US008877934B2

(12) United States Patent (10) Patent No.: US 8,877,934 B2 Berger et al. (45) Date of Patent: Nov. 4, 2014

(54) N-HETEROARYL COMPOUNDS (52) U.S. Cl. CPC ...... C07D 213/89 (2013.01); C07D401/04 (75) Inventors: Michael Berger, Schwabenheim (DE); (2013.01); C07D 213/74 (2013.01); C07D Christopher Kern, Schwabenheim 239/47 (2013.01); C07D 239/42 (2013.01); (DE); Marko Eck, Schwabenheim (DE): C07D 413/04 (2013.01); C07D491/048 Jörg Schröder, Schwabenheim (DE) (2013.01); C07D 471/04 (2013.01); C07D 215/46 (2013.01) (73) Assignee: Intervet Inc., Summit, NJ (US) USPC ...... 546/309; 514/235.8 (58) Field of Classification Search (*) Notice: Subject to any disclaimer, the term of this None patent is extended or adjusted under 35 See application file for complete search history. U.S.C. 154(b) by 0 days. (56) References Cited (21) Appl. No.: 13/876,724 FOREIGN PATENT DOCUMENTS

(22) PCT Filed: Sep. 28, 2011 CN 1.01284.812 A 10, 2008 EP 1900 772 A2 3, 2008 (86). PCT No.: WO 2004/03.5591 A1 4/2004 WO 2008/028689 A1 3, 2008 S371 (c)(1), WO 2008/028691 A1 3, 2008 (2), (4) Date: Mar. 28, 2013 OTHER PUBLICATIONS (87) PCT Pub. No.: WO2012/041873 Silva, A., Mini-Reviews in Medicinal Chemistry, 2005, vol. 5, pp. 893-1014.* PCT Pub. Date: Apr. 5, 2012 Jabbar et al., “Anthelmintic resistance: the sate of play revisited'. Life Sciences, 2006, pp. 2413-2431, vol. 79. (65) Prior Publication Data McKellar et al., “Veterinary anthelmintics: old and new”, Trends in US 2013/O196993 A1 Aug. 1, 2013 Parasitology, 2004, pp. 456-461, vol. 20010). International Search Report for corresponding PCT/EP2011/066806, mailed Dec. 14, 2011. Golisade, et al., “Anti-Malarial Activity of N6- Substituted Related U.S. Application Data Adenosine Derivates. Part I, Bioorganic & Medical Chemistry, (60) Provisional application No. 61/388,466, filed on Sep. 2002, pp. 769-777, vol. 10. 30, 2010. * cited by examiner (30) Foreign Application Priority Data Primary Examiner — Heidi Reese (57) ABSTRACT Sep. 29, 2010 (EP) ...... 10181553 This invention relates to certain N-heteroaryl compounds that (51) Int. Cl. are generally useful as medicaments, more specifically as A 6LX3/535 (2006.01) medicaments for animals. The medicament can preferably be CO7D 23/00 (2006.01) used for the treatment of helminth infections and the treat CO7D40 L/04 (2006.01) ment of parasitosis, such as caused by helminth infections. C07D 213/89 (2006.01) This invention also relates to uses of the compounds to make C07D 213/74 (2006.01) medicaments and treatments comprising the administration C07D 239/47 (2006.01) of the compounds to animals in need of the treatments. This CO7D 239/42 (2006.01) invention also relates to novel N-heteroaryl compounds and CO7D 413/04 (2006.01) the preparation of said compounds. Moreover this invention CO7D 49/048 (2006.01) relates to pharmaceutical compositions and kits comprising CO7D 47L/04 (2006.01) the compounds. CO7D 215/46 (2006.01) 21 Claims, No Drawings US 8,877,934 B2 1. 2 N-HETEROARYL COMPOUNDS SUMMARY OF THE INVENTION

CROSS-REFERENCE TO RELATED Briefly, this invention relates to compounds that can gen APPLICATIONS erally be used as a medicament for animals. The compounds 5 correspond in structure to formula (I) or its pharmaceutically This application is a national stage entry under 35 U.S.C. acceptable salts, Solvates, N-oxides or prodrugs S371 of PCT/EP2011/066806, filed on Sep. 28, 2011, which claims priority to U.S. Provisional Application No. 61/388, 466, filed on Sep. 30, 2010, and EP Application No. Formula (I) 10181553.8, filed on Sep. 29, 2010. The content of PCT/ 10 EP2011/066806 is hereby incorporated by reference in its entirety.

FIELD OF THE INVENTION 15 This invention relates to novel N-heteroaryl compounds that are useful as medicaments, the preparation of Such com pounds and the use of Such compounds. The medicament can preferably be used for the treatment of parasitic infections o such as helminth infections and especially for the treatment of parasitoses, such as caused by helminth infections. This invention also relates to uses of the compounds to make medicaments and treatments comprising the administration of the compounds to animals in need of the treatments. More- 25 over this invention relates to pharmaceutical compositions and kits comprising the compounds. wherein R" is halogen, C-C-alkyl, C-C-alkyloxy, C-C-alky BACKGROUND OF THE INVENTION lthio, C-C-alkenyl, C-C-alkynyl, C-C-alkyloxy C-C- 30 alkyl, C-C-alkylthio C-C-alkyl, C-C-alkyl carbonyl, Parasitic diseases in animals cause Substantial Suffering C-C-alkenyl carbonyl, SFs, C-C-alkyl sulfonyl, wherein and economic losses throughout the world. Thus, treatment of each of the carbon-containing radicals optionally is substi parasitic infections remains an important global endeavor. tuted by one or more halogen atoms, preferably fluorine The causative organisms include helminths, such as nema atoms, todes, cestodes, and trematodes. These organisms can infect, 35 R is hydrogen, halogen, C1-Co-alkyl, C1-Co-alkyloxy, for example, the stomach, intestinal tract, lymphatic system, C-C-alkylthio. C-C-alkenyl, C-C-alkynyl, C-C-alky muscle tissues, kidney, liver, lungs, heart, and brain of ani loxy C-C-alkyl, C-C-alkylthio C-C-alkyl, C-C-alkyl mals. There are many known drugs (or “anthelmintic agents”) carbonyl, C-C-alkenyl carbonyl, wherein each of the car available to treat various helminith parasite infections, see, 40 bon-containing radicals optionally is Substituted by one or e.g., McKellar, Q. A., et al., “Veterinary anthelmintics: old more halogen atoms, preferably fluorine atoms, and new. Review: Trends in Parasitology, 20010), 456-61 R is hydrogen, C-C-alkyl or cycloalkyl, preferably (October 2004). These anthelmintic agents treat specifically hydrogen, either nematode, cestode or trematode infections or have a R" is hydrogen, C-C-alkyl or cycloalkyl preferably broader anthelmintic spectrum. An example of an anthelm- 45 hydrogen, intic agent with sole effect on cestodes (tapeworms) is prazi R is hydrogen, C-C-alkyl, cycloalkyl, acyl or C-C- quantel. Some primary nematicidal compounds like fen alkyloxycarbonyl, bendazole, mebendazole, oxfendazole, albendazole have a R is hydrogen, C1-Co-alkyl, cycloalkyl, hydroxy, C, -Co broader spectrum than nematodes and treat cestode infections alkyloxy, phenyl C-C-alkyloxy, hydroxy C-C-alkyl, as well. Closantel, rafoxanide and triclabendazole are 50 C-C-alkyloxy C-C-alkyl, phenyl C-C-alkyloxy C-C- examples of specific compounds for the treatment of trema alkyl, thiol C-C-alkyl, C-C-alkylthio C-C-alkyl, phenyl tode infections (flukes). C-C-alkylthio C-C-alkyl, hydroxycarbonyl, hydroxycar While many parasitic infections can be treated with known bonyl C-C-alkyl, C-C-alkyloxycarbonyl, C-C-alky drugs, evolutionary development of resistance by the para loxycarbonyl C-C-alkyl, aminocarbonyl, aminocarbonyl sites can render Such drugs obsolete over time, see, e.g., 55 C-C-alkyl, C-C-alkylaminocarbonyl, C-C-alkylami Jabbar, A., et al., “Anthelmintic resistance: the state of play nocarbonyl (C-C-alkyl), di(C-C-alkyl)aminocarbonyl, revisited.” Life Sciences, 79, 2413-31 (2006). In addition, di (C-C-alkyl)aminocarbonyl (C-C-alkyl), C-C-alky known drugs may have other deficiencies, such as limited lamino C-C-alkyl, di(C-C-alkyl)amino C-C-alkyl, phe spectrum of activity and the need for repeated treatments. nyl, phenyl C-C-alkyl, wherein each phenyl group is In WO 2008/028689 A1 certain N-(1-phtalazin-1-ylpiperi- 60 optionally Substituted by hydroxy, C-C-alkyloxy or din-4-yl)-amides are described as EP2 receptor modulators. cycloalkyloxy WO 2008/028691 A1 discloses as EP2 receptors certain R’ is hydrogen, C-C-alkyl or cycloalkyl or R is joined N-(1-hetaryl-piperidin-4-yl)(het)arylamides. together with R to form a C-C-alkylene group and R7 is There still exists a need for new medicaments, such as joined together with R to form a C-C-alkylene group, antiparasitic agents to ensure safe, effective, and convenient 65 wherein one or both of said C-C-alkylene groups are treatment of a wide range of parasitic helminth infections optionally Substituted by one or more C-C-alkyl or over a long period of time. cycloalkyl radicals, US 8,877,934 B2 3 4 n is an integer from 1 to 3. This invention also relates to compounds according to for X is a carbonyl, thiocarbonyl or Sulfonyl group, preferably mula (Ia) or its pharmaceutically acceptable salts, Solvates or a carbonyl group, N-oxides A is a bond or NR, wherein R is hydrogen or C-C-alkyl, preferably hydrogen, E is a bond or NR, wherein R is hydrogen or C-C-alkyl, preferably hydrogen, Formula (Ia) B is N or CR', wherein R' is hydrogen or C-C-alkyl, preferably hydrogen, D is N or CR'', wherein R'' is hydrogen or C-C-alkyl, preferably hydrogen, 10 Y' is C or N, wherein C is substituted by R' which is hydrogen, halogen, C-C-alkyl, C-C-alkenyl, Cycloalkyl, Cycloalkyloxy, C-C-haloalkyl, C-C-alkoxy, C-C-ha loalkoxy, nitrilo, nitro, amino, C-C-alkylamino, Cycloalky lamino, di(C-C-alkyl)amino, (C-C-alkyl)-(Cycloalkyl) 15 amino, N-pyrrolidinyl, N-piperidinyl, N-morpholinyl, C-C-alkylthio, Cycloalkylthio, C-C-haloalkylthio. C-C-alkyl carbonyl, C-C-haloalkyl carbonyl, C-C- alkylcarbonylamino, aminocarbonyl, C-C-alkylaminocar bonyl, di(C-C-alkyl)aminocarbonyl, C-C-alkoxycarbo nyl, phenyl, dioxolane Such as 1,3-dioxolane, dioxane Such as 1,3-dioxane, or dioxepane Such as 1,3-dioxepane, each said ring being unsubstituted or substituted by C-C-alkyl, Y’ is C or N, wherein C is substituted by R' which is wherein hydrogen, halogen, C-C-alkyl, C-C-alkenyl, Cycloalkyl, 25 R" is hydrogen, halogen, C-C-alkyl, cycloalkyl, C-C- Cycloalkyloxy, C-C-haloalkyl, C-C-alkoxy, C-C-ha alkyloxy, cycloalkyloxy, C-C-alkylthio, cycloalkylthio. loalkoxy, nitrilo, nitro, amino, C-C-alkylamino, Cycloalky C-C-alkenyl, C-C-alkynyl, C-C-alkyloxy C-C-alkyl, lamino, di(C-C-alkyl)amino, (C-C-alkyl)-(Cycloalkyl) cycloalkyloxy C-C-alkyl, C-C-alkyloxy cycloalkyl, amino, N-pyrrolidinyl, N-piperidinyl, N-morpholinyl, thiol, cycloalkyloxy cycloalkyl, C-C-alkylthio C-C-alkyl, hydroxy, C-C-alkylthio, Cycloalkylthio, C-C-haloalky 30 cycloalkylthio C-C-alkyl, C-C-alkylthio cycloalkyl, lthio, C-C-alkyl carbonyl, C-C-haloalkyl carbonyl, ami cycloalkylthio cycloalkyl, amino, C-C-alkylamino, nocarbonyl, C-C-alkylaminocarbonyl, di(C-C-alkyl) cycloalkylamino, di-(C-C-alkyl)amino, di-(cycloalkyl) aminocarbonyl, C-C-alkylcarbonylamino, C-C- amino, C-C-alkylamino-C-C-alkyl, cycloalkylamino alkoxycarbonyl, dioxolane Such as 1,3-dioxolane, dioxane C-C-alkyl, C-C-alkylamino-cycloalkyl, cycloalky Such as 1,3-dioxane, or dioxepane Such as 1,3-dioxepane, 35 lamino-cycloalkyl, di-(C-C-alkyl)amino-C-C-alkyl, di each said ring being unsubstituted or Substituted by C-C- alkyl, (C-C-alkyl)amino-cycloalkyl, di-(cycloalkyl)amino-C- Y is C or N, wherein C is substituted by R' which is C-alkyl, di-(cycloalkyl)amino-cycloalkyl, C-C-alkyl hydrogen, halogen, C-C-alkyl, C-C-alkenyl, Cycloalkyl, carbonyl, cycloalkylcarbonyl, C-C-alkyloxy carbonyl, Cycloalkyloxy, C-C-haloalkyl, C-C-alkoxy, C-C-ha 40 cycloalkoxy carbonyl, C-C-alkenyl carbonyl, wherein each loalkoxy, nitrilo, nitro, amino, C-C-alkylamino, Cycloalky of the carbon-containing radicals optionally is Substituted by lamino, di(C-C-alkyl)amino, (C-C-alkyl)-(Cycloalkyl) one or more halogen atoms, preferably fluorine atoms, or R' amino, N-pyrrolidinyl, N-piperidinyl, N-morpholinyl, thiol, is phenyl, furanyl, imidazolinyl, or thiophenyl, wherein each hydroxy, C-C-alkylthio, Cycloalkylthio, C-C-haloalky of the rings optionally is substituted by one or more radicals lthio-C-C-alkyl carbonyl, C-C-haloalkyl carbonyl, 45 from the group of C-C-alkyl, cycloalkyl and halogen, pref C-C-alkylcarbonylamino, aminocarbonyl, C-C-alky erably fluorine, laminocarbonyl, di(C-C-alkyl)aminocarbonyl, C-C- R is hydrogen, halogen, C1-Co-alkyl, cycloalkyl, C-C- alkoxycarbonyl, dioxolane Such as 1,3-dioxolane, dioxane alkyloxy, cycloalkyloxy, C-C-alkylthio, cycloalkylthio. Such as 1,3-dioxane, or dioxepane Such as 1,3-dioxepane, C-C-alkenyl, C-C-alkynyl, C-C-alkyloxy C-C-alkyl, each said ring being unsubstituted or Substituted by C-C- 50 cycloalkyloxy C-C-alkyl, C-C-alkyloxy cycloalkyl, alkyl, cycloalkyloxy cycloalkyl, C-C-alkylthio C-C-alkyl, Y is C or N, wherein C is substituted by R' which is cycloalkylthio C-C-alkyl, C-C-alkylthio cycloalkyl, hydrogen, halogen, C-C-alkyl, C-C-alkenyl, Cycloalkyl, cycloalkylthio cycloalkyl, amino, C-C-alkylamino, Cycloalkyloxy, C-C-haloalkyl, C-C-alkoxy, C-C-ha cycloalkylamino, di-(C-C-alkyl)amino, di-(cycloalkyl) loalkoxy, nitrilo, nitro, amino, C-C-alkylamino, Cycloalky 55 amino, C-C-alkylamino-C-C-alkyl, cycloalkylamino lamino, di(C-C-alkyl)amino, (C-C-alkyl)-(Cycloalkyl) C-C-alkyl, C-C-alkylamino-cycloalkyl, cycloalky amino, N-pyrrolidinyl, N-piperidinyl, N-morpholinyl, lamino-cycloalkyl, di-(C-C-alkyl)amino-C-C-alkyl, di C-C-alkylthio, C-C-haloalkylthio C-C-alkyl carbonyl, (C-C-alkyl)amino-cycloalkyl, di-(cycloalkyl)amino-C- C-C-haloalkyl carbonyl, C-C-alkylcarbonylamino, ami Co-alkyl, di-(cycloalkyl)amino-cycloalkyl, C-C-alkyl nocarbonyl, C-C-alkylaminocarbonyl, di(C-C-alkyl) 60 carbonyl, cycloalkylcarbonyl, C-C-alkyloxy carbonyl, aminocarbonyl, C-C-alkoxycarbonyl, phenyl, dioxolane cycloalkoxy carbonyl, C-C-alkenyl carbonyl, wherein each Such as 1,3-dioxolane, dioxane Such as 1,3-dioxane, or diox of the carbon-containing radicals optionally is Substituted by epane Such as 1,3-dioxepane, each said ring being unsubsti one or more halogen atoms, preferably fluorine atoms, or R' tuted or substituted by C-C-alkyl, is phenyl, furanyl, imidazolinyl, or thiophenyl, wherein each orY and Y and/orY and Y are joined together to form a 65 of the rings optionally is substituted by one or more radicals ring System, from the group of C-C-alkyl, cycloalkyl and halogen, pref and wherein at least one of B and D is a nitrogen atom. erably fluorine, preferably R is hydrogen, US 8,877,934 B2 5 6

