WO2025193537A1 - Compounds and methods for regulating insulin secretion - Google Patents

Abstract

The invention relates to novel cycloalkyl and fluorophenyl compounds and pharmaceutical preparations thereof. The invention further relates to methods of treating or preventing diabetes using the novel cycloalkyl and fluorophenyl compounds of the invention.

Description

COMPOUNDS AND METHODS FOR REGULATING INSULIN SECRETION

RELATED APPLICATION

This application claims the benefit of U.S. Provisional Application No. 63/563,591 filed on March 11, 2024, the contents of which is fully incorporated by reference herein.

BACKGROUND

Diabetes mellitus type 2 (type 2 diabetes) is a metabolic disorder that results in patients having high blood sugar level and insulin resistance. Long-term complications from high blood sugar include heart disease, strokes, diabetic retinopathy, which can result in blindness, kidney failure, and poor blood flow in the limbs, which may lead to amputations. Type 2 diabetes is primarily due to obesity and not enough exercise in people who are genetically predisposed. It makes up about 90% of cases of diabetes, with the other 10% due primarily to diabetes mellitus type 1 and gestational diabetes. In diabetes mellitus type 1, there is an absolute lack of insulin due to breakdown of islet cells in the pancreas. Diagnosis of diabetes is by blood tests, such as fasting plasma glucose, oral glucose tolerance test, or A1C.

The number of people affected by type 2 diabetes has grown substantially over the last few decades. As of 2021, there were approximately 537 million people diagnosed with the disease as compared to around 30 million in 1985. Type 2 diabetes is associated with a ten- year-shorter life expectancy. Thus, numerous therapies have been developed to treat or ameliorate the symptoms of type 2 diabetes. One such therapy involves drugs that promote the B-cells from pancreatic islets to secrete insulin independent of how much glucose is circulating in the blood. For example, sulfonylureas induce constant insulin secretion, but in doing so, they can cause hypoglycemia and B-islet cell burnout. GLP-1 analogs require administration by injection (or, in the case of semaglutide, oral administration) and can result in pancreatitis. Thus, there is a need in the art for insulin secretagogues that are glucose-dependent, such that they activate insulin secretion only when the circulating blood glucose level is physiologically high. SUMMARY

In certain aspects, disclosed herein are compounds of Formula (I): wherein:

A is selected from monocycloalkyl, bicycloalkyl and polycycloalkyl;

R¹ is aryl; and

R² is heteroaryl; or a pharmaceutically acceptable salt thereof.

In certain aspects, disclosed herein are compounds of Formula (II): wherein:

R¹ is aryl;

R² is heteroaryl;

R³ is fluoro; and nl is 1, 2, 3, or 4; or a pharmaceutically acceptable salt thereof.

In certain aspects, disclosed herein are compounds of Formula (III): wherein:

R¹ is aryl; A is phenyl, monocycloalkyl, bicycloalkyl, or polycycloalkyl;

R⁴ is halo; and n2 is 1, 2, 3, 4, or 5; or a pharmaceutically acceptable salt thereof.

In certain aspects, disclosed herein is a compound selected from:

In certain aspects, disclosed herein is a compound selected from:

In certain aspects, disclosed herein is a compound, wherein the compound is pharmaceutically acceptable salt thereof.

In certain embodiments, the present invention provides a pharmaceutical composition suitable for use in a subject in the treatment or prevention of diabetes comprising an effective amount of any of the compounds described herein (e.g., a compound of the invention, such as a compound of Formula (I, II, or III)), or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients. In certain embodiments, the pharmaceutical preparations may be for use in treating or preventing a condition or disease as described herein.

In certain embodiments, the compounds disclosed herein are used in methods of regulating circulating insulin levels in the body.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 shows glucose stimulated secretion of luciferase in presence or absence of 4- [(3,5-dimethylisoxazol-4-yl)methoxy]-N-(2,3-dimethylphenyl)benzamide analogs. Data shown are mean ± s.d. of n=6 technical replicates. Statistical analysis was performed using unpaired t-test. DETAILED DESCRIPTION

Pancreatic beta-cell dysfunction, leading to a loss of glucose-stimulated insulin secretion (GSIS), plays a major role in type 2 diabetes (T2D). Therefore, a better understanding of GSIS and glucose responsiveness has the potential to improve our understanding of the etiology of T2D. Although several clinically used drugs improve insulin secretion, they often lack glucose dependence in their activity. Herein compounds are disclosed that can be used as insulin secretagogues in a glucose-dependent manner.

Disclosed herein are methods of treating diseases and conditions that benefit from regulating circulating insulin levels, comprising administering to a subject in need thereof an effective amount of a compound as disclosed herein (e.g., a compound of Formula (I), Formula (II), Formula (III), or any of the embodiments thereof disclosed herein). In certain embodiments, the human subject is in need of such treatment.

Disclosed herein are compounds that can be used as insulin secretagogues in a glucosedependent manner. These compounds have the advantage of working on P cells only when needed, such that they are more resilient and lead to less insulin resistance. Without wishing to be bound by theory, it is believed the compounds of the invention are capable of targeting voltage gated potassium channels to prevent or slow membrane repolarization. In normal cells, membrane polarization is required for the regulation of P cell secretion of insulin. By inhibiting repolarization, more insulin may be secreted. Because the rate of membrane repolarization occurs in a glucose dependent manner, the compounds of the invention also operate in a glucose dependent manner.

Definitions

Unless defined otherwise, all technical and scientific terms used herein have the meaning commonly understood by a person skilled in the art of the present disclosure. The following references provide one of skill with a general definition of many of the terms used in this disclosure: Singleton et al., Dictionary of Microbiology and Molecular Biology (2nd ed. 1994); The Cambridge Dictionary of Science and Technology (Walker ed., 1988); The Glossary of Genetics, 5th Ed., R. Rieger et al. (eds.), Springer Verlag (1991); and Hale & Marham, The Harper Collins Dictionary of Biology (1991). As used herein, the following terms have the meanings ascribed to them below, unless specified otherwise. In some embodiments, chemical structures are disclosed with a corresponding chemical name. In case of conflict, the chemical structure controls the meaning, rather than the name.

In this disclosure, "comprises," "comprising," "containing" and "having" and the like can have the meaning ascribed to them in U.S. Patent law and can mean " includes," "including," and the like; "consisting essentially of' or "consists essentially" likewise has the meaning ascribed in U.S. Patent law and the term is open-ended, allowing for the presence of more than that which is recited so long as basic or novel characteristics of that which is recited are not substantially changed by the presence of more than that which is recited, but excludes prior art embodiments.

Unless specifically stated or obvious from context, as used herein, the term "or" is understood to be inclusive. Unless specifically stated or obvious from context otherwise, as used herein, the terms "a", "an", and "the" are understood to be singular or plural.

The term “acyl” is art-recognized and refers to a group represented by the general formula hydrocarbylC(O)-, preferably alkylC(O)-.

The term “acylamino” is art-recognized and refers to an amino group substituted with an acyl group and may be represented, for example, by the formula hydrocarbylC(O)NH-.

The term “acyloxy” is art-recognized and refers to a group represented by the general formula hydrocarbylC(O)O-, preferably alkylC(O)O-.

The term “alkoxy” refers to an alkyl group, preferably a lower alkyl group, having an oxygen attached thereto. Representative alkoxy groups include methoxy, ethoxy, propoxy, tert-butoxy and the like.

The term “alkoxyalkyl” refers to an alkyl group substituted with an alkoxy group and may be represented by the general formula alkyl-O-alkyl.

The term “alkenyl”, as used herein, refers to an aliphatic group containing at least one double bond and is intended to include both "unsubstituted alkenyls" and "substituted alkenyls", the latter of which refers to alkenyl moieties having substituents replacing a hydrogen on one or more carbons of the alkenyl group. Such substituents may occur on one or more carbons that are included or not included in one or more double bonds. Moreover, such substituents include all those contemplated for alkyl groups, as discussed below, except where stability is prohibitive. For example, substitution of alkenyl groups by one or more alkyl, carbocyclyl, aryl, heterocyclyl, or heteroaryl groups is contemplated. An “alkyl” group or “alkane” is a straight chained or branched non-aromatic hydrocarbon which is completely saturated. Typically, a straight chained or branched alkyl group has from 1 to about 20 carbon atoms, preferably from 1 to about 10 unless otherwise defined. Examples of straight chained and branched alkyl groups include methyl, ethyl, n- propyl, iso-propyl, n-butyl, sec-butyl, tert-butyl, pentyl, hexyl, pentyl and octyl. A Ci-Ce straight chained or branched alkyl group is also referred to as a "lower alkyl" group.

Moreover, the term "alkyl" (or "lower alkyl") as used throughout the specification, examples, and claims is intended to include both "unsubstituted alkyls" and "substituted alkyls", the latter of which refers to alkyl moieties having substituents replacing a hydrogen on one or more carbons of the hydrocarbon backbone. Such substituents, if not otherwise specified, can include, for example, a halogen, a hydroxyl, a carbonyl (such as a carboxyl, an alkoxycarbonyl, a formyl, or an acyl), a thiocarbonyl (such as a thioester, a thioacetate, or a thioformate), an alkoxy, a phosphoryl, a phosphate, a phosphonate, a phosphinate, an amino, an amido, an amidine, an imine, a cyano, a nitro, an azido, a sulfhydryl, an alkylthio, a sulfate, a sulfonate, a sulfamoyl, a sulfonamido, a sulfonyl, a heterocyclyl, an aralkyl, or an aromatic or heteroaromatic moiety. It will be understood by those skilled in the art that the moieties substituted on the hydrocarbon chain can themselves be substituted, if appropriate. For instance, the substituents of a substituted alkyl may include substituted and unsubstituted forms of amino, azido, imino, amido, phosphoryl (including phosphonate and phosphinate), sulfonyl (including sulfate, sulfonamido, sulfamoyl and sulfonate), and silyl groups, as well as ethers, alkylthios, carbonyls (including ketones, aldehydes, carboxylates, and esters), -CF3, -CN and the like. Exemplary substituted alkyls are described below. Cycloalkyls can be further substituted with alkyls, alkenyls, alkoxys, alkylthios, aminoalkyls, carbonyl-substituted alkyls, -CF3, -CN, and the like.

The term “C_x-y” when used in conjunction with a chemical moiety, such as, acyl, acyloxy, alkyl, alkenyl, alkynyl, or alkoxy is meant to include groups that contain from x to y carbons in the chain. For example, the term “C_x.yalkyl” refers to substituted or unsubstituted saturated hydrocarbon groups, including straight-chain alkyl and branched-chain alkyl groups that contain from x to y carbons in the chain, including haloalkyl groups such as trifluoromethyl and 2,2,2-tirfluoroethyl, etc. Co alkyl indicates a hydrogen where the group is in a terminal position, a bond if internal. The terms “C2-_yalkenyl” and “C2-_yalkynyl” refer to substituted or unsubstituted unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but that contain at least one double or triple bond respectively.

The term “alkylamino”, as used herein, refers to an amino group substituted with at least one alkyl group.

The term “alkylthio”, as used herein, refers to a thiol group substituted with an alkyl group and may be represented by the general formula alkylS-.

The term “alkynyl”, as used herein, refers to an aliphatic group containing at least one triple bond and is intended to include both "unsubstituted alkynyls" and "substituted alkynyls", the latter of which refers to alkynyl moieties having substituents replacing a hydrogen on one or more carbons of the alkynyl group. Such substituents may occur on one or more carbons that are included or not included in one or more triple bonds. Moreover, such substituents include all those contemplated for alkyl groups, as discussed above, except where stability is prohibitive. For example, substitution of alkynyl groups by one or more alkyl, carbocyclyl, aryl, heterocyclyl, or heteroaryl groups is contemplated.

The term “amide”, as used herein, refers to a group

0

! S R³⁰

X' X

R³⁰ wherein each R³⁰ independently represents a hydrogen or hydrocarbyl group, or two R³⁰ are taken together with the N atom to which they are attached complete a heterocycle having from 4 to 8 atoms in the ring structure.

The terms “amine” and “amino” are art-recognized and refer to both unsubstituted and substituted amines and salts thereof, e.g., a moiety that can be represented by wherein each R³¹ independently represents a hydrogen or a hydrocarbyl group, or two R³¹ are taken together with the N atom to which they are attached complete a heterocycle having from 4 to 8 atoms in the ring structure. The term “aminoalkyl”, as used herein, refers to an alkyl group substituted with an amino group. The term “aralkyl”, as used herein, refers to an alkyl group substituted with an aryl group.

The term “aryl” as used herein include substituted or unsubstituted single-ring aromatic groups in which each atom of the ring is carbon. Preferably, the ring is a 5- to 7-membered ring, more preferably a 6-membered ring. The term “aryl” also includes polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjoining rings wherein at least one of the rings is aromatic, e.g., the other cyclic rings can be cycloalkyls, cycloalkenyls, cycloalkynyls, aryls, heteroaryls, and/or heterocyclyls. Aryl groups include benzene, naphthalene, phenanthrene, phenol, aniline, and the like.

The term “carbamate” is art-recognized and refers to a group wherein R³² and R³³ independently represent hydrogen or a hydrocarbyl group, such as an alkyl group, or R³² and R³³ taken together with the intervening atom(s) complete a heterocycle having from 4 to 8 atoms in the ring structure.

The terms “carbocycle”, and “carbocyclic”, as used herein, refers to a saturated or unsaturated ring in which each atom of the ring is carbon. The term carbocycle includes both aromatic carbocycles and non-aromatic carbocycles. Non-aromatic carbocycles include both cycloalkane rings, in which all carbon atoms are saturated, and cycloalkene rings, which contain at least one double bond.

The term “carbocycle” includes 5-7 membered monocyclic and 8-12 membered bicyclic rings. Each ring of a bicyclic carbocycle may be selected from saturated, unsaturated and aromatic rings. Carbocycle includes bicyclic molecules in which one, two or three or more atoms are shared between the two rings. The term “fused carbocycle” refers to a bicyclic carbocycle in which each of the rings shares two adjacent atoms with the other ring. Each ring of a fused carbocycle may be selected from saturated, unsaturated and aromatic rings. In an exemplary embodiment, an aromatic ring, e.g., phenyl, may be fused to a saturated or unsaturated ring, e.g., cyclohexane, cyclopentane, or cyclohexene. Any combination of saturated, unsaturated and aromatic bicyclic rings, as valence permits, is included in the definition of carbocyclic. Exemplary “carbocycles” include cyclopentane, cyclohexane, bicyclo[2.2.1]heptane, 1,5-cyclooctadiene, 1,2,3,4-tetrahydronaphthalene, bicyclo[4.2.0]oct- 3-ene, naphthalene and adamantane. Exemplary fused carbocycles include decalin, naphthalene, 1,2,3,4-tetrahydronaphthalene, bicyclo[4.2.0]octane, 4,5,6,7-tetrahydro-lH- indene and bicyclo[4.1.0]hept-3-ene. “Carbocycles” may be substituted at any one or more positions capable of bearing a hydrogen atom.

A “cycloalkyl” group is a cyclic hydrocarbon which is completely saturated. “Cycloalkyl” includes monocyclic and bicyclic rings. Typically, a monocyclic cycloalkyl group has from 3 to about 10 carbon atoms, more typically 3 to 8 carbon atoms unless otherwise defined. The second ring of a bicyclic cycloalkyl may be selected from saturated, unsaturated and aromatic rings. Cycloalkyl includes bicyclic molecules in which one, two or three or more atoms are shared between the two rings. The term “fused cycloalkyl” refers to a bicyclic cycloalkyl in which each of the rings shares two adjacent atoms with the other ring. The second ring of a fused bicyclic cycloalkyl may be selected from saturated, unsaturated and aromatic rings. A “cycloalkenyl” group is a cyclic hydrocarbon containing one or more double bonds.

The term “carbocyclylalkyl”, as used herein, refers to an alkyl group substituted with a carbocycle group.

The term “carbonate” is art-recognized and refers to a group -OCO2-R³⁴, wherein R³⁴ represents a hydrocarbyl group.

The term “carboxy”, as used herein, refers to a group represented by the formula - CO2H.

The term “ester”, as used herein, refers to a group -C(O)OR³⁵ wherein R³⁵ represents a hydrocarbyl group.

The term “ether”, as used herein, refers to a hydrocarbyl group linked through an oxygen to another hydrocarbyl group. Accordingly, an ether substituent of a hydrocarbyl group may be hydrocarbyl-O-. Ethers may be either symmetrical or unsymmetrical. Examples of ethers include, but are not limited to, heterocycle-O-heterocycle and aryl-O-heterocycle. Ethers include “alkoxyalkyl” groups, which may be represented by the general formula alkyl- O-alkyl.

The terms “halo” and “halogen” as used herein means halogen and includes chloro, fluoro, bromo, and iodo.

The terms “hetaralkyl” and “heteroaralkyl”, as used herein, refers to an alkyl group substituted with a heteroaryl group. The term "heteroalkyl", as used herein, refers to a saturated or unsaturated chain of carbon atoms and at least one heteroatom, wherein no two heteroatoms are adjacent.

The terms “heteroaryl” and “hetaryl” include substituted or unsubstituted aromatic single ring structures, preferably 5- to 7-membered rings, more preferably 5- to 6-membered rings, whose ring structures include at least one heteroatom, preferably one to four heteroatoms, more preferably one or two heteroatoms. The terms “heteroaryl” and “hetaryl” also include polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjoining rings wherein at least one of the rings is heteroaromatic, e.g., the other cyclic rings can be cycloalkyls, cycloalkenyls, cycloalkynyls, aryls, heteroaryls, and/or heterocyclyls. Heteroaryl groups include, for example, pyrrole, furan, thiophene, imidazole, oxazole, thiazole, pyrazole, pyridine, pyrazine, pyridazine, and pyrimidine, and the like.

The term “heteroatom” as used herein means an atom of any element other than carbon or hydrogen. Preferred heteroatoms are nitrogen, oxygen, and sulfur.

The terms “heterocyclyl”, “heterocycle”, and “heterocyclic” refer to substituted or unsubstituted non-aromatic ring structures, preferably 3- to 10-membered rings, more preferably 3- to 7-membered rings, whose ring structures include at least one heteroatom, preferably one to four heteroatoms, more preferably one or two heteroatoms. The terms “heterocyclyl” and “heterocyclic” also include polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjoining rings wherein at least one of the rings is heterocyclic, e.g., the other cyclic rings can be cycloalkyls, cycloalkenyls, cycloalkynyls, aryls, heteroaryls, and/or heterocyclyls. Heterocyclyl groups include, for example, piperidine, piperazine, pyrrolidine, morpholine, lactones, lactams, and the like.

The term “heterocyclylalkyl”, as used herein, refers to an alkyl group substituted with a heterocycle group.

The term “hydrocarbyl”, as used herein, refers to a group that is bonded through a carbon atom that does not have a =0 or =S substituent, and typically has at least one carbonhydrogen bond and a primarily carbon backbone, but may optionally include heteroatoms. Thus, groups like methyl, ethoxyethyl, 2-pyridyl, and trifluoromethyl are considered to be hydrocarbyl for the purposes of this application, but substituents such as acetyl (which has a =0 substituent on the linking carbon) and ethoxy (which is linked through oxygen, not carbon) are not. Hydrocarbyl groups include, but are not limited to aryl, heteroaryl, carbocycle, heterocyclyl, alkyl, alkenyl, alkynyl, and combinations thereof.

The term “hydroxyalkyl”, as used herein, refers to an alkyl group substituted with a hydroxy group.

The term “lower” when used in conjunction with a chemical moiety, such as, acyl, acyloxy, alkyl, alkenyl, alkynyl, or alkoxy is meant to include groups where there are ten or fewer non-hydrogen atoms in the substituent, preferably six or fewer. A “lower alkyl”, for example, refers to an alkyl group that contains ten or fewer carbon atoms, preferably six or fewer. In certain embodiments, acyl, acyloxy, alkyl, alkenyl, alkynyl, or alkoxy substituents defined herein are respectively lower acyl, lower acyloxy, lower alkyl, lower alkenyl, lower alkynyl, or lower alkoxy, whether they appear alone or in combination with other substituents, such as in the recitations hydroxyalkyl and aralkyl (in which case, for example, the atoms within the aryl group are not counted when counting the carbon atoms in the alkyl substituent).

The terms “polycyclyl”, “polycycle”, and “polycyclic” refer to two or more rings (e.g., cycloalkyls, cycloalkenyls, cycloalkynyls, aryls, heteroaryls, and/or heterocyclyl s) in which two or more atoms are common to two adjoining rings, e.g., the rings are “fused rings”. Each of the rings of the polycycle can be substituted or unsubstituted. In certain embodiments, each ring of the poly cycle contains from 3 to 10 atoms in the ring, preferably from 5 to 7.

The term “silyl” refers to a silicon moiety with three hydrocarbyl moieties attached thereto.

The term “substituted” refers to moieties having substituents replacing a hydrogen on one or more carbons of the backbone. It will be understood that “substitution” or “substituted with” includes the implicit proviso that such substitution is in accordance with permitted valence of the substituted atom and the substituent, and that the substitution results in a stable compound, e.g., which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, etc. As used herein, the term “substituted” is contemplated to include all permissible substituents of organic compounds. In a broad aspect, the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic substituents of organic compounds. The permissible substituents can be one or more and the same or different for appropriate organic compounds. For purposes of this invention, the heteroatoms such as nitrogen may have hydrogen substituents and/or any permissible substituents of organic compounds described herein which satisfy the valences of the heteroatoms. Substituents can include any substituents described herein, for example, a halogen, a hydroxyl, a carbonyl (such as a carboxyl, an alkoxycarbonyl, a formyl, or an acyl), a thiocarbonyl (such as a thioester, a thioacetate, or a thioformate), an alkoxy, a phosphoryl, a phosphate, a phosphonate, a phosphinate, an amino, an amido, an amidine, an imine, a cyano, a nitro, an azido, a sulfhydryl, an alkylthio, a sulfate, a sulfonate, a sulfamoyl, a sulfonamido, a sulfonyl, a heterocyclyl, an aralkyl, or an aromatic or heteroaromatic moiety. It will be understood by those skilled in the art that substituents can themselves be substituted, if appropriate. Unless specifically stated as “unsubstituted,” references to chemical moieties herein are understood to include substituted variants. For example, reference to an “aryl” group or moiety implicitly includes both substituted and unsubstituted variants.

The term “sulfate” is art-recognized and refers to the group -OSO3H, or a pharmaceutically acceptable salt thereof.

The term “sulfonamide” is art-recognized and refers to the group represented by the general formulae

O R36

5 tf U s-N or i^! U37 o R wherein R³⁶ and R³⁷ independently represent hydrogen or hydrocarbyl, such as alkyl, or R³⁶ and R³⁷ taken together with the intervening atom(s) complete a heterocycle having from 4 to 8 atoms in the ring structure.

The term “sulfoxide” is art-recognized and refers to the group -S(O)-R³⁸, wherein R³⁸ represents a hydrocarbyl.

The term “sulfonate” is art-recognized and refers to the group SO3H, or a pharmaceutically acceptable salt thereof.

The term “sulfone” is art-recognized and refers to the group -S(O)2-R³⁹, wherein R³⁹ represents a hydrocarbyl.

The term “thioalkyl”, as used herein, refers to an alkyl group substituted with a thiol group.

