afford 2.11 g (64%) (R)-N-(1-benzylpyrroiidin-3-yl)- 2-(4-formyl-3-methoxyphenoxy)acetamide as a solid. M.p.: 98 - 101 °C.
Calculated for C21H24N2O4.0.5H2O: C, 66.83%; H, 6.68%; N, 7.42%. Found: C, 67.15%; H, 6.57%; N, 7.75%; C, 66.96%; H, 6.57%; N, 7.77%.
The above 3-amino-4-hydroxybenzoic acid hydrazide (50 mg, 0.3 mmol) and the above (R)- N-(1-benzylpyrrolidin-3-yl)-2-(4-formyl-3-methoxyphenoxy)acetamide (110 mg, 0.3 mmol) were dissolved in 2-propanol (4 ml) and the mixture was heated at reflux temperature for 16 hours. The cooled mixture was filtered and the precipitate was washed with 2-propanol (2 x 3 ml) and dried by suction to afford 109 mg (70%) of the title compound as a solid. M.p.: 157 - 160 °C.
HPLC-MS (METHOD B): Rt = 3.10 minutes, m/z = 518.
EXAMPLE 795:
(R 2-{4-[(3-Amino-4-hydroxybenzoyπhydrazonomethyl]naphthyl-1-yloxy}-N-(1- benzylpyrrolidin-3-yl)acetamide
Figure imgf000421_0001
4-Hydroxy-1 -naphthaldehyde (2.32 g, 13 mmol) was dissolved in DMF (7 ml) and potassium carbonate (6.2 g, 45 mmol) was added followed by a suspension of the above (3R)-N-(1- Benzylpyrroiidin-3-yl)-2-bromoacetamide hydrochloride (3.0 g, 9 mmol) in DMF (16 ml). The resulting mixture was stirred at room temperature for 16 hours. The mixture was then parti- tioned between water (100 ml) and ethyl acetate (30 ml). The aqueous phase was extracted with ethyl acetate (2 x 20 ml) and the combined organic extracts were washed with saturated sodium chloride (3 x 15 ml), dried (MgSO4) and concentrated in vacuo. The residue was purified by column chromatography on silica gel (110 g) eluting with ethyl acetate to afford 1.7 g (49%) (R)-N-(1-benzylpyrrolidin-3-yl)-2-(4-formylnaphthyl-1-yloxy)acetamide as a solid. M.p.: 105 - 107 °C.
Calculated for C24H24N2O3.0.25H2O: C, 73.36%; H, 6.28%; N, 7.13%. Found:
C, 73.81 %; H, 6.22%; N, 7.11 %; C, 73.92%; H, 6.23%; N, 7.11 %.
The above 3-amino-4-hydroxybenzoic acid hydrazide (50 mg, 0.3 mmol) and the above (R)- N-(1-beπzylpyrrolidin-3-yl)-2-(4-formylnaphthyl-1-yloxy)acetamide (116 mg, 0.3 mmol) were dissolved in 2-propanol (4 ml) and the mixture was heated at reflux temperature for 16 hours. The cooled mixture was filtered and the precipitate was washed with 2-propanol (6 x 2 ml) and dried by suction to afford 140 mg (87%) of the title compound as a solid. M.p.: 187 - 192 °C.
HPLC-MS (METHOD B): Rt = 5.72 minutes, m/z = 538.
EXAMPLE 796:
(SV2-{4-[(3-Amino-4-hydroxybenzoylVhydrazonomethyl]-3-methoxyphenoxyV-N-(1- benzylpyrrolidin-3-yl)acetamide
Figure imgf000422_0001
(S)-(+)-1-Benzyl-3-aminopyrrolidine (6 g, 34 mmol) was dissolved in dichloromethane (12 ml). To this solution, a solution of bromoacetyl chloride (5.46 g, 34 mmol) in dichloromethane (5 ml) was added at room temperature. The mixture was stirred at room temperature for 16 hours. The mixture was filtered, washed with dichloromethane and dried in vacuo to afford 7.3 g (64%) of (3S)-N-(1-benzyipyrrolidin-3-yl)-2-bromoacetamide hydrochloride as a solid which was used directly in the next step.
4-Hydroxy-2-methoxybenzaldehyde (2.39 g, 16 mmol) was dissolved in DMF (10 ml) and potassium carbonate (7.3 g, 52 mmol) was added followed by a suspension of the above (3S)-N-(1-benzylpyrrolidin-3-yl)-2-bromoacetamide hydrochloride (3.5 g, 10 mmol) in DMF (20 ml). The resulting mixture was stirred at room temperature for 16 hours. The mixture was then partitioned between water (100 ml) and ethyl acetate (30 ml). The aqueous phase was extracted with ethyl acetate (2 x 20 ml) and the combined organic extracts were washed with saturated sodium chloride (3 x 15 ml), dried (MgSO4) and concentrated in vacuo. The residue (4 g) was crystallised from a mixture of diethyl ether and heptane, filtered and dried in vacuo to afford 2.7 g (71%) (S)-N-(1-benzylpyrrolidin-3-yl)-2-(4-formyl-3-methoxyphenoxy)- acetamide as a solid. M.p.: 96 - 100 °C.
Calculated for C21H24N2O4.0.25H2O: C, 67.63%; H, 6.62%; N, 7.51%. Found: C, 67.35%; H, 6.61%; N, 7.85%; C, 67.24%; H, 6.59%; N, 7.82%.
The above 3-amino-4-hydroxybenzoic acid hydrazide (50 mg, 0.3 mmol) and the above (S)- N-(1-benzylpyrrolidin-3-yl)-2-(4-formyl-3-methoxyphenoxy)acetamide (110 mg, 0.3 mmol) were dissolved in 2-propanol (4 ml) and the mixture was heated at reflux temperature for 16 hours. The cooled mixture was filtered and the precipitate was washed with 2-propanol (6 x 2 ml) and dried by suction to afford 109 mg (70%) of the title compound as a solid. M.p.: 139 - 141 °C.
HPLC-MS (METHOD B): Rt = 3.15 minutes, m/z = 518.
EXAMPLE 797: (S -2-{4-[(3-Amino-4-hydroxybenzoyl)hydrazonomethyl]naphthyl-1-yloxy}-N-(1- benzylpyrrolidin-3-yπacetamide
Figure imgf000424_0001
4-Hydroxy-1 -naphthaldehyde (2.71 g, 16 mmol) was dissolved in DMF (10 ml) and potas- sium carbonate (7.25 g, 52 mmol) was added followed by a suspension of the above (3S)-N- (1-benzylpyrrolidin-3-yl)-2-bromoacetamide hydrochloride (3.0 g, 10 mmol) in DMF (20 ml). The resulting mixture was stirred at room temperature for 16 hours. The mixture was then partitioned between water (100 ml) and ethyl acetate (30 ml). The aqueous phase was extracted with ethyl acetate (2 x 20 ml) and the combined organic extracts were washed with saturated sodium chloride (3 x 15 ml), dried (MgSO4) and concentrated in vacuo. The residue (4 g) was purified by column chromatography on silica gel (110 g) eluting with ethyl acetate to give an oil (2 g), which was crystallized from a mixture of diethyl ether and heptane to afford 1.8 g (45%) (S)-N-(1-benzylpyrrolidin-3-yl)-2-(4-formylnaphthyl-1-yloxy)- acetamide as a solid. M.p.: 96 - 97 °C.
Calculated for C24H24N2O3.0.25H2O:
C, 73.36%; H, 6.28%; N, 7.13%.
Found:
C, 73.58%; H, 6.28%; N, 7.05%; C, 73.55%; H, 6.27%; N, 7.03%.
The above 3-amino-4-hydroxybenzoic acid hydrazide (50 mg, 0.3 mmol) and the above (S)- N-(1-benzylpyrrolidin-3-yl)-2-(4-formylnaphthyl-1-yloxy)acetamide (116 mg, 0.3 mmol) were dissolved in 2-propanol (4 ml) and the mixture was heated at reflux temperature for 16 hours. The cooled mixture was filtered and the precipitate was washed with 2-propanol (3 x 3 ml) and dried by suction to afford 143 mg (89%) of the title compound as a solid. M.p.: 192 - 193 °C.
HPLC-MS (METHOD B): Rt = 5.18 minutes, m/z = 538. EXAMPLE 798:
(S 2-{4-[(3-Fluoro-4-hydroxybenzoyl)hydrazonomethyl]naphthyl-1-yloxy}-N-(1- benzylpyrrolidin-3-yπacetamide
Figure imgf000425_0001
This compound was prepared on solid phase using resin bound 3-fluoro-4-hydroxybenzoic acid hydrazide, prepared similarly as described above for the resin bound 3-chloro-4- hydroxybenzoic acid hydrazide. Thus, methyl 3-fluoro-4-hydroxybenzoate was attached to the resin. Hydrolysis of the methyl ester (aq. LiOH, dioxane, 60 °C) followed by reaction with hydrazine (PyBOP, hydrazine, DMF) afforded resin bound 3-fluoro-4-hydroxybenzoic acid hydrazide.
The resin bound 3-fluoro-4-hydroxybenzoic acid hydrazide (1 g, 0.94 mmol) was swelled in DMF (10 ml) for 30 minutes and filtered. This was repeated once more. DMF (4 ml) and the above (S)-N-(1-benzylpyrrolidin-3-yl)-2-(4-formylnaphthyl-1-yloxy)acetamide (0.4 g, 0.94 mmol) were added followed by triethyl orthoformate (1.5 ml) and the resulting mixture was shaken at room temperature for 16 hours. The mixture was filtered and the resin was successively washed with DMF (5 x 4 ml) and dichloromethane (5 x 4 ml). The compound was cleaved off the resin by addition of 50% TFA in dichloromethane (6 ml) and shaking at room temperature for 1 hour. Filtration followed by extraction of the resin with a mixture of metha- nol and dichloromethanne (4:6) (2 x 4 ml) followed by extraction with dichloromethane (4 ml). The combined filtrates were concentrated in vacuo. stripped successively with wet methanol, dichloromethane, methanol and dichloromethane. The residue (0.39 g) was purified by column chromatography on silica gel (40 g) eluting first with a mixture of dichloromethane, ethanol and 25% aq. ammonia (90:9:1), then with (85:13.5:1.5) and finally with (80:18:2). Pure fractions were pooled and concentrated in vacuo to afford 0.15 g of the title compound.
HPLC-MS (METHOD B): Rt = 8.82 minutes, m/z = 541.
Calculated for C31H29N4O4F.0.25CH2CI2: C, 66.81 %; H, 5.29%; N, 9.97%. Found: C, 67.30%; H, 5.48%; N, 10.03%; C, 67.33%; H, 5.49%; N, 10.02%.
EXAMPLE 799:
(R)-2-{4-[(3-Fluoro-4-hydroxybenzoyπhydrazonomethyl]naphthyl-1-yloxy}-N-(1- benzylpyrrolidin-3-yπacetamide
Figure imgf000426_0001
This compound was prepared similarly as described in the previous example starting from resin bound 3-fluoro-4-hydroxybenzoic acid hydrazide (1 g, 0.94 mmol) and the above (R)-N- (1-benzylpyrrolidin-3-yl)-2-(4-formylnaphthyl-1-yloxy)acetamide (0.4 g, 0.94 mmol). After cleavage the compound was purified by column chromatography to afford 0.14 g of the title compound.
HPLC-MS (METHOD B): Rt = 9.02 minutes, m/z = 541.
Calculated for C31H29N4O4F.0.25CH2CI2: C, 66.81%; H, 5.29%; N, 9.97%. Found:
C, 66.77%; H, 5.46%; N, 10.02%; C, 67.14%; H, 5.42%; N, 9.97%.
EXAMPLE 800:
(SV2-{4-[(3-Fluoro-4-hvdroxybenzoyπhydrazonomethyl]-3-methoxyphenoxy}-N-(1- benzylpyrrolidin-3-yhacetamide
Figure imgf000426_0002
This compound was prepared similarly as described in the previous example starting from resin bound 3-fluoro-4-hydroxybenzoic acid hydrazide (1 g, 0.94 mmol) and the above (S)-N- (1-benzylpyrrolidin-3-yl)-2-(4-formyl-3-methoxyphenoxy)acetamide (0.4 g, 0.94 mmol). After cleavage the compound was purified by column chromatography to afford 0.13 g of the title compound.
HPLC-MS (METHOD B): Rt = 3.68 minutes, m/z = 521.
Calculated for C28H29N4O5F.0.25CH2CI2: C, 62.63%; H, 5.49%; N, 10.34%. Found:
C, 62.92%; H, 5.83%; N, 10.15%; C, 62.71%; H, 5.81 %; N, 10.16%.
EXAMPLE 801 : fR 2-{4-[(3-Fluoro-4-hydroxybenzoylVhydrazonomethyl]-3-methoxyphenoxy}-N-(1- benzylpyrrolidin-3-ynacetamide
Figure imgf000427_0001
This compound was prepared similarly as described in the previous example starting from resin bound 3-fluoro-4-hydroxybenzoic acid hydrazide (1 g, 0.94 mmol) and the above (R)-N- (1-benzylpyrrolidin-3-yl)-2-(4-formyl-3-methoxyphenoxy)acetamide (0.4 g, 0.94 mmol). After cleavage the compound was purified by column chromatography to afford 0.16 g of the title compound.
HPLC-MS (METHOD B): R, = 4.18 minutes, m/z = 521.
Calculated for C28H29N4O5F.0.25CH2CI2: C, 62.63%; H, 5.49%; N, 10.34%. Found:
C, 62.65%; H, 5.73%; N, 10.31%; C, 62.84%; H, 5.81 %; N, 10.30%.
EXAMPLE 802: 3-Fluoro-4-hydroxybenzoic acid {4-[2-(1.2.3.4-tetrahydro-isoquinolin-2-yl)ethoxy]-2- methoxybenzylidene}hydrazide
Figure imgf000428_0001
This compound was prepared similarly as described in the previous example starting from resin bound 3-fluoro-4-hydroxybenzoic acid hydrazide (1 g, 0.94 mmol) and the above 4-[2- (1 ,2,3,4-tetrahydroisoquinolin-2-yl)ethoxy]-2-methoxybenzaldehyde (0.4 g, 0.94 mmol). After cleavage the compound was purified by column chromatography to afford 0.13 g of the title compound.
HPLC-MS (METHOD B): Rt = 7.60 minutes, m/z = 464.
Calculated for C26H26N3O4F.0.5CH2CI2: C, 62.91%; H, 5.38%; N, 8.30%. Found: C, 62.68%; H, 5.47%; N, 8.02%; C, 62.48%; H, 5.43%; N, 8.01%.
The HPLC-MS (METHOD A) analyses were performed on a PE Sciex API 100 LC/MS System using a Waters™ 3 mm x 150 mm 3.5 μ C-18 Symmetry column and positive ionspray with a flow rate of 20 μL/minute. The column was eluted with a linear gradient of 5-90% A, 85-0% B and 10% C in 15 minutes at a flow rate of 1 ml/min (solvent A = acetonitrile, solvent B = water and solvent C = 0.1% trifluoroacetic acid in water).
The HPLC-MS (METHOD B) analyses were performed on a system identical to the one de- scribed above, the only difference being the eluent. The column was eluted with a linear gradient of 30-80% A, 60-10% B and 10% D in 15 minutes at a flow rate of 1 ml/min (solvent A = acetonitrile, solvent B = water and solvent D =20 mM ammonium acetate in water, pH 7).
EXAMPLE 803: 3-Chloro-4-hydroxy-benzoic acid (4-[2-(1.2.3.4-tetrahydro-isoquinolin-2-yn-ethoxy]-8- methoxy-naphthalen-1-ylmethylene)-hvdrazide
Figure imgf000429_0001
4-hydroxy-8-methoxynaphthalene-1-carbaldehyde (1 g, 5 mmol) was dissolved in DMF (15 mL). To this mixture potassium carbonate (3.4 g, 25 mmol) and 1 ,2-dibromoethane (4 mL, 50 mmol) were added and the resulting mixture was stirred at room temperature for 16 hours. Water (150 mL) was added and the resulting mixture was extracted with ethyl acetate (3 x 90 mL). The combined organic extracts were washed with saturated sodium chloride (100 mL), dried (MgSO4) and evaporated in vacuo to afford 1.13 g (74%) of 4-(2- bromoethoxy)-8-methoxynaphthalene-1-carbaldehyde.
