Compounds and methods of their use

Abstract

Compounds useful as ACSL5 inhibitors, methods of their preparation and use, and pharmaceutical compositions comprising them are disclosed. Particular compounds are of the formula:

Description

# 1. BACKGROUNDAberrations in fatty acid trafficking and metabolism have been associated with obesity, nonalcoholic fatty liver disease (NAFLD), and type 2 diabetes. Bowman, T.A., et al., "Acyl CoA synthetase 5 (ACSL5) ablation in mice increases energy expenditure and insulin sensitivity and delays fat absorption", Mol. Metab., 2016 Jan 11;5(3):210- 220. Critical to that metabolism are acyl- CoA synthetases.Acyl- CoA synthases have been categorized as very long- chain acyl- CoA synthases, long- chain acyl- CoA synthases (ACSL5), and medium and short- chain acyl- CoA synthases, according to the carbon chain length of fatty acids upon which they act. Luo, Q., et al., "Role of ACSL5 in fatty acid metabolism", Heliyon, 2023 9:e13316. Five isoforms of ACSLs, which mainly catalyze the reaction of $\mathbf{C}\_{12 - 20}$ fatty acids, have been identified and accorded the numbers 1, 3, 4, 5, and 6. Each has a unique tissue expression, subcellular localization, and substrate preference. Id.Acyl- CoA synthetase long- chain family member 5 (ACSL5) is widely expressed in mammalian liver, small intestine, fat, spleen, uterus, lung, and skeletal muscle. Id. The enzyme catalyzes the formation of acyl- CoAs using long- chain fatty acids in the cytoplasm. These are then used to synthesize complex lipids and other products in the endoplasmic reticulum or enter mitochondria for $\beta$ - oxidation. Fatty acids catalyzed by ACSL5 include palmitic acid, palmitoleic acid, oleic acid, and linoleic acid. Id. at e13317. Studies suggest that the enzyme is involved in glucose and lipid metabolism, and may play an essential role in metabolic disorders. For example, ACSL5- / - mice have increased hepatic and serum fibroblast growth factor 21 levels, reduced adiposity, improved insulin sensitivity, increased energy expenditure, and delayed triglyceride absorption. Bowman, supra, at 210.It has also been suggested that ACSL dysregulation plays a role in some cancers. See, e.g., Sebastiano, M.R., and Konstantinidou, G., Int. J. Mol. Sci., 2019, 20:3624. For example, the expression of ACSL5 is reportedly higher in bone marrow cells obtained from acute myeloid leukemia (AML) patients than in those from healthy donors. Ye, et al., "ACSL5, a prognostic factor in acute myeloid leukemia, modulates the activity of Wnt / $\beta$ - catenin signaling by palmitoylation modification", Front Med., 2023 Aug;17(4):685- 698. Consequently, inhibition of ACSL5 may be effective in treating a variety of metabolic and oncologic diseases and disorders.# 2. SUMMARYThis invention is directed to compounds useful as ACSL5 inhibitors, methods of their preparation and use, and pharmaceutical compositions comprising them.One embodiment of the invention is directed to compounds of formula I:Iand pharmaceutically acceptable salts thereof, wherein:5 $\mathbf{X}^1$ and $\mathbf{X}^2$ is independently O or CHR; each of $\mathrm{Y}^1$ $\mathbf{Y}^2$ , and $\mathrm{Y}^3$ is independently N, $\mathbf{CR}^3$ , or $\mathbf{C - X^1 - R^1}$ , provided that only one of $\mathrm{Y}^1$ $\mathbf{Y}^2$ , and $\mathbf{Y}^3$ may be attached to $\mathbf{X}^1$ . each of $\mathbf{Z}^1$ $Z^2$ , and $Z^3$ is independently $\_\mathrm{N}$ or $\mathbf{CR}^3$each $\mathbf{R}^1$ is independently optionally substituted $\mathbf{C}\_{1 - 8}$ hydrocarbyl or 2- 9 membered heterocarbyl, 10 which optional substitution is with one or more of halo, $\mathbf{R}^{1\mathrm{A}}$ , or $\mathbf{OR}^{1\mathrm{A}}$each $\mathbf{R}^{1\mathrm{A}}$ is independently optionally substituted $\mathbf{C}\_{1 - 6}$ hydrocarbyl, which optional substitution is with one or more of halo;each of $\mathbf{R}^{2\mathrm{A}}$ and $\mathbf{R}^{2\mathrm{B}}$ is independently hydrogen or $\mathbf{C}\_{1 - 6}$ alkyl optionally substituted with one or more halo, or $\mathbf{R}^{2\mathrm{A}}$ and $\mathbf{R}^{2\mathrm{B}}$ are taken together to form a $\mathbf{C}\_{3 - 5}$ cycloalkyl or 3- 5 membered cycloheteroalkyl;15 each $\mathbf{R}^3$ is independently hydrogen, halo, or $\mathbf{C}\_{1 - 6}$ alkyl optionally substituted with one or more halo;$\mathbf{R}^4$ is hydrogen or $\mathbf{C}\_{1 - 6}$ alkyl;$\mathbf{R}^5$ is $\mathrm{N}(\mathrm{R}^{5\mathrm{A}})\_2$ $\mathrm{NHR}^{5\mathrm{A}}$ , or optionally substituted $\mathbf{C}\_{1 - 8}$ hydrocarbyl or 2- 9 membered heterocarbyl, which optional substitution is with one or more of halo, hydroxyl, nitrile, $\mathbf{R}^{5\mathrm{A}}$ $\mathrm{OR}^{5\mathrm{A}}$ $\mathrm{N}(\mathrm{R}^{5\mathrm{A}})\_2$ $\mathrm{NHR}^{5\mathrm{A}}$ , or 20 $\mathrm{NH\_2}$ .each $\mathbf{R}^{5\mathrm{A}}$ is independently optionally substituted $\mathbf{C}\_{1 - 8}$ hydrocarbyl or 2- 9 membered heterocarbyl, which optional substitution is with one or more of halo, hydroxyl, nitrile, $\mathbf{R}^{5\mathrm{B}}$ $\mathrm{OR}^{5\mathrm{B}}$ $\mathrm{N}(\mathrm{R}^{5\mathrm{B}})\_2$ $\mathrm{NHR}^{5\mathrm{B}}$ , or $\mathrm{NH\_2}$ .each $\mathbf{R}^{5\mathrm{B}}$ is independently optionally substituted $\mathbf{C}\_{1 - 8}$ hydrocarbyl or 2- 9 membered heterocarbyl, which optional substitution is with one or more of halo, hydroxyl, nitrile, $\mathbf{R}^{5\mathrm{C}}$ $\mathrm{OR}^{5\mathrm{C}}$ $\mathrm{N}(\mathrm{R}^{5\mathrm{C}})\_2$ $\mathrm{NHR}^{5\mathrm{C}}$ , or $\mathrm{NH\_2}$ .each $\mathbf{R}^{5\mathrm{C}}$ is independently optionally substituted $\mathbf{C}\_{1 - 8}$ hydrocarbyl or 2- 9 membered heterocarbyl, which optional substitution is with one or more of halo, hydroxyl, nitrile, or $\mathrm{NH\_2}$ ; and each $\mathbf{R}^6$ is independently $\mathrm{H}$ or $\mathbf{C}\_{1 - 6}$ alkyl.30 Another embodiment is directed to pharmaceutical compositions comprising a compound disclosed herein (e.g., a compound of Formula I).Another embodiment is directed to methods of preparing compounds disclosed herein.Another embodiment is directed to methods of treating or managing a disease or disorder mediated by ACSL5 function, which comprise administering to a patient in need thereof a compound ofthe invention. Certain embodiments are directed to methods of treating metabolic diseases or disorders, such as metabolic dysfunction- associated steatohepatitis (MASH), metabolic syndrome, non- alcoholic fatty liver disease (NAFLD), obesity, and type 2 diabetes. Others are directed to methods of increasing insulin sensitivity. Others are directed to methods of treating a cancer characterized by the overexpression of ACSL5, such as acute myeloid leukemia (AML), colorectal cancer, and breast cancer.# 3. BRIEF DESCRIPTION OF THE FIGURESAspects of some embodiments of the invention may be understood from the attached figures. As used herein, the terms "Figure" and "FIG." are used interchangeably and their case (e.g., lower, upper) is irrelevant. Portions of a figure X that are identified with a letter (e.g., A, B) may be referred to as FIG. XA and FIG. XB even if not explicitly identified as "FIG. XA" or "FIG. XB" on the figure. Thus, if Figure 1 has parts identified as A and B, those parts may be referred to as "Figure 1A" and "Figure 1B" or "FIG. 1A" and "FIG. 1B".FIG. 1A shows the percent reduction in the mean body weights of diet- induced obesity (DIO) mice treated with Compound A versus those in the control group as a function of time.FIG. 1B shows the percent reduction in the mean body weight of DIO mice in the control group and those in the two group treated with Compound A versus baseline as a function of time.FIG. 2A shows the percent reduction in the mean body weights of DIO mice treated with Compounds B- D versus those of the control group as a function of time.FIG. 2B shows the percent reduction in the mean body weight of DIO mice in the control group and those in the group treated with Compounds B- D versus baseline as a function of time.# 4. DETAILED DESCRIPTIONThis invention is directed to compounds useful as ACSL5 inhibitors, methods of their preparation and use, and pharmaceutical compositions comprising them. Aspects of the invention are described using terms well known in the art.# 4.1. DEFINITIONSUnless otherwise indicated, the term "about" means $\pm 10\%$ of the indicated range.When used herein, the term "alkenyl" is accorded its conventional meaning. Examples of alkenyl moieties include straight- chain and branched $\mathbf{C}\_{2 - 20}$ , $\mathbf{C}\_{2 - 12}$ and $\mathbf{C}\_{2 - 6}$ alkenyl such as vinyl, allyl, 1- butenyl, 2- butenyl, isobutylenyl, 1- pentenyl, 2- pentenyl, 3- methyl- 1- butenyl, 2- methyl- 2- butenyl, 2,3- dimethyl- 2- butenyl, 1- hexenyl, 2- hexenyl, 3- hexenyl, 1- heptenyl, 2- heptenyl, 3- heptenyl, 1- octenyl, 2- octenyl, 3- octenyl, 1- nonenyl, 2- nonenyl, 3- nonenyl, 1- decenyl, 2- decenyl and 3- decenyl.The term "alkyl" is accorded its conventional meaning. Examples of alkyl moieties include straight- chain and branched $\mathbf{C}\_{1 - 20}$ alkyl, $\mathbf{C}\_{1 - 12}$ alkyl, $\mathbf{C}\_{1 - 6}$ alkyl, $\mathbf{C}\_{1 - 4}$ alkyl, and $\mathbf{C}\_{1 - 3}$ alkyl, such as methyl,ethyl, propyl, isopropyl, n- butyl, t- butyl, isobutyl, pentyl, hexyl, isohexyl, heptyl, 4,4- dimethylpentyl, octyl, 2,2,4- trimethylpentyl, nonyl, decyl, undecyl, and dodecyl.The term "alkynyl" is accorded its conventional meaning. Examples of alkynyl moieties include straight- chain and branched $\mathbf{C}\_{2 - 20}$ , $\mathbf{C}\_{2 - 12}$ and $\mathbf{C}\_{2 - 6}$ alkynyl, such as ethynyl and 2- propynyl (propargyl).The term "aryl" refers to a single all- carbon- backbone aromatic ring or a multiple condensed all- carbon- backbone ring system wherein at least one of the rings is aromatic. Examples include $\mathbf{C}\_{6 - 20}$ , $\mathbf{C}\_{6 - 14}$ , $\mathbf{C}\_{6 - 12}$ , and $\mathbf{C}\_{2 - 10}$ rings and multiple condensed carbon ring systems (e.g., ring systems comprising 2, 3 or 4 rings) having 9 to 20 carbon atoms in which at least one ring is aromatic and wherein the other rings may be aromatic or not aromatic. The rings of multiple condensed ring systems may be connected to each other via fused, spiro, or bridged bonds when valency allows. Examples of aryl moieties include anthracenyl, azulenyl, fluorenyl, indanyl, indenyl, naphthyl, phenyl, phenanthrenyl, and 1, 2, 3, 4- tetrahydronaphthyl.The term "cycloalkyl" refers to a saturated or partially unsaturated all carbon- backbone ring having 3 to 20 carbon atoms (e.g., $\mathbf{C}\_{3 - 20}$ , $\mathbf{C}\_{3 - 15}$ , $\mathbf{C}\_{3 - 7}$ , $\mathbf{C}\_{4 - 6}$ and $\mathbf{C}\_{6}$ cycloalkyl). Examples include multicyclic carbocycles such as bicyclo[3.1.0]hexane and bicyclo[2.1.1]hexane, and polycyclic carbocycles, such as tricyclic and tetracyclic carbocycles. The rings of multiple condensed ring systems may be connected to each other via fused, spiro, and bridged bonds when valency allows. For example, multicyclic carbocycles may be connected to each other via a single carbon atom to form a spiro connection (e.g., spiropentane, spiro[4,5]decane), via two adjacent carbon atoms to form a fused connection (e.g., decahydronaphthalene, norsubinane, norcarane), or via two non- adjacent carbon atoms to form a bridged connection (e.g., norbornane, bicyclo[2.2.2]octane). Examples of cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo[2.2.1]heptane, pinane, adamantane.The term "cycloheteroalkyl" refers to a cyclic heteroalkyl moiety, defined below.The term "halo" encompass fluoro, chloro, bromo, and iodo.The term "heterocarbyl" refers to a moiety having a backbone made up of one or more carbon atoms and one or more heteroatoms. Particular heteroatoms are nitrogen, oxygen and sulfur. A heterocarbyl moiety may be thought of as a hydrocarbyl moiety wherein at least one carbon atom, $\mathrm{CH}$ , $\mathrm{CH}\_2$ , or $\mathrm{CH}\_3$ group is replaced with one or more heteroatoms and the requisite number of hydrogen atoms to satisfy valences. Heterocarbyl moieties may be nonaromatic, aromatic, partially aromatic, linear, branched, cyclic, or a combination thereof. Examples of heterocarbyl include 2- 20, 2- 12, 2- 8, 2- 6 and 2- 4 membered heterocarbyl moieties, wherein the number range refers to the sum total of carbon, nitrogen, oxygen, and / or sulfur atoms in the moiety's backbone. The term "2- 12 membered heterocarbyl" thus refers to a heterocarbyl moiety having a total of 2- 12 carbon, nitrogen, oxygen, and / or sulfur atoms. Examples of heterocarbyl moieties include straight chain and branched heteroalkyl, heteroalkenyl, and heteroalkynyl, as well as heterocycle and heteroaryl.The term "heteroalkyl" refers to a saturated or partially unsaturated moiety having 3- to 20- atom backbone of carbon and at least one heteroatom (e.g., O, N, S). Examples of heteroalkyl moieties include2- 8- membered, 2- 6- membered, and 2- 4- membered heteroalkyl moieties. Particular examples include alkoxyl, acyl (e.g., formyl, acetyl, benzoyl), alkylamino (e.g., di- (C1- 3- alkyl)amino), arylamino, aryloxime, carbamates, carbamides, alkylcarbonyl, arylcarbonyl, aminocarbonyl, alkylaminocarbonyl, alkylsulfanyl, arylsulfanyl, alkylsulfinyl, arylsulfinyl, alkylsulfonyl, arylsulfonyl, alkylsulfonylamino, and arylsulfonylamino.The term "heteroaryl" encompasses a single aromatic ring that has at least one atom other than carbon in the ring, wherein the atom is selected from the group consisting of oxygen, nitrogen and sulfur (e.g., single aromatic rings of from 1 to 6 carbon atoms and 1- 4 heteroatoms.) The term also encompasses multiple condensed ring systems that have at least one such aromatic ring. Examples include acridinyl, benzimidazolyl, benzofuranyl, benzoisothiazolyl, benzoisoxazolyl, benzoquinazolinyl, benzothiazolyl, benzoxazolyl, furyl, imidazolyl, indazolyl, indolyl, isoquinolyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxazolyl, phthalazinyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridyl, pyrimidinyl, pyrimidyl, pyrrolyl, quinolyl, quinoxalyl, quinazolinyl, quinolinyl, thienyl, tetrazolyl, thiadiazolyl, thiazolyl, triazinyl, and triazolyl.The term "hydrocarbyl" refers to a moiety having an all- carbon backbone and consisting of carbon and hydrogen atoms. Examples of hydrocarbyl groups include those having 1- 20, 1- 12, 1- 6, and 1- 4 carbon atoms (referred to as C1- 20 hydrocarbyl, C1- 12 hydrocarbyl, C1- 6 hydrocarbyl, and C1- 4 hydrocarbyl, respectively). Hydrocarbyl moieties may be aliphatic, aromatic, partially aromatic, linear, branched, cyclic, or a combination thereof. Examples include alkyl, alkenyl, alkynyl, aryl, benzyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkenylalkyl, naphthyl, phenyl, and phenylethyl.The term "heterocycle" refers to a cyclic (monocyclic or polycyclic) heterocarbyl moiety which may be aromatic, partially aromatic, or non- aromatic. Heterocycles include heteroaryls. Examples include 4- 10- membered, 4- 7- membered, 6- membered, and 5- membered heterocycles such as aziridinyl, azetidinyl, benzo[1,3]dioxoyl, benzoxazinyl, 1,3- benzodioxoyl, 1,4- benzodioxanyl, cinnolinyl, chromanyl, 2,3- dihydro- benzo[1,4]dioxinyl, dihydrooxazolyl, 1,2- dihydropyridinyl, 2,3- dihydrobenzofuranyl, 1,4- dioxane, dioxolane, butyrolactam, furanyl, homopiperidinyl, hydantoinyl, isoindolinyl- 1- one, 2- oxa- 6- azaspiro[3.3]heptanyl, hydantoin, imidazolidin- 2- one, imidazolidine, imidazolidinone, morpholinyl, oxetanyl, oxiranyl, phthalimidyl, piperazinyl, piperidinyl, pyrrolidinonyl, piperidinyl, pyrrolidinyl, pyrazolidine, spiro[cyclopropane- 1,1'- isoindolinyl]- 3'- one, tetrahydrofuranyl, tetrahydropyranyl, tetrahydropyridinyl, tetrahydropyrimidinyl, tetrahydrothiophenyl, 1,2,3,4- tetrahydroquinolyl, tetrahydrothiopyranyl, thiomorpholinyl, and valerolactamyl.The term "include" has the same meaning as "include, but are not limited to," and the term "includes" has the same meaning as "includes, but is not limited to." Similarly, the term "such as" has the same meaning as the term "such as, but not limited to."The term "lower alkyl" refers to alkyl having from 1 to 6 carbon atoms, e.g., C1- 4 alkyl. Examples include methyl, ethyl, propyl, isopropyl, and cyclobutyl.The terms "manage," "managing" and "management" mean preventing the recurrence of the specified disease or disorder in a patient who has already suffered from the disease or disorder, and / or lengthening the time that a patient who has suffered from the disease or disorder remains in remission. The terms encompass modulating the threshold, development and / or duration of the disease or disorder or changing the way that a patient responds to the disease or disorder.The term "pharmaceutically acceptable salt" refers to a salt that is generally recognized as safe to administer to a subject. Examples of pharmaceutically acceptable salts include acetate, chloride, diphosphate, hydrochloride, maleate, phosphate, potassium, sodium, and sulfate.The terms "prevent," "preventing" and "prevention" contemplate an action that occurs before a patient begins to suffer from the specified disease or disorder, which inhibits or reduces the severity of the disease or disorder. The terms encompass prophylaxis.A "prophylactically effective amount" of a compound is an amount sufficient to prevent a disease or condition, or one or more symptoms associated with the disease or condition, or prevent its recurrence. A "prophylactically effective amount" of a compound means an amount, alone or in combination with other agents, that provides a prophylactic benefit in the prevention of the disease. The term "prophylactically effective amount" can encompass an amount that improves overall prophylaxis or enhances the prophylactic efficacy of another prophylactic agent.The terms "subject" and "patient" are used interchangeably. The terms "subject" and "subjects" refer to an animal, such as a non- primate mammal (e.g., cow, pig, horse, cat, dog, rat, and mouse) and a primate (e.g., monkey, a chimpanzee, human). Preferred subjects are human (e.g., adult humans).A "therapeutically effective amount" of a compound is an amount sufficient to provide a therapeutic benefit in the treatment or management of a disease or condition, or to delay or minimize one or more symptoms associated with the disease or condition. A "therapeutically effective amount" of a compound means an amount, alone or in combination with other therapies, that provides a therapeutic benefit in the treatment or management of the disease or condition. The term "therapeutically effective amount" can encompass an amount that improves overall therapy, reduces, or avoids symptoms or causes of a disease or condition, or enhances the therapeutic efficacy of another therapeutic agent.The terms "treat," "treating" and "treatment" contemplate an action that occurs while a patient is suffering from a specified disease or disorder, which reduces the severity of the disease or disorder or retards or slows the progression of the disease or disorder.Unless otherwise indicated, an adjective before a string of nouns should be construed to apply to each. For example, the phrase "optionally substituted pyridyl, pyrazyl, or furanyl" means the same as "optionally substituted pyridyl, optionally substituted pyrazyl, or optionally substituted furanyl".A wavy line "ww" that intersects a bond in a chemical structure indicates the point of attachment of the bond that the wavy bond intersects in the chemical structure to the remainder of a molecule.Compounds disclosed herein may exist as tautomeric isomers. Although only one delocalized resonance structure may be depicted, all such forms are contemplated within the scope of the invention.Unless explicitly noted, chemical structures named or shown herein encompass derivatives wherein one or more of their constituent atoms is / are replaced or enriched (i.e., present in a quantity measurably greater than its natural abundance) with an isotope thereof. Thus, unless noted otherwise, a chemical structure that contains hydrogen atoms encompasses deuterated forms of the represented molecule or moiety.Compounds disclosed herein may exist as zwitterions (e.g., at pharmacological pH). Unless otherwise indicated, it should be understood that a chemical drawing depicting the structure of such a compound encompasses all of its zwitterionic forms.Some compounds may exist as stereoisomers. When a stereoisomer of compound is defined by its name (e.g., with the use of $R$ or $S$ ) or is depicted in a drawn structure (e.g., using a bold, bold- wedge, dashed, or dashed- wedge to depict the relevant chemical bond), the enantiomeric excess (ee) of that compound, unless otherwise indicated, is to be understood to be at least 60, 70, 80, 90, 95, or $99\%$ . A compound or composition enriched with one stereoisomer of the compound has that one stereoisomer in an amount measurably greater than the compound's other stereoisomer(s). For example, a compound enriched with an R enantiomer will have an enantiomeric excess of that enantiomer versus the S enantiomer.# 4.2. COMPOUNDSThis invention encompasses compounds of formula I:Iand pharmaceutically acceptable salts thereof, wherein:$\mathbf{X}^1$ and $\mathbf{X}^2$ is independently O or $\mathrm{CHR}^6$ each of $\mathbf{Y}^1$ $\mathbf{Y}^2$ , and $\mathbf{Y}^3$ is independently N, $\mathbf{CR}^3$ , or $\mathbf{C - X^1 - R^1}$ , provided that only one of $\mathbf{Y}^1$ $\mathbf{Y}^2$ , and $\mathbf{Y}^3$ may be attached to $\mathbf{X}^1$25 each of $\mathbf{Z}^1$ $\mathbf{Z}^2$ , and $\mathbf{Z}^3$ is independently $\mathbf{N}$ or $\mathbf{CR}^3$ each $\mathbf{R}^1$ is independently optionally substituted $\mathbf{C}\_{1 - 8}$ hydrocarbyl or 2- 9 membered heterocarbyl, which optional substitution is with one or more of halo, $\mathbf{R}^{1\mathrm{A}}$ , or $\mathbf{OR}^{1\mathrm{A}}$ each $\mathbf{R}^{1\mathrm{A}}$ is independently optionally substituted $\mathbf{C}\_{1 - 6}$ hydrocarbyl, which optional substitution is with one or more of halo; 30 each of $\mathbf{R}^{2\mathrm{A}}$ and $\mathbf{R}^{2\mathrm{B}}$ is independently hydrogen or $\mathbf{C}\_{1 - 6}$ alkyl optionally substituted with one or more halo, or $\mathbf{R}^{2\mathrm{A}}$ and $\mathbf{R}^{2\mathrm{B}}$ are taken together to form a $\mathbf{C}\_{3 - 5}$ cycloalkyl or 3- 5 membered cycloheteroalkyl; each $\mathbf{R}^3$ is independently hydrogen, halo, $\mathbf{C}\_{1 - 6}$ alkyl optionally substituted with one or more halo; $\mathbf{R}^4$ is hydrogen or $\mathbf{C}\_{1 - 6}$ alkyl;$\mathbb{R}^5$ is $\mathrm{N}(\mathrm{R}^{5\mathrm{A}})\_2$ $\mathrm{NHR}^{5\mathrm{A}}$ , or optionally substituted $\mathbf{C}\_{1 - 8}$ hydrocarbyl or 2- 9 membered heterocarbyl, which optional substitution is with one or more of halo, hydroxyl, nitrile, $\mathbf{R}^{5\mathrm{A}}$ $\mathrm{OR}^{5\mathrm{A}}$ $\mathrm{N}(\mathrm{R}^{5\mathrm{A}})\_2$ $\mathrm{NHR}^{5\mathrm{A}}$ , or $\mathrm{NH\_2}$each $\mathbb{R}^{5\mathrm{A}}$ is independently optionally substituted $\mathbf{C}\_{1 - 8}$ hydrocarbyl or 2- 9 membered heterocarbyl, which optional substitution is with one or more of halo, hydroxyl, nitrile, $\mathbb{R}^{5\mathrm{B}}$ $\mathrm{OR}^{5\mathrm{B}}$ $\mathrm{N}(\mathrm{R}^{5\mathrm{B}})\_2$ $\mathrm{NHR}^{5\mathrm{B}}$ , or $\mathrm{NH\_2}$each $\mathbb{R}^{5\mathrm{B}}$ is independently optionally substituted $\mathbf{C}\_{1 - 8}$ hydrocarbyl or 2- 9 membered heterocarbyl, which optional substitution is with one or more of halo, hydroxyl, nitrile, $\mathbb{R}^{5\mathrm{C}}$ $\mathrm{OR}^{5\mathrm{C}}$ $\mathrm{N}(\mathrm{R}^{5\mathrm{C}})\_2$ $\mathrm{NHR}^{5\mathrm{C}}$ , or $\mathrm{NH\_2}$10 each $\mathbb{R}^{5\mathrm{C}}$ is independently optionally substituted $\mathbf{C}\_{1 - 8}$ hydrocarbyl or 2- 9 membered heterocarbyl, which optional substitution is with one or more of halo, hydroxyl, nitrile, or $\mathrm{NH\_2}$ ; andeach $\mathbb{R}^6$ is independently $\mathrm{H}$ or $\mathbf{C}\_{1 - 6}$ alkyl.In some embodiments of the invention, $\mathbb{R}^{2\mathrm{A}}$ and $\mathbb{R}^{2\mathrm{B}}$ are taken together to form a $\mathbf{C}\_{3 - 5}$ cycloalkyl or 3- 5 membered cycloheteroalkyl (e.g., cyclopropyl or cyclobutyl).15 In some embodiments of the invention, $\mathbf{X}^1$ is O. In some embodiments, $\mathbf{X}^2$ is O. In some embodiments, $\mathbf{Y}$ is N. In some embodiments, n is 1 or 2.Some embodiments of the invention are directed to compounds of formula II:II20 and pharmaceutically acceptable salts thereof.In some embodiments of the invention (e.g., as represented in any of the applicable formulae herein), at least one of $\mathbf{Y}^1$ $\mathbf{Y}^2$ , and $\mathbf{Y}^3$ is N. In some embodiments, each of $\mathbf{Y}^1$ and $\mathbf{Y}^2$ is independently $\mathbf{CR}^3$ . In some embodiments, at least one of $\mathbf{Z}^1$ $\mathbf{Z}^2$ , and $\mathbf{Z}^3$ is N. In some embodiments, each of $\mathbf{Z}^2$ and $\mathbf{Z}^3$ is N. In some embodiments, each of $\mathbf{Z}^1$ and $\mathbf{Z}^3$ is N.25 Some embodiments are directed to compounds of formula III:IIIand pharmaceutically acceptable salts thereof.Some embodiments are directed to compounds of formula IV:IVand pharmaceutically acceptable salts thereof.5 In some embodiments of the invention, $\mathrm{X}^2$ is O. Preferred compounds of the invention are enantiomerically pure or enriched with $(R)$ stereochemistry at the carbon to which $\mathbf{R}^{2\mathrm{A}}$ is attached. For example, some embodiments of the invention are directed to compounds of formula $\mathrm{V(a)}$ ..V(a)and pharmaceutically acceptable salts thereof, while others are directed to compounds of formula $\mathrm{V(b)}$and pharmaceutically acceptable salts thereof.15 In some embodiments of the invention, $\mathrm{Y}^3$ is $\mathrm{N}$ . In some embodiments of the invention, $\mathrm{R}^5$ is one of:Some embodiments are directed to compounds of formula VI(a):and pharmaceutically acceptable salts thereof. Others are directed to compounds of formula VI(b):Some embodiments are directed to compounds of formula VII(a):10 and pharmaceutically acceptable salts thereof. Others are directed to compounds of formula VII(b):and pharmaceutically acceptable salts thereof.Some embodiments are directed to compounds of formula VIII(a):VIII(a)and pharmaceutically acceptable salts thereof. Others are directed to compounds of formula VIII(b):VIII(b)and pharmaceutically acceptable salts thereof.Certain embodiments of the invention are directed to compounds encompassed by the generic structures disclosed herein (e.g., structures I- VIII) wherein $\mathbb{R}^1$ is optionally substituted $\mathbf{C}\_{1 - 8}$ hydrocarbyl. Others are directed to compounds wherein $\mathbb{R}^1$ is cyclopropylmethyl, phenyl, or cyclopropyl. Others are directed to compounds wherein $\mathbb{R}^1$ is optionally substituted 2- 9 membered heterocarbyl. Others are directed to compounds wherein $\mathbb{R}^1$ is pyridyl, pyrazyl, thiophenyl, or furanyl. Others are directed to compounds wherein $\mathbb{R}^1$ is substituted with $\mathrm{OR}^{1\mathrm{A}}$ . Certain embodiments are directed to compounds wherein $\mathbb{R}^{1\mathrm{A}}$ is $\mathbf{C}\_{1 - 6}$ alkyl. In some embodiments, $\mathbb{R}^2$ is methyl or ethyl. In some embodiments, $\mathbb{R}^3$ is fluoro. In some embodiments, $\mathbb{R}^3$ is hydrogen.In some embodiments, $\mathbb{R}^{5\mathrm{A}}$ is optionally substituted alkyl or 4- or 5- membered heterocycle. In some embodiments, $\mathbb{R}^5$ is optionally substituted with $\mathbb{R}^{5\mathrm{B}}$ . In some embodiments, $\mathbb{R}^{5\mathrm{B}}$ is optionally substituted $\mathbf{C}\_{1 - 6}$ alkyl.Specific compounds of the invention include:(R)-4-(1-(5-(cyclopropylmethoxy)pyridin-2-yl)propoxy)-2,3- difluoro- $\mathcal{N}$ -((4- (2-(pyrrolidin- 1- yl)ethoxy)piperidin-1- yl)sulfonyl)benzamide; 4- ((R)-1-(5-(cyclopropylmethoxy)pyridin-2-yl)propoxy)-2,3- difluoro- $\mathcal{N}$ -((5- (2-(pyrrolidin- 1- yl)ethoxy)-2- azabicyclo[2.2.1]heptan-2-yl)sulfonyl)benzamide; (R)-4-(1-(5-(cyclopropylmethoxy)pyridin-2-yl)propoxy)-2,3- difluoro- $\mathcal{N}$ -((6- ((1- methylpiperidin25 4- yl)oxy)-2- azaspiro[3.3]heptan-2-yl)sulfonyl)benzamide; (R)-2,3- difluoro- $\mathcal{N}$ -((4- ((1- methylpiperidin-4- yl)oxy)piperidin-1- yl)sulfonyl)-4- (1- (5- (pyridin-2- yloxy)pyridin-2- yl)propoxy)benzamide;(R)-4-(1-(5-(cyclopropylmethoxy)pyridin-2-yl)propoxy)-2,3-difluoro- $N$ -((4-((1-methylpiperidin- 4-yl)oxy)piperidin-1-yl)sulfonyl)benzamide;(R)-4-(1-(5-(cyclopropylmethoxy)pyridin-2-yl)propoxy)- $N$ -((6-2-(dimethylamino)ethoxy)-2- azaspiro[3.3]heptan-2-yl)sulfonyl)-2,3-difluorobenzamide;(R)-4-(1-(5-(cyclopropylmethoxy)pyridin-2-yl)propoxy)-2,3-difluoro- $N$ -((4-((1-2- hydroxy- 2- methylpropyl)piperidin-4-yl)oxy)piperidin-1-yl)sulfonyl)benzamide;(R)-4-(1-(5-(cyclopropylmethoxy)pyridin-2-yl)propoxy)-2,3-difluoro- $N$ -((6-2-(pyrrolidin- 1- yl)ethoxy)-2- azaspiro[3.3]heptan-2-yl)sulfonyl)benzamide;(R)-4-(1-(5-(cyclopropylmethoxy)pyridin-2-yl)propoxy)-2,3-difluoro- $N$ -((4-((1-2- methoxyethyl)piperidin-4-yl)oxy)piperidin-1-yl)sulfonyl)benzamide;(R)-4-(1-(5-(cyclopropylmethoxy)pyridin-2-yl)propoxy)- $N$ -((4-((1- cyclopropylmethyl)piperidin- 4-yl)oxy)piperidin-1-yl)sulfonyl)-2,3-difluorobenzamide;(R)-4-(1-(5-(cyclopropylmethoxy)pyridin-2-yl)propoxy)- $N$ -((4-((4- ethylpiperazin- 1- yl)methyl)piperidin-1-yl)sulfonyl)-2,3-difluorobenzamide;(R)- $N$ -((4-((2-(dimethylamino)ethoxy)piperidin-1-yl)sulfonyl)-2,3-difluoro-4-((1-5-2- methoxyethoxy)pyridin-2-yl)propoxy)benzamide;(R)-2,3-difluoro-4-((1-5-2-methoxyethoxy)pyridin-2-yl)propoxy)- $N$ -((4-((1- methylpiperidin- 4- yl)oxy)piperidin-1-yl)sulfonyl)benzamide;(R)- $N$ -((4-((2-(dimethylamino)ethoxy)piperidin-1-yl)sulfonyl)-2,3-difluoro-4-((1-5-(pyridin- 2- yloxy)pyridin-2-yl)propoxy)benzamide;(R)-4-(1-(5-(cyclopropylmethoxy)pyridin-2-yl)propoxy)- $N$ -((4-2- (dimethylamino)ethoxy)piperidin-1-yl)sulfonyl)-2,3-difluorobenzamide;(R)-2,3-difluoro- $N$ -((4-methylpiperazin- 1-yl)sulfonyl)-4-((1-5-(pyridin- 2- yloxy)pyridin- 2- yl)propoxy)benzamide;(R)- $N$ -((4-2- (1H- imidazol- 1- yl)ethoxy)phenyl)sulfonyl)-2,3-difluoro-4-((1-5-2- methoxyethoxy)pyridin-2-yl)propoxy)benzamide; or(R)- $N$ -((4-2-(dimethylamino)ethoxy)phenyl)sulfonyl)-2,3-difluoro-4-((1-5-2- methoxyethoxy)pyridin-2-yl)propoxy)benzamide.Other compounds of the invention include:(R)-4-(1-(5-(cyclopropylmethoxy)pyridin-2-yl)propoxy)-2,3-difluoro- $N$ -((4-((2-(pyrrolidin- 1- yl)ethoxy)phenyl)sulfonyl)benzamide;(R)-4-(1-(5-(cyclopropylmethoxy)pyridin-2-yl)propoxy)-2,3-difluoro- $N$ -((4-2- (4- (4- (4- (4- (4- (4- (4- (4- (4- (4- (4- (4- (4- (4- (4- (4- (4- (4- (4- (4- (4- (4- (4- (4- (4- (4- (4- (4- (4- (4- (4- (4- (4- (4(R)-4-(1-(5-(cyclopropylmethoxy)pyridin-2-yl)propoxy)-2,3-difluoro- $N$ - ((4- ((1-methylpiperidin- 4- yl)oxy)phenyl)sulfonyl)benzamide;(R)-4-(1-(5-(cyclopropylmethoxy)pyridin- 2- yl)propoxy)- N- ((4- (2- (dimethylamino)ethoxy)phenyl)sulfonyl)- 2,3-difluorobenzamide;(R)-4-(1-(5-(cyclopropylmethoxy)pyridin- 2- yl)propoxy)- 2,3-difluoro- $N$ - ((4- (2- (4- methylpiperazin- 1- yl)ethoxy)phenyl)sulfonyl)benzamide;(R)-4-(1-(5-(cyclopropylmethoxy)pyridin- 2- yl)propoxy)- N- ((4- (2- (dimethylamino)ethoxy)phenyl)sulfonyl)- 2,3-difluoro- $N$ - methylbenzamide;4- ((R)- 1- (5- (cyclopropylmethoxy)pyridin- 2- yl)propoxy)- 2,3-difluoro- $N$ - ((4- (2- ((S)- 3- fluoropyrrolidin- 1- yl)ethoxy)phenyl)sulfonyl)benzamide;(R)- 4- (1- (5- (cyclopropylmethoxy)pyridin- 2- yl)propoxy)- 2,3-difluoro- $N$ - ((4- (2- (oxetan- 3- ylamino)ethoxy)phenyl)sulfonyl)benzamide;(R)- 4- (1- (5- (cyclopropylmethoxy)pyridin- 2- yl)propoxy)- 2,3-difluoro- $N$ - ((6- ((1- methylpiperidin- 4- yl)oxy)pyridazin- 3- yl)sulfonyl)benzamide;(R)- 4- (1- (5- (cyclopropylmethoxy)pyridin- 2- yl)propoxy)- 2,3-difluoro- $N$ - ((6- ((1- methylpiperidin- 4- yl)oxy)pyridin- 3- yl)sulfonyl)benzamide;(R)- N- ((4- ((1H- imidazol- 4- yl)methoxy)phenyl)sulfonyl)- 2,3-difluoro- 4- (1- (5- (2- methoxyethoxy)pyridin- 2- yl)propoxy)benzamide;(R)- 4- (1- (5- (cyclopropylmethoxy)pyridin- 2- yl)propoxy)- 2,3-difluoro- $N$ - ((4- ((1- (methyl- 20 $d\_{3}$ )piperidin- 4- yl)oxy)phenyl)sulfonyl)benzamide;(R)- N- ((4- (2- (cyclopropylamino)ethoxy)phenyl)sulfonyl)- 4- (1- (5- (cyclopropylmethoxy)pyridin- 2- yl)propoxy)- 2,3-difluorobenzamide;4- ((R)- 1- (5- (cyclopropylmethoxy)pyridin- 2- yl)propoxy)- 2,3-difluoro- $N$ - ((4- ((S)- 1- methylpyrrolidin- 3- yl)oxy)phenyl)sulfonyl)benzamide;(R)- 4- (1- (5- (cyclopropylmethoxy)pyridin- 2- yl)propoxy)- N- ((4- ((1- (cyclopropylmethyl)piperidin- 4- yl)oxy)phenyl)sulfonyl)- 2,3-difluorobenzamide;(R)- 4- (1- (5- (cyclopropylmethoxy)pyridin- 2- yl)propoxy)- 2,3-difluoro- $N$ - ((4- ((1- (2- hydroxyethyl)piperidin- 4- yl)oxy)phenyl)sulfonyl)benzamide;4- ((R)- 1- (5- (cyclopropylmethoxy)pyridin- 2- yl)propoxy)- 2,3-difluoro- $N$ - ((4- ((R)- 1- methylpyrrolidin- 3- yl)oxy)phenyl)sulfonyl)benzamide; or(R)- 4- (1- (5- (cyclopropylmethoxy)pyridin- 2- yl)propoxy)- N- ((4- ((1- ethylpiperidin- 4- yl)oxy)phenyl)sulfonyl)- 2,3-difluorobenzamide.Other compounds of the invention include:(R)- 4- (1- (5- (cyclopropylmethoxy)pyridin- 2- yl)propoxy)- 2,3-difluoro- $N$ - ((4- ((1- isopropylpiperidin- 4- yl)oxy)phenyl)sulfonyl)benzamide;(R)- 4- (1- (5- (cyclopropylmethoxy)pyridin- 2- yl)propoxy)- 2,3-difluoro- $N$ - ((4- ((1- methylazetidin- 3- yl)oxy)phenyl)sulfonyl)benzamide;(R)-4-(1-(5-(cyclopropylmethoxy)pyridin-2-yl)propoxy)-2,3-difluoro- $N$ - ((6- ((1-methylpiperidin- 4- yl)amino)pyridin- 3- yl)sulfonyl)benzamide;(R)-4-(1-(5-(cyclopropylmethoxy)pyridin- 2- yl)propoxy)-2,3-difluoro- $N$ - ((6- (2- (pyrrolidin- 1- yl)ethoxy)pyridazin- 3- yl)sulfonyl)benzamide;54- ((R)- 1- (5- (cyclopropylmethoxy)pyridin- 2- yl)propoxy)- 2,3-difluoro- $N$ - ((4- ((1,2,2- trimethylpiperidin- 4- yl)oxy)phenyl)sulfonyl)benzamide;(R)- 4- (1- (5- (cyclopropylmethoxy)pyridin- 2- yl)propoxy)- 2,3-difluoro- $N$ - ((6- ((2- (pyrrolidin- 1- yl)ethyl)amino)pyridin- 3- yl)sulfonyl)benzamide;(R)- 4- (1- (5- (cyclopropylmethoxy)pyridin- 2- yl)propoxy)- 2,3-difluoro- $N$ - ((4- (piperidin- 4- yloxy)phenyl)sulfonyl)benzamide;(R)- 4- (1- (5- (cyclopropylmethoxy)pyridin- 2- yl)propoxy)- 2,3-difluoro- $N$ - ((5- ((1- methylpiperidin- 4- yl)oxy)pyridin- 2- yl)sulfonyl)benzamide;(R)- 4- (1- (5- (cyclopropylmethoxy)pyridin- 2- yl)propoxy)- 2,3-difluoro- $N$ - ((2- ((1- methylpiperidin- 4- yl)oxy)pyrimidin- 5- yl)sulfonyl)benzamide;154- ((R)- 1- (5- (cyclopropylmethoxy)pyridin- 2- yl)propoxy)- 2,3-difluoro- $N$ - ((4- ((1R,4R,5R)- 2- methyl- 2- azabicyclo[2.2.1]heptan- 5- yl)oxy)phenyl)sulfonyl)benzamide;(R)- 4- (1- (5- (cyclopropylmethoxy)pyridin- 2- yl)propoxy)- 2,3-difluoro- $N$ - ((5- ((1- methylpiperidin- 4- yl)amino)pyridin- 2- yl)sulfonyl)benzamide;(R)- 4- (1- (5- (cyclopropylmethoxy)pyridin- 2- yl)propoxy)- N- ((4- ((1- (2,2- difluoroethyl)piperidin- 4- yl)oxy)phenyl)sulfonyl)- 2,3- difluorobenzamide;(R)- 4- (1- (5- (cyclopropylmethoxy)pyridin- 2- yl)propoxy)- 2,3- difluoro- $N$ - ((6- ((1- isopropylpiperidin- 4- yl)amino)pyridin- 3- yl)sulfonyl)benzamide;N- ((4- ((1R,4R,5R)- 2- azabicyclo[2.2.1]heptan- 5- yl)oxy)phenyl)sulfonyl)- 4- ((R)- 1- (5- (cyclopropylmethoxy)pyridin- 2- yl)propoxy)- 2,3- difluorobenzamide;25(R)- 4- (1- (5- (cyclopropylmethoxy)pyridin- 2- yl)propoxy)- 2,3- difluoro- $N$ - ((6- (2- (pyrrolidin- 1- yl)ethoxy)pyridin- 3- yl)sulfonyl)benzamide;(R)- 4- (1- (5- (cyclopropylmethoxy)pyridin- 2- yl)propoxy)- 2,3- difluoro- $N$ - ((4- ((1- (2- methoxyethyl)piperidin- 4- yl)oxy)phenyl)sulfonyl)benzamide; or(R)- 4- (1- (5- (cyclopropylmethoxy)pyridin- 2- yl)propoxy)- 2,3- difluoro- $N$ - ((4- ((1- (2- hydroxy- 2- methylpropyl)piperidin- 4- yl)oxy)phenyl)sulfonyl)benzamide.Other compounds of the invention include:(R)- 4- (1- (5- (cyclopropylmethoxy)pyridin- 2- yl)propoxy)- 2,3- difluoro- $N$ - ((6- ((1- isopropylpiperidin- 4- yl)oxy)pyridin- 3- yl)sulfonyl)benzamide;(R)- 2,3- difluoro- 4- (1- (5- (2- methoxyethoxy)pyridin- 2- yl)propoxy)- N- ((4- ((1- methylpiperidin- 4- yl)oxy)phenyl)sulfonyl)benzamide;(R)- N- ((4- ((1- azabicyclo[2.2.1]heptan- 4- yl)oxy)phenyl)sulfonyl)- 4- (1- (5- (cyclopropylmethoxy)pyridin- 2- yl)propoxy)- 2,3- difluorobenzamide;4- ((R)- 1- (5- (cyclopropylmethoxy)pyridin- 2- yl)propoxy)- 2,3- difluoro- N- ((4- (2- ((R)- 1- methylpiperidin- 2- yl)ethoxy)phenyl)sulfonyl)benzamide; (R)- 4- (1- (5- (cyclopropylmethoxy)pyridin- 2- yl)propoxy)- 2,3- difluoro- N- ((1- methylpiperidin- 4- yl)sulfonyl)benzamide; (R)- 4- (1- (5- (cyclopropylmethoxy)pyridin- 2- yl)propoxy)- 2,3- difluoro- N- ((4- (2- (piperidin- 1- yl)ethoxy)phenyl)sulfonyl)benzamide; (R)- 2,3- difluoro- 4- (1- (5- (pyridin- 2- yloxy)pyridin- 2- yl)propoxy)- N- ((2,2,4- trimethylpiperazin- 1- yl)sulfonyl)benzamide; (R)- 4- (1- (5- (cyclopropylmethoxy)pyridin- 2- yl)propoxy)- N- ((6- (4- ethylpiperazin- 1- yl)methyl)pyridin- 3- yl)sulfonyl)- 2,3- difluorobenzamide; (R)- 2,3- difluoro- N- ((1- methylpiperidin- 4- yl)sulfonyl)- 4- (1- (5- (pyridin- 2- yloxy)pyridin- 2- yl)propoxy)benzamide; (R)- 4- (1- (5- (cyclopropylmethoxy)pyridin- 2- yl)propoxy)- 2,3- difluoro- N- ((2,2,4- trimethylpiperazin- 1- yl)sulfonyl)benzamide; (R)- 4- (1- (5- (cyclopropylmethoxy)pyridin- 2- yl)propoxy)- N- ((1- (dimethylamino)- 2- methylpropan- 2- yl)sulfonyl)- 2,3- difluorobenzamide; (R)- N- (tert- butylsulfonyl)- 4- (1- (3- phenoxyphenyl)ethoxy)- 3- (trifluoromethyl)benzamide; (R)- 4- (1- (5- (cyclopropylmethoxy)pyridin- 2- yl)propoxy)- 2,3- difluoro- N- ((4- methylpiperazin- 1- yl)sulfonyl)benzamide; or (R)- N- ((1- (dimethylamino)- 2- methylpropan- 2- yl)sulfonyl)- 2,3- difluoro- 4- (1- (5- (pyridin- 2- yloxy)pyridin- 2- yl)propoxy)benzamide. Other compounds of the invention include: 4- (1- (5- ethoxypyridin- 2- yl)ethoxy)- 2,3- difluoro- N- ((4- methylpiperazin- 1- yl)sulfonyl)benzamide; rac- (R)- 2,3- dichloro- N- ((4- methylpiperazin- 1- yl)sulfonyl)- 4- (1- (3- phenoxyphenyl)ethoxy)benzamide; N- ((4- (aminomethyl)phenyl)sulfonyl)- 2,3- difluoro- 4- (1- (3- (pyridin- 3- yloxy)phenyl)ethoxy)benzamide; 4- (1- (5- ethoxypyridin- 2- yl)ethoxy)- 2,3- difluoro- N- (piperidin- 4- yl)sulfonyl)benzamide; 2- amino- 4- (1- (5- ethoxypyridin- 2- yl)ethoxy)- 3- fluoro- N- (piperidin- 4- ylsulfonyl)benzamide; N- ((3- morpholinopropyl)sulfonyl)- 4- (1- (5- (pyridazin- 3- yloxy)pyridin- 2- yl)ethoxy)- 3- (trifluoromethyl)benzamide; N- ((2- aminoethyl)sulfonyl)- 2,3- dichloro- 4- (1- (3- phenoxyphenyl)ethoxy)benzamide; 4- (1- (5- ethoxypyridin- 2- yl)ethoxy)- 2,3- difluoro- N- ((1- methylpiperidin- 4- yl)sulfonyl)benzamide; rac- (R)- N- ((4- (aminomethyl)phenyl)sulfonyl)- 2,3- dichloro- 4- (1- (3- phenoxyphenyl)ethoxy)benzamide; N- ((4- (2- aminoethyl)phenyl)sulfonyl)- 2,3- difluoro- 4- ((3- phenoxybenzyl)oxy)benzamide; rac- (R)- N- ((2- aminoethyl)sulfonyl)- 2,3- dichloro- 4- (1- (3- phenoxyphenyl)ethoxy)benzamide;rac- (R)- N- ((4- (aminomethyl)phenyl)sulfonyl)- 3- methyl- 4- (1- (3- phenoxyphenyl)ethoxy)benzamide;2,3- difluoro- N- ((4- ((methylamino)methyl)phenyl)sulfonyl)- 4- ((3- phenoxybenzyl)oxy)benzamide; rac- (R)- N- ((2- aminoethyl)sulfonyl)- 4- (1- (3- phenoxyphenyl)ethoxy)- 3-5 (trifluoromethyl)benzamide;4- (1- (5- ethoxypyridin- 2- yl)propoxy)- N- ((3- morpholinopropyl)sulfonyl)- 3- (trifluoromethyl)benzamide; 4- (1- (5- ethoxypyridin- 2- yl)propoxy)- N- ((4- (2- (methylamino)ethoxy)phenyl)sulfonyl)- 3- (trifluoromethyl)benzamide;10 N- ((4- (aminomethyl)phenyl)sulfonyl)- 4- (1- (3- (cyclopentyloxy)phenyl)ethoxy)- 3- (trifluoromethyl)benzamide; N- ((4- (aminomethyl)phenyl)sulfonyl)- 4- (1- (3- (pentyloxy)phenyl)ethoxy)- 3- (trifluoromethyl)benzamide; N- ((4- ((dimethylamino)methyl)phenyl)sulfonyl)- 2,3- difluoro- 4- ((3-15 phenoxybenzyl)oxy)benzamide;N- ((4- (aminomethyl)phenyl)sulfonyl)- 2,3- difluoro- 4- (1- (3- phenoxyphenyl)ethoxy)benzamide; N- ((4- (aminomethyl)phenyl)sulfonyl)- 4- (1- (3- (pyrimidin- 5- yloxy)phenyl)ethoxy)- 3- (trifluoromethyl)benzamide; N- ((4- (aminomethyl)phenyl)sulfonyl)- 4- (1- (3- (cyclopentylmethoxy)phenyl)ethoxy)- 3-20 (trifluoromethyl)benzamide;N- ((4- (aminomethyl)phenyl)sulfonyl)- 4- (1- (3- (thiophen- 3- yloxy)phenyl)ethoxy)- 3- (trifluoromethyl)benzamide; orN- ((4- (aminomethyl)phenyl)sulfonyl)- 4- (1- (3- (pyridin- 2- yloxy)phenyl)ethoxy)- 3- (trifluoromethyl)benzamide;25 Other compounds of the invention include:N- ((4- (aminomethyl)phenyl)sulfonyl)- 2,3- difluoro- 4- ((4- phenoxybenzyl)oxy)benzamide; N- ((4- (aminomethyl)phenyl)sulfonyl)- 4- (1- (3- (pyrazin- 2- yloxy)phenyl)ethoxy)- 3- (trifluoromethyl)benzamide; N- ((4- (aminomethyl)phenyl)sulfonyl)- 4- (1- (3- (pyridin- 3- yloxy)phenyl)ethoxy)- 3-30 (trifluoromethyl)benzamide;N- ((4- (aminomethyl)phenyl)sulfonyl)- 4- (cyclopentylmethoxy)- 3- (trifluoromethyl)benzamide; N- ((4- (aminomethyl)phenyl)sulfonyl)- 4- (2- (3- phenoxyphenyl)propoxy)- 3- (trifluoromethyl)benzamide; N- ((4- (aminomethyl)phenyl)sulfonyl)- 4- (1- (3- (cyclopentyloxy)phenyl)ethoxy)- 2,3-35 difluorobenzamide;N- ((4- (aminomethyl)phenyl)sulfonyl)- 4- (1- (3- ((1- methyl- 1H- pyrazol- 4- yl)oxy)phenyl)ethoxy)- 3- (trifluoromethyl)benzamide;N- ((4- (aminomethyl)phenyl)sulfonyl)- 4- (1- (3- ((2- methylpentyl)oxy)phenyl)ethoxy)- 3- (trifluoromethyl)benzamide;N- ((4- (aminomethyl)phenyl)sulfonyl)- 2,3- dichloro- 4- ((3- phenoxybenzyl)oxy)benzamide; N- ((4- (aminomethyl)phenyl)sulfonyl)- 2,3- dichloro- 4- (2- (3- phenoxyphenyl)propoxy)benzamide;5 4- (1- (3- (cyclopropylmethoxy)phenyl)ethoxy)- N- ((1- (2- (dimethylamino)ethyl)- 1H- pyrazol- 4- yl)sulfonyl)- 2,3- difluorobenzamide;N- ((4- (aminomethyl)phenyl)sulfonyl)- 2,3- difluoro- 4- ((3- phenoxybenzyl)oxy)benzamide; and N- ((4- (2- (1H- imidazol- 1- yl)ethoxy)phenyl)sulfonyl)- 4- (1- (5- ethoxypyridin- 2- yl)ethoxy)- 2,2- difluorobenzamide;10 N- [4- (2- aminoethyl)phenyl]sulfonyl- 2,3- difluoro- 4- [(3- phenoxyphenyl)methoxy]benzamide; $N$ - tert- butylsulfonyl- 4- [1- (5- ethoxy- 2- pyridyl)ethoxy]benzamide; $N$ - tert- butylsulfonyl- 4- [1- (5- ethoxy- 2- pyridyl)cyclobutoxy]- 2,3- difluoro- benzamide; $N$ - tert- butylsulfonyl- 4- [3- (5- ethoxy- 2- pyridyl)oxetan- 3- yl]oxy- 2,3- difluoro- benzamide; $N$ - tert- butylsulfonyl- 6- [rac- (1R)- 1- (3- phenoxyphenyl)ethoxy]pyridazine- 3- carboxamide;15 $N$ - tert- butylsulfonyl- 2- [rac- (1R)- 1- (3- phenoxyphenyl)ethoxy]- 4- (trifluoromethyl)pyrimidine- 5- carboxamide;$N$ - tert- butylsulfonyl- 5- chloro- 6- [rac- (1R)- 1- (3- phenoxyphenyl)ethoxy]pyridine- 3- carboxamide; 4- [1- (benzofuran- 5- yl)ethoxy]- 3- (trifluoromethyl)benzoic acid; $N$ - tert- butylsulfonyl- 4- [1- (5- phenoxypyrimidin- 2- yl)ethoxy]- 3- (trifluoromethyl)benzamide;20 $N$ - tert- butylsulfonyl- 4- [1- [3- methyl- 4- (2- pyridyloxy)phenyl]ethoxy]- 3- (trifluoromethyl)benzamide; $N$ - tert- butylsulfonyl- 4- [2- hydroxy- 1- [5- (2- pyridyloxy)- 2- pyridyl]ethoxy]- 3- (trifluoromethyl)benzamide;$N$ - tert- butylsulfonyl- 4- [1- methyl- 1- (5- pyrimidin- 2- yloxy- 2- pyridyl)ethoxy]- 3-25 (trifluoromethyl)benzamide; $N$ - tert- butylsulfonyl- 4- [1- (5- ethoxy- 2- pyridyl)- 3- hydroxy- propoxy]- 3- (trifluoromethyl)benzamide; $N$ - tert- butylsulfonyl- 4- [1- (5- ethoxy- 2- pyridyl)- 3- hydroxy- propoxy]- 3- (trifluoromethyl)benzamide; $N$ - tert- butylsulfonyl- 4- [3- (dimethylamino)- 1- (5- ethoxy- 2- pyridyl)[propoxy]- 3- (trifluoromethyl)benzamide;30 $N$ - tert- butylsulfonyl- 4- [1- (5- ethoxy- 2- pyridyl)- 3- methoxy- propoxy]- 3- (trifluoromethyl)benzamide;$N$ - tert- butylsulfonyl- 4- [1- (5- ethoxy- 2- pyridyl)- 2- methoxy- ethoxy]- 3- (trifluoromethyl)benzamide;$N$ - tert- butylsulfonyl- 5- [1- [3- (cyclopropylmethoxy)phenyl]ethoxy]pyridine- 2- carboxamide; 35 $N$ - tert- butylsulfonyl- 6- [1- [3- (cyclopropylmethoxy)phenyl]ethoxy]pyridazine- 3- carboxamide; $N$ - tert- butylsulfonyl- 4- [1- (5- ethoxy- 2- pyridyl)cyclopropoxy]- 2,3- difluoro- benzamide;$N$ - tert- butylsulfonyl- 8- [(1R)- 1- [3- (cyclopropylmethoxy)phenyl]ethoxy]imidazo[1,5- a]pyridine- 5- carboxamide; and4- [(1R)- 1- [5- (cyclopropylmethoxy)- 2- pyridyl]propoxy]- N- [4- [2- (dimethylamino)ethoxy]phenyl]sulfonyl- 2,3- difluoro- N- methyl- benzamide.