Bicyclic heteroaromatic agonists of the parathyroid hormone 1 receptor

Abstract

Disclosed are compounds that are parathyroid hormone receptor 1 agonists, and methods of using them for preventing or treating osteoporosis, fracture, osteomalacia, arthritis, thrombocytopenia, hypoparathyroidism, hyperphosphatemia or tumoral calcinosis.

Description

[0001]GPX-01525 BICYCLIC HETEROAROMATIC AGONISTS OF THE PARATHYROID HORMONE 1 RECEPTOR CROSS-REFERENCE TO A RELATED APPLICATION This application claims the benefit of priority to U.S. Provisional Patent Application No.63 / 671,974, filed July 16, 2024. BACKGROUND Regulation of calcium concentration is important to normal function of the gastrointestinal tract, skeletal system, nervous system, muscular nervous system and cardiovascular system. Parathyroid hormone (PTH) synthesis and release is primarily controlled by serum calcium levels. Osteoporosis is characterized by bone loss resulting in an increased incidence of fracture. This condition, which is most prevalent in the spine and hip, affects 1 in 3 postmenopausal women, a lesser but significant number of aging men, and is also caused by other conditions including hypogonadism and prolonged glucocorticoid use. Current therapies to treat osteoporosis, such as bisphosphonates, hormone replacement therapy, SERMs and calcitonin, serve to arrest further bone loss by inhibiting bone resorption. Although these treatments may slow or even prevent continued bone loss, new bone formation leading to increased bone mass and strength, does not occur. Consequently, there is still a need for a therapeutic agent capable of stimulating bone formation. Such a therapeutic agent would be beneficial both to patients who are at risk of developing osteoporosis or who present with established osteoporosis. Parathyroid hormone (PTH) is a significant regulator of calcium homeostasis and acts, in part, by mobilizing calcium from the skeleton through increased bone resorption. Additionally, pulsatile administration of PTH can stimulate new bone formation, both in laboratory animals and in humans. Thus, there is evidence to suggest that targeting of the receptor for PTH with a small molecule agonist mimicking the actions of PTH, would be a suitable approach for generating an anabolic response in bone. PTH elicits its effects by binding and activating a class B, G protein-coupled receptor of the 7 transmembrane superfamily, designated PTH1R. PTH1R activates multiple signaling pathways, but predominantly the adenylyl cyclase / cyclic AMP and the phospholipase C / calcium mobilization pathways. FoleyHoagUS12952954.4 GPX-01525 Accordingly, there is a need in the art to provide small molecule therapeutics that treat or prevent hypoparathyroidism, osteoporosis and related conditions. In particular, there is a need for providing compounds that act as PTH1R agonists. SUMMARY One aspect of the invention provides compounds, compositions, and methods useful for preventing or treating or preventing osteoporosis, fracture, osteomalacia, arthritis, thrombocytopenia, hypoparathyroidism, hyperphosphatemia or tumoral calcinosis. Accordingly, provided herein in some embodiments is a compound having the structure of Formula (I): or a pharmaceutically acceptable salt thereof; wherein: X is O or NR7; Y is phenyl optionally substituted with one, two, or three substituents selected independently for each occurrence from fluoro, chloro, cyano, hydroxyl, (C1-C6)alkyl, (C3-C8)cycloalkyl, (C1-C6)haloalkyl, (C1-C6)hydroxyalkyl, (C1-C6)alkoxyalkyl, and phenyl; n is 0, 1, or 2; R1is (C1-C6)haloalkyl; R2and R3are independently for each occurrence hydrogen, carboxy, (C1-C6)alkyl, (C1-C6)hydroxyalkyl, (C3-C8)cycloalkyl, or (C1-C6)haloalkyl; or taken together with the carbon atom to which they are attached form C=O, spiro (C3-C8)cycloalkyl, or spiro 4- to 7- membered heterocyclyl; R4and R5are independently for each occurrence hydrogen, (C1-C6)alkyl, (C1-C6)haloalkyl, or (C1-C6)hydroxyalkyl; or taken together with the carbon atom to which they are attached form a (C3-C8)cycloalkyl, wherein the cycloalkyl is optionally substituted with hydroxy; or one of R4and R5and one of R2and R3taken together with the atoms to which they are attached form a fused 5- or 6-memebered heteroaryl ring; or if n is 2, then one of R4and R5and one of R2and R3in a 1,3-relationship taken together with the atoms to which they are attached form a bridged (C3-C8)cycloalkyl; FoleyHoagUS12952954.4 GPX-01525 R6is hydrogen, (C1-C6)alkyl, (C3-C8)cycloalkyl, (C1-C6)haloalkyl, or (C1-C6)alkylsulfonyl(C1-C6)alkyl; or R6and one of R2and R3taken together with the atoms to which they are attached form a fused 5- to 6-membered heterocyclyl; and R7is hydrogen or (C1-C6)alkyl. In some embodiments, a compound has the structure of Formula (Ia) or (Ib): or a pharmaceutically acceptable salt thereof. In other embodiments, provided herein is a compound according to Formula (II): or a pharmaceutically acceptable salt thereof; wherein: A is: i) imidazolyl substituted with one or more substituents selected from (C1-C6)hydroxyalkyl, (C1-C6)alkoxyalkyl, and (C1-C6)dialkoxyalkyl alkyl; ii) pyridazinyl substituted with one or more substituents selected from -C(O)NR8R9, carboxy, (C1-C6)hydroxyalkyl, and (C1-C6)alkoxyalkyl; or iii) pyrimidinyl; R8and R9are each independently selected from hydrogen, (C1-C6)alkyl, and (C3- C8)cycloalkyl; or R8and R9taken together with the nitrogen to which they are attached form a 4- to 7-membered heterocycloalkyl; Y is phenyl optionally substituted with one, two, or three substituents selected independently for each occurrence from fluoro, chloro, cyano, hydroxyl, (C1-C6)alkyl, (C3-C8)cycloalkyl, (C1-C6)haloalkyl, (C1-C6)hydroxyalkyl, (C1-C6)alkoxyalkyl, and phenyl; and R1is (C1-C6)haloalkyl. In some embodiments, the compound has the structure of Formula (IIa) or (IIb): FoleyHoagUS12952954.4 GPX-01525 or a pharmaceutically acceptable salt thereof. Provided herein in other embodiments is a compound of Formula (III): or a pharmaceutically acceptable salt thereof, wherein: Y is phenyl optionally substituted with one, two, or three substituents selected independently for each occurrence from fluoro, chloro, cyano, hydroxyl, (C1-C6)alkyl, (C3-C8)cycloalkyl, (C1-C6)haloalkyl, (C1-C6)hydroxyalkyl, (C1-C6)alkoxyalkyl, and phenyl; R1is (C1-C6)haloalkyl; R10is hydrogen; R11is selected from: 3-(2-imidazolyl)-1-azetidinyl; 2-(fluoromethyl)cyclopropyl; 2-fluoropropyl; 2-(difluoromethyl)cyclopropyl; 1-oxa-6-azaspiro[3,3]heptyl, 2-fluorocyclobutyl; 1-spiro[2.2]pentyl; difluoromethoxypropyl; (1,3-oxazol-2-yl)cyclobutyl; and 3-azetidinyl, wherein 3-azetidinyl is optionally substituted with one or more substituents selected from (C1-C6)alkyl, and (C1-C6)carboxyalkyl; or R10and R11are taken together with the nitrogen to which they are attached form: 4-aza-4-spiro[2.3]hexyl; 3-(2-imidazolyl)-1-azetidinyl; or 1-azetdinyl substituted with at least one substituent selected from oxazole, imidazole, and thiadiazole. FoleyHoagUS12952954.4 GPX-01525 In some embodiments, the compound has the structure of Formula (IIIa) or (IIIb) (IIIb), or a pharmaceutically acceptable salt thereof. Provided herein in other embodiments is a compound of Formula (IV): or a pharmaceutically acceptable salt thereof, wherein: Y is phenyl optionally substituted with one, two, or three substituents selected independently for each occurrence from fluoro, chloro, cyano, hydroxyl, (C1-C6)alkyl, (C3-C8)cycloalkyl, (C1-C6)haloalkyl, (C1-C6)hydroxyalkyl, (C1-C6)alkoxyalkyl, and phenyl; X is CH or N; R1is (C1-C6)haloalkyl; R12is (C1-C6)alkyl; R13is hydrogen or (C1-C6)alkyl; or R12and R13taken together with the nitrogen to which they are attached form 4- to 7- membered heterocyclyl; R14is selected from OC(O)NR15R16, O(4- to 7- membered heterocyclyl), (C1-C6)alkoxy, O(C1-C6)carboxyalkyl, or (C1-C6)cyanoalkyl; and R15and R16are independently hydrogen or (C1-C6)alkyl; or R15and R16taken together with the nitrogen to which they are attached form 4- to 7-memebered heterocyclyl; provided that if X is CH, then R14is not methoxy. In some embodiments, the compound has the structure of Formula (IVa) or (IVb) or a pharmaceutically acceptable salt thereof. FoleyHoagUS12952954.4 GPX-01525 Other aspects of the disclosure provide a pharmaceutical composition comprising a compound as defined herein, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient. In still other aspects, provided herein is a method for treating or preventing osteoporosis, fracture, osteomalacia, arthritis, thrombocytopenia, hypoparathyroidism, hyperphosphatemia or tumoral calcinosis, comprising administering to a subject in need thereof an effective amount of a compound as defined herein, or a pharmaceutically acceptable salt thereof. 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. BRIEF DESCRIPTION OF THE FIGURES Figure 1 tabulates exemplary compounds of the invention, and their characterization data and biological activity. 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. FoleyHoagUS12952954.4 GPX-01525 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 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 FoleyHoagUS12952954.4 GPX-01525 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. 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 FoleyHoagUS12952954.4 GPX-01525 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 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 FoleyHoagUS12952954.4 GPX-01525 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 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. FoleyHoagUS12952954.4 GPX-01525 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, 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 FoleyHoagUS12952954.4 GPX-01525 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. 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-C30 for branched chains), and more preferably 20 or fewer. Alkyl goups 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 “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 FoleyHoagUS12952954.4 GPX-01525 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 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. As used herein, the term “halocycloalkyl” refers to a cycloalkyl group as hereinbefore defined substituted with at least one halogen. "Cycloheteroalkyl" refers to an 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. 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 FoleyHoagUS12952954.4 GPX-01525 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 and pyrimidine, 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).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, FoleyHoagUS12952954.4 GPX-01525 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. 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 FoleyHoagUS12952954.4 GPX-01525 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 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 ascompared to the reference level, or any decrease between 10-99% as compared to the absence of a given treatment. FoleyHoagUS12952954.4 GPX-01525 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 radiolabelled pharmaceutical agent, for example, a radiolabelled 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. Compounds of the Invention In some embodiments, provided herein is a compound of Formula (I): FoleyHoagUS12952954.4 GPX-01525 or a pharmaceutically acceptable salt thereof; wherein: X is O or NR7; Y is phenyl optionally substituted with one, two, or three substituents selected independently for each occurrence from fluoro, chloro, cyano, hydroxyl, (C1-C6)alkyl, (C3-C8)cycloalkyl, (C1-C6)haloalkyl, (C1-C6)hydroxyalkyl, (C1-C6)alkoxyalkyl, and phenyl; n is 0, 1, or 2; R1is (C1-C6)haloalkyl; R2and R3are independently for each occurrence hydrogen, carboxy, (C1-C6)alkyl, (C1-C6)hydroxyalkyl, (C3-C8)cycloalkyl, or (C1-C6)haloalkyl; or taken together with the carbon atom to which they are attached form C=O, spiro (C3-C8)cycloalkyl, or spiro 4- to 7- membered heterocyclyl; R4and R5are independently for each occurrence hydrogen, (C1-C6)alkyl, (C1- C6)haloalkyl, or (C1-C6)hydroxyalkyl; or taken together with the carbon atom to which they are attached form a (C3-C8)cycloalkyl, wherein the cycloalkyl is optionally substituted with hydroxy; or one of R4and R5and one of R2and R3taken together with the atoms to which they are attached form a fused 5- or 6-memebered heteroaryl ring; or if n is 2, then one of R4and R5and one of R2and R3in a 1,3-relationship taken together with the atoms to which they are attached form a bridged (C3-C8)cycloalkyl; R6is hydrogen, (C1-C6)alkyl, (C3-C8)cycloalkyl, (C1-C6)haloalkyl, or (C1-C6)alkylsulfonyl(C1-C6)alkyl; or R6and one of R2and R3taken together with the atoms to which they are attached form a fused 5- to 6-membered heterocyclyl; and R7is hydrogen or (C1-C6)alkyl. In some embodiments, a compound has the structure of Formula (Ia) or (Ib): or a pharmaceutically acceptable salt thereof. In some embodiments, X is O. In other embodiments, X is NR7. FoleyHoagUS12952954.4 GPX-01525 In some embodiments, Y is phenyl substituted with at least one fluoro, and in certain preferred embodiments, Y is 4-fluorophenyl. In some embodiments, R1is (C1-C6)fluoroalkyl, prefereably trifluoromethyl. In some embodiments, R2is (C1-C6)alkyl. In more particular embodiments, R2is methyl. In other embodiments, R2is (C3-C8)cycloalkyl. in certain more particular embodiments, R2is cyclopropyl. In other embodiments, R2is carboxy. In yet other embodiments, R2is (C1-C6)hydroxyalkyl. In more particular embodiments, R2is hydroxymethyl. In still other embodiments, R2is hydrogen. In some embodiments, R3is hydrogen. In other embodiments, R2and R3taken together with the carbon atom to which they are attached form spiro (C3-C8)cycloalkyl. In more particular embodiments, R2and R3taken together with the carbon atom to which they are attached form spiro cyclopropyl. In still other embodiments, R2and R3taken together with the carbon atom to which they are attached form a spiro 4- to 7-membered heterocyclyl. In more particular embodiments, R2and R3taken together with the carbon atom to which they are attached form a spiro tetrahydrofuran. In yet other embodiments, R2and R3taken together with the carbon atom to which they are attached form C=O. In some embodiments, at least one occurrence of R4is (C1-C6)haloalkyl. In certain preferred embodiments, R4is (C1-C6)fluoroalkyl. In other preferred embodiments, R4is fluoromethyl. In some embodiments, at least one occurrence of R4is (C1-C6)hydroxyalkyl. In more particular embodiments, at least one occurrence of R4is hydroxy methyl. In some embodiments, at least one occurrence of R4is hydrogen. In some embodiments, R5is hydrogen. In other embodiments, R4and R5taken together with the carbon atom to which they are attached form a spiro (C3-C8)cycloalkyl. In more particular embodiments, R4and R5taken together with the carbon atom to which they are attached form spiro cyclobutyl optionally substituted with hydroxy. Inb other more particular embodiments, R4and R5taken together with the carbon atom to which they are attached form spiro cyclopropyl. FoleyHoagUS12952954.4 GPX-01525 In other embodiments, R4and R5taken together with the carbon atom to which they are attached form C=O. In other embodiments, if n is 2, then one of R4and R5and one of R2and R3in a 1,3- relationship taken together with the atoms to which they are attached form a bridged (C3-C8)cycloalkyl. In other embodiments R4and R5taken together with one of R2and R3with the carbon atoms to which they are attached form a fused heteroaryl. In more particular embodiments, one of R4and R5and one of R2and R3taken together with the atoms to which they are attached form a fused pyridine-2(1H)one. In other more particular embodiments, one of R4and R5and one of R2and R3taken together with the atoms to which they are attached form a fused pyridine. In some embodiments, R6is hydrogen. In other embodiments, R6is (C1-C6)alkyl. In more particular embodiments, R6is methyl. In other more particular embodiments, R6is ethyl. In other embodiments, R6is (C3-C8)cycloalkyl. In more particular embodiments, R6is cyclopropyl. In other embodiments, R6is 2-mesylethyl. In yet other embodiments, R6is (C1-C6)fluoroalkyl. In more particular embodiments, R6is 2-fluoroethyl. In other more particular embodiments, R6is 2,2-difluoroethyl. In other embodiments, R6and one of R2and R3taken together with the atoms to which they are attached form a fused 4- to 7-membered heterocycle. In more particular embodiments, R6and one of R2and R3taken together with the atoms to which they are attached form a fused morpholino. In other more particular embodiments, R6and one of R2and R3taken together with the atoms to which they are attached form a fused pyrrolidino. In some embodiments, R7is (C1-C6)alkyl. In more particular embodiments, R7is methyl. In some embodiments, n is 0. In other embodiments, n is 1. In still other embodiments, n is 2. Also provided herein is a compound according to Formula (II): or a pharmaceutically acceptable salt thereof; FoleyHoagUS12952954.4 GPX-01525 wherein: A is: i) imidazolyl substituted with one or more substituents selected from (C1-C6)hydroxyalkyl, (C1-C6)alkoxyalkyl, and (C1-C6)dialkoxyalkyl alkyl; ii) pyridazinyl substituted with one or more substituents selected from -C(O)NR8R9, carboxy, (C1-C6)hydroxyalkyl, and (C1-C6)alkoxyalkyl; or iii) pyrimidinyl; R8and R9are each independently selected from hydrogen, (C1-C6)alkyl, and (C3- C8)cycloalkyl; or R8and R9taken together with the nitrogen to which they are attached form a 4- to 7-membered heterocycloalkyl; Y is phenyl optionally substituted with one, two, or three substituents selected independently for each occurrence from fluoro, chloro, cyano, hydroxyl, (C1-C6)alkyl, (C3-C8)cycloalkyl, (C1-C6)haloalkyl, (C1-C6)hydroxyalkyl, (C1-C6)alkoxyalkyl, and phenyl; and R1is (C1-C6)haloalkyl. In some embodiments, the compound has the structure of Formula (IIa) or (IIb): or a pharmaceutically acceptable salt thereof. In some embodiments,Y is phenyl substituted with at least one fluoro. In some preferred embodiments, Y is 4-fluorophenyl. In some embodiments, R1is (C1-C6)fluoroalkyl. In certain prepferred embodiments, R1is trifluoromethyl. In some embodiments, A is imidazolyl substituted with one substituent selected from (C1-C6)hydroxyalkyl, (C1-C6)alkoxyalkyl, and (C1-C6)dialkoxy(C1-C6)alkyl. In more particular embodiments, A is 2-imidazolyl substituted with one substituent selected from (C1- C6)hydroxyalkyl, (C1-C6)alkoxyalkyl, and (C1-C6)dialkoxy(C1-C6)alkyl. In other embodiments, A is pyridazinyl substituted with one substituent selected from -C(O)NR8R9, carboxy, (C1-C6)hydroxyalkyl, and (C1-C6)alkoxyalkyl. In more particular embodiments, A is 3-pyridazinyl substituted with one substituent selected from -C(O)NR8R9, carboxy, (C1-C6)hydroxyalkyl, and (C1-C6)alkoxyalkyl. In other embodiments, A is pyrimidinyl. In more particular embodiments, A is 2- pyrimidinyl. FoleyHoagUS12952954.4 GPX-01525 Provided herein in other embodiments is a compound of Formula (III): (III), or a pharmaceutically acceptable salt thereof, wherein Y is phenyl optionally substituted with one, two, or three substituents selected independently for each occurrence from fluoro, chloro, cyano, hydroxyl, (C1-C6)alkyl, (C3- C8)cycloalkyl, (C1-C6)haloalkyl, (C1-C6)hydroxyalkyl, (C1-C6)alkoxyalkyl, and phenyl; R1is (C1-C6)haloalkyl; R10is hydrogen; R11is selected from: 3-(2-imidazolyl)-1-azetidinyl; 2-(fluoromethyl)cyclopropyl; 2-fluoropropyl; 2-(difluoromethyl)cyclopropyl; 1-oxa-6-azaspiro[3,3]heptyl, 2-fluorocyclobutyl; 1-spiro[2.2]pentyl; difluoromethoxypropyl; (1,3-oxazol-2-yl)cyclobutyl; and 3-azetidinyl, wherein 3-azetidinyl is optionally substituted with one or more substituents selected from (C1-C6)alkyl, and (C1-C6)carboxyalkyl; or R10and R11are taken together with the nitrogen to which they are attached form: 4-aza-4-spiro[2.3]hexyl; 3-(2-imidazolyl)-1-azetidinyl; or 1-azetdinyl substituted with at least one substituent selected from oxazole, imidazole, and thiadiazole. In some embodiments, the compound has the structure of Formula (IIIa) or (IIIb): FoleyHoagUS12952954.4 GPX-01525 or a pharmaceutically acceptable salt thereof. Provided herein in other embodiments is a compound of Formula (IV): or a pharmaceutically acceptable salt thereof, wherein: Y is phenyl optionally substituted with one, two, or three substituents selected independently for each occurrence from fluoro, chloro, cyano, hydroxyl, (C1-C6)alkyl, (C3-C8)cycloalkyl, (C1-C6)haloalkyl, (C1-C6)hydroxyalkyl, (C1-C6)alkoxyalkyl, and phenyl; X is CH or N; R1is (C1-C6)haloalkyl; R12is (C1-C6)alkyl; R13is hydrogen or (C1-C6)alkyl; or R12and R13taken together with the nitrogen to which they are attached form 4- to 7- membered heterocyclyl; R14is selected from OC(O)NR15R16, O(4- to 7- membered heterocyclyl), (C1-C6)alkoxy, O(C1-C6)carboxyalkyl, or (C1-C6)cyanoalkyl; and R15and R16are independently hydrogen or (C1-C6)alkyl; or R15and R16taken together with the nitrogen to which they are attached form 4- to 7-memebered heterocyclyl; provided that if X is CH, then R14is not methoxy. Ion some embodiments, the compound has the structure of Formula (IVa) or (IVb) or a pharmaceutically acceptable salt thereof. FoleyHoagUS12952954.4 GPX-01525 In some embodiments, Y is phenyl substituted with at least one fluoro. In more prepferred embodiments, Y is 4-fluorophenyl. In some embodiments, R1is (C1-C6)fluoroalkyl. In some preferred embodiments, R1is trifluoromethyl. Also provided herein is a compound having the structure: FoleyHoagUS12952954.4 GPX-01525 FoleyHoagUS12952954.4 GPX-01525 FoleyHoagUS12952954.4 GPX-01525 FoleyHoagUS12952954.4 GPX-01525 FoleyHoagUS12952954.4 GPX-01525 FoleyHoagUS12952954.4 GPX-01525 FoleyHoagUS12952954.4 GPX-01525 FoleyHoagUS12952954.4 GPX-01525 FoleyHoagUS12952954.4 GPX-01525 FoleyHoagUS12952954.4 GPX-01525 FoleyHoagUS12952954.4 GPX-01525 or a pharmaceutically acceptable salt thereof. FoleyHoagUS12952954.4 GPX-01525 In certain embodiments, the compounds are atropisomers. Additionally, unless otherwise stated, 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 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. Such compounds are useful, for example, as analytical tools, as probes in biological assays, or as therapeutic agents in accordance with the present invention. For example, in the case of variable R1, the (C1-C4)alkyl or the -O-(C1-C4)alkyl can be suitably deuterated (e.g., -CD3, or -OCD3, respectively). Any compound of the invention can also be radiolabed for the preparation of a radiopharmaceutical agent. Methods of Treatment One aspect of the invention provides a method for treating or preventing osteoporosis, fracture, osteomalacia, arthritis, thrombocytopenia, hypoparathyroidism, hyperphosphatemia or tumoral calcinosis, comprising administering to a subject in need thereof an effective amount of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof. Another aspect of this invention is a method for preventing or treating a condition mediated by PTH which comprises administering to a mammal in need thereof an effective amount of a compound of Formula I, Ia, Ib, IIa, or IIb, or a pharmaceutically acceptable salt thereof, either alone or in admixture with a pharmaceutically excipient. Another aspect of the invention includes a compound of Formula I, Ia, Ib, IIa, or IIb, or a pharmaceutically acceptable salt thereof, for use in the treatment and prevention of diseases and conditions characterized by loss of bone mineral density, mass, or strength, as well as in conditions wherein PTH would have a beneficial pharmacological effect. The invention includes administering a compound of Formula I, Ia, Ib, IIa, or IIb for use as a PTH mimetic. Another aspect of the invention includes use of a compound of Formula I, Ia, Ib, IIa, or IIb in the manufacture of a medicament for use in the treatment of osteopenia and osteoporosis in men and women for reduction in the risk of fractures, both vertebral and nonvertebral. 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. FoleyHoagUS12952954.4 GPX-01525 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 of Formula I, Ia, Ib, IIa, or IIb; 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 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 FoleyHoagUS12952954.4 GPX-01525 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 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 FoleyHoagUS12952954.4 GPX-01525 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. 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 FoleyHoagUS12952954.4 GPX-01525 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. 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, FoleyHoagUS12952954.4 GPX-01525 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, 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 FoleyHoagUS12952954.4 GPX-01525 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., 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) ( 1-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. FoleyHoagUS12952954.4 GPX-01525 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 contemplated. Chemically modified compounds 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. FoleyHoagUS12952954.4 GPX-01525 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 beprepared in particulate form with an average particle size of less than 10 micrometers ( m),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 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 FoleyHoagUS12952954.4 GPX-01525 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. 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- FoleyHoagUS12952954.4 GPX-01525 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, sulphuric, 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 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 FoleyHoagUS12952954.4 GPX-01525 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 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 FoleyHoagUS12952954.4 GPX-01525 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. Abbreviations: FoleyHoagUS12952954.4 GPX-01525 General Schemes: FoleyHoagUS12952954.4 GPX-01525 Scheme 1: The invention is further described in the following examples, which do not limit the scope of the invention described in the claims. Example 1. (S)-1-(4-Fluorophenyl)-3-(6-(4-methyl-3-oxo-2-(trifluoromethyl)morpholin- 2-yl)benzo[d]thiazol-2-yl)urea (1) FoleyHoagUS12952954.4 GPX-01525 (S)-3,3,3-trifluoro-2-(2-(3-(4-fluorophenyl)ureido)benzo[d]thiazol-6-yl)-2-hydroxy-N-(2- hydroxyethyl)-N-methylpropanamide To a solution of (S)-3,3,3-trifluoro-2-(2-(3-(4-fluorophenyl)ureido)benzo[d]thiazol-6- yl)-2-hydroxypropanoic acid (100 mg, 233 μmol, see Example 29 for synthesis) and 2- (methylamino)ethanol (56.1 μL, 699 μmol) in DMF (2.4 mL), HOBt (96.3 mg, 699 μmol), DIPEA (328 μL, 1.86 mmol), and PyBOP (371 mg, 699 μmol) were added at ambient temperature and stirred for 16 h. Upon completion, the crude material was poured into EtOAc. It was washed with 1 N HCl, and water, dried over anhydrous Na2SO4, filtered, concentrated, and purified by reverse phase HPLC (gradient elution, 15-80% ACN / H2O, with 10 mM ammonium formate as a modifier) to afford the title compound (55 mg, 49%). MS (ESI): mass calcd. for C20H18F4N4O4S: 486.10, found: 487.4 [M+H]+. (S)-1-(4-Fluorophenyl)-3-(6-(4-methyl-3-oxo-2-(trifluoromethyl)morpholin-2- yl)benzo[d]thiazol-2-yl)urea (1) FoleyHoagUS12952954.4 GPX-01525 To a solution of triphenylphosphine (33.7 mg, 0.13 mmol) and diisopropyl azodicarboxylate (25.8 μL, 0.13 mmol) in THF (1.3 mL) at 0 °C was added (S)-3,3,3-trifluoro- 2-(2-(3-(4-fluorophenyl)ureido)benzo[d]thiazol-6-yl)-2-hydroxy-N-(2-hydroxyethyl)-N- methylpropanamide (25 mg, 51 μmol) in THF (1.3 mL). The reaction was stirred at 0 °C for 1 h and slowly rose to rt. The mixture was concentrated, and the crude was purified by reverse phase HPLC (C18, 25-100% ACN / ammonium formate 10 mM buffer) to provide the title compound (1) (10.1 mg, 21%) as a white solid. MS (ESI): mass calcd. for C18H15F4N3O3S: 468.09, found: 469.3 [M+H]+.1H NMR (400 MHz, DMSO-d6) ppm 9.25 (s, 1H), 8.22 (s, 1H), 7.73 (t, J = 6.8 Hz, 2H), 7.54 (dd, J = 8.9, 4.9 Hz, 2H), 7.17 (td, J = 8.6, 4.2 Hz, 2H), 4.07 - 4.14 (m, 1H), 3.74 - 3.82 (m, 1H), 3.62 - 3.72 (m, 1H), 3.23 - 3.31 (m, 1H), 2.98 (s, 3H). Example 2. 