The term “thioester”, as used herein, refers to a group -C(O)SR⁴⁰ or -SC(O)R⁴⁰ wherein R⁴⁰ represents a hydrocarbyl. The term “thioether”, as used herein, is equivalent to an ether, wherein the oxygen is replaced with a sulfur.

The term “urea” is art-recognized and may be represented by the general formula wherein R⁴¹ and R⁴² independently represent hydrogen or a hydrocarbyl, such as alkyl, or either occurrence of R⁴¹ taken together with R⁴² and the intervening atom(s)complete a heterocycle having from 4 to 8 atoms in the ring structure.

The term “protecting group” refers to a group of atoms that, when attached to a reactive functional group in a molecule, mask, reduce or prevent the reactivity of the functional group. Typically, a protecting group may be selectively removed as desired during the course of a synthesis. Examples of protecting groups can be found in Greene and Wuts, Protective Groups in Organic Chemistry, 3^rd Ed., 1999, John Wiley & Sons, NY and Harrison et al., Compendium of Synthetic Organic Methods, Vols. 1-8, 1971-1996, John Wiley & Sons, NY. Representative nitrogen protecting groups include, but are not limited to, formyl, acetyl, trifluoroacetyl, benzyl, benzyloxy carbonyl (“CBZ”), tert-butoxy carbonyl (“Boc”), trimethyl silyl (“TMS”), 2- trimethylsilyl-ethanesulfonyl (“TES”), trityl and substituted trityl groups, allyloxycarbonyl, 9- fluorenylmethyloxycarbonyl (“FMOC”), nitro-veratryloxycarbonyl (“NVOC”) and the like. Representative hydroxyl protecting groups include, but are not limited to, those where the hydroxyl group is either acylated (esterified) or alkylated such as benzyl and trityl ethers, as well as alkyl ethers, tetrahydropyranyl ethers, trialkylsilyl ethers (e.g., TMS or TIPS groups), glycol ethers, such as ethylene glycol and propylene glycol derivatives and allyl ethers.

In certain embodiments, compounds of the invention may be racemic. In certain embodiments, compounds of the invention may be enriched in one enantiomer. For example, a compound of the invention may have greater than about 30% enantiomeric excess (ee), about 40% ee, about 50% ee, about 60% ee, about 70% ee, about 80% ee, about 90% ee, or even about 95% or greater ee. In certain embodiments, compounds of the invention may have more than one stereocenter. In certain such embodiments, compounds of the invention may be enriched in one or more diastereomer. For example, a compound of the invention may have greater than about 30% diastereomeric excess (de), about 40% de, about 50% de, about 60% de, about 70% de, about 80% de, about 90% de, or even about 95% or greater de. In certain embodiments, the therapeutic preparation may be enriched to provide predominantly one enantiomer of a compound (e.g., of Formula (I)). An enantiomerically enriched mixture may comprise, for example, at least about 60 mol percent of one enantiomer, or more preferably at least about 75, about 90, about 95, or even about 99 mol percent. In certain embodiments, the compound enriched in one enantiomer is substantially free of the other enantiomer, wherein substantially free means that the substance in question makes up less than about 10%, or less than about 5%, or less than about 4%, or less than about 3%, or less than about 2%, or less than about 1% as compared to the amount of the other enantiomer, e.g., in the composition or compound mixture. For example, if a composition or compound mixture contains about 98 grams of a first enantiomer and about 2 grams of a second enantiomer, it would be said to contain about 98 mol percent of the first enantiomer and only about 2% of the second enantiomer.

In certain embodiments, the therapeutic preparation may be enriched to provide predominantly one diastereomer of a compound (e.g., of Formula (I)). A diastereomerically enriched mixture may comprise, for example, at least about 60 mol percent of one diastereomer, or more preferably at least about 75, about 90, about 95, or even about 99 mol percent.

The term "subject" to which administration is contemplated includes, but is not limited to, humans (i.e., a male or female of any age group, e.g., a pediatric subject (e.g., infant, child, adolescent) or adult subject (e.g., young adult, middle-aged adult or senior adult)) and/or other primates (e.g., cynomolgus monkeys, rhesus monkeys); mammals, including commercially relevant mammals such as cattle, pigs, horses, sheep, goats, cats, and/or dogs; and/or birds, including commercially relevant birds such as chickens, ducks, geese, quail, and/or turkeys. Preferred subjects are humans.

As used herein, a therapeutic that “prevents” a disorder or condition refers to a compound that, in a statistical sample, reduces the occurrence of the disorder or condition in the treated sample relative to an untreated control sample, or delays the onset or reduces the severity of one or more symptoms of the disorder or condition relative to the untreated control sample.

The term “treating” includes prophylactic and/or therapeutic treatments. The term “prophylactic or therapeutic” treatment is art-recognized and includes administration to the subject of one or more of the disclosed compositions. If it is administered prior to clinical manifestation of the unwanted condition (e.g., disease or other unwanted state of the subject) then the treatment is prophylactic (i.e., it protects the subject against developing the unwanted condition), whereas if it is administered after manifestation of the unwanted condition, the treatment is therapeutic, (i.e., it is intended to diminish, ameliorate, or stabilize the existing unwanted condition or side effects thereof).

The term “prodrug” is intended to encompass compounds which, under physiologic conditions, are converted into the therapeutically active agents of the present invention (e.g., a compound of Formula (I)). A common method for making a prodrug is to include one or more selected moieties which are hydrolyzed under physiologic conditions to reveal the desired molecule. In other embodiments, the prodrug is converted by an enzymatic activity of the subject. For example, esters or carbonates (e.g., esters or carbonates of alcohols or carboxylic acids) are preferred prodrugs of the present invention. In certain embodiments, some or all of the compounds of Formula (I) in a formulation represented above can be replaced with the corresponding suitable prodrug, e.g., wherein a hydroxyl in the parent compound is presented as an ester or a carbonate or carboxylic acid.

An “effective amount”, as used herein, refers to an amount that is sufficient to achieve a desired biological effect. A “therapeutically effective amount”, as used herein, refers to an amount that is sufficient to achieve a desired therapeutic effect. For example, a therapeutically effective amount can refer to an amount that is sufficient to improve at least one sign or symptom of cancer.

A “response” to a method of treatment can include a decrease in or amelioration of negative symptoms, a decrease in the progression of a disease or symptoms thereof, an increase in beneficial symptoms or clinical outcomes, a lessening of side effects, stabilization of disease, and partial or complete remedy of disease, among others.

In certain aspects, disclosed herein are compounds of Formula (I): wherein: A is selected from monocycloalkyl, bicycloalkyl and polycycloalkyl;

R¹ is aryl; and

R² is heteroaryl; or a pharmaceutically acceptable salt thereof.

In certain embodiments, A is monocyclyl, e.g., selected from cyclobutyl, cyclopentyl, and cyclohexyl. In further embodiments, A is cyclohexyl. In yet further embodiments, A is bicycloalkyl, e.g., selected from bicyclopentyl, spiro[3.3]heptyl, and bicyclo[2.2.2]octyl. In still further embodiments, A is bicyclo[2.2.2]octyl. In certain embodiments, A is polycyclyl, e.g., adamantyl.

In certain embodiments, R¹ is phenyl. In further embodiments, R¹ is 1,3- dihydroisobenzofuranyl. In yet further embodiments, R¹ is unsubstituted or substituted with one or more substituents selected from halo, CN, NO2, alkyl, alkoxy, amino, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, and heteroaralkyl. In still further embodiments, R¹ has one or two methyl substituents. In certain embodiments, R¹ is 2, 3 -dimethylphenyl. In further embodiments, R¹ is substituted with one or more substituents selected from isopropyl, -NH2, dimethylamino, and methoxy. In yet further embodiments, an R¹ substituent is present at the 2-position, the 3-position, or both, relative to the carbon atom bound to the nitrogen atom of the amide group. In still further embodiments, R² is isoxazolyl or pyrazolyl. In certain embodiments, R² is 3,5-dimethylisoxazolyl or 1,4-dimethylpyrazolyl.

In further embodiments, the amide and ether substituents of the compound of Formula (I) are disposed in a c/.s-relationship on a ring of A. In yet further embodiments, the amide and ether substituents of the compound of Formula (I) are disposed in a /ra/z.s-relationship on a ring of A.

In certain aspects, disclosed is a compound selected from:

In certain aspects, disclosed herein are compounds of Formula (II): wherein:

R¹ is aryl;

R² is heteroaryl;

R³ is fluoro; and nl is 1, 2, 3, or 4; or a pharmaceutically acceptable salt thereof. In certain aspects, disclosed herein is a compound selected from:

In certain embodiments, R¹ is phenyl. In further embodiments, R¹ is 1,3- dihydroisobenzofuranyl. In yet further embodiments, R¹ is unsubstituted or substituted with one or more substituents selected from halo, CN, NO2, alkyl, alkoxy, amino, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, and heteroaralkyl. In still further embodiments, R¹ has one or two methyl substituents.

In certain embodiments, R¹ is 2, 3 -dimethylphenyl or 2-m ethoxy-3 -methylphenyl. In further embodiments, R¹ is substituted with one or more substituents selected from isopropyl, -NH2, dimethylamino, and methoxy. In yet further embodiments, an R¹ substituent is present at the 2-position, the 3 -position, or both, relative to the carbon atom bound to the nitrogen atom of the amide group. In still further embodiments, nl is 1.

In certain embodiments, nl is 2. In further embodiments, R² is pyrazolyl or isoxazolyl. In yet further embodiments, R² is unsubstituted or substituted with one or more substituents selected from halo, CN, NO2, alkyl, alkoxy, amino, cycloalkyl, cycloalkylalkyl, heterocyclyl, and heterocyclylalkyl. In still further embodiments, R² is substituted with one or more substituents selected from chloro, methyl, and isopropyl.

In certain aspects, disclosed herein are compounds of Formula (III): wherein:

R¹ is aryl;

A is phenyl, monocycloalkyl, bicycloalkyl, or polycycloalkyl;

R⁴ is halo; and n2 is 1, 2, 3, 4, or 5; or a pharmaceutically acceptable salt thereof.

In certain embodiments, R¹ is phenyl. In further embodiments, R¹ is 1,3- dihydroisobenzofuranyl. In yet further embodiments, R¹ is unsubstituted or substituted with one or more substituents selected from halo, CN, NO2, alkyl, alkoxy, amino, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, and heteroaralkyl. In still further embodiments, R¹ has one or two methyl substituents.

In certain embodiments, R¹ is 2, 3 -dimethylphenyl. In further embodiments, R¹ is substituted with one or more substituents selected from isopropyl, -NH2, dimethylamino, and methoxy. In yet further embodiments, an R¹ substituent is present at the 2-position, the 3- position, or both, relative to the carbon atom bound to the nitrogen atom of the amide group. In still further embodiments, R⁴ is fluoro. In certain embodiments, n2 is 1. In further embodiments, A is phenyl.

In certain aspects, disclosed herein is a compound, wherein the compound is: Methods of Use

Pancreatic beta-cell dysfunction, leading to a loss of glucose-stimulated insulin secretion (GSIS), plays a major role in type 2 diabetes (T2D). Therefore, a better understanding of GSIS and glucose responsiveness has the potential to improve current understanding of the etiology of T2D. Although several clinically used drugs improve insulin secretion, they often lack glucose dependence in their activity. To that end, phenotypic chemical screening has been a powerful approach to discover small molecules, targets and pathways involved in cell biology. Disclosed herein are small molecules that promote insulin secretion in rodent beta cells and human islets in a glucose-dependent manner.

Insulin secretagogues known in the art include sulfonylureas (e.g., Glimepiride, Glipizide, and Glyburide) and meglitinides (e.g., Repaglinide and Nateglinide). These classes of medicines help the pancreas release or secrete insulin in subjects who do not produce enough on their own. Risks of these medicines include hypoglycemia. Thus, there is a need in the art for insulin secretagogues that are glucose-dependent, such that they activate insulin secretion only when the circulating blood glucose level is physiologically high. Bioassays exist to identify agents that are glucose-dependent, such as those in WO 2013/070796A3 and Burns et al., Cell Metab. 2015 Jan 6;21(1): 126-37. In these assays, compounds of the invention have shown significant activity as glucose-dependent insulin secretagogues.

Provided herein are methods of treating diseases and conditions that benefit from regulating circulating insulin levels, comprising administering a compound of the invention, such as a compound of Formula (I), or a pharmaceutically acceptable salt thereof. In some embodiments, a compound of the invention, such as a compound of Formula (I), or a pharmaceutically acceptable salt thereof can act as insulin secretagogues. In certain embodiments, the compound is a compound of Formula (II), or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound is a compound of Formula (III), or a pharmaceutically acceptable salt thereof. In certain embodiments, these insulin secretagogues are glucose-dependent, such that they activate insulin secretion only when the circulating blood glucose level is physiologically high.

In some embodiments, disclosed herein are methods of treating diabetes comprising administering a compound the invention, such as a compound of Formula (I), Formula (II), Formula (III), or a pharmaceutically acceptable salt thereof. In some embodiments, the methods disclosed herein treat diabetes using insulin secretagogues as disclosed herein. In some embodiments, the diabetes is diabetes mellitus.

In some embodiments, disclosed herein are methods of modulating insulin secretion, comprising contacting a P-cell with a compound having the structure of Formula I. In certain embodiments, the insulin secretion from said P-cell occurs only when said blood glucose levels exceed normoglycemic conditions. These blood glucose levels include, but are not limited to, 5 mM, 7 mM, 10 mM, 12 mM, or from about 3.5 mM to about 7 mM.

In certain embodiments, disclosed herein are methods of modulating insulin secretion, comprising administering to a subject in need thereof a compound of Formula (I), Formula (II), Formula (III), or a pharmaceutically acceptable salt thereof. In certain embodiments, disclosed herein are methods of treating diabetes, comprising administering to a subject in need thereof a compound of Formula (I), Formula (II), Formula (III), or a pharmaceutically acceptable salt thereof.

Pharmaceutical Compositions

In certain embodiments, the present invention provides a pharmaceutical preparation suitable for use in a human patient, comprising any of the compounds shown above (e.g., a compound of the invention, such as a compound of Formula (I), Formula (II), Formula (III)), and one or more pharmaceutically acceptable excipients. In certain embodiments, the pharmaceutical preparations may be for use in treating or preventing a condition or disease as described herein. Any of the disclosed compounds may be used in the manufacture of medicaments for the treatment of any diseases or conditions disclosed herein.

The compositions and methods of the present invention may be utilized to treat a subject in need thereof. In certain embodiments, the subject is a mammal such as a human, or a nonhuman mammal. When administered to a subject, such as a human, the composition or the compound is preferably administered as a pharmaceutical composition comprising, for example, a compound of the invention and a pharmaceutically acceptable carrier. Pharmaceutically acceptable carriers are well known in the art and include, for example, aqueous solutions such as water or physiologically buffered saline or other solvents or vehicles such as glycols, glycerol, oils such as olive oil, or injectable organic esters. In a preferred embodiment, when such pharmaceutical compositions are for human administration, particularly for invasive routes of administration (i.e., routes, such as injection or implantation, that circumvent transport or diffusion through an epithelial barrier), the aqueous solution is pyrogen-free, or substantially pyrogen-free. The excipients can be chosen, for example, to effect delayed release of an agent or to selectively target one or more cells, tissues or organs. The pharmaceutical composition can be in dosage unit form such as tablet, capsule (including sprinkle capsule and gelatin capsule), granule, lyophile for reconstitution, powder, solution, syrup, suppository, injection or the like. The composition can also be present in a transdermal delivery system, e.g., a skin patch. The composition can also be present in a solution suitable for topical administration, such as an eye drop.

A pharmaceutically acceptable carrier can contain physiologically acceptable agents that act, for example, to stabilize, increase solubility or to increase the absorption of a compound such as a compound of the invention. Such physiologically acceptable agents include, for example, carbohydrates, such as glucose, sucrose or dextrans, antioxidants, such as ascorbic acid or glutathione, chelating agents, low molecular weight proteins or other stabilizers or excipients. The choice of a pharmaceutically acceptable carrier, including a physiologically acceptable agent, depends, for example, on the route of administration of the composition. The preparation or pharmaceutical composition can be a self-emulsifying drug delivery system or a self-microemulsifying drug delivery system. The pharmaceutical composition (preparation) also can be a liposome or other polymer matrix, which can have incorporated therein, for example, a compound of the invention. Liposomes, for example, which comprise phospholipids or other lipids, are nontoxic, physiologically acceptable and metabolizable carriers that are relatively simple to make and administer.

The phrase "pharmaceutically acceptable" is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of a subject without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.

The phrase "pharmaceutically acceptable carrier" as used herein means a pharmaceutically acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not injurious to the subject. Some examples of materials which can serve as pharmaceutically acceptable carriers include: (1) sugars, such as lactose, glucose and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository waxes; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffering agents, such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer's solution; (19) ethyl alcohol; (20) phosphate buffer solutions; and (21) other non-toxic compatible substances employed in pharmaceutical formulations.

A pharmaceutical composition (preparation) can be administered to a subject by any of a number of routes of administration including, for example, orally (for example, drenches as in aqueous or non-aqueous solutions or suspensions, tablets, capsules (including sprinkle capsules and gelatin capsules), boluses, powders, granules, pastes for application to the tongue); absorption through the oral mucosa (e.g., sublingually); anally, rectally or vaginally (for example, as a pessary, cream or foam); parenterally (including intramuscularly, intravenously, subcutaneously or intrathecally as, for example, a sterile solution or suspension); nasally; intraperitoneally; subcutaneously; transdermally (for example as a patch applied to the skin); and topically (for example, as a cream, ointment or spray applied to the skin, or as an eye drop). The compound may also be formulated for inhalation. In certain embodiments, a compound may be simply dissolved or suspended in sterile water. Details of appropriate routes of administration and compositions suitable for same can be found in, for example, U.S. Pat. Nos. 6,110,973, 5,763,493, 5,731,000, 5,541,231, 5,427,798, 5,358,970 and 4,172,896, as well as in patents cited therein.

The formulations may conveniently be presented in unit dosage form and may be prepared by any methods well known in the art of pharmacy. The amount of active ingredient which can be combined with a carrier material to produce a single dosage form will vary depending upon the subject being treated and the particular mode of administration. The amount of active ingredient that can be combined with a carrier material to produce a single dosage form will generally be that amount of the compound that produces a therapeutic effect. Generally, out of one hundred percent, this amount will range from about 1 percent to about ninety-nine percent of active ingredient, preferably from about 5 percent to about 70 percent, most preferably from about 10 percent to about 30 percent.

Methods of preparing these formulations or compositions include the step of bringing into association an active compound, such as a compound of the invention, with the carrier and, optionally, one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing into association a compound of the present invention with liquid carriers, or finely divided solid carriers, or both, and then, if necessary, shaping the product.

Formulations of the invention suitable for oral administration may be in the form of capsules (including sprinkle capsules and gelatin capsules), cachets, pills, tablets, lozenges (using a flavored basis, usually sucrose and acacia or tragacanth), lyophile, powders, granules, or as a solution or a suspension in an aqueous or non-aqueous liquid, or as an oil-in-water or water-in-oil liquid emulsion, or as an elixir or syrup, or as pastilles (using an inert base, such as gelatin and glycerin, or sucrose and acacia) and/or as mouth washes and the like, each containing a predetermined amount of a compound of the present invention as an active ingredient. Compositions or compounds may also be administered as a bolus, electuary or paste.

To prepare solid dosage forms for oral administration (capsules (including sprinkle capsules and gelatin capsules), tablets, pills, dragees, powders, granules and the like), the active ingredient is mixed with one or more pharmaceutically acceptable carriers, such as sodium citrate or dicalcium phosphate, and/or any of the following: (1) fillers or extenders, such as starches, lactose, sucrose, glucose, mannitol, and/or silicic acid; (2) binders, such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose and/or acacia; (3) humectants, such as glycerol; (4) disintegrating agents, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; (5) solution retarding agents, such as paraffin; (6) absorption accelerators, such as quaternary ammonium compounds; (7) wetting agents, such as, for example, cetyl alcohol and glycerol monostearate; (8) absorbents, such as kaolin and bentonite clay; (9) lubricants, such a talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof; (10) complexing agents, such as, modified and unmodified cyclodextrins; and (11) coloring agents. In the case of capsules (including sprinkle capsules and gelatin capsules), tablets and pills, the pharmaceutical compositions may also comprise buffering agents. Solid compositions of a similar type may also be employed as fillers in soft and hard- filled gelatin capsules using such excipients as lactose or milk sugars, as well as high molecular weight polyethylene glycols and the like.

A tablet may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared using binder (for example, gelatin or hydroxypropylmethyl cellulose), lubricant, inert diluent, preservative, disintegrant (for example, sodium starch glycolate or cross-linked sodium carboxymethyl cellulose), surfaceactive or dispersing agent. Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.

The tablets, and other solid dosage forms of the pharmaceutical compositions, such as dragees, capsules (including sprinkle capsules and gelatin capsules), pills and granules, may optionally be scored or prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical-formulating art. They may also be formulated so as to provide slow or controlled release of the active ingredient therein using, for example, hydroxypropylmethyl cellulose in varying proportions to provide the desired release profile, other polymer matrices, liposomes and/or microspheres. They may be sterilized by, for example, filtration through a bacteria-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions that can be dissolved in sterile water, or some other sterile injectable medium immediately before use. These compositions may also optionally contain opacifying agents and may be of a composition that they release the active ingredient(s) only, or preferentially, in a certain portion of the gastrointestinal tract, optionally, in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes. The active ingredient can also be in micro-encapsulated form, if appropriate, with one or more of the above-described excipients.

Liquid dosage forms useful for oral administration include pharmaceutically acceptable emulsions, lyophiles for reconstitution, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active ingredient, the liquid dosage forms may contain inert diluents commonly used in the art, such as, for example, water or other solvents, cyclodextrins and derivatives thereof, solubilizing agents and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3- butylene glycol, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor and sesame oils), glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.

Besides inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, coloring, perfuming and preservative agents.

Suspensions, in addition to the active compounds, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof.

Formulations of the pharmaceutical compositions for rectal, vaginal, or urethral administration may be presented as a suppository, which may be prepared by mixing one or more active compounds with one or more suitable nonirritating excipients or carriers comprising, for example, cocoa butter, polyethylene glycol, a suppository wax or a salicylate, and which is solid at room temperature, but liquid at body temperature and, therefore, will melt in the rectum or vaginal cavity and release the active compound.

Formulations of the pharmaceutical compositions for administration to the mouth may be presented as a mouthwash, or an oral spray, or an oral ointment.

Alternatively, or additionally, compositions can be formulated for delivery via a catheter, stent, wire, or other intraluminal device. Delivery via such devices may be especially useful for delivery to the bladder, urethra, ureter, rectum, or intestine.

Formulations which are suitable for vaginal administration also include pessaries, tampons, creams, gels, pastes, foams or spray formulations containing such carriers as are known in the art to be appropriate.

Dosage forms for the topical or transdermal administration include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants. The active compound may be mixed under sterile conditions with a pharmaceutically acceptable carrier, and with any preservatives, buffers, or propellants that may be required.

The ointments, pastes, creams and gels may contain, in addition to an active compound, excipients, such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.

Powders and sprays can contain, in addition to an active compound, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances. Sprays can additionally contain customary propellants, such as chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons, such as butane and propane.