R is hydrogen, C-C-alkyl or cycloalkyl, preferably nyl, N-morpholinyl, thiol, hydroxy, C-C-alkylthio. C-C-6 hydrogen, alkyl carbonyl, C-C-haloalkyl carbonyl, C-C- R" is hydrogen, C-C-alkyl or cycloalkyl, preferably alkylcarbonylamino, aminocarbonyl, C-C-Y-6 hydrogen, alkylaminocarbonyl, di(C-C-alkyl)aminocarbonyl, C-C- R is hydrogen, C-C-alkyl, cycloalkyl or acyl, alkoxycarbonyl, cycloalkyl, cycloalkyloxy, cycloalkylamino, R is hydrogen, C1-Co-alkyl, cycloalkyl, hydroxy, C, -Co (C-C-alkyl)-(cycloalkyl)amino, cycloalkylthio, dioxolane alkyloxy, phenyl C-C-alkyloxy, hydroxy C-C-alkyl, Such as 1,3-dioxolane, dioxane Such as 1,3-dioxane, or diox C-C-alkyloxy C-C-alkyl, phenyl C-C-alkyloxy C-C- epane Such as 1,3-dioxepane, each said ring being unsubsti alkyl, thiol C-C-alkyl, C-C-alkylthio C-C-alkyl, phenyl tuted or substituted by C-C-alkyl or cycloalkyl, C-C-alkylthio C-C-alkyl, hydroxycarbonyl, hydroxycar 10 Y is C or N, wherein C is substituted by R' which is bonyl C-C-alkyl, C-C-alkyloxycarbonyl, C-C-alky hydrogen, halogen, C-C-alkyl, C-C-haloalkyl, C-C- loxycarbonyl C-C-alkyl, aminocarbonyl, aminocarbonyl alkoxy, C-C-haloalkoxy, nitrilo, nitro, amino, C-C-alky C-C-alkyl, C-C-alkylaminocarbonyl, C-C-alkylami lamino, di(C-C-alkyl)amino, N-pyrrolidinyl. N-piperidi nocarbonyl (C-C-alkyl), di(C-C-alkyl)aminocarbonyl, nyl, N-morpholinyl, C-C-alkylthio, C-C-alkyl carbonyl, di (C-C-alkyl)aminocarbonyl (C-C-alkyl), C-C-alky 15 C-C-haloalkyl carbonyl, C-C-alkylcarbonylamino, ami lamino C-C-alkyl, di(C-C-alkyl)amino C-C-alkyl, phe nocarbonyl, C-C-alkylaminocarbonyl, di(C-C-alkyl) nyl, phenyl C-C-alkyl, wherein each phenyl group is aminocarbonyl, C-C-alkoxycarbonyl, cycloalkyl, optionally substituted by hydroxyl, C-C-alkyloxy or cycloalkyloxy, cycloalkylamino, (C-C-alkyl)-(cycloalkyl) cycloalkoxy, amino, cycloalkylthio, phenyl, dioxolane Such as 1,3-diox R’ is hydrogen, C-C-alkyl or cycyloalkyl, or R and R' olane, dioxane Such as 1,3-dioxane, or dioxepane Such as together represent an oxo-group or a thioxo-group, or R is 1,3-dioxepane, each said ring being unsubstituted or Substi joined together with R to form a C-C-alkylene group and tuted by C-C-alkyl or cycloalkyl, R’ isjoined together with R to form a C-C-alkylene group, orY and Y and/orY and Y are joined together to forma wherein one or both of said C-C-alkylene groups are ring System, optionally Substituted by one or more C-C-alkyl or 25 and wherein at least one of B and D is a nitrogen atom cycloalkyl radicals, for treating a helminth infection. n is an integer from 1 to 3. The compounds of the formula (I) and pharmaceutically X is a carbonyl or Sulfonyl group, preferably a carbonyl acceptable solvates, N-oxides, salts and prodrugs thereof are grOup, hereinafter together referred to as "compound(s) according to A is a bond or NR, wherein R is hydrogen or C-C-alkyl, 30 this invention'. preferably hydrogen, The use of the compounds according to formula (Ia) and E is a bondor NR, wherein Rishydrogen or C-C-alkyl, pharmaceutically acceptable solvates, N-oxides and salts preferably hydrogen, thereof is hereinafter referred to as “use according to the B is N or CR", wherein R' is hydrogen or C-C-alkyl, invention'. The compounds according to formula (Ia) are preferably hydrogen, 35 hereinafter referred to as "compound(s) corresponding to the D is N or CR'', wherein R'' is hydrogen or C-C-alkyl, use according to the invention'. preferably hydrogen, This invention is directed, in part, to a novel compound of Y' is C or N, wherein C is substituted by R' which is the formula (I) and pharmaceutically acceptable solvates, hydrogen, halogen, C-C-alkyl, C-C-haloalkyl, C-C- N-oxides and salts thereof, and its use as a medicament, alkoxy, C-C-haloalkoxy, nitrilo, nitro, amino, C-C-alky 40 preferably a medicament for animals, e.g. for treating para lamino, di(C-C-alkyl)amino, N-pyrrolidinyl. N-piperidi sitic infections such as helminth infections in animals. This nyl, N-morpholinyl, C-C-alkylthio, C-C-alkyl carbonyl, invention also is directed, in part, to using at least one com C-C-haloalkyl carbonyl, C-C-alkylcarbonylamino, ami pound of the formula (I) and pharmaceutically acceptable nocarbonyl, C-C-alkylaminocarbonyl, di(C-C-alkyl) Solvates, N-oxides and salts thereof to prepare a medicament aminocarbonyl, C-C-alkoxycarbonyl, cycloalkyl, 45 for treating an infection including diseases caused by Such cycloalkyloxy, cycloalkylamino, (C-C-alkyl)-(cycloalkyl) infections (e.g., parasitoses caused by a helminth infection) in amino, cycloalkylthio, phenyl, dioxolane Such as 1,3-diox animals. olane, dioxane Such as 1,3-dioxane, or dioxepane Such as This invention also is directed, in part, to methods of mak 1,3-dioxepane, each said ring being unsubstituted or Substi ing the novel N-heteroaryl compounds, and intermediates tuted by C-C-alkyl or cycloalkyl 50 thereof. The preferred embodiments specified in this descrip Y’ is C or N, wherein C is substituted by R' which is tion for the compounds represent likewise preferred embodi hydrogen, halogen, C-C-alkyl, C-C-haloalkyl, C-C- ments for the intermediates. alkoxy, C-C-haloalkoxy, nitrilo, nitro, amino, C-C-alky This invention also is directed, in part, to pharmaceutical lamino, di(C-C-alkyl)amino, N-pyrrolidinyl. N-piperidi compositions. The pharmaceutical compositions comprise a) nyl, N-morpholinyl, thiol, hydroxy, C-C-alkylthio, C-C- 55 at least one N-heteroaryl compound according to this inven alkyl carbonyl, C-C-haloalkyl carbonyl, aminocarbonyl, tion, and b) at least one excipient, and/or at least one active C-C-alkylaminocarbonyl, di(C-C-alkyl)aminocarbonyl, compound (preferably anthelmintic compound) which differs C-C-alkylcarbonylamino, C-C-alkoxycarbonyl, in structure from the componenta). cycloalkyl, cycloalkyloxy, cycloalkylamino, (C-C-alkyl)- This invention also is directed, in part, to methods for (cycloalkyl)amino, cycloalkylthio, dioxolane Such as 1,3-di 60 treating a parasitic infection in animals, particularly a treat oxolane, dioxane Such as 1,3-dioxane, or dioxepane Such as ment of parasitoses caused by a helminth infection. The meth 1,3-dioxepane, each said ring being unsubstituted or Substi ods comprise administering at least one compound according tuted by C-C-alkyl or cycyloalkyl, to this invention to the animal. Y is C or N, wherein C is substituted by R' which is This invention also is directed, in part, to a kit. The kit hydrogen, halogen, C-C-alkyl, C-C-haloalkyl, C-C- 65 comprises at least one N-heteroaryl compound according to alkoxy, C-C-haloalkoxy, nitrilo, nitro, amino, C-C-alky this invention. In addition, the kit comprises at least one other lamino, di(C-C-alkyl)amino, N-pyrrolidinyl. N-piperidi component, such as another ingredient (e.g., an excipient or US 8,877,934 B2 7 8 active ingredient), and/or an apparatus for combining the R’ is hydrogen, C1-Co-alkyl or cycloalkyl, compound with another ingredient, and/or an apparatus for or R is joined together with R to form a C-C-alkylene administering the compound, and/or a diagnostic tool. group and R7 is joined together with R to form a C-C- Further benefits of Applicants invention will be apparent alkylene group, wherein one or both of said C-C-alkylene to one skilled in the art from reading this specification. groups are optionally substituted by one or more C-C-alkyl or cycloalkyl radicals, DETAILED DESCRIPTION OF PREFERRED n is an integer from 1 to 3 EMBODIMENTS X is a carbonyl or Sulfonyl group, preferably a carbonyl grOup, Compounds According to this Invention 10 A is a bond or NR, wherein Rishydrogenor C-C-alkyl, The present invention also relates to compounds according preferably hydrogen, to formula (I b) and pharmaceutically acceptable solvates, E is a bond or NR, wherein R is hydrogen or C-C-alkyl, N-oxides, salts and prodrugs thereof and their use as a medi preferably hydrogen, Cament. B is N or CR', wherein R' is hydrogen or C-C-alkyl, 15 preferably hydrogen, D is N or CR'', wherein R'' is hydrogen or C-C-alkyl, Formula (Ib) preferably hydrogen, Y' is C or N, wherein C is substituted by R' which is hydrogen, halogen, C-C-alkyl, C-C-haloalkyl, C-C- alkoxy, C-C-haloalkoxy, nitrilo, nitro, amino, C-C-alky lamino, di(C-C-alkyl)amino, N-pyrrolidinyl. N-piperidi nyl, N-morpholinyl, C-C-alkylthio, C-C-alkyl carbonyl, C-C-haloalkyl carbonyl, C-C-alkylcarbonylamino, ami 25 nocarbonyl, C-C-alkylaminocarbonyl, di(C-C-alkyl) aminocarbonyl, C-C-alkoxycarbonyl, phenyl, dioxolane Such as 1,3-dioxolane, dioxane Such as 1,3-dioxane, or diox epane Such as 1,3-dioxepane, each said ring being unsubsti tuted or substituted by C-C-alkyl or cycloalkyl, 30 Y is C or N, wherein C is substituted by R' which is hydrogen, halogen, C-C-alkyl, C-C-haloalkyl, C-C- alkoxy, C-C-haloalkoxy, nitrilo, nitro, amino, C-C-alky lamino, di(C-C-alkyl)amino, N-pyrrolidinyl. N-piperidi nyl, N-morpholinyl, thiol, hydroxy, C-C-alkyl carbonyl, In the compounds of the formula (Ib) the radicals, indices and 35 groups have the following meanings: C-C-haloalkyl carbonyl, aminocarbonyl, C-C-alkylami R" is halogen, C, -Co-alkyl, C1-Co-alkyloxy, C, -Co-alky nocarbonyl, di(C-C-alkyl)aminocarbonyl, C-C-alkylcar lthio, C-C-alkenyl, C-C-alkynyl, C-C-alkyloxy C-C- bonylamino, C-C-alkoxycarbonyl, dioxolane Such as 1,3- alkyl, C-C-alkylthio C-C-alkyl carbonyl, C-C-alkenyl dioxolane, dioxane Such as 1,3-dioxane, or dioxepane Such as carbonyl, wherein each of the carbon-containing radicals 40 1,3-dioxepane, each said ring being unsubstituted or Substi optionally is Substituted by one or more halogenatoms, pref tuted by C-C-alkyl or cycloalkyl, erably fluorine atoms Y is C or N, wherein C is substituted by R' which is R is hydrogen, halogen, C1-Co-alkyl, C-C-alkyloxy, hydrogen, halogen, C-C-alkyl, C-C-haloalkyl, C-C- C-C-alkylthio, C-C-alkenyl, C-C-alkynyl, C-C-alky alkoxy, C-C-haloalkoxy, nitrilo, nitro, amino, C-C-alky loxy C-C-alkyl, C-C-alkylthio C-C-alkyl, C-C-alkyl 45 lamino, di(C-C-alkyl)amino, N-pyrrolidinyl. N-piperidi carbonyl, C-C-alkenyl carbonyl, wherein each of the car nyl, N-morpholinyl, thiol, hydroxy, C-C-alkylthio, C-C- bon-containing radicals optionally is Substituted by one or alkyl carbonyl, C-C-haloalkyl carbonyl, C-C- more halogen atoms, preferably fluorine atom alkylcarbonylamino, aminocarbonyl, C-C- R is hydrogen, C-C-alkyl or cycloalkyl, preferably alkylaminocarbonyl, di(C-C-alkyl)aminocarbonyl, C-C- hydrogen, 50 alkoxycarbonyl, dioxolane Such as 1,3-dioxolane, dioxane R" is hydrogen, C-C-alkyl or cycloalkyl, preferably Such as 1,3-dioxane, or dioxepane Such as 1,3-dioxepane, hydrogen, each said ring being unsubstituted or Substituted by C-C- R is hydrogen, C, -Co-alkyl, cycloalkyl or acyl alkyl or cycloalkyl, R is hydrogen, C-C-alkyl, cycloalkyl, hydroxy, C-C- Y is C or N, wherein C is substituted by R' which is alkyloxy, phenyl C-C-alkyloxy, hydroxy C-C-alkyl, 55 hydrogen, halogen, C-C-alkyl, C-C-haloalkyl, C-C- C-C-alkyloxy C-C-alkyl, phenyl C-C-alkyloxy C-C- alkoxy, C-C-haloalkoxy, nitrilo, nitro, amino, C-C-alky alkyl, thiol C-C-alkyl, C-C-alkylthio C-C-alkyl, phenyl lamino, di(C-C-alkyl)amino, N-pyrrolidinyl. N-piperidi C-C-alkylthio C-C-alkyl, hydroxycarbonyl, hydroxycar nyl, N-morpholinyl, C-C-alkylthio, C-C-alkyl carbonyl, bonyl C-C-alkyl, C-C-alkyloxycarbonyl, C-C-alky C-C-haloalkyl carbonyl, C-C-alkylcarbonylamino, ami loxycarbonyl C-C-alkyl, aminocarbonyl, aminocarbonyl 60 nocarbonyl, C-C-alkylaminocarbonyl, di(C-C-alkyl) C-C-alkyl, C-C-alkylaminocarbonyl, C-C-alkylami aminocarbonyl, C-C-alkoxycarbonyl, phenyl, dioxolane nocarbonyl (C-C-alkyl), di(C-C-alkyl)aminocarbonyl, Such as 1,3-dioxolane, dioxane Such as 1,3-dioxane, or diox di(C-C-alkyl)aminocarbonyl (C-C-alkyl). C-C-alky epane Such as 1,3-dioxepane, each said ring being unsubsti lamino C-C-alkyl, di(C-C-alkyl)amino C-C-alkyl, phe tuted or substituted by C-C-alkyl or cycloalkyl, nyl, phenyl C-C-alkyl, wherein each phenyl group is 65 orY and Y and/orY and Y are joined together to form a optionally Substituted by hydroxy, C-C-alkyloxy or ring system, and wherein at least one of Band D is a nitrogen cycloalkyloxy atOm. US 8,877,934 B2 10 For a compound of formula (Ib), the radicals, indices and R is hydrogen, C1-Co-alkyl, cycloalkyl, hydroxy, C, -Co groups may have the following additional meaning (leading alkyloxy, phenyl C-C-alkyloxy, hydroxy C-C-alkyl, to compounds referred to here-beneath as “additional com C-C-alkyloxy C-C-alkyl, phenyl C-C-alkyloxy C-C- pound(s)): alkyl, thiol C-C-alkyl, C-C-alkylthio C-C-alkyl, phenyl A first additional compound wherein R is SFs, a second 5 C-C-alkylthio C-C-alkyl, hydroxycarbonyl, hydroxycar additional compound wherein X is thiocarbonyl and a third bonyl C-C-alkyl, C-C-alkyloxycarbonyl, C-C-alky additional compound wherein R' is SFs and X is thiocarbo loxycarbonyl C-C-alkyl, aminocarbonyl, aminocarbonyl nyl. C-C-alkyl, C-C-alkylaminocarbonyl, C-C-alkylami For a next additional compound of any of the additional nocarbonyl (C-C-alkyl), di(C-C-alkyl)aminocarbonyl, compounds mentioned here-above or beneath, R' may be a 10 di (C-C-alkyl)aminocarbonyl (C-C-alkyl), C-C-alky C-C-alkyl sulfonyl. lamino C-C-alkyl, di(C-C-alkyl)amino C-C-alkyl, phe For a next additional compound of any of the additional nyl, phenyl C-C-alkyl, wherein each phenyl group is compounds mentioned here-above or beneath, R is C-C- optionally Substituted by hydroxy, C-C-alkyloxy or alkyloxycarbonyl. 15 cycloalkyloxy. Preferably R is hydrogen, C-C-alkyl, For next additional compounds of any of the additional hydroxycarbonyl, hydroxycarbonyl C-C-alkyl, C-C- compounds mentioned here-above or beneath. Y' is C alkyloxycarbonyl, C-C-alkyloxycarbonyl C-C-alkyl, wherein C is substituted by R' which is C-C-alkenyl, or aminocarbonyl, aminocarbonyl C-C-alkyl, C-C-alky Cycloalkyl, or Cycloalkyloxy, or Cycloalkylamino, or (C- laminocarbonyl, C-C-alkylaminocarbonyl (C-C-alkyl). Co-alkyl)-(Cycloalkyl)amino, or Cycloalkylthio or C-C- di (C-C-alkyl)aminocarbonyl, di(C-C-alkyl)aminocarbo haloalkylthio. nyl (C-C-alkyl), phenyl, phenyl C-C-alkyl, more prefer For next additional compounds of any of the additional ably R' is hydrogen or C-C-alkyl. compounds mentioned here-above or beneath, Y is C R’ is hydrogen, C-C-alkyl or cycicoalkyl, preferably wherein C is substituted by R' which is C1-Co-alkenyl, or hydrogen. Cycloalkyl, or Cycloalkyloxy, or Cycloalkylamino, or (C- 25 Alternatively Risjoined together with Rto forma C-C- Co-alkyl)-(Cycloalkyl)amino, or Cycloalkylthio or C-C- alkylene group and R7 is joined together with R to form a haloalkylthio. C-C-alkylene group, wherein one or both of said C-C- For next additional compounds of any of the additional alkylene groups are optionally substituted by one or more compounds mentioned here-above or beneath, Y is C C-C-alkyl or cycloalkyl radicals. wherein C is substituted by R'" which is C-C-alkenyl, or 30 If R is joined together with R to form a C-C-alkylene Cycloalkyl, or Cycloalkyloxy, or Cycloalkylamino, or (C- group and R is joined together with R to form a C-C- C-alkyl)-(Cycloalkyl)amino, or Cycloalkylthio or C-C- alkylene group a spiro compound is formed, wherein said haloalkylthio. C-C-alkylene groups are preferably ethylene groups. One For next additional compounds of any of the additional or both of said C-C-alkylene groups are optionally Substi compounds mentioned here-above, Y is C wherein C is sub 35 tuted by one or more C-C-alkyl or cycloalkyl radicals. stituted by R' which is C-C-alkenyl, or Cycloalkyl, or The group (CRR), represents a C-C-alkylene group, Cycloalkyloxy, or Cycloalkylamino, or (C-C-alkyl)-(Cy preferably an ethylene group, which is unsubstituted or is cloalkyl)amino, or Cycloalkylthio or C-C-haloalkylthio. substituted by R’=C-C-alkyl and/or by R-C-C-alkyl, The compounds according to formula (Ib) and the addi Cycloalkyl, hydroxy, C-C-alkyloxy, phenyl C-C-alky tional compounds are also included in the terms “compounds 40 loxy, hydroxy C-C-alkyl, C-C-alkyloxy C-C-alkyl, according to this invention'. phenyl C-C-alkyloxy C-C-alkyl, thiol C-C-alkyl, The present invention also relates to compounds of formula C-C-alkylthio C-C-alkyl, phenyl C-C-alkylthio C-C- (I) and pharmaceutically acceptable Solvates, N-oxides, salts alkyl, hydroxycarbonyl, hydroxycarbonyl C-C-alkyl, and prodrugs thereof and their use as a medicament. In the C-C-alkyloxycarbonyl, C-C-alkyloxycarbonyl C-C- compounds of the formula (I) the radicals, indices and groups 45 alkyl, aminocarbonyl, aminocarbonyl C-C-alkylaminocar have the following meanings: bonyl, C-C-alkylaminocarbonyl (C-C-alkyl), di(C-C- R" is halogen, C-C-alkyl, C-C-alkyloxy, C-C-alky alkyl)aminocarbonyl, di(C-C-alkyl)aminocarbonyl (C- lthio, C-C-alkenyl, C-C-alkynyl, C-C-alkyloxy C-C- Co-alkyl), C-C-alkylamino C-C-alkyl, di(C-C-alkyl) alkyl, C-C-alkylthio C-C-alkyl, C-C-alkyl carbonyl, amino C-C-alkyl, or phenyl, phenyl C-C-alkyl, wherein C-C-alkenyl carbonyl, SFs, C-C-alkyl Sulfonyl, wherein 50 each phenyl group is optionally Substituted by hydroxy or each of the carbon-containing radicals optionally is Substi C-C-alkyloxy, preferably the group (CRR), represents a tuted by one or more halogen atoms, preferably fluorine C-C-alkylene group, preferably an ethylene group, which is atoms, unsubstituted or substituted by C-C-alkyl. R is hydrogen, halogen, C-C-alkyl, C-C-alkyloxy, The substructure A-B(R)-(CRR)-D(R)-E represents a C-C-alkylthio, C-C-alkenyl, C-C-alkynyl, C-C-alky 55 chain of 3 to 7 chain atoms, preferably of 4 to 6 chain atoms. loxy C-C-alkyl, C-C-alkylthio C-C-alkyl, C-C-alkyl In a preferred embodiment A-B(R)-(CRR)-D(R)-E carbonyl, C-C-alkenyl carbonyl, wherein each of the car represents an ethylenediamine, propylenediamine or buty bon-containing radicals optionally is Substituted by one or lenediamine chain, which is unsubstituted or substituted as more halogen atoms, preferably fluorine atoms defined in formula (I) above. R is hydrogen, C-C-alkyl or cycloalkyl, preferably 60 In another preferred embodiment A-B(R)-(CRR)-D hydrogen. (R)-E represents a semicarbazide chain with B(R), D(R) X is a carbonyl, thiocarbonyl or Sulfonyl group, preferably and E being NH, Abeing a bond, n=1, and Wand R' forming a carbonyl group. an OXO-group. R" is hydrogen, C-C-alkyl or cycloalkyl, preferably In another preferred embodiment A-B(R)-(CRR)-D hydrogen. 65 (R)-E represents a semicarbazide chain with B(R), D(R) R is hydrogen, C1-Co-alkyl, cycloalkyl, acyl or C1-Co and Abeing NH, E being a bond, n=1, and Rand R7 forming alkyloxycarbonyl. an OXO-group. US 8,877,934 B2 11 12 In another preferred embodiment A-B(R)-(CRR)-D nitrogen, Sulphur and oxygen, which is unsubstituted or Sub (R)-E represents a thiosemicarbazide chain with B(R), stituted by one or two radicals from the group of C-C-alkyl, D(R) and E being NH. A being a bond, n=1, and Rand R' C-C-alkyloxy and C-C-alkylthio, or an unsaturated, forming a thioxo-group. monocyclic orbicyclic ring system with 5 to 6 ring atoms, one In another preferred embodiment A-B(R)–(CRR)-D or two ring heteroatoms, which is unsubstituted, etc. (R)-E represents a thiosemicarbazide chain with B(R), The group of the formula (A) preferably represents a pyri D(R) and A being NH, E being a bond, n=1, and Rand R' dine (Y', Y, Y- and Y are C), pyrimidine, quinoline, forming a thioxo-group. quinazoline, thienopyrimidine, thienopyridine, triazolopyri In another preferred embodiment A-B(R)-(CRR7)-D midine, pyridopyridine, pyrrolopyridine, pyrazolopyrimi (R)-E represents an ethylamine or propylamine chain with A 10 dine, pyrazolopyridine, furopyridine, 2,3-dihydrofuropyri and E being a bond, B being N, D(R) being CH, CH(C- dine, 2,3-dihydro-1,4-dioxinopyridine, furopyrimidine, Co-alkyl) or C(C-C-alkyl), and n=1 or 2. pyridazine or cinnoline group, wherein each group is option The integer n is from 1 to 3, and is preferably 2. If n is larger ally substituted by one or more radicals, preferably by one or than 1 the CRR-groups can be identical or different. two radicals, selected from the group of C-C-alkyl, C-C- The group of the formula (A) in formula (I) and formula 15 alkenyl, Cycloalkyl, Cycloalkyloxy, C-C-haloalkyl, C-C- (II) alkoxy, C-C-haloalkoxy, halogen, nitrilo, nitro, amino, C-C-alkylamino, Cycloalkylamino, di(C-C-alkyl)amino, (C-C-alkyl)-(Cycloalkyl)amino, N-pyrrolidinyl, N-pip Formula (A) eridinyl, N-morpholinyl, thiol, hydroxy, C-C-alkylthio. Cycloalkylthio, C-C-haloalkylthio, C-C-alkyl carbonyl, C-C-alkylcarbonylamino, aminocarbonyl, C-C-alky Y.O laminocarbonyl, di(C-C-alkyl)aminocarbonyl, C-C- n N alkoxycarbonyl, dioxolane Such as 1,3-dioxolane, dioxane Such as 1,3-dioxane, or dioxepane Such as 1,3-dioxepane, represents a mono- or polycyclic heterocyclic ring system. 25 wherein each ring is unsubstituted or Substituted by C-C- A monocyclic ring system is obtained if the carbon/nitrogen alkyl. atoms Y', Y, Y- and Y are unsubstituted or substituted but In another preferred embodiment the group of formula (A) not joined together. A polycyclic ring system is obtained if is a pyridine, pyrimidine, quinoline, quinazoline, thienopyri either Y and Y are joined together or Y and Y are joined midine or thienopyridine group, wherein each group is together or both Y and Y as well as Y and Y are joined 30 optionally substituted by one or more radicals, preferably by together. one or two radicals, selected from the group of C-C-alkyl, A ring system formed by joining together Y and Y is a C-C-haloalkyl, C-C-alkoxy, C-C-haloalkoxy, nitrilo, saturated or non-Saturated ring system (e.g. an aromatic ring nitro, amino, C-C-alkylamino, di(C-C-alkyl)amino, system). The ring system itself is a monocyclic or polycyclic N-pyrrolidinyl, N-piperidinyl, N-morpholinyl, thiol, ring system, preferably a monocyclic, bicyclic or tricyclic, 35 hydroxy, C-C-alkylthio. C-C-alkyl carbonyl, aminocar preferably a monocyclic or bicyclic ring system. The ring bonyl, C-C-alkylaminocarbonyl, di(C-C-alkyl)ami system contains from 4 to 10 ring atoms, preferably from 5 to nocarbonyl, dioxolane Such as 1,3-dioxolane, dioxane Such as 8 ring atoms, more preferably from 5 to 6 ring atoms, wherein 1,3-dioxane, or dioxepane Such as 1,3-dioxepane, wherein the number of ring atoms includes Y andY. The ring system each ring is unsubstituted or Substituted by C-C-alkyl. optionally contains one or more, preferably one, two or three, 40 In another preferred embodiment the group of formula (A) more preferably one or two, ring heteroatoms, such as nitro is a pyridine, pyrimidine, quinoline, quinazoline, thienopyri gen, Sulfur or oxygen. The ring system is unsubstituted or midine or thienopyridine group (preferably a pyridine, pyri substituted, preferred substituents are one or more, preferably midine or quinoline group), wherein each group is optionally one, two or three, more preferably one or two, radicals substituted by one or more radicals, preferably by one or two selected from the group of C-C-alkyl, C-C-alkyloxy, 45 radicals, selected from the group of C-C-haloalkyl, C-C- C-C-alkoxycarbonyl and C-C-alkylthio. alkoxy, C-C-haloalkoxy, amino, C-C-alkylamino, di(C- A ring system formed by joining together Y and Y is a C-alkyl)amino, N-pyrrolidinyl, N-piperidinyl, N-morpholi saturated or non-Saturated ring system (e.g. an aromatic ring nyl, C-C-alkylthio, C-C-alkoxycarbonyl, dioxolane Such system). The ring system itself is a monocyclic or polycyclic as 1,3-dioxolane, dioxane Such as 1,3-dioxane, or dioxepane ring system, preferably a monocyclic, bicyclic or tricyclic, 50 Such as 1,3-dioxepane, each ring is unsubstituted or Substi preferably a monocyclic or bicyclic ring system. The ring tuted by C-C-alkyl. system contains from 4 to 10 ring atoms, preferably from 5 to In another preferred embodiment the group of formula (A) 8 ring atoms, more preferably from 5 to 6 ring atoms, wherein is a pyridine, pyrimidine or quinoline group, preferably a the number of ring atoms includes Y andY. The ring system pyridine or pyrimidine group, wherein each group is option optionally contains one or more, preferably one, two or three, 55 ally substituted by one or more radicals, preferably by one or more preferably one or two, ring heteroatoms, such as nitro two radicals, selected from the group of C-C-alkyl, C-C- gen, Sulfur or oxygen. The ring system is unsubstituted or haloalkyl, C-C-alkoxy, C-C-haloalkoxy, nitrilo, nitro, substituted, preferred substituents are one or more, preferably amino, C-C-alkylamino, di(C-C-alkyl)amino, N-pyrro one, two or three, more preferably one or two, radicals lidinyl, N-piperidinyl, N-morpholinyl, thio, C-C-alkylthio. selected from the group of C-C-alkyl, C-C-alkyloxy, 60 C-C-alkyl carbonyl, aminocarbonyl, C-C-alkylaminocar C-C-alkoxycarbonyl and C-C-alkylthio. bonyl, di(C-C-alkyl)aminocarbonyl, C-C-alkoxycarbo The mentioning of the preferred embodiments of the ring nyl, dioxolane Such as 1,3-dioxolane, dioxane Such as 1,3- system formed by joining togetherY' and Y and/orY andY. dioxane, or dioxepane Such as 1,3-dioxepane, wherein each is intended to disclose all combinations of the preferred ring is unsubstituted or Substituted by C-C-alkyl. embodiments, including but not limited to a saturated, mono 65 In another preferred embodiment the group of formula (A) cyclic, bicyclic or tricyclic ring system with 4 to 10 ring is a pyridine or quinoline group, preferably a pyridine group, atoms, one, two or three ring heteroatoms from the group of wherein each group is optionally substituted by one or more US 8,877,934 B2 13 14 radicals, preferably by one or two radicals, selected from the bonyl, di(C-C-alkyl)aminocarbonyl, C-C-alkoxycarbo group of C-C-alkyl, C-C-haloalkyl, C-C-alkoxy, nyl, phenyl, dioxolane Such as 1,3-dioxolane, dioxane Such as C-C-haloalkoxy, amino, C-C-alkylamino, di(C-C- 1,3-dioxane, or dioxepane Such as 1,3-dioxepane, each said alkyl)amino, N-pyrrolidinyl, N-piperidinyl, N-morpholinyl, ring being unsubstituted or Substituted by C-C-alkyl, C-C-alkylthio, dioxolane Such as 1,3-dioxolane, dioxane Y is C or N, wherein C is substituted by R' which is Such as 1,3-dioxane, or dioxepane Such as 1,3-dioxepane, hydrogen, halogen, C-C-alkyl, C-C-alkenyl, Cycloalkyl, each ring is unsubstituted or substituted by C-C-alkyl. Cycloalkyloxy, C-C-haloalkyl, C-C-alkoxy, C-C-ha In another preferred embodiment the group of formula (A) loalkoxy, nitrilo, nitro, amino, C-C-alkylamino, Cycloalky is a pyrimidine group, which is optionally Substituted by one lamino, di(C-C-alkyl)amino, (C-C-alkyl)-(Cycloalkyl) or more radicals, preferably by one or two radicals, selected 10 amino, N-pyrrolidinyl, N-piperidinyl, N-morpholinyl, thiol, from the group of C-C-alkyl, C-C-alkoxy, C-C-ha hydroxy, C-C-alkylthio, Cycloalkylthio, C-C-haloalky loalkoxy, amino, C-C-alkylamino, di(C-C-alkyl)amino, lthio, C-C-alkyl carbonyl, C-C-haloalkyl carbonyl, ami N-pyrrolidinyl, N-piperidinyl, N-morpholinyl, C-C-alky nocarbonyl, C-C-alkylaminocarbonyl, di(C-C-alkyl) lthio. aminocarbonyl, C-C-alkylcarbonylamino, C-C- In another preferred embodiment of all of the embodiments 15 alkoxycarbonyl, dioxolane Such as 1,3-dioxolane, dioxane of compounds according to the invention as described here Such as 1,3-dioxane, or dioxepane Such as 1,3-dioxepane, in, in the group of formula (A) no more than one of R', R', each said ring being unsubstituted or Substituted by C-C- R'' and R' represents a halogen atom, more preferably the alkyl, group of formula (A) contains no more than one halogenatom Y is C or N, wherein C is substituted by R'" which is in total. hydrogen, halogen, C-C-alkyl, C-C-alkenyl, Cycloalkyl, Preferably at least two of A, B, D and E contain a nitrogen Cycloalkyloxy, C-C-haloalkyl, C-C-alkoxy, C-C-ha atom. More preferably at least one of A and B and at least one loalkoxy, nitrilo, nitro, amino, C-C-alkylamino, Cycloalky of D and E contains a nitrogenatom, even more preferred one lamino, di(C-C-alkyl)amino, (C-C-alkyl)-(Cycloalkyl) of A and B and one of D and E contains a nitrogen atom. amino, N-pyrrolidinyl, N-piperidinyl, N-morpholinyl, thiol, In some embodiments each of A, B, D and E contains a 25 hydroxy, C-C-alkylthio, Cycloalkylthio, C-C-haloalky nitrogen atom. In other embodiments each of A, B and D, or lthio, C-C-alkyl carbonyl, C-C-haloalkyl carbonyl, each of A, B and E, or each of A, D and E, or each of B, D and C-C-alkylcarbonylamino, aminocarbonyl, C-C-alky E contains a nitrogenatom. In still other embodiments each of laminocarbonyl, di(C-C-alkyl)aminocarbonyl, C-C- A and D, or each of B and E, or each of B and D contains a alkoxycarbonyl, dioxolane Such as 1,3-dioxolane, dioxane nitrogen atom. 30 Such as 1,3-dioxane, or dioxepane Such as 1,3-dioxepane, In some embodiments B is N, D is N and each of A and E each said ring being unsubstituted or Substituted by C-C- is a bond. In other embodiments A is NR, B is CR'', D is N, alkyl, and E is a bond, or A is NR, B is N. D is N and E is a bond, Y is C or N, wherein C is substituted by R' which is or A is a bond, B is N, D is N and E is NR, or A is a bond, B hydrogen, halogen, C-C-alkyl, C-C-alkenyl, Cycloalkyl, is N, D is CR'' and E is NR, wherein R to R'' areas defined 35 Cycloalkyloxy, C-C-haloalkyl, C-C-alkoxy, C-C-ha above. loalkoxy, nitrilo, nitro, amino, C-C-alkylamino, Cycloalky In a preferred compound of formula (I) lamino, di(C-C-alkyl)amino, (C-C-alkyl)-(Cycloalkyl) R" is halogen, C, -Co-alkyl, C1-Co-alkyloxy, C, -Co-alky amino, N-pyrrolidinyl, N-piperidinyl, N-morpholinyl, lthio, C-C-alkenyl, C-C-alkynyl, C-C-alkyloxy C-C- C-C-alkylthio. C-C-haloalkylthio, C-C-alkyl carbonyl, alkyl, C-C-alkylthio C-C-alkyl, C-C-alkyl carbonyl, 40 C-C-haloalkyl carbonyl, C-C-alkylcarbonylamino, ami C-C-alkenyl carbonyl, SFs, C-C-alkyl Sulfonyl, wherein nocarbonyl, C-C-alkylaminocarbonyl, di(C-C-alkyl) each of the carbon-containing radicals optionally is Substi aminocarbonyl, C-C-alkoxycarbonyl, phenyl, dioxolane tuted by one or more halogen atoms, preferably fluorine Such as 1,3-dioxolane, dioxane Such as 1,3-dioxane, or diox atoms, epane Such as 1,3-dioxepane, each said ring being unsubsti R’ is hydrogen, 45 tuted or substituted by C-C-alkyl, R is hydrogen, orY and Y and/orY and Y are joined together to forma R" is hydrogen or C-C-alkyl, preferably hydrogen, ring System, R is hydrogen, C1-Co-alkyl, acyl or C1-Co-alkyloxycar and wherein at least one of B and D is a nitrogen atom. bonyl, A preferred compound has the formula (II), (CRR), is a C-C-alkylene group, preferably an ethyl 50 ene group, which is optionally substituted by one or more C-C-alkyl radicals, A is a bond or NR’, wherein R is H or C-C-alkyl, Formula (II) E is a bond or NR, wherein R is H or C-C-alkyl, B is N or CR', wherein R' is H or C-C-alkyl, 55 D is N or CR'', wherein R'' is H or C-C-alkyl, X is a carbonyl, thiocarbonyl or Sulfonyl group, preferably a carbonyl group, Y' is C or N, wherein C is substituted by R' which is hydrogen, halogen, C-C-alkyl, C-C-alkenyl, Cycloalkyl, 60 Cycloalkyloxy, C-C-haloalkyl, C-C-alkoxy, C-C-ha loalkoxy, nitrilo, nitro, amino, C-C-alkylamino, Cycloalky lamino, di(C-C-alkyl)amino, (C-C-alkyl)-(Cycloalkyl) amino, N-pyrrolidinyl, N-piperidinyl, N-morpholinyl, C-C-alkylthio, Cycloalkylthio, C-C-haloalkylthio. 65 wherein C-C-alkyl carbonyl, C-C-haloalkyl carbonyl, C-C- R" is C1-Co-alkyl, C-C-alkyloxy C, -Co-alkyl, or C-C- alkylcarbonylamino, aminocarbonyl, C-C-alkylaminocar alkylthio C-C-alkyl, wherein each of the carbon-containing US 8,877,934 B2 15 16 radicals is unsubstituted or substituted by one or more halo or substituted by one or more halogen atoms, preferably by gen atoms, preferably by one or more fluorine atoms, e.g. by one or more fluorine atoms, e.g. by 1 to 10, preferably by 1 to 1 to 10, preferably by 1 to 5, fluorine atoms, 5, fluorine atoms, R is hydrogen, C1-Co-alkyl, hydroxy, C1-Co-alkyloxy, Y' is C or N, wherein C is substituted by R' which is H, or phenyl C-C-alkyloxy, hydroxy C-C-alkyl, C-C-alky C-C-alkyl, loxy C-C-alkyl, phenyl C-C-alkyloxy C-C-alkyl, thiol Y is C, wherein C is substituted by R' is H, C, -Co-alkoxy, C-C-alkyl, C-C-alkylthio C-C-alkyl, phenyl C-C- C-C-alkyl carbonyl, Cycloalkyl, Cycloalkyloxy, C-C- alkylthio C-C-alkyl, hydroxycarbonyl, hydroxycarbonyl alkylthio. C-C-alkyl, C-C-alkyloxycarbonyl, C-C-alkyloxycar Y is C, wherein C is substituted by R'' is H. C-C-alkoxy, 10 C-C-alkyl carbonyl, Cycloalkyl, Cycloalkyloxy, C-C- bonyl C-C-alkyl, aminocarbonyl, aminocarbonyl C-C- alkylthio. alkyl, C-C-alkylaminocarbonyl, C-C-alkylaminocarbo Y is C, wherein C is substituted by R' is H. C-C-alkoxy, nyl (C-C-alkyl), di(C-C-alkyl)aminocarbonyl, di(C-C- C-C-alkylthio. alkyl)aminocarbonyl (C-C-alkyl), C-C-alkylamino orY andYorY and Y are joined together to form a 5- or C-C-alkyl, di(C-C-alkyl)amino C-C-alkyl, phenyl, 15 6-membered ring system. phenyl C-C-alkyl, wherein each phenyl group is optionally In a preferred compound of the formula (I) or (II) substituted by hydroxy or C-C-alkyloxy, preferably R' is R’ is hydrogen, hydrogen, C-C-alkyl, hydroxycarbonyl, hydroxycarbonyl R is hydrogen, C-C-alkyl, C-C-alkyloxycarbonyl, C-C-alkyloxycar R" is hydrogen or C-C-alkyl, preferably hydrogen, bonyl C-C-alkyl, aminocarbonyl, aminocarbonyl C-C- R is hydrogen or C1-Co-alkyl, preferably hydrogen, alkyl, C-C-alkylaminocarbonyl, C-C-alkylaminocarbo R is hydrogen or C-C-alkyl, preferably hydrogen, nyl (C-C-alkyl), di(C-C-alkyl)aminocarbonyl, di(C-C- R’ is hydrogen, alkyl)aminocarbonyl (C-C-alkyl), phenyl, phenyl C-C- X is a carbonyl group, alkyl, more preferably R is hydrogen or C-C-alkyl, even n is 2. more preferably hydrogen, 25 the group of formula (A) represents a pyridine, pyrimidine R’ is hydrogen or C-C-alkyl, preferably hydrogen, or quinoline group, preferably a pyridine or pyrimidine n is 2 or 3, preferably 2, group, more preferably a pyridine group, wherein each Y' is C or N, wherein C is substituted by R' which is group is optionally Substituted by one or more radicals, hydrogen, halogen, C-C-alkyl, C-C-haloalkyl, C-C- preferably by one or two radicals, selected from the alkoxy, C-C-haloalkoxy, Cycloalkyl, Cycloalkyloxy, 30 group of C-C-alkyl, C-C-haloalkyl, C-C-alkoxy, Cycloalkoxy, C-C-haloalkoxy, nitrilo, nitro, amino, nitrilo, nitro, amino, C-C-alkylamino, di(C-C-alkyl) C-C-alkylamino, di(C-C-alkyl)amino, N-pyrrolidi amino, C-C-alkylthio. C-C-alkyl carbonyl, aminocarbo nyl. N-piperidinyl, N-morpholinyl, thio. C-C-alky nyl, C-C-alkylaminocarbonyl, di(C-C-alkyl)aminocar lthio, C-C-alkyl carbonyl, aminocarbonyl, C-C- bonyl, 35 alkylaminocarbonyl, di(C-C-alkyl)aminocarbonyl, Y is C or N, preferably C, wherein C is substituted by R' dioxolane Such as 1,3-dioxolane, dioxane Such as 1,3- which is hydrogen, halogen, C-C-alkyl, C-C-haloalkyl, dioxane, or dioxepane Such as 1,3-dioxepane, wherein C-C-alkoxy, C-C-haloalkoxy, Cycloalkyl, Cycloalky each ring is unsubstituted or Substituted by C-C-alkyl, loxy, nitrilo, nitro, amino, C-C-alkylamino, di(C-C- and one of A and B and one of D and E contains a alkyl)amino, N-pyrrolidinyl, N-piperidinyl, N-morpholinyl, 40 nitrogen atom. C-C-alkylthio, C-C-alkyl carbonyl, aminocarbonyl, In another preferred compound of the formula (I) or (II) C-C-alkylaminocarbonyl, di(C-C-alkyl)aminocarbonyl, R" is C-C-alkyl which is unsubstituted or substituted by dioxolane Such as 1,3-dioxolane, dioxane Such as 1,3-diox one or more halogen atoms, preferably by one or more fluo ane, or dioxepane Such as 1,3-dioxepane, each said ring being rine atoms, e.g. by 1 to 10, preferably by 1 to 5, fluorine atoms. unsubstituted or substituted by C-C-alkyl, 45 In another preferred compound of the formula (II) the Y is C or N, preferably C, wherein C is substituted by R' group of the formula (A) which is hydrogen, halogen, C-C-alkyl, C-C-haloalkyl, C-C-alkoxy, C-C-haloalkoxy, Cycloalkyl, Cycloalky loxy, nitrilo, nitro, amino, C-C-alkylamino, di(C-C- Formula (A) alkyl)amino, N-pyrrolidinyl, N-piperidinyl, N-morpholinyl, 50 Y C-C-alkylthio, C-C-alkyl carbonyl, aminocarbonyl, C-C-alkylaminocarbonyl, di(C-C-alkyl)aminocarbonyl, Y.O Y2 dioxolane Such as 1,3-dioxolane, dioxane Such as 1,3-diox N ane, or dioxepane Such as 1,3-dioxepane, each said ring being unsubstituted or substituted by C-C-alkyl, 55 represents a pyridine, pyrimidine, quinoline, quinazoline, Y is C or N, preferably C, wherein C is substituted by R' thienopyrimidine, thienopyridine, triazolopyrimidine, which is hydrogen, halogen, C-C-alkyl, C-C-haloalkyl, pyridopyridine, pyrrolopyridine, pyrazolopyrimidine, C-C-alkoxy, C-C-haloalkoxy, nitrilo, nitro, amino, pyrazolopyridine, furopyridine, 2,3-dihydrofuropyri C-C-alkylamino, di(C-C-alkyl)amino, C-C-alkylthio. dine, 2,3-dihydro-1,4-dioxinopyridine, furopyrimidine, C-C-alkyl carbonyl, aminocarbonyl, C-C-alkylaminocar 60 pyridazine or cinnoline group, wherein each group is bonyl, di(C-C-alkyl)aminocarbonyl, optionally substituted by one or more radicals, prefer orY and Y and/orY and Y are joined together to form a ably by one or two radicals, selected from the group of 5- or 6-membered ring system. C-C-alkyl, Cycloalkyl, Cycloalkoxy, C-C-ha In a preferred compound of the formula (II) loalkyl, C-C-alkoxy, C-C-haloalkoxy, nitrilo, nitro, R" is C, -Co-alkyl, C, -Co-alkyloxy C, -Co-alkyl, or C1-Co 65 amino, C-C-alkylamino, di(C-C-alkyl)amino, alkylthio C-C-alkyl, di-(C-C-alkyl)amino-C-C-alkyl, N-pyrrolidinyl, N-piperidinyl, N-morpholinyl, thiol, wherein each of the carbon-containing radicals unsubstituted hydroxyl, C-C-alkylthio, C-C-alkyl carbonyl, ami US 8,877,934 B2 17 18 nocarbonyl, C-C-alkylaminocarbonyl, di(C-C- salts thereof and their use for treating a helminth infection. In alkyl)aminocarbonyl, C-C-alkoxycarbonyl, diox the compounds of the formula (Ia) the radicals, indices and olane Such as 1,3-dioxolane, dioxane Such as 1,3- groups have the following meanings: dioxane, or dioxepane Such as 1,3-dioxepane, wherein R" is hydrogen, halogen, C1-Co-alkyl, C1-Co-alkyloxy, each ring is unsubstituted or Substituted by C-C-alkyl. C-C-alkylthio, C-C-alkenyl, C-C-alkynyl, C-C-alky In another preferred embodiment the group of formula (A) loxy C-C-alkyl, C-C-alkylthio C-C-alkyl, amino, is a pyridine, pyrimidine, quinoline, quinazoline, thienopyri C-C-alkylamino, di-(C-C-alkyl)amino, C-C-alky midine or thienopyridine group, wherein each group is lamino-C-C-alkyl, di-(C-C-alkyl)amino-C-C-alkyl, optionally substituted by one or more radicals, preferably by C-C-alkyl carbonyl, C-C-alkyloxy carbonyl, C-C-alk one or two radicals, selected from the group of C-C-alkyl, 10 enyl carbonyl, wherein each of the carbon-containing radicals C-C-haloalkyl, C-C-alkoxy, C-C-haloalkoxy, nitrilo, optionally is Substituted by one or more halogen atoms, pref nitro, amino, C-C-alkylamino, di(C-C-alkyl)amino, erably fluorine atoms, or R' is phenyl, furanyl, imidazolinyl, N-pyrrolidinyl, N-piperidinyl, N-morpholinyl, C-C-alky or thiophenyl, wherein each of the rings optionally is Substi lthio, C-C-alkyl carbonyl, aminocarbonyl, C-C-alky tuted by one or more radicals from the group of C-C-alkyl laminocarbonyl, di(C-C-alkyl)aminocarbonyl, C-C- 15 and halogen, preferably fluorine, alkoxycarbonyl, dioxolane Such as 1,3-dioxolane, dioxane R is hydrogen, halogen, C-C-alkyl, C-C-alkyloxy, Such as 1,3-dioxane, or dioxepane Such as 1,3-dioxepane, C-C-alkylthio, C-C-alkenyl, C-C-alkynyl, C-C-alky wherein each ring is unsubstituted or Substituted by C-C- loxy C-C-alkyl, C-C-alkylthio C-C-alkyl, amino, alkyl. C-C-alkylamino, di-(C-C-alkyl)amino, C-C-alky In another preferred embodiment the group of formula (A) lamino-C-C-alkyl, di-(C-C-alkyl)amino-C-C-alkyl, is a pyridine, pyrimidine, quinoline, quinazoline, thienopyri C-C-alkyl carbonyl, C-C-alkyloxy carbonyl, C-C-alk midine or thienopyridine group (preferably a pyridine, pyri enyl carbonyl, wherein each of the carbon-containing radicals midine or quinoline group), wherein each group is optionally optionally is Substituted by one or more halogen atoms, pref substituted by one or more radicals, preferably by one or two erably fluorine atoms, or R is phenyl, furanyl, imidazolinyl, radicals, selected from the group of C-C-alkyl, C-C-ha 25 or thiophenyl, wherein each of the rings optionally is Substi loalkyl, C-C-alkoxy, C-C-haloalkoxy, amino, C-C- tuted by one or more radicals from the group of C-C-alkyl alkylamino, di(C-C-alkyl)amino, N-pyrrolidinyl. N-pip and halogen, preferably fluorine, preferably R is hydrogen, eridinyl, N-morpholinyl, C-C-alkylthio, dioxolane such as R is hydrogen or C-C-alkyl, preferably hydrogen. 1,3-dioxolane, dioxane Such as 1,3-dioxane, or dioxepane X is a carbonyl or Sulfonyl group, preferably a carbonyl Such as 1,3-dioxepane, each ring is unsubstituted or Substi 30 group. tuted by C-C-alkyl. R" is hydrogen or C1-Co-alkyl, preferably hydrogen. In another preferred embodiment the group of formula (A) R is hydrogen, C, -Co-alkyl or acyl, preferably hydrogen. is a pyridine, pyrimidine or quinoline group, preferably a R is hydrogen, C-C-alkyl, hydroxy, C-C-alkyloxy, pyridine or pyrimidine group, wherein each group is option phenyl C-C-alkyloxy, hydroxy C-C-alkyl, C-C-alky ally substituted by one or more radicals, preferably by one or 35 loxy C-C-alkyl, phenyl C-C-alkyloxy C-C-alkyl, thiol two radicals, selected from the group of C-C-alkyl, C-C- C-C-alkyl, C-C-alkylthio C-C-alkyl, phenyl C-C- haloalkyl, C-C-alkoxy, C-C-haloalkoxy, nitrilo, nitro, alkylthio C-C-alkyl, hydroxycarbonyl, hydroxycarbonyl amino, C-C-alkylamino, di(C-C-alkyl)amino, N-pyrro C-C-alkyl, C-C-alkyloxycarbonyl, C-C-alkyloxycar lidinyl, N-piperidinyl, N-morpholinyl, thio, C-C-alkylthio. bonyl C-C-alkyl, aminocarbonyl, aminocarbonyl C-C- C-C-alkyl carbonyl, aminocarbonyl, C-C-alkylaminocar 40 alkyl, C-C-alkylaminocarbonyl, C-C-alkylaminocarbo bonyl, di(C-C-alkyl)aminocarbonyl, dioxolane Such as 1,3- nyl (C-C-alkyl), di(C-C-alkyl)aminocarbonyl, di(C-C- dioxolane, dioxane Such as 1,3-dioxane, or dioxepane Such as alkyl)aminocarbonyl (C-C-alkyl), C-C-alkylamino 1,3-dioxepane, wherein each ring is unsubstituted or Substi C-C-alkyl, di(C-C-alkyl)amino C-C-alkyl, phenyl, tuted by C-C-alkyl, and preferably selected from the group phenyl C-C-alkyl, wherein each phenyl group is optionally of C-C-alkyl, C-C-alkoxy, C-C-haloalkoxy, amino, 45 substituted by hydroxy or C-C-alkyloxy. Preferably R is C-C-alkylamino, di(C-C-alkyl)amino, N-pyrrolidinyl, hydrogen, C-C-alkyl, hydroxycarbonyl, hydroxycarbonyl N-piperidinyl, N-morpholinyl, C-C-alkylthio. C-C-alkyl, C-C-alkyloxycarbonyl, C-C-alkyloxycar In another preferred embodiment the group of formula (A) bonyl C-C-alkyl, aminocarbonyl, aminocarbonyl C-C- is a pyridine or quinoline group, preferably a pyridine group, alkyl, C-C-alkylaminocarbonyl, C-C-alkylaminocarbo wherein each group is optionally Substituted by one or more 50 nyl (C-C-alkyl), di(C-C-alkyl)aminocarbonyl, di(C-C- radicals, preferably by one or two radicals, selected from the alkyl)aminocarbonyl (C-C-alkyl), phenyl, phenyl C-C- group of C-C-alkyl, C-C-haloalkyl, C-C-alkoxy, alkyl, more preferably R is hydrogen or C-C-alkyl. C-C-haloalkoxy, amino, C-C-alkylamino, di(C-C- R’ is hydrogen or C1-Co-alkyl, preferably hydrogen. alkyl)amino, N-pyrrolidinyl, N-piperidinyl, N-morpholinyl, Alternatively RandR together represent an oxo-group or C-C-alkylthio, dioxolane Such as 1,3-dioxolane, dioxane 55 a thioxo-group or R is joined together with R to form a Such as 1,3-dioxane, or dioxepane Such as 1,3-dioxepane, C-C-alkylene group and R7 is joined together with R to each ring is unsubstituted or Substituted by C-C-alkyl. form a C-C-alkylene group, wherein one or both of said In another preferred embodiment the group of formula (A) C-C-alkylene groups are optionally substituted by one or is a pyrimidine group, which is optionally Substituted by one more C-C-alkyl radicals. or more radicals, preferably by one or two radicals, selected 60 If R is joined together with R to form a C-C-alkylene from the group of C-C-alkyl, C-C-alkoxy, C-C-ha group and R7 is joined together with R to form a C-C- loalkoxy, amino, C-C-alkylamino, N-pyrrolidinyl, N-pip alkylene group a spiro compound is formed, wherein said eridinyl, N-morpholinyl, di(C-C-alkyl)amino, C-C-alky C-C-alkylene groups are preferably ethylene groups. One lthio. or both of said C-C-alkylene groups are optionally Substi Use According to this Invention 65 tuted by one or more C-C-alkyl radicals. The present invention also relates to compounds of formula The group (CRR), represents a C-C-alkylene group, (Ia) and pharmaceutically acceptable Solvates, N-oxides and preferably an ethylene group, which is unsubstituted or is US 8,877,934 B2 19 20 substituted by R’=C-C-alkyl and/or by R-C-C-alkyl, the number of ring atoms includes Y andY. The ring system hydroxy, C-C-alkyloxy, phenyl C-C-alkyloxy, hydroxy optionally contains one or more, preferably one, two or three, C-C-alkyl, C-C-alkyloxy C-C-alkyl, phenyl C-C- more preferably one or two, ring heteroatoms, such as nitro alkyloxy C-C-alkyl, thiol C-C-alkyl, C-C-alkylthio gen, Sulfur or oxygen. The ring system is unsubstituted or C-C-alkyl, phenyl C-C-alkylthio C-C-alkyl, hydroxy substituted, preferred substituents are one or more, preferably carbonyl, hydroxycarbonyl C-C-alkyl, C-C-alkyloxycar one, two or three, more preferably one or two, radicals bonyl, C-C-alkyloxycarbonyl C-C-alkyl, aminocarbonyl, selected from the group of C-C-alkyl, C-C-alkyloxy, aminocarbonyl C-C-alkyl, C-C-alkylaminocarbonyl, C-C-alkoxycarbonyl and C-C-alkylthio. C-C-alkylaminocarbonyl (C-C-alkyl), di(C-C-alkyl) A ring system formed by joining together Y and Y is a aminocarbonyl, di(C-C-alkyl)aminocarbonyl (C-C- 10 saturated or non-Saturated ring system (e.g. an aromatic ring alkyl), C-C-alkylamino C-C-alkyl, di(C-C-alkyl)amino system). The ring system itself is a monocyclic or polycyclic C-C-alkyl, or phenyl, phenyl C-C-alkyl, wherein each ring system, preferably a monocyclic, bicyclic or tricyclic, phenyl group is optionally Substituted by hydroxy or C-C- preferably a monocyclic or bicyclic ring system. The ring alkyloxy, preferably the group (CRR), represents a C-C- system contains from 4 to 10 ring atoms, preferably from 5 to alkylene group, preferably an ethylene group, which is 15 8 ring atoms, more preferably from 5 to 6 ring atoms, wherein unsubstituted or substituted by C-C-alkyl. the number of ring atoms includes Y andY. The ring system The substructure A-B(R)-(CRR)-D(R)-E represents a optionally contains one or more, preferably one, two or three, chain of 3 to 7 chain atoms, preferably of 4 to 6 chain atoms. more preferably one or two, ring heteroatoms, such as nitro In a preferred embodiment A-B(R)-(CRR)-D(R)-E gen, Sulfur or oxygen. The ring system is unsubstituted or represents an ethylenediamine, propylenediamine or buty substituted, preferred substituents are one or more, preferably lenediamine chain, which is unsubstituted or substituted as one, two or three, more preferably one or two, radicals defined in formula (I) above. selected from the group of C-C-alkyl, C-C-alkyloxy, In another preferred embodiment A-B(R)-(CRR7)-D C-C-alkoxycarbonyl and C-C-alkylthio. (R)-E represents a semicarbazide chain with B(R), D(R) The mentioning of the preferred embodiments of the ring and E being NH, Abeing a bond, n=1, and RandR forming 25 system formed by joining togetherY' and Y and/orY andY. an OXO-group. is intended to disclose all combinations of the preferred In another preferred embodiment A-B(R)-(CRR)-D embodiments, including but not limited to a saturated, mono (R)-E represents a semicarbazide chain with B(R), D(R) cyclic, bicyclic or tricyclic ring system with 4 to 10 ring and A being NH, E being a bond, n=1, and Wand R' forming atoms, one, two or three ring heteroatoms from the group of an OXO-group. 