1-(6-(1,4-Dimethyl-3-oxo-2-(trifluoromethyl)piperazin-2-yl)benzo[d]thiazol- 2-yl)-3-(4-fluorophenyl)urea (2) 2-(4-(Dibenzylamino)phenyl)-3,3,3-trifluoro-2- (methyl(2(methylamino)ethyl)amino)propanoic acid FoleyHoagUS12952954.4 GPX-01525 2-(4-(Dibenzylamino)phenyl)-3,3,3-trifluoro-2-hydroxypropanoic acid (160 mg, 0.39 mmol, ~80% ee, see Example 129 for procedure) was dissolved in THF (6.8 mL). Oxalylchloride (79.8 μL, 0.92 mmol) was added and the reaction was stirred for 20 min. N,N -Dimethylethylenediamine (175 mg, 1.93 mmol) dissolved in 0.2 mL of THF was added and the reaction was stirred at rt for 15 min. Water was added and the mixture was extracted with EtOAc and washed with NaHCO3. The combined organic layer was dried over Na2SO4, filtered and concentrated to afford the crude title compound (187 mg, 100%), which was used directly in the next step without further purification. 3-(4-(Dibenzylamino)phenyl)-1,4-dimethyl-3-(trifluoromethyl)piperazin-2-one To a solution of 2-(4-(dibenzylamino)phenyl)-3,3,3-trifluoro-2-(methyl(2- (methylamino)ethyl)amino)propanoic acid (187 mg, 0.39 mmol) in DMF (4 mL) was added N,N-diisopropylethylamine (203 μL, 1.16 mmol) followed by HATU (146 mg, 0.39 mmol) and the reaction was stirred for 1 h at rt. The crude reaction mixture was directly purified by reverse phase HPLC (C18, 0-100% ACN / ammonium bicarbonate 10 mM buffer). The fractions with product were concentrated, extracted with EtOAc, dried over Na2SO4, filtered and concentrated to provide the title compound (70 mg, 39%) as a yellow waxy solid. MS (ESI): mass calcd. for C27H28F3N3O: 467.22, found: 468.4 [M+H]+. 3-(4-Aminophenyl)-1,4-dimethyl-3-(trifluoromethyl)piperazin-2-one To a solution of 3-(4-(dibenzylamino)phenyl)-1,4-dimethyl-3- (trifluoromethyl)piperazin-2-one (70 mg, 0.15 mmol) in MeOH (3 mL) was added palladium on carbon (10 wt % loading, wet with 55% water) (63 mg) and the reaction vial was purged with hydrogen gas and stirred under a hydrogen balloon for 17 h. After purging the reaction with nitrogen, the suspension was filtered through Celite and concentrated to give the title crude compound (44 mg, quantitative) as an off-white solid, which was used in the next step without further purification. MS (ESI): mass calcd. for C13H16F3N3O: 287.12, found: 288.4 [M+H]+. 3-(2-Aminobenzo[d]thiazol-6-yl)-1,4-dimethyl-3-(trifluoromethyl)piperazin-2-one FoleyHoagUS12952954.4 GPX-01525 To a stirred solution of 3-(4-aminophenyl)-1,4-dimethyl-3-(trifluoromethyl)piperazin- 2-one (44.0 mg, 0.15 mmol) in AcOH (3 mL) was added potassium thiocyanate (59.5 mg, 0.61 mmol) followed by bromine (7.9 μL, 0.16 mmol) at rt. After stirring for 16 h at rt, the reaction was quenched with saturated aqueous sodium thiosulfate solution and stirred for 10 min. Saturated aqueous NaHCO3solution was added, and the reaction was extracted with DCM (3x). The combined organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated to afford the title compound as a yellow solid (53 mg, quantitative), which was used in the next step without further purification. MS (ESI): mass calcd. for C14H15F3N4OS: 344.09, found: 345.3 [M+H]+. 1-(6-(1,4-Dimethyl-3-oxo-2-(trifluoromethyl)piperazin-2-yl)benzo[d]thiazol-2-yl)-3-(4- fluorophenyl)urea (2) To a solution of 3-(2-aminobenzo[d]thiazol-6-yl)-1,4-dimethyl-3- (trifluoromethyl)piperazin-2-one (53 mg, 0.15 mmol) in DCM (3 mL) was added 4- fluorophenyl isocyanate (36.6 μL, 0.23 mmol) and the reaction was stirred at rt for 1 h. The reaction mixture was concentrated and purified by reverse phase HPLC (C18, 30-50% ACN / Ammonium bicarbonate 10 mM buffer) to provide the title compound (2) (18.9 mg, 26%) as a white solid. MS (ESI): mass calcd. for C21H19F4N5O2S: 481.12, found: 482.3 [M+H]+.1H NMR (400 MHz, DMSO-d6) ppm 9.27 (s, 1H), 7.91 (s, 1H), 7.64 (d, J = 8.6 Hz, 1H), 7.55 (dd, J = 9.0, 4.9 Hz, 2H), 7.37 - 7.41 (m, 1H), 7.17 (t, J = 8.9 Hz, 2H), 3.56 - 3.64 (m, 1H), 3.29 - 3.32 (m, 1H), 2.98 (s, 3H), 2.90 - 2.97 (m, 2H), 2.27 (s, 3H). Example 3. 1-(4-Fluorophenyl)-3-(6-(4-methyl-3-oxo-2-(trifluoromethyl)piperazin-2- yl)benzo[d]thiazol-2-yl)urea (3) FoleyHoagUS12952954.4 GPX-01525 2-((2-((tert-Butoxycarbonyl)(methyl)amino)ethyl)amino)-2-(4-(dibenzylamino)phenyl)- 3,3,3-trifluoropropanoic acid To a solution of 2-(4-(dibenzylamino)phenyl)-3,3,3-trifluoro-2-hydroxypropanoic acid (750 mg, 1.81 mmol, ~80% ee, see Example 129 for procedure) in THF (15 mL) was added oxalyl chloride (234 μL, 2.7 mmol) and the reaction was stirred for 30 min. N-Boc-N- methylethylenediamine (786 mg, 4.5 mmol) dissolved in 2 mL of THF was added and the reaction was stirred at rt for 15 min. Triethylamine (1.26 mL, 9.03 mmol) was added, and the solution was stirred for another 15 min. The reaction was quenched with water, extracted with EtOAc and washed with NaHCO3. The combined organic layer was dried over Na2SO4, filtered and concentrated to afford the crude title compound (1.03 g, 100%, racemized), which was used in the next step without further purification. FoleyHoagUS12952954.4 GPX-01525 2-(4-(Dibenzylamino)phenyl)-3,3,3-trifluoro-2-((2-(methylamino)ethyl)amino)propanoic acid To a solution of the crude 2-((2-((tert-butoxycarbonyl)(methyl)amino)ethyl)amino)-2- (4-(dibenzylamino)phenyl)-3,3,3-trifluoropropanoic acid (1.03 g, 1.80 mmol) in dioxane (3.0 mL) was added hydrochloric acid in dioxane (4 N, 9.0 mL, 36 mmol) and the reaction was stirred at rt for 1 h after which a precipitate had formed. The reaction was concentrated, and the crude was dissolved in DCM and washed with saturated aqueous NaHCO3solution. The organic layer was dried over Na2SO4, filtered and concentrated to afford the title compound (850 mg) which was used in the next step without further purification. 1-(4-Fluorophenyl)-3-(6-(4-methyl-3-oxo-2-(trifluoromethyl)piperazin-2- yl)benzo[d]thiazol-2-yl)urea (3) The title compound (3) was synthesized in similar procedures as described in Example 2 from 2-(4-(dibenzylamino)phenyl)-3,3,3-trifluoro-2-((2- (methylamino)ethyl)amino)propanoic acid. The crude was purified by reverse phase HPLC (C18, 0-100% ACN / ammonium formate 10 mM buffer) to provide the title compound (23 mg, 14%) as an off-white solid. MS (ESI): mass calcd. for C20H17F4N5O2S: 467.10, found: 468.3 [M+H]+.1H NMR (400 MHz, DMSO-d6) ppm 9.26 (s, 1H), 8.17 (s, 1H), 7.63 - 7.76 (m, 2H), 7.49 - 7.59 (m, 2H), 7.17 (t, J = 8.8 Hz, 2H), 4.20 (s, 1H), 3.46 (td, J = 11.5, 5.2 Hz, 1H), 3.11 (dd, J = 11.7, 3.3 Hz, 1H), 2.88 - 3.00 (m, 1H), 2.93 (s, 3H), 2.60 - 2.72 (m, 1H). Examples 79, 83, 84 were synthesized from tert-butyl (2-aminoethyl)(cyclopropyl)carbamate in the same procedures as described in Example 3. Examples 87, 91, and 92 were synthesized from tert-butyl (2-aminoethyl)(ethyl)carbamate in the same procedures as described in Example 3. FoleyHoagUS12952954.4 GPX-01525 Examples 88, 89, 96, 97, 98, and 99 were synthesized from tert-butyl (2- aminopropyl)(methyl)carbamate in the same procedures as described in Example 3. Examples 95, 110, and 111 were synthesized from tert-butyl (3- aminopropyl)(methyl)carbamate in the same procedures as described in Example 3. Examples 105, 114 and 115 were synthesized from tert-butyl (2-aminoethyl)(2- fluoroethyl)carbamate in the same procedures as described in Example 3. Examples 108, 116, 117 were synthesized from tert-butyl (R)-2-(aminomethyl)pyrrolidine-1- carboxylate and Examples 109, 118, 119 were synthesized from tert-butyl (S)-2- (aminomethyl)pyrrolidine-1-carboxylate in the same procedures as described in Example 3. Examples 122, 123 were synthesized from tert-butyl (S)-(2-amino-1- cyclopropylethyl)(methyl)carbamate and Examples 135, 136, were synthesized from tert- (R)-(2-amino-1-cyclopropylethyl)(methyl)carbamate in the same procedures as described in Example 3. Examples 124, 137 and 138 were synthesized from tert-butyl (3-aminopyridin-2- yl)(methyl)carbamate in the same procedures as described in Example 3. Examples 125, 126 were synthesized from tert-butyl (R)-(1-aminopropan-2- yl)(methyl)carbamate and Examples 127, 128, were synthesized from tert-butyl (S)-(1- aminopropan-2-yl)(methyl)carbamate in the same procedures as described in Example 3. Examples 143 and 144 were synthesized from tert-butyl (1- (aminomethyl)cyclopropyl)(methyl)carbamate in the same procedures as described in Example 3. Example 155 and 156 were synthesized from rac-tert-tert-butyl ((1s,3s)-3- aminocyclobutyl)(methyl)carbamate in the same procedures as described in Example 3. Example 5. 1-(4-Fluorophenyl)-3-(6-((2S)-5-methyl-3-oxo-2-(trifluoromethyl)morpholin- 2-yl)benzo[d]thiazol-2-yl)urea (5) FoleyHoagUS12952954.4 GPX-01525 Ethyl 3,3,3-trifluoro-2-hydroxy-2-(4-nitrophenyl)propanoate A solution of 1-iodo-4-nitro-benzene (10 g, 40.2 mmol) in THF (100 mL) was cooled to –70 °C. Then a solution of 1 M phenyl lithium in diethyl ether (60.2 mL, 60.2 mmol) was slowly added over a period of 10 min under N2. After 0.5 h, ethyl 3,3,3-trifluoro-2-oxo- propanoate (6.4 mL, 48.2 mmol) was added dropwise. The reaction was allowed to stir at 0 °C FoleyHoagUS12952954.4 GPX-01525 for another 3 h. Upon completion, the reaction was quenched with sat. NH4Cl solution (300 mL), extracted with EtOAc (200 mL x 3), washed with brine, dried over Na2SO4, filtered, and concentrated. The crude was purified by reverse phase HPLC (gradient elution, 35-65% ACN in H2O, with 0.2% FA as a modifier) to provide the title compound (7.7 g, 32.7%) as a brown solid.1H NMR (400 MHz, DMSO-d6) ppm 8.24 - 8.40 (m, 3H), 7.87 (d, J = 8.8 Hz, 2H), 4.25 - 4.34 (m, 2H), 1.22 (t, J = 7.2 Hz, 3H). 3,3,3-Trifluoro-2-hydroxy-N-(4-methoxybenzyl)-2-(4-nitrophenyl)propenamide To an ice-cold solution of PMBNH2(3.89 mL, 30 mmol) in toluene (60 mL) was added 2 M trimethylaluminum solution in toluene (9.99 mL, 20 mmol) dropwise. After 30 min, ethyl 3,3,3-trifluoro-2-hydroxy-2-(4-nitrophenyl)propanoate (5.86 g, 20 mmol) was added dropwise. It was then stirred at 80 °C for 12 h. After completion, the reaction was poured into 1 N HCl solution (200 mL) and extracted with DCM (300 mL x 2). The combined organic layer was washed with brine, dried with anhydrous Na2SO4, filtered, concentrated, and purified by silica gel column chromatography (gradient elution, 1 to 25% EtOAc in PE) to provide the title compound (5.5 g, 71.6%) as a yellow solid.1H NMR (400 MHz, DMSO-d6) ppm 8.86 (t, J = 6.0 Hz, 1H), 8.29 (d, J = 8.8 Hz, 3H), 7.96 (d, J = 8.8 Hz, 2H), 7.10 (d, J = 8.8 Hz, 2H), 6.82 (d, J = 8.8 Hz, 2H), 4.16 - 4.27 (m, 2H), 3.70 (s, 3H). 4-(4-Methoxybenzyl)-5-methylene-2-(4-nitrophenyl)-2-(trifluoromethyl)morpholin-3- one To a solution of 3,3,3-trifluoro-2-hydroxy-N-(4-methoxybenzyl)-2-(4- nitrophenyl)propenamide (0.05 g, 0.13 mmol) in THF (3 mL) was added TBAB (8.4 mg, 0.026 mmol) and 60% NaH (6.2 mg, 0.16 mmol) at rt. Then 3-bromoprop-1-yne (21 L, 0.2 mmol) was added. The resulting solution was stirred at 40 °C for 2.5 h. Upon completion, the reaction was diluted with sat. NH4Cl solution (20 mL) and extracted with EtOAc (20 mL x 3). The combined organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated. The crude was purified by prep-TLC (25% EtOAc in PE) to afford the title compound (0.04 g, 73%) as a white solid. MS (ESI): mass calcd. for C20H17F3N2O5: 422.11, found: 421.1 [M-H]- FoleyHoagUS12952954.4 GPX-01525 . 2-(4-Aminophenyl)-4-(4-methoxybenzyl)-5-methylene-2-(trifluoromethyl)morpholin-3- one A 100 mL round bottom flask was purged with N23x and charged with a suspension of Raney-Ni (1 g, 11.67 mmol) in MeOH (40 mL), followed by a solution of 4-(4- methoxybenzyl)-5-methylene-2-(4-nitrophenyl)-2-(trifluoromethyl)morpholin-3-one (4.4 g, 10.4 mmol) in MeOH (50 mL). The resulting suspension was degassed and purged with H2 (3x). The reaction was stirred at 25 °C for 2 h under H2(15 psi). Upon completion, the reaction was filtered through a celite pad. The filtrate was concentrated under reduced pressure to afford the title compound (3 g, 73.4%) as a white solid, which was directly used in the next step without further purification. MS (ESI): mass calcd. for C20H19F3N5O2: 392.13, found: 393.1 [M+H]+. (S)-2-(4-Aminophenyl)-4-(4-methoxybenzyl)-5-methylene-2-(trifluoromethyl)morpholin- 3-one & (R)-2-(4-Aminophenyl)-4-(4-methoxybenzyl)-5-methylene-2- (trifluoromethyl)morpholin-3-one 2-(4-Aminophenyl)-4-(4-methoxybenzyl)-5-methylene-2-(trifluoromethyl)morpholin- 3-one (3 g, 7.65 mmol) was separated by chiral SFC (column: DAICEL CHIRALCEL OJ (250 mm*50 mm,10 um); mobile phase: 55% EtOH, isocratic elution) to give (S)-2-(4- aminophenyl)-4-(4-methoxybenzyl)-5-methylene-2-(trifluoromethyl)morpholin-3-one (1.4 g, 46.7%) as a white solid. MS (ESI): mass calcd. for C20H19F3N2O3: 392.13, found: 393.0 [M+H]+and (R)-2-(4-aminophenyl)-4-(4-methoxybenzyl)-5-methylene-2- (trifluoromethyl)morpholin-3-one (1.37 g, 45.7%) as a white solid. MS (ESI): mass calcd. for C20H19F3N5O2: 392.13, found: 393.1 [M+H]+. Stereochemistry is arbitrarily assigned. The two enantiomers were carried separately in the following steps. (2S)-2-(4-Aminophenyl)-4-(4-methoxybenzyl)-5-methyl-2-(trifluoromethyl)morpholin-3- one FoleyHoagUS12952954.4 GPX-01525 A 100 mL round bottom flask was purged with N2(3x). It was then charged with a suspension of Raney-Ni (611.4 mg, 7.14 mmol) in THF (10 mL), followed by a solution of (S)- 2-(4-aminophenyl)-4-(4-methoxybenzyl)-5-methylene-2-(trifluoromethyl)morpholin-3-one (1.4 g, 3.57 mmol, one of the enantiomers above) in THF (2 mL). The resulting suspension was degassed and purged with H2(3x). It was allowed to stir at 25 °C for 12 h under H2(50 psi). Upon completion, the reaction was filtered through a celite pad. The filtrate was concentrated under reduced pressure to afford the title compound (1.2 g, 85.3%) as a white solid, which was directly used in the next step without further purification. MS (ESI): mass calcd. for C20H21F3N2O3: 394.15, found: 395.0 [M+H]+. Only one stereoisomer was observed after hydrogenation and stereochemistry was arbitrarily assigned. 1-(4-Fluorophenyl)-3-(6-((2S)-4-(4-methoxybenzyl)-5-methyl-3-oxo-2- (trifluoromethyl)morpholin-2-yl)benzo[d]thiazol-2-yl)urea The title compound was synthesized from (2S)-2-(4-aminophenyl)-4-[(4- methoxyphenyl)methyl]-5-methyl-2-(trifluoromethyl)morpholin-3-one in similar procedures as described in Example 129 and 130. MS (ESI): mass calcd. for C28H24F4N4O4S: 588.15, found: 589.1 [M+H]+. 1-(4-Fluorophenyl)-3-(6-((2S)-5-methyl-3-oxo-2-(trifluoromethyl)morpholin-2- yl)benzo[d]thiazol-2-yl)urea (5) To a solution of 1-(4-fluorophenyl)-3-(6-((2S)-4-(4-methoxybenzyl)-5-methyl-3-oxo- 2-(trifluoromethyl)morpholin-2-yl)benzo[d]thiazol-2-yl)urea (0.1 g, 0.17 mmol) in TFA (3 FoleyHoagUS12952954.4 GPX-01525 mL) was added H2SO4(0.1 mL). It was then allowed to stir at 60 °C for 4 h. Upon completion, the reaction was adjusted to pH = 7 with aqueous NaHCO3. The resulting solution was further diluted with H2O (10 mL) and extracted with EtOAc (10 mL x 3). The combined organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated. The crude was purified by reverse phase HPLC (gradient elution, 35-65% ACN in H2O, with 10 mM NH4HCO3as a modifier) to obtain the title compound (5) (28.4 mg, 36%) as a white solid. MS (ESI): mass calcd. for C20H16F4N4O3S: 468.09, found: 469.1 [M+H]+.1H NMR (400 MHz, DMSO-d6) ppm 10.86 (s, 1H), 9.29 (d, J = 5.6 Hz, 1H), 8.75 (d, J = 2.4 Hz, 1H), 8.25 (s, 1H), 7.71 - 7.78 (m, 2H), 7.52 - 7.56 (m, 2H), 7.17 (d, J = 8.8 Hz, 2H), 3.73 - 3.81 (m, 2H), 3.43 - 3.46 (m, 1H), 1.24 (d, J = 6.4 Hz, 3H). Stereochemistry is arbitrarily assigned. Example 4 was synthesized from (R)-2-(4-aminophenyl)-4-(4-methoxybenzyl)-5- methylene-2-(trifluoromethyl)morpholin-3-one in the same procedures as described in Example 5. Examples 6 and 7 were also synthesized in similar procedures as described in the above Example 5. Stereochemistry was arbitrarily assigned. Example 8. (S)-1-(6-(3-Cyclopropyl-2,4-dioxo-5-(trifluoromethyl)oxazolidin-5- yl)benzo[d]thiazol-2-yl)-3-(4-fluorophenyl)urea (8) 1-Fluoro-4-isocyanatobenzene FoleyHoagUS12952954.4 GPX-01525 To a solution of 4-fluoroaniline (173 L, 1.8 mmol) in ACN (10 mL) was added bis(trichloromethyl) carbonate (213.7 mg, 0.72 mmol). After heating at 75 °C for 30 min, the reaction solvent was removed under reduced pressure to afford the title compound (165.5 mg) as a crude product, which was used directly in the next step without further purification. (S)-1-(6-(3-Cyclopropyl-2,4-dioxo-5-(trifluoromethyl)oxazolidin-5-yl)benzo[d]thiazol-2- yl)-3-(4-Fluorophenyl)urea To a solution of (2S)-2-(2-amino-1,3-benzothiazol-6-yl)-N-cyclopropyl-3,3,3-trifluoro- 2-hydroxy-propanamide (200 mg, 0.60 mmol) in ACN (3 mL) was added TEA (1.68 mL, 12.1 mmol) and 1-fluoro-4-isocyanato-benzene (165.5 mg, crude). After stirring at rt for 12 h, the reaction was filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by reverse phase HPLC (gradient elution, 45-75% ACN in H2O, with 10 mM NH4HCO3 as a modifier) to afford the title compound (8) (53 mg, 8.9%) as a yellow solid. MS (ESI): mass calcd. for C21H14F4N4O4S: 494.07, found: 495.1 [M+H]+.1H NMR (400 MHz, DMSO-d6) ppm 11.01 (s, 1H), 9.27 (s, 1H), 8.31 (s, 1H), 7.73 - 7.79 (m, 2H), 7.52 - 7.56 (m, 2H), 7.18 (t, J = 8.8 Hz, 2H), 2.81 - 2.87 (m, 1H), 0.84 - 0.97 (m, 4H). Reference compounds A and B. (R)-1-(4-fluorophenyl)-3-(6-(2,2,2-trifluoro-1-hydroxy- 1-(5-methyl-1H-imidazol-2-yl)ethyl)benzo[d]thiazol-2-yl)urea (A) & (S)-1-(4- fluorophenyl)-3-(6-(2,2,2-trifluoro-1-hydroxy-1-(5-methyl-1H-imidazol-2- yl)ethyl)benzo[d]thiazol-2-yl)urea (B) FoleyHoagUS12952954.4 GPX-01525 Synthetic scheme: 5-Methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole To a solution of 5-methyl-1H-imidazole (4.5 g, 54.81 mmol) in THF (50 mL) was added 60% NaH (4.38 g, 109.6 mmol) at –70 °C under N2. After stirring at this temperature for 30 min, SEMCl (9.7 mL, 54.8 mmol) was added dropwise. The reaction was stirred for 2 h, quenched with sat. NH4Cl (100 mL) and extracted with EtOAc (100 mL x 3). The combined organic layer was washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to afford the title product (8 g, crude) as a yellow oil, which was directly used in the next step without further purification. 1-(4-Bromophenyl)-2,2,2-trifluoro-1-(5-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H- imidazol-2-yl)ethan-1-ol FoleyHoagUS12952954.4 GPX-01525 n-BuLi (1.88 mL, 4.7 mmol, 2.5 M) was added to a solution of trimethyl-[2-[(5- methylimidazol-1-yl)methoxy]ethyl]silane (0.5 g, 2.35 mmol) in THF (5 mL) dropwise at – 78 °C under N2. After 30 min, a solution of 1-(4-bromophenyl)-2,2,2-trifluoro-ethanone (0.54 mL, 3.5 mmol) in THF (5 mL) was added. The reaction was allowed to stir at –78 °C for an additional 2 h. After completion, the reaction was poured into water (10 mL) and extracted with EtOAc (10 mL x 3). The combined organic layer was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated. The crude residue was purified by silica gel column chromatography (0-100% EtOAc / PE) to afford the title product (0.6 g, 54.8%) as a yellow oil. MS (ESI): mass calcd. for C18H24BrF3N2O2Si: 464.07, found: 465.2 [M+H]+. 1-(4-Aminophenyl)-2,2,2-trifluoro-1-(5-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H- imidazol-2-yl)ethan-1-ol To a mixture of 1-(4-bromophenyl)-2,2,2-trifluoro-1-[5-methyl-1-(2- trimethylsilylethoxymethyl)imidazol-2-yl]ethanol (0.6 g, 1.3 mmol) in EtOH (10 mL) and H2O (2 mL) was added CuSO4(205.8 mg, 1.29 mmol), N1,N2-dimethylcyclohexane-1,2- diamine (110 mg, 0.77 mmol), sodium ascorbate (510.8 mg, 2.6 mmol) and NaN3(0.13 g, 2 mmol) at 25 °C under N2. After heating at 80 °C for 12 h, the reaction was poured into ice- water (10 mL), adjusted to pH = 9-10 by Na2CO3and extracted with EtOAc (10 mL x 3). The combined organic layer was washed with brine, dried with anhydrous Na2SO4, filtered and concentrated. The crude residue was purified by silica gel column chromatography (PE : EtOAc = 1 : 0 to 0 : 1) to provide the title compound (0.15 g, 29%) as a yellow solid. MS (ESI): mass calcd. for C18H26F3N3O2Si: 401.17, found: 402.3 [M+H]+. 1-(2-Aminobenzo[d]thiazol-6-yl)-2,2,2-trifluoro-1-(5-methyl-1-((2-(trimethylsilyl)ethoxy) methyl)-1H-imidazol-2-yl)ethan-1-ol FoleyHoagUS12952954.4 GPX-01525 To a solution of 1-(4-aminophenyl)-2,2,2-trifluoro-1-[5-methyl-1-(2- trimethylsilylethoxymethyl)imidazol-2-yl]ethanol (0.133 g, 0.33 mmol) in AcOH (1 mL) was added KSCN (112.7 mg, 1.16 mmol) at 25 °C. After stirring at this temperature for 1 h, Br2(58.2 mg, 0.36 mmol) was added. The resulting mixture was stirred for another 3 h, quenched with saturated NaHCO3(3 mL) and extracted with EtOAc (3 mL x 3). The combined organic layer was washed with brine, dried with anhydrous Na2SO4, filtered and concentrated. The crude residue was purified by prep-TLC (PE : EtOAc = 1 : 1) to afford the title compound (0.097 g, with impurity) as a yellow oil. MS (ESI): mass calcd. for C19H25F3N4O2SSi: 458.14, found: 459.2 [M+H]+. 1-(4-Fluorophenyl)-3-(6-(2,2,2-trifluoro-1-hydroxy-1-(5-methyl-1-((2- (trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)ethyl)benzo[d]thiazol-2-yl)urea To a mixture of 1-(2-aminobenzo[d]thiazol-6-yl)-2,2,2-trifluoro-1-(5-methyl-1-((2- (trimethylsilyl)ethoxy) methyl)-1H-imidazol-2-yl)ethan-1-ol (0.097 g, 0.21 mmol) in DMF (1 mL) was added 1-fluoro-4-isocyanatobenzene (34.8 mg, 0.25 mmol) at 0 °C under N2. After stirring at 25 °C for 4 h, the reaction was quenched with water (3 mL) and extracted with EtOAc (3 mL x 3). The combined organic layer was washed with brine, dried with anhydrous Na2SO4, filtered and concentrated. The crude residue was purified by prep-TLC (PE : Ethyl acetate = 1 : 1) to provide the title compound (0.074 g, with impurity) as a yellow powder. MS (ESI): mass calcd. for C26H29F4N5O3SSi: 595.17, found: 596.3 [M+H]+. 1-(4-Fluorophenyl)-3-(6-(2,2,2-trifluoro-1-hydroxy-1-(5-methyl-1H-imidazol-2- yl)ethyl)benzo[d]thiazol-2-yl)urea A mixture of 1-(4-fluorophenyl)-3-(6-(2,2,2-trifluoro-1-hydroxy-1-(5-methyl-1-((2- (trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)ethyl)benzo[d]thiazol-2-yl)urea (0.074 g, 0.12 mmol) in TFA (2 mL) and water (0.4 mL) was stirred at 25-40 °C for 6 h. The reaction was poured into saturated NaHCO3 (5 mL) and extracted with EtOAc (3 mL x 3). The FoleyHoagUS12952954.4 GPX-01525 combined organic layer was washed with brine, dried with anhydrous Na2SO4, filtered and concentrated. The crude product was purified by reversed-phase HPLC (mobile phase: H2O (10 mM NH4HCO3)-ACN; gradient: 30-50% B) to provide the title compound (8.7 mg, racemic) as a white solid. MS (ESI): mass calcd. for C20H15F4N5O2S: 465.09, found: 466.1 [M+H]+.1H NMR (400 MHz, DMSO-d6) ppm 11.76 - 11.89 (m, 1H), 10.86 (s, 1H), 9.17 - 9.30 (m, 1H), 8.15 (s, 1H), 7.53 - 7.65 (m, 5H), 7.17 (t, J = 8.4 Hz, 2H), 6.62 - 6.80 (m, 1H), 2.13 (d, J = 5.2 Hz, 3H). (R)-1-(4-fluorophenyl)-3-(6-(2,2,2-trifluoro-1-hydroxy-1-(5-methyl-1H-imidazol-2- yl)ethyl)benzo[d]thiazol-2-yl)urea (A) & (S)-1-(4-fluorophenyl)-3-(6-(2,2,2-trifluoro-1- hydroxy-1-(5-methyl-1H-imidazol-2-yl)ethyl)benzo[d]thiazol-2-yl)urea (B) 1-(4-Fluorophenyl)-3-(6-(2,2,2-trifluoro-1-hydroxy-1-(5-methyl-1H-imidazol-2- yl)ethyl)benzo[d]thiazol-2-yl)urea (0.1 g, 215 mol) was separated by chiral SFC (column: ChiralPak IH, (250 mm*30 mm, 10 um); mobile phase: CO2-IPA; 40% B with isocratic elution) to give the title compound (A) (16.8 mg, 17%) as a white solid. MS (ESI): mass calcd. for C20H15F4N5O2S: 465.09, found: 466.1 [M+H]+.1H NMR (400 MHz, DMSO-d6) ppm 11.71- 11.89 (m, 1H), 10.91 (s, 1H), 9.23 (s, 1H), 8.13 (s, 1H), 7.51-7.64 (m, 5H), 7.17 (t, J = 8.8 Hz, 2H), 6.60-6.82 (m, 1H), 2.13 (d, J = 4.4 Hz, 3H). And the title compound (B) (28.8 mg, 29%) as a white solid. MS (ESI): mass calcd. for C20H15F4N5O2S: 465.09, found: 466.1 [M+H]+.1H NMR (400 MHz, DMSO-d6) ppm 11.71-11.89 (m, 1H), 10.96 (s, 1H), 9.24 (s, 1H), 8.13 (s, 1H), 7.50-7.65 (m, 5H), 7.16 (t, J = 8.8 Hz, 2H), 6.60-6.82 (m, 1H), 2.13 (d, J = 4.4 Hz, 3H). The following compounds were synthesized in similar procedures as described in Reference compounds A and B. Examples 24, and 25 were made starting from pyridazine, no SEM protection was needed. Examples 142, 147 and 148 were made starting from pyrimidine. Example 27. (S)-N-ethyl-3,3,3-trifluoro-2-(2-(3-(4-fluorophenyl)-2-oxoimidazolidin-1- yl)benzo[d]thiazol-6-yl)-2-hydroxypropanamide (27) FoleyHoagUS12952954.4 GPX-01525 Synthetic scheme: (S)-2-(2-Chlorobenzo[d]thiazol-6-yl)-N-ethyl-3,3,3-trifluoro-2-hydroxypropanamide To a solution of CuCl2 (1.01 g, 7.52 mmol) in ACN (20 mL) was added t-BuONO (775.09 mg, 7.52 mmol). The mixture was stirred at 40 °C for 10 min. Then a solution of ethyl (S)-2-(2-aminobenzo[d]thiazol-6-yl)-3,3,3-trifluoro-2-hydroxypropanoate (2 g, 6.26 mmol, see Example 163 for synthesis) in ACN (4 mL) was added dropwise. After heating at 40 °C for 2 h, the reaction was filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (gradient elution, 10-17% EtOAc in PE) to afford the title compound (1.4 g, 66%) as a white solid.1H NMR (400 MHz, DMSO- d6) ppm 8.43 (d, J = 1.2 Hz, 1H), 8.28 (t, J = 5.6 Hz, 1H), 7.95-8.04 (m, 2H), 7.81-7.84 (m, 1H), 3.10-3.14 (m, 2H), 0.99 (t, J = 7.2 Hz, 3H). 1-(2-Chloroethyl)-3-(4-fluorophenyl)urea FoleyHoagUS12952954.4 GPX-01525 To a solution of 4-fluoroaniline (500 mg, 4.50 mmol) in DCM (5 mL) was added 1- chloro-2-isocyanato-ethane (712.2 mg, 6.75 mmol) at 0 °C. The mixture was stirred at 20 °C. After 16 h, the reaction was filtered and washed with DCM (20 mL). The filter cake was dried over vacuum to afford the title compound (0.9 g, 92%) as a white solid.1H NMR (400 MHz, DMSO-d6) ppm 8.66 (s, 1H), 7.32-7.47 (m, 2H), 6.96-7.15 (m, 2H), 6.37 (t, J = 6.0 Hz, 1H), 3.65 (t, J = 6.0 Hz, 2H), 3.38-3.43 (m, 2H). 