Isoxazoline derivatives as pesticides

Abstract

The present invention provides compounds of formula (I) which are useful for the long-term treatment and control of pests such as fleas and ticks in companion animals and livestock, as well as pharmaceutical compositions and methods of use thereof.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims priority to U.S. Provisional Application No. 62 / 950,018, filed on December 18, 2019, the contents of which are incorporated herein by reference in their entirety. Technical Field

[0003] The present invention relates to medicinal chemistry, pharmacology and veterinary and human medicine. Background Art

[0004] Aryl isoxazolines are used in agriculture, forestry, turf, household, wood products, nursery crop protection and veterinary fields. Veterinary fields include companion animals and livestock, including fish. For example, such inhibitors are disclosed in WO2005 / 085216, WO 2007 / 079162, US2007 / 066617, US20130131017, WO 2009 / 002809, WO 2009 / 112275, WO 2010 / 003923, WO2010 / 070068, WO 2012 / 120399 and WO 2013 / 079407.

[0005] In many applications, it is desirable to have a long-lasting effect on the pest. Long-lasting protection is particularly important for companion animals, such as cats, dogs, mice, guinea pigs, ferrets and rabbits; and domesticated animals, such as cattle, sheep, pigs and fish, especially salmon and sea bass. Summary of the invention

[0006] The present invention relates to compounds of formula (I) having an extended half-life for companion animals and livestock, particularly warm-blooded animals, especially dogs, cats and cattle, and their use in controlling ectoparasites. In many cases, compounds of formula (I) provide a long-lasting effect of several months after a single oral administration or injection.

[0007] The present invention also provides compounds of formula (I) that are effective for treating and / or controlling ectoparasites in companion animals and livestock.

[0008] In one embodiment, the present invention provides a compound having formula (I):

[0009]

[0010] in

[0011] A1 is selected from the group consisting of CF3, CHF2, CH2F and CF2CF3;

[0012] A2 is O or S;

[0013] R1 is selected from the group consisting of hydrogen and halogen;

[0014] R2 is selected from the group consisting of hydrogen, halogen, difluoromethyl and trifluoromethyl;

[0015] R3 is selected from the group consisting of hydrogen, halogen and trifluoromethyl;

[0016] R4 is selected from the group consisting of hydrogen, halogen, difluoromethyl and trifluoromethyl;

[0017] R5 is selected from the group consisting of hydrogen and halogen;

[0018] The conditions are:

[0019] R1 may be hydrogen only when R2 is trifluoromethyl, difluoromethyl or bromine;

[0020] R5 may be hydrogen only when R4 is trifluoromethyl or bromine;

[0021] R3 may be hydrogen only when one of R2 or R4 is trifluoromethyl, difluoromethyl or bromine;

[0022] When R2 and R4 are trifluoromethyl, R1, R3 and R5 cannot all be hydrogen; and

[0023] At most three of R1, R2, R3, R4 and R5 are hydrogen;

[0024] QSelect the group consisting of

[0025]

[0026] in

[0027] p is 0, 1, or 2;

[0028] q is 0, 1, 2, or 3;

[0029] r is 0 or 1;

[0030] s is 0, 1, or 2;

[0031] t is 0 or 1;

[0032] R6 is independently selected at each occurrence from the group consisting of: halogen; cyano; nitro; hydroxyl; -NH2; -NH(C1-C4 alkyl); -N(C1-C4 alkyl)2; C2-C5-alkoxycarbonyl; C1-C6-alkyl, which is optionally substituted with 1 to 5 substituents independently selected from the group consisting of: halogen, cyano, nitro, hydroxyl, oxo, C3-C6 cycloalkyl, C1-C4 alkoxy, -NH2, C1-C7 aminocarbonyl, -NH(C1-C4 alkyl), -N(C1-C4 alkyl)2, -SC1-C4 alkyl, -S(O)C1-C4 alkyl and -SO2C1-C4 alkyl; C C1-C4-alkyl), -NH2, C1-C7-aminocarbonyl, -NH(C1-C4-alkyl), -N(C1-C4-alkyl)2, -SC1-C4-alkyl, -S(O)C1-C4-alkyl and -SO2C1-C4-alkyl; -NR8C(O)(C1-C4-alkyl), which is optionally substituted on the C1-C4-alkyl by 1 to 5 substituents independently selected from the group consisting of halogen, cyano, hydroxyl, C3-C6-cycloalkyl, C1-C4-alkoxy, -NH2, C1-C7-aminocarbonyl, -NH(C1-C4-alkyl), -N(C1-C4-alkyl)2, -SC1-C4-alkyl, -S(O)C1-C4-alkyl and -SO2C1-C4-alkyl; -NR8C(O)(C1-C4-alkyl), which is optionally substituted on the C1-C4-alkyl by 1 to 5 substituents independently selected from the group consisting of halogen, cyano, hydroxyl, C3-C6-cycloalkyl, C1-C -C(O)NR8(C1-C4 alkyl), which is optionally substituted on the C1-C4 alkyl by 1 to 5 substituents independently selected from the group consisting of halogen, cyano, hydroxy, C3-C6 cycloalkyl, C1-C4 alkoxy, -NH2, C1-C7 aminocarbonyl, -NH(C1-C4 alkyl) and -N(C1-C4 alkyl)2, wherein R8 is independently selected from the group consisting of hydrogen and C1-C4 alkyl; -SC1- C6 alkyl, optionally substituted by 1 to 5 substituents independently selected from the group consisting of halogen, cyano, nitro, hydroxy, oxo, C3-C6 cycloalkyl, C1-C4 alkoxy, -NH2, C1-C7 aminocarbonyl, -NH(C1-C4 alkyl) and -N(C1-C4 alkyl)2; and -S(O)C1-C6 alkyl, optionally substituted by 1 to 5 substituents independently selected from the group consisting of halogen, cyano, nitro, hydroxy, oxo, C3-C6 cycloalkyl, C1-C4 alkoxy, -NH2, C1-C7 aminocarbonyl, -NH(C1-C4 alkyl) and -N(C1-C4 alkyl)2;

[0033] R7, at each occurrence, is independently selected from the group consisting of oxo, C1-C4 alkyl, and C3-C6 cycloalkyl;

[0034] A3 is O or S;

[0035] A4 is CH or N;

[0036] A5 is CH or N;

[0037] A6 is CH or N;

[0038] A7 is CHO, S, a bond or N;

[0039] A8 is CHO, S, a bond or N;

[0040] A9 is CH or N;

[0041] A 10 is CH or N;

[0042] A 11 is CH or N;

[0043] A 12 is CH or N;

[0044] A 13 is CH or N;

[0045] A 14 is CH or N;

[0046] A 15 is CH or N;

[0047] A 16 is NR, O or S, wherein R is selected from the group consisting of hydrogen, C1-C4 alkyl and C3-C6 cycloalkyl;

[0048] W1 is selected from -O-, -S-, -NR9-, -NC(O)R 10 -, -CH2- and -C(O)-;

[0049] W2 is selected from -O-, -S-, -NR9-, -NC(O)R 10 -, -CH2- and -C(O)-;

[0050] The conditions are:

[0051] When W1 is -O-, -S-, -NR9- or -NC(O)R 10 -, then W2 is -CH2- or -C(O)-; and

[0052] When W2 is -O-, -S-, -NR9- or -NC(O)R 10 -, then W1 is -CH2- or -C(O)-;

[0053] W3 is selected from the group consisting of zero, -O-, -S-, -S(O)-, -S(O)2-, -NR9-, -CH-, -N-, -CH2- and -C(O)-;

[0054] W4 is selected from the group consisting of zero, -O-, -S-, -S(O)-, -S(O)2-, -NR9-, -CH-, -N-, -CH2-, and -C(O)-;

[0055] W5 is selected from the group consisting of zero, -O-, -S-, -S(O)-, -S(O)2-, -NR9-, -CH-, -N-, -CH2-, and -C(O)-;

[0056] W6 is selected from the group consisting of zero, -O-, -S-, -S(O)-, -S(O)2-, -NR9-, -CH-, -N-, -CH2- and -C(O)-;

[0057] Wherein the bond between W1, W2, W3 and W4 can be a single bond or a double bond;

[0058] The conditions are:

[0059] (i) no more than two of W1, W2, W3 and W4 are zero;

[0060] (ii) no more than two of W1, W2, W3 and W4 are -O-, -S-, -S(O)-, -S(O)2-, -NR9- or -C(O)-;

[0061] (iii) if two of W1, W2, W3 and W4 are -O- and / or -S-, there is at least one carbon atom between them; and

[0062] (iv) when W1, W2, W3 or W4 is -CH- and / or -NR9-, a double bond is formed in the ring formed by W1, W2, W3 and W4;

[0063] R9 is independently selected at each occurrence from the group consisting of hydrogen, and C1-C6-alkyl, optionally substituted with 1 to 5 substituents independently selected from the group consisting of halogen, cyano, nitro, hydroxy, oxo, C3-C6 cycloalkyl, C1-C4 alkoxy, -NH2, C1-C7 aminocarbonyl, -NH(C1-C4 alkyl), -N(C1-C4 alkyl)2, -SC1-C4 alkyl, -S(O)C1-C4 alkyl and -SO2C1-C4 alkyl;

[0064] R 10 is independently selected at each occurrence from the group consisting of oxo, C1-C4 alkyl, and C3-C6 cycloalkyl;

[0065] X is a 5- to 10-membered heteroaryl group having 1 or 2 heteroatoms selected from the group consisting of O, S and N,

[0066] wherein the carbon of the 5- to 10-membered heteroaryl is optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of halogen, cyano, nitro, hydroxyl, C1-C4 alkyl, which is optionally substituted with 1 to 5 substituents independently selected from the group consisting of halogen, cyano, hydroxyl, oxo, C1-C4 alkoxy, -NH2, C1-C7 aminocarbonyl, -NH(C1-C4 alkyl), -N(C1-C4 alkyl)2, -SC1-C4 alkyl, -S(O)C1-C4 alkyl C1-C4 alkyl, -SO2C1-C4 alkyl, -C(O)NH-C3-C6 cycloalkyl, -C(O)NH-C1-C6 alkyl and -C(O)NH-C1-C6 haloalkyl, C3-C6 cycloalkyl, C1-C4 haloalkyl, C1-C4 alkoxy, -NH2, -NH(C1-C4 alkyl), -N(C1-C4 alkyl)2, -C(O)NH-C3-C6 cycloalkyl, -C(O)NH-C1-C6 alkyl and -C(O)NH-C1-C6 haloalkyl,

[0067] wherein, where valence permits, any N in the heteroaryl group is optionally substituted by a substituent selected from the group consisting of hydrogen, C1-C4 alkyl, which is optionally substituted by 1 to 5 substituents independently selected from the group consisting of halogen, cyano, hydroxy, ethynyl, oxo, C1-C4 alkoxy, -NH2, C1-C7 aminocarbonyl, -NH(C1-C4 alkyl), -N(C1-C4 alkyl)2, -SC1-C4 alkyl, -S(O)C1-C4 alkyl, -SO2C1-C4 alkyl, -C(O)NH-C3-C6 cycloalkyl, -C(O)NH-C1-C6 alkyl and -C(O)NH-C1-C6 haloalkyl, and C3-C6 cycloalkyl,

[0068] or

[0069] X is selected from the group consisting of:

[0070]

[0071] in

[0072] R 11 Selected from the group consisting of hydrogen, C1-C4 alkyl, C1-C4 haloalkyl, C3-C6 cycloalkyl, C4-C7 alkylcycloalkyl, C2-C7 alkylcarbonyl, C2-C5 alkoxycarbonyl, C2-C6 alkenyl and C2-C6 alkynyl;

[0073] W is selected from the group consisting of:

[0074] (i)Hydrogen;

[0075] (ii) C1-C6 alkyl, which is optionally substituted by 1 to 5 substituents independently selected from the group consisting of halogen; cyano; hydroxy; oxo; C1-C4 alkoxy; C3-C6 cycloalkyl, which is optionally substituted by 1 to 3 substituents independently selected from the group consisting of halogen and cyano; ethynyl; -NH2; C1-C7 aminocarbonyl; -NH(C1-C4 alkyl); -N(C1-C4 alkyl)2; -SC1-C4 alkyl; -S(O)C1-C4 alkyl; -SO2C1-C4 alkyl; -C(O)NH-C3-C6 cycloalkyl, which is optionally substituted by 1 to 3 substituents independently selected from the group consisting of halogen, hydroxy, cyano, and C1-C4 alkyl, which is optionally -C(O)NH-C1-C6 alkyl, optionally substituted by 1 to 5 substituents independently selected from the group consisting of halogen, cyano, hydroxyl, C1-C4 alkoxy, C3-C6 cycloalkyl and -NH2; -C(O)NH-C1-C6 alkyl, optionally substituted by 1 to 5 substituents independently selected from the group consisting of halogen, cyano, hydroxyl, C1-C4 alkoxy, C3-C6 cycloalkyl and -NH2; -C(O)NH-C1-C6 cyanoalkyl optionally substituted by 1 to 3 halogen; -C(O)NH-C1-C6 haloalkyl; -C(O)-4 to 7 membered heterocycloalkyl, which is connected through nitrogen and optionally has 1 or 2 other heteroatoms selected from the group consisting of O, S and N, wherein the carbon atoms of the 4 to 7 membered heterocycloalkyl are The alkyl radicals are optionally substituted with 1 to 4 substituents independently selected from the group consisting of halogen, cyano, nitro, hydroxy, oxo, -NH2, C1-C7 aminocarbonyl, C1-C4 alkyl, which are optionally substituted with 1 to 5 substituents independently selected from the group consisting of halogen, cyano, hydroxy, ethynyl, oxo, C1-C4 alkoxy, -NH2, C1-C7 aminocarbonyl, -NH(C1-C4 alkyl), -N(C1-C4 alkyl)2, -SC1-C4 alkyl, -S(O)C1-C4 alkyl, -SO2C1-C4 alkyl, -C(O)NH-C3-C6 cycloalkyl and -C(O)NH-C1-C6 alkyl, and C3-C6 cycloalkyl, wherein the alkyl radicals are optionally substituted with 1 to 4 substituents independently selected from the group consisting of halogen, cyano, nitro, hydroxy, oxo, -NH2, C1-C7 aminocarbonyl, C1-C4 alkyl, and C3-C6 cycloalkyl, wherein the alkyl radicals are optionally substituted with 1 to 5 substituents independently selected from the group consisting of halogen, cyano, hydroxy, ethynyl, oxo, C1-C4 alkoxy, -NH2, C1-C7 aminocarbonyl, -NH(C1-C4 alkyl), -N(C1-C4 alkyl)2, -SC1-C4 alkyl, -S(O)C1-C4 alkyl, -SO2C1-C4 alkyl, -C(O)NH-C3-C6 cycloalkyl and -C(O)NH-C1-C6 alkyl, and C3-C6 cycloalkyl, wherein the alkyl radicals are optionally substituted with 1 to 4 substituents independently selected from the group consisting of any other N in the 4- to 7-membered heterocycloalkyl is substituted by a substituent selected from the group consisting of hydrogen, -NH2, C1-C7 aminocarbonyl, -SO2C1-C4 alkyl, -SO2C1-C4 haloalkyl, and C1-C4 alkyl, which is optionally substituted by 1 to 5 substituents independently selected from the group consisting of halogen, cyano, hydroxy, ethynyl, C1-C4 alkoxy, -NH(C1-C4 alkyl), -N(C1-C4 alkyl)2, -SC1-C4 alkyl, -S(O)C1-C4 alkyl, -SO2C1-C4 alkyl, -C(O)NH-C3-C6 cycloalkyl, -C(O)NH-C1-C6 alkyl and -C(O)NH-C1-C6 haloalkyl;A 5- to 10-membered heteroaryl having 1 or 2 heteroatoms selected from the group consisting of O, S and N, wherein the carbons of the 5- to 10-membered heteroaryl are optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of halogen, cyano, nitro, hydroxyl, C1-C4 alkyl, which are optionally substituted with 1 to 5 substituents independently selected from the group consisting of halogen, cyano, hydroxyl, oxo, C1-C4 alkoxy, -NH2, C1-C7 aminocarbonyl, -NH(C1-C4 alkyl), -N(C1-C4 alkyl)2, -SC1-C4 alkyl, -S(O)C1-C4 alkyl, -SO2C1-C4 alkyl, -C(O) NH-C3-C6 cycloalkyl, -C(O)NH-C1-C6 alkyl and -C(O)NH-C1-C6 haloalkyl, C3-C6 cycloalkyl, C1-C4 haloalkyl, C1-C4 alkoxy, -NH2, C1-C7 aminocarbonyl, -NH(C1-C4 alkyl), -N(C1-C4 alkyl)2 and -C(O)NH-C3-C6 cycloalkyl, wherein, where valence permits, any N in the heteroaryl is optionally substituted with a substituent selected from the group consisting of hydrogen, C1-C4 alkyl, which is optionally substituted with 1 to 5 substituents independently selected from the group consisting of halogen, cyano, hydroxy, ethynyl, oxo , C3-C6 cycloalkyl, C1-C4 alkoxy, -NH2, C1-C7 aminocarbonyl, -NH(C1-C4 alkyl), -N(C1-C4 alkyl)2, -SC1-C4 alkyl, -S(O)C1-C4 alkyl, -SO2C1-C4 alkyl, -C(O)NH-C3-C6 cycloalkyl and -C(O)NH-C1-C6 alkyl, and C3-C6 cycloalkyl, wherein any S in the heteroaryl is optionally substituted by 1 or 2 oxygen atoms; phenyl, which is optionally substituted by 1 to 3 substituents selected from the group consisting of halogen, C1-C4 alkyl, cyano and hydroxy; C3-C6 cycloalkyl, which is optionally substituted by 1 to 5 independent substituents. The alkyl radicals are optionally substituted by substituents selected from the group consisting of halogen, cyano, hydroxy, oxo, C1-C4 alkoxy, C1-C4 alkyl optionally substituted by 1 to 3 groups selected from the group consisting of halogen and cyano, C1-C4 haloalkyl, -NH2, C1-C7 aminocarbonyl, -NH(C1-C4 alkyl), -N(C1-C4 alkyl)2, -SC1-C4 alkyl, -S(O)C1-C4 alkyl, -SO2C1-C4 alkyl, -C(O)NH-C3-C6 cycloalkyl, -C(O)NH-C1-C6 alkyl, -C(O)NH-C1-C6 haloalkyl, C2-C6 alkenyl and C2-C6 alkynyl;and a 4 to 7 membered heterocycloalkyl having 1 or 2 heteroatoms selected from the group consisting of O, S, B and N, wherein the heterocycloalkyl is optionally benzo-fused, wherein the carbons of the 4 to 7 membered heterocycloalkyl or the optionally benzo-fused 4 to 7 membered heterocycloalkyl are optionally substituted with 1 to 4 substituents independently selected from the group consisting of halogen, cyano, nitro, hydroxy, oxo, and C1-C4 alkyl, which are optionally substituted with 1 to 5 substituents independently selected from the group consisting of halogen, cyano, hydroxy, ethynyl, oxo, C1-C4 alkoxy , C3-C6 cycloalkyl, -NH2, C1-C7 aminocarbonyl, -NH(C1-C4 alkyl), -N(C1-C4 alkyl)2, -SC1-C4 alkyl, -S(O)C1-C4 alkyl, -SO2C1-C4 alkyl, -C(O)NH-C3-C6 cycloalkyl, -C(O)NH-C1-C6 alkyl and -C(O)NH-C1-C6 haloalkyl, wherein any B in the 4 to 7 membered heterocycloalkyl or the optionally benzo-fused 4 to 7 membered heterocycloalkyl is substituted by hydroxyl where valence permits, wherein Where valence permits, any N in the 4- to 7-membered heterocycloalkyl or optionally benzo-fused 4- to 7-membered heterocycloalkyl is substituted by a substituent selected from the group consisting of hydrogen, -NH2, C1-C7 aminocarbonyl, -SO2C1-C4 alkyl, -SO2C1-C4 haloalkyl, -C(O)-NH2, C1-C4 alkyl, which is optionally substituted by 1 to 5 substituents independently selected from the group consisting of halogen, cyano, hydroxy, ethynyl, C1-C4 alkoxy, -NH(C1-C4 alkyl), -N(C1- C4-alkyl)2, -SC1-C4-alkyl, -S(O)C1-C4-alkyl, -SO2C1-C4-alkyl, -C(O)NH-C3-C6-cycloalkyl and -C(O)NH-C1-C6-haloalkyl, C3-C6-cycloalkyl, 5- to 6-membered heteroaryl, and phenyl, which is optionally substituted with 1 to 3 substituents independently selected from the group consisting of halogen, C1-C4-alkyl, cyano and hydroxy, wherein any S in the 4- to 7-membered heterocycloalkyl or optionally benzo-fused 4- to 7-membered heterocycloalkyl is optionally substituted with 1 or 2 oxygen atoms;

[0076] (iii) C3-C6 cycloalkyl, which is optionally substituted by 1 to 5 substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, C1-C4 alkoxy, C1-C4 alkyl optionally substituted by 1 to 3 groups selected from the group consisting of halogen and cyano, C1-C4 haloalkyl, -NH2, C1-C7 aminocarbonyl, -NH(C1-C4 alkyl), -N(C1-C4 alkyl)2, -SC1-C4 alkyl, -S(O)C1-C4 alkyl, -SO2C1-C4 alkyl, -C(O)NH-C3-C6 cycloalkyl, -C(O)NH-C1-C6 alkyl, -C(O)NH-C1-C6 haloalkyl, C2-C6 alkenyl and C2-C6 alkynyl optionally substituted by 1 to 3 halogen;

[0077] (iv) a 6-membered aryl or 5- to 10-membered heteroaryl having 1, 2 or 3 heteroatoms selected from the group consisting of O, S and N, wherein the carbons of the 6-membered aryl and 5- to 10-membered heteroaryl are optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of halogen, cyano, nitro, hydroxyl, C1-C4 alkyl, which are optionally substituted with 1 to 5 substituents independently selected from the group consisting of halogen, cyano, hydroxyl, oxo, C1-C4 alkoxy, -NH2, C1-C7 aminocarbonyl, -NH(C1-C4 alkyl), -N(C1-C4 alkyl)2, -SC1-C4 alkyl, -S(O)C1-C4 alkyl, -SO2C1-C4 alkyl, -C(O)NH-C3-C6 cycloalkyl and -C(O)NH-C1-C6 alkyl, C3-C6 cycloalkyl, C C1-C4 haloalkyl, C1-C4 alkoxy, -NH2, -NH(C1-C4 alkyl), -N(C1-C4 alkyl)2 and -C(O)NH-C3-C6 cycloalkyl, wherein any N in the heteroaryl is optionally substituted with a substituent selected from the group consisting of hydrogen, and C1-C4 alkyl, which is optionally substituted with 1 to 5 substituents independently selected from the group consisting of halogen, cyano, hydroxy, ethynyl, oxo, C1-C4 alkoxy, -NH2, C1-C7 aminocarbonyl, -NH(C1-C4 alkyl), -N(C1-C4 alkyl)2, -SC1-C4 alkyl, -S(O)C1-C4 alkyl, -SO2C1-C4 alkyl, -C(O)NH-C3-C6 cycloalkyl and -C(O)NH-C1-C6 alkyl;

[0078] (v) a 4- to 7-membered heterocycloalkyl having 1 or 2 heteroatoms selected from the group consisting of O, S and N, wherein the heterocycloalkyl is optionally benzo-fused, wherein the carbons of the 4- to 7-membered heterocycloalkyl or the optionally benzo-fused 4- to 7-membered heterocycloalkyl are optionally substituted with 1 to 4 substituents independently selected from the group consisting of halogen, cyano, nitro, hydroxy, oxo, C1-C4 alkoxy, C1-C4 alkyl, which are optionally substituted with 1 to 5 substituents independently selected from the group consisting of halogen, cyano, hydroxy, ethynyl, oxo, C1-C4 alkoxy, C1-C4 alkyl -C4 alkoxy, C3-C6 cycloalkyl, -NH2, C1-C7 aminocarbonyl, -NH(C1-C4 alkyl), -N(C1-C4 alkyl)2, -SC1-C4 alkyl, -S(O)C1-C4 alkyl, -SO2C1-C4 alkyl, -C(O)NH-C3-C6 cycloalkyl, -C(O)NH-C1-C6 alkyl and -C(O)NH-C1-C6 haloalkyl, wherein any N in the 4- to 7-membered heterocycloalkyl or optionally benzo-fused 4- to 7-membered heterocycloalkyl is selected from The following substituents are substituted: hydrogen, -NH2, C1-C7 aminocarbonyl, -SO2C1-C4 alkyl, -SO2C1-C4 haloalkyl, -C(O)-NH2, C1-C4 alkyl, which is optionally substituted by 1 to 5 substituents independently selected from the group consisting of: halogen, cyano, hydroxy, ethynyl, oxo, C1-C4 alkoxy, C3-C6 cycloalkyl, -NH(C1-C4 alkyl), -N(C1-C4 alkyl)2, -SC1-C4 alkyl, -S(O)C1-C4 alkyl, -SO 2C1-C4 alkyl, -SO2NH(C1-C4 alkyl), -SO2N(C1-C4 alkyl)2, -C(O)NH-C3-C6 cycloalkyl and -C(O)NH-C1-C6 haloalkyl, C3-C6 cycloalkyl, 5 to 6 membered heteroaryl, and phenyl, which is optionally substituted with 1 to 3 substituents independently selected from the group consisting of halogen, C1-C4 alkyl, cyano and hydroxy, wherein any S in the 4 to 7 membered heterocycloalkyl or optionally benzo-fused 4 to 7 membered heterocycloalkyl is optionally substituted with 1 or 2 oxygen atoms;

