spirocyclic isoxazoline derivatives, their use and preparation process, and veterinary compositions

专利摘要:
SPIROCYCLIC ISOXAZOLINE DERIVATIVES, THEIR USE AND PREPARATION PROCESS, AND PHARMACEUTICAL OR VETERINARY COMPOSITIONS. The present invention relates to spirocyclic isoxazoline derivatives of formula (Vl), formula (V.2), formula (V11) and formula (1) stereoisomers thereof, veterinarily acceptable salts thereof, compositions thereof, processes for preparation and its use as a parasiticide in an animal. The variables A, V, Z, Wl, W2, W3, W, Y, X, Ria, Rlb, Rlc, R2, R3, R4, n and "are as described in the specification.
公开号:BR112013023068B1
申请号:R112013023068-1
申请日:2012-02-23
公开日:2020-11-17
发明作者:Denis Billen；Nathan Anthony Logan Chubb；Michael Curtis；Sean Dw Greenwood；Sanjay Menon；Timothy Stuk；Valerie A. Vaillancourt
申请人:Zoetis Llc；
IPC主号:

专利说明:

CROSS REFERENCE
[001] This invention claims priority for United States Provisional Patent Application No. 61 / 490,804 filed on May 27, 2011, now pending; United States Provisional Patent Application No. 61 / 489,913 filed May 25, 2011, now pending; and United States Provisional Patent Application No. 61 / 451,256 filed on March 10, 2011, now pending. FIELD OF THE INVENTION
[002] The present invention relates to spirocyclic isoxazoline derivatives having parasiticidal activity. The compounds of interest are derived from spirocyclic isoxazoline with a portion of azetidine. The invention also relates to processes for preparing said spirocyclic isoxazoline derivatives, compositions and methods of using them. BACKGROUND
[003] There is a need for improved antiparasitic agents for use with animals, and in particular, there is a need for improved insecticides and caries. In addition, there is a need for improved topical and oral products with convenient administration that contain one or more of such antiparasitic agents that can be used to effectively treat ectoparasites, such as insects (e.g. fleas, lice and flies) and mites ( for example, mites and ticks). Such products would be particularly useful for the treatment of animals including: birds (for example, chickens and turkeys), fish, pets (for example, cats, dogs, llamas and horses) and breeding animals (for example, cattle, bison) , swine, sheep, deer, moose and goats).
[004] The compounds currently available for insecticidal and acaricidal treatment of animals do not always demonstrate good activity, good speed of action or a long duration of action. Most treatments contain dangerous chemicals that can have serious consequences, including neurotoxicity and lethality from accidental ingestion. People applying these agents are generally advised to limit their exposure. Pet collars and tags have been used to overcome some problems, but these are susceptible to chewing, ingestion and subsequent toxicological effects on the animal. Thus, current treatments achieve varying degrees of success that partially depend on toxicity, method of administration and effectiveness. Currently, some agents are in fact becoming ineffective due to parasitic resistance.
[005] Isoxazoline derivatives have been described in the art as having insecticidal and acaricidal activity. For example, W02007 / 105814, W02008 / 122375 and W02009 / 035004 cite certain alkylene-linked amides. WO2010 / 032437 describes that the benzyl amide can be moved ortho to isoxazoline. In addition, W02007 / 075459 describes phenyl isoxazolines substituted with 5- to 6-membered heterocycles, and WO2010 / 084067 and WO2010 / 025998 describe phenyl isoxazolines substituted with 10 to 11-membered aryl and fused heteroaryls. Chiral processes for the manufacture of isoxazolines have been reported in WO2011 / 104089 and W02009 / 063910. Some spiro-azetidine isobenzofuran derivatives for the treatment of diabetes and hyperlipidemia have been described in W02008 / 096746. However, none of these citations exemplify the substituted spirocyclic isoxazolines or processes for the manufacture of espir spirocyclic compounds, nor does the previous technique indicate that such compounds would be useful against a spectrum of parasitic species relevant to companion animals, farm animals or edible birds in comparison. with the range of stages of the parasitic morphological life cycle.
[006] Despite the availability of broad-spectrum antiparasitic agents, effective, in this context there remains a need for a safe, convenient, effective and environmentally pleasant product that will overcome the ever-present threat of resistance development.
[007] The present invention overcomes one or more of the various disadvantages of or improves the properties of existing compounds. In particular, the present invention develops new azetidine compounds substituted by spirocyclic isoxazoline which demonstrate such properties. SUMMARY
[008] The present invention provides compounds of Formula (V.1), Formula (V.2), Formula (V.1.1) and Formula (1), stereoisomers thereof, which act as parasiticides, in particular ectoparasiticides; therefore, they can be used to prevent, treat, repel and control infection by mites and insects and infestation in animals. In addition, the invention contemplates the control and prevention of tick-borne diseases, for example, Lyme disease, canine and bovine anaplasmosis, canine ehrlichiosis, canine rickettsiosis, canine and bovine babesiosis, epizootic bovine abortion and theileriosis. Thus, according to the invention, a compound of Formula (V.1) and Formula (V.2) is provided
on what
[009] Y and Z are each independently C or N;
[0010] W1, W2 and W3 are each independently C or N;
[0011] VéC, N, OouS;
[0012] The employee together with Y and Z or V, Y and Z is a 5- to 7-membered saturated or partially saturated heterocyclic or carbocyclic ring where the heterocyclic ring contains at least 1 to 3 heteroatoms selected from N, O or S and where ring A is optionally substituted with at least one substituent selected from oxo, = S, = NR7, halo, hydroxyl, cyano, C1-Ce alkyl, C-Cehaloalkyl and Ci-Cealcoxy;
[0013] R1a, R1b and R1c are each independently hydrogen, halo, cyano, hydroxyl, nitro, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cealcóxi, C0-C3 alkylCa-Ce cycloalkyl, Ci-Cehaloalcóxi, -C (O) NH2, -SF5 or -S (O) PR;
[0014] R2 is halo, cyano, Ci-Cealkyl, Ci-Cehaloalkyl, nitro, hydroxyl, -C (O) NRaRb, C2-C6alkenyl, C2-C6alkynyl, -S (O) PR or -OR;
[0015] R3 is cyano, Ci-Cealquila, Ci-Cehaloalkyl, -C (O) NRaRb, C2-Ce alkenyl, C2-Cealquinyl, C2-C6haloalkenyl or C2-C6haloalquinyl;
[0016] R4 is hydrogen, Ci-Cealkyl, Co-CβalkylCs-Cecycloalkyl, -C (O) R5, -C (S) R5, -C (O) NRaR5, -C (O) C (O) NRaR5, - S (O) PRC, -S (O) 2NRaR5, -C (NR7) R5, -C (NR7) NRaR5, Co-Cealkylphenyl, Co-C6alkyl-heteroaryl or Co-Cealkyl-heterocycle;
[0017] R5 is hydrogen, C1-Cealkyl, C2-Cealkenyl, Co-CealkylCs-Cecycloalkyl, Co-C6alkylphenyl, Co-C6alkylheteroaryl or Co-C6alkylheterocycle;
[0018] R6is hydrogen, Ci-Cealquila, hydroxila or Ci-C6alkoxy;
[0019] R7is hydrogen, Ci-Cealkyl, hydroxyl, cyano, nitro, -S (O) PRC or Ci-Cθalcoxy;
[0020] R is Ci-Cealquila or Ca-Cecicloalkyl optionally substituted with at least one halo substituent;
[0021] Ra is hydrogen, C-i-Cealquila or Co-CaalquilCa- Cecicloalkyl; wherein the alkyl and the alkylcycloalkyl are optionally substituted by cyano or at least one halo substituent;
[0022] Rb is hydrogen, Ci-Cealquila, Ca-Cecicloalkyl, Co-Caalkylphenyl, Co-Csalkyl-heteroaryl or Co-Cakyl-heterocycle, each optionally substituted, where chemically possible, with at least one hydroxyl, cyan, selected substituent halo or - S (O) PR;
[0023] Rc is Ci-Cealquila, Ci-Cehaloalkyl, Ci-CehaloalkylCa-Ce cycloalkyl, Co-CaalkylCa-Cecicloalkyl, Co-Caalkylphenyl, Co-Caalkyl-heteroaryl or Co-Caalkyl-heterocycle each optionally substituted with at least one substituted substitute of cyano, halo, hydroxyl, oxo, Ci-Cealcoxy, Ci-Ce haloalkoxy, Ci-Cehaloalkyl, -S (O) PR, -SH, -S (O) pNRaRb, -NRaRb, -NRaC (O) Rb, - SC (O) R, -SCN or -C (O) NRaRb;
[0024] each R4 and R5, Ci-Cealquila or Co-CealquilCa-Ce cycloalkyl moiety can be optionally and independently substituted by at least one substituent selected from cyano, halo, hydroxyl, oxo, Ci-Cealcoxy, CI-CΘhaloalkoxy, CI- Cβhaloalkyl, Ci-Cealkyl, hydroxylCi-C6alkyl-, -S (O) PRC, -SH, -S (O) pNRaRb, -NRaRb, -NRaC (O) Rb, -SC (O) R, -SCN or -C (O) NRaRb; and
[0025] in which each of R4 and R5, Co-Cealkylphenyl, Co-Cealkyl-heteroaryl or Co-Cβalkyl-heterocycle portion can also be optionally substituted with at least one substituent selected from cyan, halo, oxo, = S, = NR7, hydroxyl, Ci-Cealcoxy, Ci- Cealkyl, hydroxylCi-Cealkyl-, Ci-Ce haloalkyl, -SH, -S (O) PR and Ci-Cehaloalkoxy;
[0026] n is the integer 0, 1 or 2, and when n is 2, each R2 can be identical or different from each other;
[0027] p is the integer 0, 1 or 2; and
[0028] 2222 is a single or double bond;
[0029] stereoisomers thereof and veterinarily acceptable salts thereof.
[0030] In another aspect of the invention are compounds of formula (V, 1) which are compounds of formula (V, 1,1)

[0031] W1, W2 and W3 are each independently C or N;
[0032] X and W are each independently -O-, -S-, -NR6-, -CH2-, -C (O) -, -C (NR7) - or -C (S) -, when X is - O-, -S- or -NR6-, then W is - CH2-, -C (O) -, -C (NR7) - or -C (S) -, and when W is -O-, -S- or -NR6-, then X is -CH2-, -C (O) -, -C (NR7) - or -C (S) -;
[0033] R1a, R1b and R1c are each independently hydrogen, halo, hydroxyl, cyano, nitro, Ci-Cβalkyl, Ci-Cβhaloalkyl, Ci-Cealoxy, C0-C3 alkylCa-Cδ cycloalkyl, Ci-Cehaloalkoxy, -C (O) NH2, -SF5 or -S (O) PR;
[0034] R2 is fluorine, chlorine or Ci-Cealquila;
[0035] R3 is cyano, Ci-Cealquila, Ci-Cβhaloalkyl, -C (O) NRaRb, C2-Cθ alkenyl, C2-C6alkynyl, C2-Cθhaloalkenyl or C2-C6haloalquinyl.
[0036] R4is hydrogen, Ci-Cθalkyl, Co-CealkylCs-Cθcycloalkyl, -C (O) R5, -C (S) R5, -C (O) NRaR5, -C (O) C (O) NRaR5, -S (O) PRC, -S (O) 2NRaR5, -C (NR7) R5, -C (NR7) NRaR5, Co-C6alkylphenyl, Co-Cθalkyl-heteroaryl or Co-Cealkyl-heterocycle;
[0037] R5 is hydrogen, C1-Cθalkyl, C2-Kealkyl, Co-CealkylC-Cθ cycloalkyl, Co-C6alkylphenyl, Co-C6alkyl-heteroaryl or Co-Cealkyl-heterocycle;
[0038] R6is hydrogen, Ci-Cθalkyl, hydroxyl or Ci-Cθalkoxy;
[0039] R7is hydrogen, Ci-Cθalkyl, hydroxyl, cyano, nitro, -S (O) PRC or Ci-Cealcoxy;
[0040] R is Ci-Cθalkyl or Cs-Cθcycloalkyl optionally substituted with at least one halo substituent;
[0041] Ra is hydrogen, Ci-Cθalkyl or Co-CsalkylCs- Cθcycloalkyl; wherein the alkyl and the alkylcycloalkyl are optionally substituted by cyano or at least one halo substituent;
[0042] Rb is hydrogen, Ci-Cθalkyl, Cs-Cθcycloalkyl, Co-Caalkylphenyl, Co-Csalkyl-heteroaryl or Co-Csalkyl-heterocycle, each optionally substituted, where chemically possible, with at least one selected hydroxyl substituent, cyan, halo or - S (O) PR;
[0043] Rc is Ci-Cθalkyl, Ci-Cθhaloalkyl, Ci-CθhaloalkylC3-Cδ cycloalkyl, Co-CsalkylCs-Cθcycloalkyl, Co-Csalkylphenyl, Co-Caalkyl-heteroaryl or Co-Csalquil-hetero-substituted with an optional less-substituted hetero-heterocycle cyano, halo, hydroxyl, oxo, Ci-Cθalkoxy, Ci-Cθ haloalkoxy, Ci-Cθhaloalkyl, -S (O) PR, -SH, -S (O) pNRaRb, -NRaRb, -NRaC (O) Rb, - SC (O) R, -SCN or -C (O) NRaRb;
[0044] each R4 and R5, Ci-Cθalkyl or Co-CθalkylCs-Cθ cycloalkyl moiety can be optionally and independently substituted by at least one substituent selected from cyano, halo, hydroxyl, oxo, Ci-Cealcoxy, Ci-Cβ haloalkoxy, Ci- Cθhaloalkyl, Ci-Cθalkyl, hydroxylCi-C6alkyl-, -S (O) PRC, -SH, -S (O) pNRaRb, -NRaRb, -NRaC (O) Rb, -SC (O) R, -SCN or -C (O) NRaRb; and
[0045] wherein each R4 and R5, Co-Cealkylphenyl, Co-Cealkyl-heteroaryl or Co-Cealkyl-heterocycle moiety may also be optionally substituted with at least one substituent selected from cyan, halo, oxo, = S, = NR7, hydroxylCi-Cealkyl-, hydroxyl, Ci-Cealcoxy, Ci- Cealkyl, Ci-Ce haloalkyl, -SH, -S (O) PR and Ci-Cehaloalkoxy;
[0046] n is the integer 0, 1 or 2, and when n is 2, each R2 can be identical or different from each other; and
[0047] p is the integer 0, 1 or 2, stereoisomers of these and veterinarily acceptable salts of these.
[0048] In another aspect of the invention are compounds of formula (V, 1.1)
[0049] where W1 is N and W2 and W3 are each C or W2 is N and W1 and W3 are each C or W3 is N and W1 and W2 are each C. In yet another aspect, W1 is N and W2 and W3 are each C. In yet another aspect, W2 is N and W1 and W3 are each C. In yet another aspect, W3 is N and W1 and W2 are each C. In each case, X is O and W is -C (O ) - either -CH2- or W is O and X is -C (O) - or -CH2- or X is -NR6- and W is -CH2- or -C (O) - or W is -NR6- and X is -CH2- or -C (O) -. In one embodiment, X is O and W is -C (O) -. In another modality, X is O and W is -CH2-. In another embodiment, X is -NR6- and W is -CH2-. In yet another modality, X is -NR6- and W is -C (O) -. In another modality, W is O and X is -C (O) -. In another modality, W is O and X is - CH2-. In another embodiment, W is -NR6- and X is -CH2-, In yet another embodiment, W is -NR6- and X is -C (O) -, stereoisomers thereof and veterinarily acceptable salts thereof.
[0050] In another aspect of the invention are compounds of formula (1)
on what
[0051] X and W are each independently -O-, -S-, -NR6-, -CH2-, -C (O) -, -C (NR7) - or -C (S) -, when X is - O-, -S- or -NR6-, then W is - CH2-, -C (O) -, -C (NR7) - or -C (S) -, and when W is -O-, -S- or -NR6-, then X is -CH2-, -C (O) -, -C (NR7) - or -C (S) -;
[0052] R1a, R1b and R1c are each independently hydrogen, halo, hydroxyl, cyano, nitro, Ci-Cβalkyl, Ci-Cehaloalkyl, Ci-Cθalkoxy, C0-C3 alkylCa-Cβ cycloalkyl, Ci-Cehaloalkoxy, -C (O) NH2, -SF5 or -S (O) PR;
[0053] R2 is fluorine, chlorine or Ci-Cβalkyl;
[0054] R3 is cyano, Ci-Cealquila, Ci-Cehaloalkyl, -C (O) NRaRb, C2-C6 alkenyl, C2-Cealquinyl, C2-Cehaloalkenyl or C2-Cθhaloalquinila;
[0055] R4 is hydrogen, C1-Cealkyl, Co-CealkylCa-Cecycloalkyl, -C (O) R5, -C (S) R5, -C (O) NRaR5, -C (O) C (O) NRaR5, - S (O) PRC, -S (O) 2NRaR5, -C (NR7) R5, -C (NR7) NRaR5, Co-Cealkylphenyl, Co-C6alkyl-heteroaryl or Co-Ce alkyl-heterocycle;
[0056] R5 is hydrogen, C1-Cealkyl, C2-Cealkenyl, Co-CealkylCa-C6 cycloalkyl, Co-C6alkylphenyl, Co-C6alkylheteroaryl or Co-C6alkylheterocycle;
[0057] R6θ hydrogen, Ci-Cθalkyl, hydroxyl or C-i-Cealcoxy;
[0058] R7 is hydrogen, C1-C6alkyl, hydroxyl, cyano, nitro, -S (O) PRCor Ci-Cealcoxy;
[0059] R is Ci-Cealquila or Ca-Cecicloalkyl optionally substituted with at least one halo substituent;
[0060] Ra is hydrogen, C-i-Cealkyl or Co-CaalkylCa-Cecycloalkyl; wherein the alkyl and the alkylcycloalkyl are optionally substituted by cyano or at least one halo substituent;
[0061] Rb is hydrogen, Ci-Cealquila, Cs-Cecicloalkyl, Co-Caalkylphenyl, Co-Caalkyl-heteroaryl or Co-Caalkyl-heterocycle, each optionally substituted, where chemically possible, with at least one hydroxyl, cyan, selected substituent halo or - S (O) PR;
[0062] Rc is Ci-Cealquila, Ci-Cehaloalkyl, Ci-CθhaloalkylCa-Ce cycloalkyl, Co-CaalkylCa-Cecicloalkyl, Co-Caalkylphenyl, Co-Caalkyl-heteroaryl or Co-Caalkyl-heterocycle each optionally substituted with at least one substituted substituted by at least one substituted cyano, halo, hydroxyl, oxo, Ci-Cealcoxy, Ci-Ce haloalkoxy, Ci-Cehaloalkyl, - S (O) PR, -SH, -S (O) pNRaRb, -NRaRb, -NRaC (O) Rb, - SC (O) R, -SCN or -C (O) NRaRb;
[0063] each R4 and R5, Ci-Cealquila or Co-CealquilCa-Ce cycloalkyl moiety can be optionally and independently substituted by at least one substituent selected from cyano, halo, hydroxyl, oxo, Ci-Cealcoxy, Ci-Ce haloalkoxy, Ci -Cehaloalkyl, Ci-Cealkyl, hydroxylCi-Cealkyl-, -S (O) PRC, -SH, -S (O) pNRaRb, -NRaRb, -NRaC (O) Rb, -SC (O) R, -SCN or - C (O) NRaRb; and
[0064] wherein each R4 and R5, Co-Cealkylphenyl, Co-Cealkyl-heteroaryl or Co-Cealkyl-heterocycle moiety may also be optionally substituted with at least one substituent selected from cyan, halo, oxo, = S, = NR7, hydroxylCi-Cealkyl-, hydroxyl, Ci-Cealcoxy, Ci- Cealkyl, Ci-Ce haloalkyl, -SH, -S (O) PR and Ci-Cehaloalkoxy;
[0065] n is the integer 0, 1 or 2, and when n is 2, each R2 can be identical or different from each other; and
[0066] p is the integer 0, 1 or 2;
[0067] stereoisomers thereof and veterinarily acceptable salts thereof.
[0068] In another aspect of the invention of formula (1), X is -O- and W is -C (O) -. The compound of formula (1) when X is -O- and W is -C (O) - is also represented as formula (1.1).

[0069] In another aspect of the invention of formula (1), X is -O- and W is -C (NR7) -.
[0070] In another aspect of the invention of formula (1), X is -O- and W is -C (S) -.
[0071] In another aspect of the invention of formula (1), X is -O- and W is -CH2-.
[0072] The compound of formula (1) when X is -O- and W is -CH2- is also represented as formula (1.2).

[0073] In another aspect of the invention of formula (1), X is -NR6- and W is -C (NR7) -.
[0074] The compound of formula (1) when X is -NR6- and W is -C (0) - is also represented as formula (1.3).

[0075] In another aspect of the invention, when W is -C (O) - and X is NR6, then R6 is hydrogen or Ci-Cealkyl. In yet another aspect of the invention, when W is -C (O) - and X is NR6, then R6 is hydrogen, methyl, ethyl, isopropyl, propyl or t-butyl. In yet another aspect of the invention, when W is -C (O) - and X is NR6, then R6 is hydrogen, methyl, ethyl or isopropyl. In yet another aspect of the invention, when W is -C (O) - and X is NR6, then R6 is hydrogen, methyl or ethyl. In yet another aspect of the invention, when W is -C (O) - and X is NR6, then R6 is hydrogen or methyl. In yet another aspect of the invention, when W is -C (O) - and X is NR6, then R6 is hydrogen. In yet another aspect of the invention, when W is -C (O) - and X is NR6, then R6 is methyl.
[0076] In another aspect of the invention of formula (1), X is -NR6- and W is -C (S) -.
[0077] In another aspect of the invention of formula (1), X is -NR6- and W is -CH2-.
[0078] In another aspect of the invention of formula (1), X is -NR6- and W is -C (O) -.
[0079] In another aspect of the invention of formula (1), X is -S- and W is -C (S) -.
[0080] In another aspect of the invention of formula (1), X is -S- and W is -C (O) -.
[0081] In another aspect of the invention of formula (1), X is -S- and W is -C (NR7) -.
[0082] In another aspect of the invention of formula (1), X is -S- and W is -CH2-.
[0083] In another aspect of the invention of formula (1), W is -O- and X is -C (O) -.
[0084] The compound of formula (1) when W is -O- and X is -C (O) - is also represented as formula (1.4)

[0085] In another aspect of the invention of formula (1), W is -O- and X is -C (NR7) -.
[0086] In another aspect of the invention of formula (1), W is -O- and X is -C (S) -.
[0087] In another aspect of the invention of formula (1), W is -O- and X is -CH2-.
[0088] The compound of formula (1) when W is -O- and X is -CH2- is also represented as formula (1.5)

[0089] In another aspect of the invention of formula (1), W is -NR6- and X is -C (S) -.
[0090] In another aspect of the invention of formula (1), W is -NR6- and Xé-C (O) -.
[0091] The compound of formula (1) when W is -NR6- and X is - C (O) - is also represented as formula (1.6)

