COMPOSIÇÕES FARMACÊUTICAS COMPREENDENDO COMPOSTOS INIBIDORES DE PEQUENAS MOLÉCULAS DA FUNÇÃO DE SLC6A19 DE MAMÍFEROS

Description

Pharmaceutical compositions comprising compounds that inhibit small molecule SLC6A19 function in mammals. Separated from BR112023018277-8, filed on March 9, 2022. RELATED ORDERS

[001] This application claims the benefit of priority from U.S. Provisional Patent Applications serial numbers 63 / 308,790, filed February 10, 2022; 63 / 292,815, filed December 22, 2021; 63 / 234,487, filed August 18, 2021; 63 / 226,551, filed July 28, 2021; and 63 / 159,271, filed March 10, 2021. BACKGROUND

[002] Phenylketonuria (PKU) is an inborn error of metabolism caused by mutations in phenylalanine hydroxylase (PAH), the enzyme responsible for metabolizing phenylalanine. PKU is an autosomal recessive metabolic disorder in which phenylalanine is not properly metabolized, resulting in abnormally high plasma phenylalanine levels. People with PKU have abnormally high blood levels of phenylalanine, which, if left untreated, can lead to irreversible neurological damage, resulting in a spectrum of complications such as intellectual disabilities, seizures, neurodevelopmental and behavioral disorders. PKU is difficult to treat because blood phenylalanine levels are directly related to diet. Patients must adhere to a lifelong and strict diet that affects all aspects of their lives.The current standard of care is enzyme cofactor and enzyme replacement therapy, but these therapies are not effective in all patients and carry a potential risk of adverse events.

[003] The enzyme responsible for metabolizing phenylalanine and, Petition 870260063816, dated 06 / 29 / 2026, page 9 / 739 2 / 315 Thus, maintaining phenylalanine homeostasis is the responsibility of phenylalanine hydroxylase (PAH). Loss-of-function (LOF) mutations in the PAH gene on chromosome 12q23.2 are known to cause most forms of PKU. These LOF mutations that result in PKU can be diagnosed as classic PKU (the most severe form) and mild or hyperfebrile PKU, a less severe form. In addition to PAH, mutations in other enzymes that affect phenylalanine metabolism, such as dihydropteridine reductase (DHPR), the enzyme responsible for the synthesis of cofactors required for PAH activity, can also result in elevated phenylalanine levels. Besides diet, blood amino acid levels, including phenylalanine levels, are regulated by SLC6A19. SLC6A19 is located in the proximal tubule of the kidney and is responsible for the reabsorption of amino acids back into the blood. SUMMARY

[004] The present invention relates to compounds, compositions and methods useful for treating or preventing a disease or disorder associated with abnormal amino acid levels by modulating SLC6A19 transport.

[005] Therefore, a compound with the structure of Formula (I) is provided in this document: in which: n is 0, 1, or 2; Li is absent or selected from among -alkyl-, -hydroxyalkyl, -cycloalkyl- and -heteroaryl-CH2-; L2 is absent or is -CH2-; Petition 870260063816, dated 06 / 29 / 2026, p. 10 / 739 3 / 315 l_3 is missing or is -C(O)-; Xi and X2 are independently selected from -H, alkyl, haloalkyl, cycloalkyl, alkyl-cycloalkyl and heterocyclyl; provided that Xi and X2 are not both -H; Yi is selected from among aryla and heteroaryla; Y 2 is selected from alkyl, alkenyl, alkynyl, alkoxy, alkoxyalkyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -NH (Y2') and -N(Y2'') 2; Y 2' is selected from -H, -OH, alkyl, alkoxy, alkoxyalkyl and cycloalkyl; each Y2'' is alkyl, or both cases taken together with the nitrogen atom to which they are attached form a 5- or 6-membered heterocycline; and Y3, Y4, Y5 and Y6 are independently selected from -H, -OH, halide, alkyl, haloalkyl and alkoxy; provided that Y3 and Y4 or Y5 and Y6 are not both -OH; when _3 is -C(O)-, then Y2 is not aryl; and the compound is not selected from: Petition 870260063816, dated 06 / 29 / 2026, p. 11 / 739 4 / 315 or a pharmaceutically acceptable salt thereof.

[006] Another aspect of the invention relates to methods of treating or preventing a disease or disorder associated with a genetic defect in phenylalanine hydroxylase in an individual in need thereof, comprising administering to the individual an effective amount of a compound of Formula (I).

[007] Another aspect of the invention relates to methods of treating or preventing phenylketonuria, hyperphenylalaninemia, tyrosinemia, nonketotic hyperglycinemia, isovaleric acidemia, methylmalonic acidemia, propionic acidemia, maple syrup urine disease, DNAJC12 deficiency, urea cycle disorders or hyperammonemia in an individual in need thereof, comprising administering to the individual an effective amount of a compound of Formula (I).

[008] Another aspect of the invention relates to methods of modulating the transport of SLC6A19 in an individual in need thereof, comprising administering to the individual an effective amount of a compound of Formula (I).

[009] Unless otherwise defined, all technical and scientific terms used in this document have the same meaning as commonly understood by a person skilled in the art to which this invention pertains. Although methods and materials similar or equivalent to those described in this document may be used in the practice or testing of the present invention, suitable methods and materials are described below. All publications, patent applications, patents and other references mentioned in this document are incorporated by reference in their entirety. In case of conflict, this descriptive report, including definitions, shall serve as the basis for control. Furthermore, the materials, methods and examples are for illustrative purposes only and are not intended to be a factor. Petition 870260063816, dated 06 / 29 / 2026, page 12 / 739 5 / 315 limiting.

[0010] Other features, objects and advantages of the invention will be evident from the detailed description and claims. BRIEF DESCRIPTION OF THE DRAWINGS

[0011] FIG. 1 is a table summarizing the isoleucine transport data for exemplary compounds of the invention. A = IC50 <500 nM; B = IC50 500 nM - 1500 nM; C = IC50 1500 nM - 5000 nM; D = IC50 5000 nM - 10000 nM; E = IC50 >10000 nM.

[0012] FIG. 2 is a table summarizing isoleucine transport data for additional exemplary compounds of the invention. A = IC50 <500 nM; B = IC50 500 nM - 1,500 nM; C = IC50 1,500 nM - 5,000 nM; D = IC50 5,000 nM - 10,000 nM; and E = IC50 >10,000 nM.

[0013] FIG. 3 is a table summarizing isoleucine transport data for additional exemplary compounds of the invention. A = IC50 <500 nM; B = IC50 500 nM - 1,500 nM; C = IC50 1,500 nM - 5,000 nM; D = IC50 5,000 nM - 10,000 nM; and E = IC50 >10,000 nM. DETAILED DESCRIPTION Definitions

[0014] For convenience, before further description of the present invention, certain terms employed in the descriptive report, examples and claims in the appendix are collected herein. These definitions should be read in the light of the remainder of the disclosure and as understood by a person skilled in the art. Unless defined otherwise, all technical and scientific terms used in this document have the same meaning as commonly understood by a person skilled in the art.

[0015] In order for the present invention to be more easily understood, certain terms and phrases are defined below and throughout the descriptive report.

[0016] The articles "a" and "an" are used in this document to Petition 870260063816, dated 06 / 29 / 2026, page 13 / 739 6 / 315 refers to one or more (i.e., at least one) of the grammatical object of the article. For example, an element means one element or more than one element.

[0017] The phrase "and / or," as used in this document, in the descriptive report, and in the claims, should be understood as one or both of the elements together, that is, elements that are present conjuncturally in some cases and present disjunctively in other cases. Multiple elements listed with "and / or" should be interpreted in the same way, that is, one or more of the elements thus joined together. Other elements may optionally be present in addition to the elements specifically identified by the "and / or" clause, whether or not they are related to those specifically identified elements.Thus, as a non-limiting example, a reference to A and / or B, when used in conjunction with open language, such as "to understand," can refer, in one way, to only A (optionally including elements other than B); in another way, to only B (optionally including elements other than A); in yet another way, to both A and B (optionally including other elements); etc.

[0018] As used in this document, in the descriptive report and in the claims, "or" should be understood as having the same meaning as "and / or" as defined above. For example, when separating items in a list, "or" or "and / or" should be interpreted as being inclusive, that is, including at least one, but also including more than one, of a series or list of elements, and optionally, of additional unlisted items. Only terms clearly indicated to the contrary, such as "only one of" or "exactly one of," or, when used in the claims, "consisting of," refer to the inclusion of exactly one element of Petition 870260063816, dated 06 / 29 / 2026, page 14 / 739 7 / 315 a series or list of elements. In general, the term "or," as used in this document, should only be interpreted as indicating exclusive alternatives (i.e., one or the other, but not both) when preceded by terms of exclusivity, such as "either... or...", "one of," "only one of," or "exactly one of." Consisting essentially of, when used in the claims, should have its common meaning as used in the field of patent law.

[0019] As used in this document, in the descriptive report and in the claims, the phrase "at least one," in reference to a list of one or more elements, should be understood as meaning at least one element selected from any one or more of the elements in the list of elements, but not necessarily including at least one of each element specifically listed in the list of elements and not excluding any combinations of elements in the list of elements. This definition also allows for the optional presence of elements other than the elements specifically identified in the list of elements to which the phrase "at least one" refers, whether or not they are related to those specifically identified elements.Thus, as a non-limiting example, at least one of A and B (or, equivalently, at least one of A or B or, equivalently, at least one of A and / or B) may refer, in one embodiment, to at least one, optionally including more than one, A, without B present (and optionally including elements other than B); in another embodiment, to at least one, optionally including more than one, B, without A present (and optionally including elements other than A); in yet another embodiment, to at least one, optionally including more than one, A, and at least one, optionally including more than one, B (and optionally including other elements); etc.

[0020] It should also be understood that, unless it is Petition 870260063816, dated 06 / 29 / 2026, p. 15 / 739 8 / 315 clearly stating otherwise, in any methods claimed in this document that include more than one step or act, the order of the steps or acts of the method is not necessarily limited to the order in which the steps or acts of the method are recited.

[0021] In the claims, as well as in the preceding descriptive report, all transitional phrases, such as comprising, including, carrying, having, containing, involving, holding, composed of and the like, shall be understood as being broad, that is, meaning to include, but not be limited to. Only the transitional phrases consisting of and consisting essentially of shall be closed or semi-closed transitional phrases, respectively, as set forth in the United States Patent Examination Procedures Manual, section 2111.03.

[0022] Certain compounds contained in the compositions of the present invention may exist in particular geometric or stereoisomeric forms. Furthermore, the polymers of the present invention may also be optically active. The present invention contemplates all such compounds, including cis- and trans-isomers, R- and S-enantiomers, diastereomers, (d)-isomers, (l)-isomers, racemic mixtures thereof, and other mixtures thereof, as falling within the scope of the invention. Additional asymmetric carbon atoms may be present in a substituent, such as an alkyl group. All such isomers, as well as mixtures thereof, are intended to be included in this invention.

[0023] Geometric isomer means isomers that differ in the orientation of the substituent atoms with respect to a carbon-carbon double bond, a cycloalkyl ring, or a bridging bicyclic system. The atoms (except H) on each side of a carbon-carbon double bond can be in an E configuration (the substituents are on opposite sides of the carbon-carbon double bond) or Z configuration (the substituents are on opposite sides of the carbon-carbon double bond). Petition 870260063816, dated 06 / 29 / 2026, page 16 / 739 9 / 315 substituents are oriented on the same side). R, S, S*, R*, E, Z, cis and trans indicate configurations relative to the central molecule. Certain disclosed compounds may exist in atropisomeric forms or as atropisomers. Atropisomers are stereoisomers resulting from hindered rotation around single bonds, where the steric deformation barrier to rotation is high enough to allow isolation of the conformers. The compounds of the invention can be prepared as individual isomers either by specific isomer synthesis or resolved from a mixture of isomers.Conventional resolution techniques include forming the salt of a free base from each isomer of an isomeric pair using an optically active acid (followed by fractional crystallization and regeneration of the free base), forming the salt of the acid form of each isomer of an isomeric pair using an optically active amine (followed by fractional crystallization and regeneration of the free acid), forming an ester or an amide from each of the isomers of an isomeric pair using an optically pure acid, amine, or alcohol (followed by chromatographic separation and removal of the chiral auxiliary), or resolving an isomeric mixture of either a starting material or an end product using various well-known chromatographic methods.

[0024] If, for example, a particular enantiomer of a compound of the present invention is desired, it can be prepared by asymmetric synthesis or by derivatization with a chiral auxiliary, where the resulting diastereomeric mixture is separated and the auxiliary group is cleaved to provide the desired pure enantiomers. Alternatively, where the molecule contains a basic functional group, such as amino, or an acidic functional group, such as carboxyl, diastereomeric salts will be formed with an appropriate optically active acid or base, followed by resolution of the diastereomers thus formed by crystallization. Petition 870260063816, dated 06 / 29 / 2026, page 17 / 739 10 / 315 fractionated or by chromatographic means well known in the art and subsequent recovery of pure enantiomers.

[0025] The percent purity by molar portion is the ratio of the moles of the enantiomer (or diastereomer) to the moles of the enantiomer (or diastereomer) plus the moles of its optical isomer. When the stereochemistry of a disclosed compound is named or represented by structure, the named or represented stereoisomer is at least about 60%, about 70%, about 80%, about 90%, about 99%, or about 99.9% in pure mole portion relative to the other stereoisomers. When a single enantiomer is named or represented by structure, the named or represented enantiomer is at least about 60%, about 70%, about 80%, about 90%, about 99%, or about 99.9% in pure mole portion. When a single diastereomer is named or represented by the structure, the diastereomer represented or named is at least about 60%, about 70%, about 80%, about 90%, about 99%, or about 99.9% in pure mole portion.

[0026] When a disclosed compound is named or represented by its structure without indicating stereochemistry and the compound has at least one chiral center, it should be understood that the name or structure encompasses either an enantiomer of the compound free of the corresponding optical isomer, a racemic mixture of the compound, or mixtures enriched in one enantiomer relative to its corresponding optical isomer. When a disclosed compound is named or represented by its structure without indicating stereochemistry and has two or more chiral centers, it should be understood that the name or structure encompasses a diastereomer free of other diastereomers, a series of diastereomers free of other diastereomeric pairs, mixtures of diastereomers, mixtures of diastereomeric pairs, mixtures of diastereomers in which one diastereomer is enriched relative to Petition 870260063816, dated 06 / 29 / 2026, page 18 / 739 11 / 315 to other diastereomer(s) or mixtures of diastereomers in which one or more diastereomers are enriched relative to the other diastereomers. The invention encompasses all such forms.

[0027] Structures represented in this document are also intended to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds produced by replacing a hydrogen with deuterium or tritium, or a carbon with a carbon enriched with 13C or 14C, are within the scope of this invention.

[0028] The term prodrug, as used in this document, encompasses compounds that, under physiological conditions, are converted into therapeutically active agents. A common method for making a prodrug is to include selected moieties that are hydrolyzed under physiological conditions to reveal the desired molecule. In other embodiments, the prodrug is converted by an enzymatic activity of the host animal.

[0029] The phrase "pharmaceutically acceptable excipient" or "pharmaceutically acceptable carrier," as used in this document, means a pharmaceutically acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, excipient, solvent, or encapsulating material, involved in loading or transporting the chemical in question from one organ or part of the body to another organ or part of the body. Each carrier must be acceptable in the sense of being compatible with the other ingredients of the formulation, not harmful to the patient, and substantially non-pyrogenic. Some examples of materials that may serve as pharmaceutically acceptable carriers include: (1) sugars, such as lactose, glucose, and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose and its derivatives, such as sodium carboxymethylcellulose, ethylcellulose. Petition 870260063816, dated 06 / 29 / 2026, page 19 / 739 12 / 315 and cellulose acetate; (4) tragacanth powder; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository waxes; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffering agents, such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline solution; (18) Ringer's solution; (19) ethyl alcohol; (20) phosphate buffer solutions; and (21) other compatible non-toxic substances employed in pharmaceutical formulations. In certain embodiments, the pharmaceutical compositions of the present invention are non-pyrogenic, that is, they do not induce significant temperature elevations when administered to a patient.

[0030] The term pharmaceutically acceptable salts refers to relatively non-toxic, inorganic and organic acid addition salts of the compound(s). These salts may be prepared in situ during the final isolation and purification of the compound(s), or by reacting a purified compound in its free base form separately with a suitable organic or inorganic acid and isolating the salt thus formed. Representative salts include hydrobromide, hydrochloride, sulfate, bisulfate, phosphate, nitrate, acetate, valerate, oleate, palmitate, stearate, laurate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, naphthylate, mesylate, glucoheptonate, lactobionate and lauryl sulfonate salts and the like. (See, for example, Berge et al. (1977) Pharmaceutical Salts, J. Pharm. Sci. 66:1-19.)

[0031] In other cases, the compounds useful in the methods of the present invention may contain one or more acidic functional groups and thus are capable of forming pharmaceutically acceptable salts with Petition 870260063816, dated 06 / 29 / 2026, p. 20 / 739 13 / 315 Pharmaceutically acceptable bases. The term pharmaceutically acceptable salts in these cases refers to the relatively non-toxic inorganic and organic base addition salts of a compound. These salts may also be prepared in situ during the final isolation and purification of the compound, or by separately reacting the purified compound in its acid-free form with a suitable base, such as the hydroxide, carbonate, or bicarbonate of a pharmaceutically acceptable metal cation, with ammonia, or with a pharmaceutically acceptable primary, secondary, or tertiary organic amine. Representative alkaline or alkaline earth salts include lithium, sodium, potassium, calcium, magnesium, and aluminum salts and the like. Representative organic amines useful for the formation of base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, and the like (see, for example, Berge et al., supra).

[0032] The term pharmaceutically acceptable cocrystals refers to solid coformers that do not form formal ionic interactions with the small molecule.

[0033] A therapeutically effective amount (or effective quantity) of a compound with respect to its use in treatment refers to an amount of the compound in a preparation which, when administered as part of a desired dosage regimen (to a mammal, preferably a human), relieves a symptom, improves a condition, or delays the onset of disease conditions in accordance with clinically acceptable standards for the disorder or condition being treated or for aesthetic purposes, for example, with a reasonable benefit / risk ratio applicable to any medical treatment.

[0034] The term prophylactic or therapeutic treatment is recognized in the art and includes the administration to the host of one or more of the compositions in question. If administered before the manifestation Petition 870260063816, dated 06 / 29 / 2026, page 21 / 739 14 / 315 clinical manifestation of the undesirable condition (e.g., disease or other undesirable state of the host animal), then the treatment is prophylactic, (i.e., it protects the host against the development of the undesirable condition), whereas if it is administered after the manifestation of the undesirable condition, the treatment is therapeutic, (i.e., it is intended to reduce, improve or stabilize the existing undesirable condition or its side effects).

[0035] The term patient or individual refers to a mammal in need of particular treatment. In certain modalities, a patient is a primate, canine, feline, or equine. In certain modalities, a patient is a human.

[0036] An aliphatic chain comprises the alkyl, alkenyl, and alkynyl classes defined below. A linear aliphatic chain is limited to unbranched carbon chain portions. As used in this document, the term aliphatic group refers to a linear chain, branched chain, or cyclic aliphatic hydrocarbon group and includes saturated and unsaturated groups, such as an alkyl group, an alkenyl group, or an alkynyl group.

[0037] Alkyl refers to a fully saturated cyclic or acyclic carbon chain portion, branched or unbranched, with the specified number of carbon atoms, or up to 30 carbon atoms if no specification is made. For example, 1 to 8 carbon atom alkyl refers to portions such as methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, and octyl, and those portions that are positional isomers of these portions. 10 to 30 carbon atom alkyl includes decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, nonadecyl, eicosyl, heneicosyl, docosyl, tricosyl, and tetracosyl. In certain embodiments, a straight-chain or branched-chain alkyl group has 30 or fewer carbon atoms in its main structure (e.g., C1-C30 for Petition 870260063816, dated 06 / 29 / 2026, p. 22 / 739 15 / 315 linear chains, C3-C30 for branched chains) and more preferably 20 or less. Alkyl groups may be substituted or unsubstituted.

[0038] As used in this document, the term heteroalkyl refers to an alkyl moiety, as defined earlier in this document, that contains one or more oxygen, sulfur, nitrogen, phosphorus, or silicon atoms in place of carbon atoms.

[0039] As used in this document, the term haloalkyl refers to an alkyl group as defined earlier in this document replaced by at least one halogen.

[0040] As used in this document, the term hydroxyalkyl refers to an alkyl group as defined earlier in this document replaced by at least one hydroxyl group.

[0041] As used in this document, the term alkylene refers to an alkyl group with a specified number of carbons, for example, from 2 to 12 carbon atoms, which contains two points of attachment to the rest of the compound in its longer carbon chain. Non-limiting examples of alkylene groups include methylene (CH2)-, ethylene (CH2CH2)-, n-propylene (CH2CH2CH2)-, isopropylene (CH2CH(CH3))- and the like. Alkylene groups may be cyclic or acyclic carbon chain portions, branched or unbranched, and may optionally be substituted by one or more substituents.

[0042] Cycloalkyl means saturated carbocyclic rings, monocyclic or bicyclic or bridging or spirocyclic or polycyclic, each with 3 to 12 carbon atoms. Cycloalkyls preferably have 3 to 10 carbon atoms in their ring structure and more preferably have 3 to 6 carbons in the ring structure. Cycloalkyl groups may be substituted or unsubstituted.

[0043] As used in this document, the term halocycloalkyl refers to a cycloalkyl group as defined previously in this document. Petition 870260063816, dated 06 / 29 / 2026, p. 23 / 739 16 / 315 document replaced by at least one halogen.

[0044] Cycloheteroalkyl refers to a cycloalkyl moiety as defined earlier in this document that contains one or more oxygen, sulfur, nitrogen, phosphorus, or silicon atoms in place of carbon atoms. Preferred cycloheteroalkyls have 4 to 8 carbon atoms and heteroatoms in their ring structure and, more preferably, have 4 to 6 carbons and heteroatoms in the ring structure. Cycloheteroalkyl groups may be substituted or unsubstituted.

[0045] Unless the number of carbons is specified otherwise, lower alkyl, as used in this document, means an alkyl group, as defined above, but with one to ten carbons, more preferably one to six carbon atoms in its main structure, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl and tert-butyl. Similarly, lower alkenyl and lower alkynyl have similar chain lengths. Throughout the application, preferred alkyl groups are lower alkyls. In certain embodiments, a substituent designated in this document as alkyl is a lower alkyl.

[0046] Alkenyl refers to any unsaturated cyclic or acyclic carbon chain portion, branched or unbranched, with the specified number of carbon atoms, or up to 26 carbon atoms if no limitation on the number of carbon atoms is specified; and with one or more double bonds in the portion. Alkenyl groups with 6 to 26 carbon atoms are exemplified by hexenyl, heptenyl, octenyl, nonenyl, decenyl, undecenyl, dodenyl, tridecenyl, tetradecenyl, pentadecenyl, hexadecenyl, heptadecenyl, octadecenyl, nonadecenyl, eicosenyl, heneicosoenyl, docosenyl, tricosenyl, and tetracosenyl, in their various isomeric forms, where the unsaturated bond(s) may be located in any of the groups. Petition 870260063816, dated 06 / 29 / 2026, p. 24 / 739 17 / 315 place in the portion and may have the (Z) or (E) configuration around the double bond(s).

[0047] Alkynyl refers to hydrocarbyl moieties of the alkenyl group, but with one or more triple bonds in the moiety.

[0048] The term aryl as used in this document includes single-ring aromatic groups, substituted or unsubstituted, of 3 to 12 members in which each ring atom is carbon (i.e., carbocyclic aryl) or in which one or more atoms are heteroatoms (i.e., heteroaryl). Preferably, aryl groups include rings of 5 to 12 members, more preferably rings of 6 to 10 members. The term aryl also includes polycyclic ring systems with two or more cyclic rings in which two or more carbons are common to two adjacent rings where at least one of the rings is aromatic, for example, the other cyclic rings may be cycloalkyls, cycloalkenyls, cycloalkynyls, aryls, heteroaryls and / or heterocyclyls. Carbocyclic aryl groups include benzene, naphthalene, phenanthrene, phenol, aniline and the like.Heteroaryl groups include substituted or unsubstituted aromatic ring structures of 3 to 12 members, more preferably rings of 5 to 12 members, more preferably rings of 5 to 10 members, whose ring structures include one to four heteroatoms. The heteroaryl group includes, for example, pyrrole, furan, thiophene, imidazole, oxazole, thiazole, triazole, pyrazole, pyridine, pyrazine, pyridazine and pyrimidine and the like. Aryl and heteroaryl groups can be monocyclic, bicyclic or polycyclic.

[0049] The term halo, halide or halogen, as used in this document, means halogen and includes, for example, but not limited to, fluorine, chlorine, bromine, iodine and the like, both in radioactive and non-radioactive forms. In a preferred embodiment, the halo is selected from the group consisting of fluorine, chlorine and bromine.

[0050] The terms heterocycline or heterocyclic group refer to Petition 870260063816, dated 06 / 29 / 2026, page 25 / 73918 / 315 to ring structures of 3 to 12 members, more preferably rings of 5 to 12 members, more preferably rings of 5 to 10 members, whose ring structures include one to four heteroatoms. Heterocycles can be monocyclic, bicyclic, spirocyclic or polycyclic. Heterocyclic groups include, for example, thiophene, thianthrene, furan, pyran, isobenzofuran, chromene, xanthene, phenoxanthene, pyrrole, imidazole, pyrazole, isothiazole, isoxazole, pyridine, pyrazine, pyrimidine, pyridazine, indolizine, isoindol, indole, indazole, purine, quinolinizine, isoquinoline, quinoline, phthalazine, naphthyridine, quinoxaline, quinazoline, cinoline, pteridine, carbazole, carbonyline, phenanthridine, acridine, pyrimidine, phenanthroline, phenazine, phenarsazine, phenothiazine, furazane, phenoxazine, pyrrolidine, oxolane, thiolane, oxazole, piperidine, piperazine, morpholine, lactones, lactams, such as azetidinones and pyrrolidones. sultamas, sultonas, and the like.The heterocyclic ring may be substituted in one or more positions by such substituents as described above, such as, for example, halogen, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, amino, nitro, sulfhydryl, imino, amido, phosphate, phosphonate, phosphinate, carbonyl, carboxyl, silyl, sulfamoyl, sulfinyl, ether, alkylthio, sulfonyl, ketone, aldehyde, ester, a heterocyclyl, an aromatic or heteroaromatic moiety, -CF3, -CN and the like.

[0051] The term substituted refers to portions with substituents that replace a hydrogen atom on one or more carbon atoms in the main structure. It will be understood that substitution or substituted by includes the implicit condition that such substitution conforms to the allowed valence of the substituted atom and the substituent, and that the substitution results in a stable compound, for example, one that does not undergo spontaneous transformation, such as by rearrangement, cyclization, elimination, etc. As used in this document, the term substituted is considered to include all substituents Petition 870260063816, dated 06 / 29 / 2026, p. 26 / 739 19 / 315 admissible substituents of organic compounds. In a broad sense, admissible substituents include cyclic and acyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic substituents of organic compounds. Admissible substituents may be one or more and the same or different, in the case of suitable organic compounds. For the purposes of the present invention, heteroatoms, such as nitrogen, may have hydrogen substituents and / or any admissible substituents of organic compounds described herein that satisfy the valences of the heteroatoms.Substituents may include any substituents described in this document, for example, a halogen, a hydroxyl group, a carbonyl group (such as a carboxyl, an alkoxycarbonyl, a formyl or an acyl group), a thiocarbonyl group (such as a thioester, a thioacetate or a thioformate group), an alkoxy group, a phosphoryl group, a phosphate group, a phosphonate group, a phosphinate group, an amino group, an amido group, an amidine group, an imine group, a cyano group, a nitro group, an azido group, a sulfhydryl group, an alkylthio group, a sulfate group, a sulfonate group, a sulfamoyl group, a sulfonamido group, a sulfonyl group, a heterocyclyl group, an aralkyl group or an aromatic or heteroaromatic moiety. In preferred embodiments, the substituents on substituted alkyl groups are selected from C1-6 alkyl, C3-6 cycloalkyl, halogen, carbonyl, cyano or hydroxyl groups. In further preferred embodiments, the substituents on substituted alkyls are selected from among fluoro, carbonyl, cyano, or hydroxyl groups.It will be understood by those skilled in the art that the substituents themselves may be substituted, if appropriate. Unless specifically indicated as unsubstituted, references to chemical moieties in this document are understood to include substituted variants. For example, a reference to an aryl moiety or group implicitly includes both substituted and unsubstituted variants. Petition 870260063816, dated 06 / 29 / 2026, p. 27 / 739 20 / 315

[0052] As used in this document, the definition of each expression, for example, alkyl, m, n etc., when it occurs more than once in any structure, is intended to be independent of its definition elsewhere in the same structure.

[0053] As used in this document, small molecules refers to small organic or inorganic molecules with a molecular weight below about 3,000 Daltons. In general, small molecules useful for the invention have a molecular weight of less than 3,000 Daltons (Da). Small molecules may be, for example, at least about 100 Da to about 3000 Da (e.g., from about 100 to about 3000 Da, about 100 to about 2500 Da, about 100 to about 2000 Da, about 100 to about 1750 Da, about 100 to about 1500 Da, about 100 to about 1250 Da, about 100 to about 1000 Da, about 100 to about 750 Da, about 100 to about 500 Da, about 200 to about 1500, about 500 to about 1000, about 300 to about 1000 Da, or about 100 to about 250 Da).

[0054] In some embodiments, a small molecule refers to an organic, inorganic, or organometallic compound typically having a molecular weight of less than about 1000. In some embodiments, a small molecule is an organic compound with a size on the order of 1 nm. In some embodiments, the small molecule drugs of the invention encompass oligopeptides and other biomolecules with a molecular weight of less than about 1000.

[0055] An effective amount is an amount sufficient to produce beneficial or desired results. For example, a therapeutic amount is one that achieves the desired therapeutic effect. This amount may be the same as or different from a prophylactically effective amount, which is an amount necessary to prevent the onset of the disease or its symptoms. An amount Petition 870260063816, dated 06 / 29 / 2026, page 28 / 739 21 / 315 effective may be administered in one or more administrations, applications, or dosages. A therapeutically effective amount of a composition depends on the composition selected. Compositions may be administered from one or more times daily to one or more times weekly; including once every other day. Those skilled in the art will understand that certain factors may influence the dosage and frequency required to treat an individual effectively, including but not limited to, severity of the disease or disorder, prior treatments, general health status and / or age of the individual, and other present illnesses. Furthermore, treatment of an individual with a therapeutically effective amount of the compositions described in this document may include a single treatment or a series of treatments.

[0056] The terms decrease, reduce, reduced, reduction, decrease and inhibit are all used in this document generally to mean a decrease in a statistically significant amount relative to a reference.However, to avoid doubt, reduce, decrease, or inhibit typically means a decrease of at least 10% compared to a reference level and may include, for example, a decrease of at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 98%, at least about 99%, up to and including, for example, the complete absence of the given entity or parameter compared to the reference level, or any decrease between 10% and 99% compared to The absence of a piece of data. Petition 870260063816, dated 06 / 29 / 2026, page 29 / 739 22 / 315 treatment.

[0057] The terms augmented, increase or enhance or activate are all used in this document to generally mean an increase in a statically significant quantity; To avoid any doubt, the terms increased, boost, or enhance or activate mean an increase of at least 10% compared to a reference level, for example, an increase of at least about 20%, or at least about 30%, or at least about 40%, or at least about 50%, or at least about 60%, or at least about 70%, or at least about 80%, or at least about 90%, or up to and including an increase of 100%, or any increase between 10 and 100% compared to a reference level, or at least about 2 times, or at least about 3 times, or at least about 4 times, or at least about 5 times, or at least about 10 times increase, or any increase between 2 times and 10 times or more compared to a reference level.

[0058] As used in this document, the term modular includes both positive and negative regulation, for example, enhancing or inhibiting a response.

[0059] A radiopharmaceutical agent, as defined in this document, refers to a pharmaceutical agent that contains at least one radiation-emitting radioisotope. Radiopharmaceutical agents are routinely used in nuclear medicine for the diagnosis and / or therapy of various diseases. The radiolabeled pharmaceutical agent, for example, a radiolabeled antibody, contains a radioisotope (RI) that serves as the radiation source. As contemplated in this document, the term radioisotope includes both metallic and non-metallic radioisotopes. The radioisotope is chosen based on the medical application of the radiolabeled pharmaceutical agents. When the radioisotope is a metallic radioisotope, a Petition 870260063816, dated 06 / 29 / 2026, page 30 / 739 23 / 315 A chelating agent is typically used to link the metallic radioisotope to the rest of the molecule. When the radioisotope is a non-metallic radioisotope, the non-metallic radioisotope is typically linked directly, or through a ligand, to the rest of the molecule.

[0060] For the purposes of this invention, chemical elements are identified in accordance with the Periodic Table of Elements, CAS version, Handbook of Chemistry and Physics, 67th Ed. 1986-87, inside cover. Compounds of the Invention

[0061] One aspect of the invention relates to a compound of Formula (I): in which: n is 0, 1, or 2; Li is absent or selected from among -alkyl-, -hydroxyalkyl, -cycloalkyl- and -heteroaryl-CH2-; L2 is absent or is -CH2-; L3 is missing or is -C(O)-; X1 and X2 are independently selected from among -H, alkyl, haloalkyl, cycloalkyl, alkyl-cycloalkyl and heterocyclyl; provided that X1 and X2 are not both -H; Y1 is selected from aryl and heteroaryl; Y 2 is selected from alkyl, alkenyl, alkynyl, alkoxy, alkoxyalkyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -NH(Y2') and -N(Y2'')2; Y 2' is selected from -H, -OH, alkyl, alkoxy, alkoxyalkyl, hydroxyalkyl and cycloalkyl; Petition 870260063816, dated 06 / 29 / 2026, page 31 / 739 24 / 315 each Y2'' is alkyl, or both cases taken together with the nitrogen atom to which they are attached form a 5- or 6-membered heterocycline; and Y3, Y4, Y5, and Y6 are independently selected from -H, -OH, halide, alkyl, haloalkyl and alkoxy; provided that Y3 and Y4 or Y5 and Y6 are not both -OH; When L3 is -C(O)-, then Y2 is not aryl; and the compound is not selected from: or a pharmaceutically acceptable salt thereof.

[0062] In certain forms, the compound is also not selected from: or a pharmaceutically acceptable salt thereof.

[0063] In certain embodiments, the compound has a structure Petition 870260063816, dated 06 / 29 / 2026, page 32 / 739 25 / 315 selected from: oo

[0064] In certain embodiments, Y2' is selected from -H, -OH, alkyl, alkoxy, alkoxyalkyl and cycloalkyl.

[0065] In certain embodiments, one of Xi and X2 is -H; and the other of X1 and X2 is selected from C1-C4 alkyl, haloalkyl, cycloalkyl, alkylcycloalkyl and heterocyclyl.

[0066] In certain embodiments, one of Xi and X2 is -H; and the other of X1 and X2 is selected from -CH3, -CH2CH3, -CH2CF3, -CH2CH2CH3, M, K> and K>.

[0067] In certain embodiments, X1 is -H and X2 is -CH3; X2 is -H and X1 is -CH3; X1 is -H and X2 is M; or X2 is -H and X1 is W.

[0068] In certain embodiments, Li is absent. In other embodiments, Li is selected from -alkyl-, -hydroxyalkyl-, -cycloalkyl-, and -heteroaryl-CH2-.

[0069] In certain embodiments, Li is selected from -CH2-, C(H)(CH3)-, -CH2CH2- and -C(H)(OH)CH2-. In other embodiments, Li . In other embodiments, Li is selected from and A In other embodiments, L1 is selected from u 7^ / \\ 7^ / w / *N\ ' , Lo , No , *-S , O'N and N^N .

[0070] In certain embodiments, the compound is selected from: Petition 870260063816, dated 06 / 29 / 2026, page 33 / 739 26 / 315

[0071] In certain forms, Yi is unsubstituted aryl, for example, unsubstituted phenyl and unsubstituted naphthyl.

[0072] In certain modalities, Yi is replaced by arila. IT

[0073] In certain modalities, Yi is R« ; and R1, R2, R3, R4 and R5 are independently selected from -H, halogen, -CN, -CF3, -CHF2, -CF2CH3, -OCF3, -OCHF2, alkyl, haloalkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl; provided that one of R1, R2, R3, R4 and R5 is not -H. Petition 870260063816, dated 06 / 29 / 2026, p. 34 / 739 27 / 315

[0074] In certain embodiments, Ri, R2, R3, R4 and R5 are independently selected from -H, -F, -Cl, -Br, -CN, -CH3, -CH2CH3, -CF3, -CHF2, -CF2CH3, -OCH3, -OCF3, -OCHF2, W , K> K> , , ,

[0075] In certain embodiments, Ri, R2, R3, R4 and R5 are independently selected from -H, -F, -Cl, -Br, -CN, -CH3, -CH2CH3-OCF3 and W.

[0076] In certain modalities, two of Ri, R2, R3, R4, and R5 are not -H. In other modalities, three of Ri, R2, R3, R4, and R5 are not -H. In certain modalities, Yi is selected from among

[0077]

[0078] In certain modalities, Yi is selected from among Yi is selected from Br, ci

[0079] In certain modalities, Yi is an unsubstituted heteroaryl. Petition 870260063816, dated 06 / 29 / 2026, page 35 / 739 28 / 315

[0080] In certain modalities, Yi is selected from among

[0081] In certain modalities, Yi is replaced by heteroaryl.

[0082] In certain modalities, Yi is selected from Each occurrence of R6, R7, R8, and R9 is independently selected from among -H, halogen, -CN, -OCF3, -OCHF2, alkyl, haloalkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, aryl, and heteroaryl; provided that at least one of R6, R7, R8, and R9 is not -H.

[0083] In certain modalities, L2 is absent. In other modalities, L2 is -CH2-.

[0084] In certain modalities, L3 is absent. In other modalities, L3 is -C(O)-.

[0085] In certain modes, n is 0. In other modes, n is 1. In other modalities, n is 2.

[0086] In certain embodiments, the compound is selected from: Petition 870260063816, dated 06 / 29 / 2026, p. 36 / 739 29 / 315

[0087] In certain embodiments, the compound is selected from: I and Y2

[0088] In certain embodiments, the compound is selected from:

[0089] In certain embodiments, Y2 is unsubstituted heteroaryl.

[0090] In certain modalities, Y2 is selected from H HN HN N

[0091] In certain modalities, Y2

[0092] In certain embodiments, Y2 is substituted heteroaryl. Petition 870260063816, dated 06 / 29 / 2026, p. 37 / 739 30 / 315

[0093] In certain modalities, Y2 is Rn ; R10, R11, and R12 are independently selected from H, halogen, -CN, -OH, -NH2, -OCF3, -OCHF2, -OAc, -NHAc, alkyl, haloalkyl, hydroxyalkyl, alkenyl, alkynyl, alkoxy, alkylaminocycloalkyl, aryl, heteroaryl, -C(O)NRi3Ri4, -CO2R15, and C(O)NHSO2R15; provided that at least one of R10, R11, and R12 is not -H; and each occurrence of R13, R14, and R15 is independently selected from -H, alkyl, aryl, and heteroaryl.

[0094] In certain modalities, Y2 is R; R10, R11, and R12 are independently selected from -H, halogen, -CN, -OH, -NH2, -OCF3, -OCHF2, -OAc, -NHAc, alkyl, haloalkyl, alkenyl, alkynyl, alkoxy, alkylaminocycloalkyl, aryl, heteroaryl, -C(O)NR13R14, -CO2R15, and -C(O)NHSO2R15; provided that at least one of R10, R11, and R12 is not -H; and each occurrence of R13, R14, and R15 is independently selected from -H, alkyl, aryl, and heteroaryl.

[0095] In certain embodiments, R10, R11 and R12 are independently selected from -H, -F, -Cl, -Br, -CN, -CH3, -CH2CH3, -CF3, -CHF2, -CF2CH3, -OCH3, -OCF3, -OCHF2, -OAc, NH2, -NHCH3, -NHAc, -C(O)NH2, -C(O)NHCH3, -C(O)NHCH2CH3, -C(O)NHSO2CH3, -C(O)NHSO2CH2CH3, -CO2H, phenyl, cyclopropyl, cyclobutyl, imidazolyl and tetrazolyl.

[0096] In certain embodiments, R10 and R12 are each -H; and R11 is selected from -CN, -CF3-CH3, -OCH3, -NH2, -NHCH3, -NHAc, -CO2H, -C(O)NH2, -C(O)NHCH3, -C(O)NHCH2CH3, W , *“0 , Petition 870260063816, dated 06 / 29 / 2026, p. 38 / 739 31 / 315 n „n' eN~N

[0097] In certain embodiments, R11 and R12 are each -H; and R10 is selected from -CN, -CF3, -CH3, -OCH3, -NH2, -NHCH3, -NHAc, -CO2H, -C(O)NH2, -C(O)NHCH3, -C(O)NHCH2CH3, ;n \\ / ,N' eN~N

[0098] In certain embodiments, R10 and R11 are each -H; and R12 is selected from -CN, -CF3, -CH3, -OCH3, -NH2, -NHCH3, -NHAc, -CO2H, -C(O)NH2, -C(O)NHCH3, -C(O)NHCH2CH3, W , *“0 , ' n^n Λί / ,Nw en~n .

[0099] In certain modalities, Y2 is selected from among R16 for each occurrence is independently selected from halogen, -CN, -NH2, -OCF3, -OCHF2, -OAc, -NHAc, alkyl, haloalkyl, alkenyl, alkynyl, alkoxy, alkylaminocycloalkyl, aryl, heteroaryl, -C(O)NRnR14, -CO2R15; and each occurrence of R13, R14 and R15 is independently selected from -H, alkyl, aryl, and heteroaryl.

[00100] In certain embodiments, R16 is selected from -CN, CH3-CF3, -C(O)NH2, -CO2CH2CH3 and W.

[00101] In certain modalities, Y2 is selected from Petition 870260063816, dated 06 / 29 / 2026, page 39 / 739 32 / 315 Rie eRi8; Each occurrence of R17, R18, R19, R20, and R21 is independently selected from -H, halogen, -CN, -NH2, OCF3, -OCHF2, -OAc, -NHAc, alkyl, haloalkyl, hydroxyalkyl, alkenyl, alkynyl, alkoxy, alkylaminocycloalkyl, aryl, heteroaryl, C(O)NRi3Ri4, and -CO2R15; provided that at least one of R17, R18, R19, R20, and R21 is not -H; and each occurrence of R13, R14, and R15 is independently selected from -H, alkyl, aryl, and heteroaryl.

[00102] In certain modalities, Y2 is selected from RR21K21 t I -¼.. I l <xr19Ri? γ Rie eRi8; Each occurrence of R17, R18, R19, R20, and R21 is independently selected from -H, halogen, -CN, -NH2, OCF3, -OCHF2, -OAc, -NHAc, alkyl, haloalkyl, alkenyl, alkynyl, alkoxy, alkylaminocycloalkyl, aryl, heteroaryl, -C(O)NRi3Ri4, and CO2R15; provided that at least one of R17, R18, R19, R20, and R21 is not -H; and each occurrence of R13, R14, and R15 is independently selected from -H, alkyl, aryl, and heteroaryl.

[00103] In certain embodiments, R17, R18, R19, R20 and R21 are independently selected from -H, -CN, -CH3 and -OCH3. Petition 870260063816, dated 06 / 29 / 2026, page 40 / 739 33 / 315

[00104] In certain modalities, Y2 is selected from among

[00105] In certain embodiments, the compound is selected from:

[00106] In certain embodiments, the compound is selected from:

[00107] In certain embodiments, the compound is selected from: Petition 870260063816, dated 06 / 29 / 2026, p. 41 / 739 34 / 315

[00108] In certain embodiments, Y2 is an unsubstituted cycloalkyl or heterocyclyl group.

[00109] In certain modalities, Y2 is selected from and Y2 is a certain cycloalkyl or heterocyclyl form.

[00110] In certain modalities, Y2 is selected from

[00111] Replaced. modalities, Y2 is selected from

[00112] In certain

[00113] In certain ho p h3co o h2n embodiments, Y2 is selected from alkyl, alkenyl, alkynyl, alkoxy, alkoxyalkyl and hydroxyalkyl. Petition 870260063816, dated 06 / 29 / 2026, p. 42 / 739 35 / 315

[00114] In certain embodiments, Y2 is selected from -CH3, CH2CH(CH3)2, -CH2CH2C CH, -CH2CH2OCH3, -C(H)(CH3)CH2OCH3, -OCH3, -CH2OH, -CH2 CH2OH, -C(CH3)2OH, and -CH2OCH3.

[00115] In certain embodiments, Y2 is selected from -CH2OH and -CH2CH2OH.

[00116]

[00117] In certain modalities, Y2 is heteroaryl. In certain modalities, Y2 is selected from among H In certain modalities, Y2 is

[00118] R10, R11, and R12 are independently selected from among - H, halogen, -CN, -OH, -NH2, -OCF3, -OCHF2, -OAc, -NHAc, alkyl, haloalkyl, hydroxyalkyl, alkenyl, alkynyl, alkoxy, alkylaminocycloalkyl, aryl, heteroaryl, -C(O)NRi3Ri4, and -CO2R15; and each occurrence of R13, R14, and R15 is independently selected from among -H, alkyl, aryl, and heteroaryl.

[00119] In certain modalities, Y2 is R10, R11, and R12 are selected independently from among Petition 870260063816, dated 06 / 29 / 2026, p. 43 / 739 36 / 315 - H, halogen, -CN, -OH, -NH2, -OCF3, -OCHF2, -OAc, -NHAc, alkyl, haloalkyl, alkenyl, alkynyl, alkoxy, alkylaminocycloalkyl, aryl, heteroaryl, -C(O)NRi3Ri4, and -CO2R15; and each occurrence of R13, R14, and R15 is independently selected from among -H, alkyl, aryl, and heteroaryl.

[00120] In certain modalities, at least one of R10, R11 and R12 is not -H.

[00121] In certain modalities, Y2 is selected from Each occurrence of R17, R18, R19, R20, and R21 is independently selected from -H, halogen, -CN, -NH2, OCF3, -OCHF2, -OAc, -NHAc, alkyl, haloalkyl, hydroxyalkyl, alkenyl, alkynyl, alkoxy, alkylaminocycloalkyl, aryl, heteroaryl, C(O)NRi3Ri4, and -CO2R15; and each occurrence of R13, R14, and R15 is independently selected from -H, alkyl, aryl, and heteroaryl.

[00122] In certain modalities, Y2 is selected from R21 A R19Rv | Ris eRie ; Petition 870260063816, dated 06 / 29 / 2026, page 44 / 739 37 / 315 each occurrence of R17, R18, R19, R20 and R21 is independently selected from -H, halogen, -CN, -NH2, OCF3, -OCHF2, -OAc, -NHAc, alkyl, haloalkyl, alkenyl, alkynyl, alkoxy, alkylaminocycloalkyl, aryl, heteroaryl, -C(O)NRi3Ri4 and CO2R15; and each occurrence of R13, R14 and R15 is independently selected from -H, alkyl, aryl and heteroaryl.

[00123] In certain modalities, at least one of R17, R18, R19, R20 and R21 is not -H.

[00124] In certain modalities, Y2 is selected from Each occurrence of R22, R23, R24, and R25 is independently selected from -H, halogen, -CN, -NH2, -OCF3, -OCHF2, -OAc, -NHAc, alkyl, haloalkyl, alkenyl, alkynyl, alkoxy, alkylaminocycloalkyl, aryl, heteroaryl, -C(O)NRi3Ri4, and -CO2R15; and each occurrence of R13, R14, and R15 is independently selected from -H, alkyl, aryl, and heteroaryl.

[00125] In certain embodiments, each occurrence of R22, R23, R24 and R25 is independently selected from -H and -CH3.

[00126] In certain embodiments, Y2 is -NH(Y2') or Y2 is -N (Y2”)2

[00127] In certain embodiments, Y2' is selected from -H, -OH, - OCH3, -CH3, -CH2CH2OCH3 and W.

[00128] In certain embodiments, each Y2'' is -CH3. In other embodiments, both Y2'' taken together with the nitrogen atom to which they are attached form a morpholinnyl.

[00129] In certain embodiments, where Y2 is -NH(Y2'). Petition 870260063816, dated 06 / 29 / 2026, page 45 / 739 38 / 315

[00130] In certain embodiments, Y2' is selected from -H, alkyl, alkoxy, and hydroxyalkyl. In other embodiments, Y2' is selected from -H, -OCH3, -CH3, and -CH2CH2OH.

[00131] In certain embodiments, Y2' is H. In other embodiments, Y2' is -CH3. In other embodiments, Y2' is -CH2CH3. In other embodiments, Y2' is -OCH3. In other embodiments, Y2' is -CH2OH. In other embodiments, Y2' is -CH2CH2OH.

[00132] In certain embodiments, Y3 and Y4 are both -H or -F. In other embodiments, Y3 is selected from -F, -CF3, -OH, and -OCH3; and Y4 is -H. In other embodiments, Y4 is selected from -F, -CF3, OH, and -OCH3; and Y3 is -H.

[00133] In certain embodiments, Y3 and Y4 are both -H. In other embodiments, Y3 and Y4 are both -F.

[00134] In certain embodiments, Y5 and Y6 are both -H or -F. In other embodiments, Y5 is selected from -F, -CF3, -OH, and -OCH3; and Y6 is -H. In other embodiments, Y6 is selected from -F, -CF3, OH, and -OCH3; and Y5 is -H.

[00135] In certain modalities, Y5 and Y6 are both -H. In other modalities, Y5 and Y6 are both -F.

[00136] In some embodiments, the compound is selected from the following Table 1: Petition 870260063816, dated 06 / 29 / 2026, p. 46 / 739 39 / 315 Table 1. Petition 870260063816, dated 06 / 29 / 2026, p. 47 / 739 40 / 315 Petition 870260063816, dated 06 / 29 / 2026, p. 48 / 739 41 / 315 Petition 870260063816, dated 06 / 29 / 2026, p. 49 / 739 42 / 315 Petition 870260063816, dated 06 / 29 / 2026, p. 50 / 739 43 / 315 Petition 870260063816, dated 06 / 29 / 2026, p. 51 / 739 44 / 315 Petition 870260063816, dated 06 / 29 / 2026, p. 52 / 739 45 / 315 Petition 870260063816, dated 06 / 29 / 2026, p. 53 / 739 46 / 315 Petition 870260063816, dated 06 / 29 / 2026, p. 54 / 739 47 / 315 Petition 870260063816, dated 06 / 29 / 2026, p. 55 / 739 48 / 315 Petition 870260063816, dated 06 / 29 / 2026, p. 56 / 739 49 / 315 Petition 870260063816, dated 06 / 29 / 2026, p. 57 / 739 50 / 315 Petition 870260063816, dated 06 / 29 / 2026, p. 58 / 739 51 / 315 Petition 870260063816, dated 06 / 29 / 2026, p. 59 / 739 52 / 315 Petition 870260063816, dated 06 / 29 / 2026, p. 60 / 739 53 / 315 Petition 870260063816, dated 06 / 29 / 2026, p. 61 / 739 54 / 315 Petition 870260063816, dated 06 / 29 / 2026, p. 62 / 739 55 / 315 Petition 870260063816, dated 06 / 29 / 2026, p. 63 / 739 56 / 315 Petition 870260063816, dated 06 / 29 / 2026, p. 64 / 739 57 / 315 Petition 870260063816, dated 06 / 29 / 2026, p. 65 / 739 58 / 315 Petition 870260063816, dated 06 / 29 / 2026, p. 66 / 739 59 / 315 Petition 870260063816, dated 06 / 29 / 2026, p. 67 / 739 60 / 315 Petition 870260063816, dated 06 / 29 / 2026, pp. 68 / 739 61 / 315

[00137] In some embodiments, the compound is selected from the following Table 2: Petition 870260063816, dated 06 / 29 / 2026, pp. 69 / 739 62 / 315 Table 2. Petition 870260063816, dated 06 / 29 / 2026, pp. 70 / 739 63 / 315 Petition 870260063816, dated 06 / 29 / 2026, pp. 71 / 739 64 / 315 Petition 870260063816, dated 06 / 29 / 2026, pp. 72 / 739 65 / 315 Petition 870260063816, dated 06 / 29 / 2026, pp. 73 / 739 66 / 315 Petition 870260063816, dated 06 / 29 / 2026, pp. 74 / 739 67 / 315 Petition 870260063816, dated 06 / 29 / 2026, pp. 75 / 739 68 / 315 Petition 870260063816, dated 06 / 29 / 2026, pp. 76 / 739 69 / 315 Petition 870260063816, dated 06 / 29 / 2026, pp. 77 / 739 70 / 315 Petition 870260063816, dated 06 / 29 / 2026, pp. 78 / 739 71 / 315

[00138] In some embodiments, the compound is selected from the following Table 3: Petition 870260063816, dated 06 / 29 / 2026, pp. 79 / 739 72 / 315 Petition 870260063816, dated 06 / 29 / 2026, p. 80 / 739 73 / 315 Petition 870260063816, dated 06 / 29 / 2026, p. 81 / 739 74 / 315 Petition 870260063816, dated 06 / 29 / 2026, p. 82 / 739 75 / 315 Petition 870260063816, dated 06 / 29 / 2026, p. 83 / 739 76 / 315 Table 5 Petition 870260063816, dated 06 / 29 / 2026, p. 84 / 739 77 / 315 Petition 870260063816, dated 06 / 29 / 2026, p. 85 / 739 78 / 315 The representations in this document are also intended to include Petition 870260063816, dated 06 / 29 / 2026, p. 86 / 739 79 / 315 compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds produced by replacing a hydrogen with deuterium or tritium, or a carbon with a carbon enriched with 13C or 14C, are within the scope of this invention. Such compounds are useful, for example, as analytical tools, as probes in biological assays, or as therapeutic agents in accordance with the present invention. For example, in the case of variable R1, (C1-C4)alkyl or -O-(C1-C4)alkyl can be suitably deuterated (e.g., -CD3, -OCD3).

[00142] Any compound of the invention can also be radiolabbed for the preparation of a radiopharmaceutical agent. Treatment Methods

[00143] One aspect of the invention provides compounds, compositions and methods useful for treating or preventing a disease or disorder associated with abnormal amino acid levels by modulating SLC6A19 transport.

[00144] Another aspect of the invention relates to methods of modulating the transport of SLC6A19 in an individual in need thereof, comprising administering to the individual an effective amount of a compound of Formula (I).

[00145] Another aspect of the invention relates to methods of treating or preventing a disease or disorder associated with a genetic defect in phenylalanine hydroxylase in an individual in need thereof, comprising administering to the individual an effective amount of a compound of Formula (I).

[00146] In some embodiments, the invention relates to methods of treating or preventing phenylketonuria in an individual in need thereof, comprising administering to the individual an effective amount of a compound of Formula (I).

[00147] In some embodiments, the invention relates to methods Petition 870260063816, dated 06 / 29 / 2026, p. 87 / 739 80 / 315 treatment or prevention of hyperphenylalaninemia in an individual in need thereof, comprising administering to the individual an effective amount of a compound of Formula (I).

[00148] In some modalities, the compound reduces systemic levels of phenylalanine in the individual.

[00149] In some embodiments, the invention relates to methods of treating or preventing tyrosinemia (Type I, II or III) in an individual in need thereof, comprising administering to the individual an effective amount of a compound of Formula (I).

[00150] In some forms, the compound reduces systemic glycine levels in the individual.

[00151] In some embodiments, the invention relates to methods of treating or preventing isovaleric acidemia, methylmalonic acidemia, propionic acidemia, maple syrup urine disease, DNAJC12 deficiency, urea cycle disorders or hyperammonemia in an individual in need thereof, comprising administering to the individual an effective amount of a compound of Formula (I).

[00152] In some modalities of any of the disclosed methods, the compound modulates SLC6A19 in the individual.

[00153] In some modalities of any of the disclosed methods, the compound inhibits SLC6A19 in the individual.

[00154] In some embodiments of any of the disclosed methods, the compound modulates SLC6A19 transport in the individual.

[00155] In some embodiments of any of the disclosed methods, the compound inhibits SLC6A19 transport in the individual.

[00156] In some forms, the compound reduces systemic levels of an amino acid in the individual.

[00157] In some modalities of any of the disclosed methods, where the individual is a mammal. In some Petition 870260063816, dated 06 / 29 / 2026, p. 88 / 739 81 / 315 modalities of any of the methods disclosed, the mammal is a human.