30 nitrogen, Sulphur and oxygen, which is unsubstituted or Sub In another preferred embodiment A-B(R)-(CRR)-D stituted by one or two radicals from the group of C-C-alkyl, (R)-E represents a thiosemicarbazide chain with B(R), C-C-alkyloxy and C-C-alkylthio, or an unsaturated, D(R) and E being NH. A being a bond, n=1, and Rand R' monocyclic orbicyclic ring system with 5 to 6 ring atoms, one forming a thioxo-group. or two ring heteroatoms, which is unsubstituted, etc. In another preferred embodiment A-B(R)-(CRR7)-D 35 The group of the formula (A) preferably represents a pyri (R)-E represents a thiosemicarbazide chain with B(R), dine (Y', Y, Y- and Y are C), pyrimidine, quinoline, D(R) and A being NH, E being a bond, n=1, and Rand R' quinazoline, thienopyrimidine, thienopyridine, triazolopyri forming a thioxo-group. midine, pyridopyridine, pyrrolopyridine, pyrazolopyrimi In another preferred embodiment A-B(R)-(CRR)-D dine, pyrazolopyridine, furopyridine, 2,3-dihydrofuropyri (R)-E represents an ethylamine or propylamine chain with A 40 dine, 2,3-dihydro-1,4-dioxinopyridine, furopyrimidine, and E being a bond, B being N, D(R) being CH, CH(C- pyridazine or cinnoline group, wherein each group is option C-alkyl) or C(C-C-alkyl), and n=1 or 2. ally substituted by one or more radicals, preferably by one or The integer n is from 1 to 3, and is preferably 2. If n is larger two radicals, selected from the group of C-C-alkyl, C-C- than 1 the CRR-groups can be identical or different. haloalkyl, C-C-alkoxy, C-C-haloalkoxy, halogen, nitrilo, The group of the formula (A) in formula (Ia) 45 nitro, amino, C-C-alkylamino, di(C-C-alkyl)amino, N-pyrrolidinyl, N-piperidinyl, N-morpholinyl, thiol, hydroxy, C-C-alkyl carbonyl, C-C-alkylcarbonylamino, Formula (A) aminocarbonyl, C-C-alkylaminocarbonyl, di(C-C-alkyl) y42N Yl aminocarbonyl, C-C-alkoxycarbonyl, dioxolane such as 50 1,3-dioxolane, dioxane Such as 1,3-dioxane, or dioxepane Y. Y2 Such as 1,3-dioxepane, wherein each ring is unsubstituted or n N1 substituted by C-C-alkyl. In another preferred embodiment the group of formula (A) represents a mono- or polycyclic heterocyclic ring system. is a pyridine, pyrimidine, quinoline, quinazoline, thienopyri A monocyclic ring system is obtained if the carbon/nitrogen 55 midine or thienopyridine group, wherein each group is atoms Y', Y, Y and Y are unsubstituted or substituted but optionally substituted by one or more radicals, preferably by not joined together. A polycyclic ring system is obtained if one or two radicals, selected from the group of C-C-alkyl, either Y and Y are joined together or Y and Y are joined C-C-haloalkyl, C-C-alkoxy, C-C-haloalkoxy, nitrilo, together or both Y and Y as well as Y and Y are joined nitro, amino, C-C-alkylamino, di(C-C-alkyl)amino, together. 60 N-pyrrolidinyl, N-piperidinyl, N-morpholinyl, thiol, A ring system formed by joining together Y and Y is a hydroxy, C-C-alkylthio. C-C-alkyl carbonyl, aminocar saturated or non-Saturated ring system (e.g. an aromatic ring bonyl, C-C-alkylaminocarbonyl, di(C-C-alkyl)ami system). The ring system itself is a monocyclic or polycyclic nocarbonyl, dioxolane Such as 1,3-dioxolane, dioxane Such as ring system, preferably a monocyclic, bicyclic or tricyclic, 1,3-dioxane, or dioxepane Such as 1,3-dioxepane, wherein preferably a monocyclic or bicyclic ring system. The ring 65 each ring is unsubstituted or Substituted by C-C-alkyl. system contains from 4 to 10 ring atoms, preferably from 5 to In another preferred embodiment the group of formula (A) 8 ring atoms, more preferably from 5 to 6 ring atoms, wherein is a pyridine, pyrimidine, quinoline, quinazoline, thienopyri US 8,877,934 B2 21 22 midine or thienopyridine group (preferably a pyridine, pyri amino-C-C-alkyl, C-C-alkyl carbonyl, C-C-alkyloxy midine or quinoline group), wherein each group is optionally carbonyl, or C-C-alkenyl carbonyl, wherein each of the substituted by one or more radicals, preferably by one or two carbon-containing radicals optionally is Substituted by one or radicals, selected from the group of C-C-alkyl, C-C-ha more halogen atoms, preferably fluorine atoms, loalkyl, C-C-alkoxy, C-C-haloalkoxy, amino, C-C- alkylamino, di(C-C-alkyl)amino, N-pyrrolidinyl. N-pip R’ is hydrogen, eridinyl, N-morpholinyl, C-C-alkylthio. C-C- R is hydrogen, alkoxycarbonyl, dioxolane Such as 1,3-dioxolane, dioxane R" is hydrogen or C-C-alkyl, preferably hydrogen, Such as 1,3-dioxane, or dioxepane Such as 1,3-dioxepane, R is hydrogen, C-C-alkyl or acyl, each ring is unsubstituted or Substituted by C-C-alkyl. 10 In another preferred embodiment the group of formula (A) (CRR), is a C-C-alkylene group, preferably an ethyl is a pyridine, pyrimidine or quinoline group, preferably a ene group, which is optionally substituted by one or more pyridine or pyrimidine group, wherein each group is option C-C-alkyl radicals, ally substituted by one or more radicals, preferably by one or A is a bond or NR, wherein R is H or C-C-alkyl, two radicals, selected from the group of C-C-alkyl, C-C- 15 haloalkyl, C-C-alkoxy, C-C-haloalkoxy, nitrilo, nitro. E is a bond or NR, wherein R is H or C-C-alkyl, amino, C-C-alkylamino, di(C-C-alkyl)amino, N-pyrro B is N or CR', wherein R' is H or C-C-alkyl, lidinyl, N-piperidinyl, N-morpholinyl, thio, C-C-alkylthio. C-C-alkyl carbonyl, aminocarbonyl, C-C-alkylaminocar D is N or CR'', wherein R'' is H or C-C-alkyl, bonyl, di(C-C-alkyl)aminocarbonyl, C-C-alkoxycarbo Y' is C or N, wherein C is substituted by R' which is nyl, dioxolane Such as 1,3-dioxolane, dioxane Such as 1,3- hydrogen, C-C-alkyl, C-C-haloalkyl, C-C-alkoxy, dioxane, or dioxepane Such as 1,3-dioxepane, wherein each C-C-haloalkoxy, nitrilo, nitro, amino, C-C-alkylamino, ring is unsubstituted or substituted by C-C-alkyl. di (C-C-alkyl)amino, C-C-alkylthio, C-C-alkyl carbo In another preferred embodiment the group of formula (A) nyl, aminocarbonyl, C-C-alkylaminocarbonyl, di(C-C- is a pyridine or quinoline group, preferably a pyridine group, 25 wherein each group is optionally Substituted by one or more alkyl)aminocarbonyl, C-C-alkoxycarbonyl, phenyl, diox radicals, preferably by one or two radicals, selected from the olane Such as 1,3-dioxolane, dioxane Such as 1,3-dioxane, or group of C-C-alkyl, C-C-haloalkyl, C-C-alkoxy, dioxepane Such as 1,3-dioxepane, each ring being unsubsti C-C-haloalkoxy, amino, C-C-alkylamino, di(C-C- tuted or substituted by C-C-alkyl, alkyl)amino, N-pyrrolidinyl, N-piperidinyl, N-morpholinyl, 30 C-C-alkylthio, dioxolane Such as 1,3-dioxolane, dioxane Y is C or N, wherein C is substituted by R' which is such as 1,3-dioxane, or dioxepane such as 1,3-dioxepane, hydrogen, C-C-alkyl, C-C-haloalkyl, C-C-alkoxy, each ring is unsubstituted or substituted by C-C-alkyl. C-C-haloalkoxy, nitrilo, nitro, amino, C-C-alkylamino, In another preferred embodiment the group of formula (A) di(C-C-alkyl)amino, N-pyrrolidinyl, N-piperidinyl, is a pyrimidine group, which is optionally Substituted by one 35 N-morpholinyl, thiol, hydroxy, C-C-alkylthio, C-C-alkyl or more radicals, preferably by one or two radicals, selected carbonyl, aminocarbonyl, C-C-alkylaminocarbonyl, di(C- from the group of C-C-alkyl, C-C-alkoxy, C-C-ha Co-alkyl)aminocarbonyl, C-C-alkoxycarbonyl, dioxolane loalkoxy, amino, C-C-alkylamino, di(C-C-alkyl)amino, N-pyrrolidinyl, N-piperidinyl, N-morpholinyl, C-C-alky Such as 1,3-dioxolane, dioxane Such as 1,3-dioxane, or diox lthio. 40 epane Such as 1,3-dioxepane, each said ring being unsubsti In another preferred embodiment of all embodiments of the tuted or substituted by C-C-alkyl, use according to the invention, in the group of formula (A) no Y is C or N, wherein C is substituted by R'" which is more than one of R', R', R'' and R' represents a halogen hydrogen, C-C-alkyl, C-C-haloalkyl, C-C-alkoxy, atom, more preferably the group of formula (A) contains no C-C-haloalkoxy, nitrilo, nitro, amino, C-C-alkylamino, more than one halogen atom in total. 45 di(C-C-alkyl)amino, N-pyrrolidinyl, N-piperidinyl, Preferably at least two of A, B, D and E contain a nitrogen N-morpholinyl, thiol, hydroxy, C-C-alkylthio, C-C-alkyl atom. More preferably at least one of A and B and at least one carbonyl, aminocarbonyl, C-C-alkylaminocarbonyl, di(C- of D and E contains a nitrogenatom, even more preferred one of A and B and one of D and E contains a nitrogen atom. Co-alkyl)aminocarbonyl, C-C-alkoxycarbonyl, dioxolane In some embodiments each of A, B, D and E contains a 50 Such as 1,3-dioxolane, dioxane Such as 1,3-dioxane, or diox nitrogen atom. In other embodiments each of A, B and D, or epane Such as 1,3-dioxepane, each said ring being unsubsti each of A, B and E, or each of A, D and E, or each of B, D and tuted or substituted by C-C-alkyl, E contains a nitrogenatom. In still other embodiments each of Y is C or N, wherein C is substituted by R' which is A and D, or each of B and E, or each of B and D contains a hydrogen, C-C-alkyl, C-C-haloalkyl, C-C-alkoxy, nitrogen atom. 55 C-C-haloalkoxy, nitrilo, nitro, amino, C-C-alkylamino, In some embodiments B is N, D is N and each of A and E di (C-C-alkyl)amino, C-C-alkylthio, C-C-alkyl carbo is a bond. In other embodiments A is NR, B is CR'', D is N, nyl, aminocarbonyl, C-C-alkylaminocarbonyl, di(C-C- and E is a bond, or A is NR, B is N, D is N and E is a bond, alkyl)aminocarbonyl, C-C-alkoxycarbonyl, phenyl, diox or A is a bond, B is N, D is N and E is NR, or A is a bond, B olane Such as 1,3-dioxolane, dioxane Such as 1,3-dioxane, or is N, D is CR'' and E is NR, wherein R to R'' areas defined 60 dioxepanesuch as 1,3-dioxepane, each said ring being unsub above. In a preferred compound of formula (Ia) stituted or substituted by C-C-alkyl, R" is hydrogen, halogen, C-C-alkyl, C-C-alkyloxy, orY and Y and/orY and Y are joined together to form a C-C-alkylthio, C-C-alkenyl, C-C-alkynyl, C-C-alky ring System, loxy C-C-alkyl, C-C-alkyloxy C-C-alkyl, C-C-alky 65 and wherein two of A, B, D and E contain a nitrogen atom lthio C-C-alkyl, C-C-alkylamino, di-(C-C-alkyl) and at least one of B and D is a nitrogen atom, preferably B amino, C-C-alkylamino-C-C-alkyl, di-(C-C-alkyl) and D represent a nitrogen atom and A and E are a bond. US 8,877,934 B2 23 24 A preferred compound for use according to the invention C-C-alkylamino, di(C-C-alkyl)amino, N-pyrrolidinyl, has the formula (II) as depicted immediately here-beneath, N-piperidinyl, N-morpholinyl, C-C-alkylthio, C-C-alkyl carbonyl, aminocarbonyl, C-C-alkylaminocarbonyl, di(C- Co-alkyl)aminocarbonyl, dioxolane Such as 1,3-dioxolane, Formula (II) 5 dioxane Such as 1,3-dioxane, or dioxepane Such as 1,3-diox epane, each said ring being unsubstituted or Substituted by C-C-alkyl, Y is C or N, preferably C, wherein C is substituted by R' 10 which is hydrogen, halogen, C-C-alkyl, C-C-haloalkyl, C-C-alkoxy, C-C-haloalkoxy, nitrilo, nitro, amino, C-C-alkylamino, di(C-C-alkyl)amino, C-C-alkylthio. C-C-alkyl carbonyl, aminocarbonyl, C-C-alkylaminocar bonyl, di(C-C-alkyl)aminocarbonyl, phenyl, 15 orY and Y and/orY and Y are joined together to forma 5- or 6-membered ring system. In a preferred compound of the formula (Ila) wherein R" is C1-Co-alkyl, C, -Co-alkyloxy C, -Co-alkyl, or C-C- R" is C, -Co-alkyl, C, -Co-alkyloxy C, -Co-alkyl, or C1-Co alkylthio C-C-alkyl, di-(C-C-alkyl)amino-C-C-alkyl, alkylthio C-C-alkyl, C-C-alkylamino-C-C-alkyl, di wherein each of the carbon-containing radicals unsubstituted (C-C-alkyl)amino-C-C-alkyl, wherein each of the car or substituted by one or more halogen atoms, preferably by bon-containing radicals is unsubstituted or Substituted by one one or more fluorine atoms, e.g. by 1 to 10, preferably by 1 to or more halogen atoms, preferably by one or more fluorine 5, fluorine atoms, atoms, e.g. by 1 to 10, preferably by 1 to 5, fluorine atoms, R is hydrogen, C1-Co-alkyl, hydroxy, C1-Co-alkyloxy, 25 Y' is C or N, wherein C is substituted by R' which is H, or phenyl C-C-alkyloxy, hydroxy C-C-alkyl, C-C-alky C-C-alkyl, loxy C-C-alkyl, phenyl C-C-alkyloxy C-C-alkyl, thiol Y is C, wherein C is substituted by R' is H, C, -Co-alkoxy, C-C-alkyl, C-C-alkylthio C-C-alkyl, phenyl C-C- C-C-alkyl carbonyl, alkylthio C-C-alkyl, hydroxycarbonyl, hydroxycarbonyl 30 Y is C, wherein C is substituted by R'' is H. C-C-alkoxy, C-C-alkyl, C-C-alkyloxycarbonyl, C-C-alkyloxycar C-C-alkyl carbonyl, bonyl C-C-alkyl, aminocarbonyl, aminocarbonyl C-C- Yis C, wherein C is substituted by R' is H, C-C-alkoxy, alkyl, C-C-alkylaminocarbonyl, C-C-alkylaminocarbo orY andYorY and Y are joined together to form a 5- or nyl (C-C-alkyl), di(C-C-alkyl)aminocarbonyl, di(C-C- 6-membered ring system. alkyl)aminocarbonyl (C-C-alkyl), C-C-alkylamino 35 C-C-alkyl, di(C-C-alkyl)amino C-C-alkyl, phenyl, In a preferred compound of the formula (Ia) or (Ila) phenyl C-C-alkyl, wherein each phenyl group is optionally R is hydrogen or C1-Co-alkyl, preferably hydrogen, substituted by hydroxy or C-C-alkyloxy, preferably R' is R is hydrogen or C1-Co-alkyl, preferably hydrogen, hydrogen, C-C-alkyl, hydroxycarbonyl, hydroxycarbonyl C-C-alkyl, C-C-alkyloxycarbonyl, C-C-alkyloxycar 40 R" is hydrogen or C1-Co-alkyl, preferably hydrogen, bonyl C-C-alkyl, aminocarbonyl, aminocarbonyl C-C- R is hydrogen or C1-Co-alkyl, preferably hydrogen, alkyl, C-C-alkylaminocarbonyl, C-C-alkylaminocarbo R is hydrogen or C1-Co-alkyl, preferably hydrogen, nyl (C-C-alkyl), di(C-C-alkyl)aminocarbonyl, di(C-C- alkyl)aminocarbonyl (C-C-alkyl), phenyl, phenyl C-C, R’ is hydrogen, alkyl, more preferably R is hydrogen or C-C-alkyl, even 45 X is a carbonyl group, more preferably hydrogen, n is 2. R’ is hydrogen or C-C-alkyl, preferably hydrogen, the group of formula (A) represents a pyridine, pyrimidine n is 2 or 3, preferably 2, or quinoline group, preferably a pyridine or pyrimidine Y' is C or N, wherein C is substituted by R' which is group, more preferably a pyridine group, wherein each hydrogen, halogen, C-C-alkyl, C-C-haloalkyl, C-C- 50 group is optionally Substituted by one or more radicals, alkoxy, C-C-haloalkoxy, nitrilo, nitro, amino, C-C-alky preferably by one or two radicals, selected from the lamino, di(C-C-alkyl)amino, C-C-alkylthio, C-C-alkyl group of C-C-alkyl, C-C-haloalkyl, C-C-alkoxy, carbonyl, aminocarbonyl, C-C-alkylaminocarbonyl, di(C- C-C-haloalkoxy, nitrilo, nitro, amino, C-C-alky C-alkyl)aminocarbonyl, phenyl, lamino, di(C-C-alkyl)amino, N-pyrrolidinyl, N-pip Y’ is C or N, preferably C, wherein C is substituted by R' 55 eridinyl, N-morpholinyl, thio. C-C-alkylthio, C-C- which is hydrogen, halogen, C-C-alkyl, C-C-haloalkyl, alkyl carbonyl, aminocarbonyl, C-C- C-C-alkoxy, C-C-haloalkoxy, nitrilo, nitro, amino, alkylaminocarbonyl, di(C-C-alkyl)aminocarbonyl, C-C-alkylamino, di(C-C-alkyl)amino, N-pyrrolidinyl, dioxolane Such as 1,3-dioxolane, dioxane Such as 1,3- N-piperidinyl, N-morpholinyl, C-C-alkylthio, C-C-alkyl dioxane, or dioxepane Such as 1,3-dioxepane, wherein carbonyl, aminocarbonyl, C-C-alkylaminocarbonyl, di(C- 60 each ring is unsubstituted or substituted by C-C-alkyl, C-alkyl)aminocarbonyl, dioxolane such as 1,3-dioxolane, and one of A and B and one of D and E contains a dioxane Such as 1,3-dioxane, or dioxepane Such as 1,3-diox nitrogen atom. epane, each said ring being unsubstituted or Substituted by C-C-alkyl, In another preferred compound of the formula (Ia) or (Ila) Y is C or N, preferably C, wherein C is substituted by R' 65 R" is C1-Co-alkyl which is unsubstituted or substituted by which is hydrogen, halogen, C-C-alkyl, C-C-haloalkyl, one or more halogen atoms, preferably by one or more fluo C-C-alkoxy, C-C-haloalkoxy, nitrilo, nitro, amino, rine atoms, e.g. by 1 to 10, preferably by 1 to 5, fluorine atoms. US 8,877,934 B2 25 26 In another preferred compound of the formula (Ila) the C-C-alkylamino, di(C-C-alkyl)amino, N-pyrrolidinyl, group of the formula (A) N-piperidinyl, N-morpholinyl, C-C-alkylthio. In another preferred embodiment the group of formula (A) is a pyridine or quinoline group, preferably a pyridine group, Formula (A) 5 wherein each group is optionally substituted by one or more 1N radicals, preferably by one or two radicals, selected from the group of C-C-alkyl, C-C-haloalkyl, C-C-alkoxy, C-C-haloalkoxy, amino, C-C-alkylamino, di(C-C- alkyl)amino, N-pyrrolidinyl, N-piperidinyl, N-morpholinyl, 10 C-C-alkylthio, dioxolane Such as 1,3-dioxolane, dioxane represents a pyridine, pyrimidine, quinoline, quinazoline, Such as 1,3-dioxane, or dioxepane Such as 1,3-dioxepane, thienopyrimidine, thienopyridine, triazolopyrimidine, pyri each ring is unsubstituted or Substituted by C-C-alkyl. dopyridine, pyrrolopyridine, pyrazolopyrimidine, pyrazol In another preferred embodiment the group of formula (A) opyridine, furopyridine, 2,3-dihydrofuropyridine, 2,3-dihy is a pyrimidine group, which is optionally Substituted by one dro-1,4-dioxinopyridine, furopyrimidine, pyridazine or 15 or more radicals, preferably by one or two radicals, selected from the group of C-C-alkyl, C-C-alkoxy, C-C-ha cinnoline group, wherein each group is optionally Substituted loalkoxy, amino, C-C-alkylamino, N-pyrrolidinyl, N-pip by one or more radicals, preferably by one or two radicals, eridinyl, N-morpholinyl, di(C-C-alkyl)amino, C-C-alky selected from the group of C-C-alkyl, C-C-haloalkyl, lthio. C-C-alkoxy, C-C-haloalkoxy, nitrilo, nitro, amino, Salts, Solvates, N-Oxides and Prodrugs C-C-alkylamino, di(C-C-alkyl)amino, N-pyrrolidinyl, A salt of the compounds of the formula (I), (Ia) or (Ib), or N-piperidinyl, N-morpholinyl, C-C-alkylthio, C-C-alkyl another compound may be advantageous due to one or more carbonyl, aminocarbonyl, C-C-alkylaminocarbonyl, di(C- of the salt's physical properties, such as pharmaceutical sta Co-alkyl)aminocarbonyl, C-C-alkoxycarbonyl, dioxolane bility in differing temperatures and humidities; crystalline Such as 1,3-dioxolane, dioxane Such as 1,3-dioxane, or diox 25 properties; and/or a desirable solubility in water, oil, or other epane Such as 1,3-dioxepane, wherein each ring is unsubsti Solvent. In some instances, a salt may be used as an aid in the tuted or substituted by C-C-alkyl. isolation, purification, and/or resolution of the compound. In another preferred embodiment the group of formula (A) Acid and base salts can typically be formed by, for example, is a pyridine, pyrimidine, quinoline, quinazoline, thienopyri mixing the compound with an acid or base, respectively, midine or thienopyridine group, wherein each group is 30 using various known methods in the art. To the extent a salt of optionally substituted by one or more radicals, preferably by the compound is intended to be administered in Vivo (i.e. to an one or two radicals, selected from the group of C-C-alkyl, animal) for a therapeutic benefit, the salt is pharmaceutically C-C-haloalkyl, C-C-alkoxy, C-C-haloalkoxy, nitrilo. acceptable. nitro, amino, C-C-alkylamino, di(C-C-alkyl)amino, Salts may also be of advantage in the synthesis of the N-pyrrolidinyl, N-piperidinyl, N-morpholinyl, C-C-alky 35 compounds according to this invention. For instance certain lthio, C-C-alkyl carbonyl, aminocarbonyl, C-C-alky intermediates may advantagously be used in form of their laminocarbonyl, di(C-C-alkyl)aminocarbonyl, C-C- salts in the preparation process of the compounds according alkoxycarbonyl, dioxolane Such as 1,3-dioxolane, dioxane to this invention. Such as 1,3-dioxane, or dioxepane Such as 1,3-dioxepane, In general, an acid addition salt can be prepared by reacting wherein each ring is unsubstituted or substituted by C-C- 40 a free base compound with an approximately stoichiometric alkyl. amount of an inorganic or organic acid. Examples of often In another preferred embodiment the group of formula (A) Suitable inorganic acids for making (pharmaceutically is a pyridine, pyrimidine, quinoline, quinazoline, thienopyri acceptable) salts include hydrochloric, hydrobromic, midine or thienopyridine group (preferably a pyridine, pyri hydroiodic, nitric, carbonic, Sulfuric, and phosphoric acid. midine or quinoline group), wherein each group is optionally 45 Examples of often Suitable organic acids for making (phar substituted by one or more radicals, preferably by one or two maceutically acceptable) salts generally include, for radicals, selected from the group of C-C-alkyl, C-C-ha example, aliphatic, cycloaliphatic, aromatic, araliphatic, het loalkyl, C-C-alkoxy, C-C-haloalkoxy, amino, C-C- erocyclic, carboxylic, and Sulfonic classes of organic acids. alkylamino, di(C-C-alkyl)amino, N-pyrrolidinyl, N-pip Specific examples of often suitable organic acids include eridinyl, N-morpholinyl, C-C-alkylthio, dioxolane Such as 50 cholic, Sorbic, lauric, acetic, trifluoroacetic, formic, propi 1,3-dioxolane, dioxane Such as 1,3-dioxane, or dioxepane onic, Succinic, glycolic, gluconic, digluconic, lactic, malic, Such as 1,3-dioxepane, each ring is unsubstituted or Substi tartaric acid, citric, ascorbic, glucuronic, maleic, fumaric, tuted by C-C-alkyl. pyruvic, aspartic, glutamic, aryl carboxylic acid (e.g., ben In another preferred embodiment the group of formula (A) Zoic), anthranilic acid, mesylic, Stearic, Salicylic, p-hydroxy is a pyridine, pyrimidine or quinoline group, preferably a 55 benzoic, phenylacetic, mandelic, embonic (pamoic), alkyl pyridine or pyrimidine group, wherein each group is option Sulfonic (e.g., ethanesulfonic), arylsulfonic (e.g., ally substituted by one or more radicals, preferably by one or benzenesulfonic), pantothenic, 2-hydroxyethanesulfonic, two radicals, selected from the group of C-C-alkyl, C-C- Sulfanilic, cyclohexylaminosulfonic, B-hydroxybutyric, haloalkyl, C-C-alkoxy, C-C-haloalkoxy, nitrilo, nitro, galactaric, galacturonic, adipic, alginic, butyric, camphoric, amino, C-C-alkylamino, di(C-C-alkyl)amino, N-pyrro 60 camphorsulfonic, cyclopentanepropionic, dodecylsulfic, gly lidinyl, N-piperidinyl, N-morpholinyl, thio, C-C-alkylthio. coheptanoic, glycerophosphic, heptanoic, hexanoic, nico C-C-alkyl carbonyl, aminocarbonyl, C-C-alkylaminocar tinic, 2-naphthalesulfonic, oxalic, palmoic, pectinic, 3-phe bonyl, di(C-C-alkyl)aminocarbonyl, dioxolane such as 1,3- nylpropionic, picric, pivalic, thiocyanic, tosylic, and dioxolane, dioxane Such as 1,3-dioxane, or dioxepane Such as undecanoic acid. In some such embodiments, for example, 1,3-dioxepane, wherein each ring is unsubstituted or Substi 65 the salt comprises a trifluoroacetate, mesylate, ortosylate salt. tuted by C-C-alkyl, and preferably selected from the group In other embodiments, the salt comprises a hydrochloric acid of C-C-alkyl, C-C-alkoxy, C-C-haloalkoxy, amino, salt. US 8,877,934 B2 27 In general, a base addition salt can be prepared by reacting a free acid compound with an approximately stoichiometric amount of an inorganic or organic base. Examples of base addition salts may include, for example, metallic salts and organic salts. Metallic salts, for example, include alkali metal (group Ia) salts, alkaline earth metal (group IIa) salts, and other physiologically acceptable metal salts. Such salts may be made from aluminum, calcium, lithium, magnesium, Elimination of MQ will generate compounds of formula (I) or potassium, Sodium, and zinc. For example, a free acid com 10 (Ib). If M is hydrogen, this type of elimination is also known pound may be mixed with sodium hydroxide to form Such a in the art as retro-Michael reaction or retro-Michael addition. Examples of such retro-Michael reactions that occur in vivo base addition salt. Organic salts may be made from amines, to generate unsaturated compounds are described in, for such as trimethylamine, diethylamine, N,N'-dibenzylethyl example, S. C. Alley, Bioconjugate Chem. 19, 759-765 enediamine, chloroprocaine, ethanolamine, diethanolamine, 15 (2008); D. Lopez, Abstracts of Papers, 231 National Meet ethylenediamine, meglumine (N-methylglucamine), and ing, Atlanta, Ga., United States, Mar. 26-30, 2006, MEDI procaine. Basic nitrogen-containing groups may be quater 292. nized with agents such as C-C-alkyl halides (e.g., methyl, Isomers The compounds according to this invention, their interme ethyl, propyl, and butyl chlorides, bromides, and iodides), diates and compounds corresponding to the use according to dialkyl Sulfates (e.g., dimethyl, diethyl, dibuytl, and diamyl the invention, may exist in various isomeric forms. A refer Sulfates), long chain halides (e.g., decyl, lauryl, myristyl, and ence to a compound according to this invention, an interme stearyl chlorides, bromides, and iodides), arylalkyl halides diate thereof or a compound corresponding to the use accord (e.g., benzyl and phenethyl bromides), and others. ing to the invention always includes all possible isomeric 25 forms of Such compound. A solvate of a compound of the formula (I), (Ia) or (Ib), or In some embodiments, such compounds may have two or another compound may be formed by aggregation of said more isomers, such as optical isomers or conformational iso compound of the formula (I) with solvent molecules such as mers. For example, the compounds can have a cis or trans water, alcohols, for example ethanol, aromatic Solvents such configuration at the CXR-CR'R' double bond. In some as toluene, ethers, halogenated organic solvents such as 30 preferred embodiments, such compound has the (E) configu dichloromethane, preferably in a definite proportion by ration, in other embodiments, the compound has the (Z) con Weight. figuration. In a preferred embodiment the compounds have An N-oxide of a compound of the formula (I), (Ia) or (Ib), (E) configuration. For instance the compounds of the formula or another compound may be formed by oxidation of an (II), the compounds of Table A wherein R=R-H and the N-atom in an amine or N-heterocycle such as pyridine by 35 compounds of Table Bexhibit (E) configuration. oxidation agents such as hydrogen peroxide, peracids or inor Unless otherwise stated, a compound structure that does ganic oxidation agents such as potassium peroxymonosulfate not indicate a particular conformation is intended to encom (Oxone). In preferred N-oxides a nitrogenatom in the group of pass compositions of all the possible conformational isomers formula (A) is oxidized, more preferred are N-oxides wherein of the compound, as well as compositions comprising fewer 40 than all the possible conformational isomers. In some the nitrogen atom in the para-position is oxidized: embodiments, the compound is a chiral compound. In some embodiments, the compound is a non-chiral compound. Treatment Methods y42Ny. This section pertains to compounds according to the inven 45 tion and compounds corresponding to the use according to the Y.O Y2 invention. The compounds and were applicable pharmaceu tically acceptable Solvates, N-oxides, salts and prodrugs O thereof may generally be used as a medicament for animals. In some embodiments of this invention, one or more, prefer 50 ably one compound according to this invention is adminis This invention also encompasses prodrug derivatives of the tered to treat infections such as parasitic infections (e.g. hel compounds of formula (I) and (Ib). The term prodrug refers to minth infections) of an animal (or make a medicament to treat compounds that are transformed in vivo to yield the parent infections such as parasitic infections of an animal). In one compound of formula (I) or (Ib). In vivo means that in the case embodiment one or more, preferably one compound accord 55 ing to this invention is administered to treat parasitoses of an of for example, treatment of a parasitic infection this trans animal (or make a medicament to treat parasitoses of an formation can occur in the host organism and/or the parasite. animal). The use according to the invention is directed to treat Various forms of prodrugs are well known in the art. For helminth infections. example, if the group of formula (A) represents a pyridine, it The term “(parasitic) infection' includes conditions asso is possible to form pyridinium salts such as, for example, 60 ciated with or caused by one or more (parasitic) pathogens; acyloxyalkylpyridinium salts, which can offer advantages in said conditions include clinical conditions (parasitoses) and terms of higher solubility for parenteral dosage forms, which sub-clinical conditions. The term “treatment of parasitic infection' thus includes both the treatment of parasitoses and are described in S. K. Davidsen et al., J. of Med. Chem. 37 the treatment of sub-clinical conditions. The treatment of a 4423-4429 (1994). Other examples of possible prodrugs are 65 parasite infection generally implies the Suppression of para compounds that form the double bond present in formula (I) site (e.g. helminth) burdens in the animal below that level at and (Ib) by elimination from a saturated precursor compound: which economic loss occurs. US 8,877,934 B2 29 30 Sub-clinical conditions are typically conditions not The reduction of parasite numbers, especially gastrointes directly leading to clinical symptoms in the parasite infected tinal helminth parasites can be alternatively measured in animal but leading to economic losses. Such economic losses directly by faecal egg or differential larval counts. In this case can be e.g. by depression of growth in young animals, lower the effective amount of the compound is determined by the feed efficiency, lower weight gain in meat producing animals, reduction of the number of excreted helminth eggs or larvae in lower milk production in ruminants, lower egg production in the faeces of the treated animal before and after treatment. For laying hens, or lower wool-production in sheep. an in vivo administration the compound according to this The term “parasitoses' relates to clinically manifest patho invention, is preferably administered to an animal in an effec logic conditions and diseases associated with or caused by an tive amount which is synonymous with “pharmaceutically infection by one or more parasites. Such as, for example 10 effective amount’ or “anthelmintically effective amount'. parasitic gastroenteritis oranemia in ruminants e.g. sheep and A single administration of a compound according to this goats or colic in horses. invention or a compound corresponding to the use according In general, the prevention or treatment of parasitic infec to the invention is typically sufficient to treat a parasitic tion including parasitoses is achieved by administering one or infection Such as a helminth infection, preferably anematode, more, preferably one compound according to this invention to 15 cestode or trematode infection, more preferably a nematode treat a parasitic infection Such as a helminth infection, the infection. Although Such a single dose is typically preferred, latter treatment being the Sole treatment of the use according it is contemplated that multiple doses can be used. When the to the invention. compound is orally administered, the total dose to treat a Thus the invention provides a method of treating a (para disease such as a helminth infection is generally greater than sitic) infection Such as a helminth infection, including para about 0.01 mg/kg (i.e., milligram of compound per kilogram sitoses, which comprises administering to the animal an anti body weight of the treated animal). In some such embodi parasitically, preferably an anthelmintically, effective amount ments, the total dose is from about 0.01 to about 100 mg/kg, of one or more compounds according to this invention, or from about 0.01 to about 50 mg/kg, from about 0.1 to about 25 where applicable, a compound corresponding to the use mg/kg, or from about 1 to about 20. For sheep, for example, according to the invention. Preferably nematode, cestode or 25 the dose is generally from about 0.5 to about 15 mg/kg, from trematode infections are treated, more preferably nematode about 1 to about 10 mg/kg. The same dose range may be infections. Suitable for other dosage routes. For example, in some “Treating (parasitic) infections' includes treating parasito embodiments, the same dose range is used for Subcutaneous ses and means to partially or completely inhibit the develop administration. The desired dose, however, may be less in ment of (parasitic) infections of an animal Susceptible to 30 Some instances where the compound according to this inven (parasitic) infection, reduce or completely eliminate the tion is administered intravenously. symptoms of infections of an animal having infections, and/ If the compound according to this invention or a compound or partially or completely cure infections of an animal having corresponding to the use according to the invention is admin infections. This can be achieved by alleviating or reducing istered parenterally via an injection, the concentration of the pathogen numbers such as parasite numbers in an animal. 35 compound in the dosage form preferably is Sufficient to pro The effect of the compounds according to this invention or vide the desired therapeutically effective amount of the com the use according to the invention can be e.g. ovicidal, larvi pound in a Volume that is acceptable for parenteral adminis cidal, and/or adulticidal or a combination thereof. The effect tration. can manifest itself directly, i.e. killing the parasites either Factors affecting the preferred dosage may include, for immediately or after Some time has elapsed, for example 40 example, the parasite species infection to be treated and the when molting occurs, or by destroying their eggs, or indi development stages of the parasites, the type (e.g., species rectly, e.g. reducing the number of eggs laid and/or the hatch and breed), age, size, sex, diet, activity, and condition of the of ingrate. Alternatively the parasite is not killed but paralyzed the infected animal; the dosage route; pharmacological con and is then dislodged and excreted by the host animal. siderations, such as the activity, efficacy, pharmacokinetic, In another aspect the present invention thus provides a 45 and toxicology profiles of the particular composition admin pharmaceutical composition comprising an anthelmintically istered; and whether the compound being administered as effective amount of one or more, preferably one compound part of a combination of active ingredients. Thus, the pre according to this invention or a compound corresponding to ferred amount of the compound can vary, and, therefore, can the use according to the invention and one or more pharma deviate from the typical dosages set forth above. Determining ceutically acceptable excipients. 50 Such dosage adjustments is generally within the skill of those The compounds and pharmaceutical compositions accord in the art. ing to this invention are useful in treating parasitic infections In a preferred embodiment the compounds according to such as helminth infections of animals. An "effective this invention are used to treat a helminth infection, Such as an amount, is the amount or quantity of a compound that is infection caused by one or more helminths selected from the required to alleviate or reduce parasite numbers in an animal, 55 group consisting of a) cestodes: e.g. Anaplocephala spp.; and/or to inhibit the development of parasite infections in an Dipylidium spp.; Diphyllobothrium spp.; Echinococcus spp.; animal, in whole or in part. Moniezia spp.; Taenia spp.; b) trematodes e.g. Dicrocoelium This amount is readily determined by observation or detec spp.; Fasciola spp.; Paramphistomum spp.; Schistosoma spp.; tion of the pathogen numbers such as parasite numbers both or c) nematodes, e.g.: Ancylostoma spp.; Anecator spp.; before and after contacting the sample of pathogens Such as 60 Ascaridia spp.; Ascaris spp.; Brugia spp., Bunostomum spp.; parasites including their stages with the compound according Capillaria spp.; Chabertia spp.; Cooperia spp.; Cyathosto to this invention, directly and/or indirectly, e.g., by contacting mum spp.; Cylicocyclus spp.; Cylicodontophorus spp., Cyli articles, Surfaces, foliage, or animals with the compound e.g. costephanus spp., Craterostomum spp.; Dictyocaulus spp.; the parasite count is reduced, after a first administration, by an Dipetalonema spp.; Dirofilaria spp.; Dracunculus spp.; amount ranging from 5% to about 100%. 65 Enterobius spp.; Filaroides spp., Habronema spp., Haemon This can be evaluated by counting parasites (especially chus spp., Heterakis spp., Hvostrongylus spp.; Metastrongy helminthes) directly after necroscopy of the host animal. lus spp.; Meullerius spp. Necator spp.; Nematodirus spp.; US 8,877,934 B2 31 32 Nippostrongylus spp., Oesophagostomum spp., Onchocerca product Suitable for administering to the animal via the envis spp., Ostertagia spp., Oxyuris spp.; Parascaris spp., Stepha aged dosage route. Such dosage forms are sometimes referred nurus spp., Strongylus spp., Syngamus spp., Toxocara spp.; to herein as formulations or pharmaceutical composition. Strongyloides spp.; Teladorsagia spp., Toxascaris spp.; Tri The formulation type chosen for a dosage form in any chinella spp.; Trichuris spp.; Tricho strongylus spp.; Triodon instance will depend upon the particular purpose envisaged tophorous spp., Uncinaria spp., and/or Wuchereria spp.; and the physical, chemical and biological properties of the It is contemplated that the compounds according to this compound according to this invention. invention and compounds corresponding to the use according Dosage forms useful in the current invention can be liquid, to the invention may be used to treat animals, including semi-solid or Solid dosage forms. humans and non-human animals, especially non-human 10 Liquid dosage forms of the compounds are generally solu mammals. Such non-human mammals include, for example, livestock mammals (e.g., Swine, livestock ruminats like tions, Suspensions or emulsions. A solution is a mixture of bovines, sheep,goats, etc.), laboratory mammals (e.g., mice, two or more components that form a single phase that is rats, jirds, etc.), companion mammals (e.g., dogs, cats, homogeneous down to the molecular level. A Suspension equines, etc.), and wild and Zoo mammals (e.g., buffalo, deer, 15 consists of insoluble solid particles dispersed in a liquid etc.). It is contemplated that the compounds also are Suitable medium, with the solid particles accounting for about 0.5% to to treat non-mammals, such as poultry (e.g., turkeys, chick about 30% of the suspension. The liquid may be aqueous, ens, ducks, etc.) and fish (e.g., salmon, trout, koi, etc.). oily, or both. An emulsion is a heterogeneous dispersion of In some embodiments, one or more, preferably one com one immiscible liquid in another; it relies on an emulsifying pound according to this invention or a compound correspond agent for stability. A dry powder (or granule) for reconstitu ing to the use according to the invention is used to treat an tion is reconstituted as a solution or as a Suspension immedi infection by a helminth, such as a nematode, cestode ortrema ately prior to injection. The principal advantage of this dosage tode, preferably a nematode (such as Haemonchus contor form is that it overcomes the problem of instability in solution tus), that is resistant to one or more other anthelmintic agents. or Suspension. In some embodiments, the compound according to this inven 25 One possible dosage route is the oral dosage route, wherein tion is active against a helminth, such as a nematode, cestode the compound is administered via the mouth. Oral dosage or trematode, preferably a nematode Such as Haemonchus forms suitable for oral administration comprise liquids (e.g. contortus, that is resistant to one or more of the following drench or drinking water formulations), semi-solids (e.g. anthelmintics: an avermectin (e.g., ivermectin, Selamectin, pastes, gels), and Solids (e.g. tablets, capsules, powders, gran doramectin, abamectin, and eprinomectin); a milbemycin 30 ules, chewable treats, premixes and medicated blocks). (moxidectin and milbemycin Oxime); a pro-benzimidazole A drench is a liquid oral formulation that is administered (e.g., febantel, netobimin, and thiophanate); a benzimidazole directly into the mouth/throat of an animal, especially a live derivative, such as a thiazole benzimidazole derivative (e.g., stock animal, by means of a “drench gun' or Syringe or thiabendazole and cambendazole) or a carbamate benzimida another suitable device. When the composition is adminis Zole derivative (e.g., fenbendazole, albendazole (oxide), 35 tered in the animal recipient’s drinking water or as a drench, mebendazole, Oxfendazole, parbendazole, oxibendazole, it may be convenient to use a solution or Suspension formu flubendazole, and triclabendazole); an imidazothiazole (e.g., lation. This formulation can be, for example, a concentrated levamisole and tetramisole); a tetrahydropyrimidine (moran Suspension that is mixed with water or a dry preparation that tel and pyrantel), an organophosphate (e.g., trichlorphon, is mixed and Suspended in the water. haloxon, dichlorvos, and naphthalophos); a salicylanilide 40 Semi-solid oral formulations (pastes or gels) are generally (e.g., closantel, oxyclozanide, rafoxanide, and niclosamide); administered via an applicator directly into the mouth of an a nitrophenolic compound (e.g., nitroxynil and nitroscanate); animal or mixed with the feed. benzoenedisulphonamide (e.g., clorSulon); a pyraZinaiso Solid oral formulations are either administered directly to quinoline (e.g., praziquantel and epsiprantel); a heterocyclic an animal (tablet, capsule) or mixed with the feed or via compound (e.g., piperazine, diethylcarbamazine, dichlo 45 medicated feedblocks. rophen, and phenothiazine); an arsenical (e.g., thiacetarsa When the oral formulation is administered via a non-hu mide, melorsamine, and arsenamide); cyclooctadepsipeptide man animals feed, it may, for example, be fed as a discrete (e.g., emodepside); and a paraherquamide. feed or as a chewable treat. Alternatively (or additionally), it In some Such embodiments, for example, the compound may, for example, be intimately dispersed in the animal according to this invention or a compound corresponding to 50 recipient's regular feed, used as a top dressing, or in the form the use according to the invention is active against a helminth of solid pellets, paste or liquid that is added to the finished (for example, Haemonchus contortus) resistant to an aver feed. When the oral formulation is administered as a feed mectin, such as ivermectin. In other embodiments, the com additive, it may be convenient to prepare a “premix' in which pound according to this invention is alternatively or addition the oral formulation is dispersed in a liquid or Solid carrier. ally active against a helminth (for example, Haemonchus 55 This "premix' is, in turn, dispersed in the animals feed using, contortus) resistant to a benzimidazole derivative, such as for example, a conventional mixer. fenbendazole. In other embodiments, the compound accord Several modified-release delivery systems have been ing to this invention is alternatively or additionally active developed, that take advantage of the unique anatomy of the against a helminth (for example, Haemonchus contortus) ruminant forestomach, i.e. for intra-ruminal administration. resistant to levamisole. And, in other embodiments, the com 60 An intraruminal bolus is a specific formulation for ruminants pound according to this invention is alternatively or addition (cattle, sheep, goats, buffalos, camelids, deer etc). It is a ally active against a helminth (for example, Haemonchus veterinary delayed release delivery system which remains in contortus) resistant to pyrantel. the rumeno-reticular sac of a ruminant animal over an The compounds according to this invention or the com extended period of time and in which the therapeutically pounds corresponding to the use according to the invention 65 active Substance has a predictable and delayed release pat may be administered in various dosage forms. The term "dos tern. Such intraruminal boluses are usually administered age form' means that the compounds are formulated into a using a balling gun or another suitable device. US 8,877,934 B2 33 34 It is contemplated that the compounds according to this Voring agents (e.g., Sweeteners), buffers, preservatives, phar invention or compounds corresponding to the use according maceutical-grade dyes or pigments, and controlled release to the invention may alternatively be administered via non agents. oral dosage routes, such as topically (e.g., via a spot-on, Oral dosage forms other than solids may be prepared by pour-on or transdermal patch), or parenterally (e.g., Subcuta mixing the compounds with, for example, one or more sol neous injection, intravenous injection, intramuscular injec vents, viscosity-enhancing agents, Surfactants, preservatives, tion, etc.). stabilizers, resins, fillers, binders, lubricants, glidants, disin For instance the compounds may be administered topically tegrants, co-solvents, Sweeteners, flavorings, perfuming using a transdermal formulation (i.e. a formulation that agents, buffers, Suspending agents, and pharmaceutical passes through the skin). Alternatively the compounds may 10 grade dyes or pigments. be administered topically via the mucosa. Contemplated binders include, for example, gelatin, aca Topical dosage forms suitable for topical administration cia, and carboxymethyl cellulose. comprise liquids (e.g. bath, spray, spot-on), semi-solids (e.g. Contemplated lubricants include, for example, magnesium creams, gels), and Solids (e.g. patches, powders, collars). 