[0079] (vi)-NR 12 R 13

[0080] in

[0081] R 12 Selected from the group consisting of hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C4-C7 alkylcycloalkyl, C1-C7 alkylcarbonyl, C1-C7 aminocarbonyl and C2-C5 alkoxycarbonyl;

[0082] R13Selected from the group consisting of: hydrogen, C1-C6 alkyl, which is optionally substituted by 1 to 5 substituents independently selected from the group consisting of: halogen, cyano, nitro, hydroxy, oxo, C3-C6 cycloalkyl, C1-C4 alkoxy, -NH2, C1-C7 aminocarbonyl, -NH(C1-C4 alkyl), -N(C1-C4 alkyl)2, -SC1-C4 alkyl, -S(O)C1-C4 alkyl and -SO2C1-C4 alkyl, C3-C6 cycloalkyl, -C(O)-C1-C6 alkyl, which is optionally substituted by 1 to 5 substituents independently selected from the group consisting of: halogen, cyano, nitro, hydroxy, oxo, C3-C6 cycloalkyl, C1-C4 alkoxy, - NH2, C1-C7 aminocarbonyl, -NH(C1-C4 alkyl), -N(C1-C4 alkyl)2, -SC1-C4 alkyl, -S(O)C1-C4 alkyl and -SO2C1-C4 alkyl, 4 to 7 membered heterocycloalkyl having 1 or 2 heteroatoms selected from the group consisting of O, S and N, wherein the heterocycloalkyl is optionally benzo-fused, wherein the carbons of the 4 to 7 membered heterocycloalkyl or the optionally benzo-fused 4 to 7 membered heterocycloalkyl are optionally substituted with 1 to 4 substituents independently selected from the group consisting of halogen, cyano, nitro, hydroxy, oxo, C1-C4 alkyl, which are optionally substituted with 1 to 5 substituents independently selected from the group consisting of halogen, cyano, hydroxy, ethyl Alkynyl, oxo, C1-C4 alkoxy, -NH2, C1-C7 aminocarbonyl, -NH(C1-C4 alkyl), -N(C1-C4 alkyl)2, -SC1-C4 alkyl, -S(O)C1-C4 alkyl, -SO2C1-C4 alkyl, -C(O)NH-C3-C6 cycloalkyl, -C(O)NH-C1-C6 alkyl and -C(O)NH-C1-C6 haloalkyl, and C3-C6 cycloalkyl, wherein any N in the 4 to 7 membered heterocycloalkyl or the optionally benzo-fused 4 to 7 membered heterocycloalkyl is substituted with a substituent selected from the group consisting of hydrogen, C1-C4 alkyl, which is optionally substituted with 1 to 5 substituted groups independently selected from the group consisting of substituted by halogen, cyano, hydroxy, ethynyl, C1-C4 alkoxy, -NH2, C1-C7 aminocarbonyl, -NH(C1-C4 alkyl), -N(C1-C4 alkyl)2, -SC1-C4 alkyl, -S(O)C1-C4 alkyl, -SO2C1-C4 alkyl, -C(O)NH-C3-C6 cycloalkyl and -C(O)NH-C1-C6 alkyl, C3-C6 cycloalkyl, 5- to 6-membered heteroaryl, and phenyl, which is optionally substituted by 1 to 3 substituents independently selected from the group consisting of halogen, C1-C4 alkyl, cyano and hydroxy, wherein any S in the 4- to 7-membered heterocycloalkyl or the optionally benzo-fused 4- to 7-membered heterocycloalkyl is optionally substituted by 1 or 2 oxygen atoms;and a 5- to 10-membered heteroaryl having 1 or 2 heteroatoms selected from the group consisting of O, S and N, wherein the carbons of the 5- to 10-membered heteroaryl are optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of halogen, cyano, nitro, hydroxyl, C1-C4 alkyl, which are optionally substituted with 1 to 5 substituents independently selected from the group consisting of halogen, cyano, hydroxyl, oxo, C1-C4 alkoxy, -NH2, C1-C7 aminocarbonyl, -NH(C1-C4 alkyl), -N(C1-C4 alkyl)2, -SC1-C4 alkyl, -S(O)C1-C4 alkyl, -SO2C1-C4 alkyl, -C(O)NH-C3-C6 cycloalkyl and -C(O)NH-C1-C6 alkyl, C3-C6 cycloalkyl, C1-C4 haloalkyl, C1-C4 alkoxy, - NH2, -NH(C1-C4 alkyl), -N(C1-C4 alkyl), -C(O)NH-C3-C6 cycloalkyl and -C(O)NH-C1-C6 alkyl, wherein, where valence permits, any N in the heteroaryl is optionally substituted with a substituent selected from the group consisting of hydrogen, C1-C4 alkyl, which is optionally substituted with 1 to 5 substituents independently selected from the group consisting of halogen, cyano, hydroxy, ethynyl, oxo, C1-C4 alkoxy, -NH2, C1-C7 aminocarbonyl, -NH(C1-C4 alkyl), -N(C1-C4 alkyl), -SC1-C4 alkyl, -S(O)C1-C4 alkyl, -SO2C1-C4 alkyl, -C(O)NH-C3-C6 cycloalkyl and -C(O)NH-C1-C6 alkyl, and C3-C6 cycloalkyl;

[0083] or

[0084] R 11and W together with the nitrogen to which they are attached form a 4 to 7 membered ring optionally containing 1 to 2 heteroatoms selected from the group consisting of N, S and O, wherein the carbons of the ring are optionally substituted with 1 to 4 substituents independently selected from the group consisting of cyano, hydroxy, oxo, halogen, C1-C2 alkoxy, N,N-diC1-C4-alkylaminocarbonyl, N-C1-C4-alkylaminocarbonyl, C1-C7aminocarbonyl, C1-C4 alkyl, which are optionally substituted with 1 to 5 substituents independently selected from the group consisting of halogen, cyano, hydroxy, C3-C6 cycloalkyl, C1-C C1-C7 alkyl, -NH2, C1-C7 aminocarbonyl, -NH(C1-C4 alkyl), -N(C1-C4 alkyl)2 and -C(O)NH-C3-C6 cycloalkyl, C3-C6 cycloalkyl, which is optionally substituted with 1 to 3 substituents selected from the group consisting of halogen, cyano, hydroxyl and C1-C4 alkoxy, -C(O)NH-C3-C6 cycloalkyl, -C(O)NH-C1-C6 alkyl, -C(O)NH-C1-C6 haloalkyl, 5 to 6 membered heteroaryl, and phenyl, which is optionally substituted with 1 to 3 substituents independently selected from the group consisting of The substituted radicals are halogen, C1-C4 alkyl, cyano, hydroxy, C1-C2 alkoxy, N,N-di-C1-C4-alkylaminocarbonyl, N-C1-C4-alkylaminocarbonyl and C1-C7 aminocarbonyl, wherein any N in the 4- to 7-membered ring is substituted by a substituent selected from the group consisting of hydrogen, C1-C4 alkyl, which is optionally substituted by 1 to 5 substituents independently selected from the group consisting of halogen, cyano, hydroxy, C3-C6 cycloalkyl, C1-C4 alkoxy, -NH2, C1-C7 aminocarbonyl, -NH(C1-C4 alkyl), -N (C1-C4 alkyl)2 and -C(O)NH-C3-C6 cycloalkyl, C3-C6 cycloalkyl, which is optionally substituted with 1 to 3 substituents independently selected from the group consisting of halogen, cyano, hydroxy, C1-C4 alkoxy, -C(O)NH-C3-C6 cycloalkyl and C(O)NH-C1-C6 alkyl, 5 to 6 membered heteroaryl, and phenyl, which is optionally substituted with 1 to 3 substituents independently selected from the group consisting of halogen, C1-C4 alkyl, cyano and hydroxy, wherein any S in the 4 to 7 membered ring is optionally substituted with 1 or 2 oxygen atoms; and

[0085] Y is C1-C6 alkyl, which is optionally substituted by 1 to 5 substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, C3-C6 cycloalkyl, C1-C4 alkoxy, ethynyl, -NH2, C1-C7 aminocarbonyl, -NH(C1-C4 alkyl), -N(C1-C4 alkyl)2, -SC1-C4 alkyl, -S(O)C1-C4 alkyl, -SO2C1-C4 alkyl, -SO2NH(C1-C4 alkyl), -SO2N(C1-C4 alkyl)2, -SO2NH(C1-C4 haloalkyl), -C(O)NH-C3-C6 cycloalkyl, which is optionally substituted by 1 to 3 substituents independently selected from the group consisting of halogen, hydroxy, C1-C4 alkyl, optionally substituted by 1 to 5 substituents independently selected from the group consisting of halogen, cyano, hydroxyl, C1-C4 alkoxy and -NH2, -C(O)NH-C1-C6 alkyl, -C(O)NH-C1-C6 cyanoalkyl optionally substituted by 1 to 3 halogens, -C(O)NH-C1-C6 haloalkyl, phenyl, optionally substituted by 1, 2 or 3 substituents independently selected from the group consisting of halogen, cyano, nitro, hydroxyl, C1-C4 alkyl, optionally substituted by 1 to 3 substituents independently selected from the group consisting of halogen, cyano, hydroxyl, C3-C6 cycloalkyl, C1-C4 haloalkyl, C1-C4 alkoxy, -NH2, -NH(C1-C4 alkyl), -N(C1-C4 alkyl)2 and -C(O)NH-C3-C6 cycloalkyl, and C3-C6 cycloalkyl, which are optionally substituted by 1 to 5 substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, C1-C4 alkoxy, -NH2, C1-C7 aminocarbonyl, -NH(C1-C4 alkyl), N(C1-C4 alkyl)2, -SC1-C4 alkyl, -S(O)C1-C4 alkyl, -SO2C1-C4 alkyl, -C(O)NH-C3-C6 cycloalkyl, -C(O)NH-C1-C6 alkyl, C2-C6 alkenyl and C2-C6 alkynyl, having 1 or 2 heteroatoms selected from the group consisting of O, S and N 5 to 10 membered heteroaryl, wherein the carbons of the 5 to 10 membered heteroaryl are optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of halogen, cyano, nitro, hydroxyl, C1-C4 alkyl, which are optionally substituted with 1 to 5 substituents independently selected from the group consisting of halogen, cyano, hydroxyl, oxo, C1-C4 alkoxy, -NH2, C1-C7 aminocarbonyl, -NH(C1-C4 alkyl), -N(C1-C4 alkyl)2, -SC1-C4 alkyl, -S(O)C1-C4 alkyl, -SO2C1-C4 alkyl, -C(O)NH-C3-C6 cycloalkyl and -C(O)NH-C1-C6 alkyl, C3-C6 cycloalkyl, C1-C4 haloalkyl,C1-C4 alkoxy, -NH2, C1-C7 aminocarbonyl, -NH(C1-C4 alkyl), -N(C1-C4 alkyl)2, -C(O)NH-C3-C6 cycloalkyl and -C(O)NH-C1-C6 alkyl, wherein any N in the heteroaryl is substituted, where valence permits, by a substituent selected from the group consisting of hydrogen, C1-C4 alkyl, optionally substituted by 1 to 5 substituents independently selected from the group consisting of halogen, cyano, hydroxy, ethynyl, oxo, C1-C4 alkoxy, -NH2, C1-C7 aminocarbonyl, -NH(C1-C4 alkyl), -N(C1-C4 alkyl)2, -S(O)C1-C4 alkyl, -S(O)C1-C4 alkyl, -SO2C1-C4 alkyl, -C(O)NH-C3-C6 cycloalkyl and -C(O)NH-C1-C6 alkyl, and C3-C6 cycloalkyl, and a 4- to 7-membered heterocycloalkyl having 1 or 2 heteroatoms selected from the group consisting of O, S and N, wherein the heterocycloalkyl is optionally benzo-fused, wherein the carbons of the 4- to 7-membered heterocycloalkyl or the optionally benzo-fused 4- to 7-membered heterocycloalkyl are optionally substituted with 1 to 4 substituents independently selected from the group consisting of halogen, cyano, nitro, hydroxy, oxo, C1-C4 alkyl, which is optionally substituted with 1 to 5 substituents independently selected from The following group of substituents are substituted: halogen, cyano, hydroxy, ethynyl, oxo, C1-C4 alkoxy, -NH2, C1-C7 aminocarbonyl, -NH(C1-C4 alkyl), -N(C1-C4 alkyl)2, -SC1-C4 alkyl, -S(O)C1-C4 alkyl, -SO2C1-C4 alkyl, -C(O)NH-C3-C6 cycloalkyl and -C(O)NH-C1-C6 alkyl, and C3-C6 cycloalkyl, wherein any N in the 4 to 7 membered heterocycloalkyl or the optionally benzo-fused 4 to 7 membered heterocycloalkyl is substituted by a substituent selected from the group consisting of: hydrogen, C1-C4 alkyl , which is optionally substituted by 1 to 5 substituents independently selected from the group consisting of halogen, cyano, hydroxy, ethynyl, C1-C4 alkoxy, -NH2, C1-C7 aminocarbonyl, -NH(C1-C4 alkyl), -N(C1-C4 alkyl)2, -SC1-C4 alkyl, -S(O)C1-C4 alkyl, -SO2C1-C4 alkyl, -C(O)NH-C3-C6 cycloalkyl and C(O)NH-C1-C6 alkyl, C3-C6 cycloalkyl, and 5- to 6-membered heteroaryl, wherein any S in the 4- to 7-membered heterocycloalkyl or optionally benzo-fused 4- to 7-membered heterocycloalkyl is optionally substituted by 1 or 2 oxygen atoms;

[0086] or a salt thereof.

[0087] In one embodiment, the present invention also provides a composition comprising: a compound having formula (I), or a salt thereof, and at least one acceptable excipient, and the composition optionally further comprises at least one additional active compound.

[0088] In one embodiment, the present invention also provides a method for treating pests, comprising: administering an effective amount of a compound of formula (I), or a salt thereof, to a subject in need thereof, the method optionally further comprising an effective amount of at least one additional active compound.

[0089] In one embodiment, the present invention also provides a method for controlling pests, comprising: administering an effective amount of a compound of formula (I), or a salt thereof, to a subject in need thereof, the method optionally further comprising an effective amount of at least one additional active compound.

[0090] In one embodiment, the present invention also provides a method for treating or controlling pests, comprising: contacting the environment of a subject with an effective amount of a compound of formula (I) or a salt thereof, the method optionally further comprising an effective amount of at least one additional active compound.

[0091] Therefore, the present invention provides the use of the compounds of the present invention as medicines, including for preparing medicines. In one embodiment, the present invention provides the preparation of medicines comprising compounds of formula (I) or salts thereof for treating parasites. In one embodiment, the present invention provides the preparation of medicines comprising compounds of formula (I) or salts thereof for controlling pests.

[0092] The present invention also provides methods for preparing the compounds of the present invention and their intermediates. DETAILED DESCRIPTION

[0093] The term "C1-C2 alkyl" refers to an alkyl chain having 1 to 2 carbon atoms and includes methyl and ethyl.

[0094] The term "C1-C4 alkyl" refers to a straight or branched alkyl chain having 1 to 4 carbon atoms, and includes methyl, ethyl, propyl, isopropyl, butyl and the like.

[0095] Likewise, the term "C1-C6 alkyl" refers to a straight or branched alkyl chain having 1 to 6 carbon atoms, and includes methyl, ethyl, propyl, isopropyl, butyl, pentyl, hexyl, and the like.

[0096] The terms "C1-C4 haloalkyl" and "C1-C4 halogenalkyl" refer to a straight or branched alkyl chain having 1 to 4 carbon atoms and 1 to 5 halogens, and include fluoromethyl, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, 1,2,2-trifluoroethyl, 3,3,3-trifluoropropyl, and the like.

[0097] The terms "C1-C6 haloalkyl" and "C1-C6 halogenalkyl" refer to a straight or branched alkyl chain having 1 to 6 carbon atoms and 1 to 5 halogens, and include fluoromethyl, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, 1,2,2-trifluoroethyl, 3,3,3-trifluoropropyl, 4,4,4-trifluorobutyl, and the like.

[0098] The term "C2-C6 alkenyl" refers to a straight or branched alkenyl chain having 2 to 4 carbon atoms and one carbon-carbon double bond, and includes ethylene, propylene, isopropylene, butene, isobutylene, sec-butylene, and the like.

[0099] The term "C2-C6 alkynyl" refers to a straight or branched alkynyl chain having 2 to 4 carbon atoms and one carbon-carbon triple bond, and includes acetylene, propargyl, and the like.

[0100] The term "C1-C2 alkoxy" refers to a C1-C2 alkyl group linked through an oxygen atom, and includes a methoxy group and an ethoxy group.

[0101] The term "C1-C4 alkoxy" refers to a C1-C4 alkyl group linked through an oxygen atom, and includes methoxy, ethoxy, propoxy, isopropoxy, butoxy and the like.

[0102] The term "C1-C6 alkoxy" refers to a C1-C6 alkyl group linked through an oxygen atom, and includes methoxy, ethoxy, propoxy, isopropoxy, butoxy and the like.

[0103] The term "C3-C6 cycloalkyl" refers to an alkyl ring of 3 to 6 carbon atoms, and includes cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. It should be understood that the cycloalkyl ring may be fused, bridged or spiro-fused.

[0104] The term "C4-C7 alkylcycloalkyl" refers to a C1-C4 alkyl substituted with a C3-C6 cycloalkyl so that the total number of carbons is four to seven, and includes cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, cyclopropylethyl, and the like.

[0105] The terms "halo," "halogen," and "halo" refer to a chlorine, fluorine, bromine, or iodine atom.

[0106] The terms "4 to 7 membered heterocycloalkyl having 1 or 2 heteroatoms selected from the group consisting of O, S, N, wherein the heterocycloalkyl is optionally benzo-fused" and "4 to 7 membered heterocycloalkyl having 1 or 2 heteroatoms selected from the group consisting of O, S, B, N, wherein the heterocycloalkyl is optionally benzo-fused" refer to a 4 to 7 membered saturated or partially (but not completely) unsaturated ring having one or two heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur or having one or two heteroatoms selected from the group consisting of nitrogen, oxygen, boron and sulfur, and the ring optionally includes a carbonyl to form a lactam or lactone. It should be understood that when sulfur is included, sulfur can be -S-, -SO- or -SO2-. The heterocycle can be monocyclic or bicyclic, and any bicyclic ring can be fused, bridged or spiro-fused. The defined 4 to 7 members do not include any optional benzo-fused rings. In addition, as those skilled in the art fully understand, saturated or partially (but not completely) unsaturated 4 to 7 yuan heterocycloalkyl ring is applicable to heterocycloalkyl ring, but is not applicable to any benzo condensed ring, which will be completely unsaturated in nature. It should also be understood that this group can be connected as a substituent by the carbon atom of any ring heteroatom, heterocycloalkyl or any benzo condensed ring under valence permission. It should also be understood that when the optional benzo fused 4 to 7 yuan heterocycloalkyl is optionally substituted on carbon, the substituent can be on the carbon atom of the heterocycle and / or benzo condensed ring. By way of example, and without limitation, the term includes azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, oxetanyl, thiooxetanyl, dioxolanyl, tetrahydropyranyl, tetrahydrothiopyranyl, tetrahydrofuranyl, hexahydropyrimidinyl, tetrahydropyrimidinyl, 2,6-diazaspiro[3.3]heptanyl, isoxazolidine, dihydroimidazolyl, indolyl, isoindolyl, and the like.

[0107] The term "5- or 6-membered heteroaryl" refers to a six-membered monocyclic fully unsaturated ring having one to five carbon atoms and one or more, typically one to four, heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur. For example, but not limited to, the term includes pyrrolyl, furanyl, thienyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, triazolyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridinyl, pyrimidinyl, and the like. It should be understood that the 6-membered heteroaryl may be attached as a substituent via a ring carbon or ring nitrogen atom where this mode of attachment is useful.

[0108] When R 11 When W and the nitrogen to which they are attached are taken together, the term "a 4- to 7-membered ring optionally containing 1 to 2 heteroatoms selected from the group consisting of N, S and O" refers to a ring having R 11and a four- to seven-membered fully saturated or partially unsaturated (but not fully) ring including the nitrogen to which W is attached, and includes azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, oxetanyl, dioxolanyl, tetrahydropyranyl, tetrahydrothiopyranyl, tetrahydrofuranyl, hexahydropyrimidinyl, tetrahydropyrimidinyl, dihydroimidazolyl, and the like.

[0109] The term "5- to 10-membered heteroaryl having 1 or 2 heteroatoms selected from the group consisting of O, S and N" refers to a five- to ten-membered monocyclic or polycyclic fully unsaturated ring or ring system having one to nine carbon atoms and one or two heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur. For example, but not limited to, the term includes furanyl, thienyl, pyrrolyl, imidazolyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxazolyl, thiazolyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridinyl, pyrimidinyl, azapinyl, diazepinyl, benzofuranyl, benzothienyl, indolyl, isoindolyl, benzimidazolyl, benzisothiazolyl, benzisoxazolyl, benzoxazolyl, benzopyrazinyl, benzopyrazolyl, quinazolinyl, thienopyridinyl, quinolinyl, isoquinolinylbenzothiazolyl, and the like. It is to be understood that the 5- to 10-membered heteroaryl group having 1 or 2 heteroatoms selected from the group consisting of O, S and N may be attached as a substituent via a ring carbon or ring nitrogen atom where such attachment mode is available.

[0110] The term "oxo" refers to an oxygen atom double-bonded to the carbon to which it is attached to form a carbonyl group of an amide, ketone or aldehyde. For example, a pyridone group is considered an oxo-substituted 6-membered heteroaryl group.

[0111] The term "carboxyl" refers to the following group:

[0112]

[0113] The term "N,N-di-C1-C4-alkylaminocarbonyl" refers to the following groups:

[0114]

[0115] wherein the hydrogen on the nitrogen is replaced by two independently selected C1-C4 alkyl groups.

[0116] Likewise, the term "N-C1-C4-alkylaminocarbonyl" refers to the following radicals:

[0117]

[0118] One of the hydrogen atoms on the nitrogen is replaced by a C1-C4 alkyl group.

[0119] The term "C2-C5 alkoxycarbonyl" refers to the following groups:

[0120]

[0121] Wherein R is a C1-C4 alkyl group.

[0122] The term "C2-C7 alkylcarbonyl" refers to the following groups:

[0123]

[0124] Wherein R is a C1-C6 alkyl group.

[0125] Likewise, the term "C2-C7 haloalkylcarbonyl" refers to the above group wherein R is C1-C6 haloalkyl.

[0126] The term "C1-C7 aminocarbonyl" refers to a group having the following:

[0127]

[0128] Wherein R is hydrogen or C1-C4 alkyl.

[0129] As used herein, the term "none" with respect to a group, substituent, moiety, etc., means that the group, substituent, or moiety is absent. Where a group, substituent, or moiety is typically bonded to two or more other groups, substituents, or moieties, the other groups, substituents, or moieties replace the zero group, substituent, or moiety bonded. For example, a compound having the structure ABC; where B is zero, then A is directly bonded to C, and the compound is AC. As another example, a compound having the structure ABC is reacted; where C is zero, then the compound is AB.

[0130] The term "salt" refers to a salt of a veterinary or pharmaceutically acceptable organic acid and base or inorganic acid and base. Such salts are well known in the art and include those described in Journal of Pharmaceutical Science, 66, 2-19 (1977). An example is a hydrochloride.

[0131] The term "substituted", including when used in "optionally substituted", refers to the replacement of one or more hydrogen groups of a group with a non-hydrogen group (substituent). It should be understood that the substituent at each substitution position may be the same or different. The combinations of groups and substituents contemplated by the present invention are those that are stable or chemically feasible. For the compounds described herein, the groups and substituents thereof may be selected based on the allowed valences of the atoms and substituents, such that the selection and substitution produce a stable compound, e.g., one that does not spontaneously transform, e.g., by rearrangement, cyclization, elimination, etc.

[0132] The term "stable" refers to a compound that is not substantially altered when subjected to conditions that permit its production. In a non-limiting example, a stable compound or chemically feasible compound is one that is not substantially altered when kept at 40° C. or less for about a week in the absence of moisture or other chemically reactive conditions.

[0133] It should be understood that when the terms defined herein refer to the number of carbon atoms, the referenced number refers to the referenced group and does not include any carbon in any optional substituent that may be present thereon or any carbon that may be present as part of a fused ring, including benzo-fused rings.

[0134] Those skilled in the art will appreciate that certain compounds of the present invention exist as isomers. All stereoisomers of the compounds of the present invention, including any ratio of geometric isomers, enantiomers and diastereomers, are included within the scope of the present invention.

[0135] As used herein, the term "(RS)" in chemical nomenclature refers to a racemic mixture at a specified stereocenter.

[0136] As used herein, the term "(R or S)" or "(S or R)" in chemical nomenclature refers to one of two possible configurations at the indicated stereocenter.

[0137] Those skilled in the art will also appreciate that certain compounds of the present invention exist as tautomers. All tautomeric forms of the compounds of the present invention are encompassed within the scope of the present invention.