[00158] In some embodiments of any of the disclosed methods, the compound of Formula (I) is defined as: (I) where: n is 0, 1, or 2; L1 is absent or is selected from among -alkyl-, -hydroxyalkyl-, -cycloalkyl- and -heteroaryl-CH2-; L2 is absent or is -CH2-; L3 is missing or is -C(O)-; Xi and X2 are independently selected from -H, alkyl, haloalkyl, cycloalkyl, alkyl-cycloalkyl and heterocyclyl; provided that X1 and X2 are not both -H; Y1 is selected from aryl and heteroaryl; Y 2 is selected from alkyl, alkenyl, alkynyl, alkoxy, alkoxyalkyl, hydroxyalkyl, aralkyl, hetaralkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -NH(Y2') and -N(Y2'')2; Y 2' is selected from -H, -OH, alkyl, alkoxy, alkoxyalkyl and cycloalkyl; each Y2'' is alkyl, or both occurrences taken together with the nitrogen atom to which they are attached form a 5- or 6-membered heterocycline; Y3, Y4, Y5, and Y6 are independently selected from -H, -OH, halide, alkyl, haloalkyl, and alkoxy; provided that Y3 and Y4 or Y5 and Y6 are not both -OH. Petition 870260063816, dated 06 / 29 / 2026, p. 89 / 739 82 / 315 or a pharmaceutically acceptable salt thereof.

[00159] In some embodiments of any of the disclosed methods, the compound is selected from: or a pharmaceutically acceptable salt thereof.

[00160] In some embodiments of any of the disclosed methods, the compound is selected from: or a pharmaceutically acceptable salt thereof.

[00161] In some embodiments of any of the disclosed methods, the compound is selected from the structure of any of the Petition 870260063816, dated 06 / 29 / 2026, page 90 / 739 83 / 315 compounds listed in Table 1.

[00162] In some embodiments of any of the disclosed methods, the compound is selected from the structure of any of the compounds listed in Table 2.

[00163] In some embodiments of any of the disclosed methods, the compound is selected from the structure of any of the compounds listed in Table 3.

[00164] In some embodiments of any of the disclosed methods, the compound is selected from the structure of any of the compounds listed in Table 4.

[00165] In some embodiments of any of the disclosed methods, the compound is selected from the structure of any of the compounds listed in Table 5. Pharmaceutical Compositions, Routes of Administration and Dosage

[00166] In certain embodiments, the invention relates to a pharmaceutical composition comprising a compound of the invention and a pharmaceutically acceptable carrier. In certain embodiments, the pharmaceutical composition comprises a plurality of compounds of the invention and a pharmaceutically acceptable carrier.

[00167] In certain embodiments, a pharmaceutical composition of the invention further comprises at least one additional pharmaceutically active agent other than a compound of the invention. The at least one additional pharmaceutically active agent may be a useful agent in the treatment of ischemia-reperfusion injury.

[00168] The pharmaceutical compositions of the invention may be prepared by combining one or more compounds of the invention with a pharmaceutically acceptable carrier and, optionally, one or more additional pharmaceutically active agents.

[00169] As mentioned above, an effective quantity refers to any quantity that is sufficient to achieve a Petition 870260063816, dated 06 / 29 / 2026, page 91 / 739 84 / 315 desired biological effect. Combined with the teachings provided in this document, by choosing from the various active compounds and weighting factors such as potency, relative bioavailability, patient body weight, severity of adverse side effects and mode of administration, an effective prophylactic or therapeutic treatment regimen can be planned that does not cause substantial undesirable toxicity and is still effective in treating the particular individual. The effective amount for any particular application may vary depending on such factors as the disease or condition being treated, the particular compound of the invention being administered, the size of the individual or the severity of the disease or condition. One skilled in the art can empirically determine the effective amount of a particular compound of the invention and / or other therapeutic agent without the need for undue experimentation.A maximum dose may be used, that is, the highest safe dose according to medical judgment. Multiple doses per day may be considered to achieve appropriate systemic levels of compounds. Appropriate systemic levels may be determined, for example, by measuring the peak or sustained plasma level of the drug in the patient. Dose and dosage are used interchangeably in this document.

[00170] In certain embodiments, the intravenous administration of a compound can typically be from 0.1 mg / kg / day to 20 mg / kg / day. In one embodiment, the intravenous administration of a compound can typically be from 0.1 mg / kg / day to 2 mg / kg / day. In one embodiment, the intravenous administration of a compound can typically be from 0.5 mg / kg / day to 5 mg / kg / day. In one embodiment, the intravenous administration of a compound can typically be from 1 mg / kg / day to 20 mg / kg / day. In one embodiment, the intravenous administration of a compound can typically be from 1 mg / kg / day to 10 mg / kg / day.

[00171] Generally, the daily oral doses of a compound will be, Petition 870260063816, dated 06 / 29 / 2026, p. 92 / 739 85 / 315 for human subjects, from approximately 0.01 milligrams / kg per day to 1000 milligrams / kg per day. Oral doses in the range of 0.5 to 50 milligrams / kg, in one or more administrations per day, are expected to produce therapeutic results. Dosage may be adjusted appropriately to achieve desired drug levels, local or systemic, depending on the route of administration. For example, intravenous administration is expected to be one order to several orders of magnitude lower per day. In the event that the response in an individual is insufficient at such doses, even higher doses (or higher effective doses via a different, more localized route of distribution) may be employed to the extent that patient tolerance permits. Multiple doses per day are contemplated to achieve appropriate systemic levels of the compound.

[00172] For any compound described in this document, the therapeutically effective amount can initially be determined from animal models. A therapeutically effective dose can also be determined from human data for compounds that have been tested in humans and for compounds that are known to exhibit similar pharmacological activities, such as other related active agents. Higher doses may be required for parenteral administration. The dose administered can be adjusted based on the relative bioavailability and potency of the compound administered. Adjusting the dose to achieve maximum efficacy based on the methods described above and other methods as are well known in the art and are well within the capabilities of those skilled in the art.

[00173] The formulations of the invention can be administered in pharmaceutically acceptable solutions, which may routinely contain pharmaceutically acceptable concentrations of salt, buffering agents, preservatives, compatible carriers, adjuvants and Petition 870260063816, dated 06 / 29 / 2026, page 93 / 739 86 / 315 optionally other therapeutic ingredients.

[00174] For use in therapy, an effective amount of the compound may be administered to an individual by any method that distributes the compound to the desired surface. Administration of a pharmaceutical composition may be carried out by any means known to those skilled in the art. Routes of administration include, but are not limited to, intravenous, intramuscular, intraperitoneal, intravesical (urinary bladder), oral, subcutaneous, direct (e.g., into a tumor or abscess), mucosal (e.g., topical to the eye), inhalation, and topical injection.

[00175] For intravenous and other parenteral routes of administration, a compound of the invention may be formulated as a lyophilized preparation, as a lyophilized preparation of the active compound intercalated or encapsulated by liposomes, as a lipid complex in aqueous suspension, or as a saline complex. Lyophilized formulations are generally reconstituted in a suitable aqueous solution, for example, in sterile water or saline solution, shortly before administration.

[00176] For oral administration, the compounds can be readily formulated by combining the active compound(s) with pharmaceutically acceptable carriers well known in the art. Such carriers allow the compounds of the invention to be formulated as tablets, pills, coated tablets, capsules, liquids, gels, syrups, fluid pastes, suspensions and the like, for oral ingestion by an individual to be treated. Pharmaceutical preparations for oral use can be obtained as a solid excipient by optionally grinding a resulting mixture and processing the granule mixture, after the addition of suitable excipients, if desired, to obtain tablet or coated tablet cores. Suitable excipients are, in particular, fillers such as sugars, including lactose, Petition 870260063816, dated 06 / 29 / 2026, page 94 / 739 87 / 315 sucrose, mannitol or sorbitol; cellulose preparations, such as, for example, corn starch, wheat starch, rice starch, potato starch, gelatin, tragacanth gum, methylcellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose and / or polyvinylpyrrolidone (PVP). If desired, disintegrating agents may be added, such as cross-linked polyvinylpyrrolidone, agar, or alginic acid or a salt thereof, such as sodium alginate. Optionally, oral formulations may also be formulated in saline solution or buffers, for example, EDTA for neutralization of internal acidic conditions, or may be administered without any carrier.

[00177] Oral dosage forms of the above component or components are specifically contemplated. The component or components may be chemically modified to make the oral delivery of the derivative effective. Generally, the chemical modification contemplated is the attachment of at least one moiety to the component molecule itself, wherein said moiety allows (a) inhibition of acid hydrolysis; and (b) absorption into the bloodstream from the stomach or intestine. Increased overall stability of the component or components and increased circulation time in the body are also desired. Examples of such moieties include: polyethylene glycol, ethylene glycol and propylene glycol copolymers, carboxymethylcellulose, dextran, polyvinyl alcohol, polyvinylpyrrolidone, and polyproline. Abuchowski and Davis, Soluble Polymer-Enzyme Adducts, In: Enzymes as Drugs, Hocenberg and Roberts, eds., Wiley-Interscience, New York, NY, pp. 367-383 (1981); Newmark et al., J Appl Biochem 4:185-9 (1982).Other polymers that can be used are poly-1,3-dioxolane and poly-1,3,6-thioxocane. For pharmaceutical use, as indicated above, polyethylene glycol moieties are suitable.

[00178] For the component (or derivative), the release location Petition 870260063816, dated 06 / 29 / 2026, page 95 / 739 88 / 315 can be the stomach, the small intestine (duodenum, jejunum or ileum) or the large intestine. Those skilled in the art have available formulations that will not dissolve in the stomach, but will release the material in the duodenum or elsewhere in the intestine. Preferably, the release will avoid the deleterious effects of the stomach environment, either by protecting the compound of the invention (or derivative) or by releasing the biologically active material beyond the stomach environment, such as into the intestine.

[00179] To ensure complete gastric resistance, a coating impermeable to at least pH 5.0 is essential. Examples of the most common inert ingredients used as enteric coatings are cellulose acetate trimellite (CAT), hydroxypropyl methylcellulose phthalate (HPMCP), HPMCP 50, HPMCP 55, polyvinyl acetate phthalate (PVAP), Eudragit L30D, Aquateric, cellulose acetate phthalate (CAP), Eudragit L, Eudragit S, and shellac. These coatings can be used as mixed films.

[00180] A coating or mixture of coatings may also be used on tablets that are not intended for stomach protection. This may include sugar coatings or coatings that make the tablet easier to swallow. Capsules may consist of a hard shell (such as gelatin) for the delivery of dry therapeutics (e.g., powder); for liquid forms, a soft gelatin shell may be used. The shell material of cachets may be thick starch or other edible paper. For pills, lozenges, molded or crushed tablets, wet mass techniques may be used.

[00181] The therapeutic agent may be included in the formulation as multiple fine particulates in the form of granules or pellets with a particle size of approximately 1 mm. The formulation of the material for capsule administration may also be as a powder, plugs Petition 870260063816, dated 06 / 29 / 2026, page 96 / 739 89 / 315 slightly compressed or even as tablets. The therapeutic agent can be prepared by compression.

[00182] Colorants and flavoring agents may all be included. For example, the compound of the invention (or derivative) may be formulated (e.g., by encapsulation of liposomes or microspheres) and then further contained within an edible product, such as a chilled beverage containing colorants and flavoring agents.

[00183] The therapeutic agent can be diluted or its volume increased with an inert material. These diluents may include carbohydrates, especially mannitol, β-lactose, anhydrous lactose, cellulose, sucrose, modified dextrans, and starch. Certain inorganic salts can also be used as fillers, including calcium triphosphate, magnesium carbonate, and sodium chloride. Some commercially available diluents are Fast-Flo, Emdex, STA-Rx 1500, Emcompress, and Avicell.

[00184] Disintegrants can be included in the therapeutic formulation in a solid dosage form. Materials used as disintegrants include, but are not limited to, starch, including the commercial starch-based disintegrant, Explotab. Sodium starch glycolate, Amberlite, sodium carboxymethylcellulose, ultramylopectin, sodium alginate, gelatin, orange peel, acidic carboxymethylcellulose, natural sponge, and bentonite can all be used. Another form of disintegrants is insoluble cation exchange resin. Powdered gums can be used as disintegrants and binders and may include powdered gums such as agar, Karaya, or tragacanth. Alginic acid and its sodium salt are also useful as disintegrants.

[00185] Binders can be used to hold the therapeutic agent together to form a hard tablet and include materials Petition 870260063816, dated 06 / 29 / 2026, page 97 / 739 90 / 315 of natural products, such as acacia, tragacanth, starch and gelatin. Others include methylcellulose (MC), ethylcellulose (EC) and carboxymethyl cellulose (CMC). Polyvinylpyrrolidone (PVP) and hydroxypropylmethylcellulose (HPMC) can both be used in alcoholic solutions to granulate the therapeutic.

[00186] An antifriction agent may be included in the formulation of the therapeutic agent to prevent adhesion during the formulation process. Lubricants may be used as a layer between the therapeutic agent and the matrix and may include, but are not limited to: stearic acid including its magnesium and calcium salts, polytetrafluoroethylene (PTFE), liquid paraffin, vegetable oils and waxes. Soluble lubricants may also be used, such as sodium lauryl sulfate, magnesium lauryl sulfate, polyethylene glycol of various molecular weights and Carbowax 4000 and 6000.

[00187] Glidants that can improve the flow properties of the drug during formulation and aid rearrangement during compression may be added. Glidants may include starch, talc, fumed silica, and hydrated silicoaluminate.

[00188] To aid the dissolution of the therapeutic agent in the aqueous environment, a surfactant may be added as a wetting agent. Surfactants may include anionic detergents such as sodium lauryl sulfate, sodium dioctyl sulfosuccinate, and sodium dioctyl sulfonate. Cationic detergents that may be used include benzalkonium chloride and benzethonium chloride. Potential nonionic detergents that could be included in the formulation as surfactants include lauromacrogol 400, polyoxyl stearate 40, polyoxyethylene hydrogenated castor oil 10, 50 and 60, glycerol monostearate, polysorbate 40, 60, 65 and 80, sucrose fatty acid ester, methylcellulose, and carboxymethylcellulose. These surfactants may be present in the formulation of the compound of Petition 870260063816, dated 06 / 29 / 2026, page 98 / 739 91 / 315 invention or derivative, whether alone or as a mixture, for different reasons.

[00189] Pharmaceutical preparations that can be used orally include hard gelatin capsules, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. Hard capsules may contain the active ingredients mixed with the filling, such as lactose, binders such as starches, and / or lubricants such as talc or magnesium stearate, and optionally, stabilizers. In soft capsules, the active compounds may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols. In addition, stabilizers may be added. Microspheres formulated for oral administration may also be used. Such microspheres have been well defined in the art. All formulations for oral administration must be in dosages suitable for such administration.

[00190] For oral administration, the compositions may take the form of conventionally formulated tablets or lozenges.

[00191] For topical administration, the compound can be formulated as solutions, gels, ointments, creams, suspensions, etc., as are well known in the art. Systemic formulations include those designed for administration by injection, for example, subcutaneous, intravenous, intramuscular, intrathecal, or intraperitoneal injection, as well as those designed for transdermal, transmucosal, oral, or pulmonary administration.

[00192] For administration by inhalation, compounds for use according to the present invention may be conveniently distributed in the form of a pressurized packet aerosol spray presentation or a nebulizer, using Petition 870260063816, dated 06 / 29 / 2026, page 99 / 739 92 / 315 a suitable propellant, for example, dichlorodifluoromethane, trichloromonofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In the case of a pressurized aerosol, the dosing unit can be determined by providing a valve to dispense a dosed quantity. Capsules and cartridges, for example, of gelatin for use in an inhaler or insufflator, may be formulated containing a powder mixture of the compound and a suitable powder base, such as lactose or starch.

[00193] This document also contemplates the pulmonary distribution of the compounds disclosed herein (or salts thereof). The compound is distributed to the lungs of a mammal during inhalation and passes through the epithelial lining of the lung into the bloodstream. Other reports of inhaled molecules include Adjei et al., Pharm Res 7: 565-569 (1990); Adjei et al., Int J Pharmaceutics 63: 135-144 (1990) (leuprolide acetate); Braquet et al., J Cardiovasc Pharmacol 13(suppl. 5):143-146 (1989) (endothelin-1); Hubbard et al., Annal Int Med 3: 206-212 (1989) (αΐ-antitrypsin); Smith et al., 1989, J Clin Invest 84:1145-1146 (α-1-proteinase); Oswein et al., 1990, Aerosolization of Proteins, Proceedings of Symposium on Respiratory Drug Delivery II, Keystone, Colorado, March (recombinant human growth hormone); Debs et al., 1988, J Immunol 140: 3482-3488 (interferon-gamma necrosis factor alpha and tumor necrosis factor) and Platz et al., US Pat. No.5,284,656 (granulocyte colony-stimulating factor; incorporated by reference). A method and composition for pulmonary delivery of drugs for systemic effect is described in U.S. Pat. No. 5,451,569 (incorporated by reference), issued September 19, 1995 to Wong et al.

[00194] Contemplated for use in the practice of this invention are a wide range of mechanical devices designed for pulmonary delivery of therapeutic products, including, but not limited to, Petition 870260063816, dated 06 / 29 / 2026, page 100 / 739 93 / 315 nebulizers, metered-dose inhalers, and dry powder inhalers, all of which are familiar to those skilled in the art.

[00195] Some specific examples of commercially available devices suitable for the practice of this invention are the Ultravent nebulizer, manufactured by Mallinckrodt, Inc., St. Louis, Mo.; the Acorn II nebulizer, manufactured by Marquest Medical Products, Englewood, Colo.; the Ventolin metered-dose inhaler, manufactured by Glaxo Inc., Research Triangle Park, North Carolina; the Spinhaler dry powder inhaler, manufactured by Fisons Corp., Bedford, Mass.

[00196] All these devices require the use of appropriate formulations for the delivery of the compounds of the invention. Typically, each formulation is specific to the type of device used and may involve the use of an appropriate propellant material, in addition to the usual diluents, adjuvants and / or carriers useful in therapy. Furthermore, the use of liposomes, microcapsules or microspheres, inclusion complexes or other types of carriers is contemplated. The chemically modified compound of the invention can also be prepared in different formulations depending on the type of chemical modification or the type of device used.

[00197] Formulations suitable for use with a nebulizer, whether jet or ultrasonic, will typically comprise a compound of the invention (or derivative) dissolved in water at a concentration of about 0.1 to 25 mg of the biologically active compound of the invention per mL of solution. The formulation may also include a buffer and a simple sugar (e.g., for inhibitor stabilization and osmotic pressure regulation). The nebulizer formulation may also contain a surfactant to reduce or prevent aggregation induced on the surface of the compound of the invention caused by atomization of the solution in aerosol formation.

[00198] Formulations for use with an inhaler device Petition 870260063816, dated 06 / 29 / 2026, page 101 / 739 94 / 315 metered-dose sprays will generally comprise a finely divided powder containing the compound of the invention (or derivative) suspended in a propellant with the aid of a surfactant. The propellant may be any conventional material used for this purpose, such as a chlorofluorocarbon, a hydrochlorofluorocarbon, a hydrofluorocarbon or a hydrocarbon, including trichlorofluoromethane, dichlorodifluoromethane, dichlorotetrafluoroethanol and 1,1,1,2-tetrafluoroethane, or combinations thereof. Suitable surfactants include sorbitan trioleate and soy lecithin. Oleic acid may also be useful as a surfactant.

[00199] Formulations for dispensing from a powder inhaler device will comprise a finely divided powder containing the compound of the invention (or derivative) and may also include a bulking agent, such as lactose, sorbitol, sucrose or mannitol in amounts that facilitate the dispersion of the powder from the device, for example, 50 to 90% by weight of the formulation. The compound of the invention (or derivative) should advantageously be prepared in the form of particles with an average particle size of less than 10 micrometers (µm), especially preferably from 0.5 to 5 µm, for more effective distribution to the deep lung.

[00200] Nasal delivery of a pharmaceutical composition of the present invention is also contemplated. Nasal delivery allows the passage of a pharmaceutical composition of the present invention into the bloodstream directly after administration of the therapeutic product to the nose, without the need for deposition of the product in the lungs. Formulations for nasal delivery include those with dextran or cyclodextran.

[00201] For nasal administration, a useful device is a small, hard bottle to which a metered-dose sprayer is attached. In one embodiment, the measured dose is dispensed by drawing the Petition 870260063816, dated 06 / 29 / 2026, page 102 / 739 95 / 315 pharmaceutical composition of the solution of the present invention in a chamber of defined volume, which chamber has an opening sized for aerosolization and aerosol formulation forming a spray when a liquid in the chamber is compressed. The chamber is compressed to administer the pharmaceutical composition of the present invention. In a specific embodiment, the chamber is a piston arrangement. Such devices are commercially available.

[00202] Alternatively, a plastic compression bottle with an opening sized to aerosolize an aerosol formulation is used, forming a spray when compressed. The opening is normally found at the top of the bottle, and the top is usually tapered to partially fit into the nasal passages for efficient administration of the aerosol formulation. Preferably, the nasal inhaler will deliver a metered amount of the aerosol formulation for administration of a measured dose of the drug.

[00203] Compounds, when systemically distributed, may be formulated for parenteral administration by injection, for example, by bolus injection or continuous infusion. Injection formulations may be presented in unit dosage form, for example, in ampoules or multi-dose containers, with an added preservative. Compositions may take forms such as suspensions, solutions or emulsions in oily or aqueous vehicles and may contain formulation agents such as suspending, stabilizing and / or dispersing agents.

[00204] Pharmaceutical formulations for parenteral administration include aqueous solutions of the active compounds in water-soluble form. Additionally, suspensions of the active compounds may be prepared as oily injection suspensions. Petition 870260063816, dated 06 / 29 / 2026, page 103 / 739 96 / 315 appropriate. Suitable lipophilic solvents or vehicles include fatty oils, such as sesame oil, or synthetic fatty acid esters, such as ethyl oleate or triglycerides or liposomes. Aqueous injection suspensions may contain substances that increase the viscosity of the suspension, such as sodium carboxymethylcellulose, sorbitol, or dextran. Optionally, the suspension may also contain suitable stabilizers or agents that increase the solubility of the compounds to allow the preparation of highly concentrated solutions.

[00205] Alternatively, the active compounds may be in powder form for mixing with a suitable vehicle, for example, sterile pyrogen-free water prior to use.

[00206] The compounds can also be formulated in rectal or vaginal compositions, such as suppositories or retention enemas, for example, containing conventional suppository bases, such as cocoa butter or other glycerides.

[00207] In addition to the formulations described above, a compound may also be formulated as a depot preparation. Such long-acting formulations may be formulated with suitable polymeric or hydrophobic materials (e.g., as an acceptable oil emulsion) or ion-exchange resins, or as moderately soluble derivatives, e.g., as a moderately soluble salt.

[00208] Pharmaceutical compositions may also comprise suitable gel or solid phase carriers or excipients. Examples of such carriers or excipients include, but are not limited to, calcium carbonate, calcium phosphate, various sugars, starches, cellulose derivatives, gelatin, and polymers such as polyethylene glycols.

[00209] Liquid or solid pharmaceutical preparation forms Petition 870260063816, dated 06 / 29 / 2026, page 104 / 739 Suitable pharmaceutical compositions include, for example, aqueous or saline solutions for inhalation, microencapsulated, encapsulated, coated with microscopic gold particles, contained in liposomes, nebulized, aerosols, pellets for implantation in the skin, or dried on a sharp object to be scratched into the skin. Pharmaceutical compositions also include granules, powders, tablets, coated tablets, (micro)capsules, suppositories, syrups, emulsions, suspensions, creams, drops, or preparations with prolonged release of active compounds, in whose preparation excipients and additives and / or auxiliaries such as disintegrants, binders, coating agents, swelling agents, lubricants, flavorings, sweeteners, or solubilizers are commonly used as described above. Pharmaceutical compositions are suitable for use in a variety of drug delivery systems.For a brief review of methods for drug delivery, see Langer R, Science 249:1527-33 (1990).

[00210] The compound of the invention and, optionally, other therapeutics may be administered per se (pure) or in the form of a pharmaceutically acceptable salt or cocrystal. When used in medicaments, the salts or cocrystals must be pharmaceutically acceptable, but non-pharmaceutically acceptable salts or cocrystals may conveniently be used to prepare pharmaceutically acceptable salts or cocrystals thereof. Such salts include, but are not limited to, those prepared from the following acids: hydrochloric, hydrobromic, sulfuric, nitric, phosphoric, maleic, acetic, salicylic, ptoluene sulfonic, tartaric, citric, methanesulfonic, formic, malonic, succinic, naphthalene-2-sulfonic and benzene sulfonic. Furthermore, such salts can be prepared as alkali or alkaline earth metal salts, such as sodium, potassium, or calcium salts of the carboxylic acid group.

[00211] Suitable buffering agents include: acetic acid and a salt Petition 870260063816, dated 06 / 29 / 2026, page 105 / 739 98 / 315 (1-2% w / v); citric acid and a salt (1-3% w / v); boric acid and a salt (0.5-2.5% w / v); and phosphonic acid and a salt (0.8-2% w / v). Suitable preservatives include benzalkonium chloride (0.003-0.03% w / v); chlorobutanol (0.3-0.9% w / v); parabens (0.01-0.25% w / v) and thimerosal (0.004-0.02% w / v).

[00212] The pharmaceutical compositions of the invention contain an effective amount of a compound as described in this document and, optionally, therapeutic agents included in a pharmaceutically acceptable carrier. The term pharmaceutically acceptable carrier means one or more compatible solid or liquid fillers, diluents or encapsulating substances that are suitable for administration to a human or other vertebrate animal. The term carrier denotes an organic or inorganic, natural or synthetic ingredient with which the active ingredient is combined to facilitate application. The components of the pharmaceutical compositions are also capable of being mixed with the compounds of the present invention, and with each other, in such a way that there is no interaction that substantially impairs the desired pharmaceutical efficacy.

[00213] The therapeutic agent(s), including specifically, but not limited to, the compound of the invention, may be provided in particles. Particles, as used in this document, means nanoparticles or microparticles (or, in some cases, larger particles) that may consist wholly or partially of the compound of the invention or the other therapeutic agent(s) as described in this document. The particles may contain the therapeutic agent(s) in a core surrounded by a coating, including, but not limited to, an enteric coating. The therapeutic agent(s) may also be dispersed within the particles. The therapeutic agent(s) may also be adsorbed onto the particles. Petition 870260063816, dated 06 / 29 / 2026, page 106 / 739 99 / 315 The particles may be of any order of release kinetics, including zero-order release, first-order release, second-order release, delayed release, sustained release, immediate release, and any combination thereof, etc. The particle may include, in addition to the therapeutic agent(s), any of these materials routinely used in the pharmaceutical and medical technique, including, but not limited to, erodible, non-erodible, biodegradable, or non-biodegradable material, or combinations thereof. The particles may be microcapsules containing the compound of the invention in a solution or in a semi-solid state. The particles may be of virtually any shape.

[00214] Both non-biodegradable and biodegradable polymeric materials can be used in the manufacture of particles to deliver the therapeutic agent(s). Such polymers can be natural or synthetic polymers. The polymer is selected based on the time period during which release is desired. Bioadhesive polymers of particular interest include bioerodible hydrogels described in Sawhney HS et al. (1993) Macromolecules 26:581-7, the teachings of which are incorporated into this document. These include polyhyaluronic acids, casein, gelatin, gluten, polyanhydrides, polyacrylic acid, alginate, chitosan, poly(methyl methacrylates), poly(ethyl methacrylates), poly(butyl methacrylate), poly(isobutyl methacrylate), poly(hexyl methacrylate), poly(isodecyl methacrylate), poly(lauryl methacrylate), poly(phenyl methacrylate), poly(methyl acrylate), poly(isopropyl acrylate), poly(isobutyl acrylate), and poly(octadecyl acrylate).

[00215] The therapeutic agent(s) may be contained in controlled-release systems. The term controlled-release refers to any drug-containing formulation in which the manner and profile of drug release from the formulation are controlled. This refers to immediate-release formulations as well as non-immediate-release formulations. Petition 870260063816, dated 06 / 29 / 2026, page 107 / 739 100 / 315 immediate, with non-immediate-release formulations including, but not limited to, sustained-release and delayed-release formulations. The term sustained-release (also called prolonged-release) is used in its conventional sense to refer to a drug formulation that provides for the gradual release of a drug over a prolonged period of time, and preferably, though not necessarily, results in substantially constant blood levels of a drug over a prolonged period of time. The term delayed-release is used in its conventional sense to refer to a drug formulation in which there is a time delay between administration of the formulation and the release of the drug from it. Delayed-release may or may not involve the gradual release of drugs over a prolonged period of time and thus may or may not be sustained-release.

[00216] The use of a long-term sustained-release implant may be particularly suitable for the treatment of chronic conditions. Long-term release, as used in this document, means that the implant is constructed and arranged to deliver therapeutic levels of the active ingredient for at least 7 days and preferably 30 to 60 days. Long-term sustained-release implants are well known to those skilled in the art and include some of the delivery systems described above.

[00217] It will be understood by one skilled in the relevant art that other modifications and adaptations suitable to the compositions and methods described in this document are readily apparent from the description of the invention contained herein in view of the information known to one skilled in the art and can be made without departing from the scope of the invention or any embodiment thereof. Having now described the present invention in detail, it will become more clearly understood by reference to the following Petition 870260063816, dated 06 / 29 / 2026, p. 108 / 739 101 / 315 examples, which are included in this document for illustrative purposes only and are not intended to be limiting of the invention. EXAMPLES

[00218] The invention will be further described in the following examples, which do not limit the scope of the invention described in the claims. Example 1: Isoleucine transport assay SLC6A19 Cell line generation and maintenance

[00219] The Flp-In™ T-REx™ 293 cell line was acquired from Thermo Fisher Scientific. The cell line was used to generate a stable cell line that inducibly expresses human SLC6A19 with a C-terminal V5 tag and stably expresses human TMEM27 (also known as Collectrin) with a C-terminal myc-DDK tag. The stable cell line was generated by transfection of plasmids encoding SLC6A19 and TMEM27 using standard protocols, followed by antibiotic selection. The stable cells were maintained in DMEM / F12 supplemented with Glutamax, 10% fetal bovine serum, 100 U / mL penicillin, 100 µg / mL streptomycin, 200 µg / mL hygromycin, 10 µg / mL blasticidin, and 300 µg / mL neomycin (Thermo Fisher). Assay: Isoleucine transport assay in 96-well format

[00220] Stable cell lines were seeded at a density of 35,000 cells per well in a 96-well cell culture-treated plate coated with poly-D-lysine on day 0. On day 1, SLC6A19 expression was induced by dispensing tetracycline at a final concentration of 1 µg / mL using a Tecan D300e digital dispenser. On day 2, the transport assay was run. Media were removed from the plate using the GentleSpin setting of a Centrifugal Blue Washer (Blue Cat Bio) and cells were washed with 175 µL of live cell imaging solution (Thermo Fisher). Petition 870260063816, dated 06 / 29 / 2026, page 109 / 739 102 / 315 using the Blue Washer. Following washing, the cells were treated with 70 µL of DMSO, positive control or compound, diluted in Krebs buffer (140 mM NaCl, 4.7 mM KCl, 2.5 mM CaCl2, 1.2 mM MgCb, 11 mM HEPES, 10 mM glucose, pH 7.4) at room temperature. After 20 to 60 minutes, 30 µL of a 3.3 mM 13C6,15N-L-isoleucine solution (Cambridge Isotope Laboratories) was added. After 20 min of incubation with the isoleucine substrate at room temperature, the cells were washed with 175 µL of live cell imaging solution using the Blue Washer. The cells were then lysed in 150 µL of 15 µM D-Leucine-d10 (CDN isotopes) in ultrapure water. The plates were placed on a shaker at 700 rpm for a minimum of 40 minutes to facilitate lysis. Following lysis, a standard dilution curve of 13C6,15N-Lysoleucine was added to wells containing lysates of untreated cells.The plates were returned to the shaker for a minimum of 2 minutes to ensure proper mixing of the standard curve. The plates were then centrifuged for 5 min at 4,000 rpm to granulate cellular debris and precipitate. The supernatants were diluted 1:10 in acetonitrile + 0.1% formic acid in polypropylene plates. Assay: Isoleucine transport assay in 384-well format

[00221] On day 0, stable cell lines were seeded at a density of 20,000 cells per well in a 384-well cell culture plate coated with poly-D-lysine in media containing 1 µg / mL tetracycline using a 384-well Viaflo pipette. Transport assays were performed the following day (day 1). Media were removed from the plate using the GentleSpin setting of a Centrifugal Blue Washer (Blue Cat Bio) and cells were washed with 80 µL of live cell imaging solution (Thermo Fisher) using the Blue Washer. Following washing, cells were treated with 20 µL of DMSO, positive control or Petition 870260063816, dated 06 / 29 / 2026, page 110 / 739 103 / 315 compound, diluted in Krebs buffer (140 mM NaCl, 4.7 mM KCl, 2.5 mM CaCb, 1.2 mM MgCb, 11 mM HEPES, 10 mM glucose, pH 7.4) using a TECAN liquid handler. After 20 to 60 minutes, 8.6 µL of a 3.3 mM 13C6,15N-L-isoleucine solution (Cambridge Isotope Laboratories) was added for incubation at room temperature. After 20 min of incubation with the isoleucine substrate at room temperature, the cells were washed with 80 µL of live cell imaging solution using the Blue Washer. The cells were then lysed in 80 µL of 15 µM D-Leucine-d10 (CDN isotopes) in ultrapure water. The plates were placed on a shaker at 700 rpm for a minimum of 2 hours to facilitate lysis. Following lysis, a standard dilution curve of 13C6,15N-L-isoleucine was added to wells containing lysates of untreated cells. The plates were returned to the shaker for a minimum of 5 minutes to ensure proper mixing of the standard curve.The plates were then centrifuged for 10 min at 4,000 rpm to granulate and precipitate cellular debris. The supernatants were diluted 1:10 in acetonitrile + 0.1% formic acid in polypropylene plates.

[00222] The analysis of 13C6,15N-L-isoleucine was performed using a RapidFire365-QTOF 6545 (Agilent). Quantitative sample analysis utilizes automated solid-phase extraction (HILIC H6 cartridge) prior to mass spectrometry injection. Samples were loaded using 95% acetonitrile, 0.1% formic acid and eluted from the cartridge with 5% acetonitrile, 0.1% formic acid directly for ESI-MS (electrospray ionization) analysis. Analyte quantification was performed using Agilent Masshunter Quant software from high-resolution full-scan data. General Procedure A: Petition 870260063816, dated 06 / 29 / 2026, page 111 / 739 104 / 315 BTC toluene TEA,DCM A4 A1 A2 Step 1: Synthesis of Compound A2

[00223] A solution of bistrichloromethyl carbonate (BTC) (0.5 eq.) in toluene at 0°C was added dropwise under a N2 atmosphere. The resulting mixture was stirred at room temperature for 15 minutes and then heated to 130°C and stirred for 2 hours under a N2 atmosphere. After cooling, the mixture was concentrated to dryness under reduced pressure to yield the crude compound A2, which was used directly in the next step without further purification. Step 2: Synthesis of Compound A4

[00224] A solution of compound A2 (1 eq.) in anhydrous DCM at 0°C was added dropwise under a N2 atmosphere to a mixture of compound A3 (1 eq.) and TEA (3 eq.) in anhydrous DCM. The resulting mixture was stirred at 0°C for 1 hour under a N2 atmosphere. Then the mixture was diluted with water and extracted twice with EtOAc. The combined organic layer was separated, washed with brine, dried with anhydrous Na2SO4, filtered, and concentrated to dryness. The residue was purified by flash column chromatography (eluted with DCM / MeOH) to yield compound A4. Example 2. Synthesis of 3-[(4-chloro-2-fluoro-5-methylphenyl)methyl]-1-cyclopropyl-1-[(3R)-1-(pyridazin-3-yl)piperidin-3-yl]urea Petition 870260063816, dated 06 / 29 / 2026, p. 112 / 739 105 / 315 k2co3,dmf H2,Pd / C EtOH M1 M2 NaBH3CN, cat. AcOH, DCM M4 NaBH(OAc)3, EtOH.THF M6 TEA,DCM Example 2 Step 1: M2 Synthesis

[00225] To a mixture of M1 (10 g, 49.93 mmol) and K2CO3 (20.7 g, 149.8 mmol) in DMF (200 mL) was added 3,6-dichloropyridazine (7.44 g, 49.93 mmol). The resulting mixture was stirred at 80°C for 16 hours. After cooling, the resulting mixture was poured into water (800 mL). The precipitated solid was collected by filtration, washed with water (100 mL) and then dissolved with EtOAc. The organic layer was dried over Na2SO4, separated, and concentrated under reduced pressure to yield M2 (12 g, 38.36 mmol, 76.83% yield) as a yellow solid. LC / MS (ESI) m / z: 313 (M+H)+. Petition 870260063816, dated 06 / 29 / 2026, p. 113 / 739 106 / 315 Step 2: M3 Synthesis

[00226] To a solution of M2 (12 g, 38.36 mmol) in MeOH (200 mL) were added Pd / C (4.0 g, 10%). The resulting mixture was stirred at room temperature for 3 hours under a hydrogen atmosphere. Then, the mixture was filtered, the filtrate was concentrated under reduced pressure to yield M3 (10 g, 35.93 mmol, 93.63% yield) as a yellow solid. LC / MS (ESI) m / z: 279 (M+H)+. Step 3: M4 Synthesis

[00227] To a solution of compound M3 (10 g, 35.93 mmol) in DCM (60 mL) TFA (60 mL) was added. The resulting mixture was stirred at room temperature for 4 hours. The resulting mixture was concentrated to dryness under reduced pressure. The residue was diluted with MeOH and added with NaHCO3. The mixture was stirred at room temperature for 40 minutes to change the pH to 8-9. Then, the mixture was filtered, and the filtrate was concentrated under reduced pressure to yield M4 (6 g, 33.7 mmol, 93.7% yield) as a yellow oil. LC / MS (ESI) m / z: 179 (M+H)+. Step 4: M5 Synthesis

[00228] To a mixture of compound M4 (5.8 g, 32.54 mmol) and 2,4-dimethoxybenzaldehyde (5.41 g, 32.54 mmol) in DCM (100 mL) was added AcOH (5.86 g, 97.62 mmol). The mixture was stirred for 1 hour at room temperature. Then, NaBH(OAc)3 (20.7 g, 97.62 mmol) was added to the above mixture. The resulting mixture was stirred for 3 hours. Then the mixture was concentrated under reduced pressure. The residue was diluted with EtOAc and washed with aqueous NaHCO3 solution at pH=8. The organic layer was washed with brine, dried over anhydrous Na2SO4 and concentrated to dryness. The crude product was purified by silica gel column chromatography (eluting with 5% MeOH in DCM) to yield M5 (5 g, 13.7 mmol, 42.10% yield) as a yellow LC / MS (ESI) solid m / z: 329 (M+H)+. Petition 870260063816, dated 06 / 29 / 2026, p. 114 / 739 107 / 315 Step 5: M6 Synthesis

[00229] To a mixture of M5 (800 mg, 2.436 mmol) and (1-ethoxycyclopropoxy)trimethylsilane (1.06 g, 6.09 mmol) in EtOH (10 mL) and THF (20 mL) was added AcOH (2.19 g, 36.54 mmol) and NaBH3CN (538 mg, 8.526 mmol). The resulting mixture was stirred for 16 hours at 80°C. After cooling, the resulting mixture was concentrated under reduced pressure. The residue was diluted with EtOAc and washed with water and brine. The organic layer was dried over anhydrous Na2SO4 and concentrated to dryness. The crude product was purified by silica column chromatography (eluting with 4% MeOH in DCM) to give M6 (560 mg, 1.52 mmol, 62.40% yield) as a yellow solid. LC / MS (ESI) m / z: 369 (M+H)+. M7 Synthesis

[00230] Compound M6 (560 mg, 1.520 mmol) was added to TFA (18 mL) and the resulting mixture was stirred at 80°C for 4 hours. After cooling, the mixture was concentrated under reduced pressure to yield crude M7 (274 mg, 0.825 mmol, 54.26%) as a TFA salt. LC / MS (ESI) m / z: 219 (M+H)+. 3-[(4-Chloro-2-fluoro-5-methylphenyl)methyl]-1-cyclopropyl-1-[(3R)-1(pyridazin-3-yl)piperidin-3-yl]urea

[00231] To a mixture of M7 (274 mg, 0.824 mmol) in DCM (10 mL) were added TEA (251 mg, 2.473 mmol). After stirring at room temperature for 30 minutes, a solution of 2 (160 mg, 0.824 mmol) in DCM (2 mL) was added to the above mixture at 0°C. The resulting solution was stirred for 30 minutes at room temperature. Then the mixture was concentrated under reduced pressure until dry. The crude product was purified by silica gel column chromatography (eluting with 5% MeOH in DCM) to yield Example 2 (103 mg, 0.247 mmol, 30.0% yield) as a light yellow solid. LC / MS (ESI) m / z: 418 (M+H)+. Petition 870260063816, dated 06 / 29 / 2026, p. 115 / 739 108 / 315

[00232] 1H NMR (400 MHz, DMSO-d6) δ 8.50 (dd, J = 4.4, 1.0 Hz, 1H), 7.36 - 7.30 (m, 2H), 7.28 - 7.21 (m, 2H), 6.89 (t, J = 5.8 Hz, 1H), 4.41 - 4.25 (m, 4H), 3.68 - 3.60 (m, 1H), 3.23 - 3.16 (m, 1H), 2.81 2.67 (m, 1H), 2.50 - 2.44 (m, 1H), 2.29 (s, 3H), 2.15 - 2.07 (m, 1H), 1.91 - 1.70 (m, 2H), 1.54 - 1.42 (m, 1H), 0.93 - 0.86 (m, 2H), 0.74 - 0.62 (m, 2H).19F NMR (400 MHz, DMSO-d6) δ -121.05 (s).

[00233] The compounds in the table below were prepared from suitable starting materials, described above or commercially available, using general procedure A above and intermediate M7 in Example 2. Exemplo Estrutura e nome Dados 3 0 O CM0_n H N,J 1-ciclopropil-3-[(3-fenil-1,2-oxazol-5il)metil]-1-[(3R)-1-(piridazin-3-il)piperidin3-il]ureia LC-MS: m / z 419 (M+H). 1H RMN (400 MHz, MeOD) δ 8,42 (d, J = 3,9 Hz, 1H), 7,87 - 7,77 (m, 2H), 7,52 - 7,43 (m, 3H), 7,36 (dd, J = 9,4, 4,4 Hz, 1H), 7,28 (dd, J = 9,4, 1,2 Hz, 1H), 6,67 (s, 1H), 4,56 (s, 2H), 4,45 - 4,31 (m, 2H), 3,88 3,71 (m,1H), 3,34 (d,J= 12,5Hz, 1H), 2,89 (td,J= 13,0, 2,7Hz, 1H), 2,62-2,53 (m,1H), 2,27 (dd,J= 12,6, 4,1Hz, 1H), 1,98 (d,J = 11,5Hz, 1H), 1,86 (d,J = 13,8Hz, 1H), 1,63 (d,J = 13,2Hz, 1H), 1,01-0,93 (m, 2H), 0,84 (dd, J = 8,0, 4,5 Hz, 2H). 4 θ ΛΑH λ M 1-ciclopropil-3-[(2,4-difluoro-5metilfenil)metil]-1-[(3R)-1-(piridazin-3- LC-MS: m / z 402,2 (M+H). 1H RMN (400 MHz, MeOD) δ 8,42 (dd, J = 4,4, 1,2 Hz, 1H), 7,36 (dd, J = 9,4, 4,4 Hz, 1H), 7,28 (dd, J = 9,4, 1,2Hz, 1H), 7,21 (t,J = 8,5Hz, 1H), 6,84 (t,J Petição 870260063816, de 29 / 06 / 2026, pág. 116 / 739 109 / 315 Exemplo Estrutura e nome Dados il)piperidin-3-il]ureia = 9,9Hz, 1H), 4,43-4,30 (m,4H), 3,77 (tt,J= 11,8, 3,9 Hz, 1H), 3,34 (s, 1H), 2,88 (td, J = 13,0, 2,7 Hz, 1H), 2,60 - 2,49 (m, 1H), 2,31 - 2,23 (m, 1H), 2,22 (s, 3H), 1,96 (d, J = 12,3 Hz, 1H), 1,90 - 1,81 (m, 1H), 1,70 - 1,54 (m, 1H), 0,99 0,91 (m, 2H), 0,78 (dd, J = 6,6, 4,1 Hz, 2H). 5 0 ΑΊ Η 1 η 1 ι Η A N'hT 3-[(4-cloro-2-fluorofenil)metil]-1ciclopropil-1-[(3R)-1-(piridazin-3il)piperidin-3-il]ureia LC-MS: m / z 404,1 (M+H). 1H RMN (400 MHz, MeOD) δ 8,42 (dd, J = 4,4, 1,2 Hz, 1H), 7,38 - 7,31 (m, 2H), 7,27 (dd, J = 9,4, 1,2 Hz, 1H), 7,20 - 7,14 (m, 2H), 4,42 (s, 2H), 4,41 4,30 (m, 2H), 3,76 (ddd, J = 15,8, 7,8, 3,9 Hz, 1H), 3,28 (s, 1H), 2,88 (td, J = 13,1, 2,7 Hz, 1H), 2,62 - 2,50 (m, 1H), 2,25 (qd, J = 12,5, 4,1 Hz, 1H), 2,03 - 1,78 (m, 2H), 1,71 - 1,54 (m, 1H), 1,00 - 0,91 (m, 2H), 0,83 0,76 (m, 2H).6 0 AA Υ^ΝΛΝ^ΝνΊ1 Η 1 h 1 . H À NV 3-[(4-chloro-3-methylphenyl)methyl]-1-cyclopropyl1-[(3R)-1-(pyridazin-3-yl)piperidin-3-yl]urea LC-MS: m / z 400.2 (M+H). 1H NMR (400 MHz, MeOD) δ 8.43 (d, J = 3.6 Hz, 1H), 7.36 (dd, J = 9.6, 4.4 Hz, 1H), 7.28 (d,J = 8.4Hz, 2H), 7.22 (s,1H), 7.1 (d,J = 4.4 Hz, 1Hz). 1H), 6.93 (t,J = 5.6 Hz, 1H), 4.40 (d,J = 13.6Hz, 1H), 4.34 (d,J= 6.0Hz, 3H), 3.77 (tt,J = 11.6, 4.0 Hz, 1H), 3.3, (d,J = 18). 13.2, 2.8 Hz, 1H), 2.59 - 2.48. Petition 870260063816, of 29 / 06 / 2026, p. 117 / 739 110 / 315 Example Name Structure Given (m, 1H), 2.35 (s, 3H), 2.26 (qd, J = 12.4, 4.0 Hz, 1H), 1.96 (d, J = 12.0 Hz, 1H), 1H), 0.94 (dd, J = 8.4, 5.6 Hz, 2H), 0.83 - 0.75 (m, 2H).

[00234] Examples 7 - 127 The compounds in the table below were prepared from the appropriate starting materials described above or commercially available, using the general procedure above and (R)-N-methyl-1-(pyridazin-3-yl)piperidin-3-amine (A3), or using intermediate M7 from Example 2.