HPLC-MS (Method A): Rt = 14.1 minutes, m/z = 309.
1H-NMR (300 MHz, DMSO-d6): δH = 3.99 (3H, s), 7.00 (1 H, d), 7.20 (1 H, d), 7.47 (1 H, t), 7.88 (2H, m), 10.9 (1 H, s).
The above resin bound 3-chloro-4-hydroxybenzoic acid hydrazide (2 g, 1.8 mmol) was swelled in DMF (25 mL) for 30 minutes and the above 4-(2-bromoethoxy)-8- methoxynaphthalene-1-carbaldehyde (1.7 g, 5.4 mmol) was added followed by triethyl orthoformate (1.2 mL) and the resulting mixture was shaken at room temperature for 16 hours. The mixture was filtered and the resin was successively washed with DMF (3 x 25 mL), dichloromethane (4 x 25 mL) and N-methyl pyrrolidin-2-one (NMP) (2 x 25 mL). NMP (25 mL) was added followed by potassium iodide (0.6 g) and 1 ,2,3,4-tetrahydro-isoquinoline (2.25 mL, 18 mmol) and the resulting mixture was shaken at room temperature for 16 hours. The mixture was filtered and the resin was successively washed with NMP (2 x 25 mL) and dichloromethane (6 x 25 mL). The compound was cleaved off the resin by addition of 50% TFA in dichloromethane (30 mL) and shaking at room temperature for 1 hour. After filtration followed by extraction of the resin with dichloromethane (2 x 30 mL) the combined filtrates were concentrated in vacuo. The residue was partitioned between ethyl acetate (80 mL) and saturated sodium hydrogen carbonate (100 mL). The aqueous phase was extracted with ethyl acetate (2 x 80 mL) and the combined organic extracts were dried (MgSO4) and concentrated in vacuo. The residue was purified by column chromatography on silica gel (200 mL) eluting with a mixture of dichloromethane and methanol (9:1 ). This afforded 217 mg of the title compound.
HPLC-MS (Method A): R, = 9.14 minutes, m/z = 530.
General Procedure for Examples 804 to 824:
The compounds were prepared as single entities according to the following equation
Resin [Building block 1]
Resin [Building block 1] [Building block 2]
Resin [Building block 1] [Building block 2] [Building block 3]
and were simultaneously deprotected (when required) and cleaved from the resin with 50% trifluoroacetic acid in dichloromethane to give the desired compounds as individual entities according to the following formula
[Building block 1] [Building block 2] [Building block 3].
The following compounds were prepared as single entities by parallel synthesis on a solid support. Preparation of Resin-[Building block 1] and attachment of [Building block 2] was done manually, whereas the attachment of [Building block 3] and cleavage from the resin were performed on an Advanced ChemTech Model 496 HTS in several runs.
The starting resin, Resin-[Building block 1], was prepared as described above.
The resin used was a polystyrene resin with a Wang linker and the substitution capacity was 0.9 mmol/g.
All compounds are based on successive attachment of [Building block 2] and [Building block 3] to Resin-[Building block 1] in a combinatorial way according to the following formulae, which are included in the general formula II:
Figure imgf000432_0001
Resιn-[Buιldιng block 1] [Building block 2] Resιn-[Buιldιπg block 1]-[Buιldιng block 2]
Figure imgf000432_0002
[Building block 3]
Figure imgf000432_0003
Figure imgf000432_0004
[Building block 1]-[Buιldιng block 2]-[Buιldιng block 3]
wherein R8, R9, R 4, R15 and
Figure imgf000432_0005
are as defined for formula I.
The following resin, here depicted as Resin-[Building block 1] was used:
where PS is polystyrene. In the following "Resin" is the polystyrene resin with the Wang linker:
Figure imgf000432_0006
Resin
Figure imgf000432_0007
The following building blocks were used:
[Building block 2]:
Figure imgf000433_0001
[Building block 3]:
Figure imgf000434_0001
Figure imgf000435_0001
Figure imgf000436_0001
Figure imgf000437_0001
Figure imgf000438_0001
Preparation of resin-[Building block 1]:
This resin was prepared as described above. Preparation of [Building block 2]:
(4-Formyl-3-methoxyphenyl)carbamic acid 9H-fluoren-9-ylmethyl ester:
NHFmoc
Figure imgf000439_0001
Methyl 4-amino-2-methoxybenzoate (14.7 g, 7.3 mmol) and Fmoc-Osu (26.1 g, 77.3 mmol) were stirred in a mixture of acetonitrile and water (1 :1 , 320 mL) at reflux for 16 hr. The reaction mixture was concentrated to half the volume and the precipitate isolated by filtration. The isolated solid was dissolved in ethyl acetate (300 mL) and washed with 0.4 N hydrochloric acid (200 mL), 0.2 N hydrochloric acid (200 mL), water (200 mL) and a 20 % saturated solution of sodium chloride (200 mL). After drying (magnesium sulphate) the organic phase was concentrated in vacuo. and the solid residue was washed with methanol and dried.
The crude product (12g) was dissolved in dichloromethane (1 L) under nitrogen and a solution of diisobutylaluminium hydride (90 mL, 1.2 M in toluene) was dropwise added at 0-5°C. The reaction mixture was stirred at 20°C for 16 hr and quenched by dropwise addition of water (58 mL) at 0-5 °C. The reaction mixture was stirred at 20°C for 3 hr and filtered. The filtrate was concentrated in vacuo. The crude product (6.8 g) was suspended in dichloromethane (400 mL) and manganese dioxide (15.6 g, 180 mmol) was added. The mixture was stirred for 16 hr at 20°C and filtered. The filtrate was concentrated in vacuo to give 5.1 g of the title compound.
m.p. 187-188°C
HPLC-MS (METHOD A): Rt = 15.1 min, m/z= 374. Micro analysis: calculated: C, 73.98; H, 5.13; N, 3.75% found: C, 73.44; H, 5.20; N, 3.56%
(4-Formyl-2-methoxyphenyl)carbamic acid 9H-fluoren-9-ylmethyl ester:
Figure imgf000440_0001
Thionylchloride (12.8 g, 108 mmol) was dropwise added to an ice cold suspension of 4- amino-3-methoxybenzoic acid (12.3 g, 72 mmol) in methanol (250 mL). The reaction mixture was stirred at 20°C for 16 hr and concentrated in vacuo. Ethyl acetate (250 mL) and a saturated solution of sodium hydrogen carbonate (150 mL) were added and the organic phase was washed with saturated solutions of sodium hydrogen carbonate (2x50 mL), dried (magnesium sulphate) and concentrated in vacuo. The crude product (12.5 g) and Fmoc- Osu (28 g, 83 mmol) was stirred in a mixture of acetonitrile and water (1 :1 , 240 mL) at 90°C for 16 hr. The reaction mixture was concentrated to half the volume. Ethyl acetate (200 mL) was added together with 0.4N hydrochloric acid (150 mL). The organic phase was washed with 0.2N hydrochloric acid (100 mL), water (100 mL) and a saturated solution of sodium chloride (2x100 mL). After drying (magnesium sulphate) the organic phase was concentrated in vacuo. and the residue was crystallized from methanol and dried.
m.p. 96-98°C
HPLC (Method 1 ) Rt= 32.4 min
Micro analysis: calculated: C, 71.45; H, 5.25; N, 3.47% found: C, 71.32; H, 5.24; N, 3.41%
The product (12 g, 29.7 mmol)) was dissolved in dichloromethane (800 mL) under nitrogen and a solution of diisobutylaluminium hydride (90 mL, 1.2M in toluene) was dropwise added at 0-5°C. The reaction mixture was stirred at 20°C for 16 hr and quenched by dropwise addi- tion of water (58 mL) at 0-5°C. The reaction mixture was stirred at 20°C for 3 hr and filtered. The filtrate was concentrated in vacuo to give 5.5 g of product (m.p. 169-171°C). The product (5.5 g) was suspended in dichloromethane (325 mL) and manganese dioxide (12.8 g, 148 mmol) was added. The mixture was stirred for 16 hr at 20°C and filtered. The filtrate was concentrated in vacuo to give 3.5 g of the title compound. Recrystallization from ethyl ace- tate. m.p. 150-152°C
HPLC (Method 1) Rt = 30.6 min
Micro analysis: calculated: C, 73.98; H, 5.13; N, 3.75% found: C, 73.54; H, 5.18; N, 3.65%
3-(tert-Butyldimethylsilanyloxy)-4-formylphenyl)carbamic acid 9H-fluoren-9-ylmethyl ester:
NHFmoc
TB yDMSOp-
4-(9H-Fluoren-9-ylmethoxycarbonylamino)-2-hydroxybenzoic acid methyl ester:
Thionylchloride (19.4g, 163 mmol) was dropwise added to an ice cold solution of 4-amino salicylic acid (10.0g, 65.3 mmol) in methanol (200 mL). The reaction mixture was hereafter heated to 65°C for 6 days. The reaction mixture was concentrated in vacuo and the crude product was dissolved in a mixture of acetonitrile and water (1 :1 , 220 mL). Fmoc-Osu (22.0 g, 65.3 mmol) was added and the reaction mixture was stirred at 90°C for 16 hr. The reaction mixture was concentrated to 100 mL in vacuo. and water (50 mL) and ethyl acetate (250 mL) added. The organic phase was isolated and washed with water (2x50 mL), a saturated solution of sodium chloride (2x50 mL), dried (magnesium sulphate) and concentrated in vacuo.
The residue was purified on silica (300 g) using ethyl acetate and n-heptane (1:2) as eluent. The product was recrystallized from methanol to give 4-(9H-fluoren-9- ylmethoxycarbonylamino)-2-hydroxybenzoic acid methyl ester.
m.p.156-9°C
HPLC (Method 1 ) Rt = 31.7 min
Micro analysis: calculated: C, 70.94; H, 4.92; N, 3.60% found: C, 70.73; H, 4.98; N, 3.37% 4-(9H-Fluoren-9-ylmethoxycarbonyiamino)-2-hydroxybenzoic acid methyl ester (4.36 g, 11.2 mmol) was dissolved in dimethylformamide (20 mL) and imidazole (1.92 g, 28 mmol) was added. tert-Butyldimethylsilylchloride (2.09 g, 13.4 mmol) dissolved in dimethylformamide (10 mL) was dropwise added and the reaction mixture was stirred at 20°C for 16 hr. The reaction mixture was poured into water (160 mL) and extracted with ethyl acetate (4x50 mL). The collected organic phases were washed with a saturated solution of sodium chloride (4x50 mL), dried (magnesium sulphate) and concentrated in vacuo. The residue was purified on silica (150 g) using ethyl acetate and n-heptane (15:85) as eluent. The isolated product (3.10 g, 6.15 mmol) was dissolved in dichloromethane (200 mL) under nitrogen. A solution of diisobutylaluminiumhydride (18.5 mL, 1.2M in toluene) was dropwise added 0-5°C. The mixture was stirred at 20°C for 3.5 hr, and quenched by dropwise addition of water at 0-5°C. After 2.5 hr at 20°C the mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified on silica using ethyl acetate and n-heptane (1 :3) as eluent. The isolated product (2.40 g) was dissolved in dichloromethane (120 mL) and manganese dioxide (4.39 g, 50.5 mmol) was added. The reaction mixture was stirred at 0°C for 16 hr and filtered. The filtrate was concentrated in vacuo and the residue purified on silica using ethyl acetate and n-heptane (15:85) as eluent to give 1.0 g of the title compound.
HPLC (Method 1 ) R, = 30.7 min and 36.8 min
(5-Formyl-2-methoxyphenyl)carbamic acid 9H-fluoren-9-ylmethyl ester:
Figure imgf000442_0001
Thionylchloride (10.3 g, 85 mmol) was dropwise added to an ice cold suspension of 3- amino-4-methoxybenzoic acid (9.48 g, 56.7 mmol) in methanol (180 mL). The reaction mixture was stirred at 20°C for 16 hr and concentrated in vacuo. Ethyl acetate (100 mL) and a saturated solution of sodium hydrogen carbonate (100 mL) were added and the organic phase was washed with saturated solutions of sodium hydrogen carbonate (2x40 mL), dried (magnesium sulphate) and concentrated in vacuo. The crude product (7.7 g) and Fmoc-Osu (12,9 g, 38.2 mmol) were stirred in a mixture of acetonitrile and water (1 :1 , 75 mL) at 20°C for 16 hr, and at reflux for 3.5 hr. The reaction mixture was concentrated to half the volume and the precipitate isolated by filtering the mixture to give 15 g of intermediate crude product.
The product (5 g, 12 mmol) was dissolved in dichloromethane (400 mL) under nitrogen and a solution of diisobutylaluminium hydride (38 mL, 1.2M in toluene) was dropwise added at 0- 5°C. The reaction mixture was stirred at 20°C for 16 hr and quenched by dropwise addition of water (23 mL) at 0-5°C. The reaction mixture was stirred at 20°C for 1.5 hr and filtered. The filtrate was concentrated in vacuo to give 4.9 g of intermediate product. The product (4.9 g) was suspended in dichloromethane (180 mL) and manganese dioxide (11.2 g, 129 mmol) was added. The mixture was stirred for 16 hr at 20°C and filtered. The filtrate was concentrated in vacuo to give 4.3 g crude product that was purified on silica (150 g) using ethyl acetate and n-heptane (3:7) as eluent to give 1.9 g of the title compound.
m.p. 139-142°C
HPLC (Method 1) Rt = 29.8 min
Micro analysis: calculated: C, 73.98; H, 5.13; N, 3.75% found: C, 73.45; H, 5.17; N, 3.72%
EXAMPLE 804:
N-(4-[3-Chloro-4-hydroxybenzoyl)hydrazonomethyl]-3-methoxyphenyπ-2-(4- trifluoromethoxyphenoxy cetamide
Figure imgf000443_0001
Step 1 : Coupling of aldehyde [building block 2] to resin[buildingblock 1] 0.75 g resin (Wang resin loaded with 3-chloro-4-hydroxybenzoic acid hydrazide) was swelled in dimethylformamide (6 mL) for 30 min and drained. The aldehyde (4-formyl-3- methoxyphenyi)carbamic acid 9H-fluoren-9-ylmethyl ester, 0.5 g, 1.36 mmol) dissolved in dimethylformamide (3 mL) was added followed by addition of triethylorthoformate (1.5 mL). The mixture was shaken for 16 hr at 20°C and drained. The resin was washed with dimethylformamide (5x4 mL), dichloromethane (5x4 mL) and dimethylformamide (5x4 mL). The coupling of the aldehyde was repeated twice.
Step 2: Deprotection of aniline
The resin was swelled in dimethylformamide (5 mL) and piperidine added (1.25 mL). After shaking for 30 min, the resin was drained and washed with dimethylformamide (5x4 mL), N- methylpyrrolidinone (5x4 mL) and dimethylformamide (5x4 mL).
Step 3: Coupling of acid [building block 3] to resin[building block 1][building block 2]
The resin[building block 1][building block 2] was swelled in dimethylformamide (2.5 mL) and the acid (4-trifluoromethoxy)phenoxy acetic acid (0.64 g, 2.7 mmol) was added together with diisopropylcarbodiimide (0.21 mL). After 5 min of shaking dimethylaminopyridine (0.34 mL) was added and the mixture was shaken for 3 hr and drained. The resin was washed with di- methylformamide (5x4 mL), dichloromethane (5x4 mL) and dimethylformamide (5x4 mL). The coupling of the acid was repeated twice, but with 16 hr reaction time for the repetition.
Step 4: Cleavage from the resin
The resin was swelled in dichloromethane (2.5 mL) and trifluoroacetic acid (2.5 mL) was added. After shaking for 1 hr the resin was drained. The eluent was collected and concentrated in vacuo. The residue was crystallized from methanol to give 0.2 g of the title compound.
m.p. 235-236.5°C HPLC-MS (METHOD A) Rt = 13.5 min m/z = 538
Micro analysis: calculated: C, 53.59; H, 3.56; N, 7.81 % found: C, 53.57; H, 3.58; N, 7.51% Further, a library of compounds of all the possible combinations of the above listed building blocks ([building block 1], [building block 2] and [building block 3]) was prepared in parallel as individual entities analogously to the previous example on an Advanced ChemTech Model 384 HTS using the following ChemFile to control the operation of the synthesizer. The compounds are all expected to be present in the respective wells.