1-(4-Fluorophenyl)imidazolidin-2-one To a solution of 1-(2-chloroethyl)-3-(4-fluorophenyl)urea (0.9 g, 4.15 mmol) in THF (9 mL) was added 60% NaH (182.77 mg, 4.57 mmol). After stirring at 20 °C for 16 h, the reaction was quenched with sat. NH4Cl (30 mL). The aqueous layer was extracted with EtOAc (20 mL x 2). The combined organic layer was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure to obtain the desired product (700 mg, 94%) as a white solid.1H NMR (400 MHz, DMSO-d6) ppm 7.47-7.63 (m, 2H), 7.06-7.20 (m, 2H), 6.94 (s, 1H), 3.80-3.84 (m, 2H), 3.39 (t, J = 8.0 Hz, 2H). (S)-N-Ethyl-3,3,3-trifluoro-2-(2-(3-(4-fluorophenyl)-2-oxoimidazolidin-1- yl)benzo[d]thiazol-6-yl)-2-hydroxypropanamide To a solution of (S)-2-(2-chlorobenzo[d]thiazol-6-yl)-N-ethyl-3,3,3-trifluoro-2- hydroxypropanamide (200 mg, 590 mol) and 1-(4-fluorophenyl)imidazolidin-2-one (117 mg, 650 mol) in dioxane (2 mL) was added Cs2CO3(577.13 mg, 1.77 mmol), XPhos (56.29 mg, 118.1 mol) and Pd(OAc)2(13.26 mg, 59 mol). The mixture was heated at 100 °C for 16 h. After completion, the reaction was quenched with water (10 mL). The aqueous layer was extracted with EtOAc (20 mL x 2). The combined organic layer was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The resulting residue was purified by reverse phase HPLC (gradient elution, 30-60% ACN / H2O, with 10 mM NH4HCO3FoleyHoagUS12952954.4 GPX-01525 as a modifier) to afford the title compound (27) (46 mg, 16%) as a white solid. MS (ESI): mass calcd. for C21H18F4N4O3S: 482.10, found: 483.1 [M+H]+.1H NMR (400 MHz, DMSO-d6) ppm 8.20-8.26 (m, 2H), 7.75-7.80 (m, 2H), 7.66-7.73 (m, 3H), 7.24-7.32 (m, 2H), 4.22-4.31 (m, 2H), 4.08-4.17 (m, 2H), 3.08-3.18 (m, 2H), 1.00 (t, J = 7.2 Hz, 3H). Example 29. (S)-3,3,3-trifluoro-2-(2-(3-(4-fluorophenyl)ureido)benzo[d]thiazol-6-yl)-2- hydroxy-N-((S)-2-oxoazetidin-3-yl)propanamide (29) Ethyl (S)-3,3,3-trifluoro-2-(2-(3-(4-fluorophenyl)ureido)benzo[d]thiazol-6-yl)-2- hydroxypropanoate To a solution of ethyl (S)-2-(2-aminobenzo[d]thiazol-6-yl)-3,3,3-trifluoro-2- hydroxypropanoate (20 g, 62.44 mmol, see Example 163 for synthesis) in DMF (200 mL) was added 1-fluoro-4-isocyanato-benzene (8.39 mL, 74.9 mmol). After stirring at 25 °C for 12 h, the reaction was quenched with saturated NH4Cl (500 mL). The aqueous layer was extracted with EtOAc (200 mL x 3). The combined organic layer was washed with brine, dried over FoleyHoagUS12952954.4 GPX-01525 Na2SO4, filtered and concentrated under reduced pressure. The resulting residue was purified by reverse phase HPLC (gradient elution, 40-70% ACN in H2O with 0.1% TFA as a modifier) to give the title compound (28 g, 98%) as a yellow solid. MS (ESI): mass calcd. for C19H15F4N3O4S: 457.07, found: 458.0 [M+H]+. (S)-3,3,3-Trifluoro-2-(2-(3-(4-fluorophenyl)ureido)benzo[d]thiazol-6-yl)-2- hydroxypropanoic acid To a solution of ethyl (S)-3,3,3-trifluoro-2-(2-(3-(4- fluorophenyl)ureido)benzo[d]thiazol-6-yl)-2-hydroxypropanoate (24 g, 52.5 mmol) in THF (200 mL) and H2O (40 mL) was added LiOH.H2O (5.03 g, 209.88 mmol). It was stirred at 25 °C for 12 h. Upon completion, the reaction was adjusted to pH = 5 by 1 N HCl. The aqueous layer was extracted with EtOAc (250 mL × 3). The combined organic layer was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure to afford the title compound as a crude product (22 g, 97.6%) as a yellow solid. MS (ESI): mass calcd. for C17H11F4N3O4S: 429.04, found: 430.0 [M+H]+. (S)-3,3,3-trifluoro-2-(2-(3-(4-fluorophenyl)ureido)benzo[d]thiazol-6-yl)-2-hydroxy-N- ((S)-2-oxoazetidin-3-yl)propanamide (29) To a solution of (S)-3,3,3-trifluoro-2-(2-(3-(4-fluorophenyl)ureido)benzo[d]thiazol-6- yl)-2-hydroxypropanoic acid (30 mg, 0.07 mmol) in DMF (0.35 mL) was added DIPEA (61 L, 0.35 mmol) and HATU (80 mg, 0.21 mmol) at 0 °C. Then (S)-3-aminoazetidin-2-one hydrogen chloride (12.8 mg, 0.11 mmol) was added. After stirring at 20 °C for 1 h, the reaction was quenched with H2O and extracted with EtOAc (3x). The combined organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purfied by reverse phase HPLC (gradient elution, 20-60% ACN / H2O, with 0.1% TFA as a modifier) to afford the title compound (29) (10.3 mg, 30%) as a white solid. MS (ESI): mass calcd. for C20H15F4N5O4S: 497.08, found: 498.1 [M+H]+.1H NMR FoleyHoagUS12952954.4 GPX-01525 (400 MHz; DMSO-d6) ppm 10.90 (br s, 1H), 9.22 (s, 1H), 8.85 (d, J = 8.5 Hz, 1H), 8.14 (s, 1H), 7.96 (s, 2H), 7.65 (s, 2H), 7.52 - 7.56 (m, 2H), 7.17 (t, J = 8.9 Hz, 2H), 4.77 - 4-81 (m, 1H), 3.46 (m, 1H), 3.17 (dd, J = 4.9, 2.8 Hz, 1H). Examples 23, 28, 32, 33, 34, 38, 39, 40, 41, 42, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 60, 62, 65, 74, and 80 were synthesized in similar procedures as described in Example 29. Example 30 and 31. (R)-N-ethyl-3,3,3-trifluoro-2-(2-(3-(4-fluorophenyl)ureido)-4- hydroxybenzo[d]thiazol-6-yl)-2-hydroxypropanamide (30) & (S)-N-ethyl-3,3,3-trifluoro- 2-(2-(3-(4-fluorophenyl)ureido)-4-hydroxybenzo[d]thiazol-6-yl)-2-hydroxypropanamide (31) FoleyHoagUS12952954.4 GPX-01525 Ethyl 2-(4-((tert-butoxycarbonyl)amino)-3-methoxyphenyl)-3,3,3-trifluoro-2- hydroxypropanoate To an ice-cold solution of tert-butyl N-(4-bromo-2-methoxy-phenyl)carbamate (20 g, 66.2 mmol) in THF (200 mL) was added 60% NaH (2.91 g, 72.8 mmol). After stirring at rt for 0.5 h, the reaction was cooled to –78 °C, followed by dropwise addition of 1.3 M t-BuLi solution in pentane (101.8 mL, 132.4 mmol). After stirring at –78 °C for 0.5 h, ethyl 3,3,3- trifluoro-2-oxo-propanoate (13.16 mL, 99.3 mmol) was added and stirring was continued for an additional hour at the same temperature. The reaction was quenched with H2O (200 mL) and extracted with EtOAc (200 mL x 3). The combined organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated. The crude was purified by silica gel column chromatography (gradient elution, 0-100% EtOAc in PE) to afford the title compound (11 g, 42.3%) as a yellow oil. MS (ESI): mass calcd. for C17H22F3NO6: 393.14, found: 394.1 [M+H]+. Ethyl 2-(4-amino-3-methoxyphenyl)-3,3,3-trifluoro-2-hydroxypropanoate Ethyl 2-(4-((tert-butoxycarbonyl)amino)-3-methoxyphenyl)-3,3,3-trifluoro-2- hydroxypropanoate (10 g, 25.4 mmol) was dissolved in a solution of DCM (80 mL) and TFA (16 mL). After stirring at 20 °C for 12 h, the reaction was poured into ice water (100 mL), adjusted to pH = 8 with Na2CO3and extracted with DCM (100 mL x 2). The combined organic layer was dried over Na2SO4, filtered, and concentrated. The crude was purified by silica gel column chromatography (gradient elution, 0-100% EtOAc in PE) to provide the title compound (7.5 g, with impurities) as a white solid. MS (ESI): mass calcd. for C12H14F3NO4: 293.09, found: 294.1 [M+H]+. 2-(2-Amino-4-methoxybenzo[d]thiazol-6-yl)-N-ethyl-3,3,3-trifluoro-2- hydroxypropanamide FoleyHoagUS12952954.4 GPX-01525 The title compound was synthesized from ethyl 2-(4-amino-3-methoxy-phenyl)-3,3,3- trifluoro-2-hydroxy-propanoate in similar procedures as described in Example 61. MS (ESI): mass calcd. for C13H14F3N3O3S: 349.07, found: 350.1 [M+H]+. 2-(2-Amino-4-hydroxybenzo[d]thiazol-6-yl)-N-ethyl-3,3,3-trifluoro-2- hydroxypropanamide To a solution of 2-(2-amino-4-methoxybenzo[d]thiazol-6-yl)-N-ethyl-3,3,3-trifluoro-2- hydroxypropanamide (2.1 g, 6.0 mmol) in DCM (20 mL) was added BBr3(9.04 g, 36.1 mmol). After stirring at 20 °C for 12 h, the reaction was poured into water (50 mL), adjusted to pH = 8 with Na2CO3 and extracted with EtOAc (50 mL x 3). The combined organic layer was dried over Na2SO4, filtered, and concentrated. The crude was purified by silica gel column chromatography (gradient elution, 0-100% EtOAc in PE) to provide the title compound (1.45 g, 71.9%) as a yellow solid. MS (ESI): mass calcd. for C12H12F3N3O4S: 335.06, found: 336.0 [M+H]+. N-Ethyl-3,3,3-trifluoro-2-(2-(3-(4-fluorophenyl)ureido)-4-hydroxybenzo[d]thiazol-6-yl)- 2-hydroxypropanamide To an ice-cold solution of 2-(2-amino-4-hydroxy-1,3-benzothiazol-6-yl)-N-ethyl-3,3,3- trifluoro-2-hydroxy-propanamide (1.4 g, 4.18 mmol) in DMF (14 mL) was added 1-fluoro-4- isocyanato-benzene (1.03 mL, 9.19 mmol) and warmed to rt. After stirring for 12 h, the reaction was washed with H2O (42 mL) and extracted with EtOAc (42 mL x 3). The combined organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated. The crude was purified by reverse phase HPLC (gradient elution, 28-58% ACN / H2O, with 10 mM FoleyHoagUS12952954.4 GPX-01525 NH4HCO3as a modifier) to afford the title compound (744 mg, 38%, racemic) as a white solid. MS (ESI): mass calcd. for C19H16F4N4O4S: 472.08, found: 473.1 [M+H]+.1H NMR (400 MHz, DMSO-d6) ppm 10.82 (s, 1H), 9.92 (s, 1H), 9.27 (s, 1H), 8.16 (t, J = 6.0 Hz, 1H), 7.65 (s, 1H), 7.48 - 7.60 (m, 3H), 7.14 - 7.22 (m, 3H), 3.07 - 3.18 (m, 2H), 1.00 (t, J = 7.2 Hz, 3H). (R)-N-ethyl-3,3,3-trifluoro-2-(2-(3-(4-fluorophenyl)ureido)-4-hydroxybenzo[d]thiazol-6- yl)-2-hydroxypropanamide (30) & (S)-N-ethyl-3,3,3-trifluoro-2-(2-(3-(4- fluorophenyl)ureido)-4-hydroxybenzo[d]thiazol-6-yl)-2-hydroxypropanamide (31) N-Ethyl-3,3,3-trifluoro-2-(2-(3-(4-fluorophenyl)ureido)-4-hydroxybenzo[d]thiazol-6- yl)-2-hydroxypropanamide was separated by chiral SFC (column: DAICEL CHIRALPAK AD (250 mm*30 mm, 10 um); mobile phase: CO2-IPA; 40% B with isocratic elution) to provide the title compound (30) as a white solid. MS (ESI): mass calcd. C19H16F4N4O4S: 472.08, found: 473.1 [M+H]+.1H NMR (400 MHz, DMSO-d6) ppm 10.85 (s, 1H), 9.94 (s, 1H), 9.26 (s, 1H), 8.17 (t, J = 5.6 Hz, 1H), 7.65 (s, 1H), 7.57 (s, 1H), 7.51-7.55 (m, 2H), 7.17 (d, J = 8.8 Hz, 3H), 3.08-3.16 (m, 2H), 0.99 (t, J = 7.2 Hz, 3H). And to provide the title compound (31). MS (ESI): mass calcd. for C19H16F4N4O4S: 472.08, found: 473.1 [M+H]+.1H NMR (400 MHz, DMSO-d6) ppm 10.80 (s, 1H), 9.92 (s, 1H), 9.25 (s, 1H), 8.17 (t, J = 6.0 Hz, 1H), 7.66 (s, 1H), 7.58 (s, 1H), 7.52 (s, 2H), 7.17 (t, J = 8.8 Hz, 3H), 3.08-3.16 (m, 2H), 0.99 (t, J = 7.2 Hz, 3H). Stereochemistry was arbitrarily assigned. Example 86 was synthesized from 6-bromo-2-methoxypyridin-3-amine in the same procedures as described in Example 30 and 31. Example 36 and 37. (R)-6-(3-(ethylamino)-1,1,1-trifluoro-2-hydroxy-3-oxopropan-2-yl)- 2-(3-(4-fluorophenyl)ureido)benzo[d]thiazol-4-yl methylcarbamate (36) & (S)-6-(3- (ethylamino)-1,1,1-trifluoro-2-hydroxy-3-oxopropan-2-yl)-2-(3-(4- fluorophenyl)ureido)benzo[d]thiazol-4-yl methylcarbamate (37) FoleyHoagUS12952954.4 GPX-01525 6-(3-(Ethylamino)-1,1,1-trifluoro-2-hydroxy-3-oxopropan-2-yl)-2-(3-(4- fluorophenyl)ureido)benzo[d]thiazol-4-yl methylcarbamate (35) To a solution of N-ethyl-3,3,3-trifluoro-2-[2-[(4-fluorophenyl)carbamoylamino]-4- hydroxy-1,3-benzothiazol-6-yl]-2-hydroxy-propanamide (75 mg, 159 mol, from Example 30 and 31) in DCM (2 mL) was added TEA (19.28 mg, 191 mol) and N-methylcarbamoyl chloride (17.82 mg, 191 mol). The mixture was stirred at 25 °C for 12 h. After completion, the reaction was diluted with H2O (6 mL). The aqueous layer was extracted with EtOAc (6 mL x 3). The combined organic layer was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The resulting residue was purified by reverse phase HPLC (gradient elution, 30-60% ACN / H2O, with 0.2% FA as a modifier) to afford the desired product (35) (46 mg, 55%) as a white solid. MS (ESI): mass calcd. for C21H19F4N5O5S: 529.1, found: 530.1 [M+H]+.1H NMR (400 MHz, DMSO-d6) ppm 11.29 (s, 1H), 9.00 (s, 1H), 8.28 (t, J = 5.6 Hz, 1H), 8.07 (s, 1H), 7.87 (s, 1H), 7.73-7.80 (m, 1H), 7.49-7.53 (m, 2H), 7.38 (s, 1H), 7.18 (t, J = 8.8 Hz, 2H), 3.08-3.17 (m, 2H), 2.69 (d, J = 4.4 Hz, 3H), 0.99 (t, J = 7.2 Hz, FoleyHoagUS12952954.4 GPX-01525 3H). (R)-6-(3-(ethylamino)-1,1,1-trifluoro-2-hydroxy-3-oxopropan-2-yl)-2-(3-(4- fluorophenyl)ureido)benzo[d]thiazol-4-yl methylcarbamate (36) & (S)-6-(3-(ethylamino)- 1,1,1-trifluoro-2-hydroxy-3-oxopropan-2-yl)-2-(3-(4- fluorophenyl)ureido)benzo[d]thiazol-4-yl methylcarbamate (37) Example 35 was separated by chiral SFC (column: DAICEL CHIRALPAK AD (250 mm*30 mm, 10 um); mobile phase: 40% EtOH, isocratic elution) to provide the title compound (36) as a white solid. MS (ESI): mass calcd. C21H19F4N5O5S: 529.1, found: 530.1 [M+H]+.1H NMR (400 MHz, DMSO-d6) ppm 11.32 (s, 1H), 9.01 (s, 1H), 8.27 (t, J = 6.0 Hz, 1H), 8.04 (s, 1H), 7.85 (s, 1H), 7.73-7.80 (m, 1H), 7.50-7.54 (m, 2H), 7.36 (s, 1H), 7.17 (t, J = 8.8 Hz, 2H), 3.08-3.16 (m, 2H), 2.69 (d, J = 4.4 Hz, 3H), 0.99 (t, J = 7.2 Hz, 3H). And to provide the title compound (37). MS (ESI): mass calcd. for C21H19F4N5O5S: 529.1, found: 530.1 [M+H]+.1H NMR (400 MHz, DMSO-d6) ppm 11.28 (s, 1H), 8.98 (s, 1H), 8.27 (t, J = 6.0 Hz, 1H), 8.04 (s, 1H), 7.85 (s, 1H), 7.73-7.78 (m, 1H), 7.50-7.53 (m, 2H), 7.36 (s, 1H), 7.17 (t, J = 8.8 Hz, 2H), 3.08-3.16 (m, 2H), 2.69 (d, J = 4.4 Hz, 3H), 0.99 (t, J = 7.2 Hz, 3H). Stereochemistry was arbitrarily assigned. Example 58 and 59. (R)-N-ethyl-3,3,3-trifluoro-2-(2-(3-(4-fluorophenyl)ureido)-4- ((tetrahydro-2H-pyran-4-yl)oxy)benzo[d]thiazol-6-yl)-2-hydroxypropanamide (58) & (S)-N-Ethyl-3,3,3-trifluoro-2-(2-(3-(4-fluorophenyl)ureido)-4-((tetrahydro-2H-pyran-4- yl)oxy)benzo[d]thiazol-6-yl)-2-hydroxypropanamide (59) FoleyHoagUS12952954.4 GPX-01525 N-Ethyl-3,3,3-trifluoro-2-(2-(3-(4-fluorophenyl)ureido)-4-((tetrahydro-2H-pyran-4- yl)oxy)benzo[d]thiazol-6-yl)-2-hydroxypropanamide (43) To a solution of N-ethyl-3,3,3-trifluoro-2-[2-[(4-fluorophenyl)carbamoylamino]-4- hydroxy-1,3-benzothiazol-6-yl]-2-hydroxy-propanamide (0.1 g, 211.68 mol, from Example 30 and 31) in DMF (3 mL) was added K2CO3(58.51 mg, 423 mol) and 4-iodotetrahydropyran (89.76 mg, 423 mol). The reaction suspension was stirred at 30 °C. After 12 h, another portion of K2CO3(58.5 mg, 423 mol) and 4-iodotetrahydropyran (107.72 mg, 508 mol) were FoleyHoagUS12952954.4 GPX-01525 added. After stirring for an additional 12 h, the reaction was diluted with H2O (15 mL). The aqueous layer was extracted with EtOAc (15 mL x 3). The combined organic layer was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The resulting residue was purified by reverse phase HPLC (gradient elution, 35-65% ACN / H2O, with 10 mM NH4HCO3 as a modifier) to afford the title compound (Example 43) (1.8 mg, 2%) as a white solid. MS (ESI): mass calcd. for C24H24F4N4O5S: 556.14, found: 557.2 [M+H]+.1H NMR (400 MHz, DMSO-d6) ppm 11.00 (s, 1H), 9.04 (s, 1H), 8.24 (t, J = 5.6 Hz, 1H), 7.76 (d, J = 10.0 Hz, 2H), 7.48-7.56 (m, 2H), 7.27 (s, 1H), 7.16 (t, J = 8.8 Hz, 2H), 4.68-4.81 (m, 1H), 3.87-3.97 (m, 2H), 3.44-3.51 (m, 2H), 3.08-3.16 (m, 2H), 1.95-2.04 (m, 2H), 1.60-1.72 (m, 2H), 0.99 (t, J = 7.2 Hz, 3H). (R)-N-ethyl-3,3,3-trifluoro-2-(2-(3-(4-fluorophenyl)ureido)-4-((tetrahydro-2H-pyran-4- yl)oxy)benzo[d]thiazol-6-yl)-2-hydroxypropanamide (58) & (S)-N-Ethyl-3,3,3-trifluoro- 2-(2-(3-(4-fluorophenyl)ureido)-4-((tetrahydro-2H-pyran-4-yl)oxy)benzo[d]thiazol-6-yl)- 2-hydroxypropanamide (59) Example 43 was separated by chiral SFC (column: DAICEL CHIRALPAK AD (250 mm*30 mm, 10 um); mobile phase: CO2-MeOH (0.1% NH3H2O); 35% B with isocratic elution) to provide the title compound (58) as a white solid. MS (ESI): mass calcd. for C24H24F4N4O5S: 556.14, found: 557.2 [M+H]+.1H NMR (400 MHz, DMSO-d6) ppm 11.17 (s, 1H), 9.05 (s, 1H), 8.24 (t, J = 6.0 Hz, 1H), 7.75-7.78 (m, 2H), 7.51-7.54 (m, 2H), 7.27 (s, 1H), 7.17 (t, J = 8.8 Hz, 2H), 4.74-4.77 (m, 1H), 3.87-3.92 (m, 2H), 3.45-3.51 (m, 2H), 3.10- 3.14 (m, 2H), 1.98-2.01 (m, 2H), 1.61-1.70 (m, 2H), 0.99 (t, J = 7.2 Hz, 3H). And to provide the title compound (59). MS (ESI): mass calcd. for C24H24F4N4O5S: 556.14, found: 557.2 [M+H]+.1H NMR (400 MHz, DMSO-d6) ppm 11.17 (s, 1H), 9.04 (s, 1H), 8.20-8.27 (m, 1H), 7.72-7.81 (m, 2H), 7.48-7.57 (m, 2H), 7.27 (s, 1H), 7.16 (t, J = 8.8 Hz, 2H), 4.69-4.81 (m, 1H), 3.85-3.95 (m, 2H), 3.45-3.51 (m, 2H), 3.07-3.17 (m, 2H), 1.94-2.05 (m, 2H), 1.58-1.73 (m, 2H), 0.92-1.05 (m, 3H). Stereochemistry was arbitrarily assigned. FoleyHoagUS12952954.4 GPX-01525 Example 61. (S)-N-((S)-2-(difluoromethoxy)propyl)-3,3,3-trifluoro-2-(2-(3-(4- fluorophenyl)ureido)benzo[d]thiazol-6-yl)-2-hydroxypropanamide (61) To a solution of tert-butyl N-[(2S)-2-hydroxypropyl]carbamate (1 g, 5.71 mmol) in DCM (17 mL) and H2O (17 mL) was added KHF2(2.67 g, 34.24 mmol) and (bromo(difluoro)methyl)-trimethyl-silane (5.8 g, 28.53 mmol) at 0 °C. The mixture was stirred at 15 °C for 16 h. Upon completion, the reaction was quenched with water (50 mL). The aqueous layer was extracted with DCM (30 mL x 2). The combined organic layer was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (2-10% PE / EtOAc) to afford the title compound (600 mg, 47%) as a colorless oil.1H NMR (400 MHz, CDCl3) ppm 6.00- 6.47 (m, 1H), 4.83 (s, 1H), 4.28-4.41 (m, 1H), 3.31-3.44 (m, 1H), 3.04-3.17 (m, 1H), 1.45 (s, 9H), 1.28 (d, J = 6.4 Hz, 3H). (S)-2-(Difluoromethoxy)propan-1-amine hydrogen chloride FoleyHoagUS12952954.4 GPX-01525 To a solution of tert-butyl (S)-(2-(difluoromethoxy)propyl)carbamate (500 mg, 2.22 mmol) in dioxane (0.2 mL) was added HCl / dioxane (4 M, 2.5 mL). It was allowed to stir at 20 °C for 2 h. Upon completion, the reaction was concentrated under reduced pressure to obtain the title compound (300 mg, 84%) as a white solid.1H NMR (400 MHz, DMSO-d6) ppm 8.22 (s, 3H), 6.58-6.96 (m, 1H), 4.41-4.56 (m, 1H), 2.95-3.04 (m, 1H), 2.85-2.94 (m, 1H), 1.26 (d, J = 6.4 Hz, 3H). (S)-N-((S)-2-(difluoromethoxy)propyl)-3,3,3-trifluoro-2-(2-(3-(4- fluorophenyl)ureido)benzo[d]thiazol-6-yl)-2-hydroxypropanamide (61) To a solution of (S)-3,3,3-trifluoro-2-(2-(3-(4-fluorophenyl)ureido)benzo[d]thiazol-6- yl)-2-hydroxypropanoic acid (100 mg, 232.91 mol, see Example 29 for synthesis) and (S)-2- (difluoromethoxy)propan-1-amine hydrogen chloride (48.9 mg, 303 mol) in DMF (1 mL) was added DIPEA (90.31 mg, 699 mol) and tripyrrolidin-1-yl(triazolo[4,5-b]pyridin-3- yloxy)phosphanium;hexafluorophosphate (133.6 mg, 256 mol). The mixture was stirred at 20 °C for 4 h. After completion, the reaction was quenched with water (10 mL). The aqueous layer was extracted with EtOAc (20 mL x 2). The combined organic layer was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The resulting residue was purified by reverse phase HPLC (gradient elution, 20-60% ACN / H2O, with 10 mM NH4HCO3as a modifier) to give the title compound (61) (62.6 mg, 50%) as a white solid. MS (ESI): mass calcd. for C21H18F6N4O4S: 536.09, found: 537.1 [M+H]+.1H NMR (400 MHz, DMSO-d6) ppm 10.88 (s, 1H), 9.21 (s, 1H), 8.30 (t, J = 6.0 Hz, 1H), 8.15 (s, 1H), 7.90 (s, 1H), 7.66 (s, 2H), 7.54 (s, 2H), 7.17 (t, J = 8.8 Hz, 2H), 6.59-6.40 (m, 1H), 4.24-4.35 (m, 1H), 3.18-3.30 (m, 2H), 1.12 (d, J = 6.0 Hz, 3H). Example 67 and 68. (S)-3,3,3-Trifluoro-2-(2-(3-(4-fluorophenyl)ureido)benzo[d]thiazol- 6-yl)-2-hydroxy-N-((1S,3R)-3-(oxazol-2-yl)cyclobutyl)propanamide (67) & (S)-3,3,3- FoleyHoagUS12952954.4 GPX-01525 trifluoro-2-(2-(3-(4-fluorophenyl)ureido)benzo[d]thiazol-6-yl)-2-hydroxy-N-((1R,3S)-3- (oxazol-2-yl)cyclobutyl)propanamide (68) tert-Butyl N-(3-oxazol-2-ylcyclobutyl)carbamate To a solution of tert-butyl N-(3-iodocyclobutyl)carbamate (0.2 g, 0.67 mmol) in DME (2 mL) was added bis[3,5-difluoro-2-[5-(trifluoromethyl)-2-pyridyl]phenyl]iridium(1+);4- tert-butyl-2-(4-tert-butyl-2-pyridyl)pyridine;hexafluorophosphate (7.6 mg, 6.7 mol), dichloronickel;1,2-dimethoxyethane (0.74 mg, 3.4 mol), Na2CO3(143 mg, 1.35 mmol), dtbbpy (0.90 mg, 3.4 mol), TTMSS (167.4 mg, 0.67 mmol) and 2-bromooxazole (149 mg, 1.01 mmol) at 25 °C. The reaction was stirred under 34 W blue LED at 25 °C for 12 h. The reaction mixture was diluted with H2O 15 mL and extracted with EtOAc 15 mL (5 mL x 3). The combined organic layer was washed with brine 15 mL (5 mL x 3), dried over Na2SO4, FoleyHoagUS12952954.4 GPX-01525 filtered and concentrated under reduced pressure. The residue was purified by reverse phase HPLC (H2O (0.2% FA)-ACN, gradient 25-60% elution) to provide the title compound (0.13 g, 81%) as a brown solid. MS (ESI): mass calcd. for C12H18N2O3: 238.13, found: 239.3 [M+H]+. 3-Oxazol-2-ylcyclobutanamine A solution of tert-butyl N-(3-oxazol-2-ylcyclobutyl)carbamate (0.13 g, 0.55 mmol) in HFIP (2 mL) and TFA (0.1 mL) was stirred at 25 °C for 12 h. The reaction was filtered and concentrated under reduced pressure to provide the title compound (0.2 g, crude, TFA salt) as a brown oil, which was used directly in the next step without further purification. MS (ESI): mass calcd. for C7H10N2O: 138.08, found: 139.3 [M+H]+. (S)-3,3,3-Trifluoro-2-(2-(3-(4-fluorophenyl)ureido)benzo[d]thiazol-6-yl)-2-hydroxy-N-(3- (oxazol-2-yl)cyclobutyl)propanamide To a solution of (S)-3,3,3-trifluoro-2-(2-(3-(4-fluorophenyl)ureido)benzo[d]thiazol-6- yl)-2-hydroxypropanoic acid (0.1 g, 0.23 mmol, see Example 29 for synthesis) in DMF (5 mL) was added DIPEA (150.5 mg, 1.16 mmol) and HATU (177 mg, 0.47 mmol) at 0 °C. After stirring at 25 °C for 15 min, 3-oxazol-2-ylcyclobutanamine (70.5 mg, crude, TFA salt) was added and the reaction was stirred at 25 °C for 2 h. The reaction was diluted with H2O (15 mL) and extracted with EtOAc (10 mL x 3). The combined organic layer was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by reverse phase HPLC (H2O (10 mM NH4HCO3)-ACN], gradient 30-60% elution) to provide the title compound (3.2 mg, 2.5%, diastereomeric mixture) as a white solid. MS (ESI): mass calcd. for C24H19F4N5O4S: 549.11, found: 550.1 [M+H]+.1H NMR (400 MHz, DMSO- d6) ppm 10.81 (s, 1H), 9.19 (s, 1H), 8.52 - 8.63 (m, 1H), 8.16 (s, 1H), 7.95 - 8.03 (m, 1H), 7.77 - 7.86 (m, 1H), 7.61 - 7.70 (m, 2H), 7.54 (d, J = 3.6 Hz, 2H), 7.17 (t, J = 8.8 Hz, 2H), 7.08 - 7.14 (m, 1H), 4.20 - 4.58 (m, 1H), 3.40 - 3.53 (m, 1H), 2.55 - 2.60 (m, 2H), 2.38 - 2.44 (m, 1H), 2.23 - 2.38 (m, 1H). FoleyHoagUS12952954.4 GPX-01525 (S)-3,3,3-Trifluoro-2-(2-(3-(4-fluorophenyl)ureido)benzo[d]thiazol-6-yl)-2-hydroxy-N- ((1S,3R)-3-(oxazol-2-yl)cyclobutyl)propanamide (67) & (S)-3,3,3-trifluoro-2-(2-(3-(4- fluorophenyl)ureido)benzo[d]thiazol-6-yl)-2-hydroxy-N-((1R,3S)-3-(oxazol-2- yl)cyclobutyl)propanamide (68) (S)-3,3,3-Trifluoro-2-(2-(3-(4-fluorophenyl)ureido)benzo[d]thiazol-6-yl)-2-hydroxy- N-(3-(oxazol-2-yl)cyclobutyl)propanamide was separated by chiral SFC (column: DAICEL CHIRALPAK AD (250 mm*30 mm, 10 um); mobile phase: CO2-IPA (0.1% NH3H2O); 50% B with isocratic elution) to provide the title compound (67). MS (ESI): mass calcd. for C24H19F4N5O4S: 549.11, found: 550.1 [M+H]+.1H NMR (400 MHz, DMSO-d6) ppm 11.07 (s, 1H), 9.26 (s, 1H), 8.54 (d, J = 7.6 Hz, 1H), 8.12 (s, 1H), 7.97 (s, 1H), 7.75 (s, 1H), 7.61 (s, 2H), 7.52-7.58 (m, 2H), 7.16 (t, J = 8.8 Hz, 2H), 7.09 (s, 1H), 4.21-4.33 (m, 1H), 3.23-3.30 (m, 1H), 2.54-2.63 (m, 2H), 2.35-2.45 (m, 1H), 2.24-2.33 (m, 1H). And to provide the title compound (68) as a white solid. MS (ESI): mass calcd. C24H19F4N5O4S: 549.11, found: 550.2 [M+H]+.1H NMR (400 MHz, DMSO-d6) ppm 10.06 (s, 1H), 9.42 (d, J = 5.2 Hz, 1H), 8.60 (d, J = 8.0 Hz, 1H), 8.10 (s, 1H), 8.01 (s, 1H), 7.74-7.88 (m, 1H), 7.59 (s, 2H), 7.53-7.58 (m, 2H), 7.11-7.17 (m, 3H), 4.46-4.57 (m, 1H), 3.47-3.51 (m, 1H), 2.54-2.61 (m, 2H), 2.39-2.47 (m, 2H). Stereochemistry was arbitrarily assigned. Example 26 was synthesized in similar procedures as described in Example 67 and 68 starting from tert-butyl 3-iodoazetidine-1-carboxylate. Example 77 was synthesized in similar procedures as described in Example 67 and 68 starting from 2-bromo-1,3,4-thiadiazole and reacting with NiCl2(dme), Mn, 2-amidinopyridine hydrochloride, NaI, and TFA at 60 °C for 12 h. Example 78. 2-((6-(3-(Ethylamino)-1,1,1-trifluoro-2-hydroxy-3-oxopropan-2-yl)-2-(3-(4- fluorophenyl)ureido)benzo[d]thiazol-4-yl)oxy)acetic acid (78) FoleyHoagUS12952954.4 GPX-01525 2-((6-(3-(Ethylamino)-1,1,1-trifluoro-2-hydroxy-3-oxopropan-2-yl)-2-(3-(4- fluorophenyl)ureido)benzo[d]thiazol-4-yl)oxy)acetic acid (78) To a solution of N-ethyl-3,3,3-trifluoro-2-[2-[(4-fluorophenyl)carbamoylamino]-4- hydroxy-1,3-benzothiazol-6-yl]-2-hydroxy-propanamide (0.05 g, 105.8 mol, see Example 30 and 31 for synthesis) and ethyl 2-bromoacetate (21.2 mg, 127 mol) in DMF (1 mL) was added K2CO3(29.26 mg, 211.7 mol) in one portion at 20 °C under N2. The mixture was stirred at 60 °C for 12 h. Upon completion, the reaction was adjusted to pH = 5 with 1 N HCl (1 mL). The aqueous layer was extracted with EtOAc (10 mL x 3). The combined organic layer was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The resulting residue was purified by reverse phase HPLC (gradient elution, 15-45% ACN / H2O, with 10 mM NH4HCO3 as a modifier) to afford the title compound (78) (5.88 mg, 10%, racemic) as a brown solid. MS (ESI): mass calcd. for C21H18F4N4O6S: 530.45, found: 531.1 [M+H]+.1H NMR (400 MHz, DMSO-d6) ppm 14.83 (s, 1H), 12.41 (s, 1H), 8.28 (t, J = 6.0 Hz, 1H), 7.80 (s, 1H), 7.77 (s, 1H), 7.68-7.70 (m, 2H), 7.62 (s, 1H), 7.33 (s, 1H), 7.16 (t, J = 8.8 Hz, 2H), 4.53 (s, 2H), 3.12-3.32 (m, 2H), 1.02 (t, J = 6.8 Hz, 3H). FoleyHoagUS12952954.4 GPX-01525 Example 66. (S)-N-ethyl-3,3,3-trifluoro-2-(2-(3-(4-fluorophenyl)-1- methylureido)benzo[d]thiazol-6-yl)-2-hydroxypropanamide (66) (S)-N-Ethyl-3,3,3-trifluoro-2-hydroxy-2-(2-(methylamino)benzo[d]thiazol-6- yl)propanamide To a solution of (S)-2-(2-chlorobenzo[d]thiazol-6-yl)-N-ethyl-3,3,3-trifluoro-2- hydroxypropanamide (100 mg, 295.2 mol, see Example 27 for synthesis) in DMF (1 mL) was added K2CO3(122.4 mg, 886 mol) and methanamine hydrochloride (39.9 mg, 590 mol). The mixture was stirred at 80 °C for 16 h. Then it was quenched with water (30 mL). The aqueous layer was extracted with EtOAc (20 mL x 2). The combined organic layer was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (0-50% EtOAc / PE) to give the title compound (60 mg, 57%) as a white solid.1H NMR (400 MHz, DMSO-d6) ppm 8.16 (t, J = 5.6 Hz, 1H), 8.05 (d, J = 4.5 Hz, 1H), 7.91 (s, 1H), 7.63 (s, 1H), 7.49 (d, J = 8.4 Hz, 1H), 7.38 (d, J = 8.8 Hz, 1H), 3.09-3.17 (m, 2H), 2.94 (d, J = 4.8 Hz, 3H), 0.99 (t, J = 7.2 Hz, 3H). (S)-N-Ethyl-3,3,3-trifluoro-2-(2-(3-(4-fluorophenyl)-1-methylureido)benzo[d]thiazol-6- yl)-2-hydroxypropanamide (66) FoleyHoagUS12952954.4 GPX-01525 Two batches of the reaction were carried out in parallel. To a solution of (S)-N-ethyl- 3,3,3-trifluoro-2-hydroxy-2-(2-(methylamino)benzo[d]thiazol-6-yl)propanamide (30 mg, 90 mol) in DMF (0.5 mL) was added 1-fluoro-4-isocyanato-benzene (14.81 mg, 108 mol). The mixture was stirred at 20 °C for 1 h. After completion, two batches of reaction mixture were combined, and concentrated under reduced pressure. The resulting residue was purified by reverse phase HPLC (gradient elution, 35-65% ACN / H2O, with 10 mM NH4HCO3as a modifier) to obtain the desired product (66) (38.3 mg, 45%) as a white solid. MS (ESI): mass calcd. for C20H18F4N4O3S: 470.10, found: 471.1 [M+H]+.1H NMR (400 MHz, DMSO-d6) ppm 9.58 (s, 1H), 8.24 (t, J = 5.6 Hz, 1H), 8.17 (d, J = 1.2 Hz, 1H), 7.74-7.81 (m, 2H), 7.66- 7.70 (m, 1H), 7.55-7.61 (m, 2H), 7.21 (d, J = 8.8 Hz, 2H), 3.79 (s, 3H), 3.07-3.18 (m, 2H), 0.99 (t, J = 7.2 Hz, 3H). Example 71 and 72. (2S,3S)-4,4,4-trifluoro-3-(2-(3-(4- fluorophenyl)ureido)benzo[d]thiazol-6-yl)-2,3-dihydroxy-N-methylbutanamide (71) & (2R,3S)-4,4,4-trifluoro-3-(2-(3-(4-fluorophenyl)ureido)benzo[d]thiazol-6-yl)-2,3- dihydroxy-N-methylbutanamide (72) Synthetic scheme: FoleyHoagUS12952954.4 GPX-01525 N-(4-Methoxybenzyl)-2-((4-methoxybenzyl)oxy)-N-methylacetamide To a solution of 2-[(4-methoxyphenyl)methoxy]acetic acid (3.78 g, 19.3 mmol) in DMF (35 mL) was added DIPEA (7.48 g, 57.9 mmol) and HATU (8.8 g, 23.2 mmol) at 0 °C. Then 1-(4-methoxyphenyl)-N-methyl-methanamine (3.5 g, 23.2 mmol) was added. It was allowed to stir at 25 °C for 12 h. After completion, the reaction was poured into H2O (20 mL), extracted with EtOAc (20 mL x 3). The combined organic layer was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The resulting residue was purified by reverse phase HPLC (gradient elution, 20-55% ACN / H2O, with 0.2% FA as a modifier) to give the title compound (2.7 g, 42.5%) as a white solid.1H NMR (400 MHz, DMSO-d6) ppm FoleyHoagUS12952954.4 GPX-01525 7.21-7.29 (m, 2H), 7.09-7.18 (m, 2H), 6.87-6.93 (m, 4H), 4.39-4.47 (m, 4H), 4.20 (s, 2H), 3.71- 3.76 (m, 6H), 2.72-2.84 (m, 3H). (3S)-3-(4-Bromophenyl)-4,4,4-trifluoro-3-hydroxy-N-(4-methoxybenzyl)-2-((4- methoxybenzyl)oxy)-N-methylbutanamide & (3R)-3-(4-bromophenyl)-4,4,4-trifluoro-3- hydroxy-N-(4-methoxybenzyl)-2-((4-methoxybenzyl)oxy)-N-methylbutanamide To a solution of 1-(4-bromophenyl)-2,2,2-trifluoro-ethanone (1.15 g, 4.55 mmol) in THF (10 mL) was added 2 N LDA in THF / heptane (3.04 mL) at –78 °C. After stirring 30 min, N-(4-methoxybenzyl)-2-((4-methoxybenzyl)oxy)-N-methylacetamide (1 g, 3.04 mmol) was added and it was stirred at –78 °C for 2 h. After completion, the reaction was poured into sat. NH4Cl (20 mL). The aqueous layer was extracted with EtOAc (20 mL x 3). The combined organic layer was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by reverse phase HPLC (gradient elution, 60-90% ACN / H2O, with 0.2% FA as a modifier) to give the title compound, (2R,3S)-3-(4- bromophenyl)-4,4,4-trifluoro-3-hydroxy-2-[(4-methoxyphenyl)methoxy]-N-[(4- methoxyphenyl)methyl]-N-methyl-butanamide (340 mg, 19.2%) as a white solid. MS (ESI): mass calcd. for C27H27BrF3NO5: 581.1, found: 604.3 / 606.3 [M+Na]+. And the title compound, (2R,3R)-3-(4-bromophenyl)-4,4,4-trifluoro-3-hydroxy-2-[(4-methoxyphenyl)methoxy]-N-[(4- methoxyphenyl)methyl]-N-methyl-butanamide (230 mg, 13%) as a white solid. MS (ESI): mass calcd. for C27H27BrF3NO5: 581.1, found: 604.3 / 606.3 [M+Na]+. (3S)-4,4,4-Trifluoro-3-(2-(3-(4-fluorophenyl)ureido)benzo[d]thiazol-6-yl)-3-hydroxy-N- (4-methoxybenzyl)-2-((4-methoxybenzyl)oxy)-N-methylbutanamide The title compound was synthesized from (3S)-3-(4-bromophenyl)-4,4,4-trifluoro-3- hydroxy-N-(4-methoxybenzyl)-2-((4-methoxybenzyl)oxy)-N-methylbutanamide in similar procedures as described in reference compounds A and B. MS (ESI): mass calcd. for C35H32F4N4O6S: 712.2, found: 713.4 [M+H]+. FoleyHoagUS12952954.4 GPX-01525 (3S)-4,4,4-Trifluoro-3-(2-(3-(4-fluorophenyl)ureido)benzo[d]thiazol-6-yl)-2,3-dihydroxy- N-methylbutanamide (64) A solution of (3S)-4,4,4-trifluoro-3-(2-(3-(4-fluorophenyl)ureido)benzo[d]thiazol-6- yl)-3-hydroxy-N-(4-methoxybenzyl)-2-((4-methoxybenzyl)oxy)-N-methylbutanamide (0.02 g, 28 mol) in TFA (0.5 mL) and H2SO4(0.5 mL) was stirred at 25 °C for 12 h. After completion, the reaction was adjusted to pH = 8-9 with aqueous Na2CO3. The aqueous layer was diluted with H2O (5 mL) and extracted with EtOAc (10 mL x 3). The combined organic layer was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by reverse phase HPLC (gradient elution, 20-55% ACN / H2O, with 10 mM NH4HCO3as a modifier) to afford the title product (64) (6.1 mg, 46%, diastereomer mixture) as a white solid. MS (ESI): mass calcd. for C19H16F4N4O4S: 472.08, found: 473.1 [M+H]+.1H NMR (400 MHz, DMSO-d6) ppm 10.37-11.23 (m, 1H), 9.21 (s, 1H), 8.09-8.23 (m, 2H), 7.65 (s, 2H), 7.54 (s, 2H), 7.27 (s, 1H), 7.17 (t, J = 8.8 Hz, 2H), 6.59 (d, J = 7.6 Hz, 1H), 4.34 (d, J = 7.6 Hz, 1H), 2.53 (d, J = 4.8 Hz, 3H). (2S,3S)-4,4,4-trifluoro-3-(2-(3-(4-fluorophenyl)ureido)benzo[d]thiazol-6-yl)-2,3- dihydroxy-N-methylbutanamide (71) & (2R,3S)-4,4,4-trifluoro-3-(2-(3-(4- fluorophenyl)ureido)benzo[d]thiazol-6-yl)-2,3-dihydroxy-N-methylbutanamide (72) (3S)-4,4,4-Trifluoro-3-(2-(3-(4-fluorophenyl)ureido)benzo[d]thiazol-6-yl)-2,3- dihydroxy-N-methylbutanamide (100 mg) was separated chiral SFC (column: DAICEL CHIRALPAK AD (250 mm *30 mm, 10 um); mobile phase: CO2-IPA (0.1% NH3H2O); 50% B with isocratic elution) to give the title compound, (2S,3S)-4,4,4-trifluoro-3-(2-(3-(4- fluorophenyl)ureido)benzo[d]thiazol-6-yl)-2,3-dihydroxy-N-methylbutanamide (71) (13.2 mg, 13%) as a white solid. MS (ESI): mass calcd. for C19H16F4N4O4S: 472.08, found: 473.1 FoleyHoagUS12952954.4 GPX-01525 [M+H]+.1H NMR (400 MHz, DMSO-d6) ppm 10.82 (s, 1H), 9.21 (s, 1H), 8.11-8.22 (m, 2H), 7.65 (s, 2H), 7.54 (s, 2H), 7.28 (s, 1H), 7.18 (t, J = 8.8 Hz, 2H), 6.60 (d, J = 7.2 Hz, 1H), 4.34 (J = 7.2 Hz, 1H), 2.53 (d, J = 4.8 Hz, 3H). And the title compound, (2R,3S)-4,4,4-trifluoro- 3-(2-(3-(4-fluorophenyl)ureido)benzo[d]thiazol-6-yl)-2,3-dihydroxy-N-methylbutanamide (72) (14.3 mg, 14%) as a white solid. MS (ESI): mass calcd. for C19H16F4N4O4S: 472.08, found: 473.1 [M+H]+.1H NMR (400 MHz, DMSO-d6) ppm 10.63 (s, 1H), 9.23 (s, 1H), 8.10- 8.22 (m, 2H), 7.60-7.69 (m, 2H), 7.51-7.58 (m, 2H), 7.28 (s, 1H), 7.17 (t, J = 8.8 Hz, 2H), 6.60 (d, J = 7.2 Hz, 1H), 4.34 (d, J = 7.2 Hz, 1H), 2.53 (d, = 4.4 Hz, 3H). Stereochemistry was arbitrarily assigned. Examples 63, 69 and 70 were synthesized in similar procedures as described in Example 71 and 72 starting from (3R)-3-(4-bromophenyl)-4,4,4-trifluoro-3-hydroxy-N-(4- methoxybenzyl)-2-((4-methoxybenzyl)oxy)-N-methylbutanamide. Example 73. N-(3,3,3-Trifluoro-2-(2-(3-(4-fluorophenyl)ureido)benzo[d]thiazol-6-yl)-2- hydroxypropyl)cyclopropanecarboxamide (73) Synthetic scheme: 2-(4-(Dibenzylamino)phenyl)-3,3,3-trifluoro-2-hydroxypropanamide FoleyHoagUS12952954.4 GPX-01525 A solution of ethyl 2-[4-(dibenzylamino)phenyl]-3,3,3-trifluoro-2-hydroxy- propanoate (5 g, 11.28 mmol, ~80% ee, see Example 129 for synthesis) in 7 M NH3 / MeOH (60 mL) was heated at 120 °C for 16 h in a sealed tube. Upon completion, the reaction was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (10-100% EtOAc / PE) to afford the title compound (3 g, 64%) as a white solid. MS (ESI): mass calcd. for C23H21F3N2O2: 414.2, found: 415.2 [M-H]+. 