[0138] The compounds of the present invention also include all isotopic variants in which at least one atom having the principal atomic mass is replaced by an atom having the same atomic number but an atomic mass different from the principal atomic mass. The use of isotopic variants (e.g., deuterium, 2 In addition, certain isotopic variations of the compounds of the invention may incorporate radioactive isotopes (e.g., tritium, 3 H or 14 C), which can be used for drug and / or substrate tissue distribution studies. Using positron emitting isotopes such as 11 C. 18 F. 15 O and 13 N substitution can be used for positron emission tomography (PET) studies.

[0139] The terms "compound of the invention" and "a compound of the invention" and "compound of the present invention" and the like include embodiments having formula (I) and other more specific embodiments encompassed by formula (I) described herein as well as exemplary compounds described herein and salts of each of these embodiments.

[0140] Compounds of formula (I) having various embodiments are as follows:

[0141] Formula (I):

[0142]

[0143]

[0144] It should be understood that for A4, A5, A6, A7, A9, A 10 , A 11 , A 12 , A 14 and / or A 15 , the R6 substituent, when present, replaces a hydrogen of CH.

[0145] It will also be understood that for compounds having formula (Ig), the X group, when present, is attached at W3, W4, W5 or W6 by replacing a hydrogen of a -CH2- or -CH- group or an R of a -NR- group.

[0146] Other examples of compounds of the present invention are provided below:

[0147] (1) One embodiment relates to a compound having the formula (I) or a salt thereof.

[0148] (a) One embodiment relates to a compound having formula (Ia) or a salt thereof.

[0149] (b) One embodiment relates to a compound having formula (Ib) or a salt thereof.

[0150] (c) One embodiment relates to a compound having formula (Ic) or a salt thereof.

[0151] (d) One embodiment relates to a compound having formula (Id) or a salt thereof.

[0152] (e) One embodiment relates to a compound having formula (Ie) or a salt thereof.

[0153] (f) One embodiment relates to a compound having formula (If) or a salt thereof.

[0154] (g) One embodiment relates to a compound having formula (Ig) or a salt thereof.

[0155] (h) One embodiment relates to embodiments (1), (a), (b), (c), (d), (e), (f) and (g), wherein R1 is hydrogen, R2 is trifluoromethyl, R3 is hydrogen, R4 is trifluoromethyl, and R5 is halogen; or a salt thereof.

[0156] (i) One embodiment relates to embodiments (1), (a), (b), (c), (d), (e), (f) and (g), wherein R1 is hydrogen, R2 is trifluoromethyl, R3 is hydrogen, R4 is halogen, and R5 is halogen; or a salt thereof.

[0157] (j) One embodiment relates to embodiments (1), (a), (b), (c), (d), (e), (f) and (g), wherein R1 is hydrogen, R2 is trifluoromethyl, R3 is hydrogen, R4 is chloro, and R5 is halogen; or a salt thereof.

[0158] (k) One embodiment relates to embodiments (1), (a), (b), (c), (d), (e), (f) and (g), wherein R1 is hydrogen, R2 is trifluoromethyl, R3 is hydrogen, R4 is halogen, and R5 is chloro; or a salt thereof.

[0159] (l) One embodiment relates to embodiments (1), (a), (b), (c), (d), (e), (f) and (g), wherein R1 is hydrogen, R2 is trifluoromethyl, R3 is hydrogen, R4 is halogen, and R5 is fluorine; or a salt thereof.

[0160] (m) One embodiment relates to embodiments (1), (a), (b), (c), (d), (e), (f) and (g), wherein R1 is hydrogen, R2 is trifluoromethyl, R3 is hydrogen, R4 is chloro, and R5 is fluoro; or a salt thereof.

[0161] (n) One embodiment relates to embodiments (1), (a), (b), (c), (d), (e), (f), (g), (h), (i), (j), (k), (l) and (m), wherein A2 is O; or a salt thereof.

[0162] (o) One embodiment relates to embodiments (1), (a), (b), (c), (d), (e), (f), (g), (h), (i), (j), (k), (l), (m) and (n), wherein A1 is CF3; or a salt thereof.

[0163] (p) One embodiment relates to embodiments (1), (a), (b), (c), (d), (e), (f), (g), (h), (i), (j), (k), (l), (m) and (n), wherein A1 is CHF2; or a salt thereof.

[0164] (q) One embodiment relates to embodiments (1), (a), (h), (i), (j), (k), (l), (m), (n), (o) and (p), wherein A3 is S; or a salt thereof.

[0165] (r) One embodiment relates to embodiment (q), wherein p is 1, and R5 is C1-C6 alkyl; or a salt thereof.

[0166] (s) One embodiment relates to embodiment (r), wherein R6 is methyl; or a salt thereof.

[0167] (t) One embodiment relates to embodiments (1), (b), (h), (i), (j), (k), (l), (m), (n), (o) and (p), wherein A4, A5 and A6 are CH; or a salt thereof.

[0168] (u) One embodiment relates to embodiment (t), wherein p is 1, and R6 is C1-C6 alkyl; or a salt thereof.

[0169] (v) One embodiment relates to embodiment (u), wherein R6 is methyl; or a salt thereof.

[0170] (w) One embodiment relates to embodiments (1), (c), (h), (i), (j), (k), (l), (m), (n), (o) and (p), wherein A7, A8, A9, A 10 , A 11 and A 12 is CH; or a salt thereof.

[0171] (x) One embodiment relates to embodiments (1), (d), (h), (i), (j), (k), (l), (m), (n), (o) and (p), wherein A 13 , A 14 and A 15 is CH; or a salt thereof.

[0172] (y) One embodiment relates to embodiment (x), wherein W1 is -CH2-, and W2 is O; or a salt thereof.

[0173] (z) One embodiment relates to embodiments (1), (a), (b), (c), (g), (h), (i), (j), (k), (l), (m), (n), (o), (p), (q), (r), (s), (t), (u), (v), (w) and (x), wherein X is

[0174]

[0175] Where R 11 is hydrogen; or a salt thereof.

[0176] (aa) One embodiment relates to embodiment (z), wherein W is C1-C6 alkyl, optionally substituted with 1 to 5 substituents independently selected from the group consisting of:

[0177] halogen,

[0178] Cyano,

[0179] Hydroxyl,

[0180] Oxygen,

[0181] C1-C4 alkoxy,

[0182] C3-C6 cycloalkyl, optionally substituted by 1 to 3 substituents independently selected from the group consisting of halogen and cyano;

[0183] Ethylene,

[0184] -NH2,

[0185] C1-C7 aminocarbonyl,

[0186] -NH(C1-C4 alkyl),

[0187] -N(C1-C4 alkyl)2,

[0188] -S-C1-C4 alkyl,

[0189] -S(O)C1-C4 alkyl,

[0190] -SO2C1-C4 alkyl,

[0191] -C(O)NH-C3-C6 cycloalkyl, optionally substituted with 1 to 3 substituents independently selected from the group consisting of:

[0192] halogen,

[0193] Hydroxyl,

[0194] Cyano, and

[0195] C1-C4 alkyl, which is optionally substituted with 1 to 5 substituents independently selected from the group consisting of:

[0196] halogen,

[0197] Cyano,

[0198] Hydroxyl,

[0199] C1-C4 alkoxy,

[0200] C3-C6 cycloalkyl, and

[0201] -NH2,

[0202] -C(O)NH-C1-C6 alkyl, optionally substituted with 1 to 5 substituents independently selected from the group consisting of:

[0203] halogen,

[0204] Cyano,

[0205] Hydroxyl,

[0206] C1-C4 alkoxy,

[0207] C3-C6 cycloalkyl, and

[0208] -NH2;

[0209] -C(O)NH-C1-C6 cyanoalkyl optionally substituted by 1 to 3 halogens,

[0210] -C(O)NH-C1-C6 haloalkyl,

[0211] -C(O)-4 to 7 membered heterocycloalkyl, which is attached via nitrogen and optionally has 1 or 2 further heteroatoms selected from the group consisting of O, S, N, wherein the carbons of the 4 to 7 membered heterocycloalkyl are optionally substituted with 1 to 4 substituents independently selected from the group consisting of:

[0212] halogen,

[0213] Cyano,

[0214] Nitro,

[0215] Hydroxyl,

[0216] Oxygen,

[0217] -NH2,

[0218] C1-C7 aminocarbonyl,

[0219] C1-C4 alkyl, which is optionally substituted with 1 to 5 substituents independently selected from the group consisting of:

[0220] halogen,

[0221] Cyano,

[0222] Hydroxyl,

[0223] Ethylene,

[0224] Oxygen,

[0225] C1-C4 alkoxy,

[0226] -NH2,

[0227] C1-C7 aminocarbonyl,

[0228] -NH(C1-C4 alkyl),

[0229] -N(C1-C4 alkyl)2,

[0230] -S-C1-C4 alkyl,

[0231] -S(O)C1-C4 alkyl,

[0232] -SO2C1-C4 alkyl,

[0233] -C(O)NH-C3-C6 cycloalkyl, and

[0234] -C(O)NH-C1-C6 alkyl, and

[0235] C3-C6 cycloalkyl;

[0236] And any other N in the 4 to 7 membered heterocycloalkyl is substituted, where valence permits, with a substituent selected from the group consisting of:

[0237] hydrogen,

[0238] -NH2,

[0239] C1-C7 aminocarbonyl,

[0240] -SO2C1-C4 alkyl,

[0241] -SO2C1-C4 haloalkyl,

[0242] C1-C4 alkyl, which is optionally substituted with 1 to 5 substituents independently selected from the group consisting of:

[0243] halogen,

[0244] Cyano,

[0245] Hydroxyl,

[0246] Ethylene,

[0247] C1-C4 alkoxy,

[0248] -NH(C1-C4 alkyl),

[0249] -N(C1-C4 alkyl)2,

[0250] -S-C1-C4 alkyl,

[0251] -S(O)C1-C4 alkyl,

[0252] -SO2C1-C4 alkyl,

[0253] -C(O)NH-C3-C6 cycloalkyl,

[0254] -C(O)NH-C1-C6 alkyl,

[0255] -C(O)NH-C1-C6 haloalkyl;

[0256] A 5- to 10-membered heteroaryl having 1 or 2 heteroatoms selected from the group consisting of O, S and N, and wherein the carbons of the 5- to 10-membered heteroaryl are optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of:

[0257] halogen,

[0258] Cyano,

[0259] Nitro,

[0260] Hydroxyl,

[0261] C1-C4 alkyl, which is optionally substituted with 1 to 5 substituents independently selected from the group consisting of:

[0262] halogen,

[0263] Cyano,

[0264] Hydroxyl,

[0265] Oxygen,

[0266] C1-C4 alkoxy,

[0267] -NH2,

[0268] C1-C7 aminocarbonyl,

[0269] -NH(C1-C4 alkyl),

[0270] -N(C1-C4 alkyl)2,

[0271] -S-C1-C4 alkyl,

[0272] -S(O)C1-C4 alkyl,

[0273] -SO2C1-C4 alkyl,

[0274] -C(O)NH-C3-C6 cycloalkyl,

[0275] -C(O)NH-C1-C6 alkyl, and

[0276] -C(O)NH-C1-C6 haloalkyl;

[0277] C3-C6 cycloalkyl,

[0278] C1-C4 haloalkyl,

[0279] C1-C4 alkoxy,

[0280] -NH2,

[0281] C1-C7 aminocarbonyl,

[0282] -NH(C1-C4 alkyl),

[0283] -N(C1-C4 alkyl)2, and

[0284] -C(O)NH-C3-C6cycloalkyl;

[0285] And where valence permits, any N in the heteroaryl group is optionally substituted with a substituent selected from the group consisting of:

[0286] hydrogen,

[0287] C1-C4 alkyl, which is optionally substituted with 1 to 5 substituents independently selected from the group consisting of:

[0288] halogen,

[0289] Cyano,

[0290] Hydroxyl,

[0291] Ethylene,

[0292] Oxygen,

[0293] C3-C6 cycloalkyl,

[0294] C1-C4 alkoxy,

[0295] -NH2,

[0296] C1-C7 aminocarbonyl,

[0297] -NH(C1-C4 alkyl),

[0298] -N(C1-C4 alkyl)2,

[0299] -S-C1-C4 alkyl,

[0300] -S(O)C1-C4 alkyl,

[0301] -SO2C1-C4 alkyl,

[0302] -C(O)NH-C3-C6 cycloalkyl, and

[0303] -C(O)NH-C1-C6alkyl; and

[0304] C3-C6 cycloalkyl;

[0305] and any S in the heteroaryl group is replaced by 1 or 2 oxygen atoms;

[0306] Phenyl, which is optionally substituted with 1 to 3 substituents selected from the group consisting of:

[0307] halogen,

[0308] C1-C4 alkyl,

[0309] Cyano, or

[0310] Hydroxyl;

[0311] C3-C6 cycloalkyl, which is optionally substituted with 1 to 5 substituents independently selected from the group consisting of:

[0312] halogen,

[0313] Cyano,

[0314] Hydroxyl,

[0315] Oxygen,

[0316] C1-C4 alkoxy,

[0317] C1-C4 alkyl optionally substituted by 1 to 3 groups selected from the group consisting of halogen and cyano,

[0318] C1-C4 haloalkyl,

[0319] -NH2,

[0320] C1-C7 aminocarbonyl,

[0321] -NH(C1-C4 alkyl),

[0322] -N(C1-C4 alkyl)2,

[0323] -S-C1-C4 alkyl,

[0324] -S(O)C1-C4 alkyl,

[0325] -SO2C1-C4 alkyl,

[0326] -C(O)NH-C3-C6 cycloalkyl,

[0327] -C(O)NH-C1-C6 alkyl,

[0328] -C(O)NH-C1-C6 haloalkyl,

[0329] C2-C6 alkenyl, and

[0330] C2-C6 alkynyl; and

[0331] A 4 to 7 membered heterocycloalkyl having 1 or 2 heteroatoms selected from the group consisting of O, S, B and N, wherein the heterocycloalkyl is optionally benzo-fused, and wherein the carbons of the 4 to 7 membered heterocycloalkyl or the optionally benzo-fused 4 to 7 membered heterocycloalkyl are optionally substituted with 1 to 4 substituents independently selected from the group consisting of:

[0332] halogen,

[0333] Cyano,

[0334] Nitro,

[0335] Hydroxyl,

[0336] Oxygen,

[0337] C1-C4 alkyl, which is optionally substituted with 1 to 5 substituents independently selected from the group consisting of:

[0338] halogen,

[0339] Cyano, hydroxyl,

[0340] Ethylene,

[0341] Oxygen,

[0342] C1-C4 alkoxy,

[0343] C3-C6 cycloalkyl,

[0344] -NH2,

[0345] C1-C7 aminocarbonyl,

[0346] -NH(C1-C4 alkyl),

[0347] -N(C1-C4 alkyl)2,

[0348] -S-C1-C4 alkyl,

[0349] -S(O)C1-C4 alkyl,

[0350] -SO2C1-C4 alkyl,

[0351] -C(O)NH-C3-C6 cycloalkyl,

[0352] -C(O)NH-C1-C6 alkyl, and

[0353] and -C(O)NH-C1-C6haloalkyl;

[0354] and any B in the 4- to 7-membered heterocycloalkyl or the optionally benzo-fused 4- to 7-membered heterocycloalkyl is substituted by hydroxyl, where valence permits,

[0355] And where valence permits, any N in the 4- to 7-membered heterocycloalkyl or the optionally benzo-fused 4- to 7-membered heterocycloalkyl is substituted with a substituent selected from the group consisting of:

[0356] hydrogen,

[0357] -NH2,

[0358] C1-C7 aminocarbonyl,

[0359] -SO2C1-C4 alkyl,

[0360] -SO2C1-C4 haloalkyl,

[0361] -C(O)-NH2,

[0362] C1-C4 alkyl, which is optionally substituted with 1 to 5 substituents independently selected from the group consisting of:

[0363] halogen,

[0364] Cyano,

[0365] Hydroxyl,

[0366] Ethylene,

[0367] C1-C4 alkoxy,

[0368] -NH(C1-C4 alkyl),

[0369] -N(C1-C4 alkyl)2,

[0370] -S-C1-C4 alkyl,

[0371] -S(O)C1-C4 alkyl,

[0372] -SO2C1-C4 alkyl,

[0373] -C(O)NH-C3-C6 cycloalkyl, and

[0374] -C(O)NH-C1-C6 haloalkyl;

[0375] C3-C6 cycloalkyl;

[0376] 5- to 6-membered heteroaryl; and

[0377] Phenyl, optionally substituted with 1 to 3 substituents independently selected from the group consisting of:

[0378] halogen,

[0379] C1-C4 alkyl,

[0380] Cyano, and

[0381] hydroxyl group; and

[0382] Any S in the 4- to 7-membered heterocycloalkyl or the optionally benzo-fused 4- to 7-membered heterocycloalkyl is substituted by 1 or 2 oxygen atoms;

[0383] or a salt thereof.

[0384] (ab) One embodiment relates to embodiment (aa), wherein W is C1-C6 alkyl, and C1-C6 alkyl is substituted with a substituent selected from the group consisting of:

[0385] -C(O)NH-C1-C6 alkyl, optionally substituted with 1 to 5 substituents independently selected from the group consisting of:

[0386] halogen,

[0387] Cyano,

[0388] Hydroxyl,

[0389] C1-C4 alkoxy,

[0390] C3-C6 cycloalkyl, and

[0391] -NH2;

[0392] -C(O)NH-C1-C6 cyanoalkyl optionally substituted by 1 to 3 halogens,

[0393] -C(O)NH-C1-C6 haloalkyl, and

[0394] -C(O)-4 to 7 membered heterocycloalkyl, which is attached via nitrogen and optionally has 1 or 2 further heteroatoms selected from the group consisting of O, S, N, wherein the carbons of the 4 to 7 membered heterocycloalkyl are optionally substituted with 1 to 4 substituents independently selected from the group consisting of:

[0395] halogen,

[0396] Cyano,

[0397] Nitro,

[0398] Hydroxyl,

[0399] Oxygen,

[0400] -NH2,

[0401] C1-C7 aminocarbonyl,

[0402] C1-C4 alkyl, which is optionally substituted with 1 to 5 substituents independently selected from the group consisting of:

[0403] halogen,

[0404] Cyano,

[0405] Hydroxyl,

[0406] Ethylene,

[0407] Oxygen,

[0408] C1-C4 alkoxy,

[0409] -NH2,

[0410] C1-C7 aminocarbonyl,

[0411] -NH(C1-C4 alkyl),

[0412] -N(C1-C4 alkyl)2,

[0413] -S-C1-C4 alkyl,

[0414] -S(O)C1-C4 alkyl,

[0415] -SO2C1-C4 alkyl,

[0416] -C(O)NH-C3-C6 cycloalkyl, and

[0417] -C(O)NH-C1-C6 alkyl, and

[0418] C3-C6 cycloalkyl;

[0419] And any other N in the 4 to 7 membered heterocycloalkyl is substituted, where valence permits, with a substituent selected from the group consisting of:

[0420] hydrogen,

[0421] -NH2,

[0422] C1-C7 aminocarbonyl,

[0423] -SO2C1-C4 alkyl,

[0424] -SO2C1-C4 haloalkyl,

[0425] C1-C4 alkyl, which is optionally substituted with 1 to 5 substituents independently selected from the group consisting of:

[0426] halogen,

[0427] Cyano,

[0428] Hydroxyl,

[0429] Ethylene,

[0430] C1-C4 alkoxy,

[0431] -NH(C1-C4 alkyl),

[0432] -N(C1-C4 alkyl)2,

[0433] -S-C1-C4 alkyl,

[0434] -S(O)C1-C4 alkyl,

[0435] -SO2C1-C4 alkyl,

[0436] -C(O)NH-C3-C6 cycloalkyl,

[0437] -C(O)NH-C1-C6 alkyl,

[0438] -C(O)NH-C1-C6 haloalkyl;

[0439] or a salt thereof.

[0440] (ac) One embodiment relates to embodiment (ab), wherein W is

[0441]

[0442] or a salt thereof.

[0443] (ad) One embodiment relates to embodiment (z), wherein W is C1-C6 alkyl substituted by -C(O)NH-C3-C6 cycloalkyl, -C(O)NH-C3-C6 cycloalkyl is optionally substituted by 1 to 3 substituents independently selected from the group consisting of halogen, hydroxy, cyano and C1-C4 alkyl, C1-C4 alkyl is optionally substituted by 1 to 5 substituents independently selected from the group consisting of halogen, cyano, hydroxy, C1-C4 alkoxy and -NH2; or a salt thereof.

[0444] (ae) One embodiment relates to embodiment (z), wherein W is C1-C6 alkyl substituted with -C(O)NH-C1-C6 alkyl, -C(O)NH-C1-C6 alkyl optionally substituted with 1 to 5 substituents independently selected from the group consisting of:

[0445] halogen,

[0446] Cyano,

[0447] Hydroxyl,

[0448] C1-C4 alkoxy,

[0449] C3-C6 cycloalkyl, and

[0450] -NH2;

[0451] or a salt thereof.

[0452] (ae1) One embodiment relates to embodiment (ae), wherein W is

[0453]

[0454] or a salt thereof.

[0455] (ae2) One embodiment relates to embodiment (ae), wherein W is

[0456]

[0457] or a salt thereof.

[0458] (af) One embodiment relates to embodiment (z), wherein W is C1-C6 alkyl, C1-C6 alkyl is substituted with a 5- to 10-membered heteroaryl having 1 or 2 heteroatoms selected from the group consisting of O, S, B and N, and wherein the carbons of the 5- to 10-membered heteroaryl are optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of halogen, cyano, nitro, hydroxy, C1-C4 alkyl, which is optionally substituted with 1 to 5 substituents independently selected from the group consisting of : halogen, cyano, hydroxy, oxo, C1-C4 alkoxy, -NH2, C1-C7 aminocarbonyl, -NH(C1-C4 alkyl), -N(C1-C4 alkyl)2, -SC1-C4 alkyl, -S(O)C1-C4 alkyl, -SO2C1-C4 alkyl, -C(O)NH-C3-C6 cycloalkyl and -C(O)NH-C1-C6 alkyl; C3-C6 cycloalkyl, C1-C4 haloalkyl, C1-C4 alkoxy, -NH2,

[0459] -NH(C1-C4 alkyl), -N(C1-C4 alkyl)2 and -C(O)NH-C3-C6 cycloalkyl; and any B in the heteroaryl is substituted by hydroxy, and any N in the heteroaryl is optionally substituted, as valence permits, by a substituent selected from the group consisting of hydrogen, C1-C4 alkyl, which is optionally substituted by 1 to 5 substituents independently selected from the group consisting of halogen, cyano, hydroxy, ethynyl, oxo, C3-C6 cycloalkyl, C1-C4 alkoxy, -NH2, C1-C7 aminocarbonyl, NH(C1-C4 alkyl), -N(C1-C4 alkyl)2, -SC1-C4 alkyl,

[0460] -S(O)C1-C4 alkyl, -SO2C1-C4 alkyl, -C(O)NH-C3-C6 cycloalkyl and -C(O)NH-C1-C6 alkyl, and any S in the heteroaryl group is substituted by 1 or 2 oxygen atoms; or a salt thereof.

[0461] (af1) One embodiment relates to embodiment (z), wherein W is C1-C6 alkyl substituted with pyridine, pyridine optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of: halogen, cyano, nitro, hydroxyl, C1-C4 alkyl, which is optionally substituted with 1 to 5 substituents independently selected from the group consisting of: halogen, cyano, hydroxyl, oxo, C1-C4 alkoxy, -NH2, C1-C7 aminocarbonyl, -NH(C1-C4 alkyl) ), -N(C1-C4 alkyl)2, -SC1-C4 alkyl, -S(O)C1-C4 alkyl, -SO2C1-C4 alkyl, -C(O)NH-C3-C6 cycloalkyl and -C(O)NH-C1-C6 alkyl; C3-C6 cycloalkyl, C1-C4 haloalkyl, C1-C4 alkoxy, -NH2, -NH(C1-C4 alkyl), -N(C1-C4 alkyl)2 and -C(O)NH-C3-C6 cycloalkyl; or a salt thereof.

[0462] (af2) One embodiment relates to embodiment (z) wherein W is C1-C6 alkyl substituted with thiazole, thiazole optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of halogen, cyano, nitro, hydroxy, C1-C4 alkyl, which is optionally substituted with 1 to 5 substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, C1-C4 alkoxy, -NH2, C1-C7 aminocarbonyl, -NH(C1-C4 alkyl) ), -N(C1-C4 alkyl)2, -SC1-C4 alkyl, -S(O)C1-C4 alkyl, -SO2C1-C4 alkyl, -C(O)NH-C3-C6 cycloalkyl and -C(O)NH-C1-C6 alkyl; C3-C6 cycloalkyl, C1-C4 haloalkyl, C1-C4 alkoxy, -NH2, -NH(C1-C4 alkyl), -N(C1-C4 alkyl)2 and -C(O)NH-C3-C6 cycloalkyl; or a salt thereof.

