HERBICIDAL COMPOUNDS
20220281827 · 2022-09-08
Assignee
Inventors
- Kenneth Bruce LING (Bracknell, Berkshire, GB)
- Peter Timothy SEDEN (Bracknell, Berkshire, GB)
- Christopher John MATHEWS (Bracknell, Berkshire, GB)
- Stephen Edward SHANAHAN (Bracknell, Berkshire, GB)
- Christiana KITSIOU (Bracknell, Berkshire, GB)
- John FINNEY (Bracknell, Berkshire, GB)
Cpc classification
C07D413/10
CHEMISTRY; METALLURGY
C07D409/10
CHEMISTRY; METALLURGY
C07D237/04
CHEMISTRY; METALLURGY
C07D405/10
CHEMISTRY; METALLURGY
C07D401/10
CHEMISTRY; METALLURGY
C07D403/10
CHEMISTRY; METALLURGY
A01N43/713
HUMAN NECESSITIES
A01N25/32
HUMAN NECESSITIES
C07D417/10
CHEMISTRY; METALLURGY
International classification
C07D237/04
CHEMISTRY; METALLURGY
A01N25/32
HUMAN NECESSITIES
A01N43/713
HUMAN NECESSITIES
A01N43/84
HUMAN NECESSITIES
C07D401/10
CHEMISTRY; METALLURGY
C07D403/10
CHEMISTRY; METALLURGY
C07D405/10
CHEMISTRY; METALLURGY
C07D409/10
CHEMISTRY; METALLURGY
C07D413/10
CHEMISTRY; METALLURGY
Abstract
The present invention relates to herbicidal substituted phenyl-pyridazine-diones and substituted phenyl-pyridazinone derivatives of formula (I), as well as to processes and intermediates used for the preparation of such derivatives. The invention further extends to herbicidal compositions comprising such derivatives, as well as to the use of such compounds and compositions in controlling undesirable plant growth: in particular the use in controlling weeds, such as broad-leaved dicotyledonous weeds, in crops of useful plants.
Claims
1. A compound of formula (I) ##STR00068## or a salt or N-oxide thereof, wherein R.sup.1 is selected from the group consisting of C.sub.1-C.sub.4alkyl, C.sub.3-C.sub.6cycloalkyl, C.sub.3-C.sub.6alkoxy, C.sub.1-C.sub.2alkoxy-C.sub.1-C.sub.2 alkyl, C.sub.2-C.sub.4alkenyl, C.sub.1-C.sub.4haloalkyl, cyano-C.sub.1-C.sub.4alkyl, C.sub.2-C.sub.4haloalkenyl, C.sub.2-C.sub.4alkynyl and C.sub.2-C.sub.4haloalkynyl; R.sup.2 is selected from the group consisting of hydrogen, halogen, cyano, C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6haloalkyl, C.sub.1-C.sub.6haloalkoxy, C.sub.1-C.sub.3haloalkoxy-C.sub.1-C.sub.3alkyl-, C.sub.1-C.sub.6alkoxy, C.sub.1-C.sub.3alkoxy-C.sub.1-C.sub.3alkyl-, C.sub.1-C.sub.3alkoxy-C.sub.1-C.sub.3alkoxy-C.sub.1-C.sub.3alkyl-, C.sub.3-C.sub.6cycloalkyl, C.sub.2-C.sub.6alkenyl, C.sub.2-C.sub.6 haloalkenyl, C.sub.2-C.sub.6alkynyl, C.sub.1-C.sub.6hydroxyalkyl-, C.sub.1-C.sub.6alkylcarbonyl-, —S(O).sub.mC.sub.1-C.sub.6alkyl, amino, C.sub.1-C.sub.6alkylamino, C.sub.1-C.sub.6dialkylamino, —C(C.sub.1-C.sub.3alkyl)=N—O—C.sub.1-C.sub.3alkyl and C.sub.2-C.sub.6 haloalkynyl; G is hydrogen, or C(O)R.sup.3; R.sup.3 is selected from the group consisting of C.sub.1-C.sub.6alkyl, C.sub.2-C.sub.6alkenyl, C.sub.2-C.sub.6alkynyl, C.sub.1-C.sub.6alkyl-S—, C.sub.1-C.sub.6alkoxy, —NR.sup.4R.sup.5 and phenyl optionally substituted by one or more R.sup.6; each R.sup.4 and R.sup.5 are independently selected from the group consisting of hydrogen, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6alkoxy, and C.sub.3-C.sub.6cycloalkyl, or R.sup.4 and R.sup.5 together can form a morpholinyl ring; and, each R.sup.4a and R.sup.5a are independently selected from the group consisting of C.sub.1-C.sub.6alkoxy, and C.sub.3-C.sub.6cycloalkyl, or R.sup.4a and R.sup.5a together can form a morpholinyl ring; and, R.sup.6 is selected from the group consisting of halogen, cyano, nitro, C.sub.1-C.sub.3alkyl, C.sub.1-C.sub.3haloalky, C.sub.1-C.sub.3alkoxy and C.sub.1-C.sub.3haloalkoxy; X and Y are each independently hydrogen, C.sub.1-C.sub.3 alkyl, cyclopropyl, C.sub.1-C.sub.3 alkoxy, C.sub.1-C.sub.3haloalkyl, C.sub.1-C.sub.3haloalkoxy, or halogen; D is a substituted monocyclic heteroaryl ring containing 1, 2, or 3 heteroatoms independently selected from oxygen, nitrogen and sulphur, substituted on at least one ring carbon atom with R.sup.8 and/or on at least one ring nitrogen atom with R.sup.9; at least one R.sup.8 is selected from the group consisting of C.sub.1-C.sub.6haloalkylcarbonyl-, C.sub.3-C.sub.6cycloalkylcarbonyl-, —S(O).sub.m—C.sub.1-C.sub.6haloalkyl, —S(O).sub.m—C.sub.3-C.sub.6cycloalkyl, —O—S(O).sub.2C.sub.1-C.sub.3alkyl, —C.sub.1-C.sub.3alkyl-S(O).sub.m—C.sub.1-C.sub.6alkyl, —C.sub.1-C.sub.3alkyl-S(O).sub.m—C.sub.1-C.sub.6haloalkyl, —C.sub.1-C.sub.3alkyl- S(O).sub.m—C.sub.3-C.sub.6cycloalkyl, cyano-C.sub.1-C.sub.6-alkyl-, —NR.sup.4aR.sup.5a, —C(S)NR.sup.4R.sup.5, —S(O).sub.2NHC(O)C.sub.1-C.sub.3alkyl, —S(O).sub.2NR.sup.4R.sup.5, —C(O)OH, —C(O)OC.sub.1-C.sub.6alkyl, —C(O)NHS—(O).sub.2C.sub.1-C.sub.6alkyl, —C(O)NR.sup.4R.sup.5, —NR.sup.4C(O)NR.sup.4R.sup.5, C.sub.1-C.sub.6alkylcarbonyl(C.sub.1-C.sub.6alkyl)amino-, C.sub.1-C.sub.6haloalkylcarbonylamino-, C.sub.1-C.sub.6haloalkylcarbonyl(C.sub.1-C.sub.6alkyl)amino-, C.sub.1-C.sub.6alkylsulfonylamino-, C.sub.1-C.sub.6alkylsulfonyl(C.sub.1-C.sub.6alkyl)amino-, C.sub.1-C.sub.6haloalkylsulfonylamino-, C.sub.1-C.sub.6haloalkylsulfonyl(C.sub.1-C.sub.6alkyl)amino-, C.sub.3-C.sub.6cycloalkylsulfonylamino-, C.sub.3-C.sub.6cycloalkylsulfonyl(C.sub.1-C.sub.6alkyl)amino-, hydroxyamino-, hydroxy(C.sub.1-C.sub.6alkyl)amino, C.sub.1-C.sub.6alkoxyamino, C.sub.1-C.sub.6alkoxy(C.sub.1-C.sub.6alkyl)amino, C.sub.1-C.sub.6haloalkoxyamino, C.sub.1-C.sub.6haloalkoxy(C.sub.1-C.sub.6alkyl)amino; and a ring system selected from the group consisting of a phenyl ring, a 5-6-membered heteroaryl ring and a 3-6-membered heterocyclyl ring, wherein said ring system is substituted by 0 to 5 R.sup.16; at least one R.sup.9 is selected from the group consisting of C.sub.5-C.sub.6alkyl, C.sub.5-C.sub.6haloalkyl, C.sub.3-C.sub.6-cycloalkyl, C.sub.1-C.sub.3alkoxy-C.sub.3alkyl-, C.sub.3alkoxy-C.sub.1-C.sub.2alkyl-, C.sub.1-C.sub.3haloalkoxy-C.sub.1-C.sub.3alkyl-, C.sub.1-C.sub.3alkoxy-C.sub.1-C.sub.3alkoxy-C.sub.1-C.sub.3alkyl-, C.sub.1-C.sub.6hydroxyalkyl-, —C.sub.1-C.sub.3alkyl-S(O).sub.m—C.sub.1-C.sub.6alkyl, —C.sub.1-C.sub.3alkyl-S(O).sub.m—C.sub.1-C.sub.6haloalkyl, —C.sub.1-C.sub.3alkyl-S(O).sub.m—C.sub.3-C.sub.6cycloalkyl, cyano-C.sub.1-C.sub.6-alkyl-, and a ring system selected from the group consisting of: a phenyl ring, a 5-6-membered heteroaryl ring and a 3-6-membered heterocyclyl ring, wherein said ring system is substituted by 0 to 5 R.sup.16; m is an integer of 0, 1, or 2; each R.sup.16 is independently halogen, cyano, C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6haloalkyl, C.sub.1-C.sub.6alkoxy or C.sub.1-C.sub.6haloalkoxy; or D is a phenyl ring substituted by at least one R.sup.8; and, W is either ##STR00069## wherein: “a” denotes the point of attachment to the phenyl-pyridazine dione/phenyl-pyridazinone moiety, “b” denotes the point of attachment to ring D, R.sup.10, R.sup.12, R.sup.14 and R.sup.15 are each independently hydrogen, C.sub.1-C.sub.3alkyl, or C.sub.1-C.sub.3haloalkyl; or R.sup.10 and R.sup.12 together with the carbon atoms to which they are joined forma a C.sub.3-C.sub.6 carbocyclic ring; and R.sup.11 and R.sup.13 are each independently hydrogen, halogen, C.sub.1-C.sub.3alkyl, or C.sub.1-C.sub.3haloalkyl; provided that when one of R.sup.11 or R.sup.13 is halogen, C.sub.1-C.sub.3alkyl or C.sub.1-C.sub.3haloalkyl, the other is hydrogen.