15 Stearate, Stearic acid, and talc. Typical topical formulations for animals are liquid or semi Contemplated disintegrants include, for example, corn liquid dosage forms. Typical formulations for transdermal starch, alginic acid, sodium carboxymethylcellulose, and and mucosal administration include, for example, pour-ons, Sodium croScarmellose. spot-ons, dips, sprays, mousses, shampoos, powders, gels, Contemplated buffers include, for example, sodium citrate, hydrogels, lotions, solutions, creams, ointments, dusting and magnesium and calcium carbonate and bicarbonate. powders, dressings, foams, films, skin patches, limb bands, Contemplated Solvents include, for example, water, petro collars, ear tags, wafers, sponges, fibers, bandages, and leum, animal oils, vegetable oils, mineral oil, and synthetic microemulsions. When a liquid formulation is used topically oil. Physiological Saline Solution or glycols (e.g., ethylene on skin, it can be administered by, for example, pouring on glycol, propylene glycol, or polyethylene glycol) also may be (pour-on or spot-on), spreading, rubbing, atomizing, spray 25 included. The solvent preferably has sufficient chemical ing, dipping, bathing, or Washing. properties and quantity to keep the compounds solubilized at The pour-on or spot-on methods, for example, comprise temperatures in which the composition is stored and used. applying the formulation to a specific location of the skin or Contemplated viscosity-enhancing agents include, for coat, such as on the neck or backbone of the animal. This may example, polyethylene, methylcellulose, Sodium carboxym 30 ethylcellulose, hydroxypropyl-methylcellulose, hydroxypro be achieved by, for example, applying a Swab or drop of the pylcellulose, Sodium alginate, carbomer, povidone, acacia, pour-on or spot-on formulation to a relatively small area of guar gum, Xanthan gum, tragacanth, methylcellulose, car the recipient animal's skin or coat (i.e., generally no greater bomer, Xanthan gum, guar gum, povidone, sodium car than about 10% of the animal recipient’s skin or coat). In boxymethylcellulose, magnesium aluminum silicate, carbox Some embodiments, the compound is dispersed from the 35 yvinyl polymers, carrageenan, hydroxyethyl cellulose, application site to wide areas of the fur due to the spreading laponite, water-soluble salts of cellulose ethers, natural gums, nature of the components in the formulation and the animals colloidal magnesium aluminum silicateor finely divided movements while, in parallel, being absorbed through the silica, homopolymers of acrylic acid crosslinked with an skin and distributed via the animal recipients fluids and/or alkyl ether of pentaerythritol oran alkyl ether of sucrose, and tissues. 40 carbomers. Parenteral formulations and delivery systems for non-oral Contemplated Surfactants include, for example, polyoxy routes comprise liquids (e.g. solutions, Suspensions, emul ethylene sorbitan fatty acid esters; polyoxyethylene sions, and dry powders for reconstitution), semi-solids and monoalkyl ethers; Sucrose monoesters; lanolin esters and Solids (e.g. implants). The majority of implants that are used ethers; alkylsulfate salts; and Sodium, potassium, and ammo in Veterinary medicine are compressed tablets or dispersed 45 nium salts of fatty acids. matrix systems in which the drug is uniformly dispersed Contemplated preservatives include, for example, phenol, within a nondegradable polymer or alternatively extrusion alkyl esters of parahydroxybenzoic acid (e.g., methyl p-hy products. droxybenzoate (or “methylparaben') and propyl p-hydroxy Pharmaceutical Compositions benzoate (or “propylparaben')), sorbic acid, o-phenylphenol This invention also is directed to pharmaceutical compo 50 benzoic acid and the salts thereof, chlorobutanol, benzyl alco sitions (or medicaments) comprising one or more, preferably hol, thimerosal, phenylmercuric acetate and nitrate, nitromer one compound according to this invention. The compositions Sol, benzalkonium chloride, and cetylpyridinium chloride. also may (and preferably will) comprise one or more phar Contemplated Stabilizers include, for example, chelating maceutically acceptable excipients. The following Subject agents and antioxidants. matter about pharmaceutical compositions is also applicable 55 Solid dosage forms also may comprise, for example, one or to pharmaceutical compositions comprising compounds cor more excipients to control the release of the compounds. For responding to the use according to this invention. example, it is contemplated that the compounds may be dis Pharmaceutical compositions of the present invention may persed in, for example, hydroxypropylmethyl cellulose. be manufactured by, for example, processes known in the art. Some oral dosage forms (e.g., tablets and pills) also may be These processes include, for example, a variety of known 60 prepared with enteric coatings. mixing, dissolving, granulating, emulsifying, encapsulating, Topical dosage route uses, for example, a concentrated entrapping, and lyophilizing processes. Optimal formulation liquid or semi-liquid solution, Suspension (aqueous or non depends on, for example, the dosage route (e.g. oral, injec aqueous), emulsion (water-in-oil or oil-in-water), or micro tion, topical). emulsion comprising a compounds dissolved, Suspended, or Solid dosage forms, for example, may be prepared by, for 65 emulgated in a pharmaceutically-acceptable liquid vehicle. example, intimately and uniformly mixing the compounds In Such embodiments, a crystallization inhibitor optionally with fillers, binders, lubricants, glidants, disintegrants, fla may generally be present. US 8,877,934 B2 35 36 Such a pour-on or spot-on formulation can be prepared by PEG 400). Contemplated solubilizing agents include, for dissolving, Suspending, or emulsifying the compounds in a example, polyvinyl pyrrolidone, polyoxyethylated castor oil, suitable skin-fitted solvent or solvent mixture. Other excipi polyoxyethylated sorbitan ester, and the like. Contemplated ents may be included as well. Such as, for example, a Surfac protecting agents include, for example, benzyl alcohol, tant, colorant, antioxidant, stabilizer, adhesive, etc. Contem trichlorobutanol, p-hydroxybenzoic acid ester, n-butanol, and plated solvents include, for example, water, alkanol, glycol, the like. polyethylene glycol, polypropylene glycol, glycerin, benzyl In some embodiments, a parenteral formulation is, for alcohol, phenylethanol, phenoxyethanol, ethyl acetate, butyl example, prepared from Sterile powders or granules having acetate, benzyl benzoate, dipropylene glycol monomethyl one or more of the carriers materials discussed above for other ether, diethylene glycol monobutyl ether, acetone, methyl 10 ethyl ketone, aromatic and/or aliphatic hydrocarbons, Veg formulations. The compound is, for example, dissolved or etable or synthetic oil, DMF, liquid paraffin, silicone, dim Suspended in a liquid comprising water, polyethylene glycol, ethylacetamide, N-methylpyrrolidone, or 2,2-dimethyl-4- propylene glycol, ethanol, corn oil, cottonseed oil, peanut oil, oxy-methylene-1,3-dioxolane. sesame oil, benzyl alcohol, Sodium chloride, and/or various In some embodiments, a topical formulation (particularly a 15 buffers. The pH generally may be adjusted, if necessary, with pour-on or spot-on formulation) comprises a carrier that pro a suitable acid, base, or buffer. motes the absorption or penetration of the compounds Otherinert ingredients may generally be added to the com through the skin into the blood stream, other bodily fluids position as desired. To illustrate, it is contemplated that these (lymph), and/or body tissue (fat tissue). Contemplated may include, for example, lactose, mannitol, Sorbitol, cal examples of dermal penetration enhancers include, for cium carbonate, sodium carbonate, tribasic calcium phos example, dimethylsulfoxide, isopropyl myristate, dipropy phate, dibasic calcium phosphate, Sodium phosphate, kaolin, lene glycol pelargonate, silicone oil, aliphatic esters, triglyc compressible Sugar, starch, calcium Sulfate, dextro or micro erides, and fatty alcohols. crystalline cellulose, colloidal silicon dioxide, starch, sodium Topical formulations also (or alternatively) may comprise, starch glycolate, crospovidone, microcrystalline cellulose, for example, one or more spreading agents. These substances 25 tragacanth, hydroxypropylcellulose, pregelatinized starch, act as carriers that assist in distributing an active ingredient poVidone, ethylcellulose, hydroxypropylcellulose, hydrox over the animal recipient’s coat or skin. They may include, for ypropylmethylcellulose, and methylcellulose. example, isopropyl myristate, dipropylene glycol pelargo Further aspects regarding formulation of drugs and various nate, silicone oils, fatty acid esters, triglycerides, and/or fatty excipients are found in, for example, Gennaro, A. R., et al., alcohols. Various spreading oil/solvent combinations also 30 eds. Remington. The Science and Practice of Pharmacy may be Suitable, such as, for example, oily solutions, alco (Lippincott Williams & Wilkins, 20th Ed., 2000). Another holic and isopropanolic solutions (e.g., solutions of 2-octyl source regarding formulation of drugs and various excipients dodecanol or oleyl alcohol), solutions of esters of monocar is found in, for example, Liberman, H. A., et al., eds., Phar boxylic acids (e.g., isopropyl myristate, isopropyl palmitate, maceutical Dosage Forms (Marcel Decker, New York, N.Y., lauric acid oxalic ester, oleic acid oleyl ester, oleic acid decyl 35 1980). ester, hexyl laurate, oleyl oleate, decyl oleate, and caproic The concentration of the compounds according to this acid esters of saturated fatty alcohols having a carbon chain of invention in the applied dosage form may vary widely 12 to 18 carbons), solutions of esters of dicarboxylic acids depending on, for example, the dosage route. In general, the (e.g., dibutyl phthalate, diisopropyl isophthalate, adipic acid concentration is from about 1 to about 70% (by weight). In diisopropyl ester, and di-n-butyl adipate), or solutions of 40 Some such embodiments, for example, the concentration is esters of aliphatic acids (e.g., glycols). When the formulation from about 1 to about 50% (by weight), or from about 10 to comprises a spreading agent, it also may be advantageous to about 50% (by weight). In other embodiments, the concen include a dispersant, such as, for example, pyrrolidin-2-one, tration is from about 35 to about 65% (by weight), from about N-alkylpyrrolidin-2-one, acetone, polyethylene glycol or 40 to about 60% (by weight), from about 45 to about 55% (by ether or ester thereof, propylene glycol, or synthetic triglyc 45 weight), or about 50% (by weight). erides. In another aspect the present invention thus provides a When formulated in, for example, an ointment, it is con pharmaceutical composition comprising an anthelmintically templated that the compounds may be mixed with, for effective amount of one or more, preferably one compound example, either a paraffinic or a water-miscible ointment according to this invention and one or more pharmaceutically base. When formulated in a cream, it is contemplated that the 50 acceptable excipients. compounds may be formulated with, for example, an oil-in The formulation type chosen for a dosage form in any water cream base. In some instances, the aqueous phase of the instance will depend upon the particular purpose envisaged cream base includes, for example at least about 30% (w/w) of and the physical, chemical and biological properties of the a polyhydric alcohol. Such as propylene glycol, butane-1,3- compound according to this invention. diol, mannitol, Sorbitol, glycerol, polyethylene glycol, or a 55 The compounds and pharmaceutical compositions accord mixture thereof. ing to this invention are useful in treating parasitic infections Injectable formulations may be prepared according to, for such as helminth infections of animals. An "effective example, the known art using Suitable solvents, solubilizing amount, is the amount or quantity of a compound that is agents, protecting agents, dispersing agents, wetting agents, required to alleviate or reduce parasite numbers in an animal, and/or Suspending agents. Contemplated carrier materials 60 and/or to inhibit the development of parasite infections in an include, for example, water, ethanol, butanol, benzyl alcohol, animal, in whole or in part. glycerin, 1,3-butanediol, Ringer's solution, isotonic sodium This amount is readily determined by observation or detec chloride solution, bland fixed oils (e.g., synthetic mono- or tion of the pathogen numbers such as parasite numbers both diglycerides), vegetable oil (e.g., corn oil), dextrose, manni before and after contacting the sample of pathogens such as tol, fatty acids (e.g., oleic acid), dimethyl acetamide, Surfac 65 parasites including their stages with the compound according tants (e.g., ionic and non-ionic detergents), N-methylpyrroli to this invention, directly and/or indirectly, e.g., by contacting done, propylene glycol, and/or polyethylene glycols (e.g., articles, Surfaces, foliage, or animals with the compound. US 8,877,934 B2 37 38 This can be evaluated by counting parasites (especially pounds (e.g. monepantel, AAD 1566); tribendimidine helminthes) directly after necroscopy of the host animal. (amidine compound); amidine compounds (e.g., amidantel The reduction of parasite numbers, especially gastrointes and tribendimidin), including all pharmaceutically accept tinal helminth parasites can be alternatively measured in able forms, such as salts, Solvates or N-oxides. directly by faecal egg or differential larval counts. In this case Preferred combinations are comprising a) one compound the effective amount of the compound is determined by the selected from the group compounds A-1 to A-697, Aa-1 to reduction of the number of excreted helminth eggs or larvae in Aa-5, and B-1 to B-204 of Tables A and B below and variants the faeces of the treated animal before and after treatment. For as mentioned at the bottom of these tables (or salts, solvates, an in vivo administration the compound according to this N-oxides or prodrugs thereof) and b) one compound selected invention, is preferably administered to an animal in an effec 10 tive amount which is synonymous with “pharmaceutically from the group consisting of anthelmintic avermectins (e.g., effective amount’ or “anthelmintically effective amount'. ivermectin, Selamectin, doramectin, abamectin, emamectin Examples of Contemplated Combination Therapies and eprinomectin); milbemycins (moxidectin and milbemy The methods and pharmaceutical compositions of this cin Oxime); pro-benzimidazoles (e.g., febantel, netobimin, invention encompass methods wherein a compound accord 15 and thiophanate); benzimidazole derivatives, such as tricla ing to this invention or a compound corresponding to the use bendazole, thiazole benzimidazole derivatives (e.g., thia according to the invention is the sole active ingredient admin bendazole and cambendazole), carbamate benzimidazole istered to the recipient animal. It is contemplated, however, derivatives (e.g., fenbendazole, albendazole (oxide), that the methods and pharmaceutical compositions also mebendazole, Oxfendazole, parbendazole, oxibendazole, encompass combination therapies wherein a compound is flubendazole); imidazothiazoles (e.g., levamisole and tetra administered in combination with one or more other pharma misole); tetrahydropyrimidines (morantel and pyrantel), ceutically acceptable active ingredients. The other active organophosphates (e.g., trichlorphon, haloxon, dichlorvos, ingredient(s) may be, for example, one or more other com and naphthalophos); Salicylanilides (e.g., closantel, oxyclo pounds according to this invention or one or more other Zanide, rafoxanide, and niclosamide); nitrophenolic com compounds corresponding to the use according to the inven 25 pounds (e.g., nitroxynil and nitroscanate); benzenedisulpho tion. Alternatively (or additionally), the other active ingredi namides (e.g., clorSulon), pyrazineisoquinolines (e.g., ent(s) may be one or more pharmaceutically acceptable com praziquantel and epsiprantel); heterocyclic compounds (e.g., pounds that are not compounds according to this invention or piperazine, diethylcarbamazine, dichlorophen, and phenothi compounds corresponding to the use according to the inven azine); arsenicals (e.g., thiacetarsamide, melorsamine, and tion. The other active ingredient(s) may target the same and/ 30 arsenamide); cyclooctadepsipeptides (e.g., emodepside); or different parasites and conditions. Contemplated active ingredient(s) that may be adminis paraherquamides (e.g. derquantel); amino-acetonitrile com tered in combination with the compounds include, for pounds (e.g. monepantel, AAD 1566); tribendimidine (ami example, pharmaceutically acceptable anthelmintics, insec dine compound); and amidantel (amidine compound); ticides and acaricides, insect growth regulators, anti-inflam 35 including all pharmaceutically acceptable forms, such as matories, anti-infectives, anti-protozoals, hormones, derma salts. tological preparations (e.g., antiseptics and disinfectants), Preferred combinations comprise at least one compound and immunobiologicals (e.g., vaccines and antisera) for dis selected from the group of compounds A-1 to A-697, Aa-1 to ease prevention. Aa-5, and B-1 to B-204 of Tables A and B below and variants Therefore this invention is also directed to the use as a 40 as mentioned at the bottom of these tables (or salts, solvates or medicament of combinations comprisinga) one or more com N-oxides thereof) and pounds according to this invention or one or more compounds abamectin, ivermectin, emamectin, eprinomectin, dor corresponding to the use according to this invention with b) amectin, moxidectin, milbemycin oxime; or one or more pharmaceutically acceptable active compounds closantel, oxyclozanide, rafoxanide, niclosamide; or which differ instructure from componenta). The active com 45 nitroxynil, nitroscanate, clorSulon; or pounds b) are preferably anthelmintic compounds, more pref praziquantel and epsiprantel; or erably selected from the group consisting of avermectins emodepside, derquantel, monepantel. (e.g., ivermectin, Selamectin, doramectin, abamectin, and Examples of such combinations are combinations of one of eprinomectin); milbemycins (moxidectin and milbemycin the compounds A-1 to A-697, Aa-1 to Aa-5, and B-1 to B-204 Oxime); pro-benzimidazoles (e.g., febantel, netobimin, and 50 of Tables A and B below and variants as mentioned at the thiophanate); benzimidazole derivatives, such as a thiazole bottom of these tables with abamectin. benzimidazole derivative (e.g., thiabendazole and cambenda Other examples are combinations of one of the compounds Zole) or a carbamate benzimidazole derivatives (e.g., fen A-1 to A-697, Aa-1 to Aa-5, and B-1 to B-204 of Tables A and bendazole, albendazole (oxide), mebendazole, Oxfendazole, B below and variants as mentioned at the bottom of these parbendazole, oxibendazole, flubendazole, and triclabenda 55 tables with ivermectin. Zole); an imidazothiazoles (e.g., levamisole and tetramisole); Other examples are combinations of one of the compounds a tetrahydropyrimidine (morantel and pyrantel), organophos A-1 to A-697, Aa-1 to Aa-5, and B-1 to B-204 of Tables A and phates (e.g., trichlorphon, haloxon, dichlorvos, and naphth B below and variants as mentioned at the bottom of these alophos); Salicylanilides (e.g., closantel, oxyclozanide, tables with emamectin. rafoxanide, and niclosamide); nitrophenolic compounds 60 Other examples are combinations of one of the compounds (e.g., nitroxynil and nitroscanate); benzenedisulphonamides A-1 to A-697, Aa-1 to Aa-5, and B-1 to B-204 of Tables A and (e.g., clorSulon); pyrazineisoquinolines (e.g., praZiquantel B below and variants as mentioned at the bottom of these and epsiprantel); heterocyclic compounds (e.g., piperazine, tables with eprinomectin. diethylcarbamazine, dichlorophen, and phenothiazine); Other examples are combinations of one of the compounds arsenicals (e.g., thiacetarsamide, melorsamine, and arsena 65 A-1 to A-697, Aa-1 to Aa-5, and B-1 to B-204 of Tables A and mide); cyclooctadepsipeptides (e.g., emodepside); paraher B below and variants as mentioned at the bottom of these quamides (e.g. derquantel); and amino-acetonitrile com tables with doramectin. US 8,877,934 B2 39 40 Other examples are combinations of one of the compounds Tables A and B below and variants as mentioned at the bottom A-1 to A-697, Aa-1 to Aa-5, and B-1 to B-204 of Tables A and of these tables with emamectin. B below and variants as mentioned at the bottom of these Other examples are combinations of a salt of one of the tables with moxidectin. compounds A-1 to A-697, Aa-1 to Aa-5, and B-1 to B-204 of Other examples are combinations of one of the compounds Tables A and B below and variants as mentioned at the bottom A-1 to A-697, Aa-1 to Aa-5, and B-1 to B-204 of Tables A and of these tables with eprinomectin. B below and variants as mentioned at the bottom of these Other examples are combinations of a salt of one of the tables with milbemycin oxime. compounds A-1 to A-697, Aa-1 to Aa-5, and B-1 to B-204 of Other examples are combinations of one of the compounds Tables A and B below and variants as mentioned at the bottom A-1 to A-697, Aa-1 to Aa-5, and B-1 to B-204 of Tables A and 10 of these tables with doramectin. B below and variants as mentioned at the bottom of these Other examples are combinations of a salt of one of the tables with closantel. compounds A-1 to A-697, Aa-1 to Aa-5, and B-1 to B-204 of Other examples are combinations of one of the compounds Tables A and B below and variants as mentioned at the bottom A-1 to A-697, Aa-1 to Aa-5, and B-1 to B-204 of Tables A and 15 of these tables with moxidectin. B below and variants as mentioned at the bottom of these Other examples are combinations of a salt of one of the tables with oxyclozanide. compounds A-1 to A-697, Aa-1 to Aa-5, and B-1 to B-204 of Other examples are combinations of one of the compounds Tables A and B below and variants as mentioned at the bottom A-1 to A-697, Aa-1 to Aa-5, and B-1 to B-204 of Tables A and of these tables with milbemycin oxime. B below and variants as mentioned at the bottom of these Other examples are combinations of a salt of one of the tables with rafoxanide. compounds A-1 to A-697, Aa-1 to Aa-5, and B-1 to B-204 of Other examples are combinations of one of the compounds Tables A and B below and variants as mentioned at the bottom A-1 to A-697, Aa-1 to Aa-5, and B-1 to B-204 of Tables A and of these tables with closantel. B below and variants as mentioned at the bottom of these Other examples are combinations of a salt of one of the tables with niclosamide. 25 compounds A-1 to A-697, Aa-1 to Aa-5, and B-1 to B-204 of Other examples are combinations of one of the compounds Tables A and B below and variants as mentioned at the bottom A-1 to A-697, Aa-1 to Aa-5, and B-1 to B-204 of Tables A and of these tables with oxyclozanide. B below and variants as mentioned at the bottom of these Other examples are combinations of a salt of one of the tables with nitroxynil. compounds A-1 to A-697, Aa-1 to Aa-5, and B-1 to B-204 of Other examples are combinations of one of the compounds 30 Tables A and B below and variants as mentioned at the bottom A-1 to A-697, Aa-1 to Aa-5, and B-1 to B-204 of Tables A and of these tables with rafoxanide. B below and variants as mentioned at the bottom of these Other examples are combinations of a salt of one of the tables with nitroscanate. compounds A-1 to A-697, Aa-1 to Aa-5, and B-1 to B-204 of Other examples are combinations of one of the compounds Tables A and B below and variants as mentioned at the bottom A-1 to A-697, Aa-1 to Aa-5, and B-1 to B-204 of Tables A and 35 of these tables with niclosamide. B below and variants as mentioned at the bottom of these Other examples are combinations of a salt of one of the tables with clorsulon. compounds A-1 to A-697, Aa-1 to Aa-5, and B-1 to B-204 of Other examples are combinations of one of the compounds Tables A and B below and variants as mentioned at the bottom A-1 to A-697, Aa-1 to Aa-5, and B-1 to B-204 of Tables A and of these tables with nitroxynil. B below and variants as mentioned at the bottom of these 40 Other examples are combinations of a salt of one of the tables with praziquantel. compounds A-1 to A-697, Aa-1 to Aa-5, and B-1 to B-204 of Other examples are combinations of one of the compounds Tables A and B below and variants as mentioned at the bottom A-1 to A-697, Aa-1 to Aa-5, and B-1 to B-204 of Tables A and of these tables with nitroscanate. B below and variants as mentioned at the bottom of these Other examples are combinations of a salt of one of the tables with epsiprantel. 45 compounds A-1 to A-697, Aa-1 to Aa-5, and B-1 to B-204 of Other examples are combinations of one of the compounds Tables A and B below and variants as mentioned at the bottom A-1 to A-697, Aa-1 to Aa-5, and B-1 to B-204 of Tables A and of these tables with clorsulon. B below and variants as mentioned at the bottom of these Other examples are combinations of a salt of one of the tables with emodepside. compounds A-1 to A-697, Aa-1 to Aa-5, and B-1 to B-204 of Other examples are combinations of one of the compounds 50 Tables A and B below and variants as mentioned at the bottom A-1 to A-697, Aa-1 to Aa-5, and B-1 to B-204 of Tables A and of these tables with praziquantel. B below and variants as mentioned at the bottom of these Other examples are combinations of a salt of one of the tables with derquantel. compounds A-1 to A-697, Aa-1 to Aa-5, and B-1 to B-204 of Other examples are combinations of one of the compounds Tables A and B below and variants as mentioned at the bottom A-1 to A-697, Aa-1 to Aa-5, and B-1 to B-204 of Tables A and 55 of these tables with epsiprantel. B below and variants as mentioned at the bottom of these Other examples are combinations of a salt of one of the tables with monepantel. compounds A-1 to A-697, Aa-1 to Aa-5, and B-1 to B-204 of Examples of Such combinations are combinations of a salt Tables A and B below and variants as mentioned at the bottom of one of the compounds A-1 to A-697, Aa-1 to Aa-5, and B-1 of these tables with emodepside. to B-204 of Tables A and B below and variants as mentioned 60 Other examples are combinations of a salt of one of the at the bottom of these tables with abamectin. compounds A-1 to A-697, Aa-1 to Aa-5, and B-1 to B-204 of Other examples are combinations of a salt of one of the Tables A and B below and variants as mentioned at the bottom compounds A-1 to A-697, Aa-1 to Aa-5, and B-1 to B-204 of of these tables with derquantel. Tables A and B below and variants as mentioned at the bottom Other examples are combinations of a salt of one of the of these tables with ivermectin. 65 compounds A-1 to A-697, Aa-1 to Aa-5, and B-1 to B-204 of Other examples are combinations of a salt of one of the Tables A and B below and variants as mentioned at the bottom compounds A-1 to A-697, Aa-1 to Aa-5, and B-1 to B-204 of of these tables with monepantel. US 8,877,934 B2 41 42 Examples of Such combinations are combinations of a Tables A and B below and variants as mentioned at the bottom solvate of one of the compounds A-1 to A-697, Aa-1 to Aa-5, of these tables with emodepside. and B-1 to B-204 of Tables A and B below and variants as Other examples are combinations of a solvate of one of the mentioned at the bottom of these tables with abamectin. compounds A-1 to A-697, Aa-1 to Aa-5, and B-1 to B-204 of Other examples are combinations of a solvate of one of the Tables A and B below and variants as mentioned at the bottom compounds A-1 to A-697, Aa-1 to Aa-5, and B-1 to B-204 of of these tables with derquantel. Tables A and B below and variants as mentioned at the bottom Other examples are combinations of a solvate of one of the of these tables with ivermectin. compounds A-1 to A-697, Aa-1 to Aa-5, and B-1 to B-204 of Other examples are combinations of a solvate of one of the Tables A and B below and variants as mentioned at the bottom compounds A-1 to A-697, Aa-1 to Aa-5, and B-1 to B-204 of 10 of these tables with monepantel. Tables A and B below and variants as mentioned at the bottom Examples of Such combinations are combinations of an of these tables with emamectin. N-oxide of one of the compounds A-1 to A-697, and B-1 to Other examples are combinations of a solvate of one of the B-204 of Tables A and B below and variants as mentioned at compounds A-1 to A-697, Aa-1 to Aa-5, and B-1 to B-204 of 15 the bottom of these tables with abamectin. Tables A and B below and variants as mentioned at the bottom Other examples are combinations of an N-oxide of one of of these tables with eprinomectin. the compounds A-1 to A-697, and B-1 to B-204 of Tables A Other examples are combinations of a solvate of one of the and B below and variants as mentioned at the bottom of these compounds A-1 to A-697, Aa-1 to Aa-5, and B-1 to B-204 of tables with ivermectin. Tables A and B below and variants as mentioned at the bottom Other examples are combinations of an N-oxide of one of of these tables with doramectin. the compounds A-1 to A-697, and B-1 to B-204 of Tables A Other examples are combinations of a solvate of one of the and B below and variants as mentioned at the bottom of these compounds A-1 to A-697, Aa-1 to Aa-5, and B-1 to B-204 of tables with emamectin. Tables A and B below and variants as mentioned at the bottom Other examples are combinations of an N-oxide of one of of these tables with moxidectin. 25 the compounds A-1 to A-697, and B-1 to B-204 of Tables A Other examples are combinations of a solvate of one of the and B below and variants as mentioned at the bottom of these compounds A-1 to A-697, Aa-1 to Aa-5, and B-1 to B-204 of tables with eprinomectin. Tables A and B below and variants as mentioned at the bottom Other examples are combinations of an N-oxide of one of of these tables with milbemycin oxime. the compounds A-1 to A-697, and B-1 to B-204 of Tables A Other examples are combinations of a solvate of one of the 30 and B below and variants as mentioned at the bottom of these compounds A-1 to A-697, Aa-1 to Aa-5, and B-1 to B-204 of tables with doramectin. Tables A and B below and variants as mentioned at the bottom Other examples are combinations of an N-oxide of one of of these tables with closantel. the compounds A-1 to A-697, and B-1 to B-204 of Tables A Other examples are combinations of a solvate of one of the and B below and variants as mentioned at the bottom of these compounds A-1 to A-697, Aa-1 to Aa-5, and B-1 to B-204 of 35 tables with moxidectin. Tables A and B below and variants as mentioned at the bottom Other examples are combinations of an N-oxide of one of of these tables with oxyclozanide. the compounds A-1 to A-697, and B-1 to B-204 of Tables A Other examples are combinations of a solvate of one of the and B below and variants as mentioned at the bottom of these compounds A-1 to A-697, Aa-1 to Aa-5, and B-1 to B-204 of tables with milbemycin oxime. Tables A and B below and variants as mentioned at the bottom 40 Other examples are combinations of an N-oxide of one of of these tables with rafoxanide. the compounds A-1 to A-697, and B-1 to B-204 of Tables A Other examples are combinations of a solvate of one of the and B below and variants as mentioned at the bottom of these compounds A-1 to A-697, Aa-1 to Aa-5, and B-1 to B-204 of tables with closantel. Tables A and B below and variants as mentioned at the bottom Other examples are combinations of an N-oxide of one of of these tables with niclosamide. 45 the compounds A-1 to A-697, and B-1 to B-204 of Tables A Other examples are combinations of a solvate of one of the and B below and variants as mentioned at the bottom of these compounds A-1 to A-697, Aa-1 to Aa-5, and B-1 to B-204 of tables with oxyclozanide. Tables A and B below and variants as mentioned at the bottom Other examples are combinations of an N-oxide of one of of these tables with nitroxynil. the compounds A-1 to A-697, and B-1 to B-204 of Tables A Other examples are combinations of a solvate of one of the 50 and B below and variants as mentioned at the bottom of these compounds A-1 to A-697, Aa-1 to Aa-5, and B-1 to B-204 of tables with rafoxanide. Tables A and B below and variants as mentioned at the bottom Other examples are combinations of an N-oxide of one of of these tables with nitroscanate. the compounds A-1 to A-697, and B-1 to B-204 of Tables A Other examples are combinations of a solvate of one of the and B below and variants as mentioned at the bottom of these compounds A-1 to A-697, Aa-1 to Aa-5, and B-1 to B-204 of 55 tables with niclosamide. Tables A and B below and variants as mentioned at the bottom Other examples are combinations of an N-oxide of one of of these tables with clorsulon. the compounds A-1 to A-697, and B-1 to B-204 of Tables A Other examples are combinations of a solvate of one of the and B below and variants as mentioned at the bottom of these compounds A-1 to A-697, Aa-1 to Aa-5, and B-1 to B-204 of tables with nitroxynil. Tables A and B below and variants as mentioned at the bottom 60 Other examples are combinations of an N-oxide of one of of these tables with praziquantel. the compounds A-1 to A-697, and B-1 to B-204 of Tables A Other examples are combinations of a solvate of one of the and B below and variants as mentioned at the bottom of these compounds A-1 to A-697, Aa-1 to Aa-5, and B-1 to B-204 of tables with nitroscanate. Tables A and B below and variants as mentioned at the bottom Other examples are combinations of an N-oxide of one of of these tables with epsiprantel. 65 the compounds A-1 to A-697, and B-1 to B-204 of Tables A Other examples are combinations of a solvate of one of the and B below and variants as mentioned at the bottom of these compounds A-1 to A-697, Aa-1 to Aa-5, and B-1 to B-204 of tables with clorsulon. US 8,877,934 B2 43 44 Other examples are combinations of an N-oxide of one of In some contemplated embodiments, the compounds are the compounds A-1 to A-697, and B-1 to B-204 of Tables A administered with dihydroazole compounds, such as, for and B below and variants as mentioned at the bottom of these example, compounds discussed in WO 2010/75591. tables with praziquantel. In some contemplated embodiments, the compounds are Other examples are combinations of an N-oxide of one of 5 administered with anthelminic proteins. Such as, for example the compounds A-1 to A-697, and B-1 to B-204 of Tables A Bacillus thuringensis crystal proteins e.g. described in WO and B below and variants as mentioned at the bottom of these 2010/053517. tables with epsiprantel. In some contemplated embodiments, the compounds are Other examples are combinations of an N-oxide of one of administered with pyridylmethylamine derivatives, such as, the compounds A-1 to A-697, and B-1 to B-204 of Tables A 10 for example, pyridylmethylamine derivatives discussed in and B below and variants as mentioned at the bottom of these European Patent Appl. EP05395.88 or Intl Patent Appl. Publ. WO2007/115643. tables with emodepside. In some contemplated embodiments, the compounds is Other examples are combinations of an N-oxide of one of administered with nodulisporic acids and derivatives thereof, the compounds A-1 to A-697, and B-1 to B-204 of Tables A 15 Such as, for example, compounds discussed in U.S. Pat. Nos. and B below and variants as mentioned at the bottom of these 5,399,582; 5,945,317; 5,962,499; 5,834,260; 6,221,894; or tables with derquantel. 5,595.991; or Intl Patent Appl. Publ. 1996/29073. Other examples are combinations of an N-oxide of one of Other antiparasitic compounds contemplated to be useful the compounds A-1 to A-697, and B-1 to B-204 of Tables A in combination therapies with the compounds include, for and B below and variants as mentioned at the bottom of these example, imidazo 1.2-bipyridazine compounds discussed in tables with monepantel. US Patent Appl. Publ. No. 2005-0182059; 1-(4-Mono and The compounds as described in this specification can be di-halomethylsulphonylphenyl)-2-acylamino-3-fluoropro combined with pharmaceutically acceptable insecticides or panol compounds discussed U.S. Pat. No. 7,361,689; trifluo acaricides. Such pharmaceutically acceptable insecticides romethanesulfonanilide oxime ether compounds discussed in and acaricides include, for example, acetamiprid, acetoprole, 25 U.S. Pat. No. 7,312.248; n-(phenyloxy)phenyl)-1,1,1-trif amitraz, amidoflumet, avermectin, azadirachtin, bifenthrin, luoromethanesulfonamide and n-(phenylsulfanyl)phenyl bifenazate, buprofezin, bistrifluoron, chlorfenapyr, chlorflua 1,1,1-trifluoromethanesulfonamide compounds discussed in Zuron, chlorantraniliprole, chlorpyrifos, chromafenozide, US Patent Appl. Publ. 2006-0281695; and 2-phenyl-3-(1H clothianidin, cyantraniliprole, cyflumetofen, B-cyfluthrin, pyrrol-2-yl)acrylonitrile compounds discussed in US Appl. cyhalothrin, A-cyhalothrin, cymiazole cypermethrin, cyro 30 Publ. 2006/0128779; isoxazoline compounds discussed in WOPatent Appl, Publ. 2005-085216, WO 2007-026965, WO mazine, deltamethrin, demiditraz, diafenthiuron, diazinon, 2007-070606, WO 2007-075459, WO 2007-079162, WO diflubenZuron, dimefluthrin, dinotefuran, emamectin, esfen 2007-105814, WO 2007-125984, WO 2008-019760, WO Valerate, ethiprole, fenoxycarb, fenpropathrin, fenvalerate, 2008-122375, WO 2008-150393, WO 2009-002809, WO fipronil, flonicamid, flubendiamide, flucythrinate, tau-flu 35 2009-003075, WO 2009-022746, WO 2009-035004, WO Valinate, flufenoXuron, halofenozide, hexaflumuron, imida 2009-045999, WO 2009-051956, WO 2009-035004. cloprid, indoxacarb, lufenuron, metaflumizone, methoprene, In the contemplated combination therapies, the com metofluthrin, methoxyfenozide, nitenpyram, novaluron, pounds according to this invention may be administered noviflumuron, permethrin, phosmet, profluthrin, protrifen before, simultaneously, and/or after the other active ingredi bute, pymetrozine, pyrafluprole, pyrethrin, pyridalyl pyriflu 40 ent(s). In addition, the compounds according to this invention quinazon, pyriprole, pyriproxyfen, rotenone, ryanodine, may be administered in the same composition as the other spinetoram, spinosad, spirodiclofen, spiromesifen, spirotet active ingredient(s) and/or in separate compositions from the ramat, sulfoxaflor, tebufenozide, tebufenpyrad, teflubenzu other active ingredient(s). Further, the compounds according ron, tefluthrin, tetrachlorvinphos, tetramethylfluthrin, thia to this invention and other active ingredient(s) may be admin cloprid, thiamethoxam, tolfenpyrad, tralomethrin, and 45 istered via the same and/or different dosage route. triflumuron. General references discussing antiparasitic When the compounds according to this invention are agents, such as insecticides and acaricides, include, for administered in a combination therapy, the weight ratio of the example, The Pesticide Manual, 13th Edition, C. D. S. Tom active ingredients may vary widely. Factors influencing this lin, Ed., British Crop Protection Council, Farnham, Surrey, ratio include, for example, the particular compounds; the U.K. (2003). 50 identity of the other active ingredient(s) be administered in The compounds as described in tis specification can be the combination therapy; the dosage route of the compounds combined with pharmaceutically acceptable insect growth and other active ingredient(s); the target condition and patho regulators. Such pharmaceutically acceptable insect growth gen; the type (e.g., species and breed), age, size, sex, diet, regulators include, for example, methoprene, pyriproxyfen, activity, and condition of the animal; and pharmacological tetrahydroazadirachtin, chlorfluaZuron, cyromazine, 55 considerations, such as the activity, efficacy, pharmacoki diflubenzuron, fluaZuron, flucycloxuron, flufenoxuron, netic, and toxicology profiles of the compounds and other hexaflumuron, lufenuron, ifenuron, tebufenozide, and triflu active ingredient(s). In some contemplated embodiments, for muron. These compounds tend to provide both initial and example, the weight ratio of the compounds to the other active Sustained treatment of parasite infections at all stages of ingredient(s) is, for example, is from about 1:3000 to about insect development, including eggs, on the animal Subject, as 60 3000:1. In some such instances, the weight ratio is from about well as within the environment of the animal subject. 1:300 to about 300:1. In other such instances, the weight ratio The compounds as described in this specification can be is from about 1:30 and about 30:1. combined with pharmaceutically acceptable anti-protozoals. In addition to other active ingredients, it is contemplated Such pharmaceutically acceptable anti-protozoals include, that the compounds may be administered with one or more for example, triazintriones like, for example, toltraZuril and 65 other compounds that beneficially affects (e.g. enhances or ponaZuril and triazindiones Such as claZuril, diclaZuril and prolongs) the activity (or other characteristic, Such as safety) letraZuril. of the compounds. For example, it is contemplated that the US 8,877,934 B2 45 46 compounds may be administered with one or more synergists, with the physical properties of the active ingredient, mode of such as, for example, piperonylbutoxide (PBO) and triphenyl application and environmental factors such as Soil type, mois phosphate (TPP). Other synergists include, for example, ture and temperature. N-(2-ethylhexyl)-8,9,10-trinorbom-5-ene-2,3-dicarboxam Invertebrate pests are controlled in agronomic and nona gronomic applications by applying one or more compounds ide (also known as “ENT8184” or “MGK264) and Verbutin 5 of formula (I), typically in the form of a composition, in a (also known as “MB-599). biologically effective amount, to the environment of the pests, This invention also is directed to kits that are, for example, including the agronomic and/or nonagronomic locus of infes suitable for use in performing the methods of treatment tation, to the area to be protected, or directly on the pests to be described above. The kit comprises a therapeutically effective controlled. amount of one or more compounds of this invention, and an 10 Examples of Suitable compositions comprising a com additional component. The additional component(s) may be, pound of the invention include granular compositions for example, one or more of the following: another ingredient wherein the additional active compound is present on the (e.g., an excipient or active ingredient), an apparatus for com- same granule as the compound of the invention or on granules bining the compound of this invention with another ingredi- is sersS.om those of Rat the invention. fth ent and/or for administering the compound of this invention, To achieve contact with a compound or composition of the invention to protect a field crop from invertebrate pests, the or a diagnostic tool. compound or composition is typically applied to the seed of The compounds used according to this invention show an the crop before planting, to the foliage (e.g., leaves, stems, excellent activity in treating parasite infections and in addi- flowers, fruits) of crop plants, or to the soil or other growth tion are acceptable for the animals treated. 20 medium before or after the crop is planted. Compounds of the current invention are useful agronomi- One embodiment of a method of contact is by spraying. cally for protecting field crops from phytophagous inverte- Alternatively, a granular composition comprising a com brate pests and also nonagronomically for protecting other pound of the invention can be applied to the plant foliage or horticultural crops and plants from phytophagous inverte- the soil. Compounds of this invention can also be effectively brate pests. 25 delivered through plant uptake by contacting the plant with a Invertebrate pests are insects, acarids, mollusks, fungi and composition comprising a compound of this invention. nematodes that cause damage to field crops or otherhorticul tural crops and plants. EXAMPLES Nonagronomic uses of the compounds of this invention and compositions include control of invertebrate pests in 30 The following examples are merely illustrative, and not stored grains, beans and other foodstuffs and in textiles Such limiting to the remainder of the disclosure in any way. as clothing and carpets. Nonagronomic uses of the com pounds of formula (I) and compositions also include inverte- A. General Description of Synthesis of Compounds brate pest control in ornamental plants, forests, in yards, According to this Specification along roadsides and railroad rights of way, and on turf such as 35 lawns, golf courses and pastures. The compounds as described in this specification can be Compounds of this invention will generally be used as an obtained by various synthesis routes. A person skilled in the invertebrate pest control active ingredient in a composition, art will choose the synthetic route to obtain compounds as i.e. formulation, with at least one additional component described in this specification depending on the nature of its selected from the group consisting of Surfactants, Solid dilu- 40 radicals as defined in Formula (I). This is illustrated in the ents and liquid diluents, which serves as a carrier. The formu- following schemes, which are merely illustrative but not lim lation or composition ingredients are selected to be consistent iting the disclosure in any way.