Transdermal patches have the added advantage of providing controlled delivery of a compound of the present invention to the body. Such dosage forms can be made by dissolving or dispersing the active compound in the proper medium. Absorption enhancers can also be used to increase the flux of the compound across the skin. The rate of such flux can be controlled by either providing a rate controlling membrane or dispersing the compound in a polymer matrix or gel.

Ophthalmic formulations, eye ointments, powders, solutions and the like, are also contemplated as being within the scope of this invention. Exemplary ophthalmic formulations are described in U.S. Publication Nos. 2005/0080056, 2005/0059744, 2005/0031697 and 2005/0004074 and U.S. Patent No. 6,583,124, the contents of which are incorporated herein by reference. If desired, liquid ophthalmic formulations have properties similar to that of lacrimal fluids, aqueous humor or vitreous humor or are compatible with such fluids. A preferred route of administration is local administration (e.g., topical administration, such as eye drops, or administration via an implant).

The phrases "parenteral administration" and "administered parenterally" as used herein means modes of administration other than enteral and topical administration, usually by injection, and includes, without limitation, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal and intrasternal injection and infusion.

Pharmaceutical compositions suitable for parenteral administration comprise one or more active compounds in combination with one or more pharmaceutically acceptable sterile isotonic aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, or sterile powders which may be reconstituted into sterile injectable solutions or dispersions just prior to use, which may contain antioxidants, buffers, bacteriostats, solutes which render the formulation isotonic with the blood of the intended recipient or suspending or thickening agents.

Examples of suitable aqueous and nonaqueous carriers that may be employed in the pharmaceutical compositions of the invention include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), and suitable mixtures thereof, vegetable oils, such as olive oil, and injectable organic esters, such as ethyl oleate. Proper fluidity can be maintained, for example, by the use of coating materials, such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.

These compositions may also contain adjuvants such as preservatives, wetting agents, emulsifying agents and dispersing agents. Prevention of the action of microorganisms may be ensured by the inclusion of various antibacterial and antifungal agents, for example, paraben, chlorobutanol, phenol sorbic acid, and the like. It may also be desirable to include isotonic agents, such as sugars, sodium chloride, and the like into the compositions. In addition, prolonged absorption of the injectable pharmaceutical form may be brought about by the inclusion of agents that delay absorption such as aluminum monostearate and gelatin.

In some cases, in order to prolong the effect of a drug, it is desirable to slow the absorption of the drug from subcutaneous or intramuscular injection. This may be accomplished by the use of a liquid suspension of crystalline or amorphous material having poor water solubility. The rate of absorption of the drug then depends upon its rate of dissolution, which, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered drug form is accomplished by dissolving or suspending the drug in an oil vehicle.

Injectable depot forms are made by forming microencapsulated matrices of the subject compounds in biodegradable polymers such as polylactide-polyglycolide. Depending on the ratio of drug to polymer, and the nature of the particular polymer employed, the rate of drug release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations are also prepared by entrapping the drug in liposomes or microemulsions that are compatible with body tissue. For use in the methods of this invention, active compounds can be given per se or as a pharmaceutical composition containing, for example, 0.1 to 99.5% (more preferably, 0.5 to 90%) of active ingredient in combination with a pharmaceutically acceptable carrier.

Methods of introduction may also be provided by rechargeable or biodegradable devices. Various slow release polymeric devices have been developed and tested in vivo in recent years for the controlled delivery of drugs, including proteinacious biopharmaceuticals. A variety of biocompatible polymers (including hydrogels), including both biodegradable and non-degradable polymers, can be used to form an implant for the sustained release of a compound at a particular target site.

Actual dosage levels of the active ingredients in the pharmaceutical compositions may be varied so as to obtain an amount of the active ingredient that is effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration, without being toxic to the patient.

The selected dosage level will depend upon a variety of factors including the activity of the particular compound or combination of compounds employed, or the ester, salt or amide thereof, the route of administration, the time of administration, the rate of excretion of the particular compound(s) being employed, the duration of the treatment, other drugs, compounds and/or materials used in combination with the particular compound(s) employed, the age, sex, weight, condition, general health and prior medical history of the subject being treated, and like factors well known in the medical arts.

A physician or veterinarian having ordinary skill in the art can readily determine and prescribe the therapeutically effective amount of the pharmaceutical composition required. For example, the physician or veterinarian could start doses of the pharmaceutical composition or compound at levels lower than that required in order to achieve the desired therapeutic effect and gradually increase the dosage until the desired effect is achieved. By “therapeutically effective amount” is meant the concentration of a compound that is sufficient to elicit the desired therapeutic effect. It is generally understood that the effective amount of the compound will vary according to the weight, sex, age, and medical history of the subject. Other factors that influence the effective amount may include, but are not limited to, the severity of the subject's condition, the disorder being treated, the stability of the compound, and, if desired, another type of therapeutic agent being administered with the compound of the invention. A larger total dose can be delivered by multiple administrations of the agent. Methods to determine efficacy and dosage are known to those skilled in the art (Isselbacher et al. (1996) Harrison’s Principles of Internal Medicine 13 ed., 1814-1882, herein incorporated by reference).

In general, a suitable daily dose of an active compound used in the compositions and methods of the invention will be that amount of the compound that is the lowest dose effective to produce a therapeutic effect. Such an effective dose will generally depend upon the factors described above.

If desired, the effective daily dose of the active compound may be administered as one, two, three, four, five, six or more sub-doses administered separately at appropriate intervals throughout the day, optionally, in unit dosage forms. In certain embodiments of the present invention, the active compound may be administered two or three times daily. In preferred embodiments, the active compound will be administered once daily.

In some embodiments, the three doses of a compound of Formula (I), Formula (II), or Formula (III) range from about 100 mg to about 1000 mg orally, such as about 200 mg to about 800 mg, such as about 400 mg to about 700 mg, such as about 100 mg to about 400 mg, such as about 500 mg to about 1000 mg, and further such as about 500 mg to about 600 mg. Dosing can be three times a day when taken with without food, or twice a day when taken with food. In certain embodiments, the three doses of a compound of Formula (I), Formula (II), or Formula (III) range from about 400 mg to about 800 mg, such as about 400 mg to about 700 mg, such as about 500 mg to about 800 mg, and further such as about 500 mg to about 600 mg twice a day. In certain preferred embodiments, a dose of greater than about 600 mg is dosed twice a day.

In certain embodiments, the dosing schedule can be about 40 mg/m² to about 100 mg/m², such as about 50 mg/m² to about 80 mg/m², and further such as about 70 mg/m² to about 90 mg/m² by IV for 3 weeks of a 4 week cycle.

In certain embodiments, compounds of the invention may be used alone or conjointly administered with another type of therapeutic agent. As used herein, the phrase “conjoint administration” refers to any form of administration of two or more different therapeutic compounds such that the second compound is administered while the previously administered therapeutic compound is still effective in the body (e.g., the two compounds are simultaneously effective in the subject, which may include synergistic effects of the two compounds). For example, the different therapeutic compounds can be administered either in the same formulation or in a separate formulation, either concomitantly or sequentially. In certain embodiments, the different therapeutic compounds can be administered within one hour, 12 hours, 24 hours, 36 hours, 48 hours, 72 hours, or a week of one another. Thus, a subject who receives such treatment can benefit from a combined effect of different therapeutic compounds.

In certain embodiments, conjoint administration of compounds of the invention with one or more additional therapeutic agent(s) (e.g., one or more additional chemotherapeutic agent(s)) provides improved efficacy relative to each individual administration of the compound of the invention (e.g., the compound of Formula (I), Formula (II), or Formula (III)) or the one or more additional therapeutic agent(s). In certain such embodiments, the conjoint administration provides an additive effect, wherein an additive effect refers to the sum of each of the effects of individual administration of the compound of the invention and the one or more additional therapeutic agent(s).

This invention includes the use of pharmaceutically acceptable salts of compounds of the invention in the compositions and methods of the present invention. In certain embodiments, contemplated salts of the invention include, but are not limited to, alkyl, dialkyl, trialkyl or tetra-alkyl ammonium salts. In certain embodiments, contemplated salts of the invention include, but are not limited to, L-arginine, benethamine, benzathine, betaine, calcium hydroxide, choline, deanol, diethanolamine, diethylamine, 2-(diethylamino)ethanol, ethanolamine, ethylenediamine, N-methylglucamine, hydrabamine, IH-imidazole, lithium, L- lysine, magnesium, 4-(2-hydroxyethyl)morpholine, piperazine, potassium, l-(2- hydroxyethyl)pyrrolidine, sodium, triethanolamine, tromethamine, and zinc salts. In certain embodiments, contemplated salts of the invention include, but are not limited to, Na, Ca, K, Mg, Zn or other metal salts.

The pharmaceutically acceptable acid addition salts can also exist as various solvates, such as with water, methanol, ethanol, dimethylformamide, and the like. Mixtures of such solvates can also be prepared. The source of such solvate can be from the solvent of crystallization, inherent in the solvent of preparation or crystallization, or adventitious to such solvent. Pharmaceutically acceptable anionic salts include acetate, aspartate, benzenesulfonate, benzoate, besylate, bicarbonate, bitartrate, bromide, camsylate, carbonate, chloride, citrate, decanoate, edetate, esylate, fumarate, gluceptate, gluconate, glutamate, glycolate, hexanoate, hydroxynaphthoate, iodide, isethionate, lactate, lactobionate, malate, maleate, mandelate, mesylate, methyl sulfate, mucate, napsylate, nitrate, octanoate, oleate, pamoate, pantothenate, phosphate, polygalacturonate, propionate, salicylate, stearate, acetate, succinate, sulfate, tartrate, teoclate, and tosylate.

Wetting agents, emulsifiers and lubricants, such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, release agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the compositions.

Examples of pharmaceutically acceptable antioxidants include: (1) water-soluble antioxidants, such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite and the like; (2) oil-soluble antioxidants, such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, alpha-tocopherol, and the like; and (3) metal-chelating agents, such as citric acid, ethylenediamine tetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, and the like.

The invention now being generally described, it will be more readily understood by reference to the following examples which are included merely for purposes of illustration of certain aspects and embodiments of the present invention, and are not intended to limit the invention.

General Synthetic Procedures

Compound numbers as used in the general synthesis section below refer only to genus structures in this section and do not apply to compounds disclosed elsewhere in this application. Compounds disclosed herein can be made by methods depicted in the reaction schemes below.

The starting materials and reagents used in preparing these compounds are either available from commercial supplier such as Aldrich Chemical Co., Bachem, etc., or can be made by methods well known in the art. The schemes are merely illustrative of some methods by which the compounds disclosed herein can be synthesized and various modifications to these schemes can be made and will be suggested to a person of skill in the art (POSITA) having referred to this disclosure. The starting materials and the intermediates and the final products of the reaction may be isolated and purified if desired using conventional techniques, including but not limited to filtration, distillation, crystallization, chromatography, and the like and may be characterized using conventional means, including physical constants and spectral data.

Unless specified otherwise, the reactions described herein take place at atmospheric pressure over a temperature range from about -78 °C to about 150 °C.

Method 1 : 1,4-transcyclohexyl analogs (Oxazole)

Method 2: 1,4-transcyclohexyl analogs (Pyrazole)

Method 5: [3.3.0] analogs

Method 8: Fluorophenyl analogs

Method 10: Difluorophenyl analogs

EXAMPLES

1,4-transcyclohexyl analogs (Oxazole) Intermediates

Step 1 : 4-(iodomethyl)-3,5-dimethyl-isoxazole

The mixture of 4-(chloromethyl)-3,5-dimethyl-isoxazole (5.00 g, 34.3 mmol, 1.0 eq) and sodium iodide (10.30 g, 68.7 mmol, 2.0 eq) in 50 mL of Acetone was stirred at 80 °C for 12 h. To the reaction mixture was added 100 mL of water, then extracted with 200 mL of EA, washed with 50 mL of brine three times, dried over Na2SC>4, filtered and concentrated under reduced pressure to give 4-(iodomethyl)-3,5-dimethyl-isoxazole (8.00 g, 98% yield) as a brown oil.

Step 2: Ethyl 4-[(3,5-dimethylisoxazol-4-yl)methoxy]cyclohexanecarboxylate

To a solution of ethyl 4-hydroxy cyclohexanecarboxylate (1.00 g, 5.81 mmol, 1.0 eq) in 30 mL of anhydrous DMF was added NaH (255 mg, 6.39 mmol, 1.1 eq) at 0 °C and stirred for 0.5 h. Then 4-(iodomethyl)-3,5-dimethyl-isoxazole (5506 mg, 23.2 mmol, 4.0 eq) was added into the mixture and stirred at 25 °C for 12 h. The reaction mixture was poured into 50 mL of saturated NH4CI solution, extracted with 100 mL of EA. The organic phase was washed with 30 mL of brine, dried over with Na2SC>4, filtered and concentrated under reduced pressure. The residue was purified by reversed-phase (FA condition) chromatography. The eluent was adjusted pH to 8 with saturated NaHCCL solution. Then the solution was extracted with 200 mL of EA, dried over with Na2SC>4, filtered and concentrated under reduced pressure to give ethyl 4-[(3 , 5- dimethylisoxazol-4-yl)methoxy]cyclohexanecarboxylate (950 mg, 82% purity, 48% yield) as a yellow oil.

Step 3: 4-[(3,5-dimethylisoxazol-4-yl)methoxy]cyclohexanecarboxylic acid To a solution of ethyl 4-[(3,5-dimethylisoxazol-4-yl)methoxy]cyclohexanecarboxylate (950 mg, 3.38 mmol, 1.0 eq) in 5 mL of THF, 5 mL of MeOH and 5 mL of water was added a solution of LiOH-H₂O (425 mg, 10.1 mmol, 3.0 eq). The mixture was stirred at 25 °C for 2 h. The reaction mixture was concentrated under reduced pressure to remove THF and MeOH. The mixture was adjusted pH to 3 with 1 N HC1. The precipitate was formed and filtered, dried over under vacuum to give 4-[(3,5-dimethylisoxazol-4-yl)methoxy]cyclohexanecarboxylic acid (650 mg, 76% yield) as a yellow solid.

Example 1

N-(2,3-dimethyl-phenyl)-4-[(3,5-dimethylisoxazol-4-yl)methoxy]cy cl ohexane carboxamide

To a solution of 4-[(3,5-dimethylisoxazol-4-yl)methoxy]cyclohexanecarboxylic acid (109 mg, 0.43 mmol, 1.0 eq) , 2,3-dimethylbenzene-l-amine (156 mg, 1.29 mmol, 3.0 eq) in 2 mL of anhydrous DMF was added HATU (181 mg, 0.48 mmol, 1.1 eq) and DIPEA (167 mg, 1.29 mmol, 3.0 eq). The mixture was stirred at 25 °C for 12 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by column chromatography (SiO₂, ethyl acetate/hexanes) to give N-(3-amino-2-methyl-phenyl)-4-[(3,5-dimethylisoxazol-4- yl)methoxy]cyclohexanecarboxamide (45 mg, 0.12 mmol, 29% yield) as a white solid. The structure was supported by LCMS and HNMR.

'HNMR (400 MHz, DMSO) 5 9.26 (s, 1H), 7.10 - 6.97 (m, 3H), 4.32 (s, 2H), 3.32 - 3.22 (m, 1H), 2.35 (s, 3H), 2.34 - 2.31 (m, 1H), 2.24 (s, 3H), 2.19 (s, 3H), 2.13 - 2.05 (m, 2H), 2.04 (s, 3H), 1.90 (d, J= 13.4 Hz, 2H), 1.49 (q, J= 12.7 Hz, 2H), 1.31 - 1.11 (m, 2H).

Example 2

N-(3-amino-2 -methyl -phenyl)-4-[(3,5-dimethylisoxazol-4-yl)methoxy]cy cl ohexane carboxamide

To a solution of 4-[(3,5-dimethylisoxazol-4-yl)methoxy]cyclohexanecarboxylic acid (50 mg, 0.197 mmol, 1.0 eq) , 2-methylbenzene-l,3-diamine (24 mg, 0.197 mmol, 1.0 eq) in 2 mL of anhydrous THF was added HATU (113 mg, 0.296 mmol, 1.5 eq) and DIPEA (38 mg, 0.296 mmol, 1.5 eq). The mixture was stirred at 25 °C for 12 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by prep-HPLC (neutral condition) to give N- (3-amino-2-methyl-phenyl)-4-[(3,5-dimethylisoxazol-4-yl)methoxy]cyclohexanecarboxamide (13 mg, 0.0341 mmol, 95% purity, 17% yield) as a white solid. The structure was supported by LCMS and HNMR.

'H NMR (400 MHz, CHLOROFORM-d) 5 7.12 - 6.89 (m, 3H), 6.60 (br d, J= 8.0 Hz, 1H), 4.34 (s, 2H), 3.66 (br s, 2H), 3.49 - 3.24 (m, 1H), 2.40 (s, 3H), 2.31 - 2.28 (m, 3H), 2.28 - 2.17 (m, 3H), 2.15 - 2.03 (m, 5H), 1.77 - 1.62 (m, 2H), 1.45 - 1.30 (m, 2H) ppm.

MS (ESI): m/z for C20H27N3O3 +H, [M+H]+ calcd.358.2, [M+H]+ found. 358.3

Example 3

4-[(3,5-dimethylisoxazol-4-yl)methoxy]-N-(2-methoxy-3-methyl-phenyl)cyclohexane carboxamide

To a solution of 4-[(3,5-dimethylisoxazol-4-yl)methoxy]cyclohexanecarboxylic acid (50 mg, 0.197 mmol, 1.0 eq) and 2-m ethoxy-3 -methyl-aniline (27 mg, 0.197 mmol, 1.0 eq) in 2 mL of anhydrous THF was added HATU (113 mg, 0.296 mmol, 1.5 eq) and DIPEA (38 mg, 0.296 mmol, 1.5 eq). The mixture was stirred at 25 °C for 12 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by prep-HPLC (neutral condition) to give 4- [(3,5-dimethylisoxazol-4-yl)methoxy]-N-(2-methoxy-3-methyl- phenyl)cyclohexanecarboxamide (26 mg, 0.0706 mmol, 99% purity, 36% yield) as a white solid. The structure was supported by LCMS and ^JH NMR.

¹HNMR (400 MHz, CHLOROFORM-d) 5 8.19 (d, J= 8.0 Hz, 1H), 7.81 (br s, 1H), 7.07 - 6.99 (m, 1H), 6.92 (d, J= 7.2 Hz, 1H), 4.34 (s, 2H), 3.79 (s, 3H), 3.40 - 3.30 (m, 1H), 2.40 (s, 3H), 2.33 (s, 3H), 2.31 - 2.25 (m, 4H), 2.24 - 2.15 (m, 2H), 2.14 - 2.01 (m, 2H), 1.73 - 1.62 (m, 2H), 1.46 - 1.30 (m, 2H) ppm.

MS (ESI): m/z for C21H28N2O4 +H, [M+H]+ calcd.373.2, [M+H]+ found. 373.2

Example 4

4-((3,5-dimethylisoxazol-4-yl)methoxy)-N-(2 isopropylphenyl)cyclohexanecarboxamide

To a solution of 4-[(3,5-dimethylisoxazol-4-yl)methoxy]cyclohexanecarboxylic acid (50 mg, 0.197 mmol, 1.0 eq) and 2-isopropylaniline (27 mg, 0.197 mmol, 1.0 eq) in 5 mL of anhydrous THF was added HATU (113 mg, 0.296 mmol, 1.5 eq) and DIEA (38 mg, 0.296 mmol, 1.5 eq). The reaction mixture was stirred at 25 °C for 12 h. The reaction mixture was poured into 10 mL of water and extracted with 5 mL of EA twice. The organic layer was dried over with Na2SC>4 and concentrated. The residue was purified by Prep-HPLC (neutral condition) to give 4-[(3,5-dimethylisoxazol-4-yl)methoxy]-N-(2-isopropylphenyl)cyclohexanecarboxamide (28 mg, 99.2% purity, 38% yield) as white solid. The structure was supported by HNMR and LCMS.

^XH NMR (400 MHz, CHLOROFORM-d): 5 7.72 - 7.65 (m, 1H), 7.29 (d, J= 6.0 Hz, 1H), 7.23 - 7.15 (m, 2H), 7.02 (s, 1H), 4.33 (s, 2H), 3.41 - 3.28 (m, 1H), 3.04-2.97 (m, 1H), 2.39 (s, 3H), 2.28 (s, 4H), 2.24 - 2.16 (m, 2H), 2.10 (d, J= 13.6 Hz, 2H), 1.72 - 1.64 (m, 3H), 1.43 - 1.33 (m, 2H), 1.26 (d, J= 6.8 Hz, 6H) ppm.

MS (ESI): m/z for C22H30N2O3 [M+H]+ calcd. 371.2, [M+H]+ found. 371.1

Example 5

N-(l,3-dihydroisobenzofuran-4-yl)-4-[(3,5-dimethylisoxazol-4-yl)methoxy]cyclohexane carboxamide

To a solution of 4-[(3,5-dimethylisoxazol-4-yl)methoxy]cyclohexanecarboxylic acid (50 mg,

0.197 mmol, 1.0 eq) and l,3-dihydroisobenzofuran-4-amine (27 mg, 0.197 mmol, 1.0 eq) in 2 mL of anhydrous THF was added HATU (113 mg, 0.296 mmol, 1.5 eq) and DIPEA (38 mg, 0.296 mmol, 1.5 eq). The mixture was stirred at 25 °C for 12 h. The mixture was concentrated under reduced pressure. The residue was purified by Prep-HPLC (basic condition) to give N- (l,3-dihydroisobenzofuran-4-yl)-4-[(3,5-dimethylisoxazol-4- yl)methoxy]cyclohexanecarboxamide (16 mg, 99.9% purity, 22% yield) as a white solid.

'H NMR (400 MHz, CHLOROFORM-d): 57.50 (d, J= 7.6 Hz, 1H), 7.32 - 7.25 (m, 2H), 7.17 - 6.91 (m, 2H), 5.15 (s, 2H), 5.07 (s, 2H), 4.34 (s, 2H), 3.45 - 3.26 (m, 1H), 2.40 (s, 3H), 2.29 (s, 3H), 2.26 - 2.14 (m, 3H), 2.11 - 1.97 (m, 2H), 1.75 - 1.64 (m, 4H), 1.42 - 1.24 (m, 2H) ppm MS (ESI): m/z for C21H26N2O4 [M+H]+ calcd. 371.2, [M+H]+ found. 371.1

Example 6

N-(2-(dimethylamino)phenyl)-4-((3,5-dimethylisoxazol-4-yl)methoxy)cyclohexane carboxamide

To a solution of 4-[(3,5-dimethylisoxazol-4-yl)methoxy]cyclohexanecarboxylic acid (50 mg, 0.197 mmol, 1.0 eq) and N,N-dimethylbenzene-l,2-diamine (27 mg, 0.197 mmol, 1.0 eq) in 5 mL of anhydrous THF was added HATU (113 mg, 0.296 mmol, 1.5 eq) and DIEA (38 mg, 0.296 mmol, 1.5 eq). The reaction mixture was stirred at 25 °C for 12 h. The reaction mixture was poured into 10 mL of water and extracted with 5 mL of EA twice. The organic layer was dried over with Na2SC>4 and concentrated. The residue was purified by Prep-HPLC (neutral condition) to give N-[2-(dimethylamino)phenyl]-4-[(3,5-dimethylisoxazol-4- yl)methoxy]cyclohexanecarboxamide (23 mg, 98.9% purity, 31% yield) as a yellow solid. The structure was supported by HNMR and LCMS.