[0092] In another aspect of the invention of formula (1), W is -NR6- and X is -CH2-.
[0093] In another aspect of the invention of formula (1), W is -NR6- and X is -C (S) -.
[0094] In another aspect of the invention of formula (1), W is -NR6- and X is -CH2-.
[0095] In another aspect of the invention of formula (1), W is -S- and X is -C (S) -.
[0096] In another aspect of the invention of formula (1), W is -S- and X is -C (O) -.
[0097] In another aspect of the invention of formula (1), W is -S- and X is -C (NR7) -.
[0098] In another aspect of the invention of formula (1), W is -S- and X is -CH2-,
[0099] In yet another aspect of the invention, each of R1a, R1b and R1c is independently selected from hydrogen, halo, cyano, Ci-Cθ haloalkyl and Co-CaalkylCa-Cβ cycloalkyl. In yet another aspect of the invention, each of R1a, R1b and R1c is independently selected from hydrogen, halo, cyano and CI-CΘhaloalkyl. In yet another aspect of the invention, each of R1a, R1b and R1c is independently selected from hydrogen, fluorine, chlorine, bromine, cyan and CI-CΘhaloalkyl. In yet another aspect of the invention, each of R1a, R1b and R1c is independently selected from hydrogen, fluorine, chlorine, bromine and C1-C6 haloalkyl. In yet another aspect of the invention, each of R1a, R1b and R1c is independently selected from hydrogen, fluorine, chlorine, bromine and -CF3. In another aspect of the invention, R1a and R1c are both chlorine and R1b is fluorine.
[00100] In another aspect of the invention, the integer n of (R2) n is 0. In another aspect of the invention, the integer n of (R2) n is 1. When the integer n is 1, then R2 is fluorine, chlorine, methyl or ethyl. In another aspect of the invention, when the integer n is 1, then R2 is fluorine. In yet another aspect of the invention, when the integer n is 1, then R2 is chlorine. In yet another aspect of the invention, when the integer n is 1, then R2 is methyl. In yet another aspect of the invention, when the integer n is 1, then R2 is ethyl. In yet another aspect of the invention, the integer n of (R2) n is 2. When the integer n is 2, then each R2 is independently fluorine or chlorine.
[00101] In yet another aspect of the invention, R3 is cyan, Ci- Cealkyl, Ci-Cehaloalkyl or -C (O) NH2. In yet another aspect of the invention, R3 is cyano, Ci-Cβalkyl or Ci-Cehaloalkyl. In yet another aspect of the invention, R3 is cyano, methyl, ethyl or Ci-Cehaloalkyl. In yet another aspect of the invention, R3 is cyano, methyl or Ci- Cehaloalkyl. In yet another aspect of the invention, R3 is cyan or Cyclehaloalkyl. In yet another aspect of the invention, R3 is Ci-Cehaloalkyl. In yet another aspect of the invention, R3 is -CF3, -CHF2, -CH2F and -CF2CI. In yet another aspect of the invention, R3 is - CF3, -CHF2 and -CH2F. In yet another aspect of the invention, R3 is -CF3.
[00102] In yet another aspect of the invention, R4 and hydrogen, C1- C6alkyl, Co-CealkylCa-Cβcycloalkyl, -C (O) R5, -C (S) R5, -C (O) NRaR5, -S (O) pRc, -S (O) 2NRaR5, -C (NR7) R5, Co-C6alkylphenyl, C0-C6alkylheteroaryl or Co-Cβalkylheterocycle. In yet another aspect of the invention, R4 is hydrogen, Ci-Cβalkyl, Co-CealkylCs-Cβcycloalkyl, - C (O) R5, -C (S) R5, -C (O) NRaR5, -S (O) PRC, -S (O) 2NRaR5 or -C (NR7) R5. In yet another aspect of the invention, R4 is hydrogen, Ci-Cβalkyl, Co-CealkylCs-Cecycloalkyl or -C (O) R5. In yet another aspect of the invention, R4 is hydrogen, Ci-Cβalkyl or -C (O) R5. In yet another aspect of the invention, R4 is hydrogen or -C (O) R5. In yet another aspect of the invention, R4 is hydrogen. In yet another aspect of the invention, R4 is -C (O) R5. R4 can be optionally substituted as defined here.
[00103] In yet another aspect of the invention, R5 is Ci-Cβalkyl, Co-CealkylCa-Cecycloalkyl, Co-Cealkylheteroaryl or Co-Cealkylheterocycle. In yet another aspect of the invention, R5 is Ci-Cealquila. In yet another aspect of the invention, R5 is methyl, ethyl, propyl, isopropyl, t-butyl and isobutyl. Each of the R5 Ci-Cealkyls can optionally be substituted as defined here, for example, with at least one substituent selected from hydroxyl, halo, trifluoromethyl, thiomethyl, tiotrifluoromethyl, -SO2CH3, -SO2CF3 and -NHCHO. In yet another aspect of the invention, R5 is Co-CealkylCa-Cβ cycloalkyl. In yet another aspect of the invention, R5 is cyclopropyl, cyclobutyl, cyclopropylmethyl, cyclopropylethyl, cyclobutylmethyl and cyclopentyl. Each of the R5 Co-CealkylCs-Cecicloalkyls can optionally be substituted as defined herein, for example, with at least one substituent selected from hydroxyl, -CH2OH, halo, methyl, ethyl and trifluoromethyl. In yet another aspect of the invention, R5 is Co-Cealkylheteroaryl. In yet another aspect of the invention, R5 is -CH2pyrazole and - CH2pyridazine. Each of R5, Co-Cealkyl-heteroaryl moieties can optionally be substituted as defined here, for example, with at least one substituent selected from hydroxyl, methyl, halo and trifluoromethyl. In yet another aspect of the invention, R5 is Co-Cealkylheterocycle. In yet another aspect of the invention R5 isoxetane, thiatane, azetidine, tetrahydrofuran, tetrahydrothiophene and pyrrolidine. Each of R5, Co-Cealkyl-heterocycle moieties can be optionally substituted as defined herein, for example, with at least one substituent selected from halo, -CH2OH, methyl, oxo and trifluoromethyl.
[00104] In yet another aspect of the invention, when X is -O- and W is -C (O) - or when X is -O- and W is -CH2-, then R1a, R1b and R1c are each independently hydrogen, halo or Ci-Cehaloalkyl, R3 is - CF3 and R4 is -C (O) R5; stereoisomers thereof and veterinarily acceptable salts thereof. In yet another aspect of the invention, when X is - O- and W is -C (O) - or when X is -O- and W is -CH2-, then R1a, R1b and R1c are each independently hydrogen, halo or Ci -Cehaloalkyl, R3 is -CF3, R4 is -C (O) R5 and R5 is Ci-Cealkyl, Co-CealkylCs- Cecycloalkyl, Co-Cealkyl-heteroaryl or Co-Ce alkyl-heterocycle, where each of R5, Ci portion -Cealkyl or Co-CealkylCs-Cecycloalkyl can be optionally and independently substituted by at least one substituent selected from cyano, halo, hydroxyl, -CH2OH, oxo, Ci-Cealcóxi, Ci-Cehaloalcóxi, Ci-Cehaloalkyl, -S (O) PRC , -SH, -S (O) pNRaRb, -NRaRb, -NRaC (O) Rb, -SC (O) R, -SCN or -C (O) NRaRb and where each of R5, Co-Cealkyl-heteroaryl portion or Co-Cealkylheterocycle can also optionally be substituted with at least one substituent selected from cyano, -CH2OH, halo, oxo, = S, = NR7, hydroxyl, Ci-Cβ alkoxy, Ci-Cβalkyl, Ci-Cβhaloalkyl, -SH , - S (O) PR and Ci-Cehaloalkoxy, stereoisomers of these and veterinary salts will be accepted of these. More specifically, R5, Ci-Cβalkyl or Co-CealkylCs-Cecicloalkyl moiety can be optionally and independently substituted by at least one substituent selected from halo, hydroxyl, Ci-Cehaloalkyl, -S (O) PRC and -NRaC (O) Rb. More specifically, R5, Co-Cealkyl-heteroaryl or Co-Cealkyl-heterocycle moiety can also optionally be substituted with at least one substituent selected from halo, oxo and C-Cθalkyl.
[00105] In another aspect of the invention, they are compounds of formula (1) selected from:
[00106] 1 - (cyclopropanecarbonyl) -5 '- (3,4,5-trichlorophenyl) -5- (trifluoro-methyl) -4,5-dihydroisoxazol-3-yl) -3'H-spiro {azetidine -3, r-isobenzofuran} -3'-one;
[00107] 5 '- (5- (3,5-dichloro-4-fluorophenyl) -5- (trifluoromethyl) -4,5-dihydroisoxazol-3-yl) -1-propionyl-3'H-spiro [ azetidine-3, T-isobenzofuran] - 3'-one;
[00108] 1 - (cyclopropanocarbonyl) -5 '- (5- (3,5-dichloro-4-fluorophenyl) -5- (trifluoromethyl) -4,5-dihydroisoxazol-3-yl) -3'H- spiro [azetidine-3, T-isobenzofuran] -3'-one;
[00109] 5 '- (5- (3,5-dichloro-4-fluorophenyl) -5- (trifluoromethyl) -4,5-dihydroisoxazol-3-yl) -1- (3-methylbutanoyl) -3' H-spiro [azetidine-3, T-isobenzofuran] -3'-one;
[00110] 5 '- (5- (3,5-dichloro-4-fluorophenyl I) -5- (trifluoromethyl) -4,5-dihydroisoxazol-3-yl) -1- (2-hydroxy- 2-methylpropanoyl) -3'H-spiro [azetidine-3,1'-isobenzofuran] -3'-one;
[00111] 1 - (2-cyclopropylacetyl) -5 '- (5- (3,5-dichloro-4-fluorophenyl) -5- (trifluoromethyl) -4,5-dihydroisoxazol-3-yl) -3' H-spiro [azetidine-3, T-isobenzofuran] -3'-one;
[00112] 1-acetyl-5 '- (5- (3,5-dichloro-4-fluorophenyl) -5- (trifluoromethyl) -4,5-dihydroisoxazol-3-yl) -3'H-spiro [ azetidine-3, T-isobenzofuran] -3'-one;
[00113] 5 '- (5- (3,5-dichloro-4-fluorophenyl) -5- (trifluoromethyl) -4,5-dihydroiso-xazol-3-yl) -1- (1-hydroxycyclopropanecarbonyl) - 3'H-spiro [azetidine-3, T-isobenzofuran] -3'-one;
[00114] 1- (cyclobutanocarbonyl) -5 '- (5- (3,5-dichloro-4-fluorophenyl) -5-
[00115] 1- (cyclobutanocarbonyl) -5 '- (5- (3,5-dichloro-4-fluorophenyl) -5-xazol-3-yl) -1-pivaloyl-3 H-spiro [azetidma-3, T -isobenzofuran] -3-one;
[00116] 5 '- (5- (3,5-dichloro-4-fluorophenyl) -5- (trifluoromethyl) -4,5-dihydroiso-xazol-3-yl) -1- (2-hydroxyacetyl) - 3'H-spiro [azetidine-3, T-isobenzofuran] - "- s- ~
[00117] 5 '- (5- (3,5-dichloro-4-fluorophenyl) -5- (trifluoromethyl) -4
[00118] 1-butyl 1-5 '- (5- (3,5-di-chloro-4-fluoro-ni I) -5- (trifluorine I) -4,5-dihydroisoxazol-3-yl ) -3'H-spiro [azetidine-3,1'-isobenzofuran] -3'-one;
[00119] 5 - (5- (3,5-dichloro-4-fluorophenyl) -5- (trifluoromethyl) -4,5-dihydroisoxazole-3 µl) -1- (2- (methyl | thio) acetyl ) -3.H-eSpiro [aZetidine-3.r- isobenzofuran] -3-one,
[00120] 5- (5- (3,5-dichloro-4-fluorophenyl) -5- (tπfluormethyl) -4,5-dihydroisoxazol-3-yl) -1- (2- (methylsulfinyl) acetyl) - 3 H-spiro [azetidine-3, T-isobenzofuran] -3'-one;
[00121] 5 '- (5- (3,5-dichloro-4-fluorophenyl) -5- (trifluoromethyl) -4,5-dihydroisoxazol-3-yl) -1- (2- (methylsulfonyl) acetyl) -3'H-spiro [azetidine-3, T-isobenzofuran] -3'-one;
[00122] 1 - (2- (1 H-pyrazol-1-i) acetyl I) -5 '- (5- (3,5-dichloro-4-fluorine ni) -5- (trifluoromethyl) -4,5-dihydroisoxazol-3-yl) -3'H-spiro [azetidine-3,1'-isobenzofuran] -3'-one;
[00123] 5 (5 3 -hydroisoxazol-3-yl) -1- (1- (tπfluormethyl) cyclopropanocarbonyl) -3 H-spiro [azetidma-3, T-isobenzofuran] -3-one;
[00124] õ ^ íS-ÍS.S-dichloro ^ -fluorfeniO-õ-ítriflúormetilH.õ-di-
[00125] 5 '- (5- (3,5-dichloro-4-fluorophenyl) -5- (trifluoromethyl) -4,5-dihydroisoxazol-3-yl) -1 - (2- (3-methyl- 1 H-pyrazol-1-yl) acetyl) -3'H-spiro [azetidine-3, T-isobenzofuran] -3'-one;
[00126] 5 '- (5- (3,5-dichloro-4-fluorophenyl) -5- (triflLiormethyl) -4,5-dihydroisoxazol-3-yl) -1- (3-hydroxy-2-methylpropanoyl ) -3'H-spiro [azetidine-3,1 '-isobenzofuran] -3'-one;
[00127] 5 '- (5- (3,5-dichloro-4-fluorophenyl) -5- (trifluoromethyl) -4,5-dihydroisoxazol-3-yl) -1- (2,2-difluoro-cyclopropanecarbonyl) - 3, H-spiro [azetidine-3, T-isobenzofuran] -3'-one;
[00128] 5 '- (5- (3,5-dichloro-4-fluorophenyl) -5- (trifluoromethyl) -4,5-dihydroisoxazol-3-yl) -1- (4,4,4-trifluorobutanoyl ) -3'H-spiro [azetidine-3, T-isobenzofuran] -3'-one;
[00129] 1 - (5 '- (5- (3,5-dichloro-4-fluorophenyl) -5- (trifluoromethyl) -4,5-dihydroisoxazol-3-yl) -3'H-spiro [azetidine -3,1'-isobenzofuran] -1-yl) -2- ((trifluoromethyl) thio) ethanone;
[00130] (5 '- (5- (3,5-dichloro-4-fluorophenyl) -5- (trifluoromethyl) -4,5-dihydroisoxazol-3-yl) -3'H-spiro [azetidine-3 , T-isobenzofuran] -1-yl) (1-oxidothietan-3-yl) methanone;
[00131] (5 '- (5- (3,5-dichloro-4-fluorophenyl) -5- (trifluoromethyl) -4,5-dihydroisoxazol-3-yl) -3'H-spiro [azetidine-3 , T-isobenzofuran] -1-yl) (1,1-antioxidotietan-3-yl) methanone;
[00132] 1 - (5 '- (5- (3,5-dichloro-4-fluorophenyl) -5- (trifluoromethyl) -4,5-dihydroisoxazol-3-yl) -3'H-spiro [azetidine -3,1'-isobenzofuran] -1-yl) -2- (methylthio) ethanone;
[00133] (R) -1 - (5 '- (5- (3,5-dichloro-4-fluorine ni I) -5- (triflurori I) -4,5-dihydroisoxazole-3- il) -3'H-spiro [azetidine-3,1'-isobenzofuran] -1-yl) -2- (methylthio) ethanone;
[00134] (S) -1 - (5 '- (5- (3,5-dichloro-4-fluorine ni I) -5- (triflurori I) -4,5-dihydroisoxazole-3- il) -3'H-spiro [azetidine-3,1'-isobenzofuran] -1-yl) -2- (methylthio) ethanone;
[00135] 1 - (5 '- (5- (3,5-dichloro-4-f uorfeni I) -5- (trifl uormeti I) -4,5-d i-hydroisoxazol-3-yl) - 3'H-spiro [azetidine-3, T-isobenzofuran] -1-yl) -2- (methylsulfinyl) ethanone;
[00136] (R) -1 - (5 '- (5- (3,5-dichloro-4-fluorine ni I) -5- (triflurori I) -4,5-dihydroisoxazole-3- il) -3'H-spiro [azetidine-3, T-isobenzofuran] -1-yl) -2- (methylsulfinyl) ethanone;
[00137] (S) -1- (5 '- (5- (3,5-dichloro-4-fluorophenyl) -5- (trifluoromethyl) -4,5-dihydroisoxazol-3-yl) -3'H -spiro [azetidine-3, T-isobenzofuran] -1-yl) -2- (methylsulfinyl) ethanone;
[00138] 1 - (5 '- (5- (3,5-dichloro-4-phosphorus I) -5- (trifluorometh I) -4,5-d i-hydroisoxazol-3-yl) -3'H-spiro [azetidine-3, T-isobenzofuran] -1-yl) -2- (methylsulfonyl) ethanone;
[00139] (R) -1 - (5 * - (5- (3,5-dichloro-4-fluorine ni I) -5- (triflurori I) -4,5-dihydroisoxazole-3- il) -3'H-spiro [azetidine-3, T-isobenzofuran] -1-yl) -2- (methylsulfonyl) ethanone;
[00140] (S) -1 - (5 '- (5- (3,5-dichloro-4-fluorophenyl) -5- (trifluoromethyl) -4,5-dihydroisoxazol-3-yl) -3'H -spiro [azetidine-3, T-isobenzofuran] -1-yl) -2- (methylsulfonyl) ethanone;
[00141] 1- (5 '- (5- (3,5-dichloro-4-fluorophenyl) -5- (trifluoromethyl) -4,5-dihydroisoxazol-3-yl) -3'H-spiro [azetidine -3, T-isobenzofuran] -1-yl) -2-methylpropan-1-one;
[00142] 1 - (S-ÍS-ÍS.S-dichloro ^ -fluorfenylJ-S-ítriflúormetilH.õ-dihydroisoxazol-3-yl) -3'H-spiro [azetidine-3,1'-isobenzofuran] - 1-yl) -2-hydroxyethanone;
[00143] cyclobutyl (5 '- (5- (3,5-dichloro-4-fluorophenyl) -5- (trifluoromethyl) -4,5-dihydroisoxazol-3-yl) -3'H-spiro [azetidine- 3, T-isobenzofuran] -1-yl) methanone;
[00144] (5 '- (5- (3,5-dichloro-4-fluorophenyl) -5- (trifluoromethyl) -4,5-dihydroisoxazol-3-yl) -3'H-spiro [azetidine-3 , 1'-isobenzofuran] -1-yl) (1-hydroxycyclopropyl) methanone;
[00145] N ^ 5hydroisoxazol-3-yl) -3H-spiro [azetidine-3,1-isobenzofuran] -1-yl) -2-oxoethyl) formamide,
[00146] 1- (5- (5- (3,5-dichloro-4-fluorophenyl) -5- (trifluoromethyl) -4,5-dihydroisoxazol-3-yl) -3'H-spiro [azetidine- 3, T-isobenzofuran] -1-yl) ethanone;
[00147] hydroisoxazol-3-yl) -3H-spiro [azetidine-3,1-isobenzofuran] -1-yl) propan-1-one,
[00148] 14 ° -3: 5-dlclOT ^ -fl∞rfe ™> -5- (πfl∞met'θ, -4; 5 ^ hydroisoxazol-3-yl) -3 H-spiro [azetidma-3, T -isobenzofuran] -1-yl) -2-hydroxy-2-methylpropan-1-one;
[00149] 14 ° -3: 5-dlclOT ^ -fl∞rfe ™> -5- (πfl∞met'θ, -4; 5 ^ hydroisoxazol-3-yl)
[00150] 14 5: 5— “- ^ uorme., LK5 ^ hydroisoxazol-3-yl) -3 H-spiro [azetidma-3, T-isobenzofuran] -1-yl) -2,2-dimethylpropan-1 - ona;
[00151] (5 '- (5- (3,5-dichloro-4-fluorophenyl) -5- (trifluoromethyl) -4,5-dihydroisoxazol-3-yl) -3'H-spiro [azetidine-3 , T-isobenzofuran] -1-yl) (1- (trifluoromethyl) cyclopropyl) -methanone;
[00152] 1 - (5 '- (5- (3,5-dichloro-4-fluorophenyl) -5- (trifluoromethyl) -4,5-dihydroisoxazol-3-yl) -3'H-spiro [azetidine -3, T-isobenzofuran] -1-yl) -3-hydroxy-2-methylpropan-1-one;
[00153] 14 5: 5— “- ^ uorme., LK5 ^ h, dolSoxazol-3ll-3H ^ Splro [aZetldlna-3,1-lSobenZofuran] -1-ll) -2- (3-methyl-1 H- pyrazol-1-yl) ethanone;
[00154] 1 - (5 '- (5- (3,5-dichloro-4-fluorophenyl) -5- (trifluoromethyl) -4,5-di-
[00155] 1 - (5 '- (5- (3,5-dichloro-4-fluorophenyl I) -5- (trifluoromethyl I) -4,5-d i-hydroisoxazol-3-yl) -3 'H-spiro [azetidine-3,1'-isobenzofuran] -1-yl) -2- (1 H-pyrazol-1-yl) ethanone;
[00156] 1 - (5 '- (5- (3,5-dichloro-4-fluorophenyl) -5- (trifluoromethyl) -4,5-dihydroisoxazol-3-yl) -3'H-spiro [azetidine -3, T-isobenzofuran] -1-yl) -3-hydroxybutan-1-one;
[00157] cyclopropyl (5 '- (5- (3,5-dichloro-4-fluorophenyl) -5- (trifluoromethyl) -4,5-dihydroisoxazol-3-yl) -3'H-spiro [azetidine- 3, T-isobenzofuran] -1-yl) methanone;
[00158] 1 - (5 '- (5- (3,5-dichloro-4-fluorophenyl) -5- (trifluoromethyl) -4,5-dihydroisoxazol-3-yl) -3'H-spiro [azetidine -3, T-isobenzofuran] -1-yl) butan-1-one;
[00159] (5 '- (5- (3,5-dichloro-4-fluorophenyl) -5- (trifluoromethyl) -4,5-dihydroisoxazol-3-yl) -3'H-spiro [azetidine-3 , r-isobenzofuran] -1-yl) (tietan-3-yl) methanone;
[00160] (5 '- (5- (3,5-dichloro-4-fluorophenyl) -5- (trifluoromethyl) -4,5-dihydroisoxazol-S-yl ^'. S'-dihydrospirotazetidine-SJ '-indenyl-1-ylXI, 1-dioxidotietan-3-yl) methanone;
[00161] (R) - (5 '- (5- (3,5-dichloro-4-fluorophenyl) -5- (trifluoromethyl) -4,5-dihydroisoxazol-3-yl) -2,, 3' dihydrospiro [azetidine-3, r-inden] -1-yl) (1,1-detoxotietan-3-yl) methanone;
[00162] (S) - (5 '- (5- (3,5-dichloro-4-fluorophenyl) -5- (trifluoromethyl) -4,5-dihydroisoxazol-3-yl) -2', 3 ' -dihydrospiro [azetidine-3,1'-inden] -1 -i I) (1,1 - dioxidotietan-3-yl) methanone;
[00163] 2- (methyl sulfone I) -1 - (5 '- (5- (3,4,5-tri chlorophenyl I) -5- (trifluoromethyl) -4,5-dihydroisoxazole-3 -yl) -3'H-spiro [azetidine-3, T-isobenzofuran] -1- yl) ethanone;
[00164] 1 - (5 '- (5- (3,5-dichlorophenyl) -5- (trifluoromethyl) -4,5-dihydroisoxazol-3-yl) -3'H-spiro [azetidine-3, r -isobenzofuran] -1-yl) -2- (methylsulfonyl) ethanone;
[00165] 1 - (5 '- (5- (3-chloro-5- (trifl uormeti I) pheni I) -5- (trifl uormeti I) -4,5-dihydroisoxazol-3-yl) -3 'H-spiro [azetidine-3,1'-isobenzofuran] -1-yl) -2- (methylsulfonyl) ethanone;
[00166] 1 - (5 '- (5- (3,4-dichloro-5- (trifluoromethyl) phenyl) -5- (trifluoromethyl) -4,5-dihydro-isoxazol-3-yl) -3' H-spiro [azetidine-3, T-isobenzofuran] -1-yl) -2- (methylsulfonyl) -ethanone;
[00167] 1 - (5, - (5- (4-bromo-3,5-dichlorophenyl) -5- (trifluoromethyl) -4,5-dihydroisoxazol-3-yl) -3'H-spiro [azetidine -3,1'-isobenzofuran] -1-yl) -2- (methylsulfonyl) ethanone;
[00168] 1 - (5 '- (5- (3,5-bis (trifl uormeti I) pheni I) -5- (trifl uormeti I) -4,5-d i-hydroisoxazol-3-yl) -3 'H-spiro [azetidine-3,1'-isobenzofuran] -1-yl) -2- (methylsulfonyl) ethanone;
[00169] (R) -1 - (5 '- (5- (3,5-bis (trifl uormeti I) pheni I) -5- (trifl uormeti I) -4,5-dihydroisoxazol-3-yl ) -3'H-spiro [azetidine-3,1'-isobenzofuran] -1-yl) -2- (methylsulfonyl) ethanone;
[00170] (S) -1 - (5 '- (5- (3,5-bis (trifluorometh I) pheni I) -5- (trifluorometh I) -4,5-dihydroisoxazole-3- il) -3'H-spiro [azetidine-3,1'-isobenzofuran] -1-yl) -2- (methylsulfonyl) ethanone;
[00171] 1- (5 '- (5- (3-bromo-5-chlorophenyl) -5- (trifluoromethyl) -4,5-dihydroisoxazol-3-yl) -3'H-spiro [azetidine-3 , T-isobenzofuran] -1-yl) -2- (methylsulfonyl) ethanone;
[00172] 1 - (5, - (5- (4-chloro-3,5-bis (trifluoromethyl) phenyl) -5- (trifluoromethyl) -4,5-dihydroisoxazol-3-yl) -3'H -spiro [azetidine-3,1 '-isobenzofuran] -1 -yl) - 2- (methylsulfonyl) ethanone;
[00173] 1 - (5 '- (5- (3-chloro-5-f uorfeni I) -5- (trifl uormeti I) -4,5-d i-hydroisoxazol-3-yl) -3'H -spiro [azetidine-3,1'-isobenzofuran] -1-yl) -2- (methylsulfonyl) ethanone;
[00174] 1 - (5 '- (5- (3-chloro-4-fluorophenyl) -5- (trifluoromethyl) -4,5-dihydroisoxazol-3-yl) -3'H-spiro [azetidine-3 , 1'-isobenzofuran] -1-yl) -2- (methylsulfonyl) ethanone;
[00175] (R) -1 - (5 '- (5- (3-chloro-4-fluorophenyl) -5- (trifluoromethyl) -4,5-dihydroisoxazol-3-yl) -3'H-spiro [azetidine-3, T-isobenzofuran] -1-yl) -2- (methylsulfonyl) ethanone;
[00176] (S) -1- (5 '- (5- (3-chloro-4-fluorophenyl) -5- (trifluoromethyl) -4,5-dihydroisoxazol-3-yl) -3'H-spiro [azetidine-3, T-isobenzofuran] -1-yl) -2- (methylsulfonyl) ethanone;
[00177] 2- (methylsulfonyl) -1- (5 '- (5- (trifluoromethyl) -5- (3- (trifluoromethyl) phenyl) -4,5-dihydroisoxazol-3-yl) -3'H- spiro [azetidine-3, T-isobenzofuran] -1-yl) ethanone;
[00178] (R) -2- (methylsulfonyl) -1- (5 '- (5- (trifluoromethyl) -5- (3- (triflOormethylXenyl ^ .S-dihydroisoxazol-S-ylJ-S'H-spirotazetidine -SJ'- isobenzofuran] -1-yl) ethanone;
[00179] (S) -2- (methylsulfonyl) -1 - (5 '- (5- (trifluoromethyl) -5- (3- (triflOormethylXenylH.S-dihydroisoxazole-S-ilJ-S'H- spirotazetidine-ST-isobenzofuran] -1-yl) ethanone;
[00180] 5 '- (5- (3,5-bis (trifluoromethyl) phenyl) -5- (trifluoromethyl) -4,5-dihydroisoxazol-3-yl) -1- (2- (methylsulfonyl) acetyl) spiro [azetidine-3, T-isoindolin] -3'-one;
[00181] 5 '- (5- (3,5-dichloro-4-fluorophenyl) -5- (trifluoromethyl) -4,5-dihydroisoxazol-3-yl) -1- (2- (methylsulfonyl) acetyl) spiro [azetidine-3, T-isoindolin] -3'-one;
[00182] 1 - (cyclopropanocarbonyl) -5 '- (5- (3,5-dichloro-4-fluorophenyl) -5- (trifluoromethyl) -4,5-dihydroisoxazol-3-yl) spiro [azetidine-3 , T-isoindolin] - 3'-one;
[00183] 5 '- (5- (3,4-dichloro-5- (trifluoromethyl) phenyl) -5- (trifluoromethyl) -4,5-dihydroisoxazol-3-yl) -1- (2- (methylsulfonyl ) acetyl) spiro [azetidine-3, T-isoindolin] -3'-one;
[00184] 1 - (2- (methylsulfonyl) acetyl) -5 '- (5- (3,4,5-trichlorophenyl) -5- (trifluoromethyl) -4,5-dihydroisoxazol-3-yl) spiro [ azetidine-3, T-isoindolin] - 3'-one;
[00185] hydroisoxazol-3-yl) -1- (2- (methylsulfonyl) acetyl) spiro [azetidine-3,1-'so'ndol'nl-3-one,
[00186] 5- (5- (4-bromo-3,5-dichlorophenyl) -5- (tπfluormethyl) -4,5-dihydroisoxazol-3-yl) -1- (2- (methylsulfonyl) acetyl) spiro [azetidine-3, T-isoindolin] -3'-one;
[00187] 5- (5- (4-bromo-3,5-dichlorophenyl) -5- (tπfluormethyl) -4,
[00188] 5- (5- (4-bromo-3,5-dichlorophenyl) -5- (tπfluormethyl) -4,
[00189] 3 ^ 3.5- ™ ^ hydroisoxazol-3-yl) -1- (1,1-dioxidothiethane-3-carbonyl) spiro [azetidma-3, T-isoindolinyl-S'-one;
[00190] h, drosoxazol-3-n) -1- (clopropranecarbonll) spiro [aZetldlna-3, -I-isomdohn] -3-one;
[00191] 5 '- (5- (3-chloro-5- (trifluoromethyl) phenyl I) -5- (trifluoromethyl I) -4,5-d i-hydroisoxazol-3-yl) -1- (cyclopropanocarbonyl) ) spiro [azetidine-3, T-isoindolin] -3'-one;
[00192] 5 '- (5- (4-bromo-3,5-dichlorophenyl) -5- (triflLiormethyl) -4,5-dihydroisoxazol-3-yl) -1- (cyclopropanecarbonyl) spiro [azetidine-3 , T-isoindolin] -3'-one;
[00193] 2'-methyl-1- (2- (methylsulfonyl) acetyl) -5 '- (5- (3,4,5-trichlorophenyl) -5- (tπfluormethyl) -4,5-dihydroisoxazole-3 -il) spiro [azetidine-3,1-isoindolin] -3 ™ '
[00194] 5- (5- (3,5-dichloro-4-fluorophenyl) -5- (trifluoromethyl) -4,5-dihydroisoxazol-3-yl) -2'-methyl-1- (2- ( methylsulfonyl) acetyl) spiro [azetidine-3, T-
[00195] 1 - (cyclopropanecarboml) -2-methyl-5 - (5- (3,4,5-tπchlorophenyl) -5- (trifluoromethyl) -4,5-dihydroisoxazol-3-yl) spiro [azetidine- 3,1 '-isoindolinj- 3'-one,
[00196] or a stereoisomer thereof or a veterinarily acceptable salt thereof.
[00197] In another aspect of the invention, they are compounds of formula (1) selected from:
