Endoparasitic depsipeptide compounds, composition comprising the same and use thereof to treat or prevent a parasitic infection.

Abstract

The present invention provides cyclic depsipeptides of formula (1), stereoisomers thereof and veterinary acceptable salts thereof wherein each of r1, r2, r3, r4, l1 and l2 is as defined herein. The present invention also contemplates compositions, methods of treatment and uses as a medicament for treating an animal exhibiting an endoparasitic infection with a compound of formula (1).

Description

"Compounds of endoparasitic depsipeptides, composition comprising the same and use thereof to treat or prevent a parasitic infection" FIELD OF THE INVENTION

[001] The present invention relates to novel endoparasitic depsipeptide compounds with enhanced activity against endoparasites. The invention also relates to compositions comprising the compounds, methods and uses of the compounds for eradicating, controlling, treating and preventing parasitic infestation and / or infection in animals. The compounds of the invention can be administered to animals, particularly non-human animals, to prevent or treat parasitic infections. FUNDAMENTALS

[002] Animals, such as non-human mammals, for example, domestic and farm animals (livestock), are frequently susceptible to parasitic infestations. These parasites can be endoparasites, including, for example, helminthiasis, which is most often caused by a group of parasitic worms described as nematodes or roundworms. These parasites cause serious economic losses in pigs, sheep, horses, and cattle, as well as affecting domestic animals (e.g., dogs and cats). Other parasites include those that occur in the gastrointestinal tract of animals and humans, such as Ancylostoma, Necator, Ascaris, Strongyloides, Trichinella, Capillaria, Toxocara, Toxascaris, Trichuris, Enterobius, and parasites that are found in the blood or other tissues and organs, such as filarial worms and the extraintestinal stages of Strongyloides, Toxocara, and Trichinella.

[003] One type of endoparasite that seriously harms animals is Dirofilaria immitis, also known as heartworm. Other filarial endoparasites include Dirofilaria repens and Dirofilaria honkongensis, which can also infect humans. The most common hosts are dogs and cats, but others Petition 870220039288, dated 06 / 05 / 2022, page 8 / 195 2 / 169 mammals, such as ferrets and raccoons, can also be infected. The heartworm goes through several life stages before becoming an adult, infecting the pulmonary artery of the mammalian host, particularly the canine. The worms need the mosquito as an intermediate host to complete their life cycle. The period between the initial infection, when the dog is bitten by a mosquito, and the maturation of the worms into adults living in the heart and pulmonary arteries, is six to seven months in dogs and is known as the prepatent period. L3 larvae migrate during the mosquito's blood feeding to the tip of the mosquito's mouth (lip), leave the mosquito, and are deposited on the dog's skin, where they then migrate through the bite to the host. Most L3 larvae molt into fourth-stage larvae (L4) in canine subcutaneous tissues within 1-3 days after infection.Next, they migrate to the muscles of the chest and abdomen and, 45 to 60 days after infection, molt into the fifth stage (LS, immature adult). Between 75 and 120 days after infection, these immature heartworms enter the bloodstream and are transported by the heart to reside in the pulmonary artery. About seven months after infection, adult Dirofilaria immitis reach maturity and reproduce sexually in the pulmonary arteries and right ventricle. Adult males are about 15 cm long and females about 25 cm, and their normal lifespan as adults is estimated at about 5 years.

[004] Heartworm infection is a serious and life-threatening disease. Canine heartworm infection is preventable, and prophylactic treatment is a priority in heartworm-endemic areas. Treatment of mature heartworm infection with an adulticide (e.g., melarsomine dihydrochloride) is expensive and can cause serious adverse side effects; therefore, prevention by monthly administration of medications that interrupt larval development is widely used. The goal of prophylactic therapies Petition 870220039288, dated 06 / 05 / 2022, page 9 / 195 The goal of commercially available preventive treatments for heartworm in dogs is to prevent the parasite from developing into adult worms, interrupting the post-infection life cycle of Dirofilaria immitis. Macrocyclic lactones (MLs, for example, ivermectin, eprinomectin, milbemycin oxime, moxidectin, and selamectin) are the most commonly used chemoprophylactic agents and are administered at monthly or semi-annual intervals. These drugs have been effective against infective third-stage (L3) larvae of Dirofilaria immitis deposited by mosquitoes, as well as against fourth-stage maturation larvae (L4). When administered monthly, MLs kill L3 and L4 larvae acquired within the first 30 days and thus prevent disease caused by adult worms.MLs can also be used monthly in infected dogs to suppress reproduction in adult worms and remove microfilariae, thereby reducing transmission and gradually causing the destruction of adult worms (Vet. Parasitol. 2005 Oct 24 133 (2-3) 197-206).

[005] In recent years, there has been a reported increase in the number of cases of ineffectiveness, in which dogs develop mature heartworm infections despite receiving monthly prophylactic doses of macrocyclic lactone medications. For example, Atkins et al., (Vet. Parasitol. 206 (2014) 106-113) recently reported a growing number of cases of dogs testing positive for heartworm antigen while receiving preventive heartworm medication, suggesting that some populations of Dirofilaria immitis have developed selective resistance to heartworm prophylactics / preventives (American Heartworm Society, 2010. Heartworm Preventive Resistance. Is it possible, vol. 37. Bulletin of the American Heartworm Society, pp. 5). Thus, there is a continuing need to develop new anthelmintic agents with enhanced activity against Dirofilaria immitis and other endoparasites.

[006] There are several parasiticides in the art for the treatment of infections by Petition 870220039288, dated 06 / 05 / 2022, page 10 / 195 4 / 169 endoparasites in animals. In addition to macrocyclic lactones, cyclic depsipeptides with antiparasitic activity are known. PF1022a, a 24-membered cyclo-octadepsipeptide isolated from the fungus Mycelia sterilia by Sasaki et al. (J Antibiotics 45: 692-697 (1992)), has been found to exhibit broad anthelmintic activity against a variety of endoparasites in vivo with low toxicity. These compounds are described, for example, in US Patents Nos. 5,514,773; 5,747,448; 5,646,244; 5,874,530; among others, which are incorporated herein by reference. Emodepside is a semi-synthetic analogue of PF1022a containing a morpholine group in the para position of the aryl ring in the phenyl lactate groups. Emodepside is a potent anthelmintic used in combination with praziquantel in the product Profender® for the treatment of parasitic worms in dogs and cats.However, the antiparasitic activity of PF1022a and emodepsid is not satisfactory for the treatment of certain parasites, especially for the control of Dirofilaria immitis in mammals in order to prevent the establishment of heartworm. Thus, there is a need in the art for more effective antiparasitic agents for the treatment and protection of animals against internal parasites, including nematodes and filarial worms, such as heartworm. SUMMARY OF THE INVENTION

[007] The invention provides novel and inventive cyclic depsipeptide compounds with selective anthelmintic activity against endoparasites in L3 and L4 stages, particularly Dirofilaria immitis L4 (DiL4). Furthermore, the invention provides compositions comprising the depsipeptide compounds and methods and uses for the treatment and prevention of parasitic infection and possibly infestation of animals using the compounds.

[008] In one aspect, the present invention provides symmetrical (i.e., Li and L2 are equal; bis) and asymmetrical (i.e., L1 is absent) cyclic depsipeptides of Formula (1). Petition 870220039288, dated 06 / 05 / 2022, p. 11 / 195 5 / 169 O) in which Li and L2 are the same and are C1-C4 alkyl, C3-C6 cycloalkyl, C1-C4 alkylaryl, C1-C4 alkylheteroaryl, or C1-C4 alkylheterocycle; or L1 is absent; and where the cycloalkyl is a 3- to 6-membered carbocyclic ring; the aryl is a 6-membered monocyclic aromatic ring or a 9- to 10-membered fused aromatic ring; A heteroaryl is a 5- or 6-membered monocyclic aromatic ring or a 9- to 10-membered fused aromatic ring, wherein each mono- or fused heteroaryl ring contains at least one heteroatom selected from N, O, and S; and a heterocycle is a 4- to 6-membered saturated or partially saturated monocyclic ring or a 9- to 10-membered saturated or partially saturated fused ring, wherein each mono- or fused heterocyclic ring contains at least one heteroatom selected from N, O, and S; and wherein the heteroaryl and heterocycle rings are linked to L1 and L2 C1-C4 alkyl or L2 C1-C4 alkyl by a carbon atom of the ring; and wherein the L1 and L2 alkyl groups of alkylcycloalkyl, alkylaryl, alkylheteroaryl and alkylheterocyclo may be replaced by a substituent Rce Rd, each selected individually and separately from the group consisting of hydroxyl, halo, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy, C1-C4 haloalkyl, -NRaRb, pyrazolyl, imidazolyl, pyrrolidinyl and morpholinyl; and when L1 is not absent, then each Rce is the same and each Rd is the same; Petition 870220039288, dated 06 / 05 / 2022, p. 12 / 195 6 / 169 and wherein the cycloalkyl, aryl, heteroaryl and heterocycle groups of Li and L2 may be substituted by (R)n; and when Li is not absent, then each (R)n is the same; and each substituent R is selected independently of the group consisting of C1C6 alkyl optionally substituted by at least one substituent selected from hydroxyl, C3-C6 cycloalkyl and -ORa; halo, oxo, cyano, hydroxyl, -OR5, -NRaRb, C1-C4 haloalkyl, C1-C4 haloalkoxy, -S(O)pRa, C1-C6 alkoxy, C3-C6 cycloalkyl, -C(O)NRaRb, C(O)Ra, -C(O)ORa, -NRaC(O)Rb, pyrazolyl, imidazolyl, pyridinyl, pyrimidinyl, piperidinyl, morpholinyl, pyrrolidinyl, dihydropyrimidinyl and phenyl; and wherein the phenyl is optionally replaced by at least one substituent selected from C1-C3 alkyl, -CF3, halo and hydroxyl; and where n is the integer 0, 1, 2 or 3; Each R1, R2, R3 and R4 is separately and independently H and C1-C6 alkyl; each Rae R is separately H and C1-C6 alkyl; and R5 is C3-C6 cycloalkyl and C1-C3 alkyl C3-C6 cycloalkyl; p is the integer 0, 1, or 2; stereoisomers thereof and veterinary acceptable salts thereof.

[009] In another aspect of the invention is a composition comprising a compound of Formula (1). In yet another aspect, the composition of Formula (1) further comprises a veterinary acceptable excipient. In another aspect of the invention is a method of treating a parasitic infection in an animal by administering a therapeutic amount of a compound of Formula (1) to the animal in need thereof. In yet another aspect is the use of a compound of Formula (1) for the treatment of a parasitic infection in an animal by administering a therapeutic amount of a compound of Formula (1) to the animal in need thereof. In yet another aspect is the use of a compound of Formula (1) for the preparation of a medicament for use in the treatment of a parasitic infection in an animal. Petition 870220039288, dated 06 / 05 / 2022, p. 13 / 195 7 / 169

[010] In one aspect of the invention, R1, R2, R3 and R4 are identical and each is C1-C6 alkyl. In another aspect, R1, R2, R3 and R4 are identical and each is methyl, ethyl, propyl, isopropyl, isobutyl and n-butyl. Preferably, each R1, R2, R3 and R4 are identical and each is ethyl, isopropyl or isobutyl. More preferably, R1, R2, R3 and R4 are identical and each is isopropyl or isobutyl. Prioritarily, R1, R2, R3 and R4 are identical and each is isobutyl.

[011] In one aspect of the invention there is a compound of Formula (1) which is a compound of Formula (1A) stereoisomers thereof and veterinary acceptable salts thereof.

[012] In another aspect of the invention is a composition comprising a compound of Formula (1A). In yet another aspect, the composition of Formula (1A) further comprises a veterinary acceptable excipient. In another aspect of the invention is a method of treating a parasitic infection in an animal by administering a therapeutic amount of a compound of Formula (1A) to the animal in need thereof. In yet another aspect is the use of a compound of Formula (1A) for the treatment of a parasitic infection in an animal by administering a therapeutic amount of a compound of Formula (1A) to the animal in need thereof. In yet another aspect is the use of a compound of Formula (1A) for the preparation of a medicament for use in the treatment of a parasitic infection in an animal.

[013] In another aspect of the invention there is a compound of Formula (1) which is a compound of Formula (2A), Petition 870220039288, dated 06 / 05 / 2022, p. 14 / 195 8 / 169 stereoisomers thereof and veterinary acceptable salts thereof.

[014] In another aspect of the invention is a composition comprising a compound of Formula (2A). In yet another aspect, the composition of Formula (2A) further comprises a veterinary acceptable excipient. In another aspect of the invention is a method of treating a parasitic infection in an animal by administering a therapeutic amount of a compound of Formula (2A) to the animal in need thereof. In yet another aspect is the use of a compound of Formula (2A) for the treatment of a parasitic infection in an animal by administering a therapeutic amount of a compound of Formula (2A) to the animal in need thereof. In yet another aspect is the use of a compound of Formula (2A) for the preparation of a medicament for use in the treatment of a parasitic infection in an animal.

[015] In one aspect of the invention, when Li and L2 are present, they are the same, i.e., a bisymmetric depsipeptide compound of Formula (1). In another aspect, Li is absent, i.e., a non-symmetric depsipeptide compound of Formula (1).

[016] In one aspect of the invention, Li and L2 are the same and each is a C1-alkyl C3-C6 cycloalkyl (-C-C3-C6 cycloalkyl); a C1-alkylaryl (-C-aryl); a -C1-alkyl-heterocycle (-C-heterocycle); or a heteroaryl -C1-alkyl (-C-heteroaryl); or Li is absent; and wherein each cycloalkyl, aryl, heterocycle or heteroaryl group may be substituted by (R)n, as described herein; and each -C-alkyl group may be substituted by Rce Rd, as described herein. Petition 870220039288, dated 06 / 05 / 2022, p. 15 / 195 9 / 169

[017] In one aspect of the invention, Li and L2 are the same and each is a C1-C3-C6 cycloalkyl (-C-C3-C6 cycloalkyl); or Li is absent. In another aspect, the cycloalkyls of Li and L2 are the same and are -C-cyclopropyl, -C-cyclobutyl, -C-cyclopentyl or -C-cyclohexyl; or Li is absent. The cycloalkyl groups of Li and L2 or L2 can be substituted by (R)n, as described herein; and each alkyl group of Li and L2 or L2 can be substituted by Rc and Rd, as described herein. In Formula (3A), Ring A and Ring B are the cycloalkyl group of Li and L2, respectively. In Formula (4A), Ring B is the cycloalkyl group L2. [0i8] In one aspect of the invention, Li and L2 are identical and each is C1-alkylaryl (-C-aryl); or Li is absent. In another aspect, the aryl groups Li and L2 are identical and each is -C-phenyl or -C-naphthyl; or Li is absent. In yet another aspect, each aryl group of Li and L2 is -C-phenyl; or Li is absent. The aryl groups of Li and L2 or L2 can be substituted by (R)n, as described herein; and each alkyl group of Li and L2 or L2 can be substituted by Rc and Rd, as described herein. [0i9] In one aspect of the invention, Li and L2 are identical and each is a C1-alkylheterocycle (-C-heterocycle); or Li is absent. In another aspect, the heterocycles of Li and L2 are identical and each is oxetanyl, thietanyl, azetidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, tetrahydropyranil, tetrahydropyridinyl, tetrahydrothiopyranyl, piperidinyl, 1,4-dioxanyl, morpholinyl, piperazinyl, azatianil, or 3,4-dihydro-2H-pyranyl; or Li is absent. In yet another aspect, the heterocycles of Li and L2 are identical and each is oxetanyl, cyclohexyl, azetidinyl, pyrrolidinyl, tetrahydropyranil, piperidinyl, or morpholinyl; or Li is absent. In yet another aspect, the Li and L2 heterocycles are identical and each is pyrrolidinyl, tetrahydropyranyl, piperidinyl, or morpholinyl; or Li is absent. In yet another aspect, the Li and L2 heterocycles are identical and each is morpholinyl; or Li is absent.The heterocyclic groups of Li and L2 or L2 can be replaced by (R)n, as described herein; and each alkyl group of Li and L2 or L2 can be replaced by Rc. Petition 870220039288, dated 06 / 05 / 2022, p. 16 / 195 10 / 169 and Rd, as described here. In Formula (3A), Ring A and Ring B are the heterocyclic groups of Li and L2, respectively. In Formula (4A), Ring B is the heterocyclic group of L2.

[020] In one aspect of the invention, Li and L2are identical and each is a C1 alkylheteroaryl (-C-heteroaryl); or He is absent. In another aspect, Li and L2 heteroaryls are identical and each is pyrrolyl, furanyl, thiophenyl, pyrazolyl, imidazolyl, isoxazolyl, oxazolyl, isothiazolyl, thiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, di-hydropyl, pyryl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, quinolinyl, isoquinolinyl, benzofuranyl, indazolyl, benzothiophenyl, indolyl, benzimidazolyl, pyrazole[1,5-a]pyridinyl, pyrazole[1,5-a]pyrimidinyl, 1Hpyrrol[3,2,2,pyridin] indazolbenzo[d][1,3]diazolyl, benzo[d]thiazolyl, furo[2,3-b]pyridinyl, 2,3-di-hydrothiene[3,4-b][1,4]dioxinyl, 3,4-dihydro-2H-pyran [2,3-b]pyridinyl, di-hydro-1Hpyrrole[3,2-b]pyridine, di-hydro-1H-pyrrole[3,2-b]pyridinyl, oxazole[5,4-b]pyridinyl or benzo[d]1,3 diaxolyl; or He is absent.In yet another aspect, the heteroaryls of Li and L2 are the same and each is thiophenyl, thiazolyl, pyrazolyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, oxazolyl, isoxazolyl, isothiazolyl or furanyl; or Li is absent. In yet another aspect, the heteroaryls of Li and L2 are the same and each is thiophenyl, thiazolyl, pyrazolyl, pyridinyl, pyridazinyl, pyrazinyl or pyrimidinyl; or Li is absent. In yet another aspect, the heteroaryls of Li and L2 are the same and each is pyrazolyl, pyridinyl, pyridazinyl, pyrazinyl and pyrimidyl; or Li is absent. In yet another aspect, the heteroaryls of Li and L2 are the same and each is pyrazolyl, pyridinyl or pyrimidinyl; or Li is absent. In yet another aspect, the heteroaryl groups of Li and L2 are identical and each is pyridazinyl; or Li is absent. In yet another aspect, the heteroaryl groups of Li and L2 are identical and each is thiazole; or Li is absent.In yet another aspect of the invention, the Li and L2 heteroaryls are identical and each is a pyrazole, or Li is absent. In yet another aspect, the Li and L2 heteroaryls are identical and each is a pyridine; or Li is absent. In yet another aspect, the Li and L2 heteroaryls are identical and each is a pyrimidine; or Li is absent. In yet another aspect, the Li and L2 heteroaryls are identical and each is... Petition 870220039288, dated 06 / 05 / 2022, p. 17 / 195 11 / 169 pyrazinyl; or Li is absent. The heteroaryl groups of Li and L20U L2 can be substituted by (R)n, as described herein; and each alkyl group of Li and L2 or L2 can be substituted by Rce Rd, as described herein. In Formula (3A), Ring A and Ring B are the heteroaryl group of Li and L2, respectively. In Formula (4A), Ring B is the heteroaryl group of L2.

[021] In one aspect of the invention there is a compound of Formula (1A) which is a compound of Formula (1A1) stereoisomers thereof and veterinary acceptable salts thereof. Each (R)n, Rce Rdé as described herein; and each (R)n is the same, each Rce the same, and each Rdé the same; stereoisomers of the same and veterinaryly acceptable salts thereof.

[022] In one aspect of the invention there is a compound of Formula (2A) which is a compound of Formula (2A1), each (R)n, Rce Rdé as described herein; stereoisomers thereof and veterinary acceptable salts thereof.

[023] Another aspect of the invention is a composition comprising Petition 870220039288, dated 06 / 05 / 2022, p. 18 / 195 12 / 169 a compound of Formula (1A1) or (2A1). In yet another aspect, the composition of Formula (1A1) or (2A1) further comprises a veterinary acceptable excipient. In another aspect of the invention is a method of treating a parasitic infection in an animal by administering a therapeutic amount of a compound of Formula (1A1) or (2A1) to the animal in need thereof. In yet another aspect, is the use of a compound of Formula (1A1) or (2A1) for the treatment of a parasitic infection in an animal by administering a therapeutic amount of a compound of Formula (1A1) or (2A1) to the animal in need thereof. In yet another aspect, is the use of a compound of Formula (1A1) or (2A1) for the preparation of a medicament for use in the treatment of a parasitic infection in an animal.

[024] In another aspect of the invention are compounds of Formula (1A) which are compounds of Formula (3A), each Ring A, Ring B, (R)n, Rce Rdé as described herein. Ring A and Ring B are the same and each (R)n is the same, each Rce the same and each Rdé the same; stereoisomers thereof and veterinary acceptable salts thereof.

[025] In yet another aspect of the invention is a compound of Formula (2A) which is a compound of Formula (4A) Petition 870220039288, dated 06 / 05 / 2022, p. 19 / 195 13 / 169 each Ring B, (R)n, Rce Rdé as described herein; stereoisomers thereof and veterinary acceptable salts thereof.

[026] Another aspect of the invention is a composition comprising a compound of Formula (3A) or (4A). In yet another aspect, the composition of Formula (3A) or (4A) further comprises a veterinary acceptable excipient. In another aspect of the invention is a method of treating a parasitic infection in an animal by administering a therapeutic amount of a compound of Formula (3A) or (4A) to the animal in need thereof. In yet another aspect is the use of a compound of Formula (3A) or (4A) for the treatment of a parasitic infection in an animal by administering a therapeutic amount of a compound of Formula (3A) or (4A) to the animal in need thereof. In yet another aspect is the use of a compound of Formula (3A) or (4A) for the preparation of a medicament for use in the treatment of a parasitic infection in an animal.

[027] As described here, o Anel A and Anel B are the groups cicloalquil, heterocyclo or heteroaryl of Li and L2 of Formula (1), respectively; and Li is absent. O Anel A and Anel B of Formula (3A) are equal; e Formula B of Formula (4A); cada um sendo ciclopropil, ciclobutil, ciclopentil, ciclo-hexil, oxetanil, tietanil, azetidinil, tetra-hidrofuranil, tetra-hidrotiofenil, pirrolidinil, tetra-hidropiranil, tetra-hidrotiopiranil, piperidinil, dioxanil, morpholinil, piperazinil, azatianil, 3,4-di-hidro-2H-piranil, 4,5,6,7-tetra-hidropirazol[1,5-a]piridinil, 4,5-tetra-hidropirazol[1,5-a]pyrimidina, pirrolil, furanil, tiofenil, pyrazolil, imidazolil, isoxazolil, oxazolil, isotiazolil, tiazolil, triazolil, oxadiazolil, tiadiazolil, Petition 870220039288, of 06 / 05 / 2022, p. 20 / 195 14 / 169 tetrazolil, di-hidropiridinil, piridinil, piridazinil, pirimidinil, pirazinil, triazinil, quinolnil, isoquinolinil, benzofuranil, indazolil, benzothiofenil, indolil, triazinil, benzimidazolil, tetra-hidropiranil, pirazol[1,5-a]piridinil, pirazol[1,5-a]pirimidinil, 1H-pyrrol[3,2-b]piridinil, indazolbenzo[d][1,3]diazolil, benzo[d]thiazolil, furo[2,3-b]piridinil, 2,3-di-hidrotieno[3,4b][1,4]dioxinil, 3,4-dihidro-2H-pirano [2,3-b]piridinil, oxazol[5,4-b]piridinil, ou benzo[d]1,3 diaxolil. Em outro aspecto, o Anel A eo Anel B de Fórmula (3A) são iguais; e Anel B de Fórmula (4A); cada um sendo pirrolidinil, tetra-hidropiranil, piperidinil, morpholinil, tiadiazolil, tiofenil, tiazolil, pirazolil, piridinil, pyrimidinil, piridazinil, pirazinil, oxazolil, isoxazolil, isotiazolil ou furanil. In yet another aspect, Analges A and B are similar and each is morpholinil, thiofenil, thiazolyl, pyrazolil, pyridinil, piridazinil, pirazinil or pirimidinil.In yet another aspect, Rings A and B of Formula (3A) are identical; and Ring B of Formula (4A); each being pyrazolyl, thiazolyl, thiadiazolyl, isothiazolyl, pyridinyl, pyridazinyl, pyrazinyl and pyrimidinyl. In yet another aspect, Rings A and B of Formula (3A) are identical; and Ring B of Formula (4A); each being pyrazolyl, pyrazinyl, isothiazolyl, thiazolyl, pyridinyl, pyridazinyl and pyrimidinyl. In yet another aspect, Rings A and B of Formula (3A) are identical; and Ring B of Formula (4A); each being pyrazolyl, isothiazolyl, thiazolyl, pyridinyl, pyrazinyl or pyrimidinyl. In yet another aspect, Rings A and B of Formula (3A) are identical; and Ring B of Formula (4A); each being isothiazolyl, thiazolyl, pyridinyl, pyrazinyl or pyrimidinyl. In yet another aspect, Rings A and B of Formula (3A) are the same; and Ring B of Formula (4A); each being pyrazolyl. In yet another aspect, Rings A and B of Formula (3A) are the same; and Ring B of Formula (4A); are isothiazolyl.In yet another aspect, Rings A and B of Formula (3A) are the same; and Ring B of Formula (4A) are thiazolyl. In yet another aspect, Rings A and B of Formula (3A) are the same; and Ring B of Formula (4A) are pyridinyl. In yet another aspect, Rings A and B of Formula (3A) are the same; and Ring B of Formula (4A) are pyrazinyl. In yet another aspect, Rings A and B of Formula (3A) are the same; and Ring B of Formula (4A) are pyrimidinyl. Petition 870220039288, dated 06 / 05 / 2022, p. 21 / 195 15 / 169

[028] In one aspect of the invention, the R of (R)n is selected independently from the group consisting of C1-C6 alkyl optionally substituted by at least one substituent selected from hydroxyl, C3-C6 cycloalkyl and -ORa; halo, oxo, cyano, hydroxyl, -OR5, -NRaRb, C1-C4 haloalkyl, C1-C4 haloalkoxy, -S(O)pRa, C1-C6 alkoxy, C3-C6 cycloalkyl, -C(O)NRaRb, -C(O)Ra, -C(O)ORa, -NRaC(O)Rb, pyrazolyl, imidazolyl, pyridinyl, pyrimidinyl, piperidinyl, morpholinyl, pyrrolidinyl, dihydropyrimidinyl and phenyl; and wherein the phenyl is optionally replaced by at least one substituent selected from C1-C3 alkyl, -CF3, halo and hydroxyl; and where n of (R)n is the integer 0, 1, 2 or 3; and wherein each (R)n of Formula (1A1) and Formula (3A) is the same.In another aspect, R of (R)n is selected independently from the group consisting of C1C6 alkyl optionally substituted by at least one substituent selected from hydroxyl, ORa, C3-C6 cycloalkyl; halo, cyano, hydroxyl, -NRaRb, C1-C4 haloalkyl, C1-C4 haloalkoxy, -S(O)pRa, C1-C6 alkoxy, -OR5, C3-C6 cycloalkyl, morpholinyl and phenyl optionally substituted by methyl, -CF3, halo and hydroxyl; and where n is the integer 0, 1, 2 or 3; and where each (R)n of Formula (1A1) and Formula (3A) is the same.In yet another aspect, R of (R)n is selected independently from the group consisting of C1-C6 alkyl optionally substituted by at least one substituent selected from hydroxyl and C3-C6 cycloalkyl; halo, cyano, hydroxyl, -NRaRb, C1-C4 haloalkyl, C1-C4 haloalkoxy, -S(O)pRa, C1-C6 alkoxy, C3-C6 cycloalkyl, morpholinyl and phenyl optionally substituted by methyl, -CF3, halo and hydroxyl; and where n is the integer 0, 1, 2 or 3; and where each (R)n of Formula (1A1) and Formula (3A) is the same. In yet another aspect, R of (R)n is selected independently from the group consisting of methyl, ethyl, propyl, isopropyl, isobutyl, cyclopropyl, cyclobutyl, -C-cyclopropyl, halo, -SCH3, -S(O)2CH3, cyano, hydroxyl, -C-CF3, -CF3, -C-CF2, -NRaRb, methoxy, ethoxy, isopropoxy, -OC-CF3, -O-CF2, COH, morpholinyl and phenyl; and wherein the phenyl may be further substituted by methyl; and where n of (R)n is the integer 0, 1, 2 or 3; and where each (R)n of Formula (1A1) and of. Petition 870220039288, dated 06 / 05 / 2022, p. 22 / 195 16 / 169 Formula (3A) is the same. In yet another aspect, R of (R)n is selected independently from the group consisting of methyl, ethyl, isopropyl, cyclopropyl, -C-cyclopropyl, halo, -SCH3, cyano, hydroxyl, -C-CF, -CF2, -CF3, -N(CHs)2, methoxy, ethoxy, -OCF3, -OCF2 and morpholinyl; and where n of (R)n is the integer 0, 1, 2 or 3; and where each (R)n of Formula (1A1) and Formula (3A) is the same.

[029] In one aspect of the invention, n of (R)n of Formula (1A1) and (3A) is the same integer; en of (R)n of Formula (2A) and (4A) is the integer 0, 1, 2 or 3. In another aspect, n is the integer 0. In yet another aspect, n is the integer 1. In yet another aspect, n is the integer 2. In yet another aspect, n is the integer 3.

[030] In one aspect of the invention, p is the integer 0, 1, or 2. In another aspect, p is the integer 0. In yet another aspect, p is the integer 1. In yet another aspect, op is the integer 2.

[031] In one aspect of the invention, each Rae Rbé is selected separately from H, methyl, ethyl, propyl, isopropyl and isobutyl. In another aspect of the invention, each Rae Rbé is selected separately from H, methyl, ethyl and isopropyl. In another aspect, each Rae Rbé is selected separately from H, methyl and ethyl.

[032] In one aspect of the invention, each Rce Rdé is selected independently and separately from the group consisting of H, hydroxyl, halo, C1-C6 alkyl, C1-C6 alkoxy, -CF3, cyclopropyl, -NRaRb, pyrazolyl, pyrrolidinyl and morpholinyl; and where each Rcda Formula (1A1) and Formula (3A) are the same and each Rdda Formula (1A1) and Formula (3A) are the same. In another aspect of the invention, each Rce Rdé is selected independently and separately from the group consisting of H, hydroxyl, halo, C1-C6 alkyl, C1-C6 alkoxy, -NRaRb, -CF3, cyclopropyl, pyrazolyl, pyrrolidinyl and morpholinyl; and where each Rcda Formula (1A1) and Formula (3A) are the same and each Rdda Formula (1A1) and Formula (3A) are the same. Petition 870220039288, dated 06 / 05 / 2022, p. 23 / 195 17 / 169

[033] In yet another aspect of the invention, each Rce Rdé is selected independently and separately from H, F, Cl, C1-C6 alkyl, methoxy, ethoxy, isopropoxy, -CF3, hydroxyl, -N(CH3)2, -N(CH2CH3)2, cyclopropyl, pyrazolyl and morpholine; and where each Rcda Formula (1A1) and Formula (3A) is the same and each Rdda Formula (1A1) and Formula (3A) is the same. In another aspect, each Rce Rdé is selected independently and separately from H, F, Cl, methyl, ethyl, isopropyl, hydroxyl, -CF3, methoxy, ethoxy, isopropoxy, cyclopropyl and -N(CH2CH3)2; and where each Rcda Formula (1A1) and Formula (3A) is the same and each Rdda Formula (1A1) and Formula (3A) is the same. In yet another aspect, each Rce Rdé selected independently and separately from H, F, methyl, ethyl, hydroxyl, -CF3, methoxy, ethoxy and -N(CH2CH3)2; and where each Rcda Formula (1A1) and Formula (3A) is the same and each Rdda Formula (1A1) and Formula (3A) is the same.In yet another aspect, each Rce Rdé is selected independently and separately from H, F, methyl, ethyl, hydroxyl, methoxy, and ethoxy; wherein each Rcda Formula (1A1) and Formula (3A) is the same and each Rdda Formula (1A1) and Formula (3A) is the same. In yet another aspect, each Rce Rdé is selected independently and separately from H, F, methyl, hydroxyl, and methoxy; wherein each Rcda Formula (1A1) and Formula (3A) is the same and each Rdda Formula (1A1) and Formula (3A) is the same. In yet another aspect, each Rce Rdé is selected independently and separately from H, hydroxyl, and methoxy; wherein each Rcda Formula (1A1) and Formula (3A) is the same and each Rdda Formula (1A1) and Formula (3A) is the same.

[034] In one aspect of the invention, R5 is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, C1-cyclopropyl, C2-cyclopropyl, C1-cyclobutyl, C2-cyclobutyl, C2-cyclopentyl, C2-cyclohexyl, C3-cyclopropyl or C3-cyclobutyl. In yet another aspect, R5 is cyclopropyl, cyclobutyl, C1-cyclopropyl, or C1-cyclobutyl. In yet another aspect, R5 is cyclopropyl, cyclobutyl or C1-cyclopropyl. In yet another aspect, R5 is cyclopropyl. In yet another aspect, R5 is cyclobutyl. In yet another aspect, R5 is C1-cyclopropyl. Petition 870220039288, dated 06 / 05 / 2022, p. 24 / 195 18 / 169

[035] In yet another aspect of the invention are compounds of Formula (1A1) selected from the group consisting of the compounds described in Table 1, stereoisomers thereof and veterinary acceptable salts thereof. In another aspect, it is a composition comprising a compound described in Table 1. In another aspect, it is a method of treating a parasitic infection in an animal in need thereof by administering a therapeutically effective amount of a compound from Table 1 to the animal. In another aspect, it is the use of a compound described in Table 1 to prepare a medicament for the treatment of a parasitic infection in an animal.

[036] In another aspect of the invention are compounds of Formula (1A1) selected from the group consisting of Examples: (1-5), (1-11) and (1-18), stereoisomers thereof and veterinary acceptable salts thereof. Preferred compounds (1A1) are Examples (1-5) and (1-11), stereoisomers thereof and veterinary acceptable salts thereof. In another aspect, it is a composition comprising one of these compounds of Formula (1A1), stereoisomers thereof and veterinary acceptable salts thereof. In another aspect, the composition further comprises a veterinary acceptable excipient. In another aspect, it is a method of treating a parasitic infection in an animal in need thereof by administering a therapeutically effective amount of one of these compounds of Formula (1A1) to the animal. In another aspect, it is the use of one of these Formula (1A1) compounds to prepare a medicine for the treatment of a parasitic infection in an animal.

[037] In yet another aspect of the invention are compounds of Formula (2A1) selected from the group consisting of the compounds described in Table 2, stereoisomers thereof and veterinary acceptable salts thereof. In another aspect, it is a composition comprising a compound described in Table 2. In another aspect, it is a method of treating a parasitic infection in an animal. Petition 870220039288, dated 06 / 05 / 2022, p. 25 / 195 19 / 169 which requires the same by administering a therapeutically effective amount of a compound from Table 2 to the animal. In another aspect, it is the use of a compound described in Table 2 to prepare a medicament for the treatment of a parasitic infection in an animal.

[038] In another aspect of the invention are compounds of Formula (2A1) selected from the group consisting of Examples: (2-1), (2-4), (2-36), (2-37), (2-38) and (2-42), stereoisomers thereof and veterinary acceptable salts thereof. Preferred compounds (2A1) are Examples (2-4), (2-36) and (2-42), stereoisomers thereof and veterinary acceptable salts thereof. In another aspect, it is a composition comprising one of these compounds of Formula (2A1), stereoisomers thereof and veterinary acceptable salts thereof. In another aspect, the composition further comprises a veterinary acceptable excipient. In another aspect, it is a method of treating a parasitic infection in an animal in need thereof by administering a therapeutically effective amount of one of these compounds of Formula (2A1) to the animal.In another aspect, it is the use of one of these compounds of Formula (2A1) to prepare a medicine for the treatment of a parasitic infection in an animal.

[039] In yet another aspect of the invention are compounds of Formula (3A) selected from the group consisting of the compounds described in Table 3, stereoisomers thereof and veterinary acceptable salts thereof. In another aspect, it is a composition comprising a compound described in Table 3. In another aspect, it is a method of treating a parasitic infection in an animal in need thereof by administering a therapeutically effective amount of a compound from Table 3 to the animal. In another aspect, it is the use of a compound described in Table 3 to prepare a medicament for the treatment of a parasitic infection in an animal.

[040] In yet another aspect of the invention is a compound of Formula (3A) Petition 870220039288, dated 06 / 05 / 2022, p. 26 / 195 20 / 169 selected from the group consisting of Examples: (3-4), (3-8), (3-12), (3-17), (3-18), (3-21), (3-24), (3-31), (3-44), (3-49), (3-50), (3-56), (3-57), (3-60), (3-69), (3-87), (3-110), (3-112), (3-118), (3-120), (3-121), (3-124), (3-125), (3-132), (3-133), (3-148), (3-155), (3-156), (3-157), (3-165), (3-173), (3-176), (3-178), (3-193), (3-194), (3-207), (3209), (3-215), (3-217), (3-218), (3-220), (3-223), (3-225), (3-228), (3-238), (3-240), (3243), (3-252), (3-253), (3-254), (3-259), (3-261), (3-268), (3-273), (3-274), (3-275), (3282), (3-283), (3-284), (3-285), (3-286), (3-287), (3-288), (3-289), (3-290), (3-291), (3292), (3-293), (3-294), (3-295), (3-296), (3-297), (3-307), (3-308), (3-309), (3-310), (3313), (3-318), (3-319), (3-321), (3-322), (3-323), (3-324), (3-326), (3-329), (3-332), (3333) and (3-334) stereoisomers thereof and veterinary acceptable salts thereof.Preferred compounds (3A) are Examples (3-4), (3-44), (3-56), (369), (3-87), (3-110), (3-118), (3-121), (3-124), (3-125), (3-133), (3-157), (3-165), (3173), (3-207), (3-225), (3-261), (3-284), (3-286), (3-287), (3-293), (3-296), (3-324), (3326) and (3-332), stereoisomers thereof and veterinary acceptable salts thereof. In yet another aspect of the invention is a composition comprising one of the compounds of Formula (3A). In yet another aspect, the composition further comprises a veterinary acceptable excipient. In another aspect, it is a method of treating a parasitic infection in an animal that needs it by administering a therapeutically effective amount of one of these compounds of Formula (3A) to the animal. In another aspect, it is the use of one of these compounds of Formula (3A) to prepare a medicament for the treatment of a parasitic infection in an animal.

[041] In yet another aspect of the invention are compounds of Formula (4A) selected from the group consisting of the compounds described in Table 4, stereoisomers thereof and veterinary acceptable salts thereof. In another aspect, it is a composition comprising a compound described in Table 4. In another aspect, it is a method of treating a parasitic infection in an animal. Petition 870220039288, dated 06 / 05 / 2022, p. 27 / 195 21 / 169 which requires the same through the administration of a therapeutically effective amount of a compound from Table 4 to the animal. In another aspect, it is the use of a compound described in Table 4 to prepare a medicament for the treatment of a parasitic infection in an animal.

[042] Yet another aspect of the invention is a compound of Formula (4A) selected from the group consisting of Examples: (4-18), (4-19), (4-21), (4-30), (4-32), (4-34), (4-40), (4-50), (4-63), (4-75), (4-105), (4-107), (4-109), (4-118), (4-126), (4-139) and (4-141), stereoisomers thereof and veterinary acceptable salts thereof. Preferred compounds of Formula (4A) are selected from the group of Examples: (4-18), (4-19) and (4-21), stereoisomers thereof and veterinary acceptable salts thereof. Yet another aspect of the invention is a composition comprising one of the compounds of Formula (4A). In yet another aspect, the composition also comprises a veterinary acceptable excipient. In another aspect, it is a method of treating a parasitic infection in an animal that needs it by administering a therapeutically effective amount of one of these compounds of Formula (4A) to the animal.In another aspect, it is the use of one of these compounds of Formula (4A) to prepare a medicine for the treatment of a parasitic infection in an animal.

[043] In yet another aspect is a compound of Formula (1) that is at least 10x selective against D. immitis L4 (i.e., DiMf / DiL4). In yet another aspect of the invention is a composition comprising a compound of Formula (1) that is at least 10x selective against D. immitis L4 and a veterinaryly acceptable excipient. In yet another aspect of the invention is a composition comprising a therapeutically effective amount of a compound of Formula (1) that is at least 10x selective for D. immitis L4. In yet another aspect of the invention is a composition comprising a therapeutically effective amount of a compound of Formula (1) that is at least 10x selective for D. immitis L4 and a Petition 870220039288, dated 06 / 05 / 2022, p. 28 / 195 22 / 169 veterinary acceptable excipient. In another aspect, compounds of Formula (1) that are at least 10x selective include Examples #: (1-18), (2-1), (2-4), (2-37), (2-38), (3-8), (3-31), (3-50), (3-58), (3-60), (3-69), (3-112), (3-121), (3-132), (3-133), (3-173), (3-176), (3-207), (3-209), (3-218), (3-228), (3-238), (3-240), (3-252), (3-259), (3-274), (3-275), (3-286), (3-288), (3-295), (3-296), (3-297), (3-308), (3-318), (3-319), (3-322), (3-323), (3-329), (3-333), (3-334), (4-18), (4-21), (4-34), (4-50), (4-75), (4-105), (4-107), (4-118) and (4-126).