[0463] (ag) One embodiment relates to embodiment (z), wherein W is a 4 to 7 membered heterocycloalkyl having 1 or 2 heteroatoms selected from the group consisting of O, S, N, wherein the heterocycloalkyl is optionally benzo-fused, and wherein the carbons of the 4 to 7 membered heterocycloalkyl or the optionally benzo-fused 4 to 7 membered heterocycloalkyl are optionally substituted with 1 to 4 substituents independently selected from the group consisting of:

[0464] halogen,

[0465] Cyano,

[0466] Nitro,

[0467] Hydroxyl,

[0468] Oxygen,

[0469] C1-C4 alkyl, which is optionally substituted with 1 to 5 substituents independently selected from the group consisting of:

[0470] halogen,

[0471] Cyano, hydroxyl,

[0472] Ethylene,

[0473] Oxygen,

[0474] C1-C4 alkoxy,

[0475] C3-C6 cycloalkyl,

[0476] -NH2,

[0477] C1-C7 aminocarbonyl,

[0478] -NH(C1-C4 alkyl),

[0479] -N(C1-C4 alkyl)2,

[0480] -S-C1-C4 alkyl,

[0481] -S(O)C1-C4 alkyl,

[0482] -SO2C1-C4 alkyl,

[0483] -C(O)NH-C3-C6 cycloalkyl,

[0484] -C(O)NH-C1-C6 alkyl,

[0485] and

[0486] -C(O)NH-C1-C6 haloalkyl; and

[0487] And where valence permits, any N in the 4- to 7-membered heterocycloalkyl or the optionally benzo-fused 4- to 7-membered heterocycloalkyl is substituted with a substituent selected from the group consisting of:

[0488] hydrogen,

[0489] -NH2,

[0490] C1-C7 aminocarbonyl,

[0491] -SO2C1-C4 alkyl,

[0492] -SO2C1-C4 haloalkyl,

[0493] -C(O)-NH2,

[0494] C1-C4 alkyl, which is optionally substituted with 1 to 5 substituents independently selected from the group consisting of:

[0495] halogen,

[0496] Cyano,

[0497] Hydroxyl,

[0498] Ethylene,

[0499] C1-C4 alkoxy,

[0500] C3-C6 cycloalkyl,

[0501] -NH(C1-C4 alkyl),

[0502] -N(C1-C4 alkyl)2,

[0503] -S-C1-C4 alkyl,

[0504] -S(O)C1-C4 alkyl,

[0505] -SO2C1-C4 alkyl,

[0506] -C(O)NH-C3-C6 cycloalkyl, and

[0507] -C(O)NH-C1-C6 haloalkyl;

[0508] C3-C6 cycloalkyl;

[0509] 5- to 6-membered heteroaryl; and

[0510] Phenyl, optionally substituted with 1 to 3 substituents independently selected from the group consisting of:

[0511] halogen,

[0512] C1-C4 alkyl,

[0513] Cyano, and

[0514] hydroxyl group; and

[0515] Any S in the 4- to 7-membered heterocycloalkyl or the optionally benzo-fused 4- to 7-membered heterocycloalkyl is substituted by 1 or 2 oxygen atoms;

[0516] or a salt thereof.

[0517] (ag1) One embodiment relates to embodiment (ag), wherein W is a 4- to 7-membered heterocycloalkyl group having 1 or 2 heteroatoms selected from the group consisting of O, S, N is selected from the group consisting of pyrrolyl, azetidinyl, 2-oxoazetidinyl, isoxazolidinyl, 2,6-diazaspiro[3.3]heptyl and 1,6-diazaspiro[3.3]heptyl wherein the carbons of the 4- to 7-membered heterocycloalkyl group are optionally substituted with 1 to 4 substituents independently selected from the group consisting of:

[0518] halogen,

[0519] Cyano,

[0520] Nitro,

[0521] Hydroxyl,

[0522] Oxygen,

[0523] C1-C4 alkyl, which is optionally substituted with 1 to 5 substituents independently selected from the group consisting of:

[0524] halogen,

[0525] Cyano, hydroxyl,

[0526] Ethylene,

[0527] Oxygen,

[0528] C1-C4 alkoxy,

[0529] C3-C6 cycloalkyl,

[0530] -NH2,

[0531] C1-C7 aminocarbonyl,

[0532] -NH(C1-C4 alkyl),

[0533] -N(C1-C4 alkyl)2,

[0534] -S-C1-C4 alkyl,

[0535] -S(O)C1-C4 alkyl,

[0536] -SO2C1-C4 alkyl,

[0537] -C(O)NH-C3-C6 cycloalkyl,

[0538] -C(O)NH-C1-C6 alkyl,

[0539] and

[0540] -C(O)NH-C1-C6 haloalkyl;

[0541] And, where valence permits, any N in the 4- to 7-membered heterocycloalkyl group is substituted with a substituent selected from the group consisting of:

[0542] hydrogen,

[0543] -SO2C1-C4 alkyl,

[0544] -SO2C1-C4 haloalkyl,

[0545] -C(O)-NH2,

[0546] C1-C4 alkyl, which is optionally substituted with 1 to 5 substituents independently selected from the group consisting of:

[0547] halogen,

[0548] Cyano,

[0549] Hydroxyl,

[0550] Ethylene,

[0551] C1-C4 alkoxy,

[0552] C3-C6 cycloalkyl,

[0553] -NH(C1-C4 alkyl),

[0554] -N(C1-C4 alkyl)2,

[0555] -S-C1-C4 alkyl,

[0556] -S(O)C1-C4 alkyl,

[0557] -SO2C1-C4 alkyl,

[0558] -C(O)NH-C3-C6 cycloalkyl, and

[0559] -C(O)NH-C1-C6 haloalkyl; and

[0560] C3-C6 cycloalkyl;

[0561] or a salt thereof.

[0562] (ah) One embodiment relates to embodiments (ag) and (ag1), wherein the carbon of the 4- to 7-membered heterocycloalkyl is optionally substituted with 1 to 2 substituents independently selected from the group consisting of oxo and C1-C4 alkyl.

[0563] And where valence permits, any N in the 4- to 7-membered heterocycloalkyl is substituted with hydrogen and C1-C4 alkyl, cyano, ethynyl or C3-C6 cycloalkyl optionally substituted with 1 to 3 halogens; or a salt thereof.

[0564] (ai) One embodiment relates to embodiments (ag), (ag1) and (ah), wherein a carbon of the 4- to 7-membered heterocycloalkyl is substituted with 1 oxo, and, where valence permits, any N of the 4- to 7-membered heterocycloalkyl is substituted with 1 cyano-substituted C1-C4 alkyl; or a salt thereof.

[0565] (aj) One embodiment relates to embodiments (ag), (ag1) and (ah), wherein a carbon of the 4- to 7-membered heterocycloalkyl is substituted with 1 oxo, and, where valence permits, any N of the 4- to 7-membered heterocycloalkyl is substituted with 1 to 3 halogen-substituted C1-C4 alkyl; or a salt thereof.

[0566] (ak) One embodiment relates to embodiments (ag), (ag1) and (ah), wherein a carbon of the 4- to 7-membered heterocycloalkyl is substituted with 1 oxo, and, where valence permits, any N of the 4- to 7-membered heterocycloalkyl is substituted with 1 C1-C4 alkyl substituted with a C3-C6 cycloalkyl; or a salt thereof.

[0567] (al) One embodiment relates to embodiments (ag), (ag1) and (ah), wherein, where valence permits, any N in the 4- to 7-membered heterocycloalkyl is substituted with 1 cyano-substituted C1-C4 alkyl; or a salt thereof.

[0568] (am) One embodiment relates to embodiments (ag), (ag1) and (ah), wherein any N in the 4- to 7-membered heterocycloalkyl is substituted with 1 to 3 halogen-substituted C1-C4 alkyl groups, as valence permits; or a salt thereof.

[0569] (an) One embodiment relates to embodiments (ag), (ag1) and (ah), wherein, where valence permits, any N in the 4- to 7-membered heterocycloalkyl is substituted with 1 C1-C4 alkyl substituted with a C3-C6 cycloalkyl; or a salt thereof.

[0570] (an1) One embodiment relates to embodiment (z), wherein W is C3-C6 cycloalkyl, which is optionally substituted with 1 to 5 substituents independently selected from the group consisting of:

[0571] halogen,

[0572] Cyano,

[0573] Hydroxyl,

[0574] Oxygen,

[0575] C1-C4 alkoxy,

[0576] C1-C4 alkyl optionally substituted by 1 to 3 groups selected from the group consisting of halogen and cyano,

[0577] C1-C4 haloalkyl,

[0578] -NH2,

[0579] C1-C7 aminocarbonyl,

[0580] -NH(C1-C4 alkyl),

[0581] -N(C1-C4 alkyl)2,

[0582] -S-C1-C4 alkyl,

[0583] -S(O)C1-C4 alkyl,

[0584] -SO2C1-C4 alkyl,

[0585] -C(O)NH-C3-C6 cycloalkyl,

[0586] -C(O)NH-C1-C6 alkyl,

[0587] -C(O)NH-C1-C6 haloalkyl,

[0588] C2-C6 alkenyl optionally substituted by 1 to 3 halogens; and

[0589] C2-C6 alkynyl;

[0590] or a salt thereof.

[0591] (ao) relates to embodiments (1), (d), (e), (f), (h), (i), (j), (k), (l), (m), (n), (o), (p), (t), (x) and (y), wherein Y is C1-C6 alkyl, which is optionally substituted with 1 to 5 substituents independently selected from the group consisting of:

[0592] halogen,

[0593] Cyano,

[0594] Hydroxyl,

[0595] Oxygen,

[0596] C3-C6 cycloalkyl,

[0597] C1-C4 alkoxy,

[0598] Ethylene,

[0599] -NH2,

[0600] C1-C7 aminocarbonyl,

[0601] -NH(C1-C4 alkyl),

[0602] -N(C1-C4 alkyl)2,

[0603] -S-C1-C4 alkyl,

[0604] -S(O)C1-C4 alkyl,

[0605] -SO2C1-C4 alkyl,

[0606] -C(O)NH-C3-C6 cycloalkyl, optionally substituted with 1 to 3 substituents independently selected from the group consisting of:

[0607] halogen,

[0608] Hydroxyl,

[0609] Cyano, and

[0610] C1-C4 alkyl, which is optionally substituted with 1 to 5 substituents independently selected from the group consisting of:

[0611] halogen,

[0612] Cyano,

[0613] Hydroxyl,

[0614] C1-C4 alkoxy, and

[0615] -NH2,

[0616] -C(O)NH-C1-C6 alkyl,

[0617] -C(O)NH-C1-C6 cyanoalkyl optionally substituted by 1 to 3 halogens,

[0618] -C(O)NH-C1-C6 haloalkyl;

[0619] or a salt thereof.

[0620] (ap) One embodiment relates to embodiment (aq), wherein Y is C1-C6 alkyl substituted with 1 -SO2C1-C4 alkyl; or a salt thereof.

[0621] (aq) One embodiment relates to embodiment (aq), wherein Y is a C1-C6 alkyl substituted with 1 -SO2CH3; or a salt thereof.

[0622] (xa) Another embodiment relates to each exemplified compound or a salt thereof.

[0623] (xb) Another embodiment is directed to each stereoisomer of each exemplified, depicted or named compound; or a salt thereof.

[0624] (xc) Another embodiment relates to a salt of each exemplary compound.

[0625] The compounds of the invention are prepared by a variety of procedures, many of which have been described in the art. For example, see WO 2005 / 085216, WO 2007 / 079162, US 2007 / 066617, US20130131017, WO 2009 / 002809, WO2009 / 112275, WO 2010 / 003923, WO 2010 / 070068, WO 2012 / 120399 and WO 2013 / 079407.

[0626] The present disclosure relates to compounds of formula (I) with extended half-life. Compounds of formula (I) have trifluoromethyl at the meta position or halogen at the para and / or ortho positions. Therefore, compounds of formula (I) include the following features: trifluoromethyl at one or two meta positions; halogen at the ortho position; halogen at each ortho and para position; or halogen at each ortho position and trifluoromethyl at the para position. It should be understood that compounds of formula (I) may have other substituents, but include the above groups. Without being bound by any particular theory, applicants believe that inhibiting metabolism at the ortho and para positions enhances duration after oral administration or injection.

[0627] The following examples are intended to be illustrative rather than limiting and represent specific embodiments of the invention.

[0628]

[0629]

[0630]

[0631]

[0632]

[0633] and each stereoisomer of the above compounds.

[0634] In another aspect, disclosed is a compound having formula (II), or a salt thereof,

[0635]

[0636] in,

[0637] A1 is -CF3 or -CHF2;

[0638] Cy1 is selected from:

[0639]

[0640] Cy2 is selected from:

[0641] and

[0642] T1 is selected from:

[0643]

[0644]

[0645]

[0646] In one embodiment, disclosed is a compound having formula (IIa), or a salt thereof,

[0647]

[0648] wherein A1, Cy1, Cy2 and T1 are as defined above.

[0649] In another embodiment, disclosed is a compound having formula (IIb), or a salt thereof,

[0650]

[0651] wherein A1, Cy1, Cy2 and T1 are as defined above.

[0652] In certain embodiments, A1 in Formula (II), (IIa) or (IIb) is -CF3.

[0653] In certain embodiments, Cy1 in formula (II), (IIa) or (IIb) is

[0654]

[0655] In certain embodiments, Cy2 in formula (II), (IIa) or (IIb) is

[0656]

[0657] In certain embodiments, T1 in formula (II), (IIa) or (IIb) is

[0658]

[0659] In certain embodiments, disclosed are compounds having formula (II), (IIa) and (IIb), or salts thereof, wherein A1 is -CF3;

[0660] Cy1 is selected from:

[0661]

[0662] Cy2

[0663] and

[0664] T1 is

[0665]

[0666]

[0667] In certain embodiments, disclosed are compounds of formula (II), (IIa) and (IIb), or salts thereof, wherein

[0668] A1 is -CF3;

[0669] Cy1

[0670]

[0671] Cy2 is selected from:

[0672] and

[0673] T1 is

[0674]

[0675]

[0676]

[0677] In certain embodiments, disclosed are compounds of formula (II), (IIa) and (IIb), or salts thereof, wherein

[0678] A1 is -CF3;

[0679] Cy1

[0680]

[0681] Cy2 is selected from:

[0682] and

[0683] T1 is

[0684]

[0685] In another aspect, disclosed is a compound having formula (III), or a salt thereof,

[0686]

[0687] in,

[0688] A1 is -CF3 or -CHF2;

[0689] Cy3 is selected from:

[0690]

[0691] Cy4 is:

[0692] and

[0693] T2 is selected from:

[0694]

[0695] In one embodiment, a compound having formula (IIIa), or a salt thereof, is disclosed.

[0696]

[0697] wherein A1, Cy3, Cy4 and T2 are as defined above.

[0698] In another embodiment, disclosed is a compound having formula (IIIb), or a salt thereof,

[0699]

[0700] wherein A1, Cy3, Cy4 and T2 are as defined above.

[0701] In certain embodiments, A1 in Formula (III), (IIIa) or (IIIb) is -CF3.

[0702] In certain embodiments, Cy3 in formula (III), (IIIa) or (IIIb) is

[0703]

[0704] In certain embodiments, T2 in formula (III), (IIIa) or (IIIb) is

[0705]

[0706] In certain embodiments, disclosed are compounds having formula (III), (IIIa) or (IIIb), or salts thereof, wherein

[0707] A1 is -CF3;

[0708] Cy3

[0709]

[0710] Cy4 is selected from:

[0711] and

[0712] T3

[0713]

[0714] The following examples are intended to be illustrative rather than limiting and represent specific embodiments of the invention.

[0715] The analysis was performed using an Agilent 1200 Infinity Series Liquid Chromatography (LC) system consisting of a 1260 HiP Degasser (G4225A), a 1260 Binary Pump (G1312B), a 1290 Autosampler (G4226A), a 1290 Thermal Stable Column Chamber (G1316C), and a 1260 Diode Array Detector (G4212B) coupled to an Agilent 6150 Single Quadrupole Mass Spectrometer (MS) Detector. The injection volume was set to 1 μL by default. UV (DAD) acquisition was performed at 40 Hz with a scan range of 190 to 400 nm (5 nm step size). A 1:1 split was used before the MS detector. The MS was operated in positive and negative ion modes using an electrospray ionization source (ESI). The nebulizer pressure was set to 345 kPa, and the drying gas temperature and flow were set to 350 °C and 12.0 L / min, respectively. The capillary voltage used was 4000 V in positive mode and 3500 V in negative mode. The MS acquisition range was set from 100 to 800 m / z with a step size of 0.2 m / z in both polarity modes. The fragmentor voltage was set to 70 (ESI+) or 120 (ESI-), the gain was set to 0.40 (ESI+) or 1.00 (ESI-), and the ion count threshold was set to 4000 (ESI+) or 1000 (ESI-). The total MS scan cycle time was 0.15 s / cycle. Data acquisition was performed using Agilent ChemStation software.

[0716] Method A: The analysis was performed on a Phenomenex Gemini-NX C18 column of 50 mm length, 2.1 mm internal diameter and 3 μm particle size. The mobile phase used was: A = water containing 0.1% formic acid / B = CH3CN containing 0.1% formic acid.

[0717] Method B: The analysis was performed on a Waters XBridge C18 column, 50 mm long, 2.1 mm internal diameter and 3.5 μm particle size. The mobile phase used was: A = water containing 10 mM ammonium bicarbonate, adjusted to pH 9 with ammonium hydroxide / B = CH3CN.

[0718] Method I: The analysis was performed on a Waters XBridge BEH C18, 50 mm long, 2.1 mm internal diameter and 2.5 μm particle size. The mobile phase used was: A = water containing 10 mM ammonium acetate / B = CH3CN.

[0719] The analysis was performed using a Waters AcquityUPLC liquid chromatography (LC) system coupled to a Waters SQ Detector 2 single quadrupole mass spectrometer (MS) detector. UV (DAD) acquisition was performed with a scan range of 200 to 400 nm (1.2 nm resolution). The MS was operated in positive and negative ion modes using an electrospray ionization source (ESI). Capillary voltage was 3.50 (kV), cone voltage was 35 (V), and desolvation temperature was 550°C. Desolvation gas flow was 1000 (L / hour), cone gas flow was 50 (L / hour). The Ms acquisition range was set to 100 to 1500 m / z. The MS scan cycle time was 0.5 seconds. Data acquisition was performed using Waters Masslynx software.

[0720] Method C: Analysis was performed on an Acquity UPLC BEH C18 column of 50 mm length, 2.1 mm inner diameter and 1.7 μm particle size. The mobile phase used was: A = water containing 0.1% formic acid / B = CH3CN containing 0.1% formic acid.

[0721] Method D: The analysis was performed on an Acquity UPLC BEH C18 column of 50 mm length, 2.1 mm inner diameter and 1.7 μm particle size. The mobile phase used was: A = water containing 0.1% formic acid / B = CH3CN.

[0722] Method E: Analysis was performed on an Acquity UPLC BEH C18 column of 50 mm length, 2.1 mm inner diameter and 1.7 μm particle size. The mobile phase used was: A = water containing 10 mM ammonium acetate / B = CH3CN.

[0723] Method H: The analysis was performed on a Luna Omega-PS C18 column of 50 mm length, 2.1 mm internal diameter and 1.6 μm particle size. The mobile phase used was: A = water containing 10 mM ammonium acetate / B = CH3CN.

[0724] An ultra-high performance liquid chromatography (UHPLC) system (Make-Thermo Scientific) coupled to an ion trap mass analyzer was used for analysis. UV acquisition was performed with a scan range of 200 to 400 nm (1 nm resolution). The MS was operated in positive and negative ion modes using an electrospray ionization source (ESI), sheath gas flow rate (arb): 40, auxiliary gas flow rate (arb): 20, purge gas flow rate (arb): 1, spray voltage (kv): 5, capillary temperature (°C): 350, capillary voltage (V): 30, tube lens (V): 30 in positive mode and -30 in negative mode. The Ms acquisition range was set from 100 to 2000 m / z. The MS scan cycle time was 3 microscans. Data acquisition was performed using Xcalibur software.

[0725] Method F: The analysis was performed on an Ascentis Express C18, 5 cm long, 2.1 mm internal diameter and 2.7 μm particle size. The mobile phase used was: A = water with 0.1% formic acid / B = 100% CH3CN.

[0726] Method G: The analysis was performed on an Ascentis Express C18, 5 cm long, 2.1 mm internal diameter and 2.7 μm particle size. The mobile phase used was: A = water containing 10 mm ammonium acetate / B = 100% CH3CN.

[0727] As used herein: aq. means aqueous, br means broad, CH3CN means acetonitrile, d means doublet, dd means double doublet, DCM means dichloromethane, DCE means dichloroethane, DIPEA means N-diisopropylethylamine, DMF means N,N-dimethylformamide, DMSO means dimethyl sulfoxide, ee means enantiomeric excess, ES means electrospray ionization, EtOAc means ethyl acetate, h means hour, HATU means 1-[bis(dimethylamino)methylene]-1H-1,2,3- triazole[4,5-b]pyridine 3-oxide, hexafluorophosphate, HPLC refers to high performance liquid chromatography, iPrOH refers to isopropanol, J refers to coupling constant, LCMS refers to liquid chromatography-mass spectrometry, m / z refers to mass-to-charge ratio, M refers to molarity, m refers to multiplet, MeOH refers to methanol, min refers to minutes, NaHCO3 refers to sodium bicarbonate, Na2CO3 refers to sodium carbonate, NEt3 refers to triethylamine, NMR refers to nuclear magnetic resonance, q refers to quartet, quint refers to quintet, rt refers to room temperature, R t refers to retention time, s refers to singlet, sat. refers to saturation, T refers to temperature, t refers to triplet, td refers to triplet of doublet, THF refers to tetrahydrofuran, wt refers to weight, and δ refers to chemical shift.

[0728] Examples 1.1 and 1.2

[0729] 2-Methylsulfonyl-1-[6-[(5S or R)-5-[3-chloro-2-fluoro-5-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-4H-isoxazol-3-yl]spiro[1H-isobenzofuran-3,3'-azetidine]-1'-yl]ethanone

[0730] and

[0731] 2-Methylsulfonyl-1-[6-[(5R or S)-5-[3-chloro-2-fluoro-5-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-4H-isoxazol-3-yl]spiro[1H-isobenzofuran-3,3'-azetidine]-1'-yl]ethanone

[0732]

[0733] In a pressure vessel containing a solution of 6-bromospiro[1H-isobenzofuran-3,3'-azetidine]-1'-carboxylic acid tert-butyl ester (8.86g, 24.7mmol) and N,N,N',N'-tetramethylethylenediamine (2.8mL, 18mmol) in toluene (50mL), palladium acetate (II) (286mg, 1.21mmol) and butyl di-1-adamantylphosphine (1.42g, 3.76mmol) were added. The container was sealed, flushed with N2 gas three times, and then flushed with CO gas and hydrogen three times to a pressure of 310kPa. The reactants were heated to 90 ° C and stirred overnight. The reactants were cooled to room temperature and then flushed with N2 gas three times. The reaction mixture was passed through Filter (rinse with EtOAc). The filtrate was concentrated in vacuo and the crude product was purified by silica gel column chromatography (0 to 20% EtOAc in cyclohexane) to give tert-butyl 6-formylspiro[1H-isobenzofuran-3,3'-azetidine]-1'-carboxylate. LC-MS (Method A) R t = 1.10 min, m / z = 234.2 [M-tBu+H] + .

[0734] NH2OH solution (50% aqueous solution, 3 mL, 49.0 mmol) was slowly added to a flask containing a stirred solution of 6-formylspiro[1H-isobenzofuran-3,3'-azetidine]-1'-carboxylic acid tert-butyl ester (6.57 g, 21.6 mmol) in MeOH (110 mL). The reactants were stirred at room temperature for 2 hours. The reactants were concentrated in vacuo, and the resulting solids were placed in a vacuum oven and dried overnight to give 6-(hydroxyiminomethyl)spiro[1H-isobenzofuran-3,3'-azetidine]-1'-carboxylic acid tert-butyl ester. LC-MS (Method A) R t= 1.00 min and 1.02 min, m / z = 303.0 [MH] - (Mixture of E / Z isomers).

[0735] N-Chlorosuccinimide (1.54 g, 11.3 mmol) was added to a flask containing a stirred solution of 6-(hydroxyiminomethyl)spiro[1H-isobenzofuran-3,3'-azetidine]-1'-carboxylic acid tert-butyl ester (3.05 g, 9.52 mmol) in DMF (10 mL). The reactants were stirred for 30 minutes. The reaction was cooled to 0 ° C, and 1-chloro-2-fluoro-5-(trifluoromethyl)-3-[1-(trifluoromethyl)vinyl]benzene (2.96 g, 8.61 mmol) was added, followed by the slow addition of NEt3 (1.9 mL, 13 mmol). The reactants were allowed to warm to room temperature and stirred overnight. The reactants were distributed between EtOAc and brine (50 mL each), and the layers were separated. The aqueous layer was extracted with EtOAc (2×25 mL), and the combined organic layers were concentrated in vacuo. The crude product was purified by silica gel column chromatography (0 to 15% EtOAc in cyclohexane) to give the title compound tert-butyl 6-[(rac)-5-[3-chloro-2-fluoro-5-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-4H-isoxazol-3-yl]spiro[1H-isobenzofuran-3,3'-azetidine]-1'-carboxylate. LC-MS (Method A) R t =1.57 min, m / z = 539.0 [M-tBu+H] + .

[0736] To a flask containing a stirred solution of 6-[(racemic)-5-[3-chloro-2-fluoro-5-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-4H-isoxazol-3-yl]spiro[1H-isobenzofuran-3,3'-azetidine]-1'-carboxylic acid tert-butyl ester (4 g, 6.38 mmol) in DCM (60 mL) at 0 ° C, TFA (5 mL) was slowly added. The reactants were allowed to warm to room temperature and stirred at room temperature overnight. The reaction mixture was concentrated in vacuo, and the residue was distributed between saturated NaHCO3 aqueous solution and DCM containing 10% MeOH (50 mL each). The layers were separated and the aqueous layer was extracted with DCM containing 10% MeOH (2×50 mL). The combined organic layers were concentrated in vacuo to give 6-[(rac)-5-[3-chloro-2-fluoro-5-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-4H-isoxazol-3-yl]spiro[1H-isobenzofuran-3,3'-azetidine]. LC-MS (Method A) R t = 1.35 min, m / z = 495.0 [M+H] + .