[00235] tert-butyl N-methyl-N-[(3R)-3-piperidyl]carbamate (2.14 g, 10 mmol), 3-bromopyridazine (2.38 g, 15.00 mmol), cesium fluoride (151.90 mg, 1.00 mmol, 36.87 µL) and potassium carbonate (3.46 g, 25.00 mmol, 1.51 mL) were dissolved in DMSO (100 mL) and heated to 150°C overnight. The reaction mixture was then cooled to room temperature, poured into 600 mL of water and extracted with ethyl acetate (3 x 200 mL). The combined organic layers were washed with water (1 x 200 mL) and brine (1 x 200 mL), dried with anhydrous sodium sulfate, and concentrated under reduced pressure to provide a crude product that was purified by flash column chromatography (ethyl acetate:heptane, 0:100 to 40:60) to provide A2, tert-butyl N-methyl-N-[(3R)-1-pyridazin-3-yl-3-piperidyl]carbamate (1.57 g, 5.37 mmol, 53.70% yield). A2 (1.57 g, 5.37 mmol) was dissolved in DCM (4.2 mL) and TFA (6.12 g, 53.70 mmol, 4.14 mL) was added. The reaction mixture was stirred for four hours.The reaction mixture was then concentrated under pressure. Petition 870260063816, dated 06 / 29 / 2026, page 118 / 739 111 / 315 reduced by rotary evaporation. The crude residue was dissolved in ethyl acetate, washed with 1 M NaOH, brine and concentrated to provide A3,(R)-N-methyl-1-(pyridazin-3-yl)piperidin-3-amine (450 mg, 2.34 mmol, 43.59% yield) which was used without further purification. Exempl o Estrutura and name Dados 7 γγΑ^,Ογ.^ JL UH i L ii 3-[2-(3,4-dimetilfenil)ciclopropil]-1metil-1-[(3R)-1-(piridazin-3-il)piperidin3-il]ureia LC-MS: m / z 380.1 (M+H). 1H RMN (400 MHz, MeOD) δ 8.46 (s, 1H), 7.37 (s, 1H), 7.30 (dd, J = 9.5, 4.2 Hz, 1H), 7.01 - 6.90 (m, 2H), 6.84 (d, J = 9.0 Hz, 1H), 4.31 (d, J = 33.8 Hz, 2H), 4.07 (s, 1H), 3.03 (t, J = 11.5 Hz, 1H), 2.91 (d, J = 13.0 Hz, 1H), 2.85 (s, 3H), 2.72 (dd, J = 7.4, 3.2 Hz, 1H), 2.20 (d, J = 7.7 Hz, 6H), 1.98 (d, J = 3.7 Hz, 1H), 1.87 (s, 3H), 1.68 (s, 1H), 1.11 (dd, J = 16.7, 10.3 Hz, 2H). 8 F / γ^Λ'-θγ'N m H 1 L jj 3-{2-[2(difluorometoxi)fenil]ciclopropil}-1metil-1-[(3R)-1-(piridazin-3-il)piperidin3-il]ureia LC-MS: m / z 418,1 (M+H).1H RMN (400 MHz, MeOD) δ 8,45 (dd, J = 3,2, 1,2 Hz, 1H), 7,37 (ddd, J = 9,4, 4,4, 0,7 Hz, 1H), 7,28 (ddd, J = 9,4, 2,3, 1,2 Hz, 1H), 7,20 7,08 (m, 3H), 7,02 (dd, J = 7,2, 1,9 Hz, 1H), 7,00 - 6,60 (m, 1H), 4,39 (t, J= 15,6 Hz,1H), 4,25 (t,J = 15,7Hz, 1H), 4,07 (d,J = 4,6Hz, 1H), 3,08 3,00 (m,1H), 2,91 (dt,J = 7,6, 3,4Hz, 2H), 2,86 (s,3H), 2,25 (dtd, J = 9,9, 6,6, 3,5Hz, 1H), 1,87 (d,J = 6,8Hz, 3H), 1,67 (d,J = 11,5Hz, 1H), 1,36 - 1,30 (m, 1H), 1,21 - 1,13 (m, 1H). Petição 870260063816, de 29 / 06 / 2026, pág. 119 / 739 112 / 315 Example Structure and name Data 9 A ° O ι^Α<νΛν'··Ι^νυν·ν F LJ hi Fm F 1-methyl- 1-[(3R)- 1-(pyridazin-3- yl)piperidin-3-yl]-3-{2-[4- (trifluoromethyl)phenyl]cyclopropyl}urea LC-MS: m / z 420 (M+H). 1H NMR (400 MHz, MeOD) δ 8.49 - 8.44 (m, 1H), 7.53 (d, J = 8.2 Hz, 2H), 7.38 (ddd, J = 9.3, 4.4, 2.9 Hz, 1H), 7.30 (dd, J = 14.5, 5.4 Hz, 3H), 4.39 - 4.25 (m, 2H), 4.05 (s, 1H), 3.03 (t, J = 11.9 Hz, 1H), 2.92 (d, J = 14.7Hz, 1H), 2.86 (s,3H), 2.83 (dd,J = 7.6, 4.3Hz, 1H), 2.13 (qd, J = 6.6, 3.5Hz, 1H), 1.87 (d,J = 5.9Hz, 3H), 1.67 (s,1H), 1.39-1.33 (m,1H), 1.26 (d,J = 7.5Hz, 1H). 10 Λ 0 Γ^Ί K if NNNLH | I n CP 3-[2-(4-methoxyphenyl)cyclopropyl]-1-methyl-1-[(3R)-1-(pyridazin-3-yl)piperidin-3yl]urea LC-MS: m / z 382 (M+H).1H RMN (400 MHz, MeOD) δ 8,47 (d, J = 4,4 Hz, 1H), 7,42 - 7,35 (m, 1H), 7,33 - 7,27 (m, 1H), 7,09 (d, J = 8,7 Hz, 2H), 6,81 (d, J = 8,4 Hz, 2H), 4,37 (d, J = 13,5 Hz, 1H), 4,32 - 4,22 (m, 1H), 4,07 (s, 1H), 3,75 (s, 3H), 3,03 (t, J = 11,9 Hz, 1H), 2,92 (d, J = 12,7 Hz, 1H), 2,86 (s, 3H), 2,72 - 2,65 (m, 1H), 2,04 - 1,96 (m, 1H), 1,88 (dd, J = 11,4, 4,1 Hz, 3H), 1,68 (s, 1H), 1,19 - 1,12 (m, 1H), 1,10 - 1,04 (m, 1H). Petição 870260063816, de 29 / 06 / 2026, pág. 120 / 739 113 / 315 Exempl o Estrutura and name Dados 11 FF Λ ° '^'n'y>n'n H 1 Ljj 1 -metil-1-[(3R)-1-(piridazin-3il)piperidin-3-il]-3-{2-[3(trifluorometil)fenil]ciclopropil}ureia LC-MS: m / z 420 (M+H). 1H RMN (400 MHz, MeOD) δ 8.47 (dt, J = 4.4, 1.4 Hz, 1H), 8.24 (s, 1H), 7.48 (s, 1H), 7.44 (d, J = 5.1 Hz, 2H), 7.42 - 7.36 (m, 2H), 7.33 7.28 (m, 1H), 4.40 - 4.25 (m, 2H), 4.05 (s, 1H), 3.08 - 2.97 (m, 1H), 2.96 - 2.88 (m, 1H), 2.86 (s, 3H), 2.83 - 2.77 (m, 1H), 2.18 - 2,11 (m, 1H), 1,92 - 1.83 (m, 3H), 1.68 (s, 1H), 1.37 - 1.30 (m, 1H), 1.28 1.20 (m, 1H). 12 -°ΥΑ^ΝΛΝ'θγΝ'Ν Η | In 3-[2-(3-metoxifenil)ciclopropil]-1-metil- 1-[(3R)- 1-(piridazin-3-il)piperidin-3- il]ureia LC-MS: m / z 382 (M+H).1HNMR (400MHz, MeOD) δ 8,46 (d,J = 4,3Hz, 1H), 7,38 (ddd, J = 9,4, 4,4, 2,0Hz, 1H), 7,30 (ddd, J = 9,4, 3,9, 1,2Hz, 1H), 7,13 (t,J = 7,9 Hz, 1H), 6,75- 6,66 (m, 3H), 4,41 4,23 (m, 2H), 4,06 (s, 1H), 3,76 (d, J = 0,8 Hz, 3H), 3,07 - 2,97 (m, 1H), 2,95 - 2,81 (m, 4H), 2,76 (dt, J = 7,7, 3,9 Hz, 1H), 2,06 - 1,99 (m, 1H), 1,88 (dd, J = 10,9, 4,5 Hz, 3H), 1,67 (s, 1H), 1,23 - 1,13 (m, 2H). Petição 870260063816, de 29 / 06 / 2026, pág. 121 / 739 114 / 315 Exempl o Estrutura e nome Dados 13 Λ 0 O 3-[2-(2,3-dihidro-1,4-benzodioxin-6il)ciclopropil]-1-metil-1-[(3R)-1(piridazin-3-il)piperidin-3-il]ureia LC-MS: m / z 410 (M+H). 1H RMN (400 MHz, MeOD) δ 8,46 (d, J = 4,4 Hz, 1H), 7,38 (ddd, J = 9,4, 4,4, 1,9 Hz, 1H), 7,32 - 7,28 (m, 1H), 6,69 (d, J = 8,0 Hz, 1H), 6,65 - 6,58 (m, 2H), 4,37 (d, J = 13,0 Hz, 1H), 4,29 - 4,24 (m, 1H), 4,19 (d, J = 5,1Hz, 4H), 4,06 (s,1H), 3,02 (s,1H), 2,91 (d,J = 12,8Hz, 1H), 2,85 (d,J = 5,2Hz, 3H), 2,67 (dd,J = 7,5, 3,6Hz, 1H), 1,97-1,92 (m,1H), 1,87 (t,J = 8,0Hz, 3H), 1,68 (s,1H), 1,14-1,09 (m,1H), 1,05 (d,J = 7,4 Hz, 1H). 14 3-[2-(2-metoxifenil)ciclopropil]-1-metil1 -[(3R)-1-(piridazin-3-il)piperidin-3il]ureia LC-MS: m / z 382 (M+H).1H RMN (400 MHz, MeOD) δ 8,46 (s, 1H), 7,39 (dd, J = 9,3, 4,3 Hz, 1H), 7,30 (d, J = 9,4 Hz, 1H), 7,15 7,08 (m, 1H), 6,93 - 6,87 (m, 2H), 6,86 - 6,80 (m, 1H), 4,39 (d, J = 12,0 Hz, 1H), 4,27 (d, J = 12,6 Hz, 1H), 4,14 - 4,03 (m, 1H), 3,84 (d, J = 2,3 Hz, 3H), 3,08 - 2,98 (m, 1H), 2,94 - 2,87 (m, 2H), 2,86 (s, 3H), 2,34 - 2,25 (m, 1H), 1,88 (t, J = 7,0 Hz, 3H), 1,77 - 1,60 (m, 1H), 1,21 1,12 (m, 1H), 1,07 - 1,01 (m, 1H). Petição 870260063816, de 29 / 06 / 2026, pág. 122 / 739 115 / 315 Exempl o Estrutura e nome Dados 15 0 λ 3-[(1R,2S)-2-(2-metoxifenil)ciclopropil]1 -metil-1-[(3R)-1-(piridazin-3il)piperidin-3-il]ureia LC-MS: m / z 382 (M+H). 1H RMN (400 MHz, MeOD) δ 8,46 (d, J = 4,2 Hz, 1H), 7,38 (dd, J = 9,3, 4,4 Hz, 1H), 7,33 - 7,28 (m, 1H), 7,15 - 7,09 (m, 1H), 6,93 6,88 (m, 2H), 6,86 - 6,81 (m, 1H), 4,39 (d, J = 12,8 Hz, 1H), 4,27 (d, J = 12,0 Hz, 1H), 4,09 (d, J = 4,1 Hz, 1H), 3,84 (s, 3H), 3,09 - 3,00 (m, 1H), 2,95 - 2,88 (m, 2H), 2,86 (s, 3H), 2,34 - 2,24 (m, 1H), 1,92 1,84 (m, 3H), 1,69 (s, 1H), 1,21 1,15 (m, 1H), 1,08 - 1,00 (m, 1H). 16 Λ ° O ^ΤΖ<ΝΛΝ'·^ΝγΝ'Ν V h 1 v 1 -metil-1-[(3R)-1-(piridazin-3il)piperidin-3-il]-3-[2-(tiofen-3il)ciclopropil]ureia LC-MS: m / z 358 (M+H).1H RMN (400 MHz, MeOD) δ 8,48 - 8,45 (m, 1H), 7,38 (ddd, J = 9,4, 4,4, 1,7 Hz, 1H), 7,32 - 7,26 (m, 2H), 7,00 (d, J = 2,9 Hz, 1H), 6,95 (dt, J = 5,0, 1,1 Hz, 1H), 4,36 (d, J = 13,3 Hz, 1H), 4,31 - 4,24 (m, 1H), 4,06 (s, 1H), 3,02 (t, J = 11,6 Hz, 1H), 2,91 (d, J = 13,0 Hz, 1H), 2,85 (s, 3H), 2,73 (td, J = 7,4, 4,1 Hz, 1H), 2,08 (ddt, J = 9,4, 6,3, 3,2 Hz, 1H), 1,90 - 1,82 (m, 3H), 1,68 (s, 1H), 1,20 - 1,14 (m, 1H), 1,10 (dd, J = 13,2, 5,9 Hz, 1H). Petição 870260063816, de 29 / 06 / 2026, pág. 123 / 739 116 / 315 Example Structure and name Dados 17 li jh । rj] 3-[2-(3,4-dichlorophenyl)cyclopropyl]-1methyl-1-[(3R)-1-(pyridazin-3-yl)piperidin3-yl]ureia LC-MS: m / z 420 (M+H). 1H NMR (400 MHz, MeOD) δ 8.47 (d, J = 3.9 Hz, 1H), 7.41 - 7.33 (m, 3H), 7.32 - 7.24 (m, 1H), 7.08 (dd, J = 8.3, 2.0 Hz, 1H), 4.40 - 4.22 (m, 2H), 4.10 - 3.96 (m, 1H), 3.07 2.97 (m, 1H), 2.94 - 2.87 (m, 1H), 2.86 (s, 3H), 2.78 - 2.72 (m, 1H), 2.07 - 1.98 (m, 1H), 1.92 - 1.82 (m, 3H), 1.73 - 1.58 (m, 1H), 1.31 1.28 (m, 1H), 1.23 - 1.16 (m, 1H). 18 λ ° 7^ il' NNN 1 JJ h । 1 h 3-[(1R,2S)-2-(3,4- dichlorophenyl)cyclopropyl]-1-methyl-1-[(3R)1-(pyridazin-3-yl)piperidin-3-yl]ureia LC-MS: m / z 420 (M+H).1H RMN (400 MHz, MeOD) δ 8,50 - 8,45 (m, 1H), 7,41 - 7,34 (m, 3H), 7,31 (dd, J = 9,4, 1,2 Hz, 1H), 7,08 (dd, J = 8,3, 2,1 Hz, 1H), 4,31 (dd, J = 21,5, 8,9 Hz, 2H), 4,09 - 3,98 (m, 1H), 3,07 - 2,99 (m, 1H), 2,95 2,87 (m, 1H), 2,86 (s, 3H), 2,78 2,73 (m, 1H), 2,06 - 2,00 (m, 1H), 1,92 - 1,84 (m, 3H), 1,74 - 1,60 (m, 1H), 1,35 - 1,28 (m, 1H), 1,23 1,16 (m, 1H). 19 A 0 Γ^Ί 7^ iT N N 7^ N L I] h । Γ h 3-[(1S,2R)-2-(3,4- diclorofenil)ciclopropil]-1-metil-1-[(3R)1-(piridazin-3-il)piperidin-3-il]ureia LC-MS: m / z 420 (M+H). 1H RMN (400 MHz, MeOD) δ 8,50 - 8,42 (m, 1H), 7,41 - 7,34 (m, 3H), 7,29 (dd, J = 9,4, 1,2 Hz, 1H), 7,08 (dd, J = 8,3, 2,1 Hz, 1H), 4,39 4,24 (m, 2H), 4,09 - 3,99 (m, 1H), 3,03 (dd, J = 12,5, 11,3 Hz, 1H), 2,95 - 2,87 (m, 1H), 2,86 (s, 3H), 2,09 - 2,00 (m, 1H), 1,92 - 1,83 (m, 3H), 1,73 - 1,61 (m, 1H), 1,33 1,27 (m, 1H), 1,24 - 1,16 (m, 1H). Petição 870260063816, de 29 / 06 / 2026, pág. 124 / 739 117 / 315 Example Given name structure 20 λ ° 44 7Γ Ν Ν NLI] H | Γ h 3-[2-(4-chloro-3-fluorophenyl)cyclopropyl]-1methyl-1-[(3R)-1-(pyridazin-3-yl)piperidin3-yl]urea LC-MS: m / z 404 (M+H). 1H NMR (400 MHz, MeOD) δ 8.50 - 8.44 (m, 1H), 7.39 (ddd, J = 9.4, 4.4, 2.5 Hz, 1H), 7.35 - 7.27 (m, 2H), 7.06 (d, J, 17, H = 6.17), H (dd, J = 8.3, 1.8 Hz, 1H), 4.31 (dd, J = 22.2, 10.9 Hz, 2H), 4.05 (d, J = 5.4 Hz, 1H), 3.03 (t, J = 11.9 Hz, 1H), (td, J = 7.7, 4.3 Hz, 1H), 2.05 (dq, J = 6.7, 3.6 Hz, 1H), 1.88 (t, J = 7.1 Hz, 3H), 1.66 (d, J = 8.0 Hz, 1H), = 13.7, 6.1 Hz, 1H). 21 LI] h . L h 3-[(1 R,2S)-2-(4-chloro-3fluorophenyl)cyclopropyl]-1-methyl-1-[(3R)1-(pyridazin-3-yl)piperidin-3-yl]urea LC-MS: m / z 404 (M+H).1H RMN (400 MHz, MeOD) δ 8,47 (d, J = 3,8 Hz, 1H), 7,40 (dd, J = 9,4, 4,4 Hz, 1H), 7,35 - 7,29 (m, 2H), 7,05 (dd, J = 10,7, 2,0 Hz, 1H), 6,97 (dd, J = 8,3, 1,8 Hz, 1H), 4,35 - 4,27 (m, 2H), 4,04 (d, J = 3,7 Hz, 1H), 3,08 - 3,00 (m, 1H), 2,95 2,83 (m, 4H), 2,76 (ddd, J = 7,7, 4,5, 3,3 Hz, 1H), 2,05 (ddd, J = 9,4, 6,2, 3,5 Hz, 1H), 1,93 - 1,83 (m, 3H), 1,72 - 1,59 (m, 1H), 1,33 1,28 (m, 1H), 1,19 (dt, J = 7,5, 6,1 Hz, 1H). Petição 870260063816, de 29 / 06 / 2026, pág. 125 / 739 118 / 315 Exempl o Estrutura e nome Dados 22 P q z— ZI R LC-MS: m / z 404 (M+H). 1H RMN (400 MHz, MeOD) δ 8,47 (d, J = 3,9 Hz, 1H), 7,38 (dd, J = 9,4, 4,3 Hz, 1H), 7,34 - 7,26 (m, 2H), 7,06 (dd, J = 10,7, 2,0 Hz, 1H), 6,97 (dd, J = 8,3, 1,9 Hz, 1H), 4,38 - 4,25 (m, 2H), 4,10 - 3,99 (m, 1H), 3,02 (dd, J = 12,4, 11,4 Hz, 1H), 2,96 - 2,82 (m, 4H), 2,75 (ddd, J = 7,7, 4,5, 3,3 Hz, 1H), 2,05 (ddd, J = 9,5, 6,3, 3,3 Hz, 1H), 1,93 - 1,81 (m, 3H), 1,74 - 1,61 (m, 1H), 1,33 1,28 (m, 1H), 1,19 (dt, J = 7,5, 6,1 Hz, 1H). 23 A v'On N rf ^1' N N N 11 J H l L jl 3-[(1R,2S)-2-(2,4- difluorofenil)ciclopropil]-1-metil-1-[(3R)1-(-94-iridazina-3-il)piperidin-3-il]ureia LC-MS: m / z 388 (M+H).1HNMR (400MHz,MeOD) δ 8,46 (dd,J = 4,4, 1,1Hz, 1H), 7,38 (dd,J = 9,4, 4,4Hz, 1H), 7,30 (dd,J = 9,4, 1,2Hz, 1H), 7,11 (td,J = 8,8, 6,4Hz, 1H), 6,90- 6,81 (m, 2H), 4,41 4,24 (m, 2H), 4,06 (dd, J = 9,6, 5,8 Hz, 1H), 3,03 (dd, J = 12,5, 11,3 Hz, 1H), 2,91 (ddd, J = 17,6, 9,0, 5,0 Hz, 2H), 2,86 (s, 3H), 2,12 (ddd, J = 9,6, 6,3, 3,4 Hz, 1H), 1,93 - 1,82 (m, 3H), 1,67 (dt, J = 14,1, 9,1 Hz, 1H), 1,31 - 1,27 (m, 1H), 1,14 (dt, J = 7,5, 6,0 Hz, 1H). Petição 870260063816, de 29 / 06 / 2026, pág. 126 / 739 119 / 315 Example named Structure Given 24 a 0 lA / AZ ·αΛμ''\ / Ν^ΝΛ| Π NN N II J h . 1 h 3-[(1S,2R)-2-(2,4- difluorophenyl)cyclopropyl]-1-methyl-1-[(3R)- 1-(pyridazin-3-yl)piperidin-3-yl]urea LC-MS: m / z 388 (M+H). 1HNMR (400MHz,MeOD) δ 8.46 (dd,J = 4.4, 1.2Hz, 1H), 7.38 (dd,J = 9.4, 4.4Hz, 1H), 7.29 (dd,J = 9.4, 1.2Hz, 1H,1Hz, 8.8, t 6.4Hz, 1H), 6.90-6.81 (m, 2H), 4.41 - 4.23 (m, 2H), 4.13 - 4.01 (m, 1H), 3.03 (dd, J = 12.5, 11.3 Hz, 1H), 3H), 2.14 (ddd, J = 9.7, 6.3, 3.4 Hz, 1H), 1.88 (dd, J = 10.9, 4.4 Hz, 3H), 1.68 (dd, J = 11.3, 6.4 Hz, 1H), 1.14 (dt, J = 7.5, 6.0 Hz, 1H). 25 A ° A ^ΑΝΛΛΝγΝ^Ν |l J h . Γ h \^^p 3-[(1R,2S)-2-(2,5- difluorophenyl)cyclopropyl]-1-methyl-1-[(3R)1-(pyridazin-3-yl)piperidin-3-yl]urea LC-MS: m / z 388 (M+H).1H RMN (400 MHz, MeOD) δ 8,46 (dd, J = 4,4, 1,2 Hz, 1H), 7,38 (dd, J = 9,4, 4,4 Hz, 1H), 7,30 (dd, J = 9,4, 1,2 Hz, 1H), 7,02 (td, J = 9,3, 4,6 Hz, 1H), 6,92 - 6,77 (m, 2H), 4,39 4,32 (m, 1H), 4,28 (dd, J = 12,7, 3,7 Hz, 1H), 4,05 (dt, J = 11,2, 7,7 Hz, 1H), 3,03 (dd, J = 12,5, 11,3 Hz, 1H), 2,96 - 2,93 (m, 1H), 2,92 2,86 (m, 1H), 2,86 (s, 3H), 2,17 (ddd, J = 9,6, 6,2, 3,4 Hz, 1H), 1,92 - 1,84 (m, 3H), 1,73 - 1,60 (m, 1H), 1,39 - 1,32 (m, 1H), 1,18 (dt, J = 7,6, 6,0 Hz, 1H). Petição 870260063816, de 29 / 06 / 2026, pág. 127 / 739 120 / 315 Exempl o Estrutura e nome Dados 26 0 O Mn-o H 1 N-'J o— 3-{[3-(2-metoxifenil)-1,2-oxazol-5il]metil}-1-metil-1-[(3R)-1-(piridazin-3il)piperidin-3-il]ureia LC-MS: m / z 423,41 (M+H). 1H RMN (400 MHz, cdcl3) δ 8,59 8,52 (m, 1H), 7,87 - 7,80 (m, 1H), 7,43 - 7,33 (m, 1H), 7,28 - 7,15 (m, 1H), 7,05 - 6,93 (m, 3H), 6,72 (s, 1H), 6,21 (s, 1H), 4,75 - 4,59 (m, 2H), 4,41 - 4,32 (m, 1H), 4,24 (d, J = 13,9 Hz, 1H), 4,01 (t, J = 12,0 Hz, 1H), 3,86 (s, 3H), 3,03 - 2,92 (m, 2H), 2,90 (s, 3H), 2,02 - 1,95 (m, 1H), 1,90 - 1,75 (m, 2H), 1,72 1,61 (m, 1H). 27 h 1 M 3-{[3-(3-fluorofenil)-1,2-oxazol-5il]metil}-1-metil-1-[(3R)-1-(piridazin-3il)piperidin-3-il]ureia LC-MS: m / z 411,4 (M+H).1H RMN (400 MHz, cdcl3) δ 8,57 (dd, J = 4,4, 1,3 Hz, 1H), 7,64 7,55 (m, 1H), 7,52 (ddd, J = 9,7, 2,7, 1,5 Hz, 1H), 7,39 (td, J = 7,9, 5,7 Hz, 1H), 7,22 (dd, J = 9,3, 4,4 Hz, 1H), 7,10 (tdd, J = 8,4, 2,6, 1,1 Hz, 1H), 7,01 (dd, J = 9,3, 1,3 Hz, 1H), 6,75 (s, 1H), 6,60 (s, 1H), , 4,69 (dd, J = 5,7, 2,8 Hz, 2H), 4,50 - 4,41 (m, 2H), 4,10 (d, J = 12,6 Hz, 1H), 3,98 - 3,87 (m, 1H), 3,12 2,90 (m, 5H), 2,02 (dd, J = 8,1, 2,6 Hz, 1H), 1,94 - 1,80 (m, 1H), 1,62 (tdd, J = 13,6, 9,1,4,2 Hz, 1H). Petição 870260063816, de 29 / 06 / 2026, pág. 128 / 739 121 / 315 Example Structure and name Dados 28 ρΛΛ·'Ογ\ II 1 h । Ij 3-[2-(2,4-dichlorophenyl)cyclopropyl]-1methyl-1-[(3R)-1-(pyridazin-3-yl)piperidin3-yl]ureia LC-MS: m / z 420 (M+H). 1H NMR (400 MHz, MeOD) δ 8.46 (dd, J = 4.4, 1.2 Hz, 1H), 7.43 7.35 (m, 2H), 7.30 (ddd, J = 9.4, 2.1, 1.3 Hz, 1H), 7.25 - 7.20 (m, 1H), 7.13 (dd, J = 8.4, 2.1 Hz, 1H), 4.32 (dd, J = 28.6, 13.0 Hz, 2H), 4.07 (d, J = 4.4 Hz, 1H), 3.08 - 3.00 (m, 1H), 2.97 (dt, J = 8.0, 3.6 Hz, 1H), 2.94 - 2.88 (m, 1H), 2.87 (s, 3H), 2.27 (dtd, J = 10.0, 6.7, 3.6 Hz, 1H), 1.88 (d, J = 6.9 Hz, 3H), 1.75 1.63 (m, 1H), 1.37 (ddd, J = 9.6, 5.6, 4.5 Hz, 1H), 1.12 - 1.02 (m, 1H). 29 Λ 0 O ^·Ζ^ΝΛΝ·^ΝγΝ'Ν II J h । Γ h 3-[(1R,2S)-2-(2,4- dichlorophenyl)cyclopropyl]-1-methyl-1-[(3R)1-(pyridazin-3-yl)piperidin-3-yl]ureia LC-MS: m / z 420 (M+H).1H RMN (400 MHz, MeOD) δ 8,46 (dd, J = 4,4, 1,1 Hz, 1H), 7,42 7,33 (m, 2H), 7,29 (d, J = 9,4 Hz, 1H), 7,23 (dd, J = 8,4, 2,1 Hz, 1H), 7,13 (d, J = 8,4 Hz, 1H), 4,38 - 4,26 (m, 2H), 4,07 (dd, J = 11,7, 7,5 Hz, 1H), 3,03 (t, J = 11,9 Hz, 1H), 2,99 - 2,94 (m, 1H), 2,91 (dd, J = 12,8, 2,2 Hz, 1H), 2,87 (s, 3H), 2,28 (ddd, J = 9,8, 6,3, 3,6 Hz, 1H), 1,87 (d, J = 5,7 Hz, 3H), 1,68 (dd, J = 11,5, 6,7 Hz, 1H), 1,37 (dq, J = 5,6, 4,5 Hz, 1H), 1,08 (dt, J = 7,5, 6,0 Hz, 1H). Petição 870260063816, de 29 / 06 / 2026, pág. 129 / 739 122 / 315 Example Structure and Name Given 30 λ ° O II J η i Γ h 3-[(1S,2R)-2-(2,4- dichlorophenyl)cyclopropyl]-1-methyl-1-[(3R)1-(pyridazin-3-yl)piperidin-3-yl]urea m / MS (MLC+420). 1H NMR (400 MHz, MeOD) δ 8.46 (dd, J = 4.4, 1.1 Hz, 1H), 7.42 7.33 (m, 2H), 7.29 (d, J = 9.4 Hz, 1H), 7.23 (dd, J = 8.4 Hz, 13 Hz), (d, J = 8.4 Hz, 1H), 4.38 - 4.26 (m, 2H), 4.07 (dd, J = 11.7, 7.5 Hz, 1H), 3.03 (t, J = 11.9 Hz, 1H), 2.99 - 2.94 (m, J = 11.9), J 2.2 Hz, 1H), 2.87 (s, 3H), 2.28 (ddd, J = 9.8, 6.3, 3.6 Hz, 1H), 1.87 (d, J = 5.7 Hz, 3H), 1.68 (dd, J = 11.5, 6.7 Hz, 1.3Hz), J 5.6, 4.5 Hz, 1H), 1.08 (dt, J = 7.5, 6.0 Hz, 1H). 31 Λ ° Ο II JH 1 L jl 3-[2-(2,4-difluorophenyl)cyclopropyl]-1methyl-1-[(3R)-1-(pyridazin-3-yl)piperidin3-yl]urea LC-MS: m / z 388.1 (M+H).1H RMN (400 MHz, MeOD) δ 8,46 (d, J = 4,4 Hz, 1H), 7,38 (dd, J = 9,4, 4,4 Hz, 1H), 7,33 - 7,27 (m, 1H), 7,11 (dd, J = 15,2, 8,6 Hz, 1H), 6,89 - 6,83 (m, 2H), 4,32 (dd,J = 33,0, 12,8Hz, 2H), 4,07 (s,1H), 3,03 (t,J = 11,9Hz, 1H), 2,91 (dd,J = 8,3, 3,9Hz, 2H), 2,86 (s,3H), 2,13 (d,J = 4,4Hz, 1H), 1,87 (d,J = 5,5Hz, 3H), 1,68 (s, 1H), 1,29 (s, 1H), 1,14 (dd, J = 13,0, 6,6 Hz, 1H). Petição 870260063816, de 29 / 06 / 2026, pág. 130 / 739 123 / 315 Example Structure and name Dados 32 Λ ° ΥΊ L 1] h । Γ h 3-[2-(3,4-difluorophenyl)cyclopropyl]-1methyl-1-[(3R)-1-(pyridazin-3-yl)piperidin3-yl]ureia LC-MS: m / z 388.1 (M+H). 1H NMR (400 MHz, MeOD) δ 8.47 (d, J = 4.0 Hz, 1H), 7.44 - 7.33 (m, 1H), 7.30 (dd, J = 9.3, 3.8 Hz, 1H), 7.10 (dt, J = 13.7, 7.6 Hz, 2H), 6.96 (dd, J = 6.3, 2.0 Hz, 1H), 4.41 4.21 (m, 2H), 4.14 - 3.90 (m, 1H), 3.01 (d, J = 11.8 Hz, 1H), 2.94 2.79 (m, 4H), 2.71 (tt, J = 8.6, 4.3 Hz, 1H), 2.04 (qd, J = 6.5, 3.4 Hz, 1H), 1.89 (dd, J = 18.7, 9.2 Hz, 3H), 1.67 (s, 1H), 1.30 - 1.21 (m, 1H), 1.16 (dd, J = 13.3, 6.3 Hz, 1H). 33 Λ 0 Υί ΤΚ π Ν Ν Ν L JJ Η ι Γ h 3-[(1R,2S)-2-(3,4- difluorophenyl)cyclopropyl]-1-methyl-1-[(3R)1-(pyridazin-3-yl)piperidin-3-yl]ureia LC-MS: m / z 388.1 (M+H).1H RMN (400 MHz, MeOD) δ 8,47 (dd, J = 4,4, 1,1 Hz, 1H), 7,39 (dd, J = 9,4, 4,4 Hz, 1H), 7,30 (dd, J = 9,4, 1,2 Hz, 1H), 7,16 - 7,04 (m, 2H), 7,00 - 6,93 (m, 1H), 4,40 - 4,24 (m, 2H), 4,04 (dd, J = 9,6, 5,7 Hz, 1H), 3,09 - 2,96 (m, 1H), 2,95 - 2,82 (m, 4H), 2,76 - 2,67 (m, 1H), 2,03 (ddd, J = 9,5, 6,3, 3,2 Hz, 1H), 1,94 1,83 (m, 3H), 1,65 (ddd, J = 22,2, 11,9, 5,9 Hz, 1H), 1,29 - 1,21 (m, 1H), 1,16 (dt, J = 7,4, 6,1 Hz, 1H). Petição 870260063816, de 29 / 06 / 2026, pág. 131 / 739 124 / 315 Example Structure and name Given 34 a 0 A^ ANNA^ N 1 h. 1 h A / 3-[(1S,2R)-2-(3,4- difluorophenyl)cyclopropyl]-1-methyl-1-[(3R)1-(pyridazin-3-yl)piperidin-3-yl]urea LC-MS: m / z 388.1 (M+H). 1H NMR (400 MHz, MeOD) δ 8.47 (d, J = 4.1 Hz, 1H), 7.38 (dd, J = 9.3, 4.3 Hz, 1H), 7.29 (d, J = 9.3 Hz, 1H), 7.15 - 7.04 (m, 2H), 6.96 (dd, J = 6.2, 1.8 Hz, 1H), 4.40 - 4.24 (m, 2H), 4.11 - 4.00 (m, 1H), 3.02 (t,J = 11.9Hz, 1H), 2.95-2.83 (m,4H), 2.71 (dq,J = 8.7, 4.3Hz, 1H), 2.04 (ddd, J = 9.4, 6.3, 3.3Hz, 1H), 1.88 (t,J = 13.8Hz, 3H), 1.66 (d,J = 9.9Hz, 1H), 1.29-1.22 (m,1H), 1.16 (dd, J = 13.5, 6.2 Hz, 1H). 35 Δ 0FA-AA^n^n''A / EXAMINATION [1 \ HI 1 ÍJ A^F AA 3-[2-(2,5-difluorophenyl)cyclopropyl]-1methyl-1-[(3R)-1-(pyridazin-3-yl)piperidin3-yl]urea LC-MS: m / z 388.1 (M+H).1H RMN (400 MHz, MeOD) δ 8,46 (dt, J = 4,4, 1,3 Hz, 1H), 7,41 - 7,34 (m, 1H), 7,29 (ddd, J = 9,4, 3,8, 1,2 Hz, 1H), 7,05 - 6,97 (m, 1H), 6,83 (dddd, J = 24,0, 9,2, 6,4, 3,1 Hz, 2H), 4,32 (dd, J = 32,7, 12,2 Hz, 2H), 4,06 (dd, J = 11,5, 7,3 Hz, 1H), 3,07 - 2,99 (m, 1H), 2,94 (dd, J = 7,8, 4,4 Hz, 1H), 2,90 (dd, J = 5,9, 3,2 Hz, 1H), 2,86 (s, 3H), 2,17 (td, J = 9,8, 4,2 Hz, 1H), 1,92 - 1,83 (m, 3H), 1,74 - 1,60 (m, 1H), 1,39 1,32 (m, 1H), 1,18 (dt, J = 7,6, 6,0 Hz, 1H). Petição 870260063816, de 29 / 06 / 2026, pág. 132 / 739 125 / 315 Example Structure with Name Given 36 a 0 Γ^Ί k H 1 JJ PHASE Ν.γ 1-cyclopropyl-3-[(1S,2R)-2-(4-fluoro-3- methylphenyl)cyclopropyl]-1-[(3R)-1-(pyridazine-3-yl-pyridine)m-l-3-m / l-m 410.2 (M+H). 1H NMR (400 MHz, CDCI3) δ 8.53 (d, J = 2.9 Hz, 1H), 7.17 (dd, J = 9.1, 4.2 Hz, 1H), 7.03 - 6.92 (m, 3H), 6.91 - 6.85 (m, 1H), 4.45 (d, J = 13.3 Hz, 1H), 4.35 to 4.26 (m, 1H), 3.83 (tt, J = 11.9, 3.9 Hz, 1H), 3.34 to 3.19 (m, 1H), 2.88 (td, J = 1.0, 2.7 Hz), H (dt, J = 12.3, 5.1 Hz, 1H), 2.48 2.40 (m, 1H), 2.33 - 2.17 (m, 4H), 2.03 - 1.91 (m, 2H), 1.84 (d, J = 12.9 Hz, 1, 6H), , 19, s 1.07 (m, 2H), 0.96 to 0.85 (m, 2H), 0.84 to 0.72 (m, 2H). 37 A ° Γ^Ί 1 -cyclopropyl-3-[(1 R,2S)-2-(4-fluoro-3methylphenyl)cyclopropyl]-1-[(3R)-1(pyridazin-3-yl)piperidin-3-yl]urea LC-MS: m / z 410.2 (M+H).1H RMN (400 MHz, CDCI3) δ 8,53 (dd, J = 4,4, 1,0 Hz, 1H), 7,18 (dd, J = 9,3, 4,4 Hz, 1H), 7,02 - 6,92 (m, 3H), 6,92 - 6,85 (m, 1H), 5,75 (s, 1H), 4,48 - 4,27 (m, 2H), 3,81 (tt, J = 11,8, 3,9 Hz, 1H), 3,33 - 3,18 (m, 1H), 2,90 (td, J = 13,0, 2,7 Hz, 1H), 2,84 - 2,76 (m, 1H), 2,48 - 2,41 (m, 1H), 2,32 - 2,19 (m, 4H), 2,03 1,93 (m, 2H), 1,87 - 1,81 (m, 1H), 1,68 - 1,56 (m, 1H), 1,20 - 1,11 (m, 2H), 0,93 - 0,85 (m, 2H), 0,84 0,73 (m, 2H). Petição 870260063816, de 29 / 06 / 2026, pág. 133 / 739 126 / 315 Exempl o Estrutura e nome Dados 38 0 n II J h | L jj 3-[(4-cloro-2-metoxifenil)metil]-1-metil1 -[(3R)-1-(piridazin-3-il)piperidin-3il]ureia LC-MS: m / z 390 (M+H). 1H RMN (400 MHz, MeOD) δ 8,44 (s, 1H), 7,37 (dd, J = 9,1, 3,9 Hz, 1H), 7,27 (d, J = 9,2 Hz, 1H), 7,17 (d, J = 8,1 Hz, 1H), 6,99 - 6,84 (m, 2H), 4,41 - 4,25 (m, 4H), 4,10 (dt, J = 11,2, 7,8 Hz, 1H), 3,83 (s, 3H), 3,07 - 2,99 (m, 1H), 2,90 (s, 3H), 2,86 (dd, J = 13,1,2,4 Hz, 1H), 1,94 - 1,83 (m, 3H), 1,74 - 1,61 (m, 1H). 39 0 l^ YY-J H 1 U —o 3-{[3-(3-metoxifenil)-1,2-oxazol-5il]metil}-1-metil-1-[(3R)-1-(piridazin-3il)piperidin-3-il]ureia LC-MS: m / z 423,4 (M+H). 1H RMN (400 MHz, cdcl3) δ 8,60 8,53 (m, 1H), 7,39 - 7,28 (m, 2H), 7,28 - 7,18 (m, 2H), 7,05 - 6,98 (m, 1H), 6,98 - 6,92 (m, 1H), 6,61 (s, 1H), 6,57 (s, 1H), 4,75 - 4,60 (m, 2H), 4,47 - 4,38 (m, 1H), 4,13 (d, 1H), 3,96 (m, 1H), 3,85 - 3,82 (m, 3H), 3,09 - 2,94 (m, 2H), 2,94 2,90 (m, 3H), 2,02 (m, 1H), 1,92 1,78 (m, 2H), 1,64 (m, 1H).40 Y U O ^ΝγΝ'Ν L Η h । Lh 1-{[2-cloro-5-(trifluorometil)fenil]metil}3-metil-3-[(3R)-1-(piridazin-3il)piperidin-3-il]ureia LC-MS: m / z 423,4 (M+H). 1H RMN (400 MHz, cdcl3) δ 8,56 8,49 (m, 1H), 7,72 (s, 1H), 7,43 (m, 2H), 7,22 - 7,17 (m, 1H), 7,02 6,97 (m, 1H), 6,37 (s, 1H), 4,73 4,55 (m, 2H), 4,45 - 4,37 (m, 1H), 4,23 - 4,15 (m, 1H), 4,05 - 3,94 (m, 1H), 3,06 - 2,93 (m, 2H), 2,92 (s, 3H), 2,06 - 1,99 (m, 1H), 1,93 - 1,78 (m, 2H), 1,73 - 1,60 (m, 1H). Petição 870260063816, de 29 / 06 / 2026, pág. 134 / 739 127 / 315 Example Structure and name Dados 41 0 ΓΑ NN ν' NL II hi Lh 1-[(2,5-dichlorophenyl)methyl]-3-methyl-3[(3R)-1-(pyridazin-3-yl)piperidin-3yl]ureia LC-MS: m / z 394.1 (M+H). 1H NMR (400 MHz, cdcl3) δ 8.55 (d, 1H), 7.43-7.40 (m, 1H), 7.277.18 (m, 2H), 7.16-7.12 (m, 1H), 7.03-6.99 (m, 1H), 6.12 (br, 1H), 4.62-4.46 (m, 2H), 4.37 (d, 1H), 4.24 (d, 1H), 4.08-3.96 (m, 1H), 3.01-2.92 (m, 2H), 2.90 (s, 3H), 2.04-1.95 (m, 1H), 1.90-1.76 (m, 2H), 1.72-1.59 (m, 1H). 42 O ^^ΝΛΝ·^ΝγΝ'Ν L II h | Γ I) 'n / 1-[(2,4-dichlorophenyl)methyl]-3-methyl-3- [(3R)-1-(pyridazin-3-yl)piperidin-3yl]urea LC-MS: m / z 394.1 (M+H). 1H NMR (400 MHz, cdcl3) δ 8,568.51 (m, 1H), 7.40 (d, 1H), 7,367.33 (m, 1H), 7.22-7.16 (m, 2H), 7.00-6.95 (d, 1H), 6.06 (br, 1H), 4.52 (d, 2H), 4.38 (d, 1H), 4.21 (d, 1H), 4.07-3.95 (m, 1H), 3.01-2.90 (m, 2H), 2.88 (s, 3H), 2.02-1.92 (m, 1H), 1.90-1.75 (m, 2H), 1.73-1.56 (m, 1H). Petition 870260063816, 06 / 29 / 2026, pág. 135 / 739 128 / 315 Exempl o Estrutura and name Dados 43 k H 1 NJ fA2 Λ N'ib 1 -ciclopropil-3-[2-(4-fluoro-3metilfenil)ciclopropil]-1-[(3R)-1(piridazin-3-il)piperidin-3-il]ureia LC-MS: m / z 410.2 (M+H). 1H RMN (400 MHz, MeOD) δ 8.43 (dd, J = 4.4, 1.1 Hz, 1H), 7.37 (dd, J = 9.4, 4.4 Hz, 1H), 7.29 (ddd, J = 9.4, 2.6, 1.3 Hz, 1H), 7.04 (d, J = 7.5 Hz, 1H), 6.99 - 6.93 (m, 1H), 6.92 - 6.85 (m, 1H), 6.67 (s, 1H), 4.37 (dd, J = 26.9, 12.9 Hz, 2H), 3.76 (tt, J = 11.9, 3.9 Hz, 1H), 3.28 - 3,09 (m, 1H), 2.89 (td, J = 13.1, 2.5 Hz, 1H), 2.71 (dt, J = 7.0, 3.6 Hz, 1H), 2.53 - 2.44 (m, 1H), 2.31 2.18 (m, 4H), 2.04 - 1.93 (m, 2H), 1.86 (d, J = 13.0 Hz, 1H), 1.62 (dtd, J = 13.0, 9.0, 4.0 Hz, 1H), 1.21 1.10 (m, 2H), 0.98 - 0.87 (m, 2H), 0.76 (d, J = 2.5 Hz, 2H). 44 0 OJ h | Li]3-[(2-metoxifenil)metil]-1-metil-1-[(3R)1-(piridazin-3-il)piperidin-3-il]ureia LC-MS: m / z 356 (M+H).1H RMN (400 MHz, MeOD) δ 8,44 (dd, J = 4,4, 1,2 Hz, 1H), 7,36 (dd, J = 9,4, 4,4 Hz, 1H), 7,27 (dd, J = 9,4, 1,2 Hz, 1H), 7,23 - 7,18 (m, 2H), 6,95 - 6,85 (m, 2H), 4,38 (d, J = 6,2 Hz, 3H), 4,28 (dd, J = 12,5, 3,9 Hz, 1H), 4,11 (dt, J = 11,1, 7,8 Hz, 1H), 3,83 (s, 3H), 3,10 - 3,01 (m, 1H), 2,92 - 2,84 (m, 4H), 1,93 - 1,84 (m, 3H), 1,76 - 1,62 (m, 1H). Petição 870260063816, de 29 / 06 / 2026, pág. 136 / 739 129 / 315 Exemplar o Estrutura and name Dados 45 0 O / νί! H 1 rj, JJ N 1-metil-3-[(5-fenil-1,3-oxazol-2-il)metil]- 1 -[(3R)-1-(piridazin-3-il)piperidin-3il]ureia LC-MS: m / z 392.1 (M+H). 1H RMN (400 MHz, MeOD) δ 8.44 (dd, J = 4.3, 1.1 Hz, 1H), 7.73 7.62 (m, 2H), 7.48 - 7.38 (m, 3H), 7.38 - 7.26 (m, 3H), 4.56 (s, 2H), 4.36 (ddd, J = 16.7, 12.9, 2.0 Hz, 2H), 4.11 (ddd, J = 15.6, 11.3, 4.3 Hz, 1H), 3.11 - 3.02 (m, 1H), 2.94 (s, 3H), 2.93 - 2.84 (m, 1H), 1.90 (dd, J = 13,4, 6,0 (Hz, 3H), 1.76 1.61 (m, 1H). 46 H 1 TJ 1-methyl-3-[(3-fenil-1,2,4-oxadiazol-5il)methyl]-1-[(3R)-1-(piridazin-3il)piperidin-3-il]ureia LC-MS: m / z 393.1 (M+H). 1H RMN (400 MHz, MeOD) δ 8.44 (dd, J = 4.3, 1.2 Hz, 1H), 8.10 7.99 (m, 2H), 7.56 - 7.47 (m, 3H), 7.33 (ddd, J = 10.6, 9.4, 2.8 Hz, 2H), 4.68 (s, 2H), 4.35 (dd, J = 15.6, 7.4 Hz, 2H), 4.08 (d, J = 4.2 Hz, 1H), 3.08 (dd, J = 12.5, 11.3 Hz, 1H), 2.99 - 2.89 (m, 4H), 1.97 1.87 (m, 3H), 1,69 (dd, J = 8.1, 4.3 Hz, 1H).47 HII JJ N 1-methyl-3-[(4-fenil-1,3-oxazol-2-il)metil]- 1-[(3R)-1-(piridazin-3-il)piperidin-3il]ureia LC-MS: m / z 392,1 (M+H). 1H RMN (400 MHz, MeOD) δ 8.43 (dd, J = 4.3, 1.1 Hz, 1H), 8.18 (s, 1H), 7.73 (dd, J = 5.2, 3.3 Hz, 2H), 7.41 - 7.33 (m, 3H), 7.30 (ddd, J = 6.3, 3.6, 1.3 Hz, 2H), 4.54 (s, 2H), 4.42 - 4.29 (m, 2H), 4.11 (d, J = 3.6 Hz, 1H), 3.06 (dd, J = 12.5, 11.3 Hz, 1H), 2.97 - 2.86 (m, 4H), 1.90 (dd, J = 13,8, 5.9 Hz, 3H), 1.68 (dd, J = 10.3, 5.4 Hz, 1H). Petition 870260063816, on 06 / 29 / 2026, page. 137 / 739 130 / 315 Exempl o Estrutura and name Dados 48 UONN' N γ·Ν ' NL II hi L h 1-{[2-fluoro-5-(trifluorometil)fenil]metil}3-metil-3-[(3R)-1-(piridazin-3il)piperidin-3-il]ureia LC-MS: m / z 412.4 (M+H). 49 hi 1-{[2-fluoro-4-(trifluorometil)fenil]metil}3-metil-3-[(3R)-1-(piridazin-3il)piperidin-3-il]ureia LC-MS: m / z 412.4 (M+H). 50 0 Γ^Ι AN iT NNNL II h । 1 h 3-[(2-fluoro-5-metoxifenil)metil]-1-metil1 -[(3R)-1-(piridazin-3-il)piperidin-3il]ureia LC-MS: m / z 374.3 (M+H). 51 fyvnÂn'''^nyn'n L II h । Γ h pXXp \ 7,257.20 (m, 1H), 7.04-7.98 (m, 1H), 6.92-6.83 (m, 1H), 6.46 (br, 1H), 4.49 (d, 2H), 4.42 (d, 1H), 4.13 (d, 1H), 10 52 ° Γ^Ί L II h । Γ ij \^^F \ Petition 870260063816, on 06 / 29 / 2026, page. 138 / 739 131 / 315 Example Given name structure 53 ° OL II h . Γ h 1-[(2,4-difluorophenyl)methyl]-3-methyl-3[(3R)-1-(pyridazin-3-yl)piperidin-3yl]urea LC-MS: m / z 362.26 (M+H). 54 0 Αί ,— / ii NNNH 1 O 1 -methyl-3-[(5-methyl-1-benzofuran-2yl)methyl]-1-[(3R)-1-(pyridazin-3yl)piperidin-3-yl]urea LC-MS: m / z 380.3 (M+H). 55 ΓΊι u ON Jk N v N γΝ, NH 1 3-[2-(3-methoxyphenyl)ethyl]-1-methyl-1-[(3R)- 1-(pyridazin-3-yl)piperidin-3-yl]urea LC-MS: m / z 370.4 (M+H). 56 Vti on H 1 U 1-[2-(3,4-difluorophenyl)ethyl]-3-methyl-3[(3R)-1-(pyridazin-3-yl)piperidin-3yl]urea LC-MS: m / z 376.37 (M+H). 57 UL-NAN''k''NY^ H 1 U 1-[2-(2-fluorophenyl)ethyl]-3-methyl-3-[(3R)- 1-(pyridazin-3-yl)piperidin-3-yl]urea LC-MS: m / z 358.36 (M+H). Petition 870260063816, of 29 / 06 / 2026, p. 139 / 739 132 / 315 Example Structure name Given 58 F u OH 1 m 3-methyl-3-[(3R)-1-(pyridazin-3yl)piperidin-3-yl]-1-{2-[4(trifluoromethyl)phenyl]ethyl}urea LC-MS: m / z 408.4 (M+H). 59 r^íi 0 O UX-A-CV FFH . U 3-methyl-3-[(3R)-1-(pyridazin-3yl)piperidin-3-yl]-1-{2-[3(trifluoromethyl)phenyl]ethyl}urea LC-MS: m / z 408.4(M+H). 60 “υί ° n C| N NV ·\ / NH 1 u 1-[2-(3,4-dichlorophenyl)ethyl]-3-methyl-3[(3R)-1-(pyridazin-3-yl)piperidin-3yl]urea LC-MS: m / z 408.3(M+0H). 1-[(4-ethynylphenyl)methyl]-3-methyl-3-[(3R)-1(pyridazin-3-yl)piperidin-3-yl]urea LC-MS: m / z 350.35 (M+H). Petition 870260063816, of 29 / 06 / 2026, p. 140 / 739 133 / 315 Example o Structure and name 3-[(4-chloro-2-fluoro-3-methylphenyl)methyl]1 -methyl-1-[(3R)-1-(pyridazine-3yl)piperidin-3-yl]urea So LC-MS: m / z 392.2 (M+H). 1H RMN (400 MHz, MeOD) δ 8.44 (dd, J = 4.4, 1.1 Hz, 1H), 7.37 (dd, J = 9.4, 4.4 Hz, 1H), 7.28 (dd, J = 9.4, 1.0 Hz, 1H), 7.18 - 7.12 (m, 2H), 4.40 (s, 2H), 4.38 - 4.25 (m, 2H), 4.09 (dd, J = 9.8, 5.6 Hz, 1H), 3.04 (dd, J = 12.4, 11.5 Hz, 1H), 2.93 2.85 (m, 4H), 2.29 (d, J = 2.4 Hz, 3H), 1,92 - 1.84 (m, 3H), 1.74 1.61 (m, 1H). 3-[(4-chloro-2-fluoro-5-methylfenil)methyl]1-methyl-1-[(3R)-1-(piridazin-3il)piperidin-3-il]ureia LC-MS: m / z 392,2 (M+H). 1H RMN (400 MHz, MeOD) δ 8.45 (d, J = 4.0 Hz, 1H), 7.38 (dd, J = 9.4, 4.4 Hz, 1H), 7.31 - 7.23 (m, 2H), 7.11 (d, J = 9.7 Hz, 1H), 4.39 4.26 (m, 4H), 4.09 (dd, J = 9.6, 5.7 Hz, 1H), 3.04 (dd, J = 12.4, 11.4 Hz, 1H), 2.93 - 2.85 (m, 4H), 2.31 (s, 3H), 1.88 (dt, J = 9.6, 3.9 Hz, 3H), 1.74 - 1.62 (m, 1H). 1-methyl-1-[(3R)-1-(piridazin-3il)piperidin-3-il]-3-{2-[4-(trifluorometoxi)fenil]etil}ureia LC-MS: m / z 424,2 (M+H). 1H RMN (400 MHz, MeOD) δ 8,46 (dd, J = 4,4, 1,1 Hz, 1H), 7,39 (dd, J = 9,4, 4,4 Hz, 1H), 7,29 (dd, J = 12,7, 4,7 Hz, 3H), 7,16 (d, J = 8,0 Hz, 2H), 4,38 - 4,21 (m, 2H), 4,01 (s, 1H), 3,41 (t, J = 7,3 Hz, 2H), 3,00 (dd, J = 12,4, 11,4 Hz, 1H), 2,93 - 2,81 (m, 6H), 1,92 - 1,80 (m, 3H), 1,65 (dd, J = 14,5, 10,3 Hz, 1H). Petição 870260063816, de 29 / 06 / 2026, pág. 141 / 739 134 / 315 Exemplar o Estrutura and name Dados 65 0 F>k AJ H । MF cr N 1 -metil-1-[(3R)-1-(piridazin-3il)piperidin-3-il]-3-{[4(trifluorometoxi)fenil]metil}ureia LC-MS: m / z 410 (M+H). 1H RMN (400 MHz, MeOD) δ 8.45 (d, J = 3.5 Hz, 1H), 7.44 - 7.34 (m, 3H), 7.28 (d, J = 9.3 Hz, 1H), 7.20 (d, J = 8.0 Hz, 2H), 4.40 (s, 2H), 4.38 - 4.26 (m, 2H), 4.10 (dt, J = 11.1, 7.7 Hz, 1H), 3.09 - 2.99 (m, 1H), 2.95 - 2.84 (m, 4H), 1.97 1.82 (m, 3H), 1.67 (dt, J = 8.2, 6.1 Hz, 1H). 66 4 jCc. a FO ^^^^ NN — ΐΐ H 1 u 1 -metil-1-[(3R)-1-(piridazin-3il)piperidin-3-il]-3-{2-[3(trifluorometoxi)fenil]etil}ureia LC-MS: m / z 410 (M+H). 1H RMN (400 MHz, MeOD) δ 8.46 (dd, J = 4.4, 1.1 Hz, 1H), 7.41 - 7.34 (m, 2H), 7.29 - 7.21 (m, 2H), 7.14 (s, 1H), 7.09 (d, J= 8.2Hz, 1H), 4.37-4.20 (m, 2H), 4.00 (d, J= 9.4Hz, 1H), 3.43(t, J= 7.3Hz, 2H), 2.99 (dd, J = 12.4, 11.5 Hz, 1H), 2.91 (d, J = 12.1 Hz, 1H), 2.86 (d, J = 7.1 Hz, 2H), 2.82 (s, 3H), 1.91 1.81 (m, 3H), 1.70 - 1.58 (m, 1H). Petition 870260063816, dated 06 / 29 / 2026, p. 142 / 739 135 / 315 Example o Estrutura and name Dados 67 Λ 0 ΥΊ Z\^VnAn^nVN'n 1 JJ h | 1 h 3-[(4-chloro-3-ciclopropilfenil)metil]-1metil-1-[(3R)-1-(piridazin-3-il)piperidin3-il]ureia LC-MS: m / z 400.1 (M+H). 1H RMN (400 MHz, MeOD) δ 8.45 (d, J = 4.0 Hz, 1H), 7.38 (dd, J = 9.4, 4.4 Hz, 1H), 7.33 - 7.24 (m, 2H), 7.08 (dd, J = 8.1.2.0 Hz, 1H), 6.94 (d, J = 1.9 Hz, 1H), 4.36 (d, J = 13.1 Hz, 1H), 4.30 (s, 2H), 4.30 4.24 (m, 1H), 4.13 - 4.03 (m, 1H), 3.08 - 3.00 (m, 1H), 2.94 - 2.86 (m, 4H), 2,16 (ddd, J = 8.4, 5.2, 3.2 Hz, 1H), 1.94 - 1.82 (m, 3H), 1.68 (dd, J = 10.6, 7.8 Hz, 1H), 1.04 - 0.93 (m, 2H), 0.66 (dt, J = 9.9, 5.1 Hz, 2H). 68 f 0 A f ν n · NVH 1 u 3-{[3-(difluorometil)fenil]metil}-1-metil1-[(3R)-1-(piridazin-3-il)piperidin-3il]ureia LC-MS: m / z 376.2(M+H).1H RMN (400 MHz, MeOD) δ 8,45 (dd, J = 4,4, 1,2 Hz, 1H), 7,50 - 7,36 (m, 5H), 7,29 (dd, J = 9,4, 1,2 Hz, 1H), 6,74 (t, J = 56,3 Hz, 1H), 4,44 - 4,26 (m, 4H), 4,17 - 4,05 (m, 1H), 3,05 (dd, J = 12,4, 11,4 Hz, 1H), 2,93 - 2,86 (m, 4H), 1,93 - 1,86 (m, 3H), 1,74 - 1,62 (m, 1H). 69 0 A r II Ν N fl H 1 u 3-[(4-ciclopropilfenil)metil]-1-metil-1[(3R)-1-(piridazin-3-il)piperidin-3il]ureia LC-MS: m / z 366,2 (M+H). 1H RMN (400 MHz, MeOD) δ 8,44 (dd, J = 4,4, 1,1 Hz, 1H), 7,38 (dd, J = 9,4, 4,4Hz, 1H),7,28 (dd, J=9,4, 1,2Hz, 1H), 7,17 (d, J=8,2Hz, 2H), 7,00 (d,J= 8,1 Hz, 2H), 4,42 - 4,23 (m, 4H), 4,17 - 4,05 (m, 1H), 3,03 (dd, J = 12,4, 11,4 Hz, 1H), 2,93 2,82 (m, 4H), 1,93 - 1,82 (m, 4H), 1,68 (s, 1H), 0,92 (ddd, J = 8,4, 6,3, 4,3 Hz, 2H), 0,67 - 0,58 (m, 2H). Petição 870260063816, de 29 / 06 / 2026, pág. 143 / 739 136 / 315 Exempl o Estrutura e nome Dados 70 λ o U H ' u 3-[(3-ciclopropilfenil)metil]-1-metil-1[(3R)-1-(piridazin-3-il)piperidin-3il]ureia LC-MS: m / z 366,2 (M+H). 1H RMN (400 MHz, MeOD) δ 8,45 (d, J = 3,5 Hz, 1H), 7,38 (dd, J = 9,4, 4,4 Hz, 1H), 7,29 (dd, J = 9,4, 1,1 Hz, 1H), 7,16 (t, J = 7,6 Hz, 1H), 7,08 - 6,97 (m, 2H), 6,92 (d, J = 7,6 Hz, 1H), 4,43 - 4,22 (m, 4H), 4,10 (dt, J = 11,3, 7,6 Hz, 1H), 3,09 2,99 (m, 1H), 2,94 - 2,84 (m, 4H), 1,95 - 1,82 (m, 4H), 1,75 - 1,62 (m, 1H), 0,96 - 0,85 (m, 2H), 0,69 0,57 (m, 2H). 71 F 0 Ι^Ί u h 1 M 3-{[3-(1,1 -difluoroetil)fenil]metil}-1metil-1-[(3R)-1-(piridazin-3-il)piperidin3-il]ureia LC-MS: m / z 390,1 (M+H). 1H RMN (400 MHz, DMSO) δ 8,52 (dd, J = 4,4, 1,2 Hz, 1H), 7,47 - 7,33 (m, 5H), 7,24 (dd, J = 9,3, 1,2 Hz, 1H), 7,06 (t, J = 5,8 Hz, 1H), 4,37 - 4,21 (m, 4H), 4,06 - 3,94 (m, 1H), 3,02 - 2,94 (m, 1H), 2,85 - 2,77 (m, 4H), 1,95 (t, J = 18,8 Hz, 3H), 1,83 - 1,70 (m, 3H), 1,62 - 1,50 (m, 1H).72 θ OA χ H 1 u F 3-{[4-(difluoromethyl)phenyl]methyl}-1-methyl1 -[(3R)-1-(pyridazin-3-yl)piperidin-3yl]urea LC-MS: m / z 376.2 (M+H). 1H NMR (400 MHz, MeOD) δ 8.44 (d, J = 2.5 Hz, 1H), 7.40 (ddd, J = 16.3, 13.6, 6.2 Hz, 5H), 7.27 (dd, J = 9.4, 0.9 Hz, 1H), 6.72 (t, J = 56.4 Hz, 1H), 4.43 (s, 2H), 4.38 - 4.26 (m, 2H), 4.10 (dt, J = 11.1, 7.8 Hz, 1H), 3.03 (dd, J = 12.4, 11.4 Hz, 1H), 2.94 - 2.82 (m, 4H), 1.92 1.81 (m, 3H), 1.72 - 1.59 (m, 1H). Petition 870260063816, dated 06 / 29 / 2026, p. 144 / 739 137 / 315 Exempl o Estrutura and name Dados 73 0 OVH 1 M 1-metil-3-[(3-metilfenil)metil]-1-[(3R)-1(piridazin-3-il)piperidin-3-il]ureia LC-MS: m / z 340.2 (M+H). 1H RMN (400 MHz, MeOD) δ 8.44 (dd, J = 4.4, 0.9 Hz, 1H), 7.37 (dd, J = 9.4, 4.4 Hz, 1H), 7.28 (dd, J = 9.4, 1.2 Hz, 1H), 7.10 (ddd, J = 31.1, 19.2, 7.5 Hz, 4H), 4.41 - 4.24 (m, 4H), 4.11 (dd, J = 9.7, 5.5 Hz, 1H), 3.04 (dd, J = 12.5, 11.3 Hz, 1H), 2.95 - 2.84 (m, 4H), 2.31 (s, 3H), 1.93 - 1.83 (m, 3H), 1.74 - 1.61 (m, 1H). 75 ο Γ^Ί <\ λ__ / NNNH । 1-metil-3-[(4-fenil-1,3-tiazol-2-il)metil]- 1 -[(3R)-1-(piridazin-3-il)piperidin-3il]ureia LC-MS: m / z 409,2 (M+H). 1H RMN (400 MHz, MeOD) δ 8.44 (dd, J = 4.4, 1.2 Hz, 1H), 7.88 (dd, J = 5.2, 3.3 Hz, 2H), 7.69 (s, 1H), 7.43 - 7.25 (m, 5H), 4.72 (s, 2H), 4.36 (t, J = 14.0 Hz, 2H), 4.18 4.05 (m, 1H), 3.15 - 3.04 (m, 1H), 2.99 - 2.85 (m, 4H), 1.97 - 1.85 (m, 3H), 1.76 - 1.62 (m, 1H).76 o O ζΧΙ H 1 M 3-[(3,4-di-hydro-2H-1-benzopyran-6yl)methyl]-1-methyl-1-[(3R)-1-(pyridazine-3yl)piperidin-3-yl]urea LC-MS: m / z 382 (M+H). Petition 870260063816, of 29 / 06 / 2026, p. 145 / 739 138 / 315 Example o Structure and Name Data 77 AJ H 1 ΛΑ FN 3-[(4-fluorophenyl)methyl]-1-methyl-1-[(3R)1-(pyridazine-3-yl)piperidine-3-yl]urea LC-MS: m / z 344.2(M+H). 1H NMR (400 MHz, DMSO) δ 8.52 (dd, J = 4.4, 1.0 Hz, 1H), 7.30 (tdd, J = 10.3, 9.3, 2.7 Hz, 4H), 7.13 (t, J = 8.9), 2.4 Hz, 7 4.15 (m, 4H), 3.99 (dd, J = 13.3, 9.4 Hz, 1H), 3.02 − 2.90 (m, 1H), 2.80 (s, 4H), 1.86 − 1.66 (m, 3H), 8 J = 1.54 (d). 78 0 ΓΊ AJ H 1 O CK N 3-[(4-chlorophenyl)methyl]-1-methyl-1-[(3R)-1(pyridazine-3-yl)piperidin-3-yl]urea LC-MS: m / z 360.2 (M+H). 1H RMN (400 MHz, DMSO) δ 8.52 (d, J = 3.5 Hz, 1H), 7.44 − 7.16 (m, 6H), 7.02 (t, J= 5.7Hz, 1H), 4,384.17 (m, 3, 4H( 1), 2.96(t, J = 11.8 Hz, 1H), 2.86 2.74 (m, 4H), 1.76 (dd, J = 22.8, 7.9 Hz, 3H), 1.55 (t, J = 13.1 Hz, 1H). 79 0 ΓΊ Cl KANYNN v Ti UH ' u 3-[(3-chlorophenyl)methyl]-1-methyl-1-[(3R)-1(pyridazine-3-yl)piperidin-3-yl]urea LC-MS: m / z 360.2 (M+H).1H RMN (400 MHz, MeOD) δ 8,45 (s, 1H), 7,38 (dd, J = 9,2, 4,2 Hz, 1H), 7,34-7,16 (m, 5H), 4,41-4,25 (m, 4H), 4,15-4,05 (m, 1H), 3,05 (dd, J = 12,5, 11,3 Hz, 1 H), 2,952,85 (m, 4H), 1,94-1,84 (m, 3H), 1,74-1,62 (m, 1H). 80 / γΑνΑ'Α LA H 1 ΛΑ Cl N 3-[(2-clorofenil)metil]-1-metil-1-[(3R)-1(piridazin-3-il)piperidin-3-il]ureia LC-MS: m / z 360,2 (M+H). 1H RMN (400 MHz, MeOD) δ 8,44 (d, J = 3,9 Hz, 1H), 7,42 - 7,18 (m, 6H), 4,48 (s, 2H), 4,41 - 4,28 (m, 2H), 4,12 (dd, J = 9,8, 5,5 Hz, 1H), 3,06 (dd, J = 12,5, 11,3 Hz, 1H), 2,96 - 2,85 (m, 4H), 1,95 - 1,84 (m, 3H), 1,76 - 1,63 (m, 1H). Petição 870260063816, de 29 / 06 / 2026, pág. 146 / 739 139 / 315 Example Structure of nouns Given 81 f F 0 44 f^a^v^n^n' 'Τ'Ύ'ν 1 IJ h | 1 h 3-{[4-methoxy-3- (trifluoromethyl)phenyl]methyl}-1-methyl-1[(3R)-1-(pyridazin-3-yl)piperidin-3yl]urea LC-MS: m / z 424.2 (M+H). 1H NMR (400 MHz, MeOD) δ 8.45 (dd, J = 4.4, 1.0 Hz, 1H), 7.52 (d, J = 7.7 Hz, 2H), 7.37 (dd, J= 9.4, 4.4Hz, 1H), 7.28 (dd, J = 1.4Hz, 19 1H), 7.11 (d, J=8.4 Hz, 1H), 4.41 4.23 (m, 4H), 4.14 - 4.03 (m, 1H), 3.87 (s, 3H), 3.04 (dd, J = 12.4, 11.3 Hz, 1.95), (m, 2.85), 1.88 (dt, J = 9.5, 4.2 Hz, 3H), 1.67 (dd, J = 11.4, 7.3 Hz, 1H). 82 0 44 UL H . A, J) FN 3-[(2-fluoro-5-methylphenyl)methyl]-1-methyl-1[(3R)-1-(pyridazin-3-yl)piperidin-3yl]urea LC-MS: m / z 358.2 (M+H).1H RMN (400 MHz, MeOD) δ 8,44 (dd, J = 4,4, 0,9 Hz, 1H), 7,37 (dd, J = 9,4, 4,4 Hz, 1H), 7,28 (dd, J = 9,4, 1,2 Hz, 1H), 7,14 (dd, J = 7,3, 1,7 Hz, 1H), 7,06 - 7,00 (m, 1H), 6,90 (dd, J = 10,1, 8,4 Hz, 1H), 4,41 4,24 (m, 4H), 4,11 (dt, J = 11,2, 7,8 Hz, 1H), 3,04 (dd, J = 12,5, 11,3 Hz, 1H), 2,92 - 2,84 (m, 4H), 2,29 (s, 3H), 1,93 - 1,84 (m, 3H), 1,69 (ddd, J = 12,6, 8,1, 3,4 Hz, 1H). Petição 870260063816, de 29 / 06 / 2026, pág. 147 / 739 140 / 315 Example Structure and name Given 83 0 OR JU. H 1 N. J) —^F 'N 3-[(2-fluoro-4-methylphenyl)methyl]-1-methyl-1[(3R)-1-(pyridazin-3-yl)piperidin-3yl]urea LC-MS: m / z 358.2 (M+H). 1H NMR (400 MHz, MeOD) δ 8.44 (dd, J = 4.4, 1.1 Hz, 1H), 7.37 (dd, J = 9.4, 4.4 Hz, 1H), 7.28 (d, J = 9.3Hz, 1H), 7.21 (t, J = 7.9Hz, 1H), 6.93(d, J=7.8Hz, 1H), 6.87(d, J=11.4Hz, 1H), 4.38(d, J=10.8Hz, 3H), 4.28(dd, J = 12.5, 3.9Hz, 1H), 4.10(d, J=9.6, 5.7Hz, 1H), 3.09 - 3.00 (m, 1H), 2.92 (m, 4H), 2.31 (s, 3H), 1.93 - 1.83 (m, 3H), 1.68 (dd, J = 12.8, 5.2 Hz, 1H). 84 0 íA ΥγΛ-'^γ^ ΧΛ H 1 n,. JFFN 3-[(2,4-difluoro-5-methylphenyl)methyl]-1- methyl-1-[(3R)-1-(pyridazin-3-yl)piperidin3-yl]urea LC-MS: m / z 376.2 (M+H).1H RMN (400 MHz, MeOD) δ 8,45 (d, J = 3,9 Hz, 1H), 7,39 (dd, J = 9,4, 4,4 Hz, 1H), 7,30 (dd, J= 9,4, 1,1Hz, 1H), 7,21 (t, J= 8,6Hz, 1H), 6,82 (t, J= 9,9Hz, 1H), 4,41 - 4,25 (m, 4H), 4,15 - 4,05 (m, 1H), 3,04 (dd, J = 12,5, 11,3 Hz, 1H), 2,93 2,84 (m, 4H), 2,21 (s, 3H), 1,93 1,82 (m, 3H), 1,75 - 1,61 (m, 1H). 85 0 O Λ1 H 1 n. JJ CU ^^ F N 3-[(4-cloro-2-fluorofenil)metil]-1-metil1 -[(3R)-1-(piridazin-3-il)piperidin-3il]ureia LC-MS: m / z 378,1(M+H). 1H RMN (400 MHz, MeOD) δ 8,45 (dd, J = 4,4, 0,9 Hz, 1H), 7,41 - 7,26 (m, 3H), 7,20 - 7,06 (m, 2H), 4,43 - 4,25 (m, 4H), 4,09 (dt, J = 11,3, 7,6 Hz, 1H), 3,04 (dd, J = 12,4, 11,4 Hz, 1H), 2,94 - 2,84 (m, 4H), 1,93 - 1,82 (m, 3H), 1,74 - 1,61 (m, 1H). Petição 870260063816, de 29 / 06 / 2026, pág. 148 / 739 141 / 315 Exempl o Estrutura e nome Dados 86 0 XX LA H n,. J F N 3-[(2-fluorofenil)metil]-1-metil-1-[(3R)1-(piridazin-3-il)piperidin-3-il]ureia LC-MS: m / z 344,2(M+H). 1H RMN (400 MHz, MeOD) δ 8,44 (d, J = 3,4 Hz, 1H), 7,40 - 7,32 (m, 2H), 7,30 - 7,20 (m, 2H), 7,15 7,08 (m, 1H), 7,07 - 7,00 (m, 1H), 4,45 (s, 2H), 4,36 (d, J = 13,2 Hz, 1H), 4,28 (dd, J = 12,6, 3,7 Hz, 1H), 4,10 (dd, J = 9,6, 5,5 Hz, 1H), 3,03 (dd, J = 12,3, 11,5 Hz, 1H), 2,92 2,84 (m, 4H), 1,87 (dd, J = 10,6, 4,6 Hz, 3H), 1,72 - 1,60 (m, 1H). 87 A 1 H XXT°XF XX ° 3-[(2,2-difluoro-2H-1,3-benzodioxol-5il)metil]-1-metil-1-[(3R)-1-(piridazin-3il)piperidin-3-il]ureia LC-MS: m / z 406 (M+H). 1H RMN (400 MHz, MeOD) δ 8,45 (s, 1H), 7,38 (s, 1H), 7,29 (d, J = 9,3 Hz, 1H), 7,17 (s, 1H), 7,11 (d, J = 0,8 Hz, 2H), 4,37 (s, 2H), 4,36 4,25 (m, 2H), 4,13 - 4,05 (m, 1H), 3,07 - 3,01 (m, 1H), 2,94 - 2,86 (m, 4H), 1,89 (dd, J = 9,9, 4,8 Hz, 3H), 1,72 - 1,62 (m, 1H).88 0 XX LA H nA FN 3-[(5-chloro-2-fluorophenyl)methyl]-1-methyl1-[(3R)-1-(pyridazin-3-yl)piperidin-3yl]urea LC-MS: m / z 378.2 (M+H). 1H NMR (400 MHz, MeOD) δ 8.45 (dd, J = 4.4, 1.1 Hz, 1H), 7.40 (dd, J = 9.4, 4.4 Hz, 1H), 7.35 - 7.29 (m, 2H), 7.24 (ddd, J = 8.6, 4.4, 2.7 Hz, 1H), 4.43 - 4.26 (m, 4H), 4.10 (dd, J = 9.6, 5.7 Hz, 1H), 3.07 (dd, J = 12.5, 11.3 Hz, 1H), 2.95 - 2.87 (m, 4H), 1.93 - 1.85 (m, 3H), 1.63 (m, 1H). Petition 870260063816, 06 / 29 / 2026, p. 149 / 7 142 / 3 Exempl o Estrutura and name Dados 89 AyACnAn'-θ ΥΊ UU H 1 u 1 -metil-3-[(naftalen-2-il)metil]-1-[(3R)1-(piridazin-3-il)piperidin-3-il]ureia LC-MS: m / z 376.1 (M+H). 1H RMN (400 MHz, MeOD) δ 8.43 (d, J = 3.7 Hz, 1H), 7.84 - 7.77 (m, 3H), 7.74 (s, 1H), 7.48 - 7.39 (m, 3H), 7.34 (dd, J = 9.4, 4.4 Hz, 1H), 7.25 (dd, J = 9.4, 1.2 Hz, 1H), 4.55 (s, 2H), 4.39 - 4.26 (m, 2H), 4.18 4.09 (m, 1H), 3.04 (dd, J = 12.4, 11.3 Hz, 1H), 2.92 (s, 3H), 2.91 2,84 (m, 1H), 1.88 (dd, J = 13.6, 5.5 Hz, 3H), 1.73 - 1.62 (m, 1H). 90 UH 1 u 3-[(3,5-dimethylfenil)methyl]-1-methyl-1[(3R)-1-(piridazin-3-il)piperidin-3il]ureia LC-MS: m / z 376.1 (M+H). 1H RMN (400 MHz, MeOD) δ 8.45 (s, 1H), 7.37 (dd, J = 9.3, 4.1 Hz, 1H), 7.28 (d, J = 9.3 Hz, 1 H), 6.90 (s, 2H), 6.85 (s, 1H), 4.38 (d, J = 13.6 Hz, 1H), 4.30 (s, 2H), 4.26 (d, J = 3.9 Hz, 1H), 4.11 (dd, J = 9.7, 5.4 Hz, 1H), 3.04 (dd, J = 12.4, 11.3 Hz, 1H), 2.95 - 2.83 (m, 3H), 2.26 (s, 5H), 1,89 (dd, J = 10.8, 4.4 Hz, 2H), 1.76 - 1.58 (m, 1H). 91 ΗΝη.o 3-[2-(1H-indol-3-il)etil]-1-metil-1-[(3R)1-(piridazin-3-il)piperidin-3-il]ureia LC-MS: m / z 379,4 (M+H). 1H RMN (400 MHz, MeOD) δ 8,45 (s, 1H), 7,56 (d, J = 7,7 Hz, 1H), 7,35 (s, 1H), 7,30 (d, J = 8,1 Hz, 1H), 7,20 (d, J = 8,8 Hz, 1H), 7,09 7,02 (m, 2H), 7,01 - 6,93 (m, 1H), 4,36 (d, J = 13,8 Hz, 1H), 4,17 (dd, J = 12,7, 3,8 Hz, 1H), 3,98 (s, 1H), 3,54 - 3,44 (m, 2H), 3,02 - 2,93 (m, 3H), 2,85 (dd, J = 18,5, 8,0 Hz, 1H), 2,79 (s, 3H), 1,92 - 1,78 (m, 3H), 1,61 (d, J = 8,6 Hz, 1H). Petição 870260063816, de 29 / 06 / 2026, pág. 150 / 739 143 / 315 Exemplar o Estrutura and name Dados 92 A° í^l nan^nvn'n LI] h । Γη 3-[(1S,2R)-2-(3-fluorofenil)ciclopropil]- 1 -metil-1-[(3R)-1-(piridazin-3il)piperidin-3-il]ureia LC-MS: m / z 370.2(M+H). 93 1H RMN (400 MHz, MeOD) δ 8.46 (dd, J = 4.4, 1.1 Hz, 1H), 7.40 (dd, J = 9.4, 4.4 Hz, 1H), 7.28 (dd, J = 9.4, 1.2 Hz, 1H), 7.16 - 7.06 (m, 2H), 6.87 - 6.77 (m, 2H), 4.36 (d, J= 13.2Hz, 1H), 4.22 (dd, J= 12.7, 3.8Hz, 1H), 4.01 (d, J=5.5 Hz, 1H), 3.73 (d, J = 3.5 Hz, 3H), 3.40 - 3.33 (m, 2H), 3,00 (dd, J = 12.5, 11.3 Hz, 1H), 2.93 - 2.81 (m, 4H), 2.74 (t, J = 7.4 Hz, 2H), 1.95 - 1.80 (m, 3H), 1.73 - 1.57 (m, 1H). 94 F ° OL Η h । Γ h 3-[(3-chloro-2-fluorofenil)metil]-1-metil1 -[(3R)-1-(piridazin-3-il)piperidin-3il]ureia LC-MS: m / z 378.3 (M+H).1H NMR (400 MHz, MeOD) δ 8.45 (s, 1H), 7.43 - 7.25 (m, 4H), 7.11 (td, J = 7.9, 1.1 Hz, 1H), 4.46 (s, 2H), 4.40 - 4.25 (m, 2H), 4.09 (dt, J = 11.2, 7.6 Hz, 1H), 3.05 (dd, J = 12.5, 11.3 Hz, 1H), 2.94 - 2.86 (m, 4H), 1.89 (tt, J = 9.6, 5.0 Hz, 3H), 1.75 - 1.63 (m, 1H). Petition 870260063816, dated 06 / 29 / 2026, p. 151 / 739 144 / 315 Exempl o Estrutura and name Dados 95 / / / NNN vA H 1 Cl 3-[2-(5-chloro-1H-indol-3-il)etil]-1-metil- 1 -[(3R)-1-(piridazin-3-il)piperidin-3il]ureia LC-MS: m / z 378.3 (M+H). 1HNMR (400MHz,MeOD) δ8.45 (d, J=3.9Hz, 1H), 7.54 (d, J=2.0Hz, 1H), 7.37 (dd, J=9.4, 4.3Hz, 1H), 7.26 (d, J=8.6Hz, 1H), 7.20 (d, J=8.7Hz, 1H), 7.12 (s, 1H), 7.02 (dd, J= 8.6, 2.0Hz, 1H), 4.36 (d, J= 13.8Hz, 1H), 4.13 (d, J= 12.3 Hz, 1H), 3.94 (s, 1H), 3.50 - 3.42 (m, 2H), 3,01 - 2,83 (m, 4H), 2.81 (s, 3H), 1.84 (t, J= 7.6Hz, 3H), 1.60 (d, J= 9.1Hz, 1H). 96 Cl / A 0 AA hnJ h 1 O 'N 3-[(5-chloro-1H-indol-3-il)metil]-1-metil1-[(3R)-1-(piridazin-3-il)piperidin-3il]ureia LC-MS: m / z 388.3 (M+H).1H RMN (400 MHz, DMSO) δ 11,04 (s, 1H), 8,57 - 8,47 (m, 1H), 7,73 (d, J = 2,0 Hz, 1H), 7,37 - 7,31 (m, 2H), 7,28 (d, J = 2,2 Hz, 1H), 7,20 (dd, J = 9,3, 1,0 Hz, 1H), 7,05 (dd, J = 8,6, 2,1 Hz, 1H), 6,77 (t, J = 5,5 Hz, 1H), 4,43 - 4,29 (m, 3H), 4,16 (d, J = 12,5 Hz, 1H), 4,00 (t, J = 11,3 Hz, 1H), 2,98 - 2,91 (m, 1H), 2,76 (s, 4H), 1,81 - 1,67 (m, 3H), 1,55 (t, J = 13,1 Hz, 1H). Petição 870260063816, de 29 / 06 / 2026, pág. 152 / 739 145 / 315 Exempl o Estrutura e nome Dados 97 0 O CIW\ / X , \ iT N N ν' N f^J^J H 1 O FH F 3-{[3-cloro-4-(trifluorometil)fenil]metil}- 1 -metil-1-[(3R)-1-(piridazin-3- il)piperidin-3-il]ureia LC-MS: m / z 428,3 (M+H). 1H RMN (400 MHz, DMSO) δ 8,52 (dd, J = 4,4, 1,1 Hz, 1H), 7,81 (d, J = 8,1 Hz, 1H), 7,59 (s, 1H), 7,44 (d, J = 8,3 Hz, 1H), 7,35 (dd, J = 9,3, 4,4 Hz, 1H), 7,25 (dd, J= 9,3, 1,1Hz, 1H), 7,14 (t, J= 5,7Hz, 1H), 4,404,18 (m, 4H), 4,03-3,93 (m, 1H), 3,03 - 2,92 (m, 1H), 2,87 - 2,76 (m, 4H), 1,78 (dt, J = 9,8, 8,7 Hz, 3H), 1,61 - 1,46 (m, 1H). 98 V Τι N N N Γ II Ί h । Γ i| 1 -metil-1-[(3R)-1-(piridazin-3il)piperidin-3-il]-3-[(quinolin-6il)metil]ureia LC-MS: m / z 377,4 (M+H).1H RMN (400 MHz, MeOD) δ 8,80 (dd, J = 4,3, 1,7 Hz, 1H), 8,44 (d, J = 3,3Hz, 1H), 8,35 (d, J=7,5Hz, 1H), 7,99 (d, J=8,7Hz, 1H), 7,84 (s, 1H), 7,77 (dd, J = 8,7, 1,9 Hz, 1H), 7,52 (dd, J = 8,3, 4,3 Hz, 1H), 7,37 (dd, J = 9,4, 4,4 Hz, 1H), 7,29 (dd, J = 9,4, 1,2 Hz, 1H), 4,59 (s, 2H), 4,35 (t, J = 14,5 Hz, 2H), 4,12 (s, 1H), 3,11 3,03 (m, 1H), 2,96 - 2,87 (m, 4H), 1,91 (t, J = 7,6 Hz, 3H), 1,68 (s, 1H). Petição 870260063816, de 29 / 06 / 2026, pág. 153 / 739 146 / 315 Exempl o Estrutura e nome Dados 99 ° O n.n 1. h । In 3-[(3-cloro-4-metilfenil)metil]-1-metil-1[(3R)-1-(piridazin-3-il)piperidin-3il]ureia LC-MS: m / z 374,4 (M+H). 1H RMN (400 MHz, DMSO) δ 8,52 (dd, J = 4,4, 1,0 Hz, 1H), 7,35 (dd, J = 9,3, 4,4 Hz, 1H), 7,31 - 7,22 (m, 3H), 7,14 (dd, J = 7,7, 1,3 Hz, 1H), 7,00 (t, J = 5,8 Hz, 1H), 4,34 (d, J = 11,7 Hz, 1H), 4,28 - 4,15 (m, 3H), 3,98 (dd, J = 13,3, 9,2 Hz, 1H), 3,01 - 2,91 (m, 1H), 2,85 - 2,76 (m, 4H), 2,29 (s, 3H), 1,85 - 1,66 (m, 3H), 1,60 - 1,47 (m, 1H). 100 0 O TK ii Ν N N L J h | L jj 3-[(4-cloro-3-metoxifenil)metil]-1-metil- 1 -[(3R)-1-(piridazin-3-il)piperidin-3il]ureia LC-MS: m / z 390,3 (M+H). 1H RMN (400 MHz, MeOD) δ 8,45 (dd, J = 4,4, 1,1 Hz, 1H), 7,38 (dd, J = 9,4, 4,4 Hz, 1H), 7,28 (dd, J = 14,0, 4,6 Hz, 2H), 7,03 (d, J = 1,7 Hz, 1H), 6,86 (dd, J = 8,1, 1,9 Hz, 1H), 4,42 - 4,25 (m, 4H), 4,09 (dd, J = 9,6, 5,5 Hz, 1H), 3,86 (s, 3H), 3,04 (dd, J = 12,4, 11,3 Hz, 1H), 2,96 - 2,81 (m, 4H), 1,96 - 1,80 (m, 3H), 1,79 - 1,59 (m, 1H).101 Λ ° Γ^Ί Μ η ι Γ h 3-[(1S,2R)-2-(2-fluorophenyl)cyclopropyl]1 -methyl-1-[(3R)-1-(pyridazin-3yl)piperidin-3-yl]ureia LC-MS: m / z 370.2 (M+H). Petition 870260063816, 06 / 29 / 2026, pág. 154 / 739 147 / 315 Example o Structure and name Given 102 A ° AA NYN'N H .1 HI li] 1-methyl-3-[(1S,2R)-2-(2- methylphenyl)cyclopropyl]-1-[(3R)-1(pyridazin-3-yl)piperidin-3-yl]urea mi-LC-3-2 (MMSH: 36,266). 103 clYá 0 O Μ^νΛν·^νΥν'ν H 1 3-[2-(4-chlorophenyl)ethyl]-1-methyl-1-[(3R)-1(pyridazin-3-yl)piperidin-3-yl]urea LC-MS: m / z 2,2 M (3+H). 104 FF 0 AA L JJ H | Lj] 3-{[4-chloro-3-(trifluoromethyl)phenyl]methyl}1 -methyl-1-[(3R)-1-(pyridazin-3yl)piperidin-3-yl]urea LC-MS: m / z 374.2 (M+H). 1H NMR (400 MHz, MeOD) δ 8.45 (dd, J = 4.4, 1.2 Hz, 1H), 7.71 (s, 1H), 7.54 (d, J = 1.1 Hz, 2H), 7.38 (dd, J = 9.4, 4.4 Hz, 2Hz), J 9.4, 1.2 Hz, 1H), 4.41 (s, 2H), 4.38 - 4.27 (m, 2H), 4.13 - 4.03 (m, 1H), 3.05 (dd, J = 12.5, 11.3 Hz, 1H), 1.84 (m, 3H), 1.68 (dd, J = 11.2, 8.5 Hz, 1H). 105 0 AA f YyV'AV'n f <i L l| h । Γ h 3-{[3-fluoro-4- (trifluorometoxi)fenil]meti l}-1-metil-1[(3R)-1-(piridazin-3-il)piperidin-3il]ureia LC-MS: m / z 428,2 (M+H).1H NMR (400 MHz, MeOD) δ 8.45 (d, J = 4.4 Hz, 1H), 7.54 - 7.14 (m, 5H), 4.47 - 4.21 (m, 4H), 4.09 (s, 1H), 3.09 - 2.98 (m, 1H), 2.96 2.82 (m, 4H), 1.88 (d, J = 7.8 Hz, 3H), 1.68 (s, 1H). Petition 870260063816, dated 06 / 29 / 2026, p. 155 / 739 148 / 315 Exempl o Estrutura e nome Dados 106 H J h । L U 1-metil-3-{[3-(1H-pirazol-1il)fenil]metil}-1-[(3R)-1-(piridazin-3il)piperidin-3-il]ureia LC-MS: m / z 392,3 (M+H). 1H RMN (400 MHz, MeOD) δ 8,44 (dd, J = 4,4, 1,1 Hz, 1H), 8,19 (d, J = 2,3 Hz, 1H), 7,76 - 7,66 (m, 2H), 7,59 (d, J = 8,1 Hz, 1H), 7,43 (t, J = 7,8 Hz, 1H), 7,36 (dd, J = 9,4, 4,4 Hz, 1H), 7,32 - 7,25 (m, 2H), 6,57 6,44 (m, 1H), 4,47 (d, J = 4,4 Hz, 2H), 4,38 (d, J = 13,2 Hz, 1H), 4,28 (d, J = 12,6 Hz, 1H), 4,18 - 4,05 (m, 1H), 3,10 - 3,00 (m, 1H), 2,92 (s, 3H), 2,91 - 2,81 (m, 1H), 1,90 (dd, J = 13,5, 6,0 Hz, 3H), 1,76 - 1,58 (m, 1H). 107 ° ΑΊ ^^ΝΛΝ·< / ΝγΝ'Ν JL 1] h । Ih 1-metil-3-[(4-metilfenil)metil]-1-[(3R)-1(piridazin-3-il)piperidin-3-il]ureia LC-MS: m / z 340,4 (M+H).1H RMN (400 MHz, DMSO) δ 8,52 (dd, J = 4,4, 1,1 Hz, 1H), 7,36 (dd, J = 9,3, 4,4 Hz, 1H), 7,25 (dd, J = 9,3, 1,1 Hz, 1H), 7,13 (dd, J = 21,8, 8,0 Hz, 4H), 6,92 (t, J= 5,8Hz, 1H), 4,34 (d, J= 11,2Hz, 1H), 4,28-4,14 (m,3H), 4,05-3,95 (m, 1H), 3,03 2,90 (m, 1H), 2,86 - 2,73 (m, 4H), 2,27 (s, 3H), 1,85 - 1,66 (m, 3H), 1,55 (dd, J = 15,2, 11,4 Hz, 1H). Petição 870260063816, de 29 / 06 / 2026, pág. 156 / 739 149 / 315 Exemplar Estrutura and name Dados o 108° 44 ___N. / yj h 1 3-[(2,3-di-hydro-1-benzofuran-2- il)metil]-1-metil-1-[(3R)-1-(piridazin-3il)piperidin-3-il]ureia LC-MS: m / z 368.4 (M+H). 1H RMN (400 MHz, MeOD) δ 8.47 (s, 1H), 7.43 - 7.36 (m, 1H), 7.29 (dd, J = 8.6, 4.6Hz, 1H), 7.16 - 6.97 (m, 2H), 6.77 (t, J = 7.4Hz, 1H), 6.69 (d, J=7.8Hz, 1H), 6.60 (d, J = 8.0 Hz, 1H), 4.88 (dd, J = 9.5, 5.2 Hz, 1H), 4.39 - 4.21 (m, 2H), 4.03 3.87 (m, 1H), 3.56 - 3.41 (m, 2H), 3.28 - 3.21 (m, (1H), 3.04 - 2.85 (m, 3H), 2.80 (s, 3H), 1.90 - 1.76 (m, 3H), 1.62 (s, 1H). 109 αΑΑτΛΝΛΝ·^ΝνΝ'Ν JL II H i Lu 1 -metil-3-[(1 S)-1-(4-metilfenil)etil]-1[(3R)-1-(piridazin-3-il)piperidin-3il]ureia LC-MS: m / z 354.4 (M+H).1H RMN (400 MHz, MeOD) δ 8,46 (s, 1H), 7,30 (s, 2H), 7,22 (d, J = 8,1 Hz, 3H), 7,10 (d, J = 7,9 Hz, 3H), 4,92 (q, J = 7,0 Hz, 1H), 4,36 (d, J = 13,3 Hz, 1H), 4,24 (d, J = 12,2 Hz, 1H), 4,15 - 4,02 (m, 1H), 3,09 - 2,96 (m, 1H), 2,95 - 2,83 (m, 5H), 2,29 (s, 4H), 1,87 (t, J = 7,7 Hz, 4H), 1,65 (d, J = 9,3 Hz, 1H), 1,47 (d, J = 7,1 Hz, 4H). 110 O u O h 1 kX 3-[2-(3-clorofenil)etil]-1-metil-1-[(3R)-1(piridazin-3-il)piperidin-3-il]ureia LC-MS: m / z 374 (M+H). 1H RMN (400 MHz, MeOD) δ 8,59 8,38 (m, 1H), 7,19 - 7,03 (m, 5H), 6,95 (dd, J = 9,3, 1,0 Hz, 1H), 5,70 (s, 1H), 4,25 (d, J = 12,8 Hz, 1H), 4,11 (d, J = 13,3 Hz, 1H), 3,81 (t, J = 11,2 Hz, 1H), 3,49 (dd, J = 13,2, 6,1 Hz, 2H), 2,97 - 2,80 (m, 5H), 2,77 (s, 3H), 1,90 (d, J = 11,0 Hz, 1H), 1,83 - 1,68 (m, 2H), 1,64 - 1,47 (m, 1H). Petição 870260063816, de 29 / 06 / 2026, pág. 157 / 739 150 / 315 Exempl o Estrutura e nome Dados 111 αΥΎα 0 ΡΊ Μ^ναΝ'··^νυν'ν Η 1 3-[2-(2,4-diclorofenil)etil]-1-metil-1[(3R)-1-(piridazin-3-il)piperidin-3il]ureia LC-MS: m / z 480,3 (M+H). 1H RMN (400 MHz, MeOD) δ 8,46 (s, 1H), 7,39 (dd, J = 8,7, 3,0 Hz, 2H), 7,26 (qd, J = 8,2, 2,8 Hz, 3H), 4,35 (d, J = 14,7 Hz, 1H), 4,23 (dd, J = 12,7, 3,9 Hz, 1H), 4,00 (s, 1H), 3,58 - 3,37 (m, 2H), 3,09 - 2,84 (m, 4H), 2,82 (s, 3H), 1,96 - 1,79 (m, 3H), 1,74 - 1,55 (m, 1H). 112 FYb ° n H 1 o 3-[2-(4-fluorofenil)etil]-1-metil-1-[(3R)- 1-(piridazin-3-il)piperidin-3-il]ureia LC-MS: m / z 358,1 (M+H). 1H RMN (400 MHz, MeOD) δ 8,46 (d, J = 3,7 Hz, 1H), 7,39 (dd, J - 9,4, 4,4 Hz, 1H), 7,27 (dd, J = 9,4, 1,1 Hz, 1H), 7,23 - 7,16 (m, 2H), 7,05 6,89 (m, 2H), 4,35 (d, J = 13,7 Hz, 1H), 4,24 (dd, J = 12,5, 3,8 Hz, 1H), 4,01 (s, 1H), 3,43 - 3,35 (m, 2H), 3,00 (dd, J = 12,5, 11,4 Hz, 1H), 2,94 - 2,85 (m, 1H), 2,85 - 2,75 (m, 5H), 1,87 (ddd, J = 12,6, 10,3, 5,4 Hz, 3H), 1,74 - 1,58 (m, 1H).113 ° OL II h । Ih 3-[(2,5-dimetilfenil)metil]-1-metil-1[(3R)-1-(piridazin-3-il)piperidin-3il]ureia LC-MS: m / z 354,1 (M+H). 1H RMN (400 MHz, MeOD) δ 8.44 (d, J = 3.8 Hz, 1H), 7.38 (dd, J = 9.4, 4.4 Hz, 1H), 7.29 (dd, J = 9.4, 1.1 Hz, 1H), 7.13 - 6.88 (m, 3H), 4.41 - 4.26 (m, 4H), 4.12 (dt, J = 11.6, 8.0 Hz, 1H), 3.10 - 3.02 (m, 1H), 2.94-2.84 (m, 4H), 2.28 (d, J = 4.9 Hz, 6H), 1.90 (dd, J = 10.9, 8.9 Hz, 3H), 1.68 (d, J = 9.4Hz, 1H). Petition 870260063816, on 06 / 29 / 2026, page. 158 / 739 151 / 315 Exempl o Estrutura e nome Dados 114 1 IJ h । 1 i| 3-[(3-cloro-4-fluorofenil)metil]-1-metil1 -[(3R)-1-(piridazin-3-il)piperidin-3il]ureia LC-MS: m / z 378,1 (M+H). 1H RMN (400 MHz, MeOD) δ 8,45 (d, J = 4,1 Hz, 1H), 7,45 - 7,33 (m, 2H), 7,33 - 7,23 (m, 2H), 7,16 (t, J = 8,7 Hz, 1H), 4,42 - 4,26 (m, 4H), 4,15 - 4,01 (m, 1H), 3,10 - 2,98 (m, 1H), 2,95 - 2,84 (m, 4H), 1,98 1,82 (m, 3H), 1,76 - 1,58 (m, 1H). 115 0 44 ιΓ Ν Ν N 1 J h | 1 h 3-[(4-cloro-3-fluorofenil)metil]-1-metil1 -[(3R)-1-(piridazin-3-il)piperidin-3il]ureia LC-MS: m / z 378,1 (M+H). 1H RMN (400 MHz, DMSO) δ 8,51 (dd, J = 4,4, 1,0 Hz, 1H), 7,51 (t, J = 8,0 Hz, 1H), 7,35 (dd, J = 9,3, 4,4 Hz, 1H), 7,30 - 7,22 (m, 2H), 7,14 (dd, J = 8,2, 1,2 Hz, 1H), 7,06 (t, J = 5,8 Hz, 1H), 4,36 - 4,18 (m, 4H), 3,97 (dd, J = 13,3, 9,1 Hz, 1H), 3,01 - 2,91 (m, 1H), 2,86 - 2,74 (m, 4H), 1,86 - 1,67 (m, 3H), 1,59 - 1,46 (m, 1H).116 0 44 r iT Ν NNH 1 44 F 1- methyl-1-[(3R)-1-(pyridazin-3-yl)piperidin3-yl]-3-{[3-(trifluoromethyl)phenyl]methyl}urea LC-MS: m / z 394.1(M+H). 117 0 44 clV4^NAN'^Ny^N 1 IJ h | 1 \\ 3-[(3,4-dichlorophenyl)methyl]-1-methyl-1[(3R)-1-(pyridazin-3-yl)piperidin-3yl]urea LC-MS: m / z 394.1(M+H). Petition 870260063816, of 29 / 06 / 2026, p. 159 / 739 152 / 315 Exemplar o Estrutura and name Dados 118 0 Γ^Ί TK π NNNLJ h । Γ h 1-[(3,4-difluorofenil)metil]-3-metil-3[(3R)-1-(piridazin-3-il)piperidin-3il]ureia LC-MS: m / z 394.1(M+H). 1H RMN (400 MHz, MeOD) δ 8.48 (s, 1H), 7.40 (s, 1H), 7.31 (d, J = 9.2 Hz, 1H), 7.25 - 7.15 (m, 2H), 7.13 (d, J = 4.3 Hz, 1H), 4.40 - 4.29 (m, 4H), 4.11 (dt, J = 11.2, 7.6 Hz, 1H), 3.06 (dd, J = 12.5, 11.3 Hz, 1H), 2.96 - 2.87 (m, 4H), 1.91 (tt, J = 9.6, 4.9 Hz, 3H), 1.69 (dd, J = 15.6, 6.3 Hz, 1H). 119 F ° O JLÜ H i Lu 1-[(2,3-difluoro-4-methylfenil)metil]-3metil-3-[(3R)-1-(piridazin-3-il)piperidin3-il]ureia LC-MS: m / z 376,1(M+H). 1H RMN (400 MHz, MeOD) δ 8.47 (s, 1H), 7.41 (s, 1H), 7.30 (d, J = 9.1 Hz, 1H), 6.99 (dt, J = 14.6, 7.6 Hz, 2H), 4.42 (s, 2H), 4.37 (d, J = 12.7 Hz, 1H), 4.28 (d, J = 12.6 Hz, 1H), 4.14 - 4.05 (m, 1H), 3.08 - 3.00 (m, 1H), 2.94 - 2.85 (m, 4H), 2.26 (d, J = 2.0 Hz, 3H), 1.93 - 1.83 (m, 3H), 1.67 (d, J = 9.1 Hz, 1H).120 F F 0 O Λ, L IJ h । Γ h 1-{[4-fluoro-3-(trifluorometil)fenil]metil}3-metil-3-[(3R)-1-(piridazin-3il)piperidin-3-il]ureia LC-MS: m / z 412,4 (M+H). 1H RMN (400 MHz, DMSO) δ 8,51 (dd, J = 4,4, 1,1 Hz, 1H), 7,64 (dd, J = 9,2, 6,1 Hz, 2H), 7,45 (dd, J = 10,8, 8,4 Hz, 1H), 7,35 (dd, J = 9,3, 4,4 Hz, 1H), 7,24 (dd, J= 9,3, 1,1Hz, 1H), 7,10 (t, J= 5,8Hz, 1H), 4,38- 4,18 (m, 4H), 3,97 (dd, J = 13,2, 9,2 Hz, 1H), 3,00 - 2,92 (m, 1H), 2,87 2,74 (m, 4H), 1,77 (dt, J = 24,0, 11,8 Hz, 3H), 1,62 - 1,47 (m, 1H). Petição 870260063816, de 29 / 06 / 2026, pág. 160 / 739 153 / 315 Exempl o Estrutura e nome Dados 121 ° XX N.n XXX H 1 Xx 1-[(3-fluoro-4-metilfenil)metil]-3-metil-3[(3R)-1-(piridazin-3-il)piperidin-3il]ureia LC-MS: m / z 358,4 (M+H). 1H RMN (400 MHz, MeOD) δ 8,46 (s, 1H), 7,29 (d, J = 9,4 Hz, 1H), 7,14 (t, J = 7,7 Hz, 1H), 6,98 (dd, J = 11,9, 9,4 Hz, 2H), 4,44 - 4,23 (m, 5H), 4,10 (s, 1H), 3,10 - 2,98 (m, 1H), 2,95 - 2,83 (m, 5H), 2,22 (d, J = 1,6 Hz, 4H), 1,97 - 1,80 (m, 4H), 1,68 (s, 1H). 122 0 XX L J h । Γ h 1-[(4-fluoro-3-metilfenil)metil]-3-metil-3[(3R)-1-(piridazin-3-il)piperidin-3il]ureia LC-MS: m / z 358,1 (M+H). 1H RMN (400 MHz, MeOD) δ 8,46 (s, 1H), 7,39 (dd, J = 9,2, 4,3 Hz, 1H), 7,30 (d, J = 8,7 Hz, 1H), 7,17(d, J=7,5Hz, 1H), 7,12 (ddd, J= 7,3, 4,9, 2,1Hz, 1H), 6,98-6,91 (m, 1H), 4,38 (d, J= 13,3Hz, 1H), 4,32 (s, 2H), 4,28 (d, J = 3,9 Hz, 1H), 4,15 - 4,07 (m, 1H), 3,04 (dd, J = 12,5, 11,3 Hz, 1H), 2,93 - 2,87 (m, 4H), 2,24 (d, J = 1,8 Hz, 3H), 1,89 (dt, J = 9,5, 3,9 Hz, 3H), 1,75 - 1,63 (m, 1H).123 Cl Xx ° xx H 1 Xx 3-[2-(3,5-diclorofenil)etil]-1-metil-1[(3R)-1-(piridazin-3-il)piperidin-3il]ureia LC-MS: m / z 408,3 (M+H). 1H RMN (400 MHz, DMSO) δ 8,52 (dd, J = 4,4, 1,2 Hz, 1H), 7,41 (t, J = 1,9 Hz, 1H), 7,36 (dd, J = 9,3, 4,4 Hz, 1H), 7,29 - 7,16 (m, 3H), 6,47 (t, J = 5,5 Hz, 1H), 4,32 (d, J = 12,7 Hz, 1H), 4,13 (d, J = 12,0 Hz, 1H), 3,91 (dd, J = 13,4, 9,2 Hz, 1H), 3,30 - 3,26 (m, 3H), 3,00 - 2,88 (m, 1H), 2,86 - 2,71 (m, 6H), 1,84 - 1,64 (m, 3H), 1,52 (t, J = 13,1 Hz, 1H). Petição 870260063816, de 29 / 06 / 2026, pág. 161 / 739 154 / 315 Exempl o Estrutura e nome Dados 124 ° O IJ H i Lu l\A 3-[(4-cianofenil)metil]-1-metil-1-[(3R)-1 (piridazin-3-il)piperidin-3-il]ureia LC-MS: m / z 351,4 (M+H). 1H RMN (400 MHz, DMSO) δ 8,51 (dd, J = 4,4, 1,2 Hz, 1H), 7,81 7,74 (m, 2H), 7,46 (d, J=8,4Hz, 2H), 7,35 (dd, J= 9,3, 4,4Hz, 1H), 7,24 (dd, J= 9,3, 1,2Hz, 1H), 7,11 (t, J = 5,8 Hz, 1H), 4,38 - 4,22 (m, 4H), 3,98 (dd, J = 13,4, 9,3 Hz, 1H), 3,01 - 2,91 (m, 1H), 2,85 - 2,75 (m, 4H), 1,77 (dt, J = 8,9, 8,4 Hz, 3H), 1,54 (dd, J = 15,2, 11,2 Hz, 1H). 125 ° O JL II H i Lu LC-MS: m / z 354,4 (M+H). 1H RMN (400 MHz, MeOD) δ 8,44 (dd, J = 4,4, 1,0 Hz, 1H), 7,37 (dd, J = 9,4, 4,4 Hz, 1H), 7,27 (dd, J = 9,4, 1,2 Hz, 1H), 7,10 - 6,96 (m, 3H), 4,47 - 4,22 (m, 4H), 4,16 - 4,02 (m, 1H), 3,03 (dd, J = 12,5, 11,3 Hz, 1H), 2,93 - 2,81 (m, 4H), 2,22 (d, J = 6,3 Hz, 6H), 1,88 (dt, J = 9,7, 4,1 Hz, 3H), 1,77 - 1,58 (m, 1H). 126 0 \ A Vy n n r π JU H N.-J cr n 1-[(4-chloro-3-methylfenil)metil]-3-metil-3[(3R)-1-(piridazin-3-il)piperidin-3il]ureia LC-MS: m / z 374,2 (M+H). 1H RMN (400 MHz, MeOD) δ 8.45 (dd, J = 4.4, 1.1 Hz, 1H), 7.39 (dd, J = 9.4, 4.4 Hz, 1H), 7.28 (dd, J = 15.2, 8.3 Hz, 2H), 7.22 (s, 1H), 7.10 (dd, J = 8.2, 1.8 Hz, 1H), 4.40 - 4.25 (m, 4H), 4.09 (dd, J = 9.7, 5.7 Hz, 1H), 3.08 - 3.00 (m, 1H), 2.94 2.85 (m, 4H), 2.33 (s, 3H), 1.89 (dd, J = 11,2, 4.4 Hz, 3H), 1.74 - 1.61 (m, 1H). Petition 870260063816, on 06 / 29 / 2026, page. 162 / 739 155 / 315 Example Given name structure 127 CK ll Ί 0 | | .ok / NNNN ν' NH 1 kJ 3-[2-(4-chloro-3-methylphenyl)ethyl]-1-methyl-1[(3R)-1-(pyridazin-3-yl)piperidin-3yl]urea LC-MS: m / z 388 (M+H). 1H NMR (400 MHz, MeOD) δ 8.46 (dd, J = 4.4, 1.1 Hz, 1H), 7.39 (dd, J = 9.4, 4.4Hz, 1H),7.27 (dd, J= 9.4, 1.2Hz, 1H), 7.27 (d, J= 9.4, 1.2Hz, 1H), 1H), 7.13 (d, J= 1.6 Hz, 1H), 7.01 (dd, J = 8.1, 1.9 Hz, 1H), 4.34 (d, J = 11.9 Hz, 1H), 4.23 (dd, J = 12.7, 4.0 Hz, J 1H), 3.39 (tt, J = 8.4, 4.4 Hz, 2H), 3.00 (dd, J = 12.5, 11.3 Hz, 1H), 2.89 (dd, J = 18.7, 8.0 Hz, 1H), 2.31 (s, 3H), 1.92 - 1.80 (m, 3H), 1.71 - 1.57 (m, 1H). Example 128: Synthesis of 3-(4-chloro-3 >-methylbenzyl)-1 -cyclopropyl-1 - ((R)-1-((S)-tetra-hydrofuran-2-carbonyl)piperidine-3-yl)urea / ~Ό O^OH α ιί Ο M2 ,Boc -------------[J HATU,TEA,DCM TFA DCM NaBH(OAc)3, AcOH.DCM M1 M6 NaBH3CN,AcOH EtOH.THF M8 Example 128

