COMPOUNDS FOR USE IN ANTHELMINTHIC TREATMENT
20170320848 · 2017-11-09
Assignee
Inventors
- Claudia Welz (Düsseldorf, DE)
- Adeline Köhler (Langenfeld, DE)
- Kirsten Börngen (Köln, DE)
- Daniel Kulke (Leverkusen, DE)
- Ulrich Görgens (Ratingen, DE)
- Hans-Georg Schwarz (Dorsten, DE)
- Kerstin ILG (Köln, DE)
Cpc classification
C07C233/73
CHEMISTRY; METALLURGY
C07D295/135
CHEMISTRY; METALLURGY
C07C233/80
CHEMISTRY; METALLURGY
C07C255/60
CHEMISTRY; METALLURGY
C07C323/42
CHEMISTRY; METALLURGY
C07C233/66
CHEMISTRY; METALLURGY
C07C233/78
CHEMISTRY; METALLURGY
C07D317/62
CHEMISTRY; METALLURGY
C07D295/155
CHEMISTRY; METALLURGY
C07D241/24
CHEMISTRY; METALLURGY
International classification
C07C323/42
CHEMISTRY; METALLURGY
C07C255/60
CHEMISTRY; METALLURGY
C07C233/66
CHEMISTRY; METALLURGY
C07D295/135
CHEMISTRY; METALLURGY
C07C233/80
CHEMISTRY; METALLURGY
Abstract
Disclosed are compounds of formula (I) which possess anthelminthic properties wherein the structural elements have the meaning as indicated in the description. Further disclosed are such compounds for the control, treatment and/or prevention of infections with helminths in animals and humans.
##STR00001##
Claims
1. A compound of formula (I) ##STR00191## wherein R.sup.1 is selected from the group consisting of hydrogen, —CHO, —OH, C.sub.1-C.sub.4-alkyl, C.sub.1-C.sub.4-halogenoalkyl having 1 to 5 halogen atoms, C.sub.1-C.sub.4-alkoxy, C.sub.1-C.sub.4-halogenoalkoxy having 1 to 5 halogen atoms, C.sub.3-C.sub.6-cycloalkyl, C.sub.3-C.sub.6-halogenocycloalkyl having 1 to 5 halogen atoms, C.sub.3-C.sub.4-alkenyl, C.sub.3-C.sub.4-alkynyl, C.sub.1-C.sub.4-alkoxy-C.sub.1-C.sub.4-alkyl, C.sub.3-C.sub.6-cycloalkyl-C.sub.1-C.sub.3-alkyl, cyano-C.sub.1-C.sub.4-alkyl, amino-C.sub.1-C.sub.4-alkyl, C.sub.1-C.sub.4-alkylamino-C.sub.1-C.sub.4-alkyl, di-(C.sub.1-C.sub.4-alkyl)amino-C.sub.1-C.sub.4-alkyl, C.sub.1-C.sub.4-alkylcarbonyl, C.sub.1-C.sub.4-halogenoalkylcarbonyl having 1 to 5 halogen atoms, C.sub.1-C.sub.4-alkoxycarbonyl, benzyloxycarbonyl, C.sub.1-C.sub.4-alkoxy-C.sub.1-C.sub.4-alkylcarbonyl, —S (O).sub.2—C.sub.1-C.sub.4-alkyl, and —S(O).sub.2—C.sub.1-C.sub.4-halogenoalkyl having 1 to 5 halogen atoms; n is 1, 2, or 3; each X is independently selected from the group consisting of halogen, nitro, cyano, hydroxy, amino, —SH, —SF.sub.5, —CHO, —OCHO, —NHCHO, —COOH, —CONH.sub.2, —CONH(OH), —OCONH.sub.2, (hydroxyimino)-C.sub.1-C.sub.6-alkyl, C.sub.1-C.sub.8-alkyl, C.sub.1-C.sub.8-halogenoalkyl having 1 to 5 halogen atoms, C.sub.2-C.sub.8-alkenyl, C.sub.2-C.sub.8-alkynyl, C.sub.1-C.sub.8-alkylamino, di-(C.sub.1-C.sub.8-alkyl)amino, C.sub.1-C.sub.8-alkoxy, C.sub.1-C.sub.8-halogenoalkoxy having 1 to 5 halogen atoms, C.sub.2-C.sub.8-alkenyloxy, C.sub.2-C.sub.8-halogenoalkenyloxy having 1 to 5 halogen atoms, C.sub.3-C.sub.8-alkynyloxy, C.sub.3-C.sub.8-halogenoalkynyloxy having 1 to 5 halogen atoms, C.sub.3-C.sub.8-cycloalkyl, C.sub.3-C.sub.8-halogenocycloalkyl having 1 to 5 halogen atoms, C.sub.1-C.sub.8-alkylcarbonyl, C.sub.1-C.sub.8-halogenoalkylcarbonyl having 1 to 5 halogen atoms, —CONH(C.sub.1-C.sub.8-alkyl), —CON(C.sub.1-C.sub.8-alkyl).sub.2, —CONH(OC.sub.1-C.sub.8-alkyl), —CON(OC.sub.1-C.sub.8-alkyl)(C.sub.1-C.sub.8-alkyl), C.sub.1-C.sub.8-alkoxycarbonyl, C.sub.1-C.sub.8-halogenoalkoxycarbonyl having 1 to 5 halogen atoms, C.sub.1-C.sub.8-alkylcarbonyloxy, C.sub.1-C.sub.8-halogenoalkylcarbonyloxy having 1 to 5 halogen atoms, C.sub.1-C.sub.8-alkylcarbonylamino, C.sub.1-C.sub.8-halogenoalkylcarbonylamino having 1 to 5 halogen atoms, —OCONH(C.sub.1-C.sub.8-alkyl), —OCON(C.sub.1-C.sub.8-alkyl).sub.2, —OCONH(OC.sub.1-C.sub.8-alkyl), —OCO(OC.sub.1-C.sub.8-alkyl), —S—C.sub.1-C.sub.8-alkyl, —S—C.sub.1-C.sub.8-halogenoalkyl having 1 to 5 halogen atoms, —S(O)—C.sub.1-C.sub.8-alkyl, —S(O)—C.sub.1-C.sub.8-halogenoalkyl having 1 to 5 halogen atoms, —S(O).sub.2—C.sub.1-C.sub.8-alkyl, —S(O).sub.2—C.sub.1-C.sub.8-halogenoalkyl having 1 to 5 halogen atoms, (C.sub.1-C.sub.6-alkoxyimino)-C.sub.1-C.sub.6-alkyl, (C.sub.2-C.sub.6-alkenyloxyimino)-C.sub.1-C.sub.6-alkyl, (C.sub.3-C.sub.6-alkynyloxyimino)-C.sub.1-C.sub.6-alkyl, (benzyloxyimino)-C.sub.1-C.sub.6-alkyl, benzyloxy, —S-benzyl, benzylamino, phenoxy, —S-phenyl, and phenylamino; m is 0, 1, 2, 3, or 4; and each Y is independently selected from the group consisting of hydrogen, halogen, nitro, cyano, hydroxy, amino, —SH, —SF.sub.5, —CHO, —OCHO, —NHCHO, —COOH, —CONH.sub.2, —CONH(OH), —OCONH.sub.2, (hydroxyimino)-C.sub.1-C.sub.6-alkyl, C.sub.1-C.sub.8-alkyl, C.sub.1-C.sub.8-halogenoalkyl having 1 to 5 halogen atoms, C.sub.2-C.sub.8-alkenyl, C.sub.2-C.sub.8-alkynyl, C.sub.1-C.sub.8-alkylamino, di-(C.sub.1-C.sub.8-alkyl)amino, C.sub.1-C.sub.8-alkoxy, C.sub.1-C.sub.8-halogenoalkoxy having 1 to 5 halogen atoms, C.sub.2-C.sub.8-alkenyloxy, C.sub.2-C.sub.8-halogenoalkenyloxy having 1 to 5 halogen atoms, C.sub.3-C.sub.8-alkynyloxy, C.sub.3-C.sub.8-halogenoalkynyloxy having 1 to 5 halogen atoms, C.sub.3-C.sub.8-cycloalkyl, C.sub.3-C.sub.8-halogenocycloalkyl having 1 to 5 halogen atoms, C.sub.1-C.sub.8-alkylcarbonyl, C.sub.1-C.sub.8-halogenoalkylcarbonyl having 1 to 5 halogen atoms, —CONH(C.sub.1-C.sub.8-alkyl), —CON(C.sub.1-C.sub.8-alkyl).sub.2, —CONH(OC.sub.1-C.sub.8-alkyl), —CON(OC.sub.1-C.sub.8-alkyl)(C.sub.1-C.sub.8-alkyl), C.sub.1-C.sub.8-alkoxycarbonyl, C.sub.1-C.sub.8-halogenoalkoxycarbonyl having 1 to 5 halogen atoms, C.sub.1-C.sub.8-alkylcarbonyloxy, C.sub.1-C.sub.8-halogenoalkylcarbonyloxy having 1 to 5 halogen atoms, C.sub.1-C.sub.8-alkylcarbonylamino, C.sub.1-C.sub.8-halogenoalkylcarbonylamino having 1 to 5 halogen atoms, —OCONH(C.sub.1-C.sub.8-alkyl), —OCON(C.sub.1-C.sub.8-alkyl).sub.2, —OCONH(OC.sub.1-C.sub.8-alkyl), —OCO(OC.sub.1-C.sub.8-alkyl), —S—C.sub.1-C.sub.8-alkyl, —S—C.sub.1-C.sub.8-halogenoalkyl having 1 to 5 halogen atoms, —S(O)—C.sub.1-C.sub.8-alkyl, —S(O)—C.sub.1-C.sub.8-halogenoalkyl having 1 to 5 halogen atoms, —S(O).sub.2—C.sub.1-C.sub.8-alkyl, —S(O).sub.2—C.sub.1-C.sub.8-halogenoalkyl having 1 to 5 halogen atoms, —CH.sub.2—S—C.sub.1-C.sub.8-alkyl, —CH.sub.2—S(O)—C.sub.1-C.sub.8-alkyl, —CH.sub.2—S(O).sub.2—C.sub.1-C.sub.8-alkyl, (C.sub.1-C.sub.6-alkoxyimino)-C.sub.1-C.sub.6-alkyl, (C.sub.2-C.sub.6-alkenyloxyimino)-C.sub.1-C.sub.6-alkyl, and (C.sub.3-C.sub.6-alkynyloxyimino)-C.sub.1-C.sub.6-alkyl; wherein two Y may additionally be selected from —O—C.sub.1-C.sub.3-alkoxy and —O—C.sub.1-C.sub.3-halogenalkoxy having 1 to 5 halogen atoms, with each oxy function being the connecting atom of the individual Y, thereby forming an annelated 5-, 6- or 7-membered ring with the phenyl moiety that they are connected to; or each Y is independently selected from the group consisting of hydrogen, halogen, cyano, C.sub.1-C.sub.6-alkyl, C.sub.1-C.sub.6-halogenoalkyl having 1 to 5 halogen atoms, and a 4 to 7 membered heterocyclic ring system with 1 to 3 heteroatoms, but not O—O, O—S or 3 heteroatoms in a row, independently substituted by oxo, thiono, or 1 to 12 substituents Z independently selected from the group consisting of hydrogen, halogen, cyano, hydroxy, amino, —SH, —CHO, —COOH, —CONH.sub.2, —CONH(OH), —OCONH.sub.2, (hydroxyimino)-C.sub.1-C.sub.6-alkyl, C.sub.1-C.sub.6-alkyl, C.sub.1-C.sub.6-halogenoalkyl having 1 to 5 halogen atoms, C.sub.2-C.sub.6-alkenyl, C.sub.2-C.sub.6-alkynyl, C.sub.1-C.sub.6-alkylamino, di-(C.sub.1-C.sub.6-alkyl)amino, C.sub.1-C.sub.6-alkoxy, C.sub.1-C.sub.6-halogenoalkoxy having 1 to 5 halogen atoms, C.sub.2-C.sub.6-alkenyloxy, C.sub.2-C.sub.6-halogenoalkenyloxy having 1 to 5 halogen atoms, C.sub.3-C.sub.6-alkynyloxy, C.sub.3-C.sub.6-halogenoalkynyloxy having 1 to 5 halogen atoms, C.sub.3-C.sub.6-cycloalkyl, C.sub.3-C.sub.6-halogenocycloalkyl having 1 to 5 halogen atoms, C.sub.1-C.sub.6-alkylcarbonyl, C.sub.1-C.sub.6-halogenoalkylcarbonyl having 1 to 5 halogen atoms, —CONH(C.sub.1-C.sub.6-alkyl), —CON(C.sub.1-C.sub.6-alkyl).sub.2, —CONH(OC.sub.1-C.sub.6-alkyl), —CON(OC.sub.1-C.sub.6-alkyl)(C.sub.1-C.sub.6-alkyl), C.sub.1-C.sub.6-alkoxycarbonyl, C.sub.1-C.sub.6-halogenoalkoxycarbonyl having 1 to 5 halogen atoms, C.sub.1-C.sub.6-alkylcarbonyloxy, C.sub.1-C.sub.6-halogenoalkylcarbonyloxy having 1 to 5 halogen atoms, C.sub.1-C.sub.6-alkylcarbonylamino, C.sub.1-C.sub.6-halogenoalkylcarbonylamino having 1 to 5 halogen atoms, —OCONH(C.sub.1-C.sub.6-alkyl), —OCON(C.sub.1-C.sub.6-alkyl).sub.2, —OCONH(OC.sub.1-C.sub.6-alkyl), —OCO(OC.sub.1-C.sub.6-alkyl), —S—C.sub.1-C.sub.6-alkyl, —S—C.sub.1-C.sub.6-halogenoalkyl having 1 to 5 halogen atoms, —S(O)—C.sub.1-C.sub.6-alkyl, —S(O)—C.sub.1-C.sub.6-halogenoalkyl having 1 to 5 halogen atoms, —S(O).sub.2—C.sub.1-C.sub.6-alkyl, and —S(O).sub.2—C.sub.1-C.sub.6-halogenoalkyl having 1 to 5 halogen atoms; and A represents a phenyl group of the formula (A1) ##STR00192## in which # depicts the bond which connects A to the rest of the molecule; o is 0, 1, 2, 3, 4, or 5; and each R is independently selected from the group consisting of halogen, nitro, —OH, NH.sub.2, SH, SF.sub.5, CHO, OCHO, NHCHO, COOH, cyano, C.sub.1-C.sub.8-alkyl, C.sub.1-C.sub.8-halogenoalkyl having 1 to 9 halogen atoms, C.sub.2-C.sub.8-alkenyl, C.sub.2-C.sub.8-alkynyl, C.sub.3-C.sub.6-cycloalkyl, —S—C.sub.1-C.sub.8-alkyl, —S—C.sub.1-C.sub.8-halogenoalkyl having 1 to 5 halogen atoms, C.sub.1-C.sub.8-alkoxy, C.sub.1-C.sub.8-halogenoalkoxy having 1 to 5 halogen atoms, C.sub.1-C.sub.8-alkoxy-C.sub.2-C.sub.8-alkenyl, C.sub.1-C.sub.8-alkoxycarbonyl, C.sub.1-C.sub.8-halogenoalkoxycarbonyl having 1 to 5 halogen atoms, C.sub.1-C.sub.8-alkylcarbonyloxy, C.sub.1-C.sub.8-halogenoalkylcarbonyloxy having 1 to 5 halogen atoms, —S(O)—C.sub.1-C.sub.8-alkyl, —S(O)—C.sub.1-C.sub.8-halogenoalkyl having 1 to 5 halogen atoms, —S(O).sub.2—C.sub.1-C.sub.8-alkyl, —S(O).sub.2—C.sub.1-C.sub.8-halogenoalkyl having 1 to 5 halogen atoms, C.sub.1-C.sub.8-alkylsulfonamide, —NH(C.sub.1-C.sub.8-alkyl), N(C.sub.1-C.sub.8-alkyl).sub.2, phenyl (optionally substituted by C.sub.1-C.sub.6-alkoxy) and phenoxy; wherein two R bonded to adjacent carbon atoms may together represent —O(CH.sub.2).sub.pO—, wherein p represents 1 or 2; A represents a heterocycle of the formula (Het-1) ##STR00193## in which # depicts the bond which connects A to the rest of the molecule; R.sup.11 is selected from the group consisting of hydrogen, halogen, hydroxy, cyano, C.sub.1-C.sub.4-alkyl, C.sub.1-C.sub.4-halogenoalkyl having 1 to 5 halogen atoms, C.sub.1-C.sub.4 alkoxy, —S—C.sub.1-C.sub.5-alkyl, S(O)—C.sub.1-C.sub.4-alkyl, —S(O).sub.2—C.sub.1-C.sub.4-alkyl, —S—C.sub.2-C.sub.5-alkenyl, —S—C.sub.1-C.sub.4-halogenoalkyl having 1 to 5 halogen atoms, and C.sub.1-C.sub.4-halogenoalkoxy having 1 to 5 halogen atoms; and R.sup.12, R.sup.13, and R.sup.14, which may be the same or be different, are selected from the group consisting of hydrogen, halogen, cyano, C.sub.1-C.sub.4-alkyl, C.sub.1-C.sub.4-halogenoalkyl having 1 to 5 halogen atoms, C.sub.1-C.sub.4-alkoxy, —S—C.sub.1-C.sub.4-alkyl, C.sub.1-C.sub.4-halogenoalkoxy having 1 to 5 halogen atoms, —S(O)—C.sub.1-C.sub.4-alkyl, and —S(O).sub.2—C.sub.1-C.sub.4-alkyl; A represents a heterocycle of the formula (Het-2) ##STR00194## in which # depicts the bond which connects A to the rest of the molecule; and R.sup.21 is selected from the group consisting of hydrogen, halogen, C.sub.1-C.sub.4-alkyl and C.sub.1-C.sub.4-halogenoalkyl having 1 to 5 halogen atoms; or A represents a heterocycle of the formula (Het-3) ##STR00195## in which # depicts the bond which connects A to the rest of the molecule; R.sup.31 is selected from the group consisting of hydrogen, halogen, hydroxy, cyano, C.sub.1-C.sub.4-alkyl, C.sub.1-C.sub.4-halogenoalkyl having 1 to 5 halogen atoms, C.sub.1-C.sub.4 alkoxy, —S—C.sub.1-C.sub.5-alkyl, S(O)—C.sub.1-C.sub.4-alkyl, —S(O).sub.2—C.sub.1-C.sub.4-alkyl, —S—C.sub.2—C.sub.5-alkenyl, —S—C.sub.1-C.sub.4-halogenoalkyl having 1 to 5 halogen atoms, and C.sub.1-C.sub.4-halogenoalkoxy having 1 to 5 halogen atoms; and R.sup.32, R.sup.33, and R.sup.34, which may be the same or be different, are selected from the group consisting of hydrogen, halogen, cyano, C.sub.1-C.sub.4-alkyl, C.sub.1-C.sub.4-halogenoalkyl having 1 to 5 halogen atoms, C.sub.1-C.sub.4-alkoxy, —S—C.sub.1-C.sub.4-alkyl, C.sub.1-C.sub.4-halogenoalkoxy having 1 to 5 halogen atoms, —S(O)—C.sub.1-C.sub.4-alkyl, and —S(O).sub.2—C.sub.1-C.sub.4-alkyl; and salts, solvates, solvates of the salts, N-oxides, metal complexes or metalloid complexes thereof.
2. The compound according to claim 1, wherein A represents a phenyl group of formula (A1) ##STR00196## in which # depicts the bond which connects A to the rest of the molecule; o is 0, 1, or 2; and each R is independently selected from the group consisting of halogen, nitro, C.sub.1-C.sub.4-halogenoalkyl having 1 to 5 halogen atoms, and C.sub.1-C.sub.4-halogenoalkoxy having 1 to 5 halogen atoms; or A represents a heterocycle of the formula (Het-1) ##STR00197## in which # depicts the bond which connects A to the rest of the molecule; R.sup.11 is halogen or C.sub.1-C.sub.4-halogenoalkyl having 1 to 5 halogen atoms; and R.sup.12, R.sup.13, and R.sup.14 are hydrogen; or A represents a heterocycle of the formula (Het-2) ##STR00198## in which # depicts the bond which connects A to the rest of the molecule; and R.sup.21 is C.sub.1-C.sub.4-halogenoalkyl having 1 to 5 halogen atoms; or A represents a heterocycle of the formula (Het-3) ##STR00199## in which # depicts the bond which connects A to the rest of the molecule; R.sup.31 is C.sub.1-C.sub.4-halogenoalkyl having 1 to 5 halogen atoms; and R.sup.32, R.sup.33, and R.sup.34 are hydrogen; R.sup.1 is selected from the group consisting of hydrogen, C.sub.1-C.sub.4-alkyl, C.sub.3-C.sub.4-alkynyl, C.sub.3-C.sub.6-cycloalkyl, C.sub.1-C.sub.4-alkylcarbonyl, C.sub.1-C.sub.4-alkoxy-C.sub.1-C.sub.4-alkyl, and C.sub.1-C.sub.4-alkoxycarbonyl; n is 1 or 2; each X is independently selected from the group consisting of halogen, nitro, cyano, C.sub.1-C.sub.4-alkyl, C.sub.1-C.sub.4-halogenoalkyl having 1 to 5 halogen atoms, C.sub.2-C.sub.4-alkenyl, C.sub.2-C.sub.4-alkynyl, C.sub.1-C.sub.4-alkylamino, di-(C.sub.1-C.sub.4-alkyl)amino, C.sub.1-C.sub.4-alkoxy, C.sub.1-C.sub.4-halogenoalkoxy having 1 to 5 halogen atoms, C.sub.2-C.sub.4-alkenyloxy, C.sub.2-C.sub.4-halogenoalkenyloxy having 1 to 5 halogen atoms, C.sub.3-C.sub.4-alkynyloxy, C.sub.3-C.sub.4-halogenoalkynyloxy having 1 to 5 halogen atoms, C.sub.3-C.sub.6-cycloalkyl, C.sub.3-C.sub.6-halogenocycloalkyl having 1 to 5 halogen atoms, C.sub.1-C.sub.4-alkylcarbonyl, C.sub.1-C.sub.4-halogenoalkylcarbonyl having 1 to 5 halogen atoms, —CONH(C.sub.1-C.sub.4-alkyl), —CON(C.sub.1-C.sub.4-alkyl).sub.2, —CONH(OC.sub.1-C.sub.4-alkyl), —CON(OC.sub.1-C.sub.4-alkyl)(C.sub.1-C.sub.4-alkyl), C.sub.1-C.sub.4-alkoxycarbonyl, C.sub.1-C.sub.4-halogenoalkoxycarbonyl having 1 to 5 halogen atoms, C.sub.1-C.sub.4-alkylcarbonyloxy, C.sub.1-C.sub.4-halogenoalkylcarbonyloxy having 1 to 5 halogen atoms, C.sub.1-C.sub.4-alkylcarbonylamino, C.sub.1-C.sub.4-halogenoalkylcarbonylamino having 1 to 5 halogen atoms, —OCONH(C.sub.1-C.sub.4-alkyl), —OCON(C.sub.1-C.sub.4-alkyl).sub.2, —OCONH(OC.sub.1-C.sub.4-alkyl), —OCO(OC.sub.1-C.sub.4-alkyl), —S—C.sub.1-C.sub.4-alkyl, —S—C.sub.1-C.sub.4-halogenoalkyl having 1 to 5 halogen atoms, —S(O)—C.sub.1-C.sub.4-alkyl, —S(O)—C.sub.1-C.sub.4-halogenoalkyl having 1 to 5 halogen atoms, —S(O).sub.2—C.sub.1-C.sub.4-alkyl, —S(O).sub.2—C.sub.1-C.sub.4-halogenoalkyl having 1 to 5 halogen atoms, (C.sub.1-C.sub.4-alkoxyimino)-C.sub.1-C.sub.4-alkyl, (C.sub.2-C.sub.6-alkenyloxyimino)-C.sub.1-C.sub.4-alkyl, (C.sub.3-C.sub.6-alkynyloxyimino)-C.sub.1-C.sub.4-alkyl, (benzyloxyimino)-C.sub.1-C.sub.6-alkyl, benzyloxy, —S-benzyl, benzylamino, phenoxy, —S-phenyl, and phenylamino; m is 1, 2, or 3; and each Y is independently selected from the group consisting of hydrogen, halogen, nitro, cyano, hydroxy, amino, —SH, —SF.sub.5, —CHO, —OCHO, —NHCHO, —COOH, —CONH.sub.2, —CONH(OH), —OCONH.sub.2, (hydroxyimino)-C.sub.1-C.sub.6-alkyl, C.sub.1-C.sub.6-alkyl, C.sub.1-C.sub.6-halogenoalkyl having 1 to 5 halogen atoms, C.sub.2-C.sub.6-alkenyl, C.sub.2-C.sub.6-alkynyl, C.sub.1-C.sub.6-alkylamino, di-(C.sub.1-C.sub.6-alkyl)amino, C.sub.1-C.sub.6-alkoxy, C.sub.1-C.sub.6-halogenoalkoxy having 1 to 5 halogen atoms, C.sub.2-C.sub.6-alkenyloxy, C.sub.2-C.sub.8-halogenoalkenyloxy having 1 to 5 halogen atoms, C.sub.3-C.sub.6-alkynyloxy, C.sub.3-C.sub.6-halogenoalkynyloxy having 1 to 5 halogen atoms, C.sub.3-C.sub.6-cycloalkyl, C.sub.3-C.sub.6-halogenocycloalkyl having 1 to 5 halogen atoms, C.sub.1-C.sub.6-alkylcarbonyl, C.sub.1-C.sub.6-halogenoalkylcarbonyl having 1 to 5 halogen atoms, —CONH(C.sub.1-C.sub.6-alkyl), —CON(C.sub.1-C.sub.6-alkyl).sub.2, —CONH(OC.sub.1-C.sub.6-alkyl), —CON(OC.sub.1-C.sub.6-alkyl)(C.sub.1-C.sub.6-alkyl), C.sub.1-C.sub.6-alkoxycarbonyl, C.sub.1-C.sub.6-halogenoalkoxycarbonyl having 1 to 5 halogen atoms, C.sub.1-C.sub.6-alkylcarbonyloxy, C.sub.1-C.sub.6-halogenoalkylcarbonyloxy having 1 to 5 halogen atoms, C.sub.1-C.sub.6-alkylcarbonylamino, C.sub.1-C.sub.6-halogenoalkylcarbonylamino having 1 to 5 halogen atoms, —OCONH(C.sub.1-C.sub.6-alkyl), —OCON(C.sub.1-C.sub.6-alkyl).sub.2, —OCONH(OC.sub.1-C.sub.6-alkyl), —OCO(OC.sub.1-C.sub.6-alkyl), —S—C.sub.1-C.sub.6-alkyl, —S—C.sub.1-C.sub.6-halogenoalkyl having 1 to 5 halogen atoms, —S(O)—C.sub.1-C.sub.6-alkyl, —S(O)—C.sub.1-C.sub.6-halogenoalkyl having 1 to 5 halogen atoms, —S(O).sub.2—C.sub.1-C.sub.6-alkyl, —S(O).sub.2—C.sub.1-C.sub.6-halogenoalkyl having 1 to 5 halogen atoms, —CH.sub.2—S—C.sub.1-C.sub.6-alkyl, —CH.sub.2—S(O)—C.sub.1-C.sub.6-alkyl, —CH.sub.2—S(O).sub.2—C.sub.1-C.sub.6-alkyl, (C.sub.1-C.sub.4-alkoxyimino)-C.sub.1-C.sub.4-alkyl, (C.sub.2-C.sub.4-alkenyloxyimino)-C.sub.1-C.sub.4-alkyl, and (C.sub.3-C.sub.6-alkynyloxyimino)-C.sub.1-C.sub.4-alkyl; wherein two Y may additionally be selected from —O—C.sub.1-C.sub.3-alkoxy and —O—C.sub.1-C.sub.3-halogenalkoxy having 1 to 5 halogen atoms, with each oxy function being the connecting atom of the individual Y, thereby forming an annelated 5-, 6- or 7-membered ring with the phenyl moiety that they are connected to; or each Y is independently selected from the group consisting of hydrogen, halogen, cyano, C.sub.1-C.sub.6-alkyl, C.sub.1-C.sub.6-halogenoalkyl having 1 to 5 halogen atoms, ##STR00200## ##STR00201## ##STR00202## in which # depicts the bond which connects Y to the rest of the molecule; W is oxygen or sulfur; p is 0, 1, 2, 3, 4, 5, or 6; Z is independently selected from the group consisting of hydrogen, halogen, cyano, hydroxy, amino, —SH, —CHO, —COOH, —CONH.sub.2, —CONH(OH), —OCONH.sub.2, (hydroxyimino)-C.sub.1-C.sub.6-alkyl, C.sub.1-C.sub.6-alkyl, C.sub.1-C.sub.6-halogenoalkyl having 1 to 5 halogen atoms, C.sub.1-C.sub.6-alkylamino, di-(C.sub.1-C.sub.6-alkyl)amino, C.sub.1-C.sub.6-alkoxy, C.sub.1-C.sub.6-halogenoalkoxy having 1 to 5 halogen atoms, C.sub.3-C.sub.6-cycloalkyl, C.sub.3-C.sub.6-halogenocycloalkyl having 1 to 5 halogen atoms, —CONH(C.sub.1-C.sub.6-alkyl), —CON(C.sub.1-C.sub.6-alkyl).sub.2, —S—C.sub.1-C.sub.6-alkyl, —S—C.sub.1-C.sub.6-halogenoalkyl having 1 to 5 halogen atoms, —S(O)—C.sub.1-C.sub.6-alkyl, —S(O)—C.sub.1-C.sub.6-halogenoalkyl having 1 to 5 halogen atoms, —S(O).sub.2—C.sub.1-C.sub.6-alkyl, and —S(O).sub.2—C.sub.1-C.sub.6-halogenoalkyl having 1 to 5 halogen atoms; Z.sup.1 is independently selected from the group consisting of hydrogen, C.sub.1-C.sub.6-alkyl, C.sub.1-C.sub.6-halogenoalkyl having 1 to 5 halogen atoms, C.sub.1-C.sub.6-alkylamino, di-(C.sub.1-C.sub.6-alkyl)amino, C.sub.1-C.sub.6-alkoxy, C.sub.1-C.sub.6-alkylcarbonyl, C.sub.3-C.sub.6-cycloalkyl, C.sub.3-C.sub.6-halogenocycloalkyl having 1 to 5 halogen atoms, —CONH(C.sub.1-C.sub.6-alkyl), and —CON(C.sub.1-C.sub.6-alkyl).sub.2; and Z.sup.2 is independently selected from the group consisting of hydrogen, C.sub.1-C.sub.6-alkyl, C.sub.1-C.sub.6-halogenoalkyl having 1 to 5 halogen atoms, C.sub.3-C.sub.6-cycloalkyl, C.sub.3-C.sub.6-halogenocycloalkyl having 1 to 5 halogen atoms, —CONH(C.sub.1-C.sub.6-alkyl), and —CON(C.sub.1-C.sub.6-alkyl).sub.2; and salts, solvates, solvates of the salts, N-oxides, metal complexes or metalloid complexes thereof.
