US008461164B2

(12) United States Patent (10) Patent No.: US 8.461,164 B2 Brewster et al. (45) Date of Patent: Jun. 11, 2013

(54) PTERIDINES AND THEIR USE AS Primary Examiner — Douglas MWillis AGROCHEMICALS (74) Attorney, Agent, or Firm — C. W. Amett; Faegre Baker Daniels LLP (75) Inventors: William K. Brewster, Indianapolis, IN (US); David A. Demeter, Fishers, IN (57) ABSTRACT (US); W. Randal Erickson, Carmel, IN (US); Christian T. Lowe, Westfield, IN The present disclosure relates to 1- or 2-(4-(aryloxy)-phenyl) (US); Carla J. R. Klittich, Zionsville, ethylamino-, oxy- or Sulfanyl)pteridines and 1- or 2-(4-(het IN (US); Jaime S. Nugent, Brownsburg, eroaryloxy)-phenyl)ethylamino-, oxy- or Sulfanyl)pteridines IN (US); Brent J. Rieder, Greenfield, IN and their use as agrochemicals and health products. (US); Thomas L. Siddall, Zionsville, IN More specifically, the invention provides new compounds of (US); Chenglin Yao, Westfield, IN (US); the formula (I-A): Carla N. Yerkes, Crawfordsville, IN (US); Yuanming Zhu, Carmel, IN (US) I-A (73) Assignee: Dow AgroSciences, LLC., Indianapolis, IN (US) -- Sey (*) Notice: Subject to any disclaimer, the term of this patent is extended or adjusted under 35 R N U.S.C. 154(b) by 0 days. n CC). 2 2 (21) Appl. No.: 12/551,008 X2 N N els X3 (22) Filed: Aug. 31, 2009 wherein: R is H, CH, phenyl, or a heterocycle comprising a (65) Prior Publication Data 5 or 6 membered single ring or a fused ring system compris ing at least one 5 or 6 membered heterocycle optionally US 2011 FOO54173 A1 Mar. 3, 2011 substituted with H, halo, lower alkyl, lower alkoxy, benzy (51) Int. Cl. loxy, lower alkenyl, lower alkynyl, haloalkyl, haloalkoxy, A 6LX3/59 (2006.01) NO, CN, lower alkoxycarbonyl, lower alkylcarbonyl, lower (52) U.S. Cl. alkyl-SO and aldoximes and lower alkyloximes, optionally USPC ...... 514/262.1; 544/257 Substituted on oxygen by lower alkyl. Z is H, a C-C single bond, CH, NH, O, S, CN, CHO, OCH, CHCHO, or (58) Field of Classification Search OCHCH: m is 4; p is 0 or 1; q is an integer from 0 to 2: R' USPC ...... 514/262.1544/257 is independently H, halo, lower alkyl, lower alkenyl, lower See application file for complete search history. alkynyl, hydroxy, lower alkoxy, haloalkyl, haloalkoxy, NO, (56) References Cited CN, lower alkylcarbonyl, lower alkoxycarbonyl, mercapto, lower alkylthio, aldoximes and lower alkyloximes, optionally U.S. PATENT DOCUMENTS substituted on oxygen by lower alkyl: Y is a C C single 5,034,393 A * 7/1991 Hackler et al...... 514,262.1 bond, C(R)O or C(R); n is 2. * cited by examiner 9 Claims, No Drawings US 8,461,164 B2 1. 2 PTERIDINES AND THEIR USE AS X is H, halogen or lower alkyl; and AGROCHEMICALS X is H. halogen or lower alkyl: with the proviso that when Y is C(R.), R, and R', may be FIELD OF THE INVENTION taken together to form 5 The present disclosure relates to 1- or 2-(4-(aryloxy)-phe nyl)ethylamino-, oxy- or Sulfanyl)pteridines and 1- or 2-(4- R (heteroaryloxy)-phenyl)ethylamino-, oxy- or Sulfanyl)pte SA ridines and their use as agrochemicals and animal health XI products. 10 R N BACKGROUND AND SUMMARY N1 SN 2-R, The present disclosure provides novel organic compounds 2 als that may demonstrate activity as pesticides, meaning that they X2 N N X3 may control fungi, , mites, and/or animal parasites. 15 The disclosure also provides novel pesticide methods and The invention also provides new compounds of formula compositions utilizing the novel compounds. (I-B): More specifically, the invention provides new compounds of the formula (I-A): I-B R, I-A R, -- Y R'm 25

R N XI C N n N N X 1. R X2 N 2 Nals 2 als 30 X2 N N X3 wherein: R is H, CH, haloalkyl, phenyl, or a heterocycle comprising wherein: a 5 or 6 membered single ring or a fused ring system com R is H, CH, phenyl, or a heterocycle comprising a 5 or 6 prising at least one 5 or 6 membered heterocycle optionally membered single ring or a fused ring system comprising at 35 substituted with H, halo, lower alkyl, lower alkoxy, benzy least one 5 or 6 membered heterocycle optionally substituted loxy, lower alkenyl, lower alkynyl, haloalkyl, haloalkoxy, with H, halo, lower alkyl, lower alkoxy, benzyloxy, lower NO, CN, lower alkoxycarbonyl, lower alkylcarbonyl, lower alkenyl, lower alkynyl, haloalkyl, haloalkoxy, NO, CN, alkyl-SO aldoximes and lower alkyloximes, optionally sub lower alkoxycarbonyl, lower alkylcarbonyl, lower alkyl-SO. stituted on oxygen by lower alkyl; and aldoximes and lower alkyloximes, optionally Substituted 40 Z is H, a C-C single bond, CH, NH, O, S, CN, CHO, on oxygen by lower alkyl. OCH, CHCHO, or OCHCH: Z is H, a C-C single bond, CH, NH, O, S, CN, CHO, m is 4: OCH, CHCHO, or OCHCH: p is 0 or 1: m is 4: q is an integer from 0 to 2: p is 0 or 1; 45 R" is independently H, halo, lower alkyl, lower alkenyl, q is an integer from 0 to 2; lower alkynyl, hydroxy, lower alkoxy, haloalkyl, haloalkoxy, R" is independently H, halo, lower alkyl, lower alkenyl, NO, CN, lower alkylcarbonyl, lower alkoxycarbonyl, mer lower alkynyl, hydroxy, lower alkoxy, haloalkyl, haloalkoxy, capto, lower alkylthio, aldoximes and lower alkyloXimes, NO, CN, lower alkylcarbonyl, lower alkoxycarbonyl, mer optionally substituted on oxygen by lower alkyl; capto, lower alkylthio, aldoximes and lower alkyloximes, 50 Y is a C C single bond, C(R)O or C(R): optionally substituted on oxygen by lower alkyl; n is 2: Y is a C-C single bond, C(R.)O or C(R.); alternatively R', Z, and R may be taken together to form n is 2: a fused 5 or 6 membered heterocycle optionally substituted alternatively R' Z, and R may be taken together to form with H, halo, lower alkyl, lower alkoxy, benzyloxy, lower a fused 5 or 6 membered heterocycle optionally substituted 55 alkenyl, lower alkynyl, haloalkyl, haloalkoxy, NO, CN, with H, halo, lower alkyl, lower alkoxy, benzyloxy, lower lower alkylcarbonyl, lower alkoxycarbonyl and lower alkyl alkenyl, lower alkynyl, haloalkyl, haloalkoxy, NO, CN, SO; lower alkylcarbonyl, lower alkoxycarbonyl and lower alkyl R are independently H or lower alkyl SO; R" is H. halogen, lower alkyl, lower alkoxy or lower R are independently H or lower alkyl: 60 haloalkyl: R is H. halogen, lower alkyl, lower alkoxy or lower Rare independently H or lower alkyl haloalkyl: X is NR, O, and S, where R is selected from H. lower Rare independently H or lower alkyl: alkyl, lower alkylcarbonyl, lower alkoxycarbonyl, hydroxy, X is NR, O, and S, where R is selected from H. lower lower alkoxy, lower alkyl-SO phenyl-SO, or substituted alkyl, lower alkylcarbonyl, lower alkoxycarbonyl, hydroxy, 65 phenyl-SO. lower alkoxy, lower alkyl-SO phenyl-SO, or substituted X is H. halogen or lower alkyl; and phenyl-SO. X is H, halogen or lower alkyl: US 8,461,164 B2 3 4 with the proviso that when Y is C(R), R, and R', may be optionally substituted pyridinyl taken together to form

R'm SA XI Nueré 4 2x R NN 1, 10 optionally substituted pyrazinyl X2 N 2 N1. X3

The invention also provides new pesticide methods and R7 compositions utilizing the compounds of formula (I-A) and 15 1 compounds of formula (I-B). The invention includes fungicidal, insecticidal, acaricidal, and anti-parasitic compositions comprising an effective amount of a compound of the present invention in a mixture with an agriculturally acceptable orpharmaceutically accept optionally substituted pyrimidinyl able adjuvant or carrier. The invention also includes methods of controlling a fungus, , mite, or parasite comprising applying an effective amount of a compound of the present invention to the fungus, insect or mite, Soil, plant, root, foli 25 age, seed, locus, or animal (for which purpose they may be administered orally, parenterally, percutaneously or topi cally) in which the infestation is to be prevented or cured.

DETAILED DESCRIPTION OF THE INVENTION 30 optionally substituted pyridazinyl The compounds of the present invention are directed to compounds of formula (I-A) and (I-B) nSA SN 35 - H 14. 2 I-A 2N !--R - - optionally substituted thiazolyl 40 R N XI C.S.

X2 C% % X3 - 45

50 optionally substituted 1,2,3-thiadiazolyl

I-B R V 55 f QNS R N XI CN N1 NN NS-R, optionally substituted 1,2,4-thiadiazolyl 60

Wherein p is 1 and R may be an optionally substituted phenyl or a heterocycle comprising a 5 or 6 membered single ring or a fused ring system comprising at least one 5 or 6 membered 65 heterocycle. More specifically, R may be selected from the list including but not limited to: US 8,461,164 B2 5 6 optionally substituted 1,3,4-thiadiazolyl The term “haloalkoxy' refers to lower alkoxy groups sub stituted with one or more halo atoms. The term “substituted phenyl refers to phenyl substituted N -N--R, with lower alkyl, lower alkenyl, lower alkynyl, lower alkoxy, lower alkylthio, halo, hydroxy, NO, haloalkyl, haloalkoxy, Q S 3) haloalkylthio, CN, phenyl, substituted phenyl, O-phenyl, O-substituted phenyl, C-C alkanoyloxy, C-C alkoxycar as well as pyridinyl-N-oxide, thienyl, furyl, oxazolyl, isox bonyl, lower alkylcarbonyl, benzyloxy, or and lower alkyl azolyl, isothiazolyl, oxadiazolyl, furazanyl, pyrrolyl pyra 10 SO, and q is an integer from 0 to 2. Zolyl, and imidazolyl, where r is 4 in the case of pyridinyl, 3 The term “fused ring system” refers to two rings joined, as defined in Moss, G. P. Pure and Applied Chemistry, 1998, 70. in the case of pyrazinyl, pyrimidinyl, and pyridazinyl. 2 in the 143: "For ring systems ... two rings which have two atoms case of thiazolyl and 1 in the case of thiadiazolyl, and R7 are and one bond in common may be regarded as being derived independently H, halo, lower alkyl, lower alkoxy, benzyloxy, from the two rings as separate entities. The process of joining lower alkenyl, lower alkynyl, haloalkyl, haloalkoxy, NO, 15 rings in this way is termed fusion.” CN, lower alkoxycarbonyl, lower alkylcarbonyl, aldoximes In the present invention, whenever multiple substituents and lower alkyloximes, optionally substituted on oxygen by are independently selected it is to be understood that they are lower alkyl. and lower alkyl-SO, and q is an integer from 0 to selected so as to be sterically compatible with each other. 2. Steric compatibility refers to the absence of steric hindrance Throughout this document, all temperatures are given in as this term is defined in The Condensed Chemical Dictio degrees Celsius, and all percentages are weight percentages nary, 7th edition, Reinhold Publishing Co., N.Y. page 893 unless otherwise stated. (1966), which definition is as follows: The terms “alkyl.” “alkenyl and “alkynyl, as well as steric hindrance. A characteristic of molecular structure in derivative terms such as “alkoxy” and “alkylthio.” as used which the molecules have a spatial arrangement of their herein, include within their scope straight chain, branched 25 atoms such that a given reaction with another molecule chain and cyclic moieties. The terms “alkenyl' and “alkynyl is prevented or retarded in rate. are intended to include one or more unsaturated bonds. Steric compatibility is characterized by substituents whose The term "halo' refers to F, Cl, Br, and I atoms. physical bulk does not require confinement within Volumes The term “lower alkyl” refers to C to C straight hydro insufficient for the exercise of their normal behavior as dis carbon chains and C to Ce branched and cyclic hydrocarbon 30 cussed in D. J. Cram and G. Hammond, Organic Chemistry groups. 2nd edition, McGraw-Hill Book Company, N.Y. page 215 The terms “lower alkenyl and “lower alkynyl refer to C. (1964). to C Straight hydrocarbon chains and C (or C in the case of The compounds of this invention are made using well lower alkynyl) to Ce branched hydrocarbon groups contain known chemical procedures. The required starting materials ing at least one unsaturated bond. 35 are commercially available or are readily synthesized using The terms “lower alkoxy” and “lower alkylthio” refer to standard procedures. O-lower alkyl and S-lower alkyl groups. The term “haloalkyl refers to lower alkyl groups substi Synthesis of Compounds of Formula (I-A) wherein tuted with one or more halo atoms. X' is O

Scheme I R. R, Y R'm H !-y R O XI 2)/ b Yx SAS 8. ex o2 NN S-X.z - Sp Z e R els2 III-A HN N X3 R=H INT-A R=aryl or - f L heteroaryl

US 8,461,164 B2 7 -continued R, R, 1-Y -/ iii. -- sey HN XI CN - C -- Ri N n N x - Rp n NN C. 2 HN Nals X3 X2 N 2 N es INT-B

The compounds of formula (I-A) wherein X" is O can be is preferably carried out in an alcohol solvent, alternatively made by condensing a compound of formula (II) 15 containing toluene, at a temperature in the range of 0°C. to reflux temperature. Compounds of formula (INT-B) can be made by reaction of II a 5,6-diaminopyrimidine compound

L HN NN als where R, X and X are as defined as for compounds of 25 HN N X3 formula (I-A); and L is a group such as F. Cl, Br, 1.2.3-triazol 1-yl, 1,2,4-triazol-1-yl, OH, arylthio, alkylthio, alkylsulfo where X and L are as defined as for compounds of formula nyl, arylsulfonyl, alkoxy, alkylsulfinyl, or arylsulfinyl; with a (II); with a compound of formula (III-A) where R. R. R.Y. Z. m, n, and pare as defined for compounds of formula (I-A) compound of the formula (III-A) 30 and X is Oasin step dof Scheme I. The reaction is preferably carried out in the presence of a base in a non-reactive solvent, III-A such as CHC1, THF, DMSO or DMF, at a temperature in the R2 range of 0°C. to reflux temperature. Alternatively, compounds of formula (INT-B) can be syn thesized by reduction of a 6-amino-5-nitropyrimidine com pound of formula (INT-A) H scNX, INT-A 40 where R. R. R. Y. Z. m, n, and p are as defined for com R, pounds of formula (I-A) and X is Oas in step e of Scheme I. R'm The reaction is preferably carried out in the presence of a base in a non-reactive solvent. Such as dichloromethane (CH2Cl2. tetrahydrofuran (THF), dimethylsulfoxide (DMSO) or N.N- 45 ON XI cN dimethylformamide (DMF), at a temperature in the range of o21 NN X- R 0° C. to reflux temperature. Alternatively, compounds of formula (I-A) can be made by HN Nals X3 reaction of a dicarbonyl or equivalent compound with a com 50 pound of formula (INT-B) where R. R. R. X, Y, Z. m, n, and p are as defined for compounds of formula (I-A) as in step b of Scheme I. Reduc tion can be achieved by hydrogenation in the presence of a 2 INT-B palladium catalyst in an alcohol solvent. Compounds of formula (INTA) can be synthesized by R R'm 55 reaction of a 5-nitro-6-aminopyrimidine compound

HN2 XINN CN S-R, L N 2l. 60 oa NN HN N X3 1. where R, R', R, X, Y, Z. m, n, and p are as defined for HN N X3 compounds of formula (I-A) and X is O, as in step c of 65 Scheme I. Representative dicarbonyl compounds include gly where X and L are as defined as for compounds of formula oxal, 2,3-butanedione and 1,4-dioxane-2,3-diol. The reaction (II); with a compound of formula (III-A) where R. R. R.Y. US 8,461,164 B2 10 Z. m, n, and pare as defined for compounds of formula (I-A) Preferably, the compounds of formula (I-A) wherein X is as in step a of Scheme I. The reaction is preferably carried out NH or N-lower alkyl and Z is as defined for compounds of in the presence of a base in a non-reactive solvent, Such as formula (I-A), can be made by condensing a compound of CHCl, THF, DMSO or DMF, at a temperature in the range formula (II) of 0° to reflux temperature. 5 Compounds of formula (III-A), where R is a phenyl or heteroaryl, may be synthesized by reaction of compounds of formula (III-A) where R is H, with a compound of formula 10 M-Het

where M is a group such as F, Cl, Br, 1,1,2,3-triazol-1-yl, II 1,2,4-triazol-1-yl, OH, arylthio, alkylthio, alkylsulfonyl, L arylsulfonyl, alkoxy, alkylsulfinyl, or arylsulfinyl; and R N wherein Het is a phenyl or heterocycle, as in step f of Scheme 15 I. Het may be optionally substituted with one or more groups selected from H. halo, lower alkyl, lower alkoxy, benzyloxy, rsrs2 als lower alkenyl, lower alkynyl, haloalkyl, haloalkoxy, NO. X2 N N X3 CN, lower alkoxycarbonyl, lower alkylcarbonyl and lower alkyl-SO. The reaction is preferably carried out in the pres ence of a base in a non-reactive solvent, such as CHCl, THF, DMSO or DMF, at a temperature in the range of 0°C. to reflux temperature.

Synthesis of Compounds of Formula (I-A) wherein 25 X is NH or N-lower alkyl where R', X, and X are as defined as for compounds of The compounds of formula (I-A) wherein X" is NH or formula (I-A); and L is a group. Such as F, Cl, Br, 1,2,3- N-lower alkyl and R,R,R,R, X, X, Y, Z, m, n and pare triazol-1-yl, 1,2,4-triazol-1-yl, OH, arylthio, alkylthio, alkyl as defined for compounds of formula (I-A), can be made in the 30 Sulfonyl, arylsulfonyl, alkoxy, alkylsulfinyl, or arylsulfinyl: same manner as described for Scheme I, from compounds of with a compound of the formula (III-A) the formulas (II), (III-A), (INT-A), (INT-B) wherein R, R', R. R. X, X, Y, Z. m., n and pare as defined for formula (I-A), and X is NH or N-lower alkyl. 35

Scheme II L

R N 40 n n N -- III-A X2 N 2 Nals X3 R2 II 45 sh N X-R, R, R1 50 H Yx 1- Y. iii.