# 4.2.1. Methods of SynthesisCompounds of the invention can be prepared by methods known in the art, by the general and specific methods disclosed herein, and by adaptation or modification of these methods using approaches well known in the art. Scheme 1 represents one general synthetic approach that may be used to prepare compounds encompassed by this invention.wherein R' is lower alkyl (e.g., methyl) and the various other substituents (e.g., Y $^3$ , R $^1$ ) are defined herein. In this approach, a nitrile is converted to an ethyl ketone 1b using the corresponding Grignard reagent. The desired aryl moiety (e.g., phenyl, pyridyl) is coupled to R $^1$ using a base mediated SN $\_2$ Ar reaction. Theketone is reduced under conditions sufficient to afford the desired enantiomer of the corresponding alcohol 1d using a chiral catalyst, which in turn undergoes Mitsunobu coupling with an optionally substituted methyl 4- hydroxybenzoate to afford esterified core 1e, which in turn is converted to the carboxylic acid 1f following saponification with a suitable agent, such as LiOH, NaOH, or trimethylsilyl iodide (TMSI). The acid is then coupled with the desired sulfonamide 1g to afford compound 1h using, for example, a base (e.g., 4- dimethylaminopyridine (DMAP), $\mathrm{Et}\_3\mathrm{N}$ , $\mathrm{Pr}\_2\mathrm{NEt}$ ) and suitable coupling reagents such as 1- ethyl- 3- (3- dimethylaminopropyl) carbodiimide hydrochloride (EDCl), benzotriazol- 1- yloxytripyrrolidinophosphonium hexafluorophosphate (PyBOP), 1- [bis(dimethylamino)methylene]- 1H- 1,2,3- triazolo[4,5- b]pyridinium 3- oxide hexafluorophosphate (HATU), and carbonyldiimidazole (CDI). (Various coupling methods in addition to those described herein are known in the art. See, e.g., Chen, L., and Luo, G., "Facile synthesis of acyl sulfonamides from carboxylic acids using the Mukaiyama reagent", Tetrahedron Let., 2019; 60:268- 271. ) The resulting product 1h may undergo additional reactions (e.g., deprotection) as needed. Racemic forms of compounds prepared according to Scheme 1 may be prepared by adapting this approach to begin with Scheme 2:Racemic forms of compounds prepared according to Scheme 1 may be prepared by adapting this 15 approach to begin with Scheme 2:If desired, enantiomers of the final racemic product can be isolated by methods known in the art, such as chiral chromatography.Other compounds of the invention may be prepared using the general approach shown below in Scheme 3:wherein the various substituents (e.g., $\mathbf{Y}^3$ , $\mathbf{R}^3$ ) are defined herein. In this approach, the acid moiety of 3a is protected under suitable conditions to provide intermediate 3b, which is then contacted with N-5 bromosuccinimide (NBS) and benzoyl peroxide (BPO) under conditions sufficient to afford the monobrominated compound 3c. That compound then undergoes a Michaelis- Arbuzov reaction to afford intermediate 3d, which is then reacted with the desired substituted benzoic acid under conditions sufficient to afford alkene 3f. Reduction of 3f affords 3g which, if desired, is resolved to the $R$ enantiomer 3h using chiral chromatograph (e.g., supercritical fluid (SFC) chromatography). (This step may be avoided if a racemic mixture of products is desired.) The carboxylic acid of that compound is then deprotected (e.g., using trifluoroacetic acid (TFA) in dichloromethane (DCM)) to afford intermediate 3i, which is then contacted with the desired sulfone 3j under conditions sufficient (e.g., EDC1, DMAP, DCM) to afford 3k.# 4.3. METHODS OF USE15 This invention encompasses methods of inhibiting ACSL5, which comprise contacting ACSL5 with a compound disclosed herein. The invention further encompasses a method of treating, managing, or preventing a disease or disorder associated with ACSL5 (e.g., its overexpression), which comprises administering to a subject in need thereof a therapeutically or prophylactically effective amount of acompound disclosed herein. Examples of such diseases and disorders include metabolic diseases and disorders and cancer.This invention encompasses methods of treating, managing, or preventing a metabolic disease or disorder. Examples of metabolic diseases and disorders that may be treated, managed, or prevented using compounds of the invention include metabolic dysfunction- associated steatohepatitis (MASH), metabolic syndrome, non- alcoholic fatty liver disease (NAFLD), obesity, and type 2 diabetes. This invention further encompasses a method of improving insulin sensitivity in a patient in need thereof, which comprises administering to the patient a compound of the invention.Examples of cancers that may be treated, managed, or prevented using compounds of the invention include cancers wherein ACSL5 is overexpressed as compared to healthy, normal cells. Examples of such cancers include acute myeloid leukemia (AML), colorectal cancer, and breast cancer.# 4.4. PHARMACEUTICAL COMPOSITIONSCompounds of the invention may be incorporated into formulations suitable for administration to a patient. While the route of administration (e.g., oral, parenteral, intravenous, intramuscular, topical, subcutaneous) will depend on the particular indication being treated, a preferred route is oral.Thus, the present compounds may be systemically administered (e.g., orally) in combination with a pharmaceutically acceptable vehicle such as an inert diluent or an assimilable edible carrier. They may be enclosed in hard or soft shell gelatin capsules or may be compressed into tablets. For oral therapeutic administration, an active compound may be combined with one or more excipients in the form of ingestible tablets, buccal tablets, capsules, caplets, troches, elixirs, suspensions, syrups, and wafers.Compounds may also be administered intravenously or intraperitoneally by infusion or injection. Solutions of an active compound or its salts may be prepared in water, optionally mixed with a nontoxic surfactant. Dispersions can also be prepared in glycerol, liquid polyethylene glycols, triacetin, and mixtures thereof and in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms.Pharmaceutical dosage forms suitable for injection or infusion may include sterile aqueous solutions or dispersions or sterile powders comprising the active ingredient which are adapted for the extemporaneous preparation of sterile injectable or infusible solutions or dispersions, optionally encapsulated in liposomes. In all cases, the ultimate dosage form should be sterile, fluid and stable under the conditions of manufacture and storage. The liquid carrier or vehicle can be a solvent or liquid dispersion medium comprising, for example, water, ethanol, a polyol (for example, glycerol, propylene glycol, liquid polyethylene glycols, and the like), vegetable oils, nontoxic glyceryl esters, and suitable mixtures thereof. The proper fluidity can be maintained, for example, by the formation of liposomes, by the maintenance of the required particle size in the case of dispersions or by the use of surfactants. The prevention of the action of microorganisms can be brought about by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like. In many cases,it will be preferable to include isotonic agents, for example, sugars, buffers or sodium chloride. Prolonged absorption of the injectable compositions can be brought about by the use in the compositions of agents delaying absorption, for example, aluminum monostearate and gelatin.Sterile injectable solutions are prepared by incorporating the active compound in the required amount in the appropriate solvent with various of the other ingredients enumerated above, as required, followed by filter sterilization. In the case of sterile powders for the preparation of sterile injectable solutions, the preferred methods of preparation are vacuum drying and the freeze drying techniques, which yield a powder of the active ingredient plus any additional desired ingredient present in the previously sterile- filtered solutions.For topical administration, compounds are typically administered as compositions containing a dermatologically acceptable carrier, which may be a solid or a liquid. Examples of solid carriers include finely divided solids such as talc, clay, microcrystalline cellulose, silica, and alumina. Useful liquid carriers include water, alcohols or glycols or water- alcohol / glycol blends, in which an active compound can be dissolved or dispersed at effective levels, optionally with the aid of non- toxic surfactants. Adjuvants such as fragrances and additional antimicrobial agents may be added to optimize the properties for a given use. The resultant liquid compositions can be applied from absorbent pads, used to impregnate bandages and other dressings, or sprayed onto the affected area using pump- type or aerosol sprayers.# 4.5. EXAMPLESCertain embodiments of the present invention are described in the examples provided below. Some common abbreviations used in the examples include the following:CMBP Cyanomethylene)tributylphosphorane CMPI 2- Chloro- 1- methylpyridinium iodide DAST Diethylaminosulfur trifluoride DCM Dichloromethane 25 DIAD Diisopropyl azodicarboxylate DIPEA Di- isopropylethylamine DMAP 4- (Dimethylamino)pyridine DMF N,N- dimethylformamide DMSO Dimethylsulfoxide 30 EDCI 1- Ethyl- 3- (3- dimethylaminopropyl)carbodiimide FCC Flash column chromatography h. Hour(s) HATU (1- [Bis(dimethylamino)methylene]- 1H- 1,2,3- triazolo[4,5- b]pyridinium 3- oxid hexafluorophosphate) 35 HPLC High performance liquid chromatography ip Intraperitoneal administration LCMS Liquid chromatography- mass spectrometry min Minute(s) NCS N- Chlorosuccinimide 40 NMI 1- Methylimidazole NMP N- Methyl- 2- pyrrolidone PE Petroleum etherpo Oral administration qd Once a day Rt Retention time RT Room temperature SC Subcutaneous administration SFC Supercritical Fluid Chromatography TCFH Chloro- N,N,N',N'- tetramethylformamidinium hexafluorophosphate TFA Trifluoroacetic acid THF TetrahydrofuranSome compounds were characterized using the LCMS conditions provided in Table 1:Table 1| | | | | | || --- | --- | --- | --- | --- | --- || Method | Column | Mobile Phase (A / B) | Gradient (%A) | Flow rate (mL / min) | Temp. (°C) || A | Acquity UPLC HSS C18 1.8 μm, 100 × 2.1 mm | MeCN / H2O (+0.1% HCOOH) | 5-95% (5.6 min); 95% (0.8 min) | 0.4 | 40 || B | Acquity UPLC BEH C18 1.7 μm, 100 × 2.1 mm | MeCN / H2O (+10mM (NH4)HCO3) | 5-95% (5.6 min); 95% (0.8 min) | 0.4 | 40 || C | Acquity UPLC BEH C18 1.7 μm, 100 × 2.1 mm | MeCN / H2O (+0.1% HCOOH) | 5-95% (5.6 min); 95% (0.8 min) | 0.4 | 40 || D | Waters CORTECS C18 2.7 μm, 4.6 × 30 mm | MeCN / H2O (+0.05% HCOOH) | 5-95% (1.4 min); 95% (0.6 min) | 1.8 | 50 || E | Waters Xbridge C18 3.5 μm, 2.1 × 50 mm | MeCN / H2O (+0.1% NH4OH) | 5-95% (1.8 min); 95% (0.7 min) | 1.0 | 50 || F | HALO C18 2.7 μm, 3.0 × 30 mm | MeCN / H2O (+0.05% TFA) | 5-95% (1.4 min); 95% (0.6 min) | 1.8 | 50 || G | Acquity UPLC BEH C18 1.7 μm, 100 × 2.1 mm | MeCN / H2O (+0.1% HCOOH) | 5-95% (1.25 min); 95% (0.75 min) | 0.8 | 40 || H | Acquity UPLC BEH C18 1.7 μm, 50 × 2.1 mm | MeCN / H2O (+0.03% NH4OH) | 8-97% (1.9 min); 97% (0.1 min) | 0.8 | 40 || I | Kinetex C18 2.6 μm, 4.6 mm × 50 mm | MeCN / H2O (+0.05% TFA) | 5-95% (1.8 min); 95% (0.7 min) | 1.8 | 50 || J | Waters Xbridge C18 2.5 μm, 2.5 × 30 mm | MeCN / H2O (+0.1% NH4OH) | 5-95% (1.8 min); 95% (0.7 min) | 1.8 | 50 || K | HALO C18 2.7 μm, 3.0 × 30 mm | MeCN / H2O (+0.05% HCOOH) | 5-95% (1.4 min); 95% (0.6 min) | 1.8 | 50 |Preparative HPLC methods used to purify compounds are set forth below in Table 2 (mobile phase gradients are provided for each specific example). All methods had a $20.0~\mathrm{mL / min}$ flowrate and were conducted at RT.Table 2| | | || --- | --- | --- || Method | Column | Mobile Phase (A / B) || A | Phenomenex Gemini C18, 5μm, 150 × 21.2 mm | MeCN / H2O (+0.1% HCOOH) || B | Phenomenex Gemini C18, 5μm, 150 × 21.2 mm | MeCN / H2O (+0.05% HCOOH) || C | Phenomenex Gemini C18, 5μm, 150 × 21.2 mm | MeCN / H2O (+0.1% NH4OH) || D | Phenomenex Gemini C18, 5μm, 150 × 21.2 mm | MeCN / H2O (+0.05% NH4OH) || E | Waters Xbridge OBD C18, 5μm, 150 × 19.0 mm | MeCN / H2O (+0.05% NH4OH) || F | Waters Xbridge OBD C18, 5μm, 150 × 19.0 mm | MeCN / H2O (+0.1% HCOOH) || G | YMC C18, 5μm, 150 × 20.0 mm | MeCN / H2O (+0.1% TFA) || H | Waters Sunfire C18, 10μm, 150 × 19.0mm | MeCN / H2O (+10mM (NH4)HCO3) || I | Waters Xbridge Phenyl C18, 10μm, 150 × 19.0 mm | MeCN / H2O (+10mM (NH4)HCO3) || J | Waters Sunfire C18, 10μm, 150 × 19.0mm | MeCN / H2O (+0.1% HCOOH) || K | Luna Phenyl-Hexyl, 1μm, 150 × 21.2 mm | MeOH / H2O (+0.1% HCOOH) |Preparative chiral SFC methods used to purify compounds are set forth below in Table 3:Table 3| | | | | || --- | --- | --- | --- | --- || Method | Column | Mobile Phase | Flow rate (ml / min) | Temp. (°C) || A | Daicel CHIRALPAK AD-H 5 μm, 250 × 20 mm | 70 / 30 CO2 / MeOH [+0.1% NH4] | 38 | 40 || B | Daicel CHIRALPAK AD-10 10 μm, 250 × 30 mm | 70 / 30 CO2 / MeOH [+0.1% HCOOH] | 80 | 40 || C | Daicel CHIRALPAK AD-H 5 μm, 250 × 20 mm | 80 / 20 CO2 / MeOH [+0.1% HCOOH] | 90 | 40 || D | Daicel CHIRALPAK OJ-10 5 μm, 250 × 20 mm | 80 / 20 CO2 / MeOH [+0.1% HCOOH] | 68 | 40 || E | Daicel CHIRALPAK AD-10 5 μm, 250 × 20 mm | 80 / 20 CO2 / MeOH [+0.1% HCOOH] | 88 | 40 || F | Daicel CHIRALPAK AD-10 SFC 10 μm, 250 × 10 mm | 60 / 40 CO2 / MeOH [+0.1% HCOOH] | 75 | 40 || G | Daicel CHIRALPAK IG SFC 5 μm, 250 × 21 mm | 80 / 20 CO2 / MeOH [+0.1% HCOOH] | 48 | 40 || H | Daicel CHIRALPAK AD-H 5 μm, 250 × 20 mm | 80 / 20 CO2 / MeOH [+0.1% HCOOH] | 90 | 40 || I | Daicel CHIRALPAK AD-H 5 μm, 250 × 20 mm | 70 / 30 CO2 / MeOH [+0.1% HCOOH] | 48 | 40 || J | Daicel CHIRALPAK OD-H 5 μm, 250 × 20 mm | 75 / 25 CO2 / MeOH [+0.1% HCOOH] | 48 | 40 || K | Daicel CHIRALPAK IG SFC 5 μm, 250 × 20 mm | 60 / 40 CO2 / MeOH [+0.1% HCOOH] | 48 | 40 |# 4.5.1. Example 1. Preparation of 4-(1-(5-ethoxypyridin-2-yl)ethoxy)-2,3-difluorobenzoic acid (Acid A)Step 1: 1- (5- ethoxypyridin- 2- yl)ethan- 1- ol5 To a solution of 5- ethoxypyridine- 2- carbaldehyde $(4.02\mathrm{g},26.6\mathrm{mmol})$ in THF ( $130\mathrm{mL}$ ) under argon cooled in an ice bath was added methylmagnesium bromide solution in diethyl ether (3M, $13~\mathrm{mL}$ $39.9\mathrm{mmol}$ ) dropwise and the resulting mixture was stirred for $4\mathrm{h}$ , allowed to warm to RT and stirred for $2\mathrm{h}$ . The reaction mixture was cooled in an ice bath, quenched with saturated aqueous $\mathrm{NH\_4Cl}$ $45~\mathrm{mL}$ allowed to warm to RT and extracted with EtOAc (x 3). The organic layers were separated, combined, 10 washed with brine and evaporated in vacuo to give the title compound $(4.41\mathrm{g},99\%$ yield) as a brown oil. ${}^{1}\mathrm{H}$ NMR (300 MHz, $\mathrm{CDCl}\_3$ , ppm) 8 8.21 (t, $J = 1.7 \mathrm{Hz}$ , 1 H), 7.21 - 7.19 (m, 2 H), 4.85 (dd, $J = 3.0$ , 6.2 Hz, 1 H), 4.08 (q, $J = 7.0 \mathrm{Hz}$ , 2 H), 3.95 (d, $J = 3.4 \mathrm{Hz}$ , 1 H), 1.50 - 1.41 (m, 6 H).Step 2: methyl 4- (1- (5- ethoxypyridin- 2- yl)ethoxy)- 2,3- difluorobenzoate15 1- (5- Ethoxypyridin- 2- yl)ethan- 1- ol $(2.50\mathrm{g},15.0\mathrm{mmol})$ , methyl 2,3- difluoro- 4- hydroxy- benzoate $(2.81\mathrm{g},15.0\mathrm{mmol})$ and $\mathrm{PPh}\_3$ $(4.71\mathrm{g},17.9\mathrm{mmol})$ were added together in THF ( $100~\mathrm{mL}$ ) and the resulting mixture was stirred at RT under $\mathbf{N}\_2$ for $15\mathrm{min}$ . The mixture was cooled in an ice bath and DIAD $(3.5\mathrm{mL},17.9\mathrm{mmol})$ was added. The resulting mixture was allowed to warm to RT and stirred for 4 h. The reaction mixture was concentrated in vacuo. The residue was purified by silica gel flash 20 chromatography (gradient $0.50\%$ EtOAc / cyclohexane) to give the title compound $(2.68\mathrm{g},53\%$ yield) as a yellow oil. LCMS (Method H) MS $\mathrm{(ES + )}$ $\mathrm{[M + H]^+ = 338}$ $\mathrm{Rt} = 1.55\mathrm{min}$ . ${}^{1}\mathrm{H}$ NMR (300 MHz, $\mathrm{CDCl}\_3$ ppm) 8 8.23 (s, 1 H), 7.57 - 7.50 (m, 1 H), 7.35 - 7.30 (m, 1 H), 7.20 - 7.14 (m, 1 H), 6.68 (t, $J = 7.7 \mathrm{Hz}$ , 1 H), 5.49 (q, $J = 6.5 \mathrm{Hz}$ , 1 H), 4.15 - 4.03 (m, 2 H), 3.88 (s, 3 H), 1.73 (d, $J = 6.1 \mathrm{Hz}$ , 3 H), 1.43 (t, $J = 7.1$ Hz, 3H).25 Step 3: 4- (1- (5- ethoxypyridin- 2- yl)ethoxy)- 2,3- difluorobenzoic acidTo a solution of methyl 4- (1- (5- ethoxypyridin- 2- yl)ethoxy)- 2,3- difluorobenzoate $(2.68\mathrm{g},7.94$ mmol) in MeOH $(17.8\mathrm{mL})$ $\mathrm{H}\_2\mathrm{O}$ $(17.8\mathrm{mL})$ and THF $(8.9\mathrm{mL})$ was added $\mathrm{LiOH}\cdot \mathrm{H}\_2\mathrm{O}$ $(1.00\mathrm{g},23.8\mathrm{mmol})$ and the resulting mixture was stirred at RT for $2\mathrm{h}$ . The solvent was removed in vacuo and the residue was acidified with 1M aqueous HCl and extracted with EtOAc $(\mathbf{x}3)$ . The organic layers were separated, combined, washed with brine, dried over $\mathrm{Na\_2SO\_4}$ and concentrated in vacuo to give the title compound $(2.61\mathrm{g},$ quant.) as a yellow solid. LCMS (Method G) MS $(\mathrm{ES + })[\mathrm{M + H}]^{+} = 324$ $\mathrm{Rt} = 1.57\mathrm{min}$ . ${}^{1}\mathrm{H}$ NMR $(300\mathrm{MHz}$ , DMSO- d6, ppm) 8 13.14 (s, 1 H), 8.26 - 8.24 (m, 1 H), 7.59 - 7.51 (m, 1 H), 7.41 - 7.38 (m, 2 H), 7.02 - 6.95 (m, 1 H), 5.66 (q, $J = 6.4\mathrm{Hz}$ , 1 H), 4.09 (dd, $J = 6.6$ $13.9\mathrm{Hz},2\mathrm{H}$ ), 1.64 (d, $J = 6.4\mathrm{Hz}$ , 3 H), 1.32 (t, $J = 6.9 \mathrm{Hz},3 \mathrm{H}$# 4.5.2. Example 2. Preparation of 4-(1-(3-(cyclopropylmethoxy)phenyl)ethoxy)-2,3-difluorobenzoic acid (Acid B)Step 1: methyl 4- (1- (3- (cyclopropylmethoxy)phenyl)ethoxy)- 2,3- difluorobenzoateTo a solution of $\mathrm{PPh}\_3$ (939 mg, 3.58 mmol) in THF (10 mL) at $0^\circ \mathrm{C}$ was added DIAD (724 mg, 3.58 mmol) and the resulting mixture was stirred for 20 min. Methyl 2,3- difluoro- 4- hydroxybenzoate (337 mg, 1.79 mmol), followed by a solution of 1- (3- (cyclopropylmethoxy)phenyl)ethanol- 1- ol (344 mg, 1.79 mmol) in THF (3 mL) were added dropwise. The reaction mixture was allowed to warm to RT and stirred for 18 h. $\mathrm{H}\_2\mathrm{O}$ (30 mL) was added, and the mixture was extracted with EtOAc (15 mL x 3). The organic layers were separated, combined, washed with brine (5 mL x 3), dried over $\mathrm{Na\_2SO\_4}$ and concentrated in vacuo. The residue was purified by silica gel flash chromatography (gradient 1- 10% EtOAc / PE) to give the title compound (498 mg, 76% yield) as a yellow solid.${}^{1}\mathrm{H}$ NMR (400 MHz, $\mathrm{CDCl}\_3$ ppm) 8 7.57- 7.44 (m, 1 H), 7.30- 7.17 (m, 1 H), 6.92 (dd, $J = 4.2$ 2.1 Hz, 2 H), 6.84- 6.76 (m, 1 H), 6.67- 6.54 (m, 1 H), 5.37 (q, $J = 6.4 \mathrm{Hz}$ 1 H), 3.86 (s, 3 H), 3.84- 3.70 (m, 2 H), 1.69 (d, $J = 6.4 \mathrm{Hz}$ 3 H), 1.38- 1.10 (m, 1 H), 0.73- 0.54 (m, 2 H), 0.40- 0.29 (m, 2 H).25Step 2: 4- (1- (3- (cyclopropylmethoxy)phenyl)ethoxy)- 2,3- difluorobenzoic acidA mixture of methyl 4- (1- (3- (cyclopropylmethoxy)phenyl)ethoxy)- 2,3- difluorobenzoate (180 mg, 0.50 mmol) and $\mathrm{LiOH}\cdot \mathrm{H}\_2\mathrm{O}$ (63 mg, 1.50 mmol) in THF / $\mathrm{H}\_2\mathrm{O}$ (3:1, 6 mL) was stirred at $40^\circ \mathrm{C}$ for 4 h.After cooling to RT, AcOH (4 mL) and $\mathrm{H}\_2\mathrm{O}$ (10 mL) were added. The mixture was extracted with DCM (10 mL x 4). The organic layers were separated, combined, dried over $\mathrm{Na\_2SO\_4}$ and concentrated in vacuo. The residue was purified by prep- HPLC (Method A, gradient: 50- 90%) to give the title compound (98 mg, 55% yield) as a white solid. LCMS (Method D) MS (ESI) $\mathrm{[M + H]^{+} = 349}$ , $\mathrm{Rt} = 1.28$ min. ${}^{1}\mathrm{H}$ NMR (400 MHz, $\mathrm{CDCl}\_3$ , ppm) $\delta$ 7.66- 7.55 (m, 1 H), 7.30- 7.22 (m, 1 H), 6.94- 6.89 (m, 2 H), 6.84- 6.77 (m, 1 H), 6.67- 6.55 (m, 1 H), 5.38 (q, $J = 6.4$ Hz, 1 H), 3.88- 3.68 (m, 2 H), 1.71 (d, $J = 6.4$ Hz, 3 H), 1.35- 1.18 (m, 1 H), 0.72- 0.57 (m, 2 H), 0.44- 0.27 (m, 2 H).# 4.5.3. Example 3. Preparation of (R)-4-(1-(5-(cyclopropylmethoxy)pyridin-2-yl)propoxy)-2,3-difluorobenzoic acid (Acid C)10Step 1: 1- (5- hydroxypyridin- 2- yl)propan- 1- oneUnder $\mathbf{N}\_2$ , to a solution of 5- hydroxypyridine- 2- carbonitrile ( $50\mathrm{g}$ , 416.28 mmol) in THF (400 mL) was added ethylmagnesium bromide ( $624~\mathrm{mL}$ $1.25\mathrm{mol}$ , 2M in THF) at $0^\circ \mathrm{C}$ . The reaction mixture was allowed to warm to RT and stirred for $0.5\mathrm{h}$ , and then heated to $60^{\circ}\mathrm{C}$ for $3\mathrm{h}$ . The reaction mixture 15 was acidified with 3 N HCl aqueous solution to pH $4\sim 5$ . The mixture was stirred at RT for $30\mathrm{min}$ . The pH was adjusted to 7 using saturated aqueous $\mathrm{NaHCO\_3}$ solution and extracted with EtOAc ( $400\mathrm{mLx}7)$ The combined organic layers were dried over $\mathrm{Na\_2SO\_4}$ and concentrated in vacuo to give the title compound (53 g, $80\%$ yield) as a yellow solid. LCMS (Method D) MS (ESI) $\mathrm{[M + H]^{+} = 152}$ $\mathrm{Rt} = 0.64$ min20Step 2: 1- (5- (cyclopropylmethoxy)pyridin- 2- yl)propan- 1- oneA mixture of 1- (5- hydroxypyridin- 2- yl)propan- 1- one (53 g, 350 mmol), $\mathrm{K}\_2\mathrm{CO}\_3$ (96.7 g, 700 mmol) and (bromomethyl)cyclopropane (70.8 g, 525 mmol) in DMF (800 mL) was stirred at $90^{\circ}\mathrm{C}$ for 1 h. The solvent was removed in vacuo. The residue was purified by silica gel flash chromatography (gradient 0- 20% EtOAc / PE) to give the title compound (59 g, 80% yield) as a colorless oil. LCMS (Method D) MS (ESI) $\mathrm{[M + H]^{+} = 206}$ , $\mathrm{Rt} = 1.35$ minStep 3: (S)- 1- (5- (cyclopropylmethoxy)pyridin- 2- yl)propan- 1- olA mixture of $\mathrm{[RuCl\_2(mesitylene)]\_2}$ (1.87 g, 3.66 mmol) and $N$ - [(1S,2S)- 2- amino- 1,2- diphenylethyl]- 4- methyl- 1- sulfonylaniline (2.15 g, 5.85 mmol) in $\mathrm{CH\_3CN}$ (300 mL) and $\mathrm{H}\_2\mathrm{O}$ (300 mL) was degassed and purged with $\mathrm{N}\_2$ (x 3) and then heated at $40^{\circ}\mathrm{C}$ for $1\mathrm{h}$ . The mixture was cooled to $0^{\circ}\mathrm{C}$ and treated with a solution of 1- [5- (cyclopropylmethoxy)pyridin- 2- yl]propan- 1- one (59 g, 287 mmol) in $\mathrm{CH\_3CN}$ (40 mL), followed by potassium formate (121 g, 1.43 mol). The resulting mixture was stirred at RT for $12\mathrm{h}$ , diluted with $\mathrm{H}\_2\mathrm{O}$ (500 mL) and extracted with EtOAc (500 mL x 3). The organic layers were separated, combined, dried over $\mathrm{Na\_2SO\_4}$ and concentrated in vacuo. The residue was purified by silica gel flash chromatography (gradient 0- 35% EtOAc / PE) to give the title compound (54 g, 86% yield) as a colorless oil. LCMS (Method D) MS (ESI) $\mathrm{[M + H]^+ = 208}$ , $\mathrm{Rt} = 0.88$ min.Step 4: methyl (R)- 4- (1- (5- (cyclopropylmethoxy)pyridin- 2- yl)propoxy)- 2,3- difluorobenzoateTo a solution of $\mathrm{PPh\_3}$ (171 g, 649 mmol) in dry THF (2.5 L) at $0^{\circ}\mathrm{C}$ was added DIAD (131 g, 647 mmol) dropwise and the resulting mixture was stirred for $20\mathrm{min}$ . Then, a solution of (1S)- 1- (5- (cyclopropylmethoxy)pyridin- 2- yl)propan- 1- ol (54 g, 259 mmol) and methyl 2,3- difluoro- 4- hydroxybenzoate (53.7 g, 285 mmol) in dry THF (500 mL) was added dropwise. The resulting mixture was allowed to warm to RT and stirred for $16\mathrm{h}$ . The solvent was removed in vacuo and the residue was purified by silica gel flash chromatography (gradient 0- 40% EtOAc / PE) to give the title compound (65 g, 66% yield) as a colorless oil. LCMS (Method D) MS (ESI) $\mathrm{[M + H]^+ = 378}$ , $\mathrm{Rt} = 1.58$ min.Step 5: (R)- 4- (1- (5- (cyclopropylmethoxy)pyridin- 2- yl)propoxy)- 2,3- difluorobenzoic acidA mixture of methyl- 4- [(1R)- 1- [5- (cyclopropylmethoxy)pyridin- 2- yl]propoxy]- 2,3- difluorobenzoate (65 g, 173 mmol) and $\mathrm{LiOH}\cdot \mathrm{H}\_2\mathrm{O}$ (12.4 g, 518 mmol) in $\mathrm{THF / H\_2O}$ (2:1, 650 mL) wasstirred at RT for $16\mathrm{h}$ . The reaction mixture was acidified with HCOOH to $\mathrm{pH} = 6 - 7$ and extracted with EtOAc $(200\mathrm{mL}\mathrm{x}3)$ . The organic layers were separated, combined, dried over $\mathrm{Na\_2SO\_4}$ and concentrated in vacuo. The residue was suspended in $\mathrm{CH\_3CN}$ $(330\mathrm{mL})$ and the resulting mixture was heated at $50^{\circ}\mathrm{C}$ until the solids had dissolved. A pure sample of $(R)$ - 4- (1- (5- (cyclopropylmethoxy)pyridin- 2- yl)propoxy)- 2,3- difluorobenzoic acid $(2\mathrm{mg})$ was added and the solution was cooled to RT slowly and left to stand for $18\mathrm{h}$ . The resulting solid was collected by filtration, washed with $\mathrm{CH\_3CN}$ $(20\mathrm{mL}\mathrm{x}2)$ and dried to give the title compound $(49\mathrm{g}, > 99\%$ ee, $78\%$ yield) as a white solid. LCMS (Method E) MS (ESI) $[\mathrm{M} + \mathrm{H}]^{+} = 364$ , $\mathrm{Rt} = 1.22\mathrm{min}$ , ${}^{1}\mathrm{H}$ NMR $(400\mathrm{MHz}$ , DMSO- $d / d$ , ppm) $\delta$ 13 13 (s, 1 H), 8.26 (s, 1 H), 7.57- 7.48 (m, 1 H), 7.38- 7.28 (m, 2 H), 6.96- 6.87 (m, 1 H), 5.41 (t, $J = 6.5\mathrm{Hz}$ , 1 H), 3.87 (d, $J = 7.1\mathrm{Hz}$ , 2 H), 2.08- 1.90 (m, 2 H), 1.27- 1.12 (m, 1 H), 0.91 (t, $J = 7.3\mathrm{Hz}$ , 3 H), 0.64- 0.42 (m, 2 H), 0.41- 0.20 (m, 2 H).# 4.5.4. Example 4. Preparation of $(R)$ -2,3-difluoro-4-(1-(5-(2-methoxyethoxy)pyridin-2-yl)propoxy)benzoic acid (Acid D)Step 1: 1- (5- (2- methoxyethoxy)pyridin- 2- yl)propan- 1- oneTo a solution of 1- (5- hydroxypyridin- 2- yl)propan- 1- one $(9.4\mathrm{g},62.2\mathrm{mmol}$ , Acid C, Step 1) and $\mathrm{K\_2CO\_3}$ $(12.9\mathrm{g},93.3\mathrm{mmol})$ in DMF $(150\mathrm{mL})$ was added 1- bromo- 2- methoxyethane $(10.4\mathrm{g},74.6\mathrm{mmol})$ . The mixture was stirred at $90^{\circ}\mathrm{C}$ for $2\mathrm{h}$ . DMF was removed in vacuo and $\mathrm{H}\_2\mathrm{O}$ $(100\mathrm{mL})$ was added. The mixture was extracted with DCM $(50\mathrm{mL}\mathrm{x}6)$ . The combined organic layers were washed with brine $(10\mathrm{mL}\mathrm{x}3)$ , dried over $\mathrm{Na\_2SO\_4}$ and concentrated in vacuo. The residue was purified by silica gel flash chromatography (gradient $0 - 10\%$ EtOAc / PE) to give the title compound $(11.3\mathrm{g},86\%$ yield) as a pale yellow solid. LCMS (Method D) MS (ESI) $[\mathrm{M} + \mathrm{H}]^{+} = 210$ , $\mathrm{Rt} = 0.87\mathrm{min}$ .Step 2: $(S)$ - 1- (5- (2- methoxyethoxy)pyridin- 2- yl)propan- 1- olA mixture of $[\mathrm{RuCl}\_2(\mathrm{mesitylene})]\_2$ $(68\mathrm{mg},0.13\mathrm{mmol})$ , $N$ - [(1S,2S)- 2- amino- 1,2- diphenylethyl]- 4- methyl- 1- sulfonylaniline $(97\mathrm{mg},0.27\mathrm{mmol})$ in MeCN $(10\mathrm{mL})$ and $\mathrm{H}\_2\mathrm{O}$ $(10\mathrm{mL})$ was stirred at $40^{\circ}\mathrm{C}$ under $\mathrm{N}\_2$ for $1\mathrm{h}$ . 1- [5- (2- methoxyethoxy)pyridin- 2- yl]propan- 1- one $(3.7\mathrm{g},17.7\mathrm{mmol})$ and MeCN $(30\mathrm{mL})$ were added and the mixture was cooled to $5^{\circ}\mathrm{C}$ . Potassium formate $(7.44\mathrm{g},88.4\mathrm{mmol})$ in $\mathrm{H}\_2\mathrm{O}$ $(5\mathrm{mL})$ was added and the reaction mixture was slowly warmed to RT over $16\mathrm{h}$ . The reaction mixture was concentrated in vacuo and the residue was extracted with DCM $(20\mathrm{mL}\mathrm{x}6)$ . The organic layers were separated, combined, dried over $\mathrm{Na\_2SO\_4}$ and concentrated in vacuo. The residue was purified by silica gelflash chromatography (gradient $0 - 7\%$ DCM / MeOH) to give the title compound (3.68 g, 92% yield) as a brown liquid. LCMS (Method E) MS (ESI) $\mathrm{[M + H]^+ = 212}$ , $\mathrm{Rt} = 1.11$ min.Step 3: methyl $(R)$ - 2,3- difluoro- 4- (1- (5- (2- methoxyethoxy)pyridin- 2- yl)propoxy)benzoateUnder an argon atmosphere, (1S)- 1- [5- (2- methoxyethoxy)pyridin- 2- yl]propan- 1- ol (3.24 g, 15.3 mmol), $\mathrm{PPh}\_3$ (1.41 g, 53.7 mmol), and methyl 2,3- difluoro- 4- hydroxybenzoate (3.12 g, 53.7 mmol) were dissolved in dry THF (150 mL). The reaction mixture was stirred for 5 min, cooled to $0^\circ \mathrm{C}$ and DIAD (1.09 g, 53.7 mmol) was added dropwise. The resulting mixture was stirred for 15 min, allowed to warm to RT and stirred for 12 h. The solvent was removed in vacuo and the residue was dissolved in $\mathrm{H}\_2\mathrm{O}$ (50 mL) and extracted with EtOAc (50 mL x 4). The organic layers were separated, combined, dried over $\mathrm{Na}\_2\mathrm{SO}\_4$ and concentrated in vacuo. The residue was purified by silica gel flash chromatography (gradient 0- 29% EtOAc / PE) to give the title compound (5.2 g, 79% yield) as a brown oil. LCMS (Method D) MS (ESI) $\mathrm{[M + H]^+ = 382}$ , $\mathrm{Rt} = 1.20$ min.Step 4: $(R)$ - 2,3- difluoro- 4- (1- (5- (2- methoxyethoxy)pyridin- 2- yl)propoxy)benzoic acid15A mixture of methyl $(R)$ - 2,3- difluoro- 4- (1- (5- (2- methoxyethoxy)pyridin- 2- yl)propoxy)benzoate (5.2 g, 13.64 mmol) and $\mathrm{LiOH}\cdot \mathrm{H}\_2\mathrm{O}$ (1.72 g, 40.91 mmol) in THF (30 mL) and $\mathrm{H}\_2\mathrm{O}$ (30 mL) was stirred for 12 h at $25^\circ \mathrm{C}$ . The reaction mixture was acidified with $\mathrm{AcOH}$ to $\mathrm{pH} = 6 - 7$ and extracted with DCM (40 mL x 5). The organic layers were separated, combined, dried over $\mathrm{Na}\_2\mathrm{SO}\_4$ and concentrated in vacuo. The residue was purified by silica gel flash chromatography (gradient 0- 6% DCM / MeOH). Further purification by chiral SFC (Method A) gave the title compound (1.24 g, >99% ee, 25% yield) as a yellow oil. LCMS (Method D) MS (ESI) $\mathrm{[M + H]^+ = 368}$ , $\mathrm{Rt} = 1.02$ min. ${}^{1}\mathrm{H}$ NMR (400 MHz, DMSO- d6, ppm) $\delta$ 13.17 (s, 1 H), 8.32- 8.25 (m, 1 H), 7.58 - 7.49 (m, 1 H), 7.44 - 7.34 (m, 2 H), 6.96 - 6.89 (m, 1 H), 5.42 (t, $J = 6.5 \mathrm{Hz}$ , 1 H), 4.22 - 4.08 (m, 2 H), 3.72 - 3.61 (m, 2 H), 3.29 (s, 3 H), 2.12 - 1.91 (m, 2 H), 0.91 (t, $J = 7.4 \mathrm{Hz}$ , 3 H).# 4.5.5. Example 5. Preparation of $(R)$ -2,3-difluoro-4-(1-(5-(pyridin-2-yloxy)pyridin-2-yl)propoxy)benzoic acid (Acid E)Step 1: 1- (5- (pyridin- 2- yloxy)pyridin- 2- yl)propan- 1- one5 A mixture of 1- (5- hydroxypyridin- 2- yl)propan- 1- one (126 g, 834 mmol, Acid C, Step 1), 2- fluoropyridine (162 g, 1.67 mol) and $\mathrm{K}\_2\mathrm{CO}\_3$ (346 g, 2501 mmol) in NMP (1 L) was heated at $140^{\circ}\mathrm{C}$ for $18\mathrm{h}$ . The mixture was poured into $\mathrm{H}\_2\mathrm{O}$ (3 L) and then extracted with EtOAc (800 mL x 3). The combined organic layers were died over $\mathrm{Na\_2SO\_4}$ and concentrated in vacuo. The residue was purified by silica gel flash chromatography (gradient 0- 30% EtOAc / PE) to give the title compound (125 g, 65% yield) as an off- white solid. LCMS (Method D) MS (ESI) $\mathrm{[M + H]^+ = 229}$ , $\mathrm{Rt} = 1.25$ mins. ${}^{1}\mathrm{H}$ NMR (400 MHz, DMSO- d6, ppm) $\delta 8.58$ (d, $J = 2.6 \mathrm{Hz}$ , 1 H), 8.20- 8.18 (m, 1 H), 8.05- 8.03 (m, 1 H), 7.97- 7.93 (m 1 H), 7.80- 7.77 (m, 1 H), 7.25- 7.21 (m, 2 H), 3.18 (q, $J = 7.3 \mathrm{Hz}$ , 2 H), 1.11 (t, $J = 7.3 \mathrm{Hz}$ , 3 H).Step 2: (S)- 1- (5- (pyridin- 2- yloxy)pyridin- 2- yl)propan- 1- ol15 A mixture of $[\mathrm{RuCl}\_2$ (mesitylene)]2 (5.62 g, 10.95 mmol) and $N$ - [(1S,2S)- 2- amino- 1,2- diphenylethyl]- 4- methyl- 1- sulfonylaniline (8.05 g, 21.9 mmol) in MeCN (300 mL) and $\mathrm{H}\_2\mathrm{O}$ (300 mL) was degassed and purged with $\mathrm{N}\_2$ for 3 times and the resulting mixture was stirred at $40^{\circ}\mathrm{C}$ for $1\mathrm{h}$ . A solution of 1- [5- (pyridin- 2- yloxy)pyridin- 2- yl]propan- 1- one (125 g, 548 mmol) in MeCN (1 L) was added at $0^{\circ}\mathrm{C}$ . $\mathrm{HCO\_2K}$ (276 g, 3.29 mol) was added, and the resulting mixture was allowed to warm to RT and stirred for $12\mathrm{h}$ . The mixture was diluted with $\mathrm{H}\_2\mathrm{O}$ (1 L) and extracted with EtOAc (700 mL x 3). The combined organic layers were dried over $\mathrm{Na\_2SO\_4}$ and concentrated in vacuo. The residue was purified by silica gel flash chromatography (gradient 0- 50% EtOAc / PE) to give the title compound (123 g, 89% yield) as a yellow oil. LCMS (Method E) MS (ESI) $\mathrm{[M + H]^+ = 231}$ , $\mathrm{Rt} = 1.26$ min. ${}^{1}\mathrm{H}$ NMR (400 MHz, DMSO- d6, ppm) $\delta 8.33$ (d, $J = 2.6 \mathrm{Hz}$ , 1 H), 8.14- 8.12 (m, 1 H), 7.94- 7.83 (m, 1 H), 7.61- 7.58 (m, 1 H), 7.53- 7.50 (m, 1 H), 7.17- 7.08 (m, 2 H), 5.33 (d, $J = 4.8 \mathrm{Hz}$ , 1 H), 4.54- 4.50 (m, 1 H), 1.88- 1.74 (m, 1 H), 1.71- 1.58 (m, 1 H), 0.88 (t, $J = 7.4 \mathrm{Hz}$ , 3 H).Step 3: methyl $(R)$ - 2,3- difluoro- 4- (1- (5- (pyridin- 2- yloxy)pyridin- 2- yl)propoxy)benzoateUnder $\mathbf{N}\_2$ , to a solution of $\mathrm{PPh}\_3$ $(420\mathrm{g},1.60\mathrm{mol})$ in dry THF (3 L) added DIAD $(324\mathrm{g},$ $1.60\mathrm{mol})$ dropwise at $0^\circ \mathrm{C}$ and the mixture was stirred for $20\mathrm{min}$ . A solution of (S)- 1- (5- (pyridin- 2- yloxy)pyridin- 2- yl)propan- 1- ol ( $123\mathrm{g},534\mathrm{mmol})$ and methyl 2,3- difluoro- 4- hydroxybenzoate ( $121\mathrm{g},$ $641~\mathrm{mmol})$ in dry THF (1 L) was added dropwise. The resulting mixture was stirred at RT for $16\mathrm{h}$ . The solvent was removed in vacuo. The residue was purified by silica gel flash chromatography (gradient 0- $70\%$ EtOAc / PE) to give the title compound ( $230\mathrm{g},75\%$ yield) as a brown oil. LCMS (Method E) MS (ESI) $\mathrm{[M + H]^+ = 401}$ $\mathrm{Rt} = 1.85\mathrm{min}$ ${}^{1}\mathrm{H}$ NMR (400 MHz, DMSO- d6, ppm) 8 8.18- 8.11 (m, 1 H), 7.95- 7.85 (m, 1 H), 7.69- 7.50 (m, 3 H), 7.22- 7.09 (m, 2 H), 7.05- 7.00 (m, 1 H), 5.55 (t, $J = 6.4\mathrm{Hz}$ , 1 H), 3.82 (s, 3 H), 2.11- 2.04 (m, 2 H), 0.96 (t, $J = 7.2\mathrm{Hz},3\mathrm{H})$Step 4: (R)- 2,3- difluoro- 4- (1- (5- (pyridin- 2- yloxy)pyridin- 2- yl)propoxy)benzoic acidA mixture of methyl $(R)$ - 2,3- difluoro- 4- (1- (5- (pyridin- 2- yloxy)pyridin- 2- yl)propoxy)benzoate (230 g, 574.5 mmol) and $\mathrm{LiOH - H\_2O}$ (27.52 g, 1149 mmol) in THF / $\mathrm{H}\_2\mathrm{O}$ (2 / 1, 3 L) was stirred at $40^{\circ}\mathrm{C}$ for $2\mathrm{h}$ . The reaction mixture was acidified with HCOOH to $\mathrm{pH} = 6 - 7$ and extracted with EtOAc (300 mL x 3). The combined organic layers were dried over $\mathrm{Na\_2SO\_4}$ and concentrated in vacuo. The residue was purified by chiral SFC (Method B) to give the title compound (90 g, $>99\%$ ee, 41% yield) as an off- white solid. LCMS (Method D) MS (ESI) $\mathrm{[M + H]^+ = 387}$ , $\mathrm{Rt} = 1.32$ mins. ${}^{1}\mathrm{H}$ NMR (400 MHz, DMSO- d6, ppm) 8 13.20 (s, 1 H), 8.48 (d, $J = 2.6\mathrm{Hz}$ , 1 H), 8.19- 8.12 (m, 1 H), 7.95- 7.86 (m, 1 H), 7.68- 7.65 (m, 1 H), 7.63- 7.56 (m, 1 H), 7.54- 7.52 (m, 1 H), 7.23- 7.10 (m, 2 H), 7.00 (t, $J = 7.8\mathrm{Hz}$ , 1 H), 5.54 (t, $J = 6.4\mathrm{Hz}$ , 1 H), 2.18- 1.98 (m, 2 H), 0.98 (t, $J = 7.2\mathrm{Hz}$ , 3 H).# 4.5.6. Example 6. Preparation of 2,3-difluoro-4-((R)-1-(5-((trans)-3-methoxycyclobutoxy)pyridin-2-yl)propoxy)benzoic acid (Acid F)Step 1: (cis)- 3- hydroxycyclobutyl 4- methylbenzenesulfonate5 A mixture of (cis)- 3- (benzyloxy)cyclobutyl 4- methylbenzenesulfonate (2 g, 6.0 mmol) and Pd / C (200 mg) in THF (20 mL) was stirred under $\mathrm{H}\_2$ at RT for 2 h. The mixture was filtered through celite and concentrated in vacuo to give the title compound (1.6 g, 98% yield) as a colorless oil. LCMS (Method F) MS (ESI) $\mathrm{[M + H]^+ = 243}$ , $\mathrm{Ri} = 0.88$ mins.Step 2: (cis)- 3- methoxycyclobutyl 4- methylbenzenesulfonate1010 A mixture of (cis)- 3- hydroxycyclobutyl 4- methylbenzenesulfonate (1.00 g, 4.13 mmol), 1,8- bis(dimethylamino)naphthalene (4.39 g, 20.5 mmol) and trimethyloxonium tetrafluoroborate (3.03 g, 20.5 mmol) in DCM (40 mL) was stirred at RT for 18 h. The reaction mixture was filtered, and the filtrate was concentrated in vacuo. The residue was purified by silica gel flash chromatography (gradient 10- 20% EtOAc / PE) to give the title compound (1.1 g, 88% yield) as a colorless oil. ${}^{1}\mathrm{H}$ NMR (400 MHz, CDCl3, ppm) $\delta$ 7.83- 7.73 (m, 2 H), 7.38- 7.30 (m, 2 H), 4.48 (p, $J = 7.3 \mathrm{Hz}$ , 1 H), 3.57- 3.39 (m, 1 H), 3.18 (s, 3 H), 2.79- 2.55 (m, 2 H), 2.45 (s, 3 H), 2.17- 2.00 (m, 2 H).Step 3: 1- (5- ((trans)- 3- methoxycyclobutoxy)pyridin- 2- yl)propan- 1- one20 A mixture of (cis)- 3- methoxycyclobutyl 4- methylbenzenesulfonate (550 mg, 2.15 mmol), 1- (5- hydroxypyridin- 2- yl)propan- 1- one (324 mg, 2.15 mmol, Acid C, Step 1) and $\mathrm{K}\_2\mathrm{CO}\_3$ (593 mg, 4.29 mmol) in DMF (10 mL) was heated at $100^{\circ}\mathrm{C}$ for 12 h. The reaction mixture was concentrated in vacuo and the residue was purified by silica gel flash chromatography (gradient 20- 30% EtOAc / PE) to give the title compound (330 mg, 56% yield) as a colorless oil. ${}^{1}\mathrm{H}$ NMR (400 MHz, CDCl3, ppm) $\delta$ 8.22 (d, $J = 2.8 \mathrm{Hz}$ , 1 H), 8.03 (d, $J = 8.7 \mathrm{Hz}$ , 1 H), 7.14 (dd, $J = 8.7$ , 2.9 Hz, 1 H), 4.99- 4.89 (m, 1 H), 4.31- 3.95 (m, 1 H), 3.29 (s, 3 H), 3.24- 3.13 (m, 2 H), 2.66- 2.38 (m, 4 H), 1.22- 1.19 (m, 3 H).# Step 4: (S)-1-(5-((trans)-3-methoxycyclobutoxy)pyridin-2-yl)propan-1-olUnder $\mathbf{N}\_2$ , a mixture of N- [(1S,2S)- 2- amino- 1,2- diphenylethyl]- 4- methyl- 1- sulfonylaniline $(20.6\mathrm{mg},0.0561\mathrm{mmol})$ and $\mathrm{[RuCl\_2(mesitylene)]\_2}$ $(16.4\mathrm{mg},0.028\mathrm{mmol})$ in $\mathrm{MeCN / H\_2O}$ (1 / 1, 3 mL) was 5 stirred at $40^{\circ}\mathrm{C}$ for $1\mathrm{h}$ . The mixture was cooled to $0^\circ \mathrm{C}$ and a solution of 1- (5- ((trans)- 3- methoxycyclobutoxy)pyridin- 2- yl)propan- 1- one ( $330\mathrm{mg}$ 1.40 mmol) in MeCN (1 mL) and HCOOK $(590\mathrm{mg},7.01\mathrm{mol})$ in $\mathrm{H}\_2\mathrm{O}$ (1 ml) were added dropwise. The reaction mixture was slowly allowed to warm to RT and stirred for an additional $12\mathrm{h}$ . The mixture was quenched with $\mathrm{H}\_2\mathrm{O}$ $20~\mathrm{mL}$ ) and extracted with EtOAc ( $20\mathrm{mL}\mathrm{x}3$ ). The combined organic layers were dried over $\mathrm{Na\_2SO\_4}$ and concentrated in 10 vacuo. The residue was purified by silica gel flash chromatography (gradient $30 - 50\%$ EtOAc / PE) to give the title compound ( $160\mathrm{mg}$ $41\%$ yield) as a colorless oil. LCMS (Method D) MS (ESI) $\mathrm{[M + H]^+ = 238}$ $\mathrm{Rt} = 0.75$ min. ${}^{1}\mathrm{H}$ NMR (400 MHz, DMSO- $d\_{6}$ , ppm) 8 8.07 (d, $J = 2.8~\mathrm{Hz}$ , 1 H), 7.37- 7.35 (m, 1 H), 7.25- 7.22 (m, 1 H), 5.16- 5.15 (m, 1 H), 4.90- 4.85 (m, 1 H), 4.45- 4.43 (m, 1 H), 4.09- 4.05 (m, 1 H), 3.17 (s, 3 H), 2.42- 2.39 (m, 2 H), 2.35- 2.22 (m, 2 H), 1.79- 1.67 (m, 1 H), 1.65- 1.51 (m, 1 H), 0.82 (t, $J = 7.4$ 15 Hz, 3 H).Step 5: methyl 2,3- difluoro- 4- ((R)- 1- (5- ((trans)- 3- methoxycyclobutoxy)pyridin- 2- yl)propoxy)benzoateTo a solution of (S)- 1- (5- ((trans)- 3- methoxycyclobutoxy)pyridin- 2- yl)propan- 1- ol ( $130\mathrm{mg}$ 20 $0.55\mathrm{mmol}$ ) and methyl 2,3- difluoro- 4- hydroxybenzoate ( $113\mathrm{mg}$ $0.60\mathrm{mmol}$ ) in toluene ( $5\mathrm{mL}$ ) was added CMBP ( $264~\mathrm{mg}$ $1.09\mathrm{mmol}$ ). The reaction mixture was sealed and stirred at $120^{\circ}\mathrm{C}$ for $16\mathrm{h}$ . The solvent was removed in vacuo. The residue was purified by silica gel flash chromatography (gradient 0- $20\%$ EtOAc / PE) to give the title compound ( $100\mathrm{mg}$ $40\%$ yield) as a yellow solid. LCMS (Method I) MS (ESI) $\mathrm{[M + H]^+ = 408}$ $\mathrm{Rt} = 1.76\mathrm{min}$ . ${}^{1}\mathrm{H}$ NMR (400 MHz, DMSO- $d\_{6}$ , ppm) 8 8.15 (d, $J = 2.8~\mathrm{Hz}$ , 1 H), 25 7.54- 7.49 (m, 1 H), 7.34- 7.24 (m, 1 H), 7.05 (dd, $J = 8.6,2.8\mathrm{Hz},1\mathrm{H})$ , 6.73- 6.54 (m, 1 H), 5.25- 5.22 (m, 1 H), 4.90- 4.75 (m, 1 H), 4.16- 4.13 (m, 1 H), 3.87 (s, 3 H), 3.27 (s, 3 H), 2.53- 2.31 (m, 4 H), 2.16- 2.04 (m, 2 H), 1.03 (t, $J = 7.4\mathrm{Hz},3\mathrm{H})$Step 6: 2,3- difluoro- 4- ((R)- 1- (5- ((trans)- 3- methoxycyclobutoxy)pyridin- 2- yl)propoxy)benzoic acidA mixture of methyl 2,3- difluoro- 4- ((R)- 1- (5- ((trans)- 3- methoxycyclobutoxy)pyridin- 2- yl)propoxy)benzoate (1.5 g, 3.68 mmol) and $\mathrm{LiOH}\cdot \mathrm{H}\_2\mathrm{O}$ (265 mg, 11.0 mmol) in THF / H $\_2$ O (3 / 1, 20 mL) was stirred for 16 h at RT. The reaction mixture was diluted with water (20 mL) and acidified to pH 5- 6 with HCOOH. The mixture was extracted with EtOAc (20 mL x 5). The combined organic layers were dried over $\mathrm{Na\_2SO\_4}$ and concentrated in vacuo. The residue was purified by chiral SFC (Method C) to give the title compound (0.75 g, >99% ee, 95% purity, 52% yield) as an off- white solid. LCMS (Method K) MS (ESI) $\mathrm{[M + H]^+ = 394}$ , $\mathrm{Rt} = 1.36$ min. ${}^{1}\mathrm{H}$ NMR (400 MHz, DMSO- $d\_{6}$ , ppm) $\delta$ 13.18 (s, 1 H), 8.19- 8.18 (m, 1 H), 7.54 (t, $J = 8.5$ Hz, 1 H), 7.38- 7.36 (m, 1 H), 7.28- 7.25 (m, 1 H), 6.93 (t, $J = 8.1$ Hz, 1 H), 5.42 (t, $J = 6.4$ Hz, 1 H), 4.93- 4.79 (m, 1 H), 4.12- 3.99 (m, 1 H), 3.15 (s, 3 H), 2.43- 2.38 (m, 2 H), 2.33- 2.21 (m, 2 H), 2.09- 1.86 (m, 2 H), 0.91 (t, $J = 7.3$ Hz, 3 H).