CHEMOTHERAPEUTIC AGENTS OF MACROCYCLIC HETEROAROMATIC ETHERS

Abstract

Heterocyclic heteroaromatic macrocyclic ether compounds, pharmaceutically acceptable salts of these compounds, and pharmaceutical compositions thereof are described. Methods for treating or preventing cancer using heterocyclic heteroaromatic macrocyclic ether compounds, pharmaceutically acceptable salts of these compounds, and pharmaceutical compositions thereof are also described.

Description

This application claims the priority benefit of PCT patent application no. PCT / CN2020 / 088589, filed May 5, 2020; and US provisional patent application no. 63 / 125,747, filed December 15, 2020; and 63 / 060,331, filed August 3, 2020; all of which are incorporated herein in their entirety by reference. BACKGROUND Receptor tyrosine kinases (RTKs) are cell surface enzymes that receive external signals, such as those to grow and divide, and transmit those signals into the cell through kinase activity. Many RTKs are proto-oncogenes; Aberrant RTK activity can drive cell survival, growth, and proliferation, leading to cancer and related disorders. This aberrant kinase activity can be caused by mutations, such as activating mutations in the kinase domain, genetic rearrangements resulting in fusion proteins containing the intact kinase domain, amplification, and other means. RTK proto-oncogenes include ROS1, anaplastic lymphoma kinase (ALK), NTRK1 (encodes TRKA), NTRK2 (encodes TRKB), and NTRK3 (encodes TRKC). ROS1 is an RTK proto-oncogene, with ROS1 rearrangements detected in non-small cell bronchopulmonary carcinomas (NSCLC), glioblastoma, inflammatory myofibroblastic tumor (IMT), cholangiocarcinoma, ovarian cancer, gastric cancer, colorectal cancer, angiosarcoma, and spitzoid melanoma. Oncogenic ROS1 gene fusions contain the ROS1 kinase domain (3' region) fused to the 5' region of a variety of partner genes. Examples of ROS1 fusion partner genes observed in NSCLC include SLC34A2, CD74, TPM3, SDC4, EZR, LRIG3, KDELR2, CEP72, CLTL, CTNND2, GOPC, GPRC6A, LIMA1, LRIG3, MSN, MYO5C, OPRM1, SLC6A17 (putative ), SLMAP, SRSF6, TFG, TMEM106B, TPD52L1, ZCCHC8 and CCDC6. Other fusion partners include CAPRIN1, CEP85L, CHCHD3, CLIP1 (putative), EEF1G, KIF21A (putative), KLC1, SART3, ST13 (putative), TRIM24 (putative), ERC1, FIP1L1, HLAA, KIAA1598, MYO5A, PPFIBP1, PWWP2A , FN1, YWHAE, CCDC30, NCOR2, NFKB2, APOB, PLG, RBP4, and GOLGB1. ALK is an RTK proto-oncogene, with ALK rearrangements detected in many cancer types, including NSCLC, anaplastic large cell lymphoma (ALCL), IMT, diffuse large B-cell lymphoma (DLBCL), esophageal squamous cell carcinoma (ESCC), renal medullary carcinoma , renal cell carcinoma, breast cancer, colon cancer, serous ovarian carcinoma, papillary thyroid cancer and spitzoid tumors, and activating ALK mutations detected in neuroblastoma. ALKoncogenic gene fusions contain the ALK kinase domain (3' region) fused to the 5' region of more than 20 different partner genes, where the most common are EML4 in NSCLC and NPMen ALCL. Other associated genes include TMP1, WDCP, GTF2IRD1, TPM3, TPM4, CLTC, LMNA, PRKAR1A, RANBP2, TFG, FN1, KLC1, VCL, STRN, HIP1, DCTN1, SQSTM1, TPR, CRIM1, PTPN3, FBXO36, A TIC and KIF5B . NTRK1, NTRK2 and NTRK3 are RTK proto-oncogenes that encode TRK family kinases, with NTRK1, NTRK2 and NTRK3 chromosomal rearrangements detected at low frequency in many cancers. However, for the treatment of ROS1-positive or ALK-positive patients, TRK inhibition, particularly in the central nervous system (CNS), has been associated with adverse reactions, including dizziness / ataxia / gait disturbance, paresthesia, weight gain and cognitive changes. Agents in the prior art used to treat oncogenic ROS1 and ALK have substantial deficiencies. These deficiencies may represent one or more of the following: associated inhibition of TRK, limited activity in the CNS, and inadequate activity against resistance mutations. Treatment of ROS1-positive or ALK-positive patients along with TRK inhibition is associated with adverse reactions, particularly in the central nervous system (CNS), including dizziness / ataxia / gait disturbance, paresthesia, weight gain, and cognitive changes. Additionally, there is a need for CNS-penetrating and TRK-sparing inhibitors of the kinase domain of wild-type ROS1 and of ROS1 with acquired resistance mutations occurring individually or in combination, including G2032R, D2033N, S1986F, S1986Y, L2026M , L1951R, E1935G, L1947R, G1971E, E1974K, L1982F, F2004C, F2004V, E2020K, C2060G, F2075V, V2089M, V2098I, G2101A, D2113N, D2113G, L2155S, L20 32K, and L2086F. Similarly, there is a need for CNS-penetrating inhibitors and TRK-sparing inhibitors of ALK with acquired resistance mutations. A variety of ALK drug resistance mutations have been reported, occurring individually or in combination, including G1202R, L1196M, G1269A, C1156Y, I1171T, I1171N, I1171S, F1174L, V1180L, S1206Y, E1210K, 1151Tins, F1174C, G1202del, D1203N, S1206Y, S1206C, L1152R, L1196Q, L1198P, L1198F, R1275Q, L1152P, C1156T, and F1245V. COMPENDIUM One aspect described herein are the compounds of Formula (I) or one of the pharmaceutically acceptable salts thereof: (i) where Q 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, sulfur and oxygen; 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 2*,3-substituted furanylene, 2,3*substituted furanylene, 3*,4-substituted furanylene, substituted r,2-imidazolylene, substituted 1*,5-imidazolylene, 1,5*-substituted imidazolylene, 4,5*-1,2,3-substituted oxadiazolylene, 3,4*-substituted 1,2-oxazolylene, 4*,5-1,2-substituted oxazolylene, 4,5* -1,2-substituted oxazolylene, 4,5*-1,3-substituted oxazolylene, 1*,2-substituted phenylene, 1,5*-substituted pyrazolylene, 4*,5-substituted pyrazolylene, 3,4*substituted pyridazinylene , 4*,5-substituted pyridinylene, 2,3*-substituted pyridinylene, 3*,4-substituted pyridinylene, 3,4*-substituted pyridinylene, 4,5*-substituted pyridinylene, 1 *,2-substituted pyrrolylene, 1,2*substituted pyrrolylene, 2,3*-substituted pyrrolylene, 3*,4-substituted pyrrolylene, 4,5*-1,2,3-substituted thiadiazolylene, 3,4*-1 ,2-substituted thiazolylene, 4*,5-1,2-substituted thiazolylene, 4,5*-1,2,3-substituted thiadiazolylene, 3,4*-1,2-substituted thiazole, 4*,5 -1,2-substituted thiazolylene, 4,5*-1,2-substituted thiazolylene, 4,5*-1,3-substituted thiazolylene, 2*,3-substituted thiazolylene, 2,3*-substituted thiazolylene, 3* 4-substituted thiophenylene, 4,5*-1,2,3-substituted triazinylene, 1,5*-1,2,3-substituted triazolylene and 3,4*-1,2,4-substituted 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 attached 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 carbon, oxygen or sulfur; R1 is selected from the group consisting of H, methyl and hydroxymethyl; each instance of R2 is independently selected from the group consisting of CN, halo, C1-4 alkoxy, C1-4 alkyl, halo-C1-4 alkyl, C3-4 cycloalkylmethyl, C3-6 cycloalkyl and C3-6 heterocyclyl; each instance of R3 is independently selected from the group consisting of H, halo, CN, C1-4 alkoxy, halo-C1-4 alkyl and C1-4 alkyl; and each of R4 and Rs is independently H or F; In certain embodiments, the present disclosure provides a pharmaceutical composition suitable for use in a subject in the treatment or prevention of cancer comprising an effective amount of any of the compounds described herein (e.g., a compound of the description , such as a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients. In certain embodiments, the pharmaceutical preparations can be used to treat or prevent a condition or disease as described herein document. One aspect of the disclosure is methods of treating cancer characterized by one or more mutations in the ROS1 or ALK genes, comprising administering to a subject in need thereof an effective amount of a compound as described herein ( for example, a compound of Formula (I) or any of the embodiments thereof described herein). In certain embodiments, the compound is an inhibitor of ROS1, in other embodiments, the compound is an inhibitor of ALK, in additional embodiments, the compound is an inhibitor of ROS1 and ALK. In certain respects, the human subject needs such treatment. These cancers include, but are not limited to, non-small cell bronchopulmonary carcinomas, inflammatory myofibroblastic tumor, ovarian cancer, spitzoid melanoma, glioblastoma, cholangiocarcinoma, gastric cancer, colorectal cancer, angiosarcoma, anaplastic large cell lymphoma, diffuse large B-cell lymphoma, squamous cell carcinoma of the esophagus, renal medullary carcinoma, renal cell carcinoma, breast cancer, papillary thyroid cancer and neuroblastoma. In some embodiments, the method of treating or preventing cancer may comprise administering a compound of Formula (I) together with one or more chemotherapeutic agents. DETAILED DESCRIPTION Definitions Unless otherwise indicated, all technical and scientific terms used herein have the same meaning commonly understood by one skilled in the art of the present disclosure. The following references provide the skilled person with a general definition of many of the terms used in this description: Singleton et al., Dictionary of Microbiology and Molecular Biology (2nd ed. 1994); The Cambridge Dictionary of Science and Technology (Walker ed., 1988); The Glossary of Genetics, 5da. Ed., R. Rieger et al. (eds.), Springer Verlag (1991); and Hale & Marham, The Harper Collins Dictionary of Biology (1991). As used herein, the following terms have the meanings ascribed to them below, unless otherwise specified. In some embodiments, chemical structures are described with a corresponding chemical name. In case of conflict, the chemical structure governs the meaning, rather than the name. In this description, comprises, comprising, containing and having and the like may have the meaning given to them in US patent law and may mean includes, including and the like; consisting essentially of or consisting essentially also has the meaning given to it in US patent law and the term is open-ended, allowing the presence of more than what is recited as long as the basic or novel features of what is recited are not substantially modified by the presence of more of what is recited, but it excludes the modalities of the previous technique. Unless specifically indicated or obvious from the context, as used herein, the term o is understood to be inclusive. Unless specifically indicated or obvious from the context to the contrary, as used herein, the terms a / a and the / la are understood to be singular or plural. The term acyl is recognized in the art and refers to a group represented by the general formula hydrocarbylC(O)-, preferably alkylC(O)-. The term acylamino is recognized in the art and refers to an amino group substituted with an acyl group and may be represented, for example, by the formula hydrocarbon(O)NH-. The term acyloxy is recognized in the art and refers to a group represented by the general formula hydrocarbylC(O)-, preferably alkylC(O)-. The term alkoxy refers to an alkyl group, preferably a lower alkyl group, that has an oxygen attached to it. Representative alkoxy groups include methoxy, ethoxy, propoxy, tert-butoxy and the like. The term alkoxyalkyl refers to an alkyl group substituted with an alkoxy group and may be represented by the general formula alkyl-O-alkyl. The term alkenyl, as used herein, refers to an aliphatic group containing at least one double bond and is intended to include both unsubstituted alkenyls and substituted alkenyls, the latter of which refers to alkenyl moieties that have substituents that replace a hydrogen on one or more carbons of the alkenyl group. Such substituents may appear on one or more carbons that are included or not included in one or more double bonds. Furthermore, such substituents include all those contemplated for alkyl groups, as discussed below, except where stability is prohibitive. For example, replacement of alkenyl groups by one or more alkyl, carbocyclyl, aryl, heterocyclyl or heteroaryl groups is contemplated. An alkyl or alkane group is a straight-chain or branched non-aromatic hydrocarbon that is fully saturated. Typically, a straight-chain or branched alkyl group has 1 to 20 carbon atoms, preferably 1 to 10, unless otherwise defined. Examples of straight-chain and branched alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tere-butyl, pentyl, hexyl, pentyl and octyl. The straight or branched chain ACi-Ce alkyl group is also called lower alkyl group. Furthermore, the term alkyl (or lower alkyl), as used in the specification, examples and claims, is intended to include both unsubstituted alkyls and substituted alkyls, the latter referring to alkyl moieties having substituents that replace a hydrogen. in one or more carbons of the main structure of the hydrocarbon. Such substituents, if not otherwise specified, may include, for example, a halogen, a hydroxyl, a carbonyl (such as a carboxyl, an alkoxycarbonyl, a formyl or an acyl), a thiocarbonyl (such as a thioester, a thioacetate, or a thioformate), an alkoxy, a phosphorite, a phosphate, a phosphonate, a phosphinate, an amino, an amido, an amidine, a mine, 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. Those skilled in the art will understand that substituted moieties in the hydrocarbon chain may themselves be substituted, if applicable. For example, substituents on a substituted alkyl may include substituted and unsubstituted forms of amino, azido, amino, amido, phosphoryl (including phosphonate and phosphinate), sulfonyl (including sulfate, sulfonamido, sulfamoyl and sulfonate) and silyl groups, as well such as ethers, alkylthios, carbonites (including ketones, aldehydes, carboxylates and esters), -CF3, -CN and the like. Examples of substituted alkyls are described below. Cycloalkyls may further be substituted with alkyls, alkenyls, alkoxys, alkylthios, aminoalkyls, carbonyl substituted alkyls, -CF3, -CN and the like. The term Cx.y when used with a chemical moiety, such as acyl, acyloxy, alkyl, alkenyl, alkynyl or alkoxy, refers to groups containing x to y carbons in the chain. For example, the term "Cx.y alkyl" refers to substituted or unsubstituted saturated hydrocarbon groups, including straight chain alkyl and branched chain alkyl groups containing x to y carbons in the chain, including haloalkyl groups such as trifluoromethyl and 2, 2,2-thyrfluoroethyl, etc. Alkyl Co indicates a hydrogen where the group is in a terminal position, a bond if internal. The terms ΜΛ / t / ZUZÓ / UUÓ4U Ί “C2-y alkenyl” and “C2-y alkynyl” refer to substituted or unsubstituted unsaturated aliphatic groups of analogous length and possible substitution to the alkyls described above, but containing at least one bond double or triple respectively. The term alkylamino, as used herein, refers to an amino group substituted with at least one alkyl group. The term alkylthio, as used herein, refers to a thiol group substituted with an alkyl group and may be represented by the general formula alkyl-. The term alkynyl, as used herein, refers to an aliphatic group containing at least one triple bond and is intended to include both unsubstituted alkynyls and substituted alkynyls, the latter referring to alkynyl moieties having substituents that replace a hydrogen in one or more carbons of the alkynyl group. Such substituents may appear on one or more carbons that are included or not included in one or more triple bonds. Furthermore, said substituents include all those contemplated for alkyl groups, as discussed above, except when stability is prohibitive. For example, replacement of alkynyl groups by one or more alkyl, carbocyclyl, aryl, heterocyclyl or heteroaryl groups is contemplated. The term amide, as used herein, refers to a group EITHER Sixr30 where each R30 independently represents a hydrogen or a hydrocarbyl group, or two R30s are taken together with the N atom to which they are attached to complete a heterocycle having 4 to 8 atoms in the ring structure. The terms amine and amino are recognized in the art and refer to both substituted and unsubstituted amines and salts thereof, for example, a moiety that may be represented by R31R31 S / . / 31 I---N ¡---N —R31\31o ^R31where each R31 independently represents a hydrogen or a hydrocarbyl group, or two R31 are taken together with the N atom to which they are attached to complete a heterocycle having 4 to 8 atoms in the ring structure. The term aminoalkyl, as used herein, refers to an alkyl group substituted with an alkyl group. The term aralkyl, as used herein, refers to an alkyl group substituted with an aryl group. The term aryl, as used herein, includes substituted or unsubstituted single ring aromatic groups in which each ring atom is carbon. Preferably, the ring is a 5 to 7 membered ring, more preferably a 6 membered ring. The term aryl also includes polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjacent rings where at least one of the rings is aromatic, for example the other cyclic rings may be cycloalkyl. , cycloalkenyls, cycloalkynyls, aryls, heteroaryls and / or heterocyclyls. Aryl groups include benzene, naphthalene, phenanthrene, phenol, aniline and the like. The term carbamate is recognized in the art and refers to a group O O A Λ ,R32< Λ ,R32rON or N O R33R33where R32and R33independently represent hydrogen or a hydrocarbyl group, such as an alkyl group or R32and R33together with the intermediate atom or atoms complete a heterocycle having 4 to 8 atoms in the ring structure. The terms carbocycle and carbocyclic, as used herein, refer to a saturated or unsaturated ring in which each ring atom is carbon. The term carbocycle includes both aromatic carbocycles and non-aromatic carbocycles. Non-aromatic carbocycles include both cycloalkane rings, in which all carbon atoms are saturated, and cycloalkene rings, which contain at least one double bond. The term carbocycle includes 5-7 membered monocyclic and 8-12 membered bicyclic rings. Each ring of a bicyclic carbocycle can be selected from saturated, unsaturated and aromatic rings. The carbocycle includes bicyclic molecules in which one, two, or three or more atoms are shared between the two rings. The term fused carbocycle refers to a bicyclic carbocycle in which each of the rings shares two adjacent atoms with the other ring. Each ring of a fused carbocycle can be selected from saturated, unsaturated and aromatic rings. In an exemplary embodiment, an aromatic ring, e.g., phenyl, may be fused to a saturated or unsaturated ring, e.g., cyclohexane, cyclopentane or cyclohexene. Any combination of saturated, unsaturated, and aromatic bicyclic rings, as valency permits, is included in the definition of carbocyclic. Exemplary carbocycles include cyclopentane, cyclohexane, bicyclo[2.2.1]heptane, 1,5-cyclooctadiene, 1,2,3,4-tetrahydronaphthalene, bicyclo[4.2.0]oct3-ene, naphthalene and adamantane. Exemplary fused carbocycles include decalin, naphthalene, 1,2,3,4-tetrahydronaphthalene, bicyclo[4.2.0]octane, 4,5,6,7-tetrahydro-1 H-indene and bicyclo[4.1,0]hept- Jan 3 The carbocycles may be substituted in any one or more positions capable of carrying a hydrogen atom. A cycloalkyl group is a cyclic hydrocarbon that is completely saturated. "Cycloalkyl" includes monocyclic and bicyclic rings. Typically, a monocyclic cycloalkyl group has 3 to about 10 carbon atoms, more typically 3 to 8 carbon atoms unless otherwise defined. The second ring of a bicyclic cycloalkyl can be selected from saturated, unsaturated and aromatic rings. Cycloalkyl includes bicyclic molecules in which one, two, or three or more atoms are shared between the two rings. The term fused cycloalkyl refers to a bicyclic cycloalkyl in which each of the rings shares two adjacent atoms with the other ring. The second ring of a fused bicyclic cycloalkyl can be selected from saturated, unsaturated and aromatic rings. A cycloalkenyl group is a cyclic hydrocarbon containing one or more double bonds. The term carbocylalkyl, as used herein, refers to an alkyl group substituted with a carbocycle group. The term C3-4 cycloalkylmethyl, as used herein, refers to a methyl group substituted with a carbocycle group containing 3 to 4 carbon atoms. The term carbonate is recognized in the art and refers to a group -OCO2-R34, where R34 represents a hydrocarbyl group. The term carboxy, as used herein, refers to a group represented by the formula -CO2H. The term ester, as used herein, refers to a group -C(O)OR35 where R35 represents a hydrocarbyl group. The term ether, as used herein, refers to a hydrocarbyl group linked through an oxygen to another hydrocarbyl group. Accordingly, an ether substituent of a hydrocarbyl group may be hydrocarbyl-O-. Ethers can be symmetric or asymmetric. Examples of ethers include, but are not limited to, heterocycle-O-heterocycle and aryl-O-heterocycle. Ethers include alkoxyalkyl groups, which may be represented by the general formula alkyl-O-alkyl. The terms halo and halogen as used herein mean halogen and include chlorine, fluoro, bromine and iodine. The terms hetaralkyl and heteroaralkyl, as used herein, refer to an alkyl group substituted with a hetaryl group. The term heteroalkyl, as used herein, refers to a saturated or unsaturated chain of carbon atoms and at least one heteroatom, where there are no two adjacent heteroatoms. The terms heteroaryl and hetaryl include substituted or unsubstituted single aromatic ring structures, preferably 5- to 7-membered rings, more preferably 5- to 6-membered rings, which ring structures include at least one heteroatom, preferably one to four heteroatoms. , more preferably one or two heteroatoms. The terms heteroaryl and hetaryl also include polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjacent rings where at least one of the rings is heteroaromatic, for example, the other cyclic rings may be cycloalkyls, cycloalkenyls, cycloalkynyls, aryls, heteroaryls and / or heterocyclyls. Heteroaryl groups include, for example, pyrrole, furan, thiophene, imidazole, oxazole, tlazol, pyrazole, pyridine, pyrazine, pyridazine and pyrimidine, and the like. The asterisk (*) notation on a heteroarylene ring residue corresponding to X or Y in the compound of Formula (I) identifies the ring atom of the residue attached to the methylene group between X and Y, as exemplified below: Formula (I) For example, substituted 1*,5-midazolelene for Y means substituted: attached to phenyl group with R4 The IUPAC numbering rules for heteroarylene rings are used throughout the specification to designate the positions of the ring atoms, as shown above. In this example, the 1-position of the imidazolylene is attached to the methylene group, so it is indicated with an asterisk. The asterisk notation is used in both the names and structures of heteroarylenes for R4. For attached to aromatic ring with Q The ring atom attached to the methylene group (position 5 in this example) is indicated with an asterisk in both the names and structures of the X ring heteroarylenes. The ring atom attached 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 sulfur. The terms heterocyclyl, heterocycle and heterocyclic refer to substituted or unsubstituted non-aromatic ring structures, preferably 3- to 10-membered rings, more preferably 3- to 7-membered rings, which 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 adjacent rings where at least one of the rings is heterocyclyl, for example, the other cyclic rings may 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 attached through a carbon atom that does not have a =0 or =S substituent, and typically has at least one carbon-hydrogen bond and a structure Mainly carbon, but may optionally include heteroatoms. Therefore, groups such as methyl, ethoxyethyl, 2-pyhdyl, and trifluoromethyl are considered 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 attached via of 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, includes groups in which there are ten or fewer non-hydrogen atoms in the substituent, preferably six or less. A lower alkyl, for example, refers to an alkyl group containing ten or fewer carbon atoms, preferably six or less. In certain embodiments, the 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 appearing alone or in combination with other substituents, as in the mentions of 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 adjacent rings, e.g. 