Scheme 1:

route 1 X A1. PG A1 PG A1 PG 1. R-Y l,41 N . " R-AcR6R) 8. R-A crop, - 1-DX R-A(CRR). Y&2Y R-y R-N H-N 1-I H es ls Yl 1-II l, , l, , Ys 1Y Ys 1Y

1-I -- 1-II (R5 = H) US 8,877,934 B2 47 48 -continued route 2 A1 H 1" RV R- R (CRR)67 CR'R'), 3 X R R5-N 1. H 1. n Y His1-VII r Y&na 2Y b YSn1 -Y 1-I 1-IV R R2 R3 21 R3 2 R2 RI d andfor O e. O OH O OH 1-V 1-Wa

S R2 S RI O R2 O R1

2 RI 2 R2 21 R1 21 R2 R- R R3 R- R R3 R- R R3 R- R R3 (CRR). (CRR). f (CRSR) (CRR7) M -- M -e- M -- M R-N R-N R-N R-N . Yl ls Yl . Yl 1. Yl YS3 N2Y2 Ys 1Y2 YS3 N2Y2 Ys 1Y2 1-X 1-Xa 1-VI 1- WIa Exemplary conditions: a: palladium acetate, 2,2'-Bis(diphenylphosphino)-1,1'-binaphthyl (BINAP), caesium carbonate, dioxane; b: 1-methoxy-2-propanol, 110° C. d: oxalyl chloride, dichloromethane (DCM), dimethylformamide (DMF) then DCM, triethylamine (TEA); e: 2-(1H-Benzotriazole-1-yl)-1,1,3,3-tetramethylaminium hexafluorophosphate (H BTU), diisopropylethylamine, DMF, room temperature; f; Lawesson's reagent, tetrahydrofuran (THF), 130° C.

A compound of general formula 1-VI can be synthesized as art; if PG is a Boc-group, for example, the protecting group shown in scheme 1: in route 2 a heteroaryl compound 1-I is can be removed by an acid like trifluoroacetic acid or hydro reacted with a diamine 1-VII to give 1-IV. 1-I contains a 45 chloric acid to give the amine 1-IV. Other suitable methods Suitable leaving group X, which is preferably a halogon like for protection and deprotection are described in, for example, chloro or bromo or a nitro group. The reaction with 1-VII Green and Wuts, Protective Groups in Organic Synthesis, 3" takes place in an inert solvent like DMF or dimethylaceta- edition, John Wiley & Sons, New York, 1999. If 1-I and 1-II mide, preferably in a diol-derived solvent like ethylenegly- are reacted and R is H, the resulting 1-VIII can be reacted colmonomethylether or propyleneglycolmonomethylether or so with 1-IX to give the intermediate 1-III. 1-IX contains a 1-methoxy-2-propanol and preferably at elevated tempera- Suitable leaving group Y, e.g. a chloro and is, depending on the tures. The reaction might also be done without any solvent nature of the radical Ranalkylating or acylating agent that is with neat reactants. 1-VII is employed preferably in excess. reacted under conditions known to a person skilled in the art. An additional base might be added. Alternatively, the reaction 1-IV is acylated with an unsaturated acid derivative 1-V to can be done in pyridine as solvent. The diamine can be pro- is give the final product 1-VI. 1-V can be accompanied by the tected with a Suitable protecting group as in 1-II of route 1. isomeric 1-Va, so that a mixture of 1-V and 1-Vais used in the Suitable protecting groups (PG) for the nitrogen in 1-II acylation step. In this case a mixture of 1-VI and 1-VIa is include, but are not limited to, preferably tert-butyl carbamate formed that can be separated by methods known to a person (Boc), benzyl carbamate (Cbz) and the like. A protected skilled in the art, e.g. by chromatography. Or 1-Vacan be used diamine 1-II can be reacted under the same conditions as 60 in a pure form in the acylation step to give 1-VIa. Thus, if in 1-VII, alternatively Pd-catalysis can be used employing a the following descriptions and Schemes the acid 1-V is men Pd-containing molecule like palladium acetate, a phospho- tioned, the same applies for the isomeric acid 1-Va, either in rus-containing ligand like BINAP, a base like caesium car- its pure form or in form of a mixture of 1-V and 1-Va. The bonate or sodium tert-butoxide in a solvent like an ether- same applies for reaction products derived from 1-V: these containing solvent like diethylether, dioxane or can be obtained in pure form if the isomerically pure 1-V or tetrahydrofuran, preferably dioxane or an inert solvent like 65 1-Vaare used in the acylation step, or they can be obtained as toluene. The protecting group in the intermediate 1-III can be a mixture if a mixture of 1-V and 1-Va is used and might be removed by suitable methods known to a person skilled in the separated then by methods known to a person skilled in the US 8,877,934 B2 49 50 art, e.g. by chromatography. There are many acylation meth C-C-alkylaminocarbonyl, di(C-C-alkyl)aminocarbonyl ods known to a person skilled in the art: 1-V can be converted or phenyl, and wherein at least one of R'' and R'=C-C- to an acid chloride with oxalyl chloride, thionyl chloride or alkoxy or C-C-haloalkoxy, B is N, A is N or a bond, n is 2, the like which can be isolated or used directly to react with RandR'—H, and Rand Rare defined as in formula (I) or 1-IV in the presence of a base like triethylamine or diisopro- 5 (II) above, are new and a subject of this invention. In one pylethylamine to give 1-VI. The base might also be polymer preferred embodiment R'—C, -Co-alkoxy or C-C-ha Supported to ease work-up. The base might be used in excess, loalkoxy, in another preferred embodiment R'—C-C- the excess might be removed using aqueous work-up or poly alkoxy or C-C-haloalkoxy. mer-supported reagents like polymer-Supported acid chlo ride. The acid I-V can also be reacted directly with the amine 10 I-IV using coupling reagents like N.N.N',N'-tetramethyl-O- (7-azabenzotriazol-1-yl)-uronium hexafluorophosphate Scheme 2: (HATU), N.N.N',N'-tetramethyl-O-(1H-benzotriazol-1-yl)- H uronium hexafluorophosphate (HBTU), 1-hydroxy-7-aza benzotriazole (HOAt), N,N'-dicyclohexylcarbodiimide is R-B 1-W and or (DCC) or the like. Other suitable amide coupling procedures V 1-Wa are described in Goodman, M., Felix, A.; Moroder, L.; (CRSR) -->a or b Toniolo, C. in volume E22a of Methods of Organic Chemistry (Houben-Weyl), Synthesis of Peptides and Peptidomimetics, R5 - 4' edition, Georg Thieme Verlag, Stuttgart N.Y., 2002. 1-VI PG and 1-VIa can be converted into their thiocarbonyl analogue 2-I 1-X and 1-Xa by treatment with, for example, Lawesson’s reagent under microwave heating. Other methods are O R2 O RI described in, for example, Smith, M.B.: March, J.; March's Advanced Organic Chemistry, John Wiley & Sons, Hoboken; 2 R1 21 R2 N.J., 2007, 1277-1280. A compound of general formula 1-VI 25 can be substituted at Y'-Y. This substituent can already be R- R R3 R- R R3 present in the heteroaryl compound 1-I. A person skilled in (CRR). -- (CRR). the art will appreciate that it can also be introduced in a M A compound 1-III, 1-IV or 1-VI. For example, Y-Y in 1-I might be substituted by a potential leaving group like, for R- R5 - example, halogen, which can be replaced by another group, 30 PG PG for example a nucleophilic group in, for example, a nucleo 2-II 2-IIa philic substitution reaction. Or, for example, Y-Y in 1-III might be substituted by a potential leaving group like, for example, halogen, which can be replaced by another group, for example a nucleophilic group in, for example, a nucleo- 3 O R2 O RI philic substitution reaction. Or, for example, Y-Y in 1-IV might be substituted by a potential leaving group like, for 2 R1 2 R2 example, halogen, which can be replaced by another group, for example a nucleophilic group in, for example, a nucleo R-B R3 R-B R3 philic Substitution reaction. 1-I might also be substituted at 40 V V Y'-Y' with a group that can react with a group present in the (CRR). -- (CRR). reaction partner 1-II or 1-VII like, for example, the amino M M group in 1-II or 1-VII. In this case the reacting group in 1-I can R- R5 - be protected by a protecting group by methods known to a H H person skilled in the art. For example, 1-I can be substituted 2-III 2-IIIa by an acyl group. This acyl group can be protected as, for 45 example, an oxolan prior to the reaction with 1-II or 1-VII and deprotected by, for example, aqueous acid after the reaction l with 1-II or 1-VII as described in, for example, Green and O R2 O R1 Wuts, Protective Groups in Organic Synthesis, 3" edition, John Wiley & Sons, New York, 1999. The same applies to the 50 A 21 RI 2 R2 following schemes in an analogous way. The heteroaryl compound 1-I can be substituted at the R-B R3 R-B R3 1-X d V V 67 N-Atom with oxygen, thus being a heteroaryl-N-oxid, for -- a- (CRSR) -- CR R’) ? example a quinoline-N-oxid or a pyridine-N-oxid. Methods 1-Xa R-N R-N for the synthesis of such heteroaryl-N-oxides are described 55 in, for example, R. Kreher (editor), volume E7a of Methods of Y4 ls Yl Y4 1. Yl Organic Chemistry (Houben-Weyl), Hetarenes II part 1, 4" I edition, Georg Thieme Verlag, Stuttgart-N.Y., 1991. A person 2 2 skilled in the art will appreciate that the synthetic transfor Ys-Y Ys-Y mations described in Scheme 1 result in this case in the cor- 60 1-VI 1-VIa responding heteroaryl-N-oxides of heteroaryl compounds of Exemplary conditions; a: oxalyl chloride, DCM, DMF then DCM, general formula 1-VI and 1-VIa, for example. triethylamine;b; HBTU, N-ethyl-diisopropylamine (EDIPA), DMF, Intermediates of formula 1-IV in whichY-Y are C, sub room temperature; c.; palladium acetate, BINAP, caesium carbonate, stituted by R. R. R'' and R'=halogen, C-C-alkyl, dioxane; d. Lawesson's reagent, THF, 130° C. C-C-haloalkyl, C-C-alkoxy, C-C-haloalkoxy, nitrilo. 65 nitro, amino, C-C-alkylamino, di(C-C-alkyl)amino, An alternative synthetic route is shown in scheme 2: the C-C-alkylthio, C-C-alkyl carbonyl, aminocarbonyl, diamine 2-I is coupled with 1-V as described for 1-IV fol US 8,877,934 B2 51 52 lowed by deprotection as described for 1-III yielding 2-III in Scheme 1. The protecting group (PG) is removed and the which is reacted with 1-I as described for the reaction of 1-I amine 3-IV is acylated with an unsaturated acid 1-V to give with 1-II. the final product 3-V by methods that have been described in

Scheme 3: A1 PG PG A1 R*-B. R-B O (CRR). n R H CRR), R5 N1 HOOC N1

Hs 1.2 3-II8. 411. Ni

2 Ys-Y Ys-YN 3-I 3-III PG | R-B Y(CR6R7) b X 3-VI

PG H

R-B (CRSR) R-B CR'R'). RS RS N1 N1

ls N 2 ls 2 YsN 1Y YsN 1Y 3-VII 3-IV v O R2 O R2

2 RI -H 2 RI R-B Y(CRSR)R3 R-B (CRSR) R-B CR-R).R3 R5 d R5 R5 N1 1-V N1 N1 ves ls Yl ves 2 2 2 YsN -Y YsN 1Y YsN -Y 3-IX 3-VIII 3-V Exemplary conditions: a: oxalyl chloride, DCM, DMF then DCM, triethylamine b: LiAlH4, THF: c: DCM, triethylamine; d: HBTU, EDIPA, DMF, room temperature

A compound of general formula 3-V can be synthesized as scheme 1. The oxo-group in 3-III can be reduced to give 3-VII shown in Scheme 3: A heteroarylaminocompound 3-I is acy- 65 employing reducing agents like, for example, lithium alu lated with an amino acid derivative 3-II by methods known to minium hydride. Other methods are described in, for a person skilled in the art, some of which have been described example, Smith, M. B.; March, J.; March's Advanced US 8,877,934 B2 53 54 Organic Chemistry, John Wiley & Sons, Hoboken; N.J., -continued 2007, 1841-1842. The sequence of deprotection and acyla tion with an unsaturated acid gives the final product 3-IX. O R2 3-VII can also be obtained by reacting heteroarylaminocom pound 3-I with 3-VI instead of 3-II. 3-VI contains a suitable - H s R1 leaving group X, like, for example, chloride or methanesulfo 8. - 3 nyl under conditions that are described in, for example, R4 O "ScRR), R S "Scre, WO2006/60461 (example 303-304.4) or EP1574504 (ex 10 ample 2). Aminoacid derivatives 3-II are commercially avail N -R N -R able and can be transformed by methods known to a person skilled in the art to compounds 3-VI. 41N 1. Intermediates of formula 3-IV in whichY'-Y are C, sub 15 stituted by R', R'R'' and R=halogen, C-C-alkyl, 's- 's- C-C-haloalkyl, C-C-alkoxy, C-C-haloalkoxy, nitrilo, 3-IV 4-III Exemplary conditions: nitro, amino, C-C-alkylamino, di(C-C-alkyl)amino, a: Lawesson's reagent; C-C-alkylthio, C-C-alkyl carbonyl, aminocarbonyl, b: HBTU, diisopropylethylamine, DMF, room temperature C-C-alkylaminocarbonyl, di(C-C-alkyl)aminocarbonyl A compound of general formula 4-III can be synthesized as or phenyl, and wherein at least one of R'' and R'=C-C- shown in Scheme 4: The oxo-group in 3-III can converted to alkoxy or C-C-haloalkoxy, B is N, A is Nora bond, n is 2 or a thioxo-group by methods known to a person skilled in the 3, RandR'—H, and Rand Rare defined as in formula (I) 25 art, for example, the Laweson's reagent can be used. This and or (II) above, are new and a subject of this invention. In one other methods is described in, for example, Smith, M. B.: preferred embodiment R'—C-C-alkoxy or C-C-ha March, J.; March's Advanced Organic Chemistry, John Wiley loalkoxy, in another preferred embodiment R'=C-C- & Sons, Hoboken; N.J., 2007, 1277-1280. The sequence of 30 deprotection and acylation with an unsaturated acid that has alkoxy or C-C-haloalkoxy. been described in scheme 1 gives the final product 4-111. Alternativly, the conversion of the oxo- into the thioXo-group Scheme 4: can be done after deprotection of 3-III to 3-IV to give the 35 thioxo compound 4-II which is then acylated to the final - PG -PG - product 4-111. R-B R-B R-B Intermediates of formula 4-II in whichY-Y is substituted CRR)- sCRR)- sCR'R'). by R', R', R'' and R'-halogen, C-C-alkyl, C-C-ha loalkyl, C-C-alkoxy, C-C-haloalkoxy, nitrilo, nitro, N N1 is N N1 is N N1 is amino, C-C-alkylamino, di(C-C-alkyl)amino, C-C- 40 alkylthio, C-C-alkyl carbonyl, aminocarbonyl, C-C-alky sy 8. sy sy laminocarbonyl, di(C-C-alkyl)aminocarbonyl or phenyl, and wherein at least one of R'' and R'—C-C-alkoxy or Ys-Y Ys-Y Ys-Y C-C-haloalkoxy, B is N, A is Nora bond, n is 2 or 3, Rand 3-III 4-I 4-II 45 R=H, and R and R are defined as in formula (I) or (II) above, are new and a Subject of this invention. In one pre ferred embodiment R'—C, -Co-alkoxy or C-C-ha loalkoxy, in another preferred embodiment R'=C-C- alkoxy or C-C-haloalkoxy.

Scheme 5: O

1.H + ...HOC --> CO2H 5-VIIa 5-III US 8,877,934 B2

-continued route 1 O OH HOC 1N CO2H OH O OH

R1 ls Oalkyl --- RI 1. Oalkyl — b" - RI lus OH --- R1 -- COEt 5-I 5-II 5-IV 5-V

R1

d R1 1S1 COEt2 - N-N 2 Et 5-VI 5-VIa /e route 2 RI R2 HOC 1n COH R. R2 - f - R3 R3 2 2 -CO2 2 R2 2 RI 5-III O CO2H CO2H 5-VII 1-V 1-Va. t R1 r COEt it NCOEt R3 R3 5-XI 5-XIa t route 3 3 O RS-CO:Et O OH ls 5-VIII COEt h COEt R1 Oalkyl 9. RI — R. 5-I R3 R3 5-IX 5-X Exemplary conditions: a: sodium borohydride, methanol; b: pyridine, piperidine; c. ethanol, HCl; d. phosphorpentoxide; e: NaOH: f: pyridine, piperidine, reflux: g: LiN(Si(CH3)3)2, THF; h; sodium borohydride, toluene; i: phosphorpentoxide

The unsaturated acids used for acylation (1-V in scheme 1) 50 Alternatively, the aldehyde 5-Vila can be condensed with can be synthesized in several ways, many of which are malonic acid to give the hydroxyacid 5-IV. The hydroxyacid described in: J. Fallbe in volume E5, part 1 of Methods of 5-IV might be isolated or used directly in a dehydration step Organic Chemistry (Houben-Weyl), Carboxylic acids, 4" to yield I-V. Preferably, the hydroxyacid is esterified to 5-V edition, Georg Thieme Verlag, Stuttgart-N.Y., 1985. The pre which is dehydrated to 5-VI and hydrolysed to the acid 1-V. ferred route will be chosen by a person skilled in the art 55 Methods for the dehydration of 5-IV and 5-V are described in, according to the nature of the radicals R, R and R. For for example, M. Jagodzinska et al.; Tetrahedron 63 (2007), example, in scheme 5, if R is H and R' is alkyl preferably 2042-2046: P. F. Bevilaqua, J. Org. Chem. 94 (1984), 1430 route 2 will be chosen. If R is Hand R' is alkylsubstituted by 1434 and include treatment of a hydroxyacid or -ester like halogen like F and/or Cl, route 1 or 3 will preferably be 5-IV or 5-V with POs at preferably elevated temperatures or chosen. According to route 2 in Scheme 5 malonic acid 5-III 60 treatment with diethylazodicarboxylate and triphenylphos is condensed with an aldehyde or ketone 5-VII to yield phine. directly the crotonic acid 1-V, which can be accompanied by According to route 3 an ester 5-I is condensed with a the isomeric 1-Va. Suitable reaction conditions include heat CH-acidic ester 5-VIII to give a beta-keto ester 5-IX which is ing the reactants in a solvent, preferably pyridine with the reduced to the hydroxyester 5-X. Methods for the condensa addition of piperidine. According to route 1, a carboxylic 65 tion of an ester with another CH-acidic ester are known to a ester 5-I is reduced to the hemiacetal 5-11, which is con person skilled in the art, as well as methods for the reduction densed with malonic acid in a manner analogous to route 1. of a keto group to a hydroxygroup and are described in, for US 8,877,934 B2 57 58 example, M. Jagodzinska et al.; Tetrahedron 63 (2007), 2042- -continued 2046; T. Kitazume; J. Fluorine Chemistry 42 (1989), 17-29. RI R3 5-X is then converted to the crotonic acid 1-V in a manner 3 analogous to the one described above for 5-V. RN2 R2 O N RI In all of the described routes, 1-V might be accompanied 5 n by the isomeric 1-Va. Depending on the nature of the radicals 2 R" and R the isomers 1-V and 1-Va can beformed in varying O N -N" O R proportions. For example if R is H, the E-isomer 1-V is N predominantly formed. The isomeric 1-V and 1-Va can be S 1. separated by methods knownto a person skilled in the art, e.g. to 6-V 4%Ny. by chromatography and can be used as pure isomers in Sub- 6-Ie 2 sequent reactions. Or 1-V and 1-Va can be used as a mixture | Ys-Y in Subsequent reactions and the resulting isomeric products N can be separated in a later step. Unsaturated acids with 6-IV R-alkyl substituted by alkylamino or dialkylamino and R3 R’—H and R=H can also be obtained as described in, for 15 H Unsaturatedexample, WO2006/127203 acids with R'—SFs or US2003,50222, and R—H and respectively. R=H can S N N N-R also be obtained as described in, for example, V. K. Brel, NH O R2 Synthesis 2006, 339-343. Unsaturated acids with HN1 R'-alkylthio and alkylsulfonyl and R=H and R=H can 20 als also be obtained as described in, for example, J. T. Moon, 421 Bioorg. Med. Chem. Letters 20 (2010) 52-55. Many unsatur- | Y ated acids 1-V used as starting materials are also commer- YS . cially available by a large number of vendors as listed in, for n1 example, the Symyx Available Chemicals Directory (ACD). 25 6-VI Scheme 6: Exemplary conditions; a: hydrazine hydrate, 150° C.;b; DCM, oxalyl chloride, DMF, room temperature; c.; benzene, room temperature; d. X -N". acetonitrile, room temperature; e: DMF, K2CO3, room temperature 1. 1. Compounds of the general formula 6-IV can be synthe 42- 42 30 sized as shown in scheme 6: A heteroaryl compound 1-I | 8. ? N containing a Suitable leaving group X is reacted with hydra HNNH. 2 Zine to give the hydrazino compound 6-I. Suitable leaving Ys-Y Ys-Y groups comprise, for example, a halogen like chloro. The reaction is performed preferably at elevated temperatures. An 1-I 6-I is unsaturated carboxylic acid 1-V is converted into its acid b chloride 6-II by methods known to a person skilled in the art, 1- V -> which is converted to the acyl isocyanate 6-III by reaction RI R1 with an isocyanate salt like, for example, silver isocyanate. R R 6-III is then reacted with the hydrazino compound 6-I to give 21 R2 AgNCO 2 R2 the final product 6-IV, for example by reaction in a solvent C 40 like DMF in the presence of a base like potassium carbonate. COC The thioxo analogue 6-VI is synthesized analogously by O N employing the acyl isothiocyanate 6-V, that is obtained from 6-II N the carboxylic acid chloride 6-II by reaction with an isothio O cyanate salt like, for example, potassium isothiocyanate in a 6-III 45 solvent like, for example, acetonitrile. Similar reactions are described in, for example, WO2004/48347; O. Tsuge, T. pses e Hatta, R. Mizuguchi, Heterocycles 38, (1994), 235-241; G. Shaw, R. N. Warrener, J. Chem. Soc. (1958) 157-161; G. Shaw, R. N. Warrener, J. Chem. Soc. (1958) 153-156. Scheme 7: O O R H R ls R NH nN.1 NN NH2 NN N1 2 es Yl a es HNNH x HO y41. Nyl Y.s Y —- Y.s Y. — - Y.s Y n1 n1 n1 3-I 7-I 7-II RI e R 21 c ord R2 CO2H US 8,877,934 B2 60 -continued

7-III

| -> 7-IV Y2 9.

7-VI 7-VII Exemplary conditions: a: sodium cyanate, acetic acid; b: water, ethanol, reflux; c.; oxalyl chloride, DCM, DMF then DCM, triethylamine; d: HBTU, diisopropylethylamine, DMF, room temperature; e: Lawesson's reagent; f. benzene, triethylamine, reflux: g: THF.

40 A compound of general formula 7-III can be synthesized as verting the carbazine 7-II to the thiocarbazine 7-IV with, for shown in scheme 7: a heteroarylamine 3-I is converted to the example, Lawesson’s reagent, followed by acylation with corresponding urea 7-I by treatment with sodium cyanate. 1-V as described above. The thiocarbazine 7-IV can also be Reaction with hydrazine according to U.S. Pat. No. 5,098.462 yields the carbazine 7-II which is acylated with an unsatur- 45 obtained by conversion of the heteroarylamine 7-VI into the ated acid 1-V as described in scheme 1 to give the final isothiocyanate 7-VII by reaction with thiophosgen followed product 7-III. The thioxo-analogue 7-V is obtained by con by addition of hydrazine.

Scheme 8:

R O route 1 route 2 X 41n s Y1 Y&n2 2Y Y&n2 2Y 8-I 8-IX R5 (EtO)2P COEt COEt 8. Y R6 8-II US 8,877,934 B2 61 62 -continued R6 R6 R R so f CO2H n Y n Y

Y&n 22Y Y&n N2Y 2 8-III 8-XIII / R6 / R route 4

COEt 41N e1 NHPG 8-XIV 2

21\-1 NHPG

8-XV

/ /-1 R6 R4 NH2 - 41 N - -- y41 Yy Y&N2 2Y Y&na 2Y Y3NN 2 8-V 8-VI VII 1-V e R6 f R3 R6 R4 R3 R N N R1 R h S R2 '''O R2 41 N 41 N Y&N N2Y YS2Y 8-XVI 8-VIII Exemplary conditions: a: THF, LiOH:b: hydrogen, ethanol, Pd, C; c: LiAlH4; d: 1. phthalimide, PPh3, N2(COOEt)2, THF, 2. NH4, methanol; e: H BTU, diisopropylethylamine, DMF; f, Zn/Cu, Pd(PPh3)2, dimethylacetamide: g: NaNH2, NH3); h: Lawesson's reagent, THF, 130° C.: i: Pd(PPh3)2Cl2. 1,4-diazabicyclo[2.2.2]octane, THF.

55 A compound of general formula 8-VIII can be synthesized intermediate phthalimide. Substitution of the nitrogen in 8-VI as shown in Scheme 8: in route 1 a heteroarylcarbonyl com to give 8-VII can be done by methods known to a person pound 8-I is reacted with a phosphonic acid derivative 8-II in skilled in the art using, for example, alkylation agents like a Horner-Wadsworth-Emmons reaction to form the unsatur alkylhalogens or using reductive alkylation procedures as ated ester 8-III which is reduced to the saturated ester 8-IV by 60 described in, for example, Smith, M.B.: March, J.; March's methods known to a person skilled in the art, e.g. hydrogena Advanced Organic Chemistry, John Wiley & Sons, Hoboken; tion with a suitable catalyst like, for example, palladium on N.J., 2007, 1288-1292. Acylation with the unsaturated acid charcoal. Reduction of the ester to the alcohol 8-V by, for 1-V under conditions that have been described in scheme 1 example, a hydride transfering reagent like lithium alu gives the final product 8-VIII. A person skilled in the art can minium hydride is followed by transformation to the amine 65 choose an alternative route depending on the availability, for 8-VI. The latter transformation can be archived by, for example commercial availability of starting materials. In example, the known Gabriel synthesis via formation of an route 2 a heteroaryl compound 8-IX containing a Suitable US 8,877,934 B2 63 64 leaving group X like a halogen, preferably a iodine, is reacted halogen, preferably an iodine or bromine, is reacted with a with a Zincorganic reagent that is synthesized, for example in protected amine 8-XIV containing a terminal triple bond in a situ, from the ester 8-X containing a halogen atom Y. prefer Sonogashira-type coupling. Reduction of the triple bond and ably an iodine, by methods known to a person skilled in the removal of the protecting group yields the amine 8-VI. Alter art, for example as described in Sakamoto, T., Synthesis, natively, 8-IV can be obtained by coupling of the protected (1988), 485-486 to give the intermediate ester 8-IV. In route 3 amine 8-XV containing a terminal double bond with 8-IX in a heteroarylalkyl compound 8-IX is reacted with a carboxylic a Heck-type reaction followed by reduction and deprotection. acid 8-XII containing a halogenatom Z to give the Substituted Conversion into the thiocarbonyl analogue 8-XVI can be acid 8-XIII as described in, for example, Adger, B.M., et. Al. achieved by treatment with, for example, Lawesson’s reagent J. Chem. Soc. Perkin Trans. I (1988), 2791-2796, that is 10 under microwave heating. Other methods are described in, for reduced to the hydroxy intermediate 8-V by methods known example, Smith, M. B.; March, J.; March's Advanced to a person skilled in the art. In route 4, a heteroaryl com Organic Chemistry, John Wiley & Sons, Hoboken; N.J., pound 8-IX containing a suitable leaving group X like a 2007, 1277-1280.

Scheme 9: R6 R R O COEt 41 N 41n | Y&na 2Y Y&na 2Y 8-IV 8-I NO l C R6 9-I

R6 R6 NO R6 R R R R CO2H NH2 afn 2 NO s ---b sy se-d s -- s Y&na 2Y Y&na 2Y Y&n2 2Y Y&na 2Y 8-XIII 9-III 9-II 9-IIa

R6 R R4 N1 H s Y&na 2Y 9-IV US 8,877,934 B2 65 66 -continued R6 O R2 R6 S R2 R 2 R 21 N RI f N R1 l 3 !. 3 n Y R R n Y R R

9-VI

Exemplary conditions: a: NaOH, H2O;b; NaNH2SO4; c. 1, DCM, TEA 2. DCM, methanesulfonyl chloride, TEA; d; hydrogen, Raney nickel, methanol; e: HBTU, diisopropylethylamine, DMF; f: Lawesson's reagent, THF, 130° C.

2O Compounds of the general formula 9-V can be synthesized example, WO2008/125839 (example 36) followed by reduc as shown in scheme 9: a heteroarylcarboxylic acid 8-XIII that tion to 9-III as described in, for example, Monti. D. et al. has been described in scheme 8 is transformed into the amine Farmaco, 36(6), (1981), 412–418. The primary amine in 9-III 9-III with a Schmidt reaction as described in, for example, is then substituted as has been described in scheme 8 and Claudi, F. et al. Eur: J. Med. Chem. 30(5), (1995), 415-421. 25 acylation with a unsaturated acid as has been described in 8-XIII can also be obtained by hydrolysis of the ester 8-IV scheme 1 gives the final product 9-V. Conversion into the that has been described in scheme 8. Alternatively, a het- thiocarbonyl analogue 9-VI can be achieved by treatment eroarylcarbonyl compound 8-I can be transformed to a mix- with, for example, Lawesson’s reagent under microwave ture of 9-II and the isomeric 9-IIa as described in, for heating.

Scheme 10: H n 3 O A. R R3 EtO OEt R4 l \ –c. N O R3 YC TN-67(CRR) S 29 C-P-OEt N O R-D -e-10-11 R*-B.| O - E - A1 V2 E 8. (CRR7) O 411. Ny R-i? R" B CRR),CRR) Y.s Y E R n1 als E 1O-I 41 Ny R2 s I, 41 Ni R1 n1 \ 1O-III Ys-Y SOCI 10-IV 10-VI d and for O RI l R2 RI R2 \ 5-VII / SOCI US 8,877,934 B2 67 68 -continued 10-W and for 10-Va. O R’ O R' s/ 21 s/ 2 M R1 M R2 R3 R3 R*-B. R*-B. (CRR). -- (CRR). 5 M 5 M R - R - E E

r 2 r 2 Ys-YN Ys-YN 10-V 10-Va. O. O. R.2 \/ O O O O 9 EtO1 2 R1 VW V/ || 1O-IX 1n 1 - - -S P-OEt VII- -- - 5 - 10-VI+10-VIa o1 N Ero1 N1 \ f RI 10-VII OEt V / 10-VIII EtO1X-l R2 10-IXa Exemplary conditions: a: DCM, TEA, 0°C.;b; LiN(Si(CH3)3)2, THF, -78°C.; c: LiBr, DBU, THF, -10°C. to room temperature; d; TEA, DCM.; e: (EtO)2POCl, n-butyllithium (n-Buli), THF, -80°C.; f. tetrabutylammonium iodide, acetone, reflux, then sulfuryl chloride, triphenylphospine, DCM.

A compound of the general formula 10-V can be synthe example, Z. Wrobel, Tetrahedron 57 (2001), 7899-7907. sized as shown in scheme 10: A compound 10-I which con Depending on the nature of the radicals R', R and R the tains an NH-group is reacted with an alkylsulfonic acid chlo- 35 isomeric final products 10-V and 10-Va can be formed in ride 10-II in the presence of a suitable base like triethylamine differing proportions. For example, if R is HandR is H, then in a solvent like dichloromethane. 10-I can be synthesized, for the E-isomer 10-V is formed predominantly. If a mixture of example, according to Schemes 1, 2, 3, 4, 8 or 9. The Sulfona- 10-V and 10-Va is formed, this can be separated by methods mide 10-III is deprotonated with a strong base like lithium known to a person skilled in the art, e.g. by chromatography. diisopropylamide, lithium hexamethyldisilazide or n-butyl- 40 Alternatively, the vinylsulfonyl chloride 10-VI can be syn lithium at low temperature like -78° C. and reacted with thesized first starting from the methanesulfonate 10-VII by diethylchlorophosphate to give 10-IV. 10-IV is then reacted deprotonation and reaction with diethylchlorophosphate, fol with a carbonyl compound 5-VII to give the final product lowed by deprotonation and reaction with a carbonylcom 10-V. The last step is carried out in the presence of lithium pound 5-VII leading to the unsaturated sulfonate 10-IX which bromide and a strong base like 1,8-diaza-7-bicyclo5.4.0] is converted to 10-VI. This sulfonyl chloride is then coupled undecene (DBU). Similar reactions are described in, for to the amino compound 10-I to give the final product 10-VI.

