Heteroaromatic macrocyclic ether chemotherapeutic agents

Abstract

Disclosed are heterocyclic heteroaromatic macrocyclic ether compounds of Formula (I), pharmaceutically acceptable salts of the compounds and pharmaceutical compositions thereof. The disclosure further relates to methods of treating or preventing cancer using the heterocyclic heteroaromatic macrocyclic ether compounds, pharmaceutically acceptable salts of the compounds and pharmaceutical compositions thereof.

Description

specification to designate ring atom positions, as shown above. In this example, the 1-position of the imidazolylene is bonded to the methylene group, so it is indicated with the asterisk. The asterisk notation is used in both the names and structures of heteroarylenes for X and Y. Here, for Y the ring atom at the 5-position is not marked because it’s bound10 to the phenyl group bearing variable R4.For X, an exemplary ring would be “l,5*-substituted-imidazolylene” as shown below.bonded to aromatic ring bearing QThe ring atom bound to the methylene group (the 5-position in this example) is 15 indicated with the asterisk in both the names and structures of ring X heteroarylenes. The ring atom bonded to the aromatic ring bearing Q is not marked.The term “heteroatom” as used herein means an atom of any element other than carbon or hydrogen. Preferred heteroatoms are nitrogen, oxygen, and sulfurThe 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 heterocyclyls) 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 polycycle 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 theretoThe 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 disclosure, 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 sulfonamide, 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 formulaewherein 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 thereofThe term “sulfone” is art-recognized and refers to the group -S(O)2-R395 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 R1" 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 formulaR41 R41wherein 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 andWuts, Protective Groups in Organic Chemistry, 3rdEd., 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, benzyloxycarbonyl (“CBZ”), tertbutoxycarbonyl (“Boc”), trimethyl silyl (“TMS”), 2-trimethyl silyl-ethanesulfonyl (“TES”), trityl and substituted trityl groups, allyloxycarbonyl, 9-fluorenylmethyloxycarbonyl (“FMOC”), nitro-veratryl oxycarbonyl (“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 disclosure may be racemic. In certain embodiments, compounds of the disclosure may be enriched in one enantiomer. For example, a compound of the disclosure may have greater than about 30% 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 disclosure may have more than one stereocenter. In certain such embodiments, compounds of the disclosure may be enriched in one or more diastereomer. For example, a compound of the disclosure may have greater than about 30% 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 (eg., 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.In some embodiments, a moiety in a compound exists as a mixture of tautomers. A “tautomer” is a structural isomer of a moiety or a compound that readily interconverts with another structural isomer. For example, a pyrazole ring has two tautomers:Hwhich differ in the positions of the pi-bonds and a hydrogen atom. Unless explicitly stated otherwise, a drawing of one tautomer of a moiety or a compound encompasses all of the possible tautomers.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. These effects are also called “prophylactic” effects. Thus, as used herein and unless otherwise specified, the terms “prevention” and “preventing” refer to an approach for obtaining beneficial or desired results including, but not limited, to prophylactic benefit. For prophylactic benefit, a therapeutic can be administered to a patient at risk of developing a particular disease, or to a patient reporting one or more of the physiological symptoms of a disease, even though a diagnosis of this disease may not have been made. In one embodiment, a therapeutic is administered prior to clinicalmanifestation of the unwanted condition (e.g., disease or other unwanted state of the subject) for prophylactic benefit (e.g., it protects the subject against developing the unwanted condition).As used herein and unless otherwise specified, the terms “treatment” and “treating” refer to therapeutic or palliative measures. Beneficial or desired clinical results include, but are not limited to, alleviation, in whole or in part, of symptoms associated with a disease or disorder or condition, diminishment of the extent of disease, stabilized (i.e., not worsening) state of disease, delay or slowing of disease progression, amelioration or palliation of the disease state (e.g., one or more symptoms of the disease), and remission (whether partial or total), whether detectable or undetectable. “Treatment” can also mean prolonging survival as compared to expected survival if not receiving treatment. In one embodiment, “treatment” comprises administration of a therapeutic after manifestation of the unwanted condition (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 disclosure (e.g., a compound of Formula (I)). A common method for making a prodrug is to include one or more selected moi eties 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 disclosure. 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, partial or complete remedy of disease, among others.As used herein and unless otherwise indicated, the term "relapsed" refers to a disorder, disease, or condition that responded to prior treatment (e.g., achieved a complete response) then had progression. The prior treatment can include one or more lines of therapy.As used herein and unless otherwise indicated, the term "refractory" refers to a disorder, disease, or condition that has not responded to prior treatment that can include one or more lines of therapy.CompoundsIn one aspect, provided herein is a compound of Formula (I), or an enantiomer, a mixture of enantiomers, or a tautomer thereof, or a pharmaceutically acceptable salt thereof:whereinQ is CH or N;Z is CRs or N;X is a 5-membered heteroarylene, comprising 1 to 3 heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur; wherein the 5-membered heteroarylene is substituted with 0, 1, or 2 occurrences of Ra;Y is a 5- or 6-membered heteroarylene, comprising 1 to 3 heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur; wherein the 5- or 6-membered heteroarylene is substituted with 0, 1, or 2 occurrences of Ra;in Y, the point of attachment to the methylene group bonded to X and Y and the point of attachment to the aromatic ring comprising Z are on adjacent atoms, and the 5- to6-membered heteroarylene ring atom alpha to the point of attachment to the methylene group and beta to the point of attachment to the aromatic ring comprising Z is nitrogen;Ri is selected from the group consisting of H, methyl, and hydroxymethyl;each R2 is independently selected from the group consisting of H, halo, CN, C1 -1 alkoxy, C1.4 alkyl, halo-Ci-4 alkyl, C3-4 cycloalkylmethyl, C3-6 cycloalkyl, and C3-6 heterocycloalkyl;each R3 is independently selected from the group consisting of H, halo, CN, C1-4 alkoxy, halo-Ci-4 alkyl, and C1.4 alkyl; andeach of R4 and Rs is independently H or F;provided that X is not 3*,4-substituted-pyrazolylene, where * indicates the point of attachment of X or Y to the methylene group bonded to X and YIn one aspect, disclosed is a compound of Formula (I) or a pharmaceutically acceptable salt thereof:(I)whereinQ is CH or N;Z is CRs or N;X is a 5-membered heteroarylene, comprising 1 to 3 heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur; wherein the 5-membered heteroarylene is substituted with 0, 1, or 2 occurrences of R2;Y is a heteroarylene selected from the group consisting of l,2*-substituted-imidazolylene, 4*,5-substituted-imidazolylene, 4*,5-substituted-l,2,3-oxadiazolylene, 3*,4-substituted-l,2,5-oxadiazolylene, 3*,4-substituted-l,2-oxazolylene, 4*,5-substituted-1,3-oxazolylene, 2*,3-substituted-pyrazinylene, l*,5-substituted-pyrazolylene, 3*,4-substituted-pyrazolylene, 3*,4-substituted-pyridazinylene, 2*,3-substituted-pyridinylene, 4*,5-substituted-pyrimidinylene, 2*,3-substituted-pyrrolylene, 5*,6-substituted-l,2,3,4-tetrazinylene, 1 *,5-substituted-l,2,3,4-tetrazolylene, l,5*-substituted-l,2,3,4-tetrazolylene, 4*,5-substituted-l,2,3-thiadiazolylene, 3*,4-substituted-l,2,5-thiadiazolylene, 3*,4-substituted-l,2-thiazolylene, 4*,5-substituted-l,3-thiazolylene, 4*,5-substituted-l,2,3-triazinylene, 5*,6-substituted-l,2,4-triazinylene, 5,6*-substituted-1,2,4-triazinylene, l*,5-substituted-l,2,3-triazolylene, 4*,5-substituted-l,2,3-triazolylene, l*,5-substituted-l,2,4-triazolylene, l,5*-substituted-l,2,4-triazolylene, and 3*,4-substituted-l,2,4-triazolylene; wherein the heteroarylene is substituted with 0, 1, or 2 occurrences of Rs;* indicates the point of attachment of X or Y to the methylene group bonded to Xand Y;in Y the heteroarylene ring atom alpha to the point of attachment to the methylene group and beta to the point of attachment to the aromatic ring comprising Z is nitrogen;Ri is selected from the group consisting of H, methyl, and hydroxymethyl;each R2 is independently selected from the group consisting of H, halo, CN, C1-4 alkoxy, C1-4 alkyl, halo-Ci-4 alkyl, Cm cycloalkylmethyl, C3-6 cycloalkyl, and C3-6 heterocycloalkyl;each R3 is independently selected from the group consisting of H, halo, CN, C1-4 alkoxy, halo-Ci-4 alkyl, and Cm alkyl; andeach of R4 and R5 is independently H or F.In one aspect, disclosed is a compound of Formula (I) or a pharmaceutically acceptable salt thereof:whereinQ is CH or N;Z is CRs or N;X is a 5-membered heteroarylene, comprising 1 to 3 heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur; wherein the 5-membered heteroarylene is substituted with 0, 1, or 2 occurrences of R2;Y is a heteroarylene selected from the group consisting of l,2*-substituted-imidazolylene, 4*,5-substituted-imidazolylene, 4,5*-substituted-imidazolylene, 4*,5-substituted-l,2,3-oxadiazolylene, 3*,4-substituted-l,2,5-oxadiazolylene, 3*,4-substituted-1,2-oxazolylene, 4*,5-substituted-l,3-oxazolylene, 2*,3-substituted-pyrazinylene, 1*,5-sub stituted-pyrazolyl ene, 3 * ,4-sub stituted-pyrazolyl ene, 3 * ,4-sub stituted-pyri dazinyl ene, 2 *, 3 -sub stituted-pyridinylene, 4 *, 5 -sub stituted-pyrimidiny 1 ene, 2 *, 3 -sub stituted-pyrrolylene, 5*,6-substituted-l,2,3,4-tetrazinylene, l*,5-substituted-l,2,3,4-tetrazolylene, l,5*-substituted-l,2,3,4-tetrazolylene, 4*,5-substituted-l,2,3-thiadiazolylene, 3*,4-substituted-l,2,5-thiadiazolylene, 3*,4-substituted-l,2-thiazolylene, 4*, 5-sub stituted-1,3-thiazolylene, 4*,5-substituted-l,2,3-triazinylene, 5*,6-substituted-l,2,4-triazinylene, 5,6*-sub stituted-1,2,4-triazinylene, 1 *, 5 -sub stituted-1,2,3 -triazolylene, 4 *, 5 -sub stituted-1,2,3-triazolylene, l*,5-substituted-l,2,4-triazolylene, l,5*-substituted-l,2,4-triazolylene, and 3*,4-substituted-l,2,4-triazolylene; wherein the heteroarylene is substituted with 0, 1, or 2 occurrences of R3;* indicates the point of attachment of X or Y to the methylene group bonded to X and Y;in Y the heteroarylene ring atom alpha to the point of attachment to the methylene group and beta to the point of attachment to the aromatic ring comprising Z is nitrogen;Ri is selected from the group consisting of H, methyl, and hydroxymethyl;each R2 is independently selected from the group consisting of H, halo, CN, C1 -1 alkoxy, C14 alkyl, halo-Ci-4 alkyl, C3-4 cycloalkylmethyl, C3-6 cycloalkyl, and C3-6 heterocycloalkyl;each R3 is independently selected from the group consisting of H, halo, CN, C1-4 alkoxy, halo-Ci-4 alkyl, and C1.4 alkyl; andeach of R< and Rs is independently H or F.In some embodiments, X is a 5-membered heteroarylene selected from the group consisting of pyrazolylene, isoxazolylene, isothiazolylene, imidazolylene, and triazolylene. In some embodiments, X is a 5-membered heteroarylene selected from the group consisting of pyrazolylene and triazolylene. In certain embodiments, X is a 5-membered heteroarylene selected from the group consisting of 4*,5-substituted-pyrazolylene, 4,5*-substituted-pyrazolylene, l*,5-substituted-pyrazolylene, 4*,5-substituted-isoxazolylene, 3*,4-substituted-isoxazolylene, 3*,4-substituted-isothiazolylene, 4*,5-substituted-isothiazolylene, 4*,5-substituted-imidazolylene, l*,5-substituted-imidazolylene, 1*,5-substituted-triazolylene, and 4*,5-substituted-triazolylene.In some embodiments, X is a 5-membered heteroarylene selected from the group consisting of pyrazolylene, isoxazolylene, isothiazolylene, imidazolylene, and triazolylene. In some embodiments, X is a 5-membered heteroarylene selected from the group consisting of pyrazolylene and triazolylene. In certain embodiments, X is a 5-membered heteroarylene selected from the group consisting of 4*,5-substituted-pyrazolylene, 4,5*-substituted-pyrazolylene, l*,5-substituted-pyrazolylene, 4*,5-substituted-isoxazolylene, 4,5*-substituted-isoxazolylene, 3 *,4-substituted-isoxazolylene, 3 *,4-substituted-isothiazolylene, 4*,5-substituted-isothiazolylene, 4,5*-substituted-isothiazolylene, 4*,5-substituted-imidazolylene, 1 *,5-substituted-imidazolylene, 1 *,5-substituted-triazolylene, and 4 *, 5 -sub stituted-triazoly 1 ene.In certain embodiments, X is a 5-membered heteroarylene selected from the group consisting of:In one embodiment, X is a pyrazolylene. In one embodiment, X is not 3*,4-r2N-N / substituted-pyrazolylene. In one embodiment, X is not R2 . In one embodiment,NC’ N-NX is not /         In another embodiment, X is 3*,4-substituted-pyrazolylene. Inanother embodiment, X is 4*,5-substituted-pyrazolylene. In another embodiment, X is 4,5*-substituted-pyrazolylene. In another embodiment, Xis l*,5-substituted-pyrazolylene.In one embodiment, X is. In one. In one embodiment, X isembodiment, X isIn one embodiment, X is isoxazolylene. In one embodiment, X is 4*,5-substituted-isoxazolylene. In one embodiment, X is 4,5*-substituted-isoxazolylene In oneembodiment, X is 3*,4-substituted-isoxazolylene. In one embodiment, X isIn one embodiment, X isIn one embodiment, X is isothiazolylene. In one embodiment, X is 3*,4-substituted-isothiazolylene. In one embodiment, X is 4*,5-substituted-isothiazolylene. In one embodiment, X is 4,5*-substituted-isothiazolylene. In one embodiment, X is. In one embodiment, X isIn one embodiment, X is imidazolylene. In one embodiment, X is 4*,5-substituted-imidazolylene. In one embodiment, X is l*,5-substituted-imidazolylene. In oneembodiment, X isIn one embodiment, X is triazolylene. In one embodiment, X is l*,5-substituted-triazolylene. In one embodiment, X is 4*,5-substituted-triazolylene. In one embodiment,XisIJWV'In one embodiment, X is n=nIn one embodiment, X is substituted with 0 occurrence of R2 (i.e., all open positions on X are H). In one embodiment, X is substituted with 1 occurrence of R2 that is not H. In one embodiment, X is substituted with 2 occurrences of R2 that are not H.R2 is independently selected from the group consisting of H, halo, CN, C1.4 alkoxy, C1-4 alkyl, halo-Ci-4 alkyl, (Nm cycloalkylmethyl, C3-6 cycloalkyl, and C3-6 heterocycloalkyl. In one embodiment, R2 is not H. In one embodiment, R2 is C1-4 alkyl. In one embodiment, R2 is methyl. In one embodiment, R2 is ethyl. In one embodiment, R2 is isopropyl. In one embodiment, Ra is cyclopropyl. In one embodiment, R2 is cyclobutyl. In one embodiment, R2 is cyclopropylmethyl. In one embodiment, R2 is -CHF2. In one embodiment, R2 is -CH2CHF2. In one embodiment, R2 is halo. In one embodiment, R2 is fluoro. In one embodiment, R2 is chloro. In one embodiment, R2 is CN. In one embodiment, R2 is methoxy.In certain embodiments, X is a 5-membered heteroarylene selected from the group consisting of:In some embodiments, Y is a heteroarylene selected from the group consisting of 1 *,5-substituted-pyrazolylene, 3*,4-substituted-pyrazolylene, l,2*-substituted-imidazolylene, 4*,5-substituted-imidazolylene, l*,5-substituted-l,2,3-triazolylene, 4*,5-substituted-l,2,3-triazolylene, l*,5-substituted-l,2,4-triazolylene, l,5*-substituted-1,2,4-triazolylene, 4*,5-substituted-l,3-thiazolylene, 2*,3-substituted-pyridinylene, 4*,5-substituted-pyrimidinylene, and 2*,3-substituted-pyrazinylene.In some embodiments, Y is a heteroarylene selected from the group consisting of 1 *,5-substituted-pyrazolylene, 3*,4-substituted-pyrazolylene, l,2*-substituted-imidazolylene, 4*,5-substituted-imidazolylene, 4,5*-substituted-imidazolylene, 1*,5-substituted-l,2,3-triazolylene, 4*,5-substituted-l,2,3-triazolylene, l*,5-substituted-l,2,4-triazolylene, l,5*-substituted-l,2,4-triazolylene, 4*,5-substituted-l,3-thiazolylene, 2*,3-substituted-pyridinylene, 4*,5-substituted-pyrimidinylene, and 2*,3-substituted-pyrazinylene.In certain embodiments, Y is a heteroarylene selected from the group consisting5 of:* indicates the point of attachment of Y to the methylene group bonded to X and10 Y; andRs is selected from the group consisting of H, halo, CN, Ci4 alkoxy, halo-Ci-4 alkyl, and Ci-4 alkyl.In one embodiment, Y is a 5-membered heteroarylene. In one embodiment, Y is pyrazolylene. In one embodiment, Y is l*,5-substituted-pyrazolylene. In one embodiment,Y is 3*,4-substituted-pyrazolylene.In one embodiment, Y isIn oneembodiment, Y isIn one embodiment, Y isIn one embodiment, Y is imidazolylene. In one embodiment, Y is l,2*-substituted-imidazolylene. In one embodiment, Y is 4*,5-substituted-imidazolylene. In oneI<TUWembodiment, Y is 4,5*-substituted-imidazolylene. In one embodiment, Y is         R=. Inone embodiment,embodiment, Y isIn one embodiment, Y isIn oneIn one embodiment, Y is triazolylene. In one embodiment, Y is l*,5-substituted-1,2,3-triazolylene. In one embodiment, Y is 4*,5-substituted-l,2,3-triazolylene. In one5 embodiment, Y is l*,5-substituted-l,2,4-triazolylene. In one embodiment, Y is 1,5*-substituted-l,2,4-triazolylene. In one embodiment, Y is         R=. In one embodiment,In one embodiment, Y isIn one embodiment, Y isIn one embodiment, Y is thiazolylene. In one embodiment, Y is 4*,5-substituted-1,3-thiazolylene. In one embodiment, Y isIn one embodiment, Y is a 6-membered heteroarylene. In one embodiment, Y ispyridinylene. In one embodiment, Y is 2*,3-substituted-pyridinylene. In one embodiment,In one embodiment, Y is pyrimidinylene. In one embodiment, Y is 4*,5-substituted-pyrimidinylene. In one embodiment, Y isIn one embodiment, Y is pyrazinylene. In one embodiment, Y is 2*,3-substituted-pyrazinylene. In one embodiment, Y isIIn one embodiment, Y is substituted with 0 occurrence of Ra (i.e., all open positions on Y are H). In one embodiment, Y is substituted with 1 occurrence of Ra that is not H. In one embodiment, Y is substituted with 2 occurrences of Ra that are not H.In one embodiment, Ra is selected from the group consisting of H, halo, CN, Ci-4 alkoxy, halo-Ci-4 alkyl, and Cm alkyl. In one embodiment, Rs is not H. In one embodiment, Rs is Cm alkyl. In one embodiment, Rs is methyl. In one embodiment, Rs is ethyl. In one embodiment, Rs is halo, hi one embodiment, Rs is flouro. In one embodiment, Rs is chloro. In one embodiment, Rs is CN.In one embodiment, X is a pyrazolylene provided herein (e.g., a 4*,5-substituted-pyrazolylene provided herein), and Y is a pyrazolylene provided herein. In another embodiment, Y is an imidazolylene provided herein. In another embodiment, Y is a triazolylene provided herein. In another embodiment, Y is a thiazolylene provided herein. In another embodiment, Y is a pyridinylene provided herein. In another embodiment, Y is a pyrimidinylene provided herein. In another embodiment, Y is a pyrazinylene provided herein.In one embodiment, X is an isoxazolylene provided herein, and Y is a pyrazolylene provided herein. In another embodiment, Y is an imidazolylene provided herein. In another embodiment, Y is a triazolylene provided herein. In another embodiment, Y is a thiazolylene provided herein. In another embodiment, Y is a pyridinylene provided herein. In another embodiment, Y is a pyrimidinylene provided herein. In another embodiment, Y is a pyrazinylene provided herein.In one embodiment, X is an isothiazolylene provided herein, and Y is a pyrazolylene provided herein. In another embodiment, Y is an imidazolylene provided herein. In another embodiment, Y is a triazolylene provided herein. In another embodiment, Y is a thiazolylene provided herein. In another embodiment, Y is a pyridinylene provided herein. In another embodiment, Y is a pyrimidinylene provided herein. In another embodiment, Y is a pyrazinylene provided herein.In one embodiment, X is an imidazolylene provided herein, and Y is a pyrazolylene provided herein. In another embodiment, Y is an imidazolylene provided herein. Inanother embodiment, Y is a triazolylene provided herein. In another embodiment, Y is a thiazolylene provided herein. In another embodiment, Y is a pyridinylene provided herein. In another embodiment, Y is a pyrimidinylene provided herein. In another embodiment, Y is a pyrazinylene provided herein.In one embodiment, X is a triazolylene provided herein, and Y is a pyrazolylene provided herein. In another embodiment, Y is an imidazolylene provided herein. In another embodiment, Y is a triazolylene provided herein. In another embodiment, Y is a thiazolylene provided herein. In another embodiment, Y is a pyridinylene provided herein. In another embodiment, Y is a pyrimidinylene provided herein. In another embodiment, Y is a pyrazinylene provided herein.In some embodiments, Q is CH. In other embodiments, Q is N.In some embodiments, Z is CRs. In particular embodiments, Rs is H. In particular embodiments, Rs is F. In other embodiments, Z is N.In some embodiments, Rt is H. In other embodiments, R4 is F.In some embodiments, the compound of Formula (I) has the structure (I-A):In other embodiments, the compound of Formula (I) has the structure (I-B):In one embodiment, the compound is a compound of any one of the following formulas, or an enantiomer, a mixture of enantiomers, or a tautomer thereof, or a pharmaceutically acceptable salt thereof:In some embodiments, R2 is each independently selected from the group consisting of H, CN, methyl, ethyl, isobutyl, methoxy, chloro, trifluoromethyl, cyclopropyl, cyclopropylmethyl, 2-fluoroethyl, difluoromethyl, 2,2-difluoroethyl, cyclobutyl, and 5 oxetanyl.In some embodiments, R3 is selected from the group consisting of H, fluoro, chloro, CN, methyl, and ethyl.In certain embodiments, the compound is selected from the group consisting of:pharmaceutically acceptable salt thereof.or an enantiomer, a mixture of enantiomers, or a tautomer thereof, or apharmaceutically acceptable salt thereof.In certain embodiments, the compound is selected from the group consisting of:pharmaceutically acceptable salt thereof.10          In certain embodiments, the compound is selected from the group consisting of:5          or an enantiomer, a mixture of enantiomers, or a tautomer thereof, or apharmaceutically acceptable salt thereofIn certain embodiments, the compound is selected from the group consisting ofandor an enantiomer, a mixture of enantiomers, or a tautomer thereof, or apharmaceutically acceptable salt thereof5          In certain embodiments, the compound is selected from the group consisting of:andoran enantiomer,a mixtureof enantiomers, or a tautomer thereof, or apharmaceutically acceptable salt thereof.5          In certain embodiments, the compound is selected from the group consisting of:or an enantiomer, a mixture of enantiomers, or a tautomer thereof, or apharmaceutically acceptable salt thereof.In certain embodiments, the compound is selected from the group consisting of:or an enantiomer, a mixture of enantiomers, or a tautomer thereof, or a pharmaceutically acceptable salt thereof.In certain embodiments, the compound is selected from the group consisting of:or an enantiomer, a mixture of enantiomers, or a tautomer thereof, or a pharmaceutically acceptable salt thereof.In certain embodiments, the compound is selected from the group consisting of:In certain embodiments, the compound is selected from the group consisting of:In certain embodiments, the compound is:In certain embodiments, the compound is:In certain embodiments, the compound is selected from the group consisting of:In certain embodiments, the compound is selected from the group consisting of:In certain embodiments, the compound is selected from the group consisting of:In certain embodiments, the compound is selected from the group consisting of:In certain embodiments, the compound is selected from the group consisting of:In certain embodiments, the compound is selected from the group consisting of:In certain embodiments, the compound is selected from the group consisting of:In certain embodiments, the compound is selected from the group consisting of:or an enantiomer, a mixture of enantiomers, or a tautomer thereof, or a pharmaceutically acceptable salt thereof.In certain embodiments, the compound is selected from the group consisting of:5 or an enantiomer, a mixture of enantiomers, or a tautomer thereof, or a pharmaceutically acceptable salt thereof.In certain embodiments, the compound is selected from the group consisting of:or a pharmaceutically acceptable salt thereof.5          In one embodiment, provided herein is a compound in Table 1:Table 1.or a pharmaceutically acceptable salt thereof.For any compound in Table 1 that has a chiral center due to the presence of nonhydrogen Ri, the R-enantiomer, the S-enantiomer, and the racemic compound of such compound are all specifically provided herein, even if not specifically shown in Table 1.5          In one embodiment, provided herein is a pharmaceutically acceptable salt of acompound of Formula (I). In one embodiment, provided herein is a pharmaceutically acceptable salt of any compound in Table 1.In certain embodiments, the pharmaceutically acceptable salt of the compound is selected from the group consisting of alkyl ammonium salts, dialkyl ammonium salts, 10 trialkyl ammonium salts, tetra-alkyl ammonium salts, L-arginine salts, benenthamine salts, benzathine salts, betaine salts, calcium hydroxide salts, choline salts, deanol salts, diethanolamine salts, diethylamine salts, 2-(diethylamino)ethanol salts, ethanolamine salts, ethylenediamine salts, N-methylglucamine salts, hydrabamine salts, IH-imidazole salts, lithium salts, L-lysine salts, magnesium salts, 4-(2-hydroxyethyl)morpholine salts,piperazine salts, potassium salts, l-(2-hydroxyethyl)pyrrolidine salts, sodium salts, triethanolamine salts, tromethamine salts, Na salts, Ca salts, K salts, Mg salts, and Zn salts.In specific embodiments, the pharmaceutically acceptable salt is a solvate selected from the group consisting of water, methanol, ethanol, and dimethylformamide.5          In certain embodiments the compound is a pharmaceutical composition including apharmaceutically acceptable carrier or excipient.In specific embodiments, the composition is in a form selected from the group consisting of a tablet, a capsule, a granule, a lyophile for reconstitution, a powder, a solution, a syrup, a suppository, an injection, atransdermal delivery system, and a solution 10 suitable for topical administration.Methods of UseProvided herein are methods of treating cancer comprising administering a compound of the disclosure, such as a compound of Formula (I), or an enantiomer, a mixture of enantiomers, or a tautomer thereof, or a pharmaceutically acceptable salt thereof.Cancer is a disease of uncontrolled cell proliferation that results from alterations in certain genes. Some of these alterations occur in genes that encode receptor tyrosine kinases (RTKs), a family of membrane-bound proteins that transmit signals from outside the cell to promote cell survival, growth, and proliferation. Aberrant RTK activation can lead to excessive cell growth and hence cancer. Generally, RTKs contain an N-terminal domain that binds extracellular ligands, a transmembrane domain, and a C-terminal kinase domain that catalyzes intracellular signal transduction.In some embodiments, the compound of Formula (I) is an inhibitor of human ROS1. ROS 1 is an RTK encoded by the ROS1 gene. The ligands and biological functions of human ROS1 are unknown, but its homologs in some other species have been shown to bind extracellular ligands and stimulate cell differentiation. For example, mouse ROS1 is essential for male gamete maturation and reproduction. In humans, ROS1 chromosomal rearrangements are a well-documented cause of cancer, representing 1-2% of non-small cell lung cancer (NSCLC) and a subset of many other cancers. These rearrangements result in the fusion of the C-terminus of ROS 1 with the N-terminus of various partner proteins, the most common of which is CD74. ROS1 fusions have constitutive kinase activity that drives tumor growth through MAPK, PI3K, and JAK / STAT signaling pathways. Smallmolecule tyrosine kinase inhibitors (TKIs) have been used to target ROS 1 fusions in cancer, including crizotinib and entrectinib. Crizotinib was the first FDA-approved TKI for the treatment of ROS 1-positive NSCLC, with an overall response rate of 60-80% and median progression-free survival of 9-19 months. Despite an initial response, most patients acquire resistance to crizotinib and relapse. The predominant mechanism of resistance is the G2032R mutation in the solvent front, which dramatically reduces crizotinib affinity. No inhibitors with activity against ROS1-G2032R fusions have been FDA-approved, indicating a need in the art.In some embodiments, the compound of Formula (I) is an inhibitor of human anaplastic lymphoma kinase (ALK). ALK, also known as cluster of differentiation 246 (CD246), is an RTK encoded by the AZA? gene. ALK and ROS1 are evolutionarily related; both belong to the insulin receptor superfamily, and their kinase domains share around 80%sequence similarity. A few ALK ligands in humans have been identified, including pleiotrophin and midkine growth factors. While the roles of ALK in humans remain inconclusive, much evidence from mouse studies suggests that it is important for the development of the nervous system. Like ROS1, ALK chromosomal rearrangements also lead to constitutively active fusion proteins that promote oncogenic transformation through MAPK, JAK / STAT, or other signaling pathways. ALK rearrangements represent 3-5% of NSCLC, roughly half of anaplastic large-cell lymphoma (ALCL), and a subset of many other cancers, with the predominant fusions being EML4-ALK for NSCLC and NPM1-ALK for ALCL. Oncogenic point mutations and amplification of ALK have also been observed, albeit at a much lower frequency than translocations. Crizotinib, ceritinib, alectinib, brigatinib, and lorlatinib are FDA-approved TKIs for the treatment of ALK-positive NSCLC and other cancers, either in front-line or after prior therapy. Crizotinib, for example, shows an overall response rate of 60-80% and median progression-free survival of 8-11 months, which is comparable to its activity in ROS 1-positive NSCLC. Despite an initial response, many resistance mutations have emerged to the aforementioned FDA-approved TKIs. Some of these mutations, such as the combined L1196M gatekeeper and G1202R solvent front mutation, are resistant to all of the approved drugs. New treatments of ALK-positive cancer harboring resistance mutations are a need in the art.In further embodiments, the compound of Formula (I) is an inhibitor of human tropomyosin receptor kinases (TRKs). The TRK family comprises receptor tyrosine kinases TRKA, TRKB, and TRKC, which are encoded by the NTRK1, NTRK2, and NTRK3 genes, respectively. Each TRK is activated by a different but overlapping set of neurotrophin ligands such as NGF, BDNF, and NT-3. All TRKs modulate similar downstream signaling pathways, consistent with sequence divergence in the ligand-binding domain but convergence in the kinase domain (90% similarity). TRKs play crucial roles in the nervous system of developing and adult mammals by regulating processes such as memory, movement, pain, and proprioception. Like ROS1 and ALK. NTRK rearrangements lead to constitutively active TRK fusions that drive oncogenic transformation through MAPK, PI3K, and other pathways. TRK fusions are found in many cancers and represent over 80% of the cases in secretory breast carcinoma, mammary analogue secretory carcinomas, infantile fibrosarcoma, and congenital mesoblastic nephroma. Thus, inhibition of TRKs is advantageous for treating cancers expressing TRK fusions.Many R0S1 and ALK inhibitors in the prior art also exhibit potent inhibition of native non-oncogenic TRKs. This is a substantial drawback because native TRKs play important functions in the nervous system, and inadvertent inhibition of native TRKs is associated with adverse reactions including dizziness, ataxia, gait disturbance, paraesthesia, weight gain, and cognitive changes. New therapies that spare TRKs while selectively targeting ROS1 and / or ALK, in their non-mutant and / or