1. p 2xZ Y R,

III-A 55 R,

Y iii. XI -- S/SR1 R N 60 where R, R', R. Y. Z. m, n, and pare as defined for com N1 NN 2. -Rp pounds of formula (I-A) and X is NH or N-lower alkyl, 2 1. optionally as a salt (e.g., HCl), as in Scheme II. The reaction X2 N N X3 is preferably carried out in the presence of base. Such as I-A 65 triethylamine, in a non-reactive solvent, such as CHCl, THF or DMF. Alternatively, the reaction may be carried out in hexamethyldisilaZane in the presence of ammonium Sulfate. US 8,461,164 B2 11 12

Scheme III R J-y R

N-N 2.X He- XINN CSix -R -e-b 2n 2 1. Z X2 N N N X2 4. as

VI V t N R. R, R'm R'm

XI o 4 XI C X2 4. Sas NX-I - X2 Y4. -as N'- IV I-A

The compounds of formula (I-A) wherein X" is NH or Certain compounds of formula (I-A) are prepared by modi N-lower alkyl and R. R. R. R. R. X. X, and Z are as 30 fications of other compounds of formula (I-A), by methods defined for compounds of formula (I-A) where R is a phenyl described in the experimental procedures of the Preparations or heterocycle optionally substituted with one or more groups and Examples section. selected from halo, lower alkyl, lower alkenyl, lower alkynyl, The compounds of formula (IV) where Z is oxygen can be lower alkoxy, haloalkyl, haloalkoxy, NO, CN, lower alkoxy prepared by treatment of compounds of formula (V) carbonyl, lower alkylcarbonyl and lower alkyl-SO, when q is 35 an integer from 0 to 2; alternatively are prepared by treatment of a compound of formula (IV) R, V

40 -- sey, IV R, R N NN C. XI --Y 21 A./ R N N 45 DC 4. X3 n NN X-H where R',R,R,R,Y, mand nareas defined for compounds X2 N 2 Nals X3 of formula (I-A), X" is NH or N-lower alkyl, Z is oxygen, and R is lower alkyl; with a reagent such as BBr in a nonreactive 50 organic solvent, Such as CH2Cl2. wherein R. R. R. X. X, Y, Z. m and n are as defined for The compounds of formula (IV) alternatively may be pre compounds of formula (I-A) and X is NH or N-lower alkyl; pared by treatment of compounds of formula (VI) wherein with a compound of formula R, X and X are as described for compound of formula M-Het 55 (I -A) s where M is a group such as F, Cl, Br, 1,1,2,3-triazol-1-yl, 1,2,4-triazol-1-yl, OH, arylthio, alkylthio, alkylsulfonyl, VI arylsulfonyl, alkoxy, alkylsulfinyl, or arylsulfinyl; and N wherein Het is a phenyl or heterocycle, as in step c of R N a Scheme III. Het may be optionally substituted with one or 60 n X3 more groups selected from H. halo, lower alkyl, lower alkoxy, benzyloxy, lower alkenyl, lower alkynyl, haloalkyl, X2 % % haloalkoxy, NO, CN, lower alkoxycarbonyl, lower alkylcar bonyl and lower alkyl-SO. The reaction is preferably carried out in the presence of a base in a non-reactive solvent, such as 65 CHCl, THF, DMSO or DMF, at a temperature in the range with a compound of formula (VII), optionally as a salt (e.g., of 0°C. to reflux temperature. HCl), US 8,461,164 B2 13 14 alkyl as defined for compounds of formula (I-A); are com VII mercially available or may be prepared by well-known meth R, ods. For example, compounds of formula (VIII-A), where R', R. mand n areas defined for compounds of formula (I-A), R H is lower alkyl, R is H, and Y is R', are prepared as their RN cR'mN-X hydrochloride salts by treatment of appropriately substituted OH (4-alkoxyphenyl)-acetonitriles with hydrogen in the presence of hydrochloric acid, a catalyst Such as palladium on carbon, where R', R, Y, m and n are as defined for compounds of 10 and an appropriate solvent Such as . formula (I-A), and R is H; in the presence of acetic acid, Alternatively, compounds of formula (VIII-A), where R', optionally as a solution in an appropriate solvent such as R. mand n areas defined for compounds of formula (I-A), R ethanol; with heating at temperatures from 25 to reflux. is lower alkyl, R is H. Y is R', are prepared by treatment of The compounds of formula (IV) alternatively may be pre 15 appropriately Substituted (4-alkoxyphenyl)-acetonitriles pared by treatment of compounds of formula (II) with borane-dimethyl sulfide complex or lithium aluminum hydride in an appropriate solvent such as tetrahydrofuran at temperatures from 20°C. to reflux. II L Alternatively, compounds of formula (VIII-A), where R', R. mand n areas defined for compounds of formula (I-A), R R N is lower alkyl, R is H, and Y is R', are prepared as their rsrs hydrochloride salts by treatment of appropriately substituted X2 N 2 N1. 1-alkoxy-4-((E)-2-nitrovinyl)-benzenes with hydrogen in the 25 presence of hydrochloric acid, a catalyst Such as palladium on where R, X and Xare as defined for compounds of formula carbon, and an appropriate solvent such as ethanol. (I-A); and L is a leaving group, Such as F. Cl, Br, I., NO, Alternatively, compounds of formula (VIII-A), where R', 1,2,3-triazol-1-yl, 1,2,4-triazol-1-yl, OSiMes, arylthio, alky R. mand n areas defined for compounds of formula (I-A), R lthio, alkylsulfonyl, arylsulfonyl, alkoxy, alkylsulfinyl or 30 is alkyl or benzyl, R is H, and Y is R', are prepared by arylsulfinyl; with a compound of formula (VII), optionally as treatment of the appropriately substituted 1-alkoxy-4-((E)-2- a salt (e.g., HCl). nitrovinyl)-benzenes with lithium aluminum hydride in an appropriate solvent Such as tetrahydrofuran. The 1-alkoxy-4-((E)-2-nitrovinyl)-benzenes are prepared VII 35 R2 by treatment of the appropriately substituted benzaldehyde with nitromethane in the presence of ammonium acetate. The compounds of formula (I-A) wherein X is NH alter su- ey natively are prepared by treatment of a compound of formula 40 (VI), as defined above, with a compound of formula (M-A), C optionally as a salt (e.g., HCl), where R. R. R.Y. Z. m, nand pare as defined for compounds of formula (I-A) and X is NH; where R', R. R.Y. m and n are as defined for compounds of in the presence of acetic acid, optionally as a solution in an formula (I-A); optionally in the presence of a base, in a appropriate solvent Such as ethanol; with heating attempera solvent such as acetonitrile, THF or DMF. 45 tures from 25 to reflux. Compounds of formula (V) are prepared by the treatment Similarly, compounds of formula (I-B), wherein X is NH of compounds of formula (VI) wherein R, X, and X are as can be prepared by treatment of a compound of formula (VI), described for compound of formula (I-A); with a compound as defined above, with a compound of formula (III-B) of formula (VIII-A), optionally as a salt (e.g., HCl). 50

III-B VIII-A R2 R2

3 R 55 st N X-R sicNX-R, 60 where R', R, Y, m and n are as defined for compounds of optionally as a salt (e.g., HCl), where R. R. R.Y. Z. m, nand formula (I-A), R is H, and R is lower alkyl as defined for pare as defined for compounds of formula (I-B) and X is NH; compounds of formula (I-A); in the presence of acetic acid, in the presence of acetic acid, optionally as a solution in an optionally as a solution in an appropriate solvent such as appropriate solvent Such as ethanol; with heating attempera ethanol; with heating at temperatures from 25°C. to reflux. 65 tures from 25 to reflux. Compounds of formula (III-B) can be Amines of formula (VIII-A) where R', R. R. Y, m and in prepared by the methods in the Preparations and Examples areas defined for compounds of formula (I-A) and R is lower section. US 8,461,164 B2 15 16 Compounds of formula (VI) -continued !-yR, VI XI S R N aN R N n n N z-Rp

X2 CO4. 4. X2 N 2 Nals 10 I-A The compounds of formula (I-A) wherein R. R. R. R. where R, X and X are as described for compound of for X, X, Y, Z. m, n, and pare as defined for compounds of mula (I-A) were prepared by treatment of a compound of formula (I-A), and X is S. can be made as in Scheme IV by formula (IX) 15 condensing a compound of formula (X)

IX N R N a Y n XI

2 R N X2 N NH2 rsrs2 als where R' and X’ are as described for compound of formula 25 X2 N N (I-A), with N,N-dimethylformamide dimethyl acetal in an appropriate solvent such as toluene, with heating attempera where R, X, and X are as defined as for compounds of ture from 25°C. up to the reflux temperature. formula (I-A); and X is S; with a compound of the formula (XI) Compounds of formula (IX) 30