Scheme 11: PG PG l X l R-B^ SIR-R) 1. R- / S(R-R) R- / S(R-R) Y4 Y' a X R7-R + 2 R- X R7-R R- X R7-R N N / ) Ys-Y N N / ) N N / ) is11-I " 41l. N 411. N 1-Vb | Ys 1Y Ys 1Y US 8,877,934 B2 69 70 -continued R2 RI

R-B /N (R-R) o, R3 R-E N / R7-R.9 ) N /N R3 R- Q O R- N IR-R) N RI R2 11-V ves Y.s Y2 21 sy | Y 2Y H /N /N R-BX (R6-R8) 14 R- X (R6-R8) R-E N / R7-R9)) - R5-E N / R7-R9) N N R R3 so RI R2 RI R2 11-VI 11-VII Exemplary conditions: a: Pd(dba)3, BINAP, potassium tert, butylat, TEA, toluene, b: HBTU, diisopropylethylamine, DMF

A spiro-compound that is formed when R is joined for example, R. Kreher (editor), volume E7b of Methods of together with R to form a C-C alkylene group and R is 40 Organic Chemistry (Houben-Weyl), Hetarenes II, part 2, 4" joined together with R to form a C-C alkylene group can be edition, Georg Thieme Verlag, Stuttgart-N.Y., 1992; pyrim synthesized as shown in scheme 11: A Spirocyclic diamine idines are described in, for example, E. Schaumann (editor), 11-I is coupled to a heteroaryl compound 1-I to give 11-II. volume E9b of Methods of Organic Chemistry (Houben 11-I can be monoprotected by a suitable protecting group like Weyl), Hetarenes IV, part 2a, 4" edition, Georg Thieme Ver the ones that have been described in scheme 1. The synthesis 45 lag. Stuttgart-N.Y., 1998; quinazoline derivatives are of compounds like 11-I has been described in, for example, described in E. Schaumann (editor), in volume E9b of Meth Burckhard, J., Carreira, E.M., Organic Lett. 10 (2008), 3525 ods of Organic Chemistry (Houben-Weyl), Hetarenes IV, part 3526 and Burckhard, J., Guerot, C., Knust, H., Rogers-Evans, 2b, 4" edition, Georg Thieme Verlag, Stuttgart-N.Y., 1997: M., Carreira, E. M., Organic Lett. 12 (2010), 1944-1947. pyridazines and cinnolines in, for example, E. Schaumann Pd-catalysis can be used employing a Pd-containing mol 50 (editor), volume E9a of Methods of Organic Chemistry ecule like palladium acetate or Pd(dba), a phosphorus-con (Houben-Weyl), Hetarenes IV, part I, 4" edition, Georg Thi taining ligand like BINAP, a base like caesium carbonate or eme Verlag, Stuttgart-N.Y., 1997; pyridopyridines in The Sodium tert-butoxide in a solvent like an ether-containing Chemistry of Heterocyclic Compounds, Volume 63, The solvent like diethylether, dioxane or tetrahydrofuran, or an Naphthyridines, D. J. Brown, P. Wipf, E. C. Taylor (Eds), inert solvent like toluene as described in, for example, Burck 55 John Wiley & Sons, New York, 2007; thienopyridines, furo hard, J., Carreira, E. M., Organic Lett. 10 (2008), 3525-3526. pyridines, thienopyrimidines, furopyrimidines, pyrrolopy Deprotection and acylation with an unsaturated acid 1-V ridines, pyrazolopyrimidines, pyrazolopyridines, pyridopy gives the final product 11-IV. The sequence might be altered ridines and triazolopyrimidines are described in, for example, so that the Spirocyclic diamine 11-I is first acylated to give A. R. Katritzky, C.W. Rees, E.F. V. Scriven (Editors), volume 11-V. Deprotection and coupling with the heteroaryl com 60 7 of Comprehensive Heterocyclic Chemistry II, Elsevier Sci pound 1-I gives 11-IV. ence Ltd., Oxford N.Y., 1996. The synthesis of furopy Heteroaryl compounds 1-I and 8-IX can be synthesized by ridines is also described in, for example, S. Shiotani, K. several methods known to those skilled in the art. Quinoline Tanaguchi, J. Heterocyclic Chem., 33, (1996), 1051-1056; S. derivatives are described in, for example, R. Kreher (editor), Shiotani, K. Tanaguchi, J. Heterocyclic Chem., 34, (1997), volume E7a of Methods of Organic Chemistry (Houben 65 925-929. 2-3-Dihydrofuropyridines are described in, for Weyl), Hetarenes II, part 1,4" edition, Georg Thieme Verlag, example, F. Suzenet, M. Khouili, S. Lazar, G. Guillaument, Stuttgart-N.Y., 1991; pyridine derivatives are described in, Synlett, (2009), 92-96.2,3-Dihydro-1,4-dioxinopyridines are US 8,877,934 B2 71 72 described in, for example, B. Joseph, A. Benarab, G. Guillau Step A: N,N-Dimethyl-N-(2-methyl-4-quinolyl) ment, Heterocycles 38, (1994), 1355-1360. Many heteroaryl ethane-1,2-diamine compounds 1-I used materials are also commercially avail able by a large number of vendors as listed in, for example, the 4-Chloroquinaldine (1.5 g., 5 mmol) was mixed with N,N'- 5 dimethylethylenediamine (2.45 ml, 25 mmol) and 1-meth Symyx Available Chemicals Directory (ACD). oxy-2-propanol (8 ml) and stirred at 110°C. overnight. The Amines 1-II, 1-VII, 2-, 3-I, 7-VI, amino acid derivatives mixture was purified by column chromatography (pre-packed 3-II, used as starting materials are commercially available by silica column, gradient of heptane/ethyl acetate each contain a large number of vendors as well as carboxylic esters 5-I and ing 1% triethylamine). 0.4 g were obtained (1.75 mmol; 5-VIII, aldehydes 5-VIIa, ketones 8-I, halocarboxylic esters 35%). MS (APCI) m/z 230.0M+H". 8-X, halocarboxylic acids 8-XII, phosphonic acid derivatives 10 8-II and carbonyl compounds 5-VII as listed in, for example, Step B: (E)-3-Cyclopropylprop-2-enoic acid the Symyx Available Chemicals Directory (ACD).). In addi tion, carboxylic esters can be obtained by methods known to Malonic acid (18.9 g, 180 mmol), cyclopropanecarbalde hyde (4.5 g. 60 mmol) and piperidine (0.7 ml) were mixed a person skilled in the art and described in, for example, J. 15 Fallbe (editor), volume E5 of Methods of Organic Chemistry with pyridine (37 ml) and stirred under reflux for 2 hours, (Houben-Weyl), Carboxylic acids and Derivatives, part I, 4" stirring was continued overnight at room temperature. The mixture was poured into 2M hydrochloric acid (200 ml), the edition, Georg Thieme Verlag, Stuttgart-N.Y., 1985. Like phases were separated and the aqueous phase was extracted wise, aldehydes can be obtained by methods described in, for with dichloromethane (60 ml). The organic phases were com example, J. Fallbe (editor), volume E3 of Methods of Organic bined, the solvent was removed under reduced pressure and Chemistry (Houben-Weyl), Aldehydes, 4" edition, Georg Thi the residue was purified by column chromatography (pre eme Verlag, Stuttgart-N.Y., 1983 and ketones as described in, packed silica column, gradient of petrolether?ethyl acetate). for example, volume VII, part 2 a-c of Methods of Organic 6.2 g of an off-white crystalline solid was obtained (51.6 Chemistry (Houben-Weyl), Ketones I-III, 4" edition, Georg mmol, 86%). MS (APCI) m/Z-112.9 M+H". Thieme Verlag, Stuttgart-N.Y., 1973-1977. 25 Step C: (E)-3-Cyclopropyl-N-methyl-N-(2-methyl B. Synthesis Examples (2-methyl-4-quinolyl)aminoethylprop-2-enamide The following examples are for illustrative purposes only (E)-3-Cyclopropylprop-2-enoic acid (22 mg, 0.2 mmol) and are not intended to limit the scope of the invention. The 30 and HBTU (76 mg, 0.2 mmol) were dissolved in a 1:1 mixture compounds were named using SymyxR draw version 3.1.Net of anhydrous THF and anhydrous DMF (2 ml). After 5 min Software (Symyx Technologies, Inc.). utes N,N-dimethyl-N-(2-methyl-4-quinolyl)ethane-1,2-di The methods described in the examples can be easily amine (52 mg, 0.23 mmol) and triethylamine (62 ul, 0.45 adapted by a person skilled in the art to make other com mmol) were added and the mixture was stirred at room tem pounds, and intermediates thereof. For instance, a person 35 perature for 2 hours. The mixture was diluted with ethyl skilled in the art could replace in the examples the exemplified acetate, washed with water, saturated Sodium bicarbonate starting compounds by other compounds of the formulae I-I. Solution, brine and dried over magnesium sulfate. The solvent was removed under reduced pressure and purified by prepara 1-II, 1-V, I-VII, 1-IX, 2-I, 3-I, 3-II, 3-VI, 5-I, 5-VII, 5-VIII, tive HPLC (gradient of water containing 0.1% NH and 5-XI, 7-VI, 8-I, 8-II, 8-IX, 8-X, 8-XI, 8-XII, 10-I, 10-II, 10-V 40 (e.g. commercially available compounds), perform routine acetonitrile) to yield 28.3 mg (0.087 mmol. 43.5%). adaptions of the reaction conditions, if any, and use them for Example 2 the synthesis of further compounds according to this inven tion. Synthesis of (E)-4.4.5.5.5-pentafluoro-N-3-methyl 45 Example 1 2-(4-quinolylamino)butylpent-2-enamide (B-4) Synthesis of (E)-3-cyclopropyl-N-methyl-N-(2-me thyl-(2-methyl-4-quinolyl)aminoethylprop-2-enam ide (A-197) 50

NH F

55 HN

N

60 2 N

Step A: 1-Ethoxy-2,2,3,3,3-pentafluoro-propan-1-ol 65 Ethyl 2,2,3,3,3-pentafluoropropionate (10.99 grams, 57.2 mmol) was dissolved in anhydrous methanol (57 ml) and US 8,877,934 B2 73 74 cooled under argon to -60° C. Sodium borohydride (2.16 stirring at reflux for 48 hours. The solvent was removed under grams, 57.2 mmol) was added in four portions. After the reduced pressure, the residue was partitioned between water addition was complete, stirring was continued for one hour and ethyl acetate, the phases were separated, the aqueous and the temperature was held below -45° C. The mixture was phase was washed 3 times with ethyl acetate and basified with cooled to -60° C. and 1M hydrochloric acid (172 ml) was 50% NaOH. A precipitate formed that was filtered off and added dropwise so that the temperature remained below -45° dried in air to give 0.2 g of a solid (0.78 mmol, 14%). MS C. The mixture was slowly warmed to room temperature and (APCI) M/Z=243.6 M+H". extracted with diethylether (3x100 ml). The combined organic phases were washed with water (two times), dried Step G: over magnesium Sulfate, the solvent was removed under 10 3-Methyl-N2-(4-quinolyl)butane-1,2-diamine reduced pressure. 9.76 g (50.3 mmol, 88%) were obtained and used directly in the next step. 3-Methyl-2-(4-quinolylamino)butanamide (460 mg, 1.9 mmol) was dissolved in anhydrous THF (30 ml) under argon, Step B: 6,6,7,7,7-Pentafluoro-3-hydroxy-pentanoic the mixture was cooled to 0°C. and a 1M solution of borane acid 15 in anhydrous THF (8 ml, 8 mmol) was added with stirring. Stirring was continued for 1 hour at 0°C., the cooling bath 1-Ethoxy-2,2,3,3,3-pentafluoro-propan-1-ol (9.76 g, 50.3 was removed and the mixture was allowed to warm to room mmol) was mixed with malonic acid (15.73 g, 0.15 mole), temperature overnight with stirring. The mixture was piperidine (0.611 ml) and pyridine (30 ml) and heated at 120° quenched with 1M NaOH and extracted with ethyl acetate. C. until gas evolution ceased (4 hours). The solvent was The organic phase was evaporated to dryness under reduced removed under reduced pressure, the residue treated with 1M hydrochloric acid and extracted with diethylether (3x). The pressure and the residue was purified by column chromatog combined organic phases were washed with water (2x), dried raphy (pre-packed silica column, gradient of ethyl acetate/ over magnesium Sulfate, the solvent was removed under methanol containing 1% ammonia). 220 mg was obtained reduced pressure. 9.81 g (47.2 mmol, 94%) were obtained 25 (0.96 mmol, 51%). MS (APCI) m/z =229.8 M+H". and used directly in the next step. Step H: (E)-4.4.5.5.5-Pentafluoro-N-3-methyl-2-(4- Step C: Ethyl quinolylamino)butylpent-2-enamide 4.4.5.5.5-pentafluoro-3-hydroxy-pentanoate 30 (E)-4,4,5,5.5-Pentafluoropent-2-enoic acid (29 mg, 0.15 6,6,7,7,7-Pentafluoro-3-hydroxy- (9.81 g, 47.2 mmol) was mmol) was dissolved in anhydrous DMF (1 ml), HBTU (60 dissolved in anhydrous ethanol (47 ml), concentrated sulfuric mg, 0.15 mmol) and diisopropylamine (26 ul, 0.15 mmol) acid was added (0.534 ml) and the mixture was heated under were added and the mixture was stirred at room temperature reflux. A solution of hydrochloric acid in anhydrous methanol for 15 minutes. 3-Methyl-N2-(4-quinolyl)butane-1,2-di 35 amine (34.4 mg., 0.15 mmol) dissolved in 1 ml anhydrous was added (1M. 8 ml) and heating was continued for 3 hours. DMF together with diisopropylethylamine (26 ul, 0.15 The solvent was removed under reduced pressure and 11.9 g, mmol) was added and the resulting mixture was stirred at were obtained which were used directly in the next step. room temperature for 3 hours. The mixture was evaporated to Step D: Ethyl (E)-4.4.5.5.5-pentafluoropent-2-enoate dryness under reduced pressure and the resulting residue was 40 purified by preparative HPLC (gradient of water containing Ethyl 4.4.5.5,5-pentafluoro-3-hydroxy-pentanoate (11.9 g, 0.1% NH and acetonitrile) to yield 7.3 mg (0.018 mmol. from step C) was placed in a 25 ml round-bottom flask and 12%). phosphorpentoxid was added in Small portions until the educt was almost completely absorbed. The temperature was raised Example 3 slowly to 140°C. until a brown syrup was obtained. The flask 45 was connected to a distilling apparatus and the product iso Synthesis of (E)-N-2-(2-methoxy-4-quinoly) lated by distillation at reduced pressure (50 mbar, 50° C.). 5.5 aminoethylhex-2-enamide (A-177) g (25.2 mmol. 50% over 2 steps) were obtained. Step E: (E)-4.4.5.5.5-Pentafluoropent-2-enoic acid 50 H Ethyl (E)-4,4,5,5,5-pentafluoropent-2-enoate (5.5g, 25.2 mmol) was suspended in 10% NaOH (14.5 ml) and heated at ^-N-N-n- reflux until a homogenous solution was obtained (40 min). N O After cooling to room temperature the mixture was washed 55 with diethylether (2x) and acidified under ice-cooling with 2 concentrated sulfuric acid. The mixture was extracted with N o1 diethylether (3x), the combined organic phases were washed with water, dried over magnesium Sulfate and the Solvent removed under reduced pressure. 2.64 g (13.9 mmol. 55%) 60 Step A: 4-Chloro-2-methoxy-quinoline were obtained. MS (ES) M/Z-189.0 M-HI. To a solution of (2.5g, 12.6 mmol) 2,4-dichloro-quinoline Step F: 3-Methyl-2-(4-quinolylamino)butanamide in anhydrous toluene (20 ml) was added a suspension of solid Sodium methoxide (2.5 g., 46.3 mmol) in anhydrous toluene 4-Chloroquinoline (0.82 g, 5 mmol), valinamide (0.64 g. 65 (20 ml). The mixture was stirred under reflux for 16 hours and 5.5 mmol) and diisopropylamine (1.9 ml, 11 mmol) were then allowed to cool to room temperature. The solid that had mixed with 1-methoxy-2-propanol (8 ml) and heated with formed was filtered off and washed with 50 ml toluene. The US 8,877,934 B2 75 76 filtrate was evaporated to dryness under reduced pressure to overnight. The reaction mixture was diluted with ethyl yield ared solid (2.1 g, 10.8 mmol.86%). MS (ES) m/Z-193.1 acetate, washed with water, saturated Sodium bicarbonate M+H". Solution and brine, dried over magnesium sulfate and evapo rated to dryness under reduced pressure. The residue was Step B: purified by preparative HPLC (gradient of water containing N-(2-Methoxy-4-quinolyl)ethane-1,2-diamine 0.1% NH and acetonitrile) to yield 9 mg (0.033 mmol. 18%). Example 5 4-Chloro-2-methoxy-quinoline (484 mg, 2.5 mmol) and 1,2-diaminoethan (751 mg, 12.5 mmol) were mixed with Synthesis of (E)-N-3-(2-methyl-4-pyridyl)amino 1-methoxy-2-propanol and stirred at 110° C. for 24 hours. 10 propylhex-2-enamide (A-89) The mixture was evaporated to dryness and the residue was purified by column chromatography (pre-packed silica col umn, gradient of ethyl acetate/methanol each containing 1% triethylamine). 0.324 g were obtained (1.49 mmol: 60%). MS O (APCI) m/z-218.0 M+H". 15 Step C: (E)-N-2-(2-Methoxy-4-quinolyl-amino ----~~ ethylhex-2-enamide N

N-(2-Methoxy-4-quinolyl)ethane-1,2-diamine (21.7 mg, 2 0.1 mmol) was dissolved in anhydrous dichloromethane (1 N ml) together with triethylamine (17.4 ul, 0.125 mmol). (E)- hex-2-enoyl chloride (16.6 mg, 0.125 mmol) was added and Step A: N-(2-Methyl-4-pyridyl)propane-1,3-diamine the mixture was shaken for 10 minutes, diluted with dichlo hydrochloride romethane and washed with 10% sodium bicarbonate solu 25 tion (2 times), water and evaporated to dryness under reduced 4-Chloro-2-picoline (441 ul, 4 mmol) was mixed with 1,3- pressure. The resulting residue was purified by preparative diaminopropane (1.67 ml, 20 mmol) and stirred in a closed HPLC (gradient of water containing 0.1% NH and acetoni vessel at 180° C. under microwave heating for one hour. The trile) to yield 3.4 mg (0.0109 mmol, 11%). Solvent was removed under reduced pressure, toluene was 30 added to the residue and the mixture was evaporated to dry Example 4 ness under reduced pressure to yield 1.076 of a solid. MS Synthesis of (E)-N-2-(5-ethyl-6-methyl-pyrimidin (APCI) m/z =165.8 M+H". 4-yl)-aminoethyl-4-methyl-pent-2-enamide (A-20) Step B: (E)-N-3-(2-Methyl-4-pyridyl)aminopro 35 pylhex-2-enamide (E)-4-Hex-2-enoic acid (23 mg, 0.2 mmol) and HBTU (76 mg, 0.2 mmol) were dissolved in a 1:1 mixture of anhydrous H DMF and anhydrous acetonitrile (2 ml), after 5 minutes tri 40 ethylamine (82 ul, 0.6 mmol) and N-(2-Methyl-4-pyridyl) ~~ propane-1,3-diamine hydrochloride (40 mg, 0.2 mmol) was added. To the mixture basic aluminium oxide was added, NN O stirring was continued for one hour, the mixture was filtered ld and the filtrate was evaporated to dryness under reduced N 45 pressure. The residue was purified by preparative HPLC (gra dient of water containing 0.1% NH and acetonitrile) to yield 20.2 mg (0.077 mmol. 39%). Step A: N-(5-Ethyl-6-methyl-pyrimidin-4-yl)ethane Example 6 1,2-diamine hydrochloride 50 Synthesis of (E)-4.4.5.5,5-pentafluoro-N-2-[2-(2- 4-Chloro-5-ethyl-6-methylpyrimidin (570 mg, 4 mmol) methyl-1,3-dioxolan-2-yl)-4-pyridylaminoethyl was mixed with 1,2-diaminoethane (2 ml, 30 mmol) and pent-2-enamide (A-133) stirred at 150° C. in a closed vessel under microwave heating. The mixture was evaporated to dryness under reduced pres sure to yield 1.255 g of a solid. MS (APCI) m/z =181.1 55 M+H". F F H Step B: (E)-N-2-(5-Ethyl-6-methyl-pyrimidin-4-yl) aminoethyl-4-methyl-pent-2-enamide ^-S-S-X.< F 60 N O F (E)-4-Methylpent-2-enoic acid (46 mg, 0.4 mmol), HBTU (152 mg, 0.4 mmol) and triethylamine (82 ul, 0.6 mmol) were 2 dissolved in a 1:1 mixture of anhydrous DMF and anhydrous N acetonitrile (2 ml), after 20 minutes N-(5-ethyl-6-methyl O O pyrimidin-4-yl)ethane-1,2-diamine hydrochloride (40 mg. 65 0.185 mmol) was added. The mixture was stirred at room temperature for 2 hours and left to stand at room temperature US 8,877,934 B2 77 78 Step A: resulting residue was purified by preparative HPLC (gradient 4-Chloro-2-(2-methyl-1,3-dioxolan-2-yl)pyridine of water containing 0.1% NH and acetonitrile) to yield 2.5 mg (0.0071 mmol. 7.9%). 1-(4-Chloro-2-pyridyl)ethanone (440 mg, 2.83 mmol) and ethyleneglycol (480 mg, 3 mmol) were mixed with toluene Example 8 (10 ml), a catalytic amount of p-toluenesulfonic acid was added and the mixture was heated at reflux overnight. The Synthesis of (E)-4.4.5.5.5-pentafluoro-N-3-(2-me mixture was evaporated to dryness to yield 523 mg of a solid thyl-4-quinolyl)aminopropylpent-2-enamide (A-217) (2.6 mmol, 93%). MS (APCI) m/z =200.0M+H". 10 Step B: N-2-(2-Methyl-1,3-dioxolan-2-yl)-4-py ridylethane-1,2-diamine O F F 4-Chloro-2-(2-methyl-1,3-dioxolan-2-yl)pyridine (500 mg, 2.5 mmol) was mixed with 1,2-diaminoethane (1.09 ml, 15 1-1. 21 F 26.2 mmol) and stirred in a closed vessel at 180° C. with F F microwave heating for 30 minutes in two batches. The mix N ture was evaporated to dryness, the solid residue was washed with acetone. The washing solution was evaporated to dry 2 ness and this solid residue was washed with acetonitrile. The N solid residues were combined and dried under reduced pres sure to yield 531 mg of a solid (2.38 mmol.95%). MS (APCI) m/Z 224.1 M+H". Step A: tert-Butyl N-2-(2-methyl-4-quinolyl)aminopropylcarbamate Step C: (E)-4.4.5.5.5-Pentafluoro-N-2-[2-(2-me 25 thyl-1,3-dioxolan-2-yl)-4-pyridylamino-ethylpent Palladium(II)acetate (126 mg, 0.56 mmol), caesium car 2-enamide bonate (2.6 g. 8 mmol) and BINAP (498 mg, 0.8 mmol) were Suspended in anhydrous dioxane under an atmosphere of (E)-4.4.5.5.5-Pentafluoropent-2-enoic acid (133 mg, 0.7 argon and Sonicated for 40 minutes. To this mixture was mmol) and HBTU (265 mg, 0.7 mmol) were dissolved in a 2:1 30 added 4-chloroquinaldine (711 mg, 4 mmol) and tert-butyl mixture of anhydrous DMF and anhydrous THF (3 ml) and N-(3-aminopropyl)carbamate (697 mg, 4 mmol) and the mix stirred at room temperature for 15 minutes. N-2-(2-Methyl ture was stirred at 110° C. overnight. After cooling to room 1,3-dioxolan-2-yl)-4-pyridylethane-1,2-diamine (100 mg. temperature, the mixture was diluted with ethyl acetate and 0.45 mmol) was added and stirring was continued for 3 hours. filtered, the filtrate was evaporated to dryness, the resulting The reaction mixture was diluted with ethyl acetate, washed 35 residue was dissolved in dichloromethane and filtered with water, saturated sodium bicarbonate solution and brine, through a column packed with basic alumina. The product dried over magnesium sulfate and evaporated to dryness was eluted with ethyl acetate, the solution evaporated to dry under reduced pressure. The residue was purified by prepara ness and 771 mg (2.44 mmol. 61%) were obtained. MS tive HPLC (gradient of water containing 0.1% NH and (APCI) m/z-315.8 M+H". acetonitrile) to yield 47 mg (0.12 mmol. 26%). 40 Step B: Example 7 N-(2-Methyl-4-quinolyl)propane-1,3-diamine hydrochloride Synthesis of (E)-N-2-(2-acetyl-4-pyridyl)amino ethyl-4,4,5,5,5-pentafluoro-pent-2-enamide (A-134) 45 tert-Butyl N-2-(2-methyl-4-quinolyl)aminopropylcar bamate (771 mg, 2.44 mmol) was dissolved in dichlo romethane (20 ml), trifluoroacetic acid (1.5 ml) was added and the mixture was stirred at room temperature for 3 hours. F F The mixture is evaporated to dryness under reduced pressure, H the residue dissolved in dioxane and evaporated again. The residue is again dissolved in dioxane and a 4MSolution ~N~< F of HCl in dioxane is added to precipitate the hydrochloride N O F salt of the product which is filtered off and dried under reduced pressure. MS (APCI) m/z 216.1 M+H". 55 le Step C: (E)-4.4.5.5.5-Pentafluoro-N-3-(2-methyl-4- quinolyl)aminopropylpent-2-enamide O (E)-4,4,5,5.5-Pentafluoropent-2-enoic acid (38 mg, 0.2 (E)-4.4.5.5.5-Pentafluoro-N-2-[2-(2-methyl-1,3-diox 60 mmol) and HBTU (76 mg, 0.2 mmol) were dissolved in a 1:1 olan-2-yl)-4-pyridylaminoethylpent-2-enamide (35 mg. mixture of anhydrous DMF and anhydrous acetonitrile (2 0.09 mmol) was dissolved in aceton (1 ml), 4M hydrochloric ml), after 5 minutes triethylamine (82 ul, 0.6 mmol) and acid (0.5 ml) was added and the mixture was stirred in a N-(2-methyl-4-quinolyl)propane-1,3-diamine hydrochloride closed vessel at 100° C. for 15 minutes with microwave (48 mg, 0.24 mmol) was added and stirring was continued for heating. The mixture was diluted with water, extracted with 65 3 hours. To the mixture basic aluminium oxide was added, ethyl acetate and the organic phase was washed with brine, stirring was continued for one hour, the mixture was filtered dried over magnesium sulfate and evaporated to dryness. The and the filtrate was evaporated to dryness under reduced US 8,877,934 B2 79 80 pressure. The residue was purified by preparative HPLC (gra in anhydrous DMF (0.5 ml), HBTU (39 mg, 0.1 mmol) was dient of water containing 0.1% NH and acetonitrile) to yield added and the mixture was stirred for 15 minutes at room 28.4 mg (0.076 mmol, 38%). temperature. N-(2-methoxy-6-methyl-pyrimidin-4-yl)-N- methyl-ethane-1,2-diamine (19.6 mg, 0.1 mmol) and diiso Example 9 propylethylamine (17.4 ul, 0.1 mmol), dissolved in anhy drous DMF (0.5 ml) were added and the mixture was stirred Synthesis of (E)-3-cyclopropyl-N-2-(2-methoxy-6- at room temperature overnight. The mixture was purified methyl-pyrimidin-4-yl)-methyl-aminoethylprop-2- directly by preparative HPLC (gradient of water containing enamide (A-77) 0.1% NH and acetonitrile) to yield 13.7 mg (0.047 mmol. 10 47.2%). Example 10 Synthesis of (E)-4,4,5,5-tetrafluoro-N-2-[2-methyl 6-(2-methylbutoxy)-4-pyridylaminoethylpent-2- 15 enamide (A-323)