3-Amino-2-(4-(dibenzylamino)phenyl)-1,1,1-trifluoropropan-2-ol To a solution of 2-(4-(dibenzylamino)phenyl)-3,3,3-trifluoro-2-hydroxypropanamide (2 g, 4.83 mmol) in THF (20 mL) was added 1 M BH3.THF (12.07 mL) at 0 °C . The mixture was stirred at 25 °C for 12 h. After completion, the reaction was quenched with MeOH (10 mL) at 40 °C. It was then diluted with H2O (10 mL) and extracted with EtOAc (15 mL x 3). The combined organic layer was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (10-100% EtOAc / PE) to obtain the desired product (0.5 g, 26%) as a white solid. MS (ESI): mass calcd. for C23H23F3N2O: 400.2, found: 401.3 [M-H]+. N-(2-(4-(Dibenzylamino)phenyl)-3,3,3-trifluoro-2- hydroxypropyl)cyclopropanecarboxamide To a solution of cyclopropanecarboxylic acid (0.2 g, 2.32 mmol) in DMF (10 mL) was added DIPEA (900.8 mg, 6.97 mmol) and HATU (883.3 mg, 2.32 mmol). The mixture was stirred at rt for 5 min. Then 3-amino-2-(4-(dibenzylamino)phenyl)-1,1,1- trifluoropropan-2-ol (744.2 mg, 1.86 mmol) was added. After stirring at 20 °C for 3 h, the reaction was completed. It was diluted with H2O (2 mL). The aqueous layer was extracted with EtOAc (3 mL x 2). The combined organic layer was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The resulting residue was purified FoleyHoagUS12952954.4 GPX-01525 by silica gel column chromatography (10-100% EtOAc / PE) to afford the title compound (0.57 g, 52%, 80% ee) as a white solid. MS (ESI): mass calcd. for C27H27F3N2O2: 468.2, found: 469.3 [M-H]+. N-(3,3,3-Trifluoro-2-(2-(3-(4-fluorophenyl)ureido)benzo[d]thiazol-6-yl)-2- hydroxypropyl)cyclopropanecarboxamide (73) The title compound (73, enantiomer mixture) was synthesized from N-(2-(4- (dibenzylamino)phenyl)-3,3,3-trifluoro-2-hydroxypropyl)cyclopropanecarboxamide in similar procedures as described in Example 2. MS (ESI): mass calcd. for C21H18F4N4O3S: 482.1, found: 483.1 [M+H]+.1H NMR (400 MHz, DMSO-d6) ppm 10.87 (s, 1H), 9.20 (s, 1H), 8.21 (t, J = 6.0 Hz, 1H), 8.07 (s, 1H), 7.61 (m, 1H), 7.50-7.58 (m, 3H), 7.17 (t, J = 8.8 Hz, 2H), 7.08 (s, 1H), 3.97-4.05 (m, 1H), 3.77-3.84 (m, 1H), 1.55-1.62 (m, 1H), 0.54-0.67 (m, 4H). Examples (75) was synthesized through chiral SFC separation of Example (73). Example 76. (S)-2-(3-(3,3,3-Trifluoro-2-(2-(3-(4-fluorophenyl)ureido)benzo[d]thiazol-6- yl)-2-hydroxypropanamido)azetidin-1-yl)acetic acid (76) Synthetic scheme: FoleyHoagUS12952954.4 GPX-01525 Methyl 2-(3-((tert-butoxycarbonyl)amino)azetidin-1-yl)acetate To a solution of tert-butyl N-(azetidin-3-yl) carbamate (1 g, 5.8 mmol) in DMF (10 mL) was added K2CO3(1.20 g, 8.7 mmol) and methyl 2-bromoacetate (888 mg, 5.8 mmol). The mixture was stirred at 100 °C for 12 h. After completion, the reaction solvent was removed under reduced pressure. The resulting residue was purified by reverse phase HPLC (gradient elution, 20-50% ACN / H2O, with 0.2% FA as a modifier) to give the title compound (200 mg, 14%) as a white oil. MS (ESI): mass calcd. for C11H20N2O4: 244.14, found: 245.3 [M+H]+. Methyl 2-(3-aminoazetidin-1-yl)acetate To a solution of methyl 2-[3-(tert-butoxycarbonylamino)azetidin-1-yl]acetate (170 mg, 696 mol) in HFIP (3 mL) was added TFA (460.5 mg, 4.04 mmol). The mixture was stirred at 20 °C for 12 h. After completion, the reaction solvent was removed under reduced pressure to provide the title compound (150 mg, 83%) as a white oil, which was directly used in the next step without further purification.1H NMR (400 MHz, DMSO-d6) ppm 8.54 (d, J = 2.8 Hz, 2H), 4.15-4.43 (m, 8H), 3.73 (s, 3H). Methyl (S)-2-(3-(3,3,3-trifluoro-2-(2-(3-(4-fluorophenyl)ureido)benzo[d]thiazol-6-yl)-2- hydroxypropanamido)azetidin-1-yl)acetate FoleyHoagUS12952954.4 GPX-01525 To an ice-cold solution of (2S)-3,3,3-trifluoro-2-[2-[(4- fluorophenyl)carbamoylamino]-1,3-benzothiazol-6-yl]-2-hydroxy-propanoic acid (446.7 mg, 1.04 mmol) in DMF (5 mL) was added DIPEA (403.40 mg, 3.12 mmol) and HATU (791.2 mg, 2.08 mmol). The reaction was stirred at this temperature for 15 min, followed by the addition of methyl 2-(3-aminoazetidin-1-yl)acetate (150 mg, 1.04 mmol). It was then allowed to stir at 20 °C for 2 h. After completion, the reaction was quenched with H2O (10 mL). The aqueous layer was extracted with EtOAc (15 mL x 3). The combined organic layer was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The resulting residue was purified by reverse phase HPLC (gradient elution, 25- 55% ACN / H2O, with 10 mM NH4HCO3 as a modifier) to obtain the desired product (100 mg, 17.3%) as a white oil. MS (ESI): mass calcd. for C23H21F4N5O5S: 555.12, found: 556.2 [M+H]+. (S)-2-(3-(3,3,3-Trifluoro-2-(2-(3-(4-fluorophenyl)ureido)benzo[d]thiazol-6-yl)-2- hydroxypropanamido)azetidin-1-yl)acetic acid (76) To a solution of methyl (S)-2-(3-(3,3,3-trifluoro-2-(2-(3-(4- fluorophenyl)ureido)benzo[d]thiazol-6-yl)-2-hydroxypropanamido)azetidin-1-yl)acetate (150 mg, 270 mol) in THF (2 mL) and H2O (0.4 mL) was added LiOH.H2O (28.33 mg, 675 mol). The resulting suspension was stirred at 20 °C for 2 h. After completion, the reaction was quenched with 1 N HCl (2 mL). The aqueous layer was extracted with EtOAc (15 mL x 3). The combined organic layer was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The crude material was purified by reverse phase HPLC (gradient elution, 20-50% ACN / H2O, with 10 mM NH4HCO3 as a modifier) to give the title compound (76) (6.3 mg, 4%) as a white solid. MS (ESI): mass calcd. for C22H19F4N5O5S: 541.10, found: 542.2 [M+H]+.1H NMR (400 MHz, DMSO-d6) 11.11 (s, 1H), 9.77 (s, 1H), 8.85 (d, J = 7.2 Hz, 1H), 8.16 (s, 1H), 8.04 (s, 1H), 7.63 (s, 2H), 7.54-7.57 (m, 2H), 7.16 (t, J FoleyHoagUS12952954.4 GPX-01525 = 8.8 Hz, 2H), 4.46-4.55 (m, 1H), 3.90-3.98 (m, 2H), 3.58-3.62 (m, 1H), 3.48-3.52 (m, 1H), 3.37 (s, 2H). Example 81.1-(4-Fluorophenyl)-3-(6-(2,2,2-trifluoro-1-hydroxy-1-(1-(2-hydroxyethyl)- 1H-imidazol-2-yl)ethyl)benzo[d]thiazol-2-yl)urea (81) 1-((2-(Trimethylsilyl)ethoxy)methyl)-1H-imidazole FoleyHoagUS12952954.4 GPX-01525 To an ice-cold solution of imidazole (15 g, 220.3 mmol) in THF (150 mL) was added 60% NaH (9.69 g, 242.4 mmol) under N2. The mixture was stirred at 20 °C for 30 min, then cooled to 0 °C. Then SEM-Cl (44.08 g, 264.4 mmol) was added dropwise. It was stirred at 20 °C for an additional 2 h. Upon completion, the reaction mixture was quenched with sat. NH4Cl (500 mL). The aqueous layer was extracted with EtOAc (200 mL x 3). The combined organic layer was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (2-100% EtOAc / PE) to afford the title compound (30.4 g, 70%) as a yellow oil. MS (ESI): mass calcd. for C9H18N2OSi: 198.1, found: 199.2 [M+H]+. 1-(4-Bromophenyl)-2,2,2-trifluoro-1-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol- 2-yl)ethan-1-ol To a solution of 1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole (20 g, 100.84 mmol) in THF (600 mL) added a solution of 1.6 M n-BuLi in hexane (69.33 mL) at –70 °C over a period of 10 min under N2. The reaction mixture was stirred at this temperature for 30 min, followed by dropwise addition of 1-(4-bromophenyl)-2,2,2-trifluoro-ethanone (30.62 g, 121 mmol). It was allowed to stir at –70 °C for an additional 4 h. Upon completion, the reaction was quenched with sat. NH4Cl (1 L). The aqueous layer was extracted with EtOAc (500 mL x 3). The combined organic layer was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The crude material was purified by reverse phase HPLC (gradient elution, 50-75% ACN / H2O, with 0.2% FA as a modifier) to give the title compound (12 g, 26%) as a yellow solid. MS (ESI): mass calcd. for C17H22BrF3N2O2Si: 450.06, found: 451.2 / 453.1 [M+H]+. 1-(4-Bromophenyl)-2,2,2-trifluoro-1-(1H-imidazol-2-yl)ethan-1-ol A solution of 1-(4-bromophenyl)-2,2,2-trifluoro-1-(1-((2- (trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)ethan-1-ol (12 g, 26.59 mmol) in TFA (100 mL) and H2O (20 mL) was stirred at 20 °C for 12 h. Upon completion, the reaction was quenched with sat. NaHCO3 (500 mL). The aqueous layer was extracted with EtOAc (500 mL FoleyHoagUS12952954.4 GPX-01525 x 3). The combined organic layer was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure to afford the title compound (8 g, 93.7%) as a white solid.1H NMR (400 MHz, DMSO-d6) ppm 12.19 (s, 1H), 7.81 (s, 1H), 7.61 (s, 4H), 7.12 (s, 1H), 6.95 (s, 1H). 1-(4-Bromophenyl)-1-(1-(2,2-dimethoxyethyl)-1H-imidazol-2-yl)-2,2,2-trifluoroethan-1- ol To a solution of 1-(4-bromophenyl)-2,2,2-trifluoro-1-(1H-imidazol-2-yl)ethan-1-ol (4 g, 12.46 mmol) and 2-bromo-1,1-dimethoxy-ethane (6.32 g, 37.37 mmol) in DMF (40 mL) was added K2CO3 (3.44 g, 24.91 mmol) and NaI (1.87 g, 12.46 mmol) at 20 °C under N2. The resulting suspension was heated to 100 °C and stirred for 12 h. After completion, the reaction was quenched with H2O (100 mL). The aqueous layer was extracted with EtOAc (100 mL x 3). The combined organic layer was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by reverse phase HPLC (gradient elution, 35-65% ACN / H2O, with 10 mM NH4HCO3as a modifier) to give the title compound (0.857 g, 17%) as a brown oil.1H NMR (400 MHz, DMSO-d6) ppm 7.98 (s, 1H), 7.65 (d, J = 8.4 Hz, 2H), 7.24 (d, J = 8.4 Hz, 2H), 7.12 (s, 1H), 6.95 (s, J = 1.2 Hz, 1H), 3.75- 3.90 (m, 2H), 3.61-3.63 (m, 1H), 3.11 (s, 3H), 3.05 (s, 3H). 1-(6-(1-(1-(2,2-Dimethoxyethyl)-1H-imidazol-2-yl)-2,2,2-trifluoro-1- hydroxyethyl)benzo[d]thiazol-2-yl)-3-(4-fluorophenyl)urea (82) The title compound was synthesized from 1-(4-bromophenyl)-1-(1-(2,2- dimethoxyethyl)-1H-imidazol-2-yl)-2,2,2-trifluoroethan-1-ol in similar procedures as described in reference compounds A and B. MS (ESI): mass calcd. for C23H21F4N5O4S: 539.1, found: 540.2 [M+H]+.1H NMR (400 MHz, DMSO-d6) ppm 10.42-11.08 (m, 1H), 9.21 (s, FoleyHoagUS12952954.4 GPX-01525 1H), 7.90 (s, 2H), 7.60-7.70 (m, 1H), 7.51-7.54 (m, 2H), 7.13-7.24 (m, 3H), 7.11 (s, 1H), 6.96 (s, 1H), 3.87 (m, 1H), 3.84-3.89 (m, 2H), 3.04 (s, 3H), 2.90 (s, 3H). 1-(4-Fluorophenyl)-3-(6-(2,2,2-trifluoro-1-hydroxy-1-(1-(2-oxoethyl)-1H-imidazol-2- yl)ethyl)benzo[d]thiazol-2-yl)urea To a solution of 1-(6-(1-(1-(2,2-dimethoxyethyl)-1H-imidazol-2-yl)-2,2,2-trifluoro- 1-hydroxyethyl)benzo[d]thiazol-2-yl)-3-(4-fluorophenyl)urea (0.03 g, 55.6 mol) in THF (0.5 mL) was added 6 N aqueous HCl (93 L). The reaction was stirred at 50 °C for 12 h. Then it was poured into ice-water (1 mL). The resulting solution was adjusted to pH = 8 with Na2CO3. The aqueous layer was extracted with EtOAc (10 mL x 2). The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure to give the crude product (30 mg) as a yellow solid, which was directly used in the next step reaction without further purification. MS (ESI): mass calcd. for C21H15F4N5O3S: 493.08, found: 494.1 [M+H]+. 1-(4-Fluorophenyl)-3-(6-(2,2,2-trifluoro-1-hydroxy-1-(1-(2-hydroxyethyl)-1H-imidazol- 2-yl)ethyl)benzo[d]thiazol-2-yl)urea (81) To a solution of 1-(4-fluorophenyl)-3-(6-(2,2,2-trifluoro-1-hydroxy-1-(1-(2-oxoethyl)- 1H-imidazol-2-yl)ethyl)benzo[d]thiazol-2-yl)urea (30 mg, 60.8 mol) in THF (0.5 mL) was added a solution of 2 M LiBH4in THF (30 L). The mixture was stirred at 20 °C for 1 h and quenched with sat. NH4Cl (10 mL). The aqueous layer was extracted with EtOAc (10 mL x 3). The combined organic layer was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The resulting residue was purified by reverse phase HPLC (gradient elution, 20-55% ACN / H2O, with 10 mM NH4HCO3as a modifier) to afford the title compound (81) (9 mg, 30%) as a white solid. MS (ESI): mass calcd. for C21H17F4N5O3S: 495.10, found: 496.0 [M+H]+.1H NMR (400 MHz, DMSO-d6) ppm 9.24 (s, 1H), 7.89 (s, 1H), 7.80 (s, 1H), 7.58-7.62 (m, 1H), 7.50-7.57 (m, 2H), 7.29-7.41 (m, 1H), FoleyHoagUS12952954.4 GPX-01525 7.25 (s, 1H), 7.10-7.20 (m, 3H), 6.93-6.97 (m, 1H), 4.78-5.02 (m, 1H), 3.66 (t, J = 5.6 Hz, 2H), 3.18-3.29 (m, 2H). Example 85. 3,4,4,4-Tetrafluoro-3-(2-(3-(4-fluorophenyl)ureido)benzo[d]thiazol-6-yl)-2- hydroxy-N-methylbutanamide (85) 3,4,4,4-Tetrafluoro-3-(2-(3-(4-fluorophenyl)ureido)benzo[d]thiazol-6-yl)-2-hydroxy-N- methylbutanamide (85) To a solution of (3R)-4,4,4-trifluoro-3-(2-(3-(4-fluorophenyl)ureido)benzo[d]thiazol- 6-yl)-2,3-dihydroxy-N-methylbutanamide (0.4 g, 847 mol) in DCM (5 mL) was added DAST (341 mg, 2.12 mmol) at –60 °C. The reaction was stirred at this temperature for 16 h. After completion, it was quenched with H2O (10 mL). The aqueous layer was extracted with EtOAc (10 mL x 2). The combined organic layer was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The resulting residue was purified by reverse phase HPLC (gradient elution, 30-65% ACN / H2O, with 0.2% FA as a modifier) to afford the title compound (85) (0.013 g, 3%) as a white solid. MS (ESI): mass calcd. C19H15F5N4O3S: 474.08, found: 475.0 [M+H]+.1H NMR (400 MHz, DMSO-d6) ppm 10.98 (s, 1H), 9.24 (s, 1H), 7.99- 8.14 (m, 1H), 7.90-7.97 (m, 1H), 7.40-7.70 (m, 4H), 7.18 (t, J = 8.8 Hz, 2H), 6.73-6.86 (m, 1H), 4.59-4.89 (m, 1H), 2.45 (dd, J = 14.8, 4.8 Hz, 3H). FoleyHoagUS12952954.4 GPX-01525 Example 90. (S)-2-(4-(Cyanomethyl)-2-(3-(4-fluorophenyl)ureido)benzo[d]thiazol-6-yl)- N-ethyl-3,3,3-trifluoro-2-hydroxypropanamide (90) (S)-2-(2-Amino-4-bromobenzo[d]thiazol-6-yl)-N-ethyl-3,3,3-trifluoro-2- hydroxypropanamide To a solution of (S)-2-(2-aminobenzo[d]thiazol-6-yl)-N-ethyl-3,3,3-trifluoro-2- hydroxypropanamide (1 g, 3.13 mmol) in ACN (10 mL) was added NBS (836.1 mg, 4.7 mmol). After stirring at 50 °C for 12 h, the reaction was diluted with H2O (10 mL) and extracted with EtOAc (10 mL x 3). The combined organic layer was washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (gradient elution, 0-50% EtOAc in PE) to afford the title FoleyHoagUS12952954.4 GPX-01525 compound (0.8 g, 64%) as a yellow solid. MS (ESI): mass calcd. for C12H11BrF3N3O2S: 396.97, found: 398.1 [M+H]+. (S)-2-(4-Bromo-2-(3-(4-fluorophenyl)ureido)benzo[d]thiazol-6-yl)-N-ethyl-3,3,3- trifluoro-2-hydroxypropanamide To a solution of (S)-2-(2-amino-4-bromobenzo[d]thiazol-6-yl)-N-ethyl-3,3,3-trifluoro- 2-hydroxypropanamide (100 mg, 251 mol) in DMF (1 mL) was added 1-fluoro-4-isocyanato- benzene (68.87 mg, 502 mol). The mixture was stirred at 20 °C for 16 h. After completion, the reaction mixture was diluted with water (10 mL). The aqueous layer was extracted with EtOAc (20 mL x 2). The combined organic layer was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by prep-TLC (50% EtOAc / PE) to obtain the desired product (65 mg, 48%) as an orange solid.1H NMR (400 MHz, DMSO-d6) ppm 11.50 (s, 1H), 9.18 (s, 1H), 8.32 (t, J = 6.0 Hz, 1H), 8.22 (s, 1H), 7.98 (s, 1H), 7.88 (s, 1H), 7.48-7.57 (m, 2H), 7.18 (t, J = 8.8 Hz, 2H), 3.06-3.19 (m, 2H), 0.99 (t, J = 7.2 Hz, 3H). (S)-2-(4-(Cyanomethyl)-2-(3-(4-fluorophenyl)ureido)benzo[d]thiazol-6-yl)-N-ethyl-3,3,3- trifluoro-2-hydroxypropanamide (90) To a solution of (S)-2-(4-bromo-2-(3-(4-fluorophenyl)ureido)benzo[d]thiazol-6-yl)-N- ethyl-3,3,3-trifluoro-2-hydroxypropanamide (30 mg, 56 mol) and 4-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)isoxazole (13.12 mg, 67 mol) in H2O (0.1 mL) and NMP (0.4 mL) was added K3PO4(23.79 mg, 112 mol) and [2-(2-aminophenyl)phenyl]-chloro- palladium;bis(1-adamantyl)-butyl-phosphane (3.75 mg, 5.6 mol). The mixture was stirred at FoleyHoagUS12952954.4 GPX-01525 80 °C. After 24 h, the reaction was filtered. The filtrate was diluted with water (30 mL) and the mixture was extracted with EtOAc (20 mL x 2). The combined organic layer was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The resulting residue was purified by reverse phase HPLC (gradient elution, 25-55% ACN / H2O, with 10 mM NH4HCO3as a modifier) to give the title compound (90) (4.5 mg, 8%) as a white solid. MS (ESI): mass calcd. for C21H17F4N5O3S: 495.10, found: 496.1 [M+H]+.1H NMR (400 MHz, DMSO-d6) ppm 11.23 (s, 1H), 9.05 (s, 1H), 8.26 (s, 1H), 8.18 (s, 1H), 7.89 (s, 1H), 7.73 (s, 1H), 7.54-7.50 (m, 2H), 7.19 (t, J = 8.8 Hz, 2H), 4.30 (s, 2H), 3.09-3.17 (m, 2H), 1.00 (t, J = 7.2 Hz, 3H). Example 93. 1-(4-Fluorophenyl)-3-(6-(4-(2-(methylsulfonyl)ethyl)-3-oxo-2- (trifluoromethyl)piperazin-2-yl)benzo[d]thiazol-2-yl)urea (93) Synthetic scheme: FoleyHoagUS12952954.4 GPX-01525 2-(((2-((2-(Methylsulfonyl)ethyl)amino)ethyl)-l2-azaneyl)carbonyl)benzoic acid To a solution of 2-(1,3-dioxoisoindolin-2-yl)acetaldehyde (5 g, 26.43 mmol) in DCM (50 mL) was added 2-methylsulfonylethanamine (3.91 g, 31.7 mmol) and NaBH(OAc)3(14 g, 66.1 mmol) at 0 °C. The mixture was stirred at 25 °C for 6 h. After completion, the reaction was quenched with sat. NaHCO3. The aqueous layer was diluted with H2O (30 mL) and extracted with EtOAc (30 mL x 3). The combined organic layer was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was triturated with EtOAc (30 mL x 2). The solid was collected by filter and dried under vacuum to give the title compound (5.4 g, 69%) as a white solid. MS (ESI): mass calcd. for C13H16N2O4S: 296.08, found: 297.2 [M+H]+. 2-(((2-((tert-Butoxycarbonyl)(2-(methylsulfonyl)ethyl)amino)ethyl)-l2- azaneyl)carbonyl)benzoic acid FoleyHoagUS12952954.4 GPX-01525 To a solution of 2-(((2-((2-(methylsulfonyl)ethyl)amino)ethyl)-l2- azaneyl)carbonyl)benzoic acid (4.4 g, 14.9 mmol) in MeOH (40 mL) was added TEA (3.0 g, 29.7 mmol) and Boc2O (6.48 g, 29.7 mmol). The mixture was stirred at 25 °C for 12 h. After completion, the reaction was diluted with H2O (30 mL). The aqueous layer was extracted with EtOAc (30 mL x 3). The combined organic layer was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (0-100% EtOAc / PE) to afford the title compound (6.4 g, 98%) as a white solid. MS (ESI): mass calcd. for C18H24N2O6S: 396.14, found: 419.2 [M+Na]+. tert-Butyl (2-aminoethyl)(2-(methylsulfonyl)ethyl)carbamate To a solution of 2-(((2-((tert-butoxycarbonyl)(2-(methylsulfonyl)ethyl)amino)ethyl)- l2-azaneyl)carbonyl)benzoic acid (2 g, 5.0 mmol) in EtOH (20 mL) was added N2H4.H2O (1.01 g, 20.2 mmol). The mixture was stirred at 60 °C for 12 h. Then the reaction solvent was removed under reduced pressure. The crude product was triturated with EtOAc (50 mL) at 25 °C for 1 h. The resulting suspension was filtered, and the filtrate was concentrated under reduced pressure and dried under vacuum to give the title compound (1.09 g, 81%) as a yellow oil.1H NMR (400 MHz, DMSO-d6) ppm 3.52-3.59 (m, 2H), 3.32-3.38 (m, 2H), 3.14 (t, J = 6.8 Hz, 2H), 3.00 (s, 3H), 2.63 (t, J = 6.4 Hz, 2H), 1.40 (s, 9H). 1-(4-Fluorophenyl)-3-(6-(4-(2-(methylsulfonyl)ethyl)-3-oxo-2- (trifluoromethyl)piperazin-2-yl)benzo[d]thiazol-2-yl)urea (93) The title compound (93) was synthesized from (2S)-2-(4-aminophenyl)-4-[(4- methoxyphenyl)methyl]-5-methyl-2-(trifluoromethyl)morpholin-3-one in similar procedures as described in Example 2. MS (ESI): mass calcd. for C22H21F4N5O4S2: 559.10, found: 560.1 FoleyHoagUS12952954.4 GPX-01525 [M+H]+.1H NMR (400 MHz, DMSO-d6) ppm 10.83 (s, 1H), 9.18 (s, 1H), 8.17 (s, 1H), 7.70 (s, 2H), 7.51-7.54 (m, 2H), 7.17 (t, J = 8.8 Hz, 2H), 4.20 (s, 1H), 3.84-3.91 (m, 1H), 3.61-3.68 (m, 1H), 3.43-3.56 (m, 3H), 3.20-3.23 (m, 1H), 3.03 (s, 3H), 2.96-3.00 (m, 1H), 2.60-2.65 (m, 1H). Examples 100 and 101 were synthesized through chiral SFC separation of Example 93. Example 94.1-(6-(4-(2,2-Difluoroethyl)-3-oxo-2-(trifluoromethyl)piperazin-2- yl)benzo[d]thiazol-2-yl)-3-(4-fluorophenyl)urea (94) Synthetic scheme: FoleyHoagUS12952954.4 GPX-01525 2-[2-(2,2-Difluoroethylamino)ethyl]isoindoline-1,3-dione To a mixture of 2,2-difluoroethanamine hydrochloride (4.97 g, 42.29 mmol) and 2- (1,3-dioxoisoindolin-2-yl)acetaldehyde (8 g, 42.3 mmol) in DCM (200 mL) was added TEA (5.14 g, 50.8 mmol) at 0 °C. Then NaBH(OAc)3(22.41 g, 105.7 mmol) was added in portions. The reaction was allowed to warm up to rt and stirred for 3 h. After completion, the reaction was poured into sat. NaHCO3(100 mL). The aqueous layer was extracted with DCM (200 mL x 2). The combined organic layer was concentrated under reduced pressure to give the title compound (11 g) as a yellow solid, which was used directly in the next step without further purification. MS (ESI): mass calcd. for C12H12F2N2O2: 254.09, found: 255.2 [M+H]+. tert-Butyl N-(2,2-difluoroethyl)-N-[2-(1,3-dioxoisoindolin-2-yl)ethyl]carbamate FoleyHoagUS12952954.4 GPX-01525 To a mixture of 2-[2-(2,2-difluoroethylamino)ethyl]isoindoline-1,3-dione (12 g, 47.2 mmol) in MeOH (200 mL) was added TEA (9.55 g, 94.4 mmol) and Boc2O (15.45 g, 70.8 mmol) at 20 °C. The mixture was stirred at 20 °C for 16 h. Upon completion, the reaction was concentrated under reduced pressure. The resulting residue was diluted with H2O (200 mL). The aqueous layer was extracted with EtOAc (200 mL x 2). The combined organic layer was dried over anhydrous Na2SO4, filtered, concentrated, and purified by silica gel column chromatography (0-5% EtOAc / PE) to give the title compound (14 g, 78.8%) as a white oil. MS (ESI): mass calcd. for C17H20F2N2O4: 354.14, found: 377.2 [M+Na]+. tert-Butyl N-(2-aminoethyl)-N-(2,2-difluoroethyl)carbamate To a solution of tert-butyl N-(2,2-difluoroethyl)-N-[2-(1,3-dioxo-3a,7a- dihydroisoindol-2-yl)ethyl]carbamate (14 g, 39.29 mmol) in EtOH (200 mL) was added N2H4.H2O (5 g, 100 mmol). It was allowed to stir at 80 °C for 16 h. After completion, the reaction solvent was removed under reduced pressure. The resulting residue was dissolved with EtOAc (200 mL) and stirred at 20 °C for 1 h. The mixture was then filtered and washed with EtOAc (200 mL). The filtrate was concentrated to afford the title compound (8.8 g, 99.9%) as a white solid, which was used directly in the next step without further purification.1H NMR (400 MHz, CDCl3) ppm 5.68-6.16 (m, 1H), 3.50-3.60 (m, 2H), 3.34 (s, 2H), 2.85 (t, J = 6.4 Hz, 2H), 1.47 (s, 9H), 1.25-1.35 (m, 2H). 1-(6-(4-(2,2-Difluoroethyl)-3-oxo-2-(trifluoromethyl)piperazin-2-yl)benzo[d]thiazol-2- yl)-3-(4-fluorophenyl)urea (94) The title compound (94) was synthesized from (2S)-2-(4-aminophenyl)-4-[(4- methoxyphenyl)methyl]-5-methyl-2-(trifluoromethyl)morpholin-3-one in similar procedures as described in Example 2. MS (ESI): mass calcd. for C21H17F6N5O2S: 517.10, found: 518.1 [M+H]+.1H NMR (400 MHz, DMSO-d6) ppm 10.92 (s, 1H), 9.19 (s, 1H), 8.16 (s, 1H), 7.70 (s, 2H), 7.54 (d, J = 2.0 Hz, 2H), 7.18 (t, J = 8.4 Hz, 2H), 6.11-6.41 (m, 1H), 4.29 (s, 1H), 3.87- FoleyHoagUS12952954.4 GPX-01525 3.99 (m, 1H), 3.69-3.81 (m, 1H), 3.53-3.60 (m, 1H), 3.21-3.24 (m, 1H), 2.96-2.99 (m, 1H), 2.64-2.70 (m, 1H). Examples 106 and 107 were synthesized through chiral SFC separation of Example 94. Example 112. (S)-N-Ethyl-2-(2-(3-(2-ethyl-4-fluorophenyl)ureido)benzo[d]thiazol-6-yl)- 3,3,3-trifluoro-2-hydroxypropanamide (112) To a solution of (2S)-2-(2-amino-1,3-benzothiazol-6-yl)-N-ethyl-3,3,3-trifluoro-2- hydroxy-propanamide (50 mg, 157 mol) in DMF (0.5 mL) was added CDI (50.8 mg, 313 mol) and 2-ethyl-4-fluoro-aniline (26.2 mg, 188 mol). The mixture was stirred at 80 °C for 12 h. Upon completion, the reaction was cooled to rt. The reaction solvent was removed under reduced pressure. The resulting residue was purified by reverse phase HPLC (gradient elution, 30-60% ACN / H2O, with 0.2% FA as a modifier) to give the title compound (112) (16 mg, 21%) as a white solid. MS (ESI): mass calcd. for C21H20F4N4O3S: 484.12, found: 485.1 [M+H]+.1H NMR (400 MHz, DMSO-d6) ppm 11.20 (s, 1H), 8.66 (s, 1H), 8.21 (t, J = 6.0 Hz, 1H), 8.17 (s, 1H), 7.71-7.81 (m, 2H), 7.68 (s, 2H), 7.08-7.14 (m, 1H), 7.01-7.08 (m, 1H), 3.08-3.17 (m, 2H), 2.60-2.67 (m, 2H), 1.18 (t, J = 7.6 Hz, 3H), 0.99 (t, J = 7.2 Hz, 3H). Examples 113 was synthesized in similar procedures as described in Example 112. FoleyHoagUS12952954.4 GPX-01525 Example 120.6-(2,2,2-Trifluoro-1-(2-(3-(4-fluorophenyl)ureido)benzo[d]thiazol-6-yl)-1- hydroxyethyl)pyridazine-4-carboxylic acid (120) (4-Bromophenyl)(5-methylpyridazin-3-yl)methanone FoleyHoagUS12952954.4 GPX-01525 To a solution of 1-bromo-4-iodo-benzene (7.59 g, 26.8 mmol) in THF (80 mL) was added a solution of 2 M chloro(isopropyl)magnesium in THF (14.8 mL) at –78°C and stirred at this temperature for 15 min under N2. Then methyl 5-methylpyridazine-3-carboxylate (4.9 g, 32.2 mmol) was added. After stirring for an additional 105 min, the reaction was quenched with sat. NH4Cl (100 mL). The aqueous layer was extracted with EtOAc (100 mL x 2). The combined organic layer was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (50% EtOAc / PE) to afford the title compound (3 g, 40%) as a brown solid. MS (ESI): mass calcd. C12H9BrN2O: 275.99, found: 276.9 / 278.9 [M+H]+. 