XI IX R2 N R N a D N 35 -- Y." 2 X2 N NH2 C. 40 where R and X’ are as defined for compounds of formula where R, R', R.Y. Z. m, n, and pare as defined for formula (I-A) are commercially available or were prepared by well (I-A); and M is as defined in the reacting partner M-Het in known synthetic procedures. Scheme III, step c. In compounds of formula (XI), M is preferably chlorine or bromine The reaction is preferably Synthesis of Compounds of Formula (I-A) wherein 45 carried out in the presence of base. Such as triethylamine, in a non-reactive solvent, such as CHCl, THF or DMF. X is S The compounds of the present invention may be pesticides that have fungitoxic activity against harmful fungi including, but not limited to, fungi that are pathogens of plants, , 50 and humans. They are active against fungi of a number of Scheme IW classes including Oomycetes, Deuteromycetes (Fungi Imper fecti), Basidiomycetes, and Ascomycetes. More particularly, x 1" one embodiment of a method of the present invention pro R N vides for activity against phytopathogenic organisms includ N1 NN 55 ing, but not limited to, Pyricularia Oryzae, Colletotrichum species, Erysiphe species, Puccinia species, Cochliobolus species. Alternaria species, Septoria species, Rhynchospo X2 N 2 N1. X3 X rium secalis, Cercospora and Cercosporella species, and R, Pyrenophora species. Additional diseases controlled include 60 powdery mildews incited by Sphaerotheca fillignea (cucurbit powdery mildew) and Uncinula necator (grape powdery mil - - - - dew), soybean rust incited by Phakopsora pachyrhizi, downy mildews such as cucumber downy mildew (PseudoperOno spora cubensis), grape downy mildew (Plasmopara viticola), 65 apple scab incited by Venturia inaequalis, late blight incited XI by Phytophthora infestans, and Maize Smut (Ustilago may dis). US 8,461,164 B2 17 18 The compounds of the present invention may have insec In another embodiment, the invention disclosed in this ticidal activity against harmful insects and mites including, document may be used to control Dermaptera (earwigs). but not limited to, insects that are pests or parasites of plants, In another embodiment, the invention disclosed in this animals, and humans. document may be used to control Dictyoptera (cockroaches). In other embodiments, the invention disclosed in this docu A non-exhaustive list of such pests includes, but is not limited ment may be used to control pests of Phylum Nematoda, the to, Blattella germanica (German cockroach), Blatta Orienta Phylum Arthropoda, the Subphylum Chelicerata, the Class lis (oriental cockroach), Parcoblatta pennsylvanica, Arachnida, the Subphylum Myriapoda, the Class Symphyla, Periplaneta americana (American cockroach), Periplaneta the Subphylum Hexapoda, the Class Insecta. Within the Class australoasiae (Australian cockroach), Periplaneta brunnea 10 (brown cockroach), Periplaneta fuliginosa (Smokybrown Insecta, the invention disclosed in this document may be use cockroach), Pycnoselus surinamensis (Surinam cockroach), to control Coleoptera (). A non-exhaustive list of these and Supella longipalpa (brownbanded cockroach). Such pests includes, but is not limited to, Acanthoscelides spp. In another embodiment, the invention disclosed in this (weevils), Acanthoscelides Obtectus (common bean weevil), document may be used to control Diptera (true flies). A non Agrilus planipennis (emeraldashborer), Agriotes spp. (wire 15 exhaustive list of such pests includes, but is not limited to, worms). Anoplophora glabripennis (Asian longhorned Aedes spp. (mosquitoes), Agromyza frontella (alfalfa blotch ), Anthonomus spp. (weevils), Anthonomus grandis leafminer), Agromyza spp. (leafminer flies), Anastrepha spp. (boll weevil), Aphidius spp., Apion spp. (weevils), Apogonia (fruit flies), Anastrepha suspensa (Caribbean fruit fly), spp. (grubs), Ataenius spretulus (Black Turfgrass Ataenius), Anopheles spp. (mosquitoes), Batrocera spp. (fruit flies), Atomaria linearis (pygmy mangold beetle), Aulacophore Bactrocera cucurbitae (melon fly), Bactrocera dorsalis (ori spp., Bothy noderes punctiventris (beet root weevil), Bruchus ental fruit fly), Ceratitis spp. (fruit flies), Ceratitis capitata spp. (weevils), Bruchus pisorum (pea weevil), Cacoesia spp., (Mediterranean fruit fly), Chrysops spp. (deer flies), Callosobruchus maculatus (Southern cow pea weevil), Car Cochliomyia spp. (screwworms), Contarinia spp. (Gall pophilus hemipteras (dried fruit beetle), Cassida vittata, midges), Culex spp. (mosquitoes), Dasineura spp. (gall Cerosterna spp., Cerotoma spp. (chrysomeids), Cerotoma 25 midges), Dasineura brassicae (cabbage gall midge), Delia trifurcata (bean leaf beetle), Ceutorhynchus spp. (weevils), spp., Delia platura (seedcorn maggot), Drosophila spp. (vin Ceutorhynchus assimilis (cabbage seedpod weevil), Ceuto egar flies), Fannia spp. (filth flies), Fannia canicularis (little rhynchus napi (cabbage curculio), Chaetocnema spp. (chry house fly), Fannia scalaris (latrine fly), Gasterophilus intes somelids), Colaspis spp. (Soil beetles), Conoderus scalaris, tinalis (horse botfly), Gracillia perseae, Haematobia irritans Conoderus stigmosus, Conotrachelus menuphar (plum curcu 30 (horn fly), Hvlemyia spp. (root maggots), Hypoderma linea lio), Cotinus initidis (Green June beetle), Crioceris asparagi tum (common cattle grub), Liriomyza spp. (leafminer flies), (asparagus beetle), Cryptolestes ferrugineus (rusty grain Liriomyza brassica (Serpentine leafminer), Melophagus Ovi beetle), Cryptolestes pusillus (flat grain beetle), Cryptolestes nus (sheep ked), Musca spp. (muscid flies), Musca autumna turcicus (Turkish grain beetle), Ctenicera spp. (wireworms), lis (face fly), Musca domestica (house fly), Oestrus Ovis Curculio spp. (weevils), Cyclocephala spp. (grubs), Cylin 35 (sheep bot fly), Oscinella frit (frit fly), Pegomyia betae (beet drocpturus adspersus (Sunflower stem weevil), Deporaus leafminer), Phorbia spp., Psila rosae (carrotrust fly), Rhago marginiatus (mango leaf-cutting weevil), Dermestes lard letis cerasi (cherry fruit fly), Rhagoletis pomonella (apple arius (larder beetle), Dermestes maculates (hide beetle), maggot), Sitodiplosis mosellana (orange wheat blossom Diabrotica spp. (chrysolemids), Epilachna varivestis (Mexi midge), Stomoxys calcitrans (stable fly), Tabanus spp. (horse can bean beetle), Faustinus cubae, Hylobius pales (pales wee 40 flies), and Tipula spp. (crane flies). vil), Hypera spp. (weevils), Hypera postica (alfalfa weevil), In another embodiment, the invention disclosed in this Hyperodes spp. (Hyperodes weevil), Hypothenemus hampei document may be used to control Hemiptera (true bugs). A (coffee berry beetle), Ips spp. (engravers), Lasioderma serri non-exhaustive list of Such pests includes, but is not limited corne (cigarette beetle), Leptinotarsa decemlineata (Colo to. Acrosternum hilare (green Stink bug), Blissus leucopterus rado potato beetle), Liogeny's fiscus, Liogenys suturalis, Lis 45 (chinch bug), Calocoris norvegicus (potato mirid), Cimex SOrhoptrus Oryzophilus (rice water weevil), Lyctus spp. hemipterus (tropical bedbug), Cimex lectularius (bed bug), (wood beetles/powder post beetles), Maecolaspis joliveti, Dagbertus fasciatus, Dichelops furcatus, Dysdercus suturel Megascelis spp., Melanotus communis, Melligethes spp., lus (cotton stainer), Edessa meditabunda, Eurygaster maura Melligethes aeneus (blossom beetle), Melolontha melolontha (cereal bug), Euschistus heros, Euschistus servus (brown (common European cockchafer), Oberea brevis, Oberealin 50 Stink bug), Helopeltis antonii, Helopeltis theivora (tea blight earis, Oryctes rhinoceros (date palm beetle), Oryzaephilus plantbug), Lagynotomus spp. (Stink bugs), Leptocorisa Ora mercator (merchant grain beetle), Oryzaephilus surinamen torius, Leptocorisa varicornis, Lygus spp. (plant bugs), Lygus sis (Sawtoothed grain beetle), Otiorhynchus spp. (weevils), hesperus (western tarnished plant bug), Maconellicoccus hir Oulema melanopus (cereal leaf beetle), Oulema Oryzae, Pan sutus, Neurocolpus longirostris, Nezara viridula (Southern tomorus spp. (weevils), Phyllophaga spp. (May/June beetle), 55 green Stink bug), Phytocoris spp. (plant bugs), Phytocoris Phyllophaga cuyabana, Phyllotreta spp. (chrysomelids), Californicus, Phytocoris relativus, Piezodorus guildingi, Phynchites spp., Popillia japonica (Japanese beetle), Pros Poecilocapsus lineatus (fourlined plant bug), Psallus vaccini tephanus truncates (larger grain borer), Rhizopertha cola, Pseudacy.sta perseae, Scaptocoris Castanea, and Tri dominica (lesser grain borer), Rhizotrogus spp. (European atoma spp. (bloodsucking conenose bugs/kissing bugs). chafer), Rhynchophorus spp. (weevils), Scolytus spp. (wood 60 In another embodiment, the invention disclosed in this beetles). Shenophorus spp. (Billbug), Sitona lineatus (pea document may be used to control Homoptera (aphids, scales, leaf weevil), Sitophilus spp. (grain weevils), Sitophilus gra whiteflies, leafhoppers). A non-exhaustive list of such pests naries (granary weevil), Sitophilus Oryzae (rice weevil), Ste includes, but is not limited to, Acrythosiphon pisum (pea gobium paniceum (drugstore beetle), Tribolium spp. (flour aphid), Adelges spp. (adelgids), Aleurodes proletella (cab beetles), Tribolium castaneum (red flour beetle), Tribolium 65 bage whitefly), Aleurodicus disperses, Aleurothrixus flocco confusum (confused flour beetle), Trogoderma variabile sus (woolly whitefly), Aluacaspis spp., Amrasca biguitella (warehouse beetle), and Zabrus tenebioides. bigutella, Aphrophora spp. (leafhoppers), Aonidiella aurantii US 8,461,164 B2 19 20 (California red scale), Aphis spp. (aphids), Aphis gossypii Reticulitermes virginicus, Schedorhinotermes spp., and Zoo (cotton aphid), Aphis pomi (apple aphid), Aulacorthum Solani termopsis spp. (rotten-wood termites). (foxglove aphid), Bemisia spp. (whiteflies), Bemisia argenti In another embodiment, the invention disclosed in this folii, Bemisia tabaci (sweetpotato whitefly), Brachycolus document may be used to control ( and noxius (Russian aphid), Brachycorynella asparagi (aspara butterflies). A non-exhaustive list of such pests includes, but gus aphid), Brevennia rehi, Brevicoryne brassicae (cabbage is not limited to, Achoea janata, Adoxophyes spp., Adoxo aphid), Ceroplastes spp. (scales), Ceroplastes rubens (red phyes Orana, Agrotis spp. (cutworms), Agrotis ipsilon (black wax scale), Chionaspis spp. (scales), Chrysomphalus spp. cutworm), Alabama argillacea (cotton leafworm), Amorbia (scales), Coccus spp. (scales), Dysaphis plantaginea (rosy cuneana, Amyelosis transitella (navel orangeworm), Ana apple aphid), Empoasca spp. (leafhoppers), Eriosoma lani 10 camptodes defectaria, Anarsia lineatella (peach twig borer), gerum (woolly apple aphid), Icerva purchasi (cottony cush Anomis Sabulifera (jute looper), Anticarsia gemmatalis (vel ion scale), Idioscopus initidulus (mango leafhopper), Laodel vetbean caterpillar), Archips argyrospila (fruittree leafroller), phax striatellus (Smaller brown planthopper), Lepidosaphes Archips rosana (rose leafroller), Argyrotaenia spp. (tortricid spp., Macrosiphum spp., Macrosiphum euphorbiae (potato moths), Argyrotaenia citrana (orange tortrix), Autographa aphid), Macrosiphum granarium (English grain aphid), Mac 15 gamma, Bonagota Cranaodes, Borbo cinnara (rice leaf rosiphum rosae (rose aphid), Macrosteles quadrilineatus (as folder), Bucculatrix thurberiella (cotton leafperforator), ter leafhopper), Mahanarva fimbiolata, Metopolophium Caloptilia spp. (leafminers), Capua reticulana, Carposina dirhodun (rose grain aphid), Mictis longicornis, Myzus per niponensis (peach fruit ), Chilo spp., Chlumetia trans sicae (green peach aphid), Nephotettix spp. (leafhoppers), versa (mango shoot borer), Choristoneura rosaceana (ob Nephotettix cinctipes (green leafhopper), Nilaparvata lugens liquebanded leafroller), Chrysodeixis spp., Cnaphalocerus (brown planthopper), Parlatoria pergandii (chaff scale), Par medinalis (grass leafroller), Colias spp., Compomorpha latoria Ziziphi (ebony scale), Peregrinus maidis (corn delpha cramerella, Cossus Cossus (carpenter moth), Crambus spp. cid), Philaenus spp. (spittlebugs), Phylloxera vitifoliae (Sod webworms), Cydia funebrana (plum fruit moth), Cydia (grape phylloxera), Physokermes piceae (spruce bud scale), molesta (oriental fruit moth), Cydia nignicana (pea moth), Planococcus spp. (mealybugs), Pseudococcus spp. (mealy 25 Cydia pomonella (codling moth), Darna diducta, Diaphania bugs), Pseudococcus brevipes (pine apple mealybug), Ouad spp. (stem borers), Diatraea spp. (stalk borers), Diatraea raspidiotus perniciosus (San Jose scale), Rhapalosiphun saccharalis (Sugarcane borer), Diatraea graniosella (South spp. (aphids), Rhapalosiphum maida (corn leaf aphid), western cornborer), Earias spp. (bollworms), Earias insulata Rhapalosiphum padi (oat bird-cherry aphid), Saissetia spp. (Egyptian bollworm), Earias vitella (rough northern boll (scales), Saissetia oleae (black scale), Schizaphis graminum 30 worm), Ecdytopopha aurantianum, Elasmopalpus lignosel (greenbug), Sitobion avenae (English grain aphid), Sogatella lus (lesser cornstalk borer), Epiphysia's postruttana (light fircifera (white-backed planthopper), Therioaphis spp. brown apple moth), Ephestia spp. (flour moths), Ephestia (aphids), Toumeyella spp. (scales), Toxoptera spp. (aphids), cautella (almond moth), Ephestia elutella (tobacco moth), Trialeurodes spp. (whiteflies), Trialeurodes vaporariorum Ephestia kuehniella (Mediterranean flour moth), Epimeces (greenhouse whitefly), Trialeurodes abutiloneus (banded 35 spp., Epinotia aporema, Erionota thrax (banana skipper), wing whitefly). Unaspis spp. (scales), Unaspis yanonensis Eupoecilia ambiguella (grape berry moth), Euxoa auxiliaris (arrowhead scale), and Zulia entreriana. (army cutworm), Feltia spp. (cutworms), Gortyna spp. (stem In another embodiment, the invention disclosed in this borers), Grapholita molesta (oriental fruit moth), Hedylepta document may be used to control Hymenoptera (ants, wasps, indicata (bean leaf webber), Helicoverpa spp. (noctuid and bees). A non-exhaustive list of Such pests includes, but is 40 moths), Helicoverpa armigera (cotton bollworm), Helicov not limited to, Acromyrrmex spp., Athalia rosae, Atta spp. erpa zea (bollworm/corn earworm), Heliothis spp. (noctuid (leafcutting ants), Camponotus spp. (carpenterants), Diprion moths), Heliothis virescens (tobacco budworm), Hellula spp. (sawflies), Formica spp. (ants), Iridomyrmex humilis undalis (cabbage webworm), Indarbela spp. (root borers), (Argentine ant), Monomorium spp., Monomorium minumum Keiferia lycopersicella (tomato pinworm), Leucinodes (little black ant), Monomorium pharaonis (Pharaoh ant), 45 Orbonalis (eggplant fruit borer), Leucoptera malifoliella, Neodiprion spp. (sawflies), Pogonomyrmex spp. (harvester Lithocollectis spp., Lobesia botrana (grapefruit moth), LOxa ants), Polistes spp. (paper wasps), Solenopsis spp. (fire ants), grotis spp. (noctuid moths), Loxagrotis albicosta (western Tapoinoma sessile (odorous house ant), Tetranomorium spp. bean cutworm), Lymantria dispar (gypsy moth), Lyonetia (pavementants), Vespula spp. (yellowjackets), and Xylocopa clerkella (apple leaf miner), Mahasena corbetti (oil palm spp. (carpenter bees). 50 bagworm), Malacosoma spp. (tent caterpillars), Mamestra In another embodiment, the invention disclosed in this brassicae (cabbage armyworm), Maruca testulalis (bean pod document may be used to control Isoptera (termites). A non borer), Metisa plana (bagworm), Mythinna unipuncta (true exhaustive list of such pests includes, but is not limited to, armyworm), Neoleucinodes elegantalis (Small tomato borer), Coptotermes spp., Coptotermes curvignathus, Coptotermes Nymphula depunctalis (rice caseworm), Operophthera bru frenchi, Coptotermes formosanus (Formosan Subterranean 55 mata (winter moth), Ostrinia nubilalis (European corn termite), Cornitermes spp. (nasute termites), Cryptotermes borer), Oxydia vesulia, Pandemis cerasana (common currant spp. (drywood termites), Heterotermes spp. (desert Subterra tortrix), Pandemis heparana (brown apple tortrix), Papilio nean termites), Heterotermes aureus, Kalotermes spp. (dry demodocus, Pectinophora gossypiella (pink bollworm), wood termites), Incistitermes spp. (drywood termites), Mac Peridroma spp. (cutworms), Peridroma saucia (variegated rotermes spp. (fungus growing termites), Marginitermes spp. 60 cutworm), Perileucoptera coffeella (white coffee leafminer), (drywood termites), Microcerotermes spp. (harvester ter Phthorimaea operculella (potato tuber moth), Phyllocnisitis mites), Microtermes obesi, Procornitermes spp., Reticuliter citrella, Phyllonorycter spp. (leafminers), Pieris rapae (im mes spp. (Subterranean termites). Reticulitermes banyulensis, ported cabbageworm), Plathypena scabra, Plodia interpunc Reticulitermes grassei, Reticulitermes flavipes (eastern Sub tella (Indian meal moth), Plutella xylostella (diamondback terranean termite), Reticulitermes hageni, Reticulitermes 65 moth), Polychrosis viteana (grape berry moth), Prays hesperus (western Subterranean termite), Reticulitermes San endocarpa, Prays oleae (olive moth), Pseudaletia spp. (noc tonensis, Reticulitermes speratus, Reticulitermes tibialis, tuid moths), Pseudaletia unipunctata (armyworm), US 8,461,164 B2 21 22 Pseudoplusia includens (soybean looper), Rachiplusia nu, mite), Epitimerus spp., Eriophyes spp., Ixodes spp. (ticks), Scirpophaga incertulas, Sesamia spp. (stemborers), Sesamia Metatetranycus spp., Notoedres cati, Oligonychus spp., Oli inferens (pink rice stem borer), Sesamia nonagrioides, Setora gonychus coffee, Oligonychus ilicus (Southern red mite), nitens, Sitotroga cerealella (Angoumois grain moth), Spar Panonychus spp., Panonychus citri (citrus red mite), Panony ganothis pilleriana, Spodoptera spp. (armyworms), chus ulmi (European red mite), Phylocoptruta oleivora (cit Spodoptera exigua (beet armyworm), Spodoptera frugiperda rus rust mite), Polyphagotarisonemun latus (broad mite), Rhi (fall armyworm), Spodoptera oridania (Southern army picephalus sanguineus (brown dog tick), Rhizoglyphus spp. worm), Synanthedon spp. (root borers). Thecla basilides, (bulb mites), Sarcoptes scabiei (itch mite), Tegolophus per Thermisia gemmatalis, Tineola bisselliella (webbing clothes seaflorae, Tetranychus spp., Tetranychus urticae (two-spot moth), Trichoplusia ni (cabbage looper), Tuta absoluta, 10 ted spider mite), and Varroa destructor (honeybee mite). Yponomeuta spp., Zeuzera coffeae (red branch borer), and In another embodiment, the invention disclosed in this Zeuzera pyrina (leopard moth). document may be used to control Nematoda (nematodes). A In another embodiment, the invention disclosed in this non-exhaustive list of Such pests includes, but is not limited document may be used to control Mallophaga (chewing lice). to, Aphelenchoides spp. (bud and leaf & pine wood nema A non-exhaustive list of such pests includes, but is not limited 15 todes), Belonolaimus spp. (sting nematodes), Criconemella to, Bovicola Ovis (sheep biting louse), Menacanthus stra spp. (ring nematodes), Dirofilaria immitis (dog heartworm), mineus (chicken body louse), and Menopon gallinea (com Dity lenchus spp. (stem and bulb nematodes), Heterodera spp. mon hen louse). (cyst nematodes), Heterodera zeae (corn cyst nematode), In another embodiment, the invention disclosed in this Hirschmanniella spp. (root nematodes), Hoplolaimus spp. document may be used to control Orthoptera (grasshoppers, (lance nematodes), Meloidogyne spp. (root knot nematodes), locusts, and crickets). A non-exhaustive list of Such pests Meloidogyne incognita (root knot nematode). Onchocerca includes, but is not limited to, Anabrus simplex (Mormon volvulus (hook-tail worm), Pratylenchus spp. (lesion nema cricket), Gryllotalpidae (mole crickets), Locusta migratoria, todes), Radopholus spp. (burrowing nematodes), and Roty Melanoplus spp. (grasshoppers), Microcentrum retinerve lenchus reniformis (kidney-shaped nematode). (angularwinged katydid), Pterophylla spp. (katydids), Schis 25 In another embodiment, the invention disclosed in this tocerca gregaria, Scudderia furcata (forktailed bush katy document may be used to control Symphyla (Symphylans). A did), and Valanga nigricornis (short horned grasshopper). non-exhaustive list of Such pests includes, but is not limited In another embodiment, the invention disclosed in this to, Scutigerella immaculata. document may be used to control Phthiraptera (Sucking lice). In another embodiment, the invention disclosed in this A non-exhaustive list of such pests includes, but is not limited 30 document may be used to control animal and human para to, Haematopinus spp. (cattle and hog lice), Linognathus sites. A non-exhaustive list of Such pests includes, but is not Ovillus (sheep louse), Pediculus humanus capitis (human limited to, such as mites (e.g., mesostigmatids, body louse), Pediculus humanus humanus (human body lice), itch, mange, Scabies, chiggers), ticks (e.g., soft-bodied and and Pthirus pubis (crab louse). hard-bodied), lice (e.g., Sucking, biting), fleas (e.g., dog flea, In another embodiment, the invention disclosed in this 35 cat flea, oriental rat flea, human flea), true bugs (e.g., bed document may be used to control Siphonaptera (fleas). A bugs, Triatomidbugs), bloodsucking adult flies (e.g., horn fly, non-exhaustive list of Such pests includes, but is not limited horse fly, stable fly, black fly, deer fly, louse fly, tsetse fly, to, Ctenocephalides canis (dog flea), Ctenocephalides felis mosquitoes), and parasitic fly maggots (e.g., botfly, blow fly, (cat flea), and Pulex irritans (human flea). screwworm, cattle grub, fleeceworm); helminths such as In another embodiment, the invention disclosed in this 40 nematodes (e.g., threadworm, lungworm, hookworm, whip document may be used to control Thysanoptera (thrips). A worm, nodular worm, stomach worm, roundworm, pinworm, non-exhaustive list of Such pests includes, but is not limited heartworm), cestodes (e.g., tapeworms) and trematodes (e.g., to, Frankliniella fisca (tobacco thrips), Frankliniella Occi liver fluke, blood fluke); protozoa Such as coccidia, trypano dentalis (western flower thrips), Frankliniella Shultzei, Fran Somes, trichomonads, amoebas and plasmodia; acanthoceph Kliniella williamsi (corn thrips), Heliothrips haemorrhaidalis 45 alans Such as thorny-headed worms (e.g., lingulatulida); and (greenhouse thrips), Riphiphorothrips cruentatus, Scirto pentastomids Such as tongueworms. thrips spp., Scirtothrips citri (citrus thrips), Scirtothrips dor Detailed information regarding pests may be found in the salis (yellow tea thrips), Taeniothrips rhopalantennalis, and “Handbook of The Behavior, Life History, and Thrips Spp. Control of Household Pests” by Arnold Mallis, 9' Edition, In another embodiment, the invention disclosed in this 50 copyright 2004 by GIE Media Inc, which is expressly incor document may be used to control Thysanura (bristletails). A porated by reference herein. non-exhaustive list of Such pests includes, but is not limited The present invention contemplates all vehicles by which to, Lepisma spp. (silverfish) and Thermobia spp. (firebrats). the composition of the present invention can be formulated In another embodiment, the invention disclosed in this for delivery and use as a pesticide composition, including document may be used to control Acarina (mites and ticks). A 55 Solutions, Suspensions, emulsions, wettable powders and non-exhaustive list of Such pests includes, but is not limited water dispersible granules, emulsifiable concentrates, gran to, Acarapsis woodi (tracheal mite of honeybees), Acarus ules, dusts, baits, and the like. Compositions suitable for spp. (food mites), Acarus siro (grain mite), Aceria administration to vertebrates or man include preparations mangiferae (mango bud mite), Aculops spp., Aculops lyco Suitable for oral, parenteral, percutaneous, e.g. pour-on, or persici (tomato russet mite), Aculops pelekasi, Aculus pelle 60 topical administration. kassi, Aculus Schlechtendali (apple rust mite), Amblyomma Compositions for oral administration comprise one or americanum (lone startick), Boophilus spp. (ticks), Brevipal more of the compounds of general formula (I-A) or (I-B) in pus Obovatus (privet mite), Brevipalpus phoenicis (red and association with pharmaceutically acceptable carriers or black flat mite), Demodex spp. (mange mites), Dermacentor coatings and include, for example, tablets, pills, capsules, spp. (hard ticks), Dermacentor variabilis (American dog 65 pastes, gels, drenches, medicated feeds, medicated drinking tick), Dermatophagoides pteronyssinus (house dust mite), water, medicated dietary Supplements, slow-release boluses Eotetranycus spp., Eotetranychus carpini (yellow spider or other slow-release devices intended to be retained within US 8,461,164 B2 23 24 the gastrointestinal tract. Any of these may incorporate active Emulsifiers which can be advantageously employed herein ingredient contained within microcapsules or coated with can be readily determined by those skilled in the art and acid-labile or alkali-labile or other pharmaceutically accept include various nonionic, anionic, cationic and amphoteric able enteric coatings. Feed premixes and concentrates con emulsifiers, or a blend of two or more emulsifiers. Examples taining compounds of the present invention for use in prepa of nonionic emulsifiers useful in preparing the emulsifiable ration of medicated diets, drinking water or other materials concentrates include the polyalkylene glycol ethers and con for consumption by animals may also be used. densation products of alkyl and aryl phenols, aliphatic alco Compositions for parenteral administration include Solu hols, aliphatic amines or fatty acids with ethylene oxide, tions, emulsions or Suspensions in any suitable pharmaceuti propylene oxides such as the ethoxylated alkyl phenols and 10 carboxylic esters esterified with the polyol or polyoxyalky cally acceptable vehicle and Solid or semisolid Subcutaneous lene. Cationic emulsifiers include quaternary ammonium implants or pellets designed to release active ingredient over compounds and fatty amine salts. Anionic emulsifiers include a protracted period and may be prepared and made sterile in the oil-soluble salts (e.g., calcium) of alkylaryl Sulfonic acids, any appropriate manner known to the art. oil-soluble salts of sulfated polyglycol ethers and appropriate Compositions for percutaneous and topical administration 15 salts of phosphated polyglycol ether. include sprays, dusts, baths, dips, showers, jets, greases, Representative organic liquids which can be employed in shampoos, creams, wax-smears, or pour-on preparations and preparing emulsifiable concentrates are the aromatic liquids devices (e.g. ear tags) attached externally to animals in Such a Such as Xylene, propylbenzene fractions; or mixed naphtha way as to provide local or systemic control. lene fractions, mineral oils, Substituted aromatic organic liq Typically, formulations for application to plants, seeds, or uids such as dioctyl phthalate; kerosene, dialkyl amides of soil are applied following dilution of the concentrated formu various fatty acids, particularly the dimethyl amides; and lation with water as aqueous solutions, Suspensions or emul glycol ethers such as the n-butyl ether, ethyl ether or methyl sions, or combinations thereof. Such solutions, Suspensions ether of diethylene glycol, and the methyl ether of triethylene or emulsions are produced from water-soluble, water-Sus glycol and the like. Mixtures of two or more organic liquids pended or water-suspendable, water-emulsified or water 25 may also be employed in the preparation of the emulsifiable emulsifiable formulations or combinations thereof which are concentrate. Surface-active emulsifying agents are typically Solids, including and usually known as wettable powders or employed in liquid formulations and in an amount of from 0.1 water dispersible granules; or liquids including and usually to 20 percent by weight based on the combined weight of the known as emulsifiable concentrates, aqueous Suspensions or emulsifying agents. The formulations can also contain other Suspension concentrates, and aqueous emulsions or emul 30 compatible additives, for example, plant growth regulators sions in water, or mixtures thereof such as Suspension-emul and other biologically active compounds used in agriculture. sions. As will be readily appreciated, any materials to which Aqueous suspensions comprise Suspensions of one or more this composition can be added may be used, provided they water-insoluble pesticidally active ingredients dispersed in an yield the desired utility without significant interference with aqueous vehicle at a concentration in the range from about 5 the desired activity of the pesticidally active ingredients as 35 to about 70 weight percent, based on the total weight of the pesticidal agents. aqueous Suspension. Suspensions are prepared by finely Wettable powders, which may be compacted to form water grinding one or more of the pesticidally active ingredients, dispersible granules, comprise an intimate mixture of one or and vigorously mixing the ground material into a vehicle more of the pesticidally active ingredients, an inert carrier and comprised of water and Surfactants chosen from the same Surfactants. The concentration of the pesticidally active ingre 40 types discussed above. Other components, such as inorganic dient in the wettable powder is usually from about 10 percent salts and synthetic or natural gums, may also be added to to about 90 percent by weight based on the total weight of the increase the density and viscosity of the aqueous vehicle. It is wettable powder, more preferably about 25 weight percent to often most effective to grind and mix at the same time by about 75 weight percent. In the preparation of wettable pow preparing the aqueous mixture and homogenizing it in an der formulations, the pesticidally active ingredients can be 45 implement Such as a sand mill, ball mill, or piston-type compounded with any finely divided solid, such as prophyl homogenizer. lite, talc, chalk, gypsum, Fuller's earth, bentonite, attapulgite, Aqueous emulsions comprise emulsions of one or more starch, casein, gluten, montmorillonite clays, diatomaceous water-insoluble pesticidally active ingredients emulsified in earths, purified silicates or the like. In such operations, the an aqueous vehicle at a concentration typically in the range finely divided carrier and surfactants are typically blended 50 from about 5 to about 70 weight percent, based on the total with the compound(s) and milled. weight of the aqueous emulsion. If the pesticidally active Emulsifiable concentrates of the pesticidally active ingre ingredient is a solid it must be dissolved in a suitable water dient comprise a convenient concentration, such as from immiscible solvent prior to the preparation of the aqueous about 10 weight percent to about 50 weight percent of the emulsion. Emulsions are prepared by emulsifying the liquid pesticidally active ingredient, in a Suitable liquid, based on 55 pesticidally active ingredient or water-immiscible Solution the total weight of the concentrate. The pesticidally active thereof into an aqueous medium typically with inclusion of ingredients are dissolved in an inert carrier, which is either a surfactants that aid in the formation and stabilization of the water miscible solvent or a mixture of water-immiscible emulsion as described above. This is often accomplished with organic solvents, and emulsifiers. The concentrates may be the aid of vigorous mixing provided by high shear mixers or diluted with water and oil to form spray mixtures in the form 60 homogenizers. of oil-in-water emulsions. Useful organic solvents include The compositions of the present invention can also be aromatics, especially the high-boiling naphthalenic and ole granular formulations, which are particularly useful for appli finic portions of petroleum Such as heavy aromatic naphtha. cations to the soil. Granular formulations usually contain Other organic Solvents may also be used. Such as, for from about 0.5 to about 10 weight percent, based on the total example, terpenic solvents, including rosin derivatives, ali 65 weight of the granular formulation of the pesticidally active phatic ketones, such as cyclohexanone, and complex alco ingredient(s), dispersed in an inert carrier which consists hols, such as 2-ethoxyethanol. entirely or in large part of coarsely divided inert material Such US 8,461,164 B2 25 26 as attapulgite, bentonite, diatomite, clay or a similar inexpen after the non-complexed solvent molecules are removed from sive Substance. Such formulations are usually prepared by the compounds. These complexes are often referred to as dissolving the pesticidally active ingredients in a suitable “Solvates. Solvent and applying it to a granular carrier which has been Certain compounds disclosed in this document can exist as preformed to the appropriate particle size, in the range of 5 one or more Stereoisomers. The various stereoisomers from about 0.5 to about 3 mm. A suitable solvent is a solvent include geometric isomers, diastereomers, and enantiomers. in which the compound is substantially or completely soluble. Thus, the compounds disclosed in this invention include race Such formulations may also be prepared by making a dough mic mixtures, individual stereoisomers, and optically active or paste of the carrier and the compound and solvent, and mixtures. It will be appreciated by those skilled in the art that crushing and drying to obtain the desired granular particle. 