2. A compound of formula (I) ##STR00070## or a salt or N-oxide thereof, wherein R.sup.1 is selected from the group consisting of C.sub.1-C.sub.4 alkyl, C.sub.3-C.sub.6cycloalkyl, C.sub.3-C.sub.6alkoxy, C.sub.1-C.sub.2 alkoxy-C.sub.1-C.sub.2alkyl, C.sub.2-C.sub.4alkenyl, C.sub.1-C.sub.4haloalkyl, cyano-C.sub.1-C.sub.4alkyl, C.sub.2-C.sub.4haloalkenyl, C.sub.2-C.sub.4alkynyl and C.sub.2-C.sub.4haloalkynyl; R.sup.2 is selected from the group consisting of hydrogen, halogen, cyano, C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6haloalkyl, C.sub.1-C.sub.6haloalkoxy, C.sub.1-C.sub.3haloalkoxy-C.sub.1-C.sub.3alkyl-, C.sub.1-C.sub.6alkoxy, C.sub.1-C.sub.3alkoxy-C.sub.1-C.sub.3alkyl, C.sub.1-C.sub.3alkoxy-C.sub.1-C.sub.3alkoxy-C.sub.1-C.sub.3alkyl-, C.sub.3-C.sub.6cycloalkyl, C.sub.2-C.sub.6alkenyl, C.sub.2-C.sub.6 haloalkenyl, C.sub.2-C.sub.6alkynyl, C.sub.1-C.sub.6hydroxyalkyl-, C.sub.1-C.sub.6alkylcarbonyl-, —S(O).sub.mC.sub.1-C.sub.6alkyl, —NR.sup.4R.sup.5, —C(C.sub.1-C.sub.3alkyl)=N—O—C.sub.1-C.sub.3alkyl and C.sub.2-C.sub.6 haloalkynyl; G is hydrogen, or C(O)R.sup.3; R.sup.3 is selected from the group consisting of C.sub.1-C.sub.6alkyl, C.sub.2-C.sub.6alkenyl, C.sub.2-C.sub.6alkynyl, C.sub.1-C.sub.6alkyl-S—, C.sub.1-C.sub.6alkoxy, —NR.sup.4R.sup.5 and phenyl optionally substituted by one or more R.sup.6 each R.sup.4 and R.sup.5 are independently selected from the group consisting of hydrogen, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6alkoxy, and C.sub.3-C.sub.6cycloalkyl, or R.sup.4 and R.sup.5 together can form a morpholinyl ring; and, R.sup.6 is selected from the group consisting of halogen, cyano, nitro, C.sub.1-C.sub.3alkyl, C.sub.1-C.sub.3haloalky, C.sub.1-C.sub.3alkoxy and C.sub.1-C.sub.3haloalkoxy; X is cyclopropyl; Y is hydrogen, C.sub.1-C.sub.3 alkyl, C.sub.1-C.sub.3alkoxy, C.sub.1-C.sub.3haloalkyl, C.sub.1-C.sub.3haloalkoxy, or halogen; D is a substituted or unsubstituted monocyclic heteroaryl ring containing 1, 2, or 3 heteroatoms independently selected from oxygen, nitrogen and sulphur, and wherein when D is substituted it is substituted on at least one ring carbon atom with R.sup.8 and/or on a ring nitrogen atom with R.sup.9; each R.sup.8 is independently oxygen, hydroxyl, halogen, cyano, C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6haloalkyl, C.sub.3-C.sub.6-cycloalkyl, C.sub.1-C.sub.6alkoxy, C.sub.1-C.sub.6haloalkoxy, C.sub.1-C.sub.3alkoxy-C.sub.1-C.sub.3alkyl, C.sub.1-C.sub.3haloalkoxy-C.sub.1-C.sub.3alkyl-, C.sub.1-C.sub.3alkoxy-C.sub.1-C.sub.3alkoxy-C.sub.1-C.sub.3alkyl-, C.sub.2-C.sub.6alkenyl, C.sub.2-C.sub.6haloalkenyl, C.sub.2-C.sub.6alkynyl, C.sub.2-C.sub.6 haloalkynyl, C.sub.1-C.sub.6hydroxyalkyl-, C.sub.1-C.sub.6alkylcarbonyl-, C.sub.1-C.sub.6haloalkylcarbonyl-, C.sub.3-C.sub.6cycloalkylcarbonyl-, —S(O).sub.m—C.sub.1-C.sub.6haloalkyl, —S(O).sub.m—C.sub.3-C.sub.6cycloalkyl, —O—S(O).sub.2C.sub.1-C.sub.3alkyl, —C.sub.1-C.sub.3alkyl-S(O).sub.m—C.sub.1-C.sub.6alkyl, —C.sub.1-C.sub.3alkyl-S(O).sub.m—C.sub.1-C.sub.6haloalkyl, —C.sub.1-C.sub.3alkyl-S(O).sub.m—C.sub.3-C.sub.6cycloalkyl, cyano-C.sub.1-C.sub.6-alkyl-, —NR.sup.4R.sup.5, —C(S)NR.sup.4R.sup.5, —S(O).sub.2NHC(O)C.sub.1-C.sub.3alkyl, —S(O).sub.2NR.sup.4R.sup.5, —C(O)OH, —C(O)OC.sub.1-C.sub.6alkyl, —C(O)NHS—(O).sub.2C.sub.1-C.sub.6alkyl, —C(O)NR.sup.4R.sup.5, —NR.sup.4C(O)NR.sup.4R.sup.5, C.sub.1-C.sub.6alkylcarbonyl(C.sub.1-C.sub.6alkyl)amino-, C.sub.1-C.sub.6haloalkylcarbonylamino-, C.sub.1-C.sub.6haloalkylcarbonyl(C.sub.1-C.sub.6alkyl)amino-, C.sub.1-C.sub.6alkylsulfonylamino-, C.sub.1-C.sub.6alkylsulfonyl(C.sub.1-C.sub.6alkyl)amino-, C.sub.1-C.sub.6haloalkylsulfonylamino-, C.sub.1-C.sub.6haloalkylsulfonyl(C.sub.1-C.sub.6alkyl)amino-, C.sub.3-C.sub.6cycloalkylsulfonylamino-, C.sub.3-C.sub.6cycloalkylsulfonyl(C.sub.1-C.sub.6alkyl)amino-, hydroxyamino-, hydroxy(C.sub.1-C.sub.6alkyl)amino, C.sub.1-C.sub.6alkoxyamino, C.sub.1-C.sub.6alkoxy(C.sub.1-C.sub.6alkyl)amino, C.sub.1-C.sub.6haloalkoxyamino, C.sub.1-C.sub.6haloalkoxy(C.sub.1-C.sub.6alkyl)amino; or a ring system selected from the group consisting: of a phenyl ring, a 5-6-membered heteroaryl ring and a 3-6-membered heterocyclyl ring, wherein said ring system is substituted by 0 to 5 R.sup.16; m is an integer of 0, 1, or 2; and each R.sup.9 is independently C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6haloalkyl, C.sub.3-C.sub.6-cycloalkyl, C.sub.1-C.sub.3alkoxy-C.sub.1-C.sub.3alkyl, C.sub.1-C.sub.3haloalkoxy-C.sub.1-C.sub.3alkyl-, C.sub.1-C.sub.3alkoxy-C.sub.1-C.sub.3alkoxy-C.sub.1-C.sub.3alkyl-, C.sub.1-C.sub.6hydroxyalkyl-, —C.sub.1-C.sub.3alkyl-S(O).sub.m—C.sub.1-C.sub.6alkyl, —C.sub.1-C.sub.3alkyl-S(O).sub.m—C.sub.1-C.sub.6haloalkyl, —C.sub.1-C.sub.3alkyl-S(O).sub.m—C.sub.3-C.sub.6cycloalkyl, cyano-C.sub.1-C.sub.6-alkyl-, or a ring system selected from the group consisting of: a phenyl ring, a 5-6-membered heteroaryl ring and a 3-6-membered heterocyclyl ring, wherein said ring system is substituted by 0 to 5 R.sup.16; each R.sup.16 is independently halogen, cyano, C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6haloalkyl, C.sub.1-C.sub.6alkoxy or C.sub.1-C.sub.6haloalkoxy; or D is a substituted or unsubstituted phenyl ring, and wherein when said phenyl ring is substituted it is substituted by 1 to 5 R.sup.8; and, W is either ##STR00071## wherein “a” denotes the point of attachment to the phenyl-pyridazine dione/phenyl-pyridazinone moiety, “b” denotes the point of attachment to ring D, R.sup.10, R.sup.12, R.sup.14 and R.sup.15 are each independently hydrogen, C.sub.1-C.sub.3alkyl, or C.sub.1-C.sub.3haloalkyl; or R.sup.10 and R.sup.12 together with the carbon atoms to which they are joined forma a C.sub.3-C.sub.6 carbocyclic ring; and R.sup.11 and R.sup.13 are each independently hydrogen, halogen, C.sub.1-C.sub.3alkyl, or C.sub.1-C.sub.3haloalkyl, provided that when one of R.sup.11 or R.sup.13 is halogen, C.sub.1-C.sub.3alkyl or C.sub.1-C.sub.3 haloalkyl, the other is hydrogen.
3. A compound of formula (I) ##STR00072## or a salt or N-oxide thereof, wherein R.sup.1 is selected from the group consisting of C.sub.1-C.sub.4alkyl, C.sub.3-C.sub.6cycloalkyl, C.sub.3-C.sub.6alkoxy, C.sub.1-C.sub.2alkoxy-C.sub.1-C.sub.2 alkyl, C.sub.2-C.sub.4alkenyl, C.sub.1-C.sub.4haloalkyl, cyano-C.sub.1-C.sub.4alkyl, C.sub.2-C.sub.4haloalkenyl, C.sub.2-C.sub.4alkynyl and C.sub.2-C.sub.4haloalkynyl; R.sup.2 is selected from the group consisting of hydrogen, halogen, cyano, C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6haloalkyl, C.sub.1-C.sub.6haloalkoxy, C.sub.1-C.sub.3haloalkoxy-C.sub.1-C.sub.3alkyl-, C.sub.1-C.sub.6alkoxy, C.sub.1-C.sub.3alkoxy-C.sub.1-C.sub.3alkyl, C.sub.1-C.sub.3alkoxy-C.sub.1-C.sub.3alkoxy-C.sub.1-C.sub.3alkyl-, C.sub.3-C.sub.6cycloalkyl, C.sub.2-C.sub.6alkenyl, C.sub.2-C.sub.6 haloalkenyl, C.sub.2-C.sub.6alkynyl, C.sub.1-C.sub.6hydroxyalkyl-, C.sub.1-C.sub.6alkylcarbonyl-, —S(O).sub.mC.sub.1-C.sub.6alkyl, —NR.sup.4R.sup.5, —C(C.sub.1-C.sub.3alkyl)=N—O—C.sub.1-C.sub.3alkyl and C.sub.2-C.sub.6haloalkynyl; G is hydrogen, or C(O)R.sup.3; R.sup.3 is selected from the group consisting of C.sub.1-C.sub.6alkyl, C.sub.2-C.sub.6alkenyl, C.sub.2-C.sub.6alkynyl, C.sub.1-C.sub.6alkyl-S—, C.sub.1-C.sub.6alkoxy, —NR.sup.4R.sup.5 and phenyl optionally substituted by one or more R.sup.6 each R.sup.4 and R.sup.5 are independently selected from the group consisting of hydrogen, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6alkoxy, and C.sub.3-C.sub.6cycloalkyl, or R.sup.4 and R.sup.5 together can form a morpholinyl ring; and, R.sup.6 is selected from the group consisting of halogen, cyano, nitro, C.sub.1-C.sub.3alkyl, C.sub.1-C.sub.3haloalky, C.sub.1-C.sub.3alkoxy and C.sub.1-C.sub.3haloalkoxy. X is hydrogen, C.sub.1-C.sub.3alkyl, C.sub.1-C.sub.3alkoxy, C.sub.1-C.sub.3haloalkyl, C.sub.1-C.sub.3haloalkoxy, or halogen; Y is cyclopropyl; D is a substituted or unsubstituted monocyclic heteroaryl ring containing 1, 2, or 3 heteroatoms independently selected from oxygen, nitrogen and sulphur, and wherein when D is substituted it is substituted on at least one ring carbon atom with R.sup.8 and/or on a ring nitrogen atom with R.sup.9; each R.sup.8 is independently