[00198] 1 - (cyclopropanocarbonyl) -5 '- (3,4,5-trichlorophenyl) -5- (trifluoromethyl) -4,5-dihydroisoxazol-3-yl) -3'H-spiro {azetidine-3 , T-isobenzofuran} -3'-one;
[00199] 5 '- (5- (3,5-dichloro-4-fluorophenyl) -5- (trifluoromethyl) -4,5-dihydroisoxazol-3-yl) -1-propionyl-3'H-spiro [ azetidine-3, T-isobenzofuran] - 3'-one;
[00200] 1- (cyclopropanocarbonyl) -5 '- (5- (3,5-dichloro-4-fluorophenyl) -5- (trifluoromethyl) -4,5-dihydroisoxazol-3-yl) -3'H- spiro [azetidine-3, T-isobenzofuran] -3'-one;
[00201] 5 '- (5- (3,5-dichloro-4-fluorophenyl) -5- (trifluoromethyl) -4,5-dihydroisoxazol-3-yl) -1- (3-methylbutanoyl) -3' H-spiro [azetidine-3, T-isobenzofuran] -3'-one;
[00202] 5 '- (5- (3,5-dichloro-4-fluorophenyl) -5- (trifluoromethyl) -4,5-dihydroisoxazol-3-yl) -1- (2-hydroxy-2-methylpropanoyl ) -3'H-spiro [azetidine-3,1 '-isobenzofuran] -3'-one;
[00203] 1- (2-cyclopropylacetyl) -5 '- (5- (3,5-dichloro-4-fluorophenyl) -5- (trifluoromethyl) -4,5-dihydroisoxazol-3-yl) -3' H-spiro [azetidine-3, T-isobenzofuran] -3'-one;
[00204] 1-acetyl-5 '- (5- (3,5-dichloro-4-fluorophenyl) -5- (trifluoromethyl) -4,5-dihydroisoxazol-3-yl) -3'H-spiro [ azetidine-3, T-isobenzofuran] -3'-one;
[00205] 5 '- (5- (3,5-dichloro-4-fluorophenyl) -5- (trifluoromethyl) -4,5-dihydroisoxazol-3-yl) -1 - (1-hydroxycyclopropanecarbonyl) -3' H-spiro [azetidine-3, T-isobenzofuran] -3'-one;
[00206] 1- (cyclobutanocarbonyl) -5 '- (5- (3,5-dichloro-4-fluorophenyl) -5- (tπfluormethyl) -4,5-dihydroisoxazol-3-yl) -3 H.sPlra [azet, dlna-3,1 -'sobenzofuranl-3-one,
[00207] ... hydroisoxazol-3-yl) -1-pivaloyl-3 H-spiro [azetidma-3, T-isobenzofuran] -3-one;
[00208] 5 '- (5- (3,5-dichloro-4-fluorophenyl) -5- (trifluoromethyl) -4,5-di-'∞2 ”1 t« -rrr .... 3.1 - isobenzofuran] -3 -one;
[00209] 5 '- (5- (3,5-dichloro-4-fluorophenyl) -5- (trifluoromethyl) -4,
[00210] 1 - ^ hydroisoxazol-3-yl) -3 H-spiro [azetidma-3, T-isobenzofuran] -3-one;
[00211] 5 '- (5- (3,5-dichloro-4-fluorophenyl) -5- (trifluoromethyl) -4,5-dihydroisoxazol-3-yl) -1- (2- (methylthio) a∞ tyl) -3 H.sPlro [aze., d, na-3,1 -isobenzofuran] -3-one,
[00212] 5- (5- (3,5-dichloro-4-fluorophenyl) -5- (trifluoromethyl) -4,5-dihydroisoxazol-3-yl) -1- (2- (methylsulfinyl) acetyl) - 3'H-spiro [azetidine-3, T-isobenzofuran] -3'-one;
[00213] 5 '- (5- (3,5-dichloro-4-fluorophenyl) -5- (trifluoromethyl) -4,5-dihydroisoxazol-3-yl) -1- (2- (methylsulfonyl) acetyl) -3'H-spiro [azetidine-3, T-isobenzofuran] -3'-one;
[00214] 1- (2- (1H-pyrazol-1-yl) acetyl) -5 '- (5- (3,5-dichloro-4-fluorophenyl) -5- (WOoHnem ^^. Sobβnzofuranp ^ na,
[00215] hydroisoxazol-3-yl) -1- (1- (tπfluormethyl) cyclopropanocarbonyl) -3 H-spiro [azetidine-3, T-isobenzofuran] -3'-one;
[00216] .hydroisoxazol-3-yl) -1-isobutyl-3 H-spiro [azetidma-3, T-isobenzofuran] - 3'-one;
[00217] 5 '- (5- (3,5-dichloro-4-f uorfeni I) -5 - (trifl uormeti I) -4, 5-d i-hydroisoxazol-3-yl) -1 - ( 2- (3-methyl-1 H-pyrazol-1-yl) acetyl) -3'H-spiro [azetidine-3, T-isobenzofuran] -3'-one;
[00218] 5 '- (5- (3,5-dichloro-4-fluorophenyl) -5- (trifluoromethyl) -4,5-dihydroisoxazol-3-yl) -1- (3-hydroxy-2-methylpropanoyl ) -3'H-spiro [azetidine-3,1 '-isobenzofuran] -3'-one;
[00219] 5 '- (5- (3,5-dichloro-4-furor ni I) - 5 - (trifluorometh I) -4,5-d i-hydroisoxazol-3-yl) -1- (2,2-difluoro-cyclopropanecarbonyl) -3'H-spiro [azetidine-3, T-isobenzofuran] -3'-one; and
[00220] 5 '- (5- (3,5-dichloro-4-fluorophenyl) -5- (trifluoromethyl) -4,5-dihydroisoxazol-3-yl) -1- (4,4,4-trifluorobutanoyl ) -3'H-spiro [azetidine-3, T-isobenzofuran] -3'-one,
[00221] or a stereoisomer thereof or a veterinarily acceptable salt thereof.
[00222] In another aspect of the invention, they are compounds of formula (1) selected from:
[00223] 1- (5 '- (5- (3,5-dichloro-4-fluorophenyl) -5- (trifluoromethyl) -4,5-dihydroisoxazol-3-yl) -3'H-spiro [azetidine -3, T-isobenzofuran] -1-yl) -2- ((trifluoromethyl) thio) ethanone;
[00224] (5 '- (5- (3,5-dichloro-4-fluorine ni) -5- (trifluorometh I) -4,5-di-hydroisoxazol-3-yl) - 3'H-spiro [azetidine-3, T-isobenzofuran] -1-yl) (1-oxothietan-3-yl) methanone;
[00225] (5 '- (5- (3,5-dichloro-4-fluorophenyl) -5- (trifluoromethyl) -4,5-dihydroisoxazol-3-yl) -3'H-spiro [azetidine-3 , T-isobenzofuran] -1-yl) (1,1-antioxidotietan-3-yl) methanone;
[00226] 1- (5 '- (5- (3,5-dichloro-4-fluorophenyl) -5- (trifluoromethyl) -4,5-dihydroisoxazol-3-yl) -3'H-spiro [azetidine -3, T-isobenzofuran] -1-yl) -2- (methylthio) ethanone;
[00227] (R) -1- (5 '- (5- (3,5-dichloro-4-fluorophenyl) -5- (trifluoromethyl) -4,5-dihydroisoxazol-3-yl) -3'H -spiro [azetidine-3, T-isobenzofuran] -1-yl) -2- (methylthio) ethanone;
[00228] (S) -1- (5 '- (5- (3,5-dichloro-4-fluorophenyl) -5- (trifluororil) -4,5-dihydroisoxazol-3-yl) -3'H -spiro [azetidine-3, T-isobenzofuran] -1-yl) -2- (methylthio) ethanone;
[00229] 1- (5 '- (5- (3,5-dichloro-4-fluorophenyl) -5- (trifluoromethyl) -4,5-dihydroisoxazol-3-yl) -3'H-spiro [azetidine -3,1'-isobenzofuran] -1-yl) -2- (methylsulfinyl) ethanone;
[00230] (R) -1- (5 '- (5- (3,5-dichloro-4-fluorophenyl) -5- (trifluoromethyl) -4,5-dihydroisoxazol-3-yl) -3'H -spiro [azetidine-3, T-isobenzofuran] -1-yl) -2- (methylsulfinyl) ethanone;
[00231] (S) -1 - (5 '- (5- (3,5-dichloro-4-fluorine ni I) -5- (triflurori I) -4,5-dihydroisoxazole-3- il) -3'H-spiro [azetidine-3, T-isobenzofuran] -1-yl) -2- (methylsulfinyl) ethanone;
[00232] 1- (5 '- (5- (3,5-dichloro-4-fluorophenyl) -5- (trifluoromethyl) -4,5-dihydroisoxazol-3-yl) -3'H-spiro [azetidine -3,1'-isobenzofuran] -1-yl) -2- (methylsulfonyl) ethanone;
[00233] (R) -1- (5 '- (5- (3,5-dichloro-4-fluorophenyl) -5- (trifluoromethyl) -4,5-dihydroisoxazol-3-yl) -3'H -spiro [azetidine-3,1'-isobenzofuran] -1-yl) -2- (methylsulfonyl) ethanone;
[00234] (S) -1 - (S-ÍS-ÍS.S-dichloro-fluorophenylJ-δ-yltrifluoromethylH.S-dihydroisoxazol-3-yl) -3'H-spiro [azetidine-3,1 ' -isobenzofuran] -1-yl) -2- (methylsulfonyl) ethanone;
[00235] 1- (5 '- (5- (3,5-dichloro-4-fluorophenyl) -5- (trifluoromethyl) -4,5-dihydroisoxazol-3-yl) -3'H-spiro [azetidine -3, T-isobenzofuran] -1-yl) -2-methylpropan-1-one;
[00236] 1- (5 '- (5- (3,5-dichloro-4-fluorophenyl) -5- (trifluoromethyl) -4,5-dihydroisoxazol-3-yl) -3'H-spiro [azetidine -3,1'-isobenzofuran] -1-yl) -2-hydroxyethanone;
[00237] cyclobutyl (5 '- (5- (3,5-dichloro-4-fluorophenyl) -5- (trifluoromethyl) -4,5-dihydroisoxazol-3-yl) -3 H-espMazet.d.na -3,1 -benzofuranM- .Dmethanone,
[00238] (1orm K Lhydroisoxazol-3-yl) -3 H-spiro [azetidma-3, T-isobenzofuran] -1-yl) (1-hydroxycyclopropyl) methanone;
[00239] N- (2- (5, - (5- (3,5-dichloro-4-fluorophenyl) -5- (trifluoromethyl) -4,5-di-I ”” 4 ”l T's H-espin> [azelidiπs-3,1 -K * yl) ethanone;
[00240] 1- (5 '- (5- (3,5-dichloro-4-fluorophenyl) -5- (trifluoromethyl) -4
[00241] hydroisoxazol-3-yl) -3 H-spiro [azetidma-3, T-isobenzofuran] -1-yl) propan-1- ° na;
[00242] 14 5 hydroisoxazo-3-yl) -3H-spiro [azetidine-3,1-isobenzofuran] -1-yl) -2-hydroxy-2-methylpropan-1-one;
[00243] 2-cyclopropyl-1- (5 '- (5- (3,5-dichloro-4-fluorophenyl) -5- (trifluoromethyl) - 4,5-dihydroisoxazol-3-yl) -3'H -spiro [azetidine-3,1 '-isobenzofuran] -1-yl) ethanone;
[00244] 1- (5 '- (5- (3,5-dichloro-4-fluorophenyl) -5- (trifluoromethyl) -4,5-dihydroisoxazol-3-yl) -3'H-spiro [azetidine -3, T-isobenzofuran] -1-yl) -2,2-dimethylpropan-1-one;
[00245] (5'15 ^ (tπfluoπnebDccloprop.D-methanone,
[00246] 1- (5 '- (5- (3,5-dichloro-4-fluorophenyl) -5- (trifluoromethyl) -4,5-dihydroisoxazol-3-yl) -3'H-spiro [azetidine -3, T-isobenzofuran] -1-yl) -3-hydroxy-2-me.ilpropan-l.na;
[00247] 1- (5 '- (5- (3,5-dichloro-4-fluorophenyl) -5- (trifluoromethyl) -4,5-dihydroisoxazol-3-yl) -3'H-spiro [azetidine -3,1'-isobenzofuran] -1-yl) -2- (3-methyl-1H-pyrazol-1-yl) ethanone;
[00248] 1- (5 '- (5- (3,5-dichloro-4-fluorophenyl) -5- (trifluoromethyl) -4,5-dihydroisoxazol-3-yl) -3'H-spiro [azetidine -3, T-isobenzofuran] -1-yl) -3-methylbutan-1-one;
[00249] 1- (5 '- (5- (3,5-dichloro-4-fluorophenyl) -5- (trifluoromethyl) -4,5-dihydroisoxazol-3-yl) -3'H-spiro [azetidine -3,1'-isobenzofuran] -1-yl) -2- (1 H-pyrazol-1-yl) ethanone;
[00250] 1- (5 '- (5- (3,5-dichloro-4-fluorophenyl) -5- (trifluoromethyl) -4,5-dihydroisoxazol-3-yl) -3'H-spiro [azetidine -3, T-isobenzofuran] -1-yl) -3-hydroxybutan-1-one;
[00251] cyclopropyl (5 '- (5- (3,5-dichloro-4-fluorophenyl) -5- (trifluoromethyl) -4,5-dihydroisoxazol-3-yl) -3'H-spiro [azetidine- 3, T-isobenzofuran] -1-yl) methanone;
[00252] 1- (5 '- (5- (3,5-dichloro-4-fluorophenyl) -5- (trifluoromethyl) -4,5-dihydroisoxazol-3-yl) -3'H-spiro [azetidine -3, T-isobenzofuran] -1-yl) butan-1-one;
[00253] (5 (5- (3,5-dichloro-4-furor ni I) -5- (trifluorometh I) -4, 5-d i-hydroisoxazole-S-ylJ-S'H spiroazazididine-ST-isobenzofuranl-1-ylXetietan-3-yl) methanone;
[00254] (5 '- (5- (3,5-dichloro-4-furor ni I) -5- (trifluorometh I) -4,5-d i-hydroisoxazol-3-yl) - 2 ', 3'-dihydrospiro [azetidine-3,1'-inden] -1-yl) (1,1-detoxotietan-3-yl) methanone;
[00255] (RXS ^ ÍS-ÍS.S-dichloro ^ -fluorfenylJ-õ-ítriflúormetilH.õ-dihydroisoxazol-3-yl) -2 ', 3'-dihydrospiro [azetidine-3,1'-inden ] -1-yl) (1,1-detoxotietan-3-yl) methanone;
[00256] (SXS ^ ÍS-ÍS.S-dichloro ^ -fluorfenylJ-õ-ítriflúormetilH.õ-dihydroisoxazol-3-yl) -2 ', 3'-dihydrospiro [azetidine-3,1'-inden ] -1-yl) (1,1-detoxotietan-3-yl) methanone;
[00257] 2- (methylsulfonyl) -1- (5, - (5- (3,4,5-trichlorophenyl) -5- (trifluoromethyl) - 4,5-dihydroisoxazol-3-yl) -3 ' H-spiro [azetidine-3,1'-isobenzofuran-1-yl) ethanone;
[00258] 1 - (5 '- (5- (3,5-dichlorophenyl) -5- (trifluoromethyl) -4,5-dihydroisoxazol-3-yl) -3'H-spiro [azetidine-3, T -isobenzofuran] -1-yl) -2- (methylsulfonyl) ethanone;
[00259] 1 - (5 '- (5- (3-chloro-5- (trifluoromethyl) phenyl I) -5- (trifluoromethyl) -4,5-dihydroisoxazol-3-yl) - 3'H-spiro [azetidine-3, T-isobenzofuran] -1-yl) -2- (methylsulfonyl) ethanone;
[00260] 1- (5 '- (5- (3,4-dichloro-5- (triflLiormethyl) phenyl) -5- (trifliiormethyl) -4,5-dihydro-isoxazol-3-yl) -3' H-spiro [azetidine-3, T-isobenzofuran] -1-yl) -2- (methylsulfonyl) -ethanone;
[00261] 1 - (5 '- (5- (4-bromo-3,5-dichlorophenyl) -5- (triflLiormethyl) -4,5-dihydroisoxazol-3-yl) -3'H-spiro [azetidine -3, T-isobenzofuran] -1-yl) -2- (methylsulfonyl) ethanone;
[00262] 1- (5 '- (5- (3,5-bis (trifluoromethyl) phenyl) -5- (trifluoromethyl) -4,5-dihydroisoxazol-3-yl) -3'H-spiro [azetidine -3, T-isobenzofuran] -1-yl) -2- (methylsulfonyl) ethanone;
[00263] (R) -1- (5 '- (5- (3,5-bis (trifliJormetyl) phenyl) -5- (triflLiormethyl) -4,5-dihydroisoxazol-3-yl) -3'H -spiro [azetidine-3, T-isobenzofuran] -1-yl) -2- (methylsulfonyl) ethanone;
[00264] (S) -1- (5 '- (5- (3,5-bis (triflLiormethyl) phenyl) -5- (trifliJormetyl) -4,5-dihydroisoxazol-3-yl) -3'H -spiro [azetidine-3, T-isobenzofuran] -1-yl) -2- (methylsulfonyl) ethanone;
[00265] 1- (5 '- (5- (3-bromo-5-chlorophenyl) -5- (trifluoromethyl) -4,5-dihydroisoxazol-3-yl) -3'H-spiro [azetidine-3 , r-isobenzofuran] -1-yl) -2- (methylsulfonyl) ethanone;
[00266] 1- (5 '- (5- (4-chloro-3,5-bis (trifltormethyl) phenyl) -5- (triflLiormethyl) -4,5-dihydroisoxazol-3-yl) -3'H -spiro [azetidine-3,1 '-isobenzofuran] -1 -yl) - 2- (methylsulfonyl) ethanone;
[00267] 1- (5 '- (5- (3-chloro-5-fluorophenyl) -5- (trifluoromethyl) -4,5-dihydroisoxazol-3-yl) -3'H-spiro [azetidine-3 , T-isobenzofuran] -1-yl) -2- (methylsulfonyl) ethanone;
[00268] 1- (5 '- (5- (3-chloro-4-fluorophenyl) -5- (trifluoromethyl) -4,5-dihydroisoxazol-3-yl) -3'H-spiro [azetidine-3 , T-isobenzofuran] -1-yl) -2- (methylsulfonyl) ethanone;
[00269] (R) -1- (5 '- (5- (3-chloro-4-fluorophenyl) -5- (trifluoromethyl) -4,5-dihydroisoxazol-3-yl) -3'H-spiro [azetidine-3, T-isobenzofuran] -1-yl) -2- (methylsulfonyl) ethanone;
[00270] (S) -1- (5 '- (5- (3-chloro-4-fluorophenyl) -5- (trifluoromethyl) -4,5-dihydroisoxazol-3-yl) -3'H-spiro [azetidine-3, T-isobenzofuran] -1-yl) -2- (methylsulfonyl) ethanone;
[00271] 2- (methyl Isulfonyl) -1 - (5 '- (5- (t rifl uormeti I) -5- (3- (t rifl uormeti I) fe ni I) -4,5-dihydroisoxazole- 3-yl) -3'H-spiro [azetidine-3,1'-isobenzofuran] -1-yl) ethanone;
[00272] (R) -2- (methylsulfonyl) -1 - (5 '- (5- (trifluoromethyl I) -5- (3- (trifluoromethyl) phenyl) -4,5-dihydroisoxazol-3-yl ) -3'H-spiro [azetidine-3, T-isobenzofuran] -1-yl) ethanone; and
[00273] (S) -2- (methyl Isulfonyl) -1 - (5 '- (5- (trifluoromethyl) -5- (3- (trifluoromethyl) phenyl) -4,5-dihydroisoxazol-3-yl ) -3'H-spiro [azetidine-3, T-isobenzofuran] -1 -yl) ethanone,
[00274] or a stereoisomer thereof or a veterinarily acceptable salt thereof.
[00275] In another aspect of the invention, they are compounds of formula (1) selected from:
[00276] 5 '- (5- (3,5-bis (trifluoromethyl) phenyl) -5- (trifluoromethyl) -4,5-dihydroisoxazol-3-yl) -1- (2- (methylsulfonyl) acetyl) spiro [azetidine-3, T-isoindolin] -3'-one;
[00277] 5 '- (5- (3,5-dichloro-4-fluorophenyl) -5- (trifluoromethyl) -4,5-dihydroisoxazol-3-yl) -1- (2- (methylsulfonyl) acetyl) spiro [azetidine-3, T-isoindolin] -3'-one;
[00278] 1- (5 '- (5- (3,5-dichloro-4-fluorophenyl) -5- (trifluoromethyl) -4,5-di - ’” 27βl 3- ~
[00279] 5- (5- (3,4-dichloro-5- (trifluoromethyl) phenyl) -5- (trifluoromethyl) -4,5-dihydroisoxazol-3-yl) -1- (2- (methylsulfonyl) acetyl) spiro [azetidine-3, T-isoindolin] -3'-one;
[00280] ^ «- 5- (tπfluormethyl) -4,5-dihydroisoxazol-3-yl) spiro [azetidine-3,1-isoindolin] - 3" ° na ’
[00281] 5 'r- {tπfl “I) fen:’ (t “Lhydroisoxazol-3-yl) -1- (2- (methylsulfonyl) acetyl) spiro [azetidma-3, T-isoindolin ^' - one;
[00282] 5- (5- (4-bromo-3,5-dichlorophenyl) -5- (trifluoromethyl) -4,5-di-10 ”2" yl) -1- (2- (methylsulfonyl) acetyl) spiro [azetidine-3, T-isomdohn] -3-one;
[00283] 5- (5- (3-chloro-5- (trifluoromethyl) phenyl) -5- (trifluoromethyl) -4,5-dihydroisoxazol-3-yl) -1- (cyclopropanecarbonyl) spiro [azetidine-3 , T-isoindolinJ-S'-one;
[00284] 5 '- (5- (3,5-dichloro-4-fluorophenyl) -5- (trifluoromethyl) -4,5-dihydroisoxazol-3-yl) -1- (tiethane-3-carbonyl) spiro [azetidine-3, T-isoindolin] - 3'-one;
[00285] 5 '- (5- (3,5-dichloro-4-fluorophenyl) -5- (trifluoromethyl) -4,5-dihydroisoxazol-3-yl) -1- (1,1-detoxotiethane-3 -carbonyl) spiro [azetidine-3, T-isoindolin] -3'-one; 'so'ndol'nl-3-one,
[00286] 5 '- (5- (3,5-dichloro-4-fluorophenyl) -5- (trifluoromethyl) -4,
[00287] 5- (5- (3-chloro-5- (trifluoromethyl) phenyl) -5- (trifluoromethyl) -4,5-dihydroisoxazol-3-yl) -1- (cyclopropanecarbonyl) spiro [azetidine-3 , T-isoindolinJ-S'-one;
[00288] 5- (5- (4-bromo-3,5-dichlorophenyl) -5- (tπfluormethyl) -4,5-dihydroisoxazol-3-yl) -1- (cyclopropanecarbonyl) spiro [azetidine-3, T-isoindolin] -3'-one;
[00289] 2, -methyl-1- (2- (methylsulfonyl) acetyl) -5 '- (5- (3,4,5-trichlorophenyl) -5- (trifluoromethyl) -4,5-dihydroisoxazole-3 -yl) spiro [azetidine-3, T-isoindolin] - 3'-one;
[00290] 5 '- (5- (3,5-dichloro-4-fluorophenyl) -5- (trifluoromethyl) -4,5-dihydroisoxazol-3-yl) -2'-methyl-1- (2- (methylsulfonyl) acetyl) spiro [azetidine-3, T-isoindolin] -3'-one; and
[00291] 1 - (cyclopropanocarbonyl) -2'-methyl-5 '- (5- (3,4,5-trichlorophenyl) -5- (trifluoromethyl) -4,5-dihydroisoxazol-3-yl) spiro [ azetidine-3, r-isoindolin] - 3'-one,
[00292] or a stereoisomer thereof or a veterinarily acceptable salt thereof.
[00293] In another aspect of the invention, it is the compound of formula (1):
[00294] 1- (5 '- (5- (3,5-dichloro-4-fluorophenyl) -5- (trifluoromethyl) -4,5-dihydroisoxazol-3-yl) -3'H-spiro [azetidine -3,1'-isobenzofuran] -1-yl) -2- (methylthio) ethanone;
[00295] (R) -1- (5 '- (5- (3,5-dichloro-4-fluorophenyl) -5- (trifluoromethyl) -4,5-dihydroisoxazol-3-yl) -3'H -spiro [azetidine-3, T-isobenzofuran] -1-yl) -2- (methylthio) ethanone;
[00296] (S) -1- (5 '- (5- (3,5-dichloro-4-fluorophenyl) -5- (trifluoromethyl) -4,5-dihydroisoxazol-3-yl) -3'H -spiro [azetidine-3,1'-isobenzofuran] -1-yl) -2- (methylthio) ethanone;
[00297] 1- (5 '- (5- (3,5-dichloro-4-fluorophenyl) -5- (trifluoromethyl) -4,5-dihydroisoxazol-3-yl) -3'H-spiro [azetidine -3, T-isobenzofuran] -1-yl) -2- (methylsulfinyl) ethanone;
[00298] (R) -1- (5 '- (5- (3,5-dichloro-4-fluorophenyl) -5- (trifluoromethyl) -4,5-dihydroisoxazol-3-yl) -3'H -spiro [azetidine-3, T-isobenzofuran] -1-yl) -2- (methylsulfinyl) ethanone;
[00299] (S) -1- (5 '- (5- (3,5-dichloro-4-fluorophenyl) -5- (trifluoromethyl) -4,5-dihydroisoxazol-3-yl) -3'H -spiro [azetidine-3, T-isobenzofuran] -1-yl) -2- (methylsulfinyl) ethanone;
[00300] 1- (5 '- (5- (3,5-dichloro-4-fluorophenyl) -5- (trifluoromethyl) -4,5-dihydroisoxazol-3-yl) -3'H-spiro [azetidine -3, T-isobenzofuran] -1-yl) -2- (methylsulfonyl) ethanone;
[00301] (R) -1 - (5 '- (5- (3,5-dichloro-4-fluorine ni I) -5- (trifluorometh I) -4,5-dihydroisoxazole-3 -yl) -3'H-spiro [azetidine-3, T-isobenzofuran] -1-yl) -2- (methylsulfonyl) ethanone;
[00302] (S) -1- (5 '- (5- (3,5-dichloro-4-fluorophenyl) -5- (trifluoromethyl) -4,5-dihydroisoxazol-3-yl) -3'H -spiro [azetidine-3, T-isobenzofuran] -1-yl) -2- (methylsulfonyl) ethanone;
[00303] (5 '- (5- (3,5-dichloro-4-fluorophenyl) -5- (trifluoromethyl) -4,5-dihydroisoxazol-3-yl) -2', 3'-dihydrospiro [azetidine-3, T-inden] -1-yl) (1,1-detoxotietan-3-yl) methanone;
[00304] (R) - (5 '- (5- (3,5-dichloro-4-fluorophenyl) -5- (trifluoromethyl) -4,5-dihydroisoxazol-3-yl) -2', 3 ' dihydrospiro [azetidine-3, r-inden] -1-yl) (1,1-detoxotietan-3-yl) methanone;
[00305] (S) - (5 '- (5- (3,5-dichloro-4-fluorophenyl) -5- (trifluoromethyl) -4,5-dihydroisoxazol-3-yl) -2', 3 ' dihydrospiro [azetidine-3, T-inden] -1-yl) (1,1-detoxotietan-3-yl) methanone;
[00306] 1- (5 '- (5- (3,5-bis (trifluoromethyl) phenyl) -5- (trifluoromethyl) -4,5-dihydroisoxazol-3-yl) -3'H-spiro [azetidine -3, T-isobenzofuran] -1-yl) -2- (methylsulfonyl) ethanone;
[00307] (R) -1- (5 '- (5- (3,5-bis (trifluoromethyl) phenyl) -5- (trifluoromethyl) -4,5-dihydroisoxazol-3-yl) -3'H -spiro [azetidine-3, T-isobenzofuran] -1-yl) -2- (methylsulfonyl) ethanone;
[00308] (S) -1- (5 '- (5- (3,5-bis (trifluoromethyl) phenyl) -5- (trifluoromethyl) -4,5-dihydroisoxazol-3-yl) -3'H -spiro [azetidine-3, T-isobenzofuran] -1-yl) -2- (methylsulfonyl) ethanone;
[00309] 1- (5 '- (5- (3-chloro-4-fluorophenyl) -5- (trifluoromethyl) -4,5-dihydroisoxazol-3-yl) -3'H-spiro [azetidine-3 , T-isobenzofuran] -1-yl) -2- (methylsulfonyl) ethanone;
[00310] (R) -1 - (5 '- (5- (3-chloro-4-fluorophenyl) -5- (trifluoromethyl) -4,5-dihydroisoxazol-3-yl) -3'H-spiro [azetidine-3, T-isobenzofuran] -1-yl) -2- (methylsulfonyl) ethanone;
[00311] (S) -1 - (5 '- (5- (3-chloro-4-fluorophenyl I) -5- (trifluoromethyl I) -4,5-d i-hydroisoxazol-3-yl) - 3'H-spiro [azetidine-3, T-isobenzofuran] -1-yl) -2- (methylsulfonyl) ethanone;
[00312] 2- (methyl Isulfoni I) -1 - (5 '- (5- (trifluoromethyl) -5- (3- (trifluoromethyl) phenyl) - 4,5-dihydroisoxazol-3-yl) -3' H-spiro [azetidine-3,1'-isobenzofuran] -1-yl) ethanone;
[00313] (R) -2- (methylsulfonyl) -1 - (5 '- (5- (trifluoromethyl I) -5- (3- (trifluoromethyl) phenyl) -4,5-dihydroisoxazol-3-yl ) -3'H-spiro [azetidine-3,1'-isobenzofuran] -1-yl) ethanone; and
[00314] (S) -2- (methyl Isulfonyl) -1 - (5 '- (5- (trifluoromethyl)) -5- (3- (trifluoromethyl) phenyl) -4,5-dihydroisoxazole- 3-yl) -3'H-spiro [azetidine-3, T-isobenzofuran] -1-yl) ethanone or a stereoisomer thereof or a veterinarily acceptable salt thereof.
[00315] In another aspect of the invention, it is a process for preparing the chiral spiroisoxazolines of formula (63) of scheme 16,
on what
[00316] R1a, R1b and R1c are each independently hydrogen, halo, hydroxyl, cyano, nitro, Ci-Cealkyl, Ci-Cβhaloalkyl, Ci-Cealoxy, C0-C3 alkylC3-C6 cycloalkyl, Ci-Cehaloalkoxy, -C (O) NH2, -SF5 or -S (O) PR;
[00317] R2 is halo, cyano, C1-Cealkyl, C1-C6haloalkyl, nitro, hydroxyl, -C (O) NRaRb, C2-Cealkenyl, C2-C6alkynyl, -S (O) PR or -OR;
[00318] R5 is hydrogen, C1-C6alkyl, C2-C6alkenyl, Co-C6alkylC3-C6 cycloalkyl, Co-C6alkylphenyl, Co-Cealkylheteroaryl or Co-C6alkylheterocycle;
[00319] R7is hydrogen, Ci-C6alkyl, hydroxyl, cyano, nitro, -S (O) PRC or Ci-Cβal∞xi;
[00320] R is Ci-C6alkyl or Cs-Cβcycloalkyl optionally substituted with at least one halo substituent;
[00321] Ra is hydrogen, C1-C6alkyl or Co-C3alkylC3-Cβcycloalkyl; wherein the alkyl and the alkylcycloalkyl are optionally substituted by cyano or at least one halo substituent;
[00322] Rb is hydrogen, C1-Cβalkyl, C3-Cecycloalkyl, Co-C3alkylphenyl, Co-C3alkylheteroaryl or C0-C3alkylheterocycle, each optionally substituted, where chemically possible, with at least one hydroxyl substituent selected, cyan, halo or - S (O) PR;
[00323] Rc is C1-C6alkyl, C1-C6haloalkyl, C1-C6haloalkylC3-Ce cycloalkyl, Co-C3alkylC3-Cβcycloalkyl, Co-C3alkylphenyl, Co-C3alkyl-heteroaryl or a co-C3alkyl substituted with an optional substituted less-heterologous heterocycle cyano, halo, hydroxyl, oxo, Ci-Cealcoxy, Ci-Cβ haloalkoxy, Ci-Cβhaloalkyl, -S (O) PR, -SH, -S (O) PNRaRb, -NRaRb, -NRaC (O) Rb, - SC (O) R, -SCN or -C (O) NRaRb;
[00324] wherein R5, Ci-Cβalkyl or Co-CealkylC3-Cβcycloalkyl moiety can be optionally and independently substituted by at least one substituent selected from cyano, halo, hydroxyl, oxo, Ci-Cealcoxy, Ci-Cβ haloalkoxy, hydroxyCi-Cealkyl -, C1-C6 haloalkyl, -S (O) PRC, -SH, -S (O) PNRaRb, -NRaRb, -NRaC (O) Rb, -SC (O) R, -SCN or -C (O) NRaRb; and
[00325] wherein R5, Co-Cβalkylphenyl, Co-Cβalkylheteroaryl or Co-Cealkylheterocycle moiety may also be optionally substituted with at least one substituent selected from cyan, halo, oxo, = S, = NR7, hydroxyl, Ci -Cealcoxy, Ci-Cβalkyl, hydroxyCi-Cβalkyl-, Ci- Cβhaloalkyl, -SH, -S (O) pR and Ci-Cehaloalkoxy;
[00326] n is the integer 0, 1 or 2, and when n is 2, each R2 can be identical or different from each other;
[00327] p is the integer 0, 1 or 2; and
[00328] depicts a chiral center, stereoisomers thereof and veterinarily acceptable salts thereof, said processes comprising, optionally in a solvent,
[00329] metallize an iodobromobenzyl derivative of formula 57 with a Grignard reagent or halogen-metal exchange with an alkillium and react with a protected azetidinone in a pot process or in a step-by-step process to provide a compound of formula 58, wherein Y2 is bromine, chlorine, iodine, hydroxyl or a sulfonate leaving group;