‘H NMR (400 MHz, CHLOROFORM-d): 5 8.61 - 8.48 (m, 1H), 8.35 (d, J= 8.0 Hz, 1H), 7.24 - 6.99 (m, 3H), 4.33 (s, 2H), 3.37-3.31 (m, 1H), 2.66 (s, 6H), 2.39 (s, 3H), 2.34 - 2.25 (m, 4H), 2.24 - 2.16 (m, 2H), 2.14 - 2.05 (m, 2H), 1.73 - 1.63 (m, 2H), 1.43 - 1.30 (m, 2H) ppm

MS (ESI): m/z for C21H29N3O3 [M+H]+ calcd. 372.2, [M+H]+ found. 372.1

1 ,4-transcyclohexyl analogs (Pyr azole) Intermediates

Stepl : 4-(hydroxymethyl)cyclohexanol i-6 1-7

To the solution of ethyl 4-hydroxy cyclohexanecarboxylate (5.0 g, 29.0 mmol, 1.0 eq) in 50 mL of anhydrous THF was added LiAlH4 (1102 mg, 29.0 mmol, 1.0 eq). The reaction mixture was stirred at 25 °C for 1 h. To the mixture was added 1 mL of water and 1 mL of 10% NaOH solution, 3 mL of water. The mixture was stirred at 25 °C for 0.5 h. Then the mixture was filtered and concentrated under reduced pressure to give 4-(hydroxymethyl)cyclohexanol (3500 mg, 93% yield) as colorless oil.

4-[[tert-butyl(diphenyl)silyl]oxymethyl]cyclohexanol -

To the mixture of 4-(hydroxymethyl)cyclohexanol (3.50 g, 26.9 mmol, 1.0 eq) in 30 mL of anhydrous DMF was added TBDPSC1 (8129 mg, 29.6 mmol, 1.1 eq) and IH-imidazole (2746 mg, 40.3 mmol, 1.5 eq). The mixture was stirred at 25 °C for 12 h. To the mixture was added 60 mL of EA and 50 mL of water. The organic phase was washed with 20 mL of brinethree times, dried over with Na2SC>4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, PE:EA=15: 1 to 5: 1) to give 4-[[tert- butyl(diphenyl)silyl]oxymethyl]cyclohexanol (5.00 g, 50% yield) as a colorless oil. The structure was supported by ^JH NMR.

'H NMR (400 MHz, DMSO-d₆): 5 7.63 - 7.57 (m, 4H), 7.48 - 7.39 (m, 6H), 4.49 (d, J = 4.4 Hz, 1H), 3.44 (d, J= 6.4 Hz, 2H), 3.33 - 3.25 (m, 1H), 1.87 - 1.78 (m, 2H), 1.77 - 1.64 (m, 2H), 1.50 - 1.35 (m, 1H), 1.19 - 1.04 (m, 2H), 1.04 - 0.88 (m, 12H) ppm.

Step 3: methyl 3-[(2,4-dimethylpyrazol-3-yl)methoxy]cyclobutanecarboxylate -

To the solution of 4-[[tert-butyl(diphenyl)silyl]oxymethyl]cyclohexanol (4.00 g, 10.9 mmol, 1.0 eq) in 30 mL of anhydrous DMF was added NaH (434 mg, 10.9 mmol, 1.0 eq) at 65 °C under N2. The reaction mixture was stirred at 65 °C for 0.5 h. Then the mixture was cooled to 25 °C. To the mixture was added 5-(chloromethyl)-l,4-dimethyl-pyrazole (1569 mg, 10.9 mmol, 1.0 eq) and stirred at 25 °C for 12 h. The reaction mixture was quenched with 80 mL of saturated NH4CI solution and extracted with 60 mL of EA. The organic phase was washed with 15 mL of brine three times, dried over with Na2SC>4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, PE : EA = 1 :0 to 3 : 1) to give crude methyl 3-[(2,4-dimethylpyrazol-3-yl)methoxy]cyclobutanecarboxylate (1200 mg, 82% yield) as yellow oil.

Step 4: [4-[(2,4-dimethylpyrazol-3-yl)methoxy]cyclohexyl]methanol

Step 5: 4-[(2,4-dimethylpyrazol-3-yl)methoxy]cyclohexanecarboxylic acid

To a solution of [4-[(2,4-dimethylpyrazol-3-yl)methoxy]cyclohexyl]methanol (660 mg, 2.77 mmol, 1.0 eq) in 33 mL of acetone was added 2.77 mL of Jones reagent. The reaction mixture was stirred at 0 °C for 1 h. The reaction mixture was poured into 30 mL of water and extracted with 25 mL of DCM three times. The organic layer was dried over with Na2SC>4 and concentrated to give 4-[(2,4-dimethylpyrazol-3-yl)methoxy]cyclohexanecarboxylic acid (420 mg, 60% yield) as a crude oil.

Example 7

4-[(2,4-dimethylpyrazol-3-yl)methoxy]-N-(2-methoxy-3-methyl-phenyl)cyclohexane carboxamide

To a solution of 4-[(2,4-dimethylpyrazol-3-yl)methoxy]cyclohexanecarboxylic acid (100 mg, 0.396 mmol, 1.0 eq) and 2-m ethoxy-3 -methyl-aniline (54 mg, 0.396 mmol, 1.0 eq) in 2 mL of anhydrous THF was added HATU (226 mg, 0.595 mmol, 1.5 eq) and DIEA (102 mg, 0.793 mmol, 2.0 eq). The reaction mixture was stirred at 25 °C for 12 h. To the mixture was added 20 mL of EA and 10 mL of water. The organic phase was washed with 20 mL of brine three times, dried over with Na2SC>4, filtered and concentrated under reduced pressure. The residue was purified by Prep-TLC (PE : EA = 1 : 1) and Prep-HPLC (basic condition) to give 4-[(2,4- dimethylpyrazol-3-yl)methoxy]-N-(2-methoxy-3-methyl-phenyl)cyclohexanecarboxamide (12 mg, 99.9% purity, 8% yield) as a white solid. The structure was supported by LCMS and 'H NMR.

^XH NMR (400 MHz, DMSO-d₆): 5 9.14 (s, 1H), 7.77 - 7.70 (m, 1H), 7.18 (s, 1H), 7.00 - 6.90 (m, 2H), 4.49 (s, 2H), 3.76 (s, 3H), 3.65 (s, 3H), 3.31 - 3.26 (m, 1H), 2.60 - 2.53 (m, 1H), 2.27 - 2.19 (m, 3H), 2.13 - 2.03 (m, 2H), 1.99 (s, 3H), 1.93 - 1.83 (m, 2H), 1.54 - 1.40 (m, 2H), 1.30 - 1.11 (m, 2H) ppm.

MS (ESI): m/z for C21H29N3O3 [M+H]+ calcd. 372.5, [M+H]+ found. 372.3

Example 8

N-(2,3-dimethylphenyl)-4-[(2,4-dimethylpyrazol-3-yl)methoxy]cyclohexanecarboxamide

To a solution of 4-[(2,4-dimethylpyrazol-3-yl)methoxy]cyclohexanecarboxylic acid (100 mg, 0.396 mmol, 1.0 eq) and 2,3-dimethylaniline (48 mg, 0.396 mmol, 1.0 eq) in 2 mL of anhydrous THF was added HATU (226 mg, 0.595 mmol, 1.5 eq) and DIPEA (102 mg, 0.793 mmol, 2.0 eq). The mixture was stirred at 25 °C for 12 h. To the mixture was added 20 mL of EA and 10 mL of water. The organic phase was washed with 20 mL of brine three times, dried over with Na2SC>4, filtered and concentrated under reduced pressure. The residue was purified by Prep- TLC (PE:EA=1 : 1) and Prep-HPLC (basic condition) to give N-(2,3-dimethylphenyl)-4-[(2,4- dimethylpyrazol-3-yl)methoxy]cyclohexanecarboxamide (11 mg, 99.6% purity, 8% yield) as a white solid. The structure was supported by LCMS and ^JH NMR.

¹ H NMR (400 MHz, DMSO-d₆): 5 9.25 (s, 1H), 7.18 (s, 1H), 7.10 - 6.97 (m, 3H), 4.50 (s, 2H), 3.76 (s, 3H), 3.31 - 3.26 (m, 1H), 2.41 - 2.31 (m, 1H), 2.24 (s, 3H), 2.14 - 2.06 (m, 2H), 2.04 (s, 3H), 1.99 (s, 3H), 1.95 - 1.85 (m, 2H), 1.57 - 1.40 (m, 2H), 1.30 - 1.11 (m, 2H) ppm.

MS (ESI): m/z for C21H29N3O2 [M+H]+ calcd. 356.5, [M+H]+ found. 356.3

Example 9

N-(l,3-dihydroisobenzofuran-4-yl)-4-[(2,4-dimethylpyrazol-3-yl)methoxy]cyclohexane carboxamide

To a solution of l,3-dihydroisobenzofuran-4-amine (54 mg, 0.396 mmol, 1.0 eq) and 4-[(2,4- dimethylpyrazol-3-yl)methoxy]cyclohexanecarboxylic acid (100 mg, 0.396 mmol, 1.0 eq) in 2 mL of anhydrous THF was added HATU (226 mg, 0.595 mmol, 1.5 eq) and DIEA (102 mg, 0.793 mmol, 2.0 eq). The mixture was stirred at 25 °C for 12 h. To the mixture was added 20 mL of EA and 10 mL of water. The organic phase was washed with 20 mL of brine three times, dried over with Na2SC>4, filtered and concentrated under reduced pressure. The residue was purified by Prep-TLC (PE:EA=1 : 1) and Prep-HPLC (basic condition) to give N-(l,3- dihydroisobenzofuran-4-yl)-4-[(2,4-dimethylpyrazol-3-yl)methoxy]cyclohexanecarboxamide (6.9 mg, 99.9% purity, 5% yield) as a white solid. The structure was supported by LCMS and 'H NMR.

'H NMR (400 MHz, DMSO-d₆): 5 9.52 (s, 1H), 7.39 (d, J = 8.0 Hz, 1H), 7.23 (t, J = 8.0 Hz, 1H), 7.18 (s, 1H), 7.06 (d, J= 7.2 Hz, 1H), 4.99 (s, 2H), 4.91 (s, 2H), 4.49 (s, 2H), 3.76 (s, 3H), 3.28 (br s, 1H), 2.41 - 2.27 (m, 1H), 2.15 - 2.03 (m, 2H), 1.99 (s, 3H), 1.94 - 1.81 (m, 2H), 1.54 - 1.39 (m, 2H), 1.27 - 1.13 (m, 2H) ppm.

MS (ESI): m/z for C21H27N3O3 [M+H]+ calcd. 370.5, [M+H]+ found. 370.3

Example 10

N-[2-(dimethylamino)phenyl]-4-[(2,4-dimethylpyrazol-3-yl)methoxy]cyclohexane carboxamide

To a solution of 4-[(2,4-dimethylpyrazol-3-yl)methoxy]cyclohexanecarboxylic acid (100 mg, 0.396 mmol, 1.0 eq) and N,N-dimethylbenzene-l,2-diamine (54 mg, 0.396 mmol, 1.0 eq) in 2 mL of anhydrous THF was added HATU (226 mg, 0.595 mmol, 1.5 eq) and DIPEA (102 mg, 0.793 mmol, 2.0 eq). The mixture was stirred at 25 °C for 12 h. To the mixture was added 20 mL of EA and 10 mL of water. The organic phase was washed with 20 mL of brine three times, dried over with Na2SC>4, filtered and concentrated under reduced pressure. The residue was purified by Prep-TLC (PE:EA=1 : 1) and Prep-HPLC (basic condition) to give N-[2- (dimethylamino)phenyl]-4-[(2,4-dimethylpyrazol-3-yl)methoxy]cyclohexanecarboxamide (13 mg, 99.5% purity, 9% yield) as a yellow solid. The structure was supported by LCMS and 'H NMR.

^XH NMR (400 MHz, DMSO-d₆): 5 = 8.93 (s, 1H), 7.88 (d, J= 6.8 Hz, 1H), 7.18 (s, 1H), 7.16 -7.12 (m, 1H), 7.08 - 6.96 (m, 2H), 4.49 (s, 2H), 3.76 (s, 3H), 3.32 - 3.21 (m, 1H), 2.61 (s, 6H), 2.50 - 2.43 (m, 1H), 2.16 - 2.04 (m, 2H), 1.99 (s, 3H), 1.95 - 1.85 (m, 2H), 1.54 - 1.39 (m, 2H), 1.29 - 1.15 (m, 2H) ppm. MS (ESI): m/z for C21H30N4O2 [M+H]+ calcd. 371.5, [M+H]+ found. 371.3

[2.2.2] analogs Intermediates

Step 1 : Methyl 4-hydroxybicyclo[2.2.2]octane-l-carboxylate

To a solution of 4-hydroxybicyclo[2.2.2]octane-l-carboxylic acid (100 mg, 0.59 mmol) in MeOH (5.9 mL) at 0 °C, was added thionyl chloride (0.21 mL, 2.94 mmol, 5.0 eq) dropwise. The resulting mixture was heated to reflux and stirred 2.5 h. Upon complete conversion, the reaction mixture was allowed to cool to RT and was poured in a sep funnel containing a 1 : 1 mixture of sat. aq. NaHCO3 solution and brine (40 mL) and EtOAc (40 mL). The layers were separated and the aqueous phase was extracted with EtOAc (3 x 40 mL). The combined organic extracts were dried over Na2SO4, filtered and concentrated to give methyl 4- hydroxybicyclo[2.2.2]octane-l-carboxylate (108.24 mg, 0.588 mmol, 100% yield) Crude material was used directly in the next step without further purification. ¹ H NMR (400 MHz, CDC13) 5 3.64 (s, 3H), 1.97 - 1.89 (m, 6H), 1.73 - 1.61 (m, 6H) ppm.

Step 2: methyl 4-[(3,5-dimethylisoxazol-4-yl)methoxy]bicyclo[2.2.2]octane-l-carboxylate

19%

In a vial were added methyl 4-hydroxybicyclo[2.2.2]octane-l-carboxylate (108 mg, 0.588 mmol, 1.0 eq), silver trifluoromethanesulfonate (906 mg, 3.53 mmol, 6.0 eq), 2,6-ditert- butylpyridine (674 mg, 3.53 mmol, 6.0 eq), and dichloromethane (2.94 mL). The mixture was cooled to 0°C, 4-(bromomethyl)-3,5-dimethyl-isoxazole (176 mg, 0.881 mmol, 1.50 eq) was added and the reaction was allowed to slowly reach room temperature and stirred under nitrogen atmosphere overnight. The mixture was filtered and concentrated, to give 1.34 g of crude product. The mixture was purified by a reversed phase flash chromatography on Cl 8 with a gradient of water (0.1% of formic acid) and acetonitrile (0.1% of formic acid). The collected product was concentrated under reduced pressure to give methyl 4-[(3,5- dimethylisoxazol-4-yl)methoxy]bicyclo[2.2.2]octane-l-carboxylate, (33 mg, 0.111 mmol, 19% yield). ^XH NMR (400 MHz, CDC13): 5 4.15 (s, 2H), 3.64 (s, 3H), 2.33 (s, 3H), 2.22 (s, 3H), 1.98 - 1.90 (m, 6H), 1.81 - 1.71 (m, 6H) ppm. MS (ESI): 294.45 [M+H]+.

Step 3: 4-[(3,5-dimethylisoxazol-4-yl)methoxy]bicyclo[2.2.2]octane-l-carboxylic acid

To a solution of methyl 4-[(3,5-dimethylisoxazol-4-yl)methoxy]bicyclo[2.2.2]octane-l- carboxylate (13 mg, 0.0340 mmol, 1.0 eq) in water (0.10 mL)/methanol (0.10 mL) was added lithium hydroxide (20 mg, 0.835 mmol, 24.6 eq). The mixture was stirred at room for 4 h. The mixture was concentrated under reduced pressure. To the semi-solid residue was added HC1 solution (IM) to adjust pH 1. The mixture was extracted with ethyl acetate and concentrated under reduced pressure to give 4-[(3,5-dimethylisoxazol-4-yl)methoxy]bicyclo[2.2.2]octane- 1-carboxylic acid ( 37 mg, 0.133 mmol, 100% yield) which was pure enough for the next step. 'H NMR (400 MHz, CDC13): 5 4.16 (s, 2H), 2.34 (s, 3H), 2.23 (s, 3H), 2.03 - 1.94 (m, 6H), 1.80 - 1.76 (m, 6H) ppm.

Example 11

4-[(3,5-dimethylisoxazol-4-yl)methoxy]-N-(2,3-dimethylphenyl)bicyclo[2.2.2]octane-l- carb oxami de

To a solution of 4-[(3,5-dimethylisoxazol-4-yl)methoxy]bicyclo[2.2.2]octane-l-carboxylic acid (44 mg, 0.158 mmol, 1.0 eq) in dimethylformamide (0.83 mL), 2,3-dimethylaniline (0.06 mL, 0.473 mmol, 3.0 eq), [dimethylamino(triazolo[4,5-b]pyridin-3-yloxy)methylene]- dimethyl-ammonium;hexafluorophosphate (69 mg, 0.173 mmol, 1.1 eq) and N,N- Diisopropylethylamine (0.08 mL, 0.473 mmol, 3.0 eq) were added. The mixture was stirred at room temperature overnight. The reaction medium was quenched with a saturated solution of sodium bicarbonate, extracted two times with ethyl acetate, and washed with a 5% solution of LiCl. Magnesium sulfate was added to the organic layer, which was filtered and concentrated under reduced pressure to give 310.4 mg of crude product. The compound was purified by flash chromatography on silica with a gradient of hexane and ethyl acetate. The collected product was dried under reduced pressure to give 4-[(3,5-dimethylisoxazol-4-yl)methoxy]-N-(2,3- dimethylphenyl)bicyclo[2.2.2]octane-l-carboxamide (54 mg, 0.142 mmol, 90% yield). ^JH NMR (400 MHz, CDC13): 5 7.47 (d, J = 7.9 Hz, 1H), 7.13 - 7.06 (m, 2H), 7.01 (d, J = 7.3 Hz, 1H), 4.19 (s, 2H), 2.36 (s, 3H), 2.30 (s, 3H), 2.25 (s, 3H), 2.12 (s, 3H), 2.08 (dd, J = 7.7, 3.4 Hz, 6H), 1.86 (dd, J = 10.3, 5.6 Hz, 6H) ppm. MS (ESI): 383.31 [M+H]+, 381.26 [M-H]-.

[1.1.1] analogs Intermediates

Step 1 : methyl 3 -hydroxybicyclo[l. l. l]pentane-l -carboxylate

To a solution of 3 -hydroxybicyclof 1.1.1 ]pentane-l -carboxylic acid (100 mg, 0.780 mmol, 1.0 eq) in methanol (3.99 mL) was added thionyl chloride (0.28 mL, 3.90 mmol, 5.0 eq) dropwise at 0 °C. The mixture was heated to reflux 4 h. The reaction medium was quenched with NaHCO3 and ice and extracted with ethyl acetate three times. Magnesium sulfate was added to the organic layer, which was filtered and concentrated under reduced pressure to give methyl 3 -hydroxybicyclo[l. l. l]pentane-l -carboxylate, (109 mg, 0.767 mmol, 98% yield) which was pure enough for the next step. 'H NMR (400 MHz, CDC13) 5 3.65 - 3.62 (m, 3H), 2.18 - 2.11 (m, 6H) ppm.

Step 2: Methyl 3-[(3,5-dimethylisoxazol-4-yl)methoxy]bicyclo[l. l. l]pentane-l-carboxylate

21%

In a vial were added methyl 3 -hydroxybicyclo[l. l. l]pentane-l -carboxylate (93 mg, 0.653 mmol, 1.0 eq), silver trifluoromethanesulfonate (1006 mg, 3.92 mmol, 6.0 eq), 2,6-ditert- butylpyridine (0.88 mL, 3.92 mmol, 6.0 eq), and dichloromethane (3.26 mL). The mixture was cooled to 0°C, 4-(iodomethyl)-3,5-dimethyl-isoxazole (464 mg, 1.96 mmol, 3.0 eq) was added and the reaction was allowed to slowly reach room temperature and stirred under nitrogen atmosphere overnight. The mixture was filtered and concentrated, to give 1.227 g of crude product, which was purified by a flash chromatography on silica with a gradient of hexane and ethyl acetate. Fractions were collected and concentrated to give methyl 3-[(3,5- dimethylisoxazol-4-yl)methoxy]bicyclo[l. l. l]pentane-l -carboxylate, (34 mg, 0.135 mmol, 21% yield). 'H NMR (400 MHz, CDC13): 5 4.27 (s, 2H), 3.69 (s, 3H), 2.36 (s, 3H), 2.25 (s, 3H), 2.21 (s, 6H) ppm. MS (ESI): 251.42 [M+H]+.

Step 3: 3-[(3,5-dimethylisoxazol-4-yl)methoxy]bicyclo[l. l. l]pentane-l-carboxylic acid To a solution of methyl 3-[(3,5-dimethylisoxazol-4-yl)methoxy]bicyclo[l. l. l]pentane-l- carboxylate (41 mg, 0.163 mmol, 1.0 eq) in water (0.48 mL)/methanol (0.48 mL) was added lithium hydroxide (96 mg, 4.01 mmol, 24.6 eq). The mixture was stirred at room for 4 h. The mixture was concentrated under reduced pressure. To the semi-solid residue was added HC1 solution (IM) to adjust pH 1. The mixture was extracted with ethyl acetate and concentrated under reduced pressure to give 3-[(3,5-dimethylisoxazol-4-yl)methoxy]bicyclo[l. l. l]pentane- 1-carboxylic acid, (39 mg, 0.163 mmol, 100% yield). 'H NMR (400 MHz, CDC13): 5 4.28 (s, 2H), 2.36 (s, 3H), 2.25 (s, 3H), 2.24 (s, 6H) ppm.

Example 12

3-[(3,5-dimethylisoxazol-4-yl)methoxy]-N-(2,3-dimethylphenyl)bicyclo[l. l. l]pentane-l- carboxamide

To a solution of 3-[(3,5-dimethylisoxazol-4-yl)methoxy]bicyclo[l. l. l]pentane-l-carboxylic acid (60 mg, 0.254 mmol, 1.0 eq) in dimethylformamide (1.34 mL), 2,3-dimethylaniline (0.09 mL, 0.761 mmol, 3.0 eq), [dimethylamino(triazolo[4,5-b]pyridin-3-yloxy)methylene]- dimethyl-ammonium;hexafluorophosphate (112 mg, 0.279 mmol, 1.1 eq) and N,N- Diisopropylethylamine (0.13 mL, 0.761 mmol, 3.0 eq) were added. The mixture was stirred at room temperature overnight. The reaction medium was quenched with a saturated solution of sodium bicarbonate, extracted two times with ethyl acetate, and washed with a 5% solution of LiCl. Magnesium sulfate was added to the organic layer, which was filtered and concentrated under reduced pressure to give 406 mg of crude product. The compound was purified by flash chromatography on silica with a gradient of hexane and ethyl acetate. The collected product was dried under reduced pressure to give 3-[(3,5-dimethylisoxazol-4-yl)methoxy]-N-(2,3- dimethylphenyl)bicyclo[l. l. l]pentane-l -carboxamide (36 mg, 0.106 mmol, 42% yield). ^JH NMR (400 MHz, CD3OD): 5 7.11 - 6.98 (m, 3H), 4.41 (s, 2H), 2.39 (s, 3H), 2.30 (s, 3H), 2.28 (s, 6H), 2.25 (s, 3H), 2.11 (s, 3H) ppm. ¹³C NMR (101 MHZ, CD3OD): 5 171.22 (C^IV), 168.65 (C^IV), 161.26 (C^IV), 138.82 (C^IV), 136.17 (C^IV), 134.22 (C^IV), 129.53 (CH), 126.69 (CH), 125.59 (CH), 112.55 (C^IV), 66.86 (C^IV), 58.71 (CEE), 53.95 (CH2), 33.86 (C^IV), 20.45 (CH3), 14.31 (CH3), 10.84 (CH3), 9.98 (CH3) ppm. MS (ESI): 341.51 [M+H]+, 339.05 [M-H]-.