# 4.5.7. Example 7. Preparation of $(R)$ -4-(1-(5-(pyridin-2-yloxy)pyridin-2-yl)propoxy)-3- (trifluoromethyl)benzoic acid (Acid G)Step 1: methyl $(R)$ - 4- (1- (5- (pyridin- 2- yloxy)pyridin- 2- yl)propoxy)- 3- (trifluoromethyl)benzoateTo a solution of $\mathrm{PPh}\_3$ (13.6 g, 52 mmol) in dry THF (20 mL) under a $\mathrm{N}\_2$ atmosphere was added DIAD (10.5 g, 52 mmol). The reaction mixture was stirred at RT for 20 minutes. A solution of (1S)- 1- [5- (pyridin- 2- yloxy)pyridin- 2- yl]propan- 1- ol (4.0 g, 17 mmol, Acid E, Step 2) and methyl 4- hydroxy- 3- (trifluoromethyl)benzoate (4.6 g, 21 mmol) in dry THF (20 mL) was slowly added dropwise. The reaction mixture was stirred at RT for 2 h. The solvent was removed in vacuo. The residue was purified by silica gel flash chromatography (eluent 3:1 PE / EtOAc) to give the title compound (11.0 g, 88% yield) as a white solid. LCMS (Method D) MS (ESI) $\mathrm{[M + H]^+ = 433}$ , $\mathrm{Rt} = 1.62$ minutes.Step 2: $(R)$ - 4- (1- (5- (pyridin- 2- yloxy)pyridin- 2- yl)propoxy)- 3- (trifluoromethyl)benzoic acidA mixture of methyl: $(R)$ - 4- (1- (5- (pyridin- 2- yloxy)pyridin- 2- yl)propoxy)- 3- (trifluoromethyl)benzoate $(11.0\mathrm{g},25.4\mathrm{mmol})$ , $\mathrm{LiOH - H\_2O}$ $(1.21\mathrm{g},50\mathrm{mmol})$ in THF $(30\mathrm{mL})$ and $\mathrm{H}\_2\mathrm{O}$ $(15\mathrm{mL})$ was stirred at RT for $16\mathrm{h}$ . The reaction mixture was acidified with HOAc to $\mathrm{pH}5\sim 6$ and extracted with EtOAc $(20\mathrm{mL}\times 3)$ . The combined organic layers were dried over $\mathrm{Na\_2SO\_4}$ , concentrated in vacuo and lyophilized. $(R)$ - 4- (1- (5- (pyridin- 2- yloxy)pyridin- 2- yl)propoxy)- 3- (trifluoromethyl)benzoic acid $(3.0\mathrm{g})$ was purified by chiral SFC (Method D) to give the title compound $(2.0\mathrm{g}, > 99\%$ ee, $19\%$ yield) as a white solid. LCMS (Method D) MS (ESI) $[\mathrm{M + H}]^{+} = 419$ , $\mathrm{Rt} = 1.42\mathrm{min}$ . ${}^{1}\mathrm{H}$ NMR $(400\mathrm{MHz}$ , DMSO- $d6$ , ppm) $\delta$ 13.09 (s, 1 H), 8.48 (d, $J = 2.5\mathrm{Hz}$ , 1 H), 8.17- 8.11 (m, 2 H), 8.11- 8.05 (m, 1 H), 7.93- 7.86 (m, 1 H), 7.66 (dd, $J = 8.6$ , $2.7\mathrm{Hz}$ , 1 H), 7.39 (d, $J = 8.6\mathrm{Hz}$ , 1 H), 7.21- 7.10 (m, 3 H), 5.62 (t, $J = 6.1\mathrm{Hz}$ , 1 H), 2.22- 1.86 (m, 2 H), 0.97 (t, $J = 7.3\mathrm{Hz}$ , 3 H).# 4.5.8. Example 8. Preparation of $(R)$ -4- (1-(5-(pyridin-2-yloxy)pyridin-2-yl)ethoxy)-3- (trifluoromethyl)benzoic acid (Acid H)Step 1: 1- (5- (pyridin- 2- yloxy)pyridin- 2- yl)ethan- 1- oneA mixture of 1- (5- hydroxypyridin- 2- yl)ethanone $(5.1\mathrm{g},37\mathrm{mmol})$ , 2- fluoropyridine $(7.22\mathrm{g}$ , $74\mathrm{mmol})$ and $\mathrm{K}\_2\mathrm{CO}\_3$ $(15.4\mathrm{g},110\mathrm{mmol})$ in NMP $(50\mathrm{mL})$ was stirred at $140^{\circ}\mathrm{C}$ for $16\mathrm{h}$ . The solution was diluted with $\mathrm{H}\_2\mathrm{O}$ $(100\mathrm{mL})$ , extracted with EtOAc $(100\mathrm{mL}\times 2)$ . The combined organic layers were washed with brine $(30\mathrm{mL}\times 3)$ , dried over anhydrous $\mathrm{Na\_2SO\_4}$ and concentrated in vacuo. The residue was purified by silica gel flash chromatography (eluent 6:1 PE / EtOAc) to give the title compound $(5.0\mathrm{g},63\%$ yield) as a yellow solid. LCMS (Method D) MS (ESI) $[\mathrm{M + H}]^{+} = 215$ , $\mathrm{Rt} = 1.11\mathrm{min}$ .Step 2: $(S)$ - 1- (5- (pyridin- 2- yloxy)pyridin- 2- yl)ethan- 1- ol25 A mixture of $[\mathrm{RuCl}\_2$ (mesitylene)] $(0.24\mathrm{g},0.40\mathrm{mmol})$ and $N$ - [(1S,2S)- 2- amino- 1,2- diphenylethyl]- 4- methyl- 1- sulfonylaniline $(0.34\mathrm{g},0.90\mathrm{mmol})$ in $\mathrm{CH}\_3\mathrm{CN}$ $(20\mathrm{mL})$ and $\mathrm{H}\_2\mathrm{O}$ $(20\mathrm{mL})$ was degassed and purged with $\mathrm{N}\_2$ $(\mathrm{x}3)$ and stirred at $40^{\circ}\mathrm{C}$ for $1\mathrm{h}$ . The reaction mixture was cooled to $0^{\circ}\mathrm{C}$and a solution of 1- (5- (pyridin- 2- yloxy)pyridin- 2- yl)ethan- 1- one $(5.0\mathrm{g},23\mathrm{mmol})$ in $\mathrm{CH\_3CN}$ $(20~\mathrm{mL})$ followed by a solution of HCOOK $(9.80\mathrm{g},120\mathrm{mmol})$ in $\mathrm{H}\_2\mathrm{O}$ $10~\mathrm{mL}$ ) were added. The resulting mixture was stirred at RT for $15\mathrm{h}$ . The solution was extracted with EtOAc ( $150\mathrm{mL}\times 2)$ , and the combined organic layers were washed with brine ( $50~\mathrm{mL}$ ), dried over $\mathrm{Na\_2SO\_4}$ and concentrated in vacuo. The residue was purified by silica gel flash chromatography (eluent 1:1 PE / EtOAc) to give the title compound $(5.0\mathrm{g},99\%$ yield) as a yellow oil. LCMS (Method D) MS (ESI) $[\mathrm{M + H}]^{+} = 217$ $\mathrm{Rt} = 0.83$ min.Step 3: methyl $(R)$ - 4- (1- (5- (pyridin- 2- yloxy)pyridin- 2- yl)ethoxy)- 3- (trifluoromethyl)benzoateTo a solution of (S)- 1- (5- (pyridin- 2- yloxy)pyridin- 2- yl)ethan- 1- ol (3.0 g, 14 mmol), methyl 4- hydroxy- 3- (trifluoromethyl)benzoate (3.67 g, 17 mmol) and $\mathrm{PPh}\_3$ (10.9 g, 42 mmol) in THF (60 mL) was added DIAD (8.43 g, 42 mmol) at $0^\circ \mathrm{C}$ under $\mathrm{N}\_2$ . The reaction mixture was stirred for 1.5 hours at RT. The solution was diluted with $\mathrm{H}\_2\mathrm{O}$ (100 mL) and extracted with EtOAc (100 mL × 2). The combined organic layers were washed with brine (50 mL), dried over $\mathrm{Na\_2SO\_4}$ and concentrated in vacuo. The residue was purified by silica gel flash chromatography (eluent 8:1 PE / EtOAc) to give the title compound (5.0 g, 27% yield) as a yellow oil. LCMS (Method D) MS (ESI) $[\mathrm{M + H}]^{+} = 419$ , $\mathrm{Rt} = 1.58$ min.Step 4: $(R)$ - 4- (1- (5- (pyridin- 2- yloxy)pyridin- 2- yl)ethoxy)- 3- (trifluoromethyl)benzoic acidTo a solution of methyl 4- [(1R)- 1- [5- (cyclopropylmethoxy)pyridin- 2- yl]propoxy]- 2,3- difluorobenzoate (5.0 g, 12 mmol) THF (40 mL) and $\mathrm{H}\_2\mathrm{O}$ (20 mL) at RT was added $\mathrm{LiOH - H\_2O}$ (1.15 g, 48 mmol). The resulting solution was stirred at RT for 3 h. The pH was adjusted to around 5 by addition of $\mathrm{AcOH}$ . The solution was extracted with DCM (150 mL × 2). The combined organic layers were washed with brine, dried over $\mathrm{Na\_2SO\_4}$ and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (eluent 60:1 DCM / MeOH). Further purification was carried out by chiral SFC (Method E) to give the title compound (2.1 g, >99% ee, 43% yield) as a white solid. LCMS (Method D) MS (ESI) $[\mathrm{M + H}]^{+} = 405$ , $\mathrm{Rt} = 1.37$ min. ${}^{1}\mathrm{H}$ NMR (400 MHz, DMSO- d6, ppm) δ 13.12 (s, 1 H), 8.47 (d, $J = 2.7$ Hz, 1 H), 8.14- 8.10 (m, 3 H), 7.94- 7.86 (m, 1 H), 7.69 (dd, $J = 8.6$ , 2.7 Hz, 1 H), 7.48 (d, $J = 8.6$ Hz, 1 H), 7.31 (d, $J = 9.2$ Hz, 1 H), 7.21- 7.11 (m, 2 H), 5.84 (q, $J = 6.3$ Hz, 1 H), 1.67 (d, $J = 6.4$ Hz, 3 H).4.5.9. Example 9. Preparation of (R)- 2,3- difluoro- 4- (1- (5- (pyridin- 2- yloxy)pyridin- 2- yl)ethoxy)benzoic acid (Acid I)Step 1: methyl (R)- 2,3- difluoro- 4- (1- (5- (pyridin- 2- yloxy)pyridin- 2- yl)ethoxy)benzoate5 $\mathrm{PPh}\_3$ (7.24 g, 28 mmol) and DIAD (5.58 g, 28 mmol) were dissolved in THF (20 mL) under a $\mathrm{N}\_2$ atmosphere and stirred for 30 min at $0^\circ \mathrm{C}$ . A solution of (1S)- 1- [5- (pyridin- 2- yloxy)pyridin- 2- yl]ethanol (2.0 g, 9.2 mmol, Acid H, Step 2) and methyl 2,3- difluoro- 4- hydroxybenzoate (2.1 g, 11 mmol) in THF (10 mL) was added dropwise. The resulting mixture was stirred at RT for 2 h. The solution was diluted with $\mathrm{H}\_2\mathrm{O}$ (50 mL) and extracted with EtOAc (100 mL × 2). The combined organic layers were washed with brine (50 mL), dried over $\mathrm{Na}\_2\mathrm{SO}\_4$ and concentrated in vacuo. The residue was purified by silica gel flash chromatography (eluent 8:1 PE / EtOAc) to give the title compound (3.0 g, 64% yield) as a yellow oil. LCMS (Method D) MS (ESI) $\left[\mathrm{M} + \mathrm{H}\right]^{+} = 387$ , $\mathrm{Rt} = 1.43$ min.Step 2: (R)- 2,3- difluoro- 4- (1- (5- (pyridin- 2- yloxy)pyridin- 2- yl)ethoxy)benzoic acid15 To a solution of methyl (R)- 2,3- difluoro- 4- (1- (5- (pyridin- 2- yloxy)pyridin- 2- yl)ethoxy)benzoate (8.0 g, 21 mmol) in THF (40 mL) and $\mathrm{H}\_2\mathrm{O}$ (20 mL) at RT was added $\mathrm{LiOH} - \mathrm{H}\_2\mathrm{O}$ (1.98 g, 83 mol). The resulting solution was stirred for 2 h. The $\mathrm{pH}$ was adjusted to around 5 by addition of $\mathrm{AcOH}$ . The solution was extracted with DCM (80 mL × 2). The combined organic layers were washed with brine (50 mL), dried over $\mathrm{Na}\_2\mathrm{SO}\_4$ , filtered and concentrated in vacuo. The residue was purified by silica gel flash chromatography (eluent 60:1 DCM / MeOH). Further purification was carried out by chiral SFC (Method F) to give the title compound (1.8 g, >99% ee, 23% yield) as a white solid.LCMS (Method D) MS (ESI) $\left[\mathrm{M} + \mathrm{H}\right]^{+} = 373$ , $\mathrm{Rt} = 1.26$ min. ${}^{1}\mathrm{H}$ NMR (400 MHz, DMSO- d6, ppm) $\delta$ 13.24 (s, 1 H), 8.47 (d, $J = 2.5 \mathrm{Hz}$ , 1 H), 8.15 (dd, $J = 4.9$ , 1.2 Hz, 1 H), 7.95- 7.84 (m, 1 H), 7.72- 7.51 (m, 3 H), 7.23- 7.11 (m, 2 H), 7.05 (t, $J = 8.2 \mathrm{Hz}$ , 1 H), 5.77 (q, $J = 6.3 \mathrm{Hz}$ , 1 H), 1.70 (d, $J = 6.4 \mathrm{Hz}$ , 3 H).4.5.10. Example 10. Preparation of $(R)$ - 4- (1- (5- (cyclopropylmethoxy)pyridin- 2- yl)propoxy)- 3- (trifluoromethyl)benzoic acid (Acid J)Step 1: methyl (R)- 4- (1- (5- (cyclopropylmethoxy)pyridin- 2- yl)propoxy)- 3 (trifluoromethyl)benzoate5Under $\mathbf{N}\_2$ , a mixture of $\mathrm{PPh}\_3$ (11.4 g, 44 mol) and DIAD (8.80 g, 44 mmol) in $100~\mathrm{mL}$ of anhydrous THF was stirred at $0^\circ \mathrm{C}$ for 30 minutes. Then, a solution of (S)- 1- (5- (cyclopropylmethoxy)pyridin- 2- yl)propan- 1- ol (3.00 g, 15 mmol, Acid C, Step 3) and methyl 4- hydroxy3- (trifluoromethyl)benzoate (3.51 g, 16 mmol) in THF (50 mL) was added dropwise. The mixture was stirred at RT for 3 hours. The solution was diluted with EtOAc ( $200~\mathrm{mL}$ ) and water ( $100~\mathrm{mL}$ ). The layers were separated and the organic layer was washed with brine ( $50~\mathrm{mL}$ ), dried over anhydrous $\mathrm{Na\_2SO\_4}$ filtered, and the solvent was removed under reduced pressure. The residue was purified by silica gel flash chromatography (eluent: EtOAc $ / \mathrm{PE} = 1 / 8$ ) to give the title compound ( $4.5\mathrm{g},68\%$ yield) as a yellow oil. LCMS (Method K) MS (ESI) $[\mathrm{M} + \mathrm{H}]^{+} = 410.1$ $\mathrm{Rt} = 1.71$ min. ${}^{1}\mathrm{H}$ NMR (400 MHz, DMSO- d6, ppm) $\delta 8.29$ (d, $J = 2.8 \mathrm{Hz}$ , 1 H), 8.12- 8.09 (m, 1 H), 8.80- 8.03 (m, 1 H), 7.38 (dd, $J = 8.7,2.9 \mathrm{Hz}$ , 1 H), 7.25 (d, $J = 8.7 \mathrm{Hz}$ , 1 H), 7.15 (d, $J = 8.9 \mathrm{Hz}$ , 1 H), 5.52 (t, $J = 6.2 \mathrm{Hz}$ , 1 H), 3.87 (d, $J = 7.1 \mathrm{Hz}$ , 2 H), 3.83 (s, 3 H), 2.08- 1.91 (m, 2 H), 1.22- 1.14 (m, 1 H), 0.94 (t, $\mathrm{J} = 7.3 \mathrm{Hz}$ , 3 H), 0.61- 0.52 (m, 2 H), 0.37- 0.26 (m, 2 H).Step 2: $(R)$ - 4- (1- (5- (cyclopropylmethoxy)pyridin- 2- yl)propoxy)- 3- (trifluoromethyl)benzoic acid20To a solution of methyl $(R)$ - 4- (1- (5- (cyclopropylmethoxy)pyridin- 2- yl)propoxy)- 3- (trifluoromethyl)benzoate (4.50 g, 11 mmol) in THF (30 mL) and $\mathrm{H}\_2\mathrm{O}$ (10 mL) at RT was added $\mathrm{LiOH}\cdot \mathrm{H}\_2\mathrm{O}$ (1.05 g, 44 mmol). The resulting solution was stirred at RT for 2 h. The solution was diluted $\mathrm{H}\_2\mathrm{O}$ (100 mL) and acidified with HCOOH until pH 5- 6. The solution was extracted with EtOAc (100 mL × 2). The combined organic layers were washed with saturated $\mathrm{NaCl}$ (50 mL), dried over anhydrous $\mathrm{Na}\_2\mathrm{SO}\_4$ , filtered and the solvent was removed under reduced pressure. The residue was purified by chiral SFC (Method G) to give the title compound (1.8 g, >99% ee, 42% yield) as a white solid.LCMS (Method K) MS (ESI) $\mathrm{[M + H]^{+} = 396.1}$ $\mathrm{Rt} = 1.52\mathrm{min}$ ${}^{1}\mathrm{H}$ NMR (400 MHz, DMSO- d6, ppm) 8 13.09 (s, 1 H), 8.28 (d, $\mathrm{J} = 2.7 \mathrm{Hz}$ , 1 H), 8.10 (d, $\mathrm{J} = 1.9 \mathrm{Hz}$ , 1 H), 8.03 (dd, $\mathrm{J} = 8.8$ $2.0\mathrm{Hz}$ , 1 H), 7.38 (dd, $\mathrm{J} = 8.7$ $2.9\mathrm{Hz}$ , 1 H), 7.24 (d, $\mathrm{J} = 8.7 \mathrm{Hz}$ , 1 H), 7.11 (d, $\mathrm{J} = 8.9 \mathrm{Hz}$ , 1 H), 5.51 (t, $\mathrm{J} = 6.1 \mathrm{Hz}$ , 1 H), 3.87 (d, $\mathrm{J} = 7.1 \mathrm{Hz}$ , 2 H), 2.07- 1.88 (m, 2 H), 1.28- 1.14 (m, 1 H), 0.93 (t, $\mathrm{J} = 7.3 \mathrm{Hz}$ , 3 H), 0.64- 0.49 (m, 2 H), 0.37- 0.23 (m, 2 H).# 4.5.11. Example 11. Preparation of 4-((R)-1-(5-(trans-3-methoxycyclobutoxy)pyridin-2-yl)propoxy)-3-(trifluoromethyl)benzoic acid (Acid K)Step 1: methyl 4- ((R)- 1- (5- (trans- 3- methoxycyclobutoxy)pyridin- 2- yl)propoxy)- 3- (trifluoromethyl)benzoate10Under $\mathbf{N}\_2$ , to a solution of (S)- 1- (5- ((trans)- 3- methoxycyclobutoxy)pyridin- 2- yl)propan- 1- ol $(2.80\mathrm{g},11.8\mathrm{mmol}$ , Acid F, Step 4) and methyl 4- hydroxy- 3- (trifluoromethyl)benzoate $(2.72\mathrm{g},$ $12.4\mathrm{mmol}$ ) in toluene $(40~\mathrm{mL})$ was added CMBP $(5.69\mathrm{g},23.6\mathrm{mmol})$ . The reaction mixture was sealed and stirred at $120^{\circ}\mathrm{C}$ for $16\mathrm{h}$ . The solvent was removed under reduced pressure. The residue was purified by slicia gel flash chromatography (eluent: EtOAc in PE, $0 - 20\%$ ) to afford the title compound $(2.3\mathrm{g},90\%$ purity, $40\%$ yield) as a yellow solid.LCMS (Method K) MS (ESI) $\mathrm{[M + H]^{+} = 440.1}$ $\mathrm{Rt} = 1.67\mathrm{min}$ ${}^{1}\mathrm{H}$ NMR (400 MHz, $\mathrm{CDCl}\_3$ , ppm) 8 8.25 (d, $J = 1.9 \mathrm{Hz}$ , 1 H), 8.15 (d, $J = 2.7 \mathrm{Hz}$ , 1 H), 7.99 (dd, $J = 8.8$ $2.0\mathrm{Hz}$ , 1 H), 7.23 (d, $J = 8.7 \mathrm{Hz}$ 1 H), 7.03 (dd, $J = 8.7$ $2.8\mathrm{Hz}$ , 1 H), 6.87 (d, $J = 8.8 \mathrm{Hz}$ , 1 H), 5.41- 5.31 (m, 1 H), 4.84- 4.80 (m, 1 H), 4.15- 4.09 (m, 1 H), 3.87 (s, 3 H), 3.26 (s, 3 H), 2.54- 2.25 (m, 4 H), 2.09- 2.00 (m, 2 H), 1.04 (t, $J = 7.4$ Hz, 3 H).Step 2: 4- ((R)- 1- (5- (trans- 3- methoxycyclobutoxy)pyridin- 2- yl)propoxy)- 3- (trifluoromethyl)benzoic acidA mixture of methyl 4- ((R)- 1- (5- (trans- 3- methoxycyclobutoxy)pyridin- 2- yl)propoxy)- 3- (trifluoromethyl)benzoate $(2.30\mathrm{g},5.23\mathrm{mmol})$ and $\mathrm{LiOH}\cdot \mathrm{H}\_2\mathrm{O}$ $(377~\mathrm{mg},15.7~\mathrm{mmol})$ in $\mathrm{THF / H\_2O}$ (3 / 1, 20 mL) was stirred for $16\mathrm{h}$ at RT. The reaction mixture was diluted with water $(20~\mathrm{mL})$ , acidified with AcOH until pH 4- 5. The mixture was extracted with EtOAc $(20\mathrm{mLx}5)$ . The combined organic layerswere dried over $\mathrm{Na\_2SO\_4}$ and concentrated in vacuo. The residue was purified by chiral SFC (Method H) to give the title compound (1.15 g, $>99\%$ ee, $90\%$ purity, $49\%$ yield,) as a yellow solid.LCMS (Method K) MS (ESI) $\mathrm{[M + H]^+ = 426.1}$ $\mathrm{Rt} = 1.48\mathrm{min}$ ${}^{1}\mathrm{H}$ NMR (400 MHz, DMSO- $d\_{6}$ ppm) 8 13.07 (s, 1 H), 8.20- 8.19 (m, 1 H), 8.09 (s, 1 H), 8.05- 8.03 (m, 1 H), 7.30- 7.23 (m, 2 H), 7.11 (d, $J = 8.8 \mathrm{Hz}$ , 1 H), 5.51 (t, $J = 6.1 \mathrm{Hz}$ , 1 H), 4.93- 4.78 (m, 1 H), 4.14- 3.96 (m, 1 H), 3.15 (s, 3 H), 2.47- 2.35 (m, 2 H), 2.33- 2.21 (m, 2 H), 2.05- 1.89 (m, 2 H), 0.93 (t, $J = 7.3 \mathrm{Hz}$ , 3 H).# 4.5.12. Example 12. Preparation of (R)-4-(1-(4-(cyclopropylmethoxy)pyridin-2-yl)propoxy)- 2,3-difluorobenzoic acid (Acid L)Step 1: 1- (4- hydroxypyridin- 2- yl)propan- 1- one10Under $\mathbf{N}\_2$ , to a solution of 4- hydroxypicolinonitrile ( $5.00\mathrm{g}$ , 41.6 mmol) in THF ( $50~\mathrm{mL}$ ) was added EtMgBr ( $4.7~\mathrm{mL}$ , 83 mmol, 2M in THF) at $0^\circ \mathrm{C}$ . The reaction mixture was stirred for $30\mathrm{min}$ at $0^\circ \mathrm{C}$ and then heated to $70^{\circ}\mathrm{C}$ for $1\mathrm{h}$ . The reaction mixture was allowed to cool to RT and was poured into ice- water ( $150\mathrm{mL}$ ) and then acidified with $3\mathrm{N}$ HCl until $\mathrm{pH}4\sim 5$ . The mixture was stirred at RT for 15 10 mins and extracted with EtOAc ( $200\mathrm{mLx8}$ . The combined organic layers were died over $\mathrm{Na\_2SO\_4}$ and concentrated in vacuo. The residue was purified by silica gel flash chromatography (eluent: MeOH / DCM: $0 - 10\%$ to give the title compound ( $5.55\mathrm{g}$ $79\%$ yield) as a light yellow solid.LCMS (Method K) MS (ESI) $\mathrm{[M + H]^+ = 151.9}$ $\mathrm{Rt} = 0.48\mathrm{min}$ ${}^{1}\mathrm{H}$ NMR (400 MHz, methanol- $d4$ ppm) 8 7.89 (d, $J = 6.8 \mathrm{Hz}$ , 1 H), 7.13- 7.07 (m, 1 H), 6.65- 6.52 (m, 1 H), 3.04 (q, $J = 7.2 \mathrm{Hz}$ , 2 H), 1.19 (t, $J = 7.2 \mathrm{Hz}$ , 3 H).Step 2: 1- (4- (cyclopropylmethoxy)pyridin- 2- yl)propan- 1- oneA mixture of 1- (4- hydroxypyridin- 2- yl)propan- 1- one (4.0 g, 27 mmol), (bromomethyl)cyclopropane (5.4 g, 40 mmol) and $\mathrm{K\_2CO\_3}$ (11 g, 80 mol) in DMF (80 mL) was stirred at $90^{\circ}\mathrm{C}$ for $16 \mathrm{h}$ . The resulting mixture was diluted with water (80 mL) and extracted with EtOAc (60 mL x 3). The combined organic phases were washed with brine (15 mL), dried over $\mathrm{Na\_2SO\_4}$ , concentrated under vacuum and the residue was purified by silica gel flash chromatography (eluent: EtOAc / PE, 0- 10%) to afford the title compound (5.4 g, 98% yield) as a yellow oil.LCMS (Method K) MS (ESI) $\mathrm{[M + H]^+ = 206.2}$ $\mathrm{Rt} = 1.23\mathrm{min}$ ${}^{1}\mathrm{H}$ NMR (400 MHz, DMSO- $d\_{6}$ ppm) 8 8.50 (d, $J = 5.6 \mathrm{Hz}$ 1H), 7.41 (d, $J = 2.6 \mathrm{Hz}$ 1H), 7.20 (dd, $J = 5.6$ $2.6\mathrm{Hz}$ 1H), 3.99 (d, $J = 7.1$ Hz, 2 H), 3.15 (q, $J = 7.3 \mathrm{Hz}$ , 2 H), 1.31- 1.19 (m, 1 H), 1.08 (t, $J = 7.3 \mathrm{Hz}$ , 3 H), 0.66- 0.53 (m, 2 H), 0.43- 0.31 (m, 2 H).Step 3: (S)- 1- (4- (cyclopropylmethoxy)pyridin- 2- yl)propan- 1- olA mixture of $\mathrm{[RuCl\_2(mesitylene)]\_2}$ $(0.28\mathrm{g},0.5\mathrm{mmol})$ and $N\cdot$ - [(1S,2S)- 2- amino- 1,2- diphenylethyl]- 4- methyl- 1- sulfonylaniline $(0.39\mathrm{g},1.0\mathrm{mol})$ in MeCN $20~\mathrm{mL}$ ) and $\mathrm{H}\_2\mathrm{O}$ $20~\mathrm{mL}$ ) was degassed and purged with $\mathbf{N}\_2$ for 3 times, and then the mixture was stirred at $40^{\circ}\mathrm{C}$ for $1\mathrm{h}$ under a $\mathbf{N}\_2$ 10 atmosphere. The mixture was cooled to $0^\circ \mathrm{C}$ and 1- [5- (pyridin- 2- yloxy)pyridin- 2- yl]ethenone $(5.5\mathrm{g},27.0$ mmol) in MeCN ( $10~\mathrm{mL}$ ) was added. Potassium formate ( $11.3\mathrm{g}$ $130\mathrm{mmol}$ ) in $\mathrm{H}\_2\mathrm{O}$ $30~\mathrm{mL}$ ) was added in the mixture and the mixture was stirred at RT for $15\mathrm{h}$ under a $\mathbf{N}\_2$ atmosphere. The solution was diluted with water ( $100~\mathrm{mL}$ ) and extracted with EtOAc ( $100\mathrm{mL}\times 2$ ). The combined organic layers were washed with saturated NaCl ( $50~\mathrm{mL}$ ), dried over anhydrous $\mathrm{Na\_2SO\_4}$ , and the solvent was removed under reduced 15 pressure. The residue was purified by silica gel flash chromatography (eluent: $\mathrm{PE / EtOAc} = 2 / 1)$ to give the title compound ( $5.4\mathrm{g}$ $84\%$ yield) as a yellow oil.LCMS (Method K) MS (ESI) $\mathrm{[M + H]^+ = 208.2}$ $\mathrm{Rt} = 0.73\mathrm{min}$Step 4: (R)- 4- (1- (4- (cyclopropylmethoxy)pyridin- 2- yl)propoxy)- 2,3- difluorobenzoateUnder $\mathbf{N}\_2$ , a mixture of $\mathrm{PPh}\_3$ ( $19.8\mathrm{g}$ 75 mmol) and DIAD ( $15.2\mathrm{g}$ 75 mmol) in anhydrous THF ( $100~\mathrm{mL}$ ) was stirred at $0^\circ \mathrm{C}$ for $30\mathrm{min}$ . A solution of (1S)- 1- [4- (cyclopropylmethoxy)pyridin- 2- yl]propan- 1- ol ( $5.2\mathrm{g}$ 25 mmol) and methyl- 2,3- difluoro- 4- hydroxybenzoate ( $6.14\mathrm{g}$ 33 mol) in THF (20 mL) was added dropwise and the mixture was stirred at RT for 2 hours. The solution was diluted with water ( $100~\mathrm{mL}$ ) and extracted with EtOAc ( $100\mathrm{mL}\times 2$ ). The combined organic layers were washed with 25 saturated NaCl ( $50~\mathrm{mL}$ ), dried over anhydrous $\mathrm{Na\_2SO\_4}$ , filtered and the solvent was removed under reduced pressure. The residue was purified by silica gel flash chromatography (eluent: PE / EtOAc = 2 / 1) to give methyl the title compound ( $15\mathrm{g}$ $100\%$ yield) as a yellow oil.LCMS (Method K) MS (ESI) $\mathrm{[M + H]^+ = 378.1}$ $\mathrm{Rt} = 1.45\mathrm{min}$ ${}^{1}\mathrm{H}$ NMR (400 MHz, DMSO- $d\_{6}$ ppm) 8 8.37 (d, $J = 5.7 \mathrm{Hz}$ 1H), 7.62- 7.54 (m, 1 H), 6.99- 6.92 (m, 2 H), 6.89 (dd, $J = 5.7$ $2.5\mathrm{Hz}$ 1H),5.40 (t, $J = 6.4 \mathrm{Hz}$ , 1 H), 3.95- 3.86 (m, 2 H), 3.82 (s, 3 H), 2.04- 1.99 (m, 2 H), 1.13- 1.05 (m, 1 H), 0.94 (t, $J = 9.2$ , 5.5 Hz, 3 H), 0.61- 0.51 (m, 2 H), 0.37- 0.28 (m, 2 H).Step 5: $(R)$ - 4- (1- (4- (cyclopropylmethoxy)pyridin- 2- yl)propoxy)- 2,3- difluorobenzoic acid5 To a solution of methyl 4- [(1R)- 1- [4- (cyclopropylmethoxy)pyridin- 2- yl]propoxy]- 2,3- difluorobenzoate ( $15\mathrm{g}$ , 40 mmol) in THF ( $60~\mathrm{mL}$ ) and $\mathrm{H}\_2\mathrm{O}$ $30~\mathrm{mL}$ ) at RT was added LiOH $\mathrm{H}\_2\mathrm{O}$ $6.66\mathrm{g}$ $160\mathrm{mmol}$ . The resulting solution was stirred at RT for $16\mathrm{h}$ . The mixture was acidified with AcOH until $\mathrm{pH}5 - 6$ . The solution was extracted with EtOAc ( $150\mathrm{mL}\times 2)$ . The combined organic layers were washed with saturated NaCl ( $50~\mathrm{mL}$ ), dried over anhydrous $\mathrm{Na\_2SO\_4}$ , filtered and the solvent was removed under 10 reduced pressure. The resultant solids were refluxed in MeOH ( $50~\mathrm{mL}$ ) until all fully dissolved. The solution was then cooled to RT slowly and was left to stand at RT for $18\mathrm{h}$ . The solids were filtered and washed with MeOH (5 mL) to give the title compound ( $3.3\mathrm{g}$ $98\%$ ee, $22\%$ yield) as a white solid.LCMS (Method K) MS (ESI) $\mathrm{[M + H]^+ = 364.1}$ $\mathrm{Rt} = 1.20\mathrm{min}$ ${}^{1}\mathrm{H}$ NMR (400 MHz, DMSO- $d\_{6}$ ppm) 8 13.20 (s, 1 H), 8.37 d, $J = 5.7 \mathrm{Hz}$ , 1 H), 7.55 (t, $J = 7.7 \mathrm{Hz}$ , 1 H), 7.03- 6.77 (m, 3 H), 5.38 (t, $J =$ 15 6.3 Hz, 1 H), 4.00- 3.78 (m, 2 H), 2.15- 1.89 (m, 2 H), 1.27- 1.11 (m, 1 H), 0.94 (t, $J = - 7.3 \mathrm{Hz}$ , 3 H), 0.63- 0.48 (m, 2 H), 0.40- 0.23 (m, 2 H).# 4.5.13. Example 13. Preparation of $(R)$ -2,3-difluoro-4-(1-(4-(pyridin-2-yloxy)pyridin-2-yl)propoxy)benzoic acid (Acid M)Step 1: 1- (4- (pyridin- 2- yloxy)pyridin- 2- yl)propan- 1- one20A mixture of 1- (4- hydroxypyridin- 2- yl)propan- 1- one (5.55 g, 36.7 mmol, Acid L, Step 1), 2- fluoropyridine (5.34 g, 54.4 mmol) and $\mathrm{K}\_2\mathrm{CO}\_3$ (7.61 g, 54.4 mmol) in DMF (100 mL) was stirred at $140^{\circ}\mathrm{C}$ for $36 \mathrm{h}$ . The mixture was allowed to cool to RT and was poured into water (300 mL), and extracted with EtOAc (300 mL x 3). The combined organic layers were dried over $\mathrm{Na}\_2\mathrm{SO}\_4$ and concentrated in vacuo. The residue was purified by silica gel flash chromatography (eluent: EtOAc / PE: 0- 40%) to give the title compound (3.77 g, 41% yield) as a light yellow solid.LCMS (Method E) MS (ESI) $\mathrm{[M + H]^+ = 229.2}$ $\mathrm{Rt} = 1.49$ min. ${}^{1}\mathrm{H}$ NMR (400 MHz, $\mathrm{CDCl}\_3$ ppm) 8 8.63 (d, $J = 5.5 \mathrm{Hz}$ 1 H), 8.29- 8.22 (m, 1 H), 7.85- 7.75 (m, 2 H), 7.28- 7.26 (m, 1 H), 7.19- 7.13 (m, 1 H), 7.05 (d, $J = 8.2 \mathrm{Hz}$ 1 H), 3.24 (q, $J = 7.3 \mathrm{Hz}$ 2 H), 1.21 (t, $J = 7.3 \mathrm{Hz}$ 3 H).Step 2: (S)- 1- (4- (pyridin- 2- yloxy)pyridin- 2- yl)propan- 1- olA mixture of $\mathrm{[RuCl\_2(mesitylene)]\_2}$ (126 mg, 0.24 mmol) and $N$ -(1S,2S)- 2-amino- 1,2- diphenylethyl)- 4- methylbenzenesulfonamide (180 mg, 0.49 mmol) in MeCN (5 mL) and $\mathrm{H}\_2\mathrm{O}$ (5 mL) was degassed and purged with $\mathrm{N}\_2$ 3 times, and the mixture was stirred at $40^{\circ}\mathrm{C}$ for $1 \mathrm{h}$ under a $\mathrm{N}\_2$ atmosphere. The mixture was cooled to $0^{\circ}\mathrm{C}$ and 1- (4- (pyridin- 2- yloxy)pyridin- 2- yl)propan- 1- one (2.80 g, 12.3 mmol) in MeCN (10 mL) was added. Potassium formate (5.10 g, 61.3 mmol) in $\mathrm{H}\_2\mathrm{O}$ (10 mL) was added and the mixture was stirred at RT for $16 \mathrm{h}$ under $\mathrm{N}\_2$ . The mixture was diluted with water (100 mL) and extracted with EtOAc (100 mL x 3). The combined organic layers were dried over $\mathrm{Na\_2SO\_4}$ and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (eluent: MeOH / DCM: 0- 10%) to give the title compound (2.80 g, 89% yield) as a yellow solid.LCMS (Method K) MS (ESI) $\mathrm{[M + H]^+ = 230.9}$ $\mathrm{Rt} = 0.64$ min. ${}^{1}\mathrm{H}$ NMR (400 MHz, $\mathrm{CDCl}\_3$ ppm) 8 8.48 (d, $J = 5.6 \mathrm{Hz}$ 1 H), 8.33- 8.22 (m, 1 H), 7.84- 7.75 (m, 1 H), 7.17- 7.12 (m, 1 H), 7.07- 7.01 (m, 2 H), 7.00- 6.95 (m, 1 H), 4.74- 4.60 (m, 1 H), 1.95- 1.82 (m, 1 H), 1.78- 1.63 (m, 1 H), 0.97 (t, $J = 7.4 \mathrm{Hz}$ 3 H).Step 3: methyl (R)- 2,3- difluoro- 4- (1- (4- (pyridin- 2- yloxy)pyridin- 2- yl)propoxy)benzoate20Under $\mathrm{N}\_2$ , to a solution of $\mathrm{PPh}\_3$ (9.31 g, 35.5 mmol) in dry THF (160 mL) was added DIAD (7.19 g, 35.5 mol) dropwise at $0^{\circ}\mathrm{C}$ and the mixture was stirred at this temperature for $20 \mathrm{min}$ . A solution of (S)- 1- (4- (pyridin- 2- yloxy)pyridin- 2- yl)propan- 1- ol (2.73 g, 11.8 mmol) and methyl 2,3- difluoro- 4- hydroxybenzoate (2.23 g, 11.8 mmol) in dry THF (40 mL) was added dropwise. The resulting reaction mixture was stirred at RT for $16 \mathrm{h}$ . The solvent was removed under reduced pressure. The residue was purified by silica gel flash chromatography (eluent: EtOAc / PE: 0- 50%) to give the title compound (5.3 g, 80% purity, 89% yield) as a yellow oil.LCMS (Method K) MS (ESI) $\mathrm{[M + H]^+ = 401.2}$ $\mathrm{Rt} = 1.50\mathrm{min}$ ${}^{1}\mathrm{H}$ NMR (400 MHz, CDCl3, ppm) 8 8.51 (d, $J = 5.6 \mathrm{Hz}$ 1 H), 8.24- 8.16 (m, 1 H), 7.82- 7.72 (m, 1 H), 7.60- 7.51 (m, 1 H), 7.17- 7.11 (m, 2 H), 7.05- 6.93 (m, 2 H), 6.72- 6.63 (m, 1 H), 5.07- 4.83 (m, 1 H), 3.89 (s, 3 H), 2.22- 1.96 (m, 2 H), 1.08 (t, $J = 7.4 \mathrm{Hz},3 \mathrm{H})$Step 4: $(R)$ - 2,3- difluoro- 4- (1- (4- (pyridin- 2- yloxy)pyridin- 2- yl)propoxy)benzoic acidMethyl $(R)$ - 2,3- difluoro- 4- (1- (4- (pyridin- 2- yloxy)pyridin- 2- yl)propoxy)benzoate (5.20 g, 13.0 mmol) and $\mathrm{LiOH}\cdot \mathrm{H}\_2\mathrm{O}$ (1.25 g, 52.0 mmol) in $\mathrm{THF / H\_2O / MeOH}$ (75 mL, 2 / 2 / 1) was stirred at RT for 3 h. The solvent was removed under reduced pressure and the residue was diluted with water (70 mL). The mixture was acidified with HCOOH to pH 5- 6 and was extracted with EtOAc (40 mL x 3). The combined organic layers were dried over $\mathrm{Na\_2SO\_4}$ and concentrated in vacuo. The residue was purified by silica gel flash chromatography (eluent: $\mathrm{DCM / MeOH} = 20 / 1$ , with 0.5% FA) to give a light yellow solid. The solids were refluxed in MeOH (16 mL) until fully dissolved. The solution was then cooled to RT slowly and allowed to stand at RT for 18 h. The solids were filtered, washed with MeOH (1 mL) and MeCN (5 mL x 2), and dried to give the title compound (2.4 g, 97% ee, 47% yield) as a white solid.15 MeCN (5 mL x 2), and dried to give the title compound (2.4 g, 97% ee, 47% yield) as a white solid.LCMS (Method E) MS (ESI) $\mathrm{[M + H]^+ = 387.2}$ $\mathrm{Rt} = 1.07\mathrm{min}$ ${}^{1}\mathrm{H}$ NMR (400 MHz, DMSO- $d\_{6}$ ppm) 8 13.21 (s, 1 H), 8.53 (d, $J = 5.6 \mathrm{Hz}$ 1 H), 8.25- 8.12 (m, 1 H), 8.01- 7.85 (m, 1 H), 7.62- 7.50 (m, 1 H), 7.33- 7.24 (m, 1 H), 7.20- 7.11 (m, 2 H), 7.10- 7.01 (m, 1 H), 7.00- 6.89 (m, 1 H), 5.50 (t, $J = 6.3 \mathrm{Hz}$ 1 H), 2.06- 1.98 (m, 2 H), 0.95 (t, $J = 7.4 \mathrm{Hz}$ 3 H).4.5.14. Example 14. Preparation of 4- ((R)- 1- (5- (trans- 3- (difluoromethoxy)cyclobutoxy)- pyridin- 2- yl)propoxy)- 2,3- difluorobenzoic acid (Acid N)Step 1: cis- 3- (difluoromethoxy)cyclobutyl 4- methylbenzenesulfonateUnder $\mathbf{N}\_2$ , to a solution of 3- hydroxycyclobutyl 4- methylbenzenesulfonate $(6.09\mathrm{g},25.1\mathrm{mmol}$ 25 Acid F, Step 1) in MeCN ( $60~\mathrm{mL}$ ) was added CuI (957 mg, 5.03 mmol). The mixture was heated to $50^{\circ}\mathrm{C}$ and difluoro(fluorosulfonyl)acetic acid (6.71 g, 37.7 mmol) in MeCN (20 mL) was added dropwise at $50^{\circ}\mathrm{C}$ over $45\mathrm{min}$ . The reaction solution was stirred for 1 h at $50^{\circ}\mathrm{C}$ . The solvent was removed under reduced pressure. The residue was purified by silica gel flash chromatography (eluent: EtOAc / PE: $0 - 9\%$ to give the title compound (4.50 g, $92\%$ purity, $27\%$ yield) as a colorless liquid.${}^{1}\mathrm{H}$ NMR (400 MHz, $\mathrm{CDCl}\_3$ ) 8 7.78 (d, $J = 8.3 \mathrm{Hz}$ , 2 H), 7.35 (d, $J = 8.1 \mathrm{Hz}$ , 2 H), 6.11 (t, $^2 J\_{H - F} =$ $73.6\mathrm{Hz}$ , 1 H), 4.48 (p, $J = 7.2 \mathrm{Hz}$ , 1 H), 4.23 (p, $J = 7.1 \mathrm{Hz}$ , 1 H), 2.76- 2.66 (m, 2 H), 2.46 (s, 3 H), 2.39- 2.31 (m, 2 H).Step 2: 1- (5- (trans- 3- (difluoromethoxy)cyclobutoxy)pyridin- 2- yl)propan- 1- one5A mixture of 1- (5- hydroxypyridin- 2- yl)propan- 1- one (2.15 g, 14.2 mmol), 3- (difluoromethoxy)cyclobutyl 4- methylbenzenesulfonate (4.37 g, 14.9 mmol) and $\mathrm{K}\_2\mathrm{CO}\_3$ (3.93 g, 28.5 mmol) in DMF (45 mL) was stirred for 6 h at $100^{\circ}\mathrm{C}$ . The reaction solvent was diluted with brine (50 mL) and extracted with EtOAc (50 mL x 4). The combined organic phases were concentrated in vacuum. The residue was purified by silica gel flash chromatography (eluent: EtOAc / PE: 0- 9%) to give the title compound (3.05 g, 91% purity, 72% yield) as a pale yellow solid.LCMS (Method K) MS (ESI) $\mathrm{[M + H]^+ = 271.9}$ $\mathrm{Rt} = 1.36\mathrm{min}$ ${}^{1}\mathrm{H}$ NMR (400 MHz, DMSO- $d\_{6}$ ppm) 8 8.31 (d, $J = 2.9 \mathrm{Hz}$ , 1 H), 7.94 (d, $J = 8.7 \mathrm{Hz}$ , 1 H), 7.41 (dd, $J = 8.7$ , 2.9 Hz, 1 H), 6.69 (t, $J =$ $75.7\mathrm{Hz}$ , 1 H), 5.13- 5.05 (m, 1 H), 4.90- 4.80 (m, 1 H), 3.11 (q, $J = 7.3 \mathrm{Hz}$ , 2 H), 2.70- 2.62 (m, 2 H), 2.57- 2.51 (m, 2 H), 1.08 (t, $J = 7.3 \mathrm{Hz}$ , 3 H).Step 3: (S)- 1- (5- (trans- 3- (difluoromethoxy)cyclobutoxy)pyridin- 2- yl)propan- 1- olUnder $\mathbf{N}\_2$ , a mixture of $[\mathrm{RuCl}\_2$ (mesitylene)]2 (115 mg, 0.22 mmol), N- [(1S,2S)- 2- amino- 1,2- diphenylethyl]- 4- methyl- 1- sulfonylaniline ( $165~\mathrm{mg}$ , 0.45 mmol) in MeCN (4 mL) / $\mathrm{H}\_2\mathrm{O}$ (4 mL) was stirred for $1\mathrm{h}$ at $40^{\circ}\mathrm{C}$ . The reaction was cooled to $5^{\circ}\mathrm{C}$ and 1- (5- (trans- 3- (difluoromethoxy)cyclobutoxy)pyridin- 2- yl)propan- 1- one (3.05 g, 11.2 mmol) in MeCN (30 mL) followed by a solution of HCOOK (4.72 g, 56.2 mmol) in $\mathrm{H}\_2\mathrm{O}$ (22 mL) were added to dropwise at $5^{\circ}\mathrm{C}$ The reaction solution was warmed to RT and was stirred for $12\mathrm{h}$ . The reaction solvent was extracted with DCM (50 mL x 4). The combined organic phases were concentrated in vacuum. The residue was purified 25 by silica gel flash Chromatography (eluent: MeOH / DCM: $0 - 6\%$ ) to give the title compound (2.70 g, $92\%$ purity, $81\%$ yield) as a yellow oil.LCMS (Method K) MS (ESI) $\mathrm{[M + H]^+ = 274.2}$ $\mathrm{Rt} = 0.95\mathrm{min}$ ${}^{1}\mathrm{H}$ NMR (400 MHz, $\mathrm{CDCl}\_3$ ) 8 8.14- 8.05 (m, 1H), 7.22- 7.10 (m, 2 H), 6.20 (t, $J = 74.2 \mathrm{Hz}$ , 1 H), 4.97- 4.84 (m, 2 H), 4.70- 4.61 (m, 1 H), 2.71- 2.52 (m, 4 H), 1.93- 1.80 (m, 1 H), 1.79- 1.65 (m, 1 H), 0.94 (t, $\mathrm{J} = 7.4 \mathrm{Hz}$ , 3 H).Step 4: methyl 4- ((R)- 1- (5- (trans- 3- (difluoromethoxy)cyclobutoxy)pyridin- 2- yl)propoxy)- 2,3- difluorobenzoateUnder $\mathbf{N}\_2$ , a mixture of (S)- 1- (5- (trans- 3- (difluoromethoxy)cyclobutoxy)pyridin- 2- yl)propan- 1- ol 5 $(2.69\mathrm{g},9.84\mathrm{mmol})$ , methyl 2,3- difluoro- 4- hydroxybenzoate $(2.13\mathrm{g},11.3\mathrm{mmol})$ , CMBP $(4.75\mathrm{g},$ $19.7\mathrm{mmol})$ in toluene $(30\mathrm{mL})$ was stirred for $12\mathrm{h}$ at $110^{\circ}\mathrm{C}$ . The solution was concentrated in vacuum. The residue was purified by silica gel flash chromatography (eluent: EtOAc / PE: $0 - 9\%$ ) to give the title compound $(2.50\mathrm{g},91\%$ purity, $52\%$ yield) as a brown solid.LCMS (Method K) MS (ESI) $\mathrm{[M + H]^+ = 444.2}$ $\mathrm{Rt} = 1.59\mathrm{min}$ ${}^{1}\mathrm{H}$ NMR (400 MHz, $\mathrm{CDCl}\_3$ ) 8 10 8.20- 8.02 (m, 1 H), 7.55- 7.46 (m, 1 H), 7.32- 7.27 (m, $J = 8.6 \mathrm{Hz}$ , 1 H), 7.07- 7.02 (m, 1 H), 6.68- 6.61 (m, 1 H), 6.19 (t, $J = 74.2 \mathrm{Hz}$ , 1 H), 5.28- 5.23 (m, 1 H), 4.94- 4.83 (m, 2 H), 3.88 (s, 3 H), 2.67- 2.53 (m, 4 H), 2.11- 2.03 (m, 2 H), 1.03 (t, $J = 7.4 \mathrm{Hz}$ , 3 H).Step 5: 4- ((R)- 1- (5- (trans- 3- (difluoromethoxy)cyclobutoxy)pyridin- 2- yl)propoxy)- 2,3- difluorobenzoic acid15To a solution of methyl 4- ((R)- 1- (5- (trans- 3- (difluoromethoxy)cyclobutoxy)pyridin- 2- yl)propoxy)- 2,3- difluorobenzoate $(2.47\mathrm{g},5.57\mathrm{mmol})$ in THF $(21\mathrm{mL}) / \mathrm{H}\_2\mathrm{O}$ $(7\mathrm{mL})$ was added $\mathrm{LiOH}\cdot \mathrm{H}\_2\mathrm{O}$ $(668~\mathrm{mg},27.9~\mathrm{mmol})$ . The mixture was stirred for $7\mathrm{h}$ at RT. The reaction mixture was acidified with HCOOH to $\mathrm{pH} = 6 - 7$ and was extracted with EtOAc $(60~\mathrm{mL~x~4})$ . The combined organic 20 phases were concentrated in vacuum. The residue was purified by silica gel flash chromatography (eluent: MeOH / DCM: $0 - 6\%$ ) and chiral SFC (Method I) to give the title compound $(1.2\mathrm{g}, > 99\%$ ee, $92\%$ purity, $46\%$ yield) as a yellow solid.LCMS (Method K) MS (ESI) $\mathrm{[M + H]^+ = 430.1}$ $\mathrm{Rt} = 1.40\mathrm{min}$ ${}^{1}\mathrm{H}$ NMR (400 MHz, DMSO- $d\_{6},$ ppm) 8 13.17 (s, 1 H), 8.23- 8.16 (m, 1 H), 7.59- 7.49 (m, 1 H), 7.41 - 7.33 (m, 1 H), 7.31- 7.24 (m, 1 H), 25 6.97- 6.89 (t, 1 H), 6.66 (t, $J = 75.7 \mathrm{Hz}$ , 1 H), 5.42 (t, $J = 6.5 \mathrm{Hz}$ , 1 H), 5.00- 4.92 (m, 1 H), 4.85- 4.77 (m, 1 H), 2.64- 2.56 (m, 2 H), 2.47- 2.42 (m, 2 H), 2.08- 1.93 (m, 2 H), 0.91 (t, $J = 7.3 \mathrm{Hz}$ , 3 H).# 4.5.15. Example 15. Preparation of $(R)$ -4-(1-(3-(cyclopropylmethoxy)phenyl)propoxy)-2,3-difluorobenzoic acid (Acid O)Step 1: 1- (3- (cyclopropylmethoxy)phenyl)propan- 1- one5 A mixture of 1- (3- hydroxyphenyl)propan- 1- one (5.0 g, 33 mmol), (bromomethyl)cyclopropane $(9.0\mathrm{g},67\mathrm{mmol})$ and $\mathrm{K}\_2\mathrm{CO}\_2$ $13.8\mathrm{g}$ $100\mathrm{mmol}$ ) in DMF $30~\mathrm{mL}$ ) was stirred at $90^{\circ}\mathrm{C}$ for $16\mathrm{h}$ . The resulting mixture was diluted with water ( $50~\mathrm{mL}$ ) and extracted with EtOAc ( $60~\mathrm{mL}$ x 3). The combined organic phases were washed with brine ( $15~\mathrm{mL}$ ), dried over $\mathrm{Na\_2SO\_4}$ , concentrated in vacuo and the residue was purified by silica gel flash chromatography (eluent: PE / EtOAc: 3 / 1) to give the title 10 compound $(6.0\mathrm{g},90\%$ purity, $79\%$ yield) as a white solid.LCMS (Method K) MS (ESI) $\mathrm{[M + H]^+ = 204.9}$ $\mathrm{Rt} = 1.43\mathrm{min}$ ${}^{1}\mathrm{H}$ NMR (400 MHz, DMSO- $d\_{6}$ ppm) 8 7.53 (d, $J = 7.7 \mathrm{Hz}$ 1H), 7.43- 7.40 (m, 2 H), 7.18 (dd, $J = 7.9$ 2.11 Hz, 1 H), 3.88 (d, $J = 7.0 \mathrm{Hz}$ 2 H), 3.03 (q, $J = 7.2 \mathrm{Hz}$ 2 H), 1.31- 1.16 (m, 1 H), 1.07 (t, $J = 7.2 \mathrm{Hz}$ 3 H), 0.72- 0.49 (m, 2 H), 0.45- 0.21 (m, 2 H).15 Step 2: (S)- 1- (3- (cyclopropylmethoxy)phenyl)propan- 1- olA mixture of $[\mathrm{RuCl}\_2(\mathrm{mesitylene})]\_2$ $0.25\mathrm{g}$ 0.4 mmol), and $N\cdot$ [(1S,2S)- 2- amino- 1,2- diphenylethyl]- 4- methyl- 1- sulfonylaniline ( $0.44\mathrm{g}$ 0.9 mmol) in MeCN ( $5\mathrm{mL}$ ) and $\mathrm{H}\_2\mathrm{O}$ $5\mathrm{mL}$ ) was degassed and purged with $\mathrm{N}\_2$ (x 3) and then stirred at $40^{\circ}\mathrm{C}$ for $1\mathrm{h}$ under $\mathrm{N}\_2$ . A solution of 1- [3- (cyclopropylmethoxy)phenyl]propan- 1- one ( $5\mathrm{g},24\mathrm{mmol})$ in MeCN $(40~\mathrm{mL})$ , followed by HCOOK $(10.3\mathrm{g},130\mathrm{mmol})$ in water $(25~\mathrm{mL})$ ) was added to the mixture at $0^\circ \mathrm{C}$ . The reaction mixture was slowly warmed to RT over $16\mathrm{h}$ . The solution was diluted with water ( $30~\mathrm{mL}$ ) and extracted with EtOAc ( $50~\mathrm{ml}$ x 2). The combined organic layers were washed with brine ( $20~\mathrm{mL}$ ), dried over anhydrous $\mathrm{Na\_2SO\_4}$ and the solvent was removed in vacuo. The residue was purified by silica gel flash chromatography (eluent:25 PE / EtOAc: 2 / 1) to give the title compound ( $5.0\mathrm{g}$ $90\%$ purity, $89\%$ yield) as a yellow oil.${}^{1}\mathrm{H}$ NMR (400 MHz, DMSO- $d\_{6}$ ppm) 8 7.18 (t, $J = 8.0 \mathrm{Hz}$ 1H), 6.95- 6.79 (m, 2 H), 6.79- 6.65 (m, 1 H), 5.06 (s, 1 H), 4.39 (t, $J = 6.0 \mathrm{Hz}$ 1H), 3.78 (d, $J = 6.9 \mathrm{Hz}$ 2 H), 1.60- 1.54 (m, 2 H), 1.31- 1.12 (m, 1 H), 0.81 (t, $J = 7.4 \mathrm{Hz}$ 3 H), 0.61- 0.48 (m, 2 H), 0.40- 0.24 (m, 2 H).Step 3: methyl $(R)$ - 4- (1- (3- (cyclopropylmethoxy)phenyl)propoxy)- 2,3- difluorobenzoateUnder $\mathbf{N}\_2$ , a mixture of $\mathrm{PPh}\_3$ (19.0 g, 73 mmol) and DIAD (14.7 g, 73 mmol) in anhydrous THF $(100\mathrm{mL})$ was stirred at $0^\circ \mathrm{C}$ for $30\mathrm{min}$ . A solution of (1S)- 1- [3- (cyclopropylmethoxy)phenyl]propan- 1- ol 5 $(5.0\mathrm{g},25\mathrm{mmol})$ and methyl- 2,3- difluoro- 4- hydroxybenzoate $(5.5\mathrm{g},29\mathrm{mmol})$ in THF $30~\mathrm{mL}$ was added dropwise. The resulting mixture was stirred at RT for $16\mathrm{h}$ . The solution was diluted with water $(100\mathrm{mL})$ and extracted with EtOAc ( $100\mathrm{mL}\mathrm{x}2$ ). The combined organic layers were washed with brine $(50~\mathrm{mL})$ , dried over anhydrous $\mathrm{Na\_2SO\_4}$ and the solvent was removed in vacuo. The residue was purified by silica gel flash chromatography (eluent: PE / EtOAc: 1 / 1) to give the title compound ( $7.0\mathrm{g}$ $90\%$ purity, 10 $67\%$ yield) as a yellow oil.${}^{1}\mathrm{H}$ NMR (400 MHz, DMSO- $d\_{6}$ ppm) $\delta$ 7.56 (t, $J = 7.9 \mathrm{Hz}$ 1 H), 7.25 (t, $J = 7.9 \mathrm{Hz}$ 1 H), 6.99 (t, $J = 8.2 \mathrm{Hz}$ 1 H), 6.97- 6.93 (m, 2 H), 6.87- 6.77 (m, 1 H), 5.45 (t, $J = 6.4 \mathrm{Hz}$ 1 H), 3.98- 3.59 (m, 5 H), 2.10- 1.95 (m, 1 H), 1.95- 1.71 (m, 1 H), 1.37- 1.09 (m, 1 H), 1.07- 0.77 (m, 3 H), 0.70- 0.45 (m, 2 H), 0.32- 0.29 (m, 2 H).Step 4: $(R)$ - 4- (1- (3- (cyclopropylmethoxy)phenyl)propoxy)- 2,3- difluorobenzoic acid)A mixture of methyl- 4- [(1R)- 1- [3- (cyclopropylmethoxy)phenyl]propoxy]- 2,3- difluorobenzoate $(7.0\mathrm{g},18\mathrm{mmol})$ and LiOH (892 mg, 37 mmol) in THF ( $50~\mathrm{mL}$ ) and $\mathrm{H}\_2\mathrm{O}$ $50~\mathrm{mL}$ ) was stirred at RT for $16\mathrm{h}$ . The pH was adjusted to around 5 by addition of AcOH. The solution was extracted with EtOAc (100 mL x 2). The combined organic layers were washed with brine ( $20~\mathrm{mL}$ ), dried over anhydrous $\mathrm{Na\_2SO\_4}$ and the solvent was removed in vacuo. The residue was purified by chiral SFC (Method J) to give the title compound ( $3.8\mathrm{g}$ $99.5\%$ purity, $>99\%$ ee, $59\%$ yield) as a white solid.LCMS (Method K) MS (ESI) $\mathrm{[M + H]^+ = 361.1}$ $\mathrm{Rt} = 1.52\mathrm{min}$ . ${}^{1}\mathrm{H}$ NMR (400 MHz, DMSO- $d\_{6}$ ppm) $\delta$ 13.16 (s, 1 H), 7.68- 7.37 (m, 1 H), 7.25 (t, $J = 8.1 \mathrm{Hz}$ 1 H), 7.05- 6.89 (m, 3 H), 6.89- 6.66 (m, 1 H), 5.43 (t, $J = 6.5 \mathrm{Hz}$ 1 H), 4.02- 3.59 (m, 2 H), 2.13- 1.92 (m, 1 H), 1.92- 1.76 (m, 1 H), 1.28- 1.02 (m, 1 H), 0.92 (t, $J = 7.3 \mathrm{Hz}$ 3 H), 0.71- 0.47 (m, 2 H), 0.43- 0.19 (m, 2 H).