3. The compound according to claim 1, wherein A represents a phenyl group of formula (A1) ##STR00203## in which # depicts the bond which connects A to the rest of the molecule; o is 0, 1, or 2; and each R is independently selected from the group consisting of halogen, nitro, C.sub.1-C.sub.4-halogenoalkyl having 1 to 5 halogen atoms, and C.sub.1-C.sub.4-halogenoalkoxy having 1 to 5 halogen atoms; A represents a heterocycle of the formula (Het-1) ##STR00204## in which # depicts the bond which connects A to the rest of the molecule; R.sup.11 is halogen or C.sub.1-C.sub.4-halogenoalkyl having 1 to 5 halogen atoms; and R.sup.12, R.sup.13, and R.sup.14 are hydrogen; A represents a heterocycle of the formula (Het-2) ##STR00205## in which # depicts the bond which connects A to the rest of the molecule; and R.sup.21 is C.sub.1-C.sub.4-halogenoalkyl having 1 to 5 halogen atoms; or A represents a heterocycle of the formula (Het-3) ##STR00206## in which # depicts the bond which connects A to the rest of the molecule; R.sup.31 is C.sub.1-C.sub.4-halogenoalkyl having 1 to 5 halogen atoms; and R.sup.32, R.sup.33, and R.sup.34 are hydrogen; R.sup.1 is selected from the group consisting of hydrogen, C.sub.1-C.sub.4-alkyl, C.sub.3-C.sub.4-alkynyl, C.sub.3-C.sub.6-cycloalkyl, C.sub.1-C.sub.4-alkylcarbonyl, C.sub.1-C.sub.4-alkoxy-C.sub.1-C.sub.4-alkyl, and C.sub.1-C.sub.4-alkoxycarbonyl; n is 1 or 2; each X is independently selected from the group consisting of halogen, cyano, C.sub.1-C.sub.4-alkyl, C.sub.1-C.sub.4-alkoxy and C.sub.1-C.sub.4-halogenoalkyl having 1 to 5 halogen atoms; m is 1, 2, or 3; and each Y is independently selected from the group consisting of hydrogen, halogen, cyano, C.sub.1-C.sub.4-alkyl, C.sub.1-C.sub.4-halogenoalkyl having 1 to 5 halogen atoms, C.sub.1-C.sub.4-alkylamino, di-(C.sub.1-C.sub.4-alkyl)amino, C.sub.1-C.sub.4-alkoxy, C.sub.1-C.sub.4-halogenoalkoxy having 1 to 5 halogen atoms, —CONH(C.sub.1-C.sub.4-alkyl), —CON(C.sub.1-C.sub.4-alkyl).sub.2, —CONH(OC.sub.1-C.sub.4-alkyl), —CON(OC.sub.1-C.sub.4-alkyl)(C.sub.1-C.sub.6-alkyl), —S—C.sub.1-C.sub.4-alkyl, —S—C.sub.1-C.sub.4-halogenoalkyl having 1 to 5 halogen atoms, —S(O)—C.sub.1-C.sub.4-alkyl, —S(O)—C.sub.1-C.sub.4-halogenoalkyl having 1 to 5 halogen atoms, —S(O).sub.2—C.sub.1-C.sub.4-alkyl, —S(O).sub.2—C.sub.1-C.sub.4-halogenoalkyl having 1 to 5 halogen atoms, and C.sub.1-C.sub.4-alkylcarbonylamino; wherein two Y may additionally be selected from —O—C.sub.1-C.sub.2-alkoxy and —O—C.sub.1-C.sub.2-halogenalkoxy having 1 to 5 halogen atoms, with each oxy function being the connecting atom of the individual Y, thereby forming an annelated 5- or 6-membered ring with the phenyl moiety that they are connected to; or each Y is independently selected from the group consisting of hydrogen, halogen, cyano, C.sub.1-C.sub.4-alkyl, C.sub.1-C.sub.4-halogenoalkyl having 1 to 5 halogen atoms, ##STR00207## in which # depicts the bond which connects Y to the rest of the molecule; W is oxygen; p is 0, 1, 2, 3, 4, 5, or 6; Z is independently selected from the group consisting of hydrogen, halogen, cyano, hydroxy, amino, —SH, —CHO, —COOH, —CONH.sub.2, —CONH(OH), —OCONH.sub.2, (hydroxyimino)-C.sub.1-C.sub.4-alkyl, C.sub.1-C.sub.4-alkyl, C.sub.1-C.sub.4-halogenoalkyl having 1 to 5 halogen atoms, C.sub.1-C.sub.4-alkylamino, di-(C.sub.1-C.sub.4-alkyl)amino, C.sub.1-C.sub.4-alkoxy, C.sub.1-C.sub.4-halogenoalkoxy having 1 to 5 halogen atoms, C.sub.3-C.sub.6-cycloalkyl, C.sub.3-C.sub.6-halogenocycloalkyl having 1 to 5 halogen atoms, —CONH(C.sub.1-C.sub.4-alkyl), —CON(C.sub.1-C.sub.4-alkyl).sub.2, —S—C.sub.1-C.sub.4-alkyl, —S—C.sub.1-C.sub.4-halogenoalkyl having 1 to 5 halogen atoms, —S(O)—C.sub.1-C.sub.4-alkyl, —S(O)—C.sub.1-C.sub.4-halogenoalkyl having 1 to 5 halogen atoms, —S(O).sub.2—C.sub.1-C.sub.4-alkyl, and —S(O).sub.2—C.sub.1-C.sub.4-halogenoalkyl having 1 to 5 halogen atoms; and Z.sup.1 is independently selected from the group consisting of hydrogen, C.sub.1-C.sub.6-alkyl, C.sub.1-C.sub.6-halogenoalkyl having 1 to 5 halogen atoms, C.sub.1-C.sub.6-alkylamino, di-(C.sub.1-C.sub.6-alkyl)amino, C.sub.1-C.sub.6-alkoxy, C.sub.1-C.sub.6-alkylcarbonyl, C.sub.3-C.sub.6-cycloalkyl, C.sub.3-C.sub.6-halogenocycloalkyl having 1 to 5 halogen atoms, —CONH(C.sub.1-C.sub.6-alkyl), and —CON(C.sub.1-C.sub.6-alkyl).sub.2; and salts, solvates, solvates of the salts, N-oxides, metal complexes or metalloid complexes thereof.
4. The compound according to claim 1, wherein A represents a phenyl group of formula (A1) ##STR00208## in which # depicts the bond which connects A to the rest of the molecule; o is 1 or 2; and each R is independently selected from the group consisting of halogen, nitro, —CF.sub.3, —OCF.sub.3, and —CHF.sub.2; A represents a heterocycle of the formula (Het-1) ##STR00209## in which # depicts the bond which connects A to the rest of the molecule; R.sup.11 is halogen or CF.sub.3; and R.sup.12, R.sup.13, and R.sup.14 are hydrogen; or A represents a heterocycle of the formula (Het-2) ##STR00210## in which # depicts the bond which connects A to the rest of the molecule; and R.sup.21 is CF.sub.3; or A represents a heterocycle of the formula (Het-3) ##STR00211## in which # depicts the bond which connects A to the rest of the molecule; R.sup.31 is CF.sub.3; and R.sup.32, R.sup.33, and R.sup.34 are hydrogen; R.sup.1 is hydrogen; n is 1 or 2; each X is independently selected from the group consisting of halogen, cyano, CH.sub.3, OCH.sub.3, and CF.sub.3; m is 1, 2, or 3; and each Y is independently selected from the group consisting of hydrogen, halogen, cyano, C.sub.1-C.sub.4-alkyl, C.sub.1-C.sub.4-halogenoalkyl having 1 to 5 halogen atoms, C.sub.1-C.sub.4-alkylamino, di-(C.sub.1-C.sub.4-alkyl)amino, C.sub.1-C.sub.4-alkoxy, C.sub.1-C.sub.4-halogenoalkoxy having 1 to 5 halogen atoms, —S—C.sub.1-C.sub.4-alkyl, —S—C.sub.1-C.sub.4-halogenoalkyl having 1 to 5 halogen atoms, —S(O)—C.sub.1-C.sub.4-alkyl, —S(O)—C.sub.1-C.sub.4-halogenoalkyl having 1 to 5 halogen atoms, —S(O).sub.2—C.sub.1-C.sub.4-alkyl, —S(O).sub.2—C.sub.1-C.sub.4-halogenoalkyl having 1 to 5 halogen atoms, and C.sub.1-C.sub.4-alkylcarbonylamino; wherein two Y may additionally be selected from —O—CH.sub.2—O— and —O—CF.sub.2—O—, with each oxy function being the connecting atom of the individual Y, thereby forming an annelated 5-membered ring with the phenyl moiety that they are connected to; or each Y is independently selected from the group consisting of hydrogen, fluoro, chloro, cyano, CF.sub.3, ##STR00212## and salts, solvates, solvates of the salts, N-oxides, metal complexes or metalloid complexes thereof.
5. The compound according to claim 1, wherein A is selected from the group consisting of ##STR00213## in which # depicts the bond which connects A to the rest of the molecule; R.sup.1 is hydrogen; n is 1 or 2; each X is independently selected from the group consisting of chloro, fluoro, cyano, CH.sub.3, OCH.sub.3, and CF.sub.3; m is 1, 2, or 3; and each Y is independently selected from the group consisting of hydrogen, halogen, cyano, C.sub.1-C.sub.4-alkyl, C.sub.1-C.sub.4-halogenoalkyl having 1 to 5 halogen atoms, C.sub.1-C.sub.4-alkylamino, di-(C.sub.1-C.sub.4-alkyl)amino, C.sub.1-C.sub.4-alkoxy, C.sub.1-C.sub.4-halogenoalkoxy having 1 to 5 halogen atoms, —S—C.sub.1-C.sub.4-alkyl, —S—C.sub.1-C.sub.4-halogenoalkyl having 1 to 5 halogen atoms, —S(O)—C.sub.1-C.sub.4-alkyl, —S(O)—C.sub.1-C.sub.4-halogenoalkyl having 1 to 5 halogen atoms, —S(O).sub.2—C.sub.1-C.sub.4-alkyl, —S(O).sub.2—C.sub.1-C.sub.4-halogenoalkyl having 1 to 5 halogen atoms, C.sub.1-C.sub.4-alkylcarbonylamino, wherein two Y may additionally be selected from —O—CH.sub.2—O— and —O—CF.sub.2—O—, with each oxy function being the connecting atom of the individual Y, thereby forming an annelated 5-membered ring with the phenyl moiety that they are connected to, or each Y is independently selected from the group consisting of hydrogen, fluoro, chloro, cyano, CF.sub.3, and ##STR00214## and salts, solvates, solvates of the salts, N-oxides, metal complexes or metalloid complexes thereof.
6. The compound according to claim 1, wherein A is selected from the group consisting of ##STR00215## in which # depicts the bond which connects A to the rest of the molecule; R.sup.1 is hydrogen; n is 1 or 2; each X is independently selected from the group consisting of chloro, fluoro, cyano, CH.sub.3, OCH.sub.3, and CF.sub.3; m is 1, 2, or 3; and each Y is independently selected from the group consisting of hydrogen, fluoro, chloro, bromo, cyano, trifluoromethyl, difluoromethyl, methoxy, trifluoromethoxy, difluoromethoxy, methylamino, dimethylamino, methylsulfanyl, trifluoromethylsulfanyl, methylsulfinyl, trifluoromethylsulfinyl, methylsulfonyl, trifluoromethylsulfonyl, and acetylamino; or each Y is independently selected from the group consisting of hydrogen, fluoro, chloro, cyano, CF.sub.3, ##STR00216## and salts, solvates, solvates of the salts, N-oxides, metal complexes or metalloid complexes thereof.
7. The compound according to claim 1, wherein A is selected from the group consisting of ##STR00217## in which # depicts the bond which connects A to the rest of the molecule; R.sup.1 is hydrogen; n is 1 or 2; each X is independently selected from the group consisting of chloro, fluoro, CH.sub.3, and CF.sub.3; m is 1, 2, or 3; and each Y is independently selected from the group consisting of hydrogen, fluoro and chloro; and salts, solvates, solvates of the salts, N-oxides, metal complexes or metalloid complexes thereof.
8. A compound of formula (I-1) ##STR00218## wherein X.sup.1 is selected from the group consisting of halogen, cyano, C.sub.1-C.sub.4-alkyl, C.sub.1-C.sub.4-alkoxy, and C.sub.1-C.sub.4-halogenoalkyl having 1 to 5 halogen atoms; X.sup.2 is selected from the group consisting of hydrogen, halogen, cyano, C.sub.1-C.sub.4-alkyl, C.sub.1-C.sub.4-alkoxy, and C.sub.1-C.sub.4-halogenoalkyl having 1 to 5 halogen atoms; m is 1, 2, or 3; each Y is independently selected from the group consisting of hydrogen, halogen, cyano, C.sub.1-C.sub.4-alkyl, C.sub.1-C.sub.4-halogenoalkyl having 1 to 5 halogen atoms, C.sub.1-C.sub.4-alkylamino, di-(C.sub.1-C.sub.4-alkyl)amino, C.sub.1-C.sub.4-alkoxy, C.sub.1-C.sub.4-halogenoalkoxy having 1 to 5 halogen atoms, —S—C.sub.1-C.sub.4-alkyl, —S—C.sub.1-C.sub.4-halogenoalkyl having 1 to 5 halogen atoms, —S(O)—C.sub.1-C.sub.4-alkyl, —S(O)—C.sub.1-C.sub.4-halogenoalkyl having 1 to 5 halogen atoms, —S(O).sub.2—C.sub.1-C.sub.4-alkyl, —S(O).sub.2—C.sub.1-C.sub.4-halogenoalkyl having 1 to 5 halogen atoms, and C.sub.1-C.sub.4-alkylcarbonylamino; and A is selected from the group consisting of ##STR00219## in which # depicts the bond which connects A to the rest of the molecule; and salts, solvates, solvates of the salts, N-oxides, metal complexes or metalloid complexes thereof.
9. A method for the control, treatment, or prevention of infections with helminths, comprising administering an effective amount of a compound of formula (I), or a salt, a solvate, a solvate of a salt, an N-oxide, a metal complex, or a metalloid complex thereof, to an animal or human in need thereof ##STR00220## wherein R.sup.1 is selected from the group consisting of hydrogen, —CHO, —OH, C.sub.1-C.sub.4-alkyl, C.sub.1-C.sub.4-halogenoalkyl having 1 to 5 halogen atoms, C.sub.1-C.sub.4-alkoxy, C.sub.1-C.sub.4-halogenoalkoxy having 1 to 5 halogen atoms, C.sub.3-C.sub.6-cycloalkyl, C.sub.3-C.sub.6-halogenocycloalkyl having 1 to 5 halogen atoms, C.sub.3-C.sub.4-alkenyl, C.sub.3-C.sub.4-alkynyl, C.sub.1-C.sub.4-alkoxy-C.sub.1-C.sub.4-alkyl, C.sub.3-C.sub.6-cycloalkyl-C.sub.1-C.sub.3-alkyl, cyano-C.sub.1-C.sub.4-alkyl, amino-C.sub.1-C.sub.4-alkyl, C.sub.1-C.sub.4-alkylamino-C.sub.1-C.sub.4-alkyl, di-(C.sub.1-C.sub.4-alkyl)amino-C.sub.1-C.sub.4-alkyl, C.sub.1-C.sub.4-alkylcarbonyl, C.sub.1-C.sub.4-halogenoalkylcarbonyl having 1 to 5 halogen atoms, C.sub.1-C.sub.4-alkoxycarbonyl, benzyloxycarbonyl, C.sub.1-C.sub.4-alkoxy-C.sub.1-C.sub.4-alkylcarbonyl, —S(O).sub.2—C.sub.1-C.sub.4-alkyl, and —S(O).sub.2—C.sub.1-C.sub.4-halogenoalkyl having 1 to 5 halogen atoms; n is 0, 1, 2, or 3; each X is independently selected from the group consisting of hydrogen, halogen, nitro, cyano, hydroxy, amino, —SH, —SF.sub.5, —CHO, —OCHO, —NHCHO, —COOH, —CONH.sub.2, —CONH(OH), —OCONH.sub.2, (hydroxyimino)-C.sub.1-C.sub.6-alkyl, C.sub.1-C.sub.8-alkyl, C.sub.1-C.sub.8-halogenoalkyl having 1 to 5 halogen atoms, C.sub.2-C.sub.8-alkenyl, C.sub.2-C.sub.8-alkynyl, C.sub.1-C.sub.8-alkylamino, di-(C.sub.1-C.sub.8-alkyl)amino, C.sub.1-C.sub.8-alkoxy, C.sub.1-C.sub.8-halogenoalkoxy having 1 to 5 halogen atoms, C.sub.2-C.sub.8-alkenyloxy, C.sub.2-C.sub.8-halogenoalkenyloxy having 1 to 5 halogen atoms, C.sub.3-C.sub.8-alkynyloxy, C.sub.3-C.sub.8-halogenoalkynyloxy having 1 to 5 halogen atoms, C.sub.3-C.sub.8-cycloalkyl, C.sub.3-C.sub.8-halogenocycloalkyl having 1 to 5 halogen atoms, C.sub.1-C.sub.8-alkylcarbonyl, C.sub.1-C.sub.8-halogenoalkylcarbonyl having 1 to 5 halogen atoms, —CONH(C.sub.1-C.sub.8-alkyl), —CON(C.sub.1-C.sub.8-alkyl).sub.2, —CONH(OC.sub.1-C.sub.8-alkyl), —CON(OC.sub.1-C.sub.8-alkyl)(C.sub.1-C.sub.8-alkyl), C.sub.1-C.sub.8-alkoxycarbonyl, C.sub.1-C.sub.8-halogenoalkoxycarbonyl having 1 to 5 halogen atoms, C.sub.1-C.sub.8-alkylcarbonyloxy, C.sub.1-C.sub.8-halogenoalkylcarbonyloxy having 1 to 5 halogen atoms, C.sub.1-C.sub.8-alkylcarbonylamino, C.sub.1-C.sub.8-halogenoalkylcarbonylamino having 1 to 5 halogen atoms, —OCONH(C.sub.1-C.sub.8-alkyl), —OCON(C.sub.1-C.sub.8-alkyl).sub.2, —OCONH(OC.sub.1-C.sub.8-alkyl), —OCO(OC.sub.1-C.sub.8-alkyl), —S—C.sub.1-C.sub.8-alkyl, —S—C.sub.1-C.sub.8-halogenoalkyl having 1 to 5 halogen atoms, —S(O)—C.sub.1-C.sub.8-alkyl, —S(O)—C.sub.1-C.sub.8-halogenoalkyl having 1 to 5 halogen atoms, —S(O).sub.2—C.sub.1-C.sub.8-alkyl, —S(O).sub.2—C.sub.1-C.sub.8-halogenoalkyl having 1 to 5 halogen atoms, (C.sub.1-C.sub.6-alkoxyimino)-C.sub.1-C.sub.6-alkyl, (C.sub.2-C.sub.6-alkenyloxyimino)-C.sub.1-C.sub.6-alkyl, (C.sub.3-C.sub.6-alkynyloxyimino)-C.sub.1-C.sub.6-alkyl, (benzyloxyimino)-C.sub.1-C.sub.6-alkyl, benzyloxy, —S-benzyl, benzylamino, phenoxy, —S-phenyl, and phenylamino; m is 0, 1, 2, 3, or 4; and each Y is independently selected from the group consisting of hydrogen, halogen, nitro, cyano, hydroxy, amino, —SH, —SF.sub.5, —CHO, —OCHO, —NHCHO, —COOH, —CONH.sub.2, —CONH(OH), —OCONH.sub.2, (hydroxyimino)-C.sub.1-C.sub.6-alkyl, C.sub.1-C.sub.8-alkyl, C.sub.1-C.sub.8-halogenoalkyl having 1 to 5 halogen atoms, C.sub.2-C.sub.8-alkenyl, C.sub.2-C.sub.8-alkynyl, C.sub.1-C.sub.8-alkylamino, di-(C.sub.1-C.sub.8-alkyl)amino, C.sub.1-C.sub.8-alkoxy, C.sub.1-C.sub.8-halogenoalkoxy having 1 to 5 halogen atoms, C.sub.2-C.sub.8-alkenyloxy, C.sub.2-C.sub.8-halogenoalkenyloxy having 1 to 5 halogen atoms, C.sub.3-C.sub.8-alkynyloxy, C.sub.3-C.sub.8-halogenoalkynyloxy having 1 to 5 halogen atoms, C.sub.3-C.sub.8-cycloalkyl, C.sub.3-C.sub.8-halogenocycloalkyl having 1 to 5 halogen atoms, C.sub.1-C.sub.8-alkylcarbonyl, C.sub.1-C.sub.8-halogenoalkylcarbonyl having 1 to 5 halogen atoms, —CONH(C.sub.1-C.sub.8-alkyl), —CON(C.sub.1-C.sub.8-alkyl).sub.2, —CONH(OC.sub.1-C.sub.8-alkyl), —CON(OC.sub.1-C.sub.8-alkyl)(C.sub.1-C.sub.8-alkyl), C.sub.1-C.sub.8-alkoxycarbonyl, C.sub.1-C.sub.8-halogenoalkoxycarbonyl having 1 to 5 halogen atoms, C.sub.1-C.sub.8-alkylcarbonyloxy, C.sub.1-C.sub.8-halogenoalkylcarbonyloxy having 1 to 5 halogen atoms, C.sub.1-C.sub.8-alkylcarbonylamino, C.sub.1-C.sub.8-halogenoalkylcarbonylamino having 1 to 5 halogen atoms, —OCONH(C.sub.1-C.sub.8-alkyl), —OCON(C.sub.1-C.sub.8-alkyl).sub.2, —OCONH(OC.sub.1-C.sub.8-alkyl), —OCO(OC.sub.1-C.sub.8-alkyl), —S—C.sub.1-C.sub.8-alkyl, —S—C.sub.1-C.sub.8-halogenoalkyl having 1 to 5 halogen atoms, —S(O)—C.sub.1-C.sub.8-alkyl, —S(O)—C.sub.1-C.sub.8-halogenoalkyl having 1 to 5 halogen atoms, —S(O).sub.2—C.sub.1-C.sub.8-alkyl, —S(O).sub.2—C.sub.1-C.sub.8-halogenoalkyl having 1 to 5 halogen atoms, —CH.sub.2—S—C.sub.1-C.sub.8-alkyl, —CH.sub.2—S(O)—C.sub.1-C.sub.8-alkyl, —CH.sub.2—S(O).sub.2—C.sub.1-C.sub.8-alkyl, (C.sub.1-C.sub.6-alkoxyimino)-C.sub.1-C.sub.6-alkyl, (C.sub.2-C.sub.6-alkenyloxyimino)-C.sub.1-C.sub.6-alkyl, and (C.sub.3-C.sub.6-alkynyloxyimino)-C.sub.1-C.sub.6-alkyl; wherein two Y may additionally be selected from —O—C.sub.1-C.sub.3-alkoxy and —O—C.sub.1-C.sub.3-halogenalkoxy having 1 to 5 halogen atoms, with each oxy function being the connecting atom of the individual Y, thereby forming an annelated 5-, 6- or 7-membered ring with the phenyl moiety that they are connected to; or each Y is independently selected from the group consisting of hydrogen, halogen, cyano, C.sub.1-C.sub.6-alkyl, C.sub.1-C.sub.6-halogenoalkyl having 1 to 5 halogen atoms, and a 4 to 7 membered heterocyclic ring system with 1 to 3 heteroatoms, but not O—O, O—S or 3 heteroatoms in a row, independently substituted by oxo, thiono or 1 to 12 substituents Z independently selected from the group consisting of hydrogen, halogen, cyano, hydroxy, amino, —SH, —CHO, —COOH, —CONH.sub.2, —CONH(OH), —OCONH.sub.2, (hydroxyimino)-C.sub.1-C.sub.6-alkyl, C.sub.1-C.sub.6-alkyl, alkyl, C.sub.1-C.sub.6-halogenoalkyl having 1 to 5 halogen atoms, C.sub.2-C.sub.6-alkenyl, C.sub.2-C.sub.6-alkynyl, C.sub.1-C.sub.6-alkylamino, di-(C.sub.1-C.sub.6-alkyl)amino, C.sub.1-C.sub.6-alkoxy, C.sub.1-C.sub.6-halogenoalkoxy having 1 to 5 halogen atoms, C.sub.2-C.sub.6-alkenyloxy, C.sub.2-C.sub.6-halogenoalkenyloxy having 1 to 5 halogen atoms, C.sub.3-C.sub.6-alkynyloxy, C.sub.3-C.sub.6-halogenoalkynyloxy having 1 to 5 halogen atoms, C.sub.3-C.sub.6-cycloalkyl, C.sub.3-C.sub.6-halogenocycloalkyl having 1 to 5 halogen atoms, C.sub.1-C.sub.6-alkylcarbonyl, C.sub.1-C.sub.6-halogenoalkylcarbonyl having 1 to 5 halogen atoms, —CONH(C.sub.1-C.sub.6-alkyl), —CON(C.sub.1-C.sub.6-alkyl).sub.2, —CONH(OC.sub.1-C.sub.6-alkyl), —CON(OC.sub.1-C.sub.6-alkyl)(C.sub.1-C.sub.6-alkyl), C.sub.1-C.sub.6-alkoxycarbonyl, C.sub.1-C.sub.6-halogenoalkoxycarbonyl having 1 to 5 halogen atoms, C.sub.1-C.sub.6-alkylcarbonyloxy, C.sub.1-C.sub.6-halogenoalkylcarbonyloxy having 1 to 5 halogen atoms, C.sub.1-C.sub.6-alkylcarbonylamino, C.sub.1-C.sub.6-halogenoalkylcarbonylamino having 1 to 5 halogen atoms, —OCONH(C.sub.1-C.sub.6-alkyl), —OCON(C.sub.1-C.sub.6-alkyl).sub.2, —OCONH(OC.sub.1-C.sub.6-alkyl), —OCO(OC.sub.1-C.sub.6-alkyl), —S—C.sub.1-C.sub.6-alkyl, —S—C.sub.1-C.sub.6-halogenoalkyl having 1 to 5 halogen atoms, —S(O)—C.sub.1-C.sub.6-alkyl, —S(O)—C.sub.1-C.sub.6-halogenoalkyl having 1 to 5 halogen atoms, —S(O).sub.2—C.sub.1-C.sub.6-alkyl, and —S(O).sub.2—C.sub.1-C.sub.6-halogenoalkyl having 1 to 5 halogen atoms; and A represents a phenyl group of the formula (A1) ##STR00221## in which # depicts the bond which connects A to the rest of the molecule; o is 0, 1, 2, 3, 4, or 5; and each R is independently selected from the group consisting of halogen, nitro, —OH, NH.sub.2, SH, SF.sub.5, CHO, OCHO, NHCHO, COOH, cyano, C.sub.1-C.sub.8-alkyl, C.sub.1-C.sub.8-halogenoalkyl having 1 to 9 halogen atoms, C.sub.2-C.sub.8-alkenyl, C.sub.2-C.sub.8-alkynyl, C.sub.3-C.sub.6-cycloalkyl, —S—C.sub.1-C.sub.8-alkyl, —S—C.sub.1-C.sub.8-halogenoalkyl having 1 to 5 halogen atoms, C.sub.1-C.sub.8-alkoxy, C.sub.1-C.sub.8-halogenoalkoxy having 1 to 5 halogen atoms, C.sub.1-C.sub.8-alkoxy-C.sub.2-C.sub.8-alkenyl, C.sub.1-C.sub.8-alkoxycarbonyl, C.sub.1-C.sub.8-halogenoalkoxycarbonyl having 1 to 5 halogen atoms, C.sub.1-C.sub.8-alkylcarbonyloxy, C.sub.1-C.sub.8-halogenoalkylcarbonyloxy having 1 to 5 halogen atoms, —S(O)—C.sub.1-C.sub.8-alkyl, —S(O)—C.sub.1-C.sub.8-halogenoalkyl having 1 to 5 halogen atoms, —S(O).sub.2—C.sub.1-C.sub.8-alkyl, —S(O).sub.2—C.sub.1-C.sub.8-halogenoalkyl having 1 to 5 halogen atoms, C.sub.1-C.sub.8-alkylsulfonamide, —NH(C.sub.1-C.sub.8-alkyl), N(C.sub.1-C.sub.8-alkyl).sub.2, phenyl (optionally substituted by C.sub.1-C.sub.6-alkoxy) and phenoxy; wherein two R bonded to adjacent carbon atoms may together represent —O(CH.sub.2).sub.pO—, wherein p represents 1 or 2; A represents a heterocycle of the formula (Het-1) ##STR00222## in which # depicts the bond which connects A to the rest of the molecule; R.sup.11 is selected from the group consisting of hydrogen, halogen, hydroxy, cyano, C.sub.1-C.sub.4-alkyl, C.sub.1-C.sub.4-halogenoalkyl having 1 to 5 halogen atoms, C.sub.1-C.sub.4 alkoxy, —S—C.sub.1-C.sub.5-alkyl, S(O)—C.sub.1-C.sub.4-alkyl, —S(O).sub.2—C.sub.1-C.sub.4-alkyl, —S—C.sub.2-C.sub.5-alkenyl, —S—C.sub.1-C.sub.4-halogenoalkyl having 1 to 5 halogen atoms, and C.sub.1-C.sub.4-halogenoalkoxy having 1 to 5 halogen atoms; and R.sup.12, R.sup.13, and R.sup.14, which may be the same or be different, are selected from the group consisting of hydrogen, halogen, cyano, C.sub.1-C.sub.4-alkyl, C.sub.1-C.sub.4-halogenoalkyl having 1 to 5 halogen atoms, C.sub.1-C.sub.4-alkoxy, —S—C.sub.1-C.sub.4-alkyl, C.sub.1-C.sub.4-halogenoalkoxy having 1 to 5 halogen atoms, —S(O)—C.sub.1-C.sub.4-alkyl, and —S(O).sub.2—C.sub.1-C.sub.4-alkyl; A represents a heterocycle of the formula (Het-2) ##STR00223## in which # depicts the bond which connects A to the rest of the molecule; and R.sup.21 is selected from the group consisting of hydrogen, halogen, C.sub.1-C.sub.4-alkyl, and C.sub.1-C.sub.4-halogenoalkyl having 1 to 5 halogen atoms; or A represents a heterocycle of the formula (Het-3) ##STR00224## in which # depicts the bond which connects A to the rest of the molecule; R.sup.31 is selected from the group consisting of hydrogen, halogen, hydroxy, cyano, C.sub.1-C.sub.4-alkyl, C.sub.1-C.sub.4-halogenoalkyl having 1 to 5 halogen atoms, C.sub.1-C.sub.4 alkoxy, —S—C.sub.1-C.sub.5-alkyl, S(O)—C.sub.1-C.sub.4-alkyl, —S(O).sub.2—C.sub.1-C.sub.4-alkyl, —S—C.sub.2-C.sub.5-alkenyl, —S—C.sub.1-C.sub.4-halogenoalkyl having 1 to 5 halogen atoms, and C.sub.1-C.sub.4-halogenoalkoxy having 1 to 5 halogen atoms; and R.sup.32, R.sup.33, and R.sup.34, which may be the same or be different, are selected from the group consisting of hydrogen, halogen, cyano, C.sub.1-C.sub.4-alkyl, C.sub.1-C.sub.4-halogenoalkyl having 1 to 5 halogen atoms, C.sub.1-C.sub.4-alkoxy, —S—C.sub.1-C.sub.4-alkyl, C.sub.1-C.sub.4-halogenoalkoxy having 1 to 5 halogen atoms, —S(O)—C.sub.1-C.sub.4-alkyl, and —S(O).sub.2—C.sub.1-C.sub.4-alkyl; and salts, solvates, solvates of the salts, N-oxides, metal complexes or metalloid complexes thereof.