The four [building block 2] aldehydes, (4-Formyl-3-methoxyphenyl)carbamic acid 9H-fluoren- 9-ylmethyl ester, (4-Formyl-2-methoxyphenyl)carbamic acid 9H-fluoren-9-ylmethyl ester, 3- (tert-Butyldimethylsilanyloxy)-4-formylphenyl)carbamic acid 9H-fluoren-9-ylmethyl ester and (5-Formyl-2-methoxyphenyl)carbamic acid 9H-fluoren-9-ylmethyl ester, were coupled to four individually batches of the resin bound 3-chloro-4-hydroxybenzoic acid hydrazide (resin- [building block 1]) using the same procedure as described for step 1 in the example above. Subsequently the Fmoc deprotection of the anilino group was carried out as described in step 2 in the example above.
The four different examples of resin[building block 1][building block 2] thus prepared were equally distributed in the wells in the synthesizer prior to the initialization of the device. The attachment of the array of [building block 3] mentioned above was carried out in a fully combinatorial way with the four types of resinfbuilding block 1][building block 2] using the general procedure as described in step 3 in the example above. The final cleavage was performed using the same general procedure as described in step 4 in the example above. During this cleavage step deprotection of acid sensible protection groups was also taken place. These two steps 3 and 4 were carried out (in several runs) on an ACT 496 HTS automated synthesizer using the following ChemFile to control the device.
ChemFile: C:\DATA\90250017.CHM
1 Empty RB1to96 for 2.000 minute(s)
2 Flush Arm1 with NMParml and DCMarml
3
4 REM Adding acids 1 to 36
5 Dispense Sequence C:\act\ACID1-36.DSP with 1000ul to RB1to96 rack using NMParmI Mix for 2.00 minutes at 600 rpm(s) Pause Mix for 2.00 minutes at 600 rpm(s) REM Adding acids 37 to 48 Dispense Sequence ACI37-48.DSP with 1000ul to RB1to96 rack using NMParmI Mix for 2.00 minutes at 600 rpm(s) Pause REM Adding DIC Transfer 300ul from Monomer1to36[12]() to RB1to96[2-48] using NMParmI Mix for 2.00 minutes at 600 rpm(s) Transfer 300ul from Monomer1to36[13]() to RB1to96[50-96] using NMParmI Mix for 10.00 minutes at 600 rpm(s) REM Adding DMAP Transfer 200ul from Monomer1to36[14]() to RB1to96[2-48] using NMParmI Transfer 200ui from Monomer1to36[14]() to RB1to96[50-96] using NMParmI REM Mixing overnight Mix for 10.00 minutes at 600 rpm(s) Wait for 20.000 minute(s) Repeat from step 32, 150 times REM wash Empty RB1to96 for 2.000 minute(s) Dispense System Fluid NMPdualarms* 1000ul to RB1to96[1-96] Mix for 3.00 minutes at 600 rpm(s) Empty RB1to96 for 2.000 minute(s) Repeat from step 39, 5 times REM de fmoc Mix for 3.00 minutes at 600 rpm(s) Dispense Sequence C:\act\DEFMOC.DSP with 1500ul to RB1to96 rack using NMParmI Mix for 15.00 minutes at 600 rpm(s) Empty RB1to96 for 3.000 minute(s) Empty RB1to24 for 3.000 minute(s) Empty RB49to72 for 2.000 minute(s) Pause REM wash Dispense System Fluid NMPdualarms* 1000ul to RB1to96[1-96] 55 Mix for 3.00 minutes at 600 rpm(s)
56 Empty RB1to96 for 3.000 minute(s)
57 Repeat from step 54, 2 times
58 Flush Arm1 with NMParmI and DCMarml , Arm2 with DCMarm2 59 Dispense System Fluid DCMdualarm* 1000ul to RB1to96[1-96]
60 Mix for 3.00 minutes at 600 rpm(s)
61 Empty RB1to96 for 3.000 minute(s)
62 Repeat from step 59, 5 times 63 64 REM TFA CLEAVAGE 65
66 Mix for 1.00 minutes at 300 rpm(s)
67 Transfer 1000ul from Reagent2[1]() to RBcleavage1to96[1-96] using DCMarml
68 Mix for 1.00 hours at 600 rpm(s) 69 Empty RBcleavage1to96 for 30 second(s)
70 Dispense System Fluid DCMdualarm* 500ul to RBcleavage1to96[1-96]
71 Mix for 5.00 minutes at 300 rpm(s)
72 Empty RBcleavage1to96 for 30 second(s) 73
Dispense sequence files C:\act\ACID1-36.DSP are subroutines that control the combinatorial addition of the amines into the 4 reaction blocks each containing 96 wells in the syntheziser.
Examples of compounds from this library were characterized by HPLC-MS (molecular mass & retention time) and includes:
EXAMPLE 805:
Quinoline-2-carboxylic acid {4-[(3-chloro-4-hydroxybenzoyhhydrazonomethyl]-3- methoxyphenyl}amide
Figure imgf000447_0001
m.p. 236-238°C
HPLC (Method 1) Rt=26.2 min
EXAMPLE 806: N-f4-[f3-chloro-4-hydroxybenzoyπhydrazonomethyl]-2-methoxyphenyl}-2-(4- trifluoromethoxyphenoy cetamide
Figure imgf000448_0001
m.p. 216-218°C
HPLC (Method 1) R,=26.6 min
EXAMPLE 807:
Quinoline-2-carboxylic acid {4-[(3-chloro-4-hydroxybenzoyl)hydrazonomethyl]-2- methoxyphenyl}amide
Figure imgf000448_0002
m.p. 159-162°C
HPLC (Method 1 ) Rt=27.7 min
EXAMPLE 808:
N-{4-[(3-Chloro-4-hydroxybenzoyπhydrazonomethyl]-3-methoxyphenyl}-2-(4- chlorophenoxy)acetamide
Figure imgf000448_0003
m.p. 216-218°C
HPLC-MS (METHOD A) Rt=13.4 min, m/z=488 EXAMPLE 809:
N-{4-[(3-Chloro-4-hydroxybenzoyhhydrazonomethyl]-3-methoxyphenyl}-6- methylnicotinamide
Figure imgf000449_0001
HPLC-MS (METHOD A) Rt=8.2 min, m/z=439
EXAMPLE 810:
N-{4-[(3-Chloro-4-hydroxybenzoyl')hydrazonomethyl]-3-methoxyphenyl}-2-(3- trifluoromethylphenyπacetamide
Figure imgf000449_0002
HPLC-MS (METHOD A) Rt=13.4 min, m/z=506
EXAMPLE 811 :
N-{4-[(3-Chloro-4-hydroxybenzoyπhydrazonomethyl]-3-methoxyphenyl}-2-(2.4- dichlorophenoxy cetamide
Figure imgf000450_0001
HPLC-MS (METHOD A) Rt=14.3 min, m/z=524
EXAMPLE 812:
N-{4-[(3-Chloro-4-hydroxybenzoyπhydrazonomethyl]-3-methoxyphenyl}-3-(4- trifluoromethylphenyl)propionamide
Figure imgf000450_0002
HPLC-MS (METHOD A) Rt=14.0 min, m/z=520
EXAMPLE 813:
lsoquinoline-1 -carboxylic acid (4-[(3-chloro-4-hydroxybenzoyπhydrazonomethyl]-3- methoxyphenyl}amide
Figure imgf000450_0003
HPLC-MS (METHOD A) Rt=13.0 min, m/z=475 EXAMPLE 814:
7-Ethoxybenzofuran-2-carboxylic acid {4-[(3-chloro-4-hydroxybenzoyl)hydrazonomethyl]-3- methoxyphenyl}amide
Figure imgf000451_0001
HPLC-MS (METHOD A) Rt=13.3 min, m/z=508
EXAMPLE 815:
N-{4-[(3-Chloro-4-hydroxybenzoyπhydrazonomethyl]-3-methoxyphenyl}-2-(toluene-4- sulonyπacetamide
Figure imgf000451_0002
HPLC-MS (METHOD A) Rt=10.8 min, m/z=517
EXAMPLE 816:
Benzofuran-2-carboxylic acid {4-[(3-Chloro-4-hydroxybenzovπhvdrazonomethyl]-3- methoxyphenyl}-amide
Figure imgf000452_0001
HPLC-MS (METHOD A) Rt=12.3 min, m/z=465
EXAMPLE 817:
N-{4-[(3-Chloro-4-hydroxybenzoyl)hydrazonomethyl]-3-methoxyphenyl}-3-cyanobenzamide
Figure imgf000452_0002
HPLC-MS (METHOD A) Rt=10.8 min, m/z=450
EXAMPLE 818:
5-Chloro-4-methoxythiophene-3-carboxylic acid {4-[(3-Chloro-4- hydroxybenzoyl)hydrazonomethyl]-3-methoxyphenyl}amide
Figure imgf000452_0003
HPLC-MS (METHOD A) Rt=9.8 min, m/z=495 EXAMPLE 819:
5-Bromofuran-2-carboxylic acid {4-[(3-Chloro-4-hydroxybenzoyl)hydrazonomethyl]-3- methoxyphenyl}amide
Figure imgf000453_0001
HPLC-MS (METHOD A) Rt=11.4 min, m/z=494
EXAMPLE 820:
2-Benzo[b]thien-3-yl-N-{4-[f3-chloro-4-hydroxybenzoyl)hydrazonomethyl]-2- methoxyphenyl}acetamide
Figure imgf000453_0002
HPLC-MS (METHOD A) Rt=13.4 min, m/z=494
EXAMPLE 821 :
N-f4-[(3-Chloro-4-hydroxybenzoyl)hydrazonomethyl]-2-methoxyphenyl}-2-(4-chlorophenoxy 2-methylpropionamide
Figure imgf000453_0003
HPLC-MS (METHOD A) Rt=14.7 min, m/z=516 EXAMPLE 822:
N-{4-[(3-Chloro-4-hydroxybenzoyl)hydrazonomethyl]-2-methoxyphenyl}-3-(3- trifluoromethylphenyl)acrylamide
Figure imgf000454_0001
HPLC-MS (METHOD A) Rt=14.3 min, m/z=518
EXAMPLE 823:
N-{4-[(3-Chloro-4-hydroxybenzoyl)hydrazonomethyl]-2-methoxyphenyl}-2-fluoro-3- phenylacrylamide
Figure imgf000454_0002
HPLC-MS (METHOD A) Rt=14.3 min, m/z=468
EXAMPLE 824:
2-Benzo[b]thieophene-2-carboxylic acid {4-[f3-chloro-4-hydroxybenzoy0hydrazonomethyl]-2- methoxyphenyl}amide
Figure imgf000455_0001
HPLC-MS (METHOD A) Rt=13.8 min, m/z=480
HPLC Method 1.
The RP-HPLC analysis was performed using UV detection at 254 nm and a Merck Hibar LiChrosorb RP-18 (5 μm) prepacked column (Cat. No. 50333), which was eluted at 1 mL/minute. Two solvent systems were used: Solvent system I: 0.1% Trifluoroacetic acid in acetonitrile. Solvent system II: 0.1% Trifluoroacetic acid in water.
The column was equilibrated with a mixture composed of 20% of solvent system I and 80% of solvent system II. After injection of the sample a gradient of 20% to 80% of solvent system I in solvent system II was run over 30 minutes. The gradient was then extended to 100% of solvent system I over 5 minutes followed by isocratic elution with 100% of this system for 6 minutes.
General Procedure for Examples 825 to 875:
The compounds were prepared as single entities according to the following equation
Resin [Building block 1] *-
Resin [Building block 1] [Building block 2] *-
Resin [Building block 1] [Building block 2] [Building block 3]
and were simultaneously deprotected and cleaved from the resin with 50% trifluoroacetic acid in dichloromethane to give the desired compounds as individual entities according to the following formula [Building block 1] [Building block 2] [Building block 3].
The following compounds were prepared as single entities by parallel synthesis on a solid support. Preparation of Resin-[Building block 1]-[Building block 2] was done manually, whereas the attachment of [Building block 3] and cleavage from the resin were performed on an Advanced ChemTech Model 384 HTS.
The starting resin, Resin-[Building block 1], was prepared as described above.
The resin used was a polystyrene resin with a Wang linker and the substitution capacity was 0.9 mmol/g.
All compounds are based on successive attachment of [Building block 2] and [Building block 3] to Resin-[Building block 1] in a combinatorial way using a nucleophilic substitution reaction according to the following formulae, which are included in the general formula II:
Figure imgf000457_0001
Resin-[Building block 1] [Building block 2]
Resin-[Building block 1]-[Building block 2]
CI-S-CH,
Figure imgf000457_0002
Figure imgf000457_0003
[Building block 1]-[Building block 2]-[Building block 3] Resin-[Building block 1]-[Building block 2]-[Building block 3]
and
Figure imgf000458_0001
Resin-[Building block 1] [Building block 2]
Resin-[Building block 1]-[Building block 2]
O
Cl- -S-CH, o
Figure imgf000458_0002
HSR* [Building block 3]
Figure imgf000458_0003
[Building block 1]-[Building block 2]-[Building block 3]
Resin-[Building block 1]-[Building block 2]-[Building block 3]
wherein R14, R15 are as defined for formula I and -NR5cR5d is
Figure imgf000458_0004
where R5a, R4a, R4b, c, q, d, and D are as defined for formula I or
-D' where -D' is defined as a subset of -D that contains a primary or a secondary amine that can react as a nucleophile; and -SR5c is
Figure imgf000459_0001
where R4a, R4 , c, q, d, and D are as defined for formula I or -D' where -D' is defined as a subset of -D that contains a thiol that can react as a nu- cleophile.
The following resin, here depicted as Resin-[Building block 1] was used:
where PS is polystyrene. In the following "Resin" is the polystyrene resin with the Wang linker:
Figure imgf000459_0002
= Resin
Figure imgf000459_0003
The following building blocks were used:
rBuilding block 2]:
4-Hydroxymethylnaphthalene-1 -
Figure imgf000459_0004
carbaldehyde
fBuilding block 3]:
Figure imgf000459_0005
Figure imgf000460_0001
Figure imgf000461_0001
Figure imgf000462_0001
Figure imgf000463_0001
Figure imgf000464_0001
Figure imgf000465_0001
Figure imgf000466_0001
Preparation of resin-[Building block 1]:
This resin was prepared as described above.
Preparation of 4-hydroxymethylnaphtaldehyde ([Building block 2]):
The preparation of this compound is described above.
Preparation of resin-[Buildinα block 1]-[Building block 2]:
Preparation of resin bound 3-chloro-4-hydroxybenzoic acid (4- hydroxymethylnaphthylmethylene)hydrazide:
Figure imgf000467_0001
Resin-[Building block 1] (4 g) was suspended in DMF (40 mL) and was allowed to swell for 15 min. and then washed with DMF (2 x 40 mL), DCM (3 x 40 mL) and DMSO (2 x 40 mL). The solvent was removed by filtration. 1.488 g (8 mmol) 4-hydroxymethylnaphtaldehyde was dissolved in 40 mL DMSO and was added to the resin followed by 4 mL glacial acetic acid. The suspension was shaken for 16 hours at 25 °C. The resin was successively washed with DMSO (2 x 40 mL), THF (3 x 40 mL), CH3OH (40 mL), CH2CI2 (40 mL), CH3OH (40 mL), CH2CI2 (40 mL) and dried in vacuo at 40 °C for 16 hours to afford resin bound 3-chloro-4- hydroxy benzoic acid (4-hydroxymethylnaphthylmethylene)hydrazide.