10 one stereoisomer may be more active than the others. Indi vidual stereoisomers and optically active mixtures may be Dusts can be prepared by intimately mixing one or more of obtained by selective synthetic procedures, by conventional the pesticidally active ingredients in powdered form with a synthetic procedures using resolved starting materials, or by Suitable dusty agricultural carrier, such as, for example, conventional resolution procedures. kaolin clay, ground Volcanic rock, and the like. Dusts can 15 The compounds of the present invention can also be com suitably contain from about 1 to about 10 weight percent of bined with other agricultural fungicides to form fungicidal the compounds, based on the total weight of the dust. mixtures and synergistic mixtures thereof. The fungicidal The formulations may additionally contain adjuvant Sur compounds of the present invention are often applied in con factants to enhance deposition, wetting and penetration of the junction with one or more other fungicides to control a wider pesticidally active ingredients onto the target site such as a variety of undesirable diseases. When used in conjunction crop or organism. These adjuvant Surfactants may optionally with other fungicide(s), the presently claimed compounds be employed as a component of the formulation or as a tank can be formulated with the other fungicide(s), tank mixed mix. The amount of adjuvant Surfactant will typically vary with the other fungicide(s) or applied sequentially with the from 0.01 to 1.0 percent by volume, based on a spray-volume other fungicide(s). Such other fungicides include but are not of water, preferably 0.05 to 0.5 volume percent. Suitable 25 limited to 2-(thiocyanatomethylthio)-benzothiazole, 2-phe adjuvant Surfactants include, but are not limited to ethoxy nylphenol, 8-hydroxyquinoline Sulfate, ametoctradin, lated nonyl phenols, ethoxylated synthetic or natural alco amisulbrom, antimycin, Ampelomyces quisqualis, azacona hols, salts of the esters of Sulfo Succinic acids, ethoxylated Zole, azoxystrobin, Bacillus subtilis, benalaxyl, benomyl. organosilicones, ethoxylated fatty amines and blends of Sur benthiavalicarb-isopropyl, benzylaminobenzene-Sulfonate factants with mineral or vegetable oils. 30 (BABS) salt, bicarbonates, biphenyl, bismerthiazol, biter tanol, bixafen, blasticidin-S, borax, Bordeaux mixture, bos The formulations may optionally include combinations calid, bromuconazole, bupirimate, BYF 1047, calcium that contain one or more other pesticidal compounds. Such polysulfide, captafol, captan, , carboxin, carpro additional pesticidal compounds may be fungicides, insecti pamid, carvone, chloroneb, chlorothalonil, chloZolinate, cides, nematicides, miticides, arthropodicides, bactericides, 35 Coniothyrium minitans, copper hydroxide, copper octanoate, plant growth stimulators or regulators, nitrification inhibitors, copper oxychloride, copper Sulfate, copper Sulfate (tribasic), nutrients, or combinations thereof that are compatible with cuprous oxide, cyaZofamid, cyflufenamid, cymoxanil, cypro the compounds of the present invention in the medium conazole, cyprodinil, coumarin, dazomet, debacarb, diam selected for application, and not antagonistic to the activity of monium ethylenebis-(dithiocarbamate), dichlofluanid, the present compounds. The compounds of the present inven 40 dichlorophen, diclocymet, diclomeZine, dichloran, tion, and the pesticidal compound in the combination can diethofencarb, difenoconazole, difenZoquat ion, diflume generally be present in a weight ratio of from 1:100 to 100:1. torim, dimethomorph, dimoxystrobin, diniconazole, dini The compounds disclosed in this invention can be in the conazole-M, dinobuton, dinocap, diphenylamine, dithianon, form of pesticidally acceptable acid addition salts. dodemorph, dodemorph acetate, dodine, dodine free base, By way of non-limiting example, an amine function can 45 edifenphos, enestrobin, epoxiconazole, ethaboxam, ethox form salts with hydrochloric, hydrobromic, sulfuric, phos ycuin, etridiazole, famoxadone, fenamidone, fenarimol, fen phoric, acetic, benzoic, citric, malonic, Salicylic, malic, buconazole, fenfuram, fenhexamid, fenoxanil, fenpiclonil. fumaric, oxalic, succinic, tartaric, lactic, gluconic, ascorbic, fenpropidin, fenpropimorph, fentin, fentin acetate, fentin maleic, aspartic, benzenesulfonic, methanesulfonic, ethane hydroxide, ferbam, ferimzone, fluazinam, fludioxonil, flu Sulfonic, hydroxymethanesulfonic, and hydroxyethane 50 morph, fluopicolide, fluopyram, fluoroimide, fluoxastrobin, Sulfonic acids. fluguinconazole, flusilazole, flusulfamide, flutianil, flutola Additionally, by way of non-limiting example, an acid nil, flutriafol, folpet, formaldehyde, fosetyl, fosetyl-alu function can form salts including those derived from alkali or minium, fuberidazole, furalaxyl, furametpyr, guaZatine, alkaline earth metals and those derived from ammonia and guazatline acetates, GY-81, hexachlorobenzene, hexacona amines Examples of preferred cations include , potas 55 Zole, hymexaZol, imazalil, imazalil Sulfate, imibenconazole, sium, magnesium, and aminium cations. iminoctadine, iminoctadine triacetate, iminoctadine tris(al The salts are prepared by contacting the free base form with besilate), ipconazole, iprobenfos, iprodione, iprovalicarb, a sufficient amount of the desired acid to produce a salt. The isoprothiolane, isopyrazam, isotianil, kasugamycin, kasuga free base forms may be regenerated by treating the salt with a mycin hydrochloride hydrate, kresoxim-methyl, mancopper, Suitable dilute aqueous base solution Such as dilute aqueous 60 mancoZeb, mandipropamid, maneb, mepanipyrim, mepronil. NaOH, potassium carbonate, ammonia, and sodium bicar mercuric chloride, mercuric oxide, mercurous chloride, bonate. As an example, in many cases, a pesticide is modified metalaxyl, mefenoxam, metalaxyl-M, metam, metam-am to a more water soluble form e.g. 2,4-dichlorophenoxyacetic monium, metam-potassium, metam-Sodium, metconazole, acid dimethyl amine salt is a more water soluble form of methasulfocarb, methyl iodide, methyl isothiocyanate, meti 2,4-dichlorophenoxyacetic acid, a well known herbicide. 65 ram, metominostrobin, metrafenone, mildiomycin, myclobu The compounds disclosed in this invention can also form tanil, nabam, nitrothal-isopropyl, nuarimol, octhillinone, ofu stable complexes with solvent molecules that remain intact race, oleic acid (fatty acids), orysastrobin, oxadixyl, oxine US 8,461,164 B2 27 28 copper, Oxpoconazole fumarate, oxycarboxin, pefurazoate, and not antagonistic to the activity of the present compounds penconazole, pencycuron, pentachlorophenol, pentachlo to form pesticidal mixtures and synergistic mixtures thereof. rophenyl laurate, penthiopyriad, phenylmercury acetate, The pesticidal compounds of the present invention are often phosphonic acid, phthalide, picoxystrobin, polyoxin B, poly applied in conjunction with one or more other , oxins, polyoxorim, potassium bicarbonate, potassium miticides, or other pesticides to control a wider variety of hydroxyquinoline Sulfate, probenazole, prochloraz, procymi undesirable pests. When used in conjunction with other pes done, , propamocarb hydrochloride, propicona ticides, the presently claimed compounds can be formulated Zole, propineb, produinazid, prothioconazole, pyraclos with the other pesticide(s), tank mixed with the other pesti trobin, pyrametostrobin, pyraoxystrobin, pyrazophos, cide(s) or applied sequentially with the other pesticide(s). pyribencarb, pyributicarb, pyrifenox, pyrimethanil, pyro 10 Typical insecticides include, but are not limited to: antibiotic quilon, quinoclamine, quinoxyfen, quintoZene, Reynoutria insecticides such as allosamidin and thuringiensin; macrocy Sachalinensis extract, sedaxane, silthiofam, Simeconazole, clic lactone insecticides Such as and spinetoram; Sodium 2-phenylphenoxide, sodium bicarbonate, sodium avermectin insecticides Such as abamectin, doramectin, ema pentachlorophenoxide, spiroxamine, sulfur, SYP-Z071, mectin, eprinomectin, ivermectin and Selamectin; milbemy SYP-Z048, tar oils, tebuconazole, tebufloquin, tecnaZene, 15 cin insecticides such as lepimectin, milbemectin, milbemycin tetraconazole, thiabendazole, thifluZamide, thiophanate-me Oxime and moxidectin; arsenical insecticides Such as calcium thyl, thiram, tiadinil, tolclofos-methyl, tolylfluanid, triadime arsenate, copper acetoarsenite, copper arsenate, lead arsen fon, triadimenol, triaZoxide, tricyclazole, tridemorph, triflox ate, potassium arsenite and sodium arsenite; botanical insec yStrobin, triflumizole, triforine, triticonazole, validamycin, ticides Such as anabasine, , d-, nicotine, Valifenalate, Valiphenal, VincloZolin, Zineb, Ziram, Zoxamide, , cinerins, cinerin I, cinerin II, jasmolin I, jasmolin Candida oleophila, Fusarium oxysporum, Gliocladium spp., II, I, pyrethrin II, quassia, rotenone, ryania and Phlebiopsis gigantea, Streptomyces griseoviridis, Tricho Sabadilla; insecticides Such as and car derma spp., (RS)-N-(3,5-dichlorophenyl)-2-(methoxym baryl; benzofuranyl methylcarbamate insecticides such as ethyl)-Succinimide, 1,2-dichloropropane, 1,3-dichloro-1,1,3, benfuracarb, , , decarbofuran and 3-tetrafluoroacetone hydrate, 1-chloro-2,4- 25 furathiocarb; dimethylcarbamate insecticides dimitan, dime dinitronaphthalene, 1-chloro-2-nitropropane, 2-(2- tilan, hyduincarb and ; oxime carbamate insecti heptadecyl-2-imidazolin-1-yl)ethanol, 2,3-dihydro-5- cides such as alanycarb, , aldoxycarb, , phenyl-1,4-dithi-line 1.1.4,4-tetraoxide, butoxycarboxim, , nitrilacarb, , tazimcarb, 2-methoxyethylmercury acetate, 2-methoxyethylmercury thiocarboxime, thiodicarb and ; phenyl methylcar chloride, 2-methoxyethylmercury silicate, 3-(4-chloro-phe 30 bamate insecticides Such as allyxycarb, , bufen nyl)-5-methylrhodanine, 4-(2-nitroprop-1-enyl)phenyl thio carb, butacarb, carbanolate, cloethocarb, dicresyl, dioxacarb, cyanateme, ampropylfos, anilazine, azithiram, barium EMPC, , fenethacarb, , isoprocarb, polysulfide, Bayer32394, benodanil, benquinox, bentaluron, , , mexacarbate, promacyl, , benzamacril; benZamacril-isobutyl, benzamorf, binapacryl, , trimethacarb. XMC and xylylcarb; diamide insec bis(methylmercury) sulfate, bis(tributyltin) oxide, buthio 35 ticides such as , and bate, cadmium calcium copper Zinc chromate Sulfate, car ; dinitrophenol insecticides such as dinex, bamorph, CECA, chlobenthiazone, chloraniformethan, chlo dinoprop, dinosam and DNOC; fluorine insecticides such as rfenazole, chlorquinox, climbazole, copper bis(3- barium hexafluorosilicate, cryolite, Sodium fluoride, sodium phenylsalicylate), copper Zinc chromate, cufraneb, cupric hexafluorosilicate and sulfluramid; formamidine insecticides hydrazinium sulfate, cuprobam, cyclafuramid, cypendazole, 40 Such as , , and formparan cyprofuram, decafentin, dichlone, dichloZoline, diclobutra ate; fumigant insecticides such as acrylonitrile, carbon disul Zol, dimethirimol, dinocton, dinosulfon, dinoterbon, dipy fide, , chloroform, chloropicrin, para rithione, ditalimfos, dodicin, drazoxolon, EBP, ESBP. eta dichlorobenzene, 1,2-dichloropropane, ethyl formate, conazole, etem, ethirim, fenaminosulf, fenapanil, fenitropan, ethylene dibromide, ethylene dichloride, ethylene oxide, fluotrimazole, furcarbanil, furconazole, furconazole-cis, fur 45 hydrogen cyanide, iodomethane, methyl bromide, methyl mecyclox, furophanate, glyodine, griseofulvin, halacrinate, chloroform, methylene chloride, naphthalene, phosphine, Hercules 3944, hexylthiofos, ICIA0858, isopamphos, isov Sulfuryl fluoride and tetrachloroethane; inorganic insecti aledione, mebenil, mecarbinzid, metaZOXolon, methfuroxam, cides Such as borax, calcium polysulfide, copper oleate, mer methylmercury dicyandiamide, metSulfovax, milineb, muco curous chloride, potassium thiocyanate and sodium thiocy chloric anhydride, myclozolin, N-3,5-dichlorophenyl-suc 50 anate; chitin synthesis inhibitors such as bistrifluoron, cinimide, N-3-nitrophenyl-itaconimide, natamycin, N-eth , chlorfluaZuron, , , ylmercurio-4-toluenesulfonanilide, nickel bis flucycloXuron, , hexaflumuron, , nov (dimethyldithiocarbamate), OCH, phenylmercury aluron, noviflumuron, penfluoron, teflubenzuron and triflu dimethyldithiocarbamate, phenylmercury nitrate, phos muron; juvenile hormone mimics Such as epolfenonane, diphen, prothiocarb; prothiocarb hydrochloride, pyracar 55 , , kinoprene, , pyriproxy bolid, pyridinitril, pyroxychlor, pyroxyfur, quinacetol; fen and triprene; juvenile hormones Such as juvenile hormone quinacetol Sulfate, quinaZamid, quinconazole, rabenzazole, I, juvenile hormone II and juvenile hormone III; moulting salicylanilide, SSF-109, Sultropen, tecoram, thiadifluor, thi hormone agonists such as chromafenozide, halofenozide, cyofen, thiochlorfenphim, thiophanate, thioquinox, methoxyfenozide and ; moulting hormones Such tioxymid, triamiphos, triarimol, triaZbutil, trichlamide, urba 60 as C.-ecdysone and ecdysterone; moulting inhibitors such as cid, XRD-563, and Zarilamid, IK-1 140, and any combina diofenolan; precocenes such as precocene I, precocene II and tions thereof. precocene III; unclassified insect growth regulators such as Additionally, the compounds of the present invention can dicyclanil; analogue insecticides such as bensul be combined with other pesticides, including insecticides, tap, cartap, thiocyclam and thiosultap; nicotinoid insecticides nematicides, miticides, arthropodicides, bactericides or com 65 Such as flonicamid; nitroguanidine insecticides Such as binations thereof that are compatible with the compounds of , , and ; the present invention in the medium selected for application, nitromethylene insecticides Such as and nithiaz US 8,461,164 B2 29 30 ine; pyridylmethyl-amine insecticides such as , ; pyrazole insecticides such as acetoprole, imidacloprid, nitenpyram and ; organochlorine cyenopyrafen, ethiprole, , pyrafluprole, , insecticides such as bromo-DDT, camphechlor, DDT, pp'- , tolfenpyrad and vaniliprole; ester DDT, ethyl-DDD, HCH, gamma-HCH, , methoxy insecticides such as , allethrin, , bar chlor, pentachlorophenol and TDE; cyclodiene insecticides thrin, , bioethanomethrin, cyclethrin, cyclopro Such as , bromocyclen, chlorbicyclen, , chlo thrin, , beta-cyfluthrin, , gamma-cyha rdecone, , dilor, , , HEOD, hep lothrin, lambda-cyhalothrin, , alpha tachlor, HHDN, isobenzan, isodrin, kelevan and : orga cypermethrin, beta-cypermethrin, theta-cypermethrin, Zeta nophosphate insecticides such as bromfenVinfos, cypermethrin, , , dimefluthrin, , crotoxyphos, , , dim 10 dimethrin, , fenfluthrin, fempirithrin, fenpropath ethylvinphos, fospirate, heptenophos, methocrotophos, rin, , , flucythrinate, fluvalinate, tau , , , naftalofos, phosphami fluvalinate, furethrin, , , , don, propaphos, TEPP and ; organothio biopermethrin, transpermethrin, , , phosphate insecticides Such as dioxabenzofos, foSmethilan profluthrin, pyresmethrin, , bioresmethrin, cis and ; aliphatic organothiophosphate insecticides 15 methrin, , terallethrin, tetramethrin, Such as acethion, amiton, cadusafos, , chlo and ; pyrethroidether insecticides such as etofen rmephos, , demephion-O, demephion-S, deme prox, flufenprox, halfenprox, protrifenbute and ; ton, -O, demeton-S, demeton-methyl, demeton-O- pyrimidinamine insecticides such as flufenerim and pyrimid methyl, demeton-S-methyl, demeton-S-methylsulphon, ifen; pyrrole insecticides such as , tetramic acid , , , IPSP, isothioate, , insecticides such as Spirotetramat, tetronic acid insecticides methacrifos, oxydemeton-methyl, oxydeprofos, OXydisulfo Such as spiromesi?en; thiourea insecticides such as diafenthi ton, , , and thiometon; aliphatic uron; urea insecticides such as flucofuron and Sulcofuron; and amide organothiophosphate insecticides Such as amidithion, unclassified insecticides such as closantel, copper naphthen cyanthoate, , ethoate-methyl, , mecar ate, crotamiton, EXD, fenaZaflor, fenoxacrim, hydramethyl bam, , , Sophamide and vamidothion; 25 non, isoprothiolane, malonoben, , nifluridide, Oxime organothiophosphate insecticides such as chlor plifenate, pyridaben, pyridalyl, pyrifluquinazon, rafoxanide, , phoxim and phoxim-methyl; heterocyclic organ Sulfoxaflor, triarathene, triazamate, and any combinations othiophosphate insecticides such as , couma thereof. phos, coumithoate, , , menazon, Additionally, the compounds of the present invention may morphothion, , pyraclofos, pyridaphenthion and 30 be combined with herbicides that are compatible with the quinothion; benzothiopyran organothiophosphate insecti compounds of the present invention in the medium selected cides such as dithicrofos and thicrofos; benzotriazine organ for application, and not antagonistic to the activity of the othiophosphate insecticides Such as azinphos-ethyl and azin present compounds to form pesticidal mixtures and Synergis phos-methyl; isoindole organothiophosphate insecticides tic mixtures thereof. The pesticidal compounds of the present Such as dialifos and , isoxazole organothiophosphate 35 disclosure may be applied in conjunction with one or more insecticides such as and Zolaprofos; pyrazolopy herbicides to control a wide variety of undesirable plants, rimidine organothiophosphate insecticides such as chlorpra diseases, and pests. When used in conjunction with herbi Zophos and pyrazophos; pyridine organothiophosphate insec cides, the presently claimed compounds may be formulated ticides such as and chlorpyrifos-methyl; with the herbicide(s), tank mixed with the herbicide(s) or pyrimidine organothiophosphate insecticides Such as 40 applied sequentially with the herbicide(s). Typical herbicides butathiofos, , etrimfos, lirimfos, pirimiphos-ethyl, include, but are not limited to: amide herbicides such as pirimiphos-methyl, primidophos, pyrimitate and tebupirim allidochlor, beflubutamid, benzadox, benzipram, bro fos, quinoxaline organothiophosphate insecticides such as mobutide, cafenstrole, CDEA, cyprazole, dimethenamid, quinallphos and -methyl; thiadiazole organothio dimethenamid-P, diphenamid, epronaz, etnipromid, fentraza phosphate insecticides such as athidathion, lythidathion, 45 mide, flupoxam, fomesafen, halosafen, isocarbamid, isoxa and prothidathion; triazole organothiophos ben, napropamide, naptalam, pethoxamid, propyZamide, phate insecticides Such as isaZofos and triaZophos; phenyl quinonamid and tebutam; anilide herbicides such as chlo organothiophosphate insecticides such as azothoate, bro ranocryl, cisanilide, clomeprop, cypromid, diflufenican, eto mophos, bromophos-ethyl, , chlorthiophos, benzanid, fenasulam, flufenacet, flufenican, mefenacet, , cythioate, dicapthon, dichlofenthion, etaphos, 50 mefluidide, metamifop, monalide, naproanilide, pen famphur, fenchlorphos, fensulfothion, , tanochlor, picolinafen and propanil; arylalanine herbicides fenthion-ethyl, heterophos, jodfemphos, mesulfenfos, par Such as benzoylprop, flampropand flamprop-M; chloroaceta athion, -methyl, phenkapton, phosnichlor, profeno nilide herbicides such as acetochlor, alachlor, butachlor, bute fos, prothiofos, Sulprofos, temephos, trichlorimetaphos-3 and nachlor, delachlor, diethatyl, dimethachlor, metaZachlor, trifenofos; phosphonate insecticides such as butonate and 55 metolachlor, S-metolachlor, pretilachlor, propachlor, prop trichlorfon, phosphonothioate insecticides Such as mecar isochlor, prynachlor, terbuchlor, thenylchlor and xylachlor; phon; phenyl ethylphosphonothioate insecticides such as sulfonanilide herbicides such as benzofluor, perfluidone, and trichloronat, phenyl phenylphosphonothioate pyrimisulfan and profluaZol; Sulfonamide herbicides such as insecticides Such as cyanofenphos, EPN and ; phos asulam, carbasulam, fenasulam and oryzalin; thioamide her phoramidate insecticides such as crufomate, , fos 60 bicides such as chlorthiamid; antibiotic herbicides such as thietan, mephosfolan, and pirimetaphos; phos bilanafos; benzoic acid herbicides such as chloramben, phoramidothioate insecticides such as , dicamba, 2.3.6-TBA and tricamba; pyrimidinyloxybenzoic isocarbophos, isofenphos, and propetam acid herbicides Such as bispyribac and pyriminobac; pyrim phos; phosphorodiamide insecticides Such as , mazi idinylthiobenzoic acid herbicides such as pyrithiobac: dox, and , oxadiazine insecticides such as 65 phthalic acid herbicides such as chlorthal; picolinic acid her ; oxadiazolone insecticides such as metoxadiaz bicides such as aminopyralid, clopyralid and picloram; one, phthalimide insecticides such as dialifos, phosmet and quinolinecarboxylic acid herbicides Such as quinclorac and US 8,461,164 B2 31 32 quinmerac; arsenical herbicides such as cacodylic acid, idinediamine herbicides such as iprymidam and tioclorim; CMA, DSMA, hexaflurate, MAA, MAMA, MSMA, potas quaternary ammonium herbicides such as cyperquat, sium arsenite and Sodium arsenite; benzoylcyclohexanedione diethamcquat, difenZoquat, diguat, morfamquat and paraquat: herbicides Such as mesotrione, Sulcotrione, tefuryltrione and thiocarbamate herbicides such as butylate, cycloate, di-allate, tembotrione; benzofuranylalkylsulfonate herbicides such as EPTC, esprocarb, ethiolate, isopolinate, methiobencarb, benfuresate and ethofumesate; benzothiazole herbicides such molinate, orbencarb, pebulate, prosulfocarb, pyributicarb, as benzazolin; carbamate herbicides such as asulam, carbox sulfallate, thiobencarb, tiocarbazil, tri-allate and vernolate: azole chlorprocarb, dichlormate, fenasulam, karbutilate and thiocarbonate herbicides such as dimexano, EXD and proxan; terbucarb; carbanilate herbicides such as barban, BCPC, car thiourea herbicides such as methiuron; triazine herbicides basulam, carbetamide, CEPC, chlorbufam, chlorpropham, 10 Such as dipropetryn, indaziflam, triaziflam and trihydroxytri CPPC, desmedipham, phenisopham, phenmedipham, phen azine; chlorotriazine herbicides such as atrazine, chlorazine, medipham-ethyl, propham and Swep; cyclohexene Oxime cyanazine, cyprazine, eglinazine, ipazine, mesoprazine, pro herbicides Such as alloxydim, butroxydim, clethodim, clo cyazine, proglinazine, propazine, Sebuthylazine, simazine, proxydim, cycloxydim, profoxydim, Sethoxydim, tepraloxy terbuthylazine and trietazine; methoxytriazine herbicides dim and tralkoxydim; cyclopropylisoxazole herbicides Such 15 Such as atraton, methometon, prometon, secbumeton, sim as isoxachlortole and isoxaflutole; dicarboximide herbicides eton and terbumeton; methylthiotriazine herbicides such as Such as cinidon-ethyl, flumeZin, flumiclorac, flumioxazin and ametryn, aZiprotryne, cyanatryn, desmetryn, dimethametryn, flumipropyn; dinitroaniline herbicides such as benfluralin, methoprotryne, prometryn, simetryn and terbutryn; triazi butralin, dinitramine, ethalfluralin, fluchloralin, isopropalin, none herbicides such as ametridione, amibuzin, hexaZinone, methalpropalin, nitralin, oryzalin, pendimethalin, prodi isomethiozin, metamitron and metribuzin, triazole herbicides amine, profluralin and trifluralin; dinitrophenol herbicides Such as amitrole, cafenstrole, epronaz and flupoxam, triaz Such as dinofenate, dinoprop, dinosam, dinoseb, dinoterb, olone herbicides Such as amicarbazone, bencarbazone, DNOC, etinofen and medinoterb; diphenyl ether herbicides carfentraZone, flucarbazone, ipfencarbazone, propoxycarba such as ethoxyfen; nitrophenyl ether herbicides such as acif Zone, SulfentraZone and thiencarbazone-methyl, triazolopy luorfen, aclonifen, bifenox, chlomethoxyfen, chlornitrofen, 25 rimidine herbicides such as cloransulam, dicloSulam, florasu etnipromid, fluorodifen, fluoroglycofen, fluoronitrofen, lam, flumetSulam, metoSulam, penoXSulam and pyroxSulam; fomesafen, furyloxyfen, halosafen, lactofen, nitrofen, nitrof uracil herbicides such as benzfendizone, bromacil, luorfen and oxyfluorfen: dithiocarbamate herbicides such as butafenacil, flupropacil, isocil, lenacil, saflufenacil and terba dazomet and metam; halogenated aliphatic herbicides such as cil; urea herbicides such as benzthiazuron, cumyluron, cyclu alorac, chloropon, dalapon, flupropanate, hexachloroacetone, 30 ron, dichloralurea, diflufenZopyr, isonoruron, isouron, iodomethane, methyl bromide, monochloroacetic acid, SMA methabenzthiaZuron, monisouron and noruron; phenylurea and TCA; imidazolinone herbicides such as imazametha herbicides such as anisuron, buturon, chlorbromuron, chlo benz, imaZamox, imaZapic, imazapyr, imaZaquin and returon, chlorotoluron, chloroXuron, daimuron, difenoXuron, imazethapyr; inorganic herbicides such as ammonium Sulfa dimefuron, diuron, fenuron, fluometuron, fluothiuron, iso mate, borax, calcium chlorate, copper Sulfate, ferrous Sulfate, 35 proturon, linuron, methiuron, methyldymron, metobenzuron, potassium azide, potassium cyanate, Sodium azide, sodium metobromuron, metoxuron, monolinuron, monuron, nebu chlorate and sulfuric acid; nitrile herbicides such as bromo ron, parafluoron, phenobenzuron, Siduron, tetrafluoron and bonil, bromoxynil, chloroxynil, dichlobenil, iodobonil, ioxy thidiaZuron; pyrimidinylsulfonylurea herbicides Such as ami nil and pyraclonil; organophosphorus herbicides such as ami dosulfuron, azimsulfuron, benSulfuron, chlorimuron, cyclo profoS-methyl, anilofos, , bilanafos, butamifos, 2,4- 40 Sulfamuron, ethoxysulfuron, flazasulfuron, flucetosulfuron, DEP. DMPA, EBEP, fosamine, glufosinate, glufosinate-P. flupyrsulfuron, foramsulfuron, halosulfuron, imaZosulfuron, glyphosate and piperophos; phenoxy herbicides Such as bro mesosulfuron, metazosulfuron, nicosulfuron, orthosulfamu mofenoxim, clomeprop, 2,4-DEB, 2,4-DEP, difenopenten, ron, oxasulfuron, primisulfuron, propyrisulfuron, pyrazosul disul, erbon, etnipromid, fenteracol and trifopsime; oxadia furon, rimsulfuron, sulfometuron, sulfosulfuron and triflox Zoline herbicides such as methazole, oxadiargyl, oxadiaZon; 45 ysulfuron; triazinylsulfonylurea herbicides such as oxazole herbicides such as fenoxasulfone; phenoxyacetic chlorSulfuron, cinosulfuron, ethametSulfuron, iodosulfuron, herbicides such as 4-CPA, 2,4-D, 3,4-DA, MCPA, MCPA metsulfuron, prosulfuron, thifensulfuron, triasulfuron, tribe thioethyl and 2,4,5-T: phenoxybutyric herbicides such as nuron, triflusulfuron and tritosulfuron; thiadiazolylurea her 4-CPB, 2,4-DB, 3,4-DB, MCPB and 2,4,5-TB; phenoxypro bicides such as buthiuron, ethidimuron, tebuthiuron, thiaz pionic herbicides such as cloprop, 4-CPP, dichlorprop, 50 afluoron and thidiaZuron; and unclassified herbicides such as dichlorprop-P, 3,4-DP, fenoprop, mecopropand mecoprop-P: acrolein, allyl alcohol, aminocyclopyrachlor, azafenidin, aryloxyphenoxypropionic herbicides such as chlorazifop, bentaZone, benzobicyclon, bicyclopyrone, buthidazole, cal clodinafop, clofop, cyhalofop, diclofop, fenoxaprop, fenox cium cyanamide, cambendichlor, chlorfenac, chlorfenprop, aprop-P, fenthiaprop, fluazifop, fluazifop-P haloxyfop, chlorflurazole, chlorflurenol, cinmethylin, clomaZone, haloxyfop-P, isoxapyrifop, metamifop, propaquizafop, 55 CPMF, cresol, cyanamide, ortho-dichlorobenzene, dimepip quizalofop, quizalofop-P and trifop; phenylenediamine her erate, endothal, fluoromidine, fluridone, fluorochloridone, bicides such as dinitramine and prodiamine; pyrazole herbi flurtamone, fluthiacet, indanofan, methyl isothiocyanate, cides such as pyroxasulfone; benzoylpyrazole herbicides OCH, oxaziclomefone, pentachlorophenol, pentoxazone, Such as benzofenap, pyrasulfotole, pyrazolynate, pyrazoxy phenylmercury acetate, prosulfalin, pyribenzoxim, pyriftalid, fen, and toprameZone; phenylpyrazole herbicides such as 60 quinoclamine, rhodethanil, Sulglycapin, thidiazimin, tridiph fluaZolate, nipyraclofen, pioxaden and pyraflufen, pyridazine ane, trimeturon, tripropindan and tritac. herbicides such as credazine, pyridafol and pyridate; The compounds of the present invention may have broad pyridaZinone herbicides Such as brompyrazon, chloridazon, ranges of efficacy as pesticides. The exact amount of the dimidazon, flufenpyr, metflurazon, norflurazon, oxapyrazon active material to be applied is dependent not only on the and pydanon; pyridine herbicides Such as aminopyralid, clio 65 specific active material being applied, but also on the particu dinate, clopyralid, dithiopyr, fluoroxypyr, haloxydine, piclo lar action desired, the pathogen or pest to be controlled, and ram, picolinafen, pyriclor, thiazopyr and triclopyr; pyrim the stage of growth thereof, as well as the part of the plant, US 8,461,164 B2 33 34 animal or other medium to be contacted with the compound. sentative examples include those expressing proteins toxic to Thus, all the compounds, and formulations containing the invertebrate pests, such as Bacillus thuringiensis or other same, may not be equally effective at similar concentrations insecticidal toxins, those expressing herbicide resistance, or against the same pathogen and pest species. such as “Roundup Ready’ seed, or those with "stacked' for The compounds are effective in use with plants in a phy eign genes expressing insecticidal toxins, herbicide resis tologically acceptable amount. The term "phytologically tance, nutrition-enhancement or any other beneficial traits. acceptable amount” refers to an amount of a compound that Furthermore, such seed treatments with the invention dis kills or inhibits the pest or plant disease for which control is closed in this document can further enhance the ability of a desired, but is not significantly toxic to the plant. This amount plant to better withstand stressful growing conditions. This will generally be from about 0.1 to about 1000 parts per 10 million (ppm), with 1 to 500 ppm being preferred. results in a healthier, more vigorous plant, which can lead to The exact concentration of compound required varies with higher yields at harvest time. the pest or disease to be controlled, the type of formulation It should be readily apparent that the invention may be used employed, the method of application, the particular plant or with plants genetically transformed to express specialized animal species, climate conditions, and the like. For fungi 15 traits, such as Bacillus thuringiensis or other insecticidal cides, dilution and rate of application will depend upon the toxins, or those expressing herbicide resistance, or those with type of equipment employed, the method and frequency of 'stacked' foreign genes expressing insecticidal toxins, her application desired and diseases to be controlled, but the bicide resistance, nutrition-enhancement or any other benefi effective amount is usually from about 0.01 kilogram (kg) to cial traits. An example of Such a use is spraying Such plants about 20 kg of active ingredient (a.i.) per hectare (ha). As a with the invention disclosed in this document. foliar fungicide, a compound of the present invention is usu The invention disclosed in this document may be suitable ally applied to growing plants at a rate of about 0.1 to about 5 for controlling endoparasites and ectoparasites in the Veteri and preferably from about 0.125 to about 0.5 kg per hectare. nary medicine sector or in the field of animal keeping. Com As a seed-applied fungicide, the amount of toxicant coated pounds according to the invention are applied here in a known on the seed is usually at a dosage rate of about 0.1 to about 250 25 manner, Such as by oral administration in the form of, for grams (g) and preferably from about 1 to about 60 g per 100 example, tablets, capsules, drinks, granules, by dermal appli kg of seed. As a soil fungicide, the chemical can be incorpo cation in the form of for example, dipping, spraying, pouring rated in the soil or applied to the surface of the soil or a rice on, spotting on, and dusting, and by parenteral administration nursery box usually at a rate of about 0.1 to about 5 kg per in the form of for example, an injection. hectare. 30 The actual amount of or miticide to be applied The invention disclosed in this document may also be to loci of pests is generally not critical and can readily be employed advantageously in livestock keeping, for example, determined by those skilled in the art. In general, concentra cattle, sheep, pigs, chickens, and geese. Suitable formulations tions from about 10 g of pesticide per hectare to about 5000 g may be administered orally to the animals with the drinking of pesticide per hectare are expected to provide good control. 35 water or feed. The dosages and formulations that are suitable The locus to which a pesticide is applied can be any locus depend on the species. inhabited by a pest, for example, vegetable crops, fruit and nut It will be understood by those in the art that the efficacy of trees, grape vines, ornamental plants, domesticated animals, the compound on the foregoing fungi and insects establishes the interior or exterior surfaces of buildings, and the soil the general utility of the compounds as fungicides and insec around buildings. Controlling pests generally means that pest 40 ticides. populations, activity, or both, are reduced in a locus. This can come about when: pest populations are repulsed from a locus; Chromatography Definitions when pests are incapacitated, partially or completely, tempo rarily or permanently, in or around a locus; or pests are exter Prep RP-HPLC (preparative reverse-phase high-performance minated, in whole or in part, in or around a locus. Of course a 45 combination of these results can occur. Generally, pest popu liquid chromatography): lations, activity, or both are desirably reduced more than fifty 20 mmx250 mm S5 um 120 AYMC-AQ, or 50 mmx250 mm percent, preferably more than 90 percent, even more prefer S10 um 120 AYMC-AQ column, using 0.1% v/v HPO. ably 99 percent. mixtures with Mecn (acetonitrile) as eluent; Generally, with baits, the baits are placed in the ground 50 HPLC (high performance liquid chromatography): acetoni where, for example, termites can come into contact with the trile/water solvent system over C8-C18 on silica gel support) bait. Baits can also be applied to a Surface of a building, (horizontal, Vertical, or slant, Surface) where, for example, TLC (thin layer chromatography): SiO/glass plates, eluted ants, termites, cockroaches, and flies, can come into contact with hexane, EtO (diethyl ether), CHCl (dichlo with the bait. 55 romethane), EtOAc (ethylacetate), MeOH (), or any Because of the unique ability of the eggs of Some pests to useful mixture of these; resist pesticides repeated applications may be desirable to GC (gas chromatography): control newly emerged larvae. GC-MS (gas chromatography-mass spectrometry) Systemic movement of pesticides in plants may be utilized LC-MS (liquid chromatography-mass spectrometry) to control pests on one portion of the plant by applying the 60 pesticides to a different portion of the plant, or to a location where the root system of a plant can uptake pesticides. For example, control of foliar-feeding insects can be controlled by drip irrigation or furrow application, or by treating the seed before planting. Seed treatment can be applied to all types of 65 seeds, including those from which plants genetically trans >J-C formed to express specialized traits will germinate. Repre US 8,461,164 B2 35 36 -continued -continued O