# 4.5.16. Example 16. Preparation of 2,3-difluoro-4-((R)-1-(4-(trans-3-methoxycyclobutoxy)pyridin-2-yl)propoxy)benzoic acid (Acid P)Step 1: 4- (trans- 3- methoxycyclobutoxy)picolinonitrileA mixture of 4- hydroxypicolinonitrile (2.71 g, 22.6 mmol), cis- 3- methoxycyclobutyl 4- methylbenzenesulfonate (5.8 g, 22.6 mmol) and $\mathrm{K}\_2\mathrm{CO}\_3$ (6.25 g, 45.2 mmol) in DMF (120 mL) was stirred for 5 h at $100^{\circ}\mathrm{C}$ . The reaction mixture was diluted with brine (500 mL) and extracted with EtOAc (250 mL x 3). The combined organic phases were concentrated in vacuo. The residue was purified by silica gel flash chromatography (eluent: EtOAc / PE: 0- 30%) to give the title compound (4 g, 90% purity, 78% yield) as a white solid.LCMS (Method K) MS (ESI) $\mathrm{[M + H]^{+} = 205.2}$ $\mathrm{Rt} = 1.09\mathrm{min}$ ${}^{1}\mathrm{H}$ NMR (400 MHz, DMSO- $d\_{6}$ ppm) $\delta 8.52$ (d, $J = 5.8 \mathrm{Hz}$ 1H), 7.59 (d, $J = 2.5 \mathrm{Hz}$ 1H), 7.23- 7.14 (m, 1H), 5.06- 4.95 (m, 1H), 4.12- 4.00 (m, 1H), 3.17 (s, 3 H), 2.49- 2.41 (m, 2 H), 2.37- 2.56 (m, 2 H).Step 2: 1- (4- (trans- 3- methoxycyclobutoxy)pyridin- 2- yl)propan- 1- one15Under $\mathbf{N}\_2$ , to a solution of 4- (trans- 3- methoxycyclobutoxy)picolinonitrile $(3.85\mathrm{g},18.8\mathrm{mmol})$ in THF ( $80~\mathrm{mL}$ ) was added EtMgBr ( $18.8\mathrm{mL}$ , 37.6 mmol, 2M in THF) at $0^\circ \mathrm{C}$ . The reaction mixture was stirred for $0.5\mathrm{h}$ at $0^\circ \mathrm{C}$ and then heated to $70^{\circ}\mathrm{C}$ for $1\mathrm{h}$ . The reaction mixture was poured into ice- water $(150\mathrm{mL})$ and then acidified with $3\mathrm{N}$ HCl to $\mathrm{pH}4\sim 5$ . The mixture was stirred at RT for $10\mathrm{min}$ and extracted with EtOAc $(200\mathrm{mLx8})$ . The combined organic layers were dried over $\mathrm{Na\_2SO\_4}$ and concentrated in vacuo. The residue was purified by silica gel flash chromatography (eluent: EtOAc / PE: 0- $40\%$ to give the title compound ( $3.4\mathrm{g}$ $90\%$ purity, $69\%$ yield) as a light yellow oil.LCMS (Method K) MS (ESI) $\mathrm{[M + H]^{+} = 235.9}$ $\mathrm{Rt} = 1.13\mathrm{min}$ ${}^{1}\mathrm{H}$ NMR (400 MHz, MeOD, ppm) $\delta 8.44$ (d, $J = 5.6 \mathrm{Hz}$ 1H), 7.41 (d, $J = 2.6 \mathrm{Hz}$ 1H), 6.89- 6.80 (m, 1 H), 4.97- 4.85 (m, 1 H), 4.16- 4.05 (m, 1 H), 3.26 (s, 3 H), 3.19 (q, $J = 7.3 \mathrm{Hz}$ 2 H), 2.53- 2.34 (m, 4 H), 1.18 (t, $J = 7.3 \mathrm{Hz}$ 3 H).Step 3: (S)- 1- (4- (trans- 3- methoxycyclobutoxy)pyridin- 2- yl)propan- 1- olA mixture of $\mathrm{[RuCl\_2(mesitylene)]\_2}$ (142 mg, 0.27 mmol) and $N\cdot$ (1S,2S)- 2- amino- 1,2- diphenylethyl)- 4- methylenzenesulfonamide (202 mg, 0.55 mmol) in MeCN (6 mL) and $\mathrm{H}\_2\mathrm{O}$ (6 mL) was degassed and purged with $\mathrm{N}\_2$ (x 3) and then stirred at $40^{\circ}\mathrm{C}$ for $1\mathrm{h}$ under $\mathrm{N}\_2$ . A solution of 1- (4- (trans- 3- methoxycyclobutoxy)pyridin- 2- yl)propan- 1- one (3.25 g, 13.8 mmol) in MeCN (15 mL), followed by HCOOK (5.8 g, 69.0 mmol) in $\mathrm{H}\_2\mathrm{O}$ (15 mL) was added to the mixture at $0^{\circ}\mathrm{C}$ . The reaction mixture was stirred at RT for $16\mathrm{h}$ under $\mathrm{N}\_2$ . The reaction mixture was diluted with water (100 mL) and extracted with EtOAc (100 mL x 3). The combined organic layers were dried over $\mathrm{Na\_2SO\_4}$ and concentrated in vacuo. The residue was purified by silica gel flash chromatography (eluent: MeOH / DCM: 0- 10%) to give the title compound (3.0 g, 90% purity, 82% yield) as a yellow solid.LCMS (Method K) MS (ESI) $\mathrm{[M + H]^{+} = 237.9}$ $\mathrm{Rt} = 0.60\mathrm{min}$ ${}^{1}\mathrm{H}$ NMR (400 MHz, $\mathrm{CDCl}\_3$ ppm) 8 8.32 (d, $J = 5.7 \mathrm{Hz}$ 1 H), 6.66- 6.55 (m, 2 H), 4.92- 4.82 (m, 1 H), 4.64- 4.56 (m, 1 H), 4.17- 4.09 (m, 1 H), 3.27 (s, 3 H), 2.53- 2.36 (m, 4 H), 1.91- 1.79 (m, 1 H), 1.75- 1.61 (m, 1 H), 0.94 (t, $J = 7.4 \mathrm{Hz}$ 3 H).15 Step 4: methyl 2,3- difluoro- 4- ((R)- 1- (4- (trans- 3- methoxycyclobutoxy)pyridin- 2- yl)propoxy)benzoateUnder $\mathrm{N}\_2$ , to a solution of $\mathrm{PPh}\_3$ $(9.60\mathrm{g},36.6\mathrm{mmol})$ in dry THF ( $150\mathrm{mL}$ ) was added DIAD (7.41 g, $36.6\mathrm{mol}$ ) dropwise at $0^\circ \mathrm{C}$ and the mixture was stirred at $0^\circ \mathrm{C}$ for $20\mathrm{min}$ . A solution of (S)- 1- (4- (trans- 3- methoxycyclobutoxy)pyridin- 2- yl)propan- 1- ol (2.90 g, 12.2 mmol) and methyl 2,3- difluoro- 4- hydroxybenzoate (2.29 g, 12.2 mmol) in dry THF (40 mL) was added dropwise. The resulting reaction mixture was stirred at $25^{\circ}C$ for $16\mathrm{h}$ . The solvent was removed in vacuo. The residue was purified by silica gel flash chromatography (eluent: EtOAc / PE: $0 - 50\%$ to give the title compound $(4.5\mathrm{g},90\%$ purity, $81\%$ yield) as a yellow oil.LCMS (Method E) MS (ESI) $\mathrm{[M + H]^{+} = 408.4}$ $\mathrm{Rt} = 1.82\mathrm{min}$ ${}^{1}\mathrm{H}$ NMR (400 MHz, $\mathrm{CDCl}\_3$ ppm) 8 8.36 (d, $J = 5.7 \mathrm{Hz}$ 1 H), 7.57- 7.48 (m, 1 H), 6.77 (d, $J = 2.4 \mathrm{Hz}$ 1 H), 6.67- 6.56 (m, 2 H), 5.26- 5.20 (m, 1 H), 4.87- 4.77 (m, 1 H), 4.13- 4.05 (m, 1 H), 3.87 (s, 3 H), 3.25 (s, 3 H), 2.51- 2.25 (m, 4 H), 2.11- 2.01 (m, 2 H), 1.05 (t, $J = 7.4 \mathrm{Hz}$ 3 H).Step 5: Preparation of 2,3- difluoro- 4- ((R)- 1- (4- (trans- 3- methoxycyclobutoxy)pyridin- 2- yl)propoxy)benzoic acidMethyl 2,3- difluoro- 4- ((R)- 1- (4- (trans- 3- methoxycyclobutoxy)pyridin- 2- yl)propoxy)benzoate $(4.5\mathrm{g},11.0\mathrm{mmol})$ and LiOH ( $10.5\mathrm{g}$ , 44.1 mmol) in THF / HO / MeOH (60 mL, 2 / 2 / 1) was stirred at RT for $2\mathrm{h}$ . The solvent was removed in vacuo and the residue was diluted with water $(70~\mathrm{mL})$ . The mixture was acidified with HCOOH to $\mathrm{pH}5 - 6$ and extracted with EtOAc ( $40~\mathrm{mL}\mathrm{x}~3$ ). The combined organic layers were dried over $\mathrm{Na\_2SO\_4}$ and concentrated in vacuo. The residue was purified by silica gel flash chromatography (eluent: DCM / MeOH: 20 / 1 and $0.5\%$ FA), followed by chiral SFC (Method K) to give the title compound $(2.8\mathrm{g}, > 99\%$ ee, $95\%$ purity, $61\%$ yield) as a light yellow solid.LCMS (Method K) MS (ESI) $\mathrm{[M + H]^{+} = 394.1}$ $\mathrm{Rt} = 1.13\mathrm{min}$ ${}^{1}\mathrm{H}$ NMR (400 MHz, DMSO- $d\_{6}$ ppm) 8 13.18 (s, 1 H), 8.36 d, $J = 5.7 \mathrm{Hz}$ , 1 H), 7.59- 7.50 (m, 1 H), 6.95- 6.88 (m, 1 H), 6.86- 6.81 (m, 1 H), 6.80- 6.76 (m, 1 H), 5.41 (t, $J = 6.3 \mathrm{Hz}$ , 1 H), 4.98- 4.85 (m, 1 H), 4.09- 3.95 (m, 1 H), 3.15 (s, 3 H), 2.46- 2.15 (m, 4 H), 2.07- 1.93 (m, 2 H), 0.94 (t, $J = 7.4 \mathrm{Hz}$ , 3 H).# 4.5.17. Example 17. Preparation of 4-(2-(4-methylpiperazin-1yl)ethoxy)benzenesulfonamide (Example Procedure A)Step 1: 4- (2- chloroethoxy)benzenesulfonamideTo a solution of 4- hydroxybenzenesulfonamide (3 g, 17.3 mmol) and $\mathrm{K}\_2\mathrm{CO}\_3$ (6 g, 43.3 mmol) in MeCN (60 mL) was added 1- bromo- 2- chloroethane (13.2 g, 91.7 mmol) at RT under $\mathrm{N}\_2$ atmosphere. The reaction mixture was stirred at $80^{\circ}\mathrm{C}$ for $12\mathrm{h}$ . The reaction was cooled to RT and was concentrated in vacuo to dryness. The residue was diluted with $\mathrm{H}\_2\mathrm{O}$ (50 mL), extracted with EtOAc (50 mL x 3). The combined organic layers were washed with $\mathrm{H}\_2\mathrm{O}$ (20 mL) followed by brine (20 mL). The organic phase was dried over anhydrous $\mathrm{Na\_2SO\_4}$ and concentrated in vacuo. The residue was purified by silica gel flash column (gradient 0- 50% EtOAc / PE) to give the title compound (2.5 g, 54% yield) as a white solid. LCMS (Method E) MS (ESI) $\mathrm{[M - H] - } = 234$ $\mathrm{Rt} = 0.82\mathrm{min}$ .Step 2: 4- (2- (4- methylpiperazin- 1- yl)ethoxy)benzenesulfonamideUnder $\mathbf{N}\_2$ , to a solution 4- (2- chloroethoxy)benzenesulfonamide ( $200\mathrm{mg}$ $0.85\mathrm{mmol}$ ) in DMF (2 mL) was added 1- methylpiperazine ( $170\mathrm{mg}$ $1.7\mathrm{mmol}$ $\mathrm{K}\_2\mathrm{CO}\_3$ $293~\mathrm{mg}$ $2.1\mathrm{mmol}$ ),KI $14\mathrm{mg}$ 0.08 mmol) in sequence. The reaction solution was stirred for $12\mathrm{h}$ at $80^{\circ}\mathrm{C}$ . The solvent was removed in vacuo. The residue was purified by Prep- TLC (eluent 5:1 $\mathrm{CH}\_2\mathrm{Cl}\_2 / \mathrm{MeOH}$ to give the title compound (120 mg, $28\%$ yield) as a white solid. LCMS (Method D) MS (ESI) $[\mathrm{M + H}] + = 300$ $\mathrm{Rt} = 0.94\mathrm{min}$# 4.5.18. Example 18. Preparation of 6-[2-(dimethylamino)ethoxy]-2-azaspiro[3.3]heptane-2-sulfonamide (Example Procedure B)Step 1: tert- butyl 6- (2- methoxy- 2- oxoethoxy)- 2- azaspiro[3.3]heptane- 2- carboxylateUnder $\mathbf{N}\_2$ , to a solution of tert- butyl 6- hydroxy- 2- azaspiro[3.3]heptane- 2- carboxylate ( $1.00\mathrm{g}$ $4.7\mathrm{mmol}$ ) in DMF ( $10~\mathrm{mL}$ ) was added NaH ( $60\%$ $0.17\mathrm{g}$ $7.0\mathrm{mmol}$ ) at $0^\circ \mathrm{C}$ . The mixture was then warmed to RT slowly and kept stirring at RT for additional $1\mathrm{h}$ . Then, methyl 2- bromoacetate ( $1.44\mathrm{g}$ , 9.4 mmol) was added. The reaction mixture was stirred at RT for $16\mathrm{h}$ . The mixture was quenched with ice- water ( $30~\mathrm{mL}$ ) slowly and extracted with EtOAc ( $50\mathrm{mL}\mathrm{x}3$ ). The combined organic layers were dried over $\mathrm{Na\_2SO\_4}$ and concentrated in vacuo. The residue was purified by silica gel flash chromatography (eluent 1:5 EtOAc / PE) to give the title compound as a colorless oil ( $750\mathrm{mg}$ $53\%$ yield). ${}^{1}\mathrm{H}$ NMR (400 MHz, $\mathrm{CDCl}\_3$ , ppm) 8 4.01- 3.93 (m, 3 H), 3.88 (d, $J = 6.6 \mathrm{Hz}$ , 4 H), 3.75 (s, 3 H), 2.55- 2.42 (m, 2 H), 2.25- 2.12 (m, 2 H), 1.42 (s, 9 H). (Note: for some examples, Rh- catalyzed O- H insertion with ethyl diazoacetate was used as an alternative method to the alkylation chemistry described above.)Step 2: tert- butyl 6- (2- hydroxyethoxy)- 2- azaspiro[3.3]heptane- 2- carboxylateTo a solution of tert- butyl 6- (2- methoxy- 2- oxoethoxy)- 2- azaspiro[3.3]heptane- 2- carboxylate (450 mg, 1.58 mmol) in THF (4 mL) and MeOH (4 mL) was added $\mathrm{NaBH\_4}$ (179 mg, 4.73 mmol) at $0^\circ \mathrm{C}$ and the mixture was then stirred at RT for $2\mathrm{h}$ . Ice- water (5 mL) was added slowly and the mixture was extracted with EtOAc (20 mL x 3). The combined organic layers were dried over $\mathrm{Na\_2SO\_4}$ and concentrated in vacuo to give the title compound (300 mg, 38% yield) as a colorless oil, which was useddirectly in next step without further purification. LCMS (Method D) MS (ESI) $\mathrm{[M - tBu + H]^{+} = 202}$ , $\mathrm{Rt} = 1.04\mathrm{min}$ .Step 3: tert- butyl 6- (2- (tosyloxy)ethoxy)- 2- azaspiro[3.3]heptane- 2- carboxylateTo a solution of tert- butyl 6- (2- hydroxyethoxy)- 2- azaspiro[3.3]heptane- 2- carboxylate ( $350~\mathrm{mg}$ $1.36\mathrm{mmol}$ ) in THF (8 mL) were added KOH (381 mg, 6.80 mmol) and TsCl (454 mg, 2.38 mmol) at 0 $^\circ \mathrm{C}$ . The reaction was then warmed to RT and stirred for $1\mathrm{h}$ . The mixture was quenched with ice- water (5 mL) and extracted with EtOAc ( $30~\mathrm{mL}\times 3$ ). The combined organic layers were dried over $\mathrm{Na\_2SO\_4}$ and concentrated in vacuo. The residue was purified by silica gel flash chromatography (eluent 1:5 EtOAc / PE) to give the title compound ( $400\mathrm{mg}$ $64\%$ yield) as a colorless oil. LCMS (Method D) MS (ESI) [M $t\mathrm{Bu + H}]^{+} = 356$ $\mathrm{Rt} = 1.46\mathrm{min}$Step 4: 2- {2- azaspiro[3.3]heptan- 6- yloxy}ethyl 4- methylbenzenesulfonatetert- Butyl 6- (2- {[4- methylbenzene)sulfonylloxy}ethoxy)- 2- azaspiro[3.3]heptane- 2- carboxylate (800 mg, 1.94 mmol) in DCM / TFA (10 / 1, 10 mL) was stirred under RT of 2 h. The solvent was removed in vacuo to give the title compound (600 mg, 89% yield) as a colorless oil, which was used directly in the next step without further purification. LCMS (Method D) MS (ESI) $\mathrm{[M + H]^{+} = 312}$ , $\mathrm{Rt} = 0.80\mathrm{min}$ .Step 5: benzyl N- [6- (2- {[4- methylbenzene)sulfonylloxy}ethoxy)- 2- azaspiro[3.3]heptane- 2- sulfonyl]carbamate20Under $\mathbf{N}\_2$ , to a solution of benzyl alcohol (248 mg, 2.30 mmol) in DCM (6 mL) was added [(chlorosulfonyl)imino]methanone (295 mg, 2.09 mmol) at $0^\circ \mathrm{C}$ . The reaction mixture was stirred at $0^\circ \mathrm{C}$ for $30\mathrm{min}$ and then 2- {2- azaspiro[3.3]heptan- 6- yloxy}ethyl 4- methylbenzenesulfonate ( $650\mathrm{mg}$ , 2.09 mmol) and $\mathrm{Et\_3N}$ $465~\mathrm{mg}$ $4.59\mathrm{mmol}$ ) were added. The reaction mixture was stirred at RT for $1\mathrm{h}$ . The mixture was quenched with MeOH ( $10~\mathrm{mL}$ ) and concentrated in vacuo. The residue was purified by silica gel flash chromatography (eluent 10:1 DCM / MeOH) to give the title compound ( $700\mathrm{mg}$ $58\%$ yield) as a colorless oil. LCMS (Method D) MS (ESI) $\mathrm{[M + H]^{+} = 525}$ $\mathrm{Rt} = 1.39\mathrm{min}$Step 6: benzyl N- {6- [2- (dimethylamino)ethoxy]- 2- azaspiro[3.3]heptane- 2- sulfonyl}carbamateA mixture of benzyl N- [6- (2- {[4- methylbenzene)sulfonyl]oxy}ethoxy)- 2- azaspiro[3.3]heptane- 2- sulfonyl]carbamate (200 mg, 0.38 mmol) in dimethylamine (2M in THF, 2 mL) was stirred at $60^{\circ}\mathrm{C}$ for 4 h. The solvent was removed in vacuo. The residue was purified by silica gel flash chromatography (eluent 10:1 DCM / MeOH) to afford the title compound (50 mg, 26% yield) as a white solid. LCMS (Method D) MS (ES+) $\mathrm{[M + H]^+ = 398}$ , $\mathrm{Rt} = 0.80$ min.Step 7: 6- [2- (dimethylamino)ethoxy]- 2- azaspiro[3.3]heptane- 2- sulfonamideUnder $\mathrm{H}\_{2}$ , a mixture of benzyl N- [6- [2- (dimethylamino)ethoxy]- 2- azaspiro[3.3]heptane- 2- sulfonyl}carbamate (50 mg, 0.13 mmol) and $\mathrm{Pd / C}$ (10 mg) in THF (1 mL) was stirred at RT for 2 h. The mixture was filtered through celite and concentrated in vacuo to give the title compound (20 mg, 54% yield) as a colorless oil. LCMS (Method I) MS (ESI) $\mathrm{[M + H]^+ = 264}$ , $\mathrm{Rt} = 0.97$ min.4.5.19. Example 19. Preparation of 4- ((1- (2- methoxyethyl)piperidin- 4- yl)oxy)benzenesulfonamide (Example Procedure C)Step 1: 4- hydroxy- N,N- bis(2- methoxy- 5- methylphenyl)benzenesulfonamideUnder $\mathbf{N}\_2$ , to a mixture of bisl(4- methoxyphenyl)methyl]amine $(72\mathrm{g},0.28\mathrm{mol})$ and 4- hydroxybenzenesulfonyl chloride $(49\mathrm{g},0.25\mathrm{mol})$ in $\mathrm{CHCl}\_3$ $450~\mathrm{mL}$ was added pyridine ( $150~\mathrm{mL}$ dropwise at $0^\circ \mathrm{C}$ . The reaction mixture was then stirred at RT for $12\mathrm{h}$ . The solvent was removed in vacuo. The residue was purified by silica gel flash chromatography (gradient $0 - 5\%$ DCM / MeOH) to give the title compound ( $30\mathrm{g},29\%$ yield) as a white solid. LCMS (Method D) MS (ESI) $\mathrm{[M + Na]}^+ = 436$ $\mathrm{Rt} =$ $1.32\mathrm{min}$Step 2: tert- butyl 4- (4- (N,N- bis(4- methoxybenzyl)sulfamoyl)phenoxy)piperidine- 1- carboxylateUnder $\mathbf{N}\_2$ , to a solution of 4- hydroxy- N,N- bis(2- methoxy- 5- methylphenyl)benzenesulfonamide $(10\mathrm{g},0.024\mathrm{mol})$ , tert- butyl 4- hydroxypiperidine- 1- carboxylate $(6.33\mathrm{g},0.031\mathrm{mol})$ and $\mathrm{PPh}\_3$ $17.77\mathrm{g},$ $0.068\mathrm{mol})$ in toluene $(10~\mathrm{mL})$ was added DIAD $(14.68\mathrm{g},0.073\mathrm{mol})$ at $0^\circ \mathrm{C}$ . The reaction solution was stirred for $12\mathrm{h}$ at $80^{\circ}\mathrm{C}$ . The solvent was removed under vacuum. The residue was purified by silica gel flash chromatography (gradient $0 - 7\%$ MeOH / DCM) to give the title compound ( $12\mathrm{g}$ $76\%$ yield) as a white solid. LCMS (Method D) MS (ESI) $\mathrm{[M + Na]^{+} = 619}$ $\mathrm{Rt} = 1.70\mathrm{min}$10 (Note: for some examples, boc- protection was not used and Mitsonobu chemistry with tertiary amino alcohols was conducted directly.)Step 3: N,N- bis(4- methoxybenzyl)- 4- (piperidin- 4- yloxy)benzenesulfonamideA mixture of tert- butyl 4- (4- (N,N- bis(4- methoxybenzyl)sulfamoyl)phenoxy)piperidine- 1-15 carboxylate $(12\mathrm{g},0.020\mathrm{mol})$ and LiBr $(24.44\mathrm{g},0.28\mathrm{mol})$ in MeCN $120~\mathrm{mL}$ was stirred at $95~^\circ \mathrm{C}$ for 16 h. The reaction was filtered, and the filtrate was concentrated in vacuo. The residue was purified by silica gel flash chromatography (eluent 20:1 DCM / MeOH) to give the title compound $(8.0\mathrm{g},70\%$ yield) as a white solid. LCMS (Method D) MS (ESI) $\mathrm{[M + H]^{+} = 497}$ $\mathrm{Rt} = 1.05\mathrm{min}$Step 4: N,N- bis(4- methoxybenzyl)- 4- ((1- (2- methoxyethyl)piperidin- 4- yl)oxy)benzenesulfonamideA mixture of N,N- bis(2- methoxy- 5- methylphenyl)- 4- (piperidin- 4- yloxy)benzenesulfonamide (300 mg, 0.60 mmol), 1- bromo- 2- methoxyethane (168 mg, 1.20 mmol) and $\mathrm{K}\_2\mathrm{CO}\_3$ (167 mg, 1.20 mmol) in MeCN (8 mL) was stirred at $80^{\circ}\mathrm{C}$ for $16\mathrm{h}$ . The reaction was filtered, and the filtrate was concentrated under vacuum. The residue was purified by silica gel flash chromatography (eluent 10:1 DCM / MeOH) to give the title compound (300 mg, 72% yield) as a yellow oil. LCMS (Method D) MS (ESI) $\mathrm{[M + H]^{+} = 555}$ $\mathrm{Rt} = 1.09\mathrm{min}$ . (Note: in some examples, reductive amination chemistry was used instead of amine alkylation.)Step 5: 4- ((1- (2- methoxyethyl)piperidin- 4- yl)oxy)benzenesulfonamideA mixture of $N,N$ - bis(4- methoxybenzyl)- 4- ((1- (2- methoxyethyl)piperidin- 4- yl)oxy)benzenesulfonamide (300 mg, 0.54 mmol) in DCM (4 mL) and TFA (2 mL) was stirred at RT for 16 h. The reaction mixture was concentrated in vacuo and freeze- dried to give the title compound (200 mg, 94% yield) as a yellow oil. LCMS (Method D) MS (ESI) $\mathrm{[M + H]^{+} = 315}$ , $\mathrm{Rt} = 0.45$ min.# 4.5.20. Example 20. Preparation of 6-((1-methylpiperidin-4-yl)oxy)pyridazine-3-sulfonamide (Example Procedure D)Step 1: 3- bromo- 6- ((1- methylpiperidin- 4- yl)oxy)pyridazine10A mixture of 1- methylpiperidin- 4- ol (536 mg, 4.65 mmol) and NaH (60%, 414 mg, 10.3 mmol) in THF (15 mL) was stirred at $20^{\circ}\mathrm{C}$ for 1 h. Then, 3- bromo- 6- chloropyridazine (1.00 g, 5.17 mmol) was added. The resulting solution was stirred for 15 h at $20^{\circ}\mathrm{C}$ . The reaction mixture was quenched with MeOH (1.5 mL) and then evaporated. The residue was purified by flash chromatography (eluent 40:1 DCM / MeOH) to give the title compound (1.00 g, 71% yield) as a white solid. LCMS (Method D) MS (ESI) $\mathrm{[M + H]^{+} = 272}$ , $\mathrm{Rt} = 0.30$ min.Step 2: 3- (benzylthio)- 6- ((1- methylpiperidin- 4- yl)oxy)pyridazineTo a solution of 3- bromo- 6- ((1- methylpiperidin- 4- yl)oxy)pyridazine (500 mg, 2.19 mmol), phenylmethanethiol (409 mg, 3.29 mmol) and DIPEA (568 mg, 4.39 mmol) in 1,4- dioxane (5 mL) was added Pd2(dba)3 (201 mg, 0.220 mmol) and Xantphos (191 mg, 0.329 mmol). The resulting solution was stirred at $110^{\circ}\mathrm{C}$ for 4 h under N2. The solution was removed under reduced pressure. The residue was purified by flash chromatography (eluent 40:1 DCM / MeOH) to give the title compound (600 mg, 87% yield) as a yellow solid. LCMS (Method D) MS (ESI) $\mathrm{[M + H]^{+} = 316}$ , $\mathrm{Rt} = 0.88$ minStep 3: 6- ((1- methylpiperidin- 4- yl)oxy)pyridazine- 3- sulfonamideTo a solution of 3- (benzylthio)- 6- ((1- methylpiperidin- 4- yl)oxy)pyridazine (600 mg, 1.90 mmol) in AcOH (12 mL) and H2O (3 mL) was added NCS (1.02 g, 7.61 mmol) slowly at $0^\circ \mathrm{C}$ . The reaction mixture was stirred at $0^\circ \mathrm{C}$ for $1 \mathrm{h}$ . Aforesaid reaction solution was added dropwise a solution of NH3- $\mathrm{H}\_2\mathrm{O}$ [28% w / w, (20 mL)]. The resulting solution was stirred at $0^\circ \mathrm{C}$ for $30 \mathrm{min}$ . The reaction was concentrated in vacuo to dryness. The residue was purified by flash chromatography (eluent 20:1 DCM / MeOH) to give the title compound (180 mg, 35% yield) as a yellow solid. LCMS (Method D) MS (ESI) $[\mathrm{M} + \mathrm{H}]^+ = 273$ , $\mathrm{Rt} = 0.20 \mathrm{min}$ .# 4.5.21. Example 21. Preparation of 6-[(1-isopropylpiperidin-4-yl)oxy]pyridine-3-sulfonamide (Example Procedure E)Step 1: 6- [(1- isopropylpiperidin- 4- yl)oxy]pyridine- 3- sulfonamideTo a solution of 6- chloropyridine- 3- sulfonamide (150 mg, 0.78 mmol) in THF (8 mL) was added 1- isopropylpiperidin- 4- ol (167 mg, 1.17 mmol) and NaH (74.8 mg, 3.11 mmol). The reaction mixture was irradiated in a microwave reactor at $100^\circ \mathrm{C}$ for $2.5 \mathrm{h}$ . The mixture was quenched with $\mathrm{NH}\_4\mathrm{Cl}$ aq. (0.1 mL), and the solvent was concentrated in vacuo. The residue was purified by silica gel flash chromatography (gradient 0- 50% MeOH / DCM) to give the title compound (100 mg, 38% yield) as a yellow solid. LCMS (Method E) MS (ESI) $[\mathrm{M} + \mathrm{H}]^+ = 300$ , $\mathrm{Rt} = 0.20 \mathrm{min}$ . (Note: in some examples, $\mathrm{SNAr}$ chemistry was performed with an amine nucleophile instead of an alcohol, using triethylamine as base instead of $\mathrm{NaH}$ .)# 4.5.22. Example 22. Preparation of 5-((1-methylpiperidin-4-yl)amino)pyridine-2-sulfonamide (Example Procedure F)Step 1: 5- bromo- $N\_{\bullet}N\_{\bullet}$ - bis(4- methoxybenzyl)pyridine- 2- sulfonamideTo a solution of bis(4- methoxybenzyl)amine (2.99 g, 0.012 mol) and triethylamine (1.76 g, 0.017 mol) in DCM (20 mL) was added 5- bromopyridine- 2- sulfonyl chloride (1.5 g, 0.0058 mol). The resultingsolution was stirred at $20^{\circ}\mathrm{C}$ for $2\mathrm{h}$ . The reaction mixture was washed with saturated aq. $\mathrm{NH\_4Cl}$ (50 mL), dried over anhydrous $\mathrm{Na\_2SO\_4}$ , filtered and the solvent was removed in vacuo. The residue was purified by silica gel flash chromatography (eluent 100:1 DCM / MeOH) to give the title compound (2.1 g, 76% yield) as a white solid. LCMS (Method D) MS (ESI) $\mathrm{[M + H]^+ = 477}$ , $\mathrm{Rt} = 1.56\mathrm{min}$ .Step 2: $N,N$ - bis(4- methoxybenzyl)- 5- ((1- methylpiperidin- 4- yl)amino)pyridine- 2- sulfonamideTo a solution of 5- bromo- N,N- bis(4- methoxybenzyl)pyridine- 2- sulfonamide (500 mg, 1.05 mmol) and 1- methylpiperidin- 4- amine (179.40 mg, 1.57 mmol) in Tol (5 mL) was added $\mathrm{Pd\_2(dba)\_3}$ (192 mg, 0.21 mmol), Xphos (200 mg, 0.42 mmol) and $\mathrm{Cs\_2CO\_3}$ (1.02 g, 3.14 mmol). The resulting solution was stirred at $100^{\circ}\mathrm{C}$ for $6\mathrm{h}$ under $\mathrm{N}\_2$ . The solvent was removed in vacuo. The residue was purified by silica gel flash chromatography (eluent 30:1 DCM / MeOH) to give the title compound (180 mg, 34% yield) as a white solid. LCMS (Method D) MS (ESI) $\mathrm{[M + H]^+ = 511}$ , $\mathrm{Rt} = 1.00\mathrm{min}$ . (Note: in some examples, alcohols were used as coupling partners instead of amines; BINAP and NaOtBu used.)Step 3: 5- ((1- methylpiperidin- 4- yl)amino)pyridine- 2- sulfonamideTo a solution of $N,N$ - bis(4- methoxybenzyl)- 5- ((1- methylpiperidin- 4- yl)amino)pyridine- 2- sulfonamide (160 mg, 0.31 mmol) in DCM (2 mL) was added TFA (2 mL) at $20^{\circ}\mathrm{C}$ . The resulting solution was stirred at $50^{\circ}\mathrm{C}$ for $2\mathrm{h}$ . The solvent was removed in vacuo to give the title compound (200 mg, 100% yield) as a yellow solid. LCMS (Method D) MS (ESI) $\mathrm{[M + H]^+ = 271}$ , $\mathrm{Rt} = 0.27\mathrm{min}$ .4.5.23. Example 23. Preparation of 4- {[1- (2- methoxyethyl)piperidin- 4- yl|oxy}piperidine- 1- sulfonamide (Example Procedure G)Step 1: tert- butyl 4- {[1- (2- methoxyethyl)piperidin- 4- yl|oxy}piperidine- 1- carboxylateA mixture of tert- butyl 4- (piperidin- 4- yloxy)piperidine- 1- carboxylate (500 mg, 1.76 mmol), $\mathrm{K\_2CO\_3}$ (729 mg, 5.27 mmol), KI (29 mg, 0.18 mmol) and 1- bromo- 2- methoxyethane (367 mg, 2.64mmol) in MeCN (5 mL) was stirred at $80^{\circ}\mathrm{C}$ for $5\mathrm{~h}$ . The reaction mixture was concentrated in vacuo. The residue was purified by silica gel flash chromatography (eluent 1:1 EtOAc / PE) to give the title compound (500 mg, 75% yield) as a yellow solid. LCMS (Method E) MS (ESI) $\mathrm{[M + H]^{+} = 343}$ , $\mathrm{Rt} = 0.74\mathrm{~min}$ . (Note: in some examples, the first step requires O- alkylation of 1- Boc- 4- hydroxypiperidine or reductive amination of 1- Boc- piperidine- 4- carboxaldehyde.)Step 2: 1- (2- methoxyethyl)- 4- (piperidin- 4- yloxy)piperidinetert- butyl 4- {[1- (2- methoxyethyl)piperidin- 4- ylloxy}piperidine- 1- carboxylate (500 mg, 1.46 mmol) in DCM / TFA (10 / 1, 5 mL) was stirred at RT for $4\mathrm{~h}$ . The reaction mixture was concentrated in vacuo and lyophilized to afford the title compound (300 mg, 76% yield) as a yellow solid. LCMS (Method D) MS (ESI) $\mathrm{[M + H]^{+} = 243}$ , $\mathrm{Rt} = 0.19\mathrm{~min}$ .Step 3: tert- butyl N- (4- {[1- (2- methoxyethyl)piperidin- 4- ylloxy}piperidine- 1- sulfonyl)carbamateTo a solution of 1- (2- methoxyethyl)- 4- (piperidin- 4- yloxy)piperidine (200 mg, 0.83 mmol) and triethylamine (167 mg, 1.65 mmol) in dry DCM (2 mL) was added [(tert- butoxy)carbonyl][4- (dimethyliminio)pyridine- 1- sulfonyl]azanide (249 mg, 0.83 mmol) at $0^{\circ}\mathrm{C}$ and the reaction was then stirred at RT for $2\mathrm{~h}$ . The final mixture was concentrated in vacuo. The residue was purified by silica gel flash chromatography (eluent 100:1 DCM / MeOH) to give the title compound (200 mg, 52% yield) as a yellow oil. LCMS (Method D) MS (ESI) $\mathrm{[M + H]^{+} = 422}$ , $\mathrm{Rt} = 0.80\mathrm{~min}$ .Step 4: 4- {[1- (2- methoxyethyl)piperidin- 4- ylloxy}piperidine- 1- sulfonamideTert- Butyl N- {6- [(1- methylpiperidin- 4- yl)oxy]- 2- azaspiro[3.3]heptane- 2- sulfonyl}carbamate (200 mg, 0.51 mmol) in DCM / TFA (10 / 1, 3 mL) was stirred under RT for $4\mathrm{~h}$ . The final mixture was concentrated in vacuo and lyophilized to afford the title compound (120 mg, 65% yield) as a yellow oil. LCMS (Method D) MS (ESI) $\mathrm{[M + H]^{+} = 322}$ , $\mathrm{Rt} = 0.31\mathrm{~min}$ .# 4.5.24. Example 24. Preparation of benzyl N-(4-{[1-(cyclopropylmethyl)piperidin-4- yl|oxy}piperidine-1-sulfonyl)carbamate (Example Procedure H)Step 1: tert- butyl 4- ((1- (N- ((benzyloxy)carbonyl)sulfamoyl)piperidin- 4- yl)oxy)piperidine- 1- carboxylate5Under $\mathbf{N}\_2$ , to a solution of [(chlorosulfonyl)imino]methanone $(29.9\mathrm{g},0.21\mathrm{mol})$ in DCM (300 mL) was added benzyl alcohol $(25.1\mathrm{g},0.23\mathrm{mol})$ at $0^\circ \mathrm{C}$ . The mixture was stirred at $0^\circ \mathrm{C}$ for $0.5\mathrm{h}$ . tertButyl 4- (piperidin- 4- yloxy)piperidine- 1- carboxylate $(60.0\mathrm{g},0.21\mathrm{mol})$ and triethylamine $(47.0\mathrm{g},$ $0.46\mathrm{mol}$ ) were added slowly. The reaction mixture was then warmed to RT and stirred for $16\mathrm{h}$ . The mixture was quenched with MeOH ( $30~\mathrm{mL}$ . The solvent was removed in vacuo. The residue was purified by silica gel flash chromatography (gradient $0 - 10\%$ MeOH / DCM) to give the title compound (66 g, $57\%$ yield) as a colorless oil. ${}^{1}\mathrm{H}$ NMR (400 MHz, $\mathbf{CDCl}\_3$ , ppm) 8 7.38- 7.34 (m, 5 H), 5.18 (s, 2 H), 3.79- 3.66 (m, 2 H), 3.63- 3.49 (m, 4 H), 3.33- 3.23 (m, 2 H), 3.15- 3.07 (m, 2 H), 1.86- 1.63 (m, 6 H), 1.52- 1.42 (m, 11 H). (Note: in some examples, the following two steps were not required when this reaction was performed N- alkylated piperazines: no boc- protection required.)Step 2: benzyl (4- (piperidin- 4- yloxy)piperidin- 1- yl)sulfonyl)carbamate4- {[1- ({[(benzyloxy)carbonyl]amino}sulfonyl)piperidin- 4- yl|oxy}piperidine- 1- carboxylate $(66.0\mathrm{g},0.10\mathrm{mol})$ in DCM / TFA $(10 / 1,572\mathrm{mL})$ was stirred at RT for $4\mathrm{h}$ . The solvent was concentrated in vacuo to give the title compound ( $66.0\mathrm{g},$ TFA salt) as a colorless oil. LCMS (Method G) MS (ESI) $\mathrm{[M + H]^{+} = 398}$ $\mathrm{Rt} = 1.03\mathrm{min}$Step 3: benzyl N- (4- {[1- (cyclopropylmethyl)piperidin- 4- yl|oxy}piperidine- 1- sulfonyl)carbamate25 To a solution of benzyl $N$ - [4- (piperidin- 4- yloxy)piperidine- 1- sulfonyl]carbamate (120 mg, 0.30 mmol) in 2,2,2- trifluoroethanol (3 mL) was added cyclopropanecarboaldehyde (169 mg, 2.41 mmol) and $\mathrm{NaBH\_4}$ (46 mg, 1.21 mmol). The reaction mixture was stirred at $78^\circ \mathrm{C}$ for $3\mathrm{h}$ . The mixture wasquenched with $\mathrm{H}\_2\mathrm{O}$ (20 mL) and extracted with EtOAc (20 mL x 3). The combined organic layers were dried over $\mathrm{Na\_2SO\_4}$ and concentrated in vacuo. The residue was purified by silica gel flash chromatography (gradient 0- 70% EtOAc / PE) to give the title compound (120 mg, 70% yield) as a yellow oil. LCMS (Method E) MS (ESI) $\mathrm{[M + H]^+ = 452}$ , $\mathrm{Rt} = 1.03$ min. (Note: in some examples, $\mathrm{NaBH\_3CN}$ is used as the reductant.)Step 4: 4- {[1- (cyclopropylmethyl)piperidin- 4- yl]oxy}piperidine- 1- sulfonamideUnder $\mathrm{H}\_2$ , a mixture of benzyl $N$ - (4- {[1- (cyclopropylmethyl)piperidin- 4- yl]oxy}piperidine- 1- sulfonyl)carbamate (200 mg, 0.44 mmol) and $\mathrm{Pd / C}$ (20 mg) in THF (2 mL) was stirred at RT for 12 h. The final mixture was filtered. The filtrate was concentrated in vacuo to give the title compound (120 mg, 68% yield) as a white solid. LCMS (Method E) MS (ESI) $\mathrm{[M + H]^+ = 318}$ , $\mathrm{Rt} = 0.47$ min.# 4.5.25. Example 25. Preparation of 1-(dimethylamino)-2-methylpropane-2-sulfonamide (Example Procedure I)Step 1: methyl 2- (N,N- bis(4- methoxybenzyl)sulfamoyl)acetate15To a solution of bis(4- methoxybenzyl)amine (3.57 g, 13.9 mmol) in $\mathrm{CHCl}\_3$ - pyridine (v:v = 2:1, 45 mL) was added methyl 2- (chlorosulfonyl)acetate (2.0 g, 11.58 mmol) dropwise at $0^\circ \mathrm{C}$ under an atmosphere of $\mathrm{N}\_2$ . The resulting solution was slowly warmed to room temperature and stirred for 16 h. The final mixture was quenched with saturated aqueous $\mathrm{NH\_4Cl}$ solution (50 mL) and extracted with EtOAc (50 mL x 3). The combined organic phases were washed with $\mathrm{H}\_2\mathrm{O}$ (20 mL) and brine (20 mL), dried over $\mathrm{Na\_2SO\_4}$ , concentrated in vacuo. The residue was purified by silica gel flash chromatography (gradient 0- 30% DCM / PE) to provide the title compound (1.50 g, 33% yield) as a pale yellow solid. LCMS (Method I) MS (ESI) $\mathrm{[M + H + H\_2O]^+ = 411}$ , $\mathrm{Rt} = 1.70$ min.Step 2: methyl 2- (N,N- bis(4- methoxybenzyl)sulfamoyl)- 2- methylpropanoateTo a solution of methyl 2- (N,N- bis(4- methoxybenzyl)sulfamoyl)acetate (1.50 g, 3.81 mmol) in dry DMF (20 mL) was added NaH (0.38 g, 9.52 mmol) portionwise at $0^\circ \mathrm{C}$ under an atmosphere of argon. After addition, the solution was stirred at $0^\circ \mathrm{C}$ for 30 min. Then, MeI (0.59 mL, 9.52 mmol) was addeddropwise. The resulting solution was slowly warmed to RT and stirred for $2\mathrm{h}$ . The reaction mixture was quenched with saturated aqueous $\mathrm{NH\_4Cl}$ solution $(50~\mathrm{mL})$ and extracted with EtOAc $(35~\mathrm{mL} \times 4)$ . The combined organic phases were washed with $\mathrm{H}\_2\mathrm{O}$ $(10~\mathrm{mL})$ and brine $(10~\mathrm{mL})$ , dried over $\mathrm{Na\_2SO\_4}$ , concentrated in vacuo. The residue was purified by silica gel flash chromatography (gradient $0 - 20\%$ EtOAc / PE) to give the title compound $(1.10\mathrm{g}, 68\%$ yield) as a white solid. LCMS (Method D) MS (ESI) $[\mathrm{M} + \mathrm{Na}]^{+} = 444$ , $\mathrm{Rt} = 1.49\mathrm{min}$ .Step 3: 2- (N,N- bis(4- methoxybenzyl)sulfamoyl)- 2- methylpropanoic acidTo a solution of methyl 2- (N,N- bis(4- methoxybenzyl)sulfamoyl)- 2- methylpropanoate $(1.0\mathrm{g}, 2.37$ mmol) in $\mathrm{MeOH / H\_2O}$ $(\mathrm{v / v} = 5 / 1, 10~\mathrm{mL})$ was added $\mathrm{LiOH - H\_2O}$ $(113.52\mathrm{mg}, 4.74\mathrm{mmol})$ . The mixture was stirred at room temperature for $16\mathrm{h}$ . The solvent was removed in vacuo. The aqueous solution was adjusted to $\mathrm{pH}2 - 3$ with $2\mathrm{N}$ HCl and extracted with EtOAc $(20~\mathrm{mL} \times 2)$ . The combined organic phases were washed with brine $(10~\mathrm{mL})$ , dried over $\mathrm{Na\_2SO\_4}$ , concentrated in vacuo to give the title compound $(750\mathrm{mg}$ , crude) as a yellow oil, which was used directly in the next step without further purification. LCMS (Method D) MS (ESI) $[\mathrm{M} + \mathrm{Na}]^{+} = 430$ , $\mathrm{Rt} = 1.32\mathrm{min}$ .Step 4: 2- (N,N- bis(4- methoxybenzyl)sulfamoyl)- N,N,2- trimethylpropanamideUnder $\mathrm{N}\_2$ , to a solution of 2- (N,N- bis(4- methoxybenzyl)sulfamoyl)- 2- methylpropanoic acid $(750\mathrm{mg}, 1.85\mathrm{mmol})$ in MeCN $(8\mathrm{mL})$ was added TCFH $(780\mathrm{mg}, 2.78\mathrm{mmol})$ , NMI $(0.44\mathrm{mL}$ , $5.55\mathrm{mmol})$ and dimethylamine $(167\mathrm{mg}, 3.7\mathrm{mmol})$ in sequence. The mixture was stirred for $2\mathrm{h}$ at RT. The reaction mixture was diluted with aq. $\mathrm{NaCl}$ $(10~\mathrm{mL})$ and extracted with EtOAc $(8\mathrm{mL} \times 4)$ . The combined organic phases were concentrated in vacuo. The residue was purified by silica gel flash chromatography (gradient $0 - 4\%$ MeOH / DCM) to give the title compound $(560\mathrm{mg}, 70\%$ yield) as an off white solid. LCMS (Method D) MS (ESI) $[\mathrm{M} + \mathrm{Na}]^{+} = 435.2$ , $\mathrm{Rt} = 1.41\mathrm{min}$ .Step 5: 1- (dimethylamino)- N,N- bis(4- methoxybenzyl)- 2- methylpropane- 2- sulfonamideTo a solution of 2- (N,N- bis(4- methoxybenzyl)sulfamoyl)- N,N,2- trimethylpropanamide $(560\mathrm{mg}, 1.29\mathrm{mmol})$ in THF $(5\mathrm{mL})$ was added dropwise 1M borane- THF complex $(6.45\mathrm{mL}, 6.45\mathrm{mmol})$ underice cooling over $3\mathrm{min}$ . The mixture was stirred at RT for $5\mathrm{h}$ . The reaction mixture was quenched with $0.5\mathrm{N}$ aqueous $\mathrm{NaOH}$ solution at $0^\circ \mathrm{C}$ , stirred for 30 minutes and extracted with EtOAc $(20\mathrm{mL}\times 4)$ . The organic layers were combined, washed with brine $(10\mathrm{mL})$ , dried over anhydrous $\mathrm{Na\_2SO\_4}$ , and concentrated in vacuo. The residue was purified by silica gel flash chromatography (gradient $0 - 2\%$ MeOH / DCM) to give the title compound $(300\mathrm{mg},55\%$ yield) as a white solid. LCMS (Method D) MS (ESI) $[\mathrm{M + H}]^{+} = 421$ , $\mathrm{Rt} = 0.94\mathrm{min}$ .# Step 6: 1-(dimethylamino)-2-methylpropane-2-sulfonamideTo a solution of 1- (dimethylamino)- N,N- bis(4- methoxybenzyl)- 2- methylpropane- 2- sulfonamide $(300\mathrm{mg},0.71\mathrm{mmol})$ in DCM $(3\mathrm{mL})$ was added dropwise TFA $(3\mathrm{mL})$ and TfOH (1- 2 drops). The mixture was stirred RT for $5\mathrm{min}$ and concentrated in vacuo to give the title compound $(200\mathrm{mg}$ , crude) as a yellow oil, which was used directly in next step without further purification. LCMS (Method D) MS (ESI) $[\mathrm{M + H}]^{+} = 181$ , $\mathrm{Rt} = 0.19\mathrm{min}$ .# 4.5.26. Example 26. Preparation of 4-(2-hydroxy-2-methylpropyl)piperazine-1-sulfonamide and 4-(2-fluoro-2-methylpropyl)piperazine-1-sulfonamide (Example Procedure J)Step 1: 2- methyl- 1- (piperazin- 1- yl)propan- 2- olUnder $\mathbf{N}\_2$ , a mixture of piperazine ( $31.8\mathrm{g}$ , 369 mmol) and 1- chloro- 2- methylpropan- 2- ol ( $10.0\mathrm{g}$ $92.0\mathrm{mmol}$ ) in EtOH ( $200\mathrm{mL}$ ) was stirred at $110^{\circ}\mathrm{C}$ for $\mathrm{6h}$ . The reaction mixture was concentrated in vacuum. The residue was purified by silica gel flash chromatography (eluent: MeOH / DCM: $0 - 20\%$ with $0.5\% \mathrm{NH\_4OH})$ to give the title compound ( $13.0\mathrm{g}$ $90\%$ purity, $22\%$ yield) as a yellow oil. ${}^{1}\mathrm{H}$ NMR (400 MHz, $\mathrm{CDCl}\_3$ ppm) 8 2.87- 2.81 (m, 4 H), 2.58- 2.53 (m, 4 H), 2.25 (s, 2 H), 1.11 (s, 6 H).Step 2: benzyl ((4- (2- hydroxy- 2- methylpropyl)piperazin- 1- yl)sulfonyl)carbamateUnder $\mathbf{N}\_2$ , to a solution of 2- methyl- 1- (piperazin- 1- yl)propan- 2- ol (12.6 g, 79.6 mmol) in DCM $(200\mathrm{mL})$ was added ((benzyloxy)carbonyl)(4- (dimethyliminio)pyridin- 1(4H)- yl)sulfonyl)amide $(26.7\mathrm{g},$ $79.6\mathrm{mmol}$ ) and $\mathrm{NEt}\_3$ $(20.1\mathrm{g},199\mathrm{mmol})$ at RT. The mixture was stirred for $1\mathrm{h}$ at RT. The reaction mixture was concentrated in vacuum. The residue was purified by C18 chromatography (eluent:MeCN / water (+0.1% HCOOH: 0- 50%) to give the title compound (15 g, 90% purity, 46% yield) as a white solid. LCMS (Method K) MS (ESI) $\mathrm{[M + H]^{+} = 371.95}$ , $\mathrm{Rt} = 0.74$ min. ${}^{1}\mathrm{H}$ NMR (400 MHz, DMSO- $d\_{6}$ , ppm) $\delta$ 8.14 (s, 1 H), 7.42- 7.29 (m, 5 H), 5.10 (s, 2 H), 3.22- 3.10 (m, 4 H), 2.65- 2.54 (m, 4 H), 2.25 (s, 2 H), 1.08 (s, 6 H).Step 3a: 4- (2- hydroxy- 2- methylpropyl)piperazine- 1- sulfonamideUnder $\mathrm{H}\_{2}$ , a mixture of benzyl ((4- (2- hydroxy- 2- methylpropyl)piperazin- 1- yl)sulfonyl)carbamate (3.00 g, 8.07 mmol) and Pd / C (0.7 g, 10% wt) in MeOH (30 mL) was stirred for 16 h at RT. The solids were filtered and the filtrate was concentrated in vacuum to give the title compound (1.8 g, 80% purity, 75% yield) as a light yellow solid. LCMS (Method E) MS (ESI) $\mathrm{[M + H]^{+} = 238.2}$ , $\mathrm{Rt} = 0.88$ min. ${}^{1}\mathrm{H}$ NMR (400 MHz, DMSO- $d\_{6}$ , ppm) $\delta$ 6.72 (s, 2 H), 4.14 (s, 1 H), 2.95- 2.90 (m, 4 H), 2.61- 2.56 (m, 4 H), 2.21 (s, 2 H), 1.08 (s, 6 H).Step 3b: ((4- (2- fluoro- 2- methylpropyl)piperazin- 1- yl)sulfonyl)carbamateUnder $\mathbf{N}\_2$ , to a solution of benzyl ((4- (2- hydroxy- 2- methylpropyl)piperazin- 1- yl)sulfonyl)carbamate $(9.55\mathrm{g},25.7\mathrm{mmol})$ in DCM $200~\mathrm{mL}$ ) was added DAST $(4.14\mathrm{g},25.7\mathrm{mmol})$ at $0^\circ \mathrm{C}$ . The mixture was stirred for 1 hours at RT. The reaction mixture was quenched by water and concentrated in vacuum. The residue was purified by silica gel flash chromatography (eluent: MeOH / DCM: $0 - 10\%$ to give the title compound ( $5.0\mathrm{g}$ $90\%$ purity, $47\%$ yield) as a yellow oil. LCMS (Method E) MS (ESI) $\mathrm{[M + H]^{+} = 374.3}$ $\mathrm{Rt} = 1.02$ min. ${}^{1}\mathrm{H}$ NMR (400 MHz, $\mathrm{CDCl}\_3$ ppm) 8 7.39- 7.35 (m, 5 H), 5.18 (s, 2 H), 3.40- 3.35 (m, 4 H), 2.64- 2.57 (m, 4 H), 2.49- 2.39 (m, 2 H), 1.38 (s, 3H), 1.32 (s, 3 H).Step 4: 4- (2- fluoro- 2- methylpropyl)piperazine- 1- sulfonamideUnder $\mathrm{H}\_{2}$ , a mixture of benzyl ((4- (2- fluoro- 2- methylpropyl)piperazin- 1- yl)sulfonyl)carbamate $(4.6\mathrm{g},12.3\mathrm{mmol})$ and $\mathrm{Pd / C}$ $(0.65\mathrm{g},10\% \mathrm{wt})$ in MeOH $(60~\mathrm{mL})$ was stirred for $16\mathrm{h}$ at RT. The reaction was filtered and the filtrate was concentrated in vacuum. The residue was freeze- dried to give the title compound $(2.85\mathrm{g},80\%$ purity, $77\%$ yield) as a light- yellow solid. LCMS (Method F) MS (ESI) $\mathrm{[M + H]^{+}}$ $= 239.9$ $\mathrm{Rt} = 0.20\mathrm{min}$ ${}^{1}\mathrm{H}$ NMR (400 MHz, DMSO- $d\_{6},$ ppm) 8 6.74 (s, 2 H), 2.98- 2.90 (m, 4 H), 2.62- 2.51 (m, 4 H), 2.49- 2.42 (m, 2 H), 1.33 (s, 3 H), 1.28 (s, 3 H).4.5.27. Example 27. Preparation of $(R)$ - 4- (1- (5- (cyclopropylmethoxy)pyridin- 2- yl)propoxy)- $N$ - ((6- (2- (dimethylamino)ethoxy)- 2- azaspiro [3.3]heptan- 2- yl)sulfonyl)- 2,3- difluorobenzamide (Coupling example procedure A)10To a solution of 4- [(1R)- 1- [5- (cyclopropylmethoxy)pyridin- 2- yl]propoxy]- 2,3- difluorobenzoic acid (Acid C, $20\mathrm{mg}$ $0.06\mathrm{mmol}$ ) in DCM (1 mL) were added CMPI (29 mg, 0.11 mmol) and DMAP (2 mg, $0.02\mathrm{mmol}$ ) at RT. The mixture was stirred at RT for $20\mathrm{min}$ and then 6- [2- (dimethylamino)ethoxy]- 2- azaspiro[3.3]heptane- 2- sulfonamide (example procedure B, $17\mathrm{mg}$ $0.07\mathrm{mmol}$ ) and $\mathrm{NEt}\_3$ (17 mg, 0.17 mmol) were added. The reaction mixture was stirred at RT for $1\mathrm{h}$ . The solvent was removed in vacuo. The residue was purified by Prep- HPLC (method A, gradient: $30 - 80\%$ ) to give the title compound (2.1 mg, $95\%$ purity, $>99\%$ ee, $60\%$ yield) as a white solid. LCMS (Method F) MS (ESI) $\mathrm{[M + H]^{+} = 609.3}$ Rt $= 0.97\mathrm{min}$ ${}^{1}\mathrm{H}$ NMR (400 MHz, DMSO- $d\_{6}$ ppm) 8 8.24 (s, 1 H), 7.43- 7.26 (m, 3 H), 6.73 (t, $J = 8.2\mathrm{Hz}$ $1\mathrm{H}$ 5.30 (t, $J = 6.4\mathrm{Hz}$ 1 H), 3.86 (d, $J = 7.1\mathrm{Hz}$ 3 H), 3.69- 3.55 (m, 4 H), 3.51- 3.42 (m, 2 H), 3.00- 2.89 (m, 2 H), 2.58 (s, 6 H), 2.37- 2.35 (m, 2 H), 2.08- 1.87 (m, 4 H), 1.22- 1.15 (m, 2 H), 0.91 (t, $J = 7.3\mathrm{Hz}$ 3 H), 0.62- 0.52 (m, 2 H), 0.35- 0.27 (m, 2 H).4.5.28. Example 28. Preparation of $(R)$ - N- ((1- (dimethylamino)- 2- methylpropan- 2- yl)sulfonyl)- 2,3- difluoro- 4- (1- (5- (pyridin- 2- yloxy)pyridin- 2- yl)propoxy)benzamide (Coupling example procedure B)25To a solution of $(R)$ - 2,3- difluoro- 4- (1- (5- (pyridin- 2- yloxy)pyridin- 2- yl)propoxy)benzoic acid (Acid E, $25\mathrm{mg}$ $0.064\mathrm{mmol}$ ) in dry DMF $(2\mathrm{mL})$ was added CMPI $(32.7\mathrm{mg},0.128\mathrm{mmol})$ and DMAP $(3.9\mathrm{mg},0.032\mathrm{mmol})$ . After addition, the solution was stirred at $25^{\circ}\mathrm{C}$ for $30\mathrm{min}$ . Then, 1- (dimethylamino)- 2- methylpropane- 2- sulfonamide (example procedure I, $23.1\mathrm{mg},0.128\mathrm{mmol}$ ) and $\mathrm{NEt}\_3$ $(0.031\mathrm{mL},0.224\mathrm{mmol})$ were added. The mixture was stirred at room temperature for $5\mathrm{h}$ . Thereaction mixture was diluted with NaCl aqueous (5 mL) and extracted with EtOAc (10 mL x 4). The combined organic phases were concentrated in vacuum. The residue was purified by Prep- HPLC (method B, gradient: 30- 50%) to give the title compound (4.2 mg, 99.4% purity, >99% ee, 11.9% yield) as a white solid. LCMS (Method D) MS (ESI) $\mathrm{[M + H]^+ = 549.1}$ , $\mathrm{Rt} = 1.11$ min. ${}^{1}\mathrm{H}$ NMR (400 MHz, DMSO- d6, ppm) $\delta$ 10.12 (s, 1 H), 8.45 (d, $J = 2.6 \mathrm{Hz}$ , 1 H), 8.15- 8.13 (m, 1 H), 7.92- 7.87 (m, 1 H), 7.66- 7.63 (m, 1 H), 7.51- 7.45 (m, 2 H), 7.18- 7.12 (m, 2 H), 6.89 (t, $J = 8.4 \mathrm{Hz}$ , 1 H), 5.45 (t, $J = 6.3 \mathrm{Hz}$ , 1 H), 3.36 (s, 2 H), 2.86 (s, 6 H), 2.08- 2.00 (m, 2 H), 1.34 (s, 6 H), 0.96 (t, $J = 7.3 \mathrm{Hz}$ , 3 H).4.5.29. Example 29. Preparation of 4- (1- (3- (cyclopropylmethoxy)phenyl)ethoxy)- N- ((1- (2- (dimethylamino)ethyl)- 1H- pyrazol- 4- yl)sulfonyl)- 2,3- difluorobenzamide (Coupling example procedure C)To a solution of 8- [(1- (3- propoxyphenyl)ethoxy]imidazo[1,2- a]pyridine- 5- carboxylic acid (Acid B, 463 mg, 1.33 mmol) and EDCI (255 mg, 1.33 mmol) in DCM (2 mL) were added 2- methylpropane- 2- sulfonamide (example procedure D, 145 mg, 0.66 mmol) and DMAP (162 mg, 1.33 mmol). The reaction mixture was stirred at RT for 18 h. The solvent was removed in vacuo and the residue was purified by Prep- HPLC (method A, gradient: 30- 35- 45%) to give the title compound (12.1 mg, 95.2% purity, 3.1% yield) as a white solid. LCMS (Method D) MS (ESI) $\mathrm{[M + H]^+ = 549.2}$ , $\mathrm{Rt} = 1.01$ min.