[3.3.0] analogs Intermediates

Step 1 : Methyl 2-[(3,5-dimethylisoxazol-4-yl)methoxy]spiro[3.3]heptane-6-carboxylate 74%

In a vial were added methyl 2-hydroxyspiro[3.3]heptane-6-carboxylate (105 mg, 0.586 mmol, 1.0 eq), silver;trifluoromethanesulfonate (903 mg, 3.52 mmol, 6.0 eq), 2,6-ditert-butylpyridine (0.79 mL, 3.52 mmol, 6.0 eq), and dichloromethane (2.93 mL). The mixture was cooled to 0°C, 4-(iodomethyl)-3,5-dimethyl-isoxazole (208 mg, 0.879 mmol, 1.5 eq) was added and the reaction was allowed to slowly reach room temperature and stirred under nitrogen atmosphere overnight. The mixture was filtered and concentrated, to give 1.180 g of crude product. The mixture was purified by a flash chromatography on Cl 8 with a gradient of water (0.1% of acid formic) and acetonitrile (0.1% of acid formic). Product was collected, reduced under reduced pressure to give methyl 2-[(3,5-dimethylisoxazol-4-yl)methoxy]spiro[3.3]heptane-6- carboxylate, (122 mg, 0.436 mmol, 74% yield). 'H NMR (400 MHz, CDC13): 4.10 (s, 2H), 3.84 (p, J = 7.0 Hz, 1H), 3.64 (s, 3H), 3.01 (p, J = 8.4 Hz, 1H), 2.45 - 2.10 (m, 14H), 1.97 - 1.87 (m, 2H) ppm. MS (ESI): 281.52 [M+H]+.

Step 2: 2-[(3,5-dimethylisoxazol-4-yl)methoxy]spiro[3.3]heptane-6-carboxylic acid To a solution of methyl 2-[(3,5-dimethylisoxazol-4-yl)methoxy]spiro[3.3]heptane-6- carboxylate (83 mg, 0.296 mmol, 1.0 eq) in water (0.87 mL)/methanol (0.87 mL) was added lithium hydroxide (174 mg, 7.26 mmol, 24.6 eq). The mixture was stirred at room temperature for 4 h. The mixture was concentrated under reduced pressure. To the semi-solid residue was added HC1 solution (IM) to adjust pH 1. The mixture was extracted with ethyl acetate and concentrated under reduced pressure to give 2-[(3,5-dimethylisoxazol-4- yl)methoxy]spiro[3.3]heptane-6-carboxylic acid, (78 mg, 0.295 mmol, 100% yield). 'H NMR (400 MHz, CDC13): 5 4.10 (s, 2H), 3.84 (p, J = 7.1 Hz, 1H), 3.03 (p, J = 8.4 Hz, 1H), 2.45 - 2.12 (m, 12H), 1.97 - 1.87 (m, 2H) ppm.

Example 13

2-[(3,5-dimethylisoxazol-4-yl)methoxy]-N-(2,3-dimethylphenyl)spiro[3.3]heptane-6- carb oxami de (±)

To a solution of 2-[(3,5-dimethylisoxazol-4-yl)methoxy]spiro[3.3]heptane-6-carboxylic acid (78 mg, 0.296 mmol, 1.0 eq) in dimethylformamide (1.56 mL), 2,3-dimethylaniline (0.11 mL, 0.887 mmol, 3.0 eq), [dimethylamino(triazolo[4,5-b]pyridin-3-yloxy)methylene]-dimethyl- ammonium;hexafhrorophosphate (130 mg, 0.325 mmol, 1.1 eq) and N,N- Diisopropylethylamine (0.15 mL, 0.887 mmol, 3.0 eq) were added. The mixture was stirred at room temperature overnight. The reaction medium was quenched with a saturated solution of sodium bicarbonate, extracted two times with ethyl acetate, and washed with a 5% solution of LiCl. Magnesium sulfate was added to the organic layer, which was filtered and concentrated under reduced pressure. The compound was purified by flash chromatography on silica with a gradient of hexane and ethyl acetate. The collected product was dried under reduced pressure to give 2-[(3,5-dimethylisoxazol-4-yl)methoxy]-N-(2,3-dimethylphenyl)spiro[3.3]heptane-6- carboxamide (68 mg, 0.184 mmol, 62% yield). ‘H NMR (400 MHz, CD3OD): 5 7.04 (s, 3H), 4.21 (s, 2H), 3.94 (p, J = 7.0 Hz, 1H), 3.22 (p, J = 8.4 Hz, 1H), 2.80 (s, 2H), 2.52 - 2.46 (m, 1H), 2.41 - 2.15 (m, 14H), 2.09 (s, 3H), 2.02 - 1.97 (m, 1H), 1.92 - 1.87 (m, 1H) ppm. ¹³C NMR (101 MHZ, CD3OD): 5 176.20 (s, C^IV), 168.77 (s, C^IV), 161.28 (s, C^IV), 138.61 (s, C^IV), 136.61 (s, C^IV), 133.42 (s, C^IV), 128.96 (s, CH), 126.54 (s, CH), 125.21 (s, CH), 112.72 (s, C^IV), 69.87 (s, CH), 59.39 (s, CH2), 43.76 (s, CH2), 43.18 (s, CH2), 38.82 (s, CH2), 38.28 (s, CH2), 36.10 (s, CH), 33.22 (s, C^IV), 20.49 (s, CH3), 14.24 (s, CH3), 10.73 (s, CH3), 9.92 (s, CH3) ppm. MS (ESI): 369.22 [M+H]+, 367.17 [M-H]-.

Adamantyl analogs Intermediates

Step 1 : Methyl 4-[(3,5-dimethylisoxazol-4-yl)methoxy]adamantane-l -carboxylate

In a vial were added methyl 4-hy droxy adamantane- 1 -carboxylate (180 mg, 0.822 mmol, 1.0 eq), 2,6-ditert-butylpyridine (1.11 mL, 4.93 mmol, 6.0 eq), 4-(chloromethyl)-3,5-dimethyl- isoxazole (0.15 mL, 1.23 mmol, 1.5 eq), and di chloromethane (4.11 mL). The mixture was cooled to 0°C, silver;trifluoromethanesulfonate (1267 mg, 4.93 mmol, 6.0 eq) was added and the reaction was allowed to slowly reach room temperature and stirred under nitrogen atmosphere overnight. The mixture was filtered and concentrated to give 3.816 g of crude mixture. The mixture was purified by a flash chromatography on Cl 8 with a gradient of water (0.1% of acid formic) and acetonitrile (0.1% of acid formic). The collected product was reduced to give methyl 4-[(3,5-dimethylisoxazol-4-yl)methoxy]adamantane-l -carboxylate (202 mg, 0.633 mmol, 100% purity, 77% yield). Mixture of diastereoisomers. ^JH NMR (400 MHz, CDC13): 5 4.27 (s, 2H), 4.27 (s, 1.28H), 3.66 (s, 3H), 3.64 (s, 2H), 3.47 (t, J = 3.5 Hz, 1H), 3.41 (t, J = 3.2 Hz, 0.68H), 2.37 (s, 3H), 2.37 (s, 2H), 2.28 (s, 3H), 2.27 (s, 2H), 2.23 - 1.77 (m, 18H), 1.67 - 1.61 (m, 2.88H), 1.47 - 1.44 (m, 2H) ppm. MS (ESI): 320.25 [M+H]+.

Step 2: 4-[(3,5-dimethylisoxazol-4-yl)methoxy]adamantane-l -carboxylic acid

To a solution of methyl 4-[(3,5-dimethylisoxazol-4-yl)methoxy]adamantane-l-carboxylate (300 mg, 0.939 mmol, 1.0 eq) in water (2.76 mL)/methanol (2.76 mL) was added lithium hydroxide (552 mg, 23.1 mmol, 24.6 eq). The mixture was stirred at room overnight. After 18h, the peak corresponding to the methyl is still present on the NMR. The mixture was stirred 3 more days. The mixture was concentrated under reduced pressure. To the semi-solid residue was added HC1 solution (IM) to adjust pH 1. The mixture was extracted with ethyl acetate and concentrated under reduced pressure to give 4-[(3,5-dimethylisoxazol-4- yl)methoxy]adamantane-l-carboxylic acid, (322 mg, 1.05 mmol, 89.4% purity, 100% yield). Mixture of diastereoisomers. ^XH NMR (400 MHz, CDC13): 5 4.28 (s, 2H), 4.27 (s, 1.2H), 3.49 (t, J = 3.2 Hz, 1H), 3.42 (t, J = 3.3 Hz, 0.7H), 2.37 (s, 3H), 2.37 (s, 1.9H), 2.25 - 1.41 (m, 24H) ppm.

Example 14

4-[(3,5-dimethylisoxazol-4-yl)methoxy]-N-(2,3-dimethylphenyl)adamantane-l -carboxamide

To a solution of 4-[(3,5-dimethylisoxazol-4-yl)methoxy]adamantane-l -carboxylic acid (180 mg, 0.589 mmol, 1.0 eq) in dimethylformamide (3.12 mL),2,3-dimethylaniline (0.22 mL, 1.77 mmol, 3.0 eq), [dimethylamino(triazolo[4,5-b]pyridin-3-yloxy)methylene]-dimethyl- ammonium;hexafluorophosphate (260 mg, 0.648 mmol, 1.1 eq) and N,N- Diisopropylethylamine (0.31 mL, 1.77 mmol, 3.0 eq)were added. The mixture was stirred at room temperature overnight. The reaction medium was quenched with a saturated solution of sodium bicarbonate, extracted two times with ethyl acetate, and washed with a 5% solution of LiCl. Magnesium sulfate was added to the organic layer, which was concentrated under reduced pressure to give 1.232g of crude product. The compound was purified by flash chromatography on silica with a gradient of hexane and ethyl acetate. The collected product was dried under reduced pressure to give a diastereomeric mixture of 4-[(3,5-dimethylisoxazol- 4-yl)methoxy]-N-(2,3-dimethylphenyl)adamantane-l-carboxamide, (313 mg, 0.765 mmol, 72.1% purity, 94% yield). 'H NMR and MS are consistent with the proposed structure. Mixture of diasteroisomeres. 'H NMR (400 MHz, CDC13): 5 7.52 (s, 0.8H), 7.50 (s, 0.8H), 7.16 (s broad, 1.5H), 7.12 - 7.06 (m, 1.9H), 7.01 - 6.98 (m, 1.7H), 4.30 (s, 3.4H), 3.55 (s, 1H), 3.47 (s, 0.7H), 2.80 (s, 7.6H), 2.39 (s, 2.9H), 2.38 (s, 2.5H), 2.30 - 2.28 (m, 10.5H), 2.25 - 2.20 (m, 4.6H), 2.14 (s, 2.9H), 2.12 (s, 2.6H), 2.10 - 1.65 (m, 15.6H) ppm. MS (ESI): 409.56 [M+H]+. The diastereomers were separated by chiral SFC chromatography to provide the individual diasteromers.

Cyclobutyl analogs Intermediates

Step 1 : methyl 3-[(2,4-dimethylpyrazol-3-yl)methoxy]cyclobutanecarboxylate

1-25 1-27 1-28

To the solution of methyl 3 -hydroxy cyclobutanecarboxylate (800 mg, 6.15 mmol, 1.0 eq) in 10 mL of anhydrous DMF was added NaH (246 mg, 6.15 mmol, 1.0 eq) under N2 at 65 °C. The reaction mixture was stirred at 65 °C for 0.5 h. 5-(chloromethyl)-l,4-dimethyl-pyrazole (889 mg, 6.15 mmol, 1.0 eq) was added into the mixture and stirred at 65 °C for 1 h. The reaction mixture was quenched with 40 mL of saturated NH4CI solution, extracted with 20 mL of EA three times, washed with 15 mL of brine, dried over with Na2SC>4, filtered and concentrated under reduced pressure. The residue was purified column chromatography (PE : EA = 1 :0 to 3: 1) to give mixture of methyl (ls,3s)-methyl 3-((l,4-dimethyl-lH-pyrazol-5- yl)methoxy)cyclobutanecarboxylate and (lr,3r)-methyl 3-((l,4-dimethyl-lH-pyrazol-5- yl)methoxy)cyclobutanecarboxylate (1200 mg crude, 82% yield, Cis : Trans = 7 : 3) as colorless oil.

Step 2: 3-[(2,4-dimethylpyrazol-3-yl)methoxy]cyclobutanecarboxylic acid

To a solution of mixture of 1-27 and 1-28 (600 mg crude, 2.52 mmol, 1.0) eq in 5 mL of THF, 5 mL of MeOH and 5 mL of water was added LiOH»H2O (317 mg, 7.55 mmol, 3.0 eq). The reaction mixture was stirred at 25 °C for 1 h. The mixture was concentrated under reduced pressure to remove solvent and acidified with 1 N HC1 to pH 2~3. The solution was extracted with 20 mL of EA by twice, washed with 15 mL of brine, dried over with Na2SC>4, filtered and concentrated under reduced pressure to give mixture of (ls,3s)-3-((l,4-dimethyl-lH-pyrazol- 5-yl)methoxy)cyclobutanecarboxylic acid and (lr,3r)-3-((l,4-dimethyl-lH-pyrazol-5- yl)methoxy)cyclobutanecarboxylic acid (250 mg, 44% yield) as colorless oil.

Example 15

N-(2,3-dimethylphenyl)-3-[(2,4-dimethylpyrazol-3-yl)methoxy]cyclobutanecarboxamide and

N-(2,3-dimethylphenyl)-3-[(2,4-dimethylpyrazol-3-yl)methoxy]cyclobutanecarboxamide

To a solution of mixture of 1-29 and 1-30 (250 mg, 1.11 mmol, 1.0 eq) and 2,3-dimethylaniline (135 mg, 1.11 mmol, 1.0 eq) in 5 mL of anhydrous THF was added HATU (636 mg, 1.67 mmol, 1.5 eq) and DIPEA (288 mg, 2.23 mmol, 2.0 eq). The reaction mixture was stirred at 25 °C for 12 h. To the mixture was added 20 mL of EA and 10 mL of water. The organic phase was washed with 20 mL of brine three times, dried over with Na2SC>4, filtered and concentrated under reduced pressure. The residue was purified by Prep-TLC (PE : EA = 1 : 1) and Prep-HPLC (basic condition). The residue was separated by SFC to give N-(2,3-dimethylphenyl)-3-[(2,4- dimethylpyrazol-3-yl)methoxy]cyclobutanecarboxamide (44 mg, 99.9% purity, 12% yield) as a white solid and N-(2,3-dimethylphenyl)-3-[(2,4-dimethylpyrazol-3- yl)methoxy]cyclobutanecarboxamide (107 mg, 99.99% purity, 29% yield) as a white solid. The two structures were supported by HNMR and LCMS.

15 (trans)

'H NMR (400 MHz, DMSO-d₆): 5 9.29 (s, 1H), 7.18 (s, 1H), 7.13 - 7.07 (m, 1H), 7.07 - 6.97 (m, 2H), 4.38 (s, 2H), 4.23 - 4.12 (m, 1H), 3.77 (s, 3H), 3.22 - 3.11 (m, 1H), 2.43 - 2.31 (m, 2H), 2.24 (s, 3H), 2.19 - 2.09 (m, 2H), 2.03 (s, 3H), 1.99 (s, 3H) ppm.

MS (ESI): m/z for C19H25N3O2 [M+H]+ calcd. 328.4, [M+H]+ found. 328.2 15 (cis)

'H NMR (400 MHz, DMSO-d₆): 5 9.26 (s, 1H), 7.18 (s, 1H), 7.12 - 7.06 (m, 1H), 7.06 - 6.94 (m, 2H), 4.39 (s, 2H), 3.98 - 3.86 (m, 1H), 3.76 (s, 3H), 2.84 - 2.69 (m, 1H), 2.43 - 2.31 (m, 2H), 2.24 (s, 3H), 2.09 - 1.94 (m, 8H) ppm. MS (ESI): m/z for C19H25N3O2 [M+H]+ calcd. 328.4, [M+H]+ found. 328.2

Fluorophenyl analogs Intermediates

Step 1 : Methyl 3 -fluoro-4-hydroxy -benzoate

To a solution of 3 -fluoro-4-hydroxy -benzoic acid (1.50 g, 9.61 mmol, 1.0 eq,) in methanol (48.26 mL) was added thionyl chloride (3.5 mL, 48.0 mmol, 5.0 eq) dropwise at 0 °C. The reaction was heated to reflux for 4 hours. The reaction medium was quenched with NaHCO3 and ice and extracted with ethyl acetate twice. Magnesium sulfate was added to the organic layer, which was concentrated under reduced pressure to provide Methyl 3-fluoro-4-hydroxy- benzoate (1.06 g, 6.26 mmol, 65% yield) as a yellow gum. LCMS (ESI) m/z: Calcd [M-H]- for C8H6FO3 169.04; found 169.06; 'H-NMR (400 MHz, CDC13) 5 = 7.75 - 7.64 (m, 2H), 6.98 (t, J = 8.6 Hz, 1H), 3.88 (s, 3H) ppm. Step 2: methyl 4-[(3,5-dimethylisoxazol-4-yl)methoxy]-3-fluoro-benzoate

To solution of methyl 3 -fluoro-4-hydroxy -benzoate (1.66 g, 9.76 mmol, 1.0 eq) and dipotassium carbonate (2.05 g, 14.6 mmol, 1.5 eq) in dimethylformamide (30 mL), 4- (chloromethyl)-3,5-dimethyl-isoxazole (1.45 mL, 11.7 mmol, 1.2 eq) was added. The mixture was stirred at 70°C for 16 hr. The mixture was diluted with water and extracted with ethyl acetate, combined organics were washed with brine, dried over magnesium sulfate, and concentrated to afford methyl 4-[(3,5-dimethylisoxazol-4-yl)methoxy]-3-fluoro-benzoate (2.72 g, 9.74 mmol, quant.), which was used without further manipulation. LCMS (ESI) m/z: Calcd [M+H]+ for C14H15FNO4 280.1; found 280.1; 'H-NMR (400 MHz, CDC13) 5 = 7.82 (dt, J = 8.5, 1.5 Hz, 1H), 7.76 (dd, J = 11.6, 2.0 Hz, 1H), 7.04 (t, J = 8.2 Hz, 1H), 4.93 (s, 2H), 3.90 (s, 3H), 2.41 (s, 3H), 2.31 (s, 3H) ppm.

Step 3: 4-[(3,5-dimethylisoxazol-4-yl)methoxy]-3-fluoro-benzoic acid

To a solution of methyl 4-[(3,5-dimethylisoxazol-4-yl)methoxy]-3-fluoro-benzoate (2.73 g, 9.77 mmol, 1.0 eq) in tetrahydrofuran (24 mL) and methanol (24 mL), a solution of 10% sodium hydroxide (2.5 M in , 20 mL, 50.0 mmol, 5.1 eq) was added. The reaction was stirred for 4 hours. The reaction medium was acidified with a HC1 solution (IM) to adjust pH to 5, a white solid was formed upon addition. The mixture was extracted with ethyl acetate two times. The organic layer was dried with magnesium sulfate and concentrated under reduced pressure to give 1.51 g of crude product. The product was purified with a silica gel chromatography with a gradient of hexane and ethyl acetate. The collected product was dried under reduced pressure to give 4-[(3,5-dimethylisoxazol-4-yl)methoxy]-3-fluoro-benzoic acid, (1.13 g, 3.32 mmol, 78% purity, 34% yield). LRMS (ESI) m/z: Calcd [M+H]+ for C13H12FNO4 266.1; found 266.18; 'H-NMR (400 MHz, CD3OD) 5 = 7.84 (ddd, J = 8.6, 2.1, 1.2 Hz, 1H), 7.72 (dd, J = 11.8, 2.0 Hz, 1H), 7.29 (t, J = 8.4 Hz, 1H), 5.06 (s, 2H), 2.43 (s, 3H), 2.29 (s, 3H) ppm.

Example 16 4-[(3,5-dimethylisoxazol-4-yl)methoxy]-N-(2,3-dimethylphenyl)-3-fluoro-benzamide

To a solution of 4-[(3,5-dimethylisoxazol-4-yl)methoxy]-3-fluoro-benzoic acid (14, 300 mg, 1.13 mmol, 1.0 eq) in DMF (5.7mL), was added 2,3 -dimethylaniline (0.42 mL, 3.39 mmol, 3.0 eq), HATU (473 mg, 1.24 mmol, 1.1 eq) and N,N-Diisopropylethylamine (0.6 mL, 3.39 mmol, 3.0 eq), and stirred at rt for 72 hr. The mixture was diluted with saturated aqueous solution of sodium bicarbonate and extracted with ethyl acetate. Combined organics were dried over magnesium sulfate and concentrated to afford a residue which was purified by a silica gel chromatography eluting with a gradient of hexanes and ethyl acetate to afford 4-[(3,5- dimethylisoxazol-4-yl)methoxy]-N-(2,3-dimethylphenyl)-3-fluoro-benzamide (140 mg, 0.379 mmol, 34% yield) as an off white solid. Calcd [M-H]- for C21H20FN2O3 367.15; found 367.26; 'H-NMR (400 MHz, CDC13) 5 = 7.73 - 7.63 (m, 2H), 7.57 - 7.56 (m, 2H), 7.18 (t, J = 7.8 Hz, 1H), 7.15 - 7.07 (m, 2H), 4.98 (s, 2H), 2.45 (s, 3H), 2.36 (s, 3H), 2.35 (s, 3H), 2.24 (s, 3H); ‘H NMR (400 MHz, DMSO) 5 9.86 (s, 1H), 7.92 - 7.77 (m, 2H), 7.43 (t, J = 8.6 Hz, 1H), 7.09 (d, J = 2.1 Hz, 3H), 5.12 (s, 2H), 2.43 (s, 3H), 2.28 (s, 3H), 2.24 (s, 3H), 2.08 (s, 3H) ppm;¹⁹F NMR (376 MHz, DMSO) 5 -134.24 ppm. ¹³C NMR (101 MHz, DMSO) 5 167.87, 163.64, 159.53, 151.37 (d, J = 244.7 Hz), 148.43 (d, J = 10.6 Hz), 136.98, 136.10, 132.76, 127.71 (d, J = 5.5 Hz), 127.58, 125.22, 124.73, 124.61 (d, J = 3.7 Hz), 115.40 (d, J = 10.6 Hz), 115.30 (d, J = 7.5 Hz), 109.84, 60.40, 20.10, 14.20, 10.62, 9.61 ppm.