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 3 to 10 ring atoms, preferably 5 to 7. The term silyl refers to a silicon moiety with three hydrocarbyl moieties attached to it. The term substituted refers to moieties that have substituents that replace a hydrogen on one or more carbons of the backbone. Substitution or substituted with shall be understood to include the implicit condition that such substitution is in accordance with the permitted valency of the substituted atom and the substituent, and that the substitution gives rise to a stable compound, for example, one that does not undergo spontaneous transformation, such as by rearrangement, cyclization, elimination, etc. As used herein, the term substituted is intended to include all permissible substituents of organic compounds. In a broad aspect, permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic substituents of organic compounds. The permitted substituents may be one or more the same or different for appropriate organic compounds. For the purposes of this description, heteroatoms such as nitrogen may have hydrogen substituents and / or any permissible substituents of the organic compounds described herein that satisfy the valences of the heteroatoms. Substituents may include any substituent 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, a mine, 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. Those skilled in the art will understand that the substituents may in turn be substituted, if appropriate. Unless specifically indicated as unsubstituted, references to chemical moieties herein are understood to include substituted variants. For example, reference to an aryl group or residue implicitly includes both substituted and unsubstituted variants. The term sulfate is recognized in the art and refers to the group -OSO3H, or a pharmaceutically acceptable salt thereof. The term sulfonamide is recognized in the art and refers to the group represented by the general formulas, ? ^36 S-N o o R37 R36 R37where R36 and R37 independently represent hydrogen or a hydrocarbyl group, such as an alkyl group or R36 and R37 together with the intermediate atom or atoms complete a heterocycle having 4 to 8 atoms in the ring structure. The term sulfoxide is recognized in the art and refers to the group -S(O)-R38, where R38 represents a hydrocarbyl group. The term sulfate is recognized in the art and refers to the SO3H group, or a pharmaceutically acceptable salt thereof. The term sulfone is recognized in the art and refers to a group -S(O)2-R39, where R39 represents a hydrocarbyl group. The term thioalkyl, as used herein, refers to an alkyl group substituted with a thiol group. He SC(O)R40 The term thioester, as used herein, refers to a group -C(O)SR40o where R10 represents a hydrocarbyl group. The term thioether, as used herein, is equivalent to an ether, where the oxygen is replaced with a sulfur. The term urea is recognized in the art and can be represented by the general formulas EITHER A A ,R42rN N R41R41where R41and R42independently represent hydrogen or a hydrocarbyl, such as alkyl, or any of the occurrences of R41together with R42and the intermediate atom or atoms complete a heterocycle having 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 can be selectively removed as desired during the course of a synthesis. Examples of protective groups can be found in Greene and Wuts, Protective Groups in Organic Chemistry, 3rd ed., 1999, John Wiley & Sons, NY and Harrison et al., Compendium of Synthetic Organic Methods, vols. 1-8, 1971-1996, John Wiley & Sons, New York. Representative nitrogen protecting groups include, but are not limited to, formyl, acetyl, trifluoroacetyl, benzyl, benzyloxycarbonyl (CBZ), tert-butoxycarbonyl (Boc), trimethylsilyl (TMS), 2-trimethylsilyl-ethanesulfonyl (TES”), triphyl and triphyl groups. substituted, allyloxycarbonyl, 9fluorenylmethyloxycarbonyl (“FMOC”), nitro-verathryloxycarbonyl (“NVOC”) and the like. Representative hydroxyl protecting groups include, but are not limited to, those in which the hydroxyl group is acylated (esterified) or alkylated, such as benzyl and triphyl 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, the compounds of the disclosure may be racemic. In certain embodiments, the compounds of the disclosure may be enriched in an enantiomer. For example, a compound of the disclosure may have more than 30% ee, about 40% ee, about 50% ee, about 60% ee, about 70% ee, about 80% ee, about 90% of ee, or even about 95% or more ee. In certain embodiments, the compounds of the disclosure may have more than one stereocenter. In certain embodiments, the compounds of the disclosure may be enriched in one or more diastereomers. For example, a compound of the disclosure may have more than 30% of, about 40% of, about 50% of, about 60% of, about 70% of, about 80% of, about 90% of of, or even about 95% or more of. In certain embodiments, the therapeutic preparation may be enriched to provide predominantly one enantiomer of a compound (e.g., of Formula (I)). An enantiomerically enriched mixture may comprise, for example, at least about 60 mole percent of an enantiomer, or more preferably at least about 75, about 90, about 95, or even about 99 mole percent. In certain embodiments, the compound enriched in one enantiomer is substantially free of the other enantiomer, where substantially free means that the substance in question constitutes less than 10%, or less than 5%, or less than 4%, or less than 3%. , or less than 2%, or less than 1% compared to the amount of the other enantiomer, for example, in the composition or mixture of compounds. For example, if a composition or mixture of compounds contains about 98 grams of a first enantiomer and about 2 grams of a second enantiomer, it would be said to contain about 98 mole 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 mole percent of a diastereomer, or more preferably at least about 75, 90, 95, or even 99 mole percent. In some embodiments, a residue in a compound exists as a mixture of tautomers. A tautomer is a structural isomer of a residue or a compound that readily interconverts with another structural isomer. For example, a pyrazole ring has two tautomers: which differ in the positions of the pi bonds and a hydrogen atom. Unless explicitly stated otherwise, the drawing of a tautomer of a residue or compound encompasses all possible tautomers. The term subject to which administration is contemplated includes, but is not limited to, human beings (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 older adult)) and / or other primates (e.g., cynomolgus monkeys, rhesus monkeys); mammals, including commercially relevant mammals such as cows, pigs, horses, sheep, goats, cats and / or dogs; and / or poultry, including commercially relevant birds such as chickens, ducks, geese, quail and / or turkeys. The preferred subjects are humans. As used herein, a therapeutic agent 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. Therefore, as used herein and unless otherwise specified, the terms prevention and prevent refer to an approach to obtaining beneficial or desired results including, but not limited to, prophylactic benefit. For prophylactic benefit, a therapeutic agent may be administered to a patient at risk of developing a particular disease, or to a patient who exhibits one or more of the physiological symptoms of a disease, even though a diagnosis of this disease has not been made. In one embodiment, a therapeutic agent is administered prior to clinical manifestation of the unwanted condition (e.g., disease or other unwanted condition of the subject) for prophylactic benefit (e.g., protects the subject against development of the unwanted condition). ). As used herein and unless otherwise specified, the terms treatment and treat refer to therapeutic or palliative measures. Beneficial or desired clinical outcomes include, but are not limited to, relief, in whole or in part, of symptoms associated with a disease, disorder or condition, decrease in the extent of the disease, stabilized (i.e., no worsening) state of the disease , delay or slowing of disease progression, improvement or palliation of the disease state (for example, one or more symptoms of the disease) and remission (whether partial or total), whether detectable or undetectable. “Treatment” can also mean prolonging survival compared to the expected survival if no treatment is received. In one embodiment, the treatment comprises the administration of a therapeutic agent after the manifestation of the unwanted condition (i.e., it is intended to decrease, improve or stabilize the existing unwanted condition or the side effects thereof). The term prodrug is intended to encompass compounds that, under physiological conditions, become the therapeutically active agents of the present disclosure (e.g., a compound of Formula (I)). A common method for preparing a prodrug is to include one or more selected moieties that are hydrolyzed under physiological conditions to reveal the desired molecule. In other embodiments, the prodrug is converted by 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 depicted above may be replaced with the corresponding suitable prodrug, for example, wherein a hydroxyl in the parent compound occurs 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 may refer to an amount that is sufficient to improve at least one sign or symptom of cancer. A response to a treatment method may include a decrease or improvement in negative symptoms, a decrease in the progression of a disease or symptoms thereof, an increase in beneficial symptoms or clinical outcomes, a decrease in side effects, stabilization of the disease, partial or total remedy for the disease, among others. As used herein and unless otherwise noted, the term relapse refers to a disorder, disease, or condition that responded to prior treatment (e.g., achieved a complete response) and then progressed. Pretreatment may 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 which may include one or more lines of therapy. Compounds In 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: (l) where Q 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 attached to and beta to the point of attachment to the aromatic ring comprising Z is carbon, oxygen or sulfur; R1 is selected from the group consisting of H, methyl and hydroxymethyl; each instance of R2 is independently selected from the group consisting of H, CN, halo, C1-4 alkoxy, C1-4 alkyl, halo-C1-4 alkyl, C3-4 cycloalkylmethyl, C3-6 cycloalkyl and heterocyclyl C3-6; each instance of R3 is independently selected from the group consisting of H, halo, CN, Ci-4 alkoxy, halo-C1-4 alkyl and C1-4 alkyl; and each of R4 and R5 is independently H or F; provided that X is not substituted 3*,4-pyrazolylene, where * indicates the point of attachment of X or Y to the methylene group attached to In one aspect, a compound of Formula (I) or a pharmaceutically acceptable salt thereof is described: (l) where Q 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, sulfur and oxygen; 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 2*,3-substituted furanylene, 2,3*substituted furanylene, 3*,4-substituted furanylene, 1*,2-substituted midazole, 1*,5-! substituted midazolilene, substituted 1,5*-imidazolylene, substituted 4,5*-1,2,3-oxadiazolylene, substituted 3,4*-1,2-oxazolylene, substituted 4*,5-1,2-oxazolylene , substituted 4,5*-1,2-oxazolylene, substituted 4,5*-1,3-oxazolylene, substituted 1*,2-phenylene, substituted 1,5*-pyrazolylene, substituted 4*,5-pyrazolylene, 3 ,4*substituted pyridinylene, 4*,5-substituted pyridinílene, 2,3*-substituted pyridinílene, 3*,4-substituted pyridinylene, 3,4*-substituted pyridinylene, 4, 5*-substituted pyrrolylene, 1*,2-substituted pyrrolylene, 1,2*substituted pyrrolylene, 2,3*-substituted pyrrolylene, 3*,4-substituted pyrrolylene, 4,5*-1, substituted 2,3-thiadiazolylene, substituted 3,4*-1,2-thiazolylene, substituted 4*,5-1,2-thiazolylene, substituted 4,5*-1,2-thiazolylene, 4,5*-1, substituted 3-thiazolylene, substituted 2*,3-thiophenylene, substituted 2,3*-thiophenylene, substituted 3*,4-thiophenylene, substituted 4,5*-1,2,3-triazinylene, 1,5*-1, substituted 2,3-triazolylene and substituted 3,4*-1,2,4triazolylene; 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 attached 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 carbon, oxygen or sulfur; Ri is selected from the group consisting of H, methyl and hydroxymethyl; each instance of R2 is independently selected from the group consisting of H, CN, halo, C1-4 alkoxy, C1-4 alkyl, halo-C1-4 alkyl, C3-4 cycloalkylmethyl, C3-6 cycloalkyl and C3-6 heterocyclyl; each instance of R3 is selected independently from the group consisting of H, halo, CN, C1-4 alkoxy, halo-C1-4 alkyl and C1-4 alkyl; and each of R4 and Rs is independently H or F; In some embodiments, In some embodiments, X is selected from the group consisting of pyrazolylene and triazolylene. In certain embodiments, substituted soxazolylene, 3*,4-substituted sothiazolylene, 4*,5-substituted sothiazolylene, 4*,5-substituted midazolilene, 1*,5-substituted imidazolylene, 1*,5-substituted triazolylene and 4* Substituted ,5-triazolylene. In some embodiments, In some embodiments, X is selected from the group consisting of pyrazolylene and triazolylene. In certain embodiments, substituted soxazolylene, 3*,4-substituted soxazolylene, 3*,4-substituted sothiazolylene, 4*,5-substituted sothiazolylene, 4,5*substituted isothiazolylene, 4*,5-substituted midazolylene, 1*, 5-substituted imidazolylene, Γ,5-substituted triazolylene and 4*,5-substituted triazolylene. In certain embodiments, X is selected from the group consisting of: indicates the point of attachment of X with the methylene group attached to X and Y; and R2 is independently selected from the group consisting of H, CN, halo, C1-4 alkoxy, C1-4 alkyl, halo-C1-4 alkyl, C3-4 cycloalkylmethyl, C3-6 cycloalkyl and C3-6 heterocyclyl. In one embodiment, X is a pyrazolylene. In one embodiment, X is not substituted 3*,4-pyrazolylene / N-NN-N. In one embodiment, X is not R2. In one embodiment, In another embodiment, X is substituted 4*,5-pyrazolylene. In another embodiment, X is substituted 4,5*-pyrazolylene. In another embodiment, X is substituted 1*,5-pyrazolylene. In one embodiment, X is an isoxazolylene. In one embodiment, X is substituted 4*,5-soxazolylene. In one embodiment, X is 4,5*-substituted soxazolylene. In one embodiment, X is substituted 3*,4isoxazolylene. In one embodiment, X is . In one embodiment, X is In one embodiment, X is an isothiazolylene. In one embodiment, X is substituted 3*,4-sothiazolylene. In one embodiment, X is substituted 4*,5-isothiazolylene. In one embodiment, X is 4.5*substituted isothiazolylene. In one embodiment, X is . In one embodiment, X is Y---N In one embodiment, X is an imidazolylene. In one embodiment, X is substituted 4*,5-midazollene. In one embodiment, X is substituted 1*,5-midazolylene. In one embodiment, X is In one embodiment, X is a triazolylene. In one embodiment, X is substituted r,5-triazolylene. x In one embodiment, X is substituted 4*,5-triazolylene. In one embodiment, X is n=n. In an X\ modality, X is n=n In one embodiment, X is replaced with 0 occurrences of R2 (i.e., all open positions in X are H). In one embodiment, X is replaced with 1 occurrence of R2 that is not H. In one embodiment, R2 is independently selected from the group consisting of H, halo, CN, alkoxy (X, C1-4 alkyl, halo-C1-4 alkyl, C3-4 cycloalkylmethyl, C3-6 cycloalkyl and C3-6 heterocyclyl. In one embodiment, R2no is 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, R2 is cyclopropyl. In one embodiment, R2 is cyclobutyl. In one embodiment, 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 modality, R2 is methoxy. In certain embodiments, X is selected from the group consisting of: In certain embodiments, , 4,5*-1,3-substituted thiazolylene, 3,4*-1,2-substituted oxazolylene, 4*,5-1,2 substituted oxazolylene, 3,4*-1,2-substituted thiazolylene, 4* Substituted ,5-1,2-thiazolylene, substituted 2,3*-pihd¡nylene, substituted 3*,4-pyridinylene, substituted 4*,3-pihd¡nylene, 4,5*-pyrimid substituted nylene, substituted 1,5*1,2,3-triazolylene and substituted 3,4*-1,2,4-triazolylene. In certain embodiments, Y is selected from the group consisting of: Yo * indicates the point of attachment of Y with the methylene group attached to X and Y; and Rs is selected from the group consisting of H, halo, CN, C1-4 alkoxy, halo-C1-4 alkyl and alkyl C1-4. In one embodiment, Y is a 5-membered heteroarylene. In one embodiment, Y is a pyrazolylene. In one embodiment, Y is substituted 1,5*-pyrazolylene. In one embodiment, Y is 4*,5-substitutedpyrazolylene. In one embodiment, Y is substituted 3,4*-pyrazolylene. In one embodiment, Y is In one embodiment, Y is In one embodiment, Y is . In one embodiment, Y is In one embodiment, Y is an imidazolylene. In one embodiment, Y is substituted 1*,2-midazollene. In one embodiment, Y is substituted 5*,1-midazollene. In one embodiment, Y is . In one embodiment, Y is K In one embodiment, Y is In one embodiment, Y is 1,2-thiazolylene. In one embodiment, Y is substituted 3,4*-1,2-thiazolylene. In one embodiment, Y is substituted 4*,5-1,2-thiazolylene. In one embodiment, Y is In one embodiment, Y is 1,3-thiazolylene. In one embodiment, Y is substituted 4,5*-1,3-thiazolylene. In one embodiment, Y is In one embodiment, Y is 1,2-oxazolylene. In one embodiment, Y is substituted 3,4*-1,2-oxazolylene. In one embodiment, Y is substituted 4*,5-1,2-oxazolylene. In one embodiment, Y is In one embodiment, Y is a triazolylene. In one embodiment, Y is substituted 1,5*-1,2,3-triazolylene. In one embodiment, Y is substituted 3,4*-1,2,4-triazolylene. In one embodiment, Y is In one embodiment, Y is In one embodiment, Y is a 6-membered heteroarylene. In one embodiment, Y is pyridinylene. In one embodiment, Y is substituted 2,3*-pyridinylene. In one embodiment, Y is substituted 3*,4-pyridinylene. In one embodiment, Y is substituted 4*,3-pyridinylene. In one embodiment, Y is a modality, and it is In one embodiment, Y is Forks In one embodiment, Y is In one embodiment, Y is X Υχ modality, Y is In one embodiment, Y is pyrimidinylene. In one embodiment, Y is substituted 4,5*-pyrimidinylene. In one embodiment, Y is replaced with 0 occurrences of R3 (i.e., all open positions in Y are H). In one embodiment, Y is replaced with 1 occurrence of R3 that is not H. In one embodiment, Y is replaced with 2 occurrences of R3 that are not H. In one embodiment, R3 is selected from the group consisting of H, halo, CN, C1.4 alkoxy, C1-4 haloalkyl and C1-4 alkyl. In one embodiment, R3 is not H. In one embodiment, R3 is C1-4 alkyl. In one embodiment, R3 is methyl. In one embodiment, R3 is ethyl. In one embodiment, R3 is halo. In one embodiment, R3 is fluoro. In one embodiment, R3 is chlorine. In one embodiment, R3 is CN. In one embodiment, In another embodiment, Y is an imidazolylene provided herein. In another embodiment, Y is a 1,2-thiazolylene provided herein. In another embodiment, Y is a 1,3-thiazolylene provided herein. In another embodiment, Y is a 1,2-oxazolylene provided herein. In another embodiment, Y is a triazolylene provided herein. In another embodiment, Y is pyridinylene provided herein. In another embodiment, Y is a pyrimidinylene 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 1,2-thiazolylene provided herein. In another embodiment, Y is a 1,3-thiazolylene provided herein. In another embodiment, Y is a 1,2-oxazolylene provided herein. In another embodiment, Y is a triazolylene provided herein. In another embodiment, Y is pyridinylene provided herein. In another embodiment, Y is a pyrimidinylene 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 1,2-thiazolylene provided herein. In another embodiment, Y is a 1,3-thiazolylene provided herein. In another embodiment, Y is a 1,2-oxazolylene provided herein. In another embodiment, Y is a triazolylene provided herein. In another embodiment, Y is pyridinylene provided herein. In another embodiment, Y is a pyrimidinylene 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. In another embodiment, Y is a 1,2-thiazolylene provided herein. In another embodiment, Y is a 1,3-thiazolylene provided herein. In another embodiment, Y is a 1,2-oxazolylene provided herein. In another embodiment, Y is a triazolylene provided herein. In another embodiment, Y is pyridinylene provided herein. In another embodiment, Y is a pyrimidinylene 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 1,2-thiazolylene provided herein. In another embodiment, Y is a 1,3-thiazolylene provided herein. In another embodiment, Y is a 1,2-oxazolylene provided herein. In another embodiment, Y is a triazolylene provided herein. In another embodiment, Y is pyridinylene provided herein. In another embodiment, Y is a pyrimidinylene 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, R4 is H. In other embodiments, R4 is F. In some embodiments, the compound of Formula (I) has the structure (l-A): (the). In other embodiments, the compound of Formula (I) has the structure (l-B): (Ι-Β). 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 certain embodiments, each R2 is independently selected from the group consisting of H, CN, methyl, ethyl, isopropyl, chloro, methoxy, trifluoromethyl, 2-fluoroethyl, difluoromethyl, 2,2difluoroethyl, 2,2,2-trifluoroethyl, cyclopropylmethyl, cyclobutyl and oxetanyl. In certain embodiments, R3 is selected from the group consisting of H, fluoro, chloro, bromo, CN, methoxy, difluoromethyl, trifluoromethyl, methyl and ethyl. 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: 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: 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: 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 salt MA / E / ZUZo / UUJ4U1 pharmaceutically acceptable of this. 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: 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: 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: 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: 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: 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 selected from the group consisting of: MA / E / ZUZo / UUJ4U1 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: 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: pharmaceutically acceptable of this. In certain embodiments, the compound is selected from the group consisting of: or a pharmaceutically acceptable salt thereof. In one embodiment, a compound of Table 1 is provided herein: Table 1 MA / IZ / ¿U¿O / UUO4m MA / IZ / ¿U¿O / UUO4m MA / E / ZUZo / UUJ4U1 For any compound in Table 1 that has a chiral center due to the presence of non-hydrogen Ri, the R-enantiomer, S-enantiomer, and racemic compound of such compound are specifically provided herein, even if not specifically shown. , in Table 1. In one embodiment, a pharmaceutically acceptable salt of a compound of Formula (I) is provided herein. In one embodiment, a pharmaceutically acceptable salt of any compound of Table 1 is provided herein. In certain embodiments, the pharmaceutically acceptable salt of the compound is selected from the group consisting of alkylammonium salts, dialkylammonium salts, trialkylammonium salts, tetraalkylammonium salts, L-arginine salts, benentamine salts, benzathine salts, betaine salts. , calcium hydroxide salts, choline salts, deanol salts, diethanolamine salts, diethylamine salts, 2-(diethylamine)ethanol salts, ethanolamine salts, ethylenediamine salts, N-methylglucamine salts, salts of hydrabamine, 1H-midazole salts, lithium salts, L-lysine salts, magnesium salts, 4-(2-hydroxyethyl)morpholine salts, piperazine salts, potassium salts, 1-(2-hydroxyethyl)pyrrolidine, 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. In certain embodiments, the compound is a pharmaceutical composition that includes a pharmaceutically 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 lyophilisate for reconstitution, a powder, a solution, a syrup, a suppository, an injection, a transdermal delivery system , and a solution suitable for topical administration. Methods of use Provided herein are methods of treating cancer comprising the administration of a compound of the invention, such as a compound of Formula (I), or an enantiomer, a mixture of enantiomers, or a tautomer thereof, or a pharmaceutical salt. acceptable of this. Cancer is a disease of uncontrolled cell proliferation that results from alterations in certain genes. Some of these alterations occur in the genes that encode receptor tyrosine kinases (RTK), a family of membrane-bound proteins that transmit signals from outside the cell to promote cell survival, growth and proliferation. Aberrant activation of RTKs can lead to excessive cell growth and therefore 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. ROS1 is an RTK encoded by the ROS1 gene. The ligands and biological functions of human ROS1 are unknown, but its homologues in some other species have been shown to bind extracellular ligands and stimulate cell differentiation. For example, mouse ROS1 is essential for the maturation and reproduction of male gametes. In humans, ROS1 chromosomal rearrangements are a well-documented cause of cancer, accounting for 1-2% of non-small cell bronchopulmonary carcinomas (NSCLC) and a subset of many other cancers. These rearrangements result in the fusion of the C terminus of ROS1 with the N terminus of several partner proteins, the most common of which is CD74. ROS1 fusions have constitutive kinase activity that drives tumor growth through the MAPK, PI3K, and JAK / STAT signaling pathways. Small molecule tyrosine kinase inhibitors (TKIs) have been used to target ROS1 fusions in cancer, including crizotinib and entrectinib. Crizotinib was the first TKI approved by the FDA for the treatment of ROS1-positive NSCLC, with an overall response rate of 60-80% and a 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 at the solvent front, which dramatically reduces the affinity of crizotinib. No inhibitor with activity against ROS1-G2032R fusions has been approved by the FDA, indicating a need in the art. In some embodiments, the compound of Formula (I) is a human anaplastic lymphoma kinase (ALK) inhibitor. ALK, also known as cluster of differentiation 246 (CD246), is an RTK encoded by the ALK gene. ALK and ROS1 are evolutionarily related; both belong to the insulin receptor superfamily and their kinase domains share a sequence similarity of approximately! 