1-(4-Bromophenyl)-2,2,2-trifluoro-1-(5-methylpyridazin-3-yl)ethan-1-ol To an ice-cold solution of (4-bromophenyl)-(5-methylpyridazin-3-yl) methanone (3 g, 10.8 mmol) in THF (30 mL) was added TMSCF3(4.62 g, 32.5 mmol) and a solution of 1 M TBAF in THF (1.1 mL). The mixture was stirred at 20 °C for 0.5 h. Upon completion, the reaction was quenched with water (5 mL). The aqueous layer was extracted with EtOAc (5 mL x 3). The combined organic layer was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The resulting residue was diluted with an ice-cold aqueous solution of 1 M HCl (10.8 mL) and allowed to stir at rt overnight. Then it was diluted with H2O (20 mL). The aqueous layer was extracted with EtOAc (20 mL x 2). The combined organic layer was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (50% EtOAc / PE) to give the title compound (2.6 g, 69%) as a brown oil. MS (ESI): mass calcd. C13H10BrF3N2O: 345.99, found: 346.8 / 348.8 [M+H]+. 6-(1-(4-Bromophenyl)-2,2,2-trifluoro-1-hydroxyethyl)pyridazine-4-carboxylic acid - 111 - FoleyHoagUS12952954.4 GPX-01525 To a solution of 1-(4-bromophenyl)-2,2,2-trifluoro-1-(5-methylpyridazin-3- yl)ethanol (2.4 g, 6.9 mmol) in dioxane (25 mL) was added SeO2(3.84 g, 34.6 mmol). The mixture was stirred at 110 °C for 12 h. After completion, the reaction was quenched with H2O (100 mL). The aqueous layer was extracted with EtOAc (100 mL x 2). The combined organic layer was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (100% EtOAc) to obtain the title compound (1.95 g, 75%) as a yellow oil. MS (ESI): mass calcd. C13H8BrF3N2O3: 375.97, found: 377.0 / 379.0 [M+H]+. Methyl 6-(1-(4-bromophenyl)-2,2,2-trifluoro-1-hydroxyethyl)pyridazine-4-carboxylate A solution of 6-[1-(4-bromophenyl)-2, 2, 2-trifluoro-1-hydroxy-ethyl] pyridazine-4- carboxylic acid (2.05 g, 5.42 mmol) in DMF (30 mL) was treated with K2CO3(1.12 g, 8.13 mmol) and subsequently stirred at 20 °C for 30 min under N2. Then MeI (1.54 g, 10.85 mmol) was added, and it was allowed to stir at 20 °C for an additional 16 h under N2. Upon completion, the reaction was quenched with H2O (50 mL). The aqueous layer was extracted with EtOAc (50 mL x 2). The combined organic layer was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (17% EtOAc / PE) to give the title compound (2 g, 94%) as a yellow oil. MS (ESI): mass calcd. C14H10BrF3N2O3: 389.98, found: 391.0 / 393.0 [M+H]+. Methyl 6-(1-(4-aminophenyl)-2, 2, 2-trifluoro-1-hydroxyethyl) pyridazine-4-carboxylate & ethyl 6-(1-(4-aminophenyl)-2,2,2-trifluoro-1-hydroxyethyl)pyridazine-4-carboxylate To a solution of methyl 6-[1-(4-bromophenyl)-2,2,2-trifluoro-1-hydroxy- ethyl]pyridazine-4-carboxylate (2 g, 5.11 mmol) in EtOH (17.5 mL) and H2O (3.5 mL) was added sodium ascorbate (2.03 g, 10.23 mmol), (1R,2R)-N1,N2-dimethylcyclohexane-1,2- diamine (436.4 mg, 3.07 mmol), copper sulfate (816.1 mg, 5.11 mmol) and sodium azide (997.2 mg, 15.34 mmol). The resulting mixture was stirred at 80 °C for 16 h under N2. After completion, it was poured into water (10 mL), adjusted to pH = 9-10 with Na2CO3and diluted with H2O (50 mL). The aqueous layer was extracted with EtOAc (50 mL x 3). The combined FoleyHoagUS12952954.4 GPX-01525 organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (50% EtOAc / PE) to afford a mixture of methyl 6-[1-(4-aminophenyl)-2,2,2-trifluoro-1-hydroxy-ethyl]pyridazine-4- carboxylate, MS (ESI): mass calcd. C15H14F3N3O3: 341.10, found: 342.2 [M+H]+, and ethyl 6- [1-(4-aminophenyl)-2,2,2-trifluoro-1-hydroxy-ethyl]pyridazine-4-carboxylate, MS (ESI): mass calcd. C15H14F3N3O3: 341.10, found: 342.2 [M+H]+, (1.14 g) as a brown oil. Methyl 6-(2, 2, 2-trifluoro-1-(2-(3-(4-fluorophenyl) ureido) benzo[d]thiazol-6-yl)-1- hydroxyethyl) pyridazine-4-carboxylate & ethyl 6-(2, 2, 2-trifluoro-1-(2-(3-(4- fluorophenyl)ureido) benzo[d]thiazol-6-yl)-1-hydroxyethyl)pyridazine-4-carboxylate The title compounds were synthesized from methyl 6-(1-(4-aminophenyl)-2, 2, 2- trifluoro-1-hydroxyethyl) pyridazine-4-carboxylate & ethyl 6-(1-(4-aminophenyl)-2,2,2- trifluoro-1-hydroxyethyl)pyridazine-4-carboxylate in similar procedures as described in Example 2. MS (ESI): mass calcd. for C21H17F6N5O2S: 517.10, found: 518.1 [M+H]+.1H NMR (400 MHz, DMSO-d6) ppm 10.92 (s, 1H), 9.19 (s, 1H), 8.16 (s, 1H), 7.70 (s, 2H), 7.54 (d, J = 2.0 Hz, 2H), 7.18 (t, J = 8.4 Hz, 2H), 6.11-6.41 (m, 1H), 4.29 (s, 1H), 3.87-3.99 (m, 1H), 3.69-3.81 (m, 1H), 3.53-3.60 (m, 1H), 3.21-3.24 (m, 1H), 2.96-2.99 (m, 1H), 2.64-2.70 (m, 1H). 6-(2,2,2-Trifluoro-1-(2-(3-(4-fluorophenyl)ureido)benzo[d]thiazol-6-yl)-1- hydroxyethyl)pyridazine-4-carboxylic acid (120) FoleyHoagUS12952954.4 GPX-01525 To a solution of methyl 6-[2,2,2-trifluoro-1-[2-[(4-fluorophenyl)carbamoylamino]-1,3- benzothiazol-6-yl]-1-hydroxy-ethyl]pyridazine-4-carboxylate and ethyl 6-[2,2,2-trifluoro-1- [2-[(4-fluorophenyl)carbamoylamino]-1,3-benzothiazol-6-yl]-1-hydroxy-ethyl]pyridazine-4- carboxylate (0.6 g) in THF (6 mL) and H2O (6 mL) was added LiOH.H2O (96.6 mg, 2.3 mmol). The reaction was stirred at 20 °C for 2 h and then adjusted to pH = 4 with 1 N HCl (4 mL). The aqueous layer was extracted with EtOAc (10 mL x 3). The combined organic layer was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The resulting residue was purified by reverse phase HPLC (gradient elution, 10-45% ACN / H2O, with 10 mM NH4HCO3 as a modifier) to afford the title compound (24.5 mg, 12%) as a white solid. MS (ESI): mass calcd. C21H13F4N5O4S: 507.06, found: 508.1 [M+H]+.1H NMR (400 MHz, DMSO-d6) ppm 9.81 (s, 1H), 9.47 (d, J = 1.6 Hz, 1H), 8.08 (s, 1H), 8.02 (s, 1H), 7.98 (d, J = 1.2 Hz, 1H), 7.60-7.66 (m, 1H), 7.56 (dd, J = 8.4, 5.2 Hz, 2H), 7.41 (d, J = 8.8 Hz, 1H), 7.16 (t, J = 8.8 Hz, 4H). Examples 131 and 132 were synthesized through chiral SFC separation of Example 120. Examples 102 was synthesized in similar procedures as described in Example 120. It was then separated by chiral SFC to afford Example 103 and 104. Example 121.1-(6-(1-(5-(Azetidine-1-carbonyl)pyridazin-3-yl)-2,2,2-trifluoro-1- hydroxyethyl)benzo[d]thiazol-2-yl)-3-(4-fluorophenyl)urea (121) 1-(6-(1-(5-(Azetidine-1-carbonyl)pyridazin-3-yl)-2,2,2-trifluoro-1- hydroxyethyl)benzo[d]thiazol-2-yl)-3-(4-fluorophenyl)urea (121) FoleyHoagUS12952954.4 GPX-01525 To a solution of 6-[2,2,2-trifluoro-1-[2-[(4-fluorophenyl)carbamoylamino]-1,3- benzothiazol-6-yl]-1-hydroxy-ethyl]pyridazine-4-carboxylic acid (0.15 g, 296 mol) in DCM (1 mL) was added a solution of 50% T4P in EtOAc (426 mg, 591 mol), azetidine (41.48 mg, 443 mol) and TEA (150 mg, 1.48 mmol). The mixture was stirred at 20 °C for 16 h. After completion, the mixture was quenched with sat. NaHCO3(10 mL). The aqueous layer was extracted with EtOAc (10 mL x 3). The combined organic layer was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by reverse phase HPLC (gradient elution, 30-60% ACN / H2O, with 10 mM NH4HCO3as a modifier) to afford (121) (55.7 mg, 34%) as a white solid. MS (ESI): mass calcd. C24H18F4N6O3S: 546.11, found: 547.1 [M+H]+.1H NMR (400 MHz, DMSO-d6) ppm 10.88 (s, 1H), 9.42 (d, J = 2.0 Hz, 1H), 9.19 (s, 1H), 8.12 (s, 1H), 8.10 (s, 1H), 7.88 (d, J = 2.0 Hz, 1H), 7.64 (s, 1H), 7.53 (s, 2H), 7.44 (d, J = 8.4 Hz, 1H), 7.17 (t, J = 8.8 Hz, 2H), 4.24-4.36 (m, 2H), 4.05 (t, J = 7.8 Hz, 2H), 2.23-2.29 (m, 2H). Examples 133 and 134 were synthesized through chiral SFC separation of Example 121. Example 129 & 130.1-(6-((2S,6R)-6-(Fluoromethyl)-4-methyl-3-oxo-2- (trifluoromethyl)pipera811zin-2-yl)benzo[d]thiazol-2-yl)-3-(4-fluorophenyl)urea (129) & 1-(6-((2R,6S)-6-(fluoromethyl)-4-methyl-3-oxo-2-(trifluoromethyl)piperazin-2- yl)benzo[d]thiazol-2-yl)-3-(4-fluorophenyl)urea (130) Synthetic scheme: FoleyHoagUS12952954.4 GPX-01525 Ethyl (S)-2-(4-(dibenzylamino)phenyl)-3,3,3-trifluoro-2-hydroxypropanoate (4S)-4-tert-butyl-2-[1-[(4S)-4-tert-butyl-4,5-dihydrooxazol-2-yl]-1-methyl-ethyl]-4,5- dihydrooxazole (5.39 g, 18.29 mmol) was added to a suspension of Cu(OTf)2(6.62 g, 18.3 mmol) in MTBE (100 mL) at rt. After stirring for 15 min, a solution of ethyl 3,3,3-trifluoro- 2-oxo-propanoate (36.4 mL, 274.4 mmol) and N,N-dibenzylaniline (50 g, 182.9 mmol) in MTBE (200 mL) was added. The resulting solution was further stirred for 18 h at rt. Upon completion, the reaction was poured into water (300 mL) and extracted with EtOAc (300 mL x 3). The combined organic layer was dried with anhydrous Na2SO4, filtered, concentrated and purified by silica gel column chromatography (0-100% EtOAc / PE) to afford the title FoleyHoagUS12952954.4 GPX-01525 compound (80 g, 98.6%, ~80% ee) as a white solid. MS (ESI): mass calcd. for C25H24F3NO3: 443.17, found: 444.2 [M+H]+. (S)-2-(4-(Dibenzylamino)phenyl)-3,3,3-trifluoro-2-hydroxypropanoic acid A suspension of ethyl (S)-2-(4-(dibenzylamino)phenyl)-3,3,3-trifluoro-2- hydroxypropanoate (550 mg, 1.24 mmol) and LiOH (149 mg, 6.2 mmol) in THF (4 mL), MeOH (1 mL), and H2O (1 mL) was stirred at rt for 16 h. After completion, the reaction solvent was removed under reduced pressure. The resulting residue was purified by reverse phase HPLC (gradient elution, 25-65% ACN in H2O with 0.1% TFA as a modifier) to provide the title product (773 mg) as a white solid. MS (ESI): mass calcd. for C23H20F3NO3: 415.14, found: 415.90 [M+H]+. 1-(Benzyl(methyl)amino)-3-fluoropropan-2-ol Benzaldehyde (640 μL, 6.3 mmol) and 1-fluoro-3-(methylamino)propan-2-ol (225 mg, 2.1 mmol) were dissolved in an ice-cold solution of EtOH / AcOH (9:1, 10 mL), followed by the addition of NaCNBH3(172 mg, 2.73 mmol). The reaction was allowed to stir at rt for 16 h. Upon completion, the reaction solvent was removed under reduced pressure. The resulting residue was purified by reverse phase HPLC (gradient elution, 5-30% ACN in H2O, with 0.1% TFA as a modifier) to afford the title compound (0.4 g, 97%). MS (ESI): mass calcd. for C11H16FNO: 197.12, found: 197.95 [M+H]+. 2-(1-(Benzyl(methyl)amino)-3-fluoropropan-2-yl)isoindoline-1,3-dione To a suspension of 1-(benzyl(methyl)amino)-3-fluoropropan-2-ol (0.4 g, 2.03 mmol), potassium phthalimide (413 mg, 2.23 mmol), and PPh3(585 mg, 2.23 mmol) in THF (10.1 mL) was added DIAD (438 μL, 2.23 mmol) dropwise. After stirring overnight, the reaction solvent was removed under reduced pressure. The resulting residue was dissolved in DCM (20 mL), followed by the addition of 10% K2CO3 aqueous solution (10 mL). It was stirred at rt for 1 h. FoleyHoagUS12952954.4 GPX-01525 The aqueous layer was separated. The organic layer was washed with water (2x), dried over anhydrous Na2SO4, concentrated, and purified by silica gel column chromatography (0-50% EtOAc / Hex) to afford the desired product as a colorless oil (255 mg, 38%). MS (ESI): mass calcd. for C19H19FN2O2: 326.14, found: 327.00 [M+H]+. N1-Benzyl-3-fluoro-N1-methylpropane-1,2-diamine To a solution of 2-(1-(benzyl(methyl)amino)-3-fluoropropan-2-yl)isoindoline-1,3- dione (257 mg, 0.79 mmol) in EtOH (3.94 mL) was added hydrazine (67.1 μL, 1.38 mmol) dropwise. After stirring at rt for 16 h, the reaction solvent was removed under reduced pressure. The resulting residue was purified by reverse phase HPLC (gradient elution, 5-25% ACN in H2O, with 0.1% TFA as a modifier) to afford the title compound (0.1 g, 65%). MS (ESI): mass calcd. for C11H17FN2: 196.14, found: 197.00 [M+H]+. 2-((1-(Benzyl(methyl)amino)-3-fluoropropan-2-yl)amino)-2-(4-(dibenzylamino)phenyl)- 3,3,3-trifluoropropanoic acid To a solution of (S)-2-(4-(dibenzylamino)phenyl)-3,3,3-trifluoro-2-hydroxypropanoic acid (50 mg, 0.12 mmol) in THF (1.2 mL) was added oxalyl chloride (20.6 μL, 0.24 mmol) and the reaction was stirred for 30 min. A solution of N1-benzyl-3-fluoro-N1-methylpropane- 1,2-diamine (118 mg, 0.6 mmol) in THF (0.5 mL) was added. After stirring at rt for 15 min, DIPEA (21 μL, 1.2 mmol) was added and the reaction was stirred for another 15 min. Upon completion, the reaction was quenched with water, extracted with EtOAc and washed with NaHCO3. The combined organic layer was dried over Na2SO4, filtered and concentrated and purified by reverse phase HPLC (gradient elution, 35-75% ACN in H2O, with 0.1% TFA as a modifier) to afford the title compound (64.4 mg, 76%). MS (ESI): mass calcd. for C34H35F4N3O2: 593.27, found: 594.15 [M+H]+. 2-((1-(Benzyl(methyl)amino)-3-fluoropropan-2-yl)amino)-2-(4-(dibenzylamino)phenyl)- 3,3,3-trifluoropropanoic acid FoleyHoagUS12952954.4 GPX-01525 A suspension of 2-((1-(benzyl(methyl)amino)-3-fluoropropan-2-yl)amino)-2-(4- (dibenzylamino)phenyl)-3,3,3-trifluoropropanoic acid (64.4 mg, 0.091 mmol) and 20% Pd(OH)2(12.8 mg, 0.018 mmol) in EtOH (0.91 mL) was purged with H2for 5 min and the reaction was stirred under hydrogen for 1 hr. The reaction was filtered through a syringe filter. The filtrate was concentrated to afford the crude product as a yellow oil (39.8 mg). It was directly used in the next step reaction without further purification. MS (ESI): mass calcd. for C13H17F4N3O2: 323.13, found: 323.95 [M+H]+. Rac-(3S,5S)-3-(4-Aminophenyl)-5-(fluoromethyl)-1-methyl-3- (trifluoromethyl)piperazin-2-one & Rac-(3S,5R)-3-(4-aminophenyl)-5-(fluoromethyl)-1- methyl-3-(trifluoromethyl)piperazin-2-one To a solution of 2-((1-(benzyl(methyl)amino)-3-fluoropropan-2-yl)amino)-2-(4- (dibenzylamino)phenyl)-3,3,3-trifluoropropanoic acid (42 mg, 0.096 mmol) and HATU (43.9 mg, 0.116 mmol) in DMF (1 mL) was added DIPEA (50.3 μL, 0.29 mmol) and the resulting mixture was stirred for 20 min. The reaction mixture was diluted with water and ACN and directly purified by reverse phase HPLC (gradient elution, 5-45% ACN in H2O, with 0.1% TFA as a modifier) to afford rac-(3S,5S)-3-(4-aminophenyl)-5-(fluoromethyl)-1-methyl-3- (trifluoromethyl)piperazin-2-one (16 mg, 54%). MS (ESI): mass calcd. for C13H15F4N3O: 305.12, found: 305.90 [M+H]+. And to afford rac-(3S,5R)-3-(4-aminophenyl)-5- (fluoromethyl)-1-methyl-3-(trifluoromethyl)piperazin-2-one (13 mg, 44%). MS (ESI): mass calcd. for C13H15F4N3O: 305.12, found: 305.90 [M+H]+. Stereochemistry was arbitrarily assigned. These two compounds were carried separately forward to make the respective final products. Rac-(3S,5R)-3-(2-Aminobenzo[d]thiazol-6-yl)-5-(fluoromethyl)-1-methyl-3- (trifluoromethyl)piperazin-2-one FoleyHoagUS12952954.4 GPX-01525 To a solution of rac-(3S,5R)-3-(4-aminophenyl)-5-(fluoromethyl)-1-methyl-3- (trifluoromethyl)piperazin-2-one (14.2 mg, 0.047 mmol) in AcOH (0.8 mL) was added KSCN (15.8 mg, 0.16 mmol). After stirring at 25 °C for 1 h, a solution of Br2(2.64 μL, 0.051 mmol) in AcOH (0.1 mL) was added and the reaction was stirred at 25 °C for 12 h. After completion, the solution was filtered, and the filter cake was washed with EtOAc (10 mL x 3). The filtrate was concentrated under reduced pressure. The resulting residue was treated with sat. NaHCO3(20 mL) to neutralize the remaining AcOH. The aqueous solution was extracted with EtOAc (20 mL x 2). The combined organic layer was washed with brine (20 mL), dried over anhydrous Na2SO4, filtered, concentrated to afford the crude (17 mg) as a yellow solid. MS (ESI): mass calcd. for C14H14F4N4OS: 362.08, found: 362.95 [M+H]+. Rac-1-(6-((2S,6R)-6-(Fluoromethyl)-4-methyl-3-oxo-2-(trifluoromethyl)piperazin-2- yl)benzo[d]thiazol-2-yl)-3-(4-fluorophenyl)urea To a solution of rac-(3S,5R)-3-(2-aminobenzo[d]thiazol-6-yl)-5-(fluoromethyl)-1- methyl-3-(trifluoromethyl)piperazin-2-one (12 mg, 0.033 mmol) in DMF (330 μL) was added 4-fluorophenyl isocyanate (6.1 μL, 0.05 mmol). After stirring at rt for 12 h, the reaction mixture was diluted with water and ACN and directly purified by reverse phase HPLC (gradient elution, 30-70% ACN in H2O, with 0.1% TFA as a modifier) to afford the title compound (12.1 mg, 73%) as a white solid. MS (ESI): mass calcd. for C19H16F3N3O4S: 439.08 found: 440.0 [M+H]+.1H NMR (400 MHz, DMSO-d6) ppm 10.85 (br s, 1H), 9.17 (s, 1H), 8.13 (s, 1H), 7.89 (s, 1H), 7.70 (d, J = 5.6 Hz, 1H), 7.48 - 7.58 (m, 3H), 7.34 (t, J = 8.0 Hz, 2H), 7.07 (t, J = 7.2 Hz, 1H), 4.24 - 4.33 (m, 2H), 1.23 (t, J = 7.2 Hz, 3H). MS (ESI): mass calcd. for C21H18F5N5O2S: 499.11, found: 500.00 [M+H]+. 1-(6-((2S,6R)-6-(Fluoromethyl)-4-methyl-3-oxo-2-(trifluoromethyl)piperazin-2- yl)benzo[d]thiazol-2-yl)-3-(4-fluorophenyl)urea (129) & 1-(6-((2R,6S)-6-(fluoromethyl)- FoleyHoagUS12952954.4 GPX-01525 4-methyl-3-oxo-2-(trifluoromethyl)piperazin-2-yl)benzo[d]thiazol-2-yl)-3-(4- fluorophenyl)urea (130) Rac-1-(6-((2S,6R)-6-(Fluoromethyl)-4-methyl-3-oxo-2-(trifluoromethyl)piperazin-2- yl)benzo[d]thiazol-2-yl)-3-(4-fluorophenyl)urea was separated by chiral SFC (column: DAICEL CHIRALPAK AD (250 mm*30 mm, 10 um); mobile phase: CO2-EtOH (0.1% NH3H2O); 40% B with isocratic elution) to provide the title compound (129). MS (ESI): mass calcd. for C21H18F5N5O2S: 499.11, found: 500.1 [M+H]+.1H NMR (400 MHz, DMSO-d6) ppm 10.61-11.11 (m, 1H), 9.17-9.24 (m, 1H), 8.18 (s, 1H), 7.63-7.77 (m, 2H), 7.50-7.60 (m, 2H), 7.17 (t, J = 8.8 Hz, 2H), 4.71-4.82 (m, 1H), 4.59-4.70 (m, 1H), 4.16 (d, J = 2.8 Hz, 1H), 3.57-3.64 (m, 1H), 2.93-3.01 (m, 4H), 2.79 (d, J = 13.2 Hz, 1H). And to provide the title compound (130) as a white solid. MS (ESI): mass calcd. C21H18F5N5O2S: 499.11, found: 500.1 [M+H]+.1H NMR (400 MHz, DMSO-d6) ppm 10.93-11.01 (m, 1H), 9.23 (s, 1H), 8.17 (s, 1H), 7.61-7.79 (m, 2H), 7.47-7.59 (m, 2H), 7.17 (t, J = 8.8 Hz, 2H), 4.71-4.82 (m, 1H), 4.59- 4.70 (m, 1H), 4.16 (d, J = 3.6 Hz, 1H), 3.60 (d, J = 6.0 Hz, 1H), 2.99 (s, 3H), 2.94-2.97 (m, 1H), 2.79 (d, J = 12.4 Hz, 1H). Stereochemistry was arbitrarily assigned. Examples 139 and 140 were synthesized in similar procedures as described in Example 129 and 130. Example 145 and 146. (R)-1-(4-fluorophenyl)-3-(6-(4-methyl-3,6-dioxo-2- (trifluoromethyl)piperazin-2-yl)benzo[d]thiazol-2-yl)urea (145) & (S)-1-(4- Fluorophenyl)-3-(6-(4-methyl-3,6-dioxo-2-(trifluoromethyl)piperazin-2- yl)benzo[d]thiazol-2-yl)urea (146) FoleyHoagUS12952954.4 GPX-01525 Synthetic scheme: 2-(Benzylamino)-2-(4-(dibenzylamino)phenyl)-3,3,3-trifluoropropanoic acid To a solution of (S)-2-(4-(dibenzylamino)phenyl)-3,3,3-trifluoro-2-hydroxypropanoic acid (200 mg, 0.48 mmol, ~80% ee) in THF (4.8 mL) was added oxalyl chloride (82.6 μL, 0.96 mmol) and the reaction was stirred for 30 min. Benzylamine (526 μL, 04.81 mmol) was added and the reaction was stirred at rt for 15 min. Upon completion, the reaction was quenched with water, extracted with EtOAc and washed with NaHCO3. The combined organic layer was dried over Na2SO4, filtered and concentrated and purified by silica gel column chromatography (0- 20% MeOH / DCM) to afford the title compound (83 mg, 34%, racemized). MS (ESI): mass calcd. for C30H27F3N2O2: 504.20, found: 505.10 [M+H]+. Methyl N-(2-(benzylamino)-2-(4-(dibenzylamino)phenyl)-3,3,3-trifluoropropanoyl)-N- methylglycinate FoleyHoagUS12952954.4 GPX-01525 To a stirred solution of 2-(benzylamino)-2-(4-(dibenzylamino)phenyl)-3,3,3- trifluoropropanoic acid (83 mg, 165 μmol) in THF (1.65 mL) at 0 °C was added DIPEA (287 μL, 1.65 mmol) followed by methyl methylglycinate (45.9 mg, 0.33 mmol) and HATU (93.8 mg, 247 μmol). The reaction was stirred at rt for 1 h. Upon completion, it was quenched with water. The aqueous was extracted with EtOAc (3x). The combined organic layer was dried over anhydrous Na2SO4, filtered, concentrated, and purified by silica gel column chromatography (0-40% EtOAc / Hex) to afford the title compound (63.7 mg, 66%, racemic) as an off-white solid. MS (ESI): mass calcd. for C34H34F3N3O3: 589.26, found: 590.20 [M+H]+. 3-(4-Aminophenyl)-1-methyl-3-(trifluoromethyl)piperazine-2,5-dione A suspension of methyl N-(2-(benzylamino)-2-(4-(dibenzylamino)phenyl)-3,3,3- trifluoropropanoyl)-N-methylglycinate (64 mg, 0.11 mmol) and 20% Pd(OH)2(16 mg, 0.022 mmol) in EtOH (1.1 mL) was purged with H2for 5 min and stirred under hydrogen for 1 h at rt. The reaction was filtered through a syringe filter. The filtrate was concentrated to afford the crude title product as a yellow oil (31 mg). It was directly used in the next step without further purification. MS (ESI): mass calcd. for C12H12F3N3O2: 287.09, found: 287.90 [M+H]+. 1-(4-Fluorophenyl)-3-(6-(4-methyl-3,6-dioxo-2-(trifluoromethyl)piperazin-2- yl)benzo[d]thiazol-2-yl)urea The title compound was synthesized from 3-(4-aminophenyl)-1-methyl-3- (trifluoromethyl)piperazine-2,5-dione in similar procedures as described in Example 129. MS (ESI): mass calcd. for C20H15F4N5O3S: 481.08, found: 481.95 [M+H]+. (R)-1-(4-fluorophenyl)-3-(6-(4-methyl-3,6-dioxo-2-(trifluoromethyl)piperazin-2- yl)benzo[d]thiazol-2-yl)urea (145) & (S)-1-(4-Fluorophenyl)-3-(6-(4-methyl-3,6-dioxo-2- (trifluoromethyl)piperazin-2-yl)benzo[d]thiazol-2-yl)urea (146) FoleyHoagUS12952954.4 GPX-01525 1-(4-Fluorophenyl)-3-(6-(4-methyl-3,6-dioxo-2-(trifluoromethyl)piperazin-2- yl)benzo[d]thiazol-2-yl)urea (18.9 mg, 39 mol) was separated by chiral SFC (column: ChiralPak IH, (250 mm*30 mm, 10 um); mobile phase: CO2-IPA (0.1% NH3H2O); 50% B with isocratic elution) to provide (R)-1-(4-fluorophenyl)-3-(6-(4-methyl-3,6-dioxo-2- (trifluoromethyl)piperazin-2-yl)benzo[d]thiazol-2-yl)urea (145) (3.6 mg) as a white solid. MS (ESI): mass calcd. for C20H15F4N5O3S: 481.08, found: 482.1 [M+H]+.1H NMR (400 MHz, DMSO-d6) ppm 10.70-11.19 (m, 1H), 9.73 (s, 1H), 9.07-9.29 (m, 1H), 8.04 (s, 1H), 7.64- 7.74 (m, 1H), 7.47-7.61 (m, 3H), 7.16 (t, J = 8.8 Hz, 2H), 3.90-4.09 (m, 2H), 2.91 (s, 3H). And to provide (S)-1-(4-fluorophenyl)-3-(6-(4-methyl-3,6-dioxo-2-(trifluoromethyl)piperazin-2- yl)benzo[d]thiazol-2-yl)urea (146) (5.7 mg) as a white solid. MS (ESI): mass calcd. for C20H15F4N5O3S: 481.08, found: 482.1 [M+H]+.1H NMR (400 MHz, DMSO-d6) ppm 10.63- 11.18 (m, 1H), 9.73 (s, 1H), 9.11-9.23 (m, 1H), 8.05 (d, J = 2.8 Hz, 1H), 7.67-7.76 (m, 1H), 7.50-7.61 (m, 3H), 7.17 (t, J = 8.8 Hz, 2H), 3.92-4.08 (m, 2H), 2.92 (s, 3H). Stereochemistry was arbitrarily assigned. Example 149.1-(4-Fluorophenyl)-3-(6-(1-methyl-2,7-dioxo-3-(trifluoromethyl)- 1,2,3,4,6,7-hexahydropyrido[3,4-b]pyrazin-3-yl)benzo[d]thiazol-2-yl)urea (149) Synthetic scheme: FoleyHoagUS12952954.4 GPX-01525 tert-Butyl (2-methoxy-5-nitropyridin-4-yl)carbamate To a solution of 2-methoxy-5-nitro-pyridin-4-amine (4.3 g, 25.42 mmol) in THF (43 mL) was added DMAP (310.6 mg, 2.54 mmol) and Boc2O (11.1 g, 50.85 mmol). The mixture was stirred at 90 °C for 1 h. After completion, the reaction was diluted with H2O (50 mL). The aqueous layer was extracted with EtOAc (35 mL x 3). The combined organic layer was washed with brine, dried over Na2SO4, filtered and concentrated under reduced FoleyHoagUS12952954.4 GPX-01525 pressure. The resulting residue was purified by silica gel column chromatography (9-33% EtOAc / PE) to give the title compound (1.39 g, 20%) as a white solid. MS (ESI): mass calcd. for C11H15N3O5: 269.10, found: 214.1 [M-56+H]+.1H NMR (400 MHz, DMSO-d6) ppm 9.77 (s, 1H), 8.92 (s, 1H), 7.38 (s, 1H), 3.95 (s, 3H), 1.48 (s, 9H). tert-Butyl (2-methoxy-5-nitropyridin-4-yl)(methyl)carbamate To an ice-cold solution of tert-butyl (2-methoxy-5-nitropyridin-4-yl)carbamate (0.44 g, 1.63 mmol) in THF (4.4 mL) was added 60% NaH (137 mg, 3.43 mmol). The mixture was allowed to warm to rt and stirred for 30 min. Then CH3I (1.39 g, 9.8 mmol) was added, and the reaction was stirred at 20 °C for 16 h. After completion, it was quenched with sat. NH4Cl (5 mL) and diluted with H2O (10 mL). The aqueous layer was extracted with EtOAc (15 mL x 3). The combined organic layer was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (5-25% EtOAc / PE) to provide the title product (0.4 g, 86.4%) as a white solid. MS (ESI): mass calcd. for C12H17N3O5: 283.12, found: 284.2 [M+H]+.1H NMR (400 MHz, DMSO-d6) ppm 8.82 (s, 1H), 7.06 (s, 1H), 3.97 (s, 3H), 3.27 (s, 3H), 1.29 (s, 9H). tert-Butyl (5-amino-2-methoxypyridin-4-yl)(methyl)carbamate To a solution of tert-butyl (2-methoxy-5-nitropyridin-4-yl)(methyl)carbamate (1.09 g, 3.85 mmol) in MeOH (11 mL) was added 10% Pd / C (0.2 g) under N2. The suspension was purged with H2(3x) and stirred under H2(30 psi) at 25 °C. After 16 h, the reaction was filtered through a celite pad. The filtrate was concentrated and purified by silica gel column chromatography (9-50% EtOAc / PE) to provide the title compound (0.86 g, 88.2%) as a white solid. MS (ESI): mass calcd. for C12H19N3O3: 253.14, found: 254.2 [M+H]+.1H NMR (400 MHz, DMSO-d6) ppm 7.65 (s, 1H), 6.49 (s, 1H), 4.55 (s, 2H), 3.72 (s, 3H), 3.01 (s, 3H), 1.36 (s, 9H). 1-(4-Fluorophenyl)-3-(6-(7-methoxy-1-methyl-2-oxo-3-(trifluoromethyl)-1,2,3,4- tetrahydropyrido[3,4-b]pyrazin-3-yl)benzo[d]thiazol-2-yl)urea FoleyHoagUS12952954.4 GPX-01525 The title compound was synthesized from (2S)-2-(4-aminophenyl)-4-[(4- methoxyphenyl)methyl]-5-methyl-2-(trifluoromethyl)morpholin-3-one in similar procedures as described in Example 2. MS (ESI): mass calcd. for C24H18F4N6O3S: 546.11, found: 547.3 [M+H]+. 1-(4-Fluorophenyl)-3-(6-(1-methyl-2,7-dioxo-3-(trifluoromethyl)-1,2,3,4,6,7- hexahydropyrido[3,4-b]pyrazin-3-yl)benzo[d]thiazol-2-yl)urea (149) To a solution of 1-(4-fluorophenyl)-3-(6-(7-methoxy-1-methyl-2-oxo-3- (trifluoromethyl)-1,2,3,4-tetrahydropyrido[3,4-b]pyrazin-3-yl)benzo[d]thiazol-2-yl)urea (94 mg, 172 mol) in DMF (2 mL) was added LiCl (36.5 mg, 860 mol) and 4- methylbenzenesulfonic acid hydrate (163.6 mg, 860 mol). The reaction was stirred at 120 °C for 1 h. After completion, the reaction was diluted with water and directly purified by reverse phase HPLC (gradient elution, 25-55% ACN / H2O, with 0.2% FA as a modifier) to provide the title compound (149) (24 mg, 26%) as a white solid. MS (ESI): mass calcd. for C23H16F4N6O3S: 532.09, found: 533.0 [M+H]+.1H NMR (400 MHz, DMSO-d6) ppm 10.98 (s, 2H), 9.22 (s, 1H), 7.97 (s, 1H), 7.67 (d, J = 8.4 Hz, 1H), 7.53 (dd, J = 8.8, 4.8 Hz, 2H), 7.47- 7.50 (m, 1H), 7.24 (s, 1H), 7.17 (t, J = 8.8 Hz, 2H), 7.12 (s, 1H), 5.89 (s, 1H), 3.28 (s, 3H). Examples 151 and 152 were synthesized through chiral SFC separation of Example 149. Example 150.1-(4-Fluorophenyl)-3-(6-(1-methyl-2,7-dioxo-3-(trifluoromethyl)- 1,2,3,4,6,7-hexahydropyrido[3,4-b]pyrazin-3-yl)benzo[d]thiazol-2-yl)urea (150) FoleyHoagUS12952954.4 GPX-01525 tert-Butyl ((1-(hydroxymethyl)cyclopropyl)methyl)carbamate DIPEA (6.9 g, 53.4 mmol) was added to a solution of [1- (aminomethyl)cyclopropyl]methanol (2.7 g, 26.7 mmol) and Boc2O (5.83 g, 26.7 mmol) in DCM (30 mL). The mixture was stirred at 20 °C for 3 h. After completion, the reaction was quenched with water (50 mL) and extracted with DCM (50 mL x 2). The combined organic layer was washed with aqueous 1 N HCl (50 mL x 2), dried over Na2SO4, filtered and FoleyHoagUS12952954.4 GPX-01525 concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (17-25% EtOAc / PE) to provide the title compound (5 g, 93%) as a white solid.1H NMR (400 MHz, CDCl3) ppm 4.93 (s, 1H), 3.39 (s, 2H), 3.12 (s, 2H), 2.57 (s, 1H), 1.47 (s, 9H), 0.44 (d, J = 12.4 Hz, 4H). tert-Butyl ((1-(((N-methyl-4- nitrophenyl)sulfonamido)methyl)cyclopropyl)methyl)carbamate To a solution of tert-butyl ((1-(hydroxymethyl)cyclopropyl)methyl)carbamate (6.6 g, 32.8 mmol) and N-methyl-4-nitro-benzenesulfonamide (7.8 g, 36.1 mmol) in THF (64 mL) was added PPh3(10.32 g, 39.4 mmol) and DEAD (6.85 g, 39.4 mmol). The mixture was stirred at 20 °C. After 2 h, the reaction solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (17-25% EtOAc / PE) to afford the title compound (10 g, 73%) as a white solid. MS (ESI): mass calcd. for C17H25N3O6S: 399.15, found: 422.2 [M+Na]+.1H NMR (400 MHz, CDCl3) ppm 7.97-8.03 (m, 1H), 7.68-7.75 (m, 2H), 7.61-7.67 (m, 1H), 5.24 (s, 1H), 3.09-3.21 (m, 4H), 2.96 (s, 3H), 1.45 (s, 9H), 0.73 (s, 2H), 0.34-0.43 (m, 2H). N-((1-(Aminomethyl)cyclopropyl)methyl)-N-methyl-4-nitrobenzenesulfonamide To a solution of tert-butyl (1-(((N-methyl-4- nitrophenyl)sulfonamido)methyl)cyclopropyl)methyl)carbamate (9 g, 22.53 mmol) in dioxane (40 mL) was added a solution of 4 N HCl in dioxane (40 mL). The mixture was stirred at 20 °C for 0.5 h and the reaction solvent was removed under reduced pressure. The resulting residue was poured into sat. NaHCO3(60 mL). The aqueous layer was extracted with EtOAc (50 mL x 2). The combined organic layer was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure to obtain the desired product (6.7 g, 96%) as a yellow oil. MS (ESI): mass calcd. for C12H17N3O4S: 299.09, found: 300.2 [M+H]+. 