Benzyl analog intermediates

Step 1 : N-(2,3-dimethylphenyl)-4-hydroxybenzamide , ,

To a solution of 4-hydroxybenzoic acid (1 g, 7.24 mmol, 1.0 eq) and 2,3-dimethylaniline (877 mg, 7.24 mmol, 884 pL, 1.0 eq) in Pyridine (50 mL) was added HATU (4.13 g, 10.86 mmol, 1.5 eq) and the mixture stirred at 50 °C for 16 hr. The mixture was diluted with ethyl acetate and washed with hydrochloric acid (2N in water), saturated aqueous sodium bicarbonate, water and brine, dried over sodium sulfate and concentrated. The residue was purified by column chromatography (SiO2, PE/A=10/l to 3/1) to give 1.8 g of mixture of N-(2,3-dimethylphenyl)- 4-hydroxybenzamide and 4-((2,3-dimethylphenyl)carbamoyl)phenyl 4-hydroxybenzoate as a brown solid. This mixture was dissolved in THF (12 mL), MeOH (6 mL) and H2O (3 mL), treated with NaOH (106 mg, 2.66 mmol, 4.0 eq), and stirred at 50 °C for 2 hr. The reaction mixture was concentrated and diluted with water (3 mL), acidified with hydrochloric acid (2N in water) to pH = 4. The resulting solid was isolated by filtration and dried under in vacuum to afford N-(2,3-dimethylphenyl)-4-hydroxybenzamide as a faintly brown solid (1 g). Calcd [M+H]+ for C15H15NO2 241.1; found 242.0; *H NMR (400 MHz, DMSO-d6) 5 = 10.06 (bs, 1H), 9.65 (s, 1H), 7.86 (d, J = 8.8 Hz, 2H), 7.14 - 7.01 (m, 3H), 6.85 (d, J = 8.8 Hz, 2H), 2.27 (s, 3H), 2.08 (s, 3H) ppm.

Example 17

N-(2,3-dimethylphenyl)-4-((2-fluorobenzyl)oxy)benzamide

To a solution of N-(2,3-dimethylphenyl)-4-hydroxybenzamide (100 mg, 414 umol, 1.0 eq) and l-(chloromethyl)-2 -fluoro-benzene (66 mg, 456 umol, 54 uL, 1.1 eq) in anhydrous DMF (6 mL) was added K2CO3 (115 mg, 829 pmol, 2.0 eq). The mixture was stirred at 80 °C for 8 h. The reaction mixture was poured into water (40 mL) and extracted with ethyl acetate three times. The combined organic phase was washed with brine and concentrated in vacuum. The crude product was triturated with MTBE:Ethyl Acetate (20 mL:4 mL) at 25 °C for 15 min to afford compound 17 (114.9 mg, 78% yield, 98.8% purity) as a white solid. Calcd [M+H]+ for C22H20FNO2 350.15; found 350.16; *H NMR (400 MHz, DMSO) 5 9.79 (s, 1H), 7.97 (d, J = 8.4 Hz, 2H), 7.63 - 7.54 (m, 1H), 7.49 - 7.39 (m, 1H), 7.26 (q, J = 8.0 Hz, 2H), 7.15 (d, J = 8.6 Hz, 2H), 7.09 (tt, J = 6.5, 3.9 Hz, 3H), 5.24 (s, 2H), 2.27 (s, 3H), 2.08 (s, 3H) ppm; ¹⁹F NMR (376 MHz, DMSO) 5 -118.21 ppm; ¹³C NMR (101 MHz, DMSO) 5 164.77, 160.67, 160.45 (d, J = 246.1 Hz), 136.92, 136.44, 132.75, 130.79 (d, J = 3.9 Hz), 130.58 (d, J = 8.3 Hz), 129.54, 127.42, 127.12, 125.20, 124.77, 124.60 (d, J = 3.5 Hz), 123.49 (d, J = 14.6 Hz), 115.46 (d, J = 20.9 Hz), 114.37, 63.78 (d, J = 3.7 Hz), 20.15, 14.25 ppm.

Difluorophenyl analog intermediates

Step 1 : 2, 6-difluoro-4-hydroxy -benzoic acid

1-37 1-38

A mixture of sodium hydroxide (2.71 g, 67.7 mmol, 3.5 eq) and 2,6-difluoro-4-hydroxy- benzonitrile (3.00 g, 19.3 mmol, 1.0 eq) in water (23 ml) was stirred at 100 C for 90 hours. After cooling to RT the mixture was acidified with HC1 (12M in water) to pH 1, the mixture was then extracted with ethyl acetate, dried over magnesium sulfate, and concentrated under reduced pressure to afford 2,6-difluoro-4-hydroxy-benzoic acid (2.47 g, 12.3 mmol, 87% purity, 64% yield). Calcd [M-H]’ for C₇H₃F₂O3 173.01; found 172.93; 'H-NMR (400 MHz, DMSO-de) 5 =13.19 (s, 1H), 10.94 (s, 1H), 6.54 - 6.45 (m, 2H) ppm.

Step 2: methyl 2,6-difluoro-4-hydroxy-benzoate

1-39

To a solution of 2, 6-difluoro-4-hydroxy -benzoic acid (10.82 g, 62.1 mmol, 1.0 eq) in methanol (100 mL) was added thionyl chloride (22.67 mL, 311 mmol, 5.0 eq) dropwise at 0 °C, the mixture was then heated to reflux for 4 hr. The mixture was cooled to RT, diluted with ice and aqueous sodium bicarbonate, extracted with ethyl acetate, combined organic phases were dried over magnesium sulfate and concentrated to afford methyl 2,6-difluoro-4-hydroxy-benzoate (10.94 g, 58.2 mmol, 94% yield) which was used without further manipulation. Calcd [M-H]’ for C₈H₅F₂O₃ 187.03; found 187.35; 'H NMR (400 MHz, CDC1₃) 5 6.47 - 6.41 (m, 2H), 3.91 (s, 3H) ppm.

Step 3: 5-(chloromethyl)-l,4-dimethyl-pyrazole

To a mixture of thionyl chloride (9.44 mL, 130 mmol, 2.0 eq) in dichloromethane (80 mL) was added (2,4-dimethylpyrazol-3-yl)methanol (8.21 g, 65.1 mmol, 1.0 eq,) and the mixture was stirred at RT for 4 h. The reaction mixture was concentrated under reduced pressure to afford 5-(chloromethyl)-l,4-dimethyl-pyrazole (9.40 g, 65.0 mmol, 100% yield). Calcd [M+H]⁺ for C₆HIOC1IN₂ 145.05; found 144.98. Step 4: methyl 4-[(2,4-dimethylpyrazol-3-yl)methoxy]-2,6-difluoro-benzoate

A mixture of methyl 2, 6-difluoro-4-hydroxy -benzoate (10.94 g, 58.2 mmol, 1.0 eq), dipotassium carbonate (18.00 g, 128 mmol, 2.2 eq), and 5-(chloromethyl)-l,4-dimethyl- pyrazole (14.07 g, 97.3 mmol, 1.7 eq) in dimethylformamide (90 mL), was stirred at 70°C for 16h. Additional 5-(chloromethyl)-l,4-dimethyl-pyrazole (14.07 g, 97.3 mmol, 1.7 eq) and dipotassium carbonate (18.00 g, 128 mmol, 2.2 eq) were added and the mixture was stirred at 70°C for 3 hours, further 5-(chloromethyl)-l,4-dimethyl-pyrazole (14.07 g, 97.3 mmol, 1.7 eq) was added and stirred at 70°C for 4 hours. The mixture was cooled to RT, diluted with brine, and extracted with ethyl acetate, combined organics were washed with sodium hydroxide (IM in water), dried over magnesium sulfate, and concentrated to afford methyl 4-[(2,4- dimethylpyrazol-3-yl)methoxy]-2,6-difluoro-benzoate (16.9 g, 57.0 mmol, 98% yield), which was used without further manipulation. Calcd [M+H]⁺ for C14H15F2N2O3 297.1; found 298.1.

Step 5: 4-[(2,4-dimethylpyrazol-3-yl)methoxy]-2,6-difluoro-benzoic acid

A mixture of methyl 4-[(2,4-dimethylpyrazol-3-yl)methoxy]-2,6-difluoro-benzoate (19.68 g,

66.4 mmol, 1.0 eq), methanol (250 mL), water (150 mL), and lithium hydroxide (7.95 g, 332 mmol, 5.0 eq) was stirred for 15 hr. The mixture was then acidified with hydrochloric acid (IM in water) to adjust pH to 1, the resulting solid was collected by filtration and the filtrate was extracted with ethyl acetate, the combined organic phases were dried over sodium sulfate, and concentrated to provide a residue. This residue was combined with the isolated solid as methyl 4-[(2,4-dimethylpyrazol-3-yl)methoxy]-2,6-difluoro-benzoic acid (14.39 g, 51.0 mmol, 77% yield) which was used without further manipulation. Calcd [M+H]⁺ for C13H13F2N2O3 283.08; found 283.44.

Example 18

N-(2,3-dimethylphenyl)-4-[(2,4-dimethylpyrazol-3-yl)methoxy]-2,6-difluoro-benzamide

A mixture of 4-[(2,4-dimethylpyrazol-3-yl)methoxy]-2,6-difluoro-benzoic acid (2.50 g, 8.86 mmol, 1.0 eq) 2,3-dimethylaniline (3.25 mL, 26.6 mmol, 3.0 eq), HATU (3.70 g, 9.74 mmol, 1.1 eq) and N,N-Diisopropylethylamine (4.64 mL, 26.6 mmol, 3.0 eq) in dimethylformamide (20 mL) was stirred at room temperature for 72 hr. The mixture was diluted with water and saturated aqueous sodium bicarbonate, extracted with ethyl acetate, combined organic layers were washed with LiCl (5% in water), and concentrated to afford a residue which was purified by silica gel eluting with a gradient of ethyl acetate in hexanes, the material was further purified by reverse phase chromatography on Cl 8 media eluting with a gradient of acetonitrile in water (containing 0.1% formic acid) to afford N-(2,3-dimethylphenyl)-4-[(2,4-dimethylpyrazol-3- yl)methoxy]-2,6-difluoro-benzamide (1.57 g, 4.08 mmol, 46% yield). Calcd [M-H]' for C21H22F2N3O2 384.2; found 384.0; 'H-NMR (400 MHz, CDCI3) 5 = 7.65 (d, J = 7.9 Hz, 1H), 7.44 (s, 1H), 7.32 (s, 1H), 7.16 (t, J = 7.7 Hz, 1H), 7.07 (d, J = 7.5 Hz, 1H), 6.62 (d, J = 9.9 Hz, 2H), 5.00 (s, 2H), 3.88 (s, 3H), 2.33 (s, 3H), 2.23 (s, 3H), 2.12 (s, 3H) ppm; ¹⁹F{^JH} NMR (376MHz, CDCI3): 5 -109.40 (d, J = 10.5 Hz) ppm. Chlorophenyl analog intermediates

Step 1 : 2-Chloro-N-(2,3-dimethyl-phenyl)-4-hydroxy-benzamide

I-44 I-45

To a stirred solution of 2-chloro-4-hydroxy-benzoic acid (1-44) (200 mg, 1.038 mmol, 1.0 eq) and 2,3-Dimethyl-phenylamine (0.128 mL, 1.038 mmol, 1.0 eq) in pyridine (3 mL), HATU (591 mg, 1.558 mmol, 1.5 eq) was added and the reaction was stirred at 50°C for 16 hours. The reaction mixture was diluted with EtOAc and washed with 2N HC1, saturated sodium bicarbonate, water and brine, dried over sodium sulfate and concentrated. The crude LCMS showed mass peak of desired product along with the ester. The crude was then dissolved in THF:MeOH: Water (4:2: 1; 10 mL) and treated with 2N NaOH (3 mL) at 60°C for 4 hours (monitored by LCMS). The reaction mixture was again evaporated to dryness, the residue was taken in 2N HC1, extracted with ethyl acetate and evaporated to afford the compound 1-45 (250 mg, 87%) as yellow gum.

Example 19

2-Chloro-4-(3,5-dimethyl-isoxazol-4-ylmethoxy)-N-(2,3-dimethyl-phenyl)-benzamide

1-45

To a stirred solution of 2-chloro-N-(2,3-dimethyl-phenyl)-4-hydroxy-benzamide (1-45) (200 mg, 0.727 mmol, 1.0 eq) in DMF (2 mL), K2CO3 (200 mg, 1.455 mmol, 2.0 eq) and 4- chloromethyl-3,5-dimethyl-isoxazole (0.101 mL, 0.800 mmol, 1.1 eq) were added and the reaction was stirred at RT for 16 hours. The reaction mixture was diluted with ethyl acetate and washed with water and brine, dried over sodium sulfate and concentrated. The crude was purified by column chromatography (silica, gradient: 20-30% EtOAc in hexanes) to afford the compound 19 (80 mg, 28%) as yellow solid. Calcd [M+H]⁺ for C21H22CIN2O3 385.1; found 385.1; 'H-NMR (400 MHz, DMSO-d6) 5 = 9.84 (1H, S), 7.56 (1H, br d, 8.1 Hz), 7.23 (1H, br s), 7.15-7.21 (1H, br m), 7.04-7.13 (3H, br m), 5.04 (2H, s), 2.15 (3H, s), 2.23 (3H, s), 2.27 (3H, s), 2.43 (3H, s) ppm.

Fluorophenyl isomer intermediate synthesis

Step 1 : methyl 4-[(3,5-dimethylisoxazol-4-yl)methoxy]-2 -fluoro-benzoate

To solution of methyl 2-fhioro-4-hydroxy-benzoate (1.86 g, 10.9 mmol, 1.0 eq) and dipotassium carbonate (2.30 g, 16.4 mmol, 1.5 eq) in dimethylformamide (25 mL), 4- (chloromethyl)-3,5-dimethyl-isoxazole (1.63 mL, 13.1 mmol, 1.20 eq) was added. The mixture was stirred at 70°C under nitrogen atmosphere overnight. The reaction medium was cooled down to room temperature, extracted twice with ethyl acetate, washed with brine five times. The organic layer was dried under magnesium sulfate and concentrated under reduced pressure to afford methyl 4-[(3,5-dimethylisoxazol-4-yl)methoxy]-2 -fluoro-benzoate, (3.05 g) which was used without further manipulation. Calcd [M+H]⁺ for C14H15FNO4 280.18; found 280.18; 'H NMR (400 MHz, CDCI3) 6 7.93 (t, J= 8.6 Hz, 1H), 6.76 (dd, J= 8.8, 2.4 Hz, 1H), 6.69 (dd, J= 12.4, 2.5 Hz, 1H), 2.82 (s, 2H), 3.91 (s, 3H), 2.42 (s, 3H), 2.29 (s, 3H) ppm.

Step 2: 4-[(3,5-dimethylisoxazol-4-yl)methoxy]-2-fluoro-benzoic acid

To a solution of methyl 4-[(3,5-dimethylisoxazol-4-yl)methoxy]-2 -fluoro-benzoate (3.05 g, 10.9 mmol, 1.0 eq) in tetrahydrofuran (24 mL) and methanol (24 mL), a solution of 10% sodium hydroxide (2.5 M in water, 22 mL, 55.0 mmol, 5.04 eq) was added. The reaction was stirred for 4 hours. The reaction medium was acidified with a HC1 solution (IM) to adjust pH to 5, a white solid was formed upon addition. The mixture was extracted with ethyl acetate twice. The organic layer was dried with magnesium sulfate and concentrated under reduced pressure to give 4-[(3,5-dimethylisoxazol-4-yl)methoxy]-2-fluoro-benzoic acid, (3.06 g, 8.42 mmol, 73% purity, 77% yield) which was used without further manipulation. Calcd [M-H]' for C₁₃H_nFNO₄264.1; found 264.1; 'H NMR (400MHz, CD3OD): 5 7.90 (t, J= 8.8 Hz, 1H), 6.91 - 6.80 (m, 2H), 4.97 (s, 2H), 2.43 (s, 3H), 2.27 (s, 3H) ppm.

Example 20

4-[(3,5-dimethylisoxazol-4-yl)methoxy]-N-(2,3-dimethylphenyl)-2 -fluoro-benzamide

To a solution of 4-[(3,5-dimethylisoxazol-4-yl)methoxy]-2-fluoro-benzoic acid (300 mg, 1.13 mmol, 1.0 eq) in dimethylformamide (5.66 mL), 2,3 -dimethylaniline (0.42 mL, 3.39 mmol, 3.0 eq), [dimethylamino(triazolo[4,5-b]pyridin-3-yloxy)methylene]-dimethyl- ammonium;hexafluorophosphate (473 mg, 1.24 mmol, 1.1 eq) and N,N- Diisopropylethylamine (0.59 mL, 3.39 mmol, 3.0 eq) were added. The reaction was stirred at room temperature over the weekend. The reaction medium was quenched with a saturated solution of sodium bicarbonate and then extracted two times with ethyl acetate. Magnesium sulfate was added to the organic layer, which was concentrated under reduced pressure to give 1.19 g of crude product. The compound was purified by a silica gel chromatography with a gradient of ethyl acetate in hexanes. The collected product was dried under reduced pressure to give 4-[(3,5-dimethylisoxazol-4-yl)methoxy]-N-(2,3-dimethylphenyl)-2 -fluoro-benzamide, (212 mg, 0.575 mmol, 51% yield). Calcd [M-H]’ for C₂₁H₂₀FN₂O₃ 367.2; found 367.3; 'H NMR (400MHz, CDCI3): 6 8.27 (d, J= 16.2 Hz, 1H), 8.20 (t, J= 9.1 Hz, 1H), 7.76 (d, J= 8.0 Hz, 1H), 7.16 (t, J= 7.8 Hz, 1H), 7.05 (d, J= 7.5 Hz, 1H), 6.90 (dd, J= 8.9, 2.5 Hz, 1H), 6.74 (dd, J= 14.0, 2.4 Hz, 1H), 4.86 (s, 2H), 2.44 (s, 3H), 2.34 (s, 3H), 2.31 (s, 3H), 2.24 (s, 3H) ppm.

2, 3 -difluorophenyl intermediate synthesis

Step 1 : methyl 2,3-difluoro-4-hydroxy-benzoate

1-49 1-50

To a solution of 2,3-difluoro-4-hydroxy-benzoic acid (1.50 g, 8.62 mmol, 1.0 eq) in methanol (44 mL) was added thionyl chloride (3.14 mL, 43.1 mmol, 5.0 eq) dropwise at 0 °C. The reaction was heated to reflux 4 hours. The reaction medium was quenched with NaHCCL and ice and extracted with ethyl acetate two times. Magnesium sulfate was added to the organic layer, which was concentrated under reduced pressure methyl 2,3-difluoro-4-hydroxy- benzoate, (1.62 g, 8.61 mmol, 100% yield) which was used without further manipulation. Calcd [M-H]’ for C₈H₅F₂O3 187.0; found 187.1; 'H NMR (400 MHz, CDC1₃) 8 7.65 (ddd, J = 9.0, 7.5, 2.3 Hz, 1H), 6.81 (ddd, J = 9.2, 7.4, 1.9 Hz, 1H), 3.91 (s, 3H) ppm.

Step 2: methyl 4-[(3,5-dimethylisoxazol-4-yl)methoxy]-2,3-difluoro-benzoate

To a solution of methyl 2, 3-difhioro-4-hydroxy -benzoate (1.65 g, 8.77 mmol, 1.0 eq) and dipotassium carbonate (1.84 g, 13.2 mmol, 1.5 eq) in dimethylformamide (20.028 mL), 4-(chloromethyl)-3,5-dimethyl-isoxazole (1.31 mL, 10.5 mmol, 1.2 eq) was added. The mixture was stirred at 70°C under nitrogen atmosphere overnight. The reaction medium was cooled down to room temperature, extracted twice with ethyl acetate, washed with brine five times. The organic layer was dried under magnesium sulfate and concentrated under reduced pressure to afford methyl 4-[(3,5-dimethylisoxazol-4-yl)methoxy]-2,3-difluoro-benzoate, (2.22 g, 7.47 mmol, 85% yield), used without further manipulation. Calcd [M+H]⁺ for C14H14F2NO4 298.1; found 298.2; 'H NMR (400 MHz, CDC13) 5 7.72 (ddd, J= 8.9, 7.4, 2.4 Hz, 1H), 6.84 (ddd, J= 8.9, 6.9, 1.9 Hz, 1H), 4. 94 (s, 2H), 3.93 (s, 3H), 2.42 (s, 3H), 2.31 (s, 3H) ppm.

Step 3: 4-[(3,5-dimethylisoxazol-4-yl)methoxy]-2,3-difluoro-benzoic acid

To a solution of methyl 4-[(3,5-dimethylisoxazol-4-yl)methoxy]-2,3-difluoro-benzoate (2.22 g, 7.47 mmol, 1.0 eq) in tetrahydrofuran (16 mL) and methanol (16 mL), a solution of 10% sodium hydroxide (2.5 M I water, 14.94 mL, 37.3 mmol, 5.0 eq) was added. The reaction was stirred for 4 hours. The reaction medium was acidified with a HC1 solution (IM) to adjust pH to 5, a white solid was formed upon addition. The mixture was extracted with ethyl acetate twice. The organic layer was dried with magnesium sulfate and concentrated under reduced pressure to give 4-[(3,5-dimethylisoxazol-4-yl)methoxy]-2,3-difluoro-benzoic acid, (1.42 g, 5.01 mmol, 67% yield) which was used without further manipulation. Calcd [M+H]⁺ for C₁₃H_nF₂NO₄ 282.07; found 282.14; 'H NMR (400MHz, CD3OD): 5 7.71 (ddd, J= 9.8, 7.9, 2.3 Hz, 1H), 7.09 (ddd, J= 9.0, 7.1, 1.9 Hz, 1H), 5.08 (s, 2H), 2.43 (s, 3H), 2.29 (s, 3H). ppm

Example 21

4-[(3,5-dimethylisoxazol-4-yl)methoxy]-N-(2,3-dimethylphenyl)-2,3-difluoro-benzamide

To a solution of 4-[(3,5-dimethylisoxazol-4-yl)methoxy]-2,3-difluoro-benzoic acid (300 mg, 1.06 mmol, 1.0 eq) in dimethylformamide (5 mL), 2,3-dimethylaniline (.39 mL, 3.18 mmol, 3.0 eq), [dimethylamino(triazolo[4,5-b]pyridin-3-yloxy)methylene]-dimethyl- ammonium;hexafluorophosphate (443 mg, 1.17 mmol, 1.1 eq) and N,N- Diisopropylethylamine (.55 mL, 3.18 mmol, 3.0 eq) were added. The reaction was stirred at room temperature over the weekend. The reaction medium was quenched with a saturated solution of sodium bicarbonate, extracted two times with ethyl acetate, and washed with a 5% solution of LiCl. Magnesium sulfate was added to the organic layer, which was concentrated under reduced pressure to give 1.151 g of crude product. The compound was purified by a silica gel chromatography with a gradient of ethyl acetate in hexanes. The collected product was dried under reduced pressure to give 4-[(3,5-dimethylisoxazol-4-yl)methoxy]-N-(2,3- dimethylphenyl)-2,3-difluoro-benzamide, (130 mg, 0.337 mmol, 32% yield). Calcd [M+H]⁺ for 02^^2^03387.14; found 387.43; 'H NMR (400MHz, CDC1₃): 8 8.16 (d, J= 14.5 Hz, 1H), 7.97 (t, J= 9.0 Hz, 1H), 7.73 (d, J= 8.0 Hz, 1H), 7.16 (t, J= 7.8 Hz, 1H), 7.06 (d, J= 7.6 Hz, 1H), 6.97 (ddd, J= 9.0, 6.9, 1.7 Hz, 1H), 4.97 (s, 2H), 2.44 (s, 3H), 2.34 (s, 3H), 2.33 (s, 3H), 2.24 (s, 3H) ppm. ¹⁹F NMR (376 MHz, CDC1₃) 8 -137.16 (ddd, J= 22.2, 14.4, 8.2 Hz), - 157.35 (dd, J= 21.6, 7.3Hz) ppm.