80%. Some ALK ligands have been identified in humans, including the growth factors pleiotrophin and midkine. While ALK's roles in humans remain inconclusive, much evidence from mouse studies suggests that it is important for nervous system development. 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 account for 3% to 5% of NSCLC, approximately 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 ALK amplification have also been observed, although at a much lower frequency than translocations. Crizotinib, ceritinib, alectinib, brigatinib, and lorlatinib are TKIs approved by the FDA for the treatment of ALK-positive NSCLC and other cancers, either in the first line or after prior therapy. Crizotinib, for example, shows an overall response rate of 60-80% and a median progression-free survival of 8-11 months, which is comparable to its activity in ROS1-positive NSCLC. Despite an initial response, many resistance mutations have emerged to the aforementioned FDA-approved TKIs. Some of these mutations, such as the gatekeeper combination L1196M and the solvent front mutation G1202R, are resistant to all approved drugs. New treatments for ALK-positive cancer harboring resistance mutations are a need in the art. In additional embodiments, the compound of Formula (I) is an inhibitor of human tropomyosin receptor kinases (TRK). The TRK family comprises the 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 account for more than 80% of cases in secretory breast carcinoma, breast analogue-secreting carcinomas, infantile fibrosarcoma, and congenital mesoblastic nephroma. Therefore, TRK inhibition is advantageous for treating cancers that express TRK fusions. Many ROS1 and ALK inhibitors in the prior art also show potent inhibition of native, non-oncogenic TRKs. This is a substantial drawback because native TRKs play important roles in the nervous system, and inadvertent inhibition of native TRKs is associated with adverse reactions including dizziness, ataxia, gait disturbances, paresthesia, weight gain, and cognitive changes. New therapies are needed that preserve TRKs while selectively targeting ROS1 and / or ALK, in their non-mutant and / or mutant forms. In one embodiment, a method of decreasing a level of ROS1 or ALK in a cell is provided herein, comprising contacting the cell with a compound or a pharmaceutical composition or a pharmaceutical combination provided herein. In one embodiment, said contact occurs in a cell of a mammal such as a human. In one embodiment, said contact occurs in a cell of a 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 non-limiting example, the selectivity ratio may 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 the selectivity may be measured by the ratio of IC50 values, among other means. In one embodiment, the selectivity of ROS1 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 TRKs (e.g., TRKA, TRKB, and / or TRBC). By way of non-limiting example, the selectivity ratio may 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 approximately 200, greater than a factor of approximately 400, greater than a factor of approximately 600, greater than a factor of approximately 800, greater than a factor of approximately 1000, greater than a factor of approximately 1500, greater than a factor of approximately 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 the ratio of IC50 values, among other means. In one embodiment, the selectivity of ROS1 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 non-limiting example, the selectivity ratio may 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 the 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 selectivity ratio may 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 approximately 200, greater than a factor of approximately 400, greater than a factor of approximately 600, greater than a factor of approximately 800, greater than a factor of approximately 1000, greater than a factor of approximately 1500, greater than a factor of approximately 2000 , greater than a factor of about 5000, or greater than a factor of about 10,000, where selectivity can be measured by the 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 selectivity ratio may 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 approximately 200, greater than a factor of approximately 400, greater than a factor of approximately 600, greater than a factor of approximately 800, greater than a factor of approximately 1000, greater than a factor of approximately 1500, greater than a factor of approximately 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 the ratio of IC50 values, among other means. In one embodiment, the selectivity of ROS1 and ALK over TRK is measured by the ratio of the value of IC50 against TRK to the value of IC50 against ROS1 and ALK. In one embodiment, a method is provided herein for selectively inhibiting ROS1 over ALK wherein the inhibition takes place in a cell. In one embodiment, a method is provided herein for selectively inhibiting ROS1 over TRKs (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 one embodiment, said contact occurs in a cell. In one embodiment, said contact occurs in a cell of a mammal such as a human. In one embodiment, said contact occurs in a cell of a human patient having a cancer provided herein. In one embodiment, a method is provided herein for selectively inhibiting ROS1 over ALK wherein the inhibition takes place in a subject suffering from cancer, wherein said method comprises 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 ROS1-associated cancer, said method comprising selectively inhibiting ROS1 over ALK by administering an amount of a compound or a pharmaceutical composition provided herein to said subject. , where said amount is sufficient to selectively inhibit ROS1 over ALK. In one embodiment, a method is provided herein for selectively inhibiting ROS1 on TRK (e.g., TRKA, TRKB and / or TRBC) wherein the inhibition takes place in a subject suffering from cancer, wherein said method comprises 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 ROS1-associated cancer, 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 to selectively inhibit ROS1 over TRK (e.g., TRKA, TRKB and / or TRBC). In one embodiment, a method is provided herein for selectively inhibiting ALK over ROS1 wherein the inhibition occurs in a cell. In one embodiment, a method is provided herein 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 one embodiment, said contact occurs in a cell. In one embodiment, said contact occurs in a cell of a mammal such as a human. In one embodiment, said contact occurs in a cell of a human patient having a cancer provided herein. In one embodiment, a method is provided herein for selectively inhibiting ALK on ROS1 wherein the inhibition takes place in a subject suffering from cancer, wherein said method comprises 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 an ALK-associated cancer, said method comprising selectively inhibiting ALK over ROS1 by administering an amount of a compound or a pharmaceutical composition provided herein to said subject. , where said amount is sufficient to selectively inhibit ALK on ROS1. In one embodiment, a method is provided herein for selectively inhibiting ALK over TRK (e.g., TRKA, TRKB and / or TRBC) wherein the inhibition takes place in a subject suffering from cancer, wherein said method comprises 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 an ALK-associated cancer, 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 to selectively inhibit 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 the methods of the present disclosure include, but are not limited to, lung cancer, e.g., non-small cell bronchopulmonary carcinomas, inflammatory myofibroblastic tumor, ovarian cancer, e.g., serous ovarian carcinoma, melanoma, e.g., spitzoid melanoma. , glioblastoma, bile duct cancer, eg, cholangiocarcinoma, gastric cancer, colorectal cancer, angiosarcoma, anaplastic large cell lymphoma, diffuse large B-cell lymphoma, large B-cell lymphoma, esophageal cancer, eg, squamous cell carcinoma esophageal, kidney cancer, for example, renal medullary carcinoma or renal cell carcinoma, breast cancer, for example, triple negative breast cancer, thyroid cancer, for example, papillary thyroid cancer, neuroblastoma, epitelloid hemangioendothelioma, cancer colon and spitzoid tumor. Cancers treated by the methods of the present disclosure include cancers that originate from one or more oncogenic proteins selected from ROS1, ALK, TRKA, TRKB and TRKC. In certain embodiments, cancers treated by the methods of the present disclosure include cancers that are drug resistant to treatments targeting 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 or the presence of a mutation in an ALK 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, an ALK mutation or mutant comprises one or more deletions, substitutions, insertions, inversions, duplications, translocations or amplifications in the amino acid or nucleotide sequences of ALK, or fragments of are. As used herein and unless otherwise specified, an ALK rearrangement refers to genetic translocations involving the ALK gene that can result in ALK fusion genes and / or ALK fusion proteins. The ALK fusion may also include one or more deletions, substitutions, insertions, inversions, duplications, translocations or amplifications or a fragment thereof, provided that 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 the methods of the present disclosure include one or more mutations in the ALK kinase. In one embodiment, the one or more ALK point mutations are selected from point mutations in L1152, C1156, 11171, F1174, V1180, L1196, L1198, 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, L1198P, L1198F, R1275Q, L1152P, C1156T 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 mutation of MA / IZ / ¿U¿O / UUO4U1 ALK is L1198F. In one embodiment, the ALK mutation is a co-mutation of G1202R and one or more mutations selected from L1196M, G1269A and L1198F. In one embodiment, the ALK mutation is the G1202R / L1196M dual mutation. In one embodiment, the ALK mutation is the G1202R / G1269A dual mutation. In one embodiment, the ALK mutation is the 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, a fusion). In some embodiments, cancers treated by the methods of the present disclosure include ALK fusions. In one embodiment, the fusion of ALK is with one of the fusion partners selected from EML4, TMP1, WDCP, GTF2IRD1, TPM3, TPM4, CLTC, LMNA, PRKAR1A, RANBP2, TFG, FN1, 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 EML4-ALK variants that differ by breakpoint junctions, with variant 1 (v1) and variant 3 (v3) being the most clinically prevalent. In one embodiment, the ALK mutation comprises an ALK rearrangement and one or more ALK point mutations. In one embodiment, the ALK mutation is wild-type EML4-ALK (variant 1). In one embodiment, the ALK mutation is EML4-ALK G1202R (variant 1). In one embodiment, the ALK mutation is EML4-ALK L1196M / 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, ALK+ cancer is determined by an FDA-approved test or other tests known in the art. Tests that can be used include, for example, FoundationOne CDx™ (F1 CDx) (a sequencing-based in vitro diagnostic device for the detection of substitutions, insertion and deletion alterations (delins) and copy number alterations (CNA). ) 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 samples. ; VENTANA ALK (D5F3) CDx Assay (Qualitative Detection of Anaplastic Lymphoma Protein Kinase (ALK) in Formalin-Fixed Paraffin-Embedded (FFPE) Non-Small Cell Pulmonary Carcinoma (NSCLC) Tissue Stained with the BenchMark XT Autostaining Instrument or BenchMark ULTRA); and testing with Vysis ALK Break Apart FISH Probe Kit (a qualitative test to detect rearrangements involving the ALK gene through fluorescence in situ hybridization (FISH) in tissue samples from non-small cell bronchopulmonary carcinomas (NSCLC) formalin-fixed paraffin-embedded (FFPE)). In one embodiment, the test is a fluorescence in situ hybridization (FISH) test, for example, the Vysis ALK Break Apart FISH Probe test. Additional information on FDA-approved tests can be found at, for example, https: / / www.fda.gov / MedicalDevices / ProductsandMedicalProcedures / lnVitroDiagnostics / ucm30303 O.htm; and additional information about testing with the Vysis ALK Break Apart FISH Probe Kit can be found at, for example, https: / / www.molecular.abbott / us / en / products / oncology / vysis-alk-breakapart-fish-probe- kits; all of which are incorporated herein by reference. Also provided are methods of treating a subject having a cancer (for example, an ALK-positive cancer) including: determining whether a cancer cell in a sample obtained from a subject having a cancer and to whom it has previously been 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 monotherapy or in combination with another antineoplastic 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 may include a substitution at one or more of the amino acid positions 1202, 1196, 1269, 1156, 1171, 1174, 1180, 1206, 1210, 1151, 1174, 1203. , 1206, 1152, 1196, 1198, 1275, 1152, 1156, and 1245, for example, G1202R, L1196M, G1269A, C1156Y, 11171T, 11171N, 11171S, F1174L, V1180L, S120 6Y, E1210K, 1151Tins, F1174C, G1202del, D1203N , S1206Y, S1206C, L1152R, L1196Q, L1198P, L1198F, R1275Q, L1152P, C1156T, and F1245V. In some embodiments, another antineoplastic is any antineoplastic known in the art. For example, another antineoplastic may 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 or polypeptide molecule. As used herein and unless otherwise specified, a ROS1 mutation or mutant comprises one or more deletions, substitutions, insertions, inversions, duplications, translocations or amplifications in the amino acid or nucleotide sequences of ROS1, or fragments of are. As used herein and unless otherwise specified, a ROS1 rearrangement refers to genetic translocations involving the ROS1 gene that can result in ROS1 fusion genes and / or ROS1 fusion proteins. The ROS1 fusion may also include one or more deletions, substitutions, insertions, inversions, duplications, translocations or amplifications or a fragment thereof, provided that 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 the methods of the present disclosure include one or more mutations in the ROS1 kinase. In one embodiment, the one or more ROS1 point mutations are selected from point mutations in 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, and L2086F. 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 a comutation 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, a fusion). In some embodiments, cancers treated by the methods of the present disclosure include ROS1 fusions. In one embodiment, the fusion of ROS1 is with one of the fusion partners selected from SLC34A2, CD74, TPM3, SDC4, EZR, LRIG3, KDELR2, CEP72, CLTL, CTNND2, GOPC (e.g., GOPC-S, GOPC-L ), GPRC6A, LIMA1, LRIG3, MSN, MYO5C, OPRM1, SLC6A17 SLMAP, SRSF6, TFG, TMEM106B, TPD52L1, ZCCHC8,CCDC6,CAPRIN1, CEP85L, CHCHD3, CLIP1, EEF1G, KIF21A, KLC1, SART3, ST13, TRIM24, ERC1 , FIP1L1, HLAA, KIAA1598, MYO5A, PPFIBP1, PWWP2A, FN1, YWHAE, CCDC30, NCOR2, NFKB2, APOB, PLG, RBP4, and GOLGB1. In one embodiment, the ROS1 fusion is a CD74-ROS1 fusion. In one embodiment, the ROS1 fusion is an SDC4-ROS1 fusion. In one embodiment, the ROS1 fusion is an EZR-ROS1 fusion. In one embodiment, the ROS1 fusion is a SLC34A2-ROS1 fusion. In one embodiment, the ROS1 fusion is the GOPC-ROS1 fusion (e.g., GOPC-ROS1 -S, GOPC-ROS1 -L). In one embodiment, the ROS1 fusion is a CEP85L-ROS1 fusion. In one embodiment, the ROS1 mutation comprises a ROS1 rearrangement and one or more ROS1 point mutations. In one embodiment, the ROS1 mutation comprises one or more ROS1 rearrangements of 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 of CD74-ROS1, EZR-ROS1 and SLC34A2-ROS1, and ROS1 point mutation of G2101A. 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 CD74ROS1 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 GOPCROS1 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, GOPCROS1-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, ROS1+ cancer is determined by an FDA-approved test or other tests known in the art. Tests that can be used include, for example, Oncomine™ Dx Target Test from Thermo Fisher Scientific. (a qualitative in vitro diagnostic test using targeted high-throughput parallel sequencing technology to detect sequence variations in 23 genes in DNA and RNA isolated from formalin-fixed paraffin-embedded (FFPE) tumor tissue samples from patients with bronchopulmonary carcinomas non-small cell (NSCLC) using the Ion PGM Dx system); Vysis ROS1 Break Apart FISH Probe Kit (a qualitative test to detect rearrangements involving ROS1 gene rearrangements at 6q22 by fluorescence in situ hybridization (FISH) in formalin-fixed, paraffin-embedded non-small cell bronchopulmonary carcinomas (NSCLC) tissue samples (FFPE)) or real-time RT polymerase chain reaction (RT-PCR) or NGSN next generation sequencing through a local diagnostic test. Also provided are methods for treating a subject having a cancer (for example, a ROS1-positive cancer) including: determining whether a cancer cell in a sample obtained from a subject having a cancer and to whom it has previously been 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 monotherapy or in combination with another antineoplastic 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, one or more ROS1 inhibitor resistance mutations may 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, E197 4K, L1982F, F2004C, F2004V, E2020K, C2060G, F2075V, V2089M, V2098I, G2101A, D2113N, D2113G, L2155S, L2032K, and L2086F. In some embodiments, another antineoplastic is any antineoplastic known in the art. For example, another antineoplastic may 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 administration of an effective amount of a compound provided herein (e.g., orally or intravenously), the compound can penetrate the CNS (e.g., blood-brain barrier) and reach a concentration in the CNS (e.g., brain) that is still sufficient to inhibit (e.g., selectively inhibit) ROS1 or ALK or both. In one embodiment, a method of treating CNS metastases of a cancer is provided herein, 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 CNS metastases are 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 the inhibition of ROS1 or mutant or non-mutant 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. Inhibition of TRK, particularly in the central nervous system (CNS), has been associated with adverse reactions, including dizziness, ataxia, gait disturbances, paresthesia, weight gain and cognitive changes. In some embodiments, a method is provided for minimizing adverse events in a subject in need of treatment for cancer (e.g., a ROS1-positive cancer or an ALK-positive cancer), wherein the method comprises administering to the subject a therapeutically effective amount. of a compound provided herein, for example, 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 ROS1-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 population of subjects or patients compared to the paradigmatic incidence of adverse events in a population of subjects or patients treated with TRK inhibitors. (for example, 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 population of subjects or patients. 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 that less than 40% of the patient population has a TRK-related CNS adverse event. In some embodiments, minimizing TRK-related CNS adverse events means that less than 35%, less than 30%, less than 25%, less than 20%, less than 15%, less than 10%, or less than 5% of patient population has a TRK-related CNS adverse event. In some embodiments, minimizing TRK-related CNS adverse events means that less than 12% of the patient population has a TRK-related CNS adverse event. In some embodiments, 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 refer to one or more of the following: dizziness, ataxia, gait disturbance, paresthesia, 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, affective lability, personality change, mood swings, affective disorder, aggression, agitation, mood altered, depressed mood, euphoric mood, or mania) and cognitive disorders (e.g., memory impairment, cognitive disorder, amnesia, confusion, impaired attention, delirium, mental impairment, attention-deficit / hyperactivity disorder , dementia or reading disorder). In one embodiment, a method of preventing or limiting TRK-related CNS side or adverse effect in an anticancer treatment is provided herein, comprising administering to a subject in need thereof an effective amount of a compound. provided herein, for example, 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 occurrence of the TRK-related CNS adverse event. In one embodiment, the method limits the frequency of occurrence 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 of treating CNS metastases of a cancer with a reduced TRK-related side effect, comprising administering to a subject in need thereof an effective amount of a compound provided in herein, for example, 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 / limitation / prevention of the CNS side effect or adverse event is determined in a statistical sample, 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, paresthesia, weight gain, cognitive impairment, mood disorder, or sleep disturbance. In one embodiment, provided herein is a method of treating cancer, comprising administering to a subject in need thereof a therapeutically effective amount of a compound provided herein, for example, 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 ROS1-associated cancer. In one modality, MA / t / ZUZÓ / UUÓ4U Ί 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 as ROS1+. In one embodiment, the cancer is identified as ALK+. In one embodiment, provided herein is a method of treating a ROS1+ cancer, comprising administering to a subject in need thereof a therapeutically effective amount of a compound provided herein, for example, 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 of treating an ALK+ cancer, comprising administering to a subject in need thereof a therapeutically effective amount of a compound provided herein, for example, 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 of treating cancer in a subject, comprising: (i) identifying that the cancer in the subject is ROS1+, and (i) administering to the subject a therapeutically effective amount of a compound provided herein, for example, 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 of treating cancer in a subject, comprising: (i) identifying that the cancer in the subject is ALK+, and (i) administering to the subject a therapeutically effective amount of a compound provided herein, for example, 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 bronchopulmonary carcinomas (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 , for example, renal medullary carcinoma or renal cell carcinoma, breast cancer, for example, triple negative breast cancer, colon cancer, thyroid cancer, for example, papillary thyroid cancer, spitzoid tumor or neuroblastoma. In one embodiment, the cancer is lung cancer. In one embodiment, the cancer is a non-small cell bronchopulmonary carcinoma. In one embodiment, the cancer is a ROS1+ non-small cell bronchopulmonary carcinoma. In one embodiment, the cancer is an ALK+ non-small cell bronchopulmonary carcinoma. In one embodiment, the cancer is a relapsed or refractory non-small cell bronchopulmonary carcinoma. In one embodiment, the cancer is a relapsed or refractory ROS1+ non-small cell bronchopulmonary carcinoma. In one embodiment, the cancer is a relapsed or refractory ALK+ non-small cell bronchopulmonary carcinoma. In one embodiment, the cancer is a newly diagnosed non-small cell bronchopulmonary carcinoma. In one embodiment, the cancer is a newly diagnosed ROS1+ non-small cell bronchopulmonary carcinoma. In one embodiment, the cancer is a newly diagnosed ALK+ non-small cell bronchopulmonary carcinoma. 