[00236] To a mixture of M2 (116 mg, 1.0 mmol) and HATU (474 ​​mg, 1.29 mmol) in DCM (20 mL), TEA (253 mg, 2.5 mmol) at 0°C was added dropwise. After stirring at room temperature for 30 minutes, M1 (200 mg, 0.83 mmol) was added to the above mixture. The resulting mixture was stirred at room temperature for 2 hours under a N2 atmosphere. Then, the mixture was diluted with DCM (20 mL) and washed with water (30 mL) and brine (30 mL). The organic layer was dried with Na2SO4, filtered, and concentrated to the Petition 870260063816, dated 06 / 29 / 2026, page 163 / 739 156 / 315 dryness. The residue was purified by flash column chromatography (eluted with PE / EtOAc = 100:0 to 3:1) to yield M3 (250 mg, 88.8%) as a colorless oil. LC / MS (ESI) m / z: 299 (M+H)+. To a solution of M3 (250 mg, 0.84 mmol) in DCM (6 mL) TFA (2 mL) at 0°C was added dropwise. The resulting mixture was stirred at room temperature for 2 h. Then, the reaction mixture was evaporated to dryness under reduced pressure to yield crude M4 (160 mg, 96.3%) as a yellow oil without further purification. LC / MS (ESI) m / z: 199 (M+H)+. To a solution of M4 (160 mg, 0.81 mmol) and M5 (148 mg, 0.89 mmol) in DCM (10 mL) was added AcOH (145 mg, 2.42 mmol) at 0°C. The resulting mixture was stirred at room temperature for 1 h. Then, NaBH(OAc)3 (510 mg, 2.42 mmol) was added to the above mixture dropwise at 0°C. The resulting mixture was stirred at room temperature overnight under a N2 atmosphere. The mixture was suppressed with a saturated solution of NaHCO3 (20 mL) and extracted with EtOAc (30 mL) twice.The combined organic layer was washed with brine (20 mL), dried with anhydrous Na2SO4, and filtered. The filtrate was evaporated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (eluted with PE / EtOAc = 100:0 to = 2:1) to yield M6 (100 mg, 35.6%) as a colorless oil. LC / MS (ESI) m / z: 349 (M+H)+. To a mixture of M6 (100 mg, 0.29 mmol), M7 (125 mg, 0.72 mmol), and AcOH (52 mg, 0.86 mmol) in THF (12 mL) and EtOH (6 mL), NaBH3CN (55 mg, 0.86 mmol) was added. The resulting mixture was stirred at 80°C overnight under a N2 atmosphere. After cooling, the reaction was suppressed with saturated aqueous NaHCO3 (20 mL) and extracted twice with EtOAc (30 mL). The combined organic layer was washed with brine (20 mL), dried with anhydrous Na2SO4, and filtered. The filtrate was evaporated to dryness under reduced pressure. The residue was purified by flash column chromatography (eluted with PE / EtOAc = 100:0 to = 2:1) to yield M8 (50 mg, 44.8%) as a colorless oil.LC / MS (ESI) m / z: 389 (M+H)+. One. Petition 870260063816, dated 06 / 29 / 2026, page 164 / 739 157 / 315 solution of M8 (50 mg, 0.13 mmol) in TFA (4 mL) was stirred at 80°C for 3 h under a N2 atmosphere. After cooling, the mixture was concentrated to dryness under reduced pressure to yield crude M9 (30 mg, 97.8%) as purple oil without further purification. LC / MS (ESI) m / z: 239 (M+H)+.

[00237] A solution of M10 (22.9 mg, 0.13 mmol) in anhydrous DCM (2 mL) at 0°C was added dropwise to a mixture of M9 (30 mg, 0.13 mmol) and TEA (39 mg, 0.39 mmol) in anhydrous DCM (10 mL). The resulting mixture was stirred at 0°C for 1 hour under a N2 atmosphere. Then, the reaction mixture was diluted with water (20 mL) and extracted twice with DCM (20 mL). The combined organic layers were separated, dried with anhydrous Na2SO4, filtered, and concentrated to dryness. The residue was purified by flash column chromatography (eluted with DCM / MeOH = 100:0 to 20:1) to yield the crude product. The crude product was purified via preparative HPLC (Gemini 5μm C18 250*21.2mm, H2O / MeCN (5-95%) / 0.1% HCOOH) to yield Example 128 (11 mg, 0.026 mmol, 20.81% yield) as a white solid. LC / MS (ESI) m / z: 420 (M+H)+.1H NMR (400 MHz, MeOD) δ 7.28 (dd, J = 8.2, 2.7 Hz, 1H), 7.21 (d, J = 5.1 Hz, 1H), 7.10 (dd, J = 10.5, 4.1 Hz, 1H), 4.74 - 4.67 (m, 1H), 4.53 - 4.39 (m, 1H), 4.39 - 4.26 (m, 2H), 4.02 - 3.87 (m, 2H), 3.86 - 3.44 (m, 2H), 3.30 - 3.10 (m, 1H), 3.00 - 2.46 (m, 2H), 2.33 (d, J = 9.2 Hz, 3H), 2.32 - 2.13 (m, 2H), 2.05 - 1.79 (m, 5H), 1.66 - 1.39 (m, 1H), 1.02 - 0.87 (m, 2H), 0.85 - 0.66 (m, 2H).

[00238] The compounds in the following table were prepared by the same route as Example 128, starting with the appropriate commercially available M2 amide and other intermediates previously described or commercially available. Petition 870260063816, dated 06 / 29 / 2026, p. 165 / 739 158 / 315 Exemployment and number Dados 129 AA o 0AynAnan^^ ° 1 H ΛΛ 1-[(4-chloro-2-fluoro-5-metilfenil)metil]-3metil-3-[(3R)-1-[(3S)-oxolano-3carbonil]piperidin-3-il]ureia LC-MS: m / z 412 (M+H). 1H RMN (400 MHz, MeOD) δ 7.24 (dd, J = 8.0, 3.5 Hz, 1H), 7.11 (dd, J = 9.7, 6.2 Hz, 1H), 4.52 - 4.29 (m, 3H), 4.12 - 3.98 (m, 1H), 3.95 - 3.74 (m, 5H), 3.48 - 3.39 (m, 1H), 3.17 - 3.09 (m, 1H), 3.05 - 2.96 (m, 1H), 2.85 (d, J = 7.5 Hz, 3H), 2.74 (t, J = 11.9 Hz, 1H), 2.51 (td, J = 13.0, 2.3 Hz, 1H), 2.31 (s, 3H), 2.12 (ddt, J = 17.1, 13.6, 7.6 Hz, 2H), 1.89 - 1.77 (m, 3H), 1.59 1.44 (m, 1H). 130 O, CA.Z / I 1 hAA 1-[(4-chloro-2-fluoro-5-methylfenil)methyl]-3methyl-3-[(3R)-1-[(2R)-oxolano-2carbonil]piperidin-3-il]ureia LC-MS: m / z 412 (M+H).1H RMN (400 MHz, MeOD) δ 7,24 (d, J = 8,0 Hz, 1H), 7,11 (dd, J = 9,7, 6,6 Hz, 1H), 4,70 (dd, J = 14,1, 8,0 Hz, 1H), 4,50 - 4,29 (m, 3H), 4,13 - 3,98 (m, 1H), 3,97 - 3,79 (m, 3H), 3,17 3,08 (m, 1H), 2,93 (dd, J = 18,6, 7,7 Hz, 1H), 2,85 (d, J = 4,9 Hz, 3H), 2,74 (t, J = 11,8 Hz, 1H), 2,52 (td, J = 13,0, 2,3 Hz, 1H), 2,31 (s, 3H), 2,28 - 2,12 (m, 1H), 2,03 (ddd, J = 12,9, 10,3, 6,6 Hz, 1H), 1,97 - 1,87 (m, 2H), 1,86 1,78 (m, 3H), 1,65 (d, J = 7,3 Hz, 1H), 1,48 (d, J = 9,6 Hz, 1H). 131 cAA o=\ A IZ LC-MS: m / z 420,2 (M+H). 1H RMN (400 MHz, MeOD) δ 7,18 (dd, J = 8,2, 2,8 Hz, 1H), 7,12 (d, J = 7,9 Hz, 1H), 7,04 -. Petição 870260063816, de 29 / 06 / 2026, pág. 166 / 739 159 / 315 Example Structure and name Data 3-[(4-chloro-3-methylphenyl)methyl]-1-cyclopropyl1-[(3R)-1-[(3S)-oxolane-3carbonyl]piperidin-3-yl]urea 6.97 (m, 1H), 6.81 (dt, J = 26.1, 5.9 Hz, 1H), 4.45 - 4.34 (m, 1H), 4.23 (dd, J = 12.3, 5.8 Hz, 2H), 3.88 (ddd, J = 16.4, 14.3, 8.2 Hz, 2H), 3.79 - 3.65 (m, 3H), 3.45 3.29 (m, 2H), 3.07 - 2.83 (m, 1H), 2.49 - 2.36 (m, 2H), 2.25 (s, 3H), 2.17 - 1.91 (m, 3H), 1.90 1.68 (m, 2H), 1.51 - 1.28 (m, 1H), 0.92 - 0.78 (m, 2H), 0.74 0.54 (m, 2H).