[00330] palladium-catalyzed condensation of a compound of formula 58 with a vinyl ether to provide a compound of formula 59, wherein R8 is a Ci-Cealkyl;

[00331] condensing a compound of formula 59 with a substituted trifluoroacetophenone of formula 56 to provide a compound of formula 60;

[00332] adding hydroxylamine to a compound of formula 60 and cyclization in the presence of a chiral catalyst based on quinin to provide a compound of formula 61;

[00333] removing the azetidine protecting group from the compound of formula 61 to provide a compound of formula 62; and

[00334] coupling the compound of formula 62 with an acid or acid chloride under standard amide formation conditions to provide a compound of formula 63.

[00335] In another aspect of the invention, it is a process for preparing the chiral spiroisoxazolines of formula (63) of scheme 16, wherein R1a, R1b and R1c are each independently hydrogen, halo or Ci-Cehaloalkyl; R5 is Ci-Cealkyl, Co-CβalkylCa-Cecycloalkyl, Co-Cealkyl-heteroaryl or Co-Cθ alkyl-heterocycle; wherein R5, C-Cealkyl or Co-CealkylCa-Ce cycloalkyl moiety can optionally and independently be substituted by at least one substituent selected from halo, hydroxyl, hydroxyCi-Cealkyl-, Ci-Cehaloalkyl or -S (O) PRC; and wherein R5, the Co-Cealkyl-heteroaryl or Co-Cealkyl-heterocycle moiety may also be optionally substituted with at least one substituent selected from oxo, hydroxyl, hydroxyCi-Cealkyl-, Ci-Cealkyl or Ci-Cθhaloalkyl; Rc is Ci-Cealquila; n is the integer 0; and
[00336] p is the integer 0, 1 or 2; stereoisomers thereof and veterinarily acceptable salts thereof.
[00337] In another aspect of the invention, it is a process for preparing the chiral spiroisoxazolines of formula (63) of scheme 16, wherein R1a, R1b and R1c are each independently hydrogen, chlorine, fluorine, bromine or trifluoromethyl;
[00338] R5 is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, cyclopropyl or cyclobutyl, where each substituent can be optionally and independently substituted by at least one substituent selected from halo, hydroxyl, Ci-Cehaloalkyl or -S (O) pRc; or R5 is tietanyl, pyrazolyl or -CHspirazolyl, wherein each substituent can also be optionally substituted with at least one substituent selected from oxo or C1-Cealkyl; and Rc is methyl or ethyl; stereoisomers thereof and veterinarily acceptable salts thereof.
[00339] In another aspect of the invention, it is a process for preparing the chiral spiroisoxazolines of formula (63) of scheme 16, optionally comprising in a solvent, in which the iodobromobenzyl derivative is 4-bromo-2- (chloromethyl) -1 -iodobenzene and the protected azetidinone is 3-oxo-oazetidine-1-carboxylic acid tert-butyl ester or 1-benzhydrylazetidin-3-one.
[00340] In another aspect of the invention, it is a process for preparing the chiral spiroisoxazolines of formula (63) of scheme 16, wherein R1a and R1c are each chlorine, R1b is fluorine and R5 is -CH2S (O) 2CH3; stereoisomers thereof and veterinarily acceptable salts thereof.
[00341] In another aspect of the invention, compounds selected from the group consisting of:
[00342] tert-butyl δ'-bromo-S'H-spiroazazididine-S.T-isobenzofuranl-1-carboxylate;
[00343] 1-benzhydryl-5, -bromo-3, H-spiro [azetidine-3, T-isobenzofuran];
[00344] 5'-acetyl-3'H-spiro [azetidine-3, T-isobenzofuran] -1- tert-butyl carboxylate;
[00345] 1-yl-benzhydryl-S'H-spiroazazididine-SJ'-isobenzofuranl-S'-yl) ethanone;
[00346] 5 '- (3- (3,5-dichloro-4-fluorophenyl) -4,4,4-trifluoro-2-enoyl) -3'H-spiro [azetidine-3, T-isobenzofuran] -1 tert-butyl carboxylate;
[00347] 5 '- (5- (3,5-dichloro-4-fluorophenyl) -5- (trifluoromethyl) -4,5-dihydroisoxazol-3-yl) -3'H-spiro [azetidine-3, (R) -tert-butyl T-isobenzofuran] -1- carboxylate;
[00348] 5 '- (5- (3,5-dichloro-4-fluorophenyl) -5- (trifluoromethyl) -4,5-dihydroisoxazol-3-yl) -3'H-spiro [azetidine-3, (S) -tert-butyl T-isobenzofuran] -1- carboxylate;
[00349] (E / Z) -1 - (1-benzhydryl-3'H-spiro [azetidine-3,1 '-isobenzofuran] -5'-yl) -3- (3,5-dichloro-4-fluorophenyl ) -4,4,4-trifliJorbut-2-en-1-one;
[00350] 5 '- (5- (3,5-dichloro-4-fluorophenyl) -5- (trifluoromethyl) -4,5-dihydroisoxazol-3-yl) -3'H-spiro [azetidine-3, Tert-butyl T-isobenzofuran] -1-carboxylate;
[00351] (R) -5 '- (5- (3,5-dichloro-4-fluorophenyl) - 5- (trifluoromethyl) -4,5-dihydroisoxazol-3-yl para-toluene sulfonate -3 'H-spiro [azetidine-3,1'-isobenzofuran];
[00352] (S) -5 '- (5- (3,5-dichloro-4-fluorophenyl) - 5- (trifluoromethyl) -4,5-dihydroisoxazol-3-yl para-toluene sulfonate -3 'H-spiro [azetidine-3, T-isobenzofuran];
[00353] 1-benzhydryl-5 '- (5- (3,5-dichloro-4-fluorophenyl) -5- (trifluoromethyl) -4,5-dihydroisoxazol-3-yl) -3'H-spiro [ azetidine-3, r-isobenzofuran];
[00354] (R) -1-benzhydryl-5 '- (5- (3,5-dichloro-4-fluorophenyl) -5- (trifluoromethyl) - 4,5-dihydroisoxazol-3-yl) -3' H-spiro [azetidine-3,1'-isobenzofuran];
[00355] (S) -1-benzhydryl-5 '- (5- (3,5-dichloro-4-fluorophenyl) -5- (trifluoromethyl) - 4,5-dihydroisoxazol-3-yl) -3' H-spiro [azetidine-3,1'-isobenzofuran]; and
[00356] 5 '- (5- (3,5-dichloro-4-fluorophenyl) -5- (trifluoromethyl) -4,5-dihydroisoxazol-3-yl) -3'H-spiro [azetidine-3, T-isobenzofuran] or a stereoisomer thereof or a veterinarily acceptable salt thereof.
[00357] In another aspect of the invention, it is a veterinary composition comprising a) compounds of formula (V.1), formula (V.2), formula (V.1.1) and formula (1), stereoisomers thereof or a salt veterinarily acceptable and (b) a veterinarily acceptable excipient, diluent or vehicle. Preferably, the composition comprises a therapeutically effective amount of the compounds of the formula (V.1), formula (V.2), formula (V.1.1) and formula (1), stereoisomer thereof or veterinarily acceptable salt thereof and an excipient , diluent or veterinarily acceptable vehicle.
[00358] The composition can comprise at least one additional veterinary agent. Preferred additional veterinary agents include endoparasiticides, endectocides, ectoparasiticides, insecticides and anthelmintics, and are described here.
[00359] The composition may comprise at least one additional veterinary agent. Preferred additional veterinary agents include endoparasiticides, endectocides, ectoparasiticides, insecticides and anthelmintics, and are described here. In one aspect of the invention, the additional veterinary agent is selected from amitraz, amino acetonitriles, anthelmintics (e.g., albendazole, cambendazole, fenbendazole, flubendazole, mebendazole, octadepsipeptides, oxfendazole, oxybendazole, paraherquamide, parbendazole, tiperazole, piperazole, piperazole, piperazole, piperazole, piperazole, piperazole, piperazole, piperazole, piperazole, piperazole. , triclabendazole, levamisole, pyrantel pamoate, oxantel, morantel and the like), avermectins (for example, abamectin, doramectin, emamectin, eprinomectin, ivermectin, moxidectin, selamectin and the like), milbemycin, milimethamine, diethylamine, demidazamine, demidazamine, demidazamine, demidazine hydroprene, kinoprene, methoprene, metaflumizone, niclosamide, permethrin, pyrethrins, pyriproxyphene and spinosad. In another aspect of the invention, the additional agent is selected from an amino acetonitrile, albendazole, cambendazole, fenbendazole, flubendazole, mebendazole, oxfendazole, oxybendazole, paraherquamide, parbendazole, praziquantel, tiabendazole, tetramisole, triclabendazole, triclabendazole, triclabendazole, triclabendazole, triclabendazole, triclabendazole, triclabendazole. oxantel, morantel, abamectin, doramectin, emamectin, eprinomectin, ivermectin, moxidectin, selamectin, milbemycin, milbemycin oxime, demiditraz, diethylcarbamazine, fipronil, hydroprene, kinoprene, metopreno, spinoidine, pyridine, pyridine, pyridine, pyridine, pyridine, pyridine, pyridine, pyridine, pyridine. In yet another aspect of the invention, the additional agent is selected from an amino acetonitrile, paraherquamide, praziquantel, abamectin, doramectin, emamectin, eprinomectin, ivermectin, moxidectin, selamectin, milbemycin and milbemycin oxime. In yet another aspect of the invention, the additional agent is selected from abamectin, doramectin, emamectin, eprinomectin, ivermectin, moxidectin, selamectin, milbemycin and milbemycin oxime. In yet another aspect of the invention, the additional agent is selected from abamectin, doramectin, eprinomectin, ivermectin, moxidectin, selamectin, milbemycin and milbemycin oxime. In yet another aspect of the invention, the additional agent is selected from moxidectin, selamectin and milbemycin oxime. In yet another aspect of the invention, the additional agent is selected from moxidectin and milbemycin oxime.
[00360] In yet another aspect of the invention is the use of a compound of formula (V.1), formula (V.2), formula (V.1.1) and formula (1) for the manufacture of a medicament.
[00361] In yet another aspect of the invention is a method for treating an infection or parasitic infestation in an animal which includes the step of administering to said animal, in need of such treatment, the therapeutically effective amount of a compound of the present invention, stereoisomer of the same or veterinarily acceptable salt thereof. In one aspect, the animal is a mammal, specifically a companion animal (for example, dog, cat or horse) or farm animals (for example, sheep, goat, cattle and pig). In another aspect, the animal is a bird, specifically, an edible bird (for example, chicken, turkey, duck and goose). In another aspect, the animal is a fish. The compounds of the present invention and the compositions thereof can be administered to the animal orally or topically. The compounds of the present invention and compositions thereof, can also be administered to the animal by intramuscular, intraperitoneal or subcutaneous injection. Preferably, the compounds of the present invention and the compositions thereof can be administered to the animal orally or topically.
[00362] In yet another aspect of the invention is a method for treating an infection or parasitic infestation in an animal which includes the step of administering to said animal, in need of such treatment, the therapeutically effective amount of a compound of the present invention, stereoisomer or veterinarily acceptable salt thereof, in combination with at least one additional veterinary agent. In one aspect, the animal is a mammal, specifically a companion animal (for example, dog, cat or horse) or farm animals (for example, sheep, goat, cattle and pig). In another aspect, the animal is a bird, specifically, an edible bird (for example, chicken, turkey, duck and goose). In another aspect, the animal is a fish. The compounds of the present invention and the compositions thereof can be administered to the animal orally or topically. The compounds of the present invention and their compositions can also be administered to the animal by intramuscular, intraperitoneal or subcutaneous injection. Preferably, the compounds of the present invention and their compositions can be administered to the animal orally or topically. Also preferred, the compounds of the present invention can be administered by injection.
[00363] The compounds of the present invention alone or in combination with an additional veterinary agent can be administered as (a) a single veterinary composition comprising a compound of the present invention, stereoisomer thereof, veterinarily acceptable salt thereof and optionally at least an additional veterinary agent as described herein and a veterinarily acceptable excipient, diluent or vehicle; or (b) two separate veterinary compositions comprising (i) a first composition comprising a compound of the present invention, stereoisomer thereof, veterinarily acceptable salt thereof and a veterinarily acceptable excipient, diluent or vehicle and (ii) a second composition comprising at least an additional veterinary agent, as described herein, and a veterinarily acceptable excipient, diluent, or vehicle. Veterinary compositions can be administered simultaneously or sequentially and in any order.
[00364] All WO patent publications mentioned here are incorporated by reference. DEFINITIONS
[00365] For the purposes of the present invention, as described and claimed here, the following terms and phrases are defined as follows:
[00366] "Additional veterinary agent (s)" as used herein, unless otherwise indicated, refers to other veterinary or pharmaceutical compounds or products that provide a therapeutically effective amount of said agents that are useful for treating a parasitic infection in an animal, as described herein.
[00367] "Aloxy", as used herein, unless otherwise indicated, refers to a portion of oxygen having another alkyl substituent. The alkyl portion (i.e., alkyl portion) of an alkoxy group has the same definition as below. Non-limiting examples include:
[00368] -OCH3, -OCH2CH3 and the like.
[00369] "Alkyl", as used herein, unless otherwise indicated, refers to saturated monovalent hydrocarbon alkane radicals of the general formula CnH2n + i- The alkane radical may be linear or branched and may be unsubstituted or substituted . For example, the term "(Ci-Cejalquila") refers to a linear or branched, monovalent aliphatic group containing 1 to 6 carbon atoms. Non-exclusive examples of (Ci-Ce) alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, sec-butyl, t-butyl, n-propyl, n-butyl, i-butyl, s-butyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, neopentyl, 3, 3-dimethylpropyl, 2-methylpentyl, hexyl and the like. The alkyl moiety can be attached to the chemical moiety by any of the carbon atoms in the aliphatic chain. Alkyl groups are optionally substituted as described herein. , said alkyl moiety has the same meaning as defined herein and can be linked to the chemical moiety by any of the carbon atoms in the aliphatic chain Non-limiting examples of the word compound, alkylphenyl, include: Ci alkylphenyl is -CH2phenyl, C2alkylphenyl is - CH2CH2phenyl, Cophenyl and phenyl es immilar.
[00370] "Alkenyl" as used herein, unless otherwise indicated, refers to a straight or branched aliphatic hydrocarbon chain having 2 to 6 carbon atoms and containing at least one carbon-carbon double bond (for example -C = C- or -C = CH2). Non-exclusive examples of alkenyl include: ethylene, 1-propenyl, 2-propenyl, isopropenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-pentenyl and similar.
[00371] "Alquinyl" as used herein, unless otherwise indicated, refers to a straight or branched aliphatic hydrocarbon chain having 2 to 6 carbon atoms and containing at least one carbon-carbon triple bond (e.g. -C = C- or -C = CH). Non-exclusive examples of alkynyl include: ethynyl, 2-propynyl, 1-methyl-2-propynyl, 2-butynyl, 3-butynyl, 2-methyl-3-butynyl and the like.
[00372] "Animal (s)", as used herein, unless otherwise indicated, refers to an individual animal that is a mammal, bird or fish. Specifically, a mammal refers to a vertebrate animal that is human and non-human, which are members of the taxonomic class Mammals. Non-exclusive examples of non-human mammals include pets and farm animals. Non-exclusive examples of a pet include: dog, cat, llama and horse. Favorite pets are dog, cat and horse. Most preferred is the dog. Non-exclusive examples of farm animals include: pig, camel, rabbits, goat, sheep, deer, elk, bovine (cattle) and bison. Preferred farm animals are vacuum and swine. Specifically, a bird refers to a vertebrate animal of the taxonomic class Birds. Birds are feathered, winged, bipedal, endothermic and lay eggs. Non-exclusive examples of birds include, poultry (for example, chicken, turkey, duck and goose), all of which are also referred to here as a domestic bird. Specifically, fish refers to the taxonomic class Chondríchthyes (cartilaginous fish, for example, sharks and rays) and Osteichthyes (fish that have spines) that live in water, have gills or mucus-covered skin for breathing, flippers and may have scales. Non-exclusive examples of fish include shark, salmon, trout, hake, catfish, tilapia, whiting, tuna, giant sole, brill, flounder, sole (sole), striped bass, eel, eye, grouper and the like.
[00373] "Carbocyclic", as used herein, unless otherwise indicated, refers to a 5- to 7-membered partially saturated or saturated ring containing only carbon atoms and may be monocyclic or part of a fused ring or portion of spiro ring. Examples of carbocyclic rings include cyclopentane, cyclohexane and cycloheptane. The carbocyclic ring is optionally substituted as described herein.
[00374] "Chiral", as used here, unless otherwise indicated, refers to the structural characteristic of a molecule that makes it impossible to superimpose it on its mirror image, (for example, "R" and "S enantiomers "). The term is also represented as an asterisk (i.e., *) in the examples and preparations and refers to a chiral center that includes both the S and R enantiomers.
[00375] "Compounds of the present invention", as used herein, unless otherwise indicated, refer to compounds of formula (V.1), formula (V.2), formula (V.1.1) and formula ( 1) and stereoisomers thereof.
[00376] "Cycloalkyl", as used herein, unless otherwise indicated, includes fully saturated or partially saturated carbocyclic alkyl moieties. Non-limiting examples of partially saturated cycloalkyls include: cyclopropene, cyclobutene, cycloheptene, cyclooctene, cyclohepta-1,3-diene and the like. Preferred cycloalkyls are 3- to 6-membered saturated monocyclic rings including cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. The cycloalkyl group can be attached to the chemical moiety by any of the carbon atoms in the carbocyclic ring. Cycloalkyl groups are optionally substituted with at least one substituent. Even when used in compound words such as alkylcycloalkyl, said alkyl and cycloalkyl moieties have the same meaning as defined herein and can be attached to the chemical moiety by any of the carbon atoms in the aliphatic chain. Examples of co-CealquilCs-Cecicloalquila include, methylcyclopropane (CialquilCacicloalquila or -CH2CÍclopropano) etilciclopropano (C2alquilC3CÍcloalquila or -CH2CH2CÍclopropano), methylcyclobutane (CialquilCzicicloalquila or -CH2Ciclobutano) etilciclobutano (C2alquilC4Cicloalquila or -CH2CH2Ciclobutano), methylcyclohexane (CialquilCecicloalquila-hexane or -CH2CÍclo ) and the like. CoalkylCs- Cθcycloalkyl is Cs-Cθcycloalkyl. The cycloalkyl moieties are optionally substituted as described herein.
[00377] "Halogen" or "halo", as used herein, unless otherwise indicated, refers to fluorine, chlorine, bromine and iodine. In addition, when used in compound words such as "haloalkyl", "haloalkoxy", "haloalkenyl" or "haloalkynyl", said alkyl, alkoxy, alkenyl and alkynyl can be partially or fully replaced with halogen atoms, which can be the same or different and said alkyl, alkoxy, alkenyl and alkynyl moieties have the same meaning as above and can be linked to the chemical moiety by any of the carbon atoms in the aliphatic chain. Examples of "haloalkyl" include F3C-, CICH2-, CF3CH2- and CF3CCI2- and the like. The term "haloalkoxy" is defined analogously to the term "haloalkyl". Examples of "haloalkoxy" include CF3O-, CCI3CH2O-, HCF2CH2CH2O- and CF3CH2O- and the like. The term "haloalkenyl is defined analogously to the term" haloalkyl "except that the aliphatic chain contains at least one carbon-carbon double bond. Examples of" haloalkenyl "include CF3C = C-, CCl3C = C-, HCF2C = C- and CF3C = CC- and the like. The term "haloalkynyl" is defined analogously to the term "haloalkyl," except that the aliphatic chain contains at least one carbon-carbon triple bond. Examples of "haloalkynyl" include CF3CEC-, CCI3CEC-, HCF2CEC- and CF3CECC - similar.
[00378] "Heteroaryl" or "Het", as used herein, unless otherwise indicated, refers to a 5- to 6-membered aromatic monocyclic ring or an 8 to 10-membered aromatic ring where said portion of monocyclic and fused ring contains one or more heteroatoms, each independently selected from N, O or S, preferably one to four heteroatoms. Non-exclusive examples of monocyclic heteroaryls include pyrrolyl, furanyl, thiophenyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, thiazolyl, isoxazolyl, oxazolyl, oxadiazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrimidinyl, pyrimidinyl, pyrimidinyl, pyrimidinyl, pyrimidinyl, pyrimidinyl, pyrimidinyl, pyrimidine and pyrimidine Non-exclusive examples of fused heteroaryls include: benzofuranyl, benzothiophenyl, indolyl, benzimidazolyl, indazolyl, benzotriazolyl, thieno [2,3-c] pyridine, thieno [3,2-b] pyridine, benzo [1,2,5] thiadiazole and similar. The heteroaryl group can be attached to the chemical moiety by any of the carbon atoms or nitrogen hetero atoms in the monocyclic or fused ring. Also when used in a compound word such as alkyl heteroaryl, said alkyl and heteroaryl portion has the same meaning as defined herein and can be linked to the chemical portion by any of the carbon atoms in the aliphatic chain. For example, Coalkylheteroaryl is heteroaryl, Cyalkylheteroaryl is -CH2heteroaryl, C2alkylheteroaryl is -CH2CH2heteroaryl and the like. Heteroarils are optionally substituted as described herein.
[00379] "Heterocycle", as used herein, unless otherwise indicated, refers to a 3 to 7 membered partially saturated or saturated monocyclic ring containing one or more heteroatoms, each independently selected from N, O or S, preferably from one to four heteroatoms. The heterocyclic ring can be part of a fused ring or spiro ring portion. Non-exclusive examples of heterocycle include oxirane, thiaran, aziridine, oxetane, azetidine, tiatan, tetrahydrofuran, tetrahydrothiophene, pyrrolidine, tetrahydropyran, piperidine, piperazine, tetrahydropyridine, 2H-azirine, 2,3-dihydro-azet, 3,4-dihydro-azet dihydro-2H-pyrrole and the like. The heterocycle group can be attached to the chemical moiety by any of the carbon atoms or nitrogen hetero atoms in the ring. Also when used in compound words such as alkylheterocycle, said alkyl and heterocycle moieties have the same meaning defined herein and can be linked to the chemical moiety by any of the carbon atoms in the aliphatic chain. For example, Coalkylheterocycle is heterocycle, Cyalkylheterocycle is -CH2heterocycle, C2alkylheterocycle is -CH2CH2heterocycle and the like. Heterocycles are optionally substituted as described herein.
[00380] "Optionally substituted", is used here alternately with the phrase substituted or unsubstituted. Unless otherwise indicated, an optionally substituted group may have a substituent at each replaceable position in the group and each substitution is independent of the other. An optionally substituted group may also have no substituent. Therefore the phrase "optionally substituted with at least one substituent" means that the number of substituents can vary from zero to a number of positions available for substitution.
[00381] "Parasite (s)", as used herein, unless otherwise indicated, refers to endoparasites and ectoparasites. Endoparasites are parasites that live inside the body of their host and include helminths (for example, trematodes, cestodes and nematodes) and protozoa. Ectoparasites are organisms of Arthropoda philum (for example, arachnids, insects and crustaceans (for example, copepod marine lice) that feed through or on their host's skin. The preferred arachnids are of the order Acarina, for example, ticks and mites. Preferred insects are powder mosquitoes, fleas, mosquitoes, biting flies (stable fly, horn fly, flowering fly, horse fly and the like), bedbugs and lice. Preferred compounds of the present invention can be used for the treatment of parasites , that is, treatment of an infection or parasitic infestation.
[00382] "Protection group" or "Pg", as used here, unless otherwise indicated, refers to a substituent that is commonly employed to block or protect an amine in the compound thereby protecting its functionality, at the same time time providing the reaction of other functional groups in the compound. Non-exclusive examples of an amino protection group include: acyl groups (eg, formyl, acetyl, chloroacetyl, trichloroacetyl, o-nitrophenylacetyl, o-nitrophenoxyacetyl, trifluoroacetyl, acetoacetyl, 4-chlorobutyryl, isobutyryl, o-nitrocinnamyl, picolinyl, acylisothiocyanate, aminocaproyl, benzoyl and the like), acyloxy groups (e.g., 1-tert-butyloxycarbonyl (Boc), methoxycarbonyl, 9-fluorenyl-methoxycarbonyl, 2,2,2-trifluoroethoxycarbonyl, 2-trimethylsiloxycarbonyl, allylyloxycarbonyl, 1,1-dimethyl-propynyloxycarbonyl, benzyloxy-carbonyl, p-nitrobenzyloxycarbonyl, 2,4-dichlorobenzyloxycarbonyl and the like), diphenylmethane and benzylcarbamates.
[00383] "Sulfonate leaving group", as used herein, unless otherwise indicated, refers to anions with the general formula RSO2O '. Non-limiting examples of a sulfonate leaving group include: mesylate (R = CH3), triflate (R = CF3), tosylate (R = CH3C6H4), besylate (R = C6Hs), tresylate (R = CH2CF3) and the like.
[00384] "Therapeutically effective amount", as used herein, unless otherwise indicated, refers to an amount of the compounds of the present invention that (i) treat the particular parasitic infection or infestation, (ii) mitigate, ameliorate or eliminate one or more symptoms of the particular parasitic infection or infestation or (iii) prevents or delays the onset of one or more symptoms of the particular parasitic infection or infestation described herein.
[00385] "Treatment", "treating" and the like, as used herein, unless otherwise indicated, refers to reversing, relieving or inhibiting the infection, infestation or parasitic condition. As used here, these terms also cover, depending on the condition of the animal, preventing the onset of a disorder or condition or symptoms associated with a disorder or condition, including reducing the severity of a disorder or condition or symptoms associated with them, prior to affliction with said infection or infestation. Thus, treatment may refer to the administration of the compounds of the present invention to an animal that is not at the time of administration afflicted with the infection or infestation. Treating also includes preventing the recurrence of an infection or infestation or symptoms associated with it, as well as references to "control" (eg, death, repelling, expelling, incapacitating, stopping, eliminating, relieving, minimizing, and eradicating).
[00386] "Veterinarily acceptable" as used here, unless otherwise indicated, indicates that the substance or composition must be chemically and / or toxicologically compatible with the other ingredients comprising a formulation, composition and / or the animal being being treated with her. The term "pharmaceutically acceptable" has the same meaning as that mentioned for "veterinarily acceptable". DETAILED DESCRIPTION
[00387] The present invention provides compounds of formula (V.1), formula (V.2), formula (V.1.1) and formula (1), stereoisomers thereof, as well as veterinary compositions that are useful as antiparasitic agents for animals , in particular, compounds that act as ectoparasiticides.
[00388] Compounds of the present invention can be synthesized by synthetic retinas that include processes analogous to those well known in chemical techniques, particularly taking into account the description contained herein. Starting materials are generally available from commercial sources such as Aldrich Chemicals (Milwaukee, Wis.) Or are easily prepared using methods well known to those skilled in the art (for example, prepared by methods generally described in Louis F. Fieser and Mary Fieser, "Reagents for Organic Synthesis", 1; 19, Wiley, New York (1967, 1999 ed.) Or Beilsteins Handbuch der orqanischen Chemie, 4, Aufl. Ed. Springer-Verlag, Berlin, including supplements (also available through from the online Beilstein database)). For illustrative purposes, the reaction schemes shown below demonstrate potential routines for synthesizing the compounds of the present invention and key intermediates. For a more detailed description of the individual reaction steps, see the Examples section below. One skilled in the art will appreciate that other suitable starting materials, reagents and synthetic routines can be used to synthesize the compounds of the present invention and a variety of derivatives thereof. In addition, many of the compounds prepared by the methods described below can also be modified taking this description into account using conventional chemistry well known to the skilled person.
[00389] Compounds of the present invention described herein contain at least one asymmetric or chiral center; and therefore, they exist in different stereoisomeric forms. The R and S configurations are based on knowledge of known chiral inversion / retention chemistry. Unless otherwise specified, it is intended that all stereoisomeric forms of the compounds of the present invention, as well as mixtures thereof, including racemic mixtures and diastereomeric mixtures, form part of the present invention.
[00390] Enantiomeric mixtures can be separated into their individual enantiomers based on their physical chemical differences by methods well known to those skilled in the art, such as chromatography and / or fractional crystallization. A more detailed description of techniques that can be used to resolve stereoisomers of compounds from their racemic mixture can be found in Jean Jacques Andre Collet, Samuel H. Wilen, Enantiomers, Racemates and Resolutions, John Wiley and Sons, Inc. (1981).
[00391] Compounds of this invention can exist as one or more stereoisomers. The various stereoisomers include enantiomers, diastereomers and atropisomers. Someone skilled in the art will appreciate that a stereoisomer can be more active and / or exhibit beneficial effects when enriched with respect to other stereoisomer (s) or when separated from the other stereoisomer (s). In addition, the skilled technician knows how to separate, enrich and / or selectively prepare said stereoisomers. The compounds of the invention can be present as a mixture of stereoisomers, individual stereoisomers or as an optically active form. For example, two possible enantiomers of formula 1 are represented as formula 1a and formula lb involving the chiral center of spirocyclic isoxazoline identified with an asterisk (*). Molecular representations traced here follow standard conventions for representing stereochemistry.

[00392] For illustrative purposes, the reaction schemes depicted below demonstrate potential routines for synthesizing key intermediates and compounds of the present invention. For a more detailed description of the individual reaction steps, see the Examples section below. Those skilled in the art will appreciate that other suitable starting materials, reagents and synthetic routines can be used to synthesize the intermediates and compounds of the present invention and a variety of derivatives thereof. In addition, many of the compounds prepared by the methods described below can also be modified taking this description into account using conventional chemistry. Schemes 1 to 17 summarized the general procedures useful for the preparation and isolation of compounds of the present invention. It should be understood, however, that the invention, as fully described here and as mentioned in the claims, is not intended to be limited by the details of the following schemes or methods of preparation.
[00393] In the preparation of compounds of the present invention, remote functionality protection from intermediates from unwanted reactions can be performed with a protection group. The term "protecting group" or "Pg" refers to a substituent that is commonly used to block or protect a particular functionality, while reacting other functional groups in the compound. For example, an amine protecting group is a substituent attached to an amine that blocks or protects the amine functionality of the compound or intermediate. Suitable amine-protecting groups include: 1-tert-butyloxycarbonyl (Boc), acyl groups including: formyl, acetyl, chloroacetyl, trichloroacetyl, o-nitrophenylacetyl, o-nitrophenoxyacetyl, trifluoracetyl, acetoacetyl, 4-chlorobutyryl, isobutyl nitrocinamoíla, picolinoíla, acilisothiocyanato, aminocaproíla, benzoyl and the like; and acyloxy groups including: methoxycarbonyl, 9-fluorenyl-methoxycarbonyl, 2,2,2-trifluoroethoxycarbonyl, 2-trimethylsilylethoxycarbonyl, vinyloxycarbonyl, allyloxycarbonyl, 1,1-dimethyl-propynyloxycarbonyl, benzyloxy-carbonyl, p-nitrobenzyloxycarbonyl, dichobenzyloxycarbonyl and the like. Similarly, diphenylmethane and benzylcarbamates can be used as amine protecting groups. Suitable protection groups and their respective uses are easily determined by someone skilled in the art. For a general description of protection groups and their use, see T. W. Greene, Protective Groups in Organic Synthesis, John Wiley & Sons, New York, 1991.
[00394] In the Schemes and Examples below, the following heterogeneous catalysts / reagents and abbreviations include: mobile phase (MP); supercritical fluid chromatography (SFC); N, N-dimethylformamide (DMF); dimethylacetamide (DMA); acetonitrile (AON or Acn); formic acid (FA); dichloromethane (DCM); N-chlorosuccinimide (NCS); ethanol (EtOH); methyl tert-butyl ether (MTBE); triethylamine (TEA); methanol (MeOH), tetrahydrofuran (THF); ethyl acetate (EtOAc); trifluoroacetic acid (TFA); triphenylphosphine palladium (Pd (PPti3) 4); (2,2,6,6-tetramethylpiperidin-1-yl) oxyl (TEMPO); and diisobutylaluminum hydride (DIBAL-H); 4-dimethylaminopyridine (DMAP); potassium bis (trimethylsilyl) (KHMDS); N-chlorosuccinimide (NCS); 1,3-bis (diphenylphosphino) propane (DPPP); amidacarbonyldiimidazole (CDI); 1-hydroxybenzotriazole hydrate (HOBt); and N, N, N ', N'-tetramethyl- O- (7-azabenzotriazol-1-yl) uranium hexafloforphosphate (HATU), methanesulfonyl chloride (mesyl chloride, MsCI); isopropylmagnesium chloride (iPrMgCI); t-butyloxycarbonyl (BOC); palladium (II) acetate (Pd (OAc) 2); and lithium borohydride (LiBH4).
heptane heptanedioxane or THF, water dioxane or THF, waterBr CF3 [lr (COD)] 2dtbpyB2pin2R1cBr '^ ~' CF3Na2CO3 (reflux) (reflux) Na2CO3dioxane or THF, waterdioxane or THF, water (reflux) 1B1 1B2
[00395] R1a, R1b and R1 are as defined here.
[00396] Aryl oleophins (1AB) can be prepared according to Scheme 1. The required organoborates can be prepared as boronate ester intermediates (1B2) from literature methods (Org. Lett.2007, 9, 761-764) or purchased as boronic acids (1A1) such as 3,5-dichloroboronic acid from Aldrich. Intermediate compounds 1A1 or 1B2 can be added to dioxane or THF and water, followed by 2-bromo-3,3,3-trifluorpropene, potassium carbonate and bis (triphenylphosphine) palladium II chloride to provide the intermediate olefin compounds (1AB).
OH „DIBAL-H 1 TIME, NaBr \ ^ - (R) n ► <X (R2) ^ f ^ Br CH2CI2 NaHCO3, NaOCII Br
[00397] R1a, R1b, R1c, R2 and n are as defined here.
[00398] Iodoester 2 can be prepared by treating aminoester 1 with sodium nitrite and potassium iodide. Ester reduction to alcohol with diisobutylaluminum hydride followed by oxidation with TEMPO or Dess-Martin provides iodoaldehyde 4. This aldehyde may undergo condensation with hydroxylamine, chlorination and cyclization to provide isoxazoline 6. Grignard formation using iPrMgCI occurs selectively with iodine and the resulting organometallic it is added to the protected N-azetidinone to provide phenylazetidine 7. Lactone 8 can be prepared through metal catalyzed cyanation followed by intramolecular cyclization in aqueous preparation. Removal of the benzhydryl protection group with chloroethylchloroformiate provides spirocyclic azetidine 9.
10b 11
[00399] R1a, R1b, R1c, R2 and n are as defined here.
[00400] Acetal 3.2 can be prepared by treating aldehyde 3.1 with tetrabutyl ammonium tribromide (TBATB) and triethyl orthoformate in EtOH. A SnAr reaction of 3.2 with a cyano-azetidine and KHMDS in THF provides intermediate 3.3. Base-mediated hydrolysis of intermediate 3.3 using aqueous NaOH in refluxing EtOH provides acid 3.4. The acid can be converted to an acyl azide using a coupling reagent such as 1-chloro-N, N, 2-trimethyl-1-propen-amine followed by addition of sodium azide. The subsequent acyl azide can be heated in toluene to form an isocyanate which can be reacted with t-BuLi to undergo an intramolecular Curtis reaction (WO 2007/006688) to provide 10-spiro-lactam. A transfer hydrogenation using a hydrogen source such as ammonium formate in the presence of Pd and in situ protection with Boc anhydride will provide intermediate 10b. Acetal 10b can undergo condensation with hydroxylamine, chlorination and cyclization to provide isoxazoline 12. Removal of the Boc protection group with HCI in methanol provides azetidine 13. Scheme 4

[00401] R1a, R1b, R1c, R2, R5 and n are as defined here.
[00402] Intermediate 14 can be prepared by treating 7 with mesyl chloride, followed by subsequent addition of thioacetate (Tetrahedron, 1995, 3045-3050). Metal catalyzed cyanation followed by acidic aqueous removal of the acetate group will result in an intramolecular cyclization to provide intermediate 16. Removal of the benzhydryl protection group with chloroethylchloroform provides the azetidine 17. Scheme 5

[00403] R1a, R1b, R1c, R2, X and n are as defined here.
[00404] Intermediate derivatives of 8, 13 or 16 can be converted to thiocarbonyl analogs using an electrophilic thioning agent such as Lawesson's reagent or P2S5 providing intermediates 19. Removal of the benzhydryl protection group with chloroethylchloroformiate provides azetidine 20. Scheme 6