oxygen, hydroxyl, halogen, cyano, C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6haloalkyl, C.sub.3-C.sub.6-cycloalkyl, C.sub.1-C.sub.6alkoxy, C.sub.1-C.sub.6haloalkoxy, C.sub.1-C.sub.3alkoxy-C.sub.1-C.sub.3alkyl, C.sub.1-C.sub.3haloalkoxy-C.sub.1-C.sub.3alkyl-, C.sub.1-C.sub.3alkoxy-C.sub.1-C.sub.3alkoxy-C.sub.1-C.sub.3alkyl-, C.sub.2-C.sub.6alkenyl, C.sub.2-C.sub.6haloalkenyl, C.sub.2-C.sub.6alkynyl, C.sub.2-C.sub.6haloalkynyl, C.sub.1-C.sub.6hydroxyalkyl-, C.sub.1-C.sub.6alkylcarbonyl-, C.sub.1-C.sub.6haloalkylcarbonyl-, C.sub.3-C.sub.6cycloalkylcarbonyl-, —S(O).sub.m—C.sub.1-C.sub.6haloalkyl, —S(O).sub.m—C.sub.3-C.sub.6cycloalkyl, —O—S(O).sub.2C.sub.1-C.sub.3alkyl, —C.sub.1-C.sub.3alkyl-S(O).sub.m—C.sub.1-C.sub.6alkyl, —C.sub.1-C.sub.3alkyl-S(O).sub.m—C.sub.1-C.sub.6haloalkyl, —C.sub.1-C.sub.3alkyl-S(O).sub.m—C.sub.3-C.sub.6cycloalkyl, cyano-C.sub.1-C.sub.6-alkyl, —NR.sup.4R.sup.5, —C(S)NR.sup.4R.sup.5, —S(O).sub.2NHC(O)C.sub.1-C.sub.3alkyl, —S(O).sub.2NR.sup.4R.sup.5, —C(O)OH, —C(O)OC.sub.1-C.sub.6alkyl, —C(O)NHS—(O).sub.2C.sub.1-C.sub.6alkyl, —C(O)NR.sup.4R.sup.5, —NR.sup.4C(O)NR.sup.4R.sup.5, C.sub.1-C.sub.6alkylcarbonyl(C.sub.1-C.sub.6alkyl)amino-, C.sub.1-C.sub.6haloalkylcarbonylamino-, C.sub.1-C.sub.6haloalkylcarbonyl(C.sub.1-C.sub.6alkyl)amino-, C.sub.1-C.sub.6alkylsulfonylamino-, C.sub.1-C.sub.6alkylsulfonyl(C.sub.1-C.sub.6alkyl)amino-, C.sub.1-C.sub.6haloalkylsulfonylamino-, C.sub.1-C.sub.6haloalkylsulfonyl(C.sub.1-C.sub.6alkyl)amino-, C.sub.3-C.sub.6cycloalkylsulfonylamino-, C.sub.3-C.sub.6cycloalkylsulfonyl(C.sub.1-C.sub.6alkyl)amino-, hydroxyamino-, hydroxy(C.sub.1-C.sub.6alkyl)amino, C.sub.1-C.sub.6alkoxyamino, C.sub.1-C.sub.6alkoxy(C.sub.1-C.sub.6alkyl)amino, C.sub.1-C.sub.6haloalkoxyamino, C.sub.1-C.sub.6haloalkoxy(C.sub.1-C.sub.6alkyl)amino; or a ring system selected from the group consisting: of a phenyl ring, a 5-6-membered heteroaryl ring and a 3-6-membered heterocyclyl ring, wherein said ring system is substituted by 0 to 5 R.sup.16; m is an integer of 0, 1, or 2; and each R.sup.9 is independently C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6haloalkyl, C.sub.3-C.sub.6-cycloalkyl, C.sub.1-C.sub.3alkoxy-C.sub.1-C.sub.3alkyl, C.sub.1-C.sub.3haloalkoxy-C.sub.1-C.sub.3alkyl-, C.sub.1-C.sub.3alkoxy-C.sub.1-C.sub.3alkoxy-C.sub.1-C.sub.3alkyl-, C.sub.1-C.sub.6hydroxyalkyl-, —C.sub.1-C.sub.3alkyl-S(O).sub.m—C.sub.1-C.sub.6alkyl, —C.sub.1-C.sub.3alkyl-S(O).sub.m—C.sub.1-C.sub.6haloalkyl, —C.sub.1-C.sub.3alkyl-S(O).sub.m—C.sub.3-C.sub.6cycloalkyl, cyano-C.sub.1-C.sub.6-alkyl-, or a ring system selected from the group consisting of: a phenyl ring, a 5-6-membered heteroaryl ring and a 3-6-membered heterocyclyl ring, wherein said ring system is substituted by 0 to 5 R.sup.16; each R.sup.16 is independently halogen, cyano, C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6haloalkyl, C.sub.1-C.sub.6alkoxy or C.sub.1-C.sub.6haloalkoxy; or D is a substituted or unsubstituted phenyl ring, and wherein when said phenyl ring is substituted it is substituted by 1 to 5 R.sup.8; and, W is either ##STR00073## wherein “a” denotes the point of attachment to the phenyl-pyridazine dione/phenyl-pyridazinone moiety, “b” denotes the point of attachment to ring D, R.sup.10, R.sup.12, R.sup.14 and R.sup.15 are each independently hydrogen, C.sub.1-C.sub.3alkyl, or C.sub.1-C.sub.3haloalkyl; or R.sup.10 and R.sup.12 together with the carbon atoms to which they are joined forma a C.sub.3-C.sub.6 carbocyclic ring; and R.sup.11 and R.sup.13 are each independently hydrogen, halogen, C.sub.1-C.sub.3alkyl, or C.sub.1-C.sub.3haloalkyl, provided that when one of R.sup.11 or R.sup.13 is halogen, C.sub.1-C.sub.3alkyl or C.sub.1-C.sub.3 haloalkyl, the other is hydrogen.
4. The compound according to claim 1, wherein G is hydrogen or —C(O)R.sup.3, and R.sup.3 is C.sub.1-C.sub.4alkyl, C.sub.2-C.sub.3alkenyl, C.sub.2-C.sub.3alkynyl, C.sub.1-C.sub.4alkoxy, —NR.sup.4R.sup.5 wherein R.sup.4 and R.sup.5 together form a morpholinyl ring, or phenyl.
5. The compound according to claim 1, wherein G is hydrogen or C(O)R.sup.3 wherein R.sup.3 is isopropyl, t-butyl, methyl, ethyl, propargyl, methoxy, ethoxy, or tert-butoxy.
6. The compound according to claim 1, wherein X is hydrogen, C.sub.1-C.sub.3alkyl, halogen, or C.sub.1haloalkyl.
7. The compound according to claim 1, wherein Y is hydrogen, C.sub.1-C.sub.3 alkyl, C.sub.1-C.sub.3haloalkyl, or halogen.
8. The compound according to claim 1 wherein X is ortho with respect to the pyrdazinone/pyridazine-dione moiety.
9. The compound according to claim 1 wherein Y is ortho with respect to the —W-D moiety.
10. The compound according to claim 1 wherein R.sup.1 is methyl, ethyl, n-propyl, cyclopropyl, propargyl, or C.sub.1haloalkyl.
11. The compound according to claim 1 wherein R.sup.2 is selected from the group consisting of hydrogen, halogen, C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6haloalkyl, C.sub.1-C.sub.6alkoxy, C.sub.1-C.sub.3alkoxy-C.sub.1-C.sub.3alkyl, C.sub.3-C.sub.6cycloalkyl, C.sub.2-C.sub.6alkenyl, C.sub.2-C.sub.6haloalkenyl, C.sub.2-C.sub.6alkynyl and C.sub.2-C.sub.6haloalkynyl.
12. The compound according to claim 1 wherein D is a substituted or unsubstituted monocyclic heteroaryl ring.
13. The compound according to claim 1 wherein D is substituted or unsubstituted phenyl ring.
14. The compound according to claim 1 wherein W is W1 and each of R.sup.10, R.sup.11, R.sup.12, and R.sup.13 is hydrogen.
15. The compound according to claim 1 wherein W is W2 and each of R.sup.14 and R.sup.15 is hydrogen.
16. The compound according to claim 1 wherein W is W3.
17. A herbicidal composition comprising a herbicidal compound according to claim 1 and an agriculturally acceptable formulation adjuvant.
18. A herbicidal composition according to claim 17, further comprising at least one additional pesticide.
19. A herbicidal composition according to claim 18, wherein the additional pesticide is a herbicide or herbicide safener.
20. A method of controlling unwanted plant growth, comprising applying a compound of formula (I) as defined in claim 1, to the unwanted plants or to the locus thereof.
21. Use of a compound of Formula (I) as defined in claim 1 as a herbicide.
22. A method of controlling unwanted plant growth, comprising applying an herbicidal composition according to claim 17, to the unwanted plants or to the locus thereof.
Description
PREPARATION EXAMPLES
Example 1 Preparation of 4-[3-chloro-6-fluoro-2-[2-(4-phenylphenyl)ethyl]phenyl]-5-hydroxy-2,6-dimethyl-pyridazin-3-one (A-1.027)
[0182] ##STR00035##
1.1 3-allyl-2-bromo-1-chloro-4-fluoro-benzene
[0183] A solution of lithium diisopropylamide (2M in tetrahydrofuran, 3.6 ml, 7.2 mmol) was cooled to −78° C. under nitrogen. A solution of 2-bromo-1-chloro-4-fluoro-benzene (1.0 g, 4.8 mmol) in tetrahydrofuran was added dropwise at −78° C. The mixture was stirred for 45 minutes at the same temperature before being treated with allyl bromide (0.3 ml, 5.7 mmol). The reaction was continued at −78° C. for 2 h then allowed to warm to room temperature. The reaction was quenched with sat. NH.sub.4Cl (aq) and extracted with ethyl acetate. The organics were separated and kept, then washed with brine. The organics were dried over sodium sulfate and concentrated under reduced pressure to give 3-allyl-2-bromo-1-chloro-4-fluoro-benzene (1.2 g, 100%) as an oil.
##STR00036##
[0184] .sup.1H NMR (400 MHz, CDCl.sub.3) δ.sub.H: 7.34-7.30 (m, 1H), 7.01-6.96 (m, 1H), 5.94-5.83 (m, 1H), 5.10-5.00 (m, 2H), 3.64-3.58 (m, 2H).
1.2 2-(2-bromo-3-chloro-6-fluoro-phenyl)acetic acid
[0185] A solution of 3-allyl-2-bromo-1-chloro-4-fluoro-benzene (15.0 g, 60.1 mmol) in dichloromethane (200 mL) in a 2-necked flask was cooled to −78° C. One side neck was connected to a trap containing an aqueous solution of KI. Ozone was bubbled through the solution until the starting material was fully consumed (5 hours). Air was bubbled through the solution for 10 minutes to remove excess ozone. Dimethyl sulfide (44 ml, 601 mmol) was added and the mixture allowed to warm to room temperature. The reaction was continued for 16 h at room temperature.
[0186] The mixture was washed with brine (2×100 mL) and the organic layer kept. The organics were dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure to give crude 2-(2-bromo-3-chloro-6-fluoro-phenyl)acetaldehyde (15.3 g) which was used for the next step without further purification.
[0187] Crude 2-(2-bromo-3-chloro-6-fluoro-phenyl)acetaldehyde (15.3 g, 60.8 mmol) was dissolved in a mixture of tert-butanol (92 mL) and water (46 mL) then cooled to 0° C. 2-methylbut-2-ene (64.5 mL, 608 mmol), sodium dihydrogen phosphate (34.6 g, 243 mmol) and sodium chlorite (16.5 g, 163 mmol) were added. The mixture was stirred for 2 h then diluted with brine (150 mL) and 2M hydrochloric acid (150 mL). The mixture was extracted with ethyl acetate (3×100 mL). The combined organic extracts were washed with a saturated aqueous solution of sodium metabisulfite (100 mL) then dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure to provide a pale yellow solid. The crude solid was dissolved in a mixture of water (100 mL) and 2.0M NaOH (30 mL). The aqueous solution was washed with ethyl acetate (100 mL) and the organics discarded. The aqueous layer was acidified by addition of concentrated hydrochloric acid (20 mL) resulting in the formation of a white suspension. The mixture was extracted with ethyl acetate (3×200 mL). The combined organics were washed with brine, dried over Na.sub.2SO.sub.4, filtered and evaporated to provide 2-(2-bromo-3-chloro-6-fluoro-phenyl)acetic acid (8.0 g, 49%) as a white solid.
##STR00037##
[0188] .sup.1H NMR (400 MHz, DMSO-d6) δ.sub.H: 12.79 (br. s, 1H), 7.67-7.59 (m, 1H), 7.39-7.31 (m, 1H), 3.82 (s, 2H).