1-(4-Fluorophenyl)-3-(6-(1-methyl-2,7-dioxo-3-(trifluoromethyl)-1,2,3,4,6,7- hexahydropyrido[3,4-b]pyrazin-3-yl)benzo[d]thiazol-2-yl)urea (150) FoleyHoagUS12952954.4 GPX-01525 The title compound was synthesized from (2S)-2-(4-aminophenyl)-4-[(4- methoxyphenyl)methyl]-5-methyl-2-(trifluoromethyl)morpholin-3-one in similar procedures as described in Example 2. MS (ESI): mass calcd. for C23H21F4N5O2S: 507.14, found: 508.1 [M+H]+.1H NMR (400 MHz, DMSO-d6) ppm 10.84 (s, 1H), 9.24 (s, 1H), 8.02 (s, 1H), 7.69 (d, J = 7.2 Hz, 1H), 7.52-7.56 (m, 2H), 7.44 (d, J = 8.4 Hz, 1H), 7.17 (t, J = 8.8 Hz, 2H), 3.65 (t, J = 6.4 Hz, 1H), 3.44 (d, J = 14.8 Hz, 1H), 2.91-3.04 (m, 4H), 2.58-2.65 (m, 1H), 2.36 (d, J = 14.8 Hz, 1H), 0.55 (m, 1H), 0.40-0.44 (m, 1H), 0.18-0.29 (m, 2H). Examples 153 and 154 were synthesized through chiral SFC separation of Example 150. Example 157 and 158. (R)-1-(4-Fluorophenyl)-3-(6-(1,1,1-trifluoro-2,4-dihydroxybutan- 2-yl)benzo[d]thiazol-2-yl)urea (157) & (S)-1-(4-fluorophenyl)-3-(6-(1,1,1-trifluoro-2,4- dihydroxybutan-2-yl)benzo[d]thiazol-2-yl)urea (158) Synthetic scheme: FoleyHoagUS12952954.4 GPX-01525 Ethyl 4,4,4-trifluoro-3-hydroxy-3-(4-nitrophenyl)butanoate A solution of 1 N LHMDS in THF (1.02 mL, 1.02 mmol) was added to THF (1.02 mL) and cooled to –78 °C. Then EtOAc (0.1 mL, 1.02 mmol) was added dropwise, and the reaction was stirred at this temperature for 30 min. Then a solution of 2,2,2-trifluoro-1-(4- nitrophenyl)ethan-1-one (269 mg, 1.23 mmol) in THF (0.2 mL) was added. It was warmed to rt and stirred overnight. The reaction was quenched with water and the aqueous layer was extracted with EtOAc (3x). The combined organic layer was dried over anhydrous Na2SO4, filtered, concentrated, and purified by silica gel column chromatography (0-40% EtOAc / Hex) to afford the desired product (221 mg, 70%) as a colorless oil. Ethyl 3-(4-aminophenyl)-4,4,4-trifluoro-3-hydroxybutanoate A suspension of ethyl 4,4,4-trifluoro-3-hydroxy-3-(4-nitrophenyl)butanoate (221 mg, 0.72 mmol) and 20% Pd(OH)2(101 mg, 0.14 mmol) in EtOH (7.2 mL) was purged with H2for 5 min and stirred under hydrogen for 1 h. The reaction mixture was filtered through a syringe FoleyHoagUS12952954.4 GPX-01525 filter. The filtrate was concentrated to afford the crude product as a yellow oil (197 mg). It was directly used in the next step without further purification. MS (ESI): mass calcd. for C12H14F3NO3: 277.09, found: 277.95 [M+H]+. Ethyl 4,4,4-trifluoro-3-(2-(3-(4-fluorophenyl)ureido)benzo[d]thiazol-6-yl)-3- hydroxybutanoate The title compound was synthesized from ethyl 3-(4-aminophenyl)-4,4,4-trifluoro-3- hydroxybutanoate in similar procedures as described in Example 129 and 130. MS (ESI): mass calcd. for C20H17F4N3O4S: 471.09, found: 471.95 [M+H]+. 4,4,4-Trifluoro-3-(2-(3-(4-fluorophenyl)ureido)benzo[d]thiazol-6-yl)-3-hydroxybutanoic acid (141) A suspension of ethyl 4,4,4-trifluoro-3-(2-(3-(4-fluorophenyl)ureido)benzo[d]thiazol- 6-yl)-3-hydroxybutanoate (50 mg, 0.11 mmol) and LiOH.H2O (7.6 mg, 0.32 mmol) in THF (0.8 mL), MeOH (0.2 mL), and H2O (0.2 mL) was stirred at rt for 16 h. After completion, the reaction solvent was removed. The resulting residue was purified by reverse phase HPLC (gradient elution, 25-65% ACN in H2O with 0.1% TFA as a modifier) to provide the title product (43.7 mg, 93%) as a white solid. MS (ESI): mass calcd. for C18H13F4N3O4S: 443.06, found: 443.95 [M+H]+.1H NMR (400 MHz; CD3OD) 8.05 (s, 1H), 7.59 (s, 2H), 7.46 (dd, J = 9.1, 4.8 Hz, 2H), 7.02 (t, J = 8.8 Hz, 2H), 3.29 (d, J = 15.9 Hz, 1H), 3.09 (d, J = 15.9 Hz, 1H). 1-(4-Fluorophenyl)-3-(6-(1,1,1-trifluoro-2,4-dihydroxybutan-2-yl)benzo[d]thiazol-2- yl)urea FoleyHoagUS12952954.4 GPX-01525 To a solution of 4,4,4-trifluoro-3-(2-(3-(4-fluorophenyl)ureido)benzo[d]thiazol-6-yl)- 3-hydroxybutanoic acid (20 mg, 0.042 mmol) in THF (424 μL) was added LiBH4(1.39 mg, 0.063 mmol) at 0 °C. It was allowed to stir at rt. After 16 h, the reaction was quenched with aqueous NH4Cl solution (5 mL) and extracted with EtOAc (10 mL x 3). The combined organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by reverse phase HPLC (gradient elution, 20-60% ACN in H2O with 0.1% TFA as a modifier) to provide the title product (16.9 mg, 93%) as a white solid. MS (ESI): mass calcd. for C18H15F4N3O3S: 429.08, found: 429.85 [M+H]+. (R)-1-(4-Fluorophenyl)-3-(6-(1,1,1-trifluoro-2,4-dihydroxybutan-2-yl)benzo[d]thiazol-2- yl)urea (157) & (S)-1-(4-fluorophenyl)-3-(6-(1,1,1-trifluoro-2,4-dihydroxybutan-2- yl)benzo[d]thiazol-2-yl)urea (158) 1-(4-Fluorophenyl)-3-(6-(1,1,1-trifluoro-2,4-dihydroxybutan-2-yl)benzo[d]thiazol-2- yl)urea was separated by chiral SFC (column: DAICEL CHIRALPAK AD (250 mm*30 mm, 10 um); mobile phase: CO2-IPA (0.1% NH3H2O); 35% B with isocratic elution) to provide the title compound (157). MS (ESI): mass calcd. for C18H15F4N3O3S: 429.08, found: 430.0 [M+H]+.1H NMR (400 MHz, DMSO-d6) ppm 10.85 (s, 1H), 9.19 (s, 1H), 8.10 (s, 1H), 7.61- 7.74 (m, 1H), 7.54 (d, J = 8.0 Hz, 3H), 7.17 (t, J = 8.4 Hz, 2H), 6.61 (s, 1H), 4.66 (t, J = 4.4 Hz, 1H), 3.44-3.49 (m, 1H), 3.17-3.23 (m, 1H), 2.36-2.45 (m, 1H), 2.21-2.31 (m, 1H). And to provide the title compound (158) as a white solid. MS (ESI): mass calcd. for C18H15F4N3O3S: 429.08, found: 430.0 [M+H]+.1H NMR (400 MHz, DMSO-d6) ppm 10.84 (s, 1H), 9.20 (s, 1H), 8.09 (s, 1H), 7.59-7.73 (m, 1H), 7.54 (d, J = 8.0 Hz, 3H), 7.17 (t, J = 8.4 Hz, 2H), 6.61 (s, 1H), 4.66 (t, J = 4.8 Hz, 1H), 3.44-3.49 (m, 1H), 3.17-3.23 (m, 1H), 2.37-2.45 (m, 1H), 2.21- 2.31 (m, 1H). Stereochemistry was arbitrarily assigned. FoleyHoagUS12952954.4 GPX-01525 Example 159.1-(4-Fluorophenyl)-3-(6-(2,2,2-trifluoro-1-hydroxy-1-(5- (hydroxymethyl)pyridazin-3-yl)ethyl)benzo[d]thiazol-2-yl)urea (159) 1-(4-Fluorophenyl)-3-(6-(2,2,2-trifluoro-1-hydroxy-1-(5-(hydroxymethyl)pyridazin-3- yl)ethyl)benzo[d]thiazol-2-yl)urea (159) To a solution of methyl 6-[2,2,2-trifluoro-1-[2-[(4-fluorophenyl)carbamoylamino]-1,3- benzothiazol-6-yl]-1-hydroxy-ethyl]pyridazine-4-carboxylate (200 mg, 373.5 mol) in THF (2 mL) was added a solution of 1 M DIBAL-H in toluene (3.74 mL) under N2at –70 °C. The mixture was stirred at this temperature for 2 h. Then the reaction was quenched with sat. NH4Cl (5 mL), 15% NaOH (5 mL) and H2O (15 mL). The aqueous layer was extracted with EtOAc (20 mL x 2). The combined organic layer was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by reverse phase HPLC (gradient elution, 25-50% ACN / H2O, with 10mM NH4HCO3as a modifier) to provide the title compound (159) (17.6 mg, 10%) as a white solid. MS (ESI): mass calcd. C21H15F4N5O3S: 493.08, found: 494.1 [M+H]+.1H NMR (400 MHz, DMSO-d6) ppm 10.82 (s, 1H), 9.13-9.28 (m, 2H), 8.05-8.13 (m, 1H), 7.96 (s, 1H), 7.75 (d, J = 0.8 Hz, 1H), 7.58-7.67 (m, 1H), 7.52 (d, J = 4.0 Hz, 2H), 7.43 (d, J = 8.4 Hz, 1H), 7.17 (t, J = 8.8 Hz, 2H), 5.62 (t, J = 5.6 Hz, 1H), 4.59 (d, J = 5.6 Hz, 2H). FoleyHoagUS12952954.4 GPX-01525 Examples 170 and 171 were synthesized through chiral SFC separation of Example 159. Example 160.1-(4-Fluorophenyl)-3-(6-((6S)-6-(hydroxymethyl)-4-methyl-3-oxo-2- (trifluoromethyl)piperazin-2-yl)benzo[d]thiazol-2-yl)ureaa (160) Methyl (2S)-2-(((benzyloxy)carbonyl)amino)-3-(2-azabicyclo[2.2.1]hept-5-en-2- yl)propanoate FoleyHoagUS12952954.4 GPX-01525 Tricyclo[5.2.1.02,6]deca-3,8-diene (1.14 g, 8.66 mmol) was distilled under 145°C. Then it was added to a solution of methyl (2S)-3-amino-2- (benzyloxycarbonylamino)propanoate hydrochloride (1 g, 3.46 mmol) and 30% aqueous formaldehyde (286 L) in H2O (5 mL) at 20 °C. The mixture was stirred at this temperature for 5 h. After completion, the reaction was washed with PE (20 mL x 2). The aqueous layer was diluted with sat. NaHCO3 (20 mL) and extracted with EtOAc (50 mL x 3). The combined organic layer was dried over anhydrous Na2SO4, filtered, concentrated and purified by silica gel column chromatography (0-100% EtOAc / PE) to afford the title product (0.8 g, 70%) as a yellow oil. MS (ESI): mass calcd. for C18H22N2O4: 330.16, found: 331.2 [M+H]+. Methyl (S)-2-(((benzyloxy)carbonyl)amino)-3-(methylamino)propanoate To a solution of methyl (2S)-2-(((benzyloxy)carbonyl)amino)-3-(2- azabicyclo[2.2.1]hept-5-en-2-yl)propanoate (592 mg, 1.79 mmol) in TFA (8 mL) and DCM (8 mL) was added Et3SiH (625 mg, 5.38 mmol) at 20 °C. The reaction was stirred at rt for 16 h. Upon completion, the reaction solvent was removed under reduced pressure to afford the title compound (680 mg, crude, TFA salt) as a yellow oil, which was used directly in the next step without further purification. MS (ESI): mass calcd. for C13H18N2O4: 266.13, found: 267.2 [M+H]+. Methyl (S)-2-(((benzyloxy)carbonyl)amino)-3-((tert- butoxycarbonyl)(methyl)amino)propanoate To a solution of methyl (S)-2-(((benzyloxy)carbonyl)amino)-3- (methylamino)propanoate (15 g, 39.44 mmol) in DCM (100 mL) and H2O (50 mL) was added Boc2O (12.91 g, 59.2 mmol) and NaHCO3(33.13 g, 394.4 mmol). The reaction was stirred at 25 °C for 12 h. After completion, it was diluted with H2O (150 mL). The aqueous layer was extracted with DCM (150 mL x 3). The combined organic layer was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (0-100% EtOAc / PE) to afford the FoleyHoagUS12952954.4 GPX-01525 title compound (15 g, crude) as a white solid. MS (ESI): mass calcd. for C18H26N2O6: 366.18, found: 267.2 [M-100+H]+. Methyl (S)-2-amino-3-((tert-butoxycarbonyl)(methyl)amino)propanoate 10% Pd / C (5.52 g) was added to a solution of methyl (2S)-2- (benzyloxycarbonylamino)-3-[tert-butoxycarbonyl(methyl)amino]propanoate (9.5 g, 25.93 mmol) in MeOH (95 mL) under N2. The resulting suspension was degassed under vacuum and purged with H2 (3x). Then it was allowed to stir under H2 (15psi) at 25 °C for 12 h. After completion, the reaction was filtered through a celite pad. The filtrate was concentrated under reduced pressure to afford the title compound (6 g) as a yellow oil, which was directly used in the next step without further purification. MS (ESI): mass calcd. for C10H20N2O4: 232.14, found: 233.2 [M+H]+. Methyl (2S)-6-(2-(3-(4-fluorophenyl)ureido)benzo[d]thiazol-6-yl)-4-methyl-5-oxo-6- (trifluoromethyl)piperazine-2-carboxylate The title compound was synthesized from (2S)-2-(4-aminophenyl)-4-[(4- methoxyphenyl)methyl]-5-methyl-2-(trifluoromethyl)morpholin-3-one in similar procedures as described in Example 2. MS (ESI): mass calcd. for C22H19F4N5O4S: 525.11, found: 526.2 [M+H]+. 1-(4-Fluorophenyl)-3-(6-((6S)-6-(hydroxymethyl)-4-methyl-3-oxo-2- (trifluoromethyl)piperazin-2-yl)benzo[d]thiazol-2-yl)ureaa (160) To an ice-cold solution of methyl (2S)-6-(2-(3-(4-fluorophenyl)ureido)benzo[d]thiazol- 6-yl)-4-methyl-5-oxo-6-(trifluoromethyl)piperazine-2-carboxylate (0.08 g, 152 mol) in THF (1 mL) was added a solution of 2.5 M LiBH4in THF (61 L). The mixture was stirred at 0 °C FoleyHoagUS12952954.4 GPX-01525 for 2 h. Upon completion, the reaction was quenched with sat. NH4Cl (3 mL) and extracted with EtOAc (3 mL x 3). The combined organic layer was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by reverse phase HPLC (gradient elution, 20-60% ACN / H2O, with 10 mM NH4HCO3as a modifier) to afford the title compound (160) (0.04 g, 53%, diastereomer mixture) as a white solid. MS (ESI): mass calcd. for C21H19F4N5O3S: 497.11, found: 498.1 [M+H]+.1H NMR (400 MHz, DMSO-d6) ppm 10.79 (s, 1H), 9.20-9.23 (m, 1H), 8.02-8.30 (m, 1H), 7.61-7.75 (m, 2H), 7.50-7.58 (m, 2H), 7.17 (t, J = 8.8 Hz, 2H), 4.86-4.98 (m, 1H), 3.35-3.76 (m, 4H), 2.84-3.21 (m, 5H). Examples 173 and 174 were synthesized through chiral SFC separation of Example 160. Example 182, 183 and 184 were synthesized in the same procedures as described in Examples 160, 173 and 174. Example 163. (S)-2-(2-(3-(2-Cyclopropyl-2,2-difluoroethyl)ureido)benzo[d]thiazol-6-yl)- N-ethyl-3,3,3-trifluoro-2-hydroxypropanamide (163) Ethyl (S)-2-(4-aminophenyl)-3,3,3-trifluoro-2-hydroxypropanoate FoleyHoagUS12952954.4 GPX-01525 To a solution of ethyl (S)-2-(4-(dibenzylamino)phenyl)-3,3,3-trifluoro-2- hydroxypropanoate (20 g, 45.1 mmol) in MeOH (200 mL) was added 10% Pd / C (4.8 g, 4.5 mmol) under N2. The resulting suspension was purged with H2 (x 3) and then stirred under H2 (15 Psi) for 12 h. The reaction was filtered through a celite pad, and the filter cake was washed with MeOH (800 mL). The filtrate was concentrated and purified by silica gel column chromatography (0-100% EtOAc / PE) to afford the title compound (46 g, 96.9%) as a white solid. MS (ESI): mass calcd. for C11H12F3NO3: 263.08, found: 264.2 [M+H]+. Ethyl (S)-2-(2-aminobenzo[d]thiazol-6-yl)-3,3,3-trifluoro-2-hydroxypropanoate To a solution of ethyl (S)-2-(4-aminophenyl)-3,3,3-trifluoro-2-hydroxypropanoate (23 g, 87.4 mmol) in AcOH (400 mL) was added KSCN (29.72 g, 305.8 mmol). The reaction was stirred at 20 °C for 1 h, followed by the dropwise addition of Br2(4.95 mL, 96.1 mmol). After stirring at 20 °C for 12 h, the reaction was filtered through Celite. The filtrate was diluted with H2O (400 mL). The aqueous layer was adjusted to pH = 5-7 using Na2CO3and then extracted with EtOAc (1 L x 3). The combined organic layer was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated and purified by silica gel column chromatography (0-100% PE / EtOAc) to afford the title compound (45.7 g, 82%) as a yellow solid. MS (ESI): mass calcd. for C12H11F3N2O3S: 320.04, found: 321.0 [M+H]+. (S)-2-(2-Aminobenzo[d]thiazol-6-yl)-N-ethyl-3,3,3-trifluoro-2-hydroxypropanamide To an ice-cold solution of ethanamine hydrochloride (25.46 g, 312.2 mmol) in toluene (150 mL) was added 2 M trimethylaluminum solution in hexanes (156.1 mL, 212.2 mmol) dropwise under N2. The reaction was heated at 40 °C for 30 min. Ethyl (S)-2-(2- aminobenzo[d]thiazol-6-yl)-3,3,3-trifluoro-2-hydroxypropanoate (10 g, 31.2 mmol) was added in portions. After heating at 80 °C for 12 h, the reaction was cooled to 0 °C. It was quenched with sat. aqueous NH4Cl (1 L). The aqueous layer was extracted with EtOAc (500 mL x 3). The combined organic layer was washed with brine, dried over anhydrous Na2SO4, FoleyHoagUS12952954.4 GPX-01525 filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (0-100% PE / EtOAc) to afford the title compound (6.6 g, 66%) as a yellow solid. MS (ESI): mass calcd. for C12H12F3N3O3S: 319.06, found: 320.1 [M+H]+. (S)-2-(2-(3-(2-Cyclopropyl-2,2-difluoroethyl)ureido)benzo[d]thiazol-6-yl)-N-ethyl-3,3,3- trifluoro-2-hydroxypropanamide (163) To a solution of (S)-2-(2-aminobenzo[d]thiazol-6-yl)-N-ethyl-3,3,3-trifluoro-2- hydroxypropanamide (25 mg, 0.078 mmol) in THF (0.8 mL) was added pyridine (63 μL, 0.78 mmol) and (4-nitrophenyl) carbonochloridate (31.6 mg, 0.16 mmol). After stirring at 25 °C for 30 min, 2-cyclopropyl-2,2-difluoroethylamine hydrogen chloride (1:1) (37 mg, 0.24 mmol) was added. After stirring for an additional 30 min, the reaction solvent was removed under reduced pressure. The resulting residue was purified by reverse phase HPLC (gradient elution, 20-60% ACN in H2O with 0.1% TFA as a modifier) to afford the title product (163) (30.9 mg, 84%) as a white solid. MS (ESI): mass calcd. for C18H19F5N4O3S: 466.11, found: 467.20 [M+H]+.1H NMR (400 MHz; DMSO-d6): 10.80 (br s, 1H), 8.19 (t, J = 5.9 Hz, 1H), 8.14 (s, 1H), 7.76 (s, 1H), 7.64 (s, 2H), 7.12 (t, J = 6.0 Hz, 1H), 3.74 (td, J = 14.4, 6.2 Hz, 2H), 3.09 - 3.16 (m, 2H), 1.37 - 1.47 (m, 1H), 0.99 (t, J = 7.2 Hz, 3H), 0.56 - 0.62 (m, 4H). Example 164, 167, 168 and 169 were synthesized in similar procedures as described in Example 163. Example 165 and 166. (S)-N-Ethyl-2-(2-(3-((1R,2R)-2- ethylcyclopentyl)ureido)benzo[d]thiazol-6-yl)-3,3,3-trifluoro-2-hydroxypropanamide (165) & (S)-N-ethyl-2-(2-(3-((1R,2S)-2-ethylcyclopentyl)ureido)benzo[d]thiazol-6-yl)- 3,3,3-trifluoro-2-hydroxypropanamide (166) FoleyHoagUS12952954.4 GPX-01525 (1R)-2-Ethyl-N-((R)-1-(4-methoxyphenyl)ethyl)cyclopentan-1-amine To a solution of 2-ethylcyclopentanone (4.7 g, 41.90 mmol) in DCM (200 mL) was added NaBH(OAc)3(22.2 g, 104.75 mmol) and (1R)-1-(4-methoxyphenyl)ethanamine (6.34 g, 41.9 mmol). The mixture was stirred at 25 °C for 12 h and then quenched with sat. NaHCO3(200 mL). The aqueous layer was extracted with DCM (200 mL x 3). The combined organic layer was washed with brine, dried over Na2SO4, filtered, concentrated and purified by silica gel column chromatography (5-100% EtOAc / PE) to afford a crude material, which contained one major pair of diastereomers and one minor pair of diastereomers. It was further purified by reverse phase HPLC (gradient elution, 35-70% ACN / H2O, with 10 mM NH4HCO3as a modifier) to give the title compound (2.3 g, 22%, major diastereomer pair) as a yellow oil. MS (ESI): mass calcd. for C16H25NO: 247.19, found: 248.3 [M+H]+. (1R)-2-Ethylcyclopentan-1-amine To a suspension of (1R)-2-ethyl-N-((R)-1-(4-methoxyphenyl)ethyl)cyclopentan-1- amine (1.3 g, 5.26 mmol) and 20% Pd(OH)2(221.4 mg) in MeOH (20 mL) was added aqueous 12 N HCl (0.56 mL). The reaction was degassed and purged with H2(3x), and stirred at 25 °C under H2(15 Psi) for 12 h. After completion, the reaction mixture was filtered through a pad of celite. The filtrate was concentrated under reduced pressure to give FoleyHoagUS12952954.4 GPX-01525 the crude title compound (2 diastereomers) as a yellow solid, which was used directly in the next step without further purification. MS (ESI): mass calcd. for C7H15N: 113.12, found: 114.2 [M+H]+. (2S)-N-Ethyl-2-(2-(3-((1R)-2-ethylcyclopentyl)ureido)benzo[d]thiazol-6-yl)-3,3,3- trifluoro-2-hydroxypropanamide To a solution of (1R)-2-ethylcyclopentanamine (531.78 mg, 4.7 mmol) and (S)-2-(2- aminobenzo[d]thiazol-6-yl)-N-ethyl-3,3,3-trifluoro-2-hydroxypropanamide (300 mg, 939 mol) in DMF (5 mL) was added CDI (304.7 mg, 1.88 mmol) at 20°C under N2. After heating at 50 °C for 12 h, the reaction was quenched with H2O (10 mL). The aqueous layer was extracted with EtOAc (30 mL x 3). The combined organic layer was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by reverse phase HPLC (gradient elution, 30-70% ACN / H2O, with 10 mM NH4HCO3as a modifier) to obtain the title compound (75.8 mg, 18%) as a white solid. MS (ESI): mass calcd. for C20H25F3N4O3S: 458.2, found: 459.2 [M+H]+.1H NMR (400 MHz, DMSO-d6) ppm 10.33 (s, 1H), 8.21 (t, J = 6.0 Hz, 1H), 8.12 (s, 1H), 7.74 (s, 1H), 7.56-7.68 (m, 2H), 6.70 (d, J = 8.8 Hz, 1H), 4.01-4.17 (m, 1H), 3.06-3.19 (m, 2H), 2.79-2.79 (m, 1H), 1.74-1.91 (m, 3H), 1.48- 1.69 (m, 3H), 1.32-1.35 (m, 1H), 1.16-1.28 (m, 2H), 0.99 (t, J = 6.8 Hz, 3H), 0.87 (t, J = 7.2 Hz, 3H). (S)-N-Ethyl-2-(2-(3-((1R,2R)-2-ethylcyclopentyl)ureido)benzo[d]thiazol-6-yl)-3,3,3- trifluoro-2-hydroxypropanamide (165) & (S)-N-ethyl-2-(2-(3-((1R,2S)-2- ethylcyclopentyl)ureido)benzo[d]thiazol-6-yl)-3,3,3-trifluoro-2-hydroxypropanamide (2S)-N-Ethyl-2-(2-(3-((1R)-2-ethylcyclopentyl)ureido)benzo[d]thiazol-6-yl)-3,3,3- trifluoro-2-hydroxypropanamide (71 mg, 155 mol) was separated by chiral SFC (column: DAICEL CHIRALPAK IG, (250 mm*30 mm, 10 um); mobile phase: CO2-IPA; 50% B with isocratic elution mode) to give (S)-N-ethyl-2-(2-(3-((1R,2R)-2- FoleyHoagUS12952954.4 GPX-01525 ethylcyclopentyl)ureido)benzo[d]thiazol-6-yl)-3,3,3-trifluoro-2-hydroxypropanamide (165) (4 mg, 6%) as a white solid. MS (ESI): mass calcd. for C20H25F3N4O3S: 458.2, found: 459.2 [M+H]+.1H NMR (400 MHz, DMSO-d6) ppm 10.33 (s, 1H), 8.21 (t, J = 6.0 Hz, 1H), 8.12 (s, 1H), 7.74 (s, 1H), 7.56-7.68 (m, 2H), 6.70 (d, J = 8.8 Hz, 1H), 4.01-4.17 (m, 1H), 3.06-3.19 (m, 2H), 1.74-1.91 (m, 3H), 1.48-1.69 (m, 3H), 1.32-1.35 (m, 1H), 1.16-1.28 (m, 2H), 0.99 (t, J = 6.8 Hz, 3H), 0.87 (t, J = 7.2 Hz, 3H). And (S)-N-ethyl-2-(2-(3-((1R,2S)-2- ethylcyclopentyl)ureido)benzo[d]thiazol-6-yl)-3,3,3-trifluoro-2-hydroxypropanamide (166) (31.71 mg, 45%) as a white solid. MS (ESI): mass calcd. for C20H25F3N4O3S: 458.2, found: 459.2 [M+H]+.1H NMR (400 MHz, DMSO-d6) ppm 10.37 (s, 1H), 8.21 (t, J = 6.0 Hz, 1H), 8.12 (s, 1H), 7.75 (s, 1H), 7.56-7.67 (m, 2H), 6.71 (d, J = 7.6 Hz, 1H), 4.03-4.16 (m, 1H), 3.06- 3.18 (m, 2H), 1.73-1.92 (m, 3H), 1.62-1.69 (m, 1H), 1.48-1.61 (m, 2H), 1.35-1.37 (m, 1H), 1.23-1.24 (m, 2H), 0.99 (t, J = 6.8 Hz, 3H), 0.88 (t, J = 7.2 Hz, 3H). Stereochemistry was arbitrarily assigned. Example 172. 1-(6-(1-(5-Ethoxypyridazin-3-yl)-2,2,2-trifluoro-1- hydroxyethyl)benzo[d]thiazol-2-yl)-3-(4-fluorophenyl)urea (172) Synthetic scheme: FoleyHoagUS12952954.4 GPX-01525 5-Chloro-N-methoxy-N-methylpyridazine-3-carboxamide To a solution of 5-chloropyridazine-3-carboxylic acid (4 g, 25.23 mmol) in DCM (40 mL) was added N-methoxymethanamine hydrochloride (2.95 g, 30.3 mmol), TEA (12.76 g, 126.2 mmol) and T4P (36.36 g, 50.5 mmol, 50% in EtOAc). The mixture was stirred at 20 °C for 16 h and quenched with H2O (50 mL). The aqueous layer was extracted with EtOAc (50 mL x 2). The combined organic layer was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (0-100% EtOAc / PE) to give the title compound (4.5 g, 88%) as a yellow oil. MS (ESI): mass calcd. C7H8ClN3O2: 201.03, found: 202.1 [M+H]+.1H NMR (400 MHz, CDCl3) ppm 9.24 (d, J = 2.0 Hz, 1H), 7.78 (s, 1H), 3.84 (s, 3H), 3.42 (s, 3H). 5-Ethoxy-N-methoxy-N-methylpyridazine-3-carboxamide FoleyHoagUS12952954.4 GPX-01525 To an ice-cold solution of 5-chloro-N-methoxy-N-methyl-pyridazine-3-carboxamide (2.5 g, 12.40 mmol) in DMA (25 mL) was added 60% NaH (743.94 mg, 18.6 mmol) under N2. After stirring at 20 °C for 15 min, EtOH (2.86 g, 62 mmol) was added, and the reaction was stirred for an additional 135 min. Upon completion, the reaction was quenched with sat. NH4Cl (50 mL). The aqueous layer was extracted with EtOAc (50 mL x2). The combined organic layer was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (0-100% EtOAc / PE) to afford the title compound (2 g, 76%) as a yellow oil. MS (ESI): mass calcd. C9H13N3O3: 211.10, found: 212.2 [M+H]+.1H NMR (400 MHz, CDCl3-d) ppm 8.91 (d, J = 2.4 Hz, 1H), 7.09-7.17 (m, 1H), 4.16-4.21 (m, 2H), 3.85 (s, 3H), 3.41-3.58 (m, 3H), 1.49 (t, J = 7.2 Hz, 3H). (4-Bromophenyl)(5-ethoxypyridazin-3-yl)methanone A solution of 2 M i-PrMgCl in THF (7.1 mL, 14.2 mmol) was added to a solution of 1- bromo-4-iodo-benzene (4.02 g, 14.2 mmol) in THF (25 mL) at –78 °C under N2. After stirring at the same temperature for 30 min, 5-ethoxy-N-methoxy-N-methyl-pyridazine-3-carboxamide (2.5 g, 11.84 mmol) was added and the reaction was stirred at –78 °C for an additional 2 h. Upon completion, the reaction was quenched with sat. NH4Cl (50 mL). The aqueous layer was extracted with EtOAc (50 mL x2). The combined organic layer was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (9-50% EtOAc / PE) to obtain a crude material, which was further purified by reverse phase HPLC (gradient elution, 30-65% ACN / H2O, with 10 mM NH4HCO3as a modifier) to obtain the desired product (560 mg, 15%) as a yellow oil. MS (ESI): mass calcd. C13H11BrN2O2: 306.00, found: 306.8 [M+H]+.1H NMR (400 MHz, DMSO- d6) ppm 9.18 (d, J = 3.2 Hz, 1H), 7.95-7.97 (m, 2H), 7.79-7.82 (m, 2H), 7.67 (d, J = 2.8 Hz, 1H), 4.29-4.35 (m, 2H), 1.40 (t, J = 7.2 Hz, 3H). 1-(4-Bromophenyl)-1-(5-ethoxypyridazin-3-yl)-2,2,2-trifluoroethan-1-ol To an ice-cold solution of (4-bromophenyl)-(5-ethoxypyridazin-3-yl)methanone (360 mg, 1.17 mmol) in THF (4 mL) was added TMSCF3(1.67 g, 11.72 mmol) and a solution of 1 FoleyHoagUS12952954.4 GPX-01525 M TBAF in THF (58.6 L, 0.059 mmol). The reaction was stirred at rt for 12 h and quenched with H2O (10 mL). The aqueous layer was extracted with EtOAc (10 mL x 3). The combined organic layer was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was dissolved in an aqueous solution of 1 N HCl (1.17 mL) and THF (4 mL) and stirred at rt for 12 h. Then it was diluted with H2O (5 mL) and extracted with EtOAc (5 mL x 3). The combined organic layer was washed with brine, dried over Na2SO4, filtered, concentrated and purified by silica gel column chromatography (0-50% EtOAc / PE) to afford the title compound (640 mg, 72%) as a yellow oil. MS (ESI): mass calcd. C14H12BrF3N2O2: 376.00, found: 377.1 [M+H]+.1H NMR (400 MHz, DMSO-d6) ppm 9.01 (d, J = 2.8 Hz, 1H), 7.99 (s, 1H), 7.60-7.62 (m, 2H), 7.49-7.52 (m, 2H), 7.25 (d, J = 2.8 Hz, 1H), 4.15-4.21 (m, 2H), 1.33 (t, J = 7.2 Hz, 3H). 1-(6-(1-(5-Ethoxypyridazin-3-yl)-2,2,2-trifluoro-1-hydroxyethyl)benzo[d]thiazol-2-yl)-3- (4-fluorophenyl)urea (172) The title compound (172) was synthesized from 1-(4-bromophenyl)-1-(5- ethoxypyridazin-3-yl)-2,2,2-trifluoroethan-1-ol in similar procedures as described in reference compounds A and B. MS (ESI): mass calcd. C14H12BrF3N2O2: 376.00, found: 377.1 [M+H]+.1H NMR (400 MHz, DMSO-d6) ppm 9.01 (d, J = 2.8 Hz, 1H), 7.99 (s, 1H), 7.60-7.62 (m, 2H), 7.49-7.52 (m, 2H), 7.25 (d, J = 2.8 Hz, 1H), 4.15-4.21 (m, 2H), 1.33 (t, J = 7.2 Hz, 3H). Examples 176, and 177 were synthesized through chiral SFC separation of Example 172. Example 175. 1-(4-Fluorophenyl)-3-(6-(2-hydroxy-8-methyl-7-oxo-6-(trifluoromethyl)- 5,8-diazaspiro[3.5]nonan-6-yl)benzo[d]thiazol-2-yl)urea (175) FoleyHoagUS12952954.4 GPX-01525 Synthetic scheme: 2-(Benzyloxy)-5,7-diazaspiro[3.4]octane-6,8-dione FoleyHoagUS12952954.4 GPX-01525 To a solution of (NH4)2CO3(54.53 g, 567.5 mmol) in H2O (100 mL) and MeOH (100 mL) was added 3-benzyloxycyclobutanone (10 g, 56.75 mmol). After stirring at 20 °C for 30 min, TMSCN (25.34 g, 255.4 mmol) was added. The reaction was heated at 60 °C for 12 h. After completion, the reaction was filtered. The solid was dried over vacuum to obtain the title compound (7.7 g, 55%) as a white solid, which was directly used in the next step without further purification. MS (ESI): mass calcd. for C13H14N2O3: 246.10, found: 247.0 [M+H]+. 1-Amino-3-(benzyloxy)cyclobutane-1-carboxylic acid A solution of 2-(benzyloxy)-5,7-diazaspiro[3.4]octane-6,8-dione (5.7 g, 23.15 mmol) in 3 N aqueous NaOH (61.72 mL) was stirred at 120 °C for 12 h in a sealed tube. After completion, the mixture was adjusted to pH = 9 with 6 N aqueous HCl (30 mL). The resulting solution was directly used in the next step without further purification. MS (ESI): mass calcd. for C12H15NO3: 221.11, found: 221.9 [M+H]+. 