[00405] R1a, R1b, R1c, R2 and n are as defined here.
[00406] Phenylazetidine 7 can undergo metal-catalyzed intramolecular cyclization in the presence of carbon monoxide to provide lactone 21. Reduction of 21 using a reducing agent such as LÍBH4 provides bis-alcohol 22. Subsequent mesylation using methanesulfonyl chloride followed by displacement from the leaving group provides ether 23. Additionally, nitrogen or sulfur analogs of ether 23 can be made in a similar manner employing an amine or thioacetate derivative. Removal of the benzhydryl protection group with chloroethylchloroformate provides azetidine 24. Scheme 7
KHMDSH + / MeOH
[00407] R1a, R1b and R1cs are as defined here.
[00408] Incorporation of a nitrile as the axial substituent of floroazetidine can be carried out as shown in Scheme 7. From aldehyde 25, formation of acetal can be carried out with ethyl formate. The aryl fluoride can then be displaced by the anion of 1-benzhydrylazetidine-3-carbonitrile to provide phenylazetidine 27. Deprotection of the benzhydryl group, followed by reprotection with Boc anhydride provides N-Boc 29 phenylazetidine. This masked aldehyde can suffer condensation with hydroxylamine, chlorination and cyclization as described in Scheme 2 to provide isoxazolines 31.
[00409] Nitrile 31 can be hydrolyzed in the presence of NaOH in an alcoholic solvent such as methanol to provide carboxylic acid 32 after acidic preparation. Acid 32 can subsequently be converted to amide 33 using a suitable amine with a coupling agent such as HATU or EDC. Spiro lactam 34 can be formed from an intramolecular cross-coupling reaction (Tett. Lett.2008, 48, 4461-4465) of amide 34 using Pd (OAc) 2, X-Phos and base such as K2CO3. Boc removal with HCI or TF A will provide the 35 lactam spiro.
O
[00410] R1a, R1b and R1c are as defined here.
[00411] Alternatively, bromophenyl isoxazoline 31 can be converted to phenol 36 via a cross-coupling reaction (Angew. Chem. Int. Ed. 2009, 48, 918-921) using Pd2 (dba) 3, a phosphine and KOH. 36 can be hydrolyzed in the presence of NaOH in an alcoholic solvent such as methanol to provide carboxylic acid 37 after acidic preparation. Catalytic p-TsOH in refluxing toluene will provide spirolactone 38. Boc removal with HCI or TFA will provide spirocyclic azetidine 39. Scheme 9

[00412] R1a, R1b and R1 are as defined here.
[00413] Reduction of carboxylic acid 37 with lithium borohydride provides the bis-alcohol 40. Subsequent mesylation using methanesulfonyl chloride followed by displacement of this leaving group will provide ether 41. Removal of the Boc protection group with HCI in methanol provides the spirocyclic azetidine 42.Scheme 10

[00414] R1a, R1b, R1c, R2, R5, X, W and n are as defined here.
[00415] Amide analogs of the azetidine ring can be prepared as shown in Scheme 10. Acylation of the azetidine ring can be carried out by reaction of azetidine 43 with an acid chloride in pyridine / DMA or by condensation with a carboxylic acid using a condensing agent such as HATU or HOBt to provide substituted azetidine 44. Scheme 11
4345
[00416] R1a, R1b, R1c, R2, R5, X, W and n are as defined here.
[00417] Azetidine ring sulfonamide analogs can be prepared as shown in Scheme 11. Reaction of azetidine 43 with sulfonyl chlorides in the presence of triethylamine can provide the desired sulfonamide-substituted azetidines 45. Scheme 12
R1a
[00418] R1a, R1b, R1c, R2, R4, X, W and n are as defined here.
[00419] Compounds in which R4 is alkyl or substituted alkyl can be prepared from azetidine 43 by standard alkylation chemistry or by reductive amination with the corresponding aldehydes as shown in Scheme 12 to prepare the 46 and 47 alkyl substituted azetidines.
4348
[00420] R1a, R1b, R1c, R2, R3, R4, x, W and n are as defined here.
[00421] Urea analogs can be prepared as shown in Scheme 13. The reaction of azetidine 43 with a preformed isocyanate or carbamoyl chloride in the presence of a tertiary amine base provides ureas 48. Scheme 14

[00422] R1a, R1b, R1c, R4, X and W are as defined here.
[00423] Thioamides and cyanoamidines can be prepared according to Scheme 14. Azetidine intermediate 43 can be converted to thioamide 49 using Lawesson's reagent in refluxing toluene. Thioamide 49 can subsequently be treated with methyl triflate in CH2 Cl2 to form a thioimidate intermediate that can be directly treated with cyanamide in a THF / Hunig base solution to provide cyanoamidine 50. Scheme 15
54 - enantiomer
[00424] R1a, R1b, R1c, R2, R5 and n are like a muff.
[00425] The simple enantiomers of the compounds described here can be obtained from separation by chiral supercritical fluid (SFC) chromatography. Separation of chiral SFC from intermediate 53 provides a chiral intermediate that can be continued for the simple enantiomer of the described spiroazetidines. Alternatively, chiral separation can be performed on the final racemic product to provide both 54 enantiomers as discrete products. Conditions for chiral separation can be found in the section. Examples 16
BrI 57R1 ° t IPrMgCI.LiCICFjCOjMeR1C
[00426] R1a, substituent R8R1b, R1c, R2, R5 and n are as defined here. It represents a Ci-Cealquila portion (for example, methyl, ethyl, propyl, isopropyl, butyl and the like). Pg is a protecting group, for example, Boc, diphenylmethane or a benzylcarbamate and Y2 can be bromine, chlorine, iodine, hydroxyl or a desulfonate leaving group. The asterisk (*) represents a chiral center, (that is, R or S stereochemistry).
[00427] A chiral synthesis of the compounds described here can be obtained according to Scheme 16. From the iodobromobenzyl derivative57, Grignard formation and condensation with tert-butyl 3-oxoazetidine-1-carboxylate provides 5'-bromo-3'H -spiro [azetidine-3, T-isobenzofuran] -1-cyclized tert-butyl carboxylate in a one-pot reaction or a step-by-step mode. Condensation catalyzed by palladium with a vinyl ether provides acetophenone 59 which can undergo condensation with trifluoroacetophenone 56 to provide chalcone 60. Addition of hydroxylamine and cyclization in the presence of a catalyst, such as 64 provides the desired enantiomer of an isoxazoline 61 with 80% ee . Removal of the protecting group Boc can be achieved under acidic conditions, such as para-toluenesulfonic acid in an ethanol / water mixture to provide chiral azetidine 62 which can undergo couplings as previously described to provide chiral amides 63. Scheme 17 - Synthesis of heterocyclic analogues

[00428] Heterocyclic analogs can be prepared according to Scheme 17. The commercially available aldehyde 64 can undergo condensation with hydroxylamine, chlorination and cyclization to provide bromo-isoxazoline 66. Grignard formation can be obtained using i-PrMgCI and The resulting organometallic is added to the protected N-azetidinone. In the aqueous preparation, an intramolecular cyclization and hydrolysis will occur to provide spiro-lactone 67. Deprotection of 67 with HCI in methanol followed by coupling acid with CDI or adding acid chloride will provide the final compounds 69. Alternatively, reduction of 67 using a reducing agent such as LBHBH4 the subsequent mesylation using methanesulfonyl chloride followed by displacement of the leaving group will provide ether 70. Deprotection of 70 with HCI in methanol followed by coupling acid with CDI or addition of acid chloride will provide the final compounds 72.
[00429] Someone skilled in the art will recognize that, in some cases, after the introduction of a particular reagent as shown in the diagrams, it may be necessary to perform additional routine synthetic steps not described in detail to complete the synthesis of formula compounds (1 ) formula (V.1), formula (V.1.1) and formula (V.2).
[00430] The present invention includes all compounds of formula (V.1), formula (V.2), formula (V.1.1) and formula (1) isotopically labeled, veterinarily acceptable, in which one or more atoms are substituted by atoms having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number usually found in nature.
[00431] Examples of suitable isotopes for inclusion in the compounds of the present invention include hydrogen isotopes, such as 2H and 3H, carbon, such as 11C, 13C and 14C, chlorine, such as 36CI, fluorine, such as 18F, iodine, such such as 123l and 125l, nitrogen, such as 13N and 15N, oxygen, such as 150.17O and 18O and sulfur, such as 35S.
[00432] The skilled person will appreciate that the compounds of the present invention can be made by methods except those described herein as incorporated herein by reference, by adapting the methods described herein and / or adapting methods known in the art, for example, the technique described here or using standard textbooks, such as "Comprehensive Organic Transformations - A Guide to Functional Group Transformations", RC Larock, Wiley-VCH (1999 or later).
[00433] The compounds of formula (V.1), formula (V.1.1), formula (V.2) and formula (1) are useful as antiparasitic agents, therefore, another embodiment of the present invention is a veterinary composition comprising a therapeutically effective amount of a compound of formula (V.1), formula (V.1.1), formula (V.2) and formula (1), stereoisomer thereof and a veterinarily acceptable excipient, diluent or vehicle. The compounds of the present invention (including the compositions and processes used herein) can also be used in the manufacture of a medicament for the therapeutic applications described herein.
[00434] A typical formulation is prepared by mixing a compound of formula (V.1), formula (V.1.1), formula (V.2) and formula (1) with a vehicle, diluent or excipient. Suitable vehicles, diluents and excipients are well known to those skilled in the art and include materials such as carbohydrates, waxes, water-soluble and / or swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water and the like. The particular vehicle, diluent or excipient used will depend on the method and purpose for which the compound of the present invention is being applied. Solvents are generally selected on the basis of solvents recognized by persons skilled in the art as safe to be administered to an animal. The formulations may also include one or more buffers, stabilizing agents, surfactants, wetting agents, lubricating agents, emulsifiers, suspending agents, preservatives, antioxidants, opacifying agents, glidants, processing aids, colorants, sweeteners, perfuming agents, flavoring agents and other additives known to provide an elegant presentation of the drug (i.e., a compound of the present invention or veterinary composition thereof) or aid in the manufacture of the veterinary product (i.e., drug).
[00435] Formulations can be prepared using conventional dissolving and mixing procedures. Such compositions and methods for their preparation can be found, for example, in 'Remington's Veterinary Sciences', 19a. Edition (Mack Publishing Company, 1995; and "Veterinary Dosage Forms: Tablets, Vol. 1", by H. Lieberman and L. Lachman, Marcel Dekker, NY, 1980 (ISBN 0-8247- 6918-X). For example, the bulk drug substance (i.e., compound of the present invention or stabilized form of the compound (e.g., complex with a cyclodextrin derivative or other known complexing agent)) is dissolved in a suitable solvent in the presence of one or more other excipients The compounds of the present invention are typically formulated in veterinary dosage forms to provide an easily controllable dosage form for administration.
[00436] The compounds can be administered alone or in a formulation appropriate for the specific use considered, the particular species of the host animal being treated and the parasite involved. They will generally be administered as a formulation in combination with one or more excipients, diluents or veterinarily acceptable vehicles. The term "excipient", "diluent" or "carrier" is used here to describe any ingredient, except compounds of formula (V.1), formula (V.1.1), formula (V.2) or formula (1) or any additional antiparasitic agent. The choice of excipient, diluent or vehicle will depend, to a large extent, on factors such as the particular mode of administration, the effect of the excipient, vehicle or diluent on solubility and stability and the nature of the dosage form.
[00437] The methods by which the compounds of the present invention can be administered include oral, topical and subcutaneous administration. The preferred method of administering the compounds of formula (V.1), formula (V.1.1), formula (V.2) and formula (1) is in an oral dosage form or oral liquid dosage form.
[00438] The compounds of formula (V.1), formula (V.1.1), formula (V.2) and formula (1) can be administered orally by capsule, cake, tablet, powders, lozenges, chewable, multi and nanoparticles, gels, solid solution, films, sprays or liquid form. This is a preferred method of administration and as such it is desirable to develop active compounds of formula (V.1), formula (V.1.1), formula (V.2) and formula (1) which are particularly adapted for such formulations. Such Formulations can be employed as fillers in soft or hard capsules and typically comprise a vehicle, for example, water, ethanol, polyethylene glycol, N-methylpyrrolidone, propylene glycol, methyl cellulose or a suitable oil and one or more emulsifying agents and / or agents suspension. Liquid forms include suspensions, solutions, syrups, purgatives and elixirs. Liquid formulations can also be prepared by reconstituting a solid, for example, a sachet. Oral purgatives are commonly prepared by dissolving or suspending the active ingredient in a suitable medium. Oral formulations can comprise from about 0.5 mg / kg to 50 mg / kg of a compound of formula (V.1), formula (V.1.1), formula (V.2) and formula (1) and preferably about from 1 mg / kg to 30 mg / kg of a compound of formula (V.1), formula (V.1.1), formula (V.2) and formula (1).
[00439] The compounds can be administered topically to the skin or mucosa, that is, dermally or transdermally. This is a preferred method of administration and as such it is desirable to develop active compounds of formula (V.1), formula (V.1.1), formula (V.2) and formula (1) which are particularly adapted for such formulations, for example. example, liquid forms. Typical formulations for this purpose include pouring, staining, multi-staining, stripe-on, comb-on, roll-on, dipping, spray, mousse, shampoo, powder formulation, gels, hydrogels, lotions, solutions, creams, ointments, dusting powders, dressings, foams, films, skin patches, wafers, implants, sponges, fibers, bandages and microemulsions. Liposomes can also be used. Typical vehicles include alcohol, water, mineral oil, liquid petrolatum, white petrolatum, glycerin, N-methyl formamide, glycol monomethyl ethers, polyethylene glycol, propylene glycol and the like. Penetration enhancers can be incorporated - see, for example, J Pharm Sei, 88 (10), 955-958 by Finnin and Morgan (October 1999). Spill or stain formulations can be prepared by dissolving the active ingredients in an acceptable liquid carrier vehicle, such as butyl digol, liquid paraffin or a non-volatile ester, optionally with the addition of a volatile component, such as propan-2-ol or a glycol ether. Alternatively, spill, stain or spray formulations can be prepared by encapsulation, to leave an active agent residue on the animal's surface, this effect can ensure that the compounds of formula (V.1), formula (V.1.1), formula (V.2) and formula (1) have increased persistence of action and are more durable, for example, they can be faster in water. Topical formulations of the combination contemplated here may comprise from about 0.5 mg / kg to 50 mg / kg of the compound of formula (V.1), formula (V.1.1), formula (V.2) and formula (1 ), and preferably about 1 mg / kg to 10 mg / kg of the compound of formula (V.1), formula (V.1.1), formula (V.2) and formula (1).
[00440] The compounds of the present invention can also be administered topically by means of a support matrix, for example, a synthetic or natural resin, plastic, fabric, leather or other such polymeric system in the form of a necklace or ear tag. Said ear tag or collar may be coated, impregnated, layered, by any method in order to provide a veterinarily acceptable amount of a compound of the present invention alone, or with a veterinarily acceptable excipient, diluent, or vehicle and optionally an agent additional veterinarian or veterinarily acceptable salt thereof.
[00441] Compositions suitable for staining application, according to the invention, can be prepared by conventional mixing methods. The volume of the applied composition can be from about 0.5 ml / kg to 5 ml / kg and preferably from about 1 ml / kg to 3 ml / kg.
[00442] Agents can be added to the formulations of the present invention to improve the persistence of such formulations on the animal's surface to which they are applied, for example, to improve their persistence on the animal's coat. It is particularly preferred to include such agents in a formulation that is to be applied as a spill or stain formulation. Examples of such agents include acrylic copolymers and, in particular, fluorinated acrylic copolymers. A particular suitable reagent is the trademark reagent "Foraperle" (Redline Products Inc, Texas, USA).
[00443] Certain topical formulations may include non-palatable additives to minimize oral exposure.
[00444] Subcutaneous injectable formulations can be prepared in the form of a sterile solution, which may contain other substances, for example, sufficient salts or glucose to make the solution isotonic with the blood. Acceptable liquid carriers include vegetable oils such as sesame oil, glycerides, such as triacetin, esters such as benzyl benzoate, isopropyl myristate and propylene glycol fatty acid derivatives, as well as organic solvents such as pyrrolidin-2-one and formal glycerol. The formulations are prepared by dissolving or suspending compounds of the present invention alone or with an additional veterinary agent in the liquid carrier, such that the final formulation contains about 0.01 to 10% by weight of the active ingredients.
[00445] Suitable devices for subcutaneous administration include needle injectors (including micro needle), needle-free injectors and infusion techniques. Subcutaneous formulations are typically aqueous solutions that may contain excipients such as salts, carbohydrates and buffering agents (preferably at a pH of 3 to 9), however, for some applications, they may be more adequately formulated as a sterile non-aqueous solution or as a dry powder form to be used in conjunction with a suitable vehicle, such as sterile pyrogen-free water. The preparation of subcutaneous formulations under sterile conditions, for example, by lyophilization, can easily be carried out, using standard veterinary techniques, well known to those skilled in the art. The solubility of compounds of formula (V.1), formula (V.1.1), formula (V.2) and formula (1) used in the preparation of subcutaneous solutions can be increased by the use of appropriate formulation techniques, such as incorporation of solubility enhancing agents.
[00446] Such formulations are prepared in a conventional manner according to standard medical or veterinary practice. In addition, these formulations will vary taking into account the weight of the active compound contained in them, depending on the species of host animal to be treated, the severity and type of infection or infestation and the body weight of the animal.
[00447] As described herein, compounds of the present invention can be administered alone or in combination with at least one additional veterinary agent including insecticides, acaricides, anthelmintics, fungicides, nematocides, antiprotozoans, bactericides and growth regulators to form a multi-agent component providing an even broader spectrum of veterinary utility. Thus, the present invention also relates to a composition comprising an effective amount of a compound of formula (V.1), formula (V.1.1), formula (V.2) or formula (1), a stereoisomer thereof and an effective amount of at least one additional veterinary agent and may also comprise one or more of a veterinarily acceptable excipient, diluent or vehicle.
[00448] The following list of additional veterinary agents together with which the compounds of the present invention can be used is intended to illustrate possible combinations, but is not limited. Non-limiting examples of additional veterinary agents include: amitraz, arylpyrazoles as mentioned in publications WO1998 / 24767 and W02005 / 060749, amino acetonitriles, anthelmintics (for example, albendazole, cambendazole, fenbendazole, flubendazole, mebendazole, octadepsipeptides, oxfendazole, oxfendazole, oxfendazole, oxfendazole, oxfendazole, oxfendazole, oxfendazole, oxibendazole, oxibendazole; parbendazole, piperazines, praziquantel, thiabendazole, tetramisol, triclabendazole, levamisole, pyrantel pamoate, oxantel, morantel and the like), avermectins (e.g., abamectin, doramectin, emamectin, eprinomectin, ivermectin, mildewectin, mildewectin, mildewectin, mildewect) milbemycin, DEET, demiditraz, diethylcarbamazine, fipronil, insect growth regulators (e.g., hydroprene, quinoprene, methoprene and the like), metaflumizone, niclosamide, permethrin, pyrethrins, pyriproxyphene, spinosad and the like. In certain cases, combinations of the compound of formula (V.1), formula (V.1.1), formula (V.2) and formula (1) with an additional veterinary agent can result in a greater effect than the additive. Reducing the amount of active ingredients released into the environment, while ensuring effective pest control is always desirable.
[00449] It may be desirable to administer a compound of the present invention, stereoisomers thereof, alone or in a composition comprising an excipient, diluent or veterinarily acceptable vehicle, for example, for the purpose of treating a particular parasitic infection or infestation or condition associated with she. It is included in the scope of the present invention that two or more veterinary compositions, at least one of which contains the compound of formula (V.1), formula (V.1.1), formula (V.2) and formula (1) of according to the invention and the other, an additional veterinary agent, can conveniently be combined in the form of a kit suitable for co-administration of the compositions.
[00450] The compounds of the present invention (including the compositions and processes used here) can also be used in the manufacture of a medicament for the therapeutic applications described here.
[00451] The compounds of the present invention, stereoisomers thereof and compositions comprising a therapeutically effective amount of the compound of formula (V.1), formula (V.1.1), formula (V.2) and formula (1) and an excipient , diluent or veterinarily acceptable vehicle are useful as ectoparasiticides for the control and treatment of infections or infestations manifested by said ectoparasites in an animal. The compounds of the present invention are useful as an ectoparasiticide, in particular, as an acaricide and insecticide. In particular, they can be used in the fields of veterinary medicine, farm animals for agricultural cultivation and the maintenance of public health: against mites, insects and copepods that are parasitic on vertebrates, particularly warm-blooded vertebrates, including companion animals, farm animals and edible birds and cold-blooded vertebrates such as fish. Some non-limiting examples of mites, insects and copepod parasites include: ticks (for example, Ixodes spp., Rhipicephalus spp., Boophilus spp., Amblyomma spp., Hyalomma spp., Haemaphysalis spp., Dermacentor spp., Ornithodorus spp. And similar); mites (for example, Dermanyssus spp., Sarcoptes spp., Psoroptes spp., Chorioptes spp., Demodex spp. and the like); chewing and sucking lice (for example, Damalinia spp., Linognathus spp. and the like); copepods (for example, sea lice within the Order Siphonostomatoida, including the genera Lepeophtheirus and Caligus); fleas (for example, Siphonaptera spp., Ctenocephalides spp. and the like); biting flies and powder mosquitoes (for example, Tabanidae spp., Haematobia spp., Stomoxis spp., Dermatobia spp., Simuliidae spp., Ceratopogonidae spp., Psychodidae spp. and the like); and bedbugs (for example, insects within the genus Cimexe family Cimicidae).
[00452] The compounds of the invention can also be used for the treatment of endoparasites, for example, worms, roundworms, hookworms, whipworms and tapeworms.
[00453] The compounds of the present invention and compositions comprising compounds of the present invention together with at least one other veterinary agent are of particular value in the control of ectoparasites, endoparasites, and insects that are harmful to, or spread or act as vectors diseases in pets, farm animals, birds and fish. Ectoparasites, insects and endoparasites that can be treated with a combination of the compound of formula (V.1), formula (V.1.1), formula (V.2) and formula (1) and an additional veterinary agent include those as here previously described and including helminths of the philum platyhelminthes (for example, trematodes, eucestoda and cestoda) and nemathelminthes (for example, nematodes).
[00454] Any of the compounds of the present invention or a suitable combination of a compound of the present invention and optionally, with at least one additional veterinary agent can be administered directly to the animal and / or indirectly by applying it to the local environment in which the animal inhabits (such as bed, enclosures and the like). Direct administration includes contacting the skin, skin or plumes of an object animal with the compound (s) or feeding or injecting the compounds into the animal.
[00455] The compounds of formula (V.1), formula (V.1.1), formula (V.2) and formula (1), stereoisomers thereof and combinations with at least one additional veterinary agent, as described here, are of value for the treatment and control of the various stages of the life cycle of insects and parasites including egg, nymph, larvae, juvenile and adult stages.
[00456] The present invention also relates to a method of administering a compound of the present invention alone or in combination with at least one additional veterinary agent, and optionally an excipient, diluent or veterinarily acceptable vehicle, to animals in good health comprising the application of said animal to reduce or eliminate the potential for human parasitic infection or infestation of parasites carried by the animal and to improve the environment in which the animals live.
[00457] The reactions mentioned below were generally carried out under a positive pressure of argon or nitrogen or with a drying tube, at room temperature (unless otherwise stated), in anhydrous solvents and the reaction flasks were equipped with a septum rubber for introducing substrates and reagents using a syringe. Glass articles were dried in the oven and / or dried by heating. Analytical thin layer chromatography (TLC) was performed using plates pre-coated with silica gel 60 F 254 reinforced with glass and eluted with appropriate solvent ratios (v / v). Reactions were tested by TLC or LCMS and terminated as judged by the consumption of starting material. Visualization of the TLC plates was done with UV light (254 wavelength) or with an appropriate TLC visualization solvent and activated with heating. Flash column chromatography (Still et al., J. Orq. Chem. 43, 2923, (1978) was performed using silica gel (RediSep Rf) or various MPLC systems, such as Biotage or ISCO purification system.
[00458] Conventional methods and / or separation and purification techniques known to someone skilled in the art can be used to isolate the compounds of the present invention, as well as the various intermediates related to them. Such techniques will be well known to someone skilled in the art and may include, for example, all types of chromatography (high pressure liquid chromatography (HPLC), column chromatography using common adsorbents, such as silica gel and thin layer chromatography (TLC ), recrystallization and differential extraction techniques (ie liquid-liquid).
[00459] The compound structures in the examples below have been confirmed by one or more of the following methods: proton magnetic resonance spectroscopy and mass spectroscopy. Proton magnetic resonance (1H NMR) spectra were determined using a Bruker spectrometer operating at a field resistance of 400 megahertz (MHz). Chemical shifts are reported in parts per million (PPM, δ) downstream from an internal tetramethylsilane standard. Mass spectra (MS) data were obtained using Agilent mass spectrometer with chemical atmospheric pressure ionization. Method: Acquity UPLC with chromatography performed on a Waters BEH C18 column (2.1 x 50 mm, 1.7 gm) at 50 ° C. The mobile phase was a binary gradient of acetonitrile (containing 0.1% trifluoroacetic acid) and water (5 to 100%).
[00460] Modalities of the present invention are illustrated by the following examples. It should be understood, however, that the modalities of the invention are not limited to the specific details of these examples, as well as other variations of them will be known or evident in the light of the present description, for someone skilled in the art. EXAMPLES
[00461] The following examples provide a more detailed description of the process conditions for preparing compounds of the present invention. It should be understood, however, that the invention, as fully described here and as mentioned in the claims, is not intended to be limited by the details of the following schemes or methods of preparation. Preparation 1: Methyl 3-bromo-4-iodobenzoate

[00462] A solution of 4-amino-3-bromo-benzoic acid methyl ester (5.0 g, 22.0 mmol of Aldrich) in acetone (35 ml) was treated with 6 M HCI (35 ml). The solution was cooled to 0 ° C and treated dropwise with NaNO2 (1.84 g, 26.1 mmol) dissolved in 10 ml of water. After stirring for 2 hours at 0 ° C, the reaction was slowly treated with potassium iodide (5.47 g, 32.6 mmol) dissolved in 20 ml of water. The reaction mixture was allowed to warm to room temperature and stir for 1 hour. The reaction mixture was diluted with water and extracted with EtOAc (2 x 150 ml). The combined organic phase was dried (Na2SO4) and concentrated in vacuo. The residue was chromatographed (80 g of Redi-Sep column) eluting from 100% heptane to 20:80 EtOAc: heptane to provide the intermediate (4.1 g, 55%) as a solid. 1HRMN (CDCh) δ ppm: 8.27 (1H), 7.98 (1H), 7.64 (1H), 3.94 (3H) .Preparation 2: (3-bromo-4-iodophenyl) methanol

[00463] A solution of methyl 3-bromo-4-iodobenzoate (4.3 g, 12.6 mmol) in CH2 Cl2 was cooled, under N2, to -78 ° C. DIBAL-H (25.2 ml_ of a 1 M solution in CH2 Cl2) was added slowly to the solution, which was stirred at -78 ° C for 45 minutes and then allowed to come to room temperature. Then, the reaction mixture was diluted with 1 M HCL (40 ml) and stirred for 30 minutes. The reaction was also diluted with water and extracted with CH2 Cl2. The organic phase was dried (Na2SO4) and concentrated in vacuo to provide the intermediate (3.2 g, 82%) as a solid. 1HRMN (CDCh) δ ppm: 7.85 (1H), 7.67 (1H), 7.02 (1H), 4.65 (2H), 1.76 (1H, OH). Preparation 3: 3-bromine -4-iodobenzaldehyde

[00464] A solution of (3-bromo-4-iodophenyl) methanol (3.1 g, 9.9 mmol) in CH2Cl2 / water (2: 1, 225 mL) was treated with NaHCOa (915 mg, 10.9 mmol), NaBr (1060 mg, 10.2 mmol) and TEMPO free radical (40 mg, 0.2 mmol). The resulting mixture was cooled to 0 ° C and NaOCI solution (0.8 ml, 10% aq.) Was added dropwise. The reaction mixture was allowed to come to room temperature while stirring. 25:75 TLC of EtOAc: heptane after 30 minutes showed approximately 50% conversion to less polar spot. The sequence is repeated using the same reagent equivalent. TLC also showed unreacted starting material. The reaction mixture was separated and the organic phase was treated with 1.0x Dess-Martin periodinane (2.1 g, 4.9 mmol) while stirring. TLC after 10 minutes showed complete conversion to less polar spot. The organic phase was washed with saturated NaHCOa, dried over Na2SO4, filtered and evaporated to provide an orange solid. The crude material was chromatographed (80 g of Red-Sep column) eluting from 100% heptane to 50:50 EtOAc / heptane to provide the intermediate (2.7 g, 87%) as a white solid. 1HRMN (CDCh) δ ppm: 9.94 (1H), 8.10 (2H), 7.50 (1H) .Preparation 4: (EZZ) -3-bromo-4-iodobenzaldehyde oxime
OHI
[00465] To a solution of 3-bromo-4-iodobenzaldehyde (1000 mg, 3.2 mmol) in EtOH (50 ml) was added NH2OH, HCI (345 mg, 4.8 mmol) and water (10 ml). The reaction was heated to 50 ° C for 1 hour and then allowed to stir for 18 hours at room temperature. The reaction mixture was concentrated in vacuo to remove EtOH. Water was added to the residue and extracted with EtOAc (2 x 75 ml). The combined organic phase was dried (Na2SO4) and concentrated in vacuo to provide the intermediate (1035 mg, 98%) as a glass, m / z (Cl) = 326 [M + H] +. Preparation 5: 3- (3 -bromo-4-iodophenyl) -5- (3,4,5-trichlorophenyl) -5- (trifluoromethyl) -4,5-dihydroisoxazole

[00466] To a solution of DMF (25 ml) of (EZZ) -3-bromo-4-iodo-benzaldehyde oxime (1000 mg, 3.1 mmol) was added NCS (500 mg, 3.7 mmol) portion a portion. The reaction was stirred at room temperature for 18 hours. 50:50 TLC of EtOAc: heptane shows slightly less polar stain, no starting material. The reaction mixture was diluted with EtOAc (100 ml) and washed with water (2 x 50 ml). The organic phase was dried over sodium sulfate and concentrated to provide the chlorooxime intermediate (1056 mg, 96%) as a solid. Then, to an ethyl acetate solution (70 mL) of chlorooxime (1 g, 2.8 mmol) and 1,2,3-trichloro-5- (1,1,1-trifluorprop-2-en-2- il) benzene (765 mg, 2.8 mmol) potassium bicarbonate (310 mg, 3.1 mmol) was added. The mixture was allowed to stir at room temperature over the weekend. The reaction mixture was filtered and concentrated in vacuo. The residue was chromatographed (80 g of Redi-Sep column) eluting from 100% heptane to 20:80 EtOAc: heptane to provide the intermediate (1.53 g, 92%) as a solid. 1HRMN (CDCh) δ ppm: 7.95 (1H), 7.88 (1H), 7.65 (2H), 7.33 (1H), 4.07 (1H), 3.67 (1H). 6: 1-benzhydryl-3- (2-bromo-4- (5- (3,4,5-trichlorophenyl) -5- (trifluoromethyl) -4,5-dihydroisoxazol-3-yl) phenyl) azetidin- 3-ol

[00467] In an oven-dried flask containing 3- (3-bromo-4-iodophenyl) -5- (3,4,5-trichlorophenyl) -5- (trifluoromethyl) -4,5-dihydroisoxazole (1000 mg , 1.67 mmol) in THF (25 mL) at -40 ° C wasopropyl magnesium chloride (1.7 mL of 2.0 m solution) was slowly added. The reaction was stirred at approximately -40 ° C for 1.5 hours under nitrogen. 1-Benzhydrylazetidin-3-one (520 mg in 4 ml of THF) was added slowly. The reaction was stirred at -40 ° C for an additional 30 minutes and allowed to warm to room temperature. Stirring was continued for 2 hours at room temperature. The reaction was quenched with saturated NH4Cl and extracted with EtOAc (2 x 75 mL). The combined organic phase was dried (Na2SOzi) and concentrated in vacuo. The crude material was chromatographed (40 g of Redi-Sep column) eluting 100% heptane to 60:40 EtOAc: heptane, collecting the intermediate (615 mg, 52%) as a glass. 1HRMN (CDCh) δ ppm: 7.87 (1H), 7.66-7.63 (3H), 7.45 (4H), 7.36-7.21 (7H), 4.39 (1H), 4.07 (1H), 3.73-3.58 (5H), 3.06 (1H); m / z (Cl) 711 [M + H] + Preparation 7: 1-benzhydryl-5 '- (5- (3,4,5-trichlorophenyl) -5- (trifluoromethyl) -4,5-dihydroisoxazole -3-yl) -3'H-spiro [azetidine-3, T-isobenzofuran] -3'-one