EXAMPLE 825:
3-chloro-4-hydroxybenzoic acid (4-(1 H-1.2.4-Triazol-3-ylsulfanylmethynnaphthyl- methylene)hydrazide
Figure imgf000468_0001
The resin bound 3-chloro-4-hydroxybenzoic acid (4-hydroxymethylnaphthylmethylene)- hydrazide (resin-[Building block 1]-[Building block 2]) (2 g, ~ 2 mmoles) was swelled in CH2Cl2 (20 mL) for 15 min, then washed twice with CH2CI2 (20 mL). 8 mL CH2CI2 and 8 ml diisopropylethylamine was subsequently added and the suspension was cooled to 0 °C. Methanesulfonylchloride (2 mL) was dissolved in CH2CI2 (6 mL) and added to the suspension. The mixture was allowed to react at 0 °C for 30 min, then at 25 °C for 1 hour. The resin was isolated by filtration and washed with CH2CI2 (2 x 20 mL) and N-methyl-2-pyrrolidone (2 x 20 mL). 1 H-1 ,2,4-Triazole-3-thiol (0.8 g) and Kl (0.4 g) was dissolved in a mixture of 10 mL N-methyl-2-pyrrolidone and 10 mL dimethylsulfoxide and was added to the resin. Then 4 mL diisopropylethylamine was added and the mixture was shaken at 25 °C for 2 days. The solvent was removed by suction and the resin was washed with N-methyl-2-pyrrolidone (3 x 20 mL) THF (3 x 20 mL), CH3OH (20 mL), CH2CI2 (20 mL), CH3OH (20 mL), CH2CI2 (4 x 20 mL). The compound was cleaved from the resin by shaking for 1 hour at 25 °C with a 50% solution of trifluoroacetic acid in CH2CI2 (20 mL). The mixture was filtered and the resin was extracted with acetonitrile (20 mL). The combined extracts were concentrated in vacuo. The residue was redissolved in a mixture of CH3OH (10 mL) and acetonitrile (10 mL) and concentrated in vacuo. The residue was treated with CH3OH (4 mL) at 25 °C providing an off- white precipitate which was isolated by filtration. The solid was washed with CH3OH (3 x 2 mL) and dried in vacuo at 40 °C.
This afforded 275 mg of the title compound.
HPLC-MS (METHOD B): R, = 2.48 min; m/z = 438 (M+1 ).
1H-NMR (300 MHz, DMSO-d6) δ = 4.9 (2H, s), 7.1 (1H, d),7.5-7.9 (5H, m), 8.0 (1H, s), 8.25 (1 H, d), 8.9 (1 H, d), 9.1 (1 H, s), 11.0 (1 H, s), 11.8 (1 H, s)
EXAMPLE 826:
3-Chloro-4-hydroxybenzoic acid (4-(isobutylaminomethyl)naphthylmethylene)hydrazide
Figure imgf000469_0001
The resin bound 3-chloro-4-hydroxybenzoic acid (4-hydroxymethylnaphthyl- methylene)hydrazide (resin-[Building block 1]-[Building block 2]) (50 mg, ~ 0.05 mmoles) was swelled in CH2CI2 (1 mL) for 15 min, then washed with CH2CI2 (2 x 0.5 mL). 0.4 mL CH2CI2 and 0.4 mL diisopropylethylamine was subsequently added and the suspension was cooled to 0 °C. Methanesulfonylchloride (0.1 mL) was dissolved in CH2CI2 (0.3 mL) and added to the suspension. The mixture was allowed to react at 0 °C for 30 min, then at 25 °C for 1 hour. The resin was isolated by filtration and washed with CH2CI2 (2 x 0.5 mL) and DMSO (0.5 mL). DMSO (0.5 mL) was added followed by 50 μL isobutylamine and 100 μL diisopropylethylamine. The mixture was shaken at 25 °C for 16 hours, filtered and washed successively with DMSO (2 x 0.5 mL), THF (3 x 0.5 mL), CH3OH (0.5 mL), CH2CI2 (0.5 mL), CH3OH (0.5 mL), CH2CI2 (4 x 0.5 mL). The compound was cleaved from the resin by shaking for 1 hour at 25 °C with a 50% solution of trifluoroacetic acid in CH2CI2 (1 mL). The mixture was filtered and the resin was extracted with acetonitrile (1 mL). The combined extracts were concentrated in vacuo. The residue was redissolved in a mixture of CH3OH (0.5 mL) and acetonitrile (0.5mL) and concentrated in vacuo to give the title compound.
HPLC-MS (METHOD B): R, = 4.20 min; m/z = 410 (M+1)
EXAMPLE 826:
3-Chloro-4-hydroxybenzoic acid ((4-(4-trifluoromethoxybenzylamino)methyπnaphthyl-
Figure imgf000469_0002
Resin bound 3-chloro-4-hydroxybenzoic acid (4-hydroxymethylnaphthylmethylene)hydrazide: (resin-[building block 1]-[building block 2]) (50 mg) was swelled in a 1 :1 mixture of CH2CI2 and N-methyl-2-pyrrolidone (0.5 mL) for 15 minutes and then washed with CH2CI2 (3 x 0.5 mL). 800 μL of a 1 :1 mixture of CH2CI2 and diisopropylethylamine was added to the resin which subsequently was cooled to -3 °C. A solution of 100 μL methanesulfonylchloride dissolved in 300 μL was added and allowed to react at -3 °C for 30 minutes then at 25 °C for 1 hour. Filtration of the resin was followed by washing with CH2CI2 (2 x 1 mL) and N-methyl-2- pyrrolidone (2 x 0.5 mL). 600 μL of a solution of 4-trifluoromethoxybenzylamine (45.8 mg, 0.24 mmol, 0.4M) and Kl (10 mg, 0.06 mmol, 0.1 M) in N-methyl-2-pyrrolidone (0.5 mL) and diisopropylethylamine (0.1 mL) was added and allowed to react at 25 °C for 16 hours. The resin was isolated by filtration and washed successively with N-methyl-2-pyrrolidone (5 x 0.5 mL), THF (3 x 0.8 mL), CH3OH (0.8 mL), CH2CI2 (0.8 mL), CH3OH (0.8 mL) and CH2CI2 (3 x 0.8 mL). The compound was cleaved from the resin by shaking 1 hour at 25 °C with a solu- tion of 50% trifluoroacetic acid in CH2CI2 (1 mL) The mixture was filtered and the resin was extracted with acetonitrile (1 mL). The combined extracts were concentrated in vacuo. The residue was redissolved in a mixture of CH3OH (0.5 mL) and acetonitrile (0.5mL) and concentrated in vacuo to give the title compound.
HPLC-MS (METHOD A): R, = 10.07 min; m/z = 528 (M+1 )
EXAMPLES 828 TO 875:
A library of compounds of all the possible combinations of the above listed building blocks ([building block 1], [building block 2] and [building block 3]) was prepared in parallel as individual entities analogously to the previous example on an Advanced ChemTech Model 384 HTS using the following ChemFile to control the operation of the synthesizer. The compounds are all expected to be present in the respective wells.
A suspension of the resin bound 3-chloro-4-hydroxybenzoic acid (4-hydroxymethyl- naphthylmethylene)hydrazide: (resin-[building block 1]-[building block 2]) (50 mg) in a 1 :1 mixture of CH2CI2 and N-methyl-2-pyrrolidone (0.5 mL) is equally distributed in the wells in the synthesizer prior to the initialization of the device.
ChemFile C:\ACT_1328\MAIN.CHM
1 REM Nucleophilic displacement of benzylic alcohol 2 REM via mesylation 3 4
5 REM Dipense resin bound benzylic alchohol to wells 6 7
8 REM Setup Diluterl =DCM, D2=NMP (N-methyl-2-pyrrolidone), D3=NMP, D4=DCM
9 REM Adjust pressure
10 REM Add 100 mL DIEA/DCM 1 :1 mixture to Reagentl 11 REM Add 70 mL MsCI/DCM 1 :3 mixture to Reagent2
12 REM Add 100 mL TFA/DCM 1 :1 mixture to Reagent3
13 REM Add 100 mL CH3CN to Reagent4
14 REM Nitrogen for cooling 15 16 Pause
17 REM Initialising...
18
19 REM Subroutine Empty 1_72_3min is called twice to remove DCM/NMP from dispensed resin 20 Go to ChemFile MTY72_3M.CHM, line 1
21 Go to ChemFile MTY72_3M.CHM, line 1
22
23 Flush Arm1 with Flush Diluterl and Flush Diluter 2 , Arm2 with Flush Diluter 3 and with
Flush Diluter 4 24
25 REM Washing with DCM, 3 times
26 Dispense System Fluid Disdu1_4* 500ul to RB1_1to96[1-72] 27 Mix "RB1_1to96" for 3.00 minutes at 300 rpm(s) and wait. 28 REM Subroutine Empty1_72_3min 29 Go to ChemFile MTY72_3M.CHM, line 1 30 Repeat from step 26, 2 times 31
32 REM Adding DCM/DIEA mixture from Reagentl
33 Transfer 800ul from REAGENT_1 [1](DCM/DIEA) to RB1_1to96[1-72] using Flush Diluterl 34 Mix "RB1_1to96" for 1.00 minutes at 300 rpm(s) and wait.
35 Set Temperature of rack "RB1_1to96" to -3.0 degrees Celsius and wait for Temperera- ture to reach setpoint
36 Mix "RB1_1to96" for 1.00 minutes at 300 rpm(s) and wait. 37 REM Ensure complete cooling 38 Wait for 15.000 minute(s) 39
40 REM Adding mesylchloride
41 Transfer 400ul from REAGENT_2[1](MsCI/DCM) to RB1_1to96[1-72] using Flush Diluterl
42 REM Reacts 30 min @ -3 °C 43 Mix "RB1_1to96" for 1.00 minutes at 300 rpm(s) and wait.
44 Wait for 4.000 minute(s)
45 Repeat from step 43, 5 times 46
47 REM Reacts 60 min @ 25 C 48 Set Temperature of rack "RB1_1to96" to 25.0 degrees Celsius and wait for Temperera- ture to reach setpoint
49 Mix "RB1_1to96" for 1.00 minutes at 300 rpm(s) and wait. 50 Wait for 4.000 minute(s) 51 Repeat from step 46, 11 times 52
53 REM Subroutine Empty1_72_3min
54 Go to ChemFile MTY72_3M.CHM, line 1 55 56 REM Initiate washing procedure, 2XDCM
57 Dispense System Fluid Disdu1_4* 1000ul to RB1_1to96[1-72] 58 Mix "RB1_1to96" for 3.00 minutes at 300 rpm(s) and wait.
59 Go to ChemFile MTY72_3M.CHM, line 1
60 Repeat from step 57, 1 times 61
62 REM NMP wash 63
64 Dispense System Fluid Disdu2_3* 500ul to RB1_1to96[1-72]
65 Mix "RB1_1to96" for 5.00 minutes at 300 rpm(s) and wait. 66 Go to ChemFile MTY72_3M.CHM, line 1
67
68 Go to ChemFile MTY72_3M.CHM, line 1
69 Repeat from step 64, 1 times 70 71 REM Make sure that nucleophiles are dissolved and ready for addition
72 Pause
73
74 Dispense Sequence C:\ACT_1328\R2-A.DSP with 600ul to RB1_1to96 rack using Flush
Diluter 2 75 REM Nucleophiles react @ 25 C for 16 hr
76 Mix "RB1_1to96" for 1.00 minutes at 300 rpm(s) and wait.
77 Wait for 4.000 minute(s)
78 Repeat from step 76, 11 times
79 Repeat from step 76, 15 times 80
81 REM End of reaction
82 Go to ChemFile MTY72_3M.CHM, line 1
83 Go to ChemFile MTY72_3M.CHM, line 1 84 85 REM Commence final washing procedure
86 Dispense System Fluid Disdu2_3* 500ul to RB1_1to96[1-72] 87 Mix "RB1_1to96" for 10.00 minutes at 300 rpm(s) and wait.
88 Go to ChemFile MTY72_3M.CHM, line 1
89 Go to ChemFile MTY72_3M.CHM, line 1 90 Repeat from step 86, 4 times
91
92 REM Change systemfluids:
93 REM * Diluter2: THF
94 REM * Diluter3: MeOH 95 Pause 96
97 Flush Arm1 with Flush Diluterl and Flush Diluter 2 , Arm2 with Flush Diluter 3 and Flush Diluter 4 98 REM THF wash 3 times
99 Dispense System Fluid Flush Diluter 2 800ul to RB1_1to96[1-72] 100 Mix "RB1_1to96" for 10.00 minutes at 300 rpm(s) and wait.
101 Go to ChemFile MTY72_3M.CHM, line 1
102 Go to ChemFile MTY72_3M.CHM, line 1 103 Repeat from step 99, 2 times
104
105 REM Alternating MeOH/DCM wash, 2 cycles
106 Dispense System Fluid Flush Diluter 3 800ul to RB1_1to96[1-72] 107 Mix "RB1_1to96" for 3.00 minutes at 300 rpm(s) and wait. 108 Go to ChemFile MTY72_3M.CHM, line 1 109
110 Dispense System Fluid Disdu1_4* 800ul to RB1_1to96[1-72]
111 Mix "RB1_1to96" for 10.00 minutes at 300 rpm(s) and wait.
112 Go to ChemFile MTY72_3M.CHM, line 1 113 Go to ChemFile MTY72_3M.CHM, line 1
114
115 Repeat from step 106, 1 times 116
117 Dispense System Fluid Disdu1_4* 800ul to RB1_1to96[1-72] 118 Mix "RB1_1to96" for 10.00 minutes at 300 rpm(s) and wait.
119 Go to ChemFile MTY72_3M.CHM, line 1
120 Repeat from step 117, 1 times 121
122 REM Washing procedure has ended 123
124 REM Setup for cleavage:
125 REM * Cleavage vials
126 REM * Lower pressure
127 REM * Add 100 mL TFA/DCM 1:1 mixture to Reagent3 128 REM * Add 100 mL CH3CN to Reagent4
129 Pause 130
131 REM Adding cleavage solution, 1hr
132 Transfer 1000ul from REAGENT_3[1] (TFA/DCM) to RB1_1to96[1-72] using Flush Di- luterl
133 Mix "RB1_1to96" for 1.00 minutes at 300 rpm(s) and wait.
134 Wait for 4.000 minute(s)
135 Repeat from step 133, 11 times
136 REM PULSE EMPTY! 137 Go to ChemFile PULSEMP1.CHM, line 1 138
139 REM Washing with CH3CN
140 Transfer 500ul from REAGENT_4[1](CH3CN) to RB1_1to96[1-72] using Flush Diluterl
141 Mix "RB1_1to96" for 10.00 minutes at 300 rpm(s) and wait. 142 REM PULSE EMPTY!
143 Go to ChemFile PULSEMP1.CHM, line 1 144
145 REM The End 146
The following chemfile is called to empty the wells of the reaction block.:
ChemFile C:\ACT_1328\MTY72_3M.CHM
1 REM Subroutine Empty1_72_3min
2 Empty RB1_1to96 for 5.000 minute(s)
3 Return
The following chemfile is called to empty the wells of the reaction block into the cleavage vials containing the final product in a controlled manner.
ChemFile C:\ACT 1328\PULSEMP1.CHM
1 Empty RB1_1to96 for 1 second(s)
2 Wait for 4 second(s)
3 Repeat from step 1 , 11 times
4 Empty RB1_1to96 for 5.000 minute(s)
5 Return
Dispense sequence C:\ACT_1328\R2-A.DSP is a subroutine that controls the combinatorial addition of the amines into the reaction block in the syntheziser.