1.3 2-(2-Bromo-3-chloro-6-fluoro-phenyl)-N-methyl-acetohydrazide
[0189] To a stirred solution of 2-(2-bromo-3-chloro-6-fluoro-phenyl)acetic acid (2.0 g, 7.5 mmol) in dichloromethane (20 ml) at 0° C. was added N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride [EDC.HCl] (1.4 g, 9.0 mmol), followed by dropwise addition of methyl hydrazine (0.4 ml, 7.5 mmol). The temperature of the reaction mixture was maintained at 0° C. for 3 h. The reaction was then quenched with water and extracted into dichloromethane. The organics were separated, washed with brine and dried over Na.sub.2SO.sub.4. Concentration under reduced pressure gave crude 2-(2-bromo-3-chloro-6-fluoro-phenyl)-N-methyl-acetohydrazide (1.8 g, 81%) which was used in the next step without further purification.
##STR00038##
[0190] .sup.1H NMR (400 MHz, DMSO-d6) δ.sub.H: 7.59 (dd, J=8.9 and 5.4, 1H), 7.30 (t, J=8.9, 1H), 4.91 (s, 2H), 4.10 (br. s, 2H), 3.02 (s, 3H).
1.4 2-{[2-(2-Bromo-3-chloro-6-fluoro-phenyl)-acetyl]-methyl-hydrazono}-propionic acid ethyl ester
[0191] To a stirred solution of 2-(2-bromo-3-chloro-6-fluoro-phenyl)-N-methyl-acetohydrazide (1.8 g, 6.09 mmol) in ethanol (5 ml) was added ethyl pyruvate (0.7 ml, 6.7 mmol) dropwise. The reaction was heated at 80° C. for 4 h. The reaction mixture was then allowed to cool to room temperature, and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent an ethyl acetate/hexane gradient) to give the desired compound 2-{[2-(2-Bromo-3-chloro-6-fluoro-phenyl)-acetyl]-methyl-hydrazono}-propionic acid ethyl ester (1.8 g, 75%) as an off-white solid.
##STR00039##
[0192] .sup.1H NMR (400 MHz, CDCl.sub.3) δ.sub.H: 7.40-7.35 (m, 1H), 7.04-6.98 (m, 1H), 4.32 (q, J=7.1, 2H), 4.24 (s, 2H), 3.41 (s, 3H), 2.32 (s, 3H), 1.36 (t, J=7.1, 3H).
1.5 4-(2-Bromo-3-chloro-6-fluoro-phenyl)-5-hydroxy-2,6-dimethyl-pyridazin-3-one
[0193] 2-{[2-(2-Bromo-3-chloro-6-fluoro-phenyl)-acetyl]-methyl-hydrazono}-propionic acid ethyl ester (500 mg, 1.27 mmol) was dissolved in acetonitrile (2.5 ml) and treated with 1,8-diazabicyclo[5.4.0]undec-7-ene [DBU] (0.47 ml, 3.2 mmol). The mixture was heated to 125° C. using microwave irradiation for 1 h. The reaction mixture was then evaporated under reduced pressure. The residue was dissolved in water and acidified to pH 1 with 2N hydrochloric acid. The mixture was extracted with DCM, the organics separated and washed with brine solution. The organic solution was dried over Na.sub.2SO.sub.4 and concentrated under reduced pressure to give crude product. The crude was purified by column chromatography on silica gel (eluent an ethyl acetate/hexane gradient) to give 4-(2-bromo-3-chloro-6-fluoro-phenyl)-5-hydroxy-2,6-dimethyl-pyridazin-3-one (340 mg, 77.1%) as an off-white solid.
##STR00040##
[0194] .sup.1H NMR (400 MHz, DMSO-d6) δ.sub.H: 11.01 (s, 1H), 7.77-7.73 (m, 1H), 7.39 (t, J=8.7, 1H), 3.58 (s, 3H), 2.24 (s, 3H).
1.6 [5-(2-bromo-3-chloro-6-fluoro-phenyl)-1,3-dimethyl-6-oxo-pyridazin-4-yl]2-methylpropanoate
[0195] To a stirred solution of 4-(2-bromo-3-chloro-6-fluoro-phenyl)-5-hydroxy-2,6-dimethyl-pyridazin-3-one (1.4 g, 4.02 mmol) in dichloromethane (32 ml) at rt were added triethylamine (1.1 ml, 8.06 mmol), 4-(dimethylamino)pyridine [DMAP] (49 mg, 0.40 mmol) and isobutyryl chloride (0.6 ml, 4.83 mmol).
[0196] Once judged complete, the reaction was diluted with dichloromethane and water. The organic layer was separated, dried over Na.sub.2SO.sub.4, and concentrated under reduced pressure to give crude product. The crude was purified by column chromatography on silica gel (eluent an ethyl acetate/hexane gradient) to give [5-(2-bromo-3-chloro-6-fluoro-phenyl)-1,3-dimethyl-6-oxo-pyridazin-4-yl] 2-methylpropanoate (1.47 g, 87%).
##STR00041##
[0197] .sup.1H NMR (400 MHz, CDCl.sub.3) δ.sub.H: 7.51-7.47 (m, 1H), 7.10-7.05 (m, 1H), 3.82 (s, 3H), 2.60-2.55 (m, 1H), 2.25 (s, 3H), 1.02-0.98 (m, 6H).
1.7 4-[3-chloro-6-fluoro-2-[(E)-2-(4-phenylphenyl)vinyl]phenyl]-5-hydroxy-2,6-dimethyl-pyridazin-3-one (A-2.027)
[0198] [5-(2-Bromo-3-chloro-6-fluoro-phenyl)-1,3-dimethyl-6-oxo-pyridazin-4-yl] 2-methylpropanoate (0.54 g, 1.3 mmol), K.sub.2CO.sub.3 (0.55 g, 3.9 mmol), trans-2-(4-phenylphenyl)vinylboronic acid (0.44 g, 2.00 mmol), PdCl.sub.2(dppf).DCM (53 mg, 0.065 mmol), 1,4-dioxane (13 ml) and H.sub.2O (3.3 mL) were combined in a 20 mL microwave vial then heated at 140° C. for 30 mins under microwave irradiation.
[0199] The reaction mixture was concentrated in vacuo to remove the 1,4-dioxane then partitioned between 2N HCl (aq) and DCM. The organic layer was separated and the aqueous layer extracted with further portions of DCM (×2). The combined organics were concentrated in vacuo to give a crude residue which was purified by column chromatography on silica gel (eluent an ethyl acetate/hexane gradient) to give 4-[3-chloro-6-fluoro-2-[(E)-2-(4-phenylphenyl)vinyl]phenyl]-5-hydroxy-2,6-dimethyl-pyridazin-3-one (343 mg, 53%, A-2.027)) as a yellow foam.
##STR00042##
[0200] .sup.1H NMR (400 MHz, chloroform) 6=7.59-7.33 (m, 10H), 7.07 (t, J=8.6 Hz, 1H), 7.01 (d, J=16.4 Hz, 1H), 6.70 (d, J=16.5 Hz, 1H), 5.63 (s, 1H), 3.73 (s, 3H), 2.28 (s, 3H)
[0201] 1.8 4-(3-Chloro-6-fluoro-2-phenethyl-phenyl)-5-hydroxy-2,6-dimethyl-pyridazin-3-one (A-1.027)
[0202] To a 10 mL round-bottom flask was added 5% Pd/C (73 mg, 0.034 mmol) followed by a solution of 4-[3-chloro-6-fluoro-2-[(E)-2-(4-phenylphenyl)vinyl]phenyl]-5-hydroxy-2,6-dimethyl-pyridazin-3-one (308 mg, 0.69 mmol) in 10:1 (v/v) DCM/MeOH (4 mL). B.sub.2(OH).sub.4 (325 mg, 3.45 mmol) was then added and the reaction mixture stirred at room temperature overnight.
[0203] The reaction mixture was then filtered through Celite®, eluting with 10:1 (v/v) DCM/MeOH. The filtrate was dry-loaded onto silica and purified by column chromatography on silica gel (eluent an ethyl acetate/hexane gradient) to give 4-[3-chloro-6-fluoro-2-[2-(4-phenylphenyl)ethyl]phenyl]-5-hydroxy-2,6-dimethyl-pyridazin-3-one (299 mg, 97% yield, A-1.027) as a yellow oil which solidified on standing.
##STR00043##
[0204] .sup.1H NMR (400 MHz, chloroform) 6=7.57-7.52 (m, 2H), 7.50-7.40 (m, 5H), 7.37-7.30 (m, 1H), 7.07 (d, J=8.2 Hz, 2H), 7.02 (t, J=8.6 Hz, 1H), 5.47 (s, 1H), 3.75 (s, 3H), 2.88-2.80 (m, 3H), 2.27 (s, 3H)
Example 2 Preparation of 4-[2-[6-chloro-3-fluoro-2-(5-hydroxy-2,6-dimethyl-3-oxo-pyridazin-4-yl)phenyl]ethyl]benzonitrile (A-1.036)
[0205] ##STR00044##
2.1 [5-[3-Chloro-2-[(E)-2-(4-cyanophenyl)vinyl]-6-fluoro-phenyl]-1,3-dimethyl-6-oxo-pyridazin-4-yl] 2-methylpropanoate (4.036)
[0206] [5-(2-Bromo-3-chloro-6-fluoro-phenyl)-1,3-dimethyl-6-oxo-pyridazin-4-yl] 2-methylpropanoate (1.10 g, 2.63 mmol) [prepared as described in Example 1] and chloro[(tri-tert-butylphosphine)-2-(2-aminobiphenyl)] palladium(II) (68 mg, 0.13 mmol) were combined in degassed toluene (12 mL). 4-vinylbenzonitrile (408 mg, 3.16 mmol) and Hunig's base (0.92 mL, 5.27 mmol) were then added and the reaction mixture heated to 95° C. for 2.5 hrs.
[0207] The reaction mixture was allowed to cool to room temperature then diluted with dichloromethane and filtered through celite, washing with further dichloromethane. The filtrate was concentrated in vacuo then purified by column chromatography on silica gel (eluent an ethyl acetate/hexane gradient) to give [5-[3-chloro-2-[(E)-2-(4-cyanophenyl)vinyl]-6-fluoro-phenyl]-1,3-dimethyl-6-oxo-pyridazin-4-yl] 2-methylpropanoate (781 mg, 64% yield, A-4.036) as a white solid
##STR00045##
[0208] .sup.1H NMR (400 MHz, chloroform) δ=7.62-7.55 (m, 2H), 7.45 (dd, J=5.0, 8.5 Hz, 1H), 7.45-7.40 (m, 1H), 7.13 (d, J=16.5 Hz, 1H), 7.05 (t, J=8.5 Hz, 1H), 6.68 (d, J=16.5 Hz, 1H), 3.69 (s, 3H), 2.65 (spt, J=7.0 Hz, 1H), 2.23 (s, 3H), 1.11 (d, J=7.0 Hz, 3H), 1.07 (d, J=7.0 Hz, 3H).
2.2 [5-[3-Chloro-2-[2-(4-cyanophenyl)ethyl]-6-fluoro-phenyl]-1,3-dimethyl-6-oxo-pyridazin-4-yl] 2-methylpropanoate (A-3.036)
[0209] [5-[3-Chloro-2-[(E)-2-(4-cyanophenyl)vinyl]-6-fluoro-phenyl]-1,3-dimethyl-6-oxo-pyridazin-4-yl] 2-methylpropanoate (900 mg, 1.93 mmol) was subjected to catalytic hydrogenation in EtOAc (20 mL) over 5% Pd/C (50% wet) catalyst (0.82 g) at 4 bar H.sub.2.
[0210] After 1.5 hrs, LC/MS showed complete reaction. The reaction mixture was filtered through a pad of Celite®, washing with ethyl acetate. The filtrate was concentrated in-vacuo to afford a crude residue.
[0211] The residue was adsorbed onto silica and purified by column chromatography on silica gel (eluent an ethyl acetate/hexane gradient) to give [5-[3-chloro-2-[2-(4-cyanophenyl)ethyl]-6-fluoro-phenyl]-1,3-dimethyl-6-oxo-pyridazin-4-yl] 2-methylpropanoate (800 mg, 81% yield, A-3.036) as a white solid.