[044] In yet another aspect is a compound of Formula (1) that is at least 100x selective against D. immitis L4 (i.e., DiMf / DiL4). In yet another aspect of the invention is a composition comprising a compound of Formula (1) that is at least 100x selective against D. immitis L4 and a veterinary acceptable excipient. In yet another aspect of the invention is a composition comprising a therapeutically effective amount of a compound of Formula (1) that is at least 100x selective against D. immitis L4. In yet another aspect of the invention is a composition comprising a therapeutically effective amount of a compound of Formula (1) that is at least 100x selective against D. immitis L4 and a veterinary acceptable excipient. In another aspect, compounds of Formula (1) that are at least 100x selective include compounds of Formula (1A1): (3S,6R,9S,12R,15S,18R,21S,24R)-3,9,15,21-tetraisobutyl-6,18-bis(4-(3-methoxybenzyl)benzyl)-4,10,12,16 ,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetra-azacyclotetracosan-2,5,8,11,14,17,20,23-octaone (1-5) and (3S,6R,9S,12R,15S,18R,21S,24R)-3,9,15,21-tetraisobutyl-6,18-bis(4-(2-methoxybenzyl)benzyl)-4,10,12,16 ,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetra-azacyclotetracosan-2,5,8,11,14,17,20,23-octaone (1-11); and compounds of Formula (2A1): (3S,6R,9S,12R,15S,18R,21S,24R)-6-benzyl-18-(4-((diethylamino)(3,4-difluorophenyl)methyl)benzyl)-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa4,10,16,22-tetra-azacyclotetracosan-2,5,8,11,14,17,20,23-octaone (2-36) and Petition 870220039288, dated 06 / 05 / 2022, page 29 / 195 23 / 169 (3S,6R,9S,12R,15S,18R,21S,24S)-6-benzyl-3,9,15,21-tetraisobutyl-4,10,12,16,22,24hexamethyl-18-[[4-[(S)-morpholino-[4-(trif luoromethoxy)phenyl]-methyl]phenyl]methyl]-1,7,13,19-tetraoxa-4,10,16,22-tetra-azacyclotetracosan-2,5,8,11,14,17,20,23-octanoa (2-42); and compounds of Formula (3A): (3S,6R,9S,12R,15S,18R,21S,24R)-3,9,15,21-tetraisobutyl-4,6,10,16,18,22-hexamethyl-12,24-bis(4-(thiophene -2-ylmethyl)benzyl)-1,7,13,19-tetraoxa4,10,16,22-tetra-azacyclotetracosan-2,5,8,11,14,17,20,23-octaona (3-4), (3S,6R,9S,12R,15S,18R,21S,24R)-3,9,15,21-tetraisobutyl-4,6,10,16,18,22-hexamethyl12,24-bis(4-((3-methylthiophen-2-yl)methyl)benzyl)-1,7,13,19-tetraoxa-4,10,16,22-tetra-azacyclotetracosane-2,5,8,11,14,17,20,23-octaano (3-44), (3S,6R,9S,12R,15S,18R,21S,24R)-3,9,15,21-tetraisobutyl-4,6,10,16,18,22hexamethyl-12,24-bis(4-(thiophen-3-ylmethyl)benzyl)-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosane-2,5,8,11,14,17,20,23-octaano (3-56), (3S,6R,9S,12R,15S,18R,21S,24R)-6,18-bis(4-((3-chlorothiofen-2-yl)metil)benzil)-3,9,15,21-tetraisobutil-4,10,12,16,22,24-hexametil-1,7,13,19-tetraoxa-4,10,16,22tetra-azaciclotetracosan-2,5,8,11,14,17,20,23-octaona (3-87), (3S,6R,9S, 12R,15S,18R,21S,24R)-3,9,15,21-tetraisobutyl-6,18-bis(4-((3-methoxythiophen2-yl)methyl)benzyl)-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetra-azacyclotetracosane-2,5,8,11,14,17,20,23-octaano (3-110), (3S,6R,9S, 12R,15S,18R,21S,24R)-6,18-bis(4-((5-fluoro-6-methoxypyridin-3yl)methyl)benzyl)-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa4,10,16,22-tetra-azacyclotetracosane-2,5,8,11,14,17,20,23-octaano (3-118), (3S,6R,9S,12R,15S,18R,21S,24R)-3,9,15,21-tetraisobutil-4,6,10,16,18,22hexametil-12,24-bis(4-((4-metilthio fen-2-yl)metil)benzil)-1,7,13,19-tetraoxa-4,10,16,22tetra-azaciclotetracosan-2,5,8,11,14,17,20,23-octaona (3-124), (3S,6R,9S,12R,15S,18R,21S,24R)-6,18-bis(4-((3-bromothiophen-2-yl)metil)benzil)-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22tetra-azacyclotetracosan-2,5,8,11,14,17,20,23-octaone (3-125), Petition 870220039288, dated 06 / 05 / 2022, p. 30 / 195 24 / 169 (3S,6R,9S,12R,15S,18R,21S,24R)-3,9,15,21-tetraisobutyl-4,6,10,16,18,22hexamethyl-12,24-bis(4-((5-methylfuran-2-yl)methyl)benzyl)-1,7,13,19-tetraoxa-4,10,16,22tetra-azacyclotetracosane-2,5,8,11,14,17,20,23-octaano (3-157), (3-165). (3S,6R,9S,12R,15S,18R,21S,24R)-6,18-bis(4-((2-ethoxypyridin-3yl)methyl)benzyl)-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa4,10,16,22-tetra-azacyclotetracosane-2,5,8,11,14,17,20,23-octaano (3-165), (3S,6R,9S,12R,15S,18R,21S,24R)-6,18-bis(4-(1-fluoro-1-(6-methoxypyridin-2yl)ethyl)benzyl)-3,9,15,21-tetraisobutyl l-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa4,10,16,22-tetra-azaciclotetracosan-2,5,8,11,14,17,20,23-octaona (3-225), (3S,6R,9S,12R,15S,18R,21S,24R)-3,9,15,21-tetraisobutyl-6,18-bis(4-(1-(2methoxypyridin-3-yl)ethyl)benzyl)-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa4,10,16,22-tetra-azacyclotetracosane-2,5,8,11,14,17,20,23-octaano (3-261), (3S,6R,9S, 12R,15S,18R,21S,24R)-6,18-bis(4-((3-cyclopropylisoxazol-5-yl)methyl)benzyl)-3,9,15,21 -tetraisobutil-4,10,12,16,22,24-hexametil-1,7,13,19-tetraoxa4,10,16,22-tetra-azaciclotetracosan-2,5,8,11,14,17,20,23-octaona (3-284), (3S,6R,9S,12R,15S,18R,21S,24R)-6,18-bis(4-((6-(difluorometil)piridin-3il)metil)benzil)-3,9,15,21-tetraisobutil-4,10,12,16,22,24-hexametil-1,7,13,19-tetraoxa4,10,16,22-tetra-azaciclotetracosan-2,5,8,11,14,17,20,23-octaona (3-287), (3S,6R,9S, 12R,15S,18R,21S,24R)-6,18-bis(4-((5-fluoro-2-metoxipiridin-3il)metil)benzil)-3,9,15,21-tetraisobutil-4,10,12,16,22,24-hexametil-1,7,13,19-tetraoxa4,10,16,22-tetra-azaciclotetracosan-2,5,8,11,14,17,20,23-octaona (3-293), (3S,6R,9S,12R,15S,18R,21S,24R)-6,18-bis(4-((2,5-difluoropiridin-3-il)metil)benzil)-3,9,15,21 -tetraisobutil-4,10,12,16,22,24-hexametil-1,7,13,19-tetraoxa4,10,16,22-tetra-azaciclotetracosan-2,5,8,11,14,17,20,23-octaona (3-324), e (3S,6R,9S,12R,15S,18R,21S,24R)-6,18-bis(4-((2,3-difluoropiridin-4-il)metil)benzil)3,9,15,21-tetraisobutil-4,10,12,16,22,24-hexametil-1,7,13,19-tetraoxa-4,10,16,22-tetra-azacyclotetracosan-2,5,8,11,14,17,20,23-octaone (3-326);, Petition 870220039288, dated 06 / 05 / 2022, page 31 / 195 25 / 169 (3S,6R,9S, 12R,15S,18R,21S,24R)-6,18-bis(4-((5-chloro-2-methoxypyridin-3yl)methyl)benzyl)-3,9,15,21-tetraisobutyl-4,10 ,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa4,10,16,22-tetra-azacyclotetracosan-2,5,8,11,14,17,20,23-octaone (3-332); and a compound of Formula (4A): (3S,6R,9S,12R,15S,18R,21S,24R)-6-benzyl18-(4-((2,4-dimethyl-1H-pyrrol-3-yl)methyl)benzyl)-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetra-azacyclotetracosan2,5,8,11,14,17,20,23-octaone; stereoisomers thereof and veterinary acceptable salts thereof.

[045] In yet another aspect of the invention are the compounds of Formula (2A1)(2-1), (2-9) and (2-38); or compounds of Formula (3A)((3-4), (3-8), (3-14), (3-17), (3-18), (3-21), (3-24), (3-36), (3-45), (3-50), (3-52), (3-56), (3-57), (3-58), (3-69), (3-73), (3-87), (3-112), (3-119), (3-120), (3-124), (3-126), (3-155), (3-193), (3-215), (3-253), (3-268), (3-273), (3-274), (3-283), (3-288), (3-290), (3-291), (3-294), (3-299), (3-303), (3-305), (3-306), (3-307), (3-310), (3-319), (3-321), (3-323), (3-324), (3-329), (3-333) and (3-334); or compounds of Formula (4A)(4-30), (4-31), (4-32), (4-34), (4-40), (4-52), (463), (4-75), (4-105), (4-107), (4-109), (4-118) and (4-139); stereoisomers thereof and veterinary acceptable salts thereof;

[046] The compounds of the present invention are intended to comprise racemic mixtures, specific stereoisomers, regioisomers and tautomeric forms of the compounds of Formula (1). DETAILED DESCRIPTION Definitions

[047] For the purposes of this invention, as described and claimed herein, the following terms and phrases are defined as follows:

[048] Additional veterinary agent(s), as used in this document, refers to other veterinary or animal compounds or products that Petition 870220039288, dated 06 / 05 / 2022, p. 32 / 195 26 / 169 provide a therapeutically effective amount of said agents that are useful for the treatment of a parasitic infection in an animal, as described in this document.

[049] Alkoxy, as used in this document, refers to -O-alkyl, wherein the term alkyl is defined below. Non-limiting examples of alkoxy include: methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, n-pentoxy, 1-methylbutoxy, 1-ethylpropoxy and the like.

[050] Alkyl, as used in this document unless otherwise indicated, refers to saturated monovalent alkane hydrocarbon radicals of formula CnH2n+1. The alkane radical may be linear or branched and may be unsubstituted or substituted. For example, the term “C1-C6 alkyl” refers to a linear or branched aliphatic monovalent group containing from 1 to 6 carbon atoms. Furthermore, the term “C1-C4 alkyl” refers to a linear or branched aliphatic monovalent group containing from 1 to 4 carbon atoms and is also described as C1 (-C-), C2 (-CC-), C3 (-CCC-) and C4 (-CCCC-) for the linear aliphatic group. Terms such as -CC-, -C-CC- and similar terms are synonymous with -CH2CH2-, -CH2CH2CH2- and similar terms, respectively.Non-exclusive examples of C1-C6 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 group may be attached to the chemical portion by any of the carbon atoms of the aliphatic chain. Alkyl groups may be substituted as described in this document. Furthermore, when used in compound words such as alkylphenyl, the aforementioned alkyl group has the same meaning as defined herein and may be attached to the chemical portion by any of the carbon atoms of the aliphatic chain. Non-limiting examples include: C1 alkylaryl which is -CH2 aryl (e.g., -CH2 phenyl); C1alkyl C3 cycloalkyl, which is -CH2 cyclopropyl; C1 alkyl heteroaryl, which can be -CH2 pyrazole, -CH2 pyridine, -CH2 pyrimidine and the like. Petition 870220039288, dated 06 / 05 / 2022, p. 33 / 195 27 / 169

[051] Animal(s), as used in this document unless otherwise indicated, refers to an individual animal that is a mammal or bird. Specifically, mammal refers to a vertebrate animal that is both human and non-human, which are members of the taxonomic class Mammalia. Non-exclusive examples of non-human mammals include domestic and farm animals. Non-exclusive examples of a domestic animal include: dog, cat, llama, and horse. Preferred domestic animals are dog, cat, and horse. The most preferred is the dog. Non-exclusive examples of farm animals include: pigs, camels, rabbits, goats, sheep, deer, moose, cattle (livestock), and bison. The preferred farm animal is cattle and pigs. Specifically, bird refers to a vertebrate animal of the taxonomic class Aves. Birds are feathered, winged, bipedal, endothermic, and egg-laying animals.Examples of poultry that are not exclusive to chickens include turkeys, ducks, and geese, and all are referred to here as poultry as well.

[052] Aryl, as used in this document, refers to a monovalent aromatic carbocyclic group of 6 to 10 carbon atoms with a single ring or multiple fused rings. Aryl groups include, but are not limited to, phenyl, biphenyl, and naphthyl. Furthermore, when used in compound words such as alkylaryl, the aforementioned alkyl and aryl groups have the same meaning as defined herein and may be attached to the chemical moiety by any of the carbon atoms of the aliphatic chain. For example, Co-alkylaryl is aryl (e.g., Co-alkylphenyl is phenyl), C1-alkylaryl is -CH2-aryl (e.g., -CH2-phenyl), C2-alkylaryl is -CH2CH2-aryl (e.g., -CH2CH2-phenyl), and the like. Aryls may be substituted as described herein.

[053] Chiral, as used in this document unless otherwise indicated, refers to the structural feature of a molecule that makes it impossible to superimpose it onto its mirror image (e.g., R and S enantiomers).

[054] Understands, as used in this document, refers to an inclusive meaning, that is, it will be understood as including not only the Petition 870220039288, dated 06 / 05 / 2022, page 34 / 195 28 / 169 listed components to which it refers directly, but also other unspecified components or elements. This logical basis will also be used when the term comprised or comprising is used in relation to one or more steps in a method or process. Contains is interpreted here as being synonymous with comprising. The term consisting of and / or consisting essentially of has a non-inclusive meaning.

[055] “Compounds of the present invention, as used in this document, unless otherwise indicated, refers to compounds of Formula (1), stereoisomers thereof and veterinary acceptable salts thereof. The phrase also refers to subgenre formulas of Formula (1) including: Formula (1A), (1A1), (2A), (2A1), (3A) and (4A), stereoisomers thereof and veterinary acceptable salts thereof. Preferred compounds are compounds of Formula (3A).

[056] Cycloalkyl, as used in this document 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 saturated monocyclic rings of 3 to 6 members including cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. The cycloalkyl group may be attached to the chemical moiety by any of the carbon atoms within the carbocyclic ring. Cycloalkyl groups may be substituted by at least one substituent as described in this document. Furthermore, when used in compound words such as alkylcycloalkyl, the said alkyl and cycloalkyl groups have the same meaning as defined herein and may be attached to the chemical moiety by any of the carbon atoms of the aliphatic chain.Examples of C1-C6 alkyl, C3C6 cycloalkyl include, methylcyclopropane (C1 alkyl, C3 cycloalkyl or -CH2cyclopropane), ethylcyclopropane (C2alkyl, C3cycloalkyl, or -CH2CH2cyclopropane), methylcyclobutane (C1alkyl, C4cycloalkyl, or -CH2cyclobutane), ethylcyclobutane (C2alkyl, or C4cycloalkyl. Petition 870220039288, dated 06 / 05 / 2022, page 35 / 195 29 / 169 (CH2CH2 cyclobutane), methylcyclohexane (C1-C6 cycloalkyl or -CH2 cyclohexane) and the like. The cycloalkyl portions may be substituted as described in this document.

[057] Halogen or halo, as used in this document, unless otherwise indicated, refers to fluorine (F), chlorine (Cl), bromine (Br), and iodine (I). The preferred halos are fluorine, chlorine, and bromine. In addition, when used in compound words, such as haloalkyl or “haloalkoxy”, said alkyl and alkoxy may be partially or wholly replaced by halogen atoms which may be the same or different, and said alkyl and alkoxy groups have the same meaning as above and may be attached to the chemical portion by any of the carbon atoms of the aliphatic chain. Examples of haloalkyl include FsC-, F2CH-ClCH2-, CF3CH2-, and CF2CCI2- and the like. The term haloalkoxy is defined analogously to the term haloalkyl. Examples of haloalkoxy include CF3O-, Q3CH2O-, HCF2CH2CH2O-, and CF3CH2O- and the like.

[058] Heteroaryl, as used in this document unless otherwise indicated, refers to a 5- to 6-membered monocyclic aromatic ring or a 9- to 10-membered fused aromatic ring, wherein said fused monocyclic ring contains one or more heteroatoms, each independently selected from N, O or S, preferably from one to four heteroatoms. Non-exclusive examples of monocyclic heteroaryls include pyrrolyl, furanil, thiophenyl, pyrazolyl, imidazolyl, triazolyl, triazinyl, tetrazolyl, thiazolyl, isoxazolyl, isothiazolyl, oxazolyl, oxadiazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, dihydropyridinyl and the like.Non-exclusive examples of fused heteroaryls include: benzofuranyl, oxazol[5,4-b]pyridine, indolyl, 3,4-dihydro2H-pyrrano[2,3-b]pyridine, 2,3-dihydrothieno[3,4-b]dioxin, benzo[d][1,3]dioxol, furo[2,3b]pyridine, benzothiophenyl, benzimidazolyl, indazolyl, quinolinyl, isoquinolinyl, cinolinyl, quinazolinyl, benzotriazolyl, quinoxaline, benzo[d]thiazolyl, thieno[2,3-c]pyridine, thieno[3,2. Petition 870220039288, dated 06 / 05 / 2022, page 36 / 195 30 / 169 b]pyridine, benzo[1,2,5]thiadiazole, pyrazol[1,5-a]pyridine, pyrazol[1,5-a]pyrimidine, dihydro-1H-pyrrol[3,2-b]pyridine, oxazol[5,5-b]pyridine and the like. The heteroaryl ring is attached to the chemical moiety by any of the carbon atoms within the monocyclic or fused ring. Furthermore, when used in compound words such as alkyl-heteroaryl, the aforementioned alkyl and heteroaryl groups have the same meaning as defined in this document and may be attached to the chemical moiety by any of the carbon atoms of the aliphatic chain. For example, C11 heteroaryl is -CH2 heteroaryl, C2 heteroaryl is -CH2CH2 heteroaryl and the like. The heteroaryls may be substituted as described in this document.

[059] Heterocycle, as used in this document unless otherwise indicated, refers to a saturated or partially saturated monocyclic ring of 4 to 6 members or a fused ring of 9 to 10 members, each containing one or more heteroatoms independently selected from N, O, or S, preferably one to four heteroatoms. Non-exclusive examples of heterocycles include oxetane, azetidine, thiatane, tetrahydrofuran, tetrahydrothiophene, pyrrolidine, morpholine, thiomorpholine, tetrahydropyran, piperidine, piperazine, tetrahydropyridine, 2H-azirine, 2,3-dihydroazete, tetrahydrocyclopentapyrazole, 3,4-dihydro-2H-pyrrole, imidazolidine, oxazolidine, isoxazolidine, tetrahydropyrimidinyl, tetrahydropyridineyl, and the like. The heterocyclic ring is linked to the chemical portion by any of the carbon atoms within the ring.Furthermore, when used in compound words, such as alkyl-heterocycle, the aforementioned alkyl and heterocycle groups have the same meaning as defined herein and may be attached to the chemical portion by any of the carbon atoms of the aliphatic chain. For example, C1 alkyl-heterocycle is -CH2 heterocycle, C2 alkyl-heterocycle is -CH2CH2 heterocycle, and so on. The heterocycles may be substituted as described in this document.

[060] Parasite(s), as used in this document, unless otherwise indicated, refers to endoparasites and ectoparasites. Endoparasites are parasites that Petition 870220039288, dated 06 / 05 / 2022, p. 37 / 195 31 / 169 live inside the body of their host and include helminths (e.g., trematodes, cestodes, and nematodes) and protozoa. Ectoparasites are organisms of the phylum Arthropoda (e.g., arachnids, insects, and crustaceans (e.g., copepods - sea lice)) that feed through or on the skin of their host. Preferred arachnids are of the order Acarina, e.g., ticks and mites. Preferred insects are midges, fleas, mosquitoes, biting flies (stable flies, horn flies, blowflies, horseflies, and the like), bedbugs, and lice. The preferred compounds of the present invention can be used for the treatment of parasites, i.e., treatment of a parasitic infection or infestation. A preferred parasite is an endoparasite. A preferred endoparasite is the heartworm (D. immitis).

[061] Percent (%), as used in this document, refers to individual percentage values. When referring to % in liquids (volume / % by volume or % v / v) as an aqueous organic solvent, the % is the % by volume of the solvent in the total volume of the solution. When referring to % solids in liquids (% by weight / volume or % w / v), the % value is interpreted as the weight of the solid in the total volume of the solution and refers to the number of grams of solute in 100 mL of solution. When referring to solids (% by weight or % by weight), it refers to the weight (mass) of a component relative to the total weight (mass) of the solid composition.

[062] Protecting group or Pg, as used in this document unless otherwise indicated, refers to a substituent that is commonly employed to block or protect an amine in the compound, thereby protecting its functionality while allowing the reaction of other functional groups in the compound. Non-exclusive examples of an amine protecting group include: acyl groups (e.g., formyl, acetyl, chloroacetyl, trichloroacetyl, o-nitrophenylacetyl, o-nitrophenoxyacetyl, trifluoroacetyl, acetoacetyl, 4-chlorobutyryl, isobutyryl, o-nitrocinnamoyl, picolinoyl, acylisothiocyanate, aminocaproyl, benzoyl, and the like), acyloxy groups (e.g., 1-tert-butyloxycarbonyl Petition 870220039288, dated 06 / 05 / 2022, page 38 / 195 32 / 169 (Boc), methoxycarbonyl, 9-fluorenyl-methoxycarbonyl, 2,2,2-trifluoroethoxycarbonyl, 2-trimethylsilylethoxycarbonyl, vinyloxycarbonyl, allyloxycarbonyl, 1,1-dimethyl-propynyloxycarbonyl, benzyloxycarbonyl, p-nitrobenzyloxycarbonyl, 2,4-dichlorobenzyloxycarbonyl and similar), diphenylmethane and benzylcarbamate.

[063] Substituted, as used in this document, refers to a substituent that is attached to the chemical moiety in place of a hydrogen atom. Common substituents of the invention for alkyl, cycloalkyl, aryl, heterocyclic, heteroaryl moieties and the like, are as described in this document and include, for example, NO2, -CN, alkyl, halo, alkoxy, haloalkyl, haloalkoxy, cycloalkyl, hydroxy, amino, alkylamino, dialkylamino and the like. The substituents may be attached to any carbon in the aliphatic chain or carbocyclic, aryl, heterocyclic or heteroaryl ring system. The substituent may also be attached to any acceptor nitrogen and / or sulfur atom.

[064] Therapeutically effective amount, as used in this document, refers to an amount of the active agent (i.e., compound of Formula (1)) that (i) treats the particular parasitic infection or infestation, (ii) attenuates, improves or eliminates one or more symptoms of the specific parasitic infection or infestation, or (iii) prevents or delays the onset of one or more symptoms of the specific parasitic infection or infestation described herein. The active agent may be sufficient in a composition to induce the desired biological response against the target parasite(s) after administration of the composition to the animal, as measured by methods known in the art and / or described in the examples herein. In some cases, an effective amount of the active agent in the composition will provide at least 70% efficacy against the target parasite compared to an untreated control.In other cases, an effective amount of the active agent will provide at least 80% efficacy, or at least 85% compared to untreated controls. More typically, an effective amount of the active agent will provide efficacy. Petition 870220039288, dated 06 / 05 / 2022, page 39 / 195 33 / 169 of at least 90%, at least 93%, at least 95%, or at least 97% against the target parasite. In certain cases, including the prevention of Dirofilaria immitis, the term effective amount may provide efficacy of up to 100%. As understood in the art, a therapeutically effective amount may be in one or more doses, i.e., a single dose or multiple doses may be required to achieve the desired treatment outcome, for example, (i) treating the particular parasitic infection or infestation, (ii) attenuating, improving, or eliminating one or more symptoms of the specific parasitic infection or infestation, or (iii) preventing or delaying the onset of one or more symptoms of the specific parasitic infection or infestation described herein. The therapeutically effective amount will vary depending on the compound, the disease and its severity, and the age, weight, etc., of the mammal to be treated.

[065] Treatment, treat and the like, as used in this document, unless otherwise indicated, refers to reversing, alleviating or inhibiting infection, infestation or parasitic condition. As used in this document, these terms also encompass, depending on the animal's condition, the prevention of the onset of a disorder or condition, or the symptoms associated with a disorder or condition, including reducing the severity of a disorder or condition or symptoms associated therewith prior to or following the onset of said infection or infestation. As such, the compounds of the invention prevent heartworm in an animal by killing D. immitis L3 and L4 before it can develop into an adult worm. Thus, treatment may refer to administering the compounds of the present invention to an animal that is not, at the time of administration, affected by the infection or infestation.Treatment also includes preventing the recurrence of an infection or infestation or the symptoms associated with it, as well as references to controlling (e.g., killing, repelling, expelling, incapacitating, stopping, eliminating, alleviating, minimizing, and eradicating).

[066] Veterinarily acceptable, as used in this document, except Petition 870220039288, dated 06 / 05 / 2022, page 40 / 195 34 / 169 unless otherwise indicated, indicates that the substance or composition must be chemically and / or toxicologically compatible with the other ingredients that constitute a formulation, composition and / or the animal being treated with it. The term veterinary acceptable has the same meaning as that designated for pharmaceutically acceptable.

[067] The compounds of Formula (1) of the invention are 24-membered cyclic depsipeptide compounds that possess potent activity against endoparasites, such as nematodes and filarial worms (larval and microfilarial stages), and also in some cases against ectoparasites, such as fleas and ticks. One aspect of the invention is a cyclic depsipeptide of Formula (1), or a veterinary acceptable salt thereof. Surprisingly, it has been found that the addition of a methylene linker between the aryl ring in one or both phenyl lactate groups in the molecule versus the parent cyclic depsipeptide PF1022 and emodepside, improves the selectivity and activity of the compounds against parasites, especially endoparasites.This improvement provides selectivity against L3 and L4 larvae and the current microfilaria by killing the L3 and L4 larvae before metamorphosis to the next life cycle change, the animal is healthier and does not need to succumb to the death of microfilariae or adult worms that can cause emboli and ultimately the death of the host animal. Furthermore, it was surprisingly discovered that replacing the compounds of Formula (1) with certain Li and L2 groups also significantly improves the in vitro metabolic stability of the compounds of the invention compared to PF1022 and emodepsid. Thus, the compounds of the invention were found to have significantly improved metabolic stability and equal or significantly improved efficacy against endoparasites, including microfilariae and / or L3 and L4 larvae of Dirofilaria immitis and / or larvae of Haemonchus contortus.In some respects, compounds of Formula (1) with certain substituents will also exhibit enhanced activity against ectoparasites. Petition 870220039288, dated 06 / 05 / 2022, page 41 / 195 35 / 169

[068] The compounds of the present invention can be synthesized by synthetic routes that include processes analogous to those well known in the chemical arts, particularly in light of the description contained in this document. 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 organischen Chemie, 4, Aufl. Ed. Springer-Verlag, Berlin, including supplements (also available through the Beilstein online database)). For illustrative purposes, the reaction schemes described below demonstrate potential routes for the synthesis of compounds of the present invention and key intermediates.For a more detailed description of the individual reaction steps, see the Examples section below. Those skilled in the art will understand that other suitable starting materials, reagents, and synthetic routes can be used to synthesize the compounds of the present invention and a variety of their derivatives. Furthermore, many of the compounds prepared by the methods described below can be further modified in light of this disclosure using conventional chemistry well known to those skilled in the art.

[069] The depsipeptides of the present invention described herein include one or more chiral centers resulting in a theoretical number of optically active isomers. When the compounds of the invention include n chiral centers, the compounds may comprise up to 2n optical isomers. The present invention encompasses the specific enantiomers or diastereomers and their mixtures of each compound. The optically active forms may be prepared, for example, by resolving the racemic forms by selective crystallization techniques, by synthesizing optically active precursors, by chiral synthesis, by chromatographic separation using a chiral stationary phase, or by enzymatic resolution. Petition 870220039288, dated 06 / 05 / 2022, page 42 / 195 36 / 169

[070] For illustrative purposes, the reaction schemes described below demonstrate potential routes 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 understand that other suitable starting materials, reagents, and synthetic routes can be used to synthesize the intermediates and compounds of the present invention and a variety of their derivatives. Furthermore, many of the compounds prepared by the methods described below can be further modified in light of this disclosure using conventional chemistry. Schemes 1-9 describe 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 herein and as set forth in the claims, should not be limited by the details of the following forms or modes of preparation.In the preparation of the compounds of the present invention, the protection of the remote functionality of intermediates from unwanted reaction can be achieved with a protecting group.

[071] In the preparation of the compounds of the present invention, the protection of the remote functionality of the intermediates from unwanted reactions can be achieved with a protecting group. The term protecting group or Pg refers to a substituent that is commonly employed to block or protect a particular functionality while reacting with 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, trifluoroacetyl, acetoacetyl, 4-chlorobutyryl, isobutyryl, o-nitrocinnamoyl, picolinoyl, acylisothiocyanate, aminocaproyl, benzoyl and the like; and acyloxy groups, including: methoxycarbonyl, 9-fluorenyl-methoxycarbonyl, 2,2,2-trifluoroethoxycarbonyl, 2-trimethylsilethoxycarbonyl, vinyloxycarbonyl, allyloxycarbonyl. Petition 870220039288, dated 06 / 05 / 2022, page 43 / 195 37 / 169 1,1-dimethylpropynyloxycarbonyl, benzyloxycarbonyl, p-nitrobenzyloxycarbonyl, 2,4-dichlorobenzyloxycarbonyl and the like. Similarly, diphenylmethane and benzylcarbamates can be used as amine protecting groups. The appropriate protecting groups and their respective uses are easily determined by a person skilled in the art. For a general description of protecting groups and their use, see T.W. Greene, Protective Groups in Organic Synthesis, John Wiley & Sons, New York, 1991.

[072] The compounds of the invention are intended to encompass racemic mixtures, specific stereoisomers and tautomeric forms of the compound. Another aspect of the invention is a salt form of the compound of the invention.

[073] The compounds of the present invention may also be present in different solid forms, such as different crystalline forms or in the form of an amorphous solid. The present invention encompasses different crystalline forms as well as the amorphous forms of the inventive compounds.

[074] Furthermore, the compounds of the invention may exist as hydrates or solvates in which a certain stoichiometric amount of water or a solvent is associated with the molecule in crystalline form. The hydrates and solvates of the compounds of Formula (I) are also the subject of the invention.

[075] In addition to the neutral compounds of Formula (1), salt forms of the compounds are also active against endoparasites. The term veterinary acceptable salt is used throughout the descriptive report to describe any salts of the compounds that are acceptable for administration in veterinary applications and that deliver the active compound upon administration.

[076] In cases where the compounds are sufficiently basic or acidic to form stable, non-toxic acid or base salts, the compounds may be in the form of a veterinary or agriculturally acceptable salt. Veterinary acceptable salts include those derived from inorganic or organic bases and acids. Petition 870220039288, dated 06 / 05 / 2022, page 44 / 195 38 / 169 veterinary or agriculturally acceptable. Suitable salts include those comprising alkali metals such as lithium, sodium or potassium, alkaline earth metals such as calcium, magnesium and barium. Salts comprising transition metals including, but not limited to, manganese, copper, zinc and iron are also suitable. In addition, salts comprising ammonium cations (NH4+) as well as substituted ammonium cations, in which one or more of the hydrogen atoms are replaced by alkyl or aryl groups are encompassed by the invention.

[077] Salts derived from inorganic acids, including but not limited to acid hydrohalides (HCl, HBr, HF, HI), sulfuric acid, nitric acid, phosphoric acid and the like, are particularly suitable. Suitable inorganic salts also include, but are not limited to, bicarbonate and carbonate salts. In some embodiments, examples of veterinary and agriculturally acceptable salts are addition salts of organic acids formed with organic acids including, but not limited to, maleate, dimaleate, fumarate, tosylate, methanesulfonate, acetate, citrate, malonate, tartrate, succinate, benzoate, ascorbate, α-ketoglutarate and α-glycerophosphate. Obviously, other acceptable organic acids may be used.

[078] Alkali metal (e.g., sodium, potassium, or lithium) or alkaline earth metal (e.g., calcium) salts of the compounds can also be produced by reacting a sufficiently acidic residue in the compounds with an alkali metal or alkaline earth metal hydroxide.

[079] Veterinary acceptable salts can be obtained using standard procedures well known in the state of the art, for example, by reacting a suitable basic compound, such as an amine, with a suitable acidic functional group present in the compound, or by reacting a suitable acid with a suitable basic functional group in the compound of the invention.

[080] The compounds of Formula (1) can be prepared by processes adapted from those described in US Patents Nos. 5,514,773; 5,747,448; Petition 870220039288, dated 06 / 05 / 2022, page 45 / 195 39 / 169 5,874,530; 5,856,436; 6,033,879; 5,763,221; 6,329,338, 5,116,815; 6,468,966; 6,369,028; 5,777,075; and 5,646,244. Furthermore, several synthesis methods for cyclic depsipeptides have been reported in the chemical literature (see Luttenberg et al., Tetrahedron 68 (20 1 2), 2068-2073; Byung H. Lee, Tetrahedron Letters, 1 997, 38 (5), 757-760; Scherkenbeck et al., Eur. J Org. Chem., 20 1 2, 1546-1553; Biosci. Biotech. Biochem., 1 994, 58 (6), 1193-1194; and Scherkenbeck et al., Tetrahedron, 1995, 51(31), 8459-8470). Those skilled in the art will understand that certain functional groups in compounds and intermediates may be unprotected or protected by suitable protecting groups, as taught by Greene and Wuts, Protective Groups in Organic Synthesis, John Wiley and Sons, Inc., 4th edition, 2006. Furthermore, those skilled in the art will understand that compounds and intermediates may be isolated under standard aqueous working conditions and, optionally, purified.For example, compounds or intermediates can be purified by chromatographic methods or crystallized to produce the desired product with adequate purity.

[081] A person skilled in the art will recognize that, in some cases, after the introduction of a particular reagent as represented in the schemes, it may be necessary to carry out additional routine synthesis steps not described in detail to complete the synthesis of the compounds of Formula (1).

[082] The present invention includes all isotopically and veterinaryly acceptable compounds of Formula (1) labeled, in which one or more atoms are replaced by atoms having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number normally found in nature. Examples of suitable isotopes for inclusion in the compounds of the present invention include isotopes of hydrogen, such as 2H and 3H; carbon, such as 11C, 13C and 14C; chlorine, such as 36Cl; fluorine, such as 18F; iodine, such as 123I and 125I; nitrogen, such as 13N and 15N; oxygen, such as 15O, 17O and 18O; and sulfur, such as 35S. Petition 870220039288, dated 06 / 05 / 2022, page 46 / 195 40 / 169

[083] Those skilled in the art will understand that the compounds of the present invention can be produced by methods other than 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 herein, or by using standard textbooks, such as Comprehensive Organic Transformations - A Guide to Functional Group Transformations, RC Larock, WileyVCH (1999 or later editions).

[084] The compounds of Formula (1) are useful as antiparasitic agents, therefore, another aspect of the present invention is a veterinary composition comprising a therapeutically effective amount of a compound of Formula (1), stereoisomers thereof and at least one veterinaryly acceptable excipient. The compounds of the present invention (including the compositions and processes used therein) can also be used in the manufacture of a medicament for the therapeutic applications described in this document.

[085] The compound of the present invention may be administered alone or in a formulation appropriate for the specific use considered, the particular species of host animal to be treated, and the parasite involved. Generally, it will be administered as a formulation in association with at least one veterinaryly acceptable excipient. The term excipient is used in this document to describe any ingredient (e.g., carrier, diluents, and the like) other than the compound of the present invention or any additional veterinary agent (e.g., antiparasitic). The choice of excipient will depend largely on factors such as the particular mode of administration, the effect of the excipient on solubility and stability, and the nature of the dosage form. In addition to the excipient(s), the amount of the compound of the present invention that is administered and the dosage regimen for the treatment of a condition or disorder with the compound will also be considered. Petition 870220039288, dated 06 / 05 / 2022, page 47 / 195 41 / 169 depends on a variety of factors, including the animal's age, weight, sex and medical conditions, the severity of the disease, the route and frequency of administration, and therefore may vary widely.

[086] In another aspect, the veterinary composition comprises a compound of Formula (1) with at least one veterinaryly acceptable excipient. The concentration range will vary depending on the composition (e.g., oral, topical, or injectable). For an oral dose, the range of the active ingredient (i.e., the compound of the present invention) is about 0.1 to 50 mg / kg, preferably about 0.2 to 25 mg / kg, and even more preferably about 0.25 to 10 mg / kg, and more preferably about 0.5 to 7 mg / kg or 1-5 mg / kg. For a topical solution, the range of the active ingredient is about 0.1 to 1000 mg / mL, and preferably about 0.5 to 500 mg / mL, and more preferably about 1 to 250 mg / mL, and even more preferably about 2 to 200 mg / mL. Depending on the final volumes of the topical solution(s), the concentration of the active ingredient may differ from that described above. Generally, injectable doses tend to be, but not always, lower in concentration.

[087] The formulations can be prepared using conventional dissolution and mixing procedures. Such compositions and methods for their preparation can be found, for example, in “Remington's Veterinary Sciences’1, 19th 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).

[088] A typical formulation is prepared by mixing a compound of Formula (1) with at least one veterinary-acceptable excipient. Suitable excipients are well known to those skilled in the art and include materials such as carbohydrates, waxes, water-soluble and / or water-expandable polymers, starches, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water and the like. The particular excipient(s) will depend on the medium and purpose for which the compound of the present invention is being applied. Solvents are generally selected Petition 870220039288, dated 06 / 05 / 2022, page 48 / 195 42 / 169 based on solvents recognized by those skilled in the art as being safe for administration 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, flavoring agents, and other additives known to provide an attractive presentation to the medicament (i.e., a compound of the present invention or its veterinary composition) or to aid in the manufacture of the veterinary product (i.e., medicament). The compound of the present invention will typically be formulated in veterinary dosage forms to provide an easily controllable dosage form for administration.

[089] The methods by which the compound of the present invention can be administered include oral, topical, and injectable administration (e.g., parenteral and subcutaneous). The particular route selected by the physician depends on factors such as the physicochemical properties of the therapeutic agent, the condition of the host, and economics. In certain cases, it is convenient and efficient to administer veterinary drugs orally by placing the therapeutic agent in a solid or liquid matrix that is suitable for oral administration. These methods include chewable drug delivery formulations. The problem associated with administering oral formulations to animals is that the therapeutic agent often provides an unpleasant taste, aroma, or texture, which causes the animals to reject the composition. This is further aggravated by compositions that are hard and difficult to swallow.

[090] The compound of the present invention can be administered orally by capsule, bolus, tablet, powder, lozenge, chewable tablets, multi- and nanoparticulates, gels, solid solution, films, sprays or liquid form. This is a preferred method of administration and as such it is desirable to develop the compound for oral administration. Such formulations can be used as fillers in Petition 870220039288, dated 06 / 05 / 2022, p. 49 / 195 43 / 169 soft or hard capsules, soft or hard palatable chewable tablets, typically comprising at least one veterinaryly acceptable excipient, for example, water, ethanol, polyethylene glycol, N-methylpyrrolidone, propylene glycol, methylcellulose or a suitable oil and one or more emulsifying agents, flavorings and / or suspending agents. Liquid forms include suspensions, solutions, syrups, potions and elixirs. Liquid formulations may also be prepared by reconstituting a solid, for example, from a sachet. Oral potions are generally prepared by dissolving or suspending the compound of the present invention in a suitable medium (for example, triethylene glycol, benzyl alcohol and the like). The compound of the present invention may also be formulated with a food substance, for example, a dietary mixture (bird feed or powder).

[091] The compound of the present invention can be administered topically to the skin or mucous membrane, i.e., dermally or transdermally. This is another preferred method of administration and, as such, it is desirable to develop the compound of the present invention to be suitable for such formulations, for example, in liquid forms. Typical formulations for this purpose include pour-on, spot-on, multispot-on, stripe-on, comb-on, roll-on, dip, spray, mousse, shampoo, powder formulation, gels, hydrogels, lotions, solutions, creams, ointments, dusting powders, dressings, foams, films, skin adhesives, wafers, implants, sponges, fibers, bandages, and microemulsions. Liposomes can also be used. Typical excipients include alcohol, water, mineral oil, liquid petrolatum, white petrolatum, glycerin, N-methylformamide, glycol monomethyl ethers, polyethylene glycol, propylene glycol, and the like.Penetration enhancers may be incorporated - see, for example, J Pharm Sci, 88 (10), 955-958 by Finnin and Morgan (October 1999). Pour-on or spot-on formulations may be prepared by dissolving the active ingredients in an acceptable liquid excipient, 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... Petition 870220039288, dated 06 / 05 / 2022, p. 50 / 195 44 / 169 glycol ether. Alternatively, pour-on, spot-on or spray formulations may be prepared by encapsulation, to leave a residue of the active agent on the animal's surface; this effect may ensure that the compound of the present invention has greater persistence of action and is more durable, for example, being more water-resistant. The topical formulations contemplated herein may comprise from about 0.1 mg / kg to 50 mg / kg of a compound of the present invention, and more preferably from about 1 mg / kg to 10 mg / kg of a compound of the present invention, and even more preferably from 1 mg / kg to 5 mg / kg.

[092] The compounds of the present invention can also be administered topically via a carrier matrix, for example, a synthetic or natural resin, plastic, fabric, leather, or other polymeric system in the form of a collar or ear tag. Said collar or ear tag can be coated and impregnated in layers by any means so as to provide a veterinary acceptable amount of a compound of the present invention alone, or with at least one veterinary acceptable excipient, and optionally with an additional veterinary acceptable antiparasitic agent or salt thereof. These formulations are prepared in a conventional manner according to standard medical or veterinary practice. Furthermore, these formulations will vary in relation to the weight of the active compound contained therein, 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.The volume of the applied composition can be from approximately 0.2 mL / kg to 5 mL / kg, and preferably from approximately 1 mL / kg to 3 mL / kg.

[093] Agents may be added to the formulations of the present invention to improve the persistence of such formulations on the surface of the animal to which they are applied, for example, to improve their persistence in the animal's fur. It is particularly preferable to include such agents in a formulation intended to Petition 870220039288, dated 06 / 05 / 2022, page 51 / 195 45 / 169 can be applied as a pour-on or spot-on formulation. Examples of such agents include acrylic copolymers and in particular fluorinated acrylic copolymers. A particularly suitable reagent is the trade name reagent “Foraperle” (Redline Products Inc, Texas, USA). Certain topical formulations may include unpleasant additives to minimize oral exposure.

[094] The compounds of the present invention can also be administered by injection. Injectable formulations (e.g., subcutaneous and parenteral) can be prepared in the form of a sterile solution, which may contain other substances, for example, salts or glucose sufficient to make the solution isotonic with blood. Acceptable liquid excipients 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 glycerol formate. The formulations are prepared by dissolving or suspending the compounds of the present invention alone or with at least one additional antiparasitic agent in the liquid excipient so that the final formulation contains from about 0.01 to 30% by weight of the active ingredients.