# 4.5.30. Example 30. Preparation of Additional CompoundsThe compounds listed below in Table 4 were prepared according to the general approach shown above in Scheme 1. They synthesized by coupling carboxylic acids A- P with sulfonamides or sulfamides (commercially available [CAS; number provided at bottom of table] or synthesized according to example procedures A- J) using coupling conditions A- D. The compounds were purified using prep HPLC methods A- K (or alternative methods such as reverse phase C18 chromatography or prep TLC). NMR and LCMS data (methods A- D) are also provided. (Captions in the table are CA = Carboxylic Acid; CP = Coupling Partner; CC = Coupling Conditions.)TaaCnnnnnnnCnnnnnnn Cnnnnnnn Cnnnnnnn Cnnnnnnn Cnnnnn Cnnnnn Cnnnnn Cnnnnn Cnnnnn Cnnnnn Cnnnnn Cnnnnn Cnnnnn Cnnnnn Cnnnnn Cnnnnn Cnnnnn Cnnnnn Cnnnnn Cnnnnn Cnnnnn Cnnnnn Cnnnnn Cnnnnn Cnnnnn Cnnnnn Cnnnnn Cnnnnn CnnnnnPronnnnnnnn| | | | | | | || --- | --- | --- | --- | --- | --- | --- || Compound Name | CA | CP | CC | Purification (Gradient) | LCMS | NMR || 4-(1-(3-cyclopropylmethoxy)phenyl)-ethoxy-N-(1-(2-(dimethylamino)ethyl)-1H- pyrazol-4-yl)isulfonyl)-2,3-difluorobenzamidate | B | D | C | Method A (30-35-45) | n / z=549.2 [M+H]+, Rt= 1.01 mins (Method D) | 1H NMR (400 MHz, DMSO-d6, ppm) δ 8.14 (d, J = 5.1 Hz, 1H), 7.69 (s, 1H), 7.34 (t, J = 8.5 Hz, 1H), 7.23 (t, J = 8.1 Hz, 1H), 6.93 (d, J = 6.7 Hz, 2.16 (s, 8.1 Hz, 1H), 8.1 Hz, 1H), 7.35 (t, J = 6.4 Hz, 1H), 7.35 (t, J = 8.1 Hz, 1H), 7.35 (t, J = 8.1 Hz, 1H), 7.35 (t, J = 8.1 Hz, 1H), 7.35 (t, J = 8.1 Hz, 1H), 7.35 (t, J = 8.1 Hz, 1H), 7.35 (t, J = 8.2 Hz, 1H), 7.35 (t, J = 8.2 Hz, 1H), 7.35 (t, J = 8.2 Hz, 1H), 7.35 (t, J = 8.2 Hz, 1H), 7.35 (t, J = 8.2 Hz, 1H), 7.35 (t, J = 8.1 Hz, 1H), 7.35 (t, J = 8.1 Hz, 1H), 7.35 (t, J = 8.1 Hz, 1H), 7.35 (t, J = 8.1 Hz, 1H), 7.35 (t, J = 8.0 Hz, 1H), 7.35 (t, J = 8.0 Hz, 1H), 7.35 (t, J = 8.0 Hz, 1H), 7.35 (t, J = 8.0 Hz, 1H), 7.35 (t, J = 8.0 Hz, 1H), 7.35 (t, J = 8.1 Hz, 1H), 7.35 (t, J = 8.1 Hz, 1H), 7.35 (t, J = 8.1 Hz, 1H), 7.35 (t, J = 8.1 Hz, 1H), 7.35 (t, J = 8.4 Hz, 1H), 7.35 (t, J = 8.4 Hz, 1H), 7.35 (t, J = 8.4 Hz, 1H), 7.35 (t, J = 8.4 Hz, 1H), 7.35 (t, J = 8.4 Hz, 1H), 7.35 (t, J = 8.5 Hz, 1H), 7.35 (t, J = 8.5 Hz, 1H), 7.35 (t, J = 8.5 Hz, 1H), 7.35 (t, J = 8.5 Hz, 1H), 7.35 (t, J = 8.5 Hz, 1H), 7.35 (t, J = 8.6 Hz, 1H), 7.35 (t, J = 8.6 Hz, 1H), 7.35 (t, J = 8.6 Hz, 1H), 7.35 (t, J = 8.6 Hz, 1H), 7.35 (t, J = 8.6 Hz, 1H), 7.35 (t, J = 8.7 Hz, 1H), 7.35 (t, J = 8.7 Hz, 1H), 7.35 (t, J = 8.7 Hz, 1H), 7.35 (t, J = 8.7 Hz, 1H), 7.35 (t, J = 8.7 Hz, 1H), 7.35 (t, J = 8.8 Hz, 1H), 7.35 (t, J = 8.8 Hz, 1H), 7.35 (t, J = 8.8 Hz, 1H), 7.35 (t, J = 8.8 Hz, 1H), 7.35 (t, J = 8.8 Hz, 1H), 7.35 (t, J = 8.9 Hz, 1H), 7.35 (t, J = 8.9 Hz, 1H), 7.35 (t, J = 8.9 Hz, 1H), 7.35 (t, J = 8.9 Hz, 1H), 7.35 (t, J = 8.9 Hz, 1H), 7.35 (t, J = 8.1 Hz, 1H), 7.35 (t, J = 8.1 Hz, 1H), 7.35 (t, J = 8.1 Hz, 1H), 7.35 (t, J = 8.1 Hz, 1H), 7.35 (t, J = 8.3 Hz, 1H), 7.35 (t, J = 8.3 Hz, 1H), 7.35 (t, J = 8.3 Hz, 1H), 7.35 (t, J = 8.3 Hz, 1H), 7.35 (t, J = 8.3 Hz, 1H), 7.35 (t, J = 8.4 Hz, 1H), 7.35 (t, J = 8.4 Hz, 1H), 7.35 (t, J = 8.4 Hz, 1H), 7.35 (t, J = 8.4 Hz, 1H), 7.35 (t, J = 8.6 Hz, 1H), 7.35 (t, J = 8.6 Hz, 1H), 7.35 (t, J = 8.6 Hz, 1H), 7.35 (t, J = 8.6 Hz, 1H), 7.35 (t, J = 8.8 Hz, 1H), 7.35 (t, J = 8.8 Hz, 1H), 7.35 (t, J = 8.8 Hz, 1H), 7.35 (t, J = 8.8 Hz, 1H), 7.35 (t, J = 8.6 Hz, 1H), 7.35 (t, J = 8.6 Hz, 1H), 7.35 (t, J = 8.6 Hz, 1H), 7.35 (t, J = 8.6 Hz, 1H), 7.35 (t, J = 8.5 Hz, 1H), 7.35 (t, J = 8.5 Hz, 1H), 7.35 (t, J = 8.5 Hz, 1H), 7.35 (t, J = 8.5 Hz, 1H), 7.35 (t, J = 8.4 Hz, 1H), 7.35 (t, J = 8.4 Hz, 1H), 7.35 (t, J = 8.4 Hz, 1H), 7.35 (t, J = 8.4 Hz, 1H), 7.35 (t, J = 8.2 Hz, 1H), 7.35 (t, J = 8.2 Hz, 1H), 7.35 (t, J = 8.2 Hz, 1H), 7.35 (t, J = 8.2 Hz, 1H), 7.35 (t, J = 8.0 Hz, 1H), 7.35 (t, J = 8.0 Hz, 1H), 7.35 (t, J = 8.0 Hz, 1H), 7.35 (t, J = 8.0 Hz, 1H), 7.35 (t, J = 8.2 Hz, 1H), 7.35 (t, J = 8.2 Hz, 1H), 7.35 (t, J = 8.2 Hz, 1H), 7.35 (t, J = 8.2 Hz, 1H), 7.35 (t, J = 8.4 Hz, 1H), 7.35 (t, J = 8.4 Hz, 1H), 7.35 (t, J = 8.4 Hz, 1H), 7.35 (t, J = 8.4 Hz, 1H), 7.35 (t, J = 8.0 Hz, 1H), 7.35 (t, J = 8.0 Hz, 1H), 7.35 (t, J = 8.0 Hz, 1H), 7.35 (t, J = 8.0 Hz, 1H), 7.35 (t, J = 8.4 Hz, 1H), 7.35 (t, J = 8.4 Hz, 1H), 7.35 (t, J = 8.4 Hz, 1H), 7.35 (t, J = 8.4 Hz, 1H), 7.35 (t, J = 8.3 Hz, 1H), 7.35 (t, J = 8.3 Hz, 1H), 7.35 (t, J = 8.3 Hz, 1H), 7.35 (t, J = 8.3 Hz, 1H), 7.35 (t, J = 8.0 Hz, 1H), 7.35 (t, J = 8.0 Hz, 1H), 7.35 (t, J = 8.0 Hz, 1H), 7.35 (t, J = 8.0 Hz, 1H), 7.35 (t, J = 8.5 Hz, 1H), 7.35 (t, J = 8.5 Hz, 1H), 7.35 (t, J = 8.5 Hz, 1H), 7.35 (t, J = 8.5 Hz, 1H), 7.35 (t, J = 8.0 Hz, 1H), 7.35 (t, J = 8.0 Hz, 1H), 7.35 (t, J = 8.0 Hz, 1H), 7.35 (t, J = 8.0 Hz, 1H), 7.35 (t, J = 8.8 Hz, 1H), 7.35 (t, J = 8.8 Hz, 1H), 7.35 (t, J = 8.8 Hz, 1H), 7.35 (t, J = 8.8 Hz, 1H), 7.35 (t, J = 8.0 Hz, 1H), 7.35 (t, J = 8.0 Hz, 1H), 7.35 (t, J = 8.0 Hz, 1H), 7.35 (t, J = 8.0 Hz, 1H), 7.35 (t, J = 8.6 Hz, 1H), 7.35 (t, J = 8.6 Hz, 1H), 7.35 (t, J = 8.6 Hz, 1H), 7.35 (t, J = 8.6 Hz, 1H), 7.35 (t, J = 8.0 Hz, 1H), 7.35 (t, J = 8.0 Hz, 1H), 7.35 (t, J = 8.0 Hz, 1H), 7.35 (t, J = 8.0 Hz, 1H), 7.35 (t, J = 8.7 Hz, 1H), 7.35 (t, J = 8.7 Hz, 1H), 7.35 (t, J = 8.7 Hz, 1H), 7.35 (t, J = 8.7 Hz, 1H), 7.35 (t, J = 8.6 Hz, 1H), 7.35 (t, J = 8.6 Hz, 1H), 7.35 (t, J = 8.6 Hz, 1H), 7.35 (t, J = 8.6 Hz, 1H), 7.35 (t, J = 8.4 Hz, 1H), 7.35 (t, J = 8.4 Hz, 1H), 7.35 (t, J = 8.4 Hz, 1H), 7.35 (t, J = 8.4 Hz, 1H), 7.35 (t, J = 8.1 Hz, 1H), 7.35 (t, J = 8.1 Hz, 1H), 7.35 (t, J = 8.1 Hz, 1H), 7.35 (t, J = 8.1 Hz, 1H), 7.35 (t, J = 7.3 Hz, 1H), 7.35 (t, J = 7.3 Hz, 1H), 7.35 (t, J = 7.3 Hz, 1H), 7.35 (t, J = 7.3 Hz, 1H), 7.35 (t, J = 7.3 Hz, 1H), 7.35 (t, J = 7.4 Hz, 1H), 7.35 (t, J = 7.4 Hz, 1H), 7.35 (t, J = 7.4 Hz, 1H), 7.35 (t, J = 7.4 Hz, 1H), 7.35 (t, J = 7.4 Hz, 1H), 7.35 (t, J = 7.5 Hz, 1H), 7.35 (t, J = 7.5 Hz, 1H), 7.35 (t, J = 7.5 Hz, 1H), 7.35 (t, J = 7.5 Hz, 1H), 7.35 (t, J = 7.5 Hz, 1H), 7.35 (t, J = 7.6 Hz, 1H), 7.35 (t, J = 7.6 Hz, 1H), 7.35 (t, J = 7.6 Hz, 1H), 7.35 (t, J = 7.6 Hz, 1H), 7.35 (t, J = 7.6 Hz, 1H), 7.35 (t, J = 7.7 Hz, 1H), 7.35 (t, J = 7.7 Hz, 1H), 7.35 (t, J = 7.7 Hz, 1H), 7.35 (t, J = 7.7 Hz, 1H), 7.35 (t, J = 7.7 Hz, 1H), 7.35 (t, J = 7.8 Hz, 1H), 7.35 (t, J = 7.8 Hz, 1H), 7.35 (t, J = 7.8 Hz, 1H), 7.35 (t, J = 7.8 Hz, 1H), 7.35 (t, J = 7.8 Hz, 1H), 7.35 (t, J = 7.9 Hz, 1H), 7.35 (t, J = 7.9 Hz, 1H), 7.35 (t, J = 7.9 Hz, 1H), 7.35 (t, J = 7.9 Hz, 1H), 7.35 (t, J = 7.9 Hz, 1H), 7.35 (t, J = 7.8 Hz, 1H), 7.35 (t, J = 7.8 Hz, 1H), 7.35 (t, J = 7.8 Hz, 1H), 7.35 (t, J = 7.8 Hz, 1H), 7.35 (t, J = 7.7 Hz, 1H), 7.35 (t, J = 7.7 Hz, 1H), 7.35 (t, J = 7.7 Hz, 1H), 7.35 (t, J = 7.7 Hz, 1H), 7.35 (t, J = 7.6 Hz, 1H), 7.35 (t, J = 7.6 Hz, 1H), 7.35 (t, J = 7.6 Hz, 1H), 7.35 (t, J = 7.6 Hz, 1H), 7.35 (t, J = 7.5 Hz, 1H), 7.35 (t, J = 7.5 Hz, 1H), 7.35 (t, J = 7.5 Hz, 1H), 7.35 (t, J = 7.5 Hz, 1H), 7.35 (t, J = 7.4 Hz, 1H), 7.35 (t, J = 7.4 Hz, 1H), 7.35 (t, J = 7.4 Hz, 1H), 7.35 (t, J = 7.4 Hz, 1H), 7.35 (t, J = 7.3 Hz, 1H), 7.35 (t, J = 7.3 Hz, 1H), 7.35 (t, J = 7.3 Hz, 1H), 7.35 (t, J = 7.3 Hz, 1H), 7.35 (t, J = 7.2 Hz, 1H), 7.35 (t, J = 7.2 Hz, 1H), 7.35 (t, J = 7.2 Hz, 1H), 7.35 (t, J = 7.2 Hz, 1H), 7.35 (t, J = 7.2 Hz, 1H), 7.35 (t, J = 7.1 Hz, 1H), 7.35 (t, J = 7.1 Hz, 1H), 7.35 (t, J = 7.1 Hz, 1H), 7.35 (t, J = 7.1 Hz, 1H), 7.35 (t, J = 7.1 Hz, 1H), 7.35 (t, J = 7.0 Hz, 1H), 7.35 (t, J = 7.0 Hz, 1H), 7.35 (t, J = 7.0 Hz, 1H), 7.35 (t, J = 7.0 Hz, 1H), 7.35 (t, J = 7.0 Hz, 1H), 7.35 (t, J = 7.1 Hz, 1H), 7.35 (t, J = 7.1 Hz, 1H), 7.35 (t, J = 7.1 Hz, 1H), 7.35 (t, J = 7.1 Hz, 1H), 7.35 (t, J = 7.2 Hz, 1H), 7.35 (t, J = 7.2 Hz, 1H), 7.35 (t, J = 7.2 Hz, 1H), 7.35 (t, J = 7.2 Hz, 1H), 7.35 (t, J = 7.3 Hz, 1H), 7.35 (t, J = 7.3 Hz, 1H), 7.35 (t, J = 7.3 Hz, 1H), 7.35 (t, J = 7.3 Hz, 1H), 7.35 (t, J = 7.5 Hz, 1H), 7.35 (t, J = 7.5 Hz, 1H), 7.35 (t, J = 7.5 Hz, 1H), 7.35 (t, J = 7.5 Hz, 1H), 7.35 (t, J = 7.7 Hz, 1H), 7.35 (t, J = 7.7 Hz, 1H), 7.35 (t, J = 7.7 Hz, 1H), 7.35 (t, J = 7.7 Hz, 1H), 7.35 (t, J = 7.9 Hz, 1H), 7.35 (t, J = 7.9 Hz, 1H), 7.35 (t, J = 7.9 Hz, 1H), 7.35 (t, J = 7.9 Hz, 1H), 7.35 (t, J = 7.7 Hz, 1H), 7.35 (t, J = 7.7 Hz, 1H), 7.35 (t, J = 7.7 Hz, 1H), 7.35 (t, J = 7.7 Hz, 1H), 7.35 (t, J = 7.5 Hz, 1H), 7.35 (t, J = 7.5 Hz, 1H), 7.35 (t, J = 7.5 Hz, 1H), 7.35 (t, J = 7.5 Hz, 1H), 7.35 (t, J = 7.2 Hz, 1H), 7.35 (t, J = 7.2 Hz, 1H), 7.35 (t, J = 7.2 Hz, 1H), 7.35 (t, J = 7.2 Hz, 1H), 7.35 (t, J = 7.0 Hz, 1H), 7.35 (t, J = 7.0 Hz, 1H), 7.35 (t, J = 7.0 Hz, 1H), 7.35 (t, J = 7.0 Hz, 1H), 7.35 (t, J = 7.2 Hz, 1H), 7.35 (t, J = 7.2 Hz, 1H), 7.35 (t, J = 7.2 Hz, 1H), 7.35 (t, J = 7.2 Hz, 1H), 7.35 (t, J = 7.4 Hz, 1H), 7.35 (t, J = 7.4 Hz, 1H), 7.35 (t, J = 7.4 Hz, 1H), 7.35 (t, J = 7.4 Hz, 1H), 7.35 (t, J = 7.2 Hz, 1H), 7.35 (t, J = 7.2 Hz, 1H), 7.35 (t, J = 7.2 Hz, 1H), 7.35 (t, J = 7.2 Hz, 1H), 7.35 (t, J = 7.5 Hz, 1H), 7.35 (t, J = 7.5 Hz, 1H), 7.35 (t, J = 7.5 Hz, 1H), 7.35 (t, J = 7.5 Hz, 1H), 7.35 (t, J = 7.0 Hz, 1H), 7.35 (t, J = 7.0 Hz, 1H), 7.35 (t, J = 7.0 Hz, 1H), 7.35 (t, J = 7.0 Hz, 1H), 7.35 (t, J = 7.5 Hz, 1H), 7.35 (t, J = 7.5 Hz, 1H), 7.35 (t, J = 7.5 Hz, 1H), 7.35 (t, J = 7.5 Hz, 1H), 7.35 (t, J = 7.3 Hz, 1H), 7.35 (t, J = 7.3 Hz, 1H), 7.35 (t, J = 7.3 Hz, 1H), 7.35 (t, J = 7.3 Hz, 1H), 7.35 (t, J = 7.0 Hz, 1H), 7.35 (t, J = 7.0 Hz, 1H), 7.35 (t, J = 7.0 Hz, 1H), 7.35 (t, J = 7.0 Hz, 1H), 7.35 (t, J = 7. || | | | | | | || --- | --- | --- | --- | --- | --- | --- || R)-4-(1-(5-cyclopropylmethoxy)pyridin-2-yl)propoxy)-2,3-difluoro-N-(4-(2-(3-hydroxy)phenyl)benzamide (pyrrolidin-1-yl)ethoxy)phenyl)benzamide (pyrrolidin-1-yl) | C | A | C | Method C (35-40) | m / z=616.2 [M+H]+, Rt=1.30 mins (Method E) | H NMR (400 MHz, DMSO-d6, ppm) δ 9.65 (s, 1H), 8.23 (d, J = 2.0 Hz, 1.1H), 7.75 (d, J = 8.8 Hz, 2.12 Hz, 7.40-7.22 (m, 3.1H), 6.98 (d, J = 8.8 Hz, 2.12 Hz, 6.76-6.67 (m, 2.12 Hz, 1.1H), 3.22-2.80 (m, 4.1H), 2.09-1.73 (m, 6.1H), 1.28-1.13 (m, 1.1H), 0.89 (t, J = 7.3 Hz, 3.1H), 0.65-0.45 (m, 2.12 Hz, 1.1H), 0.45-0.20 (m, 2.12 Hz, 1.1H), 0.45-0.20 (m, 2.12 Hz, 1.1H), 0.45-0.20 (m, 2.12 Hz, 1.1H), || 4-(R)-1-(5-cyclopropylmethoxy)pyridin-2-yl)propoxy)-2,3-difluoro-N-(4-(2-(3-hydroxy)phenyl)benzamide (pyrrolidin-1-yl)ethoxy)phenyl)benzamide (pyrrolidin-1-yl) | C | A | C | Method G (45-55) | m / z=634.2 [M+H]+, Rt=1.32 mins (Method E) | H NMR (400 MHz, DMSO-d6, ppm) δ 8.23 (d, J = 2.22 Hz, 1.1H), 7.73 (d, J = 8.7 Hz, 2.12 Hz, 1.1H), 3.55-3.15 (m, 2.12 Hz, 1.1H), 4.26-4.06 (m, 2.12 Hz, 1.1H), 3.30-3.06 (m, 2.12 Hz, 1.1H), 2.01-1.94 (m, 2.12 Hz, 1.1H), 2.30-2.06 (m, 2.12 Hz, 1.1H), 0.59-0.53 (m, 2.12 Hz, 1.1H), 0.34-0.28 (m, 2.12 Hz, 1.1H), 0.59-0.53 (m, 2.12 Hz, 1.1H), 0.34-0.28 (m, 2.12 Hz, 1.1H), 0.59-0.53 (m, 2.12 Hz, 1.1H), 0.34, 0.28 (m, 2.12 Hz, 1.1H), 0.59-0.53 (m, 2.12 Hz, 1.1H), 0.34, 0.28 (m, 2.12 Hz, 1.1H), 0.59-0.53 (m, 2.12 Hz, 1.1H), || R)-4-(1-(5-cyclopropylmethoxy)pyridin-2-yl)propoxy)-2,3-difluoro-N-(4-(2-(3-hydroxy)phenyl)benzamide (pyrrolidin-1-yl)ethoxy)phenyl)benzamide (pyrrolidin-1-yl) | C | A | C | Method A (20-70) | m / z=609.3 [M+H]+, Rt=1.08 mins (Method D) | H NMR (400 MHz, DMSO-d6, ppm) δ 8.24 (s, 1H), 7.45-7.26 (m, 3.1H), 3.68-3.71 (m, 1.1H), 3.53-3.42 (m, 1.1H), 3.41-3.35 (m, 1.1H), 1.1H), 0.62-0.71 (m, 1.1H), 1.1H), 0.62-0.71 (m, 1.1H), 1.1H), 0.62-0.72 (m, 1.1H), 1.1H), 0.62-0.73 (m, 1.1H), 1.1H), 0.62-0.74 (m, 1.1H), 1.1H), 0.62-0.75 (m, 1.1H), 1.1H), 0.62-0.76 (m, 1.1H), 1.1H), 0.62-0.77 (m, 1.1H), 1.1H), 0.62-0.78 (m, 1.1H), 1.1H), 0.62-0.79 (m, 1.1H), 1.1H), 0.62-0.79 (m, 1.1H), 1.1H), 0.62-0.70 (m, 1.1H), 1.1H), 0.62-0.71 (m, 1.1H), 1.1H), 0.62-0.72 (m, 1.1H), 1.1H), 0.62-0.73 (m, 1.1H), 1.1H), 0.62-0.75 (m, 1.1H), 1.1H), 0.62-0.76 (m, 1.1H), 1.1H), 0.62-0.77 (m, 1.1H), 1.1H), 0.62-0.79 (m, 1.1H), 1.1H), 0.62-0.70 (m, 1.1H), 1.1H), 0.62-0.71 (m, 1.1H), 1.1H), 0.62-0.71 (m, 1.1H), 1.1H), 0.62-0.72 (m, 1.1H), 1.1H), 0.62-0.79 (m, 1.1H), 1.1H), 0.62-0.70 (m, 1.1H), 1.1H), 0.62-0.71 (m, 1.1H), 1.1H), 0.62-0.79 (m, 1.1H), 1.1H), 0.62-0.70 (m, 1.1H), 1.1H), 0.62-0.71 (m, 1.1H), 1.1H), 0.62-0.70 (m, 1.1H), 1.1H), 0.62-0.71 (m, 1.1H), 1.1H), 0.62-0.71 (m, 1.1H), 1.1H), 0.62-0.71 (m, 1.1H), 1.1H), 0.62-0.70 (m, 1.1H), 1.1H), 0.62-0.71 (m, 1.1H), 1.1H), 0.62-0.70 (m, 1.1H), 1.1H), 0.62-0.70 (m, 1.1H), 1.1H), 0.62-0.71 (m, 1.1H), 1.1H), 0.62-0.71 (m, 1.1H), 1.1H), 0.62-0.70 (m, 1.1H), 1.1H), 0.62-0.70 (m, 1.1H), 1.1H), 0.62-0.70 (m, 1.1H), 1.1H), 0.62-0.70 (m, 1.1H), 1.1H), 0.62-0.71 (m, 1.1H), 1.1H), 0.62-0.70 (m, 1.1H), 1.1H), 0.62-0.72 (m, 1.1H), 1.1H), 0.62-0.72 (m, 1.1H), 1.1H), 0.62-0.72 (m, 1.1H), 1.1H), 0.62-0.71 (m, 1.1H), 1.1H), 0.62-0.71 (m, 1.1H), 1.1H), 0.62-0.71 (m, 1.1H), 1.1H), 0.62-0.79 (m, 1.1H), 1.1H), 0.62-0.79 (m, 1.1H), 1.1H), 0.62-0.79 (m, 1.1H), 1.1H), 0.62-0.71 (m, 1.1H), 1.1H), 0.62-0.71 (m, 1.1H), 1.1H), 0.62-0.71 (m, 1.1H), 1.1H), 0.62-0.75 (m, 1.1H), 1.1H), 0.62-0.75 (m, 1.1H), 1.1H), 0.62-0.75 (m, 1.1H), 1.1H), 0.62-0.71 (m, 1.1H), 1.1H), 0.62-0.71 (m, 1.1H), 1.1H), 0.62-0.71 (m, 1.1H), 1.1H), 0.62-0. || | | | | | | || --- | --- | --- | --- | --- | --- | --- || 4-(R)-1-(5-cyclopropylmethoxy)pyridin-2-yl)propoxy)-2,3-difluoro-N-(4-(2-(3-hydroxy)phenyl)benzamide (pyrrolidin-1-yl)ethoxy)phenyl)benzamide (pyrrolidin-1-yl) | C | A | B | Method D (20-70) | m / z=602.1 [M+H]+, Rt=1.01 mins (Method E) | H NMR (400 MHz, DMSO-d6, ppm) δ 8.24 (s, 1H), 7.30 (s, 1H), 7.30 (s, 1H), 6.22 (s, 1H), 5.20-5.12 (m, 1.1H), 1.1H), 0.62-0.71 (m, 1.1H), 1.1H), 0.62-0.71 (m, 1.1H), 1.1H), 0.62-0.71 (m, 1.1H), 1.1H), 0.62-0.67 (m, 1.1H), 1.1H), 0.62-0.71 (m, 1.1H), 1.1H), 0.62-0.71 (m, 1.1H), 1.1H), 0.62-0.72 (m, 1.1H), 1.1H), 0.62-0.71 (m, 1.1H), 1.1H), 0.62-0.72 (m, 1.1H), 1.1H), 0.62-0.73 (m, 1.1H), 1.1H), 0.62-0.73 (m, 1.1H), 1.1H), 0.62-0.74 (m, 1.1H), 1.1H), 0.62-0.75 (m, 1.1H), 1.1H), 0.62-0.75 (m, 1.1H), 1.1H), 0.62-0.76 (m, 1.1H), 1.1H), 0.62-0.77 (m, 1.1H), 1.1H), 0.62-0.77 (m, 1.1H), 1.1H), 0.62-0.78 (m, 1.1H), 1.1H), 0.62-0.79 (m, 1.1H), 1.1H), 0.62-0.71 (m, 1.1H), 1.1H), 0.62-0.71 (m, 1.1H), 1.1H), 0.62-0.72 (m, 1.1H), 1.1H), 0.62-0.75 (m, 1.1H), 1.1H), 0.62-0.76 (m, 1.1H), 1.1H), 0.62-0.77 (m, 1.1H), 1.1H), 0.62-0.71 (m, 1.1H), 1.1H), 0.62-0.71 (m, 1.1H), 1.1H), 0.62-0.71 (m, 1.1H), 1.1H), 0.62-0.76 (m, 1.1H), 1.1H), 0.62-0.71 (m, 1.1H), 1.1H), 0.62-0.71 (m, 1.1H), 1.1H), 0.62-0.71 (m, 1.1H), 1.1H), 0.62-0.77 (m, 1.1H), 1.1H), 0.62-0.71 (m, 1.1H), 1.1H), 0.62-0.71 (m, 1.1H), 1.1H), 0.62-0.72 (m, 1.1H), 1.1H), 0.62-0.81 (m, 1.1H), 1.1H), 0.62-0.71 (m, 1.1H), 1.1H), 0.62-0.71 (m, 1.1H), 1.1H), 0.62-0.71 (m, 1.1H), 1.1H), 0.62-0.81 (m, 1.1H), 1.1H), 0.62-0.71 (m, 1.1H), 1.1H), 0.62-0.71 (m, 1.1H), 1.1H), 0.62-0.72 (m, 1.1H), 1.1H), 0.62-0.82 (m, 1.1H), 1.1H), 0.62-0.71 (m, 1.1H), 1.1H), 0.62-0.71 (m, 1.1H), 1.1H), 0.62-0.71 (m, 1.1H), 1.1H), 0.62-0.82 (m, 1.1H), 1.1H), 0.62-0.71 (m, 1.1H), 1.1H), 0.62-0.71 (m, 1.1H), 1.1H), 0.62-0.72 (m, 1.1H), 1.1H), 0.62-0.7 || | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | || --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- || (R)-4-(1-(5-cyclopropylmethoxy)pyridin-2-yl)propoxy)-N-(4-(1-(1-ethylpiperidin-4-yl)oxy)phenyl)isofloryl)-2,3- (d-1-yl)phenyl)isofloryl)-2,3- (d-1-yl)phenyl)isofloryl)-2,3- (d-1-yl)phenyl)isofloryl)-2,3- (d-1-yl)phenyl)isofloryl)-2,3- (d-1-yl)phenyl)isofloryl)-2,3- (d-1-ethyl)phenyl)isofloryl)-2,3- (d-1-ethyl)phenyl)isofloryl)-2,3- (d-1-ethyl)phenyl)isofloryl)-2,3- (d-1-ethyl)phenyl)isofloryl)-2,3- (d-1-ethyl)phenyl)isofloryl)-2,3- (d-1-yl)phenyl)isofloryl)-2,3- (d-1-yl)phenyl)isofloryl)-2,3- (d-1-yl)phenyl)isofloryl)-2,3- (d-1-yl)phenyl)isofloryl)-2,3- (d-1- methyl)isofloryl)-2,3- (d-1-ethyl)phenyl)isofloryl)-2,3- (d-1-ethyl)phenyl)isofloryl)-2,3- (d-1-ethyl)phenyl)isofloryl)-2,3- (d-1-ethyl)phenyl)isofloryl)-2,3- (d-1-ethyl)phen)isofloryl)-2,3- (d-1-ethyl)phenyl)isofloryl)-2,3- (d-1-ethyl)phenyl)isofloryl)-2,3- (d-1-ethyl)phenyl)isofloryl)-2,3- (d-1-ethyl)phenyl)isofloryl)-2,3- (d-1-ethyl)phen)] | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | || (R)-4-(1-(5-cyclopropylmethoxy)pyridin-2-yl)propoxy)-2,3-difluoro-N-(4-(1-(1- methyl)azolidin-3- (d-1-yl)phenyl)isofloryl)-2,3- (d-1-yl)phenyl)isofloryl)-2,3- (d-1-ethyl)phenyl)isofloryl)-2,3- (d-1-ethyl)phenyl)isofloryl)-2,3- (d-1-ethyl)phenyl)isofloryl)-2, | C | C | C | Method D (40-85) | 1.13 mins (Method D) | 1.13 mins (Method D) | 1.13 mins (Method D) | 1.13 mins (Method D) | 1.13 mins (Method D) | 1.13 mins (Method D) | 1.13 mins (Method D) | 1.13 mins (Method D) | 1.13 mins (Method D) | HNR (400 MHz, DMSO-d6, ppm) 8.97 (0r, 1H), 8.23 (d, J=2.1Hz, 1H), 7.73 (d, J=8.6 Hz, 2.1H), 7.36 (m, 3.1H), 7.85 (d, J=7.1Hz, 1H), 6.12 (m, 3.0Hz, 1H), 4.85-4.55 (m, 1H), 3.85 (d, J=7.1Hz, 2.1H), 3.20 (2.91 (m, 5.1H), 3.85 (d, J=7.1Hz, 2.1H), 3.20 (2.91 (m, 5.1H), 3.85 (d, J=7.1Hz, 2.1H), 3.20 (2.91 (m, 5.1H), 3.85 (d, J=7.1Hz, 1H), 6.12 (m, 3.0Hz, 1H), 4.85-4.55 (m, 1H), 3.85 (d, J=7.1Hz, 1H), 6.12 (m, 3.0Hz, 1H), 4.85-4.55 (m, 1H), 3.85 (d, J=7.1Hz, 1H), 6.12 (m, 3.0Hz, 1H), 4.85 1.10 (m, 5.1H), 0.89 (d, J=7.4Hz, 3.1H), 0.58-0.52 (m, 2.1H), 0.33-0.26 (m, 2.1H) | 1H NMR (400 MHz, DMSO-d6, ppm) 8.24 (d, J=1.42 Hz, 1H), 7.83 (d, J=8.6 Hz, 2.1H), 7.36 (m, 3.1H), 7.85 (d, J=7.1Hz, 1H), 6.12 (m, 3.0Hz, 1H), 4.85-4.55 (m, 1H), 3.85 (d, J=7.1Hz 1H), 6.12 (m, 3.0Hz, 1H), 4.85-4.55 (m, 1H), 3.85 (d, J=7.1Hz, 1H), 6.12 (m, 3.0Hz, 1H), 4.85-4.55 (m, 1H), 3.85 (c, 1.0Hz, 1H), 6.12 (m, 3.0Hz, 1H), 4.85-4.55 (m, 1H), 3.85 (c, 1.0Hz, 1H), 6.12 (m, 3.0Hz, 1H), 4.85-4.55 (m, 1H), 3.85-4.55 (m, 1H), 3.85 (c, 1.0Hz, 1H), 6.12 (m, 3.0Hz, 1H), 4.85-4.55 (m, 1H), 3.85 (c, 1.0Hz, 1H), 6.12 (m, 3.0Hz 1H), 4.85-4.55 (m, 1H), 3.85 (c, 1.0Hz, 1H), 6.12 (m, 3.0Hz, 1H), 4.85-4.55 (m, 1H), 3.85 (c, 1.0Hz, 1H), 6.12 (m 1.10 (m, 5.1H), 0.89 (d, J=7.4Hz, 3.1H), 0.58-0.52 (m, 2.1H), 0.33-0.26 (m, 2.1H) | 1H NMR (400 MHz, DMSO-d6, ppm) 8.24, d, J=1.42 Hz, 1H), 7.83 (d, J=8.6 Hz, 2.1H), 7.36 (m, 3.1H), 7.85 (d, J=7.1Hz, 1H), 6.12 (m, 3.0Hz, 1H), 4.85-4.55 (m, 3.0Hz, 1H), 4.85-4.55 (m, 3.0Hz, 1H), 4.85-4.55 (m, 3.0Hz, 1H), 4.85-4.55 (m, 3.0Hz, 1H), 4.85-4.55 (m, 3.0H), 4.85-4.55 (m, 3.0Hz, 1H), 4.85-4.55 (m, 3.0Hz, 1H), 4.85-4.55 (m, 3.0Hz, 1H), 4.85-4.55 (m, 3.0Hz, 1H), 4.85 1.10 (m, 5.1H), 0.89 (d, J=7.4Hz, 3.1H), 0.58-0.52 (m, 2.1H), 0.33-0.26 (m, 2.1H) | 1H NMR (585.1 MHz, 1H), 7.43-7.28 (m, 3.1H), 7.23 (d, J=9.1Hz, 1H), 6.76 (d, J=7.9Hz, 1H), 5.54-5.36 (m, 1H), 5.32 (d, J=8.6Hz, 1H), 4.11-4.08 (m, 3.1H), 3.81 (d, J=7.1Hz, 1H), 3.30-3.08 (m, 4.1Hz, 1H), 2.05-1.91 (m, 3.0Hz, 1H), 2.05-1.91 (m, 3.0Hz, 1H), 2.05-1.91 (m, 3.0Hz, 1H), 2.05-1.91 (m, 3.0Hz, 1H), 2.05-1.91 (m, 3.0Hz, 1H), 1.10 (m, 5.1H), 0.89 (d, J=7.4Hz, 3.1H), 0.58-0.52 (m, 2.1H), 0.33-0.26 (m, 2.1H) | 1H NMR (400 MHz, DMSO-d6, ppm) 8.24 d, J=1.42 Hz, 1H), 7.43-7.28 (m, 3.1H), 7.23 (d, J=9.1Hz, 1H), 6.76 (d, J=7.9Hz, 1H), 5.54-5.36 (m, 1H), 5.32 (d, J=8.6Hz, 1H), 5.32 (d, J=8.6Hz, 1H), 5.32 (d, J=8.6Hz, 1H), 5.32 (d, J=8.6Hz, 1H), 5.32 (d, J=8.6Hz, 1H), 5.32 (d, J=8.6Hz, 1H) | 1H NMR (400 MHz, DMSO-d6, ppm) 8.24 d, J=1.42 Hz, 1H), 7.43-7.28 (m, 3.1H), 7.23 (d, J=9.1Hz, 1H), 6.76 (d, J=7.9Hz, 1H)), 5.54-5.36 (m, 1H), 5.32 (d, J=8.6Hz, 1H), 5.32 (d, J=8.6Hz, 1H), 5.32 (d, J=8.6Hz, 1H), 5.32 (d, J=8.6Hz, 1H), 5.32 (c, 1.0Hz, 1H), 6.12 (m, 3.0Hz, 1H), 4.85-4.55 (m, 1H), 3.85-4.55 (m, 1H), 3.85-4.55 (m, 1H), 3.85-4.55 (m, 1H), 3.85-4.55 (m, 1H), 3.85-4.55 (m, 1H), 3.85-4.55 (m, 1H) | 1H NMR (400 MHz, DMSO-d6, ppm) 8.24 d, J=1.42 Hz, 1H), 7.43-7.28 (m, 3.1H), 7.23 (d, J=9.1Hz, 1H), 6.76 (d, J=7.9Hz, 2.1H), 7.36 (m, 3.0Hz, 1H), 2.05-1.91 (m, 3.0Hz, 1H), 2.05-1.91 (m, 3.0Hz, 1H), 2.05-1.91 (m, 3.0Hz, 1H), 2.05-1.91 (m, 3.0H), 4.85-4.55 (m, 3.0Hz, 1H), 4.85-4.55 (m, 3.0Hz, 1H), 4.85-4.55 (m, 3.0Hz, 1H), 4.85-4.55 (m, 3.0Hz, 1 H), 4.85-4.55 (m, 3.0Hz, 1 H), 4.85-4.55 (m, 3.0Hz, 1 H), 4.85-4.55 (m, 3.0Hz, 1 H), 4.85-4.55 (m, 3.0Hz, 1 H), 4.85- | | | | | | | | | | | | | | |01515.050W01W02025 / 174957| | | | | | | | | | | || --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- || (R)-4-(1-(5-cyclopropylmethoxy)pyridin-2- yl)propoxy)-2,3-difluoro-N-(G-(1-(1-methylpiperidin-4-yl)amino)pyridin-3- yl)solulnyl)benzamide | C | E | B | Method A (25-70) | 1H NMR (400 MHz, DMSO-d6, 9.18 (br, 1H), 8.33 (s, 1H), 8.23 (s, 1H), 7.71 (d, J = 8.8 Hz, 1H), 7.36-7.24 (m, 3.1H), 7.07-6.94 (m, 1H), 6.72 (t, 8.30 (s, 1H), 4.05-3.92 (m, 1H), 3.86 (d, J = 7.1 Hz, 2.1H), 3.48-3.34 (m, 1H), 3.16-2.97 (m, 2H), 2.74 (s, 3.1H), 2.14-1.88 (m, 4H), 1.72-1.45 (m, 2H), 1.26-1.13 (m, 1H), 0.89 (t, 1.73 Hz, 4H), 0.60-0.49 (m, 2H), 0.34-0.25 (m, 2H) | m / z = 616.2 [Mr-H]+, Rt = 1.07 min (Method D) | m / z = 644.5 [Mr-H]+, Rt = 1.44 min (Method E) | m / z = 623.3 [Mr-H]+, Rt = 1.81 Hz, 1.1H, 3.65 (m, 1H), 3.69 (d, J = 7.1 Hz, 2.1H), 3.46 (m, 1H), 3.10 (s, 1H), 3.10 (s, 1H), 3.10 (s, 1H), 3.10 (s, 1H), 3.10 (s, 1H), 3.10 (s, 1H), 3.10 (s, 1H), 3.10 (s, 1H), 3.10 (s, 1 H), 3.10 (s, 1 H), 3.10 (s, 1 H), 3.10 (s, 1 H), 3.10 (s, 1 H), 3.10 (s, 1 H), 3.10 (s, 1 H), 3.10 (s, 1 H), 3.10 (s, 1 H), 3 10 (s, 1 H), 3.10 (s, 1 H), 3.10 (s, 1 H), 3.10 (s, 1 H), 3.10 (s, 1 H), 3.10 (s, 1 H), 3.10 (s, 1 H), 3.10 (s, 1 H), 3.10 (t, 1.1H), 3.10 (t, 1.1H), 3.10 (t, 1.1H), 3.10 (t, 1.1H), 3.10 (t, 1.1H), 3.10 (t, 1.1H), 3.10 (t, 1.1H), 3.10 (t, 1.1H), | m / z = 623.3 [Mr-H]+, Rt = 1.81 Hz, 1.1H, 3.65 (m, 1H), 3.69 (d, J = 7.1 Hz, 2.1H), 3.46 (m, 1H), 3.10 (s, 1H), 3.10 (s, 2.97 (m, 2H), 0.60-0.49 (m, 2H), 0.34-0.25 (m, 2H) | m / z = 623.3 [Mr-H]+, Rt = 1.81 Hz, 1.1H, 3.65 (m, 1H), 3.69 (d, J = 7.1 Hz, 2.1H), 3.46 (m, 1H), 3.10 (s, 1H), 3.10 (s, s, 1H), 3.10 (s, 1H), 3.10 (s, 1H), 3.10 (s, 1H), 3.10 (s, 1H), 3.10 (s, 1H), 3.10 (s, 1H), 3.10 (s, 1H), 3.10 (s, 11H), 3.10 (s, 11H), 3.10 (s, 11H), 3.10 (s, 11H), 3.10 (s, 11H), 3.10 (s, 11H), 3.10 (s, 11H), 3.10 (s, 11H), 3.10, 1.1H, 3.10 (s, 11H), 3.10 (s, 11H), 3.10 (s, 11H), 3.10 (s, 11H), 3.10 (s, 11H), 3.10 (s, 11H), 3.10 (s, 11H), 3.10 (s, s, 11H), 3.10 (s, 11H), 3.10 (s, 11H), 3.10 (s, 11H), 3.10 (s, 11H), 3.10 (s, 11H), 3.10 (s, 11H), 3.10 (s, 11H), 3 10 (s, 11H), 3.10 (s, 11H), 3.10 (s, 11H), 3.10 (s, 11H), 3.10 (s, 11H), 3.10 (s, 11H), 3.10 (s, 11H), 3.10 (s, 111H), 3.10 (s, 11H), 3.10 (s, 11H), 3.10 (s, 11H), 3.10 (s, 11H), 3.10 (s, 11H), 3.10 (s, 11H), 3.10 (s, 11H), 3.1 10 (s, 11H), 3.10 (s, 11H), 3.10 (s, 11H), 3.10 (s, 11H), 3.10 (s, 11H), 3.10 (s, 11H), 3.10 (s, 11H), 3.10 (s, 12H), 3.10 (s, 11H), 3.10 (s, 11H), 3.10 (s, 11H), 3.10 (s, 11H), 3.10 (s, 11H), 3.10 (s, 11H), 3.10 (s, 11H), 3.10 (t, 1.1H), 3.10 (s, 11H), 3.10 (s, 11H), 3.10 (s, 11H), 3.10 (s, 11H), 3.10 (s, 11H), 3.10 (s, 11H), 3.10 (s, 11H), 3.10 11H), 3.10 (s, 11H), 3.10 (s, 11H), 3.10 (s, 11H), 3.10 (s, 11H), 3.10 (s, 11H), 3.10 (s, 11H), 3.10 (s, 11H), 3. |01515.05W01| | | | | | | || --- | --- | --- | --- | --- | --- | --- || (R)-4-(1-(5-cyclopropylmethoxy)pyridin-2-yl)propoxy)-N-(4-(1-(2,2-difluorophenyl)percidin-4-yl)oxyphenyl)psulfonyl)-2,3-difluorobenzamide | C | C | B | Prep TLC (9:1 DCM: MeOH +0.5% NH3OH) | m / z = 666.5 [M+H]+, Rt = 7.38-7.32 (m, 2 H), 7.28-7.22 (m, 1 H), 7.13 (d, J = 8.9 H), 7.12 (d, J = 8.23 (s, 1 H), 7.83 (d, J = 8.9 H), 7.13 (d, J = 8.23 (s, 1 H), 7.83 (d, J = 8.23 (s, 1 H), 7.83 (d, J = 8.23 (s, 1 H), 7.83 (d, J = 8.23 (s, 1 H), 7.83 (d, J = 8.23 (s, 1 H), 7.83 (d, J = 8.23(100) | m / z = 618.3 [M+H]+, Rt = 7.26 (m, 4 H), 6.76 (J = 8.1 H), 5.91 (s, 1 H), 8.24 (s, 1 H), 8.04 (d, J = 9.1 H), 1 H), 7.42 (J = 6.16 (J= 6.16 (J= 6.16 (J= 6.16 (J= 6.16 (J= 6.16 (J= 6.16 (J= 6.16 (J= 6.16 (J= 6.16 (J= 6.16 (J= 6.16 (J= 6.16 (J= 6.20 (J= 6.20 (J= 6.20 (J= 6.20 (J= 6.20 (J= 6.20 (J= 6.20 (J= 6.20 (J= 6.20 (J= 6.20 (J= 6.20 (J= 6.20 (J= 6.20 (J= (J= 6.20 (J= 6.20 (J= 6.20 (J= 6.20 (J= 6.20 (J= 6.20 (J= 6.20 (J= 6.20 (J= 6.20 (J= 6.20 (J= 6.20 (J= 6.20 (J= = 6.20 (J= 6.20 (J= 6.20 (J= 6.20 (J= 6.20 (J= 6.20 (J= 6.20 (J= 6.20 (J= 6.20 (J= 6.20 (J= 6.20 (J= 6.20 (J= 6.16 (J= 6.16 (J= 6.16 (J= 6.16 (J= 6.16 (J= 6.16 (J= 6.16 (J= 6.16 (J= 6.16 (J= 6.16 (J= 6.16 (J= 6.16 (J= = 6.16 (J= 6.16 (J= 6.16 (J= 6.16 (J= 6.16 (J= 6.16 (J= 6.16 (J= 6.16 (J= 6.16 (J= 6.16 (J= 6.16 (J= 6.16 (J= 66.5 (J= 66.5 (J= 66.5 (J= 66.5 (J= 66.5 (J= 66.5 (J= 66.5 (J= 66.5 (J= 66.5 (J= 66.5 (J= 66.5 (J= 66.5 (J= 66.5 (J= = 66.5 (J= 66.5 (J= 66.5 (J= 66.5 (J= 66.5 (J= 66.5 (J= 66.5 (J= 66.5 (J= 66.5 (J= 66.5 (J= 66.5 (J= 66.5 (J= 666.5 (J= 66.5 (J= 66.5 (J= 66.5 (J= 66.5 (J= 66.5 (J= 66.5 (J= 66.5 (J= 66.5 (J= 66.5 (J= 66.5 (J= 66.5 (J= 66.6 (J= 66.6 (J= 66.6 (J= 66.6 (J= 66.6 (J= 66.6 (J= 66.6 (J= 66.6 (J= 66.6 (J= 66.6 (J= 66.6 (J= 66.6 (J= 66.6 (J= = 66.6 (J= 66.6 (J= 66.6 (J= 66.6 (J= 66.6 (J= 66.6 (J= 66.6 (J= 66.6 (J= 66.6 (J= 66.6 (J= 66.6 (J= 66.6 (J= 666.6 (J= 66.6 (J= 66.6 (J= 66.6 (J= 66.6 (J= 66.6 (J= 66.6 (J= 66.6 (J= 66.6 (J= 66.6 (J= 66.6 (J= 66.6 (J= 66.7 (J= 66.7 (J= 66.7 (J= 66.7 (J= 66.7 (J= 66.7 (J= 66.7 (J= 66.7 (J= 66.7 (J= 66.7 (J= 66.7 (J= 66.7 (J= 66.7 (J= = 66.7 (J= 66.7 (J= 66.7 (J= 66.7 (J= 66.7 (J= 66.7 (J= 66.7 (J= 66.7 (J= 66.7 (J= 66.7 (J= 66.7 (J= 66.7 (J= 666.7 (J= 66.7 (J= 66.7 (J= 66.7 (J= 66.7 (J= 66.7 (J= 66.7 (J= 66.7 (J= 66.7 (J= 66.7 (J= 66.7 (J= 66.7 (J= 66.6 (J= 66.6 (J= 66.6 (J= 66.6 (J= 66.6 (J= 66.6 (J= 66.6 (J= 66.6 (J= 66.6 (J= 66.6 (J= 66.6 (J= 66.6 (J= (J= 66.6 (J= 66.6 (J= 66.6 (J= 66.6 (J= 66.6 (J= 66.6 (J= 66.6 (J= 66.6 (J= 66.6 (J= 66.6 (J= 66.6 (J= 66.6 (J== 66.6 (J= 66.6 (J= 66.6 (J= 66.6 (J= 66.6 (J= 66.6 (J= 66.6 (J= 66.6 (J= 66.6 (J= 66.6 (J= 66.6 (J= 66.6 (J= 6.66.6 (J= 66.6 (J= 66.6 (J= 66.6 (J= 66.6 (J= 66.6 (J= 66.6 (J= 66.6 (J= 66.6 (J= 66.6 (J= 66.6 (J= 66.6 (J= 66. |01515.05W01| | | | | | | | | | | | | | | | | | | | | | | | | | | | | || --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- || (R)-4-(1-(5-cyclopropylmethoxy)pyridin-2- yl)propoxy)-2,3-difluoro-N-(6-(2- (pyrrolidin-1-yl)ethoxy pyridin-3- yl)isofloryl)benzamide | C | E | B | Method A (30-70) | 1H NMR (400 MHz, DMSO-d6, ppm) δ 9.58 (s, 1H), 8.54 (d, J=2.1 Hz, 1H), 8.23 (d, J=2.4 Hz, 1H), 8.09 (dd, J=8.6 Hz, 1H), 7.38 -7.22 (m, 3.1H, 8.89 (d, J=8.6 Hz, 1H), 6.74 (d, J=7.8 Hz, 1H), 5.31 (t, J=6.4 Hz, 1H), 4.61 -4.59 (m, 2.1H), 3.85 (d, J=7.1 Hz, 3.67-3.48 (m, 4 H), 3.17-3.01 (m, 2.1H), 2.05 -1.90 (m, 4H), 1.90-1.71 (m, 2.2H), 1.23 -1.17 (m, 1H), 0.89 (t, J=7.3 Hz, 0.25 (m, 2H) | m / z = 646 [MR (400 MHz, DMSO-d6, ppm) δ 8.94 (br, 1H), 8.49 (s, 1H), 8.23 (s, 1H), 8.05-8.02 (m, 1 H), 7.34-7.29 (m, 3.1H), 6.84-7.06 (m, 2.1H), 5.35-5.28 (m, 2.1H), 3.85 (d, J=7.1 Hz, 2.1H), 1.26-1.22 (m, 6.1H), 1.21-1.16 (m, 1H), 0.89 (t, J=7.3 Hz, 0.29 (m, 2H) | m / z = 646 [MR (400 MHz, DMSO-d6, ppm) δ 8.94 (br, 1H), 8.49 (s, 1H), 8.23 (s, 1H), 8.05-8.02 (m, 1 H), 7.34-7.29 (m), 6.84-7.06 (m, 2.1H), 5.35-5.28 (m, 2.1H), 3.85 (d, J=7.1 Hz, 2.1H), 1.26-1.22 (m, 6.1H), 1.21-1.16 (m, 1H), 0.99 (t, J=7.3 Hz, 0.29 (m, 2H) | m / z = 646 [MR (400 MHz, DMSO-d6, ppm) δ 8.94 (br, 1H), 8.49 (s, 1H), 8.23 (s, 1H), 8.05-8.02 (m, 1 H), 7.34-7.29 (m, 3.1H), 6.84-7.06 (m, 2.1H), 5.35-5.28 (m, 2.1H), 3.85 (d, J=7.1 Hz, 2.1H), 1.26-1.22 (m, 6.1H) | m / z = 646 [MR (400 MHz, DMSO-d6, ppm) δ 8.94 (br, 1H), 8.49 (s, 1H), 8.23 (s, 1H), 8.05-8.02 (m, 1 H), 7.34-7.29 (m), 6.84-7.06 (m, 2.1H), 5.35-5.28 (m, 2H) | m / z = 646 [MR (400 MHz, DMSO-d6, ppm) δ 8.94 (br, 1H), 8.49 (s, 1H), 8.23 (s, 1H), 8.05-8.02 (m, 1 H), 7.34-7.29 (m), 6.85-7.06 (m, 2.1H), 5.35-5.28 (m, 2H) | m / z = 646 [MR (400 MHz, DMSO-d6, ppm) δ 8.94 (br, 1H), 8.49 (s, 1H), 8.23 (s, 1H), 8.05, 1H], 7.34-7.29 (m, 1 H), 7.34-7.29 (m), 6.85-7.06 (m, 2.1H), 5.35-5.28 (m, 2H) | m / z = 646 [MR (400 MHz, DMSO-d6, ppm) δ 8.94 (br, 1H), 8.49 (s, 1 H), 7.34-7.29 (m, 1 H), 7.34-7.29 (m), 6.85-7.06 (m, 2.1H), 5.35-5.28 (m, 2H) | m / z = 646 [MR (400 MHz, DMSO-d6, ppm) δ 8.94 (Br), 8.49 (s, 1H), 8.23 (s, 1H), 8.05-8.02 (m, 1 H), 7.34-7.29 (m), 6.85-7.06 (m, 2.1H), 5.35-5.28 (m, 2H) | m / z = 645 [MR (400 MHz, DMSO-d6, ppm) δ 8.94 (Br), 8.49 (s, 1H), 8.23 (s, 1H), 8.05-8.02 (m, 1 H), 7.34-7.29 (m), 6.85-7.06 (m, 2.1H), 1.27 min (25-70) | m / z = 646 [MR (400 MHz, DMSO-d6, ppm) δ 8.94 (Br), 8.49 (s, 1H), 8.23 (s, 1H), 8.05-8.02 (m, 1 H), 7.34-7.29 (m), 6.85-7.02 (m), 6.85-7.06 (m, 2.1H), 5.35-5.28 (m, 2H) | m / z = 646 [MR (400 MHz, DMSO-d6, ppm) δ 8.94 (Br), 8.49 (s, 1H), 8.23 (s, 1H), 1.27 min (25-70) | m / z = 630 [MR (400 MHz, DMSO-d6, ppm) δ 8.94 (Br), 8.49 (s, 1H), 8.23 (s, 1H), 1.27 min (25-70) | m / z = 630 [MR (400 MHz, DMSO-d6, ppm) δ 8.94 (Br), 1.27 min (25-70) | m / z = 630 [MR (400 MHz, DMSO-d6, ppm) δ 8.94 (Br), 1.27 min (25-70) | m / z = 630 [MR (400 MHz, DMSO-d6, ppm) δ 8.94 (Br), 1H], 7.45 (d, J=7.9 Hz, 1H), 7.33-7.29 (m, 3.1H), 6.73 (t, J=8.2 Hz, 1H), 6.44 Hz, 1H), 5.30 (t, J=6.4 Hz, 1H), 3.85 (d, J=7.0 Hz, 2.1H), 3.73 (s, 2.1H), 3.51-3.36 (m, 2.1H), 3.16-2.91 (m, 6.1H), 2.44-2.41 (m, 2H) | m / z = 630 [MR (400 MHz, DMSO-d6, ppm) δ 8.94 (Br), 1.27 min (25-70) | m / z = 630 [MR (400 MHz, DMSO-d6, ppm) δ 8.94 (Br), 1.27 min (25-70) | 0.0000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000 | m / z = 630 [MR (400 MHz, DMSO-d6, ppm) δ 8.94 (Br), 1.27 min (25-70) | m / z = 630 [MR (400 MHz, DMSO-d6, ppm) δ 8.94 (Br), 1.27 min (25-70) | m / z=630 [MR (400 MHz, DMSO-d6, ppm) δ 8.94 (Br), 1.27 min (25-70) | m / z = 630 [MR (400 MHz, DMSO-d6, ppm) δ 8.94 (Br), 1.27 min (25-70) | m / z = 630 || | | | | | | | | | || --- | --- | --- | --- | --- | --- | --- | --- | --- | --- || | C | C | B | Method A (35-80) | 1H NMR (400 MHz, MeOH-4d, ppm) δ17 (s, 1H), 7.91 (d, J = 8.8 Hz, 2 H), 7.38-7.25 (m, 3 H), 1.04 (d, J = 8.9 Hz, 2 H), 6.63 (t, J = 8.1 Hz, 1 H), 5.28-5.14 (m, 1 H), 4.78-4.62 (m, 2 H), 3.87 (d, J = 7.0 Hz, 2 H), 3.76-3.62 (m, 2 H), 3.41 (s, 3 H), 3.38-3.11 (m, 3 H), 2.26-2.14 (m, 2 H), 2.13-2.01 (m, 3 H), 2.01-1.92 (m, 1 H), 1.27-1.18 (m, 3 H), 0.99 (t, J = 7.4 Hz, 3 H), 0.64-0.54 (m, 2 H), 0.38-0.30 (m, 2 H), 0.30 (m, 2 H), 0.30-0.27 (m, 2 H) | | | | || (R)-4-(1-(5-cyclopropylmethoxy)pyridin-2-yl)propoxy)-2,3-difluoro-N-(4-(1-(1-(2-hydroxyethyl)piperidin-4-yl)oxyl)phenyl)isulfonyl)benzamide | C | C | B | Method A (35-80) | m / z=660.2 [M+H]+, Rt=7.04 (d, J = 8.9 Hz, 2 H), 6.63 (t, J = 8.1 Hz, 1 H), 5.28-5.14 (m, 1 H), 4.78-4.62 (m, 2 H), 3.87 (d, J = 7.0 Hz, 2 H), 3.76-3,62 (m, 2 H), 3.41 (s, 3 H), 3.38-3.11 (m, 3 H), 2.26-2.14 (m, 2 H), 2.13-2.01 (m, 3 H), 2.01-1.92 (m, 1 H), 1.27-1.18 | m / z=674.3 [M+H]+, Rt=7.27 (m, 3 H), 7.01 (d, J = 8.5 Hz, 2 H), 6.75 (t, J = 7.9 Hz, 1 H), 5.11 (s, 3 H), 5.35-5.00 (m, 2 H), 4.66 (t, J = 7.86 (d, J = 7.1 Hz, 2 H), 3.19-2.85 (m, 4 H), 2.24-1.84 (m, 1 H), 1.29-1.08 (m, 8 H), 0.89 (t, J = 7.3 Hz, 2 H), 0.59-0.52 (m, 2 H), 0.40-0.27 (m, 2 H) | | | || (R)-4-(1-(5-cyclopropylmethoxy)pyridin-2-yl)propoxy)-2,3-difluoro-N-(4-(1-(1-(2-hydroxyethyl)piperidin-4-yl)oxyl)phenyl)isulfonyl)benzamide | C | C | G | Method B (45-95) | m / z=681.3 [M+H]+, Rt=5.32 (t, J = 6.4 Hz, 1 H), 3.86 (d, J = 7.1 Hz, 1 H), 3.62 (t, J = 6.2 Hz, 1 H), 3.60-3.45 (m, 2 H), 2.79 (m, 4 H), 2.06-1.86 (m, 4 H), 1.85-1.40 (m, 4 H), 1.45-1.36 (m, 2 H), 1.26-1.12 (m, 3 H), 2.12-1.12 (m, 3 H), 1.26-1.12 (m, 3 H), 1.26-1.12 (m, 3 H), 1.26-1.12 (m, 3 H), 1.26-1.12 (m, 3 H), 1.26-1.12 (m, 3 H), 1.26-1.12 (m, 3 H), 1,100-1.12 (m, 3 H), 1,100-1.12 (m, 3 H), 1,100-1.12 (m, 3 H), 1,100-1.12 (m, 3 H), 1,100-1.12 (m, 3 H), 1,100-1.12 (m, 4 H), 1,100-1.12 (m, 4 H), 1,100-1.12 (m, 4 H), 1,100-1.12 (m, 4 H), 1,100-1.12 (m, 4 H), 1,100-1.12 (m, 4 H), 1,100-2.06 (m, 2 H) | | | | || (R)-4-(1-(5-cyclopropylmethoxy)pyridin-2-yl)propoxy)-2,3-difluoro-N-(4-(1-(1-(2-hydroxyethyl)piperidin-4-yl)oxyl)phenyl)isulfonyl)benzamide | C | C | A | Method D (40-85) | m / z=677.3 [M+H]+, Rt=5.31 (t, J = 6.5 Hz, 1 H), 3.29 (s, 3 H), 3.20-2.98 (m, 4 H), 2.78 (s, 3 H), 3.66-3.54 (m, 3 H), 2.50-3.40 (m, 1 H), 1.39-3.33 (m, 4 H), 1.29-1.12 (m, 3 H), 1.26-1.12 (m, 3 H), 1.26-1.12 (m, 3 H), 1.26-1.12 (m, 3 H), 1.26-1.12 (m, 3 H), 1.26-1.12 (m, 3 H), 1 (m, 1 H), 1.29-1.12 (m, 3 H), 1.26-1.12 (m, 3 H), 1.26-1.12 (m, 3 H), 1.26-1.12 (m, 3 H), 1.26-1.12 (m, 3 H), 1.26-1.12 (m. 3 H), 1.26-1.12 (m. 3 H), 1.26-1.12 (m. 3 H), 1.26-1.12 (m. 3 H), 1.26-1.12 (m. 3 H), 1.26-1.12 (m. 3 H), 1.26-1.12 | m / z=663.3 [M+H]+, Rt=5.30 (t, J = 6.5 Hz, 1 H), 3.86 (d, J = 7.1 Hz, 1 H), 3.72-3.52 (m, 1 H), 3.50-3.39 (m, 1 H), 3.38-3.33 (m, 2 H), 3.18-2.69 (m, 6 H), 1.31-1.67 (m, 8 H), 1.65-1.40 (m, 4 H), 1.27-1.14 (m, 1 H), 1.08-0.95 (m, 1 H), 1.08-0.95 (m, 1 H), 1.08-0.95 (m, 1 H), 1.08-0.95 (m, 1 H), 1.08-0.95 (m, 1 H), 1.08-0.95 (m, 1 H), 1.08-0. | | | || (R)-4-(1-(5-cyclopropylmethoxy)pyridin-2-yl)propoxy)-2,3-difluoro-N-(4-(1-(1-(2-hydroxyethyl)piperidin-4-yl)oxyl)phenyl)isulfonyl)benzamide | C | C | A | Method D (40-85) | miz=663.3 [M+H]+, Rt=5.31 (t, J = 6.5 Hz, 1 H), 3.86 (d, J = 7.1 Hz, 1 H), 3.72-3.52 (m, 1 H), 3.50-3.39 (m, 1 H), 3.38-3.33 (m, 2 H), 3.18-2.69 (m,6 H), 1.31-1.67 (m, 8 H), 1.65-1.40 (m, 4 H), 1.27-1.14 (m, 1 H), 1.08-0.95 (m, 1 H), 1.08-0.95 (m, 1 H), 1.08-0.95 ( m, 1 H), 1.26-1.12 (m, 3 H), 1.26-1.12 (m, 3 H), 1.26-1.12 (m, 3 H), 1.26-1.12 (m, 3 H), 1.26-1.12 (m, 3 H), 1.26-1.12 (m. 3 H), 1,100-1.12 (m, 3 H), 1,100-1.12 (m, 3 H), 1,100-1.12 (m, 3 H), 1,100-1.12 (m, 3 H), 1,100-1.12 (m, 3 H), 1,10 | miz=636.6 [M+H]+, Rt=5.31 (t, J = 6.5 Hz, 1 H), 3.86 (d, J = 7.1 Hz, 1 H), 3.50-3.39 (m, 1 H), 3.38-3.33 (m, 2 H), 3.18-2.69 (m,6 H), 1.31-1.67 (m, 8 H), 1.65-1.40 (m, 4 H), 1.27-1.14 | miz=636.6 [M+H]+, Rt=5.31 (t, J = 6.5 Hz, 1 H), 3.86 (d, J = 7.1 Hz, 1 H), 3.50-3.39 (m, 1 H), 3.38-3.33 (m, 2 H), 3.18-2.99 (m,6 H), 1.31-1.67 (m, 8 H), 1.65-1.40 (m, 4 H), 1.27-1.14 | miz=636.6 [M+H]+, Rt=5.31 (t, J = 6.5 Hz, 1 H), 3.86 (d, J = 6.75 (t, J = 7.9 Hz, 1 H), 3.72-3.52 (m, 1 H), 3.50-3.39 (m, 1 H), 3.38-3.33 (m, 2 H), 3.18-2.69 (m,6 H), 1.31-1.67 (m, 8 H), 1.65-1.4 | miz=636.6 [M+H]+, Rt=5.31 (t, J = 6.5 Hz, 1 H), 3.86 (d, J = 7.1 Hz, 1 H), 3.50-3.39 (m, 1 H), 3.38-3.33 (m, 2 H), 3.18-2. || | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | || --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- || (R)-2,3-difluoro-4-(1-(5-(2-methoxyethoxy)pyridin-2-yl)propoxy)-N-(N-(4-(1-methyl)pyridin-4-(1-(5-(2-yl)oxy)phenyl)isofloryl)benzamide | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | || (R)-N-(4-(2-(dimethylamino)ethoxy)pyridin-1-yl)isofloryl)-2,3-difluoro-4-(1-(5-(2-methoxyethoxy)pyridin-2-yl)pyridin-1-yl)propoxy)benzamide | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | || | | | | | | | | | | | | | || --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- || (R)-2,3-difluoro-4-(1-(5-pyridin-2-yl)oxy)pyridin-2-yl)propoxy-N-(2,4-dimethylpiperazin-1-yl)solutonyl)benzamide | E | H | B | Method A (25-65) | m / z = 576.2 [M+H]+, Rt = 0.99 mins (Method D) | H NMR (400 MHz, DMSO-d6, ppm) δ 11.11 (s, 1H), 4.45 (J, J = 2.7 Hz, 1H), 8.14 (d, J = 5.1, 2.0 Hz, 1H), 7.96-7.82 (m, 1H), 7.65 (d, J = 8.5, 2.7 Hz, 1H), 7.51 (d, J = 8.5 Hz, 1H), 7.31 (J, J = 8.47 (J, J = 6.3 Hz, 1H), 3.56 (s, 2H), 2.60-2.50 (m, 2.36-2.24 (m, 51H), 2.09-2.00 (m, 2.11, 1.37 (s, 0.96 (s, 0.96 (J = 7.4 Hz, 3 H) | m / z = 547.4 [M+H]+, Rt = 1.29 mins (Method E) | m / z = 533.5 [M+H]+, Rt = 3.86 mins (Method A) | H NMR (400 MHz, DMSO-d6, ppm) δ 9.16 (br, 1H), 8.44 (J = 2.4 Hz, 1H), 8.15-8.14 (m, 1H), 7.92-7.87 (m, 1H), 7.65-7.62 (m, 1H), 7.49 (d, J = 8.4 Hz, 1H), 7.39 (J, J = 8.2 Hz, 1H), 7.18 (J, J = 7.1 Hz, 1H), 7.16 (J, J = 7.1 Hz, 1H), 7.12 (J, J = 6.81 (J, J = 8.0 Hz, 1H), 5.42 (J, J = 6.4 Hz, 1H), 3.46-3.37 (m, 3 Hz, 3.00-2.19 (m, 2.1 Hz, 2.68 (s, 3 H), 2.07-1.99 (m, 4 H), 1.84-1.82 (m, 2 H), 0.96 (J = 7.4 Hz, 3 H) | m / z = 526.3 [M+H]+, Rt = 1.16 mins (Method D) | H NMR (400 MHz, DMSO-d6, ppm) δ 8.16 (br, 1H), 8.24 (d, J = 2.4 Hz, 1H), 8.15-8.14 (m, 1H), 7.92-7.87 (m, 1H), 7.65-7.62 (m, 1H), 7.49 (d, J = 8.4 Hz, 1H), 7.39 (J, J = 8.2 Hz, 2.18 (J, J = 7.1 Hz, 1H), 7.12 (J, J = 6.81 (J, J = 8.0 Hz, 1H), 5.42 (J, J = 6.4 Hz, 1H), 3.46-3.37 (m, 3 Hz, 3.00-2.19 (m, 2.1 H), 0.96 (J = 7.4 Hz, 3 H) | m / z = 523.5 [M+H]+, Rt = 1.11 (s, 1H), 1.10 (s, 1H), 1.10 (s, 1H), 1.10 (s, 1H), 1.10 (s, 1H), 1.10 (s, 1H), 1.10 (s, 1H), 1.10 (s, 1H), 1.10 (s, 1H), 1.10 (s, s, 2 H), 1.10 (s, 1H), 1.10 (s, 1H), 1.10 (s, 1H), 1.10 (s, 1H), 1.10 (s, 1H), 1.10 (s, 1H), 1.10 (s, 1H), 1.10 (s, 1H), 1. | H NMR (400 MHz, DMSO-d6, ppm) δ 8.25 (s, 1H), 7.44 (s, 2 H), 7.25 (s, 1 H), 7.5 Hz, 1 H, 6.86 (J, J = 7.1 Hz, 1 H), 7.57 (s, 2 H), 7.25 (s, 1 H), 7.57 (s, 2 H), 7.25 (s, 1 H), 7.57 (s, 2 H), 7.25 (s, 1 H), 7.57 (s, 2 H), 7.25 (s, 1 H), 7.57 (s, 2 H), 7.25 (s, 1 Hz, 1 H), 1.14 (s, 1 H), 1.09 (s, 1 H), 1.14 (s, 1 H), 1.09 (s, 1 H), 1.14 (s, 1 H), 1.09 (s, 1 H), 1.14 (s, 1 H), 1.09 (s, 1 H), 1.14 (s, 1 H), 1.09 (s, 1 Hz, 1 H), 1.14 (s, 1 H), 1.09 (s, 1 Hz, 1 H), 1.14 (s, 1 H), 1.09 (s, 1 Hz, 1 H), 1.14 (s, 1 H), 1.09 (s, 1 Hz, 1 H), 1.14 (s, 1 Hz, 1 H), 1.14 (s, 1 Hz, 1 H), 1.14 (s, 1 Hz, 1 H), 1.14 (s, 1 Hz, 1 H), 1.14 (s, 1 Hz, 1 H), 1.14 (s, 1 Hz, 1 H), 1.14 (s, s, 2 H), 1.14 (s, 1 Hz, 1 H), 1.14 (s, 1 Hz, 1 H), 1.14 (s, 1 Hz, 1 H), 1.14 (s, 1 Hz, 1 H), 1.14 (s, 1 Hz, 1 H), 1.14 (s, 1 Hz, 1 H), 2.0 Hz, 1 Hz, 1 Hz, 1 Hz, 1 Hz, 1 Hz, 1 Hz, 1 Hz, 1 Hz, 1 Hz, 1 Hz, 1 Hz, 1 Hz, 1 Hz, 1 Hz, 1 Hz, 1 Hz, 1 Hz, 1 Hz, 1 Hz, 1 Hz, 1 Hz, 1 Hz, 1 Hz, 1 Hz, 1 Hz, 2.0 Hz, 1 Hz, 1 Hz, 1 Hz, 1 Hz, 1 Hz, 1 Hz, 1 Hz, 1 Hz, 1 Hz, 1 Hz, 1 Hz, 1 Hz, 1 Hz, 1 Hz, 1 Hz, 1 Hz, 1 Hz, 1 Hz, 1 Hz, 1 Hz, 1 Hz, 1 Hz, 1 Hz, 2.0 Hz 1.1 Hz, 1.1 Hz, 1.1 Hz, 1.1 Hz, 1.1 Hz, 1.1 Hz, 1.1 Hz, 1.1 Hz, 1.1 Hz, 1.1 Hz, 1.1 Hz, 1.1 Hz, 1.1 Hz, 1.1 Hz, 1.1 Hz, 1.1 Hz, 1.1 Hz, 1.2 Hz, 1.1 Hz, 1.1 Hz, 1.1 Hz, 1.1 Hz, 1.1 Hz, 1.1 Hz, 1.1 Hz, 1.1 Hz, 1.1 Hz, 1.1 Hz, 1.1 Hz, 1.1 Hz, 1.1 Hz, 1.1 Hz, 1.1 Hz, 1.1 Hz, 2.0 Hz, 1 Hz, 1 Hz, 1 Hz, 1 Hz, 1 Hz, 1 Hz, 1 Hz, 1 Hz, 1 Hz, 1 Hz, 1 Hz, 1 Hz, 1 Hz, 1 Hz, 1 Hz, 1 Hz, 1 Hz, 1 Hz, 1 Hz, 1 Hz, 1 Hz, 1 Hz, 1 H, 1 H, 1 H, 1 H, 1 H, 1 H, 1 H, 1 H, 1 H, 1 H, 1 H, 1 H, 1 H, 1 H, 1 H, 1 H, 1 H, 1 H, 1 H, 1 H, 1 H, 1 H, 1 H, 1 H, 1 H, 1 Hz, 1 Hz, 1 Hz, 1 Hz, 1 Hz, 1 Hz, 1 Hz, 1 Hz, 1 Hz, 1 Hz, 1 Hz, 1 Hz, 1 Hz, 1 Hz, 1 Hz, 1 Hz, 1 Hz, 1 Hz, 1 Hz, 1 Hz, 1 Hz, 1 Hz, 1 Hz, 1 Hz, 1 H, 1 H, 2.0 Hz, 1 Hz, 1 Hz, 1 Hz, 1 Hz, 1 Hz, 1 Hz, 1 Hz, 1 Hz, 1 Hz, 1 Hz, 1 Hz, 1 Hz, 1 Hz, 1 Hz, 1 Hz, 1 Hz, 1 Hz, 1 Hz, 1 Hz, 1 Hz, 1 Hz, 1 Hz, 1 Hz, || | | | | | | | | || --- | --- | --- | --- | --- | --- | --- | --- | --- || (R)-2,3-difluoro-4-(1-(5-pyridin-2-yl)oxy)pyridin-2-yl)propoxy-N-(2,4-dimethylpiperazin-1-yl)benzamide | E | H | B | Method A (25-65) | m / z = 576.2 [M+H]+, Rt = 0.99 mins (Method D) | H NMR (400 MHz, DMSO-d6, ppm) δ 11.11 (s, 1H), 4.45 (J, J = 2,7 Hz, 1H), 7.96-7.82 (m, 1H), 7.65 (d, J = 8.5 Hz, 1H), 7.31 (J, J = 8.47 (J, J = 6.3 Hz, 1H), 3.56 (s, 2H), 2.60-2.50 (m, 2.11, 1.37 (s, 0.96 (s, 0.96 (J = 7.4 Hz, 3 H) | m / z = 547.4 [M+H]+, Rt = 1.29 mins (Method E) | m / z = 533.5 [M+H]+, Rt = 1.11 (s, 1H), 1.10 (s, 1H), 1.10 (s, 1H), 1.10 (s, 1H), 1.10 (s, 1H), 1.10 (s, 1H), 1.10 (s, 1H), 1.1.1 Hz, 1H, 1.1 Hz, 1.1 Hz, 1.1 Hz, 1.1 Hz, 1.1 Hz, 1.1 Hz, 1.1 Hz, 1.1 Hz, 1.1 Hz, 1.1 Hz, 1.1 Hz, 1.1 Hz, 1.1 Hz, 1.1 Hz, 1.1 Hz, 1.1 Hz, 1 Hz, 1.1 Hz, 1.1 Hz, 1.1 Hz, 1.1 Hz, 1.1 Hz, 1.1 Hz, 1.1 Hz, 1.1 Hz, 1.1 Hz, 1.1 Hz, 1.1 Hz, 1.1 Hz, 1.1 Hz, 1.1 Hz, 1.1 Hz, 1.1 Hz,1.1 Hz, 1.1 Hz, 1.1 Hz, 1.1 Hz, 1.1 Hz, 1.1 Hz, 1.1 Hz, 1.1 Hz, 1.1 Hz, 1.1 Hz, 1.1 Hz, 1.1 Hz, 1.1 Hz, 1.1 Hz, 1.1 Hz, 1.1 Hz, 1.1 H, 1.1 H, 1.1 H, 1.1 H, 1.1 H, 1.1 H, 1.1 H, 1.1 H, 1.1 H, 1.1 H, 1.1 H, 1.1 H, 1.1 H, 1.1 H, 1.1 H, 1.1 H, 1.1 H, 1 H, 1 H, 1 H, 1 H, 1 H, 1 H, 1 H, 1 H, 1 H, 1 H, 1 H, 1 H, 1 H, 1 H, 1 H, 1 H, 1 H, 1 H, 1 H, 1 H, 1 H, 1 H, 1 H, 1 H,1 H, 1 H, 1 H, 1 H, 1 H, 1 H, 1 H, 1 H, 1 H, 1 H, 1 H, 1 H, 1 H, 1 H, 1 H, 1 H, 1 H, 1 H, 1 H, 1 H, 1 H, 1 H, 1 H, 1 H, 1 H, H, 1 H, 1 H, 1 H, 1 H, 1 H, 1 H, 1 H, 1 H, 1 H, 1 H, 1 H, 1 H, 1 H, 1 H, 1 H, 1 H, 1 H, 1 H, 1 H, 1 H, 1 H, 1 H, 1 H, 1 H, 2 H, 1 H, 1 H, 1 H, 1 H, 1 H, 1 H, 1 H, 1 H, 1 H, 1 H, 1 H, 1 H, 1 H, 1 H, 1 H, 1 H, 1 H, 1 H, 1 H, 1 H, 1 H, 1 H, 1 H, 1 H, 3 H, 1 H, 1 H, 1 H, 1 H, 1 H, 1 H, 1 H, 1 H, 1 H, 1 H, 1 H, 1 H, 1 H, 1 H, 1 H, 1 H, 1 H, 1 H, 1 H, 1 H, 1 H, 1 H, 1 H, 1 H, 4 H, 1 H, 1 H, 1 H, 1 H, 1 H, 1 H, 1 H, 1 H, 1 H, 1 H, 1 H, 1 H, 1 H, 1 H, 1 H, 1 H, 1 H, 1 H, 1 H, 1 H, 1 H, 1 H, 1 H, 1 H, 5 H, 1 H, 1 H, 1 H, 1 H, 1 H, 1 H, 1 H, 1 H, 1 H, 1 H, 1 H, 1 H, 1 H, 1 H, 1 H, 1 H, 1 H, 1 H, 1 H, 1 H, 1 H, 1 H, 1 H, 1 H, 6 H, 1 H, 1 H, 1 H, 1 H, 1 H, 1 H, 1 H, 1 H, 1 H, 1 H, 1 H, 1 H, 1 H, 1 H, 1 H, 1 H, 1 H, 1 H, 1 H, 1 H, 1 H, 1 H, 1 H, 1 H, 7 H, 1 H, 1 H, 1 H, 1 H, 1 H, 1 H, 1 H, 1 H, 1 H, 1 H, 1 H, 1 H, 1 H, 1 H, 1 H, 1 H, 1 H, 1 H, 1 H, 1 H, 1 H, 1 H, 1 H, 1 H, 9 H, 1 H, 1 H, 1 H, 1 H, 1 H, 1 H, 1 H, 1 H, 1 H, 1 H, 1 H, 1 H, 1 H, 1 H, 1 H, 1 H, 1 H, 1 H, 1 H, 1 H, 1 H, 1 H, 1 H, 1 H, 0 H, 1 H, 1 H, 1 H, 1 H, 1 H, 1 H, 1 H, 1 H, 1 H, 1 H, 1 H, 1 H, 1 H, 1 H, 1 H, 1 H, 1 H, 1 H, 1 H, 1 H, 1 H, 1 H, 1 H, 1 H, 8 H, 1 H, 1 H, 1 H, 1 H, 1 H, 1 H, 1 H, 1 H, 1 H, 1 H, 1 H, 1 H, 1 H, 1 H, 1 H, 1 H, 1 H, 1 H, 1 H, 1 H, 1 H, 1 H, 1 H, 1 H, |01515.050W01W02025 / 174957PCT / US2025 / 015714| | | | | | || --- | --- | --- | --- | --- | --- || (R)-N-(4-(2-(dimethylamino)ethoxy)phenyl)butyl)-4-(pyr-[(1-(3-pyridin-2-yl)pyridin-2-yl)propoxy-1-(3-(pyridin-2-yl)propylo-2-yl)propylo-2-yl)propylo-2-yl)propylo-2-yl)propylo-2-yl)propylo-2-yl)propylo-2-yl)propylo-2-yl)propylo-2-yl)propylo-2-yl)propylo-2-yl)propylo-2-yl)propylo-2-yr)trifluoromethyl)benzamide | G | A | A | Method A (30-80) | 1H NMR (400 MHz, DMSO-d6, ppm) δ 9.52 (s, 1H), 8.46 (d, J = 2.7Hz, 1H), 8.13 (s, 2H), 7.96-7.87 (m, 2H), 7.78 (d, J = 8.7Hz, 2.1H), 7.63 (d, J = 8.2, 2.6Hz, 1H), 7.35 (d, J = 8.6Hz, 1H), 7.17-7.11 (m, 2H), 6.98 (d, J = 8.7Hz, 3H), 5.51 (t, J = 6.1Hz, 1H), 4.32 (t, J = 4.6Hz, 2H), 3.45 (t, J = 4.6Hz, 2H), 3.13 (t, J = 4.6Hz, 2H), 3.13 (t, J = 4.6Hz, 2H), 3.13 (t, J = 4.6Hz, 2H), 3.13 (t, J = 4.6Hz, 2H), 3.13 (t, J = 4.6Hz, 2H), 3.14 (t, J = 4.6Hz, 2H), 3.14 (t, J = 4.6Hz, 2H), 3.14 (t, J = 4.6Hz, 2H), 3.14 (t, J = 4.6Hz, 2H), 3.14 (t, J = 4.6Hz, 2H), 3.15 (t, J = 4.6Hz, 2H), 3.15 (t, J = 4.6Hz, 2H), 3.15 (t, J = 4.6Hz, 2H), 3.15 (t, J = 4.6Hz, 2H), 3.15 (t, J = 4.6Hz, 2H), 3.16 (t, J = 4.6Hz, 2H), 3.16 (t, J = 4.6Hz, 2H), 3.16 (t, J = 4.6Hz, 2H), 3.16 (t, J = 4.6Hz, 2H), 3.16 (t, J = 4.6Hz, 2H), 3.17 (t, J = 4.6Hz, 2H), 3.17 (t, J = 4.6Hz, 2H), 3.17 (t, J = 4.6Hz, 2H), 3.17 (t, J = 4.6Hz, 2H), 3.17 (t, J = 4.6Hz, 2H), 3.18 (t, J = 4.6Hz, 2H), 3.18 (t, J = 4.6Hz, 2H), 3.18 (t, J = 4.6Hz, 2H), 3.18 (t, J = 4.6Hz, 2H), 3.18 (t, J = 4.6Hz, 2H), 3.19 (t, J = 4.6Hz, 2H), 3.19 (t, J = 4.6Hz, 2H), 3.19 (t, J = 4.6Hz, 2H), 3.19 (t, J = 4.6Hz, 2H), 3.19 (t, J = 4.6Hz, 2H), 3.18 (t, J = 4.6Hz, 2H), 3.18 (t, J = 4.6Hz, 2H), 3.18 (t, J = 4.6Hz, 2H), 3.19 (t, J = 4.6Hz, 2H), 3.18 (t, J = 4.6Hz, 2H), 3.19 (t, J = 4.6Hz, 2H), 3.19 (t, J = 4.6Hz, 2H), 3.19 (t, J = 4.6Hz, 2H), 3.18 (t, J = 4.6Hz, 2H), 3.19 (t, J = 4.6Hz, 2H), 3.19 (t, J = 4.6Hz, 2H), 3.18 (t, J = 4.6Hz, 2H), 3.19 (t, J = 4.6Hz, 2H), 3.18 (t, J = 4.6Hz, 2H), 3.19 (t, J = 4.6Hz, 2H), 3.18 (t, J = 4.6Hz, 2H), 3.18 (t, J = 4.6Hz, 2H), 3.19 (t, J = 4.6Hz, 2H), 3.19 (t, J = 4.6Hz, 2H), 3.18 (t, J = 4.6Hz, 2H), 3.18 (t, J = 4.6Hz, 2H), 3.19 (t, J = 4.6Hz, 2H), 3.18 (t, J = 4.6Hz, 2H), 3.18 (t, J = 4.6Hz, 2H), 3.18 (t, J = 4.6Hz, 2H), 3.18 (t, J = 4.6Hz, 2H), 3.15 (t, J = 4.6Hz, 2H), 3.15 (t, J = 4.6Hz, 2H), 3.15 (t, J = 4.6Hz, 2H), 3.15 (t, J = 4.6Hz, 2H), 3.19 (t, J = 4.6Hz, 2H), 3.19 (t, J = 4.6Hz, 2H), 3.19 (t, J = 4.6Hz, 2H), 3.19 (t, J = 4.6Hz, 2H), 3.15 (t, J = 4.6Hz, 2H), 3.19 (t, J = 4.6Hz, 2H), 3.19 (t, J = 4.6Hz, 2H), 3.19 (t, J = 4.6Hz, 2H), 3.18 (t, J = 4.6Hz, 2H), 3.15 (t, J = 4.6Hz, 2H), 3.19 (t, J = 4.6Hz, 2H), 3.19 (t, J = 4.6Hz, 2H), 3.19 (t, J = 4.6Hz, 2H), 3.15 (t, J = 4.6Hz, 2H), 3.15 (t, J = 4.6Hz, 2H), 3.19 (t, J = 4.6Hz, 2H), 3.19 (t, J = 4.6Hz, 2H), 3.15 (t, J = 4.6Hz, 2H), 3.19 (t, J = 4.6Hz, 2H), 3.15 (t, J = 4.6Hz, 2H), 3.19 (t, J = 4.6Hz, 2H), 3.19 (t, J = 4.6Hz, 2H), 3.15 (t, J = 4.6Hz, 2H), 3.15 (t, J = 4.6Hz, 2H), 3.15 (t, J = 4.6Hz, 2H), 3.19 (t, J = 4.6Hz, 2H), 3.15 (t, J = 4.6Hz, 2H), 3.19 (t, J = 4.6Hz, 2H), 3.15 (t, J = 4.6Hz, 2H), 3.15 (t, J = 4.6Hz, 2H), 3.19 (t, J = 4.6Hz, 2H), 3.15 (t, J = 4.6Hz, 2H), 3.15 (t, J = 4.6Hz, 2H), 3.15 (t, J = 4.6Hz, 2H), 3.15 (t, J = 4.6Hz, 2H), 3.18 (t, J = 4.6Hz, 2H), 3.19 (t, J = 4.6Hz, 2H), 3.19 (t, J = 4.6Hz, 2H), 3.19 (t, J = 4.6Hz, 2H), 3.15 (t, J = 4.6Hz, 2H), 3.18 (t, J = 4.6Hz, 2H), 3.19 (t, J = 4.6Hz, 2H), 3.19 (t, J = 4.6Hz, 2H), 3.15 (t, J = 4.6Hz, 2H), 3.19 (t, J = 4.6Hz, 2H), 3.18 (t, J = 4.6Hz, 2H), 3.19 (t, J = 4.6Hz, 2H), 3.15 (t, J = 4.6Hz, 2H), 3.19 (t, J = 4.6Hz, 2H), 3.15 (t, J = 4.6Hz, 2H), 3.18 (t, J = 4.6Hz, 2H), 3.19 (t, J = 4.6Hz, 2H), 3.15 (t, J = 4.6Hz, 2H), 3.19 (t, J = 4.6Hz, 2H), 3.19 (t, J = 4.6Hz, 2H), 3.18 (t, J = 4.6Hz, 2H), 3.19 (t, J = 4.6Hz, 2H), 3.15 (t, J = 4.6Hz, 2H), 3.15 (t, J = 4.6Hz, 2H), 3.19 (t, J = 4.6Hz, 2H), 3.18 (t, J = 4.6Hz, 2H), 3.19 (t, J = 4.6Hz, 2H), 3.19 (t, J = 4.6Hz, 2H), 3.15 (t, J = 4.6Hz, 2H), 3.15 (t, J = 4.6Hz, 2H), 3.18 (t, J = 4.6Hz, 2H), 3.19 (t, J = 4.6Hz, 2H), 3.15 (t, J = 4.6Hz, 2H), 3.15 (t, J = 4.6Hz, 2H), 3.15 (t, J = 4.6Hz, 2H), 3.18 (t, J = 4.6Hz, 2H), 3.15 (t, J = 4.6Hz, 2H), 3.19 (t, J = 4.6Hz, 2H), 3.15 (t, J = 4.6Hz, 2H), 3.19 (t, J = 4.6Hz, 2H), 3.18 (t, J = 4.6Hz, 2H), 3.15 (t, J = 4.6Hz, 2H), 3.19 (t, J = 4.6Hz, 2H), 3.15 (t, J = 4.6Hz, 2H), 3.15 (t, J = 4.6Hz, 2H), 3.18 (t, J = 4.6Hz, 2H), 3.15 (t, J = 4.6Hz, 2H), 3.15 (t, J = 4.6Hz, 2H), 3.19 (t, J = 4.6Hz, 2H), 3.15 (t, J = 4.6Hz, 2H), 3.18 (t, J = 4.6Hz, 2H), 3.15 (t, J = 4.6Hz, 2H), 3.19 (t, J = 4.6Hz, 2H), 3.19 (t, J = 4.6Hz, 2H), 3.15 (t, J = 4.6Hz, 2H), 3.18 (t, J = 4.6Hz, 2H), 3.15 (t, J = 4.6Hz, 2H), 3.15 (t, J = 4.6Hz, 2H), 3.15 (t, J = 4.6Hz, 2H), 3.19 (t, J = 4.6Hz, 2H), 3.18 (t, J = 4.6Hz, 2H), 3.15 (t, J = 4.6Hz, 2H), 3.15 (t, J = 4.6Hz, 2H), 3.19 (t, J = 4.6Hz, 2H), 3.19 (t, J = 4.6Hz, 2H), 3.18 (t, J = 4.6Hz, 2H), 3.15 (t, J = 4.6Hz, 2H), 3.15 (t, J = 4.6Hz, 2H), 3.15 (t, J = 4.6Hz, 2H), 3.18 (t, J = 4.6Hz, 2H), 3.10 (t, J = 4.6Hz, 2H), 3.15 (t, J = 4.6Hz, 2H), 3.15 (t, J = 4.6Hz, 2H), 3.15 (t, J = 4.6Hz, 2H), 3.15 (t, J = 4.6Hz, 2H), 3.10 (t, J = 4.6Hz, 2H), 3.15 (t, J = 4.6Hz, 2H), 3.15 (t, J = 4.6Hz, 2H), 3.15 (t, J = 4.6Hz, 2H), 3.10 (t, J = 4.6Hz, 2H), 3.10 (t, J = 4.6Hz, 2H), 3.10 (t, J = 4.6Hz, 2H), 3.10 (t, J = 4.6Hz, 2H), 3.10 (t, J = 4.6Hz, 2H), 3.15 (t, J = 4.6Hz, 2H), 3.10 (t, J = 4.6Hz, 2H), 3.10 (t, J = 4.6Hz, 2H), 3.10 (t, J = 4.6Hz, 2H), 3.15 (t, J = 4.6Hz, 2H), 3.15 (t, J = 4.6Hz, 2H), 3.10 (t, J = 4.6Hz, 2H), 3.10 (t, J = 4.6Hz, 2H), 3.15 (t, J = 4.6Hz, 2H), 3.10 (t, J = 4.6Hz, 2H), 3.15 (t, J = 4.6Hz, 2H), 3.10 (t, J = 4.6Hz, 2H), 3.10 (t, J = 4.6Hz, 2H), 3.15 (t, J = 4.6Hz, 2H), 3.15 (t, J = 4.6Hz, 2H), 3.15 (t, J = 4.6Hz, 2H), 3.19 (t, J = 4.6Hz, 2H), 3.10 (t, J = 4.6Hz, 2H), 3.15 (t, J = 4.6Hz, 2H), 3.10 (t, J = 4.6Hz, 2H), 3.15 (t, J = 4.6Hz, 2H), 3.15 (t, J = 4.6Hz, 2H), 3.10 (t, J = 4.6Hz, 2H), 3.15 (t, J = 4.6Hz, 2H), 3.10 (t, J = 4.6Hz, 2H), 3.15 (t, J = 4.6Hz, 2H), 3.19 (t, J = 4.6Hz, 2H), 3.10 (t, J = 4.6Hz, 2H), 3.15 (t, J = 4.6Hz, 2H), 3.15 (t, J = 4.6Hz, 2H), 3.10 (t, J = 4.6Hz, 2H), 3.19 (t, J = 4.6Hz, 2H), 3.10 (t, J = 4.6Hz, 2H), 3.15 (t, J = 4.6Hz, 2H), 3.10 (t, J = 4.6Hz, 2H), 3.10 (t, J = 4.6Hz, 2H), 3.19 (t, J = 4.6Hz, 2H), 3.10 (t, J = 4.6Hz, 2H), 3.10 (t, J = 4.6Hz, 2H), 3.10 (t, J = 4.6Hz, 2H), 3.10 (t, J = 4.6Hz, 2H), 3.19 (t, J = 4.6Hz, 2H), 3.10 (t, J = 4.6Hz, 2H), 3.15 (t, J = 4.6Hz, 2H), 3.15 (t, J = 4.6Hz, 2H), 3.19 (t, J = 4.6Hz, 2H), 3.10 (t, J = 4.6Hz, 2H), 3.10 (t, J = 4.6Hz, 2H), 3.10 (t, J = 4.6Hz, 2H), 3.15 (t, J = 4.6Hz, 2H), 3.19 (t, J = 4.6Hz, 2H), 3.10 (t, J = 4.6Hz, 2H), 3.10 (t, J = 4.6Hz, 2H), 3.15 (t, J = 4.6Hz, 2H), 3.10 (t, J = 4.6Hz, 2H), 3.19 (t, J = 4.6Hz, 2H), 3.10 (t, J = 4.6Hz, 2H), 3.10 (t, J = 4.6Hz, 2H), 3.15 (t, J = 4.6Hz, 2H), 3.19 (t, J = 4.6Hz, 2H), 3.15 (t, J = 4.6Hz, 2H), 3.10 (t, J = 4.6Hz, 2H), 3.10 (t, J = 4.6Hz, 2H), 3.10 (t, J = 4.6Hz, 2H), 3.19 (t, J = 4.6Hz, 2H), 3.15 (t, J = 4.6Hz, 2H), 3.10 (t, J = 4.6Hz, 2H), 3.10 (t, J = 4.6Hz, 2H), 3.15 (t, J = 4.6Hz, 2H), 3.19 (t, J = 4.6Hz, 2H), 3.19 (t, J = 4.6Hz, 2H), 3.10 (t, J = 4.6Hz, 2H), 3.10 (t, J = 4.6Hz, 2H), 3.10 (t, J = 4.6Hz, 2H), 3.19 (t, J = 4.6Hz, 2H), 3.19 (t, J = 4.6Hz, 2H), 3.10 (t, J = 4.6Hz, 2H), 3.10 (t, J = 4.6Hz, 2H), 3.15 (t, J = 4.6Hz, 2H), 3.15 (t, J = 4.6Hz, 2H), 3.19 (t, J = 4.6Hz, 2H), 3.15 (t, J = 4.6Hz, 2H), 3.10 (t, J = 4.6Hz, 2H), 3.15 (t, J = 4.6Hz, 2H), 3.10 (t, J = 4.6Hz, 2H), 3.19 (t, J = 4.6Hz, 2H), 3.15 (t, J = 4.6Hz, 2H), 3.10 (t, J = 4.6Hz, 2H), 3.15 (t, J = 4.6Hz, 2H), 3.19 (t, J = 4.6Hz, 2H), 3.15 (t, J = 4.6Hz, 2H), 3.19 (t, J = 4.6Hz, 2H), 3.10 (t, J = 4.6Hz, 2H), 3.15 (t, J = 4.6Hz, 2H), 3.19 (t, J = 4.6Hz, 2H), 3.10 (t, J = 4.6Hz, 2H), 3.19 (t, J = 4.6Hz, 2H), 3.10 (t, J = 4.6Hz, 2H), 3.10 (t, J = 4.6Hz, 2H), 3.19 (t, J = 4.6Hz, 2H), 3.10 (t, J = 4.6Hz, 2H), 3.19 (t, J = 4.6Hz, 2H), 3.10 (t, J = 4.6Hz, 2H), 3.15 (t, J = 4.6Hz, 2H), 3.19 (t, J = 4.6Hz, 2H), 3.15 (t, J = 4.6Hz, 2H), 3.15 (t, J = 4.6Hz, 2H), 3.10 (t, J = 4.6Hz, 2H), 3.10 (t, J = 4.6Hz, 2H), 3.19 (t, J = 4.6Hz, 2H), 3.15 (t, J = 4.6Hz, 2H), 3.19 (t, J = 4.6Hz, 2H), 3.10 (t, J = 4.6Hz, 2H), 3.10 (t, J = 4.6Hz, 2H), 3.19 (t, J = 4.6Hz, 2H), 3.15 (t, J = 4.6Hz, 2H), 3.15 (t, J = 4.6Hz, 2H), 3.10 (t, J = 4.6Hz, 2H), 3.15 (t, J = 4.6Hz, 2H), 3.19 (t, J = 4.6Hz, 2H), 3.19 (t, J = 4.6Hz, 2H), 3.15 (t, J = 4.6Hz, 2H), 3.10 (t, J = 4.6Hz, 2H), 3.10 (t, J = 4.6Hz, 2H), 3.19 (t, J = 4.6Hz, 2H), 3.19 (t, J = 4.6Hz, 2H), 3.15 (t, J = 4.6Hz, 2H), 3.10 (t, J = 4.6Hz, 2H), 3.19 (t, J = 4.6Hz, 2H), 3.10 (t, J = 4.6Hz, 2H), 3.19 (t, J = 4.6Hz, 2H), 3.15 (t, J = 4.6Hz, 2H), 3.10 (t, J = 4.6Hz, 2H), 3.19 (t, J = 4.6Hz, 2H), 3.15 (t, J = 4.6Hz, 2H), 3.19 (t, J = 4.6Hz, 2H), 3.15 (t, J = 4.6Hz, 2H), 3.10 (t, J = 4.6Hz, 2H), 3.19 (t, J = 4.6Hz, 2H), 3.19 (t, J = 4.6Hz, 2H), 3.10 (t, J = 4.6Hz, 2H), 3.15 (t, J = 4.6Hz, 2H), 3.19 (t, J = 4.6Hz, 2H), 3.19 (t, J = 4.6Hz, 2H), 3.19 (t, J = 4.6Hz, 2H), 3.10 (t, J = 4.6Hz, 2H), 3.19 (t, J = 4.6Hz, 2H), 3.10 (t, J = 4.6Hz, 2H), 3.19 (t, J = 4.6Hz, 2H), 3.19 (t, J = 4.6Hz, 2H), 3.10 (t, J = 4.6Hz, 2H), 3.19 (t, J = 4.6Hz, 2H), 3.15 (t, J = 4.6Hz, 2H), 3.19 (t, J = 4.6Hz, 2H), 3.19 (t, J = 4.6Hz, 2H), 3.10 (t, J = 4.6Hz, 2H), 3.19 (t, J = 4.6Hz, 2H), 3.19 (t, J = 4.6Hz, 2H), 3.15 (t, J = 4.6Hz, 2H), 3.19 (t, J = 4.6Hz, 2H), 3.10 (t, J = 4.6Hz, 2H), 3.19 (t, J = 4.6Hz, 2H), 3.15 (t, J = 4.6Hz, 2H), 3.15 (t, J = 4.6Hz, 2H), 3.19 (t, J = 4.6Hz, 2H), 3.10 (t, J = 4.6Hz, 2H), 3.19 (t, J = 4.6Hz, 2H), 3.19 (t, J = 4.6Hz, 2H), 3.19 (t, J = 4.6Hz, 2H), 3.10 (t, J = 4.6Hz, 2H), 3.15 (t, J = 4.6Hz, 2H), 3.10 (t, J = 4.6Hz, 2H), 3.19 (t, J = 4.6Hz, 2H), 3.19 (t, J = 4.6Hz, 2H), 3.15 (t, J = 4.6Hz, 2H), 3.15 (t, J = 4.6Hz, 2H), 3.10 (t, J = 4.6Hz, 2H), 3.19 (t, J = 4.6Hz, 2H), 3.15 (t, J = 4.6Hz, 2H), 3.15 (t, J = 4.6Hz, 2H), 3.15 (t, J = 4.6Hz, 2H), 3.10 (t, J = 4.6Hz, 2H), 3.19 (t, J = 4.6Hz, 2H), 3.19 (t, J = 4.6Hz, 2H), 3.19 (t, J = 4.6Hz, 2H), 3.15 (t, J = 4.6Hz, 2H), 3.10 (t, J = 4.6Hz, 2H), 3.15 (t, J = 4.6Hz, 2H), 3.15 (t, J = 4.6Hz, 2H), 3.19 (t, J = 4.6Hz, 2H), 3.19 (t, J = 4.6Hz, 2H), 3.10 (t, J = 4.6Hz, 2H), 3.15 (t, J = 4.6Hz, 2H), 3.15 (t, J = 4.6Hz, 2H), 3.15 (t, J = 4.6Hz, 2H), 3.1 || | | | | | || --- | --- | --- | --- | --- | --- || (R)-4-(1-(5-cyclopropylmethoxy)pyridin-2-yl)propoxy)-2,3-difluoro-N-(4-methyl-1,4-diazepan-1-yl)isulfonyl)benzamide | C | H | D | Method E (20-95) | m / z=539.2 [M+H]+, Rt=5.31 (1, J=6.4 Hz, 1H), 3.86 (d, J=7.0 Hz, 2.12 (1, 3.55-3.49 (m, 2.12 (1, 3.13-3.27 (m, 2.12-3.23-3.20 (m, 2.12-3.11 (1, 3.11 (1, 3.11 (1, 3.11 (1, 3.11 (1, 3.11 (1, 3.11 (1, 3.11 (1, 3.11 (1, 3.11 (1, 3.11 (1, 3.11 (1, 3.11 (1, 3.12 (1, 3.12 (1, 3.12 (1, 3.12 (1, 3.12 (1, 3.12 (1, 3.12 (1, 3.12 (1, 3.12 (1, 3.12 (1, 3.12 (1, 3.12 (1, 3.12 (1, n=539.2 (r)-N-(4-(2-(dimethylamino)ethoxy)phenyl)isulfonyl)-2,3-difluoro-4-(1-(5-cyclopropylmethoxy)pyridin-2-yl)propoxy)-2,3-difluoro-N-(3,4-trimethyl)phenyl-1,3-difluoro-N-(3,4-trimethyl)phenyl-1,3-difluoro-N-(3,4-trimethyl)phenyl-1,3-difluoro-N-(3,4-trimethyl)phenyl-1,3-difluoro-N-(3,4-trimethyl)phenyl-1,3-difluoro-N-(3,4-trimethyl)phenyl-1,3-difuropoxy-1,3-difluoro-N-(3,4-trimethyl-1,4-diazepan-1,3-difluoro-N-(3,4-trimethyl-1,4-diazepan-1,3-difuropoxy-1,3-difluoro-N-(3,4-trimethyl-1,4-diazepan-1,3-difuropoxy-1,3-difuropoxy-1,3-difuropoxy-1,3-difuropoxy-1,3-difuropoxy-1,3-difuropoxy-1,3-difuropoxy-1,3-difuropoxy-1,3-difuropoxy-1,3-difuropoxy-1,3-difuropoxy-1,3-difuropoxy 1,3-difuropoxy-1,3-difuropoxy-1,3-difuropoxy-1,3-difuropoxy-1,3-difuropoxy-1,3-difuropoxy-1,3-difuropoxy-1,3-difuropoxy-1,3-difuropoxy-1,3-difuropoxy-1,3-difuropoxy-2,3-difuropoxy-2,3-difuropoxy-2,3-difuropoxy-2,3-difuropoxy-2,3-difuropoxy-2,3-difuropoxy-2,3-difuropoxy-2,3-difuropoxy-2,3-difuropoxy-2,3-difuropoxy-2,3-difuropoxy-2.3-difuropoxy-2.3-difuropoxy-2.3-difuropoxy-2.3-difuropoxy-2.3-difuropoxy-2.3-difuropoxy-2.3-difuropoxy-2.3-difuropoxy-2.3-difuropoxy-2.3-difuropoxy-2.3-difuropoxy-2.4-difuropoxy-2.4-difuropoxy-2.4-difuropoxy-2.4-difuropoxy-2.4-difuropoxy-2.4-difuropoxy-2.4-difuropoxy-2.4-difuropoxy-2.4-difuropoxy-2.4-difuropoxy-2.4-difuropoxy-2.4.difuropoxy-2.4.difuropoxy-2.4.difuropoxy-2.4.difuropoxy-2.4.difuropoxy-2.4.difuropoxy-2.4.difuropoxy-2.4.difuropoxy-2.4.difuropoxy-2.4.difuropoxy-2.4.difuropoxy-2.4.d ifuropoxy-2.4.difuropoxy-2.4.difuropoxy-2.4.difuropoxy-2.4.difuropoxy-2.4.difuropoxy-2.4.difuropoxy-2.4.difuropoxy-2.4.difuropoxy-2.4.difuropoxy-2.4.difuropoxy-2.4.difupoxy-2.4.difupoxy-2.4.difupoxy-2.4.difupoxy-2.4.difupoxy-2.4.difupoxy-2.4.difupoxy-2.4.difupoxy-2.4.difupoxy-2.4.difupoxy-2.4.difupoxy-2.4.difupoxy-2.4.difupoxy-2,3-difuropoxy-2,3-difuropoxy-2,3-difuropoxy-2,3-difuropoxy-2,3-difuropoxy-2,3-difuropoxy-2,3-difuropoxy-2,3-difuropoxy-2,3-difuropoxy-2,3-difuropoxy-2,3-difuropxy-2,3-difuropoxy-2,3-difuropoxy-2,3-difuropoxy-2,3-difuropoxy-2,3-difuropoxy-2,3-difuropoxy-2,3-difuropoxy-2,3-difuropoxy-2,3-difuropoxy-2,3-difuropoxy-2,3-difuropoxy 1,3-difuropoxy-2,3-difuropoxy-2,3-difuropoxy-2,3-difuropoxy-2,3-difuropoxy-2,3-difuropoxy-2,3-difuropoxy-2,3-difuropoxy-2,3-difuropoxy-2,3-difuropoxy-2,3-difuropoxy-3,4-difuropoxy-3,4-difuropoxy-3,4-difuropoxy-3,4-difuropoxy-3,4-difuropoxy-3,4-difuropoxy-3,4-difuropoxy-3,4-difuropoxy-3,4-difuropoxy-3,4-difuropoxy-3,4-difuropoxy-3,4.difuropoxy-3,4.difuropoxy-3,4.difuropoxy-3,4.difuropoxy-3,4.difuropoxy-3,4.difuropoxy-3,4.difuropoxy-3,4.difuropoxy-3,4.difuropoxy-3,4.difuropoxy-3,4.difuropoxy-3,4.d ifuropoxy-3,4.difuropoxy-3,4.difuropoxy-3,4.difuropoxy-3,4.difuropoxy-3,4.difuropoxy-3,4.difuropoxy-3,4.difuropoxy-3,4.difuropoxy-3,4.difuropoxy-3,4.difuropoxy-3,4.difupoxy-3,4.difuropoxy-3,4.difuropoxy-3,4.difuropoxy-3,4.difuropoxy-3,4.difuropoxy-3,4.difuropoxy-3,4.difuropoxy-3,4.difuropoxy-3,4.difuropoxy-3,4.difuropoxy-3,4.difuropxy-3,4.difuropoxy-3,4.difuropoxy-3,4.difuropoxy-3,4.difuropoxy-3,4.difuropoxy-3,4.difuropoxy-3,4.difuropoxy-3,4.difuropoxy-3,4.difuropoxy-3,4.difuropoxy-3,4.difuropoxy 1,3-difuropoxy-2,3-difuropoxy-2,3-difuropoxy-2,3-difuropoxy-2,3-difuropoxy-2,3-difuropoxy-2,3-difuropoxy-2,3-difuropoxy-2,3-difuropoxy-2,3-difuropoxy-2,3-d ifuropoxy-2,3-difuropoxy-2,3-difuropoxy-2,3-difuropoxy-2,3-difuropoxy-2,3-difuropoxy-2,3-difuropoxy-2,3-difuropoxy-2,3-difuropoxy-2,3-difuropoxy-2,3-difuropoxy-2,3-difupoxy-2,3-difuropoxy-2,3-difuropoxy-2,3-difuropoxy-2,3-difuropoxy-2,3-difuropoxy-2,3-difuropoxy-2,3-difuropoxy-2,3-difuropoxy-2,3-difuropoxy-2,3-difuropoxy-2,3-difupoxy 1,3-difuropoxy-2,3-difuropoxy-2,3-difuropoxy-2,3-difuropoxy-2,3-difuropoxy-2,3-difuropoxy-2,3-difuropoxy-2,3-difuropoxy-2,3-difuropoxy-2,3-difuropoxy-2,3-difuropxy-2.3.difuropoxy-2.3.difuropoxy-2.3.difuropoxy-2.3.difuropoxy-2.3.difuropoxy-2.3.difuropoxy-2.3.difuropoxy-2.3.difuropoxy-2.3.difuropoxy-2.3.difuropoxy-2.3.difuropoxy-2.3.difuropoxy 1,3-difuropoxy-2,3-difuropoxy-2,3-difuropoxy-2,3-difuropoxy-2,3-difuropoxy-2,3-difuropoxy-2,3-difuropoxy-2,3-difuropoxy-2,3-difuropoxy-2,3.difuropoxy-2,3.difuropoxy-2,3.difuropoxy-2,3.difuropoxy-2,3.difuropoxy-2,3.difuropoxy-2,3.difuropoxy-2,3.difuropoxy-2,3.difuropoxy-2,3.difuropoxy-2,3.difuropoxy-2,3.d ifuropoxy-2,3.difuropoxy-2,3.difuropoxy-2,3.difuropoxy-2,3.difuropoxy-2,3.difuropoxy-2,3.difuropoxy-2,3.difuropoxy-2,3.difuropoxy-2,3.difuropoxy-2,3.difuropoxy-2,3.difupoxy-2,3.difuropoxy-2,3.difuropoxy-2,3.difuropoxy-2,3.difuropoxy-2,3.difuropoxy-2,3.difuropoxy-2,3.difuropoxy-2,3.difuropoxy-2,3.difuropoxy-2,3.difuropoxy-2,3.difuropxy-2,3.difuropoxy-2,3.difuropoxy-2,3.difuropoxy-2,3.difuropoxy-2,3.difuropoxy-2,3.difuropoxy-2,3.difuropoxy-2,3.difuropoxy-2,3.difuropoxy-2,3.difuropoxy-2,3.difuropoxy 1,3-difuropoxy-2,3-difuropoxy-2,3-difuropoxy-2,3-difuropoxy-2,3-difuropoxy-2,3.difuropoxy-2,3.difuropoxy-2,3.difuropoxy-2,3.difuropoxy-2,3.difuropoxy-2,3.difuropoxy-2.3.difuropoxy-2.3.difuropoxy-2.3.difuropoxy-2.3.difuropoxy-2.3.difuropoxy-2.3.difuropoxy-2.3.difuropoxy-2.3.difuropoxy-2.3.difuropoxy-2.3.difuropoxy-2.4.difuropoxy-2.4.difuropoxy-2.4.difuropoxy-2.4.difuropoxy-2.4.difuropoxy-2.4.difuropoxy-2.4.difuropoxy-2.4.difuropoxy-2.4.difuropoxy-2.4.difuropoxy-2.4. || | | | | | | || --- | --- | --- | --- | --- | --- | --- || 4-(R)-1-(5-cyclopropylmethoxy)pyridin-2- ylpropoxy)-N-(R)-3,4-dimethylpiperazin-1- ylpropoxy)-2,3-difluorobenzamide | C | H | A | Method F (25-60) | 1H NMR (400 MHz, DMSO-d6, ppm) 9.54 (s, 1H), 8.25-8.24 (m, 1H), 7.41-7.25 (m, 3H), 6.77 (t, J=7.9 Hz, 1H), 5.32 (s, 6.5 Hz, 1H), 3.86 (d, d, J=7.1 Hz, 2.12 Hz, 3.32 (s, 3H), 2.85-2.60 (m, 4H), 2.10-1.88 (m, 2H), 1.26-1.14 (m, 4H), 0.91 (t, J=7.1 Hz, 1H), 3.34 (m, 1H), 3.22-2.93 (m, 3H), 0.61-0.53 (m, 2H), 0.37-0.25 (m, 2H) | 1H NMR (400 MHz, DMSO-d6, ppm) 8.45 (d, J=7.2 Hz, 1H), 8.16-8.13 (m, 1H), 7.92-7.87 (m, 1H), 7.65-7.62 (m, 1H), 7.51-7.48 (m, 1H), 7.37-7.22 (m, 1H), 7.21-7.08 (m, 2H), 6.86-6.81 (m, 1H), 1.03-4.2 (m, 2H), 3.39-3.31 (m, 6H), 3.14 (s, 3H), 3.02-2.75 (m, 4H), 1.77 (m, 4H), 1.74-1.57 (m, 2H), 1.46-1.37 (s, 3H), 2.12 (s, 3H), 1.72 (s, 3H), 1.71 (s, 3H), 1.70 (s, 3H), 1.69 (s, 3H), 1.67 (s, 3H), 1.66 (s, 3H), 1.65 (s, 3H), 1.64 (s, 3H), 1.63 (s, 3H), 1.62 (s, 3H), 1.61 (s, 3H), 1.60 (s, 3H), 1.60 (s, 3H), 1.60 (s, 3H), 1.60 (s, 3H), 1.60 (s, 3H), 1.60 (s, 3H), 1.60 (s, 3H), 1.60 (s, 3H), 1.60 (s, s, 3H), 1.60 (s, 3H), 1.60 (s, 3H), 1.60 (s, 3H), 1.60 (s, 3H), 1.60 (s, 3H), 1.60 (s, 3H), 1.60 (s, 3H), 1.60 (s, 3S), 1.60 (s, 3S), 1.60 (s, 3S), 1.60 (s, 3S), 1.60 (s, 3S), 1.60 (s, 3S), 1.60 (s, 3S), 1.60 (s, 3S), 1.60 (s, 3S), 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, n, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1.1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 2, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, m, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 11, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 4, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 10, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 13, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 14, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 20, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 21, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 3, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 22, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 23, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 3 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1,1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 5, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1 |01515.05W01W025 / 174957| | | | | | | | || --- | --- | --- | --- | --- | --- | --- | --- || R-N-(4-ethylpiperazin-1-yl)stylinyl)-2,3-difluoro-4-(1-(5-pyridin-2-yl)oxy)pyridin-2- ylpropoxy)benzamide | E | H | A | Method A (20-70) | m / z=562.1 [M+H]+, Rt=0.98 mins (Method K) | 1H NMR (400 MHz, DMSO-d6, ppm) δ 9.38 (s, 1H), 8.45 (d, J=2.6 Hz, 1H), 8.18 (0.09 (m, 1H), 7.95-7.86 (m, 1H), 7.64 (dd, J=8.5, 2.7 Hz, 1H), 7.49 (d, J=8.6 Hz, 1H), 7.44-7.34 (m, 1H), 7.21-7.09 (m, 2H), 6.82 (t, J=8.0 Hz, 1H), 5.45 (t, J=6.4 Hz, 1H), 3.33-2.73 (m, 10 H), 2.12- 1.95 (m, 2H), 1.17 (t, J=7.2 Hz, 3 Hz), 0.96 (t, J=7.3 Hz, 3 Hz) | 1H NMR (400 MHz, DMSO-d6, ppm) δ 9.37 (s, 1H), 8.25 (d, J=1.6 Hz, 1H), 7.41-7.30 (m, 3 H), 6.76 (t, J=7.9 Hz, 1H), 5.32 (t, J=6.5 Hz, 1H), 3.86 (d, J=7.1 Hz, 2.34-2.71 (m, 10 H), 2.09-1.85 (m, 2 H), 1.26-1.10 (m, 4 H), 0.91 (t, J=7.3 Hz, 3 H), 0.61-0.52 (m, 2 H), 0.36-0.27 (m, 2 H) || R-4-(1-(5-cyclopropylmethoxy)pyridin-2- ylpropoxy)-N-(4-dihyphenazin-1- yl)isofloryl)-2,3-difluorobenzamide | C | H | A | Method A (20-70) | m / z=539.1 [M+H]+, Rt=1.02 mins (Method K) | 1H NMR (400 MHz, DMSO-d6, ppm) δ 8.42 (d, J=2.6 Hz, 1H), 8.27 (d, J=1.9 Hz, 1H), 8.11- 8.09 (m, 1H), 8.05 (dd, J=8.7, 1.9 Hz, 1.11, 7.90-7.78 (m, 1H), 7.59 (dd, J=8.6, 2.7 Hz, 1H), 7.44-7.34 (d, J=8.6 Hz, 1H), 7.41-7.32 (m, 10 H), 5.45 (t, J=6.2 Hz, 1H), 3.48 (s, 4 H), 3.16 (s, 4 H), 2.77 (s, 3 H), 2.12-2.05 (m, 2 H), 1.07 (t, J= 7.4 Hz, 3 Hz) | || R-N-(4-methylpiperazin-1-yl)stylinyl)-2-ylpropoxy-1-(5-(pyridin-2-yl)propoxy)-2-ylpropoxy-1-(5-(pyridin-2-yl)propoxy)-2-ylpropoxy-1-(5-(pyridin-2-yl)propoxy)-1-(5-(pyridin-2-yl)propoxy)-1-(5-(pyridin-2-yl)propoxy)-1-(5-(pyridin-2-yl)propoxy)-1-(5-(pyridin-2-yl)propoxy)-1-(5-(pyridin-2-yl)propoxy)-1-(5-(pyridin-2-yl)propoxy)-1-(5-(pyridin-2,3-H) | G | A | Method A (20-90) | m / z=655.6 [M+H]+, Rt=1.09 mins (Method K) | 1H NMR (400 MHz, DMSO-d6, ppm) δ 9.63 (s, 1H), 8.27 (d, J=2.8 Hz, 1H), 8.14 (d, J=1.8 Hz, 1 H), 8.00-7.91 (m, 1H), 7.36 (dd, J=8.7, 2.9 Hz, 1H), 7.21 (d, J=8.7 Hz, 1H), 6.92 (d, J=8.6 Hz, 1 H), 5.73-5.56 (m, 1H), 3.50-3.41 (m, 1 H), 3.41-3.35 (m, 2 H), 3.25-3.09 (m, 2 H), 3.08-8.66 (m, 2 H), 2.79 (t, J=10.4 Hz, 2 H), 2.73-2.65 (m, 1 H), 1.13 (m, 1 H), 0.92 (t, J=7.3 Hz, 3 H), 0.64-0.45 (m, 1 H), 0.38-0.23 (m, 2 H) | | || R-4-(1-(5-cyclopropylmethoxy)pyridin-2- ylpropoxy)-N-(4-(1-methylpiperidin-4- yl)oxy)pyridin-1-yl)isofloryl)-3-yl)isofloryl)-3-yl)isofloryl)-3-yl)isofloryl)-3-yl)isofloryl)-3-yl)isofloryl)-3-yl)isofloryl)-3-yl)isofloryl)-3-yl)isofloryl)-3-yl)isofloryl)-3-yl)isofloryl)-4-yl)isofloryl)-4-yl)isofloryl)-4-yl)isofloryl)-4-yl)isofloryl)-4-yl)isofloryl)-4-yl)isofloryl)-4-yl)isofloryl)-4-yl)isofloryl)-4-yl)isofloryl)-4-yl)isofloryl)-5-yl)isofloryl)-5-yl)isofloryl)-5-yl)isofloryl)-5-yl)isofloryl)-5-yl)isofloryl)-5-yl)isofloryl)-5-yl)isofloryl)-5-yl)isofloryl)-5-yl)isofloryl)-5-yl)isofloryl)-6-yl)isofloryl)-6-yl)isofloryl)-6-yl)isofloryl)-6-yl)isofloryl)-6-yl)isofloryl)-6-yl)isofloryl)-6-yl)isofloryl)-6-yl)isofloryl)-6-yl)isofloryl)-6-yl)isofloryl)-7-yl)isofloryl)-7-yl)isofloryl)-7-yl)isofloryl)-7-yl)isofloryl)-7-yl)isofloryl)-7-yl)isofloryl)-7-yl)isofloryl)-7-yl)isofloryl)-7-yl)isofloryl)-7-yl)isofloryl)-8-yl)isofloryl)-8-yl)isofloryl)-8-yl)isofloryl)-8-yl)isofloryl)-8-yl)isofloryl)-8-yl)isofloryl)-8-yl)isofloryl)-8-yl)isofloryl)-8-yl)isofloryl)-8-yl)isofloryl)-9-yl)isofloryl)-9-yl)isofloryl)-9-yl)isofloryl)-9-yl)isofloryl)-9-yl)isofloryl)-9-yl)isofloryl)-9-yl)isofloryl)-9-yl)isofloryl)-9-yl)isofloryl)-9-yl)isofloryl)-10-yl)isofloryl)-10-yl)isofloryl)-10-yl)isofloryl)-10-yl)isofloryl)-10-yl)isofloryl)-10-yl)isofloryl)-10-yl)isofloryl)-10-yl)isofloryl)-10-yl)isofloryl)-10-l)isofloryl)-10-l)isofloryl)-10-l)isofloryl)-10-l)isofloryl)-10-l)isofloryl)-10-l)isofloryl)-10-l)isofloryl)-10-l)isofloryl)-10-l)isofloryl)-10-l)isofloryl)-10-yl)isofloryl)-10-yl)isofloryl)-10-yl)isofloryl)-10-yl)isofloryl)-10-yl)isofloryl)-10-yl)isofloryl)-10-yl)isofloryl)-10-yl)isofloryl)-10-yl]isofloryl)-10-yl]isofloryl)-10-yl]isofloryl)-10-yl]isofloryl)-10-yl]isofloryl)-10-yl]isofloryl)-10-yl]isofloryl)-10-yl]isofloryl)-10-yl]isofloryl)-10-yl] isofloryl)-10-yl] isofloryl)-10-yl] isofloryl)-10-yl] isofloryl)-10-yl] isofloryl)-10-yl] isofloryl)-10-yl] isofloryl)-10-yl] isofloryl)-10-yl] isofloryl)-10-yl] is ofloryl)-10-yl] isofloryl)-10-yl] isofloryl)-10-yl] isofloryl)-10-yl] isofloryl)-10-yl] isofloryl)-10-yl] isofloryl)-10-yl] isofloryl)-10-yl] isofloryl)-10-yl] isof | | | | | | | || | | | | | | | | | || --- | --- | --- | --- | --- | --- | --- | --- | --- | --- || (R)-N-(4-cyclohexyl)perazin-1-yl)sulfonidyl-4-(1-(5-cyclopropyl)methoxy)pyridin-2-yl)propoxy-2,3-difluorozenazamide | C | H | B | C18 (5-95 MeCN / H2O+ 0.1% NH4OH) | m / z = 593.5 [M+H]+, Rt = 4.05 min (Method C) | 1H NMR (400 MHz, DMSO-d6, ppm) δ 8.23 - 8.22 (m, 1H), 7.34 - 7.32 (m, 2H), 7.32 - 7.28 (m, 1H), 6.81 - 6.75 (m, 1H), 5.29 (J=6.4 Hz, 1H), 3.90 (J=6.8 Hz, 2.1H), 1.87 - 1.83 (m, 2H), 1.78 - 1.74 (m, 2H), 1.59 - 1.56 (m, 1H), 1.31 - 1.05 (m, 6H), 0.92 (J=7.4 Hz, 3H), 0.58 - 0.53 (m, 2H), 0.34 - 0.29 (m, 2H) | | | || (R)-N-(4-cyclohexyl)perazin-1-yl)sulfonidyl-2,3-difluoro-4-(1-(5-cyclo)phen-2-yl)oxy)pyridin-2-yl)propoxy)benzamide | E | H | B | C18 (5-95 MeCN / H2O+ 0.1% NH4OH) | m / z = 616.2 [M+H]+, Rt = 3.9 min (Method C) | 1H NMR (400 MHz, DMSO-d6, ppm) δ 8.41 (d, J=2.7 Hz, 1H), 8.16 - 8.13 (m, 1H), 7.88 - 7.84 (m, 1H), 7.60 (dd, J=2.7 Hz, 1H), 7.32 (m, 1H), 7.16 - 7.13 (m, 1H), 7.09 - 7.09 (m, 1H), 7.09 - 7.09 (m, 1H), 7.09 - 7.09 (m, 1H), 7.09 - 7.09 (m, 1H), 7.09 - 7.09 (m, 1H), 7.09 - 7.09 (m, 1H), 7,99 - 7.09 (m, 1H), 7,99 - 7.09 (m, 1H), 7,99 - 7.09 (m, 1H), 7,99 - 7.09 (m, 1H), 7,99 - 7.09 (m, 1H), 7,99 - 7.09 (m. 1H), 7,99 - 7.09 (m. 1H), 7,99 - 7.09 (m. 1H), 7,99 - 7.09 (m. 1H), 7,99 - 7.09 (m. 1H), 7,99 - 7.09 (m. 1H), 7,99 1,10 - 1,10 (m, 1H), 1,10 - 1,10 (m, 1H), 1,10 - 1,10 (m, 1H), 1,10 - 1,10 (m, 1H), 1,10 - 1,10 (m, 1H), 1,10 - 1,10 (m, 1H), 1,10 - 1,20 (m, 1H), 1,10 - 1,10 (m, 1H), 1,10 - 1,10 (m, 1H), 1,10 - 1,10 (m, 1H), 1,10 - 1,10 (m, 1H), 1,10 - 1,10 (m, 1H), 2,00 - 2,00 (m, 1H), 2,00 - 2,00 (m, 1H), 2,00 - 2,00 (m, 1H), 2,00 - 2,00 (m, 1H), 2,00 - 2,00 (m, 1H), 2,00 - 2,00 (m, 1H), 3,00 - 3,00 (m, 1H), 3,00 - 3,00 (m, 1H), 3,00 - 3,00 (m, 1H), 3,00 - 3,00 (m, 1H), 3,00 - 3,00 (m, 1H), 3,00 - 3,00 (m, 1H). | | | || (R)-4-(1-(5-cyclopropyl)methoxy)pyridin-2-yl)propoxy-N-(4-(4-(2-(dimethylamino)ethoxy)phenyl)isofloryl)-3-(trifluromethyl)benzamide | J | A | A | Method D (25-65) | m / z = 622.2 [M+H]+, Rt = 1.15 min (Method K) | 1H NMR (400 MHz, DMSO-d6, ppm) δ 8.97 (s, 1H), 8.87 (s, 1H), 7.77 (s, 1H), 8.87 (s, 1H), 7.30 (s, 1H), 6.70 (s, 1H), 5.48 (s, 1H), 4.61 (s, 1H), 4.43 (s, 1H), 4.43 (s, 1H), 4.43 (s, 1H), 4.43 (s, 1H), 4.43 (s, 1H), 4.43 (s, 1H), 4.43 (s, 1H), 4.43 (s, 1H), 4.43 (s, s, 1H), 4.43 (s, 1H), 4.43 (s, 1H), 4.43 (s, 1H), 4.43 (s, 1H), 4.43 (s, 1H), 4.43 (s, 1H), 4.43 (s, 1H), 4.43 (s, 1s), 1,10 - 1,10 (m, 1H), 1,10 - 1,10 (m, 1H), 1,10 - 1,10 (m, 1H), 1,10 - 1,10 (m, 1H), 1,10 - 1,10 (m, 1H), 1,10 - 1.10 (m, 1H), 1,10 - 1,10 (m, 1H), 1,10 - 1,10 (m, 1H), 1,10 - 1,10 (m, 1H), 1,10 - 1,10 (m, 1H), 1,10 - 1,10 (m, 1H), | 1H NMR (400 MHz, DMSO-d6, ppm) δ 8.10 (s, 1H), 8.14 (s, 1H), 8.13 (s, 1H), 7.88 - 7.84 (m, 1H), 7.64 (s, 1H), 7.58 - 7.52 (m, 1H), 7.48 (s, 1H), 7.48 (s, 1H), 7.48 (s, 1H), 7.48 (s, 1H), 7.48 (s, 1H), 7.48 (s, 1H), 7.48 (s, 1H), 7.48 (s, 1H), 7.48 (s, 1s), 1,10 - 1,10 (m, 1H), 1,10 - 1,10 (m, 1H), 1,10 - 1,10 (m, 1H), 1,10 - 1,10 (m, 1H), 1,10 - 1,10 (m, 1H), 1.10 - 1,10 (m, 1H), 1,10 - 1,10 (m, 1H), 1,10 - 1,10 (m, 1H), 1,10 - 1,10 (m, 1H), 1,10 - 1,10 (m, 1H), 1,10 - 1,10 (s, 1H), 1,10 - 1,10 (s, 1H), 1,10 - 1,10 (s, 1H), 1,10 - 1,10 (s, 1H), 1,10 - 1,10 (s, 1H), 1,10 - 1,10 (s, 1H), 1,1,10 - 1,10 (s, 1H), 1,10 - 1,10 (s, 1H), 1,10 - 1,10 (s, 1H), 1,10 - 1,10 (s, 1H), 1,10 - 1,10 (s, 1H), 1,10 - 1,1,10 (s, 1H), 1,10 - 1,10 (s, 1H), 1,10 - 1,10 (s, 1H), 1,10 - 1,10 (s, 1H), 1,10 - 1,10 (s, 1H), 1,10 - 1,10 (s, 1s), 1,10 - 1,10 (s, 1H), 1,10 - 1,10 (s, 1H), 1,10 - 1,10 (s, 1H), 1,10 - 1,10 (s, 1H), 1,10 - 1,10 (s, 1H), 1,10 - 1.10 (s, 1H), 1,10 - 1,10 (s, 1H), 1,10 - 1,10 (s, 1H), 1,10 - 1,10 (s, 1H), 1,10 - 1,10 (s, 1H), 1,10 - 1,10 (s, 1H), | 1H NMR (400 MHz, DMSO-d6, ppm) δ 8.10 (s, 1H), 8.14 (s, 1H), 8.13 (s, 1H), 8.14 (s, 1H), 8.13 (s, 1H), 8.14 (s, 1H), 8.14 (s, 1H), 8.14 (s, 1H), 8.14 (s, 1H), 8.14 (s, 1H), 8.14 (s, 1H), 8.14 (s, 1H), 8.14 (s, 1H), 8.14 (s, s, 1H), 8.14 (s, 1H), 8.14 (s, 1H), 8.14 (s, 1H), 8.14 (s, 1H), 8.14 (s, 1H), 8.14 (s, 1H), 8.14 (s, 1H), 8.14 (s, 1s), 1,10 - 1,10 (m, 1H), 1,10 - 1,10 (m, 1H), 1,10 - 1,10 (m, 1H), 1,10 - 1,10 (m, 1H), 1,10 - 1,10 (m, 1H), 10 - 1,10 (m, 1H), 1,10 - 1,10 (m, 1H), 1,10 - 1,10 (m, 1H), 1,10 - 1,10 (m, 1H), 1,10 - 1,10 (m, 1H), 1,10 - 1,10 (t, 1,10 - 1,10 (m, 1H), 1,10 - 1,10 (m, 1H), 1,10 - 1,10 (m, 1H), 1,10 - 1,10 (m, 1H), 1,10 - 1,10 (m, 1H), 1,10 - 1,00 - 2,00 (m, 1H), 1,10 - 1,10 (m, 1H), 1,10 - 1,10 (m, 1H), 1,10 - 1,10 (m, 1H), 1,10 - 1,10 (m, 1H), 1,10 - 1,10 (m, 1H), 3,00 - 3,00 (m, 1H), 3,00 - 3,00 (m, 1H), 3,00 - 3,00 (m, 1H), 3,00 - 3,00 (m, 1H), 3,00 - 3,00 (m, 1H), 4,00 - 4,00 (m, 1H), 4,00 - 4,00 (m, 1H), 4,00 - 4,00 (m, 1H), 4,00 - 4,00 (m, 1H), 4,00 - 4,00 (m, 1H), 4,00 - 4,00 (m, 1H). | 1H NMR (400 MHz, DMSO-d6, ppm) δ 8.11 (s, 1H), 8.12 (s, 1H), 8.13 (s, 1H), 8.14 (s, 1H), 8.14 (s, 1H), 8.14 (s, 1H), 8.14 (s, 1H), 8.14 (s, 1H), 8.14 (s, 1H), 8.14 (s, s, 1H), 8.14 (t, 1,10 - 1,10 (m, 1H), 1,10 - 1,10 (m, 1H), 1,10 - 1,10 (m, 1H), 1,10 - 1,10 (m, 1H), 1,10 - 1,10 (m, 1H), 1,10 - - 1,10 (m, 1H), 1,10 - 1,10 (m, 1H), 1,10 - 1,10 (m, 1H), 1,10 - 1,10 (m, 1H), 1,10 - 1,10 (m, 1H), 1,10 - 1,10 (m, s, 1H), 1,10 - 1,10 (m, 1H), 1,10 - 1,10 (m, 1H), 1,10 - 1,10 (m, 1H), 1,10 - 1,10 (m, 1H), 1,10 - 1,10 (m, 1H), 1,1,10 - 1,10 (s, 1H), 1,10 - 1,10 (s, 1H), 1,10 - 1,10 (s, 1H), 1,10 - 1,10 (s, 1H), 1,10 - 1,10 (s, 1H), 10 - 1,10 (m, 1H), 1,10 - 1,10 (m, 1H), 1,10 - 1,10 (m, 1H), 1,10 - 1,10 (m, 1H), 1,10 - 1,10 (m, 1H), 1,10 - - 1,10 - 1,10 (m, 1H), 1,10 - 1,10 (m, 1H), 1,10 - 1,10 (m, 1H), 1,10 - 1,10 (m, 1H), 1,10 - 1,10 (m, 1H), 1,10 - 1, || | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | || --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- || 1H NMR (400 MHz, DMSO-d6, ppm) δ 8.51 (d, J = 5.62, 1H), 8.23-8.21 (m, 1H), 8.03-7.85 (m, 1H), 7.34 (t, J = 8.0 Hz, 1H), 7.28-7.25 (m, 1H), 7.14 (d, J = 8.2 Hz, 1H), 7.09-7.08 (m, 1H), 7.06-7.04 (m, 1H), 6.75 (t, J = 7.6 Hz, 1H), 5.38 (t, J = 6.4 Hz, 1H), 3.63-3.60 (m, 1H), 3.43 (t, J = 3.41 (m, 3H), 3.02-3.00 (m, 2H), 2.72-2.67 (m, 4H), 2.67 (s, 3H), 2.02-1.96 (m, 2H), 1.80-1.78 (m, 4H), 4.10-1.64 (m, 3H), 3.10-1.60 (m, 2H), 1.39-1.37 (m, 2H), 0.94 (t, J = 7.3 Hz, 3H) | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | || 1H NMR (400 MHz, DMSO-d6, ppm) δ 9.66 (s, 1H), 8.52 (d, J = 5.6 Hz, 1H), 8.26-8.14 (m, 1H), 7.15-7.14 (m, 1H), 7.15-7.14 (m, 1H), 7.11-7.08 (m, 1H), 7.10-7.01 (m, 1H), 7.10-7.01 (m, 1H), 7.10-7.01 (m, 1H), 7.10-7.01 (m, 1H), 7.10-7.01 (m, 1H), 7.10-7.01 (m, 1H), 7.10-7-01 (m, 1H), 7.10-7-01 (m, 1H), 7.10-7-01 (m, 1H), 7.10-7-01 (m, 1H), 7.10-7-01 (m, 1H), 7.10-7-01 (m, 1H), 7.10, 7-01 (m, 1H), 7.10-7-01 (m, 1H), 7.10-7-01 (m, 1H), 7.10-7-01 (m, 1H), 7.10-7-01 (m, 1H), 7.10-7-01 (m, 1H), 7.09-7.04 (m, 1H), 7.09-7.04 (m, 1H), 7.09-7.04 (m, 1H), 7.09-7.04 (m, 1H), 7.09-7.04 (m, 1H), 7.09-7.04 (m, 1H), 7.09-7-01 (m, 1H), 7.09-7-01 (m, 1H), 7.09-7-01 (m, 1H), 7.09-7-01 (m, 1H), 7.09-7-01 (m, 1H), 7.09-7-01 (m, 1H), 7.09-7.01 (m, 1H), 7.09-7-01 (m, 1H), 7.09-7-01 (m, 1H), 7.09-7-01 (m, 1H), 7.09-7-01 (m, 1H), 7.09-7-01 (m, 1H), 7.09, 7-01 (m, 1H), 7.09-7-01 (m, 1H), 7.09-7-01 (m, 1H), 7.09-7-01 (m, 1H), 7.09-7-01 (m, 1H), 7.09-7-01 (m, 1H), 7.10-7-01 (m, 1H), 7.10-7-01 (m, 1H), 7.10-7-01 (m, 1H), 7.10-7-01 (m, 1H), 7.10-7-01 (m, 1H), 7-01-01 (m, 1H), 7-01-01 (m, 1H), 7-01-01 (m, 1H), 7-01-01 (m, 1H), 7-01-01 (m, 1H), 7-01-01 (m, 1H), 7-01-01 (m, 1H). | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | 82 || 1H NMR (400 MHz, DMSO-d6, ppm) δ 9.66 (s, 1H), 8.52 (d, J = 5.6 Hz, 1H), 8.26-8.14 (m, 1H), 7.15-7.14 (m, 1H), 7.15-7.15 (m, 1H), 7.15-7.15 (m, 1H), 7.15-7.15 (m, 1H), 7.15-7.15 (m, 1H), 7.15-7.15 (m, 1H), 7.15-7.15 (m, 1H), 7.15-7-01 (m, 1H), 7.15-7-01 (m, 1H), 7.15-7-01 (m, 1H), 7.15-7-01 (m, 1H), 7.15-7-01 (m, 1H), 7.15-7-01 (m, 1H), 7.15-7.01 (m, 1H), 7.15-7-01 (m, 1H), 7.15-7-01 (m, 1H), 7.15-7-01 (m, 1H), 7.15-7-01 (m, 1H), 7.15-7-01 (m, 1H), 7.15, 7-01 (m, 1H), 7.15-7-01 (m, 1H), 7.15-7-01 (m, 1H), 7.15-7-01 (m, 1H), 7.15-7-01 (m, 1H), 7.15-7-01 (m, 1H), 7.09-7.04 (m, 1H), 7.09-7.04 (m, 1H), 7.09-7.04 (m, 1H), 7.09-7.04 (m, 1H), 7.09-7.04 (m, 1H), 7-01-01 (m, 1H), 7.09-7-01 (m, 1H), 7.09-7-01 (m, 1H), 7.09-7-01 (m, 1H), 7.09-7-01 (m, 1H), 7.09-7-01 (m, 1H), 7.01-01 (m, 1H), 7.01-01 (m, 1H), 7.01-01 (m, 1H), 7.01-01 (m, 1H), 7.01-01 (m, 1H), 7.01-01 (m, 1H), 7.01-01 (m, 1H). | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | || || --- || (R)-N-(4-cyclopentyl)phenyl)β-sulfonyl)4-(dimethylamino)ethoxy) phenyl)pyridin-2-yl-[(R)-1-(5-(1-(3-difluoro-4-(1-(5-(pyridin-2- yl)sulfonyl)2,3-difluoro-4-(1-(5-(pyridin-2- yl)sulfonyl)2,3-difluoro-4-(1-(5-(pyridin-2- yl)sulfonyl)2,3-difluoro-4-(1-(5-(pyridin-2- yl)sulfonyl)2,3-difluoro-4-(1-(5-(pyridin-2- yl)sulfonyl)2,3-difluoro-4-(1-(5-(pyridin-2- yl)sulfonyl)2,3-difluoro-4-(1-(5-(pyridin-2- yl)sulfonyl)2,3-difluoro-4-(1-(5-(pyridin-2- yl)sulfonyl)2,3-difluoro-4-(1-( y)2-(4,2-(4,2-(4,2-(4,2-(4,2-(4,2-(4,2-(4,2-(4,2-(4,2-(4,2-(4,2-(4,2-(4,2-(4,2-(4,2-(4,2-(4,2-(4,2-(4,2-(4,2-(4,2-(4,2-(4,2-(4,2-(4 (4,2-(4,2-(4,2-(4,2-(4,2-(4,2-(4,2-(4,2-(4,2-(4,2-(4,2-(4,2-(4,2-(4,2-(4,2-(4,2-(4,2-(4,2-(4,2-(4,2-(4,2-(4,2-(4,2-(4,2-(4,2- (4,2-(4,2-(4,2-(4,2-(4,2-(4,2-(4,2-(4,2-(4,2-(4,2-(4,2-(4,2-(4,2-(4,2-(4,2-(4,2-(4,2-(4,2-(4,2-(4,2-(4,2-(4,2-(4,2-(4,2-(4 (5,2-(4,2-(4,2-(4,2-(4,2-(4,2-(4,2-(4,2-(4,2-(4,2-(4,2-(4,2-(4,2-(4,2-(4,2-(4,2-(4,2-(4,2-(4,2-(4,2-(4,2-(4,2-(4,2-(4,2-(4,2-( (6,2-(4,2-(4,2-(4,2-(4,2-(4,2-(4,2-(4,2-(4,2-(4,2-(4,2-(4,2-(4,2-(4,2-(4,2-(4,2-(4,2-(4,2-(4,2-(4,2-(4,2-(4,2-(4,2-(4,2-(4,2-( (6,2-(4,2-(4,2-(4,2-(4,2-(4,2-(4,2-(4,2-(4,2-(4,2-(4,2-(4,2-(4,2-(4,2-(4,2-(4,2-(4,2-(4,2-(4,2-(4,2-(4,2-(4,2-(4,2-(4,2-(4, (6,2-(4,2-(4,2-(4,2-(4,2-(4,2-(4,2-(4,2-(4,2-(4,2-(4,2-(4,2-(4,2-(4,2-(4,2-(4,2-(4,2-(4,2-(4,2-(4,2-(4,2-(4,2-(4,2-(4,2-(4 (6,2-(4,2-(4,2-(4,2-(4,2-(4,2-(4,2-(4,2-(4,2-(4,2-(4,2-(4,2-(4,2-(4,2-(4,2-(4,2-(4,2-(4,2-(4,2-(4,2-(4,2-(4,2-(4,2-(4,2-(4 (6,2-(4,2-(4,2-(4,2-(4,2-(4,2-(4,2-(4,2-(4,2-(4,2-(4,2-(4,2-(4,2-(4,2-(4,2-(4,2-(4,2-(4,2-(4,2-(4,2-(4,2-(4,2-(4,2-(4,2-(4 || || --- || 4-(R)-1-(5-(IR,3R)-3-methoxycyclobutaxy)pyridin-2-ylpropoxy-N-(4-methyl)propazin-1-yl)pyridin-1-yl)pyridin-1-yl)pyridin-1-yl)pyridin-1-yl)pyridin-1-yl)pyridin-1-yl)pyridin-1-yl)pyridin-1-yl)pyridin-1-yl)pyridin-1-yl)pyridin-1-yl)pyridin-1-yl)pyridin-1(3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3,3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3 1-(4-methyl)propazin-1-yl)pyridin-1-yl)pyridin-1-yl)pyridin-1-yl)pyridin-1-yl)pyridin-1-yl)pyridin-1-yl)pyridin-1-yl)pyridin-1-yl)pyridin-1-yl)pyridin-1-yl)pyridin-1-5-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-5-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-4-5-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-4-4-5-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-4-4-4-5-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-4-4-4-4-5-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-4-4-4-4-4-5-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-4-4-4-4-4-4-5-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-4-4-4-4-4-4-4-5-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-4-4-4-4-4-4-4-4-5-3-3-3-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-5-3-3-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-5-3-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-5-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-6-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-2-2-2-2-2-2-2-2-2-2-2-2-2-2-2-2-2-2-2-2-2-2-2-2-2-2-2-2-2-2-2-2-2-2-2-2-2-2-2-2-2-2-2-2-2-2-2-2-2-2-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-6-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-6-6-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-5-6-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-2-4-2-4-2-4-2-2-2-2-2-2-2-2-2-2-2-2-2-2-2-2-2-2-2-2-2-2-2-2-2-2-2-2-2-2-2-2-2-2-2-2-2-2-2-2-2-2-2-2-2-2-2-2-3-2-2-2-2-2-2-2-2-2-2-2-2-2-2-2-2-2-2-2-2-2-2-2-2-2-2-2-2-2-2-2-2-2-2-2-2-2-2-2-2-2-2-2-2-2-2-2-2-2-6-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4-4- || || --- || (R)-2,3-difluoro-N-(4-(2-fluoro-2-methylpropyl)piphenazin-1-yl)asulfonyl)-4-(1-(1-(1-(1-(1-(1-(1-(1-(1-(1-(1-(1-(1-(1-(1-(1-(1-(1-(1-(1-(1-(1-(1-(1-(1-(1-(1-(1-(1-(1-(1-(1-(1-(1-(1-(1-(1-(1-(1-(1-(1-(1-(1-(1-(1-(1-(1-(1-(1-(1-( || | | | | | | | | | | || --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- || 2,3-difluoro-4-(R)-1-(4-(1,3R)-3-methoxycyclobutoxy)pyridin-2-ylpropoxy-N-(4-(1,3-methyl)pyridin-4-yl)oxyl)pyridin-1-yl)isoflfonyl)benzamide | P | H | B | Method A (20-60) | 1H NMR (400 MHz, DMSO-d6, ppm) δ 9.80 (s, 1H), 8.36-3.44 (m, 1H), 7.44-3.36 (m, 2H), 3.22-2.98 (m, 6H), 2.93-2.80 (m, 2H), 1H), 1H), 1H), 1H), 1H), 1H), 1H), 1H), 1H), 1H), 1H), 1H), 1H), 1H), 1H), 1H), 1H), 1H), 1H), 1H), 1H), 1H), 1H), 1H), 1H), 2H), 2H), 2H), 2H), 2H), 2H), 2H), 2H), 2H), 2H), 2H), 2H), 2H), 2H), 2H), 2H), 2H), 2H), 2H), 2H), 2H), 2H), 2H), 2H), 2H), 1H), 1H), 1H), 1H), 1H), 1H), 1H), 1H), 1H), 1H), 1H), 1H), 1H), 1H), 1H), 1H), 1H), 1H), 1H), 1H), 1H), 1H), 1H), 1H). | 1H NMR (400 MHz, DMSO-d6, ppm) δ 8.30-8.17 (m, 1H), 7.41-7.24 (m, 3H), 6.74-6.70 (m, 1H), 5.36-4.34 (m, 1H), 4.08-3.96 (m, 1H), 3.74-3.59 (m, 1H), 2.95-2.80 (m, 2H), 1.33-1.35 (m, 2H), 0.93-1.47 (m, 3H), 1.13-1.35 (m, 2H), 0.93-1.47 (m, 3H), 1.13-1.35 (m, 2H), 0.93-1.47 (m, 3H), 1.13-1.35 (m, 2H), 0.93-1.47 (m, 3H), 0.93-1.47 (m, 3H), 1.13-1.35 (m, 2H), 0.93-1.47 (m, 3H), 1.13-1.35 (m, 2H), 0.93-1.47 (m, 3H), 1.13-1.35 (m. 2H), 0.93-1.47 (m, 3H), 1.13-1.35 (m. 2H), 0.93-1.47 (m, 3H), 1.13-1.35 (m. 2H), 0.93-1.47 (m, 3H), 1.13-1.35 | 0.93-1.47 (m, 3H), 1.13-1.35 (m, 2H), 0.93-1.47 (m, 3H), 1.13-1.35 (m. 2H), 0.93-1.47 (m, 3H), 1.13-1.35 (m. 2h), 0.93-1.47 (m, 3H), 1.13-1.35 (m. 2H), 0.93-1.47 (m, 3H), 1.13-1.35 (m. 2H), 0.93-1.47 (m, 3H), 1.13-1.35 (m.2H), 0.93-1.47 (m, 3H), 1.13-1.35 (m. 2H), 0.93-1.47 (m, 3H), 1.13-1.35 (m. 2H), 0.93-1.47 (m, 3H), 1.13-1.35 ( m, 2H), 0.93-1.47 (m, 3H), 1.13-1.35 ( m, 2H), 0.93-1.47 (m, 3H), 1.13-1.35 ( m, 2H), 0.93-1.47 (m, 3H), 1.13-1.35 | 0.93-1.47 (m, 3H), 1.13-1.35 (m. 2H), 0.93-1.47 (m, 3H), 1.13-1.35 (m. 2H), 0.93-1.47 (m, 3H), 1.13-1.35 (m. 2h), 0.93-1.47 (m, 3H), 1.13-1.35 | 0.93-1.47 (m, 3H), 1.13-1.35 (m. 2H), 0.93-1.47 (m, 3H), 1.13-1.35 (m. 2H), 1.13-1.35 (m. 2H), 0.93-1.47 (m, 3H), 1.13-1.35 (m. 2H), 0.93-1.47 (m, 3H), 1.13-1.35 (m. 2H), 0.93-1.47 (m. 3H), 1.13-1.35 (m. 2H), 0.93-1.47 (m. 3H), 1.13-1.35 (m. 2H), 0.93-1.47 (m. 3H), 1.13-1.35 (m. 2H), 0.93-1.47 | 0.93-1.47 (m, 3H), 1.13-1.35 (m. 2H), 0.93-1.47 (m. 3H), 1.13-1.35 (m. 2H), 0.93-1.47 (m. 3H), 1.13-1.35 (m. 2h), 0.93-1.47 (m. 3H), 1.13-1.35 (m. 2H), 0.93-1.47 (m. 3H), 1.13-1.35 (m. 2H), 0.93-1.47 (m. 3H), 1.13-1.35 (m.2H), 0.93-1.47 (m. 3H), 1.13-1.35 (m. 2H), 0.93-1.47 (m. 3H), 1.13-1.35 (m. 2H), 0.93-1.47 (m. 3H), 1.13-1.35 ( m. 2H), 0.93-1.47 (m. 3H), 1.13-1.35 (m. 2H), 0.93-1.47 (m. 3H), 1.13-1.35 (m. 2H), 0.93-1.47 (m. 3H), 1.13-1.3 |01515.05W01w e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e| | | | | | | | | || --- | --- | --- | --- | --- | --- | --- | --- | --- || 4-(R)-1-(5-cyclopropylmethoxy)pyridin-2- ylpropoxy)-2,3-difluoro-N-(4-(CH3)-1- methylpiperidin-3- yloxy)phenyl)isoflfonyl)benzamide | C | B | Method A (30-60) | m / z=616.2 [M+H]+, Rt= 1.39 mins (Method E) | 1H NMR (400 MHz, DMSO-dc, ppm) δ 9.29 (s, 1H), 8.25-8.21 (m, 1H), 7.77-7.74 (m, 2H), 7.40- 7.25 (m, 3H), 7.03-7.00 (m, 2H), 6.76-6.72 (m, 1H), 5.91-1.4-6.4 Hz, 1H), 4.97-4.65 (m, 1H), 3.85 (d, J=7.2 Hz, 2H), 3.13-2.96 (m, 4H), 2.74 (s, 3H), 2.13-1.61 (m, 6H), 1.23-1.16 (m, 1H), 0.89 (t, J=7.4 Hz, 3H), 0.67-0.46 (m, 2H), 0.33-0.28 (m, 2H) | m / z=616.2 [M+H]+, Rt= 1.16 mins (Method F) | 1H NMR (400 MHz, DMSO-dc, ppm) δ 9.49 (s, 1H), 8.28-8.16 (m, 1H), 7.80-7.65 (m, 2H), 7.37- 7.26 (m, 3H), 7.05-6.96 (m, 2H), 6.78-6.68 (m, 1H), 5.11-1.4-6.5 Hz, 1H), 4.99-4.57 (m, 1H), 3.85 (d, J=7.1 Hz, 2H), 3.34-2.09 (m, 4H), 2.75-3.1H), 2.06-1.66 (m, 6H), 1.25-1.13 (m, 1H), 0.89 (t, J=7.3 Hz, 3H), 0.62-0.48 (m, 2H), 0.36-0.23 (m, 2H) | 1H NMR (400 MHz, DMSO-dc, ppm) δ 10.28-11.1H), 8.48-8.36 (m, 1H), 8.17-8.13 (m, 1H), 7.93-7.85 (m, 1H), 7.68-7.59 (m, 1H), 7.54-7.46 (m, 1H), 7.43-7.34 (m, 1H), 7.20-7.09 (m, 2H), 6.86-6.77 (m, 1H), 5.43-1.1H), 1.6-4.4 Hz, 1H), 4.35-4.05 (m, 1H), 3.89-3.64 (m, 4H), 3.05-2.80 (m, 1H), 1.1H), 2.57 (s, 3H), 2.13-1.97 (m, 2H), 1.95-1.81 (m, 1H), 0.93-6.0 (t, J=7.3 Hz, 3H) || 4-(R)-1-(5-cyclopropylmethoxy)pyridin-2- ylpropoxy)-2,3-difluoro-N-(4-(CH3)-1- methylpiperidin-3- yloxy)phenyl)isoflfonyl)benzamide | C | B | Method A (30-70) | m / z=560.2 [M+H]+, Rt= 1.79-7.85 (m, 1H), 7.68-7.59 (m, 1H), 7.54-7.46 (m, 1H), 7.43-7.34 (m, 1H), 7.20-7.09 (m, 2H), 6.86-6.77 (m, 1H), 5-43 (t, J=6.4 Hz, 1H), 4.35-4.05 (m, 1H), 3.89-3.64 (m, 4H), 3.05-2.80 (m, 1H), 1.1H), 2.57 (s, 3H), 2.13-1.97 (m, 2H), 1.95, 1.81 (m, 1H), 0.93-6.0 (t, J=7.3 Hz, 3H), 0.62-0.48 (m, 2H), 0.36-0.23 (m, 2H) | 1H NMR (400 MHz, DMSO-dc, ppm) δ 10.28-11.1H), 8.48-8.36 (m, 1H, 8.17-8.13 (m, 1H), 7.93-7.85 (m, 1H), 7.68-7.59 (m, 1H), 7.54-7.46 (m, 1H), 7.43-7.34 (m, 1H), 7.20-7.09 (m, 1H), 6.86-6.77 (m, 1H), 5-43 (t, J=6.4 Hz, 1H), 4.35-4.05 (m, 1H), 3.89-3.64 (m, 4H), 3.05-2.80 (m, 1H), 1.1H), 2.52 (s, 3H), 2.13-1.97 (m, 2H), 1.95, 1.81 (m, 1H), 0.93-6.0 (t, J=7.3 Hz, 3H), 0.62-0.48 (m, 2H), 0.36-0.23 (m, 2H) | | | |# 4.5.31. Example 31. Preparation of 4-(1-(5-ethoxypyridin-2-yl)ethoxy)-2,3-difluoro-N-((4-methylpiperazin-1-yl)sulfonyl)benzamideStep 1: 4- (1- (5- ethoxypyridin- 2- yl)ethoxy)- 2,3- difluorobenzamide4- [1- (5- Ethoxy- 2- pyridyl)ethoxy]- 2,3- difluoro- benzoic acid (Acid A, 2.61 g, 8.07 mmol), HATU $(4.60\mathrm{g},12.1\mathrm{mmol})$ and DIPEA ( $5.6\mathrm{mL}$ $32.3\mathrm{mmol}$ ) were added together in DMF ( $50~\mathrm{mL}$ ) and the resulting mixture was stirred at RT under $\mathbf{N}\_2$ for $20\mathrm{min}$ . NH4Cl ( $864~\mathrm{mg}$ , 16.1 mmol) was added and the mixture stirred for a further $18\mathrm{h}$ . The reaction mixture was diluted with sat. sodium bicarbonate solution and extracted with EtOAc $(\mathbf{x}2)$ . The organic layers were separated, combined, washed with $\mathrm{H}\_2\mathrm{O}$ $(\mathbf{x}2)$ and brine, dried over $\mathrm{Na\_2SO\_4}$ and concentrated in vacuo. The residue was purified by silica gel flash chromatography (gradient $0.100\%$ EtOAc / cyclohexane) to give the title compound ( $1.58\mathrm{g},60\%)$ as a beige solid. LCMS (Method G) MS $(\mathrm{ES + })[\mathrm{M + H}] + = 323$ $\mathrm{Rt} = 1.44\mathrm{min}$ . ${}^{1}\mathrm{H}$ NMR (300 MHz, DMSOd6, ppm) 8 8.24 (s, 1 H), 7.59 (d, $\mathrm{J = 9.3Hz}$ , 2 H), 7.41 - 7.31 (m, 3 H), 6.95 (t, $\mathrm{J = 7.8Hz}$ , 1 H), 5.63 (q, $\mathrm{J = 6.0Hz}$ , 1 H), 4.09 (q, $\mathrm{J = 6.8Hz}$ , 2 H), 1.63 (d, $\mathrm{J = 6.1Hz}$ , 3 H), 1.32 (t, $\mathrm{J = 6.9Hz}$ , 3 H).15 Step 2: 4- (1- (5- ethoxypyridin- 2- yl)ethoxy)- 2,3- difluoro- N- ((4- methylpiperazin- 1- yl)sulfonyl)benzamideTo a solution of 4- (1- (5- ethoxypyridin- 2- yl)ethoxy)- 2,3- difluorobenzamide ( $50.0\mathrm{mg}$ , 0.155 mmol) and NaH ( $60\%$ $12.0\mathrm{mg}$ , 0.310 mmol) in anhydrous THF ( $1.5\mathrm{mL}$ ) under N2 at $0^\circ \mathrm{C}$ was added 4- methylpiperazine- 1- sulfonyl chloride ( $46.0\mathrm{mg}$ , 0.233 mmol). The reaction was heated to $40^{\circ}\mathrm{C}$ and was stirred for $64~\mathrm{h}$ . The reaction was cooled to RT, diluted with H2O, and extracted with EtOAc (x 3). The combined organic layers were dried over $\mathrm{Na\_2SO\_4}$ and concentrated in vacuo. The residue was purified by prep- HPLC (method H, gradient: $5 - 60\%$ ) to give the title compound ( $24.6\mathrm{mg}$ $32\%$ ) as an off- white solid. LCMS (Method A) MS $(\mathrm{ES + })[\mathrm{M + H}] + = 485.2$ $\mathrm{Rt} = 3.54\mathrm{min}$ . ${}^{1}\mathrm{H}$ NMR (400 MHz, DMSO- d6, ppm) 8 9.64 (s, 1 H), 8.25 (dd, $\mathrm{J = 1.3}$ , $2.3\mathrm{Hz}$ , 1 H), 7.42 - 7.34 (m, 3 H), 6.83 (t, $\mathrm{J = 7.7Hz}$ , 1 H), 5.58 (q, $\mathrm{J = 6.4}$ Hz, 1 H), 4.12 - 4.06 (m, 2 H), 3.27 - 3.16 (m, 4 H), 3.06 (s, 3 H), 2.69 (s, 3 H), 2.31 (s, 1 H), 1.62 (d, $\mathrm{J =}$ $6.5\mathrm{Hz}$ , 3 H), 1.33 (t, $\mathrm{J = 7.0Hz}$ , 3 H).