[00239] Procedure available The following examples were synthesized according to General Method A, using commercially available building blocks: Example Structure and name Data 132 ,N'NvN0 Â / AH 1-[(4-chloro-2-fluoro-5-methylphenyl)methyl]-3cyclopropyl-3-[(3S)-1-(pyridazin-3yl)pyrrolidin-3-yl]urea LC-MS: m / z 404 (M+H).1H RMN (400 MHz, MeOD) δ 8,30 (dd, J = 4,5, 1,1 Hz, 1H), 7,25 (dd, J = 9,2, 4,5 Hz, 1H), 7,15 (d, J = 8,0 Hz, 1H), 7,02 (d, J = 9,8 Hz, 1H), 6,81 (dd, J = 9,2, 1,2 Hz, 1H), 4,48 (dd, J = 9,2, 7,9 Hz, 1H), 4,28 (s, 2H), 3,65 (dd, J = 15,3, 6,8 Hz, 2H), 3,50 (dd, J = 10,2, 8,1 Hz, 1H), 3,34 (dd, J = 17,7, 9,0 Hz, 1H), 2,50 - 2,39 (m, 2H), 2,23 - 2,14 (m, 4H), 0,85 (ddd, J = 6,9, 4,8, 2,8 Hz, 2H), 0,66 (qd, J = 6,4, 3,1 Hz, 2H). (m, 1H), 2,49 - 2,36 (m, 2H), 2,25 (s, 3H), 2,17 - 1,91 (m, 3H), 1,90 - 1,68 (m, 2H),. Petição 870260063816, de 29 / 06 / 2026, pág. 167 / 739 160 / 315 Example Structure and Name Dice 1.51 - 1.28 (m, 1H), 0.92 - 0.78 (m, 2H), 0.74 - 0.54 (m, 2H). 133 0 / t NN Ti Ar \J . H JLJL F ^^CI 1-[(4-chloro-2-fluoro-5-methylphenyl)methyl]-3methyl-3-{[1-(pyridazine-3-yl)pyrrolidin-2yl]methyl}ureia LC-MS: m / z 392 (M+H). 1H NMR (400 MHz, MeOD) δ 8.42 (d, J = 4.4 Hz, 1H), 7.35 (dd, J = 9.2, 4.5 Hz, 1H), 7.28 (d, J = 8.0 Hz, 1H), 7.7,09 1,2 (d, J = = 9.2 Hz, 1H), 4.45 (s, 2H), 4.36 (s, 1H), 3.68 (d, J = 14.5 Hz, 1H), 3.57 (t, J = 8.7 Hz, 1H), 3.31 (s, 17, 3.1 Hz), 3.3 J =18 ( (s, 3H), 2.29 (d, J = 15.1 Hz, 3H), 2.12 (ddd, J = 26.3, 13.1, 5.9 Hz, 4H). 134 í / N 0 / 1 NN η AT \J . H JL JL F ^^CI 1-[(4-chloro-2-fluoro-5-methylphenyl)methyl]-3methyl-3-{[(2S)-1-(pyridazine-3-yl)pyrrolidin-2yl]methyl}ureia LC-MS: m / z 392 (M+H).1HNMR (400MHz, MeOD) δ 8.42 (d, J=4.3Hz, 1H), 7.35 (dd, J=9.2, 4.4Hz, 1H), 7.28 (d, J=8.0Hz, 1H), 7.09 (d, J=9.7Hz, 1H), 7.02 (d, J= 9.1Hz ,1H), 4.45(s,2H), 4.36(s,1H), 3.68(d,J = 14.1Hz,1H), 3.57(t,J=8.7Hz,1H), 3.31(s,4H), 3.17(s,1H), 3.02(s,3H), 2.27 (s, 3H), 2.12 (ddd, J = 26.1, 13.1, 5.8 Hz, 4H). 135 rA 0 h ,\ ih II Ί 3-[(4-chloro-2-fluoro-5-methylphenyl)methyl]-1ethyl-1-[(3R)-1-(pyridazin-3-yl)piperidin-3yl]urea LC-MS: m / z 392 (M+H). 1H NMR (400 MHz, MeOD) δ 8.44 (dd, J = 4.4, 1.1 Hz, 1H), 7.38 (dd, J = 9.4, 4.4 Hz, 1H), 7.31 - 7.20 (m, 2H), 7.11 (d, J = 9.8 Hz, 1H), 4.30 (m, 4H), 4.05 - 3.95 (m, 1H), 3.36 (ddd, J = 14.3, 7.2, 3.5 Hz, 2H), 3.09 -. Petition 870260063816, 06 / 29 / 2026, p. 168 / 7 161 / 3 Exemploy time and time Dados 3.01 (m, 1H), 2.92 (td, J = 13.1, 2.4 Hz, 1H), 2.30 (s, 3H), 1.98 1.83 (m, 3H), 1.74 - 1.58 (m, 1H), 1.19 (t, J = 7.1 Hz, 3H). 136 AU 1-[(4-chloro-3-metilfenil)metil]-3-ciclopropil3-[(3S)-1-(piridazin-3-il)pirrolidin-3-il]ureia LC-MS: m / z 386 (M+H). 1H RMN (400 MHz, MeOD) δ 8.40 (dd, J = 4.4, 1.1 Hz, 1H), 7.36 (dd, J = 9.2, 4.5 Hz, 1H), 7.27 (d, J = 8.2 Hz, 1H), 7.21 (s, 1H), 7.10 (dd, J = 8.2, 1.8 Hz, 1H), 6.97 (t, J = 6.0 Hz, 1H), 6.92 (d, J= 9.3Hz, 1H), 4.65-4.52 (m, 1H), 4.33 (d, J=4.4Hz, 2H), 3.75 (t, J= 9.3Hz, 2H), 3.61 (dd, J= 10,1, 8.1Hz, 1H), 3.45 (dd, J= 17.7, 9.0Hz, 1H), 2.55 (ddd, J= 13.1, 8.4, 4.7Hz, 2H), 2.34 (s, 3H), 2.31 - 2.24 (m, 1H), 0.98 0.91 (m, 2H), 0.81 - 0.71 (m, 2H). 137 ° nn ||J i η Η Ί AA \f3 3-[(4-chloro-3-methylfenil)methyl]-1-[(3R)-1(piridazin-3-il)piperidin-3-il]-1-(2,2,2trifluoroetil)ureia LC-MS: m / z 442(M+H).1HNMR (400MHz, MeOD) δ8.50 (d, J= 4.0Hz, 1H), 7.40 (dd, J= 9.4, 4.4Hz, 1H), 7.30 (dd, J= 9.4, 1.1Hz, 1H), 7.25 (d, J= 8.3Hz, 2H), 7.14 (dd, J=8.2, 1.8Hz, 1H), 4.50 (d, J= 13.0Hz, 1H), 4.42 (d, J= 4.6Hz, 2H), 4.38-4.29 (m, 1H), 4.20 (d, J= 13.7Hz, 1H), 3.97(dd, J= 16.4, 8.7Hz, 1H), 3.80 (td, J=11.3, 5.6 Hz, 1H), 3.11 - 3.01 (m, 2H), 2.01 - 1.87 (m, 3H), 1.70 - 1.59 (m, 1H). Petition 870260063816, on 06 / 29 / 2026, page. 169 / 739 162 / 315 ExemEstrutura e nome Dados plo 138 3-[(4-chloro-3-methylfenil)methyl]-1-propyl-1[(3R)-1-(piridazin-3-il)piperidin-3-il]ureia LC-MS: m / z 402 (M+H). 1H RMN (400 MHz, DMSO) δ 8,51 (dd, J = 4,4, 1,1 Hz, 1H), 7,37 - 7,32 (m, 2H), 7,26 - 7,21 (m, 2H), 7,10 (dd, J = 8,2, 1,8 Hz, 1H), 6,98(d, J= 5,6 Hz, 1H), 4,31-4,18 (m, 4H), 3,87(d, J= 11,6 Hz, 1H), 3,11 (dd, J = 12,7, 6,8 Hz, 2H), 2,97 (t, J = 11,8 Hz, 1H), 2,84 (t, J = 12,2 Hz, 1H), 2,30 (s, 3H), 1,79 (t, J = 15,2 Hz, 3H), 1,50 (dd, J = 14,6, 7,0 Hz, 3H), 0,85 (t, J = 7,3 Hz, 3H). 139 140 1-[(4-cloro-3-metilfenil)metil]-3-etil-3[(3S)-1-(piridazin-3-il)pirrolidin-3-il]ureia LC-MS: m / z 374,1 (M+H). 1H RMN (400 MHz, MeOD) δ 8,42 (d, J = 4,4 Hz, 1H), 8,21 (s, 1H), 7,40 (dd, J = 9,2, 4,4 Hz, 1H), 7,27 (d, J= 8,4 Hz, 1H), 7,21 (s, 1H), 7,10 (d, J=8,0 Hz, 1H), 6,98 (dd, J= 9,2, 1,2 Hz, 1H), 4,87-4,80 (m, 1H), 4,32 (s, 2H), 3,78 - 3,71 (m, 2H), 3,50 - 3,39 (m, 2H), 3,37 - 3,33 (m, 2H), 2,34 (s, 3H), 2,26 (dd, J = 8,4, 6,0 Hz, 2H), 1,20 (t, J = 7,2 Hz, 3H). 3-[(4-chloro-3-methylphenyl)methyl]-1(cyclobutylmethyl)-1-[(3R)-1-(pyridazin-3yl)piperidin-3-yl]urea LC-MS: m / z 428.2 (M+H). 1H NMR (400 MHz, MeOD) δ 8.46 (d, J = 3.5 Hz, 1H), 7.38 (dd, J = 9.4, 4.4 Hz, 1H), 7.31 7.22 (m, 3H), 7.14 - 7.08 (m, 1H), 4.44 - 4.22 (m, 4H), 3.75 (ddd, J = 15.2, 7.7, 3.9 Hz, 1H), 3.42 (dd, J = 15.1, 7.6 Hz, 1H), Petition 870260063816, dated 06 / 29 / 2026, p. 170 / 739 163 / 315 Exemplo Estrutura e nome Dados 3,26 (dd, J = 15,2, 6,8 Hz, 1H), 3,14 - 3,05 (m, 1H), 2,97 (td, J = 13,2, 2,5 Hz, 1H), 2,59 (dt, J = 15,0, 7,5 Hz, 1H), 2,33 (s, 3H), 2,11 - 1,74 (m, 9H), 1,70 - 1,56 (m, 1H). 141 A u [X Ν ' N Ύ''Ν N [1^ H 3-[2-(4-cloro-3-metilfenil)etil]-1-etil-1- [(3R)-1-(piridazin-3-il)piperidin-3-il]ureia LC-MS: m / z 428,2 (M+H). 1H RMN (400 MHz, MeOD) δ 8,46 (dd, J = 4,4, 1,2 Hz, 1H), 7,39 (dd, J = 9,6, 4,4 Hz, 1H), 7,27 (dd, J= 9,6, 1,2Hz, 1H), 7,20 (d, J=8,0Hz, 1H), 7,13 (d, J= 1,6Hz, 1H), 7,01 (dd, J = 8,0, 2,0Hz, 1H), 4,34-4,23 (m,2H), 3,87 (d, J= 4,8Hz, 1H), 3,42 (t, J=7,2Hz, 1H), 3,37 - 3,32 (m, 1H), 3,25 (dd, J = 15,2, 7,2 Hz, 1H), 3,03 - 2,88 (m, 2H), 2,78 (t, J = 7,2 Hz, 2H), 2,29 (s, 3H), 1,94 - 1,83 (m, 3H), 1,71 - 1,52 (m, 1H), 1,11 (t, J = 7,2 Hz, 3H). 142 γγνΥν·» Cl 3-[(4-cloro-3-metilfenil)metil]-1-metil-1[(3R)-1-(6-fenilpiridazin-3-il)piperidin-3il]ureia LC-MS: m / z 450,2 (M+H).1H RMN (400 MHz, MeOD) δ 7,93 - 7,88 (m, 2H), 7,83 (d, J = 9,6 Hz, 1H), 7,50 - 7,40 (m, 3H), 7,35 (d, J = 9,6 Hz, 1H), 7,29 7,23 (m, 2H), 7,12 (dd, J = 8,2, 1,8 Hz, 1H), 4,45 - 4,32 (m, 4H), 4,14 (dt, J = 13,7, 7,0 Hz, 1H), 3,10 (dd, J = 12,4, 11,4 Hz, 1H), 2,97 (dd, J = 12,9, 2,3 Hz, 1H), 2,91 (s, 3H), 2,33 (s, 3H), 1,92 (dd, J = 15,3, 5,2 Hz, 3H), 1,71 (d, J = 12,4 Hz, 1H). Petição 870260063816, de 29 / 06 / 2026, pág. 171 / 739 164 / 315 Example Structure and name Data 143 o _N A. n Ar nny Ar ll \ 1 Η II 1 A b^cl 0 3-[(4-chloro-3-methylphenyl)methyl]-1-(oxetan-3yl)-1-[(3R)-1-(pyridazine-3-yl)pyridine-pyridine-3-3-LC-MS: m 416 (M+H). 1H NMR (400 MHz, MeOD) δ 8.47 (d, J = 4.0 Hz, 1H), 7.38 (dd, J = 9.6, 4.4 Hz, 1H), 7.30 7.16 (m, 3H), 7.12 - 7.05 (m, 1Hz, 4.8), J Hz, 1H), 4.84 to 4.73 (m, 3H), 4.56 to 4.48 (m, 1H), 4.32 (s, 2H), 4.27 (s, 1H), 4.20 (d, J = 13.2 Hz, 1H), 3.68 m (m, 1H), 3.00 (td, J = 13.2, 2.8 Hz, 1H), 2.32 (s, 3H), 2.08 - 1.78 (m, 3H), 1.62 (dt, J = 13.2, 4.0 Hz, 1H). 144 o N'n ii J 1 η Η 1 O 3-[(1R,2S)-2-(4-fluorophenyl)cyclopropyl]-1methyl-1-[(3R)-1-(pyridazin-3-yl)piperidin-3yl]urea LC-MS: m / z 414.4 (M+H). 145 / 7'ΝνΝ0 Â / 1 H IL JL 1-[(4-chloro-3-methylphenyl)methyl]-3-methyl-3[(3S)-1-(pyridazin-3-yl)pyrrolidin-3-yl]urea LC-MS: m / z 360.2 (M+H).1H NMR (400 MHz, MeOD) δ 8.43 (dd, J = 4.5, 1.2 Hz, 1H), 7.39 (dd, J = 9.2, 4.5 Hz, 1H), 7.27 (d, J = 8.2 Hz, 1H), 7.22 (s, 1H), 7.10 (dd, J = 8.2, 1.7 Hz, 1H), 6.97 (dd, J = 9.2, 1.2 Hz, 1H), 5.04 (p, J = 7.8 Hz, 1H), 4.32 (s, 2H), 3.80 - 3.64 (m, 2H), 3.46 (ddd, J = 18.1, 13.5, 7.9 Hz, 2H), 2.89 (s, 3H), 2.36 (d, J = 9.7 Hz, 3H), 2.27 - 2.14 (m, 2H). General Intermediary Summary, Methods BG Petition 870260063816, 06 / 29 / 2026, pág. 172 / 739 165 / 315 Methods BG Me TFA DCM Me Method B: K2CO3 / CSF / DMSO at 90°C for 16 hours Method C: Pd(OAC)2 / DavePhos / t-BuONa / toluene at 100°C for 16 h Method D: Pd(OAC)2 / RuPhos / LiHMDS / THF at 70°C for 2~8 h Method E: XPhos-Pd-G1 / XPhos / LiHMDS / THF at 70°C for 2~8 h Method F: RuPhos-Pd-G2 / RuPhos / LiHMDS / THF at 70°C for 2~16 h Method G: CuI / L-proline / K2CO3 / DMSO General Procedure B: RX K2CO3, CsF, DMSO R 1 X = Cl or Br B2

[00240] To a mixture of compound B1 (1.0 eq) and aryl halide (1.1 eq) in DMSO (0.1 mol / L) were added K2CO3 (3.0 eq) and CsF (0.2 eq). The resulting mixture was stirred at 90°C for 16 h. Then, the mixture was diluted with H2O and extracted twice with EtOAc. The combined organic layers were washed with brine, dried with anhydrous Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography to yield compound B2. Example of a summary of general procedure B: Br K2CO3, CsF, DMSO B3 B4

[00241] To a mixture of compound B3 (100 mg, 0.47 mmol) and compound 2 (101 mg, 0.47 mmol) in DMSO (8 mL) were added K2CO3 (194 mg, 1.40 mmol) and CsF (15 mg, 0.09 mmol). The resulting mixture was stirred at 90°C for 16 h. Then, the mixture was diluted with H2O (30 mL) and extracted with EtOAc (20 mL * 2). The organic layers Petition 870260063816, dated 06 / 29 / 2026, p. 173 / 739 166 / 315 combined were washed with brine, dried over anhydrous Na2SÜ4 and concentrated to dryness. The residue was purified by silica gel column chromatography (eluted with PE: EtOAc = 10:1 to 2:1) to yield compound B4 (140 mg, 87.5% yield) as a yellow solid. LC / MS (ESI) m / z: 349 (M+H)+. General procedure C: C1 RX Pd(OAc)2,DavePhos, t-BuONa, toluene X = Cl or Br C2

[00242] To a mixture of compound C1 (1.2 eq.) and aryl halide (1.0 eq.) in toluene, t-BuONa (2.0 eq.), DavePhos (0.1 eq.) and Pd(OAc)2 (0.1 eq.) were added under a N2 atmosphere. The resulting mixture was stirred at 100°C for 16 h under a N2 atmosphere. Then, the mixture was diluted with EtOAc, filtered and concentrated to dryness. The residue was purified by silica gel column chromatography to generate compound C2. Example of a summary of the general procedure C: Rd(OAc)2,DavePhos, t-BuONa, toluene C3 C

[00243] To a mixture of C3 (0.58 g, 2.72 mmol) and C4 (0.3 g, 2.09 mmol) in toluene (15 mL) was added t-BuONa (410 mg, 4.18 mmol), DavePhos (83 mg, 0.21 mmol) and Pd(OAc)2 (47 mg, 0.21 mmol) under a N2 atmosphere. The resulting mixture was stirred at 120°C for 16 h under a N2 atmosphere. Then, the mixture was diluted with EtOAc (30 mL), filtered and concentrated to dryness. The residue was purified by silica gel column chromatography (eluted with PE:EtOAc = 50:1 to 20:1) to yield compound C5 (0.58 g, 87% yield) as a colorless oil. LC / MS (ESI) m / z: 322 (M+H)+. Petition 870260063816, dated 06 / 29 / 2026, p. 174 / 739 167 / 315 General procedure D: RX Pd(OAc)2,RuPhos, LiHMDS.THF D1 R = Cl or Br D2

[00244] A mixture of amine D1 (1.1 eq.) and aryl halide (1.0 eq.) in THF was added to a solution of LiHMDS in THF (5.0 eq., 1 M), RuPhos (0.1 eq.) and Pd(OAc)2 (0.1 eq.) under a N2 atmosphere. The resulting mixture was stirred at 80°C for 4 h under a N2 atmosphere. Then, the mixture was quenched with NH4Cl and extracted with EtOAc twice. The combined organic layers were dried with anhydrous Na2SO4, filtered, and concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography to yield compound D2. Example of a summary of the general procedure D: Pd(OAc)2, RuPhos. LiHMDS.THF D2

[00245] To a mixture of D2 (153 mg, 0.72 mmol) and D3 (100 mg, 0.65 mmol) in THF (12 mL) were added LiHMDS (3.3 mL, 1 M in THF), RuPhos (31 mg, 0.07 mmol) and Pd(OAc)2 (15 mg, 0.07 mmol) under a N2 atmosphere. The resulting mixture was stirred at 80°C for 4 h under a N2 atmosphere. Then, the mixture was suppressed with aq. NH4Cl (30 mL) and extracted with EtOAc (20 mL) twice. The combined organic layers were dried with anhydrous Na2SO4, filtered, and concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (eluted with PE: EtOAc = 50:1 to 5:1) to yield D4 (115 mg, 53% yield) as a light yellow solid. LC / MS (ESI) m / z: 332 (M+H)+. Petition 870260063816, dated 06 / 29 / 2026, p. 175 / 739 168 / 315 Example of General Procedure E: E1 E3

[00246] To a mixture of E1 (100 mg, 0.65 mmol) and E2 (182 mg, 0.85 mmol) in THF (18 mL) was added XPhos-Pd-G1 (25 mg, 0.03 mmol), XPhos (33 mg, 0.07 mmol) and LiHMDS (2.6 mL, 1 M in THF). The resulting mixture was stirred at 80°C for 16 h under a N2 atmosphere. Then, the mixture was suppressed with aq. NH4Cl (40 mL) and extracted with EtOAc (25 mL) twice. The combined organic layers were dried with anhydrous Na2SO4, filtered, and concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (eluted with PE: EtOAc = 20:1 to 3:1) to yield E3 (130 mg, 60% yield), a light yellow oil. LC / MS (ESI) m / z: 332 (M+H)+. Example of General Procedure F: H HN-Λ n. A z HN~n kJ 'NBoc ί|Ί1 F21 / A RuPhos-Pd-G2, n RuPhos,LiHMDS, < > ClTHFLJ·,, .Boc I F1 F3

[00247] To a mixture of F1 (200 mg, 1.311 mmol) and F2 (280 mg, 1.311 mmol) in THF (20 mL) was added RuPhos (61 mg, 0.131 mmol) and RuPhos-Pd-G2 (101 mg, 0.131 mmol). After stirring at 0°C for 10 min, LiHMDS (3.14 mL, 1M in THF) was added dropwise and the resulting mixture was stirred at 70°C for a further 3 h under a N2 atmosphere. After cooling, the mixture was suppressed with NH4Cl aq. (30 mL) and extracted with EtOAc (20 mL) twice. The organic layers Petition 870260063816, dated 06 / 29 / 2026, p. 176 / 739 169 / 315 combined were dried with anhydrous Na2SÜ4, filtered and concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (eluted with PE:EtOAc=50:1 to 2:1) to yield F3 (160 mg, 37% yield) as a yellow oil. LC / MS (ESI) m / z: 331(M+H)+. Example of General Procedure G: \-NH / *VBrk NNN-N G2 _ I « N \Y 'zn-B°cCuI, L-proline, < 'η । K2CO3,DMSO [I.Boc 'N I G1G3

[00248] To a solution of G2 (200 mg, 1.235 mmol) and G1 (265 mg, 1.235 mmol) in DMSO (10 mL) was added CuI (47 mg, 0.247 mmol), L-proline (28 mg, 0.247 mmol) and K2CO3 (512 mg, 3.704 mmol) and the resulting mixture was stirred at 100°C for 16 hours under a N2 atmosphere. After cooling, the mixture was suppressed with aqueous NH4Cl (30 mL) and extracted twice with EtOAc (20 mL). The combined organic layers were dried with anhydrous Na2SO4, filtered and concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (eluted with DCM: MeOH = 100:1 to 20:1) to yield G3 (160 mg, 44% yield) as a yellow oil. LC / MS (ESI) m / z: 296 (M+H)+.

[00249] The examples in the table below were prepared from the appropriate starting materials described above or commercially available starting materials using similar methods as described above. Petition 870260063816, dated 06 / 29 / 2026, page 177 / 739 170 / 315 Exemplo Método Estrutura e Nome Dados 146 B π Π 1 h í| | 3f (R)-3-(4-cloro-3-metilbenzil)-1metil-1-(1-(6-metilpiridazin-3il)piperidin-3-il)ureia LC-MS: m / z 416 (M+H). 1H RMN (400 MHz, MeOD) δ 7,38 (d, J = 0,8 Hz, 2H), 7,26 (d, J = 8,2 Hz, 1H), 7,21 (s, 1H), 7,10 (dd, J = 8,2, 1,8 Hz, 1H), 4,32 (s, 2H), 4,31 - 4,18 (m, 2H), 4,11 (dt, J = 11,2, 7,7 Hz, 1H), 3,07 - 2,99 (m, 1H), 2,94 - 2,85 (m, 4H), 2,49 (s, 3H), 2,33 (s, 3H), 1,92 - 1,83 (m, 3H), 1,74 - 1,61 (m, 1H). 147 B í Ί 1 H íl 1 k,_____J 0 (R)-3-(4-cloro-3-metilbenzil)-1-(1(6-cianopiridin-2-il)piperidin-3-il)1-metilureia LC-MS: m / z 398 (M+H). 1H RMN (400 MHz, MeOD) δ 7,59 (dd, J = 8,9, 7,2 Hz, 1H), 7,27 (d, J = 8,2 Hz, 1H), 7,21 (s, 1H), 7,12 - 7,05 (m, 2H), 7,01 (d, J = 7,0 Hz, 1H), 4,37 4,24 (m, 4H), 4,11 - 4,01 (m, 1H), 2,96 (dd, J = 12,5, 11,3 Hz, 1H), 2,89 (s, 3H), 2,81 (td, J = 13,0, 2,4 Hz, 1H), 2,33 (d, J = 5,1 Hz, 3H), 1,89 - 1,81 (m, 3H), 1,69 - 1,57 (m, 1H).148 C Cl 1 HN^O N ' (Al (R)-3-(4-cloro-3-metilbenzil)-1metil-1-(1-(ftalazin-1-il)piperidin3-il)ureia LC-MS: m / z 424 (M+H). 1H RMN(400 MHz, MeOD) δ 9,15 (s, 1H), 8,19 (dd, J = 6,0, 3,5 Hz, 1H), 8,05 (dd, J = 6,1, 3,1 Hz, 1H), 7,96 - 7,90 (m, 2H), 7,26 - 7,21 (m, 2H), 7,10 (dd, J = 8,2, 1,8 Hz, 1H), 4,53 (s, 1H), 4,35 (s, 2H), 3,89 (dd, J = 27,3, 12,2 Hz, 2H), 3,12 (t, J = 11,6 Hz, 1H), 3,03 (s, 1H), 2,91 (s, 3H), 2,30 (s, 3H), 1,97. Petição 870260063816, de 29 / 06 / 2026, pág. 178 / 739 171 / 315 Exemplo Método Estrutura e Nome Dados (dd, J = 6,4, 3,5 Hz, 3H), 1,92 1,84 (m, 1H). 149 C ^0 Cl N ^I | Π II 1 H IL .N. .N. JL 0 (R)-3-(4-cloro-3-metilbenzil)-1-(1(6-metoxipirimidin-4-il)piperidin3-il)-1-metilureia LC-MS: m / z 404 (M+H). 150 C Y i 1 h li i N0 (R)-3-(4-cloro-3-metilbenzil)-1- metil-1-(1-(5-metilpiridin-2il)piperidin-3-il)ureia LC-MS: m / z 387 (M+H). 1H RMN (400 MHz, DMSO) δ 8,18 (s, 1H), 7,82 (d, J = 2,0 Hz, 1H), 7,34 (d, J = 8,0 Hz, 2H), 7,24 (s, 1H), 7,12 (dd, J = 8,2, 1,8 Hz, 1H), 6,93 (t, J= 5,7 Hz,1H), 6,75 (d, J= 8,7 Hz, 1H), 4,27- 4,16 (m, 2H), 4,15 - 4,05 (m, 2H), 3,93 (d, J = 5,1 Hz, 1H), 2,76 (d, J = 10,3 Hz, 4H), 2,70 - 2,62 (m, 1H), 2,31 (s, 3H), 2,11 (s, 3H), 1,75 - 1,65 (m, 3H), 1,51 (dd, J = 14,0, 9,7 Hz, 1H). 151 C íi Ί । H (l 1 N 7 ρ·Ύ 0 (R)-3-(4-cloro-3-metilbenzil)-1metil-1-(1-(5-metilpiridazin-3il)piperidin-3-il)ureia LC-MS: m / z 388 (M+H).1H NMR (400 MHz, MeOD) δ 8.34 (s, 1H), 7.26 (d, J = 8.2 Hz, 1H), 7.22 (s, 1H), 7.13 7.08 (m, 2H), 4.38 - 4.24 (m, 4H), 4.08 (dd, J = 9.9, 5.4 Hz, 1H), 3.05 - 2.97 (m, 1H), 2.89 (s, 3H), 2.88 - 2.82 (m, 1H),. Petition 870260063816, dated 06 / 29 / 2026, p. 179 / 739 172 / 315 Exemplo Método Estrutura e Nome Dados 2,33 (s, 3H), 2,27 (s, 3H), 1,92 - 1,82 (m, 3H), 1,74 - 1,60 (m, 1H). 152 B O 1 h PT (R)-3-(4-cloro-3-metilbenzil)-1metil-1-(1-(pirimidin-4-il)piperidin3-il)ureia LC-MS: m / z 374 (M+H). 1H RMN (400 MHz, MeOD) δ 8,47 (s, 1H), 8,09 (d, J = 6,8 Hz, 1H), 7,27 (d, J = 8,2 Hz, 1H), 7,22 (s, 1H), 7,10 (dd, J= 8,2, 1,7Hz, 1H), 6,90 (d, J= 6,3Hz, 1H), 4,48 (d, J= 20,4Hz, 2H), 4,36-4,27 (m, 2H), 4,13 4,02 (m, 1H), 3,10 (t, J = 12,0 Hz, 1H), 2,94 (dd, J = 9,8, 6,3 Hz, 1H), 2,90 (s, 3H), 2,34 (s, 3H), 1,98 - 1,82 (m, 3H), 1,61 (dt, J = 12,5, 3,5 Hz, 1H). 153 E 4 |i 1 i h \\ t IJ 0 (R)-1-(1-(1H-imidazo[4,5b]piridin-5-il)piperidin-3-il)-3-(4cloro-3-metilbenzil)-1-metilureia LC-MS: m / z 413 (M+H). 154 C xo A. ^Cl N ^N । fi ii i 1 H 1 l_____J 0 (R)-3-(4-cloro-3-metilbenzil)-1-(1(2-metoxipirimidin-4-il)piperidin3-il)-1-metilureia LC-MS: m / z 404,2 (M+H).1H NMR (400 MHz, MeOD) δ 7.90 (d, J = 6.3 Hz, 1H), 7.29 7.19 (m, 2H), 7.09 (dd, J= 8.0, 1.8Hz, 1H), 6.42 (d, J= 6.3Hz, 1H), 4.40 (s, 1H), 4.31 (d, J= 4.7 Hz, 2H), 4.11 - 4.03 (m, 1H), 3.85 (s, 3H), 3.03 (t, J =. Petition 870260063816, dated 06 / 29 / 2026, p. 180 / 739 173 / 315 Exemplo Método Estrutura e Nome Dados 11,9 Hz, 1H), 2,87 (d, J = 11,8 Hz, 4H), 2,34 (s, 3H), 1,99 1,80 (m, 4H), 1,65 - 1,54 (m, 1H). 155 B ^.Cl rí n । ir F I 1 HFX\ N ] <»9 XX X / \z^\ F \z^ 0 (R)-3-(4-cloro-3-metilbenzil)-1metil-1-(1-(5(trifluorometil)piridazin-3il)piperidin-3-il)ureia LC-MS: m / z 442 (M+H). 1H RMN (400 MHz, MeOD) δ 8,70 (d, J = 1,3 Hz, 1H), 7,53 (s, 1H), 7,26 (d, J = 8,2 Hz, 1H), 7,22 (s, 1H), 7,11 (dd, J = 8,2, 1,6 Hz, 1H), 4,48 (d, J = 12,7 Hz, 1H), 4,39 (dd, J = 12,6, 3,7 Hz, 1H), 4,32 (s, 2H), 4,17 - 4,07 (m, 1H), 3,15 3,07 (m, 1H), 3,00 - 2,93 (m, 1H), 2,91 (d, J = 6,2 Hz, 3H), 2,34 (s, 3H), 1,91 (ddd, J = 12,7, 10,2, 5,5 Hz, 3H), 1,75 - 1,61 (m, 1H). 156 C (R)-3-(3-cloro-2-metilbenzil)-1-(1(6-metoxipicolinoil)piperidin-3-il)1-metilureia LC-MS: m / z 431,2 (M+H).1H RMN (400 MHz, MeOD) δ 7,79 - 7,67 (m, 1H), 7,25 (dd, J = 13,3, 8,3 Hz, 1H), 7,13 (dd, J = 13,9, 6,7 Hz, 2H), 7,04 - 6,79 (m, 2H), 4,65 - 4,51 (m, 1H), 4,36 - 4,11 (m, 3H), 3,94 3,77 (m, 4H), 3,20 (t, J = 12,0 Hz, 1H), 3,03 - 2,88 (m, 3H), 2,81 - 2,66 (m, 2H), 2,33 (d, J = 10,4 Hz, 3H), 1,96 - 1,67 (m, 4H). Petição 870260063816, de 29 / 06 / 2026, pág. 181 / 739 174 / 315 Exemplo Método Estrutura e Nome Dados 157 B Pi 1 h ΓΎ 0Y (R)-3-(4-cloro-3-metilbenzil)-1metil-1-(1-(pirimidin-2-il)piperidin3-il)ureia LC-MS: m / z 374,1 (M+H). 1H RMN (400 MHz, MeOD) δ 8,24 (d, J = 4,8 Hz, 2H), 7,31 7,20 (m, 2H), 7,11 (d, J= 8,1Hz, 1H), 6,91 (d, J= 5,5Hz, 1H), 6,54 (t, J= 4,8Hz, 1H), 4,71 4,59 (m, 2H), 4,34 - 4,26 (m, 2H), 3,97 (dd, J = 10,1, 5,2 Hz, 1H), 2,97 (t, J = 11,9 Hz, 1H), 2,89 (s, 3H), 2,85 - 2,76 (m, 1H), 2,34 (s, 3H), 1,91 - 1,79 (m, 3H), 1,66 - 1,53 (m, 1H). 158 B -Cl II । 1 h || | N p) Y LJ 0 3-[(4-cloro-3-metilfenil)metil]-1metil-1-[(3R)-1-(pirazin-2il)piperidin-3-il]ureia LC-MS: m / z 374,2 (M+H). 1H RMN (400 MHz, MeOD) δ 8,20 (d, J = 1,2 Hz, 1H), 7,99 (dd, J= 2,4, 1,5Hz, 1H), 7,71 (d, J=2,7Hz, 1H), 7,27 (d, J= 8,2 Hz, 1H), 7,22 (s, 1H), 7,10 (dd, J = 8,1, 1,6 Hz, 1H), 4,36 4,26 (m, 4H), 4,07 (dd, J = 9,6, 5,5 Hz, 1H), 3,01 - 2,94 (m, 1H), 2,89 (s, 3H), 2,87 - 2,79 (m, 1H), 2,34 (s, 3H), 1,90 1,81 (m, 3H), 1,71 - 1,59 (m, 1H). 159 B -N>. -zs.-Cl Ti XN I íí 1 1 H i* . XT χ^χ ° (R)-3-(4-chloro-3-methylbenzyl)-1-(1- (6-cyanopyridazin-3-yl)piperidin-3yl)-1-methylurea LC-MS: m / z 374.2 (M+H). 1H NMR (400 MHz, DMSO) δ 7.84 (d, J = 9.7 Hz, 1H), 7.34 (dd, J = 9.0, 4.9 Hz, 2H), 7.22 (s, 1H), 7.11 (dd, J = 8.2, 1.7 Hz, t 5.8 Hz, 1H), 4.44 (dd, J = 31.8, 11.2 Hz, 2H), 4.20 (qd, J = 15.5, 5.8). Petition 870260063816, of 29 / 06 / 2026, p. 182 / 739 175 / 315 Exemplo Método Estrutura e Nome Dados Hz, 2H), 4,04 - 3,94 (m, 1H), 3,11 (t, J = 12,0 Hz, 1H), 2,99 2,89 (m, 1H), 2,80 (s, 3H), 2,31 (s, 3H), 1,87 - 1,65 (m, 3H), 1,58 - 1,45 (m, 1H). 160 B N N' N L J] H | Γ Jj cr—' CT^OH Ácido (R)-6-(3-(3-(4-cloro-3metilbenzil)-1metilureido)piperidin-1 il)piridazina-4-carboxílico LC-MS: m / z 418,1 (M+H). 1H RMN (400 MHz, MeOD) δ 8,84 (d, J = 1,2 Hz, 1H), 7,78 (d, J = 1,4 Hz, 1H), 7,26 (d, J = 8,2 Hz, 1H), 7,22 (s, 1H), 7,11 (dd, J = 8,1, 1,8 Hz, 1H), 4,44 4,33 (m, 2H), 4,32 (s, 2H), 4,13 (dd, J = 10,2, 5,9 Hz, 1H), 3,16 - 3,09 (m, 1H), 3,02 - 2,94 (m, 1H), 2,90 (s, 3H), 2,34 (s, 3H), 1,97 - 1,87 (m, 3H), 1,72 (dd, J = 14,0, 9,8 Hz, 1H). 161 C ll Ί 1 H l| Ί N. .Ν. X Ν N Y ° 3-[(4-cloro-3-metilfenil)metil]-1metil-1-[(3R)-1-(4-metilpiridazin3-il)piperidin-3-il]ureia LC-MS: m / z 388,4 (M+H). 162 B 0 \ ______ JL N ν ν' Ní* X XJ H 1 w Cl ξ (R)-3-(4-cloro-3-metilbenzil)-1metil-1-(1-(5-metil-1,3,4tiadiazol-2-il)piperidin-3-il)ureia LC-MS: m / z 394,2 (M+H).1H NMR (400 MHz, MeOD) δ 7.27 (d, J = 8.2 Hz, 1H), 7.21 (s, 1H), 7.10 (dd, J = 8.2, 1.7 Hz, 1H), 4.30 (d, J = 2.8 Hz, 2H), 4.20 (ddd, J = 11.2, 10.3, 4.8 Hz, 1H), 3.83 - 3.72 (m, 2H), 3.20 (t, J = 11.8 Hz, 1H),. Petition 870260063816, dated 06 / 29 / 2026, p. 183 / 739 176 / 315 Exemplo Método Estrutura e Nome Dados 3,09 - 3,01 (m, 1H), 2,86 (s, 3H), 2,54 (s, 3H), 2,34 (s, 3H), 1,90 - 1,80 (m, 3H), 1,79 1,70 (m, 1H). 163 B ° \ ^-N N ΧΓ । A N (R)-3-(4-cloro-3-metilbenzil)-1-(1(5-ciano-1,3,4-tiadiazol-2il)piperidin-3-il)-1-metilureia LC-MS: m / z 405,1 (M+H). 1HNMR (400MHz, MeOD) δ 7,27 (d, J= 8,2Hz, 1H), 7,21 (s,1H), 7,10 (dd, J= 8,2, 1,7Hz, 1H), 4,31 (d, J= 4,1Hz, 2H), 4,22 (d, J= 7,3Hz, 1H), 4,00 (d, J= 11,3 Hz, 1H), 3,91 (dd, J = 12,4, 4,3 Hz, 1H), 3,43 - 3,35 (m, 1H), 3,23 (td, J = 12,7, 2,9 Hz, 1H), 2,88 (s, 3H), 2,35 (s, 3H), 1,97 - 1,74 (m, 4H). 164 B Xjj H 1 m Cl F 3-[(4-cloro-3-metilfenil)metil]-1metil-1-[(3R)-1-[5-(trifluorometil)1,3,4-tiadiazol-2-il]piperidin-3il]ureia LC-MS: m / z 448,1 (M+H).1H RMN (400 MHz, MeOD) δ 7,27 (d, J = 8,2 Hz, 1H), 7,21 (s, 1H), 7,10 (dd, J = 8,2, 1,9 Hz, 1H), 4,31 (d, J = 5,0 Hz, 2H), 4,26 - 4,19 (m, 1H), 3,96 (d, J = 12,8 Hz, 1H), 3,88 (dd, J = 12,4, 4,5 Hz, 1H), 3,36 (d, J = 11,9 Hz, 1H), 3,19 (td, J = 12,7, 2,7 Hz, 1H), 2,88 (s, 3H), 2,33 (d, J = 6,3 Hz, 3H), 1,95 - 1,84 (m, 3H), 1,82 - 1,72 (m, 1H). 165 B Z~~\ _ 0 “-V / AnA / -\ N»-(W / / N T=N Ϊ (R)-3-(4-cloro-3-metilbenzil)-1-(1(5-ciclopropil-1,3,4-tiadiazol-2- LC-MS: m / z 420 (M+H). 1H RMN (400 MHz, MeOD) δ 7,27 (d, J = 8,2 Hz, 1H), 7,21 (s, 1H), 7,10 (dd, J = 8,2, 1,8 Hz, 1H), 4,36 - 4,26 (m, 2H), 4,18 (td, J = 10,8, 5,5 Hz, 1H),. Petição 870260063816, de 29 / 06 / 2026, pág. 184 / 739 177 / 315 Example Method Structure and Name Given il)piperidine-3-yl)-1-methylurea 3.83 − 3.70 (m, 2H), 3.19 (t, J = 11.8 Hz, 1H), 3.08 − 3.00 (m, 1H), (2,34), (3,34), (3,34 2.20 (tt, J = 8.3, 5.0 Hz, 1H), 1.90 - 1.72 (m, 4H), 1.14 1.08 (m, 2H), 0.95 - 0.89 (m, 2H). 166 B 0 H2N—Y \ -ZS. XI / Ί . h ]|YN ¥ JW Y (R)-5-(3-(3-(4-chloro-3methylbenzyl)-1methylureido)piperidine-1-yl)-1,3,4thiadiazol-2-carboxamide LC-MS: m / z 420 (M+H). 1H NMR (400 MHz, MeOD) δ 7.30 − 7.24 (m, 1H), 7.21 (s, 1H), 7.09 (dd, J = 8.2, 1.7 Hz, 1H), 4.29 (d, J = 6.5, 3 J 4, = 2H), Hz, 1H), 3.92 (d, J = 12.5 Hz, 2H), 3.35 – 3.31 (m, 1H), 3.16 (td, J = 12.8, 2.8 Hz, 1H), 2.87 (s, 3H), 2.85 -H (s, 1 3H), 1.81 − 1.72 (m, 1H). 167 E .nX Jk Ί--- 11 IH ks ,n 1 kx >xn ci (R)-3-(4-chloro-3-methylbenzyl)-1-(1(5-methoxypyridazine-3-yl)piperidin3-yl)-1-methylurea LCH-40).4 (M / z1H RMN (400 MHz, MeOD) δ 8,20 (s, 1H), 7,30 - 7,19 (m, 2H), 7,10 (dd, J = 8,2, 1,7 Hz, 1H), 6,69 (d, J=2,3Hz, 1H), 4,34 (d, J= 18,1Hz, 3H), 4,23 (dd, J= 12,7, 3,5Hz, 1H), 4,10 (dt, J= 10,3, 7,4Hz, 1H), 3,89 (s, 3H), 3,04 (dd, J = 12,4, 11,4 Hz, 1H), 2,96 - 2,85 (m, 4H), 2,33 (s, 3H), 1,94 - 1,82 (m, 3H), 1,77 - 1,59 (m, 1H). Petição 870260063816, de 29 / 06 / 2026, pág. 185 / 739 178 / 315 Example Method Structure and Data Name 168 CHY ] . H ί 1 N. xJk ---- \N. -N. Jí N ί ί 'w Y \x 0 (R)-3-(4-chloro-3-methylbenzyl)-1methyl-1-(1-(6(methylamino)pyridazine-3yl)piperidin-3-yl)urea LC-MS: m / z 403.4 (M+H). 1H NMR (400 MHz, MeOD) δ 8.50 (s, 1H), 7.36 (d, J = 9.9 Hz, 1H), 7.28 - 7.20 (m, 2H), 7.10 (dd, J = 8.2, 1.8 Hz, 1H, 97), d, J = 9.8 Hz, 1H), 4.32 (s, 2H), 4.22 - 4.13 (m, 1H), 4.05 - 3.90 (m, 2H), 2.95 2.88 (m, 4H), 2.87 (s, 3H), 2.83 - 2.75 (m, 1.3H), 1.77 (m, 3H), 1.77 1.62 (m, 1H). 169 F Cl HN 'hh-St (R)-1-(1-(7H-pyrrolo[2,3c]pyridazin-3-yl)piperidin-3-yl)-3-(4chloro-3-methylbenzyl)-1-methylurea LC-MS: m / z 413.2 (M+H). 170 E À HN^O Φ 0 (R)-1-(1-(6-(1H-imidazol-1yl)pyridazin-3-yl)piperidin-3-yl)-3-(4chloro-3-methylbenzyl)-1-methylurea LC-MS: m / z 440.1 (M+H).1H RMN (400 MHz, DMSO) δ 8,43 (s, 1H), 7,92 - 7,87 (m, 2H), 7,56 (d, J= 9,8Hz, 1H), 7,34 (d, J= 8,2Hz, 1H), 7,23 (s, 1H), 7,14-7,09 (m, 2H), 6,96 (t, J = 5,8 Hz, 1H), 4,35 (d, J = 11,2 Hz, 1H), 4,28 - 4,17 (m, 3H), 4,00 (d, J = 11,0 Hz, 1H), 3,06 - 2,99 (m, 1H), 2,86 (t, J = 11,9 Hz, 1H), 2,81 (s, 3H), 2,31 (s, 3H), 1,84 - 1,69 (m, 3H),. Petição 870260063816, de 29 / 06 / 2026, pág. 186 / 739 179 / 315 Example Method Structure and Name Data 1.56 (d, J = 12.8 Hz, 1H). 171 B Nx ZK Χϊχ .Cl Ti ^·Ν | in II 1 1 H N. ,A .N^ . N. JL \z^ 0 (R)-3-(4-chloro-3-methylbenzyl)-1-(1(5-cyanopyrazine-2-yl)piperidin-3-yl)1-methylurea LC-MS: m / z 399.2 (M+H). 1H NMR (400 MHz, MeOD) δ 8.31 (d, J = 12.6 Hz, 2H), 7.28 (d, J = 8.2 Hz, 1H), 7.22 (s, 1H), 7.10 (dd, J = 8.2, 1.7 Hz, 1H), 4.4, J = 7.4, J 12.4 Hz, 2H), 4.36 - 4.26 (m, 2H), 4.07 (td, J = 11.2, 5.6 Hz, 1H), 3.13 - 3.06 (m, 1H), 2.98 2.88 (m, 4H), 2.35 - 1.84 (s), (m, 3H), 1.63 (dt, J = 22.3, 8.6 Hz, 1H). 172 B íi Ί 1 h lí | N. X\ VN. .N. A / AN p»; γ LJ 0 (R)-3-(4-chloro-3-methylbenzyl)-1-(1(4-cyanopyridazin-3-yl)piperidin-3yl)-1-methylurea LC-MS: m / z 399.2 (M+H).1H NMR (400 MHz, MeOD) δ 8.77 (d, J = 4.9 Hz, 1H), 7.78 (d, J = 4.9 Hz, 1H), 7.23 (dd, J = 12.7, 4.8 Hz, 2H), 7.10 (dd, J = 8.1, 1.8 Hz, 1H), 4.39 (dd, J = 13.4, 2.2 Hz, 1H), 4.35 - 4.28 (m, 3H), 4.25 - 4.13 (m, 1H), 3.24 (dd, J= 12.4, 11.3Hz, 1H), 3.14-3.05 (m, 1H), 2.90 (d, J= 4.9Hz, 3H), 2.31 (d, J=7.9Hz, 3H), 1.97 - 1.77 (m, 4H). 173 D nh2 xL· χΖ-χχ01 íl 1 1 H í| 1 N- A ____ AzA. n^n^ >-;RJ γ ------- 0 (R)-1-(1-(5-aminopyridazin-3yl)piperidin-3-yl)-3-(4-chloro-3methylbenzyl)-1-methylurea LC-MS: m / z 389.1 (M+H). 1H NMR (400 MHz, MeOD) δ 8.49 (s, 1H), 7.94 (d, J = 2.2 Hz, 1H), 7.27 (d, J = 8.2 Hz, 1H), 7.21 (s, 1H), 7.10 (dd, J = 8.1, 1.9 Hz, 1H), 6.33 (d, J = 2.3 Hz, 1H), 4.32(s, 2H), Petition 870260063816, 06 / 29 / 2026, p. 187 / 7 180 / 3 Exemplo Método Estrutura e Nome Dados - 4,09 (m, 1H), 4,05 (d, J= 13,3Hz, 1H), 3,94 (d, J= 12,7Hz, 1H), 3,12- 3,05 (m, 1H), 2,96 (dd, J = 18,7, 7,8 Hz, 1H), 2,89 (s, 3H), 2,34 (s, 3H), 1,88 (dd, J = 10,1,4,8 Hz, 3H), 1,74 - 1,62 (m, 1H). 174 E U 1 H kl Cl ° I (R)-3-(4-cloro-3-metilbenzil)-1-(1(4-metoxipirimidin-2-il)piperidin3-il)-1-metilureia LC-MS: m / z 404,2 (M+H). 1H RMN (400 MHz, MeOD) δ 7,92 (d, J = 5,7 Hz, 1H), 7,26 (d, J = 8,2 Hz, 1H), 7,21 (s, 1H), 7,12 - 7,07 (m, 1H), 5,99 (d, J = 5,7 Hz, 1H), 4,71 - 4,54 (m, 2H), 4,37 - 4,24 (m, 2H), 4,06 - 3,95 (m, 1H), 3,83 (s, 3H), 2,97 (t, J = 11,8 Hz, 1H), 2,88 (s, 3H), 2,81 (dd, J = 19,3, 7,8 Hz, 1H), 2,31 (d, J = 14,5 Hz, 3H), 1,91 - 1,77 (m, 3H), 1,67 - 1,52 (m, 1H). 175 B ΛΙ । η ΓΥ IJ 0 (R)-1-(1-(1,3,4-tiadiazol-2il)piperidin-3-il)-3-(4-cloro-3metilbenzil)-1-metilureia LC-MS: m / z 404,2 (M+H).1H RMN (400 MHz, DMSO) δ 8,79 (s, 1H), 7,33 (d, J = 8,2 Hz, 1H), 7,22 (s, 1H), 7,11 (dd, J = 8,1, 1,9 Hz, 1H), 6,97 (t, J = 5,8 Hz, 1H), 4,23 - 4,17 (m, 2H), 4,15 - 4,08 (m, 1H), 3,79 (d, J = 12,0 Hz, 1H), 3,69 (dd, J = 12,0, 4,4 Hz, 1H), 3,18 (d, J = 11,7 Hz, 1H), 3,04 (dt, J = 12,6, 6,2 Hz, 1H), 2,77 (s, 3H), 2,31 (s, 3H), 1,81 - 1,62 (m, 4H). Petição 870260063816, de 29 / 06 / 2026, pág. 188 / 739 181 / 315 Example Method Structure and Given Name 176 G / N=NI íi — N 1 1 H \ANY AA \ IJ ° (R)-3-(4-chloro-3-methylbenzyl)-1- methyl-1-(1-(1-methyl-1H-1,2,3- triazole-4-yl-pyridine) m / l-3-MS: LC 377.2 (M+H). 1H NMR (400 MHz, MeOD) δ 7.31 (s, 1H), 7.27 (d, J = 8.2 Hz, 1H), 7.21 (d, J = 1.4 Hz, 1H), 7.10 (dd, J = 8.1, 1.7 Hz, 1.2H), (4.21 Hz), (dt, J = 8.9, 3.9 Hz, 1H), 3.98 (s, 3H), 3.62 (d, J = 11.1 Hz, 1H), 3.53 (dd, J = 11.4, 4.2 Hz, 1H), 2.86 (s, 3.2 Hz), t 2.63 (td, J = 11.8, 2.9 Hz, 1H), 2.34 (s, 3H), 1.87 - 1.67 (m, 4H). 177 C XQ .uXX N ϊ iw Y lj 0 3-[(4-chloro-3-methylphenyl)methyl]-1[(3R)-1-(5-methoxypyrimidin-2yl)piperidin-3-yl]-1-methylurea LC-MS: m / z 404.2 (M+H).1H RMN (400 MHz, MeOD) δ 7,98 (s, 2H), 7,28 (d, J = 8,2 Hz, 1H), 7,23 (s, 1H), 7,12 (dd, J = 8,2, 1,7 Hz, 1H), 4,60 4,51 (m, 1H), 4,46 (dd, J = 12,5, 4,1 Hz, 1H), 4,38 - 4,28 (m, 2H), 3,98 - 3,87 (m, 1H), 3,76 (s, 3H), 2,94 (dd, J = 12,4, 11,4 Hz, 1H), 2,88 (s, 3H), 2,79 (td, J = 12,9, 2,5 Hz, 1H), 2,34 (s, 3H), 1,83 (ddd, J = 16,9, 11,3, 3,2 Hz, 3H), 1,64 - 1,53 (m, 1H). 178 D / k zk .ci N I Π II 1 H N. X j j»Y (R)-3-(4-cloro-3-metilbenzil)-1-(1(3-hidroxipiridazin-4-il)piperidin- LC-MS: m / z 390,2 (M+H). 1H RMN (400 MHz, MeOD) δ 7,67 (d, J = 5,0 Hz, 1H), 7,30 7,19 (m, 2H), 7,10 (dd, J = 8,2, 1,8 Hz, 1H), 6,59 (d, J = 5,0 Hz, 1H), 4,28 (d, J = 18,3 Hz, 3H), 4,11 (dd, J = 50,5, 11,3 Hz,. Petição 870260063816, de 29 / 06 / 2026, pág. 189 / 739 182 / 315 Example Method Structure and Name Given 3-yl)-1-methylurea 2H), 2.95 - 2.88 (m, 1H), 2.87 (s, 3H), 2.72 (t, J = 11.2 Hz, 1H), 2.34 (s, 3H), 1.90 - 1.71 (m, 4H). 179 B wi jCC / o (R)-2-(3-(3-(4-chloro-3methylbenzyl)-1methylureido)piperidin-1-yl)oxazole4-carboxylate of ethyl LC-MS: m / z 435.2 (M+H). 1H NMR (400 MHz, MeOD) δ 7.98 (s, 1H), 7.26 (d, J = 8.2 Hz, 1H), 7.21 (s, 1H), 7.10 (dd, J = 8.2, 1.7 Hz, 1H), 4.32 4.28 (m, 4H), 4.13 (s, 1H), 3.98 (d, J = 12.6 Hz, 2H), 3.09 (t, J = 11.8 Hz, 1H), 2.93 (d, J = 2.8 Hz, 1H), 2.86 (s, 3H), 2.34 (s, 3H), 1.89 - 1.70 (m, 4H), 1.32 (t, J = 7.1 Hz, 3H). 180 CY | 1 h í| | N 1 IW Y \z«J 0 1-[(3R)-1-(6-aminopyridazin-3yl)piperidin-3-yl]-3-[(4-chloro-3methylphenyl)methyl]-1-methylurea LC-MS: m / z 389.2 (M+H). 181 C η η 1 H IL IN. ΐ'Ύ (R)-3-(4-chloro-3-methylbenzyl)-1-(1(6-methoxypyridazin-3-yl)piperidin3-yl)-1-methylurea LC-MS: m / z 4031 (M+H).1H RMN (400 MHz, MeOD) δ 7,36 (d, J = 9,7 Hz, 1H), 7,29 7,21 (m, 2H), 7,12 (dd, J = 8,2, 1,7 Hz, 1H), 6,98 (d, J = 9,7 Hz, 1H), 4,33 (s, 2H), 4,17 - 4,03 (m, 3H), 3,94 (s, 3H), 2,97 (t, J = 11,6 Hz, 1H), 2,88 (s, 3H), 2,88 - 2,80 (m, 1H), 2,33 (s, 3H), 1,90 - 1,76 (m, 3H), 1,75 1,60 (m, 1H). Petição 870260063816, de 29 / 06 / 2026, pág. 190 / 739 183 / 315 Exemplo Método Estrutura e Nome Dados 182 C \ .Cl Ίϊ 1 II 1 1 H yN. -N. Jí ? p Y 0 (R)-3-(4-cloro-3-metilbenzil)-1metil-1-(1-(5-metilpirazin-2il)piperidin-3-il)ureia LC-MS: m / z 388,4 (M+H). 1H RMN (400 MHz, MeOD) δ 8,10 (d, J = 1,5 Hz, 1H), 7,80 (s, 1H), 7,28 (d, J = 8,2 Hz, 1H), 7,23 (s, 1H), 7,11 (dd, J = 8,1, 1,7 Hz, 1H), 4,32 (s, 2H), 4,27 - 4,17 (m, 2H), 4,07 (dd, J = 11,8, 7,4 Hz, 1H), 2,98 - 2,90 (m, 1H), 2,89 (s, 3H), 2,84 (td, J = 13,2, 2,4 Hz, 1H), 2,35 (s, 3H), 2,33 (s, 3H), 1,85 (t, J = 9,8 Hz, 3H), 1,74 - 1,57 (m, 1H). 183 B í | 1 H ll 1 N ΐ lw L___) 0 (R)-3-(4-cloro-3-metilbenzil)-1metil-1-(1-(piridin-2-il)piperidin-3il)ureia LC-MS: m / z 388,4 (M+H).1H NMR (400 MHz, MeOD) δ 7.93 (dd, J = 5.1, 1.1 Hz, 1H), 7.52 (ddd, J = 8.9, 7.1,2.0 Hz, 1H), 7.31 - 7.16 (m, 2H), 7.11 (dd, J = 8.2, 1.7 Hz, 1H), 6.85 (d, J = 8.7Hz, 1H), 6.61 (dd, J = 6.7, 5.4Hz, 1H), 4.34 (d, J= 1.9Hz, 2H), 4.23-4.12 (m, 2H), 4.05 (d, J= 10.7Hz, 1H), 2,972.75 (m, 5H), 2.33 (d, J=10.8 Hz, 3H), 1.85 (td, J = 12.6, 5.9 Hz, 3H), 1.65 (dd, J = 12.3, 3.4 Hz, 1H). General Procedure H:

[00250] As a general procedure, the examples below have been synthesized according to the following general scheme. Petition 870260063816, dated 06 / 29 / 2026, p. 191 / 739 184 / 315 H4

[00251] To a solution of compound H1 (1 eq.) in toluene, TEA (2 eq.) and DPPA (1.2 eq.) were added. The resulting mixture was stirred at 110°C for 2 hours under a N2 atmosphere. After cooling, the resulting mixture was concentrated under reduced pressure until dry. The crude compound was used in the next step directly without further purification. To a solution of compound H3 (1 eq.) in DCM, TEA (3 eq.) and compound H2 (1 eq.) were added at 0°C. The resulting mixture was stirred for 30 min at room temperature under a N2 atmosphere. Then the mixture was concentrated under reduced pressure until dry. The crude product was purified by silica gel column chromatography (eluted with DCM / MeOH) to provide compound H4. Example 184: Synthesis of 3-((1S,2R)-2-(4-chloro-3-methylphenyl)cyclopropyl)-1-cyclopropyl-1-((R)-1-(pyridazin-3-yl)piperidin-3-yl)urea Petition 870260063816, dated 06 / 29 / 2026, page 192 / 739 185 / 315 M3 TEA,DCM Example 184

[00252] To a solution of M1 (200 mg, 0.952 mmol) in toluene (10 mL) were added TEA (192 mg, 1.904 mmol) and DPPA (314 mg, 1.142 mmol). The resulting mixture was stirred at 110°C for 2 h under a N2 atmosphere. After cooling, the mixture was concentrated under reduced pressure to yield crude M2 ​​(197 mg, 99.9% yield) without further purification. To a solution of M3 (207 mg, 0.952 mmol) in dry DCM (10 mL) were added TEA (288 mg, 2.856 mmol) and M2 (197 mg, 0.952 mmol) at 0°C. The resulting mixture was stirred for 30 min at room temperature under a N2 atmosphere. Then the mixture was concentrated under reduced pressure until dry. The crude product was purified by silica gel column chromatography (eluted with 1% MeOH in DCM to 5% MeOH in DCM) to give Example 184 (61.1 mg, 15.1% yield) as a white solid. LC-MS: m / z 426 (M+H)+.1H NMR (400 MHz, MeOD) δ 8.43 (dd, J = 4.4, 1.2 Hz, 1H), 7.37 (dd, J = 9.4, 4.4 Hz, 1H), 7.29 (dd, J = 9.4, 1.2 Hz, 1H), 7.21 (d, J = 8.2 Hz, 1H), 7.09 (d, J = 1.9 Hz, 1H), 6.95 (dd, J = 8.2, 2.1 Hz, 1H), 6.69 (s, 1H), 4.43 - 4.31 (m, 2H), 3.80 - 3.69 (m, 1H), 2.91 2.81 (m, 1H), 2.78 - 2.71 (m, 1H), 2.51 - 2.45 (m, 1H), 2.32 (s, 3H), 2.30 - 2.20 (m, 1H), 2.03 - 1.94 (m, 2H), 1.90 - 1.83 (m, 1H), 1.66 - 1.57 (m, 1H), 1.24 - 1.14 (m, 2H), 0.95 - 0.89 (m, 2H), 0.79 - 0.72 (m, 2H).