Examples of compounds from this library were characterised by HPLC-MS (molecular mass & retention time) including the following examples 828 to 875:
Figure imgf000475_0001
Figure imgf000476_0001
Figure imgf000477_0001
Figure imgf000477_0002
Figure imgf000478_0001
Figure imgf000479_0001
Figure imgf000480_0001
EXAMPLE 874:
Figure imgf000480_0002
1H NMR (DMSO-D6) d 2.37 (m, 8H), 3.44 (s, 2H), 3.90 (s, 2H), 7.10 (d, J = 8.5 Hz, 1 H), 7.30 (d, J = 8.5 Hz, 2H), 7.37 (d, J = 8.5 Hz, 2H), 7.55 (d, J = 7.4 Hz, 1 H), 7.67 (m, 2H), 7.81 (d, J = 8.7 Hz, 1 H), 7.86 (d, J = 7.3 Hz, 1 H), 8.02 (d, J = 1.8 Hz, 1 H), 8.36 (dd, J = 1.7, 7.0 Hz, 1 H), 8.83 (d, J = 8.0 Hz, 1H), 9.08 (s, 1H), 10.99 (s, 1H), 11.78 (s, 1H). MS (APCI, pos.): 547.1 , 550.1
EXAMPLE 875:
Figure imgf000481_0001
1H NMR (DMSO-D6) d 2.66 - 2.75 (m, 4H), 3.69 (s, 2H), 4.06 (s, 2H), 6.36 (m, 1 H), 6.40 (m, 1H), 7.06 (d, J = 8.5 Hz, 1H), 7.51 - 7.66 (m, 4H), 7.77 (d, J = 8.0 Hz, 1H), 7.83 (d, J = 7.1 Hz, 1 H), 7.98 (s, 1 H), 8.26 (d, J = 8.5 Hz, 1 H), 8.80 (d, J = 8.5 Hz, 1 H), 9.04 (s, 1 H), 10.94 (s, 1 H), 11.77 (s, 1 H). MS (APCI, pos.): 485.1 , 487.1
General Procedure for Examples 876 to 877:
The compounds were prepared as single entities according to the following equation
Resin — [Building block 1] *-
Resin — [Building block 1] — [Building block 2] »-
Resin — [Building block 1] — [Building block 2] [Building block 3] *-
Resin — [Building block 1] — [Building block 2] [Building block 3] [Building block 4
and were simultaneously deprotected and cleaved from the resin with 50% trifluoroacetic acid in dichloromethane to give the desired compounds as individual entities according to the following formula [Building block 1] [Building block 2] [Building block 3] [Building block 4].
The following compounds were prepared as single entities by parallel synthesis on a solid support. Preparation of Resin-[Building block 1]-[Building block 2] was done manually, whereas the attachment of [Building block 3], attachment of [Building block 4] and cleavage from the resin were performed on an Advanced ChemTech Model 384 HTS.
The starting resin, Resin-[Building block 1], was prepared as described above.
The resin used was a polystyrene resin with a Wang linker and the substitution capacity was 0.9 mmol/g.
All compounds are based on successive attachment of [Building block 2] and [Building block 3] to Resin-[Building block 1] in a combinatorial way using a nucleophilic substitution reaction followed by an acylation reaction attaching [Building block 4] according to the following formulae, which are included in the general formula II:
Figure imgf000483_0001
Resιn-[Buιldιng block 1] [Building block 2]
Resιn-[Buιldιπg block 1]-[Buιldιng block 2]
O
CI-S-CH,
O
[Building block 3]
Figure imgf000483_0002
Figure imgf000483_0003
Resιn-[Buιldιng block 1]-[Buιldιng block 2]-[Buιldιng block 3] o
R^Lea " [Building block 4]
Figure imgf000483_0004
Resιn-[Buιldιng block 1]-[Buιldιng block 2]-[Buιldιng block 3]-[Buιldιng block 4] [Building block 1]-[Buιldιng block 2]-[Buιldιng block 3]-[Buιldιng block 4]
wherein R5a, R14, R15 are as defined for formula I and R5c is
Figure imgf000483_0005
where R4a, R4b, c, q, d, and D are as defined for formula I or
-D' where -D' is defined as a subset of -D that contains an activated carboxylic acid capable of reacting as an electrophile and
Lea is a leaving group such as chloro, bromo, iodo, carboxylate,
Figure imgf000484_0001
The following resin, here depicted as Resin-[Building block 1] was used:
where PS is polystyrene. In the following "Resin" is the polystyrene resin with the Wang linker:
Figure imgf000484_0002
= Resin
Figure imgf000484_0003
The following building blocks were used:
Building block 2~[:
4-Hydroxymethylnaphthalene-1 - carbaldehyde
Figure imgf000484_0004
[Building block 3]:
Figure imgf000485_0001
[Building block 4]:
Acetic anhyN-tert Butoxycarbonyl- dride proline anhydride
Figure imgf000486_0001
Preparation of resin-[Building block 1]:
This resin was prepared as described above.
Preparation of resin-[Building block 11-fBuilding block 2]:
This resin was prepared as described above.
EXAMPLE 876:
N-f4-[(3-Chloro-4-hydroxybenzoyπ-hydrazonomethyl]naphthylmethyl}-N-isobutylprolinamide
Figure imgf000486_0002
The resin bound 3-chloro-4-hydroxybenzoic acid (4-hydroxymethylnaphthyl- methylene)hydrazide (resin-[Building block 1]-[Building block 2]) (50 mg, ~ 50 μmoles) was swelled in CH2CI2 (0.5 mL) for 15 min, then washed twice with CH2CI2 (0.5 mL). 0.4 mL CH2CI2 and 0.4 mL diisopropylethylamine were subsequently added and the suspension was cooled to 0 °C. Methanesulfonylchloride (0.1 mL) was dissolved in CH2CI2 (0.3 mL) and added to the suspension. The mixture was allowed to react at 0 °C for 30 min, then at 25 °C for 1 hour. The resin was isolated by filtration and washed with CH2CI2 (2 x 0.5 mL) and DMSO (0.5 mL). 0.5 mL DMSO was added to the resin followed by isobutylamine (50 μL) and diisopropylethylamine (100 μL). The mixture was shaken at 25 °C for 16 hours. The solvent was removed by suction and the resin was washed with DMSO (2 x 0.5 mL) andTHF (3 x 0.5 mL). To a solution of N-te/ϊ- butoxycarbonyl-proline (46 mg, 0.21 mmol) in THF (0.5 mL) was added diisopropylcarbodiimide (16 μL, 0.2 mmol). This solution was allowed to re- act at 25 °C for 10 minutes and then added to the resin. The suspension was shaken at 25 °C for 16 hours after which the resin was isolated by suction and washed with THF (3 x 0.5 mL), DMF (3 x 0.5 mL) THF (3 x 0.5 mL), CH3OH (0.5 mL), CH2CI2 (0.5 mL), CH3OH (0.5 mL), CH2CI2 (4 x 0.5 mL). The compound was cleaved from the resin by shaking for 1 hour at 25 °C with a 50% solution of trifluoroacetic acid in CH2CI2 (1 mL). The mixture was filtered and the resin was extracted with acetonitrile (1 mL). The combined extracts were concentrated in vacuo. The residue was redissolved in a mixture of CH3OH (0.5 mL) and acetonitrile (0.5 mL) and concentrated in vacuo to give the title compound.
HPLC-MS (METHOD B): R, = 3.90 min; m/z = 507 (M+1 ).
EXAMPLE 877:
3-Chloro-4-hydroxybenzoic acid ((4-(4-trifluoromethoxybenzylamino)methy0naphthyl- methylene)hydrazide
Figure imgf000487_0001
Resin bound 3-chloro-4-hydroxybenzoic acid (4-hydroxymethylnaphthylmethylene)hydrazide (resin-[building block 1]-[building block 2]) (50 mg) was swelled in a 1 :1 mixture of CH2CI2 and N-methyl-2-pyrrolidone (0.5 mL) for 15 minutes and then washed with CH2CI2 (3 x 0.5 mL). 800 μL of a 1 :1 mixture of CH2CI2 and diisopropylethylamine was added to the resin which subsequently was cooled to -3 °C. A solution of 100 μL methanesulfonylchloride dissolved in 300 μL was added and allowed to react at -3 °C for 30 minutes then at 25 °C for 1 hour. Filtration of the resin was followed by washing with CH2CI2 (2 x 1 mL) and N-methyl-2- pyrrolidone (2 x 0.5 mL). 600 μL of a solution of 4-trifluoromethoxybenzylamine (45.8 mg, 0.24 mmol, 0.4M) and Kl (10 mg, 0.06 mmol, 0.1 M) in N-methyl-2-pyrrolidone (0.5 mL) and diisopropylethylamine (0.1 mL) was added and allowed to react at 25 °C for 16 hours. The resin was isolated by filtration and washed successively with N-methyl-2-pyrrolidone (5 x 0.5 mL) and THF (3 x 0.5 mL). 600 μL of a solution of acetic anhydride (120 μL, 130 mg, 1.27 mmol) in THF (480 μL) was added to the resin. The mixture was allowed to react at 25 °C for 16 hr. The resin was filtered and washed successively with THF (2 x 0.8 mL), CH3OH (0.8 mL), CH2CI2 (0.8 mL), CH3OH (0.8 mL) and CH2CI2 (3 x 0.8 mL). The compound was cleaved from the resin by shaking for 1 hour at 25 °C with a solution of 50% trifluoroacetic acid in CH2CI2 (1 mL). The mixture was filtered and the resin was extracted with acetonitrile (1 mL). The combined extracts were concentrated in vacuo. The residue was redissolved in a mix- ture of CH3OH (0.5 mL) and acetonitrile (0.5mL) and concentrated in vacuo to give the title compound.
HPLC-MS (METHOD B): R, = 6.42 min; m/z = 492 (M+1)
EXAMPLES 878 TO 881 :
A library of compounds of all the possible combinations of the above listed building blocks ([building block 1], [building block 2], [building block 3] and acetic anhydride as [building block 4]) was prepared in parallel as individual entities analogously to the previous example on an Advanced ChemTech Model 384 HTS using the following ChemFile to control the operation of the synthesizer. The compounds are all expected to be present in the respective wells.
A suspension of the resin bound 3-chloro-4-hydroxybenzoic acid (4-hydroxymethyl- naphthylmethylene)hydrazide (resin-[building block 1]-[building block 2]) (50 mg) in a 1 :1 mixture of CH2CI2 and N-methyl-2-pyrrolidone (0.5 mL) is equally distributed in the wells in the synthesizer prior to the initialization of the device.
ChemFile C:\ACT 1328\MAIN.CHM
1 REM Nucleophilic displacement of benzylic alcohol
2 REM via mesylation 3
4 5 REM Dipense resin bound benzylic alchohol to wells 6 7
8 REM Setup Diluterl =DCM, D2=NMP (N-methyl-2-pyrrolidone), D3=NMP, D4=DCM 9 REM Adjust pressure
10 REM Add 100 mL DIEA/DCM 1 :1 mixture to Reagentl
11 REM Add 70 mL MsCI/DCM 1 :3 mixture to Reagent2
12 REM Add 100 mL TFA/DCM 1 :1 mixture to Reagent3
13 REM Add 100 mL CH3CN to Reagent4 14 REM Nitrogen for cooling
15
16 Pause
17 REM Initialising... 18 19 REM Subroutine Empty 1_72_3min is called twice to remove DCM/NMP from dispensed resin
20 Go to ChemFile MTY72_3M.CHM, line 1
21 Go to ChemFile MTY72_3M.CHM, line 1 22 23 Flush Arm1 with Flush Diluterl and Flush Diluter 2 , Arm2 with Flush Diluter 3 and with Flush Diluter 4 24
25 REM Washing with DCM, 3 times
26 Dispense System Fluid Disdu1_4* 500ul to RB1_1to96[1-72] 27 Mix "RB1_1to96" for 3.00 minutes at 300 rpm(s) and wait.
28 REM Subroutine Empty1_72_3min
29 Go to ChemFile MTY72_3M.CHM, line 1
30 Repeat from step 26, 2 times 31 32 REM Adding DCM/DIEA mixture from Reagentl
33 Transfer 800ul from REAGENT_1 [1](DCM/DIEA) to RB1_1to96[1-72] using Flush Diluterl
34 Mix "RB1_1to96" for 1.00 minutes at 300 rpm(s) and wait.
35 Set Temperature of rack "RB1_1to96" to -3.0 degrees Celsius and wait for Temperature to reach setpoint 36 Mix "RB1_1to96" for 1.00 minutes at 300 rpm(s) and wait.
37 REM Ensure complete cooling
38 Wait for 15.000 minute(s) 39
40 REM Adding mesylchloride 41 Transfer 400ul from REAGENT_2[1](MsCI/DCM) to RB1_1to96[1-72] using Flush Diluterl
42 REM Reacts 30 min @ -3 °C
43 Mix "RB1_1to96" for 1.00 minutes at 300 rpm(s) and wait.
44 Wait for 4.000 minute(s)
45 Repeat from step 43, 5 times 46
47 REM Reacts 60 min @ 25 C
48 Set Temperature of rack "RB1_1to96" to 25.0 degrees Celsius and wait for Temperature to reach setpoint
49 Mix "RB1_1to96" for 1.00 minutes at 300 rpm(s) and wait. 50 Wait for 4.000 minute(s)
51 Repeat from step 46, 11 times 52
53 REM Subroutine Empty1_72_3min 54 Go to ChemFile MTY72_3M.CHM, line 1 55
56 REM Initiate washing procedure, 2XDCM
57 Dispense System Fluid Disdu1_4* 1000ul to RB1_1to96[1-72]
58 Mix "RB1_1to96" for 3.00 minutes at 300 rpm(s) and wait. 59 Go to ChemFile MTY72_3M.CHM, line 1
60 Repeat from step 57, 1 times
61
62 REM NMP wash
63 64 Dispense System Fluid Disdu2_3* 500ul to RB1_1to96[1-72]
65 Mix "RB1_1to96" for 5.00 minutes at 300 rpm(s) and wait.
66 Go to ChemFile MTY72_3M.CHM, line 1
67
68 Go to ChemFile MTY72_3M.CHM, line 1 69 Repeat from step 64, 1 times
70
71 REM Make sure that nucleophiles are dissolved and ready for addition
72 Pause 73 74 Dispense Sequence C:\ACT_1328\R2-A.DSP with 600ul to RB1_1to96 rack using Flush Diluter 2
75 REM Nucleophiles react @ 25 C for 16 hr
76 Mix "RB1_1to96" for 1.00 minutes at 300 rpm(s) and wait.
77 Wait for 4.000 minute(s) 78 Repeat from step 76, 11 times 79 Repeat from step 76, 15 times 80
81 REM End of nucleophilic substitution reaction
82 Go to ChemFile MTY72_3M.CHM, line 1 83 Go to ChemFile MTY72_3M.CHM, line 1
84
85 REM Commence washing procedure
86 Dispense System Fluid Disdu2_3* 500ul to RB1_1to96[1-72]
87 Mix "RB1_1to96" for 10.00 minutes at 300 rpm(s) and wait. 88 Go to ChemFile MTY72_3M.CHM, line 1
89 Go to ChemFile MTY72_3M.CHM, line 1
90 Repeat from step 86, 4 times 91
92 REM Change systemfluids: 93 REM * Diluter2: THF
94 REM * Diluter3: MeOH
95 Pause 96 97 Flush Armi with Flush Diluterl and Flush Diluter 2 , Arm2 with Flush Diluter 3 and Flush Diluter 4
98 REM THF wash 3 times
99 Dispense System Fluid Flush Diluter 2 500ul to RB1_1to96[1-72] 100 Mix "RB1_1to96" for 10.00 minutes at 300 rpm(s) and wait.