mutant forms, are a need in the art.In one embodiment, provided herein is a method of decreasing a level of ROS1 or ALK in a cell, comprising contacting the cell with a compound or a pharmaceutical composition or a pharmaceutical combination provided herein. In an embodiment, such contact occurs in a cell in a mammal such as a human. In an embodiment, such contact occurs in a cell in human patient having a cancer provided herein.In one embodiment, a compound provided herein selectively inhibits ROS1. In one embodiment, the compound selectively inhibits ROS1 over ALK. By way of nonlimiting example, the ratio of selectivity can be greater than a factor of about 1.5, greater than a factor of about 2, greater than a factor of about 3, greater than a factor of about 4, greater than a factor of about 5, greater than a factor of about 10, greater than a factor of about 20, greater than a factor of about 30, greater than a factor of about 50, or greater than a factor of about 100, where selectivity can be measured by ratio of IC50 values, among other means. In one embodiment, the selectivity of ROS 1 over ALK is measured by the ratio of the IC50 value against ALK to the IC50 value against ROS1.In one embodiment, the compound selectively inhibits ROS1 over TRK (e.g., TRKA, TRKB, and / or TRBC). By way of non-limiting example, the ratio of selectivity can be greater than a factor of about 5, greater than a factor of about 10, greater than a factor of about 50, greater than a factor of about 100, greater than a factor of about 200, greater than a factor of about 400, greater than a factor of about 600, greater than a factor of about 800, greater than a factor of about 1000, greater than a factor of about 1500, greater than a factor of about 2000, greater than a factor of about 5000, greater than a factor of about 10,000, or greater than a factor of about 20,000, where selectivity can be measured by ratio of IC50 values, among other means. In one embodiment, the selectivity of ROS 1 over TRK is measured by the ratio of the IC50 value against TRK to the IC50 value against ROS1.In one embodiment, a compound provided herein selectively inhibits ALK. In one embodiment, the compound selectively inhibits ALK over ROS1. By way of nonlimiting example, the ratio of selectivity can be greater than a factor of about 1.5, greater than a factor of about 2, greater than a factor of about 3, greater than a factor of about 4, greater than a factor of about 5, or greater than a factor of about 10, where selectivity can be measured by ratio of IC50 values, among other means. In one embodiment, the selectivity of ALK over ROS1 is measured by the ratio of the IC50 value against ROS1 to the IC50 value against ALK.In one embodiment, the compound selectively inhibits ALK over TRK (e.g., TRKA, TRKB, and / or TRBC). By way of non-limiting example, the ratio of selectivity can be greater than a factor of about 5, greater than a factor of about 10, greater than a factor of about 50, greater than a factor of about 100, greater than a factor of about 200, greater than a factor of about 400, greater than a factor of about 600, greater than a factor of about 800, greater than a factor of about 1000, greater than a factor of about 1500, greater than a factor of about 2000, greater than a factor of about 5000, or greater than a factor of about 10,000, where selectivity can be measured by ratio of IC50 values, among other means. In one embodiment, the selectivity of ALK over TRK is measured by the ratio of the IC50 value against TRK to the IC50 value against ALK.In one embodiment, the compound selectively inhibits ROS1 and ALK over TRK (e.g., TRKA, TRKB, and / or TRBC). By way of non-limiting example, the ratio of selectivity can be greater than a factor of about 5, greater than a factor of about 10, greater than a factor of about 50, greater than a factor of about 100, greater than a factor of about 200, greater than a factor of about 400, greater than a factor of about 600, greater than a factor of about 800, greater than a factor of about 1000, greater than a factor of about 1500, greater than a factor of about 2000, greater than a factor of about 5000, greater than a factor of about 10,000, or greater than a factor of about 20,000, where selectivity can be measured by ratio of IC50 values, among other means. In one embodiment, the selectivity of ROS 1 and ALK over TRK is measured by the ratio of the IC50 value against TRK to the IC50 value against ROS1 and ALK.In one embodiment, provided herein is a method for selectively inhibiting ROS1 over ALK wherein the inhibition takes place in a cell. In one embodiment, provided herein is a method for selectively inhibiting ROS1 over TRK (e.g., TRKA, TRKB, and / or TRBC) wherein the inhibition takes place in a cell. In one embodiment, the method comprises contacting ROS1 with an effective amount of a compound provided herein. In an embodiment, such contact occurs in a cell. In an embodiment, such contact occurs in acell in a mammal such as a human. In an embodiment, such contact occurs in a cell in human patient having a cancer provided herein.In one embodiment, provided herein is a method for selectively inhibiting ROS1 over ALK wherein the inhibition takes place in a subject suffering from cancer, said method comprising administering an effective amount of a compound or a pharmaceutical composition provided herein to said subject. In certain embodiments, provided herein is a method of treating a subject suffering from a cancer associated with ROS1, said method comprising selectively inhibiting ROS1 over ALK by administering an amount of a compound or a pharmaceutical composition provided herein to said subject, wherein said amount is sufficient for selective inhibiting ROS1 over ALK.In one embodiment, provided herein is a method for selectively inhibiting ROS1 over TRK (e.g., TRKA, TRKB, and / or TRBC) wherein the inhibition takes place in a subject suffering from cancer, said method comprising administering an effective amount of a compound or a pharmaceutical composition provided herein to said subject. In certain embodiments, provided herein is a method of treating a subject suffering from a cancer associated with ROS1, said method comprising selectively inhibiting ROS1 over TRK (e.g., TRKA, TRKB, and / or TRBC) by administering an amount of a compound or a pharmaceutical composition provided herein to said subject, wherein said amount is sufficient for selective inhibiting ROS1 over TRK (e.g., TRKA, TRKB, and / or TRBC).In one embodiment, provided herein is a method for selectively inhibiting ALK over ROS1 wherein the inhibition takes place in a cell. In one embodiment, provided herein is a method for selectively inhibiting ALK over TRK (e g., TRKA, TRKB, and / or TRBC) wherein the inhibition takes place in a cell. In one embodiment, the method comprises contacting ALK with an effective amount of a compound provided herein. In an embodiment, such contact occurs in a cell. In an embodiment, such contact occurs in a cell in a mammal such as a human. In an embodiment, such contact occurs in a cell in human patient having a cancer provided herein.In one embodiment, provided herein is a method for selectively inhibiting ALK over ROS1 wherein the inhibition takes place in a subject suffering from cancer, said method comprising administering an effective amount of a compound or a pharmaceutical composition provided herein to said subject. In certain embodiments, provided herein is a method of treating a subject suffering from a cancer associated with ALK, said method comprising selectively inhibiting ALK over ROS1 by administering an amount of acompound or a pharmaceutical composition provided herein to said subject, wherein said amount is sufficient for selective inhibiting ALK over ROS1.In one embodiment, provided herein is a method for selectively inhibiting ALK over TRK (e.g., TRKA, TRKB, and / or TRBC) wherein the inhibition takes place in a subject suffering from cancer, said method comprising administering an effective amount of a compound or a pharmaceutical composition provided herein to said subject. In certain embodiments, provided herein is a method of treating a subject suffering from a cancer associated with ALK, said method comprising selectively inhibiting ALK over TRK (e.g., TRKA, TRKB, and / or TRBC) by administering an amount of a compound or a pharmaceutical composition provided herein to said subject, wherein said amount is sufficient for selective inhibiting ALK over TRK (e.g., TRKA, TRKB, and / or TRBC).As used herein and unless otherwise specified, inhibition of ROS1 includes inhibition of wild type ROS1, or a mutation thereof; inhibition of ALK includes inhibition of wild type ALK, or a mutation thereof; and inhibition of TRK includes inhibition of wild type TRK, or a mutation thereof.Cancers treated by methods of the present disclosure include, but are not limited to, lung cancer, e.g., non-small cell lung cancer, inflammatory myofibroblastic tumor, ovarian cancer, e.g., serous ovarian carcinoma, melanoma, e.g., spitzoid melanoma, glioblastoma, bile duct cancer, e.g., cholangiocarcinoma, gastric cancer, colorectal cancer, angiosarcoma, anaplastic large cell lymphoma, diffuse large B-cell lymphoma, large B-cell lymphoma, esophageal cancer, e.g., esophageal squamous cell carcinoma, kidney cancer, e.g., renal medullary carcinoma or renal cell carcinoma, breast cancer, e.g., triple negative breast cancer, thyroid cancer, e.g., papillary thyroid cancer, neuroblastoma, epithelioid hemangioendothelioma, colon cancer, and spitzoid tumor.Cancers treated by methods of the present disclosure include cancers originating from one or more oncogenic proteins selected from ROS1, ALK, TRKA, TRKB, and TRKC. In certain embodiments, cancers treated by methods of the present disclosure include cancers that are drug resistant to treatments directed at one or more oncogenic proteins selected from ROS1, ALK, TRKA, TRKB, and TRKC.In one embodiment, the cancer in a method provided herein is anaplastic lymphoma kinase positive (ALK+). As used herein and unless otherwise specified, an “ALK positive” (ALK+) cancer, disease, or disorder refers to a cancer, disease, or disorder characterized by inappropriately high expression of an ALK gene and / or the presence of a mutation in anALK gene. In one embodiment, the mutation alters the biological activity of an ALK nucleic acid molecule or polypeptide. As used herein and unless otherwise specified, a “mutation” or “mutant” of ALK comprises one or more deletions, substitutions, insertions, inversions, duplications, translocations, or amplifications in the amino acid or nucleotide sequences of ALK, or fragments thereof. As used herein and unless otherwise specified, an ALK “rearrangement” refers to genetic translocations involving the ALK gene that may result in ALK fusion genes and / or ALK fusion proteins. The ALK fusion can also include one or more deletions, substitutions, insertions, inversions, duplications, translocations, or amplifications or a fragment thereof, as long as the mutant retains kinase phosphorylation activity.In one embodiment, the ALK mutation comprises one or more ALK point mutations. In some embodiments, cancers treated by methods of the present disclosure include one or more mutations in ALK kinase. In one embodiment, the one or more ALK point mutations are selected from point mutations at LI 152, Cl 156, Il 171, Fl 174, VI180, LI 196, LI 198, G1202, D1203, S1206, E1210, F1245, G1269, and R1275. In one embodiment, the one or more ALK point mutations are selected from G1202R, G1202K, L1196M, G1269A, C1156Y, I1171T, I1171N, I1171S, F1174L, V1180L, S1206Y, E1210K, 1151Tins, F1174C, G1202del, D1203N, S1206Y, S1206C, L1152R, L1196Q, LI 198P, L1198F, R1275Q, LI 152P, Cl 156T, and F1245V. In one embodiment, the ALK mutation is G1202R. In one embodiment, the ALK mutation is L1196M. In one embodiment, the ALK mutation is G1269A. In one embodiment, the ALK mutation is L1198F. In one embodiment, the ALK mutation is co-mutation of G1202R and one or more mutations selected from L1196M, G1269A, and L1198F. In one embodiment, the ALK mutation is G1202R / L1196M dual mutation. In one embodiment, the ALK mutation is G1202R / G1269A dual mutation. In one embodiment, the ALK mutation is G1202R / L1198F dual mutation.In one embodiment, the ALK mutation comprises one or more ALK rearrangements (in one embodiment, one rearrangement). In one embodiment, the ALK mutation comprises one or more ALK fusions (in one embodiment, one fusion). In some embodiments, cancers treated by methods of the present disclosure include ALK fusions. In one embodiment, the ALK fusion is with one of the fusion partners selected from EML4, TMP1, WDCP, GTF2IRD1, TPM3, TPM4, CLTC, BANA, PRKAR1A, RANBP2, TFG, FNJ, KLC1, VCL, STRN, HIP1, NPM1, DCTN1, SQSTM1, TPR, CRIM1, PTPN3, FBXO36,ATIC and KIF5B. In one embodiment, the ALK mutation is EML4-ALK, a fusion between the echinoderm microtubule-associated protein-like 4 (EML4) gene and the ALK tyrosine kinase domain. There are many variants of EML4-ALK that differ by breakpoint junctions, with variant 1 (vl) and variant 3 (v3) being the most prevalent clinically.In one embodiment, the ALK mutation comprises one ALK rearrangement and one or more ALK point mutations. In one embodiment, the ALK mutation is EML4-ALK wt (variant 1). In one embodiment, the ALK mutation is EML4-ALK G1202R (variant 1). In one embodiment, the ALK mutation is EML4-ALK LI 196M / G1202R(variant 1). In one embodiment, the ALK mutation is EML4-ALK G1202R / G1269A(variant 1). In one embodiment, the ALK mutation is EML4-ALK G1202R / L1198F(variant 1).In one embodiment, the ALK+ cancer is determined by an FDA-approved test or other tests known in the art. The tests that can be used include, e.g., FoundationOne CDx™ (FICDx) (a sequencing based in vitro diagnostic device for detection of substitutions, insertion and deletion alterations (indels), and copy number alterations (CNAs) in 324 genes and select gene rearrangements, as well as genomic signatures including microsatellite instability (MSI) and tumor mutational burden (TMB) using DNA isolated from formalin-fixed paraffin embedded (FFPE) tumor tissue specimens); VENTANA ALK (D5F3) CDx Assay (qualitative detection of the anaplastic lymphoma kinase (ALK) protein in formalin-fixed, paraffin-embedded (FFPE) non-small cell lung carcinoma (NSCLC) tissue stained with the BenchMark XT or BenchMark ULTRA automated staining instrument); and Vysis ALK Break Apart FISH Probe Kit test (a qualitative test to detect rearrangements involving the ALK gene via fluorescence in situ hybridization (FISH) in formalin-fixed, paraffin-embedded (FFPE) non-small cell lung cancer (NSCLC) tissue specimens). In one embodiment, the test is a fluorescence in situ hybridization (FISH) test, e.g., Vysis ALK Break Apart FISH Probe Kit test. Additional information for FDA-approved         tests         can         be         found         at,         e.g.,https: / / www.fda.gov / MedicalDevices / ProductsandMedicalProcedures / InVitroDiagnostics / ucm303030.htm; and additional information for Vysis ALK Break Apart FISH Probe Kit can be found at, e.g., https: / / www.molecular.abbott / us / en / products / oncology / vysis-alk-break-apart-fish-probe-kit; the entirety of which are incorporated herein by reference.Also provided are methods of treating a subject having a cancer (e.g., a ALK positive cancer) that include: determining whether a cancer cell in a sample obtained froma subject having a cancer and previously administered a first ALK inhibitor, has one or more ALK inhibitor resistance mutations; and administering a compound of Formula (I) or a pharmaceutically acceptable salt or solvate thereof as a monotherapy or in combination with another anticancer agent to the subject if the subject has a cancer cell that has one or more ALK inhibitor resistance mutations. In some embodiments, the one or more ALK inhibitor resistance mutations confer increased resistance to a cancer cell or tumor to treatment with the first ALK inhibitor. In some embodiments, the one or more ALK inhibitor resistance mutations include one or more ALK inhibitor resistance mutations. For example, the one or more .ALK inhibitor resistance mutations can include a substitution at one or more of amino acid positions 1202, 1196, 1269, 1156, 1171, 1174, 1180, 1206, 1210, 1151, 1174, 1203, 1206, 1152, 1196, 1198, 1275, 1152, 1156, and 1245, e g., G1202R, L1196M, G1269A, C1156Y, Il 171T, I1171N, I1171S, F1174L, V1180L, S1206Y, E1210K, 1151Tins, F1174C, G1202del, D1203N, S1206Y, S1206C, L1152R, L1196Q, L1198P, L1198F, R1275Q, L1152P, C1156T, andF1245V. In some embodiments, another anticancer agent is any anticancer agent known in the art. For example, another anticancer agent can be another ALK inhibitor (e.g., a second ALK inhibitor).In one embodiment, the cancer in a method provided herein is ROS1 positive (ROS1+). As used herein and unless otherwise specified, a “ROS1 positive” (ROS1+) cancer, disease, or disorder refers to a cancer, disease, or disorder characterized by inappropriately high expression of a ROS1 gene and / or the presence of a mutation in a ROS1 gene. In one embodiment, the mutation alters the biological activity of a ROS1 nucleic acid molecule or polypeptide. As used herein and unless otherwise specified, a “mutation” or “mutant” of ROS 1 comprises one or more deletions, substitutions, insertions, inversions, duplications, translocations, or amplifications in the amino acid or nucleotide sequences of ROS 1, or fragments thereof. As used herein and unless otherwise specified, a ROS1 “rearrangement” refers to genetic translocations involving the ROS1 gene that may result in ROS1 fusion genes and / or ROS1 fusion proteins. The ROS1 fusion can also include one or more deletions, substitutions, insertions, inversions, duplications, translocations, or amplifications or a fragment thereof, as long as the mutant retains kinase phosphorylation activity.In one embodiment, the ROS1 mutation comprises one or more ROS1 point mutations. In some embodiments, cancers treated by methods of the present disclosureinclude one or more mutations in ROS1 kinase. In one embodiment, the one or more ROS1 point mutations are selected from point mutations at E1935, L1947, L1951, G1971, E1974, L1982, S1986, F2004, E2020, L2026, G2032, D2033, C2060, F2075, L2086, V2089, V2098, G2101, D2113, and L2155. In one embodiment, the one or more ROS1 point mutations are selected from G2032R, G2032K, D2033N, S1986F, S1986Y, L2026M, L1951R, E1935G, L1947R, G1971E, E1974K, L1982F, F2004C, F2004V, E2020K, C2060G, F2075V, V2089M, V2098I, G2101A, D2113N, D2113G, L2155S, andL2086F.. In one embodiment, the ROS1 mutation is G2032R. In one embodiment, the ROS1 mutation is S1986F. In one embodiment, the ROS1 mutation is S1986Y. In one embodiment, the ROS1 mutation is L2026M. In one embodiment, the ROS1 mutation is D2033N. In one embodiment, the ROS1 mutation is L2086F. In one embodiment, the ROS1 mutation is F2004C. In one embodiment, the ROS1 mutation is F2004V. In one embodiment, the ROS1 mutation is G2101A. In one embodiment, the ROS1 mutation is L1982F. In one embodiment, the ROS1 mutation is co-mutation of G2032R and one or more of S1986F, S1986Y, F2004C, F2004V, L2026M, or D2033N.In one embodiment, the ROS1 mutation comprises one or more ROS1 rearrangements (in one embodiment, one rearrangement). In one embodiment, the ROS1 mutation comprises one or more ROS1 fusions (in one embodiment, one fusion). In some embodiments, cancers treated by methods of the present disclosure include ROS1 fusions. In one embodiment, the ROS1 fusion is with one of the fusion partners selected from SLC34A2, CD74, TPMS, SDC4, EZR, LRIG3, KDELR2, CEP72, CLIP, CTNND2, GOPC (e.g., GOPC-S, GOPC-L), GPRC6A, LIMA1, LRIG3, MSN, MYO5C, 0PRM1, SLC6AJ7 SLMAP, SRSF6, TEG, TMEM106B, TPD52L1, ZCCHC8,CCDC6,CAPRIN1, CEP85L, CHCHD3, CLIP1, EEF1G, KIF21A, KLC1, SART3, STI3, TRIM24, ERC1, FIP1L1, HLAA, K1AA1598, MYO5A, PPFIBP1, PWWP2A, FN1, YWHAE, CCDC30, NCOR2, NFKB2, APOB, PLG, RBP4, and GOLGB1. In one embodiment, the ROS1 fusion is CD74-ROS1 fusion. In one embodiment, the ROS1 fusion is SDC4-ROS1 fusion. In one embodiment, the ROS1 fusion is EZR-ROS1 fusion. In one embodiment, the ROS1 fusion is SLC34A2-ROS1 fusion. In one embodiment, the ROS1 fusion is GOPC-ROS1 fusion (e.g., GOPC-ROS1-S, GOPC-ROS1-L). In one embodiment, the ROS1 fusion is CEP85L-ROS1 fusionIn one embodiment, the ROS1 mutation comprises one ROS1 rearrangement and one or more ROS1 point mutations. In one embodiment, the ROS1 mutation comprisesone ormoreROSl rearrangements from CD74-ROS1, EZR-ROS1, SLC34A2-ROS1, GOPC-ROS1 (e.g., GOPC-ROS1-S, GOPC-ROS1-L), and CEP85L-ROS1, and one or more ROS1 point mutations selected from F2004C, F2004V, and G2032R. In one embodiment, the ROS1 mutation comprises one or more ROS1 rearrangements from CD74-ROS1, EZR-ROS1, and SLC34A2-ROS1, and ROS1 point mutation of G2101 A.In one embodiment, the ROS1 mutation is CD74-ROS1 F2004C. In one embodiment, the ROS1 mutation is CD74-ROS1 F2004V. In one embodiment, the ROS1 mutation is CD74-ROS1 G2101A. In one embodiment, the ROS1 mutation is CD74-ROS1 G2032R. In one embodiment, the ROS1 mutation is CD74-ROS1 S1986F. In one embodiment, the ROS1 mutation is CD74-ROS1 L2026M. In one embodiment, the ROS1 mutation is CD74-ROS1 D2033N. In one embodiment, the ROS1 mutation is EZR-ROS1 F2004C. In one embodiment, the ROS1 mutation is EZR-ROS1 F2004V. In one embodiment, the ROS1 mutation is EZR-ROS1 G2101A. In one embodiment, the ROS1 mutation is EZR-ROS1 G2032R. In one embodiment, the ROS1 mutation is SLC34A2-ROS1 F2004C. In one embodiment, the ROS1 mutation is SLC34A2-ROS1 F2004V. In one embodiment, the ROS1 mutation is SLC34A2-ROS1 G2101A. In one embodiment, the ROS1 mutation is SLC34A2-ROS1 G2032R. In one embodiment, the ROS1 mutation is GOPC-ROS1 F2004C (e.g., GOPC-ROS1-S F2004C, GOPC-ROS1-L F2004C). In one embodiment, the ROS1 mutation is GOPC-ROS1 F2004V (e.g., GOPC-ROS1-S F2004V, GOPC-ROS1-L F2004V). In one embodiment, the ROS1 mutation is GOPC-ROS1 G2032R (e.g., GOPC-ROS1-S G2032R, GOPC-ROS1-L G2032R). In one embodiment, the ROS1 mutation is CEP85L-ROS1 F2004C. In one embodiment, the ROS1 mutation is CEP85L-ROS1 F2004V. In one embodiment, the ROS1 mutation is CEP85L-ROS1 G2032R. In one embodiment, the ROS1 mutation is GOPC-ROS1 L1982F (e.g., GOPC-ROS1-S L1982F, GOPC-ROS1-L L1982F). In one embodiment, the ROS1 mutation is CD74-ROS1 L1982F.In one embodiment, the ROS1+ cancer is determined by an FDA-approved test or other tests known in the art. The tests that can be used include, e.g., Oncomine™ Dx Target Test by Thermo Fisher Scientific, (a qualitative in vitro diagnostic test that uses targeted high-throughput, parallel-sequencing technology to detect sequence variations in 23 genes in DNA and RNA isolated from formalin-fixed, paraffin-embedded tumor (FFPE) tissue samples from patients with non-small cell lung cancer (NSCLC) using the Ion PGM Dx System); Vysis ROS1 Break Apart FISH Probe Kit (a qualitative test to detectrearrangements involving R0S1 gene rearrangements at 6q22 via fluorescence in situ hybridization (FISH) in formalin-fixed, paraffin-embedded (FFPE) non-small cell lung cancer (NSCLC) tissue specimens) or RTReal Time-Polymerase Chain Reaction (RT-PCR) or NGSNext Generation Sequencing via a local diagnostic test.Also provided are methods of treating a subject having a cancer (e.g., a ROS1 positive cancer) that include: determining whether a cancer cell in a sample obtained from a subject having a cancer and previously administered a first ROS1 inhibitor, has one or more ROS1 inhibitor resistance mutations; and administering a compound of Formula (I) or a pharmaceutically acceptable salt or solvate thereof as a monotherapy or in conjunction with another anticancer agent to the subject if the subject has a cancer cell that has one or more ROS1 inhibitor resistance mutations. In some embodiments, the one or more ROS1 inhibitor resistance mutations confer increased resistance to a cancer cell or tumor to treatment with the first ROS1 inhibitor. In some embodiments, the one or more ROS1 inhibitor resistance mutations include one or more ROS1 inhibitor resistance mutations. For example, the one or more ROS1 inhibitor resistance mutations can include a substitution at one or more of amino acid positions 2032, 2033, 1986, 2026, 1951, 1935, 1947, 1971, 1974, 1982, 2004, 2020, 2060, 2075, 2089, 2098, 2101, 2113, 2155, 2032, and 2086, e.g., G2032R, D2033N, S1986F, S1986Y, L2026M, L1951R, E1935G, L1947R, G1971E, E1974K, L1982F, F2004C, F2004V, E2020K, C2060G, F2075V, V2089M, V2098I, G2101A, D2113N, D2113G, L2155S, L2032K, and L2086F. In some embodiments, another anticancer agent is any anticancer agent known in the art. For example, another anti cancer agent can be another ROS1 inhibitor (e.g., a second ROS1 inhibitor).In one embodiment, a compound provided herein is a CNS-penetrating compound. In one embodiment, after the administration of an effective amount of a compound provided herein (e.g., orally or intravenously), the compound is able to penetrate CNS (e.g., blood-brain barrier) and achieve a concentration in CNS (e.g., brain) that is still sufficient to inhibit (e.g., selectively inhibit) ROS1 or ALK or both.In one embodiment, provided herein is a method for treating CNS metastases of a cancer, comprising administering to a subject in need thereof an effective amount of a compound provided herein, e g., a compound of Formula (I), or an enantiomer, a mixture of enantiomers, or a tautomer thereof, or a pharmaceutically acceptable salt thereof. Inone embodiment, the CNS metastases is brain metastases. In one embodiment, the cancer is a ROS1+ cancer. In one embodiment, the cancer is an ALK+ cancer.In some embodiments, the compound is an inhibitor of human tropomyosin receptor kinase A, B, or C. In certain embodiments, the IC50 of the compound for inhibition of mutant or non-mutant ROS1 or ALK is no more than one-fifth of the IC50 of the compound for inhibition of wild-type tropomyosin receptor kinase A, B, or C. TRK inhibition, particularly in the central nervous system (CNS), has been associated with adverse reactions, including dizziness / ataxia / gait disturbance, paraesthesia, weight gain and cognitive changes.In some embodiments, provided is a method of minimizing adverse events in a subject in need of treatment for cancer (e.g., a ROS1 positive cancer or an ALK positive cancer), the method comprising administering to the subject a therapeutically effective amount of a compound provided herein, e.g., a compound of Formula (I), an enantiomer, a mixture of enantiomers, or a tautomer thereof, or a pharmaceutically acceptable salt thereof, and wherein the method minimizes adverse events associated with TRK inhibitors. In some embodiments, the cancer is a ROS 1-associated cancer or an ALK-associated (or ALK+) cancer. In some embodiments, the adverse events are TRK-related CNS adverse events.As used herein “minimizing” adverse events refers to a reduction in the incidence of adverse events in a subject or patient population compared to the paradigmatic incidence of adverse events in a subject or patient population treated with TRK inhibitors (e.g., entrectinib, repotrectinib, or lorlatinib). In some embodiments, the incidence of an adverse event refers to the frequency or percentage of a specific adverse event over a subject or patient population. In some embodiments, the incidence of an adverse event refers to the total number of adverse events experienced by an individual subject. In some embodiments, minimizing adverse events refers to minimizing TRK-related CNS adverse events. In some embodiments, minimizing TRK-related CNS adverse events means less than 40% of the patient population has a TRK-related CNS adverse event. In some embodiments, minimizing TRK-related CNS adverse events means less than 35%, less than 30%, less than 25%, less than 20%, less than 15%, less than 10% or less than 5% of the patient population has a TRK-related CNS adverse event. In some embodiments, minimizing TRK-related CNS adverse events means less than 12% of the patient population have more than one TRK-related CNS adverse event. In someembodiments, minimizing TRK-related CNS adverse events means less than 11%, less than 10%, less than 9%, less than 8%, less than 7%, less than 6%, less than 5%, less than 4%, or less than 3% of the patient population have more than one TRK-related CNS adverse event.In some embodiments, TRK-related CNS adverse events refers to one or more of the following: dizziness, ataxia, gait disturbance, paraesthesia, weight gain, hyperphagia, paresthesias, abnormal movement, cognitive changes, speech effects (e.g, dysarthria, slow speech, or speech disorder), mood disorder (e.g., irritability, anxiety, depression, affect lability, personality change, mood swings, affective disorder, aggression, agitation, mood altered, depressed mood, euphoric mood, or mania), and cognitive disorder (e.g., memory impairment, cognitive disorder, amnesia, confusion, disturbance in attention, delirium, mental impairment, attention deficit / hyperactivity disorder, dementia, or reading disorder).In one embodiment, provided herein is a method for preventing or limiting TRK-related CNS side effect or adverse event in a cancer treatment, comprising administering to a subject in need thereof an effective amount of a compound provided herein, e.g., a compound of Formula (I), or an enantiomer, a mixture of enantiomers, or a tautomer thereof, or a pharmaceutically acceptable salt thereof. In one embodiment, the method prevents the occurance of the TRK-related CNS adverse event. In one embodiment, the method limits the frequency of occurance of the TRK-related CNS adverse event. In one embodiment, the method limits the severity of the TRK-related side effect. In one embodiment, provided herein is a method for treating CNS metastases of a cancer with reduced TRK-related side effect, comprising administering to a subject in need thereof an effective amount of a compound provided herein, e.g., a compound of Formula (I), or an enantiomer, a mixture of enantiomers, or a tautomer thereof, or a pharmaceutically acceptable salt thereof. In one embodiment, the reduction / limiting / prevention in CNS side effect or adverse event is determined in a statistical sample, as compared to a standard of care treatment, e.g., an approved ROS1 and / or ALK inhibitor (e.g., crizotinib, entrectinib, lorlatinib, or repotrectinib) for ROS1+ and / or ALK+ cancer. In one embodiment, the TRK-related side effect is a TRKB-related CNS side effect. In one embodiment, the TRK-related CNS side effect or adverse event is dizziness, ataxia, gait disturbance, paraesthesia, weight gain, cognitive impairment, a mood disorder, or sleep disturbance.In one embodiment, provided herein is a method for treating cancer, comprising administering to a subject in need thereof a therapeutically effective amount of a compound provided herein, e.g., a compound of Formula (I), or an enantiomer, a mixture of enantiomers, or a tautomer thereof, or a pharmaceutically acceptable salt thereof. In one embodiment, the cancer is a ROS 1-associated cancer. In one embodiment, the cancer is a ROS1+ cancer. In one embodiment, the cancer is an ALK-associated cancer. In one embodiment, the cancer is an ALK+ cancer. In one embodiment, the cancer is identified to be ROS1+. In one embodiment, the cancer is identified to be ALK+.In one embodiment, provided herein is a method for treating a ROS1+ cancer, comprising administering to a subject in need thereof a therapeutically effective amount of a compound provided herein, e.g., a compound of Formula (I), or an enantiomer, a mixture of enantiomers, or a tautomer thereof, or a pharmaceutically acceptable salt thereof.In one embodiment, provided herein is a method for treating an ALK+ cancer, comprising administering to a subject in need thereof a therapeutically effective amount of a compound provided herein, e.g., a compound of Formula (I), or an enantiomer, a mixture of enantiomers, or a tautomer thereof, or a pharmaceutically acceptable salt thereof.In one embodiment, provided herein is a method for treating cancer in a subject, comprising: (i) identifying the cancer in the subject to be ROS1+, and (ii) administering to the subject a therapeutically effective amount of a compound provided herein, e.g., a compound of Formula (I), or an enantiomer, a mixture of enantiomers, or a tautomer thereof, or a pharmaceutically acceptable salt thereof.In one embodiment, provided herein is a method for treating cancer in a subject, comprising: (i) identifying the cancer in the subject to be ALK+, and (ii) administering to the subject a therapeutically effective amount of a compound provided herein, e.g., a compound of Formula (I), or an enantiomer, a mixture of enantiomers, or a tautomer thereof, or a pharmaceutically acceptable salt thereof.In one embodiment, the cancer (or ROS1+ cancer, or ALK+ cancer) is a solid tumor. In one embodiment, the cancer (or ROS1+ cancer, or ALK+ cancer) is lung cancer, e.g., non-small cell lung cancer (NSCLC), glioblastoma, inflammatory myofibroblastic tumor (IMT), bile duct cancer, e.g., cholangiocarcinoma, ovarian cancer, e.g., serous ovarian carcinoma, gastric cancer, colorectal cancer, angiosarcoma,melanoma, e.g., spitzoid melanoma, epithelioid hemangioendothelioma, esophageal cancer, e.g., esophageal squamous cell carcinoma (ESCC), kidney cancer, e.g., renal medullary carcinoma or renal cell carcinoma, breast cancer, e.g., triple negative breast cancer, colon cancer, thyroid cancer, e.g., papillary thyroid cancer, spitzoid tumor, or neuroblastoma.In one embodiment, the cancer is lung cancer. In one embodiment, the cancer is non-small cell lung cancer. In one embodiment, the cancer is ROS1+ non-small cell lung cancer. In one embodiment, the cancer is ALK+ non-small cell lung cancer. In one embodiment, the cancer is relapsed or refractory non-small cell lung cancer. In one embodiment, the cancer is relapsed or refractory ROS 1+ non-small cell lung cancer. In one embodiment, the cancer is relapsed or refractory ALK+ non-small cell lung cancer In one embodiment, the cancer is newly diagnosed non-small cell lung cancer. In one embodiment, the cancer is newly diagnosed ROS 1+ non-small cell lung cancer. In one embodiment, the cancer is newly diagnosed ALK+ non-small cell lung cancer.In one embodiment, the cancer is glioblastoma. In one embodiment, the cancer is ROS1+ glioblastoma. In one embodiment, the cancer is ALK+ glioblastoma. In one embodiment, the cancer is relapsed or refractory glioblastoma. In one embodiment, the cancer is relapsed or refractory ROS1+ glioblastoma. In one embodiment, the cancer is relapsed or refractory ALK+ glioblastoma. In one embodiment, the cancer is newly diagnosed glioblastoma. In one embodiment, the cancer is newly diagnosed ROS1+ glioblastoma. In one embodiment, the cancer is newly diagnosed ALK+ glioblastoma.In one embodiment, the cancer is IMT. In one embodiment, the cancer is ROS1 + IMT. In one embodiment, the cancer is ALK+ IMT. In one embodiment, the cancer is relapsed or refractory IMT. In one embodiment, the cancer is relapsed or refractory ROS1+ IMT. In one embodiment, the cancer is relapsed or refractory ALK+ IMT. In one embodiment, the cancer is newly diagnosed IMT. In one embodiment, the cancer is newly diagnosed ROS1+ IMT. In one embodiment, the cancer is newly diagnosed ALK+ IMT.In one embodiment, the cancer is bile duct cancer. In one embodiment, the cancer is cholangiocarcinoma. In one embodiment, the cancer is ROS1+ cholangiocarcinoma. In one embodiment, the cancer is ALK+ cholangiocarcinoma. In one embodiment, the cancer is relapsed or refractory cholangiocarcinoma. In one embodiment, the cancer is relapsed or refractory ROS1+ cholangiocarcinoma. In one embodiment, the cancer isrelapsed or refractory ALK+ cholangiocarcinoma. In one embodiment, the cancer is newly diagnosed cholangiocarcinoma. In one embodiment, the cancer is newly diagnosed ROS1+ cholangiocarcinoma. In one embodiment, the cancer is newly diagnosed ALK+ cholangiocarcinoma.In one embodiment, the cancer is ovarian cancer. In one embodiment, the cancer is ROS1+ ovarian cancer. In one embodiment, the cancer is ALK+ ovarian cancer. In one embodiment, the cancer is relapsed or refractory ovarian cancer. In one embodiment, the cancer is relapsed or refractory ROS1+ ovarian cancer. In one embodiment, the cancer is relapsed or refractory ALK+ ovarian cancer. In one embodiment, the cancer is newly diagnosed ovarian cancer. In one embodiment, the cancer is newly diagnosed ROS1 + ovarian cancer. In one embodiment, the cancer is newly diagnosed ALK+ ovarian cancer. In one embodiment, the ovarian cancer is serous ovarian carcinoma. In one embodiment, the ovarian cancer is high grade serous ovarian carcinoma.In one embodiment, the cancer is gastric cancer. In one embodiment, the cancer is ROS1+ gastric cancer. In one embodiment, the cancer is ALK+ gastric cancer. In one embodiment, the cancer is relapsed or refractory gastric cancer. In one embodiment, the cancer is relapsed or refractory ROS1+ gastric cancer. In one embodiment, the cancer is relapsed or refractory ALK+ gastric cancer. In one embodiment, the cancer is newly diagnosed gastric cancer. In one embodiment, the cancer is newly diagnosed ROS1+ gastric cancer. In one embodiment, the cancer is newly diagnosed ALIO gastric cancer.In one embodiment, the cancer is colorectal cancer. In one embodiment, the cancer is ROS1+ colorectal cancer. In one embodiment, the cancer is ALIO colorectal cancer. In one embodiment, the cancer is relapsed or refractory colorectal cancer. In one embodiment, the cancer is relapsed or refractory ROS 1 + colorectal cancer. In one embodiment, the cancer is relapsed or refractory ALK+ colorectal cancer. In one embodiment, the cancer is newly diagnosed colorectal cancer In one embodiment, the cancer is newly diagnosed ROS1+ colorectal cancer. In one embodiment, the cancer is newly diagnosed ALK+ colorectal cancer.In one embodiment, the cancer is angiosarcoma. In one embodiment, the cancer is ROS1+ angiosarcoma. In one embodiment, the cancer is ALK+ angiosarcoma. In one embodiment, the cancer is relapsed or refractory angiosarcoma. In one embodiment, the cancer is relapsed or refractory ROS1+ angiosarcoma. In one embodiment, the cancer is relapsed or refractory ALK+ angiosarcoma. In one embodiment, the cancer is newlydiagnosed angiosarcoma. In one embodiment, the cancer is newly diagnosed ROS1 + angiosarcoma. In one embodiment, the cancer is newly diagnosed ALK+ angiosarcoma.In one embodiment, the cancer is melanoma. In one embodiment, the cancer is spitzoid tumor. In one embodiment, the cancer is spitzoid melanoma. In one embodiment, the cancer is ROS1+ spitzoid melanoma. In one embodiment, the cancer is ALK+ spitzoid melanoma. In one embodiment, the cancer is relapsed or refractory spitzoid melanoma. In one embodiment, the cancer is relapsed or refractory ROS1 + spitzoid melanoma. In one embodiment, the cancer is relapsed or refractory ALK+ spitzoid melanoma. In one embodiment, the cancer is newly diagnosed spitzoid melanoma. In one embodiment, the cancer is newly diagnosed ROS1+ spitzoid melanoma. In one embodiment, the cancer is newly diagnosed ALK+ spitzoid melanoma.In one embodiment, the cancer is epithelioid hemangioendothelioma. In one embodiment, the cancer is ROS1+ epithelioid hemangioendothelioma. In one embodiment, the cancer is ALK+ epithelioid hemangioendothelioma. In one embodiment, the cancer is relapsed or refractory epithelioid hemangioendothelioma. In one embodiment, the cancer is relapsed or refractory ROS1+ epithelioid hemangioendothelioma. In one embodiment, the cancer is relapsed or refractory ALK+ epithelioid hemangioendothelioma. In one embodiment, the cancer is newly diagnosed epithelioid hemangioendothelioma. In one embodiment, the cancer is newly diagnosed ROS1+ epithelioid hemangioendothelioma. In one embodiment, the cancer is newly diagnosed ALK+ epithelioid hemangioendothelioma.In one embodiment, the cancer is esophageal cancer. In one embodiment, the cancer is ESCC. In one embodiment, the cancer is ROS1+ ESCC. In one embodiment, the cancer is ALK+ ESCC. In one embodiment, the cancer is relapsed or refractory ESCC. In one embodiment, the cancer is relapsed or refractory ROS1+ ESCC. In one embodiment, the cancer is relapsed or refractory ALK+ ESCC. In one embodiment, the cancer is newly diagnosed ESCC. In one embodiment, the cancer is newly diagnosed ROS1+ ESCC. In one embodiment, the cancer is newly diagnosed ALK+ ESCC.In one embodiment, the cancer is kidney cancer. In one embodiment, the cancer is renal medullary carcinoma. In one embodiment, the cancer is ROS1+ renal medullary carcinoma. In one embodiment, the cancer is ALK+ renal medullary carcinoma. In one embodiment, the cancer is relapsed or refractory renal medullary carcinoma. In oneembodiment, the cancer is relapsed or refractory ROS 1 + renal medullary carcinoma. In one embodiment, the cancer is relapsed or refractory ALK+ renal medullary carcinoma In one embodiment, the cancer is newly diagnosed renal medullary carcinoma. In one embodiment, the cancer is newly diagnosed ROS 1+ renal medullary carcinoma. In one embodiment, the cancer is newly diagnosed ALK+ renal medullary carcinoma. In one embodiment, the cancer is renal cell carcinoma. In one embodiment, the cancer is ROS1+ renal cell carcinoma. In one embodiment, the cancer is ALK+ renal cell carcinoma. In one embodiment, the cancer is relapsed or refractory renal cell carcinoma In one embodiment, the cancer is relapsed or refractory ROS1+ renal cell carcinoma. In one embodiment, the cancer is relapsed or refractory ALK+ renal cell carcinoma. In one embodiment, the cancer is newly diagnosed renal cell carcinoma. In one embodiment, the cancer is newly diagnosed ROS1+ renal cell carcinoma. In one embodiment, the cancer is newly diagnosed ALK+ renal cell carcinoma.In one embodiment, the cancer is breast cancer. In one embodiment, the cancer is ROS1+ breast cancer. In one embodiment, the cancer is ALK+ breast cancer. In one embodiment, the cancer is relapsed or refractory breast cancer. In one embodiment, the cancer is relapsed or refractory ROS1+ breast cancer. In one embodiment, the cancer is relapsed or refractory ALK+ breast cancer. In one embodiment, the cancer is newly diagnosed breast cancer. In one embodiment, the cancer is newly diagnosed ROS1+ breast cancer. In one embodiment, the cancer is newly diagnosed ALK+ breast cancer. In one embodiment, the breast cancer is triple negative breast cancer.In one embodiment, the cancer is colon cancer. In one embodiment, the cancer is ROS1+ colon cancer. In one embodiment, the cancer is ALK+ colon cancer. In one embodiment, the cancer is relapsed or refractory colon cancer. In one embodiment, the cancer is relapsed or refractory ROS1+ colon cancer. In one embodiment, the cancer is relapsed or refractory ALK+ colon cancer. In one embodiment, the cancer is newly diagnosed colon cancer. In one embodiment, the cancer is newly diagnosed ROS1+ colon cancer. In one embodiment, the cancer is newly diagnosed ALK+ colon cancer.In one embodiment, the cancer is thyroid cancer. In one embodiment, the cancer is papillary thyroid cancer. In one embodiment, the cancer is ROS1 + papillary thyroid cancer. In one embodiment, the cancer is ALK+ papillary thyroid cancer. In one embodiment, the cancer is relapsed or refractory papillary thyroid cancer. In one embodiment, the cancer is relapsed or refractory ROS 1 + papillary thyroid cancer. In oneembodiment, the cancer is relapsed or refractory ALK+ papillary thyroid cancer. In one embodiment, the cancer is newly diagnosed papillary thyroid cancer. In one embodiment, the cancer is newly diagnosed ROS1 + papillary thyroid cancer. In one embodiment, the cancer is newly diagnosed ALK+ papillary thyroid cancer.In one embodiment, the cancer is neuroblastoma. In one embodiment, the cancer is ROS1+ neuroblastoma. In one embodiment, the cancer is ALK+ neuroblastoma. In one embodiment, the cancer is relapsed or refractory neuroblastoma. In one embodiment, the cancer is relapsed or refractory ROS1+ neuroblastoma. In one embodiment, the cancer is relapsed or refractory ALK+ neuroblastoma. In one embodiment, the cancer is newly diagnosed neuroblastoma. In one embodiment, the cancer is newly diagnosed ROS1 + neuroblastoma. In one embodiment, the cancer is newly diagnosed ALK+ neuroblastoma.In one embodiment, the cancer (or ROS1+ cancer, or ALK+ cancer) is a hematological cancer. In one embodiment, the cancer (or ROS1+ cancer, or ALK+ cancer) is lymphoma. In one embodiment, the lymphoma is non-Hodgkin lymphoma. In one embodiment, the lymphoma is anaplastic large cell lymphoma (ALCL), diffuse large B-cell lymphoma (DLBCL), or large B-cell lymphoma. In addition to hematological cancer, methods for treating other blood disorder or hematologic malignancy that is ROS1+ or ALK+ are also provided herein.In one embodiment, the cancer is ALCL. In one embodiment, the cancer is ROS1+ ALCL. In one embodiment, the cancer is ALKA ALCL. In one embodiment, the cancer is relapsed or refractory ALCL. In one embodiment, the cancer is relapsed or refractory ROS1+ ALCL. In one embodiment, the cancer is relapsed or refractory ALKA ALCL. In one embodiment, the cancer is newly diagnosed ALCL. In one embodiment, the cancer is newly diagnosed ROS1+ ALCL. In one embodiment, the cancer is newly diagnosed ALKA ALCL.In one embodiment, the cancer is DLBCL. In one embodiment, the cancer is ROS1+ DLBCL. In one embodiment, the cancer is ALK+ DLBCL. In one embodiment, the cancer is relapsed or refractory DLBCL. In one embodiment, the cancer is relapsed or refractory ROS1+ DLBCL. In one embodiment, the cancer is relapsed or refractory ALKA DLBCL. In one embodiment, the cancer is newly diagnosed DLBCL. In one embodiment, the cancer is newly diagnosed ROS 1+ DLBCL. In one embodiment, the cancer is newly diagnosed ALK+ DLBCL.In one embodiment, the cancer is large B-cell lymphoma. In one embodiment, the cancer is ROS 1+ large B-cell lymphoma. In one embodiment, the cancer is ALK+ large B-cell lymphoma. In one embodiment, the cancer is relapsed or refractory large B-cell lymphoma. In one embodiment, the cancer is relapsed or refractory ROS1+ large B-cell lymphoma. In one embodiment, the cancer is relapsed or refractory ALK+ large B-cell lymphoma. In one embodiment, the cancer is newly diagnosed large B-cell lymphoma. In one embodiment, the cancer is newly diagnosed ROS1+ large B-cell lymphoma. In one embodiment, the cancer is newly diagnosed ALK+ large B-cell lymphoma.In one embodiment, the cancer (or ROS1+ cancer, or ALK+ cancer) is new diagnosed. In one embodiment, the cancer (or ROS 1+ cancer, or ALK+ cancer) is previously untreated.In one embodiment, the cancer (or ROS1+ cancer, or ALK+ cancer) is relapsed or refractory. In one embodiment, the cancer is relapsed. In one embodiment, the cancer (or ROS1+ cancer, or ALK+ cancer) is refractory.In one embodiment, the subject is previously untreated. In one embodiment, the subject is treatment naive to tyrosine kinase inhibitor (TKI) therapy. In one embodiment, the subject has received one or more prior lines of therapy In one embodiment, the subject has received two or more prior lines of therapy. In one embodiment, the subject has developed resistance to one or more of the prior line of therapy. In one embodiment, the prior therapy comprises a tyrosine kinase inhibitor (TKI). In one embodiment, the prior therapy comprises one or more of crizotinib, ceritinib, alectinib, brigatinib, lorlatinib, entrectinib, repotrectinib, cabozantinib, foretinib, taletrectinib, merestinib, masitinib, and ensartinib. In one embodiment, the prior therapy comprises one or more chemotherapies. In one embodiment, the one or more chemotherapies are in addition to the TKI therapy.In one embodiment, the cancer (or ROS1+ cancer, or ALK+ cancer) is resistant to a tyrosine kinase inhibitor (TKI).In one embodiment, the cancer is resistant lung cancer. In one embodiment, the cancer is resistant non-small cell lung cancer. In one embodiment, the cancer is nonsmall cell lung cancer resistant to a TKI. In one embodiment, the cancer is ROS1+ non-small cell lung cancer resistant to a TKI. In one embodiment, the cancer is ALK+ non-small cell lung cancer resistant to a TKI.In one embodiment, the cancer is lung cancer (e.g., NSCLC), and the cancer is relapsed after, or refractory to, prior treatment by a TKI.In one embodiment, a compound provided herein is administered as first-line treatment. In one embodiment, a compound provided herein is administered as second-line treatment. In one embodiment, a compound provided herein is administered as third or fourth-line treatment.In one embodiment, the cancer (or ROS1+ cancer, or ALK+ cancer) is metastatic. In one embodiment, the cancer has CNS metastases. In one embodiment, the cancer has brain metastases. In one embodiment, the cancer is metastatic non-small cell lung cancer (NSCLC). In one embodiment, the cancer is metastatic ROS1+ NSCLC. In one embodiment, the cancer is metastatic ALK+ NSCLC.In one embodiment, provided herein is a method for treating a patient with metastatic ALK+ non-small cell lung cancer (NSCLC), comprising administering to the patient a therapeutically effective amount of a compound provided herein, e.g., a compound of Formula (I), or an enantiomer, a mixture of enantiomers, or a tautomer thereof, or a pharmaceutically acceptable salt thereof.In one embodiment, provided herein is a method for treating a patient with metastatic ROS1+ non-small cell lung cancer (NSCLC), comprising administering to the patient a therapeutically effective amount of a compound provided herein, e.g., a compound of Formula (I), or an enantiomer, a mixture of enantiomers, or a tautomer thereof, or a pharmaceutically acceptable salt thereof.In one embodiment, the patient is an adult patient, hi one embodiment, the patient is a pediatric patient.In one embodiment, provided herein is a method for treating an adult patient with metastatic ROS 1+ NSCLC, comprising administering to the patient a therapeutically effective amount of a compound provided herein, e.g., a compound of Formula (I), or an enantiomer, a mixture of enantiomers, or a tautomer thereof, or a pharmaceutically acceptable salt thereof.In one embodiment, provided herein is a method for treating an adult patient with metastatic ROS 1+ NSCLC, comprising administering to the patient a therapeutically effective amount of a compound provided herein, e.g., a compound of Formula (I), or an enantiomer, a mixture of enantiomers, or a tautomer thereof, or a pharmaceuticallyacceptable salt thereof, wherein the patient has progressed on or is intolerant of at least 1 prior TKI therapy.In one embodiment, provided herein is a method for treating an adult patient with metastatic NSCLC that is ROS1+ with solvent front mutation G2032R, comprising administering to the patient a therapeutically effective amount of a compound provided herein, e.g., a compound of Formula (I), or an enantiomer, a mixture of enantiomers, or a tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein the patient has progressed on or is intolerant of at least 1 prior TKI therapyIn one embodiment, provided herein is a method for treating a ROSl-associated (or ROS1+) cancer in a subject in need thereof, wherein the cancer has developed resistance to a tyrosine kinase inhibitor (TKI), the method comprising administering to the subject a therapeutically effective amount of a compound provided herein, e.g., a compound of Formula (I), or an enantiomer, a mixture of enantiomers, or a tautomer thereof, or a pharmaceutically acceptable salt thereof.In one embodiment, provided herein is a method for treating a ROSl-associated (or ROS1+) cancer in a subject in need thereof, wherein the cancer has developed resistance to a tyrosine kinase inhibitor (TKI), and wherein the cancer has been identified as having one or more ROS1 inhibitor resistance mutations, the method comprising administering to the subject a therapeutically effective amount of a compound provided herein, e.g., a compound of Formula (I), or an enantiomer, a mixture of enantiomers, or a tautomer thereof, or a pharmaceutically acceptable salt thereof. In one embodiment, the one or more ROS1 inhibitor resistance mutations comprise one or more amino acid substitutions at an amino acid position selected from 1986, 2004, 2026, 2032, and 2033. In one embodiment, the one or more ROS1 inhibitor resistance mutations comprise one or more amino acid substitutions selected from S1986F, S1986Y, F2004C, F2004V, L2026M, G2032R, D2033N, L2086F, and G2101A. In one embodiment, the one or more ROS1 inhibitor resistance mutations is G2032R. In one embodiment, the one or more ROS1 inhibitor resistance mutations comprise G2032R and one or more of S1986F, S1986Y, F2004C, F2004V, L2026M, D2033N, or G2101A. In one embodiment, the ROS1 inhibitor resistance mutation is L2086F.In one embodiment, provided herein is a method for treating a ALK-associated (or ALK+) cancer in a subject in need thereof, wherein the cancer has developed resistance to a tyrosine kinase inhibitor (TKI), the method comprising administering to the subject atherapeutically effective amount of a compound provided herein, e.g., a compound of Formula (I), or an enantiomer, a mixture of enantiomers, or a tautomer thereof, or a pharmaceutically acceptable salt thereofIn one embodiment, provided herein is a method for treating a ALK-associated (or ALK+) cancer in a subject in need thereof, wherein the cancer has developed resistance to a tyrosine kinase inhibitor (TKI), and wherein the cancer has been identified as having one or more ALK inhibitor resistance mutations, the method comprising administering o the subject a therapeutically effective amount of a compound provided herein, e.g., a compound of Formula (I), or an enantiomer, a mixture of enantiomers, or a tautomer thereof, or a pharmaceutically acceptable salt thereof. In one embodiment, the one or more ALK inhibitor resistance mutations comprise one or more amino acid substitutions at an amino acid position selected from 1196, 1198, 1202, and 1269. In one embodiment, the one or more ALK inhibitor resistance mutations comprise one or more amino acid substitutions selected from LI 196M, LI 198F, G1202R, and G1269A. In one embodiment, the one or more ALK inhibitor resistance mutations is G1202R. In one embodiment, the one or more ALK inhibitor resistance mutations comprise G1202R and one or more of L1196M, L1198F, and G1269A.In one embodiment, provided herein is a method for treating an adult patient with metastatic NSCLC that is ALK+ with mutation G1202R, comprising administering to the patient a therapeutically effective amount of a compound provided herein, e.g., a compound of Formula (I), or an enantiomer, a mixture of enantiomers, or a tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein the patient has progressed on or is intolerant of at least 1 prior TKI therapy.In one embodiment, provided herein is a method for treating a ALK-associated (or ALK+) cancer in a subject in need thereof, wherein the cancer has developed resistance to a tyrosine kinase inhibitor (TKI), the method comprising administering to the subject a therapeutically effective amount of a compound provided herein, e.g., a compound of Formula (I), or an enantiomer, a mixture of enantiomers, or a tautomer thereof, or a pharmaceutically acceptable salt thereof.In one embodiment, the TKI is a ROS1 inhibitor. In one embodiment, the TKI is an ALK inhibitor In one embodiment, the TKI is crizotinib, ceritinib, alectinib, brigatinib, lorlatinib, entrectinib, repotrectinib, cabozantinib, foretinib, merestinib,taletrectinib, masitinib, or ensartinib. In one embodiment, the TKI is crizotinib. In one embodiment, the TKI is entrectinib.In certain embodiments, the subject has relapsed after first-line treatment of the cancer. In other embodiments, the subject has relapsed after second-line treatment of the cancer.In one embodiment, the cancer or disease is in a pediatric patient (including an infantile patient). In one embodiment, the cancer is systemic anaplastic large cell lymphoma (ALCL) that is ALK+ in pediatric patients 1 year of age or older, and young adults. In another embodiment, the cancer is relapsed or refractory systemic anaplastic large cell lymphoma (ALCL) that is ALK+ in pediatric patients 1 year of age or older, and young adults. In one embodiment, the cancer is systemic anaplastic large cell lymphoma (ALCL) that is ROS1+ in pediatric patients 1 year of age or older, and young adults. In another embodiment, the cancer is relapsed or refractory systemic anaplastic large cell lymphoma (ALCL) that is ROS1+ in pediatric patients 1 year of age or older, and young adults.In certain embodiments, the methods for treating or preventing cancer can be demonstrated by one or more responses such as increased apoptosis, inhibition of tumor growth, reduction of tumor metastasis, inhibition of tumor metastasis, reduction of microvessel density, decreased neovascularization, inhibition of tumor migration, tumor regression, and increased survival of the subject.Combination TreatmentsIn some embodiments, the method of treating or preventing cancer may comprise administering a compound of Formula (I) conjointly with one or more other chemotherapeutic agent(s).As used herein and unless otherwise specified, by “conjointly” or “in combination with”, it is not intended to imply that the other agent and the compound of Formula (I) must be administered at the same time and / or formulated for delivery together, although these methods of delivery are within the scope of this disclosure. The compound provided herein can be administered concurrently with, prior to (e.g., 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, 12 weeks, or 16 weeks before), or subsequent to (e.g., 5 minutes, 15 minutes, 30minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, 12 weeks, or 16 weeks after), one or more other agents (e.g., one or more other additional agents). In general, each therapeutic agent is administered at a dose and / or on a time schedule determined for that particular agent. The other therapeutic agent can be administered with the compound provided herein in a single composition or separately in a different composition. Triple therapy is also contemplated herein.Chemotherapeutic agents that may be conjointly administered with compounds of the disclosure include: l-amino-4-phenylamino-9,10-dioxo-9,10-dihydroanthracene-2-sulfonate (acid blue 25), l-amino-4-[4-hydroxyphenyl-amino]-9,10-dioxo-9,10-dihydroanthracene-2-sulfonate, l-amino-4-[4-aminophenylamino]-9,10-dioxo-9,10-dihydroanthracene-2-sulfonate,           l-amino-4-[l-naphthylamino]-9,10-dioxo-9,10-dihydroanthracene-2-sulfonate, l-amino-4-[4-fluoro-2-carboxyphenylamino]-9,10-dioxo-9,10-dihydroanthracene-2-sulfonate, l-amino-4-[2-anthracenylamino]-9,10-dioxo-9,10-dihydroanthracene-2-sulfonate, ABT-263, afatinib dimaleate, axitinib, aminoglutethimide, amsacrine, anastrozole, APCP, asparaginase, AZD5363, Bacillus Calmette-Guerin vaccine (beg), bicalutamide, bleomycin, bortezomib, P-methylene-ADP (AOPCP), buserelin, busulfan, cabazitaxel, cabozantinib, campothecin, capecitabine, carboplatin, carfilzomib, carmustine, ceritinib, chlorambucil, chloroquine, cisplatin, cladribine, clodronate, cobimetinib, colchicine, crizotinib, cyclophosphamide, cyproterone, cytarabine, dacarbazine, dactinomycin, daunorubicin, demethoxyviridin, dexamethasone, di chloroacetate, dienestrol, diethyl stilbestrol, docetaxel, doxorubicin, epirubicin, eribulin, erlotinib, estradiol, estramustine, etoposide, everolimus, exemestane, filgrastim, fludarabine, fludrocortisone, fluorouracil, fluoxymesterone, flutamide, gefitinib, gemcitabine, genistein, goserelin, GSK1120212, hydroxyurea, idarubicin, ifosfamide, imatinib, interferon, irinotecan, ixabepilone, lenalidomide, letrozole, leucovorin, leuprolide, levamisole, lomustine, lonidamine, mechlorethamine, medroxyprogesterone, megestrol, melphalan, mercaptopurine, mesna, metformin, methotrexate, miltefosine, mitomycin, mitotane, mitoxantrone, MK-2206, mutamycin, N-(4-sulfamoylphenylcarbamothioyl) pivalamide, NF279, NF449, nilutamide, nocodazole, octreotide, olaparib, oxaliplatin, paclitaxel, pamidronate, pazopanib, pemexetred, pentostatin, perifosine, PF-04691502, plicamycin, pomalidomide, porfimer, PPADS, procarbazine, quercetin, raltitrexed, ramucirumab, reactive blue 2, rituximab, rolofylline,romidepsin, rucaparib, selumetinib, sirolimus, sodium 2,4-dinitrobenzenesulfonate, sorafenib, streptozocin, sunitinib, suramin, talazoparib, tamoxifen, temozolomide, temsirolimus, teniposide, testosterone, thalidomide, thioguanine, thiotepa, titanocene dichloride, tonapofylline, topotecan, trametinib, trastuzumab, tretinoin, veliparib, vinblastine, vincristine, vindesine, vinorelbine, and vorinostat (SAHA). In other embodiments, chemotherapeutic agents that may be conjointly administered with compounds of the disclosure include: ABT-263, dexamethasone, 5-fluorouracil, PF-04691502, romidepsin, and vorinostat (SAHA). In other embodiments, chemotherapeutic agents that may be conjointly administered with compounds of the disclosure include: 1-amino-4-phenylamino-9,10-dioxo-9,10-dihydroanthracene-2-sulfonate (acid blue 25), 1-amino-4-[4-hydroxyphenyl-amino]-9,10-di oxo-9,10-dihydroanthracene-2-sulfonate, 1-amino-4-[4-aminophenylamino]-9,10-di oxo-9,10-dihydroanthracene-2-sulfonate, 1-amino-4-[ 1 -naphthylamino]-9,10-dioxo-9,10-dihydroanthracene-2-sulfonate, 1 -amino-4-[4-fluoro-2-carboxyphenylamino]-9,10-di oxo-9,10-dihydroanthracene-2-sulfonate, 1-amino-4-[2-anthracenylamino]-9,10-dioxo-9,10-dihydroanthracene-2-sulfonate, APCP, P-methylene-ADP (AOPCP), capecitabine, cladribine, cytarabine, fludarabine, doxorubicin, gemcitabine, N-(4-sulfamoylphenylcarbamothioyl) pivalamide, NF279, NF449, PPADS, quercetin, reactive blue 2, rolofylline sodium 2,4-dinitrobenzenesulfonate, sumarin, and tonapofylline.Many combination therapies have been developed for the treatment of cancer. In certain embodiments, compounds of the disclosure (e.g., compounds of Formula (I)) may be conjointly administered with one or more combination therapies. Examples of combination therapies with which compounds of the disclosure may be conjointly administered are included in Table 2.Table 2: Exemplary combinatorial therapies for the treatment of cancerName Therapeutic agents ABV Doxorubicin, Bleomycin, Vinblastine ABVD Doxorubicin, Bleomycin, Vinblastine, Dacarbazine AC (Breast) Doxorubicin, Cyclophosphamide AC (Sarcoma) Doxorubicin, Cisplatin AC (Neuroblastoma) Cyclophosphamide, Doxorubicin Name Therapeutic agents ACE Cyclophosphamide, Doxorubicin, Etoposide ACe Cyclophosphamide, Doxorubicin AD Doxorubicin, Dacarbazine AP Doxorubicin, Cisplatin ARAC-DNR Cytarabine, Daunorubicin B-CAVe Bleomycin, Lomustine, Doxorubicin, Vinblastine BCVPP Carmustine, Cyclophosphamide, Vinblastine, Procarbazine, Prednisone BEACOPP Bleomycin, Etoposide, Doxorubicin, Cyclophosphamide, Vincristine, Procarbazine, Prednisone, Filgrastim BEP Bleomycin, Etoposide, Cisplatin BIP Bleomycin, Cisplatin, Ifosfamide, Mesna BOMP Bleomycin, Vincristine, Cisplatin, Mitomycin CA Cytarabine, Asparaginase CABO Cisplatin, Methotrexate, Bleomycin, Vincristine CAF Cyclophosphamide, Doxorubicin, Fluorouracil CAL-G Cyclophosphamide, Daunorubicin, Vincristine, Prednisone, Asparaginase CAMP Cyclophosphamide, Doxorubicin, Methotrexate, Procarbazine CAP Cyclophosphamide, Doxombicin, Cisplatin CAV Cyclophosphamide, Doxombicin, Vincristine CAVE ADD CAV and Etoposide CA-VP16 Cyclophosphamide, Doxombicin, Etoposide CC Cyclophosphamide, Carboplatin CDDP / VP-16 Cisplatin, Etoposide CEF Cyclophosphamide, Epimbicin, Fluorouracil CEPP(B) Cyclophosphamide, Etoposide, Prednisone, with or without / Bleomycin CEV Cyclophosphamide, Etoposide, Vincristine CF Cisplatin, Fluorouracil or Carboplatin Fluorouracil Name Therapeutic agents CHAP Cyclophosphamide or Cyclophosphamide, Altretamine, Doxorubicin, Cisplatin ChlVPP Chlorambucil, Vinblastine, Procarbazine, Prednisone CHOP Cyclophosphamide, Doxorubicin, Vincristine, Prednisone CHOP-BLEO Add Bleomycin to CHOP CISCA Cyclophosphamide, Doxorubicin, Cisplatin CLD-BOMP Bleomycin, Cisplatin, Vincristine, Mitomycin CMF Methotrexate, Fluorouracil, Cyclophosphamide CMFP Cyclophosphamide, Methotrexate, Fluorouracil, Prednisone CMF VP Cyclophosphamide, Methotrexate, Fluorouracil, Vincristine, Prednisone CMV Cisplatin, Methotrexate, Vinblastine CNF Cyclophosphamide, Mitoxantrone, Fluorouracil CNOP Cyclophosphamide, Mitoxantrone, Vincristine, Prednisone COB Cisplatin, Vincristine, Bleomycin CODE Cisplatin, Vincristine, Doxorubicin, Etoposide COMLA Cyclophosphamide, Vincristine, Methotrexate, Leucovorin, Cytarabine COMP Cyclophosphamide, Vincristine, Methotrexate, Prednisone Cooper Regimen Cyclophosphamide, Methotrexate, Fluorouracil, Vincristine, Prednisone COP Cyclophosphamide, Vincristine, Prednisone COPE Cyclophosphamide, Vincristine, Cisplatin, Etoposide COPP Cyclophosphamide, Vincristine, Procarbazine, Prednisone CP(Chronic lymphocytic leukemia) Chlorambucil, Prednisone CP (Ovarian Cancer) Cyclophosphamide, Cisplatin CVD Cisplatin, Vinblastine, Dacarbazine CVI Carboplatin, Etoposide, Ifosfamide, Mesna CVP Cyclophosphamide, Vincristine, Prednisome Name Therapeutic agents CVPP Lomustine, Procarbazine, Prednisone CYVADIC Cyclophosphamide, Vincristine, Doxorubicin, Dacarbazine DA Daunorubicin, Cytarabine DAT Daunorubicin, Cytarabine, Thioguanine DAV Daunorubicin, Cytarabine, Etoposide DCT Daunorubicin, Cytarabine, Thioguanine DHAP Cisplatin, Cytarabine, Dexamethasone DI Doxorubicin, Ifosfamide DTIC / T am oxifen Dacarbazine, Tamoxifen DVP Daunorubicin, Vincristine, Prednisone EAP Etoposide, Doxorubicin, Cisplatin EC Etoposide, Carboplatin EFP Etoposie, Fluorouracil, Cisplatin ELF Etoposide, Leucovorin, Fluorouracil EMA 86 Mitoxantrone, Etoposide, Cytarabine EP Etoposide, Cisplatin EVA Etoposide, Vinblastine