[00253] The compounds in the table below were prepared from Petition 870260063816, dated 06 / 29 / 2026, p. 193 / 739 186 / 315 of suitable starting materials, described above or commercially available, using general procedure B as detailed in Example 184. Exemployment and name Dados 185 í? 1 h ΓΎ O OTvu 3-[(1 R,2S)-2-(4-chloro-3metilfenil)ciclopropil]-1-metil-1-[(3R)-1[(3R)-oxolano-3-carbonil]piperidin-3il]ureia LC-MS: m / z 420 (M+H). 1H RMN (400 MHz, MeOD) δ 7.20 (dd, J = 8.2, 3.4 Hz, 1H), 7.08 (s, 1H), 6.93 (dd, J = 8.2, 2.1 Hz, 1H), 4.53 - 4.40 (m, 1H), 4.14 - 3.99 (m, 1H), 3.96 - 3.77 (m, 5H), 3.51 - 3.40 (m, 1H), 3.16 - 3.08 (m, 1H), 2.99 (dd, J = 18.7, 7.8 Hz, 1H), 2.80 (d, J = 3.9 Hz, 3H). 10,3, 8,9, 4.4 Hz, 1H), 2.55 - 2.47 (m, 1H), 2.31 (s, 3H), 2.27 - 2.21 (m, 1H), 2.11 (ddd, J = 20.5, 14.1.6.7 Hz, 2H), 2.00 1.94 (m, 1H), 1.88 - 1.76 (m, 3H), 1.58 - 1.43 (m, 1H), 1.21 - 1.11 (m, 2H). 186 I? 1 h 4Y γαΥνΑΛ 3-[(1S,2R)-2-(4-chloro-3- metilfenil)ciclopropil]-1-metil-1-[(3R)-1[(3R)-oxolano-3-carbonil]piperidin-3il]ureia LC-MS: m / z 420 (M+H).1H RMN (400 MHz, MeOD) δ 7,20 (dd, J = 8,2, 3,0 Hz, 1H), 7,07 (s, 1H), 6,93 (dd, J = 8,2, 2,2 Hz, 1H), 4,54 - 4,39 (m, 1H), 4,14 - 3,98 (m, 1H), 3,96 - 3,74 (m, 5H), 3,45 (t, J = 9,5 Hz, 1H), 3,15 - 3,08 (m, 1H), 2,99 (dd, J = 18,8, 7,8 Hz, 1H), 2,80 (d, J = 4,3 Hz, 3H), 2,76 - 2,67 (m, 2H), 2,51 (dd, J = 13,0, 10,7 Hz, 1H), 2,31 (s, 3H), 2,22 (ddd, J = 12,6, 9,7, 6,1 Hz, 1H), 2,09 (tt, J = 13,9, 7,0 Hz, 2H), 1,95 (ddt, J = 9,2, 6,0, 2,9 Hz, 1H), 1,90. Petição 870260063816, de 29 / 06 / 2026, pág. 194 / 739 187 / 315 Exemplo Estrutura e nome Dados - 1,76 (m, 3H), 1,52 (dd, J = 22,8, 15,9 Hz, 1H), 1,22 - 1,10 (m, 2H). 187 ? 1 H \—1 AA o 3-[(1 R,2S)-2-(4-cloro-3metilfenil)ciclopropil]-1-metil-1-[(3R)-1[(2S)-oxolano-2-carbonil]piperidin-3il]ureia LC-MS: m / z 420,1 (M+H). 1H RMN (400 MHz, MeOD) δ 7,10 (dd, J = 8,2, 3,7 Hz, 1H), 6,98 (d, J = 1,8 Hz, 1H), 6,83 (dd, J = 8,2, 1,9 Hz, 1H), 4,62 (dd, J = 8,5, 4,4 Hz, 1H), 4,42 - 4,25 (m, 1H), 3,94 (dd, J = 37,3, 10,8 Hz, 1H), 3,86 3,68 (m, 3H), 3,05-2,94 (m, 1H), 2,82 (dd, J= 19,0, 8,1Hz, 1H), 2,71 (d, J= 9,5Hz, 3H), 2,62 (tt, J= 7,5, 4,4Hz, 2H), 2,46-2,36 (m, 1H), 2,23 (d, J= 11,1Hz, 3H), 2,20-2,14 (m,1H), 2,12-2,02 (m,1H), 1,981,90 (m, 1H), 1,86 (ddd, J = 18,3, 9,8, 5,0 Hz, 3H), 1,76 - 1,65 (m, 3H), 1,59 - 1,46 (m, 1H), 1,38 (dd, J = 10,6, 4,9 Hz, 1H), 1,13 - 0,99 (m, 2H). 188 ? । H ílT 0 ο I 3-[(1S,2R)-2-(4-cloro-3metilfenil)ciclopropil]-1-metil-1-[(3R)-1[(2S)-oxolano-2-carbonil]piperidin-3il]ureia LC-MS: m / z 420,1 (M+H).1H RMN (400 MHz, MeOD) δ 7,10 (dd, J = 8,2, 3,3 Hz, 1H), 6,98 (d, J = 1,6 Hz, 1H), 6,83 (dd, J = 8,2, 1,7 Hz, 1H), 4,61 (dd, J = 10,4, 4,9 Hz, 1H), 4,41 - 4,25 (m, 1H), 3,94 (dd, J = 36,8, 10,8 Hz, 1H), 3,77 (ddd, J = 21,1, 14,8, 7,4 Hz, 3H), 3,05 - 2,96 (m, 1H), 2,83 (t, J = 12,2 Hz, 1H), 2,71 (d, J = 9,3 Hz, 3H), 2,66 - 2,57 (m, 2H), 2,45 2,37 (m, 1H), 2,22 (s, 3H), 2,20 2,13 (m, 1H), 2,07 (dd, J = 12,1, 7,0 Hz, 1H), 1,93 (dd, J = 12,4, 6,6. Petição 870260063816, de 29 / 06 / 2026, pág. 195 / 739 188 / 315 Example: Structure and name (Hz, 1H), 1.83 (td, J = 13.5, 6.8 Hz, 3H), 1.78 - 1.66 (m, 3H), 1.61 1.48 (m, 1H), 1.39 (s, 1H), 1.06 (tdd, J = 13.5, 6.5, 2.6 Hz, 2H). 189 ? 1 H íPY 3-[2-(4-chloro-3-methylfenil)ciclopropil]-1methyl-1-[(3R)-1-[(3R)-oxolano-3carbonil]piperidin-3-il]ureia LC-MS: m / z 420,1 (M+H). 1H RMN (400 MHz, MeOD) δ 7.20 (dd, J = 8.2, 3.0 Hz, 1H), 7.07 (s, 1H), 6.93 (dd, J = 8.2, 1.9 Hz, 1H), 4.46 (dd, J = 31.7, 11.9 Hz, 1H), 4.14 - 3.98 (m, 1H), 3.87 (dddd, J = 30.0, 21.6, 11.4, 5.5 Hz, 5H), 3.45 (dd, J = 17.7, 6.1 Hz, 1H), 3.12 (t, J = 12.1 Hz, 1H), 2.99 (dd, J = 19.0, 7.8 Hz, 1H), 2.80 (d, J = 4.4 Hz, 3H), 2.71 (ddd, J = 10.8, 10.2, 4.8 Hz, 2H), 2.55 - 2.47 (m, 1H), 2.31 (s, 3H), 2.28 - 2.19 (m, 1H), 2.11 (ddd, J = 22.0, 10.8, 5.2 Hz, 1H), 2.00 - 1.92 (m, 1H), 1.90 - 1.76 (m, 3H), 1.60 - 1.43 (m, 1H), 1.22 - 1.09 (m, 2H). 190? 1 h ίιΎ Vk ov 3-[2-(4-chloro-3-methylfenil)ciclopropil]-1metil-1-[(3R)-1-[(2S)-oxolano-2carbonil]piperidin-3-il]ureia LC-MS: m / z 420,1 (M+H).1H RMN (400 MHz, MeOD) δ 7,20 (dd, J = 8,2, 3,5 Hz, 1H), 7,08 (s, 1H), 6,94 (d, J = 8,2 Hz, 1H), 4,72 (dd, J = 11,6, 5,5 Hz, 1H), 4,43 (dd, J = 34,1, 10,5 Hz, 1H), 4,14 3,98 (m, 1H), 3,89 (ddd, J = 22,1, 13,8, 6,9 Hz, 3H), 3,10 (t, J = 12,2 Hz, 1H), 2,93 (t, J = 12,3 Hz, 1H), 2,80 (d, J = 5,4 Hz, 3H), 2,75 - 2,66 (m, 2H), 2,52 (t, J = 12,0 Hz, 1H), 2,32 (s, 3H), 2,27 (dd, J = 12,8, 6,8 Hz, 1H), 2,21 - 2,12 (m,. Petição 870260063816, de 29 / 06 / 2026, pág. 196 / 739 189 / 315 Exemplo Etrutura e nome Dados 1H), 2,05 (dd, J = 10,9, 6,6 Hz, 1H), 1,95 (dt, J = 12,4, 6,5 Hz, 3H), 1,82 (d, J = 13,0 Hz, 3H), 1,64 (s, 1H), 1,49 (s, 1H), 1.21 1.10 (m, 2H). 191 Vi HYL J1 ,N N. NN ^Ύγνο vo Ay \= / 1 -ciclopropil-3-[(1 R,2S)-2-(4-fluoro-3metilfenil)ciclopropil]-1-[(3S)-1(piridazin-3-il)pirrolidin-3-il]ureia LC-MS: m / z 396.1 (M+H). 1H RMN (400 MHz, MeOD) δ 8.41 (d, J = 3.8 Hz, 1H), 7.37 (dd, J = 9.2, 4.5 Hz, 1H), 7.06 - 7.01 (m, 1H), 6.99 - 6.92 (m, 2H), 6.91 6.84 (m, 1H), 6.71 (s, 1H), 4.58 (dd, J = 9.3, 7.8 Hz, 1H), 3.77 (t, J = 9.2 Hz, 2H), 3.62 (dd, J = 10.2, 8.1 Hz, 1H), 3.50 - 3.42 (m, 1H), 2.70 (dd, J = 7,4, 3,3 Hz, 1H), 2.53 (ddd, J = 10.1, 9.4, 6.1 Hz, 2H), 2.34 - 2.24 (m, 1H), 2.21 (d, J = 1.8 Hz, 3H), 2.00 (ddd, J = 9.5, 6.4, 3.3 Hz, 1H), 1.20 - 1.10 (m, 2H), 0.93 (ddd, J = 9.4, 5.9, 3.2 Hz, 2H), 0.81 - 0.67 (m, 2H). 192 A ° n ° \ Ak JU .L Ã.T γ NNY Uf OH LH hi । 1 A 6-[(3R)-3-(1-cyclopropyl{[(1S,2R)- 2-(4-chloro-3-methylphenyl)cyclopropyl]carbamoyl}amino)piperidin-1-yl]pyridazine-4-carboxylic acid LC-MS: m / z 396.1 (M+H). 1H NMR (400 MHz, MeOD) δ 8.73 (s, 1H), 7.58 (s, 1H), 7.10 (d, J = 8.2 Hz, 1H), 6.99 (s, 1H), 6.85 (dd, J = 8.1,2.0 Hz, 1H), 4.30 (t, J = 14.7 Hz, 2H), 3.64 (t, J = 11.7 Hz, 1H), 3.32 (t, J = 11.8 Hz, 1H), 2.85 (t, J = 12.1 Hz, 1H), 2.67 - 2.60 (m, 1H), 2.41 (dd, J = 6.8, 3.2 Hz, 1H), 2.24 - 2.11 (m, 4H), 1.94 - 1.75 (m, 3H), 1.54 (d, J = 13.1 Hz, 1H), 1.15 - 1.04 (m, 2H), 0.85 0.78 (m, 2H), 0.69 (dd, J = 10.4,. Petition 870260063816, dated 06 / 29 / 2026, p. 197 / 739 190 / 315 Exemplo Estrutura e nome Dados 6,8 Hz, 2H). 193 CIXJ H A V Ácido 6-[(3R)-3-(1-ciclopropil{[(1 R,2S)- 2-(4-cloro-3- metilfenil)ciclopropil]carbamoil}amino)pi peridin-1-il]piridazina-4-carboxílico LC-MS: m / z 396,1 (M+H). 1H RMN (400 MHz, MeOD) δ 8,83 (s, 1H), 7,69 (s, 1H), 7,20 (d, J = 8,2 Hz, 1H), 7,09 (s, 1H), 6,95 (d, J = 8,2 Hz, 1H), 4,40 (t, J = 15,0 Hz, 2H), 3,74 (t, J = 12,0 Hz, 1H), 3,40 (t, J = 12,0 Hz, 1H), 2,95 (t, J = 11,8 Hz, 1H), 2,77 - 2,70 (m, 1H), 2,51 (dd, J = 6,7, 3,5 Hz, 1H), 2,34 - 2,23 (m, 4H), 2,05 - 1,86 (m, 3H), 1,64 (d, J = 12,8 Hz, 1H), 1,19 (ddd, J = 19,3, 11,3, 5,1 Hz, 2H), 0,95 - 0,88 (m, 2H), 0,81 0,71 (m, 2H). 194 U a H A 3-[(1S,2R)-2-(4-bromo-3metilfenil)ciclopropil]-1-ciclopropil-1[(3R)-1-(piridazin-3-il)piperidin-3-il]ureia LC-MS: m / z 472 (M+H).1H RMN (400 MHz, MeOD) δ 8,34 (s, 1H), 7,29 (d, J = 8,3 Hz, 2H), 7,20 (d, J = 9,3 Hz, 1H), 7,00 (s, 1H), 6,77 (dd, J = 8,2, 2,0 Hz, 1H), 4,33 - 4,20 (m, 2H), 3,66 (tt, J = 11,9, 3,8 Hz, 1H), 3,24 (d, J = 7,3 Hz, 1H), 2,79 (td, J = 13,1,2,5 Hz, 1H), 2,64 (dt, J = 7,5, 3,9 Hz, 1H), 2,43 - 2,34 (m, 1H), 2,22 (d, J = 16,6 Hz, 3H), 2,19 - 2,08 (m, 1H), 1,89 (ddd, J = 23,0, 11,4, 8,3 Hz, 2H), 1,76 (d, J = 13,3 Hz, 1H), 1,52 (dtd, J = 13,0, 9,2, 4,0 Hz, 1H), 1,10 (ddd, J = 19,5, 11,2, 5,2 Hz, 2H), 0,86 - 0,79 (m, 2H), 0,70 - 0,59 (m, 2H). Petição 870260063816, de 29 / 06 / 2026, pág. 198 / 739 191 / 315 Exemploy energy and temperature 195 (M+H). 1H RMN (400 MHz, MeOD) δ 8.34 (d, J = 3.6 Hz, 1H), 7.33 - 7.23 (m, 2H), 7.22 - 7.15 (m, 1H), 7.00 (d, J = 1.9 Hz, 1H), 6.77 (dd, J = 8.2, 2.1 Hz, 1H), 6.60 (d, J = 2.0 Hz, 1H), 4.35 - 4.19 (m, 2H), 3.66 (tt, J = 11.9, 3.9 Hz, 1H), 3.18 (d, J = 12.2 Hz, 1H), 2.79 (td, J = 13.1, 2.6 Hz, 1H), 2.65 (td, J = 7.5, 4.1 Hz, 1H), 2.44 - 2.35 (m, 1H), 2.23 (d, J = 15.9 Hz, 3H), 2.14 (td, J = 12.5, 4.0 Hz, 1H), 1.95 - 1.82 (m, 2H), 1.76 (d, J = 13.0 Hz, 1H), 1.58 - 1.47 (m, 1H), 1.10 (ddd, J = 19.5, 11.4, 5.2 Hz, 2H), 0.81 (dt, J = 11.4, 7.3 Hz, 2H), 0.74 - 0.58 (m, 2H). 196 CIT1 HY JL 1 \NN, NN ^x / y CnO vo A / ^==7 3-[(1 R,2S)-2-(4-chloro-3- metilfenil)ciclopropil]-1-ciclopropil-1[(3S)-1-(piridazin-3-il)pirrolidin-3-il]ureia LC-MS: m / z 412 (M+H).1H RMN (400 MHz, MeOD) δ 8,41 (d, J = 4,0 Hz, 1H), 7,38 (dd, J = 9,2, 4,4 Hz, 1H), 7,20 (d, J = 8,2 Hz, 1H), 7,09 (d, J = 1,9 Hz, 1H), 6,95 (ddd, J = 5,3, 4,1, 1,6 Hz, 2H), 6,73 (s, 1H), 4,62 - 4,54 (m, 1H), 3,81 - 3,73 (m, 2H), 3,61 (dd, J = 10,2, 8,0 Hz, 1H), 3,46 (dd, J = 17,8, 8,8 Hz, 1H), 2,74 (dd, J = 7,4, 3,4 Hz, 1H), 2,54 (ddd, J = 9,6, 8,6, 6,1 Hz, 2H), 2,31 (s, 3H), 2,29 (dd, J = 8,4, 3,9 Hz, 1H), 2,00 (ddd, J = 9,5, 6,3, 3,2 Hz, 1H), 1,24 - 1,13 (m, 2H), 0,96 - 0,89 (m, 2H), 0,80 - 0,69 (m, 2H). Petição 870260063816, de 29 / 06 / 2026, pág. 199 / 739 192 / 315 Example Structure with Name Given 197 “ΊΑ Η Y 1J„ .NN, NN VIGO 3-[(1S,2R)-2-(4-chloro-3methylphenyl)cyclopropyl]-1-cyclopropyl-1[(3S)-1-(pyridazine-3-yl)pyrrolidine-3-ml / LC-MS] 412 (M+H) 1H NMR (400 MHz, MeOD) δ 8.41 (d, J = 3.6 Hz, 1H), 7.37 (dd, J = 9.2, 4.5 Hz, 1H), 7.20 (d, J = 8.2 Hz, 1Hz, 1H), J 6.94 (dd, J = 7.6, 1.6 Hz, 2H), 6.73 (s, 1H), 4.58 (dd, J = 9.3, 7.9 Hz, 1H), 3.76 (t, J = 9.3 Hz, 2H), (dd, J = 17.7, 9.0 Hz, 1H), 2.78 2.69 (m, 1H), 2.59 - 2.47 (m, 2H), 2.31 (s, 3H), 2.30 - 2.24 (m, 1H), 2.00 (ddd, J = 9.6, 3,3, 3 Hz 1H), 1.25 - 1.15 (m, 2H), 0.93 (ddd, J = 9.0, 4.6, 1.9 Hz, 2H), 0.75 (dt, J = 8.1, 3.9 Hz, 2H). 3-[(1C,2R)-2-(3-bromo-4methylphenyl)cyclopropyl]-1-cyclopropyl-1[(3R)-1-(pyridazin-3-yl)piperidin-3-yl]urea LC-MS: m / z 472 (M+H).1H RMN (400 MHz, MeOD) δ 8,43 (d, J = 4,4 Hz, 1H), 7,37 (dd, J = 9,4, 4,4 Hz, 2H), 7,31 - 7,27 (m, 1H), 7,16 (d, J = 8,0 Hz, 1H), 7,04 - 7,00 (m, 1H), 4,37 (dd, J = 33,8, 13,1 Hz, 2H), 3,76 (t, J = 11,7 Hz, 1H), 3,27 (s, 1H), 2,89 (dd, J = 13,2, 10,4 Hz, 1H), 2,75 - 2,70 (m, 1H), 2,48 (dd, J = 7,1, 3,3 Hz, 1H), 2,32 (s, 3H), 2,25 (dd, J = 12,6, 4,0 Hz, 1H), 2,05 - 1,94 (m, 2H), 1,86 (d, J = 12,8 Hz, 1H), 1,62 (d, J = 13,0 Hz, 1H), 1,24 - 1,14 (m, 2H), 0,94 - 0,90 (m, 2H), 0,77 (d, J = 2,1 Hz, 2H). Petição 870260063816, de 29 / 06 / 2026, pág. 200 / 739 193 / 315 Extrutura e nome Dados 199 kk ° Λ r ii NNUAHA 3-[(1 R,2S)-2-(3-bromo-4- metilfenil)ciclopropil]-1-ciclopropil-1[(3R)-1-(piridazin-3-il)piperidin-3-il]ureia LC-MS: m / z 472 (M+H). 1H RMN (400 MHz, MeOD) δ 8.43 (dd, J = 4.4, 1.2 Hz, 1H), 7.40 - 7.35 (m, 2H), 7.30 (dd, J = 9.4, 1.2 Hz, 1H), 7.16 (d, J = 7.8 Hz, 1H), 7.02 (dd, 2.52 2,44 (m, 1H), 2.33 (s, 3H), 2.25 (dd, J = 12.5, 3.9 Hz, 1H), 2.05 - 1.96 (m, 2H), 1.91 - 1.82 (m, 1H), 1.62 (dd, J = 9.0, 4.0 Hz, 1H), 1.25 - 1.15 (m, 2H), 0.92 (dd, J = 7.6, 5.4 Hz, 2H), 0.79 - 0.73 (m, 2H). 200 Λ ° H ° A Α^ν^,χ^ Jk nn oh AJ H 1 iA cr n Ácido 6-[(3R)-3-({[(1 S,2R)-2-(4-chloro-3metilfenil)ciclopropil]carbamoil}(metil)am ino)piperidin-1-il]piridazina-4-carboxílico LC-MS: m / z 444.2 (M+H).1H RMN (400 MHz, MeOD) δ 8,86 (s, 1H), 7,70 (s, 1H), 7,20 (d, J = 8,2 Hz, 1H), 7,10 (d, J = 1,7 Hz, 1H), 6,95 (dd, J = 8,2, 2,0 Hz, 1H), 4,42 - 4,32 (m, 2H), 4,05 (s, 1H), 3,15 - 3,05 (m, 1H), 3,03 - 2,93 (m, 1H), 2,87 (s, 3H), 2,78 - 2,70 (m, 1H), 2,32 (s, 3H), 2,05 - 1,98 (m, 1H), 1,97 - 1,85 (m, 3H), 1,70 (s, 1H), 1,27 - 1,21 (m, 1H), 1,18 - 1,10 (m, 1H). 201 λ ° ιΆ ° AAr' N'' N AJ H 1 O cr n Ácido 6-[(3R)-3-({[(1 R,2S)-2-(4-cloro-3metilfenil)ciclopropil]carbamoil}(metil)am ino)piperidin-1-il]piridazina-4-carboxílico LC-MS: m / z 444,2 (M+H). 1H RMN (400 MHz, MeOD) δ 8,87 (s, 1H), 7,72 (s, 1H), 7,20 (d, J = 8,2 Hz, 1H), 7,09 (s, 1H), 7,00 6,90 (m, 1H), 4,37 (d, J = 12,5 Hz, 2H), 4,06 (s, 1H), 3,16 - 3,05 (m,. Petição 870260063816, de 29 / 06 / 2026, pág. 201 / 739 194 / 315 Exemplo Estrutura e nome Dados 1H), 3,04 - 2,93 (m, 1H), 2,87 (s, 3H), 2,80 - 2,71 (m, 1H), 2,32 (s, 3H), 2,04 - 1,98 (m, 1H), 1,95 - 1,85 (m, 3H), 1,69 (d, J = 11,3 Hz, 1H), 1,27 - 1,21 (m, 1H), 1,19 - 1,10 (m, 1H). 202 1 v H rrcl V-O o v 3-[(1 R,2S)-2-(4-cloro-3metilfenil)ciclopropil]-1-ciclopropil-1- [(3R)-1-[(2S)-oxolano-2- carbonil]piperidin-3-il]ureia LC-MS: m / z 446,2 (M+H). 1H RMN (400 MHz, CDCI3) δ 7,14 (dd, J = 8,1, 5,5 Hz, 1H), 6,94 (d, J = 1,8 Hz, 1H), 6,84 (dd, J = 8,2, 2,0 Hz, 1H), 5,51 (d, J = 26,8 Hz, 1H), 4,65 - 4,37 (m, 2H), 4,05 3,72 (m, 4H), 3,31 - 2,80 (m, 2H), 2,78 - 2,69 (m, 1H), 2,45 - 2,15 (m, 6H), 2,13 - 1,76 (m, 6H), 1,75 - 1,69 (m, 1H), 1,50 - 1,41 (m, 1H), 1,11 - 1,05 (m, 2H), 0,89 0,78 (m, 3H), 0,68 - 0,60 (m, 1H). 203 V-o o v 3-[(1S,2R)-2-(4-cloro-3metilfenil)ciclopropil]-1-ciclopropil-1- [(3R)-1-[(2S)-oxolano-2- carbonil]piperidin-3-il]ureia LC-MS: m / z 446,2 (M+H).1H NMR (400MHz, CDCI3) δ 7.14 (dd, J = 8.2, 3.6Hz, 1H), 6.95 (d, J = 5.3Hz, 1H), 6.83 (d, J = 8.2Hz, 1H), 5.50 (d, J = 23.3Hz, 1H), 4.67 - 4.38 (m, 2H), 4.08 - 3.69 (m, 4H), 3.27 - 2.80 (m, 2H), 2.78 - 2.67 (m, 1H), 2.44 - 2.15 (m, 6H), 2.11 - 1.75 (m, 6H), 1.72 (d, J = 13.1 Hz, 1H), 1.47 - 1.37 (m, 1H), 1.14 - 1.04 (m, 2H), 0.89 0.75 (m, 3H), 0.69 - 0.56 (m, 1H). Petition 870260063816, dated 06 / 29 / 2026, p. 202 / 739 195 / 315 Example Structure and name Data LC-MS: m / z 430.2 (M+H). 204 3-[(1R,2S)-2-(4-chloro-2-fluoro-5methylphenyl)cyclopropyl]-1-cyclopropyl-1[(3S)-1-(pyridazin-3-yl)pyrrolidin-3-yl]urea 1H RMN (400 MHz, MeOD) δ 8,41 (dd, J = 4,4, 1,1 Hz, 1H), 7,37 (dd, J = 9,2, 4,5 Hz, 1H), 7,07 (d, J = 9,9 Hz, 1H), 6,95 (dd, J = 16,7, 8,6 Hz, 2H), 4,58 (p, J = 8,2 Hz, 1H), 3,77 (t, J = 9,3 Hz, 2H), 3,61 (ddd, J= 10,3, 8,1, 4,4Hz, 1H), 3,46 (dd, J= 17,4, 9,1Hz, 1H), 2,91 (dt, J= 7,5, 3,8Hz, 1H), 2,65-2,45 (m,2H), 2,36-2,23 (m,4H), 2,11 (d, J= 8,5Hz, 1H), 1,31-1,24 (m, 1H), 1,19 (dd, J= 12,7, 6,1 Hz, 1H), 0,97 - 0,88 (m, 2H), 0,83 - 0,69 (m, 2H). 205 1-ciclopropil-3-[-2-(4-fluoro-3metilfenil)ciclopropil]-1-[(3S)-1(piridazin-3-il)pirrolidin-3-il]ureia 206 LC-MS: m / z 396,2 (M+H). 1H RMN (400 MHz, MeOD) δ 8,41 (dd, J = 4,4, 1,1 Hz, 1H), 7,42 (ddd, J = 9,2, 4,4, 2,4 Hz, 1H), 7,06 - 6,97 (m, 2H), 6,95 (dd, J = 6,7, 4,1 Hz, 1H), 6,88 (t, J = 9,0 Hz, 1H), 6,72 (s, 1H), 4,66 - 4,48 (m, 1H), 3,85 - 3,70 (m, 2H), 3,68 - 3,58 (m, 1H), 3,51 - 3,43 (m, 1H), 2,70 (dt, J = 7,4, 3,6 Hz, 1H), 2,62 - 2,45 (m, 2H), 2,36 - 2,25 (m, 1H), 2,21 (s, 3H), 2,00 (ddd, J = 9,5, 6,3, 3,3 Hz, 1H), 1,22 - 1,09 (m, 2H), 0,98 - 0,88 (m, 2H), 0,82 - 0,65 (m, 2H). LC-MS: m / z 470,2 (M+H). 1H RMN (400 MHz, MeOD) δ 8,84 (s, 1H), 7,64 (s, 1H), 7,20 (dd, J = Petição 870260063816, de 29 / 06 / 2026, pág. 203 / 739 196 / 315 Exemploy energy and name Dados Ácido 6-[(3R)-3-(1-ciclopropil{[2-(4chloro-3metilfenil)ciclopropil]carbamoil}amino)piperidin-1-il]piridazina-4-carboxílico 8.2, 1.5 Hz, 1H), 7.08 (s, 1H), 6.97 - 6.91 (m, 1H), 6.68 (s, 1H), 4.39 (t, J = 12.0 Hz, 2H), 3.74 (dd, J = 15.5, 7.9 Hz, 1H), 3.36 (t, J = 11.7 Hz, 1H), 2.92 (t, J = 12.3 Hz, 1H), 2.80 - 2.69 (m, 1H), 2.56 - 2.43 (m, 1H), 2.31 (s, 3H), 2.29 - 2.19 (m, 1H), 2.04 - 1.84 (m, 3H), 1.64 (dd, J = 14.8, 11.3 Hz, 1H), 1.19 (ddd, J = 18.1, 10.7, 5.2 Hz, 2H), 0.91 (dd, J = 12.2, 9.3 Hz, 2H), 0.82 - 0.71 (m, 2H). 207 AA 0 Λ MAH 3-[2-(3-bromo-4-metilfenil)ciclopropil]-1ciclopropil-1-[(3R)-1-(piridazin-3il)piperidin-3-il]ureia LC-MS: m / z 472 (M+H).1H RMN (400 MHz, MeOD) δ 8,43 (dd, J = 4,4, 1,1 Hz, 1H), 7,40 7,34 (m, 2H), 7,29 (ddd, J = 9,4, 3,1, 1,2 Hz, 1H), 7,16 (d, J = 7,5 Hz, 1H), 7,02 (d, J = 7,7 Hz, 1H), 4,37 (dd, J = 30,0, 12,7 Hz, 2H), 3,75 (ddd, J = 12,2, 7,5, 4,1 Hz, 1H), 3,26 (d, J = 4,2 Hz, 1H), 2,89 (td, J = 13,1,2,5 Hz, 1H), 2,73 (td, J = 7,6, 3,2 Hz, 1H), 2,52 - 2,46 (m, 1H), 2,32 (s, 3H), 2,28 - 2,19 (m, 1H), 2,05 - 1,94 (m, 2H), 1,86 (d, J = 12,9 Hz, 1H), 1,68 - 1,58 (m, 1H), 1,25 - 1,14 (m, 2H), 0,96 - 0,89 (m, 2H), 0,81 - 0,71 (m, 2H). 208 AA 0 A U A H V.Br 3-[2-(4-bromo-3-metilfenil)ciclopropil]-1- LC-MS: m / z 470,2 (M+H). 1H RMN (400 MHz, MeOD) δ 8,43 (dd, J = 4,4, 1,0 Hz, 1H), 7,41 7,34 (m, 2H), 7,29 (ddd, J = 9,4, 2,6, 1,3 Hz, 1H), 7,10 (s, 1H), 6,87. Petição 870260063816, de 29 / 06 / 2026, pág. 204 / 739 197 / 315 Example Structure and name of cyclopropyl-1-[(3R)-1-(piridazin-3il)piperidin-3-il]ureia (d, J = 8.2 Hz, 1H), 6.69 (s, 1H), 4.37 (dd, J = 26.7, 12.9 Hz, 2H), 3.75 (ddd, J = 15.8, 7.8, 3.9 Hz, 1H), 3.26 (d, J = 3.7 Hz, 1H), 2.89 (td, J = 13.0, 2.5 Hz, 1H), 2.75 (dt, J = 6.9, 3.5 Hz, 1H), 2.53-2.44 (m, 1H), 2.34 (d, J = 1.4 Hz, 3H). 2,312,18 (m, 1H), 2,04-1,93 (m, 2H), 1,86 (d, J=13,1 Hz, 1H), 1,68-1,54 (m, 1H), 1,26-1,14 (m, 2H), 0,96-0,88 (m, 2H), 0,80-0,71 (m, 2H). 209 CI Y1 HY JL 1 NN, NN Y ΓΜ J v 0 3-[2-(4-chloro-3-methylfenil)ciclopropil]-1ciclopropil-1-[(3S)-1-(piridazin-3-il)pirrolidin-3-il]ureia LC-MS: m / z 412,1 (M+H).1H RMN (400 MHz, MeOD) δ 8,41 (d, J = 4,0 Hz, 1H), 7,38 (dd, J = 9,2, 4,4 Hz, 1H), 7,20 (d, J = 8,2 Hz, 1H), 7,08 (s, 1H), 6,99 - 6,91 (m, 2H), 6,73 (d, J = 2,0 Hz, 1H), 4,63 - 4,52 (m, 1H), 3,77 (dd, J = 10,3, 8,0 Hz, 2H), 3,65 - 3,58 (m, 1H), 3,46 (dd, J = 17,8, 8,9 Hz, 1H), 2,73 (ddd, J = 6,1,4,4, 3,1 Hz, 1H), 2,61 - 2,47 (m, 2H), 2,31 (s, 3H), 2,28 (dd, J = 8,5, 4,0 Hz, 1H), 2,00 (ddd, J = 9,5, 6,3, 3,3 Hz, 1H), 1,25 - 1,13 (m, 2H), 0,95 - 0,89 (m, 2H), 0,81 - 0,67 (m, 2H). 210 Λ 0 1—\ N-n à A / N A ΥΥ / Γ ''N N*^7 W JL J| Η I Br^-^ 3-[(1S,2R)-2-(4-bromo-3metilfenil)ciclopropil]-1-metil-1-[(3S)-1- LC-MS: m / z 430 (M+H). 1H RMN (400 MHz, MeOD) δ 8,35 (d, J = 4,4 Hz, 1H), 7,36 (d, J = 4,7 Hz, 1H), 7,29 (d, J = 8,2 Hz, 1H), 7,00 (d, J = 6,8 Hz, 2H), 6,77 (dd, J = 8,2, 2,1 Hz, 1H), 4,98 - 4,90. Petição 870260063816, de 29 / 06 / 2026, pág. 205 / 739 198 / 315 Example: Structure and name of Dados (piridazin-3-il)pirrolidin-3-il]ureia (m, 1H), 3.70 - 3.58 (m, 2H), 3.43 - 3.30 (m, 2H), 2.74 (s, 3H), 2.67 - 2.61 (m, 1H), 2.24 (s, 3H), 2.13 (t, J = 7.7 Hz, 2H), 1.86 (ddd, J = 9.5, 6.3, 3.3 Hz, 1H), 1.13 - 1.04 (m, 2H). 211 Λ 0 r-Λ Nn Υπ'' ^N N7'''7 \= / LJH i Br 3-[(1 R,2S)-2-(4-bromo-3- metilfenil)ciclopropil]-1-metil-1-[(3S)-1(piridazin-3-il)pirrolidin-3-il]ureia LC-MS: m / z 431.9 (M+H). 1H RMN (400 MHz, MeOD) δ 8.44 (dd, J = 4.4, 1.2 Hz, 1H), 7.44 (dd, J = 9.3, 4.5 Hz, 1H), 7.39 (d, J = 8.2 Hz, 1H), 7.10 (d, J = 2.0 Hz, 1H), 7.05 2.76 - 2.71 (m, 1H), 2.34 (s, 3H), 2.25 - 2.17 (m, 2H), 2.00 - 1.93 (m, 1H), 1.22 - 1.14 (m, 2H). 212 AA çApA N Ν' YY OH AJ H 1 O cr n Ácido 6-[(3R)-3-({[2-(4-chloro-3- metilfenil)ciclopropil]carbamoil}(metil)am ino)piperidin-1-il]piridazina-4-carboxílico LC-MS: m / z 444,2 (M+H).1H RMN (400 MHz, MeOD) δ 8,86 (s, 1H), 7,73 (d, J = 3,4 Hz, 1H), 7,20 (d, J = 8,2 Hz, 1H), 7,09 (s, 1H), 6,95 (d, J = 8,1 Hz, 1H), 4,39 - 4,28(m, 2H), 4,07 (s, 1H), 3,16 3,06 (m, 1H), 3,02 - 2,92 (m, 1H), 2,87 (s, 3H), 2,77 - 2,71 (m, 1H), 2,31 (s, 3H), 2,02 (d, J = 9,2 Hz, 1H), 1,97 - 1,84 (m, 3H), 1,70 (s, 1H), 1,19 - 1,11 (m, 1H), 0,89 (d, J = 7,6 Hz, 1H). 213 A . P >— z IZ X LC-MS: m / z 444,1 (M+H). 1H RMN (400 MHz, MeOD) δ 8,33 (dd, J = 4,4, 1,1 Hz, 1H), 7,26 (dt,. Petição 870260063816, de 29 / 06 / 2026, pág. 206 / 739 199 / 315 Example Structure with Nomenclature Given 3-[(1S,2R)-2-(4-chloro-2-fluoro-5methylphenyl)cyclopropyl]-1-cyclopropyl-1[(3R)-1-(pyridazin-3-yl)piperidin-3-yl]urea J = 19.6, 9.8H, J, 17, = d 9.4 Hz, 1H), 6.98 (d, J = 9.9 Hz, 1H), 6.86 (t, J = 12.3 Hz, 1H), 6.59 (d, J = 2.5 Hz, 1H), 4.27 (dd, J = 27.1, 12.8 Hz, J = 66, J 12.0, 3.9 Hz, 1H), 3.19 (d, J = 8.8 Hz, 1H), 2.80 (ddd, J = 16.7, 10.4, 7.6 Hz, 2H), 2.44 - 2.34 (m, 1H), = 9.7, 6.3, 3.4 Hz, 1H), 1.86 (d, J = 11.8 Hz, 1H), 1.76 (d, J = 13.4 Hz, 1H), 1.53 (ddd, J = 21.6, 12.8, 8.1 Hz, 1, 3.8 Hz), J 3.8 Hz, 1H), 1.10 (dd, J = 13.5, 6.1 Hz, 1H), 0.85 to 0.79 (m, 2H), 0.72 0.62 (m, 2H). 214 44 ° λ ,n. A» A Μ AH ΑΛ 3-[(1R,2S)-2-(4-chloro-2-fluoro-5methylphenyl)cyclopropyl]-1-cyclopropyl-1[(3R)-1-(pyridazin-3-yl)piperidin-3-yl]urea LC-MS: m / z 1,1 (44 M+H).1H RMN (400 MHz, MeOD) δ 8,43 (dd, J = 4,4, 1,2 Hz, 1H), 7,36 (dd, J = 9,4, 4,4 Hz, 1H), 7,29 (d, J = 9,2 Hz, 1H), 7,08 (d, J = 9,9 Hz, 1H), 6,98 (d, J = 8,1 Hz, 1H), 6,70 (d, J = 2,4 Hz, 1H), 4,35 (ddd, J = 15,1, 12,6, 7,5 Hz, 2H), 3,76 (tt, J = 11,9, 3,9 Hz, 1H), 3,26 (s, 1H), 2,97 - 2,83 (m, 2H), 2,54 - 2,43 (m, 1H), 2,32 - 2,18 (m, 4H), 2,11 (ddd, J = 9,7, 6,3, 3,4 Hz, 1H), 1,96 (d, J = 12,8 Hz, 1H), 1,86 (d, J = 13,3 Hz, 1H), 1,70 - 1,53 (m, 1H), 1,31 (dd, J = 9,8, 5,4 Hz, 1H), 1,19 (dd, J = 13,5, 6,1 Hz, 1H), 0,99 - 0,88 (m, 2H), 0,83 - 0,71. Petição 870260063816, de 29 / 06 / 2026, pág. 207 / 739 200 / 315 Example Structure and name Data (m, 2H). 215 i ν h rrc' Vo YY ov 3-[2-(4-chloro-3-methylphenyl)cyclopropyl]-1cyclopropyl-1-[(3R)-1-[(2S)-oxolano-2carbonyl]piperidin-3-yl]urea LC-MS: m / z 446.2 (M+H). 1H NMR (400 MHz, CDCI3) δ 7.24 - 7.16 (m, 1H), 7.02 (d, J = 4.8 Hz, 1H), 6.90 (d, J = 8.1 Hz, 1H), 5.58 (dd, J = 23.2, 2.0 Hz, 1H), 4.72 - 4.40 (m, 2H), 4.07 - 3.68 (m, 4H), 3.42 - 2.86 (m, 2H), 2.85 - 2.74 (m, 1H), 2.53 - 2.42 (m, 1H), 2.40 - 2.30 (m, 4H), 2.28 1.86 (m, 6H), 1.80 (d, J = 14.5 Hz, 1H), 1.55 - 1.44 (m, 1H), 1.19 1.10 (m, 2H), 0.87 (ddd, J = 22.2, 14.4, 7.2 Hz, 3H), 0.77 - 0.66 (m, 1H). 216 A 0 ΧΊ ΓΓ Ν Ν Α^ Ν 1 II η ι 1 jj θίΑΑΑγ ΑΑ 3-[(1S,2R)-2-(4-chloro-2-fluoro-5- methylphenyl)cyclopropyl]-1-methyl-1-[(3R)-1(pyridazin-3-yl)piperidin-3-yl]ureia LC-MS: m / z 418.1 (M+H).1H NMR (400 MHz, MeOD) δ 8.46 (dd, J = 4.4, 1.2 Hz, 1H), 7.38 (dd, J = 9.4, 4.4 Hz, 1H), 7.30 (dd, J = 9.4, 1.1 Hz, 1H, 7.7, J = 9.9 Hz, 1H), 6.98 (d, J = 8.1 Hz, 1H), 4.36 (d, J = 13.4 Hz, 1H), 4.28 (dd, J = 12.6, 3.7 Hz, 1H), 4.06 (dt, J = 11.3, 7.7 Hz, 1H). 11.4 Hz, 1H), 2.96 2.87 (m, 2H), 2.86 (s, 3H), 2.28 (s, 3H), 2.10 (ddd, J = 9.7, 6.3, 3.4 Hz, 1H), 1.59 (m, 1H), 1.33 1.29 (m, 1H), 1.16 (dt, J = 7.5, 6.0 Hz, 1H). Petition 870260063816, of 29 / 06 / 2026, p. 208 / 739 201 / 315 Example 217 218 Structure and name 3-[(1R,2S)-2-(4-chloro-2-fluoro-5methylphenyl)cyclopropyl]-1-methyl-1-[(3R)-1(pyridazin-3-yl)piperidin-3-yl]urea So LC-MS: m / z 418.1 (M+H). 1H RMN (400 MHz, MeOD) δ 8,48 - 8,42 (m, 1H), 7,38 (dd, J = 9,4, 4,4 Hz, 1H), 7,29 (d, J = 9,4 Hz, 1H), 7,06 (d, J = 9,9 Hz, 1H), 6,98 (d, J = 8,1 Hz, 1H), 4,36 (d, J = 12,0 Hz, 1H), 4,32 - 4,23 (m, 1H), 4,14 - 4,00 (m, 1H), 3,03 (t, J = 11,9 Hz, 1H), 2,96 - 2,87 (m, 2H), 2,86 (s, 3H), 2,28 (s, 3H), 2,11 (ddd, J = 9,7, 6,3, 3,4 Hz, 1H), 1,87 (t, J = 6,5 Hz, 3H), 1,67 (s, 1H), 1,33 - 1,27 (m, 1H), 1,16 (dd, J = 13,5, 6,0 Hz, 1H). 3-[(1S,2R)-2-(4-cloro-3metilfenil)ciclopropil]-1-etil-1-[(3S)-1(piridazin-3-il)pirrolidin-3-il]ureia LC-MS: m / z 400,2 (M+H). 1H RMN (400 MHz, Clorofórmio-d) δ 8,55 (d, J = 3,9 Hz, 1H), 7,23 7,16 (m, 2H), 7,05 (d, J = 1,9 Hz, 1H), 6,94 (dd, J = 8,2, 2,2 Hz, 1H), 6,62 (dd, J = 9,1, 1,1 Hz, 1H), 5,08 - 4,94 (m, 1H), 4,85 (s, 1H), 3,88 - 3,71 (m, 2H), 3,54 - 3,42 (m, 1H), 3,37 (dd, J = 10,5, 8,1 Hz, 1H), 3,25 - 3,16 (m, 2H), 2,82 (qd, J = 4,6, 1,8 Hz, 1H), 2,33 (s, 3H), 2,27 (ddd, J = 14,3, 6,2, 2,8 Hz, 1H), 2,16 - 2,07 (m, 1H), 1,99 (ddd, J = 9,5, 6,3, 3,3 Hz, 1H), 1,23 - 1,10 (m, 5H). 219 LC-MS: m / z 400,2 (M+H). 1H RMN (400 MHz, Clorofórmio-d) δ 8,56 (d, J = 3,6 Hz, 1H), 7,26 7,18 (m, 2H), 7,06 (d, J = 1,9 Hz, 1H), 6,95 (dd, J = 8,2, 2,2 Hz, 1H), Petição 870260063816, de 29 / 06 / 2026, pág. 209 / 739 202 / 315 Example Structure and Name of the molecule 3-[(1R,2S)-2-(4-chloro-3methylfenil)ciclopropyl]-1-etil-1-[(3S)-1(piridazin-3-il)pirrolidin-3-il]urea 6.67 (dd, J = 9.2, 1.2 Hz, 1H), 5.06 - 4.93 (m, 2H), 3.86 - 3.75 (m, 2H), 3.50 (td, J = 9.9, 7.2 Hz, 1H), 3.37 (dd, J = 10.4, 8.2 Hz, 1H), 3.29 - 3.16 (m, 2H), 2.83 (dt, J = 7.2, 3.5 Hz, 1H), 2.34 (s, 3H), 2.29 (ddd, J = 14.2, 6.2, 2.7 Hz, 1H), 2.16 - 2.08 (m, 1H), 2.01 (ddd, J = 9.5, 6.5, 3.3 Hz, 1H), 1.26 - 1.13 (m, 5H). 220 A 0 H if NN v NL 1] h । 1 Jj 3-[(1S,2R)-2-(3-bromo-4methylfenil)ciclopropil]-1-metil-1-[(3R)-1(piridazin-3-il)piperidin-3-il]ureia LC-MS: m / z 444.1 (M+H).1H RMN (400 MHz, MeOD) δ 8,47 (dd, J = 4,4, 1,2 Hz, 1H), 7,42 7,35 (m, 2H), 7,30 (dd, J = 9,4, 1,1 Hz, 1H), 7,15 (d, J = 7,8 Hz, 1H), 7,02 (dd, J = 7,9, 1,7 Hz, 1H), 4,32 (dd, J = 28,5, 13,1 Hz, 2H), 4,05 (s, 1H), 3,07 - 2,99 (m, 1H), 2,89 (dd, J = 18,4, 7,7 Hz, 1H), 2,85 (s, 3H), 2,75 - 2,70 (m, 1H), 2,32 (s, 3H), 2,00 (ddd, J = 9,4, 6,2, 3,3 Hz, 1H), 1,92 - 1,83 (m, 3H), 1,67 (s, 1H), 1,22 (dd, J = 9,5, 4,4 Hz, 1H), 1,17 - 1,11 (m, 1H). 221 A ° O Brw\cAA.l.VNx / zN.| K' Π' N N k N Μ h । Th 3-[(1 R,2S)-2-(3-bromo-4metilfenil)ciclopropil]-1-metil-1-[(3R)-1(piridazin-3-il)piperidin-3-il]ureia LC-MS: m / z 446,1 (M+H). 1H RMN (400 MHz, MeOD) δ 8,47 (dd, J = 4,4, 1,2 Hz, 1H), 7,41 - 7,35 (m, 2H), 7,29 (dd, J = 9,4, 1,2 Hz, 1H), 7,15 (d, J = 7,8 Hz, 1H), 7,02 (dd, J = 7,9, 1,8 Hz, 1H), 4,31 (dd, J = 37,5, 13,1 Hz, 2H), 4,05 (s, 1H), 3,07 - 2,98 (m, 1H), 2,94 - 2,87 (m, 1H), 2,85 (s, 3H), 2,75 - 2,69 (m, 1H), 2,32 (s, 3H), 2,01. Petição 870260063816, de 29 / 06 / 2026, pág. 210 / 739 203 / 315 Exemplo Estrutura e nome Dados (ddd, J = 9,4, 6,2, 3,2 Hz, 1H), 1,88 (dd, J = 10,5, 4,7 Hz, 3H), 1,68 (s, 1H), 1,26 - 1,19 (m, 1H), 1,17 - 1,10 (m, 1H). 222 Λ 0 rA Vbr N N N Nn 1 h । 1 i| Br^^^ 3-[(1S,2R)-2-(4-bromo-3metilfenil)ciclopropil]-1-metil-1-[(3R)-1(piridazin-3-il)piperidin-3-il]ureia LC-MS: m / z 446,1 (M+H). 1H RMN (400 MHz, MeOD) δ 8,47 (dd, J = 4,4, 1,2 Hz, 1H), 7,39 (dd, J = 9,1,4,4 Hz, 2H), 7,30 (dd, J = 9,4, 1,1 Hz, 1H), 7,10 (d, J = 1,8 Hz, 1H), 6,87 (dd, J = 8,3, 2,2 Hz, 1H), 4,32 (dd, J = 23,0, 14,8 Hz, 2H), 4,05 (s, 1H), 3,07 - 2,98 (m, 1H), 2,92 (d, J = 13,1 Hz, 1H), 2,85 (s, 3H), 2,77 - 2,72 (m, 1H), 2,34 (s, 3H), 1,99 (ddd, J = 9,4, 6,2, 3,2 Hz, 1H), 1,88 (dd, J = 11,6, 4,6 Hz, 3H), 1,67 (s, 1H), 1,27 - 1,20 (m, 1H), 1,15 (dd, J = 13,5, 6,0 Hz, 1H). 223 Λ ° (Ά N N N 1 JJ H I 1 LC-MS: m / z 444,1 (M+H).1H RMN (400 MHz, MeOD) δ 8,46 (dd, J = 4,4, 1,2 Hz, 1H), 7,41 - 7,35 (m, 2H), 7,29 (dd, J = 9,4, 1,2 Hz, 1H), 7,10 (d, J = 2,1 Hz, 1H), 6,87 (dd, J = 8,3, 2,2 Hz, 1H), 4,31 (dd, J = 35,1, 12,7 Hz, 2H), 4,06 (s, 1H), 3,06 - 2,99 (m, 1H), 2,90 (t, J = 11,8 Hz, 1H), 2,85 (s, 3H), 2,76 - 2,71 (m, 1H), 2,34 (s, 3H), 2,00 (ddd, J = 9,4, 6,3, 3,2 Hz, 1H), 1,88 (t, J = 7,7 Hz, 3H), 1,68 (s, 1H), 1,26 - 1,20 (m, 1H), 1,15 (dt, J = 12,0, 6,0 Hz, 1H). Petição 870260063816, de 29 / 06 / 2026, pág. 211 / 739 204 / 315 Exhibition and number Dados 224 °Q,, °A rNJ..,NANA^A 0 । “11 3-[(1 R,2S)-2-(4-chloro-3metilfenil)ciclopropil]-1-metil-1-[(3S)-1[(3R)-oxolano-3-carbonil]pirrolidin-3il]ureia LC-MS: m / z 406.2 (M+H). 1H RMN (400 MHz, CDCI3) δ 7.21 (dd, J = 8.2, 1.9 Hz, 1H), 7.05 (d, J = 1.9 Hz, 1H), 6.94 (d, J = 8.1 Hz, 1H), 5.12 - 5.00 (m, 1H), 4.92 (d, J = 13.2 Hz, 1H), 4.03 (td, J = 8.2, 4.4 Hz, 1H), 3.96 - 3.81 (m, 3H), 3.79 - 3.60 (m, 2H), 3.53 - 3.32 (m, 1H), 3.31 - 3.22 (m, 1H), 3.18 - 3.04 (m, 1H), 2.82 - 2.70 (m, 4H), 2.33 (s, 3H), 2.25 - 1.94 (m, 5H), 1.22 - 1.08 (m, 2H). 225 AA ° Λ U AH ACI 3-[(1S,2R)-2-(4-chloro-3-methylfenil)ciclopropil]-1-ciclopropil-1[(3R)-1-(piridazin-3-il)piperidin-3-il]ureia LC-MS: m / z 426,2 (M+H).1H RMN (400 MHz, MeOD) δ 8,33 (dd, J = 4,4, 1,2 Hz, 1H), 7,26 (dd, J = 9,4, 4,4 Hz, 1H), 7,18 (dd, J = 9,4, 1,2 Hz, 1H), 7,10 (d, J = 8,2 Hz, 1H), 6,99 (d, J = 1,9 Hz, 1H), 6,84 (dd, J = 8,2, 2,2 Hz, 1H), 4,25 (ddd, J = 15,0, 12,5, 7,6 Hz, 2H), 3,72 - 3,60 (m, 1H), 2,78 (td, J = 13,1,2,6 Hz, 1H), 2,63 (ddd, J = 7,6, 4,4, 3,4 Hz, 1H), 2,42 - 2,35 (m, 1H), 2,22 (s, 3H), 2,13 (td, J = 12,6, 4,1 Hz, 1H), 1,93 - 1,83 (m, 2H), 1,75 (dd, J = 10,1,2,8 Hz, 1H), 1,58 - 1,46 (m, 1H), 1,14 - 1,04 (m, 2H), 0,86 - 0,78 (m, 2H), 0,71 - 0,62 (m, 2H). 226 °0 n o A 0 । « II LC-MS: m / z 406,2 (M+H). 1H RMN (400 MHz, CDCI3) δ 7,21 (dd, J = 8,2, 2,4 Hz, 1H), 7,04 (d, J = 1,9 Hz, 1H), 6,93 (dd, J = 8,2, 2,1 Hz, 1H), 5,13 - 4,97 (m, 1H),. Petição 870260063816, de 29 / 06 / 2026, pág. 212 / 739 205 / 315 Extrusion and name Dados 3-[(1 R,2S)-2-(4-chloro-3metilfenil)ciclopropil]-1-metil-1-[(3S)-1[(3S)-oxolano-3-carbonil]pirrolidin-3il]ureia 4.85 (d, J = 13.8 Hz, 1H), 4.01 (q, J = 8.3 Hz, 1H), 3.94 - 3.79 (m, 3H), 3.79 - 3.63 (m, 2H), 3.49 3.35 (m, 1H), 3.25 (ddd, J = 18.5, 11.2, 8.5 Hz, 1H), 3.16 - 3.02 (m, 1H), 2.84 - 2.70 (m, 4H), 2.32 (s, 3H), 2.23 - 2.03 (m, 3H), 2.03 - 1.84 (m, 2H), 1.22 - 1.08 (m, 2H). 227 A 0 Ak ANK ιί NNNL h । l· h 3-[(1R,2S)-2-(4-chlorofenil)ciclopropil]-1metil-1-[(3R)-1-(piridazin-3-il)piperidin-3il]ureia LC-MS: m / z 386,1 (M+H).1H RMN (400 MHz, MeOD) δ 8,47 (d, J = 4,0 Hz, 1H), 7,38 (dd, J = 9,4, 4,4 Hz, 1H), 7,30 (dd, J = 9,4, 1,1 Hz, 1H), 7,27 - 7,19 (m, 2H), 7,14 (d, J = 8,4 Hz, 2H), 4,39 4,23 (m, 2H), 4,05 (dd, J = 9,4, 5,6 Hz, 1H), 3,10 - 2,97 (m, 1H), 2,90 (td, J = 13,2, 2,5 Hz, 1H), 2,86 (s, 3H), 2,78 - 2,72 (m, 1H), 2,03 (ddd, J = 9,5, 6,3, 3,3 Hz, 1H), 1,88 (t, J = 8,0 Hz, 3H), 1,67 (dd, J = 10,7, 8,3 Hz, 1H), 1,27 - 1,21 (m, 1H), 1,16 (dt, J = 12,1,6,0 Hz, 1H). 228 On / -N / -N FA uvv- 1-etil-3-[(1S,2R)-2-(4fluorofenil)ciclopropil]-1-[(3S)-1(piridazin-3-il)pirrolidin-3-il]ureia LC-MS: m / z 370,2 (M+H). 1H RMN (400 MHz, MeOD) δ 8,43 (dd, J = 4,5, 1,1 Hz, 1H), 7,39 (dd, J = 9,2, 4,5 Hz, 1H), 7,18 (dd, J = 8,6, 5,4 Hz, 2H), 7,03 - 6,88 (m, 3H), 4,83 - 4,77 (m, 1H), 3,75 (dt, J = 10,4, 5,8 Hz, 2H), 3,52 - 3,32 (m, 4H), 2,74 - 2,68 (m, 1H), 2,24 (dt, J = 9,1,6,4 Hz, 2H), 2,02 (ddd, J = 9,5, 6,3, 3,2 Hz, 1H), 1,22 - 1,10 (m, 5H). Petição 870260063816, de 29 / 06 / 2026, pág. 213 / 739 206 / 315 Example Structure of names Given 229 CJN f N=N 3-[(1R,2S)-2-(4-fluorophenyl)cyclopropyl]-1methyl-1-[(3S)-1-(pyridazin-3-yl)pyrrolidin-3yl]urea LC-MS: m / z 356.2 (M+H). 1H NMR (400 MHz, MeOD) δ 8.43 (dd, J = 4.5, 1.1 Hz, 1H), 7.39 (dd, J = 9.2, 4.5 Hz,1H), 7.22 - 7.13 (m, 2H), 7.02 - 6.92 (m, J, 5,32), (p 7.8 Hz, 1H), 3.82 to 3.63 (m, 2H), 3.56 to 3.37 (m, 2H), 2.83 (s, 3H), 2.74 to 2.68 (m, 1H), 9.5, 6.3, 3.4 Hz, 1H), 1.22 - 1.10 (m, 2H). 230 Λ 0 γΆ AAAoΑ.Λ e Α-ΝΆΝ'Ν A^ Π NNAN 1 JJ h . 1 Jj CI^AA AA 3-[(1 R,2S)-2-(4-chloro-3- methylphenyl)cyclopropyl]-1-methyl-1-[(3R)-1(pyridazin-3-yl)piperidin-3-yl]urea LC-MS: m / z 400.2 (M+H).1H RMN (400 MHz, MeOD) δ 8,47 (dd, J = 4,4, 1,2 Hz, 1H), 7,38 (dd, J = 9,4, 4,4 Hz, 1H), 7,30 (dd, J = 9,4, 1,0 Hz, 1H), 7,20 (d, J = 8,2 Hz, 1H), 7,09 (d, J = 1,9 Hz, 1H), 6,94 (dd, J = 8,2, 2,1 Hz, 1H), 4,37 - 4,25 (m, 2H), 4,12 - 4,00 (m, 1H), 3,06 - 2,99 (m, 1H), 2,94 2,87 (m, 1H), 2,85 (s, 3H), 2,74 (ddd, J = 7,6, 4,4, 3,4 Hz, 1H), 2,32 (s, 3H), 2,00 (ddd, J = 9,5, 6,3, 3,3 Hz, 1H), 1,91 - 1,83 (m, 3H), 1,65 (dt, J = 13,7, 8,6 Hz, 1H), 1,25 - 1,20 (m, 1H), 1,14 (dt, J = 7,4, 6,0 Hz, 1H). 231 δ 0 ΑΊ 'n^n'—n^nn 1 JJ H I 1 Jj CIa^ AA 3-[(1S,2R)-2-(4-cloro-3- metilfenil)ciclopropil]-1-metil-1-[(3R)-1(piridazin-3-il)piperidin-3-il]ureia LC-MS: m / z 400,2 (M+H). 1H RMN (400 MHz, MeOD) δ 8,49 (dd, J = 4,2, 1,4 Hz, 1H), 7,56 7,43 (m, 2H), 7,20 (d, J = 8,2 Hz, 1H), 7,09 (d, J = 2,0 Hz, 1H), 6,94 (dd, J = 8,2, 2,2 Hz, 1H), 4,30 (dd, J = 37,8, 12,3 Hz, 2H), 4,10 (dt, J. Petição 870260063816, de 29 / 06 / 2026, pág. 214 / 739 207 / 315 Example Structure and name Data = 11.2, 6.1 Hz, 1H), 3.12 - 3.04 (m, 1H), 2.95 (dd, J = 18.6, 7.8 Hz, 1H), 2.86 (s, 3H), 2.77 - 2.65 (m, 1H), 2.31 (s, 3H), 2.00 (ddd, J = 9.5, 6.2, 3.2 Hz, 1H), 1.93 - 1.85 (m, 3H), 1.72 - 1.66 (m, 1H), 1,251.20 (m, 1H), 1.17-1.12 (m, 1H). General Procedure I:

[00254] As a general procedure, the examples below have been synthesized according to the following general scheme. EDCI, HOBt, DIEA, DMF I3

[00255] To a mixture of compound I1 (1 eq.) and DIEA (5 eq.) in DMF, the corresponding acids I2 (1.2 eq.), EDCI (1.2 eq.), and HOBt (1.2 eq.) were added. The resulting mixture was stirred at room temperature for 16 h. Then, the mixture was diluted with water and extracted twice with EtOAc. The combined organic layers were washed with saturated NH4Cl solution and brine, dried with anhydrous Na2SO4, and filtered. The filtrate was concentrated to dryness under vacuum. The residue was purified via preparative HPLC (Xbudge prep C18 250 * 19 mm 5um OBD, H2O / MeCN (595%) / 0.1% FA) to yield compound I3. Example 232: Synthesis of (R )-3-(4-chloro3-methylbenzyl)-1-methyl-1-(1(pyrimidine-4-carbonyl)piperidin-3-yl)urea M1 EDCI, HOBt DIEA, DMF Example 232

[00256] A mixture of compound M1 (50 mg, 0.12 mmol) and DIEA Petition 870260063816, dated 06 / 29 / 2026, page 215 / 739 208 / 315 (79 mg, 0.61 mmol) in DMF was added pyrimidine-4-carboxylic acid M2 (19 mg, 0.14 mmol), EDCI (28 mg, 0.144 mmol) and HOBt (20 mg, 0.144 mmol). The resulting mixture was stirred at room temperature for 16 h. Then, the mixture was diluted with water (20 mL) and extracted twice with EtOAc (20 mL). The combined organic layers were washed with saturated NH4Cl solution and brine, dried with anhydrous Na2SO4 and filtered, and the filtrate was concentrated to dryness under vacuum. The residue was purified via preparative HPLC (Xbudge Prep C18 250 * 19 mm 5um OBD, H2O / MeCN (5-95%) / 0.1% FA) to provide Sample 232 (9 mg, 18.7% yield) as a white solid. LC / MS: m / z 402 (M+H)+. 1H NMR (400 MHz, MeOD) δ 9.21 - 9.12 (m, 1H), 8.94 - 8.90 (m, 1H), 7.66 - 7.63 (m, 1H), 7.28 - 7.23 (m, 1H), 7.14 (s, 1H), 7.12 7.00 (m, 1H), 4.64 - 4.49 (m, 1H), 4.38 - 4.11 (m, 3H), 3.70 - 3.54 (m, 1H), 3.28 - 3.18 (m, 1H), 3.08 - 2.42 (m, 5H), 2.36 - 2.29 (m, 3H), 1.98 - 1.76 (m, 3H), 1.76 - 1.62 (m, 1H).