[095] Suitable devices for injectable administration include needle injectors (including microneedle injectors), needleless injectors, and infusion techniques. Injectable formulations are typically aqueous solutions that may contain excipients such as salts, carbohydrates, and buffering agents (preferably at a pH of 3 to 9), but for some applications, they may be more suitablely 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 injectable formulations under sterile conditions, for example, by lyophilization, can be easily achieved using standard veterinary techniques well known to those skilled in the art. The solubility of a compound of the present invention used in the preparation of an injectable solution can be increased by using Petition 870220039288, dated 06 / 05 / 2022, page 52 / 195 46 / 169 of appropriate formulation techniques, such as the incorporation of solubility-enhancing agents.

[096] Administration of the compound of the present invention is considered to be once a month. However, an extended-duration formulation may allow for dosing once every 2, 3, 4, 5, or 6 months.

[097] These formulations are prepared in a conventional manner according to standard medical or veterinary practice. In addition, these formulations will vary in relation to the weight of the active compound contained therein, depending on the species of host animal to be treated, the severity and type of infection or infestation, and the animal's body weight.

[098] The composition of the present invention can be administered alone, as described above, or in combination with at least one other additional antiparasitic agent to form a multicomponent parasiticide providing an even broader spectrum of veterinary use. Thus, the present invention also provides a veterinary combination composition comprising an effective amount of the compound of the present invention in combination with at least one other additional antiparasitic agent and may further comprise at least one veterinaryly acceptable excipient.

[099] The following list of additional antiparasitic agents, together with which the compound of the present invention may be used, is intended to illustrate possible combinations, but does not impose any limitation. Non-limiting examples of additional antiparasitic agents include: amitraz, aminoacetonitriles, albendazole, cambendazole, fenbendazole, flubendazole, thiabendazole, mebendazole, cyclic octadepsipeptides, oxfendazole, oxibendazole, paraherquamide, parbendazole, piperazines, praziquantel, thiabendazole, tetramisole, triclabendazole, levamisole, pyrantel (including the salt forms - pamoate, citrate, and tartrate), oxantel, morantel, abamectin, doramectin, emamectin, eprinomectin, ivermectin, moxidectin, selamectin, dimadectin, Petition 870220039288, dated 06 / 05 / 2022, page 53 / 195 47 / 169 latidectin, lepimectin, milbemycin, milbemycin oxime, demiditraz, emodepsídeo, fipronil, metopreno, diethylcarbamazine, hidropreno, quinopreno, lufenuron, metaflumizona, niclosamida, permethrin, pyrethrins, piriproxifeno, closantel, clorsulon, novaluron, fluazuron, spinosad, sarolaner ((S)-1-(5'-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)4,5-di-hidroisoxazol-3-yl)-3'H-spiro[azetidine-3,1 '-isobenzofuran]-1 -yl)-2-(methylsulfonyl)ethan-1 -ona), fluralaner (4-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-di-hidro-isoxazol-3yl)-2-methyl-N-(2-oxo-2-((2,2,2-trifluoroethyl)amino)ethyl)benzamida), afoxolaner (4-(5-(3chloro-5-(trifluoromethyl)phenyl)-5-(trifluoromethyl)-4,5-di-hidro-isoxazol-3-yl)-N-(2-oxo-2((2,2,2-trifluoroethyl)amino)ethyl)-1-naftamida), lotilaner (3-methyl-N-{2-oxo-2-[(2,2,2-trifluoroethyl)amino]ethyl}-5-[(5S)-5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-di-hidro-1,2-oxazol3-yl]thiopheno-2-carboxamida); and double mixtures.Preferred antiparasitic agents include moxidectin, doramectin, selamectin, abamectin, milbemycin, milbemycin oxime, pyrantel, praziquatel, sarolaner, afoxolaner, lotilaner, fluralaner, and levamisole.

[0100] The veterinary composition for application to an animal may be packaged in various ways, depending on the method used to administer the compound of the present invention or a combination thereof. Generally, a distribution article includes a container that holds the veterinary composition in an appropriate form. Suitable containers are well known to those skilled in the art and include materials such as bottles (plastic and glass), sachets, ampoules, plastic bags, metal cylinders, and the like. The container may also include a tamper-evident assembly to prevent indiscreet access to the contents of the package. In addition, the container has a label describing the contents of the container. The label may also include appropriate warnings.

[0101] The compounds of the present invention (including the compositions and processes used therein) can also be used in the manufacture of a medicament for the therapeutic applications described herein. Petition 870220039288, dated 06 / 05 / 2022, p. 54 / 195 48 / 169

[0102] The compounds of the present invention, their stereoisomers and compositions comprising a therapeutically effective amount of a compound of Formula (1) and at least one veterinary acceptable excipient are useful as ectoparasiticides for the control and treatment of infections or infestations manifested by said ectoparasite in an animal. The compounds of the present invention are useful as ectoparasiticides in particular, such as acaricides and insecticides. They can be used especially in the fields of veterinary medicine, livestock and public health maintenance: against mites, insects and copepods that are parasites of vertebrates, particularly warm-blooded vertebrates, including domestic animals, farm animals and birds, and cold-blooded vertebrates, such as fish.

[0103] The compounds of the present invention are useful for the treatment of parasitic worms categorized as cestodes (tapeworms), nematodes (roundworms) and trematodes (flatworms or flukes). Gastrointestinal roundworms include, for example, Ostertagia ostertagi (including inhibited larvae), O. lyrata, Haemonchus placei, H. similis, H. contortus, Toxocara canis, T. leonina, T. cati, Trichostrongylus axei, T. colubriformis, T. longispicularis, Cooperia oncophora, C. pectinata, C. punctata, C. surnabada (syn. mcmasteri), C. spatula, Ascaris suum, Hyostrongylus rubidus, Bunostomum phlebotomum, Capillaria bovis, B. trigonocephalum, Strongyloides papillosus, S. ransomi Oesophagostomum radiatum, O. dentatum, O. columbianum, O. quadrispinulatum, Trichuris spp. and the like. Other parasites include: hookworms (e.g., Ancylostoma caninum, A. tubaeforme, A.braziliense, Uncinaria stenocephala); lungworms (e.g., Dictyocaulus viviparus and Metastrongylus spp); eyeworms (e.g., Thelazia spp.); parasitic stage larvae (e.g., Hypoderma bovis, H. lineatum, Dermatobia hominis); kidney worms (e.g., Stephanurus dentatus); screwworm (e.g., Cochliomyia hominivorax (larvae)); filarial nematodes of the superfamily Filarioidea and the family Onchocercidae. Petition 870220039288, dated 06 / 05 / 2022, p. 55 / 195 49 / 169 Non-limiting examples of filarial nematodes within the Onchocercidae family include Brugia spp. (i.e., B. malayi, B. pahangi, B. timori and similar), Wuchereria spp. (i.e., W. bancrofti and similar), Dirofilaria spp. (D. immitis, D. repens, D. ursi, D. tenuis, D. spectans, D. lutrae and similar), Dipetalonema spp. (i.e., D. reconditum, D. repens and similar), Onchocerca spp. (i.e., O. gibsoni, O. gutturosa, O. volvulus and similar), Elaeophora spp. (E. bohmi, E. elaphi, E. poeli, E. sagitta, E. schneideri and similar), Mansonella spp. (i.e., M. ozzardi, M. perstans and the like) and Loa spp. (i.e., L. loa). In another aspect of the invention, the compound of the present invention is useful for the treatment of endoparasitic infection by filarial nematodes belonging to the genus Dirofilaria (i.e., D. immitis, D. repens, D. ursi, D. tenuis and the like). The compounds of Formula (1) are preferably endoparasiticidal.

[0104] The compounds of the present invention can also be used against ectoparasites, alone or in combination with at least one additional antiparasitic agent. Some non-limiting examples of ectoparasites include: ticks (e.g., Ixodes spp., (e.g., I. ricinus, I. hexagonus), Rhipicephalus spp., (e.g., R. sanguineus), Boophilus spp., Amblyomma spp. (e.g., A. maculatum, A. triste, A. parvum, A. cajennense, A. ovale, A. oblongoguttatum, A. aureolatum, A. cajennense), Hyalomma spp., Haemaphysalis spp., Dermacentor spp. (e.g., D. variabilis, D. andersoni, D. marginatus), Ornithodorus spp., mites (e.g., Dermanyssus spp., Sarcoptes spp., (e.g., S. scabiei), Psoroptes spp., (e.g., P. bovis). Otodectes spp., Chorioptes spp., Demodex spp., (e.g., D. folliculorum, D. canis, and D. brevis) and similar lice); chewing and sucking lice (e.g., Damalinia spp., Linognathus spp., Cheyletiella spp., Haematopinus spp., Solenoptes spp., Trichodectes spp., Felicola spp. and similar); fleas (e.g., Siphonaptera spp., Ctenocephalides spp. and similar); biting flies, midges and mosquitoes (e.g., Tabanidae spp., Haematobia spp., Petition 870220039288, dated 06 / 05 / 2022, page 56 / 195 50 / 169 Musca spp., Stomoxys spp., Dematobia spp., Cochliomyia spp., Simuliidae spp., Ceratopogonidae spp., Psychodidae spp., Aedes spp., Culex spp., Anopheles spp. and similar); true bugs (e.g., insects of the genus Cimex and the family Cimicidae); and larvae (e.g., Hypoderma bovis, H. lineatum); and copepods (e.g., sea lice within the Order Siphonostomatoida, including the genera Lepeophtheirus and Caligus).

[0105] The compounds of the present invention and compositions comprising compounds of the present invention together with at least one other antiparasitic agent have important value in controlling ectoparasites and endoparasites that are harmful, or spread or act as vectors of disease in domestic animals, farm animals, birds and fish. Ectoparasites and endoparasites that can be treated with a combination of a compound of Formula (1) and an additional antiparasitic agent include those as described above herein.

[0106] 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 antiparasitic agent, may be administered directly to the animal and / or indirectly by application to the local environment in which the animal lives (such as bedding, enclosures and the like). Direct administration includes contact of an animal's skin, fur or feathers with the compound(s), or feeding or injecting the compounds into the animal.

[0107] The compound of Formula (1), stereoisomers thereof, veterinary acceptable salts thereof and combinations thereof with at least one additional antiparasitic agent, as described in this document, are valuable for the treatment and control of the various life cycle stages of parasites, including egg, nymph, larvae, juvenile and adult stages.

[0108] The present invention also relates to a method of administering a compound of the present invention alone or in combination with at least Petition 870220039288, dated 06 / 05 / 2022, p. 57 / 195 51 / 169 an additional antiparasitic agent for animals in good health, comprising applying it to said animal to reduce or eliminate the potential for human parasitic infection or infestation from parasites carried by the animal and to improve the environment in which the animals live.

[0109] 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 antiparasitic agent and, optionally, at least one veterinaryly acceptable excipient, to a human in good or poor health comprising applying it to said human to reduce or eliminate the potential for human parasitic infection or infestation by human-borne parasites and to improve the environment in which the human lives.

[0110] 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 antiparasitic agent and, optionally, at least one veterinary-acceptable excipient, to a plant or soil to prevent parasitic infection of the plant.

[0111] The reactions presented below were generally carried out under positive argon or nitrogen pressure or with a drying tube, at room temperature (unless otherwise indicated) in anhydrous solvents, and the reaction flasks were fitted with rubber septa for the introduction of substrates and reagents via syringe. The glassware was oven-dried and / or heat-dried. Analytical thin-layer chromatography (TLC) was performed using glass-backed silica gel 60 F 254 pre-coated plates and eluted with appropriate solvent ratios (v / v). The reactions were tested by TLC or LCMS and terminated as assessed by the consumption of the starting material. Visualization of the TLC plates was performed with UV light (wavelength 254 nM) or with a suitable heat-activated TLC visualization solvent. Flash column chromatography (Still et al., J. Org.) Petition 870220039288, dated 06 / 05 / 2022, page 58 / 195 52 / 169 Chem. 43, 2923, (1978) was performed using silica gel (RediSep Rf) or various MPLC systems, such as the Biotage or ISCO purification systems.

[0112] Conventional separation and purification methods and / or techniques known to a person 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 those skilled in the art and may include, for example, all types of chromatography (e.g., high-performance liquid chromatography (HPLC), column chromatography using common adsorbents such as silica gel and thin-layer chromatography (TLC), recrystallization and differential extraction techniques (i.e., liquid-liquid).

[0113] The compound structures in the examples below were confirmed by one or more of the following methods: proton magnetic resonance spectroscopy and mass spectrometry. Proton magnetic resonance (1H NMR) spectra were determined using a Bruker spectrometer operating at a field intensity of 400 megahertz (MHz). Chemical shifts are reported in parts per million (ppm) in a field lower than an internal tetramethylsilane standard. Mass spectra (MS) data were obtained using an Agilent mass spectrometer with chemical ionization at atmospheric pressure. Method: Acquity UPLC with chromatography performed on a Waters BEH C18 column (2.1 x 50 mm, 1.7 μm) at 50°C. The mobile phase was a binary gradient of acetonitrile (containing 0.1% trifluoroacetic acid) and water (5-100%).

[0114] Certain aspects of the present invention are illustrated by the following Examples. It should be understood, however, that the aspects of the invention are not limited to the specific details of these Examples, since other variations thereof will be known or evident in the light of this disclosure to a person skilled in the art. Petition 870220039288, dated 06 / 05 / 2022, p. 59 / 195 53 / 169

[0115] The compounds of this invention may exist as one or more stereoisomers. A person skilled in the art will understand that one stereoisomer may be more active and / or may exhibit beneficial effects when enriched relative to the other stereoisomer(s) or when separated from the other stereoisomer(s). Furthermore, a person skilled in the art knows how to selectively separate, enrich, and / or prepare said stereoisomers. The compounds of the invention may be present as a mixture of stereoisomers. EXAMPLES

[0116] The following examples were prepared in accordance with the Schemes and Preparations as presented in this document.

[0117] PF1022a: (3S,6R,9S,12R,15S,18R,21S,24R)-6,18-dibenzyl-3,9,15,21tetraisobutyl-4,10,12,16,22,24-hexa methyl-1,7,13,19-tetraoxa-4,10,16,22-tetra-azacyclotetracosan-2,5,8,11,14,17,20,23-octaone

[0118] Emodepsid: (3S,6R,9S,12R,15S,18R,21S,24R)-3,9,15,21-tetraisobutyl-4,6,10,16,18,22-hexamethyl-12,24-bis(4-mor folinobenzyl)-1,7,13,19-tetraoxa4,10,16,22-tetra-azacyclotetracosan-2,5,8,11,14,17,20,23-octaone Petition 870220039288, dated 06 / 05 / 2022, page 60 / 195 54 / 169

[0119] In the Schemes and Examples described below, the following abbreviations for catalysts / reagents and other miscellaneous substances include: room temperature (RT); dichloromethane (DCM); methanol (MeOH); dimethylformamide (DMF); ethyl acetate (EtOAc); propylphosphonic anhydride (T3P); acetonitrile (MeCN or ACN); ethanol (EtOH); tributyltin hydride (HSnBu3); tributyline chloride (Bu3SnCl); sodium borohydride (NaBH4); sodium nitrite (NaNO2); sulfuric acid (H2SO4); zinc chloride (ZnCl2); tetrahydrofuran (THF); cesium carbonate (CsCO3); denatured alcohol or industrial methylated alcohol (IMS); trifluoromethyltrimethylsilane (CF3TMS); 4-dimethylaminopyridine (DMAP); t-butyloxycarbonyl (BOC, boc); palladium (Pd); N,N-diisopropylethylamine (DIPEA); 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDCI); methoxymethyl (MOM); sodium azide (NaN3); tetra-n-butylammonium fluoride (TBAF); benzyl bromide (BnBr); tetrakis(triphenylphosphine)palladium(O)(Pd(PPh3)4);FurCat (Pd catalyst containing succinimide: Pd(N-succ)Br(P(2-Fu)3)2)); isopropylmagnesium chloride lithium chloride (iPrMgCl-LiCl); hour (h, hr); minute(s) (min); bis(triphenylphosphine)palladium(II) dichloride (PdCl2(PPh3)2), Ghosez's reagent (1-chloro-N,N,2-trimethyl-1-propenylamine; Dess-Martin (periodinane); iodomethane (MeI); saturated (sat); aqueous (aq); equivalents (eq or equiv); 1-ethyl-3(3-dimethylaminopropyl)carbodiimide (EDC); hydrochloric acid (HCl); dichloromethane (DCM); dichloroethane (DCE); N-methylmorpholine (NMM); palladium on carbon (Pd-C or Pd / C); triphenylphosphine (PPh3); di-tert-butyl azodicarboxylate; trifluoroacetic acid (TFA); 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazol[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU); hydrogen bromide (HBr); acetic acid (AcOH); p-toluenesulfonic acid (PTSA); triethylsilane (Et3SiH); copper iodide (CuI); potassium iodide (KI); methylene chloride (CH2Q2); triethanolamine (TEA); methyl tert-butyl ether (MTBE);tetramethylsilane (TMS); trimethylsilyl cyanide (TMSCN); diethylaminesulfuric trifluoride (DAST); tert-butyl nitrite (TBN or tBuONO); sodium hydride (NaH); tetrakis(triphenylphosphine)palladium(O)(Pd(TPP)4); tetra-n-butylammonium fluoride (nBu4F); di-tert-butyl azodicarboxylate (DBAD); and phosphorus tribromide (PBr3). Petition 870220039288, dated 06 / 05 / 2022, p. 61 / 195 55 / 169 Scheme 1: Synthesis Scheme for Preparation of M1, M2, M3 and M4. Cs2CO3 M1 BnBr DMF 30-40% NaNO2, H2SO4, acetone, water, etc. RT RT Fe, EtOAc, IMS, H2O, NH4Cl THE Cl EtOAc Sat. aq. NaHCOs ~ 80% ~90% M3 BnBr Cs2CO3 97% M4

[0120] In Scheme 1, the synthesis of monomers M1, M2, M3, and M4 was carried out using procedures well known in the literature. (Journal of Organic Chemistry, 79 (17), 8491-8497; 2014; Organic Letters, 15 (24), 6132-6135; 2013; ChemBioChem, 9 (8), 1235-1242; 2008) These monomers were used in a stepwise synthesis of the PF1022a nucleus as shown in the subsequent schemes. Furthermore, allyl-protected monomers, allyl (S)-2-hydroxypropanoate and allyl (R)-2-hydroxy-3-(4-nitrophenyl)propanoate and allyl (R)-2-hydroxy-3-phenylpropanoate were also prepared according to the following procedures from the literature: Faming Zhuanli Shenqing, Petition 870220039288, dated 06 / 05 / 2022, page 62 / 195 56 / 169 101962323, 02 / 02 / 2011 and Journal of Organic Chemistry, 67(4), 1061-1070; 2002). These allyl-protected monomers were used in an alternative route that also yielded Bis-Iodine PF1022a using the same coupling conditions described below and the chemistry required to remove the allyl protecting group, as described in TW Greene, Protective Groups in Organic Synthesis, John Wiley & Sons, New York, 1991. Synthesis of Boc-Methyl-L-Leucine (M1):

[0121] Sodium hydride (65.16 g, 1.63 mol) was added in portions over 1.25 hours to a mixture of Boc-L-leucine (125 g, 0.50 mol) and iodomethane (160 mL, 2.50 mol) in THF (2 L) cooled to 0°C. The temperature was maintained below 5°C during the addition and then allowed to warm to room temperature and stirred for 2.5 days. The reaction mixture was cooled to 0°C and stopped with water (2 L); the temperature was maintained below 5°C during the addition and then allowed to warm to room temperature. The aqueous layer was extracted with EtOAc (2 χ 750 mL), then the aqueous phase was acidified to pH 5 with a 10% aqueous citric acid solution, extracted with EtOAc (3 χ 1 L), dried over MgSO4, filtered, and the solvent was removed under vacuum (50°C) and azeotropated with DCM. The two batches were combined to produce 236.09 g, M1.94% yield.1H NMR (CDCh, 300 MHz): δ 4.85 (t, 0.5H), 4.61 (dd, 0.5H), 2.81 (s, 1.5H), 2.78 (s, 1.5H), 1.77-1.65 (m, 2H), 1.57-1.51 (m, 1H), 1.45 (s, 9H), 0.95-0.92 (m, 6H). Chiral analysis: 99.5% ee by GC. Synthesis of Benzyl-L-Lactate (M2):

[0122] L-lactic acid (467 g, 5.2 mol, anhydrous) was dissolved in DMF (1 L). Cesium carbonate (847 g, 2.6 mol, 0.5 eq) was added with stirring, followed by benzyl bromide (886 g, 5.18 mol, 0.99 eq) for about 45 minutes. The mixture was stirred at room temperature for 4 days, after which analysis showed that the reaction was complete. The heterogeneous mixture was filtered through Celite®; the filter cake was washed with ethyl acetate (2 χ² 500 mL). The filtrate was extracted with Petition 870220039288, dated 06 / 05 / 2022, p. 63 / 195 57 / 169 water (2 χ 500 mL), saturated aqueous Na2CO3 (4 χ 500 mL) and brine (2 χ 500 mL) were then concentrated under vacuum to produce a thick orange oil, M2, 775 g, 80%. This was purified by dry flash chromatography using EtOAc / heptane (0% to 10%) as eluent. The appropriate fractions were combined and concentrated under vacuum to produce benzyl-L-lactate, 385 g, 41%. 1H NMR (CDCb, 300 MHz): δ 7.40-7.35 (m, 5H), 5.21 (s, 2H), 4.37-4.27 (m, 1H), 2.79 (d, 1H), 1.43 (d, 3H) Synthesis of benzyl (R)-2-hydroxy-3-(4-((methoxycarbonyl)amino)phenyl)propanoate (M3): Step 1:

[0123] NaNO2 (147.6 g, 2.13 mol) in water (600 mL) was added dropwise to a mixture of 4-nitro-D-phenylalanine (150 g, 0.71 mol) in 1 M H2SO4 (aqueous, 900 mL), water (750 mL) and acetone (2.25 L) maintaining a temperature between -5°C and -3°C. The mixture was stirred at -5°C for 1.5 h, then allowed to warm to room temperature and stirred for 3 days. The mixture was concentrated under vacuum to remove acetone and the mixture was extracted with EtOAc (5 x ~ 375 mL), the combined organic phases were dried over MgSO4, filtered and the solvent removed under vacuum to produce a yellow solid that was recrystallized from isopropyl acetate (~ 2.5 volumes) to produce p-nitrophenyl-D-lactic acid (68.38 g, 45%) as a yellow solid; a second collection of 6.25 g (combined yield of 50%) was obtained from the residue by suspension on DCM.1H NMR (CDCl3, 300 MHz): δ 8.18 (d, 2H), 7.45 (d, 2H), 4.59-4.54 (m, 1H), 3.31 (dd, 1H), 3.10 (dd, 1H).No chiral analysis was performed. Step 2:

[0124] Cs2CO3 (123.3 g, 378 mmol) was added to a mixture of pnitophenyl-d-lactic acid (156.75 g, 742 mmol) in DMF (700 mL) and stirred for 15 minutes; the gas evolved and the clear heterogeneous solution resulted in a homogeneous brown solution (a mild exothermic reaction was observed). Benzyl bromide (124.39 Petition 870220039288, dated 06 / 05 / 2022, page 64 / 195 A concentration of 58 / 169 g, 727 mmol) in DMF (140 mL) was added at room temperature for about 5 minutes; a precipitate formed and the mixture was stirred for about 20 hours at room temperature. The mixture was filtered through Celite® and the filter cake was washed with EtOAc (2 χ 500 mL), the filtrate was washed with water (2 χ 500 mL), saturated aqueous NaHCO3 (3 χ 500 mL) and then brine (500 mL). Heptane (about 1 L) was added to the organic layer and the resulting whitish precipitate was removed by filtration; other collections were obtained from the mother liquors after concentration and trituration with heptanes. The batches were dried at 40°C for approximately 18 hours and combined to produce a whitish solid (197.6, 88% yield). 1H NMR (CDCh, 300 MHz): δ 8.04 (m, 2H), 7.45-7.25 (m, 7H), 5.20 (dd, 2H), 4.55-4.48 (m, 1H), 3.25-3.00 (dd, 2H), 2.86 (d, 1H). UPLC (CSH_C18, short acid 2-95%): 0.73 min. No ionic mass was observed. Step 3:

[0125] Iron powder (256 g, 4.59 mol) was added to a stirred mixture of (R)-benzyl 2-hydroxy-3-(4-nitrophenyl)propanoate (197.5 g, 0.66 mol), ammonium chloride (455 g, 8.52 mol), EtOAc (1 L), water (900 mL), IMS (100 mL), which was heated to 60°C. The reaction darkened in color and was stirred for 18 hours at 50°C. The mixture was cooled, filtered through Celite®, and the filter cake was washed with EtOAc (approximately 600 mL). The layers were separated, and the organic layer was washed with water (3 χ 500 mL). The organic layer was extracted with 1 M aqueous HCl (4 χ 250 mL); Next, the acidic extracts were alkalized with saturated aqueous NaHCO3 to a pH of about 8-9. This was extracted in EtOAc (1 L, then 2 χ 500 mL); the combined organic layers were concentrated under vacuum to produce a solid that was azeotropated with toluene, EtOAc and then DCM. The residue was dried at 50°C to produce a whitish solid (146.5 g, 82%).1H NMR (CDCl3, 300 MHz): δ 7.42-7.30 (m, 5H), 6.91 (d, 2H), 6.56 (d, 2H), 5.13 (s, 2H), 4.42 (t, 1H), 3.54 (s, br 1H), 3.08-2.80 (m, 2H). UPLC (CSH_C18, short acid 2-95%): 0.32 min. Petition 870220039288, dated 06 / 05 / 2022, p. 65 / 195 59 / 169 271.43 Da [M+H]+. Step 4:

[0126] Methyl chloroformate (24.5 mL, 316 mmol, 1.5 eq.) was added dropwise to a stirred mixture of (R)-benzyl 3-(4-aminophenyl)-2-hydroxypropanoate (57.30 g, 211 mmol), EtOAc (375 mL) and saturated aqueous NaHCO3 (300 mL, 5.2 vol) at room temperature for about 20 minutes (a moderate exothermic reaction around 25°C was observed along with the evolution of the gas). The mixture was stirred for another 10 minutes, the organic layer was removed and washed with brine (200 mL), dried over Na2SO4, filtered and concentrated under vacuum to produce M3 as a white solid (73.48 g, 99% yield). 1H NMR (CDCl3, 300 MHz): δ 7.42-7.31 (m, 5H), 7.26-7.13 (m, 2H), 7.12-7.01 (m, 2H), 6.70 (s, 1H), 5.13-5.22 (m, 2H), 4.49-4.43 (m, 1H), 3.74 (s, 3H), 3.06 (dd, 1H), 2.93 (dd, 1H), 2.82 (d, 1H). UPLC (CSH_C18, short acid 2-95%): 0.64 min, 330.4 Da [M+H]+. Synthesis of benzyl (R)-2-hydroxy-3-phenylpropanoate (M4)

[0127] Cs2CO3 (97.5 g, 300 mmol) was added to a mixture of (R)2-hydroxy-3-phenylpropanoic acid (100 g, 602 mmol) in DMF (700 mL) and stirred for 15 minutes; gas was released and the clear heterogeneous solution resulted in a homogeneous brown solution (a mild exothermic reaction was observed). Benzyl bromide (102.0 g, 602 mmol) was added to DMF (100 mL) at room temperature for about 5 minutes; a precipitate was formed and the mixture was stirred for about 20 hours at room temperature. The mixture was filtered through Celite® and the filter cake was washed with EtOAc (2 x 400 mL), the filtrate was washed with water (2 x 400 mL), saturated aqueous NaHCO3 (3 x 400 mL) and then with brine (300 mL). Heptane (approximately 1 L) was added to the organic layer and the resulting whitish precipitate was removed by filtration; other samples were obtained from the mother liquors after concentration and trituration with heptanes.The batches were dried at 40°C for approximately 18 hours and combined to produce a whitish solid (M4). Petition 870220039288, dated 06 / 05 / 2022, p. 66 / 195 60 / 169 151 g, 89% yield). 1H). Scheme 2: Stepwise Pathway for Bis-Iodine Synthesis PF1022a M1 + M3 EDC. HCl NMM DMAP DCM IMS D1 D1 + D2 PPh3 DBAD THF RT RT M1 + M2 --------Boc OBn TFA, DCM THE HATU DIPEA DCM H2, Pd / C, IMS D2 T1-1 Boc THE- HN OH THE T1-2 Petition 870220039288, dated 06 / 05 / 2022, p. 67 / 195 61 / 169 Boc Petition 870220039288, dated 06 / 05 / 2022, p. 68 / 195 62 / 169 Bis-lodo-PF1022a

[0128] As shown in Scheme 2, dimers D1 and D2 are prepared using standard amide linkage formation methods and standard ester linkage formation methods followed by standard protecting group removal steps. Tetramer T1 is formed from the reaction of D1 with D2 using routine amide linkage formation methods. T1 is then selectively deprotected to generate either of the two tetramers, T1-1 and T1-2, which, when coupled, yield the corresponding linear octadepsipeptide, O1. Sequential deprotection and cyclization yielded the appropriate aryl-functionalized cyclic octadepsipeptide, C1. Conversion to the advanced intermediate Bis-Iodine PF1022a was performed by carrying out a two-step sequence that included protecting group removal followed by the routine sequence to convert the amino group to an iodine group. The Petition 870220039288, dated 06 / 05 / 2022, p. 69 / 195 63 / 169 technicians in the field will understand that mono-Iodine PF1022a can be easily obtained from the route shown in Scheme 2 by the appropriate use of M3 and M4. Synthesis of (R)-1-(benzyloxy)-3-(4-((methoxycarbonyl)amino)phenyl)-1-oxopropan2-yl N-(tert-butoxycarbonyl)-N-methyl-L-leucinate (D1): Step 1:

[0129] EDC.HCl (134.8 g, 703 mmol) was added in a portion to a mixture of (R)-benzyl 2-hydroxy-3-(4-((methoxycarbonyl)amino)phenyl)propanoate (178.2 g, 541 mmol), Boc-Methyl-L-Leucine (146.0 g, 595 mmol), DMAP (6.60 g, 54 mmol), 4-methylmorpholine (154.6 mL, 406 mmol), and DCM (3.4 L). EDC.HCl dissolves slowly, forming an orange solution; a mild exothermic reaction was controlled by cooling after approximately 15 minutes. After 5 hours, the reaction was washed with water (2 χ² L), 10% aqueous citric acid solution (2 χ² L), 5% aqueous citric acid solution (1 χ² L), saturated aqueous NaHCO₃, water (1 L), dried over MgSO₄, filtered, and the solvent removed under vacuum to yield a 296.1 g, 98% oil. 1H NMR (CDCl₃, 400 MHz): δ 7.44-6.95 (m, 9H), 6.67-6.45 (m, 1H), 5.36-4.64 (m, 4H), 4.14-3.63 (m, 3H), 3.22-2.92 (m, 2H), 2.74-2.50 (m, 3H), 1.69-1.32 (m, 12H), 1.01-0.79 (m, 6H). UPLC (CSH_C18, short acid, 2-95%): 1.06 min, 457.6 Da, [M-Boc+H]+. Step 2:

[0130] 10% w / w Pd-C (20.7 g, 19 mmol) was washed in a solution of (R)1-(benzyloxy)-3-(4-((methoxycarbonyl)amino)phenyl)-1-oxopropan-2-yl N-(tert-butoxycarbonyl)-N-methyl-L-leucinate (296 g, 532 mmol) in industrial methylated spirits (IMS, 3 L) with toluene (approximately 80 mL). The mixture was stirred for approximately 18 hours under hydrogen (1 atm) for 2 days. The mixture was filtered through Celite®, the filter cake was washed with IMS (approximately 500 mL), and the mixture was concentrated under vacuum. The residue was purified by filtration through a silica buffer, eluting with 40% EtOAc in heptanes and concentrating under vacuum to yield D1. (232.72 g, 91%). 1H NMR (CDCls, 300 MHz): δ 7.35-7.25 (m, 2H), 7.17-7.11 (m, 2H), Petition 870220039288, dated 06 / 05 / 2022, p. 70 / 195 64 / 169 6.94 (s, br 1H), 5.27-5.18 (m, 1H), 4.73-4.67 (m, 1H), 3.76 (s, 3H), 3.20-3.05 (m, 2H), 2.80-2.70 (m, 3H), 1.76-1.40 (m, 11H), 0.95-0.85 (M, 6H), 96.72% pure w / w by HRMN with 0.34% DCM and 1.60% EtOAc equivalent to 225.08 g, 90.6%. UPLC (CSH_C18, short acid 2-95%): 0.86 min, 367.6 Da [M-Boc+H]+. Synthesis of (R)-1-(benzyloxy)-1-oxopropan-2-yl N-(tert-butoxycarbonyl)-N-methylL-leucinate(D2X Step 1:

[0131] Triphenylphosphine (192 g, 732 mmol), Boc-Methyl-L-Leucine (165 g, 672.6 mmol) and benzyl-L-Lactate (120 g, 666 mmol) were dissolved in tetrahydrofuran (700 mL). The resulting solution was cooled to 0°C, then di-tert-butylazodicarboxylate (192 g, 834 mmol, 1.25 eq.) was added in portions, maintaining the internal temperature at < 5°C. Once the addition was complete, the mixture was left to stir and heat to room temperature overnight, during which time a whitish precipitate formed. Heptane (500 mL) was added and the resulting mixture was filtered through Celite®. The cake was washed with heptane (2 x 100 mL). The filtrate was concentrated under vacuum to produce a thick orange oil (602 g). Heptane (500 mL) was added and the mixture was vigorously stirred for about 1 hour, resulting in the formation of more white precipitate. This was removed by filtration; the cake was washed with heptane (2 x 300 mL).The resulting filtrate was loaded directly onto silica (2 kg) and eluted with EtOAc / heptane (1% to 10%). The first fraction (72.6 g) still contained triphenylphosphine oxide; this was relocated (about 700 g of silica, about 10% loading), using EtOAc / heptane (0% to 6%), to produce 68.2 g (25.1%) of Boc-MeLeu-DLac-OBn. The second fraction from the initial column was concentrated under vacuum to yield 100.1 g (combined = 168.3 g, 62%) of (R)-1-(benzyloxy)1-oxopropan-2-yl N-(tert-butoxycarbonyl)-N-methyl-L-leucinate as a straw-colored oil. 1H NMR (CDCl3): δ 7.46-7.30 (m, 5H), 5.21-5.08 (m, 3H), 4.99-4.70 (ddd, 1H), 2.73 (d, 3H), 1.73-1.40 (m, 18H), 0.92 (t, 6H). UPLC (CSH_C18, short acid 2-95%): Petition 870220039288, dated 06 / 05 / 2022, p. 71 / 195 65 / 169 1.08 min, 308.5 Da [M-Boc+H]+. Step 2:

[0132] (R)-1-(benzyloxy)-1-oxopropan-2-yl N-(tert-butoxycarbonyl)-N-methyl-L-leucinate (100.1 g, 243 mmol) was dissolved in dichloromethane (575 mL, 5.75 vol) and subsequently cooled to 0°C. Trifluoroacetic acid (150 mL, 1.96 mol, 8 eq., 1.5 vol) was then introduced. UPLC data after 4 hours indicated that the reaction was approximately 50% complete. Another portion of trifluoroacetic acid (75 mL, 980 mmol, 4 eq., 0.75 vol) was added. UPLC indicated that it was not complete after 7 hours, so the mixture was stirred overnight for approximately 16 hours. Toluene (300 mL) was added and the mixture was concentrated under vacuum to produce a thick orange oil. 2,1H NMR indicates residual toluene and trifluoroacetic acid. 1H NMR (CDCl3, 300 MHz): 9.67-9.15 (br s, 1H), 8.65-8.10 (br s, 1H), 7.47-7.26 (m, 5H), 5.29-5.09 (m, 3H), 3.97-3.85 (m, 1H), 1.92-1.78 (m, 1H), 1.77-1.66 (m, 2H), 1.59-1.54 (s, 3H), 0.98-0.90 (m, 6H).UPLC (CSH_C18, short acid 2-95%): 0.43 min, 308.5 Da [M+H]+. Synthesis of (R)-1-(benzyloxy)-1-oxopropan-2-yl N-((R)-2-((N-(tert-butoxycarbonyl)-N-methyl-L-leucyl)oxy)-3-(4-((methoxycarbonyl)amino)phenyl)propanoyl)-N-methyl-L-leucinate (T1):

[0133] D1 (193 g, 458 mmol) and D2 (225 g, 482 mmol) were stirred in dichloromethane (2 L). HATU (250 g, 658 mmol, 1.36 eq.) was added, followed by diisopropylethylamine (375 mL, 2150 mmol) through a dropping funnel. The reaction temperature was maintained using an external ice bath. The mixture was left to stir overnight at room temperature. The reaction mixture was washed with water (3 χ² 2 L), aqueous citric acid (10%, 2 χ² 1 L), saturated aqueous NaHCO₃ (2 χ² 1 L), and water (1 L). The organic phase was dried over MgSO₄, filtered, and concentrated under vacuum to obtain an orange oil. This was purified by dry flash chromatography using EtOAc / heptane as eluent (0% to 30%), to yield T1 (313 g, Petition 870220039288, dated 06 / 05 / 2022, p. 72 / 195 66 / 169 83%). 1H NMR (CDCI3, 300 MHz): δ 7.41-7.26 (m, 7H), 7.20-7.10 (m, 2H), 6.59 (s, 1H), 5.42-4.60 (m, 6H), 3.82-3.71 (m, 3H), 3.10-2.96 (m, 2H), 2.93-2.71 (m, 6H), 1,771.36 (m, 18H), 1.01-0.83 (m, 12H). UPLC (CSH_C18, short acid, 2-95%): 1.14 min, 656.9 Da [M-Boc+H]+. Synthesis of (R)-1-(benzyloxy)-1-oxopropan-2-yl N-((R)-3-(4-((methoxycarbonyl)amino)phenyl)-2-((methyl-L-leucyl)oxy)propanoyl)-N-methyl-L-leucinate (T1-1):

[0134] T1 (48.7 g, 64.4 mmol) was dissolved in dichloromethane (300 mL, 6 vol). The resulting solution was cooled to 0°C with an external ice bath. TFA (75 mL, 980 mmol, 1.5 vol) was added to the reaction mixture and the mixture was stirred to completion. Toluene (300 mL) was added and the mixture concentrated under vacuum produced a thick orange oil, 65.3 g, approximately 125% (containing ~16 g of TFA) which was used without further purification. 1H NMR (CDCl3, 300 MHz): δ 7.40-7.23 (m, 9H), 6.73 (s, 1H), 5.50-5.42 (m, 1H), 5.29-5.08 (m, 4H), 3.87-3.83 (m, 1H), 3.79-3.77 (m, 3H), 3.06 (d, 2H), 3.01-2.90 (m, 3H), 2.70-2.64 (m, 3H), 2.36 (m, 3H), 1.76-1.42 (m, 6H), 1.39-1.25 (m, 2H), 1.04-0.96 (m, 1H), 0.94-0.87 (m, 6H), 0.79-0.76 (m, 6H). UPLC (CSH_C18, short acid 2-95%): 0.65 min, 656.91 Da [M+H]+. Acid synthesis (6S,9R,12S,15R)-6,12-diisobutyl-9-(4-((methoxycarbonyl)amino)benzyl)-2,2,5,11,15-pentamethyl-4,7,10,13-tetraoxo-3,8,14-trioxa-5,11-diazahexadecan-16-ojco_(T1:2X

[0135] Pd-C (10% w / w, 2.5 g, 2.3 mmol) was washed in a T1 solution (48.3 g, 63.9 mmol) in IMS (500 mL) with toluene (about 20 mL), stirred under hydrogen (1 atm) for 4 hours, and filtered and the solvent removed under vacuum and then azeotropated with DCM to produce Boc-MeLeu-DCbmPheLac-MeLeu-DLacOH as a whitish foam 48.87 g, T1-2, 115% yield (used crude in the subsequent reaction) 1H NMR (CDCl3, 400 MHz): δ 7.05-7.29 (m, 4H), 5.70 (t, 1H), 4.65-5.45 (m, 5H), 3.75 (d, 3H), 2.68-3.19 (m, 8H), 2.30-2.34 (m, 1H), 1.38 Petition 870220039288, dated 06 / 05 / 2022, page 73 / 195 67 / 169 1.74 (m, 17H), 1.10-1.29 (m, 1H), 0.83-0.99 (m, 13H). UPLC (CSH_C18, short acid 2-95%): 0.97 min, 610.8 Da [M-'Bu+H]+, 664.8 Da [MH]-. Dimethyl synthesis ((((2S,5R,8S,11R,14S,17R,20S,23R)-5,11,17,23-tetraisobutyl-4,8,10,16,20,22-hexamethyl-3,6,9,12,15,18, 21,24-octaoxo-1,7,13,19-tetraoxa-4,10,16,22-tetra-azacyclotetracosan-2,14-diyl)bis(methylene))bis(4,1 -phenylene))dicarbamate (C1): Stage 1:

[0136] T1-1 (49.3 g, actual mass 65.3 g, contains ~16 g of trifluoroacetic acid, 64.4 mmol) and T1-2 (42.5 g, actual mass 48.5 g, contains residual solvent from hydrogenation) were dissolved in dichloromethane (500 mL). The mixture was cooled with an external ice bath. HATU (36.4 g, 95.7 mmol, 1.5 eq.) was added, followed by diisopropylethylamine (70 mL, 400 mmol, 6.3 eq.). The resulting mixture was stirred for 20 hours. Water (1 L) was added to the reaction mixture and stirred vigorously for 0.83 hours. The layers were separated and the organic phase washed with aqueous citric acid. (10%, 3 χ 700 mL), saturated aqueous NaHCO3 (1 χ 700 mL) and brine (1 χ 500 mL), then dried over MgSO4, filtered and concentrated under vacuum directly onto Celite® (150 g) and silica gel (20 g). The material was loaded dry onto a silica column (1 kg) and purified by dry flash chromatography using EtOAc / heptane (0-50%) as eluent.This yielded, after concentration under vacuum, O1.85 g, 101% (some traces of heptane observable in the 1H NMR spectrum). 1H NMR (CDCl3, 300 MHz): δ 7.06-7.34 (m, 13H), 6.61 (s, 1H), 4.58-5.46 (m, 10H), 3.73-3.76 (m, 6H), 2.66-3.16 (m, 15H), 1.16-1.69 (m, 28H), 0.83-0.98 (m, 24H). UPLC (CSH_C18, long acid, 2-95%): retention time of 3.53 minutes, 1204.5 Da, [M-Boc+H]+. Step 2:

