| CPC C07D 417/04 (2013.01) | 20 Claims |
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1. A method for preparing a halopyrazolylthiazole of formula (Ia)
 wherein
X is a halogen;
L1 is selected from the group consisting of a bond, —C(O)—, —S—, —S(O)1-2—, —O—, —NR6—, —C(O)NR6—, —NR6C(O)—, —C(S)NR6—, —NR6C(S)—, —C(O)O—, —OC(O)—, —C(O)S—, —SC(O)—, —C(S)O—, —OC(S)—, —C(S)S—, —SC(S)—, —S(O)1-2O—, —OS(O)1-2—, —S(O)1-2NR6— and —NR6S(O)1-2—;
R1 is selected from the group consisting of C1-C8 alkyl, C1-C8 alkenyl and C1-C8 alkynyl, each unsubstituted or fluorinated;
Q1 is selected from the group consisting of —C(O)OR2C, —C(O)NR2BR2C, —C(O)NR2BS(O)2R2C, —C(O)NR2BS(O)2NR2BR2C, —S(O)2R2C, —N(R2B)S(O)2R2C, —S(O)2NR2BR2C, and —C(O)NH—O(C1-C3 alkyl), in which
each R2B is independently selected from H and C1-C3 alkyl, and
each R2C is independently selected from C1-C3 alkyl and a protecting group;
R3 is phenyl or heteroaryl each (i) optionally substituted with a single substituent selected from -L3C-(phenyl optionally substituted with 1-5 R3D), -L3C-(heteroaryl optionally substituted with 1-5 R3D), -L3C-(cycloalkyl optionally substituted with 1-5 R3D), -L3C-(heterocycloalkyl optionally substituted with 1-5 R3D) and (ii) optionally substituted with 1-5 R3E,
in which
each L3C is a bond, methylene, ethylene, —C(O)—, —S—, —S(O)1-2—, —O—, or —NR3G—;
each R3D is independently selected from oxo optionally-substituted C1-C4 alkyl, C1-C4 fluoroalkyl, halogen, —CN, —SF5, —N3, —C(O)R3F, —SR3F, —S(O)1-2R3F, —OR3F, —NR3GR3F, —C(O)R3F, —C(O)NR3GR3F, —NR3GC(O)R3F, —C(S)NR3GR3F, —NR3GC(S)R3F, —C(O)OR3F, —OC(O)R3F, —C(O)SR3F, —SC(O)R3F, —C(S)OR3F, —OC(S)R3F, —C(S)SR3F, —SC(S)R3F, —S(O)1-2OR3F, —OS(O)1-2R3F, —S(O)1-2NR3GR3F, and —NR3GS(O)1-2R3F;
each R3E is independently selected from oxo, optionally-substituted C1-C4 alkyl, C1-C4 fluoroalkyl, halogen, —CN, —SF5, —N3, —C(O)R3F, —SR3F, —S(O)1-2R3F, —OR3F, —NR3GR3F, —C(O)R3F, —C(O)NR3GR3F, —NR3GC(O)R3F, —C(S)NR3GR3F, —NR3GC(S)R3F, —C(O)OR3F, —OC(O)R3F, —C(O)SR3F, —SC(O)R3F, —C(S)OR3F, —OC(S)R3F, —C(S)SR3F, —SC(S)R3F, —S(O)1-2OR3F, —OS(O)1-2R3F, —S(O)1-2NR3GR3F, and —NR3GS(O)1-2R3F;
each R3F is independently selected from H, C1-C3 alkyl and C1-C3 fluoroalkyl and
each R3G is independently selected from H, C1-C3 alkyl, and C1-C3 fluoroalkyl; and
R4 is selected from the group consisting of hydrogen, optionally substituted C1-C8 alkyl, optionally-substituted C1-C8 alkenyl and optionally substituted C1-C8 alkynyl;
wherein
each R6 is selected from the group consisting of hydrogen, C1-C3 alkyl and —C(O)(C1-C3 alkyl);
each optionally substituted alkyl, alkenyl and alkynyl is unsubstituted, fluorinated or substituted with one or two hydroxyl groups;
each cycloalkyl has 3-10 ring carbons and is saturated or partially unsaturated;
each heterocylcloalkyl has 3-10 ring members and 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur, and is saturated or partially unsaturated; and
each heteroaryl is a 5-6 membered monocyclic heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur,
the method comprising:
reacting a thiazolylhydrazine of formula (Ib)
 wherein X, R1, and L1 are as described for formula (Ia),
with a dione of formula (II)
 wherein R3 and R4 are as described for formula (Ia),
optionally in a solvent, under conditions sufficient to form a hydrazone; and
contacting the hydrazone with an compound of formula X1—CH2-Q1 wherein Q1 is as described for formula (Ia), and X1 is a halogen or a leaving group, to obtain the halopyrazolylthiazole of formula (Ia).
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