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 IMT ALK+. 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 IMT ALK+. 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 IMT ALK+. 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 is relapsed 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 a serous ovarian carcinoma. In one embodiment, the ovarian cancer is a 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 ALK+ 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 ALK+ colorectal cancer. In one embodiment, the cancer is relapsed or refractory colorectal cancer. In one embodiment, the cancer is relapsed or refractory ROS1+ 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 newly diagnosed 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 a spitzoid tumor. In one embodiment, the cancer is a spitzoid melanoma. In one embodiment, the cancer is a ROS1+ spitzoid melanoma. In one embodiment, the cancer is an ALK+ spitzoid melanoma. In one embodiment, the cancer is a relapsed or refractory spitzoid melanoma. In one embodiment, the cancer is a relapsed or refractory ROS1+ spitzoid melanoma. In one embodiment, the cancer is a relapsed or refractory ALK+ spitzoid melanoma. In one embodiment, the cancer is a newly diagnosed spitzoid melanoma. In one embodiment, the cancer is a newly diagnosed ROS1+ spitzoid melanoma. In one embodiment, the cancer is a newly diagnosed ALK+ spitzoid melanoma. In one embodiment, the cancer is an epithelioid hemangioendothelioma. In one embodiment, the cancer is a ROS1+ epithelioid hemangioendothelioma. In one embodiment, the cancer is an ALK+ epithelioid hemangioendothelioma. In one embodiment, the cancer is a relapsed or refractory epithelioid hemangioendothelioma. In one embodiment, the cancer is a relapsed or refractory ROS1+ epithelioid hemangioendothelioma. In one embodiment, the cancer is a relapsed or refractory ALK+ epithelioid hemangioendothelioma. In one embodiment, the cancer is a newly diagnosed epithelioid hemangioendothelioma. In one embodiment, the cancer is a newly diagnosed ROS1+ epithelioid hemangioendothelioma. In one embodiment, the cancer is a 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 ESCC ALK+. 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 ESCC ALK+. In one embodiment, the newly diagnosed ESCC cancers. 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 one embodiment, the cancer is relapsed or refractory ROS1+ 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 ROS1+ 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 a 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 ROS1+ papillary thyroid cancer. In one embodiment, 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 a non-Hodgkin's 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 disorders or hematological malignancies that are 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 ALCL ALK+. 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 ALK+ 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 ALCL ALK+. 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 ALK+ DLBCL. In one embodiment, the cancer is newly diagnosed DLBCL. In one embodiment, the cancer is newly diagnosed ROS1+ DLBCL. In one embodiment, the cancer is newly diagnosed ALK+ DLBCL. In one embodiment, the cancer is a large B cell lymphoma. In one embodiment, the cancer is a ROS1+ large B cell lymphoma. In one embodiment, the cancer is an ALK+ large B cell lymphoma. In one embodiment, the cancer is a relapsed or refractory large B cell lymphoma. In one embodiment, the cancer is a relapsed or refractory ROS1+ large B cell lymphoma. In one embodiment, the cancer is a relapsed or refractory ALK+ large B cell lymphoma. In one embodiment, the cancer is a newly diagnosed large B cell lymphoma. In one embodiment, the cancer is a newly diagnosed ROS1+ large B cell lymphoma. In one embodiment, the cancer is a newly diagnosed ALK+ large B cell lymphoma. In one embodiment, the cancer (or ROS1+ cancer, or ALK+ cancer) was newly diagnosed. In one embodiment, the cancer (or ROS1+ cancer, or ALK+ cancer) has not been previously treated. In one embodiment, the cancer (or ROS1+ cancer, or ALK+ cancer) is relapsed or refractory. In one embodiment, the cancer is recurrent. In one embodiment, the cancer (or ROS1+ cancer, or ALK+ cancer) is refractory. In one embodiment, the subject has not been previously treated. In one embodiment, the subject has not received prior treatment with 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 above lines of therapy. In one embodiment, the above therapy comprises a tyrosine kinase inhibitor (TKI). In one embodiment, the above therapy comprises one or more of crizotinib, ceritinib, alectinib, brigatinib, lorlatinib, entrectinib, repotrectinib, cabozantinib, foretinib, taletrectinib, merestinib, masitinib and ensartinib. In one embodiment, the above 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 a resistant lung cancer. In one embodiment, the cancer is a refractory non-small cell bronchopulmonary carcinoma. In one embodiment, the cancer is TKI-resistant non-small cell bronchopulmonary carcinoma. In one embodiment, the cancer is TKI-resistant ROS1+ non-small cell bronchopulmonary carcinoma. In one embodiment, the cancer is TKI-resistant ALK+ non-small cell bronchopulmonary carcinoma. In one embodiment, the cancer is lung cancer (e.g., NSCLC), and the cancer is relapsed or refractory after prior TKI treatment. In one embodiment, a compound provided herein is administered as a first-line treatment. In one embodiment, a compound provided herein is administered as a second-line treatment. In one embodiment, a compound provided herein is administered as a third or fourth line treatment. In one embodiment, the cancer (or ROS1+ cancer, or ALK+ cancer) is metastatic. In one embodiment, the cancer metastasizes to the CNS. In one embodiment, the cancer has brain metastases. In one embodiment, the cancer is metastatic non-small cell bronchopulmonary carcinoma (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 of treating a patient with a metastatic ALK+ non-small cell bronchopulmonary carcinoma, comprising administering to the patient a therapeutically effective amount of a compound provided herein, for example, 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 of treating a patient with a metastatic ROS1+ non-small cell bronchopulmonary carcinoma, comprising administering to the patient a therapeutically effective amount of a compound provided herein, for example, 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. In one embodiment, the patient is a pediatric patient. In one embodiment, provided herein is a method of treating an adult patient with metastatic ROS1+ 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 of treating an adult patient with metastatic ROS1+ 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, wherein the patient has experienced progression or is intolerant to at least one prior TKI therapy. In one embodiment, provided herein is a method of treating an adult patient with metastatic NSCLC that is ROS1+ with G2032R solvent front mutation, 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 experienced progression or is intolerant to at least one prior TKI therapy . In one embodiment, provided herein is a method of treating a ROS1 (or ROS1+) associated cancer in a subject in need thereof, wherein the cancer has developed resistance to a tyrosine kinase inhibitor (TKI), wherein the The method comprises administering to the subject a therapeutically effective amount of a compound provided herein, for example, a compound of Formula (I), or an enantiomer, a mixture of enantiomers, or a tautomer thereof, or a pharmaceutically acceptable salt of this. In one embodiment, provided herein is a method of treating a ROS1 (or ROS1+) associated cancer in a subject in need thereof, wherein the cancer has developed resistance to a tyrosine kinase inhibitor (TKI), and in wherein the cancer has been identified as having one or more ROS1 inhibitor resistance mutations, wherein the method comprises administering to the subject a therapeutically effective amount of a compound provided herein, for example, 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. ROS1 inhibitor resistance mutations comprise one or more amino acid substitutions selected from S1986F, S1986Y, F2004C, F2004V, L2026M, G2032R, D2033N, L2086F, and G2101 A. In one embodiment, the one or more ROS1 inhibitor resistance mutations are 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, a method is provided herein for treating an ALK-associated (or ALK+) cancer in a subject in need thereof, wherein the cancer has developed resistance to a tyrosine kinase inhibitor (TKI), wherein the The method comprises administering to the subject a therapeutically effective amount of a compound provided herein, for example, a compound of Formula (I), or an enantiomer, a mixture of enantiomers, or a tautomer thereof, or a pharmaceutically acceptable salt of this. In one embodiment, a method is provided herein for treating an ALK-associated (or ALK+) cancer in a subject in need thereof, wherein the cancer has developed resistance to a tyrosine kinase inhibitor (TKI), and in wherein the cancer has been identified as having one or more ALK inhibitor resistance mutations, wherein the method comprises administering to the subject a therapeutically effective amount of a compound provided herein, for example, 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 ALK inhibitor comprise one or more amino acid substitutions selected from L1196M, L1198F, G1202R, and G1269A. In one embodiment, the one or more ALK inhibitor resistance mutations are 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 of treating an adult patient with metastatic NSCLC who is ALK+ with the G1202R mutation, 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 experienced progression or is intolerant to at least one prior TKI therapy . In one embodiment, a method is provided herein for treating an ALK-associated (or ALK+) cancer in a subject in need thereof, wherein the cancer has developed resistance to a tyrosine kinase inhibitor (TKI), wherein the The method comprises administering to the subject a therapeutically effective amount of a compound provided herein, for example, a compound of Formula (I), or an enantiomer, a mixture of enantiomers, or a tautomer thereof, or a pharmaceutically acceptable salt of this. 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 cancer treatment. In certain embodiments, the subject has relapsed after second-line treatment of the MA / IZ / ¿U¿O / UUO4U 1 cancer. In one embodiment, the cancer or disease is found in a pediatric patient (including a child patient). In one embodiment, the cancer is a 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 a 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 a systemic anaplastic large cell lymphoma (ALCL) that is ROS1+ in pediatric patients 1 year of age or older and young adults. In one embodiment, the cancer is a 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, methods of treating or preventing cancer may be demonstrated by one or more responses such as increasing apoptosis, inhibiting tumor growth, reducing tumor metastasis, inhibiting tumor metastasis, reduction of microvessel density, decreased neovascularization, inhibition of tumor migration, tumor regression and increased subject survival. Combined treatments In some embodiments, the method of treating or preventing cancer may comprise administering a compound of Formula (I) together with one or more chemotherapeutic agents. As used herein and unless otherwise specified, together 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 delivery methods are within the scope of this description. The compound provided herein can be administered simultaneously, before (for example, 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 after (for example, 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 later) of one or more agents (for example, one or more additional agents). In general, each therapeutic agent is administered at a dose and / or at a schedule determined for that particular agent. The other therapeutic agent may be administered with the compound provided herein in a single composition or separately in a different composition. Triple therapy is also contemplated at present. MA / LEFT / ¿U¿O / UUO4U 1 Chemotherapeutic agents that can be administered concomitantly with the compounds of the description include: 1-amino-4-phenylamino-9,10-dioxo-9,10-dihydroanthracene-2sulfonate (acid blue 25), 1-amino-4-[4-hydroxyl-amino]-9,10-dioxo-9,10-dihydroanthracene-2sulfonate, 1-amino-4-[4-aminophen lam¡no]-9,10-dioxo-9,10-dih¡droanthracene-2-sulfonate, 1-amino-4[1-naphthylam¡no]-9,10-dioxo-9,10-d Hydroanthracene-2-sulfonate, 1-amino-4-[4-fluoro-2carboxyphenylamino]-9,10-dioxo-9,10-dihydroanthracene-2-sulfonate, 1-amino-4-[2- anthracenílamino]9,10-dioxo-9,10-dihydroanthracene-2-sulfonate, ABT-263, afatinib dimaleate, axitinib, aminoglutethimide, amsacrine, anastrozole, APCP, asparaginase, AZD5363, Bacillus Calmette-Guérin vaccine ( bcg), bicalutamide, bleomycin, bortezomib, β-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, demethoxyviridine, dexamethasone, dichloroacetate, dienestrol, diethylstilbestrol, docetaxel, doxorubicin, epirubicin, eribulin, erlotinib, estradiol, estramustine, etoposide, everolimus, exemestane, fil grastim, 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-sulfamoylphenylcarbamot¡o¡l) pivalamide, NF279, NF449, nilutamide, nocodazole, octreotide, olaparib , oxaliplatin, paclitaxel, pamidronate, pazopanib, pemexetred, pentostatin, perifosine, PF-046 91502, plicamycin, pomalidomide, porfimer, PPADS, procarbazine, quercetin, raltitrexed, ramucirumab, reagent blue 2, rituximab, rolophilin, romidepsin, rucaparib, selumetinib, sirolimus, sodium 2,4-dinitrobenzenesulfonate, sorafenib, streptozocin, sunitinib, suramin, talazoparib, tamoxifen, temozolomide, temsirolimus, teniposide, testosterone, thalidomide, thioguanine, thiotepa, titanocene dichloride, tonapophylline, topotecan, trametinib, trastuzumab, tretinoin, veliparib, vinblastine, vincristine, vindesine, vinorelbine and vorinostat (SAHA). In other embodiments, chemotherapeutic agents that may be co-administered with the compounds of the invention include: ABT-263, dexamethasone, 5-fluorouracil, PF-04691502, romidepsin and vorinostat (SAHA). In other embodiments, chemotherapeutic agents that may be co-administered with the compounds of the disclosure include: 1-amino-4-phenylamino9,10-dioxo-9,10-dihydroanthracene-2-sulfonate (acid blue 25), 1- amino -4-[4-hydroxyphenyl-amino]9,10-dioxo-9,10-dihydroanthracene-2-sulfonate, 1 -amino-4-[4-aminophenylamine]-9,10-dioxo-9 ,10-dihydroanthracene-2-sulfonate, 1-amino-4-[1-naphthylamino]-9,10-dioxo-9,10-dihydroanthracene-2-sulfonate, 1-amino-4-[4- fluoro-2-carboxyphenylamine-9,10-dioxo-9,10-dihydroanthracene-2-sulfonate, 1-amino-4-[2-anthracenelano]-9,10-dioxo-9,10-dihydroanthracene-2-sulfonate, APCP, β-methyleneADP (AOPCP), capecitabine, cladribine , cytarabine, fludarabine, doxorubicin, gemcitabine, N-(4sulfamoylphenylcarbamothioyl) pivalamide, NF279, NF449, PPADS, quercetin, reagent blue 2, rolophilin sodium 2,4dinitrobenzenesulfonate, sumarin, and tonafophilin. Many combination therapies have been developed for the treatment of cancer. In certain embodiments, the compounds of the disclosure (e.g., compounds of Formula (I)) may be coadministered with one or more combination therapies. Examples of combination therapies with which the compounds of the disclosure can be co-administered are included in Table 2. Table 2: Examples of combination therapies for cancer treatment Name Therapeutic Agents ABV Doxorubicin, bleomycin, vinblastine ABVD Doxorubicin, bleomycin, vinblastine, dacarbazine AC (breast) Doxorubicin, cyclophosphamide AC (sarcoma) Doxorubicin, cisplatin AC (neuroblastoma) Cyclophosphamide, doxorubicin 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 Citarabine Cita, Asparaginase Cabo Cisplatino, Metrexate, Bleomicin, Vincristina CAF Cycrophosphamide, Doxorubicin, Fluorour Cal-G Cyclophosphate. Orubicine, Vincristina, Prednisone, Name Therapeutic Agents asparaginase CAMP Cyclophosphamide, doxorubicin, methotrexate, procarbazine CAP Cyclophosphamide, doxorubicin, cisplatin CAV Cyclophosphamide, doxorubicin, vincristine CAVE ADD CAV and etoposide CA-VP16 Cyclophosphamide, doxorubicin, etoposide CC Cyclophosphamide, carboplatin CDDP / VP-1 6 Cisplatin, etoposide CEF Cyclophosphamide, epirubicin, fluorouracil CEPP(B) Cyclophosphamide, etoposide, prednisone, with or without bleomycin CEV Cyclophosphamide, etoposide, vincristine CF Cisplatin, fluorouracil or carboplatin fluorouracil CHAP Cyclophosphamide or cyclophosphamide, altretamine, doxorubicin, cisplatin ChIVPP 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 CMFVP C iclofosfamide, methotrexate, fluorouracil, vincristine, prednisone CMV Cisplatin, methotrexate, vincristine CNF Cyclophosphamide, mitoxantrone, fluorouracil CNOP Cyclophosphamide, mitoxantrone, vincristine, prednisone COB Cisplatin, vincristine, bleomycin CODE Cisplatin, vincristine, doxorubicin, etoposide COMLA Cyclophosphamide, vin cristina, methotrexate, leucovorin, cytarabine COMP Cyclophosphamide, vincristine, methotrexate, prednisone MA / E / ZUZo / UUJ4U1 Name Therapeutic agents 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 close to ovary) Cyclophosphamide, cisplatin CVD Cisplatin, vinblastine, dacarbazine CVI Carboplatin, etoposide, ifosfamide, mesna CVP Cyclophosphamide, vincristine, prednisone CVPP Lomustine, procarbazine, prednisone CYVADIC Cyclophosphamide, vincristine, doxorubicin, dacarbazine DA Daunorubicin, cytarabine DAT Daunor rubicin, cytarabine, thioguanine DAV Daunorubicin, cytarabine, etoposide DCT Daunorubicin, cytarabine, thioguanine DHAP Cisplatin, cytarabine, dexamethasone DI Doxorubicin, ifosfamide DTIC / tamoxifen Dacarbazine, tamoxifen DVP Daunorubicin, vincristine, prednisone EAP Etoposide, doxorubicin, cisplatin EC Etoposide, carboplat ino EFP Etoposide, 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 Name Therapeutic Agents F-CL Fluorouracil, leucovorin FEC Fluorouracil, cyclophosphamide, epirubicin FED Fluorouracil, etoposide, cisplatin FL Flutamide, leuprolide FZ Flutamide, goserelin acetate implant HDMTX Methotrexate, leucovorin Hexa-CAF Altretamine, cyclophosphamide, methotrexate, fluorouracil IDMTX / 6 -MP Methotrexate, mercaptopurine, leucovorin IE Ifosfamide, etoposide, mesna IfoVP Ifosfamide, etoposide, mesna IPA Ifosfamide, cisplatin, doxorubicin M-2 Vincristine, carmustine, cyclophosphamide, prednisone, melphalan MACHI Methotrexate, leucovorin, dactinomycin, cyclophosphamide MACC Methotrexate, doxor rubicin, 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, procar MOPP bazine Mechlorethamine, vincristine, procarbazine, prednisone MOPP / ABV Mechlorethamine, vincristine, procarbazine, prednisone, doxorubicin, bleomycin, vinblastine MP (multiple myeloma) Melphalan, prednisone Name Therapeutic agents MP (prostate cancer) Mitoxantrone, prednisone MTX / 6-MO Methotrexate, mercaptopurine MTX / 6-MP / VP Methotrexate, mercaptopurine, vincristine, prednisone MTX-CDDPAdr Methotrexate, leucovorin, cisplatin, doxorubicin MV (breast cancer) Mitomycin, vinblastine MV (acute myelocytic leukemia) Mitoxantrone, etoposide Methotrexate M-VAC Vinblastine, doxorubicin, cisplatin MVP mitomycin Vinblastine, cisplatin MVPP Mechlorethamine, vinblastine, procarbazine, prednisone NFL Mitoxantrone, fluorouracil, leucovorin NOVP Mitoxantrone, vinblastine, vincris tub 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 amide, 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, ten PVA iposide Prednisone, vincristine , asparaginase PVB Cisplatin, vinblastine, bleomycin Name Therapeutic Agents PVDA Prednisone, vincristine, daunorubicin, asparaginase SMF Streptozocin, mitomycin, fluorouracil TAD Mechlorethamine, doxorubicin, vinblastine, vincristine, bleomycin, etoposide, prednisone TTT Methotrexate, cytarabine, hydrocortisone Topo / CTX Cyclophosphamide, topotecan, mesna VAB-6 Cycle phosphamide, dactinomycin, vinblastine, cisplatin, bleomycin VAC Vincristine, dactinomycin, cyclophosphamide VACAdr Vincristine, cyclophosphamide, doxorubicin, dactinomycin, vincristine VAD Vincristine, doxorubicin, dexamethasone VATH Vinblastine, doxorubicin, thiotepa, fluoxymesterone 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, pred nisona 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, cytar bina, dacarbazine In certain embodiments, the co-therapies of the description comprise co-administration with other types of chemotherapeutic agents, such as ΜΛ / t / ZUZÓ / UUÓ+U Ί immuno-oncology. Cancer cells often have specific cell surface antigens that the immune system can recognize. Therefore, immuno-oncology agents, such as monoclonal antibodies, can selectively bind to cancer cell antigens and cause cell death. Other immuno-oncology agents may suppress tumor-mediated inhibition of the native immune response or otherwise activate the immune response and thus facilitate tumor recognition by the immune system. Examples of 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 (mAb), anti-CD39 mAb, anti-PD-1 mAb, and anti-CTLA4 mAb. Therefore, in some embodiments, the methods of the disclosure comprise the co-administration of one or more immuno-oncology agents, such as the agents mentioned above. In some embodiments, the combination therapy comprises coadministration of a compound of the invention, such as a compound of Formula (I), with SH2 inhibitors, such as CGP78850, CPG85793, C90, 0126, G7-18NATE, G7-B1, and NSC642056. In some embodiments, the combination therapy comprises the coadministration of a compound of the invention, 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 the coadministration of a compound of the invention, such as a compound of Formula (I), with a MET inhibitor selected from JNJ-38877605, PF-04217903, foretinib, AMG 458, tivantinib, cabozantinib , crizotinib, capmatinib hydrochloride, tepotinib hydrochloride and savolitinib. In some embodiments, the combination therapy comprises coadministration of a compound of the invention, such as Formula (I), with an SHP2 inhibitor selected from TNO-155, RMC-4630, JAB-3068, or RLY-1971. In some embodiments, the combination therapy comprises coadministration 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 embodiments, the combination therapy comprises the administration of a compound provided herein, for example, 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 coadministration of a compound of the disclosure, such as the compound of Formula (I), with an anti-PD-1 therapy. In some embodiments, the combination therapy comprises coadministration of a compound of the disclosure, such as the compound of Formula (I), with oxaliplatin. In some embodiments, the combination therapy comprises coadministration of a compound of the disclosure, such as the compound of Formula (I), with doxorubicin. In certain embodiments, a compound of the disclosure may be administered concomitantly with non-chemical methods of cancer treatment. In certain embodiments, a compound of the disclosure may be administered concomitantly with radiation therapy. In certain embodiments, a compound of the disclosure may be administered concomitantly with surgery, with thermoablation, with focused ultrasound therapy, with cryotherapy, or with any combination of these. In certain embodiments, the compounds of the disclosure may be co-administered with one or more compounds of the disclosure. Furthermore, such combinations may be co-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, coadministration of one or more additional chemotherapeutic agents with a compound of the invention provides a synergistic effect. In certain embodiments, coadministration of one or more additional chemotherapeutic agents provides an additive effect. Pharmaceutical compositions In certain embodiments, the present description provides a pharmaceutical preparation suitable for use in a human patient, comprising any of the compounds shown above (for example, a compound of the description, such as a compound of Formula (I), and one or plus pharmaceutically acceptable excipients. In certain embodiments, the pharmaceutical preparations can be used to treat or prevent a condition or disease as described herein. Any of the described compounds can be used in the manufacture of medicaments for the treatment of any disease or condition disclosed in this document. The compositions and methods of the present description can be used 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 a subject, such as a human, the composition or compound is preferably administered as a pharmaceutical composition comprising, for example, a compound of the description 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 carriers such as glycols, glycerol, oils such as olive oil or injectable organic esters. In a preferred embodiment, when said 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 across an epithelial barrier), the aqueous solution is pyrogen-free, or substantially pyrogen-free. Excipients may 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 may be in the form of dosage units, such as tablets, capsules (including capsule with dispersible granules and gelatin capsules), granules, lyophilized for reconstitution, powders, solutions, syrups, suppositories, injections or the like. The composition may also be present in a transdermal delivery system, for example, a skin patch. The composition may also be present in a solution suitable for topical administration, such as eye drops. A pharmaceutically acceptable carrier may contain physiologically acceptable agents that act, for example, to stabilize, increase the solubility or increase the absorption of a compound such as a compound of the invention. Such physiologically acceptable agents include, for example, carbohydrates, such as glucose, sucrose or dextrans, antioxidants, such as ascorbic acid or glutathione, chelating agents, low molecular weight proteins or other stabilizers or excipients. The choice of a pharmaceutically acceptable carrier, including a physiologically acceptable agent, depends, for example, on the route of administration of the composition. The pharmaceutical preparation or composition may be a self-emulsifying drug delivery system or a self-microemulsifying drug delivery system. The pharmaceutical composition (preparation) may also be a liposome or other polymeric matrix, which may have incorporated, for example, a compound of the description. Liposomes, for example, comprising phospholipids or other lipids, are non-toxic, physiologically acceptable and metabolizable carriers that are relatively simple to prepare and administer. As used herein, the term “pharmaceutically acceptable” refers to those compounds, materials, compositions and / or dosage forms that, in medical judgment, are suitable for use in contact with tissues of a subject, without cause excessive toxicity, irritation, allergic response or other problem or complication, with a corresponding reasonable benefit / risk ratio. The phrase pharmaceutically acceptable carrier, as used herein, means a pharmaceutically acceptable material, composition or carrier, such as a liquid or solid filler, diluent, excipient, solvent or encapsulation material. Each vehicle must be acceptable in the sense of being compatible with the other ingredients of the formulation and not being harmful to the subject. Some examples of materials that can serve as pharmaceutically acceptable carriers include: (1) sugars, such as lactose, glucose, and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose and its derivatives, such as sodium carboxymethylcellulose, ethylcellulose and cellulose acetate; (4) tragacanth powder; (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) osotonic saline solution; (18) Ringer's solution; (19) ethyl alcohol; (20) phosphate buffer solution; and (21) other compatible non-toxic substances used in pharmaceutical formulations. A pharmaceutical composition (preparation) can be administered to a subject by any of various routes of administration including, for example, orally (for example, potions such as aqueous or non-aqueous solutions or suspensions, tablets, capsules (including capsules with granules gelatin capsules), boluses, powders, granules, pastes to apply on the tongue); absorption through the oral mucosa (for example, sublingually); anally, rectally or vaginally (for example, as a pessary, cream or foam); parenterally (including intramuscularly, intravenously, subcutaneously or intrathecally, such as 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 in the form of eye drops). The compound can also be formulated for inhalation. In certain embodiments, a compound may simply be dissolved or suspended in sterile water. Details of appropriate routes of administration and suitable compositions thereof can be found, for example, in US Pat. 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 the patents cited therein. The formulations may conveniently be presented in unit dosage form and may be prepared by any method well known in the pharmaceutical art. The amount of active ingredient that is combined with one or more carrier materials to produce a single dosage form will vary depending on the subject being treated, the particular mode of administration. The amount of active ingredient that is combined with one or more carrier materials to produce a single dosage form will generally be the amount of the compound that produces a therapeutic effect. Generally, of one hundred percent, this amount will range from about 1 percent to about ninety-nine percent of the active ingredient, preferably from about 5 percent to about 70 percent, more preferably from about 10 percent. and approximately 30 percent. Methods for preparing these formulations or compositions include the step of associating an active compound, such as a compound of the invention, with the carrier and, optionally, one or more auxiliary ingredients. In general, formulations are prepared by uniformly and intimately associating a compound of the present disclosure with liquid carriers, or finely divided solid carriers, or both, and then, if necessary, molding the product. Formulations of the disclosure suitable for oral administration may be in the form of capsules (including capsules with dispersible granules and gelatin capsules), capsules, pills, tablets, lozenges (using a flavored base, usually sucrose and acacia or tragacanth). lyophilic, powders, granules, or as a solution or suspension in an aqueous or non-aqueous liquid, or as a liquid emulsion of oil in water or water in oil, or as an elixir or syrup, or as tablets (using a inert base, such as gelatin and glycerin, or sucrose and acacia) and / or as mouthwashes and the like, each of which contains a predetermined amount of a compound of the present description as an active ingredient. The compositions or compounds may also be administered as a bolus, electuary or paste. To prepare solid dosage forms for oral administration (capsules (including capsules with dispersible granules 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, carboxymethyl cellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and / or acacia; (3) humectants, such as glycerol; (4) disintegrating agents, such as agaragar, 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 as 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 capsules with dispersible granules and gelatin capsules), tablets and pills, the pharmaceutical compositions may also comprise buffering agents. Solid compositions of similar type can also be used as fillers in soft and hard gelatin capsules using excipients such 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. Tablets can be prepared using binders (for example, gelatin or hydroxypropylmethylcellulose), lubricant, inert diluent, preservative, disintegrant (for example, sodium starch glycolate or cross-linked sodium carboxymethylcellulose), surfactant or dispersant. Molded tablets can be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent. Tablets and other solid dosage forms of pharmaceutical compositions, such as dragees, capsules (including sprinkle capsules and gelatin capsules), pills and granules, may, optionally, be scored or prepared with coatings and coatings, such as enteric coatings and other coatings well known in the art of pharmaceutical formulation. They can also be formulated to provide a slow or controlled release of the active ingredient using, for example, hydroxypropylmethylcellulose in varying proportions to provide! desired release profile, other polymer matrices, liposomes and / or microspheres. They can be sterilized, for example, by filtration through a filter that retains bacteria, or by incorporating sterilizing agents in the form of sterile solid compositions that can be dissolved in sterile water, or in some other sterile injectable medium immediately before use. These compositions may also optionally contain opacifying agents and may be of a composition that releases the active ingredient(s) alone, or preferably, in a certain portion of the gastrointestinal tract, optionally, in a delayed manner. Examples of inclusion compositions that can be used include polymeric substances and waxes. The active ingredient may also be in microencapsulated form, if appropriate, with one or more of the excipients described above. Liquid dosage forms for oral administration include emulsions, reconstitution lyophiles, microemulsions, pharmaceutically acceptable solutions, suspensions, syrups and / or elixirs. In addition to the active ingredients, liquid dosage forms may comprise inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing and emulsifying agents such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate , benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (in particular cottonseed, peanut, corn, germ, olive, castor and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and acid esters sorbitan fatty acids and mixtures thereof. In addition to inert diluents, oral compositions may also include adjuvants such as wetting agents, emulsifiers and suspending agents, sweeteners, flavorings, colorants, perfumes and preservatives. The suspensions, in addition to the active compounds, may contain suspending agents such 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 non-irritant excipients or vehicles 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 will therefore melt in the rectum or vaginal cavity and release the active compound. Formulations of the pharmaceutical compositions for oral administration may be presented as a mouthwash, an oral spray or an oral ointment. Alternatively or additionally, the compositions may be formulated for administration via a catheter, stent, wire or other intraluminal device. Delivery through such devices may be especially useful for delivery to the bladder, urethra, ureter, rectum or intestine. Formulations that are suitable for vaginal administration also include weighs, tampons, creams, gels, pastes, foams or aerosol formulations containing suitable carriers known in the art. Dosage forms for 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 necessary. Ointments, pastes, creams and gels may contain, in addition to an active ingredient, 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 of these. Powders and aerosols may contain, in addition to an active ingredient, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances. Aerosols may also contain common propellants such as chlorofluorohydrocarbons and unsubstituted volatile 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 prepared by dissolving or dispersing the active compound in the appropriate medium. Absorption enhancers can also be used to increase the flow of the compound through the skin. The rate of such flow can be controlled by providing a rate control membrane or by dispersing the compound in a polymer matrix or a gel. Ophthalmic formulations, eye ointments, powders, solutions and the like are also contemplated within the scope of this description. Exemplary ophthalmic formulations are described in US publications no. 2005 / 0080056, 2005 / 0059744, 2005 / 0031697 and 2005 / 004074 and US Patent No. 6,583,124, the contents of which are incorporated herein by reference. If desired, liquid ophthalmic formulations have properties similar to those 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, as eye drops, or administration via an implant). The phrases parenteral administration and parenterally administered, as used herein, mean modes of administration other than enteral and topical administration, usually by injection, and include, but are not limited to, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbitaha, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal and intrasternal. Pharmaceutical compositions suitable for parenteral administration comprise one or more active compounds in combination with one or more sterile pharmaceutically acceptable isotonic aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, or sterile powders that can be reconstituted into sterile injectable solutions or dispersions just before its use, which may contain antioxidants, buffers, bacteriostatics, solutes that make the formulation isotonic with the blood of the intended recipient, or suspending or thickening agents. Examples of suitable aqueous and non-aqueous 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 asters, such as ethyl oleate. Adequate fluidity can be maintained, for example, by the use of coating materials, such as lecithin, by maintaining the required particle size in the case of dispersions and by the use of surfactants. These compositions may also contain adjuvants such as preservatives, humectants, emulsifiers and dispersants. Prevention of the action of microorganisms can 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 in the compositions. Additionally, prolonged absorption of the injectable dosage form can be achieved by the inclusion of agents that delay absorption, such as aluminum monostearate and gelatin. In some cases, to prolong the effect of a drug, it is desirable to delay the absorption of the drug by subcutaneous or intramuscular injection. This can be achieved by using a liquid suspension of crystalline or amorphous material that has poor solubility in water. The rate of drug absorption then depends on its dissolution rate, which, in turn, may depend on the size and shape of the crystal. Alternatively, delayed absorption of a parenterally administered form of drug is achieved by dissolving or suspending the drug in an oil vehicle. Injectable depot forms are manufactured by forming microencapsulated matrices of the compounds in question 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). Injectable depot formulations are also prepared by trapping the drug in liposomes or microemulsions that are compatible with body tissue. For use in the methods of this disclosure, the active compounds may be administered 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 can also be provided by rechargeable or biodegradable devices. In recent years, several slow-release polymeric devices have been developed and tested in vivo for the controlled delivery of drugs, including proteinaceous biopharmaceuticals. Various biocompatible polymers (including hydrogels), both biodegradable and non-degradable, can be used to form an implant that allows sustained release of a compound at a given site. The actual dosage levels of the active ingredients in the pharmaceutical compositions can be varied to obtain an amount of the active ingredient that is effective for 100 achieve the desired therapeutic response for a patient, a particular composition and mode of administration, without being toxic to the patient. The dosage level selected will depend on a variety of factors including the activity of the particular compound or combination of compounds used, or the ester, salt or amide thereof, the route of administration, the time of administration, the rate of excretion of the particular compounds being used, the duration of treatment, other drugs, compounds and / or materials used in combination with the particular compounds used, age, sex, weight, condition, general health and history prior medical condition of the subject being treated, and similar factors well known in the medical art. A physician or veterinarian having general knowledge in the art can easily determine and prescribe the therapeutically effective amount of the pharmaceutical composition required. For example, the physician or veterinarian could begin doses of the pharmaceutical composition or compound at levels lower than those necessary to achieve the desired therapeutic effect and gradually increase the dose until the desired effect is achieved. Therapeutically effective amount means the concentration of a compound that is sufficient to cause the desired therapeutic effect. It is generally understood that the effective amount of the compound will vary depending on the subject's weight, sex, age, and medical history. Other factors influencing 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 to be administered with the compound. the description. A larger total dose can be administered by multiple administrations of the agent. Methods for determining 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, incorporated herein by reference). In general, an adequate 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 effective dose to produce a therapeutic effect. Said effective dose will generally depend on 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 subdoses administered separately at appropriate intervals throughout the day, optionally, in unit dosage forms. In certain embodiments of the present disclosure, the active compound can be administered two or three times a day. In certain embodiments, the active compound will be administered once a day. In certain embodiments, the compounds of the invention can be used alone or co-administered with another type of therapeutic agent. As used herein, the phrase joint administration refers to any form of administration of two or more 101 different therapeutic compounds, such that the second compound is administered while the previously administered therapeutic compound is still effective in the body (for example, 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 in the same formulation or in a separate formulation, either concomitantly or sequentially. In certain embodiments, the different therapeutic compounds can be administered one hour, 12 hours, 24 hours, 36 hours, 48 ​​hours, 72 hours or one week apart. In this way, a subject receiving said treatment can benefit from a combined effect of different therapeutic compounds. In certain embodiments, coadministration of the compounds of the invention with one or more additional therapeutic agents (e.g., one or more additional chemotherapeutic agents) provides improved efficacy relative to each individual administration of the compound of the invention (e.g., compound of Formula I or la) or one or more additional therapeutic agents. In certain such embodiments, coadministration provides an additive effect, wherein an additive effect refers to the sum of each of the effects of the individual administration of the compound of the invention and one or more additional therapeutic agents. 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 description include, but are not limited to, alkyl, dialkyl, trialkyl or tetraalkylammonium salts. In certain embodiments, contemplated salts of the disclosure include, but are not limited to, L-arginine, benentamine, benzathine, betaine, calcium hydroxide, choline, deanol, diethanolamine, diethylamine, 2-(diethylamine)ethanol, ethanolamine, ethylenediamine, Nmethylglucamine, hydrabamine, 1H-midazole, lithium, L-lysine, magnesium, 4-(2-hydroxyethyl)morpholine, piperazine, potassium, 1-(2-hydroxyethyl)pyrrolidine, sodium, triethanolamine, tromethamine, and zinc salts. In certain embodiments, contemplated salts of the description include, but are not limited to, salts of Na, Ca, K, Mg, Zn or other metals. Pharmaceutically acceptable acid addition salts may also exist as various solvates, such as with water, methanol, ethanol, dimethylformamide and the like. Mixtures of said solvates can also be prepared. The source of such solvate may be from the crystallization solvent, inherent to the preparation or crystallization solvent, or advent of said solvent. Pharmaceutically acceptable anionic salts include acetate, aspartate, benzenesulfonate, benzoate, besylate, bicarbonate, bitartrate, bromide, camsylate, carbonate, chloride, citrate, decanoate, edetate, esylate, fumarate, gluceptate, gluconate, glutamate, glycolate, 102 hexanoate, hydroxynaphthoate, iodide, isethionate, lactate, lactobionate, malate, maleate, mandelate, mesylate, methylsulfate, mucate, napsylate, nitrate, octanoate, oleate, pamoate, pantothenate, phosphate, polygalacturonate, propionate, salicylate, stearate, acetate, succinate , sulfate, tartrate, theoclate and cough i lato. Wetting, emulsifying and lubricating agents, such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, releasing agents, coating agents, sweetening agents, flavoring and perfuming agents, preservatives and antioxidants may also be present in the compositions. Examples of pharmaceutically acceptable antioxidants include: (1) water-soluble antioxidants, such as ascorbic acid, cysteine ​​hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite and the like; (2) oil-soluble antioxidants, such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, alpha-tocopherol and the like; and (3) metal chelating agents, such as citric acid, ethylenediaminetetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid and the like. The disclosure now described generally will be more easily understood by reference to the following examples which are included merely for purposes of illustrating certain aspects and embodiments of the present description, and are not intended to limit it. General synthetic procedures Starting materials and reagents used in the preparation of these compounds are available from commercial suppliers such as Aldrich Chemical Co., Bachem, etc., or can be manufactured by methods well known in the art. The schemes are merely illustrative of some methods by which the compounds described herein can be synthesized and various modifications can be made to these schemes, which will be suggested to one skilled in the art who has referred to this description. The starting materials, intermediates and end products of the reaction can be isolated and purified, if desired, by conventional techniques, including, but not limited to, filtration, distillation, crystallization, chromatography and the like, and can be characterized by conventional means, including physical constants and spectral data. In some cases, reactions may produce more than one regioisomeric product. In these cases, chromatography can be used to separate the isomers and NOE or NOESY NMR spectroscopy to aid in structural assignment. Unless otherwise specified, the reactions described herein take place at atmospheric pressure over a temperature range of about -78°C to about 150°C. 103 Abbreviations Definition Solvents EA, EtOAc ethyl acetate PE, pet ether. petroleum ether THF tetrahydrofuran DCM dichloromethane DMF Ν,Ν-dimethylform amide DMA Ν,Ν-dimethylacetamide NMP N-methyl-2-pyrrolidone DMSO dimethyl sulfoxide IPA isopropyl alcohol DME dimethoxyethane MeCN, ACN acetonitrile DCE dichloroethane Reagents DAST diethylaminosulfur trifluoride DIAD diisoprop azodicarboxylate ilo DEAD diethyl azodicarboxylate DBAD di-tert-butyl azodicarboxylate DIPEA, DIEA Ν,Ν-diisopropylethylamine TEA triethylamine ATP adenosine triphosphate TFA trifluoroacetic acid FA formic acid DIBAL, DIBAL-H, DIBALH diisobutylaluminum hydride AcOH, HOAc acetic acid TES triethylsilane n -BuLi, BuLi n-butyllithium LDA lithium diisopropylamide NBS N-bromosuccinimide NIS N-iodosuccinimide NCS N-chlorosuccinimide 104 Abbreviations Definition DMP periodinane Dess-Martin DEA diethylamine DMF-DMA 1,1 -dimethoxy¡-N,N-dimethylmethanam¡na TMP 2,2,6,6-tetramethylpiperidine NMO N-methylmorpholine N-oxide TBSCI tert-butyldimethylsil chloride KOAc, AcOK potassium acetate NaOAc, AcONa sodium acetate SEMCI 2-(trimethylsilyl)ethoxymethyl chloride tBuLi, t-BuL¡ tert-butyllithium NFSI N-fluorobenzenesulfonimide AIBN azobisisobutyronitrile EDCI 1-ethyl-3-(3-dimethylam nopropyl)carbomide HOBT hydroxybenzotriazole TBAF tetra-n-butylammonium fluoride HATU 1-[bis(dimethylamino)methylene]-1 H-1,2,3-triazole 3-oxide hexafluorophosphate [4,5-b]pyrininio XPos 2-dicyclohex¡lphosphino-2',4',6'-tr¡soprop¡lb¡phenyl cataCXium A di(1-adamantyl)-n-but¡ lphosphine