[0137] O1 (199.5 g, 153 mmol) was dissolved in IMS (400 mL, 2 vol) and loaded into the 2 L autoclave. 5% Pd / C (2 g) was added as a paste in toluene. The autoclave was closed and loaded under a hydrogen pressure of 150 psi. Petition 870220039288, dated 06 / 05 / 2022, p. 74 / 195 68 / 169 After stirring for 5 hours at room temperature, 16% of starting material remained, and the autoclave was charged to 150 psi and left to stir at room temperature overnight. The reaction was completed by UPLC, then the autoclave was vented and the catalyst removed by filtration through Whatman GF / A medium, washing with IMS (50 mL) and ethyl acetate (200 mL). The solvent was removed by spinning to obtain a white foam, O1-1 (175 g, 94% yield). 1H NMR (CDCls, 300 MHz): δ 7.06-7.34 (m, 8H), 4.58-5.46 (m, 10H), 3.73-3.76 (m, 6H), 2.66-3.16 (m, 15H), 1.16-1.69 (m, 28H), 0.83-0.98 (m, 24H). UPLC (long acid, 295%): RT 3.36 min, 1113.5 Da, [M-Boc+H]+. Step 3:

[0138] O1 -1 (245 g, 202 mmol) was dissolved in DCM (1.5 L, 6 vol) and cooled to < 10°C (ice / water bath). Trifluoroacetic acid (370 mL, 551 g, 1.5 vol) was added and the solution was allowed to warm to room temperature and stirred overnight. The solvent was removed by rotation and azeotropated with toluene (2 x 500 mL). The product was obtained as a thick orange oil O1-2 (359.5 g, overweight - estimated purity by NMR is 65%, yielding a calculated mass of 234 g, 94% yield).1H NMR (CDCls, 300 MHz): δ 11.91 (s, TFA), 7.1-7.35 (m, 8H), 4.6-5.65 (m, 8H), 3.79 (s, 6H), 2.6-3.2 (m, 18H), 1.1-1.9 (m, 16H), 0.65-1.07 (m, 28H). Step 4:

[0139] A solution of O1-2 (359.5 g, 65% purity, 0.190 mol) in DCM (2.5 L) was slowly added over 1.5 hours to a solution of propylphosphonic anhydride (50% solution in EtOAc, 670 mL, 1.126 mol) and diisopropylethylamine (392 mL, 2.25 mol) in DCM (2.5 L), maintaining the temperature between 20 and 22°C. When the addition was complete, the solution was stirred for a further 20 minutes and the reaction was checked for completion by UPLC. The solvent was removed by rotation and replaced with EtOAc (5 L). The solution was washed with potassium hydrogen sulfate solution (1 M, 2 x 1 L), 3% sodium carbonate solution (2 x 1.5 L) and Petition 870220039288, dated 06 / 05 / 2022, p. 75 / 195 69 / 169 brine (1 L). The organic layer was dried over MgSO4 and filtered twice through Fisherbrand QL100 filter paper. The solvent was removed to obtain a yellow foam (233 g). This was recrystallized from ethanol (660 mL) and water (130 mL) and the product was washed with ethanol / water (600 mL, 3:1). The product was dried on a filter bed and subsequently spin-dried at 60°C. The product, C1, was obtained as a white solid (159.2 g, 77% yield). 1H NMR (CDCls, 300 MHz): δ 7.3 (m, 4H), 7.15 (m, 4H), 4.4-5.67 (m, 8H), 3.76 (s, 6H), 2.7-3.1 (m, 16H), 1.16-1.8 (m, 16H), 0.731.1 (m, 28H). UPLC (short acid 2-95%): 1.08 min, 1095.5 Da [M+H]+. Synthesis of Bis-Iodine PF1022a: Step 1:

[0140] C1 (151.5 g, 0.138 mol) was added in portions to a 33% HBr solution in acetic acid (750 mL) and stirred at 35°C for 6.5 hours. The reaction mixture was cooled to 15°C (ice / water bath) and ice / water (1.75 L) was added. A 10% sodium carbonate solution was carefully added (approximately 2.5 L) to alkalize the mixture to pH 4-5. The mixture was extracted with ethyl acetate (2 L). The organic layer was separated and washed with saturated aqueous NaHCOa (2 x 1.5 L) and brine (1 L). The organic layer was dried over Na2SO4 and evaporated to obtain a crisp foam (143 g). The foam was recrystallized from 2-propanol (600 mL) and dried to obtain the product, C1-1, as a free-flowing white powder (117.0 g, 87% yield). 1H NMR (CDCls, 300 MHz): δ 6.99 (m, 4H), 6.58 (m, 4H), 4.4-5.6 (m, 8H), 3.62 (br s, 4H), 2.7-3.1 (m, 16H), 1.16-1.9 (m, 14H), 0.73-1.1 (m, 28H). UPLC (long acid 2-95%): 2.79 min, 980.3 Da [M+H]+. Step 2:

[0141] To a solution of C1-1 (10 g, 10.2 mmol) in CH3CN (125 mL) was added pTSA (7.1 g, 40.8 mmol, 4.0 eq) at room temperature and then cooled to -2°C using an ice-salt bath. A 1.5M NaNO2 solution (1.70 g, 24.5 mmol, 2.4 eq) in water (15 mL) was added slowly over a period of time. Petition 870220039288, dated 06 / 05 / 2022, p. 76 / 195 70 / 169 for 7 minutes maintaining the temperature at approximately -1°C. After 15 minutes, CuI (8.7 g, 46.0 mmol, 4.5 eq) was added over 5 minutes and rinsed with water (20 mL). The resulting brown mixture was stirred at approximately -1°C for 30 minutes and then stirred at approximately -2 to 5°C for 30 minutes without cooling. The reaction was cooled to 2°C by adding ice to the reaction and stopped with 25% sodium thiosulfate solution (100 mL). The organic layer was separated and the aqueous layer extracted with ethyl acetate (2 χ² 75 mL). The combined organic solution was washed with water (100 mL) and saturated NaHCO3 (75 mL), brine (100 mL), dried over concentrated Mg2SO4e under vacuum to obtain 16 g of solid. The solid obtained was dissolved in DCM (30 mL), adsorbed onto silica gel (60 g), and filtered through a silica gel bed (100 g) using 50% EtOAC / hexane.The organic solution was concentrated under vacuum until a solid was obtained and dried under vacuum at 40°C overnight to obtain Bislodo PF1022a, (7.5 g, 62%). 1H NMR (600 MHz, CDCh) d: 0.68-0.98 (m, 29H), 1.24-1.7 (m, 13H), 2.67-3.07 (m, 16H), 4.36-4.43 (m, 1H), 4.96-5.63 (m, 7H), 6.98-7.05 (m, 4H), 7.60-7.69 (m, 4H). LC-MS (m / z): [M+] = 1200. Scheme 3: Route for Preparation of Bis-CH2Cl PF1022a: Petition 870220039288, dated 06 / 05 / 2022, p. 77 / 195 71 / 169

[0142] As shown in Scheme 3, the conversion of Bis-Iodine PF1022a to Bis-Aldehyde PF1022a is carried out by a sequence of three steps. Palladium-catalyzed carbonylation in a carbon monoxide atmosphere to install the aldehyde, which is then reduced with a hydride reagent to form Bis-CH2OH PF1022a, which is readily converted, using a standard functional group, to the intermediate Bis-CH2Cl PF1022a. In the preparation of Bis-Aldehyde PF1022a, a small but appreciable amount (2%-20%) of 4(((2R,5S,8R,11S,14R,17S,20R,23S)-14-benzyl-5,11,17,23-tetraisobutyl4,8,10,16,20,22-hexamethyl-3,6,9,12,15,18,21,24-octaoxo-1,7,13,19-tetraoxa4,10,16,22-tetra-aazacyclotetracosan-2-yl)methyl)benzaldehyde (Mono-Aldehyde PF1022a) is also formed. Mono-Aldehyde PF1022a can be separated from Bis-Aldehyde PF1022a using standard reversed-phase HPLC methods. Mono-Aldehyde PF1022a was also used as a starting material to prepare some of the Petition 870220039288, dated 06 / 05 / 2022, p. 78 / 195 72 / 169 compounds are presented in Tables 1-4, according to Scheme 8. Synthesis procedures for the preparation of BIS-CH2CI PF1022a (Scheme 3): Step 1:

[0143] A 2 L pressure reactor was charged with Bis-Iodine PF1022a (130.0 g, 101.7 mmol), HSi(octyl)3 (225 g, 610.1 mmol), DMF (700 mL), TEA (131 mL, 938.8 mmol) and Pd(TPP)4 (5.6 g, 4.8 mmol) and then purged with nitrogen and carbon monoxide. The reaction was heated to 65°C under carbon monoxide (55 psi) and stirred for 2 hours. The reaction was cooled to 22°C, slowly diluted with ice water (2.5 L). The solid was collected, washed with water (2 x 250 mL), hexane (2 x 200 mL) and dried under vacuum at 50°C overnight to obtain crude Bis-Aldehyde PF1022a as a light brown solid (130 g). Step 2:

[0144] A 3 L round-bottom flask was charged with crude Bis-Aldehyde PF1022a (130 g) and methanol (1100 mL) and then cooled to -35°C using an acetonitrile / dry ice bath. NaBH4 (5.0 g, 130 mmol) was slowly added to the mixture, maintaining the temperature below -30°C, and stirred between -35 and 37°C for 1 hour. The reaction was slowly stopped with saturated NH4Cl (100 mL), brought to 10°C, and concentrated to approximately 3 / 4 of the volume under vacuum at 40°C. The mixture was diluted with water (150 mL), extracted with ethyl acetate (3 χ 150 mL). The organic solution was dried over MgSO4, filtered, and concentrated under vacuum at 45°C to a dark brown solid. The solid was heated in a 1:2 mixture of EtOAc / hexane (200 mL) at 60°C and stirred at room temperature for 4 hours. The solid was collected, washed with 25% ethyl acetate in hexane (2 χ 50 mL), hexane (50 mL) and dried under vacuum to obtain Bis-CH2OH PF1022a (103.5 g, 91% yield for 2 steps).1H RMN (600 MHz, CDCh) δ: 0,75-1,17 (m, 26H), 1,231,96 (m, 16H), 2,70-2,92 (m, 9H), 3,01-3,23 (m, 7H), 4,45-4,53 (m, 1H), 4,65-4,74 (m,. Petição 870220039288, de 06 / 05 / 2022, pág. 79 / 195 73 / 169 4H), 5,03-5,14 (m, 1H), 5,19-5,72 (m, 6H), 7,20-7,36 (m, 8H). LC-MS (m / z): [M+H] = 1009 e [(M+23] = 1031 Etapa 3:

[0145] A 1 L round-bottom, three-necked flask was charged with BisCH2OH PF1022a (98 g, 90.30 mmol) and DCM (300 mL) and then cooled to 10°C with an external ice-water bath. Thionyl chloride (25 mL, 343.2 mmol) was added for 7 minutes, the cooling bath was removed, and the mixture was stirred at room temperature. After 1 hour, the reaction was concentrated under vacuum at 35°C to a syrup, diluted with heptane (2 χ 75 mL), and concentrated to a solid. The brown solid was dissolved in ethyl acetate (250 mL), washed with aqueous Na2CO3 (150 mL), and 50 mL of saturated Na2CO3 solution diluted with water (100 mL) to pH 7.8 was added. The organic layer was separated and the aqueous layer extracted with ethyl acetate (2 x 100 mL). The combined organic solution was dried over MgSO4 and concentrated under vacuum to a brown solid.The crude product in ethyl acetate (300 mL) was stirred with activated charcoal (12 g) for 4 hours at room temperature, filtered through a celite bed, and concentrated to a solid. The crude material obtained in MTBE (110 mL) was heated under reflux, diluted with hexane (50 mL), and stirred at room temperature overnight. The solid was collected, washed with 20% MTBE / hexane (50 mL), hexane (50 mL) and dried under vacuum at 50°C to obtain BisCH2Cl PF1022a as a whitish solid (98 g, 98% yield). 1H NMR (600 MHz, CDCh) d: 0.75-1.17 (m, 26H), 1.25-1.95 (m, 16H), 2.70-2.90 (m, 9H), 3.04-3.26 (m, 7H), 4.44-4.57 (m, 1H), 4.54-4.62 (m, 4H), 5.05-5.13 (m, 1H), 5.24-5.74 (m, 6H), 7.20-7.39 (m, 8H). LC-MS (m / z): [M+H] = 1045, [M+2] = 1046, [M+3] = 1047 and [M+4] = 1047. Scheme 4: Grignard Process [4.1 - 4.4] [4.1] Petition 870220039288, dated 06 / 05 / 2022, p. 80 / 195 74 / 169 I I THE THE O2A R*^ R' R'alquil or H Bis-Iodine PF1022a HO 1. iPrMgCl [4.2] 1a R R —N THE O —N THE R' (- R* OH N TFA, Et3SiHxou ou PdCl2, Et3SiH, iProH R' = H and [4.3] and [4.4] R\ R' THE THE R' (- R* OH N 1a O —N N R\ R' THE HO R THE N— THE THE N THE THE 2b 2c Petition 870220039288, dated 06 / 05 / 2022, p. 81 / 195 75 / 169 R*\ R' HO^ after Pd / C y alkylalkyl

[0146] In Scheme 4, R* represents the aryl, cycloalkyl, heteroaryl and heterocyclo Li and L2 moieties, each of which can be substituted as described herein; and R' can represent H or an alkyl group (e.g., methyl).

[0147] As shown in Scheme 4, Bis-Iodine PF1022a will undergo halogen-metal exchange when treated with iPrMgCl-LiCl to produce a depsipeptide Grignard reagent that can react with a variety of electrophiles, such as aldehydes or ketones, to obtain compounds 1a and 1b. The reaction produces the monosubstituted product, 1b, in small quantities for most of these reactions. Compounds 1a and 1b can be deoxygenated by treatment with triethylsilane in TFA or triethylsilane with PdCl2 to obtain compounds of type 2a and 2b. Compounds 1a and 1b can be separated by preparative HPLC to prepare compounds 2a, 2d, and 2e from 1a; and 2b, 2c, and 2f from 1b; as shown in Scheme 4. Alternatively, a mixture of 1a and 1b can react to generate the mixtures of 2a and 2b, 2d and 2c, and 2e and 2f, respectively, which can then be separated by preparative HPLC. Preparation of Examples 3-7, 3-9, 4-6 and 4-8 (Scheme 4). (3-7). (3S,6R,9S,12R,15S,18R,21S,24R)-6,18-bis(4-(hydroxy(6-methoxypyridin3-yl)methyl)benzyl)-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetra-azacyclotetracosane-2,5,8,11,14,17,20,23-octaano. Petition 870220039288, de 06 / 05 / 2022, pág. 82 / 195 76 / 169 (3-9). (3S,6 R,9S,12R,15S,18R,21 S,24R)-6-benzyl-18-(4-(hydroxy(6-methoxypyridin-3-yl)methyl)benzyl)-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetra-azacyclotetracosane-2,5,8,11,14,17,20,23-octaano. (4-6). (3S,6R,9S,12R,15S,18R,21S,24R)-6-benzyl-18-(4-(hydroxy(6-methoxypyridin-3-yl)methyl)benzyl)-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetra-azacyclotetracosane-2,5,8,11,14,17,20,23-octaano. (4-8). (3S,6R,9S,12R,15S,18R,21S,24R)-6-benzyl-3,9,15,21-tetraisobutyl-18 (4-((6-methoxypyridin-3-yl)methyl)benzyl)-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa4,10,16,22-tetra-azacyclotetracosane-2,5,8,11,14,17,20,23-octaano Stage 1:

[0148] Bis-Iodine PF1022a (200 mg, 0.16 mmol) was dissolved in THF (6 mL) in a nitrogen atmosphere. The solution was cooled to -78°C using a dry ice / iPrOH bath. An excess of Turbo Grignard (iPrMgCl-LiCl, 1.3 M in THF, 0.90 mL, 1.17 mmol) was added and the mixture was stirred at -78°C for 10 minutes. The dry ice bath was then replaced with an ice water bath (0°C). The solution was stirred at 0°C for 20 minutes. A solution in THF (2 mL) of 6-methoxynicotinaldehyde (137 mg, 1.0 mmol) that had been cooled to 0°C was then added to the Grignard mixture. The solution was stirred for a further 30 minutes at 0°C before the reaction was stopped with AcOH (0.150 mL). The reaction mixture was added to EtOAc (25 mL) and the organic phase was washed with water (20 mL), dried over sodium sulfate, and concentrated to obtain a viscous oil which was dissolved in acetonitrile (3 mL) and purified by reverse-phase HPLC to obtain the following products: Petition 870220039288, dated 06 / 05 / 2022, page 83 / 195 77 / 169 Example (3-7), 115 mg; and Example (4-6), 39 mg. Step 2:

[0149] Example (3-7) (100 mg, 0.07 mmol) was dissolved in 1,2-DCE (4 mL). TFA (0.5 mL) and triethylsilane (0.5 mL, 4.3 mmol) were then added and the solution was heated to 90°C in a nitrogen atmosphere for 6 hours. The solution was concentrated and purified using reversed-phase HPLC to obtain Example (3-9) (51 mg) of the product. From Steps 1 and 2, a small amount of Example (48) - 13 mg - is also obtained.

[0150] When compounds, such as 1a and 1b, contain an R' substituent, such as a methyl group (Scheme 4.4), treatment with triethylsilane and TFA provides an alkene intermediate from the dehydration of the alcohol. The crude intermediate can then be reduced to alkanes 2e and 2f by further addition of Pd / C. Ç / 0 O-7 ^= / Q \ / =o \ N— —N ÍPrMgCI-LiCI O= / then 0 'χΑιψ bis-lodo PF1022a c 0 \ MO \ Preparation of Example (3-207) “ Λ / γ°,-ΥΛ — / / -O 1 0-7' \= / ' >0 N- -Nz oY \ . \y=\ -° . μ J γ 0+ ο Λ / 0 Υ^Νγ° — / γ / 0Η I— / -0 1 °Υ V-, >Ο X ΧΝ Ν- —Ν 1= / Ο=< 0 \Υ=\ ho , ο-Α- / \^~'oArV0 r γ 0 1 TFA, Et3SiH, 90 °C then Pd / C 0 / q'^nY^ hl / Y^o 1 oj v=X X_ Y >0 XY 0=K_ 0 \ Y | o- / \ / Aoγγ·Α / Y 0 3-207 Petition 870220039288, de 06 / 05 / 2022, pág. 84 / 195 78 / 169

[0151] To a solution of Bis-Iodine PF1022a (441.9 mg, 0.3679 mmol) in THF (26.5 mL) at -78°C, the iPrMgCLUCl complex in THF (1.3 M, 2.8 mL) was added dropwise over 2 minutes and the mixture was stirred for 5 minutes at this temperature. The solution was heated to 0°C in an ice bath and after 30 minutes a solution of 1-(6-methoxy-3-pyridyl)ethanone (1.0 g, 6.62 mmol) in THF (2.95 mL) was added all at once down the sides of the flask before the mixture was rapidly heated to room temperature. The reaction mixture was stirred at this temperature for 1 hour before being stopped with saturated aqueous NH4Cl and extracted with EtOAC. The combined organic products were washed with brine, dried, and concentrated. The residue was purified by reverse-phase HPLC to obtain 83 mg (18%) of the bis-substituted product and 92 mg (22%) of the mono-substituted product.

[0152] For a solution of (3S,6R,9S,12R,15S,18R,21S,24R)-6,18-bis[[4-[1-hydroxy-1-(6-methoxy-3-pyridyl)ethyl]phenyl]methyl]-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetra-azacyclotetracosan-2,5,8,11,14,17,20,23octaone (35.0 mg, 0.0280 mmol) in 1,2-dichloroethane (1.0 mL) TFA (0.3 mL, 4 mmol) followed by triethylsilane (0.3 mL, 2 mmol) was added to an MW flask. The reaction mixture was heated to 90°C for 1 hour and then cooled to room temperature. Pd / C (30 mg) was added to the cooled reaction mixture and gas evolution continued. After 30 minutes, the crude mixture was filtered through celite and the cake washed with DCM. The combined filtrates were concentrated and purified by reverse-phase HPLC to obtain 18 mg (52%) of Example (3-207) as a white powder.

[0153] Compounds 1a and 1b can also undergo deoxyfluorination with reagents such as DAST to obtain compounds such as 2c and 2d (Scheme 4.3). Example Preparation (3-252) Petition 870220039288, dated 06 / 05 / 2022, page 85 / 195 79 / 169 3-252a 3-252

[0154] A solution of (3S,6R,9S,12R,15S,18R,21S,24R)-6,18-bis({4-[hydroxy(5-methoxypyrazin-2-yl)methyl]phenyl}methyl)-4,10,12,16,22,24-hexamethyl-3,9,15,21-tetrakis(2-methylpropyl)-1,7,13,19-tetraoxa-4,10,16,22-tetra-azacyclotetracosan2,5,8,11,14,17,20,23-octaone 2 (200 mg, 0.16 mmol) in DCM (10 mL) was cooled to -78°C and a solution of DAST (0.32 mL, 2.39 mmol) in DCM (2 mL) was added slowly. The resulting mixture was heated to room temperature and stirred for 16 hours. The reaction mixture was stopped with ice water and extracted with 10% methanol in dichloromethane. The combined organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude material was purified by preparative HPLC to obtain Example (3-252) (5 mg, 3%) as a whitish solid. Diagram 5: Halogen-metal exchange process or reverse Grignard process Petition 870220039288, dated 06 / 05 / 2022, page 86 / 195 80 / 169 Bis-Aldehyde PF1022A2a ÍPrMgCI-LiCI or n-BuLi R*'X I aryl or heteroaryl I 1or:I or Br

[0155] In Scheme 5, R* represents the aryl, cycloalkyl, heteroaryl and heterocyclo Li and L2 moieties, each of which can be substituted as described herein; and R' is H.

[0156] As shown in Scheme 5, an aryl halide, cycloalkyl, heterocycle or heteroaryl (such as iodide or bromide) will undergo halogen-metal exchange when treated with iPrMgCl-LiCl to obtain a Grignard reagent that can react with Bis-Aldehyde PF1022a to obtain compounds 1a and 1b (Scheme 4). The reaction produces the monosubstituted product, 1b, in small quantities for most of these reactions. Compounds 1a and 1b can be deoxygenated by treatment with triethylsilane in TFA or triethylsilane with PdCl2 to obtain compounds of type 2a and 2b (Scheme 4). Preparation of (3S,6R,9S,12R,15S,18R,21S,24R)-6,18-Bis-[4-(5-cyclopropyl[1,3,4]oxadiazol-2-ylmethyl)-benzyl-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetra-azacyclotetracosan-2,5,8,11,14,17,20,23-octaone (3-330) in view of Scheme 5. Petition 870220039288, dated 06 / 05 / 2022, page 87 / 195 81 / 169

[0157] A stirred solution of 2-bromo-5-cyclopropyl-[1,3,4]oxadiazole (941 mg, 4.98 mmol) in dry THF (5 mL) was cooled to -78°C and iPrMgCl LiCl (1.3 M, 3 mL, 3.984 mmol) was added dropwise. The reaction mixture was stirred at -10°C for 40 minutes. A solution of bis-Aldehyde PF1022a (500 mg, 0.498 mmol) in dry THF (1 mL) was added to the mixture in a single portion and stirred at -10°C for 1.5 hours followed by 2 hours at room temperature. The reaction mixture was stopped with saturated NH4Cl solution and extracted with ethyl acetate (2 χ 150 mL). The combined organic layer was washed with water, brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure to obtain the crude product (3S,6R,9S,12R,15S,18R,21S,24R)-6,18-Bis-{4-[(5-cyclopropyl[1,3,4]oxadiazol-2-yl)-hydroxymethyl]-benzyl}-3,9,15,21-tetraisobutyl-4,10,12,16,22,24hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetra-azacyclotetracosan2,5,8,11,14,17,20,23-octaone as a gum.

[0158] To a solution of the above intermediate (crude, 750 mg, 3.065 mmol) in DCE (5 mL) were added triethylsilane (5 mL) and TFA (5 mL) at 23°C. The resulting mixture was heated to 100°C for 1 hour under microwave irradiation. A Petition 870220039288, dated 06 / 05 / 2022, page 88 / 195 82 / 169 reaction mass was poured into saturated NaHCO3 solution and extracted with DCM (2 χ 100 mL). The combined organic layers were washed with water, brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure to obtain the crude compound (3-330) (650 mg) as a gum. The crude material was purified by preparative HPLC to provide the desired Example (3-330) (35 mg) as a whitish solid. Diagram 6. Stille and Suzuki coupling process

[0159] In Scheme 6, R* represents the aryl, cycloalkyl, heterocycle and heteroaryl moieties Li and L2, each of which can be substituted as described herein. “Pd” represents a palladium catalyst.

[0160] As shown in Scheme 6, compounds such as 2a can be accessed directly from Bis-CH2Cl PF1022a via palladium-catalyzed cross-coupling reactions, such as in the Stille or Suzuki reaction. In this case, BisCH2Cl PF1022a is treated with an organoboronic acid, organoboronate ester, or organostanane in the presence of a palladium catalyst with or without a base to provide the desired products after heating. Organostanane reagents and organoboronic acids / esters are commercially available or prepared by standard methods found in the literature (European Journal of Organic Chemistry (2014), 24, 5153-5157; Journal of the American Chemical Society (2002), 12, 8001); Organic Letters (2012), 14 (2), 502-505; Journal of Medicinal Chemistry (2005), 48 (22), 7080-7083; and publications of PCT applications WO2006 / 108591, Petition 870220039288, dated 06 / 05 / 2022, page 89 / 195 83 / 169 WO2003 / 087102 and WO2012 / 177714; as well as from commercially available starting materials.

[0161] For Examples 3-50 and 4-40, to a stirred solution of TMP (137 mg, 0.967 mmol) in THF (1 mL), 2.3 M n-BuLi in THF (0.37 mL, 0.86 mmol) was added at 0°C, then stirred for 30 minutes. Furan-3-carbonitrile (100 mg, 1.074 mmol) in THF (1 mL) was added at -78°C and stirred at the same temperature for 2 hours. Then, Bu3SnCl (0.321 mL, 1.182 mmol) in THF (1 mL) was added at -78°C and the reaction mixture was left under stirring at room temperature for 15 hours. The reaction was stopped with a saturated NH4Cl solution and extracted with DCM (2 χ 15 mL). The combined organic layer was washed with brine solution (5 mL), dried over Na2SO4, filtered, and concentrated. The crude product was purified by column chromatography using silica gel eluting with 20 DCM-hexane to obtain the crude stanane monomer, 2-(tributylstanyl)furan-3-carbonitrile, as a clear yellow liquid.

[0162] For Example 3-209, to a stirred solution of 2-methoxy-4-methylthiazole (75 mg, 0.581 mmol) in THF (5 mL) at -78°C, n-BuLi (0.30 mL) was added and the reaction mixture was stirred for 1 hour at that temperature. Then, tributyltin chloride (0.18 mL, 0.64 mmol) was added at -78°C and the reaction mixture was stirred for 2 hours at room temperature. Water (10 mL) was added to the reaction mixture and extracted with ethyl acetate (2 χ 20 mL). The total organic matter was washed with brine solution, dried (Na2SO4) and evaporated at 25°C to give the stanane monomer, 2-methoxy-4-methyl-5-(tributylstanyl)thiazole, as a dark brown liquid.

[0163] For Example 3-238, to a stirred solution of 3-bromo-2-(trifluoromethyl)pyridine (400 mg, 1.77 mmol) in THF (15 mL) at -78°C, n-BuLi (1.8 mL, 1.1 equiv) was added and the reaction mixture was stirred for 1 hour at that temperature. Then, tributyltin chloride (0.52 mL, 1.947 mmol, 1.1 equiv) was added to Petition 870220039288, dated 06 / 05 / 2022, pp. 90 / 195 84 / 169 78°C and the reaction mixture was stirred for 1.5 hours at room temperature. Water (10 mL) was added to the reaction mixture and extracted with ethyl acetate (2 x 20 mL). The total organic matter was washed with brine solution, dried (Na2SO4) and evaporated to obtain the crude stanne monomer, 3-(tributylstanyl)-2-(trifluoromethyl)pyridine, as a dark liquid. Preparation of (3S,6R,9S,12R,15S,18R,21S,24R)-3,9,15,21-tetraisobutyl6,18-bis(4-((5-methoxypyrazin-2-yl)methyl)benzyl)-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa4,10,16,22-tetra-azacyclotetracosan-2,5,8,11,14,17,20,23-octaone, Example (3-33) using the Stille process shown below.

[0164] Similar compounds, as described in Tables 1-4, were also readily prepared using the Stille process. Bis-CH2CI PF1022a (3-33)

[0165] To a stirred solution of Bis-CH2Cl PF1022a (150 mg, 0.14 mmol) and 2-methoxy-5-(tributylstanyl)pyrazine (0.40 g, 1.0 mmol) in p-dioxane (5 mL) was added Pd(PPh3)4 (75 mg, 0.065 mmol). The solution was heated to 100°C in a N2 atmosphere for 5 hours. The reaction mixture was cooled to room temperature and filtered through Celite. The filtrate was concentrated to a viscous black oil which was dissolved in a small volume of DMSO and purified by reverse-phase HPLC to obtain Example (3-33). Preparation of (3S,6R,9S,12R,15S,18R,21S,24R)-6,18-bis[[4-[[2-(difluoromethyl)-3-pyridyl]methyl]phenyl]methyl]-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl1,7,13,19-tetraoxa-4,10,16,22-tetra-azacyclotetracosan-2,5,8,11,14,17,20,23-octaone, Petition 870220039288, dated 06 / 05 / 2022, p. 91 / 195 85 / 169 Example (3-290) using the Suzuki process shown below.

[0166] Similar compounds, as described in Tables 1-4, were also readily prepared using the Suzuki process.

[0167] A solution of Bis-CH2Cl PF1022a (120 mg, 0.11 mmol) in EtOH:Toluene (4 mL, 1:1) was added to 2-(difluoromethyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (120 mg, 0.46 mmol), NaHCO3 (1 mL of 2 M solution) and Pd(dppf)2Cl2 (15 mg, 0.014 mmol). The reaction mixture was purged with N2 and heated to 100°C for 15 minutes in a microwave oven. After cooling to room temperature, the reaction mixture was diluted with EtOAc / water and the organic phase was separated and concentrated under reduced pressure. The residue was purified by reverse-phase chromatography to obtain 88 mg (62%) of Example (3-290) as a white solid. Scheme 7. Process for the preparation of compounds 2g and 2h. Petition 870220039288, dated 06 / 05 / 2022, page 92 / 195 86 / 169

[0168] In Scheme 7, R* represents the aryl, cycloalkyl, heteroaryl and heterocycle Li and L2 moieties, each of which may be substituted as described herein; and R' is H. Nuc represents a nucleophilic functional group, for example, alcohols, acyclic and cyclic amines, heterocycles (e.g., morpholine), heteroaryls (e.g., pyrazole) and any nucleophilic organometallic cycloalkyl, heterocycle, aryl or heteroaryl group, such as organolithium or Grignard reagents.

[0169] In Scheme 7, compounds 1a and 1b (Scheme 4) are treated individually with phosphorus tribromide to convert the hydroxyl group into a bromine group using conditions readily found in the literature. The bromine group is readily displaced by nucleophiles (Nuc) to form 2g and 2h type compounds which are described in Tables 1-4. Preparation of Compound (3S,6R,9S,12R,15S,18R,21S,24R)-6-benzyl-18-(4((3,4-difluorophenyl)(methoxy)methyl)benzyl)-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetra-azacyclotetracosan-2,5,8,11,14,17,20,23octaone (2-37) HO O: '-Z n °AO“ O Hi oa^o N.> Br PBr3, CH2Cl· THE OO NA.........\ RT, 5 hrs. OO THE THE THE MeO MeOH, 50°C 3 hrs. THE THE OO THE THE THE N THE THE THE OO 2-37 Step 1:

[0170] Compound 1 (300 mg, 0.275 mmol) was dissolved in DCM (5 mL) and the solution was cooled to 0°C in an ice bath. PBr3 (0.27 g, 1.0 mmol) was then added and the solution was stirred for 1 hour at 0°C and for 2 hours at Petition 870220039288, dated 06 / 05 / 2022, page 93 / 195 87 / 169 room temperature. The mixture was diluted with methylene chloride (25 mL) and ice water (20 mL) was added. The layers were mixed and then separated. The organic phase was collected, dried over sodium sulfate, and then concentrated to obtain the crude product as an amorphous amber vitreous solid. The solid was used as in Step 2. Step 2:

[0171] Crude bromide, 2, (150 mg, 0.13 mmol) was added to MeOH (2 mL) and the solution was stirred at 45°C for 3 hours. The mixture was purified directly by reversed-phase HPLC to obtain Example (2-37) (42 mg, 0.038 mmol) as a white solid after lyophilization. Scheme 8: Organometallic Process for Preparing Bis-Iodine Compounds PF1022a

[0172] In Scheme 8, R* represents the aryl, cycloalkyl, heteroaryl and moieties. Petition 870220039288, dated 06 / 05 / 2022, page 94 / 195 88 / 169 Li and L2 heterocycles, each of which can be substituted as described herein. Nuc represents a nucleophilic functional group as defined above.

[0173] As shown in Scheme 8, compounds with general structures 4a and 4b are prepared from 1a and 1b (when R'= H) by a two-step process. In the first step, alcohol 1a or 1b is treated with an oxidizing reagent, such as Dess-Martin periodinane, to produce a ketone (2i and 2j) which will react with a Grignard reagent to obtain compounds of type 4a and 4b in the second step; for example, Example (4-26) can be prepared. Step 1:

[0174] Compound 4-6 (50 mg, 0.046 mmol) was dissolved in DCM (3 mL) and Dess-Martin periodan (42 mg, 1 mmol) was added to the solution while stirring. The solution was stirred at room temperature for 3 hours. The reaction mixture was diluted with DCM (10 mL) and cooled to 0°C. Then, a 1 M aqueous solution of sodium bisulfite (2 mL) was added and the mixture was stirred at 0°C for 0.5 hours. The organic phase was collected and washed with water (2 ≈ 3 mL). The organic phase was dried with sodium sulfate and then concentrated to obtain crude compound 5, which was used without further purification. Step 2:

[0175] Compound 5 (39 mg, 0.035 mmol) was dissolved in anhydrous THF (5 mL) and the solution was cooled to 0°C before MeMgBr (3 M in THF, 0.5 mL, 1.5 mmol) was added. Petition 870220039288, dated 06 / 05 / 2022, pages 95 / 195 89 / 169 added. The solution was then heated to room temperature and stirred for 30 minutes. The solution was cooled again to 0°C and stopped by the addition of AcOH (0.2 mL). The solution was then diluted with EtOAc (15 mL), washed with water (1 ≈ 5 mL) and concentrated to obtain crude Example (4-26). Purification was performed by reversed-phase HPLC to obtain Example (4-26) as a white solid after lyophilization. Scheme 9: Process for the preparation of pyrrole-containing compounds

[0176] As shown in Scheme 9, pyrroles reacted with BisCH2Cl PF1022a under basic conditions to generate bis-C linked pyrroles as products. (R)n is as defined herein. It will be understood that monoCH2Cl PF1022a can react similarly with pyrroles to obtain mono-C linked pyrroles as products; for example, example (3-29) can be prepared using this scheme, as shown below. Petition 870220039288, dated 06 / 05 / 2022, pages 96 / 195 90 / 169 H

[0177] A ((3S,6R,9S,12R,15S,18R,21S,24R)-6,18-bis[[4-(chloromethyl)phenyl]-methyl]-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetra-azacyclotetracosan-2,5,8,11,14,17,20,23-octaone (50.0 mg, 0.048 mmol) was added to 2,4-dimethyl-1H-pyrrole (5.0 equiv., 0.24 mmol), potassium bicarbonate (24 mg) and potassium iodide (4.0 equiv., 0.191 mmol) followed by acetonitrile (1.00 mL) The reaction mixture was then heated to 50°C for 48 hours. The reaction was cooled and filtered through celite and washed with DCM. The crude material was absorbed on celite and purified by reverse-phase chromatography with a 60-95% acetonitrile gradient in H2O. Similar fractions were combined and lyophilized overnight to provide the product, Example (3-29), (20 mg, 32%), as a purplish solid.

[0178] In addition, other C-linked heterocyclic compounds, for Examples (3-5) and (3-14), can be prepared using the following procedural steps. Petition 870220039288, dated 06 / 05 / 2022, page 97 / 195 91 / 169 Step 1:

[0179] Premixed tetrabutylammonium fluoride (4 eq) and TMSCN (4 eq) in acetonitrile were heated to 40°C for 1 hour, after the addition of depsibenzyl chloride (500 mg) at room temperature and stirred for 16 hours. After aqueous processing, the residue was purified by preparative HPLC to obtain bisbenzylnitrile. Step 2:

[0180] A mixture of bisbenzylnitrile (40 mg), thiosemicarbazide (5 eq) and TFA was stirred at 90°C for 16 hours. After cooling to room temperature, the mixture was subjected to aqueous processing and purified by preparative HPLC to obtain bisaminothiadiazole, Example (3-5). Step 3:

[0181] Aminothiadiazole (3-5; 23.5 mg), t-BuONO (10 eq), THF, 0°C at room temperature, was stirred for 16 hours. The solvent was evaporated and the residue purified by preparative HPLC to obtain bistiadiazole, Example (3-14). Similarly, tetrazole Example (3-6) can be prepared. Petition 870220039288, dated 06 / 05 / 2022, page 98 / 195 92 / 169

[0182] Mass data (ESI-MS m / z [M+H]+), unless otherwise defined, are presented in each of Tables 1-4. The compounds described in the upper section of each of Tables 1-4 are those compounds where the D / L4 data were < 1 nM; the compounds in the lower section of each of Tables 1-4 had D / L4 data > 1 nM. The upper and lower sections of Tables 1-4 are separated by the shaded line. Examples with an asterisk (*) have DME HcL3 values ​​< 1 μM. Examples with a caret (Λ) have DME HcL3 values ​​> 1 and < 3.3 μM. The compounds were named by Perkin Elmer ChemBioDraw Ultra 2014, Version 14.0.0.117; CambridgeSoft Corporation.

[0183] The compounds of Formula (1A1) described below in Table 1 were prepared according to the schemes and examples described herein. Each compound of Formula (1A1) listed in the table is a bis substitution; that is, each (R) is the same; each R is the same and each R is the same and are as described in the Table. TABLE 1. Compounds of Formula (1A1) Ex# Rc Rd n R Mass 1-5 HH 1 3-methoxy 1190 1-11 HH 1 2-methoxy 1190 1-18 H 1H-pyrazol-1-yl 2 3,4-difluoro 1-134 HH 1-4 1190 1-2 HH 1 4-F 1165 1-3 HH 1 4-CI 1198 1-4 HH 1 4-CN 1180 1-6 HH 1 3-F 1165 1-7 HH 0 — 1129 1-8 HH 2 2-methoxy; 4-F 1198 1-9 H -OH 1 4-methoxy 1222 Petition 870220039288, of 06 / 05 / 2022, p. 99 / 195 93 / 169 1-10 H -OH 1 2-methoxy 1222 1-12 H -OH 2 3-F; 4-F 1233 1-13 HH 2 3-F; 4-F 1201 1-14 H -OH 1 4-F 1197 1-15 H -OH 1 4-(1H-pyrazol-1-yl) 1294 1-16 H -OH 1 4-(1H-imidazol-1-yl) 1294 1-17 HH 1-Methyl sulfonyl 2-196 HH 1 4-(1H-pyrazol-1-yl) 1262 1-20 HH 1 4-(1H-imidazol-1-yl) 1262 1-21 HH 1 4-(1,2-di-hydropyrimidine-5-yl) 1290 1-22 HH 1 4-(hydryl-pyrimidine-5-yl) 1290 1-23 -OH -CF3 1 3-isopropyl 1382 1-24 HH 1 4-(pyridin-4-yl) 1284 1-25 -OH -CF3 0 -- 1297 1-26 HH 2 3-fluoro; 4-methoxy 1225 1-27 HH 1 4-methoxy 1175 1-28 HH 1 4-methylsulfonyl 1286 1-29 H -OH 1 4-(pyrimidine-5-yl) 1318 1-30 H -OH 1 4-(pyrimidine-2-318)

[0184] The following compound names and example #'s refer to the compounds in the top section of Table 1. (1-5). (3S,6R,9S,12R,15S,18R,21S,24R)-3,9,15,21-tetraisobutyl-6,18-bis(4(3-methoxybenzyl)benzyl)-4,10,12,16, 22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetra-azacyclotetracosane-2,5,8,11,14,17,20,23-octaone; (1-11). (3S,6R,9S,12R, 15S,18R,21S,24R)-3,9,15,21-tetraisobutyl-6,18-bis(4(2-methoxybenzyl)benzyl)-4,10,12,16,22,24-h Examil-1,7,13,19-tetraoxa-4,10,16,22-tetra-azacyclotetracosan-2,5,8,11,14,17,20,23-octaone; and (1-18). (3S,6R,9S,12R,15S,18R,21S,24R)-6,18-bis(4-((3,4-difluorophenyl)(1H-pyrazol-1-yl)methyl)benzyl)-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetra-azacyclotetracosan-2,5,8,11,14,17,20,23-octaone, stereoisomers thereof and veterinary acceptable salts thereof.