F F ~...~X-H 21 O F 25 a Step A: 4-Chloro-2-methoxy-6-methyl-pyrimidine N r To anhydrous methanol (10 ml) was added sodium (230 mg, 10 mmol) and the mixture was stirred under an argon 30 Step A: 2-Chloro-6-methyl-pyridine 1-oxide atmosphere until a clear solution had formed. This solution was added dropwise over two hours with stirring to a solution 2-Chloro-6-methylpyridine (12.76 g., 0.1 mol) was dis of 2,4-dichloro-6-methylpyrimidine (1.79 g, 11 mmol) in solved together with m-chloroperbenzoic acid (17.56 g., 0.15 anhydrous methanol (10 ml) under cooling so that the tem mol) in DCM (100 ml) and stirred at 40° C. for 90 minutes. perature remained below 10° C. Stirring was continued for 30 35 The heating bath was removed and stirring was continued minutes, then water was added (2 ml), the mixture was filtered overnight at room temperature. The reaction mixture was and the filtrate was evaporated to dryness under reduced quenched with Saturated Sodium thiosulfate solution and the pressure. The residue was purified by column chromatogra pH was adjusted to 8 with 1M NaOH. The phases were phy (pre-packed silica column, gradient of heptane/ethyl separated, the aqueous phase extracted with DCM and the acetate). 750 mg was obtained (4.75 mmol, 47%). MS (APCI) 40 combined organic phases were dried over magnesium sulfate. The solvent was removed under reduced pressure and unre m/Z-159.2 M+H". acted 2-chloro-6-methylpyridine was removed by distillation Step B: N-(2-Methoxy-6-methyl-pyrimidin-4-yl)-N- (2 mbar, 65° C.). 2-Chloro-6-methyl-pyridine 1-oxide was methyl-ethane-1,2-diamine obtained as residue (6.0 g of a yellow oil, 0.042 mol, 42%). 45 MS (ESI) m/z =144.0 M+1". 4-Chloro-2-methoxy-6-methyl-pyrimidine (320 mg, 2 mmol) was mixed with N-Boc-N'-methyl-2,3-diaminoethan Step B: 2-Chloro-4-nitro-6-methyl-pyridine 1-oxide (464 mg, 2.2 mmol), diisopropylethylamine (285 mg, 2.2 2-Chloro-6-methyl-pyridine 1-oxide (5.0 g, 0.035 mol) mmol) and dipropyleneglycolmomomethylether (4 ml) and was dissolved in concentrated sulfuric acid (20 ml) at 0°C. An stirred overnight at 120° C. The mixture was evaporated to 50 ice-cooled mixture of concentrated nitric acid (12 ml) in dryness. The residue was dissolved in a 1:1 mixture of dichlo concentrated sulfuric acid (20 ml) was added dropwise with romethane and trifluoroacetic acid and stirred at room tem stirring at 0°C. The cooling bath was removed, stirring was perature for 3 hours. The volatiles were removed under continued for 3 hours at 90° C. The mixture was poured into reduced pressure, the residue taken up in dichloromethane a mixture of icewater and ethyl acetate and the resulting and evaporated again. Dissolving in dichloromethane and 55 precipitate was removed by filtration. The phases of the fil evaporation was repeated two times. The residue was dis trate were separated, the aqueous phase was extracted several solved in water, basified with 5N NaOH and extracted with times with ethyl acetate, basified with NaOH and extracted ethyl acetate. Evaporation of the organic phase yielded 450 again with ethyl acetate. The combined organic phases were mg of light brown, viscous oil (quantitative). MS (APCI) dried over magnesium Sulfate and the solvent removed under m/Z-197.1 M+H". 60 reduced pressure. The residue was combined with the filtered residue above to yield 6.21 g of a yellow solid (0.033 mol, Step C: (E)-3-Cyclopropyl-N-2-(2-methoxy-6- 94%). MS (ESI) m/z =189.0 M+1". methyl-pyrimidin-4-yl)-methyl-aminoethylprop-2- enamide Step C: 2-Chloro-4-nitro-6-methyl-pyridine 65 (E)-3-Cyclopropylprop-2-enoic acid (11.2 mg, 0.1 mmol) 2-Chloro-4-nitro-6-methyl-pyridine 1-oxide (6.2g, 0.033 and diisopropylethylamine (17.4 ul, 1 mmol) were dissolved mol) was dissolved in chloroform (100 ml), phosphorus US 8,877,934 B2 81 82 trichloride was added (22.6 g., 0.165 mol) and the mixture was overnight with stirring. The mixture was then cooled to 0°C. heated under reflux for 2 days. The mixture was cooled to and acidified with 1M HC1. The phases were separated, the room temperature, poured into icewater and the mixture was aqueous phase was extracted two times with ethyl acetate, the neutralized with solid potassium carbonate. The phases were combined organic phases were dried over magnesium Sulfate separated, the aqueous phase was extracted three times with and the solvent was reduced under reduced pressure. The chloroform, the combined organic phases were dried over residue was dissolved in a minimum amount of methanol and magnesium sulfate. The solvent was removed under reduced evaporated to dryness under reduced pressure to yield 22.9 g, pressure after which 5.326 g of a brown oil was obtained (0.105 mol, 88%) that were used directly in the next step. (0.031 mol, 94%) which was used directly in the next step. 10 Step H: Ethyl (E)-4,4,5,5-tetrafluoropent-2-enoate Step D: N-(2-Chloro-6-methyl-4-pyridyl)ethane-1,2-diamine Ethyl 4.4.5.5-tetrafluoro-3-hydroxy-pentanoate (22.9 g, 0.105 mol) was mixed with phosphorus pentoxide (7.5 g. 2-Chloro-4-nitro-6-methyl-pyridine (5.29 g, 0.031 mol) 0.053 mol) and the resulting mixture was stirred at 80°C. for was dissolved in ethanol (100 ml) and added dropwise with 15 two hours. The product was isolated by vacuum distillation stirring to a solution of ethylenediamine (18.4g, 0.31 mol) in (53 mbar, 92°C.) to yield 15.9 g of a liquid (0.08 mol, 76%) ethanol (200 ml). The mixture was stirred at 60°C. for 2 days. that was used directly in the next step. The solvent was removed under reduced pressure and excess of ethylenediamine was removed by repeated azeotropic Step I: (E)-4,4,5,5-tetrafluoropent-2-enoic acid evaporation with toluene under reduced pressure. The raw product was dissolved in chloroform, extracted three times Ethyl (E)-4,4,5,5-tetrafluoropent-2-enoate (15.9 g, 0.08 with 1M HCl, the combined aqueous extracts were basified with NaOH and extracted with DCM and ethyl acetate. The mol) was dissolved in ethanol (30 ml). 4MNaOH was added combined organic extracts were dried over magnesium Sul (15 ml) and the mixture was stirred at room temperature 25 overnight. The mixture was diluted with water, washed with fate, the solvent was removed under reduced pressure to yield ethylacetate, acidified with 1M HCl and extracted with ethyl 3.92 g of a solid residue (0.021 mol. 68%). MS (APCI) acetate. The organic extract was dried over magnesium Sul m/Z-186.0 M+1". fate, the solvent was removed under reduced pressure. 12.8 g. Step E: N-2-Methyl-6-(2-methylbutoxy)-4-pyridyl of a colourless oil was obtained (0.074 mmol.93%). MS (ESI, ethane-1,2-diamine 30 negative detection) m/z = 170.9 M-1. Step J: (E)-4,4,5,5-tetrafluoro-N-2-[2-methyl-6-(2- N-(2-Chloro-6-methyl-4-pyridyl)ethane-1,2-diamine methylbutoxy)-4-pyridylaminoethyl-pent-2-enam (0.205 g, 1.2 mmol) was combined with the sodium salt of ide 2-methylbutan-1-ol (0.66 g. 6 mmol, that had been obtained by treating 2-methylbutan-1-ol with sodium hydride disper 35 (E)-4,4,5,5-tetrafluoropent-2-enoic acid (21 mg, 0.12 sion in THF), diphenylether (2.2g)and DMSO (0.75 ml). The mmol) was dissolved in DCM (1 ml), oxalyl chloride was mixture was heated at 160° C. for 16 hours and purified by added (10 ul, 0.12 mmol) followed by a drop of DMF. The column chromatography (silica, ethyl acetate/methanol, 1% mixture was stirred for 10 minutes at room temperature. N-2- concentrated NH) to yield 200 mg of a brown oil (0.84 methyl-6-(2-methylbutoxy)-4-pyridyl-ethane-1,2-diamine mmol, 70%). MS (APCI) m/z-237.9 M+1". 40 (18 mg, 0.1 mmol) was dissolved in DMF (0.5 ml), the mix tures were combined, TEA (42 ul, 0.3 mmol) was added and Step F: Ethyl 4.4.5.5-tetrafluoro-3-oxo-pentanoate the resulting mixture was stirred at room temperature for 1 Lithium hexamethyldisilazide (250 ml of a 1M solution in hour. The mixture was diluted with ethyl acetate, washed with THF, 0.25 mol) was cooled in an argon atmosphere to -78°C. 45 water and saturated sodium bicarbonate solution, dried over and ethyl acetate (23 ml, 0.26 mol) was added dropwise with magnesium Sulfate, the solvent was removed under reduced stirring. Stirring was continued for one hour at -78°C., then pressure. The residue was purified by preparative HPLC (gra methyl 2,2,3,3-tetrafluoropropionate (22 g, 0.137 mol) was dient of water containing 0.1% NH and acetonitrile) to yield added dropwise with stirring. Stirring was continued for three 13 mg of a white solid (0.039 mmol. 39%). hours at -78° C., then a saturated solution of ammonium 50 Example 11 chloride (175 ml) was added dropwise. The mixture was allowed to reach room temperature overnight. The mixture Synthesis of (E)-3-methyl-N-2-(2-methyl-4- was acidified with 1M HCl, the phases were separated. The quinolyl)aminoethylbut-1-ene-1-sulfonamide aqueous phase was extracted with ethyl acetate, the combined (A-447) organic phases were washed two times with 1M HCl, brine, 55 dried over sodium sulfate. The solvent was removed under reduced pressure and the residue was purified by vacuum distillation to yield 25.7 g (0.119 mmol, 87%) of a colourless liquid that was used directly in the next step. 60 N Step G: Ethyl N1,N1 Nl N 4.4.5.5-tetrafluoro-3-hydroxy-pentanoate els Ethyl 4,4,5,5-tetrafluoro-3-oxo-pentanoate (25.7g, 0.119 mol) was dissolved in toluene (260 ml) and cooled to 0°C. 65 N Sodium borohydride (5.4g, 0.143 mol) was added portion wise, and the mixture was allowed to reach room temperature US 8,877,934 B2 83 84 Step A: Ethyl diethoxyphosphorylmethanesulfonate 2.51 mmol) in acetonitrile (5 ml) was added a solution of (E)-3-methylbut-1-ene-1-sulfonyl chloride (102 mg of step A solution of ethyl methanesulfonate (4.14 mL, 40.2 D) in dichloromethane (1 ml). The mixture was stirred 30 mmol) in anhydrous tetrahydrofuran (100 ml) was cooled to minutes at room temperature, concentrated under reduced -78°C. under a nitrogen atmosphere. N-Butyllithium (20 ml, pressure and the residue was purified by column chromatog 50.0 mmol) was added slowly in 7 minutes after which stir ring was continued for 15 minutes. Diethyl phosphorochlo raphy over aluminum oxide using a gradient of methanol ridate (4.36 mL, 30.2 mmol) was added, the reaction mixture (2-10%) in dichloromethane to yield 83 mg of an off-white was stirred for 2.5 h, the cooling bath was removed and the foam (0.25 mmol; 13% over 4 steps). mixture was allowed to reach room temperature. The reaction mixture was quenched with aqueous saturated ammonium 10 Example 12 chloride (150 ml) and the resulting mixture was extracted with EtOAc (2x100 ml). The combined extracts were dried Synthesis of (E)-N-2-(2,6-dimethyl-4-pyridyl) over Sodium Sulfate and concentrated under reduced pressure aminopropyl-4,4,4-trifluoro-but-2-enamide (B-13) to yield 9.20 g of a yellow oil. The oil was purified over silicagel (600g) using a gradient of ethyl acetate (0-100%) in 15 heptane to yield 1.75 g of the product (6.7 mol, 17%). Step B: Ethyl (E)-3-methylbut-1-ene-1-sulfonate Mineral oil was removed from sodium hydride (84.4 mg. 2.110 mmol) with heptane (2x4 ml) under a nitrogen atmo sphere after which anhydrous tetrahydrofuran (10 ml) was added. To this suspension was added dropwise a solution of ethyl (diethoxyphosphoryl)methanesulfonate (500 mg, 1.921 mmol) in anhydrous tetrahydrofuran (10 ml) upon which hydrogen gas evolved from the mixture. After 5 minutes a 25 clear slightly yellow solution was obtained. Isobutyraldehyde Step A: tert-Butyl N-2-(2,6-dimethyl-4-pyridyl) (200 ul, 2.191 mmol) was added and the resulting mixture aminopropylcarbamate was stirred at room temperature over night. The reaction mixture was quenched with a mixture of brine (50 ml) and A mixture of 4-Chloro-2,6-dimethylpyridine (131 mg, aqueous Saturated ammonium chloride solution (150ml). The 30 0.925 mmol), tert-butyl 2-aminopropylcarbamate hydrochlo aqeuous mixture was extracted with dichloromethane (3x70 ride (151 mg, 0.717 mmol), cesium carbonate (750 mg, 2.302 ml), the combined organic layers were dried over sodium mmol), and anhydrous 1,4-dioxane (3 ml) was treated with sulfate and concentrated under reduced pressure to yield 550 tris(dibenzylideneacetone)dipalladium(0) (39 mg 0.043 mg of a slightly yellow oil that was used directly in the next mmol) and 9,9-dimethyl-4,5-bis(diphenylphosphino)xan step. 35 thene (74 mg., 0.128 mmol) under an atmosphere of argon. The mixture was heated at 110° C. for 8 hours, allowed to Step C: Tetrabutylammonium reach room temperature and filtered. The filter residue was (E)-3-methylbut-1-ene-1-sulfonate washed with DCM, the combined filtrates were evaporated. The residue was purified by column chromatography using a A solution of (E)-ethyl 3-methylbut-1-ene-1-sulfonate 40 gradient of methanol (1-10%) in dichloromethane to yield (550 mg of step B) and tetrabutylammonium iodide (1128 241 mg of a yellow oil. MS (ESI) m/z 280.2. mg, 3.05 mmol) in acetone (40 ml) was refluxed over night after which volatiles were removed under reduced pressure. Step B: 1.26 g of a white Solid was obtained and used as such in the N2-(2,6-Dimethyl-4-pyridyl)propane-1,2-diamine next reaction step. 45 hydrochloride Step D: (E)-3-Methylbut-1-ene-1-sulfonyl chloride To tert-butyl 2-(2,6-dimethylpyridin-4-ylamino)propyl carbamate (147 mg, 0.526 mmol) dissolved in 1,4-dioxane (1 To a solution of triphenylphosphine (1.055 g, 4.02 mmol) ml) a 4N solution of HCl in dioxane (2 ml, 8.00 mmol) was in dichloromethane (50 ml) under a nitrogen atmosphere was 50 added. Within a few minutes a precipitate started to form. The added at 0° C. sulfuryl dichloride (0.359 ml, 4.42 mmol). The Solvent was removed in a stream of nitrogen, to the residue mixture was stirred at 0° C. for 15 minutes after which a was added diethylether and the mixture was allowed to stand solution of tetrabutylammonium (E)-3-methylbut-1-ene-1- at room temperature overnight. The solvent was filtered off, sulfonate (1.25 g of Step C) in dichloromethane (10 ml) was the residue was dried under reduced pressure to yield 135 mg added dropwise. The reaction mixture was stirred at room 55 of an off-white solid MS (ESI) m/z =180.0. temperature for 5 h after which the mixture was concentrated under reduced pressure. The residue was taken up in diethyl Step C: (E)-N-2-(2,6-Dimethyl-4-pyridyl)amino ether and filtered over a glass filter to remove triphenylphos propyl-4,4,4-trifluoro-but-2-enamide phinoxide. The filtrate was concentrated under reduced pres sure to yield 102 mg of a brown oil which was used directly in 60 (E)-4,4,4-Trifluorobut-2-enoic acid (15.4 mg., 0.11 mmol) the next step. was dissolved in DCM (0.75 ml containing one drop of dim ethyl formamide), oxalyl chloride was added (14 mg., 0.11 Step E: (E)-3-methyl-N-2-(2-methyl-4-quinolyl) mmol) and the solution was stirred at room temperature for 15 aminoethylbut-1-ene-1-sulfonamide minutes. This solution was added to a solution of N2-(2,6- 65 dimethyl-4-pyridyl)propane-1,2-diamine (21.6 mg, 0.1 To a solution of N1-(2-methylduinolin-4-yl)ethane-1,2-di mmol) and diisopropylethylamine (44 ul, 0.25 mmol) dis amine (161 mg, 0.800 mmol) and triethylamine (0.350 ml, solved in dimethylformamide (1 ml) and the resulting mix US 8,877,934 B2 85 86 ture was stirred at room temperature overnight. The volatiles and 397 mg of a beige solid was obtained that was used were removed under reduced pressure and the residue was directly in the next step. MS (ESI) m/Z-182.2 M+1". purified by preparative HPLC (gradient of water containing 0.1% NH and acetonitrile) to yield 10.7 mg (0.035 mmol. Step D: (E)-N-2-(2,6-Dimethyl-1-oxo-4-pyridyl) 35%). aminoethyl-4-methyl-pent-2-enamide Example 13 (E)-4-Methylpent-2-enoic acid (118 mg, 1.034 mmol), HATU (327 mg, 0.861 mg) and N,N-diisopropylethylamine Synthesis of (E)-N-2-(2,6-dimethyl-1-oxo-4-py (0.236 ml, 1.378 mmol) were mixed with DCM (2 ml) and ridyl)aminoethyl-4-methyl-pent-2-enamide (Aa-4) stirred at room temperature for 30 minutes. The resulting Solution was added with stirring to a Suspension of N-(2,6- dimethyl-1-oxo-4-pyridyl)ethane-1,2-diamine hydrochlo ride (125 mg, 0.574 mmol) and N,N-diisopropylethylamine (0.098 ml, 0.574 mmol) in DCM (2 ml). The resulting mixture H 15 was stirred overnight at room temperature. The solvent was N1\- S removed in a stream of nitrogen and the residue was purified by column chromatography (silica, gradient of 2.5% of 7N ammonia in methanol in DCM to 10% of 7N ammonia in methanol in DCM) to yield 53.1 mg of a yellow solid (0.191 mmol, 33%). Example 14 Synthesis of (E)-4,4,4-trifluoro-N-2-(furo3.2-b 25 pyridin-7-ylamino)-2-oxo-ethylbut-2-enamide Step A: 4-Bromo-2,6-dimethyl-pyridine 1-oxide (B-44) 4-Bromo-2,6-dimethylpyridine (0.5 g, 2.69 mmol) was dissolved in DCM (10 ml), cooled to 0°C. and combined with O a solution of m-chloroperbenzoic acid in DCM (75%, 0.928 30 g, 4.03 mmol in 5 ml). The resulting mixture was stirred at 0° C. for 15 minutes and for 5 hours at room temperature. The mixture was washed with saturated sodium bicarbonate solu HN r- 3 tion, the phases were separated with a phase separator, the ON21 O organic phase was evaporated under reduced pressure. The 35 residue was purified by column chromatography (silica, gra Sull dient of 0.5 to 10% methanol in DCM). 475 of a yellow solid N was obtained (2.35 mmol, 88%). MS (ESI) m/z. 204.0 M+1". 40 Step A: tert-Butyl N-2-(furo3.2-bipyridin-7- Step B: tert-Butyl N-2-(2,6-dimethyl-1-oxo-4-py ylamino)-2-oxo-ethylcarbamate ridyl)aminoethylcarbamate To a solution of 2-(tert-butoxycarbonylamino)acetic acid 4-Bromo-2,6-dimethyl-pyridine 1-oxide (475 mg, 2.35 (660 mg, 3.77 mmol) in acetonitrile (20 ml) was added HBTU mmol), tert-butyl N-(2-aminoethyl)carbamate (452 mg, 2.82 45 (1.491 g, 3.93 mmol) and the resulting solution was stirred 40 mmol), cesium carbonate (1.68 g. 5.17 mmol) and BI NAP minutes at room temperature. Then triethylamine (0.785 ml, (racemic, 73.2 mg 0.118 mmol) were mixed with anhydrous 5.63 mmol) was added and the mixture was stirred another dioxane (10 ml) under an argon atmosphere. Tris(diben five minutes at room temperature. Next furoI2,3-bipyridin-4- Zylideneacetone)dipalladium(0) was added (108 mg, 0.118 amine (253 mg, 1.886 mmol) was added and the reaction mmol) and the mixture was stirred at 100° C. overnight. The 50 mixture was stirred at 60°C. over night. The acetonitrile was mixture was diluted with dioxane, filtered through Celite, the removed under reduced pressure and the residue was redis filter residue was washed three times with dioxane, the com solved in dichloromethane (50 ml). The solution in dichlo bined filtrates were evaporated under reduced pressure. The romethane was washed with aqueous 1N NaOH (40 ml). The residue was purified by column chromatography (silica, gra aqueous phase was extracted with dichloromethane (2x15 dient of DCM to DCM containing 10% 7N ammonia in 55 ml), the combined organic phases were dried over Sodium methanol) to yield 482 mg (1.71 mmol, 73%). MS (ESI) sulfate and concentrated under reduced pressure to yield 1.03 m/Z 282.2 M+1". g of a slightly brown oil. The crude product was purified by column chromatography (silica gel using a gradient of 2 to Step C: 6% MeOH in DCM to yield 350 mg of a white foam (1.2 N-(2,6-Dimethyl-1-oxo-4-pyridyl)ethane-1,2-diamine 60 mmol. 64%). MS (ESI) m/z 292.2 M+1". hydrochloride Step B: tert-Butyl N-2-(2,6-dimethyl-1-oxo-4-pyridyl)amino 2-Amino-N-furo3,2-bipyridin-7-yl-acetamide ethylcarbamate (482 mg, 1.71 mmol) was dissolved in DCM hydrochloride (50 ml) and a 4N solution of HCl in dioxane was added (2.15 65 ml, 8.6 mmol). The mixture was stirred at room temperature Tert-Butyl 2-(furo 2,3-bipyridin-4-ylamino)-2-oxoethyl overnight. The solvent was removed under reduced pressure carbamate (350 mg, 1.2 mmol) was placed in ethanol (96%) US 8,877,934 B2 87 88 (3.0 ml) and hydrogen chloride in dioxane (5.0 ml, 20.00 added sodium hydroxide (4.02 g, 101 mmol) in water (10 ml) mmol) was added after which the resulting mixture was and the resulting mixture was heated at reflux for 1.5 hours. stirred at room temperature over night. The solids were fil The mixture was allowed to cool to -50° C. after which tered off, washed subsequently with EtOH and diethylether ammonium chloride (6.07 g., 113 mmol) was added. The and dried in a stream of air. 230 mg of a white powder was mixture was stirred at reflux for 15 minutes after which the obtained (1.01 mmol, 84%). MS (ESI) m/Z-191.9 M+1". solids were filtered off. The solids were washed with ethanol Step C: (E)-4,4,4-Trifluoro-N-2-(furo3.2-bipyridin (150 ml) and the combined filtrates were concentrated under 7-ylamino)-2-oxo-ethylbut-2-enamide reduced pressure to yield 2.32 g of a white solid that was purified by filtration over a pad of silicagel in a glassfilter (E)-4,4,4-Trifluorobut-2-enoic acid (15.4 mg., 0.11 mmol) 10 was dissolved in DCM (0.75 ml containing one drop of dim using 10% (1% AcOH in MeOH) in DCM. The filtrate was ethyl formamide), oxalyl chloride was added (14 mg., 0.11 concentrated under reduced pressure to yield 240 mg (0.687 mmol) and the solution was stirred at room temperature for 15 mmol, 86%). MS (ESI) m/z. 350.2 M+1". minutes. This solution was added to a solution of 2-amino N-furo3.2-bipyridin-7-yl-acetamide hydrochloride (25.3 Step C. tert-Butyl N-2-5-(4-methoxyphenyl)me mg, 0.11 mmol) and diisopropylethylamine (44 ul, 0.25 15 thylcarbamoyl-1,3-dimethyl-pyrazolo 3,4-bipyri mmol) dissolved in dimethylformamide (1 ml) and the result din-4-ylaminoethylcarbamate ing mixture was stirred at room temperature overnight. The volatiles were removed under reduced pressure and the resi To a solution of 4-2-(tert-butoxycarbonylamino)ethy due was purified by preparative HPLC (gradient of water lamino-1,3-dimethyl-pyrazolo 3,4-bipyridine-5-carboxylic containing 0.1% NH and acetonitrile) to yield 6.9 mg (0.022 acid (96.1 mg, 0.275 mmol) in N,N-dimethylformamide (2.5 mmol. 20%). ml) was subsequently added N1-((ethylimino)methylene)- N3.N3-dimethylpropane-1,3-diamine hydrochloride (91.8 Example 15 mg, 0.479 mmol), 3-hydroxytriazolo 4,5-b]pyridine (39.7 Synthesis of 1,3-dimethyl-4-2-(E)-4,4,4-trifluo mg, 0.292 mmol) and triethylamine (0.115 ml, 0.825 mmol). robut-2-enoylamino-ethylaminolpyrazolo-3,4-b- 25 The reaction mixture was stirred for five minutes after which pyridine-5-carboxamide (A-381) (4-methoxyphenyl)methanamine (0.072 ml, 0.550 mmol) was added. The reaction mixture was stirred at room tempera ture over night. The reaction mixture was partitioned between water (40 ml) and EtOAc (50 ml). The organic layer was 30 separated and the aqueous phase was further extracted with EtOAc (3x40 ml) and dichloromethane (1x50 ml). The com 's--" bined organic layers were dried over sodium sulfate and con centrated under reduced pressure to yield 360 mg of a yellow liquid which was purified by column chromatography (sili 35 cagel using a gradient of MeCH (1-7%) in dichloromethane) cNH O to give 43 mg of a colorless sticky oil (0.092 mmol, 33%) MS (ESI) m/z 469.3 M+1". N NH Step D: 4-(2-Aminoethylamino)-1,3-dimethyl-pyra K 2 2 40 Zolo3.4-bipyridine-5-carboxamide trifluo /N N romethanesulfonate To a solution of tert-Butyl N-2-5-(4-methoxyphenyl) Step A: Ethyl 4-2-(tert-butoxycarbonylamino)ethy methylcarbamoyl-1,3-dimethyl-pyrazolo 3,4-bipyridin-4- lamino-1,3-dimethyl-pyrazolo 3,4-bipyridine-5- 45 yl)aminoethylcarbamate (43 mg, 0.092 mmol) in dichlo carboxylate romethane (2.0 ml) was added trifluoromethanesulfonic acid (2.0 mL. 22.60 mmol) and the resulting orange-red mixture To a mixture of ethyl 4-chloro-1,3-dimethyl-1H-pyrazolo was stirred at room temperature over night. The reaction 3,4-bipyridine-5-carboxylate (500 mg, 1.971 mmol) and mixture was diluted with dichloromethane (40 ml) and dieth potassium carbonate (817 mg, 5.91 mmol) in acetonitrile (15 50 ylether (100 ml) subsequently upon which a white precipitate ml) was slowly added tert-butyl N-(2-aminoethyl)carbamate was formed. The mixture was stirred for 15 minutes after (1.248 ml, 7.88 mmol) via a syringe. The reaction mixture which the white solids were filtered off, washed with dieth was stirred at room temperature for 3 hours. The solids were ylether and dried in a stream of air. 43 mg of an off-white solid filtered off over a glass filter and washed with a 1:1 mixture of was obtained and used directly in the next step. MS (ESI) EtOH and DCM. The combined filtrates were concentrated 55 m/Z=249.2. under reduced pressure to give a white semisolid, which was Step E: 1,3-Dimethyl-4-2-(E)-4,4,4-trifluorobut-2- purified by column chromatography (silica gel using a gradi enoyl)aminoethylaminolpyrazolo-3,4-b-pyridine ent of ethanol (0-5%) in DCM) to yield 658 mg of a white 5-carboxamide solid (1.743 mmol, 88%). MS (ESI) m/z. 378.2 M+1". 60 Step B: 4-2-(tert-Butoxycarbonylamino)ethy (E)-4,4,4-Trifluorobut-2-enoic acid (21 mg, 0.15 mmol) lamino-1,3-dimethyl-pyrazolo 3,4-bipyridine-5- was dissolved in DCM (2 ml containing one drop of dimethyl carboxylic acid formamide), oxalyl chloride was added (19 mg, 0.15 mmol) and the solution was stirred at room temperature for 15 min To a solution of ethyl 4-2-(tert-butoxycarbonylamino) 65 utes. This solution was added to a solution of 4-(2-aminoet ethylamino-1,3-dimethyl-pyrazolo 3,4-bipyridine-5-car hylamino)-1,3-dimethyl-pyrazolo 3,4-bipyridine-5-car boxylate (303 mg, 0.803 mmol) in methanol (30 ml) was boxamide trifluoromethanesulfonate (40 mg, 0.1 mmol) and US 8,877,934 B2 89 90 diisopropylethylamine (60 ul, 0.35 mmol) dissolved in dim sulfate, the solvent was removed under reduced pressure. The ethylformamide (1 ml) and the resulting mixture was stirred residue was purified by preparative HPLC (gradient of water at room temperature overnight. The volatiles were removed containing 0.1% NH and acetonitrile) to yield 3.3 mg of a under reduced pressure and the residue was purified by pre white solid (0.001 mmol. 18%). parative HPLC (gradient of water containing 0.1% NH and 5 Example 17 acetonitrile) to yield 2.1 mg (0.005 mmol. 5.7%). Synthesis of (E)-N-2-(5-ethyl-6-methyl-pyrimidin Example 16 4-yl)aminobutyl-4,4,4-trifluoro-but-2-enamide (A-347) Synthesis of (E)-N-2-(6-amino-2-methylsulfanyl 10 pyrimidin-4-yl)amino-ethyl-4,4,4-trifluoro-but-2- enamide (A-374)

15 H HN N1,N1 N N CF a NN O N HN CuN-s- Step A: N2-(5-Ethyl-6-methyl-pyrimidin-4-yl)-N1, 25 N2-bis(4-methoxyphenyl)methylbutane-1,2-di Step A: tert-Butyl N-2-(6-amino-2-methylsulfanyl amine pyrimidin-4-yl)aminoethylcarbamate N1,N1-Bis(4-methoxybenzyl)butane-1,2-diamine dihy 6-Chloro-2-methylsulfanyl-pyrimidin-4-amine (176 mg, 1 drochloride (552 mg, 1.375 mmol), 4-chloro-5-ethyl-6-me mmol) was dissolved together with tert-butyl N-(2-aminoet 30 thylpyrimidine (331 mg, 2.113 mmol) and N,N-diisopropyl hyl)carbamate (200 mg, 1.25 mmol) and triethylamine (174 ethylamine (824 ul, 4.81 mmol) were mixed with acetonitrile (1.5 ml) and heated in a closed vial at 150° C. in an argon ul, 1.25 mmol) in THF (2 ml). The mixture was stirred at 180° atmosphere for two days. The mixture was concentrated C. under microwave heating for 8 hours. The mixture was under reduced pressure and purified by column chromatog diluted with ethyl acetate and the resulting solution was raphy (silica, gradient from DCM to DCM containing 5% washed with a solution of sodium bicarbonate (5%) and brine, 35 methanol) to yield 353 mg of a yellow oil (0.787 mmol. 57%). dried over magnesium sulfate, the volatiles were removed MS (ESI) m/z–449.2 M+1". under reduced pressure. The residue dissolved in DCM and purified by filtration over silica to yield 105 mg (0.35 mmol. Step B: N2-(5-Ethyl-6-methyl-pyrimidin-4-yl)bu tane-1,2-diamine 35%) MS (ESI) m/z-300.2 M+1". 40 Step B: N6-(2-Aminoethyl)-2-methylsulfanyl-pyri N2-(5-Ethyl-6-methyl-pyrimidin-4-yl)-N1,N2-bis(4- midine-4,6-diamine trifluoromethane-Sulfonate methoxyphenyl)methylbutane-1,2-diamine (353 mg, 0.787 mmol) was dissolved in acetic acid (2 ml), the vial was Tert-Butyl N-2-(6-amino-2-methylsulfanyl-pyrimidin flushed with argon, palladium (10% on activated carbon, 109 45 mg, 0.102 mmol) was added, and the mixture was stirred in an 4-yl)aminoethylcarbamate (105 mg, 0.35 mmol) was dis atmosphere of hydrogen at room temperature overnight. The solved in a mixture of DCM (20 ml) and trifluoromethane mixture was filtered, the filter residue was washed with acetic sulfonic acid (5 ml) and stirred at room temperature for 2 acid, the combined filtrates were concentrated under reduced hours. The volatiles were removed under reduced pressure, pressure to yield 472 mg of a brown oil. The residue was the residue was taken up in THF and evaporated again to yield 50 dissolved in DCM, washed with a saturated solution of 182 mg of a residue that was used directly in the next step. Sodium bicarbonate, the combined aqueous solutions were extracted three times with DCM. The organic phases were Step C: (E)-N-2-(6-Amino-2-methylsulfanyl-pyri combined and concentrated under reduced pressure, the resi midin-4-yl)aminoethyl-4,4,4-trifluoro-but-2-enam due was purified by column chromatography (silica, gradient from DCM to a 9 to 1 mixture of DCM and 7N NH in ide 55 methanol) to yield 94.6 mg of a yellow oil. The oil was dissolved in a mixture of diethylether and DCM. 1M HCl in (E)-4,4,4-Trifluorobut-2-enoic acid (21 mg, 0.15 mmol) diethylether was added until the product precipitated. The was dissolved in DCM (1 ml containing one drop of DMF), precipitate was isolated by decantation, washed with diethyl oxalyl chloride was added (13 ul, 0.15 mmol) and the solution ether and dried in stream of nitrogen and under reduced was stirred at room temperature for 15 minutes. This solution 60 pressure to give 127 mg of a white solid (0.498 mmol. 63%). was added to a solution of N6-(2-Aminoethyl)-2-methylsul MS (ESI) m/z–209.2 M+1". fanyl-pyrimidine-4,6-diamine trifluoromethanesulfonate (20 mg, 0.057 mmol) and diisopropylethylamine (51 ul, 0.3 Step C: (E)-N-2-(5-Ethyl-6-methyl-pyrimidin-4-yl) mmol) dissolved in dimethylformamide (1 ml) and the result aminobutyl-4,4,4-trifluoro-but-2-enamide ing mixture was stirred at room temperature for 2 hours. The 65 mixture was diluted with ethyl acetate, washed with water and (E)-4,4,4-Trifluorobut-2-enoic acid (15 mg, 0.11 mmol) saturated Sodium bicarbonate Solution, dried over magnesium was dissolved in DCM (1 ml containing one drop of dimethyl US 8,877,934 B2 91 92 formamide), oxalyl chloride was added (9.5 ul, 0.11 mmol) Chromatographic System: and the solution was stirred at room temperature for 15 min Column: Waters Xbridge C-18, 4.6*50 mm, 2.5u utes. This solution was added to a solution of N2-(5-Ethyl-6- Oven: 40° C. methyl-pyrimidin-4-yl)butane-1,2-diamine (24.5 mg, 0.1 Injection: 2.0 ul Eluents: mmol) and diisopropylethylamine (44 ul, 0.25 mmol) dis Solvent A: waterfammonia: 99.9/0.1 Vol./vol. solved in DMF (1 ml) and the resulting mixture was stirred at Solvent B: acetonitrile? ammonia: 99.9/0.1 Vol.?vol. room temperature overnight. The volatiles were removed Flow: 1.0 ml/min under reduced pressure and the residue was purified by pre Gradient: parative HPLC (gradient of water containing 0.1% NH and acetonitrile) to yield 12.7 mg (0.038 mmol, 38%). 10 Time Solvent A Solvent B Example 18 min % % O.O 95 5 Synthesis of (E)-4-methyl-N-2-(2-methyl-4- 5 O 1OO quinolyl)aminoethylpent-2-enethioamide (A-449) 7 O 1OO Run time: 10 min (equilibration included) Detection Methods: UV at 254 nm, 210 nm. H APCI/MS (100-1500 m/z), positive ions Comment: Samples diluted in a 1 to 1 mixture of solvents. A ~~ and B prior to analysis 21 S Method 2 HPLC-MS System: 25 N Agilent LC/MSD Trap 1100 series composed of: N Binary pump G 1312A included degasser G 1379A, well plate sampler G 1367A, column oven G1316A, diode array detec tor G 1315B, and mass detector G2445D with APCI-source. Step A: (E)-N-2-(2-Methyl-4-quinolyl)amino Chromatographic System: 30 Column: Waters Xbridge C-18, 4.6*50 mm, 2.5u ethylbut-2-enamide Oven: 40° C. Injection: 2.0 ul (E)-4-Methylpent-2-enoic acid (190 mg, 1.3 mmol) was Eluents: mixed together with HBTU (470 mg, 1.3 mmol) and N-(2- Solvent A: waterfammonia: 99.9/0.1 Vol./vol. methyl-4-quinolyl)ethane-1,2-diamine (250 mg, 1.2 mmol) 35 Solvent B: acetonitrile? ammonia: 99.9/0.1 Vol.?vol. in acetonitrile (5 ml). Triethylamine (1 ml) was added with Flow: 1.0 ml/min stirring at 0°C. over 15 minutes and the resulting mixture was Gradient: stirred at room temperature overnight. The volatiles were removed under reduced pressure, the residue was dissolved in DCM and washed with a saturated solution of sodium bicar 40 Time Solvent A Solvent B bonate. The combined aqueous solutions were extracted three min % % times with DCM. The organic layers were combined, dried O.O 90 10 over sodium sulfate, the solvent was removed under reduced 4 O 1OO pressure to give 245 mg of a yellow solid (0.82 mmol. 66%). 5 O 1OO MS (APCI) m/z 298.2 M+1. 45 Run time: 7 min (equilibration included) Step B: (E)-4-Methyl-N-2-(2-methyl-4-quinolyl) Detection Methods: aminoethylpent-2-enethioamide UV at 254 nm, 210 nm. APCI/MS (80-1000 m/z), positive ions (E)-4-Methyl-N-2-(2-methyl-4-quinolyl)aminoethyl 50 Comment: Samples diluted in a 1 to 1 mixture of solvents. A pent-2-enamide (50 mg, 0.15 mmol) was dissolved in diox and B prior to analysis ane (2 ml), Lawesson’s reagent (75 mg, 0.18 mmol) was Method 3 added in one portion and the resulting mixture was stirred at HPLC-MS System: 130° C. under microwave heating for 0.5 hrs. The volatiles Agilent HPLC/MSD 1100 series composed of: were removed under reduced pressure and the residue was 55 Binary pump G 1312A included degasser G 1379A, well plate purified by preparative HPLC (gradient of water containing sampler G 1367A, column oven G1316A, diode array detec 0.1% ammonia and acetonitrile) to yield 15 mg (0.047 mmol. tor G 1315B, mass detector G1946D SL with ESI-source and 28.5%). evaporative light scattering detector Sedex 75. Chromatographic System: C. Analytics: HPLC Methods 60 Column: Chromolith FastGradient RP-18e from Merck, 2*50 Method 1 Oven: 30° C. HPLC-MS System: Injection: 1.0 ul Agilent LC/MSD Trap 1100 series composed of: Eluents: Binary pump G 1312A included degasser G 1379A, well plate 65 Solvent A: water/formic acid: 99.9/0.1 vol./vol. sampler G 1367A, column oven G 1316A, diode array detec Solvent B: acetonitrile? formic acid: 99.9/0.1 vol/vol. tor G 1315B, and mass detector G2445D with APCI-source. Flow: 1.2 ml/min US 8,877,934 B2 94 Gradient: Injection: 2.0 ul Eluents: Solvent A: water/formic acid: 99.9/0.1 vol./vol. Time Solvent A Solvent B Solvent B: acetonitrile? formic acid: 99.9/0.1 vol/vol. min % % Flow: 1.0 ml/min Gradient: O.O 98 2 O.2 98 2 2.2 2 98 2.7 2 98 Time Solvent A Solvent B min % % 10 Run time: 3.5 min (equilibration included) O.O 90 10 Detection Methods: 4 O 1OO 5 O 1OO UV at 210 nm and 254 nm. ESI/MS (100-1000 m/z), positive ions 15 Run time: 7.5 min (equilibration included) ELSD (Sedex 75) Detection Methods: Comment: Samples diluted in a 1 to 1 mixture of solvents. A UV at 254 nm, 210 nm. and B prior to analysis APCI/MS (80-1000 m/z), positive ions Method 4 Comment: Samples diluted in a 1 to 1 mixture of solvents. A HPLC-MS System: and B prior to analysis Agilent HPLC/MSD 1100 series composed of: Binary pump G 1312A included degasser G 1379A, well plate D. Specific Compounds sampler G 1367A, column oven G 1316A, diode array detec tor G 1315B, mass detector G1946D SL with ESI-source and Table A below provides for each of the exemplified com evaporative light scattering detector Sedex 75. pounds of the formula (A') the structure, the calculated Chromatographic System: 25 molecular weight (MVV) (gram/mol), the observed MS sig nal (m/z), the HPLC retention time (Rt) in minutes, and the Column: Chromolith FastGradient RP-18e from Merck, 2*50 number of the HPLC-method as described in paragraph C above (Analytics: HPLC-Methods”) used for analysis. From Oven: 30° C. compound A-451 until the end of Table A the methods by Injection: 1.0 ul 30 which the compounds are synthesized are identified by refer Eluents: ring to the synthetic steps described in the synthesis examples Solvent A: water/formic acid: 99.9/0.1 vol/vol. of paragraph Babove (“Synthesis Examples'). If a compound Solvent B: acetonitrile? formic acid: 99.9/0.1 vol/vol. contains a chiral center, mentioning of Such compound is Flow: 1.2 ml/min indicating the racemate. Gradient: 35 In Table A in case of a) a ring formation between Y and Y by the substituents R'' and R' or b) a ring formation between Y and Y by the substituents R'' and R' in the Time Solvent A Solvent B columns for R'' and R' or in the columns for R'' and R', as min % % the case may, be the symbols Y1, Y2, Y3 and Y4 indicate the O.O 90 10 40 ring atoms Y', Yi, Y and Y in formula (A') to which the 2 O 1OO group joining them is bound. 2.7 O 1OO

Run time: 3.5 min (equilibration included) Formula (A') Detection Methods: 45 R3 UV at 210 nm and 254 nm. N R ESI/MS (105-1000 m/z), positive ions X ELSD (Sedex 75) R-N R2 Comment: Samples diluted in a 1 to 1 mixture of solvents. A V and B prior to analysis 50 Method 5 CH) HPLC-MS System: R-D Agilent LC/MSD Trap 1100 series composed of: R3 1. R12 Binary pump G 1312A included degasser G 1379A, well plate N 4 y11 sampler G 1367A, column oven G 1316A, diode array detec 55 tor G 1315B, and mass detector G2445D with APCI-source. O. Chromatographic System: R 141 N- NR 13 Column: Waters Sunfire C-18, 4.6*50 mm, 3.5u Oven: 40° C. US 8,877,934 B2 95 96

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OOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOO ZZZZZZZZZZZZ, ZOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOO OO OO OO OO OO OO OO OO OO OO OO OO OO OO OO OO OO OO OO OO OO OO OO OO OO OO OO OO OO OO OO OO OO OO OO OO OO OO OO OO OO OO OO OO OO OO OO OO OO OO OO OO OO US 8,877,934 B2 103 104

Z, Z, Z, Z, Z, Z, Z, Z, Z, Z, Z, Z, Z, Z, Z, Z, Z, Z, Z, Z, Z, Z, Z, Z, Z, Z, Z, Z, Z, Z, Z, Z, Z, Z, Z, Z, Z, Z, Z, Z, Z, Z, Z, Z, Z, Z, Z, Z, Z, Z, Z, ZZ

O or or r OO

r aa. it 5 T. T. T. T. T.

...... OOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOO

OOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOO

OOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOO OOOOOOOOOOOOOOOOOOOOOOOOOOOOOO ZZZZZZZ, O ZZZZ, O Z, ZOOO ZZZZZ OO OO OO OO OO OO OO OO OO OO OO OO OO OO OO OO OO OO OO OO OO OO OO OO OO OO OO OO OO OO OO OO OO OO OO OO OO OO OO OO OO OO OO OO OO OO OO OO OO OO OO OO OO

r O

O

US 8,877,934 B2 107 108

Z, Z, Z, Z, Z, Z, Z, Z, Z, Z, Z, Z, Z, Z, Z, Z, Z, Z, Z, Z, Z, Z, Z, Z, Z, Z, Z, Z, Z, Z, Z, Z, Z, Z, Z, Z, Z, Z, Z, Z, Z, Z, Z, Z, Z, Z, Z, Z, Z, Z, Z, ZZ

r

r C. C, O TO O O O r r 5:r ......

III. I. T.

...... | | | | | | | | | | | | | | | | | | | | | | | | | OOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOO

OOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOO

OOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOO OOOOOOOOOOOOOOZ Z, ZOOOOO Z, ZOOOOOOOOOOO ZOOOOOOOO ZZO ZZZZZO OO OO OO OO OO OO OO OO OO OO OO OO OO OO OO OO OO OO OO OO OO OO OO OO OO OO OO OO OO OO OO OO OO OO OO OO OO OO OO OO OO OO OO OO OO OO OO OO OO OO OO OO OO US 8,877,934 B2 109 110

Z, Z, Z, Z, Z, Z, Z, Z, Z, Z, Z, Z, Z, Z, Z, Z, Z, Z, Z, Z, Z, Z, Z, Z, Z, Z, Z, Z, Z, Z, Z, Z, Z, Z, Z, Z, Z, Z, Z, Z, Z, Z, Z, Z, Z, Z, Z, Z, Z, Z, Z, ZZ

it \ C. r O O OO O

r O

H

“HNOO II I I I I I I I I I I I I I I I I I I I I I I I I | | | | | | | | OOOOOOOOOOOOO ZOOOOOOOOOOO ZOOOOOOOOOOOOOOOOOOOOOOO ZOOO

OOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOO OOOOOOOOOOOOOOOOOOOOOOO ZOOOOOOOOOOOOOOOOOOOOOOOOOOOOO OZ OOOOOOOZ, ZOOOOOOOOOOOOO ZOOOOOOOOOOOOOOOOZ, O ZZZOOOOOOO OO OO OO OO OO OO OO OO OO OO OO OO OO OO OO OO OO OO OO OO OO SO OO OO OO OO OO OO OO OO OO OO OO OO OO OO OO OO OO OO OO OO OO OO OO OO OO OO OO OO OO OO OO

O US 8,877,934 B2 111 112

HZ(Viz:V6 HZ(Viz:V6 HZ(Viz:V6

ca, S - S - S - S - S - S - S - S - a can ca S S - S - S - S - S - or a A Z, Z, Z, Z, Z, Z, Z, Z, Z, Z, Z, Z, Z, Z, O O O O O O Z, Z, Z, Z, Z, Z, Z, Z, Z, Z, Z, Z, Z. 2

r 2 ======O (S dS (S (S (S (S (S (S (S (S (S (S (S (S - - - - ca (S - c. (S (S (S (S (S (S (S (S (S (S (S

...... OOOOOOOOOOOOOOO OOOOOOOOOOOOOOOOOOOOOOOOOOOOOO ZOO

OOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOO OOOOOOOOOOOOOOO

OOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOO OOOOOOOOOOOOOOOOOOOOOOOOOOOOOOZ, O O > O O OOZ, ZOOO ZOOOOZ

22 US 8,877,934 B2 113 114

r r r

O O O

r re. r r re. r re r r it 5 T TEST. T. 5 T 5 - T55 - T55 T. T. T. T. T. T. T. it 555 555 555 5555 555 ......

r r r | | | | | | | | | | | | | | | | | | | | | | | | O5 | | | | | | | | | | | | | | | | | | | | | | | | | |

OOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOO

OOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOO

OOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOO

Z, O OZ, O OOOZZO OZ, O OO OZ, ZOOO ZOOOOOOOOOOOOOOOOOOOOOOOOOOOOOO US 8,877,934 B2 115 116

it. I I I I I ITT I I I II. T. T. 555

OOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOO

OOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOO

OOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOO

OOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOO US 8,877,934 B2 117 118

r re. re. H - T55 T. T. T. T. T. T. T. T. T. 5.5 T. T. T. T. T. T. T. T. T. 5.5 T I I ITT

r re. it. TT I I I I I I 55 ITT I I I I I I I I I I I I I IT 5

re. re. re. OO OO ...... OO

OOOOOOOOOOOOOOO ZOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOO

OOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOO

OOOOOOOOOOOOOOOOO ZOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOO

OOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOO US 8,877,934 B2 119 120

re. re. re. it. I I I I I ITT I I I I I I I I I I I I I ITT T. T. 5.5 T I I I I I I I I I I I I ITT 55

r r r re. it. TT 5 T5 ... I I I I ITT T. T. T. T. T. T. T. T. T. 5.5 T. T. T. T. T. T.

r re. EE O O O OO OO

OOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOO

OOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOO

OOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOO

OOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOO US 8,877,934 B2 121 122

I I I I I I I I I I I I I I I | | |

OOOOOOOOOOOOOOOOOOOO

OOOOOOOOOOOOOOOOOOOO

OOOOOOOOOOOOOOOOOOOO

OOOOOOOOOOOOOOO ZZZZO US 8,877,934 B2 123 Further examples of specific compounds of the present inven -continued tion include each of the compounds of table A above wherein X—SO instead of CO and each of the compounds of table A No Structure HPLC Rt mz MW wherein X=CS instead of CO if not already contained in table A and wherein n is equal to 2 or wherein n is equal to 3. 5 Aa-4 2 2.53 278.2 277.4 Further examples of specific compounds of the present O N invention include each of the compounds in table A and analogues wherein X=SO or wherein X=CS and whereinn is equal to 2 or wherein n is equal to 3 in form of its pyridine 10 N-oxide such as the N-oxides shown in the table below: NH

No Structure HPLC Rt mz MW 21 15 Aa-1 2 2.48 264.2 263.3 Sn O N O

NH

21 25

N

Aa-5 F 2 2.57 3O4.2 3O3.3 O F 30 O N F

Aa-2 F 2 240 290.1 289.3 F O 35 N F NH

21

40 N NH

21 O

N 45 Table B below provides for each of the exemplified com O pounds of the formula (B) the structure, the calculated molecular weight (MVV) (gram/mol), the observed MS sig nal (m/z), the HPLC retention time (Rt) in minutes, and the 50 number of the HPLC-method as described in paragraph C Aa-3 F 2 2.62 3O4.2 3O3.3 F above (Analytics: HPLC-Methods”) used for analysis. From O compound B-51 until the end of the table the methods by N F which the compounds are synthesized are identified by refer HN 55 ring to the synthetic steps described in the synthesis examples of paragraph Babove ("Synthesis Examples'). If a compound contains one or more chiral centers, the mentioning of Such l N H compound is indicating the racemate. 60 In Table B in case of a) a ring formation between Y and Y by the substituents R'' and R' or b) a ring formation between Y and Y by the substituents R'' and R' in the columns for R'' and R' or in the columns for R'' and R', as 65 the case may be, the symbols Y1, Y2, Y3 and Y4 indicate the ring atoms Y.Y.Y. andY'informula (B) to which the group joining them is bound. US 8,877,934 B2 125 126

Formula (B)

10

15

US 8,877,934 B2 129 130

s cal can ca A E. : : - ...... O ...... O ......