3,5 difluorophenyl intermediate synthesis

Step 1 : methyl 4-[(3,5-dimethylisoxazol-4-yl)methoxy]-2,6-difluoro-benzoate

To solution of methyl 2,6-difluoro-4-hydroxy-benzoate (0.98 g, 5.21 mmol, 1.0 eq) and dipotassium carbonate (1.10 g, 7.81 mmol, 1.5 eq) in dimethylformamide (11.895 mL), 4-(chloromethyl)-3,5-dimethyl-isoxazole (0.78 mL, 6.25 mmol, 1.2 eq) was added. The mixture was stirred at 70°C under nitrogen atmosphere overnight. The reaction medium was cooled down to room temperature, extracted twice with ethyl acetate, washed with brine five times. The organic layer was dried under magnesium sulfate and concentrated under reduced pressure to afford methyl 4-[(3,5-dimethylisoxazol-4-yl)methoxy]-2,6-difluoro-benzoate, (1.55 g, 5.20 mmol, 100% yield), was used without further manipulation. Calcd [M+H]⁺ for C₁₄H₁₄F₂NO₄ 298.08; found 298.15; 'H NMR (400 MHz, CDCI3) 6 6.56 - 6.49 (m, 2H), 4.79 (s, 2H), 3.92 (s, 3H), 2.42 (s, 3H), 2.28 (s, 3H) ppm.

Step 2: 4-[(3,5-dimethylisoxazol-4-yl)methoxy]-2,6-difluoro-benzoic acid To a solution of methyl 4-[(3,5-dimethylisoxazol-4-yl)methoxy]-2,6-difluoro-benzoate (1.97 g, 6.63 mmol, 1.0 eq) in tetrahydrofuran (14 mL) and methanol (14 mL), a solution of 10% sodium hydroxide (2.5 M in water, 13.25 mL, 33.1 mmol, 5.0 eq) was added. The reaction was stirred for 4 hours. The reaction medium was acidified with a HC1 solution (IM) to adjust pH to 5, a white solid was formed upon addition. The mixture was extracted with ethyl acetate twice. The organic layer was dried with magnesium sulfate and concentrated under reduced pressure to give 4-[(3,5-dimethylisoxazol-4-yl)methoxy]-2,6-difluoro-benzoic acid, (1.49 g, 5.26 mmol, 79% yield) used without further manipulation. Calcd [M+H]⁺ for C₁₃H₁₂F₂NO₄ 284.07; found 284.15; 'H NMR (400MHz, CD₃OD): 5 6.77 - 6.70 (m, 2H), 4.96 (s, 2H), 2.43 (s, 3H), 2.27 (s, 3H) ppm.

Example 22

4-[(3,5-dimethylisoxazol-4-yl)methoxy]-N-(2,3-dimethylphenyl)-2,6-difluoro-benzamide

To a solution of 4-[(3,5-dimethylisoxazol-4-yl)methoxy]-2,6-difluoro-benzoic acid (300 mg, 1.06 mmol, 1.0 eq) in dimethylformamide (5.296 mL), 2,3-dimethylaniline (0.39 mL, 3.18 mmol, 3.0 eq), [dimethylamino(triazolo[4,5-b]pyridin-3-yloxy)methylene]-dimethyl- ammonium hexafluorophosphate (443 mg, 1.17 mmol, L I eq) and N,N-diisopropylethylamine (0.55 mL, 3.18 mmol, 3.0 eq) were added. The reaction was stirred at room temperature over the weekend. The reaction medium was quenched with a saturated solution of sodium bicarbonate, extracted two times with ethyl acetate, and washed with a 5% solution of LiCl. Magnesium sulfate was added to the organic layer, which was concentrated under reduced pressure to give 0.732 g of crude product. The compound was purified by a silica gel chromatography with a gradient of ethyl acetate in hexanes. The collected product was dried under reduced pressure to give 4-[(3,5-dimethylisoxazol-4-yl)methoxy]-N-(2,3- dimethylphenyl)-2,6-difluoro-benzamide, (112 mg, 0.290 mmol, 27% yield). Calcd [M+H]⁺ for C₂₁H₂₁F₂N₂O₃ 387.14; found 387.48; 'H NMR (400MHz, CDC1₃): 8 7.65 (d, J= 8.0 Hz, 1H), 7.44 (s, 1H), 7.16 (t, J= 7.8 Hz, 1H), 7.07 (d, J= 7.6 Hz, 1H), 6.59 (d, J= 10.2 Hz, 2H), 4.81 (s, 2H), 2.44 (s, 3H), 2.33 (s, 3H), 2.30 (s, 3H), 2.23 (s, 3H); ¹⁹F NMR (376 MHz, CDC13): 5 -109.46 (d, J= 10.8 Hz) ppm.

Example 23

N-[2-(dimethylamino)phenyl]-4-[(3,5-dimethylisoxazol-4-yl)methoxy]-2,6-difluoro- benzamide

To a solution of 4-[(3,5-dimethylisoxazol-4-yl)methoxy]-2,6-difluoro-benzoic acid (300 mg, 1.06 mmol, 1.0 eq) in dimethylformamide (4 mL), N2,N2-dimethylbenzene-l,2-diamine (433 mg, 3.18 mmol, 3.0 eq), [dimethylamino(triazolo[4,5-b]pyridin-3-yloxy)methylene]-dimethyl- ammonium hexafluorophosphate (443 mg, 1.17 mmol, 1.1 eq) andN,N-Diisopropylethylamine (0.55 mL, 3.18 mmol, 3.00 eq) were added. The reaction was stirred at room temperature one day. The reaction medium was quenched with a saturated solution of sodium bicarbonate, extracted two times with ethyl acetate, and washed with a 5% solution of LiCl. Magnesium sulfate was added to the organic layer, which was concentrated under reduced pressure to give 1.46 g of crude product. The compound was purified by a silica gel chromatography with a gradient of ethyl acetate in hexanes. The collected product was dried under reduced pressure to give N-[2-(dimethylamino)phenyl]-4-[(3,5-dimethylisoxazol-4-yl)methoxy]-2,6-difluoro- benzamide, (282 mg, 0.702 mmol, 66% yield). Calcd [M-H]' for C₂₁H₂₀F₂N₃O₃ 400.16; found 400.16; ^XH NMR (400MHz, CDCI3): 6 9.08 (s, 1H), 8.52 (d, J= 8.0 Hz, 1H), 7.25 - 7.05 (m, 3H), 6.58 (d, J= 9.7 Hz, 2H), 4.81 (s, 2H), 2.66 (s, 6H), 2.44 (s, 3H), 2.30 (s, 3H) ppm.

Example 24

N-[2-(dimethylamino)phenyl]-4-[(3,5-dimethylisoxazol-4-yl)methoxy]-3-fluoro-benzamide

To a solution of 4-[(3,5-dimethylisoxazol-4-yl)methoxy]-3-fluoro-benzoic acid (210 mg, 0.792 mmol, 1.0 eq) in dimethylformamide (3.5 mL), N2,N2-dimethylbenzene-l,2-diamine (323 mg, 2.38 mmol, 3.0 eq), [dimethylamino(triazolo[4,5-b]pyridin-3-yloxy)methylene]-dimethyl- ammonium hexafluorophosphate (331 mg, 0.871 mmol, 1.1 eq) and N,N- Diisopropylethylamine (.41 mL, 2.38 mmol, 3.0 eq) were added. The reaction was stirred at room temperature one day. The reaction medium was quenched with a saturated solution of sodium bicarbonate, extracted two times with ethyl acetate, and washed with a 5% solution of LiCl. Magnesium sulfate was added to the organic layer, which was concentrated under reduced pressure to give 0.91g of crude product. The compound was purified by a silica gel chromatography with a gradient of ethyl acetate in hexanes. The collected product was dried under reduced pressure to give N-[2-(dimethylamino)phenyl]-4-[(3,5-dimethylisoxazol-4- yl)methoxy]-3-fluoro-benzamide, (200 mg, 0.523 mmol, 66% yield). Calcd [M-H]’ for C21H23FN3O3 384.16; found 384.62; 'H NMR (400MHz, CDC13): 5 9.31 (s, 1H), 8.48 (d, J= 8.1 Hz, 1H), 7.67 (s, 2H), 7.25 - 7.04 (m, 4H), 4.95 (s, 2H), 2.71 (s, 6H), 2.43 (s, 3H), 2.33 (s, 3H) ppm; ¹⁹F NMR (376MHz, CDC13): 5 -131.61 ppm.

Example 25

N-(l,3-dihydroisobenzofuran-4-yl)-4-[(3,5-dimethylisoxazol-4-yl)methoxy]-3-fluoro- benzamide To a solution of 4-[(3,5-dimethylisoxazol-4-yl)methoxy]-3-fluoro-benzoic acid (160 mg, 0.603 mmol, 1.0 eq) in dimethylformamide (2.4 mL), l,3-dihydroisobenzofuran-4-amine (245 mg, 1.81 mmol, 3.0 eq), [dimethylamino(triazolo[4,5-b]pyridin-3-yloxy)methylene]-dimethyl- ammonium hexafluorophosphate (252 mg, 0.664 mmol, 1.1 eq) and N,N- diisopropylethylamine (.32 mL, 1.81 mmol, 3.0 eq) were added. The reaction was stirred at room temperature one day. The reaction medium was quenched with a saturated solution of sodium bicarbonate, extracted two times with ethyl acetate, and washed with a 5% solution of LiCl. Magnesium sulfate was added to the organic layer, which was concentrated under reduced pressure. The compound was purified by a silica gel chromatography with a gradient of ethyl acetate in hexanes. The collected product was dried under reduced pressure to give N- (l,3-dihydroisobenzofuran-4-yl)-4-[(3,5-dimethylisoxazol-4-yl)methoxy]-3-fluoro- benzamide(197 mg, 0.514 mmol, 85% yield). Calcd [M+H]⁺ for C₂₁H₂₀FN₂O₄ 383.13; found 383.22; 'H NMR (400MHz, CDC1₃): 8 7.68 - 7.59 (m, 2H), 7.51 (d, J= 8.0 Hz, 1H), 7.45 (s, 1H), 7.32 (t, J= 7.7 Hz, 1H), 7.12 - 7.08 (m, 2H), 5.15 (d, J= 14.8 Hz, 4H), 4.96 (s, 2H), 2.43 (s, 3H), 2.32 (s, 4H) ppm; ¹⁹F NMR (376MHz, CDCI3): 6 -131.15 ppm.

Synthesis of mono-fluorophenyl pyrazole intermediates

Step 1 : methyl 4-[(2,4-dimethylpyrazol-3-yl)methoxy]-3-fluoro-benzoate

To solution of methyl 3 -fluoro-4-hydroxy -benzoate (538 mg, 3.16 mmol, 1.0 eq) and dipotassium carbonate (13.75 g, 98.0 mmol, 31.0 eq) in dimethylformamide (17.933 mL), 5-(chloromethyl)-l,4-dimethyl-pyrazole hydrochloride (693 mg, 3.64 mmol, 1.15 eq) was added. The mixture was stirred at 70°C under nitrogen atmosphere overnight. The reaction medium was cooled down to room temperature, extracted two times with ethyl acetate, washed with brine five times. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure to afford methyl 4-[(2,4-dimethylpyrazol-3-yl)methoxy]-3-fluoro- benzoate, (876 mg, 3.15 mmol, 100% yield). Calcd [M-H]' for C₁₄H₁₄FN₂O₃ 277.1; found 277.0; 'H NMR (400 MHz, CDC1₃) 8 7.84 - 7.74 (m, 2H), 7.28 (s, 1H), 7.06 (t, J= 8.2 Hz, 1H), 5.11 (s, 2H), 3.91 (s, 3H), 3.90 (s, 3H), 2.08 (s, 3H) ppm.

Step 2: 4-[(2,4-dimethylpyrazol-3-yl)methoxy]-3-fluoro-benzoic acid

To a solution of methyl 4-[(2,4-dimethylpyrazol-3-yl)methoxy]-3-fluoro-benzoate (928 mg, 3.33 mmol, 1.0 eq) in tetrahydrofuran (10 mL) and methanol (10 mL), a solution of 10% sodium hydroxide (2.5 M in water, 15 mL, 37.5 mmol, 11.2 eq) was added. The reaction was stirred for 4.5 hours. The reaction medium was acidified with a HC1 solution (IM) to adjust pH to 5, a white solid was formed upon addition. The mixture was extracted with ethyl acetate twice. The organic layer was dried with magnesium sulfate and concentrated under reduced pressure to give 4-[(2,4-dimethylpyrazol-3-yl)methoxy]-3-fluoro-benzoic acid, (780 mg, 2.95 mmol, 89% yield). Calcd [M-H]’ for C₁₃H₁₂FN₂O₃ 263.1; found 263.1; 'H NMR (400MHz, CD3OD): 5 7.85 (ddd, J= 8.6, 2.1, 1.2 Hz, 1H), 7.72 (dd, J= 11.7, 2.0 Hz, 1H), 7.33 (t, .7= 8,4 Hz, 1H), 7.28 (s, 1H), 5.25 (s, 2H), 3.88 (s, 3H), 2.09 (s, 3H) ppm.

Example 26

N-[2-(dimethylamino)phenyl]-4-[(2,4-dimethylpyrazol-3-yl)methoxy]-3-fluoro-benzamide To a solution of 4-[(2,4-dimethylpyrazol-3-yl)methoxy]-3-fluoro-benzoic acid (100 mg, 0.378 mmol, 1.0 eq) in dimethylformamide (2 mL), N2,N2-dimethylbenzene-l,2-diamine (155 mg, 1.14 mmol, 3.0 eq), [dimethylamino(triazolo[4,5-b]pyridin-3-yloxy)methylene]-dimethyl- ammonium hexafluorophosphate (167 mg, 0.416 mmol, 1.1 eq) and N,N- Diisopropylethylamine (.2 mL, 1.14 mmol, 3.00 eq) were added. The reaction was stirred at room temperature over the weekend. The reaction medium was quenched with a saturated solution of sodium bicarbonate, extracted two times with ethyl acetate, and washed with a 5% solution of LiCl. Magnesium sulfate was added to the organic layer, which was concentrated under reduced pressure to give 501.3 mg of crude product. The compound was purified by a silica gel chromatography with a gradient of ethyl acetate in hexanes. The collected product was dried under reduced pressure to give N-[2-(dimethylamino)phenyl]-4-[(2,4- dimethylpyrazol-3-yl)methoxy]-3-fluoro-benzamide (133 mg, 0.348 mmol, 92% yield). Calcd [M+H]⁺ for C₂₁H₂₄FN₄O₂ 383.18; found 383.27; 'H NMR (400MHz, CDC13): 5 9.31 (s, 1H), 8.47 (s, 1H), 7.71 - 7.68 (m, 2H), 7.30 (s, 1H), 7.24 - 7.06 (m, 4H), 5.13 (s, 2H), 3.93 (s, 3H), 2.71 (s, 6H), 2.09 (s, 3H) ppm; ¹⁹F NMR (376 MHz, CDC1₃): 8 -131.44 ppm.

Example 27

N-(l,3-dihydroisobenzofuran-4-yl)-4-[(2,4-dimethylpyrazol-3-yl)methoxy]-3-fluoro- benzamide

To a solution of l,3-dihydroisobenzofuran-4-amine (26 mg, 0.189 mmol, 1.0 eq) and 4-[(2,4- dimethylpyrazol-3-yl)methoxy]-3-fluoro-benzoic acid (50 mg, 0.189 mmol, 1.0 eq) in 3 mL of anhydrous THF was added HATU (108 mg, 0.284 mmol, 1.5 eq) and DIPEA (37 mg, 0.284 mmol, 1.5 eq). The mixture was stirred at 25 °C for 12 h. To the mixture was added 10 mL of EA and 5 mL of water. The organic phase was washed with 5 mL of brine, dried over with Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by prep- HPLC (basic condition) to give N-(l,3-dihydroisobenzofuran-4-yl)-4-[(2,4-dimethylpyrazol- 3-yl)methoxy]-3-fluoro-benzamide (39 mg, 99.99% purity, 54% yield) as a white solid. Calcd [M+H]+ for C₂₁H₂₁FN₃O₃ 382.4; found. 382.1; 'H NMR (400 MHz, CHLOROFORM-d): 5 7.70 - 7.61 (m, 2H), 7.56 - 7.47 (m, 2H), 7.38 - 7.30 (m, 2H), 7.19 - 7.10 (m, 2H), 5.28 - 5.03 (m, 6H), 3.95 (s, 3H), 2.12 (s, 3H) ppm.

Example 28

N-(2,3-dimethylphenyl)-4-[(2,4-dimethylpyrazol-3-yl)methoxy]-3-fluoro-benzamide

To a solution of 4-[(2,4-dimethylpyrazol-3-yl)methoxy]-3-fluoro-benzoic acid (100 mg, 0.378 mmol, 1.0 eq) in dimethylformamide (2 mL), 2,3-dimethylaniline (.14 mL, 1.14 mmol, 3.0 eq), [dimethylamino(triazolo[4,5-b]pyridin-3-yloxy)methylene]-dimethyl-ammonium hexafluorophosphate (167 mg, 0.416 mmol, 1.1 eq) and N,N-diisopropylethylamine (0.2 mL, 1.14 mmol, 3.0 eq) were added. The reaction was stirred at room temperature over the weekend. The reaction medium was quenched with a saturated solution of sodium bicarbonate, extracted two times with ethyl acetate, and washed with a 5% solution of LiCl. Magnesium sulfate was added to the organic layer, which was concentrated under reduced pressure to give 355 mg of crude product. The compound was purified by a silica gel chromatography with a gradient of ethyl acetate hexanes. The collected product was dried under reduced pressure to give N-(2,3-dimethylphenyl)-4-[(2,4-dimethylpyrazol-3-yl)methoxy]-3 -fluoro-benzamide, (104 mg, 0.283 mmol, 75% yield). Calcd [M+H]+ for C₂₁H₂₃FN₃O₂368.17; found. 368.24; 'H NMR (400MHz, CDC13): 5 7.71 - 7.61 (m, 2H), 7.55 - 7.53 (m, 2H), 7.30 (s, 1H), 7.18 - 7.04 (m, 3H), 5.14 (s, 2H), 3.93 (s, 3H), 2.33 (s, 3H), 2.21 (s, 3H), 2.09 (s, 3H) ppm; ¹⁹F NMR (376MHz, CDC13): 5 -131.18 ppm.

Example 29 4-[(2,4-dimethylpyrazol-3-yl)methoxy]-3-fluoro-N-(2-methoxy-3-methyl-phenyl)benzamide

To a solution of 4-[(2,4-dimethylpyrazol-3-yl)methoxy]-3-fluoro-benzoic acid (100 mg, 0.378 mmol, 1.0 eq) in dimethylformamide (2 mL), 2-methoxy-3 -methyl -aniline (0.14 mL, 1.14 mmol, 3.0 eq), [dimethylamino(triazolo[4,5-b]pyridin-3-yloxy)methylene]-dimethyl- ammonium hexafluorophosphate (167 mg, 0.416 mmol, 1.1 eq) and N,N- Diisopropylethylamine (.2 mL, 1.14 mmol, 3.0 eq) were added. The reaction was stirred at room temperature over the weekend. The reaction medium was quenched with a saturated solution of sodium bicarbonate, extracted two times with ethyl acetate, and washed with a 5% solution of LiCl. Magnesium sulfate was added to the organic layer, which was concentrated under reduced pressure to give 665.5 mg of crude product. The compound was purified by a silica gel chromatography with a gradient of ethyl acetate in hexanes. The collected product was dried under reduced pressure to give 4-[(2,4-dimethylpyrazol-3-yl)methoxy]-3-fluoro-N- (2-methoxy-3-methyl-phenyl)benzamide, (134 mg, 0.350 mmol, 92% yield). Calcd [M+H]+ for C₂₁H₂₃FN₃O₃ 384.16; found 384.82; 'H NMR (400MHz, CDC1₃): 8 8.43 (s, 1H), 8.28 (dd, J= 8.1, 1.5 Hz, 1H), 7.73 - 7.59 (m, 2H), 7.30 (s, 1H), 7.13 (t, J= 8.2 Hz, 1H), 7.07 (t, J = 7.9 Hz, 1H), 6.98 - 6.91 (m, 1H), 5.13 (s, 2H), 3.93 (s, 3H), 3.81 (s, 3H), 2.34 (s, 3H), 2.09 (s, 3H) ppm. ¹⁹F NMR (376MHz, CDCI3): 6 -131.16 ppm.

Example 30

N-(l,3-dihydroisobenzofuran-4-yl)-4-[(2,4-dimethylpyrazol-3-yl)methoxy]-2,6-difluoro- benzamide

To a solution of l,3-dihydroisobenzofuran-4-amine (38 mg, 0.283 mmol, 1.0 eq) and 4-[(2,4- dimethylpyrazol-3-yl)methoxy]-2,6-difluoro-benzoic acid (80 mg, 0.283 mmol, 1.0 eq) in 2 mL of anhydrous THF was added HATU (162 mg, 0.425 mmol, 1.5 eq) and DIEA (73 mg, 0.567 mmol, 2.0 eq). The mixture was stirred at 25 °C for 12 hrs. To the mixture was added 10 mL EA and 5 mL water. The organic phase was washed with 20 mL of brine, dried over with Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by Prep- TLC (PE:EA=1 : 1) and further purification by prep-HPLC (basic condition) to give N-(l,3- dihydroisobenzofuran-4-yl)-4-[(2,4-dimethylpyrazol-3-yl)methoxy]-2,6-difluoro-benzamide (30 mg, 98.4% purity, 26% yield) as a white solid. Calcd [M+H]⁺ for C21H20F2N3O3 400.1; found 400.1; *H NMR (400 MHz, DMSO -d₆) 8: 10.38 (s, 1H), 7.55 - 7.44 (m, 1H), 7.31 (t, J = 7.6 Hz, 1H), 7.26 (s, 1H), 7.16 (d, J= 7.6 Hz, 1H), 7.01 (d, J= 9.6 Hz, 2H),5.21 (s, 2H), 5.03 (s, 3H), 4.95 (s, 3H), 3.79 (s, 3H), 2.04 (s, 3H) ppm.