[0185] The fH NMR data (400 MHz, DMSO-c^, δ ppm) for the compounds named in Table 1 are shown below: (1-5) 6 H), 7.12-7.25 (m, 10 H); Petition 870220039288, dated 06 / 05 / 2022, pages 100 / 195 94 / 169 (1-11), δ: 0.63-0.98 (m, 26 Η) 1.09-1.78 (m, 16 Η) 2.66-3.07 (m, 20 Η) 3,753.77 (m, 3 Η) 3.85 (s, 3 Η) 4.37-4.45 (m, 1 Η) 4.99-5.72 (m, 7 Η) 6.80-7.23 (m, 16 H); and (1-18) 6.91-6.97 (m, 2H) 6.97-7.04 (m, 2H) 7.07-7.22 (m, 6H) 7.32 (br d, J=7.82Hz, 4H) 7.37-7.49 (m, 2H) 7.55 (s, 2H) 7.677.79 (m,2H),

[0186] The following compounds of Formula (2A1) described in Table 2 were prepared according to the schemes and examples described herein. Each (R)n, Rce Rdé as described in the Table. TABLE 2 • Compounds with Formula (2A1) Ex# Rc Rd n R Massa 2-1* HH 0 — 1039 2-4Λ HH 1 4-F 1057 2-36 H -N(CH2CH3)2 2 3-F; 4-F 1146 2-37A H -OCH3 2 3-F; 4-F 1105 2-38* H -OCH2CH3 2 3-F; 4-F 1119 2-42 H morpholina 1 4-OCF3 1208 2-2 ​​HH 1 4-methoxy 1069 2-3 ​​H -OH 1 4-OCF3 1139 2-5 HH 1 4-CI 1074 2-6 HH 1 4-CN 1064 2-7 HH 1 3-F 1057 2-8 HH 1 4-OCF3 1123 2-9* HH 2 2-methoxy; 4-F 1087 2-10 H -OH 1 4-methoxy 1085 2-11 H -OH 1 2-methoxy 1085 2-1 2a HH 1 2-methoxy 1069 Petition 870220039288, of 06 / 05 / 2022, page. 101 / 195 95 / 169 2-13 H -OH 1 4-OH 1071 2-14 HH 2 3-F; 4-F 1075 2-15 H -OH 1 3-OCF3 1139 2-16 H -OH 1 4-Cl 1090 2-17 H -OH 1 4-(1H-imidazol-1-yl) 1121 2-18 H -OH 1 4-F 13 -OH 19 4-(1H-pyrazol-1-yl) 1121 2-20 -OH -CF3 1 4-methoxy 1153 2-21 H -OH 1 3-(pyrimidin-5-yl) 1133 2-22 H -OH 1 3-(pyrimidin-2-yl) 1133 H 2-H 1 4-(1H-pyrazol-1-yl) 1105 2-24 HF 1 4-Cl 1092 2-25 HH 1 4-(1H-imidazol-1-yl) 1105 2-26 -CH3 -OH 1 4-OCF3 1153 HH 1-27 3-(1,6-di-hydropyrimidine-2-yl) 1119 2-28 HH 1 3-(1,2-di-hydropyrimidine-5-yl) 1119 2-29 -OH -CF3 1 3-isopropyl 1165 2-30 HF 1 4-F 3-(pyridin-4-yl) 1132 2-32 HH 1 3-(pyridin-4-yl) 1116 2-33 H -OH 1 3-OCF3 1139 2-34 H -OH 1 2-OCF3 1139 2-35 H -OH 1 4-OCF 3-39 -OH -- 1123 2-40 HH 2 3-F; 4-methoxy 1087 2-41 H imidazolyl 1 4-OCF3 1189 2-43 H pyrrolidin-1-yl 2 3-F; 4-F 1144

[0187] The following compound names and example #'s refer to the compounds in the upper section of Table 2. (2-1). (3S,6R,9S,12R,15S,18R,21S,24R)-6-benzil-18-(4-benzilbenzil)3,9,15,21-tetraisobutil-4,10,12,16,22,24-hexametil-1,7,13,19-tetraoxa-4,10,16,22-tetra-azaciclotetracosan-2,5,8,11,14,17,20,23-octaona; (2-4). (3S,6R,9S,12R, 15S,18R,21S,24R)-6-benzil-18-(4-(4-fluorobenzil)benzil)-3,9,15,21-tetraisobutil-4,10,12,16,22,24-hexametil-1,7,13,19-tetraoxa-4,10,16,22tetra-azaciclotetracosan-2,5,8,11,14,17,20,23-octaona; (2-36). (3S,6R,9S,12R,15S,18R,21S,24R)-6-benzil-18-(4-((dietilamino)(3,4difluorofenil)metil)benzil)-3,9,15,21-tetraisobutil-4,10,12,16,22,24-hexametilPetição 870220039288, de 06 / 05 / 2022, pág. 102 / 195 96 / 169 1,7,13,19-tetraoxa-4,10,16,22-tetra-azaciclotetracosan-2,5,8,11,14,17,20,23-octaona; (2-37). (3S,6R,9S,12R,15S,18R,21S,24R)-6-benzil-18-(4-((3,4-difluorofenil)(metoxi)metil)benzil)-3,9,15,21-tetraisobutil-4,10,12,16,22,24-hexametil-1,7,13,19tetraoxa-4,10,16,22-tetra-azaciclotetracosan-2,5,8,11,14,17,20,23-octaona; (2-38). (3S,6R,9S,12R,15S,18R,21S,24R)-6-benzyl-18-(4-((3,4-difluorophenyl)(ethoxy)methyl)benzyl)-3,9,15,21-tetraisobutyl -4,10,12,16,22,24-hexamethyl-1,7,13,19tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone; and (2-42). (3S,6R,9S,12R,15S,18R,21S,24S)-6-benzyl-3,9,15,21-tetraisobutyl4,10,12,16,22,24-hexamethyl-18-[[4-[(S)-morpholino-[4-(trifluoromethoxy)phenyl]methyl]phenyl]methyl]-1,7,13,19-tetraoxa-4,10,16,22-tetra-azacyclotetracosan2,5,8,11,14,17,20,23-octaone; stereoisomers thereof and veterinary acceptable salts thereof.

[0188] The fH NMR data (400 MHz, DMSO-d>, δ ppm) for the compounds named in Table 2 are shown below: (2-1). Not available (2-4). Not available (2-36), δ: 0.64-1.79 (m, 48 H) 2.58-3.22 (m, 21 H) 4.32-4.51 (m, 1 H) 4.96-5.82 (m, 7 H) 7.18-7.90 (m, 12 H); (2-37), δ: 0.53-1.76 (m, 42 H) 2.58-3.18 (m, 16 H) 3.25 (s, 3 H) 4.29-4.59 (m, 1 H) 4.92-5.89 (m, 8 H) 7.03-7.51 (m, 12 H); (2-38), δ: 0.65-1.82 (m, 45 H) 2.63-3.14 (m, 16 H) 3.35-3.47 (q, 3 H) 4.35-4.47 (m, 1 H) 4.98-5.79 (m, 8 H) 7.14-7.42 (m, 12 H); and (2-42), δ: 0.64-1.79 (m, 42 H) 2.60-3.12 (m, 21 H) 3.58-4.57 (br, 5 H) 4,965.78 (m, 7 H) 7.20-7.67 (m, 13 H),

[0189] The compounds of Formula (3A) described below in Table 3 were prepared according to the schemes and examples described herein. Each compound Petition 870220039288, dated 06 / 05 / 2022, p. 103 / 195 97 / 169 of Formula (3A) tabulated is a bis substitution; that is, Ring A is equal to Ring B, each (R)n is the same; each Rc is the same and each Rd is the same and are as described in the Table. TABLE 3. Compounds of Formula (3A) z Rings A and B with (R)n Rc Rd Mass 3-4* HH 1142 3-8* HH 1109 3-12Λ l HH 1144 3-17* d HH 1144 3-18* HH 1111 3-21* 3n HH 1168 3-24* / HH 1137 3-31Λ 0 HH 1191 Petition 870220039288, dated 06 / 05 / 2022, p. 104 / 195 98 / 169 z Rings A and B com (R)n Rc Rd Mass 3-44Λ S yj HH 1170 3-49Λ 1 NNHH 1166 3-50* NC HH 1159 3-56* HH 1142 3-57* N^i 1 HH 1151 1 HH 1178 178 H^i H^i 3-60 / ^.CN 1 HH 1159 3-69* O— HH 1191 3-87* ^ÇJ Cl HH 1210 3-110 0— HH 1202 3-112* HH 1212 Petition 870220039288, of 06 / 05 / 2022, p. 105 / 195 99 / 169 z Rings A and B com (R)n Rc Rd Mass 3-118 / =N 0°\ FHH 1227 3-120* / \ ω HH 1173 3-121Λ / NHH 1220 3-124* VHH 1170 3-125 s Br H 129 139 . / · Br H -OH 1331 3-133 9—ZONHH 1220 3-148Λ 0 HH 1111 3-155* HH 1172 3-156 ) / pj1 HH 1143 3-157 HH 1137 3-165 o HH 122 Petition 870220039288, of 06 / 05 / 2022, p. 106 / 195 100 / 169 z Rings A and B with (R)n Rc Rd Mass 3-173Λ HH 1109 3-176Λ —N\ HH 1218 3-178 z— N / y 9— / NO \=N / HH 1304 3-193* N^=\ NO^ HH 1193 3-194 FHH 1167 3-207 9— / o N \ H -CH3 1220 3-209 HH 1191 3-215* O 41 HH 1192 3-217Λ o— N—' HH 1193 3-218 o— 45 NHH 1193 3-220 —OF -CH3 1255 Petition 870220039288, dated 06 / 05 / 2022, p. 107 / 195 101 / 169 z Rings A and B with (R)n Rc Rd Mass 3-223 HH 1159 3-225 O— -CH3 F 1255 3-228 , ZZ N II VN HH 1230 3-238 f3c HH 1267 3-240 HH 1188 3-243 , / ^N JX\ । HH 1137 3-252 / =N / -X —QF -CH3 1257 3-253* t / Nn ^vJ HH 1165 3-254 / ^N 1 HH 1143 3-259Λ / =N -9-^ —0H H -OCH3 1223 3-261 H -CH3 1220 Petition 870220039288, dated 06 / 05 / 2022, p. 108 / 195 102 / 169 z Rings A and B com (R)n Rc Rd Mass 3-268* 4: \l HH 1189 3-273* >=NHH 1159 3-274* z=N / N— H -CH3 1201 3-275Λ HH 3-282 0 HH3 1201 / -283 HH* 1218 3-284 HH 1191 3-285 V] HF 1179 3-286 -wi \^NHH 1201 3-287 / =NFFHH 1231 3-288* HH 1172 Petition 870220039288, of 06 / 05 / 2022, p. 109 / 195 103 / 169 z Rings A and B com (R)n Rc Rd Mass 3-289Λ / =NHH 1214 3-290* NF—Ç FHH 1231 3-291* N\ X] H -CH3 1172 3-292Λ ξ —N o HH 1302 3-293 1 —27 HH 3-294* —NHH 1161 3-295Λ FF—ζ rí HH 1231 3-296Λ HH 1212 3-297 θι FHH 1263 3-307* GN HH 1181 Petition 870220039288, of 06 / 05 / 2022, p. 110 / 195 104 / 169 z Rings A and B com (R)n Rc Rd Mass 3-308Λ 4 #— NHH 1223 3-309Λ N—JHH 1167 3-310* N\ NHH 1189 3-313 .F {Ύ HH 1167 3-318 f HH 1167 3-318 f HH 1393 Cl HH 1199 3-321* / =NFHH 1233 3-322 / =N #—FHH 1195 3-323* FHH 1167 3-324* FFHH 1195 3-326 FFHH 1203 Petition 870220039288, of 06 / 05 / 2022, p. 111 / 195 105 / 169 z Rings A and B com (R)n Rc Rd Mass 3-329* Br \=NHH 1286 3-332 HH 1260 3-333* Yj HH 1267 3-334* z— N / \ z*- 0 o— HH 1252 3-1\^H / 16 HH χ / Ύ \ / \^NHH 1137 3-3Λ OHH 1131 3-5 YrNH2 N—NHH 1176 3-6 T n nn HHH 1113 3-7 9— / QNH -OH 1224 3-9 X—119 -10 -2 NHH3—) < / / 0 H -OH 1178 3-11 -O H -OH 1210 Petition 870220039288, of 06 / 05 / 2022, p. 112 / 195 106 / 169 z Rings A and B com (R)n Rc Rd Mass 3-13 NHH 1139 3-14* S \ # N—NHH 1146 3-15 N—' H -OH 1232 3-16 0^0— NH -OH 1358 3-19 m U / ^ZH -OH -1239 H 3-22 0-0— N / HH 1290 3-23 HH 1146 3-25 N^\ o—' HH 1204 3-26 HH 1139 3-27Λ HH 1131 3-28 H -OH 1264 3-29 114 HHH Petition 870220039288, of 06 / 05 / 2022, p. 113 / 195 107 / 169 z Rings A and B com (R)n Rc Rd Mass 3-30 XO H -OH 1242 3-32 Yr N—NHH 1141 3-33 / =NN—' ' HH 1194 3-34 S -OH -CF3 1310 3-35 / =N ΑΧ \—CN 1361 Hj* \ SA \=AHH 1296 3-37 HH 1200 3-38Λ Xχ HH 1172 3-39 . .s. N—JHH 1172 3-40 X__S _. « HH 1296 3-41 ίΑ HH 1228 3-42 <0 HH 1244 3-43 HH 1210 3-45* HH 1144 Petition 870220039288, of 06 / 05 / 2022, p. 114 / 195 108 / 169 z Rings A and B com (R)n Rc Rd Mass 3-46 se / S\^CN HH 1192 3-47 0—' HH 1204 3-48 H -OH 1174 3-51 \ / HH 1137 3-52* S yV HH 1200 3-53 -OH -154 HH 1204 3-55 SH -OH 1232 3-59 ONHHH 1139 3-61 s^ / \ / HH 1324 3-62 s < / SX^CF3 VJ H -OH 1278 3-63 / ^0 τΗ 1 H -OH 1141 3-64 O Λ\ N H -OH 1171 Petition 870220039288, of 06 / 05 / 2022, p. 115 / 195 109 / 169 z Rings A and B com (R)n Rc Rd Mass 3-65 N cf3 H -OH 1305 3-66 H -OH 1204 3-67 T NX HHH 1113 3-68 --0 N 0 HH 1252 3-70 NHH 1172 3-7 XP H- 17 H-OH 1191 3-73* N= / HH 1133 3-74 π— N 9—__ HH 1248 3-75 z—N 9— / V- cf3 H -OH 1299 3-76Λ HH -OH 1232 Petition 870220039288, of 06 / 05 / 2022, p. 116 / 195 110 / 169 z Rings A and B com (R)n Rc Rd Mass 3-79 yÇ— N / ^ °\ O— H -OH 1284 3-80 Cl H -OH 1244 3-81Λ o fr HH 1167 3-82 X cf3 HH 1279 3-83 SA I o H - 3 H-3 H -OH 1244 3-85 X^s ,__. o~o HH 1294 3-86 H -OH 1328 3-88 X^S ___ « H -OH 1328 3-89 Cl Kl H -OH 1242 3-90 / 7 S kç ΐ HH 1198 Petition 870220039288, of 06 / 05 / 2022, p. 117 / 195 111 / 169 z Anéis A e B com (R)n Rc Rd Massa 3-91 Χλο HH 1310 3-92 s H -OH 1232 3-93 s yj oz \ H -OH 1234 3-94 o— H -OH 1223 s H3—1-95 Π -OH 1230 3-97 NH -OH 1204 3-98 / Οχ e XHJ HH 1356 3-99 N VJ H -OH 1167 3-100 ΧλΟ H -OH 1342 3-101 H -OH -OH 119 HH 1210 Petition 870220039288, dated 06 / 05 / 2022, p. 118 / 195 112 / 169 z Anneis A and B com (R)n Rc Rd Massa 3-103 H -OH 1204 3-104 1 VN H -OH 1177 3-105 aY Ϊ ΌΙ H -OH 1242 3-106 o H -OH / 1279—1=HN=3-H 3-108 Cl HH 1200 3-109 0 Λ HH 1302 3-111 / =N / — 9—Z \—NHH 1274 3-113 aY TH -OH 1230 3-114 c HH 1212 H 3—1 / Z 11 3-116 A or HH 1262 3-117 IHJ S --- HH 1296 3-119* F \^NHH 1209 Petition 870220039288, dated 06 / 05 / 2022, p. 119 / 195 113 / 169 z Rings A and B com (R)n Rc Rd Mass 3-122 y / v '—NHH 1286 3-123 S __ / vr· HH 1228 3-126* s N 1 / / / —NH -OH 1205 3-127 CO H -OH 1311 3-OH -OH 1311 3-129 H-129 s / tr H -OH 1260 3-130 kVa / H -OH 1296 3-131 L / V / H -OH 1294 3-134 9—Z \—o cf3 HH 1327 3-135 / =N / --CF3 9—Z \—o HH 1327 H -OH 9—124 s —H 3-137 0 HH 1314 3-138 Z=N -w Va JHHH 1270 Petition 870220039288, of 06 / 05 / 2022, p. 120 / 195 114 / 169 z Rings A and B com (R)n Rc Rd Mass 3-139 N \^= / H -OH 1328 3-140 N cf3 HH 1279 3-141 HH 1189 3-142 sv) 3-145 0 / V- NH -OH 1223 3-146 AHH 1139 3-147 HH 1290 3-149 sx Çj H -OH 1175 3-150 z^NHH 1244 3-151 / =N / 9— / )>— 2 ° H -OH 25 Petition 870220039288, of 06 / 05 / 2022, p. 121 / 195 115 / 169 z Rings A and B com (R)n Rc Rd Mass 3-152 H -OH 1234 3-153 HH 1258 3-154 N^t __„ λ '— NHH 1265 3-158 HH 1202 3-159Λ sx V / HH 172 v-HH 160 1135 3-161 τ' NHH 1224 3-162 lr > HH 1213 3-163 e ir HH 1260 3-164 / =N )—F 9- / \—o HH 1263 3-166 HH 1244! Petition 870220039288, of 06 / 05 / 2022, p. 122 / 195 116 / 169 z Rings A and B com (R)n Rc Rd Mass 3-167 YZ' HH 1265 3-168 \ / \^NHH 1194 3-169 / N— N—v HH 1264 çf3 3-170 \ 1 \^NHH 1273 -3-191 HH 3-172 HH 1131 3-174 0^ ,N=( 0—' HH 1255 3-175 HH 1159 3-177 9—NN= / HH 1133 3-179 -o \ cf3 HH 1299 3-180 \ HH 1299 3-180 \ N\H 1819 \ 1819 HH / \^NHH 1226 3-182 N -0^ HH 1232 Petition 870220039288, of 06 / 05 / 2022, p. 123 / 195 117 / 169 z Rings A and B com (R)n Rc Rd Mass 3-183 z— N \=N — HH 1221 3-184 HH 1159 3-185 n— N jXÇ O\ HH 1272 3-186 o— HH 1191 3-187 \=NH 3-183 NH \=183 OH HH 1191 3-189 ^ / 1 o-^ O\ HH 1197 3-190 ) / \^O \=NHH 1211 3-191 / 0—' HH 1220 3-192Λ o— HH 1191 3-195 n— NO — \— / s · \ n= · z OHH 1290 3-196 9—^ NN=< / - HH 1250 3-197 9—NN=<^ o— HH 1193 Petition 870220039288, of 06 / 05 / 2022, p. 124 / 195 118 / 169 z Rings A and B com (R)n Rc Rd Mass 3-198 -4—f XN=( Cl HH 1202 3-199 yÇ”N ) j 9— / V- o HH 1272 3-200 Π— N f 9— / ^>—o HH 1244 3-2 -- N 10 Π— N= 9 o HH 1221 3-202 o HH 1159 3-203 π— N XX°\ \=N x HH 1193 3-204 cf3 nX ;_ / / XHH 1267 3-205 S v—NHH 1232 3-206 yÇ—NA 1232 3-206 yÇ—NA 124 o HH=ς= 3-208 Π—N / 9— / —\ 0H HH 1248 3-210 yÇ— N 9— / / ^°\ HH 1177 3-211Λ A 1 \ JXn / XHH 1221 3-212 Z—N / N= / HH 1179 Petition 870220039288, of 06 / 05 / 2022, p. 125 / 195 119 / 169 z Rings A and B com (R)n Rc Rd Mass 3-213 NHH 1189 3-214 9— / o \=NHH 1205 3-216 N—' / HH 1230 3-219 —0 N / m”>-0 \=NHH 1253 3-HH 1217 °H 3-222 HH 1133 3-224 o HH 1253 3-226 HH 1173 3-227 -00o -CH3 F 1181 3-229 / =N )-- 0” / )~0 HH 1250 3-230 HH 12039 HH-χ 3-χ 1139 Petition 870220039288, of 06 / 05 / 2022, p. 126 / 195 120 / 169 z Rings A and B com (R)n Rc Rd Mass 3-232 \^NFHH 1237 3-233 , / ^N 1 HH 1137 3-234 ==N\ X / HH 1161 3-235 N = \=NHH 1211 3-236 3-235 H-ON—1272—H , / ^N Ή\ . HH 1218 3-239 / -χχ HH 1144 3-241 = Ν / { ι HH 1145 3-242 ο HH 1316 3-244 J—Ζ —ΝΗ Ν HH 1189 3-245 Ν\HH 1144 3-245 Ν\HH] 1137 Petition 870220039288, of 06 / 05 / 2022, p. 127 / 195 121 / 169 z Rings A and B com (R)n Rc Rd Mass 3-247 ΚΖΗθΛ HH 1344 3-248 0 HH 1200 3-249 \ N\ HH 1137 3-250 F / =NHH 1195 3-251 / ^N . HH 1218 3-255 z=N —NHH 1214 3-256 0 / N 0 HH 1288 3-257 AjH HH 1115 3-258 / ----s. 0 j— HH 1228 3-260 O—\ n=< A Ή NHH 1221 3-262 . ,0 HH 1171 3-263 . o ^\ / N \ HH 1228 3-264 — HH 1115 Petition 870220039288, of 06 / 05 / 2022, p. 128 / 195 122 / 169 z Rings A and B com (R)n Rc Rd Mass 3-265 2=0 HH 1248 3-266 )“0\_ 7 / =NHH 1248 3-267 J—\—OH NHH 1163 3-269 HVN\ N x HH 1274 3-269 HHH H XI HH 1189 3-272 jX 2=0 HH 1191 3-276 N—< 1 / N\ HH 1238 3-277 / =N^ / °~ HH 1220 3-278 AHH 1165 3-279 hn^n 4jL / HH 183 183 H-NH^ 1137 Petition 870220039288, of 06 / 05 / 2022, p. 129 / 195 123 / 169 z Rings A and B com (R)n Rc Rd Mass 3-281 H \=NHH 1209 3-298Λ o^\ HH 1139 3-299* ο— N—JHH 1229 3-300Λ ^N\ y. L 'N—\ / HH 1217 3-301Λ HH 1109 3-302 xJ HF 1227 3-303* / ^NHH 1193 3-304 1 N^ / HH 1189 3-305* / \ / / n—y HH 1193 - 3-13 HH* 3-311 / FHH 1243 Petition 870220039288, of 06 / 05 / 2022, p. 130 / 195 124 / 169 z Rings A and B com (R)n Rc Rd Mass 3-312 CN ϊτ NHH 1181 3-314 z=NHH 1269 3-315 / =N / --\ Z \—NOHH 1301 3-316 ~^l=^ HH 1211 HH 3-317 H-1321 / N~\ / FFHH 1231 3-325 ú FNHH 1195 3-327 HH 1159 3-328 / =N --<1 N— HH 1213 3-330 ) CLNNH -OH 1204 3-331 \ Cl HH 1200

[0190] The following compound names and example #'s refer to the compounds in the upper section of Table 3. (3-4). (3S,6R,9S,12R,15S,18R,21S,24R)-3,9,15,21-tetraisobutyl4,6,10,16,18,22-hexamethyl-12,24-bis(4-(thiophen-2-ylmethyl)benzyl)-1,7,1,1,13-peteoxa 870220039288, of 06 / 05 / 2022, p. 131 / 195 125 / 169 4,10,16,22-tetra-azaciclotetracosan-2,5,8,11,14,17,20,23-octano; (3-8). (3S,6R,9S,12R,15S,18R,21S,24R)-6,18-bis(4-(furan-2-ylmethyl)benzyl)3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetra-azacyclotetracosane-2,5,8,11,14,17,20,23-octaano; (3-12). (3S,6R,9S,12R,15S,18R,21S,24R)-3,9,15,21-tetraisobutyl4,6,10,16,18,22-hexamethyl-12,24-bis(4-(thiazol-5-ylmethyl)benzyl)-1,7,13,19-tetraoxa4,10,16,22-tetra-azacyclotetracosane-2,5,8,11,14,17,20,23-octaano; (3-17). (3S,6R,9S,12R,15S,18R,21S,24R)-3,9,15,21-tetraisobutyl4,6,10,16,18,22-hexamethyl-12,24-bis(4-(thiazol-2-ylmethyl)benzyl)-1,7,13,19-tetraoxa4,10,16,22-tetra-azacyclotetracosane-2,5,8,11,14,17,20,23-octaano; (3-18). (3S,6R,9S,12R,15S,18R,21S,24R)-3,9,15,21-tetraisobutyl4,6,10,16,18,22-hexamethyl-12,24-bis(4-(oxazol- 2-ylmethyl)benzyl)-1,7,13,19-tetraoxa4,10,16,22-tetra-azaciclotetracosan-2,5,8,11,14,17,20,23-octaona; (3-21). (3S,6R,9S,12R,15S,18R,21S,24R)-6,18-bis(4-((3,5-dimethylisoxazol-4yl)metil)benzyl)-3,9,15,21-tetraisobutyl-4, 10,12,16,22,24-hexametil-1,7,13,19-tetraoxa4,10,16,22-tetra-azaciclotetracosan-2,5,8,11,14,17,20,23-octaona; (3-24). (3S,6R,9S,12R,15S,18R,21S,24R)-3,9,15,21-tetraisobutyl4,6,10,16,18,22-hexamethyl-12,24-bis(4-((1-methyl-1H-pyrazol-5-yl)methyl)benzyl)1,7,13,19-tetraoxa-4,10,16,22-tetra-azacyclotetracosane-2,5,8,11,14,17,20,23-octaano; (3-31). (3S,6R,9S,12R, 15S,18R,21S,24R)-3,9,15,21-tetraisobutyl-6,18-bis(4((2-methoxypyridin-3-yl)methyl)benzyl)-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa4,10,16,22-tetra-azacyclotetracosane-2,5,8,11,14,17,20,23-octaano; (3-44). (3S,6R,9S,12R,15S,18R,21S,24R)-3,9,15,21-tetraisobutyl4,6,10,16,18,22-hexametil-12,24-bis(4-((3-metilthiof en-2-yl)methyl)benzyl)-1,7,13,19-tetraoxa-4,10,16,22-tetra-azaciclotetracosan-2,5,8,11,14,17,20,23-octaone; (3-49). (3S,6R,9S,12R,15S,18R,21S,24R)-6,18-bis(4-((1,3-dimethyl-1H-pyrazol Petition 870220039288, 06 / 05 / 2022, pág. 132 / 195 126 / 169 5-yl)methyl)benzyl)-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetra-azacyclotetracosan-2,5,8,11,14,17,20,23-octaona; (3-50). 2,2'-(((((2R,5S,8R,11 S,14R,17S,20R,23S)-5,11,17,23-tetraisobutyl4,8,10,16,20,22-hexamethyl-3,6,9,12,15,18,21,24-octaoxo-1,7,13,19-tetraoxa4,10,16,22-tetra-azacyclotetracosan-2,14-diyl)bis(methyleno))bis(4,1 -phenyleno))bis(methyleno))bis(furan-3-carbonitrila); (3-56). (3S,6R,9S,12R,15S,18R,21S,24R)-3,9,15,21-tetraisobutyl4,6,10,16,18,22-hexamethyl-12,24-bis(4-(thiophen- 3-ylmethyl)benzyl)-1,7,13,19-tetraoxa4,10,16,22-tetra-azacyclotetracosan-2,5,8,11,14,17,20,23-octaona; (3-57). (3S,6R,9S,12R,15S,18R,21S,24R)-3,9,15,21-tetraisobutil4,6,10,16,18,22-hexametil-12,24-bis(4-(oxazol-4-ilmetil)benzil)-1,7,13,19-tetraoxa4,10,16,22-tetra-azaciclotetracosan-2,5,8,11,14,17,20,23-octaona; (3-60). 4,4'-(((((2R,5S,8R,11 S,14R,17S,20R,23S)-5,11,17,23-tetraisobutil4,8,10,16,20,22-hexametil-3,6,9,12,15,18,21,24-octaoxo-1,7,13,19-tetraoxa4,10,16,22-tetra-azaciclotetracosan-2,14-diil)bis(metileno))bis(4,1 -fenileno))bis(metileno))bis(furan-2-carbonitrila); (3-69). (3S,6R,9S,12R, 15S,18R,21S,24R)-3,9,15,21-tetraisobutil-6,18-bis(4((6-metoxipiridin-2-il)metil)benzil)-4,10,12,16,22,24-hexametil-1,7,13,19-tetraoxa4,10,16,22-tetra-azaciclotetracosan-2,5,8,11,14,17,20,23-octaona; (3-87). (3S,6R,9S,12R, 15S,18R,21S,24R)-6,18-bis(4-((3-clorotiofen-2-il)metil)benzil)-3,9,15,21 -tetraisobutil-4,10,12,16,22,24-hexametil-1,7,13,19-tetraoxa4,10,16,22-tetra-azaciclotetracosan-2,5,8,11,14,17,20,23-octaona; (3-110). (3S,6R,9S,12R,15S,18R,21S,24R)-3,9,15,21-tetraisobutyl-6,18-bis(4((3-methoxythiophen-2-yl)methyl)benzyl)-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa4,10,16,22-tetra-azacyclotetracosane-2,5,8,11,14,17,20,23-octaano; (3-112). (3S,6R,9S,12R,15S,18R,21S,24R)-6,18-bis(4-((4-chlorothiazol-5-yl)metil)benzil)-3,9,15,21 -tetraisobutil-4,10,12,16,22,24-hexametil-1,7,13,19-tetraoxaPetição 870220039288, de 06 / 05 / 2022, pág. 133 / 195 127 / 169 4,10,16,22-tetra-azaciclotetracosan-2,5,8,11,14,17,20,23-octaone; (3-118). (3S,6R,9S,12R, 15S,18R,21S,24R)-6,18-bis(4-((5-fluoro-6-methoxypyridin-3-yl)methyl)benzyl)-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetra-azacyclotetracosane-2,5,8,11,14,17,20,23-octaano; (3-120). (3S,6R,9S,12R,15S,18R,21S,24R)-3,9,15,21-tetraisobutyl4,6,10,16,18,22-hexamethyl-12,24-bis(4-((4-methyl-1,2,3-thiadiazol-5-yl)methyl)benzyl)1,7,13,19-tetraoxa-4,10,16,22-tetra-azacyclotetracosane-2,5,8,11,14,17,20,23-octaano; (3-121). (3S,6R,9S,12R,15S,18R,21S,24R)-3,9,15,21-tetraisobutyl-6,18-bis(4((6-methoxy-2-methylpyridin-3-yl)methyl)benzyl)- 4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetra-azaciclotetracosan-2,5,8,11,14,17,20,23-octaona; (3-124). (3S,6R,9S,12R,15S,18R,21S,24R)-3,9,15,21-tetraisobutyl4,6,10,16,18,22-hexamethyl-12,24-bis(4-((4-methylthiophen-2-yl)methyl)benzyl)-1,7,13,19-tetraoxa-4,10,16,22-tetra-azacyclotetracosane-2,5,8,11,14,17,20,23-octaano; (3-125). (3S,6R,9S,12R,15S,18R,21S,24R)-6,18-bis(4-((3-bromothiophen-2yl)methyl)benzyl)-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa4,10,16,22-tetra-azacyclotetracosane-2,5,8,11,14,17,20,23-octaano; (3-132). (3S,6R,9S,12R, 15S,18R,21S,24R)-6-(4-((R)-(3-bromothiophen-2-yl)(hidroxi)metil)benzil)-18-(4-((S)-(3-bromothiofen-2-yl)(hidroxi)metil)benzil)-3,9,1 5,21-tetraisobutil-4,10,12,16,22,24-hexametil-1,7,13,19-tetraoxa-4,10,16,22-tetra-azaciclotetracosan-2,5,8,11,14,17,20,23-octaona; (3-133). (3S,6R,9S,12R,15S,18R,21S,24R)-3,9,15,21-tetraisobutyl-6,18-bis(4((6-methoxy-4-methylpyridin-3-yl)methyl)benzyl)-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetra-azacyclotetracosane-2,5,8,11,14,17,20,23-octaone; (3-148). (3S,6R,9S,12R,15S,18R,21S,24R)-3,9,15,21-tetraisobutyl4,6,10,16,18,22-hexametil-12,24-bis(4-(oxazol- 5-ylmethyl)benzyl)-1,7,13,19-tetraoxa4,10,16,22-tetra-azaciclotetracosan-2,5,8,11,14,17,20,23-octaone; Petition 870220039288, de 06 / 05 / 2022, pág. 134 / 195 128 / 169 (3-155). (3S,6R,9S,12R,15S,18R,21S,24R)-3,9,15,21-tetraisobutyl4,6,10,16,18,22-hexamethyl-12,24-bis(4-((4-methylthiazol-5-yl)methyl)benzyl)-1,7,13,19-tetraoxa-4,10,16,22-tetra-azacyclotetracosane-2,5,8,11,14,17,20,23-octaano; (3-156). (3S,6R,9S,12R,15S,18R,21S,24R)-3,9,15,21-tetraisobutyl-6,18-bis(4(isothiazol-5-ylmethyl)benzyl)-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22tetra-azacyclotetracosane-2,5,8,11,14,17,20,23-octaano; (3-157). (3S,6R,9S,12R,15S,18R,21S,24R)-3,9,15,21-tetraisobutyl4,6,10,16,18,22-hexamethyl-12,24-bis(4-((5-methylfuran-2-yl)methyl)benzyl)-1,7,13,19-tetraoxa-4,10,16,22-tetra-azacyclotetracosane-2,5,8,11,14,17,20,23-octaano; (3-165). (3S,6R,9S,12R,15S,18R,21S,24R)-6,18-bis(4-((2-ethoxypyridin-3yl)methyl)benzyl)-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa4,10,16,22-tetra-azacyclotetracosane-2,5,8,11,14,17,20,23-octaano; (3-173). (3S,6R,9S,12R,15S,18R,21S,24R)-6,18-bis(4-(furan-3-ylmethyl)benzyl)3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetra-azacyclotetracosane-2,5,8,11,14,17,20,23-octaano; (3-176). (3S,6R,9S,12R,15S,18R,21S,24R)-6,18-bis(4-((2-(dimethylamino)pyridin-3-yl)methyl)benzyl)-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetra-azacyclotetracosane-2,5,8,11,14,17,20,23-octaano; (3-178). (3S,6R,9S,12R,15S,18R,21S,24R)-3,9,15,21-tetraisobutyl4,6,10,16,18,22-hexamethyl-12,24-bis(4-((2-morpholinopyrimidin-5-yl)methyl)benzyl)1,7,13,19-tetraoxa-4,10,16,22-tetra-azacyclotetracosane-2,5,8,11,14,17,20,23-octaano; (3-193). (3S,6R,9S,12R,15S,18R,21S,24R)-3,9,15,21-tetraisobutyl-6,18-bis(4((3-methoxypyrazin-2-yl)methyl)benzyl)-4,10 ,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa4,10,16,22-tetra-azaciclotetracosan-2,5,8,11,14,17,20,23-octaona; (3-194). (3S,6R,9S,12R,15S,18R,21S,24R)-6,18-bis(4-((5-fluoropyridin-3yl)metil)benzil)-3,9,15,21-tetraisobutil-4,10,12,16,22,24-hexametil-1,7,13,19-tetraoxa Petition 870220039288, de 06 / 05 / 2022, pág. 135 / 195 129 / 169 4,10,16,22-tetra-azaciclotetracosan-2,5,8,11,14,17,20,23-octaone; (3-207). (3S,6R,9S,12R,15S,18R,21S,24R)-3,9,15,21-tetraisobutyl-6,18-bis(4(1-(6-methoxypyridin-3-yl)ethyl)benzyl)-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa4,10,16,22-tetra-azacyclotetracosane-2,5,8,11,14,17,20,23-octaano; (3-209). (3S,6R,9S,12R,15S,18R,21S,24R)-3,9,15,21-tetraisobutyl-6,18-bis(4((2-methoxy-4-methylthiazol-5-yl)methyl)benzyl)-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetra-azacyclotetracosane-2,5,8,11,14,17,20,23-octaano; (3-215). 3S,6R,9S,12R, 15S,18R,21S,24R)-3,9,15,21-tetraisobutyl-6,18-bis(4((3-methoxypyridin-2-yl)methyl)benzyl)-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa4,10,16,22-tetra-azacyclotetracosane-2,5,8,11,14,17,20,23-octaano; (3-217). (3S,6R,9S,12R,15S,18R,21S,24R)-3,9,15,21-tetraisobutyl-6,18-bis(4((4-methoxypyrimidin-2-yl)methyl)benzyl)-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa4,10,16,22-tetra-azacyclotetracosane-2,5,8,11,14,17,20,23-octaano; (3-218). (3S,6R,9S,12R,15S,18R,21S,24R)-3,9,15,21-tetraisobutyl-6,18-bis(4((6-methoxypyrazin-2-yl)methyl)benzyl)-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa4,10,16,22-tetra-azacyclotetracosane-2,5,8,11,14,17,20,23-octaano; (3-220). (3S,6R,9S, 12R,15S,18R,21S,24R)-6,18-bis(4-(1-fluoro-1 -(2-methoxypyridin-3-yl)ethyl)benzyl)-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetra-azacyclotetracosane-2,5,8,11,14,17,20,23-octaano; (3-223). (3S,6R,9S,12R,15S,18R,21S,24R)-3,9,15,21-tetraisobutyl4,6,10,16,18,22-hexametil-12,24-bis(4-((4-metilpyrid in-3-yl)methyl)benzyl)-1,7,13,19-tetraoxa-4,10,16,22-tetra-azaciclotetracosan-2,5,8,11,14,17,20,23-octaona; (3-225). (3S,6R,9S, 12R,15S,18R,21S,24R)-6,18-bis(4-(1-fluoro-1 -(6-methoxypyridin-2-yl)ethyl)benzyl)-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetra-azacyclotetracosane-2,5,8,11,14,17,20,23-octaano; (3-228). (3S,6R,9S,12R,15S,18R,21S,24R)-3,9,15,21-tetraisobutyl-6,18-bis(4Petição 870220039288, de 06 / 05 / 2022, pág. 136 / 195 130 / 169 ((4-isopropyl-1,2,3-thiadiazol-5-yl)metil)benzil)-4,10,12,16,22,24-hexametil-1,7,13,19-tetraoxa-4,10,16,22-tetra-azaciclotetracosan-2,5,8,11,14,17,20,23-octaone; (3-238). (3S,6R,9S,12R,15S,18R,21S,24R)-3,9,15,21-tetraisobutil4,6,10,16,18,22-hexametil-12,24-bis(4-((2-(trifluoromethyl )pyridin-3-yl)metil)benzyl)1,7,13,19-tetraoxa-4,10,16,22-tetra-azaciclotetracosan-2,5,8,11,14,17,20,23-octaone; (3-240). (3S,6R,9S,12R,15S,18R,21S,24R)-6,18-bis(4-((2,6-dimethylpyridin-3yl)metil)benzyl)-3,9,15,21-tetraisobutyl-4, 10,12,16,22,24-hexametil-1,7,13,19-tetraoxa4,10,16,22-tetra-azaciclotetracosan-2,5,8,11,14,17,20,23-octaona; (3-243). (3S,6R,9S,12R,15S,18R,21S,24R)-3,9,15,21-tetraisobutyl4,6,10,16,18,22-hexamethyl-12,24-bis(4-((5-methyl-1H-pyrazol-4-yl)methyl)benzyl)1,7,13,19-tetraoxa-4,10,16,22-tetra-azacyclotetracosane-2,5,8,11,14,17,20,23-octaano; (3-252). (3S,6R,9S, 12R,15S,18R,21S,24R)-6,18-bis(4-(1-fluoro-1 -(5-methoxypyrazin-2-yl)ethyl)benzyl)-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-1,7,13,19tetraoxa-4,10,16,22-tetra-azacyclotetracosane-2,5,8,11,14,17,20,23-octaano; (3-253). (3S,6R,9S,12R,15S,18R,21S,24R)-6,18-bis(4-((1-ethyl-1 H-pyrazol-5yl)methyl)benzyl)-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa4,10,16,22-tetra-azacyclotetracosane-2,5,8,11,14,17,20,23-octaano; (3-254). (3S,6R,9S,12R,15S,18R,21S,24R)-3,9,15,21-tetraisobutyl-6,18-bis(4(isothiazol-4-ylmetil)benzil)-4,10,12, 16,22,24-hexametil-1,7,13,19-tetraoxa-4,10,16,22tetra-azaciclotetracosan-2,5,8,11,14,17,20,23-octaona; (3-259). (3S,6R,9S,12R,15S,18R,21S,24R)-6,18-bis(4-((6-hydroxypyridin-3yl)(methoxy)methyl)benzyl)-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-1,7,13,19tetraoxa-4,10,16,22-tetra-azacyclotetracosane-2,5,8,11,14,17,20,23-octaone; (3-261). (3S,6R,9S,12R,15S,18R,21S,24R)-3,9,15,21-tetraisobutyl-6,18-bis(4(1-(2-methoxypyridin-3-yl)ethyl)benzyl)-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxaPetition 870220039288, of 06 / 05 / 2022, pág. 137 / 195 131 / 169 4,10,16,22-tetra-azaciclotetracosan-2,5,8,11,14,17,20,23-octaone; (3-268). (3S,6R,9S, 12R, 15S,18R,21S,24R)-6,18-bis(4-((1-ciclopropil-1 H-pyrazol-5-yl)methyl)benzyl)-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetra-azacyclotetracosane-2,5,8,11,14,17,20,23-octaano; (3-273). (3S,6R,9R,12R,15R,18R,21S,24S)-3,9,15,21-tetraisobutil4,6,10,16,18,22-hexametil-12,24-bis[[4-[(2-metil-3-pi ridil)metil]fenil]metil]-1,7,13,19tetraoxa-4,10,16,22-tetra-azaciclotetracosan-2,5,8,11,14,17,20,23-octaone; (3-274). (3R,6R,9R,12R,15S,18S,21S,24R)-3,9,15,21-tetraisobutyl-6,18-bis(4((5-methoxypyrazin-2-yl)methyl)benzyl)-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa4,10,16,22-tetra-azacyclotetracosane-2,5,8,11,14,17,20,23-octaano; (3-275). (3S,6R,9S,12R,15S,18R,21S,24R)-6,18-bis(4-((1-(ciclopropilmetil)1H-pyrazol-5-yl)methyl)benzyl)-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexametil1,7,13,19-tetraoxa-4,10,16,22-tetra-azacyclotetracosane-2,5,8,11,14,17,20,23-octaone; (3-282). (3S,6R,9S,12R,15S,18R,21S,24R)-3,9,15,21-tetraisobutyl-6,18-bis(4((4-methoxypyridin-3-yl)methyl)benzyl)-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa4,10,16,22-tetra-azacyclotetracosane-2,5,8,11,14,17,20,23-octaano; (3-283). (3S,6R,9S,12R,15S,18R,21S,24R)-3,9,15,21-tetraisobutil-6,18-bis(4((4-isopropylpyrimidin-5-yl)metil)benzil)-4 ,10,12,16,22,24-hexametil-1,7,13,19-tetraoxa4,10,16,22-tetra-azaciclotetracosan-2,5,8,11,14,17,20,23-octaona; (3-284). (3S,6R,9S,12R, 15S,18R,21S,24R)-6,18-bis(4-((3-ciclopropylisoxazol5-yl)metil)benzil)-3,9,15,21-tetraisobutyl-4,10,12, 16,22,24-hexametil-1,7,13,19-tetraoxa-4,10,16,22-tetra-azaciclotetracosan-2,5,8,11,14,17,20,23-octaone; (3-285). (3S,6R,9S,12R, 15S,18R,21S,24R)-6-(4-((R)-fluoro(tiazol-2-il)metil)benzil)-18-(4-((S)-fluoro(tiazol-2-il)metil)benzil)-3,9,15,21-tetraisobutil4,10,12,16,22,24-hexametil-1,7,13,19-tetraoxa-4,10,16,22-tetra-azaciclotetracosan2,5,8,11,14,17,20,23-octaona; Petição 870220039288, de 06 / 05 / 2022, pág. 138 / 195 132 / 169 (3-286). (3S,6R,9S,12R,15S,18R,21S,24R)-6,18-bis(4-((1-(2-fluoroetil)-1H-pirazol-4-il)metil)benzil)-3,9,15,21-tetraisobutil-4,10,12,16,22,24-hexametil-1,7,13,19tetraoxa-4,10,16,22-tetra-azaciclotetracosan-2,5,8,11,14,17,20,23-octaona; (3-287). (3S,6R,9S,12R,15S,18R,21S,24R)-6,18-bis(4-((6-(difluorometil)piridin-3-il)metil)benzil)-3,9,15,21-tetraisobutil-4,10,12,16,22,24-hexametil-1,7,13,19-tetraoxa-4,10,16,22-tetra-azaciclotetracosan-2,5,8,11,14,17,20,23-octaona; (3-288). (3S,6R,9S,12R,15S,18R,21S,24R)-3,9,15,21-tetraisobutyl4,6,10,16,18,22-hexamethyl-12,24-bis(4-((4-methylisothiazol-5-yl)methyl)benzyl)-1,7,13,19tetraoxa-4,10,16,22-tetra-azacyclotetracosane-2,5,8,11,14,17,20,23-octaano; (3-289). (3S,6R,9S,12R,15S,18R,21S,24R)-6,18-bis(4-((4-cyclopropylpyrimidin-5-yl)methyl)benzyl)-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetra-azacyclotetracosane-2,5,8,11,14,17,20,23-octaano; (3-290). (3S,6R,9S,12R,15S,18R,21S,24R)-6,18-bis(4-((2-(difluoromethyl)pyridin-3-yl)methyl)benzyl)-3,9,15,21-tetraisobutyl -4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetra-azaciclotetracosan-2,5,8,11,14,17,20,23-octaona; (3-291). (3S,6R,9S,12R,15S,18R,21S,24R)-3,9,15,21-tetraisobutyl4,6,10,16,18,22-hexamethyl-12,24-bis(4-((R)-1-(thiazol-2-yl)ethyl)benzyl)-1,7,13,19-tetraoxa-4,10,16,22-tetra-azacyclotetracosane-2,5,8,11,14,17,20,23-octaano; (3-292). (3S,6R,9S,12R,15S,18R,21S,24R)-3,9,15,21-tetraisobutyl4,6,10,16,18,22-hexametil-12,24-bis(4-((2-morpholinopi ridin-4-yl)metil)benzyl)-1,7,13,19tetraoxa-4,10,16,22-tetra-azaciclotetracosan-2,5,8,11,14,17,20,23-octaone; (3-293). (3S,6R,9S,12R, 15S,18R,21S,24R)-6,18-bis(4-((5-fluoro-2-methoxypyridin-3-yl)methyl)benzyl)-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetra-azacyclotetracosane-2,5,8,11,14,17,20,23-octaano; (3-294). (3S,6R,9S,12R,15S,18R,21S,24R)-3,9,15,21-tetraisobutil4,6,10,16,18,22-hexametil-12,24-bis(4-((4-metilpirim idin-5-yl)metil)benzyl)-1,7,13,19tetraoxa-4,10,16,22-tetra-azaciclotetracosan-2,5,8,11,14,17,20,23-octaona; Petition 870220039288, de 06 / 05 / 2022, pág. 139 / 195 133 / 169 (3-295). (3S,6R,9S,12R, 15S,18R,21S,24R)-6,18-bis(4-((4-(difluorometil)piridin-3-il)metil)benzil)-3,9,15,21-tetraisobutil-4,10,12,16,22,24-hexametil-1,7,13,19-tetraoxa-4,10,16,22-tetra-azaciclotetracosan-2,5,8,11,14,17,20,23-octaona; (3-296). (3S,6R,9S,12R, 15S,18R,21S,24R)-6,18-bis(4-((2-ciclopropilpiridin-3il)metil)benzil)-3,9,15,21-tetraisobutil-4,10,12,16,22,24-hexametil-1,7,13,19-tetraoxa4,10,16,22-tetra-azaciclotetracosan-2,5,8,11,14,17,20,23-octaona; e (3-297). (3S,6R,9S,12R,15S,18R,21S,24R)-6,18-bis(4-((2-(difluorometoxi)piridin-3-il)metil)benzil)-3,9,15,21-tetraisobutil-4,10,12,16,22,24-hexametil-1,7,13,19-tetraoxa-4,10,16,22-tetra-azaciclotetracosan-2,5,8,11,14,17,20,23-octaona, (3-307). 3,3'-(((((2R,5S,8R,11S,14R,17S,20R,23S)-5,11,17,23-tetraisobutil4,8,10,16,20,22-hexametil-3,6,9,12,15,18,21,24-octaoxo-1,7,13,19-tetraoxa4,10,16,22-tetra-azaciclotetracosan-2,14-diil)bis(metileno))bis(4,1 -fenileno))bis(metileno))di-isonicotinonitrila; (3-308). (3S,6R,9S,12R,15S,18R,21S,24R)-3,9,15,21-tetraisobutyl4,6,10,16,18,22-hexamethyl-12,24-bis(4-((2-(methylthio)pyridin-3-yl)methyl)benzyl)-1,7,13,19tetraoxa-4,10,16,22-tetra-azacyclotetracosane-2,5,8,11,14,17,20,23-octaano; (3-309). (3S,6R,9S,12R,15S,18R,21S,24R)-6-(4-((3-fluoropyridin-4-yl)methyl)benzyl)-3,9,15,21 -tetraisobutyl-4,10,12,16,22,24-hexamethyl-18-(4-((3-methylpyridin-4yl)methyl)benzyl)-1,7,13,19-tetraoxa-4,10,16,22-tetra-azaciclotetracosan2,5,8,11,14,17,20,23-octanoa; (3-310). (3S,6R,9S,12R,15S,18R,21S,24R)-6,18-bis(4-((4-ethylpyrimidin-5yl)methyl)benzyl)-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa4,10,16,22-tetra-azacyclotetracosane-2,5,8,11,14,17,20,23-octaano; (3-313). (3S,6R,9S,12R,15S,18R,21S,24R)-6,18-bis(4-((6-fluoropyridin-2yl)methyl)benzyl)-3,9,15,21-tetraisobutyl-4,10 ,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa4,10,16,22-tetra-azaciclotetracosan-2,5,8,11,14,17,20,23-octaona; (3-318). (3S,6R,9S,12R,15S,18R,21S,24R)-3,9,15,21-tetraisobutil Petição 870220039288, de 06 / 05 / 2022, pág. 140 / 195 134 / 169 4,6,10,16,18,22-hexametil-12,24-bis(4-((4-(trifluorometil)pirimidin-5-il)metil)benzil)1,7,13,19-tetraoxa-4,10,16,22-tetra-azaciclotetracosan-2,5,8,11,14,17,20,23-octaona; (3-319). (3S,6R,9S,12R,15S,18R,21S,24R)-6,18-bis(4-((2-cloropiridin-3il)metil)benzil)-3,9,15,21-tetraisobutil-4,10,12,16,22,24-hexametil-1,7,13,19-tetraoxa4,10,16,22-tetra-azaciclotetracosan-2,5,8,11,14,17,20,23-octaona; (3-321). (3S,6R,9S,12R,15S,18R,21S,24R)-6,18-bis(4-((4-(difluorometil)pirimidin-5-il)metil)benzil)-3,9,15,21-tetraisobutil-4,10,12,16,22,24-hexametil-1,7,13,19tetraoxa-4,10,16,22-tetra-azaciclotetracosan-2,5,8,11,14,17,20,23-octaona; (3-322). (3S,6R,9S,12R, 15S,18R,21S,24R)-6,18-bis(4-((6-fluoro-4-metilpiridin-3-il)metil)benzil)-3,9,15,21-tetraisobutil-4,10,12,16,22,24-hexametil-1,7,13,19-tetraoxa-4,10,16,22-tetra-azaciclotetracosan-2,5,8,11,14,17,20,23-octaona; (3-323). (3S,6R,9S,12R,15S,18R,21S,24R)-6,18-bis(4-((2-fluoropiridin-3il)metil)benzil)-3,9,15,21-tetraisobutil-4,10,12,16,22,24-hexametil-1,7,13,19-tetraoxa4,10,16,22-tetra-azaciclotetracosan-2,5,8,11,14,17,20,23-octaona; (3-324). (3S,6R,9S,12R,15S,18R,21S,24R)-6,18-bis(4-((2,5-difluoropiridin-3il)metil)benzil)-3,9,15,21-tetraisobutil-4,10,12,16,22,24-hexametil-1,7,13,19-tetraoxa4,10,16,22-tetra-azaciclotetracosan-2,5,8,11,14,17,20,23-octaona; (3-326). (3S,6R,9S,12R,15S,18R,21S,24R)-6,18-bis(4-((2,3-difluoropiridin-4il)metil)benzil)-3,9,15,21-tetraisobutil-4,10,12,16,22,24-hexametil-1,7,13,19-tetraoxa4,10,16,22-tetra-azaciclotetracosan-2,5,8,11,14,17,20,23-octaona; (3-329). (3S,6R,9S,12R,15S,18R,21S,24R)-6,18-bis(4-((2-bromopiridin-3il)metil)benzil)-3,9,15,21-tetraisobutil-4,10,12,16,22,24-hexametil-1,7,13,19-tetraoxa4,10,16,22-tetra-azaciclotetracosan-2,5,8,11,14,17,20,23-octaona; (3-332). (3S,6R,9S,12R,15S,18R,21S,24R)-6,18-bis(4-((5-cloro-2-metoxipiridin-3-il)metil)benzil)-3,9,15,21-tetraisobutil-4,10,12,16,22,24-hexametil-1,7,13,19-tetraoxa-4,10,16,22-tetra-azaciclotetracosan-2,5,8,11,14,17,20,23-octaona; Petição 870220039288, de 06 / 05 / 2022, pág. 141 / 195 135 / 169 (3-333). (3S,6R,9S,12R,15S,18R,21S,24R)-3,9,15,21-tetraisobutil4,6,10,16,18,22-hexametil-12,24-bis(4-((4-(trifluorometil)piridin-3-il)metil)benzil)1,7,13,19-tetraoxa-4,10,16,22-tetra-azaciclotetracosan-2,5,8,11,14,17,20,23-octaona; (3-334). (3S,6R,9S, 12R, 15S,18R,21S,24R)-6,18-bis(4-((2,3-dimethoxypyridin-4yl)methyl)benzyl)-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa4,10,16,22-tetra-azacyclotetracosan-2,5,8,11,14,17,20,23-octaone, stereoisomers thereof and veterinary acceptable salts thereof.