[00468] To a solution of 1-benzhydryl-3- (2-bromo-4- (5- (3,4,5-trichlorophenyl) -5- (trifluoromethyl) -4,5-dihydroisoxazol-3-yl ) phenyl) azetidin-3-ol (500 mg, 0.7 mmol) in DMF (12 mL) Zn (CN) 2 (180 mg, 1.5 mmol) was added and the reaction was degassed with N2 purge. Pd (PPh3) 4 (40 mg, 0.04 mmol) was added and the reaction mixture was heated at 150 ° C for 15 minutes under microwave irradiation. The reaction mixture was diluted with water extracted with EtOAc, dried and concentrated in vacuo. The crude material was chromatographed (40 g of Redi-Sep column) eluting from 100% heptane to 50:50 EtOAc: heptane to provide the intermediate (268 mg, 58%) as a glass. 1HRMN (CDCh) δ ppm: 8.32 (1H), 8.18 (1H), 7.95 (1H), 7.68 (2H), 7.51 (4H), 7.35-7.23 ( 6H), 4.55 (1H), 4.15 (1H), 3.79-3.69 (3H), 3.60 (2H); m / z (Cl) 657 ([M + H] +. Preparation 8: 5 '- (3,4,5-trichlorophenyl) -5- (trifluoromethyl) -4,5-dihydroisoxazol-3-yl) - 3'H-spiro {azetidine-3, T-isobenzofuran} -3'-one

[00469] To a solution of 1-benzhydryl-5 '- (5- (3,4,5-trichlorophenyl) -5- (trifluoromethyl) -4,5-dihydroisoxazol-3-yl) -3'H- spiro [azetidine-3,1'-isobenzofuran] -3'-one (260 mg, 0.39 mmol) in MeCN / CI-hCh (5: 1, 60 ml_) at 0 ° C 1-chloroethyl chloroformate was added (150 pL, 1.4 mmol). The reaction was heated to reflux for 2 hours then allowed to cool to room temperature while stirring for 18 hours. Then, the reaction mixture was concentrated in vacuo, again dissolved in anhydrous MeOH (50 ml) and refluxed for 1 hour. The reaction was cooled, concentrated under reduced pressure and diethyl ether was added to the residue. The resulting precipitate was filtered, rinsed with diethyl ether and dried in air to provide the intermediate (148 mg, 71%) as a solid, m / z (Cl) 491 [M + H] + Example 1: 1 - (cyclopropanecarbonyl) ) -5 '- (3,4,5-trichlorophenyl) -5- (trifluoromethyl) -4,5-dihydroisoxazol-3-yl) -3'H-spiro {azetidine-3, T-isobenzofuran} -3 '-one

[00470] 5 '- (3,4,5-Trichlorophenyl) -5- (trifluoromethyl) -4,5-dihydroisoxazol-3-yl) -3'H-spiro {azetidine-3, T-isobenzofuran} - 3'-one (140 mg, 0.3 mmol) was dissolved in CH2 Cl2 (5 mL) at 0 ° C and TEA (0.15 mL, 1.1 mmol) was added. The reaction was stirred at room temperature for 5 minutes and cyclopropanecarbonyl chloride (35 mg, 0.3 mmol) was added. The resulting solution was stirred at room temperature for 15 minutes. Then, a few drops of MeOH were added and the reaction was concentrated to ~ 3 mL under vacuum and injected directly into a 24 g Redi Sep column. The crude material was chromatographed eluting from 100% heptane to 60:40 EtOAc: heptane to provide the final product (68 mg, 46%) as a solid. 1HRMN (CDCh) δ ppm: 8.29 (1H), 8.04 (1H), 7.85 (1H), 7.67 (2H) 4.94-4.83 (1H), 4.86-4 , 58 (2H), 4.49-4.37 (1H), 4.16 (1H), 3.78 (1H), 1.50 (1H), 1.11 (2H), 0.90 (2H ); m / z (Cl) 559 [M + H] + Example 2: 5 '- (5- (3,5-dichloro-4-fluorophenyl) -5- (trifluoromethyl) -4,5-dihydroisoxazole-3 -yl) -1-propionyl-3'H-spiro [azetidine-3, T-isobenzofuran] - 3'-one

[00471] The compound was prepared similarly to that of Example 1 except that the cyclopropanocarbonyl chloride was replaced with propionyl chloride (10 mg, 0.1 mmol) and the olefin (1AB) was 1,3-dichloro-2-fluorine- 5- (1-trifluoromethyl-vinyl) -benzene instead of 1,2,3-trichloro- (1-trifluoromethyl-vinyl) -benzene.
[00472] The reaction was injected directly into a 24 g Redi Sep column. The crude material was chromatographed eluting from 100% heptane to 50:50 EtOAc: heptane to provide the final product (25 mg, 48%) as a solid, m / z (Cl) 531 [M + H] +. 9: 1-benzhydryl-3- (2-bromo-4- (5- (3,5-dichloro-4-fluorophenyl) -5- (trifluoromethyl) -4,5-dihydroisoxazol-3-yl) phenyl) azetidin-3-ol

[00473] This compound was made from Preparation 4 according to procedures 5 and 6, using 1,3-dichloro-2-fluoro-5- (1,1,1-trifluoroprop-2-en-2 -yl) benzene instead of 1,2,3-trichloro-5- (1,1,1-trifluoroprop-2-en-2-yl) benzene. m / z (Cl) = 695 [M + H] + Preparation 10: 1-benzhydryl-5 '- (5- (3,5-dichloro-4-fluorophenyl) -5- (trifluoromethyl) -4,5- dihydroisoxazol-3-yl) -3'H-spiro [azetidine-3, T-isobenzofuran] -3'-one

[00474] A stream of carbon monoxide gas was bubbled through a solution of 1-benzhydryl-3- (2-bromo-4- (5- (3,5-dichloro-4-fluorophenyl) -5- (trifluoromethyl ) -4,5-dihydroisoxazol-3-yl) phenyl) azetidin-3-ol (Preparation 9, 50 g, 72 mmol) in toluene (100 ml) and triethylamine (100 ml) for 30 seconds. To this were added palladium acetate (260 mg) and Xantphos (680 mg, 1.2 mmol). A flask containing carbon monoxide was connected to a reaction flask and it was heated to 85 ° C for 4 hours. At this point, an additional and identical amount of both palladium acetate and Xantphos was added. The reaction was heated for an additional eight hours at 85 ° C. The reaction was cooled to room temperature and filtered to remove the catalyst. The product was isolated by silica column chromatography: 400 mg of silica, eluting with a 0% to 10% ethyl acetate gradient in a 1: 1 mixture of CH2Cl2: hexane. The material was dried under vacuum at 50 ° C to provide 35 g of a white solid, m / z (Cl) = 642 [M + H] + Preparation 11: 1-benzhydryl-3- (2-hydroxymethyl-4- (5- (3,5-dichloro-4fluorfenyl) -5- (trifluoromethyl) -4,5-dihydroisoxazol-3-yl) phenyl) azetidin-3-ol

[00475] To a solution of 1-benzhydryl-5 '- (5- (3,5-dichloro-4-fluorophenyl) - 5- (trifluoromethyl) -4,5-dihydroisoxazol-3-yl) -3' H-spiro [azetidine-3, T-isobenzofuran] -3'-one (Preparation 10, 20.0 g, 31 mmol) in THF (200 mL) was added lithium borohydride (1.03 g, 47 mmol) in room temperature. The reaction was stirred for 16 hours and was then quenched by the slow addition of methanol (20 ml). The solution was concentrated under reduced pressure and the residue was dissolved in EtOAc (200 ml) and then washed with saturated aqueous Na2COa (2 x 100 ml). The organics were concentrated and the residue was purified on a silica column: 400 g of silica with eluent gradient from 0% to 30% EtOAc in CH2 Cl2. The product was dried under vacuum at 50 ° C to provide 10.0 mg of a white solid, m / z (Cl) = 646 [M + H] +. Preparation 12: 1-benzhydryl-5 '- (5- (3,5-dichloro-4-fluorophenyl) -5- (trifluoromethyl) -4,5-dihydroisoxazol-3-yl) -3'H-spiro [ azetidine-3,1'-isobenzofuran]

[00476] A solution of 1-benzhydryl-3- (2-hydroxymethyl-4- (5- (3,4,5-trichlorophenyl) -5- (trifluoromethyl) -4,5-dihydroisoxazol-3-yl) phenyl) azetidin-3-ol (Preparation 11, 9.8 g, 15.2 mmol) in toluene (100 ml) was cooled to 0 ° C. To this was added triethylamine (5 g) followed by p-toluene sulfonic anhydride (5.7 g, 17.4 mmol). The reaction was allowed to warm to room temperature and was stirred for 16 hours. The reaction was washed with saturated aqueous Na2COa (2 x 50 ml) and then with water (50 ml). The organic solution was filtered through a silica plug (10 g) and was concentrated under reduced pressure, m / z (Cl) = 628 [M + H] +. Preparation 13: 5 '- (5- (3.5 -dichloro-4-fluorophenyl) -5- (trifluoromethyl) -4,5-dihydroisoxazol-3-yl) -3'H-spiro [azetidine-3, T-isobenzofuran]

[00477] To a solution of 1-benzhydryl-5 '- (5- (3,5-dichloro-4-fluorophenyl) -5- (trifluoromethyl) -4,5-dihydroisoxazol-3-yl) -3' H-spiro [azetidine-3,1'-isobenzofuran] (Preparation 12, 10.0 g, 16 mmol) in MeCN (100 mL) at room temperature 1-chloroethyl-chloroformate (9.8 g, 68 mmol) was added . The reaction was heated to 75 ° C for 2 hours. The reaction was cooled to room temperature and was concentrated in vacuo. The residue was dissolved in anhydrous methanol (200 ml) and was heated to reflux for 1 hour. The reaction was concentrated under reduced pressure and the residue was purified on a column of silica: 200 g of silica, gradient from 0 to 20% EtOH in methylene chloride. 1HRMN (de-DMSO) δ ppm: 8.10 (1H), 7.81 (3H), 7.70 (1H), 5.10 (2H), 4.37 (2H), 4.24 (2H) , 4.15 (2H), m / z (Cl) 462 [M + H] + Example 3: 1- (5 '- (5- (3,5-dichloro-4-fluorophenyl) -5- (trifluoromethyl ) -4,5-dihydroisoxazol-3-yl) -3'H-spiro [azetidine-3, T-isobenzofuran] -1-yl) -2- ((trifluoromethyl) thio) ethanone

[00478] 5 '- [5- (3,5-Dichloro-4-fluorophenyl) -5- (trifluoromethyl) -4,5-dihydro-1,2-oxazol-3-yl] -3'H- spiro [azetidine-3, T- [2] benzofuran] (0.05 mmol) was dissolved in DMF (0.5 mL); this was added to [(trifluoromethyl) sulfanyl] acetic acid (0.1 mmol), followed by a solution of O- (7-azabenzotriazol-1-yl) -N, N, N ', N, -tetramethyl-uronioexafluorophosphate in DMF (0.5 mL) and triethylamine (0.5 mmol). The resulting mixture was stirred at room temperature for 16 hours. The solvent was removed by vacuum distillation and the crude product purified by preparative HPLC to provide 3.2 mg of the title compound, m / z [M + H] + 603; retention time 4.21 minutes. Example 4: (5 '- (5- (3,5-dichloro-4-fluorophenyl) -5- (trifluoromethyl) -4,5-dihydroisoxazol-3-yl) -3 'H-spiro [azetidine-3, T-isobenzofuran] -1-yl) (1-oxothietan-3-yl) methanone

[00479] To a solution of tiethane-3-carboxylic acid 1-oxide (53 mg, 0.4 mmol) in DMF (5 mL) was added CDI (65 mg, 0.4 mmol). The reaction was stirred at room temperature for 15 minutes and TEA (0.25 mL, 1.6 mmol) and 5 '- (5- (3,5-dichloro-4-fluorophenyl) -5- (trifluoromethyl) -4, 5-dihydroisoxazol-3-yl) -3'H-spiro [azetidine-3, T-isobenzofuran] (Preparation 13, 150 mg, 0.3 mmol) were added. The reaction was stirred at room temperature for 18 hours, then diluted with water and extracted with EtOAc (2 x 75 ml). The combined organic phase was dried (Na2SOzi) and concentrated in vacuo to provide the intermediate (100 mg, 53%) as a solid, m / z (Cl) 577 [M + H] +. Example 5: (5 '- ( 5- (3,5-dichloro-4-fluorophenyl) -5- (trifluoromethyl) -4,5-dihydroisoxazol-3-yl) -3'H-spiro [azetidine-3, T-isobenzofuran] -1- il) (1,1-dioxidotietan-3-yl) methanone

[00480] To a 20 mL vial containing a solution of oxonium (320 mg, 0.52 mmol) in water (2 mL) at 0 ° C was added (5 '- (5- (3,5-dichloro-4 -fluorfenyl) -5- (trifluoromethyl) -4,5-dihydroisoxazol-3-yl) -3'H-spiro [azetidine-3,1 '-isobenzofuranJ-1 -i I) (1 -oxidotietan-3- il) methanone from Example 4 (100 mg, 0.17 mmol) as a solution in methanol (4 ml). The reaction was stirred at 0 ° C and allowed to warm to room temperature while stirring for 2 hours. Then, the reaction mixture was concentrated to remove excess MeOH and diluted with water. The crude product was extracted with CH2 Cl2 (75 ml) and the organic phase was dried (Na2 SOzi) and concentrated in vacuo. The residue was purified by preparative HPLC to provide the final product (16 mg, 16%) as a solid. 1HRMN (CDCh) δ ppm: 7.69 (1H), 7.63-7.60 (3H), 7.49 (1H), 5.19 (2H), 4.61 - 4.45 (4H), 4.36 (2H), 4.24 - 4.09 (3H), 3.72 (1H), 3.30 (1H); m / z (Cl) 593 [M + H] + Preparation 14: General amide coupling can be done in a parallel way

[00481] The respective amine (0.05 mmol) was dissolved in DMF (0.5 ml); this was added to the respective acid (0.1 mmol), followed by a solution of O- (7-azabenzotriazol-1-yl) -N, N, N ', N'- tetramethyluronioexaflúphosphate in DMF (0.5 ml) and triethylamine (0.5 mmol). The resulting mixture was stirred at room temperature for 16 hours. The solvent was removed by vacuum distillation and the crude product purified by preparative HPLC.
[00482] HPLC conditions: Instrument: Waters Alliance 2795 with ZQ MS-ESI +; Column: 4.6 x 100 NXC18, 5 pm; Flow rate: 1.0 mL / minute; solvent At 0.05% TFA in water; solvent B ACN; Gradient: 50 to 95% B from 0 to 10 minutes; Injection volume: 2 pl; Execution time: 12 minutes; Detection: 254 nm and appropriate mass. Preparation 15: 2-bromo-4- (dietoxymethyl) -1-fluorbenzene

[00483] A 250 mL flask was loaded with 3-bromo-4-fluorobenzaldehyde (13.5 g, 66.5 mmol), triethyl orthoformate (13.3 mL, 79.8 mmol) and anhydrous EtOH (150 mL ). Tetrabutylammonium tribromide was added and the reaction mixture was allowed to stir at room temperature for 48 hours. The crude reaction was poured into aqueous NaHCOa and extracted with ethyl acetate (75 mL). The organic layers were combined, dried with Na2SO4 and reduced in vacuo to provide the intermediate (16.2 g, 88%) as a clear oil. 1HRMN (CDCh) δ ppm: 7.71 (1H), 7.40 (1H), 7.12 (1H), 5.48 (1H), 3.65-3.51 (4H), 1.28- 1.24 (6H) .Preparation 16: 1-benzhydryl-3- (2-bromo-4- (dietoxymethyl) phenyl) azetidine-3-carbonitrile

[00484] To a solution of 2-bromo-4- (dietoxymethyl) -1-fluorbenzene (Preparation 15, 10.0 g, 36.0 mmol) in THF (125 mL) were added 1-benzhydrylazetidine-3-carbonitrile ( 13.4 g, 54.1 mmol) and KHMDS (10.8 g, 54.1 mmol). The reaction mixture is allowed to stir at room temperature for 1 hour. Then, the reaction mixture is concentrated to an oil in vacuo, diluted with EtOAc and washed 2x with water. The organic phase was dried (Na2SOzi) and concentrated in vacuo. The crude material was chromatographed (220 g of Redi-Sep column) eluting from 100% heptane to 20:80 EtOAc: heptane to provide the intermediate (13.7 g, 75%) as a solid. 1HRMN (CDCh) δ ppm: 7.73 (1H), 7.48-7.44 (5H), 7.37-23 (6H), 7.13 (1H), 5.47 (1H), 4, 33 (1H), 4.14 (2H), 3.65-3.52 (4H), 3.41 (2H), 1.29-1.25 (6H) .Preparation 17: 1-benzhydryl-3 acid - (2-bromo-4- (dietoxymethyl) phenyl) azetidine-3-carboxylic

[00485] To a suspension of 1-benzhydryl-3- (2-bromo-4- (dietoxymethyl) phenyl) -azetidine-3-carbonitrile (Preparation 16, 13.5 g, 26.7 mmol) in EtOH (150 mL ) aq NaOH (85 mL of a 25% weight solution) was added. The reaction mixture was heated to reflux for 36 hours. The contents were concentrated in vacuo to remove EtOH to a concentration of ~ 100 ml and the solution became cloudy. The residue was placed in an ice bath and cooled. The pH of the residue was lowered to ~ 5-7 by the slow addition of HCI at 3 m time when a precipitate formed. More water was added and the mixture was stirred for 15 minutes and filtered. The precipitate was again dissolved in EtOAc (250 ml) and washed with saturated NH4 Cl and brine. The organic phase was dried (Na2SO4) and concentrated in vacuo. The solid was placed under high vacuum for 18 h to provide the acid (14.1 g, 100%) as a solid. 1HRMN (CDCh) δ ppm: 7.55 (1H), 7.34-7.13 (11H), 7.02 (1H), 5.37 (1H), 4.40 (1H), 4.16 ( 2H), 3.58-3.44 (6H), 1.22-1.19 (6H); m / z (Cl) 524 [M + H] + Preparation 18: 1-benzhydryl-5 '- (dietoxymethyl) spiro [azetidine-3, T-isoindolin] -3'-one

[00486] To a solution of 1-benzhydryl-3- (2-bromo-4- (dietoxymethyl) phenyl) -azetidine-3-carboxylic acid (Preparation 17, 5.00 g, 9.5 mmol) in CH2 Cl2 (100 ml) 1-chloro-N, N, 2-trimethyl-1-propen-1-amine (1.4 ml, 10.5 mmol) was added. The reaction was stirred at room temperature for 1.5 hours. Then, the reaction was concentrated in vacuo and again dissolved in anhydrous DMF (75 ml). Sodium azide (950 mg, 8.6 mmol) was added and the reaction mixture was stirred at room temperature for 18 hours. MTBE was then added (200 ml) and the mixture was washed with 0.5 m Na2CO3 (2 x 100 ml), water (100 ml) and brine (100 ml). The organic phase was dried (Na2SO4), diluted with toluene (100 ml) and concentrated in vacuo to remove MTBE. The acyl azide / toluene solution was then heated to 90 ° C for 1 hour. After heating, evolution of N2 gas was observed. The reaction was then cooled and concentrated in vacuo to provide the raw isocyanate (2.4 g). The residue was dissolved in THF (100 ml) and cooled to - 78 ° C. After ~ 15 minutes, tert-butyl lithium (5.4 ml, 9.2 mmol) was added dropwise and stirring continued for an additional 10 minutes at -78 ° C. The reaction mixture was then heated to 0 ° C and maintained at that temperature for ~ 10 minutes. The reaction was quenched with NH4Cl sat. and heated to room temperature. More saturated NH4CI was added and the reaction was extracted with MTBE. The organic phase was dried (Na2SO4) and concentrated in vacuo. The crude material was chromatographed (80 g of Redi-Sep column) eluting 100% hexanes to 50:50 EtOAc: hexanes to provide the intermediate (1.41 g, 33%) as a solid. 1HRMN (CDCh) δ ppm: 8.12 (1H), 7.95 (1H), 7.86 (1H), 7.53-7.51 (4H), 7.34-7.21 (6H), 6.88 (1H), 5.61 (1H), 4.49 (1H), 3.68-3.56 (6H), 3.45 (2H), 1.29-1.26 (6H); m / z (Cl) 443 [M + H] + Preparation 19: δ'-idietoxymethylJ-S'-oxospiroIazetidine-ST-isoindoline] - tert-butyl 1-carboxylate

[00487] To a deoxygenated solution of 1-benzhydryl-5 '- (dietoxymethyl) spiro- [azetidine-3, T-isoindolin] -3'-one (Preparation 18, 1.4 g, 3.2 mmol) in EtOH (75 mL) were added ammonium formate (1.4 g, 22.1 mmol), Boc anhydride (2.1 g, 9.5 mmol) and 10% Pd / C (504 mg, 0.5 mmol ). The resulting suspension was heated to reflux while stirring under N2 for 1 hour. The reaction mixture was cooled, filtered through a pad of celite and the filtrate was concentrated in vacuo. The crude residue was chromatographed (40 g of Redi-Sep column) eluting 100% hexanes to 50:50 EtOAc: hexanes to provide the intermediate (885 mg, 74%) as a solid. 1H NMR (CDCh) δ ppm: 7.96 (1H), 7.83 (1H), 7.74 (1H), 7.13 (1H), 5.60 (1H), 4.38-4.29 (4H), 3.66 - 3.54 (4H), 1.53 (9H), 1.29-1.25 (6H) .Preparation 20: 5 '- ((hydroxy imino) methyl) -3' -oxospiro [azetidine-3, r-isoindoline] (EZZ) -tert-butyl -1-carboxylate

[00488] To a solution of tert-butyl 5 '- (dietoxymethyl) -3'-oxospiro [azetidine-3, T-isoindoline] -1-carboxylate (Preparation 19, 880 mg, 2.3 mmol) in EtOH ( 40 ml) NH2OH.HCI (330 mg, 4.7 mmol) and water (5 ml) were added. The reaction mixture was heated to 50 ° C for 1 hour. The reaction mixture was then cooled and concentrated in vacuo to remove EtOH. Water was added to the residue and extracted with CH2 Cl2 (2 x 50 ml). The combined organic phases were dried (Na2SOzi) and concentrated in vacuo to provide the intermediate (755 mg, 100%) as a solid, m / z (Cl) 262 [M-56 + H] +. Preparation 21: 5'- (5- (3,5-bis (trifluoromethyl) phenyl) -5- (trifluoromethyl) -4,5-dihydroisoxazol-3-yl) -3'-oxospiro [azetidine-3, T-isoindoline] -1- tert-butyl carboxylate

[00489] To a solution of DMF (15 mL) of 5 '- ((hydroxyimino) methyl) - 3'-oxospiro [azetidine-3, T-isoindoline] -1-carboxylate (EZZ) -tert-butyl (Preparation 20, 250 mg, 0.8 mmol) NCS (122 mg, 0.9 mmol) was added portion by portion. The reaction was then heated to 50 ° C for 1 hour. More NCS (60 mg, 0.4 mmol) was added and heating continued for 30 minutes. The reaction mixture was cooled to room temperature and diluted with EtOAc (15 ml). Then, 1,3-bis (trifluoromethyl) -5- (1,1,1-trifluorprop-2-en-2-yl) benzene (243 mg, 0.8 mmol) and K2CO3 (174 mg, 1.7 mmol) were added. The mixture was allowed to stir at room temperature for 18 hours. The reaction mixture was diluted with EtOAc and washed with water and brine. The organic phase was dried (Na2SO4) and concentrated in vacuo. The residue was chromatographed (24 g of silica gel column) eluting from 100% hexanes to 50:50 EtOAc: hexanes to provide the intermediate (245 mg, 50%) as a solid. 1H NMR (CDCh) δ ppm: 8.22 (1H), 8.12 (2H), 8.00-7.97 (2H), 7.86 (1H), 7.23 (1H), 4.40 (2H), 4.32-4.26 (3H), 3.87 (1H), 1.53 (9H); m / z (Cl) 568 [M-56 + H] + Preparation 22: 5 '- (5- (3,5-bis (trifluoromethyl) phenyl) -5- (trifluoromethyl) -4,5-dihydroisoxazole -3-yl) spiro [azetidine-3, T-isoindolin] -3'-one

[100490] A 100 ml vial equipped with stir bar was loaded with 5 '- (5- (3,5-bis (trifluoromethyl) phenyl) -5- (trifluoromethyl) -4,5-dihydroisoxazol-3-yl ) Tert-butyl-3'-oxospiro [azetidine-3, T-isoindoline] -1-carboxylate (Preparation 21, 240 mg, 0.4 mmol) and anhydrous methanol (25 ml). A methanolic HCI solution (1 ml of a 1.25 m solution) was added and the reaction was heated to 65 ° C for 6 hours. The reaction was cooled and concentrated in vacuo. The residue was rinsed with diethyl ether, concentrated in vacuo and subsequently placed under high vacuum for 1 hour to provide the intermediate (216 mg, 95%) as an HCI salt. m / z (Cl) 524 [M + H] + Example 6: 5 '- (5- (3,5-bis (trifluoromethyl) phenyl) -5- (trifluoromethyl) -4,5-dihydroisoxazole-3 -yl) -1- (2- (methylsulfonyl) acetyl) spiro [azetidine-3, T-isoindolin] -3'-one

[00491] To a solution of 2-methanesulfonylacetic acid (40 mg, 0.3 mmol) in DMF (5 mL) was added CDI (40 mg, 0.2 mmol). The reaction was stirred at room temperature for 30 minutes and TEA (0.15 mL, 1.0 mmol) and 5 '- (5- (3,5-bis (trifluoromethyl) phenyl) -5- (trifluoromethyl) - 4, 5-dihydroisoxazol-3-yl) spiro [azetidine-3, T-isoindolin] -3'-one (Preparation 22, 100 mg, 0.2 mmol) were added. The reaction was stirred at room temperature for 18 hours, then diluted with 0.1 Ne NaOH extracted with EtOAc (2 x 75 ml). The combined organic phase was dried (Na2SO4) and concentrated in vacuo. The crude product purified by preparative HPLC (Instrument: Waters Alliance 2795 with ZQ MS-ESI +; Column: 4.6 x 100 NXC18, 5 pm; Flow rate: 1.0 mL / min; solvent At 0.05% TFA in water; solvent B ACN; Gradient: 50 to 95% B in 0 to 10 minutes; Injection volume: 2 pl; Run time: 12 minutes; Detection: 254 nm and appropriate mass) to provide the final product (54 mg, 44%) as a solid. 1HRMN (CDCh) δ ppm: 8.22 (1H), 8.13 (2H), 8.00 (2H), 7.88 (1H), 7.55 (1H) 4.84 (2H), 4, 55 (2H), 4.29 (1H), 3.95 (2H), 3.89 (1H), 3.24 (3H); m / z (Cl) 644 [M + H] + Preparation 23: Coupling of general amide for parallel synthesis

[00492] The respective amine (0.05 mmol) was dissolved in DMF (0.5 ml); this was added to the respective acid (0.1 mmol), followed by a solution of O- (7-azabenzotriazol-1-yl) -N, N, N ', N'- tetramethyluronioexaflúphosphate in DMF (0.5 ml) and triethylamine (0.5 mmol). The resulting mixture was stirred at room temperature for 16 hours. The solvent was removed by vacuum distillation and the crude product purified by preparative HPLC.
[00493] Preparative HPLC conditions:
[00494] Instrument - Waters Autopurifer
[00495] Column - Gemini-NX 5pm, C18, 110A, 100x21.1 mm
[00496] Flow - 20 mL / minute
[00497] MP A - water with 0.1% formic acid
[00498] MP B - Acetonitrile with 0.1% formic acid
[00499] Gradient - 60% B to 95% B in 5 minutes, maintained 5 minutes
[00500] Injection volume - 1000 pl
[00501] Run time -10 minutes
[00502] Detector - PDA (260 nm) and ESI +
[00503] Preparation 24: Chiral separation of racemic products
[00504] Chiral separation of enantiomers from racemic products was performed on a preparative SFC column. SFC Prep = Berger Multigram, Column = Chiralcel OJ 30 x 250 mm 5 pm, MP A = CO2 MP B = 0.1% TEA in MeOH: CH2 Cl2, Isocratic 23% B, 120 bar, 100 mL / minute. 25: tert-butyl δ'-bromo-S'H-spiroazazididine-ST-isobenzofuranl-1-carboxylate

[00505] 4-Bromo-2- (chloromethyl) -1-iodobenzene (500 g, 1.509 moles) was dissolved in tetrahydrofuran (3750 ml) and cooled to -20 ° C. / - PrMgCI-LiCI (1.3 m solution in THF) (1275 mL, 1.66 moles) was added at less than -15 ° C. The reaction mixture was cooled to -20 ° C. 3-Oxo-azetidine-1-carboxylic acid, tert-butyl ester (310 g, 1.81 moles), as a solution in tetrahydrofuran (750 ml) was added. The reaction was warmed to room temperature for 90 minutes and then stirred overnight. A 1 m (2L) aqueous citric acid solution was added, followed by tert-butylmethyl ether (2 L). The mixture was stirred. The organic phase was separated, dried over anhydrous magnesium sulfate, filtered and evaporated to dryness to provide an orange oil. The oil was dissolved in EtOH (2.5 L) and the solution diluted with water (1 L). The mixture remained at room temperature overnight. The resulting crystals of tert-butyl 5'-bromo-3'H-spiro [azetidine-3, T-isobenzofuran] -1-carboxylate were filtered under reduced pressure and dried under vacuum at 50 ° C, providing 290 g. 1H NMR (CDCh) δ ppm: 1.49 (9H, s), 4.15 (2H, d), 4.34 (2H, d), 5.11 (2H, s), 7.38 (2H, m), 7.56 (1 H, d) .Preparation 26: tert-butyl 5'-acetyl-3'H-spiro [azetidine-3,1 '-isobenzofuran] -1 -carboxylate