HN C NN1 NN else 10 N N

Example 1 > --O c 15 2-(4-Benzyloxyphenyl)-ethyl-pteridin-4-yl-amine To a mixture of pteridin-4-ol (282 mg, 1.9 mmol) and 2-(4-benzyloxyphenyl)-ethylamine (476 mg, 2.1 mmol) and hexamethyldisilazane (5 mL) in a 25 mL round bottom flask, equipped with reflux condenser, drying tube and magnetic stir bar, was added ammonium sulfate (100 mg. 0.76 mmol). The mixture was heated to 114°C. overnight and then the solvent was removed in vacuo. The residue was suspended in H2O HN and filtered. The filter cake was dissolved in CHCl, dried 25 with NaSO filtered, and concentrated in vacuo to provide 2-(4-benzyloxyphenyl)-ethyl-pteridin-4-yl-amine as a white solid (501 mg): "H NMR (300 MHz) 89.01 (d. J=1.9 HZ, 1H), 8.81 (s, 1H), 8.61 (d. J=1.9 HZ, 1H), 7.49-7.29 (m, 30 6H), 7.25-7.15 (m,3H), 6.96 (dd, J=6.8, 4.8 Hz, 2H), 5.06 (s, Preparation 1. 2-(4-Benzyloxyphenyl)-ethylamine 2H), 3.93 (dd, J=13.2, 6.9 Hz, 2H), 3.00 (t, J–7.0 Hz, 2H): ESIMS m/z. 358.1 (IM+H"). To a suspension of potassium carbonate (KCO, 1.4 grams (g), 10.11 millimole (mmol)) in acetone (40 milliliters (mL)) was added bromomethylbenzene (1.73 g, 10.11 mmol) 35 N a and tert-butyl 2-(4-hydroxyphenyl)ethylcarbamate (2 g, 8.4 C n mmol). The reaction mixture was heated at reflux for 15 hours 2n 2 -- (h) and then concentrated in vacuo. The residue was parti N 4n 1 tioned between diethyl ether (EtO) and water (HO), and the 40 organic fraction was washed with brine, dried over sodium OH Sulfate (Na2SO4). Suction filtered, and concentrated in vacuo. The residue was purified by silica gel (SiO2) flash chroma He tography with 25% EtO in hexane to afford 2-(4-benzylox HN yphenyl)-ethyl-carbamic acid tert-butyl ester as a white solid 45 OH (2.4 g). This was dissolved in CHCl (50 mL) and trifluoro acetic acid (5 mL) was added. After stirring 16 h, the solvent was removed in vacuo, and the residue was redissolved in HN CHCl, washed with 1 M sodium hydroxide (NaOH), dried N (NaSO) and filtered. The solvent was removed in vacuo to 50 N1 SN yield 2-(4-benzyloxyphenyl)-ethylamine (1.5 g). This was used without purification in the next step. N elseN