##STR00046##
[0212] .sup.1H NMR (400 MHz, chloroform) δ=7.56-7.51 (m, 2H), 7.42 (dd, J=5.2, 8.9 Hz, 1H), 7.26-7.21 (m, 2H), 7.00 (t, J=8.9 Hz, 1H), 3.84 (s, 3H), 3.02-2.92 (m, 1H), 2.91-2.80 (m, 2H), 2.75-2.65 (m, 1H), 2.54 (spt, J=7.0 Hz, 1H), 2.25 (s, 3H), 0.98 (d, J=7.0 Hz, 3H), 0.95 (d, J=7.0 Hz, 3H).
2.3 4-[2-[6-Chloro-3-fluoro-2-(5-hydroxy-2,6-dimethyl-3-oxo-pyridazin-4-yl)phenyl]ethyl]benzonitrile (A-1.036)
[0213] [[5-[3-Chloro-2-[2-(4-cyanophenyl)ethyl]-6-fluoro-phenyl]-1,3-dimethyl-6-oxo-pyridazin-4-yl] 2-methylpropanoate (400 mg, 0.855 mmol) was dissolved in ethanol (6 mL). The mixture was treated with a solution of lithium hydroxide (108 mg, 2.56 mmol) in water (2 mL). The reaction was stirred at room temperature for 2 hrs.
[0214] The reaction mixture was concentrated in-vacuo to remove ethanol. The remaining aqueous solution was diluted with water (15 mL) then acidified to ˜pH 3 with 2M HCl and extracted with DCM (3×10 mL). The combined organics were dried over MgSO.sub.4, filtered and concentrated in vacuo to afford crude product.
[0215] The crude product was purified by column chromatography on silica gel (eluent an ethyl acetate/hexane gradient) to give 4-[2-[6-chloro-3-fluoro-2-(5-hydroxy-2,6-dimethyl-3-oxo-pyridazin-4-yl)phenyl]ethyl]benzonitrile (83 mg, 91% yield, A-1.036)) as a white solid.
##STR00047##
[0216] .sup.1H NMR (400 MHz, CDCl.sub.3) δ ppm 7.46-7.51 (m, 2H) 7.26-7.31 (m, 1H) 7.08 (d, J=8.19 Hz, 2H) 6.86 (t, J=8.50 Hz, 1H) 3.63 (s, 3H) 2.61-2.77 (m, 4H) 2.24 (s, 3H).
Example 4 Preparation of 4-[2-[6-chloro-3-fluoro-2-(5-hydroxy-2,6-dimethyl-3-oxo-pyridazin-4-yl)phenyl]ethyl]-N-ethyl-2-fluoro-N-methyl-benzamide (A-1.028)
[0217] ##STR00048##
[0218] 4.1 [5-[3-Chloro-6-fluoro-2-[(E)-2-(6-methyl-4,8-dioxo-1,3,6,2-dioxazaborocan-2-yl)vinyl]phenyl]-1,3-dimethyl-6-oxo-pyridazin-4-yl] 2-methylpropanoate
[0219] [5-(2-Bromo-3-chloro-6-fluoro-phenyl)-1,3-dimethyl-6-oxo-pyridazin-4-yl] 2-methyl-propanoate (5.00 g, 11.97 mmol, 1.0 eq), 6-methyl-2-vinyl-1,3,6,2-dioxazaborocane-4,8-dione (2.63 g, 14.36 mmol, 1.2 eq) and chloro[(tri-tert-butylphosphine)-2-(2-aminobiphenyl)] palladium(II) (307 mg, 0.60 mmol, 0.05 eq) were charged into a 250 ml round bottom flask fitted with a condenser, stirrer bar and nitrogen bubbler. THE (100 mL) was added followed by N,N-diisopropylethylamine (4.2 mL, 23.94 mmol, 2.0 eq) against a flow of nitrogen and the mixture heated to reflux for 3 h.
[0220] The reaction mixture was allowed to cool to room temperature then diluted in DCM and filtered through Celite®, washing with further portions of DCM. The eluent was then concentrated to dryness.
[0221] The crude product purified by flash column chromatography to afford [5-[3-chloro-6-fluoro-2-[(E)-2-(6-methyl-4,8-dioxo-1,3,6,2-dioxazaborocan-2-yl)vinyl]phenyl]-1,3-dimethyl-6-oxo-pyridazin-4-yl] 2-methylpropanoate (5.91 g, 11.4 mmol, 95% yield) as an off white solid.
##STR00049##
[0222] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ=7.63 (dd, J=5.1, 8.9 Hz, 1H), 7.31 (t, J=8.9 Hz, 1H), 6.65 (d, J=18.3 Hz, 1H), 5.68 (d, J=18.3 Hz, 1H), 4.24 (dd, J=11.9, 17.2 Hz, 2H), 3.95-3.83 (m, 2H), 3.70 (s, 3H), 2.66 (spt, J=7.0 Hz, 1H), 2.16 (s, 3H), 0.90 (d, J=7.0 Hz, 3H), 0.89 (d, J=7.0 Hz, 3H)
4.2 [5-[3-Chloro-2-[2-[4-[ethyl(methyl)carbamoyl]-3-fluoro-phenyl]ethyl]-6-fluoro-phenyl]-1,3-dimethyl-6-oxo-pyridazin-4-yl] 2-methylpropanoate (A-3.028)
[0223] [5-[3-chloro-6-fluoro-2-[(E)-2-(6-methyl-4,8-dioxo-1,3,6,2-dioxazaborocan-2-yl)vinyl]phenyl]-1,3-dimethyl-6-oxo-pyridazin-4-yl] 2-methylpropanoate (500 mg, 0.96 mmol), K.sub.3PO.sub.4 (886 mg, 3.85 mmol) and 1,1-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex [PdCl.sub.2(dppf).DCM] (39 mg, 0.05 mmol) were added to a 20 mL microwave vial. THE (10 mL), 4-bromo-N-ethyl-2-fluoro-N-methyl-benzamide (500 mg, 1.92 mmol) and water (0.35 mL) were added then the reaction mixture was heated to 100° C. for 2 hours under microwave irradiation.
[0224] The reaction mixture was concentrated in vacuo to remove THF, then diluted with water (20 mL) and DCM (20 mL). The organic layer was separated and the aqueous layer extracted with DCM (3×5 mL). The combined organics were dried and concentrated in vacuo to give a crude residue which was purified by column chromatography on silica gel, eluting with a cyclohexane/ethyl acetate gradient, to give [5-[3-chloro-2-[(E)-2-[4-[ethyl(methyl)carbamoyl]-3-fluoro-phenyl]vinyl]-6-fluoro-phenyl]-1,3-dimethyl-6-oxo-pyridazin-4-yl] 2-methylpropanoate (397 mg, 76% yield, A-4.028) as an off white solid.
[0225] [5-[3-Chloro-2-[(E)-2-[4-[ethyl(methyl)carbamoyl]-3-fluoro-phenyl]vinyl]-6-fluoro-phenyl]-1,3-dimethyl-6-oxo-pyridazin-4-yl] 2-methylpropanoate (300 mg, 0.55 mmol) was subjected to catalytic hydrogenation in EtOAc (6 mL) over 5% Pd/C (50% wet) catalyst (0.12 g) at 3 bar H.sub.2.
[0226] After 5.5 hrs, LC/MS showed complete reaction. The reaction mixture was filtered through a pad of Celite®, washing with ethyl acetate/methanol. The filtrate was concentrated in-vacuo to afford a crude residue.
[0227] The residue was adsorbed onto silica and purified by column chromatography on silica gel (eluent an ethyl acetate/hexane gradient) to give [5-[3-chloro-2-[2-[4-[ethyl(methyl)carbamoyl]-3-fluoro-phenyl]ethyl]-6-fluoro-phenyl]-1,3-dimethyl-6-oxo-pyridazin-4-yl] 2-methylpropanoate (285 mg, 95% yield, A-3.028) as a colourless gum.
##STR00050##
[0228] [NMR of mixture of rotamers] .sup.1H NMR (400 MHz, chloroform) δ=7.42 (dd, J=5.1, 8.9 Hz, 1H), [7.25 (t, J=7.2 Hz, 0.5H), 7.21 (t, J=7.5 Hz, 0.5H)], 6.99 (t, J=8.9 Hz, 1H), 6.96 (dd, J=1.2, 7.5 Hz, 1H), [6.89 (dd, J=1.2, 6.9 Hz, 1H), 6.86 (dd, J=1.2, 6.9 Hz, 1H)], 3.85 (s, 3H), [3.59 (q, J=7.4 Hz, 1H), 3.24 (q, J=7.4 Hz, 1H)], [3.08 (s, 1.5H), 2.90 (br s, 1.5H)], 2.88-2.78 (m, 3H), 2.75-2.64 (m, 1H), 2.55 (spt, J=7.0 Hz, 1H), 2.26 (s, 3H), [1.23 (t, J=7.2 Hz, 1.5H), 1.10 (t, J=7.2 Hz, 1.5H)], 0.98 (d, J=7.0 Hz, 3H), 0.96 (d, J=7.1 Hz, 3H)
4.3 4-[2-[6-Chloro-3-fluoro-2-(5-hydroxy-2,6-dimethyl-3-oxo-pyridazin-4-yl)phenyl]ethyl]-N-ethyl-2-fluoro-N-methyl-benzamide (A-1.028)
[0229] [5-[3-Chloro-2-[2-[4-[ethyl(methyl)carbamoyl]-3-fluoro-phenyl]ethyl]-6-fluoro-phenyl]-1,3-dimethyl-6-oxo-pyridazin-4-yl] 2-methylpropanoate (300 mg, 0.55 mmol) was dissolved in ethanol (3 mL). The mixture was treated with a solution of lithium hydroxide (69 mg, 1.65 mmol) in water (3 mL). The reaction was stirred at room temperature for 2 hrs.
[0230] The reaction mixture was concentrated in vacuo to remove ethanol. The remaining aqueous solution was diluted with water (15 mL) then acidified to ˜pH 3 with 2M HCl and extracted with DCM (3×10 mL). The combined organics were dried and concentrated in-vacuo to afford crude product.
[0231] The crude product was purified by column chromatography on silica gel (eluent a DCM/methanol gradient) to give 4-[2-[6-chloro-3-fluoro-2-(5-hydroxy-2,6-dimethyl-3-oxo-pyridazin-4-yl)phenyl]ethyl]-N-ethyl-2-fluoro-N-methyl-benzamide (224 mg, 86% yield, A-1.028) as a white solid.
##STR00051##
[0232] [NMR of mixture of rotamers] .sup.1H NMR (400 MHz, DMSO-d6) δ=10.86 (br s, 1H), 7.55-7.49 (m, 1H), 7.25-7.19 (m, 2H), 6.95-6.89 (m, 2H), 3.61 (s, 3H), 3.46 (q, J=7.1 Hz, 1H), 3.12 (q, J=7.1 Hz, 1H), 2.95 (s, 1.5H), 2.78 (s, 1.5H), 2.78-2.63 (m, 4H), 2.26 (s, 3H), 1.11 (t, J=7.1 Hz, 1.5H), 1.00 (t, J=7.1 Hz, 1.5H).
Example 5 Preparation of [5-[3-chloro-2-[(E)-2-(4-cyclopropylphenyl)vinyl]-6-fluoro-phenyl]-1,3-dimethyl-6-oxo-pyridazin-4-yl] 2-methylpropanoate (A-4.038)
[0233] ##STR00052##
5.1 [5-(3-Chloro-6-fluoro-2-vinyl-phenyl)-1,3-dimethyl-6-oxo-pyridazin-4-yl] 2-methylpropanoate
[0234] [5-(2-Bromo-3-chloro-6-fluoro-phenyl)-1,3-dimethyl-6-oxo-pyridazin-4-yl] 2-methylpropanoate (4.177 g, 10.00 mmol, 1.0 eq) and tributyl(vinyl)stannane (4.384 mL, 15.00 mmol, 1.50 eq) were dissolved in toluene (60.00 mL) then 1,1-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex [PdCl.sub.2(dppf).DCM] (408 mg, 0.50 mmol, 0.05 eq) was added. The reaction mixture was heated at reflux overnight.