DPPP 1,3-bis(diphenylphosphino)propane DPPF 1,1 '-bis(diphenylphosphino)ferrocene TfOH triflic acid HMTA 1,3,5,7-tetraseedamtane PMBCI p-methoxybenzyl chloride HEPES acid 4-( 2-hydroxyethyl)-1 -piperazineethanesulfonic acid EGTA ethylene glycol-bis(2-aminoethyl ether)-N,N,N',N'-tetraacetic acid Others HPLC high pressure liquid chromatography Preparative prep weight type wild rt, r.t., RT room temperature 105 Abbreviations Definition SFC supercritical fluid chromatography 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 here. aqueous TLC thin layer chromatography retention time The compounds of the invention can be prepared by a variety of synthetic methods, as further described and illustrated herein. Those skilled in the art will understand that the following general synthetic methods are representative and are not intended to be limiting. Racemic compounds can be enantiomerically enriched by chiral, preparative, SFC, or HPLC separation. Variable A denotes a carbon, nitrogen, or sulfur atom that may be the same as or different from another instance of variable A. Variable X. The variable Z denotes a nitrogen atom, or a C-H or C-F group that may be the same or different from another instance of the variable Z. Method A Base, ligand, Pd cat., solvent I II III IV Polyhalide I can be coupled with stannane II using Stille coupling conditions to provide type III compounds. Various additives can optionally be used including 106 (among others) LiCl or Cul to facilitate this reaction. Intramolecular ring closure of polyhalide III can be accomplished using two-step one-pot Suzuki cross-coupling / borylation conditions to provide type IV compounds. Method B Halide V can be coupled with stannane II using Stille coupling conditions to provide type VI compounds. Various additives including (but not limited to) LICI or Cul may optionally be employed to facilitate this reaction. Intramolecular ring closure of halide VI can be accomplished using C-H insertion cross-coupling conditions to produce type IV compounds. Potassium acetate or potassium pivalate are effective bases for the macrocyclization step. Method C Fe. NH4CI OR SnCI2, HCI Solvent Vil VIII IX Nitropyridine Vil can be reduced using Fe metal conditions to provide type VIII aminopyridines. In cases where the substrate contains an isoxazole moiety, yields can be improved by using SnCh conditions instead. Intramolecular ring closure of VIII can be carried out using two-stage one-pot Suzuki cross-coupling / borylation conditions to provide type IX compounds. Method D Fe, NH4CI or SnCk, HCI Solvent Base, ligand, Pd cat., solvent IX Nitropyridine X can be reduced using Fe metal conditions to provide type XI aminopyridines. In cases where the substrate contains an isoxazole moiety, yields can be improved by using SnCl2 conditions instead. Intramolecular ring closure of XI can be accomplished using C-H insertion cross-coupling conditions to produce type IX compounds. Potassium acetate or potassium pivalate are effective bases for the macrocyclization step. Method E CL Base, solvent XII XIII XV Alcohol XII can be reacted with chloropyrazine XIII using SNAr coupling conditions to form ether XIV. Intramolecular ring closure of XIV can be carried out using two-stage Suzuki cross-coupling / borylation conditions to provide compounds of type XV. Method F XVI XIII XV Alcohol XVI can be reacted with chloropyrazine XIII using SNAr coupling conditions to form ether XVII. Intramolecular ring closure of XVII can be carried out using C-H insertion cross-coupling conditions to produce type XV compounds. Potassium acetate or potassium pivalate are effective bases for the macrocyclization step. G Method NBS, solvent 1. CsF, solvent 2. Β2ρίΠ2, base, ligand, Pd cat., solvent XIX XX Aminopyridine XVIII can be brominated with a suitable bromination reagent to provide bromide XIX. Desilylation of XIX using a suitable fluoride ion source, followed by intramolecular ring closure using two-step one-pot borylation / Suzuki cross-coupling conditions can produce type XX compounds. Method H XXI Fe, NH4CI OR SnCh, HCI Solvent 1. Base, ligand, Pd cat., solvent 2. TBAF, solvent H.O. XXII XX Nitropyridine XXI can be reduced using Fe metal conditions to provide 109 type XXII aminopyridines. In cases where the substrate contains an isoxazole moiety, yields can be improved by using SnCL conditions instead. Intramolecular ring closure of XXII using C–H insertion cross-coupling conditions, followed by desilylation with TBAF yields type XX compounds. Potassium acetate or potassium pivalate are effective bases for the macrocyclization step. 2. NBS, solvent 1. Fe, NH4CI, solvent IX Nitropyridine XXIII can be converted to compound XI by reduction using Fe metal conditions followed by bromination with a suitable bromination reagent. Intramolecular ring closure of XI can be accomplished using C-H insertion cross-coupling conditions to produce type IX compounds. Potassium acetate or potassium pivalate are effective bases for the macrocyclization step. acid, solvent IV Type XXIV compounds can be deprotected to provide type IV compounds by treatment with a suitable acid in solution (for example, TFA or HCl). Protecting groups amenable to this method include, but are not limited to, methoxymethyl, 2-(trimethylsilyl)ethoxymethyl, tetrahydropyranyl, and p-methoxybenzyl groups. K-method Fe, NHiCI or SnCk, HCI Solvent 1.TES, TFA or TMSI. solvent 2. Base, ligand, Pd cat., solvent IX Nitropyridine XXV can be reduced using Fe metal conditions to provide type XI aminopyridines. In cases where the substrate contains an isoxazole moiety, yields can be improved by using SnCl2 conditions instead. Intramolecular ring closure of XI can be accomplished using C-H insertion cross-coupling conditions to produce type IX compounds. Potassium acetate or potassium pivalate are effective bases for the macrocyclization step. Bzpins, base, ligand, Pd cat., solvent IX Nitropyridine X can be reduced using metallic iron and then brominated with NBS to provide type XXVI aminopyridines. In cases where the substrate contains an isoxazole moiety, yields can be improved by using SnCk-reducing conditions instead of iron. Intramolecular ring closure of XXVI can be accomplished using two-step one-pot Suzuki cross-coupling / borylation conditions to provide type IX compounds. Method M .Η2, Pd / C, solvent 2.R1-X, base, solvent XXVII XXVIII Type XXVII compounds can be first deprotected by hydrogenolysis using palladium on carbon in a hydrogen atmosphere, followed by alkylation of the resulting hydroxyl group with an alkyl halide (e.g., methyl iodide) to provide type XXVIII compounds. Protecting groups amenable to this method include, but are not limited to, benzyl and pmethoxybenzyl groups. Fe, NH4Cl or SnCla, HCI Solvent Base, ligand, Pd cat., solvent XXX XXXI NaBH.i, solvent TES, TFA, solvent XXXII IX Nitropyridine XXIX can be reduced using Fe metal conditions to provide type XXX aminopyridines. In cases where the substrate contains an isoxazole moiety, yields can be improved by using SnCls conditions instead. Intramolecular ring closure of XXX can be accomplished using C-H insertion cross-coupling conditions to produce type XXXI ketones. Potassium acetate or potassium pivalate are effective bases for the macrocyclization step. The reduction of ketone XXXI to alcohols of type XXXII can be carried out using sodium borohydride. Finally, deoxygenation can be 112 performed using triethylsilane and trifluoroacetic acid to produce type IX compounds. Those skilled in the art will recognize that starting materials and reaction conditions can be varied, the reaction sequence altered, and additional steps employed to produce compounds encompassed by the present disclosure, as demonstrated in 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 for such protecting groups, as well as the conditions necessary to attach and remove such groups, will be apparent to experienced organic chemists. The descriptions of all articles and references mentioned in this application, including patents, are incorporated herein by reference. The preparation of the compounds of the present description is further illustrated by the following examples, which should not be construed as limiting the description in scope or spirit to the specific procedures and compounds described therein. Analytical methods LCMS data was collected using one of the following methods: 113 LCMS Methods Method Details A Instrument: Agilentl 260-6125B Column: YMC Triart C18, 50x4.6 mm, 5 pm Mobile phase: A is H2O (+0.05% FA) and B is CH3CN (+0.05% FA ) Execution 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 C18, 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 (0.7 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 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: 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 114 E Instrument: SHIMADZU 2020 Column: Inertsustain C18, 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 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: 220 nm / 254 nm G Instrument: SHIMADZU 2020 Column: Shim-pack GIST 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 H Instrument: SHIMADZU 2020 Column: Inertsil ODS-3 C18, 50x4 .6 mm, 5 pm Mobile phase: A is H2O (+0.04% NH3 aqueous solution) 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 115 I Instrument: SHIMADZU 2010 Column: Shim-pack GIST C18.50x4.6 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 minutes) Flow rate: 2.3 mL / min Column temperature: 40 °C Wavelength: 220 nm / 254 nm J Instrument: SHIMADZU 2020 Column: Inertsil ODS-3 C18, 50x4 .6 mm, 5 pm Mobile phase: A is H2O (+0.04% NH3 aqueous solution) 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: 220 nm / 254 nm K Instrument: SHIMADZU 2020 Column: Kromasil EternityXT 018, 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: 220 nm / 254 nm L 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: 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: 220 nm / 254 nm 116 M Instrument: SHIMADZU 2020 Column: Shim-pack GIST 018.50x4.6 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: 220 nm / 254 nm synthetic examples Intermediates Synthesis of 3-chloro-4-iodo-1 H-pyrazole Yo To a stirred solution of 3-chloro-1H-pyrazole (25.00 g, 243.8 mmol) in DMF (250 ml) was added NIS (71.3 g, 317 mmol) in portions at 0 °C for 30 min. After addition, the mixture was stirred at 25 °C for 1 h and then concentrated with an oil pump to remove DMF. The residue was diluted with EtOAc, washed with saturated NaHCOs solution (250 ml x 2) and brine (250 ml x 2), dried over Na2SO4 and concentrated to dryness to give 3-chloro-4-iodo-1 H -crude pyrazole (55.7 g, 96%) as a brown oil LC / MS (ESI) m / z: 229 [M+H]+. The following intermediates were synthesized using a similar experimental protocol: 3-(benzyloxy)-5-bromo-1 -ethyl-4-iodo-1 H-pyrazole Br ___ ! Br / 1 w vj V m / z (ESI): 407 [M+H] Synthesis of 1-methyl-3-vinyl-1 H-pyrazole To a mixture of 3-iodo-1-methyl-1 H-pyrazole (14.00 g, 67.31 mmol) and potassium vinyltrifluoroborate (27.06 g, 201.9 mmol) in 1,4-dioxane (200 mL) and water (50 mL), K2CO3 (27.9 g, 202 mmol) and Pd(dppf)CI2 (0.98 g, 1.4 mmol) were added at room temperature. The mixture was degassed three times under N2 atmosphere and this mixture was stirred at 100 °C for 12 h. The mixture was filtered and the filtrate was diluted with EtOAc (100 ml), washed with water (100 ml) and brine (100 ml), dried in 117 Anhydrous Na2SO4 and concentrated to dryness. The residue was purified by silica gel column chromatography (PE:EtOAc = 20:1) to give 1-methyl-3-vinyl-1 H-pyrazole (4.25 g, 58% yield) as a yellow oil. . LC / MS (ESI) m / z: 109 [M+H]+. The following intermediates were synthesized using a similar experimental protocol: ΜΛ / t / ZUZJ / UUJ+U Ί 1 -ethyl-3-vinyl-1 H-pyrazole f 7 f=\ r=\ F N 1 N m / z (ESI): 123 [M+H] 2-(2-ethenyl-4-fluorophenyl)-1 - {[2-(trimethylsilyl)ethoxy]methyl}-1 H-imidazole F F Br O 'o F F m / z (ESI): 319 [M+H] 1 -methyl-3-vinyl-1 H-pyrazole- Methyl 5-carboxylate or 0 F -F + V / / V 7 F N-N^ N-N^ m / z (ESI): 167 [M+H] Synthesis of (4-bromooxazol-5-yl)methanol O Br Br To a solution of ethyl 4-bromooxazole-5-carboxylate (5.0 g, 22.7 mmol) in THF (100 ml) was added diisobutylaluminum hydride (1.5 M in THF, 45.5 ml, 68 .2 mmol) drop by drop at 0 °C. The mixture was stirred at 0 °C for 2 h and then diluted with EA (50 ml). To this mixture, water (3 ml) was added first, then NaOH aqueous solution (15%, 3 mL), followed again by water (27 mL), all at 0 °C. After warming to room temperature, the mixture was stirred for 15 min, anhydrous MgSCh was added and stirring was continued for another 15 min, then the mixture was filtered to remove solids. The filtrate was concentrated in vacuo to give crude (4-bromooxazol-5yl)methanol (2.9 g, 72%) as a yellow solid. LC / MS (ESI) m / z: 178 [M+H]+. The following intermediates were synthesized using a similar experimental protocol: (3-iodopyridin-4-yl)methanol 118 \ O I I m / z (ESI): 236 [M+H] (2-(5-((4-bromo-3-ethyl-1 -methyl-1 H-pi razol-5-yl)methyl)-3- met¡ I-1 H-pyrazol-1 -yl)-5-fluorophenyl)methanol F F Br Br Y N'N\ ^-0 N'Nx '~oh m / z (ESI): 407 [M+H] ( 2-chloro-4-methoxypyrid¡n-3-¡l)methanol \ o Q °\ o U A z m / z (ESI): 174 [M+H] (3-bromo-1 -(4-fluoro- 2-iodophenyl)-1 H-pyrazol-5-yl)methanol HO m / z (ESI): 397 [M+H] [3-(4-fluoro-2-iodophenyl)-1,2-thiazol-4- il]methanol C OH °Ύ° Jk ' N_S \ n-S 1 1 m / z (ESI): 336 [M+H] [5-(2-bromo-4-fluorophenyl)-3-methyl-1,2-oxazole -4-yl]methanol 1 -OH O^° ( — FOvV \ II ' O_N ' O-N Br Br m / z (ESI): 286 [M+H] (5-(cycloprop¡ Imeti I)-1 -methyl- 1 H-pyrazol-3-yl)methanol 119 ► H0A or m / z (ESI): 167 [M+H] Synthesis of 1-ethyl-3-iodo-1 H-pyrazole To a solution of 3-iodo-1 H-pyrazole (10 g, 51.5 mmol) in DMF (50 mL) was added iodoethane (12.4 mL, 155 mmol) and K2CO3 (21.4 g, 155 mmol ) at 25 °C. After stirring at 25 °C for 16 h, the reaction mixture was filtered and the filtrate was diluted with EtOAc (100 mL). This solution was washed with brine (3 x 30 ml), dried over anhydrous Na2SO4 and concentrated. The residue was purified by silica gel column chromatography (0—>20% EA in PE) to give 1-ethyl-3-iodo-1 H-pyrazole (8.4 g, yield: 73% yield) as a colorless oil. LC / MS (ESI) m / z: 223 [M+H]+. The following intermediates were synthesized using a similar experimental protocol: 3-bromo-1 -ethyl-4-iodo-1 H-pyrazole Br Br + / * ^n’ | I m / z (ESI): 301 [M+H] 1 -ethyl-3-methyl-1 H-pyrazole-4-carbaldehyde I z. / z 0 + □0 z. / z Vk 0 m / z (ESI): 139 [M+H] 1 -(cyclopropylmethyl)-3-methyl-1 H-pyrazole-4-carbaldehyde T vk 0 + 0 m / z (ESI): 165 [M+H] 1 -((3-iodo-1 -methyl-1 H-pyrazol-4-yl)methyl)-1 H-pyrazol-4-carbonitrile A z z-z: / A lll A 0 m / z (ESI): 314 [M+H] 1 -((2-bromo-5-fluoropyridin-3-yl)methyl)-1 H-pyrazole-4-carbaldehyde A 9 0 A 00 0 m / z (ESI) : 284 [M+H] 3-(benzylox¡)-1 -ethyl-1 H-pyrazole 120 9 O ¿ + (T?z o m / z (ESI): 203 [M+H] 1 -(2,2-dif luoroethyl)-3-methyl-1 H-pyrazole-4-carbaldehyde I \ / •z Vk o + / •z Vk o m / z (ESI): 175 [M+H] 4-bromo-1 -(cyclopropylmethyl)-1 H-pyrazole-3-carbonitrile Br Br 'ν'νΉ ¿ m / z (ESI): 226 [M+H] 1 -((2-chloropyrid i n-3-yl)methyl)-1 H-pyrazole-4-carbaldehyde Cl Cl Η'ΝΎ^ + νΑΑΒγ ---► N= / or N=^ ° m / z (ESI): 222 [M+H] 4-iodo-1 -isobutyl-1 H-pyrazole X l 1 I^N + ' m / z (ESI): 251 [M+H] 1 -( (1 -(4-fluoro-2-iodophenyl)-1 H-pyrazol-5-yl)methyl)-1 H-pyrazol-4-carbonitrile I 1 z o / / z + ryo vy z o z^ m / z (ESI) : 394 [M+H] 1 -((2,4-dibromothiazol-5-¡l)methyl)-1 H-pyrazole-4-carbonitrile Br Br _ ΛΝ S— N / =?N X^N N = Vn, + ci JL Αβγ * N=—L A 'Χβγ m / z (ESI): 347 [M+H] 1-((4-bromo-2-methylthiazol-5-¡l)methyl)-1 H- pyrazole-4-carbaldehyde Br .. Br z—yz Ν + Π \\__ ______y . ¡I \\__ 0 \=N Cl^— m / z (ESI): 286 [M+H] 1 -(cyclopropylmethyl) -4-iodo-3-methyl-1 H-pyrazole 121 z + ^z T m / z (ESI): 263 [M+H] 1 -(cyclopropylmethyl)-3-methyl-1 H-pyrazole Br m / z (ESI): 137 [M+H] Synthesis of 5-chloro-3-iodo-1-methyl-1H-pyrazole Methyl iodide (0.03 mL, 0.5 mmol) at 25 °C. The mixture was then stirred at room temperature for 30 min. The reaction mixture was quenched with ice water, extracted twice in EA, washed with brine, dried over anhydrous Na2SO4, filtered and concentrated to give 5-chloro-3-iodo-1 -methyl-1 H- Crude pyrazole (100 mg, 94% yield) as a yellow liquid. The material can be used as is or can be further purified by fast, high pressure or supercritical fluid chromatography to separate potential regioisomers. LC / MS (ESI) m / z: 243 [M+H]+. The following intermediates were synthesized using a similar experimental protocol: Ethyl 5-bromo-1-(2,2-difluoroethyl)-1 H-pyrazole-4-carboxylate ° T 0 I N'H + Br^\^F ----► nA-F 7 U F Z p m / z (ESI): 283 [M+H] 3-((3-iodo-1 -methyl-1 H-pyrazol-4-yl)methyl)-1 -methyl-1 H-pyrazol-5-carbonitrile I z z' \ O Z= / / \ ^z Jl z I z z: \ y 1 \ T' \ Jl z + m / z (ESI): 328 [M+H] (R)-3-((1 -(2-(1 -((5-bromo-2-nitropyridan-3-yl)oxy)ethyl)-4-f luorophenyl)-1 H-pyrazole-5-¡ I) methyl)-1 -ethyl-1Hpyrazole-5 -carbonitrile Br LDA (2.0 M in THF, 28.8 mL, 57.7 mmol) under N2 atmosphere for 20 min. After addition, the mixture was stirred at −70 °C for 30 min, then a solution of CBr4 (19.0 g, 57.7 mmol) in THF (40 mL) was added dropwise. The resulting mixture was stirred at 70 °C for 1 h. The mixture was quenched with a saturated NH4CI solution, and then diluted with EA (200 mL). The organic layer was separated, washed with brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by silica gel column chromatography (2% EA in PE) to give the objective product as a brown oil (11 g, yield: 80%). LC / MS ESI (m / z): 287 [M+H]+. The following intermediates were synthesized using a similar experimental protocol: 5-bromo-1 -cyclobutyl-4-iodo-1 H-pyrazole - JTÜ z Z‘ h z + m m .X. m cq m / z (ESI): 327 [M+H] 5-bromo-1 -ethyl-4-iodo-1 H-pyrazole Br ___ 4 Br N= / N= / m / z (ESI): 301 [ M+H] 123 5-bromo-1 -(cyclopropylmethyl)-3-methyl-1 H-pyrazole Br Br m / z (ESI): 215 [M+H] Synthesis of 3-bromo-4-iodo-1-methyl-1H-pyrazole To a solution of 3-bromo-1-methyl-1H-pyrazole (10.0 g, 62.1 mmol) in DMF (32 ml) was added NIS (16.8 g, 74.5 mmol). After addition, the resulting solution was stirred at 50 °C for 5 h. The mixture was diluted with water and extracted in EA. The combined organic phase was washed with brine (30 ml x 4), dried over anhydrous Na2SÜ4 and concentrated in vacuo. The residue was purified by flash chromatography (0—>10% EA in PE) to give 3-bromo-4-iodo-1-methyl-1 H-pyrazole (15.0 g, 76% yield) as a yellow solid. . LC / MS (ESI) m / z: 287 [M+H]+. The following intermediates were synthesized using a similar experimental protocol: 1 -ethyl-4-iodo-1 H-pyrazole-3-carbonitrile I N^N I N m / z (ESI): 248 [M+H] 5-bromo-1 -(cyclopropylmethyl)-4-iodo-3-methyl-1 H-pyrazole m / z (ESI): 341 [M+H] Synthesis of 3-etjlisoxazol-5-carbaldehyde To a solution of (3-ethylisoxazol-5-1)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 room temperature for 1 h (additional equivalents of oxidizing agent may be added to ensure complete oxidation of substrates containing multiple alcohol groups). The mixture was washed with saturated NajSsOs solution (100 mL) and saturated NaHCOs solution (100 mL), dried over anhydrous Na2SO4 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]+. 124 The following intermediates were synthesized using a similar experimental protocol: 1 -((2-(trimethylsil¡l)ethoxy)methyl)-1 H-pyrazole-3,5-dicarbaldehyde HO 0 \ \\ N N m / z (ESI): 255 [M+H] 2-chloro-5 -fluoropyridine-3-carbaldehyde CI^K CI^N^ \ 1 \ 1 HO F O F m / z (ESI): 160 [M+H] 2-(5-((tetrahydro-2H-pyran-2-ylox ¡)methyl)¡soxazol-3-¡l)acetaldehyde δ z ° \ o o / / z o m / z (ESI): 226 [M+H] 3-bromo-1 -(4-fluoro-2-iodophenyl)-1 H-pyrazole-5-carbaldehyde OH O — -q-í. Br Br m / z (ESI): 395 [M+H] 5-(2-bromo-4-fluorophenyl)-3-methylsoxazole-4-carbaldehyde OH 0 ► F^kX^ \ ll ' / / ' ο-N ' ON Br Br m / z (ESI): 284 [M+H] methyl 1-methyl-3-(2-oxoethyl)-1H-pyrazole-5-carboxylate o o ► o^ W^o- N-N^ N-N m / z (ESI): 183 [M+H] methyl 3-formyl-1-methyl-1 H-pyrazole-5-carboxylate 0 0 N-N N-N \ \ m / z (ESI) : 169 [M+H] 3-(cyclopropylmethyl)-1 -methyl-1 H-pyrazole-5-carbaldehyde MA / LEFT / ¿U¿O / UUO4U 1 125 Λ N-NZ Λ N-^ m / z (ESI): 165 [M+H] 5-(cyclopropylmethyl)-1 -methyl-1 H-pyrazole-3-carbaldehyde m / z (ESI): 165 [M+ H] Synthesis of 4-(chloromethyl)-1-ethyl-1H-pyrazole To a solution of (1-ethyl-1H-pyrazol-4-yl)methanol (1.40g, 11.1 mmol) in DCM (15 ml) at 0 °C was added dropwise SOCl2 (3.96 g, 33.3 mmol) under an N2 atmosphere. After addition, the mixture was stirred at 0 °C for 2 h. The mixture was concentrated to dryness to give crude 4-(chloromethyl)-1ethyl-1H-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-1 H-pyrazole Br Br 1 Cl 1 T^OH+ C|-S. ----- m / z (ESI): 223 [M+H] 5-bromo-4-(chloromethyl)-1 -(difluoromethyl)-l H-pyrazole Br Br 1 F Cl 1 F + Cl-S - ---► CI^V^ F or F m / z (ESI): 245 [M+H] 5-(chloromethyl)-1 -(4-fluoro-2-iodophenyl)-1 H-pyrazole I I ΓΝ· X ci ΓΝ· X J V'F O J W' HO^ Cl m / z (ESI): 337 [M+H] Synthesis of 5-(chloromethyl)-3-ethylisoxazole N-0 Cl0H+ Cl-S O To a stirred solution of (3-ethyl-1,2-oxazol-5-yl)methanol (4.10 g, 32.3 mmol) in dry DCM (10 ml) was added trlethylamine (5.8 ml, 42 mmol), followed by the addition of thionyl chloride (2.8 mL, 126 mmol) at 0 °C for 10 min. After addition, the reaction mixture was stirred at room temperature for 5.0 h in N2. The reaction mixture was cooled to 0 °C and quenched with 10% aqueous NaCl solution. The mixture was then extracted twice with DCM and the combined extracts were washed with saturated NaHCOs aqueous solution, dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by silica gel column chromatography (1030% EA in PE) to give 5-(chloromethyl)-3-ethyl-1,2-oxazole (4.20 g, yield: 90%) as a yellow oil. LC / MS (ESI) m / z: 146 [M+H]+. Synthesis of 3-bromo-1-methylpyrazole-4-carbaldehyde Cl ci-p.Cl or POCI3 (12.00 ml) was added dropwise to a flask of DMF (12.00 ml) at 0°C. The resulting mixture was stirred at room temperature for 30 min. To the above mixture, 3-bromo-1-methylpyrazole (4.00 g, 24.8 mmol) was added dropwise at room temperature. Then, the resulting mixture was stirred for 3 h at 95 °C. The reaction was quenched with H2O at room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by flash reverse phase chromatography (C18, 0—>30% MeCN in water + 0.1% FA) to provide 3-bromo1-methylpyrazole-4-carbaldehyde (3.94 g, 84%) like a solid light brown. LC / MS (ESI) m / z: 189 [M+H]+. Synthesis of 4-bromo-2-methylthiazol-5-carbaldehyde To a mixture of 2,4-dibromo-1,3-thiazol-5-carbaldehyde (2.00 g, 7.38 mmol) and methylboronic acid (486 mg, 8.12 mmol) in 1,4-dioxane (20 mi) K2CO3 (2.00 g, 14.8 mmol) and Pd(PPh3)4 (853 mg, 0.740 mmol) were added at room temperature. The mixture was degassed three times in N2 and then stirred at 110 °C under a N2 atmosphere for 12 h. The reaction was cooled to room temperature, filtered and concentrated to dryness. The residue was purified by flash chromatography (silica gel, 25% EtOAc in PE) to give 4-bromo-2-methyl-1,3-thiazol-5-carbaldehyde (728 mg, 31% yield) as a yellow solid. . LC / MS (ESI) m / z: 206 [M+H]+. The following intermediates were synthesized using a similar experimental protocol: 5-[(4-bromo-2-methyl-1,3-thiazol-5-yl)methyl]-1 -methyl-1 H-pyrazole-3-carbonitol 127 Br N l N HO A Vs A B-OH + Vi Λύ ----' ÍT^ / WX ,ν WX ,n Br N Br N m / z (ESI): 297 [M+H] 4-bromo-5 -((3-ethyl-1-methyl-1 H-pyrazol-5-yl)methyl)-2-methylthiazole .8 OT 1 O T + k^Z^ [ z — ω — / cp | 2 — ω —( / A ^z^? m / z (ESI): 300 [M+H] 4-[(4-bromo-2-methyl-1,3-thiazol-5-yl)methyl] -1 -ethyl-1 H-1,2,3-triazole m Br .. Br .. \ -N'N Va \ -N'N Va B-OH + XN i II '>-ΒΓ ----- - VN i II >— / m / z (ESI): 287 [M+H] 4-[(4-bromo-2-methyl-1,3-thiazol-5-yl) methyl]-1 -(cyclopropylmethyl l)-1 H-1,2,3-triazole s. .8 CD O I + ω^ζ I to^z € m / z (ESI): 313 [M+H] 4-bromo-5-((1 -(cyclopropylmethyl)-3-methyl-1 H-pyrazol-4-yl)methyl)-2-methylthazol ho B\ / —N B\y—N B-OH+ / =1 V-N Λ -- --► V N Λ / N^s N. s VA Br ' m / z (ESI): 326 [M+H] 1 -[(4-bromo-2-methyl-1,3-thiazol-5-yl) methyl]-1 H-imidazole-4-carbonitrile a .. Br .. Br HO N~, \^N N~. \^N B-OH+ N Ñ X>-Br ---- N Á -- / s χζ s m / z (ESI): 283 [M+H] 1-((4-bromo-2-methylthiazol-5-¡l)methyl)-1 H-pyrazole-4-carbonitrile Ho bVn / ^n bVn B-OH+ N=—ά · II '}_Br ----► n^V n / 1 ')-- / <— s x^ -— s m / z (ESI): 283 [M+H] 4-bromo-5- {[1 -(dif luoromethi I)-1 H-pi razol-4-yl]methyl}-2-met¡ 1-1,3-thiazol 128 ΗΟ N— / Br F N— / ΒΓ λΝ F B-OH + Br-^ Ü N—( ------ --(( N—( m / z (ESI): 308 [M+H] 4- bromo-5-[(1-ethyl-1 H-pyrazol-4-yl)methyl]-2-methyl-1,3-thiazole ΗΟ n _ ΒΓχ^Ν B-OH + Jl '>-Br ------► \^N JJ '>-- / \^\^S Xvx / '-'s m / z (ESI): 286 [M+H] Synthesis of 5-bromoisothiazole-4-carboxylic acid Br x Br Br Br Br To a solution of isothiazole-4-carboxylic acid (800 mg, 6.20 