101 Go to ChemFile MTY72_3M.CHM, line 1
102 Go to ChemFile MTY72_3M.CHM, line 1
103 Repeat from step 99, 2 times
104 Go to ChemFile Acylation.CHM, line 1 105 Go to ChemFile WASH.CHM, line 1
106 Go to ChemFile Cleavage.CHM, line 1
107 REM The End
The following chemfile is called to acylate the amines:
ChemFile C:\ACT_1328\Acetyl.CHM
1 REM Acetylation procedure
2 REM Charge REAGENT_5 with 100 mL Acetic anhydride/THF 1 :4 v/v 3 REM * Diiuter2: THF
4 REM Addition of acylation reagent
5 Dispense Sequence C:\R3-A.DSP with 600 μL to RB1to96 rack using Flush Diluter 2
6 Mix for 1.00 minutes at 300 rpm(s)
7 Wait for 5.000 minute(s) 8 Repeat from step 6, 60 times
9 Go to ChemFile MTY72_3M.CHM, line 1
10 Go to ChemFile MTY72_3M.CHM, line 1
11 Return
The following chemfile is called to wash the resin bound products:
ChemFile C:\ACT 1328WVASH.CHM
1 REM Washing procedure 2 REM Systemfluids: 3
4 REM * Diluter2: THF
5 REM * Diluter3: MeOH 6 7 Flush Armi with Flush Diluterl and Flush Diluter 2 , Arm2 with Flush Diluter 3 and Flush Diluter 4
8 REM THF wash 3 times
9 Dispense System Fluid Flush Diluter 2 800ul to RB1_1to96[1-72]
10 Mix "RB1_1to96" for 10.00 minutes at 300 rpm(s) and wait. 11 Go to ChemFile MTY72_3M.CHM, line 1
12 Go to ChemFile MTY72_3M.CHM, line 1
13 Repeat from step 9, 2 times 14 15 REM Alternating MeOH/DCM wash, 2 cycles
16 Dispense System Fluid Flush Diluter 3 800ul to RB1_1to96[1-72] 17 Mix "RB1_1to96" for 3.00 minutes at 300 rpm(s) and wait. 18 Go to ChemFile MTY72_3M.CHM, line 1 19 20 Dispense System Fluid Disdu1_4* 800ul to RB1_1to96[1-72]
21 Mix "RB1_1to96" for 10.00 minutes at 300 rpm(s) and wait.
22 Go to ChemFile MTY72_3M.CHM, line 1
23 Go to ChemFile MTY72_3M.CHM, line 1 24 25 Repeat from step 16, 1 times 26
27 Dispense System Fluid Disdu1_4* 800ul to RB1_1to96[1-72]
28 Mix "RB1_1to96" for 10.00 minutes at 300 rpm(s) and wait.
29 Go to ChemFile MTY72_3M.CHM, line 1 30 Repeat from step 117, 1 times
31
32 REM Washing procedure has ended
33 Return
The following chemfile is called to cleave the products from the resin:
ChemFile C:\ACT_1328\Cleavage.CHM
I REM Setup for cleavage: 2 REM * Cleavage vials
3 REM * Lower pressure
4 REM * Add 100 mL TFA/DCM 1 :1 mixture to Reagent3
5 REM * Add 100 mL CH3CN to Reagent4
6 Pause 7
8 REM Adding cleavage solution, 1hr
9 Transfer 1000ul from REAGENT_3[1](TFA/DCM) to RB1_1to96[1-72] using Flush Diluterl
10 Mix "RB1_1to96" for 1.00 minutes at 300 rpm(s) and wait.
I I Wait for 4.000 minute(s) 12 Repeat from step 133, 11 times
13 REM PULSE EMPTY!
14 Go to ChemFile PULSEMP1.CHM, line 1 15
16 REM Washing with CH3CN 17 Transfer 500ul from REAGENT_4[1](CH3CN) to RB1_1to96[1-72] using Flush Diluterl 18 Mix "RB1_1to96" for 10.00 minutes at 300 rpm(s) and wait. 19 REM PULSE EMPTY!
20 Go to ChemFile PULSEMP1.CHM, line 1
21 Return
The following chemfile is called to empty the wells of the reaction block.:
ChemFile C:\ACT_1328\MTY72_3M.CHM Page 1
1 REM Subroutine Empty 1_72_3min 2 Empty RB1_1to96 for 5.000 minute(s)
3 Return
The following chemfile is called to empty the wells of the reaction block into the cleavage vials containing the final product in a controlled manner.
ChemFile C:\ACT_1323\PULSEMP1.CHM Page 1
1 Empty RB1_1to96 for 1 second(s)
2 Wait for 4 second(s) 3 Repeat from step 1 , 11 times
4 Empty RB1_1to96 for 5.000 minute(s)
5 Return
Dispense sequence C:\ACT_132δ\R2-A. DSP is a subroutines that control the combinatorial addition of the amines into the reaction block in the syntheziser.
Dispense sequence C:\ACT_1328\R3-A.DSP is a subroutines that control the combinatorial addition of the acylating agents into reaction block in the syntheziser.
Examples of compounds from this library were characterised by HPLC-MS (molecular mass
6 retention time) including the following examples 878 to 881.
Figure imgf000494_0001
EXAMPLE 882:
N-{4-[3-chloro-4-hydroxybenzoyl)-hydrazonemethyl]-1 -naphthyl}methyl /so-propyl amide
Figure imgf000495_0001
Preparation of Λ -4-Formylnaphthylmethyl isopropyl amide:
A mixture of 4-bromomethyl-1 -naphthaldehyde ethyleneacetal (447 mg, 1.52 mmol) and NaN3 (221 mg, 3.4 mmol) in 10 mL DMF was warmed up to 100 °C and stirred for 30 min. Solution turned orange. The reaction was filtered and the clear solution was concentrated to 391 mg of yellow oil. This oil (249 mg) together with triphenylphosphine (260 mg, 0.99 mmol) was dissolved in 10 mL of THF. The reaction mixture was left overnight followed by the addition of water. Ninhydrin test revealed the formation of an amine. This amine was extracted into ethyl acetate layer, dried to give an oil. This oil was dissolved in CH2CI2, EDC, DMAP and 2-methylpropionic acid were added. The reaction mixture was left for 2 days. Column chromatography eluted with ethyl acetate afforded the amide. Deprotection of di- ethyleneacetal was achieved by 10% HCI in THF to give the title compound (50 mg).
1H NMR (CDCI3): d 1.2 (d, 6H), 2.4 (m, 1 H), 4.9 (d, 2H), 6.1 (b, 1 H), 7.5 (d, 1 H), 7.6 (m, 2H), 7.8 (d, 1 H), 8.0 (d, 1 H), 9.2 (d, 1 H), 10.3 (s, 1 H).
The title compound was prepared similarly as described above.
1H NMR (DMSO-D6): d 1.0 (d, 6H), 2.4 (m, 1 H), 4.7 (s, 2H), 7.0 (d, 1 H), 7.4 (d, 1 H), 7.6 (m, 2H), 7.7 (d, 1 H), 7.8 (d, 1 H), 7.9 (s, 1 H), 8.1 (d, 1 H), 8.3 (s, 1 H), 8.8 (d, 1 H), 9.0 (s, 1 H), 10.9 (s, 1 H), 11.7 (s, 1 H); ms (APCI negative); 422.
EXAMPLE 883:
4-[3-chloro-4-hydroxybenzovB-hvdrazonomethyl1-1-naphthylmethyl iso-propylsulfoxide
Figure imgf000496_0001
4-Ethyleneacetal-4-fomnyl-naphthy!methyl /so-propylthioether:
A mixture of 4-bromomethyl naphthaldehyde ethyleneacetal (232 mg, 0.79 mmol) and iso- propyl thioalcohol (0.08 mL, 0.81 mmol) and 0.12 mL of triethylamine was left at room temperature for 12 h. The reaction mixture was concentrated and the residue was purified by column chromatography eluted with ethyl acetate /hexane (1/5) to afford 93 mg of the desired product as pale radish oil.
1H NMR (CDCI3): d 1.3 (d, 6H), 2.9 (m, 1 H), 4.2 (m, 6H), 6.5 (s, 1 H), 7.4 (d, 1 H), 7.6 (m, 2H), 7.7 (d, 1 H), 8.2 (m, 1H).
4-Ethyleneacetal-naphthylmethyl /so-propylsulfoxide:
To a mixture of the above 4-ethyleneacetal-naphthylmethyl /so-propylthioether (79 mg, 0.27 mmol) in 5 mL of dichloromethane at -78 °C was added m-chloro perbenzoic acid (82 mg, 55% purity, 0.28 mmol). The reaction mixture was left for 1 hour and 40 min. Then, NaHSO3 solution was added followed by NaHCO3. The mixture was extracted with water and dichloromethane. The organic layer was combined and dried over MgSO4. Solvent was removed and the residue was purified by column chromatography eluted with ethyl acetate to yield 56 mg of desired product as an oil.
Η NMR (CDCI3): d 1.3 (d, 3H), 1.4 (d, 3H), 2.7 (m, 1 H), 4.2 (m, 4H), 4.4 (dd, 2H), 6.5 (s, 1 H), 7.5 (d, 1 H), 7.6 (m, 2H), 7.7 (d, 1 H), 8.1 (m, 1 H), 8.2 (m, 1 H). This compound was hydrolyzed in aqueous 10% HCI in THF for 1 hr to give the corresponding aldehyde.
4-[3-chloro-4-hydroxybenzoyl)-hydrazonomethyl]-1-naphthylmethyl iso-propylsulfoxide: The title compound was prepared similarly as described above. 1H NMR (DMSO-Dβ): d 1.3 (dd, 6H), 3.0 (m, 1H), 4.3 (d, 1H), 4.7 (d, 1H), 7.1 (d, 1H), 7.6 (m, 3H), 7.8 (d, 1H), 7.9 (d, 1H), δ.O (s, 1H), δ.2 (d, 1H), 8.8 (d, 1H), 9.1 (s, 1H), 11.0 (s, 1H), 11.8 (s, 1H); ms (APCI negative); 427, 337.
EXAMPLE 884: 4-[3-chloro-4-hydroxybenzoyl)-hydrazonomethyl]-1-naphthylmethyl iso-propylsulfone
Figure imgf000497_0001
Similarly, the title compound was prepared.
1H NMR (DMSO-D6): d 1.3 (d, 6H), 3.4 (m, 1H), 5.0 (s, 2H), 7.0 (d, 1H), 7.6 (m, 3H), 7.7 (d, 1H), 7.9 (d, 2H), 8.2 (d, 1H), 8.7 (d, 1H), 9.0 (s, 1H), 10.9 (s, 1H), 11.8 (s, 1H); ms (APCI negative); 443, 336.
EXAMPLE 885:
4-[3-chloro-4-hydroxybenzoyl)-hydrazonomethyl]-1-naphthylmethyl iso-propylsulfide
Figure imgf000497_0002
Similarly, the title compound was prepared. Further examples of the invention are the following compounds:
EXAMPLE 886:
Figure imgf000498_0001
EXAMPLE 887:
Figure imgf000498_0002
EXAMPLE 888:
Figure imgf000498_0003
EXAMPLE 889:
Figure imgf000498_0004
EXAMPLE 890:
Figure imgf000499_0001
EXAMPLE 891 :
Figure imgf000499_0002
EXAMPLE 892:
Figure imgf000499_0003
EXAMPLE 893:
Figure imgf000499_0004
EXAMPLE 894:
Figure imgf000499_0005
It should be apparent from the foregoing that other starting materials and other intermediate compounds can be substituted in the above procedures to prepare all of the compounds of the invention. The methods disclosed herein are based on established chemical techniques, as will be apparent to those skilled in the art, and therefore all of the compounds of the invention are broadly enabled by the preceding disclosure.
Accordingly, the invention may be embodied in other specific forms without departing from its spirit or essential characteristics. The described embodiments are to be considered in all re- spects only as illustrative and not restrictive, and the scope of the invention is, therefore, indicated by the appended claims rather than by the foregoing description. All modifications which come within the meaning and range of the lawful equivalency of the claims are to be embraced within their scope.

Claims

Claims
A compound of the general formula I:
Figure imgf000501_0001
wherein:
R1 and R2 independently are hydrogen or lower alkyl or together form a valence bond;
R3 and R4 independently are hydrogen or lower alkyl;
n is 0, 1 , 2 or 3;
m is O oM ;
X is >C=O, >C=S, >C=NR5 or >SO2;
wherein R5 is hydrogen, lower alkyl, aryl-lower alkyl or -OR6;
wherein R6 is hydrogen, lower alkyl, aryl or aryl-lower alkyl;
A is
Figure imgf000502_0001
Figure imgf000502_0002
wherein: R7 is hydrogen, halogen, -CN, -CF3, -OCF3, -OCH2CF3, -NO2, -OR11, -NR11R12, lower alkyl, aryl, aryl-lower alkyl, -SCF3, -SO2NR1 R12, -SR11, -CHF2, -OCHF2, -OSO2R11, -CONR11R12, -OCH2CONR11R12, -CH2OR11, -CH2NR11R12, -OCOR11, -CO2R13or -OSO2CF3;
R8 and R9 independently are hydrogen, halogen, -CN, -CF3, -OCF3, -OCH2CF3, -NO2, -OR11, -NR11R12, lower alkyl, aryl, -SCF3l -SR11, -CHF2, -OCHF2, -OSO2R11, -CONR11R12, -CH2OR11, -CH2NR11R12, -OCOR11, -CO2R13or -OSO2CF3, or R8 and R9 together form a bridge -OCH2O- or -OCH2CH2O-;
wherein R11 and R12 independently are hydrogen, -COR13, -SO2R13, lower alkyl or aryl;
wherein R13 is hydrogen, lower alkyl, aryl-lower alkyl or aryl; and
R10 is hydrogen, lower alkyl, aryl-lower alkyl or aryl;
B is
Figure imgf000503_0001
or a valence bond;
wherein: R14and R15 independently are hydrogen, halogen, -CN, -CF3, -OCF3l -O(CH2)|CF3, -NO2, -OR16, -NR16R17, lower alkyl, aryl, aryl-lower alkyl, -SCF3, -SR16, -CHF2, -OCHF2, -OCF2CHF2, -OSO2CF3, -CONR16R17, -(CH2),CONR16R17, -O(CH2),CONR16R17, -(CH2),COR16, -(CH2),COR16, -(CH2),OR16, -O(CH2),OR16, -(CH2),NR 6R17, -O(CH2),NR16R17, -OCOR16, -CO2R18 ,
-O(CH2),CO2R18, -O(CH2),CN, -O(CH2),CI, or R14and R15 together form a bridge -O(CH2),O- or -(CH2)r;
wherein I is 1 , 2, 3 or 4;
R16 and R17 independently are hydrogen, -COR18, -SO2R18, lower alkyl, aryl, or R 6 and R17 together form a cyclic alkyl bridge containing from 2 to 7 carbon atoms;
wherein R18 is hydrogen, lower alkyl, aryl or aryl-lower alkyl;
W is -N= or -CR19=;
Y is -N= or -CR20=;
Z is -N= or -CR21=;
V is -N= or -CR22=; and
Q is -NR23-, -O- or -S-;
wherein:
R19, R20, R21 and R22 independently are hydrogen, halogen, -CN, -CF3, -OCF3, -OCH2CF3l -NO2, -OR24, -NR24R25, lower alkyl, aryl, aryl-lower alkyl, -SCF3, -SR24, -CHF2, -OCHF2, -OCF2CHF2, -OSO2CF3, -CONR24R25, -CH2CONR24R25, -OCH2CONR24R25, -CH2OR24,
-CH2NR24R25, -OCOR24 or -CO2R24, or R19and R20, R20and R21, or R21 and R22 together form a bridge -OCH2O-; wherein R24 and R25 independently are hydrogen, -COR26, -SO2R26, lower alkyl, aryl or aryl- lower alkyl;
wherein R26 is hydrogen, lower alkyl, aryl or aryl-lower alkyl; and
R23 is hydrogen, lower alkyl, aryl or aryl-lower alkyl;
K is
Figure imgf000505_0001
wherein:
R3a, R3b, R4a and R4b independently are hydrogen, halogen, -CN, -CF3, -OCF3, -OCH2CF3, -NO2, -OR24a, -NR24aR25a, lower alkyl, aryl, aryl-lower alkyl, -SCF3l -SR24a, -CHF2, -OCHF2, -OCF2CHF2, -OSO2CF3, -CONR24aR25a, -CH2CONR24aR25a, -OCH2CONR24aR25a, -CH2OR24a, -CH2NR24aR25a, -OCOR24a or -CO2R24a;
wherein R24a and R25a independently are hydrogen, -COR26a, -SO2R26a, lower alkyl, aryl or aryl-lower alkyl;
wherein R26ais hydrogen, lower alkyl, aryl or aryl-lower alkyl;
or
R3a and R3b, R4a and R4b, or R3a and R b together form a bridge -(CH2)r;
wherein i is 1 , 2, 3 or 4;
a, b, c and d independently are 0, 1 , 2, 3 or 4;
e, f and p independently are 0 or 1 ; q is 0, 1 or 2; and
L and M independently are
-O-, -S-, -CH=CH-, -CΓëíC-, -NR5a-, -CH2NR5a-, -CO-, -OCO-, -COO-, -CONR5a-, -CONR5b-, -NR5aCO-, -SO-, -SO2-, -OSO2-, -SO2NR5a-, -NR5aSO2-, -NR5aCONR5b-, -CONR5aNR5b-, -NR5aCSNR5 -, -OCONR5"-, -CH2CONR5b-, -OCH2CONR5 -,
-P(O)(OR5a)O-, -NR5aC(O)O- or
Figure imgf000506_0001
wherein R5aand R5 independently are hydrogen, lower alkyl, -OH, -(CH2)k-OR6a, -COR6a, -(CH2)k-CH(OR6a)2, -(CH2)k-CN, -(CH2)k-NR6aR6b, aryl, aryl-lower alkyl, -(CH2)g-COOR43 or (CH2)g-CF3;
wherein k is 1 , 2, 3 or 4;
R6a and R6 independently are hydrogen, lower alkyl, aryl or aryl-lower alkyl;
g is O, 1 , 2, 3 or 4;
R43 is hydrogen or lower alkyl;
G" is -OCH2CO-, -CH2CO-, -CO- or a valence bond; and
E" is -CH2-, -CH2CH2-, -CH=CH-, -CH2NH- or -CH2CH2NH-;
D is hydrogen,
Figure imgf000507_0001
wherein:
r is 0 or 1; s is 0, 1 , 2 or 3;
E, E', F, G and G" independently are -CHR38-, >C=O, >NR39, -O- or -S-;
F' is >CR38- or >N-;
Y* is -N= or -CR32=;
Z' is -N= or -CR33=;
V is -N= or -CR34^
W is -N= or -CR35=; and
Q' is -NR36-, -O- or -S-;
wherein:
R27, R28, R32, R33, R^and R35 independently are hydrogen, halogen, -CN, -CF3, -O(CH2)yCF3, -(CH2)yNHCOCF3, -NO2, lower alkyl, aryl, aryl-lower alkyl, -SCF3, -SR29, -CHF2, -OCHF2, -OCF2CHF2, -OSO2R29, -OSO2CF3, -(CH2)yCONR29R30, -O(CH2)yCONR29R30, -(CH2)yOR29, -(CH2)yNR29R30, -OCOR29, -COR29 or -CO2R29;
or
R27and R28, R32and R33, R33and R34, or R^and R35 together form a bridge -O(CH2)yO-;
wherein y is 0, 1 , 2, 3 or 4; and
R29 and R30 independently are hydrogen, -COR31, -CO2R31, -SO2R31, lower alkyl, aryl or aryl-lower alkyl;
wherein R3 is hydrogen, lower alkyl, aryl or aryl-lower alkyl; R36 and R39 independently are hydrogen, lower alkyl, aryl or aryl-lower alkyl; and
R38 is hydrogen, -OR40, -NR40R41, lower alkyl, aryl, aryl-lower alkyl, -SCF3, -SR40, -CHF2, -OCHF2, -OCF2CHF2, -CONR40R41, -(CH2)XCONR40R41, -O(CH2)XCONR40R41, -(CH2)xOR40, -(CH2)XNR40R41, -OCOR40 or -CO2R40;
wherein x is 1 , 2, 3 or 4;
R40 and R41 independently are hydrogen, -COR42, -SO2R42, lower alkyl, aryl or aryl-lower al- kyl;
wherein R42is hydrogen, lower alkyl, aryl or aryl-lower alkyl;
as well as any optical or geometric isomer or tautomeric form thereof including mixtures of these or a pharmaceutically acceptable salt thereof.