[0191] The NMR data (1H NMR: 400 MHz, DMSO-de, δ ppm) for the compounds named in Table 3 are shown below: (3-4) (3-8) 1.1-1.8 (m, 18H), 0.6-1.0 (m, 28H); (3-12) 7.18-7.26 (m, 8H), 7.70 (brs, 2H), 8.92 (s, 2H); (3-17), δ: 0,70-0,94 (m, 26H), 1,23-1,70 (m, 16H), 2,67-3,04 (m, 16H), 4,30 (s, 4H), 4,40-4,42 (m, 1H), 5,02-5,71 (m, 7H), 7,26-7,28 (m, 8H), 7,57(d, J= 2,8Hz, 2H), 7,70 (d, J= 2,8Hz, 2H); (3-18), δ: 0,70-0,94 (m, 26H), 1,23-1,70 (m, 16H), 2,67-3,04 (m, 16H), 4,09 (s, 4H), 4,40-4,42 (m, 1H), 5,02-5,71 (m, 7H), 7,12 (brs, 2H), 7,18-7,28 (m, 8H), 7,98 (brs, 2H); (3-21), δ: 0,68-0,94 (m, 26H), 1,23-1,70 (m, 16H), 1,99 (s, 6H), 2,31 (s, 6H), 2,66-3,02 (m, 16H), 3,65 (s, 4H), 4,40-4,42 (m,1H), 5,02-5,69 (m,7H), 7,06-7,23 (m, 8H); (3-24), δ: 7,2-7,35 (m, 6H), 7,1-7,2 (m, 4H), 5,9-5,95 (m, 2H), 5,0-5,8 (m, 8H), Petição 870220039288, de 06 / 05 / 2022, pág. 142 / 195 136 / 169 4,4 (m, 0,8H), 4,0 (s, 4H), 3,65 (s, 6H), 2,7-3,1 (m, 15H), 1,1-1,8 (m, 16H), 0,6-1,0 (m, 29H); (3-31), δ: 0,62-1,79 (m, 42H) 2,65-3,10 (m, 16H) 3,80-3,90 (m, 10H) 4,36-4,46 (m, 1H) 4,99-5,74 (m, 7H) 6,84-6,96 (m, 2H) 7,09-7,17 (m, 4H) 7,18-7,27 (m, 4H) 7,377,47 (m, 2H) 7,96-8,06 (m, 2H); (3-44), δ: 0,68-0,94 (m, 26H), 1,23-1,70 (m, 16H), 2,12 (s, 6H), 2,66-3,06 (m, 16H), 4,01 (s, 4H), 4,40-4,42 (m, 1H), 5,02-5,71 (m, 7H), 6,82-6,83 (m, 2H), 7,11-7,22 (m, 10H); (3-49), δ: 0,68-0,94 (m, 26H), 1,23-1,70 (m, 16H), 2,04 (s, 6H), 2,66-3,06 (m, 16H), 3,56 (s, 6H), 3,90 (s, 4H), 4,40-4,42 (m, 1H), 5,02-5,71 (m, 9H), 7,11-7,25 (m, 8H); (3-50), δ: 0,67-0,94 (m, 26H), 1,23-1,71 (m, 16H), 2,67-3,05 (m, 16H), 4,15 (s, 4H), 4,40-4,42 (m, 1H), 5,02-5,70 (m, 7H), 6,89 (brs, 2H), 7,15-7,18 (m, 4H), 7,27-7,30 (m, 4H), 7,78 (brs, 2H); (3-56), δ: 0,68-0,95 (m, 26H), 1,23-1,69 (m, 16H), 2,67-3,05 (m, 16H), 3,90 (s, 4H), 4,40-4,42 (m, 1H), 5,03-5,70 (m, 7H), 6,91-7,43 (m, 14H); (3-57), δ: 0,70-0,94 (m, 26H), 1,23-1,70 (m, 16H), 2,67-3,04 (m, 16H), 3,79 (s, 4H), 4,40-4,42 (m, 1H), 5,02-5,73 (m, 7H), 7,17-7,21 (m, 8H), 7,79-7,81 (m, 2H), 8,26 (s, 2H); (3-58), δ: 0,68-0,94 (m, 26H), 1,23-1,70 (m, 16H), 2,39 (s, 6H), 2,66-3,06 (m, 16H), 3,99 (s, 4H), 4,40-4,42 (m, 1H), 5,02-5,69 (m, 7H), 7,11-7,21 (m, 8H), 8,78 (s, 2H); (3-60), δ: 0,68-0,94 (m, 26H), 1,23-1,70 (m, 16H), 2,66-3,02 (m, 16H), 4,05 (s, 4H), 4,40-4,42 (m, 1H), 5,02-5,70 (m, 7H), 6,45 (brs, 2H), 7,17-7,36 (m, 8H), 7,52 (brs, 2H); (3-69), δ: 0,61-0,99 (m, 27H), 1,15-1,76 (m, 15H), 2,64-2,94 (m, 12H), 2,963,11 (m, 3H), 3,82 (s, 6H), 3,95 (s, 4H), 4,36-4,48 (m, 1H), 4,99-5,54 (m, 6H), 5,63 Petição 870220039288, de 06 / 05 / 2022, pág. 143 / 195 137 / 169 5,75 (m, 2H), 6,61 (d, J = 8,2Hz, 2H) 6,73-6,82 (m, 2H), 7,13-7,30 (m, 1H), 7,23 (s, 7H), 7,54-7,64 (m, 2H); (3-87), δ: 0,68-0,95 (m, 26H), 1,23-1,70 (m, 16H), 2,67-3,05 (m, 16H), 4,07 (s, 4H), 4,40-4,42 (m, 1H), 5,02-5,73 (m, 7H), 7,01(d, J= 5,2Hz, 2H), 7,15-7,17(m, 4H), 7,24-7,27 (m, 4H), 7,48-7,50 (m, 2H); (3-110), δ: 0,67-0,94 (m, 27H), 1,23-1,68 (m, 15H), 2,67-3,10 (m, 16H), 3,77 (s, 6H), 3,91 (s, 4H), 4,39-4,4,42 (m, 1H), 5,01-5,70 (m, 7H), 6,96-6,99 (m, 2H), 7,107,25 (m, 10H); (3-112), δ: 0,68-0,95 (m, 26H), 1,24-1,70 (m, 16H), 2,67-3,05 (m, 16H), 4,12 (s, 4H), 4,40-4,42 (m, 1H), 5,04-5,70 (m, 7H), 7,17-7,27 (m, 8H), 8,98 (s, 2H); (3-118), δ: 0,68-0,95 (m, 26H), 1,24-1,69 (m, 16H), 2,67-3,05 (m, 16H), 3,87 (s, 4H), 3,89 (s, 6H), 4,40-4,42 (m, 1H), 5,04-5,70 (m, 7H), 7,17-7,24 (m, 8H), 7,467,50 (m, 2H), 7,88 (s, 2H); (3-120), δ: 0,70-0,94 (m, 26H), 1,23-1,70 (m, 16H), 2,60 (s, 6H), 2,67-3,04 (m, 16H), 4,29 (s, 4H), 4,40-4,42 (m, 1H), 5,03-5,71 (m, 7H), 7,20-7,28 (m, 8H); (3-121), δ: 0,68-0,94 (m, 26H), 1,23-1,70 (m, 16H), 2,26 (s, 6H), 2,66-3,02 (m, 16H), 3,76 (s, 6H), 3,84 (s, 4H), 4,40-4,42 (m, 1H), 5,02-5,70 (m, 7H), 6,54-6,56 (m, 2H), 7,02-7,20 (m, 8H), 7,38-7,40 (m, 2H); (3-124), δ 0,65-0,94 (m, 27H), 1,02-1,80 (m, 15H), 2,12 (s, 6H), 2,67-3,10 (m, 16H), 4,03 (bs, 4H), 4,42-4,46 (m, 1H), 5,02-5,69 (m, 7H), 6,65 (s, 2H), 6,83-6,87 (m, 2H), 7,11-7,23 (m, 8H); (3-125), δ 0,68-0,94 (m, 27H), 1,23-1,75 (m, 15H), 2,68-3,08 (m, 16H), 4,07 (s, 4H), 4,40-4,45 (m, 1H), 5,02-5,73 (m, 7H), 7,04-7,27 (m, 10H), 7,50-7,51 (m, 2H); (3-132), δ 0,68-0,94 (m, 26H), 1,20-1,78 (m, 16H), 2,66-3,10 (m, 16H), 4,364,42 (m, 1H), 5,02-5,72 (m, 7H), 5,88-5,91(m, 2H), 6,40-6,50 (m, 2H), 6,99 (d, J = 5Hz, 2H), 7,25-7,38 (m, 8H), 7,54-7,60 (m, 2H); (3-133), δ: 0,68-0,94 (m, 26H), 1,23-1,70 (m, 16H), 2,08 (s, 6H), 2,66-3,02 (m, Petição 870220039288, de 06 / 05 / 2022, pág. 144 / 195 138 / 169 16H), 3,79 (s, 6H), 3,86 (s, 4H), 4,40-4,42 (m, 1H), 5,02-5,70 (m, 7H), 6,61 (s, 2H), 7,04-7,22 (m, 8H), 7,89 (s, 2H); (3-148), δ: 0,70-0,94 (m, 26H), 1,23-1,68 (m, 16H), 2,67-3,04 (m, 16H), 4,00 (s, 4H), 4,40-4,42 (m, 1H), 5,03-5,71 (m, 7H), 6,88 (s, 2H), 7,16-7,25 (m, 8H), 8,21 (s, 2H); (3-155), δ: 8,76-8,95 (m, 2H), 7,02-7,35 (m, 8H), 4,95-5,81 (m, 10H), 4,36-4,45 (m, 1H), 4,02-4,12 (m, 4H), 2,59-3,19 (m, 16H), 2,26-2,42 (m, 6H), 1,10-1,80 (m, 16H), 0,62-1,01 (m, 26H); (3-156), δ: 0,68-0,95 (m, 26H), 1,21-1,70 (m, 16H), 2,68-3,05 (m, 16H), 4,28 (s, 4H), 4,40-4,42 (m, 1H), 5,02-5,71 (m, 7H), 7,18-7,30 (m, 10H), 8,40-8,42 (m, 2H); (3-157), δ: 0,68-0,94 (m, 26H), 1,23-1,70 (m, 16H), 2,17 (s, 6H), 2,66-3,06 (m, 16H), 3,85 (s, 4H), 4,40-4,42 (m, 1H), 5,02-5,69 (m, 7H), 5,91-5,93 (m, 4H), 7,12-7,23 (m, 8H); (3-165), δ: 0,68-0,94 (m, 26H), 1,23-1,70 (m, 22H), 2,66-3,06 (m, 16H), 3,82 (s, 4H), 4,29 (q, J= 7Hz, 4H), 4,40-4,42 (m, 1H), 5,02-5,69 (m, 7H), 6,85-6,89 (m, 2H), 7,15-7,23 (m, 8H), 7,43-7,46 (m, 2H), 7,97-7,99 (m, 2H); (3-173), δ: 0,68-0,94 (m, 26H), 1,23-1,70 (m, 16H), 2,66-3,06 (m, 16H), 3,69 (s, 4H), 4,40-4,42 (m, 1H), 5,02-5,71 (m, 7H), 6,28-6,29 (m, 2H), 7,11-7,24 (m, 8H), 7,43-7,44 (m, 2H), 7,55 (brs, 2H); (3-176), δ: 0,68-0,95 (m, 26H), 1,24-1,69 (m, 16H), 2,67-3,05 (m, 28H), 3,95 (s, 4H), 4,40-4,42 (m, 1H), 5,04-5,72 (m, 7H), 6,83-6,87 (m, 2H), 7,08-7,10 (m, 4H), 7,19-7,31 (m, 6H), 8,08-8,09 (m, 2H); (3-178), δ: 8,16-8,40 (m, 4H), 7,03-7,48 (m, 8H), 4,99-5,82 (m, 8H), 4,33-4,44 (m, 1H), 3,70-3,86 (m, 4H), 3,3-3,5 (m, 4H), 2,62-3,14 (m, 16H), 1,02-1,88 (m, 16H), 0,61-0,97 (m, 27H); (3-193), δ: 0,68-0,94 (m, 26H), 1,23-1,70 (m, 16H), 2,66-3,06 (m, 16H), 3,89 (s, 6H), 4,04 (s, 4H), 4,40-4,42 (m, 1H), 5,02-5,71 (m, 7H), 7,13-7,21 (m, 8H), 8,07Petição 870220039288, de 06 / 05 / 2022, pág. 145 / 195 139 / 169 8,09 (m, 4H); (3-194), δ: 8,21-8,68 (m, 4H), 7,48-7,81 (m, 2H), 7,12-7,42 (m, 8H), 4,96-5,80 (m, 8H), 4,32-4,55 (m, 1H), 3,76-4,08 (m, 4H), 2,63-3,17 (m, 16H), 1,07-1,79 (m, 16H), 0,62-1,01 (m, 26H); (3-207), δ: 0,61-1,01 (m, 26H), 1,13-1,77 (m, 16H), 2,64-3,10 (m, 16H), 3,75 (s, 6H), 4,12 (m, 2H), 4,37-4,46 (m, 1H), 4,98-5,74 (m, 8H), 6,72 (d, 2H), 7,15-7,28 (m, 8H), 7,54 (d, 2H), 8,02-8,11 (m, 2H); (3-209), δ: 0,68-0,95 (m, 26H), 1,24-1,69 (m, 16H), 2,17 (s, 6H), 2,67-3,05 (m, 16H), 3,90 (s, 10H), 4,40-4,42 (m, 1H), 5,04-5,69 (m, 7H), 7,11-7,13 (m, 4H), 7,227,25 (m, 4H); (3-215), δ: 0,69-0,94 (m, 26H), 1,23-1,68 (m, 16H), 2,67-3,05 (m, 16H), 3,76 (s, 6H), 4,00 (s, 4H), 4,40-4,42 (m, 1H), 5,02-5,68 (m, 7H), 7,08-7,21 (m, 10H), 7,327,35 (m, 2H), 8,00-8,02 (m, 2H); (3-217), δ: 0,69-0,94 (m, 26H), 1,23-1,68 (m, 16H), 2,67-3,05 (m, 16H), 3,88 (s, 6H), 4,05 (s, 4H), 4,40-4,42 (m, 1H), 5,02-5,68 (m, 7H), 6,74-6,76 (m, 2H), 7,237,25 (m, 8H), 8,39-8,40 (m, 2H); (3-218), δ: 0,69-0,94 (m, 26H), 1,23-1,70 (m, 16H), 2,67-3,05 (m, 16H), 3,87 (s, 6H), 4,00 (s, 4H), 4,40-4,42 (m, 1H), 5,02-5,70 (m, 7H), 7,23-7,25 (m, 8H), 8,098,12 (m, 4H); (3-220), δ: 0,65-0,94 (m, 26H), 1,23-1,68 (16H), 2,01 (s, 3H), 2,07 (3H), 2,673,04 (m, 16H), 3,67 (s, 6H), 4,41-4,43 (m, 1H), 5,03-5,70 (m, 7H), 7,05-7,08 (m, 2H), 7,25-7,29 (m, 8H), 7,85-7,87 (m, 2H), 8,10-8,15 (m, 2H); (3-223), δ: 0,69-0,94 (m, 26H), 1,23-1,68 (m, 16H), 2,16 (s, 6H), 2,67-3,05 (m, 16H), 3,96 (s, 4H), 4,40-4,42 (m, 1H), 5,02-5,68 (m, 7H), 7,06-7,24 (m, 10H), 8,288,30 (m, 4H); (3-225), δ: 0,63-0,92 (m, 26H), 1,23-1,69 (m, 16H), 1,98 (s, 3H), 2,04 (s, 3H), 2,67-3,04 (m, 16H), 3,83 (s, 6H), 4,38-4,43 (m, 1H), 5,01-5,73 (m, 7H), 6,72 (d, J = Petição 870220039288, de 06 / 05 / 2022, pág. 146 / 195 140 / 169 8,2Hz, 2H), 7,09 (d, J = 7,0Hz, 2H), 7,30-7,31 (m, 4H), 7,40-7,42 (m, 4H), 7,71 (t, J = 7,8Hz, 2H); (3-228), δ: 7,15-7,45 (m, 8H), 4,94-5,77 (m, 8H), 4,37-4,53 (m, 1H), 4,24-4,35 (m, 4H), 3,24-3,49 (m, 2H), 2,60-3,12 (m, 15H), 1,14-1,84 (m, 28H), 0,61-1,07 (m, 26H); (3-238), δ: 0,69-0,94 (m, 26H), 1,23-1,68 (m, 16H), 2,67-3,05 (m, 16H), 4,15 (s, 4H), 4,40-4,42 (m, 1H), 5,02-5,70 (m, 7H), 7,07-7,26 (m, 8H), 7,65-7,67(m, 2H), 7,80-7,82 (m, 2H), 8,60-8,61 (m, 2H); (3-240), δ: 0,69-0,95 (m, 26H), 1,20-1,74 (m, 16H), 2,60-3,07 (m, 28H), 4,10 (s, 4H), 4,39-5,72 (m, 8H), 7,14 (d, 4H), 7,28 (d, 4H), 7,69 (d, 2H), 8,17 (d, 2H); (3-243), δ: 0,69-0,94 (m, 26H), 1,23-1,68 (m, 16H), 2,05 (s, 6H), 2,67-3,05 (m, 16H), 3,66 (s, 4H), 4,40-4,42 (m, 1H), 5,02-5,70 (m, 7H), 7,07-7,20 (m, 10H), 12,25 (brs, 2H); (3-252), δ: 0,64-0,92 (m, 26H), 1,19-1,57 (m, 16H), 2,00 (s, 3H), 2,06 (s, 3H), 2,67-3,05 (m, 16H), 3,90 (s, 6H), 4,42-4,48 (m, 1H), 5,02-5,72 (m, 7H), 7,31-7,33 (m, 8H), 8,28-7,32 (m, 4H); (3-253), δ: 0,64-0,99 (m, 27H), 1,09-1,77 (m, 21H,) 2,64-2,94 (m, 13H), 3,03 (br d, 3H), 3,93-4,05 (m, 8H), 4,99-5,77 (m, 7H), 5,60-5,76 (m, 1H), 5,90-5,98 (m, 2H), 7,06-7,19 (m, 4H), 7,24-7,36 (m, 6H); (3-254), δ: 0,69-0,94 (m, 26H), 1,23-1,68 (m, 16H), 2,67-3,05 (m, 16H), 4,01 (s, 4H), 4,40-4,42 (m, 1H), 5,02-5,70 (m, 7H), 7,18-7,25 (m, 8H), 8,42 (s, 2H), 8,67 (s, 2H); (3-259), não disponível (3-261), δ: 0,67-0,93 (m, 26H), 1,23-1,68 (22H), 2,67-2,88 (s, 12H), 2,99-3,02 (m, 4H), 3,81 (s, 6H), 4,30-4,42 (m, 3H), 5,03-5,67 (m, 7H), 6,91-6,94 (m, 2H), 7,127,21 (m, 8H), 7,51-7,54 (m, 2H), 7,99-8,01 (m, 2H); (3-268), δ: 0,67-1,01 (m, 34H), 1,20-1,75 (m, 16H), 2,68-3,08 (m, 16H), 3,35 Petição 870220039288, de 06 / 05 / 2022, pág. 147 / 195 141 / 169 3,40 (m, 2H), 4,07 (s, 4H), 4,39-5,71 (m, 8H), 5,91 (s, 2H), 7,16 (d, 4H), 7,23-7,28 (m, 6H); (3-273), δ: 0,69-0,94 (m, 26H), 1,23-1,68 (m, 16H), 2,36 (s, 6H), 2,67-3,05 (m, 16H), 3,94 (s, 4H), 4,40-4,42 (m, 1H), 5,02-5,70 (m, 7H), 7,06-7,25 (m, 10H), 7,437,45 (m, 2H), 8,28-8,29 (m, 2H); (3-274), δ: 0,67-0,92 (m, 26H), 1,23-1,66 (m, 22H), 2,67-3,00 (m, 16H), 3,85 (s, 6H), 4,26-4,28 (m, 2H), 4,37-4,43 (m, 1H), 5,02-5,69 (m, 7H), 7,22 (brs, 8H), 8,11 (brs, 2H), 8,23 (s, 2H); (3-275), δ: 0,22-0,28 (m, 4H), 0,38-0,44 (m, 4H), 0,69-1,01 (m, 26H), 1,06-1,15 (m, 2H), 1,21-1,76 (m, 16H), 2,68-3,07 (m, 16H), 3,86 (d, 4H), 4,00 (s, 4H), 4,40-5,70 (m, 8H), 5,88-5,91 (m, 2H), 7,14 (d, 4H), 7,24-7,28 (d, 4H), 7,30-7,33 (m, 2H); (3-282), não disponível (3-283), δ: 0,69-1,08 (m, 38H), 1,18-1,74 (m, 16H), 2,66-3,07 (m, 16H), 3,193,27 (m, 2H), 4,02 (s, 4H), 4,38-5,69 (m, 8H), 7,11 (d, 4H), 7,23-7,28 (m, 4H), 8,56 (s, 2H), 9,00 (s, 2H); (3-284), δ: 0,61-0,97 (m, 34H), 1,23-1,93 (m, 18H), 2,67-3,05 (m, 16H), 4,01 (s, 4H), 4,40-4,42 (m, 1H), 5,08-5,70 (m, 7H), 5,91-5,93 (m, 2H), 7,18-7,27 (m, 8H); (3-285), δ: 0,69-0,94 (m, 26H), 1,23-1,68 (m, 16H), 2,67-3,05 (m, 16H), 4,404,42 (m, 1H), 5,02-5,70 (m, 7H), 6,95 (d, J= 44Hz, 2H), 7,41 (brs, 8H), 7,86 (brs, 4H); (3-286), δ: 0,67-0,96 (m, 26H), 1,18-1,76 (m, 16H), 2,68-3,07 (m, 16H), 3,72 (s, 4H), 4,28-5,72 (m, 16H), 7,14 (d, 4H), 7,19-7,27 (m, 6H), 7,50 (s, 2H); (3-287), δ: 0,66-0,94 (m, 26H), 1,15-1,76 (m, 16H), 2,67-3,07 (m, 16H), 4,02 (s, 4H), 4,39-5,73 (m, 8H), 6,90 (t, 2H), 7,19-7,28 (m, 8H), 7,61 (d, 2H), 7,80 (d, 2H), 8,58 (s, 2H); (3-288), δ: 0,69-0,94 (m, 26H), 1,23-1,68 (m, 16H), 2,17 (s, 6H), 2,67-3,05 (m, 16H), 4,15 (s, 4H), 4,40-4,42 (m, 1H), 5,02-5,70 (m, 7H), 7,18-7,29 (m, 8H), 8,30 (s, 2H); Petição 870220039288, de 06 / 05 / 2022, pág. 148 / 195 142 / 169 (3-289), δ: 0,66-1,05 (m, 34H), 1,18-1,73 (m, 16H), 2,19-2,26 (m, 2H), 2,683,06 (m, 16H), 4,11 (s, 4H), 4,39-5,70 (m, 8H), 7,16 (d, 4H), 7,23-7,28 (m, 4H), 8,458,48 (m, 2H), 8,84 (s, 2H); (3-290), δ: 0,67-0,97 (m, 26H), 1,17-1,76 (m, 16H), 2,68-3,07 (m, 16H), 4,16 (s, 4H), 4,39-5,71 (m,8H), 6,96-7,28 (m,10H), 7,49-7,53 (m,2H), 7,69 (d,2H), 8,52-8,54 (m,2H) (3-291), δ: 0,69-0,94 (m, 26H), 1,23-1,68 (m, 22H), 2,67-3,05 (m, 16H), 4,404,42 (m, 1H), 4,51-4,53 (m, 2H), 5,02-5,70 (m, 7H), 7,27 (brs, 8H), 7,54-7,56 (m, 2H), 7,69-7,71 (m, 2H); (3-292), δ: 0,69-0,94 (m, 26H), 1,23-1,68 (m, 16H), 2,67-3,05 (m, 16H), 3,373,39 (m, 8H), 3,65-3,68 (m, 8H), 3,81 (s, 4H), 4,40-4,42 (m, 1H), 5,07-5,70 (m, 7H), 6,47-6,48 (m, 2H), 6,73 (s, 2H), 7,16-7,23 (m, 8H), 7,97-7,98 (m, 2H); (3-293), δ: 0,67-0,95 (m, 26H), 1,19-1,76 (m,16H), 2,68-3,06 (m,16H), 3,833,86 (m, 10H), 4,39-5,72 (m, 8H), 7,16-7,26 (m, 8H), 7,38-7,43 (m, 2H), 7,98-8,00 (m, 2H); (3-294), δ: 0,68-1,01 (m, 26H), 1,18-1,74 (m, 16H), 2,36 (s, 6H), 2,68-3,07 (m, 16H), 3,98 (s, 4H), 4,39-5,71 (m, 8H), 7,12 (d, 4H), 7,24-7,28 (m, 4H), 8,49-8,52 (m, 2H), 8,90 (s, 2H); (3-295), δ: 0,68-1,00 (m, 26H), 1,18-1,73 (m, 16H), 2,67-3,07 (m, 16H), 4,14 (s, 4H), 4,38-5,71 (m, 8H), 7,13-7,40 (m, 10H), 7,56 (d, 2H), 8,53 (s, 2H), 8,62 (d, 2H); (3-296), δ: 0,68-1,06 (m, 34H), 1,18-1,74 (m, 16H), 2,21-2,30 (m, 2H), 2,683,07 (m, 16H), 4,18 (s, 4H), 4,39-5,71 (m, 8H), 7,15 (d, 4H), 7,24-7,39 (m, 6H), 7,737,80 (m, 2H), 8,37 (d, 2H); (3-297), δ: 0,67-0,96 (m, 26H), 1,18-1,76 (m, 16H), 2,68-3,07 (m, 16H), 3,90 (s, 4H), 4,39-5,71 (m, 8H), 7,14-7,27 (m, 10H), 7,52-7,89 (m, 4H), 8,09-8,13 (m, 2H); (3-307), δ: 0,64-1,01 (m, 27H), 1,15-1,74 (m, 15H), 2,60-2,97 (m, 13H), 2,973,10 (m, 3H), 3,86-4,24 (m, 4H), 4,31-4,49 (m, 1H), 4,95-5,80 (m, 9H), 7,13-7,36 (m, Petição 870220039288, de 06 / 05 / 2022, pág. 149 / 195 143 / 169 8H), 7,76-7,96 (m, 2H), 8,48-9,01 (m, 2H), 8,56-8,86 (m, 2H); (3-308), δ: 0,64-1,03 (m, 27H), 1,17-1,74 (m, 15H), 2,51-2,56 (m, 3H), 2,602,96 (m, 13H), 2,96-3,12 (m, 3H), 3,90 (s, 4H), 4,41 (br dd, 1H), 4,96-5,77 (m, 8H), 7,01-7,16 (m, 6H), 7,16-7,28 (m, 4H), 7,35-7,45 (m, 2H), 8,30-8,40 (m, 2H); (3-309), δ: 0,65-1,01 (m, 27H), 1,12-1,74 (m, 15H), 2,63-2,98 (m, 13H), 2,983,09 (m, 3H), 3,92-4,10 (m, 4H), 4,34-4,49 (m, 1H), 4,95-5,76 (m, 7H), 7,18 (br d, 4H), 7,26 (br d, 4H), 7,34 (t, 2H), 8,28-8,41 (m, 2H), 8,44-8,57 (m, 2H); (3-310), δ: 0,62-1,03 (m, 28H), 1,04-1,14 (m, 6H), 1,17-1,80 (m, 16H), 2,592,96 (m, 17H), 2,96-3,11 (m, 3H), 3,89-4,06 (m, 4H), 4,33-4,48 (m, 1H), 4,98-5,75 (m, 7H), 7,03-7,19 (m, 4H), 7,19-7,33 (m, 4H), 8,48-8,57 (m, 2H), 8,91-9,01 (m, 2H); (3-313), δ: 0,41-1,00 (m, 27H), 1,06-1,80 (m, 15H), 2,52-3,17 (m, 1H), 2,582,96 (m, 12H), 2,96-3,14 (m, 3H), 4,00 (s, 4H), 4,36-4,48 (m, 1H), 4,98-5,77 (m, 7H), 6,87-7,04 (m, 2H), 7,11-7,50 (m, 10H), 7,82-7,96 (m, 2H); (3-318), δ: 0,51-1,02 (m, 27H), 1,09-1,77 (m, 15H), 2,59-3,14 (m, 15H), 4,074,24 (m, 4H), 4,34-4,48 (m, 1H), 4,99-5,76 (m, 8H), 7,12 (br d, 4H), 7,20-7,36 (m, 4H), 8,96-9,08 (m, 2H), 9,25-9,37 (m, 2H); (3-319), δ: 0,61-1,02 (m, 27H), 1,15-1,79 (m, 15H), 2,61-3,12 (m, 16H), 4,324,52 (m, 1H), 4,96-5,77 (m, 7H), 7,07-7,30 (m, 8H), 7,31-7,45 (m, 2H), 7,66-7,82 (m, 2H), 8,21-8,34 (m, 2H); (3-321), δ: 0,67-1,01 (m, 27H), 1,16-1,74 (m, 15H), 2,62-3,09 (m, 16H), 4,344,48 (m, 1H), 4,98-5,75 (m, 8H), 7,00-7,36 (m, 10H), 8,80-8,92 (m, 2H), 9,12-9,26 (m, 2H); (3-322), δ: 0,64-0,97 (m, 27H), 1,16-1,75 (m, 15H), 2,20 (s, 6H), 2,63-3,09 (m, 16H), 3,95 (s, 4H), 4,36-5,71 (m, 8H), 6,99 (s, 2H), 7,05-7,11 (m, 4H), 7,18-7,30 (m, 4H), 7,94-7,80 (m, 2H); (3-323), δ: 0,63-0,97 (m, 27H), 1,14-1,75 (m, 15H), 2,65-3,10 (m, 16H), 3,94 (s, 4H), 4,37-5,74 (m, 8H), 7,12-7,18 (m, 4H), 7,21-7,27 (m, 4H), 7,27-7,33 (m, 2H), Petição 870220039288, de 06 / 05 / 2022, pág. 150 / 195 144 / 169 7,77-7,86 (m, 2H), 8,05-8,11 (m, 2H); (3-324), δ: 0,62-0,98 (m, 27H), 1,13-1,76 (m, 15H), 2,24 (s, 6H), 2,64-3,10 (m, 16H), 3,89 (s, 4H), 4,37-5,74 (m, 8H), 7,10-7,18 (m, 4H), 7,21-7,28 (m, 4H), 7,61-7,68 (m, 2H), 7,88 (s, 2H); (3-326), δ: 0,62-0,97 (m, 27H), 1,13-1,76 (m, 15H), 2,64-3,13 (m, 16H), 4,07 (s, 4H), 4,37-5,75 (m, 8H), 7,17-7,24 (m, 4H), 7,24-7,32 (m, 6H), 7,92-7,98 (m, 2H); (3-329), δ: 0,69-0,94 (m, 26H), 1,23-1,68 (m, 16H), 2,67-3,04 (m, 16H), 4,03 (s, 4H), 4,40-4,42 (m, 1H), 5,02-5,70 (m, 7H), 7,13-7,15 (m, 4H), 7,24-7,27 (m, 4H), 7,39-7,42 (m, 2H), 7,67-7,69 (m, 2H), 8,24-8,26 (m, 2H); (3-332) 5.00-5.75 (m, 7H) 7.13-7.30 (m, 8H) 7.49 (br s, 2H) 8.02-8.12 (m, 2H) (3-333), δ: 0.60-1.05 (m, 27H) 1.16-1.74 (m, 15H) 2.64-2.96 (m, 13H) 2,973.15 (m, 3H) 4.11-4.22 (m, 4H) 4.48 (s, 1H) 4.95-5.76 (m, 7H) 7.09 (m, 4H) 7.20-7.34 (m, 4H) 7.72 (m, 2H) 8.62-8.79 (m, 4H); and (3-334) 4.98-5.74 (m, 7H), 6.69-6.80 (m, 2H), 7.08-7.28 (m, 8H), 7.71-7.81 (m, 2H),