mmol) in THF (15 mL) was added tBuLi (1.3 M in heptane, 10.9 mL, 14.3 mmol) at -78 °C. Then a solution of CBr4 (4.10 g, 12.4 mmol) in THF (10 ml) was added dropwise. The mixture was stirred at -78 °C for 2 h. This reaction solution was quenched with the addition of saturated aqueous NH4CI solution and extracted with EtOAc. The aqueous layer was adjusted to pH 1 by adding aqueous HCl solution (1 M) and then extracted with EtOAc. This second organic layer was dried over anhydrous MgSO4, filtered and concentrated in vacuo to give crude 5-bromoisothiazole-4-carboxylic acid (750 mg) as a pale yellow oil. LC / MS (ESI) m / z: 208 [M+H]+. Synthesis of 5-iodo-1-methyl-3-vinyl-1H-pyrazole To a stirred solution of 1-methyl-3-vinyl-1 H-pyrazole (4.25 g, 39.30 mmol) in THF (40 ml) was added dropwise n-BuLi ( 24 ml, 58.95 mmol, 2.5 M in THF) via syringe at -78 °C in N2. After stirring at -78 °C for 1 h, a solution of iodine (14.97 g, 58.95 mmol) in THF (25 mL) was added and the reaction was stirred at -78 °C in N2 for another 2 h. The reaction was allowed to warm to 0 °C, quenched with saturated aqueous NH4Cl solution (25 ml) and extracted with EtOAc (25 mL x 2). The combined organic phases were washed with Na2S2O2 (20 mL), dried over anhydrous Na2SO4 and concentrated to dryness. The residue was purified by silica gel column chromatography (5% EtOAc in PE) to give 5-iodo-1-methyl-3-vinyl-1 H-pyrazole (2.70 g, 29 % yield) as a yellow oil. LC / MS (ESI) m / z: 235.0 [M+H]+. Synthesis of (5-iodo-1-methyl-1H-pyrazol-4-íl)methanol i Yo 129 To a mixture of 5-iodo-1-methyl-1 H-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 resulting mixture was stirred at 20 °C for 1 h. The mixture was quenched with a saturated NH4Cl solution (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 silica gel column chromatography (5% MeOH in DCM) to provide (5-iodo-1-methyl-1 H-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)-1 H-pyrazole-4-yl)methanol At 140 A m / z (ESI): 153 [M+H] [1 -(cyclopropylmethyl)-3-methyl-1 H-pyrazole -4-yl]methanol Δ NR\o ---. Δ NR OH --- m / z (ESI): 167 [M+H] (3-bromo-1-methylpyrazol-4-yl)methanol o o I m / z (ESI): 191 [M+H] (5 -bromo-1 -eti I-1 H-pyrazol-4-yl)( 1 -(4-f luoro-2-(hydroxymet¡ l)phenyl)-1 H-pyrazol-5-yl)methanol 0 OHN^ Re - — Rm- / ---' Br / ---' Br F F m / z (ESI): 395 [M+H] (5-bromo-1 -eti I-1 H-pyrazol-4-yl)( 4-f luoro-1 -(4-f luoro-2-(h idroxy methyl)phenyl)-1 H-pyrazol-5-yl)methanol R R Rvn^ / Br / Br F F m / z (ESI): 413 [ M+H] [1 -(4-fluoro-2-iodophenyl)-3-methyl-1 H-pyrazol-5-yl]methanol 130 O HO l .n-O'f [n-O'f ' 1 1 m / z (ESI): 333 [M+H] (1 -ethyl-1 H-pyrazol-4-yl)(1 -(4 -fluoro-2-(hydroxymethyl)phenyl)-3-methyl-1 H-pyrazol-5-yl)methanol O Nr-X OHN^Z m / z (ESI): 331 [M+H] (4- bromo-2-methylthiazol-5-¡l)methanol Br Br N— / '—N ><<0 --X X ^OH s s m / z (ESI): 208 [M+H] MA / IZ / x'Uj'O / UUO^m Synthesis of (3-iodo-1-methyl-1H-pyrazol-4-yl)methanol OH To a solution of 3-iodo-1-methyl-1 / - / -pyrazole-4-carbaldehyde (2.00 g, 8.47 mmol) in dry THF (20 mL) was added DIBAL-H (1.0 M in toluene, 12 mL, 12 mmol) dropwise at -70 °C (additional equivalents of reducing agent may be used in cases where more than one hydride transfer is required). The mixture was stirred at −70 °C for 2 h before being quenched with saturated aqueous NH4Cl solution. The resulting mixture was filtered and the filtrate residue was washed with THF. The combined filtrates were concentrated under reduced pressure; the residue was diluted with DCM, washed with water and brine, dried over anhydrous Na2SO4 and concentrated. The residue was purified by silica gel column chromatography (0—>20% EA in PE) to give (3-iodo-1-methyl-1 Hpyrazol-4-yl)methanol (1.6 g, 79% performance) as a yellow oil. LC / MS ESI (m / z): 239 [M+H]+. The following intermediates were synthesized using a similar experimental protocol: 1 -(4-fluoro-2-iodophenyl)-3-methyl-1 H-pyrazole-5-carbaldehyde ο·ϊζο n η ( N=\ I 0 - f-<3-nS 1 m / z (ESI): 331 [M+H] 131 5-bromoisothiazol-4-carbaldehyde ω o l 0 / m / z (ESI): 192 [M+H] [3-(2-bromo-4-fluorophenyl)-1,2-oxazol-4-yl]methanol OH ° Ύ° í ^ / ~\\ / ' N-O ' N-O Br Br m / z (ESI): 272 [M+H] (2-(5-((1 -(cyclopropylmethyl)-1 H-pyrazole-4 -yl)methyl l)-3-methyl-1 H-pyrazol-1 -yl)-5-fluorophenyl)methanol \ 1 1 O OHn^ 0=(^N- / y^N ___\__ / N~\ / ^N F F m / z (ESI): 341 [M+H] Synthesis of 3-chloro-1-ethyl-4-iodo-1H-pyrazole Yo To a stirred mixture of 3-chloro-4-iodo-1 H-pyrazole (55.34 g, 242.2 mmol) and CS2CO3 (118.7 g, 364.1 mmol) in DMF (150 mL) was added Etl (29.3 mL, 370 mmol)) dropwise at -10 °C. After stirring at −10 °C for 3 h, the reaction was concentrated. The residue was diluted with EtOAc, washed with brine (150 ml x 2), dried over Na2SO4 and concentrated to dryness. The residue was purified by silica gel column chromatography (0—>20% EA in PE) to give 3-chloro-1-ethyl-4-iodo-1 Hpyrazole (37.5 g, 60%) as a yellow oil. LC / MS (ESI) m / z: 257 [M+H]+. Synthesis of 4-(chloromethyl)-3-iodo-1 -methyl-1 H-pyrazole ci Cl-s '0 To a solution of (3-iodo-1-methyl-1 H-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 at room temperature for 3 h and then concentrated to give crude 4-(chloromethyl)-3-iodo-1-methyl-1 Hpyrazole (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: 132 4-(chloromethyl)-1 -(cyclopropylmethyl)-1 H-pyrazole HO A -Cl ______ Cl A Ul - '—xs^N^X-^ O m / z (ESI): 171 [M+H] 4- (chloromethyl)-1 -(cyclopropylmethyl)-3-methyl-1 H-pyrazole Vk 0 I + 0 tn. O' Q 7^ Vk 0 m / z (ESI): 185 [M+H] 5-bromo-4-(chloromethyl)-1-(cycloprop¡lmethyl)-3-methyl¡l-1 H -pyrazole A Nk” oh „ A ci γ o γ Br Br m / z (ESI): 263 [M+H] 3-bromo-4-(chloromethyl)-1-met¡lp¡razole Br ™ Br NsX Cl N ~Z ^Nx^X.OH + Cl ' ^N'\xk^CI Q xvxz m / z (ESI): 209 [M+H] 2,4-dibromo-5-(chloromethyl)thiazole Br Br Ν — / Cl Ν— / Br^ JL OH + Cl §· ' Br-Cl s 0 s m / z (ESI): 290 [M+H] 4-bromo-5-(chloromethyl)-2-methylthazol Ν- γΒΓ Cl N—ZBr —4 A OH+ Cl §· ' —Jj<.CI s 0 s m / z (ESI): 226 [M+H] Synthesis of 1-ethyl-3-(propan-2-yl)-1H-pyrazole To a solution of 1-ethyl-3-iodo-1 H-pyrazole (3.20 g, 14.4 mmol) in H2O (0.5 mL) and 1,4-dioxane (2.5 mL) in a tube sealed, K2CO3 (7.97 g, 57.6 mmol), Pd(dppf)Cl2 (1.05 g, 1.44 mmol) was added. The mixture was stirred at 100 °C for 16 h, then poured into water (80 ml) and extracted with EA (80 ml). The organic layer was washed with brine (60 ml), dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE / EA = 10 / 1 to 1 / 1) to give 1-ethyl-3-(prop-1-en-2-yl)-1 H-pyrazole ( 1.2 g, yield: 61% yield) as a white solid. LC / MS (ESI): m / z = 137.1 [M+H]+. MA / LEFT / ¿U¿O / UUO4U 1 133 To a solution of 1-ethyl-3-(prop-1-en-2-yl)-1 H-pyrazole (1.0 g, 7.3 mmol) in EtOAc (15 ml) was added PtO2(0. 17 g, 0.73 mmol) and then this mixture was stirred at room temperature for 16 h under OH2 (15 psi). The reaction mixture was filtered and the filtrate was concentrated to give crude 1-ethyl-3-(propan2-yl)-1H-pyrazole (800 mg, yield: 79%) as a white solid. LC / MS (ESI): m / z = 139.1 [M+H]+. Synthesis of 1-(difluoromethyl)-1H-pyrazole-4-carbaldehyde A mixture of 1H-pyrazole-4-carbaldehyde (2.00 g, 20.8 mmol), diethyl (bromodifluoromethyl)phosphonate (9.45 g, 35.3 mmol) and KF (3.63 g, 62. 4 mmol) in MeCN (20 ml) was stirred at room temperature overnight. The mixture was filtered and concentrated in vacuo to give a residue, which was purified by silica gel column chromatography (10% EtOAc in PE) to give 1-(difluoromethyl)1 H-pyrazole-4-carbaldehyde (2, 1 g, 69%) as a light yellow oil. LC / MS (ESI) m / z: 147 [M+H]+. The following intermediates were synthesized using a similar experimental protocol: Ethyl 5-bromo-1-(difluoromethyl)-1H-pyrazole-4-carboxylate 0 J o o Br F ^o-Xn-h · ^0·Ρ. F * F—K --- / oVA >=N “Λ '“►i F m / z (ESI): 269 [M+H] Synthesis of 3-chloro-1-(cyclopropylmethyl)-1H-pyrazole To a solution of 3-chloro-1 H-pyrazole (2.00 g, 19.5 mmol) in MeCN (50 ml) was added K2COs (5.40 g, 39.0 mmol) and (bromomethyl)cyclopropane ( 2.90 g, 21.5 mmol). The reaction mixture was stirred at 80 °C for 12 h. The reaction mixture was cooled and filtered and the filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography (0—>30% EtOAc in PE) to give 3-chloro-1-(cyclopropylmethyl)-1 H-pyrazole (2.3 g, 75%) as a colorless oil. LC / MS (ESI) (m / z): 157 [M+H]+. The following intermediates were synthesized using a similar experimental protocol: 3-chloro-1-(2,2-difluoroethyl)-1 H-pyrazole 134 o I + Ü0 o z A m / z (ESI): 167 [M+H] 1 -ethyl-4-iodo-3-(trif luoromethyl)-1 H-pyrazole F F N —ÍT + X ____► F ' F I I m / z (ESI): 291 [M+H] 3-methyl-1-(propan-2-yl)-1H-pyrazol-5-carbon¡trilo í + m / z (ESI): 150 [M+H] Synthesis of 5-bromo-1-ethyl-1H-pyrazole-4-carbaldehyde Br To a solution of 5-bromo-1-ethyl-1 H-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 for 16 h. After cooling to room temperature, the mixture was concentrated under reduced pressure to remove most of the TFA. The residue was diluted with DCM (600 mL), washed with saturated NaHCOs solution and brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by silica gel column chromatography (10% EtOAc in PE) to give 5-bromo-1-ethyl1 H-pyrazole-4-carbaldehyde as a white solid (60 g, yield: 52%). LC / MS ESI (m / z): 203 [M+H]+. The following intermediates were synthesized using a similar experimental protocol: 5-chloro-3-iodo-(1 -methyl-1 H-pyrazole-4-carbaldehyde) NC N^1 O' * -v — NÍ / Γ Cl — — N J Cl m / z (ESI): 271 [M +H] 3-chloro-1-(2,2-difluoroethyl)-1 H-pyrazole-4-carbaldehyde N^XKI -N^c| / c / —N J \ JP H \=J F zCI / N=< m / z (ESI): 195 [M+H] 135 3-iodo-1,5-dimethyl-1 H-pyrazole-4-carbaldehyde N^1 N^1 m / z (ESI): 251 [M+H] 3-chloro-1-(cyclopropylmethyl)-1H -pyrazole-4-carbaldehyde .N. C| Λ ,CI / ΑΝ-, . Z^n _ Λ N=< x >N <1 \=J ----” ¿A ¿ m / z (ESI): 185 [M+H] 3,5-dibromo-1 -methyl-1 H- pyrazole-4-carbaldehyde NX N^Br N^Br Q' * _N^ — Br Br m / z (ESI): 267 [M+H] 3-bromo-1 -(tert-butyl)-1 H-pyrazole- 4-carbaldehyde 4¼ * jAC. —- Α-ΌΡ0 NÍ / 7 ΝΛΓ ' νΛγ m / z (ESI): 231 [M+H] 1 -ethyl-3-(propan-2-yl)-1 H-pyrazole-4-carbaldehyde nx N \ N \ m / z (ESI): 167 [M+H] 1,3-diethyl-1 H-pyrazole-4-carbaldehyde m / z (ESI): 153 [M+H] Synthesis of 3-bromo-1-(tert-butyl)-1 H-pyrazole u ,N^Br __ / \ ,N. Brh~n y + —K ----► oHI X^J To a mixture of 3-bromo-1H-pyrazole (3.00 g, 20.4 mmol) and 2-methylpropan-2-ol (5 ml) was added H2SO4 (1.98 ml, 20.4 mmol) slowly at room temperature. The resulting mixture was heated at 100 °C for 16 h. The reaction mixture was diluted with H2O (20 mL) and then extracted with ethyl acetate (20 mL). The organic layer was washed with brine (20 mL), dried over anhydrous Na2SO4, filtered, concentrated, and then purified by silica gel chromatography (0^100% EtOAc in PE) to give 3-bromo-1- tert-butyl-1 H-pyrazole (1.4 g, 34% yield) as a yellow oil. 136 LC / MS (ESI) m / z: 203.0 [M+H]+. Synthesis of 1,3-diethyl-1H-pyrazole N N MA / IZ / ¿U¿O / UUO4U1 A mixture of 3-ethenyl-1-ethyl-1 H-pyrazole (1.00 g, 8.18 mmol) and platinum dioxide (0.190 g, 0.82 mmol) in EtOAc (10 mL) was stirred at room temperature in H2(15 psi) overnight. This mixture was filtered and the filtrate was concentrated. The residue was purified by silica gel column chromatography (0^100% EtOAc in PE) to give 1,3-diethyl-1 H-pyrazole (1.00 g, 98% yield) as a colorless oil. LC / MS (ESI) (m / z): 125 [M+H]+ The following intermediates were synthesized using a similar experimental protocol: 3-ethyl-5-iodo-1 -methyl-1 H-pyrazole j z1 m / z 237 [M+H] (ESI): Synthesis of 3-(bromomethyl)-2-chloro-5-fluoropyridine Br CI^J^ Cl^ / K P-Br + T ----- L %B' HO F Br F To a solution of (2-chloro-5-fluoropyridin-3-1)methanol (4.0 g, 25 mmol) in DMF (20 ml) tribromophosphane (2.4 ml, 26 mmol) was added dropwise. at 0 °C. After stirring at 25 °C for 1 h, the mixture was made basic to pH 7 with saturated NaHCOs solution and extracted with EA (30 ml x 3). The combined organic phase was dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by preparative TLC (8% EA in PE) to give 3-(bromomethyl)-2-chloro-5-fluoropyridine (2.7 g, 46% yield) as a colorless oil. LC / MS ESI (m / z): 224 [M+H]+ The following intermediates were synthesized using a similar experimental protocol: 3-(bromomethyl)-2-chloro-6-methoxy¡pinea Rr HO,___. Br,___. P-Br + ► / lo' Br Z~N Λ-Ν Cl Cl m / z (ESI): 236 [M+H] 3-(2-bromo-4-fluorophenyl)-4-(bromomethyl)¡sot¡ azole Br Br Br zS'V / ^ zS'V / ^ P-Br + vz'v \. ----- ^z u V J VAf j VAf SICKLE Br m / z (ESI): 352 [M+H] 137 3-(bromomet¡ I) -5-cyclobutyl-1 -methyl-1 H-pyrazole / / Br N N NN .p'Br + HOX ------ Br —<f\ Br V m / z (ESI) : 229 [M+H] Synthesis of 1-cyclobutyl-4-iodo-1 H-pyrazole A mixture of 4-iodo-1 H-pyrazole (10.0 g, 51.6 mmol), bromocyclobutane (20.9 g, 155 mmol), and K2CO3 (28.5 g, 206 mmol) in DMF (200 mL) was heated at 70 °C for 12 h. The reaction mixture was filtered and the filtrate was extracted with EA (300 ml x 2). The combined organic layers were washed with brine, dried over anhydrous Na2SO4 and concentrated. The residue was purified by silica gel column chromatography (0^5% EtOAc in PE) to give the objective product (9.73 g, 76% yield) as a yellow oil. LC / MS ESI (m / z): 249 [M+H]+. The following intermediates were synthesized using a similar experimental protocol: 1 -(cyclopropylmethyl)-4-iodo-1 H-pyrazole Λ ΛΝ T^N A Br m / z (ESI): 249 [M+H] 5-bromo-1-cyclobutíl-1 H-pyrazole-4- ethyl carboxylate O Br O Br Br^^ + N m / z (ESI): 273 [M+H] ethyl 5-bromo-1-(2-fluoroethyl)-1 H-pyrazole-4-carboxylate + >0 CD z z l ΞΕ ViO [Í'S— ro m / z (ESI): 265 [M+H] Synthesis of (4-fluoro-2-iodophenyl)hydrazine ,N-n Or one To a mechanically stirred solution of 4-fluoro-2-iodoaniline (5.0 g, 21 mmol) in AcOH (10 ml) was slowly added concentrated HCl (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 is 138 stirred for 1 h, then a solution of SnClg (8.46 g, 44.5 mmol) in concentrated HCl (8 ml) was slowly added. The reaction was allowed to warm to room temperature for 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)-1-ethyl-1 H-pyrazole Br Combine stirred solution of (5-bromo-1-ethyl-1 H-pyrazol-4-yl)methanol (4.00 g, 19.5 mmol) and triphenylphosphine (6.14 g, 23.4 mmol) in dry DCM (50 ml) a solution of tetrabromomethane (7.76 g, 23.4 mmol) in DCM was added dropwise at 0 °C. After addition, the reaction mixture was stirred at room temperature 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)-1-ethyl -1 H-pyrazole (3.0 g, 57% yield) as a white solid. LC / MS ESI (m / z): 267 [M+H]+. The following intermediates were synthesized using a similar experimental protocol: 5-bromo-4-(bromomethyl)-1 -cyclobuty I-1 H-pyrazole Br Br ΓΝ / X / X XB + HO^ ,N~<> ----► Br Br Br '^Y V Br Br m / z (ESI): 293 [M+H] 5-bromo-4-(bromomethyl)-1 -(2,2-difluoroethyl)-1 H-pyrazole Br Br Br □ 1 1 VBr + F-Y'n'Va ---► Br Br F N—' 0H F N—' Br m / z (ESI): 303 [M+H] 5-bromo-4-(bromomethyl)-1 -(2-fluoroethyl)-1 H-pyrazole Br Br P^Br + F^N --- F^NVsr Br “ m / z (ESI): 285 [M+H] 3-(bromomethyl)-1 -((2-(trimethylsilyl)ethoxy¡)methyl)- 1 H-pyrazole-5-carbonitrile ,N / / y / B%Br r=< / Γ—\ / Λη + HO L ' O^Si ----► Br L ' O^^Si Br N ' N ' m / z (ESI): 316 [M+H] Synthesis of 2-bromo-3-(bromomethyl)-5-fluorop¡r¡dina 139 A mixture consisting of 2-bromo-5-fluoro-3-methylpyridine (2.00 g, 10.5 mmol), AIBN (52 mg, 0.32 mmol) and NBS (2.44 g, 13.7 mmol) in DCE (20 ml) was degassed three times with N2 and heated to 85 °C with stirring for 1 h. After cooling to room temperature, the mixture was quenched with water, diluted with EtOAc and washed with brine. The final organic layer was dried over Na2SO4, filtered and the filtrate was concentrated in vacuo to give a residue, which was purified by flash column chromatography on silica gel (PE:EA=50:1) to give 2-bromo- 3-(bromomethyl)5-fluoropyridine (1.20 g, 42%) as a white solid. LC-MS ESI (m / z): 268 [M+H]+. The following intermediates were synthesized using a similar experimental protocol: 4-bromo-3-(bromomethyl)-1 -isopropy I-1 H-pyrazole-5-carbonitrile ,n ,N Br 7 / Br Br 7 / )=( y + -----► Br y n % '— ' n and m / z 306 [M+H] (ESI): 4-bromo-3-(bromomethyl)-1 -methyl-1 H-pyrazole-5-carbonitrile \ Br \ N-N ' N-N ^^A. % + Ος^ Ν^Ο ----► ___A Λ Br Λ_Γ Br Br m / z 278 [M+H] (ESI): Synthesis of 3-bromo-1-(difluoromethyl)-4-iodo-1H-pyrazole + F---K To a solution of 3-bromo-4-iodo-1 H-pyrazole (5.42 g, 19.9 mmol) and diethyl (bromodifluoromethyl)phosphonate (7.95 g, 29.8 mmol) in acetonitrile (50 ml ) potassium fluoride (2.3 g, 40 mmol) was added. The reaction mixture was stirred at 40 °C for 3 h. The reaction was cooled to room temperature, diluted with DCM (50 ml), washed with water (50 ml) and brine (50 ml), dried over Na2SO4, and concentrated to dryness. The residue was purified by silica gel column chromatography (15% EtOAc in PE) to give 3-bromo-1-(difluoromethyl)-4-iodo-1 H-pyrazole (5.12 g, 80% yield). like a white solid. LC / MS (ESI) m / z: 323 [M+H]+. Synthesis of acid (S-cyano-l-methyl-IH-pyrazole-S-iOboronic 140 To a solution of 1-methyl-1H-pyrazole-3-carbonitrile (1.0 g, 9.3 mmol) in THF (15 ml) was added dropwise LDA (2 M in THF, 4.7 ml , 9.3 mmol) in an atmosphere of N2a -78 °C. After stirring 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 saturated aqueous ammonium chloride solution. The reaction was diluted with EtOAc and washed first with H2O and then with brine. The organic layer was dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (0—>80% EtOAc in PE) to give (3-cyano-1methyl-1 H-pyrazol-5-yl)boronic acid (800 mg, 57% performance) as a yellow oil. LC / MS ESI (m / z): 152 [M+H]+. Synthesis of 3-(azidomethyl)-2-bromopyridine Br Br To a solution of 2-bromo-3-(chloromethyl)pineapple (1.15 g, 5.58 mmol) in MeCN (20 ml) was added NaN3 (1.09 g, 16.8 mmol) at room temperature. The mixture was stirred at 40 °C overnight, then partitioned between EtOAc (20 ml) and water (20 ml). The organic phase was washed with brine (20 ml), dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by flash chromatography (silica gel, 0—>33% EA in PE) to give 3-(azidomethyl)-2-bromopyridine (955 mg, 80% yield in 2 steps) as a yellow oil. LC / MS (ESI) m / z: 213 [M+H]+. The following intermediates were synthesized using a similar experimental protocol: 4-(azidomethyl)-3-iodo-1 -methyl-1 H-pyrazole + N=N+=N-Na ------► >=N >=N r i m / z (ESI): 264 [M+ H] 3-(azidomethyl)-2-bromo-5-fluoropyrid¡na F F '''''•S - + M4-* / ''-Τ' π Br y \) + N=N=N- Na ------- N Λ U Br N Br N m / z (ESI): 231 [M+H] 5-(azidomethyl)-3-ethyl-1,2-oxazole 141 + N=N-N-Na m / z (ESI): 153 [M+H] Synthesis of 2-(5-bromo-1-ethyl-1H-pyrazol-4-yl)acetonitrile Br Br To a solution of 5-bromo-4-(chloromethyl)-1-ethyl-1 H-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 Na2SO4, filtered and concentrated. The residue was purified by silica gel column chromatography (20% EtOAc in PE) to give 2-(5-bromo-1-ethyl-1H-pyrazol-4-1)acetonitrile (4.5 g, yield: 94%) as a light yellow oil. LC / MS ESI (m / z): 214 [M+H]+. Synthesis of 1-(5-Bromo-1-ethyl-1H-pyrazol-4-yl)ethanol ---Mg—Br+ To a solution of 5-bromo-1-ethyl-1 / - / -pyrazole-4-carbaldehyde (10.00 g, 49.25 mmol) in THF (120 ml), methylmagnesium bromide (18, 8 ml, 56.4 mmol, 3.0 M in THF) at 0 °C for 10 min. The resulting mixture was stirred at 0 °C for 1 h. The mixture was quenched with saturated NH4Cl solution (30 mL) at 0 °C and then extracted with EA (100 mL x 3), the combined extracts were dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (20% EtOAc in PE) to give 1-(5-bromo-1-ethyl1 H-pyrazol-4-yl)ethanol as a light yellow solid (9.28 g , 86% performance). LC / MS ESI (m / z): 219 [M+H]+. The following intermediates were synthesized using a similar experimental protocol: cyclopropyl(3-iodo-1 -methyl-1 H-pyrazol-5-yl)methanol p7 0H J N'Ns * 1 V IV7 Mg X '' Λ v / N'\ V Br m / z (ESI): 279 [M+H] 1 -(2-(1 -((5-bromo-1 -(difluoromethyl)-1 H-pyrazol-4-yl)methyl)-1 H-¡ midazol-2-yl)-5 -f luorofen il)ethane-1 -ol 142 o P ^_N / =N --Mg — Br + \— / '—— \ — / Br F HO- / V-N / =N \ — / Br F m / z (ESI): 415 [M+H] F F (5-bromo-1 -eti I-1 H-pyrazol-4-yl)(4-f luoro-1 -(4-fluoro-2-(1 -hydroxyethyl)phenyl)-1 H-pyrazole -5-yl)methanone F 4 nV Vn o N^A'F F - P+Y' Ηθ\ \ n^f m / z (ESI): 425 [M+H] 1 -(5-bromoisothiazol-4-¡ l)prop-2-¡n-1 -ol Br __ Mg Br + O^^Y^^g * χί OH Br N m / z (ESI): 218 [M+H] (1 -ethyl-1 H- pyrazol-4-yl)(3-fluoro-1 -(4-fluoro-2-(1 -hydroxyethyl)phenyl)-1 H-pyrazol-5-yl)methanone F O M9 Br+ 0 “Op N m / z (ESI): 347 [M+H] F F 1 -[3-(4-fluoro-2-iodophenyl)-1,2-thiazol-4-yl]prop-2-¡n-1 -ol I N-S _ __ Mg Br + y YF ----F^5^ ^0 Ί1 A m / z (ESI): 360 [M+H] 1 -((5-(4-fluoro-2-(1 -hydroxyethyl )phen i I)-1 -methyl-1 H-pyrazol-4-i l)methyl)-1 H-imidazole-4-carbonitrile ,i+ N Y O=\ \=\ / =N ---Mg — Br + )— / '—N, ^A G· N HO—\ y=\ / =N ----- \A O m / z (ESI): 326 [M+H] F F 3-(1 -(4-f luoro- 2-(1-hydroxyethyl)phenyl)-1 H-pyrazole-5-carbonyl)-1 -methyl-1 H-pyrazole-5-carbonitrile 143 --Mg—Br + )—\ T ---- VA / Ά ' 4 n-< n-nx hoA n- / n-\ O x m / z (ESI): 340 [M+H] MA / IZ / ¿U¿O / UUO4m Synthesis of 3-(bromomethyl)-2-chloro-5-methoxypyridine XVociA To a solution of 2-chloro-5-methoxy-3-methylpyridine (500 mg, 3.17 mmol) in CCU (12 ml) was added NBS (565 mg, 3.17 mmol) and benzoyl peroxide (76.8 mg, 0.317 mmol). The mixture was stirred at 80 °C for 3 h, then poured into water (80 ml) and extracted with EA (80 ml x 3). The combined organic layers were washed with brine (60 mL), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by eluted silica gel column chromatography (1—>10% EtOAc in PE) to give 2-chloro-3-(dibromomethyl)-5-methoxypyridine (200 mg, yield: 20%) as a white solid. LC / MS (ESI): m / z = 315.8 [M+H]+. To a solution of 2-chloro-3-(dibromomethyl)-5-methoxypyridine (200 mg, 0.634 mmol) in THF (4 mL) was added diethoxyphosphinous acid (0.161 mL, 1.27 mmol), DIPEA (164 mg, 1.27 mmol) and then this mixture was stirred at room temperature for 16 h. The mixture was poured into water (80 ml) and extracted with EA (80 ml x 3). The combined organic layers were washed with brine (60 mL), dried with Na2SO4, filtered, and concentrated in vacuo. This residue was purified by column chromatography on eluted silica gel (1—>10% EtOAc in PE) to give 3-(bromomethyl)2-chloro-5-methoxypyridine (100 mg, yield: 67%) like a white solid. LC / MS (ESI): m / z = 236 [M+H]+. Synthesis of 1-(3-iodo-1-methyl-1H-pyrazol-4-yl)-prop-2-n-1-ol OH Ethynylmagnesium bromide ( 12.7 mi, 6.36 mmol). The mixture was stirred at room temperature for 2 h. The reaction was quenched with saturated aqueous NH4Cl solution (13 mL) and extracted with EA (15 mL x 3). The organic layer was separated, washed with brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by silica gel column chromatography (20^90% EA in PE) to give 1 -(3-iodo-1 -methyl-1 H-pyrazol-4-yl)prop-2-¡n- 1-ol (780 mg, 70%) as a white solid. LC-MS (ESI) m / z: 262.9 [M+H]+. The following intermediates were synthesized using a similar experimental protocol: 144 1 -(2-chloro-5-f luoropyridin-3-yl)prop-2-i η-1 -ol II <Q I + o y Q V O \__ / I o m / z (ESI): 186 [M+H] 1 -(2-bromo-4-fluorophenyl)prop-2-in-1 -ol Br Br and HO ) __ Mg Br + 6 G \ ° F W VjZ F m / z (ESI): 229 [M+H] 1- (2-(1-((5-bromo-1-cyclobutyl-1 H-pyrazol-4-¡l)methyl)-1 H-imidazole-2-¡l)-5-fluorophen¡l)ethane-1- ol or you / / / \\ k. / s N / \\ k. / s N A Y—N / · HO—< / -N / · ---Mg — Br + \X\X \_ / Br \_ / Br F F m / z (ESI): 419 [M+H] 1- (2-(1-((5-bromo-1-(2,2-difluoroethyl)-1 H-pyrazol-4-yl)methyl)-1 H-imidazole-2-yl)-5-fluorophen ¡l)ethane-1-ol F F Br / = / Br / =^ --Mg —Br - V / ---. V / F N^ / N-< ,) F N= / N-¿ y—OH 0 <^N ' m / z (ESI): 429 [M+H] 1 -[2-(1 -{[5-bromo -1 -(2-f luoroethyl)-1 H-pi razol-4-yl]methyl}-1 H-imidazol-2-yl)-5-fluorophenyl]ethane-1 -ol F F Br / =( Br y / / f.___y / / ---Mg — Br + N Ni—\ >—( ----- N χ ¿ N-^ / ) N=v N-^ 5—OH O ' m / z (ESI) : 411 [M+H] (5-bromo-1 -ethyl-1 H-pyrazol-4-yl)(1 -(4-fluoro-2-(1 -hydroxyethyl)phenyl)-1 H- pyrazol-5-yl)methanone F F 0 I H o Í <x N- / \^N ΗΟ-\ Ν-Ϊ O N,^ x N.