2. A compound according to claim 1 having the following formula II:
Figure imgf000509_0001
wherein A, B, K, D, R3, R4, n and m are as defined in claim 1.
3. A compound according to claim 1 having the following formula III:
Figure imgf000509_0002
wherein A, B, K, D, R3, R4, n and m are as defined in claim 1.
4. A compound according to claim 1 having the following formula IV:
Figure imgf000510_0001
wherein A, B, K, D, R3, R4, n and m are as defined in claim 1.
5. A compound according to any one of the preceding claims, wherein R3 is hydrogen.
6. A compound according to any one of the preceding claims, wherein R4 is hydrogen.
7. A compound according to any one of the preceding claims, wherein A is selected from the group consisting of
Figure imgf000510_0002
wherein R7, R8, R9 and R 1100 are as defined in claim 1.
8. A compound according to claim 7, wherein A is
Figure imgf000510_0003
wherein R7, R8and R9 are as defined in claim 1.
9. A compound according to claim 7 or 8, wherein R7 is halogen, lower alkyl, -OH, -NO2, -CN, -CO2H, -O-lower alkyl, aryl, aryl-lower alkyl, -CO2CH3, -CONH2, -OCH2CONH2, -NH2, -N(CH3)2, -SO2NH2, -OCHF2, -CF3 or -OCF3.
10. A compound according to any one of the claims 7 to 9, wherein R8and R9 independently are hydrogen, halogen, -OH, -NO2, -NH2, -CN, -OCF3l -SCF3, -CF3, -OCH2CF3, -O-lower alkyl, lower alkyl or phenyl and R10 is hydrogen, lower alkyl or phenyl.
11. A compound according to claim 10, wherein R8 and R9 independently are hydrogen, halogen, -O-lower alkyl, -NH2, -CN or -NO2and R10 is hydrogen.
12. A compound according to claim 8, wherein A is
Figure imgf000511_0001
wherein R8 and R9 independently are as defined in any one of the claims 10 or 11.
13. A compound according to claim 12, wherein A is
Figure imgf000511_0002
wherein R8 is hydrogen, halogen, -O-lower alkyl, -NH2, -CN or -NO2; and R9 is hydrogen or halogen.
14. A compound according to any one of the claims 7 to 13 having the following formula
V:
Figure imgf000512_0001
wherein R8 and R9 are as defined in any one of the claims 1 , 10, 11 or 13 and R4, B, K, D and m are as defined in claim 1.
15. A compound according to any one of the preceding claims, wherein B is
Figure imgf000512_0002
wherein V, W, Z, Y and Q are as defined in claim 1 ; and R14and R15 independently are hydrogen, halogen, -CF3╬╣ -OCF3, -OR16, -NR16R17, lower alkyl, aryl, aryl-lower alkyl, -OSO2CF3, -CONR16R17, -CH2OR16, -CH2NR16R17, -OCOR16 or -CO2R18; or R14and R15 together form a bridge -OCH2O- or -(CH2)r; wherein I, R16, R17 and R18 are as defined in claim 1.
16. A compound according to claim 15, wherein Q is -O- or -NH-
17. A compound according to claim 15, wherein B is
Figure imgf000513_0001
wherein R14 and R15 are as defined in claim 15, and V, W, Z and Y are as defined in claim 1.
18. A compound according to claim 17 having the following formula VI:
Figure imgf000513_0002
Figure imgf000513_0004
wherein R14 and R15 are as defined in claim 15, R8and R9 are as defined in any one of the claims 1 , 10, 11 or 13, and K, D and m are as defined in claim 1.
19. A compound according to claim 17 having the following formula VII:
Figure imgf000513_0003
wherein R14 and R15 are as defined in claim 15, R8and R9 are as defined in any one of the claims 1 , 10, 11 or 13, and K, D and m are as defined in claim 1.
20. A compound according to claim 17 having the following formulae Villa or Vlllb:
(Villa) or
Figure imgf000514_0001
(Vlllb)
Figure imgf000514_0002
wherein R14 and R15 are as defined in claim 15, R8 and R9 are as defined in any one of the claims 1 ,10, 11 or 13, and K, D and m are as defined in claim 1.
21. A compound according to any one of the claims 15 to 20, wherein R14 and R15 independently are hydrogen, halogen, lower alkyl, -O-lower alkyl or aryl.
22. A compound according to any one of the preceding claims, wherein K is selected from the group consisting of
(CHA-OΓÇö (CH2)d , ΓÇö (CH2 (CH,)dΓÇö , (CH2)ΓÇö CH=CH-(CH2)d
-(CH - -(CH2)d , _(CH A-NΓÇö (CH2)d- -(CH '22)',b -O- (CH '2A'd
(CH 'A2'b -(C
Figure imgf000515_0001
- -(CH,),ΓÇö ΓÇö (CH2)b-0 -(CH2)d
Figure imgf000515_0002
Figure imgf000515_0003
-,3a
OΓÇö (CHAΓÇö CHR*-(CH2)-N (CH2)d -0-(CH2)-^NΓÇö (CH, 2)',d
O
-0-(CHΛ— N-U-(CH. -o-tcH-fc-lLo— (CHA 2'd
"┬░~ (CHA-
Figure imgf000515_0004
-0-(CH2)b OΓÇö (CH2)dΓÇö , ΓÇöo-tCH^CHR33- . -o-(CH2)5ΓÇö O-U-N (CH,),-
Figure imgf000515_0005
Figure imgf000516_0001
CH2)dΓÇö
Figure imgf000516_0002
Figure imgf000516_0003
ΓÇö OΓÇö CH2ΓÇö uΓÇö N N-(CH 2A'b -CH,- N-(CH2)b-
Figure imgf000516_0004
-OΓÇö CH2 ΓÇö LL- (CHAΓÇö S-(CHA- ΓÇö CH,- -(CH 2'b -O (CHAΓÇö
,5b
Figure imgf000517_0001
(CH 2A'b-0-( VC«H' '2'd
Figure imgf000517_0002
Figure imgf000517_0003
wherein R3a, R3b, R4a, R4 , R5a, R5b, a, b, c, d, p and q are as defined in claim 1.
23. A compound according to claim 22, wherein K is selected from the group consisting of
-(CHA-OΓÇö (CHA- ΓÇö (CH2)b-N- "(CH2)d- OΓÇö (CHA-NΓÇö (CH2 5a
OΓÇö (CH2 -CHRΓÇö (CHA- -(CH 2. 'd -C-(CHA- -NΓÇö (CHAΓÇö
-0-(CH,)-^0ΓÇö (CHA- -0-(CHA 2'b "(CH2 2)',d
O
-0-S-(CH2)d- ΓÇö (CH2)d ΓÇö -0-(CH2 N- "(CHA o I-
-O- (CHA ΓÇö CHR ,3' a
-(CH2)bΓÇö O- -(CHAΓÇö -(CH2)b-S-(CH2)d-
Figure imgf000518_0001
Figure imgf000519_0001
ΓÇö OΓÇö CH, -NΓÇö (CH2)bΓÇö S-(CH2)dΓÇö ΓÇö 0-(CH2)bΓÇö OΓÇö (CHAΓÇö
Figure imgf000520_0001
and ΓÇö CH2-^-N-(CH2)bΓÇö 0ΓÇö (CH2)d-
\5b
wherein R3a, R3b, R4a, R4b, R5a, R5b, a, b, c, d, p and q are as defined in claim 1.
24. A compound according to claim 23, wherein K is selected from the group consisting of
ΓÇö (CHAΓÇö OΓÇö (CH 'A2'd ΓÇö (CH j-NΓÇö (CHA ΓÇö OΓÇö (CH22)'.2 -N- "(CH, l _.
FT
I
-O-CH,- -CHR- -CH2 NΓÇö (CH, 2)',d -O CH2ΓÇö "-NΓÇö (CHA-
-CH, LL-OΓÇö (CH2)2 -(CH2)b-S-(CHA-
Figure imgf000521_0001
-O (CH^j-CHR ,3a
ΓÇö O-^-CH,- ΓÇö OΓÇö CH,-
Figure imgf000521_0002
-(CHA 2'b -CHRΓÇö CHj- -C -SO-CR^RΓÇö
Figure imgf000521_0003
-CH,- -CHΓÇö NΓÇö^ ΓÇö CR^R4-0-
Figure imgf000522_0001
ΓÇö CH,- M A N N-(CH2)b-N-(CH2)dΓÇö N ' N-(CH2)b-
Figure imgf000522_0002
-CH, -NΓÇö (CH2)bΓÇö S-(CH2)d- -0-(CH2)ΓÇö 0-(CHAΓÇö
)-SΓÇö (CH2)d-
Figure imgf000523_0002
N-(CH2)bΓÇö NΓÇö (CHA-
Figure imgf000523_0003
and ΓÇö CH2ΓÇö ^-N-.CH.,)ΓÇö O ΓÇö (CH2)ΓÇö
R5b
wherein R3a, R3b, R4a, R4b, R5a, R5b, b, c, d, p and q are as defined in claim 1.
25. A compound according to any one of the claims 22 to 24, wherein R5a and R5b independently are hydrogen, lower alkyl, -OH, -(CH2)kOR6a, aryl, aryl-lower alkyl, -CH2CF3, -(CH2)g-COOR43, -COOR43, -(CH2)k-CN or -(CH2)k-NR6aR6b wherein g, k, R43, R6a and R6b are as defined in claim 1.
26. A compound according to claim 25, wherein g and k independently are 1 , 2 or 3, R6a and R6b independently are hydrogen, lower alkyl such as methyl or ethyl, or aryl such as phenyl,
27. A compound according to any one of the claims 22 to 26, wherein R3a and R3b independently are hydrogen, halogen, -OH, -O-lower alkyl, -COO-lower alkyl, lower alkyl or aryl- lower alkyl.
28. A compound according to any one of the claims 22 to 27, wherein R4a and R4b independently are hydrogen, -CN, -CONH2, -(CH2)-N(CH3)2, -O-lower alkyl, -CH2OH, -CH2O-aryl, -N(CH3)2l -OH, -CO2-lower alkyl or lower alkyl.
29. A compound according to any one of the preceding claims, wherein D is hydrogen,
Figure imgf000524_0001
wherein s, r, R27, R28, V, Y', Q', Z', W, E, E\ F, F, G and G' are as defined in claim 1.
30. A compound according to claim 29, wherein D is hydrogen,
Figure imgf000525_0001
Figure imgf000525_0002
wherein s, r, R27, R28, V, Y', Z', Q', Z', W, E, E\ F, F', G and G' are as defined in claim 1.
31. A compound according to claim 29, wherein D is hydrogen,
Figure imgf000526_0001
Figure imgf000526_0002
Figure imgf000526_0003
Figure imgf000526_0004
wherein E and E' independently are >CHR38, >NR39 or -O-; F, G and G' independently are >CHR38, >C=O or >NR39; F* is >CR38- or >N-; and s, r, R27, R28, R38, R39, V, Y', Z', Q' and W are as defined in claim 1.
32. A compound according to any one of the claims 29 to 31 , wherein R27 and R28 independently are hydrogen; halogen such as -Cl, -Br or -F; -CF3; -OCF3; -OCHF2; -OCH2CF3; -(CH2)yNHCOCF3; -NHCOCF3; -CN; -NO2; -COR29, -COOR29, -(CH2)yOR29 or -OR29 wherein R29 is hydrogen, aryl or lower alkyl and y is 1 , 2, 3 or 4; lower alkyl such as methyl, ethyl, 2-propenyl, isopropyl, tert-butyl or cyclohexyl; lower alkylthio; -SCF3; aryl such as phenyl; -(CH2)yNR29R30 or -NR29R30 wherein R29 and R30 independently are hydrogen, -COO-lower alkyl or lower alkyl and y is 1 , 2, 3 or 4; or -CONH2; or R27and R28 together form a bridge -OCH2O-; R38 is hydrogen; -OCHF2; -OR40 wherein R40 is hydrogen or lower alkyl; lower alkyl such as methyl, isopropyl or tert-butyl; lower alkylthio; -SCF3; -CH2OH; -COO-lower alkyl or -CONH2; and R39 is hydrogen, lower alkyl, aryl or aryl-lower alkyl.
33. A compound according to any one of the claims 1 to 32 for use as a medicament.
34. A pharmaceutical composition comprising, as an active ingredient, at least one compound according to any one of the claims 1 to 32 together with one or more pharmaceutically acceptable carriers or excipients.
35. A pharmaceutical composition according to claim 34 in unit dosage form, comprising from about 0.05 mg to about 1000 mg, preferably of from about 0.1 mg to about 500 mg such as of from about 0.5 mg to about 250 mg of the compound according to any one of the claims 1 to 32.
36 A method of treating type I or type II diabetes, comprising administering to a subject in need thereof an effective amount of a compound according to any one of the claims 1 to
32.