[0235] The reaction mixture was allowed to cool to room temperature then concentrated in vacuo. The crude product was then purified by flash column chromatography to afford [5-(3-chloro-6-fluoro-2-vinyl-phenyl)-1,3-dimethyl-6-oxo-pyridazin-4-yl] 2-methylpropanoate as an off-white solid (3.02 g, 83% yield).
##STR00053##
[0236] .sup.1H NMR (400 MHz, CDCl.sub.3) δ=7.40 (dd, J=5.1, 8.7 Hz, 1H), 6.99 (t, J=8.7 Hz, 1H), 6.65 (dd, J=11.6, 17.6 Hz, 1H), 5.37-5.30 (m, 2H), 3.79 (s, 3H), 2.59 (spt, J=7.0 Hz, 1H), 2.23 (s, 3H), 1.04 (d, J=7.0 Hz, 4H), 1.03 (d, J=7.0 Hz, 1H)
5.2 [5-[3-Chloro-2-[(E)-2-(4-cyclopropylphenyl)vinyl]-6-fluoro-phenyl]-1,3-dimethyl-6-oxo-pyridazin-4-yl] 2-methylpropanoate (A-4.038)
[0237] A stirred mixture of [5-(3-chloro-6-fluoro-2-vinyl-phenyl)-1,3-dimethyl-6-oxo-pyridazin-4-yl]2-methylpropanoate (300 mg, 1.0 eq), chloro[(tri-tert-butylphosphine)-2-(2-aminobiphenyl)]palladium(II) (21 mg, 0.05 eq), 1-bromo-4-cyclopropylbenzene (243 mg, 1.5 eq) and N,N-diisopropylethylamine (0.29 mL, 2.0 eq) in toluene (5 mL) under nitrogen was heated at reflux for 3 hrs.
[0238] The reaction mixture was allowed to cool to room temperature then diluted with DCM and filtered through a pad of Celite, eluting with further portions of DCM. The filtrate was concentrated in vacuo to give the crude product.
[0239] The crude product was purified by flash column chromatography to give [5-[3-chloro-2-[(E)-2-(4-cyclopropylphenyl)vinyl]-6-fluoro-phenyl]-1,3-dimethyl-6-oxo-pyridazin-4-yl] 2-methylpropanoate (285 mg, 72% yield) as a pale yellow gum.
##STR00054##
[0240] .sup.1H NMR (400 MHz, CDCl.sub.3) δ=7.41 (dd, J=5.1, 8.9 Hz, 1H), 7.26-7.22 (m, 2H), 7.02-6.98 (m, 2H), 6.99 (t, J=8.9 Hz, 1H), 6.93 (d, J=16.5 Hz, 1H), 6.59 (d, J=16.5 Hz, 1H), 3.71 (s, 3H), 2.62 (spt, J=7.0 Hz, 1H), 2.19 (s, 3H), 1.87 (tt, J=5.0, 8.4 Hz, 1H), 1.07 (d, J=7.0 Hz, 3H), 1.06 (d, J=7.0 Hz, 1H), 0.99-0.93 (m, J=2.0, 8.4 Hz, 2H), 0.73-0.64 (m, 2H).
Example 6 Preparation of 4-[3-chloro-6-fluoro-2-[2-(4-methylsulfanylphenyl)ethyl]-phenyl]-5-hydroxy-2,6-dimethyl-pyridazin-3-one (A-1.039)
[0241] ##STR00055##
6.1 [5-[3-Chloro-6-fluoro-2-[2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)ethyl]phenyl]-1,3-dimethyl-6-oxo-pyridazin-4-yl] 2-methylpropanoate
[0242] An oven-dried round-bottom flask was then charged with Ir(COD)Cl.sub.2 (299 mg, 0.45 mmol) and 4-diphenylphosphanylbutyl(diphenyl)phosphane (0380 mg, 0.89 mmol). The flask was evacuated and backfilled with nitrogen (×3), then THE (75 mL) was added and the reaction was stirred at room temperature for 30 mins. A solution of [5-(3-chloro-6-fluoro-2-vinyl-phenyl)-1,3-dimethyl-6-oxo-pyridazin-4-yl] 2-methylpropanoate [prepared as described in Example 4] (6.7 g, 17.8 mmol) in THE was added dropwise and the mixture was stirred for 10 mins, followed by the dropwise addition of 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (3.02 mL, 20.8 mmol). The reaction was stirred at 60° C. overnight.
[0243] After 24 h, the reaction was allowed to cool to room temperature then concentrated in vacuo. The crude product was purified by column chromatography on silica gel, eluting with a cyclohexane/ethylacetate gradient, to give [5-[3-chloro-6-fluoro-2-[2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)ethyl]phenyl]-1,3-dimethyl-6-oxo-pyridazin-4-yl] 2-methylpropanoate (4.50 g, 51% yield) as a yellow solid.
##STR00056##
[0244] .sup.1H NMR (500 MHz, chloroform) δ=7.35 (dd, J=5.2, 8.9 Hz, 1H), 6.90 (t, J=8.6 Hz, 1H), 3.81 (s, 3H), 2.59 (t, J=8.5 Hz, 2H), 2.53 (spt, J=7.0 Hz, 1H), 2.24 (s, 3H), 1.32-1.16 (m, 12H), 1.08-1.00 (m, 2H), 0.98 (d, J=7.0 Hz, 3H), 0.94 (d, J=7.0 Hz, 3H).
6.2 4-[3-Chloro-6-fluoro-2-[2-(4-methylsulfanylphenyl)ethyl]phenyl]-5-hydroxy-2,6-dimethyl-pyridazin-3-one (A-1.039)
[0245] [5-[3-Chloro-6-fluoro-2-[2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)ethyl]phenyl]-1,3-dimethyl-6-oxo-pyridazin-4-yl] 2-methylpropanoate (100 mg, 0.20 mmol), 1-bromo-4-methylsulfanyl-benzene (62 mg, 0.30 mmol), chloro(2-dicyclohexylphosphino-2′,6′-diisopropoxy-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II) (24 mg, 0.03 mmol), K.sub.2CO.sub.3 (84 mg, 0.61 mmol), 1,4-dioxane (2 mL) and water (0.2 mL) were combined in a 5 mL microwave vial. The reaction mixture was then heated at 140° C. for 90 minutes under microwave irradiation.
[0246] The reaction mixture was allowed to cool to room temperature then diluted with water (10 mL), acidified to ˜pH 3 with 2M HCl and extracted with DCM (4 x). The combined organics were concentrated in vacuo to give the crude product was purified by mass-directed reverse-phase HPLC to afford 4-[3-chloro-6-fluoro-2-[2-(4-methylsulfanylphenyl)ethyl]phenyl]-5-hydroxy-2,6-dimethyl-pyridazin-3-one as a white solid (22 mg, 22% yield, A-1.039).
##STR00057##
[0247] .sup.1H NMR (400 MHz, chloroform) δ=7.46-7.39 (m, 3H), 7.12 (d, J=8.0 Hz, 2H), 6.98 (t, J=8.6 Hz, 1H), 6.90 (d, J=8.0 Hz, 2H), 3.73 (s, 3H), 2.84-2.64 (m, 4H), 2.45 (s, 3H), 2.29 (s, 3H).
Example 7 Preparation of 4-[3-chloro-6-fluoro-2-[2-[4-(methylsulfanylmethyl)phenyl]ethyl]phenyl]-5-hydroxy-2,6-dimethyl-pyridazin-3-one (A-1.388)
[0248] ##STR00058##
7.1 4-[3-chloro-6-fluoro-2-[(E)-2-[4-(methylsulfanylmethyl)phenyl]vinyl]phenyl]-5-hydroxy-2,6-dimethyl-pyridazin-3-one
[0249] [5-[3-chloro-6-fluoro-2-[(E)-2-(6-methyl-4,8-dioxo-1,3,6,2-dioxazaborocan-2-yl)vinyl]phenyl]-1,3-dimethyl-6-oxo-pyridazin-4-yl] 2-methylpropanoate (500 mg, 0.96 mmol), 1-bromo-4-(methylsulfanylmethyl)benzene (324 mg, 1.44 mmol), 1,1-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex [PdCl.sub.2(dppf).DCM] (41 mg, 0.05 mmol) and POTASSIUM CARBONATE (417 mg, 2.89 mmol) were added to a 10-20 ml microwave vial under an atmosphere of nitrogen. De-gassed acetonitrile (11.5 mL) and water (2.9 mL) were added and the mixture heated to 150° C. for 20 min under microwave irradiation.
[0250] The reaction mixture was concentrated to dryness. The residue was treated with water (20 ml) and the aqueous phase acidified to pH 3 by addition of 2M HCl leading to formation of a precipitate. DCM (20 ml) was added to take up the precipitate. Brine (20 ml) was added and the phases separated. The aqueous phase was extracted with two further portions of DCM then the combined organic extracts were dried and concentrated directly onto silica. The crude material was purified by automated flash chromatography on silica gel, eluting with a cyclohexane/ethyl acetate gradient to give 4-[3-chloro-6-fluoro-2-[(E)-2-[4-(methylsulfanylmethyl)phenyl]vinyl]phenyl]-5-hydroxy-2,6-dimethyl-pyridazin-3-one (341 mg, 82% yield) as an off-white solid.
##STR00059##
[0251] .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ=10.78 (br s, 1H), 7.60 (dd, J=5.2, 8.7 Hz, 1H), 7.30-7.24 (m, 5H), 6.93 (d, J=16.5 Hz, 1H), 6.56 (d, J=16.5 Hz, 1H), 3.67 (s, 2H), 3.54 (s, 3H), 2.19 (s, 3H), 1.94 (s, 3H)
7.2 4-[3-chloro-6-fluoro-2-[2-[4-(methylsulfanylmethyl)phenyl]ethyl]phenyl]-5-hydroxy-2,6-dimethyl-pyridazin-3-one (A-1.388)
[0252] To a solution of 4-[3-chloro-6-fluoro-2-[(E)-2-[4-(methylsulfanylmethyl)phenyl]vinyl]phenyl]-5-hydroxy-2,6-dimethyl-pyridazin-3-one (335 mg, 0.78 mmol) in tetrahydrofuran (12 ml) under a nitrogen atmosphere, was added N,N-Diisopropylethylamine (1.08 ml, 6.20 mmol). The stirred reaction mixture was heated to 70° C. and 2,4,6-Triisopropylbenzenesulfonyl hydrazide (2.06 g, 6.21 mmol) was added portionwise over 6 h then the mixture heated to reflux for 16 h. Additional N,N-Diisopropylethylamine (0.68 ml, 3.89 mmol) was added to the reaction mixture, followed by 2,4,6-Triisopropylbenzenesulfonyl hydrazide (1.29 g, 3.89 mmol) and the mixture heated to reflux for a further 6 h.
[0253] The reaction mixture was allowed to cool to room temperature, then concentrated directly onto silica. The crude material was partially purified by automated flash chromatography on silica gel eluting with a cyclohexane/ethyl acetate gradient. The material obtained was further purified by mass-directed reverse-phase HPLC to afford 4-[3-chloro-6-fluoro-2-[2-[4-(methylsulfanylmethyl)phenyl]ethyl]phenyl]-5-hydroxy-2,6-dimethyl-pyridazin-3-one as a white solid (208 mg, 62% yield, A-1.388)
##STR00060##
[0254] .sup.1H NMR (400 MHz, d6-DMSO), δ=10.83 (s, 1H), 7.56-7.53 (m, 1H), 7.23-7.16 (m, 3H), 6.96-6.94 (d, 2H), 3.62 (s, 2H), 3.60 (s, 3H), 2.68-2.54 (m, 4H), 2.26 (s, 3H), 1.92 (s, 3H)
Example 8 4-[3-chloro-6-fluoro-2-[2-[4-(1,2,4-triazol-1-yl)phenyl]ethyl]phenyl]-5-hydroxy-2,6-dimethyl-pyridazin-3-one (A-1.385)
[0255] ##STR00061##
8.1 [4-(1,2,4-triazol-1-yl)phenyl] trifluoromethanesulfonate
[0256] 4-(1,2,4-triazol-1-yl)phenol (1.22 g, 7.57 mmol) was dissolved dichloromethane (10 ml) under nitrogen and cooled to ˜0° C. A solution of pyridine (1.22 ml, 15.1 mmol) in dichloromethane (5 ml) was added dropwise over ˜2 minutes. The mixture was stirred 5 minutes, then a solution of trifluoromethanesulfonic anhydride (1.53 ml, 9.08 mmol) in dichloromethane (5 ml) was added dropwise over ˜2 minutes. Cooling was removed and the reaction mixture allowed to warm to room temperature then stirred at room temperature for 16 h.