[0192] The following compounds of Formula (4A) described in Table 4 were prepared according to the schemes and examples described herein. Each (R)n, Rce Rdé as described in the Table. Petition 870220039288, dated 06 / 05 / 2022, pp. 151 / 195 145 / 169 TABLE 4. Compounds of Formula (4A) Ex# Ring B com (R)n Rc Rd Mass 4-18 HHH 1079 4-19 <X-NH H H 1056 4-21 H -OH 1095 4-30* hT H H 1030 4-32* Yj H H 1029 4-34* S_ Y] H H 1059 4-40* YJ NC H H 1054 4-50Λ H H 1045 4-63* \ H H 1043 Petition 870220039288, of 06 / 05 / 2022, p. 152 / 195 146 / 169 Ex# Ring Β com (R)n Rc Rd Mass 4-75* Cl ] HH 1080 4-105* ] HH 1075 4-107* Cl HH 1081 4-109* Cl HH 1058 4-118* -9- / \—c / -N / -NH 1084-124 Λ 9— / V- o \=n \ HH 1084 4-139* HH 1054 4-141Λ wXi HH 4-1 WY \^NH -OH 1059 4-2 / =N\> H -OH 1056 4-3Λ N -X 1 HH 1057 Petition 870220039288, of 06 / 05 / 2022, p. 153 / 195 147 / 169 Ex# Ring B com (R)n Rc Rd Mass 4-4 γΎ \^NHH 1043 4-5Λ Yj HH 1045 4-6 / =N -)-Ç y—o H -OH 1086 4-7 χ / ^NH HH 1031 4-8 / =NH 100 H-3 <3 H-OH -OH 1063 4-10 Y— H -OH 1061 4-11 N—JH Cl 1091 4-12 zY H -OH 1135 4-13 H -OH 1170 4-14 \rN HH -OH 1095 4-15 CO H -OH 1106 4-OH-OH 0^ HH 1083 Petition 870220039288, of 06 / 05 / 2022, p. 154 / 195 148 / 169 Ex# Ring B com (R)n Rc Rd Mass 4-20 H -OH 1106 4-22Λ ON^ HH 1070 4-23 / =N -)-ζ —o N— HH 1071 4-24 -OH -CF3 1129 4-25 HH 1090 —4 -OH -= CH-^ 1100 4-27 / =N —0 -OH -CH2CH3 1114 4-28 / =N 4-^ —o -CH(CH3)2 -OH 1128 4-29 / =N -)-Ç y—o -OH 1126 4-31* HH 1046 4-380 HH 1046 HH 1046 4-3 4-36Λ HH 1046 4-37 Ή^χ0Ν HH 1070 Petition 870220039288, of 06 / 05 / 2022, p. 155 / 195 149 / 169 Ex# Ring B com (R)n Rc Rd Mass 4-38 d II HH 1076 4-39 d Nd^ HH 1076 4-41 d H -OH 1061 4-42Λ \ X AN HH 1057 4-43 d ΌΝ HH 1054-4-4-4 14 HH 4-45 / =\ iHJ H -OH 1137 4-46 H -OH 1075 4-47 d H -OH 1046 4-48 d H -OH 1045 4-49 H -OH 1090 4-51 HH 1059 4-52* d HH 10530-OH 1060 Λ Petition 870220039288, of 06 / 05 / 2022, p. 156 / 195 150 / 169 Ex# Anel B com (R)n Rc Rd Mass 4-54 x An A^ji HH 1044 4-55 HH 1113 4-56Λ H -OH 1076 4-57 x An AJL HH 1060 4-58 \ x An Aa cf3 H -OH 11527 170 X-OH -OH 4-60 H -OH 1076 4-61 Aja y— nxo HH 1100 4-62 A, XCF3 HH 1108 4-64 \> 9— / Vo N \ HH 1100 4-65 H -OH 1070 4-66Λ Al N^XHH 1071 H-HH 1061 Petition 870220039288, of 06 / 05 / 2022, p. 157 / 195 151 / 169 Ex# Ring B com (R)n Rc Rd Mass 4-68 A. V CF3 NH -OH 1124 4-69 UO H -OH 1145 4-70 QAH -OH 1097 4-71 pj 1 H -OH 1089 4-72 / =\ VA? HH 1121 4-73 \ za cf3 HH 1111 4-74 ΛΛ IH ) oAs HH 1152 4-76 A^N / =\ s^z H -OH 1138 4-77Λ A] Cl H -OH 1096 4-78 HH 14 172 A-H-172<H 4-80 AH -OH 1090 4-81 A^n / ^x 1 / PS^Z X_Z HH 1131 Petition 870220039288, of 06 / 05 / 2022, p. 158 / 195 152 / 169 Ex# Ring B com (R)n Rc Rd Mass 4-82 / °^JH -OH 1091 4-83Λ If HH 1044 4-84 / \ U v—N ? H -OH 1147 4-85 -W 11 Cl H -OH 1097 4-86 aXO HH 1122 4-87 CO yo H -OH 1119 4-88 \ XJ H -OH 1058 4-89 ÍH ) X^N - HH 1106 4-90Λ H-OH 1916 ONHH 1058 4-92 0 HH 1130 4-93 ST N cf3 HH 1114 4-94Λ HH 1060 Petition 870220039288, of 06 / 05 / 2022, p. 159 / 195 153 / 169 Ex# Ring B com (R)n Rc Rd Mass 4-95 9—Z λ—Ο Ν H -OH 1116 4-96 O^ANH -OH 1074 4-97 XH -OH 1063 4-98 χ Cl HH 1080 4-99 XX Cl OH -OH -10 06 H 1080 4-101Λ HH 1054 4-102 / =Ν χ y—Ν HH 1083 4-103 0 XX HH 1129 4-104 XI Ν^Χ H -OH 1060 4-106 ^0 / =\ H -OH -OH 1054 4-102 ) H -OH 1138 4-110 XX H -OH 1089 Petition 870220039288, of 06 / 05 / 2022, p. 160 / 195 154 / 169 Ex# Ring B com (R)n Rc Rd Mass 4-111Λ o xCI HH 1081 4-112 H -OH 1089 4-113 Xo HH 1122 4-114 FHH 1088 4-115Λ XX HH 1074 4-1111 NHH / S^NΛ XXX 1061 4-117 XHH 1105 4-119 ^VN HH 1117 4-120 ~^Cn HH 1088 4-121 TXw HH 1105 4-122 / S^N -X\ II V- NH -OH 1077 4-123 S^OH H>13 n>13 Petition 870220039288, of 06 / 05 / 2022, p. 161 / 195 155 / 169 Ex# Ring B com (R)n Rc Rd Mass 4-124 / =\ LHj H -OH 1121 4-125 HH 1060 4-127 cf3 HH 1138 4-128 9— / o N CF3 HH 1138 4-129 HH 1-080 HH 1138 4-129 HH 1-080 H-OH 1138 4-129 HH 1-080 H-OH 1121 / =\ J v—NHH 1109 4-131 -)X / ° N\ HH 1084 4-132 HH 1075 4-133 AHH 1044 4-134 / =\ ΧλΌ HH 1119 4-135Λ Xi HH 1030 4-136 4 vNH / HH / HH 1084 4-136 1125 4-137 / S^NH -OH 1062 Petition 870220039288, of 06 / 05 / 2022, p. 162 / 195 156 / 169 Ex# Ring B com (R)n Rc Rd Mass 4-138 \ II VN HH 1103 4-140 / ° \=N XF FHH 1106 4-142 Cho HH 1069 4-143 Cho HH 1067

[0193] The following compound names and example #'s refer to the compounds in the upper section of Table 4. (4-18). (3S,6R,9S,12R,15S,18R,21S,24R)-6-(4-((1H-indazol-6-yl)methyl)benzyl)18-benzyl-3,9,15,21-tetraisobutyl-4,10 ,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa4,10,16,22-tetra-azacyclotetracosan-2,5,8,11,14,17,20,23-octaone; (4-19). (3S,6R,9S,12R, 15S,18R,21S,24R)-6-benzyl-18-(4-((2,4-dimethyl-1 H-pyrrol-3-yl)methyl)benzyl)-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetra-azacyclotetracosan-2,5,8,11,14,17,20,23-octaone; (4-21). (3S,6R,9S,12R,15S,18R,21S,24R)-6-(4-(benzofuran-3-yl (hydroxy)methyl)benzyl)-18-benzyl-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetra-azacyclotetracosan-2,5,8,11,14,17,20,23-octaone; (4-30). (3S,6R,9S, 12R, 15S,18R,21S,24R)-6-benzil-3,9,15,21-tetraisobutil4,10,12,16,22,24-hexametil-18-(4-(oxazol-2-ilmetil)benzil)-1,7,13,19-tetraoxa4,10,16,22-tetra-azaciclotetracosan-2,5,8,11,14,17,20,23-octaona; (4-32). (3S,6R,9S,12R, 15S,18R,21S,24R)-6-benzil-18-(4-(furan-2-ilmetil)benzil)-3,9,15,21-tetraisobutil-4,10,12,16,22,24-hexametil-1,7,13,19-tetraoxa-4,10,16,22tetra-azaciclotetracosan-2,5,8,11,14,17,20,23-octaona; Petição 870220039288, de 06 / 05 / 2022, pág. 163 / 195 157 / 169 (4-34). (3S,6R,9S, 12R, 15S,18R,21S,24R)-6-benzil-3,9,15,21-tetraisobutil4,10,12,16,22,24-hexametil-18-(4-((3-metiltiofen-2-il)metil)benzil)-1,7,13,19-tetraoxa4,10,16,22-tetra-azaciclotetracosan-2,5,8,11,14,17,20,23-octaona; (4-40). 2-(4-(((2R,5S,8R,11S,14R,17S,20R,23S)-14-benzil-5,11,17,23-tetraisobutil-4,8,10,16,20,22-hexametil-3,6,9,12,15,18,21,24-octaoxo-1,7,13,19-tetraoxa-4,10,16,22-tetra-azaciclotetracosan-2-il)metil)benzil)furan-3-carbonitrila; (4-50). (3S,6R,9S,12R, 15S,18R,21S,24R)-6-benzyl-3,9,15,21-tetraisobutyl4,10,12,16,22,24-hexametil-18-(4-(thiophen-3-yl) ethyl)benzyl)-1,7,13,19-tetraoxa4,10,16,22-tetra-azaciclotetracosane-2,5,8,11,14,17,20,23-octaone; (4-63). (3S,6R,9S, 12R, 15S,18R,21S,24R)-6-benzyl-3,9,15,21-tetraisobutyl4,10,12,16,22,24-hexamethyl-18-(4-((1 -methyl-1 H-pyrazol-5-yl)methyl)benzyl)-1,7,13,19-tetraoxa-4,10,16,22-tetra-azacyclotetracosane-2,5,8,11,14,17,20,23-octaano; (4-75). (3S,6R,9S,12R,15S,18R,21 S,24R)-6-benzil-18-(4-((3-chlorothiofen-2yl)metil)benzil)-3,9,15,21-tetraisobutyl-4,10,12,16,22,2 4-hexametil-1,7,13,19-tetraoxa4,10,16,22-tetra-azaciclotetracosan-2,5,8,11,14,17,20,23-octaona; (4-105). (3S,6R,9S,12R,15S,18R,21S,24R)-6-benzyl-3,9,15,21-tetraisobutyl18-(4-((3-methoxythiophen-2-yl)methyl)benzyl)-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetra-azacyclotetracosane-2,5,8,11,14,17,20,23-octaano; (4-107). (3S,6R,9S,12R, 15S,18R,21S,24R)-6-benzil-18-(4-((4-clorotiazol-5il)metil)benzil)-3,9,15,21-tetraisobutil-4,10,12,16,22,24-hexametil-1,7,13,19-tetraoxa4,10,16,22-tetra-azaciclotetracosan-2,5,8,11,14,17,20,23-octaona; (4-109). (3S,6R,9S,12R, 15S,18R,21 S,24R)-6-benzil-18-(4-((3,5-dimetilisoxazol-4-il)metil)benzil)-3,9,15,21-tetraisobutil-4,10,12,16,22,24-hexametil-1,7,13,19-tetraoxa-4,10,16,22-tetra-azaciclotetracosan-2,5,8,11,14,17,20,23-octaona; (4-118). (3S,6R,9S,12R,15S,18R,21S,24R)-6-benzil-3,9,15,21-tetraisobutil18-(4-((6-metoxi-2-metilpiridin-3-il)metil)benzil)-4,10,12,16,22,24-hexametilPetição 870220039288, de 06 / 05 / 2022, pág. 164 / 195 158 / 169 1,7,13,19-tetraoxa-4,10,16,22-tetra-azaciclotetracosan-2,5,8,11,14,17,20,23-octaona; (4-126). (3S,6R,9S,12R,15S,18R,21S,24R)-6-benzyl-3,9,15,21-tetraisobutyl18-(4-((6-methoxy-4-methylpyridin-3-yl)methyl)benzyl )-4,10,12,16,22,24-hexamethyl1,7,13,19-tetraoxa-4,10,16,22-tetra-azacyclotetracosan-2,5,8,11,14,17,20,23-octaone; (4-139). (3S,6R,9S,12R,15S,18R,21S,24R)-3,9,15,21-tetraisobutyl4,6,10,16,18,22-hexamethyl-12,24-bis(4-((2-methylpyrid in-3-yl)methyl)benzyl)-1,7,13,19-tetraoxa-4,10,16,22-tetra-azacyclotetracosan-2,5,8,11,14,17,20,23-octaone; and (4-141). (3S,6R,9S,12R,15S,18R,21S,24R)-3,9,15,21-tetraisobutyl4,6,10,16,18,22-hexamethyl-12,24-bis(4-((4-methylisothiazol-5-yl)methyl)benzyl)-1,7,13,19-tetraoxa-4,10,16,22-tetra-azacyclotetracosan-2,5,8,11,14,17,20,23-octaone; stereoisomers thereof and veterinary acceptable salts thereof.

[0194] The NMR data (1H NMR: 400 MHz, DMSO-d6, δ ppm) for the compounds named in Table 4 are shown below: (4-18), δ: 0,56,1,85 (m, 42H) 2,62,3,19 (m, 16H) 4,05 (s, 2H) 3,94-4,44 (m, 1H) 4,97,5,83 (m, 9H) 6,97 (m, 1H) 7,15,7,39 (m, 10H) 7,65 (m, 1H) 7,99 (s, 1H); (4-19), δ: 0,62,1,02 (m, 26H), 1,13,1,78 (m, 16H), 1,81,1,91 (m, 3H), 2,00,2,13 (m, 3H), 2,63,3,18 (m, 16H), 3,70 (s, 2H), 4,42 (m, 1H), 4,95,5,82 (m, 7H), 7,02,7,41 (m, 10H), 9,93,10,06 (m, 1H); (4-21), δ: 0,65,0,99 (m, 27H), 1,14,1,80 (m, 15H), 2,47,2,62,2,99 (m, 13H), 2,99,3,15 (m, 3H), 4,38,4,46 (m, 2H), 4,98,5,77 (m, 8H), 5,88,5,93 (m, 1H), 7,07,7,17 (m, 1H), 7,17,7,35 (m, 9H), 7,37,7,44 (m, 2H), 7,51 (d, J = 8,31Hz, 1H), 7,78,7,83 (m, 1H); (4-30), δ: 0,68,0,94 (m, 26H), 1,23,1,70 (m, 16H), 2,66,3,02 (m, 16H), 4,09 (s, 2H), 4,40,4,42 (m, 1H), 5,02,5,70 (m, 7H), 7,12-7,31 (m, 10H), 7,98-7,99 9m, 1H); (4-32), δ: 0,70-0,94 (m, 26H), 1,23,1,70 (m, 16H), 2,67,3,04 (m, 16H), 3,93 (s, Petição 870220039288, de 06 / 05 / 2022, pág. 165 / 195 159 / 169 2H), 4,40,4,42 (m, 1H), 5,02,5,71 (m, 7H), 6,07 (brs, 1H), 6,34-6,35 (m, 1H), 7,13,7,16 (m, 2H), 7,22-7,31(m, 7H), 7,50 (brs, 1H); (4-34), δ: 0,68,0,94 (m, 26H), 1,23,1,70 (m, 16H), 2,12 (s, 3H), 2,66,3,06 (m, 16H), 4,01 (s, 2H), 4,40,4,42 (m, 1H), 5,02,5,71 (m, 7H), 6,82-6,83 (m, 1H), 7,11,7,31 (m, 10H); (4-40), δ: 0,70-0,94 (m, 26H), 1,23-1,71 (m, 16H), 2,67,3,05 (m, 16H), 4,15 (s, 2H), 4,40,4,42 (m, 1H), 5,04,5,70 (m, 7H), 6,87 (s, 1H), 7,16-7,30 (m, 9H), 7,79 (s, 1H); (4-50), δ: 0,68-0,95 (m, 26H), 1,23-1,69 (m, 16H), 2,67,3,05 (m, 16H), 3,90 (s, 2H), 4,40,4,42 (m, 1H), 5,03,5,70 (m, 7H), 6,91-7,43 (m, 12H); (4-63), δ: 0,68,0,94 (m, 26H), 1,23,1,70 (m, 16H), 2,66,3,06 (m, 16H), 3,65 (s, 3H), 3,98 (s, 2H), 4,40,4,42 (m, 1H), 5,02,5,70 (m, 7H), 5,92 (brs, 1H), 7,11,7,31 (m, 10H); (4-75), δ: 0,68-0,95 (m, 26H), 1,23-1,70 (m, 16H), 2,67,3,05 (m, 16H), 4,07 (s, 2H), 4,40,4,42 (m, 1H), 5,02,5,73 (m, 7H), 7,01-7,50(m, 11H); (4-105), δ: 0,68-0,94 (m, 27H), 1,20-1,80 (m, 15H), 2,66-3,10 (m, 16H), 3,77 (s, 3H), 3,91 (s, 2H), 4,38-4,44 (m, 1H), 5,02-5,75 (m, 7H), 6,97-7,31 (m, 11H); (4-107), δ: 0,68-0,95 (m, 26H), 1,24-1,70 (m, 16H), 2,67,3,05 (m, 16H), 4,12 (s, 2H), 4,40,4,42 (m, 1H), 5,04,5,70 (m, 7H), 7,17-7,30 (m, 9H), 8,98 (s, 1H); (4-109), δ: 0,68-0,94 (m, 26H), 1,23-1,70 (m, 16H), 1,99 (s, 3H), 2,30 (s, 3H), 2,67,3,05 (m, 16H), 3,65 (s, 2H), 4,40,4,42 (m, 1H), 5,09,5,67 (m, 7H), 7,06-7,08 (m, 2H), 7,22-7,31 (m, 7H); (4-118), δ: 0,68,0,94 (m, 26H), 1,23,1,70 (m, 16H), 2,26 (s, 3H), 2,66,3,02 (m, 16H), 3,76 (s, 3H), 3,84 (s, 2H), 4,40,4,42 (m, 1H), 5,02,5,70 (m, 7H), 6,54-6,56 (m, 1H), 7,02-7,40 (m, 10H); (4-126), δ: 0,68,0,94 (m, 26H), 1,23,1,70 (m, 16H), 2,08 (s, 3H), 2,66,3,02 (m, 16H), 3,79 (s, 3H), 3,86 (s, 2H), 4,40,4,42 (m, 1H), 5,02,5,70 (m, 7H), 6,61 (s, 1H), 7,04-7,31 (m, 9H), 7,89 (s, 1H); Petition 870220039288, 06 / 05 / 2022, pág. 166 / 195 160 / 169 (4-139), δ: 0.68,0.95 (m, 26H), 1.23,1.72 (m, 16H), 2.37 (s, 3H), 2.66,3.06 (m, 18H), 3.94 (s, 4H), 4.40,4.42 (m, 1H), 5,02,5,71 (m, 7H), 7,06,7,31 (m, 10H), 7,43-7,46 (m, 1H), 8,28-8,29 (m, 1H); and (4-141), δ: 0.69 -0.94 (m, 26H), 1.23 -1.68 (m, 16H), 2.17 (s, 3H), 2.67,3.05 (m, 16H), 4.15 (s, 2H), 4.40,4.42 (m, 1H), 5.02,5.70 (m, 7H), 7.18-7.31 (m, 9H), 8.30 (s, 1H), Biological

[0195] Heartworm infection, caused by the endoparasite Dirofilaria immitis (D. immitis), can be a serious and life-threatening disease in animals such as dogs and cats. Heartworm has a complicated life cycle involving several life stages before becoming adults, which will eventually infect the pulmonary artery of the host animal. Heartworm transmission also requires a mosquito to act as an intermediate host to complete this life cycle. For example, the beginning of the heartworm life cycle and transmission process involves a mosquito biting a previously infected dog and ingesting blood containing heartworm microfilariae (larval stage 1). Inside the mosquito, the microfilariae transform into infective larval stage 3 (L3) worms over a period of two weeks.As soon as the mosquito bites another dog, the infectious L3 worms will move through the bite wound to enter the host and migrate to the tissues, where they will begin to molt into stage 4 larval worms (L4), usually 1 to 3 days after infection. Subsequently, the L4 worms will continue their migration through the tissues and transform into sexually immature adults or adolescents (stage 5 larval, immature adult), approximately 50-70 days after infection. The sexually mature worms will eventually migrate to the dog's heart and lungs, around 70 days after infection. Approximately 6-7 months after infection, adult D. immitis worms reach maturity and reproduce sexually in the pulmonary artery, leading to the production of microfilariae. Petition 870220039288, dated 06 / 05 / 2022, pp. 167 / 195 161 / 169 (MF) and circulates in the dog's blood, thus completing the life cycle of the heartworm.

[0196] The most commonly used heartworm prophylactics are macrocyclic lactones (MLs), such as ivermectin, moxidectin, and selamectin. These agents are administered monthly, killing host-acquired D. immitis L3 and L4 worms within the first 30 days. Their primary action is to interrupt the heartworm life cycle by killing L3 and L4 worms, thus preventing adult formation and subsequent disease. Although very effective in preventing heartworm, owners are advised to test dogs for heartworm infections (i.e., heartworm-positive dogs) before initiating treatment with MLs due to their potential to kill circulating microfilariae. A rapid reduction in the number of microfilariae in the blood can lead to hypersensitivity reactions and circulatory shock (e.g., anaphylaxis), presumably due to dead or dying microfilariae.These potential adverse effects can be fatal to the dog and, as such, are presented as cautionary statements on the labels of many ML products. Therefore, the discovery of a novel heartworm prophylactic that would selectively target worms in the L3 and L4 stages versus microfilariae would offer a potential safety advantage. By not killing circulating microfilariae in heartworm-positive dogs, a targeted treatment would avoid the adverse effects known to occur with other heartworm prophylactics that lack selectivity at the D. immitis stage.

[0197] To identify new prophylactics against heartworm, compounds were selected for nematocidal activity using in vitro motility assays. The compounds described here demonstrated nematocidal activity against Dirofilaria immitis (larval stage 4 (DiL4)) and / or Dirofilaria immitis microfilariae (DiMF) as determined by reductions in nematode motility due to paralysis or death. Examples of active and selective compounds (DiL4 vs. DiMF potency) Petition 870220039288, dated 06 / 05 / 2022, pages 168 / 195 162 / 169 were subsequently evaluated in studies with heartworm-positive dogs to correlate the in vitro selectivity profile with in vivo effects on circulating microfilariae.

[0198] The in vitro (DiL4 and DiMF) and in vivo (studies in dogs with heartworm) biological activity against Dirofilaria immitis of the compounds of the invention can be measured using the test methods described below. In vitro assay for Dirofilaria immitis, Microfilaria (DiMf)

[0199] The compounds were dissolved and serially diluted in DMSO. Aliquots were placed in the empty wells of assay plates. Dirofilaria immitis media and microfilariae were added to each well to dilute the test compounds to the desired concentrations. The assay plates were incubated for approximately 72 hours, and the larvae in each well were observed microscopically for drug effect. The microfilariae in each well were subjectively assessed for survival or paralysis, and the results were reported as Minimum Effective Dose (MED). In vitro assay for Dirofilaria immitis, L4 stage (DiL4)

[0200] The compounds were initially dissolved in DMSO. The stock concentration was subsequently diluted in basal medium and serially diluted to generate a concentration-response curve starting at 100 μM (> 11 total concentrations). After serial dilution, the compound solution was transferred to an assay plate (384 wells), where D. immitis L4 larvae (10 / well), which had molted from L3 larvae in vitro, were subsequently added. The assay plates were observed at 72 hours for drug effect. Each compound was evaluated for decreased L4 motility by subjective visual assessment, and the results data were recorded as minimum effective concentration (MEC) in μM after the incubation period. Examples with DME DiL4 data < 1 nM are presented in Tables 1-4 (i.e., top sections). Examples with data > 1 nM are also shown. Petition 870220039288, dated 06 / 05 / 2022, pages 169 / 195 163 / 169 are presented in Tables 1-4 (i.e., lower sections). Studies with dogs tested positive for heartworm.

[0201] Dogs with pre-existing heartworm infections, via surgical transplantation, were used for these studies. To confirm that the dogs had circulating microfilariae, blood samples were taken from each dog and examined for microfilariae using the modified Knott method. All dog cohorts included in the studies exhibited mean microfilariae counts of at least 15,000 MF / mL of blood (pre-dose). At approximately Day-7, dogs were randomly allocated to treatments (based on Day-7 MF counts) and cages according to a randomized complete block design with a one-sided structure. Dogs fasted overnight before dosing and were fed immediately after dosing of the test articles. Compounds were administered by point-dose in liquid-filled oral capsules on Day 0 (group of 3 dogs / treatment).Blood samples were collected to measure MF counts on days 0 (pre-dose and 2 hours post-dose), 1, 7, 21, and 28. Clinical observations were conducted by a suitably experienced veterinarian on days -7, 0 (immediately before treatment, 1-2 hours post-treatment), 1, and 2, where any abnormal clinical signs were documented using standard veterinary medical terminology. In addition, general health observations were conducted throughout the study, including (but not limited to) general physical appearance and behavior, abnormalities in food and water consumption, vomiting / regurgitation, presence in urine and feces, and any signs of MF anaphylaxis.

[0202] The reference depsipeptide, emodepside, has equivalent in vitro potency against DiL4 (30 nM) and DiMF (30 nM) when evaluated in nematode motility assays and therefore represents a non-selective compound. As such, emodepside was evaluated for effects against circulating microfilariae in a Petition 870220039288, dated 06 / 05 / 2022, pp. 170 / 195 164 / 169 study in dogs positive for heartworm. At a dose of 1 mg / kg (po), emodepside demonstrated rapid death of circulating microfilariae, reducing mean MF counts from 61,000 MF / mL of blood pre-dose to 8,300 MF / mL of blood 2 hours post-dose (87% reduction; Table 5). Furthermore, all treated dogs exhibited adverse effects consistent with dead or dying circulating microfilariae (e.g., lethargy, tremors, ataxia, hypersalivation) within 2 hours of emodepside administration. All dogs were treated with dexamethasone, epinephrine, and valium to help them recover from the symptoms.

[0203] Unlike emodepsid, the compounds described here demonstrate larval stage selectivity (i.e., potency of DiL4 vs DiMF) as shown in Table 5. Emodepsid (1 mg / kg) and Example (3-9; 3 mg / kg) were evaluated in a study of heartworm-positive dogs in order to correlate the in vitro selectivity profile with in vivo effects on circulating microfilariae. Both compounds were administered orally. Selectivity is shown as a DiMF / DiL4 ratio. The DME over DiL4 and DiMF for emodepsid was 10 nM. There was no selectivity (1x) between these larval stages with emodepsid. In contrast, for Example (3-9), the DME over DiMF and DiL4 was 60 nM and 3 nM, respectively; thus providing a larval selectivity ratio of 20x. Furthermore, no adverse effects were observed after administration of Example (3-9), consistent with the absence of microfilarial death in the blood. The mean MF counts were 18.Pre-dose blood levels were 000 MF / mL and remained elevated throughout the study, with an average of 24,000 MF / mL of blood on day 21 of the study in dogs. Furthermore, no adverse clinical observations were noted throughout the study, consistent with the lack of potency against circulating MF in dogs. These data emphasize the importance of generating selective compounds for the larval stage as novel prophylactics against heartworm. Specifically, targeting the L4 stage versus the MF stage of D. immitis worms provides better results. Petition 870220039288, dated 06 / 05 / 2022, pp. 171 / 195 165 / 169 safety profile when administering prophylactics to dogs with an already active adult heartworm infection. In fact, the compounds described in this document exhibit improved selectivity ratios, which also provide improved safety profiles compared to older prophylactics and reference depsipeptides, such as emodepside. TABLE 5. Studies in dogs positive for heartworm by evaluating the effects on circulating microfilariae (MF) after administration of the compound. Compound Day 0 Predose Day 0, Postdose, 2 hours Day 1 Day 7 Day 14 Day 21 Emodepside Average MF / mL 61,000 8,300 4,500 8,800 NDND % Reduction 87% 93% 86% NDND Example 3-9 Average MF / mL 18,000 20,000 23,000 25,000 22,000 24,000 % Reduction -11% -28% -50% -22% -33% ND = Not Determined; crude microfilariae counts are presented as mean MF / mL (3 dogs / treatment) in blood. Percentage reductions were calculated from counts on the day of evaluation compared to pre-dose levels (day 0). Negative percentage reductions reflect natural variability over time due to active adult heartworm infection and continuous microfilariae production. In vitro assay for Haemonchus contortus, Larval Stage 3 (Hc L3)

[0204] The Haemonchus contortus L3 strain was obtained from the University of Georgia and is a relatively recent multi-resistant field isolate (International Journal for Parasitology 37 (2007) 795-804). The compounds were dissolved and serially diluted in DMSO. Aliquots were placed in the empty wells of the assay plates. Medium and third-stage larvae of Haemonchus contortus were added to each well to dilute the test compounds to the desired concentrations. Petition 870220039288, dated 06 / 05 / 2022, pages 172 / 195 166 / 169 The assay plates were incubated for approximately 96 hours, and the larvae in each well were observed microscopically for the effect of the drug. The larvae in each well were subjectively evaluated for survival or paralysis, and the results were reported as Minimum Effective Dose (MED). Examples with MED data HcL3 < 1 μM (Ex # *) and data 1 > χ < 3.3 μM (Ex #λ) are presented in Tables 1-4.

[0205] Summary data for worms are presented in Table 6 for those compounds with a DME DiL4 (nM) value of < 1 nM. In addition, DME DiMf (nM), DME HcL3 (μM) and DiMf / / DiL4 specificity data are also shown. TABLE 6. Data for DiL4, Dimf, Dimf / DiL4 and HcL3 Ex.# DiL4 (nM) DiMf (nM) DiMf / DiL4 HcL3 (μM) Ex.# DiL4 (nM) DiMf (nM) DiMf / DiL4 HcL3 (μM) (1-5) 1 500 500 >100 (3- 274) 0.3 10 33.3 1 (1-11) 1 300 300 >10 (3- 275) 1 10 10 1.8 (1-18) <0.1 3 >30 >100 (3- 282) 1 5 5 30 (2-1) 1 20 20 0.65 (3- 283) 0.5 3 6 1 (2-4) 0.7 50 71.4 3.3 (3- 284) 0.5 100 200 >10 (2-36) 0.2 30 150 1 (3- 285) 0.5 3 6 5.7 (2-37) 1 20 20 3.3 (3- 286) 0.5 30 60 >10 (2-38) 0.6 30 50 0.5 (3- 287) 0.5 50 100 >10 (2-42) 0.3 300 1000 >10 (3- 288) 0.1 3 30 0.2 (3-4) 0.1 20 200 0.5 (3- 289) 0.5 3 6 3.3 (3-8) 0.3 10 33.3 1 (3- 290) 0.1 0.3 3 0.2 (3-12) 1 0.7 0.7 3.3 (3- 291) 0.1 0.3 3 0.3 (3-17) 0.3 0.3 1 0.5 (3- 268) 0.5 2 4 1 Petition 870220039288, dated 06 / 05 / 2022, pp. 173 / 195 167 / 169 Ex.# DiL4 (nM) DiMf (nM) DiMf / DiL4 HcL3 (μM) Ex.# DiL4 (nM) DiMf (nM) DMf / DiL4 HcL3 (μM) (3-18) 0.1 0.2 2 1 (3- 273) 0.3 2 6.7 1 (3-21) <0.03 0.1 >3.3 0.3 (3- 274) 0.3 10 33.3 1 (3-24) 0.03 0.1 3.3 1 (3- 275) 1 10 10 1.8 (3-31) 0.2 5 25 2.4 (3- 282) 1 5 5 30 (3-44) 0.1 100 1000 1.8 (3- 283) 0.5 3 6 1 (3-49) 1 5 5 3.3 (3- 284) 0.5 100 200 >10 (3-50) 0.1 1 10 0.3 (3- 285) 0.5 3 6 5.7 (3-56) 0.5 100 200 0.5 (3- 286) 0.5 30 60 >10 (3-57) 0.3 0.3 1 1 (3- 287) 0.5 50 100 >10 (3-58) 0.2 5 25 1 (3- 288) 0.1 3 30 0.2 (3-60) 1 50 50 >10 (3- 289) 0.5 3 6 3.3 (3-69) 0.7 30 42.9 0.5 (3- 290) 0.1 0.3 3 0.2 (3-87) 0.3 100 333 0.3 (3- 291) 0.1 0.3 3 0.3 (3110) 0.1 30 300 >100 (3- 292) 0.3 1 3.3 1.8 (3112) 0.03 1 33.3 1 (3- 293) 0.3 50 167 5.7 (3118) 1 100 100 >100 (3- 294) 0.1 0.1 1 1 (3- 120) 0.1 0.4 4 1 (3- 295) 0.3 5 16.7 1.8 (3121) 0.05 3 60 1.8 (3- 296) 0.5 30 60 1.8 (3124) 1 100 100 0.3 (3- 297) 1 30 30 >10 (3- 125) <0.2 30 >150 >100 (3- 307) 0.1 0.3 3 1 (3- 132) 0.4 10 25 >10 (3- 308) 1 10 10 3,3 (3- 133) 0.3 20 66.7 57 (3- 309) 0.55 3 5.5 3.3 (3- 0.3 1 3.3 3 (3- 1 0.3 0.3 1, Petition 870220039288, dated 06 / 05 / 2022, pp. 174 / 195 168 / 169 Ex.# DiL4 (nM) DiMf (nM) DiMf / DiL4 HcL3 (μM) Ex.# DiL4 (nM) DiMf (nM) DiMf / DiL4 HcL3 (μM) 148) 310) (3- 155) 0.02 0.1 5 0.5 (3- 313) 0.55 3 5.5 0.55 (3- 156) 0.1 0.5 5 5.6 (3- 318) 0.03 0.3 10 0.55 (3- 157) 1 100 100 >100 (3- 319) 0.055 1.73 31.5 0.55 (3- 165) 1 200 200 >100 (3- 321) 0.02 0.05 2.5 0.3 (3- 173) <0.1 3 >30 3.3 (3- 322) 0.3 10 33.3 10 (3- 176) 0.3 4 13.3 1.2 (3- 323) 0.1 1 10 0.3 (3- 178) 1 1 1 >100 (3- 324) 0.1 10 100 1 (3- 193) 0.4 2 5 1 (3- 326) 0.3 30 100 10 (3194) 1 1 1 >100 (3- 329) 0.1 1 10 — (3- 207) 1 50 50 >100 (3- 332) 0.5 300 548 — (3- 209) 0.5 10 20 >100 (3- 333) 0.2 3 17 — (3- 215) <0.2 0.7 >3.5 1 (3- 334) 0.3 3 10 0.1 (3- 217) <0.7 3 >4.3 3.3 (418) 1 50 50 >10 (3- 218) 0.8 10 12.5 >23 (419) 1 100 100 >10 (3- 220) 0.7 5 7.1 >100 (4- 21) 1 50 50 >10 (3- 223) 0.7 5 7.1 5.7 (4- 30) 1 1 1 1 (3- 225) 0.7 300 429 >100 (4- 32) 1 3 3 1 (3- 228) 0.5 10 20 >100 (4- 34) 0.3 10 33.3 0.5 (3- 238) 0.1 2 20 >5 (4- 40) 0.2 0.5 2.5 0.5 (3- 240) 1 20 20 5.7 (4- 50) 1 10 10 1,8 (3- 243) 1 1 1 7.5 (4- 63) 1 1 1 1 (3- 252) 0.7 20 28.6 >42 (4- 75) 0.5 10 20 1. Petition 870220039288, dated 06 / 05 / 2022, pages 175 / 195 169 / 169 Ex.# DiL4 (nM) DiMf (nM) DiMf / DiL4 HcL3 (μΜ) Ex.# DiL4 (nM) DiMf (nM) DMf / DiL4 HcL3 (μM) (3- 253) 1 0.3 0.3 1 (4105) 0.2 5 25 0.3 (3- 254) 1 3 3 10 (4107) 0.2 3 15 0.3 (3- 259) 0.5 10 20 3.3 (4109) 0.4 1 2.5 1 (3261) <0.1 30 >300 >100 (4118) 0.1 1 10 0.3 (3- 268) 0.5 2 4 1 (4126) 0.2 3 15 1.8 (3- 273) 0.3 2 6.7 1 (4139) 0.4 1 2.5 1 (4141) 1 3 3 1.8

Claims

1. Compound CHARACTERIZED by the fact that it is a compound of Formula (1A1): wherein each (R)n is the same and is independently selected from the group consisting of C1-C6 alkyl optionally substituted with at least one substituent selected from hydroxyl and C3-C6 cycloalkyl; halo, cyano, hydroxy, -NRaRb, C1-C4 haloalkyl, C1-C4 haloalkoxy, -S(O)pRa, C1-C6 alkoxy, C3-C6 cycloalkyl and morpholinyl; and wherein n is the integer 0, 1, 2 or 3; p is the integer 0, 1 or 2; each Ra and Rb is independently H, methyl and ethyl; Each Rc and Rd is selected independently from the group consisting of H, hydroxyl, halo, C1-C6 alkyl, C1-C6 alkoxy, -NRaRb, -CF3, cyclopropyl, pyrazolyl, pyrrolidinyl and morpholinyl; wherein each Ra is the same and each Rb is the same and each Rc is the same and each Rd is the same; and veterinary acceptable salts thereof;or a compound of Formula (1A1) which is: (3S,6R,9S,12R,15S,18R,21S,24R)-3,9,15,21-tetraisobutyl-6,18-bis(4-(3-methoxybenzyl)benzyl)-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone; (3S,6R,9S,12R,15S,18R,21S,24R)-3,9,15,21-tetraisobutyl-6,18-bis(4-(2-methoxybenzyl)benzyl)-4,10,12,16 ,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone; or (3S,6R,9S,12R, 15S, 18R,21S,24R)-6,18-bis(4-((3,4-difluorophenyl)(1 H-pyrazole)-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone, and veterinary acceptable salts thereof.

2. The compound is characterized by the fact that it is a compound of Formula (3A): in which Enel A and Enel B are similar and are selected from the group consisting of cyclopropyl, ciclobutyl, cicopentil, cyclo-hexyl, oxetanil, azetidinil, piperidinil, pyrrolidinil, morpholinil, tetra-hidropiridinil, tetra-hidropirimidinil, tetra-hidropiridinil, tetra-hydropiranil, thiofenil, furanil, tiazolil, oxazolil, pyrrolil, pirazolil, imidazolil, piridinil, tiadiazolil, isotiazolil, triazinil, pirimidinil, pirazinil, piridazinil, isoxazolil, tetrazolil, oxadiazolil, 1,2-di-hidropiridinil, triazolil, quinolinil, isoquinolinil, benzofuranil, 2,3-di-hidrotieno[3,4b][1,4]dioxin, 3,4-di-hidro-2H-pirano[2,3-b]piridinil, oxazol[5,4-b]piridinil, pirazol[1,5a]piridinil, pirazol[1,5-a]pirimidina, 4,5,6,7-tetra-hidropirazol[1,5-a]piridinil, 4,5-tetra-hidropirazol[1,5-a]pirimidina, 1H-pyrrol[3,2-b]piridinil, indazolil, furo[2,3-b]pyridinil, e benzo[d][1,3]dioxol;and wherein the heteroaryl and heterocycle rings are methylene-linked by a carbon atom of the ring; and wherein each (R)n is the same and is independently selected from the group consisting of C1-C6 alkyl optionally substituted with at least one of hydroxyl and C3-C6 cycloalkyl; halo, cyano, hydroxyl, -NRaRb, C1-C4 haloalkyl, C1-C4 haloalkoxy, -S(O)pRa, C1-C6 alkoxy, C3-C6 cycloalkyl and morpholinyl, where n is the integer 0, 1, 2 or 3; each Ra and Rb is independently H, methyl and ethyl; p is the integer 0, 1 or 2; Each Rc and Rd is selected independently from the group consisting of H, hydroxyl, F, methyl, ethyl, methoxy, and ethoxy; and where each Ra is the same and each Rb is the same and each Rc is the same and each Rd is the same; and veterinary acceptable salts thereof.