37 A method of treating hyperglycemia, comprising administering to a subject in need thereof an effective amount of a compound according to any one of the claims 1 to 32.
38. A method of lowering blood glucose in a mammal, comprising administering to said mammal an effective amount of a compound according to any one of the claims 1 to 32.
39. The method according to any one of the claims 36 to 38 comprising administering to a subject in need thereof an amount of the compound as defined in claim 1 to 33 in the range of from about 0.05 mg to about 1000 mg, preferably of from about 0.1 mg to about 500 mg such as of from about 0.5 mg to about 250 mg one or more times per day such as 1 to 3 times per day.
40. Use of a compound according to any one of the claims 1 to 32 for the manufacture of a medicament for treating type I or type II diabetes.
41. Use of a compound according to any one of the claims 1 to 32 for the manufacture of a medicament for treating hyperglycemia.
42. Use of a compound according to any one of the claims 1 to 32 for the manufacture of a medicament for lowering blood glucose in a mammal.
43. A compound according to any one of the claims 1 to 32 characterized by having a giucagon antagonistic activity as determined by the Giucagon Binding Assay I or Giucagon Binding Assay II disclosed herein corresponding to an IC50 value of less than 1 ╬╝M, prefera- bly of less than 500 nM and even more preferred of less than 100 nM.
AMENDED CLAIMS
[received by the International Bureau on 01 December 1998 (01.12.98) original claims 19-43 replaced by new claims 19-47; remaining claims unchanged (18 pages)]
17. A compound according to claim 15, wherein B is
Figure imgf000529_0001
5 wherein R1 and R are as defined in claim 15, and V, W, 2 and Y are as defined in claim 1.
18. A compound according to claim 17 having the following formula VI:
Figure imgf000529_0002
10 wherein R14 and R15 are as defined in claim 15, R8and R9 are as defined in any one of the claims 1 , 10, 11 or 13, and K, D and m are as defined in claim 1.
19. A compound according to claim 18 except for the following compounds:
15
Figure imgf000529_0003
Figure imgf000530_0001
20. A compound according to claim 18 of the formula Via:
Figure imgf000530_0002
wherein R14 and R15 are as defined in claim 15, R8 is halogen, R9 is as defined in any one of the claims 1 , 10, 11 or 13, and K, D and m are as defined in claim 1.
21. A compound according to claim 17 having the following formula VII:
Figure imgf000530_0003
wherein R14 and R15 are as defined in claim 15, R8 and R9 are as defined in any one of the claims 1 , 10, 11 or 13, and K, D and m are as defined in claim 1.
22. A compound according to claim 21 of the formula Vila:
Figure imgf000531_0001
wherein R14 and R15 are as defined in claim 15, R8 is halogen, R9 is as defined in any one of the claims 1 , 10, 11 or 13, and K, D and m are as defined in claim 1.
23. A compound according to claim 17 having the following formulae Villa or Vlllb:
(Villa) or
Figure imgf000531_0002
(Vlllb)
Figure imgf000531_0003
wherein R14 and R15 are as defined in claim 15, R8 and R9 are as defined in any one of the claims 1 ,10, 11 or 13, and K, D and m are as defined in claim 1.
24. A compound according to claim 17 having the following formulae Villa' or Vlllb': (Villa') or
Figure imgf000532_0001
(Vlllb')
Figure imgf000532_0002
wherein R14 and R15 are as defined in claim 15, R8 is halogen, R9 is as defined in any one of the claims 1 ,10, 11 or 13, and K, D and m are as defined in claim 1.
25. A compound according to any one of the claims 15 to 24, wherein R14and R15 independently are hydrogen, halogen, lower alkyl, -O-lower alkyl or aryl.
26. A compound according to any one of the preceding claims, wherein K is selected from the group consisting of
-(CHΛ-O— (CH2)d (CHΛ-S— (CH2)d- (CH,)— CH=CH-(CH2)d
"(CHΛ- -(CH2)d -(CHΛ-N— (CH2)d- -(CH-L- -0-(CH2)-
(CH2)d-
Figure imgf000533_0001
O
-(CH2)b-SΓÇö (CH2)d- II
"(CHΛ -s- "(CH2)d- — (CHA— O- -(CH,)d-
o
II
-O- -s- (CH2)d- -(CH2)d- -OΓÇö (CH2)-NΓÇö (CH2)dΓÇö
R*
-OΓÇö (CH2fcΓÇö CHR*-(CH2)- (CH2)d-
Figure imgf000533_0002
-O-tCHjk-N- CH-Jir -0-(CH2)ΓÇö U-OΓÇö (CHA-
"0 (CHA-
Figure imgf000533_0003
-0-(CH2)b OΓÇö (CH2)dΓÇö , ΓÇö o-(CH2)ΓÇö CHR3a- ,
Figure imgf000533_0004
O
I I
-0-(CH2)b-N-(CH2)c (V)q (CH2)dΓÇö -OΓÇö (CH2)bΓÇö -sS-ΓÇö (CH2)d-
I I o -(CHA- " -(CH2)C- ^f "(CH22)',d -(CH2)b-S0-(CH2)c (V) (CH
-(CH2)b-S02-(CH2)c (V) (CH2),
Figure imgf000534_0001
O
I I
-0-(CHA -P- -0- V(CHA- - (CHA "(CH2)dΓÇö
OR*
-(CHA ΓÇö 0-(CHA -(CH-tΓÇö Mp-tCH,),ΓÇö U-NΓÇö (CH2)d-
Figure imgf000534_0002
-OΓÇö CH2ΓÇö UΓÇö N N-(CH2)j -CH,- N-ICHjl
Figure imgf000534_0003
-CH, uΓÇö N N-Ra N ' N-R ΓÇö 0ΓÇö CH2^N- (CH2)ΓÇö S-(CH2)d- -CH,- -(CH2)bΓÇö O (CH2 R5b
ΓÇö CH,-AL (CH2)b -(CHA-
Figure imgf000535_0001
Figure imgf000535_0002
wherein R3a, R3b, R4a, R4b, R5a, R5b, a, b, c, d, p and q are as defined in claim 1.
27. A compound according to claim 26, wherein K is selected from the group consisting of
ΓÇö (CHA-OΓÇö (CH2)d ΓÇö (CHA-NΓÇö (CH2)d- -OΓÇö (CHA-NΓÇö (CH2
-O— (CHA— CHR«-(CH2),-N- -(CH. -O-(CH 2A'b -N- "(CH 1 ',2)',d R!
O
ΓÇö O- CHjfc-U-OΓÇö (CH2)dΓÇö -CΓÇö (CHA "(CH2 2)',d
Figure imgf000536_0001
O
-0-(CH2)bΓÇö CHRJ -(CHAΓÇö O- "(CH2)d- -(CH2)-S-(CH2)dΓÇö
-(CH
Figure imgf000536_0002
-,4a R4b
(CH2 N-(CH2)C (V) (CH2)d ΓÇö (CH2)b-SO-(CH2)c _f )_(CH A _
R┬░"
-(CH2)b-S02-(CH2)c (V)q (CH2),
Figure imgf000536_0003
Figure imgf000536_0004
Figure imgf000537_0001
RM
ΓÇö OΓÇö CH,- ,N-(CH2)b- ΓÇö OΓÇö CH,- N-CH,ΓÇö
Figure imgf000537_0002
ΓÇö OΓÇö CH, N-(CH '22)'bb-N-(CH '22)',d
Figure imgf000537_0003
Figure imgf000537_0004
-CH, uΓÇö N N-Ra N N-Ra \ /
-OΓÇö CH, -NΓÇö (CH2)b- -S-(CH2)d- ΓÇö ┬░-(CH ΓÇö OΓÇö (CHAΓÇö
R5b
(CH2)b-N- -(CHA
Figure imgf000538_0001
Figure imgf000538_0002
(CH2)b- ( V)P (CHA-SΓÇö (CHA-
Figure imgf000538_0003
-CH2-N-(CH2)b Op (CH2)-0-(CHAΓÇö
CHΓÇö N-(CH2)b (V)p (CH2)C 0ΓÇ₧ (CH2)d- ,
Figure imgf000538_0004
and ΓÇö CH2-^-N-(CH2)ΓÇö OΓÇö (CH2)dΓÇö
R5b
wherein R3a, R3b, R4a, R4 , R5a, R5b, a, b, c, d, p and q are as defined in claim 1.
28. A compound according to claim 27, wherein K is selected from the group consisting of
(CH2)bΓÇö 0-(CH2)d ΓÇó ΓÇö (CH2)B-NΓÇö (CH2)d -0-(CHA -N- "(CHA I,
Figure imgf000539_0001
-CH2-^-CΓÇö (CH2)2ΓÇö , _(CH2)b-S-(CH2)dΓÇö
-O-S ΓÇö , a valence bond ΓÇö CΓÇö (CH2)2
II o o II o II
-O (CH2)- CHR- -CH,- -OΓÇö CH '.2 ,4a
O ┬░ R4a,
-(CH2)-LL-N-(CH2)c- V(CH2); ΓÇö O- (CHA -N- -(CH2)e ( q (CHA-
H
,4a -,4b
-(CH2)bΓÇö N-CHR^-CHjΓÇö _ ΓÇö CHj-SO-CR"^
Figure imgf000539_0002
O
— CH2 , — CH— N — U — CR*»R«!>_
Figure imgf000540_0001
-OΓÇö CH,- N-CH,-
Figure imgf000540_0002
Figure imgf000540_0003
-OΓÇö CH,- N-(CH2), -CH,- N-(CH2)b-
Figure imgf000540_0004
-CH2— i Uι-N r~χ_ (CH2)b— -O— CHj-^- ^ -R"
-CH,- -N N-R* N ' N-R*
-0ΓÇö CH, NΓÇö (CHAΓÇö S-(CHA- ΓÇö 0-(CH2)bΓÇö O- (CHAΓÇö
Figure imgf000541_0001
and ΓÇö CH2ΓÇö UΓÇö -(CH2)bΓÇö O ΓÇö (CH2)╬▒ ΓÇö R5"
wherein R3a, R3b, R4a, R4b, R5a, R5 , b, c, d, p and q are as defined in claim 1.
29. A compound according to any one of the claims 26 to 28, wherein R5a and R5 independently are hydrogen, lower alkyl, -OH, -(CH2)kOR6a, aryl, aryl-lower alkyl, -CH2CF3, -(CH2)g-COOR43, -COOR43, -(CH2)k-CN or -(CH2)k-NR6aR6b wherein g, k, R43, R6a and R6 are as defined in claim 1.
30. A compound according to claim 29, wherein g and k independently are 1 , 2 or 3, R6a and R6 independently are hydrogen, lower alkyl such as methyl or ethyl, or aryl such as phenyl,
31. A compound according to any one of the claims 26 to 30, wherein R3a and R3b inde- pendently are hydrogen, halogen, -OH, -O-lower alkyl, -COO-lower alkyl, lower alkyl or aryl- lower alkyl.
32. A compound according to any one of the claims 26 to 31 , wherein R4a and R4b independently are hydrogen, -CN, -CONH2l -(CH2)-N(CH3)2, -O-lower alkyl, -CH2OH, -CH20-aryl, -N(CH3)2, -OH, -C02-lower alkyl or lower alkyl.
33. A compound according to any one of the preceding claims, wherein D is hydrogen,
Figure imgf000542_0001
wherein s, r, R27, R28, V, Y', Q', Z', W, E, E', F, F', G and G' are as defined in claim 1.
34. A compound according to claim 33, wherein D is hydrogen,
Figure imgf000543_0001
Figure imgf000543_0002
wherein s, r, R27, R28, V, Y\ Z', Q', Z', W, E, E\ F, F, G and G' are as defined in claim 1.
35. A compound according to claim 34, wherein D is hydrogen,
Figure imgf000543_0003
Figure imgf000544_0001
Figure imgf000544_0002
Figure imgf000544_0003
wherein E and E' independently are >CHR38, >NR39 or -0-; F, G and G' independently are >CHR38, >C=0 or >NR39; F' is >CR38- or >N-; and s, r, R27, R28, R38, R39, V, Y\ Σ, Q' and W are as defined in claim 1.
36. A compound according to any one of the claims 33 to 35, wherein R27 and R28 independently are hydrogen; halogen such as -Cl, -Br or -F; -CF3; -OCF3, -OCHF2; -0CH2CF3; -(CH2)yNHCOCF3; -NHCOCF3; -CN; -N02; -COR29, -COOR29, -(CH2)yOR29 or -OR29 wherein R29 is hydrogen, aryl or lower alkyl and y is 1 , 2, 3 or 4; lower alkyl such as methyl, ethyl, 2-propenyl, isopropyl, tert-butyl or cyclohexyl; lower alkylthio; -SCF3; aryl such as phenyl; -(CH2)yNR29R30 or -NR29R30 wherein R29 and R30 independently are hydrogen, -COO-lower alkyl or lower alkyl and y is 1 , 2, 3 or 4; or -CONH2; or R27and R28 together form a bridge -OCH20-; R38 is hydrogen; -OCHF2; -OR40 wherein R40 is hydrogen or lower alkyl; lower alkyl such as methyl, isopropyl or tert-butyl; lower alkylthio; -SCF3; -CH2OH; -COO-lower alkyl or -CONH2; and R39 is hydrogen, lower alkyl, aryl or aryl-lower alkyl.
37. A compound according to any one of the claims 1 to 36 for use as a medicament.
38. A pharmaceutical composition comprising, as an active ingredient, at least one compound according to any one of the claims 1 to 36 together with one or more pharmaceutically acceptable carriers or excipients.
39. A pharmaceutical composition according to claim 38 in unit dosage form, comprising from about 0.05 mg to about 1000 mg, preferably of from about 0.1 mg to about 500 mg such as of from about 0.5 mg to about 250 mg of the compound according to any one of the claims 1 to 36.
40. A method of treating type I or type II diabetes, comprising administering to a subject in need thereof an effective amount of a compound according to any one of the claims 1 to 36.
41. A method of treating hyperglycemia, comprising administering to a subject in need thereof an effective amount of a compound according to any one of the claims 1 to 36.
42. A method of lowering blood glucose in a mammal, comprising administering to said mammal an effective amount of a compound according to any one of the claims 1 to 36.
43. The method according to any one of the claims 40 to 42 comprising administering to a subject in need thereof an amount of the compound as defined in claim 1 to 36 in the range of from about 0.05 mg to about 1000 mg, preferably of from about 0.1 mg to about 500 mg such as of from about 0.5 mg to about 250 mg one or more times per day such as 1 to 3 times per day.
44. Use of a compound according to any one of the claims 1 to 36 for the manufacture of a medicament for treating type I or type II diabetes.
45. Use of a compound according to any one of the claims 1 to 36 for the manufacture of a medicament for treating hyperglycemia.
46. Use of a compound according to any one of the claims 1 to 36 for the manufacture of a medicament for lowering blood glucose in a mammal.
47. A compound according to any one of the claims 1 to 36 characterized by having a giucagon antagonistic activity as determined by the Giucagon Binding Assay I or Giucagon Binding Assay II disclosed herein corresponding to an IC50 value of less than 1 ╬╝M, preferably of less than 500 nM and even more preferred of less than 100 nM.
STATEMENT UNDER ARTICLE 19
In order to delimit the present compounds from the documents cited in the International Search Report a new claim 19 has been added in which 9 disclaimers have been inserted. The compounds disclaimed are known from US 4,334,015, Table I, No11 ; US No 3,859,281 , Example XVII (= US No 3,746,703, Example XVII = US No 3,836,580, Example XVII); and US No 5,229,038, Compounds 3 to 10.
Furthermore, new claims 20, 22 and 24, respectively, have been added in which R8 has been restricted to halogen in meta-position.
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BR9810378-4A BR9810378A (en) 1997-07-01 1998-06-30 Compound, use of the same, pharmaceutical composition, and, processes of treating type i or type ii diabetes, of treating hyperglycemia, and of decreasing blood glucose in a mammal
IL13337798A IL133377A0 (en) 1997-07-01 1998-07-01 Glucagon antagonists/inverse agonists
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KR20010020590A (en) 2001-03-15
EP0994848A1 (en) 2000-04-26
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