3-(Benzyloxy)-1-((tert-butoxycarbonyl)amino)cyclobutane-1-carboxylic acid To a solution of the crude 1-amino-3-(benzyloxy)cyclobutane-1-carboxylic acid and Boc2O (20.71 g, 94.9 mmol) was added THF (50 mL). It was stirred at 20 °C for 12 h. Then the reaction was added sat. NH4Cl and extracted with ethyl acetate (100 mL x 3). The combined organic layer was washed with brine, dried over Na2SO4, filtered, concentrated and purified by silica gel column chromatography (9-100% EtOAc / PE) to afford the title compound (5.4 g, 53%) as a yellow solid. MS (ESI): mass calcd. for C17H23NO5: 321.16, found: 221.9 [M-100+H]+.1H NMR (400 MHz, DMSO-d6) ppm 12.40 (s, 1H), 7.57 (s, 1H), 7.24-7.40 (m, 5H), 4.37 (s, 2H), 3.93-4.06 (m, 1H), 2.65-2.80 (m, 2H), 1.97-2.10 (m, 2H), 1.30-1.42 (m, 9H). (1-Amino-3-(benzyloxy)cyclobutyl)methanol FoleyHoagUS12952954.4 GPX-01525 To an ice-cold solution of 3-(benzyloxy)-1-((tert-butoxycarbonyl)amino)cyclobutane- 1-carboxylic acid (5 g, 15.56 mmol) in THF (50 mL) was added a solution of 10 M BH3- Me2S in THF (3.11 mL, 31.1 mmol). The mixture was stirred at 20 °C for 12 h. Upon completion, the reaction was quenched with H2O (50 mL). The aqueous layer was extracted with EtOAc (50 mL x 3). The combined organic layer was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure to give the crude title compound (3 g) as a white solid, which was directly used in the next step without further purification. MS (ESI): mass calcd. for C12H17NO2: 207.13, found: 207.9 [M+1]+. tert-Butyl (3-(benzyloxy)-1-(hydroxymethyl)cyclobutyl)carbamate To a solution of (1-amino-3-benzyloxy-cyclobutyl)methanol (3 g, 14.47 mmol) in THF (30 mL) was added Boc2O (4.74 g, 21.7 mmol) and TEA (4.39 g, 43.4 mmol). The mixture was stirred at 20 °C for 12 h. Upon completion, the reaction was quenched with sat. NH4Cl (30 mL). The aqueous was extracted with EtOAc (30 mL x 3). The combined organic layer was washed with brine, dried over Na2SO4, filtered, concentrated and purified by silica gel column chromatography (5-100% EtOAc / PE) to afford the title compound (1.34 g, 30%) as a white solid. MS (ESI): mass calcd. for C17H25NO4: 307.18, found: 207.9 [M- 100+H]+. tert-Butyl (3-(benzyloxy)-1-(((N-methyl-4- nitrophenyl)sulfonamido)methyl)cyclobutyl)carbamate To a solution of tert-butyl (3-(benzyloxy)-1-(hydroxymethyl)cyclobutyl)carbamate (2.7 g, 8.78 mmol) in toluene (30 mL) was added N-methyl-4-nitro-benzenesulfonamide (2.85 g, 13.2 mmol) and 2-(tributyl-phosphanylidene)acetonitrile (3.18 g, 13.2 mmol) at 0 °C. The mixture was heated to 110 °C and stirred for 12 h. After completion, the reaction was cooled to rt. The reaction solvent was removed under reduced pressure. The resulting residue was purified by silica gel column chromatography (9-100% EtOAc / PE) to obtain the title compound (1.1 g, 25%) as a white solid. MS (ESI): mass calcd. for C24H31N3O7S: 505.19, found: 406.0 [M-100+H]+. FoleyHoagUS12952954.4 GPX-01525 N-((1-Amino-3-(benzyloxy)cyclobutyl)methyl)-N-methyl-4-nitrobenzenesulfonamide To a solution of tert-butyl (3-(benzyloxy)-1-(((N-methyl-4- nitrophenyl)sulfonamido)methyl)cyclobutyl)carbamate (1.1 g, 2.18 mmol) in dioxane (5 mL) was added 4 N HCl in dioxane (2.72 mL, 10.9 mmol). It was stirred at 20 °C for 12 h. Then the reaction solvent was removed under reduced pressure. The crude product was triturated with EtOAc (2 mL) at 20 °C for 10 min to afford the title compound (750 mg, 85%) as a yellow solid. MS (ESI): mass calcd. for C19H23N3O5S: 405.14, found: 406.0 [M+1]+. 2-((3-(Benzyloxy)-1-(((N-methyl-4-nitrophenyl)sulfonamido)methyl)cyclobutyl)amino)- 2-(4-(dibenzylamino)phenyl)-3,3,3-trifluoropropanoic acid To a solution of 2-[4-(dibenzylamino)phenyl]-3,3,3-trifluoro-2-hydroxy-propanoic acid (700 mg, 1.69 mmol) in THF (10 mL) was added 1 M (COCl)2 (1.85 mL, 1.85 mmol). The mixture was stirred at 20 °C for 30 min, followed by addition of N-((1-amino-3- (benzyloxy)cyclobutyl)methyl)-N-methyl-4-nitrobenzenesulfonamide (751.58 mg, 1.85 mmol) and TEA (852.6 mg, 8.43 mmol). It was allowed to stir at rt for 12 h. Upon completion, the reaction was quenched with sat. NH4Cl (30 mL). The aqueous layer was extracted with EtOAc (10 mL x 3). The combined organic layer was washed with brine, dried over Na2SO4, filtered, concentrated and purified by silica gel column chromatography (9-100% EtOAc / PE) to give the crude product (750 mg) as a yellow solid. MS (ESI): mass calcd. for C42H41F3N4O7S: 802.26, found: 803.2 [M+1]+. 2-((3-(Benzyloxy)-1-((methylamino)methyl)cyclobutyl)amino)-2-(4- (dibenzylamino)phenyl)-3,3,3-trifluoropropanoic acid FoleyHoagUS12952954.4 GPX-01525 To a solution of 2-((3-(benzyloxy)-1-(((N-methyl-4- nitrophenyl)sulfonamido)methyl)cyclobutyl)amino)-2-(4-(dibenzylamino)phenyl)-3,3,3- trifluoropropanoic acid (700 mg, 872 mol) in DMF (7 mL) was added K2CO3(361.5 mg, 2.62 mmol) and PhSH (336.2 mg, 3.05 mmol). The mixture was stirred at 30 °C for 12 h. Then the reaction was quenched with sat. NH4Cl (10 mL). The aqueous layer was extracted with EtOAc (10 mL x 3). The combined organic layer was washed with brine, dried over Na2SO4, filtered, concentrated and purified by silica gel column chromatography (9-100% EtOAc / PE) to give the crude title compound (530 mg) as a brown solid, which was directly used in the next step without further purification. 1-(6-(2-(Benzyloxy)-8-methyl-7-oxo-6-(trifluoromethyl)-5,8-diazaspiro[3.5]nonan-6- yl)benzo[d]thiazol-2-yl)-3-(4-fluorophenyl)urea The title compound was synthesized from 2-((3-(benzyloxy)-1- ((methylamino)methyl)cyclobutyl)amino)-2-(4-(dibenzylamino)phenyl)-3,3,3- trifluoropropanoic acid in similar procedures as described in Example 2. MS (ESI): mass calcd. for C30H27F4N5O3S: 613.18, found: 614.2 [M+1]+.1H NMR (400 MHz, DMSO-d6) ppm 10.89 (s, 1H), 9.17 (s, 1H), 8.09 (s, 1H), 7.46-7.73 (m, 4H), 7.12-7.34 (m, 7H), 4.13 (s, 1H), 3.99-4.07 (m, 1H), 3.74 (t, J = 7.2 Hz, 1H), 3.28 (s, 1H), 3.12 (d, J = 12.0 Hz, 1H), 2.99 (s, 3H), 2.25-2.31 (m, 1H), 2.11-2.19 (m, 1H), 1.90-1.97 (m, 1H), 1.37-1.46 (m, 1H). 1-(4-Fluorophenyl)-3-(6-(2-hydroxy-8-methyl-7-oxo-6-(trifluoromethyl)-5,8- diazaspiro[3.5]nonan-6-yl)benzo[d]thiazol-2-yl)urea (175) FoleyHoagUS12952954.4 GPX-01525 To a solution of 1-(6-(2-(benzyloxy)-8-methyl-7-oxo-6-(trifluoromethyl)-5,8- diazaspiro[3.5]nonan-6-yl)benzo[d]thiazol-2-yl)-3-(4-fluorophenyl)urea (20 mg, 32.6 mol) in DCM (0.5 mL) was added 1 M BBr3 (163 L, 0.16 mmol) at –70 °C under N2. The mixture was allowed to warm to –20 °C and stirred for 12 h. After completion, the reaction was filtered. The filtrate was concentrated under reduced pressure. The resulting residue was purified by reverse phase HPLC (gradient elution, 25-55% ACN / H2O, with 10 mM NH4HCO3as a modifier) to give the title compound (175) (17 mg, 100%, mixture of two diastereomers) as a white solid. The stereochemistry of the OH was confirmed to be cis to the amine. MS (ESI): mass calcd. for C23H21F4N5O3S: 523.13, found: 524.2 [M+1]+.1H NMR (400 MHz, DMSO- d6) ppm 10.75 (s, 1H), 9.11-9.34 (m, 1H), 8.07 (s, 1H), 7.59-7.68 (m, 2H), 7.51-7.59 (m, 2H), 7.17 (t, J = 8.8 Hz, 2H), 4.94 (d, J = 4.8 Hz, 1H), 3.94 (s, 1H), 3.79-3.83 (m, 1H), 3.25-3.29 (m, 1H), 3.09-3.12 (m, 1H), 2.99 (s, 3H), 2.19-2.26 (m, 1H), 2.00-2.07 (m, 1H), 1.86-1.93 (m, 1H), 1.25-1.32 (m, 1H). Example 178 and 179. 1-(4-Fluorophenyl)-3-(6-((2S,5S)-5-(hydroxymethyl)-4-methyl-3- oxo-2-(trifluoromethyl)piperazin-2-yl)benzo[d]thiazol-2-yl)urea (178) & 1-(4- fluorophenyl)-3-(6-((2R,5S)-5-(hydroxymethyl)-4-methyl-3-oxo-2- (trifluoromethyl)piperazin-2-yl)benzo[d]thiazol-2-yl)urea (179) Synthetic scheme: FoleyHoagUS12952954.4 GPX-01525 Methyl (S)-2-(((benzyloxy)carbonyl)amino)-3-((tert-butoxycarbonyl)amino)propanoate To a solution of (2S)-2-(benzyloxycarbonylamino)-3-(tert- butoxycarbonylamino)propanoic acid (24 g, 70.9 mmol) in DMF (240 mL) was added MeI (12.08 g, 85.1 mmol) and K2CO3(9.80 g, 70.9 mmol). The reaction was stirred at 25 °C for 12 h. After completion, the reaction was quenched with H2O (720 mL). The aqueous layer was extracted with EtOAc (240 mL x 3). The combined organic layer was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (9-50% EtOAc / PE) to afford the title compound (24.3 g, 97%) as a yellow oil.1H NMR (400 MHz, DMSO-d6) (ppm) 7.59 (d, J FoleyHoagUS12952954.4 GPX-01525 = 7.6 Hz, 1H), 7.25-7.40 (m, 5H), 6.88 (t, J = 6.0 Hz, 1H), 4.99-5.08 (m, 2H), 4.09-4.16 (m, 1H), 3.54-3.65 (m, 3H), 3.24-3.32 (m, 2H), 1.36 (s, 9H). Methyl (S)-2-amino-3-((tert-butoxycarbonyl)amino)propanoate 10% Pd / C (1.47 g) was added to a solution of methyl (S)-2- (((benzyloxy)carbonyl)amino)-3-((tert-butoxycarbonyl)amino)propanoate (24.3 g, 69 mmol) in MeOH (240 mL) under N2. The resulting suspension was degassed and purged with H2 (3x). After stirring at 25 °C for 12 h under H2(15 psi), the reaction was filtered through a celite pad. The filtrate was concentrated under reduced pressure to afford the title compound (15.9 g, crude) as a green oil, which was directly used in the next step without further purification. MS (ESI): mass calcd. for C9H18O4N2: 218.25, found: 219.2 [M+H]+.1H NMR (400 MHz, DMSO- d6) (ppm) 6.84 (t, J = 6.0 Hz, 1H), 3.58 (s, 3H), 3.35-3.38 (m, 1H), 3.08-3.11 (m, 2H), 1.77 (s, 2H), 1.36 (s, 9H). Methyl (S)-3-((tert-butoxycarbonyl)amino)-2-((4-nitrophenyl)sulfonamido)propanoate To an ice-cold solution of methyl (S)-2-amino-3-((tert- butoxycarbonyl)amino)propanoate (15.9 g, 72.85 mmol) in DCM (160 mL) was added DIPEA (28.25 g, 218.6 mmol) and 4-nitrobenzenesulfonyl chloride (16.15 g, 72.9 mmol). It was stirred at 0 °C for 1 h. Upon completion, the reaction was diluted with H2O (160 mL). The aqueous layer was extracted with DCM (160 mL x 3). The combined organic layer was washed with brine, dried over Na2SO4, filtered, concentrated, and purified by silica gel column chromatography (9-100% EtOAc / PE) to obtain the title compound (25.4 g, 86%) as a yellow solid.1H NMR (400 MHz, DMSO-d6) ppm 8.76 (d, J = 1.2 Hz, 1H), 8.40 (d, J = 8.8 Hz, 2H), 8.00 (d, J = 8.8 Hz, 2H), 6.87 (t, J = 5.6 Hz, 1H), 4.00 (s, 1H), 3.39 (s, 3H), 3.03-3.24 (m, 2H), 1.31 (s, 9H). Methyl (S)-3-((tert-butoxycarbonyl)amino)-2-((N-methyl-4- nitrophenyl)sulfonamido)propanoate FoleyHoagUS12952954.4 GPX-01525 To a solution of methyl (S)-3-((tert-butoxycarbonyl)amino)-2-((4- nitrophenyl)sulfonamido)propanoate (25.4 g, 63 mmol) in DMF (250 mL) was added MeI (8.94 g, 63 mmol) and Cs2CO3(61.54 g, 189 mmol). It was stirred at 25 °C for 12 h. After completion, the reaction was quenched with H2O (750 mL). The aqueous layer was extracted with EtOAc (250 mL x 3). The combined organic layer was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The resulting residue was purified by reverse phase HPLC (gradient elution, 35-65% ACN / H2O, with 0.02% FA as a modifier) to give the title compound (13.5 g, 51%) as a yellow oil.1H NMR (400 MHz, DMSO-d6) (ppm) 8.39 (d, J = 8.8 Hz, 2H), 8.03 (d, J = 9.2 Hz, 2H), 6.99 (t, J = 6.0 Hz, 1H), 4.69-4.73 (m, 1H), 3.47 (s, 3H), 3.39-3.45 (m, 1H), 3.18-3.25 (m, 1H), 2.82 (s, 3H), 1.33 (s, 9H). Methyl (S)-3-amino-2-((N-methyl-4-nitrophenyl)sulfonamido)propanoate A solution of 4 N HCl in dioxane (65 mL) was added to a solution of methyl (S)-3- ((tert-butoxycarbonyl)amino)-2-((N-methyl-4-nitrophenyl)sulfonamido)propanoate (13.5 g, 32.3 mmol) in dioxane (65 mL). After stirring at 25 °C for 12 h, the reaction solvent was removed under reduced pressure to afford the title compound (12.48 g, HCl salt) as a yellow solid, which was directly used in the next step without further purification. MS (ESI): mass calcd. for C11H15O6N3S: 317.32, found: 318.2 [M+H]+.1H NMR (400 MHz, DMSO-d6) ppm 8.43 (d, J = 8.8 Hz, 2H), 8.19 (s, 3H), 8.09 (d, J = 8.8 Hz, 2H), 4.94-4.97 (m, 1H), 3.39 (s, 3H), 3.16-3.31 (m, 2H), 2.82 (s, 3H). (HCl salt). Methyl (2S)-5-(2-(3-(4-fluorophenyl)ureido)benzo[d]thiazol-6-yl)-1-methyl-6-oxo-5- (trifluoromethyl)piperazine-2-carboxylate The title compound (diastereomer mixture) was synthesized from (2S)-2-(4- aminophenyl)-4-[(4-methoxyphenyl)methyl]-5-methyl-2-(trifluoromethyl)morpholin-3-one in similar procedures as described in Example 2. MS (ESI): mass calcd. for C22H19F4N5O4S: 525.11, found: 526.0 [M+H]+. FoleyHoagUS12952954.4 GPX-01525 1-(4-Fluorophenyl)-3-(6-((2S,5S)-5-(hydroxymethyl)-4-methyl-3-oxo-2- (trifluoromethyl)piperazin-2-yl)benzo[d]thiazol-2-yl)urea (178) & 1-(4-fluorophenyl)-3- (6-((2R,5S)-5-(hydroxymethyl)-4-methyl-3-oxo-2-(trifluoromethyl)piperazin-2- yl)benzo[d]thiazol-2-yl)urea (179) To a solution of methyl (2S)-5-(2-(3-(4-fluorophenyl)ureido)benzo[d]thiazol-6-yl)-1- methyl-6-oxo-5-(trifluoromethyl)piperazine-2-carboxylate (200 mg, 381 mol) in THF (2 mL) was added a solution of 2.5 M LiBH4in THF (457 L) under N2. The mixture was stirred at 0 °C for 2 h. After completion, the reaction was quenched with sat. NH4Cl (10 mL). The aqueous layer was extracted with EtOAc (20 mL x 2). The combined organic layer was washed with brine, dried over Na2SO4, filtered, concentrated and purified by reverse phase HPLC (gradient elution, 20-45% ACN / H2O, with 10 mM NH4HCO3as a modifier) to give the title compound (178) (50 mg, 26%) as a white solid. MS (ESI): mass calcd. for C21H19F4N5O3S: 497.11, found: 498.1 [M+H]+.1H NMR (400 MHz, DMSO-d6) ppm 10.92 (s, 1H), 9.23 (s, 1H), 8.20 (s, 1H), 7.73-7.78 (m, 1H), 7.68 (d, J = 6.8 Hz, 1H), 7.53-7.55 (m, 2H), 7.17 (t, J = 8.8 Hz, 2H), 5.00 (t, J = 5.2 Hz, 1H), 4.02 (s, 1H), 3.68-3.76 (m, 1H), 3.59-3.67 (m, 1H), 3.14-3.20 (m, 1H), 3.04-3.05 (m, 1H), 2.96 (s, 3H), 2.70 (d, J = 10.8 Hz, 1H). And to give the title compound (179) (50 mg, 26%) as a white solid. MS (ESI): mass calcd. for C21H19F4N5O3S: 497.11, found: 498.1 [M+H]+.1H NMR (400 MHz, DMSO-d6) ppm 10.93 (s, 1H), 9.23 (s, 1H), 8.16 (s, 1H), 7.70-7.75 (m, 1H), 7.66 (s, 1H), 7.53-7.56 (m, 2H), 7.17 (t, J = 8.8 Hz, 2H), 4.67 (t, J = 5.2 Hz, 1H), 4.00 (t, J = 3.2 Hz, 1H), 3.39-3.48 (m, 2H), 3.23-3.31 (m, 1H), 3.01-3.09 (m, 1H), 2.97 (s, 3H), 2.67-2.76 (m, 1H). Example 180, and 181 were synthesized the same procedures as described in Example 178 and 179. Example 185 and 186. (2S,5S)-5-(2-(3-(4-Fluorophenyl)ureido)benzo[d]thiazol-6-yl)-1- methyl-6-oxo-5-(trifluoromethyl)piperazine-2-carboxylic acid (185) & (2S,5R)-5-(2-(3-(4- FoleyHoagUS12952954.4 GPX-01525 fluorophenyl)ureido)benzo[d]thiazol-6-yl)-1-methyl-6-oxo-5- (trifluoromethyl)piperazine-2-carboxylic acid (186) (2S)-5-(2-(3-(4-fluorophenyl)ureido)benzo[d]thiazol-6-yl)-1-methyl-6-oxo-5- (trifluoromethyl)piperazine-2-carboxylic acid (161) To a solution of methyl (2S)-5-(2-(3-(4-fluorophenyl)ureido)benzo[d]thiazol-6-yl)-1- methyl-6-oxo-5-(trifluoromethyl)piperazine-2-carboxylat (200 mg, 381 mol) in THF (1 mL) and H2O (1 mL) was added LiOH.H2O (24 mg, 571 mol). The mixture was stirred at 20 °C for 12 h. After completion, the reaction was adjusted to pH = 6 with 1 N HCl. The solvent was removed under reduced pressure. The resulting residue was purified by reverse phase HPLC (gradient elution, 8-38% ACN / H2O, with 10 mM NH4HCO3as a modifier) to give the title compound (145 mg, 74%) as a white solid. MS (ESI): mass calcd. for C21H17F4N5O4S: 511.09, found: 512.1 [M+H]+.1H NMR (400 MHz, DMSO-d6) ppm 11.07 (s, 1H), 9.98 (s, FoleyHoagUS12952954.4 GPX-01525 1H), 8.16 (s, 1H), 7.79-8.11 (m, 1H), 7.65-7.76 (m, 2H), 7.53-7.62 (m, 2H), 7.07-7.21 (m, 2H), 4.01-4.21 (m, 1H), 3.86-3.99 (m, 1H), 3.27 (s, 1H), 2.92-3.01 (m, 3H), 2.86-2.90 (m, 1H). (2S,5S)-5-(2-(3-(4-Fluorophenyl)ureido)benzo[d]thiazol-6-yl)-1-methyl-6-oxo-5- (trifluoromethyl)piperazine-2-carboxylic acid (185) & (2S,5R)-5-(2-(3-(4- fluorophenyl)ureido)benzo[d]thiazol-6-yl)-1-methyl-6-oxo-5- (trifluoromethyl)piperazine-2-carboxylic acid (186) (2S)-5-(2-(3-(4-Fluorophenyl)ureido)benzo[d]thiazol-6-yl)-1-methyl-6-oxo-5- (trifluoromethyl)piperazine-2-carboxylic acid (140 mg) was separated by chiral SFC (column: Chiral Pak IH, (250 mm*30 mm, 10 um); mobile phase: CO2-MeOH (0.1% NH3H2O); 45% B with isocratic elution) to give the title compound (185) (52.6 mg, 38%) as a white solid. MS (ESI): mass calcd. for C21H17F4N5O4S: 511.09, found: 512.1 [M+H]+.1H NMR (400 MHz, DMSO-d6) ppm 12.91 (s, 1H), 11.52 (s, 1H), 9.90 (s, 1H), 8.17 (s, 1H), 7.66-7.76 (m, 2H), 7.54-7.61 (m, 2H), 7.13-7.22 (m, 2H), 4.03-4.28 (m, 1H), 3.96 (s, 1H), 3.27 (d, J = 12.8 Hz, 1H), 2.94 (s, 3H), 2.87-2.91 (m, 1H). And to provide the title compound (186) (33.9 mg, 24%) as a white solid. MS (ESI): mass calcd. for C21H17F4N5O4S: 511.09, found: 512.1 [M+H]+.1H NMR (400 MHz, DMSO-d6) ppm 11.91 (s, 1H), 10.01 (s, 1H), 8.11 (s, 1H), 7.72-7.77 (m, 1H), 7.69 (s, 1H), 7.53-7.57 (m, 2H), 7.14 (t, J = 8.8 Hz, 2H), 4.19 (s, 1H), 4.08 (s, 1H), 3.38- 3.39 (m, 1H), 2.87-2.98 (m, 4H). Example 162, 187 and 188 were synthesized in similar procedures as described in Example 185 and 186. Example 189 and 190. 1-(4-Fluorophenyl)-3-(6-((7S,9R,9aS)-9-(hydroxymethyl)-6-oxo- 7-(trifluoromethyl)octahydropyrazino[2,1-c][1,4]oxazin-7-yl)benzo[d]thiazol-2-yl)urea (189)& 1-(4-Fluorophenyl)-3-(6-((7R,9R,9aS)-9-(hydroxymethyl)-6-oxo-7- (trifluoromethyl)octahydropyrazino[2,1-c][1,4]oxazin-7-yl)benzo[d]thiazol-2-yl)urea (190) FoleyHoagUS12952954.4 GPX-01525 Synthetic scheme: FoleyHoagUS12952954.4 GPX-01525 tert-Butyl (S)-3-(2-methoxy-2-oxoethyl)morpholine-4-carboxylate FoleyHoagUS12952954.4 GPX-01525 To a solution of 2-[(3S)-4-tert-butoxycarbonylmorpholin-3-yl]acetic acid (1 g, 4.08 mmol) in DMF (10 mL) was added MeI (636.6 mg, 4.48 mmol) and K2CO3(281.7 mg, 2.04 mmol). The reaction was stirred at 25 °C for 12 h. After completion, the reaction was diluted with H2O (15 mL). The aqueous layer was extracted with EtOAc (15 mL x 3). The combined organic layer was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (1- 100% EtOAc / PE) to afford the title compound (0.8 g, 76%) as a white solid.1H NMR (400 MHz, CDCl3) ppm 4.36 (s, 1H), 3.70-3.89 (m, 3H), 3.67 (s, 3H), 3.55-3.61 (m, 1H), 3.40- 3.49 (m, 1H), 3.11 (s, 1H), 2.75-2.85 (m, 1H), 2.54-2.64 (m, 1H), 1.45 (s, 9H). tert-Butyl (S)-3-((R)-1-azido-2-methoxy-2-oxoethyl)morpholine-4-carboxylate To a solution of tert-butyl (S)-3-(2-methoxy-2-oxoethyl)morpholine-4-carboxylate (0.2 g, 771.31 mol) in THF (10 mL) was added a solution of 1 M NaHMDS in THF (1.16 mL) at –70 °C. The reaction was stirred at this temperature for 1 h. Then N-diazo-2,4,6-triisopropyl- benzenesulfonamide (381.9 mg, 1.23 mmol) was added. After stirring at –70 °C for 1 h, AcOH (231.6 mg, 3.86 mmol) was added. The reaction was warmed to rt, stirred for 3 h, and quenched with sat. NaHCO3(15 mL). The aqueous layer was extracted with EtOAc (15 mL x 3). The combined organic layer was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (2-100% EtOAc / PE) to give the title compound (30 mg, 5%) as a white solid.1H NMR (400 MHz, CDCl3) ppm 4.32 (d, J = 9.6 Hz, 1H), 4.05-4.18 (m, 2H), 3.84-3.95 (m, 2H), 3.77-3.80 (m, 3H), 3.46-3.57 (m, 2H), 3.12-3.31 (m, 1H), 1.46 (s, 9H). tert-Butyl (S)-3-((R)-1-amino-2-methoxy-2-oxoethyl)morpholine-4-carboxylate FoleyHoagUS12952954.4 GPX-01525 10% Pd / C (5.32 mg) was added to a solution of tert-butyl (S)-3-((R)-1-azido-2- methoxy-2-oxoethyl)morpholine-4-carboxylate (30 mg, 99.9 mol) in EtOAc (2 mL). The reaction was purged with H2 (3x) and then stirred under H2 (15 psi) for 12 h. After completion, the reaction was filtered through a celite pad. The filtrate was concentrated under reduced pressure. The residue was purified by prep-TLC (100% EtOAc) to give the title compound (20 mg, 73%) as a white solid.1H NMR (400 MHz, CDCl3) ppm 4.32 (d, J = 11.2 Hz, 1H), 3.76- 3.93 (m, 4H), 3.71 (s, 3H), 3.44-3.52 (m, 2H), 3.25-3.36 (m, 1H), 1.77 (s, 2H), 1.45 (s, 9H). Methyl (9R,9aS)-7-(2-(3-(4-fluorophenyl)ureido)benzo[d]thiazol-6-yl)-6-oxo-7- (trifluoromethyl)octahydropyrazino[2,1-c][1,4]oxazine-9-carboxylate The title compound was synthesized from (2S)-2-(4-aminophenyl)-4-[(4- methoxyphenyl)methyl]-5-methyl-2-(trifluoromethyl)morpholin-3-one in similar procedures as described in Example 2. MS (ESI): mass calcd. for C24H21F4N5O5S: 567.12, found: 568.3 [M+H]+.1H NMR (400 MHz, DMSO-d6) ppm 10.57-11.01 (m, 1H), 9.23 (s, 1H), 8.18 (s, 1H), 7.63-7.75 (m, 2H), 7.50-7.59 (m, 2H), 7.17 (t, J = 8.8 Hz, 2H), 4.45 (d, J = 11.6 Hz, 1H), 4.30-4.37 (m, 1H), 3.81-3.88 (m, 3H), 3.77-3.80 (m, 1H), 3.73 (s, 3H), 3.57-3.66 (m, 2H), 2.94- 3.03 (m, 1H). 1-(4-Fluorophenyl)-3-(6-((9R,9aS)-9-(hydroxymethyl)-6-oxo-7- (trifluoromethyl)octahydropyrazino[2,1-c][1,4]oxazin-7-yl)benzo[d]thiazol-2-yl)urea FoleyHoagUS12952954.4 GPX-01525 To a solution of methyl (9R,9aS)-7-(2-(3-(4-fluorophenyl)ureido)benzo[d]thiazol-6- yl)-6-oxo-7-(trifluoromethyl)octahydropyrazino[2,1-c][1,4]oxazine-9-carboxylate (0.06 g, 105.7 mol) in THF (2 mL) was added LiBH4(2.5 M in THF, 42 L). The reaction was stirred at 0 °C for 2 h. Upon completion, the reaction was diluted with sat. NH4Cl (5 mL). The aqueous layer was extracted with EtOAc (10 mL x 3). The combined organic layer was washed with brine, dried over Na2SO4, filtered, concentrated and purified by reverse phase HPLC (gradient elution, 25-55% ACN / H2O, with 10 mM NH4HCO3as a modifier) to give the title compound (32 mg, 56%) as a white solid. MS (ESI): mass calcd. for C23H21F4N5O4S: 539.12, found: 539.9 [M+1]+. 1-(4-Fluorophenyl)-3-(6-((7S,9R,9aS)-9-(hydroxymethyl)-6-oxo-7- (trifluoromethyl)octahydropyrazino[2,1-c][1,4]oxazin-7-yl)benzo[d]thiazol-2-yl)urea (189) & 1-(4-Fluorophenyl)-3-(6-((7R,9R,9aS)-9-(hydroxymethyl)-6-oxo-7- (trifluoromethyl)octahydropyrazino[2,1-c][1,4]oxazin-7-yl)benzo[d]thiazol-2-yl)urea (190) 1-(4-Fluorophenyl)-3-(6-((9R,9aS)-9-(hydroxymethyl)-6-oxo-7- (trifluoromethyl)octahydropyrazino[2,1-c][1,4]oxazin-7-yl)benzo[d]thiazol-2-yl)urea (32 mg, 59 mol) was separated by chiral SFC (column: DAICEL CHIRALPAK AD (250 mm * 30 mm, 10 um); mobile phase: CO2-EtOH; 40% B with isocratic elution) to provide the title compound (189) (32 mg, 56%) as a white solid. MS (ESI): mass calcd. for C23H21F4N5O4S: 539.12, found: 540.1 [M+1]+.1H NMR (400 MHz ,DMSO-d6) (ppm) 10.97 (s, 1H), 9.25 (s, 1H), 8.14 (s, 1H), 7.68 (s, 2H), 7.50-7.58 (m, 2H), 7.17 (t, J = 8.8 Hz, 2H), 5.05 (t, J = 5.6 Hz, 1H), 4.45 (d, J = 12.0 Hz, 1H), 3.80-3.87 (m, 2H), 3.68 (s, 1H), 3.50-3.62 (m, 3H), 3.37-3.45 (m, 2H), 3.00 (d, J = 5.2 Hz, 1H), 2.86-2.94 (m, 1H). And to provide the title compound (190) (4.7 mg, 15%) as a white solid. MS (ESI): mass calcd. for C23H21F4N5O4S: 539.12, found: 540.1 [M+1]+.1H NMR (400 MHz ,DMSO-d6) (ppm) 10.97 (s, 1H), 9.25 (s, 1H), 8.14 (s, 1H), 7.68 (s, 2H), 7.50-7.58 (m, 2H), 7.17 (t, J = 8.8 Hz, 2H), 5.05 (t, J = 5.6 Hz, 1H), 4.45 (d, J = 12.0 Hz, 1H), 3.80-3.87 (m, 2H), 3.68 (s, 1H), 3.50-3.62 (m, 3H), 3.37-3.45 (m, 2H), 3.00 (d, J = 5.2 Hz, 1H), 2.86-2.94 (m, 1H). Stereochemistry was arbitrarily assigned. FoleyHoagUS12952954.4 GPX-01525 Example 191.1-(4-Fluorophenyl)-3-(6-(6-methyl-7-oxo-8-(trifluoromethyl)-2-oxa-6,9- diazaspiro[4.5]decan-8-yl)benzo[d]thiazol-2-yl)urea (191) 3-(Methylamino)tetrahydrofuran-3-carbonitrile Methanamine hydrochloride (20.39 g, 302 mmol) was added to a solution of tetrahydrofuran-3-one (13 g, 151 mmol) in MeOH (130 mL), followed by addition of NaCN FoleyHoagUS12952954.4 GPX-01525 (8.14 g, 166 mmol) in one portion. The reaction was heated at 50 °C for 2 h. After completion, the reaction solvent was removed under reduced pressure. The resulting residue was diluted with EtOAc (100 mL) and stirred at rt for 15 min. The slurry was filtered, and the filter cake was washed with EtOAc (100 mL x 2). The filtrate was concentrated and purified by column chromatography (5 to 100% EtOAc / PE) to give the title compound (8 g, 42%) as a yellow oil.1H NMR (400 MHz, DMSO-d6) ppm 3.92 (d, J = 8.8 Hz, 1H), 3.80-3.87 (m, 2H), 3.64 (d, J = 8.8 Hz, 1H), 2.92-2.98 (m, 1H), 3.31 (d, J = 6.0 Hz, 3H), 2.24-2.28 (m, 1H), 2.04-2.11 (m, 1H). tert-Butyl (3-cyanotetrahydrofuran-3-yl)(methyl)carbamate To a solution of 3-(methylamino)tetrahydrofuran-3-carbonitrile (8 g, 63.4 mmol) in THF (80 mL) was added Boc2O (27.68 g, 126.8 mmol), DMAP (774.7 mg, 6.34 mmol) and DIPEA (16.39 g, 126.8 mmol). The mixture was stirred at 50 °C for 12 h. After completion, the reaction was quenched with sat. NH4Cl (100 mL). The aqueous layer was extracted with EtOAc (100 mL x 3). The combined organic layer was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (5-100% EtOAc / PE) to give the title compound (10 g, 70%) as a white solid.1H NMR (400 MHz, DMSO-d6) ppm 4.36 (d, J = 9.2 Hz, 1H), 3.86-3.92 (m, 2H), 3.80 (d, J = 9.6 Hz, 1H), 2.89 (s, 3H), 2.62-2.68 (m, 1H), 2.41-2.47 (m, 1H), 1.44 (s, 9H). tert-Butyl (3-(aminomethyl)tetrahydrofuran-3-yl)(methyl)carbamate To a solution of tert-butyl (3-cyanotetrahydrofuran-3-yl)(methyl)carbamate (10 g, 44.19 mmol) in MeOH (150 mL) and NH3.H2O (50 mL) was added Raney-Ni (10 g) under N2. The suspension was degassed and purged with H2(3x). The reaction was stirred under H2(50 Psi) at 45 °C for 12 h and was filtered through a celite pad. The filtrate was concentrated under reduced pressure to give the title compound (9 g) as a yellow oil, which was directly used in the next step reaction without further purification. MS (ESI): mass calcd. for C11H22N2O3: 230.16, found: 231.1 [M+H]+.1H NMR (400 MHz, DMSO-d6) ppm 3.94 (d, J = 8.8 Hz, 1H), FoleyHoagUS12952954.4 GPX-01525 3.62-3.74 (m, 3H), 2.86 (s, 3H), 2.71-2.84 (m, 2H), 2.13-2.16 (m, 1H), 1.98-2.06 (m, 1H), 1.37 (s, 9H). 1-(4-Fluorophenyl)-3-(6-(6-methyl-7-oxo-8-(trifluoromethyl)-2-oxa-6,9- diazaspiro[4.5]decan-8-yl)benzo[d]thiazol-2-yl)urea (191) The title compound (191) was synthesized from (2S)-2-(4-aminophenyl)-4-[(4- methoxyphenyl)methyl]-5-methyl-2-(trifluoromethyl)morpholin-3-one in similar procedures as described in Example 2. MS (ESI): mass calcd. for C23H21F4N5O3S: 523.13, found: 524.2 [M+H]+.1H NMR (400 MHz, DMSO-d6) ppm 10.97 (s, 1H), 9.24 (s, 1H), 8.20 (s, 1H), 7.73- 7.75 (m, 1H), 7.65 (s, 1H), 7.52-7.56 (m, 2H), 7.17 (t, J = 8.8 Hz, 2H), 4.35 (d, J = 2.8 Hz, 1H), 3.95-4.05 (m, 1H), 3.79 (d, J = 10.4 Hz, 1H), 3.52-3.55 (m, 1H), 3.13 (d, J = 10.4 Hz, 1H), 2.88-2.91 (m, 4H), 2.61 (d, J = 12.8 Hz, 1H), 2.31-2.38 (m, 1H), 1.97-2.06 (m, 1H). Examples 192, 193, 194, and 195 were synthesized through chiral SFC separation of Example 191. Biological Assay Assays were performed using Expi293F Inducible cells (Invitrogen) stably expressing hPTH1R via a pcZeo TetO DNA plasmid. Cell lines were maintained in suspension in Expi293 Expression Medium (ThermoFisher Scientific) supplemented with 10 μg / mL Blasticidin and 10 μg / mL Zeocin and incubated at 37°C, 8% CO2, with shaking. To induce receptor expression, hPTH1R cells were incubated in induction medium (Expi293 Expression Medium with 4 μg / mL Doxycycline (Millipore Sigma), 5 mM sodium butyrate (Millipore Sigma) and 100 ng / mL Pertussis toxin (Millipore Sigma)) for 24 hours at 32°C, 5% CO2, with shaking. Assay-ready aliquots were prepared by harvesting cells 24-hour post-induction. Cells were pelleted at 4°C, resuspended in Expi293 Expression medium + 10% DMSO, aliquoted, and kept frozen at -80°C until ready for use. For the assay, concentration-response curves of test and reference compounds were added to 384-well plates using an Apricot liquid handler (SPT Labtech) and backfilled with FoleyHoagUS12952954.4 GPX-01525 DMSO to a final concentration of 0.3%. cAMP was measured using the cisbio cAMP Gs dynamic HTRF kit (PerkinElmer) according to manufacturer instructions. Aliquots of frozen hPTH1R cells were quickly thawed and washed with phosphate-buffered saline (Sigma- Aldrich) to remove media and DMSO. The cells were resuspended in kit-supplied Stimulation Buffer at 0.2 x 106cells / mL.10 μl of the hPTH1R cell dilution were added to each well of the assay plate and incubated with the compounds for 1 hour in a 37°C, 0% CO2 incubator. Following this incubation, the cells were lysed and accumulated cAMP was detected through the addition of kit-supplied lysis buffer containing d2-reagent and Eu- cryptate antibody. The HTRF signal was quantified using a BMG PHERAstar FSX plate reader optimized for HTRF assays. The HTRF ratio was determined by dividing the signal output at 665 nm by that at 620 nm. Data were normalized to the signal produced by 1 μM PTH(1-34) (100% activation) and vehicle (0% activation). A complete listing of the compounds, characterization data, and assay data are set forth in the Tabel in Figure 1. The pEC50activity bins are: pEC50>7: +++; pEC50between 6 and 7: ++; and pEC50<6: +. INCORPORATION BY REFERENCE All of the U.S. patents and U.S. and PCT patent application publications cited herein are hereby incorporated by reference. EQUIVALENTS Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments of the invention described herein. Such equivalents are intended to be encompassed by the following claims. FoleyHoagUS12952954.4