[0257] The reaction was quenched by addition of 2M HCl aq. (20 ml), then the organic phase separated. The aqueous phase was further extracted with dichloromethane (2×20 ml). The combined organics were washed with water (20 ml), dried, then concentrated under reduced pressure to give a cream solid. The crude material was purified by automated flash chromatography on silica eluting with a cyclohexane/ethyl acetate gradient to give [4-(1,2,4-triazol-1-yl)phenyl] trifluoromethanesulfonate as a white solid (2.02 g, 91% yield).
##STR00062##
[0258] .sup.1H NMR (400 MHz, chloroform) 6=8.59 (s, 1H), 8.14 (s, 1H), 7.86-7.78 (m, 2H), 7.50-7.41 (m, 2H).
8.2 [5-[3-chloro-6-fluoro-2-[(E)-2-[4-(1,2,4-triazol-1-yl)phenyl]vinyl]phenyl]-1,3-dimethyl-6-oxo-pyridazin-4-yl] 2-methylpropanoate
[0259] [5-[3-chloro-6-fluoro-2-[(E)-2-(6-methyl-4,8-dioxo-1,3,6,2-dioxazaborocan-2-yl)vinyl]phenyl]-1,3-dimethyl-6-oxo-pyridazin-4-yl] 2-methylpropanoate (500 mg, 0.96 mmol), 1,1-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex [PdCl.sub.2(dppf).DCM] (39 mg, 0.048 mmol), [4-(1,2,4-triazol-1-yl)phenyl] trifluoromethanesulfonate (367 mg, 1.25 mmol) and potassium phosphate (834 mg, 3.85 mmol) were added to a 10-20 ml microwave vial.
[0260] Tetrahydrofuran (10 ml) and water (0.5 ml) were added, then the reaction mixture degassed by stirring under vacuum then back-filling with nitrogen (×3). The reaction mixture heated in the microwave at 120° C. for 60 mins under microwave irradiation.
[0261] The reaction mixture was filtered through a plug of Celite®, washing through with EtOAc & EtOH. The filtrate was concentrated under reduced pressure to give a brown gum (840 mg). The crude material was purified by automated flash chromatography on silica gel eluting with a cyclohexane/ethyl acetate gradient to give a pale yellow gum (389 mg). The purified material was dissolved in acetonitrile (10 ml) and treated with SiliCycle SiliaMetS® Thiol (SH) metal scavenger resin (365 mg) at room temperature. The suspension was stirred at room temperature for 3 h, then filtered to remove the resin, washing with further acetonitrile. The filtrate was concentrated in vacuo to provide [5-[3-chloro-6-fluoro-2-[(E)-2-[4-(1,2,4-triazol-1-yl)phenyl]vinyl]phenyl]-1,3-dimethyl-6-oxo-pyridazin-4-yl] 2-methylpropanoate as a colourless gum (361 mg, 73% yield).
##STR00063##
[0262] .sup.1H NMR (400 MHz, chloroform) δ ppm 8.55 (s, 1H), 8.11 (s, 1H), 7.60-7.66 (m, 2H), 7.42-7.53 (m, 3H), 7.01-7.10 (m, 2H), 6.69 (d, J=16.5 Hz, 1H), 3.70 (s, 3H), 2.66 (spt, J=7.0 Hz, 1H), 2.23 (s, 3H), 1.11 (d, J=7.0 Hz, 1H), 1.08 (d, J=7.1 Hz, 1H)
8.3 [5-[3-chloro-6-fluoro-2-[2-[4-(1,2,4-triazol-1-yl)phenyl]ethyl]phenyl]-1,3-dimethyl-6-oxo-pyridazin-4-yl] 2-methylpropanoate (A-3.385)
[0263] [5-[3-chloro-6-fluoro-2-[(E)-2-[4-(1,2,4-triazol-1-yl)phenyl]vinyl]phenyl]-1,3-dimethyl-6-oxo-pyridazin-4-yl] 2-methylpropanoate (365 mg, 0.72 mmol) was subjected to catalytic hydrogenation in EtOAc (10 mL) over 5% Pd/C (50% wet) catalyst (0.15 g) at 3 bar H.sub.2 for 24 h.
[0264] The reaction mixture was filtered through a pad of Celite®, washing with ethyl acetate. The filtrate was concentrated in-vacuo to afford a crude residue (350 mg) which was adsorbed onto silica and purified by automated flash chromatography on silica gel, eluting with a cyclohexane/ethyl acetate gradient. [5-[3-chloro-6-fluoro-2-[2-[4-(1,2,4-triazol-1-yl)phenyl]ethyl]phenyl]-1,3-dimethyl-6-oxo-pyridazin-4-yl] 2-methylpropanoate (A-3.385) was obtained as a colourless gum (321 mg, 88% yield).
##STR00064##
[0265] .sup.1H NMR (400 MHz, chloroform) δ=8.51 (s, 1H), 8.09 (s, 1H), 7.55 (d, J=8.2 Hz, 2H), 7.43 (dd, J=5.2, 8.7 Hz, 1H), 7.27 (d, J=8.2 Hz, 2H), 7.00 (t, J=8.7 Hz, 1H), 3.84 (s, 3H), 2.97-2.80 (m, 3H), 2.79-2.67 (m, 1H), 2.55 (spt, J=7.0 Hz, 1H), 2.25 (s, 3H), 0.98 (d, J=7.0 Hz, 3H), 0.96 (d, J=7.0 Hz, 1H)
8.4 4-[3-chloro-6-fluoro-2-[2-[4-(1,2,4-triazol-1-yl)phenyl]ethyl]phenyl]-5-hydroxy-2,6-dimethyl-pyridazin-3-one (A-1.385)
[0266] [5-[3-chloro-6-fluoro-2-[2-[4-(1,2,4-triazol-1-yl)phenyl]ethyl]phenyl]-1,3-dimethyl-6-oxo-pyridazin-4-yl] 2-methylpropanoate (320 mg, 0.63 mmol) stirred in ethanol (5 ml) at room temperature.
[0267] A solution of lithium hydroxide monohydrate (81 mg, 1.88 mmol) in water (2 ml) was added dropwise and the reaction stirred at room temperature for 1 h.
[0268] The ethanol solvent was removed under reduced pressure, then residue diluted with water (20 ml). The aqueous phase was acidified to ˜pH 3-4 by the addition of 2M HCl (aq.), then extracted with EtOAc (3×10 ml). The combined organic extracts were concentrated under reduced pressure to give a white solid (292 mg). The crude residue was purified by automated flash chromatography on silica, eluting with a cyclohexane/ethyl acetate and ethyl acetate/ethanol gradient to afford 4-[3-chloro-6-fluoro-2-[2-[4-(1,2,4-triazol-1-yl)phenyl]ethyl]phenyl]-5-hydroxy-2,6-dimethyl-pyridazin-3-one (A-1.365) as a white solid (260 mg, 94% yield).
##STR00065##
[0269] .sup.1H NMR (400 MHz, methanol), δ ppm 9.03 (s, 1H), 8.14 (s, 1H), 7.65-7.70 (m, 2H), 7.51 (dd, J=5.2, 8.7 Hz, 1H), 7.20 (m, 2H), 7.11 (t, J=8.7 Hz, 1H), 3.72 (s, 3H), 2.72-2.89 (m, 4H), 2.32 (s, 3H)
Example 9 4-[3-cyclopropyl-6-fluoro-2-[2-(2-fluoro-4-pyridyl)ethyl]phenyl]-5-hydroxy-2,6-dimethyl-pyridazin-3-one (C-1.013)
[0270] [5-[3-chloro-6-fluoro-2-[2-(2-fluoro-4-pyridyl)ethyl]phenyl]-1,3-dimethyl-6-oxo-pyridazin-4-yl] 2-methylpropanoate (250 mg, 0.54 mmol), tripotassium phosphate monohydrate (374 mg., 1.62 mmol) and RuPhos Pd G2 (42 mg, 0.05 mmol) were charged into a 2-5 ml microwave vial equipped with a stirrer bar. The reaction vessel was evacuated and back filled with nitrogen (×3). 1,4-dioxane (4 ml) was added followed by cyclopropylboronic acid (139 mg, 1.62 mmol) and water (1 ml) (both solvents degassed). The mixture was then heated to 120° C. for 1 h under microwave irradiation.
[0271] The reaction was cooled to room temperature, before additional cyclopropylboronic (139 mg, 1.62 mmol) and RuPhos Pd G2 (42 mg, 0.05 mmol) were added and the reaction heated to 120° C. for a further 2.5 hours:
[0272] The reaction mixture was concentrated in vacuo to remove the dioxane. The residue was diluted with water (20 ml) and DCM (20 mL) and the layers separated. The aqueous phase was extracted with further portions of DCM (3×5 ml) then the combined organic extracts dried and concentrated to give a dark solid (331 mg)
[0273] The crude residue was purified by mass-directed reverse-phase HPLC to afford 4-[3-cyclopropyl-6-fluoro-2-[2-(2-fluoro-4-pyridyl)ethyl]phenyl]-5-hydroxy-2,6-dimethyl-pyridazin-3-one (C-1.013) as a white solid
##STR00066##
[0274] .sup.1H NMR (400 MHz, methanol) 6=8.01 (d, J=5.1 Hz, 1H), 7.13 (dd, J=5.6, 8.3 Hz, 1H), 7.02-6.93 (m, 2H), 6.72 (br s, 1H), 3.72 (s, 3H), 3.02-2.75 (m, 4H), 2.32 (s, 3H), 1.97-1.87 (m, 1H), 1.02-0.89 (m, 2H), 0.74-0.61 (m, 2H)
[0275] Compounds A-1.023, A-1.024, A-1.025, A-1.026, A-1.027, A-1.028, A-1.029, A-1.030, A-1.031, A-1.032, A-1.033, A-1.034, A-1.035, A-1.036, A-1.037, A-1.038, A-1.039, A-1.040, A-1.041, A-1.042, A-1.043, A-1.044, A-2.027, A-2.030, A-2.037, A-3.028, A-3.029, A-3.030, A-3.035, A-3.036, A-3.038, A-4.029, A-4.030, A-4.035, A-4.036, A-1.373, A-1.374, A-1.375, A-1.376, A-1.377, A-1.378, A-1.379, A-1.380, A-1.381, A-1.382, A-1.383, A-1.384, A-1.386, A-1.387, A-1.389, A-1.390, A-1.391 and A-1.392 were prepared using the general methods as described supra. Table 4 below shows the structure of these compounds and NMR characterising data.