[00506] In a scintillation vial containing 15 mL of EtOH, Pd (OAc) 2 (8.3 mg, 0.037 mmol) and DPPP (31 mg, 0.073 mmol) were added. The reaction vessel was purged with nitrogen gas, buffered and heated to 60 ° C for 18 hours. To this were added 5'-bromo-3'H-spiro [azetidine-3,1 '-isobenzofuran] -1 - tert-butyl carboxylate (Preparation 25, 250 mg, 0.74 mmol) and triethylamine (205 pL, 1.5 mmol) and the mixture was heated to 90 ° C for 5 minutes. Butyl vinyl ether (190 µL, 1.5 mmol) was subsequently added and the reaction was heated to 90 ° C for 4 hours under nitrogen. The reaction was cooled and 1.0 N HCI (2ml) was added at room temperature and stirred for 2 hours. The reaction was neutralized with saturated NaHCOa and extracted with EtOAc. The organic phase was dried (Na2SO4) and concentrated in vacuo. The crude material was chromatographed (12 g of Redi-Sep column) eluting from 100% hexanes to 35:65 EtOAc: hexanes to provide the intermediate (172 mg, 77%) as a solid. 1HRMN (CDCh) δ ppm: 8.01 (1H), 7.83 (1H), 7.58 (1H), 5.17 (2H) 4.35 (2H), 4.16 (2H), 2, 64 (3H), 1.51 (9H); m / z (Cl) 204 ([M + H-100] +. Preparation 27: 1 - (4-chloro-3,5-difluorophenyl) -2,2,2-trifluorethanone
OF
[00507] 5-Bromo-2-chloro-1,3-diflúorbenzene (2000 mg, 8.2 mmol) was stirred at room temperature in THF under N2 and the isopropylmagnesium chloride / LiCI reagent (1310 mg, 9.02 mmol, 6.94 ml_) was added over about 1 minute - very slight exotherm observed at ~ 30 ° C. The reaction was stirred at room temperature for 30 minutes followed by the addition of methyl trifluoroacetate (1580 mg, 12.3 mmol, 1.24 ml) for about 1 minute - slight exotherm to ~ 40 ° C. The solvents were evaporated under reduced pressure to provide the desired product. 1H NMR (CDCh) δ ppm: 8.05 (s, 2H) .Preparation 28: 5 '- (3- (3,5-dichloro-4-fluorophenyl) -4,4,4-trifluoro-2-enoyl) - tert-butyl 3'H-spiro [azetidine-3, T-isobenzofuran] -1-carboxylate

[00508] 1- (3,5-Dichloro-4-fluorophenyl) -2,2,2-trifluorethanone (Preparation 27, 59.4 g, 227 mmols) and 5'-acetyl-3'H-spiro [azetidine- 3, tert-butyl T-isobenzofuran] -1-carboxylate (Preparation 26, 60.0 g, 198 mmols) were mixed in a 1: 1 mixture of toluene and trifluoromethylbenzene (250 mL) in a three-necked flask of 1 L. A bottleneck was equipped with a modified Dean-Stark short reaction series heated with a condenser over the top and the other with a very low flow nitrogen consumption (the nitrogen input is off at the beginning of the reaction). The reaction was heated to 110 ° C. The starting material rapidly dissolved and CS2CO3 (5 g, 16 mmols) was then added. A vigorous effervescence was observed and the nitrogen flow was connected. The reaction was stirred for 1 hour, emptying the Dean-Stark trap as needed. HPLC-MS shows about 75% progress. An additional 1 g of CS2CO3 was added to the crude mixture and the reaction was stirred for an additional 1 hour. An HPLC-MS shows> 95% conversion. The crude reaction was then poured into 500 ml of TBME and filtered through a 2 "silica mass. The solvents are removed under vacuum and the resulting brown gum is again dissolved in a 1: 1 mixture of TBME: hexanes, filtered over a 5 "mass of silica and eluted with 2 L of the same solution. The organics were concentrated to dryness. The solids were dissolved in a 95: 5 mixture of hot heptane: TBME (approximately 250 mL). The solution was then slowly cooled to 0 ° C with agitation and seeded with previous batch solids. A beige solid formed after 30 minutes. The suspension was allowed to stir at 0 ° C for 2 hours. A pale beige solid was filtered (90 g, 83% yield), showed> 99% HPLC purity, and 85:15 ratio of double bonded isomers. The remaining mother liquor was concentrated to an oil (approximately 30 g) and was purified on a silica cartridge. (400 g, 10-100% TBME in hexanes over 12 CV, 100 mL / minute, ~ 254 nm). Another 13 g of material is isolated. Analytical method: Xbridge phenyl column (250 mm x 3.0 mm); 70% to 100% for 25 minutes, methanol with 0.1% TFA in water with 0.1% TFA, ~ 254 nm: 16.019 minutes (84.5% largest isomer) and 16.439 minutes (14.9%, smaller isomer). LC-MS method: Xbridge C18 column; 90% to 100% Acetonitrile / Methanol 1: 1 with water; [546] Ms + - 4,970 minutes, ~ 254 nm (single peak). Preparation 29: 5 '- (5- (3,5-dichloro-4-fluorophenyl) -5- (trifluoromethyl) -4,5-dihydroisoxazole -3-yl) -3'H-spiro [azetidine-3, T-isobenzofuran] -1- chiral tert-butyl carboxylate

[00509] A solution of 5 '- (3- (3,5-dichloro-4-fluorophenyl) -4,4,4-trifluoro-2-enoyl) -3'H-spiro [azetidine-3, T-isobenzofuran ] (Z) -tert-butyl -1-carboxylate (Preparation 28, 1.0 g, 1.83 mmol) in dichloroethane (8 mL) was cooled to -2 ° C. The catalyst, (2S) -1- (acridin-9-ylmethyl) -2 - ((F ) - hydroxy (6-methoxyquinolin-4-yl) methyl) -5-vinylquinuclidin-1-yl (180 mg , 0.37 mmol) was added and stirred to dissolve. In a separate flask, 10N aqueous sodium hydroxide (0.42 ml) was cooled to 5 ° C and 50 wt% aqueous hydroxylamine (254 mg, 3.84 mmol) was added and stirred for 10 minutes. This basic solution was added in one dose to the reaction solution. The resulting solution was stirred at 0 ° C for 1 hour. The reaction mixture was washed with water (2x10 ml). The solution was concentrated to a volume of 3 ml, and then 15 ml of methyl tert-butyl ether were added and the heterogeneous mixture was stirred at room temperature for 15 minutes. The precipitated catalyst was removed by filtration. The organic solution at this point contained a 90:10 mixture of isoxazoline enantiomers. The organics were concentrated to a volume of 3 ml and the product was allowed to slowly crystallize at room temperature and was then cooled to 0 ° C. The product was isolated by filtration to provide 910 mg (89%) of white crystals. Crystallization generally provided an enantiomeric improvement such that the percentage of active isomer is> 95%. Chiral LC: Chiralpak AD 250 x 3.0 mm column, 70:30 hexane: ethanol (0.2% diethylamine), 1.0 mL / minute, Detection at 260 nm. Retention times: 5.4 minutes and 12.4 minutes. 1H NMR, 600 mHz (CDCh) δ ppm: 7.70 (d, 1H), 7.60 (m, 4H), 5.18 (s, 2H), 4.36 (d, 2H), 4.15 (m, 3H), 3.72 (d, 1H), 1.55 (s, 9H). m / z 462 ([M + H] -Boc). The asterisk (*) depicts a chiral center.Preparation 30: 5 'hydrochloride - (5- (3,5-dichloro-4-fluorophenyl) -5- (trifluoromethyl) -4,5-dihydroisoxazol-3-yl ) -3'H-spiro [azetidine-3, T-isobenzofuran] chiral

[00510] 5 '- (5- (3,5-Dichloro-4-fl »jorfenyl) -5- (trifliJormetil) -4,5-dihydroisoxazol-3-yl) -3'H-spiro [azetidine- 3, chiral tert-butyl T-isobenzofuran] -1-carboxylate (Preparation 29, 1.1 g, 2.0 mmol) was dissolved in methanol (50 mL). A methanolic HCI solution (5 mL of a 1.25 m solution) was added and the reaction was heated to 65 ° C for 18 hours. The reaction was cooled and concentrated in vacuo to provide the intermediate (980 mg, 100%) as a solid. 1HRMN, 300 mHz (d6-DMSO) δ ppm: 9.86 (1H), 9.45 (1H), 8.14 (1H), 7.82 (3H), 7.70 (1H), 5.15 (2H), 4.41 - 4.30 (6H); m / z (Cl) 461 [M + H] (free amine). The asterisk (*) depicts a chiral center.Preparation 31: 5 'para-toluene sulfonate - (5- (3,5-dichloro-4-fluorophenyl) -5- (trifluoromethyl) -4,5-dihydroisoxazole- 3-yl) -3'H-spiro [azetidine-3, T-isobenzofuran] chiral
-TsOH.
[00511] 5 '- (5- (3,5-dichloro-4-fluorophenyl) -5- (trifluoromethyl) -4,5-dihydroisoxazol-3-yl) -3'H-spiro [azetidine-3, Chiral tert-butyl T-isobenzofuran] -1- carboxylate (Preparation 29, 162 g, 289 mmol) was dissolved in ethanol (1800 ml) and water (200 ml). P-Toluenesulfonic acid monohydrate (113 g, 577 mmol) was added and the solution was heated to 75 ° C for 3 hours. The reaction was cooled to 20 ° C and filtered to isolate the product. The product was dried to provide 167.4 g (92%) of a white powder. 1H NMR, 600 mHz (dθ-DMSO) δ ppm: 8.98 (br s, 2H), 7.92 (d, 1H), 7.80 (m, 3H), 7.70 (s, 1H), 7.50 (d, 2H), 7.15 (d, 2H), 5.15 (s, 2H), 4.40 (m, 6H), 2.25 (s, 3H); m / z (Cl) 461 [M + H] (free amine). The asterisk (*) depicts a chiral center. Example 7: 1- (5 '- (5- (3,5 <lichloro-4-fluorophenyl) -5- (trifluoromethyl) -4,5-dihydroisoxazole-3- il) -3'H-spiro [azetidine-3, T-isobenzofuran] -1-yl) -2- (methylthio) chiral ethanone
O
[00512] To a solution of 2- (methylthio) acetic acid (210 mg, 2.0 mmol) in DMF (15 mL) was added CDI (390 mg, 2.3 mmol). The reaction was stirred at room temperature for 15 minutes then TEA (1.4 mL, 9.7 mmol) and 5 '- (5- (3,5-dichloro-4-fluorophenyl) -5- (trifluoromethyl) hydrochloride -4,5-dihydroisoxazol-3-yl) -3'H-spiro [azetidine-3, T-isobenzofuran] chiral (Preparation 30, 970 mg, 2.0 mmol) were added. The reaction was stirred at room temperature for 18 hours, then diluted with 0.1 Ne NaOH extracted with EtOAc (2 x 75 ml). The combined organic phase was dried (Na2SOzi) and concentrated in vacuo. The residue was chromatographed (40 g of silica gel column) eluting 100% hexanes to 40:60 EtOAc: hexanes to provide the desired product (772 mg, 72%) as a solid. 1HRMN (CDCh) δ ppm: 7.68 (1H), 7.60 (3H), 7.54 (1H), 5.18 (2H), 4.64 (1H), 4.45 (2H), 4 , 32 (1H) 4.11 (1H), 3.72 (1H), 3.15 (2H), 2.30 (3H); m / z (Cl) 549 [M + H] +. The asterisk (*) depicts a chiral center. Example 8: 1- (5 '- (5- (3,5-dichloro-4-fluorophenyl) -5- (trifluoromethyl) -4,5-dihydroisoxazole-3- il) -3'H-spiro [azetidine-3, T-isobenzofuran] -1-yl) -2- (methylsulfinyl) chiral ethanone - mixture of diastereomers in sulfoxide

[00513] To a flask containing 18 ml of water at 0 ° C was added sodium periodate (345 mg, 1.6 mmol). Then, a solution of 1- (5 '- (5- (3,5-dichloro-4-fluorophenyl) -5- (trifluoromethyl) -4,5-dihydroisoxazol-3-yl) -3'H- spiro [azetidine-3, r-isobenzofuran] -1-yl) -2- (methylthio) chiral ethanone (Example 7, 770 mg, 1.4 mmol) in methanol (30 mL) was added while stirring. The reaction was allowed to warm to room temperature and stir overnight. Then, the reaction was diluted with water (100 ml) and the crude product was extracted with CH2 Cl2 (2 x 75 ml). The combined organic phase was dried (Na2SO4) and concentrated in vacuo. The residue was chromatographed (40 g of silica gel column) eluting from 100% hexanes to 90:10 CH2Cl2: MeOH to provide the product (658 mg, 83%) as a mixture of diastereomers. 1HRMN (CDCh) δ ppm: 7.72-7.60 (5H), 5.18 (2H), 4.69-4.62 (2H), 4.48-4.38 (2H), 4.10 (1H) 3.86-3.33 (3H), 2.87-2.83 (3H); m / z (Cl) 565 [M + H] +. The asterisk (*) depicts a chiral center. Example 9: 1- (5 '- (5- (3,5-dichloro-4-fluorophenyl) -5- (trifluoromethyl) -4,5-dihydroisoxazole-3- il) -3'H-spiro [azetidine-3, T-isobenzofuran] -1-yl) -2- (methylsulfonyl) chiral ethanone

[00514] 5 '- (5- (3,5-dichloro-4-fluorophenyl) -5- (trifluoromethyl) -4,5-dihydroisoxazol-3-yl) -3' p-toluenesulfonic acid salt Chiral H-spiro [azetidine-3, T-isobenzofuran] (Preparation 31.157 g, 248 mmol) was stirred as a suspension in methyl tert-butyl ether (700 mL) at room temperature. To this was added 0.5 N aqueous sodium hydroxide (600 ml, 300 mmol) and the mixture was stirred for 15 minutes during which time the two layers were clear. The aqueous layer was separated and the organics were washed with saturated brine (200 ml) and dried with sodium sulfate (5 gm). The organics were filtered to remove the solids.
[00515] In a separate flask, 43.2 gm (297 mmol) of 2-methanesulfonylacetic acid were dissolved in DMF (300 mL) at room temperature. Carbonyldiimidazole (45.1 gm, 271 mmol) was added portion by portion to the solution over 15 minutes to control defoaming. After addition, the solution was stirred for 15 minutes at room temperature. The ethereal solution above the amine was added to this reaction in one portion. The resulting solution was stirred at room temperature for 30 minutes. Water (800 mL) was added to quench the reaction. After stirring for two minutes, the aqueous layer is established and removed. The organic layer is stirred at room temperature for one hour. During this time, the racemate precipitated out of the reaction mixture. The mixture is then filtered through a filter aid (Celita 545) to remove the racemic material. The sulfonamide remaining in solution is greater than 99% of a single isomer. The organic solution is washed with water twice (2x1 L) and concentrated to a not entirely white solid. (138.2 gm, 96%) The residual color can be removed by dissolving the material in ethanol, stirring with 10 weight% charcoal (Darco G-60), filtering and concentrating to a solid.
[00516] Chiral HPLC of sulfonamide enantiomers: Chiralpak IA column (250 x 3.0 mm), 50/50 isocratic methyl tert-butyl ether / ethanol with 0.2% diethylamine, flow rate 1.0 mL / minute, detection at 260 nm. Retention times: 8.5 minutes (active isomer product), 16.5 minutes (inactive minor isomer). The isolated solid is 99% active isomer and 1% or less of the inactive isomer. Further enantiomeric enrichment can be obtained by stirring in MTBE (for example) and filtering out any solids that form. The product was identical to the first racemate elution enantiomer under the preparative chiral SFC conditions described in Preparation 24. 1H NMR, 600 mHz (d6-DMSO): 7.88 (d, 2H), 7.82 (d, 1H ), 7.73 (m, 2H), 5.18 (s, 2H), 4.62 (dd, 2H), 4.42 (dd, 2H), 4.28 (m, 4H), 3.20 (s, 3H); m / z (CI) 582 [M + H], The asterisk (*) depicts a chiral center.
[00517] The following chromatographic conditions were used to obtain the retention times cited for the synthesized compounds of tables 1, 2 and 3. Standard conditions
[00518] Instrument - Waters Alliance 2795 with ZQ MS ESI +
[00519] Column - Gemini-NX 5 pm, C18, 110A, 100 x 4.6 mm
[00520] Flow -1 mL / minute
[00521] MP A - water with 0.1% formic acid
[00522] MPB - Acetonitrile with 0.1% formic acid
[00523] Gradient - 50% B to 95% B in 5 minutes, maintained 5 minutes
[00524] Injection volume - 2 pl
[00525] Run time -10 minutes
[00526] Detector - PDA (260 nm) and ESI +
[00527] By the methods described here, the following examples of spirocyclic lactate from table 1 were prepared of formula 1.1a.
(1.1a) Table 1. Spirocyclic lactones


[00528] The Examples in Table 1 were named using ChemBioDraw Ultra 12.0 from ChemBioOffice 2010 and include:
[00529] 1- (cyclopropanocarbonyl) -5 '- (5- (3,5-dichloro-4-fluorophenyl) -5- (trifluoromethyl) -4,5-dihydroisoxazol-3-yl) -3'H- spiro [azetidine-3,1'-isobenzofuran] -3'-one (10);
[00530] 5 '- (5- (3,5-dichloro-4-fluorophenyl) -5- (trifluoromethyl) -4,5-dihydroisoxazol-3-yl) -1- (3-methylbutanoyl) -3' H-spiro [azetidine-3, T-isobenzofuran] -3'-one (11);
[00531] 5 '- (5- (3,5-dichloro-4-fluorophenyl) -5- (trifluoromethyl) -4,5-dihydroisoxazol-3-yl) -1- (2-hydroxy-2-methylpropanoyl ) -3'H-spiro [azetidine-3, T-isobenzofuran] -3'-one (12);
[00532] 1- (2-cyclopropylacetyl) -5 '- (5- (3,5-dichloro-4-fluorophenyl) -5- (trifluoromethyl) -4,5-dihydroisoxazol-3-yl) -3' H-spiro [azetidine-3, T-isobenzofuran] -3'-one (13);
[00533] 1-acetyl-5 '- (5- (3,5 <lichloro-4-fluorophenyl) -5- (trifluoromethyl) -4,5-dihydroisoxazol-3-yl) -3'H-spiro [ azetidine-3, T-isobenzofuran] -3'-one (14);
[00534] 5 '- (5- (3,5-dichloro-4-fluorophenyl) -5- (trifluoromethyl) -4,5-dihydroisoxazol-3-yl) -1- (1-hydroxycyclopropanecarbonyl) -3' H-spiro [azetidine-3,1'-isobenzofuran] -3'-one (15);
[00535] 1 - (cyclobutanocarboni I) -5 '- (5- (3,5-dichloro-4-fluoropheni) -5- (trifluoromethyl) -4,5-dihydroisoxazol-3-yl) -3 'H-spiro [azetidine-3, T-isobenzofuran] -3'-one (16);
[00536] 5 '- (5- (3,5-dichloro-4-fluorophenyl) -5- (trifluoromethyl) -4,5-dihydroisoxazol-3-yl) -1-pivaloyl-3'H-spiro [ azetidine-3,1 '-isobenzofuran] -3'-one (17);
[00537] 5 '- (5- (3,5-dichloro-4-fluorophenyl) -5- (trifluoromethyl) -4,5-dihydroisoxazol-3-yl) -1- (2-hydroxyacetyl) -3' H-spiro [azetidine-3, T-isobenzofuran] -3'-one (18);
[00538] 5 '- (5- (3,5-dichloro-4-fluorophenyl) -5- (trifluoromethyl) -4,5-dihydroisoxazol-3-yl) -1- (2- (1-hydroxycyclopropyl) acetyl) -3'H-spiro [azetidine-3, T-isobenzofuran] -3'-one (19);
[00539] 1-butyryl-5 '- (5- (3,5-dichloro-4-fluorophenyl) -5- (trifluoromethyl) -4,5-dihydroisoxazol-3-yl) -3'H-spiro [ azetidine-3, T-isobenzofuran] -3'-one (20);
[00540] 5 '- (5- (3,5-dichloro-4-fluorophenyl) -5- (trifluoromethyl) -4,5-dihydroisoxazol-3-yl) -1- (2- (methylthio) acetyl) -3'H-spiro [azetidine-3, T-isobenzofuran] -3'-one (21);
[00541] 5 '- (5- (3,5-dichloro-4-fluorophenyl) -5- (triflLiormethyl) -4,5-dihydroisoxazol-3-yl) -1- (2- (methylsulfinyl) acetyl) -3'H-spiro [azetidine-3, T-isobenzofuran] -3'-one (21-sulfinyl);
[00542] 5 '- (5- (3,5-dichloro-4-fluorophenyl) -5- (trifluoromethyl) -4,5-dihydroisoxazol-3-yl) -1- (2- (methylsulfonyl) acetyl) -3'H-spiro [azetidine-3, T-isobenzofuran] -3'-one (sulfonyl 21);
[00543] 1 - (2- (1 H-pyrazol-1-i) acetyl I) -5 '- (5- (3,5-dichloro-4-fluorine ni) -5- (trifluoromethyl) -4,5-dihydroisoxazol-3-yl) -3'H-spiro [azetidine-3, T-isobenzofuran] -3'-one (22);
[00544] 5 '- (5- (3,5-dichloro-4-fluorophenyl) -5- (trifluoromethyl) -4,5-dihydroisoxazol-3-yl) -1- (1- (trifluoromethyl) cyclopropanecarbonyl) -3'H-spiro [azetidine-3, T-isobenzofuran] -3'-one (23);
[00545] 5 '- (5- (3,5-dichloro-4-fluorophenyl) -5- (trifluoromethyl) -4,5-dihydroisoxazol-3-yl) -1-isobutyryl-3'H-spiro [ azetidine-3, T-isobenzofuran] - 3'-one (24);
[00546] 5 '- (5- (3,5-dichloro-4-fluorophenyl) -5- (triflLiormethyl) -4,5-dihydroisoxazol-3-yl) -1 - (2- (3-methyl- 1 H-pyrazol-1-yl) acetyl) -3'H-spiro [azetidine-3, T-isobenzofuran] -3'-one (25);
[00547] 5 '- (5- (3,5-dichloro-4-fluorophenyl) -5- (trifluoromethyl) -4,5-dihydroisoxazol-3-yl) -1- (3-hydroxy-2-methylpropanoyl ) -3'H-spiro [azetidine-3, T-isobenzofuran] -3'-one (26);
[00548] 5 '- (5- (3,5-dichloro-4-fluorophenyl) -5- (trifluoromethyl) -4,5-dihydroisoxazol-3-yl) -1- (2,2-difluoro-cyclopropanecarbonyl) - 3'H-spiro [azetidine-3, T-isobenzofuran] -3'-one (27); and
[00549] 5 '- (5- (3,5-dichloro-4-f uorfeni I) -5- (trifluorometh I) -4,5-d i-hydroisoxazol-3-yl) -1 - (4,4,4-trifluorobutanoyl) -3'H-spiro [azetidine-3, T-isobenzofuran] -3'-one (28).
[00550] By the methods described here, the following examples of spirocyclic ether from Table 2 were prepared of formula 1.2a.
Table 2. Spirocyclic ethers


>
[00551] The single enantiomer obtained by separating chiral SFC from racemic product.
[00552] Aa indicates first eluting enantiomer.
[00553] Ab indicates second eluting enantiomer.
[00554] nt - not tested.
[00555] The Examples in Table 2 were named using ChemBioDraw Ultra 12.0 from ChemBioOffice 2010 and include:
[00556] 1- (5 '- (5- (3,5-dichloro-4-fluorophenyl) -5- (trifluoromethyl) -4,5-dihydroisoxazol-3-yl) -3'H-spiro [azetidine -3, T-isobenzofuran] -1-yl) -2-methylpropan-1-one (29);
[00557] 1- (5 '- (5- (3,5-dichloro-4-fluorophenyl) -5- (trifluoromethyl) -4,5-dihydroisoxazol-3-yl) -3'H-spiro [azetidine -3, T-isobenzofuran] -1-yl) -2-hydroxyethanone (30);
[00558] cyclobutyl (5 '- (5- (3,5-dichloro-4-fluorophenyl) -5- (trifluoromethyl) -4,5-dihydroisoxazol-3-yl) -3'H-spiro [azetidine- 3, T-isobenzofuran] -1-yl) methanone (31);
[00559] (5 '- (5- (3,5-dichloro-4-fluorophenyl) -5- (trifluoromethyl) -4,5-dihydroisoxazol-3-yl) -3'H-spiro [azetidine-3 , T-isobenzofuran] -1-yl) (1-hydroxycyclopropyl) methanone (32);
[00560] N- (2- (5 '- (5- (3,5-dichloro-4-fluorophenyl) -5- (trifluororil) -4,5-dihydroisoxazol-3-yl) -3'H- spiro [azetidine-3, T-isobenzofuran] -1-yl) -2-oxoethyl) formamide (33);
[00561] 1 - (5 '- (5- (3,5-dichloro-4-fluorophen I) -5- (trifluorometh I) -4,5-d i-hydroisoxazole-S-ilJ-S'H spiroazazididine-ST-isobenzofuran-1-yl-methanone (34);
[00562] l-ÍS-íõ-ÍS.S-dichloro-fluorfenylJ-S-QriflúormetilH.õ-dihydroisoxazol-S-ilJ-S'H-spiroIazetidina-ST-isobenzofuranl-l-ilJpropan- 1-one (35 );
[00563] 1- (5 '- (5- (3,5-dichloro-4-fluorophenyl) -5- (trifluoromethyl) -4,5-dihydroisoxazol-3-yl) -3'H-spiro [azetidine -3,1'-isobenzofuran] -1-yl) -2-hydroxy-2-methylpropan-1-one (36);
[00564] 2-cyclopropyl-1- (5, - (5- (3,5-dichloro-4-fluorophenyl) -5- (trifluoromethyl) - 4,5-dihydroisoxazol-3-yl) -3'H -spiro [azetidine-3,1 '-isobenzofuran] -1-yl) ethanone (37);
[00565] 1 - (5 '- (5- (3,5-dichloro-4-fluorophenyl) -5- (trifluoromethyl) -4,5-dihydroisoxazol-3-yl) -3'H-spiro [azetidine -3,1'-isobenzofuran] -1-yl) -2,2-dimethylpropan-1-one (38);
[00566] (S-íõ-ÍS.S-dichloro-fluoro-phenyl-6-yltrifluoromethylH.õ-dihydroisoxazol-3-yl) -3'H-spiro [azetidine-3, T-isobenzofuran] -1-yl ) (1- (trifluoromethyl) cyclopropyl) -methanone (39);
[00567] 1- (5 '- (5- (3,5-dichloro-4-fluorophenyl) -5- (trifluoromethyl) -4,5-dihydroisoxazol-3-yl) -3'H-spiro [azetidine -3, T-isobenzofuran] -1-yl) -3-hydroxy-2-methylpropan-1-one (40);
[00568] 1- (5 '- (5- (3,5-dichloro-4-fluorophenyl) -5- (trifluoromethyl) -4,5-dihydroisoxazol-3-yl) -3'H-spiro [azetidine -3,1'-isobenzofuran] -1-yl) -2- (3-methyl-1H-pyrazol-1-yl) ethanone (41);
[00569] 1- (5 '- (5- (3,5-dichloro-4-fluorophenyl) -5- (trifluoromethyl) -4,5-dihydroisoxazol-3-yl) -3'H-spiro [azetidine -3, T-isobenzofuran] -1-yl) -3-methylbutan-1-one (42);
[00570] 1- (5 '- (5- (3,5-dichloro-4-fluorophenyl) -5- (trifluoromethyl) -4,5-dihydroisoxazol-3-yl) -3'H-spiro [azetidine -3,1'-isobenzofuran] -1-yl) -2- (1H-pyrazol-1-yl) ethanone (43);
[00571] 14 5hydroisoxazol-3-yl) -3H-spiro [azetidma-3,1-isobenzofuran] -1-yl) -3-hydroxybutan-1-one (44),
[00572] cyclopropyl (5- (5- (3,5-dichloro-4-fluorophenyl) -5- (tπfluormethyl) -4,5-dihydroisoxazol-3-yl) -3'H-spiro [azetidine-3 , T-isobenzofuran] -1-yl) methanone (45);
[00573], h, drolsoxazol-3-ll) -3H-esplro [azetldlna-3,1-lsobenZofuran] -1-ll) butan-l-one (46),
[00574] (5L 5j: hydroisoxazol-3-yl) -3 H-spiro [azetidma-3, T-isobenzofuran] -1-yl) (tietan-3-yl) methanone (47);
[00575] 1- (5- (5- (3,5-dichloro-4-fluorophenyl) -5- (trifluoromethyl) -4,5-dihydroisoxazol-3-yl) -3'H-spiro [azetidine- 3, r-isobenzofuran] -1-yl) -2 - (- emsulfoniDetanone (48),
[00576] 14 5: 5— “- ^ uormeblK5 ^ hydroisoxazol-3-yl) -3 H-spiro [azetidma-3, T-isobenzofuran] -1-yl) -2- (methylsulfonyl) chiral ethanone (48a, b );
[00577] (5 '- (5- (3,5-dichloro-4-fluorophenyl) -5- (trifluororil) -4,5-dihydroisoxazol-3-yl) -2', 3'-dihydrospiro [azetidine-3,1'-isobenzofuran] -1-yl) (1,1-dioxidotietan-3-yl) chiral methanone (49a);
[00578] 2- (methylsulfonyl) -1- (5, - (5- (3,4,5-trichlorophenyl) -5- (trifluoromethyl) -4,5-dihydroisoxazol-3-yl) -3'H -spiro [azetidine-3,1 '-isobenzofuran] -1-yl) ethanone (50);
[00579] 14'5 hydrosoxazol-3-yl) -3H-spiro [azetidine-3,1-isobenzofuran] -1-yl) -2- (methylsulfonyl) ethanone (51);
[00580] 1- (5 '- (5- (3-chloro-5- (trifluoromethyl) phenyl) -5- (trifluoromethyl) -4,5-di- (methylsulfonyl) ethanone (52);
[00581] 1 - (5 '- (5- (3,4-dichloro-5- (trifl uormeti I) pheni I) -5- (trifl uormeti I) -4,5-dihydro-isoxazole-3 -yl) -3'H-spiro [azetidine-3, T-isobenzofuran] -1-yl) -2- (methylsulfonyl) -ethanone (53);
[00582] 1- (5 '- (5- (4-bromo-3,5-dichlorophenyl) -5- (trifluoromethyl) -4,5-dihydroisoxazol-3-yl) -3'H-spiro [azetidine -3, T-isobenzofuran] -1-yl) -2- (methylsulfonyl) ethanone (54);
[00583] 1- (5 '- (5- (3,5-bis (trifluoromethyl) phenyl) -5- (trifluoromethyl) -4,5-dihydroisoxazol-3-yl) -3'H-spiro [azetidine -3, T-isobenzofuran] -1-yl) -2- (methylsulfonyl) ethanone (55);
[00584] 1- (5 '- (5- (3-bromo-5-chlorophenyl) -5- (trifluoromethyl) -4,5-dihydroisoxazol-3-yl) -3'H-spiro [azetidine-3 , T-isobenzofuran] -1-yl) -2- (methylsulfonyl) ethanone (56);
[00585] 1- (5, - (5- (4-chloro-3,5-bis (trifluoromethyl) phenyl) -5- (trifluoromethyl) - 4,5-dihydroisoxazol-3-yl) -3'H -spiro [azetidine-3,1 '-isobenzofuran] -1-yl) - 2- (methylsulfonyl) ethanone (57);
[00586] 1- (5 '- (5- (3-chloro-5-fluorophenyl) -5- (trifluoromethyl) -4,5-dihydroisoxazol-3-yl) -3'H-spiro [azetidine-3 , T-isobenzofuran] -1-yl) -2- (methylsulfonyl) ethanone (58);
[00587] 1 - (5 '- (5- (3-chloro-4-phosphorus I) -5- (trifluoromethyl I) -4,5-d i-hydroisoxazol-3-yl) -3'H -spiro [azetidine-3, T-isobenzofuran] -1-yl) -2- (methylsulfonyl) ethanone (59); and
[00588] 2- (methylsulfonyl) -1- (5, - (5- (trifluoromethyl) -5- (3- (trifluoromethyl) phenyl) - 4,5-dihydroisoxazol-3-yl) -3'H- spiro [azetidine-3,1 '-isobenzofuran] -1-yl) ethanone (60).
[00589] By the methods described here, the following examples of spirocyclic lactam from Table 3 were prepared of formula 1.3a.
Table 3. Spirocyclic lactams