[00257] The compounds in the table below were prepared from suitable starting materials, described above or commercially available, using general procedure I above and intermediate M1 in Example 232. Example Structure and name Data 233 O ±(R) Cl 3-[(4-chloro-3-methylphenyl)methyl]-1[(3R)-1-[(2S)-3-methoxy-2-methylpropanoyl]piperidin-3-yl]-1-methylurea LC-MS: m / z 396.2 (M+H). 1H NMR (400 MHz, MeOD) δ 7.28 (dd, J = 8.2, 2.0 Hz, 1H), 7.23 (s, 1H), 7.12 (d, J = 8.1 Hz, 1H), 4.58 - 4.46 (m, 1H), 4.40 - 4.27 (m, 2H), 4.02 (dd, J = 41.8, 11.1 Hz, 2H), 3.56 (td, J = 8.7, 6.1 Hz, 1H), 3.31 (d, J = 11.4 Hz, 3H), 3.12 (ddt, J = 51.0, 24.2, 9.1 Hz, 2H), 2.87 (d, J = 7.6 Hz, 3H), 2.79 - 2.46 (m, 1H), 2.36 (s, 3H), 1.84 (t, J = 5.9 Hz, 3H), 1.68 1.43 (m, 1H), 1.31 (d, J = 6.5 Hz, 1H), 1.08 (dd, J = 19.5, 6.9 Hz, 3H). Petition 870260063816, dated 06 / 29 / 2026, p. 216 / 739 209 / 315 234 3-[(4-cloro-3-metilfenil)metil]-1[(3R)-1-(3metoxipropanoil)piperidin-3-il]-1 metilureia 235 236 3-[(4-cloro-3-metilfenil)metil]-1metil-1-[(3R)-1-(1,3-oxazol-2carbonil)piperidin-3-il]ureia LC-MS: m / z 382,2 (M+H). 1H RMN (400 MHz, MeOD) δ 7,27 (d, J = 8,2 Hz, 1H), 7,21 (s, 1H), 7,09 (dd, J = 8,2, 2,0 Hz, 1H), 4,47 - 4,24 (m, 3H), 4,07 (d, J = 6,0 Hz, 1H), 3,56 3,39 (m, 1H), 3,28 - 3,07 (m, 1H), 3,03 (t, J = 6,5 Hz, 3H), 2,99 (s, 1H), 2,91 (d, J = 3,6 Hz, 2H), 2,86 (t, J = 6,9 Hz, 3H), 2,72 - 2,62 (m, 1H), 2,34 (s, 3H), 1,95 - 1,81 (m, 3H), 1,70 - 1,52 (m, 1H). 3-[(4-cloro-3-metilfenil)metil]-1[(3R)-1-(2-hidroxiacetil)piperidin-3il]-1-metilureia LC-MS: m / z 542,2 (M+H). 1H RMN (400 MHz, MeOD) δ 7,26 (dd, J = 8,1, 1,8 Hz, 1H), 7,20 (s, 1H), 7,09 (d, J = 8,2 Hz, 1H), 4,49 - 4,37 (m, 1H), 4,33 - 4,15 (m, 4H), 4,03-3,95 (m, 1H), 3,71 - 3,53 (m, 1H), 3,12 - 2,88 (m, 1H), 2,86 (s , 3H), 2,78 - 2,48 (m, 1H), 2,35 (s , 3H), 1,85-1,79 (m, 3H), 1,63 - 1,46 (m, 1H). LC-MS: m / z 391,1 (M+H). 1H RMN (400 MHz, MeOD) δ 8,09 8,01 (m, 1H), 7,34 - 7,16 (m, 3H), 7,10 (dd, J = 10,9, 4,7 Hz, 1H), 4,83 - 4,73 (m, 1H), 4,63 - 4,48 (m, 1H), 4,39 4,25 (m, 2H), 4,17 - 4,04 (m, 1H), 3,31 - 3,04 (m, 1H), 2,99 - 2,74 (m, 4H), 2,35 (t, J = 7,3 Hz, 3H), 1,99 - 1,81 (m, 3H), 1,77 - 1,59 (m, 1H). Petição 870260063816, de 29 / 06 / 2026, pág. 217 / 739 210 / 315 237 1-[(4-cloro-3-metilfenil)metil]-3metil-3-[(3R)-1-[(3S)-oxolano-3carbonil]piperidin-3-il]ureia 238 (3R)-3-({[(4-cloro-3metilfenil)metil]carbamoil}(metil)a mino)piperidina-1-carboxilato de metila LC-MS: m / z 416,1 (M+H). 1H RMN (400 MHz, MeOD) δ 7,27 (dd, J = 8,2, 3,5 Hz, 1H), 7,21 (d, J = 3,7 Hz, 1H), 7,10 (dd, J = 9,7, 3,7 Hz, 1H), 4,54 - 4,41 (m, 1H), 4,37 - 4,25 (m, 2H), 4,09 - 3,89 (m, 3H), 3,89 - 3,74 (m, 3H), 3,51 - 3,40 (m, 1H), 3,20 2,95 (m, 1H), 2,85 (d, J = 8,0 Hz, 3H), 2,79 - 2,47 (m, 1H), 2,34 (s, 3H), 2,20 - 2,00 (m, 2H), 1,91 - 1,77 (m, 3H), 1,67 - 1,44 (m, 1H). LC-MS: m / z 354,2 (M+H). 1H RMN (400 MHz, MeOD) δ 7,27 (d, J = 8,2 Hz, 1H), 7,20 (s, 1H), 7,09 (d, J = 8,1 Hz, 1H), 4,31-4,28 (m, 2H), 4,083,95 (m, 3H), 3,67 (s,3H), 2,88-2,81 (m, 4H), 2,70-2,64 (m, 1H), 2,34 (s,3H), 1,80-1,68 (m, 3H), 1,60-1,50 (m, 1H). 239 LC-MS: m / z 368,2 (M+H). 1H RMN (400 MHz, MeOD) δ 7,27 (dd, J = 8,1,2,6 Hz, 1H), 7,21 (s, 1H), 7,09 (d, J = 8,1 Hz, 1H), 4,50 - 4,38 (m, 1H), 4,37 - 4,25 (m, 2H), 4,23 - 4,08 3-[(4-chloro-3-methylfenil)methyl]-1[(3R)-1-(2-metoxiacetil)piperidin-3il]-1-metilureia (m, 2H), 4.07 - 3.95 (m, 1H), 3.84 3.65 (m, 1H), 3.38 (s, 3H), 3.16 - 2.90 (m, 1H), 2.85 (d, J = 1.7 Hz, 3H), 2.78 - 2.47 (m, 1H), 2.34 (s, 3H), 1.85-1.76 (m, 3H), 1.67 - 1.44 (m, 1H). Petition 870260063816, on 06 / 29 / 2026, page. 218 / 739 211 / 315 240 241 3-[(4-chloro-3-methylfenil)methyl]-1methyl-1-[(3R)-1-(3methylbutanoil)piperidin-3-il]ureia LC-MS: m / z 380,2 (M+H). 1H RMN (400 MHz, MeOD) δ 7.29 7.15 (m, 2H), 7.09 (dd, J = 6.4, 3.8 Hz, 1H), 4.59 - 4.42 (m, 1H), 4.39 - 4.22 (m, 2H), 4.15 - 3.77 (m, 2H), 3.15 2.93 (m, 1H), 2.84 (d, J = 5.5 Hz, 3H), 2.74 - 2.42 (m, 1H), 2.33 (s , 3H), 2.28 - 220 (m, 2H), 2.12 - 1.99 (m, 1H), 1.88 - 1.71 (m, 3H), 1,62 - 1.42 (m, 1H), 0.98 - 0.88 (m, 6H). 3-[(4-chloro-3-metilfenil)metil]-1[(3R)-1ciclopropanocarbonilpiperidin-3-il]LC-MS: m / z 364.2 (M+H). 1H RMN (400 MHz, MeOD) δ 7,26 (d, J = 8,2 Hz, 1H), 7,21 (s, 1H), 7,09 (d, J = 7,7 Hz, 1H), 4,63 - 4,22 (m, 4H), 4,19 - 3,90 (m, 1H), 3,25 - 2,98 (m, 1H), 2,94 - 2,82 (m, 3H), 2,79 - 2,45 (m, 1H), 2,34 (s, 3H), 2,01 - 1,73 (m, 4H), 1,67 - 1,48 (m, 1H), 0,93 - 0,72 (m, 4H). 1-metilureia 242 LC-MS: m / z 338,2 (M+H). 1H RMN (400 MHz, MeOD) δ 7,287,25 (m, 1H), 7,21 (s, 1H), 7,14 - 7,05 (m, 1H), 4,52 - 4,40 (m, 1H), 4,38 4,22 (m, 2H), 4,10 - 3,95 (m, 1H), 3,89 -[(3R)-1-acetilpiperidin-3-il]-3-[(4cloro-3-metilfenil)metil]-1metilureia - 3,73 (m, 1H), 3,18 - 2,96 (m, 1H), 2,86 (s, 3H), 2,74 - 2,43 (m, 1H), 2,35 (s, 3H), 2,18 - 2,03 (m, 3H), 1,88 1,72 (m, 3H), 1,65 - 1,44 (m, 1H). Petição 870260063816, de 29 / 06 / 2026, pág. 219 / 739 212 / 315 243 244 1-[(4-cloro-3-metilfenil)metil]-3metil-3-[(3R)-1-[(2S)-oxolano-2carbonil]piperidin-3-il]ureia LC-MS: m / z 394 (M+H). 1H RMN (400 MHz, MeOD) δ 7,27 (dd, J = 8,2, 3,9 Hz, 1H), 7,21 (s, 1H), 7,10 (dd, J = 5,7, 2,3 Hz, 1H), 4,78 - 4,65 (m, 1H), 4,51 - 4,25 (m, 3H), 4,13 3,79 (m, 4H), 3,19 - 2,90 (m, 1H), 2,85 (d, J = 5,7 Hz, 3H), 2,78 - 2,47 (m, 1H), 2,34 (s, 3H), 2,29 - 2,10 (m, 1H), 2,06 - 1,78 (m, 6H), 1,69 - 1,42 (m, 1H). 1-[(4-cloro-3-metilfenil)metil]-3metil-3-[(3R)-1-{1H-pirrolo[2,3LC-MS: m / z 440,2 (M+H). 1H RMN (400 MHz, MeOD) δ 8,098,00 (m, 1H), 7,53-7,41 (m, 1H), 7,337,20 (m, 2H), 7,12 (d, J = 7,8 Hz, 1H), 7,06 - 6,87 (m, 1H), 6,57 - 6,50 (m, 1H), 4,69 - 4,55 (m, 1H), 4,42 - 4,14 (m, 3H), 3,88-3,82 (m, 1H), 3,26 - 3,00 (m, 1H), 2,99 - 2,71 (m, 4H), 2,38 2,19 (m, 3H), 1,99 - 1,65 (m, 4H). b]piridina-6-carbonil}piperidin-3il]ureia 245 1-[(4-cloro-3-metilfenil)metil]-3metil-3-[(3R)-1-[2-(piridin-2il)acetil]piperidin-3-il]ureia LC-MS: m / z 415,2 (M+H). 1H RMN (400 MHz, MeOD) δ 8,64 (s, 1H), 8,25 - 8,13 (m, 1H), 7,73 - 7,60 (m, 2H), 7,30 -7,16 (m, 2H), 7,11 7,05 (m, 1H), 4,56 - 4,41 (m, 1H), 4,37 - 4,26 (m, 2H), 4,14 - 3,86 (m, 2H), 3,23 - 3,02 (m, 1H), 2,92 - 2,83 (m, 3H), 2,81 - 2,48 (m, 1H), 2,33 (s, 3H), 1,93 - 1,78 (m, 3H), 1,64 - 1,44 (m, 1H). Petição 870260063816, de 29 / 06 / 2026, pág. 220 / 739 213 / 315 246 / X Cl líj Η 1 Hí| | Ύ^γ 1H RMN (400 MHz, MeOD) δ 9.15 9.03 (m, 1H), 7.67 (dd, J = 8.5, 4.7 Hz, 2H), 7.30 - 7.16 (m, 2H), 7.11-7.06 (m, 1H), 4.52 - 3.93 (m, 7H), 3.28 - 3.03 (m, 1H), 2.91 - 2.53 (m, 4H), 2.32 (d, J = 5.6 Hz, 3H), 1.92 - 1.78 (m, 3H), 1.65 - 1.45 (m, 1H). 247 .Cl 0 1 íi 1-[(4-chloro-3-methylfenil)metil]-3metil-3-[(3R)-1-(oxano-3carbonil)piperidin-3-il]ureia LC-MS: m / z 408,2 (M+H). 1H RMN (400 MHz, MeOD) δ 7.28 7.25 (m, 1H), 7.21 (d, J = 6.9 Hz, 1H), 7.09 (t, J = 7.8 Hz, 1H), 4.53 - 4.24 (m, 3H), 4.14 - 3.81 (m, 4H), 3.54 3.33 (m, 2H), 3.19 - 2.79 (m, 5H), 2.74 - 2.39 (m, 1H), 2.34 (s, 3H), 2.08 1.54 (m, 8H). 248 _____ ^Cl 0 1 h χΛο-ϊ021 1-[(4-chloro-3-metilfenil)metil]-3[(3R)-1-(6-metoxipiridazina-3carbonil)piperidin-3-il]-3-metilureia LC-MS: m / z 432.2 (M+H).1H RMN (400 MHz, MeOD) δ 7,72 7,86 (m, 1H), 7,30 - 7,00 (m, 4H), 4,70 - 4,54 (m, 1H), 4,42 - 4,30 (m, 2H), 4,20 - 3,99 (m, 4H), 3,98 - 3,84 (m, 1H), 3,15 - 2,95 (m, 1H), 2,93 - 2,74 (m, 4H), 2,36 - 2,28 (m, 3H), 2,01 1,67 (m, 4H). Petição 870260063816, de 29 / 06 / 2026, pág. 221 / 739 214 / 315 249 s 1-[(4-cloro-3-metilfenil)metil]-3metil-3-[(3R)-1-[2-(1,3-tiazol-4il)acetil]piperidin-3-il]ureia LC-MS: m / z 421,1 (M+H). 1H RMN (400 MHz, MeOD) δ 8,95 8,81 (m, 1H), 7,42 -7,33 (m, 1H), 7,24 (dd, J = 8,2, 3,2 Hz, 1H), 7,18 (d, J = 4,1 Hz, 1H), 7,07 (d, J = 8,3 Hz, 1H), 4,59 -4,45 (m, 1H), 4,37 - 4,22 (m, 2H), 4,08 - 3,86 (m, 4H), 3,24 - 2,95 (m, 1H), 2,84 (d, J = 9,6 Hz, 3H), 2,80 -2,46 (m, 1H), 2,31 (d, J = 7,5 Hz, 3H), 1,89 -1,73 (m, 3H), 1,55 - 1,39 (m, 1H). 250 1-[(4-cloro-3-metilfenil)metil]-3metil-3-[(3R)-1-[2-(1H-pirazol-3il)acetil]piperidin-3-il]ureia 251 Cl 1-[(4-cloro-3-metilfenil)metil]-3[(3R)-1-(2,4-dimetil-1,3-tiazol-5carbonil)piperidin-3-il]-3-metilureia LC-MS: m / z 404,2 (M+H). 1H RMN (400 MHz, CDCI3) δ 7,557,51 (m, 1H), 7,25 (dd, J = 8,2, 1,5 Hz, 1H), 7,19 (d, J = 4,3 Hz, 1H), 7,07 (d, J = 8,1 Hz, 1H), 6,24 - 6,14 (m, 1H), 4,57 - 4,40 (m, 1H), 4,37 - 4,21 (m, 2H), 4,02 - 3,72 (m, 4H), 3,15 - 2,93 (m, 1H), 2,82 (d, J = 1,5 Hz, 3H), 2,81 - 2,45 (m, 1H), 2,32 (d, J = 5,6 Hz, 3H), 1,87 - 1,70 (m, 3H), 1,58 - 1,36 (m, 1H). LC-MS: m / z 435,1 (M+H). 1H RMN (400 MHz, CDCI3) δ 7,30 7,02 (m, 3H), 4,70 - 3,94 (m, 5H), 3,23 - 2,73 (m, 5H), 2,66 (s, 3H), 2,36 (s, 3H), 2,33 (s, 3H), 1,91 - 1,76 (m, 3H), 1,60 (s, 1H). Petição 870260063816, de 29 / 06 / 2026, pág. 222 / 739 215 / 315 252 1-[(4-cloro-3-metilfenil)metil]-3metil-3-[(3R)-1-(1,3-oxazol-5carbonil)piperidin-3-il]ureia LC-MS: m / z 391,1 (M+H). 1H RMN (400 MHz, MeOD) δ 8,31 (s, 1H), 7,73 - 7,62 (m, 1H), 7,26 (d, J = 8,2 Hz, 1H), 7,20 (s, 1H), 7,09 (d, J = 7,9 Hz, 1H), 4,61 - 4,13 (m, 5H), 3,21 - 2,68 (m, 5H), 2,34 (s, 3H), 1,94 1,85 (m, 3H), 1,65 (s, 1H). 253 1-[(4-cloro-3-metilfenil)metil]-3metil-3-[(3R)-1-(oxano-4carbonil)piperidin-3-il]ureia 254 1-[(4-cloro-3-metilfenil)metil]-3metil-3-[(3R)-1-(oxano-2carbonil)piperidin-3-il]ureia LC-MS: m / z 480,2 (M+H). 1H RMN (400 MHz, MeOD) δ 7,26 (dd, J = 8,1, 5,3 Hz, 1H), 7,20 (s, 1H), 7,11 - 7,06 (m, 1H), 4,61 - 4,41(m, 1H), 4,36 - 4,23 (m, 2H), 4,14 - 3,84 (m, 4H), 3,55 - 3,41 (m, 2H), 3,16 - 2,89 (m, 2H), 2,84 (d, J = 9,1 Hz, 3H), 2,75 - 2,43 (m, 1H), 2,34 (s, 3H), 1,91- 1,40 (m, 8H). LC-MS: m / z 480,2 (M+H). 1H RMN (400 MHz, MeOD) δ 7,29 7,16 (m, 2H), 7,09 (t, J = 7,7 Hz, 1H), 4,51 - 4,14 (m, 4H), 4,10 - 3,80 (m, 3H), 3,63 - 3,38 (m, 1H), 3,15 - 2,87 (m, 1H), 2,84 (d, J = 6,4 Hz, 3H), 2,76 - 2,44 (m, 1H), 2,33 (s, 3H), 1,95 1,76 (m, 4H), 1,75 - 1,39 (m, 6H). Petição 870260063816, de 29 / 06 / 2026, pág. 223 / 739 216 / 315 255 A ο 1 lí NO^ NH 1-[(4-chloro-3-metilfenil)metil]-3metil-3-[(3R)-1-(6-oxo-1,6dihydropiridazina-3carbonil)piperidin-3-il]ureia LC-MS: m / z 418.1 (M+H). 1H RMN (400 MHz, MeOD) δ 7.43 (dd, J = 9.8, 3.8 Hz, 1H), 7.06 (dd, J = 8.2, 3.8 Hz, 1H), 7.04-6.96 (m, 1H), 6.91 6.68 (m, 2H), 4.37-4.27 (m, 1H). 256 Cl 1-[(4-chloro-3-methylfenil)methyl]-3methyl-3-[(3R)-1-(6-methylpiridazina3-carbonil)piperidin-3-il]ureia LC-MS: m / z 416,1 (M+H). 1H RMN (400 MHz, MeOD) δ 7.82 7.66 (m, 2H), 7.29 - 6.96 (m, 3H), 4.72 - 4.54 (m, 1H), 4.39 - 4.26 (m, 2H), 4.24 - 4.01 (m, 1H), 3.80 - 3.72 (m, 1H), 3.11 - 2.96 (m, 1H), 2.95 - 2.74 (m, 4H), 2.74 - 2.66 (m, 3H), 2.35 2.28 (m, 3H), 2.01 - 1.62 (m, 4H). 257 νΠ U 1 Η ΓΥ ΐ Y χ __J o 1-[(4-chloro-3-metilfenil)metil]-3- metil-3-[(3R)-1-[2-(1,3-tiazol-5il)acetil]piperidin-3-il]ureia LC-MS: m / z 421.1 (M+H).1H RMN (400 MHz, MeOD) δ 8,98 (s, 1H), 7,75 (d, J = 9,6 Hz, 1H), 7,30 7,18 (m, 2H), 7,14 - 7,05 (m, 1H), 4,53 - 4,41 (m, 1H), 4,35 - 4,27 (m, 2H), 4,16 - 3,87 (m, 4H), 3,24 - 2,98 (m, 1H), 2,90 - 2,83 (m, 3H), 2,81 - 2,52 (m, 1H), 2,34 (s, 3H), 1,92 - 1,77 (m, 3H), 1,62 - 1,45 (m, 1H). Petição 870260063816, de 29 / 06 / 2026, pág. 224 / 739 217 / 315 258 1-[(4-cloro-3-metilfenil)metil]-3[(3R)-1-[2-(1H-imidazol-4il)acetil]piperidin-3-il]-3-metilureia LC-MS: m / z 404,1 (M+H). 1H RMN (400 MHz, MeOD) δ 7,84 (s, 1H), 7,26-7,19 (m, 2H), 7,13 - 6,99 (m, 2H), 4,56 - 4,39 (m, 1H), 4,32 (d, J = 7,3 Hz, 2H), 4,00-3,92 (m, 2H), 3,823,71 (m, 2H), 3,20-2,95 (m, 1H), 2,84 (d, J = 10,0 Hz, 3H), 2,77 - 2,48 (m, 1H), 2,31 (d, J = 5,5 Hz, 3H), 1,85-1,74 (m, 3H), 1,055-1,39 (m, 1H). 259 LC-MS: m / z 407,1 (M+H). 1H RMN (400 MHz, MeOD) δ 8.89 9.03 (m, 1H), 8.11 - 8.00 (m, 1H), 7.26 (d, J = 8.1 Hz, 1H), 7.22 - 7.18 (m, 1H), 7.14-7.03 (m, 1H), 4.63 - 4,54 (m, 1H), 4,35 - 4,24 (m, 2H), 4,13 (d, J = 1-[(4-chloro-3-methylfenil)methyl]-3methyl-3-[(3R)-1-(1,3-tiazol-4carbonil)piperidin-3-il]ureia 8.0 Hz, 2H), 3.27 - 2.69 (m, 5H), 2.33 (s, 3H), 1.98 - 1.74 (m, 3H), 1.74 1.57 (m, 1H). 260 LC-MS: m / z 405,1 (M+H). 1H RMN (400 MHz, MeOD) δ 7.25 (dd, J = 8.2, 4.2 Hz, 1H), 7.19 (d, J = 14.2 Hz, 1H), 7.15- 7.03 (m, 1H), 6.32 (dd, J = 11.6, 0.7 Hz, 1H), 4.65 - 4.52 (m, 1H), 4.37 - 4.23 (m, 2H), 4.14 - 3.99 1-[(4-chloro-3-methylfenil)methyl]-3- (m, 2H), 3.28 - 2.99 (m, 1H), 2.97 metil-3-[(3R)-1-(5-methyl-1,2-oxazol-2.70 (m, 4H), 2.44 (d, J = 16.7 Hz, 3H), 3-carbonyl)piperidin-3-il]ureia 2.33 (d, J = 3.8 Hz, 3H), 1.95 - 1.80 (m, 3H), 1.67 - 1.55(m, 1H). Petition 870260063816, on 06 / 29 / 2026, page. 225 / 739 218 / 315 261 1-[(4-cloro-3-metilfenil)metil]-3metil-3-[(3R)-1-(4-metil-1,3-oxazol5-carbonil)piperidin-3-il]ureia LC-MS: m / z 405,1 (M+H). 1H RMN (400 MHz, MeOD) δ 8,24 8,08 (m, 1H), 7,26 (d, J = 8,2 Hz, 1H), 7,19 (s, 1H), 7,07 (d, J = 7,6 Hz, 1H), 4,51 - 3,98 (m, 5H), 3,15 - 2,67 (m, 5H), 2,33 (s, 3H), 2,31 (s, 3H), 1,94 1,80 (m, 3H), 1,71 - 1,57 (m, 1H). 262 1-[(4-cloro-3-metilfenil)metil]-3metil-3-[(3R)-1-(1,2-oxazol-3carbonil)piperidin-3-il]ureia LC-MS: m / z 391,1 (M+H). 1H RMN (400 MHz, MeOD) δ 8,77 (dd, J = 9,2, 1,6 Hz, 1H), 7,26 (dd, J = 8,2, 5,4 Hz, 1H), 7,25-7,22 (m, 1H), 7,14 7,04 (m, 1H), 6,70 (dd, J = 12,6, 1,8 Hz, 1H), 4,68 - 4,52 (m, 1H), 4,39 4,21 (m, 2H), 4,20 - 4,02 (m, 2H), 3,13 - 2,71 (m, 5H), 2,34 (d, J = 5,2 Hz, 3H), 1,98 - 1,79 (m, 3H), 1,74 - 1,58 (m, 1H). 263 LC-MS: m / z 404,2 (M+H). 1H NMR (400 MHz, CDCI3) δ 8.03 (s, 1H), 7.75 (s, 1H), 7.27 (d, J = 8.2 Hz, 1H), 7.20 (s, 1H), 7.09 (d, J = 8.2 Hz, 1H), 4.66 - 4.41 (m, 1H), 4.31 (s, 2H), 4.26 - 3.99 (m, 2H), 3.86 (s, 3H), 3.26 1-[(4-chloro-3-methylphenyl)methyl]-3methyl-3-[(3R)-1-(1-methyl-1H-pyrazol4-carbonyl)piperidin-3-yl]urea - 2.98 (m, 1H), 2.93 - 2.60 (m, 4H), 2.33 (s, 3H), 1.97 - 1.79 (m, 3H), 1.71 - 1.53 (m, 1H). Petition 870260063816, 06 / 29 / 2026, pág. 226 / 739 219 / 315 264 .Cl 0 i η ην-ν Ο 0 1-[(4-chloro-3-metilfenil)metil]-3metil-3-[(3R)-1-(1 H-pirazol-3carbonil)piperidin-3-il]ureia LC-MS: m / z 390 (M+H). 1H RMN (400 MHz, MeOD) δ 7.67 (d, J = 6.4 Hz, 1H), 7.30 -6.99 (m, 3H), 6.62 (s, 1H), 4.67 -4.36 (m, 2H), 4.30 (s, 2H), 4.10 (s, 1H), 3.29 -2.98 (m, 1H), 2.96 -2.63 (m, 4H), 2.33 (d, J = 5.8 Hz, 3H), 1.86-1.52 (m, 4H). 265 Cl S । h [ii 1-[(4-chloro-3-methylfenil)methyl]-3methyl-3-[(3R)-1-(pirazina-2carbonil)piperidin-3-il]ureia LC-MS: m / z 402,1 (M+H). 1H RMN (400 MHz, MeOD) δ 8.82 (dd, J = 5.1, 1.3 Hz, 1H), 8.68-8.50 (m, 2H), 7.29 - 6.99 (m, 3H), 4.67-4.54 (m, 1H), 4.36-4.10 (m, 3H), 3.83-3.71(m, 1H), 3.09-2.95(m, 1H), 2.92-2.71(m, 4H), 2.33(s, 3H), 1.95-1.65(m, 4H). 266 .ci o 1 1. O / A 1-[(4-chloro-3-metilfenil)metil]-3metil-3-[(3R)-1-(piridina-3carbonil)piperidin-3-il]ureia LC-MS: m / z 400.2 (M+H).1H RMN (400 MHz, MeOD-d) δ 8,55 (d, J = 3,9 Hz, 1H), 7,23 - 7,16 (m, 2H), 7,05 (d, J = 1,9 Hz, 1H), 6,94 (dd, J = 8,2, 2,2 Hz, 1H), 6,62 (dd, J = 9,1, 1,1 Hz, 1H), 5,08 - 4,94 (m, 1H), 4,85 (s, 1H), 3,88 - 3,71 (m, 2H), 3,54 3,42 (m, 1H), 3,37 (dd, J = 10,5, 8,1 Hz, 1H), 3,25 - 3,16 (m, 2H), 2,82 (qd, J = 4,6, 1,8 Hz, 1H), 2,33 (s, 3H), 2,27 (ddd, J = 14,3, 6,2, 2,8 Hz, 1H), 2,16 2,07 (m, 1H), 1,99 (ddd, J = 9,5, 6,3, 3,3 Hz, 1H), 1,23 - 1,10 (m, 5H). Petição 870260063816, de 29 / 06 / 2026, pág. 227 / 739 220 / 315 267 Cl AoA0' 3-[(3R)-1-benzoilpiperidin-3-il]-1[(4-chloro-3-metilfenil)metil]-3metilureia LC-MS: m / z 400.1 (M+H). 1H RMN (400 MHz, MeOD) δ 7,457.40 (m, 5H), 7.29-6.95 (m, 3H), 4.56 (br, 1H), 4.32-4.10 (m, 3H), 3.64 (br, 1H), 3.19-2.67 (m, 5H), 2.32 (s, 3H), 1.94-1.70 (m, 3H), 1.61 (br, 1H). 268 Γ lí] 1 h í T 0 1 lw V IJ 0 1-[(4-chloro-3-metilfenil)metil]-3metil-3-[(3R)-1-(3fenilpropanoil)piperidin-3-il]ureia LC-MS: m / z 428.4 (M+H). 1H RMN (400 MHz, DMSO) δ 7.357.13 (m, 7H), 7.08 (t, J = 8.4 Hz, 1H), 6.91 (t, J = 5.7 Hz, 1H), 4.38-4.15 (m, 3H), 3.95-3.61 (m, 2H), 3.05-2.70 (m, 6H), 2.6-2.52 (m, 3H), 2.28 (s, 3H), 1.77-.55 (m, 3H), 1.41-1.22 (m, 1H). 269 ​​N\Ay° _N. 11 0 I \.(R> JL _____ _____ — 'ZN N Π । HL JL ηΑΧι 1-[(4-chloro-3-metilfenil)metil]-3metil-3-[(3R)-1-(1-metil-1Himidazol-4-carbonil)piperidin-3il]ureia LC-MS: m / z 404,4 (M+H).1H RMN (400 MHz, DMSO) δ 7,60 (s, 2H), 7,32 (d, J = 8,2 Hz, 1H), 7,21 (s, 1H), 7,09 (d, J = 8,0 Hz, 1H), 7,06 5,78 (m, 1H), 5,09 (d, J = 83,9 Hz, 1H), 4,35 (s, 1H), 4,20 (d, J = 5,6 Hz, 2H), 3,91 (s, 1H), 3,66 (s, 3H), 3,13 (s, 1H), 2,71 (d, J = 34,3 Hz, 4H), 2,30 (s, 3H), 1,72 (s, 3H), 1,45 (d, J = 12,4 Hz, 1H). Petição 870260063816, de 29 / 06 / 2026, pág. 228 / 739 221 / 315 270 1-[(4-cloro-3-metilfenil)metil]-3metil-3-[(3R)-1-(piridina-2carbonil)piperidin-3-il]ureia LC-MS: m / z 401,4 (M+H). 1H RMN (400 MHz, DMSO) δ 8,55 (dd, J = 29,7, 4,5 Hz, 1H), 7,95 - 7,85 (m, 1H), 7,53 (d, J = 7,8 Hz, 1H), 7,45 (ddd, J = 11,8, 6,2, 3,0 Hz, 1H), 7,38 7,20 (m, 2H), 7,12 (d, J = 8,4 Hz, 1H), 7,02 - 6,92 (m, 1H), 4,41 (dd, J = 48,2, 12,2 Hz, 1H), 4,26 - 3,91 (m, 3H), 3,52 (dd, J = 42,7, 10,9 Hz, 1H), 3,20 - 2,89 (m, 1H), 2,73 (d, J = 50,5 Hz, 3H), 2,29 (d, J = 16,6 Hz, 3H), 1,84 - 1,61 (m, 3H), 1,57 - 1,43 (m, 1H). 271 LC-MS: m / z 402.2 (M+H). 1H NMR (400 MHz, MeOD) δ 9.24 (ddd, J = 14.4, 5.0, 1.8 Hz, 1H), 7.94 7.79 (m, 2H), 7.30 - 6.99 (m, 3H), 4.70 - 4.57 (m, J, 3H), (J, 4.34). 9.2 Hz, 1H), 4.28 (s, 1H), 4.25 - 4.03 (m, 1H), 3.73 1-[(4-chloro-3-methylphenyl)methyl]-3methyl-3-[(3R)-1-(pyridazine-3carbonyl)piperidin-3-yl]urea (dd, J = 29.6, 12.1 Hz, 2H), 3.14 - 2.97 (m, 1H), 2.96, - 45, (m 2.33 (d, J = 15.4 Hz, 3H), 2.01 - 1.65 (m, 4H). General Procedure J: Example 272: Synthesis of (R )-3-(4-chloro-3-methylbenzyl)-1-(1(cyclopropanocarbonyl)piperidin-3-yl)-1-cyclopropylurea HATU.DIEA, DMF Example 272 J1

[00258] To a mixture of J1 (67 mg, 0.21 mmol) and DIEA (81 mg, 0.63 mmol) in anhydrous DMF (5 mL) was added cyclopropanecarboxylic acid J2 (19 mg, 0.22 mmol) and HATU (84 mg, 0.22 mmol). The resulting mixture was stirred at room temperature for 1 h. Then, the mixture was poured Petition 870260063816, dated 06 / 29 / 2026, p. 229 / 739 222 / 315 in water (10 mL) and extracted with EtOAc (20 mL) twice. The combined organic layers were washed with saturated NH4Cl solution and brine, dried with anhydrous Na2SO4, filtered, and concentrated to dryness. The residue was purified via preparative HPLC to provide Example 272 (17 mg, 20.73% yield) as a light yellow solid. LC / MS (ESI) m / z: 390 (M+H)+. 1H NMR (400 MHz, MeOD) δ 7.27 (d, J = 8.2 Hz, 1H), 7.24 7.17 (m, 1H), 7.13 - 7.05 (m, 1H), 4.54 - 4.39 (m, 1H), 4.37 - 4.21 (m, 3H), 3.57 - 3.34 (m, 1H), 3.22 - 2.91 (m, 1H), 2.65 - 2.43 (m, 2H), 2.34 (s, 3H), 2.28 - 2.12 (m, 1H), 1.99 - 1.76 (m, 3H), 1.62 - 1.36 (m, 1H), 0.97 - 0.68 (m, 8H).

[00259] The compounds in the table below were prepared from suitable starting materials, described above or commercially available, using the general procedure J above and the intermediate J1 in Example 272. Example Structure and name Data 273 — NNKY 1 H LJL --- Cl 1-[(4-chloro-3-methylphenyl)methyl]-3methyl-3-[(3R)-1-(pent-4inoyl)piperidin-3-yl]urea LC-MS: m / z 376.3 (M+H). 1H NMR (400 MHz,cdci3) δ 7.32 - 7.24 (m, 1H), 7.18 (s, 1H), 7.11 - 7.04 (m, 1H), 4.97 - 4.67 (m, 1H), 4.65 - 4.49 (m, 1H), 4.45 - 4.26 (m, 2H), 4.22 - 4.11 (m, 1H), 3.85 - 3.72 (m, 1H), 2.98 - 2.86 (m, 1H), 2.80 (s, 3H), 2.70 - 2.47 (m, 5H), 2.43 - 2.37 (m, 1H), 2.35 (s, 3H), 1.95 (s, 1H), 1.91 - 1.46 (m, 3H). General Procedure K: Example 274: Synthesis of (R)-3-(4-chloro-3-methylbenzyl)-1-methyl-1-(1-(6-(trifluoromethyl)pyridazin-3-yl)piperidin-3-yl)urea Petition 870260063816, dated 06 / 29 / 2026, pp. 230 / 739 223 / 315 Example 274 K1

[00260] To a mixture of K1 (59 mg, 0.2 mmol) and K2CO3 (56 mg, 0.4 mmol) in DMF (6 mL) was added 3-chloro-6-(trifluoromethyl)pyridazine K2 (44 mg, 0.24 mmol). The resulting mixture was stirred at 80°C for 10 h. After cooling, the mixture was diluted with saturated NH4Cl solution (20 mL) and extracted twice with EtOAc (20 mL). The combined organic layers were washed with saturated NH4Cl solution and brine, dried with anhydrous Na2SO4, filtered, and concentrated to dryness. The residue was purified via preparative HPLC to give Example 274 (8 mg, 9.1% yield) as a white solid. LC / MS (ESI) m / z: 442 (M+H)+. 1H NMR (400 MHz, MeOD) δ 7.64 (d, J = 9.7 Hz, 1H), 7.35 (d, J = 9.7 Hz, 1H), 7.27 (d, J = 8.2 Hz, 1H), 7.24 7.20 (m, 1H), 7.11 (dd, J = 8.2, 1.7 Hz, 1H), 4.57 - 4.47 (m, 1H), 4.45 4.36 (m, 1H), 4.31 (s, 2H), 4.12 - 4.02 (m, 1H), 3.19 - 3.09 (m, 1H), 3.04 - 2.94 (m, 1H), 2.90 (s, 3H), 2.33 (s, 3H), 1.98 - 1.84 (m, 3H), 1.75 - 1.60 (m, 1H). Example Structure and name Data 275 n. ci ]l ] । h ll 1 Xs. ,,N___N JLxfL NA N LJ 0 3-[(4-chloro-3-methylphenyl)methyl]-1[(3R)-1-(6-cyanopyrazin-2yl)piperidin-3-yl]-1-methylurea LC-MS: m / z 399.2 (M+H). 1H NMR (400 MHz, MeOD) δ 8.47 (s, 1H), 8.09 (s, 1H), 7.27 (d, J = 8.2 Hz, 1H), 7.21 (s, 1H), 7.10 (dd, J = 8.2, 1.7 Hz, 1H), 4.46 - 4.29 (m, 4H), 4.10 (dt, J = 10.9, 7.5 Hz, 1H), 3.04 (dd, J = 12.5, 11.5 Hz, 1H), 2.94 - 2.83 (m, 4H), 2.34 (s, 3H), 1.89 (ddd, J = 15.8, 9.8, 3.4 Hz, 3H), 1.73 - 1.58 (m, 1H).

[00261] The following examples were prepared by Petition 870260063816, dated 06 / 29 / 2026, pp. 231 / 739 224 / 315 General Procedure A Exemplo Estrutura / nome Dados 278 7^- Ã A nn \=4 V 3-ciclopropil-1-{[2-fluoro-4-(1Hpirazol-1-il)fenil]metil}-3-[(3R)-1(piridazin-3-il)piperidin-3-il]ureia LC-MS: 435,2 m / z (M+H). 1H RMN (400 MHz, MeOD) δ 8.42 (dd, J = 4.4, 1.2 Hz, 1H), 8.25 (d, J = 2.5 Hz, 1H), 7.72 (d, J = 1.6 Hz, 1H), 7.59 - 7.51 (m, 2H), 7.46 (dd, J = 16.5, 8.4 Hz, 1H), 7.37 (dd, J = 9.4, 4.4 Hz, 1H), 7.29 (dd, J = 9.4, 1.2 Hz, 1H), 6.53 (dd, J = 2.5, 1.9 Hz, 1H), 4.53 - 4.44 (m, 2H), 4.43 - 4,31 (m, 2H), 3.78 (tt, J = 11.8, 3.9 Hz, 1H), 3.33 (d, J = 12.4 Hz, 1H), 2.88 (td, J = 13.0, 2.7 Hz, 1H), 2.62 - 2.51 (m, 1H), 2.26 (qd, J = 12.5, 4.0 Hz, 1H), 2.01 - 1.81 (m, 2H), 1.69 - 1.56 (m, 1H), 1.04 - 0.93 (m, 2H), 0.88 - 0.74 (m, 2H). 279 ^Á1H RMN (400 MHz, MeOD) δ 8,42 (d, J = 4,3 Hz, 1H), 7,89 - 7,84 (m, 1H), 7,71 (dd, J = 18,7, 9,5 Hz, 2H), 7,64 - 7,60 (m, 1H), 7,46 (t, J = 7,7 Hz, 1H), 7,36 (dd, J = 8,8, 3,8 Hz, 1H), 7,27 (d, J= 9,4Hz , 1H), 6,98 (d, J= 5,7Hz, 1H), 4,50 (d, J= 4,9Hz, 2H), 4,37 (dd, J= 23,6, 12,7Hz, 2H), 3,78 (t, J= 11,8Hz, 1H), 3,35 (s, 1H), 2,88 (t, J= 12,9Hz, 1H), 2,58 (s, 1H), 2,32-2,20 (m, 1H), 1,92 (dd, J = 46,2, 12,0 Hz, 2H), 1,62 (q, J = 13,3 Hz, 1H), 0,98 (d, J = 6,7 Hz, 2H), 0,82 (s, 2H). Petição 870260063816, de 29 / 06 / 2026, pág. 232 / 739 225 / 315 Example Structure / name Data 280 Λ οΧγ h THAT 3-cyclopropyl-1-{[2-fluoro-5-(1,3thiazol-2-yl)phenyl]methyl}-3-[(3R)-1(pyridazin-3-yl)piperidin-3-yl]urea 4-MLC (mL / z 53+z). 1H NMR (400 MHz, MeOD) δ 8.44 8.38 (m, 1H), 7.95 (dd, J = 7.1, 2.2 Hz, 1H), 7.90 - 7.82 (m, 2H), 7.58 (d, J= 3.3Hz, 1Hz, 3.4, J = 4,49). 4.4Hz, 1H), 7.30-7.16 (m, 2H), 7.07 (t, J= 6.0Hz, 1H), 4.52 (d, J = 2.5 Hz, 2H), 4.36 (ddd, J = 13.2, 12.6, 7.7 Hz, J = 7.7Hz), 12.0, 3.9 Hz, 1H), 3.36 (d, J = 12.3 Hz, 1H), 2.88 (td, J = 13.1, 2.6 Hz, 1H), 2.67 - 2.57 (m, 1H), (dd, J = 53.6, 12.6 Hz, 2H), 1.63 (ddt, J = 17.1, 13.1, 6.6 Hz, 1H), 1.02 to 0.95 (m, 2H), 0.89 to 0.82 (m, 2H). 281 Λ Ϊ J ξ η T |1 v 0 NV 3-cyclopropyl-1-{[2-fluoro-5-(1Hpyrazol-1-yl)phenyl]methyl}-3-[(3R)-1(pyridazin-3-yl)piperidin-3-yl]urea LC-MS: 4 m / z (M+H).1H RMN (400MHz, MeOD) δ 8,41 (dd, J= 4,4, 1,2Hz, 1H), 8,15 (d, J=2,4Hz, 1H), 7,74 (dd, J= 6,4, 2,8Hz, 1H), 7,70 (d, J= 1,7Hz, 1H), 7,61 (ddd, J=8,7, 4,2, 2,9 Hz, 1H), 7,34 (dd, J = 9,4, 4,4 Hz, 1H), 7,29 - 7,18 (m, 2H), 6,52 - 6,49 (m, 1H), 4,56 - 4,47 (m, 2H), 4,35 (ddd, J = 18,6, 12,5, 7,5 Hz, 2H), 3,78 (tt, J = 11,9, 3,9 Hz, 1H), 3,33 (d, J = 12,8 Hz, 1H), 2,87 (td, J = 13,0, 2,7 Hz, 1H), 2,65 - 2,52 (m, 1H), 2,26 (qd, J = 12,6, 4,2 Hz, 1H), 1,97 (d, J = 11,5 Hz, 1H), 1,85 (d, J = 12,8 Hz, 1H), 1,68 - 1,54 (m, 1H), 1,02 - 0,92 (m, 2H), 0,87 - 0,75 (m, 2H). Petição 870260063816, de 29 / 06 / 2026, pág. 233 / 739 226 / 315 Example Structure / name Given 282 Â Y ΎΎΥ Ν''ΝγΝΥ 1 -[(4-chloro-2-fluoro-5methylphenyl)methyl]-3-cyclopropyl-3[(3R)-1-(1,2,4-9-MS]triazineperiazine-LC3-yl m / z (M+H). 1H NMR (400 MHz, MeOD) δ 8.45 (d, J = 2.2 Hz, 1H), 8.26 (d, J = 2.2 Hz, 1H), 7.25 (d, J = 8.0 Hz, 1H), 7.13 (d, 7, J = 8, 8, 8 (H 5), Hz, 1H), 4.75 (d, J = 8.6 Hz, 2H), 4.39 (d, J = 5.4 Hz, 2H), 3.71 - 3.63 (m, 1H), 3.42 (t, J = 11.9 Hz, 1H), 17, H 2, J =7 (t 2.60 – 2.55 (m, 1H), 2.32 (s, 3H), 2.31 – 2.23 (m, 1H), 1.90 (dd, J = 27.9, 12.4 Hz, 2H), 1.57 (dt, J = 1.40 Hz), 4.0, dd, 4 9.9, 6.9, 3.7 Hz, 2H), 0.83 0.73 (m, 2H). 283 N / —n CW H 9 AAn¥n^ / o 1 -[(4-chloro-2-fluoro-5methylphenyl)methyl]-3-ethyl-3-[(3S)-1(phthalazine-1-yl)pyrrolidin-3-yl]urea LC-MS: (442 m). / z.1H RMN (400 MHz, MeOD) δ 8,88 (s, 1H), 8,42 - 8,38 (m, 1H), 7,94 (tdd, J = 6,9, 5,4, 2,0 Hz, 3H), 7,24 (d, J = 8,0 Hz, 1H), 7,10 (d, J = 9,8 Hz, 1H), 4,80 (d, J = 9,0 Hz, 1H), 4,38 (s, 2H), 4,04 - 3,90 (m, 4H), 3,42 (dd, J= 7,1, 1,7 Hz, 2H), 2,29 (d, J= 5,8 Hz, 5H), 1,23(t, J= 7,0 Hz, 3H). 284 Ti Ν N H J H ? 3-[(4-cloro-2,5-difluorofenil)metil]- 1 -ciclopropil-1-[(3R)-1-(piridazin-3il)piperidin-3-il]ureia LC-MS: 422 m / z (M+H). 1H RMN (400 MHz, MeOD) δ 8,43 (dd, J = 4,3, 1,0 Hz, 1H), 7,37 (dd, J = 9,4, 4,4 Hz, 1H), 7,29 (ddd, J = 9,3, 3,5, 2,3 Hz, 2H), 7,21 (dd, J = 9,5, 6,5 Hz, 1H), 7,02 (t, J = 5,7 Hz, 1H), 4,42 - 4,30 (m, 4H), 3,76 (tt, J = 11,9, 3,9 Hz, 1H), 3,35 (s, 1H), 2,88 (td, J = 13,1,2,7 Hz, 1H), 2,61 - 2,51 (m, 1H), 2,25 (qd, J = 12,6, 4,2 Hz, 1H), 1,96 (d, J = 11,5 Hz, 1H), 1,86 (d, J = 13,1 Hz, 1H), 1,68 - 1,54 (m, 1H), 1,02 - 0,92 (m, 2H), 0,81 (dd, J. Petição 870260063816, de 29 / 06 / 2026, pág. 234 / 739 227 / 315 Example Structure / name Data = 6.6, 4.1 Hz, 2H). 285 / Α / ^ΝΛΝΌγΝ'Ν PVó H . M Cl 3-{[3-(3-chlorophenyl)-1,2-oxazol-5yl]methyl}-1-methyl-1-[(3R)-1- (pyridazin-3-yl)piperidin-3-yl]urea LC-MS: 427.3 m / z (M+H). 1H NMR (400 MHz, CDCI3) δ 8.58 (dt, J = 4.4, 1.3 Hz, 1H), 7.84 - 7.78 (m, 1H), 7.69 (dq, J = 6.9, 1.5 Hz, 1H), 7.4 , 7.3 (m, 292 H), 7.19 (m, 4H), 7.01 (dd, J = 9.3, 1.3 Hz, 1H), 6.61 (t, J = 0.8 Hz, 1H), 4.77 - 4.62 (m, 2H), 4.47 (d, J = 12.9 Hz, J 1H), 3.98 to 3.88 (m, 1H), 3.07 (t, J = 12.9 Hz, 1H), 3.02 to 2.91 (m, 5H), 2.03 (s, 0H), 1.89 (td, J = 12.9, 4.5 Hz, 2H), 8H), 1.26 (s, 3H).). 286 [ \ ο- ν η ^γ^ο^Ο v O 1-cyclopropyl-3-{[5-(3-methoxyphenyl)- 1,3-oxazol-2-yl]methyl}-1-[(3R)-1(pyridazin-3-yl)piperidin-3-yl urea] (4MH / 4MH-mH / z]:1H RMN (400 MHz, MeOD) δ 8.42 (dd, J = 4.4, 1.2 Hz, 1H), 7.41 (d, J = 8.5 Hz, 1H), 7.37 - 7.24 (m, 4H), 7.23 - 7.19 (m, 1H), 6.91 (dd, J = 8.2, 1.7 Hz, 1H), 4.57 (s, 2H), 4.38 (dd, J = 27.6, 13.2 Hz, 2H), 3.84 - 3.78 (m, 4H), 2.95 - 2.82 (m, 1H), 2.65 - 2.57 (m, 1H), 2.27 (tt, J = 13.0, 6.4 Hz, 1H), 1.82 (ddd, J = 94.5, 29.2, 12.5 Hz, 4H), 1.01 - 0.95 (m, 2H), 0.92 - 0.86 (m, 2H). 287 U N-9 vo 1-ciclopropil-3-[(5-fenil-1,2-oxazol3-il)methyl]-1-[(3R)-1-(piridazin-3-il)piperidin-3-il]ureia LC-MS: 419 m / z (M+H). 1H RMN (400 MHz, MeOD) δ 8.43 (s, 1H), 7.81 (dd, J = 7.8, 1.4 Hz, 2H), 7.51 - 7.41 (m, 3H), 7.35 (d, J = 3.2 Hz, 1H), 7.29 (d, J = 9.3 Hz, 1H), 7.04 (t, J = 5.8 Hz, 1H), 6.72 (s, 1H), 4.53 - 4.44 (m, 2H), 4.44-4.27 (m, 2H), 3.80 (tt, J = 11.9, 3.9 Hz, 1H), 3.36-3.31 (m,1H), 2.87 (dd,. Petition 870260063816, on 06 / 29 / 2026, page. 235 / 739 228 / 315 Exemplo Estrutura / nome Dados J= 18,4, 7,6Hz, 1H), 2,61-2,51 (m, 1H), 2,26 (qd, J= 12,6, 4,0Hz, 1H), 1,98 (d, J= 11,6Hz, 1H), 1,86 (d, J= 13,3Hz, 1H), 1.62 (dtd, J = 13.0, 9.3, 4.0 Hz, 1H), 1.02 - 0.91 (m, 2H), 0.88 - 0.77 (m, 2H). 288 Λ θ i H 11 JL AF^Al Ov Οξ 2-[(3R)-3-(1-ciclopropil{[(4-chloro-2fluoro-5- metilfenil)metil]carbamoil}amino)pi peridin-1-il]-1,3-oxazol-4carboxilato de etila LC-MS: 479 m / z (M+H). 1H RMN (400 MHz, MeOD) δ 7.99 (s, 1H), 7.25 (d, J = 8.0 Hz, 1H), 7.13 (d, J = 9.8 Hz, 1H), 4.38 (s, 2H), 4.30 (q, J = 7.1 Hz, 2H), 4.03 (dd, J = 12.4, 4.0 Hz, 2H), 3.82 - 3.69 (m, 1H), 3.46 - 3.37 (m, 1H), 2.97 - 2.87 (m, 1H), 2.61 2.51 (m, 1H), 2.32 (s, 3H), 2.22 - 2.10 (m, 1H), 1.95 - 1.82 (m, 2H), 1.72 1.58 (m, 1H), 1.36 - 1.29 (m, 3H), 0.99 - 0.89 (m, 2H), 0.81 - 0.72 (m, 2H). 289 ON / nvna / 1 / ) 1-ciclopropil-3-{[3-(3-metoxifenil)1,2-oxazol-5-il]metil}-1-[(3R)-1(piridazin-3-il)piperidin-3-il]ureia LC-MS: 449 m / z (M+H).1H RMN (400 MHz, MeOD) δ 8,42 (dd, J = 4,3, 1,0 Hz, 1H), 7,42 - 7,34 (m, 4H), 7,29 (dd, J = 9,4, 1,2 Hz, 1H), 7,16 (t, J = 5,9 Hz, 1H), 7,06 - 6,99 (m, 1H), 6,66 (s, 1H), 4,55 (d, J = 5,7 Hz, 2H), 4,42 - 4,30 (m, 2H), 3,84 (s, 3H), 3,78 (ddd, J = 15,8, 7,9, 4,0 Hz, 1H), 3,36 3,32 (m, 1H), 2,89 (td, J = 13,0, 2,7 Hz, 1H), 2,62 - 2,54 (m, 1H), 2,25 (td, J = 12,5, 4,1 Hz, 1H), 1,92 (dd, J = 46,8, 12,7 Hz, 2H), 1,70 - 1,55 (m, 1H), 1,03 - 0,95 (m, 2H), 0,84 (dd, J = 7,9, 4,4 Hz, 2H). Procedimento Geral M: Petição 870260063816, de 29 / 06 / 2026, pág. 236 / 739 229 / 315 R NCO M1 TEA, DCM 20% Piperdina / DMF M3 Etapa 1

[00262] A solution of compound (R)-3 (cyclopropylamino)piperidine-1-carboxylate of (9H-fluoren-9-yl)methyl (1 eq.) and TEA (3 eq.) in anhydrous DCM was added dropwise to a solution of compound M1 (1 eq.) in anhydrous DCM at 0°C under a N2 atmosphere. The resulting mixture was stirred at 0°C for 1 hour under a N2 atmosphere. Then, the mixture was diluted with water and extracted twice with EtOAc. The combined organic layers were washed with brine, dried with anhydrous Na2SO4, filtered, and concentrated to dryness. The residue was purified by flash column chromatography (eluted with heptane / ethyl acetate) to yield compound M2. Step 2

[00263] M2 (1 eq) was dissolved in 20% Piperidine / DMF (0.1 M) and the reaction mixture was stirred at room temperature for 1-2 hours. The reaction mixture was then concentrated under vacuum and the crude product was purified by flash column chromatography using DCM / DCM:7N NH4 MeOH (10:0 to 0:10) to provide product M3. Step 3

[00264] M3 (1 eq), the appropriate carboxylic acid M4 (1.2 eqs) and HATU (1.3 eqs) were dissolved in DMF (0.1 M), then DIEA (2 eqs) was added and the reaction was stirred at room temperature until complete conversion. Water was added and the reaction mixture was extracted twice with DCM. The combined organic layers were dried with anhydrous Na2SO4, filtered and concentrated under vacuum. The crude product was purified. Petition 870260063816, dated 06 / 29 / 2026, pp. 237 / 739 230 / 315 by preparatory HPLC to generate the M5 product. Synthesis of 1-cyclopropyl-1-[(3R)-1-(2-hydroxyacetyl)piperidin-3-yl]-3[(3-phenyl-1,2-oxazol-5-yl)methyl]urea, Example 290 X1 20% Piperdine / DMF °~N X2 HATU, DIEA DMF Example 290

[00265] To a solution of (R)-3-(cyclopropylamino)piperidine-1-carboxylate of (9H-fluoren-9-yl)methyl (400 mg, 1.10 mmol) and TEA (0.460 mL, 3.30 mmol) in anhydrous DCM (11 mL) was added a solution of 5-(isocyanatomethyl)-3-phenylisoxazole (220 mg, 1.10 mmol) in anhydrous DCM (5.5 mL) at 0°C in drops under a N2 atmosphere. The resulting mixture was stirred at 0°C for 1 hour under a N2 atmosphere. Then, the mixture was diluted with water and extracted twice with EtOAc. The combined organic layers were washed with brine, dried with anhydrous Na2SO4, filtered, and concentrated to dryness. The residue was purified by flash column chromatography (eluted with heptane / ethyl acetate) to yield X1 (280 mg, 45% yield). X1 (280 mg, 0.498 mmol) was dissolved in 20% piperidine / DMF (4.98 mL) and the reaction mixture was stirred at room temperature for 1 hour.The reaction mixture was then concentrated under vacuum and the crude product was purified by flash column chromatography using DCM / DCM:7N NH4 MeOH (10 / 0 to 0 / 10) to yield X2 (150 mg, 88% yield). X2 (20 mg, 0.06 mmol), 2-hydroxyacetic acid (5.4 mg, 0.072 mmol) and HATU (29 mg, 0.076 mmol) were dissolved in DMF (0.56 mL), then DIEA (21 µL, 0.12 mmol) was added and the reaction was stirred at room temperature for 5 minutes. Water was added and the reaction mixture was extracted with DCM twice. The combined organic layers were dried with anhydrous Na2SO4, filtered, and concentrated under vacuum. The crude product was... Petition 870260063816, dated 06 / 29 / 2026, pp. 238 / 739 231 / 315 purified by preparative HPLC to generate Example 290 (11 mg, 47% yield) as a white powder. LC / MS (ESI) m / z: 399.1 (M+H)+.