TABLE-US-00004 TABLE 4 Preparation examples of compounds of formula (I). The numbering system used to describe the positions of X and Y is shown for the purposes of clarity only. (I)
B1 Post-Emergence Efficacy—Test 1
[0276] Seeds of a variety of test species are sown in standard soil in pots:—Solanum nigrum (SOLNI), Amaranthus retoflexus (AMARE), Setaria faberi (SETFA), Echinochloa crus-galli (ECHCG), Ipomoea hederacea (IPOHE), Lolium perenne (LOLPE). After 8 days cultivation (post-emergence) under controlled conditions in a glasshouse (at 24/16° C., day/night; 14 hours light; 65% humidity), the plants are sprayed with an aqueous spray solution derived from the formulation of the technical active ingredient in acetone/water (50:50) solution containing 0.5% Tween 20 (polyoxyethylene sorbitan monolaurate, CAS RN 9005-64-5). Compounds are applied at 1000 g/ha. The test plants are then grown in a glasshouse under controlled conditions in a glasshouse (at 24/16° C., day/night; 14 hours light; 65% humidity) and watered twice daily. After 13 days, the test is evaluated for the percentage damage caused to the plant. The biological activities are assessed on a five point scale (5=80-100%; 4=60-79%; 3=40-59%; 2=20-39%; 1=0-19%). A blank value in the table is indicative that the compound was not tested on that species.
TABLE-US-00005 TABLE 5 Control of weed species by compounds of formula (I) after post-emergence application Com- pound AMARE SOLNI SETFA LOLPE ECHCG IPOHE A-1.036 5 5 5 5 5 5
B2 Post-Emergence Efficacy—Test 2
[0277] Seeds of a variety of test species are sown in standard soil in pots:—Solanum nigrum (SOLNI), Amaranthus retoflexus (AMARE), Setaria faberi (SETFA), Echinochloa crus-galli (ECHCG), Ipomoea hederacea (IPOHE), Lolium perenne (LOLPE). After 8 days cultivation (post-emergence) under controlled conditions in a glasshouse (at 24/16° C., day/night; 14 hours light; 65% humidity), the plants are sprayed with an aqueous spray solution derived from the formulation of the technical active ingredient in acetone/water (50:50) solution containing 0.5% Tween 20 (polyoxyethylene sorbitan monolaurate, CAS RN 9005-64-5). Compounds are applied at 250 g/ha. The test plants are then grown in a glasshouse under controlled conditions in a glasshouse (at 24/16° C., day/night; 14 hours light; 65% humidity) and watered twice daily. After 13 days, the test is evaluated for the percentage damage caused to the plant. The biological activities are assessed on a five point scale (5=80-100%; 4=60-79%; 3=40-59%; 2=20-39%; 1=0-19%). A blank value in the table is indicative that the compound was not tested on that species.
TABLE-US-00006 TABLE 6 Control of weed species by compounds of formula (I) after post-emergence application Com- pound AMARE SOLNI SETFA LOLPE ECHCG IPOHE A-1.024 5 5 5 5 4 5 A-1.025 5 5 5 5 5 5 A-1.026 4 4 2 1 0 0 A-1.027 5 4 5 5 5 4 A-1.028 5 5 5 5 5 5 A-1.029 4 5 4 4 2 5 A-1.030 4 5 4 5 4 5 A-1.031 5 5 4 4 4 4 A-1.032 5 5 5 5 5 5 A-1.033 5 5 5 5 4 5 A-1.034 5 5 5 5 1 5 A-1.035 4 5 4 4 4 4 A-1.036 5 5 5 5 5 5 A-1.037 1 5 5 1 3 5 A-1.038 5 5 5 5 5 5 A-1.039 5 5 5 5 5 5 A-1.040 3 3 0 0 0 0 A-1.041 5 5 4 1 1 2 A-1.042 5 5 5 5 5 3 A-1.044 5 5 5 4 3 0 A-2.030 3 4 0 1 0 4 A-2.037 1 2 1 1 2 2 A-3.028 4 5 4 5 5 5 A-3.029 4 5 2 2 1 5 A-3.030 5 5 5 4 2 5 A-3.035 5 5 5 5 4 5 A-3.036 5 5 4 4 4 5 A-3.038 5 5 5 5 2 5 A-4.029 4 4 0 1 1 4 A-4.030 2 3 0 1 1 3 A-4.035 1 3 0 0 0 3 A-4.036 2 5 1 3 3 4 A-4.038 1 5 0 1 1 2 A-1.383 5 5 5 5 5 5 A-1.384 5 5 5 4 3 5 A-1.385 5 5 5 5 5 5
B3 Post-Emergence Efficacy—Test 3
[0278] Seeds of a variety of test species are sown in standard soil in pots:—Amaranthus retoflexus (AMARE), Setaria faberi (SETFA), Echinochloa crus-galli (ECHCG), Ipomoea hederacea (IPOHE), Zea Mays (ZEAMX), Abutilon theophrasti (ABUTH). After 8 days cultivation (post-emergence) under controlled conditions in a glasshouse (at 24/16° C., day/night; 14 hours light; 65% humidity), the plants are sprayed with an aqueous spray solution derived from the formulation of the technical active ingredient in acetone/water (50:50) solution containing 0.5% Tween 20 (polyoxyethylene sorbitan monolaurate, CAS RN 9005-64-5). Compounds are applied at 250 g/ha. The test plants are then grown in a glasshouse under controlled conditions in a glasshouse (at 24/16° C., day/night; 14 hours light; 65% humidity) and watered twice daily. After 13 days, the test is evaluated for the percentage damage caused to the plant. The biological activities are assessed on a five point scale (5=80-100%; 4=60-79%; 3=40-59%; 2=20-39%; 1=0-19%). A blank value in the table is indicative that the compound was not tested on that species.
TABLE-US-00007 TABLE 7 Control of weed species by compounds of formula (I) after post-emergence application Com- pound AMARE ZEAMX SETFA ABUTH ECHCG IPOHE A-1.380 4 2 3 3 1 3 A-1.381 4 1 2 3 0 4 A-1.382 4 5 4 4 4 5 A-3.386 4 5 4 4 5 4 C-1.013 5 4 4 4 5 4 A-1.386 4 4 4 3 4 4 A-1.387 4 4 4 4 4 4 A-1.388 5 4 4 5 4 4 A-1.389 4 5 5 4 5 5 A-1.390 5 1 5 4 4 A-1.391 4 1 4 2 3 A-1.392 5 2 5 4 3
B4 Pre-Emergence Efficacy—Test 1
[0279] Seeds of a variety of test species were sown in standard soil in pots: Solanum nigrum (SOLNI), Amaranthus retoflexus (AMARE), Setaria faberi (SETFA), Echinochloa crus-galli (ECHCG), Ipomoea hederacea (IPOHE), Lolium perenne (LOLPE). After cultivation for one day (pre-emergence) under controlled conditions in a glasshouse (at 24/16° C., day/night; 14 hours light; 65% humidity), the plants were sprayed with an aqueous spray solution derived from the formulation of the technical active ingredient in acetone/water (50:50) solution containing 0.5% Tween 20 (polyoxyethelyene sorbitan monolaurate, CAS RN 9005-64-5). Compounds are applied at 1000 g/ha. The test plants were then grown in a glasshouse under controlled conditions (at 24/16° C., day/night; 14 hours light; 65% humidity) and watered twice daily. After 13 days, the test is evaluated for the percentage damage caused to the plant. The biological activities are assessed on a five point scale (5=80-100%; 4=60-79%; 3=40-59%; 2=20-39%; 1=0-19%). A blank value in the table is indicative that the compound was not tested on that species.
TABLE-US-00008 TABLE 8 Control of weed species by compounds of formula (I) after pre-emergence application Com- pound AMARE SOLNI SETFA LOLPE ECHCG IPOHE A-1.036 5 5 5 5 5 5
B5 Pre-Emergence Efficacy—Test 2
[0280] Seeds of a variety of test species were sown in standard soil in pots: Solanum nigrum (SOLNI), Amaranthus retoflexus (AMARE), Setaria faberi (SETFA), Echinochloa crus-galli (ECHCG), Ipomoea hederacea (IPOHE), Lolium perenne (LOLPE). After cultivation for one day (pre-emergence) under controlled conditions in a glasshouse (at 24/16° C., day/night; 14 hours light; 65% humidity), the plants were sprayed with an aqueous spray solution derived from the formulation of the technical active ingredient in acetone/water (50:50) solution containing 0.5% Tween 20 (polyoxyethelyene sorbitan monolaurate, CAS RN 9005-64-5). Compounds are applied at 250 g/ha. The test plants were then grown in a glasshouse under controlled conditions (at 24/16° C., day/night; 14 hours light; 65% humidity) and watered twice daily. After 13 days, the test is evaluated for the percentage damage caused to the plant. The biological activities are assessed on a five point scale (5=80-100%; 4=60-79%; 3=40-59%; 2=20-39%; 1=0-19%). A blank value in the table is indicative that the compound was not tested on that species.
TABLE-US-00009 TABLE 9 Control of weed species by compounds of formula (I) after pre-emergence application Com- pound AMARE SOLNI SETFA LOLPE ECHCG IPOHE A-1.024 5 5 5 4 2 0 A-1.025 5 5 5 4 5 1 A-1.026 0 0 0 0 0 0 A-1.027 5 4 3 2 1 4 A-1.028 5 5 5 5 4 5 A-1.029 3 5 1 2 5 1 A-1.030 5 5 5 4 5 0 A-1.031 3 2 1 1 2 1 A-1.032 5 5 5 5 5 2 A-1.033 1 1 2 1 0 1 A-1.034 0 2 0 0 0 0 A-1.035 4 3 3 3 1 1 A-1.036 5 5 5 5 5 5 A-1.037 1 2 0 0 2 0 A-1.038 5 5 0 5 5 2 A-1.039 5 5 5 4 5 3 A-1.040 0 0 0 0 0 0 A-1.041 4 0 0 0 0 0 A-1.042 5 5 5 1 2 2 A-1.044 5 5 5 2 3 1 A-2.030 0 0 0 0 0 0 A-2.037 0 0 1 1 0 1 A-3.028 5 5 5 5 5 5 A-3.029 4 5 2 2 3 3 A-3.030 5 5 5 4 4 3 A-3.035 4 5 5 5 4 5 A-3.036 5 5 5 5 5 5 A-3.038 5 5 1 5 2 5 A-4.029 2 4 0 0 0 0 A-4.030 3 4 1 2 1 1 A-4.035 0 0 0 1 1 1 A-4.036 2 5 0 1 1 3 A-4.038 2 1 0 0 0 0 A-1.383 5 5 4 3 4 5 A-1.384 2 1 0 0 0 2 A-1.385 5 5 5 5 5 5
B6 Pre-Emergence Efficacy—Test 3
[0281] Seeds of a variety of test species were sown in standard soil in pots: Amaranthus retoflexus (AMARE), Setaria faberi (SETFA), Echinochloa crus-galli (ECHCG), Ipomoea hederacea (IPOHE), Zea Mays (ZEAMX), Abutilon theophrasti (ABUTH). After cultivation for one day (pre-emergence) under controlled conditions in a glasshouse (at 24/16° C., day/night; 14 hours light; 65% humidity), the plants were sprayed with an aqueous spray solution derived from the formulation of the technical active ingredient in acetone/water (50:50) solution containing 0.5% Tween 20 (polyoxyethelyene sorbitan monolaurate, CAS RN 9005-64-5). Compounds are applied at 250 g/ha. The test plants were then grown in a glasshouse under controlled conditions (at 24/16° C., day/night; 14 hours light; 65% humidity) and watered twice daily. After 13 days, the test is evaluated for the percentage damage caused to the plant. The biological activities are assessed on a five point scale (5=80-100%; 4=60-79%; 3=40-59%; 2=20-39%; 1=0-19%). A blank value in the table is indicative that the compound was not tested on that species.
TABLE-US-00010 TABLE 10 Control of weed species by compounds of formula (I) after pre-emergence application Com- pound AMARE ZEAMX SETFA ABUTH ECHCG IPOHE A-1.380 5 2 1 4 0 4 A-1.381 3 1 0 1 0 3 A-1.382 5 4 5 4 5 5 A-3.386 5 5 5 5 5 5 C-1.013 5 4 5 5 5 5 A-1.386 2 2 5 2 5 4 A-1.387 5 4 5 4 5 5 A-1.388 5 4 5 5 5 5 A-1.389 5 4 5 3 5 5 A-1.390 5 1 5 5 5 A-1.391 5 0 5 2 2 A-1.392 5 2 5 5 5 5