10. A pharmaceutical composition comprising at least one compound of formula (I) according to claim 1, or a salt, a solvate, a solvate of a salt, an N-oxide, a metal complex, or a metalloid complex thereof.
11. A method for the control, treatment, or prevention of infections with helminths, comprising administering to an animal or human in need thereof the pharmaceutical composition according to claim 10.
12-14. (canceled)
15. A method for the control, treatment or prevention of infections with helminths, comprising the step of administering an effective amount of a compound of formula (I) of anyone of claim 1, or a salt, a solvate, a solvate of a salt, an N-oxide, a metal complex, or a metalloid complex thereof, to an animal or human in need thereof.
Description
PREPARATION EXAMPLES
[1131] LC-MS
[1132] Method L0:
[1133] Measurement of LogP values was performed according to EEC directive 79/831 Annex V.A8 by HPLC (High Performance Liquid Chromatography) on reversed phase columns with the following methods: [1134] .sup.[a] LogP value is determined by measurement of LC-UV, in an acidic range, with 0.1% formic acid in water and acetonitrile as eluent (linear gradient from 10% acetonitrile to 95% acetonitrile). [1135] .sup.[b] LogP value is determined by measurement of LC-UV, in a neutral range, with 0.001 molar ammonium acetate solution in water and acetonitrile as eluent (linear gradient from 10% acetonitrile to 95% acetonitrile).
[1136] Calibration was done with straight-chain alkan-2-ones (with 3 to 16 carbon atoms) with known LogP values (measurement of LogP values using retention times with linear interpolation between successive alkanones). Lambda-max-values were determined using UV-spectra from 200 nm to 400 nm and the peak values of the chromatographic signals.
[1137] In table 1, M+1 (or M+H) means the molecular ion peak, plus or minus 1 a.m.u. (atomic mass unit) respectively, as observed in mass spectroscopy by electrospray ionization (ESI + or −).
[1138] Method L1:
[1139] MS instrument type: Agilent Technologies 6130 Quadrupole LC-MS; HPLC instrument type: Agilent Technologies 1260 Infinity; column: Waters XSelect (C18, 30×2.1 mm, 3.5μ); flow: 1 mL/min; column temp: 35° C.; eluent A: 0.1% formic acid in acetonitrile; eluent B: 0.1% formic acid in water; lin. gradient: t=0 min 5% A, t=1.6 min 98% A, t=3 min 98% A; detection: DAD (220-320 nm); detection: MSD (ESI pos/neg) mass range: 100-800; detection: ELSD (PL-ELS 2100): gas flow 1.2 mL/min, gas temp: 70° C., neb: 50° C.
[1140] Method L2:
[1141] MS instrument type: Agilent Technologies 6130 Quadrupole LC-MS; HPLC instrument type: Agilent Technologies 1260 Infinity; column: Waters XSelect (C18, 50×2.1 mm, 3.5μ); flow: 0.8 mL/min; column temp: 35° C.; eluent A: 0.1% formic acid in acetonitrile; eluent B: 0.1% formic acid in water; lin. gradient: t=0 min 5% A, t=3.5 min 98% A, t=6 min 98% A; detection: DAD (220-320 nm); detection: MSD (ESI pos/neg) mass range: 100-800; detection: ELSD (PL-ELS 2100): gas flow 1.2 mL/min, gas temp: 70° C., neb: 50° C.
[1142] Method L3:
[1143] MS instrument type: Agilent Technologies LC/MSD SL; HPLC instrument type: Agilent Technologies 1100 Series; column: Waters XSelect (C18, 30×2.1 mm, 3.5μ); flow: 1 mL/min; column temp: 25° C., eluent A: 95% acetonitrile+5% ammoniumbicarbonate in water, eluent B: 10 mmM ammoniumbicarbonate in water pH=9.0; lin. gradient: t=0 min 5% A, t=1.6 min 98% A, t=3 min 98% A; detection: DAD (220-320 nm); detection: MSD (ESI pos/neg) mass range: 100-800.
[1144] Method L4:
[1145] MS instrument type: Agilent Technologies LC/MSD SL; HPLC instrument type: Agilent Technologies 1100 Series; column: Waters XSelect (C18, 50×2.1 mm, 3.5μ; flow: 0.8 mL/min; column temp: 25° C.; eluent A: 95% acetonitrile+5% ammoniumbicarbonate in water; eluent B: 10 mmM ammoniumbicarbonate in water pH=9.0; lin. gradient: t=0 min 5% A, t=3.5 min 98% A, t=6 min 98% A; detection: DAD (220-320 nm); detection: MSD (ESI pos/neg) mass range: 100-800.
[1146] Method L5:
[1147] instrument type: Reveleris™ Flash Chromatography System; columns: Reveleris™ C18 Flash Cartridge; 4 g, flow 18 mL/min; 12 g, flow 30 mL/min; 40 g, flow 40 mL/min; 80 g, flow 60 mL/min; 120 g, flow 80 mL/min; eluent A: 0.1% formic acid in acetonitrile; eluent B: 0.1% formic acid in water; gradient: t=0 min 5% A, t=1 min 5% A, t=13 min 100% A, t=16 min 100% A; detection: UV (200-360 nm), ELSD.
[1148] Method L6:
[1149] instrument type: Reveleris™ Flash Chromatography System; columns: GraceResolv™ Silica Cartridge; 4 g, flow 15 mL/min; 12 g, flow 28 mL/min; 40 g, flow 40 mL/min; 80 g, flow 55 mL/min; 120 g, flow 80 mL/min and Davisil™ Chromatographic Silica Media (LC60A 20-45 micron); 300 g, flow 70 mL/min; 500 g, flow 70 mL/min; eluents: see experiment; detection: UV (200-360 nm), ELSD.
[1150] Method L7:
[1151] instrument type: Büchi Pump Manager C-615, Büchi Pump Module C-601; columns: GraceResolv™ Silica Cartridge; 4 g, flow 15 mL/min; 12 g, flow 28 mL/min; 40 g, flow 40 mL/min; 80 g, flow 55 mL/min; 120 g, flow 80 mL/min and Davisil™ Chromatographic Silica Media (LC60A 20-45 micron); 300 g, flow 70 mL/min; 500 g, flow 70 mL/min; eluents: see experiment; detection: TLC plates; TLC Silica gel 60 F.sub.254 (Merck).
[1152] Method L8:
[1153] MS instrument type: Agilent Technologies G1956B Quadrupole MS; HPLC instrument type: Agilent Technologies 1200 preparative LC; column: Waters XSelect (C18, 150×19 mm, 5μ); flow: 25 mL/min; column temp: room temperature; eluent A: 0.1% formic acid in acetonitrile; eluent B: 0.1% formic acid in water; a) lin. gradient: t=0 min 20% A, t=2.5 min 20% A t=11 min 60% A, t=13.5 min 100% A, t=17 min 100% A, b) lin. gradient: t=0 min 10% A, t=12 min 60% A, t=13.5 min 100% A, t=17 min 100% A; detection: DAD (220-320 nm); detection: MSD (ESI pos/neg) mass range: 100-800; fraction collection based on MS and DAD.
[1154] .sup.1H-NMR Data
[1155] .sup.1H-NMR-data were determined with a Bruker Avance 400 (Method M1) equipped with a flow cell (60 μl volume) or with a Bruker AVIII 400 equipped with 1.7 mm cryo CPTCI probe head or with a Bruker AVII 600 (600.13 MHz) equipped with a 5 mm cryo TCI probe head or with a Bruker AVIII 600 (601.6 MHz) equipped with a 5 mm cryo CPMNP probe head with tetramethylsilane as reference (0.0) and the solvents CD.sub.3CN, CDCl.sub.3 or D.sub.6-DMSO.
[1156] Alternatively .sup.1H-NMR-data were determined with a Bruker DMX300 (.sup.1H-NMR: 300 MHz) using tetramethylsilane as reference standard (Method M2).
Preparation Example 1
Step 1: 2-(4-bromo-2-chloro-phenyl)-2,2-difluoro-ethanamine
[1157] ##STR00128##
[1158] Synthesis of 2-(4-bromo-2-chloro-phenyl)-2,2-difluoro-ethanamine was performed in analogy to WO 2013/064460 A1 (referred as intermediates IIa-14 and IIa-15).
[1159] .sup.1H-NMR (400 MHz, d.sub.6-DMSO, Method M1); δ 7.91 (s, 1H), 7.74 (d, 1H), 7.57 (d, 1H), 4.68 (bs, 2H, NH.sub.2), 3.46 (t, 2H).
Step 2a: N-[2-(4-bromo-2-chloro-phenyl)-2,2-difluoro-ethyl]-2-(trifluoromethyl)benzamide
[1160] ##STR00129##
[1161] 1.395 g (13.7 mmol) of triethylamine were added to a solution of 1.49 g (5.51 mmol) of 2-(4-bromo-2-chloro-phenyl)-2,2-difluoro-ethanamine (from step 1) in 30 mL dichloromethane at room temperature. 1.15 g (5.51 mmol) of 2-(trifluoromethyl)benzoyl chloride in 10 mL dichloromethane were slowly added to the reaction mixture at room temperature. After completion of reaction, the reaction mixture was diluted with dichloromethane and washed with water. The combined organic layers were evaporated under reduced pressure. The remaining residue was purified by flash silica gel chromatography resulting in 1.08 g as colorless crystalline solid (yield: 43.8%).
[1162] .sup.1H-NMR (400 MHz, d.sub.6-DMSO, Method M1); δ 8.98 (t, 1H, NH), 7.91 (s, 1H), 7.77-7.56 (m, 5H), 7.36 (d, 1H), 4.17 (dt, 2H).
Step 2b: 2-[2-chloro-4-(4-fluorophenyl)phenyl]-2,2-difluoro-ethanamine (intermediate VII-1)
[1163] ##STR00130##
[1164] 42 mg (0.3 mmol) (4-fluorophenyl)boronic acid and 100 mg (0.3 mmol) 2-(4-bromo-2-chloro-phenyl)-2,2-difluoro-ethanamine from step 1 were dissolved in 4.6 mL dioxane followed by addition of 195.5 mg (0.6 mmol) cesium carbonate in 0.58 mL water and 22.14 mg (0.03 mmol) dichloro-bis(tricyclohexylphosphine)-palladium-(II) catalyst. The reaction mixture was kept under stirring in a closed vial for 16 h at 100° C. The reaction mixture was filtered via a silica gel/sodium sulfate cartridge, solvents have been evaporated under reduced pressure and the remaining yellow-coloured solid was purified by MPLC on silicagel (solvent gradient cyclohexane/ethylacetate) to afford 73 mg the title compound as colorless crystalline solid (yield: 68%).
[1165] LC-MS (Method L0): IgP.sup.b=3.10; M+1=286.0
[1166] .sup.1H-NMR (400 MHz, d.sub.6-DMSO, Method M1); δ 7.85-7.52 (m, 5H), 7.36-7.30 (t, 2H), 3.35-3.28 (broad m, NH.sub.2, 2H).
Step 3: N-[2-[2-chloro-4-(4-fluorophenyl)phenyl]-2,2-difluoro-ethyl]-2-(trifluoromethyl)benzamide (Example 3)
[1167] ##STR00131##
[1168] 0.724 g (5.17 mmol) (4-fluorophenyl)boronic acid and 2.9 g (5.17 mmol) N-[2-(4-bromo-2-chloro-phenyl)-2,2-difluoro-ethyl]-2-(trifluoromethyl)benzamide from step 2a were dissolved in 80 mL dioxane followed by addition of 3.37 g (10.3 mmol) cesium carbonate in 10 mL water and 37.6 mg (0.51 mmol) (1,1′-bis(diphenylphosphino)-ferrocen)-palladium-dichloromethan complex. The reaction mixture is treated with microwaves (Biotage Initiator) at 100° C. for 30 min. The reaction mixture was filtered via a silica gel/sodium sulfate cartridge, solvents have been evaporated under reduced pressure and the remaining dark coloured oil was purified by MPLC on silicagel (solvent gradient cyclohexane/ethylacetate) to afford 1.95 g the title compound as colorless crystalline solid (yield: 80.4%).
[1169] LC-MS (Method L0): IgP.sup.a=4.14; M+1=438.0 (target mass−HF)
[1170] .sup.1H-NMR (400 MHz, d.sub.6-DMSO, Method M1); δ 9.02 (t, NH), 7.90 (s, 1H), 7.84-7.62 (m, 6H), 7.39-7.30 (m, 3H), 4.25-4.17 (m, 2H).
Preparation Example 2
Step 1: Ethyl 2-(4-bromo-2-fluorophenyl)-2,2-difluoroacetate
[1171] ##STR00132##
[1172] Ethyl bromodifluoroacetate (14.2 g, 70.0 mmol, 9.0 mL) and copper-tin alloy (25.3 g, 139.0 mmol) were added to a solution of 1-bromo-3-fluoro-4-iodobenzene (19.9 g, 66.0 mmol) in dimethyl sulfoxide (150 mL). The mixture was stirred at 50° C. for 5 h. A solution of monobasic potassium phosphate (11.7 g, 86.0 mmol) in water (150 mL) was added and the mixture was stirred for 18 h. The mixture was filtered over kieselguhr and the residue was washed with ethyl acetate. Water (100 mL) was added to the filtrate and the mixture was extracted with ethyl acetate (3×100 mL). The combined organic layers were washed with brine and dried with sodium sulfate. Solvents were removed in vacuo. Purification by flash column chromatography (Method L7; 80 g; heptane, 0%-10% ethyl acetate) afforded 14.4 g (41.2 mmol; 62% of theory) of the title compound with a purity of 85% according to LC-MS.
[1173] LC-MS (Method L1): R.sub.t=2.21 min; no mass detected
[1174] .sup.1H NMR (300 MHz, DMSO-d.sub.6, Method M2) δ 7.88-7.82 (m, 1H), 7.71-7.61 (m, 2H), 4.35 (q, J=7.1 Hz, 2H), 1.23 (t, J=7.1 Hz, 3H).
Step 2: 2-(4-Bromo-2-fluorophenyl)-2,2-difluoroethanol
[1175] ##STR00133##
[1176] At 0° C. sodium borohydride (1.4 g, 36.4 mmol) was added portion wise to a solution of ethyl 2-(4-bromo-2-fluorophenyl)-2,2-difluoroacetate (14.4 g, 48.5 mmol) in ethanol (100 mL). The mixture was stirred at temperatures below 10° C. for 2 h. Aqueous hydrochloric acid (1M; 30 mL) and water (100 mL) were added and the mixture was extracted with ethyl acetate (3×100 mL). The combined organic layers were washed with brine and dried with sodium sulfate. Solvents were removed in vacuo. Purification by flash column chromatography (Method L7; 120 g; heptane, 0%-20% ethyl acetate) afforded 11.6 g (45.6 mmol; 94% of theory) of the title compound.
[1177] LC-MS (Method L1): R.sub.t=1.93 min; no mass detected
[1178] .sup.1H NMR (300 MHz, DMSO-d.sub.6, Method M2) δ 7.79-7.68 (m, 1H), 7.61-7.44 (m, 2H), 5.71 (t, J=6.5 Hz, 1H), 3.98-3.78 (m, 2H).
Step 3: 2-(4-Bromo-2-fluorophenyl)-2,2-difluoroethanamine
[1179] ##STR00134##
[1180] To a degassed (argon, 5 min) solution of 2-(4-bromo-2-fluorophenyl)-2,2-difluoroethanol (11.6 g, 45.5 mmol) in acetonitrile (600 mL) was added pyridine (5.8 g, 72.8 mmol, 5.9 mL). The mixture was cooled to 0° C. Trifluoromethanesulfonic acid anhydride (14.1 g, 50.0 mmol, 8.3 mL) was added drop wise while keeping the temperature below 8° C. The mixture was stirred at 0° C. for 30 min. To this solution aqueous ammonia (35%; 55.3 g, 1137 mmol, 63 mL) was added. The mixture was stirred at room temperature overnight. Brine (50 mL) was added and the reaction mixture was extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with brine (50 mL) and dried with sodium sulfate. Solvents were removed in vacuo. The crude product was absorbed on isolute. Flash column chromatography (Method L6; 120 g; heptane, 0%-50% ethyl acetate) afforded 8.8 g (34.6 mmol; 76% of theory) of the title compound.
[1181] LC-MS (Method L3): R.sub.t=2.00 min; m/z=254/256 (M+H).sup.+
Step 4: N-(2-(4-Bromo-2-fluorophenyl)-2,2-difluoroethyl)-2-(trifluoromethyl)benzamide
[1182] ##STR00135##
[1183] N-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (7.3 g, 38.1 mmol) and 1-hydroxy-7-azabenzotriazole (0.9 g, 6.9 mmol) were added to a solution of 2-(4-bromo-2-fluorophenyl)-2,2-difluoroethanamine (8.8 g, 34.6 mmol) and 2-(trifluoromethyl)benzoic acid (6.6 g, 34.6 mmol) in N,N-dimethylformamide (500 mL). The mixture was stirred at room temperature for 16 h. Solvents were removed in vacuo. The residue was partitioned between ethyl acetate and water. The organic layer was washed with brine and dried with sodium sulfate. Solvents were removed in vacuo. The crude product was absorbed on isolute. Flash column chromatography (Method L6; 120 g; heptane, 0%-50% ethyl acetate) and subsequent recrystallization from 2-propanol afforded 7.9 g (18.5 mmol; 53% of theory) of the title compound.
[1184] LC-MS (Method L1): R.sub.t=2.17 min; m/z=426/428 (M+H).sup.+
[1185] .sup.1H NMR (300 MHz, DMSO-d.sub.6, Method M2) δ 9.00 (t, J=6.2 Hz, 1H), 7.80-7.48 (m, 6H), 7.36 (d, J=7.2 Hz, 1H), 4.14-3.98 (m, 2H).
Step 5: N-(2-(3,4′-Difluoro-[1,1′-biphenyl]-4-yl)-2,2-difluoroethyl)-2-(trifluoromethyl)benzamide (Example 7)
[1186] ##STR00136##
[1187] To a degassed (argon, 5 min) solution of N-(2-(4-bromo-2-fluorophenyl)-2,2-difluoroethyl)-2-(trifluoromethyl)benzamide (150 mg, 0.35 mmol), (4-fluorophenyl)boronic acid (54 mg, 0.39 mmol) and saturated aqueous sodium carbonate (1.06 mmol, 0.52 mL) in 1,2-dimethoxyethane (2 mL) was added bis(triphenylphosphine)palladium(II) chloride (12 mg, 0.02 mmol). The mixture stirred at 100° C. for 16 h and was allowed to cool to room temperature. Dichloromethane (5 mL) was added. The layers were separated in a phase separator and the organic layer was dried with sodium sulfate. Solvents were removed in vacuo. The crude product was purified by flash column chromatography (Method L6; heptane, 0%-100% ethyl acetate). 110 mg (0.25 mmol; 70% of theory) of the title compound were obtained.
[1188] LC-MS (Method L2): R.sub.t=3.79 min; m/z=440 (M−H).sup.−
[1189] .sup.1H NMR (300 MHz, DMSO-d.sub.6, Method M2) δ 9.12-8.90 (m, 1H), 7.92-7.11 (m, 11H), 4.22-3.95 (m, 2H).
Preparation Example 3
Step 1: Ethyl 2-(4-bromo-2-(trifluoromethyl)phenyl)-2,2-difluoroacetate
[1190] ##STR00137##
[1191] Ethyl bromodifluoroacetate (15.2 g, 75.0 mmol, 9.6 mL) and copper-tin alloy (27.2 g, 149.0 mmol) were added to a solution of 4-bromo-1-iodo-2-(trifluoromethyl)benzene (25.0 g, 71.0 mmol) in dimethyl sulfoxide (500 mL). The mixture was stirred at 50° C. for 5 h. A solution of monobasic potassium phosphate (12.5 g, 92.0 mmol) in water (500 mL) was added and the mixture was stirred for 18 h. The mixture was filtered over kieselguhr and the residue was washed with ethyl acetate. Water (100 mL) was added to the filtrate and the mixture was extracted with ethyl acetate (3×100 mL). The combined organic layers were washed with brine and dried with sodium sulfate. Solvents were removed in vacuo. Purification by flash column chromatography (Method L6; 300 g; heptane, 0%-30% ethyl acetate) afforded 14.8 g (42.6 mmol; 51% of theory) of the title compound with a purity of 86% according to LC-MS.
[1192] LC-MS (Method L1): R.sub.t=2.29 min; no mass detected
Step 2: 2-(4-Bromo-2-(trifluoromethyl)phenyl)-2,2-difluoroethanol
[1193] ##STR00138##
[1194] At 0° C. sodium borohydride (1.6 g, 42.6 mmol) was added portion wise to a solution of ethyl 2-(4-bromo-2-fluorophenyl)-2,2-difluoroacetate (14.8 g, 42.6 mmol) in ethanol (250 mL). The mixture was stirred at temperatures below 10° C. for 2 h. Aqueous hydrochloric acid (1M; 30 mL) and water (200 mL) were added. Solids were filtered off and dried in vacuo at 40° C. 11.4 g (37 mmol, 88% of theory) of the title compound were obtained.
[1195] LC-MS (Method L1): R.sub.t=2.05 min; no mass detected
[1196] .sup.1H NMR (300 MHz, DMSO-d.sub.6, Method M2) δ 8.12-7.99 (m, 2H), 7.67 (d, J=8.4 Hz, 1H), 5.77 (t, J=6.5 Hz, 1H), 3.88 (td, J=14.2, 6.4 Hz, 2H).
Step 3: 2-(4-Bromo-2-(trifluoromethyl)phenyl)-2,2-difluoroethanamine
[1197] ##STR00139##
[1198] To a degassed (argon, 5 min) solution of 2-(4-bromo-2-(trifluoromethyl)phenyl)-2,2-difluoroethanol (11.4 g, 37 mmol) in acetonitrile (600 mL) was added pyridine (4.8 g, 60 mmol, 4.8 mL). The mixture was cooled to 0° C. Trifluoromethanesulfonic acid anhydride (11.6 g, 41 mmol, 6.8 mL) was added drop wise while keeping the temperature below 8° C. The mixture was stirred at 0° C. for 30 min. To this solution aqueous ammonia (35%; 46.0 g, 935 mmol, 52 mL) was added. The mixture was stirred at room temperature overnight. Brine (50 mL) was added and the reaction mixture was extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with brine (50 mL) and dried with sodium sulfate. Solvents were removed in vacuo. The crude product was absorbed on isolute. Flash column chromatography (Method L6; 120 g; heptane, 0%-50% ethyl acetate) afforded 6.8 g (22 mmol; 59% of theory) of the title compound.
[1199] LC-MS (Method L3): R.sub.t=2.11 min; m/z=304/306 (M+H).sup.+
[1200] .sup.1H NMR (300 MHz, DMSO-d.sub.6, Method M2) δ 8.04 (d, J=7.2 Hz, 2H), 7.68 (d, J=9.0 Hz, 1H), 3.16 (t, J=15.1 Hz, 2H), 1.77 (s, 2H).
Step 4: N-(2-(4-Bromo-2-(trifluoromethyl)phenyl)-2,2-difluoroethyl)-2-(trifluoromethyl)benzamide
[1201] ##STR00140##
[1202] N-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (2.1 g, 10.8 mmol) and 1-hydroxy-7-azabenzotriazole (0.3 g, 2.0 mmol) were added to a solution of 2-(4-bromo-2-(trifluoromethyl)phenyl)-2,2-difluoroethanamine (3.0 g, 9.9 mmol) and 2-(trifluoromethyl)-benzoic acid (1.9 g, 9.9 mmol) in N,N-dimethylformamide (100 mL). The mixture was stirred at room temperature for 16 h. Solvents were removed in vacuo. The residue was partitioned between ethyl acetate and water. The organic layer was washed with brine and dried with sodium sulfate. Solvents were removed in vacuo. The crude product was purified by reversed phase flash column chromatography (Method L5; 120 g). The product containing fractions were combined. Organic solvents were removed in vacuo. A precipitate formed, was filtered off and dried in vacuo at 40° C. 4.1 g (8.6 mmol; 87% of theory) of the title compound were obtained.