FAC Fluorouracil, Doxorubicin, Cyclophosphamide FAM Fluorouracil, Doxorubicin, Mitomycin FAMTX Methotrexate, Leucovorin, Doxorubicin FAP Fluorouracil, Doxorubicin, Cisplatin F-CL Fluorouracil, Leucovorin FEC Fluorouracil, Cyclophosphamide, Epirubicin FED Fluorouracil, Etoposide, Cisplatin FL Flutamide, Leuprolide FZ Flutamide, Goserelin acetate implant FIDMTX Methotrexate, Leucovorin Flexa-CAF Altretamine, Cyclophosphamide, Methotrexate, Fluorouracil IDMTX / 6-MP Methotrexate, Mercaptopurine, Leucovorin Name Therapeutic agents IE Ifosfamide, Etoposie, Mesna IfoVP Ifosfamide, Etoposide, Mesna IPA Ifosfamide, Cisplatin, Doxorubicin M-2 Vincristine, Carmustine, Cyclophosphamide, Prednisone, Melphalan MAC-III Methotrexate, Leucovorin, Dactinomycin, Cyclophosphami de MACC Methotrexate, Doxorubicin, Cyclophosphamide, Lomustine MACOP-B Methotrexate, Leucovorin, Doxorubicin, Cyclophosphamide, Vincristine, Bleomycin, Prednisone MAID Mesna, Doxorubicin, Ifosfamide, Dacarbazine m-BACOD Bleomycin, Doxorubicin, Cyclophosphamide, Vincristine, Dexamethasone, Methotrexate, Leucovorin MBC Methotrexate, Bleomycin, Cisplatin MC Mitoxantrone, Cytarabine MF Methotrexate, Fluorouracil, Leucovorin MICE Ifosfamide, Carboplatin, Etoposide, Mesna MINE Mesna, Ifosfamide, Mitoxantrone, Etoposide mini-BEAM Carmustine, Etoposide, Cytarabine, Melphalan MOBP Bleomycin, Vincristine, Cisplatin, Mitomycin MOP Mechlorethamine, Vincristine, Procarbazine MOPP Mechlorethamine, Vincristine, Procarbazine, Prednisone MOPP / ABV Mechlorethamine, Vincristine, Procarbazine, Prednisone, Doxorubicin, Bleomycin, Vinblastine MP (multiple myeloma) Melphalan, Prednisone MP (prostate cancer) Mitoxantrone, Prednisone MTX / 6-MO Methotrexate, Mercaptopurine MTX / 6-MP / VP Methotrexate, Mercaptopurine, Vincristine, Prednisone MTX-CDDPAdr Methotrexate, Leucovorin, Cisplatin, Doxorubicin Name Therapeutic agents MV (breast cancer) Mitomycin, Vinblastine MV (acute myelocytic leukemia) Mitoxantrone, Etoposide M-VAC Methotrexate Vinblastine, Doxorubicin, Cisplatin MVP Mitomycin Vinblastine, Cisplatin MVPP Meehlorethamine, Vinblastine, Procarbazine, Prednisone NFL Mitoxantrone, Fluorouracil, Leucovorin NOVP Mitoxantrone, Vinblastine, Vincristine OPA Vincristine, Prednisone, Doxorubicin OPPA Add Procarbazine to OPA. PAC Cisplatin, Doxorubicin PAC-I Cisplatin, Doxorubicin, Cyclophosphamide PA-CI Cisplatin, Doxorubicin PCV Lomustine, Procarbazine, Vincristine PFL Cisplatin, Fluorouracil, Leucovorin POC Prednisone, Vincristine, Lomustine ProMACE Prednisone, Methotrexate, Leucovorin, Doxorubicin, Cyclophosphamide, Etoposide ProMACE / cytaBOM Prednisone, Doxorubicin, Cyclophosphamide, Etoposide, Cytarabine, Bleomycin, Vincristine, Methotrexate, Leucovorin, Cotrimoxazole PRoMACE / MOPP Prednisone, Doxorubicin, Cyclophosphamide, Etoposide, Mechlorethamine, Vincristine, Procarbazine, Methotrexate, Leucovorin Pt / VM Cisplatin, Teniposide PVA Prednisone, Vincristine, Asparaginase PVB Cisplatin, Vinblastine, Bleomycin PVDA Prednisone, Vincristine, Daunorubicin, Asparaginase SMF Streptozocin, Mitomycin, Fluorouracil TAD Mechlorethamine, Doxorubicin, Vinblastine, Vincristine, Bleomycin, Etoposide, Prednisone Name Therapeutic agents TTT Methotrexate, Cytarabine, Hydrocortisone Topo / CTX Cyclophosphamide, Topotecan, Mesna VAB-6 Cyclophosphamide, Dactinomycin, Vinblastine, Cisplatin, Bleomycin VAC Vincristine, Dactinomycin, Cyclophosphamide VACAdr Vincristine, Cyclophosphamide, Doxorubicin, Dactinomycin, Vincristine VAD Vincristine, Doxorubicin, Dexamethasone VATH Vinblastine, Doxorubicin, Thiotepa, Flouxymesterone VBAP Vincristine, Carmustine, Doxorubicin, Prednisone VBCMP Vincristine, Carmustine, Melphalan, Cyclophosphamide, Prednisone VC Vinorelbine, Cisplatin VCAP Vincristine, Cyclophosphamide, Doxorubicin, Prednisone VD Vinorelbine, Doxorubicin VelP Vinblastine, Cisplatin, Ifosfamide, Mesna VIP Etoposide, Cisplatin, Ifosfamide, Mesna VM Mitomycin, Vinblastine VMCP Vincristine, Melphalan, Cyclophosphamide, Prednisone VP Etoposide, Cisplatin V-TAD Etoposide, Thioguanine, Daunorubicin, Cytarabine 5 + 2 Cytarabine, Daunorubicin, Mitoxantrone 7 + 3 Cytarabine with / , Daunorubicin or Idarubicin or Mitoxantrone "8 in 1" Methylprednisolone, Vincristine, Lomustine, Procarbazine, Hydroxyurea, Cisplatin, Cytarabine, Dacarbazine In certain embodiments, the conjoint therapies of the disclosure comprise conjoint administration with other types of chemotherapeutic agents, such as immuno-oncology agents. Cancer cells often have specific cell surface antigens that can be recognized by theimmune system. Thus, immuno-oncology agents, such as monoclonal antibodies, can selectively bind to cancer cell antigens and effect cell death. Other immuno-oncology agents can suppress tumor-mediated inhibition of the native immune response or otherwise activate the immune response and thus facilitate recognition of the tumor by the immune system. Exemplary antibody immuno-oncology agents, include, but are not limited to, abagovomab, adecatumumab, afutuzumab, alemtuzumab, anatumomab mafenatox, apolizumab, blinatumomab, BMS-936559, catumaxomab, durvalumab, epacadostat, epratuzumab, indoximod, inotuzumab ozogamicin, intelumumab, ipilimumab, isatuximab, lambrolizumab, MED14736, MPDL3280A, nivolumab, obinutuzumab, ocaratuzumab, ofatumumab, olatatumab, pembrolizumab, pidilizumab, rituximab, ticilimumab, samalizumab, and tremelimumab. In some embodiments, the antibody immuno-oncology agents are selected from anti-CD73 monoclonal antibody (mAh), anti-CD39 mAh, anti-PD-1 mAb, and anti-CTLA4 mAb. Thus, in some embodiments, the methods of the disclosure comprise conjoint administration of one or more immuno-oncology agents, such as the agents mentioned above.In some embodiments, the combination therapy comprises conjoint administration of a compound of the disclosure, such as a compound of Formula (I), with SH2 inhibitors, such as CGP78850, CPG85793, C90, C126, G7-18NATE, G7-B1, and NSC642056.In some embodiments, the combination therapy comprises conjoint administration of a compound of the disclosure, such as a compound of Formula (I), with MEK inhibitors, such as trametinib, cobimetinib, binimetinib, selumetinib, PD-325901, CI-1040, and TAK-733.In some embodiments, the combination therapy comprises conjoint administration of a compound of the disclosure, such as a compound of Formula (I), with a MET inhibitor selected from JNJ-38877605, PF-04217903, foretinib, AMG458, tivantinib, cabozantinib, crizotinib, capmatinib hydrochloride, tepotinib hydrochloride, and savolitinib.In some embodiments, the combination therapy comprises conjoint administration of a compound of the disclosre, such as Formula (I), with a SHP2 inhibitor selected from TNO-155, RMC-4630, JAB-3068, or RLY-1971.In some embodiments, the combination therapy comprises conjoint administration of a compound of the disclosure, such as a compound of Formula (I), with a RAS inhibitor selected from aliskiren, captopril, losartan, irbesartan, olmesartan, candesartan, valsartan,fimasartan, azilsartan, telmisartan, eprosartan, benazepril, enalapril, lisinopril, perindopril, quinapril, ramipril, and trandolapril.In some embodiment, the combination therapy comprises administration of a compound provided herein, e.g., a compound of Formula (I), in combination with a TKI. In one embodiment, the TKI is a ROS1 inhibitor. In one embodiment, the TKI is an ALK inhibitor. In one embodiment, the TKI is crizotinib, ceritinib, alectinib, brigatinib, lorlatinib, entrectinib, repotrectinib, cabozantinib, foretinib, merestinib, taletrectinib, masitinib, or ensartinib. In one embodiment, the TKI is crizotinib In one embodiment, the TKI is entrectinib. In one embodiment, the TKI is alectinib. In one embodiment, the TKI is brigatinib.In some embodiments, the combination therapy comprises conjoint administration of a compound of the disclosure, such as a compound of Formula (I), with anti-PD-1 therapy. In certain embodiments, the combination therapy comprises conjoint administration of a compound of the disclosure, such as a compound of Formula (I), with oxaliplatin. In other embodiments, the combination therapy comprises conjoint administration of a compound of the disclosure, such as a compound of Formula (I), with doxorubicin.In certain embodiments, a compound of the disclosure may be conjointly administered with non-chemical methods of cancer treatment. In certain embodiments, a compound of the disclosure may be conjointly administered with radiation therapy. In certain embodiments, a compound of the disclosure may be conjointly administered with surgery, with thermoablation, with focused ultrasound therapy, with cryotherapy, or with any combination of these.In certain embodiments, compounds of the disclosure may be conjointly administered with one or more other compounds of the disclosure. Moreover, such combinations may be conjointly administered with other therapeutic agents, such as other agents suitable for the treatment of cancer, immunological or neurological diseases, such as the agents identified above. In certain embodiments, conjointly administering one or more additional chemotherapeutic agents with a compound of the disclosure provides a synergistic effect. In certain embodiments, conjointly administering one or more additional chemotherapeutic agents provides an additive effectPharmaceutical CompositionsIn certain embodiments, the present disclosure provides a pharmaceutical preparation suitable for use in a human patient, comprising any of the compounds shown above (e g., a compound of the disclosure, such as a compound of Formula (I), 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 disclosure may be utilized to treat a subject in need thereof. In certain embodiments, the subject is a mammal such as a human, or a non-human mammal. When administered to subject, such as a human, the composition or the compound is preferably administered as a pharmaceutical composition comprising, for example, a compound of the disclosure 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, eg., 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 disclosure. 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 disclosure. Liposomes, for example, which comprise phospholipids or other lipids, are nontoxic, physiologically acceptable and metabolizable carriers that are relatively simple to make and administerThe 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 earner" 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 com 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 nontoxic 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 forapplication 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, 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 which 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 disclosure, 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 disclosure with liquid carriers, or finely divided solid carriers, or both, and then, if necessary, shaping the product.Formulations of the disclosure 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 presentdisclosure 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), surface-active 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 desiredrelease 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 disclosure 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 disclosure. Exemplary ophthalmic formulations are described in U.S. Publication Nos. 2005 / 0080056, 2005 / 0059744, 2005 / 0031697 and 2005 / 004074 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 disclosure 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 disclosure, 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 desiredtherapeutic 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 which 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 disclosure. 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 disclosure 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 disclosure, the active compound may be administered two or three times daily. In preferred embodiments, the active compound will be administered once daily.In certain embodiments, compounds of the disclosure 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 disclosure 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 disclosure (e.g., compound of Formula I or la) 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 disclosure and the one or more additional therapeutic agent(s).This disclosure includes the use of pharmaceutically acceptable salts of compounds of the disclosure in the compositions and methods of the present disclosure. In certain embodiments, contemplated salts of the di sclosure include, but are not limited to, alkyl, dialkyl, trialkyl or tetra-alkyl ammonium salts. In certain embodiments, contemplated salts of the disclosure include, but are not limited to, L-arginine, benenthamine, benzathine, betaine, calcium hydroxide, choline, deanol, diethanolamine, diethylamine, 2-(diethylamino)ethanol, ethanolamine, ethylenediamine, N-m ethyl glucamine, 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 disclosure 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.Phamaceutically 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 bi sulfate, 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 disclosure 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 disclosure, and are not intended to limit the disclosure.General Synthetic ProceduresThe 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 one of skill in the art having referred to this disclosure. The starting materials and the intermediates and the final products of the reacton may be isolated and purified if desired using convential 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. In some instances, reactions may produce more than one regioisomeric product. In these cases, chromatography may be used to separate the isomers and NOE or NOESY NMR spectroscopy may be used to aid structural assignment.Unless specified otherwise, the reactions described herein take place at atmospheric pressure over a temperature range from about -78 °C to about 150 °C.Abbreviations Definition Solvents EA, EtOAc ethyl acetate PE, pet. ether petroleum ether Abbreviations Definition THF tetrahydrofuran DCM di chloromethane DMF N,N-dimethylformamide DMA N,N-dimethyl acetamide NMP N-methyl-2-pyrrolidone DMSO dimethyl sulfoxide IPA isopropyl alcohol DME dimethoxyethane MeCN, ACN acetonitrile DCE di chloroethane Reagents DAST diethylaminosulfur trifluoride DIAD diisopropyl azodicarboxylate DEAD diethyl azodi carboxyl ate DBAD di-tert-butyl azodi carb oxy late DIPEA, DIEA N,N-diisopropyl ethylamine TEA triethylamine ATP adenosine triphosphate TFA trifluoroacetic acid FA formic acid DIBAL, DIBAL-H, DIBALH diisobutylaluminium hydride AcOH, HO Ac acetic acid TES triethylsilane n-BuLi, BuLi n-butyllithium LDA lithium diisopropylamide NBS N-bromosuccinimide NIS N-iodosuccinimide NCS N-chl orosuc cinimi de DMP Dess-Martin periodinane DEA di ethylamine Abbreviations Definition DMF-DMA 1,1 -dimethoxy-N,N-dimethylmethanamine TMP 2,2,6,6-tetramethylpiperidine NMO N-methylmorpholine N-oxide TBSC1 tert-butyldimethylsilyl chloride KO Ac, AcOK potassium acetate NaOAc, AcONa sodium acetate SEMC1 2-(trimethylsilyl)ethoxymethyl chloride tBuLi, t-BuLi tert-butyllithium NFSI N-fluorobenzenesulfonimide AIBN azobi si sobutyroni tril e EDCI l-ethyl-3-(3-dimethylaminopropyl)carbodiimide EIOBT hydroxybenzotriazole TBAF tetra-n-butylammonium fluoride HATU 1 -[bi s(dimethylamino)methylene] -1H-1,2,3 -tri azol o[4,5 -b]pyridinium 3-oxide hexafluorophosphate XPhos 2-di cyclohexyl phosphino-2', 4', 6 '-triisopropylbiphenyl cataCXium A di( 1 -adamantyl)-n-butylphosphine DPPP l,3-bis(diphenylphosphino)propane DPPF 1,1 '-bi s(di phenylphosphino)ferrocene TfOH triflic acid HMTA 1,3,5,7-tetraazaadamantane PMBC1 p-methoxybenzyl chloride FIEPES 4-(2-hydroxyethyl)-1 -piperazineethanesulfonic acid EGTA ethylene glycol-bis(2-aminoethylether)-N,N,N',N'-tetraacetic acid Other HPLC high-pressure liquid chromatography Prep preparative wt wild-type rt, r.t., RT room-temperature SFC supercritical fluid chromatography Abbreviations Definition V / V volume / volume LC / MS, LC-MS, LCMS liquid chromatography-mass spectrometry MS mass spectrometry ESI, ES+, ES- electrospray ionization NMR nuclear magnetic resonance ppm parts per million sat saturated aq aqueous TLC thin layer chromatography ty? retention time The compounds of the invention can be prepared by a variety of synthetic methods, as further described and illustrated herein. It will be understood by those with skill in the art that the following general synthetic methods are representative and not intended to be5 limiting. Racemic compounds can be enantiomerically enriched via chiral, preparative, SFC or HPLC separation. Variable A denotes a carbon, nitrogen or sulfur atom that can be the same or different as another instance of variable A. Variable X denotes a chloride, bromide or iodide atom that can be the same or different as another instance of variable X. Variable Z denotes a nitrogen atom, or C-H or C-F group that can be the same or different10 as another instance of variable ZMethod A Br W R A            H2N   o—( A0|           X\ /               Me3Sn——F Additive, Ligand, AxfA R2           Pd cat., Solvent 1-2 I                                   II Br—(    NH2 A=\ ,Ra          -\-° OVL          I 2 „ A in °-<              .7...b~b.-r. N^\                     Base, Ligand,               I      R^ / Z \ R2                  Pd cat., Solvent           5eVA'---'ATwA R1^                      R1 A-A >> X III                                                      IV Poly-halide I may be coupled with stannane II using Stille coupling conditions to provide compounds of type III. Various additives including (but not limited to) LiCl or Cui may be optionally employed to facilitate this reaction. Intramolecular ring closure of poly-halide III may be effected using two-step, one-pot borylation / Suzuki cross-coupling conditions to afford compounds of type IV.Method BHalide V may be coupled with stannane II using Stille coupling conditions to provide compounds of type VI. Various additives including (but not limited to) LiCl or Cui may be optionally employed to facilitate this reaction. Intramolecular ring closure of halide VI may be effected using C-H insertion cross-coupling conditions to afford compounds of type IV. Potassium acetate or potassium pivalate are effective bases for the macrocyclization step.B2pin2, Base, Ligand, Pd cat., SolventNitropyridine VII may be reduced using Fe metal conditions to provide aminopyridines of type VIII. In cases where the substrate contains an isoxazole moiety, yields can be improved by using SnCh conditions instead. Intramolecular ring closure of VIII may beeffected using two-step, one-pot borylation / Suzuki cross-coupling conditions to afford compounds of type IX.Method DBase, Ligand, Pd cat., SolventIXNitropyridine X may be reduced using Fe metal conditions to provide aminopyridines of type XI. In cases where the substrate contains an isoxazole moiety, yields can be improved by using SnCb conditions instead. Intramolecular ring closure of XI may be effected using 10 C-H insertion cross-coupling conditions to afford compounds of type IX. Potassium acetate or potassium pivalate are effective bases for the macrocyclization step.Method EB2pin2, Base, Ligand. Pd cat., SolventXVXII                  XIIIAlcohol XII may be reacted with chloropyrazine XIII using SNAr coupling conditions to form ether XIV. Intramolecular ring closure of XIV may be effected using two-step, one-pot borylation / Suzuki cross-coupling conditions to afford compounds of type XV.Method FXVIBase, Ligand, Pd cat., SolventXVXIII               XVII5 Alcohol XVI may be reacted with chloropyrazine XIII using SNAr coupling conditions to form ether XVII. Intramolecular ring closure of XVII may be effected using C-H insertion cross-coupling conditions to afford compounds of type XV. Potassium acetate or potassium pivalate are effective bases for the macrocyclization step.10 Method GNBS, SolventXVIII1. CsF, Solvent2. B2pin2, Base, Ligand, Pd cat., SolventXIXXXAminopyridine XVIII may be brominated with a suitable brominating reagent to provide bromide XIX. Desilylation of XIX using a suitable fluoride ion source, followed by15 intramolecular ring closure using two-step, one-pot borylation / Suzuki cross-coupling conditions may afford compounds of type XX.1. Base, Ligand, Pd cat.. Solvent2. TBAF, SolventNitropyridine XXI may be reduced using Fe metal conditions to provide aminopyridines 5 of type XXII. In cases where the substrate contains an isoxazole moiety, yields can be improved by using SnCh conditions instead. Intramolecular ring closure of XXII using C-H insertion cross-coupling conditions, followed by TBAF desilylation affords compounds of type XX. Potassium acetate or potassium pivalate are effective bases for the macrocyclization step.Method I2.NBS, SolventXXIII1. Fe, NH4CI, SolventBase, Ligand,Pd cat.. SolventXI                                     IXNitropyridine XXIII may be converted to compound XI by reduction using Fe metal 15 conditions followed by bromination with a suitable brominating reagent. Intramolecular ring closure of XI may be effected using C-H insertion cross-coupling conditions to afford compounds of type IX. Potassium acetate or potassium pivalate are effective bases for the macrocyclization step.Method JAcid, SolventXXIVIVCompounds of type XXIV may be deprotected to provide compounds of type IV by 5 treatment with a suitable acid in solution (e.g. TFA or HC1). Protecting groups amenable to this method include, but are not limited to, the methoxymethyl, 2-(trimethylsilyl)ethoxymethyl, tetrahydropyranyl, and p-methoxybenzyl groups.Method K2. Base, Ligand, Rd cat., Solvent1. TES, TFA or TMSI, SolventIXNitropyridine XXV may be reduced using Fe metal conditions to provide aminopyridines of type XI. In cases where the substrate contains an isoxazole moiety, yields can be improved by using SnCh conditions instead. Intramolecular ring closure of XI may be 15 effected using C-H insertion cross-coupling conditions to afford compounds of type IX.Potassium acetate or potassium pivalate are effective bases for the macrocyclization step.1. Fe, NH4CI or SnCI2, HCI SolventB2pin2, Base, Ligand, Pd cat,, SolventXXVIIX2. NBS, SolventNitropyridine X may be reduced using iron metal, and then brominated with NBS to 5 provide aminopyridines of type XXVI. In cases where the substrate contains an isoxazole moiety, yields can be improved by using SnCB reducing conditions instead of iron. Intramolecular ring closure of XXVI may be effected using two-step, one-pot borylation / Suzuki cross-coupling conditions to afford compounds of type IX.10 Method M1. H2, Pd / C, Solvent2. R4-X, Base, SolventXXVIIXXVIIICompounds of type XXVII may be first deprotected by hydrogenolysis using palladium on carbon under a hydrogen atmosphere, followed by alkylation of the resulting hydroxyl 15 group with an alkyl halide (e.g. methyl iodide) to provide compounds of type XXVIII.Protecting groups amenable to this method include, but are not limited to, the benzyl and p-methoxybenzyl groups.Method NXXIXFe, NH4CI or SnCI2, HCISolventBase, Ligand, Pd cat., SolventXXX                          XXXIXXXIIIXNitropyridine XXIX may be reduced using Fe metal conditions to provide aminopyridines of type XXX. In cases where the substrate contains an isoxazole moiety, yields can be improved by using SnCh conditions instead. Intramolecular ring closure of XXX may be10 effected using C-H insertion cross-coupling conditions to afford ketones of type XXXI. Potassium acetate or potassium pivalate are effective bases for the macrocyclization step. Reduction of the ketone XXXI to the alcohols of type XXXII can be effected using sodium borohydride. Finally, deoxygenation may be performed using triethylsilane and trifluoroacetic acid to afford compounds of type IX.15           Those having skill in the art will recognize that the starting materials and reactionconditions may be varied, the sequence of the reactions altered, and additional steps employed to produce compounds encompassed by the present disclosure, as demonstrated by the following examples. In some cases, protection of certain reactive functionalities may be necessary to achieve some of the above transformations. In general, the need for20 such protecting groups as well as the conditions necessary to attach and remove such groups will be apparent to experienced organic chemists. The disclosures of all articlesand references mentioned in this application, including patents, are incorporated herein by reference.The preparation of the compounds of the present disclosure is illustrated further by the following examples, which are not to be construed as limiting the disclosure in 5 scope or spirit to the specific procedures and compounds described in them.Analytical MethodsLCMS data was collected using one of the following methods:LCMS Method Method Details A Instrument: Agilent 1260-6125B Column: YMC Triart Cl8, 50x4.6 mm, 5 gm Mobile phase: A is H2O (+ 0.05% FA) and B is CH3CN (+ 0.05% FA) Run Time: 20% B (0.1 min); 20-95% B (1.4 min); 95% B (0.7 min); 20% B (0.5 min) Flow rate: 2.5 mL / min Column temperature: 35 °C Wavelength: 220 nm / 254 nm B Instrument: SHIMADZU 2020 Column: Inertsustain Cl8, 50x4.6 mm, 5 gm Mobile phase: A is H2O (+ 0.1% FA) and B is CH3CN Run Time: 15% B (0.6 min); 15-95% B (3.2 min); 95% B (0.5 min); 15% B (0.7 min) Flow rate: 2.5 mL / min Column temperature: 35 °C Wavelength: 220 nm / 254 nm C Instrument: SHIMADZU 2020 Column: YMC-Triart C18, 50x4.6 mm, 5 gm Mobile phase: A is H2O (+ 0.1% FA) and B is CH3CN Run Time: 20% B (0.1 min); 20-95% B (1 7 min); 95% B (0.7 min); 20% B (0.4 min) Flow rate: 2.5 mL / min Column temperature: 35 °C Wavelength: 220 nm / 254 nm D Instrument: SHIMADZU 2020 Column: YMC-Triart C18, 50x4.6 mm, 5 pm Mobile phase: A is H2O (+ 0.1% FA) and B is CH3CN Run Time: 0% B (0.6 min); 0-50% B (3.2 min); 50% B (0.5 min); 0% B (0.4 min) Flow rate: 2.5 mL / min Column temperature: 35 °C Wavelength: 220 nm / 254 nm E Instrument: SHIMADZU 2020 Column: Inertsustain Cl8, 50x4.6 mm, 5 pm Mobile phase: A is H2O (+ 0.1% FA) and B is CH3CN Run Time: 0% B (0.1 min); 0-50% B (1.7 min); 50% B (0.7 min); 0% B (0.4 min) Flow rate: 2.5 mL / min Column temperature: 35 °C Wavelength: 220 nm / 254 nm F Instrument: SHIMADZU 2020 Column: Shim-pack GIST Cl8, 50x4.6 mm, 5 pm Mobile phase: A is H2O (+ 0.1% FA) and B is CH3CN Run Time: 20% B (0.1 min); 20-95% B (1.7 min); 95% B (0.7 min); 20% B (0.4 min) Flow rate: 2.5 mL / min Column temperature: 35 °C Wavelength: 220nm / 254nm G Instrument: SHIMADZU 2020 Column: Shim-pack GIST Cl8, 50x4.6 mm, 5 pm Mobile phase: A is H2O (+ 0.1% FA) and B is CH3CN Run Time: 0% B (0.6 min); 0-50% B (3.2 min); 50% B (0.5 min); 0% B (0.4 min) Flow rate: 2.5 mL / min Column temperature: 35 °C Wavelength: 220nm / 254nm H Instrument: SHIMADZU 2020 Column: Inertsil ODS-3 C18, 50x4.6 mm, 5 pm Mobile phase: A is H2O (+ 0.04% aq. NH3) and B is CH3CN Run Time: 20% B (0.1 min); 20-95% B (1.7 min); 95% B (0.7 min); 20% B (0.4 min) Flow rate: 2.5 mL / min Column temperature: 35 °C Wavelength: 220nm / 254nm I Instrument: SHIMADZU 2010 Column: Shim-pack GIST Cl8,50x4.6 mm, 5 pm Mobile phase: A is 10% CH3CN in H2O + 0.05% FA and B is CH3CN Run Time: 20-95% B (1.8 min); 95% B (0.9 min) Flow rate: 2.3 mL / min Column temperature: 40 °C Wavelength: 220nm / 254nm J Instrument: SHIMADZU 2020 Column: Inertsil ODS-3 C18, 50x4.6 mm, 5 pm Mobile phase: A is H2O (+ 0.04% aq. NH3) and B is CH3CN Run Time: 15% B (0.6 min); 15-95% B (3.2 min); 95% B (0.5 min); 15% B (0.4 min) Flow rate: 2.5 mL / min Column temperature: 35 °C Wavelength: 220nm / 254nm K Instrument: SHIMADZU 2020 Column: Kromasil EternityXT C18, 50x4.6 mm, 5 pm Mobile phase: A is H2O (+ 0.1% FA) and B is CH3CN Run Time: 20% B (0.1 min); 20-95% B (1.7 min); 95% B (0.7 min); 20% B (0.4 min) Flow rate: 2.5 mL / min Column temperature: 35 °C Wavelength: 220nm / 254nm L Instrument: SHIMADZU 2020 Column: YMC Triart Cl8, 50x4.6 mm, 5 pm Mobile phase: A is H2O (+ 0.1% FA) and B is CH3CN Run Time: 15% B (0.6 min); 15-95% B (3.2 min); 95% B (0.5 min); 15% B (0.4 min) Flow rate: 2.5 mL / min Column temperature: 35 °C Wavelength: 220nm / 254nm M Instrument: SHIMADZU 2020 Column: Shim-pack GIST Cl8,50x4.6 mm, 5 pm Mobile phase: A is H2O (+ 0.05% FA) and B is CH3CN Run Time: 0% B (0.6 min); 0-70% B (3.2 min); 70% B (0.5 min); 0% B (0.4 min) Flow rate: 2.5 mL / min Column temperature: 35 °C Wavelength: 220nm / 254nm Synthetic ExamplesSynthesis of 3-chloro-5-iodo-lH-pyrazoleIntermediatesHN-N 5                         1-++0Under a nitrogen atmosphere, to a solution of 3-chloro-N,N-dimethyl-lH-pyrazole-l-sulfonamide (1.90 g, 9.06 mmol) in THF (40 mL) was added n-butyllithium (4.35 mL, 10.9 mmol) dropwise at -78 °C. A thick precipitate formed, and the solution was allowed to stir for 30 min after the addition. To the stirred suspension, a solution of 1-iodopyrrolidine-2,5-dione (2.24 g, 9.97 mmol) in THF 10   (10 mL) was added dropwise at -78 °C. After 1 h, the resulting clear solution was warmed to roomtemperature. The reaction was quenched by sat. NH4CI at 0 °C and extracted with DCM (3 x 50 mL). Tire organic layer was separated, washed with brine, dried over anhydrous Na2SO4 and concentrated. The residue was purified by column chromatography on silica gel (30% EtOAc in PE) to give 3-chloro-5-iodo-N,N-dimethyl-lH-pyrazole-l-sulfonamide (3.0 g, yield: 89%) as a 15 white solid. LC / MS (ESI): m / z = 336 [M+H]+.In a round bottom flask with magnetic stirrer, 3-chloro-5-iodo-N,N-dimethyl-lH-pyrazole-l-sulfonamide (3.00 g, 8.94 mmol) in DCM (8 mL) was cooled to 0 °C and treated with TFA (8.0 mL, 108 mmol). The mixture was stirred for 1.5 h. The reaction was quenched with sat. NaHCO; and extracted with EA (2 x 50 mL). Tire extracts were dried over with anhydrous Na2SO4 and concentrated under reduced pressure to give crude 3-chloro-5-iodo-lH-pyrazole (2.1 g, yield: 100%) as a yellow solid. LC / MS (ESI): m / z = 229 [M+H]+.Synthesis of (nitromethyl)cyclobutaneTo a solution of (nitromethylidene)cyclobutane (9.8 g, 86.63 mmol) in MeOH (50 mL), was added NaBEL (4.94 g, 130 mmol) at 0 °C, and stirred at 0 °C for 60 min. The reaction was quenched by adding cold water and filtered. The filtrate was dissolved in EtOAc, washed once with water, once with brine, dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated to give a residue, which was purified by flash chromatography (0^5% MeOH in DCM) to give (nitromethyl)cyclobutane (4.4 g, 44% yield) as a colorless oil. LC / MS ESI (m / z): 116 [M+H]+.Synthesis of (5-bromo-l,3-thiazol-4-yl)methanolTo a solution of methyl 5-bromo-l,3-thiazole-4-carboxylate (5.00 g, 22.5 mmol) in THF (100 mL) at 0 °C was added LiBH4 (2.94 g, 135 mmol). Then MeOH (10 mL) was added dropwise to the above solution. The mixture was stirred at r.t. for 16 h. The reaction was quenched with water and extracted with EA (50 mL x 3). The organic phase was washed with brine, dried over N^SO^ and concentrated under vacuum to yield crude (5-bromo-l,3-thiazol-4-yl)methanol as a light-yellow solid (1.00 g, 23% yield). LC / MS ESI (m / z): 194 [M+H]+.Synthesis of 5-chIoro-3-iodo-l-methyl-lH-pyrazoleTo a mixture of 5-chloro-3-iodo-lH-pyrazole (100 mg, 0.440 mmol) and K2CO3 (121 mg, 0.880 mmol) in DMF (8 mL) was added methyl iodide (0.03 mL, 0.5 mmol) at 25 °C. The mixture was then stirred at r.t. for 30 min. The reaction mixture was quenched with ice water, extracted twice into EA, washed with brine, dried over anhydrous Na2SO4, filtered and concentrated to give crude5-chloro-3-iodo-l-methyl-lH-pyrazole (100 mg, 94% yield) as a yellow liquid. The material can be used as-is, or further purified by flash-, high-pressure-, or supercritical fluid-chromatography to separate possible regioisomers. LC / MS (ESI) m / z: 243 [M+H]+.The following intermediates were synthesized using a similar experimental protocol:l-ethyl-3-methyl-lH-pyrazole-4-carbaldehyde N—( ) + 3r ,0 m / z (ESI): 139 [M+H] l-(cyclopropylmethyl)-3-methyl-lH-pyrazole-4-carbaldehyde N=^ ) + 3r > zo ______„ zA N ^\^NS m / z (ESI): 165 [M+H] 5-bromo-l-ethyl-4-((3-fluoro-5-iodo-lH-pyrazol-l-yl)methyl)-lH-pyrazole Br / —N Cl + N 11 r H                           Br -N X— F ------'    z— N N X\_F V m / z (ESI): 399 [M+H] 5-bromo-l-ethyl-4-((5-iodo-3-methyl-lH-pyrazol-l-yl)methyl)-lH-pyrazole Br / —N J ^ci + H'n r Br 'N               X ’  ------ / ~N '   N- ^N'V_ m / z (ESI): 395 [M+H] 3-chloro-5-iodo-l-(prop-2-yn-l-yl)-lH-pyrazole Br ix + H k ^NZ^CI     ’ KzN 'N Cl m / z (ESI): 267 [M+H] 3-chloro-l-{ [ 1-(2,2-difluoroethyl)-lH-pyrazol-4-yl]methyl}-5-iodo-lH-pyrazole F J k _                F r        XA             J N k / CI *         °'       ' H   N                         > :=1 < / N'N m / z (ESI): 373 [M+H] 1 -i so butyl -3 -methyl-1 Fl-py razole -4 -carbaldehyde I. x * h'n^ 1 N O° m / z (ESI): 167 [M+H] l-ethyl-3-(trifluoromethyl)-lH-pyrazole )+ NX w -4-F ------- xX F F T-F F m / z (ESI): 165 [M+H] 5-bromo-l-((l-ethyl-lH-pyrazol-4-yl)methyl)-3-methoxy-lH-pyrazole .     