Claims

GPX-01525 We claim:

1. A compound of Formula (I):or a pharmaceutically acceptable salt thereof; wherein: X is O or NR7; Y is phenyl optionally substituted with one, two, or three substituents selected independently for each occurrence from fluoro, chloro, cyano, hydroxyl, (C1-C6)alkyl, (C3-C8)cycloalkyl, (C1-C6)haloalkyl, (C1-C6)hydroxyalkyl, (C1-C6)alkoxyalkyl, and phenyl; n is 0, 1, or 2; R1is (C1-C6)haloalkyl; R2and R3are independently for each occurrence hydrogen, carboxy, (C1-C6)alkyl, (C1-C6)hydroxyalkyl, (C3-C8)cycloalkyl, or (C1-C6)haloalkyl; or taken together with the carbon atom to which they are attached form C=O, spiro (C3-C8)cycloalkyl, or spiro 4- to 7- membered heterocyclyl; R4and R5are independently for each occurrence hydrogen, (C1-C6)alkyl, (C1-C6)haloalkyl, or (C1-C6)hydroxyalkyl; or taken together with the carbon atom to which they are attached form a (C3-C8)cycloalkyl, wherein the cycloalkyl is optionally substituted with hydroxy; or one of R4and R5and one of R2and R3taken together with the atoms to which they are attached form a fused 5- or 6-memebered heteroaryl ring; or if n is 2, then one of R4and R5and one of R2and R3in a 1,3-relationship taken together with the atoms to which they are attached form a bridged (C3-C8)cycloalkyl; R6is hydrogen, (C1-C6)alkyl, (C3-C8)cycloalkyl, (C1-C6)haloalkyl, or (C1- C6)alkylsulfonyl(C1-C6)alkyl; or R6and one of R2and R3taken together with the atoms to which they are attached form a fused 5- to 6-membered heterocyclyl; and R7is hydrogen or (C1-C6)alkyl.

2. The compound of claim 1, having the structure of Formula (Ia) or (Ib): FoleyHoagUS12952954.4GPX-01525or a pharmaceutically acceptable salt thereof.

3. The compound of claim 1 or 2, wherein X is O.

4. The compound of claim 1 or 2, wherein X is NR7.

5. The compound of any one of claims 1 to 4, wherein Y is phenyl substituted with at least one fluoro.

6. The compound of claim 5, wherein Y is 4-fluorophenyl.

7. The compound of any one of claims 1 to 6, wherein R1is (C1-C6)fluoroalkyl.

8. The compound of claim 7, wherein R1is trifluoromethyl.

9. The compound of any one of claims 1 to 8, wherein R2is (C1-C6)alkyl.

10. The compound of claim 9, wherein R2is methyl.

11. The compound of any one of claims 1 to 8, wherein R2is (C3-C8)cycloalkyl.

12. The compound of claim 11, wherein R2is cyclopropyl.

13. The compound of any one of claims 1 to 8, wherein R2is carboxy.

14. The compound of any one of claims 1 to 8 wherein R2is (C1-C6)hydroxyalkyl.

15. The compound of any one of claims 1 to 8, wherein R2is hydroxymethyl.

16. The compound of any one of claims 1 to 8, wherein R2is hydrogen.

17. The compound of any one of claims 1 to 16, wherein R3is hydrogen.

18. The compound of any one of claims 1 to 8, wherein R2and R3taken together with the carbon atom to which they are attached form spiro (C3-C8)cycloalkyl.

19. The compound of claim 18, wherein R2and R3taken together with the carbon atom to which they are attached form spiro cyclopropyl.

20. The compound of any one of claims 1 to 8, wherein R2and R3taken together with the carbon atom to which they are attached form a spiro 4- to 7-membered heterocyclyl.

21. The compound of claim 20, wherein R2and R3taken together with the carbon atom to which they are attached form a spiro tetrahydrofuran.

22. The compound of any one of claims 1 to 8, wherein R2and R3taken together with the carbon atom to which they are attached form C=O. FoleyHoagUS12952954.4GPX-01525 23. The compound of any one of claims 1 to 22, wherein at least one occurrence of R4is (C1-C6)haloalkyl.

24. The compound of claim 23, wherein at least one occurrence of R4is (C1-C6)fluoroalkyl.

25. The compound of claim 24, wherein at least one occurrence of R4is fluoromethyl.

26. The compound of any one of claims 1 to 22, wherein at least one occurrence of R4is (C1-C6)hydroxyalkyl.

27. The compound of any one of claims 1 to 22, wherein at least one occurrence of R4is hydrogen.

28. The compound of any one of claims 1 to 27, wherein R5is hydrogen.

29. The compound of any one of claims 1 to 22, wherein R4and R5taken together with the carbon atom to which they are attached form a spiro (C3-C8)cycloalkyl.

30. The compound of claim 29, wherein R4and R5taken together with the carbon atom to which they are attached form spiro cyclobutyl optionally substituted with hydroxy.

31. The compound of claim 29, wherein R4and R5taken together with the carbon atom to which they are attached form spiro cyclopropyl.

32. The compound of any one of claims 1 to 22, wherein R4and R5taken together with the carbon atom to which they are attached form C=O.

33. The compound of any one of claims 1 to 32, wherein n is 2, and one of R4and R5and one of R2and R3in a 1,3-relationship taken together with the atoms to which they are attached form a bridged (C3-C8)cycloalkyl.

34. The compound of any one of claims 1 to 8, wherein one of R4and R5taken together with one of R2and R3with the carbon atoms to which they are attached form a fused heteroaryl.

35. The compound of claim 34, wherein one of R4and R5and one of R2and R3taken together with the atoms to which they are attached form a fused pyridine-2(1H)one.

36. The compound of claim 34, wherein one of R4and R5and one of R2and R3taken together with the atoms to which they are attached form a fused pyridine.

37. The compound of any one of claims 1 to 36, wherein R6is hydrogen.

38. The compound of any one of claims 1 to 36, wherein R6is (C1-C6)alkyl.

39. The compound of claim 38, wherein R6is methyl.

40. The compound of claim 38, wherein R6is ethyl.

41. The compound of any one of claims 1 to 36, wherein R6is (C3-C8)cycloalkyl.

42. The compound of claim 41, wherein R6is cyclopropyl. FoleyHoagUS12952954.4GPX-01525 43. The compound of any one of claims 1 to 36, wherein is R6is 2-mesylethyl.

44. The compound of any one of claims 1 to 36 wherein R6is (C1-C6)fluoroalkyl.

45. The compound of claim 45, wherein R6is 2-fluoroethyl 46. The compound of claim 45, wherein R6is 2,2-difluoroethyl.

47. The compound of any one of claims 1 to 8, wherein R6and one of R2and R3taken together with the atoms to which they are attached form a fused 4- to 7-membered heterocycle.

48. The compound of claim 47, wherein R6and one of R2and R3taken together with the atoms to which they are attached form a fused morpholino.

49. The compound of claim 47, wherein R6and one of R2and R3taken together with the atoms to which they are attached form a fused pyrrolidino.

50. The compound of any one of claims 1 to 49, wherein R7is (C1-C6)alkyl.

51. The compound of claim 50, wherein R7is methyl.

52. The compound of any one of claims 1 to 32 and 34-51, wherein n is 0.

53. The compound of any one of claims 1 to 32 and 34-51, wherein n is 1.

54. The compound of any one of claims 1 to 32 and 34-51, wherein n is 2.

55. A compound according to Formula (II):or a pharmaceutically acceptable salt thereof; wherein: A is: i) imidazolyl substituted with one or more substituents selected from (C1-C6)hydroxyalkyl, (C1-C6)alkoxyalkyl, and (C1-C6)dialkoxyalkyl alkyl; ii) pyridazinyl substituted with one or more substituents selected from -C(O)NR8R9, carboxy, (C1-C6)hydroxyalkyl, and (C1-C6)alkoxyalkyl; or iii) pyrimidinyl; R8and R9are each independently selected from hydrogen, (C1-C6)alkyl, and (C3- C8)cycloalkyl; or R8and R9taken together with the nitrogen to which they are attached form a 4- to 7-membered heterocycloalkyl; FoleyHoagUS12952954.4GPX-01525 Y is phenyl optionally substituted with one, two, or three substituents selected independently for each occurrence from fluoro, chloro, cyano, hydroxyl, (C1-C6)alkyl, (C3-C8)cycloalkyl, (C1-C6)haloalkyl, (C1-C6)hydroxyalkyl, (C1-C6)alkoxyalkyl, and phenyl; and R1is (C1-C6)haloalkyl.

56. The compound of claim 55, having the structure of Formula (IIa) or (IIb):or a pharmaceutically acceptable salt thereof.

57. The compound of claim 55 or 56, wherein Y is phenyl substituted with at least one fluoro.

58. The compound of claim 57, wherein Y is 4-fluorophenyl.

59. The compound of any one of claims 55 to 58, wherein R1is (C1-C6)fluoroalkyl.

60. The compound of claim 59, wherein R1is trifluoromethyl.

61. The compound of any one of claims 55 to 60, wherein A is imidazolyl substituted with one substituent selected from (C1-C6)hydroxyalkyl, (C1-C6)alkoxyalkyl, and (C1-C6)dialkoxy(C1-C6)alkyl.

62. The compound of claim 61, wherein A is 2-imidazolyl substituted with one substituent selected from (C1-C6)hydroxyalkyl, (C1-C6)alkoxyalkyl, and (C1-C6)dialkoxy(C1-C6)alkyl.

63. The compound of any one of claims 55 to 60, wherein A is pyridazinyl substituted with one substituent selected from -C(O)NR8R9, carboxy, (C1-C6)hydroxyalkyl, and (C1- C6)alkoxyalkyl.

64. The compound of claim 63, wherein A is 3-pyridazinyl substituted with one substituent selected from -C(O)NR8R9, carboxy, (C1-C6)hydroxyalkyl, and (C1-C6)alkoxyalkyl.

65. The compound of any one of claims 55 to 60, wherein A is pyrimidinyl.

66. The compound of claim 65, wherein A is 2-pyrimidinyl.

67. A compound of Formula (III): FoleyHoagUS12952954.4GPX-01525or a pharmaceutically acceptable salt thereof, wherein: Y is phenyl optionally substituted with one, two, or three substituents selected independently for each occurrence from fluoro, chloro, cyano, hydroxyl, (C1-C6)alkyl, (C3-C8)cycloalkyl, (C1-C6)haloalkyl, (C1-C6)hydroxyalkyl, (C1-C6)alkoxyalkyl, and phenyl; R1is (C1-C6)haloalkyl; R10is hydrogen; R11is selected from: 3-(2-imidazolyl)-1-azetidinyl; 2-(fluoromethyl)cyclopropyl; 2-fluoropropyl; 2-(difluoromethyl)cyclopropyl; 1-oxa-6-azaspiro[3,3]heptyl, 2-fluorocyclobutyl; 1-spiro[2.2]pentyl; difluoromethoxypropyl; (1,3-oxazol-2-yl)cyclobutyl; and 3-azetidinyl, wherein 3-azetidinyl is optionally substituted with one or more substituents selected from (C1-C6)alkyl, and (C1-C6)carboxyalkyl; or R10and R11are taken together with the nitrogen to which they are attached form: 4-aza-4-spiro[2.3]hexyl; 3-(2-imidazolyl)-1-azetidinyl; or 1-azetdinyl substituted with at least one substituent selected from oxazole, imidazole, and thiadiazole.

68. A compound of claim 67, having the structure of Formula (IIIa) or (IIIb)or a pharmaceutically acceptable salt thereof. FoleyHoagUS12952954.4GPX-01525 69. The compound of claim 67 or 68, wherein Y is phenyl substituted with at least one fluoro.

70. The compound of claim 69, wherein Y is 4-fluorophenyl.

71. The compound of any one of claims 67 to 69, wherein R1is (C1-C6)fluoroalkyl.

72. The compound of claim 71, wherein R1is trifluoromethyl.

73. A compound of Formula (IV):or a pharmaceutically acceptable salt thereof, wherein: Y is phenyl optionally substituted with one, two, or three substituents selected independently for each occurrence from fluoro, chloro, cyano, hydroxyl, (C1-C6)alkyl, (C3-C8)cycloalkyl, (C1-C6)haloalkyl, (C1-C6)hydroxyalkyl, (C1-C6)alkoxyalkyl, and phenyl; X is CH or N; R1is (C1-C6)haloalkyl; R12is (C1-C6)alkyl; R13is hydrogen or (C1-C6)alkyl; or R12and R13taken together with the nitrogen to which they are attached form 4- to 7- membered heterocyclyl; R14is selected from OC(O)NR15R16, O(4- to 7- membered heterocyclyl), (C1-C6)alkoxy, O(C1-C6)carboxyalkyl, or (C1-C6)cyanoalkyl; and R15and R16are independently hydrogen or (C1-C6)alkyl; or R15and R16taken together with the nitrogen to which they are attached form 4- to 7-membered heterocyclyl; provided that if X is CH, then R14is not methoxy.

74. The compound of claim 73, having the structure of Formula (IVa) or (IVb)or a pharmaceutically acceptable salt thereof.

75. The compound of claim 73 or 74, wherein Y is phenyl substituted with at least one fluoro. FoleyHoagUS12952954.4GPX-01525 76. The compound of claim 75, wherein Y is 4-fluorophenyl.

77. The compound of any one of claims 73 to 76, wherein R1is (C1-C6)fluoroalkyl.

78. The compound of claim 77, wherein R1is trifluoromethyl.

79. A compound having the structure:FoleyHoagUS12952954.4GPX-01525FoleyHoagUS12952954.4GPX-01525FoleyHoagUS12952954.4GPX-01525FoleyHoagUS12952954.4GPX-01525FoleyHoagUS12952954.4GPX-01525FoleyHoagUS12952954.4GPX-01525FoleyHoagUS12952954.4GPX-01525FoleyHoagUS12952954.4GPX-01525FoleyHoagUS12952954.4GPX-01525FoleyHoagUS12952954.4GPX-01525FoleyHoagUS12952954.4GPX-01525or a pharmaceutically acceptable salt thereof. FoleyHoagUS12952954.4GPX-01525 80. A pharmaceutical composition, comprising a compound of any one of claims 1 to 79, or a pharmaceutically acceptable salt thereof; and at least one pharmaceutically acceptable excipient.

81. A method for treating or preventing osteoporosis, fracture, osteomalacia, arthritis, thrombocytopenia, hypoparathyroidism, hyperphosphatemia or tumoral calcinosis, comprising administering to a subject in need thereof an effective amount of a compound of any one of claims 1 to 79, or a pharmaceutically acceptable salt thereof. FoleyHoagUS12952954.4

Images