[1203] LC-MS (Method L1): R.sub.t=2.23 min; m/z=476/478 (M+H).sup.+
[1204] .sup.1H NMR (300 MHz, DMSO-d.sub.6, Method M2) δ 9.06 (t, J=6.3 Hz, 1H), 8.09 (d, J=7.6 Hz, 2H), 7.81-7.61 (m, 4H), 7.43 (d, J=7.3 Hz, 1H), 4.13-3.97 (m, 2H).
Step 5: N-(2,2-Difluoro-2-(4′-fluoro-3-(trifluoromethyl)-[1,1′-biphenyl]-4-yl)ethyl)-2-(trifluoromethyl)benzamide (Example 12)
[1205] ##STR00141##
[1206] To a degassed (argon, 5 min) solution of N-(2-(4-bromo-2-(trifluoromethyl)phenyl)-2,2-difluoroethyl)-2-(trifluoromethyl)benzamide (150 mg, 0.32 mmol), (4-fluorophenyl)boronic acid (48.5 mg, 0.35 mmol) and saturated aqueous sodium carbonate (0.95 mmol, 0.47 mL) in 1,2-dimethoxyethane (2 mL) was added bis(triphenylphosphine)palladium(II) chloride (11.1 mg, 0.02 mmol). The mixture was stirred at 100° C. for 16 h and was allowed to cool to room temperature. Dichloromethane (5 mL) was added. The layers were separated in a phase separator and the organic layer was dried with sodium sulfate. Solvents were removed in vacuo. The crude product was triturated in diethylether. The solid was filtered off and dried at 40° C. in vacuo. 155 mg (0.31 mmol; 100% of theory) of the title compound were obtained.
[1207] LC-MS (Method L2): R.sub.t=3.71 min; m/z=492 (M+H).sup.+
[1208] .sup.1H NMR (300 MHz, DMSO-d.sub.6, Method M2) δ 9.10 (t, J=6.2 Hz, 1H), 8.12 (d, J=11.1 Hz, 2H), 7.91-7.81 (m, 3H), 7.81-7.61 (m, 3H), 7.45 (d, J=7.4 Hz, 1H), 7.41-7.32 (m, 2H), 4.17-4.01 (m, 2H).
Preparation Example 4
Step 1: N-(2-(4-Bromo-2-(trifluoromethyl)phenyl)-2,2-difluoroethyl)-2-(trifluoromethyl)nicotinamide
[1209] ##STR00142##
[1210] N-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.26 g, 6.6 mmol) and 1-hydroxy-7-azabenzotriazole (0.9 g, 6.6 mmol) were added to a solution of 2-(4-bromo-2-(trifluoromethyl)phenyl)-2,2-difluoroethanamine (2.0 g, 6.6 mmol) and 2-(trifluoromethyl)-nicotinic acid (1.4 g, 7.2 mmol) in N,N-dimethylformamide (50 mL). The mixture was stirred at room temperature for 16 h. Solvents were removed in vacuo. The residue was partitioned between ethyl acetate and water. The organic layer was washed with brine and dried with sodium sulfate. Solvents were removed in vacuo. The crude product was purified by reversed phase flash column chromatography (Method L5; 120 g). 1.75 g (3.7 mmol; 55% of theory) of the title compound were obtained.
[1211] LC-MS (Method L2): R.sub.t=3.24 min; m/z=477/479 (M+H).sup.+
[1212] .sup.1H NMR (300 MHz, DMSO-d.sub.6, Method M2) δ 9.23 (s, 1H), 8.80 (d, J=4.7 Hz, 1H), 8.09 (d, J=8.7 Hz, 2H), 7.91 (d, J=7.8 Hz, 1H), 7.82-7.69 (m, 2H), 4.15-3.99 (m, 2H).
Step 2: N-(2,2-Difluoro-2-(4′-fluoro-3-(trifluoromethyl)-[1,1′-biphenyl]-4-yl)ethyl)-2-(trifluoromethyl)-nicotinamide (Example 17)
[1213] ##STR00143##
[1214] To a degassed (argon, 5 min) solution of N-(2-(4-bromo-2-(trifluoromethyl)phenyl)-2,2-difluoroethyl)-2-(trifluoromethyl)nicotinamide (150 mg, 0.31 mmol), (4-fluorophenyl)boronic acid (48 mg, 0.35 mmol) and saturated aqueous sodium carbonate (0.94 mmol, 0.47 mL) in 1,2-dimethoxyethane (2 mL) was added bis(triphenylphosphine)palladium(II) chloride (11 mg, 0.02 mmol). The mixture was stirred at 100° C. for 16 h and was allowed to cool to room temperature. Dichloromethane (5 mL) was added. The layers were separated in a phase separator and the organic layer was dried with sodium sulfate. Solvents were removed in vacuo. The crude product was triturated in diethylether. The solid was filtered off and dried at 40° C. in vacuo. 127 mg (0.25 mmol; 82% of theory) of the title compound were obtained.
[1215] LC-MS (Method L2): R.sub.t=3.44 min; m/z=493 (M+H).sup.+
[1216] .sup.1H NMR (300 MHz, DMSO-d.sub.6, Method M2) δ 9.27 (t, J=5.9 Hz, 1H), 8.80 (s, 1H), 8.17-8.08 (m, 2H), 7.96-7.75 (m, 5H), 7.42-7.31 (m, 2H), 4.20-4.04 (m, 2H).
TABLE-US-00001 TABLE 1 Examples 1 to 38 show compounds according to formula (I) (I)
TABLE-US-00002 TABLE 2 Example VII-1 shows a compound according to formula (VII) (VII)
[1217] NMR Peak Lists
[1218] .sup.1H-NMR data of selected examples are written in form of .sup.1H-NMR-peak lists. The δ-value in ppm and the signal intensity are listed to each signal peak in round brackets. Between the δ-value—signal intensity pairs are semicolons as delimiters.
[1219] The peak list of an example has therefore the form:
[1220] δ.sub.1 (intensity.sub.1); δ.sub.2 (intensity.sub.2); . . . ; δ.sub.i (intensity.sub.i); . . . ; δ.sub.n (intensity.sub.n)
[1221] Intensity of sharp signals correlates with the height of the signals in a printed example of a NMR spectrum in cm and shows the real relations of signal intensities. From broad signals several peaks or the middle of the signal and their relative intensity in comparison to the most intensive signal in the spectrum can be shown.
[1222] Tetramethylsilane and/or the chemical shift of the used solvent, especially in the case of spectra measured in DMSO (dimethylsulfoxide), have been used for calibrating. Therefore, tetramethylsilane peak can occur but not necessarily in NMR peak lists.
[1223] The .sup.1H-NMR peak lists are similar to classical .sup.1H-NMR prints and contain therefore usually all peaks, which are listed at classical NMR-interpretation.
[1224] Additionally they can show like classical .sup.1H-NMR prints signals of solvents, stereoisomers of the target compounds, which are also object of the invention, and/or peaks of impurities.
[1225] The usual peaks of solvents, for example peaks of DMSO in D.sub.6-DMSO and the peak of water, are given in the .sup.1H-NMR peak lists to show compound signals in the delta-range of solvents and/or water. They have usually on average a high intensity.
[1226] The peaks of stereoisomers of the target compounds and/or peaks of impurities have usually on average a lower intensity than the peaks of target compounds (for example with a purity >90%).
[1227] Such stereoisomers and/or impurities can be typical for the specific preparation process. Therefore, their peaks can help to recognize the reproduction of our preparation process via “side-products-fingerprints”.
[1228] An expert, who calculates the peaks of the target compounds with known methods (MestreC, ACD-simulation, but also with empirically evaluated expectation values) can isolate the peaks of the target compounds as needed optionally using additional intensity filters. This isolation would be similar to relevant peak picking at classical .sup.1H-NMR interpretation.
[1229] Further details of NMR-data description with peak lists can be found in the publication “Citation of NMR Peaklist Data within Patent Applications” (cf. Research Disclosure Database Number 564025, 2011, 16 Mar. 2011 or http://www.rdelectronic.co.uk/rd/free/rd564025.pdf).
TABLE-US-00003 Table with NMR Peaklists Example 4: .sup.1H-NMR (400.0 MHz, d.sub.6-DMSO): δ = 9.202 (2.0); 9.186 (4.4); 9.171 (2.1); 8.795 (4.3); 8.785 (4.2); 8.783 (4.3); 7.935 (7.2); 7.932 (8.0); 7.870 (3.5); 7.853 (5.1); 7.850 (5.1); 7.822 (4.2); 7.815 (13.1); 7.810 (4.5); 7.798 (9.1); 7.793 (16.0); 7.786 (6.6); 7.774 (4.6); 7.767 (3.2); 7.755 (3.3); 7.744 (8.8); 7.723 (5.4); 7.583 (1.6); 7.577 (14.9); 7.572 (4.6); 7.560 (3.8); 7.555 (12.6); 7.549 (1.4); 4.284 (1.7); 4.268 (1.8); 4.247 (4.0); 4.232 (3.9); 4.211 (2.0); 4.195 (1.9); 3.331 (61.8); 2.677 (0.3); 2.672 (0.5); 2.668 (0.4); 2.543 (11.3); 2.526 (1.0); 2.512 (26.9); 2.508 (55.7); 2.503 (74.4); 2.499 (54.3); 2.494 (26.4); 2.335 (0.3); 2.330 (0.5); 2.325 (0.3); 0.000 (0.9) Example 9: .sup.1H-NMR (400.0 MHz, d.sub.6-DMSO): δ = 9.202 (2.9); 9.187 (6.0); 9.171 (2.9); 8.794 (6.3); 8.783 (6.2); 8.317 (0.6); 7.904 (11.1); 7.868 (4.9); 7.849 (8.0); 7.839 (8.3); 7.835 (4.3); 7.826 (9.0); 7.817 (9.7); 7.809 (4.5); 7.804 (9.3); 7.796 (5.2); 7.786 (7.1); 7.774 (13.0); 7.767 (4.9); 7.755 (4.1); 7.731 (11.7); 7.710 (6.6); 7.362 (8.4); 7.340 (16.0); 7.318 (7.8); 4.281 (2.5); 4.265 (2.7); 4.245 (5.7); 4.229 (5.6); 4.208 (3.0); 4.192 (2.8); 3.330 (325.2); 2.676 (1.4); 2.671 (1.9); 2.667 (1.4); 2.507 (220.1); 2.502 (283.4); 2.498 (216.5); 2.329 (1.9); 2.325 (1.5); 2.075 (0.4); 1.299 (0.6); 0.000 (0.8) Example 16: .sup.1H-NMR (400.0 MHz, d.sub.6-DMSO): δ = 9.158 (2.7); 9.142 (5.6); 9.127 (2.7); 8.318 (0.4); 7.894 (7.6); 7.890 (3.7); 7.881 (8.7); 7.872 (9.1); 7.864 (4.0); 7.859 (8.3); 7.778 (5.5); 7.758 (8.0); 7.733 (6.4); 7.715 (4.4); 7.669 (4.6); 7.646 (13.5); 7.631 (2.9); 7.617 (10.8); 7.416 (6.6); 7.397 (6.0); 7.364 (8.4); 7.342 (16.0); 7.320 (7.8); 4.155 (2.4); 4.139 (2.6); 4.120 (5.4); 4.104 (5.2); 4.085 (2.8); 4.069 (2.6); 3.333 (212.1); 2.676 (0.8); 2.672 (1.1); 2.668 (0.8); 2.507 (133.3); 2.503 (170.8); 2.499 (126.1); 2.334 (0.8); 2.330 (1.1); 2.325 (0.8); 1.398 (2.1); 0.008 (0.6); 0.000 (14.5) Example 21: .sup.1H-NMR (400.0 MHz, d.sub.6-DMSO): δ = 9.049 (3.0); 9.033 (6.1); 9.018 (3.1); 8.317 (0.5); 8.169 (3.0); 8.156 (3.8); 8.148 (3.9); 8.136 (3.8); 8.127 (5.8); 8.110 (5.7); 8.075 (0.4); 8.048 (11.2); 7.890 (4.9); 7.869 (6.4); 7.770 (5.9); 7.752 (16.0); 7.731 (8.1); 7.707 (6.6); 7.686 (7.1); 7.658 (10.1); 7.637 (9.1); 7.619 (2.4); 7.394 (6.8); 7.375 (6.1); 4.263 (2.6); 4.248 (2.9); 4.227 (5.8); 4.212 (5.8); 4.191 (3.1); 4.176 (2.9); 3.330 (170.2); 2.672 (1.8); 2.503 (268.4); 2.330 (1.8); 0.000 (21.8) Example 22: .sup.1H-NMR (400.0 MHz, d.sub.6-DMSO): δ = 9.053 (5.2); 9.038 (8.8); 9.023 (4.1); 8.319 (0.4); 8.080 (16.0); 8.026 (8.1); 7.996 (8.0); 7.941 (8.3); 7.921 (13.9); 7.901 (9.6); 7.881 (7.5); 7.850 (11.2); 7.829 (6.0); 7.785 (14.8); 7.770 (12.9); 7.764 (13.6); 7.752 (11.5); 7.729 (4.4); 7.710 (9.5); 7.692 (7.0); 7.659 (7.4); 7.640 (8.4); 7.621 (3.1); 7.391 (9.8); 7.373 (8.3); 4.271 (4.4); 4.255 (4.9); 4.235 (9.0); 4.220 (8.2); 4.199 (4.6); 4.184 (3.8); 3.340 (30.7); 3.332 (98.4); 2.677 (1.2); 2.673 (1.3); 2.508 (179.1); 2.504 (189.9); 2.499 (128.8); 2.335 (1.2); 2.330 (1.2); 2.077 (1.0); 0.007 (5.3); 0.000 (19.2) Example 23: .sup.1H-NMR (400.0 MHz, d.sub.6-DMSO): δ = 9.051 (2.2); 9.036 (4.8); 9.020 (2.3); 7.987 (8.6); 7.941 (9.9); 7.920 (16.0); 7.876 (3.5); 7.872 (3.4); 7.849 (15.7); 7.828 (9.0); 7.792 (0.4); 7.773 (9.5); 7.752 (8.9); 7.726 (2.1); 7.708 (4.9); 7.690 (3.6); 7.656 (3.7); 7.637 (4.5); 7.618 (1.7); 7.389 (5.2); 7.371 (4.7); 4.270 (1.9); 4.255 (2.0); 4.234 (4.3); 4.219 (4.2); 4.198 (2.2); 4.183 (2.0); 3.335 (78.8); 2.677 (0.4); 2.673 (0.5); 2.669 (0.4); 2.508 (58.4); 2.504 (76.5); 2.499 (57.4); 2.331 (0.5); 2.326 (0.4); 1.357 (0.5); 1.309 (1.5); 0.008 (0.3); 0.000 (9.8) Example 24: .sup.1H-NMR (400.0 MHz, d.sub.6-DMSO): δ = 9.053 (0.6); 9.038 (1.4); 9.023 (0.8); 8.065 (0.4); 8.042 (16.0); 8.024 (3.3); 7.900 (1.0); 7.883 (1.4); 7.879 (1.4); 7.792 (2.2); 7.771 (2.8); 7.750 (1.8); 7.728 (0.6); 7.710 (1.4); 7.691 (1.1); 7.657 (1.1); 7.638 (1.4); 7.619 (0.6); 7.394 (1.4); 7.375 (1.4); 4.276 (0.5); 4.260 (0.6); 4.239 (1.2); 4.224 (1.3); 4.204 (0.7); 4.188 (0.7); 3.333 (15.2); 3.282 (12.4); 2.507 (19.0); 2.503 (24.5); 2.499 (19.7); 0.000 (2.6) Example 25: .sup.1H-NMR (400.0 MHz, d.sub.6-DMSO): δ = 9.050 (0.4); 9.034 (0.8); 9.019 (0.4); 8.094 (1.3); 8.091 (1.4); 8.084 (0.8); 8.063 (1.1); 8.056 (0.9); 8.046 (0.8); 8.033 (0.8); 8.029 (0.8); 7.953 (0.6); 7.949 (0.6); 7.933 (0.8); 7.928 (0.8); 7.876 (0.9); 7.872 (0.9); 7.855 (0.8); 7.851 (0.8); 7.782 (1.4); 7.766 (0.8); 7.761 (1.2); 7.747 (1.0); 7.724 (0.3); 7.706 (0.8); 7.688 (0.6); 7.655 (0.6); 7.636 (0.8); 7.383 (0.9); 7.365 (0.8); 4.250 (0.3); 4.229 (0.7); 4.214 (0.7); 4.193 (0.4); 4.177 (0.3); 4.038 (0.8); 4.020 (0.9); 3.331 (61.9); 2.671 (0.3); 2.525 (0.8); 2.511 (19.9); 2.507 (40.6); 2.503 (53.6); 2.498 (39.5); 2.494 (19.9); 2.329 (0.3); 1.989 (3.7); 1.398 (16.0); 1.193 (1.0); 1.175 (1.9); 1.157 (0.9); 0.146 (0.4); 0.008 (2.8); 0.000 (80.6); −0.009 (3.5); −0.019 (0.3); −0.150 (0.4) Example 26: .sup.1H-NMR (400.0 MHz, d.sub.6-DMSO): δ = 9.033 (2.0); 9.018 (4.3); 9.002 (2.0); 8.317 (0.5); 7.886 (7.1); 7.883 (7.7); 7.797 (3.0); 7.793 (2.9); 7.776 (5.1); 7.771 (6.5); 7.748 (5.6); 7.730 (11.5); 7.726 (6.1); 7.715 (11.6); 7.709 (16.0); 7.694 (5.6); 7.687 (3.6); 7.654 (3.4); 7.635 (4.1); 7.616 (1.5); 7.385 (6.4); 7.379 (13.4); 7.363 (5.8); 7.357 (11.5); 4.251 (1.7); 4.235 (1.8); 4.215 (3.9); 4.199 (3.7); 4.179 (2.0); 4.163 (1.8); 4.037 (0.8); 4.020 (0.8); 3.382 (0.4); 3.334 (435.6); 2.698 (0.3); 2.676 (1.1); 2.671 (1.5); 2.667 (1.1); 2.552 (0.7); 2.525 (60.6); 2.511 (83.9); 2.507 (168.1); 2.502 (220.1); 2.498 (161.2); 2.494 (80.1); 2.333 (1.0); 2.329 (1.4); 2.325 (1.0); 1.989 (3.3); 1.397 (1.5); 1.234 (0.6); 1.193 (0.9); 1.175 (1.7); 1.157 (0.9); 1.120 (0.4); 0.982 (0.4); 0.146 (1.7); 0.008 (14.2); 0.000 (355.5); −0.009 (15.0); −0.150 (1.7) Example 27: .sup.1H-NMR (400.0 MHz, d.sub.6-DMSO): δ = 9.047 (0.6); 9.031 (1.3); 9.016 (0.6); 8.019 (2.3); 8.016 (2.5); 8.004 (0.5); 7.980 (16.0); 7.958 (0.4); 7.898 (1.0); 7.894 (1.0); 7.878 (1.4); 7.874 (1.4); 7.778 (2.4); 7.766 (1.4); 7.757 (1.9); 7.747 (1.7); 7.724 (0.5); 7.706 (1.4); 7.688 (1.0); 7.654 (1.0); 7.635 (1.3); 7.617 (0.4); 7.387 (1.5); 7.368 (1.3); 4.265 (0.5); 4.249 (0.6); 4.230 (1.2); 4.214 (1.2); 4.194 (0.6); 4.178 (0.6); 3.331 (60.6); 2.671 (0.4); 2.525 (1.0); 2.507 (43.0); 2.503 (56.3); 2.498 (41.8); 2.329 (0.4); 1.989 (0.3); 0.146 (0.4); 0.008 (3.3); 0.000 (84.1); −0.009 (3.8); −0.150 (0.4) Example 28: .sup.1H-NMR (400.0 MHz, d.sub.6-DMSO): δ = 9.019 (0.4); 9.004 (0.8); 8.988 (0.4); 7.778 (1.5); 7.769 (0.8); 7.749 (1.0); 7.716 (0.6); 7.712 (0.6); 7.704 (0.9); 7.695 (1.0); 7.691 (1.0); 7.653 (0.7); 7.643 (1.6); 7.631 (2.5); 7.623 (1.2); 7.609 (2.1); 7.383 (0.9); 7.364 (0.8); 6.813 (1.9); 6.791 (1.8); 4.196 (0.7); 4.180 (0.7); 4.161 (0.4); 4.144 (0.3); 3.328 (43.3); 2.963 (16.0); 2.675 (0.4); 2.671 (0.5); 2.506 (55.8); 2.502 (72.6); 2.498 (54.5); 2.329 (0.5); 2.324 (0.4); 0.146 (0.5); 0.008 (4.4); 0.000 (100.4); −0.008 (4.7); −0.150 (0.5) Example 29: .sup.1H-NMR (400.0 MHz, d.sub.6-DMSO): δ = 9.015 (2.0); 9.000 (4.1); 8.984 (2.0); 8.317 (0.4); 7.768 (3.8); 7.748 (5.9); 7.738 (7.9); 7.723 (1.9); 7.704 (4.4); 7.685 (3.5); 7.654 (7.9); 7.633 (4.6); 7.625 (8.1); 7.615 (2.1); 7.604 (3.6); 7.547 (9.2); 7.525 (9.7); 7.381 (4.5); 7.362 (4.0); 6.635 (9.3); 6.613 (9.0); 6.030 (1.7); 4.226 (1.7); 4.210 (1.8); 4.190 (3.7); 4.174 (3.6); 4.153 (1.9); 4.138 (1.8); 4.038 (0.5); 4.020 (0.5); 3.858 (0.4); 3.781 (0.5); 3.413 (0.4); 3.334 (164.2); 2.719 (16.0); 2.671 (1.3); 2.502 (184.6); 2.329 (1.2); 1.989 (1.8); 1.352 (0.5); 1.314 (0.8); 1.249 (0.4); 1.232 (0.7); 1.193 (0.5); 1.175 (1.0); 1.157 (0.5); 0.146 (1.2); 0.000 (236.6); −0.150 (1.2) Example 30: .sup.1H-NMR (400.0 MHz, d.sub.6-DMSO): δ = 10.102 (2.9); 9.030 (0.8); 9.014 (1.6); 8.999 (0.8); 7.856 (2.9); 7.770 (2.0); 7.750 (3.5); 7.724 (1.2); 7.710 (16.0); 7.683 (2.3); 7.654 (1.2); 7.634 (1.5); 7.615 (0.6); 7.382 (1.7); 7.364 (1.6); 4.246 (0.6); 4.231 (0.7); 4.211 (1.4); 4.195 (1.3); 4.174 (0.7); 4.159 (0.7); 4.055 (0.6); 4.038 (2.0); 4.020 (2.0); 4.002 (0.7); 3.330 (25.9); 2.671 (0.4); 2.507 (43.4); 2.502 (55.5); 2.498 (41.4); 2.329 (0.4); 2.071 (13.9); 1.989 (8.5); 1.972 (0.6); 1.234 (0.3); 1.193 (2.2); 1.175 (4.4); 1.157 (2.2); 0.146 (0.4); 0.008 (3.6); 0.000 (81.9); −0.008 (4.2); −0.150 (0.4) Example 31: .sup.1H-NMR (400.0 MHz, d.sub.6-DMSO): δ = 9.059 (3.2); 9.043 (6.6); 9.028 (3.2); 8.318 (1.1); 7.785 (9.7); 7.765 (16.0); 7.746 (11.4); 7.741 (12.3); 7.714 (2.6); 7.695 (7.0); 7.677 (5.6); 7.657 (5.6); 7.638 (6.4); 7.613 (6.9); 7.590 (6.1); 7.572 (3.3); 7.568 (3.0); 7.551 (5.9); 7.535 (3.2); 7.530 (3.7); 7.514 (1.6); 7.354 (7.4); 7.335 (6.7); 7.304 (1.6); 7.294 (9.8); 7.274 (15.9); 7.253 (8.0); 7.243 (1.3); 4.290 (2.9); 4.274 (3.0); 4.254 (6.5); 4.238 (6.3); 4.218 (3.3); 4.202 (3.1); 3.330 (143.9); 2.676 (1.4); 2.672 (1.8); 2.667 (1.3); 2.507 (214.0); 2.503 (274.0); 2.498 (201.8); 2.334 (1.3); 2.329 (1.8); 2.325 (1.3); 0.146 (1.5); 0.008 (15.6); 0.000 (330.3); −0.008 (16.2); −0.150 (1.6) Example 32: .sup.1H-NMR (400.0 MHz, d.sub.6-DMSO): δ = 9.045 (1.6); 9.029 (3.5); 9.013 (1.7); 8.317 (0.5); 8.032 (5.9); 8.028 (6.3); 7.905 (0.5); 7.887 (6.7); 7.870 (7.8); 7.865 (7.2); 7.846 (4.0); 7.829 (0.4); 7.770 (3.3); 7.750 (4.7); 7.737 (6.5); 7.726 (1.8); 7.716 (5.3); 7.709 (4.0); 7.690 (2.7); 7.657 (2.9); 7.638 (3.4); 7.619 (1.2); 7.380 (3.9); 7.362 (3.5); 4.255 (1.5); 4.240 (1.5); 4.219 (3.3); 4.203 (3.2); 4.183 (1.7); 4.167 (1.6); 3.331 (282.8); 2.676 (1.0); 2.672 (1.4); 2.667 (1.0); 2.525 (3.6); 2.511 (75.3); 2.507 (154.7); 2.503 (205.7); 2.498 (152.3); 2.494 (76.7); 2.334 (0.9); 2.329 (1.3); 2.325 (1.0); 1.989 (0.5); 1.398 (16.0); 0.008 (1.2); 0.000 (35.8); −0.008 (1.5) Example 33: .sup.1H-NMR (400.0 MHz, d.sub.6-DMSO): δ = 9.043 (0.6); 9.027 (1.3); 9.012 (0.6); 7.968 (2.2); 7.965 (2.8); 7.945 (0.6); 7.939 (0.7); 7.934 (0.7); 7.928 (0.6); 7.914 (0.6); 7.909 (0.6); 7.844 (1.0); 7.840 (0.9); 7.824 (1.4); 7.819 (1.4); 7.769 (1.2); 7.750 (1.6); 7.732 (2.6); 7.711 (2.7); 7.690 (1.0); 7.675 (0.4); 7.667 (0.5); 7.656 (1.7); 7.638 (1.8); 7.618 (0.5); 7.600 (0.7); 7.579 (1.1); 7.574 (0.8); 7.557 (0.6); 7.553 (1.1); 7.531 (0.5); 7.385 (1.4); 7.367 (1.3); 4.256 (0.5); 4.241 (0.6); 4.220 (1.2); 4.204 (1.2); 4.184 (0.6); 4.168 (0.6); 3.331 (22.6); 2.525 (0.5); 2.512 (11.9); 2.508 (24.6); 2.503 (32.6); 2.499 (23.7); 2.494 (11.5); 1.990 (0.8); 1.397 (16.0); 1.175 (0.4); 0.000 (7.2) Example 34: .sup.1H-NMR (400.0 MHz, d.sub.6-DMSO): δ = 9.044 (0.5); 9.028 (1.0); 9.012 (0.5); 7.956 (1.9); 7.824 (0.7); 7.820 (0.7); 7.804 (1.1); 7.800 (1.1); 7.772 (1.0); 7.752 (1.3); 7.721 (2.1); 7.709 (1.2); 7.700 (1.5); 7.691 (0.9); 7.657 (0.8); 7.638 (1.0); 7.619 (0.4); 7.506 (0.9); 7.502 (1.0); 7.483 (1.1); 7.390 (1.1); 7.371 (1.0); 7.335 (1.6); 7.328 (1.0); 7.323 (0.9); 7.311 (2.4); 4.256 (0.4); 4.240 (0.4); 4.220 (0.9); 4.205 (0.9); 4.184 (0.5); 4.169 (0.5); 4.037 (0.4); 4.020 (0.4); 3.953 (12.0); 3.330 (45.8); 2.671 (0.4); 2.667 (0.3); 2.525 (1.1); 2.511 (24.1); 2.507 (50.1); 2.502 (66.8); 2.498 (49.5); 2.494 (25.0); 2.329 (0.4); 1.989 (1.8); 1.398 (16.0); 1.193 (0.5); 1.175 (0.9); 1.157 (0.5); 0.008 (0.3); 0.000 (11.2); −0.008 (0.5) Example 35: .sup.1H-NMR (400.0 MHz, d.sub.6-DMSO): δ = 9.047 (1.2); 9.031 (2.7); 9.015 (1.3); 8.036 (4.4); 8.032 (4.8); 7.903 (2.1); 7.899 (2.0); 7.883 (2.7); 7.879 (2.7); 7.770 (2.5); 7.751 (3.6); 7.741 (5.0); 7.727 (1.4); 7.720 (4.1); 7.710 (2.9); 7.691 (2.1); 7.657 (2.2); 7.638 (2.6); 7.620 (1.5); 7.608 (3.1); 7.603 (4.0); 7.586 (4.1); 7.580 (3.1); 7.569 (0.6); 7.385 (3.0); 7.366 (2.7); 7.356 (0.9); 7.350 (1.3); 7.344 (0.8); 7.332 (1.6); 7.327 (2.5); 7.321 (1.3); 7.309 (0.8); 7.304 (1.3); 7.298 (0.6); 4.261 (1.1); 4.245 (1.1); 4.225 (2.5); 4.209 (2.5); 4.189 (1.3); 4.173 (1.2); 3.332 (39.6); 2.672 (0.4); 2.526 (1.0); 2.512 (22.5); 2.508 (46.2); 2.503 (60.9); 2.499 (44.5); 2.494 (21.9); 2.330 (0.4); 1.990 (0.8); 1.397 (16.0); 1.176 (0.4); 0.008 (0.4); 0.000 (12.3); −0.008 (0.4) Example 36: .sup.1H-NMR (400.0 MHz, d.sub.6-DMSO): δ = 9.050 (2.7); 9.035 (5.5); 9.019 (2.7); 8.318 (0.6); 7.769 (16.0); 7.750 (8.4); 7.742 (10.5); 7.723 (2.6); 7.704 (6.6); 7.687 (8.7); 7.671 (10.7); 7.657 (6.6); 7.649 (7.5); 7.639 (6.0); 7.620 (2.1); 7.465 (2.4); 7.459 (2.6); 7.441 (3.1); 7.436 (4.6); 7.431 (3.2); 7.414 (2.5); 7.408 (2.6); 7.381 (6.2); 7.362 (5.5); 7.269 (2.4); 7.264 (2.3); 7.248 (4.4); 7.243 (4.2); 7.227 (2.2); 7.222 (2.1); 4.269 (2.4); 4.253 (2.6); 4.232 (5.3); 4.217 (5.2); 4.196 (2.8); 4.181 (2.6); 3.331 (107.4); 2.672 (1.8); 2.507 (223.8); 2.503 (279.1); 2.329 (1.8); 1.398 (1.4); 0.000 (8.2) Example 37: .sup.1H-NMR (400.0 MHz, d.sub.6-DMSO): δ = 8.886 (0.7); 8.871 (1.5); 8.855 (0.7); 8.317 (0.5); 7.814 (2.1); 7.809 (1.0); 7.801 (2.4); 7.792 (2.6); 7.784 (1.0); 7.779 (2.3); 7.755 (1.5); 7.736 (2.0); 7.702 (0.7); 7.684 (1.7); 7.666 (1.3); 7.637 (1.2); 7.618 (1.5); 7.599 (0.6); 7.546 (2.2); 7.525 (2.7); 7.368 (3.0); 7.353 (0.3); 7.345 (2.4); 7.340 (1.0); 7.329 (2.5); 7.323 (4.9); 7.313 (3.4); 7.301 (2.8); 4.198 (0.7); 4.183 (0.7); 4.161 (1.5); 4.146 (1.5); 4.125 (0.8); 4.109 (0.7); 3.965 (16.0); 3.891 (0.3); 3.329 (120.9); 2.675 (1.0); 2.671 (1.3); 2.667 (1.0); 2.524 (3.4); 2.506 (156.4); 2.502 (206.0); 2.498 (151.8); 2.333 (1.0); 2.329 (1.4); 2.324 (1.0); 0.000 (7.5) Example 38: .sup.1H-NMR (400.0 MHz, d.sub.6-DMSO): δ = 9.080 (2.5); 9.064 (5.2); 9.048 (2.5); 7.785 (6.0); 7.777 (8.2); 7.763 (12.7); 7.754 (9.6); 7.746 (3.9); 7.741 (10.2); 7.720 (6.0); 7.702 (4.3); 7.667 (4.4); 7.648 (5.5); 7.620 (10.0); 7.591 (7.6); 7.573 (12.6); 7.553 (4.0); 7.390 (6.3); 7.371 (5.7); 7.346 (1.0); 7.338 (8.5); 7.333 (3.0); 7.316 (16.0); 7.298 (2.7); 7.293 (7.8); 7.286 (0.9); 4.102 (2.3); 4.087 (2.4); 4.064 (5.3); 4.049 (5.1); 4.026 (2.7); 4.010 (2.5); 3.334 (31.5); 2.676 (0.4); 2.672 (0.5); 2.668 (0.4); 2.557 (24.9); 2.525 (1.6); 2.507 (61.0); 2.503 (80.1); 2.498 (58.8); 2.334 (0.4); 2.330 (0.5); 0.000 (3.6) Example 39: 1H-NMR (400.0 MHz, d6-DMSO): = 9.045 (2.2); 9.029 (4.8); 9.014 (2.3); 8.318 (1.1); 7.941 (8.1); 7.937 (9.1); 7.915 (1.4); 7.907 (13.8); 7.902 (5.1); 7.891 (4.7); 7.885 (16.0); 7.878 (2.0); 7.830 (3.3); 7.826 (3.3); 7.810 (5.6); 7.805 (5.8); 7.768 (4.7); 7.751 (13.8); 7.731 (6.5); 7.707 (5.2); 7.689 (3.8); 7.655 (3.9); 7.636 (4.7); 7.617 (1.8); 7.504 (9.5); 7.484 (8.6); 7.387 (5.4); 7.368 (4.9); 4.262 (1.9); 4.247 (2.1); 4.226 (4.5); 4.211 (4.4); 4.190 (2.4); 4.175 (2.2); 3.330 (195.8); 2.676 (1.3); 2.672 (1.8); 2.667 (1.3); 2.525 (4.3); 2.520 (6.7); 2.511 (97.7); 2.507 (205.8); 2.503 (276.0); 2.498 (203.6); 2.494 (101.9); 2.334 (1.3); 2.329 (1.8); 2.325 (1.3); 1.989 (0.5); 1.398 (1.1); 0.146 (1.0); 0.008 (7.3); 0.000 (224.7); −0.009 (9.3); −0.150 (0.9) Example 40: 1H-NMR (400.0 MHz, d6-DMSO): δ = 9.045 (2.4); 9.029 (5.2); 9.014 (2.4); 8.318 (1.3); 7.961 (9.5); 7.922 (9.5); 7.901 (12.0); 7.859 (3.7); 7.855 (3.5); 7.838 (5.7); 7.835 (5.6); 7.766 (13.1); 7.745 (9.5); 7.726 (2.3); 7.708 (16.0); 7.688 (12.4); 7.655 (4.2); 7.636 (5.0); 7.617 (1.8); 7.389 (5.7); 7.371 (5.1); 7.248 (3.5); 7.109 (8.5); 6.969 (4.0); 4.265 (2.1); 4.250 (2.2); 4.230 (4.8); 4.214 (4.6); 4.194 (2.4); 4.178 (2.3); 4.037 (0.4); 4.020 (0.4); 3.328 (174.7); 2.676 (2.0); 2.671 (2.8); 2.667 (2.1); 2.524 (6.7); 2.507 (327.3); 2.502 (427.4); 2.498 (311.9); 2.333 (2.0); 2.329 (2.7); 2.325 (2.0); 1.989 (1.6); 1.398 (0.8); 1.193 (0.4); 1.175 (0.8); 1.157 (0.4); 0.983 (0.3); 0.146 (1.3); 0.008 (9.8); 0.000 (286.1); −0.008 (11.5); −0.150 (1.3) Example 41: 1H-NMR (400.0 MHz, d6-DMSO): δ = 9.050 (2.3); 9.035 (5.0); 9.019 (2.3); 8.318 (0.7); 8.005 (16.0); 7.985 (11.7); 7.888 (3.8); 7.884 (3.8); 7.870 (14.1); 7.850 (9.1); 7.784 (9.5); 7.763 (7.6); 7.749 (6.5); 7.726 (2.0); 7.709 (5.3); 7.690 (3.9); 7.656 (4.0); 7.637 (4.8); 7.618 (1.7); 7.392 (5.5); 7.373 (4.9); 4.271 (2.0); 4.255 (2.1); 4.235 (4.6); 4.219 (4.5); 4.199 (2.3); 4.183 (2.2); 3.330 (103.9); 2.676 (1.1); 2.672 (1.6); 2.667 (1.2); 2.525 (3.8); 2.520 (5.8); 2.511 (86.0); 2.507 (178.1); 2.503 (236.3); 2.498 (172.6); 2.494 (84.9); 2.334 (1.1); 2.329 (1.5); 2.325 (1.1); 1.989 (0.4); 1.398 (1.3); 0.146 (0.8); 0.008 (5.8); 0.000 (187.2); −0.008 (7.3); −0.150 (0.8) Example 42: 1H-NMR (400.0 MHz, d6-DMSO): δ = 9.043 (1.2); 9.028 (2.6); 9.012 (1.3); 8.318 (0.4); 7.990 (4.7); 7.869 (2.0); 7.865 (1.9); 7.848 (2.8); 7.844 (2.9); 7.834 (2.5); 7.814 (2.9); 7.779 (4.0); 7.769 (3.1); 7.751 (7.1); 7.730 (3.6); 7.707 (2.8); 7.689 (2.0); 7.664 (2.6); 7.655 (2.4); 7.643 (4.9); 7.637 (2.9); 7.624 (2.7); 7.462 (2.1); 7.442 (1.7); 7.392 (2.9); 7.373 (2.6); 4.263 (1.1); 4.248 (1.1); 4.227 (2.4); 4.212 (2.4); 4.191 (1.3); 4.175 (1.2); 3.329 (82.6); 2.671 (1.1); 2.507 (132.2); 2.502 (172.8); 2.498 (132.2); 2.329 (1.1); 2.325 (0.9); 1.989 (0.9); 1.398 (16.0); 1.175 (0.5); 0.146 (0.5); 0.000 (100.2); −0.008 (6.4); −0.150 (0.5) Example 43: 1H-NMR (400.0 MHz, d6-DMSO): δ = 9.046 (0.8); 9.030 (1.7); 9.014 (0.8); 8.317 (0.6); 7.962 (4.1); 7.952 (4.4); 7.939 (1.2); 7.858 (1.2); 7.854 (1.2); 7.838 (1.9); 7.834 (2.0); 7.766 (4.6); 7.745 (3.5); 7.725 (0.7); 7.707 (1.8); 7.688 (1.6); 7.665 (2.5); 7.655 (5.1); 7.651 (5.4); 7.636 (1.8); 7.617 (0.6); 7.391 (1.9); 7.372 (1.7); 7.242 (1.5); 7.102 (3.3); 6.963 (1.6); 4.266 (0.7); 4.250 (0.7); 4.230 (1.6); 4.215 (1.6); 4.194 (0.8); 4.178 (0.8); 4.038 (0.4); 4.020 (0.4); 3.328 (81.5); 2.676 (0.7); 2.671 (1.0); 2.667 (0.8); 2.525 (2.3); 2.520 (3.8); 2.511 (57.6); 2.507 (121.0); 2.502 (162.7); 2.498 (121.8); 2.494 (62.4); 2.333 (0.8); 2.329 (1.1); 2.325 (0.8); 1.989 (1.5); 1.398 (16.0); 1.193 (0.4); 1.175 (0.8); 1.157 (0.4); 0.146 (0.5); 0.008 (3.8); 0.000 (118.6); −0.008 (5.6); −0.150 (0.5) Example 44: 1H-NMR (400.0 MHz, d6-DMSO): δ = 8.882 (0.7); 8.866 (1.6); 8.851 (0.7); 7.922 (3.3); 7.901 (5.7); 7.839 (4.8); 7.818 (2.9); 7.751 (1.5); 7.732 (2.0); 7.700 (0.7); 7.682 (1.6); 7.664 (1.2); 7.635 (1.3); 7.616 (1.5); 7.597 (0.7); 7.589 (2.2); 7.569 (2.7); 7.454 (2.9); 7.410 (1.7); 7.407 (1.6); 7.390 (1.5); 7.386 (1.4); 7.312 (1.7); 7.294 (1.6); 4.210 (0.6); 4.195 (0.7); 4.174 (1.4); 4.158 (1.4); 4.137 (0.7); 4.122 (0.7); 3.980 (16.0); 3.315 (24.6); 2.675 (0.3); 2.670 (0.5); 2.666 (0.4); 2.541 (2.9); 2.524 (1.4); 2.510 (26.1); 2.506 (53.2); 2.501 (71.9); 2.497 (54.6); 2.492 (27.8); 2.333 (0.4); 2.328 (0.5); 2.323 (0.4); 0.146 (0.5); 0.021 (0.4); 0.018 (0.4); 0.008 (4.0); 0.000 (105.6); −0.008 (4.4); −0.150 (0.4) Example 45: 1H-NMR (400.0 MHz, d6-DMSO): δ = 9.062 (0.8); 9.046 (1.7); 9.031 (0.8); 8.257 (0.5); 8.233 (16.0); 8.217 (0.4); 8.209 (0.6); 8.103 (2.8); 8.099 (3.0); 7.964 (1.2); 7.960 (1.2); 7.944 (1.7); 7.940 (1.7); 7.826 (2.9); 7.805 (2.2); 7.768 (1.5); 7.749 (2.1); 7.727 (0.7); 7.709 (1.7); 7.690 (1.3); 7.657 (1.3); 7.638 (1.6); 7.619 (0.6); 7.392 (1.8); 7.373 (1.6); 4.280 (0.6); 4.265 (0.7); 4.245 (1.5); 4.229 (1.4); 4.209 (0.8); 4.193 (0.7); 3.333 (45.1); 2.672 (0.3); 2.543 (1.4); 2.526 (0.8); 2.508 (39.1); 2.503 (51.4); 2.499 (37.6); 2.330 (0.3); 2.076 (1.2); 0.146 (0.4); 0.014 (0.3); 0.008 (2.7); 0.000 (73.4); −0.009 (2.8); −0.150 (0.3) Example 46: 1H-NMR (400.0 MHz, d6-DMSO): δ = 9.169 (1.8); 9.153 (3.7); 9.137 (1.8); 8.318 (0.6); 8.041 (5.4); 8.019 (15.8); 7.996 (16.0); 7.974 (5.8); 7.774 (10.3); 7.756 (6.1); 7.747 (8.3); 7.732 (4.8); 7.713 (3.0); 7.669 (3.1); 7.649 (3.9); 7.630 (1.4); 7.581 (0.4); 7.415 (4.5); 7.396 (4.0); 4.164 (1.5); 4.148 (1.7); 4.129 (3.5); 4.113 (3.4); 4.094 (1.8); 4.078 (1.7); 3.329 (96.6); 2.676 (1.2); 2.671 (1.7); 2.667 (1.2); 2.507 (202.9); 2.502 (265.3); 2.498 (199.7); 2.333 (1.3); 2.329 (1.8); 2.325 (1.4); 1.989 (1.0); 1.397 (2.8); 1.235 (0.4); 1.175 (0.5); 0.146 (1.7); 0.024 (0.5); 0.020 (0.4); 0.008 (12.1); 0.000 (335.8); −0.028 (0.5); −0.040 (0.4); −0.150 (1.7) Example 47: 1H-NMR (400.0 MHz, d6-DMSO): = 9.171 (2.6); 9.155 (5.4); 9.139 (2.8); 9.120 (0.8); 9.105 (0.4); 8.319 (0.4); 7.979 (11.6); 7.958 (16.0); 7.850 (14.3); 7.829 (10.6); 7.777 (5.4); 7.757 (8.2); 7.735 (14.8); 7.710 (11.1); 7.669 (5.0); 7.650 (5.6); 7.632 (2.3); 7.417 (6.0); 7.398 (5.5); 7.386 (1.1); 7.368 (0.8); 4.167 (2.2); 4.151 (2.3); 4.132 (4.7); 4.116 (4.7); 4.097 (2.7); 4.081 (2.5); 4.055 (0.8); 4.036 (0.4); 4.020 (0.4); 3.568 (0.4); 3.331 (110.5); 2.672 (1.4); 2.507 (175.6); 2.503 (219.9); 2.499 (162.5); 2.329 (1.4); 1.397 (1.8); 0.146 (1.4); 0.029 (0.6); 0.024 (0.6); 0.000 (272.0); −0.150 (1.4) Example 48: 1H-NMR (400.0 MHz, d6-DMSO): δ = 9.164 (2.4); 9.149 (5.0); 9.133 (2.5); 8.318 (1.1); 7.963 (1.5); 7.955 (14.1); 7.950 (5.1); 7.938 (4.9); 7.933 (16.0); 7.926 (1.8); 7.778 (5.0); 7.758 (7.2); 7.733 (6.0); 7.714 (4.2); 7.686 (9.7); 7.669 (5.1); 7.658 (10.3); 7.631 (2.1); 7.509 (9.9); 7.489 (9.0); 7.416 (5.8); 7.397 (5.2); 7.366 (0.4); 4.161 (2.0); 4.146 (2.1); 4.126 (4.6); 4.110 (4.5); 4.090 (2.5); 4.074 (2.3); 4.054 (0.5); 3.568 (0.4); 3.357 (0.4); 3.329 (180.0); 2.676 (2.0); 2.671 (2.8); 2.667 (2.1); 2.569 (0.5); 2.525 (7.3); 2.520 (11.4); 2.511 (155.0); 2.507 (321.4); 2.502 (426.8); 2.498 (313.1); 2.493 (153.1); 2.459 (0.5); 2.333 (2.0); 2.329 (2.7); 2.324 (2.0); 1.398 (1.1); 0.146 (2.9); 0.034 (0.5); 0.028 (1.0); 0.008 (22.7); 0.000 (653.9); −0.009 (26.0); −0.019 (1.1); −0.022 (1.0); −0.024 (1.0); −0.048 (0.3); −0.150 (2.9) Example 49: 1H-NMR (400.0 MHz, d6-DMSO): δ = 9.088 (1.3); 9.073 (2.7); 9.057 (1.3); 7.972 (2.1); 7.966 (1.2); 7.950 (16.0); 7.943 (15.3); 7.927 (1.0); 7.921 (2.2); 7.784 (2.5); 7.765 (3.4); 7.736 (5.6); 7.720 (4.7); 7.701 (4.7); 7.666 (2.2); 7.647 (2.6); 7.625 (5.3); 7.605 (3.2); 7.387 (3.0); 7.368 (2.7); 5.758 (9.2); 4.113 (1.1); 4.097 (1.1); 4.075 (2.5); 4.059 (2.4); 4.038 (2.7); 4.020 (2.7); 4.003 (0.6); 3.569 (3.5); 3.332 (24.1); 2.891 (0.5); 2.732 (0.4); 2.672 (0.4); 2.576 (11.8); 2.525 (1.1); 2.512 (22.6); 2.508 (45.7); 2.503 (59.8); 2.499 (43.7); 2.494 (21.5); 2.330 (0.4); 1.990 (6.9); 1.397 (1.5); 1.193 (1.8); 1.175 (3.6); 1.158 (1.8); 0.146 (0.4); 0.008 (3.5); 0.000 (96.6); −0.008 (4.3); −0.150 (0.4) Example 50: 1H-NMR (400.0 MHz, d6-DMSO): δ = 9.088 (1.7); 9.073 (3.6); 9.057 (1.7); 9.032 (0.4); 7.893 (6.8); 7.888 (3.1); 7.872 (14.6); 7.833 (12.0); 7.812 (6.0); 7.784 (3.8); 7.765 (5.0); 7.738 (1.6); 7.720 (4.6); 7.706 (7.0); 7.670 (4.8); 7.647 (3.9); 7.628 (1.7); 7.618 (6.6); 7.597 (4.0); 7.573 (0.6); 7.512 (0.4); 7.428 (0.7); 7.407 (0.5); 7.387 (4.1); 7.368 (3.9); 7.348 (0.4); 5.758 (3.4); 4.115 (1.5); 4.099 (1.5); 4.077 (3.3); 4.061 (3.4); 4.038 (2.8); 4.021 (2.4); 4.008 (0.5); 4.003 (0.5); 3.569 (2.2); 3.333 (68.6); 2.732 (0.3); 2.676 (0.5); 2.672 (0.6); 2.667 (0.5); 2.628 (0.3); 2.574 (16.0); 2.525 (1.6); 2.512 (36.0); 2.507 (73.9); 2.503 (97.5); 2.498 (71.8); 2.494 (35.6); 2.480 (2.2); 2.334 (0.5); 2.330 (0.6); 2.325 (0.5); 1.989 (4.6); 1.397 (4.2); 1.193 (1.2); 1.175 (2.4); 1.157 (1.2); 0.146 (0.7); 0.008 (5.7); 0.000 (156.8); −0.008 (6.9); −0.150 (0.7) Example 51: 1H-NMR (400.0 MHz, d6-DMSO): δ = 8.895 (0.6); 8.879 (1.2); 8.863 (0.6); 7.970 (16.0); 7.753 (1.2); 7.733 (1.5); 7.701 (0.5); 7.682 (1.3); 7.664 (0.9); 7.636 (1.0); 7.617 (1.2); 7.597 (2.0); 7.576 (2.0); 7.471 (2.3); 7.439 (1.4); 7.419 (1.1); 7.312 (1.3); 7.294 (1.2); 4.207 (0.5); 4.191 (0.5); 4.170 (1.1); 4.155 (1.1); 4.134 (0.6); 4.118 (0.5); 3.983 (11.6); 3.331 (70.9); 3.314 (0.4); 2.671 (0.5); 2.524 (1.0); 2.506 (54.3); 2.502 (70.8); 2.498 (52.9); 2.329 (0.5); 2.325 (0.4); 0.146 (0.4); 0.007 (3.1); 0.000 (79.9); −0.008 (4.0); −0.019 (0.4); −0.150 (0.4) Example 57: 1H-NMR (400.0 MHz, d6-DMSO): δ = 8.907 (2.3); 8.891 (5.0); 8.876 (2.4); 7.887 (9.9); 7.858 (7.1); 7.836 (10.2); 7.830 (3.5); 7.822 (8.5); 7.813 (9.1); 7.805 (3.5); 7.800 (8.3); 7.792 (3.4); 7.788 (2.6); 7.771 (7.5); 7.767 (7.7); 7.751 (12.9); 7.730 (4.4); 7.438 (3.0); 7.436 (3.2); 7.420 (6.5); 7.417 (7.0); 7.401 (4.1); 7.398 (4.2); 7.357 (8.3); 7.352 (2.8); 7.335 (16.0); 7.318 (2.6); 7.313 (7.7); 7.185 (4.8); 7.181 (7.6); 7.172 (5.0); 7.166 (5.6); 7.162 (6.5); 7.153 (6.9); 7.149 (5.1); 7.134 (3.3); 7.130 (2.8); 4.242 (2.2); 4.227 (2.2); 4.206 (4.9); 4.191 (4.7); 4.171 (2.5); 4.155 (2.3); 3.669 (0.3); 3.659 (0.4); 3.648 (0.4); 3.640 (0.4); 3.591 (0.4); 3.570 (0.3); 3.545 (0.7); 3.508 (0.7); 3.494 (0.4); 3.483 (0.4); 3.468 (1.0); 3.459 (1.1); 3.447 (1.0); 3.439 (0.9); 3.417 (3.2); 3.401 (3.3); 3.397 (4.1); 3.390 (4.1); 3.384 (5.8); 3.379 (5.6); 3.347 (2869.6); 3.314 (7.4); 3.308 (4.4); 3.302 (3.9); 3.287 (1.9); 3.260 (1.3); 3.239 (1.0); 3.231 (0.8); 3.214 (1.2); 3.195 (0.8); 3.163 (0.7); 3.133 (0.4); 3.115 (0.4); 3.088 (0.4); 2.996 (0.7); 2.676 (4.4); 2.672 (6.3); 2.667 (4.7); 2.618 (0.4); 2.603 (0.4); 2.562 (1.2); 2.542 (32.5); 2.535 (3.3); 2.525 (15.1); 2.520 (22.9); 2.512 (358.4); 2.507 (751.2); 2.503 (1001.1); 2.498 (734.3); 2.494 (359.9); 2.468 (2.8); 2.463 (1.8); 2.452 (0.6); 2.447 (0.5); 2.442 (0.4); 2.417 (0.5); 2.405 (0.4); 2.370 (0.6); 2.334 (4.5); 2.330 (6.3); 2.325 (4.9); 2.291 (0.7); 1.434 (0.3); 1.258 (0.5); 1.234 (1.0); 0.146 (0.4); 0.008 (2.5); 0.000 (83.7); −0.009 (3.0); −0.150 (0.4) Example 58: 1H-NMR (400.0 MHz, d6-DMSO): δ = 9.235 (0.3); 8.955 (2.1); 8.940 (4.0); 8.924 (1.9); 7.892 (7.9); 7.889 (7.3); 7.834 (6.5); 7.828 (3.4); 7.820 (7.5); 7.816 (5.0); 7.812 (7.3); 7.803 (3.9); 7.798 (6.6); 7.789 (3.6); 7.785 (2.7); 7.769 (6.2); 7.765 (5.5); 7.735 (9.1); 7.714 (4.2); 7.685 (0.7); 7.664 (0.5); 7.625 (5.2); 7.622 (4.7); 7.605 (6.0); 7.602 (5.2); 7.501 (0.4); 7.428 (2.0); 7.425 (1.9); 7.410 (5.4); 7.407 (4.8); 7.391 (4.3); 7.388 (3.5); 7.360 (10.6); 7.355 (6.2); 7.338 (16.0); 7.321 (5.3); 7.316 (7.8); 7.308 (0.7); 7.251 (5.6); 7.246 (4.7); 7.232 (4.6); 7.228 (3.6); 7.158 (0.6); 7.139 (0.8); 7.118 (0.5); 4.254 (1.9); 4.239 (2.2); 4.219 (4.2); 4.203 (4.0); 4.183 (2.1); 4.167 (1.9); 3.382 (0.4); 3.340 (59.3); 3.335 (169.8); 3.311 (0.6); 2.676 (0.8); 2.671 (0.9); 2.667 (0.7); 2.546 (7.4); 2.542 (29.9); 2.511 (66.8); 2.507 (115.2); 2.503 (133.7); 2.498 (91.0); 2.494 (40.8); 2.334 (0.6); 2.329 (0.8); 2.325 (0.5); 0.004 (3.2); 0.000 (13.0); −0.008 (0.5) Example 59: 1H-NMR (400.0 MHz, d6-DMSO): δ = 8.967 (2.4); 8.952 (4.9); 8.936 (2.3); 7.893 (8.9); 7.890 (9.4); 7.843 (1.1); 7.835 (7.2); 7.830 (3.6); 7.821 (8.4); 7.813 (8.7); 7.804 (3.8); 7.799 (7.8); 7.786 (3.8); 7.783 (3.5); 7.766 (6.6); 7.762 (6.5); 7.721 (11.1); 7.700 (6.0); 7.686 (0.6); 7.665 (0.3); 7.470 (2.3); 7.466 (3.2); 7.450 (8.3); 7.446 (9.5); 7.443 (6.1); 7.439 (4.8); 7.426 (6.1); 7.421 (6.0); 7.406 (2.7); 7.401 (2.8); 7.393 (0.5); 7.385 (3.7); 7.380 (3.4); 7.366 (7.0); 7.361 (12.9); 7.348 (4.6); 7.344 (6.7); 7.339 (16.0); 7.322 (3.0); 7.317 (7.7); 7.309 (1.0); 7.287 (6.7); 7.284 (6.4); 7.269 (4.9); 7.265 (4.3); 7.159 (0.4); 7.139 (0.5); 7.119 (0.3); 4.259 (2.3); 4.243 (2.5); 4.223 (5.1); 4.208 (4.9); 4.188 (2.6); 4.172 (2.4); 3.364 (0.6); 3.338 (178.2); 3.315 (0.6); 3.309 (0.4); 3.298 (0.5); 2.998 (0.7); 2.676 (0.5); 2.672 (0.7); 2.667 (0.5); 2.542 (17.1); 2.525 (2.0); 2.512 (41.9); 2.507 (84.7); 2.503 (110.1); 2.498 (80.4); 2.494 (39.4); 2.468 (0.6); 2.463 (0.5); 2.458 (0.5); 2.454 (0.4); 2.334 (0.5); 2.330 (0.7); 2.325 (0.5); 0.008 (0.3); 0.000 (9.7); −0.009 (0.4) Example 60: 1H-NMR (400.0 MHz, d6-DMSO): δ = 9.250 (2.4); 9.235 (5.1); 9.219 (2.4); 7.902 (9.0); 7.899 (9.7); 7.853 (0.8); 7.845 (7.4); 7.840 (3.4); 7.831 (8.3); 7.823 (9.0); 7.814 (3.5); 7.809 (8.1); 7.801 (1.0); 7.786 (4.0); 7.783 (3.8); 7.766 (5.9); 7.762 (5.8); 7.684 (10.0); 7.664 (6.9); 7.538 (1.2); 7.521 (2.7); 7.517 (2.5); 7.500 (4.9); 7.484 (2.5); 7.479 (3.0); 7.463 (1.3); 7.369 (0.9); 7.361 (8.4); 7.356 (2.9); 7.339 (16.0); 7.322 (2.5); 7.317 (7.8); 7.165 (1.5); 7.158 (8.5); 7.139 (11.5); 7.118 (7.1); 7.111 (1.4); 4.276 (2.2); 4.261 (2.3); 4.241 (5.1); 4.225 (5.0); 4.205 (2.6); 4.189 (2.4); 3.375 (0.5); 3.358 (0.9); 3.335 (369.1); 