OH 55 Example 2 NN1 N N else 4-2-(Pteridin-4-ylamino)-ethyl-phenol N N 60 To a solution of N'-(3-cyanopyrazin-2-yl)-N,N-dimethyl O formamidine (prepared as in Albert and Ohta, J. Chem. Soc. C 1971, 3727-3730, which is expressly incorporated by refer -- ence herein; 2.0 g, 11.4 mmol) in ethyl alcohol (EtOH: 50 HN mL) was added 4-(2-aminoethyl)-phenol (4.7 g., 34 mmol) and acetic acid (3.9 mL, 4.1 g, 68 mmol). The solution was heated to reflux for 19 h, concentrated in vacuo, and the residue was slurried with H2O and suction filtered. The filter US 8,461,164 B2 37 38 cake was washed with HO and dried in a vacuum oven (80° C., 0.5 torr) to yield 4-2-(pteridin-4-ylamino)-ethyl-phenol OH (2.7g) as a white solid: mp>210°C.; H NMR (DMSO-d) & 9.20 (s, 1H), 9.08 (s, 1H), 8.94 (s, 1H), 8.95 (t, J=6.0 Hz, 1H), 8.82 (s, 1H), 8.64 (s, 1H), 7.06 (d. J=8.5 Hz, 2H), 6.69 (d. HN J=8.2 Hz, 2H), 3.75 (t, J=6.2 Hz, 2H), 2.85 (t, J=7.6 Hz, 2H): -- ESIMS m/z 268 (M). CN NN OH 10 N elseN F F HN -- N F Ho N 15 2 C N1 NN C N else O N N rs N F HN 21 F F N F F C NN N F Her 25 N2 N2 2 C N Example 3 30 Alt. Pteridin-4-yl-2--(4-trifluoromethylpyridin-2- O yloxy)-phenyl-ethyl-amine N F HN -u C 2N 35 To a solution of 4-2-(pteridin-4-ylamino)ethylphenol F (2.5g, 9.3 mmol) and DMSO (20 mL) in a 100 mL round N F bottom flask, equipped with reflux condenser, drying tube and C N1 NN magnetic stir bar, was added 2-fluoro-4-(trifluoromethyl)py 2 2 ridine (prepared as in U.S. Pat. No. 4,775,762, which is N N 40 expressly incorporated by reference herein; 1.7 g. 10 mmol) and cesium carbonate (CSCO: 3.7 g, 11.5 mmol). This mixture was heated to 57°C. for 16 h, then cooled to ambient Example 3 temperature and poured into ice H2O (150 mL), precipitating 45 an off-white solid. This was collected by suction filtration and the filter cake was washed with HO and then pentane. The Pteridin-4-yl-2-4-(5-trifluoromethylpyridin-2- cake was then dissolved in CHCl, dried with NaSO, and yloxy)-phenyl-ethyl-amine the solution was filtered. The solution was concentrated in vacuo to afford pteridin-4-yl-2-[4-(4-trifluoromethylpyri To a solution of 4-2-(pteridin-4-ylamino)ethylphenol 50 din-2-yloxy)-phenyl-ethyl-amine (3.0 g) as an off-white (270 mg, 1.0 mmol) and dry DMSO (5 mL) was added solid: mp 147-149° C.; H NMR (300 MHz, CDC1) & 9.04 (d. 2-chloro-5-trifluoromethylpyridine (155 mg. 0.85 mmol) and J=1.9 HZ, 1H), 8.85 (s, 1H), 8.64 (d. J=1.9 HZ, 1H), 8.35 (d. KCO (280 mg, 2.0 mmol). This mixture was heated to 80° J=5.2 Hz, 1H), 7.40-729 (m, 3H), 7.22 (dd, J=5.2, 0.8 Hz, C. for 3 h, cooled to ambient temperature, poured into HO 1H), 7.19-7.05 (m,3H), 4.01 (dd, J=13.3, 7.0 Hz, 2H), 3.10 (t, (20 mL) and extracted with CHCl (20 mL). The CH-Cl 55 J=7.1 Hz, 2H), ESIMS m/z 413 (M+H"). solution was washed with HO (2x10 mL), dried with NaSO, and the solution was filtered. The solution was con centrated in vacuo, redissolved in a minimum Volume of OH CHCl and treated with hexane to precipitate a solid. The solid was collected by filtration and dried under vacuum to 60 afford pteridin-4-yl-2-4-(5-trifluoromethylpyridin-2- HN yloxy)-phenyl-ethyl-amine (310 mg) as an off-white solid: -- mp 147-150° C.; H NMR (300 MHz, CDC1,) 89.04 (d.J=1.9 N HZ, 1H), 8.85 (s, 1H), 8.64 (d. J=1.9 HZ, 1H), 8.35 (d. J–5.2 HZ, 1H), 7.40-729 (m, 3H), 7.22 (dd, J=5.2, 0.8 Hz, 1H), 65 rsrs 7.19-7.05 (m, 3H), 4.01 (dd, J=13.3, 7.0 Hz, 2H), 3.10 (t, N.else N. J=7.1 Hz, 2H), ESIMS m/z 413 (IM+H"). US 8,461,164 B2 39 40 -continued Example 5 F F {2-4-(6-Methoxypyridin-2-yloxy)-phenyl-ethyl F pteridin-4-yl-amine N {2-4-(6-Fluoropyridin-2-yloxy)-phenyl-ethyl-pteridin 2 4-ylamine (200 mg. 0.55 mmol) was dissolved in 4 mL dry F N DMSO and treated with (300 mg, 5.5 F 10 mmol. 10 eq) and stirred for 20 h at 25°C. The mixture was O poured into HO (15 mL) and extracted with CHCl (2x25 F ml). The pooled CHCl extracts were washed with HO and N brine, dried (NaSO), filtered, and evaporated. The gummy HN -u C 2 s residue was dissolved in a minimum quantity of CH2Cl and 15 treated with hexane to precipitate the product as a solid that N was collected by suction filtration, washed with hexane and C S1 NN dried in vacuo to afford 2-4-(6-methoxypyridin-2-yloxy)- else phenyl-ethyl-pteridin-4-yl-amine (139 mg) as a tan solid: N N mp 152-153° C.; H NMR (DMSO-d) & 9.09 (s, 1H), 9.00 (t, J=5.9 Hz, 1H), 8.82 (s, 1H), 8.63 (s, 1H), 7.70 (t, J=8.0 Hz, 1H), 7.30 (d. J=8.3 Hz, 2H), 7.05 (d. J=8.4 Hz, 2H), 6.51 (d. Example 4 J=8.0 Hz, 2H), 6.36 (d. J–7.7 Hz, 2H), 3.83 (m, 2H), 3.65 (s, 3H), 3.00 (m, 2H); ESIMS m/z. 375 (IM+H"). Also prepared by Example 5. Pteridin-4-yl-2-4-(pyrazin-2-yloxy)-phenyl 25 Pteridin-4-yl-(2-4-6-(2.2.2-trifluoroethoxy)-pyridin-2- ethyl-amine yloxy)-phenyl-ethyl)-amine from sodium 2.2.2-trifluoroet hoxide, prepared by treatment of 2.2.2-trifluoroethanol with sodium hydride. To a solution of 4-2-(pteridin-4-ylamino)ethylphenol {2-4-(6-Ethoxypyridin-2-yloxy)-phenyl-ethyl-pteri (0.267 g, 1.0 mmol) and 2-chloropyrazine (0.114 g, 1.0 30 mmol) in anhydrous DMF (7 mL) was added 60% sodium din-4-yl-amine, from Sodium ethoxide, prepared by treatment hydride (NaH) in mineral oil (0.060 g, 1.5 mmol) portion of ethanol with sodium hydride. wise. The mixture was stirred at 55° C. overnight and then at 70° C. for a total reaction time of 32 h. The solvent was C removed in vacuo and the residue was suspended in H.O.The 35 solid was collected by suction filtration, washed with HO and EtO, dried in a vacuum oven at 55° C. overnight to afford pteridin-4-yl-2-[4-(pyrazin-2-yloxy)-phenyl-ethyl-amine (0.291 g, 84%) as a light brown solid: "H NMR (300 MHz, CDC1) & 9.02 (d. J=1.9 Hz, 1H), 8.82 (s, 1H), 8.63 (d. J=1.9 40 HZ, 1H), 8.43 (d. J=1.5 Hz, 1H), 8.26 (d. J=2.4 Hz, 1H), 8.10 (dd, J=2.4, 1.5 Hz, 1H), 7.33 (d. J=8.4 Hz, 2H), 7.13 (d. J–8.4 Preparation 2. Hz, 2H), 3.99 (dd, J=13.6, 6.9 Hz, 2H), 3.08 (t, J=6.9 Hz, 2H): 6-Chloro-4,5-diamino-2-methylpyrimidine ESIMS m/z 346.24 (M+H"). 45 A 200 mL stainless steel Parr vessel was loaded with 5-amino-4,6-dichloro-2-methylpyrimidine (7.2g, 40 mmol) and 2 Mammonia in isopropanol (100 mL), and then was sealed and heated at 150° C. for 16 h. HPLC analysis indi 50 cated complete conversion. The mixture was concentrated in HN UOCN 21 vacuo, and the residue was suspended in a mixture of H2O (10 mL) and isopropanol (35 mL). This was stirred at 50° C. for N NN F 1 hand then was cooled to room temperature. The precipitate was collected by Suction filtration, washed sparingly with 55 isopropanol, then air dried on the filter to afford 6-chloro-4, CC 5-diamino-2-methylpyrimidine (5.8 g.91%) as a brown pow der, which was used without further purification in the next step. HN N 2 UOC 60 C N NN 19

CC 65 US 8,461,164 B2 41 42 -continued 2. 2-Methylsulfonyl-4-(2.2.2)-trifluoroethoxypyrimi dine To a solution of 1.0 g. (4.46 mmol) of the product from 5 Preparation 3, Step 1, in CHCl (5 mL), was added meta N chloroperoxybenzoic acid (MCPBA: 1.6 g. 6.7 mmol) in N1so SN O CHCl (6 mL). After 3 h, the reaction mixture was diluted with CHCl (20 mL) and washed with saturated aqueous N N sodium bicarbonate (NaHCO) solution. The organic layer was dried (NaSO), filtered and concentrated in vacuo to 10 yield 2-methylsulfonyl-4-(2.2.2)-trifluoroethoxypyrimidine (1.3 g, 70% pure by LC). This was used without further Example 6 purification. 1-(4-Methoxyphenyl)ethyl-2-methylpteridin-4-yl 15 amine O F A mixture of 6-chloro-4,5-diamino-2-methylpyrimidine F (317 mg, 2.0 mmol) and 1,4-dioxane-2,3-diol (240 mg, 2.0 N -- N mmol) in EtOH (15 mL) was stirred at 25°C. for 1 h. TLC analysis (1:1 hexane/EtOAc on SiO) indicated complete 2 2 consumption of starting material. 1-(4-Methoxyphenyl)- C N C N ethylamine (332 mg, 2.2 mmol) and triethylamine (EtN, 0.3 mL, 2.2 mmol) were added, and the reaction was stirred overnight. The majority of solvent was removed in vacuo and 25 Preparation 4. the residue was partitioned between EtOAc and H2O. The 2-Chloro-4-(1,1-difluoroethyl)-pyridine organic layer was concentrated in vacuo to leave a brown residue that was purified by column chromatography over To a solution of 2-chloro-4-acetylpyridine (2.6 g. 17.2 SiO, eluting with 2:1 EtOAc/hexane, then 100% EtOAc to mmol) in CHCl (50 mL) was added diethylamino-sulfurtri afford 1-(4-methoxyphenyl)ethyl-2-methylpteridin-4-yl 30 fluoride (8 mL, 60 mmol) at 25°C. and the mixture was stirred for 16 h. The reaction was quenched by addition of saturated amine (126 mg) as a brown oil. aqueous NaHCOs dropwise at 0°C. After separation of the two phases, the organic phase was dried over NaSO, fil tered, and concentrated in vacuo. The residue was purified by S N column chromatography over SiO, with 10% EtOAc in hex 35 ane to yield 2-chloro-4-(1,1-difluoroethyl)pyridine (1.72 g) as a light brown oil: EIMS m/z. 177 (MI). 1. N’s 1. C Also prepared by this method: NC 2 He- O -- 2-Bromo-6-(1,1-difluoroethyl)-pyridine, from bromo-pyridin-2-yl)-ethanone. EIMS m/Z 222 (MI). 40 2-Chloro-4-difluoromethylpyridine, from 2-chloropyri C dine-4-carbaldehyde. EIMS m/z 163 (LM"). F O N/ N /N1's 45 Her / O Na2 H O F O N OSN. He O 55 Preparation 3. 1. 2-Methylthio-4-(2.2.2)-trifluoroethoxy F O N pyrimidine To a suspension of 60% NaH (524 mg, 130.1 mmol) in HN DMSO (30 mL) was added 2.2.2-trifluoroethanol (1.31 g, oHCI 130.1 mmol). The reaction mixture was stirred 0.5 hat 25°C. 60 and then 4-chloro-2-(methylthio)pyrimidine (2.0 g, 12.5 mmol) was added and stirred for 16 h. The reaction was diluted with HO and extracted with EtO. The EtO layer Preparation 5. 1.2-Fluoro-4-methoxy-1-((E)-2-nitro was washed with brine, concentrated in vacuo, and filtered vinyl)benzene through SiO, to yield 2.16 g of yellow oil which appeared to 65 be 60% pure by HPLC and was used without further purifi A solution of 2-fluoro-4-methoxybenzaldehyde (5.0 g, 33 cation in the following step. mmol) and ammonium acetate (1.0 g, 13 mmol) in US 8,461,164 B2 43 44 nitromethane (40 mL) was heated on a steam bath for 2.5 h. The reaction mixture was concentrated under reduced pres C sure, and the sticky residue was partitioned between CHCl and H2O. The organic layer was washed with half-saturated o21 N NN brine, dried (MgSO), filtered, and concentrated. The residue -- was triturated in hexane and the solid was filtered and washed 2 with hexane and dried to give 2-fluoro-4-methoxy-1-((E)-2- HN N nitrovinyl)benzene (5.57 g) as an orange solid: mp 80-82°C.; H NMR (CDC1): 88.02 (d. J=13.5 Hz, 1H), 7.66 (d. J=13.5 HZ, 1H), 7.43 (m. 1H), 6.68-6.80 (m, 2H), 3.87 (s.3H); EIMS 10 HN m/z, 197 (MI). This material was used in the next step N -- o2 NN OH without additional purification. e 2. 2-(2-Fluoro-4-methoxyphenyl)ethylamine 15 HN N hydrochloride Under a nitrogen atmosphere, 2-fluoro-4-methoxy-1-(E)- HN 2-nitrovinyl)benzene (26.5g, 134.5 mmol) was added in por HN tions to a suspension of LiAlH4 (16 g. 195 mmol) in THF (1 NN OH e L) at 0°C. The mixture then was heated at reflux, and after 3.5 h, the reaction mixture was cooled to 0°C. and quenched HN N2 carefully with HO (34.6 mL) and 10% aqueous NaOH (28 mL). After removal of green precipitates by Suction filtration, 25 the filtrate was dried over MgSO, filtered and evaporated HN under reduced pressure. The oily residue was dissolved in N EtOAc (150 mL) and then conc. HCl was added to adjust the N1 NN OH pH to approximately 1. EtO (1 L) was added with stirring and the solid was collected by suction filtration and washed with 30 2 2 a small amount of acetone, then dried under vacuum to give N N 12.3 g of 2-(2-fluoro-4-methoxyphenyl)ethylamine hydro chloride as a white solid, mp 162-165° C. The filtrate was concentrated under reduced pressure, and the residue was Preparation 7. 1. 4-1-(6-Amino-5-nitropyrimidin-4- dried azeotropically by Suspending intoluene and concentrat 35 ylamino)-ethyl-phenol ing in vacuo. The residue was dissolved in methanol, and the solution was diluted with EtOAc to precipitate additional 4-Amino-5-nitro-6-chloropyrimidine (5.0 g, 29 mmol), product. The second crop was collected by suction filtration 4-(1-aminoethyl)phenol (4.3 g, 32 mmol) and EtN (4.5 mL, and washed with ethyl acetate, affording another 7.3 g of 3.2g, 32 mmol) were combined in anhydrous DMF (30 mL). 40 After stirring 2 hat 25°C., the mixture was poured into dilute product. The total yield was 19.6 g (72%). "H NMR (CDC1): citric acid (150 mL; pH ca. 3) and the precipitated product & 8.29 (br, 3H), 7.24 (t, J=8.7 Hz, 1H), 6.73-6.84 (m, 2H), was collected by suction filtration and washed with H2O. The 3.74 (s, 3H), 2.83-2.99 (m, 4H); ESIMS m/z 169.9 (M- solid was recrystallized from a refluxing mixture of HO (100 HCl). mL) and EtOH (50 mL) to yield 6.6 g (84%). 45 2. 4-1-(5,6-Diaminopyrimidin-4-ylamino)-ethyl O ano 1. phenol

N N The product from Preparation 7, Step 1, was dissolved in 50 hot EtOH (200 mL), the solution cooled and sparged with 2 2 nitrogen for 15 minutes (min), treated with Raney nickel (10 C N C N g), and hydrogenated for 2 hina Parr shaker. The catalyst was removed by suction filtration and the solvent removed in vacuo to yield 3.8 g. (98%). 55 Preparation 6. Example 7 2-Chloro-4-methoximinoacetylpyridine 4-1-(Pteridin-4-ylamino)-ethyl-phenol

To a solution of methoxylamine hydrochloride (0.37 g. 4.5 60 The product from Preparation 7, Step 2 (1.1 g, 4.5 mmol) mmol) and sodium acetate (NaOAc: 0.37g, 4.5 mmol) in HO was dissolved in EtOH (5 mL) and treated with 40 wt.% (0.6 mL) and MeOH (5 mL) was added 2-chloro-4-acetylpy aqueous glyoxal Solution (1.3g, 9.0 mmol) plus H2O (10 mL) ridine (0.47 g., 3 mmol), and the reaction was stirred over and heated at 75° C. for 40 min. After cooling, the mixture night. The MeOH was evaporated, HO added, and the solu was diluted with HO (20 mL), and the precipitated product tion was extracted with CHC1. The organic layer was dried 65 was collected by suction filtration, washed with HO and (NaSO), filtered, and concentrated in vacuo to provide 0.50 dried in vacuo at 80° C. to give 4-1-(pteridin-4-ylamino)- g of crude product. EIMS m/z, 184 (M'.). ethyl-phenol (900 mg, 75%): 'H NMR (300 MHz, CDC1) & US 8,461,164 B2 45 46 9.33 (s, 1H), 9.06 (s, 1H), 8.99 (s, 1H), 8.85 (s, 1H), 8.63 (s, 1H), 7.32 (d. J=9 Hz, 2H), 6.73 (d. J=9 Hz, 2H), 5.52 (t, J=9 F HZ, 1H), 1.60 (d. J=9 Hz, 3H). F

5 HN uC N N2 F --

10 C NN C HO s e

15

F F

N HN uC 21N F CN NN O N-1\o 1. 25 OH NN - N 2 HNEn-1\o 30 Example 8 Preparation 8. 4-(2-aminoethoxy)-phenol. 1. (2-4-6-(2-Methoxyethoxy)-4-trifluoromethyl-pyri (4-Benzyloxyphenoxy)-acetonitrile din-2-yloxy)-phenyl-ethyl)-pteridin-4-yl-amine 35 A mixture of 4-benzyloxyphenol (9.4g, 47 mmol), bro To a solution of 2-4-(6-chloro-4-trifluoromethylpyridin moacetonitrile (6.8 g., 56.7 mmol) in acetone (50 mL) with 2-yloxy)-phenyl-ethyl-pteridin-4-yl-amine (320 mg. 0.7 KCO (2 g, 14.5 mmol) was heated to reflux 1 min, then at mmol) in anhydrous methoxyethanol (5 mL) was added NaH 40°C. for 1 h with stirring. The reaction mixture was filtered, (50 mg, 60% dispersion in oil). This was heated at 100° C. the solids washed with acetone, and the filtrate concentrated 40 in vacuo to afford a tan oil which crystallized on Standing, until TLC indicated completion. The reaction was evaporated providing 10.70g of (4-benzyloxyphenoxy)-acetonitrile. under N, and the residue was taken up in HO (125 mL) and treated with dilute HCl to adjust the pH to 7. The aqueous 2.4-(2-Aminoethyloxy)-phenol mixture was washed with EtOAc, the layers were separated, 45 and the organic layer was concentrated in vacuo to provide 0.22 g of a gum. This was dissolved in Et2O, hexane was In a Parr bottle the product from Preparation 8, Step 1. added, and the EtO boiled off to precipitate a solid. The (10.7 g., 44.7 mmol) was dissolved in absolute EtOH (100 product was collected by suction filtration to afford (2-4-6- mL). The solution was treated with 37% HCl (9 g) and 10% (2-methoxyethoxy)-4-trifluoromethyl-pyridin-2-yloxy Pd/C (1.8 g). The reaction mixture was de-aerated, then charged with hydrogen (initial pressure: 50 pso H2) and 50 phenyl-ethyl)-pteridin-4-yl-amine (97 mg) as a beige pow shaken for 16 h. The mixture was filtered and the filtrate was der: mp 101-104°C.; H NMR (CDC1) 89.03 (d. J=2.0 Hz, concentrated in vacuo to afford 4-(2-aminoethoxy)-phenol 1H), 8.84 (s, 1H), 8.63 (d. J=1.8 Hz, 1H), 7.31-7.29 (m, 2H), hydrochloride salt (7.22 g, 85%) as a beige solid. This mate 7.27-7.23 (m, 1H), 7.13-7.09 (m, 2H), 6.73 (s, 1H), 6.55 (s, 1H), 4.30-4.28 (m, 2H), 4.01-3.96 (m, 2H), 3.63-3.61 (m, rial was used without further purification. 55 Also prepared by Preparation 8: 3 (2 Aminoethyloxy)- 2H), 3.38 (s.3H), 3.10-3.07 (m,2H); EIMS m/z 487.3 (IMI). phenol hydrochloride salt, from 3-benzyloxyphenol. Also prepared by Preparation 8, Step 2. 2 (4 Methoxy-2,5-dimethylphenyl)-ethylamine hydro 60 NN chloride, from (4-methoxy-2,5-dimethylphenyl)-acetoni HN Na2 trile. 2 (4 Methoxy-2-methylphenyl)-ethylamine hydrochloride, -e- from (4-methoxy-2-methylphenyl)-acetonitrile. 2 (4-Methoxy-2,3-dimethylphenyl)-ethylamine hydro 65 chloride, from (4-methoxy-2,3-dimethylphenyl)-acetoni CCN.1.2 N. trile. US 8,461,164 B2 47 48 -continued with H2O. The organic fractions were pooled and concen F trated in vacuo. The residue (229 mg) was purified by pre parative RP-HPLC to afford {2-4-(6-fluoropyridin-3-yl)- O O phenyl-ethyl-pteridin-4-yl-amine (20 mg) as an orange F solid: mp 184-186° C.; EIMS m/z 346 (MI"). N HN uC 2N N