[0737] To a flask containing a stirred solution of 6-[(rac)-5-[3-chloro-2-fluoro-5-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-4H-isoxazol-3-yl]spiro[1H-isobenzofuran-3,3'-azetidine] (3.94 g, 7.57 mmol) and 2-methanesulfonylacetic acid (1.49 g, 10.3 mmol) in EtOAc (25 mL) was slowly added NEt3 (1.5 mL, 11 mmol). The reaction was cooled to 0 °C and 2,4,6-tripropyl-1,3,5,2,4,6-trioxytriphosphate-2,4,6-trioxide (50 wt% in EtOAc) (9.1 mL, 15 mmol) was added dropwise over 10 minutes. The reaction was allowed to warm to room temperature and stirred overnight. The reaction mixture was diluted with EtOAc (50 mL), washed with aqueous NaHCO3 (50 mL), brine (100 mL), and concentrated in vacuo. The crude product was purified by silica gel column chromatography (20 to 70% EtOAc in cyclohexane) to give the title compound. LC-MS (Method A) R t =1.36 min, m / z=615.0 [M+H] + . 1 H NMR(CDCl3,400MHz)δ8.03(dd,J=2,6Hz,1H),7.81(dd,1.6,6Hz,1H),7.59-7.71( m,3H),5.17(s,2H),4.64-4.70(m,2H),4.1-4.47(m,3H),3.87(m,3H)3.20(s,3H).

[0738] The two enantiomers were separated by SFC. OJ-H with a column size of 250 mm × 30 mm (5 μm), a flow rate of 175 mL / min, and a CO2-based mobile phase of 12% iPrOH containing 0.2% N,N-dimethylethylamine as an additive to give Example 1.1: 2-methylsulfonyl-1-[6-[(5S or R)-5-[3-chloro-2-fluoro-5-(trifluoromethyl)phenyl]-5-(trifluoromethyl)- 4H-isoxazol-3-yl]spiro[1H-isobenzofuran-3,3'-azetidine]-1'-yl]ethanone, and Example 1.2: 2-methylsulfonyl-1-[6-[(5R or S)-5-[3-chloro-2-fluoro-5-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-4H-isoxazol-3-yl]spiro[1H-isobenzofuran-3,3'-azetidine]-1'-yl]ethanone.

[0739] Examples 2.1 and 2.2

[0740] N-[2-Oxo-2-(2,2,2-trifluoroethylamino)ethyl]-4-[(5S or R)-5-[3-chloro-2-fluoro-5-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-4H-isoxazol-3-yl]naphthalene-1-carboxamide

[0741] and

[0742] N-[2-Oxo-2-(2,2,2-trifluoroethylamino)ethyl]-4-[(5R or S)-5-[3-chloro-2-fluoro-5-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-4H-isoxazol-3-yl]naphthalene-1-carboxamide

[0743]

[0744] A solution of 4-bromo-1-naphthaldehyde (3.04 g, 12.31 mmol) in 1,4-dioxane (30 mL) and MeOH (30 mL) in a round bottom pressure flask was treated with NEt3 (36.6 mmol, 5.10 mL) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.95 g, 1.23 mmol) and then stirred overnight at 90 °C under a CO atmosphere (380 kPa). The reaction mixture was directly diluted onto silica gel and subjected to silica gel column chromatography (0 to 15% EtOAc in cyclohexane) to afford methyl 4-formylnaphthalene-1-carboxylate. LC-MS (Method A) R t =1.06 min, m / z=215.0 [M+H] + .

[0745] A solution of methyl 4-formylnaphthalene-1-carboxylate (2.52 g, 11.2 mmol) in THF (50 mL) in a flask was treated with aqueous NaOH (2 M, 52.0 g, 100 mmol) and stirred at room temperature for 4 hours. The reaction mixture was acidified to pH ˜1 with concentrated HCl and extracted with DCM (3×40 mL). The combined organic layers were washed with water and then evaporated to room temperature. The mixture was concentrated in vacuo to give 4-formylnaphthalene-1-carboxylic acid. LC-MS (Method A) R t = 0.36 min, m / z = 199.0 [MH] - .

[0746] A suspension of 4-formylnaphthalene-1-carbonyl chloride (2.54 g, 10.8 mmol, 85%) in DCM (55 mL) was placed under a N2 atmosphere and treated with DMF (0.02 mL). The resulting mixture was then slowly treated with oxalyl chloride (13.8 mmol, 1.20 mL) and further stirred at room temperature for 30 minutes. The reaction mixture was concentrated in vacuo and used directly in the next step. A mixture of 4-formylnaphthalene-1-carbonyl chloride (2.36 g, 10.8 mmol) and 2-amino-N-(2,2,2-trifluoroethyl)acetamide HCl (2.14 g, 10.9 mmol) was placed under a N2- atmosphere and treated with DCM (55 mL) and DIPEA (29 mmol, 5.0 mL). The reaction mixture was diluted with HCl solution (2 M, 40 mL) and the two layers were separated. The aqueous layer was extracted with DCM (2×30 mL), and the combined organic layers were separated by HPLC. The product was concentrated in vacuo and then subjected to silica gel column chromatography (60 to 80% EtOAc in cyclohexane) to afford 4-formyl-N-[2-oxo-2-(2,2,2-trifluoroethylamino)ethyl]naphthalene-1-carboxamide. LC-MS (Method A) R t = 0.86 min, m / z = 339.0 [M+H] + .

[0747] A suspension of 4-formyl-N-[2-oxo-2-(2,2,2-trifluoroethylamino)ethyl]naphthalene-1-carboxamide (3.05 g, 8.55 mmol) in EtOH (45 mL) was placed under N2 atmosphere, treated with NH2OH solution (50% aqueous solution, 3 mL, 49.0 mmol), and stirred at room temperature for 4 hours. The reaction mixture was concentrated in vacuo to give 4-(hydroxyiminomethyl)-N-[2-oxo-2-(2,2,2-trifluoroethylamino)ethyl]naphthalene-1-carboxamide. LC-MS (Method A) R t = 0.77 min, m / z = 354.0 [M+H] + .

[0748] To a flask equipped with a condenser was added [3-chloro-2-fluoro-5-(trifluoromethyl)phenyl]boronic acid (6.1 g, 24.41 mmol) and XPhos Pd(crotyl)Cl(Pd-170) (537 mg, 0.76 mmol). The flask was flushed with N2 gas and THF (50 mL) was added followed by a degassed solution of tripotassium phosphate (10.9 g, 49.8 mmol) in water (100 mL). 2-Bromo-3,3,3-trifluoro-prop-1-ene (4.0 mL, 37 mmol) was added and the reaction was heated to 70 °C and stirred for 1 hour. The reaction was allowed to cool to room temperature and the layers were separated. The aqueous layer was extracted with Et2O (2 x 50 mL) and the combined organic layers were filtered through Filter and remove the solvent in vacuo. Purify the crude product by silica gel column chromatography (isocratic isohexane) to give 1-chloro-2-fluoro-5-(trifluoromethyl)-3-[1-(trifluoromethyl)vinyl]benzene. LC-MS (Method A) R t = 1.45 minutes (no ionization).

[0749] A mixture of 4-(hydroxyiminomethyl)-N-[2-oxo-2-(2,2,2-trifluoroethylamino)ethyl]naphthalene-1-carboxamide (1.54 g, 3.71 mmol) and N-chlorosuccinimide (0.63 g, 4.59 mmol) was placed under a N2 atmosphere and treated with DMF (7.5 mL). The resulting solution was warmed to 40°C and stirred for 10 minutes. LC-MS (Method A) R t = 0.88 min, m / z = 350.0 [MH] - . The reaction mixture was cooled on ice and treated with 1-chloro-2-fluoro-5-(trifluoromethyl)-3-[1-(trifluoromethyl)vinyl]benzene (1.29 g, 3.76 mmol) and NEt3 (5.7 mmol, 0.80 mL). The ice bath was then removed and the reaction mixture was stirred for 4 hours. The reaction mixture was diluted with saturated aqueous NaHCO3 (60 mL) and extracted with tert-butyl methyl ether (3×30 mL). The combined organic layers were dried over anhydrous MgSO4, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (cyclohexane containing 40 to 75% EtOAc) to give the title compound. LC-MS (Method A) R t =1.39 min, m / z=644.0[M+H] + . 1H-NMR(DMSO-d6,400MHz)δ8.95(t,J=6Hz,1H),8.79(d,J=8Hz,1H)8.71(t,J=6.4Hz,1H),8 .39(d,J=7.6Hz,2H),7.94-8.01(m,2H),7.64-7.74(m,3H),4.70(m,2H),4.4-3.95(m,4H).

[0750] The two enantiomers were separated by SFC. OJ-H with a column size of 250 mm×30 mm (5 μm), a flow rate of 120 mL / min, and a CO2-based mobile phase of 10% MeOH containing 0.2% N,N-dimethylethylamine as an additive to give Example 2.1: N-[2-Oxo-2-(2,2,2-trifluoroethylamino)ethyl]-4-[(5S or R)-5-[3-chloro-2-fluoro-5-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-4H-isoxazol-3-yl]naphthalene-1-carboxamide, and Example 2.2: N-[2-Oxo-2-(2,2,2-trifluoroethylamino)ethyl]-4-[(5R or S)-5-[3-chloro-2-fluoro-5-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-4H-isoxazol-3-yl]naphthalene-1-carboxamide.

[0751] Examples 3.1 and 3.2

[0752] 2-Methyl-N-[2-oxo-2-(2,2,2-trifluoroethylamino)ethyl]-4-[(5S or R)-5-[3-chloro-2-fluoro-5-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-4H-isoxazol-3-yl]benzamide

[0753] and

[0754] 2-Methyl-N-[2-oxo-2-(2,2,2-trifluoroethylamino)ethyl]-4-[(5R or S)-5-[3-chloro-2-fluoro-5-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-4H-isoxazol-3-yl]benzamide

[0755]

[0756] A mixture of 4-bromo-2-methyl-benzoic acid methyl ester (10.0 g, 42.3 mmol), N,N,N',N'-tetramethylethylenediamine (3.96 mL, 26.3 mmol), palladium(II) acetate (0.5 g, 2.12 mmol), butyldi-1-adamantylphosphine (2 g, 5.29 mmol) and toluene (65 mL) was charged into a pressure vessel. The reactants were pressurized with CO gas (~414 kPa) and heated to 85 °C overnight. The reactants were cooled to room temperature. The reaction mixture was stirred for 2 hours. Filter, wash with toluene and remove the solvent under reduced pressure. The resulting residue is purified by silica gel column chromatography (0 to 10% EtOAc in cyclohexane) to give 4-formyl-2-methyl-benzoic acid methyl ester. LC-MS (Method A) R t = 0.95 min (no ionization).

[0757] A mixture of MeOH (65 mL) containing methyl 4-formyl-2-methyl-benzoate (2.05 g, 11.2 mmol) and water (2 M, 65 mL) containing NaOH was stirred at room temperature for 5 hours. The reaction mixture was acidified with concentrated HCl until pH ~ 1. The reaction was diluted with EtOAc, the organic layer was separated, and the aqueous layer was washed with EtOAc. The organic layers were then combined, dried over anhydrous MgSO4, filtered, and concentrated in vacuo to give 4-formyl-2-methyl-benzoic acid. LC-MS (Method B) R t =0.71 min, m / z=163.0 [MH]-.

[0758] At room temperature, DMF (25 μL) was added to a suspension of 4-formyl-2-methyl-benzoic acid (1.8 g, 10.4 mmol) and oxalyl chloride (995 μL, 11.5 mmol) in DCM (35 mL) under N2 atmosphere. The reactant was stirred at room temperature for 3 hours. The reaction mixture was concentrated to give a crude acyl chloride. A solution of 2-amino-NN-(2,2,2-trifluoroethyl)acetamide HCl (2.25 g, 11.5 mmol) and NEt3 (3.2 mL, 23 mmol) in DCM (35 mL) was added to the crude acyl chloride at 0 ° C, and the reactant was then warmed to room temperature and stirred for 30 minutes. The reactant was diluted with DCM / water, the organic layer was collected, and the solvent was removed under reduced pressure. The crude product was purified by silica gel column chromatography (0 to 10% MeOH in DCM) to give 4-formyl-2-methyl-N-[2-oxo-2-(2,2,2-trifluoroethylamino)ethyl]benzamide. LC-MS (Method A) R t = 0.69 min, m / z = 303.0 [M+H] + .

[0759] NH2OH solution (32.6M in water, 385 μL, 6.28 mmol) was added to MeOH (15 mL) containing 4-formyl-2-methyl-N-[2-oxo-2-(2,2,2-trifluoroethylamino)ethyl]benzamide (1.00 g, 3.14 mmol) and the reaction was stirred at room temperature for 6 hours. The solvent was removed under reduced pressure to give 4-[(E and Z)-hydroxyiminomethyl]-2-methyl-N-[2-oxo-2-(2,2,2-trifluoroethylamino)ethyl]benzamide. LC-MS (Method B) R t = 0.68 min and 0.70 min, m / z = 318.0 [M+H] + .

[0760] To a solution of 4-[(E and Z)-hydroxyiminomethyl]-2-methyl-N-[2-oxo-2-(2,2,2-trifluoroethylamino)ethyl]benzamide (1.08g, 3.16mmol,) in DMF (3.34mL) was added N-chlorosuccinimide (548mg, 4.10mmol), and the reactant was heated to 40°C for 15 minutes. The reactant was cooled to 0°C, 1-chloro-2-fluoro-5-(trifluoromethyl)-3-[1-(trifluoromethyl)vinyl]benzene (1.03g, 3.15mmol) was added, and NEt3 (484μL, 3.47mmol) was then added. The reactant was stirred at room temperature. The reactant was diluted with EtOAc and brine. The organic layer was separated and washed with more brine, dried over anhydrous MgSO4, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (0 to 60% EtOAc in cyclohexane) to afford the title compound. LC-MS (Method A) R t =1.38 min, m / z=608.0 [M+H] + . 1 HNMR(CDCl3,400MHz)δ8.04(dd,J=2,6Hz,1H),7.81(dd,J=2,6Hz,1H),7.47-7.56(m,3H),6.90(br s,1H),6.71(br s,1H),4.18-4.23(m,3H),3.84-4.00(m,3H),2.48(s,3H).

[0761] exist The two enantiomers were separated by SFC on AS-H with a column size of 250 mm × 30 mm (5 μm), a flow rate of 152 ml / min, and a CO2-based mobile phase of 10% MeOH containing 0.2% N,N-dimethylethylamine as an additive to give Example 3.1: 2-methyl-N-[2-oxo-2-(2,2,2-trifluoroethylamino)ethyl]-4-[(5S or R)-5 -[3-chloro-2-fluoro-5-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-4H-isoxazol-3-yl]benzamide, and Example 3.2: 2-methyl-N-[2-oxo-2-(2,2,2-trifluoroethylamino)ethyl]-4-[(5R or S)-5-[3-chloro-2-fluoro-5-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-4H-isoxazol-3-yl]benzamide.

[0762] The following compounds were prepared similarly by the methods of Examples 3.1 and 3.2:

[0763]

[0764]

[0765]

[0766]

[0767]

[0768]

[0769]

[0770]

[0771]

[0772]

[0773]

[0774] Example 3.9

[0775] 3-Methyl-N-[2-oxo-2-(2,2,2-trifluoroethylamino)ethyl]-5-[(5RS)-5-(trifluoromethyl)-5-(2,4,6-trifluorophenyl)-4H-isoxazol-3-yl]thiophene-2-carboxamide

[0776]

[0777] 2,4,6-Trifluorobromobenzene (1.00 g, 4.76 mmol) was dissolved in dry Et2O (5 mL) and cooled to -78°C. A solution of n-BuLi in THF (3.25 mL, 5.2 mmol, 1.6 M) was added dropwise over 30 minutes, and the resulting solution was stirred at -78°C for 1 hour. A solution of ethyl trifluoroacetate (675 mg, 4.76 mmol) in Et2O (5 mL) was then added all at once, and the reaction was stirred at -78°C for 20 minutes, and at -40°C for another 40 minutes. A cooled (-78°C) solution of 2,2,2-trifluoro-1-(2,4,6-trifluorophenyl)ethan-1-one (866 mg, 3.8 mmol) and LiHMDS (6.6 mL, 6.6 mmol) in dry Et2O (5 mL) that had been prepared was then added dropwise, and the resulting reaction mixture was stirred for 4 h, where it was allowed to warm to room temperature. The reaction mixture was quenched by adding saturated NH4Cl aqueous solution and extracted with EtOAc. The combined organic layer was washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. 1-(5-bromo-4-methyl-2-thienyl)-4,4,4-trifluoro-3-hydroxy-3-(2,4,6-trifluorophenyl)butan-1-one was obtained as a light yellow liquid and used in the next step without further purification. LC-MS (Method E) R t = 2.88 min, m / z = 447.2 / 449.1 [M+H] + .

[0778] A mixture of 1-(5-bromo-4-methyl-2-thienyl)-4,4,4-trifluoro-3-hydroxy-3-(2,4,6-trifluorophenyl)butan-1-one (800 mg, 1.79 mmol) and pyridine (0.578 mL, 7.16 mmol) in DCM (10 mL) was cooled to 0 ° C in an ice bath. Then, SOCl2 (0.43 mL, 3.58 mmol) was added dropwise at 0 ° C. The ice bath was removed and the reaction mixture was stirred at room temperature for 4 hours. Thereafter, saturated NH4Cl aqueous solution was slowly added. The aqueous layer was separated and extracted with DCM (3×). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The desired product was obtained as a light yellow liquid and used in the next step without further purification. LC-MS (Method C) R t = 2.52 and 2.56 min (mixture of E / Z isomers), m / z = 429.1 / 431.1 [M+H] + .

[0779] To the above solution of 1-(5-bromo-4-methylthiophen-2-yl)-4,4,4-trifluoro-3-(2,4,6-trifluorophenyl)but-2-en-1-one (450 mg, 1.05 mmol) in DCE (10 mL) was added NH2OH solution (50% aqueous solution, 52 mg, 1.57 mmol) and DBU (0.319 mg, 2.10 mmol) at room temperature. The mixture was stirred at room temperature for 3 hours. Thereafter, water was added, the aqueous layer was separated, and extracted with DCM (3×). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. 3-(5-bromo-4-methylthiophen-2-yl)-5-(2,4,6-trifluorophenyl)-5-(trifluoromethyl)-isoxazole was obtained as a light yellow solid and used in the next step without further purification. LC-MS (Method C) R t = 2.53 min, m / z = 444.1 / 449.1 [M+H] + .

[0780] 3-(5-bromo-4-methylthiophene-2-yl)-5-(2,4,6-trifluorophenyl)-5-(trifluoromethyl)-isoxazole (220 mg, 485 μmol) was dissolved in THF (5 mL) at 0 ° C under N2 atmosphere. A solution of iPrMgCl in THF (0.77 mL, 1.49 mmol, 2 M) was added dropwise, and the mixture was stirred in an ice bath at 0 ° C for 30 minutes. Then, CO2 gas was bubbled through the solution at 0 ° C for 1 hour. The reactant was quenched by adding HCl aqueous solution (1 M). The aqueous layer was separated and extracted with EtOAc (3×). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The desired product was obtained as a yellow liquid and used immediately in the next step without further purification. LC-MS (Method C) R t = 2.53 min, m / z = 410.1 [M+H] + .

[0781] The above 3-methyl-5-(5-(trifluoromethyl)-5-(2,4,6-trifluorophenyl)-4,5-dihydroisoxazol-3-yl)thiophene-2-carboxylic acid (200 mg, 0.49 mmol), PyBOP (307 mg, 0.59 mmol) and NEt3 (144 mg, 1.47 mmol)) were mixed in DMF (10 mL) and cooled to 0°C in an ice bath. 2-amino-N-(2,2,2-trifluoroethyl)acetamide (92 mg, 0.59 mmol) was then added at 0°C. The ice bath was removed and the reaction mixture was stirred at room temperature for 4 hours. Thereafter, cold water was added. The aqueous layer was separated and extracted with EtOAc (3×). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by silica gel column chromatography (5 to 14% EtOAc in petroleum ether) to give Example 3.9: 3-methyl-N-[2-oxo-2-(2,2,2-trifluoroethylamino)ethyl]-5-[(5RS)-5-(trifluoromethyl)-5-(2,4,6-trifluorophenyl)-4H-isoxazol-3-yl]thiophene-2-carboxamide as a colorless solid. LC-MS (Method D) R t = 2.07 min, m / z = 546.1 [MH] - . 1 H-NMR (DMSO-d6, 400MHz) δ 8.61 (br s, 1H), 8.38 (br s, 1H), 7.53 (s, 1H), 7.41 (t, J = 9.6Hz, 2H), 4.42 (q, J = 18Hz, 2H), 3.98-3.87 (m, 4H), 2.43 (s, 3H).

[0782] Example 3.56

[0783] 3-Methyl-N-[2-oxo-2-(2,2,2-trifluoroethylamino)ethyl]-5-[(5RS)-5-[2,4-difluoro-5-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-4H-isoxazol-3-yl]thiophene-2-carboxamide

[0784]

[0785] To a solution of 5-bromo-4-methyl-thiophene-2-carbaldehyde (4.74 g, 22.7 mmol) in MeOH (113 mL) was added NH2OH solution (50% aqueous solution, 2.7 mL, 44 mmol) dropwise. The reaction was stirred at room temperature for 4.5 hours. Thereafter, the reaction was concentrated in vacuo and the resulting solid was dried in a vacuum oven to give 5-bromo-4-methyl-thiophene-2-carbaldehyde oxime as a cream-colored solid. LC-MS (Method A) R t= 0.99 and 1.02 min, m / z = 217.6 / 219.6 [M+H] + (Mixture of E / Z isomers).

[0786] A mixture of 2-[2,4-difluoro-5-(trifluoromethyl)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (2.75 g, 5.80 mmol), methanesulfonic acid (2-dicyclohexylphosphine-2',4',6'-tri-isopropyl-1,1'-biphenyl) (2'-methylamino-1,1'-biphenyl-2-yl) palladium (II) (256 mg, 292 μmol) and 2-bromo-3,3,3-trifluoropropene (2.53 g, 14.5 mmol) was placed under N2 atmosphere and treated with potassium phosphate (0.5 M aqueous solution, 11.0 mmol, 22 mL) and THF (11 mL). The resulting reaction mixture was stirred at 70 ° C for 30 minutes. The reaction mixture was cooled to room temperature, diluted with water (30 mL), and extracted with DCM (3×25 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (100% isohexane) to afford 1,5-difluoro-2-(trifluoromethyl)-4-[1-(trifluoromethyl)vinyl]benzene as a colorless oil. LC-MS (Method A) R t = 1.37 min (no significant mass ions observed).

[0787] A mixture of the above 5-bromo-4-methyl-thiophene-2-carbaldehyde oxime (950mg, 4.10mmol) and N-chlorosuccinimide (0.73g, 5.36mmol) was placed under a N2 atmosphere, treated with DMF (3.0mL), and stirred at 40°C for 5 minutes, during which time a bright yellow precipitate was formed. The reaction mixture was cooled to 0°C in an ice bath and treated with the above 1,5-difluoro-2-(trifluoromethyl)-4-[1-(trifluoromethyl)vinyl]benzene (1.34g, 4.12mmol). NEt3 (0.47g, 4.6mmol) was then slowly added, and the resulting mixture was stirred at 0°C for 10 minutes and then stirred at room temperature for another 30 minutes. The reaction mixture was diluted with saturated NaHCO3 aqueous solution (40mL) and extracted with DCM (3×25mL). The combined organic layers were concentrated under reduced pressure. The residue was purified by silica gel column chromatography (0 to 10% tert-butyl methyl ether in cyclohexane) to give 3-(5-bromo-4-methyl-2-thienyl)-5-[2,4-difluoro-5-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-4H-isoxazole as a light yellow semi-solid. LC-MS (Method A) R t =1.64 min, m / z=493.8 / 495.8 [M+H] + .

[0788] A solution of 3-(5-bromo-4-methyl-2-thienyl)-5-[2,4-difluoro-5-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-4H-isoxazole (851 mg, 1.29 mmol) in THF (6.5 mL) was placed under a N2 atmosphere, cooled to 0 ° C in an ice bath, and treated with a solution of iPrMgCl in THF (1.3 mL, 2.6 mmol, 2.0 M). The resulting mixture was stirred at 0 ° C for 30 minutes. CO2 gas was then bubbled through the reaction mixture for 15 minutes. Thereafter, the reaction mixture was acidified to pH ~ 2 with 2M HCl solution and then extracted with DCM (3×15 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was dissolved in MeOH, filtered, and purified by preparative HPLC (Phenomenex Gemini-NX 10 micron 50*150 mm C-18) (CH3CN, water - both containing 0.1% formic acid, 30 to 100% CH3CN, over 11 minutes, 120 ml / min) (2 injections). 5-[5-[2,4-difluoro-5-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-4H-isoxazol-3-yl]-3-methyl-thiophene-2-carboxylic acid was obtained as a cream solid from the main peak. LC-MS (Method A) R t =1.02 min, m / z=458.0 [MH] - .