3.301 (0.4); 2.676 (1.1); 2.671 (1.6); 2.667 (1.2); 2.542 (3.7); 2.525 (3.7); 2.520 (5.8); 2.511 (88.9); 2.507 (186.5); 2.502 (248.6); 2.498 (182.7); 2.493 (89.9); 2.334 (1.1); 2.329 (1.6); 2.325 (1.2); 1.234 (0.4); 0.008 (0.8); 0.000 (27.3); −0.009 (1.0) Example 61: 1H-NMR (400.0 MHz, d6-DMSO): δ = 9.345 (3.0); 9.329 (6.3); 9.314 (3.1); 9.025 (9.7); 9.019 (12.0); 8.967 (11.6); 8.961 (10.4); 7.913 (12.7); 7.840 (7.7); 7.826 (9.0); 7.819 (10.2); 7.805 (8.8); 7.785 (4.8); 7.764 (7.9); 7.710 (12.2); 7.689 (7.3); 7.365 (8.3); 7.343 (16.0); 7.322 (8.0); 4.324 (2.9); 4.308 (3.0); 4.286 (6.5); 4.271 (6.4); 4.249 (3.4); 4.234 (3.1); 3.375 (0.3); 3.340 (272.1); 3.309 (0.6); 2.673 (1.1); 2.543 (14.2); 2.504 (169.7); 2.331 (1.1); 0.000 (13.0) Example 62: 1H-NMR (400.0 MHz, d6-DMSO): δ = 9.165 (2.5); 9.149 (5.3); 9.133 (2.5); 8.865 (5.6); 8.855 (5.6); 8.853 (5.6); 8.302 (5.2); 8.300 (5.4); 8.282 (5.6); 8.280 (5.6); 7.902 (8.9); 7.899 (9.9); 7.841 (0.9); 7.834 (7.5); 7.828 (3.7); 7.820 (8.4); 7.811 (9.3); 7.803 (3.7); 7.798 (8.2); 7.790 (1.2); 7.771 (3.7); 7.767 (3.8); 7.756 (4.8); 7.751 (7.2); 7.746 (9.6); 7.737 (4.2); 7.724 (3.5); 7.696 (11.1); 7.675 (6.5); 7.368 (0.9); 7.361 (8.4); 7.356 (3.2); 7.339 (16.0); 7.322 (2.6); 7.316 (7.8); 4.284 (2.3); 4.268 (2.4); 4.247 (5.3); 4.231 (5.1); 4.210 (2.7); 4.195 (2.5); 3.362 (0.6); 3.358 (0.6); 3.355 (0.7); 3.336 (169.6); 3.321 (0.9); 3.316 (0.3); 2.677 (0.6); 2.672 (0.8); 2.668 (0.6); 2.543 (6.7); 2.526 (2.3); 2.521 (3.6); 2.512 (45.0); 2.508 (94.4); 2.503 (126.4); 2.499 (93.6); 2.494 (46.7); 2.467 (0.3); 2.451 (0.3); 2.447 (0.3); 2.335 (0.6); 2.330 (0.8); 2.326 (0.6); 0.008 (0.5); 0.000 (16.2); −0.008 (0.8) Example 63: 1H-NMR (400.0 MHz, d6-DMSO): δ = 9.143 (2.6); 9.128 (5.4); 9.112 (2.6); 8.464 (6.6); 8.459 (7.2); 8.452 (7.1); 8.447 (7.2); 7.899 (10.4); 7.846 (0.8); 7.838 (7.4); 7.833 (3.7); 7.825 (8.5); 7.816 (9.2); 7.808 (3.8); 7.803 (8.5); 7.793 (4.0); 7.789 (3.7); 7.772 (6.9); 7.768 (7.2); 7.761 (7.1); 7.756 (7.0); 7.742 (8.0); 7.737 (8.1); 7.730 (12.3); 7.709 (6.3); 7.696 (0.4); 7.491 (7.2); 7.479 (6.9); 7.472 (6.5); 7.460 (6.3); 7.372 (0.9); 7.364 (8.4); 7.342 (16.0); 7.325 (2.7); 7.320 (7.8); 4.280 (2.3); 4.265 (2.4); 4.244 (5.4); 4.229 (5.3); 4.209 (2.8); 4.193 (2.6); 3.338 (175.5); 3.316 (0.9); 3.304 (0.4); 2.998 (0.3); 2.677 (0.5); 2.673 (0.7); 2.668 (0.6); 2.543 (35.2); 2.526 (1.4); 2.512 (41.7); 2.508 (87.5); 2.503 (116.4); 2.499 (86.5); 2.495 (43.5); 2.465 (0.4); 2.335 (0.5); 2.330 (0.7); 2.326 (0.6); 0.008 (0.3); 0.000 (11.5) Example 64: 1H-NMR (400.0 MHz, d6-DMSO): δ = 9.093 (2.6); 9.078 (5.5); 9.062 (2.6); 8.371 (6.3); 8.366 (7.2); 8.359 (6.9); 8.354 (7.0); 7.896 (10.9); 7.845 (0.9); 7.838 (7.4); 7.832 (3.9); 7.824 (8.5); 7.815 (9.3); 7.807 (3.9); 7.802 (8.5); 7.796 (3.4); 7.775 (8.5); 7.771 (9.5); 7.761 (14.4); 7.740 (3.6); 7.511 (3.7); 7.505 (4.4); 7.492 (9.5); 7.487 (9.2); 7.468 (9.0); 7.457 (8.4); 7.449 (4.1); 7.438 (4.1); 7.367 (0.9); 7.359 (8.4); 7.355 (3.3); 7.337 (16.0); 7.315 (7.9); 4.261 (2.4); 4.245 (2.5); 4.225 (5.3); 4.210 (5.1); 4.189 (2.7); 4.174 (2.5); 3.370 (0.5); 3.336 (247.6); 3.312 (0.9); 2.997 (1.1); 2.712 (0.9); 2.676 (0.8); 2.672 (1.1); 2.667 (0.8); 2.576 (0.5); 2.562 (0.7); 2.557 (1.1); 2.542 (225.5); 2.525 (2.7); 2.511 (59.6); 2.507 (122.6); 2.503 (162.8); 2.498 (121.1); 2.494 (60.6); 2.368 (1.0); 2.334 (0.7); 2.330 (1.0); 2.325 (0.8); 1.234 (0.4); 0.008 (0.5); 0.000 (14.6) Example 65: 1H-NMR (400.0 MHz, d6-DMSO): δ = 9.033 (2.2); 9.017 (4.7); 9.002 (2.2); 8.314 (0.5); 7.964 (8.2); 7.961 (8.9); 7.847 (3.6); 7.843 (3.5); 7.826 (5.4); 7.822 (5.4); 7.767 (4.6); 7.748 (15.5); 7.728 (7.7); 7.706 (5.1); 7.688 (3.8); 7.654 (7.7); 7.635 (10.1); 7.617 (1.8); 7.577 (6.0); 7.570 (5.8); 7.565 (8.5); 7.558 (16.0); 7.537 (4.5); 7.389 (5.4); 7.373 (14.7); 7.261 (4.0); 7.256 (3.7); 7.241 (3.5); 7.236 (3.4); 7.188 (5.8); 4.262 (2.0); 4.247 (2.1); 4.227 (4.6); 4.211 (4.5); 4.190 (2.4); 4.175 (2.2); 4.038 (0.5); 4.021 (0.5); 3.318 (83.4); 2.680 (0.4); 2.675 (0.9); 2.671 (1.3); 2.666 (1.0); 2.662 (0.5); 2.524 (3.4); 2.519 (5.4); 2.511 (70.0); 2.506 (142.2); 2.502 (188.1); 2.497 (139.5); 2.493 (69.6); 2.337 (0.4); 2.333 (0.9); 2.328 (1.2); 2.324 (0.9); 1.988 (1.9); 1.398 (8.1); 1.193 (0.5); 1.175 (1.1); 1.158 (0.5); 0.146 (0.6); 0.008 (5.3); 0.000 (153.4); −0.008 (6.2); −0.150 (0.7) Example 66: 1H-NMR (400.0 MHz, d6-DMSO): δ = 9.037 (2.8); 9.022 (6.1); 9.006 (2.9); 8.314 (1.7); 8.053 (10.2); 8.050 (10.9); 7.911 (4.8); 7.907 (4.7); 7.891 (6.2); 7.886 (6.1); 7.857 (1.6); 7.850 (3.0); 7.842 (14.8); 7.819 (14.3); 7.812 (3.3); 7.804 (1.4); 7.768 (5.7); 7.746 (16.0); 7.725 (11.1); 7.707 (6.4); 7.689 (4.7); 7.656 (4.9); 7.637 (5.8); 7.619 (2.1); 7.482 (4.5); 7.382 (6.7); 7.363 (6.0); 7.302 (9.6); 7.121 (4.9); 4.260 (2.4); 4.245 (2.5); 4.224 (5.5); 4.209 (5.4); 4.188 (2.9); 4.173 (2.7); 3.354 (0.5); 3.321 (428.2); 3.301 (1.0); 3.297 (1.0); 2.680 (0.6); 2.675 (1.4); 2.671 (1.9); 2.666 (1.4); 2.662 (0.7); 2.524 (5.1); 2.520 (7.7); 2.511 (106.7); 2.506 (220.7); 2.502 (295.1); 2.497 (218.1); 2.493 (107.7); 2.338 (0.7); 2.333 (1.4); 2.329 (2.0); 2.324 (1.5); 2.319 (0.7); 1.988 (0.5); 1.398 (5.7); 0.146 (1.0); 0.008 (7.7); 0.000 (245.5); −0.008 (9.8); −0.020 (0.3); −0.150 (1.0) Example 67: 1H-NMR (400.0 MHz, d6-DMSO): δ = 9.041 (2.2); 9.026 (4.6); 9.010 (2.2); 8.091 (10.3); 8.076 (5.0); 8.045 (8.1); 8.041 (8.5); 7.907 (3.8); 7.903 (3.6); 7.887 (5.1); 7.883 (5.0); 7.819 (3.1); 7.799 (5.7); 7.766 (16.0); 7.746 (15.5); 7.725 (3.8); 7.708 (5.1); 7.690 (3.8); 7.656 (3.8); 7.637 (4.6); 7.618 (1.7); 7.398 (5.3); 7.379 (4.7); 5.755 (2.0); 4.272 (1.9); 4.256 (2.1); 4.236 (4.5); 4.220 (4.4); 4.200 (2.3); 4.184 (2.2); 3.322 (51.7); 2.677 (0.4); 2.672 (0.6); 2.668 (0.4); 2.526 (1.5); 2.512 (33.3); 2.508 (66.4); 2.503 (86.6); 2.499 (64.0); 2.494 (31.8); 2.334 (0.4); 2.330 (0.6); 2.325 (0.4); 1.397 (0.4); 1.259 (0.5); 1.250 (0.4); 1.233 (0.8); 0.146 (0.3); 0.008 (2.8); 0.000 (75.8); −0.009 (3.0); −0.150 (0.3) Example 68: 1H-NMR (400.0 MHz, d6-DMSO): δ = 9.027 (2.7); 9.012 (5.7); 8.996 (2.8); 8.974 (0.4); 8.313 (1.2); 7.901 (10.9); 7.844 (14.5); 7.822 (16.0); 7.804 (4.1); 7.801 (3.9); 7.784 (6.8); 7.780 (6.8); 7.766 (5.7); 7.747 (7.8); 7.731 (11.2); 7.710 (8.1); 7.687 (4.6); 7.654 (4.8); 7.635 (5.7); 7.616 (2.1); 7.586 (0.7); 7.564 (0.5); 7.513 (5.3); 7.385 (6.4); 7.366 (5.9); 7.344 (0.5); 7.329 (11.2); 7.309 (14.2); 7.287 (13.3); 7.144 (5.5); 6.548 (0.3); 4.257 (2.3); 4.241 (2.5); 4.220 (5.3); 4.205 (5.2); 4.185 (2.8); 4.169 (2.6); 3.383 (0.4); 3.319 (580.0); 3.295 (1.4); 3.276 (0.6); 3.270 (0.5); 2.675 (2.4); 2.671 (3.2); 2.666 (2.4); 2.566 (0.5); 2.506 (378.5); 2.501 (484.5); 2.497 (362.7); 2.333 (2.4); 2.328 (3.2); 2.324 (2.4); 1.988 (0.4); 1.398 (5.8); 1.236 (0.4); 0.146 (1.7); 0.000 (350.4); −0.150 (1.7) Example 69: 1H-NMR (400.0 MHz, d6-DMSO): δ = 9.016 (0.6); 7.970 (1.1); 7.966 (1.2); 7.850 (1.7); 7.832 (0.7); 7.828 (0.7); 7.767 (0.6); 7.747 (1.6); 7.739 (1.4); 7.735 (0.8); 7.730 (1.0); 7.725 (0.8); 7.718 (1.0); 7.707 (0.8); 7.689 (0.5); 7.654 (0.5); 7.636 (0.7); 7.553 (0.3); 7.533 (1.0); 7.516 (1.4); 7.515 (1.4); 7.513 (1.6); 7.508 (0.8); 7.387 (0.7); 7.368 (0.7); 4.224 (0.6); 4.208 (0.6); 4.187 (0.3); 4.172 (0.3); 3.316 (20.9); 2.524 (1.0); 2.510 (17.2); 2.506 (33.7); 2.501 (43.8); 2.497 (32.2); 2.492 (16.1); 1.988 (0.4); 1.398 (16.0); 0.008 (1.5); 0.000 (36.9); −0.009 (1.6) Example 70: 1H-NMR (400.0 MHz, d6-DMSO): δ = 9.030 (1.3); 9.014 (2.8); 8.999 (1.3); 8.313 (0.3); 8.087 (5.7); 8.082 (5.8); 8.013 (4.8); 8.009 (5.1); 7.875 (2.2); 7.872 (2.1); 7.855 (3.0); 7.851 (3.0); 7.801 (1.5); 7.796 (1.3); 7.780 (4.9); 7.775 (5.4); 7.763 (10.0); 7.741 (7.4); 7.720 (4.4); 7.706 (3.0); 7.687 (2.2); 7.655 (2.2); 7.636 (2.7); 7.617 (1.0); 7.386 (3.1); 7.367 (2.8); 4.257 (1.2); 4.241 (1.2); 4.221 (2.6); 4.205 (2.6); 4.184 (1.4); 4.169 (1.3); 3.316 (43.9); 2.675 (0.6); 2.671 (0.8); 2.666 (0.6); 2.541 (6.6); 2.524 (2.1); 2.510 (46.9); 2.506 (93.1); 2.501 (123.5); 2.497 (93.5); 2.493 (48.1); 2.333 (0.6); 2.328 (0.8); 2.324 (0.6); 2.073 (16.0); 0.008 (1.2); 0.000 (33.7); −0.008 (1.5) Example 71: 1H-NMR (400.0 MHz, d6-DMSO): δ = 9.032 (3.6); 9.017 (7.4); 9.001 (3.8); 8.974 (0.8); 8.960 (0.4); 8.314 (0.8); 7.933 (14.5); 7.893 (13.9); 7.890 (16.0); 7.814 (5.7); 7.794 (9.1); 7.767 (8.4); 7.747 (10.8); 7.730 (13.5); 7.708 (14.0); 7.687 (6.5); 7.655 (6.9); 7.637 (14.2); 7.620 (10.8); 7.616 (12.7); 7.585 (1.4); 7.564 (1.1); 7.543 (14.2); 7.522 (9.5); 7.508 (1.5); 7.384 (8.4); 7.366 (8.4); 7.347 (1.0); 4.255 (3.2); 4.240 (3.5); 4.220 (7.1); 4.204 (7.2); 4.183 (4.0); 4.168 (3.9); 4.138 (0.6); 4.124 (0.4); 4.039 (0.7); 4.021 (0.7); 3.378 (0.4); 3.320 (273.0); 2.671 (2.4); 2.506 (261.0); 2.502 (349.7); 2.498 (299.8); 2.329 (2.2); 1.989 (2.6); 1.398 (4.6); 1.298 (0.6); 1.259 (0.9); 1.232 (2.1); 1.193 (0.9); 1.176 (1.6); 1.158 (0.9); 0.868 (0.4); 0.852 (0.4); 0.000 (25.4) Example 72: 1H-NMR (400.0 MHz, d6-DMSO): δ = 9.124 (2.6); 9.108 (5.5); 9.093 (2.6); 8.410 (9.3); 8.406 (9.5); 8.314 (0.5); 8.193 (4.4); 8.189 (4.3); 8.172 (5.0); 8.168 (5.1); 7.965 (14.2); 7.943 (16.0); 7.881 (8.4); 7.860 (7.5); 7.761 (5.1); 7.741 (7.3); 7.727 (2.4); 7.709 (5.9); 7.690 (4.3); 7.656 (4.4); 7.637 (5.3); 7.618 (1.9); 7.528 (10.6); 7.507 (9.7); 7.416 (6.2); 7.398 (5.5); 4.255 (2.2); 4.239 (2.4); 4.220 (5.0); 4.205 (4.9); 4.186 (2.6); 4.170 (2.4); 3.318 (86.7); 2.675 (0.9); 2.671 (1.2); 2.667 (0.9); 2.506 (137.7); 2.502 (180.6); 2.498 (136.6); 2.333 (0.9); 2.329 (1.2); 2.324 (0.9); 1.989 (0.5); 1.398 (0.5); 0.008 (0.6); 0.000 (16.3) Example 73: 1H-NMR (400.0 MHz, d6-DMSO): δ = 9.128 (1.7); 9.112 (3.6); 9.096 (1.7); 8.491 (5.9); 8.487 (6.2); 8.259 (2.8); 8.255 (2.8); 8.239 (3.2); 8.234 (3.3); 8.053 (5.2); 8.048 (2.5); 8.037 (3.5); 8.031 (16.0); 8.010 (15.9); 8.005 (3.9); 7.993 (2.3); 7.988 (5.3); 7.909 (5.8); 7.888 (5.2); 7.760 (3.3); 7.740 (4.6); 7.726 (1.5); 7.709 (3.7); 7.690 (2.8); 7.656 (2.8); 7.637 (3.4); 7.618 (1.2); 7.419 (4.0); 7.400 (3.6); 4.259 (1.4); 4.243 (1.5); 4.224 (3.3); 4.209 (3.2); 4.190 (1.7); 4.174 (1.6); 4.039 (0.5); 4.021 (0.5); 3.320 (63.0); 2.676 (0.5); 2.671 (0.7); 2.667 (0.5); 2.525 (1.5); 2.520 (2.2); 2.511 (34.4); 2.507 (72.0); 2.502 (96.7); 2.498 (71.7); 2.493 (35.8); 2.334 (0.4); 2.329 (0.6); 2.324 (0.5); 1.989 (2.3); 1.398 (2.2); 1.193 (0.6); 1.176 (1.3); 1.158 (0.6); 0.000 (11.1); −0.008 (0.4) Example 74: 1H-NMR (400.0 MHz, d6-DMSO): δ = 9.118 (3.3); 9.103 (6.5); 9.087 (3.3); 8.367 (12.0); 8.314 (0.7); 8.159 (5.7); 8.138 (6.5); 7.898 (8.5); 7.884 (10.4); 7.876 (10.4); 7.862 (10.3); 7.855 (10.8); 7.834 (8.3); 7.761 (6.3); 7.742 (8.8); 7.728 (3.2); 7.709 (7.3); 7.691 (5.4); 7.656 (5.4); 7.637 (6.5); 7.618 (2.4); 7.416 (7.8); 7.397 (7.2); 7.382 (8.9); 7.360 (16.0); 7.338 (7.6); 4.247 (3.0); 4.231 (3.3); 4.213 (6.5); 4.197 (6.3); 4.178 (3.5); 4.163 (3.1); 3.320 (164.5); 2.671 (1.4); 2.502 (211.0); 2.329 (1.4); 1.988 (0.6); 1.398 (0.7); 1.249 (0.4); 1.235 (1.0); 1.175 (0.4); 1.133 (0.3); 0.000 (16.1) Example 75: 1H-NMR (400.0 MHz, d6-DMSO): δ = 9.014 (1.9); 8.999 (4.0); 8.983 (1.9); 8.313 (0.4); 7.813 (7.2); 7.766 (3.6); 7.745 (6.3); 7.722 (6.0); 7.719 (5.6); 7.703 (4.1); 7.685 (3.2); 7.667 (16.0); 7.645 (13.2); 7.634 (4.4); 7.614 (1.4); 7.383 (4.3); 7.365 (3.9); 7.053 (9.1); 7.030 (8.7); 4.239 (1.5); 4.223 (1.6); 4.203 (3.5); 4.187 (3.4); 4.167 (1.8); 4.151 (1.6); 3.924 (1.4); 3.764 (9.8); 3.752 (12.9); 3.740 (10.6); 3.320 (126.5); 3.292 (0.3); 3.202 (10.3); 3.190 (12.6); 3.178 (9.3); 2.675 (0.6); 2.670 (0.8); 2.666 (0.6); 2.510 (50.9); 2.506 (98.4); 2.501 (127.5); 2.497 (94.5); 2.493 (47.8); 2.333 (0.6); 2.328 (0.8); 2.324 (0.6); 1.988 (0.4); 1.070 (8.7); 0.146 (0.6); 0.008 (6.6); 0.000 (134.5); −0.009 (6.4); −0.150 (0.6) Example 76: 1H-NMR (400.0 MHz, d6-DMSO): δ = 9.070 (1.7); 9.055 (3.8); 9.039 (1.8); 7.857 (1.1); 7.849 (10.6); 7.844 (3.8); 7.833 (3.7); 7.827 (12.3); 7.820 (1.5); 7.783 (3.6); 7.763 (4.8); 7.736 (1.5); 7.718 (4.0); 7.700 (2.9); 7.664 (3.4); 7.663 (3.4); 7.654 (7.0); 7.647 (6.7); 7.625 (5.7); 7.598 (7.8); 7.577 (3.4); 7.483 (7.3); 7.463 (6.6); 7.388 (4.2); 7.370 (3.8); 4.111 (1.5); 4.095 (1.5); 4.073 (3.5); 4.057 (3.4); 4.035 (1.7); 4.019 (1.6); 3.320 (29.5); 2.672 (0.4); 2.567 (16.0); 2.542 (38.2); 2.525 (0.9); 2.520 (1.0); 2.511 (16.6); 2.507 (35.2); 2.502 (48.4); 2.498 (37.0); 2.493 (19.0); 2.329 (0.3); 0.146 (0.4); 0.008 (3.0); 0.000 (89.3); −0.009 (4.1); −0.017 (0.5); −0.150 (0.4) Example 77: 1H-NMR (400.0 MHz, d6-DMSO): δ = 8.879 (0.8); 8.863 (1.7); 8.847 (0.8); 7.889 (0.5); 7.882 (4.3); 7.877 (1.6); 7.865 (1.6); 7.860 (5.1); 7.853 (0.6); 7.752 (1.5); 7.733 (2.1); 7.701 (0.7); 7.683 (1.7); 7.664 (1.3); 7.636 (1.3); 7.617 (1.6); 7.598 (0.6); 7.570 (2.3); 7.550 (2.8); 7.491 (3.2); 7.471 (2.9); 7.407 (3.1); 7.363 (1.8); 7.361 (1.7); 7.343 (1.5); 7.340 (1.5); 7.314 (1.8); 7.296 (1.7); 4.207 (0.7); 4.191 (0.7); 4.170 (1.5); 4.154 (1.5); 4.133 (0.8); 4.118 (0.7); 3.971 (16.0); 3.317 (30.1); 2.541 (17.1); 2.524 (0.6); 2.506 (27.7); 2.501 (37.4); 2.497 (28.7); 0.008 (2.3); 0.000 (54.9); −0.008 (2.5); −0.016 (0.4) Example 78: 1H-NMR (400.0 MHz, d6-DMSO): δ = 9.003 (1.9); 8.987 (4.0); 8.972 (2.0); 8.313 (1.3); 7.764 (9.2); 7.746 (5.1); 7.720 (1.7); 7.702 (6.5); 7.682 (7.0); 7.651 (3.2); 7.631 (11.4); 7.621 (9.9); 7.611 (6.6); 7.599 (10.1); 7.573 (0.4); 7.554 (0.5); 7.509 (0.4); 7.487 (0.4); 7.470 (0.3); 7.449 (0.3); 7.382 (4.3); 7.364 (3.9); 6.636 (8.9); 6.614 (8.8); 6.479 (0.3); 4.227 (1.6); 4.212 (1.7); 4.192 (3.5); 4.176 (3.4); 4.156 (1.8); 4.140 (1.7); 3.353 (0.3); 3.314 (176.9); 3.299 (7.7); 3.283 (15.6); 3.266 (6.6); 3.237 (0.8); 3.220 (0.3); 2.674 (2.6); 2.670 (3.5); 2.666 (2.8); 2.589 (0.4); 2.523 (10.0); 2.505 (391.6); 2.501 (525.8); 2.497 (408.0); 2.426 (0.4); 2.332 (2.6); 2.328 (3.5); 2.324 (2.7); 2.073 (1.3); 1.989 (6.1); 1.973 (16.0); 1.957 (6.3); 1.932 (0.5); 1.251 (4.2); 1.236 (0.7); 0.146 (3.3); 0.039 (0.7); 0.028 (0.8); 0.008 (28.7); 0.000 (665.3); −0.008 (38.3); −0.032 (1.4); −0.041 (0.4); −0.150 (3.4) Example 79: 1H-NMR (400.0 MHz, d6-DMSO): δ = 9.123 (2.9); 9.108 (6.2); 9.092 (2.9); 8.445 (10.7); 8.440 (11.0); 8.313 (2.6); 8.221 (5.1); 8.217 (5.0); 8.201 (5.8); 8.196 (5.8); 8.022 (10.9); 8.006 (5.1); 7.996 (3.5); 7.993 (3.9); 7.892 (10.4); 7.871 (9.3); 7.760 (5.9); 7.741 (8.2); 7.727 (2.7); 7.708 (7.4); 7.687 (14.4); 7.674 (16.0); 7.672 (15.9); 7.655 (5.3); 7.636 (6.1); 7.617 (2.2); 7.421 (7.1); 7.402 (6.3); 7.240 (5.5); 7.101 (12.2); 6.961 (5.9); 4.257 (2.6); 4.242 (2.7); 4.223 (5.8); 4.207 (5.7); 4.188 (3.0); 4.172 (2.8); 4.038 (0.3); 4.020 (0.3); 3.315 (112.0); 3.291 (0.9); 2.675 (1.7); 2.670 (2.3); 2.666 (1.7); 2.662 (0.9); 2.524 (5.8); 2.519 (9.0); 2.510 (118.7); 2.506 (241.3); 2.501 (323.9); 2.497 (241.0); 2.492 (119.1); 2.333 (1.6); 2.328 (2.2); 2.324 (1.6); 1.988 (1.3); 1.398 (2.2); 1.193 (0.4); 1.175 (0.7); 1.158 (0.4); 0.146 (1.1); 0.008 (7.9); 0.000 (236.0); −0.008 (8.6); −0.150 (1.0) Example 80: 1H-NMR (400.0 MHz, d6-DMSO): δ = 9.070 (1.8); 9.055 (3.7); 9.039 (1.8); 7.871 (7.0); 7.851 (8.8); 7.783 (3.6); 7.764 (4.8); 7.736 (1.6); 7.718 (4.2); 7.690 (11.7); 7.671 (8.6); 7.655 (4.6); 7.650 (5.1); 7.627 (1.5); 7.610 (7.2); 7.589 (4.0); 7.389 (4.2); 7.370 (3.8); 7.236 (2.7); 7.096 (6.5); 6.956 (3.1); 5.753 (1.9); 4.113 (1.5); 4.097 (1.6); 4.075 (3.5); 4.059 (3.4); 4.036 (1.8); 4.021 (1.7); 3.317 (28.7); 2.675 (0.4); 2.671 (0.5); 2.666 (0.4); 2.574 (16.0); 2.524 (1.4); 2.511 (27.9); 2.506 (55.8); 2.502 (74.3); 2.497 (54.9); 2.493 (27.0); 2.333 (0.4); 2.328 (0.5); 2.324 (0.3); 0.008 (1.7); 0.000 (48.5); −0.009 (1.8) Example 81: 1H-NMR (400.0 MHz, d6-DMSO): δ = 9.152 (2.0); 9.137 (4.3); 9.121 (2.0); 8.314 (0.4); 7.963 (8.3); 7.943 (9.9); 7.776 (4.2); 7.756 (6.3); 7.733 (4.9); 7.706 (16.0); 7.686 (8.4); 7.677 (8.9); 7.649 (4.4); 7.630 (1.6); 7.419 (5.0); 7.400 (4.5); 7.243 (3.0); 7.104 (7.2); 6.964 (3.4); 4.166 (1.7); 4.150 (1.9); 4.131 (3.9); 4.115 (3.8); 4.095 (2.0); 4.080 (1.9); 3.316 (49.4); 2.675 (0.6); 2.671 (0.9); 2.666 (0.7); 2.524 (2.4); 2.510 (51.1); 2.506 (101.7); 2.501 (135.3); 2.497 (101.6); 2.493 (51.6); 2.333 (0.7); 2.328 (0.9); 2.324 (0.7); 1.398 (2.6); 0.146 (0.5); 0.008 (3.5); 0.000 (97.9); −0.008 (4.1); −0.150 (0.5) Example 82: 1H-NMR (400.0 MHz, d6-DMSO): δ = 9.154 (1.9); 9.138 (4.0); 9.122 (2.0); 8.003 (8.4); 7.987 (3.3); 7.984 (3.0); 7.776 (4.0); 7.756 (6.0); 7.732 (4.8); 7.706 (8.3); 7.674 (16.0); 7.659 (6.6); 7.649 (4.8); 7.639 (1.4); 7.630 (1.8); 7.420 (4.7); 7.401 (4.2); 7.220 (3.4); 7.080 (7.2); 6.941 (3.5); 4.167 (1.7); 4.151 (1.9); 4.132 (3.8); 4.116 (3.7); 4.096 (2.1); 4.081 (1.9); 3.316 (39.2); 2.675 (0.7); 2.671 (0.9); 2.666 (0.7); 2.506 (98.4); 2.502 (128.8); 2.497 (98.3); 2.333 (0.6); 2.329 (0.8); 2.324 (0.6); 1.398 (4.1); 0.146 (0.4); 0.008 (4.2); 0.000 (90.6); −0.008 (5.3); −0.149 (0.4) Example 83: 1H-NMR (400.0 MHz, d6-DMSO): δ = 9.126 (2.2); 9.110 (4.8); 9.095 (2.3); 8.458 (7.8); 8.454 (8.2); 8.314 (0.5); 8.237 (3.7); 8.233 (3.7); 8.216 (4.2); 8.212 (4.3); 7.994 (11.2); 7.990 (4.6); 7.973 (16.0); 7.901 (7.4); 7.880 (7.2); 7.870 (13.3); 7.849 (9.6); 7.759 (4.3); 7.740 (6.0); 7.727 (2.0); 7.708 (4.9); 7.690 (3.7); 7.655 (3.7); 7.636 (4.5); 7.617 (1.6); 7.417 (5.2); 7.398 (4.7); 4.260 (1.9); 4.245 (2.0); 4.226 (4.2); 4.210 (4.2); 4.191 (2.2); 4.175 (2.0); 3.316 (59.6); 2.675 (0.8); 2.671 (1.1); 2.666 (0.8); 2.541 (1.3); 2.524 (2.9); 2.511 (57.2); 2.506 (115.6); 2.502 (155.0); 2.497 (117.3); 2.493 (59.7); 2.333 (0.7); 2.329 (1.0); 2.324 (0.8); 0.146 (0.4); 0.008 (3.5); 0.000 (97.0); −0.008 (4.0); −0.150 (0.4) Example 84: 1H-NMR (400.0 MHz, d6-DMSO): δ = 9.010 (1.8); 8.994 (3.2); 8.979 (1.6); 8.313 (0.6); 8.036 (0.6); 7.910 (0.5); 7.888 (0.5); 7.802 (5.7); 7.765 (3.9); 7.746 (4.9); 7.732 (2.7); 7.708 (4.8); 7.703 (4.8); 7.683 (3.2); 7.674 (2.3); 7.660 (5.9); 7.641 (9.4); 7.620 (7.8); 7.509 (0.5); 7.489 (0.5); 7.381 (3.9); 7.363 (3.5); 7.039 (6.2); 7.017 (5.9); 6.871 (0.6); 6.850 (0.5); 6.518 (0.4); 4.236 (1.5); 4.220 (1.7); 4.200 (3.0); 4.184 (2.9); 4.163 (1.6); 4.149 (1.4); 3.316 (113.3); 3.224 (9.0); 3.212 (7.1); 3.172 (1.0); 3.127 (0.4); 3.115 (0.4); 3.103 (0.3); 2.670 (2.0); 2.599 (0.3); 2.505 (232.8); 2.501 (299.7); 2.497 (234.2); 2.465 (10.8); 2.328 (2.1); 2.233 (16.0); 2.073 (2.1); 1.988 (0.4); 1.973 (0.6); 1.356 (0.6); 1.258 (3.2); 1.251 (1.8); 1.235 (1.4); 0.000 (58.8) Example 85: 1H-NMR (400.0 MHz, d6-DMSO): δ = 9.128 (2.5); 9.112 (5.3); 9.097 (2.6); 8.475 (8.9); 8.472 (9.2); 8.314 (0.7); 8.249 (4.3); 8.245 (4.3); 8.228 (4.9); 8.224 (4.9); 8.059 (9.4); 8.039 (12.2); 7.913 (8.4); 7.893 (16.0); 7.874 (10.0); 7.761 (4.9); 7.741 (6.9); 7.728 (2.4); 7.710 (5.7); 7.691 (4.2); 7.656 (4.2); 7.637 (5.1); 7.619 (1.9); 7.423 (6.0); 7.404 (5.3); 4.263 (2.2); 4.247 (2.4); 4.228 (4.9); 4.212 (4.8); 4.193 (2.6); 4.178 (2.4); 3.316 (95.4); 2.675 (1.2); 2.671 (1.7); 2.666 (1.3); 2.506 (193.5); 2.502 (253.5); 2.497 (192.3); 2.333 (1.3); 2.329 (1.7); 2.324 (1.3); 2.073 (1.1); 0.146 (0.3); 0.008 (3.0); 0.000 (72.7); −0.008 (3.4) Example 86: 1H-NMR (400.0 MHz, d6-DMSO): δ = 9.159 (3.1); 9.143 (6.5); 9.128 (3.1); 8.311 (0.8); 8.043 (12.0); 8.023 (15.5); 7.874 (16.0); 7.853 (12.8); 7.777 (6.5); 7.756 (11.3); 7.745 (13.6); 7.733 (8.6); 7.716 (16.0); 7.670 (5.3); 7.651 (6.7); 7.632 (2.5); 7.421 (7.6); 7.402 (6.9); 4.171 (2.7); 4.155 (3.0); 4.136 (6.2); 4.120 (6.0); 4.101 (3.3); 4.085 (3.0); 3.481 (0.4); 3.467 (0.4); 3.457 (0.4); 3.441 (0.5); 3.429 (0.6); 3.413 (0.8); 3.391 (1.8); 3.336 (1201.9); 3.267 (0.8); 3.249 (0.5); 3.238 (0.4); 3.221 (0.3); 2.677 (1.4); 2.672 (1.9); 2.668 (1.4); 2.663 (0.7); 2.559 (0.4); 2.525 (5.9); 2.512 (105.2); 2.508 (210.2); 2.503 (278.5); 2.499 (207.5); 2.494 (105.2); 2.334 (1.3); 2.330 (1.8); 2.325 (1.3); 2.073 (1.6); 0.146 (0.3); 0.008 (2.9); 0.000 (82.5); −0.009 (3.4); −0.150 (0.3) Example 87: 1H-NMR (400.0 MHz, d6-DMSO): δ = 8.884 (0.8); 8.868 (1.6); 8.852 (0.7); 7.986 (2.7); 7.966 (3.8); 7.856 (3.9); 7.835 (2.9); 7.752 (1.5); 7.733 (2.0); 7.701 (0.7); 7.683 (1.7); 7.665 (1.3); 7.636 (1.3); 7.617 (1.5); 7.600 (2.7); 7.580 (2.8); 7.461 (2.9); 7.423 (1.8); 7.420 (1.7); 7.403 (1.5); 7.400 (1.4); 7.317 (1.8); 7.298 (1.6); 4.214 (0.6); 4.198 (0.7); 4.178 (1.5); 4.162 (1.4); 4.141 (0.8); 4.125 (0.7); 3.985 (16.0); 3.317 (18.1); 2.524 (0.8); 2.510 (16.1); 2.506 (32.3); 2.502 (42.9); 2.497 (32.3); 2.493 (16.4); 0.008 (0.4); 0.000 (12.0); −0.009 (0.5) Example 88: 1H-NMR (400.0 MHz, d6-DMSO): δ = 9.077 (1.7); 9.062 (3.6); 9.046 (1.7); 8.023 (0.3); 7.955 (6.1); 7.934 (9.0); 7.873 (0.4); 7.850 (9.4); 7.829 (6.4); 7.784 (3.5); 7.764 (4.8); 7.737 (1.8); 7.718 (10.3); 7.701 (4.7); 7.685 (4.1); 7.667 (3.1); 7.647 (3.8); 7.629 (7.8); 7.609 (4.0); 7.391 (4.1); 7.373 (3.7); 4.119 (1.6); 4.103 (1.6); 4.080 (3.5); 4.065 (3.3); 4.042 (1.8); 4.027 (1.6); 3.322 (13.1); 2.891 (0.4); 2.733 (0.4); 2.676 (0.3); 2.672 (0.4); 2.582 (16.0); 2.525 (1.3); 2.507 (43.4); 2.503 (56.3); 2.498 (42.0); 2.329 (0.3); 0.000 (5.4) Example 89: 1H-NMR (400.0 MHz, d6-DMSO): δ = 9.123 (2.7); 9.107 (5.7); 9.091 (2.7); 8.867 (0.5); 8.433 (9.8); 8.430 (9.8); 8.313 (0.9); 8.219 (4.7); 8.216 (4.5); 8.199 (5.3); 8.195 (5.2); 7.976 (11.1); 7.956 (13.1); 7.894 (8.8); 7.873 (7.9); 7.856 (1.4); 7.836 (1.0); 7.781 (0.4); 7.761 (5.7); 7.741 (8.3); 7.729 (14.5); 7.709 (16.0); 7.691 (4.9); 7.656 (4.7); 7.637 (6.0); 7.618 (2.6); 7.600 (0.9); 7.580 (0.9); 7.461 (1.0); 7.420 (7.0); 7.401 (6.3); 7.317 (0.6); 7.298 (0.5); 7.253 (3.8); 7.113 (8.9); 6.974 (4.2); 4.257 (2.4); 4.242 (2.6); 4.223 (5.4); 4.207 (5.3); 4.188 (2.9); 4.173 (2.9); 3.985 (4.8); 3.892 (0.6); 3.316 (94.5); 2.675 (1.7); 2.671 (2.2); 2.666 (1.7); 2.580 (0.4); 2.506 (259.2); 2.501 (332.8); 2.497 (248.3); 2.333 (1.7); 2.328 (2.2); 2.324 (1.6); 2.073 (7.4); 0.008 (1.4); 0.000 (32.1) Example 90: 1H-NMR (400.0 MHz, d6-DMSO): δ = 9.073 (1.7); 9.057 (3.5); 9.042 (1.7); 7.898 (6.9); 7.784 (3.5); 7.764 (4.7); 7.736 (1.7); 7.718 (4.1); 7.699 (3.3); 7.684 (6.5); 7.666 (5.6); 7.646 (10.6); 7.626 (6.5); 7.618 (6.1); 7.611 (8.3); 7.599 (2.1); 7.591 (3.8); 7.391 (4.1); 7.372 (3.7); 7.244 (2.8); 7.105 (6.0); 6.965 (2.9); 4.113 (1.5); 4.098 (1.6); 4.075 (3.4); 4.060 (3.4); 4.037 (1.8); 4.022 (1.7); 3.985 (0.4); 3.319 (31.7); 2.671 (0.6); 2.577 (16.0); 2.506 (60.6); 2.502 (78.3); 2.497 (59.2); 2.332 (0.4); 2.328 (0.5); 2.324 (0.4); 2.074 (2.0); 0.000 (5.6) Example 91: 1H-NMR (400.0 MHz, d6-DMSO): δ = 8.879 (0.7); 8.863 (1.6); 8.847 (0.8); 8.313 (0.4); 7.903 (3.0); 7.882 (3.7); 7.752 (1.5); 7.733 (2.1); 7.698 (3.8); 7.679 (3.7); 7.664 (1.5); 7.635 (1.4); 7.617 (1.6); 7.598 (0.6); 7.581 (2.2); 7.561 (2.7); 7.432 (3.0); 7.397 (1.8); 7.377 (1.5); 7.373 (1.5); 7.315 (1.8); 7.296 (1.6); 7.241 (1.1); 7.101 (2.6); 6.961 (1.2); 4.209 (0.7); 4.193 (0.7); 4.172 (1.5); 4.157 (1.5); 4.136 (0.8); 4.120 (0.7); 3.978 (16.0); 3.315 (39.7); 2.675 (0.7); 2.670 (0.9); 2.666 (0.7); 2.569 (0.5); 2.523 (2.9); 2.510 (52.0); 2.506 (101.9); 2.501 (134.0); 2.497 (101.4); 2.332 (0.6); 2.328 (0.9); 2.323 (0.7); 0.008 (0.5); 0.000 (12.7); −0.008 (0.6) Example 92: 1H-NMR (400.0 MHz, d6-DMSO): δ = 8.883 (0.8); 8.867 (1.7); 8.852 (0.8); 7.933 (1.5); 7.921 (4.3); 7.753 (1.7); 7.734 (2.4); 7.700 (0.8); 7.682 (2.0); 7.672 (0.9); 7.664 (1.6); 7.653 (2.0); 7.633 (5.0); 7.616 (2.2); 7.598 (0.7); 7.585 (2.3); 7.565 (2.8); 7.425 (3.3); 7.388 (2.0); 7.368 (1.9); 7.316 (1.9); 7.298 (1.8); 7.244 (1.4); 7.104 (2.8); 6.965 (1.4); 4.211 (0.7); 4.196 (0.8); 4.175 (1.6); 4.160 (1.6); 4.138 (0.9); 4.123 (0.8); 3.985 (16.0); 3.892 (1.3); 3.318 (15.2); 2.506 (31.3); 2.501 (40.7); 2.497 (31.3); 0.000 (3.2) Example 93: 1H-NMR (400.0 MHz, d6-DMSO): δ = 9.045 (2.3); 9.030 (4.8); 9.014 (2.3); 8.314 (0.4); 8.054 (5.8); 8.029 (4.9); 8.026 (4.9); 7.860 (9.6); 7.841 (16.0); 7.826 (6.4); 7.802 (5.5); 7.782 (9.9); 7.766 (4.5); 7.745 (9.0); 7.720 (4.9); 7.703 (4.9); 7.684 (3.7); 7.656 (3.8); 7.637 (4.5); 7.619 (1.6); 7.381 (5.2); 7.362 (4.6); 4.277 (1.9); 4.262 (2.0); 4.241 (4.4); 4.225 (4.2); 4.205 (2.3); 4.190 (2.1); 3.319 (98.6); 3.296 (0.4); 2.891 (0.8); 2.732 (0.6); 2.676 (0.6); 2.671 (0.9); 2.667 (0.6); 2.511 (52.0); 2.506 (101.2); 2.502 (132.5); 2.497 (98.5); 2.493 (50.2); 2.333 (0.7); 2.329 (0.9); 2.324 (0.7); 1.989 (0.8); 1.398 (0.7); 1.298 (1.7); 1.176 (0.5); 1.159 (0.8); 0.000 (4.2) Example 94: 1H-NMR (400.0 MHz, d6-DMSO): δ = 9.033 (0.9); 9.018 (1.9); 9.002 (0.9); 8.054 (1.8); 8.048 (1.9); 8.036 (1.9); 8.030 (1.9); 7.977 (3.4); 7.847 (1.4); 7.844 (1.4); 7.823 (2.9); 7.818 (1.4); 7.812 (1.2); 7.806 (1.2); 7.802 (1.3); 7.796 (1.2); 7.790 (1.2); 7.784 (1.1); 7.768 (1.8); 7.749 (2.5); 7.731 (3.7); 7.710 (4.0); 7.689 (1.5); 7.656 (1.6); 7.637 (1.9); 7.618 (0.7); 7.567 (2.0); 7.544 (3.2); 7.522 (1.7); 7.388 (2.1); 7.369 (1.9); 4.257 (0.8); 4.242 (0.9); 4.222 (1.8); 4.206 (1.8); 4.186 (1.0); 4.170 (0.9); 3.320 (19.4); 2.507 (25.1); 2.503 (32.5); 2.498 (24.6); 1.989 (1.1); 1.398 (16.0); 1.176 (0.6); 0.000 (1.1) Example 95: 1H-NMR (400.0 MHz, d6-DMSO): δ = 9.038 (1.6); 9.022 (3.1); 9.007 (1.6); 8.469 (5.7); 8.464 (6.0); 8.165 (2.9); 8.160 (2.9); 8.144 (3.5); 8.138 (3.4); 8.075 (5.7); 7.973 (0.3); 7.952 (0.5); 7.920 (2.5); 7.917 (2.5); 7.900 (3.2); 7.897 (3.3); 7.878 (5.9); 7.857 (5.2); 7.786 (0.4); 7.765 (7.0); 7.744 (5.8); 7.725 (1.5); 7.707 (3.4); 7.689 (2.5); 7.656 (2.7); 7.637 (3.2); 7.619 (1.2); 7.387 (3.5); 7.369 (3.2); 5.753 (16.0); 4.261 (1.3); 4.246 (1.5); 4.226 (3.0); 4.210 (2.9); 4.190 (1.6); 4.174 (1.4); 4.039 (0.6); 4.021 (0.6); 3.319 (30.9); 2.892 (2.0); 2.733 (1.7); 2.672 (0.4); 2.507 (51.3); 2.503 (66.0); 2.498 (51.5); 2.329 (0.4); 1.989 (2.5); 1.398 (2.5); 1.260 (0.5); 1.250 (0.5); 1.233 (2.3); 1.194 (0.7); 1.176 (1.4); 1.158 (0.7); 0.000 (2.0) Example 96: 1H-NMR (400.0 MHz, d6-DMSO): δ = 10.163 (0.3); 9.038 (1.6); 9.023 (3.4); 9.007 (1.7); 8.428 (3.2); 8.422 (3.5); 8.413 (3.4); 8.407 (3.4); 8.226 (1.7); 8.220 (1.7); 8.213 (2.0); 8.207 (2.3); 8.204 (2.3); 8.198 (2.1); 8.191 (2.0); 8.185 (1.8); 8.041 (6.1); 8.038 (6.2); 7.889 (2.7); 7.885 (2.6); 7.868 (3.7); 7.864 (3.6); 7.768 (3.4); 7.756 (7.1); 7.750 (5.3); 7.735 (5.0); 7.727 (1.8); 7.708 (3.8); 7.686 (5.0); 7.663 (7.0); 7.658 (3.5); 7.640 (5.9); 7.619 (1.3); 7.388 (3.9); 7.369 (3.6); 5.753 (16.0); 4.261 (1.4); 4.246 (1.5); 4.225 (3.3); 4.209 (3.2); 4.189 (1.8); 4.173 (1.6); 4.039 (0.8); 4.021 (0.8); 3.320 (55.9); 2.892 (0.4); 2.733 (0.4); 2.676 (0.3); 2.672 (0.4); 2.667 (0.3); 2.525 (1.2); 2.511 (30.3); 2.507 (58.7); 2.502 (75.9); 2.498 (56.5); 2.494 (29.0); 2.334 (0.4); 2.329 (0.5); 2.325 (0.4); 1.989 (3.6); 1.398 (9.8); 1.353 (0.7); 1.337 (0.3); 1.260 (0.4); 1.250 (0.6); 1.232 (1.1); 1.194 (1.0); 1.176 (2.0); 1.158 (1.0); 1.122 (0.3); 0.000 (2.5) Example 97: 1H-NMR (400.0 MHz, d6-DMSO): δ = 9.046 (1.6); 9.030 (3.2); 9.015 (1.5); 8.346 (6.6); 8.308 (16.0); 8.184 (5.7); 8.181 (5.7); 8.007 (2.6); 7.987 (3.2); 7.983 (3.1); 7.800 (5.4); 7.779 (4.5); 7.766 (3.1); 7.747 (4.1); 7.723 (1.3); 7.705 (3.4); 7.686 (2.5); 7.655 (2.6); 7.636 (3.0); 7.617 (1.1); 7.393 (3.6); 7.374 (3.2); 4.273 (1.3); 4.256 (1.4); 4.236 (3.0); 4.221 (2.9); 4.201 (1.5); 4.185 (1.4); 3.348 (0.5); 3.316 (322.1); 3.281 (0.4); 2.675 (2.6); 2.670 (3.4); 2.666 (2.5); 2.578 (0.4); 2.506 (393.2); 2.501 (508.1); 2.497 (377.1); 2.333 (2.5); 2.328 (3.3); 2.324 (2.5); 1.988 (0.5); 1.398 (1.2); 0.000 (6.7) Example 104: 1H-NMR (400.0 MHz, d6-DMSO): δ = 9.014 (0.9); 8.998 (1.9); 8.983 (0.9); 8.313 (0.8); 7.815 (3.2); 7.766 (1.7); 7.745 (3.1); 7.722 (2.7); 7.703 (2.0); 7.684 (1.6); 7.668 (6.3); 7.647 (6.4); 7.633 (2.2); 7.613 (0.8); 7.568 (0.3); 7.548 (0.4); 7.527 (0.3); 7.382 (1.9); 7.363 (1.7); 7.067 (3.7); 7.045 (3.6); 4.238 (0.7); 4.222 (0.9); 4.203 (1.6); 4.186 (1.6); 4.165 (0.9); 4.151 (0.8); 3.589 (5.2); 3.316 (156.9); 3.279 (2.5); 3.267 (3.0); 3.213 (2.1); 3.200 (2.7); 3.187 (1.8); 2.670 (2.8); 2.505 (354.9); 2.501 (438.9); 2.328 (3.1); 2.073 (0.7); 2.049 (16.0); 0.146 (2.3); 0.000 (453.8); −0.089 (0.3); −0.150 (2.4) Example 105: 1H-NMR (400.0 MHz, d6-DMSO): δ = 9.040 (0.7); 9.025 (1.6); 9.009 (0.7); 8.218 (3.3); 8.214 (3.4); 8.113 (2.7); 8.100 (3.0); 8.092 (3.7); 7.981 (2.0); 7.977 (2.1); 7.961 (1.6); 7.956 (2.1); 7.932 (1.6); 7.928 (1.6); 7.777 (2.7); 7.766 (1.6); 7.757 (2.4); 7.746 (2.1); 7.724 (0.7); 7.706 (1.6); 7.688 (1.2); 7.655 (1.2); 7.636 (1.5); 7.617 (0.5); 7.386 (1.7); 7.367 (1.6); 4.265 (0.6); 4.250 (0.7); 4.230 (1.4); 4.214 (1.4); 4.193 (0.7); 4.178 (0.7); 4.056 (0.6); 4.038 (1.8); 4.021 (1.8); 4.003 (0.6); 3.318 (34.9); 2.891 (1.4); 2.732 (1.2); 2.524 (0.9); 2.511 (19.2); 2.507 (38.2); 2.502 (50.7); 2.498 (38.3); 2.494 (19.8); 2.329 (0.3); 1.989 (7.6); 1.398 (16.0); 1.193 (2.0); 1.176 (4.0); 1.158 (2.0); 0.015 (0.3); 0.008 (2.5); 0.000 (63.5); −0.008 (3.1) Example 106: 1H-NMR (400.0 MHz, d6-DMSO): δ = 9.037 (2.8); 9.022 (5.9); 9.006 (2.8); 8.315 (0.5); 8.009 (16.0); 7.985 (5.3); 7.980 (5.5); 7.880 (4.5); 7.877 (4.4); 7.860 (6.2); 7.856 (6.4); 7.767 (6.1); 7.756 (14.2); 7.749 (10.8); 7.735 (14.1); 7.728 (9.7); 7.707 (10.1); 7.688 (9.6); 7.667 (2.3); 7.655 (4.9); 7.636 (5.8); 7.617 (2.1); 7.384 (6.7); 7.366 (6.1); 4.262 (2.4); 4.247 (2.6); 4.226 (5.6); 4.211 (5.4); 4.190 (2.9); 4.175 (2.7); 3.318 (81.4); 2.675 (1.0); 2.671 (1.4); 2.666 (1.0); 2.506 (156.9); 2.502 (209.4); 2.497 (159.3); 2.333 (1.0); 2.329 (1.4); 2.324 (1.1); 1.964 (0.3); 1.398 (2.4); 0.146 (1.4); 0.023 (0.4); 0.008 (12.1); 0.000 (300.3); −0.008 (15.6); −0.150 (1.4) Example 107: 1H-NMR (400.0 MHz, d6-DMSO): δ = 9.122 (4.3); 9.107 (9.0); 9.091 (4.3); 8.488 (15.2); 8.484 (16.0); 8.314 (1.3); 8.254 (7.3); 8.250 (7.3); 8.233 (8.1); 8.229 (8.2); 7.974 (1.0); 7.966 (1.8); 7.956 (10.7); 7.939 (11.4); 7.933 (11.3); 7.916 (10.3); 7.897 (0.9); 7.875 (14.6); 7.854 (13.3); 7.763 (8.7); 7.744 (12.2); 7.728 (3.9); 7.710 (10.0); 7.691 (7.3); 7.658 (7.6); 7.639 (9.0); 7.620 (3.3); 7.412 (10.6); 7.393 (9.4); 4.248 (3.9); 4.233 (4.1); 4.214 (8.9); 4.198 (8.7); 4.179 (4.6); 4.163 (4.2); 3.317 (300.9); 2.675 (2.9); 2.671 (4.1); 2.666 (3.1); 2.524 (11.9); 2.506 (468.7); 2.502 (620.0); 2.497 (462.8); 2.333 (2.9); 2.328 (4.1); 2.324 (3.1); 2.288 (0.4); 1.988 (0.5); 1.398 (0.5); 1.148 (0.5); 0.146 (2.8); 0.032 (0.4); 0.024 (0.8); 0.008 (20.9); 0.000 (586.9); −0.008 (26.9); −0.038 (0.4); −0.150 (2.8) Example 108: 1H-NMR (400.0 MHz, d6-DMSO): δ = 9.154 (2.5); 9.138 (5.4); 9.123 (2.7); 8.315 (0.4); 7.964 (0.6); 7.956 (1.2); 7.946 (6.7); 7.929 (7.1); 7.922 (6.9); 7.906 (6.4); 7.896 (1.2); 7.888 (0.6); 7.777 (16.0); 7.758 (9.1); 7.749 (13.1); 7.732 (7.0); 7.714 (4.6); 7.671 (4.7); 7.652 (5.9); 7.633 (2.4); 7.409 (6.5); 7.390 (6.0); 4.155 (2.4); 4.139 (2.5); 4.120 (5.3); 4.104 (5.3); 4.085 (2.8); 4.069 (2.7); 3.319 (29.3); 2.676 (0.7); 2.671 (0.9); 2.667 (0.7); 2.525 (2.3); 2.511 (49.5); 2.507 (100.5); 2.502 (133.3); 2.498 (98.5); 2.494 (49.8); 2.334 (0.6); 2.329 (0.8); 2.325 (0.6); 1.398 (5.5); 0.146 (0.8); 0.008 (6.7); 0.000 (176.5); −0.008 (7.8); −0.023 (0.5); −0.150 (0.8) Example 109: 1H-NMR (400.0 MHz, d6-DMSO): δ = 9.073 (0.5); 9.057 (1.1); 9.042 (0.5); 7.788 (1.7); 7.785 (1.7); 7.772 (1.7); 7.765 (3.0); 7.748 (1.4); 7.732 (2.2); 7.719 (1.5); 7.702 (1.6); 7.685 (1.2); 7.667 (1.0); 7.648 (1.2); 7.629 (0.5); 7.583 (2.0); 7.563 (1.5); 7.380 (1.4); 7.361 (1.3); 4.102 (0.5); 4.087 (0.5); 4.064 (1.2); 4.048 (1.1); 4.026 (0.6); 4.010 (0.6); 3.319 (4.8); 2.559 (5.3); 2.524 (0.5); 2.506 (19.1); 2.502 (25.2); 2.498 (19.1); 1.989 (0.5); 1.398 (16.0); 0.008 (1.1); 0.000 (30.2); −0.008 (1.6) Example 110: 1H-NMR (400.0 MHz, d6-DMSO): δ = 9.035 (2.2); 9.019 (4.6); 9.004 (2.2); 8.314 (0.4); 8.069 (8.2); 7.929 (3.6); 7.925 (3.5); 7.908 (4.6); 7.905 (4.5); 7.886 (1.6); 7.875 (10.8); 7.853 (10.6); 7.768 (4.5); 7.748 (13.7); 7.727 (7.8); 7.707 (5.0); 7.688 (3.6); 7.656 (3.7); 7.637 (4.5); 7.618 (1.6); 7.381 (5.2); 7.362 (4.6); 4.258 (1.9); 4.242 (2.1); 4.222 (4.4); 4.206 (4.2); 4.186 (2.3); 4.170 (2.1); 4.038 (0.5); 4.021 (0.5); 3.318 (117.8); 2.676 (0.9); 2.671 (1.2); 2.667 (0.9); 2.524 (3.7); 2.506 (142.2); 2.502 (184.7); 2.498 (136.8); 2.333 (0.9); 2.329 (1.2); 2.324 (0.9); 1.989 (2.2); 1.398 (16.0); 1.193 (0.6); 1.175 (1.2); 1.158 (0.6); 0.146 (0.8); 0.020 (0.4); 0.008 (6.5); 0.000 (167.3); −0.150 (0.8) Example 111: 1H-NMR (400.0 MHz, d6-DMSO): δ = 9.341 (3.5); 9.325 (7.1); 9.310 (3.4); 9.020 (10.8); 9.015 (13.2); 8.965 (12.9); 8.960 (11.4); 8.040 (13.8); 7.902 (0.9); 7.882 (12.0); 7.860 (16.0); 7.844 (8.0); 7.718 (11.9); 7.698 (9.4); 4.322 (3.3); 4.306 (3.4); 4.285 (7.3); 4.269 (7.1); 4.248 (3.8); 4.232 (3.5); 3.327 (359.7); 2.712 (1.7); 2.672 (1.4); 2.583 (0.5); 2.542 (350.2); 2.525 (4.7); 2.503 (215.4); 2.455 (0.5); 2.368 (1.8); 2.330 (1.4); 1.234 (0.3); 0.008 (1.2); 0.000 (31.8) Example 112: 1H-NMR (400.0 MHz, d6-DMSO): δ = 9.159 (3.8); 9.143 (8.0); 9.127 (3.8); 8.863 (8.8); 8.852 (8.9); 8.299 (8.5); 8.280 (9.0); 8.026 (15.0); 7.894 (0.9); 7.886 (1.6); 7.876 (9.4); 7.859 (16.0); 7.853 (11.3); 7.837 (14.6); 7.756 (5.9); 7.744 (5.9); 7.737 (5.8); 7.724 (5.5); 7.704 (14.1); 7.683 (11.2); 4.283 (3.6); 4.267 (3.7); 4.246 (8.2); 4.230 (8.0); 4.209 (4.2); 4.193 (3.9); 3.365 (0.7); 3.329 (438.6); 2.712 (0.6); 2.676 (0.9); 2.672 (1.3); 2.668 (1.0); 2.578 (0.3); 2.568 (0.4); 2.542 (145.0); 2.525 (3.4); 2.508 (146.4); 2.503 (193.1); 2.499 (145.4); 2.368 (0.6); 2.334 (0.9); 2.330 (1.2); 2.326 (0.9); 0.008 (1.1); 0.000 (31.3) Example 113: 1H-NMR (400.0 MHz, d6-DMSO): δ = 9.011 (2.3); 8.995 (5.1); 8.980 (2.4); 8.310 (1.1); 7.899 (9.2); 7.800 (3.7); 7.797 (3.6); 7.780 (5.3); 7.776 (5.4); 7.764 (4.9); 7.745 (6.5); 7.720 (2.1); 7.703 (5.5); 7.689 (10.2); 7.668 (6.8); 7.657 (5.6); 7.653 (8.6); 7.633 (5.0); 7.622 (4.4); 7.616 (6.2); 7.578 (4.2); 7.573 (3.8); 7.557 (4.6); 7.552 (4.3); 7.380 (5.6); 7.361 (5.0); 7.143 (3.8); 7.121 (6.1); 7.099 (3.5); 4.245 (2.0); 4.229 (2.1); 4.209 (4.5); 4.193 (4.4); 4.172 (2.3); 4.157 (2.2); 3.772 (12.8); 3.761 (16.0); 3.749 (13.9); 3.307 (152.4); 3.091 (13.2); 3.079 (16.0); 3.068 (12.5); 2.674 (1.4); 2.670 (2.0); 2.665 (1.5); 2.523 (4.8); 2.510 (116.8); 2.505 (240.6); 2.501 (321.7); 2.496 (237.2); 2.492 (120.3); 2.332 (1.5); 2.328 (2.1); 2.323 (1.5); 1.988 (0.5); 0.146 (0.8); 0.008 (5.7); 0.000 (173.6); −0.008 (7.4); −0.150 (0.8) Example 114: 1H-NMR (400.0 MHz, d6-DMSO): δ = 8.901 (2.2); 8.885 (4.7); 8.870 (2.2); 8.014 (8.6); 7.899 (0.5); 7.890 (1.1); 7.879 (7.6); 7.858 (16.0); 7.840 (11.6); 7.760 (8.4); 7.740 (6.1); 7.437 (2.7); 7.418 (6.1); 7.400 (3.5); 7.399 (3.5); 7.179 (6.9); 7.173 (4.6); 7.160 (5.9); 7.154 (6.3); 7.150 (4.5); 7.135 (2.7); 7.131 (2.3); 4.244 (2.0); 4.229 (2.1); 4.209 (4.4); 4.193 (4.3); 4.173 (2.3); 4.158 (2.1); 3.380 (0.3); 3.362 (0.8); 3.330 (313.1); 2.712 (0.9); 2.676 (0.6); 2.672 (0.8); 2.667 (0.6); 2.575 (0.4); 2.542 (197.1); 2.525 (2.8); 2.507 (90.5); 2.502 (119.8); 2.498 (90.5); 2.368 (0.9); 2.333 (0.5); 2.329 (0.8); 2.325 (0.6); 0.008 (0.5); 0.000 (14.5) Example 115: 1H-NMR (400.0 MHz, d6-DMSO): δ = 8.960 (3.4); 8.945 (7.1); 8.929 (3.4); 8.021 (13.4); 7.899 (0.8); 7.880 (12.7); 7.864 (10.1); 7.858 (16.0); 7.841 (8.3); 7.729 (13.0); 7.708 (10.1); 7.470 (2.9); 7.467 (4.3); 7.450 (11.4); 7.447 (13.7); 7.440 (6.8); 7.426 (7.8); 7.422 (8.2); 7.407 (3.5); 7.402 (3.6); 7.391 (0.5); 7.384 (4.7); 7.379 (4.5); 7.365 (7.7); 7.361 (7.9); 7.348 (4.1); 7.344 (4.0); 7.281 (9.1); 7.279 (9.3); 7.263 (6.6); 7.259 (6.3); 4.258 (3.2); 4.242 (3.3); 4.222 (7.2); 4.207 (7.0); 4.187 (3.7); 4.171 (3.4); 3.324 (394.7); 3.295 (0.7); 2.711 (0.4); 2.675 (1.0); 2.671 (1.5); 2.667 (1.1); 2.541 (94.2); 2.524 (4.1); 2.506 (175.3); 2.502 (231.6); 2.498 (174.1); 2.367 (0.5); 2.333 (1.1); 2.329 (1.5); 2.324 (1.1); 0.008 (0.9); 0.000 (29.1) Example 116: 1H-NMR (400.0 MHz, d6-DMSO): δ = 8.949 (3.3); 8.933 (6.9); 8.918 (3.3); 8.019 (13.3); 7.899 (0.8); 7.881 (13.2); 7.857 (16.0); 7.841 (8.2); 7.744 (12.5); 7.723 (9.5); 7.625 (8.3); 7.623 (8.5); 7.606 (9.7); 7.604 (9.7); 7.427 (3.2); 7.425 (3.3); 7.409 (8.6); 7.406 (8.6); 7.390 (6.7); 7.388 (6.4); 7.360 (5.1); 7.356 (6.2); 7.341 (6.6); 7.337 (7.5); 7.322 (3.0); 7.318 (3.0); 7.245 (8.2); 7.241 (8.5); 7.227 (6.9); 7.223 (6.7); 4.253 (3.1); 4.237 (3.3); 4.218 (6.9); 4.202 (6.8); 4.182 (3.6); 4.166 (3.3); 3.369 (0.5); 3.326 (495.1); 2.711 (1.3); 2.675 (1.1); 2.671 (1.6); 2.667 (1.2); 2.572 (0.3); 2.541 (292.9); 2.524 (4.5); 2.506 (192.7); 2.502 (253.5); 2.498 (193.6); 2.439 (0.4); 2.431 (0.4); 2.368 (1.4); 2.333 (1.3); 2.329 (1.7); 2.324 (1.3); 1.235 (0.3); 0.008 (0.8); 0.000 (23.6) Example 117: 1H-NMR (400.0 MHz, d6-DMSO): δ = 9.246 (3.6); 9.230 (7.2); 9.215 (3.7); 8.030 (14.1); 7.889 (9.6); 7.882 (9.9); 7.873 (11.3); 7.864 (13.5); 7.849 (9.1); 7.692 (10.9); 7.671 (9.1); 7.537 (1.3); 7.517 (3.4); 7.500 (5.9); 7.480 (3.9); 7.462 (1.6); 7.155 (9.8); 7.135 (16.0); 7.115 (8.6); 4.278 (3.3); 4.263 (3.6); 4.243 (7.4); 4.227 (7.2); 4.206 (3.9); 4.191 (3.5); 3.325 (410.2); 2.711 (0.8); 2.671 (1.9); 2.541 (156.1); 2.502 (287.9); 2.367 (0.8); 2.329 (1.8); 1.235 (0.5); −0.001 (17.8) Example 118: 1H-NMR (400.0 MHz, d6-DMSO): δ = 8.880 (0.8); 8.865 (1.6); 8.849 (0.8); 8.313 (0.8); 7.845 (1.9); 7.828 (2.1); 7.821 (2.0); 7.805 (1.8); 7.753 (1.6); 7.734 (2.1); 7.702 (0.7); 7.684 (1.7); 7.666 (1.3); 7.637 (1.3); 7.618 (1.5); 7.599 (0.6); 7.553 (2.1); 7.533 (2.8); 7.452 (3.0); 7.427 (1.9); 7.407 (1.4); 7.308 (1.8); 7.289 (1.6); 4.194 (0.7); 4.179 (0.7); 4.157 (1.6); 4.142 (1.5); 4.120 (0.8); 4.105 (0.7); 3.982 (16.0); 3.367 (0.4); 3.357 (0.5); 3.319 (369.4); 2.675 (1.7); 2.670 (2.3); 2.666 (1.8); 2.541 (1.1); 2.506 (282.0); 2.501 (363.1); 2.497 (270.2); 2.438 (0.4); 2.332 (1.7); 2.328 (2.3); 2.324 (1.7); 0.000 (37.4); −0.008 (1.8) Example 119: 1H-NMR (400.0 MHz, d6-DMSO): δ = 9.072 (1.4); 9.057 (3.0); 9.041 (1.4); 8.314 (0.4); 7.784 (2.9); 7.765 (3.8); 7.731 (1.2); 7.713 (3.2); 7.695 (2.4); 7.667 (2.5); 7.648 (4.1); 7.630 (2.5); 7.626 (3.2); 7.609 (2.7); 7.600 (3.8); 7.586 (2.2); 7.578 (4.7); 7.485 (7.8); 7.468 (2.2); 7.420 (1.4); 7.414 (1.5); 7.396 (1.7); 7.391 (2.5); 7.386 (2.0); 7.375 (3.6); 7.357 (3.2); 7.244 (1.3); 7.238 (1.2); 7.223 (2.4); 7.217 (2.3); 7.202 (1.2); 7.196 (1.1); 4.114 (1.3); 4.099 (1.3); 4.076 (2.8); 4.060 (2.8); 4.038 (1.5); 4.022 (1.4); 3.318 (93.6); 2.671 (0.9); 2.548 (13.6); 2.506 (100.6); 2.502 (128.1); 2.497 (96.3); 2.328 (0.8); 2.324 (0.6); 1.398 (16.0); 0.000 (10.6) Example 120: 1H-NMR (400.0 MHz, d6-DMSO): δ = 9.069 (3.2); 9.054 (6.5); 9.038 (3.2); 7.865 (2.9); 7.861 (3.0); 7.846 (3.1); 7.841 (3.5); 7.835 (3.5); 7.830 (3.2); 7.816 (3.0); 7.810 (3.0); 7.784 (6.5); 7.764 (8.6); 7.737 (2.8); 7.719 (7.2); 7.701 (5.3); 7.675 (12.0); 7.658 (5.8); 7.648 (7.8); 7.637 (7.9); 7.614 (1.9); 7.609 (2.0); 7.592 (5.0); 7.586 (6.2); 7.579 (16.0); 7.558 (8.2); 7.548 (4.9); 7.527 (4.9); 7.506 (1.9); 7.386 (7.5); 7.367 (6.8); 5.754 (12.9); 4.102 (2.8); 4.087 (3.0); 4.064 (6.3); 4.049 (6.1); 4.026 (3.3); 4.011 (3.0); 3.322 (56.3); 3.178 (0.9); 3.165 (0.9); 2.891 (1.0); 2.733 (0.9); 2.671 (0.7); 2.667 (0.5); 2.559 (29.1); 2.506 (77.3); 2.502 (97.7); 2.498 (75.0); 2.329 (0.6); 1.989 (0.5); 1.398 (2.5); 0.000 (9.0) Example 121: 1H-NMR (400.0 MHz, d6-DMSO): δ = 9.073 (1.8); 9.057 (3.5); 9.042 (1.7); 7.783 (3.5); 7.764 (4.8); 7.742 (6.9); 7.719 (6.5); 7.699 (5.8); 7.666 (2.9); 7.647 (3.6); 7.628 (1.3); 7.589 (5.6); 7.568 (4.2); 7.536 (0.9); 7.520 (5.4); 7.502 (5.3); 7.486 (0.9); 7.384 (4.1); 7.365 (3.7); 7.298 (1.0); 7.293 (1.6); 7.275 (2.0); 7.270 (3.0); 7.252 (1.1); 7.247 (1.5); 5.754 (1.8); 4.105 (1.5); 4.090 (1.6); 4.067 (3.4); 4.052 (3.3); 4.029 (1.8); 4.013 (1.6); 3.321 (37.4); 2.891 (1.6); 2.732 (1.5); 2.671 (0.4); 2.563 (16.0); 2.502 (63.3); 2.328 (0.4); 0.000 (5.3) Example 122: 1H-NMR (400.0 MHz, d6-DMSO): δ = 9.069 (1.6); 9.054 (3.1); 9.038 (1.5); 8.008 (7.0); 7.955 (0.4); 7.783 (3.2); 7.764 (4.4); 7.738 (16.0); 7.718 (8.9); 7.696 (3.4); 7.668 (5.1); 7.647 (3.2); 7.628 (1.2); 7.590 (5.3); 7.570 (3.7); 7.386 (3.6); 7.368 (3.2); 5.754 (5.1); 4.103 (1.4); 4.087 (1.5); 4.065 (3.1); 4.049 (2.9); 4.027 (1.6); 4.011 (1.4); 3.319 (48.8); 3.176 (0.3); 2.891 (0.8); 2.732 (0.8); 2.671 (0.7); 2.564 (14.1); 2.506 (84.3); 2.502 (104.4); 2.498 (81.7); 2.329 (0.6); 1.398 (3.7); 0.000 (14.7) Example 123: 1H-NMR (400.0 MHz, d6-DMSO): δ = 9.070 (1.1); 9.054 (2.3); 9.039 (1.1); 7.781 (6.5); 7.764 (3.2); 7.736 (1.1); 7.719 (2.7); 7.701 (4.2); 7.686 (6.0); 7.666 (3.6); 7.646 (4.9); 7.628 (1.0); 7.589 (4.3); 7.568 (2.6); 7.535 (1.7); 7.515 (4.0); 7.496 (2.9); 7.473 (3.1); 7.469 (2.5); 7.456 (1.2); 7.451 (1.4); 7.390 (2.7); 7.371 (2.4); 5.753 (16.0); 4.107 (1.1); 4.094 (1.1); 4.091 (1.1); 4.082 (0.9); 4.068 (2.4); 4.053 (2.2); 4.030 (1.2); 4.015 (1.1); 3.320 (21.9); 3.178 (1.7); 3.165 (1.7); 2.891 (1.0); 2.732 (0.9); 2.566 (10.6); 2.506 (30.1); 2.502 (39.4); 2.498 (30.4); 1.989 (0.3); 1.398 (1.3); 0.000 (4.4) Example 124: 1H-NMR (400.0 MHz, d6-DMSO): δ = 9.069 (1.7); 9.054 (3.5); 9.038 (1.7); 7.967 (3.4); 7.962 (3.7); 7.950 (3.6); 7.944 (3.6); 7.783 (3.6); 7.765 (6.1); 7.754 (2.3); 7.748 (2.2); 7.744 (2.6); 7.738 (3.7); 7.733 (3.1); 7.727 (2.5); 7.718 (4.1); 7.700 (3.2); 7.685 (6.3); 7.664 (4.5); 7.644 (5.3); 7.579 (6.3); 7.559 (4.1); 7.549 (3.7); 7.526 (5.8); 7.504 (3.0); 7.388 (4.2); 7.369 (3.7); 5.754 (9.9); 4.102 (1.5); 4.087 (1.6); 4.064 (3.5); 4.048 (3.3); 4.039 (1.3); 4.026 (1.8); 4.010 (1.7); 3.569 (1.2); 3.320 (31.8); 3.178 (0.7); 3.164 (0.7); 2.891 (1.4); 2.732 (1.3); 2.671 (0.4); 2.560 (16.0); 2.506 (49.8); 2.502 (65.7); 2.498 (52.5); 2.334 (0.3); 2.329 (0.4); 1.989 (2.0); 1.398 (3.5); 1.193 (0.5); 1.176 (1.0); 1.158 (0.5); 0.000 (6.0) Example 125: 1H-NMR (400.0 MHz, d6-DMSO): δ = 9.068 (1.8); 9.053 (3.5); 9.037 (1.7); 8.314 (0.4); 7.842 (3.4); 7.837 (3.5); 7.814 (3.4); 7.809 (3.5); 7.783 (3.6); 7.763 (4.9); 7.735 (1.7); 7.714 (11.1); 7.693 (8.8); 7.673 (8.3); 7.646 (3.7); 7.632 (5.0); 7.628 (5.5); 7.611 (2.7); 7.606 (2.7); 7.589 (6.3); 7.569 (4.3); 7.383 (4.1); 7.364 (3.7); 4.102 (1.5); 4.087 (1.6); 4.064 (3.5); 4.048 (3.3); 4.026 (1.8); 4.010 (1.6); 3.568 (0.9); 3.319 (110.0); 2.675 (0.7); 2.671 (0.9); 2.666 (0.7); 2.561 (16.0); 2.506 (101.3); 2.502 (131.9); 2.497 (100.0); 2.333 (0.6); 2.328 (0.8); 2.324 (0.6); 1.988 (0.8); 1.398 (8.1); 1.175 (0.4); 0.000 (11.4); −0.008 (0.5) Example 126: 1H-NMR (400.0 MHz, d6-DMSO): δ = 9.075 (1.8); 9.059 (3.6); 9.044 (1.7); 7.789 (9.9); 7.782 (8.5); 7.768 (12.1); 7.750 B (3.2); 7.721 (4.9); 7.701 (2.9); 7.667 (3.0); 7.648 (3.6); 7.629 (1.3); 7.596 (5.7); 7.575 (4.5); 7.382 (4.1); 7.363 (3.7); 4.106 (1.6); 4.090 (1.6); 4.068 (3.5); 4.052 (3.3); 4.039 (0.9); 4.029 (1.8); 4.014 (1.6); 3.569 (0.8); 3.323 (37.6); 2.672 (0.4); 2.565 (16.0); 2.507 (42.6); 2.503 (52.7); 2.499 (40.4); 2.330 (0.4); 1.989 (0.8); 1.398 (9.5); 1.176 (0.4); 0.000 (4.8) Example 127: 1H-NMR (400.0 MHz, d6-DMSO): δ = 9.079 (1.7); 9.064 (3.4); 9.048 (1.7); 7.785 (3.3); 7.766 (4.5); 7.735 (1.5); 7.716 (3.8); 7.698 (2.8); 7.669 (2.9); 7.650 (3.5); 7.627 (3.9); 7.605 (4.8); 7.538 (10.0); 7.519 (3.0); 7.492 (2.2); 7.471 (2.1); 7.450 (1.0); 7.400 (1.4); 7.380 (6.6); 7.361 (5.2); 7.338 (2.1); 7.333 (2.3); 7.320 (2.1); 7.301 (0.7); 5.754 (12.2); 4.124 (1.5); 4.109 (1.7); 4.086 (3.4); 4.071 (3.3); 4.048 (1.8); 4.033 (1.6); 3.569 (0.4); 3.320 (32.1); 3.177 (0.8); 3.164 (0.8); 2.892 (1.1); 2.733 (1.1); 2.671 (0.4); 2.560 (16.0); 2.505 (60.1); 2.502 (67.0); 2.329 (0.4); 1.398 (0.7); 0.000 (4.8) Example 128: 1H-NMR (400.0 MHz, d6-DMSO): δ = 9.074 (1.7); 9.059 (3.7); 9.043 (1.8); 7.999 (13.4); 7.983 (13.5); 7.952 (0.6); 7.785 (3.5); 7.764 (5.8); 7.755 (6.3); 7.738 (1.6); 7.720 (6.3); 7.701 (6.2); 7.667 (2.9); 7.648 (3.5); 7.630 (1.3); 7.581 (5.9); 7.560 (4.5); 7.386 (4.1); 7.367 (3.7); 5.754 (2.4); 4.101 (1.5); 4.085 (1.5); 4.063 (3.3); 4.047 (3.2); 4.025 (1.7); 4.009 (1.6); 3.319 (115.2); 2.891 (3.5); 2.731 (3.1); 2.675 (0.8); 2.671 (1.1); 2.666 (0.8); 2.560 (16.0); 2.541 (0.9); 2.506 (122.5); 2.501 (163.3); 2.497 (126.5); 2.333 (0.8); 2.328 (1.1); 2.324 (0.8); 0.000 (6.5)
[1230] Formulation Examples
[1231] An example for a formulation according to the present invention is the following:
TABLE-US-00004 8 mg compound of Example 3 0.2 mL Diethylene glycol monoethyl ether 0.2 mL Polyoxyl 35 Castor Oil 1.6 mL physiological sodium chloride solution
[1232] An example for a preparation of such a formulation is as follows. The compound of the present invention was dissolved in 1 part diethylene glycol monoethyl ether and mixed with 1 part Polyoxyl 35 Castor Oil and 8 parts physiological sodium chloride solution.
[1233] Such a formulation is suitable for oral or parenteral application.
[1234] Formulations of other compounds of the present invention can be prepared in an analogue way and show analogue or identical compositions.
[1235] Biological Examples
[1236] A. In-Vitro Assays
[1237] Cooperia Curticei—Assay (COOPCU)
[1238] Solvent: dimethyl sulfoxide
[1239] To produce a suitable preparation, 10 mg of active compound are dissolved in 0.5 ml solvent, and the concentrate is diluted with “Ringer's solution” to the desired concentration.
[1240] Approximately 40 nematode larvae (Cooperia curticei) are transferred into a test tube containing the compound solution.
[1241] After 5 days percentage of larval mortality is recorded. 100% efficacy means all larvae are killed; 0% efficacy means no larvae are killed.
[1242] In this test, for example, the following compounds from the preparation examples showed good activity of 100% at an application rate of 20 ppm: 1, 2, 3, 5, 7, 9, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 25, 26, 27, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 45, 46, 47, 48, 49, 50, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 76, 80, 81, 82, 84, 86, 88, 89, 90, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128.
[1243] In this test for example, the following compounds from the preparation examples showed good activity of 90% at an application rate of 20 ppm: 51, 74, 78, 87.
[1244] In this test for example, the following compounds from the preparation examples showed good activity of 80% at an application rate of 20 ppm: 6, 10, 28, 29, 79, 91.
[1245] In this test for example, the following compounds from the preparation examples showed good activity of 100% at an application rate of 4 ppm: 4.
[1246] Haemonchus Contortus—Assay (HAEMCO)
[1247] Solvent: dimethyl sulfoxide
[1248] To produce a suitable preparation, 10 mg of active compound are dissolved in 0.5 ml solvent, and the concentrate is diluted with “Ringer's solution” to the desired concentration.
[1249] Approximately 40 larvae of the red stomach worm (Haemonchus contortus) are transferred into a test tube containing compound solution.
[1250] After 5 days percentage of larval mortality are recorded. 100% efficacy means all larvae are killed, 0% efficacy means no larvae are killed.
[1251] In this test, for example, the following compounds from the preparation examples showed good activity of 100% at an application rate of 20 ppm: 1, 2, 3, 9, 12, 16, 17, 18, 19, 23, 25, 26, 27, 32, 33, 34, 35, 36, 38, 39, 40, 42, 43, 47, 49, 50, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 76, 80, 88, 90, 92, 93, 94, 95, 96, 98, 99, 100, 101, 102, 103, 105, 106, 108, 109, 110, 111, 112, 114, 115, 116, 117, 121, 122, 123, 124, 125, 126, 127, 128.
[1252] In this test, for example, the following compounds from the preparation examples showed good activity of 90% at an application rate of 20 ppm: 7, 13, 14, 15, 20, 21, 22, 37, 41, 45, 46, 48, 81, 82, 86, 107, 119, 120.
[1253] In this test, for example, the following compounds from the preparation examples showed good activity of 80% at an application rate of 20 ppm: 5, 31, 97.
[1254] In this test, for example, the following compounds from the preparation examples showed good activity of 90% at an application rate of 4 ppm: 4.
[1255] Nippostrongylus Brasiliensis—Assay (NIPOBR)
[1256] Adult Nippostrongylus brasiliensis were washed with saline buffer containing 100 U/ml penicillin, 0.1 mg/ml streptomycin and 2.5 μg/ml amphotericin B. Test compounds were dissolved in DMSO and worms were incubated in medium in a final concentration of 10 μg/ml (10 ppm) respectively 1 μg/ml (1 ppm). An aliquot of the medium was used to determine the acetylcholine esterase activity in comparison to a negative control. The principle of measuring acetylcholine esterase as readout for anthelmintic activity was described in Rapson et al (1986) and Rapson et al (1987).
[1257] For the following examples, activity (reduction of AChE compared to negative control) was 75% or higher at 10 μg/ml: 1, 2, 3, 7, 12, 13.
[1258] 1, 2, 3, 5, 7, 12, 13, 17, 21, 22, 23, 25, 27, 32, 33, 35, 36, 37, 38, 39, 41, 42, 43, 47, 50, 52, 53, 55, 56, 57, 59, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 76, 80, 82, 88, 90, 93, 94, 95, 96, 98, 99, 100, 101, 103, 105, 106, 108, 109, 110, 111, 112, 114, 115, 116, 119, 120, 121, 122, 123, 124, 125, 126, 127
[1259] Dirofilaria Immitis Microfilariae—Assay (DIROM L1)
[1260] ≧250 Dirofilaria immitis microfilariae, which were freshly purified from blood, were added to wells of a microtitre plate containing a nutrient medium and the test compound in DMSO. Compounds were tested in a five point concentration-response assay in duplicate. Larvae exposed to DMSO and no test compounds were used as negative controls. Larvae were evaluated after 72 h of incubation with the compound. Efficacy was determined as the reduction of motility in comparison to the negative control. Based on the evaluation of five concentrations, concentration-response curves as well as EC.sub.50-values were calculated.
[1261] For the following examples, the EC50 was <10 ppm: 12, 25, 38, 43, 69, 121, 124, 125.
[1262] For the following examples, the EC50 was <1 ppm: 1, 2, 3, 33, 126.
[1263] Meloidogyne Incognita—Assay (MELGIN)
[1264] Solvent: 125.0 parts by weight of acetone
[1265] To produce a suitable preparation, 1 part by weight of active compound is mixed with the stated amount of solvent, and the concentrate is diluted with water to the desired concentration.
[1266] Vessels are filled with sand, a solution of the active ingredient, a suspension containing eggs and larvae of the southern root-knot nematode (Meloidogyne incognita) and salad seeds. The salad seeds germinate and the seedlings grow. Galls develop in the roots.
[1267] After 14 days the nematicidal activity is determined on the basis of the percentage of gall formation. 100% means no galls were found and 0% means the number of galls found on the roots of the treated plants was equal to that in untreated control plants.
[1268] In this test, for example, the following compounds from the preparation examples showed good activity of 100% at an application rate of 20 ppm: 9, 25, 27, 32, 35, 38, 43, 49, 50, 52, 53, 60, 61, 62, 63, 64, 65, 68,69,94,95,101,105,109,112,115,117,119,120,121,122,123,124,125.
[1269] In this test, for example, the following compounds from the preparation examples showed good activity of 90% at an application rate of 20 ppm: 17, 47, 70, 108, 126, 127.
[1270] B. In-Vivo Assay
[1271] Haemonchus Contortus/Trichostrongylus Colubriformis/Gerbil
[1272] Gerbils, experimentally infected with Haemonchus and/or Trichostrongylus, were treated once during late prepatency. Test compounds were formulated as solutions or suspensions and applied subcutaneously or intraperitoneally.
[1273] Efficacy was determined per group as reduction of worm count in stomach and small intestine, respectively, after necropsy compared to worm count in an infected and placebo-treated control group.
[1274] The following examples were tested and had an activity of 90% or higher at the given treatment:
TABLE-US-00005 Trichostrongylus Treatment Haemonchus contortus colubriformis 20 mg/kg 3, 7, 12, 32, 33, 38, 109 3, 7, 32, 33 intraperitoneally 10 mg/kg 3, 32, 33, 36, 62, 70, 109 3, 33, 62, 109 subcutaneously