[00590] nt - not tested.
[00591] The Examples in Table 3 were named using ChemBioDraw Ultra 12.0 from ChemBioOffice 2010 and include:
[00592] 5 '- (5- (3,5-dichloro-4-fluorophenyl) -5- (trifluoromethyl) -4,5-dihydroisoxazol-3-yl) -1- (2- (methylsulfonyl) acetyl) spiro [azetidine-3, T-isoindolin] -3'-one (61);
[00593] 1- (cyclopropanocarbonyl) -5 '- (5- (3,5-dichloro-4-fluorophenyl) -5- (trifluoromethyl) -4,5-dihydroisoxazol-3-yl) spiro [azetidine-3 , T-isoindolin] - 3'-one (62);
[00594] 5 '- (5- (3,4-dichloro-5- (trifliJormetyl) phenyl) -5- (trifliJormetyl) -4,5-dihydroisoxazol-3-yl) -1- (2- (methylsulfonyl ) acetyl) spiro [azetidine-3, T-isoindolin] -3'-one (63);
[00595] 1- (2- (methylsulfonyl) acetyl) -5 '- (5- (3,4,5-trichlorophenyl) -5- (trifluoromethyl) -4,5-dihydroisoxazol-3-yl) spiro [ azetidine-3, T-isoindolin] -3'-one (64);
[00596] 5 '- (5- (3-chloro-5- (trifluoromethyl) phenyl I) -5- (trifluoromethyl) -4,5-dihydroisoxazol-3-yl) -1- (2 - (methylsulfonyl) acetyl) spiro [azetidine-3, T-isoindolin] -3'-one (65);
[00597] 5, - (5- (4-bromo-3,5-dichlorophenyl) -5- (trifluoromethyl) -4,5-dihydroisoxazol-3-yl) -1- (2- (methylsulfonyl) acetyl) spiro [azetidine-3, T-isoindolin] -3'-one (66);
[00598] 5 '- (5- (3,5-dichlorophenyl) -5- (trifluoromethyl) -4,5-dihydroisoxazol-3-yl) -1 - (2- (methylsulfonyl) acetyl) spiro [azetidine- 3,1isoindolin] -3'-one (67);
[00599] 5 '- (5- (3,5-dichloro-4-fluorophenyl) -5- (trifluoromethyl) -4,5-dihydroisoxazol-3-yl) -1- (tiethane-3-carbonyl) spiro [azetidine-3, T-isoindolin] - 3'-one (68);
[00600] 5 '- (5- (3,5-dichloro-4-fluorophenyl) -5- (trifluoromethyl) -4,5-dihydroisoxazol-3-yl) -1- (1,1-dioxidotiethane-3 -carbonyl) spiro [azetidine-3, T-isoindolin] -3'-one (69);
[00601] 5 '- (5- (3,5-bis (trifliJormetyl) phenyl) -5- (triflLiormethyl) -4,5-dihydroisoxazol-3-yl) -1- (cyclopropanecarbonyl) spiro [azetidine-3 , T-isoindolin] -3'-one (70);
[00602] 5 '- (5- (3-chloro-5- (trifluoromethyl) phenyl I) -5- (trifluoromethyl) -4,5-dihydroisoxazol-3-yl) -1- (cyclopropanecarbonyl) ) spiro [azetidine-3, T-isoindolin] -3'-one (71);
[00603] 5 '- (5- (4-bromo-3,5-dichlorophenyl) -5- (trifluoromethyl) -4,5-dihydroisoxazol-3-yl) -1- (cyclopropanecarbonyl) spiro [azetidine-3 , T-isoindolin] -3'-one (72);
[00604] 2, -methyl-1- (2- (methylsulfonyl) acetyl) -5 '- (5- (3,4,5-trichlorophenyl) -5- (trifluoromethyl) -4,5-dihydroisoxazole-3 -yl) spiro [azetidine-3, T-isoindolin] - 3'-one (73);
[00605] 5 '- (5- (3,5-dichloro-4-fluorophenyl) -5- (trifluoromethyl) -4,5-dihydroisoxazol-3-yl) -2'-methyl-1- (2- (methylsulfonyl) acetyl) spiro [azetidine-3, T-isoindolin] -3'-one (74); and
[00606] 1- (cyclopropanocarbonyl) -2'-methyl-5 '- (5- (3,4,5-trichlorophenyl) -5- (trifluoromethyl) -4,5-dihydroisoxazol-3-yl) spiro [ azetidine-3, T-isoindolin] - 3'-one (75).
[00607] More NMR data is provided for specific examples in Table 4.Table 4. NMR data obtained for specific examples


BIOLOGICAL TESTS
[00608] The biological activity of the compounds of the present invention can be tested against hard tick larvae, soft ticks, fleas and horn flies, using the test methods described below. Adult Flea Membrane Feeding Test (Ctenocephalides fel is)
[00609] The compounds of formula (1) were dissolved in DMSO and aliquots added to citrated bovine blood in a membrane coated Petri dish preheated to 37 ° C. Feed tubes containing approximately 30 to 35 adult fleas were placed on Petri dishes. Fleas were allowed to feed for approximately 2 hours. Fleas were observed for slaughter and / or death in approximately 2 and 24 hours. Final data were recorded as the 80% lethal dose (LD80) in pg / mL. In this assay, Examples 1-3, 5, 9, 13, 20, 21, 27-30, 35, 37, 42-43, 45-46, 48, 49a, 52 and 54-60 had an LD80 <1 pg / ml; Examples 8, 10-11, 36, 48b, 51 and 53 had an LD80 <3 pg / ml; Examples 14-19 and 25 had an LD80 <30 pg / ml; and Examples 61-64 had an LD80 <100 pg / ml. Soft Tick Blood Feeding Test (Ornitidorus turicata)
[00610] Compounds of formula (1) were dissolved in dimethylsulfoxide (DMSO) and aliquots added to citrated bovine blood in a membrane-coated Petri dish. The Petri dish was placed on a heating tray. Approximately 5 nymph stage ticks were placed on the membrane, covered and allowed to feed. The fed ticks were removed and placed in a petri dish with sand. The fed ticks were observed in approximately 24, 48 and 72 hours for paralysis and / or death. Final data were recorded as an ED100 and / or an LD100 in pg / mL. Positive control was fipronil and DMSO was used as the negative control. In this assay, Examples 5, 9, 29, 35, 49a and 51-59 had an LD100 <0.01 pg / ml_; Examples 3, 13, 21, 28, 30, 36-37, 42- 43, 45-46, 48, 50 and 60 had an LD100 <0.03 pg / ml; and Examples 1-2, 11 and 27 had an LD100 <0.1 pg / ml. Horn Fly Feed Test (Haematobia irritans)
[00611] Compounds of formula (1) were dissolved in DMSO and aliquots added to citrated bovine blood in a membrane-coated Petri dish. Approximately ten horn flies were placed over each petri dish and covered. The flies were then allowed to feed on the treated blood cell. The flies were kept at approximately 80 ° F with a minimum of approximately 50% relative humidity. The flies were examined for slaughter and mortality in approximately 2 and 24 hours. Final data were recorded as a 90% lethal dose (LD90) in pg / mL. In this assay, Examples 9, 35, 37 and 49a had an LD90 of <0.3 pg / ml; Examples 2, 29, 30, 45, 46 and 48 had an LD90 of <1 pg / ml; and Examples 1, 3, 5, 42 and 43 had an LD90 of <3 pg / ml.

权利要求:
Claims (20)
[0001]
1. Compound, characterized by the fact that it presents the formula (1)
[0002]
2. Compound according to claim 1, characterized by the fact that R3 is -CF3, stereoisomers thereof, and veterinarily acceptable salts thereof.
[0003]
3. Compound according to claim 2, characterized by the fact that it is selected from the group consisting of: 1- (5 '- (5- (3,5-dichloro-4-fluorophenyl) -5- (trifluoromethyl) -4,5-dihydroisoxazol-3-yl) -3'H-spiro [azetidine-3, T-isobenzofuran] -1-yl) -2- ((trifluoromethyl) thio) ethanone; (5 (5- ( 3,5-dichloro-4-fluorine ni I) -5- (trifluoromethyl) -4,5-dihydroisoxazol-3-yl) -3'H-spiro [azetidine-3, T -isobenzofuran] -1-yl) (1-oxothietan-3-yl) methanone; (5 '- (5- (3,5-dichloro-4-fluorophenyl) -5- (trifluoromethyl) -4,5-di- hydroisoxazol-3-yl) -3'H-spiro [azetidine-3, T-isobenzofuran] -1-yl) (1,1-dioxidotietan-3-yl) methanone; 1- (5 '- (5- (3 , 5-dichloro-4-fluorophenyl) -5- (trifluoromethyl) -4,5-dihydroisoxazol-3-yl) -3'H-spiro [azetidine-3, T-isobenzofuran] -1-yl) -2 - (methylthio) ethanone; (R) -1- (5 '- (5- (3,5-dichloro-4-fluorophenyl) -5- (trifluoromethyl) -4,5-dihydroisoxazol-3-yl) - 3'H-spiro [azetidine-3, T-isobenzofuran] -1-yl) -2- (methylthio) ethanone; (S) -1- (5 '- (5- (3,5-dichloro-4-fluorophenyl) ) -5- (trifluoromethyl) -4,5-dihydroisoxazol-3-yl) -3'H-spiro [az ethidine-3, T-isobenzofuran] -1-yl) -2- (methylthio) ethanone; 1- (5 '- (5- (3,5-dichloro-4-fluorophenyl) -5- (trifluoromethyl) -4, 5-dihydroisoxazol-3-yl) -3'H-spiro [azetidine-3, T-isobenzofuran] -1-yl) -2- (methylsulfinyl) ethanone; (R) -1- (5 '- (5 - (3,5-dichloro-4-fluorophenyl) -5- (trifluoromethyl) -4,5-dihydroisoxazol-3-yl) -3'H-spiro [azetidine-3, T-isobenzofuran] -1-yl ) -2- (methylsulfinyl) ethanone; .... (S) l1 * h, dr ° "'D-3 H-spiro [azetidma-3,1 ^ enzofu-anH - ^ - (methylsulfimyl) ethanone, 1 - (5 - (5- (3,5-dichloro- 4-fluorophenyl) -5- (tnfluormethyl) -4,5-dihydroisoxazol-3-yl) -3'H-spiro [azetidine-3, T-isobenzofuran] -1-yl) -2- (methylsulfonyl) ethanone ; .... (R 1: <T (3'5-d “: 5- (nfluorm“ Z H-esP — na-3,1 ^ enzofu-anH - ^ - (methylsulfoml) ethanone, .... (S) l1 "z -3 -") - 3 H-spiro [azetidma-3.1 nsoPenzofu-anH ^ - (methylsulfoml) ethanone, .... H: (5jh, dr "3HD-3 H-spiro [ azetidma-3,1 nsoPenzofu-anH - ^ - metHpropan-l-one, 1 - (5 - (5- (3,5-dichloro-4-fluorine ni I) -5- (tnfl úormeti I) - 4,5-d i-hydroisoxazol-3-yl) -3'H-spiro [azetidine-3, T-isobenzofuran] -1-yl) -2-hydroxyethanone; cyclobutyl (5 '- (5- (3,5 -dichloro-4-fluorophenyl) -5- (trifluoromethyl) -4,5-dihydroisoxazol-3-yl) -3'H-spiro [azetidine-3, T-isobenzofuran] -1- iDmethanone; (5- ( 5- (3,5-dichloro-4-fluorophen I) -5- (tnfl úormeti I) -4,5-d i .... H1 - (5 - (5- (3,5-dichloro- 4-fluorophenyl) -5- (tnfluormethyl) -4,5-dihydroisoxazol-3-yl) -3'H-spiro [azetidine-3, T-isobenzofuran] -1-yl) propan -.... ' ■ ““ “- 'W H-spire [aietidins-3,1 -.> - 3-2-cyclopropyl-1- (5- (5- (3,5-dichloro-4-fluorophenyl) -5- (tπfluormethyl) - 4,5-di -hydroisoxazol-3-yl) -3'H-spiro [azetidine-3,1 '-isobenzofuranJ-1 - .... “- iip3H-aspira [.zaiiaina-3, iasabanzofur.n | -ia!) (i -.... H -5-1 ™ - "“ ■ w-31 - (5 - (5- (3,5-dichloro-4-fluorophenyl) -5- (tπfluormethyl) -4,5-dihydroisoxazole -3-yl) -3'H-spiro [azetidine-3, T-isobenzofuran] -1-yl) -2- (3-methyl-1H-pyrazol-1-yl) ethanone; 1- (5'- (5- (3,5-dichloro-4-fluorophenyl) -5- (trifluoromethyl) -4,5-dihydroisoxazol-3-yl) -3'H-spiro [azetidine-3, T-isobenzofuran] -1 -yl) -3- methylbutan-1-one; 1- (5- (5- (3,5-dichloro-4-fluorophenyl) -5- (tπfluormethyl) -4,5-di - '"" -' I "" ”'.... HH-spiro | azeli3ins-3,1« -, ..> - 3-cyclopropyl (5- (5- (3,5-dichloro-4-fluorophenyl) -5- (tπfluormethyl ) -4,5-dihydroisoxazol-3-yl) -3'H-spiro [azetidine-3, T-isobenzofuran] -1- .... '■. hd [0! SoxszolO-i!) - 3 H-8spi [0 [8istidiπs-3,1 ^ sobaπzoiuranl-l-ill & utsn-l-one, (5 - (5- (3,5-d I chlorine-4- f I uorfe ni I) -5- (t π fluormeti I) -4, 5-d i -hydroisoxazol-3-yl) -3'H-spiro [azetidine-3, T-isobenzofuran] -1-yl) (tietan-, RMd -_, ^ iSH -3 Hdspiro [aze, ld! dd-3.12- (methylsulfonyl) -1- (5- (5- (3,4,5-tπchlorophenyl) -5- (tπfluormethyl) - 4,5-dihydroisoxazol-3-yl) -3'H-spiro [azetidine-3,1 '-isobenzofuranJ-1-yl) ethanone; 1- (5' - (5- (3,5-dichlorophenyl) -5- (trifluoromethyl) -4,5-dihydroisoxazol-3-yl) -3'H-spiro [azetidine-3, T-isobenzofuran] -1-yl) -2- (methylsulfonyl) ethanone; 1- ( 5 '- (5- (3-chloro-5- (trifliJormethyl) phenyl) -5- (trifliJormethyl) -4,5-di- I ™ ”» ”» -' 1 - (5 - (5- (4- bromo-3,5-dichlorophenyl) -5- (tπfluormethyl) -4,5-dihydroisoxazol-3-yl) -3'H-spiro [azetidine-3, T-isobenzofuran] -1-yl) -2- 1- (5 '- (5- (3,5-bis (trifluoromethyl) phenyl) -5- (trifluoromethyl) -4,5-dihydroisoxazol-3-yl) -3'H-spiro [azetidine-3, T-isobenzofuran] -1-yl) -2- (methylsulfonyl) ethanone; (R) -1- (5- (5- (3,5-bis (tnfluormethyl) phenyl) -5- (tπfluormethyl) -4,5 -di- hydroisoxa zol-3-yl) -3'H-spiro [azetidine-3, T-isobenzofuran] -1-yl) -2 -...., s <'* ....' ■ hd [θ! sαxs; o-3-i!) - 3H-8spi [θ [azst! diiia <3,1-i8θbβiizotijrsπ | -1-il) -2- «" 'W — 1 - (5 - (5- (3-chloro- 5-fluorophenyl) -5- (tπfluormethyl) -4,5-dihydroisoxazol-3-yl) -3'H-spiro [azetidine-3, T-isobenzofuran] -1-yl) -2- (methylsulfonyl) ethanone ; 1- (5 '- (5- (3-chloro-4-fluorine ni I) -5- (trifluoromethyl) -4,5-d i-hydroisoxazol-3-yl) -3'H- spiro [azetidine-3,1'-isobenzofuran] -1-yl) -2- (methylsulfonyl) ethanone; (R) -1- (5 '- (5- (3-chloro-4-fluorophenyl) -5- ( trifluoromethyl) -4,5-di-hid ™ ^^ (mewsulfondjetanone, .... - <^ - <3 - ^^ hydro soxazol-S-ylJ-SH-spirofazetidine-SI-isobenzofuran] -1-yl) -2- (meblsulfomljetanone, 2- (methyl Isulfonyl) -1 - (5 - (5- (tnfl uormeti I) -5- (3- (t rifl uormeti I) fe n 11) - 4,5-dihydroisoxazol-3-yl) -3'H-spiro [azetidine-3,1 '-isobenzofuran- 1 - yl) ethanone; (R) -2- (methyl Isulfonyl) -1 - (5 '- (5- (trifluoromethyl) -5- (3- (trifluoromethyl) phenyl) -4,5-di- hydroisoxazol-3-yl) -3'H-spiro [azetidine-3,1'-isobenzofuran] -1-yl) ethanone; (S) -2- (methylsulfonyl) -1- (5 '- (5- (trifluoromethyl ) -5- (3- (trifluoromethyl) phenyl) -4,5-dihydroisoxazol-3-yl) -3'H-spiro [azetidine-3, T-isobenzofuran] -1 -yl) ethanone; or a stereoisomer or a veterinarily acceptable salt thereof.
[0004]
4. Compound according to claim 3, characterized by the fact that it is selected from the group consisting of: 1- (5 '- (5- (3,5-dichloro-4-fluorophenyl) -5- (trifluoromethyl) - 4,5-dihydroisoxazol-3-yl) -3'H-spiro [azetidine-3, T-isobenzofuran] -1-yl) -2- (methylthio) ethanone; (R) -1- (5'- (5- (3,5-dichloro-4-fluorophenyl) -5- (trifluoromethyl) -4,5-dihydroisoxazol-3-yl) -3'H-spiro [azetidine-3, T-isobenzofuran] -1 -yl) -2- (methylthio) ethanone; (S) -1- (5 '- (5- (3,5-dichloro-4-fluorophenyl) -5- (trifluoromethyl) -4,5-dihydroisoxazole- 3-yl) -3'H-spiro [azetidine-3, T-isobenzofuran] -1-yl) -2- (methylthio) ethanone; 1- (5 '- (5- (3,5-dichloro-4- fluorophenyl) -5- (trifluoromethyl) -4,5-dihydroisoxazol-3-yl) -3'H-spiro [azetidine-3, T-isobenzofuran] -1-yl) -2- (methylsulfinyl) ethanone; ( R) -1- (5 '- (5- (3,5-dichloro-4-fluorophenyl) -5- (trifluoromethyl) -4,5-dihydroisoxazol-3-yl) -3'H-spiro [azetidine -3, T-isobenzofuran] -1-yl) -2- (methylsulfinyl) ethanone; (S) -1- (5 '- (5- (3,5-dichloro-4-fluorophenyl) -5- (triflLiormethyl) -4,5-dihydroisoxazol-3-yl) -3'H-spiro [azetidine-3, T-is obenzofuran] -1-yl) -2- (methylsulfinyl) ethanone; 1- (5 '- (5- (3,5-dichloro-4-fluorophenyl) -5- (trifluoromethyl) -4,5-di-h, dro are -3-.D-3 H-spiro [azetidma-3,1 -.sobenzofuranM -,! ^ (methylsulfoml) ethanone, .... (R “z H-esP — na-3,1 -, sobenzofuranl-1-, l) -2- (methylsulfoml) ethanone, (S) -1- (5- (5- (3,5-dichloro-4 -fluorfenil) -5- (tπfluormetil) -4,5-di- - Td! l> iaroi∞xszoW-i!) - 3H-8sp! ro | aist.ains-3,1-.sobsmαiuranl-l-.IXU - dioxidotietan-3-yl) methanone; 1- (5 '- (5- (3,5-bis (triflLiormethyl) phenyl) -5- (triflLiormethyl) -4,5-dihydroisoxazol-3-yl) -3 'H-spiro [azetidine-3, T-isobenzofuran] -1-yl) -2- (methylsulfonyl) ethanone; (R) -1- (5' - (5- (3,5-bis (trifliJormethyl) phenyl) -5- (trifliJormetil) -4,5-dihydroisoxazol-3-yl) -3'H-spiro [azetidine-3, T-isobenzofuran] -1-yl) -2- (methylsulfonyl) ethanone; ... ...... (R) -1- (5- (5- (3-chloro-4-fluorophenyl) -5- (tπfluormethyl) -4,5-dihydroisoxazol-3-yl) -3'H -spiro [azetidine-3, T-isobenzofuran] -1-yl) -2- (methylsulfonyl) ethanone; (S) -1- (5 '- (5- (3-chloro-4-fluorophenyl) -5- ( trifluoromethyl) -4,5-dihydroisoxazol-3-yl) -3'H-spiro [azetidine-3, T-isobenzofuran] -1-yl) -2- (methylsulfonyl) ethanone; 2- (methyl Isulfonyl) - 1 - (5 '- (5- (fluorine I) -5- (3- (fluorine I) fe ni I) - 4,5-dihydroisoxazol-3-yl) -3'H-spiro [azetidine -3,1 '-isobenzofuranJ-1 - yl) ethanone; (R) -2- (methyl Isulfonyl) -1 - (5' - (5- (trifluoromethyl)) -5- (3- (trifluoromethyl) phenyl) -4,5-dihydroisoxazol-3-yl) -3'H-spiro [azetidine-3, T-isobenzofuran] -1-yl) ethanone; and (S) -2- (methyl Isulfonyl) -1 - (5 '- (5- (trifluoromethyl)) -5- (3- (trifluoromethyl) phenyl) -4,5-dihydroisoxazol-3-yl ) -3'H-spiro [azetidine-3, T-isobenzofuran] -1-yl) ethanone or an stereoisomer of the same, or a veterinarily acceptable salt thereof.
[0005]
5. Compound according to claim 4, characterized by the fact that it is selected from: 1 - (5 '- (5- (3,5-dichloro-4-fluorine ni I) -5- (t fluoromethyl I) -4,5-dihydroisoxazol-3-yl) -3'H-spiro [azetidine-3, T-isobenzofuran] -1-yl) -2- (methylsulfonyl) ethanone; (R) - 1- (5 '- (5- (3,5-dichloro-4-fluorophenyl) -5- (trifluoromethyl) -4,5-dihydroisoxazol-3-yl) -3'H-spiro [azetidine-3, T-isobenzofuran] -1-yl) -2- (methylsulfonyl) ethanone; (S) -1- (5 '- (5- (3,5-dichloro-4-fluorophenyl) -5- (trifluoromethyl) -4, 5-dihydroisoxazol-3-yl) -3'H-spiro [azetidine-3, T-isobenzofuran] -1-yl) -2- (methylsulfonyl) ethanone; or a stereoisomer thereof, or a veterinarily acceptable salt of themselves.
[0006]
6. Compound, characterized by the fact that it is selected from the group consisting of: tert-butyl S'-bromo-S'H-spiroIazetidine-SJ'-isobenzofuranJ-1-carboxylate; 1-benzhydryl-5, -bromo-3, H-spiro [azetidine-3, T-isobenzofuran]; tert-butyl δ'-acetyl-S'H-spiroazazididine-ST-isobenzofuranJ-1-carboxylate; l-yl-benzhydryl-S'H-spiroIazetidine-ST- isobenzofuranl-S'-yl) ethanone; 5 '- (3- (3,5-dichloro-4-furor ni I) -4,4,4-triflur ut-2-e noi I) -3 'H - spiro [azetidine-3, T-isobenzofuran] -1-tert-butylcarboxylate; 5' - (5- (3,5-dichloro-4-fluorine ni I) -5- (trifluorine) I) -4,5-di-hydroisoxazol-3-yl) -3'H-spiro [azetidine-3, T-isobenzofuran] -1- (R) -tert-butyl carboxylate; 5 '- (5- ( 3,5-dichloro-4-fluorine n I) -5- (trifluoromethyl) -4,5-d i -hydroisoxazol-3-yl) -3'H-spiro [azetidine-3, (S) -tert-butyl T-isobenzofuran] -1- (E / Z) -1 - (1-benzhydryl-3'H-spiro [azetidine-3,1 '-isobenzofuranj-5'-yl) -3- (3,5-dichloro-4-fluorophenyl) -4,4,4-trifluoro-2-en-1-one; 5 '- (5- (3,5-dichloro -4-f uorphi ni) -5- (trifl uormeti I) -4,5-d i-hydroisoxazol-3-yl) -3'H-spiro [azetidine-3, T-isobenzofuran] -1- carboxylate tert-butyl; (R) -5 '- (5- (3,5-dichloro-4-fluorophenyl) - 5- (trifluoromethyl) -4,5-dihydroisoxazol-3-yl para-toluene sulfonate) -3'H-spiro [azetidine-3, r-isobenzofuran]; (S) -5 '- (5- (3,5-dichloro-4-fluorophenyl) para-toluene sulfonate - 5- (trifluoromethyl) -4 , 5-dihydroisoxazol-3-yl) -3'H-spiro [azetidine-3, r-isobenzofuran]; 1-benzhydryl-5 '- (5- (3,5-dichloro-4-fluorophenyl) -5 - (trifluoromethyl) -4,5-dihydroisoxazol-3-yl) -3'H-spiro [azetidine-3, T-isobenzofuran]; (R) -1-benzhydryl-5 '- (5- (3, 5-dichloro-4-fluorophenyl) -5- (trifliJormethyl) - 4,5-dihydroisoxazol-3-yl) -3, H-spiro [azetidine-3, T-isobenzofuran]; (S) -1-benzhydryl -5 '- (5- (3,5-dichloro-4-fluorophenyl) -5- (trifluoromethyl) -4,5-dihydroisoxazol-3-yl) -3'H-spiro [azetidine-3.1' -isobenzofuran]; and 5 '- (5- (3,5-dichloro-4-fluorophenyl) -5- (trifluoromethyl) -4,5-dihydroisoxazol-3-yl) -3'H-spiro [azetidine para-toluene sulfonate -3, T-isobenzofuran], or a stereoisomer thereof, or a veterinarily acceptable salt thereof.
[0007]
7. Veterinary composition, characterized by the fact that it comprises a compound as defined in any one of claims 1 to 6, stereoisomers thereof, and veterinarily acceptable salts thereof.
[0008]
8. Veterinary composition according to claim 7, characterized by the fact that it further comprises an excipient, a diluent or a veterinarily acceptable vehicle.
[0009]
9. Veterinary composition according to claim 8, characterized by the fact that it also comprises at least one additional veterinary agent.
[0010]
10. Veterinary composition according to claim 9, characterized by the fact that said additional veterinary agent is selected from the group consisting of abamectin, ivermectin, avermectin, moxidectin, emamectin, eprinomectin, selamectin, doramectin, nemadectin, albendazole, cambendazole, fenbendazole, flubendazole, mebendazole, oxfenbendazole, oxybendazole, parbendazole, tetramisol, levamisole, pyrantel pamoate, oxantel, morantel, indoxacarb, closantel, triclabendazole, clorsulon, refoxanide, pyroxamide, pyrolamide, niclosamide eespiromesifen, tebufenozide, eespinosad, espinetoram, imidacloprid, dinotefuran, metaflumizone, tibendiamide, chlorantraniliprol, indoxacarb, pyridalil, pyrimidifene, pyrifluquinazon, milbemycin oxime, milbemyline, hydroxymethrin, myrethine, demiditraz, themselves.
[0011]
11. Use of a compound of formula 1
[0012]
12. Use, according to claim 11, characterized by the fact that said drug is administered topically, orally or subcutaneously.
[0013]
13. Use, according to claim 12, characterized by the fact that the animal is a pet animal.
[0014]
14. Process for the preparation of a compound of
[0015]
15. Process according to claim 14, characterized in that: R1a, R1b and R1c are each independently hydrogen, chlorine, fluorine, bromine or trifluoromethyl; R5 is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t- butyl, cyclopropyl or cyclobutyl, wherein each substituent can be optionally and independently substituted by at least one substituent selected from halo, hydroxyl, Ci-Cehaloalkyl, Ci- Cβalkyl or -S (O) PRC; or R5 is tiethanyl, pyrazolyl or -CH2pyrazolyl, wherein each substituent can also optionally be substituted with at least one substituent selected from oxo or C1-Cealkyl; eRc is methyl or ethyl, stereoisomers thereof, and veterinarily acceptable salts thereof.
[0016]
16. Process according to claim 15, characterized by the fact that: R1a and R1c are each chlorine, R1b is fluorine; R5 is -CH2S (O) 2CH3; stereoisomers thereof, and veterinarily acceptable salts thereof.
[0017]
17. Process according to claim 14, characterized in that, optionally in a solvent, the iodobromobenzyl derivative is 4-bromo-2- (chloromethyl) -1-iodobenzene and the protected azetidinone is tert-butyl acid ester 3-oxo-oazetidine-1-carboxylic or 1-benzhydrylazetidin-3-one.
[0018]
18. A compound according to claim 1, characterized by the fact that it is (S) -1- (5 '- (5- (3,5-dichloro-4-fluorophenyl) -5- (trifluoromethyl) -4,5 -dihydroisoxazol-3-yl) -3'H-spiro [azetidine-3, T-isobenzofuran] -1-yl) -2- (methylsulfonyl) ethanone and veterinarily acceptable salts thereof.
[0019]
19. Veterinary composition, characterized by the fact that it comprises a compound as defined in claim 18, and veterinarily acceptable salts thereof.
[0020]
20. Use of the compound as defined in claim 18, and veterinarily acceptable salts thereof, characterized by the fact that it is for the manufacture of a medicament for the treatment of a parasitic infection in an animal.

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法律状态:
2019-02-05| B07D| Technical examination (opinion) related to article 229 of industrial property law [chapter 7.4 patent gazette]|Free format text: DE ACORDO COM O ARTIGO 229-C DA LEI NO 10196/2001, QUE MODIFICOU A LEI NO 9279/96, A CONCESSAO DA PATENTE ESTA CONDICIONADA A ANUENCIA PREVIA DA ANVISA. CONSIDERANDO A APROVACAO DOS TERMOS DO PARECER NO 337/PGF/EA/2010, BEM COMO A PORTARIA INTERMINISTERIAL NO 1065 DE 24/05/2012, ENCAMINHA-SE O PRESENTE PEDIDO PARA AS PROVIDENCIAS CABIVEIS. |

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2019-12-17| B07G| Grant request does not fulfill article 229-c lpi (prior consent of anvisa) [chapter 7.7 patent gazette]|

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2020-01-28| B06U| Preliminary requirement: requests with searches performed by other patent offices: procedure suspended [chapter 6.21 patent gazette]|

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2020-06-16| B06A| Notification to applicant to reply to the report for non-patentability or inadequacy of the application [chapter 6.1 patent gazette]|

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2020-06-30| B09A| Decision: intention to grant [chapter 9.1 patent gazette]|

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2020-11-17| B16A| Patent or certificate of addition of invention granted|Free format text: PRAZO DE VALIDADE: 20 (VINTE) ANOS CONTADOS A PARTIR DE 23/02/2012, OBSERVADAS AS CONDICOES LEGAIS. |

优先权:

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申请号 | 申请日 | 专利标题

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US201161451256P| true| 2011-03-10|2011-03-10|

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US61/451,256|2011-03-10|

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US201161489913P| true| 2011-05-25|2011-05-25|

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US61/489,913|2011-05-25|

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US201161490804P| true| 2011-05-27|2011-05-27|

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US61/490,804|2011-05-27|

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PCT/IB2012/050842|WO2012120399A1|2011-03-10|2012-02-23|Spirocyclic isoxazoline derivatives as antiparasitic agents|

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