Example 31

4-[(2,4-dimethylpyrazol-3-yl)methoxy]-2,6-difluoro-N-(2-methoxy-3 -methyl- pheny l)b enzami de

To a solution of 2-methoxy-3 -methyl -aniline (39 mg, 0.283 mmol, 1.0 eq) and 4-[(2,4- dimethylpyrazol-3-yl)methoxy]-2,6-difluoro-benzoic acid (80 mg, 0.283 mmol, 1.0 eq) in 2 mL of anhydrous THF was added HATU (162 mg, 0.425 mmol, 1.5 eq) and DIEA (73 mg, 0.567 mmol, 2.0 eq). The mixture was stirred at 25 °C for 12 hrs. To the mixture was added 10 mL EA and 5 mL water. The organic phase was washed with 20 mL of brine, dried over with Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by prep- TLC (PE:EA=1 : 1) and then further purification by prep-HPLC (basic condition) to give 4- [(2,4-dimethylpyrazol-3-yl)methoxy]-2,6-difluoro-N-(2-methoxy-3-methyl- phenyl)benzamide (18 mg, 96.77% purity, 15% yield) as a white solid. Calcd [M+H]⁺ for ^C21^H22^F2^N3°3 ⁴⁰²-²; ^{found 402}-²; ‘H NMR (400 MHz, DMSO-de) 8: 10.02 (s, 1H), 7.81-7.76 (m, 1H), 7.27 (s, 1H), 7.05 (d, J= 5.2 Hz, 2H), 6.98 (d, J= 9.6 Hz, 2H), 5.22 (s, 2H), 3.80 (s, 3H), 3.68(s, 3H), 2.26 (s, 3H), 2.05 (s, 3H) ppm.

Synthesis of N1 ,N1 ,6-trimethylbenzene- 1 ,2-diamine

Step 1 : N,N,2-trimethyl-6-nitroaniline

1-58

To a solution of 2-fluoro-l-methyl-3-nitro-benzene (1000 mg, 6.45 mmol, 1.0 eq) in 10 mL of anhydrous DMSO was added K2CO3 (1379 mg, 9.98 mmol, 2.0 eq) and N-methylmethanamine (563 mg, 4.99 mmol, 1.0 eq). The mixture was stirred at 90 °C for 2 hrs. To the mixture was added 40 mL of EA and 20 mL of water. The organic phase was washed with 100 mL of brine, dried over with Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (PE:EA=L0 to 10: 1, SiCL) to give N,N,2-trimethyl-6- nitro-aniline (1000 mg, 86% yield) as a red oil. ¹ H NMR (400 MHz, CDCI3 -d) 6 = 7.45 (d, J = 4.0 Hz, 1H), 7.38 - 7.32 (m, 1H), 7.03 (t, J= 8.0 Hz 1H), 2.77 (s, 6H), 2.36 (s, 3H) ppm.

Step 2: Nl,Nl,6-trimethylbenzene-l,2-diamine The solution of N,N-2-trimethyl-6-nitro-aniline (200 mg, 1.11 mmol, 1.0 eq) in 3 mL of anhydrous MeOH was added Pd/C (235 mg, 0.111 mmol, 0.1 eq). The reaction mixture was purged with EE for three times and stirred with EE (15 psi) three times. The mixture was stirred at 25 °C for 12 hrs. The reaction mixture was filtered and concentrated under reduced pressure to give N,N-3 -trimethylbenzene- 1,2-diamine (130 mg, crude) as a red oil and used for next step directly.

Example 32

4-((l,4-dimethyl-lH-pyrazol-5-yl)methoxy)-N-(2-(dimethylamino)-3-methylphenyl)-2,6- difluorob enzami de

To a solution of N,N-3 -trimethylbenzene- 1,2-diamine (43 mg, 0.283 mmol, 1.0 eq) and 4-[(2,4- dimethylpyrazol-3-yl)methoxy]-2,6-difluoro-benzoic acid (80 mg, 0.283 mmol, 1.0 eq) in 2 mL of anhydrous THF was added HATU (162 mg, 0.425 mmol, 1.5 eq) and DIEA (73 mg, 0.567 mmol, 2.0 eq). The mixture was stirred at 25 °C for 12 hrs. The mixture was added 10 mL of EA and 5 mL of water. The organic phase was washed with 10 mL of brine, dried over with Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by prep-TLC (PE:EA=1 : 1) and further purification by prep-HPLC (basic condition) to give N-[2- (dimethylamino)-3-methyl-phenyl]-4-[(2,4-dimethylpyrazol-3-yl)methoxy]-2,6-difluoro- benzamide (54 mg, 99.67% purity, 46% yield) as a white solid. Calcd [M+H]⁺ for ^C22^H25^F2^N4°2 415.2; ^found 415.3; ^JH NMR (400 MHz, DMSO-d₆) 8: 9.86 (s, 1H), 7.98 (d, J = 8.0 Hz, 1H), 7.26 (s, 1H), 7.07 (t, J= 8.0 Hz, 1H), 7.01 (d, J= 10.0 Hz, 2H), 6.93(d, J= 7.2 Hz, 1H), 5.21 (s, 2H), 3.80 (s, 3H), 2.73 (s, 6H), 2.31 (s, 3H), 2.04 (s, 3H) ppm. Synthesis of isopropyl pyrazole intermediates

Step 1 : ethyl l-isopropyl-lH-pyrazole-5-carboxylate

To a solution of propan-2-ol (3216 mg, 53.5 mmol, 1.5 eq), PPhs (18716 mg, 71.4 mmol, 2.0 eq) and ethyl lH-pyrazole-5-carboxylate (5000 mg, 35.7 mmol, 1.0 eq) in 50 mL of anhydrous THF was added DIAD (10822 mg, 53.5 mmol, 1.5 eq) slowly. The reaction mixture was stirred at 25 °C for 1 hr. To the mixture was added 30 mL of water and 40 mL of EA. The organic phase was washed with 30 mL of brine, dried over with ISfeSCU, filtered and concentrated under pressured to give a residue. The residue was purified by column chromatography (PE:EA=L0 to 10 : 1) to give ethyl l-isopropyl-lH-pyrazole-5-carboxylate (4000 mg, 62% yield) as a yellow oil. 'H NMR (400 MHz, DMSO-d₆) 8: 7.61 - 7.50 (m, 1H), 6.87 - 6.75 (m, 1H), 5.53 - 5.29 (m, 1H), 4.29 (q, = 7.2 Hz, 2H), 1.39 (d, J= 6.8 Hz, 6H), 1.29 (d, = 7.2 Hz, 3H) ppm.

Step 2: ethyl 4-chloro-l-isopropyl-lH-pyrazole-5-carboxylate

To a solution of ethyl 2-isopropylpyrazole-3-carboxylate (500 mg, 2.74 mmol, 1.0 eq) in 4 mL of anhydrous DMF was added NCS (366 mg, 2.74 mmol, 1.0 eq). The reaction mixture was stirred at 60 °C for 12 hrs. Then another batch of NCS (366 mg, 2.74 mmol, 1.0 eq) was added into the mixture and stirred at 60 °C for 6 hrs. The mixture was purified by reversed-phase to give ethyl 4-chl oro-2 -isopropyl -pyrazole-3 -carboxylate (350 mg, 59% yield) as a yellow solid. ‘HNMR (400 MHz, DMSO-d₆) 6: 7.75 (s, 1H), 5.35 - 5.22 (m, 1H), 4.35 (q, J= 7.2 Hz, 2H),

1.39 (d, J= 6.8 Hz, 6H), 1.32 (d, J= 7.2 Hz, 3H) ppm.

Step 3: (4-chloro-l-isopropyl-lH-pyrazol-5-yl)methanol

1-62 1-63

To a solution of ethyl 4-chloro-2-isopropyl-pyrazole-3-carboxylate (350 mg, 1.62 mmol, 1.0 eq) in 5 mL of anhydrous THF was added LAH (61 mg, 1.62 mmol, 1.0 eq). The mixture was stirred at 25 °C for 12 hrs. The mixture was quenched with 0.05 mL of water, 0.05 mL of 10%

NaOH solution and 0.15 mL of water. The mixture was stirred at 25 °C for 0.5 h and filtered.

The organic layer was dried over with Na2SO4, concentrated under reduced pressure to give (4-chloro-2-isopropyl-pyrazol-3-yl)methanol (300 mg, crude) as a yellow solid. Calcd [M+H]⁺ for C7H12CIN2O calcd. 175.1, [M+H]+ found. 175.1.

Step 4: 4-chloro-5-(chloromethyl)-l-isopropyl-lH-pyrazole

To a solution of (4-chloro-2-isopropyl-pyrazol-3-yl)methanol (300 mg, 1.72 mmol, 1.0 eq) in 2 mL of anhydrous DCM was added SOCI2 (307 mg, 2.58 mmol, 1.5 eq). The reaction mixture was stirred at 25 °C for 1 hr. The reaction mixture was concentrated under reduced pressure to give 4-chloro-5-(chloromethyl)-l-isopropyl-pyrazole (310 mg, crude) as a yellow solid. Calcd [M+H]⁺ for C7H11CI2N2 193.02; found 193.1.

Step 5: methyl 4-((4-chloro-l-isopropyl-lH-pyrazol-5-yl)methoxy)-2,6-difluorobenzoate To a solution of methyl 2, 6-difluoro-4-hydroxy -benzoate (200 mg, 1.06 mmol, 1.0 eq) and 4- chloro-5-(chloromethyl)-l-isopropyl-pyrazole (308 mg, 1.59 mmol, 1.5 eq) in 5 mL of anhydrous DMF was added K2CO3 (294 mg, 2.13 mmol, 2.0 eq). The reaction mixture was stirred at 25 °C for 12 hrs. To the mixture was added 30 mL of H2O and 30 mL of EA. The organic phase was washed with 30 mL of brine, dried over with ISfeSCU, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (PE: EA=l :0 to 5: 1) to give methyl 4-[(4-chloro-2-isopropyl-pyrazol-3-yl)methoxy]-2,6- difluoro-benzoate (250 mg, 68% yield) as a yellow solid. Calcd [M+H]⁺ for C15H16CIF2N2O3 345.1; found. 345.1.

Step 6: 4-((4-chloro-l-isopropyl-lH-pyrazol-5-yl)methoxy)-2,6-difluorobenzoic acid

To a solution of methyl 4-[(4-chloro-2-isopropyl-pyrazol-3-yl)methoxy]-2,6-difluoro-benzoate (250 mg, 0.725 mmol, 1.0 eq) in 2 mL of THF, 2 mL of MeOH and 2 mL of water was added LiOH»H2O (91 mg, 2.18 mmol, 3.0 eq). The reaction mixture was stirred at 25 °C for 1 hr. The mixture was concentrated under reduced pressure to remove solvent. The mixture was acidified with 1 N HC1 to pH =3. The mixture was extracted with 10 mL of EA by twice. The organic phase was dried over with Na2SO4, filtered and concentrated under reduced pressure to give 4- [(4-chloro-2-isopropyl-pyrazol-3-yl)methoxy]-2,6-difluoro-benzoic acid (120 mg, crude) as a white solid. 'HNMR (400 MHz, DMSO-d₆) 8: 7.64 (s, 1H), 6.83 (d, J= 9.6 Hz, 2H), 5.20 (s, 2H), 4.67 - 4.57 (m, 1H), 1.38 (d, J= 8.0 Hz, 6H) ppm.

Example 33

4-((4-chloro-l-isopropyl-lH-pyrazol-5-yl)methoxy)-N-(2,3-dimethylphenyl)-2,6- difluorob enzami de

To a solution of 2,3-dimethylaniline (33 mg, 0.272 mmol, 1.5 eq) and 4-[(4-chloro-2-isopropyl- pyrazol-3-yl)methoxy]-2,6-difluoro-benzoic acid (60 mg, 0.181 mmol, 1.0 eq) in 3 mL of anhydrous THF was added HATU (103 mg, 0.272 mmol, 1.5 eq) and DIEA (47 mg, 0.363 mmol, 2.0 eq). The reaction mixture was stirred at 25 °C for 12 hrs. To the mixture was added 10 mL of EA and 5 mL of water. The organic phase was washed with 10 mL of brine, dried over with ISfeSCL, filtered and concentrated under reduced pressure. The residue was purified by prep-TLC (PE:EA=1 : 1) and further purification by prep-HPLC (basic condition) to give 4- ((4-chloro- 1 -i sopropyl- 1 H-pyrazol -5 -yl)methoxy)-N-(2, 3 -dimethylphenyl)-2, 6- difluorobenzamide (20.42 mg, 99.99% purity, 26% yield) as a white solid. Calcd [M+H]⁺ for C22H23CIF2N3O2 434.1; found 434.3; ^XH NMR (400 MHz, DMSO-d₆) 8: 10.11 (s, 1H), 7.66 (s, 1H), 7.19 - 7.14 (m, 1H), 7.13 - 7.06 (m, 2H), 7.05 - 6.97 (m, 2H), 5.28 (s, 2H), 4.70 - 4.57 (m, 1H), 2.27 (s, 3H), 2.13 (s, 3H), 1.39 (d, J= 6.4 Hz, 6H) ppm.

Example 34

4-((4-chl oro-1 -isopropyl-lH-pyrazol-5-yl)methoxy)-2, 6-difluoro-N-(2-m ethoxy-3 - methylphenyl)benzamide

To a solution of 2-m ethoxy-3 -methyl-aniline (37 mg, 0.272 mmol, 1.5 eq) and 4-[(4-chloro-2- isopropyl-pyrazol-3-yl)methoxy]-2,6-difluoro-benzoic acid (60 mg, 0.181 mmol, 1.0 eq) in 3 mL of anhydrous THF was added HATU (103 mg, 0.272 mmol, 1.5 eq) and DIEA (47 mg, 0.363 mmol, 2.0 eq). The reaction mixture was stirred at 25 °C for 12 hrs. The reaction mixture was poured in 20 mL of water and extracted with 20 mL of EA by twice. The organic layer was concentrated to give a residue. The residue was purified by prep-HPLC (basic condition) to give 4-((4-chl oro-1 -isopropyl-lH-pyrazol-5-yl)methoxy)-2, 6-difluoro-N-(2 -m ethoxy-3 - methylphenyl)benzamide (28.15 mg, 99% purity, 55% yield) as a white solid. Calcd [M+H]⁺ for C22H23CIF2N3O2 450.1; found. 450.2; ^XH NMR (400 MHz, DMSO-d₆) 8 = 10.03 (s, 1H), 7.77 (t, J = 5.6 Hz, 1H), 7.66 (s, 1H), 7.07 - 6.94 (m, 4H), 5.27 (s, 2H), 4.70 - 4.59 (m, 1H), 3.67 (s, 3H), 2.26 (s, 3H), 1.40 (d, J= 6.4 Hz, 6H) ppm.

Example 35

In-vitro Profiling

INS1-E cells engineered to express luciferase in the C-peptide of proinsulin [Burns et al., Cell Metabolism 2015, PMID 25565210] were grown to 80-90% confluency in flasks. Media was removed and the flask was rinsed with PBS. 15 mL of KRB (milliQ water, 138 mM NaCl, 5.4 mM KC1, 2.6 mM MgCh, 2.6 mM CaCl₂, 5 mM NaHCO₃, 0.1%BSA) buffer were added, and cells were incubated for 30 minutes in a 37 °C, 5% CO2 incubator. KRB, 0.1%BSA buffer was removed and the cells were rinsed with PBS 2 times, trypsinized, and incubated at 37 °C, 5% CO2 for 5 minutes or until cells started to detach. Immediately 20 ml of KRB, 0.1%BSA, 10% FBS was added and the cells were harvested into 50 ml conical tube and spun at 1000 RPM for 5 minutes.

Supernatant was aspirated and the cell pellet was resuspended in KRB, 0.1% BSA buffer. Cells were counted and the live cell density was used in calculating the cell seeding suspension. Cells were diluted to a concentration of 5k/30 pL in KRB, 0.1% BSA. The cell suspension was mixed thoroughly but gently, glucose was added to cell suspension to get 16 mM (for high glucose plates set) and 2.8 mM (to get low glucose plates set) final concentration and plated quickly.

30 pl of cell suspension was added to each well of a 384 Corning assay ready plates (ARPs). ARPs already have 100 nL of 10 mM compounds dispensed into assay wells. Cells are incubated with compounds for 2 hours at 37 °C, 5% CO2 in the Liconic Incubator. The substrate was diluted thirty minutes prior to addition to plates. To reconstitute the Native Coelenterazine substrate, first acidified methanol (10 ml of methanol added 200 pl of 3N HC1) was prepared. Native Coelenterazine was then diluted in PBS to a concentration of 80 uM. Diluted Native Coelenterazine was added (10 pl/well of assay plates) for a final concentration of 20 pM. Plates were gently shaken for 5 seconds.

Luminescence was read at 2 minutes immediately on ViewLux instrument. Raw data values were transferred to Genedata Screener Software along with compound plate mapping for more detailed plate QC and compound activity/dose response analysis. Spotfire was then used for drug screen hit calling with the finalized Genedata output.

The Emax 100% is arbitrarily set to the amount of insulin secretion induced by the high glucose condition. For active compounds (Emax > 25%) a curve is fit to generate the ACso value.

ND = not determined

INCORPORATION BY REFERENCE

All publications and patents mentioned herein are hereby incorporated by reference in their entirety as if each individual publication or patent was specifically and individually indicated to be incorporated by reference. In case of conflict, the present application, including any definitions herein, will control. EQUIVALENTS

While specific embodiments of the subject invention have been discussed, the above specification is illustrative and not restrictive. Many variations of the invention will become apparent to those skilled in the art upon review of this specification and the claims below. The full scope of the invention should be determined by reference to the claims, along with their full scope of equivalents, and the specification, along with such variations.

Claims

We claim:

1. A compound of F ormula (I) : wherein:

A is selected from monocycloalkyl, bicycloalkyl and polycycloalkyl;

R¹ is aryl; and

R² is heteroaryl; or a pharmaceutically acceptable salt thereof.

2. The compound of claim 1, wherein A is monocyclyl, e.g., selected from cyclobutyl, cyclopentyl, and cyclohexyl.

3. The compound of claim 1 or 2, wherein A is cyclohexyl.

4. The compound of claim 1, wherein A is bicycloalkyl, e.g., selected from bicyclopentyl, spiro[3.3]heptyl, and bicyclo[2.2.2]octyl.

5. The compound of claim 4, wherein A is bicyclo[2.2.2]octyl.

6. The compound of claim 1, wherein A is polycyclyl, e.g., adamantyl.

7. The compound of any one of claims 1-6, wherein R¹ is phenyl.

8. The compound of any one of claims 1-6, wherein R¹ is 1,3-dihydroisobenzofuranyl.

9. The compound of claim 7 or 8, wherein R¹ is unsubstituted or substituted with one or more substituents selected from halo, CN, NO2, alkyl, alkoxy, amino, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, and heteroaralkyl.

10. The compound of claim 9, wherein R¹ is substituted with one or more substituents selected from isopropyl, -NH2, dimethylamino, and methoxy.

11. The compound of claim 9, wherein R¹ has one or two methyl substituents.

12. The compound of any one of claims 9-11, wherein an R¹ substituent is present at the 2 -position, the 3 -position, or both, relative to the carbon atom bound to the nitrogen atom of the amide group.

13. The compound of claim 11 or 12, wherein R¹ is 2,3 -dimethylphenyl.

14. The compound of any one of claims 1-13, wherein R² is isoxazolyl or pyrazolyl.

15. The compound of claim 14, wherein R² is 3,5-dimethylisoxazolyl or 1,4- dimethylpyrazolyl .

16. The compound of claim 1, wherein the amide and ether substituents of the compound of Formula (I) are disposed in a c/.s-relationship on a ring of A.

17. The compound of claim 1, wherein the amide and ether substituents of the compound of Formula (I) are disposed in a /ra/z.s-relationship on a ring of A.

18. A compound selected from:

wherein:

R¹ is aryl;

R² is heteroaryl;

R³ is fluoro; and nl is 1, 2, 3, or 4; or a pharmaceutically acceptable salt thereof.

20. The compound of claim 19, wherein R¹ is phenyl.

21. The compound of claim 19, wherein R¹ is 1,3-dihydroisobenzofuranyl.

22. The compound of any one of claims 19-21, wherein R¹ is unsubstituted or substituted with one or more substituents selected from halo, CN, NO2, alkyl, alkoxy, amino, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, and heteroaralkyl.

23. The compound of claim 22, wherein R¹ is substituted with one or more substituents selected from isopropyl, -NH2, dimethylamino, and methoxy.

24. The compound of claim 22, wherein R¹ has one or two methyl substituents.

25. The compound of any one of claims 22-24, wherein an R¹ substituent is present at the 2-position, the 3 -position, or both, relative to the carbon atom bound to the nitrogen atom of the amide group.

26. The compound of claim 24 or 25, wherein R¹ is 2,3 -dimethylphenyl or 2-methoxy-3- methylphenyl.

27. The compound of any one of claims 19-26, wherein nl is 1.

28. The compound of any one of claims 19-26, wherein nl is 2.

29. The compound of any one of claims 19-28, wherein R² is pyrazolyl or isoxazolyl.

30. The compound of claim 29, wherein R² is unsubstituted or substituted with one or more substituents selected from halo, CN, NO2, alkyl, alkoxy, amino, cycloalkyl, cycloalkylalkyl, heterocyclyl, and heterocyclylalkyl.

31. The compound of claim 30, wherein R² is substituted with one or more substituents selected from chloro, methyl, and isopropyl.

32. A compound selected from:

acceptable salt thereof.

33. A compound of F ormula (III) : wherein:

R¹ is aryl;

A is phenyl, monocycloalkyl, bicycloalkyl, or polycycloalkyl;

R⁴ is halo; and n2 is 1, 2, 3, 4, or 5; or a pharmaceutically acceptable salt thereof.

34. The compound of claim 33, wherein R¹ is phenyl.

35. The compound of claim 33, wherein R¹ is 1,3-dihydroisobenzofuranyl.

36. The compound of any one of claims 33-35, wherein R¹ is unsubstituted or substituted with one or more substituents selected from halo, CN, NO2, alkyl, alkoxy, amino, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, and heteroaralkyl.

37. The compound of claim 36, wherein R¹ is substituted with one or more substituents selected from isopropyl, -NH2, dimethylamino, and methoxy.

38. The compound of claim 36, wherein R¹ has one or two methyl substituents.

39. The compound of any one of claims 36-38, wherein an R¹ substituent is present at the 2-position, the 3 -position, or both, relative to the carbon atom bound to the nitrogen atom of the amide group.

40. The compound of claim 38 or 39, wherein R¹ is 2,3 -dimethylphenyl.

41. The compound of any one of claims 33-40, wherein R⁴ is fluoro.

42. The compound of any one of claims 33-41, wherein n2 is 1.

43. The compound of any one of claims 33-42, wherein A is phenyl.

44. A compound, wherein the compound pharmaceutically acceptable salt thereof.

45. A pharmaceutical composition comprising a compound of any one of claims 1-44, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

46. A method of modulating insulin secretion, comprising contacting a P-cell with a compound according to any one of claims 1-44.

47. The method of claim 46, wherein insulin secretion from said P-cell occurs only when said blood glucose levels exceed normoglycemic conditions.

48. The method according to claim 47, wherein said blood glucose levels are greater than about 5 mM.

49. The method according to claim 47, wherein said blood glucose levels are greater than about 7 mM.

50. The method according to claim 47, wherein said blood glucose levels are greater than about 10 mM.

51. The method according to claim 47, wherein said blood glucose levels are greater than about 12 mM.

52. The method according to claim 47, wherein said normoglycemic conditions comprise a blood glucose concentration from about 3.5 mM to about 7 mM.

53. A method of modulating insulin secretion, comprising administering to a subject in need thereof a compound according to any one of claims 1-44, or a pharmaceutically acceptable salt thereof.

54. A method of treating diabetes, comprising administering to a subject in need thereof a compound according to any one of claims 1-44, or a pharmaceutically acceptable salt thereof.