C Co -

f & == Y

r r r r r r r r r | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | O O O O O O O O O

2

r 2 it 5 T. T. T. T. 5 T 5: I. T. T. T. T. T. T. T. T. T. T. T. T. T. T. T. T. T. T. T. T. T. S. T. T. T. T. T. T.

H „TH

H H

| | | | | | | | | | | | | | | | | | | | | | | | | | | | | |

OOOOOO ZZ OOOOOOOOOOOOO ZZZZZZZ, ZOOOOOOOOOOOOOO

US 8,877,934 B2 137 138 Further examples of specific compounds of the present inven ml). 1.2-Propanediol (0.75 ml) and water was added until a tion include each of the compounds of table Babove wherein total Volume of 5.0 ml was reached to give a homogeneous X—SO instead of CO and each of the compounds of table B solution with a content by weight of 5% compound C. wherein X-CS instead of CO. The formulations can be used i.a. for parenteral and oral Further examples of specific compounds of the present inven administration to animals, e.g. sheep or cattle. tion include each of the compounds in table B and analogues wherein X=SO or wherein X=CS, in form of its pyridine DEFINITIONS N-oxide. The term “acyl (alone or in combination with (an)other E Biological Examples 10 term(s)) means a the radical derived from an oxo acid, pref erably from a carboxylic acid, by removal of the OH-group. Determining Activity Against Ascaridia galli and Preferred acyl groups have the formula R—CO, wherein R is Oesophagostomum dentatum Horan aromatic or heteroaromatic ring, preferably of 4 to 10 ring atoms, or an aliphatic hydrocarbon radical, preferably of Anthelmintic effects of compounds of this invention were 15 1 to 10 carbon atoms, more preferred are unsubstituted or tested in vitro using gut-welling larval stages of two parasitic substituted alkyl of 1 to 6 carbon atoms. nematode species: Ascaridia galli (intestinal roundworm of The term “alkyl (alone or in combination with (an)other chicken), larval stage 3 ("L3’); and Oesophagostumum den term(s)) means a straight-chain or branched-chain Saturated tatum (nodular worm of Swine), larval stages 3 and 4 (respec hydrocarbyl Substituent (i.e., a Substituent containing only tively “L3’ and “L4). When conducting these experiments, carbon and hydrogen) which unless otherwise specified typi DMSO-solutions of various concentrations of compounds of cally contains from 1 to 6 carbon atoms, and even more this invention were prepared and incubated in 96-well micro typically from 1 to about 4 carbon atoms. Examples of Such titer plates. The parasites were then distributed at 20 larvae Substituents include methyl, ethyl, n-propyl, isopropyl. n-bu per well. The anthelmintic effects were classified by micro tyl, iso-butyl, Sec-butyl, tert-butyl, pentyl, iso-pentyl, hexyl, scopic examination. The microscopic examination included 25 and octyl. For instance the term "C-C-alkyl includes but is assessing mortality, damage, motility, progression of devel not limited to methyl, ethyl, n-propyl, isopropyl. n-butyl, opment, and neutral reduptake by the larvae in comparison to iso-butyl, sec-butyl, tert-butyl, n-pentyl, iso-pentyl, neo-pen a DMSO-control. The anthelmintic effects were defined by tyl, n-hexyl, iso-hexyl. the minimum effective concentration (“MEC), which is the The term “alkenyl (alone or in combination with (an)other concentration by which at least one of the larvae shows mor 30 term(s)) means a straight- or branched-chain hydrocarbyl tality, damage, change in motility, change in progression of Substituent containing one or more double bonds and unless development, or no neutral red uptake. The following com otherwise specified typically contains from 2 to 6 carbon pounds showed at least Some activity against one or more of atoms, even more typically from 2 to 4 carbon atoms. the nematodes at an MEC of 50 uM or less: A-1-A-5, A-7-A- Examples of such substituents include ethenyl (vinyl); 2-pro 9, A-1 1-A-14, A-17, A-19-A-22, A-25-A-27, A-29-A-31, 35 penyl: 3-propenyl: 1,4-pentadienyl: 1,4-butadienyl: 1-bute A-33-A-35, A-41-A-44, A-46-A-52, A-55-A-56, A-60-A-75, nyl: 2-butenyl: 3-butenyl; and 2-hexenyl. A-78-A-81, A-83, A-86-A-89, A-91-A-92, A-95-A-100, The term “alkynyl (alone or in combination with (an)other A-102-A-103, A-105-A-107, A-111, A-113-A-119, A-121 term(s)) means a straight- or branched-chain hydrocarbyl A-123, A-125, A-129-A153, A-156-A-159, A-163, A-166-A- Substituent containing one or more triple bonds and unless 168, A-170-A-180, A-182-A-187, A-189-A-190, A-192-A- 40 otherwise specified typically from 2 to 6 atoms, even more 206, A-210-A-226, A-229, A-231-A-234, A-236-A-248, typically from 2 to 4 carbon atoms. Examples of Such Sub A-251-A-255, A-257-A-267, A-269-A-276, A-279-A-290, stituents include ethynyl, 2-propynyl, 3-propynyl, 1-butynyl, A-292-A-296, A-298-A-303, A-305-A-329, A-331, A-333 2-butynyl, 3-butynyl, and 2-hexynyl. A-352, A-354-A-393, A-395-A-404, A-406-A-413, A-415 The term "cycloalkyl (alone or in combination with (an) A-421, A-428-A-429, A-431-A-432, A-434-A-437, A-440 45 other term(s)) means a cyclic Saturated hydrocarbyl Substitu A-446, Aa2, Aa3, AaS, B-1-B-9, B-11-B-19, B-21-B-49. ent (i.e., a Substituent containing only carbon and hydrogen) which unless otherwise specified typically contains from 3 to F Formulation Examples 8 carbon atoms. The cycle or ring in the “cycloalkyl sub stituent may be formed by all carbonatoms of the substituent, Formulation A: 5% Suspension: 50 or may be formed by some, but not all of the carbonatoms of 4.5g of compound A (a compound according to this inven the substituent. In the latter case, the substituent may be tion, but which may be any compound in line with the inven connected at a carbon atom that is part of a cycle or that is not tion) was dissolved in DMSO, the resulting solution was part of a cycle. Examples of Such substituents include cyclo mixed with a 0.1% solution of methyl cellulose in isotonic propyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, NaCl to give a homogeneous Suspension of compound A (5% 55 2-methylcyclopropyl, cyclopropylmethyl, cyclohexylm by weight). ethyl. Formulation B: 0.5% Suspension: The term “halogen' (alone or in combination with (an) 18.6 mg of compound B (a compound according to this other term(s)) means a fluorine radical (“fluoro’, which may invention, but which may be any compound in line with the be depicted as F), chlorine radical (“chloro’, which may be invention) was dissolved in DMSO, the resulting solution was 60 depicted as Cl), bromine radical (“bromo, which may be mixed with a 0.1% solution of methyl cellulose in isotonic depicted as Br), or iodine radical (“iodo’, which may be NaCl to give a homogeneous Suspension of compound B depicted as I). Typically, fluoro or chloro is preferred. (0.5% by weight). When a chemical formula is used to describe a mono Formulation C: 5% Solution: valent substituent, the dash on the left side of the formula 0.25 g of Compound C (a compound according to this 65 indicates the portion of the substituent that has the free invention, but which may be any compound in line with the valence. To illustrate, benzene substituted with —C(O)—OH invention) was dissolved in 1-methyl-2-pyrrolidinone (3.25 has the following structure: US 8,877,934 B2 139 140 each of the carbon-containing radicals optionally is Sub stituted by one or more halogen atoms, R is hydrogen, C1-Co-alkyl or cycloalkyl, R" is hydrogen, C1-Co-alkyl or cycloalkyl, OH. R is hydrogen, C1-Co-alkyl, cycloalkyl, acyl, cycloalky loxycarbony or C-C-alkyloxycarbonyl, R is hydrogen, C-C-alkyl, cycloalkyl, hydroxy, C-C- alkyloxy, phenyl C-C-alkyloxy, hydroxy C-C-alkyl, When a chemical formula is used to describe adi-valent (or C-C-alkyloxy C-C-alkyl, phenyl C-C-alkyloxy “linking') component between two other components of a 10 C-C-alkyl, thiol C-C-alkyl, C-C-alkylthio C-C- depicted chemical structure (the right and left components), alkyl, phenyl C-C-alkylthio C-C-alkyl, hydroxycar the leftmost dash of the linking component indicates the bonyl, hydroxycarbonyl C-C-alkyl, C-C-alkyloxy portion of the linking component that is bound to the left carbonyl, C-C-alkyloxycarbonyl C-C-alkyl, component in the depicted structure. The rightmost dash, on aminocarbonyl, aminocarbonyl C-C-alkyl, C-C- the other hand, indicates the portion of the linking component 15 alkylaminocarbonyl, C-C-alkylaminocarbonyl (C- that is bound to the right component in the depicted structure. C-alkyl), di(C-C-alkyl)aminocarbonyl, di(C-C- The term “pharmaceutically acceptable' is used adjecti alkyl)aminocarbonyl (C-C-alkyl), C-C-alkylamino vally to mean that the modified noun is appropriate for use in C-C-alkyl, di(C-C-alkyl)amino C-C-alkyl, phe a pharmaceutical product. When it is used, for example, to nyl, phenyl C-C-alkyl, wherein each phenyl group is describe a salt, Solvate, N-oxide, active compound or excipi optionally substituted by hydroxy, cycloalkyloxy or ent, it characterizes the salt, Solvate, N-oxide, active com C-C-alkyloxy, pound or excipient as being compatible with the other ingre R’ is hydrogen, C1-Co-alkyl or cycloalkyl, dients of the composition, and not deleterious to the intended or R is joined together with R to form a C-C-alkylene recipient animal, e.g. to the extent that the benefit(s) out group and Risjoined together with R to form a C-C- weigh (s) the deleterious effect(s). 25 alkylene group, wherein one or both of said C-C- The above detailed description of preferred embodiments alkylene groups are optionally Substituted by one or is intended only to acquaint others skilled in the art with the more C-C-alkyl or cycloalkyl radicals, invention, its principles, and its practical application so that n is an integer from 1 to 3. others skilled in the art may adapt and apply the invention in X is a carbonyl, thiocarbonyl or Sulfonyl group, its numerous forms, as they may be best Suited to the require 30 A is a bond or NR, wherein R is hydrogen or C-C-alkyl, ments of a particular use. This invention, therefore, is not E is a bond or NR, wherein R is hydrogen or C-C-alkyl, limited to the above embodiments, and may be variously B is N or CR', wherein R' is hydrogen or C-C-alkyl, modified. D is N or CR'', wherein R'' is hydrogen or C-C-alkyl, The invention claimed is: Y'=C R', wherein R' is hydrogen, halogen, C-C- 1. A compound of the formula (I) or pharmaceutically 35 alkyl, C-C-alkenyl, Cycloalkyl, Cycloalkyloxy, acceptable salts, or N-oxides thereof, C-C-haloalkyl, C-C-alkoxy, C-C-haloalkoxy, nitrilo, nitro, amino, C-C-alkylamino, Cycloalky lamino, di(C-C-alkyl)amino, (C-C-alkyl)-(Cy Formula (I) cloalkyl)amino, N-pyrrolidinyl, N-piperidinyl, N-mor 40 pholinyl, C-C-alkylthio. Cycloalkylthio. C-C- haloalkylthio, C-C-alkyl carbonyl, C-C-haloalkyl carbonyl, C1-C6-alkylcarbonylamino, aminocarbonyl, C-C-alkylaminocarbonyl, di(C-C-alkyl)aminocar bonyl, C-C-alkoxycarbonyl, phenyl, dioxolane, diox 45 ane, or dioxepane, wherein each ring is unsubstituted or substituted by C-C-alkyl, Y is CR', wherein R' which is hydrogen, halogen, C-C-alkyl, C-C-alkenyl, Cycloalkyl, Cycloalky loxy, C-C-haloalkyl, C-C-alkoxy, C-C-ha 50 loalkoxy, nitrilo, nitro, amino, C1-C6-alkylamino, Cycloalkylamino, di(C-C-alkyl)amino, (C-C- alkyl)-(Cycloalkyl)amino, N-pyrrolidinyl, N-piperidi nyl, N-morpholinyl, thiol, hydroxy, C-C-alkylthio. Cycloalkylthio. C-C-haloalkylthio, C-C-alkyl car 55 bonyl, C-C-haloalkyl carbonyl, aminocarbonyl, C-C-alkylaminocarbonyl, di(C-C-alkyl)aminocar wherein bonyl, C-C-alkylcarbonylamino, C-C-alkoxycarbo R" is halogen, C, -Co-alkyl, C1-Co-alkyloxy, C, -Co-alky nyl, dioxolane, dioxane, or dioxepane, wherein each lthio, C-C-alkenyl, C-C-alkynyl, C-C-alkyloxy ring is unsubstituted or Substituted by C-C-alkyl, C-C-alkyl, C-C-alkylthio C-C-alkyl, C-C-alkyl 60 Y is CR'', wherein R'' is hydrogen, halogen, C-C- carbonyl, C-C-alkenyl carbonyl, SFs C-C-alkylsul alkyl, C-C-alkenyl, Cycloalkyl, Cycloalkyloxy, fonyl, wherein each of the carbon-containing radicals C-C-haloalkyl, C-C-alkoxy, C-C-haloalkoxy, optionally is Substituted by one or more halogen atoms, nitrilo, nitro, amino, C-C-alkylamino, Cycloalky R is hydrogen, halogen, C1-Co-alkyl, C1-Co-alkyloxy, lamino, di(C-C-alkyl)amino, (C-C-alkyl)-(Cy C-C-alkylthio, C-C-alkenyl, C-C-alkynyl, C-C- 65 cloalkyl)amino, N-pyrrolidinyl, N-piperidinyl, N-mor alkyloxy C-C-alkyl, C-C-alkylthio C-C-alkyl, pholinyl, thiol, hydroxy, C-C-alkylthio. C-C-alkyl carbonyl, C-C-alkenyl carbonyl, wherein Cycloalkylthio, C-C-haloalkylthio, C-C-alkyl car US 8,877,934 B2 141 142 bonyl, C-C-haloalkyl carbonyl, C-C-alkylcarbony Y is CR'', wherein R'' is hydrogen, halogen, C-C- lamino, aminocarbonyl, C-C-alkylaminocarbonyl, alkyl, C-C-alkenyl, Cycloalkyl, Cycloalkyloxy, di (C-C-alkyl)aminocarbonyl, C-C-alkoxycarbonyl, C-C-haloalkyl, C-C-alkoxy, C-C-haloalkoxy, dioxolane, dioxane, or dioxepane, wherein each ring is nitrilo, nitro, amino, C-C-alkylamino, Cycloalky unsubstituted or substituted by C-C-alkyl, lamino, di(C-C-alkyl)amino, (C-C-alkyl)-(Cy Y is CR", wherein R' is hydrogen, halogen, C-C- cloalkyl)amino, N-pyrrolidinyl, N-piperidinyl, N-mor alkyl, C-C-alkenyl, Cycloalkyl, Cycloalkyloxy, pholinyl, thiol, hydroxy, C-C-alkylthio. C-C-haloalkyl, C-C-alkoxy, C-C-haloalkoxy, Cycloalkylthio. C-C-haloalkylthio, C-C-alkyl car nitrilo, nitro, amino, C-C-alkylamino, Cycloalky bonyl, C-C-haloalkyl carbonyl, C-C-alkylcarbony lamino, di(C-C-alkyl)amino, (C-C-alkyl)-(Cy 10 lamino, aminocarbonyl, C-C-alkylaminocarbonyl, cloalkyl)amino, N-pyrrolidinyl, N-piperidinyl, N-mor di(C-C-alkyl)aminocarbonyl, C-C-alkoxycarbonyl, pholinyl, C-C-alkylthio, C-C-haloalkylthio, C-C- dioxolane, dioxane, or dioxepane, wherein each ring is alkyl carbonyl, C-C-haloalkyl carbonyl, C-C- unsubstituted or substituted by C-C-alkyl, alkylcarbonylamino, aminocarbonyl, C-C- Y is CR', wherein R' is hydrogen, halogen, C-C- alkylaminocarbonyl, di(C-C-alkyl)aminocarbonyl, 15 alkyl, C-C-alkenyl, Cycloalkyl, Cycloalkyloxy, C-C-alkoxycarbonyl, phenyl, dioxolane, dioxane, or C-C-haloalkyl, C-C-alkoxy, C-C-haloalkoxy, dioxepane, wherein each ring is unsubstituted or Substi nitrilo, nitro, amino, C-C-alkylamino, Cycloalky tuted by C-C-alkyl, lamino, di(C-C-alkyl)amino, (C-C-alkyl)-(Cy orY and Y and/orY and Y are joined together to form a cloalkyl)amino, N-pyrrolidinyl, N-piperidinyl, N-mor ring System, pholinyl, C-C-alkylthio, C-C-haloalkylthio, C-C- and wherein at least one of B and D is a nitrogen atom. alkyl carbonyl, C-C-haloalkyl carbonyl, C-C- 2. A compound according to claim 1, wherein alkylcarbonylamino, aminocarbonyl, C-C- R" is halogen, C, -Co-alkyl, C1-Co-alkyloxy, C, -Co-alky alkylaminocarbonyl, di(C-C-alkyl)aminocarbonyl, lthio, C-C-alkenyl, C-C-alkynyl, C-C-alkyloxy 25 C-C-alkoxycarbonyl, phenyl, dioxolane, dioxane, or C-C-alkylthio C-C-alkyl, C-C-alkyl carbonyl, dioxepane, wherein each ring is unsubstituted or Substi C-C-alkenyl carbonyl, SFs, C-C-alkyl Sulfonyl, tuted by C-C-alkyl, wherein each of the carbon-containing radicals option orY and Y and/orY and Y are joined together to form a ally is Substituted by one or more halogen atoms, ring system, R’ is hydrogen, 30 and wherein at least one of B and D is a nitrogen atom. R is hydrogen, 3. A compound of the formula (II) according to claim 1, R" is hydrogen or C-C-alkyl, R is hydrogen, C-C-alkyl, acyl or C-C-alkyloxycar Formula (II) bonyl (CRR), is a C-C-alkylene group, which is O RI optionally substituted by one or more C-C-alkyl radi 35 cals, HN A is a bond or NR, wherein R is H or C-C-alkyl, V E is a bond or NR, wherein R is H or C-C-alkyl, (CRR). B is N or CR', wherein R' is H or C-C-alkyl, / D is N or CR'', wherein R'' is H or C-C-alkyl, 40 HN X is a carbonyl, thiocarbonyl or Sulfonyl group, Y'=CR'', wherein R' is hydrogen, halogen, C-C- Y4 Yl alkyl, C-C-alkenyl, Cycloalkyl, Cycloalkyloxy, C-C-haloalkyl, C-C-alkoxy, C-C-haloalkoxy, Y.O Y2 nitrilo, nitro, amino, C-C-alkylamino, Cycloalky 45 n lamino, di(C-C-alkyl)amino, (C-C-alkyl)-(Cy cloalkyl)amino, N-pyrrolidinyl, N-piperidinyl, N-mor wherein pholinyl, C-C-alkylthio, Cycloalkylthio, C-C- R" is C1-Co-alkyl, C, -Co-alkyloxy C, -Co-alkyl, or C-C- haloalkylthio, C-C-alkyl carbonyl, C-C-haloalkyl alkylthio C-C-alkyl, wherein each of the carbon-con carbonyl, C-C-alkylcarbonylamino, aminocarbonyl, 50 taining radicals is unsubstituted or Substituted by one or C-C-alkylaminocarbonyl, di(C-C-alkyl)aminocar more halogen atoms, bonyl, C-C-alkoxycarbonyl, phenyl, dioxolane, diox R is hydrogen, C1-Co-alkyl, hydroxy, C1-Co-alkyloxy, ane, or dioxepane, wherein each ring is unsubstituted or phenyl C-C-alkyloxy, hydroxy C-C-alkyl, C-C- substituted by C-C-alkyl, alkyloxy C-C-alkyl, phenyl C-C-alkyloxy C-C- Y is CR', wherein R' which is hydrogen, halogen, 55 alkyl, thiol C-C-alkyl, C-C-alkylthio C-C-alkyl, C-C-alkyl, C-C-alkenyl, Cycloalkyl, Cycloalky phenyl C-C-alkylthio C-C-alkyl, hydroxycarbonyl, loxy, C-C-haloalkyl, C-C-alkoxy, C-C-ha hydroxycarbonyl C-C-alkyl, C-C-alkyloxycarbo loalkoxy, nitrilo, nitro, amino, C-C-alkylamino, nyl, C-C-alkyloxycarbonyl C-C-alkyl, aminocarbo Cycloalkylamino, di(C-C-alkyl)amino, (C-C- nyl, aminocarbonyl C-C-alkyl, C-C-alkylaminocar alkyl)-(Cycloalkyl)amino, N-pyrrolidinyl, N-piperidi 60 bonyl, C-C-alkylaminocarbonyl (C-C-alkyl), di(C- nyl, N-morpholinyl, thiol, hydroxy, C-C-alkylthio. C-alkyl)aminocarbonyl, di(C-C-alkyl) Cycloalkylthio, C-C-haloalkylthio, C-C-alkyl car aminocarbonyl (C-C-alkyl), C-C-alkylamino bonyl, C-C-haloalkyl carbonyl, aminocarbonyl, C-C-alkyl, di(C-C-alkyl)amino C-C-alkyl, phe C-C-alkylaminocarbonyl, di(C-C-alkyl)aminocar nyl, phenyl C-C-alkyl, wherein each phenyl group is bonyl, C-C-alkylcarbonylamino, C-C-alkoxycarbo 65 optionally Substituted by hydroxy or C-C-alkyloxy, nyl, dioxolane, dioxane, or dioxepane, wherein each R’ is hydrogen or C1-Co-alkyl, ring is unsubstituted or Substituted by C-C-alkyl, n is 2 or 3, US 8,877,934 B2 143 144 Y'=CR'', wherein R' is hydrogen, halogen, C-C- amino, N-pyrrolidinyl, N-piperidinyl, N-morpholinyl, alkyl, C-C-haloalkyl, C-C-alkoxy, C-C-ha thiol, hydroxy, C-C-alkylthio. C-C-alkyl carbonyl, loalkoxy, Cycloalkyl, Cycloalkyloxy, nitrilo, nitro, C-C-alkylcarbonylamino, aminocarbonyl, C-C- amino, C-C-alkylamino, di(C-C-alkyl)amino, alkylaminocarbonyl, di(C-C-alkyl)aminocarbonyl, C-C-alkylthio, C-C-alkyl carbonyl, aminocarbonyl, C-C-alkoxycarbonyl, dioxolane, dioxane, or diox C1-C6-alkylaminocarbonyl, di(C-C-alkyl)aminocar epane, wherein each ring is unsubstituted or Substituted bonyl, by C-C-alkyl. Y=CR', wherein R' is hydrogen, halogen, C-C- 6. A compound according to claim 1, wherein alkyl, C-C-haloalkyl, C-C-alkoxy, C-C-ha R’ is hydrogen, loalkoxy, Cycloalkyl, Cycloalkyloxy, nitrilo, nitro, 10 amino, C-C-alkylamino, di(C-C-alkyl)amino, R is hydrogen, N-pyrrolidinyl, N-piperidinyl, N-morpholinyl, C-C- R" is hydrogen or C-C-alkyl, alkylthio, C-C-alkyl carbonyl, aminocarbonyl, C-C- R is hydrogen or C1-Co-alkyl, alkylaminocarbonyl, di(C-C-alkyl)aminocarbonyl, R is hydrogen or C1-Co-alkyl, dioxolane, dioxane, or dioxepane, wherein each ring is 15 R’ is hydrogen, unsubstituted or substituted by C-C-alkyl, X is a carbonyl group, Y=CR'', wherein R'' is hydrogen, halogen, C-C- n is 2. alkyl, C-C-haloalkyl, C-C-alkoxy, C-C-ha the group of formula (A) represents a pyridine or quinoline loalkoxy, Cycloalkyl, Cycloalkyloxy, nitrilo, nitro, grOup, amino, C-C-alkylamino, di(C-C-alkyl)amino, wherein each group is optionally Substituted by one or N-pyrrolidinyl, N-piperidinyl, N-morpholinyl, C-C- more radicals, selected alkylthio, C-C-alkyl carbonyl, aminocarbonyl, C-C- from the group of C-C-alkyl, C-C-haloalkyl, C-C- alkylaminocarbonyl, di(C-C-alkyl)aminocarbonyl, alkoxy, Cycloalkoxy, C-C-haloalkoxy, nitrilo, nitro, dioxolane, dioxane, or dioxepane, wherein each ring is amino, C-C-alkylamino, di(C-C-alkyl)amino, unsubstituted or substituted by C-C-alkyl, 25 N-pyrrolidinyl, N-piperidinyl, N-morpholinyl, thio. Y=CR', wherein R' is hydrogen, halogen, C-C- C-C-alkylthio. C-C-alkyl carbonyl, aminocarbonyl, alkyl, C1-C6-haloalkyl, C-C-alkoxy, C-C-ha C-C-alkylaminocarbonyl, di(C-C-alkyl)aminocar loalkoxy, nitrilo, nitro, amino, C-C-alkylamino, bonyl, dioxolane, dioxane, or dioxepane, wherein each di (C-C-alkyl)amino, C-C-alkylthio, C-C-alkyl ring is unsubstituted or substituted by C-C-alkyl, and carbonyl, aminocarbonyl, C-C-alkylaminocarbonyl, 30 di (C-C-alkyl)aminocarbonyl, one of A and B and one of D and E contains a nitrogen orY and Y and/orY and Yarejoined together to form a atOm. 5- or 6-membered ring system. 7. A pharmaceutical composition, wherein the composi 4. A compound according to claim 3, wherein tion comprises: R" is C-C-alkyl, C-C-alkyloxy C-C-alkyl, or C-C- 35 a) one or more compounds as defined in claim 1; and alkylthio C-C-alkyl, b) one or more pharmaceutically acceptable excipients and wherein each of the carbon-containing radicals is unsub optionally one or more pharmaceutically acceptable stituted or Substituted by one or more halogen atoms, active ingredients which differ instructure from compo Y'—C R', where R' is H or C-C-alkyl, nenta). Y is C, wherein C is substituted by R' is H. C-C-alkyl, 40 8. A compound of formula (1-IV), C-C-alkoxy, C-C-alkyl carbonyl, Cycloalkyl, Cycloalkyloxy, C-C-alkylthio Y is C, wherein C is substituted by R'' is H, C, -Co-alkyl, Formula 1-IV C-C-alkoxy, C-C-alkyl carbonyl, Cycloalkyl, Cycloalkyloxy, C-C-alkylthio 45 Y is C, wherein C is substituted by R' is H, C, -Co-alkyl, C-C-alkoxy, C-C-alkylthio orY andYorY andYarejoined together to form a 5- or 6-membered ring system. 5. A compound according to claim 1, wherein the group of 50 the formula (A)

Formula (A) y42\ Yl 55 wherein Y', Y, Y and Y are C, substituted by R', R', Y. Y2 RandR'respectively and which are selected from the n R1 group of hydrogen, halogen, C-C-alkyl, C-C-ha loalkyl, C-C-alkoxy, C-C-haloalkoxy, nitrilo, nitro, represents a pyridine, thienopyridine, pyridopyridine, pyr 60 amino, C-C-alkylamino, di(C-C-alkyl)amino, rolopyridine, pyrazolopyridine, furopyridine, 2,3-dihy C-C-alkylthio, C-C-alkyl carbonyl, aminocarbonyl, drofuropyridine, 2,3-dihydro-1,4-dioxinopyridine, or C-C-alkylaminocarbonyl, di(C-C-alkyl)aminocar cinnoline group, wherein each group is optionally Sub bonyl and phenyl, and wherein at least one of R'' and stituted by one or more radicals, selected from the group R" is C, -Co-alkoxy or of C-C-alkyl, Cycloalkyl, Cycloalkyloxy, C-C-ha 65 C-Ca-haloalkoxy, and B is N, A is NR or a bond, n is 2, loalkyl, C-C-alkoxy, C-C-haloalkoxy, halogen, R. R', and Rare H, and R and Rare defined as in nitrilo, nitro, amino, C-C-alkylamino, di(C-C-alkyl) claim 1. US 8,877,934 B2 145 146 9. A kit, wherein the kit comprises: C-C-alkylamino, cycloalkylamino, di-(C-C-alkyl) a) one or more compounds as defined in claim 1, and amino, di-(cycloalkyl)amino, C-C-alkyl-cycloalky b) one or more other components selected from the group lamino, C-C-alkylamino-C-C-alkyl, cycloalky consisting of an excipient, an active ingredient, an appa lamino-C-C-alkyl, C-C-alkylamino-cycloalkyl, ratus for combining the compound of componenta) with 5 cycloalkylamino-cycloalkyl, di-(C-C-alkyl)amino an excipient and/or active ingredient, an apparatus for C-C-alkyl, di-(C-C-alkyl)amino-cycloalkyl, di-(cy administering the compound of componenta) to an ani cloalkyl)amino-C-C-alkyl, di-(cycloalkyl)amino-cy mal, and a diagnostic tool. cloalkyl, C-C-alkyl-cycloalkylamino-C-C-alkyl, 10. A method of treating a parasitic infection, wherein the C-C-alkyl-cycloalkylamino-cycloalkyl, C-C-alkyl method comprises administering to an the pharmaceutical 10 carbonyl, cycloalkylcarbonyl, C-C-alkyloxy carbo composition as defined in claim 7. nyl, cycloalkoxy carbonyl, C-C-alkenyl carbonyl, 11. A method as claimed in claim 10, wherein the animal is wherein each of the carbon-containing radicals option a non-human animal. ally is substituted by one or more halogen atoms, or R 12. A compound of the formula (Ia) or pharmaceutically is phenyl, furanyl, imidazolinyl, or thiophenyl, wherein acceptable N-oxides or salts thereof, 15 each of the rings optionally is Substituted by one or more radicals from the group of C-C-alkyl, cycloalkyl and halogen, Formula (Ia) R is hydrogen, C1-Co-alkyl or cycloalkyl R" is hydrogen, C1-Co-alkyl or cycloalkyl R is hydrogen, C1-Co-alkyl, cycloalkyl or acyl, R is hydrogen, C-C-alkyl, cycloalkyl, hydroxy, C-C- alkyloxy, phenyl C-C-alkyloxy, hydroxy C-C-alkyl, C-C-alkyloxy C-C-alkyl, phenyl C-C-alkyloxy C-C-alkyl, thiol C-C-alkylthio C-C-alkyl, phenyl 25 C-C-alkylthio C-C-alkyl, hydroxycarbonyl, hydroxycarbonyl C-C-alkyl, C-C-alkyloxycarbo nyl, C-C-alkyloxycarbonyl C-C-alkyl, aminocarbo nyl, aminocarbonyl C-C-alkyl, C-C-alkylaminocar bonyl, C-C-alkylaminocarbonyl (C-C-alkyl), di(C- 30 C-alkyl)aminocarbonyl, di(C-C-alkyl) aminocarbonyl (C-C-alkyl), C-C-alkylamino C-C-alkyl, di(C-C-alkyl)amino C-C-alkyl, phe nyl, phenyl C-C-alkyl, wherein each phenyl group is optionally substituted by hydroxyl, C-C-alkyloxy or 35 cycloalkyloxy, wherein R’ is hydrogen, C1-Co-alkyl or cycloalkyl, R" is hydrogen, halogen, C1-Co-alkyl, cycloalkyl, C, -Co or R and R together represent an oxo-group or a thioxo alkyloxy, cycloalkyloxy, C-C-alkylthio, cycloalky group, or Risjoined together with R to form a C-C- lthio, C-C-alkenyl, C-C-alkynyl, C-C-alkyloxy alkylene group and Risjoined together with R to form C-C-alkyl, cycloalkyloxy C-C-alkyl, C-C-alky 40 a C-C-alkylene group, wherein one or both of said loxy cycloalkyl, cycloalkyloxy cycloalkyl, C-C-alky C-C-alkylene groups are optionally Substituted by one lthio C-C-alkyl, cycloalkylthio C-C-alkyl, C-C- or more C-C-alkyl or cycloalkyl radicals, alkylthio cycloalkyl, cycloalkylthio cycloalkyl, amino, n is an integer from 1 to 3. C-C-alkylamino, cycloalkylamino, di-(C-C-alkyl) X is a carbonyl or Sulfonyl group, amino, di-(cycloalkyl)amino, C-C-alkyl-cycloalky 45 A is a bond or NR, wherein R is hydrogen or C-C-alkyl, lamino, C-C-alkylamino-C-C-alkyl, cycloalky E is a bond or NR, wherein R is hydrogen or C-C-alkyl, lamino-C-C-alkyl, C-C-alkylamino-cycloalkyl, B is N or CR', wherein R' is hydrogen or C-C-alkyl, cycloalkylamino-cycloalkyl, di-(C-C-alkyl)amino D is N or CR'', wherein R'' is hydrogen or C-C-alkyl, C-C-alkyl, di-(C-C-alkyl)amino-cycloalkyl, di-(cy Y' is CR', wherein R' is hydrogen, halogen, C-C- cloalkyl)amino-C-C-alkyl, di-(cycloalkyl)amino-cy 50 alkyl, C-C-haloalkyl, C-C-alkoxy, C-C-ha cloalkyl, C-C-alkyl-cycloalkylamino-C-C-alkyl, loalkoxy, nitrilo, nitro, amino, C-C-alkylamino, C-C-alkyl-cycloalkylamino-cycloalkyl, C-C-alkyl di(C-C-alkyl)amino, N-pyrrolidinyl, N-piperidinyl, carbonyl, cycloalkylcarbonyl, C-C-alkyloxy carbo N-morpholinyl, C-C-alkylthio, C-C-alkyl carbonyl, nyl, cycloalkoxy carbonyl, C-C-alkenyl carbonyl, C-C-haloalkyl carbonyl, C-C-alkylcarbonylamino, wherein each of the carbon-containing radicals option 55 aminocarbonyl, C-C-alkylaminocarbonyl, di(C-C- ally is substituted by one or more halogen atoms, or R' alkyl)aminocarbonyl, C1-C6-alkoxycarbonyl, is phenyl, furanyl, imidazolinyl, or thiophenyl, wherein cycloalkyl, cycloalkyloxy, cycloalkylamino, (C-C- each of the rings optionally is Substituted by one or more alkyl)-(cycloalkyl)amino, cycloalkylthio, phenyl, diox radicals from the group of C-C-alkyl, cycloalkyl and olane, halogen, 60 dioxane, or dioxepane, wherein each ring is unsubstituted R is hydrogen, halogen, C-C-alkyl, cycloalkyl, C-C- or substituted by C-C-alkyl or cycloalkyl, alkyloxy, cycloalkyloxy, C-C-alkylthio, cycloalky Y is CR' wherein R' is hydrogen, halogen, C-C-alkyl, lthio, C-C-alkenyl, C-C-alkynyl, C-C-alkyloxy C-C-haloalkyl, C-C-alkoxy, C-C-haloalkoxy, C-C-alkyl, cycloalkyloxy C-C-alkyl, C-C-alky nitrilo, nitro, amino, C-C-alkylamino, di(C-C-alkyl) loxy cycloalkyl, cycloalkyloxy cycloalkyl, C-C-alky 65 amino, N-pyrrolidinyl, N-piperidinyl, N-morpholinyl, lthio C-C-alkyl, cycloalkylthio C-C-alkyl, C-C- thiol, hydroxy, C-C-alkylthio, C-C-alkyl carbonyl, alkylthio cycloalkyl, cycloalkylthio cycloalkyl, amino, C-C-haloalkyl carbonyl, aminocarbonyl, C-C-alky US 8,877,934 B2 147 148 laminocarbonyl, di (C-C-alkyl)aminocarbonyl, 17. The compound of claim 1, wherein the compound is C-C-alkylcarbonylamino, C-C-alkoxycarbonyl, cycloalkyl, cycloalkyloxy, cycloalkylamino, (C-C- alkyl)-(cycloalkyl)amino, cycloalkylthio, dioxolane, dioxane, or dioxepane, wherein each ring is unsubsti- 5 F F tuted or substituted by C-C-alkyl or cycloalkyl, Y is CR'', wherein R'' is hydrogen, halogen, C-C- F alkyl, C-C-haloalkyl, C-C-alkoxy, C-C-ha loalkoxy, nitrilo, nitro, amino, C-C-alkylamino, to V di(C-C-alkyl)amino, N-pyrrolidinyl, N-piperidinyl, (CH2) N-morpholinyl, thiol, hydroxy, C-C-alkylthio, C-C- in? alkyl carbonyl, C-C-haloalkyl carbonyl, C-C-alkyl carbonylamino, aminocarbonyl, C-C-alkylaminocar- 21 bonyl, di (C-C-alkyl)aminocarbonyl, C-C- 15 alkoxycarbonyl, cycloalkyl, cycloalkyloxy, N 1N cycloalkylamino, (C-C-alkyl)-(cycloalkyl)amino, N O cycloalkylthio, dioxolane, dioxane, or dioxepane, wherein each ring is unsubstituted or substituted by C-C-alkyl or cycloalkyl, 2O Y is CR", wherein R' is hydrogen, halogen, C-C- or the pharmaceutically acceptable salts or N-oxides alkyl, C-C-haloalkyl, C-C-alkoxy, C-C-ha thereof. loalkoxy, nitrilo, nitro, amino, C-C-alkylamino, di(C-C-alkyl)amino, N-pyrrolidinyl, N-piperidinyl, as 18. The compound of claim 1, wherein the compound is N-morpholinyl, C-C-alkylthio, C-C-alkyl carbonyl, C-C-haloalkyl carbonyl, C-C-alkylcarbonylamino, aminocarbonyl, C1-C6-alkylaminocarbonyl, di(C-C- alkyl)aminocarbonyl, C-C-alkoxycarbonyl, cycloalkyl, cycloalkyloxy, cycloalkylamino, (C-C- so O N alkyl)-(cycloalkyl)amino, cycloalkylthio, phenyl, diox- F olane, dioxane, or dioxepane, wherein each ring is unsubstituted or substituted by C-C-alkyl or V cycloalkyl, y".) orY and Y and/orY and Y are joined together to form a 35 HN ring system, and wherein at least one of B and D is a nitrogen atom, for treating a helminth infection. 21 13. Ananthelmintic composition, wherein the composition comprises: N 1. 40 N S a) one or more compounds as defined in claim 12; and b) one or more pharmaceutically acceptable excipients and-optionally one or more pharmaceutically accept able active ingredients which differ from the said one or more compounds as defined in claim 12. 45 or the pharmaceutically acceptable salts or N-oxides 14. The method of claim 11, wherein the parasitic infection thereof. is a helminth infection. 19. The compound of claim 1, wherein the compound is 15. The method of claim 14, wherein the helminth infection is selected from the group consisting of a nematode infection, 50 cestode infection and a trematode infection. F F 16. The compound of claim 1, wherein the compound is S-X.

O CFCH HN San 1s1 2-13 55 (CH2)2 / HN HN N (CH2) HN 21 60 N N O 1.

65 or the pharmaceutically acceptable salts or N-oxides or pharmaceutically acceptable salts, or N-oxides thereof. thereof. US 8,877,934 B2 149 150 20. The compound of claim 1, wherein the compound is 21. The compound of claim 1, wherein the compound is

F F F F O S. F O S 5 F HN F HN (CH2) (CH2)2 HN / HN 10 21 21 N 1. N O s o1 15 or the pharmaceutically acceptable salts or N-oxides or the pharmaceutically acceptable salts or N-oxides thereof. thereof. k . . . .