3. Compound according to claim 2, CHARACTERIZED in that Ring A and Ring B are identical and are selected from the group consisting of thiophenyl, furanil, thiazolyl, oxazolyl, pyrazolyl, pyridinyl, thiadiazolyl, isothiazolyl, triazinyl, pyrimidinyl, pyrazinyl, pyridazinyl, isoxazolyl, benzofuranil, indazolyl and tetrahydropyranil; and veterinary acceptable salts thereof.

4. Compound according to claim 3, CHARACTERIZED in that Ring A and Ring B are identical and are selected from the group consisting of pyrazolyl, isothiazolyl, thiazolyl, pyridinyl, pyrimidinyl, pyrazinyl and pyridazinyl; and wherein each (R)n is the same and is selected independently from the group consisting of methyl, ethyl, isopropyl, propyl, isobutyl, fluorine, chlorine, bromine, cyano, hydroxyl, -NH2, -NHCH3, N(CH3)2, -N(CH2CH3)2, methoxy, ethoxy, isopropoxy, -CF3, -CHF2, -CH2CH2F, -CH2CF3, cyclopropyl, cyclobutyl, -CH2cyclopropyl, -OCHF2, -OCF3, -OCH2CF3, -C(CH3)2OH, -SCH3, -S(O)2CH3 and morpholinyl; and veterinary acceptable salts thereof.

5. Compound according to claim 4, CHARACTERIZED in that Rings A and B are identical and are selected from the group consisting of pyrazolyl, pyrazinyl, isothiazolyl, thiazolyl, pyridinyl, pyridazinyl and pyrimidinyl.

6. Compound according to claim 4 or 5, CHARACTERIZED in that each (R)n is the same and is independently selected from the group consisting of methyl, ethyl, isopropyl, fluorine, chlorine, bromine, cyanoacrylate, hydroxyl, -N(CH3)2, methoxy, ethoxy, isopropoxy, -CHF2, -CH2CH2F, -CF3, cyclopropyl, -CH2cyclopropyl, -OCHF2, OCF3, -SCH3 and morpholinyl; and wherein each Rc and Rd is independently selected from the group consisting of H, hydroxyl, methyl, methoxy, ethoxy and -N(CH2CH3)2; and veterinary acceptable salts thereof.

7. Compound according to claim 2, CHARACTERIZED in that it is selected from the group consisting of: (3S,6R,9S,12R,15S,18R,21S,24R)-3,9,15,21-tetraisobutyl-4,6,10,16,18,22-hexamethyl-12,24-bis(4-(thiophen-2-ylmethyl)benzyl)-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone; (3S,6R,9S,12R,15S,18R,21S,24R)-6,18-bis(4-(furan-2-ylmethyl)benzyl)3,9,15,21-tetraisobutyl-4,10,12,16 ,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetra-azacyclotetracosan-2,5,8,11,14,17,20,23-octaone; (3S,6R,9S,12R,15S,18R,21S,24R)-3,9,15,21-tetraisobutyl-4,6,10,16,18,22hexamethyl-12,24-bis(4-(thiazol-5 -ylmethyl)benzyl)-1,7,13,19-tetraoxa-4,10,16,22-tetra-azacyclotetracosan-2,5,8,11,14,17,20,23-octaone; (3S,6R,9S,12R,15S,18R,21S,24R)-3,9,15,21-tetraisobutyl-4,6,10,16,18,22hexamethyl-12,24-bis(4-(thiazol-2 -ylmethyl)benzyl)-1,7,13,19-tetraoxa-4,10,16,22-tetra-azacyclotetracosan-2,5,8,11,14,17,20,23-octaone;(3S,6R,9S,12R,15S,18R,21S,24R)-3,9,15,21-tetraisobutyl-4,6,10,16,18,22hexametil-12,24-bis(4-(oxazol- 2-ylmethyl)benzyl)-1,7,13,19-tetraoxa-4,10,16,22-tetraazaciclotetracosan-2,5,8,11,14,17,20,23-octaone; (3S,6R,9S,12R,15S,18R,21S,24R)-6,18-bis(4-((3,5-dimethylisoxazol-4-yl)metil)benzil)-3,9,15,21 -tetraisobutil-4,10,12,16,22,24-hexametil-1,7,13,19-tetraoxa4,10,16,22-tetra-azaciclotetracosan-2,5,8,11,14,17,20,23-octaona; (3S,6R,9S,12R,15S,18R,21S,24R)-3,9,15,21-tetraisobutyl-4,6,10,16,18,22hexamethyl-12,24-bis(4-((1-methyl-1H-pyrazol-5-yl)methyl)benzyl)-1,7,13,19-tetraoxa4,10,16,22-tetra-azacyclotetracosane-2,5,8,11,14,17,20,23-octaano; (3S,6R,9S,12R,15S,18R,21S,24R)-3,9,15,21-tetraisobutyl-6,18-bis(4-((2-methoxypyridin-3-yl)methyl)benzyl)-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxaPetition 870260057804, of 15 / 06 / 2026, pág. 12 / 44 5 / 18 4,10,16,22-tetra-azacyclotetracosane-2,5,8,11,14,17,20,23-octaone;(3S,6R,9S,12R,15S,18R,21S,24R)-3,9,15,21-tetraisobutil-4,6,10,16,18,22hexametil-12,24-bis(4-((3-metiltiofen-2-il)metil)benzil)-1,7,13,19-tetraoxa-4,10,16,22tetra-azaciclotetracosan-2,5,8,11,14,17,20,23-octaona; (3S,6R,9S,12R,15S,18R,21S,24R)-6,18-bis(4-((1,3-dimetil-1H-pirazol-5il)metil)benzil)-3,9,15,21-tetraisobutil-4,10,12,16,22,24-hexametil-1,7,13,19-tetraoxa4,10,16,22-tetra-azaciclotetracosan-2,5,8,11,14,17,20,23-octaona; 2,2'-(((((2R,5S,8R,11S,14R,17S,20R,23S)-5,11,17,23-tetraisobutil4,8,10,16,20,22-hexametil-3,6,9,12,15,18,21,24-octaoxo-1,7,13,19-tetraoxa4,10,16,22-tetra-azaciclotetracosan-2,14-diil)bis(metileno))bis(4,1 -fenileno))bis(metileno))bis(furan-3-carbonitrila); (3S,6R,9S,12R,15S,18R,21S,24R)-3,9,15,21-tetraisobutil-4,6,10,16,18,22hexametil-12,24-bis(4-(tiofen-3-ilmetil)benzil)-1,7,13,19-tetraoxa-4,10,16,22-tetraazaciclotetracosan-2,5,8,11,14,17,20,23-octaona;(3S,6R,9S,12R,15S,18R,21S,24R)-3,9,15,21-tetraisobutil-4,6,10,16,18,22hexametil-12,24-bis(4-(oxazol-4-ilmetil)benzil)-1,7,13,19-tetraoxa-4,10,16,22-tetraazaciclotetracosan-2,5,8,11,14,17,20,23-octaona; 4,4'-(((((2R,5S,8R,11S,14R,17S,20R,23S)-5,11,17,23-tetraisobutil4,8,10,16,20,22-hexametil-3,6,9,12,15,18,21,24-octaoxo-1,7,13,19-tetraoxa4,10,16,22-tetra-azaciclotetracosan-2,14-diil)bis(metileno))bis(4,1 -fenileno))bis(metileno))bis(furan-2-carbonitrila); (3S,6R,9S,12R,15S,18R,21S,24R)-3,9,15,21-tetraisobutil-6,18-bis(4-((6-metoxipiridin-2-il)metil)benzil)-4,10,12,16,22,24-hexametil-1,7,13,19-tetraoxa4,10,16,22-tetra-azaciclotetracosan-2,5,8,11,14,17,20,23-octaona; (3S,6R,9S,12R,15S,18R,21S,24R)-6,18-bis(4-((3-clorotiofen-2-il)metil)benzil)-3,9,15,21-tetraisobutil-4,10,12,16,22,24-hexametil-1,7,13,19-tetraoxa-4,10,16,22tetra-azaciclotetracosan-2,5,8,11,14,17,20,23-octaona;Petition 870260057804, de 15 / 06 / 2026, pág. 13 / 44 6 / 18 (3S,6R,9S,12R,15S,18R,21S,24R)-3,9,15,21-tetraisobutil-6,18-bis(4-((3-methoxythiophen-2-yl)metil)benzyl)-4,10,12,16,22,24-hexamethyl-1 ,7,13,19-tetraoxa-4,10,16,22tetra-azaciclotetracosan-2,5,8,11,14,17,20,23-octaona; (3S,6R,9S, 12R,15S,18R,21S,24R)-6,18-bis(4-((4-chlorothiazol-5-yl)metil)benzyl)-3,9,15,21-tetraisobutyl-4,10,12,1 6,22,24-hexametil-1,7,13,19-tetraoxa-4,10,16,22tetra-azaciclotetracosan-2,5,8,11,14,17,20,23-octaona; (3S,6R,9S, 12R,15S,18R,21S,24R)-6,18-bis(4-((5-fluoro-6-methoxypyridin-3yl)methyl)benzyl)-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa4,10,16,22-tetra-azacyclotetracosane-2,5,8,11,14,17,20,23-octaano; (3S,6R,9S,12R,15S,18R,21S,24R)-3,9,15,21-tetraisobutil-4,6,10,16,18,22hexametil-12,24-bis(4-((4-metil-1,2,3-ti adiazol-5-yl)metil)benzyl)-1,7,13,19-tetraoxa4,10,16,22-tetra-azaciclotetracosan-2,5,8,11,14,17,20,23-octaone;(3S,6R,9S,12R,15S,18R,21S,24R)-3,9,15,21-tetraisobutyl-6,18-bis(4-((6-methoxy-2-methylpyridin-3-yl)methyl)benzyl) -4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa4,10,16,22-tetra-azaciclotetracosan-2,5,8,11,14,17,20,23-octaona; (3S,6R,9S,12R,15S,18R,21S,24R)-3,9,15,21-tetraisobutyl-4,6,10,16,18,22hexamethyl-12,24-bis(4-((4-methylthiophen-2-yl)methyl)benzyl)-1,7,13,19-tetraoxa-4,10,16,22tetra-azacyclotetracosane-2,5,8,11,14,17,20,23-octaano; (3S,6R,9S,12R,15S,18R,21S,24R)-6,18-bis(4-((3-bromothiophen-2-yl)methyl)benzyl)-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22tetra-azacyclotetracosane-2,5,8,11,14,17,20,23-octaano; (3S,6R,9S,12R,15S,18R,21S,24R)-6-(4-((R)-(3-bromothiophen-2-yl)(hydroxy)methyl)benzyl)-18-(4-((S)-(3-bromothiophen-2-yl)(hydroxy)methyl)benzyl)-3,9,15,21-tetraisobutyl4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetra-azacyclotetracosane2,5,8,11,14,17,20,23-octaano;(3S,6R,9S,12R,15S,18R,21S,24R)-3,9,15,21-tetraisobutyl-6,18-bis(4-((6-methoxy-4-methylpyridin-3-yl)methyl)benzyl)-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxaPetição 870260057804, from 15 / 06 / 2026, pág. 14 / 44 7 / 18 4,10,16,22-tetra-azaciclotetracosan-2,5,8,11,14,17,20,23-octaona; (3S,6R,9S,12R,15S,18R,21S,24R)-3,9,15,21-tetraisobutyl-4,6,10,16,18,22hexamethyl-12,24-bis(4-(oxazol- 5-ylmethyl)benzyl)-1,7,13,19-tetraoxa-4,10,16,22-tetraazaciclotetracosan-2,5,8,11,14,17,20,23-octaona; (3S,6R,9S,12R,15S,18R,21S,24R)-3,9,15,21-tetraisobutyl-4,6,10,16,18,22hexamethyl-12,24-bis(4-((4-methylthiazol-5-yl)methyl)benzyl)-1,7,13,19-tetraoxa-4,10,16,22tetra-azacyclotetracosane-2,5,8,11,14,17,20,23-octaano; (3S,6R,9S,12R,15S,18R,21S,24R)-3,9,15,21-tetraisobutyl-6,18-bis(4-(isothiazol-5-ylmethyl)benzyl)-4,10,12 ,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetraazaciclotetracosan-2,5,8,11,14,17,20,23-octaona;(3S,6R,9S,12R,15S,18R,21S,24R)-3,9,15,21-tetraisobutyl-4,6,10,16,18,22hexamethyl-12,24-bis(4-((5-methylfuran-2-yl)methyl)benzyl)-1,7,13,19-tetraoxa-4,10,16,22tetra-azacyclotetracosane-2,5,8,11,14,17,20,23-octaano; (3S,6R,9S,12R,15S,18R,21S,24R)-6,18-bis(4-((2-ethoxypyridin-3-yl)methyl)benzyl)-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22tetra-azacyclotetracosane-2,5,8,11,14,17,20,23-octaano; (3S,6R,9S,12R,15S,18R,21S,24R)-6,18-bis(4-(furan-3-ylmethyl)benzyl)3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetra-azacyclotetracosane-2,5,8,11,14,17,20,23-octaano; (3S,6R,9S,12R,15S,18R,21S,24R)-6,18-bis(4-((2-(dimethylamino)pyridin-3yl)methyl)benzyl)-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa4,10,16,22-tetra-azacyclotetracosane-2,5,8,11,14,17,20,23-octaano;(3S,6R,9S,12R,15S,18R,21S,24R)-3,9,15,21-tetraisobutyl-4,6,10,16,18,22hexamethyl-12,24-bis(4-((2-morpholinopyrimidin-5-yl)methyl)benzyl)-1,7,13,19-tetraoxa4,10,16,22-tetra-azacyclotetracosane-2,5,8,11,14,17,20,23-octaano; (3S,6R,9S,12R,15S,18R,21S,24R)-3,9,15,21-tetraisobutyl-6,18-bis(4-((3-methoxypyrazin-2-yl)methyl)benzyl)-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxaPetição 870260057804, from 15 / 06 / 2026, pág. 15 / 44 8 / 18 4,10,16,22-tetra-azaciclotetracosan-2,5,8,11,14,17,20,23-octaona; (3S,6R,9S,12R,15S,18R,21S,24R)-6,18-bis(4-((5-fluoropyridin-3-yl)methyl)benzyl)-3,9,15,21-tetraisobutyl-4,1 0,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22tetra-azaciclotetracosan-2,5,8,11,14,17,20,23-octaona; (3S,6R,9S,12R,15S,18R,21S,24R)-3,9,15,21-tetraisobutyl-6,18-bis(4-(1-(6methoxypyridin-3-yl)ethyl)benzyl)-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa4,10,16,22-tetra-azacyclotetracosane-2,5,8,11,14,17,20,23-octaano;(3S,6R,9S,12R,15S,18R,21S,24R)-3,9,15,21-tetraisobutyl-6,18-bis(4-((2-methoxy-4-methylthiazol-5-yl)methyl)benzyl)-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa4,10,16,22-tetra-azacyclotetracosane-2,5,8,11,14,17,20,23-octaano; (3S,6R,9S,12R, 15S,18R,21S,24R)-3,9,15,21-tetraisobutyl-6,18-bis(4-((3-methoxypyridin-2-yl)methyl)benzyl)-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22tetra-azacyclotetracosane-2,5,8,11,14,17,20,23-octaano; (3S,6R,9S,12R,15S,18R,21S,24R)-3,9,15,21-tetraisobutyl-6,18-bis(4-((4-methoxypyrimidin-2-yl)methyl)benzyl)-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa4,10,16,22-tetra-azacyclotetracosane-2,5,8,11,14,17,20,23-octaano; (3S,6R,9S,12R,15S,18R,21S,24R)-3,9,15,21-tetraisobutyl-6,18-bis(4-((6-methoxypyrazin-2-yl)methyl)benzyl)-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa4,10,16,22-tetra-azacyclotetracosane-2,5,8,11,14,17,20,23-octaano;(3S,6R,9S,12R,15S,18R,21S,24R)-6,18-bis(4-(1-fluoro-1-(2-methoxypyridin-3yl)ethyl)benzyl)-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa4,10,16,22-tetra-azacyclotetracosane-2,5,8,11,14,17,20,23-octaano; (3S,6R,9S,12R,15S,18R,21S,24R)-3,9,15,21-tetraisobutil-4,6,10,16,18,22hexametil-12,24-bis(4-((4-metilpyri din-3-yl)methyl)benzyl)-1,7,13,19-tetraoxa-4,10,16,22tetra-azaciclotetracosan-2,5,8,11,14,17,20,23-octaone; (3S,6R,9S,12R,15S,18R,21S,24R)-6,18-bis(4-(1-fluoro-1-(6-methoxypyridin-2yl)ethyl)benzyl)-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxaPetition 870260057804, of 15 / 06 / 2026, pág. 16 / 44 9 / 18 4,10,16,22-tetra-azacyclotetracosane-2,5,8,11,14,17,20,23-octaone; (3S,6R,9S,12R,15S,18R,21S,24R)-3,9,15,21-tetraisobutil-6,18-bis(4-((4-isopropyl-1,2,3-thiadiazol-5-yl)metil)benzi l)-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa4,10,16,22-tetra-azaciclotetracosan-2,5,8,11,14,17,20,23-octaona;(3S,6R,9S,12R,15S,18R,21S,24R)-3,9,15,21-tetraisobutil-4,6,10,16,18,22hexametil-12,24-bis(4-((2-(trifluoromethyl )pyridin-3-yl)methyl)benzyl)-1,7,13,19-tetraoxa4,10,16,22-tetra-azaciclotetracosan-2,5,8,11,14,17,20,23-octaone; (3S,6R,9S,12R,15S,18R,21S,24R)-6,18-bis(4-((2,6-dimethylpyridin-3-yl)metil)benzil)-3,9,15,21 -tetraisobutil-4,10,12,16,22,24-hexametil-1,7,13,19-tetraoxa4,10,16,22-tetra-azaciclotetracosan-2,5,8,11,14,17,20,23-octaona; (3S,6R,9S,12R,15S,18R,21S,24R)-3,9,15,21-tetraisobutyl-4,6,10,16,18,22hexamethyl-12,24-bis(4-((5-methyl-1H-pyrazol-4-yl)methyl)benzyl)-1,7,13,19-tetraoxa4,10,16,22-tetra-azacyclotetracosane-2,5,8,11,14,17,20,23-octaano; (3S,6R,9S, 12R,15S,18R,21S,24R)-6,18-bis(4-(1-fluoro-1-(5-methoxypyrazin-2yl)ethyl)benzyl)-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa4,10,16,22-tetra-azacyclotetracosane-2,5,8,11,14,17,20,23-octaano;(3S,6R,9S, 12R,15S,18R,21S,24R)-6,18-bis(4-((1-ethyl-1H-pyrazol-5-yl)methyl)benzyl)-3,9,15,21 -tetraisobutyl-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa4,10,16,22-tetra-azacyclotetracosane-2,5,8,11,14,17,20,23-octaano; (3S,6R,9S,12R,15S,18R,21S,24R)-3,9,15,21-tetraisobutil-6,18-bis(4-(isothiazol-4-ylmetil)benzil)-4,10,12 ,16,22,24-hexametil-1,7,13,19-tetraoxa-4,10,16,22-tetraazaciclotetracosan-2,5,8,11,14,17,20,23-octaona; (3S,6R,9S,12R,15S,18R,21S,24R)-6,18-bis(4-((6-hydroxypyridin-3-yl)(methoxy)methyl)benzyl)-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetra-azacyclotetracosane-2,5,8,11,14,17,20,23-octaane; (3S,6R,9S,12R,15S,18R,21S,24R)-3,9,15,21-tetraisobutyl-6,18-bis(4-(1-(2methoxypyridin-3-yl)ethyl)benzyl)-4,10,12,16,22,24-hexametil-1,7,13,19-tetraoxaPetição 870260057804, de 15 / 06 / 2026, pág. 17 / 44 10 / 18 4,10,16,22-tetra-azaciclotetracosan-2,5,8,11,14,17,20,23-octaona;(3S,6R,9S,12R,15S,18R,21S,24R)-6,18-bis(4-((1-cyclopropyl-1H-pyrazol-5yl)methyl)benzyl)-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa4,10,16,22-tetra-azacyclotetracosane-2,5,8,11,14,17,20,23-octaano; (3S,6R,9R,12R,15R,18R,21S,24S)-3,9,15,21-tetraisobutil-4,6,10,16,18,22hexametil-12,24-bis[[4-[(2-metil-3-pi ridil)metil]fenil]metil]-1,7,13,19-tetraoxa4,10,16,22-tetra-azaciclotetracosan-2,5,8,11,14,17,20,23-octaone; (3R,6R,9R,12R,15S,18S,21S,24R)-3,9,15,21-tetraisobutyl-6,18-bis(4-((5-methoxypyrazin-2-yl)methyl)benzyl)-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa4,10,16,22-tetra-azacyclotetracosane-2,5,8,11,14,17,20,23-octaano; (3S,6R,9S,12R,15S,18R,21S,24R)-6,18-bis(4-((1-(cyclopropylmethyl)-1H-pyrazol-5-yl)methyl)benzyl)-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetra-azacyclotetracosane-2,5,8,11,14,17,20,23-octaano;(3S,6R,9S,12R,15S,18R,21S,24R)-3,9,15,21-tetraisobutyl-6,18-bis(4-((4-methoxypyridin-3-yl)methyl)benzyl)-4,1 0,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa4,10,16,22-tetra-azaciclotetracosan-2,5,8,11,14,17,20,23-octaona; (3S,6R,9S,12R,15S,18R,21S,24R)-3,9,15,21-tetraisobutyl-6,18-bis(4-((4-isopropylpyrimidin-5-yl)methyl)benzyl)-4 ,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa4,10,16,22-tetra-azaciclotetracosan-2,5,8,11,14,17,20,23-octaona; (3S,6R,9S, 12R,15S,18R,21S,24R)-6,18-bis(4-((3-cyclopropylisoxazol-5-yl)methyl)benzyl)-3,9,15,21 -tetraisobutyl-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa4,10,16,22-tetra-azacyclotetracosane-2,5,8,11,14,17,20,23-octaano; (3S,6R,9S, 12R,15S,18R,21S,24R)-6-(4-((R)-fluoro(thiazol-2-yl)methyl)benzyl)-18(4-((S)-fluoro(thiazol-2-yl)methyl)benzyl)-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetra-azacyclotetracosane-2,5,8,11,14,17,20,23-octaano;(3S,6R,9S,12R,15S,18R,21S,24R)-6,18-bis(4-((1-(2-fluoroetil)-1H-pirazol-4 Petição 870260057804, de 15 / 06 / 2026, pág. 18 / 44 11 / 18 il)metil)benzil)-3,9,15,21-tetraisobutil-4,10,12,16,22,24-hexametil-1,7,13,19-tetraoxa4,10,16,22-tetra-azaciclotetracosan-2,5,8,11,14,17,20,23-octaona; (3S,6R,9S,12R,15S,18R,21S,24R)-6,18-bis(4-((6-(difluorometil)piridin-3il)metil)benzil)-3,9,15,21-tetraisobutil-4,10,12,16,22,24-hexametil-1,7,13,19-tetraoxa4,10,16,22-tetra-azaciclotetracosan-2,5,8,11,14,17,20,23-octaona; (3S,6R,9S,12R,15S,18R,21S,24R)-3,9,15,21-tetraisobutil-4,6,10,16,18,22hexametil-12,24-bis(4-((4-metilisotiazol-5-il)metil)benzil)-1,7,13,19-tetraoxa4,10,16,22-tetra-azaciclotetracosan-2,5,8,11,14,17,20,23-octaona; (3S,6R,9S,12R,15S,18R,21S,24R)-6,18-bis(4-((4-ciclopropilpirimidin-5-il)metil)benzil)-3,9,15,21 -tetraisobutil-4,10,12,16,22,24-hexametil-1,7,13,19-tetraoxa4,10,16,22-tetra-azaciclotetracosan-2,5,8,11,14,17,20,23-octaona;(3S,6R,9S,12R,15S,18R,21S,24R)-6,18-bis(4-((2-(difluoromethyl)pyridin-3yl)methyl)benzyl)-3,9,15,21-tetraisobutyl -4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa4,10,16,22-tetra-azaciclotetracosan-2,5,8,11,14,17,20,23-octaona; (3S,6R,9S,12R,15S,18R,21S,24R)-3,9,15,21-tetraisobutyl-4,6,10,16,18,22hexamethyl-12,24-bis(4-((R)-1 -(thiazol-2-yl)ethyl)benzyl)-1,7,13,19-tetraoxa-4,10,16,22-tetra-azacyclotetracosane-2,5,8,11,14,17,20,23-octaano; (3S,6R,9S,12R,15S,18R,21S,24R)-3,9,15,21-tetraisobutyl-4,6,10,16,18,22hexamethyl-12,24-bis(4-((2-morpholinopyridin-4-yl)methyl)benzyl)-1,7,13,19-tetraoxa4,10,16,22-tetra-azacyclotetracosane-2,5,8,11,14,17,20,23-octaano; (3S, 6R, 9S, 12R,15S,18R,21S,24R)-6,18-bis(4-((5-fluoro-2-methoxypyridin-3yl)methyl)benzyl)-3,9,15,21-tetraisobutyl-4,10 ,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa4,10,16,22-tetra-azaciclotetracosan-2,5,8,11,14,17,20,23-octaona;(3S,6R,9S,12R,15S,18R,21S,24R)-3,9,15,21-tetraisobutyl-4,6,10,16,18,22hexamethyl-12,24-bis(4-((4-methylpyrimidin-5-yl)methyl)benzyl)-1,7,13,19-tetraoxa4,10,16,22-tetra-azacyclotetracosane-2,5,8,11,14,17,20,23-octaano; (3S,6R,9S,12R,15S,18R,21S,24R)-6,18-bis(4-((4-(difluoromethyl)pyridine-3Petição 870260057804, of 15 / 06 / 2026, pág. 19 / 44 12 / 18 yl)methyl)benzyl)-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa4,10,16,22-tetra-azaciclotetracosan-2,5,8,11,14,17,20,23-octaone; (3S,6R,9S,12R,15S,18R,21S,24R)-6,18-bis(4-((2-cyclopropylpyridin-3-yl)methyl)benzyl)-3,9,15,21 -tetraisobutyl-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa4,10,16,22-tetra-azacyclotetracosane-2,5,8,11,14,17,20,23-octaano; (3S,6R,9S,12R,15S,18R,21S,24R)-6,18-bis(4-((2-(difluoromethoxy)pyridin-3yl)methyl)benzyl)-3,9,15,21-tetraisobutyl -4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa4,10,16,22-tetra-azaciclotetracosan-2,5,8,11,14,17,20,23-octaona;3,3'-(((((2R,5S,8R,11S,14R,17S,20R,23S)-5,11,17,23-tetraisobutil4,8,10,16,20,22-hexametil-3,6,9,12,15,18,21,24-octaoxo-1,7,13,19-tetraoxa4,10,16,22-tetra-azaciclotetracosan-2,14-diil)bis(metileno))bis(4,1 -fenileno))bis(metileno))di-isonicotinonitrila; (3S,6R,9S,12R,15S,18R,21S,24R)-3,9,15,21-tetraisobutil-4,6,10,16,18,22hexametil-12,24-bis(4-((2-(metiltio)piridin-3-il)metil)benzil)-1,7,13,19-tetraoxa4,10,16,22-tetra-azaciclotetracosan-2,5,8,11,14,17,20,23-octaona; (3S,6R,9S,12R,15S,18R,21S,24R)-6-(4-((3-fluoropiridin-4-il)metil)benzil)3,9,15,21-tetraisobutil-4,10,12,16,22,24-hexametil-18-(4-((3-metilpiridin-4-il)metil)benzil)-1,7,13,19-tetraoxa-4,10,16,22-tetra-azaciclotetracosan2,5,8,11,14,17,20,23-octaona; (3S,6R,9S,12R,15S,18R,21S,24R)-6,18-bis(4-((4-etilpirimidin-5-il)metil)benzil)-3,9,15,21-tetraisobutil-4,10,12,16,22,24-hexametil-1,7,13,19-tetraoxa-4,10,16,22tetra-azaciclotetracosan-2,5,8,11,14,17,20,23-octaona;(3S,6R,9S,12R,15S,18R,21S,24R)-6,18-bis(4-((6-fluoropiridin-2-il)metil)benzil)-3,9,15,21-tetraisobutil-4,10,12,16,22,24-hexametil-1,7,13,19-tetraoxa-4,10,16,22tetra-azaciclotetracosan-2,5,8,11,14,17,20,23-octaona; (3S,6R,9S,12R,15S,18R,21S,24R)-3,9,15,21-tetraisobutil-4,6,10,16,18,22hexametil-12,24-bis(4-((4-(trifluorometil)pirimidin-5-il)metil)benzil)-1,7,13,19-tetraoxaPetição 870260057804, de 15 / 06 / 2026, pág. 20 / 44 13 / 18 4,10,16,22-tetra-azaciclotetracosan-2,5,8,11,14,17,20,23-octaona; (3S,6R,9S,12R,15S,18R,21S,24R)-6,18-bis(4-((2-cloropiridin-3-il)metil)benzil)-3,9,15,21-tetraisobutil-4,10,12,16,22,24-hexametil-1,7,13,19-tetraoxa-4,10,16,22tetra-azaciclotetracosan-2,5,8,11,14,17,20,23-octaona; (3S,6R,9S,12R,15S,18R,21S,24R)-6,18-bis(4-((4-(difluorometil)pirimidin-5il)metil)benzil)-3,9,15,21-tetraisobutil-4,10,12,16,22,24-hexametil-1,7,13,19-tetraoxa4,10,16,22-tetra-azaciclotetracosan-2,5,8,11,14,17,20,23-octaona;(3S,6R,9S, 12R,15S,18R,21S,24R)-6,18-bis(4-((6-fluoro-4-metilpiridin-3il)metil)benzil)-3,9,15,21-tetraisobutil-4,10,12,16,22,24-hexametil-1,7,13,19-tetraoxa4,10,16,22-tetra-azaciclotetracosan-2,5,8,11,14,17,20,23-octaona; (3S,6R,9S,12R,15S,18R,21S,24R)-6,18-bis(4-((2-fluoropiridin-3-il)metil)benzil)-3,9,15,21-tetraisobutil-4,10,12,16,22,24-hexametil-1,7,13,19-tetraoxa-4,10,16,22tetra-azaciclotetracosan-2,5,8,11,14,17,20,23-octaona; (3S,6R,9S,12R,15S,18R,21S,24R)-6,18-bis(4-((2,5-difluoropiridin-3-il)metil)benzil)-3,9,15,21 -tetraisobutil-4,10,12,16,22,24-hexametil-1,7,13,19-tetraoxa4,10,16,22-tetra-azaciclotetracosan-2,5,8,11,14,17,20,23-octaona; (3S,6R,9S,12R,15S,18R,21S,24R)-6,18-bis(4-((2,3-difluoropiridin-4-il)metil)benzil)-3,9,15,21 -tetraisobutil-4,10,12,16,22,24-hexametil-1,7,13,19-tetraoxa4,10,16,22-tetra-azaciclotetracosan-2,5,8,11,14,17,20,23-octaona;(3S,6R,9S,12R,15S,18R,21S,24R)-6,18-bis(4-((2-bromopyridin-3-yl)methyl)benzyl)-3,9,15,21-tetraisobutyl-4,10 ,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22tetra-azacyclotetracosan-2,5,8,11,14,17,20,23-octaone; (3S,6R,9S, 12R,15S,18R,21S,24R)-6,18-bis(4-((5-chloro-2-methoxypyridin-3yl)methyl)benzyl)-3,9,15,21-tetraisobutyl-4,10, 12,16,22,24-hexamethyl-1,7,13,19-tetraoxa4,10,16,22-tetra-azacyclotetracosan-2,5,8,11,14,17,20,23-octaone; (3S,6R,9S,12R,15S,18R,21S,24R)-3,9,15,21-tetraisobutyl-4,6,10,16,18,22-hexamethyl-12,24-bis(4-((4-(trifluoromethyl)pyridin-3-yl)methyl)benzyl)-1,7,13,19-tetraoxaPetition 870260057804, dated 06 / 15 / 2026, page 21 / 44 14 / 18 4,10,16,22-tetra-azacyclotetracosan-2,5,8,11,14,17,20,23-octaone; and (3S,6R,9S,12R,15S,18R,21S,24R)-6,18-bis(4-((2,3-dimethoxypyridin-4-yl)methyl)benzyl)-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa4,10,16,22-tetra-azacyclotetracosan-2,5,8,11,14,17,20,23-octaone, and veterinary acceptable salts thereof.

8. Compound CHARACTERIZED by the fact that it is a compound of Formula (2A1) or Formula (4A): (R)n wherein Ring B is selected from the group consisting of pyrrolyl, thiophenyl, furanyl, thiazolyl, oxazolyl, pyrazolyl, pyridinyl, isothiazolyl, isoxazolyl, benzofuranyl and indazolyl; and wherein Ring B is linked to the methylene carbon by a carbon atom of the ring; and wherein each (R)n is selected independently from the group consisting of methyl, ethyl, isopropyl, propyl, isobutyl, fluorine, chlorine, bromine, cyano, hydroxyl, -NH2, NHCH3, -N(CH3)2, -N(CH2CH3)2, methoxy, ethoxy, isopropoxy, -CF3, -CHF2, -CH2CH2F, CH2CF3, cyclopropyl, cyclobutyl, -CH2cyclopropyl, -OCHF2, -OCF3, -OCH2CF3, C(CH3)2OH, -SCH3, -S(O)2CH3 and morpholinyl; and wherein each Rc and Rd is independently H, F, Cl, methyl, ethyl, isopropyl, -CF3, methoxy, ethoxy, isopropoxy, cyclopropyl, Petition 870260057804, dated 15 / 06 / 2026, page 22 / 44 15 / 18 N(CH2CH3)2 and hydroxyl; and veterinary acceptable salts thereof.

9. Compound according to claim 8, CHARACTERIZED in that it is a compound of Formula (2A1) selected from the group consisting of: (3S,6R,9S,12R,15S,18R,21S,24R)-6-benzyl-18-(4-benzylbenzyl)-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetra-azacyclotetracosan-2,5,8,11,14,17,20,23-octaone; (3S,6R,9S,12R,15S,18R,21S,24R)-6-benzyl-18-(4-(4-fluorobenzyl)benzyl)3,9,15,21-tetraisobutyl-4,10,12,1 6,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetra-azacyclotetracosan-2,5,8,11,14,17,20,23-octaone; (3S,6R,9S,12R,15S,18R,21S,24R)-6-benzyl-18-(4-((diethylamino)(3,4-difluorophenyl)methyl)benzyl)-3,9,15,21-tetraisobut yl-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetra-azacyclotetracosan-2,5,8,11,14,17,20,23-octaone;(3S,6R,9S,12R,15S,18R,21S,24R)-6-benzyl-18-(4-((3,4-difluorophenyl)(methoxy)methyl)benzyl)-3,9,15,21-tetraisobutyl -4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetra-azacyclotetracosan-2,5,8,11,14,17,20,23-octaone; and (3S,6R,9S,12R,15S,18R,21S,24R)-6-benzyl-18-(4-((3,4-difluorophenyl)(ethoxy)methyl)benzyl)-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetra-azacyclotetracosan-2,5,8,11,14,17,20,23-octaone; and veterinary acceptable salts thereof; or a compound of Formula (4A) selected from the group consisting of: (3S,6R,9S,12R,15S,18R,21S,24R)-6-(4-((1H-indazol-6-yl)methyl)benzyl)-18benzyl-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa4,10,16,22-tetra-azacyclotetracosan-2,5,8,11,14,17,20,23-octaone;(3S,6R,9S,12R,15S,18R,21S,24R)-6-benzil-18-(4-((2,4-dimetil-1H-pirrol-3il)metil)benzil)-3,9,15,21-tetraisobutil-4,10,12,16,22,24-hexametil-1,7,13,19-tetraoxa4,10,16,22-tetra-azaciclotetracosan-2,5,8,11,14,17,20,23-octaona; Petição 870260057804, de 15 / 06 / 2026, pág. 23 / 44 16 / 18 (3S,6R,9S, 12R,15S,18R,21S,24R)-6-(4-(benzofuran-3-il(hidroxi)metil)benzil)18-benzil-3,9,15,21-tetraisobutil-4,10,12,16,22,24-hexametil-1,7,13,19-tetraoxa4,10,16,22-tetra-azaciclotetracosan-2,5,8,11,14,17,20,23-octaona; (3S,6R,9S,12R,15S,18R,21S,24R)-6-benzil-3,9,15,21-tetraisobutil4,10,12,16,22,24-hexametil-18-(4-(oxazol-2-ilmetil)benzil)-1,7,13,19-tetraoxa4,10,16,22-tetra-azaciclotetracosan-2,5,8,11,14,17,20,23-octaona; (3S,6R,9S,12R,15S,18R,21S,24R)-6-benzil-18-(4-(furan-2-ilmetil)benzil)3,9,15,21-tetraisobutil-4,10,12,16,22,24-hexametil-1,7,13,19-tetraoxa-4,10,16,22-tetra-azaciclotetracosan-2,5,8,11,14,17,20,23-octaona;(3S,6R,9S,12R,15S,18R,21S,24R)-6-benzyl-3,9,15,21-tetraisobutyl4,10,12,16,22,24-hexamethyl-18-(4-((3-methylthiophen-2-yl)methyl)benzyl)-1,7,13,19-tetraoxa4,10,16,22-tetra-azacyclotetracosane-2,5,8,11,14,17,20,23-octaano; 2-(4-((((2R,5S,8R,11S,14R,17S,20R,23S)-14-benzyl-5,11,17,23-tetraisobutyl4,8,10,16,20,22-hexamethyl-3,6,9,12,15,18,21,24-octaoxo-1,7,13,19-tetraoxa4,10,16,22-tetra-azacyclotetracosan-2-yl)methyl)benzyl)furan-3-carbonitrile; (3S,6R,9S,12R,15S,18R,21S,24R)-6-benzyl-3,9,15,21-tetraisobutyl4,10,12,16,22,24-hexamethyl-18-(4-(thiophen-3-ylmethyl)benzyl)-1,7,13,19-tetraoxa4,10,16,22-tetra-azacyclotetracosane-2,5,8,11,14,17,20,23-octaano; (3S,6R,9S,12R,15S,18R,21S,24R)-6-benzyl-3,9,15,21-tetraisobutyl4,10,12,16,22,24-hexamethyl-18-(4-((1 -methyl-1 H-pyrazol-5-yl)methyl)benzyl)-1,7,13,19-tetraoxa-4,10,16,22-tetra-azaciclotetracosan-2,5,8,11,14,17,20,23-octaona;(3S,6R,9S, 12R,15S,18R,21S,24R)-6-benzil-18-(4-((3-clorotiofen-2-il)metil)benzil)-3,9,15,21 -tetraisobutil-4,10,12,16,22,24-hexametil-1,7,13,19-tetraoxa4,10,16,22-tetra-azaciclotetracosan-2,5,8,11,14,17,20,23-octaona; (3S,6R,9S,12R,15S,18R,21S,24R)-6-benzil-3,9,15,21-tetraisobutil-18-(4-((3metoxitiofen-2-il)metil)benzil)-4,10,12,16,22,24-hexametil-1,7,13,19-tetraoxa4,10,16,22-tetra-azaciclotetracosan-2,5,8,11,14,17,20,23-octaona; Petição 870260057804, de 15 / 06 / 2026, pág. 24 / 44 17 / 18 (3S,6R,9S, 12R,15S,18R,21S,24R)-6-benzil-18-(4-((4-clorotiazol-5-il)metil)benzil)-3,9,15,21 -tetraisobutil-4,10,12,16,22,24-hexametil-1,7,13,19-tetraoxa4,10,16,22-tetra-azaciclotetracosan-2,5,8,11,14,17,20,23-octaona; (3S,6R,9S, 12R,15S,18R,21S,24R)-6-benzil-18-(4-((3,5-dimetilisoxazol-4il)metil)benzil)-3,9,15,21-tetraisobutil-4,10,12,16,22,24-hexametil-1,7,13,19-tetraoxa4,10,16,22-tetra-azaciclotetracosan-2,5,8,11,14,17,20,23-octaona;(3S,6R,9S,12R,15S,18R,21S,24R)-6-benzyl-3,9,15,21-tetraisobutyl-18-(4-((6methoxy-2-methylpyridin-3-yl)methyl)benzyl)-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa4,10,16,22-tetra-azacyclotetracosane-2,5,8,11,14,17,20,23-octaano; (3S,6R,9S,12R,15S,18R,21S,24R)-6-benzyl-3,9,15,21-tetraisobutyl-18-(4-((6methoxy-4-methylpyridin-3-yl)methyl)benzyl)-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa4,10,16,22-tetra-azacyclotetracosane-2,5,8,11,14,17,20,23-octaano; (3S,6R,9S,12R,15S,18R,21S,24R)-3,9,15,21-tetraisobutyl-4,6,10,16,18,22hexamethyl-12,24-bis(4-((2-methylpyridin-3-yl)methyl)benzyl)-1,7,13,19-tetraoxa-4,10,16,22tetra-azacyclotetracosane-2,5,8,11,14,17,20,23-octaano; e (3S,6R,9S,12R,15S,18R,21S,24R)-3,9,15,21-tetraisobutyl-4,6,10,16,18,22hexamethyl-12,24-bis(4-((4-methylisothi azol-5-yl)methyl)benzyl)-1,7,13,19-tetraoxa4,10,16,22-tetra-azaciclotetracosan-2,5,8,11,14,17,20,23-octaona; and sais veterinamente aceitáveis ​​do mesmo.; 10. Composition CHARACTERIZED in that it comprises a compound, as defined in any one of claims 1 to 9, and veterinary acceptable salts thereof, and in that the composition further comprises a veterinary acceptable excipient.

11. Use of a compound, as defined in any one of claims 1 to 9, and veterinary acceptable salts thereof, CHARACTERIZED in that it is for the manufacture of a medicament to treat or prevent a parasitic infection in an animal. Petition 870260057804, dated 06 / 15 / 2026, page 25 / 44 18 / 18 12. Use according to claim 11, CHARACTERIZED in that the parasitic infection is an endoparasitic infection and the animal is a domestic animal; and in that the compound is formulated to be administered orally, topically or parenterally.