N—,                                             M    Br ^Cl   ,N-N x H                                      N m / z (ESI): 285 [M+H] methyl 3-ethyl-1 -methyl- lH-pyrazole-5-carboxylate O                      O 1 + N-N                      N-N H                              X m / z (ESI): 169 [M+H] Synthesis of l-ethyl-lH-pyrrole-3-carbaldehydeTo a solution of lH-pyrrole-3-carbaldehyde (5.00 g, 52.6 mmol) in DMF (30 mL) was added K2CO3 (12.4 g, 89.4 mmol) and lodoethane (5.0 mL, 63 mmol) at 0 °C. The mixture was stirred at r.t. for5    16 h, filtered, and the filtrate was diluted with ethyl acetate (30 mL). The solution was washed withbrine (50 mL), dried over anhydrous Na2SO4 and concentrated. The residue was purified by flash chromatography (0% —» 35% EA in PE) to give l-ethyl-lH-pyrrole-3-carbaldehyde (4.0 g, 62% yield) as a yellow oil. LC / MS (ESI) m / z: 124.1 [M+H] *The following intermediates were synthesized using a similar experimental protocol:1-(2,2-difluoroethyl)-lH-pyrazole-4-carbaldehyde F                                    z=N F k       O. /   •             . O.       -     1 Br^ / ^F    ^x>-N'h m / z (ESI): 161 [M+H] 4-chloro-l-((l-ethyl-lH-pyrazol-4-yl)methyl)-lH-pyrazole 0 (fS z-z A z 0 A z-z r' + 0 A m / z (ESI): 211 [M+H] l-((5-bromopyrimidin-4-yl)methyl)-lH-imidazole-4 -carbonitrile N^N       P=N            N^N  pzN + ,   —=N ---" yjy^Ny =N Br                                             Br m / z (ESI): 264 [M+H] 1 -(ethyl -d5) -1 H-pyrazole -4-carbal dehyde -H       ?H 2?h                       / =n >H 2;h + 2h ’ * 0    "        2h2h                     2h2h m / z (ESI): 130 [M+H] 4-iodo-l -(oxetan-3-yl)- IH-pyrazole 0 A 0 ’A m / z (ESI): 251 [M+H] 1 -(cyclopropylmethyl)- lH-pyrazole-4-carbaldehyde ox N          0         A r + Br m / z (ESI): 151 [M+H] Synthesis of 3-ethylisoxazole-5-carbaldehydeN-0To a solution of (3-ethylisoxazol-5-yl)methanol (4.00 g, 31.5 mmol) in DCM (100 mL) was added DMP (16.01 g, 37.75 mmol) at 0 °C and the mixture was stirred at r.t. for 1 h (additional equivalents 5 of oxidizing agent may be added to ensure complete oxidation of substrates containing multiple alcohol groups). The mixture was washed with sat. NaaSsO? (100 mL) and sat. NaHCOs (100 mL), dried over anhydrous NaaSCL and concentrated to dryness. The residue was purified by flash chromatography on silica gel (20% EtOAc in PE) to give 3-ethylisoxazole-5-carbaldehyde (3.37 g, yield: 86%) as a yellow oil. LC / MS (ESI): m / z = 126 [M+H]+.10 Synthesis of (l-ethyl-lH-pyrazol-4-yl)methanolTo a solution of 1 -ethyl-lH-pyrazole-4-carbaldehyde (2.10 g, 16.9 mmol) in THF (10 mL) was added diisobutylaluminium hydride (13.5 mL, 20.3 mmol) at -78 °C (this protocol can be modified to enable full reduction of esters to alcohols by increasing the number of equivalents of reducing 15 agent). The mixture was stirred -78 °C for 0.5 h, then warmed to 25 °C for 1 h. The reaction was quenched by sat. aq. NH4CI (5 mL), then extracted with EtOAc (15 mL x 3). The combined organic layers were washed with brine (15 mL) and dried over anhydrous NaaSO4, then concentrated. The residue was purified by flash chromatography (50^100% EtOAc in PE) to give (l-ethyl-1 / 7-pyrazol-4-yl)methanol (480 mg, yield: 23%) as a light-yellow oil. LCMS (ESI) m / z: 127 [M+H]+.Synthesis of 4-(chloromethyl)-l-ethyl-lH-pyrazoleClCl-s'.To a solution of (l-ethyl-lH-pyrazol-4-yl)methanol (1.40 g, 11.1 mmol) in DCM (15 mL) at 0 °C was added SOCh (3.96 g, 33.3 mmol) dropwise under an N2 atmosphere. After the addition, the5 mixture was stirred at 0 °C for 2 h. The mixture was concentrated to dryness to give crude 4-(chloromethyl)-l-ethyl-lH-pyrazole (1.60 g, 100% yield) as a yellow oil. LC / MS (ESI) m / z: 145 [M+H]+.The following intermediates were synthesized using a similar experimental protocol:5-bromo-4-(chloromethyl)-1 -ethyl-lH-pyrazole Br                                          Br 1                          Cl                                   1 OH+ Cl S-           ‘                  C| N= /           O m / z (ESI): 223 [M+H] 5-bromo-4-(chloromethyl)-1 -(difluoromethyl)-lH-pyrazole Br                                           Br 1 F              Cl                               1 F N-\  + Ci'S        •  CI^^Z' N-^ F 0 F m / z (ESI): 245 [M+H] Synthesis of 5-(chloromethyl)-3-ethylisoxazoleciCl-s.To a stirred solution of (3-ethyl-l,2-oxazol-5-yl)methanol (4.10 g, 32.3 mmol) in dry DCM (10 mL) was added triethylamine (5.8 mL, 42 mmol), followed by the addition of thionyl chloride (2.8 mL, 39 mmol) at 0 °C over a period of 10 min. After the addition, the reaction mixture was stirred at r.t. for 5.0 h under N2. The reaction mixture was cooled to 0 °C and quenched with 10% aq. NaCl.15 The mixture was then extracted with DCM twice, and the combined extracts were washed with sat.aq. NaHCOr, dried over anhydrous Na2SO4 and concentrated in vacuo. Tire residue was purified by column chromatography on silica gel (10—»30% EA in PE) to give 5-(chloromethyl)-3-ethyl-l,2-oxazole (4.20 g, yield: 90%) as a yellow oil. LC / MS ESI (m / z): 146 [M+H]+.The following intermediates were synthesized using a similar experimental protocol:5-(chloromethyl)-3-cyclobutylisoxazole Cl             / X  A ho         + ci-s  —* ci ry-A / O-N            O             O-N m / z (ESI): 172 [M+H] Synthesis of 5-(bromomethyl)isoxazole-3-carbonitrileTo a solution of 5-methylisoxazole-3-carbonitrile (3.0 g, 28 mmol) and NBS (3.2 g, 56 mmol) in DCE (120 mL) was added AIBN (230 mg, 1.40 mmol) under N2 at 25 °C. Then the resulting solution was heated to 80 °C and stirred for 16 h. After cooling to r.t., the reaction mixture was diluted with DCM, washed with sat. NaHCOs solution and brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by column chromatography on silica gel (10% EtOAc in PE) to give 5-(bromomethyl)isoxazole-3-carbonitrile as a yellow oil (2.2 g, yield: 42%). LC / MS ESI (m / z): 187 [M+H]+.Synthesis of 5-bromo-2-methylthiazole-4-carbaldehydeBrTo a solution of ethyl 5-bromo-2-methylthiazole-4-carboxylate (4.13 g, 16.5 mmol) in THF (120 mL) was added diisobutylaluminium hydride (16.5 mL, 24.8 mmol, 1.5 M in THF) dropwise at -78 °C. The mixture was stirred at -78 °C for 3 h. After 3 h, the reaction mixture was sequentially diluted with EA (50 mL), water (1.0 mL), aq. NaOH solution (15%, 1.0 mL), and then water (10 mL) at 0 °C. After wanning to r.t., the mixture was stirred for 15 min. Anhydrous MgSO4 was added, stirring was continued for 15 min, and then the mixture was filtered to remove solids. The filtrate was concentrated in vacuo to give crude 5-bromo-2-methylthiazole-4-carbaldehyde (2.59 g, 76%) as a yellow solid. LC / MS ESI (m / z): 206 [M+H]+.Synthesis of 5-bromo-3-chloro-l-ethyl-lH-pyrazoleBr XBrClBrBrTo a solution of 3-chloro-l-ethyl-lH-pyrazole (3.00 g, 23 0 mmol) in THF (20 mL) was added n-BuLi (2.5 M in hexanes, 10.1 mL, 25.3 mmol) at -78 °C. The mixture was stirred at -78 °C for 1 h. Then a solution of CBu (7.6 g, 23 mmol) in THF (15 mL) was added dropwise. The mixture was stirred at -78 °C for 1 h, then quenched with water (10 mL). The mixture was extracted with EA (20 mL) for three times. The organic layer was combined, dried over NaaS^, concentrated under reduced pressure. The residue was purified by flash chromatography eluting with EA in PE (0 —»10%) to give 5-bromo-3-chloro-l-ethyl-lH-pyrazole (3.5 g, 73%) as a pale-yellow oil. LC / MS (ESI): m / z = 209 [M+H]+.The following intermediates were synthesized using a similar experimental protocol:5-bromo-l-(cyclopropyhnethyl)-3-methyl-lH-pyrazole Br Br                    A Br^Br * m / z (ESI): 215 [M+H] Synthesis of 5-iodo-2-methyl-2H-l,2,3-triazole-4-carbaldehydeTo a solution of 4,5-diiodo-2-methyl-2H-l,2,3-triazole (2.5 g, 7.4 mmol) in THF (30 mL) was added n-butylhthmm (2.5 M in hexane, 3.2 mL, 8.2 mmol) and stirred at -78 °C for 1 h. Then DMF (0.57 mL, 7.4 mmol) was added to the mixture and stirred at -78 °C for 1 h. The mixture was quenched with sat. aq. NH4CI (30 mL) at 0 °C and extracted with EA (100 mL x 3). The combined organic layers were combined, dried over anhydrous Na2SO4, fdtered, and concentrated in vacuo. The residue was purified by column chromatography on silica gel (PE : EA = 3 : 1, V / V) to give 5-iodo-2-methyl-2H-l,2,3-triazole-4-carbaldehyde (1.15 g, 65%) as a light-yellow solid. LC / MS (ESI) m / z: 238 [M+H]+.Synthesis of (5-iodo-l-methyl-lH-pyrazol-4-yl)methanolTo a mixture of 5-iodo-l-methyl-lH-pyrazole-4-carbaldehyde (2.00 g, 8.47 mmol) in MeOH (30 mL) was added NaBH4 (84 mg, 2.5 mmol) at -10 °C. The mixture was stirred at 20 °C for 1 h. The mixture was quenched with sat. NH4CI (10 mL) and extracted with EA (60 mL x 3). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by column chromatography on silica gel (5% MeOH in DCM) to afford (5-iodo-l-methyl-lH-pyrazol-4-yl)methanol as a light-yellow solid (840 mg, yield: 41%). LC / MS ESI (m / z): 239 [M+H]+.The following intermediates were synthesized using a similar experimental protocol:(1 -(cyclopropylmethyl)-lH-pyrazol-4-yl)methanol o AN A      H0 AN A —"A / N              ”   ''"'"A, N m / z (ESI): 153 [M+H] [ 1 -(cyclopropylmethyl)-3 -methyl- lH-pyrazol-4-yl]methanol A Vk 0 Az Vk 0 1 m / z (ESI): 167 [M+H] (1 -ethyl-3-methyl-lH-pyrazol-4-yl)methanol 0 / Z 0 1 m / z (ESI): 141 [M+H] [l-(2,2-difluoroethyl)-lH-pyrazol-4-yl]methanol z=N                      r=N f O, A- 1   ___HO A k —A-^'-'-A-f        x-An'Af m / z (ESI): 163 [M+H] (1 -(ethyl-d5)- lH-pyrazol-4-yl)methanol I 1 A? A1 ~ / z V 0 T T r A? A? V 0 m / z (ESI): 132 [M+H] Synthesis of (3-iodo-l-methyl-lH-pyrazol-4-yl)methanolTo a solution of 3-iodo-1 -methyl-1 / 7-pyrazolc-4-carbaidchydc (2.00 g, 8.47 mmol) in dry THF (20 5 mb) was added DIBAL-FI (1.0 M in toluene, 12 mL, 12 mmol) dropwise at -70 °C (additional equivalents of reducing agent may be utilized in cases where more than one hydride transfer is required). The mixture was stirred at -70 °C for 2 h before quenching with sat. aq. NH4CI. The resulting mixture was filtered, and the filter cake was washed with THF. The combined filtrates were concentrated under reduced pressure; the residue was diluted with DCM, washed with water 10 and brine, dried over anhydrous NajSCE and concentrated. The residue was purified by column chromatography on silica gel (0^20% of EA in PE) to give (3-iodo-l-methyl-17 / -pyrazol-4-yl)methanol (1.6 g, 79% yield) as a yellow oil. LC / MS ESI (m / z): 239 [M+H]+.The following intermediates were synthesized using a similar experimental protocol:(1 -ethyl -3 -methoxy-1 H-py razol-4 -yl )methanol 0 p-V'" on m / z (ESI): / — N J                *   \ / N^o 1 — N 3 'n o 157 [M+H] Synthesis of (5-iodo-2-methyI-2H-l,2,3-triazol-4-yl)methanolA mixture of 5-iodo-2-methyl-2H-l,2,3-triazole-4-carbaldehyde (1.05 g, 4.40 mmol) in MeOH (55 mL) was added NaBH4 (0.15 g, 4.4 mmol) and stirred at 0 °C for 1 h. The mixture was quenched with sat. aq. NH4C1 solution (30 mL) at 0 °C and extracted with EA (50 mL x 3). The combined organic layers were dried over anhydrous NazSCU, filtered, and concentrated in vacuo. The residue was purified by flash chromatography (PE : EA = 1 : 1, V / V) to give (5-iodo-2-methyl-2H-l,2,3-triazol-4-yl)methanol (960 mg, 91%) as a light-yellow solid. LC / MS (ESI) m / z: 240 [M+H]+.10 The following intermediates were synthesized using a similar experimental protocol:(1 -isobutyl-3 -methyl -1 H-pyrazol-4-yl)methanol /   N=<                     / N= / m / z (ESI): ---* -A OH 169 [M+H] Synthesis of 4-(chloromethyl)-3-iodo-l-methyl-lH-pyrazoleClCl-s'.'0To a solution of (3-iodo-l-methyl-lH-pyrazol-4-yl)methanol (1.00 g, 4.20 mmol) in DCM (20 mL) was added thionyl chloride (0.90 mL, 13 mmol) at 0 °C. After addition, the mixture was stirred at15 r.t. for 3 h, and then concentrated to give crude 4-(chloromethyl)-3-iodo-l-methyl-lH-pyrazole (1.0 g, 93%) as a yellow oil. LCMS (ESI): m / z = 257 [M+H]+.The following intermediates were synthesized using a similar experimental protocol:4-(chl oromethyl)-1 -(cyclopropylmethyl)- IH-pyrazole HO / ^N A       Cl         of         A + ci-s. -------- 0                      ' m / z (ESI): 171 [M+H] 4-(chloromethyl)-l-(cyclopropylmethyl)-3-methyl-lH-pyrazole A   N=^ Z          Cl           A N=Z L OH + Cl-S -------► +A \ Cl m / z (ESI): 185 [M+H] 4-(chl oromethyl)-1 -ethyl-3 -methoxy-1 H-pyrazole N A' OH     Cl              ^A'CI (       + Cl-S. -------►   \_N_ %"    O          N^O^ m / z (ESI): 175 [M+H] 5-bromo-4-(chloromethyl)-1 -cyclobutyl-lH-pyrazole Br -             ci                      r=N. _ + ci-s. -----* cis-Ax / N Br m / z (ESI): 249 [M+H] 4-(chloromethyl)-! -ethyl-3-methyl-lH-pyrazole nJ /           Cl                 N=rZ L OH+ Cl-S.         ”   \_N A Cl 0 m / z (ESI): 159 [M+H] 4-(chloromethyl)-l-(2,2-difluoroethyl)-lH-pyrazole HO V-X^N F             Cl                        N F + ci-s.  —*      n^f O m / z (ESI): 181 [M+H] 5-(chloromethyl)-3-(cyclopropylmethyl)isoxazole zrX 1 \ Q O. .O CO ’ 0 + m / z (ESI): 172 [M+H] 4-(chl oromethyl)-! -(2-fluoroethyl)- IH-pyrazole Cl Cl-S. + F 0 p 0 T 0 m / z (ESI): 163 [M+H] Synthesis of 5-bromo-l-ethyl-4-iodo-lH-pyrazoleBr X BrBrBrBrTo a solution of l-ethyl-4-iodo-lH-pyrazole (105.0 g, 425.6 mmol) in THF (900 mL) at -78 °C was 5 added LDA (2.0 M in heptane / THF / ethylbenzene, 212.8 mL, 425.6 mmol) dropwise under a N2 atmosphere over 1 h. After the addition, the mixture was stirred at -78 °C for 0.5 h, and then asolution of tetrabromomethane (148.0 g, 445.0 mmol) in THF (50 mL) was added dropwise over 0.5 h. The resulting mixture was stirred at -78 °C for an additional 1 h. The reaction flask was transferred to an ice bath, and the mixture was quenched with sat. NH4CI aq. solution (200 mL). The aq. phase was extracted with DCM twice (250 mL x 2). The combined organic layers were5 washed with brine, dried over anhydrous Na2SO4. filtered and concentrated. The residue was purified by column chromatography on silica gel (2% EtOAc in PE) to give the target product as a brown solid (90 g, yield: 70%). LC / MS ESI (m / z): 301 [M+H]+.The following intermediates were synthesized using a similar experimental protocol:5 -bromo-1 -cyclobutyl-4-iodo-1 H-pyrazole co" \ ,z h ^z^ + co m m / z (ESI): 327 [M+H] 5 -bromo-1 -cyclopropyl-4-iodo-1 H-pyrazole co~\ 2 z* z + m co co m m / z (ESI): 313 [M+H] 4-chloro-l-((l-ethyl-lH-pyrazol-4-yl)methyl)-5-iodo-lH-pyrazole ^z Z \ z -z o + T z -z 0 m / z (ESI): 337 [M+H] Synthesis of 2-ethyl-4,5-diiodo-2H-l,2,3-triazole / 1                                          zl\                         .N=Y' + H'n A          * -N AIQ                                               I             'n 1                             'N 1To a solution of 4,5-diiodo-2H-l,2,3-triazole (50 mg, 0.18 mmol) in THF (5 mL) was added NaH (14 mg, 0.36 mmol, 60% in mineral oil) at 0 °C. Then iodoethane (2.94 g, 0.890 mmol) was added and the mixture was stirred at 25 °C for 16 h. The reaction was quenched by H2O (5 mL) at 0 °C, then extracted with EtOAc (15 mL x 3). The combined organic layers were washed with brine (1515 mL), dried over anhydrous Na2SO4, then concentrated. The residue was purified by flash chromatography (silica gel, 0^25% EtOAc in PE) to give 2-ethyl-4,5-diiodo-2H-l,2,3-triazole (1.47 g, yield: 68%) as a white solid. LC / MS (ESI) m / z: 350 [M+H]+.Synthesis of l-(cyclopropylmethyl)-3-methyl-lH-pyrazoleBrk'N'A mixture of 3-methyl-lH-pyrazole (5.90 mL, 73.1 mmol), (bromomethyl)cyclopropane (7.90 mL, 80.4 mmol) and KaCOs (20.20 g, 146.2 mmol) in DMF (100 mL) was stirred at 80 °C for 16 h. The5 reaction mixture was added water and extracted with EtOAc. Tire organic layer was washed with brine, dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by flash column chromatography to afford l-(cyclopropylmethyl)-3-methyl-lH-pyrazole (6.00 g, 60%) as a yellow solid. LC / MS (ESI) m / z: 137 [M+H]+.The following intermediates were synthesized using a similar experimental protocol:1-cyclobutyl-4-iodo-lH-pyrazole co + 4 m / z (ESI): 249 [M+H] ethyl 1 -ethyl-3 -methoxy- lH-pyrazole-4-carboxylate \         H                O \ + Br         O T N                      / -N °x m / z (ESI): 199 [M+H] 3 -chloro-1 -(2,2-difluoroethyl)- IH-pyrazole r         r=\                       F Br^AF + m / z (ESI): 167 [M+H] l-(2,2-difluoroethyl)-4-iodo-lH-pyrazole £      FN'H ___ / =” F m / z (ESI): 259 [M+H] l-(cyclopropylmethyl)-4-iodo-3-methyl-lH-pyrazole a    y'          y 2 * yy * ‘X'Q- m / z (ESI): 263 [M+H] methyl 1 -(2-fluoroethyl)-lH-pyrazole-4-carboxylate \ o-° fii z-2 LL \ 0^° z-2 / T + m / z (ESI): 173 [M+H] l-((3-chloropyrazin-2-yl)methyl)-lH-pyrazole-4-carbonitrile Jk Al +      —SN      " Y         H                     t Cl                                                   Cl m / z (ESI): 220 [M+H] Synthesis of 5-bromo-l-ethyl-lH-pyrazole-4-carbaldehydeBrBrTo a solution of 5-bromo-l-ethyl-IH-pyrazole (100 g, 571 mmol) in TFA (700 mL) at 0 °C was added 1,3,5,7-tetraazaadamantane (120 g, 857 mmol). The resulting mixture was stirred at 90 °C 5 for 16 h. After cooling to r.t., the mixture was concentrated under reduced pressure to remove most of the TFA. The residue was diluted with DCM (600 mL), washed with sat. NaHCO? and brine, dried over anhydrous Na^SOi, filtered and concentrated. The residue was purified by column chromatography on silica gel (10% EtOAc in PE) to give 5-bromo-1-ethyl-lH-pyrazole-4-carbaldehyde as a white solid (60 g, yield: 52%). LC / MS ESI (m / z): 203 [M+H]+.10 The following intermediates were synthesized using a similar experimental protocol:5 -chloro-3 -iodo -(1 -methyl -1 H-py razole -4 -carbal dehyde) N^1         'V < ‘ n< /             r                     ! Cl                                Cl J m / z (ESI): 271 [M+H] 5-bromo-l -(cyclopropylmethyl)-3-methyl-lH-pyrazole-4-carbaldehyde 'AN> .           ___- A Br                    V Br \ ,0 m / z (ESI): 243 [M+H] 5 -bromo-3 -chloro-1 -ethyl - lH-pyrazole-4-carbaldehyde < r                  r Br                               Br Cl m / z (ESI): 237 [M+H] 3-chloro-l-(2,2-difluoroethyl)-lH-pyrazole-4-carbaldehyde . F z-N-V1        J V    y kA     C ,0 m / z (ESI): 195 [M+H] l-ethyl-3-(trifluoromethyl)-lH-pyrazole-4-carbaldehyde /          +       N A f ------►     / —N 1 F 'N^F       / N^F F                             F m / z (ESI): 193 [M+H] Synthesis of l-(5-bromo-l,3-thiazol-4-yl)prop-2-yn-l-olOH BrTo a solution of 5-bromo-l,3-thiazole-4-carbaldehyde (1.80 g, 9.37 mmol) in THF (20 mL) was added ethynylmagnesium bromide (28.1 mL, 14.1 mmol). The mixture was stirred at r.t. overnight 5 and then quenched with water. The mixture was twice extracted with EA (100 mL). The combined organic layers were concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel eluting with EA in PE (0 —> 30%) to give l-(5-bromo-l,3-thiazol-4-yl)prop-2-yn-l-ol (1.50 g, 73%) as a colorless oil. LC / MS (ESI): m / z = 218 [M+H]+.The following intermediates were synthesized using a similar experimental protocol:1 -(2-bromo-4-fluorophenyl)prop-2-yn-1 -ol Br                                Br \                          HO \ = Mg Br +        L   -----   , / \\ 0 Vy F           / / 7        F m / z (ESI): 229 [M+H] l-(5-iodo-2-methyl-2H-l,2,3-triazol-4-yl)prop-2-yn-l-ol 11 (Q CO + / 0 1 .z A? )-0 / 1 m / z (ESI): 264 [M+H] 10 Synthesis of (4-bromo-3-ethylisothiazol-5-yl)methanolBrTo a stirred mixture of 5-((tetrahydro-2H-pyran-2-yl)oxy)pent-3-yn-2-one (5.00 g, 25.5 mmol) and (aminooxy)sulfonic acid (3.20 g, 25.1 mmol) in H2O (100 mL) at 0 °C. The resulting mixture was stirred at ambient temperature for 4 h. And then was added NaHCOs (2.40 g, 28.1 mmol) and 15 sodium hydrosulfide (2.20 g, 38.3 mmol). The resulting mixture was stirred at 80 °C for 16 h. The filtrate was extracted with ethyl acetate and washed with brine, dried over Na2SO4 and concentrated under vacuum. The residue was purified by flash chromatography on silica gel (0^20% ethylacetate in petroleum ether) to afford (3-ethylisothiazol-5-yl)methanol (1 46 g, 40% yield) as a yellow oilA mixture of (3-ethylisothiazol-5-yl)methanol (1.80 g, 12.6 mmol), dibromine (7.00 g, 44.1 mmol) and potassium acetate (1.96 g, 20.0 mmol) in AcOH (40 mL) was stirred at ambient temperature for 16 h. The resulting mixture was quenched with Na^STH The solution was basified with NaHCOj and extracted with DCM, dried over Na2SO4 and concentrated under vacuum. The residue was purified by flash phase chromatography on silica gel (0—»15% ethyl acetate in petroleum ether) to afford (4-bromo-3-ethylisothiazol-5-yl)methanol (2.04 g, 73% yield) as a yellow oil. LC-MS (ESI) m / z: 222 [M+H]+.Synthesis of 4-fluoro-2-iodobenzonitrileA mixture of 4-fluoro-2-iodobenzamide (4.00 g, 15.1 mmol) in thionyl chloride (30 mL) was stirred at 90 °C for 16 h. The mixture was concentrated to give crude 4-fluoro-2-iodobenzonitrile (2.40 g, 64% yield) as a yellow oil. LC / MS (ESI) m / z: 248 [M+H]+.The following intermediates were synthesized using a similar experimental protocol:5-((5 -iodo-2-methyl-2H-1,2,3 -triazol-4-yl)methyl)isoxazole-3 -carbonitrile H2N N~o 'VsN                   n-0 Jo ,N —       "  Nz=—C .4 Jo .N~~ m / z (ESI): 316 [M+H] Synthesis of (4-fluoro-2-iodophenyl)hydrazinelTo a mechanically stirred solution of 4-fluoro-2-iodoaniline (5.0 g, 21 mmol) in AcOH (10 mL) was slowly added cone. HC1 (40 mL). The solution quickly became a thick suspension. The reaction was then cooled to 0 °C in an ice bath and treated slowly dropwise with a solution of sodium nitrite (1.63 g, 23.6 mmol) in water (8 mL). The reaction was stirred for 1 h, then a solution of SnCL (8.46 g, 44.5 mmol) in cone. HC1 (8 mL) was added slowly. The reaction was allowed to warm to r.t. over 2 h. The suspension was filtered, washed with water and dried under vacuum to give crude (4-fluoro-2-iodophenyl)hydrazine hydrochloride (4.1 g, yield: 77%) as a gray solid. LC / MS (ESI) m / z: 253 [M+H]+.Synthesis of 5-bromo-4-(bromomethyl)-l-ethyl-lH-pyrazoleBrBrTo a stirred solution of (5-bromo-l-ethyl-lH-pyrazol-4-yl)methanol (4.00 g, 19.5 mmol) and triphenylphosphine (6.14 g, 23.4 mmol) in dry DCM (50 mL) was added a solution of tetrabromomethane (7.76 g, 23.4 mmol) in DCM dropwise at 0 °C. After the addition, the reaction mixture was stirred at r.t. for 24 h. The reaction mixture was concentrated in vacuo and the residue was purified by silica gel column chromatography (eluent: PE / EtOAc 50 / 1 to 10 / 1) to give 5-bromo-4-(bromomethyl)-l-ethyl-lH-pyrazole (3.0 g, 57% yield) as a white solid. LC / MS ESI (m / z): 267 [M+H]+.Synthesis of (3-cyano-l-methyl-lH-pyrazol-5-yl)boronic acidOHTo a solution of 1-methyl-lH-pyrazole-3-carbonitrile (1.0 g, 9.3 mmol) in THF (15 mL) was added LDA (2 M in THF, 4.7 mL, 9.3 mmol) dropwise under the atmosphere ofN2 at -78 °C. After stirnng for 0.5 h at -78 °C, trimethyl borate (1.9 g, 19 mmol) in THF (2 mL) was added dropwise. After stirring at -78 °C for 1 h, the reaction was quenched with sat. aq. ammonium chloride. The reaction was diluted with EtOAc and washed first with H2O and then brine. The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified by silica gel column chromatography (0—>80% EtOAc in PE) to give (3-cyano-l-methyl-lH-pyrazol-5-yl)boronic acid (800 mg, 57% yield) as a yellow oil. LC / MS ESI (m / z): 152 [M+H]+.Synthesis of 3-cyclobutyl-l,2-oxazole-5-carbaldehydeo-nTo a solution of (3-cyclobutyl-l,2-oxazol-5-yl)methanol (500 mg, 3.26 mmol) in DCM (100 mL) was added M11O2 (2.80 g, 32.64 mmol). The mixture was stirred at r.t. overnight and then filtered. The filtrate was concentrated under reduced pressure and purified by flash column chromatography(silica gel eluting with 0^15% EA in PE) to give 3-cyclobutyl-l,2-oxazole-5-carbaldehyde (260mg, 53%) as a colorless oil. LC / MS (ESI): m / z = 152 [M+H]+.The following intermediates were synthesized using a similar experimental protocol:5 -ethylisothiazole-3 -carbaldehyde oh          -              / / 'o S-N                    S-N m / z (ESI): 142 [M+H] 3 -ethyl-1 -methyl- lH-pyrazole-5 -carbaldehyde OH ------ n-N^                   n-N^ m / z (ESI): 139 [M+H] Synthesis of 3-(cyclopropylmethyl)isoxazole-5-carbaldehydeTo a solution of | 3-(cyclopropylmethyl)-l,2-oxazol-5-yl |methanol (1.10 g, 7.18 mmol) in DCM (10 mL) was added Dess-Martin periodinane (3.65 g, 8.62 mmol) at 0 °C. After stirring at 0 °C for 2 h, the reaction mixture was diluted with sat. aq. Na2CCh solution (20 mL) and DCM (10 mL). The organic layer was separated, washed with brine (10 mL), dried over anhydrous NajSO^ filtered and concentrated in vacuo to give a residue, which was purified by column chromatography on silica gel (0^25% of EA in PE, V / V) to give 3-(cyclopropylmethyl)-l,2-oxazole-5-carbaldehyde (0.90 g, 83%) as a yellow oil. LC / MS ESI (m / z): 152 [M+H]4Synthesis of 2-(5-bromo-l-ethyl-lH-pyrazol-4-yl)acetonitrileBrTo a solution of 5-bromo-4-(chloromethyl)-l-ethyl-IH-pyrazole (5.00 g, 22.4 mmol) in DMSO (50 mL) was added NaCN (2.20 g, 44.7 mmol) at 25 °C. After stirring at 25 °C for 2 h, the mixture was treated with EtOAc and H2O. The organic layer was separated, washed with brine, dried over anhydrous NazSO^ filtered, and concentrated. The residue was purified by column chromatography on silica gel (20% EtOAc in PE) to give 2-(5-bromo-l-ethyl-lH-pyrazol-4-yl)acetonitrile (4.5 g, yield: 94%) as a light-yellow oil. LC / MS ESI (m / z): 214 [M+H] \The following intermediates were synthesized using a similar experimental protocol:2-(5-bromo-1-cyclobutyl-lH-pyrazol-4-yl)acetonitrile Br                                                 Br N—k> + N_ Na      •          N-^O* m / z (ESI): 240 [M+H] Synthesis of l-(3-bromo-5-fluoropyridin-2-yI)ethan-l-oneBrTo a solution of 3-bromo-5-fluoropicolinic acid (4.80 g, 21.8 mmol) in DMF (20 mL) were added N,O-dimethylhydroxylamine hydrochloride (3.19 g, 32.7 mmol), HOBT (5.90 g, 43.6 mmol), EDCI (8.45 g, 43.6 mmol) and DIPEA (14.1 g, 109 mmol) at 0 °C. The mixture was stirred for 12 h at room temperature. The mixture was filtered through celite to remove solids. The filtrate was concentrated under reduced pressure and tire residue was purified by flash chromatography on silica gel (0—*10% of EtOAc in PE) to give 3-bromo-5-fluoro-N-methoxy-N-methylpicolinamide (4.5 g, 78% yield) as a pale-yellow solid. LC / MS ESI (m / z): 263 [M+H]+.To a solution of 3-bromo-5-fluoro-N-methoxy-N-methylpicolinamide (3.50 g, 13.3 mmol) in THF (5 mL) cooled to -20 °C was added methylmagnesium bromide (4.43 mL, 13.3 mmol, 3 M in THF). The mixture was stirred at -20 °C for 2 h and then quenched with ice water. The resulting mixture was extracted with EtOAc twice and the combined extracts were washed with brine, dried over anhydrous NaaSO^ filtered and concentrated. The residue was purified by flash chromatography on silica gel (0—>30% of EtOAc in PE) to give 1-(3-bromo-5-fluoropyridin-2-yl)ethan-l-one (2.6 g, 90% yield) as a white solid. LC / MS ESI (m / z): 218 [M+H]+.Synthesis of 5-(cyclopropylmethyl)-3-iodo-l-methyl-lH-pyrazolelN ITo a stirred solution of 3-iodo-l-methyl-lH-pyrazole-5-carbaldehyde (2.3 g, 9.7 mmol) in THF (40 mL) was added cyclopropylmagnesium bromide (0.5 M in hexane, 20.5 mL, 10.3 mmol) at 0 °C under Na. The reaction was stirred at 0 °C for 1.5 h, then quenched with sat. NFLCl (5 mL) and concentrated to dryness. The residue was purified by flash chromatography (0 - 50% of EtOAc in PE) to get cyclopropyl(3-iodo-l-methyl-lH-pyrazol-5-yl)methanol (1.6 g, 19% yield) as a yellow solid. LC / MS (ESI) (m / z): 279 [M+H]+.To a stirred solution of cyclopropyl(3-iodo-l-methyl-lH-pyrazol-5-yl)methanol (1.0 g, 3.6 mmol) in DCM (18 mL) was added TES (4.20 g, 36.0 mmol) and TFA (2.7 mL, 36 mmol) at 0 °C. The reaction was stirred at r.t. overnight. The reaction was concentrated to dryness. The residue was purified by flash chromatography (0—»10% EtOAc in PE) to give 5-(cyclopropylmethyl)-3-iodo-l-methyl-lH-pyrazole (0.60 g, 51% yield) as a yellow solid. LC / MS (ESI) (m / z): 263 [M+H]+.Synthesis of 4-fluoro-2-iodobenzamideTo a solution of 4-fluoro-2-iodobenzoic acid (5.00 g, 18.8 mmol) in DCM (100 mL) was added oxalyl chloride (5.00 g, 39.4 mmol), followed by the addition of DMF (0.07 mL, 0.9 mmol) at 0 °C. After the addition, the resulting mixture was stirred at 25 °C for 2 h. The mixture was concentrated in vacuo to dryness to give crude 4-fluoro-2-iodobenzoyl chloride as a yellow oil.To a solution of 4-fluoro-2-iodobenzoyl chloride in dry DCM (50 mL) cooled to 0 °C, was added a pre-cooled solution of aq. NIL (14 mL, 370 mmol, 28% in H2O) dropwise over 10 min. The internal temperature was maintained below 5 °C during the addition. The resulting mixture was stirred at r.t. for 4 h and then concentrated to dryness. The residual white solids were triturated with water and PE, and then dried in a vacuum oven to give target product 4-fluoro-2-iodobenzamide (11g, 92% yield over 2 steps) as a white solid. LC / MS (ESI): m / z = 266 [M+H]+.Synthesis of 5-bromo-l-cyclopropyl-lH-pyrazole-4-carbaldehydeTo a solution of 5-bromo-l-cyclopropyl-4-iodo-lH-pyrazole (2.5 g, 7.98 mmol) in THF (30 mL) at -78 °C was added 1-PrMgCl (1.3 M in THF, 7.37 mL, 9.58 mmol) dropwise under N2 atmosphere. After the addition, the mixture was stirred at 0 °C for 60 min, cooled back to -78 °C, and then anhydrous DMF (0.80 mL, 10 mmol) was added. The resulting mixture was stirred at -78 °C for an additional 2 h. The mixture was quenched with sat. NH4CI solution, then extracted with DCM (200 mL x 2). The organic layer was separated, washed with brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by column chromatography on silica gel (PE:EA = 2:1-1:1, V / V) to give the target product as a yellow oil (932 mg, yield: 54%). LC / MS ESI (m / z): 215 [M+H]+.Synthesis of ethyl 5-ethylisothiazole-3-carboxylateN-STo a mixture of butan-2-one (10.0 g, 139 mmol) and diethyl oxalate (20.3 g, 139 mmol), was added sodium ethoxide (3.0 M in EtOH, 57.6 mL, 166 mmol) at 0 °C, and the resulting mixture was stirred at r.t. overnight. Then the reaction mixture was quenched by adding sat. aq. NH4CI solution (50 mL), acidified by 1.0 M HC1 to pH 3 and concentrated in vacuo to remove EtOH. The residue was extracted with EtOAc (3 x 20 mL). Then the combined organic layers were washed with sat. aq. NH4CI solution (20 mL) and brine (20 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography with EtOAc in PE (0^75%, V / V) to give ethyl 2,4-dioxohexanoate (19.0 g, 80%) as an orange oil. LC / MS (ESI) (m / z): 173 [M+H]+.To a solution of ethyl 2,4-dioxohexanoate (3.00 g, 17.4 mmol) in toluene (30 mL) and acetic acid (3 mL) was added ammonium acetate (3.36 g, 43.6 mmol) at 0 °C. Then the resulting mixture was stirred at 80 °C overnight. Then the reaction mixture was concentrated in vacuo to dryness. The residue was basified by adding sat. aq. NaHCXL solution to pH 7 and extracted with EtOAc (3 x 20 mL). Then the combined organic phases were washed with sat. aq. NaHCO? solution (20 mL) and brine (20 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel with EtOAc in PE (0^30%, V / V) to give ethyl 4-amino-2-oxohex-3-enoate (19.0 g, 80%) as a yellow solid. The product was a mixture of {Z)- and (E)-olefins. LC / MS (ESI) (m / z): 172 [M+H]+.To a solution of ethyl 4-amino-2-oxohex-3-enoate (1.30 g, 7.59 mmol) in THF (15 mL), was added phosphorus pentasulfide (0.84 g, 7.6 mmol) at r.t. and the resulting mixture was stirred at r.t. overnight. After overnight, the reaction mixture was concentrated in vacuo to dryness. The residue was dissolved in EtOAc (50 mL), then aq. 30% H2O2 (6 mL) was added at 0 °C and stirred at 0 °C for 10 min. After 10 min, the reaction mixture was extracted with EtOAc (3 x 20 mL). Then the combined organic phases were washed with sat. aq. NH4CI solution (20 mL) and brine (20 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica with EtOAc in PE (0—>30%. NIN) to give ethyl 5-ethylisothiazole-3-carboxylate (0.72 g, 51%) as a yellow oil. LC / MS (ESI) (m / z): 186 [M+H]+.Synthesis of 5-bromo-l-cyclobutyl-lH-pyrazole-4-carbaldehydeBrTo a solution of 5-bromo-l-cyclobutyl-4-iodo-lH-pyrazole (11.0 g, 33.6 mmol) in THF (60 mL) was added i-PrMgClLiCl (1.3 M in THF, 31.0 mL, 40.4 mmol) at -5 °C to -10 °C. After stirring at -10 °C for 15 min, anhydrous DMF (3.38 mL, 43.7 mmol) was added. The solution was stirred at -10 °C for 30 min, then slowly poured into stirred ice-water. The mixture was extracted with ethyl acetate (100 mL x 2), then washed with brine (50 mL x 2), dried over anhydrous Na2SO4 and concentrated. The residue was purified by flash chromatography (silica gel, 0 > l()°o ethyl acetate in petroleum ether) to afford 5-bromo-l-cyclobutyl-lH-pyrazole-4-carbaldehyde (6.0 g, 78%) as a yellow solid. LC / MS ESI (m / z): 229 [M+H]+.Synthesis of 4-(azidomethyl)-5-bromo-l-ethyl-lH-pyrazoleBr+ N = N = N-NaTo a solution of 5-bromo-4-(bromomethyl)-l-ethyl-lH-pyrazole (1.0 g, 3.7 mmol) in DMF (50 mL) was added NabL (728 mg, 89.5 mmol) at 0 °C. The mixture was stirred at 0 °C for 0.5 h. Tire reaction mixture was diluted with EtOAc and washed with brine twice. The final organic layer was dried over anhydrous Na^SOr, filtered and concentrated. The residue was purified by column chromatography on silica gel (20% EtOAc in PE) to give 4-(azidomethyl)-5-bromo-l-ethyl-lH-pyrazole as a yellow oil (750 mg, yield: 87%). LC / MS (ESI) m / z: 230 [M+H]+Synthesis of 2-(5-bromo-l-ethyl-lH-pyrazol-4-yl)acetamideO+ HO-S-OHOBr2-(5-bromo-l-ethyl-lH-pyrazol-4-yl)acetonitrile (4.00 g, 18.7 mmol) was added to cone. H2SO4 (12 mL) at 0 °C. After the addition, the mixture was wanned to r.t. and stirred for 14 h. Then, the reaction mixture was added dropwise to ice-water (150 mL) and basified to pH 8 with chilled aq. 1 N NaOH solution. The resulting solution was concentrated in vacuo to dryness by oil pump. The residue was suspended in DCM (188 mL) and MeOH (12 mL) and the solids were removed by filtration. The filtrate was concentrated in vacuo to give 2-(5-bromo-l-ethyl-lH-pyrazol-4-yl)acetamide (4.1 g, 95%) as a white solid. LC / MS (ESI): m / z = 232 [M+H]+The following intermediates were synthesized using a similar experimental protocol:2-(5-bromo-1-cyclobutyl-lH-pyrazol-4-yl)acetamide O                         0 / \-N J      + ho-s-oh ----- Jk X / r                                            NH, '    O       12 Br                                                    Br m / z (ESI): 258 [M+H] Synthesis of methyl 3-bromo-5-fIuoropicolinateBr                           BrTo a solution of 3-bromo-5-fluoropyridine-2-carboxylic acid (1.0 g, 4.5 mmol) and MeOH (30 mL) 5 at 0 °C was added SOCh (1.7 mL, 23 mmol) dropwise under N2 atmosphere. Afterthe addition, the mixture was stirred at 0 °C for 2 h. The mixture was quenched with ice-water, then extracted with DCM (40 mL * 2). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by column chromatography on silica gel (PE : EA = 5 : 1) to give methyl 3-bromo-5-fluoropicolinate as a pale-yellow solid (1.0 g, yield: 10   94%). LC / MS ESI (m / z): 234 [M+H]+.Synthesis of 3-bromo-5-fluoro-2-(trimethylstannyl (pyridineA mixture of 2,3-dibromo-5-fluoropyridme (1.0 g, 3.9 mmol), hexamethyldistannane (1.35 g, 4.12 mmol) and Pd(PPh,)4 (0.23 g, 0.20 mmol) in toluene (50 mL) was heated to 110 °C under N2 for 16 15 h. The mixture was concentrated, diluted with EtOAc (50 mL), washed with brine (30 mL), dried over anhydrous Na2SO4 and concentrated. The residue was purified by neutral AI2O3 chromatography (100% petroleum ether) to afford 3-bromo-5-fluoro-2-(trimethylstannyl)pyridine (1.2 g, 90% yield) as a colorless oil. LC / MS (ESI) m / z: 340 [M+H]+.Synthesis of (3-ethyl-l-methyl-lH-pyrazoI-5-yl)methanolTo a solution of methyl 3-ethyl-l-methyl-lH-pyrazole-5-carboxylate (3.10 g, 18.4 mmol) in THF (60 mL) was added D1BAL-H (46,1 mL, 46.1 mmol, 1.0 M in toluene) at -78 °C over 30 min. During the addition, the internal temperature was monitored to stay below -60 °C. The reaction was stirred for 1 h in a dry ice / acetone bath and then 1 h in an ice bath. The mixture was cooled back to -78 °C, and excess EtOAc was slowly added. A separate three-neck flask equipped with a mechanical stirrer was charged with a sat. aq. solution of HC1 (IM). The organic solution was slowly poured with stirring into the HC1 solution, and the mixture was stirred at r.t. for 1 h. The layers of the biphasic mixture were separated, and the aq. layer was washed with EtOAc. The combined organics were washed with brine, dried over MgSO4, filtered, and concentrated in vacuo The resulting material was purified by silica gel column chromatography (50% EtOAc in PE) to give (3-ethyl-l-methyl-lH-pyrazol-5-yl)methanol (2.2g, 85%) asacolorlessoil. LC / MS ESI (m / z): 141 [M+H]+.Synthesis of (l-(2-fluoroethyl)-lH-pyrazoI-4-yl)methanoloTo a solution of methyl l-(2-fluoroethyl)-lH-pyrazole-4-carboxylate (530 mg, 3.08 mmol) in THF (10 mL) was added DIBAL-H (2.5 M in MePh, 5.13 mL, 12.8 mmol) at -78 °C. Then the mixture was stirred at r.t. for 16 h, then water (0.3 mL), aq. NaOH (1 M, 0.3 mL), and additional water (0.8 mL) were added sequentially with stirring. The mixture was partitioned between EA and water and then the water layer was further extracted with EA (3 x 10 mL). The combined organic solution was washed with sat aq. NH4CI (10 mL) and brine (10 mL), dried over anhydrous NasSO^ and concentrated in vacuo to give a residue. The residue was purified by flash chromatography (0^50% EA in PE) to give [l-(2-fluoroethyl)-lH-pyrazol-4-yl]methanol (380 mg, yield: 86%) as a colorless liquid. LC / MS ESI (m / z): 145 [M+H]+.The following intermediates were synthesized using a similar experimental protocol:(5-ethylisothiazol-3-yl)methanol S-N S-N * X A A OH m / z (ESI): 0 144 [M+H] Synthesis of (5-bromo-l-cyclobutyl-lH-pyrazol-4-yl)methanolTo a solution of 5-bromo-l-cyclobutyl-lH-pyrazole-4-carbaldehyde (6.00 g, 26.2 mmol) in THF (50 mL) was added diisobutylaluminium hydride (1.0 M in toluene, 39.28 mL, 39.28 mmol) at -78 °C over 30 min (This protocol can be modified to enable full reduction of esters to alcohols by increasing the number of equivalents of reducing agent). During the addition, the internal temperature was monitored to stay below -60 °C. The reaction was stirred for 1 h at -78 °C, then the mixture was poured into aq. HC1 (IM) and extracted with ethyl acetate (100 mL x 2), then washed with brine (50 mL x 2), dried over anhydrous Na2SO4 and concentrated. The residue was purified by silica gel chromatography (30% ethyl acetate in petroleum ether) to give (5-bromo-1-cyclobutyl-lH-pyrazol-4-yl)methanol (4.4 g, 73%) as a colorless oil. LC / MS ESI (m / z): 231 [M+H]+.The following intermediates were synthesized using a similar experimental protocol:(5-bromo-l-(difluoromethyl)-lH-pyrazol-4-yl)methanol 0 Br Br 1      F m / z (ESI): n-A F ‘ HO C' N—(, F 227 [M+H] Synthesis of (3-bromo-5-fluoropyridin-2-yl)methanolBr                              BrTo a solution of methyl 3-bromo-5-fluoropyridine-2-carboxylate (1.00 g, 4.27 mmol) in THF (15 mL) at -78 °C was added DIBAL-H (1.21 mL, 8.54 mmol) dropwise under N2 atmosphere. The mixture was stirred at 0 °C for 2 h., then quenched with ice-water, and extracted with DCM (40 mL x 2). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by column chromatography on silica gel (DCM : MeOH = 20 : 1) to give (3-bromo-5-fluoropyridin-2-yl)methanol as a pale-yellow solid (600 mg, yield: 68%). LC / MS ESI (m / z): 206 [M+H]+.The following intermediates were synthesized using a similar experimental protocol:(3-ethyl-1 -(4-methoxybenzyl)- lH-pyrazol-5 -yl)methanol o <             W X               / 0              / kJ n m / z (ESI): 247 [M+H] o Synthesis of 5-(4-fluoro-2-iodophenyl)-lH-tetrazoleA mixture of 4-fluoro-2-iodobenzonitrile (2.5 g, 10 mmol), trimethylsilylazide (2.92 g, 25.3 mmol)5 and dibutylstannanone (0.50 g, 2.0 mmol) in toluene (20 mL) was stirred at 120 °C for 18 h. After cooling to r.t., the mixture was fdtered, the filtrate was concentrated under reduced pressure. The residue was diluted with DCM (50 mL), then washed with water and brine, dried over anhydrous Na^SCL, filtered and concentrated. Tire residue was purified by flash chromatography (silica gel, 0—>50% EA in PE) to give 5-(4-fluoro-2-iodophenyl)-lH-tetrazole (2.4 g, 82% yield) as a yellow10 oil. LC / MS (ESI) m / z: 291 [M+HJ +.Synthesis of 4-(azidomethyl)-5-bromo-l-cyclobutyI-lH-pyrazoleN = N-N-NaBrTo a solution of 5-bromo-4-(chloromethyl)-l-cyclobutyl-lH-pyrazole (3.00 g, 12.0 mmol) in DMF (60 mL) was added NaNsQ.l? g, 18.0 mmol) portion-wise at 0 °C. After the addition, the resulting 15 mixture was stirred at 60 °C for 2.5 h. After cooling to 0 °C, the reaction was diluted with water (200 mL) and extracted with EA (2 x 100 mL). The combined extracts were washed with brine, concentrated in vacuo and purified by flash chromatography (10% of EtOAc in PE) to give 4-(azidomethyl)-5-bromo-l-cyclobutyl-lH-pyrazole (2.91 g, yield: 95%) as a colorless oil. LC / MS ESI (m / z): 256 [M+H]+.Synthesis of 5-((5-bromo-lH-l,2,4-triazol-l-yl)methyl)-3-ethylisoxazoIeBrN-0A mixture of 5-(chloromethyl)-3-ethyl-l,2-oxazole (2.00 g, 13.7 mmol), 3-bromo-lH-l,2,4-triazole (2.03 g, 13.7 mmol), ethylbis(propan-2-yl)amine (4.54 mb, 27.47 mmol), potassium iodide (1.14 g, 6.87 mmol) in anhydrous MeCN (20 mb) was stirred at 80 °C for 2 h. The reaction mixture was filtered to remove solid, and the filtrate was partitioned between EA and water, and the layers separated. The water layer was further extracted with EA and the combined organic layers were dried over anhydrous Na2SO4 and concentrated. The residue was purified by flash chromatography (0—>3% MeOH in DCM) to provide a 5:1 mixture of regioisomers (3.0 g, yield: 85.7%) as a colorless oil. The isomers were separated by prep-SFC (ChiralPak IG, 250x21.2mm I.D., 5pm, 40% MeOH + 0.1% aq. NH; in CO?, 50 mL / min) to give 5-((5-bromo-lH-l,2,4-triazol-l-yl)methyl)-3-ethylisoxazole (peak 1, minor isomer, 650 mg, assigned with NOESY analysis) as a colorless oil. LC / MS ESI (m / z): 257 [M+H]+.Synthesis of ethyl 5-bronio-l-(difluoromethyl)-lH-pyrazole-4-carboxylate+ F----KTo a solution of ethyl 5-bromo-lH-pyrazole-4-carboxylate (14.0 g, 63.9 mmol) and KF (7.96 g, 63.9 mmol) in MeCN (60 mb) was added diethyl (bromodifluoromethyl)phosphonate (27.43 g, 102.7 mmol) at 0 °C. The resulting mixture was stirred at r.t. overnight. The mixture was slowly poured into ice-water and extracted with EA twice. The combined extracts were washed with brine, dried over anhydrous Na2SO4 and concentrated. The residue was purified by flash chromatography (silica gel, 0^5% of EtOAc in petroleum ether) to afford ethyl 5-bromo-l -(difluoromethyl)- 1H-pyrazole-4-carboxylate (4.0 g, 23% yield) as a white solid. LC / MS ESI (m / z): 269 [M+FI]+.The following intermediates were synthesized using a similar experimental protocol:4-(( 1-( cyclopropylmethyl)-lH-pyrazol-4-yl)methyl)-2-(difluoromethyl)-5-iodo-2H-l,2,3-triazoleSynthesis of l-[(5-bromo-l,3-thiazol-4-yl)methyl]pyrazole-4-carbonitrileBrTo a solution of (5-bromo-l,3-thiazol-4-yl)methanol (400 mg, 2.06 mmol), 4-cyanopyrazole (288 mg, 3.09 mmol) and PPI13 (649 mg, 2.47 mmol) in THF (6 mL) was added DIAD (500 mg, 2.47 5 mmol) at 0 °C dropwise. The mixture was then stirred at r.t. for 16 h. The solvent was removed under vacuum, and the residue was purified via silica gel (PE / EA = 1:1) to yield l-[(5-bromo-l,3-thiazol-4-yl)methyl]pyrazole-4-carbonitrile (460 mg, 83%) as a white solid. LC / MS ESI (m / z): 269 [M+HnThe following intermediates were synthesized using a similar experimental protocol:5-(( 1H-1,2,4-triazol-1 -yl)methyl)-4-bromo-3 -ethylisothiazole 0 + z-z z 1 ZE l'*> z m / z (ESI): 273 [M+H] 3,5 -dibromo-1 - [(1 -ethyl -1 H-pyrazol -4-yl)methyl] -1 H-pyrazole M             Br                                    Br \ -N=T        VA            \ .N=n VA OH* n ' / ~Br        *   \~N J N ' / -Br m / z (ESI): 333 [M+H] 1-((3-chloropyrazin-2-yl)methyl)-lH-imidazole-4-carbonitrile 2p 0 V z •p z m / z (ESI): 220 [M+H] 10 Synthesis of 5-((5-iodo-lH-pyrazol-l-yl)methyl)isoxazoIe-3-carbonitrileTo a solution of 5-(bromomethyl)isoxazole-3-carbonitrile (2.20 g, 11.7 mmol) in DMF (100 mL) were added 5-iodo-lH-pyrazole (2.50 g, 12.9 mmol) and K2CO3 (4.90 g, 35.3 mmol) at 25 °C. After stirring at 25 °C for 2 h, the reaction mixture was diluted with EtOAc and then washed with H2O15 and brine. The organic layer was dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under vacuum. The residue was processed by SFC (ChiralPak AD, 40% MeOH + 0.1% NH3H2O) to purify and separate regioisomers to give 5-((5-iodo-lH-pyrazol-l-yl)methyl)isoxazole-3-carbonitrile as a light-yellow oil (350 mg, yield: 10%, minor regioisomer). LC / MS ESI (m / z): 301 [M+H]+.The following intermediates were synthesized using a similar experimental protocol:l-[(5-bromo-l-ethyl-lH-pyrazol-4-yl)methyr|-4-fluoro-5-iodo-lH-pyrazole Br 1 H. J Cl + N n=v Br -F        ’    / "N 1 nV -F m / z (ESI): 399 [M+H] 5-bromo-l-ethyl-4-((5-iodo-lH-pyrazol-l-yl)methyl)-lH-pyrazole Br Z—NJ' Br + N N% 1                                Bk \  ----*   / ~N / i nV m / z (ESI): 381 [M+H] l-((5-bromo-l-ethyl-lH-pyrazol-4-yl)methyl)-5-iodo-lH-pyrazole-4-carbonitrile Br 1 + N=— 1 zH                 L N -----~ N                Vs Br N j— m / z (ESI): 406 [M+H] 5-bromo-l-(difluoromethyl)-3-((5-iodo-lH-pyrazol-l-yl)methyl)-lH-pyrazole F F Br 7 + -N- X-CI    H "HL. z m □.A IX 1 Ni; / m / z (ESI): 403 [M+H] 3 -ethyl-5 -((5 -iodo-1 H-pyrazol-1 -yl)methyl)isoxazole J* N~O ^Cl + N< h'N- Cc 1 nA N< / m / z (ESI): 304 [M+H] 5-bromo-l-[(l-ethyl-3-methyl-lH-pyrazol-4-yl)methyl]-lH-l,2,4-triazole / "nj N=\ +  j Cl + nZ Br \---* Br \ N< / m / z (ESI): 270 [M+H] 5-((5 -bromo-1 H-1,2,4-triazol-1 -yl)methyl) -3 -cyclobutylisoxazole zN'O .A I Z’Z I + Q ) '0    Nsr' E ,N r m / z (ESI): 283 [M+H] 5-bromo-l-{[l-(cyclopropylmethyl)-3-methyl-lH-pyrazol-4-yl]methyl}-lH-l,2,4-triazole N V   N=\ H, Cl + Br (                        nz ,N           V   N z-z U A Br N m / z (ESI): 296 [M+H] Synthesis of 3-ethyl-5-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)isoxazoleTo a stirred solution of 2-(prop-2-yn-l-yloxy)tetrahydro-2H-pyran (5.00 g, 36.7 mmol) and 1-nitropropane (7.00 g, 78.6 mmol) in toluene (40 mL) was added phenyl isocyanate (17.0 mL, 119 5 mmol), followed by the addition of triethylamine (2.94 mL, 21.2 mmol). The reaction mixture was heated to 120 °C and stirred for 24 h. After cooling to r.t., the reaction mixture was quenched with 1 mL of water, and the mixture was stirred at r.t. for 1 h. The precipitates were removed by filtration, and the filtrate was concentrated. The residue was purified by column chromatography on silica gel (0^20% EtOAc in PE) to give 3-ethyl-5-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)isoxazole (10.0 10 g, 61%yield) as a yellow syrup LC / MS ESI (m / z): 212 [M+H]+.The following intermediates were synthesized using a similar experimental protocol:3-(cyclopropylmethyl)-5-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)isoxaz:ole X: Z r ° 0 / 0 + 0 0^^ m / z (ESI): 238 [M+H] 3-cyclobutyl-5-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)isoxazole — / °^\ / + O—zN'0                 0-\^J —                                n-o m / z (ESI): 238 [M+H] Synthesis of (2-(3-chloro-lH-pyrazol-l-yl)-5-fluorophenyl)methanolTo a solution of (5-fluoro-2-iodophenyl)methanol (25.0 g, 99.2 mmol) in toluene (250 mL) were 15 added 3-chloro-lH-pyrazole (11.2 g, 109 mmol), K2CO3 (27.4 g, 198.4 mmol) and Cui (1.9 g, 9.9 mmol). The reaction was stirred at 120 °C under N2 for 12 h. The reaction was filtered and concentrated. The residue was purified by flash chromatography (5^25% EtOAc in PE) to give (2-(3-chloro-lH-pyrazol-l-yl)-5-fluorophenyl)methanol (21.1 g, 85% yield) as a white solid. LC / MS (ESI) (m / z): 227 [M+H]+.Synthesis of 3-methoxy-l-((2-(trimethylsilyl)ethoxy)methyl)-lH-pyrazoIe+ C|^ ' / 4 WTo a stirred solution of 3-methoxy-IH-pyrazole (1.00 g, 10.2 mmol) in THF (15 mL) was added NaH (0.46 g, 12 mmol, 60% in mineral oil) at 0 °C under N?. After stirring at 0 °C for 1 h, a solution5 of [2-(chloromethoxy)ethyl]trimethylsilane (2.5 mL, 14 mmol) in THF (3 mL) was added dropwise. The reaction was stirred at 0 °C for 1 h, quenched with sat. NH4CI (10 mL) and extracted with EtOAc (100 mL). The organic phase was separated, dried over anhydrous Na2SO4 and concentrated to dryness to give 3-methoxy-l-((2-(trimethylsilyl)ethoxy)methyl)-lH-pyrazole (2.20 g, 91% yield) as a yellow oil. LC / MS (ESI) (m / z): 229.1 [M+H]+.10 The following intermediates were synthesized using a similar experimental protocol:4,5-diiodo-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-l,2,3-triazole 1                                                                                                                                                                                                                                                                    1 H 'N^|                                   \          'N ! m / z (ESI): 452 [M+H] Synthesis of (E)-l-(3-bromo-5-fluoropyridin-2-yl)-3-(dimethylamino)prop-2-en-l-oneA solution of l-(3-bromo-5-fluoropyridin-2-yl)ethan-l-one (2.60 g, 11.9 mmol) in (dimethoxymethyl)dimethylamine (10 mL) was stirred at 120 °C for 12 h. After cooling to r.t., the 15 mixture was concentrated by oil pump and the residue was purified by flash chromatography on silica gel (0—>40% EtOAc in PE) to give (E)-l-(3-bromo-5-fluoropyridin-2-yl)-3-(dimethylamino)prop-2-en-l-one (3.0 g, 92% yield) as a yellow solid. LC / MS ESI (m / z): 273 [M+H]+.The following intermediates were synthesized using a similar experimental protocol:N-[(lE)-(dimethylamino)methylidene]-4-fluoro-2-iodobenzamide ° 1 ° 1 m / z (ESI): h2n                          VJl 321 [M+H] 2-(5 -bromo-1 -ethyl- lH-pyrazol-4-yl)-N -(1 -(dimethylamino)ethylidene)acetamide 0 r=N                         / O H2N-^k^4yN'~ / /        ’ Br                                            Br m / z (ESI): 301 [M+H] Synthesis of (5-bromo-l,3-thiazol-4-yl)(l-ethyl-lH-l,2,3-triazol-4-yl)methanolIn a sealed tube a solution of bromoethane (1.68 g, 15.1 mmol), sodium azide (0.98 g, 15.1 mmol) in THF (5 mL) and H2O (5 mL) was stirred at 80 °C for 4 h. Tire resulting mixture was cooled to r.t., and then l-(5-bromo-l,3-thiazol-4-yl)prop-2-yn-l-ol (1.10 g, 5.04 mmol), Na ascorbate (0.20 g, 1.01 mmol), CuSO4 (0.16 g, 1.01 mmol), t-BuOH (10 mL) were added successively. The mixture was stirred at 50 °C for 18 h and then filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (0—>10% MeOH in DCM) to give (5-bromothiazol-4-yl)(l-ethyl-lH-l,2,3-triazol-4-yl)methanol (0.7 g, 48%) as a colorless oil. MS (ESI): m / z = 289 [M+H]+.Synthesis of l-[(3-iodopyridin-2-yl)methyl]-lH-imidazole-4-carbonitrileThe solution of triphenylphosphane (712 mg, 2.72 mmol) in THF (7 mL) was cooled to 0 °C under N2. Then DIAD (549 mg, 2.71 mmol) in THF (7 mL) was added. And then the mixture was stirred at 0 °C until a white solid is precipitated. Then to the mixture was added lH-imidazole-4-carbonitrile (152 mg, 1.63 mmol) in THF (4 mL) at 0 °C. And then to the mixture was added (3-iodopyridin-2-yl)methanol (319 mg, 1.36 mmol) in THF (6 mL). The mixture was stirred at r.t. for 2 h. The reaction mixture was concentrated and diluted by DCM. The solution was washed with sat. aq. NaCl and dried over anhydrous NfeSO^ filtered, and concentrated. The residue was purified by flash chromatography (silica gel, 0^100% EA in PE) to give l-[(3-iodopyridin-2-yl)methyl]-lH-imidazole-4-carbonitrile (309 mg, yield: 73%) as a yellow oil. LC / MS (ESI) m / z: 311 [M+H]+.The following intermediates were synthesized using a similar experimental protocol:1 -((3 -bromo-5 -fluoropyridin-2-yl)methyl)- lH-imidazole-4-carbonitrile n 7 =N +                   ‘                  ==N h'                  y                      y Br                           Br m / z (ESI): 281 [M+H] Synthesis of 4-[(3-chloro-5-iodo-lH-pyrazol-l-yl)-methyl]-l-ethyl-lH-l,2,3-triazoleTo asolution of 3-chloro-5-iodo-l-(prop-2-yn-l-yl)-lH-pyrazole (0.550g, 2.06 mmol) in tert-butyl alcohol (15 mL) were added water (15 mL), CuSO4 (20 mg, 0.14 mmol) and sodium ascorbate (20 mg, 0.10 mmol), followed by the addition of ethylazide (10 mL, 5.0 mmol, 0.5 N in THF) at 25 °C. After addition, the resulting mixture was stirred at 50 °C in a sealed tube for 16 h. The mixture was then concentrated in vacuo to remove most of tert-butyl alcohol. The residue was treated with DCM (20 inL) and FLO (10 mL). The organic layer was separated, dried over anhydrous Ma^SO^ filtered and concentrated under vacuum. The residue was purified by flash chromatography (0^50% EtOAc in PE) and SFC (ChiralPak AD, 250*4.6mm 5um, 30% EtOH + 0.1% aq. NIL in COj) to afford 4-[(3-chloro-5-iodo-lH-pyrazol-l-yl)methyl]-l-ethyl-lH-l,2,3-triazole (210 mg, 30%yield) as a white solid. LC / MS (ESI): m / z = 338 [M+H]+.The following intermediates were synthesized using a similar experimental protocol:(l-(cyclopropyhnethyl)-lH-l,2,3-tri azol-4-yl)(5-iodo-2-methyl-2H-1,2,3-tri azol-4 -yl)methanol z, z z" + ^z, X Z A ~\  )-O >— / i ~ z z 1 m / z (ESI): 361 [M+H] To a mixture of 3-chloro-5-iodo-lH-pyrazole (1.83 g, 8 02 mmol) and CS2CO3(7.84 g, 24.06 mmol) in DMF (30 mL) was added a solution of 4-(chloromethyl)-l-(ethyl-d5)-lH-pyrazole (1.20 g, 8.02 mmol) in DMF (3 mL) at 0 °C under N2. The reaction was stirred at 80 °C for 1 h. The reaction mixture was poured into water (60 mL) and extracted with EtOAc (30 mL x 2). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na2SO4and concentrated to dryness. The residue was purified by column chromatography on silica gel (PE:EA = 3:1), then recrystallized from DCM and PE to afford 3-chloro-l-((l-(ethyl-d5)-lH-pyrazol-4-yl)methyl)-5-iodo-lH-pyrazole (700 mg, 26% yield) as a white solid. LC / MS (ESI) (m / z): 342 | M+H| .Synthesis of 4-bromo-3-ethyl-5-((5-iodo-lH-l,2,4-triazol-l-yl)methyl)isothiazoleTo a stirred solution of 5-((lH-l,2,4-triazol-l-yl)methyl)-4-bromo-3-ethylisothiazole (1.90 g, 6.99 mmol) in AcOH (60 mL) at ambient temperature was added NIS (3.60 g, 21.0 mmol). The resulting mixture was stirred at 80 °C for 16 h. The filtrate was extracted with EtOAc. The combined organic layers were washed with brine, dried over NaaSO^ and concentrated under vacuum. The residue was purified by flash phase chromatography on silica gel (0^30% EtOAc in petroleum ether) to afford 4-bromo-3-ethyl-5-((5-iodo-lH-l,2,4-triazol-l-yl)methyl)isotliiazole (2.0 g) as an off-white solid. LC-MS (ESI) m / z: 399 [M+H]+.Synthesis of (3-ethylisoxazol-5-yl)methanolTo a solution of 3-ethyl-5-[(oxan-2-yloxy)methyl]-l,2-oxazole (17.4 g, 82.4 mmol) in MeOH (10 mL) was added Amberlyst 15 (26 mg, 83 mmol). The mixture was stirred vigorously at 45 °C for 6 h. Filtration and removal of solvent in vacuum gave a red residue, which was purified by column chromatography on silica gel (15 —>30% EtOAc in PE) to give (3-ethyl-l,2-oxazol-5-yl)methanol (8.05 g, yield: 77%) as a pale-yellow oil. LC / MS ESI (m / z): 128 [M+H]+.The following intermediates were synthesized using a similar experimental protocol:(3-(cyclopropylmethyl)isoxazol-5-yl)methanol 0 >0 X O m / z (ESI): 154 [M+H] (3-cyclobutyhsoxazol-5-yl)methanol r^o O-n __► HOZ O-n m / z (ESI): 154 [M+H] Synthesis of 5-bromo-3-methoxy-lH-pyrazole\ z^Br o—c I n-nhTo a stirred solution of 3-methoxy-l-((2-(trimethylsilyl)ethoxy)methyl)-lH-pyrazole (2.20 g, 9.63 mmol) in THF (30 ml) was added n-BuLi (4.0 mL, 10 mmol, 2.5 M in THF) at -78 °C under N2. After stirring at -78 °C for 1 h, a solution of CBn (2.20 g, 6.63 mmol) in THF (10 mL) was added dropwise. The reaction was stirred at 0 °C for 1 h, quenched with sat. NH4CI (10 mL), and extracted with EtOAc (150 mL). The organic phase was separated, dried over anhydrous Na2SO4 and concentrated. The residue was purified by column chromatography on silica gel (PE:EtOAc = 4.: 1, V / V) to give 5-bromo-3-methoxy-l-((2-(trimethylsilyl)ethoxy)methyl)-lH-pyrazole (1.8 g, 58% yield) as a yellow oil. LC / MS (ESI) (m / z): 307.0 [M+H]+.A solution of 5-bromo-3-methoxy-l-((2-(trimethylsilyl)ethoxy)methyl)-lH-pyrazole (1.80 g, 5.86 mmol) and TFA (3.00 mL, 40.4 mmol) in DCM (15 mL) was stirred at 25 °C for 4 h. The reaction mixture was concentrated under reduced pressure. The residue was diluted with acetonitrile (15 mL) and aq. NH4OH (3.0 mL, 22 mmol). The mixture was stirred at 25 °C for 3 h. The reaction was concentrated under reduced pressure to give 5-bromo-3-methoxy-IH-pyrazole (1.5 g, 87% yield) as a yellow oil. LC / MS ESI (m / z): 177.0 [M+H]+.Synthesis of 5-bromo-l-((l-(cyclopropylmethyl)-lH-pyrazol-4-yl)methyl)-lH-l,2,4-triazoleBrTo a mixture of 4-(chloromethyl)-l-(cyclopropylmethyl)-!H-pyrazole (950 mg, 5.56 mmol) and K2CO3 (1.50 g, 11.1 mmol) in DMF (15 mL) was added 3-bromo-4H-l,2,4-triazole (906 mg, 6.10 mmol). And then the mixture was stirred at 50 °C for 2 h. The reaction mixture was concentrated by oil pump and diluted with EtOAc. The solution was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by prep-HPLC (Column: YMC TA C18 250*20mm 5um, MeCN in FLO + 0.1% FA) to give 5-bromo-l-((l-(cyclopropylmethyl)-lH-pyrazol-4-yl)methyl)-lH-l,2,4-triazole (100 mg, 6% yield over two steps) as a white solid. LC / MS ESI (m / z): 282 [M+H]+.The following intermediates were synthesized using a similar experimental protocol:l-((5-bromo-l-cyclobutyl-lH-pyrazol-4-yl)methyl)-5-iodo-lH-pyrazole-4-carbonitrileBr                               1                                          1                Br A 7X         X -H              L     J / x Cl Yn- / > + NS—N ---* NS—zz N AAn—4 / Vn          Vn m / z (ESI): 432 [M+H] 5-bromo-4-((3 -chloro-5 -iodo- IH-pyrazol-1 -yl)methyl)-1 -ethyl- IH-pyrazole Br                                                   Br \   ,,,      H—,N                        L       n + O'01 ----* Z-N 7            1^^                N' | / ^ / m / z (ESI): 415 [M+H] 1 -ethyl-4-[(5 -iodo-3 -methyl-lH-pyrazol-1 -yl)methyl] -3-methoxy-IH-pyrazole A A 7 + Cl zo            1                              1 m / z (ESI): 347 [M+H] 5-((5 -bromo-1 H-l,2,4-triazol-l-yl)methyl)-3-(cyclopropylmethyl)isoxazole ’'z ci + N v -------'    <-7 v /    N"^ V   N’°        N< / N                 N’° N^ / N m / z (ESI): 283 [M+H] 3-chloro-l-((l-(cyclopropylmethyl)-lH-pyrazol-4-yl)methyl)-5-iodo-lH-pyrazole Q h z + Q A A / / A S7 m / z (ESI): 363 [M+H] 3-chloro-l-((l-(cyclopropylmethyl)-3-methyl-lH-pyrazol-4-yl)methyl)-5-iodo-lH-pyrazole m / z (ESI): 377 [M+H]5-bromo-1-[(1-ethyl-lH-pyrazol-4-yl)methyl]-3-(trifhioromethyl) - IH-pyrazole 4 o + III      I I A X m / z (ESI): 323 [M+H] 5-bromo-l -((1 -(2-fluoroethyl)-lH-pyrazol-4-yl)methyl)-3 -methyl-IH-pyrazole -4 A CO X + o z m / z (ESI): 287 [M+H] 3-ethyl-5-((5-(4-fluoro-2-iodophenyl)-lH-tetrazol-l-yl)methyl)isoxazole .N, , N 'N c' °'N         k An + A h ,N. Az \ A'n 0 m / z (ESI): 400 [M+H] F - Synthesis of 4-[(5-bromo-l,3-thiazol-4-yl)methyl]-l-ethyI-lH-l,2,3-triazoleBrTo a solution of (5-bromo-l,3-thiazol-4-yl)(l-ethyl-lH-l,2,3-triazol-4-yl)methanol (700 mg, 2.42 mmol) in TFA (20 mL) was added triethylsilane (7.8 mL, 48 mmol). The vessel was sealed, and the5 resulting mixture was stirred at 50 °C for 16 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel eluting with EA in PE (0—>100%) to give 4-[(5-bromo-l,3-thiazol-4-yl)methyl]-l-ethyl-lH-l,2,3-triazole (0.6 g, 91%) as a pale-yellow solid. LC / MS (ESI): m / z = 273 [M+H]+.The following intermediates were synthesized using a similar experimental protocol:5-bromo-l-ethyl-4-((5-iodo-l-methyl-lH-imidazol-4-yl)methyl)-lH-pyrazole Br OH ।                             Br Z~N O ' n-      ' / ~NZ fA N=y                n- 1 7    ' N — m / z (ESI): 395 [M+H] 5-bromo-l-ethyl-4-((4-iodo-l -methyl-lH-imidazol-5-yl)methyl)-lH-pyrazole Br OH z                        Br A-Ax^N           a / ~~n t    \  -----*   / —n “    N= / 7 V> |AN m / z (ESI): 395 [M+H] 4-((5-bromo-l-cyclopropyl-lH-pyrazol-4-yl)methyl)-5-iodo-2-methyl-2H-l,2,3-triazole OH Br N.A A            -Av nA, Br L N—<3 4 N‘ m / z (ESI): 408 [M+H] ethyl 5-((5-iodo-2-methyl-2H-l,2,3-triazol-4-yl)methyl)isoxazole-3-carboxylate ,z Z’ z y / / - Vo / I z o ° ,z f\ if O O-n^O^ 1 m / z (ESI): 363 [M+H] 4-((1 -(2,2-difliiorocthyl)-IH-pyrazol-4-yl (methyl )-5-iodo-2 -methyl -2H-1,2,3 -triazole F F"^^ k N~. O f         k 1 N— ______      / N=n -1 Jn- •^N m / z (ESI): 354 [M+H] 4-[(3-cyclobutyl-l,2-oxazol-5-yl)methyl]-5-iodo-2-methyl-2H-l,2,3-triazole 1 2. -z* Z Co OH “A z M x\ m / z (ESI): 345 [M+H] 4-[(5-ethyl-l,2-oxazol-3-yl)methyl]-5-iodo-2-methyl-2H-1,2,3-triazole k \ P'N C d it       I OH k N—   _    \   °~N y ^n'                ’ N N — 'n' m / z (ESI): 319 [M+H] 3-ethyl-5-((5-iodo-2-methyl-2H-l,2,3-triazol-4-yl)methyl)isoxazole k N-° \ OH k N—___ \ N~O 1 -N N— 'N m / z (ESI): 319 [M+H] 4-((lH-imidazol-2-yl)methyl)-5-bromo-l-ethyl-lH-pyrazole Br OH / —N      U /           N. \ •~Si" Br         H / -0       ------ / —N / jl N                    7 m / z (ESI): 255 [M+H] 2-((5 -bromo-1-ethyl-lH-pyrazol-4-yl)methyl)-3-chloropyrazine Br OH Cl                       Br n ------- Z                                                   N, Cl m / z (ESI): 301 [M+H] 3-bromo-2-((5 -bromo-1 -ethyl-lH-pyrazol-4-yl)methyl)pyri dine Br OH Br                       Br / -N     h Br m / z (ESI): 344 [M+H] 5-((5-bromothiazol-4-yl)methyl)-l-methyl-lH-pyrazole-3-carbonitrile NS n-\ OH Br                                Br 1 s                                        '        1 s N^ /                N'nx Nii / m / z (ESI): 283 [M+H] l-(cyclopropylmethyl)-4-((5-iodo-2-methyl-2H-l,2,3-triazol-4-yl)methyl)-lH-l,2,3-tri azole n5 — N 2 N = o             , |     N-N      / OH -................~— H J N-N m / z (ESI): 345 [M+H] 3-(cyclopropylmethyl)-5-((5-iodo-2-methyl-2H-1,2,3-triazol-4-yl)methyl)isoxazole N- —N _ N' O            . | O-N L 1 / OH -----► — N j 1                      . O-N £> m / z (ESI): 345 [M+H] 4-((3-chloro-1 -(2,2-difluoroethyl)-lH-pyrazol-4-yl)methyl)-5-iodo-2 -methyl -2H-1,2,3-tri azole N 1 / - ' y-X<N H0 I /           ,N f —- "RJ F — N? Cl m / z (ESI): 388 [M+H] 5-((5 -bromo -2 -methy Ithiazol -4-yl)methyl) -1 -methyl -1 H-pyrazole -3 -carbonitrile H --. s .n               r Br ' N                     Br HO 1 A N 1 m / z (ESI): 297 [M+H] 3-bromo-2-((l-(cyclopropylmethyl)-lH-pyrazol-4-yl)methyl)-5-fluoropyridine OH Br n j SF 1 N LL m-A / z m / z (ESI): 310 [M+H] 3-bromo-2-((l-(2,2-difluoroethyl)-lH-pyrazol-4-yl)methyl)-5-fluoropyridine F— F OH Br N' 1 -----* F" / ~~N \     N" F Br T "J F m / z (ESI): 320 [M+H] 2-chloro-3-((l-(cyclopropylmethyl)-3-methyl-lH-pyrazol-4-yl)methyl)pyrazine Cl n^ 1¾. HO N C --------► 0 N / An v7 m / z (ESI): 263 [M+H] 5-ethyl-3-((5-iodo-2-methyl-2H-l,2,3-triazol-4-yl)methyl)isothiazole S-n 'VN *1 Jk .N VS / 'n OH \ S-N 'yN L N— m / z (ESI): 335 [M+H] 4-{[3 -chloro-1 -(cyclopropylmethyl)-1 H-pyrazol-4-yl]methyl} -5 -iodo-2-methyl-2H-1,2,3 -tri azole3 - {[3 -chloro-1 -(cyclopropylmethyl)-1 H-pyrazol-4-yl]methyl} -4-iodo-1 -methyl- IH-pyrazole(R)-3-(2-(l-((5-bromo-2-nitropyridin-3-yl)oxy)ethyl)-4-fluorophenyl)-4-((l-ethyl-lH-pyrazol-4-yl)methyl)-l,2,5 -thiadiazole4-((3-ethyl-1-methyl-lH-pyrazol-5-yl )methyl)-5-iodo-2-methyl-2H-1,2,3-tri azole4-{[3-(cyclopropylmethyl)-l-methyl-lH-pyrazol-5-yl|methyl}-5-iodo-2-methyl-2H-l,2,3-triazoleSynthesis of 5-((5-bromothiazol-4-yl)(hydroxy)methyl)-l-methyl-lH-pyrazole-3-carbonitrileTo a stirred solution of 5-iodo-l-methyl-lH-pyrazole-3-carbonitrile (650 mg, 2.79 mmol) in THF (20 mL) was added isopropylmagnesium bromide (3.1 mL, 1 M in THF, 3.1 mmol) at 0 °C. After5 stirring at 0 °C for 30 min, a solution of 5-bromo-l,3-thiazole-4-carbaldehyde (643 mg, 3.35 mmol)in THF (2 mL) was added dropwise. The reaction was stirred at 0 °C for another 30 min, quenched with sat. NH4CI (10 mL), extracted with EtOAc (20 mL x 2). The combined organic phase was washed with brine (20 mL), dried over Na?SO4 and concentrated. The residue was purified by column chromatography on silica gel (50% EtOAc in PE) to give 5-((5-bromotliiazol-4-5 yl)(hydroxy)methyl)-l-methyl-lH-pyrazole-3-carbonitrile (450 mg, 54% yield) as a yellow oil. LC / MS (ESI) (m / z): 299 [M+H]+.The following intermediates were synthesized using a similar experimental protocol:(5-bromo-l-ethyl-lH-pyrazol-4-yl)(5-iodo-2-methyl-2H-l,2,3-triazol-4-yl)methanol pX    /         N / 1                               , + — N Tk        - — N 3 X.N- / T                'rr%                   N ।    \ B                                      OH Br m / z (ESI): 412 [M+H ] (5-bromo-l -ethyl-lH-pyrazol-4-yl)(4-iodo-l-methyl-lH-pyrazol-3-yl)methanol ,          __ / 1                    / = / 1 r=N / + -N 3 n--* -N J I'X         'N'^0          N 7"% Br                                                 OH Br m / z (ESI): 411 [M+H ] (5-bromo-l-cyclobutyl-lH-pyrazol-4-yl)(5-iodo-2-methyl-2H-l,2,3-triazol-4-yl)methanol / x 2X        k N              zx        ’Vn ONA>O • x .N- --- <>NAJY.~-- 1         i-^n                   r t n Br                                             Br 0H m / z (ESI): 438 [M+H ] (5-bromo-l-cyclopropyl-lH-pyrazol-4-yl)(5-iodo-2-methyl-2H-l,2,3-triazol-4-yl)methanol Y z z' ym z M z + Y 7’ 0 m / z (ESI): 424 [M+H ] ethyl 5-(hydroxy(5-iodo-2-methyl-2H-l,2,3-triazol-4-yl)methyl)isoxazole-3-carboxylate „                                    OH cX / y    + -n' y ---•   • O-N °"\       N^,                 °'N m / z (ESI): 379 [M+H ] (3-ethylisoxazol-5-yl)(5-iodo-2-methyl-2H-1,2,3-triazol-4-yl)methanolk + N'O        , / ^N N— ___.        - N-C OH ’ f N — m / z (ESI): 335 [M+H ] (5-bromo-1 -ethyl- lH-pyrazol-4-yl)( 1 -((2-(trimethylsilyl)ethoxy)methyl)- lH-imidazol-2-yl)methanol o w \ + Z-Z / A / =0  _____, kN \ / -Si Br -X / \>N ^ / N m / z (ESI): 401 [M+H ] (5-bromo-l-ethyl-lH-pyrazol-4-yl)(3-bromopyridin-2-yl)methanol Br + °' Br II J             ’      / NSC / Br ~N C )H Br U m / z (ESI): 360 [M+H ] (l-(cyclopropylmethyl)-lH-pyrazol-4-yl)(5-iodo-2-methyl-2H-l,2,3-triazol-4-yl)methanol k + V N-J       , / rSN. 7 ,’n—     — / ~~n' 1         N OH L N~ m / z (ESI): 360 [M+H ] (3-(cyclopropylmethyl)isoxazol-5-yl)(5-iodo-2-methyl-2H-l,2,3-triazol-4-yl)methanol _           k z          + V   N"°      < .z z 1 h -0 OH I N — N m / z (ESI): 361 [M+H ] (5-iodo-2-methyl-2H-l,2,3-triazol-4-yl)(l-(oxetan-3-yl)-lH-pyrazol-4-yl)methanol / ,z / / o + z O 1 OH ^N—<0° m / z (ESI): 362 [M+H ] (l-ethyl-3-(trifluoromethyl)-lH-pyrazol-4-yl)(5-iodo-2-methyl-2H-l,2,3-triazol-4-yl)methanol (5-ethylisothiazol-3-yl)(5-iodo-2-methyl-2H-l,2,3-triazol-4-yl)methanol z o I ° \ ~ / =: z / \ co 1 z z' ‘Z M + o m / z (ESI): 351 [M+H ] (1 -ethyl- lH-pyrazol-4-yl)(2-ethyl-5 -iodo-2H-1,2,3 -tnazol -4-yl)methanol I                                         0H / —N J     +    / N— /   -----* Z~N T T N-A N'        |^N               Z              X m / z (ESI): 348 [M+H ] (l-(cyclopropylmethyl)-lH-pyrazol-4-yl)(5-iodo-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-l,2,3-triazol-4-yl)methanol O z + \ / co O — o f z. o o —\  " I \_ O z L m / z (ESI): 476 [M+H ] (3-ethyl-l-methyl-lH-pyrazol-5-yl)(5-iodo-2-methyl-2H-l,2,3-triazol-4-yl)methanol V- V t / ZN m / z (ESI): 348 [M+H ] (l-ethyl-lH-pyrrol-3-yl)(5-iodo-2-methyl-2H-l,2,3-triazol-4-yl)methanol o + z 1 ^z \__ / T zH z m / z (ESI): 333 [M+H ] Synthesis of [2-(1,3-dioxolan-2-yl)-4-fluorophenyl]trimethylstannaneTo a mixture of 2-(2-bromo-5-fluorophenyl)-l,3-dioxolane (1.0 g, 4.0 mmol) in THF (20 mL) was added n-BuLi (1.78 mL, 4.45 mmol, 2.5 M) dropwise at -78 °C. The mixture was stirred at -78 °C5 for 1 h. Then, tnmethyltin chloride (4.45 mL, 4.45 mmol, 1.0 M in THF) was added dropwise to the mixture. The resulting mixture was stirred at -78 °C for 15 min. The mixture was quenched withsat. NH4CI (50 mL) at 0 °C and extracted with EtOAc (50 mL x 3). The combined extracts were washed with brine (20 mL x 2), dried over anhydrous NazSOu, filtered and concentrated. The residue was purified by flash chromatography on silica gel (10% EtOAc in PE) to give [2-(1,3-dioxolan-2-yl)-4-fluorophenyl]trimethylstannane (600 mg, yield: 44%) as a colorless oil. LC / MS ESI (m / z): 333 [M+H]+.Synthesis of 4-(5-ethyl-l,2-oxazole-3-carbonyl)-5-iodo-2-methyl-2H-l,2,3-triazoleTo a mixture of 5-ethyl-l,2-oxazole-3-carboxylic acid (1.6 g, 11.3 mmol), EDCI (3.36 g, 17.5 mmol), HOBt (2.37 g, 17.5 mmol), N,O-dimethylhydroxylamine hydrochloride (1.25 g, 12.9 mmol) and TEA (2.29 g, 22.7 mmol) in DMF (10 mL) was stirred at 0 °C. The mixture was stirred at r.t. for 2 h. The mixture was concentrated in vacuo and extracted with EA (80 mL x 3). The organic layer was separated and washed with sat. aq. NaHCOs solution (40 mL x 3) and brine (10 mL), dried over anhydrous NazSCL, filtered and concentrated. The residue was purified by column chromatography on silica gel (DCM : MeOH = 20 : 1, V / V) to give 5-ethyl-N-methoxy-N-methyl-l,2-oxazole-3-carboxamide (1.5 g, 70%) as a light-yellow solid. LC / MS ESI (m / z): 185 [M+H]+.To a mixture of 4,5-diiodo-2-methyl-2H-l,2,3-triazole (1.65 g, 4.93 mmol) in THF (20 mL) was degassed with 1¾ for three times and added isopropylmagnesium bromide (3.79 mL, 4.93 mmol, 1.3 M in 2-methyltetrahydrofuran) at 0 °C for 2 h. 5-ethyl-N-methoxy-N-methyl-l,2-oxazole-3-carboxamide (0.91 g, 4.93 mmol) was added to the mixture and stirred at 0 °C for 2 h. The mixture was quenched with sat. aq. NH4CI solution (100 mL) and extracted with EA (80 mL x 3). The organic layer was separated, dried over anhydrous NazSO4, filtered and concentrated in vacuo to give a residue, which was purified by column chromatography on silica gel (PE : EA = 2 : 1, V / V) to give 4-(5-ethyl-l,2-oxazole-3-carbonyl)-5-iodo-2-methyl-2H-l,2,3-triazole (310 mg, 19%) as a light-yellow oil. LC / MS ESI (m / z): 333 [M+H]+.Synthesis of 5-bromo-l-((3-(cyclopropylmethyl)-l-methyl-lH-pyrazol-5-yl)methyl)-lH-l,2,4-triazoleBr y % N— \7 N-N ' N "        \  N< / To a stirred solution of (3-(cyclopropylmethyl)-l-methyl-lFI-pyrazol-5-yl) methanol (1.05 g, 6.32 mmol) in DCM (20 mL) was added SOCL (1.40 mL, 19 mmol) at 0 °C. After stirring at r.t. for 2 h,the reaction mixture was concentrated to give crude 5-(chloromethyl)-3-(cyclopropylmethyl)-l-methyl-lH-pyrazole (1.16g, 99% yield) as a yellow oil.To a mixture of 5-bromo-lH-l,2,4-triazole (0.88 g, 5.96 mmol) and CS2CO3 (1.94 g, 5.96 mmol) in DMF (30 mL) was added a solution of 5-(chloromethyl)-3-(cyclopropylmethyl)-l-methyl-lH-pyrazole (1.10g, 5.96 mmol) in DMF (3 mL) dropwise. The reaction was stirred at 80 °C for 5 h. The reaction mixture was poured into water and extracted with EtOAc twice. The organic layers were washed with brine, dried over anhydrous Na2SO+and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (PE:EA = 2:1) and SFC (ChiralPak IA, 250x21.2mm I.D., 5pm, 30% MeOH + 0.1% aq. NFL in CO2) to afford 5-bromo-l-((3-(cyclopropylmethyl)-l-methyl-lH-pyrazol-5-yl)methyl)-lH-l,2,4-triazole (300 mg, 18% yield) as a colorless oil. LC / MS (ESI) (m / z): 296 [M+H]+.Synthesis of 5-bromo-l-((l-isobutyl-3-methyl-lH-pyrazol-4-yl)methyl)-lH-l,2,4-triazoleTo a solution of (l-isobutyl-3-methyl-lH-pyrazol-4-yl)methanol (800 mg, 4.76 mmol) in anhydrous dichloromethane (30 mL) was added thionyl chloride (3.45 mL, 47.6 mmol). The resulting mixture was stirred at r.t. for 2 h. This reaction solution was concentrated directly to afford crude 4-(chloromethyl)-l-isobutyl-3-methyl-lH-pyrazole (950 mg) as a white solid.To a solution of crude 4-(chloromethyl)-l-isobutyl-3-methyl-IH-pyrazole (500 mg, 2.68 mmol) in DMF (20 mL) was added 3-bromo-4H-l,2,4-triazole (594 mg, 4.01 mmol) and K2CO3 (925 mg, 6.70 mmol) under N2 atmosphere. The resulting mixture was stirred at r.t. for 18 h. This solution was diluted with EtOAc. This solution was washed with water (30 mL x 3) and brine (30 mL), dried over Na2SO4 and concentrated to dryness. The residue was purified by chromatography on silica gel (50% EtOAc in PE) followed by SFC (ChiralCel OD, 250x21.2 mm, 30% MeOH + 0.1% aq. NH3 in CO2) to obtain 5-bromo-l-((l-isobutyl-3-methyl-lH-pyrazol-4-yl)methyl)-lH-l,2,4-triazole (92 mg, yield: 12%) as a colorless liquid. LC / MS (ESI): m / z = 298 [M+H]+.Synthesis of 5-((5-bromo-2-methyIthiazol-4-yl)(hydroxy)methyl)-l-methyl-lH-pyrazole-3-carbonitrileHO ITo a solution of 5-iodo-l-methyl-177-pyrazole-3-carbonitrile (900 mg, 3.86 mmol) in THF (9 mL) was added isopropylmagnesium chloride - lithium chloride complex (3.27 mL, 4.25 mmol, 1.3 M in THF) dropwise at 0 °C, and the mixture was stirred at r.t. for 2 h. After 2 h, 5-bromo-2-methylthiazole-4-carbaldehyde (796 mg, 3.86 mmol) was added and the resulting mixture was stirred at r.t. overnight. After overnight, the reaction mixture was quenched by adding sat. aq. NH4CI solution (10 mL), extracted with EA (3 * 10 mL), combined all organic phases, washed with sat. aq. NH4CI solution (10 mL) and brine (10 mL), dried over anhydrous NazSCL, filtered and concentrated in vacuo. Hie residue was purified by flash chromatography (0^5% MeOH in DCM) to give 5-((5-bromo-2-methylthiazol-4-yl)(hydroxy)methyl)-l-methyl-117-pyrazole-3-carbonitrile (553 mg, 46%) as a yellow gum. LC / MS ESI (m / z): 313 [M+H]+.The following intermediates were synthesized using a similar experimental protocol:Synthesis of (5-bromo-l-ethyl-lFI-pyrazol-4-yl)(3-chloropyrazin-2-yl)methanolBr OH ciTo a solution of 2-chloropyrazine (1.00 g, 8.73 mmol) in THF (35 mL) at -78 °C was added LiTMP (1.0 M in THF, 11.4 mL, 11.4 mmol) dropwise under N2 atmosphere. After the addition, the mixture was stirred at -70 °C for 0.5 h, then a solution of 5-bromo-l-ethyl-lH-pyrazole-4-carbaldehyde (2.13 g, 10.5 mmol) in THF (5 mL) was added. The resulting mixture was stirred at -70 °C for an additional 1.5 h. The mixture was quenched with sat. NH4CI solution, then extracted with DCM twice (40 mL * 2). The combined organic layer was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by column chromatography on silicagel (30% EtOAc in PE) to give (5-bromo-l-ethyl-lH-pyrazol-4-yl)(3-chloropyrazin-2-yl)methanol as a yellow oil (1.29 g, 47% yield). LC / MS ESI (m / z): 317 [M+H]+.Synthesis of (l-ethyl-lH-pyrrol-3-yl)(5-iodo-2-methyl-2H-l,2,3-triazol-4-yl)methanoneOHOTo a solution of (l-ethyl-lH-pyrrol-3-yl)(5-iodo-2-methyl-2H-l,2,3-triazol-4-yl)methanol (400 mg, 1.20 mmol) in DCM (10 mL) was added manganese(IV) oxide (1.57 g, 18.1 mmol). Then the mixture was stirred at r.t. for 2 h. The reaction was filtered, and the residue was washed by DCM. The filtrate was concentrated and the residue was purified by chromatography on silica gel (0%-50% of PE in EA) to give (l-ethyl-lH-pyrrol-3-yl)(5-iodo-2-methyl-2H-l,2,3-triazol-4-yl)methanone (188 mg, 47% yield) as a yellow solid. LC / MS (ESI) m / z: 331.3 [M+H]+.Synthesis of 4-[(4-cyclobutyl-lH-l,2,3-triazol-l-yl)methyl]-5-iodo-2-methyl-2H-l,2,3-triazoleA mixture of (5-iodo-2-methyl-2H-l,2,3-triazol-4-yl)methanol (900 mg, 4.00 mmol) in SOC12(5.8 mL, 80 mmol) was stirred at r.t. for 1 h. The mixture was quenched with sat. aq. NaHCO; solution (20 mL) at 0 °C and extracted with EA (50 mL x 3). The organic layer was combined and dried over anhydrous NaaSO^ filtered and concentrated in vacuo to give a residue, which was purified by flash chromatography (50% EtOAc in PE) to give 4-(chloromethyl)-5-iodo-2-methyl-2H-l,2,3-triazole (900 mg, 87%) as a light-yellow oil. LC / MS (ESI) m / z: 258 [M+H]+.To a mixture of 4-(chloromethyl)-5-iodo-2-methyl-2H-l,2,3-triazole (900 mg, 3.40 mmol) and NaNs (454 mg, 6.90 mmol) in DMF (10 mL) was stirred at 0 °C. The mixture was stirred at r.t. for 2 h. Tire mixture was extracted with EA (50 mL x 3). The organic layer was combined and dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give a residue, which was purified by flash chromatography (50% EtOAc in PE) to give 4-(azidomethyl)-5-iodo-2-methyl-2H-1,2,3-triazole (880 mg, 95%) as a light-yellow oilA mixture of 4-(azidomethyl)-5-iodo-2-methyl-2H-1,2,3-triazole (200 mg, 0.75 mmol), ethynylcyclobutane (182 mg, 2.27 mmol), CuSO4 (20 mg, 0.12 mmol), and sodium ascorbate (20 mg, 0.10 mmol) in t-BuOH (10 mL) and LEO (10 mL) was stirred at r.t. for 2 h. The mixture was extracted with EA (40 mL x 3). Tire organic layer was combined, washed with brine (10 mL), driedover anhydrous Na2SO4, filtered and concentrated in vacuo to give a residue, which was purified by flash chromatography (5% MeOH in DCM) to give 4-cyclobutyl-1 -[(5-iodo-2-methyl-2H-1,2,3-triazol-4-yl)methyl]-lH-l,2,3-triazole (100 mg, 38%) as a light-yellow oil. LC / MS ESI (m / z): 345 [M+H]+.Synthesis of (5-bromo-l-ethyl-lH-pyrazol-4-yl)(5-iodo-l-methyl-lH-imidazol-4-yl)methanol 8r OH । / -NN5 / To a suspension of 4,5-diiodo-lH-imidazole (8.0 g, 25.01 mmol) and LiCl (0.13 g, 3.13 mmol) in THF (50 mL) at -10 °C was added methylmagnesium bromide (3 M, 6.59 mb, 6.59 mmol) dropwise under N2 atmosphere. The mixture was stirred at -10 °C for 30 min. Then to the mixture was added isopropylmagnesium bromide (1.3 M, 2.65 mL, 3.44 mmol) dropwise, the resulting mixture was stirred at r.t. for 1.5 h. After this, to the mixture was added 5-bromo-l-ethyl-lH-pyrazole-4-carbaldehyde (6.09 g, 30.0 mmol) at -10 °C and the resulting mixture was stirred at r.t. for additional 2 h. The reaction mixture was quenched with sat. aq. NH4CI solution (50 mL), extracted with EtOAc (3 x 50 mL), washed with brine (30 mL), dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by flash chromatography (silica gel, 0^30% MeOH in DCM) to give (5-bromo-l-ethyl-lH-pyrazol-4-yl)(5-iodo-lH-imidazol-4-yl)methanol as a white solid (3.5 g, yield: 35%) LC / MS (ESI) m / z: 397 [M+H]+.To a solution of (5-bromo-l-ethyl-lH-pyrazol-4-yl)(5-iodo-lH-imidazol-4-yl)methanol (3.50 g, 8.82 mmol) in DMF (60 mL) at -10 °C was added cesium carbonate (4.31 g, 13.2 mmol) The mixture was stirred at -10 °C for 15 min. After this, to the suspension was added iodomethane (0.60 mL, 9.7 mmol) dropwise and the resulting mixture was stirred at -10 °C for 1.5 h. Then the reaction mixture was filtered, the filtrate was diluted with water (50 mL), extracted with EtOAc (3 x 50 mL). The combined organic layers were concentrated, washed with sat. aq. NH4CI solution (3x30 mb) and brine (30 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by flash chromatography (silica gel, 0^10% MeOH in DCM) to give (5-bromo-l-ethyl -lH-pyrazol-4-yl)(5-iodo-l-methyl-lH-imidazol-4-yl)methanol as a white solid (903 mg, yield: 25%). LC / MS (ESI) m / z: 411 [M+H]+.Synthesis of (5-bromo-l-ethyl-lH-pyrazol-4-yl)(4-iodo-l-methyl-lH-imidazol-5-yl)methanolTo a solution of 4,5-diiodo-l-methyl-lH-imidazole (2.00 g, 5 99 mmol) in DCM (100 mL) at -70 °C was added ethylmagnesium bromide (1 M, 6.59 mL, 6.59 mmol) dropwise underNj atmosphere. The mixture was stirred at -70 °C for 30 min. Then to the mixture was added a solution of 5-bromo-l-ethyl-lH-pyrazole-4-carbaldehyde (1.34 g, 6.59 mmol) in DCM (10 mL) and stirred at -70 °C for 2 h. The reaction mixture was quenched with sat. aq. NFfiCl solution (50 mL), extracted with DCM (3 x 50 mL), washed with brine, dried over anhydrous         filtered and concentrated. Theresidue was purified by column chromatography on silica gel (30% EtOAc in PE) to give (5-bromo-l-ethyl-lH-pyrazol-4-yl)(4-iodo-l-methyl-lH-imidazol-5-yl)methanol as a yellow oil (1.80 g, yield: 73%). LC / MS (ESI) m / z: 411 [M+H]+.Synthesis of (4-bromo-l-methyl-lH-pyrazol-3-yl)(l-(cyclopropylinethyl)-lH-pyrazol-4-yl)methanolOHTo a stirred solution of l-(cyclopropylmethyl)-4-iodo-lH-pyrazole (415 mg, 1.67 mmol) in THF (5 mL) was added i-PrMgCl LiCl (1.3 mL, 1.3 M in THF, 1.7 mmol) dropwise at 0 °C under N?. After stirring at 0 °C for 1 h, a solution of 4-bromo-l-methyl-lH-pyrazole-3-carbaldehyde (316 mg, 1.67 mmol) in THF (1 mL) was added at 0 °C. The reaction was stirred at r.t. for 2 h, quenched with sat. NH4CI (10 mL), extracted with EtOAc (10 mL), dried over Na?SO4 and concentrated to dryness. The residue was purified by column chromatography on silica gel (PE:EtOAc = 1:1) to give (4-bromo-1 -methyl-lH-pyrazol-3-yl)( 1-(cyclopropylmethyl)-lH-pyrazol-4-yl)methanol (258 mg, 50% yield) as a yellow oil. LC / MS (ESI) (m / z): 311 [M+H]+.The following intermediates were synthesized using a similar experimental protocol:(3-chloropyrazm-2-yl)(l-(cyclopropylmethyl)-3-methyl-lH-pyrazol-4-yl)methanol Cl                     1                                  Cl H° +       A              n"x N '        A               nz 4        Y? m / z (ESI): 279 [M+H] Synthesis of tert-butyl (E)-2-((5-bromo-l-ethyl-lH-pyrazol-4-yl)methylene)hydrazine-l-carboxylateA solution of 5-bromo-l-ethyl-lH-pyrazole-4-carbaldehyde (3 g, 14.8 mmol) and (tert-5 butoxycarbonyl )hydrazine (1.9 g, 14.8 mmol) in MeOH (30 mL) was stirred at 25 °C for 12 h. The mixture was concentrated under reduced pressure to give crude tert-butyl (E)-2-((5-bromo-l-ethyl-lH-pyrazol-4-yl)methylene)hydrazme-l-carboxylate (4.71 g, 100% yield) as a yellow solid which was used in the next step without further purification. LC / MS (ESI): m / z = 317 [M+H] +.The following intermediates were synthesized using a similar experimental protocol:(E)-tert-butyl 2-((5-bromo-l-cyclobutyl-lH-pyrazol-4-yl)methylene)hydrazinecarboxylate / / z Z X °=< 0 tA / / 0 X* z zx m / z (ESI): 343 [M+H] tert-butyl (E)-2-((5-bromo-3-chloro-l-ethyl-lH-pyrazol-4-yl)methylene)hydrazine-l -carboxylate Cl                                      Cl 0 \ /       \                        \ -N A      0 \ / h%AcA +        ‘ AyANAA H                         Br                                 Br          H m / z (ESI): 351 [M+H] tert-butyl (E)-2-((l-(cyclopropylmethyl)-lH-pyrazol-4-yl)methylene)hydrazine-l-carboxylate 0 \ /                                 "A      u H                                                            H m / z (ESI): 265 [M+H] 10 Synthesis of (5-ethyl-l,2-oxazol-3-yl)(5-iodo-2-methyl-2H-l,2,3-triazol-4-yl)methanolA mixture of 4-(5-ethyl-l,2-oxazole-3-carbonyl)-5-iodo-2-methyl-2H-l,2,3-triazole (310 mg, 0.93 mmol) in MeOH (2 mb) was added NaBH4 (35 mg, 0.93 mmol) stirred at r.t. for 1 h. The mixture was quenched with sat. aq. N+LCl solution (10 mL) at 0 °C and extracted with EA (20 mL x 3).15 The organic layer was separated, dried over anhydrous Na2SO4, filtered and concentrated to give a residue, which was purified by column chromatography on silica gel (PE : EA = 1 : 1, V / V) to give (5-ethyl-l,2-oxazol-3-yl)(5-iodo-2-methyl-2H-l,2,3-triazol-4-yl)methanol (150 mg, 48 1%) as a light-yellow oil. LC / MS ESI (m / z): 335 [M+H]+.The following intermediates were synthesized using a similar experimental protocol:l-(2-{l-[(5-bromo-l-ethyl-lH-pyrazol-4-yl)methyl]-lH-l,2,4-triazol-5-yl}-5-fluorophenyl)ethan-1 -olm / z (ESI): 394 [M+H]1 -(2-( 1 -((5 -bromo-1 -cyclobutyl-lH-pyrazol-4-yl)methyl)- 1H-1,2,4-triazol-5 -yl)-5-fluorophenyl)ethanolm / z (ESI): 420 [M+H]1 -(2-( 1 -((5 -bromo-1 -ethyl- lH-pyrazol-4-yl)methyl)-3 -methyl- 1H-1,2,4-triazol-5-yl)-5-fluorophenyl)ethanolm / z (ESI): 408 [M+H]1-(2-(5 -((5-bromo-l-ethyl-lH-pyrazol-4-yl)methyl)-3-methyl-lH-l,2,4-triazol-l-yl)-5-fluorophenyl)ethan-1 -olm / z (ESI): 408 [M+H]l-(2-{l-[(5-bromo-3-chloro-l-ethyl-lH-pyrazol-4-yl)methyl]-lH-l,2,4-triazol-5-yl}-5-fluorophenyl)ethan-1 -olm / z (ESI): 428 [M+H]1 -(2-( 1 -((5 -bromo-1 -ethyl- lH-pyrazol-4-yl)methyl)-l H-pyrazol-5 -yl)-5-fluoropyridin-3 -yl)ethan-l-olm / z (ESI): 394 [M+H]1-(2-(4-((3-chloro-1-ethyl-lH-pvrazol-4-yl)methvl)-2-methyloxazol-5-yl)-5-fluorophenyl)ethan-1-01m / z (ESI): 364 [M+H](4-(2-( (R)-l-((5-bromo-2-nitropyridin-3-yl)oxy)ethyl)-4-fluorophenyl)-l, 2,5-thiadiazol-3-yl)(l-ethyl-lH-pyrazol-4-yl)methanol1-(2-(1-((3-ethylisoxazol-5-yl)methyl)-lH-tetrazol-5-yl)-5-fluorophenyl)ethan-l-olF F m / z _. AV\ W (ESI): N'O N- / Vo N - q    N —(   \ °   « 0 / "OH 318 N, ,N / 'N N, N / 'N [M+H] 1-(2-(4-(( l-ethyl-lH-pyrazol-4-yl)methyl)-2-methyloxazol-5-yl)-5-fluorophenyl)ethan-l-olF F / ^\ / =\ m / z V? (ESI): Ns / N= / )~OH 330 n^o / Nyo / [M+H] 1-(2-( 1-(( 1-(cyclopropylmethyl)-lH-pyrazol-4-yl)methyl)-3-methyl-lH-l,2,4-triazol-5-yl)-5-fluorophenyl)ethan-1 -olF F m / z (ESI): V   N= / N<yN / V   N= / •N \\    / - OH N^N / 356 [M+H] Synthesis of 2-ethyl-4-[(l-ethyl-lH-pyrazol-4-yl)methyl]-5-iodo-2H-l,2,3-triazoleOHTo a solution of (I -ethyl-l / 7-pyrazol-4-yl)(2-cthyl-5-iodo-2 / 7-1.2.3-triazol-4-yl)methanol (190 mg, 0.547 mmol) in DCM (1 mL), were added E+SiH (191 mg, 1.64 mmol) and TFA (250 mg, 2.19 5 mmol) at 0 °C, and then the mixture was stirred at 25 °C for 2 h. The mixture was concentrated, basified with sat. aq. NaHCOs to pH 7, then extracted with DCM (15 mL x 3). The combined organic layers were washed with brine (15 mL) and dried over NajSCL, then concentrated. The residue purified by flash chromatography (silica gel, 10^50% EtOAc in PE) to give 2-ethyl-4-[(l-ethyl-l H-pyrazol-4-yl)mcthyl |-5-iodo-2 / / -L2.3-triazole (184 mg, yield: 98%) as a light-yellow oil. 10 LC / MS (ESI) m / z: 332.0 [M+H]+.The following intermediates were synthesized using a similar experimental protocol:4-[(5 -bromo-1 -cyclobutyl-lH-pyrazol-4-yl)methyl] -5 -iodo-2 -methyl -2H-1,2,3 -triazole OH gr                                    Br J    .                  A             / K -n y              ► -N t y- n-<> nA, ^n' v           N > m / z (ESI): 422 [M+H] 4-iodo-2-methyl-5-(( l-(oxetan-3-yl)-lH-pyrazol-4-yl)methyl)-2H-l,2,3-triazole N— / 1 r-N                         J — N, J  kN ~< O 1                                                 N OH m / z (ESI): 346 [M+H] Synthesis of (3-cyclobutylisoxazol-5-yl)(5-iodo-2-methyl-2H-l,2,3-triazol-4-yl)methanolTo a solution of 4,5-diiodo-2-methyl-2H-l,2,3-triazole (1.1 g, 3.18 mmol) in THF (20 mL) was added isopropylmagnesium bromide (3.2 mL) at -15 °C. After the mixture was stirred for 1 h, a5 solution of 3-cyclobutyl-1,2-oxazole-5-carbaldehyde (400 mg, 2.65 mmol) in THF (10 mL) was added. The resulting mixture was stirred at r.t. for 1 h. The reaction mixture was quenched with water and extracted with EtOAc (100 mL). The combined EtOAc layers were washed with brine, dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel eluting with MeOH in DCM (0 —» 5%) to give (3-10 cyclobutylisoxazol-5-yl)(5-iodo-2-methyl-2H-l,2,3-triazol-4-yl)methanol (420 mg, 44%) as a pale-yellow oil. LC / MS (ESI): m / z = 361 [M+H]+.The following intermediates were synthesized using a similar experimental protocol:(l-(2,2-difluoroethyl)-lH-pyrazol-4-yl)(5-iodo-2-methyl-2H-l,2,3-triazol-4-yl)methanol "W z z z' + p o z z z’ m / z (ESI): 370 [M+H] (3-chloro-l-(2,2-difluoroethyl)-lH-pyrazol-4-yl)(5-iodo-2-methyl-2H-l,2,3-tri azol-4-yl)methanol 1                   / -v • X” F -1         1        0 Cl 1 N,            F N ,N —         v / rvN H0 Cl m / z (ESI): 404 [M+FI] (3-bromo-5-fluoropyridin-2-yl)(l-(cyclopropylmethyl)-lH-pyrazol-4-yl)methanol .N"\. + FZ Br zK / ^O x II          -------- N FZ Br OH m / z (ESI): 326 [M+H] (3-bromo-5-fluoropyridin-2-yl)( 1-(2,2-difluoroethyl)-lH-pyrazol-4-yl)methanol LL LL Z. Br zKZ^O II            ----------* F Br OH F m / z (ESI): 336 [M+H] [3-chloro-l-(cyclopropyhnethyl)-lH-pyrazol-4-yl](5-iodo-2-methyl-2H-l,2,3-triazol-4-yl)methanol v? % X N-n'n ’ ~X-N y.           N' HO f N N       X—<. m / z (ESI): 394 [M+H] [3-chloro-l-(cyclopropylmethyl)-lH-pyrazol-4-yl](4-iodo-l -methyl-lH-pyrazol-3-yl)methanol o          ci N                                N 1                                                                                       1 h° 5* Zv- ,N m / z (ESI): 393 [M+H] [3-(cyclopropylmethyl)-l-methyl-lH-pyrazol-5-yl](5-iodo-2-methyl-2H-l,2,3-triazol-4-yl)methanol k 1 o '                                         , \ / 1      V N,                      k W + K ,N    ___. A VN 1                                                                                                      i HO S -Ka z N      X—-<. m / z (ESI): 374 [M+H] Synthesis of 5-bromo-l-ethyl-4-((4-iodo-l-methyl-lH-pyrazol-3-yl)methyl)-lH-pyrazoleBr OHBrTo a solution of (5-bromo-l-ethyl-lH-pyrazol-4-yl)(4-iodo-l-methyl-lH-pyrazol-3-yl)methanol (800 mg, 1.90 mmol) in DCM (5 mL) were added triethylsilane (1.80 g, 15.6 mmol) and TFA (1.45 5 mL, 19.5 mmol) at 0 °C. After stirring at 0 °C for 2 h, the mixture was neutralized to pH 8 with sat.NaHCOx The resulting mixture was diluted with EtOAc, washed with brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by column chromatography on silica gel (0—>60% EA in PE) to give 5-bromo-l-ethyl-4-((4-iodo-l-methyl-lH-pyrazol-3-yl)methyl)-IH-pvrazolc as a yellow oil (700 mg, yield: 91%). LC / MS ESI (m / z): 395 [M+H]+.Synthesis of 4-[(5-bromo-l-ethyl-lH-pyrazol-4-yl)methyl|-5-iodo-2-methyl-2H-l,2,3-triazoleBr OHBrA mixture of (5-bromo-l-ethyl-lH-pyrazol-4-yl)(5-iodo-2-methyl-2H-l,2,3-triazol-4-yl)methanol (800 mg, 1.94 mmol) and TES (2.8 mL, 16 mmol) in TFA (5 mL) was stirred at 30 °C for 0.5 h.5 The mixture was adjusted to pH 8 with NaHCO? at 0 °C, and then extracted with EA (50 mL x 2). The combined organic phases were dried over anhydrous NASth. filtered, and concentrated. The residue was purified by flash chromatography on silica gel (30% EtOAc in PE) to give 4-[(5-bromo-l-ethyl-lH-pyrazol-4-yl)methyl]-5-iodo-2-methyl-2H-l,2,3-triazole (750 mg, yield: 97%) as a light-yellow solid. LC / MS ESI (m / z): 396 [M+H]+.10 The following intermediates were synthesized using a similar experimental protocol:4-{[l-(cyclopropylmethyl)-3-methyl-lH-pyrazol-4-yl]methyl}-5-iodo-2-methyl-2H-1,2,3-triazole I V N HO 1                                       1 N ,N       '--<1            N. ,N       '--<1 M                                N 1 m / z (ESI): 358 [M+H] 4-((1 -(cyclopropylmethyl)-lH-pyrazol-4-yl)methyl)-5-iodo-2 -methyl -2H-1,2,3-triazole U \\ z z z' 1 r=N                  N^’       K L L               ....... N I / •     / - OH m / z (ESI): 344 [M+EI] 4-bromo-3-(( 1-(cyclopropylmethyl)-lH-pyrazol-4-yl)methyl)-l-methyl-IH-pyrazole — N " YA A r=N O                  K I £         * At P* OH m / z (ESI): 295 [M+H] 4-((1 -ethyl -3-(trifluoromethyl)-lH-pyrazol-4-yl)methyl)-5-iodo-2 -methyl -2H-1,2,3-triazole FVF HO 1              FvF      1 F \ kA          F \     a ' N -------- " N N. J N-N                 N- JJ N-N m / z (ESI): 386 [M+H] 4-(( 1-( cyclopropylmethyl)-lH-pyrazol-4-yl)methyl)-5-iodo-2H-l, 2,3-tnazole \ — w ^0 z z' z £ I 1 z z^^ m / z (ESI): 330 [M+H] HO Synthesis of 5-bromo-l-(cyclopropylmethyl)-4-((5-iodo-lH-pyrazol-l-yl)methyl)-3-methyl-IH-pyrazoleBrTo a solution of 5-bromo-l-(cyclopropylmethyl)-3-methyl-lH-pyrazole-4-carbaldehyde (1.00 g, 4.11 mmol) in THF (20 mL) was added dropwise DIBAL-H (5.50 mb, 8.23 mmol) at -78 °C under N2. The reaction mixture was stirred at -78 °C for 2 h under No. The reaction mixture was allowed to warm to r.t. The reaction mixture was added sat. potassium sodium tartrate tetrahydrate solution and stirred at r.t. for 2 h. The mixture was extracted with EtOAc twice and the combined organic layers were washed with brine, dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by flash column chromatography to afford (5-bromo-l-(cyclopropylmethyl)-3-methyl-lH-pyrazol-4-yl)methanol (800 mg, 79%) as a white solid. LC / MS (ESI) m / z: 245 [M+HJ+.To a solution of (5-bronio-l-(cyclopropyhnethyl)-3-methyl-lH-pyrazol-4-yl)methanol (1.50 g, 6.12 mmol) in DCM (20 mL) was added SOCL (1.4 mL, 18 mmol). The mixture was stirred at r.t. for 2 h. The reaction mixture was concentrated to afford crude 5-bromo-4-(chloromethyl)-l-(cyclopropylmethyl)-3-methyl-IH-pyrazole (1.6 g, 99%) as a colorless oil.To a mixture of 5-iodo-lH-pyrazole (662 mg, 3.42 mmol) and K2CO3 (1.41 g, 10.2 mmol) in DMF (30 mL) was added a solution of 5-bromo-4-(chloromethyl)-l-(cyclopropyhnethyl)-3-methyl-lH-pyrazole (900 mg, 3.45 mmol) in DMF (1mL) dropwise at 0 °C. The mixture was stirred at 80 °C for 8 h under N2. The mixture was cooled to r.t. and diluted with EtOAc. This mixture was washed with brine, dried over anhydrous Na2SO4, concentrated. Tire residue was purified by flash column chromatography and further purified by SFC to afford 5-bromo-l-(cyclopropylmethyl)-4-((5-iodo-lH-pyrazol-l-yl)methyl)-3-methyl-IH-pyrazole (170 mg, 12%) as a colorless oil. LC / MS (ESI) m / z: 421 [M+H]+.Synthesis of tert-butyl 2-((5-bromo-l-ethyl-lH-pyrazoI-4-yl)methyl)hydrazine-l-carboxylateTo a solution of tert-butyl (E)-2-((5-bromo-1 -ethyl-lH-pyrazol-4-yl)methylene)hydrazine-l-carboxylate (4.71 g, 14.8 mmol) in AcOH (15 mL) andMeOH (10 mb) was added NaBHjCN (1.20 g, 18.9 mmol) at r.t. The resulting mixture was stirred at 25 °C for 12 h. After concentration under reduced pressure, the residue was dissolved in EtOAc, washed with aq. Na2COs and brine, dried over anhydrous Na?SOt and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (0^30% EtOAc in PE) to give tert-butyl 2-((5-bromo-l-ethyl-lH-pyrazol-4-yl)methyl)hydrazine-l-carboxylate (3.5 g, 69% yield) as a white solid. LC / MS (ESI): m / z = 319 [M+FI]+.The following intermediates were synthesized using a similar experimental protocol:tert-butyl 2-((5-bromo-3-chloro-1 -ethyl- lH-pyrazol-4-yl)methyl)hydrazine-1 -carboxylate Cl                                                  Cl ,                 O v z                 ,    N~Z        O K , Br         H                                 Br         H m / z (ESI): 353 [M+H] tert-butyl2 -((1 -(cyclopropylmethyl) -1 H-pyrazol -4 -yl)methyl)hydrazine-1 -carboxylate / T z >° Z I / I z >° m / z (ESI): 267 [M+H] Synthesis of (R)-l-(5-fluoro-2-iodophenyl)ethyl benzoateOH      OHTo amixture of (lS)-l-(5-fluoro-2-iodophenyl)ethan-l-ol (1.00 g, 3.76 mmol), benzoic acid (0.550 g, 4.51 mmol) and triphenylphosphine (1.18g, 4.51 mmol) in THF (30 mL) was added DIAD (0.89 mL, 4.5 mmol) dropwise at 0 °C under N?. The resulting mixture was stirred at r.t. overnight, poured into water, and then extracted with EtOAc (50 mLx2). The combined organic layers were washed with brine, dried over anhydrous Na2SO4 and concentrated. Tire residue was purified by column chromatography (silica gel, 1—>5% ethyl acetate in petroleum ether) to afford (lR)-l-(5-fluoro-2-iodophenyl)ethyl benzoate (1.2 g, 86%) as a yellow solid. LC / MS (ESI): m / z = 371 |M+H| .The following intermediates were synthesized using a similar experimental protocol:(R)-3-( 1 -(5-fluoro-2-iodophenyl)ethoxy)-2 -nitropyridine ^ / 1                           °'N*°~ m / z (ESI): 389 [M+H] Synthesis of l-[(5-bromo-l-ethyl-lH-pyrazol-4-yl)methyl]-5-iodo-4-(trimethylsilyl)-lH-l,2,3-triazole5 To a solution of 4-(azidomethyl)-5-bromo-l-ethyl-lH-pyrazole (1.20 g, 5.21 mmol) in MeCN (15 mL) were added Cui (1.12 g, 5.89 mmol), DIPEA (760 mg, 5.89 mmol), NBS (1.05 g, 5.89 mmol) and ethynyltrimethylsilane (0.83 mL, 5.9 mmol). Then the mixture was degassed with N2 three times and stirred at 25 °C for 16 h. Tire reaction mixture was concentrated, and the residue was treated with ice water and EtOAc. The organic layer was separated, washed with brine, dried over10 anhydrous Na?SO;. fdtered, and concentrated to dryness. The residue was purified by flash chromatography (silica gel, 0^20% MeOH in DCM) to give l-[(5-bromo-l-ethyl-lH-pyrazol-4-yl)methyl]-5-iodo-4-(trimethylsilyl)-lH-l,2,3-triazole (320 mg, yield: 14%) as ayellowoil. LC / MS (ESI) m / z: 454[M+H]+.The following intermediates were synthesized using a similar experimental protocol:l-((5-bromo-l-cyclobutyl-lH-pyrazol-4-yl)methyl)-5-iodo-4-(trimethylsilyl)-lH-l,2,3 -tri azole HI                                                 / \ -N*l N'\ ' 1   +                ,  * cu —1  -----* \                  Br            K                                     Br          1 m / z (ESI): 480 [M+H] was purified by column chromatography on silica gel (0—>30% EA in PE) to give 5-fluoro-2-iodobenzaldehyde (9.1 g, yield: 92%) as a pale-yellow solid. LC-MS ESI (m / z): 251 [M+H]+Under a N2 atmosphere, a solution of methyltriphenylphosphonium bromide (14.7 g, 41.1 mmol) in dry THF (100 mL) was cooled to -10 °C and potassium tert-butoxide (4.60 g, 41.1 mmol) was added. After 15 min, 5-fluoro-2-iodobenzaldehyde (8.60 g, 34.2 mmol) was added and the reaction mixture was stirred at ambient temperature for 2 h. Ice-water (150 mL) was added and the mixture was extracted with EA (3x50 mL). The combined organic layers were dried overNa2SO4, filtered, and evaporated in vacuo at 25 °C. The residue was purified by flash chromatography (0^20% EA in PE) to give 2-ethenyl-4-fluoro-1 -iodobenzene (10 g, yield: 118%) as a colorless oil containing solvents. LC / MS (ESI) m / z: 249 |M+H]+.To a solution of 2-ethenyl-4-fluoro-l-iodobenzene (8.50 g, 34.3 mmol) in t-BuOH (75 mL) and H2O (25 mL) was added N-methylmorpholine N-oxide (12.0 g, 51.4 mmol, 50% in water) and K2OSO4 2H2O (0.10 g, cat.). The reaction was stirred at r.t. for 48 h. The reaction was quenched by the addition of sat. aq. ^282()3 solution. The mixture was stirred at r.t. for another 4 h. The mixture was extracted with EA (50mLx3), dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by flash chromatography (0^100% EA in PE) to give l-(5-fluoro-2-iodophenyl)ethane-l,2-diol (6.1 g, yield: 63%) as a white solid. LC-MS ESI (m / z): 283 [M+H]+To a solution of l-(5-fluoro-2-iodophenyl)ethane-l,2-diol (5.30 g, 18.8 mmol) in DMF (50 mL) were added imidazole (2.60 g, 37.6 mmol) and tert-butyldimethylsilyl chloride (3.00 g, 19.7 mmol). The mixture was stirred at r.t. overnight, diluted with water, and then extracted with EA (30 ml x3). The combined organic layers were washed with bnne (50 mL), dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by flash chromatography (0^50% EA in PE) to give 2-[(tert-butyldimethylsilyl)oxy]-l-(5-fluoro-2-iodophenyl)ethan-l-ol (6.4 g, yield: 86%). LC-MS ESI (m / z): 397 [M+H]+To solution of 2-[(tert-butyldimethylsilyl)oxy]-l-(5-fluoro-2-iodophenyl)ethan-l-ol (3.0 g, 7.6 mmol) in THF (40.0 mL) was added i-PrMgCl (14.6 mL, 18.9 mmol, 1.3 M) dropwise at 0 °C. The mixture was stirred at r.t. for 1 h. Trimethyl borate (2 00 g, 18 9 mmol) was added dropwise to the mixture at 0 °C and stirring was continued at r.t. for 2 h. The reaction was quenched by sat. aq. NH4CI and extracted with EA (3x30 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by column chromatography on silica gel (0^100% EA in PE) to give 3-{[(tert-butyldimethylsilyl)oxy]methyl}-5-fluoro-l,3-dihydro-2,l-benzoxaborol-l-ol (1.3 g, yield: 58%) as a colorless oil. LC-MS ESI (m / z): 297 [M+H]+.Synthesis of 5-bromo-l-ethyl-4-(hydrazinylmethyl)-lH-pyrazole hydrochlorideBrTo a solution of tert-butyl 2-((5-bromo-l-ethyl-lH-pyrazol-4-yl)methyl)hydrazine-l-carboxylate (3.5 g, 11 mmol) in MeOH (15 mL) was added a solution of HC1 in dioxane (10 mb, 4 N). The 5 reaction mixture was stirred at 25 °C for 12 h. The mixture was concentrated under reduced pressure and the residue was triturated with PE. The resulting solids were collected by filtration, washed with PE and dried in vacuo to give 5-bromo-l-ethyl-4-(hydrazinylmethyl)-lH-pyrazole hydrochloride (2.5 g, 89% yield) as a white solid. LC / MS (ESI): m / z = 219 [M+H]+.The following intermediates were synthesized using a similar experimental protocol:5-bromo-l-cyclobutyl-4-(hydrazinylmethyl)-lH-pyrazole hydrochloride H      T .                    f + HCI / \ 0 H ^~N                    H ^~N m / z (ESI): 245 [M+H] 5-bromo-3-chloro-l-ethyl-4-(hydrazineylmethyl)-lH-pyrazole hydrochloride Br                                    Br H / L - -.....-            N'X + HO / \     H                         H    / —N '      0        Cl                                       Cl m / z (ESI): 253 [M+H] l-(cyclopropylmethyl)-4-(hydrazinylmethyl)-lH-pyrazole hydrochloride MN                               — 0^ nh      v      .              &n...