# 4.5.32. Example 32. Preparation of 4-(1-(5-ethoxypyridin-2-yl)ethoxy)-2,3-difluoro-N-(piperidin-4-ylsulfonyl)benzamideStep 1: benzyl 4- [[4- [1- (5- ethoxy- 2- pyridyl)ethoxy]- 2,3- difluoro- benzoyl]sulfamoyl]- piperidine- 1- carboxylate5To a solution of 4- (1- (5- ethoxypyridin- 2- yl)ethoxy)- 2,3- difluorobenzamide ( $120\mathrm{mg}$ $0.372\mathrm{mmol}$ ) and NaH ( $60\%$ $30\mathrm{mg}$ $0.745\mathrm{mmol}$ ) in anhydrous THF ( $3\mathrm{mL}$ ) under $\mathbf{N}\_2$ at $0^\circ \mathrm{C}$ was added benzyl 4- chlorosulfonyl piperidine- 1- carboxylate ( $148~\mathrm{mg}$ $0.465\mathrm{mmol}$ ). The reaction was heated to $40^{\circ}\mathrm{C}$ and was stirred for $16\mathrm{h}$ . The reaction was cooled to RT, diluted with $\mathrm{H}\_2\mathrm{O}$ , and extracted with EtOAc (x 10 3). The combined organic layers were dried over $\mathrm{Na\_2SO\_4}$ and concentrated in vacuo. The residue was purified by silica gel flash chromatography (gradient $50 - 100\%$ EtOAc / cyclohexane then $10\%$ DCM / MeOH) to give the title compound ( $192\mathrm{mg}$ $85\%$ ) as a yellow oil. LCMS (Method H) MS $\mathrm{(ES + )}$ $[\mathrm{M} + \mathrm{H}]^{+} = 604.4$ $\mathrm{Rt} = 1.10\mathrm{min}$Step 2: 4- (1- (5- ethoxypyridin- 2- yl)ethoxy)- 2,3- difluoro- N- (piperidin- 4- ylsulfonyl)benzamide15To a solution of benzyl 4- [[4- [1- (5- ethoxy- 2- pyridyl)ethoxy]- 2,3- difluorobenzoyl]sulfamoyl]piperidine- 1- carboxylate ( $130\mathrm{mg}$ $0.215\mathrm{mmol}$ ) in EtOH ( $12~\mathrm{mL}$ ) was added Pd / C $10\mathrm{wt}\%$ $173\mathrm{mg}$ $0.163\mathrm{mmol}$ ) and ammonium formate ( $220\mathrm{mg}$ $3.49\mathrm{mmol}$ ). The reaction was heated to $80^{\circ}\mathrm{C}$ and was stirred for $2\mathrm{h}$ . The reaction was cooled to RT and was filtered through a short silica pad. 20 The silica pad was washed with DCM. The filtrate was concentrated in vacuo and the residue was purified by silica gel flash chromatography (gradient $0 - 20\%$ MeOH / DCM) then prep- HPLC (method H, gradient: $5 - 60\%$ ) to give the title compound ( $7.7\mathrm{mg}$ $7\%$ ) as an off- white solid. LCMS (Method B) MS $\mathrm{(ES + )}$ $[\mathrm{M} + \mathrm{H}]^{+} = 470.2$ $\mathrm{Rt} = 3.56\mathrm{min}$ . ${}^{1}\mathrm{H}$ NMR (400 MHz, methanol- d4, ppm) $\delta 8.22 - 8.21$ (m, 1 H), 8.03 (s, 1 H), 7.99 - 7.95 (m, 2 H), 7.40 - 7.39 (m, 2 H), 7.34 (s, 1 H), 7.24 - 7.19 (m, 1 H), 7.16 - 7.12 (m, 2 H), 6.75 - 6.70 (m, 1 H), 5.30 - 5.26 (m, 1 H), 5.16 (s, 2 H), 4.18 - 4.15 (m, 2 H), 3.75 - 3.72 (m, 2 H), 3.40 (s, 3 H), 2.15 - 1.94 (m, 2 H), 1.00 (t, $\mathrm{J} = 7.4\mathrm{Hz}$ , 3 H).4.5.33. Example 33. Preparation of $N$ - ((4- (2- (1H- imidazol- 1- yl)ethoxy)phenyl)sulfonyl)- 4- (1- (5- ethoxypyridin- 2- yl)ethoxy)- 2,3- difluorobenzamideStep 1: $N$ - [4- (2- chloroethoxy)phenyl]sulfonyl- 4- [1- (5- ethoxy- 2- pyridyl)ethoxy]- 2,3- difluorobenzamide5To a solution of 4- [1- (5- Ethoxy- 2- pyridyl)ethoxy]- 2,3- difluoro- benzoic acid (Acid A, $500\mathrm{mg}$ $1.55\mathrm{mmol}$ ) in DMF ( $10~\mathrm{mL}$ ) were added 4- (2- chloroethoxy)benzenesulfonamide (547 mg, 2.32 mmol), EDCI ( $821~\mu \mathrm{L}$ $4.64\mathrm{mmol}$ ) and DMAP ( $567~\mathrm{mg}$ $4.64\mathrm{mmol}$ ). The reaction was stirred at RT for $18\mathrm{h}$ . The reaction mixture was concentrated in vacuo and the residue was purified by silica gel flash chromatography (gradient $30 - 100\%$ EtOAc / cyclohexane) to give the title compound ( $225~\mathrm{mg}$ $27\%$ ) as a white solid. LCMS (Method G) MS $\mathrm{(ES + )}$ $\mathrm{[M + H]^+ = 541.2}$ $\mathrm{Rt} = 1.83\mathrm{min}$Step 2: $N$ - ((4- (2- (1H- imidazol- 1- yl)ethoxy)phenyl)sulfonyl)- 4- (1- (5- ethoxypyridin- 2- yl)ethoxy)- 2,3- difluorobenzamide15 A solution of $N$ - [4- (2- chloroethoxy)phenyl]sulfonyl- 4- [1- (5- ethoxy- 2- pyridyl)ethoxy]- 2,3- difluoro- benzamide ( $30\mathrm{mg}$ $0.056\mathrm{mmol}$ ), imidazole ( $4.0\mathrm{mg}$ $0.056\mathrm{mmol}$ ) and $\mathrm{Cs\_2CO\_3}$ ( $54\mathrm{mg}$ $0.166\mathrm{mmol}$ ) in DMF ( $0.5\mathrm{mL}$ ) was heated to $160^{\circ}\mathrm{C}$ under microwave irradiation for $1\mathrm{h}$ . The reaction was cooled to RT, diluted with $\mathrm{H}\_2\mathrm{O}$ , and extracted with EtOAc (x 3). The combined organic layers were dried over $\mathrm{Na\_2SO\_4}$ and concentrated in vacuo. The residue was purified by prep- HPLC (method H, gradient: $5 - 60\%$ ) to give the title compound ( $4.1\mathrm{mg}$ $13\%$ ) as an off- white solid. LCMS (Method B) MS $\mathrm{(ES + )}$ $\mathrm{[M + H]^+ = 573.2}$ $\mathrm{Rt} = 3.31\mathrm{min}$ . ${}^{1}\mathrm{H}$ NMR (400 MHz, DMSO- d6) $\delta 8.28 - 8.25$ (m, 1 H), 8.17 - 8.15 (m, 1 H), 7.72 - 7.69 (m, 2 H), 7.43 (s, 1 H), 7.30 - 7.29 (m, 2 H), 7.25 - 7.20 (m, 1 H), 7.16 (s, 1 H), 6.96 - 6.92 (m, 2 H), 6.79 - 6.74 (m, 1 H), 6.46 (s, 1 H), 5.51 (q, $\mathrm{J} = 6.4\mathrm{Hz}$ , 1 H), 4.43 - 4.39 (m, 2 H), 4.29 (t, $\mathrm{J} = 5.1\mathrm{Hz}$ , 2 H), 4.00 (q, $\mathrm{J} = 7.0\mathrm{Hz}$ , 2 H), 1.54 (d, $\mathrm{J} = 6.5\mathrm{Hz}$ , 3 H), 1.25 (t, $\mathrm{J} = 7.0\mathrm{Hz}$ , 3 H).4.5.34. Example 34. Preparation of $(R)$ - 4- (1- (5- (cyclopropylmethoxy)pyridin- 2- yl)propoxy)- 2,3- difluoro- $N$ - ((4- (2- (oxetan- 3- ylamino)ethoxy)phenyl)sulfonyl)benzamideStep 1: $(R)$ - $N$ - ((4- (2- chloroethoxy)phenyl)sulfonyl)- 4- (1- (5- (cyclopropylmethoxy)pyridin- 2- yl)propoxy)- 2,3- difluorobenzamide5A mixture of $(R)$ - 4- (1- (5- (cyclopropylmethoxy)pyridin- 2- yl)propoxy)- 2,3- difluorobenzoic acid (Acid C, 220 mg, 0.61 mmol), DMAP (148 mg, 1.21 mmol), EDCI (255 mg, 1.33 mmol), and 4- (2- chloroethoxy)benzenesulfonamide (200 mg, 0.85 mmol) in DCM (10 mL) was stirred for 12 h at RT. The reaction mixture was quenched with $\mathrm{H}\_2\mathrm{O}$ (10 ml) and extracted with DCM (20 mL). The organic layer was washed with $\mathrm{NaCl}$ (aq.) (5 mL), dried over $\mathrm{Na}\_2\mathrm{SO}\_4$ and concentrated in vacuo. The residue was purified by flash chromatography (eluent 1:100 DCM / MeOH) to give the title compound (230 mg, 63% yield) as a white solid. LCMS (Method D) MS (ESI) $[\mathrm{M} + \mathrm{H}]^{+} = 581.1$ , $\mathrm{Rt} = 1.49$ min.Step 2: $(R)$ - 4- (1- (5- (cyclopropylmethoxy)pyridin- 2- yl)propoxy)- 2,3- difluoro- $N$ - ((4- (2- (oxetan- 3- ylamino)ethoxy)phenyl)sulfonyl)benzamideA solution of $(R)$ - $N$ - ((4- (2- chloroethoxy)phenyl)sulfonyl)- 4- (1- (5- (cyclopropylmethoxy)pyridin- 2- yl)propoxy)- 2,3- difluorobenzamide (60 mg, 0.10 mmol), KI (0.9 mg, 0.0051 mmol) in oxetan- 3- amine / MeCN (0.3 mL:0.3 mL) was stirred at $80^{\circ}\mathrm{C}$ for 4 h. The reaction mixture was concentrated in vacuo and purified by prep- HPLC (method G, gradient: 45- 55%) to give the title compound (17.3 mg, 97% purity, >99% ee, 26% yield) as a white solid. LCMS (Method E) MS (ESI) $[\mathrm{M} + \mathrm{H}]^{+} = 618.2$ , $\mathrm{Rt} = 1.21$ min. ${}^{1}\mathrm{H}$ NMR (400 MHz, DMSO- $d6$ , ppm) $\delta$ 8.23 (d, $J = 2.3$ Hz, 1 H), 7.71 (d, $J = 8.8$ Hz, 2 H), 7.36- 7.27 (m, 3 H), 6.92 (d, $J = 8.8$ Hz, 2 H), 6.71 (t, $J = 8.0$ Hz, 1 H), 5.30 (t, $J = 6.4$ Hz, 1 H), 4.65 (t, $J = 6.8$ Hz, 2 H), 4.39 (t, $J = 6.2$ Hz, 2 H), 4.10- 3.98 (m, 3 H), 3.85 (d, $J = 7.1$ Hz, 2 H), 2.03- 2.88 (m, 2 H), 2.02- 1.92 (m, 2 H), 1.19- 1.16 (m, 1 H), 0.89 (t, $J = 7.4$ Hz, 3 H), 0.58- 0.53 (m, 2 H), 0.33- 0.30 (m, 2 H).4.5.35. Example 35. Preparation of $(R)$ - N- ((4- (2- (cyclopropylamino)ethoxy)phenyl)- sulfonyl)- 4- (1- (5- (cyclopropylmethoxy)pyridin- 2- yl)propoxy)- 2,3- difluorobenzamideA mixture of $(R)$ - N- ((4- (2- chloroethoxy)phenyl)sulfonyl)- 4- (1- (5- (cyclopropylmethoxy)pyridin- 2- yl)propoxy)- 2,3- difluorobenzamide (50 mg, 0.09 mmol) and KI (1.4 mg, 0.01 mmol) in cyclopropanamine (1 mL) was stirred at $50^{\circ}\mathrm{C}$ for $12\mathrm{h}$ . The reaction mixture was concentrated in vacuo and the residue was purified by prep- HPLC (method C, gradient: $35 - 40\%$ ) to afford the title compound (9.1 mg, $98.5\%$ purity, $>99\%$ ee, $13\%$ yield) as a white solid. LCMS (Method E) MS (ESI) $\mathrm{[M + H]^{+} = 602.22}$ , $\mathrm{Rt} = 1.29\mathrm{min}$ . ${}^{1}\mathrm{H}$ NMR (400 MHz, DMSO- d6, ppm) $\delta 8.73$ (s, 1 H), 8.23 (s, 1 H), 7.76 (d, $J = 8.2\mathrm{Hz},2\mathrm{H}$ ), 7.43- 7.18 (m, 3 H), 7.00 (s, 2 H), 6.81- 6.66 (m, 1 H), 5.30 (t, $J = 6.9\mathrm{Hz},1\mathrm{H}$ ), 4.38- 4.20 (m, 2 H), 3.85 (d, $J = 6.9\mathrm{Hz},2\mathrm{H}$ ), 3.56- 3.40 (m, 2 H), 2.84- 2.69 (m, 1 H), 2.07- 1.87 (m, 2 H), 1.28- 1.12 (m, 1 H), 0.89 (t, $J = 7.3\mathrm{Hz},3\mathrm{H}$ ), 0.81- 0.71 (m, 4 H), 0.61- 0.51 (m, 2 H), 0.36- 0.26 (m, 2 H).4.5.36. Example 36. (R)- 4- (1- (5- (cyclopropylmethoxy)pyridin- 2- yl)propoxy)- 2,3- difluoro- N- ((4- (2- (methylamino)ethoxy)phenyl)sulfonyl)benzamide15A mixture of $(R)$ - N- ((4- (2- chloroethoxy)phenyl)sulfonyl)- 4- (1- (5- (cyclopropylmethoxy)pyridin- 2- yl)propoxy)- 2,3- difluorobenzamide (130 mg, 0.18 mmol) and KI (59 mg, 0.36 mmol) in methylamine (40% in water, 2 mL) was stirred at $50^{\circ}\mathrm{C}$ for $3\mathrm{h}$ . The solution was blown down under a nitrogen stream to a volume of ca. $1\mathrm{mL}$ . The solution was diluted with MeOH (2 mL) and was loaded onto an SCX- 2 cartridge (5 g). The cartridge was washed with MeOH (2CV) and the product was eluted with $2\mathrm{M}$ ammonical MeOH. The basic fraction was concentrated in vacuo to dryness the residue was purified by prep- HPLC (method K, gradient: $40 - 100\%$ ) to afford the title compound (17.3 mg, $>99\%$ ee, $17\%$ yield) as a white solid. LCMS (Method C) MS (ESI) $\mathrm{[M + H]^{+} = 576.6}$ , $\mathrm{Rt} = 4.13\mathrm{min}$ . ${}^{1}\mathrm{H}$ NMR (400 MHz, DMSO- d6, ppm) $\delta 8.45$ (s, 1 H), 8.23 (d, $J = 1.8\mathrm{Hz},1\mathrm{H}$ ), 7.75 - 7.72 (m, 2 H), 7.34 - 7.29 (m, 3 H), 6.97 - 6.94 (m, 2 H), 6.74 - 6.68 (m, 1 H), 5.29 (t, $J = 6.5\mathrm{Hz},1\mathrm{H}$ ), 4.22 (t, $J = 5.0\mathrm{Hz},2\mathrm{H}$ ), 3.87 - 3.84 (m, 2H), 2.62 (s, 3 H), 2.55 - 2.52 (m, 2 H), 2.05 - 1.90 (m, 2 H), 1.25 - 1.15 (m, 1 H), 0.92 - 0.87 (m, 3 H), 0.59 - 0.53 (m, 2 H), 0.33 - 0.28 (m, 2 H).4.5.37. Example 37. Preparation of $(R)$ - N- ((4- ((1H- imidazol- 4- yl)methoxy)phenyl)sulfonyl)- 2,3- difluoro- 4- (1- (5- (2- methoxyethoxy)pyridin- 2- yl)propoxy)benzamideStep 1: tert- butyl 4- [(4- sulfamoylphenoxy)methyl]imidazole- 1- carboxylateTo a solution of 4- hydroxybenzenesulfonamide (255 mg, 1.47 mmol) in DMF (3.7 mL) was added $\mathrm{K}\_2\mathrm{CO}\_3$ (509 mg, 3.69 mmol) and the resulting mixture was stirred at RT under $\mathrm{N}\_2$ for 0.5 h. A solution of tert- butyl 4- (bromomethyl)imidazole- 1- carboxylate (385 mg, 1.47 mmol) in DMF (3.70 mL) was added and the mixture was stirred for a further 4 h. The reaction mixture was diluted with EtOAc, filtered and the filtrate was concentrated in vacuo. The residue was triturated with DCM. The solid was removed by filtration and the filtrate was purified by silica gel flash chromatography (gradient 0- 100% EtOAc / cyclohexane) to give the title compound (79 mg, 15%) as a white solid. LCMS (Method G) MS $(\mathrm{ES}^+)$ $[\mathrm{M - Boc + H}]^+ = 254.1$ , $\mathrm{Rt} = 1.55$ min.15 Step 2: tert- butyl 4- [(4- [(2,3- difluoro- 4- [(1R)- 1- [5- (2- methoxyethoxy)- 2- pyridyl]propoxylbenzoyl)sulfamoyl]phenoxy]methyl]imidazole- 1- carboxylate2,3- difluoro- 4- [(1R)- 1- [5- (2- methoxyethoxy)- 2- pyridyl]propoxylbenzoic acid (Acid D, 45 mg, 0.12 mmol), tert- butyl 4- [(4- sulfamoylphenoxy)methyl]imidazole- 1- carboxylate (65 mg, 0.18 mmol), DMAP (45 mg, 0.368 mmol) and EDCl HCl (70 mg, 0.37 mmol) were added together in DMF (1.2 mL) and the resulting mixture was stirred at RT for 18 h. The solvent was removed in vacuo and the residue was purified by flash chromatography (gradient 0- 100% EtOAc / cyclohexane) to give the title compound (48 mg, 56%) as a white solid. LCMS (Method G) MS $(\mathrm{ES}^+)$ $[\mathrm{M - Boc + H}]^+ = 603.3$ , $\mathrm{Rt} = 1.92$ min.Step 3: $(R)$ - N- ((4- (1H- imidazol- 4- yl)methoxy)phenyl)sulfonyl)- 2,3- difluoro- 4- (1- (5- (2- methoxyethoxy)pyridin- 2- yl)propoxy)benzamideTFA $(0.25\mathrm{mL})$ was added to a solution of tert- butyl 4- [(4- [(2,3- difluoro- 4- [(1R)- 1- [5- (2- methoxyethoxy)- 2- pyridyl]propoxy]benzoyl)sulfamoyl]phenoxy]methyl]imidazole- 1- carboxylate (48 mg, 0.068 mmol) in DCM $(0.25\mathrm{mL})$ and the resulting mixture was stirred at RT for $0.5\mathrm{h}$ . The solvent was removed in vacuo and the residue was purified by reverse phase chromatography (C18, gradient: $10 - 95\%$ MeCN in $\mathrm{H}\_2\mathrm{O}$ $[+0.1\% \mathrm{HCOOH}]$ to give the title compound $(30\mathrm{mg},72\%)$ as a white amorphous solid. LCMS (Method C) MS $(\mathrm{ES} + )$ $[\mathrm{M} + \mathrm{H}]^{+} = 603.4$ $\mathrm{Rt} = 3.04\mathrm{min}$ . ${}^{1}\mathrm{H}$ NMR $(400\mathrm{MHz}$ , methanol- $d / 4$ , ppm) $\delta$ 8.22 - 8.21 (m, 1 H), 8.03 (s, 1 H), 7.99 - 7.95 (m, 2 H), 7.40 - 7.39 (m, 2 H), 7.34 (s, 1 H), 7.24 - 7.19 (m, 1 H), 7.16 - 7.12 (m, 2 H), 6.75 - 6.70 (m, 1 H), 5.30 - 5.26 (m, 1 H), 5.16 (s, 2 H), 4.18 - 4.15 (m, 2 H), 3.75 - 3.72 (m, 2 H), 3.40 (s, 3 H), 2.15 - 1.94 (m, 2 H), 1.00 (t, $\mathrm{J} = 7.4\mathrm{Hz},3\mathrm{H}$ ).154.5.38. Example 38. Preparation of $(R)$ - 4- (1- (5- (cyclopropylmethoxy)pyridin- 2- yl)propoxy)- 2,3- difluoro- N- ((4- [(1- (2- hydroxyethyl)piperidin- 4- yl)oxy)phenyl)sulfonyl)- benzamideStep 1: $N$ - ({4- [(1- {2- [(tert- butyldiphenylsilyl)oxy]ethyl}piperidin- 4- yl)oxy]benzene}sulfonyl)- 4- [(1R)- 1- [5- (cyclopropylmethoxy)pyridin- 2- yl]propoxy]- 2,3- difluorobenzamideTo a solution of $(R)$ - 4- (1- (5- (cyclopropylmethoxy)pyridin- 2- yl)propoxy)- 2,3- difluorobenzoic acid (Acid C, 49 mg, 0.13 mmol), EDCI (70 mg, 0.37 mmol) and DMAP (41 mg, 0.33 mmol) in DCM (1 mL) was added 4- [(1- {2- [(tert- butyldiphenylsilyl)oxy]ethyl}piperidin- 4- yl)oxy]benzenesulfonamide (synthesized analogously to example procedure C, 90 mg, 0.17 mmol) at RT and the reaction was stirred for $3\mathrm{h}$ . The reaction was concentrated in vacuo and the residue was purified by flash chromatography(gradient $0 - 50\%$ EtOAc / PE) to give the title compound ( $60~\mathrm{mg}$ $37\%$ yield) as a colorless oil. LCMS (Method F) MS (ESI) $\mathrm{[M + H]}^+ = 884.4$ $\mathrm{Rt} = 1.37$ min.Step 2: $(R)$ - 4- (1- (5- (cyclopropylmethoxy)pyridin- 2- yl)propoxy)- 2,3- difluoro- $N$ - ((4- ((1- (2- hydroxyethyl)piperidin- 4- yl)oxy)phenyl)sulfonyl)benzamide5$N$ - ({4- [(1- {2- [(tert- butyldiphenylsilyl)oxy]ethyl}piperidin- 4- yl)oxy]benzene}sulfonyl)- 4- [(1R)- 1- [5- (cyclopropylmethoxy)pyridin- 2- yl]propoxy]- 2,3- difluorobenzamide ( $100\mathrm{mg}$ 0.11 mmol) in THF (2 mL) was added TBAF (1 M in THF, $0.44~\mathrm{mL}$ 0.44 mmol) dropwise. The reaction mixture was stirred at RT for $2\mathrm{h}$ . The solvent was removed in vacuo and purified by prep- HPLC (method A, gradient: $35 - 80\%$ to give the title compound ( $24.3\mathrm{mg}$ $98.6\%$ purity, $46\%$ yield, $>99\%$ ee) as a white solid. LCMS (Method F) MS (ESI) $\mathrm{[M + H]}^+ = 884.4$ $\mathrm{Rt} = 1.37$ min. ${}^{1}\mathrm{H}$ NMR (400 MHz, DMSO- $d6$ ppm) $\delta$ 8.23 (s, 1 H), 7.74 (d, $J = 8.7\mathrm{Hz}$ 2 H), 7.43- 7.17 (m, 3 H), 6.99 (d, $J = 8.7\mathrm{Hz}$ 2 H), 6.73 (t, $J = 7.9\mathrm{Hz}$ 1 H), 5.30 (t, $J = 6.4$ Hz, 2 H), 4.69 (s, 1 H), 3.85 (d, $J = 7.1\mathrm{Hz}$ 2 H), 3.77- 3.67 (m, 2 H), 3.24- 2.94 (m, 6 H), 2.22- 2.07 (m, 2 H), 2.06- 1.82 (m, 4 H), 1.26- 1.11 (m, 1 H), 0.89 (t, $J = 7.3\mathrm{Hz}$ 3 H), 0.64- 0.46 (m, 2 H), 0.41- 0.19 (m, 2 H).# 4.5.39. Example 39. Preparation of $(R)$ -4-(1-(5-(cyclopropylmethoxy)pyridin-2-yl)propoxy)-2,3-difluoro- $N$ -((4-(piperidin-4-yloxy)phenyl)sulfonyl)benzamideStep 1: tert- butyl 4- [4- (benzylsulfanyl)phenoxy]piperidine- 1- carboxylateUnder $\mathbf{N}\_2$ , to a solution of tert- butyl 4- (4- bromophenoxy)piperidine- 1- carboxylate ( $1.0\mathrm{g}$ $2.8\mathrm{mmol}$ ) in 1,4- dioxane ( $10~\mathrm{mL}$ ) was added phenylmethanethiol $(0.52\mathrm{g},4.2\mathrm{mmol})$ $\mathrm{Pd\_2(dba)\_3}$ $(0.26\mathrm{g}$ $0.2\mathrm{mmol}$ ), Xanthphos $(0.32\mathrm{g},0.5\mathrm{mmol})$ and DIPEA $(0.9\mathrm{g},7.0\mathrm{mmol})$ . The mixture was stirred at $110^{\circ}\mathrm{C}$ for $16\mathrm{h}$ . The solvent was removed in vacuo. The residue was purified by silica gel flash chromatography (eluent 40:1 DCM / MeOH) to give the title compound ( $800~\mathrm{mg}$ $64\%$ yield) as a yellow oil. LCMS (Method F) MS (ESI) $\mathrm{[M + Na]}^+ = 422.2$ $\mathrm{Rt} = 1.53\mathrm{min}$Step 2: tert- butyl 4- (4- sulfamoylphenoxy)piperidine- 1- carboxylateTo a solution of tert- butyl 4- [4- (benzylsulfanyl)phenoxy]piperidine- 1- carboxylate (270 mg, 0.68 mmol) in AcOH (2 mL) and $\mathrm{H}\_2\mathrm{O}$ (1 mL) was added NCS (360 mg, 2.70 mmol) slowly at $0^\circ \mathrm{C}$ . The reaction mixture was stirred at $0^\circ \mathrm{C}$ for $1\mathrm{~h}$ . The aforesaid reaction solution was added dropwise to $\mathrm{NH}\_3$ - $\mathrm{H}\_2\mathrm{O}$ (28% w / w) (20 mL) at $0^\circ \mathrm{C}$ . The resulting solution was stirred at $0^\circ \mathrm{C}$ for $30\mathrm{~min}$ . The reaction mixture was concentrated in vacuo. The residue was purified by silica gel flash chromatography (eluent 20:1 DCM / MeOH) to give the title compound (60 mg, 27% yield) as a yellow solid. LCMS (Method D) MS (ESI) $\left[\mathrm{M} - t\mathrm{Bu} + \mathrm{H}\right]^+ = 301.1$ , $\mathrm{Rt} = 1.14\mathrm{~min}$ .Step 3: tert- butyl 4- {4- I({4- I({1R)- 1- [5- (cyclopropylmethoxy)pyridin- 2- ylpropoxy}- 2,3- difluorophenyl}methane)sulfonyl}phenoxy}piperidine- 1- carboxylateTo a solution of $(R)$ - 4- (1- (5- (cyclopropylmethoxy)pyridin- 2- yl)propoxy)- 2,3- difluorobenzoic acid (Acid C, 150 mg, 0.41 mmol), EDCI (158 mg, 0.83 mmol) and DMAP (101 mg, 0.83 mmol) in DCM (3 mL) was added tert- butyl 4- (4- sulfamoylphenoxy)piperidine- 1- carboxylate (177 mg, 0.50 mmol) at RT and the reaction was stirred for $3\mathrm{~h}$ . The reaction was concentrated in vacuo and the residue was purified by silica gel flash chromatography (eluent 30:1 DCM / MeOH) to give the title compound (120 mg, 37% yield) as a white solid. LCMS (Method D) MS (ESI) $\left[\mathrm{M} + \mathrm{H}\right]^+ = 702.2$ , $\mathrm{Rt} = 1.51\mathrm{~min}$ .Step 4: $(R)$ - 4- (1- (5- (cyclopropylmethoxy)pyridin- 2- yl)propoxy)- 2,3- difluoro- $N$ - ((4- (piperidin- 4- yloxy)phenyl)sulfonyl)benzamideA solution of tert- butyl 4- {4- I({4- I({1R)- 1- [5- (cyclopropylmethoxy)pyridin- 2- yl]propoxy}- 2,3- difluorophenyl}methane)sulfonyl}phenoxy}piperidine- 1- carboxylate (70 mg, 0.08 mmol) in DCM / TFA = 10:1 (1 mL) was stirred at RT for $2\mathrm{~h}$ . The reaction was concentrated in vacuo and the residue was purified by prep- HPLC (method D, gradient: 45- 95%) to give the title compound (23.9 mg, 97.1% purity,$34.7\%$ yield, $>99\%$ ee) as a white solid. LCMS (Method D) MS (ESI) $\mathrm{[M + H]^{+} = 602.2}$ $\mathrm{Rt} = 1.11\mathrm{min}$ ${}^{1}\mathrm{H}$ NMR (400 MHz, DMSO- d6, ppm) $\delta$ 8.31 (br, 1 H), 8.23 (s, 1 H), 7.71 (d, $J = 8.7 \mathrm{Hz}$ , 2 H), 7.47- 7.16 (m, $3\mathrm{H}$ ), 6.96 (d, $J = 8.8 \mathrm{Hz}$ , 2 H), 6.71 (t, $J = 8.0 \mathrm{Hz}$ , 1 H), 5.29 (t, $J = 6.4 \mathrm{Hz}$ , 1 H), 4.72- 4.56 (m, 1 H), 3.85 (d, $J = 7.1 \mathrm{Hz}$ , 2 H), 3.26- 3.14 (m, 2 H), 3.12- 2.96 (m, 2 H), 2.13- 2.03 (m, 2 H), 2.02- 1.91 (m, 2 H), 1.84- 1.73 (m, 2 H), 1.29- 1.10 (m, 1 H), 0.89 (t, $J = 7.3 \mathrm{Hz}$ , 3 H), 0.66- 0.44 (m, 2 H), 0.36- 0.25 (m, 2 H).4.5.40. Example 40. Preparation of $N$ - ((4- (((1R,4R,5R)- 2- azabicyclo[2.2.1]heptan- 5- yl)oxy)phenyl)sulfonyl)- 4- ((R)- 1- (5- (cyclopropylmethoxy)pyridin- 2- yl)propoxy)- 2,3- difluorobenzamideStep 1: (9H- fluoren- 9- yl)methyl (1R,4R,5R)- 5- (4- (N- (4- ((R)- 1- (5- (cyclopropylmethoxy)- pyridin- 2- yl)propoxy)- 2,3- difluorobenzoyl)sulfamoyl)phenoxy)- 2- azabicyclo[2.2.1]heptane- 2- carboxylateTo a solution of (R)- 4- (1- (5- (cyclopropylmethoxy)pyridin- 2- yl)propoxy)- 2,3- difluorobenzoic acid (Acid C, 35 mg, 0.10 mmol) and CMPI (38 mg, 0.14 mmol) in DMF (2 mL) was added DMAP (3.5 mg, 0.03 mmol) and the mixture was stirred at RT for 20 min. Then, 9H- fluoren- 9- ylmethyl (1R,4R,5R)- 5- (4- sulfamoylphenoxy)- 2- azabicyclo[2.2.1]heptane- 2- carboxylate (synthesized using example procedure D, 56 mg, 0.12 mmol) and NEt3 (29 mg, 0.29 mmol) were added. The reaction mixture was stirred at RT for 1 h. The solvent was concentrated in vacuo. The residue was purified by prep- TLC (eluent 20:1 DCM / MeOH) to give the title compound (30 mg, 30% yield) as a yellow oil. LCMS (Method D) MS (ESI) $\mathrm{[M + H] + = 836.3}$ $\mathrm{Rt} = 1.73 \mathrm{min}$ .Step 2: $N$ - ((4- (((1R,4R,5R)- 2- azabicyclo[2.2.1]heptan- 5- yl)oxy)phenyl)sulfonyl)- 4- ((R)- 1- (5- (cyclopropylmethoxy)pyridin- 2- yl)propoxy)- 2,3- difluorobenzamideA solution of 9H- fluoren- 9- ylmethyl (1R,4R,5R)- 5- {4- I({4- I(1R}- 1- [5- (cyclopropylmethoxy)pyridin- 2- yl]propoxy]- 2,3- difluorophenyl}methane)sulfonyl]phenoxy}- 2-azabicyclo[2.2.1]heptane- 2- carboxylate (30 mg, 0.04 mmol) in DCM (1.2 mL) and $\mathrm{Et}\_2\mathrm{NH}$ (0.6 mL) was stirred at RT for 2 h. The reaction was concentrated in vacuo and the residue was purified by prep- HPLC (method D, gradient: 35- 65%) to give the title compound (7.4 mg, 98% purity, 33% yield) as a white solid. LCMS (Method E) MS (ESI) $[\mathrm{M} + \mathrm{H}]^{+} = 614.4$ , $\mathrm{Rt} = 1.43$ min. ${}^{1}\mathrm{H}$ NMR (400 MHz, DMSO- d6, ppm) $\delta 8.23$ (s, 1 H), 7.71 (d, $\mathrm{J} = 8.8 \mathrm{Hz}$ , 2 H), 7.33- 7.30 (m, 3 H), 6.90 (d, $\mathrm{J} = 8.8 \mathrm{Hz}$ , 2 H), 6.71 (t, $\mathrm{J} = 8.0 \mathrm{Hz}$ , 1 H), 5.31- 5.26 (m, 1 H), 4.89- 4.86 (m, 1 H), 3.97 (s, 1 H), 3.85 (d, $\mathrm{J} = 7.1 \mathrm{Hz}$ , 2 H), 3.44- 3.35 (m, 1 H), 2.99- 2.94 (m, 2 H), 2.34- 2.32 (m, 1 H), 2.07- 1.87 (m, 2 H), 1.84- 1.77 (m, 1 H), 1.73- 1.67 (m, 1 H), 1.60- 1.57 (m, 1 H), 1.50- 1.48 (m, 1 H), 1.23- 1.19 (m, 1 H), 0.89 (t, $\mathrm{J} = 7.3 \mathrm{Hz}$ , 3 H), 0.59- 0.50 (m, $\mathrm{J} = 8.0$ , 1.7 Hz, 2 H), 0.33- 0.26 (m, 2 H).4.5.41. Example 41. Preparation of $(R)$ - N- ((4- ((1- azabicyclo[2.2.1]heptan- 4- yl)oxy)phenyl)sulfonyl)- 4- (1- (5- (cyclopropylmethoxy)pyridin- 2- yl)propoxy)- 2,3- difluorobenzamideStep 1: 4- ((1- azabicyclo[2.2.1]heptan- 4- yl)oxy)- 3- nitrobenzenesulfonamideTo a solution of 1- azabicyclo[2.2.1]heptan- 4- ol ( $p$ - toluenesulfonate salt) $(10\mathrm{g},3.5\mathrm{mmol})$ in dry DMF $20~\mathrm{mL}$ was added $\mathrm{NaH}$ $60\%$ in oil, $0.28\mathrm{g},7.0\mathrm{mmol})$ at $0^\circ \mathrm{C}$ under an atmosphere of $\mathbf{N}\_2$ , and the reaction was stirred at this temperature for $30\mathrm{min}$ . 4- Fluoro- 3- nitrobenzenesulfonamide $(0.770\mathrm{g},3.5$ mmol) was added and the resulting solution was slowly warmed to RT and stirred for $2\mathrm{h}$ . The reaction mixture was quenched with $\mathrm{NH\_4Cl}$ (aq.) ( $10~\mathrm{mL}$ ) and extracted with EtOAc ( $10\mathrm{mL}\mathrm{x}3$ ). The combined organic phases were washed with brine ( $5\mathrm{mL}$ ), dried over $\mathrm{Na\_2SO\_4}$ and then concentrated in vacuo. The residue was purified by silica gel flash chromatography (gradient $0 - 40\%$ EtOAc / PE) to give the title compound (600 mg, $55\%$ yield) as a white solid. LCMS (Method E) MS (ESI) $[\mathrm{M} + \mathrm{H}]^{+} = 314.1$ $\mathrm{Rt} = 1.05$ min.Step 2: $(R)$ - N- ((4- ((1- azabicyclo[2.2.1]heptan- 4- yl)oxy)- 3- nitrophenyl)sulfonyl)- 4- (1- (5- (cyclopropylmethoxy)pyridin- 2- yl)propoxy)- 2,3- difluorobenzamide# WO 2025 / 174957A mixture of $(R)$ - 4- 6- (5- (cyclopropylmethoxy)pyridin- 2- yl)propoxy)- 2,3- difluorobenzoic acid (Acid C, 600 mg, 1.65 mmol), CMPI (614 mg, 2.40 mmol) and DMAP (20 mg, 0.16 mmol) in DCM (10 mL) was stirred at RT for 30 min. 4- ((1- Azabicyclo[2.2.1]heptan- 4- yl)oxy)- 3- nitrobenzenesulfonamide (517 mg, 1.65 mmol) and $\mathrm{NEt}\_3$ (0.688 mL, 4.95 mmol) were added. The resulting solution was stirred for 2 h at $25^{\circ}\mathrm{C}$ . The reaction mixture was quenched with $\mathrm{NH\_4Cl}$ (aq.) (10 mL) and extracted with EtOAc (10 mL x 3). The combined organic phases were washed with brine (10 mL), dried over $\mathrm{Na\_2SO\_4}$ , and concentrated in vacuo. The residue was purified by silica gel flash chromatography (gradient 0- 10% MeOH / DCM) to give the title compound (500 mg, 46% yield) as a yellow solid. LCMS (Method F) MS (ESI) $\mathrm{[M + H]^+ = 659.3}$ , $\mathrm{Rt} = 1.04$ min.10 Step 3: $(R)$ - N- ((4- ((1- azabicyclo[2.2.1]heptan- 4- yl)oxy)- 3- aminophenyl)sulfonyl)- 4- (1- (5- (cyclopropylmethoxy)pyridin- 2- yl)propoxy)- 2,3- difluorobenzamideTo a stirred solution of $(R)$ - N- ((4- ((1- azabicyclo[2.2.1]heptan- 4- yl)oxy)- 3- nitrophenyl)sulfonyl)- 4- (1- (5- (cyclopropylmethoxy)pyridin- 2- yl)propoxy)- 2,3- difluorobenzamide (500 mg, 0.76 mmol) in MeOH (10 mL) was added $\mathrm{PdC}$ (50 mg, 10% wt / v) at RT under $\mathrm{N}\_2$ atmosphere. The resulting atmosphere was evacuated under vacuum and purged with $\mathrm{H}\_2$ several times. The mixture was stirred for 16 h at RT under $\mathrm{H}\_2$ . After completion, the mixture was filtered. The filtrate was concentrated in vacuo to give the title compound (300 mg, 63% yield) as a yellow solid. The crude product was used directly in the next step without further purification. LCMS (Method D) MS (ESI) $\mathrm{[M + H]^+ = 629.2}$ , $\mathrm{Rt} = 1.10$ min.20Step 4: $(R)$ - N- ((4- ((1- azabicyclo[2.2.1]heptan- 4- yl)oxy)phenyl)sulfonyl)- 4- (1- (5- (cyclopropylmethoxy)pyridin- 2- yl)propoxy)- 2,3- difluorobenzamideTo a solution of $(R)$ - N- ((4- ((1- azabicyclo[2.2.1]heptan- 4- yl)oxy)- 3- aminophenyl)sulfonyl)- 4- (1- (5- (cyclopropylmethoxy)pyridin- 2- yl)propoxy)- 2,3- difluorobenzamide (150 mg, 0.45 mmol) in THF (5 mL) was added $t$ - BuONO (0.267 mL, 2.25 mmol) dropwise at $0^{\circ}\mathrm{C}$ under $\mathrm{N}\_2$ . The mixture was then heated at $60^{\circ}\mathrm{C}$ for 2 h. The solvent was removed in vacuo. The residue was purified by Prep- HPLC (method D, gradient: 45- 95%) to give the title compound (6.4 mg, 91.6% purity, 2.3% yield) as a yellowsolid. LCMS (Method E) MS (ESI) $\mathrm{[M + H]^+ = 614.5}$ $\mathrm{Rt} = 1.37$ min. ${}^{1}\mathrm{H}$ NMR (400 MHz, DMSO- d6, ppm) $\delta 8.22$ (s, 1 H), 7.80 (d, $J = 8.6 \mathrm{Hz}$ , 2 H), 7.37- 7.24 (m, 3 H), 7.06 (d, $J = 8.7 \mathrm{Hz}$ , 2 H), 6.72 (t, $J =$ $8.2\mathrm{Hz}$ , 1 H), 5.27 (t, $J = 6.3 \mathrm{Hz}$ , 1 H), 3.88 (d, $J = 6.9 \mathrm{Hz}$ , 2 H), 3.53- 3.50 (m, 2 H), 3.44- 3.27 (m, 4 H), 2.21- 1.90 (m, 6 H), 1.25- 1.19 (m, 1 H), 0.90 (t, $J = 7.3 \mathrm{Hz}$ , 3 H), 0.61- 0.41 (m, 2 H), 0.37- 0.23 (m, 2 H).4.5.42. Example 42. Preparation of $(R)$ - 4- (1- (5- (cyclopropylmethoxy)pyridin- 2- yl)propoxy)- 2,3- difluoro- $N$ - ((6- ((1- methylpiperidin- 4- yl)oxy)- 2- azaspiro[3.3]heptan- 2- yl)sulfonyl)benzamideStep 1: tert- butyl 6- (pyridin- 4- yloxy)- 2- azaspiro[3.3]heptane- 2- carboxylateTo a stirred solution of tert- butyl 6- hydroxy- 2- azaspiro[3.3]heptane- 2- carboxylate (19.0 g, 89.1 mmol) and pyridin- 4- oil (8.47 g, 89.1 mmol) in THF (200 mL) was added $\mathrm{PPh}\_3$ (30.4 g, 116 mmol) and DIAD (23.42 g, 115.8 mmol). The mixture was stirred at $60^{\circ}\mathrm{C}$ for $12 \mathrm{h}$ . The solvent was removed in vacuo. The residue was purified by silica gel flash chromatography (gradient: $0 - 10\%$ MeOH / DCM $0 - 10\%$ to give the title compound (17 g, 59% yield) as a yellow solid. LCMS (Method D) MS (ESI) $\mathrm{[M + H]^+ = 291.4}$ $\mathrm{Rt} = 0.86 \mathrm{min}$ .Step 2: 1- benzyl- 4- ((2- (tert- butoxycarbonyl)- 2- azaspiro[3.3]heptane- 6- yl)oxy)pyridin- 1- ium bromideA mixture of tert- butyl 6- (pyridin- 4- yloxy)- 2- azaspiro[3.3]heptane- 2- carboxylate (17.0 g, 58.5 mmol) and BnBr (11.0 g, 64.4 mmol) in MeCN (170 mL) was stirred at $80^{\circ}\mathrm{C}$ for $16 \mathrm{h}$ . The reaction mixture was cooled to RT. The precipitate was collected by filtration to give the title compound (10 g, 33% yield) as a white solid, which was used directly in the next step without further purification. LCMS (Method D) MS (ESI) $\mathrm{[M + H]^+ = 461.1}$ $\mathrm{Rt} = 1.06 \mathrm{min}$ .Step 3: tert- butyl 6- ((1- benzyl- 1,2,3,6- tetrahydropyridin- 4- yloxy)- 2- azaspiro[3.3]heptane- 2- carboxylateUnder $\mathbf{N}\_2$ atmosphere, to a solution of 1- benzyl- 4- ((2- (tert- butoxycarbonyl)- 2-5 azaspiro[3.3]heptan- 6- vl)oxy)pyridin- 1- ium bromide ( $10\mathrm{g},21.6\mathrm{mmol})$ in MeOH ( $100~\mathrm{mL}$ was added $\mathrm{NaBH\_4}$ $(4.9\mathrm{g},129.6\mathrm{mmol})$ and the reaction mixture was stirred at RT for $12\mathrm{h}$ . The solvent was removed in vacuo. The residue was purified by silica gel flash chromatography (gradient $0 - 2\%$ MeOH / DCM) to give the title compound ( $6\mathrm{g},68\%$ yield) as a white solid. ${}^{1}\mathrm{H}$ NMR (400 MHz, DMSO- d6, ppm) 8 7.36- 7.18 (m, 5 H), 4.44 (s, 1 H), 4.28- 4.20 (m, 1 H), 3.87- 3.72 (m, 4 H), 3.51 (s, 2 H), 2.87 (s, 2 H), 2.58- 2.51 (m, 4 H), 2.12- 1.95 (m, 4 H), 1.35 (s, 9H).Step 4: tert- butyl 6- (piperidin- 4- yloxy)- 2- azaspiro[3.3]heptane- 2- carboxylateUnder $\mathbf{H}\_2$ atmosphere, a mixture of tert- butyl 6- {[1- (1- methylphenyl)- 3,6- dihydro- 2H- pyridin- 4- ylloxy}- 2- azaspiro[3.3]heptane- 2- carboxylate (4.5 g, 11.7 mmol), 1,1,2- trichloroethane (1.71 g, 12.8 mmol) and $10\%$ Pd / C (1.24 g, 11.7 mmol) in THF / EtOH (25 mL / 17.5 mL) was stirred at RT for $24\mathrm{h}$ . Then the mixture was filtered through celite. The filtrate was concentrated in vacuo to give the title compound (3.15 g, 82% yield) as a white solid, which was used directly in next step without further purification. LCMS (Method D) MS (ESI) $\mathrm{[M + H]^+ = 297.4}$ , $\mathrm{Rt} = 1.38\mathrm{min}$ .Step 5: tert- butyl 6- ((1- methylpiperidin- 4- yloxy)- 2- azaspiro[3.3]heptane- 2- carboxylateUnder $\mathbf{N}\_2$ atmosphere, to a mixture of tert- butyl 6- (piperidin- 4- yloxy)- 2- azaspiro[3.3]heptane- 2- carboxylate (3 g, 10.1 mmol) and paraformaldehyde (1.57 g, 25.3 mmol) in $\mathrm{CF}\_3\mathrm{CH}\_2\mathrm{OH}$ (30 mL) was added $\mathrm{NaBH\_4}$ (1.15 g, 30.3 mmol) and the resulting mixture was stirred at $78^{\circ}\mathrm{C}$ for $2\mathrm{h}$ . The solvent was removed in vacuo. The residue was purified by silica gel flash chromatography (gradient 0- 25%MeOH / DCM) to give the title compound (3 g, 86% yield) as a yellow oil. LCMS (Method D) MS (ESI) $\mathrm{[M + H]^{+} = 311.4}$ , $\mathrm{Rt} = 1.60\mathrm{min}$ .Step 6: 6- ((1- methylpiperidin- 4- yl)oxy)- 2- azaspiro[3.3]heptaneTo a solution of tert- butyl 4- (4- {1- [(tert- butoxy)carbonyl]azetidin- 3- yl}phenoxy)pyrazole- 1- carboxylate (3 g, 9.7 mmol) in dry DCM (30 mL) was added TFA (6 mL) and the reaction was stirred at RT for 1 h. The solvent was removed in vacuo. The residue was purified by silica gel flash chromatography (gradient 0- 25% MeOH / DCM with 0.4% $\mathrm{NH\_3H\_2O}$ ) to give the title compound (2 g, 89% yield) as a yellow oil. LCMS (Method D) MS (ESI) $\mathrm{[M + H]^{+} = 211.3}$ , $\mathrm{Rt} = 0.16\mathrm{min}$ .Step 7: (tert- butoxycarbonyl)((4- (dimethyliminio)pyridin- 1(4H)- yl)sulfonyl)amide15To a cooled solution of 2- methylpropan- 2- ol (2.73 g, 36.8 mmol) in DCM (80 mL) was added chlorosulfonyl isocyanate (5.21 g, 36.8 mmol) at $0^\circ \mathrm{C}$ . DMAP (8.99 g, 73.6 mmol) was added, and the reaction was stirred at RT for 1 h. The reaction mixture was washed with $\mathrm{H}\_2\mathrm{O}$ (10 mL x 3), dried, filtered and concentrated in vacuo to give the title compound (12 g, 97% yield) as a white solid. LCMS (Method E) MS (ESI) $\mathrm{[M + H]^{+} = 302.3}$ , $\mathrm{Rt} = 1.12\mathrm{min}$ .Step 8: tert- butyl ((6- ((1- methylpiperidin- 4- yl)oxy)- 2- azaspiro[3.3]heptan- 2- yl)sulfonyl)carbamateTo a solution of 6- ((1- methylpiperidin- 4- yl)oxy)- 2- azaspiro[3.3]heptane (1.8 g, 5.4 mmol) and $\mathrm{NEt\_3}$ (1.64 g, 16.2 mmol) in dry DCM (20 mL) was added (tert- butoxycarbonyl)((4- (dimethyliminio)pyridin- 1(4H)- yl)sulfonyl)amide (3.25 g, 5.4 mmol) at $0^\circ \mathrm{C}$ and the reaction was stirred at RT for 2 h. The mixture was concentrated in vacuo. The residue was purified by silica gel flashchromatography (gradient $0 - 20\%$ MeOH / DCM) to give the title compound (0.6 g, 20% yield) as a white solid. LCMS (Method D) MS (ESI) $\mathrm{[M + H]^+ = 390.5}$ , $\mathrm{Rt} = 0.71$ min.Step 9: 6- ((1- methylpiperidin- 4- yl)oxy)- 2- azaspiro[3.3]heptane- 2- sulfonamideTo a solution of tert- butyl ((6- ((1- methylpiperidin- 4- yl)oxy)- 2- azaspiro[3.3]heptan- 2- yl)sulfonyl)carbamate (400 mg, 1.02 mmol) in dry DCM (4 mL) was added TFA (0.8 mL) and the reaction was stirred at RT for 1 h. The reaction mixture was concentrated in vacuo and lyophilized to give the title compound (400 mg, 94% yield) as a yellow oil. LCMS (Method E) MS (ESI) $\mathrm{[M + H]^+ = 290.4}$ , $\mathrm{Rt} = 0.3$ min.Step 10: (R)- 4- (1- (5- (cyclopropylmethoxy)pyridin- 2- yl)propoxy)- 2,3- difluoro- N- ((6- ((1- methylpiperidin- 4- yl)oxy)- 2- azaspiro[3.3]heptan- 2- yl)sulfonyl)benzamideA solution of 4- [(1R)- 1- [5- (cyclopropylmethoxy)pyridin- 2- yl]propoxy]- 2,3- difluorobenzoic acid (Acid C, 200 mg, 0.55 mmol), CMPI (211 mg, 0.83 mmol) and DMAP (20 mg, 0.17 mmol) in DMF (4 mL) was stirred at RT for 20 min. 6- [(1- methylpiperidin- 4- yl)oxy]- 2- azaspiro[3.3]heptane- 2- sulfonamide (400 mg, 0.97 mmol) and $\mathrm{NEt}\_3$ (223 mg, 2.20 mmol) were added. The reaction mixture was stirred at RT for 2 h. The mixture was purified by C18 chromatography (gradient 50- 60% $\mathrm{MeCN / H\_2O}$ ) to afford the title compound (67.3 mg, 96.5% purity, 100% ee, 19% yield) as a white solid. LCMS (Method D) MS (ESI) $\mathrm{[M + H]^+ = 635.7}$ , $\mathrm{Rt} = 1.10$ min. ${}^{1}\mathrm{H}$ NMR (400 MHz, DMSO- d6, ppm) $\delta$ 10.35 (s, 1 H), 8.26 (s, 1 H), 7.42- 7.25 (m, 3 H), 6.90 (t, $J = 7.9$ Hz, 1 H), 5.39 (t, $J = 6.4$ Hz, 1 H), 4.00- 3.80 (m, 7 H), 3.66- 3.52 (m, 1 H), 3.20- 2.88 (m, 4 H), 2.69 (s, 3 H), 2.43- 2.36 (m, 2 H), 2.04- 1.95 (m, 4 H), 1.92- 1.50 (m, 4 H), 1.22- 1.17 (m, 1 H), 0.91 (t, $J = 7.3$ Hz, 3 H), 0.65- 0.53 (m, 2 H), 0.36- 0.28 (m, 2 H).# 4.5.43. Example 43. Preparation of $(R)$ -4-(1-(5-(cyclopropylmethoxy)pyridin-2-yl)propoxy)-2,3-difluoro- $N$ -((3-((1-methylpiperidin-4-yl)oxy)azetidin-1-yl)sulfonyl)benzamideStep 1: tert- butyl 3- (pyridin- 4- yloxy)azetidine- 1- carboxylate5 To a solution of 4- chloropyridine hydrochloride $(21.7\mathrm{g},0.14\mathrm{mol})$ in DMSO $250\mathrm{mL}$ ) was added tert- butyl 3- hydroxyazetidine- 1- carboxylate $(25.0\mathrm{g},0.14\mathrm{mol})$ and $t\cdot$ BuONa $(38.8\mathrm{g},0.41\mathrm{mol})$ . The mixture was stirred at $80^{\circ}\mathrm{C}$ for $16\mathrm{h}$ . The solvent was removed under vacuum. The residue was purified by silica gel column chromatography (eluting with EtOAc / PE, $0\%$ to $50\%$ ) to give the title compound $(20.0\mathrm{g},90\%$ purity, $50\%$ yield) as a yellow oil. LCMS (Method F) MS (ESI) $[\mathrm{M + H}]^{+} = 250.95$ $\mathrm{Rt} = 0.74$ 10 min. ${}^{1}\mathrm{H}$ NMR (400 MHz, DMSO- $d\_{6}$ ppm) 8 8.42- 8.40 (m, 2 H), 6.88- 6.86 (m, 2 H), 5.20- 4.97 (m, 1 H), 4.40- 4.25 (m, 2 H), 3.83- 3.79 (m, 2 H), 1.39 (s, 9 H).# Step 2: tert-butyl 3-(piperidin-4-yloxy)azetidine-1-carboxylateTo a solution of tert- butyl 3- (pyridin- 4- yloxy)azetidine- 1- carboxylate $(18.0\mathrm{g},71.9\mathrm{mmol})$ in 15 AcOH $(200~\mathrm{mL})$ was added PtO2 $(3.6\mathrm{g})$ in a $500\mathrm{- mL}$ pressure vessel. The reaction mixture was stirred at $40^{\circ}\mathrm{C}$ for 48 hours under 3 atmosphere $\mathrm{H}\_{2}$ . The mixture was filtered through celite and concentrated under vacuum to give the title compound ( $14\mathrm{g}$ $95\%$ purity, $76\%$ yield) as a yellow oil, which was used directly in next step without further purification. LCMS (Method F) MS (ESI) $[\mathrm{M + H}]^{+} = 257.3$ $\mathrm{Rt} = 3.53\mathrm{min}$ ${}^{1}\mathrm{H}$ NMR (400 MHz, DMSO- $d\_{6}$ ppm) 8 4.41- 4.33 (m, 1 H), 4.10- 3.91 (m, 2 H), 3.73- 3.48 (m, 3 H), 3.17- 20 3.03 (m, 2 H), 2.94- 2.73 (m, 2 H), 1.88- 1.87(m, 2 H), 1.68- 1.52 (m, 2 H), 1.37 (s, 9 H).Step 3: tert- butyl 3- ((1- methylpiperidin- 4- yl)oxy)azetidine- 1- carboxylateA mixture of tert- butyl 3- (piperidin- 4- yloxy)azetidine- 1- carboxylate $(4.0\mathrm{g},15.60\mathrm{mmol})$Paraformaldehyde (1.17 g, 39 mmol) and HCOOH (2.94 mL, 78.0 mmol) in dioxane (50 mL) was stirred at $80^{\circ}\mathrm{C}$ for $1\mathrm{~h}$ . The solvent was removed under vacuum. The residue was purified by silica gel chromatography (eluting with MeOH / DCM, $0\%$ to $10\%$ ) to give the title compound (3.0 g, $95\%$ purity, $71\%$ yield) as a colorless oil. LCMS (Method F) MS (ESI) $\mathrm{[M + H]^{+} = 271.2}$ , $\mathrm{Rt} = 0.87\mathrm{~min}$ . ${}^{1}\mathrm{H}$ NMR (400 MHz, DMSO- $d\_{6}$ , ppm) $\delta 4.41 - 4.27$ (m, 1 H), 4.02 (t, $J = 7.6\mathrm{~Hz}$ , 2 H), 3.66- 3.64 (m, 2 H), 3.54- 3.41 (m, 1 H), 3.01- 3.00 (m, 2 H), 2.70- 2.69 (m, 2 H), 2.51- 2.49 (m, 3 H), 1.97- 1.79 (m, 2 H), 1.64- 1.62 (m, 2 H), 1.37 (s, 9 H).Step 4: tert- butyl 4- (azetidin- 3- yloxy)- 1- methylpiperidineTo a solution of tert- butyl 3- ((1- methylpiperidin- 4- yl)oxy)azetidine- 1- carboxylate (3.0 g, 11.1 mmol) in DCM (30 mL) was added TFA (6 mL). The mixture was stirred for 3 hours at RT. The mixture was concentrated under vacuum to afford the title compound (1.5 g, $79\%$ yield) and was used in the next reaction without any further purification. LCMS (Method F) MS (ESI) $\mathrm{[M + H]^{+} = 171.2}$ , $\mathrm{Rt} = 0.21\mathrm{~min}$ .Step 5: benzyl ((3- (1- methylpiperidin- 4- yl)oxy)azetidin- 1- yl)sulfonyl)carbamateTo a solution of tert- butyl 4- (azetidin- 3- yloxy)- 1- methylpiperidine (2.9 g, 17.0 mmol) and $\mathrm{NEt}\_3$ (7.10 mL, 51.12 mmol) in dry DCM (50 mL) was added ((benzyloxy)carbonyl) ((4- (dimethyliminio)pyridin- 1(4H)- yl)sulfonyl)amide (6.85 g, 20.5 mmol) at $0^{\circ}\mathrm{C}$ and the reaction was stirred at RT for $2\mathrm{~h}$ . The mixture was concentrated in vacuo. The residue was purified by reverse- phas column chromatography (C18 column, eluting with $10\%$ to $90\%$ MeCN / H $\_2$ O, containing $0.1\%$ HCOOH) to afford the title compound (1.5 g, $80\%$ purity, $18\%$ yield) as an off- white solid. LCMS (Method F) MS (ESI) $\mathrm{[M + H]^{+} = 384.2}$ , $\mathrm{Rt} = 0.69\mathrm{~min}$ . ${}^{1}\mathrm{H}$ NMR (400 MHz, DMSO- $d\_{6}$ , ppm) $\delta 7.42 - 7.35$ (m, 5 H), 5.19 (s, 2 H), 4.39- 4.33 (m, 1 H), 4.18- 4.11 (m, 2 H), 3.90- 3.82 (m, 2 H), 3.52- 3.42 (m, 2 H), 3.26- 3.213 (m, 1 H), 3.07- 2.83 (m, 2 H), 2.76 (s, 3 H), 2.10- 1.94 (m, 1 H), 1.92- 1.75 (m, 2 H), 1.59- 1.51 (m, 1 H).Step 6: 3- ((1- methylpiperidin- 4- yl)oxy)azetidine- 1- sulfonamideTo a stirred solution of benzyl ((3- ((1- methylpiperidin- 4- yl)oxy)azetidin- 1- yl)sulfonyl)carbamate $(1.4\mathrm{g},3.65\mathrm{mmol})$ in MeOH ( $20~\mathrm{mL}$ ) was added Pd / C ( $150\mathrm{mg}$ $10\% \mathrm{wt / wt}$ ) at RT under a nitrogen 5 atmosphere. The resulting solution was evacuated under vacuum and purged with $\mathrm{H}\_2$ several times. The mixture stirred for 16 hours at RT under $\mathrm{H}\_2$ (1 atm). After completion, the mixture was filtered. The filtrate was concentrated under reduced pressure to give the title compound $(0.7\mathrm{g},80\%$ purity, $62\%$ yield) as an off- white solid. LCMS (Method F) MS (ESI) $\mathrm{[M + H]^{+} = 250.1}$ $\mathrm{Rt} = 0.21$ min. ${}^{1}\mathrm{H}$ NMR (400 MHz, MeOD- $d\_{\cdot}$ ppm) 8 4.42- 4.36 (m, 1 H), 3.98- 3.93 (m, 2 H), 3.70- 3.65 (m, 2 H), 3.55- 3.51 (m, 1 H), 3.36- 10 3.30 (m, 2 H), 3.22- 3.18 (m, 1 H), 3.06- 3.00 (m, 1 H), 2.86 (s, 3 H), 2.19- 2.16 (m, 1 H), 2.05- 1.92 (m, 2 H), 1.77- 1.66 (m, 1 H).Step 7: $(R)$ - 4- (1- (5- (cyclopropylmethoxy)pyridin- 2- yl)propoxy)- 2,3- difluoro- N- ((3- ((1- methylpiperidin- 4- yl)oxy)azetidin- 1- yl)sulfonyl)benzamide15 To a solution of $(R)$ - 4- (1- (5- (cyclopropylmethoxy)pyridin- 2- yl)propoxy)- 2,3- difluorobenzoic acid (Acid C, $300~\mathrm{mg}$ $0.83\mathrm{mmol}$ ) in DCM ( $5\mathrm{mL}$ ) was added DMAP ( $10.1\mathrm{mg}$ $0.083\mathrm{mmol}$ ), CMPI ( $319\mathrm{mg}$ $1.25\mathrm{mmol}$ ) at RT and the mixture was stirred for 30 mins. 3- ((1- methylpiperidin- 4- yl)oxy)azetidine- 1- sulfonamide (413.52 mg, 1.18 mmol) was added and the mixture was stirred at RT for 10 mins. EtN (252 mg, 2.49 mmol) was added and the mixture was stirred for 1 hour at RT. The mixture was concentrated to 20 dryness and the residue was purified by Prep- HPLC (method A, gradient: 20- 80) to give the title compound ( $240\mathrm{mg}$ $99.4\%$ purity, $>99\%$ ee, $40\%$ yield) as a yellow solid.LCMS (Method F) MS (ESI) $\mathrm{[M + H]^{+} = 595.3}$ $\mathrm{Rt} = 1.06\mathrm{min}$ ${}^{1}\mathrm{H}$ NMR (400 MHz, DMSO- $d\_{6}$ ppm) 8 9.39 (s, 1 H), 8.26- 8.24 (m, 1 H), 7.40- 7.29 (m, 3 H), 6.75 (t, $J = 8.2\mathrm{Hz}$ , 1 H), 5.32 (t, $J = 6.4\mathrm{Hz}$ 1 H), 4.30- 4.11 (m, 1 H), 3.86 (d, $J = 7.1\mathrm{Hz}$ , 2 H), 3.80- 3.77 (m, 2 H), 3.69- 3.59 (m, 2 H), 3.58- 3.48 (m, 25 1 H), 3.18- 3.06 (m, 4 H), 2.73 (s, 3 H), 2.06- 1.68 (m, 6 H), 1.24- 1.18 (m, 1 H), 0.91 (t, $J = 7.3\mathrm{Hz}$ , 3 H), 0.62- 0.47 (m, 2 H), 0.37- 0.20 (m, 2 H).4.5.44. Example 44. $(R)$ - 2,3- difluoro- $N$ - ((3- ((1- methylpiperidin- 4- yl)oxy)azetidin- 1- yl)sulfonyl)- 4- (1- (5- (pyridin- 2- yloxy)pyridin- 2- yl)propoxy)benzamideStep 1: $(R)$ - 2,3- difluoro- $N$ - ((3- ((1- methylpiperidin- 4- yl)oxy)azetidin- 1- yl)sulfonyl)- 4- (1- (5- (pyridin- 2- yloxy)pyridin- 2- yl)propoxy)benzamide5To a solution of $(R)$ - 2,3- difluoro- 4- (1- (5- (pyridin- 2- yloxy)pyridin- 2- yl)propoxy)benzoic acid (Acid E, $300\mathrm{mg}$ , $0.77\mathrm{mmol}$ ) in DCM (5 mL) was added DMAP (9.41 mg, $0.077\mathrm{mmol}$ ), CMPI (296 mg, $1.16\mathrm{mmol}$ ) at RT and the mixture was stirred for 30 mins. 3- ((1- methylpiperidin- 4- yl)oxy)azetidine- 1- sulfonamide (289.22 mg, $1.16\mathrm{mmol}$ ) was added and the mixture was stirred at RT for 10 mins. $\mathrm{Et}\_3\mathrm{N}$ (233.96 mg, $2.31\mathrm{mmol}$ ) was added and the mixture was stirred for 1 hour at RT. The mixture was concentrated to dryness and the residue was purified by Prep- HPLC (method A, gradient: 20- 70) to give the title compound (234 mg, $99\%$ purity, $>99\%$ ee, $38\%$ yield) as a white solid.LCMS (Method F) MS (ESI) $\mathrm{[M + H]^+ = 618.1}$ , $\mathrm{Rt} = 1.02\mathrm{min}$ . ${}^{1}\mathrm{H}$ NMR (400 MHz, DMSO- $d\_{6}$ , ppm) $\delta$ 9.33 (s, 1 H), 8.45 (d, $J = 2.5\mathrm{Hz}$ , 1 H), 8.16- 8.14 (m, 1 H), 7.97- 7.78 (m, 1 H), 7.65- 7.63 (m, 1 H), 7.51- 7.49 (m, 1 H), 7.42- 7.38 (m, 1 H), 7.25- 7.03 (m, 2 H), 6.82 (t, $J = 8.1\mathrm{Hz}$ , 1 H), 5.42 (t, $J = 6.3\mathrm{Hz}$ , 1 H), 4.30- 4.11 (m, 1 H), 3.85- 3.74 (m, 2 H), 3.66- 3.55 (m, 3 H), 3.23- 2.72 (m, 4 H), 2.72 (s, 3 H), 2.13- 1.46 (m, 6 H), 0.96 (t, $J = 7.3\mathrm{Hz}$ , 3 H).# 4.5.45. Example 45. Biochemical AssaysVarious assays were used to determine the ability of compounds to inhibit human and mouse ACSL5, as well as to determine the compounds' cross- reactivity with other isoforms of the enzyme.# Human Long-chain-fatty-acid--CoA ligase 5 (ACSL5, Uniprot ID Q9ULC5)Human ACSL5 (33- 683) was cloned with a C- terminal 6 His tag and expressed in insect cells (sf9) as per standard insect cell expression protocols. Human ACSL5 was enriched by affinity nickel affinity chromatography followed by Superdex S200 gel filtration column equilibrated in $20\mathrm{mM}$ HEPES pH 7.8, $500\mathrm{mM}$ NaCl, $1\mathrm{mM}$ TCEP, $5\%$ glycerol, $0.1\%$ Triton X100.Inhibition of ACSL5 enzyme activity was monitored with a coupled enzyme Amplex Red assay. The assay is carried out in 384- well microtiterplates. In a total volume of $40~\mu \mathrm{L}$ , compounds are preincubated with $20\mathrm{nM}$ ACSL5, in a buffer containing $150\mathrm{mM}$ MOPS- NaOH, $12\mathrm{mM}$ MgCl2, $0.03\%$ (v / v) Triton X- 100, $2.79\mathrm{U}$ mL- 1 Peroxidase and $24\mathrm{U}$ mL- 1 Acyl- CoA Oxidase (pH 7.6). The reaction is started by the addition of substrate and co factors ( $25~\mu \mathrm{M}$ oleate, $30~\mu \mathrm{M}$ CoA, $1\mathrm{mM}$ ATP and $50~\mu \mathrm{M}$Amplex Red) and the fluorescence detected after 10 minutes at $25^{\circ}\mathrm{C}$ with a fluorescence reader (BMG- Fluostar; BMG- Technologies) using an excitation wavelength of $535~\mathrm{nm}$ and an emission wavelength of $590~\mathrm{nm}$ .# Mouse Lo...

Claims

# CLAIMSWhat is claimed is:

1. A compound, which compound is a compound of formula I:or a pharmaceutically acceptable salt thereof, wherein:$\mathbf{X}^1$ and $\mathbf{X}^2$ is independently O or $\mathrm{CHR}^6$each of $\mathbf{Y}^1$ $\mathbf{Y}^2$ , and $\mathbf{Y}^3$ is independently N, $\mathbf{CR}^3$ , or $\mathbf{C - X^1 - R^1}$ , provided that only one of $\mathbf{Y}^1$ $\mathbf{Y}^2$ , and $\mathbf{Y}^3$ may be attached to $\mathbf{X}^1$ .each of $\mathbf{Z}^1$ $\mathbf{Z}^2$ , and $Z^3$ is independently $\mathbf{N}$ or $\mathbf{CR}^3$each $\mathbf{R}^1$ is independently optionally substituted $\mathbf{C}\_{1 - 8}$ hydrocarbyl or 2- 9 membered heterocarbyl, which optional substitution is with one or more of halo, $\mathbf{R}^{1\mathrm{A}}$ , or $\mathbf{OR}^{1\mathrm{A}}$each $\mathbf{R}^{1\mathrm{A}}$ is independently optionally substituted $\mathbf{C}\_{1 - 6}$ hydrocarbyl, which optional substitution is with one or more of halo;each of $\mathbf{R}^{2\mathrm{A}}$ and $\mathbf{R}^{2\mathrm{B}}$ is independently hydrogen or $\mathbf{C}\_{1 - 6}$ alkyl optionally substituted with one or more halo, or $\mathbf{R}^{2\mathrm{A}}$ and $\mathbf{R}^{2\mathrm{B}}$ are taken together to form a $\mathbf{C}\_{3 - 5}$ cycloalkyl or 3- 5 membered cycloheteroalkyl, each $\mathbf{R}^3$ is independently hydrogen, halo, $\mathbf{C}\_{1 - 6}$ alkyl optionally substituted with one or more halo;$\mathbf{R}^4$ is hydrogen or $\mathbf{C}\_{1 - 6}$ alkyl;$\mathbf{R}^5$ is $\mathrm{N}(\mathrm{R}^{5\mathrm{A}})\_2$ $\mathrm{NHR}^{5\mathrm{A}}$ , or optionally substituted $\mathbf{C}\_{1 - 8}$ hydrocarbyl or 2- 9 membered heterocarbyl, which optional substitution is with one or more of halo, hydroxyl, nitrile, $\mathbf{R}^{5\mathrm{A}}$ $\mathrm{OR}^{5\mathrm{A}}$ $\mathrm{N}(\mathrm{R}^{5\mathrm{A}})\_2$ $\mathrm{NHR}^{5\mathrm{A}}$ , or $\mathrm{NH\_2}$each $\mathbf{R}^{5\mathrm{A}}$ is independently optionally substituted $\mathbf{C}\_{1 - 8}$ hydrocarbyl or 2- 9 membered heterocarbyl, which optional substitution is with one or more of halo, hydroxyl, nitrile, $\mathbf{R}^{5\mathrm{B}}$ $\mathrm{OR}^{5\mathrm{B}}$ $\mathrm{N}(\mathrm{R}^{5\mathrm{B}})\_2$ $\mathrm{NHR}^{5\mathrm{B}}$ , or $\mathrm{NH\_2}$each $\mathbf{R}^{5\mathrm{B}}$ is independently optionally substituted $\mathbf{C}\_{1 - 8}$ hydrocarbyl or 2- 9 membered heterocarbyl, which optional substitution is with one or more of halo, hydroxyl, nitrile, $\mathbf{R}^{5\mathrm{C}}$ $\mathrm{OR}^{5\mathrm{C}}$ $\mathrm{N}(\mathrm{R}^{5\mathrm{C}})\_2$ $\mathrm{NHR}^{5\mathrm{C}}$ , or $\mathrm{NH\_2}$each $\mathbf{R}^{5\mathrm{C}}$ is independently optionally substituted $\mathbf{C}\_{1 - 8}$ hydrocarbyl or 2- 9 membered heterocarbyl, which optional substitution is with one or more of halo, hydroxyl, nitrile, or $\mathrm{NH\_2}$ ; and each $\mathbf{R}^6$ is independently $\mathrm{H}$ or $\mathbf{C}\_{1 - 6}$ alkyl.

2. The compound of claim 1, wherein $\mathbf{R}^{2\mathrm{A}}$ and $\mathbf{R}^{2\mathrm{B}}$ are taken together to form a $\mathbf{C}\_{3 - 5}$ cycloalkyl or 3-5 membered cycloheteroalkyl.

3. The compound of claim 2, wherein the carbocycle is cyclopropyl or cyclobutyl.

4. The compound of claim 1, which is of formula II:IIor a pharmaceutically acceptable salt thereof.

5. The compound of any of the preceding claims, wherein at least one of $\mathbf{Y}^{1}$ , $\mathbf{Y}^{2}$ , and $\mathbf{Y}^{3}$ is $\mathbf{N}$ .

6. The compound of any of the preceding claims, wherein each of $\mathbf{Y}^{1}$ and $\mathbf{Y}^{2}$ is independently $\mathbf{CR}^{3}$ .

7. The compound of any of the preceding claims, wherein at least one of $Z^{1}$ $Z^{2}$ , and $Z^{3}$ is N.

8. The compound of any of the preceding claims, wherein each of $Z^{2}$ and $Z^{3}$ is $\mathbf{N}$9. The compound of any of the preceding claims, wherein each of $Z^{1}$ and $Z^{3}$ is $\mathbf{N}$10. The compound of any of claims 1-7, wherein $Z^{3}$ is $\mathbf{CR}^{3}$11. The compound of claim 1, which is of formula III:IIIor a pharmaceutically acceptable salt thereof.

12. The compound of any of the preceding claims, wherein $\mathbf{X}^{1}$ is $\mathbf{O}$ .

13. The compound of any of the preceding claims, wherein $\mathbf{R}^{4}$ is hydrogen.

14. The compound of claim 1, which is of formula IV:IVor a pharmaceutically acceptable salt thereof.

15. The compound of claim 11 or 14, wherein $Z^{3}$ is $\mathbf{CR}^{3}$ .

16. The compound of any of the preceding claims, wherein $\mathbf{X}^{2}$ is $\mathbf{O}$ .

17. The compound of any of the preceding claims, wherein the stereochemistry at the carbon to which $\mathrm{R}^{2\mathrm{A}}$ is attached is $(R)$ .

18. The compound of claim 1, which is of formula V(a):or a pharmaceutically acceptable salt thereof.

19. The compound of claim 1, which is of formula V(b):or a pharmaceutically acceptable salt thereof.

20. The compound of any of the preceding claims, wherein $\mathrm{Y}^{3}$ is N.

21. The compound of any of the preceding claims, wherein $\mathrm{R}^{5}$ is one of:

22. The compound of claim 21, which is of formula VI(a):or a pharmaceutically acceptable salt thereof.

23. The compound of claim 21, which is of formula VI(b):or a pharmaceutically acceptable salt thereof.

24. The compound of claim 21, which is of formula VII(a):or a pharmaceutically acceptable salt thereof.

25. The compound of claim 21, which is of formula VII(b):or a pharmaceutically acceptable salt thereof.

26. The compound of claim 21, which is of formula VIII(a):VIII(a)or a pharmaceutically acceptable salt thereof.

27. The compound of claim 21, which is of formula VIII(b):VIII(b)or a pharmaceutically acceptable salt thereof.

28. The compound of any of the preceding claims, wherein $\mathbf{R}^1$ is optionally substituted $\mathbf{C}\_{1 - 8}$ hydrocarbyl.

29. The compound of claim 28, wherein $\mathbf{R}^1$ is cyclopropylmethyl, phenyl, or cyclopropyl.

30. The compound of any of claims 1-27, wherein $\mathbf{R}^1$ is optionally substituted 2-9 membered heterocarbyl.

31. The compound of claim 30, wherein $\mathbf{R}^1$ is pyridyl, pyrazyl, thiophenyl, or furanyl.

32. The compound of any of the preceding claims, wherein $\mathbf{R}^1$ is substituted with $\mathbf{OR}^{1\mathrm{A}}$33. The compound of claim 32, wherein $\mathbf{R}^{1\mathrm{A}}$ is $\mathbf{C}\_{1 - 6}$ alkyl.

34. The compound of any of claims 1 or 4-33, wherein $\mathbf{R}^{2\mathrm{A}}$ is methyl or ethyl.

35. The compound of any of claims 1 or 4-33, wherein $\mathbf{R}^{2\mathrm{B}}$ is hydrogen.

36. The compound of any of the preceding claims, wherein at least one of $\mathbf{R}^3$ is hydrogen.

37. The compound of any of the preceding claims, wherein each $\mathbf{R}^3$ is hydrogen.

38. The compound of any of claims 1-35, wherein at least one $\mathbf{R}^3$ is $\mathbf{-CF}\_3$39. The compound of any of claims 1-35, wherein at least one $\mathbf{R}^3$ is fluoro.

40. The compound of any of the preceding claims, wherein $\mathbf{R}^{5\mathrm{A}}$ is optionally substituted alkyl or 4- or 5-membered heterocycle.

41. The compound of claim 40, wherein $\mathbf{R}^{5\mathrm{A}}$ is optionally substituted with $\mathbf{R}^{5\mathrm{B}}$42. The compound of claim 41, wherein $\mathbf{R}^{5\mathrm{B}}$ is optionally substituted $\mathbf{C}\_{1 - 6}$ alkyl.

43. A compound, which compound is selected from those listed in Table 4 or Table 5, or a pharmaceutically acceptable salt thereof.

44. A pharmaceutical composition comprising a compound of any of the preceding claims and a pharmaceutically acceptable excipient.

45. A method of preparing a compound of formula 1h:1hwhich comprises contacting a compound of formula 1f:1fwith a compound of formula 1g:1gin mixture (e.g., in a solvent) under conditions sufficient to provide the compound of formula 1h, wherein: $\mathbf{Y}^3$ is $\mathbf{N}$ or $\mathbf{CR}^3$each $\mathbf{R}^1$ is independently optionally substituted $\mathbf{C}\_{1 - 8}$ hydrocarbyl or 2- 9 membered heterocarbyl, which optional substitution is with one or more of halo, $\mathbf{R}^{1\mathrm{A}}$ , or $\mathbf{OR}^{1\mathrm{A}}$each $\mathbf{R}^{1\mathrm{A}}$ is independently optionally substituted $\mathbf{C}\_{1 - 6}$ hydrocarbyl, which optional substitution is with one or more of halo;$\mathbf{R}^{2\mathrm{A}}$ is $\mathbf{C}\_{1 - 6}$ alkyl optionally substituted with one or more halo;each $\mathbf{R}^3$ is independently hydrogen, halo, or $\mathbf{C}\_{1 - 6}$ alkyl optionally substituted with one or more halo;$\mathbf{R}^5$ is $\mathrm{N}(\mathrm{R}^{5\mathrm{A}})\_2$ $\mathrm{NHR}^{5\mathrm{A}}$ , or optionally substituted $\mathbf{C}\_{1 - 8}$ hydrocarbyl or 2- 9 membered heterocarbyl, which optional substitution is with one or more of halo, hydroxyl, $\mathbf{R}^{5\mathrm{A}}$ $\mathrm{OR}^{5\mathrm{A}}$ $\mathrm{N}(\mathrm{R}^{5\mathrm{A}})\_2$ $\mathrm{NHR}^{5\mathrm{A}}$ , or $\mathrm{NH\_2}$each $\mathbf{R}^{5\mathrm{A}}$ is independently optionally substituted $\mathbf{C}\_{1 - 8}$ hydrocarbyl or 2- 9 membered heterocarbyl, which optional substitution is with one or more halo, hydroxyl, or $\mathbf{R}^{5\mathrm{B}}$ $\mathrm{OR}^{5\mathrm{B}}$ $\mathrm{N}(\mathrm{R}^{5\mathrm{B}})\_2$ $\mathrm{NHR}^{5\mathrm{B}}$ , or $\mathrm{NH\_2}$each $\mathbf{R}^{5\mathrm{B}}$ is independently optionally substituted $\mathbf{C}\_{1 - 8}$ hydrocarbyl or 2- 9 membered heterocarbyl, which optional substitution is with one or more of halo, hydroxyl, or $\mathbf{R}^{5\mathrm{C}}$ $\mathrm{OR}^{5\mathrm{C}}$ $\mathrm{N}(\mathrm{R}^{5\mathrm{C}})\_2$ $\mathrm{NHR}^{5\mathrm{C}}$ , or $\mathrm{NH\_2}$ and each $\mathbf{R}^{5\mathrm{C}}$ is independently optionally substituted $\mathbf{C}\_{1 - 8}$ hydrocarbyl or 2- 9 membered heterocarbyl, which optional substitution is with one or more of halo, hydroxyl, or $\mathrm{NH\_2}$46. The method of claim 45, wherein the conditions sufficient to provide the compound of formula 1h comprise a base (e.g., DMAP, $\mathrm{Et}\_3\mathrm{N}$ , $\mathrm{Pr}\_2\mathrm{NEt}$ ) and coupling reagent (e.g., EDCl, PyBOP, HATU, CDI).

47. The method of claim 45, wherein the compound of formula 1f is prepared by contacting a compound of formula 1e:1ewith a saponification agent (e.g., LiOH, NaOH, TMSI), wherein R' is lower alkyl (e.g., methyl).

48. A method of preparing a compound of formula 3k:which comprises contacting a compound of formula 3i:3iwith a compound of formula 3j:3jin solution under conditions sufficient to provide the compound of formula 3k, wherein:$\mathbb{R}^1$ is optionally substituted $\mathbf{C}\_{1 - 8}$ hydrocarbyl or 2- 9 membered heterocarbyl, which optional substitution is with one or more of halo, $\mathbb{R}^{1\mathrm{A}}$ , or $\mathbf{OR}^{1\mathrm{A}}$each $\mathbb{R}^{1\mathrm{A}}$ is independently optionally substituted $\mathbf{C}\_{1 - 6}$ hydrocarbyl, which optional substitution is with one or more of halo;each $\mathbb{R}^3$ is independently hydrogen, halo, or $\mathbf{C}\_{1 - 6}$ alkyl optionally substituted with one or more halo;$\mathbb{R}^5$ is $\mathrm{N}(\mathrm{R}^{5\mathrm{A}})\_2$ $\mathrm{NHR}^{5\mathrm{A}}$ , or optionally substituted $\mathbf{C}\_{1 - 8}$ hydrocarbyl or 2- 9 membered heterocarbyl, which optional substitution is with one or more of halo, hydroxyl, $\mathbb{R}^{5\mathrm{A}}$ $\mathrm{OR}^{5\mathrm{A}}$ $\mathrm{N}(\mathrm{R}^{5\mathrm{A}})\_2$ $\mathrm{NHR}^{5\mathrm{A}}$ , or $\mathrm{NH\_2}$each $\mathbb{R}^{5\mathrm{A}}$ is independently optionally substituted $\mathbf{C}\_{1 - 8}$ hydrocarbyl or 2- 9 membered heterocarbyl, which optional substitution is with one or more halo, hydroxyl, or $\mathbb{R}^{5\mathrm{B}}$ $\mathrm{OR}^{5\mathrm{B}}$ $\mathrm{N}(\mathrm{R}^{5\mathrm{B}})\_2$ $\mathrm{NHR}^{5\mathrm{B}}$ , or $\mathrm{NH\_2}$each $\mathbb{R}^{5\mathrm{B}}$ is independently optionally substituted $\mathbf{C}\_{1 - 8}$ hydrocarbyl or 2- 9 membered heterocarbyl, which optional substitution is with one or more of halo, hydroxyl, or $\mathbb{R}^{5\mathrm{C}}$ $\mathrm{OR}^{5\mathrm{C}}$ $\mathrm{N}(\mathrm{R}^{5\mathrm{C}})\_2$ $\mathrm{NHR}^{5\mathrm{C}}$ , or $\mathrm{NH\_2}$ and each $\mathbb{R}^{5\mathrm{C}}$ is independently optionally substituted $\mathbf{C}\_{1 - 8}$ hydrocarbyl or 2- 9 membered heterocarbyl, which optional substitution is with one or more of halo, hydroxyl, or $\mathrm{NH\_2}$49. The method of claim 48, wherein the conditions sufficient to provide the compound of formula 3k comprise a base (e.g., DMAP, $\mathrm{Et}\_3\mathrm{N}$ , $\mathrm{Pr}\_2\mathrm{NEt}$ ) and coupling reagent (e.g., EDCl, PyBOP, HATU, CDI).

50. A method of inhibiting acyl-CoA synthetase 5 (ACSL5), which comprises contacting ACSL5 with a compound of any of claims 1-43.

51. A method of treating or managing a metabolic disease or disorder, which comprises administering to a patient in need thereof a therapeutically or prophylactically effective amount of a compound or composition of any of claims 1-44.

52. The method of claim 51, wherein the metabolic disease or disorder is metabolic syndrome, obesity, non-alcoholic fatty liver disease (NAFLD), metabolic dysfunction-associated steatohepatitis (MASH), or type 2 diabetes.

53. A method of increasing insulin sensitivity in a patient, which comprises administering to a patient in need thereof a therapeutically effective amount of a compound or composition of any of claims 1-44.

54. A method of treating or managing a cancer characterized by the overexpression of ACSL5, which comprises administering to a patient in need thereof a therapeutically or prophylactically effective amount of a compound or composition of any of claims 1-44.

55. The method of claim 54, wherein the cancer is acute myeloid leukemia (AML), colorectal cancer, or breast cancer.