N O

else 10 HO 21 CCN N -e- N N C O Example 9 15 Pteridin-4-yl-(2-4-4-(2.2.2-trifluoroethoxy)-pyri O 21 -e- din-2-yloxy)-phenyl-ethyl)-amine N N C O F To a solution of N-(2-4-(4-iodopyridin-2-yl)oxyl F phenylethyl)pteridin-4-amine (300 mg. 0.64 mmol) and 2.2, -e- 2-trifluoroethanol (5 mL, 1.27 mmol) in a 45 mL Parr Bomb O 21 F -- was added CSCOs (412 mg, 1.27 mmol), 1,10-phenanthro Sn line (22 mg, 0.127 mmol), and Cut (12 mg, 0.064 mmol). The N O F reaction was held at 110° C. for 72 h, diluted with CHCl, 25 and washed with H2O. The organic layer was concentrated in F vacuo and the residue was purified by preparative HPLC to C 21 F afford pteridin-4-yl-(2-4-4-(2.2.2-trifluoroethoxy)-pyri -e- din-2-yloxy)-phenyl-ethyl)-amine (74 mg. 26%) as a yellow N N O solid: mp 166° C.: EIMS m/z 442 (MI). 30 F F Br 2 21 F 2 Her Sa 35 N O HN F -> F N HN 2N21 NN 2 21 F

N N J 40 Sa N N N O F 21 N N Preparation 9. 2-6-(4-Trifluoromethylphenoxy)- 45 pyridin-3-yl-ethylamine

HN 1.6-Chloronicotinic acid, methyl ester N 21 a NN To a solution of 6-chloronicotinic acid (20.0 g, 0.127 mol) 50 in CHCl (250 mL) was added oxalyl chloride (123.3 mL, N N J 0.15 mol) with 1-5 drops of DMF. The solution was stirred 18 N N h and concentrated in vacuo. The residue was dissolved in CHCl (100 mL) and cooled in an ice bath. To this was added MeOH (20 mL) and the solution was stirred for 15 min while maintaining a tempbelow 40°C. The solvent was removed in Example 10 55 vacuo, and the residue was dissolved in EtO, washed with H2O and brine, dried with NaSO, and filtered through SiO. {2-4-(6-Fluoropyridin-3-yl)-phenyl-ethyl-pteri The solvent was removed in vacuo to yield 6-chloronicotinic din-4-yl-amine acid, methyl ester (21 g) as an off-white solid: 'H-NMR (300 MHz, CDC1) & 9.02 (d. J=13.8 Hz, 1H), 8.51-8.06 (m. 1H), To a round bottom flask was added 2-(4-bromophenyl)- 60 7.76-7.30 (m, 1H), 4.01 (s.3H); EIMS m/z. 171 (IMI), which ethyl-pteridin-4-yl-amine (200 mg. 0.61 mmol), 2-fluoro-5- was used in Step 2 without further purification. pyridineboronic acid (102 mg, 0.73 mmol), NaHCO (102 mg, 1.21 mmol), PdCl(PPh), (213 mg) and 50% aqueous 2. 6-(4-Trifluoromethylphenoxy)-nicotinic acid ethylene glycol dimethyl ether (DME: 3.0 mL). The reaction methyl ester was heated to reflux for 4.5 h, after which the reaction was 65 cooled and the resulting orange precipitate filtered. The fil To a suspension of NaH (60% dispersion in oil; 1.2g, 30 tered material was washed with EtOAc and the filtratewashed mmol) in 30 mL of DMSO was added a solution of 4-(trif US 8,461,164 B2 49 50 luoromethyl)phenol (1.86 g., 30 mmol) in 20 mL of DMSO allowed to cool to room temperature, and after 2 h, the reac and the mixture was stirred for 30 min. To this was added tion was quenched by careful addition of 5 mL of saturated methyl 6-chloronicotinate (5.13 g, 30 mmol) and the solution aqueous ammonium chloride. The resulting mixture was was heated overnight at 70° C. The reaction was cooled to made alkaline by addition of 2M NaOH solution. The pre room temperature and then diluted with EtO. The solution 5 cipitate which formed was removed by filtration through was washed with HO, brine, dried with NaSO, suction Celite. The filtrate phases were separated, and the aqueous filtered, and the solvent removed in vacuo. The residue was phase was extracted 3 times with EtO. The pooled organic purified via normal phase column chromatography over SiO, fractions were dried with NaSO and suction filtered. The using 15% EtO/pentane to yield 6-(4-trifluoromethylphe solvent was removed in vacuo to yield 2-6-(4-trifluorometh noxy)-nicotinic acid methyl ester (4.5 g) as a colorless solid: 10 ylphenoxy)-pyridin-3-yl-ethylamine (200 mg), as a brown 'H-NMR (300 MHz, CDC1) & 8.81 (dd, J=2.5, 0.6 Hz, 1H), oil. 8.33 (dd, J=8.6.2.4 Hz, 1H), 7.69 (d. J=8.5 Hz, 2H), 7.31-7.24 Also prepared by Preparation 9, Steps 4 and 5. 2 (4 Meth (m. 2H), 7.02 (dd, J=8.5,0.6 Hz, 1H), 3.93 (s.3H); EIMS m/z oxy-3-trifluoromethylphenyl)-ethylamine hydrochloride, 297 (IMI). from (4-methoxy-3-trifluoromethylphenyl)-methanol. 15 Also prepared by Preparation 9, Step 5. 3. 5-Chloromethyl-2-(4-trifluoromethylphenoxy)- 2 (3 Fluoro-4-methoxyphenyl)-ethylamine hydrochloride, pyridine from (3-fluoro-4-methoxyphenyl)-acetonitrile. 2 (4 Methoxy-3-methylphenyl)-ethylamine hydrochloride, To a suspension of LiAlH4 (0.051 g, 13.5 mmol) in THF from (4-methoxy-3-methylphenyl)-acetonitrile. (20 mL) was added dropwise a solution of 6-(4-trifluorom ethylphenoxy)-nicotinic acid methyl ester (4.0g, 13.5 mmol) in THF (10 mL). After the mixture was stirred 1 h, the reaction C OH was quenched by the addition of 4MNaOH (3 mL) followed HN N by HO (3 mL). A precipitate formed and the THF was NN He- n NN decanted. The precipitate was washed with hot THF 2 times. 25 The organic fractions were combined and the solvent 2 2 2 removed in vacuo to yield 3.5 g of yellow oil which was HN N N N dissolved in toluene (15 mL) and cooled in an ice bath. To this solution was added SOCl (3.9 mL) dropwise. The solution was allowed to warm to RT and stirred 2 h, at which point the 30 Preparation 10. 6,7-Dimethyl-pteridin-4-ol reaction was concentrated in vacuo. The residue was dis solved in EtO and washed with 1M NaOH. The EtO phase A mixture of 6-chloropyrimidine-4,5-diamine (1.4g, 10 was dried with NaSO and suction filtered through SiO. The mmol) and 2,3-butanedione (2.0g, 23 mmol) in toluene (35 Solvent was removed in vacuo yielding 5-chloromethyl-2-(4- mL) and methanol (10 mL) was stirred at reflux for 1 h. Upon trifluoromethylphenoxy)-pyridine (1.8 g) as a yellow solid: 35 cooling, the product precipitated and was collected by Suction H NMR (300 MHz, CDC1) & 8.17 (d. J–2.5 Hz, 1H), 7.80 filtration and rinsed with a MeOH/EtO mixture (ca. 1:2), (dd, J=8.5, 2.5 Hz, 1H), 7.66 (dd, J=5.5, 3.5 Hz, 2H), 7.30 then air dried to afford 6,7-dimethylpteridin-4-ol (1.4g, 72%) 7.17 (m, 2H), 7.00 (d. J=8.4 Hz, 1H), 4.57 (s. 2H); EIMS m/z as a gold powder. 287 (IMI). 40 4.6-(4-Trifluoromethylphenoxy)-pyridin-3-yl)-ac OH etonitrile

To a solution of 5-chloromethyl-2-(4-trifluoromethylphe HN noxy)-pyridine (1.8 g. 6.27 mmol) in EtOH (12 mL) was 45 -e- added NaCN (1.23g, 25 mmol). The reaction mixture was N heated to 50° C. for 16 h. More ethanol (6 mL) was added, and the reaction mixture clarified. After an additional 3 h, the C NN Solvent was removed in vacuo, the residue taken up in Et2O N elseN and washed with HO. The organic layer was dried with 50 O NaSO, suction filtered and concentrated in vacuo. The resi due was purified by flash chromatography (50% EtO in petroleum ether over SiO) to yield 6-(4-trifluoromethylphe HN noxy)-pyridin-3-yl)-acetonitrile (1.3 g) as a pink solid; "H N NMR (300 MHz, CDC1) & 8.17-8.09 (m, 1H), 7.81-7.71 (m, 55 1H), 7.70-7.61 (m, 2H), 7.29-7.19 (m, 2H), 7.04 (d. J=8.4 Hz, C NN 1H), 3.73 (s. 2H); EIMS m/z 278 (MI). N elseN 5. 2-6-4-(Trifluoromethyl)phenoxypyridin-3- yl)ethylamine 60 Example 11 To a solution of AlCls (268 mg, 1.8 mmol) in Et2O cooled to 0°C. in an ice bath was added LiAlH (66 mg, 1.8 mmol) {2-4-(4-Isopropylphenoxy)-phenyl-ethyl-pteridin in one portion, under N. After stirring 15 min, a solution of 4-yl-amine 6-(4-trifluoromethylphenoxy)-pyridin-3-yl)-acetonitrile 65 (500 mg, 1.8 mmol) in Et2O (2 mL) and THF (1 mL) was 4-2-(Pteridin-4-ylamino)-ethyl-phenol (500 mg, 1.9 added dropwise resulting in an exotherm. The reaction was mmol), 4-isopropylphenylboronic acid (400 mg, 2.4 mmol), US 8,461,164 B2 51 52 anh. Cu(OAc) (360 mg, 2.0 mmol) and powdered, freshly vacuo to give 2-4-(tert-butyldimethylsilanyloxy)-phenyl activated 4 A molecular sieves (approximately 1 g) were ethyl-pteridin-4-yl-amine (1.3 g) as a white solid: mp 164 combined in CHCl (15 mL), treated with pyridine (920 uL. 165° C.; H NMR (300 MHz, CDC1) & 8.99 (s, 1H), 8.61 (s, 900 mg, 11.4 mmol) and sealed and stirred for 20 h with a 1H), 8.59 (s, 1H), 8.26 (d. J=5.9 HZ, 1H), 6.8-7.2 (m, 5H), moisture trap. The reaction was suction filtered and the filtrate 5 3.98 (t, J=6.2 Hz, 2H), 2.99 (t, 6.3 Hz, 2H), 1.02 (s, 6H), 0.18 shaken with dilute aqueous NH-OH. The organic phase was (s, 9H). washed with HO and brine and concentrated in vacuo. The residue was purified by preparative RP-HPLC using 80% MeCN/HO to yield 2-4-(4-isopropylphenoxy)-phenyl Example 13 ethyl-pteridin-4-yl-amine (78 mg, 11%) as a tan solid: mp 10 105-106.5° C. {2-4-(tert-Butyldimethylsilanyloxy)-phenyl-ethyl pteridin-4-yl-carbamic acid tert-butyl ester OH 15 {2-4-(tert-Butyldimethylsilanyloxy)-phenyl-ethyl-pte ridin-4-yl-amine (10.15g, 3.0 mmol) was dissolved in dry HN DMF (50 mL), treated with di-tert-butyldicarbonate (730 mg. -e- 3.3 mmol) plus approximately DMAP(N,N-dimethyl-4-ami N nopyridine; 25 mg) and stirred at 25°C. for 22h. The mixture was diluted with HO and extracted with EtOAc. The EtOAc else extracts were washed with H2O, dried (NaSO), suction N N filtered and concentrated in vacuo to give 2-4-(tert-bu OS/ tyldimethylsilanyloxy)-phenyl-ethyl-pteridin-4-yl-car Si bamic acid tert-butyl ester (1.2 g; 83%), as a yellow gum; 25 ESIMS m/z 482 (M+H"). HN 7% C NN -e- Example 14 1.2 30 2-(4-Hydroxyphenyl)-ethyl-pteridin-4-yl-carbamic N N acid tert-butyl ester {2-4-(tert-Butyldimethylsilanyloxy)-phenyl-ethyl-pte 35 ridin-4-yl-carbamic acid tert-butyl ester (680 mg, 1.4 mmol) was dissolved in 5 mL CH2Cl and treated with tetrabutylam monium fluoride3HO in 10 mL THF. After stirring for 18 h, the solution was washed with HO, dried (NaSO), suction filtered, and concentrated in vacuo to give 2-(4-hydroxyphe 40 nyl)-ethyl-pteridin-4-yl-carbamic acid tert-butyl ester as a tan solid, mp 132-134°C. (dec.); ESIMS m/z (M+H")368.

Br F

45 O F u? N N F N HN 2 Her C N1 NN N N elseN C NN N elseN

Example 12 55 {2-4-(tert-Butyldimethylsilanyloxy)-phenyl-ethyl pteridin-4-yl-amine

4-2-(Pteridin-4-ylamino)-ethyl-phenol (1.0g, 3.7 mmol) 60 was partially dissolved in dry DMF (75 mL), treated with imidazole (630 mg, 9.3 mmol), cooled to 0-5°C. and treated dropwise with a solution of t-butyldimethylsilyl chloride (680 mg, 4.5 mmol) in DMF (15 mL). After warming to 25° C. the mixture was stirred for 20h, diluted with H2O (75 mL) 65 and extracted with EtOAc. The extracts were washed with HO, brine, dried (NaSO), filtered and concentrated in US 8,461,164 B2 53 Example 15 5-2-(Pteridin-4-ylamino)-ethyl-2-(4-trifluorom ethyl-pyridin-2-yloxy)-benzoic acid, methyl ester To a solution of 2-3-bromo-4-(4-trifluoromethylpyridin 2-yloxy)-phenyl-ethyl-pteridin-4-yl-amine (243 mg. 0.5 mmol), in methanol in a 45 mL Parr bomb was added Pd(OAc) (5.6 mg, 0.25 mmol), DPPB (21 mg 0.5 mmol), and KCO (138 mg, 1 mmol). The reactor was sealed and charged with 300 psi of CO. The reaction was heated to 110° C. for 15 h, cooled to ambient temperature, filtered through Celite, and concentrated in vacuo. The residue was dissolved in CHCl, washed with HO, brine, dried over NaSO, 15 Suction filtered and concentrated in vacuo. The residue was slurried in EtO and pentane. The solvent was decanted to leave 5-2-(pteridin-4-ylamino)-ethyl-2-(4-trifluorometh ylpyridin-2-yloxy)-benzoic acid, methyl ester (55 mg; 23% yield) as a light yellow solid: mp 171-172°C.; H NMR (300 MHz, CDC1) & 9.04 (d. J–2.0 Hz, 1H), 8.84 (s, 1H), 8.64 (d. J=1.9 Hz, 1H),8.23 (d. J=5.0 Hz, 1H), 7.94 (d.J=2.3 Hz, 1H), 7.52 (dd, J=8.2, 2.2 Hz, 1H), 7.26-7.12 (m, 4H), 4.02 (dd. Example 17 J=13.7, 6.9 Hz, 2H), 3.67 (s, 3H), 3.13 (t, J=7.3 Hz, 2H): 25 ESIMS m/z, 471. (2-4-2-(4-Benzyloxy-phenyl)-ethoxyl-phenyl ethyl)-pteridin-4-yl-amine OH 4-2-(Pteridin-4-ylamino)-ethyl-phenol (300 mg, 10.1 30 mmol), triphenylphosphine (790 mg, 3.0 mmol) and 2-(4- HN -e- benzyloxyphenyl)ethanol (700 mg, 3.0 mmol) were com N bined in 10 mL anh. dioxane, treated with diisopropylazodi carboxylate (590 u, 610 mg, 3.0 mmol) and stirred for 18 h. 35 The volatiles were removed in vacuo and the residue was CCNN - N2 chromatographed on SiO, with EtOAc (10% to 40%) in F F CHCl to obtain (2-4-2-(4-benzyloxyphenyl)-ethoxy F phenyl-ethyl)-pteridin-4-ylamine (105 mg: 20%) as a white O solid: mp 120-122° C.; ESIMS m/z 478 (M+H"); H NMR rN\, 40 (300 MHz, CDC1) & 9.23 (s, 1H), 8.96 (s, 1H), 8.80 (s, 1H), N HN 21N 6.8-7.5 (m. 13H), 4.1 (m, 2H), 3.90 (m, 2H), 3.01 (m, 4H). N F 1 45 O F F CCN N - N2 Nrs Example 16 HN Na2 He 50 Pteridin-4-yl-2-4-(3,5,6-trifluoro-4-trifluorom ethyl-pyridin-2-yloxy)-phenyl-ethyl-amine CCN.else N. 4-2-(Pteridin-4-ylamino)-ethyl-phenol (0.27 g, 1.0 55 mmol), 2,3,5,6-tetrafluoro-4-trifluoromethylpyridine (0.24g, OH F F 1.0 mmol) and DMF (5 mL) were added to a 25 mL round bottom flask equipped with magnetic stirring bar and dry NS nitrogen line. To the reaction mixture was added EtN (0.12g, N HN 21 1.2 mmol). After stirring 24hat room temperature, the reac 60 tion mixture was concentrated in vacuo, and the residue was partitioned between HO and EtOAc. The organic layer was concentrated in vacuo and the residue was purified by column chromatography (EtOAc/hexane over SiO) to afford pteri else din-4-yl-2-4-(3,5,6-trifluoro-4-trifluoromethyl-pyridin-2- 65 N. N. yloxy)-phenyl-ethyl-amine (110 mg) as a beige solid: mp 103-1089 C. US 8,461,164 B2 55 56 Example 18 dant. The pH was adjusted to 7 with saturated aqueous NaHCO Solution, the phases separated and the aqueous 2-4-(1,1-Difluoroethyl)-pyridin-2-yloxy-5-[2-(pte phase extracted once with CH2Cl2. The organic phases were ridin-4-ylamino)-ethyl-phenol pooled and washed twice with H2O, once with brine, dried (NaSO) and concentrated in vacuo to afford 2-chloro-4-t- To a solution of (2-4-4-(1,1-difluoroethyl)-pyridin-2- butylpyridine-N-oxide (5.0 g, 90%), which crystallized to yloxy-3-methoxyphenyl-ethyl)-pteridin-4-yl-amine (1.37 long white needles on standing. g, 3.13 mmol) in CHCl (15 mL) cooled to 0°C., was added 1M BBr/hexane (9.4 mL, 9.4 mmol). The solution was allowed to warm to room temperature and stirred overnight. 10 OH F The reaction was quenched with methanol and concentrated in vacuo. The residue was dissolved in Small amount of O N F methanol and poured into aqueous NaHCO. The F hydroxyaryl product precipitated and was collected by Suc HN Na2 -e- tion filtration and washed with HO. The filter cake was air 15 dried on the filter to yield 2-4-(1,1-difluoroethyl)-pyridin-2- yloxy-5-2-(pteridin-4-ylamino)-ethyl-phenol (0.76 g), as a s NN light brown solid: "H NMR (300 MHz, d-DMSO) & 9.53 (br s, 1H), 9.45 (s, 1H), 9.12 (s, 1H), 8.91 (d. J=1.5 Hz, 1H), 8.78 CCN N (br. 1H), 8.20 (d. J=5.3 Hz, 1H), 7.22 (d. J=5.3 Hz, 1H), 7.08 (s, 1H), 6.98 (d. J=8.1 Hz, 1H), 6.85 (d. J=1.8 Hz, 1H), 6.72 (dd, J=8.1, 1.8 Hz, 1H), 3.84 (dd, J=14.7, 7.4 Hz, 2H), 2.93 (t, 1. F J=7.4 Hz, 2H), 1.98 (t, J=19.2 Hz, 3H); ESIMS m/z 425 (M+H"). O N F 25 F

F F HN Na2 F F C C N N F N F n NN He 30 Na2 Na2 CC C 1.O 35 Example 19 Preparation 11. {2-3-(Isopropoxy)-4-(4-trifluoromethyl-pyridin-2- 2-Methoxy-6-chloro-4-trifluoromethylpyridine yloxy)-phenyl-ethyl-pteridin-4-ylamine To a solution of 2,6-dichloro-4-trifluoromethylpyridine 40 To a solution of 5-2-(pteridin-4-ylamino)-ethyl-2-(4-tri (10g, 46.3 mmol) in methanol (200 mL) was added 25% fluoromethylpyridin-2-yloxy)-phenol (200 mg, 0.47 mmol) NaOH/MeOH (12.5g, 13.2 mL, 231 mmol), which was then in 2 mL of DMSO was added 2-iodopropane (62 mg, 0.5 stirred at 50° C. for 2 hand then at room temperature over mmol), and KCO (97 mg, 0.7 mmol). The solution was night. The reaction mixture was extracted with pentane, and heated 2 h at 50° C., after which TLC analysis indicated the extract was concentrated in vacuo to afford 2-methoxy 45 absence of starting material. The mixture was poured onto 6-chloro-4-trifluoromethylpyridine (9.79 g), used without ice. The product precipitated and was collected by Suction further purification. filtration, washed with HO, and air dried, yielding 2-3- (isopropoxy)-4-(4-trifluoromethylpyridin-2-yloxy)-phenyl ethyl-pteridin-4-ylamine (180 mg; 81% yield) as a light 50 brown solid: ESIMS m/z. 471 (M+H").