[00266] The examples below were prepared by the Procedure General M Exemplo Structure / name Dados 291 AAâVi 1 à 1-[(4-chloro-2-fluoro-5-methylphenyl)methyl]3-cyclopropyl-3-[(3R)-1-(2oxopyrrolidina-3-carbonyl)piperidin-3yl]ureia LC-MS: m / z 451 (M+H). 1H NMR (400 MHz, MeOD) δ 7.28 - 7.20 (m, 1H), 7.13 (dd, J = 9.8, 3.8 Hz, 1H), 6.91 (s, 1H), 6.83 (dd, J = 11.8, 5.9 Hz, 1H), 4.53 (d, J = 12.3 Hz, 1H), 4.45 - 4.31 (m, 2H), 4.12 (dd, J = 25.2, 12.2 Hz, 1H), 4.01 - 3.88 (m, 1H), 3.87 - 3.59 (m, 1H), 3.59 - 3.32 (m, 3H), 3.26 2.94 (m, 1H), 2.64 - 2.54 (m, 1H), 2.51 - 2.44 (m, 1H), 2.38 - 2.14 (m, 5H), 1.99 - 1.77 (m, 2H), 1.62 1.37 (m, 1H), 1.03 - 0.88 (m, 2H), 0.87 - 0.60 (m, 2H). 292 i·»·] OF LC-MS: m / z 486 (M+H).1H RMN (400 MHz, MeOD) δ 7,27 - 7,21 (m, 1H), 7,13 (dd, J = 9,8, 2,5 Hz, 1H), 4,54 (dd, J = 39,0, 7,8 Hz, 2H), 4,44 - 4,33 (m, 2H), 4,12 (d, J = 12,9 Hz, 1H), 3,88 - 3,81 (m, 1H), 3,51 - 3,44 (m, 1H), 3,26 (s, 1H), 3,22 - 3,01 (m, 3H), 2,74 2,43 (m, 3H), 2,32 (s, 3H), 2,30 2,21 (m, 2H), 2,18 - 2,12 (m, 1H), 2,01 (s, 1H), 1,90 - 1,77 (m, 2H), 1,55 - 1,44 (m, 1H), 0,99 - 0,89 (m, 2H), 0,82 - 0,68 (m, 2H). Petição 870260063816, de 29 / 06 / 2026, pág. 239 / 739 232 / 315 Exemplo Estrutura / nome Dados 293 H 1 À Ϋ- 1-[(4-cloro-2-fluoro-5-metilfenil)metil]3-ciclopropil-3-[(3R)-1-(5oxopirrolidina-3-carbonil)piperidin-3il]ureia LC-MS: m / z 451 (M+H). 1H RMN (400 MHz, MeOD) δ 7,29 - 7,21 (m, 1H), 7,13 (dd, J = 9,8, 4,6 Hz, 1H), 4,49 (t, J = 14,4 Hz, 1H), 4,44 - 4,32 (m, 2H), 3,91 (t, J = 14,0 Hz, 1H), 3,85 - 3,65 (m, 2H), 3,60 - 3,42 (m, 2H), 3,30 - 3,21 (m, 1H), 3,19 - 3,08 (m, 1H), 3,07 2,93 (m, 1H), 2,68 - 2,58 (m, 1H), 2,58 - 2,50 (m, 2H), 2,50 - 2,44 (m, 1H), 2,32 (s, 3H), 2,19 (dtd, J = 8,6, 6,8, 4,5 Hz, 1H), 2,03 (s, 1H), 2,02 - 1,79 (m, 2H), 1,57 - 1,43 (m, 1H), 1,03 - 0,87 (m, 2H), 0,86 - 0,64 (m, 2H). 294 1 A 1-[(4-cloro-2-fluoro-5-metilfenil)metil]3-ciclopropil-3-[(3R)-1-(1-metil-2oxopirrolidina-3-carbonil)piperidin-3il]ureia LC-MS: m / z 465 (M+H).1H RMN (400 MHz, MeOD) δ 7,24 (t, J = 7,0 Hz, 1H), 7,13 (dd, J = 9,8, 3,2 Hz, 1H), 4,51 (d, J = 12,9 Hz, 1H), 4,41 - 4,31 (m, 2H), 4,15 3,92 (m, 2H), 3,78 (d, J = 25,7 Hz, 1H), 3,64 - 3,37 (m, 3H), 3,21 - 2,93 (m, 1H), 2,87 - 2,80 (m, 3H), 2,59 - 2,46 (m, 2H), 2,42 - 2,34 (m, 1H), 2,31 (s, 3H), 2,28 - 2,14 (m, 2H), 1,95 - 1,77 (m, 2H), 1,64 1,35 (m, 1H), 0,98 - 0,67 (m, 4H). 295 ÔeOeÂY T A H V“ 1-[(4-cloro-2-fluoro-5-metilfenil)metil]- LC-MS: m / z 454 (M+H). 1H RMN (400 MHz, MeOD) δ 7,29 - 7,21 (m, 1H), 7,13 (dd, J = 9,8, 3,8 Hz, 1H), 4,48 - 4,33 (m, 4H), 3,98 (dd, J = 44,7, 12,1 Hz, 1H), 3,86 - 3,74 (m, 3H), 3,73 - 3,67 (m, 2H), 3,66 - 3,55 (m, 2H), 3,51 (dd, J. Petição 870260063816, de 29 / 06 / 2026, pág. 240 / 739 233 / 315 Example Structure / Name of 3-ciclopropil-3-[(3R)-1-[(2S)-1,4dioxano-2-carbonil]piperidin-3-il]ureia = 11.4, 6.5 Hz, 1H), 3.17 - 2.92 (m, 1H), 2.60 - 2.52 (m, 1H), 2.48 (dd, J = 13.0, 2.7 Hz, 1H), 2.32 (s, 3H), 2.30 - 2.17 (m, 1H), 1.94 - 1.77 (m, 2H), 1.60 - 1.37 (m, 1H), 0.99 0.87 (m, 2H), 0.83 - 0.68 (m, 2H). 296 o^\f JL___. Jk NN íl ° AH Va 1-[(4-chloro-2-fluoro-5-metilfenil)metil]- 3-ciclopropil-3-[(3R)-1-(oxetano-3carbonil)piperidin-3-il]ureia LC-MS: m / z 424 (M+H). 1H RMN (400 MHz, MeOD) δ 7.24 (t, J = 8.1 Hz, 1H), 7.13 (dd, J = 9.8, 5.5 Hz, 1H), 4.84 - 4.76 (m, 4H), 4.53 - 4.35 (m, 3H), 4.21 - 4.14 (m, 1H), 3.71 - 3.61 (m, 1H), 3.51 (td, J = 11.8, 5.7 Hz, 1H), 3.36 (dd, J = 17.0, 8.4 Hz, 1H), 3.15 (dd, J = 23.8, 12.1 Hz, 1H), 2.90 (td, J = 13.3, 2.7 Hz, 1H), 2.57 - 2.45 (m, 2H), 2.32 (d, J = 3.2 Hz, 3H), 2.14 (ddd, J = 23.0, 13.2, 3.5 Hz, 1H), 1.97 - 1.77 (m, 2H), 1.53 - 1.39 (m, 1H), 0.94 (ddd, J = 16.0, 8.7, 4.3 Hz, 2H), 0.81 - 0.63 (m, 2H). 297 AOS í L J.rç Λ o 'V v ° À k 1-[(4-chloro-2-fluoro-5-methylphenyl)methyl]3-cyclopropyl-3-[(3R)-1-[(2R)-1,4dioxane-2-carbonyl]piperidin-3-yl]urea LC-MS: m / z 454 (M+H). 1H NMR (400 MHz, CDCI3) δ 7.21 (dd, J = 17.7, 8.0 Hz, 1H), 7.08 (dd, J = 9.6, 6.9 Hz, 1H), 5.80 - 5.64 (m, 1H), 4.58 - 4.24 (m, 4H), 4.06 3.59 (m, 8H), 3.37 - 3.17 (m, 2H), 2.91 (t, J = 11.7 Hz, 1H), 2.56 2.33 (m, 2H), 2.31 (d, J = 2.6 Hz, 3H), 1.96 - 1.75 (m, 2H), 1.59 1.47 (m, 1H), 0.94 - 0.66 (m, 4H). Petition 870260063816, dated 06 / 29 / 2026, p. 241 / 739 234 / 315 Exemplo Estrutura / nome Dados 298 f ''l 0 4) à H Ak ^c> 1-[(3R)-1-(3-aminooxolano-3carbonil)piperidin-3-il]-3-[(4-chloro-2fluoro-5-metilfenil)metil]-1ciclopropilureia LC-MS: m / z 453,1 (M+H). 1H RMN (400 MHz, MeOD) δ 7.24 (d, J = 8.0 Hz, 1H), 7.13 (d, J = 9.8 Hz, 1H), 4.53 - 4.22 (m, 4H), 4.12 (dd, J = 19.6, 9.3 Hz, 1H), 4.01 3.74 (m, 3H), 3.62 (dd, J = 9.2, 4.2 Hz, 2H), 3.16 (dd, J = 24.0, 7.3 Hz, 1H), 2.54 - 2.38 (m, 2H), 2.32 (s, 3H), 2.25 - 2.15 (m, 1H), 2.00 1.77 (m, 3H), 1,53 (d, J = 11.4 Hz, 1H), 0.94 (d, J = 5.8 Hz, 2H), 0.75 (s, 2H). 299 0 0, ,N JL xx / HA AH Ao 3-[(4-chloro-2-fluoro-5-methylfenil)methyl]-1-ciclopropil-1-[(3R)-1-(3hidroxioxolano-3-carbonil)piperidin-3il]ureia LC-MS: m / z 454 (M+H).1H RMN (400 MHz, MeOD) δ 7,23 (d, J = 8,0 Hz, 1H), 7,13 (d, J = 9,8 Hz, 1H), 4,42 (d, J = 14,8 Hz, 2H), 4,37 (s, 2H), 4,24 - 4,01 (m, 1H), 4,00 - 3,82 (m, 2H), 3,77 (dd, J = 13,5, 9,6 Hz, 1H), 3,70 - 3,32 (m, 2H), 3,22 - 2,79 (m, 1H), 2,71 2,50 (m, 2H), 2,32 (s, 3H), 2,26 1,97 (m, 2H), 1,85 (d, J = 48,8 Hz, 2H), 1,49 (s, 1H), 1,01 - 0,88 (m, 2H), 0,83 - 0,68 (m, 2H). 300 0 o. JL·? Jl / n^l. i H 1 1 / \ F^\^CI ^c> 3-[(4-cloro-2-fluoro-5-metilfenil)metil]1 -[(3R)-1-(3-cianooxolano-3carbonil)piperidin-3-il]-1ciclopropilureia LC-MS: m / z 463 (M+H). 1H RMN (400 MHz, CDCI3) δ 7,19 (d, J = 8,0 Hz, 1H), 7,12 - 7,05 (m, 1H), 5,76 (d, J = 29,9 Hz, 1H), 4,59 - 4,45 (m, 1H), 4,41 - 4,22 (m, 4H), 3,98 (ddd, J = 27,0, 12,5, 4,7 Hz, 3H), 3,68 (t, J = 11,1 Hz, 2H), 3,49 - 3,28 (m, 1H), 3,10 (d, J = 13,1 Hz, 1H), 2,90 - 2,68 (m, 1H), 2,58 - 2,47 (m, 2H), 2,29 (d, J = 25,8 Hz,. Petição 870260063816, de 29 / 06 / 2026, pág. 242 / 739 235 / 315 Exemplo Estrutura / nome Dados 4H), 1.93 - 1.82 (m, 2H), 1.57 1.47 (m, 1H), 0.87 (dd, J = 13.1.6.8 Hz, 3H), 0.76 (d, J = 19.4 Hz, 1H). 301 Z\ 0 F 0. JL _____ JL — 0 N Ti A T3 AH Ve, ^C> 1 3-[(4-chloro-2-fluoro-5-metilfenil)metil]1-ciclopropil-1-[(3R)-1-[3(metoximetil)oxolano-3carbonil]piperidin-3-il]ureia LC-MS: m / z 482 (M+H). 1H RMN (400 MHz, CDCI3) δ 7.20 (dd, J = 8.0, 2.6 Hz, 1H), 7.08 (d, J = 9.7 Hz, 1H), 5.73 (t, J = 5.6 Hz, 1H), 4.39 (d, J =5.9 Hz, 2H), 4.04 3.75 (m, 5H), 3.56 (d, J = 8.0 Hz, 1H), 3.49 (q, J = 8.9 Hz, 2H), 3.35 (d, J = 4.6 Hz, 3H), 3.23 (t, J = 11.3 Hz, 1H), 2.46 (s, 1H), 2.31 (s, 3H), 2,29 - 2.14 (m, 2H), 1.99 (dt, J = 13.3, 8.1 Hz, 1H), 1.86 (d, J = 11.6 Hz, 1H), 1.77 (dd, J = 13.6, 2.6 Hz, 1H), 1.62 (s, 3H), 1.53 - 1.42 (m, 1H), 0.88 (d, J = 6.0 Hz, 2H), 0.75 (d, J = 12.6 Hz, 2H). 302 y N—\r-^-N HN F / Q Cl 3-[(4-chloro-2-fluoro-5-metilfenil)metil]1-ciclopropil-1-[(3R)-1-{2oxabiciclo[2.1.1 ]hexano-4carbonil}piperidin-3-il]ureia LC-MS: m / z 450.1 (M+H).1H NMR (400 MHz, MeOD) δ 7.28 - 7.20 (m, 1H), 7.13 (d, J = 9.8 Hz, 1H), 4.54 - 4.30 (m, 4H), 3.86 (dd, J = 33.0, 5.6 Hz, 1H), 3.78 - 3.46 (m, 3H), 3.28 (d, J = 10.9 Hz, 1H), 3.07 (dt, J = 24.5, 12.7 Hz, 1H), 2.56 2.47 (m, 1H), 2.31 (s, 3H), 2.24 2.07 (m, 3H), 1.97 - 1.76 (m, 4H), 1.48 (qd, J = 13.3, 6.6 Hz, 1H), 1.00 - 0.87 (m, 2H), 0.73 (ddd, J = 25.6, 15.2, 8.2 Hz, 2H). Petition 870260063816, dated 06 / 29 / 2026, p. 243 / 739 236 / 315 Example Data Structure / Name 303 <a o -n. a? jl °73 â aa ^c>3-[(4-chloro-2-fluoro-5-metilfenil)metil]1-ciclopropil-1-[(3R)-1-(3metoxioxolano-3-carbonil)piperidin-3il]ureia LC-MS: m / z 468 (M+H). 1H RMN (400 MHz, MeOD) δ 7.24 (d, J = 8.1 Hz, 1H), 7.13 (d, J = 9.7 Hz, 1H), 6.85 (s, 1H), 4.49 (t, J= 13.0Hz, 1H), 4.38 (s,3H), 4.06 (d, J= 9.8Hz, 1H), 3.97-3.85 (m, 2H), 3.82 (dt, J= 8.2, 4.1Hz, 1H), 3.51 (dd, J = 47.8, 10.0 Hz, 1H), 3.26 3.22 (m, 3H), 3.16 - 2.89 (m, 1H), 2.61 - 2.43 (m, 3H), 2.32 (s, 3H), 2.21 (dd, J = 16.7, 11.4 Hz, 2H), 1.94 - 1.81 (m, 2H), 1.58 - 1.44 (m, 1H), 0.98 - 0.90 (m, 2H), 0.75 (s, 2H). 304 VHA ° Ο-ΖΛ / 1-ciclopropil-3-{[3-(3-metoxifenil)-1,2oxazol-5-il]metil}-1-[(3R)-1-[(2S)oxolano-2-carbonil]piperidin-3-il]ureia LC-MS: m / z 469 (M+H).1H RMN (400 MHz, MeOD) δ 7,38 (dd, J = 4,4, 1,8 Hz, 3H), 7,21 (s, 1H), 7,05 - 7,00 (m, 1H), 6,65 (d, J = 6,9 Hz, 1H), 4,69 - 4,34 (m, 4H), 3,92 (ddd, J = 21,4, 13,8, 6,4 Hz, 3H), 3,84 (d, J = 6,6 Hz, 3H), 3,79 (d, J=6,1Hz, 1H), 3,56 - 3,32 (m, 1H), 3,08 (t, J=47,9Hz, 1H), 2,51 (dd, J=6,8, 2,9Hz, 1H), 2,32-2,14 (m, 2H), 2,05 - 1,84 (m, 5H), 1,63 1,43 (m, 1H), 1,06 - 0,94 (m, 2H), 0,85 - 0,73 (m, 2H). 305 I o o x >° LC-MS: m / z 424 (M+H). 1H RMN (400 MHz, CDCI3) δ 7,21 (d, J = 8,0 Hz, 1H), 7,07 (d, J = 9,7 Hz, 1H), 5,74 (t, J = 5,8 Hz, 1H), 4,48 (t, J = 13,6 Hz, 2H), 4,39 (d, J = 5,9 Hz, 2H), 3,75 (s, 1H), 3,10 (t, J = 11,8 Hz, 1H), 2,61 (s,1H), 2,45-. Petição 870260063816, de 29 / 06 / 2026, pág. 244 / 739 237 / 315 Exemplo Estrutura / nome Dados 3-[(4-chloro-2-fluoro-5-metilfenil)metil]1 -ciclopropil-1-[(3R)-1-(1hidroxiciclopropanocarbonil)piperidin3-il]ureia 2.38 (m, 1H), 2.31 (s, 3H), 2,232.12 (m, 1H), 1.97 (d, J= 11.8Hz, 1H), 1.81 (d, J= 13.5Hz, 1H), 1.58 (dt, J= 13.2, 4.1Hz, 1H), 1.15 (d, J= 7.4Hz, 1H), 1.00-0.86 (m, 5H), 0.75 (t, J = 4.3 Hz, 2H). 306 cl^fF V 0 0 HO 3-[(4-chloro-2-fluoro-5-metilfenil)metil]1 -ciclopropil-1-[(3R)-1-(2-hidroxi-2metilpropanoil)piperidin-3-il]ureia LC-MS: m / z 426 (M+H). 1H RMN (400 MHz, CDCI3) δ 7.20 (d, J = 8.0 Hz, 1H), 7.08 (d, J = 9.7 Hz, 1H), 5.74 (t, J = 5.7 Hz, 1H), 4.80 - 4.10 (m, 5H), 3.45 (dd, J = 78.1.29.3 Hz, 2H), 2.46 (s, 1H), 2.31 (s, 3H), 2.25 (d, J = 11.1 Hz, 1H), 1.93 - 1.78 (m, 3H), 1.53 (s, 3H), 1.48 (s, 3H), 0.89 (t, J = 5.8 Hz, 2H), 0.74 (s, 2H). 3071H RMN (400 MHz, MeOD) δ 7,24 (d, J = 8,0 Hz, 1H), 7,13 (d, J = 9,8 Hz, 1H), 6,85 (s, 1H), 4,41 (dd, J = 27,0, 12,4 Hz, 3H), 4,24 - 3,87 (m, 5H), 3,79 - 3,40 (m, 2H), 3,15 (dd, J = 49,8, 38,8 Hz, 1H), 2,76 - 2,43 (m, 3H), 2,32 (s, 3H), 2,23 (d, J = 13,1 Hz, 1H), 1,99 - 1,79 (m, 2H), 1,51 (d, J = 13,4 Hz, 1H), 0,94 (s, 2H), 0,74 (d, J = 10,6 Hz, 2H). 308 S Λ H AA A V Cl 3-[(4-cloro-2-fluoro-5-metilfenil)metil]- LC-MS: m / z 451 (M+H). 1H RMN (400 MHz, MeOD) δ 9,11 (s, 1H), 8,25 (s, 1H), 7,23 (d, J = 8,0 Hz, 1H), 7,12 (d, J = 9,8 Hz, 1H), 6,85 (s, 1H), 4,61 - 4,02 (m, 4H), 3,85 - 3,57 (m, 1H), 3,50 - 3,35 (m,. Petição 870260063816, de 29 / 06 / 2026, pág. 245 / 739 238 / 315 Example Structure / Name of the molecule 1-cyclopropyl-1-[(3R)-1-(1,3-tiazol-5carbonyl)piperidin-3-il]urea 1H), 3.11 - 2.67 (m, 1H), 2.60 - 2.44 (m, 1H), 2.32 - 2.21 (m, 4H), 2.02 - 1.82 (m, 2H), 1.61 (dd, J = 26.3, 13.2 Hz, 1H), 0.94 (d, J = 6.4 Hz, 2H), 0.81 - 0.56 (m, 2H). 309 < Ί 0 0. .N. Jj? JL __________ / 'V Ã H fXXi 3-[(4-chloro-2-fluoro-5-metilfenil)metil]- 1 -ciclopropil-1-[(3R)-1-(1metilciclopropanocarbonil)piperidin-3il]ureia LC-MS: m / z 422 (M+H). 1H RMN (400 MHz, MeOD) δ 7.24 (d, J = 8.0 Hz, 1H), 7.13 (d, J = 9.8 Hz, 1H), 4.36 (t, J = 9.9 Hz, 4H), 3.71 - 3.54 (m, 1H), 3.29 - 3.02 (m, 1H), 2.53 (ddd, J = 10.4, 6.7, 3.9 Hz, 1H), 2.32 (s, 3H), 2.19 (qd, J = 12.6, 4.1 Hz, 1H), 1.87 (dd, J = 28.7, 12.7 Hz, 2H), 1.57 - 1.41 (m, 1H), 1,38 - 1,12 (m, 4H), 0,98 0,83 (m, 4H), 0,75 (s, 2H), 0,60 (d, J = 1,4 Hz, 2H). 310 0 A 3-[(4-chloro-2-fluoro-5-metilfenil)metil]1-[(3R)-1ciclopropanocarbonilpiperidin-3-il]-1ciclopropilureia LC-MS: m / z 408 (M+H).1H RMN (400 MHz, MeOD) δ 7,32 - 7,19 (m, 1H), 7,13 (d, J = 9,6 Hz, 1H), 4,44 (d, J = 9,3 Hz, 1H), 4,38 (d, J = 8,7 Hz, 2H), 4,32 - 4,22 (m, 1H), 3,75 (d, J = 11,4 Hz, 1H), 3,56 - 3,35 (m, 1H), 3,20 - 2,98 (m, 1H), 2,52 (d, J = 11,0 Hz, 2H), 2,31 (s, 3H), 2,26 - 2,14 (m, 1H), 2,01 - 1,75 (m, 3H), 1,63 - 1,40 (m, 1H), 1,02 - 0,90 (m, 2H), 0,88 - 0,75 (m, 5H), 0,72 (s, 1H). Petição 870260063816, de 29 / 06 / 2026, pág. 246 / 739 239 / 315 Example Structure / name Dice 311 CL JL \7 Ai A ν zxoh H 1 1 L xjX χΝ. x\ Jx [JN ° FO k,___J 3-[(4-chloro-2-fluoro-5-methylphenyl)methyl]- 1-cyclopropyl-1-[(3R)-1-(3hydroxypropanoyl)piperidin-3-yl]urea LC-MS: m / z +H 412).,1 (M). 1H NMR (400 MHz, MeOD) δ 7.24 (t, J = 7.6 Hz, 1H), 7.13 (dd, J = 9.8, 3.7 Hz, 1H), 6.85 (dt, J = 11.7, 5.6 Hz, J = 11 (t, 4), 4.36 (dd, J = 9.8, 5.9 Hz, 2H), 3.93 (t, J = 11.6 Hz, 1H), 3.79 (dt, J = 16.1, 5.4 Hz, 2H), 3.75 − m 3.44 (m, 3, 31H), − 3.16 2.90 (m, 1H), 2.79 - 2.61 (m, 1H), 2.59 - 2.49 (m, 2H), 2.32 (s, 3H), 2.26 - 2.09 (m, 1H), 1.49 - 1.73 (m, 1H), 1.49 - 1.73 (m, 1H), 0.94 (ddd, J = 16.8, 10.1,4.6 Hz, 2H), 0.74 (dddd, J = 12.3, 8.4, 5.6, 2.2 Hz, 2H). 312 what is it ? F 0 3-[(4-chloro-2-fluoro-5-methylphenyl)methyl]1-cyclopropyl-1-[(3R)-1-(2hydroxyacetyl)piperidin-3-yl]urea LC-MS: m / z 398 (M+H).1H RMN (400 MHz, MeOD) δ 7,28 - 7,21 (m, 1H), 7,13 (d, J = 9,6 Hz, 1H), 4,59 - 4,33 (m, 3H), 4,31 4,13 (m, 2H), 3,73 - 3,48 (m, 2H), 3,26 (d, J = 12,5 Hz, 1H), 3,17 - 2,86 (m, 1H), 2,57 - 2,49 (m, 1H), 2,32 (s, 3H), 2,18 (dd, J = 24,7, 14,2 Hz, 1H), 1,99 - 1,76 (m, 2H), 1,58 - 1,42 (m, 1H), 1,01 - 0,84 (m, 2H), 0,75 (dd, J = 21,6, 8,8 Hz, 2H). 313 OAS A ΟΧ o Ο-ΖΛ / \== / 1-ciclopropil-3-{[3-(3-metoxifenil)-1,2- LC-MS: m / z 469 (M+H). 1H RMN (400 MHz, MeOD) δ 7,44 - 7,33 (m, 3H), 7,22 - 7,07 (m, 1H), 7,03 (ddd, J = 6,5, 4,2, 2,6 Hz, 1H), 6,66 (d, J = 7,7 Hz, 1H), 4,57 - 4,48 (m, 4H), 4,04 - 3,86 (m, 3H), 3,85 (s, 3H), 3,84 - 3,71 (m, 3H), 3,55 -. Petição 870260063816, de 29 / 06 / 2026, pág. 247 / 739 240 / 315 Example Structure / Name of oxazol-5-il]methyl}-1-[(3R)-1-[(3R)- oxolano-3-carbonil]piperidin-3-il]ureia 3.44 (m, 1H), 3.43 - 3.32 (m, 1H), 3.05 (ddd, J = 24.4, 18.5, 11.6 Hz, 1H), 2.60 - 2.52 (m, 1H), 2.25 - 2.05 (m, 3H), 1.99 - 1.78 (m, 2H), 1.55 - 1.41 (m, 1H), 1.03 - 0.91 (m, 2H), 0.87 - 0.72 (m, 2H). 314 VH Ã ° o 1-ciclopropil-1-[(3R)-1-[(3R)-oxolano-3carbonil]piperidin-3-il]-3-[(3-fenil-1,2oxazol-5-il)methyl]ureia LC-MS: m / z 439 (M+H). 1H RMN (400 MHz, CDCI3) δ 7.79 (dd, J = 6.5, 2.9 Hz, 2H), 7.48 - 7.42 (m, 3H), 6.50 (s, 1H), 5.87 (s, 1H), 4.60 (d, J = 4.4 Hz, 2H), 3.97 (d, J = 8.1 Hz, 1H), 3.92 - 3.79 (m, 4H), 3.29 - 3.15 (m, 2H), 2.68 - 2.01 (m, 5H), 1.92 (s, 1H), 1.82 (d, J = 13.2 Hz, 1H), 1.68 (s, 2H), 1.48 (s, 1H), 0.88 (d, J = 56.6 Hz, 4H). 314A a^F À ° 1-[(4-chloro-2-fluoro-5-methylfenil)methyl]3-ciclopropil-3-[(3R)-1-[(3R)-oxolano-3carbonil]piperidin-3-il]ureia LC-MS: m / z 438 (M+H).1H RMN (400 MHz, MeOD) δ 7,24 (t, J = 8,5 Hz, 1H), 7,13 (dd, J = 9,8, 4,8 Hz, 1H), 6,86 (d, J = 23,0 Hz, 1H), 4,42 (dt, J = 26,8, 12,8 Hz, 3H), 4,04 - 3,72 (m, 6H), 3,45 (dt, J = 14,7, 9,6 Hz, 2H), 3,27 (d, J= 12,4Hz, 1H), 3,12 (t, J= 11,8Hz, 1H), 2,99 (t, J= 12,1Hz, 1H), 2,592,43 (m, 2H), 2,28 (d, J= 25,5Hz, 3H), 2,22-2,00 (m, 3H), 1,99-1,78 (m, 2H), 1,55-1,35 (m, 1H), 1,040,84 (m, 2H), 0,82 - 0,60 (m, 2H). Petição 870260063816, de 29 / 06 / 2026, pág. 248 / 739 241 / 315 Exemplo Estrutura / nome Dados 315 cMF λ 0 1-[(4-chloro-2-fluoro-5-metilfenil)metil]3-ciclopropil-3-[(3R)-1-[(2S)-oxolano-2carbonil]piperidin-3-il]ureia LC-MS: m / z 438.1 (M+H). 1H RMN (400 MHz, MeOD) δ 7.24 (t, J = 7.9 Hz, 1H), 7.13 (dd, J = 9.8, 4.4 Hz, 1H), 6.85 (dt, J = 18.8, 5.7 Hz, 1H), 4.70 (dd, J = 9.8, 4.0 Hz, 1H), 4.52 - 4.32 (m, 3H), 4.02 3.87 (m, 2H), 3.86 - 3.73 (m, 2H), 3.48 (ddd, J = 15.6, 7.9, 3.9 Hz, 1H), 3.26 (s, 1H), 3.13 (t, J = 11.8 Hz, 1H), 2.99 - 2.85 (m, 1H), 2.61-2.45 (m, 2H), 2.32 (s, 3H), 2.28-2.11 (m, 2H), 2.05-1.79 (m, 5H), 1.62-1.40 (m, 1H), 1.00-0.86 (m, 2H), 0.84-0.64 (m, 2H). 316 A hat 1-[(4-chloro-3-methylfenil)methyl]-3ciclopropil-3-[(3R)-1-[(3R)-oxolano-3carbonil]piperidin-3-il]ureia LC-MS: m / z 420 (M+H).1H RMN (400 MHz, MeOD) δ 7,27 (dt, J = 14,1, 7,0 Hz, 1H), 7,21 (d, J = 6,9 Hz, 1H), 7,10 (dd, J = 10,9, 4,5 Hz, 1H), 6,91 (d, J = 29,3 Hz, 1H), 4,55 - 4,43 (m, 1H), 4,40 4,27 (m, 2H), 3,86 (dddd, J = 19,0, 17,4, 14,8, 11,4 Hz, 6H), 3,53 3,38 (m, 2H), 3,27 (d, J = 12,0 Hz, 1H), 3,13 (t, J = 11,9 Hz, 1H), 2,99 (t, J = 13,1 Hz, 1H), 2,57 - 2,46 (m, 2H), 2,34 (s, 3H), 2,25 - 2,04 (m, 3H), 2,01 - 1,80 (m, 2H), 1,55 1,37 (m, 1H), 0,98 - 0,86 (m, 2H), 0,83 - 0,61 (m, 2H). Procedimento Geral N: Petição 870260063816, de 29 / 06 / 2026, pág. 249 / 739 242 / 315 TEA, DCM R^NCO N1 N2 PhSH K2CO3, DMF HATU, DIEA DMF N5

[00267] A solution of compound (R)-N-cyclopropyl-1-((2-nitrophenyl)sulfonyl)piperidin-3-amine (1 eq.) and TEA (3 eq.) in anhydrous DCM was added dropwise to a solution of compound N1 (1 eq.) in anhydrous DCM at 0°C under a N2 atmosphere. The resulting mixture was stirred at 0°C for 1 hour under a N2 atmosphere. Then, the mixture was diluted with water and extracted twice with EtOAc. The combined organic layers were washed with brine, dried with anhydrous Na2SO4, filtered, and concentrated to dryness. The residue was purified by flash column chromatography (eluted with heptane / ethyl acetate) to yield compound N2. N2 (1 eq) was dissolved in DMF (0.1 M) followed by potassium carbonate (2 eqs) and thiophenol (1.5 eqs), and the reaction mixture was stirred at room temperature for 1-2 hours. 1 M HCl was added until pH 2-3, and the resulting mixture was extracted twice with DCM. The acidic solution was then brought to pH 10-11 by a careful addition of 6 N NaOH.The resulting basic solution was then extracted with DCM (x3). The combined organic layers were dried with Na2SO4, filtered, and concentrated under vacuum. Crude N3 was used directly for the next step without any further purification. N3 (1 eq), the appropriate carboxylic acid N4 (1.2 eqs), and HATU (1.3 eqs) were dissolved in DMF (0.1 M), then DIEA (2 eqs) was added, and the reaction was stirred at room temperature until complete conversion. Water was added, and the reaction mixture was extracted with DCM twice. The combined organic layers were dried with anhydrous Na2SO4, filtered, and concentrated under vacuum. The crude product was purified by... Petition 870260063816, dated 06 / 29 / 2026, page 250 / 739 243 / 315 Preparatory HPLC for generating product N5. General procedure O: GDI, DMFR1xn,R2 H 02

[00268] O1 was synthesized using Procedure M or N O3 synthesis

[00269] The appropriate amine O2 (2 eqs) and CDI (2 eqs) were dissolved in DMF (0.1 M) and the reaction was stirred at room temperature for 2-3 hours. Then, O1 (1 eq) was added and the reaction was stirred at 50°C until complete conversion (1 to 4 hours). The reaction mixture was concentrated under vacuum and the crude product was purified by preparative HPLC to generate the product O3. Synthesis of (3R)-N-cyclopropyl-3-(3-cyclopropyl{[(4-chloro-2-fluoro-5-methylphenyl)methyl]carbamoyl}amino)piperidine-1-carboxamide, (Example 317) X1 Example 317 Cyclopropylamine (8.3 µL, 0.12 mmol) and CDI (19.5 mg, 0.12 mmol) were dissolved in DMF and the reaction was stirred at room temperature for 2 hours. Then, X1 (20 mg, 0.06 mmol) was added and the reaction was heated to 50°C and stirred for 2 hours. The reaction mixture was then cooled to room temperature and concentrated under vacuum. The crude product was purified by preparative HPLC to yield X1 (10 mg, 39% yield) as a white powder. LC / MS (ESI) m / z: 423.1 (M+H)+. 1H NMR (400 MHz, MeOD) δ 7.24 (d, J = 8.0 Hz, 1H), 7.13 (d, J = 9.8 Hz, 1H), 6.86 (t, J = 5.7 Hz, 1H), 4.37 (t, J = 4.7 Hz, 2H), 3.96 (d, J = 12.8 Hz, 1H), 3.84 (d, J = 12.5 Hz, 1H), 3.61 (ddd, J = 11.8, 7.9, 4.1 Hz, 1H), Petition 870260063816, dated 06 / 29 / 2026, p. 251 / 739 244 / 315 3,13 - 3,06 (m, 1H), 2,61 (td, J = 13,0, 2,4 Hz, 1H), 2,55 - 2,47 (m, 2H), 2,32 (s, 3H), 2,07 (td, J = 12,5, 3,8 Hz, 1H), 1,87 (d, J = 11,6 Hz, 1H), 1,74 (d, J = 13,0 Hz, 1H), 1,47 (dt, J = 13,3, 4,2 Hz, 1H), 0,96 - 0,89 (m, 2H), 0,73 (d, J = 3,6 Hz, 2H), 0,66 - 0,60 (m, 2H), 0,47 - 0,40 (m, 2H). Exemplo Estrutura / nome Dados 318 ciy 441 (M+H). 1H RMN (400 MHz, MeOD) δ 7.24 (d, J = 8.0 Hz, 1H), 7.13 (d, J = 9.8 Hz, 1H), 4.43 - 4.30 (m, 2H), 4.00 3.84 (m, 2H), 3.66 - 3.56 (m, 1H), 3.45 - 3.40 (m, 2H), 3.33 (s, 3H), 3.31 - 3.28 (m, 2H), 3.19 - 3.08 (m, 1H), 2.68 - 2.57 (m, 1H), 2.55 - 2.47 (m, 1H), 2.31 (s, 3H), 2,18 - 2,04 (m, 1H), 1.90 (t, J = 13.4 Hz, 1H), 1.80 1.69 (m, 1H), 1.56 - 1.40 (m, 1H), 1.00 - 0.85 (m, 2H), 0.80 - 0.67 (m, 2H). 319 O 0 FL -N. JL _____ 1 AH Va 1-[(4-chloro-2-fluoro-5-methylfenil)methyl]-3ciclopropil-3-[(3R)-1-(morfolina-4carbonil)piperidin-3-il]ureia LC-MS: m / z 453.1 (M+H).1H NMR (400 MHz, MeOD) δ 7.24 (d, J = 8.0 Hz, 1H), 7.13 (d, J = 9.8 Hz, 1H), 6.84 (t, J = 5.7 Hz, 1H), 4.44 - 4.29 (m, 2H), 3.82 - 3.73 (m, 1H), 3.67 - 3.56 (m, 6H), 3.27 - 3.16 (m, 4H), 3.07 (t, J = 11.8 Hz, 1H), 2.77 2.62 (m, 1H), 2.53 - 2.42 (m, 1H), 2.32 (s, 3H), 2.17 - 2.01 (m, 1H), 1.96 - 1.85 (m, 1H), 1.82 - 1.73 (m, 1H), 1.63 - 1.47 (m, 1H), 0.99 - 0.87 (m, 2H), 0.80 - 0.63 (m, 2H). Petition 870260063816, dated 06 / 29 / 2026, p. 252 / 739 245 / 315 Example 320 Structure / name Data (3R)-3-(3-cyclopropyl{[(4-chloro-2fluoro-5methylphenyl)methyl]carbamoyl}amino)-Nmethylpiperidine-1-carboxamide LC-MS: m / z 397 (M+H). 1H RMN (400 MHz, MeOD) δ 7,24 (d, J = 8,0 Hz, 1H), 7,13 (d, J = 9,8 Hz, 1H), 4,43 - 4,31 (m, 2H), 3,99 3,91 (m, 1H), 3,90 - 3,80 (m, 1H), 3,66 - 3,55 (m, 1H), 3,17 - 3,06 (m, 1H), 2,69 (s, 3H), 2,68 - 2,60 (m, 1H), 2,55 - 2,47 (m, 1H), 2,31 (s, 3H), 2,18 - 2,04 (m, 1H), 1,88 (d, J = 11,4 Hz, 1H), 1,79 - 1,70 (m, 1H), 1,58 - 1,42 (m, 1H), 1,58 - 1,42 (m, 1H), 0,97 - 0,89 (m, 2H), 0,79 - 0,67 (m, 2H), 0,79 - 0,70 (m, 2H). 321 LC-MS: m / z 383 (M+H). (3R)-3-(3-ciclopropil{[(4-cloro-2fluoro-5metilfenil)metil]carbamoil}amino)piper idina-1-carboxamida 1H RMN (400 MHz, MeOD) δ 7,24 (d, J = 8,0 Hz, 1H), 7,13 (d, J = 9,8 Hz, 1H), 6,89 - 6,81 (m, 1H), 4,42 4,32 (m, 2H), 4,01 - 3,85 (m, 2H), 3,69 - 3,58 (m, 1H), 3,23 - 3,14 (m, 1H), 2,72 - 2,61 (m, 1H), 2,56 - 2,48 (m, 1H), 2,31 (s, 3H), 2,17 - 2,05 (m, 1H), 1,93 - 1,84 (m, 1H), 1,79 - 1,69 (m, 1H), 1,58 - 1,45 (m, 1H), 0,97 0,89 (m, 2H), 0,77 - 0,70 (m, 2H). Petition 870260063816, 06 / 29 / 2026, pág. 253 / 739 246 / 315 Exemplo Estrutura / name Dados 322 1 XN\[^·0 .NI 1 0 F LJ-í? A nn π λ h Va (3R)-3-(3-cyclopropyl{[(4-chloro-2fluoro-5methylphenyl)methyl]carbamoyl}amino)N,N-dimethylpiperidine-1-carboxamida LC-MS: m / z 411 (M+H). 1H NMR (400 MHz, CD3OD) δ 7.24 (d, J = 8.0 Hz, 1H), 7.12 (d, J = 9.8 Hz, 1H), 4.37 (s, 2H), 3.78 (ddd, J = 15.5, 8.0, 3.9 Hz, 1H), 3.61 - 3.53 (m, 2H), 3.08 (t, J = 11.8 Hz, 1H), 2.82 (s, 6H), 2.67 (dt, J = 13.0, 6.6 Hz, 1H), 2.52 - 2.47 (m, 1H), 2.31 (s, 3H), 2.09 (td, J = 12.5, 8.5 Hz, 1H), 1.89 (d, J = 12.3 Hz, 1H), 1.79 - 1.73 (m, 1H), 1.63 - 1.53 (m, 1H), 0.96 0.90 (m, 2H), 0.76 - 0.70 (m, 2H). HCl (HCl (4.0M Dioxane) General Procedure P: Fmoc-CI DIPEA Fmoc' P3 NH3CI 2,4-dimetroxibenzaldeído NaBH(OAc)3 P6 TFA TMSO OEt X NaCNBH3AcOH H P4

[00271] The protected intermediate 3-amino-piperidines can be prepared by the general route shown above or by the general procedure Q.

[00272] A solution of tert-butyl N-[(3R)-3-piperidyl]carbamate P1 (25 g, 124.83 mmol) and DIPEA (19.36 g, 149.79 mmol, 26.09 mL) in 500 mL of DCM was added dropwise to the solution of Fmoc-Cl (44.28 g, 137.31 mmol) in DCM (150 mL), in an ice bath, dropwise over two hours. Then the reaction mixture was stirred for a further hour, then heated to room temperature, filtered and concentrated to give (3R)-3-(tert-butoxycarbonylamino)piperidine-1-carboxylate Petition 870260063816, dated 06 / 29 / 2026, p. 254 / 739 247 / 315 of 9H-fluoren-9-ylmethyl P2 (81 g, 191.71 mmol, 153.58% yield) as a crude white solid was used without further purification. To a suspension of (3R)-3-(tert-butoxycarbonylamino)piperidine-1-carboxylate of 9H-fluoren-9-ylmethyl P2 (20 g, 47.34 mmol) in THF (200 mL) was added dioxane / HCl (4.0 M) (4.0 M, 59.17 mL) and the reaction mixture was stirred at 60°C after three hours. The reaction mixture was then concentrated under reduced pressure by rotary evaporation and the resulting solid was washed twice with Et2O to give (3R)-3-aminopiperidine-1-carboxylate of 9H-fluoren-9-ylmethyl P3 (13.91 g, 38.76 mmol, 81.89% yield, HCl) as a white solid. To a suspension of (3R)-3-aminopiperidine-1-carboxylate of 9H-fluoren-9-ylmethyl P3 (13.91 g, 38.76 mmol, HCl) in DCM (250 mL) was added 2,4-dimethoxybenzaldehyde (6.12 g, 36.82 mmol), DIPEA (5.51 g, 42.64 mmol, 7.43 mL) and sodium triacetoxyborohydride (8.22 g, 38.76 mmol).The reaction mixture was kept under agitation overnight and then washed with 1 M NaOH, brine, and dried with anhydrous sodium sulfate. The reaction mixture was then concentrated and purified by chromatography (DCM:MeOH 100:0 to 95:5) to provide (3R)-3-[(2,4-dimethoxyphenyl)methylamino]piperidine-1-carboxylate 9H-fluoren-9ylmethyl P4 (9.26 g, 19.59 mmol, 50.55% yield) as a yellow oil. To a solution of (3R)-3-[(2,4-dimethoxyphenyl)methylamino]piperidine-1-carboxylate 9H-fluoren-9ylmethyl (5.75 g, 12.17 mmol) P4 in THF (50 mL) and ethanol (100 mL) was added (1-ethoxycyclopropoxy)-trimethylsilane (5.30 g, 30.43 mmol, 6.12 mL), acetic acid (10.96 g, 182.55 mmol, 10.44 mL) and sodium cyanoborohydride (2.68 g, 42.60 mmol). The reaction mixture was stirred overnight at 80°C, then concentrated and the residue dissolved in DCM. The organic layer was washed with aqueous saturated sodium carbonate, brine, and dried with anhydrous sodium sulfate. The organic layer was... Petition 870260063816, dated 06 / 29 / 2026, p. 255 / 739 248 / 315 concentrated and purified by chromatography (DCM:MeOH 10:0 to 9:1) to provide (3R)-3-[cyclopropyl-[(2,4-dimethoxyphenyl)methyl]amino]piperidine-1-carboxylate of 9H-fluoren-9ylmethyl P5 as a white foam. A solution of (3R)-3-[cyclopropyl-[(2,4-dimethoxyphenyl)methyl]amino]piperidine-1-carboxylate of 9H-fluoren-9-ylmethyl P5 (2.0 g, 3.90 mmol) in TFA (59.20 g, 519.19 mmol, 40 mL) was heated to 80°C and...

Claims

1. Pharmaceutical composition, characterized in that it comprises a pharmaceutically acceptable vehicle or excipient; and a compound of Formula (I): wherein: n is 1; M is CH2; L2 is absent; Xi and X2 are independently selected from -H and cyclopropyl; provided that Xi and X2 are not both -H; Yi is R4, wherein Ri, R2, R3, R4, and Rs are independently selected from -H, -F, -Cl, -Br, -CN, -CH3, CH2CH3, -OCF3 and W; Y2 is selected from hydroxyalkyl with 1 to 3 carbons and NH(Y2'); Y2' is selected from -H and alkyl with 1 to 3 carbons; and Y3, Y4, Y5 and Y6 are independently selected from -H and halide; or a pharmaceutically acceptable salt thereof.

2. Pharmaceutical composition, according to claim 1, characterized in that: Y2' is an alkyl group with 1 to 3 carbons. Petition 870260063816, dated 06 / 29 / 2026, page 324 / 739 2 / 39 3. Pharmaceutical composition according to claim 1 or 2, characterized in that either of the following statements (A)-(B) applies: FF cr γ (A) Yi is selected from I , fe λ ; 0a 0a (B) Yi is selected from Br , ci, 4. Pharmaceutical composition, according to any one of claims 1 to 3, characterized in that Yi is selected from 5. Pharmaceutical composition, characterized in that Petition 870260063816, dated 29 / 06 / 2026, p. 325 / 739 3 / 39 comprises a pharmaceutically acceptable vehicle or excipient; and a pharmaceutically acceptable compound or salt thereof having the structure of any of the following compounds in (A), (B), (C) or (D): (A) Petition 870260063816, dated 29 / 06 / 2026, p. 326 / 739 4 / 39 Petition 870260063816, dated 29 / 06 / 2026, p. 327 / 739 5 / 39 Petition 870260063816, dated 29 / 06 / 2026, p. 328 / 739 6 / 39 Petition 870260063816, dated 06 / 29 / 2026, p. 329 / 739 7 / 39 Petition 870260063816, dated 06 / 29 / 2026, p. 330 / 739 8 / 39 Petition 870260063816, dated 06 / 29 / 2026, p. 331 / 739 9 / 39 Petition 870260063816, dated 06 / 29 / 2026, p. 332 / 739 10 / 39 Petition 870260063816, dated 06 / 29 / 2026, p. 333 / 739 11 / 39 Petition 870260063816, dated 06 / 29 / 2026, p. 334 / 739 12 / 39 Petition 870260063816, dated 06 / 29 / 2026, p. 335 / 739 13 / 39 Petition 870260063816, dated 06 / 29 / 2026, p. 336 / 739 14 / 39 Petition 870260063816, dated 06 / 29 / 2026, p.337 / 739 15 / 39 Petition 870260063816, dated 06 / 29 / 2026, p. 338 / 739 16 / 39 Petition 870260063816, dated 06 / 29 / 2026, p. 339 / 739 17 / 39 Petition 870260063816, dated 06 / 29 / 2026, p. 340 / 739 18 / 39 Petition 870260063816, dated 06 / 29 / 2026, p. 341 / 739 19 / 39 Petition 870260063816, dated 06 / 29 / 2026, p. 342 / 739 20 / 39 Petition 870260063816, dated 06 / 29 / 2026, p. 343 / 739 21 / 39 Petition 870260063816, dated 06 / 29 / 2026, p. 344 / 739 22 / 39 Petition 870260063816, dated 06 / 29 / 2026, p. 345 / 739 23 / 39 Petition 870260063816, dated 06 / 29 / 2026, p. 346 / 739 24 / 39 Petition 870260063816, dated 06 / 29 / 2026, p. 347 / 739 25 / 39 Petition 870260063816, dated 06 / 29 / 2026, p. 348 / 739 26 / 39 Petition 870260063816, dated 06 / 29 / 2026, p. 349 / 739 27 / 39 Petition 870260063816, dated 06 / 29 / 2026, p. 350 / 739 28 / 39 Petition 870260063816, dated 06 / 29 / 2026, p. 351 / 739 29 / 39 Petition 870260063816, dated 06 / 29 / 2026, p. 352 / 739 30 / 39 Petition 870260063816, dated 06 / 29 / 2026, p. 353 / 739 31 / 39 (B) Petition 870260063816, dated 06 / 29 / 2026, p.354 / 739 32 / 39 Petition 870260063816, dated 06 / 29 / 2026, p. 355 / 739 33 / 39 Petition 870260063816, dated 06 / 29 / 2026, p. 356 / 739 34 / 39 (C) Petition 870260063816, dated 06 / 29 / 2026, p. 357 / 739 35 / 39 (D) Petition 870260063816, dated 06 / 29 / 2026, p. 358 / 739 36 / 39 Petition 870260063816, dated 06 / 29 / 2026, p. 359 / 739 37 / 39 Petition 870260063816, dated 06 / 29 / 2026, p. 360 / 739 38 / 39.

6. Pharmaceutical composition according to claim 5, characterized in that the compound of Formula (I) has the following structure: or a pharmaceutically acceptable salt thereof.

7. Pharmaceutical composition, according to claim 5, characterized in that the compound of Formula (I) has the structure: Petition 870260063816, dated 06 / 29 / 2026, page 361 / 739 39 / 39 8. Pharmaceutical composition, according to claim 5, characterized in that the compound of Formula (I) has the structure: or a pharmaceutically acceptable salt thereof.

9. Pharmaceutical composition according to claim 5, characterized in that the compound of Formula (I) has the following structure: