3,4-dihydroquinolin-2(1H)-one inhibitors of tshr

Abstract

Disclosed are compounds that are thyroid stimulating hormone receptor antagonists, and methods useful for preventing or treating a thyroid disease.

Description

[0001]GPX-02125 3,4-DIHYDROQUINOLIN-2(1H)-ONE INHIBITORS OF TSHR CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of priority to U.S. Provisional Patent Application Nos.63 / 807,181, filed May 16, 2025; 63 / 697,053, filed September 20, 2024; and 63 / 654,477, filed May 31, 2024; each of which is incorporated herein by reference in its entirety. BACKGROUND About 40% of hyperthyroidism patients suffer from Graves' disease (Morbus Basedow), an autoimmune disease in which autoantibodies activate the thyrotropin receptor, mimicking its natural hormone ligand, the thyroid-stimulating hormone (TSH). This pathological activation of TSH-Receptor (TSHR) leads to uncontrolled production of thyroid hormones (e.g., T3 and T4) causing hyperthyroidism. TSH and the TSHR are important proteins for controlling thyroid function. TSHR is primarily expressed in follicular epithelial cells of the thyroid gland, but also is expressed in a variety of additional cell types, such as retro-orbital fibroblasts, kidney cells, adipocytes and bone cells. TSH binds to its receptor and leads to the stimulation of second messenger pathways involving predominantly cAMP. Inositol 1,4,5-triphosphate (IP3) and diacylglycerol (DAG) pathways are also activated at higher TSH concentrations. The treatment of choice applied in the clinics for decades involves thyrostatic drugs that block the production of thyroid hormones. These medications play a role further downstream in the signal cascade of the thyroid upon activation of the TSHR. Since thyroid hormones T3 and T4 are secreted in the thyroid gland, thyrostatic drugs induce an inhibition of their synthesis. Thus, the current primary anti-thyroid treatment does not target the causative molecular activation of the TSHR by autoantibodies and patients are therefore burdened by a rate of at least 5% adverse effects. This demands frequent controls of the thyroid hormone levels and adjustments of thyrostatics dosage. In contrast to these drugs, which regulate the thyroid hormone level, another promising target is the TSHR itself. However, small allosteric antagonists acting directly at the TSHR are not available on the market yet. Additionally, about 25% of Graves' disease patients also develop an orbitopathy referred to as “Graves' ophthalmopathy”, a related organ-specific autoimmune disease affecting the appearance and functioning of the eyes. There is considerable evidence that expression of the TSHR in the orbital fibroblasts and orbital adipocytes behind the eye may - 1 - FH12898416.1 GPX-02125 contribute to this difficult-to-treat orbitopathy, and thyroid stimulating antibodies titer tend to correlate with severity of Grave’s ophthalmopathy. Orbital fibroblast has been recognized as primary target cells of autoimmune attack and TSHR acts as a primary autoantigen in Grave’s ophthalmopathy. The pathological activation of TSHR leads to the production of the extracellular matrix by involvement of hyaluronic acid, fibrosis and swelling of extraocular muscle as well as adipogenesis of orbital fibroblasts (orbital fat expansion). The increase in tissue volume in the orbit often causes diplopia and compression of the optic nerve and exophthalmos. Thus, the TSHR is also potential target for pharmacological intervention of Grave’s ophthalmology and thyroid eye disease. Accordingly, there is a need in the art to provide additional means for the treatment of hyperthyroidism, in particular compounds that act as TSHR antagonists. SUMMARY The present disclosure provides in some embodiments a compound of Formula (I): 1. A compound of Formula (I): or a pharmaceutically acceptable salt thereof; wherein: A is a fused 6-membered aryl or fused 6-membered heteroaryl ring; B is (C6-C10)aryl, 5- to 10-membered heteroaryl, (C3-C8)cycloalkyl, or 4- to 7- membered heterocycloalkyl; X is linear or branched (C1-C6)alkylene optionally substituted with one or more substituents independently selected from halo, hydroxy, (C1-C6)alkoxy, and cyano; or X is absent; W is -O-, -NH- or -CH2-; R1is independently for each occurrence selected from halo, SF5, cyano, hydroxy, (C1- C6)alkyl, (C1-C6)haloalkyl, (C1-C6)hydroxyalkyl, (C6-C10)aryloxy(C1-C6)alkyl, (C1- C6)alkoxy, (C1-C6)haloalkoxy, (C1-C6)alkoxy(C1-C6)alkyl, (C1-C6)haloalkoxy(C1-C6)alkyl, (C3-C8)cycloalkoxy(C1-C6)alkyl, (C6-C10)aryloxy, NRaRb, N(Ra)C(O)Rb, SO2Ra, SORa, FH12898416.1 GPX-02125 S(O)NRaRb, S(O)2NRaRb, S(O)(NH)Ra, C(O)Ra, C(O2)Rb, C(O)NRaRb, (C3-C8)cycloalkyl, and (C3-C8)cycloalkyl(C1-C6)alkyl; R2is independently for each occurrence selected from (C1-C6)alkyl, (C2-C6)alkynyl, (C2-C6)alkenyl, (C3-C8)cycloalkyl, (C3-C8)cycloalkoxy, (C6-C10)aryl, (C6-C10)aryloxy, (C6- C10)aryl(C1-C6)alkyl, 4- to 7-membered heterocycloalkyl, (C1-C6)alkoxy, (C1-C6)alkoxy(C1-C6)alkyl, halo, cyano, NRaRb, N(Ra)C(O)Rb, SO2Ra, SORa, S(O)NRaRb, S(O)2NRaRb, S(O)(NH)Ra, C(O)Ra, C(O)2Rb, C(O)NRaRb, C(O)Ra, and (C1-C6)alkoxycarbonyl; wherein (C1-C6)alkyl, (C2-C6)alkynyl, (C2-C6)alkenyl, (C3-C8)cycloalkyl, C3-C8)cycloalkoxy, (C6-C10)aryl, (C6-C10)aryloxy, (C6-C10)aryl(C1-C6)alkyl, (C1-C6)alkoxy, (C1- C6)alkoxy(C1-C6)alkyl, and 4- to 7-membered heterocycloalkyl are each optionally substituted with one or more substituents independently selected from halo, hydroxy, cyano, amido, sulfonamido, (C1-C6)alkyl, (C3-C8)cycloalkyl, 4- to 7-membered heterocycloalkyl, 5- to 6-membered heteroaryl, 6-10-membered aryl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, (C1-C6)fluoroalkoxy, 6-10-membered aryloxy, and 5- to 6-membered heteroaryloxy; or two vicinal occurrences of R2taken together with the atoms to which they are attached form a fused 5- to 7-membered cycloalkyl, 5- to 7-membered heterocycloalkyl ring, 5- to 6-membered heteroaryl ring or phenyl ring, any of which is optionally substituted with one or more substituents independently selected from halo, hydroxy, cyano, amido, sulfonamido, (C1-C6)alkyl, (C1-C6)haloalkyl (C3-C8)cycloalkyl, and (C1-C6)alkoxy; R3is hydrogen, (C1-C6)alkyl, or (C1-C6)fluoroalkyl; R4is NRaRb, (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)hydroxyalkyl, (C1-C6)alkoxy(C1- C6)alkyl, (C1-C6)haloalkoxy(C1-C6)alkyl, (C3-C8)cycloalkyl, or (C3-C8)cycloalkyl(C1- C6)alkyl; wherein (C3-C8)cycloalkyl is optionally substituted with one or more hydroxy; Raand Rbare independently for each occurrence hydrogen, (C1-C6)alkyl, C1-C6)haloalkyl; or Raand Rbtaken together with the nitrogen to which they are attached for a 4- to 7-membered heterocycloalkyl; m is 0, 1, 2, 3, 4, or 5; and n is 0, 1, 2, 3, or 4. Other aspects of the disclosure provide a pharmaceutical composition comprising a compound of the present invention, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient. Other aspects of the disclosure provide a method of inhibiting a thyroid stimulating hormone receptor, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of the disclosure. FH12898416.1 GPX-02125 In still other aspects, provided herein is a method for treating hyperthyroidism, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of the present invention. In some embodiments, the subject has Graves' disease. In more particular embodiments, the subject has Graves' ophthalmopathy. In other embodiments, the subject has Graves' dermopathy. In still other embodiments, the subject has thyroid cancer. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although methods and materials similar or equivalent to those described herein can 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 herein are incorporated by reference in their entirety. In case of conflict, the present specification, including definitions, will control. In addition, the materials, methods, and examples are illustrative only and not intended to be limiting. Other features, objects, and advantages of the invention will be apparent from the detailed description, and from the claims. DETAILED DESCRIPTION Definitions For convenience, before further description of the present invention, certain terms employed in the specification, examples and appended claims are collected here. These definitions should be read in light of the remainder of the disclosure and as understood by a person of skill in the art. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by a person of ordinary skill in the art. In order for the present invention to be more readily understood, certain terms and phrases are defined below and throughout the specification. The articles “a” and “an” are used herein to refer to one or to more than one (i.e., to at least one) of the grammatical object of the article. By way of example, “an element” means one element or more than one element. The phrase “and / or,” as used herein in the specification and in the claims, should be understood to mean “either or both” of the elements so conjoined, i.e., elements that are conjunctively present in some cases and disjunctively present in other cases. Multiple FH12898416.1 GPX-02125 elements listed with “and / or” should be construed in the same fashion, i.e., “one or more” of the elements so conjoined. Other elements may optionally be present other than the elements specifically identified by the “and / or” clause, whether related or unrelated to those elements specifically identified. Thus, as a non-limiting example, a reference to “A and / or B”, when used in conjunction with open-ended language such as “comprising” can refer, in one embodiment, to A only (optionally including elements other than B); in another embodiment, to B only (optionally including elements other than A); in yet another embodiment, to both A and B (optionally including other elements); etc. As used herein in the specification and in the claims, “or” should be understood to have the same meaning as “and / or” as defined above. For example, when separating items in a list, “or” or “and / or” shall be interpreted as being inclusive, i.e., the inclusion of at least one, but also including more than one, of a number or list of elements, and, optionally, 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,” will refer to the inclusion of exactly one element of a number or list of elements. In general, the term “or” as used herein shall 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,” “one of,” “only one of,” or “exactly one of.” “Consisting essentially of,” when used in the claims, shall have its ordinary meaning as used in the field of patent law. As used herein in the specification and in the claims, the phrase “at least one,” in reference to a list of one or more elements, should be understood to mean 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 and every element specifically listed within the list of elements and not excluding any combinations of elements in the list of elements. This definition also allows that elements may optionally be present other than the elements specifically identified within the list of elements to which the phrase “at least one” refers, whether related or unrelated to those elements specifically identified. 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”) can refer, in one embodiment, to at least one, optionally including more than one, A, with no B present (and optionally including elements other than B); in another embodiment, to at least one, optionally including more than one, B, with no 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. FH12898416.1 GPX-02125 It should also be understood that, unless clearly indicated to the contrary, in any methods claimed herein 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. In the claims, as well as in the specification above, all transitional phrases such as “comprising,” “including,” “carrying,” “having,” “containing,” “involving,” “holding,” “composed of,” and the like are to be understood to be open-ended, i.e., to mean including but not 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 Office Manual of Patent Examining Procedures, Section 2111.03. Certain compounds contained in compositions of the present invention may exist in particular geometric or stereoisomeric forms. In addition, 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, the 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. “Geometric isomer" means isomers that differ in the orientation of substituent atoms in relationship to a carbon-carbon double bond, to a cycloalkyl ring, or to a bridged bicyclic system. Atoms (other than H) on each side of a carbon- carbon double bond may be in an E (substituents are on opposite sides of the carbon- carbon double bond) or Z (substituents are oriented on the same side) configuration. "R," "S," "S*," "R*," "E," "Z," "cis," and "trans," indicate configurations relative to the core molecule. Certain of the disclosed compounds may exist in “atropisomeric” forms or as “atropisomers.” Atropisomers are stereoisomers resulting from hindered rotation about single bonds where the steric strain barrier to rotation is high enough to allow for the isolation of the conformers. The compounds of the invention may be prepared as individual isomers by either isomer-specific synthesis or resolved from a mixture of isomers. Conventional resolution techniques include forming the salt of a free base of 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 amide of each of the isomers of an isomeric pair using an optically pure acid, amine or alcohol (followed by chromatographic separation FH12898416.1 GPX-02125 and removal of the chiral auxiliary), or resolving an isomeric mixture of either a starting material or a final product using various well known chromatographic methods. If, for instance, a particular enantiomer of compound of the present invention is desired, it may be prepared by asymmetric synthesis, or by derivation with a chiral auxiliary, where the resulting diastereomeric mixture is separated and the auxiliary group cleaved to provide the pure desired enantiomers. Alternatively, where the molecule contains a basic functional group, such as amino, or an acidic functional group, such as carboxyl, diastereomeric salts are formed with an appropriate optically-active acid or base, followed by resolution of the diastereomers thus formed by fractional crystallization or chromatographic means well known in the art, and subsequent recovery of the pure enantiomers. Percent purity by mole fraction is the ratio of the moles of the enantiomer (or diastereomer) or over the moles of the enantiomer (or diastereomer) plus the moles of its optical isomer. When the stereochemistry of a disclosed compound is named or depicted by structure, the named or depicted stereoisomer is at least about 60%, about 70%, about 80%, about 90%, about 99% or about 99.9% by mole fraction pure relative to the other stereoisomers. When a single enantiomer is named or depicted by structure, the depicted or named enantiomer is at least about 60%, about 70%, about 80%, about 90%, about 99% or about 99.9% by mole fraction pure. When a single diastereomer is named or depicted by structure, the depicted or named diastereomer is at least about 60%, about 70%, about 80%, about 90%, about 99% or about 99.9% by mole fraction pure. When a disclosed compound is named or depicted by structure without indicating the stereochemistry, and the compound has at least one chiral center, it is to be understood that the name or structure encompasses either enantiomer of the compound free from 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 depicted by structure without indicating the stereochemistry and has two or more chiral centers, it is to be understood that the name or structure encompasses a diastereomer free of other diastereomers, a number of diastereomers free from other diastereomeric pairs, mixtures of diastereomers, mixtures of diastereomeric pairs, mixtures of diastereomers in which one diastereomer is enriched relative to the other diastereomer(s) or mixtures of diastereomers in which one or more diastereomer is enriched relative to the other diastereomers. The invention embraces all of these forms. Structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds produced by FH12898416.1 GPX-02125 the replacement of a hydrogen with deuterium or tritium, or of a carbon with a13C- or14C- enriched carbon are within the scope of this invention. The term “prodrug” as used herein 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. The phrase “pharmaceutically acceptable excipient” or “pharmaceutically acceptable carrier” as used herein means a pharmaceutically acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material, involved in carrying or transporting the subject chemical from one organ or portion of the body, to another organ or portion of the body. Each carrier must be “acceptable” in the sense of being compatible with the other ingredients of the formulation, not injurious to the patient, and substantially non-pyrogenic. Some examples of materials which can 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 carboxymethyl cellulose, ethyl cellulose, and cellulose acetate; (4) powdered tragacanth; (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; (18) Ringer’s solution; (19) ethyl alcohol; (20) phosphate buffer solutions; and (21) other non-toxic compatible substances employed in pharmaceutical formulations. In certain embodiments, pharmaceutical compositions of the present invention are non-pyrogenic, i.e., do not induce significant temperature elevations when administered to a patient. The term “pharmaceutically acceptable salts” refers to the relatively non-toxic, inorganic and organic acid addition salts of the compound(s). These salts can be prepared in situ during the final isolation and purification of the compound(s), or by separately reacting a purified compound(s) in its free base form with a suitable organic or inorganic acid, and isolating the salt thus formed. Representative salts include the hydrobromide, hydrochloride, sulfate, bisulfate, phosphate, nitrate, acetate, valerate, oleate, palmitate, stearate, laurate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, FH12898416.1 GPX-02125 naphthylate, mesylate, glucoheptonate, lactobionate, and laurylsulphonate salts, and the like. (See, for example, Berge et al. (1977) “Pharmaceutical Salts”, J. Pharm. Sci.66:1-19.) 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 pharmaceutically acceptable bases. The term “pharmaceutically acceptable salts” in these instances refers to the relatively non-toxic inorganic and organic base addition salts of a compound(s). These salts can likewise be prepared in situ during the final isolation and purification of the compound(s), or by separately reacting the purified compound(s) in its free acid 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 organic primary, secondary, or tertiary amine. Representative alkali or alkaline earth salts include the 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). The term “pharmaceutically acceptable cocrystals” refers to solid coformers that do not form formal ionic interactions with the small molecule. A “therapeutically effective amount” (or “effective amount”) of a compound with respect to 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) alleviates a symptom, ameliorates a condition, or slows the onset of disease conditions according to clinically acceptable standards for the disorder or condition to be treated or the cosmetic purpose, e.g., at a reasonable benefit / risk ratio applicable to any medical treatment. The term “prophylactic or therapeutic” treatment is art-recognized and includes administration to the host of one or more of the subject compositions. If it is administered prior to clinical manifestation of the unwanted condition (e.g., disease or other unwanted state of the host animal) then the treatment is prophylactic, (i.e., it protects the host against developing the unwanted condition), whereas if it is administered after manifestation of the unwanted condition, the treatment is therapeutic, (i.e., it is intended to diminish, ameliorate, or stabilize the existing unwanted condition or side effects thereof). The term “patient” or “subject” refers to a mammal in need of a particular treatment. In certain embodiments, a patient is a primate, canine, feline, or equine. In certain embodiments, a patient is a human. FH12898416.1 GPX-02125 An aliphatic chain comprises the classes of alkyl, alkenyl and alkynyl defined below. A straight aliphatic chain is limited to unbranched carbon chain moieties. As used herein, the term “aliphatic group” refers to a straight chain, branched-chain, or cyclic aliphatic hydrocarbon group and includes saturated and unsaturated aliphatic groups, such as an alkyl group, an alkenyl group, or an alkynyl group. “Alkyl” refers to a fully saturated cyclic or acyclic, branched or unbranched carbon chain moiety having the number of carbon atoms specified, or up to 30 carbon atoms if no specification is made. For example, alkyl of 1 to 8 carbon atoms refers to moieties such as methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, and octyl, and those moieties which are positional isomers of these moieties. Alkyl of 10 to 30 carbon atoms 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 has 30 or fewer carbon atoms in its backbone (e.g., C1-C30for straight chains, C3-C30for branched chains), and more preferably 20 or fewer. Alkyl groups may be substituted or unsubstituted. As used herein, the term “heteroalkyl” refers to an alkyl moiety as hereinbefore defined which contain one or more oxygen, sulfur, nitrogen, phosphorus, or silicon atoms in place of carbon atoms. As used herein, the term “haloalkyl” refers to an alkyl group as hereinbefore defined substituted with at least one halogen. As used herein, the term “haloalkoxy” refers to an alkoxy group as defined herein substituted with at least one halogen atom. For example, haloalkoxy groups include fluoroalkoxy groups, such as trifluoromethoxy, difluoromethoxy, and the like. As used herein, the term “hydroxyalkyl” refers to an alkyl group as hereinbefore defined substituted with at least one hydroxyl. As used herein, the term “alkylene” refers to an alkyl group having the specified number of carbons, for example from 2 to 12 carbon atoms, that contains two points of attachment to the rest of the compound on its longest carbon chain. Non-limiting examples of alkylene groups include methylene -(CH2)-, ethylene -(CH2CH2)-, n-propylene - (CH2CH2CH2)-, isopropylene -(CH2CH(CH3))-, and the like. Alkylene groups can be cyclic or acyclic, branched or unbranched carbon chain moiety, and may be optionally substituted with one or more substituents. "Cycloalkyl" means mono- or bicyclic or bridged or spirocyclic, or polycyclic saturated carbocyclic rings, each having from 3 to 12 carbon atoms. Preferred cycloalkyls FH12898416.1 GPX-02125 have from 3-10 carbon atoms in their ring structure, and more preferably have 3-6 carbons in the ring structure. Cycloalkyl groups may be substituted or unsubstituted. “1,2-Disubstituted cyclohexyl” as used herein refers to a cyclohexane ring that contains points of attachment at the 1 and 2 positions of the cyclohexane ring to the rest of the compound. Similarly, “1,2-disubstituted cyclopentyl” as used herein refers to a cyclopentane ring that contains points of attachment at the 1 and 2 positions of the cyclopentane ring to the rest of the compound.1,2-Disubstituted cyclohexyl and 1,2- disubstituted cyclopentyl can also be referred to as 1,2-cyclohexylene and 1,2- cyclopentylene, respectively. As used herein, the term “halocycloalkyl” refers to a cycloalkyl group as hereinbefore defined substituted with at least one halogen. "Cycloheteroalkyl" refers to a cycloalkyl moiety as hereinbefore defined which contain one or more oxygen, sulfur, nitrogen, phosphorus, or silicon atoms in place of carbon atoms. Preferred cycloheteroalkyls have from 4-8 carbon atoms and heteroatoms in their ring structure, and more preferably have 4-6 carbons and heteroatoms in the ring structure. Cycloheteroalkyl groups may be substituted or unsubstituted. Unless the number of carbons is otherwise specified, “lower alkyl,” as used herein, means an alkyl group, as defined above, but having from one to ten carbons, more preferably from one to six carbon atoms in its backbone structure such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and tert-butyl. Likewise, “lower alkenyl” and “lower alkynyl” have similar chain lengths. Throughout the application, preferred alkyl groups are lower alkyls. In certain embodiments, a substituent designated herein as alkyl is a lower alkyl. “Alkenyl” refers to any cyclic or acyclic, branched or unbranched unsaturated carbon chain moiety having the number of carbon atoms specified, or up to 26 carbon atoms if no limitation on the number of carbon atoms is specified; and having one or more double bonds in the moiety. Alkenyl of 6 to 26 carbon atoms is 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) can be located anywhere in the moiety and can have either the (Z) or the (E) configuration about the double bond(s). “Alkynyl” refers to hydrocarbyl moieties of the scope of alkenyl, but having one or more triple bonds in the moiety. FH12898416.1 GPX-02125 The term “aryl” as used herein includes 3- to 12-membered substituted or unsubstituted single-ring aromatic groups in which each atom of the ring is carbon (i.e., carbocyclic aryl) or where one or more atoms are heteroatoms (i.e., heteroaryl). Preferably, aryl groups include 5- to 12-membered rings, more preferably 6- to 10-membered rings The term “aryl” also includes polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjoining rings wherein at least one of the rings is aromatic, e.g., the other cyclic rings can be cycloalkyls, cycloalkenyls, cycloalkynyls, aryls, heteroaryls, and / or heterocyclyls. Carboycyclic aryl groups include benzene, naphthalene, phenanthrene, phenol, aniline, and the like. Heteroaryl groups include substituted or unsubstituted aromatic 3- to 12-membered ring structures, more preferably 5- to 12- membered rings, more preferably 5- to 10-membered rings, whose ring structures include one to four heteroatoms. Heteroaryl groups include, for example, pyrrole, furan, thiophene, imidazole, oxazole, thiazole, triazole, pyrazole, pyridine, pyrazine, pyridazine, pyrimidine, indazole, quinoline, benzofuran, and the like. Aryl and heteroaryl can be monocyclic, bicyclic, or polycyclic. The term “halo”, “halide”, or “halogen” as used herein means halogen and includes, for example, and without being limited thereto, fluoro, chloro, bromo, iodo and the like, in both radioactive and non-radioactive forms. In a preferred embodiment, halo is selected from the group consisting of fluoro, chloro and bromo. The terms “heterocyclyl” or “heterocyclic group” or “heterocycloalkyl” refer to 3- to 12-membered ring structures, more preferably 5- to 12- membered rings, more preferably 5- to 10-membered rings, whose ring structures include one to four heteroatoms. Heterocycles can be monocyclic, bicyclic, spirocyclic, or polycyclic. Heterocyclyl groups include, for example, thiophene, thianthrene, furan, pyran, isobenzofuran, chromene, xanthene, phenoxathiin, pyrrole, imidazole, pyrazole, isothiazole, isoxazole, pyridine, pyrazine, pyrimidine, pyridazine, indolizine, isoindole, indole, indazole, purine, quinolizine, isoquinoline, quinoline, phthalazine, naphthyridine, quinoxaline, quinazoline, cinnoline, pteridine, carbazole, carboline, phenanthridine, acridine, pyrimidine, phenanthroline, phenazine, phenarsazine, phenothiazine, furazan, phenoxazine, pyrrolidine, oxolane, thiolane, oxazole, piperidine, piperazine, morpholine, lactones, lactams such as azetidinones and pyrrolidinones, sultams, sultones, and the like. Heterocycloalkyl groups can be fully saturated or partially saturated. Heterocycloalkyl groups include, for example, bicyclic ring systems having either or both constituent rings saturated (e.g., 2,3-dihydroindole, 4,5,6,7- tetrahydro-benzofuran, decahydroquinoline, and the like) or partially saturated (e.g., octahydroquinoline and the like). FH12898416.1 GPX-02125 The heterocyclic ring can be substituted at one or more positions with such substituents as described above, 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. The term “substituted” refers to moieties having substituents replacing a hydrogen on one or more carbons of the backbone. It will be understood that “substitution” or “substituted with” includes the implicit proviso that such substitution is in accordance with permitted valence of the substituted atom and the substituent, and that the substitution results in a stable compound, e.g., which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, etc. As used herein, the term “substituted” is contemplated to include all permissible substituents of organic compounds. In a broad aspect, the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic substituents of organic compounds. The permissible substituents can be one or more and the same or different for appropriate organic compounds. For purposes of this invention, the heteroatoms such as nitrogen may have hydrogen substituents and / or any permissible substituents of organic compounds described herein which satisfy the valences of the heteroatoms. Substituents can include any substituents described herein, for example, a halogen, a hydroxyl, a carbonyl (such as a carboxyl, an alkoxycarbonyl, a formyl, or an acyl), a thiocarbonyl (such as a thioester, a thioacetate, or a thioformate), an alkoxy, a phosphoryl, a phosphate, a phosphonate, a phosphinate, an amino, an amido, an amidine, an imine, a cyano, a nitro, an azido, a sulfhydryl, an alkylthio, a sulfate, a sulfonate, a sulfamoyl, a sulfonamido, a sulfonyl, a heterocyclyl, an aralkyl, or an aromatic or heteroaromatic moiety. In preferred embodiments, the substituents on substituted alkyls are selected from C1-6alkyl, C3-6cycloalkyl, halogen, carbonyl, cyano, or hydroxyl. In more preferred embodiments, the substituents on substituted alkyls are selected from fluoro, carbonyl, cyano, or hydroxyl. It will be understood by those skilled in the art that substituents can themselves be substituted, if appropriate. Unless specifically stated as “unsubstituted,” references to chemical moieties herein are understood to include substituted variants. For example, reference to an “aryl” group or moiety implicitly includes both substituted and unsubstituted variants. FH12898416.1 GPX-02125 As used herein, the definition of each expression, e.g., 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. As used herein, “small molecules” refers to small organic or inorganic molecules of 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). The small molecules can be, e.g., from at least about 100 Da to about 3,000 Da (e.g., between about 100 to about 3,000 Da, about 100 to about 2500 Da, about 100 to about 2,000 Da, about 100 to about 1,750 Da, about 100 to about 1,500 Da, about 100 to about 1,250 Da, about 100 to about 1,000 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). 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, small molecule drugs of the invention encompass oligopeptides and other biomolecules having a molecular weight of less than about 1000. An “effective amount” is an amount sufficient to effect beneficial or desired results. For example, a therapeutic amount is one that achieves the desired therapeutic effect. This amount can be the same or different from a prophylactically effective amount, which is an amount necessary to prevent onset of disease or disease symptoms. An effective amount can be administered in one or more administrations, applications or dosages. A therapeutically effective amount of a composition depends on the composition selected. The compositions can be administered from one or more times per day to one or more times per week, including once every other day. The skilled artisan will appreciate that certain factors may influence the dosage and timing required to effectively treat a subject, including but not limited to the severity of the disease or disorder, previous treatments, the general health and / or age of the subject, and other diseases present. Moreover, treatment of a subject with a therapeutically effective amount of the compositions described herein can include a single treatment or a series of treatments. The terms “decrease,” “reduce,” “reduced”, “reduction”, “decrease,” and “inhibit” are all used herein generally to mean a decrease by a statistically significant amount relative to a reference. However, for avoidance of doubt, “reduce,” “reduction” or “decrease” or “inhibit” typically means a decrease by at least 10% as compared to a reference level and can include, for example, a decrease by at least about 20%, at least about 25%, at least about 30%, at least FH12898416.1 GPX-02125 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 as compared to the reference level, or any decrease between 10-99% as compared to the absence of a given treatment. The terms “increased”, “increase” or “enhance” or “activate” are all used herein to generally mean an increase by a statically significant amount; for the avoidance of any doubt, the terms “increased”, “increase” or “enhance” or “activate” means an increase of at least 10% as 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 a 100% increase or any increase between 10-100% as compared to a reference level, or at least about a 2-fold, or at least about a 3-fold, or at least about a 4-fold, or at least about a 5-fold or at least about a 10-fold increase, or any increase between 2-fold and 10-fold or greater as compared to a reference level. As used herein, the term “modulate” includes up-regulation and down-regulation, e.g., enhancing or inhibiting a response. A “radiopharmaceutical agent,” as defined herein, refers to a pharmaceutical agent which 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) which serves as the radiation source. As contemplated herein, the term “radioisotope” includes 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 chelator is typically employed to bind 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 via a linker, to the rest of the molecule. For purposes of this invention, the chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 67th Ed., 1986-87, inside cover. FH12898416.1 GPX-02125 Compounds of the Invention The present disclosure provides in some embodiments a compound of Formula (I): 1. A compound of Formula (I): or a pharmaceutically acceptable salt thereof; wherein: A is a fused 6-membered aryl or fused 6-membered heteroaryl ring; B is (C6-C10)aryl, 5- to 10-membered heteroaryl, (C3-C8)cycloalkyl, or 4- to 7- membered heterocycloalkyl; X is linear or branched (C1-C6)alkylene optionally substituted with one or more substituents independently selected from halo, hydroxy, (C1-C6)alkoxy, and cyano; or X is absent; W is -O-, -NH- or -CH2-; R1is independently for each occurrence selected from halo, SF5, cyano, hydroxy, (C1- C6)alkyl, (C1-C6)haloalkyl, (C1-C6)hydroxyalkyl, (C6-C10)aryloxy(C1-C6)alkyl, (C1- C6)alkoxy, (C1-C6)haloalkoxy, (C1-C6)alkoxy(C1-C6)alkyl, (C1-C6)haloalkoxy(C1-C6)alkyl, (C3-C8)cycloalkoxy(C1-C6)alkyl, (C6-C10)aryloxy, NRaRb, N(Ra)C(O)Rb, SO2Ra, SORa, S(O)NRaRb, S(O)2NRaRb, S(O)(NH)Ra, C(O)Ra, C(O2)Rb, C(O)NRaRb, (C3-C8)cycloalkyl, and (C3-C8)cycloalkyl(C1-C6)alkyl; R2is independently for each occurrence selected from (C1-C6)alkyl, (C2-C6)alkynyl, (C2-C6)alkenyl, (C3-C8)cycloalkyl, (C3-C8)cycloalkoxy, (C6-C10)aryl, (C6-C10)aryloxy, (C6- C10)aryl(C1-C6)alkyl, 4- to 7-membered heterocycloalkyl, (C1-C6)alkoxy, (C1-C6)alkoxy(C1-C6)alkyl, halo, cyano, NRaRb, N(Ra)C(O)Rb, SO2Ra, SORa, S(O)NRaRb, S(O)2NRaRb, S(O)(NH)Ra, C(O)Ra, C(O)2Rb, C(O)NRaRb, C(O)Ra, and (C1-C6)alkoxycarbonyl; wherein (C1-C6)alkyl, (C2-C6)alkynyl, (C2-C6)alkenyl, (C3-C8)cycloalkyl, C3-C8)cycloalkoxy, (C6-C10)aryl, (C6-C10)aryloxy, (C6-C10)aryl(C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)alkoxy(C1-C6)alkyl, and 4- to 7-membered heterocycloalkyl are each optionally substituted with one or more substituents independently selected from halo, hydroxy, cyano, FH12898416.1 GPX-02125 amido, sulfonamido, (C1-C6)alkyl, (C3-C8)cycloalkyl, 4- to 7-membered heterocycloalkyl, 5- to 6-membered heteroaryl, 6-10-membered aryl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, (C1-C6)fluoroalkoxy, 6-10-membered aryloxy, and 5- to 6-membered heteroaryloxy; or two vicinal occurrences of R2taken together with the atoms to which they are attached form a fused 5- to 7-membered cycloalkyl, 5- to 7-membered heterocycloalkyl ring, 5- to 6-membered heteroaryl ring or phenyl ring, any of which is optionally substituted with one or more substituents independently selected from halo, hydroxy, cyano, amido, sulfonamido, (C1-C6)alkyl, (C1-C6)haloalkyl (C3-C8)cycloalkyl, and (C1-C6)alkoxy; R3is hydrogen, (C1-C6)alkyl, or (C1-C6)fluoroalkyl; R4is NRaRb, (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)hydroxyalkyl, (C1-C6)alkoxy(C1- C6)alkyl, (C1-C6)haloalkoxy(C1-C6)alkyl, (C3-C8)cycloalkyl, or (C3-C8)cycloalkyl(C1- C6)alkyl; wherein (C3-C8)cycloalkyl is optionally substituted with one or more hydroxy; Raand Rbare independently for each occurrence hydrogen, (C1-C6)alkyl, C1-C6)haloalkyl; or Raand Rbtaken together with the nitrogen to which they are attached for a 4- to 7-membered heterocycloalkyl; m is 0, 1, 2, 3, 4, or 5; and n is 0, 1, 2, 3, or 4. In some embodiments, A is selected from fused phenyl, pyridine, pyrimidine, pyridazine, pyrazine, and pyridone. In some preferred embodiments, A is fused phenyl. In other preferred embodiments, A is fused pyridyl. In other embodiments, A is fused pyrimidyl. In other embodiments, A is fused pyrazyl. In yet other embodiments, A is fused pyridonyl. In some embodiments, B is 6-membered aryl or heteroaryl. In some preferred embodiments, B is selected from phenyl, pyrimidine, pyridazine, pyrazine, and pyridine, and in more preferred embodiments, B is phenyl. In other embodiments, B is pyrimidyl. In other embodiments, B is pyrazyl. In yet other embodiments, B is pyridonyl. In some embodiments, X is CH2, CHCH3, CH3CH3, or C(CH3)2, each of which is optionally substituted with one or more fluorine atoms. In some embodiments, X is -CH2-, - CH(CH3)-, or -C(CH3)2-.In some embodiments, X is CH2, CHCH3, or C(CH3)2.In some preferred embodiments, X is CHCH3. In other embodiments, X is CH2-. In some embodiments, X is linear or branched (C1-C6)alkylene substituted with one or more fluorine atoms. In some embodiments, X is linear or branched (C1-C6)alkylene substituted with two or more fluorine atoms. In some embodiments, X is linear or branched (C1-C6)alkylene substituted with three or more fluorine atoms. In some embodiments, X is linear or branched FH12898416.1 GPX-02125 (C1-C6)alkylene substituted with four or more fluorine atoms. In some embodiments, X is - CHCH2F-. In some embodiments, W is -NH-. In other embodiments, W is -CH2-.In still further embodiments, W is O. In some embodiments, R1is independently for each occurrence selected from halo, cyano, hydroxy, (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)hydroxyalkyl, (C6-C10)aryloxy(C1- C6)alkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, (C1-C6)alkoxy(C1-C6)alkyl, (C1- C6)haloalkoxy(C1-C6)alkyl, (C6-C10)aryloxy, NRaRb, N(Ra)C(O)Rb, (C3-C8)cycloalkyl, and (C3-C8)cycloalkyl(C1-C6)alkyl. In other embodimetns, R1is independently for each occurrence selected from fluoro, chloro, cyano, (C1-C6)fluoroalkoxy, (C3-C8)cycloalkyl, and (C1-C6)alkoxy(C1-C6)alkyl. In some embodiments, The compound of any one of claims 1 to 19, wherein R2is independently for each occurrence selected from (C1-C6)alkyl, (C2-C6)alkynyl, (C2-C6)alkenyl, (C3-C8)cycloalkyl, (C3-C8)cycloalkoxy, (C6-C10)aryl, (C6-C10)aryloxy, (C6-C10)aryl(C1-C6)alkyl, 4- to 7-membered heterocycloalkyl, (C1-C6)alkoxy, (C1-C6)alkoxy(C1-C6)alkyl, halo, cyano, NRaRb, NRa(CO)Rb, formyl, carboxy, and (C1-C6)alkoxycarbonyl; wherein (C1-C6)alkyl, (C2-C6)alkynyl, (C2-C6)alkenyl, (C3-C8)cycloalkyl, C3-C8)cycloalkoxy, (C6-C10)aryl, (C6-C10)aryloxy, (C6-C10)aryl(C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)alkoxy(C1-C6)alkyl, and 4- to 7-membered heterocycloalkyl are each optionally substituted with one or more substituents independently selected from halo, hydroxy, cyano, amido, sulfonamido, (C1-C6)alkyl, (C3-C8)cycloalkyl, 4- to 7-membered heterocycloalkyl, 5- to 6-membered heteroaryl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, (C1-C6)fluoroalkoxy, and 5- to 6-membered heteroaryloxy. In some embodiments, R2is (C1-C6)alkyl. In some embodiments, R2is (C2-C6)alkynyl. In some embodiments, R2is (C2-C6)alkenyl. In some embodiments, R2is (C3-C8)cycloalkyl. In some embodiments, R2is C3-C8)cycloalkoxy. In some embodiments, R2is (C6-C10)aryl. In some embodiments, R2is (C6-C10)aryloxy. In some embodiments, R2is (C6-C10)aryl(C1-C6)alkyl. In some embodiments, R2is (C1-C6)alkoxy. In some embodiments, R2is (C1-C6)alkoxy(C1-C6)alkyl. In some embodiments, R2is 4- to 7-membered heterocycloalkyl. FH12898416.1 GPX-02125 In some embodiments, R2is halo. In some embodiments, R2is hydroxy. In some embodiments, R2is cyano. In some embodiments, R2is formyl. In some embodiments, R2is carboxy. In some embodiments, R2is formyl. In some embodiments, R2is NRaRbIn some embodiments, R2is NRa(CO)Rb. In some embodiments, R2is (C1-C6)alkoxycarbonyl. In some embodiments, at least one instance of R2is chloro. In some embodiments, at least one instance of R2is fluoro. In some embodiments, at least one instance of R2is (C1-C6)fluoroalkyl. In some embodiments, at least one instance of R2is trifluoromethyl. In some embodiments, at least one instance of R2is (C1-C6)fluoroalkoxy. In some embodiments, at least one instance of R2is trifluoromethoxy. In some embodiments, at least one instance of R2is difluoromethoxy. In some embodiments, at least one instance of R2is phenoxy. In some embodiments, n is 1. In other embodiments, n is 2. In still other embodiments, n is 0. In some embodiments, m is 1. In other embodiments, m is 2. In still other embodiments, m is 0. In some embodiments, R3is hydrogen, (C1-C6)alkyl, or (C1-C6)fluoroalkyl. In some embodiments, R3is (C1-C6)alkyl. In some embodiments, R3is (C1-C6)fluoroalkyl. In some embodiments, R3is hydrogen, methyl, or trifluoromethyl. In some preferred embodiments, R3is hydrogen. In some preferred embodiments, R3is methyl. In some preferred embodiments, R3is trifluoromethyl. In some embodiments, R4is NRaRb, (C1-C6)alkyl, (C1-C6)haloalkyl, (C1- C6)hydroxyalkyl, (C1-C6)alkoxy(C1-C6)alkyl, (C1-C6)haloalkoxy(C1-C6)alkyl, (C3- C8)cycloalkyl, or (C3-C8)cycloalkyl(C1-C6)alkyl; wherein (C3-C8)cycloalkyl is optionally substituted with one or more hydroxy. In some embodiments, R4is (C1-C6)haloalkyl. In some embodiments, R4is (C1-C6)hydroxyalkyl. In some embodiments, R4is (C1-C6)alkoxy(C1-C6)alkyl. In some embodiments, R4is (C1-C6)haloalkoxy(C1-C6)alkyl. FH12898416.1 GPX-02125 In some embodiments, R4is (C3-C8)cycloalkyl optionally substituted with one or more hydroxy. In some embodiments, R4is (C3-C8)cycloalkyl substituted with one or more hydroxy. In some embodiments, R4is (C3-C8)cycloalkyl(C1-C6)alkyl. In some embodiments, R4is NH2, NHRa, or NRaRb. In some embodiments, R4is NHRa. In some embodiments, R4is NRaRb. In some embodiments, R4is NH2. In other embodiments, R4is (C1-C6)alkyl or (C3-C8)cycloalkyl. In some embodiments, R4is (C1-C6)alkyl. In other embodiments, R4is cyclopropyl, and in still other embodiments, R4is NH2. In some embodiments, R4is NRaRb, (C1-C6)alkyl, (C1-C6)hydroxyalkyl, or (C3- C8)cycloalkyl optionally substituted with one or more hydroxy. In some embodiments, R4is (C1-C6)alkyl or (C3-C8)cycloalkyl. In some embodiments, R4is (C1-C6)alkyl. In some embodiments, R4is or (C3-C8)cycloalkyl. In some embodiments, R4is cyclopropyl. In some embodiments, one or both of Raand Rbis hydrogen. In some embodiments, Raor Rbis (C1-C6)alkyl. In some embodiments, Raor Rbis methyl. In some embodiments, Raor Rbis ethyl. In some embodiments, Raor Rbis methyl. In some embodiments, a compound is selected from the following table: FH12898416.1 GPX-02125 - 21 - FH12898416.1 GPX-02125 - 22 - FH12898416.1 GPX-02125 FH12898416.1 GPX-02125 FH12898416.1 GPX-02125 - 25 - FH12898416.1 GPX-02125 FH12898416.1 GPX-02125 FH12898416.1 GPX-02125 FH12898416.1 GPX-02125 FH12898416.1 GPX-02125 FH12898416.1 GPX-02125 FH12898416.1 GPX-02125 FH12898416.1 GPX-02125 or a pharmaceutically acceptable salt thereof. Methods of Treatment One aspect of the invention provides methods of inhibiting a thyroid stimulating hormone receptor, comprising administering to a subject in need thereof a therapeutically effective amount of a compound described herein. Another aspect of the invention comprises treating or preventing a thyroid disease, comprising administering to a subject in need thereof a therapeutically effective amount of a compound described herein. Another aspect of the invention comprises a method of treating hyperthyroidism, comprising administering to a subject in need thereof a therapeutically effective amount of a compound described herein. In certain embodiments, the subject has Graves' disease. In certain embodiments, the subject has Graves' ophthalmopathy. In certain embodiments, the subject has Graves' dermopathy. In certain embodiments, the subject has thyroid cancer. While not being bound by theory, TSHR in thyroid cells, and likely in fibroblasts and adipocytes in the supporting tissue behind the eye (in the retro-orbital space), also are stimulated by TSHR-stimulating antibodies (TSAbs), resulting in Graves' disease. Graves' disease, which is an autoimmune disease that occurs in 1% of the US population, has two important clinical components: 1) hyperthyroidism from stimulation of TSHR on thyroid FH12898416.1 GPX-02125 cells and 2) Graves' orbitopathy (or Graves' ophthalmopathy or thyroid eye disease), which appears to result from stimulation of TSHR on retro-orbital fibroblasts and / or adipocytes. Hyperthyroidism, in particular Graves' hyperthyroidism, is a hypermetabolic state that affects virtually every tissue / cell in the body and can lead to, in particular, cardiovascular dysfunction and death. Graves' ophthalmopathy, also known as Graves' orbitopathy, occurs in 80% of Graves' hyperthyroid patients as diagnosed by computerized tomographic scan. Symptoms range from mild to moderate to severe to sight-threatening. Protrusion of the eyeball (proptosis) and varying degrees of extra-ocular muscle weakness or paralysis leading to double vision (diplopia) can be disfiguring and incapacitating. Graves dermopathy, also known as Pretibial myxedema, thyroid dermopathy, Jadassohn-Dössekker disease or Myxoedema tuberosum, is an infiltrative dermopathy, resulting as a complication of Graves' disease, with an incidence rate of about 1-5% in patients. The disease usually presents itself as a waxy, discolored induration of the skin on the anterior aspect of the lower legs. In certain embodiments, a disease that can be treated o prevented by TSHR antagonists is thyroid cancer. While not being bound by theory, TSHR is expressed in thyroid cancer cells and regulates the growth, proliferation and metastatic potential of thyroid cancer cells. The thyroid gland is, as is well known, one site of metabolic control within the body. Cancer of the thyroid gland is not particularly common, but the high rate of disease re- occurrence necessitates long-term surveillance. Usually, during treatment for cancer of the thyroid, the majority of the thyroid tumor is removed, but a small amount often remains that must be treated by radioactive iodide therapy. Indeed, thyroid cancer is characterized by a high likelihood of relapses in up to 30% of patients, even after successful therapy. In rare cases, the TSHR contains a hereditary mutation that makes it more active than the normal TSHR, resulting in hereditary non-immune hyperthyroidism. TSHR antagonists could be effective treatment for these patients also. A “TSHR antagonist” as described herein blocks or inhibits the action of the agonists (TSH or thyroid-stimulating antibodies for TSHR. Small-molecule ligands for the TSHR (antagonists) typically bind to an intra-membrane domain of the receptor, and act by inducing a conformational change rather than simply competing for TSH binding to its extracellular site on the receptor. FH12898416.1 GPX-02125 In certain embodiments, the antagonists may be selective antagonists for TSHR (i.e, the compounds do not activate or modulate other hormone receptors, particularly luteinizing hormone / chorionic gonadotropin receptor (LHCGR) and follicle-stimulating hormone receptor (FSHR)). In certain embodiments, the antagonists disclosed herein may be used for treating hyperthyroidism in a subject. For example, the antagonists may inhibit mutant TSHRs with higher than normal basal signaling activities (CAMs) that cause an unusual form of hyperthyroidism. In another example, the antagonists may inhibit stimulation by antibodies found in Graves' disease, which is the most common form of hyperthyroidism. In certain embodiments, the TSHR antagonists are useful for treating TSHR-mediated thyroid cancer or hyperthyroidism by blocking TSHR-stimulating antibodies (TSAbs) in Graves' hyperthyroidism. In certain embodiments, the compound is administered orally to the subject. In certain embodiments, the compound is administered parenterally to the subject. In certain embodiments, the disease is prevented. In other embodiments, the disease is treated. Pharmaceutical Compositions, Routes of Administration, and Dosing In certain embodiments, the invention is directed to a pharmaceutical composition, comprising a compound of the invention, e.g. a compound according to the present invention, and a pharmaceutically acceptable carrier. In certain embodiments, the invention is directed to a pharmaceutical composition, comprising a compound of any of the disclosed embodiments, and a pharmaceutically acceptable carrier. In certain embodiments, the pharmaceutical composition comprises a plurality of compounds of the invention and a pharmaceutically acceptable carrier. Pharmaceutical compositions of the invention can 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. As stated above, an “effective amount” refers to any amount that is sufficient to achieve a desired biological effect. Combined with the teachings provided herein, by choosing among the various active compounds and weighing 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 FH12898416.1 GPX-02125 which does not cause substantial unwanted toxicity and yet is effective to treat the particular subject. The effective amount for any particular application can vary depending on such factors as the disease or condition being treated, the particular compound of the invention being administered, the size of the subject, or the severity of the disease or condition. One of ordinary skill in the art can empirically determine the effective amount of a particular compound of the invention and / or other therapeutic agent without necessitating undue experimentation. A maximum dose may be used, that is, the highest safe dose according to some medical judgment. Multiple doses per day may be contemplated to achieve appropriate systemic levels of compounds. Appropriate systemic levels can be determined by, for example, measurement of the patient’s peak or sustained plasma level of the drug. “Dose” and “dosage” are used interchangeably herein. In certain embodiments, intravenous administration of a compound may typically be from 0.1 mg / kg / day to 20 mg / kg / day. In one embodiment, intravenous administration of a compound may typically be from 0.1 mg / kg / day to 2 mg / kg / day. In one embodiment, intravenous administration of a compound may typically be from 0.5 mg / kg / day to 5 mg / kg / day. In one embodiment, intravenous administration of a compound may typically be from 1 mg / kg / day to 20 mg / kg / day. In one embodiment, intravenous administration of a compound may typically be from 1 mg / kg / day to 10 mg / kg / day. Generally, daily oral doses of a compound will be, for human subjects, from about 0.01 milligrams / kg per day to 1000 milligrams / kg per day. It is expected that oral doses in the range of 0.5 to 50 milligrams / kg, in one or more administrations per day, will yield therapeutic results. Dosage may be adjusted appropriately to achieve desired drug levels, local or systemic, depending upon the mode of administration. For example, it is expected that intravenous administration would be from one order to several orders of magnitude lower dose per day. In the event that the response in a subject is insufficient at such doses, even higher doses (or effective higher doses by a different, more localized delivery route) may be employed to the extent that patient tolerance permits. Multiple doses per day are contemplated to achieve appropriate systemic levels of the compound. For any compound described herein the therapeutically effective amount can be initially determined from animal models. A therapeutically effective dose can also be determined from human data for compounds which have been tested in humans and for compounds which are known to exhibit similar pharmacological activities, such as other related active agents. Higher doses may be required for parenteral administration. The applied dose can be adjusted based on the relative bioavailability and potency of the FH12898416.1 GPX-02125 administered compound. Adjusting the dose to achieve maximal efficacy based on the methods described above and other methods as are well-known in the art is well within the capabilities of the ordinarily skilled artisan. 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 optionally other therapeutic ingredients. For use in therapy, an effective amount of the compound can be administered to a subject by any mode that delivers the compound to the desired surface. Administering a pharmaceutical composition may be accomplished by any means known to the skilled artisan. Routes of administration include but are not limited to intravenous, intramuscular, intraperitoneal, intravesical (urinary bladder), oral, subcutaneous, direct injection (for example, into a tumor or abscess), mucosal (e.g., topical to eye), inhalation, and topical. For intravenous and other parenteral routes of administration, a compound of the invention can be formulated as a lyophilized preparation, as a lyophilized preparation of liposome-intercalated or -encapsulated active compound, as a lipid complex in aqueous suspension, or as a salt complex. Lyophilized formulations are generally reconstituted in suitable aqueous solution, e.g., in sterile water or saline, shortly prior to administration. For oral administration, the compounds can be formulated readily by combining the active compound(s) with pharmaceutically acceptable carriers well known in the art. Such carriers enable the compounds of the invention to be formulated as tablets, pills, dragees, capsules, liquids, gels, syrups, slurries, suspensions and the like, for oral ingestion by a subject to be treated. Pharmaceutical preparations for oral use can be obtained as solid excipient, optionally grinding a resulting mixture, and processing the mixture of granules, after adding suitable auxiliaries, if desired, to obtain tablets or dragee cores. Suitable excipients are, in particular, fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol; cellulose preparations such as, for example, maize starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methyl cellulose, hydroxypropylmethyl-cellulose, sodium carboxymethylcellulose, and / or polyvinylpyrrolidone (PVP). If desired, disintegrating agents may be added, such as the cross-linked polyvinyl pyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate. Optionally the oral formulations may also be formulated in saline or buffers, e.g., EDTA for neutralizing internal acid conditions or may be administered without any carriers. FH12898416.1 GPX-02125 Also specifically contemplated are oral dosage forms of the above component or components. The component or components may be chemically modified so that oral delivery of the derivative is efficacious. Generally, the chemical modification contemplated is the attachment of at least one moiety to the component molecule itself, where said moiety permits (a) inhibition of acid hydrolysis; and (b) uptake into the blood stream from the stomach or intestine. Also desired is the increase in overall stability of the component or components and increase in circulation time in the body. Examples of such moieties include: polyethylene glycol, copolymers of ethylene glycol and propylene glycol, carboxymethyl cellulose, dextran, polyvinyl alcohol, polyvinyl pyrrolidone and polyproline. Abuchowski and Davis, “Soluble Polymer-Enzyme Adducts”, In: Enzymes as Drugs, Hocenberg and Roberts, eds., Wiley-Interscience, New York, N.Y., pp.367-383 (1981); Newmark et al., J Appl Biochem 4:185-9 (1982). Other polymers that could be used are poly-1,3-dioxolane and poly-1,3,6-tioxocane. For pharmaceutical usage, as indicated above, polyethylene glycol moieties are suitable. For the component (or derivative) the location of release may be the stomach, the small intestine (the duodenum, the jejunum, or the ileum), or the large intestine. One skilled in the art has available formulations which will not dissolve in the stomach, yet 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 protection of the compound of the invention (or derivative) or by release of the biologically active material beyond the stomach environment, such as in the intestine. To ensure full gastric resistance a coating impermeable to at least pH 5.0 is essential. Examples of the more common inert ingredients that are used as enteric coatings are cellulose acetate trimellitate (CAT), hydroxypropylmethylcellulose 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 may be used as mixed films. A coating or mixture of coatings can also be used on tablets, which are not intended for protection against the stomach. This can include sugar coatings, or coatings which make the tablet easier to swallow. Capsules may consist of a hard shell (such as gelatin) for delivery of dry therapeutic (e.g., powder); for liquid forms, a soft gelatin shell may be used. The shell material of cachets could be thick starch or other edible paper. For pills, lozenges, molded tablets or tablet triturates, moist massing techniques can be used. FH12898416.1 GPX-02125 The therapeutic can be included in the formulation as fine multi-particulates in the form of granules or pellets of particle size about 1 mm. The formulation of the material for capsule administration could also be as a powder, lightly compressed plugs or even as tablets. The therapeutic could be prepared by compression. Colorants and flavoring agents may all be included. For example, the compound of the invention (or derivative) may be formulated (such as by liposome or microsphere encapsulation) and then further contained within an edible product, such as a refrigerated beverage containing colorants and flavoring agents. One may dilute or increase the volume of the therapeutic with an inert material. These diluents could include carbohydrates, especially mannitol, α-lactose, anhydrous lactose, cellulose, sucrose, modified dextrans and starch. Certain inorganic salts may be 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. Disintegrants may be included in the formulation of the therapeutic into a solid dosage form. Materials used as disintegrates include but are not limited to starch, including the commercial disintegrant based on starch, Explotab. Sodium starch glycolate, Amberlite, sodium carboxymethylcellulose, ultramylopectin, sodium alginate, gelatin, orange peel, acid carboxymethyl cellulose, natural sponge and bentonite may all be used. Another form of the disintegrants are the insoluble cationic exchange resins. Powdered gums may be used as disintegrants and as binders and these can include powdered gums such as agar, Karaya or tragacanth. Alginic acid and its sodium salt are also useful as disintegrants. Binders may be used to hold the therapeutic agent together to form a hard tablet and include materials from natural products such as acacia, tragacanth, starch and gelatin. Others include methyl cellulose (MC), ethyl cellulose (EC) and carboxymethyl cellulose (CMC). Polyvinyl pyrrolidone (PVP) and hydroxypropylmethyl cellulose (HPMC) could both be used in alcoholic solutions to granulate the therapeutic. An anti-frictional agent may be included in the formulation of the therapeutic to prevent sticking during the formulation process. Lubricants may be used as a layer between the therapeutic and the die wall, and these can 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, FH12898416.1 GPX-02125 magnesium lauryl sulfate, polyethylene glycol of various molecular weights, Carbowax 4000 and 6000. Glidants that might improve the flow properties of the drug during formulation and to aid rearrangement during compression might be added. The glidants may include starch, talc, pyrogenic silica and hydrated silicoaluminate. To aid dissolution of the therapeutic into the aqueous environment a surfactant might be added as a wetting agent. Surfactants may include anionic detergents such as sodium lauryl sulfate, dioctyl sodium sulfosuccinate and dioctyl sodium sulfonate. Cationic detergents which can be used and can include benzalkonium chloride and benzethonium chloride. Potential non-ionic detergents that could be included in the formulation as surfactants include lauromacrogol 400, polyoxyl 40 stearate, polyoxyethylene hydrogenated castor oil 10, 50 and 60, glycerol monostearate, polysorbate 40, 60, 65 and 80, sucrose fatty acid ester, methyl cellulose and carboxymethyl cellulose. These surfactants could be present in the formulation of the compound of the invention or derivative either alone or as a mixture in different ratios. Pharmaceutical preparations which can be used orally include push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. The push-fit capsules can contain the active ingredients in admixture with filler 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 should be in dosages suitable for such administration. For buccal administration, the compositions may take the form of tablets or lozenges formulated in conventional manner. For topical administration, the compound may 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, e.g., subcutaneous, intravenous, intramuscular, intrathecal or intraperitoneal injection, as well as those designed for transdermal, transmucosal oral or pulmonary administration. For administration by inhalation, compounds for use according to the present invention may be conveniently delivered in the form of an aerosol spray presentation from pressurized packs or a nebulizer, with the use of a suitable propellant, e.g., FH12898416.1 GPX-02125 dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In the case of a pressurized aerosol the dosage unit may be determined by providing a valve to deliver a metered amount. Capsules and cartridges of e.g., gelatin for use in an inhaler or insufflator may be formulated containing a powder mix of the compound and a suitable powder base such as lactose or starch. Also contemplated herein is pulmonary delivery of the compounds disclosed herein (or salts thereof). The compound is delivered to the lungs of a mammal while inhaling and traverses across the lung epithelial lining to the blood stream. 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) (α1- antitrypsin); Smith et al., 1989, J Clin Invest 84:1145-1146 (a-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 and tumor necrosis factor alpha) and Platz et al., U.S. 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 Sep.19, 1995 to Wong et al. Contemplated for use in the practice of this invention are mechanical devices designed for pulmonary delivery of therapeutic products, including but not limited to nebulizers, metered dose inhalers, and powder inhalers, all of which are familiar to those skilled in the art. 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; and the Spinhaler powder inhaler, manufactured by Fisons Corp., Bedford, Mass. All such devices require the use of formulations suitable for the dispensing of the compounds of the invention. Typically, each formulation is specific to the type of device employed and may involve the use of an appropriate propellant material, in addition to the usual diluents, adjuvants and / or carriers useful in therapy. Also, the use of liposomes, microcapsules or microspheres, inclusion complexes, or other types of carriers is FH12898416.1 GPX-02125 contemplated. Chemically modified compound of the invention may also be prepared in different formulations depending on the type of chemical modification or the type of device employed. Formulations suitable for use with a nebulizer, either 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 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 regulation of osmotic pressure). The nebulizer formulation may also contain a surfactant, to reduce or prevent surface induced aggregation of the compound of the invention caused by atomization of the solution in forming the aerosol. Formulations for use with a metered-dose inhaler device 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 employed 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 soya lecithin. Oleic acid may also be useful as a surfactant. Formulations for dispensing from a powder inhaler device will comprise a finely divided dry powder containing a compound of the invention (or derivative) and may also include a bulking agent, such as lactose, sorbitol, sucrose, or mannitol in amounts which facilitate dispersal of the powder from the device, e.g., 50 to 90% by weight of the formulation. The compound of the invention (or derivative) should advantageously be prepared in particulate form with an average particle size of less than 10 micrometers (μm), most preferably 0.5 to 5 μm, for most effective delivery to the deep lung. 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 to the blood stream directly after administering the therapeutic product to the nose, without the necessity for deposition of the product in the lung. Formulations for nasal delivery include those with dextran or cyclodextran. For nasal administration, a useful device is a small, hard bottle to which a metered dose sprayer is attached. In one embodiment, the metered dose is delivered by drawing the pharmaceutical composition of the present invention solution into a chamber of defined FH12898416.1 GPX-02125 volume, which chamber has an aperture dimensioned to aerosolize and aerosol formulation by 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. Alternatively, a plastic squeeze bottle with an aperture or opening dimensioned to aerosolize an aerosol formulation by forming a spray when squeezed is used. The opening is usually found in the top of the bottle, and the top is generally tapered to partially fit in the nasal passages for efficient administration of the aerosol formulation. Preferably, the nasal inhaler will provide a metered amount of the aerosol formulation, for administration of a measured dose of the drug. The compounds, when it is desirable to deliver them systemically, may be formulated for parenteral administration by injection, e.g., by bolus injection or continuous infusion. Formulations for injection may be presented in unit dosage form, e.g., in ampoules or in multi-dose containers, with an added preservative. The compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and / or dispersing agents. 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 appropriate oily injection suspensions. 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 which increase the viscosity of the suspension, such as sodium carboxymethylcellulose, sorbitol, or dextran. Optionally, the suspension may also contain suitable stabilizers or agents which increase the solubility of the compounds to allow for the preparation of highly concentrated solutions. Alternatively, the active compounds may be in powder form for constitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use. The compounds may also be formulated in rectal or vaginal compositions such as suppositories or retention enemas, e.g., containing conventional suppository bases such as cocoa butter or other glycerides. 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 (for example as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt. FH12898416.1 GPX-02125 The pharmaceutical compositions also may comprise suitable solid or gel 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. Suitable liquid or solid pharmaceutical preparation forms are, for example, aqueous or saline solutions for inhalation, microencapsulated, encochleated, coated onto microscopic gold particles, contained in liposomes, nebulized, aerosols, pellets for implantation into the skin, or dried onto a sharp object to be scratched into the skin. The pharmaceutical compositions also include granules, powders, tablets, coated tablets, (micro)capsules, suppositories, syrups, emulsions, suspensions, creams, drops or preparations with protracted 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 customarily used as described above. The 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). The compound of the invention and optionally other therapeutics may be administered per se (neat) or in the form of a pharmaceutically acceptable salt or cocrystal. When used in medicine the salts or cocrystals should 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, p-toluene sulphonic, tartaric, citric, methane sulphonic, formic, malonic, succinic, naphthalene-2-sulphonic, and benzene sulphonic. Also, such salts can be prepared as alkaline metal or alkaline earth salts, such as sodium, potassium or calcium salts of the carboxylic acid group. Suitable buffering agents include: acetic acid and a salt (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 phosphoric 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). Pharmaceutical compositions of the invention contain an effective amount of a compound as described herein and optionally therapeutic agents included in a pharmaceutically acceptable carrier. The term “pharmaceutically acceptable carrier” means one or more compatible solid or liquid filler, diluents or encapsulating substances which are suitable for administration to a human or other vertebrate animal. The term “carrier” denotes FH12898416.1 GPX-02125 an organic or inorganic ingredient, natural or synthetic, with which the active ingredient is combined to facilitate the application. The components of the pharmaceutical compositions also are capable of being commingled with the compounds of the present invention, and with each other, in a manner such that there is no interaction which would substantially impair the desired pharmaceutical efficiency. The therapeutic agent(s), including specifically but not limited to a compound of the invention, may be provided in particles. Particles as used herein means nanoparticles or microparticles (or in some instances larger particles) which can consist in whole or in part of the compound of the invention or the other therapeutic agent(s) as described herein. 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) also may be dispersed throughout the particles. The therapeutic agent(s) also may be adsorbed into the particles. The particles may be of any order 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 those materials routinely used in the art of pharmacy and medicine, including, but not limited to, erodible, nonerodible, biodegradable, or nonbiodegradable material or combinations thereof. The particles may be microcapsules which contain the compound of the invention in a solution or in a semi-solid state. The particles may be of virtually any shape. Both non-biodegradable and biodegradable polymeric materials can be used in the manufacture of particles for delivering the therapeutic agent(s). Such polymers may be natural or synthetic polymers. The polymer is selected based on the period of time over which release is desired. Bioadhesive polymers of particular interest include bioerodible hydrogels described in Sawhney H S et al. (1993) Macromolecules 26:581-7, the teachings of which are incorporated herein. These include polyhyaluronic acids, casein, gelatin, glutin, polyanhydrides, polyacrylic acid, alginate, chitosan, poly(methyl methacrylates), poly(ethyl methacrylates), poly(butylmethacrylate), poly(isobutyl methacrylate), poly(hexylmethacrylate), poly(isodecyl methacrylate), poly(lauryl methacrylate), poly(phenyl methacrylate), poly(methyl acrylate), poly(isopropyl acrylate), poly(isobutyl acrylate), and poly(octadecyl acrylate). The therapeutic agent(s) may be contained in controlled release systems. The term “controlled release” is intended to refer to any drug-containing formulation in which the manner and profile of drug release from the formulation are controlled. This refers to FH12898416.1 GPX-02125 immediate as well as non-immediate release formulations, with non-immediate release formulations including but not limited to sustained release and delayed release formulations. The term “sustained release” (also referred to as “extended release”) is used in its conventional sense to refer to a drug formulation that provides for gradual release of a drug over an extended period of time, and that preferably, although not necessarily, results in substantially constant blood levels of a drug over an extended time period. 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 there from. “Delayed release” may or may not involve gradual release of drug over an extended period of time, and thus may or may not be “sustained release.” Use of a long-term sustained release implant may be particularly suitable for treatment of chronic conditions. “Long-term” release, as used herein, means that the implant is constructed and arranged to deliver therapeutic levels of the active ingredient for at least 7 days, and preferably 30-60 days. Long-term sustained release implants are well-known to those of ordinary skill in the art and include some of the release systems described above. It will be understood by one of ordinary skill in the relevant arts that other suitable modifications and adaptations to the compositions and methods described herein are readily apparent from the description of the invention contained herein in view of information known to the ordinarily skilled artisan, and may be made without departing from the scope of the invention or any embodiment thereof. Having now described the present invention in detail, the same will be more clearly understood by reference to the following examples, which are included herewith for purposes of illustration only and are not intended to be limiting of the invention. EXAMPLES The invention is further described in the following examples, which do not limit the scope of the invention described in the claims. Synthesis of Compound 1: [(3R)-2-oxo-1-[(1S)-1-phenylethyl]-3,4-dihydroquinolin-3- yl]urea FH12898416.1 GPX-02125 Step 1: Preparation of methyl (2S)-2-[(tert-butoxycarbonyl)amino]-3- (iodozincio)propanoate (Intermediate 1) To a solution of methyl (2S)-2-[(tert-butoxycarbonyl)amino]-3-iodopropanoate (10 g, 30.383 mmol, 1 equiv.) in DMF (60 mL) was added Zn powder (3.97 g, 60.766 mmol, 2 equiv.) at 0°C. The reaction was stirred at 25 °C for 16 h. TLC showed the desired product Intermediate 1 was generated. The crude product was used in the next step directly without further purification. Step 2: Preparation of methyl (2R)-2-[(tert-butoxycarbonyl)amino]-3-(2- nitrophenyl)propanoate FH12898416.1 GPX-02125 To a solution of o-chloronitrobenzene (1 g, 6.347 mmol, 1 equiv.) in DMF (20 mL) was added Xphos (0.61 g, 1.269 mmol, 0.2 equiv.), Pd(OAc)2(0.14 g, 0.635 mmol, 0.1 equiv.) and methyl (2S)-2-[(tert-butoxycarbonyl)amino]-3-(iodozincio)propanoate (Intermediate 1) (7.51 g, 19.041 mmol, 3 equiv, 0.5 M in DMF) at 0 °C under N2. The reaction was stirred at 25 °C for 2h under N2. The resulting mixture was filtered, the filter cake was washed with EA (3 x 100 mL). Diluted with water (200 mL) and extracted with EA (3 x 200 mL). The combined extracts were washed with water, brine, dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography on silica gel with EA / PE (0-100 %) to give methyl (2R)-2-[(tert-butoxycarbonyl)amino]-3-(2-nitrophenyl)propanoate (420 mg, 20.40% yield) as yellow oil. LC / MS (ESI): mass calcd. for C15H20N2O6: 324.10 m / z, found:225.15 [M+H-100]+. Step 3: Preparation of tert-butyl N-[(3R)-2-oxo-3,4-dihydro-1H-quinolin-3- yl]carbamate To a solution of methyl (2R)-2-[(tert-butoxycarbonyl)amino]-3-(2- nitrophenyl)propanoate (810 mg, 2.497 mmol, 1 equiv.) in EtOH (20 mL) and H2O (2 mL) was added Fe (1.39 g, 24.970 mmol, 10 equiv.) and NH4Cl (1.34 g, 24.970 mmol, 10 equiv.). The reaction was stirred at 80 °C for 2h. The resulting mixture was filtered, the filter cake was washed with EA(3 x 100 mL). Diluted with water (200 mL) and extracted with EA (3 x 200 mL). The combined extracts were washed with water, brine, dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography on silica gel with EA / PE (0-100 %) to give tert-butyl N-[(3R)-2-oxo-3,4-dihydro-1H-quinolin-3-yl]carbamate (430 mg, 65.64% yield) as yellow oil. LC / MS (ESI): mass calcd. for C14H18N2O3: 262.10 m / z, found:285.15 [M+Na]+. Step 4: Preparation of tert-butyl N-[(3R)-2-oxo-1-[(1S)-1-phenylethyl]-3,4- dihydroquinolin-3-yl]carbamate FH12898416.1 GPX-02125 To a solution of tert-butyl N-[(3R)-2-oxo-3,4-dihydro-1H-quinolin-3- yl]carbamate (400 mg, 1.525 mmol, 1 equiv.) in THF (10 mL) was added PPh3(600 mg, 2.287 mmol, 1.5 equiv.) and (R)-1-phenylethan-1-ol (279 mg, 2.287 mmol, 1.5 equiv.) at 0 °C under N2. The reaction was stirred at 25 °C for 0.5 h. Then DIAD (463 mg, 2.287 mmol, 1.5 equiv.) was added at 0 °C under N2. The reaction was stirred at 25 °C for 16 h. Quenched with water (50 mL) and extracted with EA (3 x 50 mL). The combined extracts were washed with water, brine, dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography on silica gel with EA / PE (0-100 %) to give tert-butyl N-[(3R)-2-oxo-1-[(1S)- 1-phenylethyl]-3,4-dihydroquinolin-3-yl]carbamate (240 mg, 42.95% yield) as yellow oil. LC / MS (ESI): mass calcd. for C22H26N2O3: 366.46 m / z, found:367.15 [M+H]+. Step 5: Preparation of (3R)-3-amino-1-[(1S)-1-phenylethyl]-3,4-dihydroquinolin-2-one Tert-butyl N-[(3R)-2-oxo-1-[(1S)-1-phenylethyl]-3,4-dihydroquinolin-3- yl]carbamate (230 mg, 0.628 mmol, 1 equiv.) was dissolved in HCl in 1,4-dioxane(4.0 M) (6 mL). The reaction was stirred at 25 °C for 1h. The solvent was removed to give (3R)-3-amino- 1-[(1S)-1-phenylethyl]-3,4-dihydroquinolin-2-one (160 mg) as yellow oil. LC / MS (ESI): mass calcd. for C17H18N2O: 266.46 m / z, found:267.10 [M+H]+. Step 6: Preparation of [(3R)-2-oxo-1-[(1S)-1-phenylethyl]-3,4-dihydroquinolin-3-yl]urea (Compound 1) FH12898416.1 GPX-02125 To a solution of (3R)-3-amino-1-[(1S)-1-phenylethyl]-3,4-dihydroquinolin-2- one (155 mg, 0.582 mmol, 1 equiv.) in THF (3 mL) and H2O (0.3 mL) was added methanesulfonic acid (67 mg, 0.698 mmol, 1.2 equiv.) and isocyanatopotassium (142 mg, 1.746 mmol, 3 equiv.) at 0°C. The reaction was stirred at 25 °C for 0.5h. Quenched with saturated sodium bicarbonate solution (30 mL) and extracted with DCM (3 x 30 mL). The combined extracts were washed with water, brine, dried over Na2SO4, filtered and concentrated. The residue was purified by preparative HPLC using a XBridge Prep Shield RP18 OBD Column 150 mm x 30 mm x 5 m column (eluent: 20% to 50% (v / v) CH3CN and H2O with 10 mmol / L NH4HCO3) to afford (3R)-2-oxo-1-[(1S)-1-phenylethyl]-3,4- dihydroquinolin-3-ylurea (60.9 mg, 33.83% yield) as a white solid. LC / MS (ESI): mass calcd. for C18H19N3O2:309.37 m / z, found:310.15 [M+H]+. 1H NMR (400 MHz, DMSO-d6) 7.41 – 7.35 (m, 2H), 7.34 – 7.24 (m, 4H), 7.12 – 6.97 (m, 2H), 6.68 (d, J = 8.1 Hz, 1H), 6.43 (d, J = 6.2 Hz, 1H), 6.25 (q, J = 7.1 Hz, 1H), 5.83 (s, 2H), 4.40 – 4.28 (m, 1H), 3.19 – 3.07 (m, 1H), 2.83 (t, J = 14.4 Hz, 1H), 1.68 (d, J = 7.2 Hz, 3H). Alternative synthesis of Compound 1 via synthesis of Intermediate 1: (S)-(2-((tert- butoxycarbonyl)amino)-3-methoxy-3-oxopropyl)zinc(II) iodide Scheme 2 Step 1: Preparation of (S)-(2-((tert-butoxycarbonyl)amino)-3-methoxy-3- oxopropyl)zinc(II) iodide (Intermediate 1) To a solution of methyl (2S)-2-[(tert-butoxycarbonyl)amino]-3-iodopropanoate (10 g, 30.4 mmol, 1 equiv.) in DMF (60 mL) was added zinc powder (3.97 g, 60.8 mmol, 2 equiv.) at 0 °C. The reaction was stirred at 25 °C for 16 h. The crude product was used in the next step directly without further purification. Synthesis of Intermediate 2: tert-butyl N-[(3R)-2-oxo-3,4-dihydro-1H-quinolin-3- yl]carbamate FH12898416.1 GPX-02125 Scheme 3 Step 1: Preparation of methyl (2R)-2-[(tert-butoxycarbonyl)amino]-3-(2- nitrophenyl)propanoate To a solution of o-bromonitrobenzene (2 g, 9.90 mmol, 1 equiv.) in DMF (10 mL) was added Intermediate 1 (1 M in DMF, 19.8 ml, 19.8 mmol, 2 equiv.), palladium(II) acetate (0.33 g, 1.49 mmol, 0.15 equiv.) and Xphos (1.42 g, 2.97 mmol, 0.3 equiv.) under nitrogen at 0 °C. The reaction was stirred at 25 °C under nitrogen for 16 h. The resulting mixture was filtered, and the filter cake was washed with ethyl acetate (2 x 100 mL). The filtrate was extracted with water (100 mL), and the aqueous layer then extracted with ethyl acetate (3 x 100 mL). The combined organic extracts were washed with water, brine, dried over sodium sulfate, filtered and concentrated. The crude product was purified by silica gel chromatography (0-100% ethyl acetate / petroleum ether) to afford the title compound as a yellow oil (800 mg, 24.9% yield). LCMS (ESI): m / z [M+H]+calcd for C15H20N2O6: 325.14, found 269.10 [M+H-tBu]+. Step 2: Preparation of tert-butyl N-[(3R)-2-oxo-3,4-dihydro-1H-quinolin-3-yl]carbamate (Intermediate 2) To a solution of methyl (2R)-2-[(tert-butoxycarbonyl)amino]-3-(2- nitrophenyl)propanoate (810 mg, 2.49 mmol, 1 equiv.) in ethanol (20 mL) and water (2 mL) was added iron powder (1.39 g, 24.9 mmol, 10 equiv.) and ammonium chloride (1.34 g, 24.9 mmol, 10 equiv.). The reaction was stirred at 80 °C for 2 h. The resulting mixture was filtered, and the filter cake was washed with ethyl acetate (2 x 100 mL). The organic extracts were extracted with water (100 mL) and the aqueous layer was then extracted with ethyl acetate (3 x 100 mL). The combined organic extracts were washed with water, brine, dried over sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel chromatography (0-100% ethyl acetate / petroleum ether) to afford the title compound as a yellow oil (430 mg, 65.6% yield). LCMS (ESI): m / z [M+Na]+calcd for C14H18N2O3: 285.12, found 285.15. FH12898416.1 GPX-02125 Synthesis of Intermediate 3: tert-butyl N-[(3R)-7-chloro-2-oxo-3,4-dihydro-1H-quinolin- 3-yl]carbamate Step 1: Preparation of methyl (R)-3-(2-amino-4-chlorophenyl)-2-((tert- butoxycarbonyl)amino)propanoate To a solution of 2-bromo-5-chloroaniline (5 g, 24.2 mmol, 1 equiv.) in DMF (50 mL) was added palladium(II) acetate (0.82 g, 3.63 mmol, 0.15 equiv.), Xphos (3.46 g, 7.27 mmol, 0.3 equiv.) and Intermediate 1 (19.11 g, 48.43 mmol, 2.0 equiv.) at 0 °C under nitrogen. The reaction was stirred at 25 °C for 16 h under nitrogen. The resulting mixture was filtered, the filter cake was washed with ethyl acetate (3 x 200 mL). The organic filtrate was then extracted with water (500 mL), and the aqueous layer then extracted with ethyl acetate (3 x 600 mL). The combined organic extracts were washed with water, brine, dried over sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel chromatography (0- 100% ethyl acetate / petroleum ether) to afford the title compound as a yellow oil (5 g, 62.8% yield). LCMS (ESI): m / z [M+H]+calcd for C15H21ClN2O4: 329.12, found 329.10. Step 2: Preparation of tert-butyl N-[(3R)-7-chloro-2-oxo-3,4-dihydro-1H-quinolin-3- yl]carbamate (Intermediate 3) A solution of methyl (2R)-3-(2-amino-4-chlorophenyl)-2-[(tert- butoxycarbonyl)amino]propanoate (2 g, 6.08 mmol, 1 equiv.) in acetic acid (20 mL) was stirred at 90 °C for 0.5 h. The mixture was allowed to cool to room temperature, then the solution was concentrated. The residue was taken up in saturated sodium bicarbonate solution (100 mL) and extracted with ethyl acetate (3 x 200 mL). The combined organic extracts were washed with water, brine, dried over sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel chromatography (0-100% ethyl acetate / petroleum ether) to afford the title compound as a white solid (1.5 g, 83.1% yield). LCMS (ESI): m / z [M+Na]+calcd for C14H17ClN2O3: 319.08, found 319.05. FH12898416.1 GPX-02125 Synthesis of Compound 1: (3R)-2-oxo-1-[(1S)-1-phenylethyl]-3,4-dihydroquinolin-3- ylurea Step 1: Preparation of tert-butyl N-[(3R)-2-oxo-1-[(1S)-1-phenylethyl]-3,4- dihydroquinolin-3-yl]carbamate To a solution of Intermediate 3 (400 mg, 1.53 mmol, 1 equiv.) in THF (10 mL) was added triphenylphosphine (600 mg, 2.29 mmol, 1.5 equiv.) and (R)-1-phenyl-ethanol (279.4 mg, 2.287 mmol, 1.5 equiv.) at 0 °C under nitrogen. The reaction was stirred at 25 °C for 0.5 h under nitrogen, then diisopropyl azodicarboxylate (462.5 mg, 2.287 mmol, 1.5 equiv.) was added at 0 °C under nitrogen. The reaction was stirred at 25 °C for 2 h under nitrogen, then was quenched with water (50 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic extracts were washed with water, brine, dried over sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel chromatography (0-100% ethyl acetate / petroleum ether) to afford the title compound as a yellow oil (240 mg, 42.9% yield). LCMS (ESI): m / z [M+Na]+calcd for C22H26N2O3: 367.20, found 367.15. Step 2: Preparation of (3R)-3-amino-1-[(1S)-1-phenylethyl]-3,4-dihydroquinolin-2-one FH12898416.1 GPX-02125 A solution of tert-butyl N-[(3R)-2-oxo-1-[(1S)-1-phenylethyl]-3,4-dihydroquinolin-3- yl]carbamate (230 mg, 0.628 mmol, 1 equiv.) in hydrochloride acid (4 M in 1,4-dioxane, 5 mL) was stirred at 25 °C for 1 h. The solvent was then removed. The residue was taken up in saturated sodium bicarbonate solution (50 mL) and extracted with ethyl acetate (3 x 30 mL). The combined organic extracts were washed with water, brine, dried over sodium sulfate, filtered, and concentrated to provide the title compound as a yellow oil (160 mg, 95.8% yield). LCMS (ESI): m / z [M+H]+calcd for C17H18N2O: 267.15, found 267.10. Step 3: Preparation of (3R)-2-oxo-1-[(1S)-1-phenylethyl]-3,4-dihydroquinolin-3-ylurea (Compound 1) To a solution of (3R)-3-amino-1-[(1S)-1-phenylethyl]-3,4-dihydroquinolin-2-one (155 mg, 0.582 mmol, 1 equiv.) in THF (3 mL) and water (0.3 mL) was added methanesulfonic acid (67.1 mg, 0.698 mmol, 1.2 equiv.) and potassium cyanate (141.6 mg, 1.746 mmol, 3 equiv.) at 0 °C. The reaction was stirred at 25 °C for 0.5 h. The reaction was quenched by addition to saturated sodium bicarbonate solution (100 mL) and extracted with dichloromethane (3 x 100 mL). The combined organic extracts were washed with water, brine, dried over sodium sulfate, filtered, and concentrated. The crude product was purified by preparative HPLC (XBridge Prep Shield RP18 OBD Column, 20-50% acetonitrile / water with 10 mmol ammonium formate) to afford the title compound as a white solid (60.9 mg, 33.8% yield). LCMS (ESI): m / z [M+H]+calcd for C18H19N3O2: 310.15, found 310.15.1H NMR (400 MHz, DMSO-d6) 7.41 – 7.35 (m, 2H), 7.34 – 7.24 (m, 4H), 7.12 – 6.97 (m, 2H), 6.68 (d, J = 8.1 Hz, 1H), 6.43 (d, J = 6.2 Hz, 1H), 6.25 (q, J = 7.1 Hz, 1H), 5.83 (s, 2H), 4.40 – 4.28 (m, 1H), 3.19 – 3.07 (m, 1H), 2.83 (t, J = 14.4 Hz, 1H), 1.68 (d, J = 7.2 Hz, 3H). Proposed synthesis of Compound 2: 1-((R)-7-chloro-2-oxo-1-((S)-1-phenylethyl)-1,2,3,4- tetrahydroquinolin-3-yl)urea Scheme 6 FH12898416.1 GPX-02125 Proposed preparation 1-((R)-7-chloro-2-oxo-1-((S)-1-phenylethyl)-1,2,3,4- tetrahydroquinolin-3-yl)urea (Compound 2) Compound 2 may be prepared following methods similar to Compound 1, wherein 1-bromo-4-chloro-2-nitrobenzene is used as the starting material in Step 1. Proposed synthesis of Compound 3: (R)-1-(1-benzyl-7-chloro-2-oxo-1,2,3,4- tetrahydroquinolin-3-yl)urea Scheme 7 FH12898416.1 GPX-02125 Proposed preparation (R)-1-(1-benzyl-7-chloro-2-oxo-1,2,3,4-tetrahydroquinolin-3- yl)urea (Compound 3) Compound 3 may be prepared following methods similar to Compound 1, wherein 1-bromo-4-chloro-2-nitrobenzene is used as the starting material in Step 1, and benzyl alcohol is used as a reagent in Step 3. Proposed synthesis of Compound 4: 1-((R)-1-((S)-1-(3-chlorophenyl)ethyl)-2-oxo- 1,2,3,4-tetrahydroquinolin-3-yl)urea Scheme 8 FH12898416.1 GPX-02125 Proposed preparation 1-((R)-7-chloro-2-oxo-1-((S)-1-phenylethyl)-1,2,3,4- tetrahydroquinolin-3-yl)urea (Compound 4) Compound 4 may be prepared following methods similar to Compound 1, wherein (R)-1-(3-chlorophenyl)ethan-1-ol is used as a reagent in Step 3. Proposed synthesis of Compound 5: 1-((R)-2-oxo-1-((S)-1-(3- (trifluoromethoxy)phenyl)ethyl)-1,2,3,4-tetrahydroquinolin-3-yl)urea Scheme 9 FH12898416.1 GPX-02125 Proposed preparation 1-((R)-2-oxo-1-((S)-1-(3-(trifluoromethoxy)phenyl)ethyl)-1,2,3,4- tetrahydroquinolin-3-yl)urea (Compound 5) Compound 5 may be prepared following methods similar to Compound 1, wherein (R)-1-(3-(trifluoromethoxy)phenyl)ethan-1-ol is used as a reagent in Step 3. Proposed synthesis of Compound 6: 1-((R)-2-oxo-1-((S)-1-(3-phenoxyphenyl)ethyl)- 1,2,3,4-tetrahydroquinolin-3-yl)urea Scheme 10 FH12898416.1 GPX-02125 Proposed preparation 1-((R)-2-oxo-1-((S)-1-(3-phenoxyphenyl)ethyl)-1,2,3,4- tetrahydroquinolin-3-yl)urea (Compound 6) Compound 6 may be prepared following methods similar to Compound 1, wherein (R)-1-(3-phenoxyphenyl)ethan-1-ol is used as a reagent in Step 3. Proposed synthesis of Compound 7: 1-((R)-2-oxo-1-((R)-1-phenylethyl)-1,2,3,4- tetrahydroquinolin-3-yl)urea Scheme 11 FH12898416.1 GPX-02125 Proposed preparation 1-((R)-7-chloro-2-oxo-1-((S)-1-phenylethyl)-1,2,3,4- tetrahydroquinolin-3-yl)urea (Compound 7) Compound 7 may be prepared following methods similar to Compound 1, wherein (S)-1-phenylethan-1-ol is a reagent in step 3. Proposed synthesis of Compound 8: N-((R)-2-oxo-1-((S)-1-phenylethyl)-1,2,3,4- tetrahydroquinolin-3-yl)cyclopropanecarboxamide Scheme 12 FH12898416.1 GPX-02125 Proposed preparation N-((R)-2-oxo-1-((S)-1-phenylethyl)-1,2,3,4-tetrahydroquinolin-3- yl)cyclopropanecarboxamide (Compound 8) Compound 8 may be prepared following methods similar to Compound 1, wherein step 5 is an amide coupling using HATU and cyclopropanecarboxylic acid. Proposed synthesis of Compound 10: 1-((R)-1-((S)-1-(3-(difluoromethoxy)phenyl)ethyl)- 2-oxo-1,2,3,4-tetrahydroquinolin-3-yl)urea Scheme 13 FH12898416.1 GPX-02125 Proposed preparation 1-((R)-1-((S)-1-(3-(difluoromethoxy)phenyl)ethyl)-2-oxo-1,2,3,4- tetrahydroquinolin-3-yl)urea (Compound 10) Compound 10 may be prepared following methods similar to Compound 1, wherein (R)-1-(3-(difluoromethoxy)phenyl)ethan-1-ol is a reagent in step 3. Proposed synthesis of Compound 11: 1-((R)-2-oxo-1-((S)-1-(3- (trifluoromethyl)phenyl)ethyl)-1,2,3,4-tetrahydroquinolin-3-yl)urea Scheme 14 FH12898416.1 GPX-02125 Proposed preparation 1-((R)-2-oxo-1-((S)-1-(3-(trifluoromethyl)phenyl)ethyl)-1,2,3,4- tetrahydroquinolin-3-yl)urea (Compound 11) Compound 11 may be prepared following methods similar to Compound 1, wherein (R)-1-(3-(trifluoromethyl)phenyl)ethan-1-ol is a reagent in step 3. Proposed synthesis of Compound 12: 1-((R)-1-((S)-1-(2,5-difluorophenyl)ethyl)-2-oxo- 1,2,3,4-tetrahydroquinolin-3-yl)urea Scheme 15 FH12898416.1 GPX-02125 Proposed preparation 1-((R)-1-((S)-1-(2,5-difluorophenyl)ethyl)-2-oxo-1,2,3,4- tetrahydroquinolin-3-yl)urea (Compound 12) Compound 12 may be prepared following methods similar to Compound 1, wherein (R)-1-(2,5-difluorophenyl)ethan-1-ol is a reagent in step 3. Proposed synthesis of Compound 13: 1-((R)-1-((S)-1-(2-fluoro-5- (trifluoromethyl)phenyl)ethyl)-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl)urea Scheme 16 FH12898416.1 GPX-02125 Proposed preparation 1-((R)-1-((S)-1-(2-fluoro-5-(trifluoromethyl)phenyl)ethyl)-2-oxo- 1,2,3,4-tetrahydroquinolin-3-yl)urea (Compound 13) Compound 13 may be prepared following methods similar to Compound 1, wherein (R)-1-(2-fluoro-5-(trifluoromethyl)phenyl)ethan-1-ol is a reagent in step 3. Proposed synthesis of Compound 14: 1-((R)-2-oxo-1-((S)-1-(6-(trifluoromethyl)pyridin- 2-yl)ethyl)-1,2,3,4-tetrahydroquinolin-3-yl)urea Scheme 17 FH12898416.1 GPX-02125 Proposed preparation 1-((R)-2-oxo-1-((S)-1-(6-(trifluoromethyl)pyridin-2-yl)ethyl)- 1,2,3,4-tetrahydroquinolin-3-yl)urea (Compound 14) Compound 14 may be prepared following methods similar to Compound 1, wherein (R)-1-(6-(trifluoromethyl)pyridin-2-yl)ethan-1-ol is a reagent in step 3. Synthesis of Compound 2: 1-((R)-7-chloro-2-oxo-1-((S)-1-phenylethyl)-1,2,3,4- tetrahydroquinolin-3-yl)urea Scheme 18 FH12898416.1 GPX-02125 Step 1: Preparation of tert-butyl N-[(3R)-7-chloro-2-oxo-1-[(1S)-1-phenylethyl]-3,4- dihydroquinolin-3-yl]carbamate To a solution of Intermediate 3 (1.5 g, 5.06 mmol, 1.0 equiv.) in THF (15 mL) was added (R)-1-phenyl-ethanol (0.74 g, 6.07 mmol, 1.2 equiv.) and triphenylphosphine (1.99 g, 7.58 mmol, 1.5 equiv.). The reaction was stirred at room temperature for 0.5 h under a nitrogen atmosphere. To the above mixture was added diisopropyl azodicarboxylate (1.53 g, 7.58 mmol, 1.5 equiv.) dropwise at 0 °C. The resulting mixture was stirred at 25 °C for an additional 1 h. The reaction was quenched by addition to water (50 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic extracts were washed with water, brine, dried over sodium sulfate, filtered and concentrated. The crude product was purified by silica gel chromatography (0-100% ethyl acetate / petroleum ether) to afford the title compound as a yellow oil (1 g, 49.35% yield). LCMS (ESI): m / z [M+Na]+calcd for C22H25ClN2O3: 423.15, found 423.10. Step 2: Preparation of (3R)-3-amino-7-chloro-1-[(1S)-1-phenylethyl]-3,4- dihydroquinolin-2-one The transformation was carried out similarly to in the synthesis of Compound 1 to afford the title compound as a yellow oil (740 mg, 98.7% yield). LCMS (ESI): m / z [M+H]+calcd for C17H17ClN2O: 301.10, found 301.10. Step 3: Preparation of 1-((R)-7-chloro-2-oxo-1-((S)-1-phenylethyl)-1,2,3,4- tetrahydroquinolin-3-yl)urea (Compound 2) The transformation was carried out similarly to in the synthesis of Compound 1. The crude product was purified by preparative HPLC (XBridge Prep C18 OBD Column, 35-60% acetonitrile / water with 10 mmol ammonium formate) to afford the title compound as a white solid (356.6 mg, 42.2% yield). LCMS (ESI): m / z [M+H]+calcd for C18H18ClN3O2: 344.11, FH12898416.1 GPX-02125 found 344.10.1H NMR (300 MHz, Methanol-d4) 7.21 – 7.47 (m, 6H), 6.99 – 7.06 (m, 1H), 6.71 – 6.77 (m, 1H), 6.33 – 6.47 (m, 1H), 4.39 – 4.54 (m, 1H), 3.13 – 3.25 (m, 1H), 2.81 – 2.97 (m, 1H), 1.67 – 1.78 (m, 3H). Synthesis of Compound 3: (R)-1-(1-benzyl-7-chloro-2-oxo-1,2,3,4-tetrahydroquinolin-3- yl)urea Step 1: Preparation of tert-butyl N-[(3R)-1-benzyl-7-chloro-2-oxo-3,4-dihydroquinolin-3- yl]carbamate To a solution of Intermediate 3 (400 mg, 1.35 mmol, 1 equiv.), benzyl alcohol (291.5 mg, 2.696 mmol, 2 equiv.) in THF (10 mL) was added triphenylphosphine (530.3 mg, 2.022 mmol, 1.5 equiv.). The reaction was stirred at 25°C for 0.5 h under nitrogen. Then diisopropyl azodicarboxylate (408.8 mg, 2.022 mmol, 1.5 equiv.) was added at 0 °C. The reaction was stirred at 25 °C for 3 h. The reaction was quenched by addition to water (50 mL) and was then extracted with ethyl acetate (3 x 50 mL). The combined organic extracts were washed with water, brine, dried over sodium sulfate, filtered, and concentrated. The residue was purified by silica gel chromatography (0-100% ethyl acetate / petroleum ether) to afford the title compound as a yellow oil (490 mg, 93.9% yield). LCMS (ESI): m / z [M+Na]+calcd for C22H25ClN2O3: 409.13, found 409.10. FH12898416.1 GPX-02125 Step 2: Preparation of (3R)-3-amino-1-benzyl-7-chloro-3,4-dihydroquinolin-2-one The transformation was carried out similarly to in the synthesis of Compound 1 to afford the title compound as a yellow oil (360 mg, 99.2% yield). LCMS (ESI): m / z [M+H]+calcd for C16H15ClN2O: 287.09, found 287.05. Step 3: Preparation of (R)-1-(1-benzyl-7-chloro-2-oxo-1,2,3,4-tetrahydroquinolin-3- yl)urea (Compound 3) The transformation was carried out similarly to in the synthesis of Compound 1. The crude product was purified by preparative HPLC (XBridge Prep C18 OBD Column, 27-48% acetonitrile / water with 10 mmol ammonium formate and 0.5% ammonia) to afford the title compound as a white solid. The chiral purity was improved through purification by chiral HPLC (CHIRALPAK-IB column, 50 / 50 MTBE / Ethanol with 0.5% of 2M ammonia in methanol) to again afford the title compound as a white solid (52.2 mg, 22.7% yield). LCMS (ESI): m / z [M+H]+calcd for C17H16ClN3O2: 330.09, found 330.05.1H NMR (400 MHz, DMSO-d6) 7.43 – 7.18 (m, 6H), 7.16 – 6.96 (m, 2H), 6.47 (d, J = 6.7 Hz, 1H), 5.83 (s, 2H), 5.33 – 5.03 (m, 2H), 4.54 – 4.36 (m, 1H), 3.27 – 3.11 (m, 1H), 2.96 – 2.79 (m, 1H). Synthesis of Compound 4: 1-((R)-1-((S)-1-(3-chlorophenyl)ethyl)-2-oxo-1,2,3,4- tetrahydroquinolin-3-yl)urea Scheme 20 FH12898416.1 GPX-02125 Step 1: Preparation of tert-butyl ((R)-1-((S)-1-(3-chlorophenyl) ethyl)-2-oxo-1,2,3,4- tetrahydroquinolin-3-yl) carbamate To a solution of Intermediate 2 (800 mg, 3.05 mmol, 1 equiv.) in tetrahydrofuran (30 mL) was added (1R)-1-(3-chlorophenyl) ethanol (716.4 mg, 4.575 mmol, 1.5 equiv.) and triphenylphosphine (1199.9 mg, 4.575 mmol, 1.5 equiv.). The reaction was stirred at room temperature for 1 h under nitrogen. Then diisopropyl azodicarboxylate (925.0 mg, 4.575 mmol, 1.5 equiv.) was added at 0 °C. The reaction was stirred at room temperature for 1 h under nitrogen, then was quenched by addition to water (100 mL) and extracted with ethyl acetate (3 x 100 mL). The combined organic extracts were washed with water, brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (0- 100% ethyl acetate / petroleum ether) to afford the title compound (420 mg, 34.4% yield). LCMS (ESI): m / z [M+H]+calcd for C22H25ClN2O3: 401.16, found 401.20. Step 2: Preparation of (R)-3-amino-1-((S)-1-(3-chlorophenyl) ethyl)-3,4-dihydroquinolin- 2(1H)-one The transformation was carried out similarly to in the synthesis of Compound 1 to afford the title compound as a yellow oil (250 mg, 83.3% yield). LCMS (ESI): m / z [M+H]+calcd for C17H17ClN2O: 301.10, found 301.10. Step 3: Preparation of 1-((R)-1-((S)-1-(3-chlorophenyl)ethyl)-2-oxo-1,2,3,4- tetrahydroquinolin-3-yl)urea (Compound 4) The transformation was carried out similarly to in the synthesis of Compound 1. The crude product was purified by preparative HPLC (YMC-Actus Triart C18 ExRS Column, 49- 73% acetonitrile / water with 10 mmol ammonium formate) to afford the title compound (66.5 FH12898416.1 GPX-02125 mg, 23.3% yield). LCMS (ESI): m / z [M+H]+calcd for C18H18ClN3O2: 344.11, found 344.15.1H NMR (400 MHz, DMSO-d6) 7.22 - 7.44 (m, 5H), 7.09 - 7.18 (m, 1H), 6.99 - 7.07 (m, 1H), 6.70 (d, J = 8.0 Hz, 1H), 6.42 (d, J = 8.0 Hz, 1H), 6.11 - 6.21 (m, 1H), 5.82 (s, 2H), 4.29 - 4.41 (m, 1H), 3.08 - 3.18 (m, 1H), 2.77 - 2.88 (m, 1H),1.68 (d, J = 8.0 Hz, 3H). Synthesis of Compound 5: 1-((R)-2-oxo-1-((S)-1-(3-(trifluoromethoxy)phenyl)ethyl)- 1,2,3,4-tetrahydroquinolin-3-yl)urea Step 1: Preparation of (R)-1-(3-(trifluoromethoxy)phenyl)ethan-1-ol To a stirred solution of (S)-1-methyl-3,3-diphenylhexahydropyrrolo[1,2- c][1,3,2]oxazaborole (1.0 M in THF, 1.63 g, 5.88 mmol, 0.4 equiv.) in THF (40 mL) was added borane dimethyl sulfide complex (2.0 M in THF, 1.67 g, 22.0 mmol, 1.5 equiv.) in portions at 0 °C. To the above mixture was added 1-[3-(trifluoromethoxy)phenyl]ethanone (3.00 g, 14.7 mmol, 1 equiv.) in portions at 0 °C. The resulting mixture was stirred at 0 °C for an additional 1 h, at which point the reaction was judged complete by TLC. The reaction was quenched with saturated ammonium chloride solution at 0 °C, then was added to water (50 mL). The resulting mixture was extracted with ethyl acetate (3 x 50 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica FH12898416.1 GPX-02125 gel column chromatography (1:5 ethyl acetate / petroleum ether) to afford the title compound as a yellow oil (2.10 g, 69.3% yield). Step 2: Preparation of tert-butyl ((R)-2-oxo-1-((S)-1-(3-(trifluoromethoxy)phenyl)ethyl)- 1,2,3,4-tetrahydroquinolin-3-yl)carbamate To a stirred solution of (R)-1-(3-(trifluoromethoxy)phenyl)ethan-1-ol (0.83 g, 4.03 mmol, 1.5 equiv.) and triphenylphosphine (1.06 g, 4.026 mmol, 1.5 equiv.) in THF (8 mL) was added Intermediate 2 (0.70 g, 2.68 mmol, 1 equiv.) in portions at room temperature. The resulting mixture was stirred at room temperature for 15 min under a nitrogen atmosphere. To the above mixture was added diisopropyl azodicarboxylate (0.81 g, 4.03 mmol, 1.5 equiv.) in portions at 0 °C. The resulting mixture was stirred at room temperature for an additional 2 h. The reaction was quenched with water (20 mL), and the resulting mixture was extracted with ethyl acetate (3 x 20 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (1:5 ethyl acetate / petroleum ether) to afford the title compound as a yellow oil (0.40 g, 33.1% yield). LCMS (ESI): m / z [M+H]+calcd for C23H25F3N2O4: 451.18, found 451.10. Step 3: Preparation of (R)-3-amino-1-((S)-1-(3-(trifluoromethoxy)phenyl)ethyl)-3,4- dihydroquinolin-2(1H)-one The transformation was carried out similarly to in the synthesis of Compound 1 to afford the title compound as a yellow oil (0.33 g, 96.4% yield). LCMS (ESI): m / z [M+H]+calcd for C18H17F3N2O2: 351.13, found 351.05. Step 4: Preparation of 1-((R)-2-oxo-1-((S)-1-(3-(trifluoromethoxy)phenyl)ethyl)-1,2,3,4- tetrahydroquinolin-3-yl)urea (Compound 5) The transformation was carried out similarly to in the synthesis of Compound 1. The crude product was purified by preparative HPLC (XBridge Shield RP18 OBD Column, 55- 65% acetonitrile / water with 0.05% ammonium formate) to afford the title compound as a white solid (52.0 mg, 16.0% yield). LCMS (ESI): m / z [M+H]+calcd for C19H18F3N3O3: 394.13, found 394.15.1H NMR (400 MHz, DMSO-d6) 7.45 – 7.57 (m, 1H), 7.23 – 7.39 (m, 4H), 7.11 – 7.19 (m, 1H), 7.00 – 7.09 (m, 1H), 6.65 – 6.77 (m, 1H), 6.34 – 6.48 (m, 1H), 6.08 – 6.21 (m, 1H), 5.78 – 5.90 (m, 2H), 4.26 – 4.42 (m, 1H), 3.08 – 3.20 (m, 1H), 2.76 – 2.91 (m, 1H), 1.68 – 1.76 (m, 3H).19F NMR (376 MHz, DMSO-d6) -56.63. FH12898416.1 GPX-02125 Synthesis of Compound 6: 1-((R)-2-oxo-1-((S)-1-(3-phenoxyphenyl)ethyl)-1,2,3,4- tetrahydroquinolin-3-yl)urea Step 1: Preparation of (R)-1-(3-phenoxyphenyl)ethan-1-ol To a stirred solution of (S)-1-methyl-3,3-diphenylhexahydropyrrolo[1,2- c][1,3,2]oxazaborole (1.04 g, 3.77 mmol, 0.4 equiv.) in THF (15 mL) was added borane dimethyl sulfide complex (2.0 M in THF, 3.2 mL, 0.66 eq) and 1-(3-phenoxyphenyl)ethan-1- one (2.01 g, 9.42 mmol, 1 equiv.) in portions at 0 °C. The resulting mixture was stirred at 0 °C for 1 h, at which point the reaction was judged complete by TLC. The reaction was quenched with water (50 mL), then the resulting mixture was extracted with ethyl acetate (3 x 50 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by silica gel column chromatography (1:1 ethyl acetate / petroleum ether) to afford the title compound as a colorless oil (1.70 g, 84.2% yield ). Step 2: Preparation of tert-butyl ((R)-2-oxo-1-((S)-1-(3-phenoxyphenyl)ethyl)-1,2,3,4- tetrahydroquinolin-3-yl)carbamate To a stirred solution of Intermediate 2 (700.1 mg, 2.669 mmol, 1 equiv.) in THF (8 mL) was added (R)-1-(3-phenoxyphenyl)ethan-1-ol (686.1 mg, 3.203 mmol, 1.2 equiv.) and triphenylphosphine (1049.9 mg, 4.003 mmol, 1.5 equiv.) in portions at room temperature under a nitrogen atmosphere. The mixture was stirred for 1 h at room temperature under a nitrogen FH12898416.1 GPX-02125 atmosphere. To the above mixture was added diisopropyl azodicarboxylate (809.4 mg, 4.003 mmol, 1.5 equiv.) in portions over 5 min at 0 °C under a nitrogen atmosphere. The resulting mixture was stirred at room temperature for an additional 2 h. The reaction was quenched with water (20 mL), and the resulting mixture was extracted with ethyl acetate (3 x 20 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by silica gel column chromatography (1:1 ethyl acetate / petroleum ether) to afford the title compound as a yellow oil (620.0 mg, 50.67% yield). LCMS (ESI): m / z [M+H]+calcd for C28H30N2O4: 459.22, found 459.15. Step 3: Preparation of (R)-3-amino-1-((S)-1-(3-phenoxyphenyl)ethyl)-3,4- dihydroquinolin-2(1H)-one The transformation was carried out similarly to in the synthesis of Compound 1 to afford the title compound as a yellow oil (732.5 mg, 70% yield). LCMS (ESI): m / z [M+H]+calcd for C23H22N2O2: 359.17, found 359.05. Step 4: Preparation of 1-((R)-2-oxo-1-((S)-1-(3-phenoxyphenyl)ethyl)-1,2,3,4- tetrahydroquinolin-3-yl)urea (Compound 6) The transformation was carried out similarly to in the synthesis of Compound 1. The crude product was purified by preparative HPLC (XBridge Shield RP18 OBD Column, 40- 65% acetonitrile / water with 0.1% ammonium bicarbonate) to afford the title compound as a white solid (48.7 mg, 14.5% yield). LCMS (ESI): m / z [M+H]+calcd for C24H23N3O3: 402.18, found 402.10.1H NMR (400 MHz, DMSO-d6) 7.32 – 7.50 (m, 3H), 7.29 (d, J = 7.4 Hz, 1H), 6.95 – 7.20 (m, 7H), 6.82 – 6.90 (m, 1H), 6.75 (d, J = 8.1 Hz, 1H), 6.42 (s, 1H), 6.17 (q, J = 7.0 Hz, 1H), 5.80 (d, J = 3.0 Hz, 2H), 4.70 (s, 1H), 3.02 – 3.20 (m, 1H), 2.70 – 2.90 (m, 1H), 1.66 (d, J = 7.1 Hz, 3H). Synthesis of Compound 7: 1-((R)-2-oxo-1-((R)-1-phenylethyl)-1,2,3,4- tetrahydroquinolin-3-yl)urea Scheme 23 FH12898416.1 GPX-02125 Step 1: Preparation of tert-butyl ((R)-2-oxo-1-((R)-1-phenylethyl)-1,2,3,4- tetrahydroquinolin-3-yl)carbamate To a solution of Intermediate 2 (600 mg, 2.29 mmol, 1 equiv.) and (S)-1-phenylethanol (558.8 mg, 4.574 mmol, 2.0 equiv.) in THF (10 mL) was added triphenylphosphine (899.9 mg, 3.431 mmol, 1.5 equiv.) at room temperature under nitrogen. The reaction was stirred at room temperature for 0.5 h under nitrogen. Then diisopropyl azodicarboxylate (693.8 mg, 3.431 mmol, 1.5 equiv.) was added at 0 °C under a nitrogen atmosphere. The reaction was stirred at room temperature for 2 h under nitrogen, then was quenched with water (30 mL) and extracted with ethyl acetate (3 x 30 mL). The combined organic extracts were washed with water, brine, dried over sodium sulfate, filtered and concentrated. The crude product was purified by silica gel chromatography (0-100% ethyl acetate / petroleum ether) to afford the title compound as a white solid (220 mg, 26.3%). MS (ESI): mass calcd for C22H26N2O3: 367.20, found 367.20. Step 2: Preparation of (R)-3-amino-1-((R)-1-phenylethyl)-3,4-dihydroquinolin-2(1H)-one The transformation was carried out similarly to in the synthesis of Compound 1 to afford the title compound as a yellow oil (150 mg, 93.8% yield). LCMS (ESI): m / z [M+H]+calcd for C17H18N2O: 367.15, found 267.15. Step 3: Preparation of 1-((R)-2-oxo-1-((R)-1-phenylethyl)-1,2,3,4-tetrahydroquinolin-3- yl)urea (Compound 7) The transformation was carried out similarly to in the synthesis of Compound 1. The crude product was purified by preparative HPLC (C18 Column, 0-100% acetonitrile / water) to afford the title compound as a white solid (50.4 mg, 19.7% yield). LCMS (ESI): m / z [M+H]+calcd for C18H19N3O2: 310.15, found 310.15.1H NMR (300 MHz, Methanol-d4) 7.21 - 7.40 FH12898416.1 GPX-02125 (m, 4H), 7.10 - 7.21 (m, 2H), 6.80 - 7.10 (m, 3H), 6.10 (q, J = 7.1 Hz, 1H), 4.27 - 4.45 (m, 1H), 3.09 - 3.22 (m, 1H), 2.85 - 3.09 (t, J = 14.0 Hz, 1H), 1.91 (d, J = 7.1 Hz, 3H). Synthesis of Compound 8: N-((R)-2-oxo-1-((S)-1-phenylethyl)-1,2,3,4- tetrahydroquinolin-3-yl)cyclopropanecarboxamide Scheme 24 Step 1: Preparation of N-((R)-2-oxo-1-((S)-1-phenylethyl)-1,2,3,4-tetrahydroquinolin-3- yl)cyclopropanecarboxamide (Compound 8) (3R)-3-amino-1-[(1S)-1-phenylethyl]-3,4-dihydroquinolin-2-one was prepared as described in the synthesis of Compound 1. To a solution of (3R)-3-amino-1-[(1S)-1-phenylethyl]-3,4-dihydroquinolin-2-one (200 mg, 0.751 mmol, 1 equiv.) in dichloromethane (5 mL) was added an aqueous 0.4 M sodium carbonate solution (0.5 mL) and cyclopropanecarbonyl chloride (157.0 mg, 1.502 mmol, 2.0 equiv.). The reaction was stirred at room temperature for 3 h, then was quenched with water (50 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic extracts were washed with water, brine, dried over sodium sulfate, filtered and concentrated. The crude product was purified by preparative HPLC (YMC-Actus Triart C18 ExRS Column, 49-73% acetonitrile / water with 10 mmol ammonium bicarbonate) to afford the title compound (31.1 mg, 12.4% yield). LCMS (ESI): m / z [M+H]+calcd for C21H22N2O2: 335.17, found 335.15.1H NMR (400 MHz, DMSO-d6) 8.53 (d, J = 12.0 Hz, 1H), 7.34 - 7.42 (m, 2H), 7.23 - 7.33 (m, 4H), 7.05 - 7.14 (m, 1H), 6.97 - 7.04 (m, 1H), 6.69 (d, J = 6.0 Hz, 1H), 6.20 - 6.30 (m, 1H), 4.56 - 4.68 (m, 1H), 2.88 - 3.05 (m, 2H), 1.73 - 1.82 (m, 1H), 1.68 (d, J = 8.0 Hz, 3H), 0.66 - 0.75 (m, 4H). FH12898416.1 GPX-02125 Synthesis of Compound 9: 2-((S)-2-oxo-1-((S)-1-phenylethyl)-1,2,3,4-tetrahydroquinolin- 3-yl)acetamide Step 1: Preparation of 1-[(1S)-1-phenylethyl]-3,4-dihydroquinolin-2-one To a solution of 3,4-dihydro-1H-quinolin-2-one (2 g, 13.6 mmol, 1 equiv.) in toluene (20 mL) was added (R)-1-phenyl-ethanol (2.49 g, 20.4 mmol, 1.5 equiv.) and (tributylphosphoranylidene)acetonitrile (9.84 g, 40.767 mmol, 3 equiv.) under nitrogen. The reaction was stirred at 100 °C for 16 h under nitrogen. The mixture was allowed to cool to room temperature, then was quenched with water (300 mL) and extracted with ethyl acetate (3 x 200 mL). The combined extracts were washed with water, brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (0-100% ethyl acetate / petroleum ether) to provide the title compound as a yellow oil (1.8 g, 52.7% yield). LCMS (ESI): m / z [M+H]+calcd for C17H17NO: 252.13, found 252.15. Step 2: Preparation of tert-butyl 2-{2-oxo-1-[(1S)-1-phenylethyl]-3,4-dihydroquinolin-3- yl}acetate To a solution of 1-[(1S)-1-phenylethyl]-3,4-dihydroquinolin-2-one (2.8 g, 11.1 mmol, 1 equiv.) in THF (20 mL) was added lithium diisopropylamide (11.1 mL, 22.3 mmol, 2 equiv.) FH12898416.1 GPX-02125 at -78 °C under nitrogen. The reaction was stirred at -78 °C for 1 h under nitrogen, then tert- butyl 2-bromoacetate (4.35 g, 22.3 mmol, 2 equiv.) was added at -78 °C under nitrogen. The reaction was stirred at 25 °C for 2 h under nitrogen, then was quenched with water (100 mL) and extracted with ethyl acetate (3 x 100 mL). The combined organic extracts were washed with water, brine, dried over sodium sulfate, filtered and concentrated. The crude product was purified by silica gel chromatography (0-100% ethyl acetate / petroleum ether) to afford the title compound as a yellow oil (1.9 g, 46.7% yield). LCMS (ESI): m / z [M+H]+calcd for C23H27NO3: 366.20, found 366.25. Step 3: Preparation of {2-oxo-1-[(1S)-1-phenylethyl]-3,4-dihydroquinolin-3-yl}acetic acid To a solution of tert-butyl 2-{2-oxo-1-[(1S)-1-phenylethyl]-3,4-dihydroquinolin-3- yl}acetate (1 g, 2.74 mmol, 1 equiv.) in THF (4 mL), MeOH (4 mL) and water (2 mL) was added lithium hydroxide monohydrate (1.15 g, 27.4 mmol, 10 equiv.). The reaction was stirred at 25 °C for 3 h. The mixture was acidified to pH<7 with 1N hydrochloric acid. The resulting mixture was added to water (300 mL) and extracted with ethyl acetate (3 x 200 mL). The combined organic extracts were washed with water, brine, dried over sodium sulfate, filtered and concentrated to afford the title compound as yellow solid (800 mg, 94.8% yield). LCMS (ESI): m / z [M+H]+calcd for C19H19NO3: 310.14, found 310.10. Step 4: Preparation of 2-((S)-2-oxo-1-((S)-1-phenylethyl)-1,2,3,4-tetrahydroquinolin-3- yl)acetamide (Compound 9) To a solution of {2-oxo-1-[(1S)-1-phenylethyl]-3,4-dihydroquinolin-3-yl}acetic acid (500 mg, 1.62 mmol, 1 equiv.) in DMF (10 mL) was added N,N-diisopropylethylamine (835.5 mg, 6.464 mmol, 4 equiv.), HATU (614.5 mg, 1.616 mmol, 1 equiv.) and ammonium chloride (345.8 mg, 6.464 mmol, 4 equiv.). The reaction was stirred at 25 °C for 1 h, then was quenched with water (100 mL) and extracted with ethyl acetate (3 x 100 mL). The combined organic extracts were washed with water, brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by preparative HPLC (Xselect CSH Phenyl Hexy Column, 32-48% acetonitrile / water with 0.05% trifluoroacetic acid) to afford the title compound as a white solid (45.5 mg, 9.13% yield). LCMS (ESI): m / z [M+H]+calcd for C19H20N2O2: 309.16, found 309.05.1H NMR (400 MHz, DMSO-d6) 7.51 – 7.13 (m, 7H), 7.04 – 6.96 (m, 1H), 6.96 – 6.82 (m, 2H), 6.81 – 6.66 (m, 1H), 6.17 – 6.01 (m, 1H), 3.02 – 2.88 (m, 2H), 2.87 – 2.72 (m, 1H), 2.70 – 2.58 (m, 1H), 2.27 – 2.13 (m, 1H), 1.77 (d, J = 7.1 Hz, 3H). FH12898416.1 GPX-02125 Synthesis of Compound 10: 1-((R)-1-((S)-1-(3-(difluoromethoxy)phenyl)ethyl)-2-oxo- 1,2,3,4-tetrahydroquinolin-3-yl)urea Step 1: Preparation of (R)-1-(3-(difluoromethoxy)phenyl)ethan-1-ol To a stirred solution of (S)-(-)-2-methyl-CBS-oxazaborolidine (1.19 g, 4.29 mmol, 0.4 equiv.) in THF (15 mL) was added borane dimethyl sulfide complex (2.0 M in THF, 3.6 mL, 0.66 equiv.) and 1-(3-(difluoromethoxy)phenyl)ethan-1-one (2.00 g, 10.7 mmol, 1 equiv.) in portions at 0 °C. The resulting mixture was stirred at 0 °C for 1 h, at which point the reaction was judged complete by TLC. The reaction was quenched with water (50 mL), and the resulting mixture was extracted with ethyl acetate (3 x 50 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by silica gel chromatography (1:1 ethyl acetate / petroleum ether) to afford the title compound as a colorless oil (1.61 g, 79.1% yield). Step 2: tert-butyl ((R)-1-((S)-1-(3-(difluoromethoxy)phenyl)ethyl)-2-oxo-1,2,3,4- tetrahydroquinolin-3-yl)carbamate To a solution of Intermediate 2 (600.1 mg, 2.287 mmol, 1 equiv.) in THF (7 mL) was added (R)-1-(3- (difluoromethoxy)phenyl) ethan-1-ol (516.5 mg, 2.744 mmol, 1.2 equiv.) and triphenylphosphine (899.9 mg, 3.430 mmol, 1.5 equiv.). The reaction was stirred at room temperature for 0.5 h under nitrogen. Diisopropyl azodicarboxylate (693.8 mg, 3.430 mmol, FH12898416.1 GPX-02125 1.5 equiv.) was then added at 0 °C under nitrogen. The resulting mixture was stirred for an additional 1 h at room temperature, then was quenched with water (20 mL) and extracted with ethyl acetate (3 x 20 mL). The combined organic extracts were washed with water, brine, dried over sodium sulfate, filtered and concentrated. The crude product was purified by silica gel chromatography (1:1 ethyl acetate / petroleum ether) to afford the title compound as a yellow oil (390.0 mg, 39.43% yield). LCMS (ESI): m / z [M+Na]+calcd for C23H26F2N2O4: 455.18, found 455.10. Step 3: Preparation of (R)-3-amino-1-((S)-1-(3-phenoxyphenyl)ethyl)-3,4- dihydroquinolin-2(1H)-one The transformation was carried out similarly to in the synthesis of Compound 1 to afford the title compound as a colorless oil (349.8 mg, 92.46% yield). LCMS (ESI): m / z [M+H]+calcd for C18H18F2N2O2: 333.14, found 333.10. Step 4: Preparation of 1-((R)-1-((S)-1-(3-(difluoromethoxy)phenyl)ethyl)-2-oxo-1,2,3,4- tetrahydroquinolin-3-yl)urea (Compound 10) The transformation was carried out similarly to in the synthesis of Compound 1. The crude product was purified by preparative HPLC (XBridge Shield RP18 OBD Column, 27- 47% acetonitrile / water with 0.05% ammonium bicarbonate) to afford the title compound as a white solid (69.9 mg, 30.9% yield). LCMS (ESI): m / z [M+H]+calcd for C19H19F2N3O3: 376.14, found 376.15.1H NMR (400 MHz, DMSO-d6) 7.40 – 7.50 (m, 1H), 7.25 – 7.35 (m, 2H), 7.09 – 7.20 (m, 4H), 6.82 – 7.00 (m, 1H), 6.70 (d, J = 8.1 Hz, 1H), 6.42 (d, J = 6.2 Hz, 1H), 6.18 (q, J = 7.1 Hz, 1H), 5.83 (s, 2H), 4.22 – 4.45 (m, 1H), 3.10 – 3.20 (m, 1H), 2.78 – 2.90 (m, 1H), 1.68 (d, J = 7.1 Hz, 3H).19F NMR (376 MHz, DMSO-d6) -82.01. Synthesis of Compound 11: 1-((R)-2-oxo-1-((S)-1-(3-(trifluoromethyl)phenyl)ethyl)- 1,2,3,4-tetrahydroquinolin-3-yl)urea Scheme 27 FH12898416.1 GPX-02125 Step 1: Preparation of tert-butyl N-[(3R)-2-oxo-1-[(1S)-1-[3- (trifluoromethyl)phenyl]ethyl]-3,4-dihydroquinolin-3-yl]carbamate To a stirred solution of (1R)-1-[3-(trifluoromethyl)phenyl]ethanol (347.9 mg, 1.830 mmol, 1 equiv.) in THF (30.0 mL) was added Intermediate 2 (480.0 mg, 1.830 mmol, 1 equiv.) and triphenylphosphine (719.9 mg, 2.745 mmol, 1.5 equiv.) at 0 °C under a nitrogen atmosphere. The resulting mixture was stirred for 30 min at 0 °C under a nitrogen atmosphere. Diisopropyl azodicarboxylate (555.0 mg, 2.745 mmol, 1.5 equiv.) was then added dropwise at 0 °C. The resulting mixture was stirred for 30 min at room temperature under a nitrogen atmosphere. The reaction was quenched with water (30 mL), then the resulting mixture was extracted with ethyl acetate (3 x 30 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated. The crude proudct was purified by silica gel chromatography (0-60% ethyl acetate / petroleum ether) to afford the title compound as a yellow oil (400.0 mg, 50.31% yield). LCMS (ESI): m / z [M+H]+calcd for C23H25F3N2O3: 435.19, found 435.10. Step 2: Preparation of (3R)-3-amino-1-[(1S)-1-[3-(trifluoromethyl)phenyl]ethyl]-3,4- dihydroquinolin-2-one The transformation was carried out similarly to in the synthesis of Compound 1 to afford the title compound as a colorless oil (280.0 mg, 84.34% yield). LCMS (ESI): m / z [M+H]+calcd for C18H17F3N2O: 335.13, found 335.00. Step 3: Preparation of 1-((R)-2-oxo-1-((S)-1-(3-(trifluoromethyl)phenyl)ethyl)-1,2,3,4- tetrahydroquinolin-3-yl)urea (Compound 11) The transformation was carried out similarly to in the synthesis of Compound 1. The crude product was purified by preparative HPLC (XBridge Prep OBD C18 Column, 32-48% FH12898416.1 GPX-02125 acetonitrile / water with 10 mmol ammonium bicarbonate and 0.05% ammonia) to afford the title compound as a white solid (63.5 mg, 22.5% yield). LCMS (ESI): m / z [M+H]+calcd for C19H18F3N3O2: 378.14, found 378.15.1H NMR (400 MHz, DMSO-d6) 7.72 – 7.51 (m, 4H), 7.32 (d, J = 7.3 Hz, 1H), 7.16 (t, J = 7.8 Hz, 1H), 7.05 (t, J = 7.4 Hz, 1H), 6.76 (d, J = 8.2 Hz, 1H), 6.41 (d, J = 6.3 Hz, 1H), 6.17 – 6.09 (m, 1H), 5.81 (s, 2H), 4.39 – 4.28 (m, 1H), 3.18 – 3.09 (m, 1H), 2.82 (t, J = 14.4 Hz, 1H), 1.75 (d, J = 7.1 Hz, 3H).19F NMR (376 MHz, DMSO- d6) -60.91. Synthesis of Compound 12: 1-((R)-1-((S)-1-(2,5-difluorophenyl)ethyl)-2-oxo-1,2,3,4- tetrahydroquinolin-3-yl)urea Step 1: Preparation of tert-butyl N-[(3R)-1-[(1S)-1-(2,5-difluorophenyl)ethyl]-2-oxo-3,4- dihydroquinolin-3-yl]carbamate To a solution of Intermediate 2 (894 mg, 3.408 mmol, 1.1 equiv.) in tetrahydrofuran (20 mL) was added (1R)-1-(2,5-difluorophenyl)ethanol (490 mg, 3.098 mmol, 1.00 equiv.), triphenylphosphine (1219.0 mg, 4.647 mmol, 1.5 equiv.). The reaction was stirred at 25 °C for 0.5 h under nitrogen. Diisopropyl azodicarboxylate (939.8 mg, 4.647 mmol, 1.5 equiv.) was FH12898416.1 GPX-02125 then added at 0 °C. The reaction was stirred at 25 °C for 3 h, then was quenched with water (100 mL) and extracted with ethyl acetate (3 x 100 mL). The combined organic extracts were washed with water, brine, dried over sodium sulfate, filtered and concentrated. The crude product was purified by silica gel chromatography (0-100% ethyl acetate / petroleum ether) to afford the title compound as a yellow oil (290 mg, 23.3% yield). LCMS (ESI): m / z [M+H]+calcd for C22H24F2N2O3: 403.18, found 403.20. Step 2: Preparation of (3R)-3-amino-1-[(1S)-1-(2,5-difluorophenyl)ethyl]-3,4- dihydroquinolin-2-one The transformation was carried out similarly to in the synthesis of Compound 1 to afford the title compound as a yellow oil (200 mg, 92.2% yield). LCMS (ESI): m / z [M+H]+calcd for C17H16F2N2O: 303.13, found 303.05. Step 3: Preparation of 1-((R)-1-((S)-1-(2,5-difluorophenyl)ethyl)-2-oxo-1,2,3,4- tetrahydroquinolin-3-yl)urea (Compound 12) The transformation was carried out similarly to in the synthesis of Compound 1. The crude product was purified by preparative HPLC (YMC-Actus Triart C18 ExRS Column, 28- 53% acetonitrile / water with 10 mmol ammonium bicarbonate) to afford the title compound as a white solid (58.6 mg, 25.7% yield). LCMS (ESI): m / z [M+H]+calcd for C18H17F2N3O2: 346.13, found 346.05.1H NMR (300 MHz, DMSO-d6) 7.44 – 7.26 (m, 3H), 7.25 – 6.99 (m, 4H), 6.33 (d, J = 6.3 Hz, 1H), 5.83 – 5.64 (m, 3H), 4.23 – 4.06 (m, 1H), 3.13 – 2.97 (m, 1H), 2.78 – 2.55 (m, 1H), 1.79 (d, J = 7.0 Hz, 3H).19F NMR (282 MHz, DMSO-d6) -119.28, - 121.71. Synthesis of Compound 13: 1-((R)-1-((S)-1-(2-fluoro-5-(trifluoromethyl)phenyl)ethyl)-2- oxo-1,2,3,4-tetrahydroquinolin-3-yl)urea Scheme 29 FH12898416.1 GPX-02125 Step 1: Preparation of (1R)-1-[2-fluoro-5-(trifluoromethyl) phenyl] ethanol To a stirred solution of (S)-(-)-2-methyl-CBS-oxazaborolidine (0.27 g, 0.970 mmol, 0.2 equiv.) in THF (10 mL) was added 1-[2-fluoro-5-(trifluoromethyl) phenyl] ethanone (1 g, 4.85 mmol, 1 equiv.) and borane dimethyl sulfide complex (2.0 M in THF, 0.24 g, 3.202 mmol, 0.66 equiv.) in portions at 0 °C. The resulting mixture was stirred at 0 °C for 1 h, at which point the reaction was judged complete by TLC. The reaction was quenched with water at 0 °C, and the resulting mixture was extracted with ethyl acetate (3 x 30 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel chromatography (1:1 ethyl acetate / petroleum ether) to afford the title compound as a yellow oil (760 mg, 75.26% yield). Step 2: Preparation of tert-butyl N-[(3R)-1-[(1S)-1-[2-fluoro-5-(trifluoromethyl) phenyl] ethyl]-2-oxo-3,4-dihydroquinolin-3-yl] carbamate A solution of (1R)-1-[2-fluoro-5-(trifluoromethyl) phenyl] ethanol (750.3 mg, 3.605 mmol, 1 equiv.) in THF (6 mL) was treated with Intermediate 2 (1418.2 mg, 5.407 mmol, 1.5 equiv.) and triphenylphospine (1418.1 mg, 5.407 mmol, 1.5 equiv.) at room temperature for 30 min under a nitrogen atmosphere. The resulting mixture was stirred at room temperature for 1 h under nitrogen atmosphere. Diisopropyl azodicarboxylate (1093.3 mg, 5.407 mmol, 1.5 equiv.) was then added dropwise at 0 °C. The resulting mixture was stirred at room temperature for 1 h under nitrogen. The reaction was quenched with water at room temperature, then the resulting mixture was extracted with ethyl acetate (3 x 30 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was FH12898416.1 GPX-02125 purified by silica gel chromatography (1:5 ethyl acetate / petroleum ether) to afford the title compound as a yellow oil (410 mg, 25.1% yield). LCMS (ESI): m / z [M+H]+calcd for C23H24F4N2O3: 453.18, found 453.10. Step 3: Preparation of (3R)-3-amino-1-[(1S)-1-[2-fluoro-5-(trifluoromethyl) phenyl] ethyl]-3,4-dihydroquinolin-2-one The transformation was carried out similarly to in the synthesis of Compound 1 to afford the title compound as a yellow oil (340.5 mg, 96.70% yield). LCMS (ESI): m / z [M+H]+calcd for C18H16F4N2O: 353.12, found 353.05. Step 4: Preparation of 1-((R)-1-((S)-1-(2-fluoro-5-(trifluoromethyl)phenyl)ethyl)-2-oxo- 1,2,3,4-tetrahydroquinolin-3-yl)urea (Compound 13) The transformation was carried out similarly to in the synthesis of Compound 1. The crude product was purified by preparative HPLC (YMC-Actus Triart C18 ExRS Column, 32- 48% acetonitrile / water with 10 mmol ammonium bicarbonate and 0.05% ammonia) to afford the title compound as a white solid (67.2 mg, 20.0% yield). LCMS (ESI): m / z [M+H]+calcd for C19H17F4N3O2: 396.13, found 396.15.1H NMR (300 MHz, DMSO-d6) 7.86 (d, J = 6.9 Hz, 1H), 7.71 (s, 1H), 7.42 – 7.21 (m, 4H), 7.21 – 7.00 (m, 1H), 6.30 (d, J = 6.3 Hz, 1H), 5.70 (s, 3H), 4.11 (dt, J = 14.2, 5.8 Hz, 1H), 3.04 (dd, J = 14.6, 5.4 Hz, 1H), 2.61 (d, J = 14.3 Hz, 1H), 1.87 (d, J = 7.0 Hz, 3H).19F NMR (282 MHz, DMSO-d6) -60.156, -110.127. Synthesis of Compound 14: 1-((R)-2-oxo-1-((S)-1-(6-(trifluoromethyl)pyridin-2-yl)ethyl)- 1,2,3,4-tetrahydroquinolin-3-yl)urea Scheme 30 FH12898416.1 GPX-02125 Step 1: Preparation of (R)-1-(6-(trifluoromethyl)pyridin-2-yl)ethan-1-ol To a stirred solution of (3aS)-1-methyl-3,3-diphenyl-hexahydropyrrolo[1,2- c][1,3,2]oxazaborole (293.1 mg, 1.057 mmol, 0.20 equiv.) in tetrahydrofuran (15 mL) was added borane-dimethyl sulfide complex (2.0 M in tetrahydrofuran, 602.4 mg, 7.930 mmol, 1.50 equiv.) and 1-(6-(trifluoromethyl)pyridin-2-yl)ethan-1-one 1-[6-(trifluoromethyl)pyridin-2- yl]ethanone (1 g, 5.287 mmol, 1 equiv.) under air at 0 °C. The reaction was stirred at 0 °C for 3h. The resulting mixture was quenched with water (50 mL) and extracted with ethyl acetate (3 x 50 mL). The combined extracts were washed with water, brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by column chromatography on silica gel (0-100% ethyl acetate / petroleum ether) to give the title compound as a yellow oil (900 mg, 89.1% yield). LCMS (ESI): m / z [M+H]+calcd. for C8H8F3NO: 192.06, found 192.05. Step 2: Preparation of tert-butyl ((R)-2-oxo-1-((S)-1-(6-(trifluoromethyl)pyridin-2- yl)ethyl)-1,2,3,4-tetrahydroquinolin-3-yl)carbamate To a solution of (R)-1-(6-(trifluoromethyl)pyridin-2-yl)ethan-1-ol (500 mg, 2.616 mmol, 1 equiv.) in tetrahydrofuran (8 mL) was added Intermediate 2 (686.1 mg, 2.616 mmol, 1.00 equiv.) and triphenylphosphine (1029.1 mg, 3.923 mmol, 1.50 equiv.) under nitrogen. The reaction was stirred at rt for 0.5 h under nitrogen then diisopropyl azodicarboxylate (793.3 mg, 3.923 mmol, 1.50 equiv.) was added to the mixture at 0 °C. The reaction was stirred at room temperature for 1h under nitrogen. Then the reaction was quenched with water (50 mL) and extracted with dichloromethane (3 x 50 mL). The combined extracts were washed with water, brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by column chromatography on silica gel (0-100% ethyl acetate / petroleum ether) to give tert-butyl ((R)-2- FH12898416.1 GPX-02125 oxo-1-((S)-1-(6-(trifluoromethyl)pyridin-2-yl)ethyl)-1,2,3,4-tetrahydroquinolin-3- yl)carbamate (440 mg, 38.6% yield) as a yellow oil. LCMS (ESI): m / z [M+H]+calcd. for C22H24F3N3O3: 436.18, found 379.95 [M+H-tBu]+. Step 3: Preparation of (R)-3-amino-1-((S)-1-(6-(trifluoromethyl)pyridin-2-yl)ethyl)-3,4- dihydroquinolin-2(1H)-one The transformation was carried out similarly to in the synthesis of Compound 1 to afford the title compound as a hydrochloride salt as a yellow oil (300 mg, 87.6% yield). LCMS (ESI): m / z [M+H]+calcd. for C17H16F3N3O: 336.13, found: 336.00. Step 4: Preparation of 1-((R)-2-oxo-1-((S)-1-(6-(trifluoromethyl)pyridin-2-yl)ethyl)- 1,2,3,4-tetrahydroquinolin-3-yl)urea (Compound 14) The transformation was carried out similarly to in the synthesis of Compound 1. The crude product was purified by preparative HPLC (XBridge Prep OBD C18 Column, 28-44% acetonitrile / water with 10 mmol ammonium bicarbonate) to afford the title compound as a white solid (90.1 mg, 26.8% yield). LCMS (ESI): m / z [M+H]+calcd. for C18H17F3N4O2: 379.13, found 379.10.1H-NMR (400 MHz, DMSO-d6) 8.00 – 8.08 (m, 1H), 7.78 (d, J = 7.7 Hz, 1H), 7.69 (d, J = 8.1 Hz, 1H), 7.33 (d, J = 7.3 Hz, 1H), 7.16 – 7.25 (m, 1H), 7.02 – 7.11 (m, 1H), 6.90 (d, J = 8.2 Hz, 1H), 6.34 (d, J = 6.2 Hz, 1H), 5.94 (d, J = 7.2 Hz, 1H), 5.78 (s, 2H), 4.21 – 4.32 (m, 1H), 3.08 – 3.17 (m, 1H), 2.79 – 2.90 (m, 1H), 1.80 (d, J = 7.0 Hz, 3H).19F-NMR (376 MHz, DMSO-d6) -66.50. Synthesis of Compound 15: 1-((R)-1-((S)-1-(3-(benzyloxy)phenyl)ethyl)-2-oxo-1,2,3,4- tetrahydroquinolin-3-yl)urea Scheme 31 FH12898416.1 GPX-02125 Step 1: Preparation of (1R)-1-[3-(benzyloxy)phenyl] ethanol To a stirred solution of (3aS)-1-methyl-3,3-diphenyl-hexahydropyrrolo[1,2-c] [1,3,2] oxazaborole (0.24 g, 0.884 mmol, 0.2 equiv.) in tetrahydrofuran (10 mL) were added 1-[3- (benzyloxy) phenyl] ethanone (1 g, 4.419 mmol, 1 equiv.) and borane dimethyl sulfide complex (2.0 M in tetrahydrofuran, 0.22 g, 2.917 mmol, 0.66 equiv.) in portions at 0 °C. The resulting mixture was stirred at 0 °C for 1 h. The reaction was monitored by TLC. The reaction was quenched with ice water at 0 °C. The resulting mixture was extracted with ethyl acetate (3 x 30 mL). The combined organic layers were dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (1 / 1 ethyl acetate / petroleum ether) to afford (1R)-1-[3- (benzyloxy) phenyl] ethanol as a yellow oil (810.2 mg, 80.3% yield). Step 2: Preparation of tert-butyl N-[(3R)-1-[(1S)-1-[3-(benzyloxy) phenyl] ethyl]-2-oxo- 3,4-dihydroquinolin-3-yl] carbamate A solution of (1R)-1-[3-(benzyloxy) phenyl] ethanol (800.3 mg, 3.506 mmol, 1 equiv.) in tetrahydrofuran (15 mL) was treated with Intermediate 2 (1379.33 mg, 5.259 mmol, 1.5 equiv.) and triphenylphosphine (1379.24 mg, 5.259 mmol, 1.5 equiv.) at room temperature for 30 min under nitrogen atmosphere. The resulting mixture was stirred at room temperature for 1 h under nitrogen. Then diisopropyl azodicarboxylate (1063.3 mg, 5.259 mmol, 1.5 equiv.) was added dropwise at 0 °C. The resulting mixture was stirred at room temperature for 1 h under nitrogen. The reaction was quenched with water at room temperature. The resulting mixture was extracted with ethyl acetate (3 x 30 mL). The combined organic layers were dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with petroleum ether / ethyl acetate (5:1) to afford the title compound as FH12898416.1 GPX-02125 a yellow oil (300 mg, 18.1% yield). LCMS (ESI): m / z [M+Na]+calcd. for C29H32N2O4: 496.23, found 495.15. Step 3: Preparation of (3R)-3-amino-1-[(1S)-1-[3-(benzyloxy) phenyl] ethyl]-3,4- dihydroquinolin-2-one The transformation was carried out similarly to in the synthesis of Compound 1 to afford the title compound as a yellow oil (220.3 mg, 87.7% yield). LCMS (ESI): m / z [M+H]+calcd. for C24H24N2O2: 373.19, found 373.15. Step 4: Preparation of (3R)-1-[(1S)-1-[3-(benzyloxy) phenyl] ethyl]-2-oxo-3,4- dihydroquinolin-3-ylurea (Compound 15) The transformation was carried out similarly to in the synthesis of Compound 1. The crude product was purified by preparative HPLC (YMC-Actus Tiart C18 ExRS, 40-65% acetonitrile / water with 10 mmol ammonium bicarbonate) to afford the title compound as a white solid (98.4 mg, 46.0% yield). LCMS(ESI): m / z [M+H]+calcd. for C25H25N3O3: 416.19, found: 416.20.1H NMR (300 MHz, DMSO-d6) 7.52 – 7.24 (m, 7H), 7.14 – 6.83 (m, 5H), 6.66 (d, J = 7.9 Hz, 1H), 6.43 (d, J = 6.3 Hz, 1H), 6.30 – 6.04 (m, 1H), 5.83 (s, 2H), 5.09 (s, 2H), 4.33 (dt, J = 14.5, 5.8 Hz, 1H), 3.17 – 2.75 (m, 2H), 1.63 (d, J = 7.2 Hz, 3H). Synthesis of Compound 16: 1-((R)-7-chloro-1-((S)-1-(4-fluorophenyl)ethyl)-2-oxo- 1,2,3,4-tetrahydroquinolin-3-yl)urea Scheme 32 FH12898416.1 GPX-02125 Step 1: Preparation of tert-butyl N-[(3R)-7-chloro-1-[(1S)-1-(4-fluorophenyl)ethyl]-2-oxo- 3,4-dihydroquinolin-3-yl]carbamate To a solution of Intermediate 3 (500 mg, 1.685 mmol, 1 equiv.) in tetrahydrofuran (20 mL) was added (1R)-1-(4-fluorophenyl)ethanol (472.3 mg, 3.370 mmol, 2 equiv.) and triphenylphosphine (662.9 mg, 2.527 mmol, 1.5 equiv.). The reaction was stirred at 25°C for 0.5 h under nitrogen. Then diisopropyl azodicarboxylate (511.1 mg, 2.527 mmol, 1.5 equiv.) was added at 0 °C. The reaction was stirred at 25°C for 3 h. Quenched with water (100 mL) and extracted with ethyl acetate (3 x 100 mL). The combined extracts were washed with water, brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by column chromatography on silica gel (0-100% ethyl acetate / petroleum ether) to give the title compound as a yellow oil (500 mg, 70.8%). LCMS (ESI): m / z [M+Na]+calcd. for C22H24ClFN2O3: 441.14, found 441.10. Step 2: Preparation of (3R)-3-amino-7-chloro-1-[(1S)-1-(4-fluorophenyl)ethyl]-3,4- dihydroquinolin-2-one The transformation was carried out similarly to in the synthesis of Compound 1 to afford the title compound as a yellow oil (350 mg, 95.9% yield). LCMS (ESI): m / z [M+H]+calcd. for C17H16ClFN2O: 319.09, found 319.05. Step 3: Preparation of (3R)-7-chloro-1-[(1S)-1-(4-fluorophenyl)ethyl]-2-oxo-3,4- dihydroquinolin-3-ylurea (Compound 16) FH12898416.1 GPX-02125 The transformation was carried out similarly to in the synthesis of Compound 1. The crude product was purified by preparative HPLC (XBridge Prep OBD C18 Column, 35-60% acetonitrile / water with 10 mmol ammonium bicarbonate) to afford the title compound as a white solid (57.8 mg, 14.6%). LCMS (ESI): m / z [M+H]+calcd. for C18H17ClFN3O2: 362.10, found 362.05.1H NMR (400 MHz, DMSO-d6) 7.42 – 7.28 (m, 3H), 7.26 – 7.14 (m, 2H), 7.13 – 6.98 (m, 1H), 6.73 (d, J = 2.1 Hz, 1H), 6.41 (d, J = 6.3 Hz, 1H), 6.17 – 6.04 (m, 1H), 5.81 (s, 2H), 4.41 – 4.26 (m, 1H), 3.23 – 3.04 (m, 1H), 2.92 – 2.68 (m, 1H), 1.69 (d, J = 7.0 Hz, 3H).19F NMR (376 MHz, DMSO-d6) -116.21. Synthesis of Compound 17: 1-((R)-7-chloro-1-((S)-1-(3-fluorophenyl)ethyl)-2-oxo- 1,2,3,4-tetrahydroquinolin-3-yl)urea Step 1: Preparation of tert-butyl ((R)-7-chloro-1-((S)-1-(3-fluorophenyl)ethyl)-2-oxo- 1,2,3,4-tetrahydroquinolin-3-yl)carbamate FH12898416.1 GPX-02125 To a solution of Intermediate 3 (500 mg, 1.685 mmol, 1 equiv.) and (1R)-1-(3- fluorophenyl)ethanol (472.3 mg, 3.370 mmol, 2 equiv.) in tetrahydrofuran (7 mL) was added triphenylphosphine (662.9 mg, 2.527 mmol, 1.5 equiv.) at room temperature under nitrogen. The reaction was stirred at room temperature for 0.5 h under nitrogen. Then diisopropyl azodicarboxylate (511.0 mg, 2.527 mmol, 1.5 equiv.) was added at 0 °C under a nitrogen atmosphere. The reaction was stirred at room temperature for 2 h under nitrogen and then quenched with water (30 mL) and extracted with ethyl acetate (3 x 30 mL). The combined extracts were washed with water, brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by column chromatography on silica gel (0-100% ethyl acetate / petroleum ether) to give the title compound as a yellow oil (300 mg, 42.5% yield). LCMS (ESI): m / z [M+Na]+calcd. for C22H24ClFN2O3: 441.14, found 441.15. Step 2: Preparation of (R)-3-amino-7-chloro-1-((S)-1-(3-fluorophenyl)ethyl)-3,4- dihydroquinolin-2(1H)-one The transformation was carried out similarly to in the synthesis of Compound 1 to afford the title compound as a yellow oil (200 mg, 97.4% yield). LCMS (ESI): m / z [M+H]+calcd. for C17H16ClFN2O: 319.09, found 319.05. Step 3: Preparation of 1-((R)-7-chloro-1-((S)-1-(3-fluorophenyl)ethyl)-2-oxo-1,2,3,4- tetrahydroquinolin-3-yl)urea (Compound 17) The transformation was carried out similarly to in the synthesis of Compound 1. The crude product was purified by preparative HPLC (XBridge Prep C18 OBD Column, 35-60% acetonitrile / water with 10 mmol ammonium bicarbonate) to afford the title compound as a white solid (63.8 mg, 20.8% yield). LCMS (ESI): m / z [M+H]+calcd. for C18H17ClFN3O2: 362.10, found 362.10.1H NMR (300 MHz, Methanol-d4) 7.31-7.49 (m, 1H), 7.21-7.31 (m, 1H), 6.93-7.21 (m, 4H), 6.75 (d, J = 2.0 Hz, 1H), 6.32 (q, J = 7.2 Hz, 1H), 4.39-4.51 (m, 1H), 3.11-3.22 (m, 1H), 2.78-3.00 (m, 1H), 1.74 (d, J = 7.2 Hz, 3H).19F NMR (282 MHz, Methanol- d4) -114.52. Synthesis of Compound 18: 1-((R)-7-chloro-1-((S)-1-(2-fluorophenyl)ethyl)-2-oxo- 1,2,3,4-tetrahydroquinolin-3-yl)urea FH12898416.1 GPX-02125 Step 1: Preparation of tert-butyl ((R)-7-chloro-1-((S)-1-(2-fluorophenyl)ethyl)-2-oxo- 1,2,3,4-tetrahydroquinolin-3-yl)carbamate To a solution of Intermediate 3 (500 mg, 1.685 mmol, 1 equiv.) and (1R)-1-(2- fluorophenyl)ethanol (472.3 mg, 3.370 mmol, 2.0 equiv.) in tetrahydrofuran (7 mL) was added triphenylphosphine (662.9 mg, 2.527 mmol, 1.5 equiv.) at room temperature under nitrogen. The reaction was stirred at room temperature for 0.5 h under nitrogen. Then diisopropyl azodicarboxylate (511.0 mg, 2.527 mmol, 1.50 equiv.) was added at 0 °C under a nitrogen atmosphere. The reaction was stirred at room temperature for 2 h under nitrogen. The reaction was quenched with water (30 mL) and extracted with ethyl acetate (3 x 30 mL). The combined extracts were washed with water, brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by column chromatography on silica gel (0-100% ethyl acetate / petroleum ether) to give the title compound as a yellow oil (300 mg, 42.5% yield). LCMS (ESI): m / z [M+H]+calcd. for C22H24ClFN2O3: 419.15, found 419.15. FH12898416.1 GPX-02125 Step 2: Preparation of (R)-3-amino-7-chloro-1-((S)-1-(2-fluorophenyl)ethyl)-3,4- dihydroquinolin-2(1H)-one The transformation was carried out similarly to in the synthesis of Compound 1 to afford the title compound as a yellow oil (210 mg, 91.4% yield). LCMS (ESI): m / z [M+H]+calcd. for C17H16ClFN2O: 319.09, found 319.05. Step 3: Preparation of 1-((R)-7-chloro-1-((S)-1-(2-fluorophenyl)ethyl)-2-oxo-1,2,3,4- tetrahydroquinolin-3-yl)urea (Compound 18) The transformation was carried out similarly to in the synthesis of Compound 1. The crude product was purified by preparative HPLC (XBridge Prep Shield RP18 OBD Column, 26-56% acetonitrile / water with 10 mmol ammonium bicarbonate and 0.05% ammonia in water) to afford the title compound as a white solid (42.9 mg, 18.9% yield). LCMS (ESI): m / z [M+H]+calcd. for C18H17ClFN3O2: 362.10, found 362.10.1H NMR (300 MHz, Methanol-d4) 7.49-7.62 (m, 1H), 7.11-7.38 (m, 4H), 6.93-7.11 (m, 2H), 5.97 (q, J = 7.2 Hz, 1H), 4.21-4.40 (m, 1H), 3.01-3.20 (m, 1H), 2.65 – 2.82 (m, 1H), 1.88 (d, J = 7.2 Hz, 3H).19F NMR (282 MHz, Methanol-d4) -117.67. Synthesis of Compound 19: 1-((R)-7-chloro-1-((S)-1-(4-chlorophenyl)ethyl)-2-oxo- 1,2,3,4-tetrahydroquinolin-3-yl)urea Scheme 35 FH12898416.1 GPX-02125 Step 1: Preparation of tert-butyl N-[(3R)-7-chloro-1-[(1S)-1-(4-chlorophenyl)ethyl]-2- oxo-3,4-dihydroquinolin-3-yl]carbamate To a solution of Intermediate 3 (500 mg, 1.685 mmol, 1 equiv.) in tetrahydrofuran (10 mL) was added (1R)-1-(2-chlorophenyl)ethanol (263.9 mg, 1.685 mmol, 1 equiv.) and triphenylphosphine (662.9 mg, 2.527 mmol, 1.5 equiv.). The reaction was stirred at 0 °C for 0.5 h under nitrogen atmosphere. To the above mixture was added diisopropyl azodicarboxylate (511.0 mg, 2.527 mmol, 1.5 equiv.) dropwise at 0 °C. The resulting mixture was stirred at 25 °C for an additional 1 h. The reaction was quenched with water (50 mL) and extracted with ethyl acetate (3 x 50 mL). The combined extracts were washed with water, brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by column chromatography on silica gel (0-100% ethyl acetate / petroleum ether) to give the title compound as a yellow oil (450 mg, 61.7% yield). LCMS (ESI): m / z [M+Na]+calcd. for C22H24Cl2N2O3: 457.11, found 457.10. Step 2: Preparation of (R)-3-amino-7-chloro-1-((S)-1-(4-chlorophenyl)ethyl)-3,4- dihydroquinolin-2(1H)-one The transformation was carried out similarly to in the synthesis of Compound 1 to afford the title compound as a yellow oil (340 mg, 92.9% yield). LCMS (ESI): m / z [M+H]+calcd. for C17H16Cl2N2O: 335.06, found 335.05. Step 3: Preparation of 1-((R)-7-chloro-1-((S)-1-(4-chlorophenyl)ethyl)-2-oxo-1,2,3,4- tetrahydroquinolin-3-yl)urea (Compound 19) FH12898416.1 GPX-02125 The transformation was carried out similarly to in the synthesis of Compound 1. The crude product was purified by preparative HPLC (XBridge Prep OBD C18 Column, 38-63% acetonitrile / water with 10 mmol ammonium bicarbonate) to afford the title compound (39.4 mg, 8.6% yield). LCMS (ESI): m / z [M+H]+calcd. for C18H17Cl2N3O2: 378.07, found 378.05.1H NMR (400 MHz, DMSO-d6) 7.40 – 7.46 (m, 2H), 7.30 – 7.37 (m, 3H), 7.07 – 7.15 (m, 1H), 6.71 – 6.79 (m, 1H), 6.35 – 6.45 (m, 1H), 6.02 – 6.12 (m, 1H), 5.08 (s, 2H), 4.25 – 4.41 (m, 1H), 3.08 – 3.21 (m, 1H), 2.71 – 2.88 (m, 1H), 1.63 – 1.76 (m, 3H). Synthesis of Compound 20: 1-((R)-7-chloro-1-((S)-1-(2-chlorophenyl)ethyl)-2-oxo- 1,2,3,4-tetrahydroquinolin-3-yl)urea Step 1: Preparation of tert-butyl N-[(3R)-7-chloro-1-[(1S)-1-(2-chlorophenyl)ethyl]-2- oxo-3,4-dihydroquinolin-3-yl]carbamate To a solution of Intermediate 3 (500 mg, 1.685 mmol, 1 equiv.) in tetrahydrofuran (10 mL) was added (1R)-1-(2-chlorophenyl)ethanol (263.9 mg, 1.685 mmol, 1 equiv.) and triphenylphosphine (662.9 mg, 2.527 mmol, 1.5 equiv.). The reaction was stirred at 0 °C for 0.5 h under a nitrogen atmosphere. To the above mixture was added diisopropyl azodicarboxylate (511.0 mg, 2.527 mmol, 1.5 equiv.) dropwise at 0 °C. The resulting mixture FH12898416.1 GPX-02125 was stirred at 25 °C for an additional 1 h. The reaction was quenched with water (50 mL) and extracted with ethyl acetate (3 x 50 mL). The combined extracts were washed with water, brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by column chromatography on silica gel (0-100% ethyl acetate / petroleum ether) to give the title compound as a yellow oil (450 mg, 61.7% yield). LCMS (ESI): m / z [M+Na]+calcd. for C22H24Cl2N2O3: 457.11, found 457.10. Step 2: Preparation of (3R)-3-amino-7-chloro-1-[(1S)-1-phenylethyl]-3,4- dihydroquinolin-2-one The transformation was carried out similarly to in the synthesis of Compound 1 to afford the title compound as a yellow oil (340 mg, 92.9% yield). LCMS (ESI): m / z [M+H]+calcd. for C17H16Cl2N2O: 335.06, found 335.05. Step 3: Preparation of 1-((R)-7-chloro-1-((S)-1-(2-chlorophenyl)ethyl)-2-oxo-1,2,3,4- tetrahydroquinolin-3-yl)urea (Compound 20) The transformation was carried out similarly to in the synthesis of Compound 1. The crude product was purified by preparative HPLC (XBridge Prep C18, 35-60% acetonitile / water with 10 mmol ammonium bicarbonate) to afford the title compound as a white solid (81.4 mg, 21.9% yield). LCMS (ESI): m / z [M+H]+calcd. for C18H17Cl2N3O2: 378.07, found 378.05.1H NMR (400 MHz, DMSO-d6) 7.66 – 7.82 (m, 1H), 7.21 – 7.47 (m, 5H), 7.07 – 7.17 (m, 1H), 6.28 (d, J = 6.6 Hz, 1H), 5.66 (s, 2H), 5.33 – 5.46 (m, 1H), 3.99 – 4.16 (m, 1H), 2.98 – 3.11 (m, 1H), 2.52 – 2.59 (m, 1H), 1.74 – 1.93 (m, 3H). Synthesis of Compound 21: 1-((R)-7-chloro-2-oxo-1-((S)-1-(4- (trifluoromethyl)phenyl)ethyl)-1,2,3,4-tetrahydroquinolin-3-yl)urea Scheme 37 FH12898416.1 GPX-02125 Step 1: Preparation of tert-butyl ((R)-7-chloro-2-oxo-1-((S)-1-(4- (trifluoromethyl)phenyl)ethyl)-1,2,3,4-tetrahydroquinolin-3-yl)carbamate To a solution of Intermediate 3 (500 mg, 1.685 mmol, 1 equiv.) and (1R)-1-[4- (trifluoromethyl)phenyl]ethanol (640.8 mg, 3.370 mmol, 2.0 equiv.) in tetrahydrofuran (7 mL) was added triphenylphosphine (662.9 mg, 2.527 mmol, 1.5 equiv.) at room temperature under nitrogen. The reaction was stirred at room temperature for 0.5h under nitrogen. Then diisopropyl azodicarboxylate (511.0 mg, 2.527 mmol, 1.5 equiv.) was added at 0 °C under a nitrogen atmosphere. The reaction was stirred at room temperature for 2 h under nitrogen. The reaction was quenched with water (30 mL) and extracted with ethyl acetate (3 x 30 mL). The combined extracts were washed with water, brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by column chromatography on silica gel (0-100% ethyl acetate / petroleum ether) to give the title compound as a yellow oil (300 mg, 37.9% yield). LCMS (ESI): m / z [M+Na]+calcd. for C23H24ClF3N2O3: 491.13, found 491.20. Step 2: Preparation of (R)-3-amino-7-chloro-1-((S)-1-(4-(trifluoromethyl)phenyl)ethyl)- 3,4-dihydroquinolin-2(1H)-one The transformation was carried out similarly to in the synthesis of Compound 1 to afford the title compound as a as a yellow oil (220 mg, 96.5% yield). LCMS (ESI): m / z [M+H]+calcd. for C18H16ClF3N2O: 369.09, found 369.05. Step 3: Preparation of 1-((R)-7-chloro-2-oxo-1-((S)-1-(4-(trifluoromethyl)phenyl)ethyl)- 1,2,3,4-tetrahydroquinolin-3-yl)urea (Compound 21) FH12898416.1 GPX-02125 The transformation was carried out similarly to in the synthesis of Compound 1. The crude product was purified by preparative HPLC (XBridge Prep C18 OBD Column, 35-60% acetonitrile / water with 10 mmol ammonium bicarbonate) to afford the title compound as a white solid (72.2 mg, 22.3% yield). LCMS (ESI): m / z [M+H]+calcd. for C19H17ClF3N3O2: 412.10, found 412.10.1H-NMR (300 MHz, Methanol-d4) 7.70 (d, J = 8.3 Hz, 2H), 7.57 (d, J = 8.2 Hz, 2H), 7.20-7.35 (m, 1H), 6.92 - 7.02 (m, 1H), 6.78 (d, J = 2.0 Hz, 1H), 6.28 (q, J = 7.1 Hz, 1H), 4.39 - 4.51 (m, 1H), 3.10 - 3.22 (m, 1H), 2.78 - 2.98 (m, 1H), 1.80 (d, J = 7.2 Hz, 3H).19F NMR (282 MHz, Methanol-d4) -63.97. Synthesis of Compound 22: 1-((R)-7-chloro-2-oxo-1-((S)-1-(2- (trifluoromethyl)phenyl)ethyl)-1,2,3,4-tetrahydroquinolin-3-yl)urea Step 1: Preparation of tert-butyl N-[(3R)-7-chloro-2-oxo-1-[(1S)-1-[2- (trifluoromethyl)phenyl]ethyl]-3,4-dihydroquinolin-3-yl]carbamate To a solution of Intermediate 3 (500 mg, 1.685 mmol, 1 equiv.) in tetrahydrofuran (10 mL) was added (1R)-1-[2-(trifluoromethyl)phenyl]ethanol (320.4 mg, 1.685 mmol, 1 FH12898416.1 GPX-02125 equiv.) and triphenylphosphine (662.9 mg, 2.527 mmol, 1.5 equiv.). The reaction was stirred at 0 °C for 0.5 h under nitrogen atmosphere. To the above mixture was added diisopropyl azodicarboxylate (511.0 mg, 2.527 mmol, 1.5 equiv.) dropwise at 0 °C. The resulting mixture was stirred at 25 °C for an additional 1 h. The reaction was quenched with water (50 mL) and extracted with ethyl acetate (3 x 50 mL). The combined extracts were washed with water, brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by column chromatography on silica gel (0-100% ethyl acetate / petroleum ether) to give the title compound as a yellow oil (400 mg, 50.6% yield). LCMS (ESI): m / z [M+Na]+calcd. for C23H24ClF3N2O3: 491.13, found 491.15. Step 2: Preparation of (3R)-3-amino-7-chloro-1-[(1S)-1-[2- (trifluoromethyl)phenyl]ethyl]-3,4-dihydroquinolin-2-one The transformation was carried out similarly to in the synthesis of Compound 1 to afford the title compound as a as a yellow oil (300 mg, 98.0% yield). LCMS (ESI): m / z [M+H]+calcd. for C18H16ClF3N2O: 369.09, found: 369.10. Step 3: Preparation of 1-((R)-7-chloro-2-oxo-1-((S)-1-(2-(trifluoromethyl)phenyl)ethyl)- 1,2,3,4-tetrahydroquinolin-3-yl)urea (Compound 22) The transformation was carried out similarly to in the synthesis of Compound 1. The crude product was purified by preparative HPLC (XBridge Prep C18 OBD, 40-65% acetonitrile / water with 10 mmol ammonium bicarbonate) to afford the title compound as a white solid (82.1 mg, 22.3% yield). LCMS (ESI): m / z [M+H]+calcd. for C19H17ClF3N3O2: 412.10, found 412.10.1H NMR (400 MHz, DMSO-d6) 7.88 – 8.01 (m, 1H), 7.62 – 7.80 (m, 2H), 7.43 – 7.54 (m, 1H), 7.35 – 7.41 (m, 1H), 7.28 – 7.35 (m, 1H), 7.09 – 7.19 (m, 1H), 6.24 – 6.35 (m, 1H), 5.69 – 5.79 (m, 1H), 5.60 – 5.69 (m, 2H), 4.04 – 4.16 (m, 1H), 2.97 – 3.10 (m, 1H), 2.52 – 2.59 (m, 1H), 1.79 – 1.92 (m, 3H).19F NMR (376 MHz, DMSO-d6) -58.70. Synthesis of Compound 23: 1-((R)-7-chloro-2-oxo-1-((S)-1-phenylpropyl)-1,2,3,4- tetrahydroquinolin-3-yl)urea FH12898416.1 GPX-02125 Scheme 39 Step 1: Preparation of tert-butyl ((R)-7-chloro-2-oxo-1-((S)-1-phenylpropyl)-1,2,3,4- tetrahydroquinolin-3-yl)carbamate To a solution of Intermediate 3 (500 mg, 1.685 mmol, 1 equiv.) and (1R)-1- phenylpropan-1-ol (458.9 mg, 3.369 mmol, 2.0 equiv.) in tetrahydrofuran (10 mL) was added triphenylphosphine (662.9 mg, 2.527 mmol, 1.5 equiv.) at room temperature under nitrogen. The reaction was stirred at room temperature for 0.5 h under nitrogen. Then diisopropyl azodicarboxylate (511.0 mg, 2.527 mmol, 1.5 equiv.) was added at 0 °C under a nitrogen atmosphere. The reaction was stirred at room temperature for 2 h under nitrogen. The reaction was quenched with water (30 mL) and extracted with ethyl acetate (3 x 30 mL). The combined extracts were washed with water, brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by column chromatography on silica gel (0-100% ethyl acetate / petroleum ether) to give the title compound as a yellow oil (300 mg, 47.0% yield). LCMS (ESI): m / z [M+Na]+calcd. for C23H27ClN2O3: 437.16, found 437.15. Step 2: Preparation of (R)-3-amino-7-chloro-1-((S)-1-phenylpropyl)-3,4- dihydroquinolin-2(1H)-one The transformation was carried out similarly to in the synthesis of Compound 1 to afford the title compound as a as a yellow oil (210 mg, 91.4% yield). LCMS (ESI): m / z [M+H]+calcd. for C18H19ClN2O: 315.12, found 315.05. FH12898416.1 GPX-02125 Step 3: Preparation of 1-((R)-7-chloro-2-oxo-1-((S)-1-phenylpropyl)-1,2,3,4- tetrahydroquinolin-3-yl)urea (Compound 23) The transformation was carried out similarly to in the synthesis of Compound 1. The crude product was purified by preparative HPLC (Kinetex EVO C18, 41-54% acetonitrile / water with 10 mmol ammonium bicarbonate) to afford the title compound as a white solid (46.6 mg, 14.1% yield). LCMS (ESI): m / z [M+H]+calcd. for C19H20ClN3O2: 358.12, found 358.15.1H NMR (300 MHz, DMSO-d6) 7.23 - 7.50 (m, 6H), 7.02 - 7.12 (m, 1H), 6.65 (d, J = 2.0 Hz, 1H), 6.52 (d, J = 6.4 Hz, 1H), 6.01 - 6.17 (m, 1H), 5.82 (s, 2H), 4.27 - 4.52 (m, 1H), 3.10 - 3.23 (m, 1H), 2.70 - 2.88 (m, 1H), 2.30 - 2.42 (m, 1H), 1.92 - 2.15 (m, 1H), 0.68 - 0.80 (m, 3H). Synthesis of Compound 24: 1-((R)-7-chloro-1-((S)-1-(3-(difluoromethoxy)phenyl)ethyl)- 2-oxo-1,2,3,4-tetrahydroquinolin-3-yl)urea Step 1: Preparation of (1R)-1-[3-(difluoromethoxy)phenyl]ethanol To a solution of (S)-1-Methyl-3,3-diphenylhexahydropyrrolo[1,2- c][1,3,2]oxazaborole (1.0 M in tetrahydrofuran, 297.7 mg, 1.074 mmol, 0.4 equiv.) in tetrahydrofuran (10 mL) was added borane dimethyl sulfide complex (2.0 M in tetrahydrofuran) (244.8 mg, 3.223 mmol, 1.2 equiv.) and 1-[3- (difluoromethoxy)phenyl]ethanone (500 mg, 2.686 mmol, 1 equiv.). The reaction was stirred FH12898416.1 GPX-02125 at 0 °C for 1 h under nitrogen atmosphere. The reaction was quenched with water (50 mL) and extracted with ethyl acetate (3 x 50 mL). The combined extracts were washed with water, brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by column chromatography on silica gel (0-100% ethyl acetate / petroleum ether) to give the title compound as a yellow oil (250 mg, 49.5% yield). Step 2: Preparation of tert-butyl N-[(3R)-7-chloro-1-[(1S)-1-[3- (difluoromethoxy)phenyl]ethyl]-2-oxo-3,4-dihydroquinolin-3-yl]carbamate To a solution of Intermediate 3 (250 mg, 0.842 mmol, 1.0 equiv.) in tetrahydrofuran (5 mL) was added (1R)-1-[3-(difluoromethoxy)phenyl]ethanol (158.5 mg, 0.842 mmol, 1 equiv.) and triphenylphosphine (331.4 mg, 1.263 mmol, 1.5 equiv.). The reaction was stirred at 0 °C for 0.5 h under nitrogen. To the above mixture was added diisopropyl azodicarboxylate (255.5 mg, 1.263 mmol, 1.5 equiv.) dropwise at 0 °C under nitrogen. The resulting mixture was stirred at 25 °C for an additional 1 h. The reaction was quenched with water (50 mL) and extracted with ethyl acetate (3 x 50 mL). The combined extracts were washed with water, brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by column chromatography on silica gel (0-100% ethyl acetate / petroleum ether) to give the title compound as a yellow oil (350 mg, 88.9% yield). LCMS (ESI): m / z [M+Na]+calcd. for C23H25ClF2N2O4: 489.14, found 489.15. Step 3: Preparation of (3R)-3-amino-7-chloro-1-[(1S)-1-[3- (difluoromethoxy)phenyl]ethyl]-3,4-dihydroquinolin-2-one The transformation was carried out similarly to in the synthesis of Compound 1 to afford the title compound as a yellow oil (260 mg, 97.4% yield). LCMS (ESI): m / z [M+H]+calcd. for C18H17ClF2N2O2: 367.09, found 367.05. Step 4: Preparation of 1-((R)-7-chloro-1-((S)-1-(3-(difluoromethoxy)phenyl)ethyl)-2-oxo- 1,2,3,4-tetrahydroquinolin-3-yl)urea (Compound 24) The transformation was carried out similarly to in the synthesis of Compound 1. The crude product was purified by preparative HPLC (XBridge Prep C18, 35-60% acetonitrile / water with 10 mmol ammonium bicarbonate) to afford the title compound as a white solid (43.4 mg, 13.9% yield). LCMS (ESI): m / z [M+H]+calcd. for C19H18ClF2N3O3: 410.10, found 410.10.1H NMR (400 MHz, DMSO-d6) 7.40 – 7.50 (m, 1H), 7.30 – 7.39 (m, 1H), 7.27 (s, 1H), 7.13 – 7.21 (m, 1H), 7.04 – 7.13 (m, 3H), 6.70 – 6.80 (m, 1H), 6.41 (d, J = FH12898416.1 GPX-02125 6.3 Hz, 1H), 6.04 – 6.19 (m, 1H), 5.81 (s, 2H), 4.28 – 4.42 (m, 1H), 3.08 – 3.20 (m, 1H), 2.73 – 2.87 (m, 1H), 1.61 – 1.79 (m, 3H).19F NMR (376 MHz, DMSO-d6) -82.20. Synthesis of Compound 25: 1-((R)-7-fluoro-2-oxo-1-((S)-1-phenylethyl)-1,2,3,4- tetrahydroquinolin-3-yl)urea Step 1: Preparation of methyl (R)-3-(2-amino-4-fluorophenyl)-2-((tert- butoxycarbonyl)amino)propanoate To a stirred solution of 2-bromo-5-fluoroaniline (1.00 g, 5.263 mmol, 1 equiv.) in dimethyl formamide (10 mL) was added palladium(II) acetate (0.24 g, 1.053 mmol, 0.2 equiv.) and XPhos (1.00 g, 2.105 mmol, 0.4 equiv.) in portions at room temperature under air atmosphere. To the above mixture was added Intermediate 1 (6.23 g, 15.789 mmol, 3 equiv.) in portions at 0 °C under nitrogen atmosphere. The resulting mixture was stirred at room temperature overnight under nitrogen atmosphere. The reaction was quenched with saturated, aqueous ammonium chloride at 0 °C. The reaction was quenched with water (30 mL). The resulting mixture was extracted with ethyl acetate (3 x30 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (0-100% ethyl acetate / petroleum ether) to FH12898416.1 GPX-02125 afford the title compound as a yellow oil (1.50 g, 91.3% yield). LCMS (ESI): m / z [M+H]+calcd. for C15H21FN2O4: 313.15, found 256.15 [M+H-tBu]+. Step 2: Preparation of tert-butyl (R)-(7-fluoro-2-oxo-1,2,3,4-tetrahydroquinolin-3- yl)carbamate To a stirred solution of acetic acid (10 mL) was added methyl (R)-3-(2-amino-4- fluorophenyl)-2-((tert-butoxycarbonyl)amino)propanoate (1.50 g, 4.802 mmol, 1 equiv.) in portions at room temperature under air atmosphere. The resulting mixture was stirred at 90 °C for 30 min under air. The mixture was allowed to cool down to room temperature. The residue was basified to pH 8 with saturated aqueous sodium bicarbonate. The reaction was quenched with water (20 mL). The resulting mixture was extracted with ethyl acetate (3 x 20 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography eluted with petroleum ether / ethyl acetate (1:1) to afford the title compound as a yellow oil (1.00 g, 74.3% yield). LCMS (ESI): m / z [M+Na]+calcd. for C14H17FN2O3: 303.11, found 303.10. Step 3: Preparation of tert-butyl ((R)-7-fluoro-2-oxo-1-((S)-1-phenylethyl)-1,2,3,4- tetrahydroquinolin-3-yl)carbamate To a stirred solution of tert-butyl (R)-(7-fluoro-2-oxo-1,2,3,4-tetrahydroquinolin-3- yl)carbamate (0.50 g, 1.784 mmol, 1 equiv.) and (1R)-1-phenylethan-1-ol (0.44 g, 3.568 mmol, 2 equiv.) in tetrahydrofuran (6 mL) was added triphenylphosphine (0.70 g, 2.676 mmol, 1.5 equiv.) in portions at room temperature under air atmosphere. The resulting mixture was stirred at room temperature for 30 min under nitrogen atmosphere. To the above mixture was added diisopropyl azodicarboxylate (0.54 g, 2.676 mmol, 1.5 equiv.) in portions at 0 °C. The resulting mixture was stirred at room temperature for an additional 2 h. The reaction was quenched with water (20 mL). The resulting mixture was extracted with ethyl acetate (3 x 20 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography, eluted with petroleum ether / ethyl acetate (1:1) to afford the title compound as a yellow oil (0.60 g, 87.5% yield). LCMS (ESI): m / z [M+Na]+calcd. for C22H25FN2O3: 407.17, found 407.20. Step 4: Preparation of (R)-3-amino-7-fluoro-1-((S)-1-phenylethyl)-3,4-dihydroquinolin- 2(1H)-one hydrochloride FH12898416.1 GPX-02125 The transformation was carried out similarly to in the synthesis of Compound 1 to afford the hydrochloride title compound as a white oil (0.24 g, 96.0% yield). LCMS (ESI): m / z [M+H]+calcd. for C17H17FN2O: 285.13, found 285.15. Step 5: Preparation of 1-((R)-7-fluoro-2-oxo-1-((S)-1-phenylethyl)-1,2,3,4- tetrahydroquinolin-3-yl)urea (Compound 25) The transformation was carried out similarly to in the synthesis of Compound 1. The crude product was purified by preparative HPLC (XBridge Shield RP18 OBD, 55-65% methanol / water with 0.05% ammonium bicarbonate) to afford the title compound as a white solid (22.4 mg, 9.7% yield). LCMS (ESI): m / z [M+H]+calcd. for C18H18FN3O2: 328.14, found 328.05.1H NMR (300 MHz, Methanol-d4) 7.20 – 7.48 (m, 6H), 6.68 – 6.82 (m, 1H), 6.42 – 6.52 (m, 1H), 6.29 – 6.41 (m, 1H), 6.32 – 6.53 (m, 1H), 3.10 – 3.25 (m, 1H), 2.79 – 2.97 (m, 1H), 1.62 – 1.78 (m, 3H).19F NMR (282 MHz, Methanol-d4) (ppm) -115.90. Synthesis of Compound 26: 1-((R)-2-oxo-1-((S)-1-phenylethyl)-7-(trifluoromethyl)- 1,2,3,4-tetrahydroquinolin-3-yl)urea FH12898416.1 GPX-02125 Step 1: Preparation of methyl (R)-3-(2-amino-4-(trifluoromethyl)phenyl)-2-((tert- butoxycarbonyl)amino)propanoate To a stirred solution of 2-bromo-5-(trifluoromethyl)aniline (2.00 g, 8.333 mmol, 1 equiv.) in dimethyl formamide (20 mL) was added palladium(II) acetate (0.37 g, 1.667 mmol, 0.2 equiv.) and Xphos (1.59 g, 3.333 mmol, 0.4 equiv.) in portions at room temperature under air atmosphere. To the above mixture was added Intermediate 1 (9.86 g, 24.999 mmol, 3 equiv.) in portions at 0 °C under nitrogen atmosphere. The resulting mixture was stirred at room temperature overnight under nitrogen atmosphere. The reaction was quenched with saturated, aqueous ammonium chloride at 0 °C. The reaction was quenched with water (30 mL). The resulting mixture was extracted with ethyl acetate (3 x 30 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography, eluted with petroleum ether / ethyl acetate (1:1) to afford the title compound as a yellow oil (2.30 g, 76.2% yield). LCMS (ESI): m / z [M+H]+calcd. for C16H21F3N2O4: 363.15, found 307.10 [M+H-tBu]+. Step 2: Preparation of tert-butyl (R)-(2-oxo-7-(trifluoromethyl)-1,2,3,4- tetrahydroquinolin-3-yl)carbamate To a stirred solution of acetic acid (12 mL) was added methyl (R)-3-(2-amino-4- (trifluoromethyl)phenyl)-2-((tert-butoxycarbonyl)amino)propanoate (2.30 g, 6.347 mmol, 1 equiv.) in portions at room temperature under air atmosphere. The resulting mixture was stirred at 90 °C for 30 min under air atmosphere. The mixture was allowed to cool down to room temperature. The residue was basified to pH 8 with saturated, aqueous sodium bicarbonate. The reaction was quenched with water (30 mL). The resulting mixture was extracted with ethyl acetate (3 x 30 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography, eluted with petroleum ether / ethyl acetate (1:1) to afford the title compound as a yellow oil (1.80 g, 85.9% yield). LCMS (ESI): m / z [M+Na]+calcd. for C15H17F3N2O3: 353.11, found 353.10. Step 3: Preparation of tert-butyl ((R)-2-oxo-1-((S)-1-phenylethyl)-7-(trifluoromethyl)- 1,2,3,4-tetrahydroquinolin-3-yl)carbamate To a stirred solution of tert-butyl (R)-(2-oxo-7-(trifluoromethyl)-1,2,3,4- tetrahydroquinolin-3-yl)carbamate (1.20 g, 3.633 mmol, 1 equiv.) and (1R)-1-phenylethan-1- ol (0.89 g, 7.266 mmol, 2 equiv.) in tetrahydrofuran (8 mL) was added triphenylphosphine (1.43 g, 5.450 mmol, 1.5 equiv.) in portions at room temperature under air atmosphere. The FH12898416.1 GPX-02125 resulting mixture was stirred at room temperature for 30 min under nitrogen atmosphere. To the above mixture was added diisopropyl azodicarboxylate (1.10 g, 5.450 mmol, 1.5 equiv.) in portions at 0 °C. The resulting mixture was stirred at room temperature for an additional 2 h under nitrogen. The reaction was quenched with water (20 mL). The resulting mixture was extracted with ethyl acetate (3 x 20 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography, eluted with petroleum ether / ethyl acetate (1:1) to afford the title compound as a yellow oil (1.40 g, 88.7% yield). LCMS (ESI): m / z [M+Na]+calcd. for C23H25F3N2O3: 457.17, found 457.15. Step 4: Preparation of (R)-3-amino-1-((S)-1-phenylethyl)-7-(trifluoromethyl)-3,4- dihydroquinolin-2(1H)-one hydrochloride The transformation was carried out similarly to in the synthesis of Compound 1 to afford the hydrochloride title compound as a white oil (1.10 g, 92.4% yield). LCMS (ESI): m / z [M+H]+calcd. for C18H17F3N2O: 335.13, found 335.10. Step 5: Preparation of 1-((R)-2-oxo-1-((S)-1-phenylethyl)-7-(trifluoromethyl)-1,2,3,4- tetrahydroquinolin-3-yl)urea (Compound 26) The transformation was carried out similarly to in the synthesis of Compound 1. The crude product was purified by preparative HPLC (XBridge Shield RP18 OBD 55-65% methanol / water with 0.05% ammonium bicarbonate) to afford the title compound as a white solid (414.3 mg, 33.4% yield). LCMS (ESI): m / z [M+H]+calcd. for C19H18F3N3O2: 378.14, found 378.05.1H NMR (300 MHz, Methanol-d4) 7.21 – 7.60 (m, 7H), 6.84 – 7.04 (m, 1H), 6.40 – 6.62 (m, 1H), 4.40 – 4.62 (m, 1H), 3.22 – 3.31 (m, 1H), 2.91 – 3.09 (m, 1H), 1.62 – 1.82 (m, 3H).19F NMR (282 MHz, Methanol-d4) (ppm) -64.49. Synthesis of Compound 27: 1-((R)-2-oxo-1-((S)-1-phenylethyl)-7-(trifluoromethoxy)- 1,2,3,4-tetrahydroquinolin-3-yl)urea Scheme 43 FH12898416.1 GPX-02125 Step 1: Preparation of methyl 3-[2-amino-4-(trifluoromethoxy)phenyl]-2-[(tert- butoxycarbonyl)amino]propanoate To a solution of 2-bromo-5-(trifluoromethoxy)aniline (2 g, 7.812 mmol, 1 equiv.), palladium(II) acetate (0.18 g, 0.781 mmol, 0.1 equiv.), and Xphos (0.74 g, 1.562 mmol, 0.2 equiv.) in dimethyl formamide (30 mL) was added Intermediate 1 (46.9 mL, 23.436 mmol, 3 equiv.) at 0 °C under nitrogen. The reaction was stirred at 25°C for 16 h under nitrogen. The reaction was quenched with water (100 mL) and extracted with ethyl acetate (3 x 100 mL). The combined extracts were washed with water, brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by column chromatography on silica gel (0-100% ethyl acetate / petroleum ether) to give the title compound as a yellow oil (2.5 g, 84.6% yield). LCMS (ESI): m / z [M+H]+calcd. for C16H21F3N2O5: 379.14, found 323.05 [M+H-tBu]+. Step 2: Preparation of tert-butyl N-[(3R)-2-oxo-7-(trifluoromethoxy)-3,4-dihydro-1H- quinolin-3-yl]carbamate Methyl (2R)-3-[2-amino-4-(trifluoromethoxy)phenyl]-2-[(tert- butoxycarbonyl)amino]propanoate (2.5 g, 6.608 mmol, 1 equiv.) was dissolved in acetic acid (20 mL). The reaction was stirred at 90°C for 0.5h. The mixture was allowed to cool down to room temperature. The mixture was neutralized with saturated, aqueous sodium bicarbonate (300 mL) and extracted with ethyl acetate (3 x 300 mL). The combined extracts were washed with water, brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by column chromatography on silica gel (0-100% ethyl acetate / petroleum ether) to give the title compound as a yellow oil (1.7 g, 74.3% yield). LCMS (ESI): m / z [M+Na]+calcd. for C15H17F3N2O4: 369.10, found 369.10. FH12898416.1 GPX-02125 Step 3: Preparation of tert-butyl N-[(3R)-2-oxo-1-[(1S)-1-phenylethyl]-7- (trifluoromethoxy)-3,4-dihydroquinolin-3-yl]carbamate To a solution of tert-butyl N-[(3R)-2-oxo-7-(trifluoromethoxy)-3,4-dihydro-1H- quinolin-3-yl]carbamate (700 mg, 2.021 mmol, 1 equiv.) in tetrahydrofuran (20 mL) was added (1R)-1-phenylethan-1-ol (493.9 mg, 4.042 mmol, 2 equiv.) and triphenylphosphine (795.3 mg, 3.031 mmol, 1.5 equiv.). The reaction was stirred at 25°C for 0.5 h under nitrogen. Then diisopropyl azodicarboxylate (613.1 mg, 3.031 mmol, 1.5 equiv.) was added at 0 °C. The reaction was stirred at 25°C for 3 h. The reaction was quenched with water (100 mL) and extracted with ethyl acetate (3 x 100 mL). The combined extracts were washed with water, brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by column chromatography on silica gel (0-100% ethyl acetate / petroleum ether) to give the title compound as a yellow oil (780 mg, 85.7% yield). LCMS (ESI): m / z [M+Na]+calcd. for C23H25F3N2O4: 473.17, found 473.20. Step 4: Preparation of (3R)-3-amino-1-[(1S)-1-phenylethyl]-7-(trifluoromethoxy)-3,4- dihydroquinolin-2-one The transformation was carried out similarly to in the synthesis of Compound 1 to afford the title compound as a yellow oil (300 mg, 96.5% yield). LCMS (ESI): m / z [M+H]+calcd. for C18H17F3N2O2: 351.12, found 351.15. Step 5: Preparation of (3R)-2-oxo-1-[(1S)-1-phenylethyl]-7-(trifluoromethoxy)-3,4- dihydroquinolin-3-ylurea (Compound 27) The transformation was carried out similarly to in the synthesis of Compound 1. The crude product was purified by preparative HPLC (XBridge Prep OBD C18 Column, 35-56% acetonitrile / water with 10 mmol ammonium bicarbonate and 0.05%) to afford the title compound as a white solid (56.1 mg, 16.7% yield). LCMS (ESI): m / z [M+H]+calcd. for C19H18F3N3O3: 394.13, found 394.10.1H NMR (400 MHz, DMSO-d6) 7.48 – 7.35 (m, 3H), 7.37 – 7.24 (m, 3H), 7.03 – 6.95 (m, 1H), 6.61 – 6.50 (m, 1H), 6.49 – 6.39 (m, 1H), 6.37 – 6.26 (m, 1H), 5.84 (s, 2H), 4.52 – 4.34 (m, 1H), 3.25 – 3.14 (m, 1H), 2.95 – 2.79 (m, 1H), 1.67 (d, J = 7.1 Hz, 3H).19F NMR (376 MHz, DMSO-d6) -57.16. Synthesis of Compound 28: 1-((R)-7-cyano-2-oxo-1-((S)-1-phenylethyl)-1,2,3,4- tetrahydroquinolin-3-yl)urea FH12898416.1 GPX-02125 Step 1: Preparation of methyl (2R)-2-[(tert-butoxycarbonyl)amino]-3-(4-cyano-2- nitrophenyl)propanoate To a solution of 4-bromo-3-nitrobenzonitrile (2 g, 8.810 mmol, 1 equiv.) in dimethyl formamide (10 mL) was added Intermediate 1 (6.95 g, 17.620 mmol, 2 equiv.), palladium(II) acetate (0.30 g, 1.322 mmol, 0.15 equiv.) and XPhos (1.26 g, 2.643 mmol, 0.3 equiv.) under nitrogen at 0 °C. The reaction was stirred at 25 °C under nitrogen for 16 h. The resulting mixture was filtered, the filter cake was washed with ethyl acetate (3 x 200 ml). The reaction was quenched with water (200 mL) and extracted with ethyl acetate (3 x 200 mL). The combined extracts were washed with water, brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by column chromatography on silica gel (0-100% ethyl acetate / petroleum ether) to give the title compound as a yellow oil (1.2 g, 38.9% yield). LCMS (ESI): m / z [M+Na]+calcd. for C16H19N3O6: 372.12, found 372.10. Step 2: Preparation of tert-butyl N-[(3R)-7-cyano-2-oxo-3,4-dihydro-1H-quinolin-3- yl]carbamate To a solution of methyl (2R)-2-[(tert-butoxycarbonyl)amino]-3-(4-cyano-2- nitrophenyl)propanoate (1.18 g, 3.378 mmol, 1 equiv.) in ethanol (20 mL) and water (10 mL) - 111 - FH12898416.1 GPX-02125 was added iron (1.89 g, 33.780 mmol, 10 equiv.) and ammonium chloride (1.81 g, 33.780 mmol, 10 equiv.). The reaction was stirred at 80 °C for 2 h. The resulting mixture was filtered, the filter cake was washed with ethyl acetate (3 x 100 mL). The mixture was diluted with water (200 mL) and extracted with ethyl acetate (3 x 200 mL). The combined extracts were washed with water, brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by column chromatography on silica gel (0-100% ethyl acetate / petroleum ether) to the title compound as yellow oil (640 mg, 65.9% yield). LCMS (ESI): m / z [M+Na]+calcd. for C15H17N3O3: 310.12, found 310.10. Step 3: Preparation of tert-butyl N-[(3R)-7-cyano-2-oxo-1-[(1S)-1-phenylethyl]-3,4- dihydroquinolin-3-yl]carbamate To a solution of tert-butyl N-[(3R)-7-cyano-2-oxo-3,4-dihydro-1H-quinolin-3- yl]carbamate (630 mg, 2.193 mmol, 1 equiv.) in tetrahydrofuran (10 mL) was added (1R)-1- phenylethan-1-ol (401.8 mg, 3.290 mmol, 1.5 equiv.), triphenylphosphine (862.7 mg, 3.290 mmol, 1.5 equiv.). The reaction was stirred at 25°C under nitrogen for 0.5 h. Then diisopropyl azodicarboxylate (665.1 mg, 3.290 mmol, 1.5 equiv.) was added at 0 °C. The reaction was stirred at 25°C for 3 h. The mixture was quenched with water (100 mL) and extracted with ethyl acetate (3 x 100 mL). The combined extracts were washed with water, brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by column chromatography on silica gel (0-100% ethyl acetate / petroleum ether) to give the title compound as yellow oil (450 mg, 52.4% yield). LCMS (ESI): m / z [M+Na]+calcd. for C23H25N3O3: 414.18, found 414.15. Step 4: Preparation of (3R)-3-amino-2-oxo-1-[(1S)-1-phenylethyl]-3,4-dihydroquinoline- 7-carbonitrile The transformation was carried out similarly to in the synthesis of Compound 1 to afford the title compound as a yellow oil (300 mg, 93.75% yield). LCMS (ESI): m / z [M+H]+calcd. for C18H17N3O: 292.14, found 292.10. Step 5: Preparation of (3R)-7-cyano-2-oxo-1-[(1S)-1-phenylethyl]-3,4-dihydroquinolin-3- ylurea (Compound 28) The transformation was carried out similarly to in the synthesis of Compound 1. The crude product was purified by preparative HPLC (XBridge Prep OBD C18 Column, 27-45% acetonitrile / water with 10 mmol ammonium bicarbonate) to afford the title compound as a FH12898416.1 GPX-02125 white solid (45.7 mg, 11.4% yield). LCMS (ESI): m / z [M+H]+calcd. for C19H18N4O2: 335.14, found 335.05.1H NMR (400 MHz, DMSO-d6) 7.63 – 7.47 (m, 2H), 7.44 – 7.24 (m, 5H), 7.06 (s, 1H), 6.43 (d, J = 6.4 Hz, 1H), 6.23 – 6.11 (m, 1H), 5.83 (s, 2H), 4.48 – 4.30 (m, 1H), 3.31 – 3.17 (m, 1H), 3.04 – 2.84 (m, 1H), 1.71 (d, J = 7.1 Hz, 3H). Synthesis of Compound 29: 1-((R)-7-cyclopropyl-2-oxo-1-((S)-1-phenylethyl)-1,2,3,4- tetrahydroquinolin-3-yl)urea Step 1: Preparation of tert-butyl N-[(3R)-7-chloro-2-oxo-1-[(1S)-1-phenylethyl]-3,4- dihydroquinolin-3-yl]carbamate To a solution of Intermediate 2 (1.5 g, 5.06 mmol, 1.00 equiv.) in THF (15 mL) was added (R)-1-phenyl-ethanol (0.74 g, 6.07 mmol, 1.2 equiv.) and triphenylphosphine (1.99 g, 7.58 mmol, 1.5 equiv.). The reaction was stirred at 25 °C for 0.5 h under nitrogen. Diisopropyl azodicarboxylate (1.53 g, 7.58 mmol, 1.5 equiv.) was then added dropwise at 0 °C. The resulting mixture was stirred at 25 °C for an additional 1 h, then was quenched with water (50 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic extracts were washed with water, brine, dried over sodium sulfate, filtered and concentrated. The crude product was purified by silica gel chromatography (0-100% ethyl acetate / petroleum ether) to afford the title compound as a yellow oil (1 g, 49.4% yield). LCMS (ESI): m / z [M+H]+calcd for C22H25ClN2O3: 401.16, found 401.15. FH12898416.1 GPX-02125 Step 2: Preparation of tert-butyl N-[(3R)-7-cyclopropyl-2-oxo-1-[(1S)-1-phenylethyl]-3,4- dihydroquinolin-3-yl]carbamate To a solution of tert-butyl N-[(3R)-7-chloro-2-oxo-1-[(1S)-1-phenylethyl]-3,4- dihydroquinolin-3-yl]carbamate (240 mg, 0.599 mmol, 1 equiv.) in toluene (5 mL) and water (0.5 mL) was added cyclopropylboronic acid (154.2 mg, 1.797 mmol, 3.0 equiv.), palladium(II) acetate (13.4 mg, 0.060 mmol, 0.1 equiv.), butyldi-1-adamantylphosphine (43.0 mg, 0.120 mmol, 0.2 equiv.) and potassium phosphate tribasic (254.1 mg, 1.198 mmol, 2.0 equiv.). The reaction was stirred at 100 °C for 2 h under a nitrogen atmosphere. The mixture was allowed to cool to room temperature, then was quenched with water (50 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic extracts were washed with water, brine, dried over sodium sulfate, filtered and concentrated. The crude product was purified by silica gel chromatography (0-100% ethyl acetate / petroleum ether) to afford the title compound as a yellow oil (150 mg, 61.6% yield). LCMS (ESI): m / z [M+H]+calcd for C25H30N2O3: 407.23, found 407.25. Step 3: Preparation of (3R)-3-amino-7-cyclopropyl-1-[(1S)-1-phenylethyl]-3,4- dihydroquinolin-2-one The transformation was carried out similarly to in the synthesis of Compound 1 to afford the title compound as a yellow oil (100 mg, 94.8% yield). LCMS (ESI): m / z [M+H]+calcd for C20H22N2O: 307.18, found 307.20. Step 4: Preparation of 1-((R)-7-cyclopropyl-2-oxo-1-((S)-1-phenylethyl)-1,2,3,4- tetrahydroquinolin-3-yl)urea (Compound 29) The transformation was carried out similarly to in the synthesis of Compound 1. The crude product was purified by preparative HPLC (XBridge Prep C18 OBD Column, 40-65% acetonitrile / water with 10 mmol ammonium bicarbonate) to afford the title compound as a white solid (35.7 mg, 31.3% yield). LCMS (ESI): m / z [M+H]+calcd for C21H23N3O2: 350.18, found 350.15.1H NMR (400 MHz, DMSO-d6) 7.34 – 7.45 (m, 2H), 7.22 – 7.33 (m, 3H), 7.07 – 7.17 (m, 1H), 6.69 – 6.83 (m, 1H), 6.41 (d, J = 6.2 Hz, 1H), 6.20 – 6.30 (m, 2H), 5.81 (s, 2H), 4.21 – 4.36 (m, 1H), 3.00 – 3.14 (m, 1H), 2.66 – 2.80 (m, 1H), 1.56 – 1.78 (m, 4H), 0.67 – 0.93 (m, 2H), 0.30 – 0.44 (m, 1H), 0.12 – 0.22 (m, 1H). Synthesis of Compound 30: 1-((R)-6-chloro-2-oxo-1-((S)-1-phenylethyl)-1,2,3,4- tetrahydroquinolin-3-yl)urea FH12898416.1 GPX-02125 Step 1: Preparation of methyl (2R)-3-(2-amino-5-chlorophenyl)-2-[(tert- butoxycarbonyl)amino]propanoate To a solution of 2-bromo-4-chloroaniline (1 g, 4.84 mmol, 1 equiv.), palladium(II) acetate (0.11 g, 0.484 mmol, 0.1 equiv.), and Xphos (0.46 g, 0.969 mmol, 0.2 equiv.) in DMF (10 mL) was added Intermediate 1 (14.5 mL, 7.26 mmol, 1.5 equiv.) under nitrogen at 0 °C. The reaction was stirred at 25 °C for 2h, then was quenched with water (100 mL) and extracted with ethyl acetate (3 x 100 mL). The combined organic extracts were washed with water, brine, dried over sodium sulfate, filtered and concentrated. The crude product was purified by silica gel chromatography (0-100% ethyl acetate / petroleum ether) to afford the title compound as a yellow oil (1.14 g, 71.6% yield). LCMS (ESI): m / z [M+H]+calcd for C15H21ClN2O4: 329.12, found 329.10. Step 2: Preparation of tert-butyl N-[(3R)-6-chloro-2-oxo-3,4-dihydro-1H-quinolin-3- yl]carbamate Methyl (2R)-3-(2-amino-5-chlorophenyl)-2-[(tert-butoxycarbonyl)amino]propanoate (1.13 g, 3.44 mmol, 1 equiv.) was dissolved in acetic acid (20 mL). The reaction was stirred at 90 °C for 0.5 h. The mixture was allowed to cool to room temperature, then was neutralized with saturated sodium bicarbonate solution (300 mL) and extracted with ethyl acetate (3 x 300 mL). The combined organic extracts were washed with water, brine, dried FH12898416.1 GPX-02125 over sodium sulfate, filtered and concentrated. The crude product was purified by silica gel chromatography (0-100% ethyl acetate / petroleum ether) to afford the title compound as a yellow oil (750 mg, 73.5% yield). LCMS (ESI): m / z [M+Na]+calcd for C14H17ClN2O3: 319.08, found 319.10. Step 3: Preparation of tert-butyl N-[(3R)-6-chloro-2-oxo-1-[(1S)-1-phenylethyl]-3,4- dihydroquinolin-3-yl]carbamate To a solution of tert-butyl N-[(3R)-6-chloro-2-oxo-3,4-dihydro-1H-quinolin-3- yl]carbamate (740 mg, 2.49 mmol, 1 equiv.) in THF (20 mL) was added (R)-1-phenyl-ethanol (456.9 mg, 3.741 mmol, 1.5 equiv.) and triphenylphosphine (981.1 mg, 3.741 mmol, 1.5 equiv.). The reaction was stirred at 25 °C for 0.5 h under nitrogen. Diisopropyl azodicarboxylate (756.4 mg, 3.741 mmol, 1.5 equiv.) was then added at 0 °C. The reaction was stirred at 25 °C for 3 h, then quenched with water (100 mL) and extracted with ethyl acetate (3 x 100 mL). The combined organic extracts were washed with water, brine, dried over sodium sulfate, filtered and concentrated. The crude product was purified by silica gel chromatography (0-100% ethyl acetate / petroleum ether) to afford the title compound as a yellow oil (850 mg, 85.0% yield). LCMS (ESI): m / z [M+Na]+calcd for C22H25ClN2O3: 423.15, found 423.25. Step 4: Preparation of (3R)-3-amino-6-chloro-1-[(1S)-1-phenylethyl]-3,4- dihydroquinolin-2-one The transformation was carried out similarly to in the synthesis of Compound 1 to afford the title compound as a yellow oil (340 mg, 90.7% yield). LCMS (ESI): m / z [M+H]+calcd for C17H17ClN2O: 301.10, found 301.10. Step 5: Preparation of 1-((R)-6-chloro-2-oxo-1-((S)-1-phenylethyl)-1,2,3,4- tetrahydroquinolin-3-yl)urea The transformation was carried out similarly to in the synthesis of Compound 1. The crude product was purified by preparative HPLC (XBridge Prep C18 OBD Column, 30-55% acetonitrile / water with 10 mmol ammonium bicarbonate and 0.05% ammonia) to afford the title compound as a white solid (32.0 mg, 14.0% yield). LCMS (ESI): m / z [M+H]+calcd for C18H18ClN3O2: 344.1, found 344.05.1H NMR (400 MHz, DMSO-d6) 7.45 – 7.41 (m, 1H), 7.41 – 7.34 (m, 2H), 7.33 – 7.25 (m, 3H), 7.20 – 7.12 (m, 1H), 6.65 (d, J = 8.8 Hz, 1H), 6.42 (d, J = 6.4 Hz, 1H), 6.28 – 6.18 (m, 1H), 5.84 (s, 2H), 4.46 – 4.29 (m, 1H), 3.24 – 3.08 (m, 1H), 2.95 – 2.76 (m, 1H), 1.66 (d, J = 7.1 Hz, 3H). FH12898416.1 GPX-02125 Synthesis of Compound 31: 1-((R)-6-fluoro-2-oxo-1-((S)-1-phenylethyl)-1,2,3,4- tetrahydroquinolin-3-yl)urea Step 1: Preparation of methyl (R)-2-((tert-butoxycarbonyl)amino)-3-(5-fluoro-2- nitrophenyl)propanoate To a solution of 2-bromo-4-fluoro-1-nitrobenzene (2.13 g, 9.68 mmol, 1 equiv.) and Xphos (1.85 g, 3.87 mmol, 0.4 equiv.) in DMF (20 mL) was added palladium(II) acetate (0.43 g, 1.94 mmol, 0.2 equiv.) and Intermediate 1 (19.10 g, 48.41 mmol, 5 equiv.) at 0 °C. The reaction was stirred at room temperature under nitrogen for 2 h. To the above mixture was added ammonium chloride solution (10 mL). The resulting mixture was stirred for 10 minutes at room temperature and was then filtered. The filter cake was washed with ethyl acetate. The filtrate was quenched with water (40 mL) and extracted with ethyl acetate (3 x 40 mL). The combined organic extracts were washed with water, brine, dried over sodium sulfate, filtered and concentrated. The crude product was purified by silica gel chromatography (0-100% ethyl acetate / petroleum ether) to afford the title compound as a yellow oil (1.52 g, 45.9% yield). LCMS (ESI): m / z [M+H]+calcd for C15H19FN2O6: 343.13, found 243.05 [M+H-Boc]+. FH12898416.1 GPX-02125 Step 2: Preparation of tert-butyl (R)-(6-fluoro-2-oxo-1,2,3,4-tetrahydroquinolin-3- yl)carbamate To a solution of methyl (R)-2-[(tert-butoxycarbonyl)amino]-3-(5-fluoro-2- nitrophenyl)propanoate (1.52 g, 4.44 mmol, 1 equiv.) in ethanol (15 mL) and water (1.5 mL) was added iron powder (2.48 g, 44.4 mmol, 10 equiv.) and ammonium chloride (2.38 g, 44.4 mmol, 10 equiv.). The reaction was stirred at 80 °C for 2 h, then was quenched with water (30 mL) and extracted with ethyl acetate (3 x 30 mL). The combined organic extracts were washed with water, brine, dried over sodium sulfate, filtered and concentrated. The crude product was purified by silica gel chromatography (0-100% ethyl acetate / petroleum ether) to provide the title compound as a yellow oil (1.03 g, 82.8% yield). LCMS (ESI): m / z [M+H]+calcd for C14H17FN2O3: 281.13, found 281.05. Step 3: Preparation of tert-butyl ((R)-6-fluoro-2-oxo-1-((S)-1-phenylethyl)-1,2,3,4- tetrahydroquinolin-3-yl)carbamate To a solution of tert-butyl (R)-(6-fluoro-2-oxo-1,2,3,4-tetrahydroquinolin-3- yl)carbamate (600.2 mg, 2.141 mmol, 1 equiv.) in THF (10 mL) was added (R)-1-phenyl- ethanol (523.2 mg, 4.282 mmol, 2 equiv.) and triphenylphosphine (842.5 mg, 3.212 mmol, 1.5 equiv.). The reaction was stirred at room temperature under nitrogen for 0.5 h. Diisopropyl azodicarboxylate (649.5 mg, 3.212 mmol, 1.5 equiv.) was then added at 0 °C. The resulting mixture was stirred for an additional 1 h at room temperature, then was quenched with water (20 mL) and extracted with ethyl acetate (3 x 20 mL). The combined organic extracts were washed with water, brine, dried over sodium sulfate, filtered and concentrated. The crude product was purified by silica gel chromatography (0-100% ethyl acetate / petroleum ether) to provide the title compound as a yellow oil (600.6 mg, 72.96% yield). LCMS (ESI): m / z [M+H]+calcd for C22H25FN2O3: 385.19, found 385.05. Step 4: Preparation of (R)-3-amino-6-fluoro-1-((S)-1-phenylethyl)-3,4-dihydroquinolin- 2(1H)-one The transformation was carried out similarly to in the synthesis of Compound 1 to afford the title compound as a yellow oil (400 mg, 80.0% yield). LCMS (ESI): m / z [M+H]+calcd for C17H17FN2O: 285.14, found 285.00. Step 5: Preparation of 1-((R)-6-fluoro-2-oxo-1-((S)-1-phenylethyl)-1,2,3,4- tetrahydroquinolin-3-yl)urea (Compound 31) FH12898416.1 GPX-02125 The transformation was carried out similarly to in the synthesis of Compound 1. The crude product was purified by preparative HPLC (XBridge Prep C18 OBD Column, 25-55% acetonitrile / water with 10 mmol ammonium bicarbonate) to afford the title compound as a white solid (50.6 mg, 21.7% yield). LCMS (ESI): m / z [M+H]+calcd for C18H18FN3O2: 328.14, found 328.15.1H NMR (300 MHz, Methanol-d4) 7.20 – 7.41 (m, 5H), 7.07 (ddd, J = 9.0, 2.9, 1.0 Hz, 1H), 6.73 (dd, J = 9.0, 4.9 Hz, 2H), 6.21 – 6.50 (m, 1H), 4.47 (dd, J = 14.3, 5.5 Hz, 1H), 3.18 (dd, J = 14.8, 5.5 Hz, 1H), 2.93 (td, J = 14.4, 1.1 Hz, 1H), 1.72 (d, J = 7.2 Hz, 3H).19F NMR (282 MHz, Methanol-d4) -121.10. Synthesis of Compound 32: 1-((R)-6-(difluoromethyl)-2-oxo-1-((S)-1-phenylethyl)- 1,2,3,4-tetrahydroquinolin-3-yl)urea Step 1: Preparation of methyl (R)-2-((tert-butoxycarbonyl)amino)-3-(5-(difluoromethyl)- 2-nitrophenyl)propanoate To a stirred solution of methyl 2-bromo-4-(difluoromethyl)-1-nitrobenzene (1.00 g, 2.54 mmol, 1 equiv.) and Intermediate 1 (1.57 g, 3.97 mmol, 1 equiv.) iodide in DMF (30 mL) was added palladium(II) acetate (0.09 g, 0.397 mmol, 0.1 equiv.) and Xphos (0.19 g, 0.397 mmol, 0.1 equiv.) in portions at room temperature. The resulting mixture was stirred at room temperature for 2 h under a nitrogen atmosphere, at which point the reaction was judged complete by TLC. The reaction was quenched with water (30 mL), and the resulting FH12898416.1 GPX-02125 mixture was extracted with ethyl acetate (3 x 30 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by silica gel chromatography (0-100% ethyl acetate / petroleum ether) to afford the title compound as a colorless oil (600.1 mg, 63.23% yield). Step 2: Preparation of tert-butyl (R)-(6-(difluoromethyl)-2-oxo-1,2,3,4- tetrahydroquinolin-3-yl)carbamate To a stirred solution of methyl (R)-2-((tert-butoxycarbonyl)amino)-3-(5- (difluoromethyl)-2-nitrophenyl)propanoate (590.2 mg, 1.576 mmol, 1 equiv.) and iron powder (880.1 mg, 15.76 mmol, 10 equiv.) in ethanol (6 mL) and water (2 mL) was added ammonium chloride (843.1 mg, 15.760 mmol, 10 equiv.) in portions at room temperature. The resulting mixture was stirred at 80 °C for 2 h, at which point the reaction was judged complete by LCMS. The reaction was cooled to room temperature, quenched with water (20 mL), and the resulting mixture was extracted with ethyl acetate (3 x 20 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by silica gel chromatography (1:2 ethyl acetate / petroleum ether) to afford the title compound as a yellow oil (140.0 mg, 28.44% yield). LCMS (ESI): m / z [M- H]- calcd for C15H18F2N2O3: 311.13, found 311.10. Step 3: Preparation of tert-butyl ((R)-6-(difluoromethyl)-2-oxo-1-((S)-1-phenylethyl)- 1,2,3,4-tetrahydroquinolin-3-yl)carbamate To a solution of tert-butyl (R)-(6-(difluoromethyl)-2-oxo-1,2,3,4-tetrahydroquinolin- 3-yl)carbamate (345.1 mg, 1.105 mmol, 1 equiv.) in THF (5 mL) was added (R)-1- phenylethan-1-ol (135.2 mg, 1.105 mmol, 1 equiv.) and triphenylphosphine (434.7 mg, 1.657 mmol, 1.5 equiv.). The reaction was stirred at room temperature for 0.5 h under nitrogen. Diisopropyl azodicarboxylate (335.1 mg, 1.657 mmol, 1.5 equiv.) was then added at 0 °C under nitrogen. The resulting mixture was stirred at room temperature for an additional 1 h, then was quenched with water (20 mL) and extracted with ethyl acetate (3 x 20 mL). The combined organic extracts were washed with water, brine, dried over sodium sulfate, filtered and concentrated. The crude product was purified by silica gel chromatography (1:1 ethyl acetate / petroleum ether) to afford the title compound as a colorless oil (97.0 mg, 21.1% yield). LCMS (ESI): m / z [M+H]+calcd for C23H26F2N2O3: 417.19, found 417.15. Step 4: Preparation of (R)-3-amino-6-(difluoromethyl)-1-((S)-1-phenylethyl)-3,4- dihydroquinolin-2(1H)-one FH12898416.1 GPX-02125 The transformation was carried out similarly to in the synthesis of Compound 1 to afford the title compound as a colorless oil (184 mg, 45.9% yield). LCMS (ESI): m / z [M+H]+calcd for C18H18F2N2O: 317.14, found 317.05. Step 5: Preparation of 1-((R)-6-(difluoromethyl)-2-oxo-1-((S)-1-phenylethyl)-1,2,3,4- tetrahydroquinolin-3-yl)urea (Compound 32) The transformation was carried out similarly to in the synthesis of Compound 1. The crude product was purified by preparative HPLC (XBridge Shield RP18 OBD Column, 21- 51% acetonitrile / water with 0.05% ammonium bicarbonate) to afford the title compound as a white solid (50.6 mg, 21.7% yield). LCMS (ESI): m / z [M+H]+calcd for C19H19F2N3O2: 360.15, found 360.12.1H NMR (400 MHz, DMSO-d6) 7.52 (s, 1H),7.20 – 7.42 (m, 6H), 6.72 – 7.15 (m, 2H), 6.45 (s, 1H), 6.25 (q, J = 7.1 Hz, 1H), 5.84 (s, 2H), 4.30 – 4.50 (m, 1H), 3.15 – 3.30 (m, 1H), 2.80 – 3.00 (m, 1H), 1.69 (d, J = 7.2 Hz, 3H).19F NMR (376 MHz, DMSO-d6) -108.55. Synthesis of Compound 33: 1-((R)-6-((R)-1-hydroxyethyl)-2-oxo-1-((S)-1-phenylethyl)- 1,2,3,4-tetrahydroquinolin-3-yl)urea Step 1: Preparation of tert-butyl ((R)-6-bromo-2-oxo-1-((S)-1-phenylethyl)-1,2,3,4- tetrahydroquinolin-3-yl)carbamate FH12898416.1 GPX-02125 To a stirred mixture of tert-butyl N-[(3R)-6-bromo-2-oxo-3,4-dihydro-1H-quinolin-3- yl] carbamate (1.40 g, 4.10 mmol, 1 equiv.) and (R)-1-phenyl-ethanol (601.5 mg, 4.924 mmol, 1.20 equiv.) in THF (15 mL) was added triphenylphosphine (1614.3 mg, 6.154 mmol, 1.5 equiv.) in portions at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at room temperature for an additional 20 min. Diisopropyl azodicarboxylate (1244.5 mg, 6.154 mmol, 1.5 equiv.) was then added in portions at 0 °C. The resulting mixture was stirred at room temperature for 1 h, at which point the reaction was judged complete by LCMS. The reaction mixture was quenched with water (20 mL) and extracted with dichloromethane (3 x 20 mL). The combined organic extracts were washed with water, brine, dried over sodium sulfate, filtered and concentrated. The crude product was purified by silica gel chromatography (1:1 ethyl acetate / petroleum ether) to afford the title compound as a yellow oil (1.10 g, 60.2% yield). LCMS (ESI): m / z [M+H]+calcd for C22H25BrN2O3: 445.10, found 444.95. Step 2: Preparation of tert-butyl ((R)-6-acetyl-2-oxo-1-((S)-1-phenylethyl)-1,2,3,4- tetrahydroquinolin-3-yl)carbamate To a stirred mixture of tert-butyl N-{6-bromo-2-oxo-1-[(1S)-1-phenylethyl]-3,4- dihydroquinolin-3-yl}carbamate (1.10 g, 2.47 mmol, 1 equiv.) and tributyl(1- ethoxyethenyl)stannane (1338.0 mg, 3.705 mmol, 1.5 equiv.) in 1,4-dioxane (10 mL) was added bis(triphenylphosphine)palladium(II) dichloride (173.3 mg, 0.247 mmol, 0.1 equiv.) in portions at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 100 °C for an additional 2 h, at which point the reaction was judged complete by LCMS. The mixture was allowed to cool to room temperature, and then 1 N hydrochloric acid (5 mL) was added. The resulting mixture was stirred for additional 1 h at room temperature, then was quenched with water (20 mL) and extracted with ethyl acetate (3 x 20 mL). The combined organic extracts were washed with water, brine, dried over sodium sulfate, filtered and concentrated. The crude product was purified by silica gel chromatography (0-100% ethyl acetate / petroleum ether) to afford the title compound as a yellow oil (550.4 mg, 54.51% yield). LCMS (ESI): m / z [M+H]+calcd for C24H28N2O4: 409.21, found 409.15. Step 3: Preparation of (R)-6-acetyl-3-amino-1-((S)-1-phenylethyl)-3,4-dihydroquinolin- 2(1H)-one FH12898416.1 GPX-02125 The transformation was carried out similarly to in the synthesis of Compound 1 to afford the title compound as a yellow oil (350 mg, 93.7% yield). LCMS (ESI): m / z [M+H]+calcd for C19H20N2O2: 309.16, found 309.05. Step 4: Preparation of 1-((R)-6-acetyl-2-oxo-1-((S)-1-phenylethyl)-1,2,3,4- tetrahydroquinolin-3-yl)urea The transformation was carried out similarly to in the synthesis of Compound 1. The crude product was purified by silica gel chromatography (0-100% ethyl acetate / petroleum ether) to afford the title compound as a yellow oil. LCMS (ESI): m / z [M+H]+calcd for C16H15F3N4O2: 352.16, found 352.10. Step 5: Preparation of 1-((R)-6-((R)-1-hydroxyethyl)-2-oxo-1-((S)-1-phenylethyl)-1,2,3,4- tetrahydroquinolin-3-yl)urea (Compound 33) To a stirred mixture of (S)-(-)-2-methyl-CBS-oxazaborolidine (47.3 mg, 0.171 mmol, 0.4 equiv.) in THF (10 mL) was added borane-dimethyl sulfide complex (48.64 mg, 0.640 mmol, 1.5 equiv.) in portions at 0 °C. To the resulting mixture was added 1-((R)-6-acetyl-2- oxo-1-((S)-1-phenylethyl)-1,2,3,4-tetrahydroquinolin-3-yl)urea (150.2 mg, 0.427 mmol, 1 equiv.) in portions at 0 °C. The resulting mixture was stirred at 0 °C for an additional 1 h, at which point the reaction was judged complete by LCMS. The reaction was quenched with water (30 mL) and extracted with ethyl acetate (3 x 30 mL). The combined organic extracts were washed with water, brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (0-100% ethyl acetate / petroleum ether) to afford the title compound as a yellow oil (150.2 mg). The product was further purified by preparative HPLC (XBridge Shield RP18 OBD column, 25-41% acetonitrile / water with 0.05% trifluoroacetic acid) to afford the title compound as a white solid (75.7 mg, 50.2% yield). LCMS (ESI): m / z [M+H]+calcd for C20H23N3O3: 354.18, found 354.20.1H NMR (400 MHz, Methanol-d4) 7.42 – 7.32 (m, 4H), 7.29 (s, 2H), 7.06 (dd, J = 8.4, 2.1 Hz, 1H), 6.72 (d, J = 8.5 Hz, 1H), 6.30 – 6.38 (m, 1H), 4.70 – 4.82 (m, 1H), 4.40 – 4.55 (m, 1H), 3.10 – 3.25 (m, 1H), 2.88 – 3.00 (m, 1H), 1.73 (d, J = 7.2 Hz, 3H), 1.34 – 1.44 (m, 3H). Synthesis of Compound 34: 1-((R)-2-oxo-1-((S)-1-phenylethyl)-7-(trifluoromethyl)- 1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)urea FH12898416.1 GPX-02125 Step 1: Preparation of methyl (R)-3-(3-amino-4-(trifluoromethyl)pyridin-2-yl)-2-((tert- butoxycarbonyl)amino)propanoate To a solution of 2-bromo-5-(trifluoromethyl)pyridin-3-amine (2 g, 8.30 mmol, 1 equiv.) in DMF (10 mL) was added Intermediate 1 (6.55 g, 16.6 mmol, 2 equiv.) and dichlorobis(triphenylphosphine)palladium(II) (582.5 mg, 0.830 mmol, 0.10 equiv.) under nitrogen. The reaction was stirred at 40 °C under nitrogen for 3 h. The mixture was quenched with water (100 mL) and extracted with ethyl acetate (3 x 100 mL). The combined organic extracts were washed with water, brine, dried over sodium sulfate, filtered and concentrated. The crude product was purified by silica gel chromatography (0-100% ethyl acetate / petroleum ether) to afford the title compound as a yellow oil (2.5 g, 82.9% yield). LCMS (ESI): m / z [M+H]+calcd for C15H20F3N3O4: 364.14, found 364.00. Step 2: Preparation of tert-butyl (R)-(2-oxo-7-(trifluoromethyl)-1,2,3,4-tetrahydro-1,5- naphthyridin-3-yl)carbamate To a solution of methyl (R)-3-(3-amino-4-(trifluoromethyl)pyridin-2-yl)-2-((tert- butoxycarbonyl)amino)propanoate (2.5 g, 6.88 mmol, 1 equiv.) in DMF (30 mL) was added potassium carbonate (1.90 g, 13.8 mmol, 2 equiv.). The reaction was stirred at 80 °C for 3 h, then the mixture was quenched with water (100 mL) and extracted with ethyl acetate (3 x 100 mL). The combined organic extracts were washed with water, brine, dried over sodium FH12898416.1 GPX-02125 sulfate, filtered and concentrated. The crude product was purified by silica gel chromatography (0-100% ethyl acetate / petroleum ether) to afford the title compound as a yellow oil (1.8 g, 78.9% yield). LCMS (ESI): m / z [M+H]+calcd for C14H16F3N3O3: 332.12, found 275.95 [M+H-tBu]+. Step 3: Preparation of tert-butyl ((R)-2-oxo-1-((S)-1-phenylethyl)-7-(trifluoromethyl)- 1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)carbamate To a solution of tert-butyl (R)-(2-oxo-7-(trifluoromethyl)-1,2,3,4-tetrahydro-1,5- naphthyridin-3-yl)carbamate (500 mg, 1.51 mmol, 1 equiv.) in THF (10 mL) was added (R)- 1-phenylethan-1-ol (184.4 mg, 1.509 mmol, 1.00 equiv.) and triphenylphospine (593.1 mg, 2.261 mmol, 1.50 equiv.) under nitrogen. The reaction was stirred at room temperature under nitrogen for 0.5 h. Diisopropyl azodicarboxylate (457.7 mg, 2.263 mmol, 1.50 equiv.) was then added at 0 °C. The resulting mixture was stirred for an additional 1 h at room temperature, then was quenched with water (30 mL) and extracted with dichloromethane (3 x 30 mL). The combined organic extracts were washed with water, brine, dried over sodium sulfate, filtered and concentrated. The crude product was purified by silica gel chromatography (0-100% ethyl acetate / petroleum ether) to afford the title compound as a yellow oil (350 mg, 53.3% yield). LCMS (ESI): m / z [M+H]+calcd for C22H24F3N3O3: 436.18, found 379.95 [M+H-tBu]+. Step 4: Preparation of (R)-3-amino-1-((S)-1-phenylethyl)-7-(trifluoromethyl)-3,4- dihydro-1,5-naphthyridin-2(1H)-one The transformation was carried out similarly to in the synthesis of Compound 1 to afford the title compound as a yellow oil (260 mg, 87.0% yield). LCMS (ESI): m / z [M+H]+calcd for C17H16F3N3O: 336.13, found 336.00. Step 5: Preparation of 1-((R)-2-oxo-1-((S)-1-phenylethyl)-7-(trifluoromethyl)-1,2,3,4- tetrahydro-1,5-naphthyridin-3-yl)urea (Compound 34) The transformation was carried out similarly to in the synthesis of Compound 1. The crude product was purified by preparative HPLC (XBridge Prep OBD C18 Column, 29-45% acetonitrile / water with 10 mmol ammonium bicarbonate) to afford the title compound as a white solid (100 mg, 39.31% yield). Chiral HPLC showed significant racemization had occurred, so the compound was further purified by chiral HPLC (CHIRALPAK IG Column, 25% hexane / dichloromethane with 0.5% ammonia) to provide the desired enantiomer as a white solid (39.9 mg, 41.6% yield). LCMS (ESI): m / z [M+H]+calcd for C18H17F3N4O2: FH12898416.1 GPX-02125 379.13, found 379.05.1H-NMR (400 MHz, DMSO-d6) 8.56 (s, 1H), 7.28 – 7.44 (m, 5H), 7.20 (s, 1H), 6.48 (d, J = 6.5 Hz, 1H), 6.26 (d, J = 7.3 Hz, 1H), 5.84 (s, 2H), 4.59 – 4.70 (m, 1H), 3.18 – 3.32 (m, 2H), 1.69 (d, J = 7.1 Hz, 3H).19F-NMR (376 MHz, DMSO-d6) -61.06. Synthesis of Compound 35: 1-((R)-7-chloro-2-oxo-1-((S)-1-phenylethyl)-1,2,3,4- tetrahydro-1,5-naphthyridin-3-yl)urea Step 1: Preparation of methyl (R)-3-(3-amino-5-chloropyridin-2-yl)-2-((tert- butoxycarbonyl)amino)propanoate To a solution of 2-bromo-5-chloropyridin-3-amine (3 g, 14.5 mmol, 1 equiv.) in DMF (50 mL) was added Intermediate 1 (11.4 g, 28.9 mmol, 2.00 equiv.) and dichlorobis(triphenylphosphine)palladium(II) (1.01 g, 1.45 mmol, 0.1 equiv.) under nitrogen. The reaction was stirred at 40 °C under nitrogen for 3 h, then the mixture was allowed to cool to room temperature. The resulting mixture was quenched with water (150 mL) and extracted with ethyl acetate (3 x 150 mL). The combined organic extracts were washed with water, brine, dried over sodium sulfate, filtered and concentrated. The crude product was purified by silica gel chromatography (0-100% ethyl acetate / petroleum ether) to afford the title compound as a yellow oil (2.5 g, 52.4% yield). LCMS (ESI): m / z [M+H]+calcd for C14H20ClN3O4: 330.11, found 330.05. FH12898416.1 GPX-02125 Step 2: Preparation of tert-butyl (R)-(7-chloro-2-oxo-1,2,3,4-tetrahydro-1,5- naphthyridin-3-yl)carbamate Methyl (R)-3-(3-amino-5-chloropyridin-2-yl)-2-((tert- butoxycarbonyl)amino)propanoate (2.5 g, 7.58 mmol, 1 equiv.) was added to acetic acid (50 mL) at 0 °C. The reaction was stirred at 90 °C for 1.5 h. The mixture was neutralized to pH 8 with sodium bicarbonate solution and diluted with water (200 mL), then was extracted with dichloromethane (3 x 200 mL). The combined organic extracts were washed with water, brine, dried over sodium sulfate, filtered and concentrated. The crude product was purified by silica gel chromatography (0-100% ethyl acetate / petroleum ether) to afford the title compound as a yellow oil (1.8 g, 79.8% yield). LCMS (ESI): m / z [M+H]+calcd for C13H16ClN3O3: 298.09, found 297.90. Step 3: Preparation of tert-butyl ((R)-7-chloro-2-oxo-1-((S)-1-phenylethyl)-1,2,3,4- tetrahydro-1,5-naphthyridin-3-yl)carbamate To a solution of tert-butyl (R)-(7-chloro-2-oxo-1,2,3,4-tetrahydro-1,5-naphthyridin-3- yl)carbamate (400 mg, 1.34 mmol, 1 equiv.) in THF (6 mL) was added (R)-1-phenylethan-1- ol (164.1 mg, 1.343 mmol, 1.00 equiv.), and triphenylphosphine (528.5 mg, 2.015 mmol, 1.50 equiv.). The reaction was stirred at room temperature for 0.5 h under nitrogen. Diisopropyl azodicarboxylate (407.5 mg, 2.015 mmol, 1.50 equiv.) was then added at 0 °C. The resulting mixture was stirred at room temperature for an additional 1h under nitrogen, then was quenched with water (20 mL) and extracted with dichloromethane (3 x 20 mL). The combined organic extracts were washed with water, brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (0-100% ethyl acetate / petroleum ether) to afford the title compound as a yellow oil (300 mg, 55.6% yield). LCMS (ESI): m / z [M+H]+calcd for C21H24ClN3O3: 402.15, found 402.00. Step 4: Preparation of (R)-3-amino-7-chloro-1-((S)-1-phenylethyl)-3,4-dihydro-1,5- naphthyridin-2(1H)-one The transformation was carried out similarly to in the synthesis of Compound 1 to afford the title compound as a yellow oil (210 mg, 89.1% yield). LCMS (ESI): m / z [M+H]+calcd for C16H16ClN3O: 302.10, found 302.0. Step 5: Preparation of 1-((R)-7-chloro-2-oxo-1-((S)-1-phenylethyl)-1,2,3,4-tetrahydro- 1,5-naphthyridin-3-yl)urea (Compound 35) FH12898416.1 GPX-02125 The transformation was carried out similarly to in the synthesis of Compound 1. The crude product was purified by preparative HPLC (XBridge Prep OBD C18 Column, 22-38% acetonitrile / water with 10 mmol ammonium bicarbonate) to afford the title compound as a white solid (53.6 mg, 23.5% yield). LCMS (ESI): m / z [M+H]+calcd for C17H17ClN4O2: 345.10, found 345.00.1H-NMR (400 MHz, DMSO-d6) 8.23 (d, J = 2.0 Hz, 1H), 7.25 – 7.43 (m,5H), 7.08 (d, J = 2.1 Hz, 1H), 6.45 (d, J = 6.5 Hz, 1H), 6.11 – 6.21 (d, 1H), 5.83 (s, 2H), 4.51 – 4.62 (m, 1H), 3.21 – 3.31 (m, 1H), 3.05 – 3.17 (m, 1H), 1.69 (d, J = 7.1 Hz, 3H). Synthesis of Compound 36: 1-((R)-7-chloro-8-fluoro-2-oxo-1-((S)-1-phenylethyl)-1,2,3,4- tetrahydroquinolin-3-yl)urea Step 1: Preparation of (R)-3-(2-amino-4-chloro-3-fluorophenyl)-2-((tert- butoxycarbonyl)amino)propanoate To a solution of 6-bromo-3-chloro-2-fluoroaniline (1 g, 4.46 mmol, 1 equiv.) in DMF (10 mL) was added palladium(II) acetate (0.15 g, 0.668 mmol, 0.15 equiv.), Xphos (0.64 g, 1.34 mmol, 0.3 equiv.) and Intermediate 1 (3.52 g, 8.91 mmol, 2 equiv.) at 0 °C under nitrogen. The reaction was stirred at 25 °C for 16 h under nitrogen, then was quenched with water (500 mL) and extracted with ethyl acetate (3 x 600 mL). The combined organic extracts were washed with water, brine, dried over sodium sulfate, filtered and concentrated. The FH12898416.1 GPX-02125 crude product was purified by silica gel chromatography (0-100% ethyl acetate / petroleum ether) to afford the title compound as a yellow oil (1.1 g, 71.2% yield). LCMS (ESI): m / z [M+H]+calcd for C15H20ClFN2O4: 347.11, found 291.05 [M+H-tBu]+. Step 2: Preparation of tert-butyl N-[(3R)-7-chloro-8-fluoro-2-oxo-3,4-dihydro-1H- quinolin-3-yl]carbamate Methyl (2R)-3-(2-amino-4-chloro-3-fluorophenyl)-2-[(tert-butoxycarbonyl)amino]propanoate (1.08 g, 3.11 mmol, 1 equiv.) was dissolved in acetic acid (12 mL). The reaction was stirred at 90 °C for 0.5 h. The mixture was allowed to cool to room temperature, then the solvent was removed. The residue was quenched with saturated sodium bicarbonate solution (100 mL) and extracted with ethyl acetate (3 x 200 mL). The combined organic extracts were washed with water, brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (0-100% ethyl acetate / petroleum ether) to afford the title compound as a white solid (800 mg, 81.6% yield). LCMS (ESI): m / z [M+Na]+calcd for C14H16ClFN2O3: 337.07, found 337.05. Step 3: Preparation of tert-butyl ((R)-7-chloro-8-fluoro-2-oxo-1-((S)-1-phenylethyl)- 1,2,3,4-tetrahydroquinolin-3-yl)carbamate To a solution of tert-butyl N-[(3R)-7-chloro-8-fluoro-2-oxo-3,4-dihydro-1H-quinolin- 3-yl]carbamate (500 mg, 1.59 mmol, 1 equiv.) and (R)-1-phenyl-ethanol (388.1 mg, 3.178 mmol, 2 equiv.) in THF (7 mL) was added triphenylphosphine (625.0 mg, 2.383 mmol, 1.5 equiv.) at room temperature under nitrogen. The reaction was stirred at room temperature for 0.5 h under nitrogen. Diisopropyl azodicarboxylate (481.8 mg, 2.383 mmol, 1.5 equiv.) was then added at 0 °C under a nitrogen atmosphere. The reaction was stirred at room temperature for 2 h under nitrogen, then was quenched with water (50 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic extracts were washed with water, brine, dried over sodium sulfate, filtered and concentrated. The crude product was purified by silica gel chromatography (0-100%) to afford the title compound as a yellow oil (300 mg, 45.1% yield). LCMS (ESI): m / z [M+Na]+calcd for C22H24ClFN2O3: 441.14, found 441.15. Step 4: Preparation of (R)-3-amino-7-chloro-8-fluoro-1-((S)-1-phenylethyl)-3,4- dihydroquinolin-2(1H)-one The transformation was carried out similarly to in the synthesis of Compound 1 to afford the title compound as a yellow oil (190 mg, 96.1% yield). LCMS (ESI): m / z [M+H]+calcd for C17H16ClFN2O: 319.09, found 319.05. FH12898416.1 GPX-02125 Step 5: Preparation of 1-((R)-7-chloro-8-fluoro-2-oxo-1-((S)-1-phenylethyl)-1,2,3,4- tetrahydroquinolin-3-yl)urea (Compound 36) The transformation was carried out similarly to in the synthesis of Compound 1. The crude product was purified by preparative HPLC (Kinetex EVO C18 Column, 42-54% acetonitrile / water with 10 mmol ammonium bicarbonate) to afford the title compound as a white solid (53.6 mg, 23.5% yield). LCMS (ESI): m / z [M+H]+calcd for C18H17ClFN3O2: 362.10, found 362.15.1H NMR (300 MHz, DMSO-d6) 7.10-7.48 (m, 7H), 6.33 (d, J = 6.5 Hz, 1H), 5.76 (s, 2H), 5.39 - 5.53 (m, 1H), 4.12 - 4.39 (m, 1H), 3.00 - 3.18 (m, 1H), 2.36 - 2.80 (m, 1H), 1.70 - 1.85 (m, 3H).19F NMR (282 MHz, DMSO-d6) -119.37. Synthesis of Compound 37: 1-((R)-7-chloro-5-fluoro-2-oxo-1-((S)-1-phenylethyl)-1,2,3,4- tetrahydroquinolin-3-yl)urea Step 1: Preparation of 2-bromo-5-chloro-N-[(2,4-dimethoxyphenyl)methyl]-3- fluoroaniline To a solution of 2-bromo-5-chloro-1,3-difluorobenzene (2 g, 8.79 mmol, 1 equiv.) in DMSO (20 mL) was added 1-(2,4-dimethoxyphenyl)methanamine (1.76 g, 10.6 mmol, 1.2 equiv.) and N,N-diisopropylethylamine (4.55 g, 35.2 mmol, 4 equiv.). The reaction was stirred at 60 °C for 16 h, then was quenched with water (100 mL) and extracted with ethyl acetate (3 x 100 mL). The combined organic extracts were washed with water, brine, dried over sodium sulfate, filtered and concentrated. The crude product was purified by silica gel FH12898416.1 GPX-02125 chromatography (0-100% ethyl acetate / petroleum ether) to afford the title compound as a yellow oil (1.1 g, 33.4% yield). Step 2: Preparation of 2-bromo-5-chloro-3-fluoroaniline To a solution of 2-bromo-5-chloro-N-[(2,4-dimethoxyphenyl)methyl]-3-fluoroaniline (1.09 g, 2.91 mmol, 1 equiv.) in dichloromethane (10 mL) was added trifluoroacetic acid (10 mL). The reaction was stirred at 25 °C for 2 h, then the solvent was removed. The residue was quenched with saturated sodium bicarbonate solution (50 mL) and extracted with ethyl acetate (3 x 80 mL). The combined organic extracts were washed with water, brine, dried over sodium sulfate, filtered and concentrated. The crude product was purified by silica gel chromatography (0-100% ethyl acetate / petroleum ether) to afford the title compound as a brown oil (400 mg, 61.3% yield). LCMS (ESI): m / z [M+H]+calcd for C6H4BrClFN: 225.92, found 225.95. Step 3: Preparation of tert-butyl N-[(3R)-7-chloro-5-fluoro-2-oxo-3,4-dihydro-1H- quinolin-3-yl]carbamate To a solution of 2-bromo-5-chloro-3-fluoroaniline (400 mg, 1.78 mmol, 1 equiv.) in DMF (3 mL) was added Intermediate 1 (1.41 g, 3.56 mmol, 2 equiv.), palladium(II) acetate (60.0 mg, 0.267 mmol, 0.15 equiv.) and Xphos (254.9 mg, 0.535 mmol, 0.3 equiv.) at 0 °C under nitrogen. The reaction was stirred at 25 °C for 16 h under nitrogen, then was quenched with water (100 mL) and extracted with ethyl acetate (3 x 100 mL). The combined organic extracts were washed with water, brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (0-100% ethyl acetate / petroleum ether) to afford the title compound as a yellow oil (300 mg, 53.5% yield). LCMS (ESI): m / z [M+Na]+calcd for C14H16ClFN2O3: 337.07, found 337.05. Step 4: Preparation of tert-butyl ((R)-7-chloro-5-fluoro-2-oxo-1-((S)-1-phenylethyl)- 1,2,3,4-tetrahydroquinolin-3-yl)carbamate To a solution of tert-butyl N-[(3R)-7-chloro-5-fluoro-2-oxo-3,4-dihydro-1H-quinolin- 3-yl]carbamate (260 mg, 0.826 mmol, 1 equiv.) and (R)-1-phenylethan-1-ol (201.8 mg, 1.652 mmol, 2.00 equiv.) in THF (7 mL) was added triphenylphosphine (325.0 mg, 1.239 mmol, 1.50 equiv.) at room temperature under nitrogen. The reaction was stirred at room temperature for 0.5 h under nitrogen. Diisopropylazodicarboxylate (250.5 mg, 1.239 mmol, 1.50 equiv.) was then added at 0 °C under a nitrogen atmosphere. The reaction was stirred at room temperature for 2h under nitrogen, then was quenched with water (50 mL) and FH12898416.1 GPX-02125 extracted with ethyl acetate (3 x 30 mL). The combined organic extracts were washed with water, brine, dried over sodium sulfate, filtered and concentrated. The crude product was purified by silica gel chromatography (0-100% ethyl acetate / petroleum ether) to afford the title compound as a yellow oil (270 mg, 78.0% yield). LCMS (ESI): m / z [M+Na]+calcd for C22H24ClFN2O3: 441.14, found 441.10. Step 5: Preparation of (R)-3-amino-7-chloro-5-fluoro-1-((S)-1-phenylethyl)-3,4- dihydroquinolin-2(1H)-one The transformation was carried out similarly to in the synthesis of Compound 1 to afford the title compound as a yellow oil (180 mg, 87.6% yield). LCMS (ESI): m / z [M+H]+calcd for C17H16ClFN2O: 319.09, found 319.10. Step 6: Preparation of 1-((R)-7-chloro-5-fluoro-2-oxo-1-((S)-1-phenylethyl)-1,2,3,4- tetrahydroquinolin-3-yl)urea (Compound 37) The transformation was carried out similarly to in the synthesis of Compound 1. The crude product was purified by preparative HPLC (XBridge Prep OBD C18 Column, 33-63% acetonitrile / water with 10 mmol ammonium bicarbonate) to afford the title compound as a white solid (44.9 mg, 21.9% yield). LCMS (ESI): m / z [M+H]+calcd for C18H17ClFN3O2: 362.10, found 362.15.1H NMR (300 MHz, DMSO-d6) 7.34 - 7.43 (m, 2H), 7.25 - 7.34 (m, 3H), 7.12 - 7.21 (m, 1H), 6.59 (s, 1H), 6.47 (d, J = 6.1 Hz, 1H), 6.15 - 6.26 (m, 1H), 5.85 (s, 2H), 4.32 - 4.47 (m, 1H), 3.25 - 3.30 (m,1H), 2.59 - 2.78 (m, 1H), 1.69 (d, J = 7.1 Hz, 3H).19F NMR (282 MHz, DMSO-d6) -115.14. Synthesis of Compound 38: 1-((R)-7-chloro-6-fluoro-2-oxo-1-((S)-1-phenylethyl)-1,2,3,4- tetrahydroquinolin-3-yl)urea Scheme 54 FH12898416.1 GPX-02125 Step 1: Preparation of methyl (2R)-3-(2-amino-4-chloro-5-fluorophenyl)-2-[(tert- butoxycarbonyl)amino]propanoate To a solution of 2-bromo-5-chloro-4-fluoroaniline (2 g, 8.91 mmol, 1 equiv.) in DMF (20 mL) was added Intermediate 1 (6.95 g, 17.6 mmol, 2 equiv.), palladium(II) acetate (0.30 g, 1.34 mmol, 0.15 equiv.) and XPhos (1.26 g, 2.64 mmol, 0.3 equiv.) at 0°C under nitrogen. The reaction was stirred at 25 °C for 16 h under nitrogen, then was quenched with water (100 mL) and extracted with ethyl acetate (3 x 100 mL). The combined organic extracts were washed with water, brine, dried over sodium sulfate, filtered and concentrated. The crude product was purified by silica gel chromatography (0-100% ethyl acetate / petroleum ether) to afford the title compound as a yellow oil (1.8 g, 58.3% yield). LCMS (ESI): m / z [M+H]+calcd for C15H20ClFN2O4: 347.11, found 347.00. Step 2: Preparation of tert-butyl N-[(3R)-7-chloro-6-fluoro-2-oxo-3,4-dihydro-1H- quinolin-3-yl]carbamate A solution of methyl (2R)-3-(2-amino-4-chloro-5-fluorophenyl)-2-[(tert- butoxycarbonyl)amino]propanoate (1.8 g, 5.19 mmol, 1 equiv.) in acetic acid (20 mL) was stirred at 90 °C for 1 h. The mixture was allowed to cool to room temperature, then the solvent was removed. The residue was quenched with saturated sodium bicarbonate solution (100 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic extracts were washed with water, brine, dried over sodium sulfate, filtered and concentrated to afford the title compound as a yellow oil (1.6 g, 97.9% yield). LCMS (ESI): m / z [M+H]+calcd for C14H16ClFN2O3: 315.08, found 259.10 [M+H-tBu]+. Step 3: Preparation of tert-butyl ((R)-7-chloro-6-fluoro-2-oxo-1-((S)-1-phenylethyl)- 1,2,3,4-tetrahydroquinolin-3-yl) carbamate FH12898416.1 GPX-02125 To a solution of tert-butyl N-[(3R)-7-chloro-6-fluoro-2-oxo-3,4-dihydro-1H-quinolin- 3-yl] carbamate (600 mg, 1.91 mmol, 1 equiv.) in tetrahydrofuran (20 mL) was added (R)-1- phenyl-ethanol (349.4 mg, 2.861 mmol, 1.50 equiv.) and triphenylphospine (750.1 mg, 2.860 mmol, 1.50 equiv.). The reaction was stirred at room temperature for 1 h under nitrogen, then diisopropyl azodicarboxylate (578.2 mg, 2.860 mmol, 1.50 equiv.) was added. The reaction was stirred at room temperature for 1 h under nitrogen, then was quenched with water (100 mL) and extracted with ethyl acetate (3 x 100 mL). The combined organic extracts were washed with water, brine, dried over sodium sulfate, filtered and concentrated. The crude product was purified by silica gel chromatography (0-100% ethyl acetate / petroleum ether) to afford the title compound (510 mg, 63.8% yield). LCMS (ESI): m / z [M+H]+calcd for C22H24ClFN2O3: 419.15, found 419.25. Step 4: Preparation of (R)-3-amino-7-chloro-6-fluoro-1-((S)-1-phenylethyl)-3,4- dihydroquinolin-2(1H)-one The transformation was carried out similarly to in the synthesis of Compound 1 to afford the title compound as a yellow oil (200 mg, 87.7% yield). LCMS (ESI): m / z [M+H]+calcd for C17H16ClFN2O: 319.09, found 319.10. Step 5: Preparation of 1-((R)-7-chloro-6-fluoro-2-oxo-1-((S)-1-phenylethyl)-1,2,3,4- tetrahydroquinolin-3-yl)urea (Compound 38) The transformation was carried out similarly to in the synthesis of Compound 1. The crude product was purified by preparative HPLC (YMC-Actus Triart C18 ExRS Column, 49- 73% acetonitrile / water with 10 mmol ammonium bicarbonate) to afford the title compound as a white solid (47.5 mg, 20.9% yield). LCMS (ESI): m / z [M+H]+calcd for C18H17ClFN3O2: 362.10, found 362.10.1H NMR (400 MHz, DMSO-d6) 7.48 (d, J = 8.0 Hz, 1H), 7.35 - 7.43 (m, 2H), 7.25 - 7.34 (m, 3H), 6.77 (d, J = 8.0 Hz, 1H), 6.41 (d, J = 6.48.0 Hz, 1H), 6.13 - 6.23 (m, 1H), 5.83 (s, 2H), 4.31 - 4.42 (m, 1H), 3.12 - 3.21 (m, 1H), 2.78 - 2.90 (m, 1H), 1.68 (d, J = 4.0 Hz, 3H). Synthesis of Compound 39: 1-((R)-5,7-difluoro-2-oxo-1-((S)-1-phenylethyl)-1,2,3,4- tetrahydroquinolin-3-yl)urea FH12898416.1 GPX-02125 Step 1: Preparation of tert-butyl N-[(3R)-5,7-difluoro-2-oxo-3,4-dihydro-1H-quinolin-3- yl]carbamate To a solution of 2-bromo-3,5-difluoroaniline (2.5 g, 12.0 mmol, 1 equiv.) in DMF (15 mL) was added palladium(II) acetate (0.40 g, 1.80 mmol, 0.15 equiv.) and Xphos (1.72 g, 3.61 mmol, 0.3 equiv.) at 0 °C under nitrogen. Intermediate 1 (9.48 g, 24.0 mmol, 2 equiv.) was then added at 0 °C under nitrogen. The reaction was stirred at 25 °C for 16 h, then was quenched with water (500 mL) and extracted with ethyl acetate (3 x 600 mL). The combined organic extracts were washed with water, brine, dried over sodium sulfate, filtered and concentrated. The crude product was purified by silica gel chromatography (0-100% ethyl acetate / petroleum ether) to afford the title compound as a yellow oil (2.3 g, 64.2% yield). LCMS (ESI): m / z [M+Na]+calcd for C14H16F2N2O3: 321.10, found 321.10. Step 2: Preparation of tert-butyl ((R)-5,7-difluoro-2-oxo-1-((S)-1-phenylethyl)-1,2,3,4- tetrahydroquinolin-3-yl)carbamate To a solution of tert-butyl N-[(3R)-5,7-difluoro-2-oxo-3,4-dihydro-1H-quinolin-3- yl]carbamate (1 g, 3.35 mmol, 1 equiv.) and (R)-1-phenyl-ethanol (0.82 g, 6.70 mmol, 2 equiv.) in THF (20 mL) was added triphenylphosphine (1.32 g, 5.03 mmol, 1.5 equiv.) at FH12898416.1 GPX-02125 room temperature under nitrogen. The reaction was stirred at room temperature for 0.5 h under nitrogen. Diisopropyl azodicarboxylate (1.02 g, 5.03 mmol, 1.5 equiv.) was then added at 0 °C under a nitrogen atmosphere. The reaction was stirred at room temperature for 2 h under nitrogen, then was quenched with water (30 mL) and extracted with ethyl acetate (3 x 30 mL). The combined organic extracts were washed with water, brine, dried over sodium sulfate, filtered and concentrated. The crude product was purified by silica gel chromatography (0-100% ethyl acetate / petroleum ether) to afford the title compound as a yellow oil (600 mg, 44.4% yield). LCMS (ESI): m / z [M+Na]+calcd for C22H24F2N2O3: 425.17, found 425.20. Step 3: Preparation of (R)-3-amino-5,7-difluoro-1-((S)-1-phenylethyl)-3,4- dihydroquinolin-2(1H)-one The transformation was carried out similarly to in the synthesis of Compound 1 to afford the title compound as a yellow oil (140 mg, 93.1% yield). LCMS (ESI): m / z [M+H]+calcd for C17H16F2N2O: 303.13, found 303.10. Step 4: Preparation of 1-((R)-5,7-difluoro-2-oxo-1-((S)-1-phenylethyl)-1,2,3,4- tetrahydroquinolin-3-yl)urea (Compound 39) The transformation was carried out similarly to in the synthesis of Compound 1. The crude product was purified by preparative HPLC (Xbridge Prep Shield RP18 Column, 30- 50% acetonitrile / water with 10 mmol ammonium bicarbonate) to afford the title compound as a white solid (41.0 mg, 18.0% yield). LCMS (ESI): m / z [M+H]+calcd for C18H17F2N3O2: 346.13, found 346.15.1H NMR (400 MHz, Methanol-d4) 7.16 - 7.52 (m, 5H), 6.55 - 6.81 (m, 1H), 6.21-6.51 (m, 2H), 4.32-4.61 (m, 1H), 3.38 - 3.59 (m, 1H), 2.51 - 2.69 (m, 1H), 1.73 (d, J = 7.2 Hz, 3H).19F NMR (376 MHz, Methanol-d4) -112.91, -115.61. Synthesis of Compound 40: 2,2-difluoro-N-((R)-2-oxo-1-((S)-1-phenylethyl)-1,2,3,4- tetrahydroquinolin-3-yl)acetamide Scheme 56 FH12898416.1 GPX-02125 Step 1: Preparation of 2,2-difluoro-N-((R)-2-oxo-1-((S)-1-phenylethyl)-1,2,3,4- tetrahydroquinolin-3-yl)acetamide (Compound 40) The transformation was carried out similarly to the synthesis of Compound 8. The crude product was purified by preparative HPLC (Xbridge Prep Shield RP18 Column, 20- 50% acetonitrile / water with 10 mmol ammonium bicarbonate) to afford the title compound as a white solid (102.7 mg, 39.7% yield). LCMS (ESI): m / z [M+H]+calcd for C19H18F2N2O2: 345.14, found 345.15.1H NMR (400 MHz, DMSO-d6) 9.20 (d, J = 7.9 Hz, 1H), 7.51 – 7.22 (m, 6H), 7.18 – 7.01 (m, 2H), 6.70 (d, J = 8.1 Hz, 1H), 6.59 – 6.14 (m, 2H), 4.84 – 4.61 (m, 1H), 3.21 – 2.96 (m, 2H), 1.69 (d, J = 7.2 Hz, 3H).19F NMR (376 MHz, DMSO-d6) - 125.95. Synthesis of Compound 41: 1-hydroxy-N-((R)-2-oxo-1-((S)-1-phenylethyl)-1,2,3,4- tetrahydroquinolin-3-yl)cyclopropane-1-carboxamide Scheme 57 Step 1: Preparation of 1-hydroxy-N-((R)-2-oxo-1-((S)-1-phenylethyl)-1,2,3,4- tetrahydroquinolin-3-yl)cyclopropane-1-carboxamide (Compound 41) FH12898416.1 GPX-02125 The transformation was carried out similarly to the synthesis of Compound 8. The crude product was purified by preparative HPLC (XBridge Prep OBD C18 Column, 35-60% acetonitrile / water with 10 mmol ammonium bicarbonate) to afford the title compound as a white solid (44.6 mg, 17.0% yield). LCMS (ESI): m / z [M+H]+calcd for C21H22N2O3: 351.17, found 351.10.1H NMR (400 MHz, DMSO-d6) 8.16 (d, J = 6.9 Hz, 1H), 7.47 – 7.23 (m, 6H), 7.16 – 6.92 (m, 2H), 6.66 (d, J = 8.1 Hz, 1H), 6.49 (s, 1H), 6.40 – 6.25 (m, 1H), 4.66 – 4.51 (m, 1H), 3.20 – 3.02 (m, 2H), 1.68 (d, J = 7.1 Hz, 3H), 1.18 – 1.03 (m, 2H), 0.98 – 0.79 (m, 2H). Synthesis of Compound 42: 2-hydroxy-2-methyl-N-((R)-2-oxo-1-((S)-1-phenylethyl)- 1,2,3,4-tetrahydroquinolin-3-yl)propenamide Scheme 58 Step 1: Preparation of 2-hydroxy-2-methyl-N-((R)-2-oxo-1-((S)-1-phenylethyl)-1,2,3,4- tetrahydroquinolin-3-yl)propenamide (Compound 42) The transformation was carried out similarly to the synthesis of Compound 8. The crude product was purified by preparative HPLC (XBridge Prep OBD C18 Column, 32-53% acetonitrile / water with 10 mmol ammonium bicarbonate) to afford the title compound as a white solid (52.5 mg, 19.8% yield). LCMS (ESI): m / z [M+H]+calcd for C21H24N2O3: 353.18, found 353.15.1H NMR (300 MHz, Methanol-d4) 7.31-7.48 (m, 4H), 7.21-7.31 (m, 2H), 6.99-7.17 (m, 2H), 6.63-6.84 (m,1H), 6.41 (q, J = 7.2 Hz, 1H), 4.45-4.61 (m, 1H), 3.10-3.23 (m, 1H), 2.90-3.10 (m, 1H), 1.73 (d, J = 7.2 Hz, 3H), 1.44 (d, J = 3.7 Hz, 6H). FH12898416.1 GPX-02125 Synthesis of Compound 43: 1-((R)-1-((R)-2-fluoro-1-phenylethyl)-2-oxo-1,2,3,4- tetrahydroquinolin-3-yl)urea Step 1: Preparation of (1S)-2-fluoro-1-phenylethanol To a solution of (S)-(-)-2-methyl-CBS-oxazaborolidine (0.80 g, 2.89 mmol, 0.4 equiv.) in THF (10 mL) was added fluoromethyl phenyl ketone (1.01 g, 7.24 mmol, 1 equiv.) and borane dimethyl sulfide complex (2.0 M in THF, 0.82 g, 10.9 mmol, 1.5 equiv.) in portions at 0 °C. The resulting mixture was stirred at 0 °C for an additional 1 h. The reaction was quenched with water at 0 °C and extracted with ethyl acetate (3 x 20 mL). The combined organic extracts were washed with water, brine, dried over sodium sulfate, filtered and concentrated. The crude product was purified by silica gel chromatography (0-100% ethyl acetate / petroleum ether) to afford the title compound as a yellow oil (700.2 mg, 68.99% yield). Step 2: Preparation of tert-butyl N-[(3R)-1-[(1R)-2-fluoro-1-phenylethyl]-2-oxo-3,4- dihydroquinolin-3-yl]carbamate To a solution of (1S)-2-fluoro-1-phenylethanol (380.2 mg, 2.711 mmol, 1.2 equiv.) and Intermediate 2 (592.6 mg, 2.259 mmol, 1 equiv.) in THF (6 mL) was added triphenylphosphine (888.9 mg, 3.389 mmol, 1.5 equiv.) in portions at room temperature FH12898416.1 GPX-02125 under a nitrogen atmosphere. The resulting mixture was stirred at room temperature for an additional 20 min. Diisopropyl azodicarboxylate (685.3 mg, 3.389 mmol, 1.5 equiv.) was then added in portions at 0 °C. The resulting mixture was stirred at room temperature for an additional 1 h, at which point the reaction was judged complete by LCMS. The reaction was quenched with water (10 mL) and extracted with ethyl acetate (3 x 20 mL). The combined organic extracts were washed with water, brine, dried over sodium sulfate, filtered and concentrated. The crude product was purified by silica gel chromatography (0-100% ethyl acetate / petroleum ether) to afford the title compound as a yellow oil (500.6 mg, 57.56% yield). LCMS (ESI): m / z [M+Na]+calcd for C22H25FN2O3: 407.17, found 407.05. Step 3: Preparation of (3R)-3-amino-1-[(1R)-2-fluoro-1-phenylethyl]-3,4- dihydroquinolin-2-one The transformation was carried out similarly to in the synthesis of Compound 1 to afford the title compound as a yellow solid (236 mg, 94.7% yield). LCMS (ESI): m / z [M+H]+calcd for C17H17FN2O: 285.14, found 285.00. Step 4: Preparation of 1-((R)-1-((R)-2-fluoro-1-phenylethyl)-2-oxo-1,2,3,4- tetrahydroquinolin-3-yl)urea (Compound 43) The transformation was carried out similarly to in the synthesis of Compound 1. The crude product was purified by preparative HPLC (Xselect CSH C18 OBD Column, 16-46% acetonitrile / water with 0.1% formic acid) to afford the title compound as a white solid (46.6 mg, 20.2% yield). LCMS (ESI): m / z [M+H]+calcd for C18H18FN3O2: 328.14, found 328.15.1H NMR (300 MHz, DMSO-d6) 7.19 – 7.45 (m, 6H), 7.00 – 7.18 (m, 2H), 6.85 – 6.99 (m, 1H), 6.20 – 6.50 (m, 1H), 4.98 – 5.48 (m, 2H), 4.38 – 4.58 (m, 1H), 3.17 – 3.25 (m, 1H), 2.80 – 2.99 (m, 1H).19F NMR (282 MHz, DMSO-d6) -223.32. Synthesis of Compound 44: 1-((R)-7-(methylsulfonyl)-2-oxo-1-((S)-1-phenylethyl)- 1,2,3,4-tetrahydroquinolin-3-yl)urea Scheme 48 FH12898416.1 GPX-02125 Step 1: Preparation of methyl (R)-3-(2-amino-4-(methylsulfonyl)phenyl)-2-((tert- butoxycarbonyl)amino)propanoate The transformation was carried out similarly to the synthesis of Compound 1. After purification by column chromatography on silica gel (ethyl acetate / petroleum ether, 50-80%) the title compound was afforded as a yellow solid (700 mg, 47.0%). Step 2: Preparation of tert-butyl (R)-(7-(methylsulfonyl)-2-oxo-1,2,3,4- tetrahydroquinolin-3-yl)carbamate The transformation was carried out similarly to the synthesis of Compound 1. After purification by column chromatography on silica gel (ethyl acetate / petroleum ether, 30-60%) the title compound was afforded as a yellow solid (500 mg, 78.1%). LC / MS (ESI): m / z [M+H- Boc]+calcd. for C15H20N2O5S: 340.11, found 241.10. Step 3: Preparation of tert-butyl ((R)-7-(methylsulfonyl)-2-oxo-1-((S)-1-phenylethyl)- 1,2,3,4-tetrahydroquinolin-3-yl)carbamate The transformation was carried out similarly to the synthesis of Compound 1. After purification by column chromatography on silica gel (ethyl acetate / petroleum ether, 20-50%) the title compound was afforded as a yellow solid (400 mg, 61.2%). LC / MS (ESI): m / z [M+H]+calcd. for C23H28N2O5S: 444.17, found: 445.10. Step 4: Preparation of (R)-3-amino-7-(methylsulfonyl)-1-((S)-1-phenylethyl)-3,4- dihydroquinolin-2(1H)-one The transformation was carried out similarly to the synthesis of Compound 1 to afford the title hydrochloride compound without further purification (280 mg, 90.61%). LC / MS (ESI): m / z [M+H]+calcd. for C18H20N2O3S: 344.12, found: 345.00. Step 5: Preparation of 1-((R)-7-(methylsulfonyl)-2-oxo-1-((S)-1-phenylethyl)-1,2,3,4- tetrahydroquinolin-3-yl)urea (Compound 44) FH12898416.1 GPX-02125 The transformation was carried out similarly to the synthesis of Compound 1. The crude product was purified by preparative HPLC (YMC Triart C18 ExRs Column 250 mm x 20 mm x 5 m column, 15-40% acetonitrile and water with 0.05% NH4HCO3) to afford the title Compound 44 as a white solid (20.4 mg, 18.1%). LC / MS (ESI): m / z [M+H]+calcd. for C19H21N3O4S: 387.13, found 388.05.1H NMR (400 MHz, DMSO) 7.53 – 7.63 (m, 2H), 7.24 – 7.42 (m, 5H), 7.20 (d, J = 1.7 Hz, 1H), 6.44 (d, J = 6.4 Hz, 1H), 6.20 – 6.30 (m, 1H), 5.83 (s, 2H), 4.35 – 4.46 (m, 1H), 3.22 – 3.31 (m, 1H), 3.05 (s, 3H), 2.96 (t, J = 14.6 Hz, 1H), 1.71 (d, J = 7.1 Hz, 3H). Synthesis of Compound 45: 1-((R)-7-((R)-1-hydroxyethyl)-2-oxo-1-((S)-1-phenylethyl)- 1,2,3,4-tetrahydroquinolin-3-yl)urea Step 1: Preparation of methyl (R)-3-(4-acetyl-2-aminophenyl)-2-((tert- butoxycarbonyl)amino)propanoate The transformation was carried out similarly to the synthesis of Compound 1 using Intermediate 1. After purification by column chromatography on silica gel (petroleum FH12898416.1 GPX-02125 ether / ethyl acetate, 1:1) the title compound was afforded as a yellow oil (2.05 g, 63.6 %). LC / MS (ESI): m / z [M+H]+calcd. for C17H24N2O5: 336.17, found 337.05. Step 2: Preparation of tert-butyl (R)-(7-acetyl-2-oxo-1,2,3,4-tetrahydroquinolin-3- yl)carbamate The transformation was carried out similarly to the synthesis of Compound 1. After purification by column chromatography on silica gel (petroleum ether / ethyl acetate, 1:1) the title compound was afforded as a yellow oil (1.50 g, 82.9 %). LC / MS (ESI): m / z [M+H]+calcd. for C16H20N2O4: 304.14, found 305.05. Step 3: Preparation of tert-butyl ((R)-7-acetyl-2-oxo-1-((S)-1-phenylethyl)-1,2,3,4- tetrahydroquinolin-3-yl)carbamate The transformation was carried out similarly to the synthesis of Compound 1. After purification by column chromatography on silica gel (ethyl acetate / petroleum ether, 2:1) the title compound was afforded as a yellow oil (800.5 mg, 59.6%). LC / MS (ESI): m / z [M+H]+calcd. for C24H28N2O4: 408.20, found 409.15. Step 4: Preparation of (R)-7-acetyl-3-amino-1-((S)-1-phenylethyl)-3,4-dihydroquinolin- 2(1H)-one The transformation was carried out similarly to the synthesis of Compound 1 to afford the title hydrochloride compound without further purification as a white solid (650.1 mg, 96.7%). LC / MS (ESI): m / z [M+H]+calcd. for C19H20N2O2: 308.15, found 309.05. Step 5: Preparation of 1-((R)-7-acetyl-2-oxo-1-((S)-1-phenylethyl)-1,2,3,4- tetrahydroquinolin-3-yl)urea The transformation was carried out similarly to the synthesis of Compound 1. The crude product was purified by silica gel chromatography (dichloromethane / methanol, 5:1) to afford the title compound as a yellow oil (450.5 mg, 67.8%). LC / MS (ESI): m / z [M+H]+calcd. for C20H21N3O3: 351.16, found: 352.20. Step 6: Preparation of 1-((3R)-7-(1-hydroxyethyl)-2-oxo-1-((S)-1-phenylethyl)-1,2,3,4- tetrahydroquinolin-3-yl)urea (Compound 45) FH12898416.1 GPX-02125 To a solution of 1-((R)-7-acetyl-2-oxo-1-((S)-1-phenylethyl)-1,2,3,4-tetrahydroquinolin-3- yl)urea (450.5 mg, 1.281 mmol, 1 equiv.) in methanol (4 mL) was added NaBH4 (193.8 mg, 5.124 mmol, 4 equiv.) in portions at 0 °C. The resulting mixture was stirred at room temperature for 30 min. Desired product could be detected by LCMS. The reaction was treated with water at 0 °C. The resulting mixture was extracted with dichloromethane (3 x 20 mL). The combined organic layers were washed with water (20 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC (YMC-Triart C18 EXRS 30x150mm, 5um column 14-34% acetonitrile and water, with 10mmol / L NH4HCO3and 0.05% ammonium hydroxide) to the title compound as mixture of diastereomers as a white solid (110.2 mg, 24.33%). LC / MS (ESI): m / z [M+H]+calcd. for C20H23N3O3: 353.17, found: 354.05. The mixture was further purified by chiral HPLC (CHIRALPAK IE, 2x25 cm, 5 m column, 25% ethanol in hexanes with 0.5% 2M ammonia in methanol) to afford the title Compound 45 as second eluting peak as a white solid (22.4 mg, 24.8%). LC / MS (ESI): m / z [M+H]+calcd. for C20H23N3O3: 353.17, found: 354.20.1H NMR (400 MHz, DMSO-d6) 7.35 – 7.43 (m, 2H), 7.25 – 7.34 (m, 3H), 7.19 – 7.24 (m, 1H), 6.90 – 7.02 (m, 1H), 6.70 – 6.80 (m, 1H), 6.38 – 6.50 (m, 1H), 6.12 – 6.30 (m, 1H), 5.60 – 5.98 (m, 2H), 4.82 – 5.20 (m, 1H), 4.40 – 4.65 (m, 1H), 4.20 – 4.40 (m, 1H), 3.03 – 3.20 (m, 1H), 2.75 – 2.89 (m, 1H), 1.60 – 1.79 (m, 3H), 1.03 – 1.20 (m, 3H). Synthesis of Compound 46: 1-((R)-7-(hydroxymethyl)-2-oxo-1-((S)-1-phenylethyl)- 1,2,3,4-tetrahydroquinolin-3-yl)urea Scheme 50 FH12898416.1 GPX-02125 Step 1: Preparation of 2-bromo-5-(((tert-butyldimethylsilyl)oxy)methyl)aniline A solution of (3-amino-4-bromophenyl)methanolm (2.01 g, 9.898 mmol, 1 equiv.), tert- butyl(chloro)dimethylsilane (2.24 g, 14.847 mmol, 1.5 equiv.) and imidazole (2.02 g, 29.694 mmol, 3 equiv.) in DMF (30 mL) was stirred at rt for 1 h. The reaction was treated with water (50 mL). The resulting mixture was extracted with ethyl acetate (3 x 50 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (0-40% ethyl acetate / petroleum ether) to afford the title compound as a yellow oil (2.01 g, 63.8%). LC / MS (ESI): m / z [M+H]+, [M+H+2]+calcd. for C13H22BrNOSi: 315.07, found: 315.95, 317.95. Step 2: Preparation of methyl (R)-3-(2-amino-4-(((tert- butyldimethylsilyl)oxy)methyl)phenyl)-2-((tert-butoxycarbonyl)amino)propanoate The transformation was carried out similarly to the synthesis of Compound 1. After purification by column chromatography on silica gel (0-50% ethyl acetate / petroleum ether) the title compound was afforded as a yellow oil (2.50 g, 89.9%). LC / MS (ESI): m / z [M+H]+calcd. for C22H38N2O5Si: 438.25, found: 439.20. Step 3: Preparation of tert-butyl (R)-(7-(((tert-butyldimethylsilyl)oxy)methyl)-2-oxo- 1,2,3,4-tetrahydroquinolin-3-yl)carbamate FH12898416.1 GPX-02125 The transformation was carried out similarly to the synthesis of Compound 1. After purification by column chromatography on silica gel (0-60% ethyl acetate / petroleum ether) the title compound was afforded as a yellow oil (2.01 g, 86.5%). LC / MS (ESI): m / z [M+H]+calcd. for C21H34N2O4Si: 406.23, found:407.10. Step 4: Preparation of tert-butyl ((R)-7-(((tert-butyldimethylsilyl)oxy)methyl)-2-oxo-1- ((S)-1-phenylethyl)-1,2,3,4-tetrahydroquinolin-3-yl)carbamate The transformation was carried out similarly to the synthesis of Compound 1. After purification by column chromatography on silica gel (0-40% ethyl acetate / petroleum ether) the title compound was afforded as a yellow oil (400.2 mg, 31.9%). LC / MS (ESI): m / z [M+H]+calcd. for C29H42N2O4Si: 510.29, found: 511.25. Step 5: Preparation of (R)-3-amino-7-(hydroxymethyl)-1-((S)-1-phenylethyl)-3,4- dihydroquinolin-2(1H)-one The transformation was carried out similarly to the synthesis of Compound 1 to afford the title hydrochloride compound without further purification as a white solid (200.3 mg crude, 61.9%). LC / MS (ESI): m / z [M+H]+calcd. for C18H20N2O2: 296.15, found: 297.20. Step 6: Preparation of 1-((R)-7-(hydroxymethyl)-2-oxo-1-((S)-1-phenylethyl)-1,2,3,4- tetrahydroquinolin-3-yl)urea (Compound 46) The transformation was carried out similarly to the synthesis of Compound 1. The crude product was purified by preparative HPLC (XBridge Prep OBD C18 Column 150 mm x 30 mm x 5 m column, 32-48% acetonitrile and water with 10mmol / L NH4HCO3and 0.05% ammonium hydroxide) to afford the title Compound 46 as a white solid (31.5 mg, 15.4%). LC / MS (ESI): m / z [M+H]+calcd. for C19H21N3O3: 339.16, found: 340.10.1H NMR (400 MHz, DMSO-d6) 7.20 – 7.43 (m, 6H), 6.96 (d, J = 7.6 Hz, 1H), 6.77 (s, 1H), 6.42 (d, J = 6.2 Hz, 1H), 6.11 – 6.21 (m, 1H), 5.83 (s, 2H), 5.08 (t, J = 5.6 Hz, 1H), 4.22 – 4.36 (m, 3H), 3.05 – 3.17 (m, 1H), 2.77 (t, J = 14.4 Hz, 1H), 1.70 (d, J = 7.2 Hz, 3H). Synthesis of Compound 47: 1-((R)-2-oxo-1-((S)-1-phenylpropan-2-yl)-7- (trifluoromethyl)-1,2,3,4-tetrahydroquinolin-3-yl)urea FH12898416.1 GPX-02125 Step 1: Preparation of tert-butyl (2-oxo-1-((S)-1-phenylpropan-2-yl)-7-(trifluoromethyl)- 1,2,3,4-tetrahydroquinolin-3-yl)carbamate To a solution of tert-butyl N-[(3R)-2-oxo-7-(trifluoromethyl)-3,4-dihydro-1H-quinolin-3- yl]carbamate (200.0 mg, 0.605 mmol, 1 equiv.) in methylbenzene (10 mL) was added (2R)-1- phenylpropan-2-ol (82.4 mg, 0.605 mmol, 1 equiv.) and CMBP (438.4 mg, 1.815 mmol, 3 equiv.) at ambient temperature. The reaction was stirred at 110oC for 1 h under nitrogen. The mixture was allowed to cool down to room temperature. The mixture was quenched with water (20 mL) and extracted with ethyl acetate (3 x 20 mL). The combined extracts were washed with water, brine, dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography on silica gel (ethyl acetate / petroleum ether, 0-40%) to afford the title compound as a yellow oil (248.0 mg, 42.3%). LC / MS (ESI): m / z [M+H]+calcd. for C24H27F3N2O3: 448.20, found 449.20. Step 2: Preparation of 3-amino-1-((S)-1-phenylpropan-2-yl)-7-(trifluoromethyl)-3,4- dihydroquinolin-2(1H)-one FH12898416.1 GPX-02125 The transformation was carried out similarly to the synthesis of Compound 1 to afford the title compound without further purification as a white solid (361.0 mg, 57.1%). LC / MS (ESI): m / z [M+H]+calcd. for C19H19F3N2O: 348.14, found 349.10. Step 3: Preparation of 2-oxo-1-[(2S)-1-phenylpropan-2-yl]-7-(trifluoromethyl)-3,4- dihydroquinolin-3-ylurea (Compound 47) The transformation was carried out similarly to the synthesis of Compound 1. The crude product was purified by preparative HPLC (YMC-Actus Triart C18 ExRS 70x250 mm column 35-51% acetonitrile and water with 10mmol / L NH4HCO3+ 0.05% ammonium hydroxide) to afford the title compound as a mixture of diastereomers as a white solid (60.0 mg, 16.2%). LC / MS (ESI): m / z [M+H]+calcd. for C20H20F3N3O2: 391.15, found 392.10. The product mixture was further purified by chiral HPLC (CHIRALPAK IK 2x25 cm, 5 m column, 10% ethanol in hexanes with 0.5% 2M ammonia in methanol to yield the title Compound 47 as a white solid (28.3 mg, 47.1%). LC / MS (ESI): m / z [M+H]+calcd. for C20H20F3N3O2: 391.15, found 392.15.1H NMR (400 MHz, DMSO-d6) 7.28 – 7.41 (m, 3H), 6.99 – 7.19 (m, 5H), 6.34 (d, J = 6.3 Hz, 1H), 5.81 (s, 2H), 4.43 – 4.68 (m, 1H), 3.85 – 4.09 (m, 1H), 3.40 – 3.58 (m 1H), 2.81 – 3.05 (m, 2H), 2.11 (t, J = 14.4 Hz, 1H), 1.49 – 1.72 (m, 3H).19F NMR (282 MHz, DMSO-d6) (ppm): -60.718. Synthesis of Compound 48: (R)-1-(2-oxo-1-phenyl-7-(trifluoromethyl)-1,2,3,4- tetrahydroquinolin-3-yl)urea Scheme 52 FH12898416.1 GPX-02125 Step 1: Preparation of tert-butyl (2-oxo-1-phenyl-7-(trifluoromethyl)-1,2,3,4- tetrahydroquinolin-3-yl)carbamate To a stirred solution of tert-butyl (R)-(2-oxo-7-(trifluoromethyl)-1,2,3,4-tetrahydroquinolin-3- yl)carbamate (300.0 mg, 0.908 mmol, 1.00 equiv.) and iodobenzene (555.9 mg, 2.724 mmol, 3 equiv.) in dioxane (7 mL) was added trans-1,2-diaminocyclohexane (41.5 mg, 0.363 mmol, 0.4 equiv.) , CuI (34.6 mg, 0.182 mmol, 0.20 equiv.) and potassium carbonate (502.1 mg, 3.632 mmol, 4 equiv.) in portions at room temperature. The resulting mixture was stirred at 100 °C for 2 h under nitrogen atmosphere. Desired product could be detected by LCMS. After cooling down to rt, the resulting mixture was extracted with ethyl acetate (3 x 20 mL). The combined organic layers were washed with water (20 mL), dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by column chromatography on silica gel (ethyl acetate / petroleum ether, 0-50%) to afford the title compound as a yellow solid (290.5 mg, 93.5%). LC / MS (ESI): m / z [M+H-tBu]+calcd for C21H26ClFN4O3: 406.2, found 350.95. Step 2: Preparation of 3-amino-1-phenyl-7-(trifluoromethyl)-3,4-dihydroquinolin-2(1H)- one The transformation was carried out similarly to the synthesis of Compound 1 to afford the title hydrochloride compound without further purification as a yellow oil (185.3 mg, 86.1%). LC / MS (ESI): m / z [M+H]+calcd. for C16H13F3N2O: 306.1, found: 307.00. Step 3: Preparation of (R)-1-(2-oxo-1-phenyl-7-(trifluoromethyl)-1,2,3,4- tetrahydroquinolin-3-yl)urea (Compound 48) The transformation was carried out similarly to the synthesis of Compound 1. The crude product was purified by preparative HPLC (XBridge Prep C18 OBD Column, 19x250 mm, FH12898416.1 GPX-021255 m column, 20-45% acetonitrile and water with 0.05% NH4HCO3) to afford the titlecompound as a mixture of diastereomers as a white solid (30.0 mg, 11.67%). LC / MS (ESI): m / z [M+H]+calcd for C17H14F3N3O2: 349.1, found: 350.00. The mixture was further purified (CHIRALPAK IK 2x25 cm, 5 m column, 35% hexanes containing 0.5% 2M ammonia in methanol, in EtOH to yield the title Compound 48 as a white solid (11.2 mg, 37.3%). LC / MS (ESI): m / z [M-H]- calcd for C17H14F3N3O2: 349.1, found: 348.10.1H NMR (300 MHz, DMSO- d6) 7.20 - 7.70 (m, 8H), 6.40 - 6.52(m, 1H), 6.45 (d, J = 6.7 Hz, 1H), 5.80 (s, 2H), 4.48 - 4.70(m, 1H), 3.10 - 3.20(m, 1H).19F NMR (282 MHz, DMSO) - 61.13. Synthesis of Compound 49: (3R)-1-(cyclopentylmethyl)-2-oxo-7-(trifluoromethyl)-3,4- dihydroquinolin-3-ylurea Step 1: Preparation of tert-butyl N-[(3R)-1-(cyclopentylmethyl)-2-oxo-7- (trifluoromethyl)-3,4-dihydroquinolin-3-yl]carbamate The transformation was carried out similarly to the synthesis of Compound 1. After purification by column chromatography on silica gel (ethyl acetate / petroleum ether, 0-20%) the title compound was afforded as a white solid (358 mg, 70.2%). LC / MS (ESI): m / z [M+H]+calcd. for C21H27F3N2O3: 412.20, found 413.20. FH12898416.1 GPX-02125 Step 2: Preparation of (3R)-3-amino-1-(cyclopentylmethyl)-7-(trifluoromethyl)-3,4- dihydroquinolin-2-one The transformation was carried out similarly to the synthesis of Compound 1 to afford the title compound without further purification as a white solid (259.0 mg, 95.5%). LC / MS (ESI): m / z [M+H]+calcd. for C16H19F3N2O: 312.14, found 313.20. Step 3: Preparation of (3R)-1-(cyclopentylmethyl)-2-oxo-7-(trifluoromethyl)-3,4- dihydroquinolin-3-ylurea (Compound 49) The transformation was carried out similarly to the synthesis of Compound 1. The crudeproduct was purified by preparative HPLC (Xbridge Prep Shield RP185 m OBD 30x150mmcolumn, 34-49% acetonitrile and water with 10mmol / L NH4HCO3+ 0.05% ammonium hydroxide) to afford the title Compound 49 as a white solid (57.4 mg, 24.2%). LC / MS (ESI): m / z [M+H]+calcd. for C17H20F3N3O2: 355.15, found 356.15.1H NMR (300 MHz, Methanol- d4) 7.32 – 7.50 (m, 6H), 4.39 (dd, J = 14.2, 5.7 Hz, 1H), 4.22 (dd, J = 14.4, 9.1 Hz, 1H), 3.87 (dd, J = 14.3, 6.3 Hz, 1H), 3.26 (d, J = 5.6 Hz, 1H), 2.82 – 2.99 (m, 2H), 2.09-2.48 (m, J = 14.9, 7.3 Hz, 1H), 1.46 – 1.84 (m, 6H), 1.34 (s, 2H). Synthesis of Compound 50: -(1-cyclopentyl-2-oxo-7-(trifluoromethyl)-1,2,3,4- tetrahydroquinolin-3-yl)urea Scheme 54 FH12898416.1 GPX-02125 Step 1: Preparation of tert-butyl (1-cyclopentyl-2-oxo-7-(trifluoromethyl)-1,2,3,4- tetrahydroquinolin-3-yl)carbamate To a stirred solution of tert-butyl N-[(3R)-2-oxo-7-(trifluoromethyl)-3,4-dihydro-1H-quinolin- 3-yl]carbamate (400.0 mg, 1.211 mmol, 1 equiv.) and bromocyclopentane (360.9 mg, 2.422 mmol, 2 equiv.) in DMF (10 mL) was added cesium carbonate (1183.7 mg, 3.633 mmol, 3 equiv.) in portions at room temperature. The resulting mixture was stirred at 80 °C for 1 h. Desired product could be detected by LCMS. After cooling down to room temperature, the reaction was treated with water (30 mL). The resulting mixture was extracted with ethyl acetate (3 x 30 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography, (petroleum ether / ethyl acetate, 1:1) to afford the title compound as a yellow oil (250.0 mg, 51.8%). LC / MS (ESI): m / z [M+H]+calcd. for C20H25F3N2O3: 398.18, found: 399.05. Step 2: Preparation of 3-amino-1-cyclopentyl-7-(trifluoromethyl)-3,4-dihydroquinolin- 2(1H)-one The transformation was carried out similarly to the synthesis of Compound 1 to afford the title compound without further purification as a yellow solid (170.0 mg, 94.6%). LC / MS (ESI): m / z [M+H]+calcd. for C22H24N2O4: 298.13, found: 299.05. Step 3: Preparation of (R)-1-(1-cyclopentyl-2-oxo-7-(trifluoromethyl)-1,2,3,4- tetrahydroquinolin-3-yl)urea (Compound 50) The transformation was carried out similarly to the synthesis of Compound 1. The crude product was purified by preparative HPLC (XBridge Shield RP18 OBD 250 mm x 19 mm x 10 m column, 55-65% methanol and water with 0.05% NH4HCO3) to afford the title FH12898416.1 GPX-02125 compound as a mixture of diastereomers as a white solid (40.0 mg, 23.25%). LC / MS (ESI): m / z [M+H]+calcd. for C16H18F3N3O2: 341.14, found: 342.05. The mixture of diastereomers was subjected to further purification by chiral-HPLC (CHIRALPAK IG 2x25 cm, 5 m, 30% ethanol and hexanes containing 0.5% 2M ammonium in methanol) to afford the title Compound 50 as a white solid (16.0 mg, 32.0%). LC / MS (ESI): m / z [M+H]+calcd. for C16H18F3N3O2: 341.14, found: 342.10.1H NMR (300 MHz, DMSO-d6) 7.32 – 7.58 (m, 3H), 6.34 – 6.52 (m, 1H), 5.70 – 5.88 (m, 2H), 4.59 – 4.78 (m, 1H), 4.02 – 4.22 (m, 1H), 3.08 – 3.21 (m, 1H), 2.78 – 2.91 (m, 1H), 2.04 – 2.18 (m, 1H), 1.79 – 2.02 (m, 5H), 1.50 – 1.68 (m, 2H).19F NMR (282 MHz, DMSO) -60.80. Synthesis of Compound 51: 1-((R)-8-methoxy-2-oxo-1-((S)-1-phenylethyl)-1,2,3,4- tetrahydroquinolin-3-yl)urea Step 1: Preparation of tert-butyl N-[(3R)-8-methoxy-2-oxo-3,4-dihydro-1H-quinolin-3- yl]carbamate The transformation was carried out similarly to the synthesis of Compound 1. After purification by column chromatography on silica gel (ethyl acetate / petroleum ether, 50-70%) FH12898416.1 GPX-02125 the title compound was afforded as a yellow oil (1.0 g, 68.8%). LC / MS (ESI): m / z [M+H]+calcd. for C15H20N2O4: 292.14, found: 293.10. Step 2: Preparation of tert-butyl N-[(3R)-8-methoxy-2-oxo-1-[(1S)-1-phenylethyl]-3,4- dihydroquinolin-3-yl]carbamate To a solution of tert-butyl N-[(3R)-8-methoxy-2-oxo-3,4-dihydro-1H-quinolin-3-yl]carbamate (600.0 mg, 2.052 mmol, 1 equiv.) in toluene (10 mL) was added (R)-1-phenyl-ethanol (1.25 g, 10.260 mmol, 5.00 equiv.) and CMBP (1.49 g, 6.156 mmol, 3.00 equiv.). The reaction was stirred at 110°C for 3 h under nitrogen. The mixture was allowed to cool down to room temperature. The mixture was treated with water (50 mL) and extracted with ethyl acetate (3 x 50 mL). The combined extracts were washed with water, brine, dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography on silica gel (ethyl acetate / petroleum ether, 50-80%) to afford the title compound as a yellow oil (800.0 mg, 98.3%). LC / MS (ESI): m / z [M+H]+calcd. for C23H28N2O4: 396.21, found:397.15. Step 3: Preparation of (3R)-3-amino-8-methoxy-1-[(1S)-1-phenylethyl]-3,4- dihydroquinolin-2-one The transformation was carried out similarly to the synthesis of Compound 1 to afford the title compound without further purification as a yellow oil (370.0 mg, 99.1%). LC / MS (ESI): m / z [M+H]+calcd. for C18H20N2O2: 296.15, found: 297.15. Step 5: Preparation of (3R)-8-methoxy-2-oxo-1-[(1S)-1-phenylethyl]-3,4- dihydroquinolin-3-ylurea (Compound 51) The transformation was carried out similarly to the synthesis of Compound 1. The crude product was purified by preparative HPLC (XSelect CSH C18 Column 150 mm x 30 mm x 5 m column 30-55% acetonitrile and water containing 0.1% formic acid) to afford the title Compound 51 as a white solid (65.8 mg, 19.1%). LC / MS (ESI): m / z [M+H]+calcd. for C19H21N3O3: 339.16, found: 340.15.1H NMR (300 MHz, Methanol-d4) 7.12 – 7.36 (m, 6H), 6.89 – 7.11 (m, 2H), 5.17 – 5.34 (m, 1H), 4.12 – 4.26 (m, 1H), 3.84 (s, 3H), 2.90 – 3.04 (m, 1H), 2.56 – 2.72 (m, 1H), 1.98 (d, J = 7.0 Hz, 3H). Synthesis of Compound 52: 1-(2-oxo-1-phenethyl-7-(trifluoromethyl)-1,2,3,4- tetrahydroquinolin-3-yl)urea FH12898416.1 GPX-02125 Step 1: Preparation of tert-butyl (R)-(2-oxo-1-phenethyl-7-(trifluoromethyl)-1,2,3,4- tetrahydroquinolin-3-yl)carbamate To a stirred solution of Intermediate 4 (300.1 mg, 0.908 mmol, 1 equiv.) and (2- bromoethyl)benzene (336.1 mg, 1.816 mmol, 2 equiv.) in DMF (4 mL) was added K2CO3(376.5 mg, 2.724 mmol, 3 equiv.) in portions at room temperature. The resulting mixture was stirred at room temperature for 2 h under air atmosphere. Desired product could be detected by LCMS. The reaction was quenched with water (10 mL). The resulting mixture was extracted with ethyl acetate (3 x 10 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate 2:1) to afford tert-butyl (R)-(2-oxo-1- phenethyl-7-(trifluoromethyl)-1,2,3,4-tetrahydroquinolin-3-yl)carbamate (250.1 mg, 63.3%) as a yellow oil. LCMS (ESI): m / z [M+H-Boc]+calcd for C23H25F3N2O3: 434.18, found 335.1. Step 2: Preparation of (R)-3-amino-1-phenethyl-7-(trifluoromethyl)-3,4- dihydroquinolin-2(1H)-one To a stirred solution of tert-butyl (R)-(2-oxo-1-phenethyl-7-(trifluoromethyl)-1,2,3,4- tetrahydroquinolin-3-yl)carbamate (250.1 mg, 0.575 mmol, 1 equiv.) in dioxane (3 mL) was added HCl (4 M in dioxane) (2 mL) in portions at room temperature. The resulting mixture FH12898416.1 GPX-02125 was stirred at room temperature for 2 h under air atmosphere. Desired product could be detected by LCMS. The resulting mixture was concentrated. The crude product was used in the next step directly without further purification. Crude (R)-3-amino-1-phenethyl-7- (trifluoromethyl)-3,4-dihydroquinolin-2(1H)-one hydrochloride (110.6 mg, 57.2%) was obtained as a yellow oil. LCMS (ESI): m / z[M+H]+calcd for C18H17F3N2O: 334.13, found 335.1. Step 3: Preparation of 2-oxo-1-(2-phenylethyl)-7-(trifluoromethyl)-3,4-dihydroquinolin- 3-ylurea (Compound 52) To a stirred solution of (R)-3-amino-1-phenethyl-7-(trifluoromethyl)-3,4-dihydroquinolin- 2(1H)-one hydrochloride (110.6 mg, 0.299 mmol, 1 equiv.) and methanesulfonic acid (43.1 mg, 0.449 mmol, 1.5 equiv.) in tetrahydrofuran (4 mL) was added isocyanatopotassium (72.7 mg, 0.897 mmol, 3 equiv.) in water (0.4 mL) at room temperature. The resulting mixture was stirred at room temperature for 2 h under air atmosphere. Desired product could be detected by LCMS. The reaction was quenched with water (10 mL). The resulting mixture was extracted with ethyl acetate (3 x 10 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by Prep-HPLC (XBridge Shield RP18 OBD 250 mm x 19 mm x 10 m, 55-65% methanol in water with 0.05% NH4HCO3) to afford the title Compound 52 as a white solid (54.8 mg, 48.5%). LCMS (ESI): m / z [M+H]+calcd for C19H18F3N3O2: 377.14, found 378.05.1H NMR (400 MHz, DMSO-d6) 7.48 (d, J = 7.7 Hz, 1H), 7.37 (d, J = 7.9 Hz, 1H), 7.32 (s, 1H), 7.25 (t, J = 7.3 Hz, 2H), 7.12 – 7.22 (m, 3H), 6.36 (d, J = 6.4 Hz, 1H), 5.82 (s, 2H), 4.15 – 4.31 (m, 3H), 3.18 (dd, J = 15.2, 5.7 Hz, 1H), 2.85 (dt, J = 10.6, 4.8 Hz, 2H), 2.68 (t, J = 14.6 Hz, 1H).19F NMR (376 MHz, DMSO) -60.80. Synthesis of Compound 53: 1-((R)-1-((S)-1-(3-((3-(1H-pyrazol-4- yl)benzyl)oxy)phenyl)ethyl)-7-chloro-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl)urea Scheme 57 FH12898416.1 GPX-02125 Step 1: Preparation of 1-(3-((3-bromobenzyl)oxy)phenyl)ethan-1-one To a solution of 1-bromo-3-(bromomethyl)benzene (1 g, 4.001 mmol, 1 equiv.) in DMF (20 mL) was added 3-hydroxyacetophenone (0.65 g, 4.801 mmol, 1.2 equiv.) and Cs2CO3(2.61 g, 8.002 mmol, 2.0 equiv.) at 20oC. The resulting mixture was stirred at 100 °C for 2 hours. The reaction was monitored by TLC. The mixture was allowed to cool down to room temperature. The reaction was quenched with water (20 mL) and extracted with ethyl acetate (20 mL x 3). The combined extracts were washed with water, brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by column chromatography on silica gel (ethyl acetate / petroleum ether, 10-20%) to afford the title compound as a white solid (1.0 g, 81.9%). LCMS (ESI): m / z [M+ACN, M+ACN+2]+calcd for C15H13BrO2: 304.01, found 345.95, 347.95. Step 2: Preparation of (R)-1-(3-((3-bromobenzyl)oxy)phenyl)ethan-1-ol To a solution of (3aS)-1-methyl-3,3-diphenyl-hexahydropyrrolo[1,2-c][1,3,2]oxazaborole (0.36 g, 1.311 mmol, 0.4 equiv.) in tetrahydrofuran (12 mL) was added borane-dimethyl sulfide complex (94%, 5 mL, 4.915 mmol, 1.5 equiv.) at 0 °C. After stirring at 0 °C for 5 minutes, a solution of 1-(3-((3-bromobenzyl)oxy)phenyl)ethan-1-one (1 g, 3.277 mmol, 1 equiv.) in tetrahydrofuran (12 mL) was added dropwise over a period of 10 minutes. The reaction mixture was stirred at 0 °C for 30 minutes. The reaction was monitored by TLC. The reaction was quenched with water (20 mL) and extracted with ethyl acetate (20 mL x 3). The combined extracts were washed with water, brine, dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography on silica gel (ethyl acetate / petroleum ether, 20-30%) to afford (R)-1-(3-((3-bromobenzyl)oxy)phenyl)ethan-1-ol as a white solid (800 mg, 79.4%). LCMS (ESI): m / z [M+H-OH2, M+H+2-OH2]+calcd for C15H15BrO2: 306.03, found 288.95, 290.95. FH12898416.1 GPX-02125 Step 3: Preparation of tert-butyl ((R)-1-((S)-1-(3-((3-bromobenzyl)oxy)phenyl)ethyl)-7- chloro-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl)carbamate To a solution of (R)-1-(3-((3-bromobenzyl)oxy)phenyl)ethan-1-ol (800 mg, 2.604 mmol, 1 equiv.) and Intermediate 3 (927.4 mg, 3.125 mmol, 1.2 equiv.) in tetrahydrofuran (10 mL) was added triphenylphosphine (1.10 g, 3.906 mmol, 1.5 equiv.) at 0oC under nitrogen. After stirring at 20 °C for 40 minutes under nitrogen, DIAD (1.05 g, 5.208 mmol, 2.0 equiv.) was added dropwise over a period of 5 minutes. The reaction mixture was stirred at room temperature for an additional 60 minutes under nitrogen. The reaction was monitored by TLC. The reaction was quenched with water (20 mL) and extracted with ethyl acetate (20 mL x 3). The combined extracts were washed with water, brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by column chromatography on silica gel (ethyl acetate / petroleum ether, 30-60%) to afford tert-butyl ((R)-1-((S)-1-(3-((3- bromobenzyl)oxy)phenyl)ethyl)-7-chloro-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl)carbamate (800 mg, 52.4%) as a yellow solid. LCMS (ESI): m / z [M+H-Boc, M+H+2-Boc]+calcd for C29H30BrCIN2O: 584.11, found: 484.95, 486.95. Step 4: Preparation of (R)-3-amino-1-((S)-1-(3-((3-bromobenzyl)oxy)phenyl)ethyl)-7- chloro-3,4-dihydroquinolin-2(1H)-one A solution of tert-butyl ((R)-1-((S)-1-(3-((3-bromobenzyl)oxy)phenyl)ethyl)-7-chloro-2-oxo- 1,2,3,4-tetrahydroquinolin-3-yl)carbamate (500 mg, 0.853 mmol, 1 equiv.) in HCl (4.0 M in 1,4-dioxane) (10 mL) was stirred at 20 °C for 2 hours. The reaction was monitored by TLC. After concentration, crude product (R)-3-amino-1-((S)-1-(3-((3- bromobenzyl)oxy)phenyl)ethyl)-7-chloro-3,4-dihydroquinolin-2(1H)-one hydrochloride (350 mg, 84.4%) was used in the next step without further purification. LCMS (ESI): m / z [M+H, M+H+2]+calcd for C24H22BrCIN2O: 484.06, found: 484.95, 486.95. Step 5: Preparation of 1-((R)-1-((S)-1-(3-((3-bromobenzyl)oxy)phenyl)ethyl)-7-chloro-2- oxo-1,2,3,4-tetrahydroquinolin-3-yl)urea To a solution of (R)-3-amino-1-((S)-1-(3-((3-bromobenzyl)oxy)phenyl)ethyl)-7-chloro-3,4- dihydroquinolin-2(1H)-one hydrochloride (300 mg, 0.618 mmol, 1 equiv.) in tetrahydrofuran (10 mL) was added potassium cyanate (100 mg, 1.236 mmol, 2.0 equiv.) in water (1 mL), then methanesulfonic acid (77.2 mg, 0.803 mmol, 1.3 equiv.) was added at 0 °C. The reaction was stirred at 20 °C for 1h. The reaction was treated with water (5 mL) and extracted with ethyl acetate (5 mL x 3). The combined extracts were washed with water, brine, dried over sodium FH12898416.1 GPX-02125 sulfate, filtered and concentrated. The residue was purified by column chromatography on silica gel (methanol / dichloromethane, 5-15% to afford the product 1-((R)-1-((S)-1-(3-((3- bromobenzyl)oxy)phenyl)ethyl)-7-chloro-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl)urea as a yellow solid. (250 mg, 76.5%). LC / MS (ESI): m / z [M+H, M+H+2]+calcd for C25H23BrClN3O3: 527.06, found: 527.95, 529.95. Step 6: Preparation of 1-((R)-1-((S)-1-(3-((3-(1H-pyrazol-4-yl)benzyl)oxy)phenyl)ethyl)- 7-chloro-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl)urea (Compound 53) To a solution of 1-((R)-1-((S)-1-(3-((3-bromobenzyl)oxy)phenyl)ethyl)-7-chloro-2-oxo- 1,2,3,4-tetrahydroquinolin-3-yl)urea (100 mg, 0.206 mmol, 1 equiv.) in dioxane (5 mL) was added 1H-pyrazol-4-ylboronic acid (27.6 mg, 0.247 mmol, 1.2 equiv.), Pd(dppf)Cl2(30.1 mg, 0.04 mmol, 0.2 equiv.) and potassium carbonate (56.9 mg, 0.412 mmol, 2.0 equiv.) at 20°C. The resulting mixture was stirred at 80oC for 4 h under nitrogen atmosphere. After cooling down to room temperature, the reaction was treated with water (5 mL) and extracted with ethyl acetate (5 mL x 3). The combined extracts were washed with water, brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by column chromatography on silica gel (methanol / dichloromethane, 5-15%). The obtained material was further purified byPrep-HPLC ( XSelect CSH Fluoro Phenyl, 30 x 150 mm, 5 m; 45-65% (v / v) acetonitrile inwater with 0.1% NH4HCO3) to afford Compound 53 as an off-white solid (18.1 mg, 17.0%). LCMS (ESI): m / z [M+H]+calcd for C28H26ClN5O3: 515.17, found 516.15.1H NMR (300 MHz, DMSO-d6) 12.94 (s, 1H), 7.80 - 8.30 (m, 2H), 7.68 (d, J = 1.9 Hz, 1H), 7.55 (d, J = 7.6 Hz, 1H), 7.20 – 7.37 (m, 4H), 7.02 – 7.12 (m, 1H), 6.94 – 7.02 (m, 1H), 6.84 – 6.94 (m, 2H), 6.69 (d, J = 2.0 Hz, 1H), 6.42 (d, J = 6.4 Hz, 1H), 6.10 – 6.21 (m, 1H), 5.82 (s, 2H), 5.10 (s, 2H), 4.29 – 4.44 (m, 1H), 3.06 – 3.19 (m, 1H), 2.79 (t, J = 14.5 Hz, 1H), 1.65 (d, J = 7.1 Hz, 3H). Synthesis of Compound 54: 1-((R)-2-oxo-1-((S)-1-phenylethyl)-7-(trifluoromethoxy)- 1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)urea Scheme 58 FH12898416.1 GPX-02125 Step 1: Preparation of 3-azido-2-chloro-5-(trifluoromethoxy)pyridine To a solution of 2-chloro-3-fluoro-5-(trifluoromethoxy)pyridine (450 mg, 2.088 mmol, 1 equiv.) in DMF (10 mL) was added sodium azide (162.8 mg, 2.506 mmol, 1.2 equiv.). The reaction was stirred at 25 °C for 1 h. The reaction was quenched with water (20 mL) and extracted with ethyl acetate (3 x 20 mL). The combined extracts were washed with water, brine, dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography on silica gel (ethyl acetate / petroleum ether, 0-20%) to afford the product 3- azido-2-chloro-5-(trifluoromethoxy)pyridine as a yellow oil (220 mg, 44.1%). LCMS (ESI): m / z [M+H]+calcd for C6H2ClF3N4O: 237.99, found: 239.00. Step 2: Preparation of (3R)-3-amino-1-(1-cyclopentylethyl)-7-(trifluoromethyl)-3,4- dihydroquinolin-2-one To a solution of 3-azido-2-chloro-5-(trifluoromethoxy)pyridine (210 mg, 0.880 mmol, 1 equiv.) in tetrahydrofuran (5 mL) and water (0.2 mL) was added trimethylphosphine (1.0M in tetrahydrofuran) (1.7 mL, 1.760 mmol, 2 equiv.). The reaction was stirred at 25 °C for 1 h. The reaction was treated with water (20 mL) and extracted with ethyl acetate (3 x 20 mL). The combined extracts were washed with water, brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by column chromatography on silica gel (ethyl acetate / petroleum ether, 0-100%) to afford the title compound 2-chloro-5- (trifluoromethoxy)pyridin-3-amine as a yellow oil (130 mg, 69.4%). LCMS (ESI): m / z [M+H]+calcd for C6H4ClF3N2O: 212.00, found: 213.00. FH12898416.1 GPX-02125 Step 3: Preparation of methyl (2R)-3-[3-amino-5-(trifluoromethoxy)pyridin-2-yl]-2- [(tert-butoxycarbonyl)amino]propanoate To a solution of 2-chloro-5-(trifluoromethoxy)pyridin-3-amine (120 mg, 0.565 mmol, 1 equiv.) in DMF (5 mL) was added Pd(OAc)2(25.3 mg, 0.113 mmol, 0.2 equiv.), Xphos (107.6 mg, 0.226 mmol, 0.4 equiv.) and Intermediate 1 (5.7 mL, 2.825 mmol, 5 equiv, 0.5 M in DMF). The reaction was stirred at 80 °C for 1 h under nitrogen. The mixture was allowed to cool down to room temperature. The reaction was quenched with sat., aq. ammonium chloride at room temperature. The resulting mixture was filtered, the filter cake was washed with ethyl acetate (3 x 10 mL). The resulting mixture was extracted with ethyl acetate (3 x 20 mL). The combined organic layers were dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (ethyl acetate / petroleum ether, 0-40%) to afford the product tert-butyl N-[(3R)-2- oxo-7-(trifluoromethoxy)-3,4-dihydro-1H-1,5-naphthyridin-3-yl]carbamate (100 mg, 51.0%) as a yellow oil. LCMS (ESI): m / z [M+H-tBu]+calcd for C14H16F3N3O4: 347.11, found: 292.00. Step 4: Preparation of tert-butyl N-[(3R)-2-oxo-1-[(1S)-1-phenylethyl]-7- (trifluoromethoxy)-3,4-dihydro-1,5-naphthyridin-3-yl]carbamate The transformation was carried out similarly to the synthesis of Compound 1 to afford the title compound as a yellow oil (100 mg, 85.4%). LCMS (ESI): m / z [M+H-tBu]+calcd. for C22H24F3N3O4:451.17, found: 396.05. Step 5: Preparation of (3R)-3-amino-1-[(1S)-1-phenylethyl]-7-(trifluoromethoxy)-3,4- dihydro-1,5-naphthyridin-2-one The transformation was carried out similarly to the synthesis of Compound 1 to afford the title compound (3R)-3-amino-1-[(1S)-1-phenylethyl]-7-(trifluoromethoxy)-3,4-dihydro-1,5- naphthyridin-2-one (60 mg, 85.8%), which was used in the next step directly without further purification. LCMS (ESI): m / z [M+H]+calcd for C17H16F3N3O2: 351.12, found: 352.10. Step 5: Preparation of 1-((R)-2-oxo-1-((S)-1-phenylethyl)-7-(trifluoromethoxy)-1,2,3,4- tetrahydro-1,5-naphthyridin-3-yl)urea (Compound 54) The transformation was carried out similarly to the synthesis of Compound 1. The crudeproduct was purified by preparative HPLC (XBridge Prep OBD C18 30 x150 mm, 5 mcolumn, 28-48% acetonitrile in water with 10mmol / L NH4HCO3) to afford the title compound 1-((R)-2-oxo-1-((S)-1-phenylethyl)-7-(trifluoromethoxy)-1,2,3,4-tetrahydro-1,5-naphthyridin- FH12898416.1 GPX-02125 3-yl)urea (Compound 54) as a white solid (41.5 mg, 61.6%). LCMS (ESI): m / z calcd. for [M+H]+C18H17F3N4O3: 394.13, found: 395.10.1H NMR (400 MHz, DMSO-d6) 8.27 (s, 1H),7.22 – 7.56 (m, 6H), 6.93 (s, 1H), 6.42 – 6.54 (m, 1H), 6.20 – 6.33 (m, 1H), 5.85 (s, 2H), 4.55 – 4.77 (m, 1H), 3.07 – 3.25 (m, 1H), 1.62 – 1.85 (m, 3H).19F NMR (376 MHz, DMSO) -57.54. Synthesis of Compound 55: 1-((R)-7-oxo-8-((S)-1-phenylethyl)-2-(trifluoromethyl)- 5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-6-yl)urea Step 1: Preparation of N-[(1S)-1-phenylethyl]-2-(trifluoromethyl)pyrimidin-4-amine To a solution of 4-chloro-2-(trifluoromethyl)pyrimidine (4.0 g, 21.914 mmol, 1 equiv.) in i-PrOH (20 mL) was added (S)- -phenylethylamine (3.2 g, 26.406 mmol, 1.20 equiv.) andDIethyl acetate (8.5 g, 65.766 mmol, 3.00 equiv.). The reaction was stirred at 150 °C for 3 h. FH12898416.1 GPX-02125 The mixture was allowed to cool down to room temperature. The mixture was treated with water (150 mL) and extracted with ethyl acetate (3 x 150 mL). The combined extracts were washed with water, brine, dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography on silica gel (ethyl acetate / petroleum ether, 30-70%) the title compound was afforded as a yellow oil (5.5 g, 93.9%). LC / MS (ESI): m / z [M+H]+calcd. for C13H12F3N3:267.10, found: 268.10. Step 2: Preparation of 5-bromo-N-[(1S)-1-phenylethyl]-2-(trifluoromethyl)pyrimidin-4- amine To a solution of N-[(1S)-1-phenylethyl]-2-(trifluoromethyl)pyrimidin-4-amine (5.5 g, 20.580 mmol, 1 equiv.) in DMF (20 mL) was added NBS (3.7 g, 20.788 mmol, 1.01 equiv.) at 0 °C. The reaction was stirred at 25 °C for 1 h. The mixture was treated with water (150 mL) and extracted with ethyl acetate (3 x 150 mL). The combined extracts were washed with water, brine, dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography on silica gel (ethyl acetate / petroleum ether, 0-50%) to afford the title compound as a yellow oil (6.0 g, 84.2%). LC / MS (ESI): m / z [M+H, M+H+2]+calcd. for C13H11BrF3N3: 345.01, found: 346.00, 348.00. Step 3: Preparation of methyl (2R)-2-[(tert-butoxycarbonyl)amino]-3-(4-{[(1S)-1- phenylethyl]amino}-2-(trifluoromethyl)pyrimidin-5-yl)propanoate The transformation was carried out similarly to the synthesis of Compound 1. After purification by column chromatography on silica gel (ethyl acetate / petroleum ether, 30-70%) the title compound was afforded as a yellow oil (1.2 g, 88.6%). LC / MS (ESI): m / z [M+H]+calcd. for C22H27F3N4O4: 468.20, found: 469.25. Step 4: Preparation of (2R)-2-[(tert-butoxycarbonyl)amino]-3-(4-{[(1S)-1- phenylethyl]amino}-2-(trifluoromethyl)pyrimidin-5-yl)propanoic acid To a solution of methyl (2R)-2-[(tert-butoxycarbonyl)amino]-3-(4-{[(1S)-1- phenylethyl]amino}-2-(trifluoromethyl)pyrimidin-5-yl)propanoate (400.0 mg, 0.854 mmol, 1 equiv.) in dichloroethane (10 mL) was added trimethyltin hydroxide (464.7 mg, 2.570 mmol, 3.01 equiv.). The reaction was stirred at 70 °C for 3 h. The mixture was allowed to cool down to room temperature. The mixture was treated with water (50 mL) and extracted with ethyl acetate (3 x 50 mL). The combined extracts were washed with water, brine, dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography on silica gel FH12898416.1 GPX-02125 (ethyl acetate / petroleum ether, 50-100%) to afford the title compound as a yellow oil (290.0 mg, 74.7%). LC / MS (ESI): m / z [M+H]+calcd. for C21H25F3N4O4: 454.18, found:455.25. Step 5: Preparation of tert-butyl N-[(6R)-7-oxo-8-[(1S)-1-phenylethyl]-2- (trifluoromethyl)-5H,6H-pyrido[2,3-d]pyrimidin-6-yl]carbamate To a solution of (2R)-2-[(tert-butoxycarbonyl)amino]-3-(4-{[(1S)-1-phenylethyl]amino}-2- (trifluoromethyl)pyrimidin-5-yl)propanoic acid (275.0 mg, 0.605 mmol, 1 equiv.) in DMF (10 mL) was added Hexafluorophosphate Azabenzotriazole Tetramethyl Uronium (230.1 mg, 0.605 mmol, 1.00 equiv.) and N,N-Diisopropylethylamine (313.7 mg, 2.427 mmol, 4.01 equiv.). The reaction was stirred at 25 °C for 1 h. The mixture was treated with water (50 mL) and extracted with ethyl acetate (3 x 50 mL). The combined extracts were washed with water, brine, dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography on silica gel (ethyl acetate / petroleum ether, 20-70% to afford the title compound as a yellow oil (240.0 mg, 90.8%). LC / MS (ESI): m / z [M+H]+calcd. for C21H23F3N4O3: 436.17, found:437.15. Step 6: Preparation of (6R)-6-amino-8-[(1S)-1-phenylethyl]-2-(trifluoromethyl)-5H,6H- pyrido[2,3-d]pyrimidin-7-one The transformation was carried out similarly to the synthesis of Compound 1 to afford the title compound without further purification as a yellow oil (170.0 mg, 96.0%). LC / MS (ESI): m / z [M+H]+calcd. for C16H15F3N4O: 336.12, found: 337.15. Step 7: Preparation of (6R)-7-oxo-8-[(1S)-1-phenylethyl]-2-(trifluoromethyl)-5H,6H- pyrido[2,3-d]pyrimidin-6-ylurea (Compound 55) The transformation was carried out similarly to the synthesis of Compound 1. The crude product was purified by preparative HPLC (XBridge Prep OBD C18 Column 75 mm x 30 mm x 3.5 m column, 35-55% acetonitrile in water with 10mmol / L NH4HCO3) to afford the title Compound 55 (56.8 mg, 29.6%) as a white solid. LC / MS (ESI): m / z [M+H]+calcd. for C17H16F3N5O2: 379.13, found: 380.05.1H NMR (300 MHz, DMSO-d6) 8.75 (s, 1H), 7.12 – 7.43 (m, 5H), 6.49 (d, J = 7.3 Hz, 1H), 6.21 – 6.35 (m, 1H), 5.77 (s, 2H), 4.56 – 4.73 (m, 1H), 3.24 – 3.32 (m, 1H), 2.94 – 3.10 (m, 1H), 1.80 (d, J = 7.1 Hz, 3H).19F NMR (282 MHz, DMSO) -69.33, -69.42 FH12898416.1 GPX-02125 Synthesis of Compound 56: 1-((R)-1-((S)-1-cyclobutylethyl)-2-oxo-7-(trifluoromethyl)- 1,2,3,4-tetrahydroquinolin-3-yl)urea Step 1: Preparation of tert-butyl N-[(3R)-1-(1-cyclobutylethyl)-2-oxo-7-(trifluoromethyl)- 3,4-dihydroquinolin-3-yl]carbamate To a solution of tert-butyl N-[2-oxo-7-(trifluoromethyl)-3,4-dihydro-1H-quinolin-3- yl]carbamate (300.0 mg, 0.908 mmol, 1 equiv.) in toluene (10 mL) was added 1- cyclobutylethanol (300.2 mg, 2.996 mmol, 3.30 equiv.) and CMBP (657.6 mg, 2.725 mmol, 3.00 equiv.). The reaction was stirred at 110 °C for 3 h under nitrogen. The mixture was allowed to cool down to room temperature. The mixture was treated with water (50 mL) and extracted with ethyl acetate (3 x 50 mL). The combined extracts were washed with water, brine, dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography on silica gel (ethyl acetate / petroleum ether, 30-70%) to afford the title compound as a yellow oil (150.0 mg, 40.0%). LC / MS (ESI): m / z [M+H]+calcd. for C21H27F3N2O3: 412.20, found: 413.20. Step 2: Preparation of (3R)-3-amino-1-(1-cyclobutylethyl)-7-(trifluoromethyl)-3,4- dihydroquinolin-2-one FH12898416.1 GPX-02125 The transformation was carried out similarly to the synthesis of Compound 1 to afford the title compound without further purification as a yellow oil (100.0 mg, 94.3%). LC / MS (ESI): m / z [M+H]+calcd. for C16H19F3N2O: 312.15, found: 313.05. Step 3: Preparation of (3R)-1-[(1S)-1-cyclobutylethyl]-2-oxo-7-(trifluoromethyl)-3,4- dihydroquinolin-3-ylurea The transformation was carried out similarly to the synthesis of Compound 1. The crude product was purified by preparative HPLC (XBridge Prep OBD C18 Column 150 mm x 30 mm x 5 m column 35-56% acetonitrile and water with 10mmol / L NH4HCO3and 0.05% ammonium hydroxide) to afford the title compound compound as mixture of diastereomers (40 mg) which was further purified by chiral HPLC (CHIRALPAK IE 250 mm x 20 mm x 5 m column, 15% ethanol and 0.5% 2M ammonia in methanol) to yield the title Compound 56 as a white solid (8.0 mg, 7.0%). LC / MS (ESI): m / z [M+H]+calcd. for C17H20F3N3O2: 355.15, found: 356.10.1H NMR (300 MHz, DMSO-d6) 7.37 – 7.55 (m, 3H), 6.38 (d, J = 6.4 Hz, 1H), 5.79 (s, 2H), 4.21 – 4.36 (m, 1H), 4.00 – 4.17 (m, 1H), 3.09 – 3.29 (m, 2H), 2.64 – 2.81 (m, 1H), 1.98 – 2.10 (m, 1H), 1.64 – 1.88 (m, 4H), 1.48 – 1.60 (m, 1H), 1.31 – 1.40 (m, 3H).19F NMR (282 MHz, DMSO) -60.69. Synthesis of Compound 57: 1-((R)-1-((S)-1-cyclohexylethyl)-2-oxo-7-(trifluoromethyl)- 1,2,3,4-tetrahydroquinolin-3-yl)urea Scheme 61 FH12898416.1 GPX-02125 Step 1: Preparation of tert-butyl ((R)-1-((S)-1-cyclohexylethyl)-2-oxo-7-(trifluoromethyl)- 1,2,3,4-tetrahydroquinolin-3-yl) carbamate To a solution of tert-butyl N-[(3R)-2-oxo-7-(trifluoromethyl)-3,4-dihydro-1H-quinolin-3-yl] carbamate (500 mg, 1.514 mmol, 1 equiv.) and (1R)-1-cyclohexylethanol (582.2 mg, 4.541 mmol, 3.00 equiv.) in toluene (10 mL) was added CMBP (1.10 g, 4.541 mmol, 3.00 equiv.) under nitrogen. The reaction was stirred at 110 °C for 3 h under nitrogen. After cooling down to room temperature, the mixture was treated with water (50 mL) and extracted with ethyl acetate (3 x 50 mL). The combined extracts were washed with water, brine, dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography on silica gel (ethyl acetate / petroleum ether, 0-100%) to afford the title compound as a yellow oil (200 mg, 30.0%). LC / MS (ESI): m / z [M+H-tBu]+calcd. for C23H31F3N2O3: 440.23, found: 385.15. Step 2: Preparation of (R)-3-amino-1-((S)-1-cyclohexylethyl)-7-(trifluoromethyl)-3,4- dihydroquinolin-2(1H)-one The transformation was carried out similarly to the synthesis of Compound 1 to afford the title compound without further purification as a yellow oil (140 mg, 95.2%). LC / MS (ESI): m / z [M+H]+calcd. for C18H23F3N2O: 340.18, found: 341.20. Step 5: Preparation of 1-((R)-1-((S)-1-cyclohexylethyl)-2-oxo-7-(trifluoromethyl)-1,2,3,4- tetrahydroquinolin-3-yl)urea (Compound 57) FH12898416.1 GPX-02125 The transformation was carried out similarly to the synthesis of Compound 1. The crude product was purified by preparative HPLC (XBridge BEH Shield RP18 Column, 19x250 mm, 5 m column, 48-68% acetonitrile and water with 10mmol / L NH4HCO3) to afford the title compound as mixture of diastereomers (70 mg) that was further purified by chiral HPLC (CHIRALPAK IF, 3x25 cm, 5 m column, 20% ethanol and hexanes with 0.5% 2M ammonia in methanol to afford the title Compound 57 as a white solid (25.4 mg, 16.1%). LC / MS (ESI): m / z [M+H]+calcd for C19H24F3N3O2: 383.18, found: 384.10.1H NMR (300 MHz, DMSO-d6) 7.52 (d, J = 8.1 Hz, 1H), 7.32 - 7.42 (m, 2H), 6.42 (d, J = 6.4 Hz, 1H), 5.79 (s, 2H), 3.95 - 4.20 (m, 2H), 3.17 (dd, J = 14.9, 5.4 Hz, 1H), 2.71 - 2.85 (m, 1H), 2.08 - 2.13 (m, 1H), 1.89 (d, J = 12.7 Hz, 1H), 1.73 (d, J = 12.6 Hz, 1H), 1.49 - 1.61 (m, 3H), 1.43 (d, J = 6.7 Hz, 3H), 0.81 - 1.25 (m, 4H), 0.60 - 0.75 (m, 1H).19F NMR (282 MHz, DMSO-d6) -60.72. Synthesis of Compound 58: 1-((R)-7-cyclobutyl-2-oxo-1-((S)-1-phenylethyl)-1,2,3,4- tetrahydroquinolin-3-yl)urea FH12898416.1 GPX-02125 Step 1: Preparation of tert-butyl N-[(3R)-7-nitro-1,2,3,4-tetrahydroquinolin-3- yl]carbamate The transformation was carried out similarly to the synthesis of Compound 1. The crude product purified by column chromatography on silica gel (ethyl acetate / petroleum ether, 0- 100%) to give the title compound as a yellow oil (500 mg, 18.5%). LCMS (ESI): m / z [M+H- tBu]+calcd for C14H19N3O4: 293.14, found: 238.10. Step 2: Preparation of tert-butyl N-[(3R)-7-nitro-2-oxo-1-[(1S)-1-phenylethyl]-3,4- dihydroquinolin-3-yl]carbamate The transformation was carried out similarly to the synthesis of Compound 1. The crude product purified by column chromatography on silica gel (ethyl acetate / petroleum ether, 0- 100%) to give the title compound as a yellow oil (400 mg, 60.9%). LCMS (ESI): m / z [M+Na]+calcd for C22H25N3O5: 411.18, found: 434.25. Step 3: Preparation of tert-butyl N-[(3R)-7-amino-2-oxo-1-[(1S)-1-phenylethyl]-3,4- dihydroquinolin-3-yl]carbamate To a solution of tert-butyl N-[(3R)-7-nitro-2-oxo-1-[(1S)-1-phenylethyl]-3,4-dihydroquinolin- 3-yl]carbamate (390 mg, 0.948 mmol, 1 equiv.) in ethanol (5 mL) and water (1 mL) was added iron (529.3 mg, 9.480 mmol, 10 equiv.) and ammonium chloride (507 mg, 9.480 mmol, 10 equiv.). The reaction was stirred at 80 °C for 1 h. The mixture was allowed to cool down to room temperature. The resulting mixture was filtered, the filter cake was washed with ethyl acetate (3 x 20 mL). The filtrate was concentrated under reduced pressure. The combined extracts were washed with water, brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by column chromatography on silica gel (ethyl acetate / petroleum ether, 0-50%) to give the title compound as a yellow oil (180 mg, 49.7%). LCMS (ESI): m / z [M+H]+calcd for C22H27N3O3: 381.21, found: 382.15. Step 4: Preparation of tert-butyl N-[(3R)-7-bromo-2-oxo-1-[(1S)-1-phenylethyl]-3,4- dihydroquinolin-3-yl]carbamate To a solution of tert-butyl N-[(3R)-7-amino-2-oxo-1-[(1S)-1-phenylethyl]-3,4- dihydroquinolin-3-yl]carbamate (170 mg, 0.446 mmol, 1 equiv.) in acetonitrile (3 mL) was added copper(II) bromide (298.6 mg, 1.338 mmol, 3 equiv.) and tert-butylnitrite (137.8 mg, 1.338 mmol, 3 equiv.) at 0 °C. The reaction was stirred at 25 °C for 1 h. The mixture was treated with water (50 mL) and extracted with ethyl acetate (3 x 50 mL). The combined extracts FH12898416.1 GPX-02125 were washed with water, brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by column chromatography on silica gel (ethyl acetate / PA, 0-50%) to give the title compound as a yellow oil (90 mg, 45.3%). LCMS (ESI): m / z [M+H, M+H+2]+calcd. for C22H25BrN2O3: 444.10, found: 445.10, 447.10. Step 5: Preparation of tert-butyl N-[(3R)-7-cyclobutyl-2-oxo-1-[(1S)-1-phenylethyl]-3,4- dihydroquinolin-3-yl]carbamate To a solution of tert-butyl N-[(3R)-7-bromo-2-oxo-1-[(1S)-1-phenylethyl]-3,4- dihydroquinolin-3-yl]carbamate (75 mg, 0.168 mmol, 1 equiv.) in toluene (3 mL) and water (0.3 mL) was added potassium cyclobutyltrifluoroboranuide (54.5 mg, 0.336 mmol, 2 equiv.), Pd(dppf)Cl2(12.3 mg, 0.017 mmol, 0.1 equiv.) and Cs2CO3(109.7 mg, 0.336 mmol, 2 equiv.). The reaction was stirred at 90 °C for 1 h under nitrogen. The mixture was allowed to cool down to room temperature. The mixture was treated with water (50 mL) and extracted with ethyl acetate (3 x 50 mL). The combined extracts were washed with water, brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by column chromatography on silica gel (ethyl acetate / petroleum ether, 0-50%) to give the title compound tert-butyl N-[(3R)- 7-cyclobutyl-2-oxo-1-[(1S)-1-phenylethyl]-3,4-dihydroquinolin-3-yl]carbamate as a yellow oil (30 mg, 42.3%). LCMS (ESI): m / z [M+H-tBu]+calcd. for C26H32N2O3:420.24, found: 365.15. Step 6: Preparation of (3R)-3-amino-7-cyclobutyl-1-[(1S)-1-phenylethyl]-3,4- dihydroquinolin-2-one The transformation was carried out similarly to the synthesis of Compound 1 to afford the title compound (3R)-3-amino-7-cyclobutyl-1-[(1S)-1-phenylethyl]-3,4-dihydroquinolin-2-one (15 mg, 79.4%) without further purification. LCMS (ESI): m / z [M+H]+calcd for C21H24N2O: 320.19, found: 321.15. Step 7: Preparation of (3R)-7-cyclobutyl-2-oxo-1-[(1S)-1-phenylethyl]-3,4- dihydroquinolin-3-ylurea (Compound 58) The transformation was carried out similarly to the synthesis of Compound 1. The crudeproduct was purified by preparative HPLC (XSelect CSH Pheny-Hexy 19 x 250 mm, 5 mcolumn, 40- 65% acetonitrile in water with 10mmol / L NH4HCO3) to afford the title Compound 58 as a white solid (7.1 mg, 31.3%). LC / MS (ESI): m / z [M+H]+calcd. for C22H25N3O2: 363.19, found: 364.25.1H NMR (400 MHz, Methanol-d4) 7.35 – 7.51 (m, 4H), 7.22 – 7.35 (m, 1H), 7.10 – 7.20 (m, 1H), 6.79 – 6.88 (m, 1H), 6.58 – 6.67 (m, 1H), 6.43 – 6.52 FH12898416.1 GPX-02125 (m, 1H), 4.40 – 4.50 (m, 1H), 3.26 – 3.32 (m, 1H), 3.09 – 3.19 (m, 1H), 2.79 – 2.94 (m, 1H), 2.05 – 2.24 (m, 2H), 1.78 – 1.96 (m, 2H), 1.64 – 1.78 (m, 5H). Synthesis of Compound 59: 1-((R)-6-fluoro-2-oxo-1-((S)-1-phenylethyl)-7- (trifluoromethyl)-1,2,3,4-tetrahydroquinolin-3-yl)urea Step 1: Preparation of tert-butyl (R)-(6-fluoro-2-oxo-7-(trifluoromethyl)-1,2,3,4- tetrahydroquinolin-3-yl)carbamate The transformation was carried out similarly to the synthesis of Compound 1 to afford the title compound after purification by column chromatography on silica gel (ethyl acetate / petroleum ether, 0-50%) as a yellow oil (2.6 g, 77.1%). LCMS (ESI): m / z [M+Na]+calcd for C16H20F4N2O4: 348.11, found: 371.10. Step 2: Preparation of tert-butyl N-[(3R)-6-fluoro-2-oxo-1-[(1S)-1-phenylethyl]-7- (trifluoromethyl)-3,4-dihydroquinolin-3-yl]carbamate FH12898416.1 GPX-02125 The transformation was carried out similarly to the synthesis of Compound 1 to afford the title compound after purification by column chromatography on silica gel (ethyl acetate / petroleum ether, 0-50%) as a yellow oil (0.82 g, 63.0%). LCMS (ESI): m / z [M+Na]+calcd for C23H24F4N2O3: 452.17, found: 475.20. Step 3: Preparation of (R)-3-amino-6-fluoro-1-((S)-1-phenylethyl)-7-(trifluoromethyl)- 3,4-dihydroquinolin-2(1H)-one The transformation was carried out similarly to the synthesis of Compound 1 to afford the title compound as yellow oil (350 mg, 97.7%). LCMS (ESI): m / z [M+H]+calcd. for C18H16F4N2O: 352.12, found: 353.10. Step 4: Preparation of 1-((R)-6-fluoro-2-oxo-1-((S)-1-phenylethyl)-7-(trifluoromethyl)- 1,2,3,4-tetrahydroquinolin-3-yl)urea (Compound 59) The transformation was carried out similarly to the synthesis of Compound 1. The crude product was purified by preparative HPLC (YMC-Actus Triart C18150 mm x 30 mm column, 39-60% acetonitrile in water with 10 mmol / L NH4HCO4) to afford Compound 59 (51.8 mg, 13.3%). LCMS (ESI): m / z [M+H]+calcd for C19H17F4N3O2: 395.10, found: 396.15.1H NMR (300 MHz, DMSO-d6) 7.59 (d, J = 10.7 Hz, 1H), 7.22 – 7.47 (m, 5H), 6.85 (d, J = 6.2 Hz, 1H), 6.45 (d, J = 6.4 Hz, 1H), 6.31 (d, J = 7.2 Hz, 1H), 5.86 (s, 2H), 4.34 – 4.51 (m, 1H), 3.19 – 3.31 (m, 1H), 2.85 – 3.07 (m, 1H), 1.66 (d, J = 7.2 Hz, 3H). Synthesis of Compound 60: 1-((R)-1-((S)-1-cyclopentylethyl)-2-oxo-7-(trifluoromethyl)- 1,2,3,4-tetrahydroquinolin-3-yl)urea Scheme 64 FH12898416.1 GPX-02125 Step 1: Preparation of tert-butyl N-[(3R)-1-(1-cyclopentylethyl)-2-oxo-7- (trifluoromethyl)-3,4-dihydroquinolin-3-yl]carbamate To a solution of tert-butyl N-[(3R)-2-oxo-7-(trifluoromethyl)-3,4-dihydro-1H-quinolin-3- yl]carbamate (500 mg, 1.514 mmol, 1 equiv.) in toluene (8 mL) was added 1- cyclopentylethanol (518.5 mg, 4.542 mmol, 3 equiv.) and CMBP (1096.0 mg, 4.542 mmol, 3 equiv.). The reaction was stirred at 110 °C for 1 h under nitrogen. The mixture was allowed to cool down to room temperature. The mixture was treated with water (40 mL) and extracted with ethyl acetate (3 x 40 mL). The combined extracts were washed with water, brine, dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography on silica gel (ethyl acetate / petroleum ether, 0-20%) to afford the title compound as a yellow oil (300 mg, 46.4%). LC / MS (ESI): m / z [M+H-tBu]+calcd. for C22H29F3N2O3: 426.21, found: 371.15. Step 2: Preparation of (3R)-3-amino-1-(1-cyclopentylethyl)-7-(trifluoromethyl)-3,4- dihydroquinolin-2-one The transformation was carried out similarly to the synthesis of Compound 1 to afford the title compound without further purification (200 mg, 90.2%). LC / MS (ESI): m / z [M+H]+calcd. for C17H21F3N2O: 326.16, found: 327.15. Step 3: Preparation of (3R)-1-[(1R)-1-cyclopentylethyl]-2-oxo-7-(trifluoromethyl)-3,4- dihydroquinolin-3-ylurea (Compound 60) The transformation was carried out similarly to the synthesis of Compound 1. The crude product was purified by preparative HPLC (Xselect CSH Phenyl Hexy 250 mm x 19 mm x 5 FH12898416.1 GPX-02125 m column, 45-64% acetonitrile and water with 10 mmol / L NH4HCO3) to afford the title compound as a mixture of diastereomers as a white solid (80 mg, 35.34%). This mixture was further purified by chiral HPLC (CHIRALPAK IK 2x25 cm, 5 m column, 30% hexanes with 0.5% 2M ammonia in methanol, in isopropylalcohol) to afford the title Compound 60 (22.1 mg, 27.6%). LC / MS (ESI): m / z [M+H]+calcd. for C18H22F3N3O2: 369.17, found 370.20.1H NMR (400 MHz, DMSO-d6) 7.50 – 7.60 (m, 1H), 7.36 – 7.49 (m, 2H), 6.40 (d, J = 6.6 Hz, 1H), 5.79 (s, 2H), 4.41 (s, 1H), 4.10 – 4.28 (m, 1H), 3.08 – 3.23 (m, 1H), 2.72 – 2.85 (m, 1H), 1.79 – 1.91 (m, 1H), 1.59 – 1.73 (m, 1H), 0.94 – 1.57 (m, 10H).19F NMR (376 MHz, DMSO) -60.87. Synthesis of Compound 61: 1-((R)-7-(1-hydroxycyclopropyl)-2-oxo-1-((S)-1- phenylethyl)-1,2,3,4-tetrahydroquinolin-3-yl)urea Scheme 65 FH12898416.1 GPX-02125 Step 1: Preparation of methyl (3R)-3-[(tert-butoxycarbonyl)amino]-2-oxo-3,4-dihydro- 1H-quinoline-7-carboxylate The transformation was carried out similarly to the synthesis of Compound 1. After purification by column chromatography on silica gel (ethyl acetate / petroleum ether, 0-100%), the title compound was obtained as a yellow oil (1.2 g, 43.09%). LCMS (ESI): m / z [M+H- tBu]+calcd for C16H20N2O5: 320.14, found: 265.05. Step 2: Preparation of methyl (3R)-3-[(tert-butoxycarbonyl)amino]-2-oxo-1-[(1S)-1- phenylethyl]-3,4-dihydroquinoline-7-carboxylate The transformation was carried out similarly to the synthesis of Compound 1. After purification by column chromatography on silica gel (ethyl acetate / petroleum ether, 0-100%), the title compound was obtained as a yellow oil (500 mg, 54.6%). LCMS (ESI): m / z [M+Na]+calcd for C24H28N2O5: 424.20, found: 447.20. Step 3: Preparation of tert-butyl N-[(3R)-7-(1-hydroxycyclopropyl)-2-oxo-1-[(1S)-1- phenylethyl]-3,4-dihydroquinolin-3-yl]carbamate FH12898416.1 GPX-02125 To a solution of methyl (3R)-3-[(tert-butoxycarbonyl)amino]-2-oxo-1-[(1S)-1-phenylethyl]- 3,4-dihydroquinoline-7-carboxylate (490 mg, 1.154 mmol, 1 equiv.) in tetrahydrofuran (10 mL) was added tetrakis(propan-2-yloxy)titanium (524.9 mg, 1.846 mmol, 1.6 equiv.) and ethylmagnesium bromide (1.0M in tetrahydrofuran, 6.5 mL, 6.462 mmol, 5.6 equiv.) at 0 °C under nitrogen. The reaction was stirred at 25 °C for 1 h. The reaction was treated with water (20 mL) and extracted with ethyl acetate (3 x 20 mL). The combined extracts were washed with water, brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by column chromatography on silica gel (ethyl acetate / petroleum ether, 0-100%) to give a mixture of tert-butyl N-[(3R)-7-(1-hydroxycyclopropyl)-2-oxo-1-[(1S)-1-phenylethyl]-3,4- dihydroquinolin-3-yl]carbamate and tert-butyl N-[(3R)-2-oxo-1-[(1S)-1-phenylethyl]-7- propanoyl-3,4-dihydroquinolin-3-yl]carbamate that was obtained as a yellow oil (100 mg, 20.5%). LCMS (ESI): m / z [M+Na]+calcd for C25H30N2O4: 422.22, found: 445.20. Step 4: Preparation of (3R)-3-amino-7-(1-hydroxycyclopropyl)-1-[(1S)-1-phenylethyl]- 3,4-dihydroquinolin-2-one The transformation was carried out similarly to the synthesis of Compound 1 to afford without further purification the title compound as a mixture of (3R)-3-amino-7-(1- hydroxycyclopropyl)-1-[(1S)-1-phenylethyl]-3,4-dihydroquinolin-2-one and (3R)-3-amino-1- [(1S)-1-phenylethyl]-7-propanoyl-3,4-dihydroquinolin-2-one (60 mg, 87.4%). LCMS (ESI): m / z [M+H]+calcd for C20H22N2O2: 322.17, found: 323.15. Step 5: Preparation of (3R)-7-(1-hydroxycyclopropyl)-2-oxo-1-[(1S)-1-phenylethyl]-3,4- dihydroquinolin-3-ylurea (Compound 61) The transformation was carried out similarly to the synthesis of Compound 1. The crude product was purified by preparative HPLC (XBridge Prep Xselect CSH Phenyl Hexy 19 x 250mm, 5 m column, 32-50% acetonitrile and water with 10mmol / L NH4HCO3) to affordCompound 61 (4.6 mg, 5.8%) as a white solid. LCMS (ESI): m / z [M+H]+calcd. for C21H23N3O3: 365.17, found: 366.10.1H NMR (400 MHz, Methanol-d4) 7.35 – 7.53 (m, 4H), 7.26 – 7.35 (m, 1H), 7.16 – 7.26 (m, 1H), 6.99 – 7.11 (m, 1H), 6.58 – 6.68 (m, 1H), 6.38 – 6.50 (m, 1H), 4.35 – 4.53 (m, 1H), 3.09 – 3.24 (m, 1H), 2.77 – 2.95 (m, 1H), 1.68 – 1.79 (m, 3H), 0.93 – 1.15 (m, 2H), 0.65 – 0.79 (m, 1H), 0.45 – 0.62 (m, 1H). Synthesis of Compound 62: (3R)-2-oxo-1-[(1S)-1-phenylethyl]-7-propanoyl-3,4- dihydroquinolin-3-ylurea FH12898416.1 GPX-02125 Scheme 66 Step 1: Preparation of (3R)-2-oxo-1-[(1S)-1-phenylethyl]-7-propanoyl-3,4- dihydroquinolin-3-ylurea (Compound 62) To a solution of (3R)-3-amino-7-(1-hydroxycyclopropyl)-1-[(1S)-1-phenylethyl]-3,4- dihydroquinolin-2-one and (3R)-3-amino-1-[(1S)-1-phenylethyl]-7-propanoyl-3,4- dihydroquinolin-2-one (60 mg, mixture obtained during step 4 of Compound 61) in tetrahydrofuran (3 mL) and water (3 mL) was added potassium cyanate (37.7 mg, 0.465 mmol, 2.5 equiv.) and methanesulfonic acid (19.6 mg, 0.205 mmol, 1.1 equiv.). The reaction was stirred at 25 °C for 4 h. The reaction was treated with water (20 mL) and extracted with dichloromethane / methanol (10 / 1, 3 x 20 mL). The combined extracts were washed with water, brine, dried over sodium sulfate, filtered and concentrated. The residue was purified bypreparative HPLC (XBridge Prep Xselect CSH Phenyl Hexy 19 x 250 mm, 5 m column, 32-50% acetonitrile and water with 10mmol / L NH4HCO3) to afford Compound 62 as a white solid (22.5 mg, 28.3%). LCMS (ESI): m / z [M+H]+calcd for C21H23N3O3: 365.17, found: 366.20.1H NMR (400 MHz, Methanol-d4) 7.57 – 7.75 (m, 1H), 7.36 – 7.50 (m, 6H), 7.28 – 7.36 (m, 1H), 6.31 – 6.62 (m, 1H), 4.43 – 4.56 (m, 1H), 3.20 – 3.31 (m, 1H), 2.90 – 3.07 (m, 1H), 2.58 – 2.84 (m, 2H), 1.66 – 1.86 (m, 3H), 0.96 – 1.12 (m, 3H). Synthesis of Compound 63: 1-((R)-2-oxo-1-((S)-1-phenylethyl)-1,2,3,4-tetrahydro-1,7- naphthyridin-3-yl)urea FH12898416.1 GPX-02125 Scheme 67 Step 1: Preparation of tert-butyl N-[(3R)-2-oxo-3,4-dihydro-1H-1,7-naphthyridin-3- yl]carbamate The transformation was carried out similarly to the synthesis of Compound 1 using Intermediate 1. After purification by column chromatography on silica gel (ethyl acetate / petroleum ether, 30-70%) the title compound was afforded as a yellow oil (525.5 mg, 17.0%). LC / MS (ESI): m / z [M+H]+calcd. for C13H17N3O3: 263.13, found: 264.10. Step 2: Preparation of tert-butyl N-[(3R)-2-oxo-1-(1-phenylethyl)-3,4-dihydro-1,7- naphthyridin-3-yl]carbamate To a solution of tert-butyl N-[(3R)-2-oxo-3,4-dihydro-1H-1,7-naphthyridin-3-yl]carbamate (350.0 mg, 1.329 mmol, 1 equiv.) in DMF (10 mL) was added (1-bromoethyl)benzene (492.0 mg, 2.659 mmol, 2.0 equiv.) and potassium carbonate (551.2 mg, 3.988 mmol, 3.00 equiv.). The reaction was stirred at 25 °C for 3 h. The mixture was treated with water (50 mL) and extracted with ethyl acetate (3 x 50 mL). The combined extracts were washed with water, brine, dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography on silica gel with (ethyl acetate / petroleum ether, 20-50%) to afford the title compound as a yellow oil (310.0 mg, 63.4%). LC / MS (ESI): m / z [M+H]+calcd. for C21H25N3O3: 367.19, found: 368.20. FH12898416.1 GPX-02125 Step 3: Preparation of (3R)-3-amino-1-(1-phenylethyl)-3,4-dihydro-1,7-naphthyridin-2- one The transformation was carried out similarly to the synthesis of Compound 1 to afford the title compound without further purification (200 mg, 91.7%) as a yellow oil. LC / MS (ESI): m / z [M+H]+calcd. for C16H17N3O: 267.14, found 268.15. Step 4: Preparation of (3R)-2-oxo-1-[(1S)-1-phenylethyl]-3,4-dihydro-1,7-naphthyridin- 3-ylurea (Compound 63) The transformation was carried out similarly to the synthesis of Compound 1. The crude product was purified by preparative HPLC (YMC Triart C18 Column 75 mm x 30 mm x 3 m column, 14-35% acetonitrile in water with 10mmol / L NH4HCO3) to afford the title compound as mixture of diastereomers (95 mg). The mixture was furhter purified by chiral-HPLC (CHIRALPAK IB 250 mm x 20 mm x 5 m column, 40% IPA with 0.5% 2M ammonia in methanol) to yield the title Compound 63 (43.7 mg, 17.0%) as a white solid. LC / MS (ESI): m / z [M+H]+calcd. for C17H18N4O2: 310.14, found: 311.10.1H NMR (300 MHz, DMSO-d6) 8.18 (d, J = 4.7 Hz, 1H), 7.87 (s, 1H), 7.22 – 7.49 (m, 6H), 6.45 (d, J = 6.4 Hz, 1H), 6.22 – 6.38 (m, 1H), 5.85 (s, 2H), 4.31 – 4.52 (m, 1H), 3.11 – 3.27 (m, 1H), 2.84 – 3.08 (m, 1H), 1.70 (m, 3H). Synthesis of Compound 64: 1-((R)-6-(difluoromethoxy)-2-oxo-1-((S)-1-phenylethyl)- 1,2,3,4-tetrahydroquinolin-3-yl)urea Scheme 68 FH12898416.1 GPX-02125 Step 1: Preparation of tert-butyl N-[(3R)-6-(difluoromethoxy)-2-oxo-3,4-dihydro-1H- quinolin-3-yl]carbamate The transformation was carried out similarly to the synthesis of Compound 1 using Intermediate 1. After purification by column chromatography on silica gel (ethyl acetate / petroleum ether, 30-70%) the title compound was afforded as a yellow oil (330.0 mg, 21.6%). LC / MS (ESI): m / z [M+H-tBu]+calcd. for C15H18F2N2O4: 328.12, found: 273.10. Step 2: Preparation of tert-butyl N-[(3R)-6-(difluoromethoxy)-2-oxo-1-[(1S)-1- phenylethyl]-3,4-dihydroquinolin-3-yl]carbamate The transformation was carried out similarly to the synthesis of Compound 1. After purification by column chromatography on silica gel (ethyl acetate / petroleum ether, 20-70%) the title compound was afforded (200.5 mg, 47.6%). LC / MS (ESI): m / z [M+Na]+calcd. for C23H26F2N2O4: 432.19, found: 455.15. Step 3: Preparation of (3R)-3-amino-6-(difluoromethoxy)-1-[(1S)-1-phenylethyl]-3,4- dihydroquinolin-2-one The transformation was carried out similarly to the synthesis of Compound 1 to afford the title compound without further purification as a yellow oil (140 mg, 98.0%). LC / MS (ESI): m / z [M+H]+calcd. for C18H18F2N2O2: 332.13, found 333.10. Step 5: Preparation of (3R)-6-(difluoromethoxy)-2-oxo-1-[(1S)-1-phenylethyl]-3,4- dihydroquinolin-3-ylurea (Compound 64) FH12898416.1 GPX-02125 The transformation was carried out similarly to the synthesis of Compound 1. The crude product was purified by preparative HPLC (XBridge Prep C18 OBD Column 250 mm x 19 mm x 5 m column, 31-56% acetonitrile in water with 10mmol / L ammonium bicarbonate) to afford the title Compound 64 as a white solid (35.2 mg, 22.26%). LC / MS (ES...

Claims

GPX-02125 CLAIMS We claim:

1. A compound of Formula (I):or a pharmaceutically acceptable salt thereof; wherein: A is a fused 6-membered aryl or fused 6-membered heteroaryl ring; B is (C6-C10)aryl, 5- to 10-membered heteroaryl, (C3-C8)cycloalkyl, or 4- to 7- membered heterocycloalkyl; X is linear or branched (C1-C6)alkylene optionally substituted with one or more substituents independently selected from halo, hydroxy, (C1-C6)alkoxy, and cyano; or X is absent; W is -O-, -NH- or -CH2-; R1is independently for each occurrence selected from halo, SF5, cyano, hydroxy, (C1- C6)alkyl, (C1-C6)haloalkyl, (C1-C6)hydroxyalkyl, (C6-C10)aryloxy(C1-C6)alkyl, (C1- C6)alkoxy, (C1-C6)haloalkoxy, (C1-C6)alkoxy(C1-C6)alkyl, (C1-C6)haloalkoxy(C1-C6)alkyl, (C3-C8)cycloalkoxy(C1-C6)alkyl, (C6-C10)aryloxy, NRaRb, N(Ra)C(O)Rb, SO2Ra, SORa, S(O)NRaRb, S(O)2NRaRb, S(O)(NH)Ra, C(O)Ra, C(O2)Rb, C(O)NRaRb, (C3-C8)cycloalkyl, and (C3-C8)cycloalkyl(C1-C6)alkyl; R2is independently for each occurrence selected from (C1-C6)alkyl, (C2-C6)alkynyl, (C2-C6)alkenyl, (C3-C8)cycloalkyl, (C3-C8)cycloalkoxy, (C6-C10)aryl, (C6-C10)aryloxy, (C6- C10)aryl(C1-C6)alkyl, 4- to 7-membered heterocycloalkyl, (C1-C6)alkoxy, (C1-C6)alkoxy(C1-C6)alkyl, halo, cyano, NRaRb, N(Ra)C(O)Rb, SO2Ra, SORa, S(O)NRaRb, S(O)2NRaRb, S(O)(NH)Ra, C(O)Ra, C(O)2Rb, C(O)NRaRb, C(O)Ra, and (C1-C6)alkoxycarbonyl; wherein (C1-C6)alkyl, (C2-C6)alkynyl, (C2-C6)alkenyl, (C3-C8)cycloalkyl, C3-C8)cycloalkoxy, (C6-C10)aryl, (C6-C10)aryloxy, (C6-C10)aryl(C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)alkoxy(C1-C6)alkyl, and 4- to 7-membered heterocycloalkyl are each optionally substituted with one or more substituents independently selected from halo, hydroxy, cyano, FH12898416.1GPX-02125 amido, sulfonamido, (C1-C6)alkyl, (C3-C8)cycloalkyl, 4- to 7-membered heterocycloalkyl, 5- to 6-membered heteroaryl, 6-10-membered aryl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, (C1-C6)fluoroalkoxy, 6-10-membered aryloxy, and 5- to 6-membered heteroaryloxy; or two vicinal occurrences of R2taken together with the atoms to which they are attached form a fused 5- to 7-membered cycloalkyl, 5- to 7-membered heterocycloalkyl ring, 5- to 6-membered heteroaryl ring or phenyl ring, any of which is optionally substituted with one or more substituents independently selected from halo, hydroxy, cyano, amido, sulfonamido, (C1-C6)alkyl, (C1-C6)haloalkyl (C3-C8)cycloalkyl, and (C1-C6)alkoxy; R3is hydrogen, (C1-C6)alkyl, or (C1-C6)fluoroalkyl; R4is NRaRb, (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)hydroxyalkyl, (C1-C6)alkoxy(C1- C6)alkyl, (C1-C6)haloalkoxy(C1-C6)alkyl, (C3-C8)cycloalkyl, or (C3-C8)cycloalkyl(C1- C6)alkyl; wherein (C3-C8)cycloalkyl is optionally substituted with one or more hydroxy; Raand Rbare independently for each occurrence hydrogen, (C1-C6)alkyl, C1-C6)haloalkyl; or Raand Rbtaken together with the nitrogen to which they are attached for a 4- to 7-membered heterocycloalkyl; m is 0, 1, 2, 3, 4, or 5; and n is 0, 1, 2, 3, or 4.

2. The compound of claim 1, wherein A is selected from fused phenyl, pyridine, pyrimidine, pyridazine, pyrazine, and pyridone.

3. The compound of claim 1, wherein A is fused phenyl.

4. The compound of claim 1, wherein A is fused pyridyl.

5. The compound of any one of claims 1 to 4, wherein B is 6-membered aryl or heteroaryl.

6. The compound of any one of claims 1 to 5, wherein B is selected from phenyl, pyridine, pyrimidine, pyridazine, pyrazine, and pyridone.

7. The compound of any one of claims 1 to 6, wherein B is phenyl.

8. The compound of any one of claims 1 to 7, wherein X is linear or branched (C1- C6)alkylene optionally substituted with one or more substituents independently selected from halo, hydroxy, (C1-C6)alkoxy, and cyano.

9. The compound of any one of claims 1 to 8, wherein X is CH2, CHCH3, CH3CH3, or C(CH3)2, each of which is optionally substituted with one or more fluorine atoms.

10. The compound of any one of claims 1 to 9, wherein X is -CH2-, -CH(CH3)-, or - C(CH3)2-.

11. The compound of any one of claims 1 to 10, wherein X is -CH(CH3)-. FH12898416.1GPX-02125 12. The compound of any one of claims 1 to 10, wherein X is -CH2-.

13. The compound of any one of claims 1 to 10, wherein X is substituted with one or more fluorine atoms.

14. The compound of any one of claims 1 to 9, wherein X is -CHCH2F-.

15. The compound of any one of claims 1 to 14, wherein W is -NH- or -CH2-.

16. The compound of any one of claims 1 to 15, wherein W is -NH-.

17. The compound of any one of claims 1 to 15, wherein W is -CH2-.

18. The compound of any one of claims 1 to 18, wherein R1is independently for each occurrence selected from halo, cyano, hydroxy, (C1-C6)alkyl, (C1-C6)haloalkyl, (C1- C6)hydroxyalkyl, (C6-C10)aryloxy(C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, (C1- C6)alkoxy(C1-C6)alkyl, (C1-C6)haloalkoxy(C1-C6)alkyl, (C6-C10)aryloxy, NRaRb, N(Ra)C(O)Rb, (C3-C8)cycloalkyl, and (C3-C8)cycloalkyl(C1-C6)alkyl.

19. The compound of any one of claims 1 to 18, wherein R1is independently for each occurrence selected from fluoro, chloro, cyano, (C1-C6)fluoroalkoxy, (C3-C8)cycloalkyl, and (C1-C6)alkoxy(C1-C6)alkyl.

20. The compound of any one of claims 1 to 19, wherein R2is independently for each occurrence selected from (C1-C6)alkyl, (C2-C6)alkynyl, (C2-C6)alkenyl, (C3-C8)cycloalkyl, (C3-C8)cycloalkoxy, (C6-C10)aryl, (C6-C10)aryloxy, (C6-C10)aryl(C1-C6)alkyl, 4- to 7-membered heterocycloalkyl, (C1-C6)alkoxy, (C1-C6)alkoxy(C1-C6)alkyl, halo, cyano, NRaRb, NRa(CO)Rb, formyl, carboxy, and (C1-C6)alkoxycarbonyl; wherein (C1-C6)alkyl, (C2-C6)alkynyl, (C2-C6)alkenyl, (C3-C8)cycloalkyl, C3- C8)cycloalkoxy, (C6-C10)aryl, (C6-C10)aryloxy, (C6-C10)aryl(C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)alkoxy(C1-C6)alkyl, and 4- to 7-membered heterocycloalkyl are each optionally substituted with one or more substituents independently selected from halo, hydroxy, cyano, amido, sulfonamido, (C1-C6)alkyl, (C3-C8)cycloalkyl, 4- to 7-membered heterocycloalkyl, 5- to 6-membered heteroaryl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, (C1-C6)fluoroalkoxy, and 5- to 6-membered heteroaryloxy.

21. The compound of any one of claims 1 to 20, wherein at least one instance of R2is chloro.

22. The compound of any one of claims 1 to 21, wherein at least one instance of R2is fluoro.

23. The compound of any one of claims 1 to 22, wherein at least one instance of R2is (C1-C6)fluoroalkyl. FH12898416.1GPX-02125 24. The compound of any one of claims 1 to 23, wherein at least one instance of R2is trifluoromethyl.

25. The compound of any one of claims 1 to 24, wherein at least one instance of R2is (C1-C6)fluoroalkoxy.

26. The compound of any one of claims 1 to 25, wherein at least one instance of R2is trifluoromethoxy.

27. The compound of any one of claims 1 to 25, wherein at least one instance of R2is difluoromethoxy.

28. The compound of any one of claims 1 to 27, wherein at least one instance of R2is phenoxy.

29. The compound of any one of claims 1 to 28, wherein n is 1.

30. The compound of any one of claims 1 to 28, wherein n is 2.

31. The compound of any one of claims 1 to 17 and 20-28, wherein n is 0.

32. The compound of any one of claims 1 to 31, wherein m is 1.

33. The compound of any one of claims 1 to 31, wherein m is 2.

34. The compound of any one of claims 1 to 19 and 29-31, wherein m is 0.

35. The compound of any one of claims 1 to 34, wherein R3is hydrogen, methyl, or trifluoromethyl.

36. The compound of any one of claims 1 to 35, wherein R3is hydrogen.

37. The compound of any one of claims 1 to 36, wherein R4is NRaRb, (C1-C6)alkyl, (C1- C6)haloalkyl, (C1-C6)hydroxyalkyl, (C1-C6)alkoxy(C1-C6)alkyl, (C1-C6)haloalkoxy(C1- C6)alkyl, (C3-C8)cycloalkyl, or (C3-C8)cycloalkyl(C1-C6)alkyl.

38. The compound of any one of claims 1 to 37, wherein R4is NH2, NHRa, or NRaRb.

39. The compound of any one of claims 1 to 37, wherein R4is (C1-C6)alkyl, (C1- C6)hydroxyalkyl, or (C3-C8)cycloalkyl optionally substituted with one or more hydroxy.

40. The compound of any one of claims 1 to 37, wherein R4is (C1-C6)alkyl or (C3- C8)cycloalkyl.

41. The compound of any one of claims 1 to 37, wherein R4is cyclopropyl; or wherein R4is NH2.

42. The compound of any one of claims 1 to 37, wherein R4is cyclopropyl.

43. The compound of any one of claims 1 to 37, wherein R4is NH2.

44. A compound selected from the following table:FH12898416.1GPX-02125FH12898416.1GPX-02125 7 8 9 111 12 - 263 - FH12898416.1GPX-02125FH12898416.1GPX-02125FH12898416.1GPX-02125FH12898416.1GPX-02125- 267 - FH12898416.1GPX-02125FH12898416.1GPX-02125FH12898416.1GPX-02125FH12898416.1GPX-02125FH12898416.1GPX-02125FH12898416.1GPX-02125FH12898416.1GPX-02125FH12898416.1GPX-02125or a pharmaceutically acceptable salt thereof.

45. A pharmaceutical composition, comprising a compound of any one of claims 1 to 44; and at least one pharmaceutically acceptable excipient.

46. A method of inhibiting a thyroid stimulating hormone receptor, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of any one of claims 1 to 44 or the pharmaceutical composition of claim 45.

47. A method of treating hyperthyroidism, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of any one of claims 1 to 44 or the pharmaceutical composition of claim 45.

48. The method of claim 46 or 47, wherein the subject has Graves' disease.

49. The method of claim 46 or 47, wherein the subject has Graves' ophthalmopathy.

50. The method of any one of claims 46 to 49, wherein the subject has Graves' dermopathy.

51. The method of any one of claims 46 to 50, wherein the subject has thyroid cancer. FH12898416.1

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