O OH O -k N N 55 C N5 C 5 O 2 2 60 C N C N Preparation 12. 2-Chloro-4-t-butylpyridine-N-oxide 2-Chloro-4-t-butylpyridine (5.0g, 30 mmol) was dissolved Preparation 13.2-Chloroisonicotinic acid, in chloroform (75 mL), treated with MCPBA, ca. 75% (8.3g, 2,2-dimethyl-propyl ester 36 mmol. 1.2 equivalents) and heated to reflux for 19 h. The 65 mixture was stirred with sodium bisulfate solution until test 2-Chloroisonicotinic acid (2.0g, 13 mmol) was suspended ing with starch-iodide paper indicated consumption of oxi in 50 mL dry CHCl and treated with oxalyl chloride (3.5 US 8,461,164 B2 57 58 mL, 5.0 g, 39 mmol) plus 3 drops DMF. The mixture was -continued stirred for 4 h, the volatiles removed in vacuo and the residue O taken up in 50 mL CHC1. After cooling to 0°C. and treating with neopentyl alcohol (1.7 ml, 1.4g, 16 mmol), Et N (2.5 -N F mL, 1.8 g., 18 mmol) was added in portions. The mixture was O warmed to 25°C., stirred for 15h, washed sequentially with N F 15 mL, H2O, 15 mL saturated aqueous NaHCO, and 15 mL F N brine, then dried (NaSO), filtered, and concentrated in HN 2 vacuo to give 2.4 g (80%) of 2-chloroisonicotinic acid, 2.2- 10 dimethyl-propyl ester as an oil, used without additional puri N fication: "H NMR (300 MHz, CDC1) & 8.56 (d. J=5.6 Hz, N1 SN 1H), 7.88 (s, 1H), 7.78 (d.J=5.0 Hz, 1H), 4.06 (s. 2H), 1.05 (s, 9H). N elseN Also prepared by Preparation 13. 2 Chloroisonicotinic 15 acid, tert-butyl ester, from tert-butanol. Example 20 Acetic acid 5-2-(pteridin-4-ylamino)-ethyl-2-(4- trifluoromethylpyridin-2-yloxy)-phenyl ester To 4 mL of acetic anhydride was added 5-2-(Pteridin-4- ylamino)-ethyl-2-(4-trifluoromethylpyridin-2-yloxy)-phe C N C N nol (330 mg. 0.7 mmol), pyridine (0.5 mL), and 5 mg DMAP. n n 25 The solution was stirred at ambient temperature for 15h, then 2 2 diluted with CHCl and washed sequentially with HO and saturated aqueous NaHCO Solution. The organic fraction was dried with NaSO, suction filtered, and concentrated in F F 30 vacuo. The residue was diluted with 1:1 EtO/pentane. The F F product precipitated, was collected by filtration, and the cake washed with cool 1:1 EtO/pentane. This afforded 184 mg (56% yield) of acetic acid 5-2-(pteridin-4-ylamino)-ethyl 2-(4-trifluoromethylpyridin-2-yloxy)-phenyl ester, an off 35 white solid: ESIMS m/z: 471 (MI).

F F Preparation 14. 2-chloro-4-(1,1-difluoro)ethylpyridine-N-oxide O 40 N To a solution of 1.27 g (7 mmol) 2-chloro-4-(1,1-difluoro) HN uC -N4N Her ethylpyridine (Preparation 4) in TFA was added 30% hydro gen peroxide (6 mL) and the solution was heated at reflux for N 2.5h. The TFA was removed in vacuo and the residue poured 45 C NN into ice-cold H.O.The mixture was neutralized with NaCO N elseN and extracted with EtOAc and CHC1. The pooled organic F F layers were dried (NaSO), filtered and concentrated in vacuo to give 2-chloro-4-(1,1-difluoroethyl)-pyridine 1-ox O ide (1.00 g) as a brown oil: "H NMR (CDC1): 88.39 (d. J=6.6 50 N HZ, 1H), 7.63 (d. J=2.4 Hz, 1H), 7.33 (dd, J–6.6, 2.4 Hz, 1H), HN -u C 2N 1.94 (t, J=18 Hz, 3H); EIMS m/z 193 (LMI). N O 55 C NN 1. OH F 1.2 O N N N F F N HN 21 -- 60 Example 21 N (2-4-4-(1,1-Difluoroethyl)-6-methoxypyridin-2- C NN yloxy)-phenyl-ethyl)-pteridin-4-yl-amine N elseN 65 A round bottom flask was charged with (2-4-4-(1,1-dif luoroethyl)-1-oxy-pyridin-2-yloxyl-phenyl-ethyl)-pteri din-4-yl-amine (0.52 g, 1.13 mmol), ethyl chloroformate US 8,461,164 B2 59 60 (0.43 mL, 4.5 mmol), EtN (0.95 mL, 6.81 mmol) and MeOH further purification: EIMS m/z 139 (MI"). H NMR (10 mL), and heated at reflux for 2 days. The solvent was (CDC1): 8 8.25 (dd. 1H), 7.47 (d. 1H), 7.21 (m. 1H). removed and the residue dissolved in CHC1. The solution was washed with brine, dried over NaSO, filtered, concen 3.2-Fluoro-4-(1,1-difluoroethyl)pyridine trated in vacuo and purified by preparative RP-HPLC to give (2-4-4-(1,1-difluoroethyl)-6-methoxypyridin-2-yloxy 1-(2-Fluoropyridin-4-yl)-ethanone (6.2 g., 44.6 mmol) phenyl-ethyl)-pteridin-4-yl-amine (0.130g, 24% yield) as a from the previous reaction was treated with diethylamino pale yellow solid: "H NMR (300 MHz, CDC1) & 9.02 (d. sulfurtrifluoride (17 mL, 130 mmol), as in Preparation 4, to J=1.9 Hz, 1H), 883 (s, 1H), 8.62 (d. J=1.9 Hz, 1H), 7.29 (d. yield 3.5 g of 2-fluoro-4-(1,1-difluoroethyl)pyridine (45% J=8.1 Hz, 2H), 7.12 (d. J=8.1 Hz, 2H), 6.54 (s, 1H), 6.44 (s, 10 yield), as a light yellow oil: EIMS m/z 161 (MI). 1H), 3.98 (dd, J=13.2, 6.9 Hz, 2H), 3.79 (s.3H), 3.08 (t, J=6.9 Hz, 2H), 1.86 (t, J=18.3 Hz, 3H); ESIMS m/z 439.2 (M+ HI). HO 15 2 NS OH Na2 HO NS 2 Na2 25 O F F F F

Na2Nrn YnNa2

Preparation 15. 4-(1,1-Difluoroethyl)-2-fluoropyridine 35

1.2-Fluoroisonicotinonitrile Cesium fluoride (30 g, 0.22 mmol) was slurried in dry sulfolane (150 mL) and concentrated via vacuum distillation 40 at 0.5 mm Hg. After removal of 20% of the solvent, the Suspension was cooled and 2-chloroisonicotinonitrile (15g, 0.11 mmol) was added, then stirred and heated at 100° C. for 20 h. It was cooled to 25°C., poured into H2O (200 mL) and extracted with EtO. The EtO phase was washed with H.O. 45 then brine, dried over NaSO filtered and concentrated in vacuo. The residue was purified by column chromatography over SiO, with CHCl to give 2-fluoroisonicotinonitrile (12.0 g) as a low-melting colorless solid: EIMS m/z: 122 (MI); H NMR (CDC1): 8 8.45 (dd. 1H), 7.47 (dd. 1H), 50 HN 1N1 O 7.24 (m. 1H). oHCI 2. 1-(2-Fluoropyridin-4-yl)-ethanone OH

To a solution of 2-fluoroisonicotinonitrile (10g, 82 mmol) 55 in anhydrous EtO (250 mL) cooled in an ice-HO bath was slowly added 3M methyl magnesium bromide in hexane (40 Preparation 16. 4-(2-Aminoethoxy)-3-methylphenol mL, 120 mmol). The mixture was stirred at 25°C. overnight. hydrochloride The reaction was quenched slowly with 1N aq. citric acid solution at 0°C. until all solids dissolved. Brine was added 60 1. 4-Benzyloxy-2-methylphenol and the two phases were separated. The organic phase was dried over NaSO4, filtered, and concentrated in vacuo to give 2-Methylbenzene-1,4-diol (12.4g, 0.1 mol) was dissolved 1-(2-fluoropyridin-4-yl)-ethanone (6.2 g) as a brown oil. The in acetone (200 mL) in a 500 mL round bottom flask equipped aqueous phase was stirred at 25°C. for 3 h, then extracted with magnetic stirrer, reflux condenser and dry nitrogen line. with CHC1. The CHCl layer was dried over NaSO, 65 To the solution was added KCO (20.5 g), followed by ben filtered, and concentrated in vacuo to give an additional 1.1 g Zyl bromide (12.2 mL, 0.1 mol) with vigorous stirring. After of the product, for a total of 7.3 g used in the next step without stirring at room temperature for 72 h, the reaction mixture US 8,461,164 B2 61 62 was filtered and concentrated in vacuo. The residue was par titioned between slightly acidic HO (pH adjusted to 5 with F N 0.1N HCl) and a 1:1 mixture of EtO and pentane. The OH organic layer was filtered and concentrated in vacuo to pro vide a black oil (20.66 g). The oil was extracted with isopen- 5 -- 41 - tane (3x150 mL) and the pooled isopentane fractions were HO concentrated in vacuo to provide an orange oil (10g); the dark F F insoluble residue was set aside. The orange oil was passed F over a SiO2 column with EtO/pentane (1:1) eluent. The O N appropriate fractions were pooled and concentrated in vacuo 10 to provide 7.0 g of 1,4-bisbenzyloxy-2-methylbenzene as a -e- pale yellow oil, which solidified on standing. HO -u O 2n The dark insoluble residue from above was passed over a SiO, column with EtO/pentane (1:2) eluent. The appropriate 15 F F fractions were pooled and concentrated in vacuo to provide F 7.2 g 4-benzyloxy-2-methylphenol and 4-benzyloxy-3-meth O N ylphenol (approximately 1:1 mixture of monobenzylated iso mers) as an orange solid, used in the next step without further O O -u C 2N purification. 2O -e- N 2. (4-Benzyloxy-2-methylphenoxy)-acetonitrile o2 NN F F F 4-Benzyloxy-2-methylphenol and 4-benzyloxy-3-meth 2 ylphenol product from step 1 (5.76g, 27 mmol) and bromoac- 25 HN N etonitrile (3.24.g. 27 mmol) were dissolved in tetrahydrofu O N ran (100 mL) in a 500 mL round bottom flask equipped with magnetic stir bar, reflux condenser and dry nitrogen line. The O -u O 21n solution was treated with NaH (60% dispersion in oil: 1.4g, -e- 35 mmol) and stirred at room temperature overnight. The 30 HN reaction mixture was diluted with dimethyl formamide (20 nN. F F mL), and then stirred another 2 hat room temperature. The F reaction mixture was concentrated in vacuo, then taken up in 2 HO (200 mL). After adjusting pH to 4 with 2N HCl, the HN N aqueous layer was washed with an equivolume of Et2O/pen- 35 tane (1:1). The organic layer was concentrated in vacuo to provide a yellow-brown oil (6.45 g). The oil was subjected to preparative HPLC to provide a slightly purified product, after pooling appropriate fractions. This product was extracted with boiling isopentane (3x100 mL) and the pooled isopen- 40 tane fractions were concentrated in vacuo to provide 2.25 g of (4-benzyloxy-2-methylphenoxy)-acetonitrile (isomer A) and (4-benzyloxy-3-methylphenoxy)-acetonitrile (isomer B). approximately 2:1 mixture of A:B (determined by 'H-NMR integrations), as a pale yellow oil. The insoluble residue was 45 digested in boiling pentane, decanted, and cooled to room Example 22 temperature. After 24 hours, crystals had formed. The super natant was decanted, and concentrated in vacuo to provide 4-2-4-(4-Trifluoromethylpyridin-2-yloxy)-phenyl 750 mg of isomers A and B in 1:3 ratio (H-NMR analysis). ethoxy)-pteridine. 1. 2-4-(4-Trifluoromethylpyri The crystals were found to be the desired isomer A. Succes- 50 din-2-yloxy)-phenyl-ethanol sive pentane digestions of the crude residues and crystalliza tion eventually led to the recovery of 1.95 g of the highly 2-(4-Hydroxyphenyl)ethanol (4.0 g, 29 mmol), KCO, enriched (4-benzyloxy-2-methylphenoxy)-acetonitrile (iso (8.0 g, 58 mmol) and 2-fluoro-4-trifluoromethylpyridine (3.6 mer A). g, 22 mmol) were combined in DMSO (30 mL) and stirred at 55 25° C. for 20 h. The mixture was poured into H2O and 3. 4-(2-Aminoethoxy)-3-methylphenol extracted twice with EtO. The combined EtO extracts were hydrochloride washed with 1M NaOH, H2O, brine, and concentrated in vacuo to give 2-4-(4-trifluoromethylpyridin-2-yloxy)-phe (4-Benzyloxy-2-methylphenoxy)-acetonitrile (isomer A nyl-ethanol (4.7 g.: 57%), mp 78-79°C.: EIMS m/z 283; "H from Step 2: 1.95 g, 7.7 mmol) was dissolved in absolute 60 NMR (300 MHz, DMSO-d) 88.38 (d. J=5.3 Hz, 1H), 7.0–7.5 ethanol (100 mL) in a Parr bottle. The solution was treated (m, 8H), 4.67 (t, J=5.0 Hz, 2H), 2.74 (t, J–5.2 Hz, 2H). with con. aq. HCl (1.55g) and 10% Pd C (0.3 g), degassed, charged with hydrogen (55 psig), and shaken for 72 h. The 2.4-Nitro-6-2-4-(4-trifluoromethylpyridin-2- Suspension was filtered and concentrated in vacuo to afford yloxy)-phenyl-ethoxy-pyrimidin-5-ylamine 1.92 g 4-(2-aminoethoxy)-3-methylphenol hydrochloride as 65 a beige solid, used without further purification: EIMS m/z. 2-4-(4-Trifluoromethylpyridin-2-yloxy)-phenyl-ethanol 167 (IMI). (product from Step 1: 400 mg, 1.4 mmol) was dissolved in US 8,461,164 B2 63 64 DMSO (10 mL), treated with 95% NaH (36 mg, 1.5 mmol) Example 23 and the mixture was warmed to 50-60° C. to produce a clear Solution. Upon cooling the mixture was treated with 4-amino {2-4-(4-tert-Butylpyridin-2-yloxy)-phenyl-ethyl 5-nitro-6-chloropyrimidine (260 mg, 1.5 mmol) and heated at pteridin-4-ylamine 45° C. for 6h. After cooling the mixture was poured into HO (60 mL) and the precipitate was collected by suction filtra {2-4-(4-ten-Butyl-1-oxypyridin-2-yloxy)-phenyl tion, washed with HO and air-dried on the filter: "H NMR ethyl-pteridin-4-ylamine (500 mg, 1.2 mmol) and triph (300 MHz, CDC1) & 8.39 (s, 1H), 8.33 (s, 1H), 8.18 (s, 1H), enylphosphine (310 mg, 1.2 mmol) were dissolved in dry 7.38 (m, 2H), 7.15 (m, 4H), 4.69 (t, J=6.8 Hz, 2H), 3.15 (t, 6.6 THF (15 mL) and treated with rhenium bis-thiolate catalyst (5 Hz, 2H). This material was used in the next step without 10 mg; prepared according to Y. Wang and J. H. Espenson, Org. further purification. Lett., 2000, 2022), 3525-26: expressly incorporated by refer ence herein). The mixture was stirred for 1.5 h, evaporated, and the residue purified by preparative RP-HPLC using 85% 6-2-4-(4-Trifluoromethylpyridin-2-yloxy)-phenyl MeCN to give 2-4-(4-tert-butylpyridin-2-yloxy)-phenyl ethoxy-pyrimidine-4,5-diamine 15 ethyl-pteridin-4-ylamine as a tan solid (155 mg, 32%); mp: 156-157°C.; ESIMS m/z 400 (IM+H"); H NMR (300 MHz, 4-Nitro-6-2-4-(4-trifluoromethylpyridin-2-yloxy)-phe CDC1) & 9.02 (s, 1H), 8.82 (s, 1H), 8.62 (s, 1H), 8.08 (d. nyl-ethoxy-pyrimidin-5-ylamine was taken up in 75 mL J=5.9 Hz, 1H), 6.9-7.3 (m, 7H), 3.99 (t, J–7.0 Hz, 2H), 3.055 absolute ethanol, treated with 100 mg 5% Pd/C and shaken (t, 7.0 Hz, 2H). under 50 psi hydrogen for 20h. After removal of the catalyst by filtration, the crude diamino ether (6-2-4-(4-trifluorom ethylpyridin-2-yloxy)-phenyl-ethoxy-pyrimidine-4,5-di C amine) was obtained by removal of the solvent in vacuo to HN NN provide 6-2-4-(4-trifluoromethylpyridin-2-yloxy)-phe 25 nyl-ethoxy-pyrimidine-4,5-diamine, which was used in the He 2 next step without further purification. HN N OH

4. 4-2-4-(4-Trifluoromethylpyridin-2-yloxy)-phe N nyl-ethoxy)-pteridine 30 D n NN -e-

6-2-4-(4-Trifluoromethylpyridin-2-yloxy)-phenyl N 2 N es ethoxy-pyrimidine-4,5-diamine (75 mg, 0.19 mmol) was O N combined with 50% aqueous glyoxal solution (1 mL) in 35 EtOH (5 mL) and stirred overnight at 25°C. The solution was evaporated and the residue extracted with CHC1. The HN CHCl layer was washed with HO and concentrated in vacuo. The residue was recrystallized from hot MeCN to give N 4-2-4-(4-trifluoromethyl-pyridin-2-yloxy)-phenyl 40 D N1 NN ethoxy)-pteridine (16 mg, 20%): mp 172-173° C.; EIMS m/z 2 es 413: "H NMR (300 MHz, CDC1) & 9.24 (s, 1H), 9.07 (s, 1H), N N 9.02 (s, 1H), 8.30 (s, 1H), 7.43 (d. J=9.5 Hz, 2H), 7.28 (d. J=9.0 Hz, 2H), 4.63 (t, 6.8 Hz, 2H), 3.17 (t, J=70 Hz, 2H). 45 Example 24 2-(4-Methoxyphenyl)-ethyl-(2,6,7-trimethylpteri din-4-yl)-amine

50 1. 2,6,7-Trimethylpteridin-4(1H)-one A mixture of 6-chloro-2-methylpyrimidine-4,5-diamine (3.2 g, 20 mmol) and 2,3-butanedione (3.6 g., 42 mmol) in s NN n-butanol (40 mL) was stirred at 75-80° C. for 1 h. After 55 cooling, the reaction was diluted with EtO (50 mL) and the CCN N solid collected by suction filtration. This was dried in vacuo affording, 2,6,7-trimethylpteridin-4(1H)-one (3.9 g), as a gold powder which was used in the next step without further purification. 60 2. 2-(4-Methoxyphenyl)-ethyl-(2,6,7-trimethylpte N NN ridin-4-yl)-amine A mixture of 2,6,7-trimethylpteridin-4(1H)-one (1.1 g, 6.0 CCN N 65 mmol), 4-methoxyphenethylamine (1.6 g., 11 mmol) and ammonium Sulfate (0.56 g, 4.2 mmol) in hexamethyldisila Zane (16 mL) was heated at 115° C. for 6 h. After cooling, the US 8,461,164 B2 65 66 majority of solids were dissolved by addition of CH2Cl and HO and the solvents removed in vacuo. The residue was slurried in a mixture of MeOH (5 mL) and H2O (50 mL) and stirred for 45 min. The bronze solid was collected by suction filtration and dried in vacuo at 50° C. The residue was dis 5 solved in MeCH/CH2Cl and diluted with EtO, causing crystallization. All solvent was allowed to evaporate, and the remaining Solid dried in vacuo to afford 2-(4-methoxyphe nyl)-ethyl-(2,6,7-trimethylpteridin-4-yl)-amine as a brown powder (1.3 g.: 67%): 'H NMR (300 MHz, CDC1) & 7.22 10 7.14 (m, 2H), 6.95 (t, J=6.3 Hz, 1H), 6.90-6.83 (m, 2H), 3.87 (dd, J=13.5, 6.8 Hz, 2H), 3.80 (s.3H), 2.97 (t, J=7.2 Hz, 2H), 2.69 (s.3H), 2.66 (s.3H), 2.61 (s, 3H).

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US 8,461,164 B2 173 174

US 8,461,164 B2 175 176

US 8,461,164 B2 179 180

US 8,461,164 B2 181 182

US 8,461,164 B2 183 184

US 8,461,164 B2 187 188

US 8,461,164 B2 189 190

US 8,461,164 B2 191 192

US 8,461,164 B2 193 194

US 8,461,164 B2 195 196

US 8,461,164 B2 197 198