Claims

CLAIMS1. A compound of Formula (I), or an enantiomer, a mixture of enantiomers, or a tautomer thereof, or a pharmaceutically acceptable salt thereof:(I)whereinQ is CH or N;Z is CRs or N;X is a 5-membered heteroarylene, comprising 1 to 3 heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur; wherein the 5-membered heteroarylene is substituted with 0, 1, or 2 occurrences of R2;Y is a 5- or 6-membered heteroarylene, comprising 1 to 3 heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur; wherein the 5- or 6-membered heteroarylene is substituted with 0, 1, or 2 occurrences of R3;in Y, the point of attachment to the methylene group bonded to X and Y and the point of attachment to the aromatic ring comprising Z are on adjacent atoms, and the 5- to 6-membered heteroarylene ring atom alpha to the point of attachment to the methylene group and beta to the point of attachment to the aromatic ring comprising Z is nitrogen;Ri is selected from the group consisting of H, methyl, and hydroxymethyl;each R2 is independently selected from the group consisting of H, halo, CN, C1-4 alkoxy, C1-4 alkyl, halo-Ci-4 alkyl, Cm cycloalkylmethyl, C3.6 cycloalkyl, and C3-6 heterocycloalkyl;each R3 is independently selected from the group consisting of H, halo, CN, C1-4 alkoxy, halo-Ci-4 alkyl, and C1.4 alkyl; andeach of R4 and R? is independently H or F;provided that X is not 3*,4-substituted-pyrazolylene, where * indicates the point of attachment of X or Y to the methylene group bonded to X and Y.

2. A compound of Formula (I), or an enantiomer, a mixture of enantiomers, or a tautomer thereof, or a pharmaceutically acceptable salt thereof:whereinQ is CH or N;Z is CR5 or N;X is a 5-membered heteroarylene, comprising 1 to 3 heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur; wherein the 5-membered heteroarylene is substituted with 0, 1, or 2 occurrences of R2;Y is a heteroarylene selected from the group consisting of l,2*-substituted-imidazolylene, 4*,5-substituted-imidazolylene, 4,5*-substituted-imidazolylene, 4*,5-substituted-l,2,3-oxadiazolylene, 3*,4-substituted-l,2,5-oxadiazolylene, 3*,4-substituted-1,2-oxazolylene, 4*,5-substituted-l,3-oxazolylene, 2*,3-substituted-pyrazinylene, 1*,5-substituted-pyrazolylene, 3 *,4-substituted-pyrazolylene, 3 *,4-substituted-pyridazinylene, 2 *, 3 -sub stituted-pyridinylene, 4 *, 5 -sub stituted-pyrimidinylene, 2 *, 3 -sub stituted-pyrrolylene, 5*,6-substituted-l,2,3,4-tetrazinylene, 1*, 5-substituted-1,2,3,4-tetrazolylene, l,5*-substituted-l,2,3,4-tetrazolylene, 4*,5-substituted-l,2,3-thiadiazolylene, 3*,4-substituted-l,2,5-thiadiazolylene, 3*,4-substituted-l,2-thiazolylene, 4*,5-substituted-l,3-thiazolylene, 4*,5-substituted-l,2,3-triazinylene, 5*,6-substituted-l,2,4-triazinylene, 5,6*-substituted-l,2,4-triazinylene, l*,5-substituted-l,2,3-triazolylene, 4*,5-substituted-l,2,3-triazolylene, l*,5-substituted-l,2,4-triazolylene, l,5*-substituted-l,2,4-triazolylene, and3*,4-substituted-l,2,4-triazolylene; wherein the heteroarylene is substituted with 0, 1, or 2 occurrences of Ra;* indicates the point of attachment of X or Y to the methylene group bonded to X and Y;in Y the heteroarylene ring atom alpha to the point of attachment to the methylene group and beta to the point of attachment to the aromatic ring comprising Z is nitrogen;Ri is selected from the group consisting of H, methyl, and hydroxymethyl;each Ra is independently selected from the group consisting of H, halo, CN, Ci-4 alkoxy, Ci-4 alkyl, halo-Ci-4 alkyl, Cm cycloalkylmethyl, C3.6 cycloalkyl, and C3-6 heterocycloalkyl;each R3 is independently selected from the group consisting of H, halo, CN, C1.4 alkoxy, halo-Ci-4 alkyl, and Ci-1 alkyl; andeach of R4 and R5 is independently H or F.

3. The compound of claim 1 or 2, wherein X is a 5-membered heteroarylene selected from the group consisting of pyrazolylene, isoxazolylene, imidazolylene, isothiazolylene, and tri azol yl ene.

4. The compound of claim 1 or 2, wherein X is a 5-membered heteroarylene selected from the group consisting of 4*,5-substituted-pyrazolylene, 4,5*-substituted-pyrazolylene, 1 *,5-substituted-pyrazolylene, 4*,5-substituted-isoxazolylene, 4,5*-substituted-isoxazolylene, 3*,4-substituted-isoxazolylene, 3*,4-substituted-isothiazolylene, 4*,5-substituted-isothiazolylene, 4,5*-substituted-isothiazolylene, 4*,5-substituted-imidazolylene, l*,5-substituted-imidazolylene, l*,5-substituted-triazolylene, and 4*5-sub stituted-tri azol yl ene.

5. The compound of claim 1 or 2, wherein X is a 5-membered heteroarylene selected from the group consisting of:* indicates the point of attachment of X to the methylene group bonded to X andY; andRz is independently selected from the group consisting of H, halo, CN, Ci-4 alkoxy, Ci4 alkyl, halo-Ci-4 alkyl, C3-4 cycloalkylmethyl, C3-6 cycloalkyl, and C3-6heterocycloalkyl.

6. The compound of any one of claims 1-5, wherein Y is a heteroarylene selected from the group consisting of l*,5-substituted-pyrazolylene, 3*,4-substituted-pyrazolylene, l,2*-substituted-imidazolylene, 4*,5-substituted-imidazolylene, 4,5*-substituted-imidazolylene, l*,5-substituted-l,2,3-triazolylene, 4*,5-substituted-l,2,3-triazolylene, l*,5-substituted-l,2,4-triazolylene, l,5*-substituted-l,2,4-triazolylene, 4*,5-sub stitu ted-1,3 -thi azol yl ene, 2 *, 3 - sub stituted-pyri di ny 1 ene, 4 *, 5 - sub stituted-pyrimidinylene, and 2*,3-substituted-pyrazinylene.

7. The compound of any one of claims 1-5, wherein Y is a heteroarylene selectedfrom the group consisting of:* indicates the point of attachment of Y to the methylene group bonded to X and Y; andR; is selected from the group consisting of H, halo, CN, C i -1 alkoxy, halo-Ci-4 alkyl, and Ci-4 alkyl.

8.     The compound of any one of claims 1-7, wherein Q is CH.

9.     The compound of any one of claims 1-7, wherein Q is N.

10.    The compound of any one of claims 1-9, wherein Z is CRs.

11.    The compound of any one of claims 1-10, wherein Rs is H.

12.    The compound of any one of claims 1-10, wherein R5 is F.

13. The compound of any one of claims 1-12, wherein Z is N.

14.    The compound of any one of claims 1-13, wherein R4 is H.

15.    The compound of any one of claims 1-13, wherein R4 is F.

16. The compound of any one of claims 1-15, wherein the compound of Formula (I) has the structure (I-A):

17. The compound of any one of claims 1-15, wherein the compound of Formula (I) has the structure (I-B):

18. The compound of any one of claims 1-17, wherein R2 is each independently selected from the group consisting of H, chloro, CN, methyl, ethyl, isobutyl, methoxy, trifluoromethyl, cyclopropylmethyl, 2-fluoroethyl, difluoromethyl, 2,2-difluoroethyl, cyclopropyl, cyclobutyl, and oxetanyl.

19. The compound of any one of claims 1-18, wherein R3 is each independently selected from the group consisting of H, fluoro, chloro, CN, methyl, and ethyl20. The compound of claim 1 or 2, which is a compound of any of the following15 formula:or an enantiomer, a mixture of enantiomers, or a tautomer thereof, or a pharmaceuticallyacceptable salt thereof.

21. A compound in Table 1, or a pharmaceutically acceptable salt thereof.

22. The compound of any one of claims 1-21, wherein the compound is in the form of a pharmaceutically acceptable salt; and the salt is selected from the group consisting of alkyl ammonium salts, dialkyl ammonium salts, trialkyl ammonium salts, tetra-alkyl ammonium salts, L-arginine salts, benenthamine salts, benzathine salts, betaine salts, 10 calcium hydroxide salts, choline salts, deanol salts, diethanolamine salts, diethylaminesalts, 2-(diethylamino)ethanol salts, ethanolamine salts, ethylenediamine salts, N-methylglucamine salts, hydrabamine salts, IH-imidazole salts, lithium salts, L-lysine salts, magnesium salts, 4-(2-hydroxyethyl)morpholine salts, piperazine salts, potassium salts, 1-(2-hydroxyethyl)pyrrolidine salts, sodium salts, triethanolamine salts, tromethamine salts, Na salts, Ca salts, K salts, Mg salts, and Zn salts.

23. The compound of claim 22, wherein the pharmaceutically acceptable salt is a solvate comprising a solvent molecule selected from the group consisting of water, methanol, ethanol, and dimethylformamide.

24. A pharmaceutical composition, comprising the compound or pharmaceutically acceptable salt of any one of claims 1-23; and a pharmaceutically acceptable carrier or excipient.

25. The pharmaceutical composition of claim 24, wherein the composition is a tablet, a capsule, a granule, a lyophile for reconstitution, a powder, a solution, a syrup, a suppository, an injection, a transdermal delivery system, or a solution suitable for topical administration.

26. A method of treating cancer, comprising administering to a subject in need thereof a therapeutically effective amount of the compound or pharmaceutically acceptable salt of any one of claims 1-23.

27.    The method of claim 26, wherein the subject is a human.

28.    The method of claim 26 or 27, wherein the cancer is a solid tumor or a hematologicmalignancy.

29. The method of claim 28, wherein the cancer is a solid tumor; and the solid tumor is selected from lung cancer, glioblastoma, inflammatory myofibroblastic tumor (IMT), bile duct cancer, ovarian cancer, gastric cancer, colorectal cancer, angiosarcoma, melanoma, epithelioid hemangioendothelioma, esophageal cancer, kidney cancer, breast cancer, colon cancer, thyroid cancer, spitzoid tumor, and neuroblastoma30. The method of claim 28, wherein the cancer is a hematologic malignancy; and the hematologic malignancy is anaplastic large cell lymphoma (ALCL), diffuse large B-cell lymphoma (DLBCL), or large B-cell lymphoma.

31. The method of any one of claims 26 to 30, wherein the cancer is an ALK positive or RO SI positive cancer.

32. The method of claim 26 or 27, wherein the compound or salt thereof is an inhibitor of ROS 1 and ALK.

33.    The method of any one of claims 26-27 and 32, wherein the cancer is non-small celllung cancer.

34. The method of any one of claims 26-27 and 32, wherein the cancer is inflammatory myofibroblastic tumor.

35. The method of any one of claims 26-27 and 32, wherein the cancer is ovarian cancer.

36. The method of any one of claims 26-27 and 32, wherein the cancer is spitzoid melanoma.

37.    The method of claim 26 or 27, wherein the compound is an inhibitor of ROS 1.

38.    The method of any one of claims 26-27 and 37, wherein the cancer is glioblastoma.

39.    The method of any one of claims 26-27 and 37, wherein the cancer ischolangiocarcinoma.

40. The method of any one of claims 26-27 and 37, wherein the cancer is gastric cancer.

41. The method of any one of claims 26-27 and 37, wherein the cancer is colorectal cancer.

42. The method of any one of claims 26-27 and 37, wherein the cancer is angiosarcoma.

43.    The method of claim 26 or 27, wherein the compound is an inhibitor of ALK44.    The method of any one of claims 26-27 and 43, wherein the cancer is anaplasticlarge cell lymphoma.

45. The method of any one of claims 26-27 and 43, wherein the cancer is diffuse large B-cell lymphoma.

46. The method of any one of claims 26-27 and 43, wherein the cancer is esophageal squamous cell carcinoma.

47. The method of any one of claims 26-27 and 43, wherein the cancer is renal medullary carcinoma.

48. The method of any one of claims 26-27 and 43, wherein the cancer is renal cell carcinoma.

49. The method of any one of claims 26-27 and 43, wherein the cancer is breast cancer.

50. The method of any one of claims 26-27 and 43, wherein the cancer is papillary thyroid cancer.

51. The method of any one of claims 26-27 and 43, wherein the cancer is neuroblastoma.

52. The method of any one of claims 26-27 and 32-42, wherein the cancer comprises expression of an oncogenic ROS1 gene or oncogenic ROS1 gene-fusion.

53. The method of claim 52, wherein the oncogenic ROS1 gene or oncogenic ROS1 gene-fusion contains one or more mutations of the human ROS1 gene.

54. The method of claim 52, wherein the mutations in the oncogenic ROS1 gene or oncogenic ROS1 gene-fusion results in expression of a ROS1 protein with a G2032R mutation.

55. The method of any one of claims 26-27, 32-36, and 43-51, wherein the cancer comprises expression of an oncogenic ALK gene or oncogenic ALK gene-fusion.

56. The method of claim 55, wherein the oncogenic ALK gene or the oncogenic ALK gene-fusion contains one or more mutations of the human ALK gene.

57. The method of claim 56, wherein the mutations in the oncogenic ALK gene or the oncogenic ALK gene-fusion results in expression of an ALK protein with one or more mutations selected from the group consisting of G1202R, LI 196M, G1269A, D1203N, and I1171N.58 The method of any one of claims 26-57, wherein the subject has received one prior cancer therapy.

59. The method of any one of claims 26-57, wherein the subject has received at least two prior cancer therapies.

60. The method of any one of claims 26-59, wherein the compound is an inhibitor of human tropomyosin receptor kinase A, B, or C.

61. The method claim 60, wherein the IC50 of the compound for inhibition of mutant or non-mutant ROS1 or ALK is no more than one-fifth of the IC50 of the compound for inhibition of wild-type tropomyosin receptor kinase A, B, or C.

62. A method for selectively inhibiting ROS1 over TRK, wherein the inhibition takes place in a subject suffering from cancer, said method comprising administering an effective amount of a compound of any one of claims 1 to 23 or a pharmaceutical composition of claim 24 or 25 to said subject.

63. A method for selectively inhibiting ALK over TRK, wherein the inhibition takes place in a subject suffering from cancer, said method comprising administering an effective amount of a compound of any one of claims 1 to 23 or a pharmaceutical composition of claim 24 or 25 to said subject.

64. The method of any one of claims 26 to 63, further comprising administering to the subject an effective amount of one or more additional therapeutic agents.

65.    The method of claim 64, wherein the additional therapeutic agent is a TKI.

66.    The method of claim 65, wherein the TKI is crizotinib, ceritinib, alectinib,brigatinib, lorlatinib, entrectinib, repotrectinib, cabozantinib, foretinib, taletrectinib, merestinib, masitinib, or ensartinib.

67. A method of decreasing a level of ROS 1 or ALK in a cell, comprising contacting the cell with a compound of any one of claims 1-23 or a pharmaceutical composition of claim 24 or 25.

68. The method of claim 67, further comprising contacting the cell with one or more additional therapeutic agents.

69.    The method of claim 68, wherein the additional therapeutic agent is a TKI.

70.    The method of claim 69, wherein the TKI is crizotinib, ceritinib, alectinib,brigatinib, lorlatinib, entrectinib, repotrectinib, cabozantinib, foretinib, taletrectinib, merestinib, masitinib, or ensartinib

Images