[0789] A mixture of 5-[5-[2,4-difluoro-5-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-4H-isoxazol-3-yl]-3-methyl-thiophene-2-carboxylic acid (154 mg, 318 μmol), 2-amino-N-(2,2,2-trifluoroethyl)acetamide HCl (96.0 mg, 473 μmol) and PYBOP (254 mg, 488 μmol) was placed under N2 atmosphere and treated with THF (1.6 mL) and NEt3 (94.4 mg, 933 μmol, 0.13 mL) and then stirred at room temperature for 30 minutes. The reaction mixture was diluted with saturated aqueous NaHCO3 solution (20 mL) and extracted with DCM (3×10 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was dissolved in MeOH (plus ~1 mL DMF), filtered, and purified by preparative HPLC (Phenomenex Gemini-NX 10 micron 50*150 mm C-18) (CH3CN, water containing 10 mM ammonium bicarbonate, adjusted to pH 9 with ammonium hydroxide, 30 to 100% CH3CN over 10 minutes, 120 ml / min) (1 injection). Example 3.56: 3-Methyl-N-[2-oxo-2-(2,2,2-trifluoroethylamino)ethyl]-5-[rac-(5R)-5-[2,4-difluoro-5-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-4H-isoxazol-3-yl]thiophene-2-carboxamide was obtained as a colorless solid from the main peak. LC-MS (Method A) R t =1.33 min, m / z=598.0 [M+H] + . 1H-NMR(DMSO-d6,400MHz)δ8.62(t,J=6Hz,1H),8.38(t,J=5.6Hz,1H),7.92- 7.97(m,2H),7.49(s,1H),4.30-4.55(m,2H),3.89-3.97(m,4H),2.43(s,3H).

[0790] Examples 4.1 and 4.2

[0791] 3-Methyl-N-[2-oxo-2-(2,2,2-trifluoroethylamino)ethyl]-5-[(5S or R)-5-[3-chloro-2-fluoro-5-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-4H-isoxazol-3-yl]thiophene-2-carboxamide

[0792] and

[0793] 3-Methyl-N-[2-oxo-2-(2,2,2-trifluoroethylamino)ethyl]-5-[(5R or S)-5-[3-chloro-2-fluoro-5-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-4H-isoxazol-3-yl]thiophene-2-carboxamide

[0794]

[0795] Under N2-atmosphere, a mixture of 5-bromo-4-methyl-thiophene-2-carbaldehyde oxime (3.36g, 14.5mmol) and N-chlorosuccinimide (2.74g, 20.1mmol) was combined in DMF (11mL). The resulting solution was warmed to 40°C and stirred for 5 minutes, during which time a bright yellow precipitate was observed. The mixture was cooled to 0°C in an ice bath and treated with 1-chloro-2-fluoro-5-(trifluoromethyl)-3-[1-(trifluoromethyl) vinyl] benzene (4.35g, 11.2mmol), and then NEt3 (2.40mL, 17.0mmol) was slowly added. When the addition of NEt3 was completed, the ice bath was removed, and the reaction mixture was stirred at room temperature for 15 minutes. The reaction mixture was stirred at room temperature for another 30 minutes, then diluted with NaOH solution (1M, 60mL), and extracted with tert-butyl methyl ether (3×40mL). The combined organic layers were dried over anhydrous MgSO4, filtered, and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (0 to 10% DCM in cyclohexane) to give 3-(5-bromo-4-methyl-2-thienyl)-5-[3-chloro-2-fluoro-5-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-4H-isoxazole as a colorless solid. LC-MS (Method B): R t =1.65 min, m / z=509.8[M+H] + .

[0796] A solution of 3-(5-bromo-4-methyl-2-thienyl)-5-[3-chloro-2-fluoro-5-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-4H-isoxazole (2.84 g, 5.28 mmol) in THF (26 mL) was placed under N2 atmosphere, cooled to 0 ° C in an ice bath, and treated with a solution of iPrMgCl in THF (2.0 M, 5.50 mL, 11 mmol), and then stirred for 30 minutes. Then, carbon dioxide (232 mg, 5.28 mmol) was bubbled through the reaction mixture for 15 minutes. The reaction mixture was then treated with HCl solution (2 M, 40 mL) and extracted with DCM (3 × 30 mL). The combined organic layer was washed with saturated NaHCO3 aqueous solution (20 mL), and the aqueous layer was back extracted with DCM (2 × 20 mL). The combined organic layers were dried over anhydrous MgSO4, filtered, and concentrated in vacuo to give 3-methyl-5-[rac-(5R)-5-[3-chloro-2-fluoro-5-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-4H-isoxazol-3-yl]thiophene-2-carboxylic acid as a light yellow solid. LC-MS (Method B) R t =1.06 min, m / z=473.8 [MH] - .

[0797] A mixture of 5-[5-[3-chloro-2-fluoro-5-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-4H-isoxazol-3-yl]-3-methyl-thiophene-2-carboxylic acid (2.48 g, 4.17 mmol), 2-amino-N-(2,2,2-trifluoroethyl)acetamide HCl and PYBOP (3.26 g, 6.27 mmol) was placed under N2-atmosphere and treated with THF (20 mL) and NEt3 (1.31 g, 12.9 mmol). The resulting mixture was stirred at room temperature for 30 minutes. The reaction mixture was then diluted with aqueous NaHCO3 solution (40 mL) and extracted with DCM (3×40 mL). The combined organic layers were dried over anhydrous MgSO4, filtered and concentrated in vacuo. The crude product was purified by silica gel column chromatography (cyclohexane containing 0 to 50% EtOAc) to give the desired product. LC-MS (Method B) R t =1.40 min, m / z=614.0 [M+H] + . 1 H-NMR (DMSO-d6, 400MHz) δ 8.62 (t, J = 6Hz, 1H), 8.35 (m, 2H), 7.87-7.87 (m, 1H), 7.50 (s, 1H), 4.38-4.59 (m, 2H), 3.89-3.97 (m, 4H), 2.43 (s, 3H).

[0798] The two enantiomers were separated by SFC. OJ-H with a column size of 250 mm × 30 mm (5 μm), a flow rate of 160 mL / min, and a CO2-based mobile phase of 6% MeOH containing 0.2% N,N-dimethylethylamine as an additive to give Example 4.1: 3-methyl-N-[2-oxo-2-(2,2,2-trifluoroethylamino)ethyl]-5-[(5S or R)-5-[3-chloro-2-fluoro- 5-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-4H-isoxazol-3-yl]thiophene-2-carboxamide, and Example 4.2: 3-methyl-N-[2-oxo-2-(2,2,2-trifluoroethylamino)ethyl]-5-[(5R or S)-5-[3-chloro-2-fluoro-5-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-4H-isoxazol-3-yl]thiophene-2-carboxamide.

[0799] The following compounds were prepared similarly by the methods of Examples 4.1 and 4.2:

[0800]

[0801]

[0802] Example 5.1

[0803] (RS)-4-[5-[3-chloro-2-fluoro-5-(trifluoromethyl)phenyl]-5-(difluoromethyl)-4H-isoxazol-3-yl]-2-methyl-N-[2-oxo-2-(2,2,2-trifluoroethylamino)ethyl]benzamide

[0804]

[0805] To a stirred solution of 2-chloro-1-fluoro-4-(trifluoromethyl)benzene (5.0 g, 25.1 mmol) in anhydrous THF (40 mL) was added LDA in THF (2 M, 18.8 mL, 37.78 mmol) at -78 °C. The reaction mixture was stirred at -78 °C for 2.5 hours. A solution of ethyl 2,2-difluoroacetate (3.75 g, 30.2 mmol) in THF (10 ml) was added, and the reaction mixture was stirred at -10 °C for 1 hour. The reactants were quenched with HCl solution (1 M) at -10 °C and extracted with EtOAc (2 × 100 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure to give 1-[3-chloro-2-fluoro-5-(trifluoromethyl)phenyl]-2,2-difluoro-ethanone, which was used in the next step without further purification.

[0806] To a stirred solution of 1-(4-bromo-3-methyl-phenyl)ethanone (3.0 g, 14 mmol) in dry THF (10 mL) was added THF (1 M, 28 mL) containing LiHMDS at -78 °C, and the resulting mixture was stirred for 2.5 hours. A solution of 1-[3-chloro-2-fluoro-5-(trifluoromethyl)phenyl]-2,2-difluoro-ethanone (5.84 g, 21.1 mmol) in THF (5 mL) was added dropwise to the reaction mixture at -78 °C and maintained for 1 hour. The reaction mixture was allowed to warm to room temperature over 16 hours. The reactants were quenched with saturated NH4Cl aqueous solution (20 mL) at -10 °C and extracted with EtOAc (2 × 80 mL). The combined organic layers were washed with brine (70 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure to give crude 1-(4-bromo-3-methyl-phenyl)-3-[3-chloro-2-fluoro-5-(trifluoromethyl)phenyl]-4,4-difluoro-3-hydroxy-butan-1-one, which was purified by silica gel column chromatography (5% EtOAc in petroleum ether).

[0807] To a stirred solution of 1-(4-bromo-3-methyl-phenyl)-3-[3-chloro-2-fluoro-5-(trifluoromethyl)phenyl]-4,4-difluoro-3-hydroxy-butan-1-one (1.0 g, 2.04 mmol) in dry DCM (10 mL) at 0°C was added pyridine (0.64 g, 8.16 mmol) followed by dropwise addition of SOCl2 (0.3 mL, 4 mmol). The reaction mixture was stirred at 0°C for 1 hour. The reaction was quenched with water (25 mL) and extracted with EtOAc (2×20 mL). The combined organic layers were washed with brine (35 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure to give (Z)-1-(4-bromo-3-methyl-phenyl)-3-[3-chloro-2-fluoro-5-(trifluoromethyl)phenyl]-4,4-difluoro-but-2-ene-1-one which was used in the next step without further purification. LC-MS (Method B) R t = 3.06 and 3.13 min, m / z = 469.0 [MH] - .

[0808] To a stirred solution of (Z)-1-(4-bromo-3-methyl-phenyl)-3-[3-chloro-2-fluoro-5-(trifluoromethyl)phenyl]-4,4-difluoro-but-2-ene-1-one (1.0 g, 2.12 mmol) in dry DCE (10 mL) was added NH2OH solution (50% aqueous solution, 0.58 g, 8.48 mmol) at 0°C, followed by dropwise addition of DBU (0.645 g, 4.20 mmol). The reaction mixture was allowed to warm to room temperature over 1 hour. The reactant was quenched with water (30 mL) and extracted with EtOAc (2×20 mL). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude mixture was purified by silica gel column chromatography (2% EtOAc in petroleum ether) to give 3-(4-bromo-3-methyl-phenyl)-5-[3-chloro-2-fluoro-5-(trifluoromethyl)phenyl]-5-(difluoromethyl)-4H-isoxazole. LC-MS (Method B) R t = 2.66 min, m / z = 487.9 [M+H] + .

[0809] A stirred solution of 3-(4-bromo-3-methyl-phenyl)-5-[3-chloro-2-fluoro-5-(trifluoromethyl)phenyl]-5-(difluoromethyl)-4H-isoxazole (0.80 g, 1.64 mmol) and NaOAc (0.27 g, 3.28 mmol) in anhydrous MeOH (10 mL) was degassed with N gas for 5 min, and Pd(dppf)Cl (0.24 g, 0.32 mmol) was added. The reaction mixture was transferred to an autoclave and stirred at 100° C. under a CO gas atmosphere at 500 psi pressure for 20 h. The reaction mixture was stirred by The mixture was filtered through a plug and washed with MeOH (10 mL). The filtrate was evaporated under reduced pressure. The crude product was purified by silica gel column chromatography (50 to 90% EtOAc in petroleum ether) to give 4-[5-[3-chloro-2-fluoro-5-(trifluoromethyl)phenyl]-5-(difluoromethyl)-4H-isoxazol-3-yl]-2-methyl-benzoic acid methyl ester. LC-MS (Method B) R t = 2.56 minutes, m / z = 466.4 [M+H] + .

[0810] To a solution of 4-[5-[3-chloro-2-fluoro-5-(trifluoromethyl)phenyl]-5-(difluoromethyl)-4H-isoxazol-3-yl]-2-methyl-benzoic acid methyl ester (0.8 g, 1.71 mmol) in THF:water (1:1, 10 mL) was added LiOH.H2O (0.288 g, 6.87 mmol) and the resulting mixture was stirred at 70°C for 6 hours. The reaction mixture was concentrated under reduced pressure, the residue was diluted with 2.5 mL of water and acidified with HCl solution (1 M) until pH ~ 6. The aqueous layer was extracted with EtOAc (2 x 50 mL) and the combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure to give 4-[5-[3-chloro-2-fluoro-5-(trifluoromethyl)phenyl]-5-(difluoromethyl)-4H-isoxazol-3-yl]-2-methyl-benzoic acid. LC-MS (Method B) R t = 2.30 min, m / z = 452.3 [M+H] + .

[0811] To a solution of 4-[5-[3-chloro-2-fluoro-5-(trifluoromethyl)phenyl]-5-(difluoromethyl)-4H-isoxazol-3-yl]-2-methyl-benzoic acid (0.2 g, 0.44 mmol) in dry DMF (3 mL) was added DIPEA (0.193 mL, 1.10 mmol) and HATU (0.2 g, 0.53 mmol), and the resulting mixture was stirred at room temperature for 10 minutes. A solution of 2-amino-N-(2,2,2-trifluoroethyl)acetamide (0.083 g, 0.53 mmol) in dry DMF (1 mL) was added, and the resulting reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was quenched with cold water (10 mL) and extracted with EtOAc (2×15 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude mixture was purified by silica gel column chromatography (30 to 70% EtOAc in petroleum ether) to give Example 5.1: (RS)-4-[5-[3-chloro-2-fluoro-5-(trifluoromethyl)phenyl]-5-(difluoromethyl)-4H-isoxazol-3-yl]-2-methyl-N-[2-oxo-2-(2,2,2-trifluoroethylamino)ethyl]benzamide. LC-MS (Method B) R t = 2.19 minutes, m / z = 590.2 [M+H] +. 1H-NMR(DMSO-d6,400MHz)δ8.65-8.58(m,2H),8.27(dd,J=6,2Hz,1H),7.84(dd,J=6,2Hz,1H),7.64-7.5 9(m,2H),7.49(d,J=8Hz,1H),6.54(t,J=54Hz,1H),4.18(q,J=18Hz,2H),4.0-3.89(m,4H),2.40(s,3H).

[0812] Examples 6.1 and 6.2

[0813] 4-Methyl-N-[2-oxo-2-(2,2,2-trifluoroethylamino)ethyl]-6-[(5R or S)-5-[3-chloro-2-fluoro-5-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-4H-isoxazol-3-yl]pyridazine-3-carboxamide

[0814] and

[0815] 4-Methyl-N-[2-oxo-2-(2,2,2-trifluoroethylamino)ethyl]-6-[(5S or R)-5-[3-chloro-2-fluoro-5-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-4H-isoxazol-3-yl]pyridazine-3-carboxamide

[0816]

[0817] In a 100 ml steel bottle, a mixture of 3,6-dibromo-4-methylpyridazine (4.00 g, 15.9 mmol) and Et3N (6.69 mL, 47.6 mmol) in MeOH (40 mL) was degassed with N2 gas for 10 minutes, and then Pd(dppf)Cl2 (1.16 g, 1.59 mmol) was added. The reaction mixture was then heated at 65°C under CO gas pressure (~60 psi) for 16 hours. The reaction mixture was passed through (Washed with EtOAc (2 x 30 mL). The combined filtrates were concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (20% EtOAc in petroleum ether) to give methyl 6-bromo-5-methylpyridazine-3-carboxylate as a yellow solid.

[0818] NaBH4(1.08g, 28.6mmol) was added in batches to a solution of 6-bromo-5-methylpyridazine-3-carboxylic acid methyl ester (3.30g, 14.3mmol) in MeOH (28mL) and DCM (7mL) at 0°C, and the resulting reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in EtOAc (50mL). The organic layer was washed with HCl aqueous solution (0.1M, 30mL), brine (30mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (containing 0 to 100% EtOAc petroleum ether) to obtain (6-bromo-5-methylpyridazine-3-yl) methanol as a yellow solid. LC-MS (method C) R t = 0.99 min, m / z = 203.1 [M+H] + .

[0819] To a stirred solution of (6-bromo-5-methylpyridazin-3-yl)methanol (1.70 g, 8.37 mmol) in chloroform (30 mL) was added MnO2 (7.30 g, 83.7 mmol) portionwise at 0°C. The reaction mixture was then allowed to warm to room temperature and stirred for 2 hours. The residue was washed with EtOAc (2 x 20 mL). The reaction mixture was filtered through a pad of Celite®. The combined filtrates were concentrated under reduced pressure to give 6-bromo-5-methylpyridazine-3-carbaldehyde, which was used immediately in the next step without purification. LC-MS (Method E) R t =1.08 min, m / z=202.9[M+H] + .

[0820] To a stirred solution of 6-bromo-5-methylpyridazine-3-carboxaldehyde (1.30 g, 6.47 mmol) in MeOH (6 mL) was added NH2OH solution (50% aqueous solution, 6 mL), and the resulting mixture was stirred at room temperature for 16 hours. Thereafter, the reaction mixture was concentrated under reduced pressure. Saturated NaHCO3 aqueous solution (2 × 20 mL) was added, and the mixture was extracted with EtOAc (3 × 25 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude compound was purified by silica gel column chromatography (petroleum ether containing 10% EtOAc) to give 6-bromo-5-methylpyridazine-3-carboxaldehyde oxime as a brown semisolid. LC-MS (Method D) R t =1.12 min, m / z=216.1[M+H] + .

[0821] NCS (253 mg, 1.90 mmol) was added to a stirred solution of 6-bromo-5-methylpyridazine-3-carbaldehyde oxime (315 mg, 1.46 mmol) in DMF (4 mL) at 0 ° C in an ice bath, and the mixture was stirred at 40 ° C for 30 minutes. The reactant was then cooled to 0 ° C in an ice bath, and NEt3 (0.22 mL, 1.60 mmol) and 1-chloro-2-fluoro-5-(trifluoromethyl)-3-(3,3,3-trifluoroprop-1-ene-2-yl)benzene (512 mg, 1.75 mmol) were added dropwise. The mixture was slowly warmed to room temperature and stirred for 3 hours. The reaction mixture was quenched by adding water (15 mL) and then extracted with EtOAc (3 × 20 mL). The combined organic layer was washed with brine, dried over anhydrous Na2SO4, and then concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (5% EtOAc in petroleum ether) to give 3-(6-bromo-5-methyl-pyridazin-3-yl)-5-[3-chloro-2-fluoro-5-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-4H-isoxazole as a brown semi-solid. LC-MS (Method D) R t = 2.66 minutes, m / z = 506.1 [M+H] + .

[0822] In a 100 ml steel bottle, a mixture of 3-(6-bromo-5-methyl-pyridazin-3-yl)-5-[3-chloro-2-fluoro-5-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-4H-isoxazole (200 mg, 395 mmol) in MeOH (10 mL) and Et3N (0.16 mL, 1.18 mmol) was degassed with N2 gas for 10 minutes, and then Pd(dppf)Cl2 (29.0 mg, 39.4 mmol) was added. The reaction mixture was then heated at 70°C under CO gas pressure (~120 psi) in a pressure vessel for 16 hours. The reaction mixture was stirred for 12 hours. Filter and wash with EtOAc (2×20 mL). The combined filtrate was concentrated under reduced pressure. The crude compound was purified by silica gel column chromatography (petroleum ether containing 20% ​​EtOAc) to give 6-[5-[3-chloro-2-fluoro-5-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-4H-isoxazol-3-yl]-4-methyl-pyridazine-3-carboxylic acid methyl ester as a light yellow solid. LC-MS (Method D) R t = 2.52 minutes, m / z = 486.6 [M+H] + .

[0823] To a stirred solution of 6-[5-[3-chloro-2-fluoro-5-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-4H-isoxazol-3-yl]-4-methyl-pyridazine-3-carboxylic acid methyl ester (67.0 mg, 138 mmol) in THF (1 mL) and water (1 mL) was added LiOH.HO (17.3 mg, 414 mmol), and the resulting reaction mixture was stirred at room temperature for 1 hour. Water (5 mL) was added, and the reaction mixture was extracted with EtOAc (3×10 mL). The combined organic layers were washed with brine, dried over anhydrous NaSO and concentrated under reduced pressure to give 6-[5-[3-chloro-2-fluoro-5-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-4H-isoxazol-3-yl]-4-methyl-pyridazine-3-carboxylic acid, which was used in the next step without further purification. LC-MS (Method G) R t = 2.00 min, m / z = 472.2 [M+H] + .

[0824] HATU (64.8 mg, 170 mmol) was added to a stirred solution of 6-[5-[3-chloro-2-fluoro-5-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-4H-isoxazol-3-yl]-4-methyl-pyridazine-3-carboxylic acid (67 mg, 142 mmol) in DMF (2 mL), and the resulting reaction mixture was stirred at room temperature for 10 minutes. 2-amino-N-(2,2,2-trifluoroethyl)acetamide HCl (33.0 mg, 170 mmol) was then added, followed by DIPEA (0.70 mL, 426 mmol), and the resulting mixture was stirred at room temperature for 2 hours. The reaction mixture was quenched by the addition of ice water (10 mL) and extracted with EtOAc (3×15 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether containing 0 to 10% EtOAc) to give the title compound. LC-MS (Method D) R t =2.41 min, m / z=610.5[M+H] + . 1 H-NMR(DMSO-d6,400MHz)δ9.36(s,1H),8.36-8.34(m,1H),7.92-7.89(m,1H),7.69-7.62(m,2H),7.58(d,J=8.0Hz,1H),4.51( d,J=18Hz,1H),4.36(d,J=18Hz,1H),3.50-3.40(m,1H),3.20-3.09(m,1H),2.60-2.50(m,2H),2.35-2.22(m,2H),2.25(s,3H).

[0825] The two enantiomers were separated by SFC. The separation was carried out on AS-H with a column size of 250 mm × 30 mm (5 μm), a flow rate of 95.0 g / min, and a CO2-based mobile phase of 15% MeOH containing 0.2% N,N-dimethylethylamine as an additive to give Example 6.1: 4-methyl-N-[2-oxo-2-(2,2,2-trifluoroethylamino)ethyl]-6-[(5R or S)-5-[3-chloro-2-fluoro -5-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-4H-isoxazol-3-yl]pyridazine-3-carboxamide, and Example 6.2: 4-methyl-N-[2-oxo-2-(2,2,2-trifluoroethylamino)ethyl]-6-[(5S or R)-5-[3-chloro-2-fluoro-5-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-4H-isoxazol-3-yl]pyridazine-3-carboxamide.

[0826] Examples 7.1 and 7.2

[0827] 3-Methyl-N-[2-oxo-2-(2,2,2-trifluoroethylamino)ethyl]-5-[(5R or S)-5-[3-chloro-2-fluoro-5-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-4H-isoxazol-3-yl]pyrazine-2-carboxamide

[0828] and

[0829] 3-Methyl-N-[2-oxo-2-(2,2,2-trifluoroethylamino)ethyl]-5-[(5S or R)-5-[3-chloro-2-fluoro-5-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-4H-isoxazol-3-yl]pyrazine-2-carboxamide

[0830]

[0831] To a stirred solution of 3-methylpyrazine-2-carboxylic acid methyl ester (15g, 98.6mmol) in chloroform (300mL) was added meta-chloroperbenzoic acid (34g, 197mmol), and the mixture was stirred at 80°C for 4 hours. The mixture was cooled to room temperature, diluted with DCM (200mL), and washed with NaHCO3 aqueous solution (2×150mL). The organic layer was washed with brine (150mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether containing 0 to 100% EtOAc) to give 3-methyl-4-oxo-pyrazine-2-carboxylic acid methyl ester. LC-MS (Method D) R t = 0.81 min, m / z = 169.4 [M+H] + .

[0832] Phosphorus oxychloride (22mL, 235mmol) was added dropwise to a stirred solution of 3-methyl-4-oxo-pyrazine-2-carboxylic acid methyl ester (11g, 65.4mmol) in DMF (110mL) at 0°C, and the mixture was heated to 120°C for 15 minutes. The reaction mixture was then cooled to room temperature and poured into ice water and extracted with EtOAc (300mL). The organic layer was washed with brine (4×100mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether containing 0 to 100% EtOAc) to give a mixture of 5-chloro-3-methyl-pyrazine-2-carboxylic acid methyl ester and 6-chloro-3-methyl-pyrazine-2-carboxylic acid methyl ester. LC-MS (Method D) R t =1.43 min, m / z=186.9[M+H] + .

[0833] To a stirred solution of a mixture of isomers (8.12 g, 43.5 mmol) in 1,4-dioxane (80 mL) was added 5 M NaOH (13.1 g) at room temperature, and the mixture was stirred for 2 hours and then concentrated under reduced pressure. The resulting residue was diluted with water (15 mL), acidified to pH 2 to 3 with 2N HCl aqueous solution, and extracted with EtOAc (2×100 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure to give a mixture of 5-chloro-3-methyl-pyrazine-2-carboxylic acid and 6-chloro-3-methyl-pyrazine-2-carboxylic acid, which was used immediately in the next step without further purification.

[0834] To a stirred solution of a mixture of carboxylic acid isomers (7.0 g, 40.6 mmol) and 2-amino-N-(2,2,2-trifluoroethyl)acetamide HCl (8.40 g, 44.0 mmol) in DMF (70 mL) was added HATU (18.2 g, 48.0 mmol) at room temperature, followed by DIPEA (21.0 mL, 120 mmol). After 1 hour, the reaction mixture was quenched by the addition of water (5 mL) and then extracted with EtOAc (100 mL). The organic layer was washed with brine (3×75 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (0 to 100% EtOAc in petroleum ether) to give a mixture of isomers: 5-chloro-3-methyl-N-[2-oxo-2-(2,2,2-trifluoroethylamino)ethyl]pyrazine-2-carboxamide and 6-chloro-3-methyl-N-[2-oxo-2-(2,2,2-trifluoroethylamino)ethyl]pyrazine-2-carboxamide. LC-MS (Method D) R t =1.40 / 1.44 min, m / z=311.1 [M+H] + .

[0835] To a stirred solution of 5-chloro-3-methyl-N-[2-oxo-2-(2,2,2-trifluoroethylamino)ethyl]pyrazine-2-carboxamide (8.00 g, 26.0 mmol) in MeOH (160 mL) in an autoclave vessel was added NEt3 (11.0 mL, 78.0 mmol), and the mixture was degassed with N2 gas for 15 minutes, followed by the addition of 1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (1.88 g, 2.57 mmol). The reaction mixture was then heated at 80°C under 150 psi of CO gas for 16 hours. The mixture was allowed to cool to room temperature and filtered. The solid was washed with ether to give methyl 6-methyl-5-[[2-oxo-2-(2,2,2-trifluoroethylamino)ethyl]carbamoyl]pyrazine-2-carboxylate. LC-MS (Method D) R t =1.99 min, m / z=333.1[MH] - .

[0836] To a stirred solution of 6-methyl-5-[[2-oxo-2-(2,2,2-trifluoroethylamino)ethyl]carbamoyl]pyrazine-2-carboxylic acid methyl ester (1.30 g, 3.90 mmol) in THF (65 mL) was added sodium borohydride (0.44 g, 12.0 mmol) in portions at 0 ° C under N2 atmosphere, and the resulting mixture was stirred at room temperature for 3 hours. The reactants were quenched by adding ice and extracted with EtOAc (2×50 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether containing 0 to 100% EtOAc) to give 5-(hydroxymethyl)-3-methyl-N-[2-oxo-2-(2,2,2-trifluoroethylamino)ethyl]pyrazine-2-carboxamide. LC-MS (Method D) R t =1.41 min, m / z=307.1[M+H] + .

[0837] To a stirred solution of 5-(hydroxymethyl)-3-methyl-N-[2-oxo-2-(2,2,2-trifluoroethylamino)ethyl]pyrazine-2-carboxamide (370 mg, 1.20 mmol) in DCM (20 mL) was added Dess-Martin periodinane (750 mg, 1.80 mmol), and the mixture was stirred at room temperature for 6 hours. The reaction mixture was diluted with DCM (30 mL) and washed with saturated NaHCO3 aqueous solution (2×40 mL). The organic layer was concentrated under reduced pressure to give 5-formyl-3-methyl-N-[2-oxo-2-(2,2,2-trifluoroethylamino)ethyl]pyrazine-2-carboxamide, which was used immediately in the next step without further purification.

[0838] To a stirred solution of 5-formyl-3-methyl-N-[2-oxo-2-(2,2,2-trifluoroethylamino)ethyl]pyrazine-2-carboxamide (500 mg, 1.63 mmol) in EtOH (10 mL) and water (5 mL) was added hydroxylammonium chloride (0.17 g, 2.40 mmol) and sodium acetate (200 mg, 2.44 mmol) at room temperature, and the resulting mixture was stirred for 3 hours. The mixture was concentrated under reduced pressure, and the residue was diluted with water (10 mL) and extracted with EtOAc (2×25 mL). The combined organic layers were washed with aqueous NaHCO3 solution (30 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give 5-(hydroxyiminomethyl)-3-methyl-N-[2-oxo-2-(2,2,2-trifluoroethylamino)ethyl]pyrazine-2-carboxamide. LC-MS (Method D) R t =1.18 min, m / z=318.2[MH] - .

[0839] To a stirred solution of 5-(hydroxyiminomethyl)-3-methyl-N-[2-oxo-2-(2,2,2-trifluoroethylamino)ethyl]pyrazine-2-carboxamide (0.28 g, 0.88 mmol) in DMF (3 mL) was added N-chlorosuccinimide (152 mg, 1.14 mmol) at room temperature, and the mixture was heated at 40 ° C for 10 minutes. The mixture was then cooled to 0 ° C, 1-chloro-2-fluoro-5-(trifluoromethyl)-3-[1-(trifluoromethyl)vinyl]benzene (0.29 g, 0.99 mmol) was added, and then NEt3 (0.13 mL, 0.92 mmol) was added: the reactants were stirred at room temperature for 16 hours. The reaction mixture was then quenched by the addition of water (5 mL) and extracted with EtOAc (25 mL). The organic layer was washed with brine (3×10 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (0 to 100% EtOAc in petroleum ether) to give the title compound. LC-MS (Method D) R t = 2.51 min, m / z = 610.4 [M+H] + . 1H-NMR(DMSO-d6,400MHz)δ9.10-9.03(m,2H),8.65(t,J=6.0Hz,1H),8.40-8 .35(m,1H),7.96-7.92(m,1H),4.49(s,2H),4.00-3.87(m,4H),2.82(s,3H).

[0840] The two enantiomers were separated by SFC. Separation was performed on a DCPAK P4VP with a column size of 250 mm×21 mm (5 μm), a flow rate of 60.0 g / min, and a CO2-based mobile phase of 10% MeOH to give Example 7.1: 3-methyl-N-[2-oxo-2-(2,2,2-trifluoroethylamino)ethyl]-5-[(5R or S)-5-[3-chloro-2-fluoro-5-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-4H-isoxazol-3-yl]pyrazine-2-carboxamide, and Example 7.2: 3-methyl-N-[2-oxo-2-(2,2,2-trifluoroethylamino)ethyl]-5-[(5S or R)-5-[3-chloro-2-fluoro-5-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-4H-isoxazol-3-yl]pyrazine-2-carboxamide.

[0841] Examples 8.1 and 8.2

[0842] 2-Methyl-N-[2-oxo-2-(2,2,2-trifluoroethylamino)ethyl]-4-[(5R or S)-5-[3-bromo-2-fluoro-5-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-4H-isoxazol-3-yl]benzamide

[0843] and

[0844] 2-Methyl-N-[2-oxo-2-(2,2,2-trifluoroethylamino)ethyl]-4-[(5S or R)-5-[3-bromo-2-fluoro-5-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-4H-isoxazol-3-yl]benzamide

[0845]

[0846] To a stirred solution of 2-[3-bromo-2-fluoro-5-(trifluoromethyl)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.3 g, 3.5 mmol) in THF (15 mL) and water (7.5 mL) was added dipotassium carbonate (1.02 g, 7.38 mmol), and the mixture was degassed with N2 gas for 10 minutes. 2-Bromo-3,3,3-trifluoro-prop-1-ene (0.76 g, 4.3 mmol) and bis(triphenylphosphine)palladium(II) dichloride (0.25 g, 0.36 mmol) were added, and the reaction mixture was heated at 80°C for 3 hours. Then, the mixture was cooled to room temperature and extracted with diethyl ether (2×10 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure to give 1-bromo-2-fluoro-5-(trifluoromethyl)-3-[1-(trifluoromethyl)vinyl]benzene as a brown liquid, which was used immediately in the next step without further purification.

[0847] At room temperature, N-chlorosuccinimide (0.45g, 3.4mmol) was added to a stirred solution of 4-(hydroxyiminomethyl)-2-methyl-benzoic acid methyl ester (500mg, 2.59mmol) in DMF (5mL), and the mixture was heated at 40°C for 10 minutes. Then, the mixture was cooled to 0°C, 1-bromo-2-fluoro-5-(trifluoromethyl)-3-[1-(trifluoromethyl) vinyl] benzene (1.05g, 3.12mmol) was added, and NEt3(0.40mL, 2.85mmol) was then added, and the reactant was stirred at room temperature for 3 hours. The reaction mixture was quenched by adding water (10mL) and extracted with EtOAc (30mL). The organic layer was washed with brine (3×15mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (0 to 20% EtOAc in petroleum ether) to give 4-[5-[3-bromo-2-fluoro-5-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-4H-isoxazol-3-yl]-2-methyl-benzoic acid methyl ester as a beige semisolid. LC-MS (Method C) R t = 2.78 min, m / z = 528.1 [M+H] + .

[0848] To a stirred solution of 4-[5-[3-bromo-2-fluoro-5-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-4H-isoxazol-3-yl]-2-methyl-benzoic acid methyl ester (500 mg, 0.9 mmol) in THF (5 mL) and water (5 mL) was added lithium hydroxide monohydrate (0.12 g, 2.9 mmol) at room temperature, and the mixture was heated at 60° C. for 16 hours. The mixture was then cooled to room temperature, and the solvent was evaporated under reduced pressure. The residue was dissolved in water (5 mL), acidified to pH 2 to 3 with HCl solution (1 M), and extracted with EtOAc (2×25 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure to give 4-[5-[3-bromo-2-fluoro-5-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-4H-isoxazol-3-yl]-2-methyl-benzoic acid as a beige solid. LC-MS (Method F) R t = 2.74 min, m / z = 514.3 [M+H] + .

[0849] To a stirred solution of 4-[5-[3-bromo-2-fluoro-5-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-4H-isoxazol-3-yl]-2-methyl-benzoic acid (0.31 g, 0.60 mmol) and 2-amino-N-(2,2,2-trifluoroethyl)acetamide HCl (0.14 g, 0.73 mmol) in DMF (5 mL) was added HATU (0.28 g, 0.74 mmol) at room temperature, followed by DIPEA (0.32 mL, 1.8 mmol), and the mixture was stirred for 2 hours. The reaction mixture was quenched by adding water (5 mL) and extracted with EtOAc (3×15 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether containing 0 to 50% EtOAc) to give the title compound. LC-MS (Method F) R t = 2.66 min, m / z = 652.0 [M+H] + . 1H-NMR(DMSO-d6,400MHz)δ8.65-8.58(m,2H),8.45-8.41(m,1H),7.96-7.91(m,1H),7.69-7.63(m,2 H),7.49(d,J=7.6Hz,1H),4.56(d,J=18Hz,1H),4.39(d,J=18Hz,1H),4.00-3.89(m,4H),2.40(s,3H).

[0850] The two enantiomers were separated by SFC. The separation was performed on Chiralcel-OJ-H with a column size of 250 mm × 30 mm (5 μm), a flow rate of 95.0 g / min, and a CO2-based mobile phase of 10% iPrOH containing 0.2% N,N-isopropylamine as an additive to give Example 8.1: 2-methyl-N-[2-oxo-2-(2,2,2-trifluoroethylamino)ethyl]-4-[(5R or S)-5 -[3-bromo-2-fluoro-5-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-4H-isoxazol-3-yl]benzamide, and Example 8.2: 2-methyl-N-[2-oxo-2-(2,2,2-trifluoroethylamino)ethyl]-4-[(5S or R)-5-[3-bromo-2-fluoro-5-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-4H-isoxazol-3-yl]benzamide.

[0851] The following compounds were prepared similarly by the methods of Examples 8.1 and 8.2:

[0852]

[0853]

[0854] Examples 9.1 and 9.2

[0855] 2-Methyl-N-[2-oxo-2-(2,2,2-trifluoroethylamino)ethyl]-4-[(5R or S)-5-[3-(difluoromethyl)-2-fluoro-5-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-4H-isoxazol-3-yl]benzamide

[0856] and

[0857] 2-Methyl-N-[2-oxo-2-(2,2,2-trifluoroethylamino)ethyl]-4-[(5S or R)-5-[3-(difluoromethyl)-2-fluoro-5-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-4H-isoxazol-3-yl]benzamide

[0858]

[0859] In a sealed tube, 1-bromo-3-(difluoromethyl)-2-fluoro-5-(trifluoromethyl)benzene (500mg, 1.71mmol), trifluoro-potassium-[1-(trifluoromethyl)vinyl]boron (515mg, 2.55mmol), palladium(II) acetate (0.020g, 0.089mmol), triphenylphosphine (0.053g, 0.20mmol) and cesium carbonate (1.65g, 5.08mmol) were dissolved in THF (4mL) and water (2mL) under N2 atmosphere. The sealed tube was closed and stirred at 80°C for 6 hours. The reaction mixture was cooled to room temperature, and Et2O and water were added. The organic layer was separated, and the solvent was evaporated under reduced pressure. The crude product (1-(difluoromethyl)-2-fluoro-5-(trifluoromethyl)-3-[1-(trifluoromethyl)vinyl]benzene) was used in the next step without further purification.

[0860] Under N2 atmosphere, methyl 4-[(E)-hydroxyiminomethyl]-2-methyl-benzoate (200mg, 1.03mmol) and 1-chloropyrrolidine-2,5-dione (0.413g, 3.09mmol) are mixed in dry DMF (5mL). The reaction mixture is stirred at 40 ° C for 1 hour. Then, the reaction mixture is cooled to 0 ° C in an ice bath, and crude 1-(difluoromethyl)-2-fluoro-5-(trifluoromethyl)-3-[1-(trifluoromethyl) vinyl] benzene (350mg, 1.14mmol) and NEt3 (0.15mL) are added. The resulting reaction mixture is stirred at room temperature for 12 hours. After the reaction is complete, ice is added, and the mixture is extracted with Et2O. The organic layer is separated and concentrated in vacuo. The crude product was purified by silica gel column chromatography (1% EtOAc in petroleum ether) to give 4-[5-[3-(difluoromethyl)-2-fluoro-5-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-4H-isoxazol-3-yl]-2-methyl-benzoic acid methyl ester. LC-MS (Method D) R t = 2.53 min, m / z = 500.2 [M+H] + .

[0861] To a solution of 4-[5-[3-(difluoromethyl)-2-fluoro-5-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-4H-isoxazol-3-yl]-2-methyl-benzoic acid methyl ester (100 mg, 0.20 mmol) in THF (2 mL) and water (2 mL) was added lithium hydroxide monohydrate (0.025 g, 0.60 mmol). The resulting mixture was stirred at 60 ° C for 6 hours. After the reaction was completed, the solvent was evaporated under reduced pressure and the aqueous layer was acidified to pH ~ 3 using HCl aqueous solution (1 M). The precipitate was filtered off and dried in vacuo to give 4-[5-[3-(difluoromethyl)-2-fluoro-5-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-4H-isoxazol-3-yl]-2-methyl-benzoic acid. LC-MS (Method D) R t =2.29 minutes, m / z=484.2[MH] - .

[0862] To a solution of 4-[5-[3-(difluoromethyl)-2-fluoro-5-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-4H-isoxazol-3-yl]-2-methyl-benzoic acid (0.085 g, 0.18 mmol) and HATU (100 mg, 263 μmol) in dry DMF (1 mL) was added dropwise a solution of 2-amino-N-(2,2,2-trifluoroethyl)acetamide (0.050 g, 0.32 mmol) in dry DMF (1 mL) at 0 ° C. Then, DIPEA (0.1 mL, 0.6 mmol) was added, and the resulting reaction mixture was stirred at room temperature for 4 hours. The reaction mixture was quenched by adding ice water and extracted with EtOAc (3×). The combined organic layer was washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (0 to 100% EtOAc in petroleum ether) to give the title compound. LC-MS (Method D) R t = 2.23 minutes, m / z = 624.3 [M+H] + . 1H-NMR(DMSO-d6,400MHz)δ8.66-8.57(m,2H),8.26-8.23(m,1H),8.17-8.11(m,1H),7.69-7.64(m,2H),7.49(d ,J=7.6Hz,1H),7.36(t,J=53Hz,1H),4.59(d,J=18Hz,1H),4.37(d,J=18Hz,1H),4.00-3.88(m,4H),2.40(s,3H).

[0863] The two enantiomers were separated by SFC. Separation was performed on a Chiralcel OJ-H with a column size of 250 mm×21 mm (5 μm), a flow rate of 90.0 g / min, and an 8% MeOH based on CO2 mobile phase to give Example 9.1: 2-methyl-N-[2-oxo-2-(2,2,2-trifluoroethylamino)ethyl]-4-[(5R or S)-5-[3-(difluoromethyl)-2-fluoro-5-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-4H-isoxazol-3-yl]benzamide, and Example 9.2: 2-methyl-N-[2-oxo-2-(2,2,2-trifluoroethylamino)ethyl]-4-[(5S or R)-5-[3-(difluoromethyl)-2-fluoro-5-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-4H-isoxazol-3-yl]benzamide.

[0864] The following compounds were prepared similarly by the methods of Examples 9.1 and 9.2:

[0865]

[0866]

[0867] Examples 10.1 and 10.2

[0868] 2-Methyl-N-[2-oxo-2-(2,2,2-trifluoroethylamino)ethyl]-4-[(5R or S)-5-[3,5-bis(difluoromethyl)phenyl]-5-(trifluoromethyl)-4H-isoxazol-3-yl]benzamide

[0869] and

[0870] 2-Methyl-N-[2-oxo-2-(2,2,2-trifluoroethylamino)ethyl]-4-[(5S or R)-5-[3,5-bis(difluoromethyl)phenyl]-5-(trifluoromethyl)-4H-isoxazol-3-yl]benzamide

[0871]

[0872] DAST (6.2 g, 38 mmol) was added dropwise to a stirred solution of 5-bromobenzene-1,3-dicarboxaldehyde (2.00 g, 9.4 mmol) in DCM (40 mL) at 0 ° C, and the resulting mixture was stirred at room temperature for 3 hours. The mixture was quenched by adding water at 0 ° C, the aqueous layer was separated, and extracted with DCM (3 ×). The combined organic layer was dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by silica gel column chromatography (100% petroleum ether) to give 1-bromo-3,5-bis(difluoromethyl)benzene.

[0873] A mixture of 1-bromo-3,5-bis(difluoromethyl)benzene (1.2g, 4.7mmol) and trifluoro potassium-[1-(trifluoromethyl) vinyl] boron (1.44g, 7.09mmol) in THF (6mL) and water (3mL) was degassed under N2 atmosphere for 10 minutes. Palladium acetate (168mg, 1.02mmol), triphenylphosphine (156mg, 595μmol) and Cs2CO3 (3.72g, 11.4mmol) were then added, and the reaction mixture was stirred at 80 °C for 24 hours. The mixture was quenched by adding water. The aqueous layer was separated, extracted with ether, and the solvent was evaporated under reduced pressure. The crude product was purified by silica gel column chromatography (100% petroleum ether) to give 1,3-bis(difluoromethyl)-5-[1-(trifluoromethyl) vinyl]benzene.

[0874] To a stirred solution of methyl 4-[(E)-hydroxyiminomethyl]benzoate (465 mg, 2.60 mmol) in DMF (2.0 mL) was added NCS (0.36 g, 2.7 mmol), and the mixture was heated at 40 ° C for 10 minutes. The reaction mixture was then cooled to 0 ° C, and a solution of 1,3-bis(difluoromethyl)-5-[1-(trifluoromethyl)vinyl]benzene (0.75 g, 2.8 mmol) and NEt3 (0.3 mL) in DMF (1 mL) was added. The resulting mixture was stirred at room temperature for 3 hours. The reactants were quenched by adding water, the aqueous layer was separated, and extracted with EtOAc (3×). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (0 to 100% EtOAc in petroleum ether) to give 4-[5-[3,5-bis(difluoromethyl)phenyl]-5-(trifluoromethyl)-4H-isoxazol-3-yl]-2-methyl-benzoic acid methyl ester. LC-MS (Method D) R t = 2.37 minutes, m / z = 464.18 [M+H] + .

[0875] A mixture of 4-[5-[3,5-bis(difluoromethyl)phenyl]-5-(trifluoromethyl)-4H-isoxazol-3-yl]-2-methyl-benzoic acid ethyl ester (0.3 g, 0.6 mmol) and LiOH (81.0 mg, 3.4 mmol) in 1,4-dioxane (5.0 mL) and water (5.0 mL) was heated at 90 ° C overnight. Then, the reaction mixture was concentrated under reduced pressure and acidified by adding HCl solution (1 M). The aqueous layer was extracted with 5% MeOH-DCM solution (3×). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The crude product was used in the next step without further purification. LC-MS (Method D) R t = 2.47 minutes, m / z = 450.29 [M+H] + .

[0876] A mixture of 4-[5-[3,5-bis(difluoromethyl)phenyl]-5-(trifluoromethyl)-4H-isoxazol-3-yl]-2-methyl-benzoic acid (246 mg, 548 μmol), 1-amino-3-(trifluoromethylamino)propan-2-one HCl (164 mg, 1.05 mmol), HATU (317 mg, 834 μmol) and DIPEA (351 μL, 2.0 mmol) in DMF (4.0 mL) was stirred at room temperature for 2 hours. After the reaction was completed, the mixture was quenched with water, and the aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by silica gel column chromatography (petroleum ether containing 0 to 10% EtOAc) to give the title compound. LC-MS (Method D) R t = 2.08 min, m / z = 588.28 [M+H] + . 1H-NMR(DMSO-d6,400MHz)δ8.64-8.57(m,2H),7.98(s,2H),7.93(s,1H),7.66-7.60(m,2H),7.49(d,J=8. 4Hz, 1H), 7.23 (t, J = 55Hz, 2H), 4.50 (d, J = 18Hz, 1H), 4.29 (d, J = 18Hz, 1H), 3.99-3.88 (m, 4H), 2.40 (s, 3H).

[0877] The two enantiomers were separated by SFC. The separation was performed on a Chiralcel OJ-H with a column size of 250 mm×21 mm (5 μm), a flow rate of 60.0 g / min, and a mobile phase of 10% MeOH based on CO2 to give Example 10.1: 2-methyl-N-[2-oxo-2-(2,2,2-trifluoroethylamino)ethyl]-4-[(5R or S)-5-[3,5-bis(difluoromethyl)phenyl]-5-(trifluoromethyl)-4H-isoxazol-3-yl]benzamide, and Example 10.2: 2-methyl-N-[2-oxo-2-(2,2,2-trifluoroethylamino)ethyl]-4-[(5S or R)-5-[3,5-bis(difluoromethyl)phenyl]-5-(trifluoromethyl)-4H-isoxazol-3-yl]benzamide.

[0878] Experimental details of the compounds in the table:

[0879]

[0880]

[0881]

[0882]

[0883]

[0884]

[0885]

[0886]

[0887]

[0888] The compounds of the present invention are valuable active ingredients for pest control. The term "pest" includes external and internal parasites on and in animals and in the field of hygiene. In particular, pests are fleas, ticks, mites, flies, worms and lice. Even more particularly, pests are fleas and ticks.

[0889] In the context of the present invention, animals are understood to include vertebrates. In this article, the term vertebrate is understood to include mammals such as fish, amphibians, reptiles, birds and humans. One group of preferred vertebrates of the present invention comprises warm-blooded animals, including farm animals such as cattle, horses, pigs, sheep and goats, poultry such as chickens, turkeys, guinea fowls and geese, fur animals such as minks, foxes, chinchillas, rabbits, etc., and companion animals such as ferrets, guinea pigs, rats, hamsters, cats and dogs, and humans. Another group of preferred vertebrates of the present invention comprises fish, including salmon.

[0890] In the context of the present invention, ectoparasites are understood to be, in particular, insects, acarina (mites and ticks) and crustaceans (sea lice). These include insects of the following orders: Lepidoptera, Coleoptera, Homoptera, Hemiptera, Heteroptera, Diptera, Dictyoptera, Thysanoptera, Orthoptera, Anoplura, Siphonaptera, Mallophaga, Thysanura, Isoptera, Psocoptera and Hymenoptera. However, ectoparasites that may be mentioned in particular are those that plague humans or animals and carry pathogens, for example flies, such as the housefly (Musca domestica), the Australian bushfly (Muscavetustissima), the fall housefly (Musca autumnalis), the summer toilet fly (Fannia canicularis), the flesh-eating flesh fly (Sarcophaga carnaria), the copper green fly (Lucilia cuprina), the silk green fly (Lucilia sericata), the cow hide fly (Hypoderma bovis), the skin fly (Hypoderma lineatum), the green-tailed goldfly (Chrysomyia chloropyga), the human skin fly (Dermatobia hominis), the American blowfly (Cochliomyia hominivorax), the intestinal fly (Gasterophilus intestinalis), the sheep fly (Oestrus ovis), biting flies such as the western horn fly (Haematobia irritans irritans), the oriental horn fly (Haematobia irritans exigua), the stable fly (Stomoxys calcitrans, Tabanids and the subfamily Tabanidae, such as Haematopota spp. (e.g. Haematopota pluvialis) and Tabanus spp. (e.g. Tabanus nigrovittatus), and the subfamily Chrysopsinae, such as Chrysops spp.) (e.g., Chrysops caecutiens); Hippoboscids, such as Melophagus ovinus (sheep tick); tsetse flies, such as Glossinia spp.; other biting insects, such as midges, such as Ceratopogonidae (biting midges), Simuliidae (black mosquitoes), Psychodidae (sand flies); and blood-sucking insects, such as mosquitoes, such as Anopheles spp., Aedes spp., and Culex spp., fleas, such as Ctenocephalides felis and Ctenocephalides canis (cat and dog fleas), Xenopsylla spp. cheopis), human flea (Pulexirritans), chicken horned leaf flea (Ceratophyllus gallinae), skin-piercing tick (Dermatophilus penetrans), blood-sucking lice (Anoplura), such as long jaw lice species (Linognathus spp.), blood lice species (Haematopinus spp.), tube lice species (Solenopotes spp.), human lice (Pediculus humanis); and chewing hair lice (Mallophaga), such as wool lice (Bovicola (Damalinia) ovis), cattle hair lice (Bovicola (Damalinia) bovis), and other feather lice species (Bovicola spp.). Ectoparasites also include members of the order Acarina, such as mites (e.g., Chorioptes bovis, Cheyletiella spp., Dermanyssus gallinae, Ortnithonyssus spp., Demodex canis, Sarcoptes scabiei, Psoroptes ovis, and Psorergates spp.), and ticks. Representative ticks are, for example, Boophilus, Amblyomma, Anocentor, Dermacentor, Haemaphysalis, Hyalomma, Ixodes, Rhipicentor, Margaropus, Rhipicephalus, Argas, Otobius, and Ornithodoros, etc., which preferably infect vertebrates, such as warm-blooded animals, including farm animals such as cattle, horses, pigs, sheep and goats, poultry such as chickens, turkeys, guinea fowls and geese, fur animals such as minks, foxes, chinchillas, rabbits, etc., and companion animals such as ferrets, guinea pigs, rats, hamsters, cats and dogs, as well as humans and fish. .

[0891] The compounds of the invention according to the invention are also active against all or individual developmental stages of animal pests that show normal sensitivity, as well as those that show resistance to widely used parasiticides. This is especially true for resistant insects and members of the order Acarina. The insecticidal, ovicidal and / or acaricidal effect of the active substances of the invention can be manifested directly, i.e. killing the pests immediately or after a period of time, for example when molting occurs or by destroying their eggs, or indirectly, for example by reducing the number of eggs laid and / or the hatching rate, with good efficacy, equivalent to an insecticide rate (mortality) of at least 50 to 60%.

[0892] The compounds of the invention can also be used against hygiene pests, in particular of the families Muscidae, Sarcophagidae, Anophilidae and Culicidae of the order Diptera; the orders Orthoptera, Dictyoptera (for example Blattidae (cockroaches), such as Blatella germanica, Blatta orientalis, Periplaneta americana) and Hymenoptera (for example Formicidae (ants) and Vespidae (wasps)).

[0893] The compounds of formula (I) are also effective against ectoparasites of fish, in particular Copepoda, such as Siphonostomatoida (sea lice), while being well tolerated by fish.

[0894] The compounds of formula (I) may also be used against helminths of the class Cestoda, including the subclasses Eucestoda and Cestodaria.

[0895] The compounds of the invention also have a sustainable effect on parasitic mites and insects of plants. For spider mites of the order Acarina, they are effective against eggs, nymphs and adults of the family Tetranychidae (Tetranychus spp. and Panonychus spp.).

[0896] They are highly active against sucking insects of the order Homoptera, in particular against Aphididae, Delphacidae, Cicadellidae, Psyllidae, Loccidae, Diaspididae and Eriophydidae (e.g. rust mites on citrus fruits); pests of the orders Hemiptera, Heteroptera and Thysanoptera, and plant-feeding insects of the orders Lepidoptera, Coleoptera, Diptera and Orthoptera.

[0897] They are also suitable as soil insecticides to combat soil-borne pests.

[0898] Thus, the compounds of formula (I) are effective against all developmental stages of sucking and feeding insects on crops such as corn, cotton, rice, corn, soybeans, potatoes, vegetables, fruit, tobacco, hops, citrus, avocado and other crops.

[0899] The compounds of formula I are also effective against plant nematodes of the genera Meloidogyne, Heterodera, Pratylenchus, Ditylenchus, Radopholus, Rizoglyphus, and the like.

[0900] The compounds of the invention are effective against helminths. Helminths are commercially important because they cause serious diseases in mammals and poultry, for example sheep, pigs, goats, cattle, horses, donkeys, camels, dogs, cats, rabbits, guinea pigs, hamsters, chickens, turkeys, guinea fowl and other farmed birds as well as exotic birds. Typical nematodes are: Haemonchus, Trichostrongylus, Ostertagia, Nematodirus, Cooperia, Ascaris, Bunostomum, Oesophagostonum, Charbertia, Trichuris, Strongylus, Trichonema, Dictyocaulus, Capillaria, Heterakis, Toxocara, Ascaridia, Oxyuris, Ancylostoma, Uncinaria, Toxascaris and Parascaris. The flukes include, in particular, the family Fasciolideae, especially Fasciola hepatica.

[0901] The pesticidal activity of the compound of formula (I) according to the present invention corresponds to a mortality of about 50 to 60% of the mentioned pests, more preferably corresponding to a mortality of more than 90%, most preferably up to 95 to 100%. The compound of formula (I) is preferably used internally and externally in an unmodified form, or preferably used together with adjuvants conventionally used in the field of formulations, and can therefore be processed in a known manner to obtain, for example, liquid preparations (e.g., spot-on, pouring, spraying, emulsions, suspensions, solutions, emulsifiable concentrates, solution concentrates), semisolid preparations (e.g., creams, ointments, pastes, gels, liposome preparations) and solid preparations (e.g., food additive tablets, including, for example, capsules, powders, including soluble powders, granules, or active ingredients are embedded in polymeric substances, such as implants and microparticles). As with the composition, the method of application is selected according to the intended purpose and the prevailing environment.

[0902] The compounds of the present invention can be administered alone or in the form of a composition. In practice, the compounds of the present invention are usually administered in the form of a composition, i.e., mixed with at least one acceptable excipient. The proportion and nature of any acceptable excipient are determined by the properties of the selected compounds of the present invention, the selected route of administration, and standard practice in veterinary and pharmaceutical fields.

[0903] In one embodiment, the present invention provides a composition comprising: a compound of the present invention and at least one acceptable excipient.

[0904] In achieving such treatment and / or control, the compounds of the present invention can be administered in any form and route that makes the compounds bioavailable. The compounds of the present invention can be administered by a variety of routes, including oral, particularly by tablets and capsules. The compounds of the present invention can be administered parenterally, more particularly by inhalation, subcutaneous, intramuscular, intravenous, intraarterial, transdermal, intranasal, rectal, vaginal, ocular, topical, sublingual and buccal, intraperitoneal, intrafatty, intrathecal and via local delivery, for example, by catheter or stent.

[0905] Those skilled in the art can easily select the appropriate form and route of administration according to the specific characteristics of the selected compound, the disorder or condition to be treated, the stage of the disorder or condition and other relevant circumstances. The pharmaceutical compositions of the present invention can be administered to a subject, for example, in the form of tablets (including chewable tablets), capsules, cachets, papers, lozenges, wafers, elixirs, pills, ointments, transdermal patches, aerosols, inhalants, suppositories, enemas, solutions, injections and suspensions.

[0906] The term "acceptable excipient" refers to those excipients that are commonly used in the preparation of veterinary and pharmaceutical compositions, and should be pure and nontoxic in the amount used. They are generally solid, semisolid or liquid materials that can be used as vehicles or media for active ingredients in aggregates. Some examples of acceptable excipients are found in "Remington's Pharmaceutical Sciences" and "The Handbook of Pharmaceutical Excipients", and include diluents, vehicles, carriers, ointment bases, adhesives, disintegrants, lubricants, glidants, sweeteners, flavorings, gel bases, sustained release bases, stabilizers, preservatives, solvents, suspending agents, buffers, emulsifiers, dyes, propellants, coating agents, etc.

[0907] In one embodiment, the composition is suitable for oral administration, such as a tablet or capsule or a liquid preparation, such as a solution or suspension suitable for oral administration. In one embodiment, the composition is suitable for oral administration, such as a chewable preparation suitable for oral administration. In another embodiment, the composition is a liquid or semisolid preparation, such as a solution or suspension or paste suitable for parenteral administration.

[0908] In one embodiment, the composition is suitable for injectable administration, such as a solution or suspension suitable for injectable administration.

[0909] Specific compositions for use in subjects to treat and / or control nematodes / helminths include solutions; injections; emulsions, including classical emulsions, microemulsions, and self-emulsifying compositions, which are anhydrous organic compositions, preferably oily compositions, which form an emulsion with body fluids after addition to the body of a subject; suspensions (drenches); pour-on preparations; food additives; powders; tablets, including effervescent tablets; boluses (boli); capsules, including microcapsules; and chewable snacks. In particular, the composition is in the form of a tablet, capsule, food additive, or chewable snack.

[0910] The compositions of the present invention are prepared in a manner well known in the veterinary and pharmaceutical fields and include at least one compound of the present invention as an active ingredient. The amount of the compound of the present invention may vary depending on its specific form and may conveniently be 1% to about 50% by weight of the unit dosage form. The pharmaceutical composition of the present invention is preferably formulated in a unit dosage form, each dose typically containing from about 0.5 mg to about 100 mg of the compound of the present invention. One or more unit dosage forms may be used to affect the therapeutic dose.

[0911] In one embodiment, the present invention also provides a method for treating pests, comprising: administering an effective amount of a compound of formula (I), or a salt thereof, to a subject in need thereof, the method optionally further comprising an effective amount of at least one additional active compound.

[0912] In one embodiment, the present invention also provides a method for controlling pests, comprising: administering an effective amount of a compound of formula (I), or a salt thereof, to a subject in need thereof, the method optionally further comprising an effective amount of at least one additional active compound.

[0913] In one embodiment, the present invention also provides a method for treating or controlling pests, comprising: contacting the environment of a subject with an effective amount of a compound of formula (I) or a salt thereof, the method optionally further comprising an effective amount of at least one additional active compound.

[0914] Therefore, the present invention provides the use of the compounds of the present invention as medicines, including for preparing medicines. In one embodiment, the present invention provides the preparation of medicines comprising compounds of formula (I) or their salts for treating pests. In one embodiment, the present invention provides the preparation of medicines comprising compounds of the present invention or their salts for controlling pests.

[0915] The term "treating, treatment, or treatment" includes, but is not limited to, inhibiting, slowing, stopping, reducing, ameliorating, reversing the progression or severity of existing symptoms, or preventing a disorder, condition, or disease. For example, adult heartworm infection will be treated by administering the compounds of the present invention. Treatment may be applied or administered by therapy.

[0916] The term "control" refers to, but is not limited to, reducing, reducing or ameliorating the risk of a symptom, disorder, condition or disease, and protecting an animal from experiencing a symptom, disorder, condition or disease. Control may refer to therapeutic, prophylactic or preventive administration. For example, larvae or immature pests may be asymptomatic, but control will be performed by acting on the larvae or immature pests to prevent the infection from developing into a symptomatic or debilitating infection caused by mature pests.

[0917] Therefore, the use of the compounds of the present invention in the treatment and / or control of pests that are endoparasitic nematodes and trematodes, in particular helminths, refers to the use of the compounds of the present invention to act on various forms of pests throughout their life cycle, regardless of whether the subject shows symptoms (including morbidity or mortality) and regardless of the attack stage.

[0918] As used herein, "administering to a subject" includes, but is not limited to, dermal, subcutaneous, intramuscular, mucosal, submucosal, transdermal, oral or intranasal administration. Administration may include injection or topical administration, for example, pouring or spot-on administration. Pouring or spot-on administration is particularly advantageous for herd animals, such as cattle, horses, sheep or pigs, which are difficult or time-consuming to treat orally or by injection. Due to its simplicity, the method can of course also be used for all other animals, including individual livestock or pets, and is greatly favored by animal breeders because it can usually be performed without the presence of a veterinary expert.

[0919] The terms "subject" and "patient" are meant to include human and non-human mammals and fish, vertebrates as described herein, such as dogs, cats, mice, rats, guinea pigs, rabbits, ferrets, cows, horses, sheep, goats and pigs. Specific subjects are mammalian pets or companion animals, such as dogs and cats, as well as mice, guinea pigs, ferrets and rabbits.

[0920] The term "effective amount" refers to an amount that gives the subject the desired benefit, and includes administration for treatment and control. This amount will vary between individual subjects and will depend on a variety of factors, including the subject's overall physical condition and the severity of the underlying cause of the condition to be treated, concomitant treatment, and the amount of the compound of the invention used to maintain the desired response at a beneficial level.

[0921] The effective amount can be easily determined by the attending diagnostician who is a person skilled in the art by using known techniques and by observing the results obtained in similar situations. When determining the effective amount, dosage, the attending diagnostician considers many factors, including but not limited to: the variety of the patient; size, age, general health; the specific condition, disorder, infection or disease involved; the degree or involvement or severity of the condition, disorder or disease, the response of the individual patient; the specific compound given; the mode of administration; the bioavailability characteristics of the formulation administered; the selected dosing regimen; the use of concomitant medication; and other relevant circumstances. The effective amount of the present invention, i.e. the therapeutic dose, is expected to be in the range of 0.5 mg to 100 mg. The specific amount can be determined by those skilled in the art. Although these doses are based on subjects with a mass of about 1 kg to about 20 kg, the diagnostician will be able to determine the appropriate dose for subjects whose mass falls outside this weight range. The effective amount of the present invention, i.e. the therapeutic dose, is expected to be 0.1 mg to 10 mg / kg subject. The dosing regimen is expected to be monthly, quarterly, semi-annual or annual administration.

[0922] The compounds of the present invention can be used in combination with one or more other active compounds or therapies to treat one or more disorders, diseases or conditions, including the treatment of pests for which they are applicable. The compounds of the present invention can be administered simultaneously, sequentially or separately with one or more compounds or therapies for the treatment of pests and other conditions.

[0923] Therefore, it should be understood that the compositions and methods of the present invention optionally include an effective amount of at least one additional active compound. Additional active compounds useful in the present invention include those compounds used to treat fleas, ticks, flies and mosquitoes, and include macrolides such as milbemycin oxime, imidacloprid, spinosad, pyriproxyfen, premethrin, S-methoprene, praziquantel and moxidectin. Other exemplary additive active compounds include, but are not limited to, afoxolaner, fluralaner, lotilaner, sarolaner, albendazole, cambendazole, fenbendazole, flubendazole, mebendazole, oxfendazole, parabendazole, tiabendazole, triclabendazole, amitraz, demiditraz, clorsulon, closantel, oxyclonazide, rafenibendazole, chloramphenicol ... foxanide, cyphenothrin, flumethrin, permethrin, cyromazine, derquantel, diamphenetide, dicyclanil, dinotefuran, imidacloprid, nitenpyram, thiamethoxam, thiamethoxam, doramectin, emamectin, eprinomectin, ivermectin, moxidectin, selamectin, milbemycinoxime), emodepside, epsiprantel, fipronil, fluazuron, fluhexafon, indoxacarb, levamisol, lufenuron, metaflumizone, methoprene, monepantel, morantel, niclosamide de), nitroscanate, nitroxynil, novaluron, oxantel, praziquantel, pyrantel, pyriprole, pyriproxyfen, sisapronil, spinosad, spinetoram and triflumezopyrim, or a salt of any one of the foregoing.

[0924] The activity of the compounds of the invention can be determined by a variety of methods, both in vitro and in vivo.

[0925] Example A

[0926] In vitro evaluation of feeding activity against fleas (Ctenocephalides felis)

[0927] For flea ingestion assays, compound stocks were serially diluted in DMSO to achieve an EC 50 and EC 90 Desired range for the assay. Aliquots of each compound dilution were added to organic bovine blood with a final DMSO concentration of 0.5% and placed in artificial feeding containers. Fipronil was included as a positive control. Ten newly emerged, unfed adult fleas, 0 to 7 days old Ctenocephalides felis from a laboratory colony were sucked into each vial or cage 0. Cages for flea ingestion assays were maintained in a temperature-controlled artificial feeding device to allow continuous access to organic bovine blood containing the desired concentration of compounds. Fresh aliquots of bovine blood spiked with compounds were provided daily during the study. The percentage mortality of fleas was evaluated at various time points between 2 hours and 48 hours after infestation. Fleas that exhibited normal movement and / or jumping ability were considered vigorous, while fleas that exhibited no movement after tapping the vial were assessed as dead.

[0928] In this test, for example, the following compounds from the Preparative Examples showed EC50 < 1 ppm: Example 2.1 or 2.2; 3.1 or 3.2; 3.3 or 3.4; 3.8; 3.19 or 3.20; 3.21 or 3.22; 3.23; 3.27, 3.28, 3.29 or 3.30; 3.34 or 3.35; 3.36 or 3.37; 3.38 or 3.39; 3.40 or 3.41; 3.43 or 3.44; 3.45 or 3.46; 3.49; 3.50 or 3.51; 3.52 or 3.53; 3.54 or 3.55; 3.56 or 3.57; 3.58 or 3.59; 3.60 or 3.61; 3.62 or 3.63; 3.64 or 3.65 50; 3.51; 3.52; 3.53; 3.55; 3.62; 3.65; 3.66; 3.71; 3.73; 3.74; 3.76; 3.77; 3.78 or 3.79; 3.80:3.83; 3.84; 3.85; 3.86; 3.87; 3.90; 3.91; 3.93; 5.1; 8.1 or 8.2; 8.3 or 8.4; 8.5 or 8.6; 9.1 or 9.2; and 9.3 or 9.4; and 10.1 or 10.2.

[0929] In this test, for example, the following compounds from the Preparative Examples showed EC50 < 3 ppm: Examples 1.1 or 1.2; 3.5 or 3.6; 3.15; 3.16 or 3.17; 3.25; 3.26; 3.47; 3.61; 3.72; and 3.75; 3.81; 3.75; 3.92; and 4.3 or 4.4.

[0930] For the above data, when a single isomer is tested, without knowing the absolute configuration of the isomer, the data indicates that the test article is one isomer or the other, e.g. a single isomer from Example 2 is tested and EC 50 of<1ppm, so the above data show that the results are obtained for "2.1 or 2.2".

[0931] Example B

[0932] In vitro evaluation of contact activity against adult ticks (Rhipicephalus sanguineus)

[0933] For the tick assay, vial caps were pre-drilled with a single hole in the center of each cap to allow air exchange. Filter paper (Whatman grade 540 2.1 cm) was placed in the cap of each vial. An aliquot from each compound stock solution was added to the acetone / triton solution to give the highest dose required for the study. Serial dilutions were performed from the highest dose to achieve an EC 50 and EC 90The desired titration range for the assay. The final DMSO concentration in each test vial was 0.5%. A 459 μL aliquot of each compound preparation was transferred to a vial containing Whatman grade 5402.1 cm filter paper. The vial was immediately placed on an unheated roller unit so that the vial wall was evenly coated. After the vial was coated, 41 μL of each compound preparation was added to the filter paper embedded in the cap of each vial. Allow each cap to dry. The vials were loosely capped and allowed to dry in a chemical fume hood for at least 4 hours. 10 adult ticks were added to each vial and maintained at 24 ° C, 80% humidity for a 12-hour light / dark cycle. The percentage mortality of adult ticks was assessed at different time points between 2 hours and 48 hours after infestation. Ticks were stimulated on a heated roller device and evaluated. Ticks that did not show movement or very slow and uncoordinated movement were recorded as dead.

[0934] Example C

[0935] PK assay after administration to beagle dogs

[0936] Beagle dogs were evaluated for the behavior of a single oral or intravenous dose of the desired compound. Animals (n=6) received the compound by oral gavage (3 or 10 mg / kg) or intravenous dose (1 or 2 mg / kg). Blood samples were collected before and after dosing at 0.25, 0.5, 1, 2, 4, 8, 24, 48, 72, 96, 168, 336, 504, 672, 1008, 1344, 1680, 2016, 2352, 2688, 2856 and 3024 hours. A portion of each whole blood sample was processed into plasma. LC-MS / MS was used to determine the test article concentration in plasma and whole blood.

[0937] The results for the test articles are summarized in the following table:

[0938]

[0939]

Claims

1. A compound having formula (I): in A1 is selected from the group consisting of CF3, CHF2, CH2F and CF2CF3; A2 is O or S; R1 is hydrogen; R2 is trifluoromethyl; R3 is hydrogen; R4 is halogen; R5 is halogen; QSelect the group consisting of in p is 0, 1, or 2; q is 0, 1, 2, or 3; s is 0, 1, or 2; R6 is independently selected at each occurrence from the group consisting of: halogen; cyano; nitro; hydroxy; -NH2; -NH(C1-C4 alkyl); -N(C1-C4 alkyl)2; C2-C5-alkoxycarbonyl; C1-C6-alkyl, R7 at each occurrence is independently selected from C1-C4 alkyl; A3 is S; A4 is CH; A5 is CH; A6 is CH; A7 is CH; A8 is CH; A9 is CH; A 10 for CH; A 11 for CH; A 12 for CH; A 13 for CH; A 14 for CH; A 15 for CH; W1 is selected from -CH2; W2 chooses from -O-; X is selected from: in R 11 Selected from the group consisting of: hydrogen, C1-C4 alkyl, C1-C4 haloalkyl, W is selected from C1-C6 alkyl, which is optionally substituted by 1 to 5 substituents independently selected from the group consisting of: halogen; oxo; C1-C7 aminocarbonyl; -NH(C1-C4 alkyl); -N(C1-C4 alkyl)2; -C(O)NH-C1-C6 haloalkyl; Y is C1-C6 alkyl, optionally substituted with 1 to 5 substituents independently selected from the group consisting of: oxo, -SO2C1-C4 alkyl; or a salt thereof.

2. The compound according to claim 1, wherein R1 is hydrogen, R2 is trifluoromethyl, R3 is hydrogen, R4 is chlorine, and R5 is halogen; or a salt thereof.

3. The compound according to claim 1, wherein R1 is hydrogen, R2 is trifluoromethyl, R3 is hydrogen, R4 is halogen, and R5 is chloro; or a salt thereof.

4. The compound according to claim 1, wherein R1 is hydrogen, R2 is trifluoromethyl, R3 is hydrogen, R4 is halogen, and R5 is fluorine; or a salt thereof.

5. The compound according to claim 1, wherein R1 is hydrogen, R2 is trifluoromethyl, R3 is hydrogen, R4 is chlorine, and R5 is fluorine; or a salt thereof.

6. The compound according to claim 1, wherein R1 is hydrogen, R2 is trifluoromethyl, R3 is hydrogen, R4 is bromine, and R5 is fluorine; or a salt thereof.

7. The compound according to any one of claims 1 to 6, wherein A1 is CF3; or a salt thereof.

8. The compound according to any one of claims 1 to 6, wherein A1 is CHF2; or a salt thereof.

9. A compound selected from the group consisting of: Or a salt of any of the foregoing.

10. A compound selected from the group consisting of: 2-methylsulfonyl-1-[6-[(5S)-5-[3-chloro-2-fluoro-5-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-4H-isoxazol-3-yl]spiro[1H-isobenzofuran-3,3'-azetidine]-1'-yl]ethanone; 2-methylsulfonyl-1-[6-[(5R)-5-[3-chloro-2-fluoro-5-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-4H-isoxazol-3-yl]spiro[1H-isobenzofuran-3,3'-azetidine]-1'-yl]ethanone; N-[2-Oxo-2-(2,2,2-trifluoroethylamino)ethyl]-4-[(5S)-5-[3-chloro-2-fluoro-5-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-4H-isoxazol-3-yl]naphthalene-1-carboxamide; N-[2-Oxo-2-(2,2,2-trifluoroethylamino)ethyl]-4-[(5R)-5-[3-chloro-2-fluoro-5-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-4H-isoxazol-3-yl]naphthalene-1-carboxamide; 2-Methyl-N-[2-oxo-2-(2,2,2-trifluoroethylamino)ethyl]-4-[(5S)-5-[3-chloro-2-fluoro-5-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-4H-isoxazol-3-yl]benzamide; 2-methyl-N-[2-oxo-2-(2,2,2-trifluoroethylamino)ethyl]-4-[(5R)-5-[3-chloro-2-fluoro-5-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-4H-isoxazol-3-yl]benzamide; 3-methyl-N-[2-oxo-2-(2,2,2-trifluoroethylamino)ethyl]-5-[(5S)-5-[3-chloro-2-fluoro-5-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-4H-isoxazol-3-yl]thiophene-2-carboxamide; 3-methyl-N-[2-oxo-2-(2,2,2-trifluoroethylamino)ethyl]-5-[(5R)-5-[3-chloro-2-fluoro-5-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-4H-isoxazol-3-yl]thiophene-2-carboxamide; 2-methyl-N-[2-oxo-2-(2,2,2-trifluoroethylamino)ethyl]-4-[(5R)-5-[3-bromo-2-fluoro-5-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-4H-isoxazol-3-yl]benzamide; and 2-Methyl-N-[2-oxo-2-(2,2,2-trifluoroethylamino)ethyl]-4-[(5S)-5-[3-bromo-2-fluoro-5-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-4H-isoxazol-3-yl]benzamide; Or a salt of any of the foregoing.

11. A compound selected from the group consisting of: 2-methyl-N-[2-oxo-2-(2,2,2-trifluoroethylamino)ethyl]-4-[(5R)-5-[3-bromo-2-fluoro-5-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-4H-isoxazol-3-yl]benzamide; and 2-Methyl-N-[2-oxo-2-(2,2,2-trifluoroethylamino)ethyl]-4-[(5S)-5-[3-bromo-2-fluoro-5-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-4H-isoxazol-3-yl]benzamide; Or a salt of any of the foregoing.

12. A composition comprising a compound or a salt thereof according to any one of claims 1 to 11, and at least one acceptable carrier.

13. Use of the compound or salt thereof according to any one of claims 1 to 11 in the preparation of a medicament for controlling pests.

14. Use of a compound according to any one of claims 1 to 11 or a salt thereof in the preparation of a medicament for controlling fleas.

15. Use of a compound according to any one of claims 1 to 11 or a salt thereof in the preparation of a medicament for controlling ticks.

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