^ m / z (ESI): 407 [M+H] 145 1 -(3-chloro-1 -(4-fluoro-2-((R)-1 -((4-methoxybenzyl)oxy)ethyl l)phenyl)-1 H-pyrazol-5-yl)prop-2- ¡n-1 -ol Cl Cl , ? N / 7. ? Λ Mg-Br ♦ ^0 0« F F m / z (ESI): 415 [M+H] (1-((2-chloropyridin-3-¡l)methyl)-1 H-pyrazol-4-yl )(cyclopropyl)methanol Y ho ci / V Br m / z (ESI): 264 [M+H] 1 -(2-(1 -((5-bromo-1 -ethyl-1 H-pyrazol-4-yl )methyl)-1 H-imidazol-2-yl)-5-f luorophenyl)ethanol F F Br / ^0 Br / ^0 --Mg —Br + 00 ---„ 00 Ni / N0 ¿ ,N0 / —OH N O 0 / N ' m / z (ESI): 393 [M+H] methyl 3-(cycloprop¡l(hydroxy)methyl)-1-methyl-1 H-pyrazole-5-carboxylate And H? ° M' N-N 0 Mg \ v N_N o / ' Br m / z (ESI): 211 [M+H] Synthesis of 4-fluoro-2-iodobenzamide Yo To 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 addition of DMF (0.07 mL, 0.9 mmol) at 0 °C. After 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, a pre-cooled solution of aqueous NH3 solution (14 ml, 370 mmol, 28% in H2O) was added. drop by drop for 10 min. The internal temperature was maintained below 5 °C during the addition. The resulting mixture was stirred at room temperature for 4 h and then concentrated to MA / LEFT / ¿U¿O / UUO4U 1 146 dryness. The residual white solids were ground with water and PE and then dried in a vacuum oven to give the target product 4-fluoro-2-iodobenzamide (11 g, 92% yield in 2 steps) as a white solid. LC / MS (ESI): m / z = 266 [M+H]+. Synthesis of 3-bromo-5-methoxy¡-1 -methyl-1 H-pyrazole-4-carbaldehyde — O-Na To a stirred solution of 3,5-dibromo-1-methyl-1 / - / -pyrazole-4-carbaldehyde (5.00 g, 20.8 mmol) in MeOH (40 mL), sodium methanolate ( 12.5 mL, 62.5 mmol, 5.0 M in methanol) and the resulting mixture was stirred at 60 °C for 1 h. After 1 h, the reaction mixture was concentrated in vacuo to remove the solvent. The residue was diluted with a saturated aqueous solution of NH4Cl (30 ml) and EtOAc (30 ml), and then extracted with EtOAc (3 x 30 ml). The organic phases were combined, washed with brine (30 ml), dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give 3-bromo-5-methoxy¡-1-methyl-1 H-pyrazole-4-carbaldehyde. crude (3.31 g, yield: 59%) as a light yellow solid. LC / MS (ESI) (m / z): 219 [M+H]+. Synthesis of 1-(2,4-dibromothiazol-5-yl)prop-2-¡n-1-ol Mg—Br To a solution of 2,4-dibromo-1,3-thiazol-5-carbaldehyde (2.0 g, 7.3 mmol) in THF (20 mL) at -78 °C was added ethinyl magnesium bromide (7, 3 mL, 7.3 mmol, 1 M in THF) under a N2 atmosphere. After addition, the mixture was stirred at −78 °C for 2 h. The reaction was quenched with a saturated aqueous solution of ammonium chloride (30 mL). The reaction mixture was concentrated in vacuo and then diluted with DCM (30 mL). The mixture was then washed with brine (30 ml) and dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give the residue, which was purified by flash chromatography (30% EtOAc in PE) to give 1 -(2, 4-dibromothiazol-5-¡l)prop-2-¡n-1 -ol (1.5 g, 68%) as a white solid. LC / MS ESI (m / z): 296 [M+H]+. The following intermediates were synthesized using a similar experimental protocol: 1 -(3,5-difluoro-2-iodophenyl)ethane-1 -ol F I F 1 OH m / z (ESI): Mg Dr + Gh ’ F ° F 285 [M+H] Synthesis of 1-[(1-methylcyclopropyl)methyl]-1 H-pyrazole-4-carbaldehyde 147 > π N c K G C c G c To a solution of (1-methylcyclopropyl)methanol (0.56 mL, 5.8 mmol) and TEA (0.89 mL, 6.4 mmol) in DCM (20 mL) was added methanesulfonyl chloride (0.49 mL, 6.4 mmol). The mixture was stirred at 0 °C for 1 h. This solution was added to a mixture of 1H-pyrazole-4-carbaldehyde (836 mg, 8.70 mmol) and K2CO3 (1.60 g, 11.6 mmol) in DMF (10 ml) and the reaction was stirred at 0 °C for 2 h. The mixture was filtered and concentrated in vacuo to give a residue, which was purified by silica gel column chromatography (25% EtOAc in PE) to give 1-[(1-methylcyclopropyl)methyl]-1. / - / -pyrazole-4carbaldehyde (350 mg, yield: 37%) as a light yellow solid. LC / MS ESI (m / z): 165 [M+H]+. Synthesis of methyl 3-(hydroxymethyl)-1 -methyl-1 H-pyrazole-5-carboxylate To a solution of 5-(methoxycarbonyl)-1-methyl-1 H-pyrazole-3-carboxylic acid (5.70 g, 30.9 mmol) in THF (80 mL) at 0 °C in N2, was added slowly BHs-THF (61.9 ml, 61.9 mmol, 1 N). The reaction was allowed to warm to room temperature for 30 min and then heated to 65 °C for 4 h. After cooling to room temperature, MeOH (12 mL) was added slowly and then the solvent was removed under reduced pressure. The residue was redissolved in MeOH (12 ml), stirred for 20 min at room temperature and then evaporated to dryness. The residue was diluted with water and extracted with DCM (50.0 mL x 3). The combined organic phases were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude mixture was then purified by silica gel chromatography (33—>100% EA in PE) to give methyl 3-(hydroxymethyl)1-methyl-1 H-pyrazole-5-carboxylate (3, 2 g, yield: 61%) as a white solid. LC-MS ESI (m / z): 171 [M+H]+. Synthesis of ethyl 5-ethyl-1,2-thiazole-3-carboxylate To a solution of ethyl 2,4-dioxohexanoate (3.00 g, 17.4 mmol) in toluene (30 ml) was added ammonium acetate (3.36 g, 43.6 mmol), AcOH (3, 0 mi, 52 mmol). The reaction mixture was stirred at 80 °C for 18 h, allowed to cool, and then concentrated under reduced pressure. The residue was diluted with water and the pH was adjusted to 8 with 10% aqueous Na2CO3 solution. The resulting mixture was extracted with EtOAc (2 x 50 ml). The combined organic extracts were dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by fast column chromatography. 148 on silica gel (0^20% EtOAc in PE) to give ethyl 4-amino-2-oxohex-3-enoate (1.2 g, 40%) as a pale yellow oil. 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, 3.8 mmol ). The reaction mixture was stirred at room temperature overnight. The mixture was concentrated and the residue was dissolved in EA (50 ml). This solution was cooled to 0 °C and H2O2 (30%, 5 ml) was added. The mixture was stirred at room temperature for 10 min and then extracted with EtOAc (50 ml x 2). The combined organic extracts were dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (0—>30% EtOAc in PE) to give ethyl 5-ethyl-1,2-thiazol3-carboxylate (0.75 g, 53%) as a solid. white. LC / MS (ESI): m / z = 186 [M+H]+. Synthesis of 1-(5-Bromo-1-ethyl-1 H-pyrazol-4-yl)ethanone To a solution of 1-(5-bromo-1-ethyl-1 F / -pyrazol-4-yl)ethanol (9.28 g, 42.4 mmol) in DCM (50 ml) was added a portion of DMP (21.5 g, 50.8 mmol) at 0 °C for 10 min. After addition, the mixture was stirred at 0 °C for another 10 min. The mixture was adjusted to pH 8 with a saturated NaHCO3 solution and extracted with EA (100 mi x 3). The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (20% EtOAc in PE) to give 1-(5-bromo-1-ethyl-1 / - / -pyrazol-4-yl)ethanone as a light yellow solid ( 8.6g, yield: 93%). LC / MS ESI (m / z): 217 [M+H]+. Synthesis of 4-bromo-3-methyl-1 -(propan-2-yl)-1 H-pyrazole-5-carbonitrile A mixture of 3-methyl-1 -(propan-2-yl)-1 H-pyrazole-5-carbonitrile (470 mg, 3.15 mmol), TFA (0.25 ml, 3.4 mmol) and NBS ( 673 mg, 3.78 mmol) in MeCN (20 ml) was stirred at room temperature for 1 h. The reaction mixture was diluted with EtOAc (30 mL), washed with saturated Na2S2O3 solution (20 mL), dried over Na2SO4, filtered and concentrated to dryness. The residue was purified by silica gel column chromatography (25% EtOAc in PE) to give 4-bromo-3-methyl-1 -(propan2-yl)-1 H-pyrazole-5-carbonitrile (460 mg, 64 % yield) as a light yellow solid. LC / MS (ESI) m / z: 228 [M+H]+. Synthesis of 5-bromo-N-methoxy-N-methylisothiazole-4-carboxamide 149 O Br To a solution of 5-bromoisothiazole-4-carboxylic acid (700 mg, crude) in DCM (15 ml), HATU (1.6 g, 4.4 mmol), TEA (1.0 g, 10 mmol) and Ν,Ο-dimethylhydroxylamine hydrochloride (427 mg, 4.40 mmol). After stirring at 25 °C for 16 h, the reaction was diluted with DCM. The resulting mixture was washed with H2O and then with brine. The organic layer was dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (0^17% EtOAc in PE) to give 5-bromo-N-methoxy-N-methylisothazole-4-carboxamide (220 mg, 14% 2-step performance) as a yellow oil. LC / MS ESI (m / z): 251 [M+H]+The following intermediates were synthesized using a similar experimental protocol: 5-ethyl-N-methoxy-N-methyl¡soxazol-3-carboxamide 0 °» / °'ΝΖ + ho^^^)—\ ' \ Η N-O ' N-O m / z (ESI): 185 [M +H] Synthesis of 3-bromo-5-fluoro-2-(trimethylstannyl)pyridine A mixture of 2,3-dibromo-5-fluorodine (1.0 g, 3.9 mmol), hexamethyldistanane (1.35 g, 4.12 mmol) and Pd(PPh3)4 (0.23 mmol) was heated. g, 0.20 mmol) in toluene (50 ml) at 110 °C in N2 for 16 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 provide 3-bromo-5-fluoro-2-(trimethylstannyl)pyridine (1.2 g, 90% yield). like a colorless oil. LC / MS (ESI) m / z: 340 [M+H]+. Synthesis of methyl 3-(2-hydroxyethyl)-1 -methyl-1 H-pyrazole-5-carboxylate Under nitrogen, 9-borabicyclo[3.3.1]nonane (31.34 ml, 15.67 mmol) was added to a solution of methyl 3-ethenyl-1-methyl-1 H-pyrazole-5-carboxylate ( 1.50 g, 9.04 mmol) in dioxane (50 mL) at 0 °C, and the mixture was stirred at 100 °C for 1 h. To the reaction mixture, water (10 ml), aqueous sodium hydroxide solution (3.50 ml, 31.0 mmol, 10%) was successfully added dropwise. 150 in water) and hydrogen peroxide (3.2 ml, 10% in water) at 0 °C. The mixture was stirred at room temperature for 0.5 h, then water (20 ml) and ethyl acetate (30 ml) were added. The layers were separated and the aqueous layer was extracted with ethyl acetate (20 ml). The combined organic layers were washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography (1.6% MeOH in DCM) to provide methyl 3-(2-hydroxyethyl)-1-methyl-1 H-pyrazole-5-carboxylate (1, 10 g, 66%) as a white solid. LC / MS ESI (m / z): 185 [M+H]+. Synthesis of methyl 2-chloro-4-methoxynicotinate + —O-Na A mixture of methyl 2,4-dichloropyridine-3-carboxylate (2.40 g, 11.6 mmol) and sodium methoxide (2.06 g, 11.6 mmol) in MeOH (20 e) was heated to reflux in N2 for 16 h. The mixture was filtered through celite and the filtrate was diluted with EA (30 ml). This solution was washed with brine, dried over anhydrous Na2SO4 and concentrated. The residue was purified by silica gel column chromatography (0—>30% EA in PE) to give methyl 2-chloro-4-methoxynicotinate (1.70 g, yield: 72%) as a white solid. . LC / MS (ESI) (m / z): 202 [M+H]+. Potassium synthesis (E)-3-cyano-1-ethoxy-1-oxopent-2-en-2-olate To a stirred solution of t-BuOK (8.10 g, 72.4 mmol) and 18-crown-6 (1.91 g, 7.24 mmol) in THF (60 ml) was added a solution of sodium oxalate. diethyl (10.57 g, 72.35 mmol) in THF (10 mL) via syringe at 0 °C in N2. The reaction was heated to 60 °C and then a solution of butyronitrile (5.00 g, 72.3 mmol) in THF (10 ml) was added and stirring was continued at 60 °C for 30 min. The reaction was evaporated to dryness to give crude potassium (E)-3-cyano-1-ethoxy-1-oxopent-2-en-2-olate (14.20 g, yield: 93%) as a yellow solid. LC / MS ESI (m / z): 170 [M+H]+. Synthesis of 2-(2-bromo-4-fluorophenyl)-1H-imidazole Br Br h To a mixture of 2-bromo-4-fluorobenzaldehyde (50.00 g, 246.3 mmol) and oxalaldehyde (52.56 mL, 492.6 mmol, 40% in H2O) in EtOH (200 mL) was added ΝΗ3 ·Η2Ο (113.8 mL, 738.9 mmol, 25% in H2O) dropwise in N2 atmosphere at room temperature After addition, the mixture The resulting 151 was degassed, heated to 50 °C and stirred for 72 h. The reaction mixture was concentrated in vacuo and the residue was diluted with EA, washed with brine, dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (PE / EA = 3:1 to 2:1) to produce 2-(2-bromo-4-fluorophenyl)-1 H-imidazole (35.0 g, 59% yield) as a yellow solid. LC / MS ESI (m / z): 241 [M+H]+. The following intermediates were synthesized using a similar experimental protocol: 2-(4-fluoro-2-iodophenyl)-4-methyl-1 H-imidazole m / z (ESI): 303 [M+H] Synthesis of [5-bromo-1-(cyclopropylmethyl)-3-methyl-1H-pyrazol-4-yl]methanol Br Br To a solution of 5-bromo-1-(cyclopropylmethyl)-3-methyl-1H-pyrazole-4-carbaldehyde (1.80 g, 7.41 mmol) in EtOH (15 ml) was added NaBH4(0.33 g, 9.6 mmol) at 0 °C. This mixture was stirred at 0 °C for 1 h. The reaction mixture was concentrated, diluted with H2O (10 mL) and extracted with EtOAc (15 mL x 3). The combined organic solutions were washed with brine (15 mL), dried over anhydrous Na2SO4, and then concentrated to give crude (5-bromo-1-(cyclopropylmethyl)-3methyl-1 H-pyrazol-4-yl)methanol ( 1.4 g, yield: 77%) as a light yellow solid. LC-MS (ESI) m / z: 245 [M+H]+. The following intermediates were synthesized using a similar experimental protocol: [1 -(4-fluoro-2-iodophenyl)-1 H-pyrazol-5-yl]methanol O OH M+H] 3-(hydroxymet¡ l)-1 -((2-(trimethylsil¡l)ethoxy¡)methyl)-1 H-pyrazole-5-carbonitrile ,N z,N 0. OH^Si --- -► HO Z'.. OA^Si Hv ,N^ / \ ,N^ / x N ' N ' m / z (ESI): 254 [M+H] Synthesis of 2-(2-bromo-5-fluorophenyl)-1,3-dioxolane 152 A mixture of 2-bromo-5-fluorobenzaldehyde (10.0 g, 49.3 mmol) and ethane-1,2-diol (9.16 g, 148 mmol) in toluene (100 mL) at 25 °C was added 4-methylbenzenesulfonic acid (1.69g, 9.87 mmol) in one portion under a N2 atmosphere. After addition, the mixture was stirred at 120 °C for 16 h. The resulting mixture was cooled to 2-5 °C and then diluted with water and EtOAc. The organic layer was separated, washed with brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (20 >30% EtOAc in PE) to give the objective product as a yellow oil (10.0 g, yield: 82%). LC / MS ESI (m / z): 247 [M+H]+. Synthesis of 5-(cyclopropylmethyl)-3-iodo-1-methyl-1 H-pyrazole To a stirred solution of cyclopropyl(3-iodo-1-methyl-1H-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 room temperature overnight. The reaction was concentrated to dryness. The residue was purified by flash chromatography (0^10% EtOAc in PE) to give 5-(cyclopropylmethyl)-3-iodo1-methyl-1H-pyrazole (0.60 g, 51% yield) as a yellow solid. LC / MS (ESI) (m / z): 263 [M+H]+. The following intermediates were synthesized using a similar experimental protocol: To a solution of ethyl 5-ethyl-1,2-thiazol-3-carboxylate (750 mg, 4.05 mmol) in THF (15 ml) was added DIBAL-H (13.5 ml, 20.2 mmol ) at 0 °C. The reaction mixture was stirred at room temperature for 2 h and then quenched by sequential addition of MeOH (0.5 mL) and then water (15 mL). The resulting mixture was extracted with EtOAc (2 x 50 ml). The combined organic extracts 153 were dried in Na2SO4 and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (0^50% EtOAc in PE) to give (5-ethyl-1,2-thiazol3-¡l)methanol (510 mg, 88%) as a colorless oil. . LC / MS (ESI): m / z = 144 [M+H]+. The following intermediates were synthesized using a similar experimental protocol: (1-((2-(trimethylsil¡l)ethoxy¡)methyl)-1 H-pyrazole-3,5-di¡l)dimethanol o <o ° / \ I o <o m / z (ESI): 259 [ M+H] (1 -(4-fluoro-2-iodophenyl)-1 H-imidazole-5-¡l)methanol OH _ °Ύ° £ 'Ό-Χ, - νά I m / z (ESI): 319 [M+H] (3-(2-bromo-4-fluorophenyl)isot¡azol-4-yl)methanol OH °Ύ° í V / ' N-S ' N-S Br Br m / z (ESI): 288 [M+ H] (3-(cyclopropylmethyl)-1 -methyl-1 H-pyrazol-5-yl)methanol O m / z (ESI): 167 [M+H] Synthesis of 5-fluoro-2-(1 H-imidazol-2-yl)benzaldehyde or n-BuLI (21.54 mL, 53.86 mmol, 2.5 N) and Ν,Ν-dimethylformamide (6.25 mL, 80.79 mmol) were added dropwise simultaneously through two different syringes during 30 min to a solution of 2-(2-bromo-4-fluorophenyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1 H-imidazole (10.00 g, 26.93 mmol) in anhydrous THF (20 mL) while maintaining the internal temperature at -78 °C. After the addition, the 154 mixture was stirred at -78 °C for 10 min before quenching with a saturated aqueous NH4Cl solution. The resulting mixture was slowly warmed to room temperature and acidified to pH 6 with 2 N HCl. The mixture was then extracted with ether (150 ml). The organic layer was washed with water and brine, dried over anhydrous MgSO4, filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (30% EtOAc in PE) to give 5-fluoro-2-(1{[2(trimethylsilyl)ethoxy]methyl}-1 H-imidazol-2-íl )benzaldehyde (6.0 g, 70% yield) as an orange oil. LC / MS ESI (m / z): 321 [M+H]+. To a TEA flask (209 ml) was added portionwise 5-fluoro-2-(1-{[2(trimethylsilyl)ethoxy]methyl}-1Hmidazol-2-yl)benzaldehyde (45.0 g, 141 mmol) at 20 °C. The resulting solution was stirred at room temperature for 6 h and the reaction mixture was concentrated in vacuo to remove most of the TFA. The residue was slowly poured into a saturated aqueous NaHCO3a solution at 0 °C. The resulting mixture was then extracted with EA (3 x 200 ml) and the combined extracts were dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (0—>3% MeOH in DCM) to give 5-fluoro-2-(1 H-imidazol-2yl)benzaldehyde (23.0 g, 86% yield ) as a white solid. LC / MS ESI (m / z): 191 [M+H]+. Synthesis of methyl 5-(cyclopropylmethyl)-1-methyl-1 H-pyrazole-3-carboxylate A mixture of 5-(cyclopropylmethyl)-3-iodo-1-methyl-1 H-pyrazole (2.50 g, 9.54 mmol), tnetylamine (2.90 g, 28.6 mmol), MeOH ( 50 ml) and Pd(dppf)CI2(698 mg, 0.950 mmol) was degassed three times in CO atmosphere and then stirred in a CO balloon at 60 °C for 12 h. The mixture was cooled to room temperature, filtered and concentrated to dryness. The residue was purified by silica gel column chromatography (PE:EA = 5:1) to give methyl 5-(cyclopropylmethyl)-1-methyl-1Hpyrazole-3-carboxylate (1.50 g, 81% performance) as a brown oil. LC / MS (ESI) (m / z): 195.1 [M+H]+. The following intermediates were synthesized using a similar experimental protocol: Synthesis of 1-((4-bromothiazol-5-yl)methyl)-1 H-imidazole-4-carbonitrile 155 Br To a mixture of (4-bromo-1,3-thiazol-5-yl)methanol (480 mg, 2.40 mmol), 1H-imidazole-4-carbonátrilo (276 mg, 2.90 mmol) and triphenylphosphine (1.3 g, 4.9 mmol) in dry THF (30 ml) DIAD (0.98 ml, 4.9 mmol) was added dropwise at 0 °C for 10 min. After addition, the reaction mixture was stirred at room temperature for 2 h. The mixture was concentrated in vacuo and the residue was purified by flash chromatography on silica gel (30% EtOAc in PE) to give 1-((4-bromothiazol-5yl)methyl)-1 H-imidazole-4-carbonitrile (220 mg, yield: 33%) as a light yellow solid. LC / MS ESI (m / z): 269 [M+H]+. The following intermediates were synthesized using a similar experimental protocol: 1 -((4-bromopy ridin-3-yl)methyl)-1 H-imidazole-4-carbonitrile and ili + o I fur ili m / z (ESI): 263 [M+H] 1 -((2 -bromopyridin-3-yl)methyl)-1 H-imidazole-4-carbonitrile + Z —y W “ / O T fur ih m / z (ESI): 263 [M+H] 1 -((2- bromopiridin-3-yl)methyl)-1 H-pyrazole-4-carbonitrile N^\ fAl fVl ΝΛ —=N + =n H | | Br Br m / z (ESI): 263 [M+H] 1-((2-bromopyridín-3-yl)methyl)-2-methyl-1 H-imidazole-4-carbonitrile V —SN + N<yV°H —~N Η I 1 Br Br m / z (ESI): 277 [M+H] 1 -{[1 -(4-fluoro-2-iodophenyl)-1 H-pyrazole -5-yl]methyl}-1 H-imidazol-4-carbonitrile nA> a / ^N k N-k k N-X z-m Xn yy w X F F m / z (ESI): 394 [M+H] 156 1 -[(5-iodo-1 -methyl-1 H-pyrazol-4-yl)methyl]-1 H-pyrazol-4-carbonitrile I + o rL· z I i Z. z I m / z (ESI) : 314 [M+H] Synthesis of 5-(2-bromo-4-fluorophenyl)-1,3,4-oxathiazol-2-one To a solution of 2-bromo-4-fluorobenzamide (4.43 g, 20.3 mmol) in toluene (50 ml) was added chloro(chlorosulfanyl)methanone (2.53 ml, 30.5 mmol). The mixture was stirred at 100°C for 2 h, concentrated in vacuo, and the residue was purified by silica gel column chromatography (0^50% EtOAc in PE) to give 5-(2-bromo-4- fluorophenyl)-1,3,4-oxathiazol-2-one (3.90 g, 69% yield) as a white solid. LC / MS (ESI) m / z: 276 [M+H]+. The following intermediates were synthesized using a similar experimental protocol: 5-(4-fluoro-2-iodophenyl)-1,3,4-oxathiazol-2-one \___ Cl k / Λ- / s y h2n Cl S-N m / z (ESI): 324 [M+H] Synthesis of S-ethyl-l^-thiazole-S-carbaldehyde Y-N Y-N To a solution of (5-ethyl-1,2-thiazol-3-yl)methanol (510 mg, 3.56 mmol) in DCM (15 ml) was added MnÜ2 (3.10 g, 35.6 mmol) . The reaction mixture was stirred at room temperature for 20 h. After filtration, the filtrate was concentrated under reduced pressure to give 5-ethyl-1,2-thiazol-3carbaldehyde (120 mg, 24%) as a pale yellow oil. LC / MS (ESI): m / z = 142 [M+H]+. The following intermediates were synthesized using a similar experimental protocol: 1 -(4-fluoro-2-iodophenyl)-1 H-imidazole-5-carbaldehyde OH 0 I I m / z (ESI): 317 [M+H] 3-(2-bromo-4-fluorophenyl)-1, 2-oxazol-4-carbaldehyde 157 OH 0 N-O N-O Br Br m / z 270 [M+H] (ESI): 3-(2,2-dif luoroethyl)-1 -methyl-1 H-pyrazole-5-carbaldehyde F^ / ^V OH -- -► ' N-N ' N-N F \ F \ m / z 175 [M+H] (ESI): Synthesis of methyl 3-(2.2-difluoroethyl)-1-methy 1-1 H-pyrazole-5-carboxylate Under a nitrogen atmosphere, diethylaminosulfur trifluoride (0.40 ml, 3.0 mmol) was slowly added to a solution of crude methyl 1-methyl-3-(2-oxoethyl)-1H-pyrazole-5-carboxylate. (1.5 g, 2.9 mmol) in DCM (20 ml) at 0 °C. The reaction was stirred at this temperature for 0.5 h, then quenched with saturated aqueous NaHCOa solution (50 mL). The resulting mixture was extracted with DCM (3 x 10 ml). The combined extracts were washed sequentially with water (1 x 30 ml) and brine (30 ml), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by preparative TLC (0—>50% EtOAc in PE) to provide methyl 3-(2,2-difluoroethyl)1-methyl-1H-pyrazole-5-carboxylate (500 mg, 85% ) as a solid white. LC / MS ESI (m / z): 205 [M+H]+. The following intermediates were synthesized using a similar experimental protocol: 2-bromo-3-((4-(difluoromethyl)-1 H-pyrazol-1 -yl)methyl)-5-fluoropyridine / F Br _ \ · íT ·Ύ .o N-S-F + II I ·, A—' / ---- ( F J+ +r _ ίΓ ''ΊΓ f - m / z (ESI): 306 [M+H] (R)-1 -(2-(1 - (benci loxi) eti l)-4-f I u orof en i I )-3-(dif I uorometi I) -1 H-pyrazole Z=O / _ ·Ν=\ < F / TVv n-s-f + 1 — ( F / ¡> m / z (ESI): 347 [M+H] Synthesis of (R)-1 -(5-fluoro-2-(1 H-pyrazol-1 -yl)phenyl)ethane-1 -ol ΜΛ / t / ZUZÓ / UUÓ+U 1 A mixture of methyl[2-(methylamino)ethyl]amine (0.41 ml, 3.8 mmol), (1R)1-(5-fluoro-2-iodophenyl)ethane was stirred in a sealed tube. -1-ol (5.0 g, 19 mmol), 1H -pyrazole (1.09 mL, 22.6 mmol), K2CO3 (5.19 g, 37.6 mmol) and Cul (60 mg, 1.9 mmol) in NMP (150 mL) at 120 °C in N2 for 18 h. The reaction mixture was poured into water (100 ml) and then extracted with EtOAc (100 ml x 2). The combined organic layers were washed with brine, dried over anhydrous Na2SÜ4 and concentrated. The residue was purified by column chromatography (silica gel, 1^10% ethyl acetate in petroleum ether) to give (1 R)-1-[5-fluoro-2-(1 H-pyrazole-1- yl)phenyl]ethane-1-ol (3.6 g, 93%) as a yellow oil. LC / MS (ESI) m / z: 207.1 [M+H]+. The following intermediates were synthesized using a similar experimental protocol: (R)-1 -(2-(3-chloro-1 H-pyrazol-1 -yl)-5-fluorophenyl)ethane-1 -ol + zc 1 0 1 ,N^CI HO m / z (ESI): 241 [M+H] (R)-1 -(5-fluoro-2-(3-methoxy¡-1 H-pyrazol-1 -yl)phenyl)ethane-1 -ol n^o + η-ν^ HO n.___.0^ ____► N HO m / z (ESI): 237 [M+H] Synthesis of ethyl 5-cyclobutyl-1-methyl-1H-pyrazole-3-carboxylate To a solution of ethyl 4-cyclobutyl-2,4-dioxobutanoate (6.2 g, 31 mmol) in acetic acid (15 ml) was added methylhydrazine (3.6 g, 31 mmol) and the resulting mixture It was stirred at 100 °C for 3 h. After 3 h, the reaction mixture was cooled to room temperature and concentrated in vacuo to remove the solvent and give the residue, which was diluted with toluene (20 ml) and concentrated in vacuo. The residue was purified by silica gel chromatography (0^50% EA in PE) to give ethyl 5-cyclobutyl-1 methyl-1 / - / -pyrazole-3-carboxylate (4.2 g, 20%) as a yellow oil. LC / MS ESI (m / z): 209 [M+H]+. Synthesis of 3-ethyl-5-(((tetrahydro-2H-pyran-2-yl)ox¡)methyl)¡soxazole 159 To a stirred solution of 2-(prop-2-¡n-1-¡lox¡)tetrahydro-2H-pyrane (5.00 g, 36.7 mmol) and 1nitropropane (7.00 g, 78.6 mmol) in toluene (40 mL) was added to phenyl isocyanate (17.0 mL, 119 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 room temperature, the reaction mixture was quenched with 1 mL of water and the mixture was stirred at room temperature for 1 h. The precipitates were removed by filtration and the filtrate was concentrated. The residue was purified by silica gel column chromatography (0—>20% EtOAc in PE) to give 3-ethyl-5-(((tetrahydro-2Hpyran-2-yl)ox¡)methyl)¡soxazole (10.0 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)ox¡)methyl)¡soxazole 5 0 'b + oz m / z (ESI): 238 [M+H] 3-( 2-((tert-but¡ldimethyllsilyl)ox¡)ethyl)-5-(((tetrahydro-2H-pyran-2-¡l)ox¡)methyl)¡soxazole Ó x z 0 Ó x O:^ b + m / z (ESI): 342 [M+H] Synthesis of (2-(3-chloro-1H-pyrazol-1-yl)-5-fluorophenyl)methanol To a solution of (5-fluoro-2-iodophenyl)methanol (25.0 g, 99.2 mmol) in toluene (250 ml) was added 3-chloro-1 H-pyrazole (11.2 g, 109 mmol), K2CO3 (27.4 g, 198.4 mmol) and Cul (1.9 g, 9.9 mmol). The reaction mixture was stirred at 120 °C in N2 for 12 h. The solution was filtered and concentrated. The residue was purified by flash chromatography (5^25% EtOAc in PE) to give (2-(3-chloro-1 H-pyrazol1-¡l)-5-fluorophenyl)methanol (21.1 g, 85% yield ) as a solid white. LC / MS (ESI) (m / z): 227 [M+H]+. Synthesis of 1 -[(2-bromopyridin-3-yl)methyl]-1 H-1,2,3-triazole-4-carbonitrile Br 160 A mixture of 3-(azidomethyl)-2-bromopyridine (955 mg, 4.48 mmol) and 2-chloroprop-2-enenitrile (0.90 ml, 11 mmol) in water (30 ml) was stirred at 80 °C. for 12 hours. The reaction was cooled to room temperature, extracted with DCM (20 mL), washed with saturated brine (20 mL), dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by flash chromatography (silica gel, 0—>100% EA in PE) to give 1-[(2-bromopyridin-3-yl)methyl]-1H-1,2,3-triazole -4-carbonitrile (639 mg, 54% yield) as a white solid. LC / MS (ESI) m / z: 264 [M+H]+. The following intermediates were synthesized using a similar experimental protocol: 1 -((3-iodo-1 -methyl-1 H-pyrazol-4-yl)methyl)-1 H-1,2,3-triazol-4-carbonitrilo L I Cl \sN N;n N ' m / z (ESI): 315 [M+H] Synthesis of [5-Bromo-1-(2-fluoroethyl)-1H-pyrazole-4-¡l]methanol To a solution of ethyl 5-bromo-1-(2-fluoroethyl)-1 H-pyrazole-4-carboxylate (3.10 g, 11.3 mmol) in THF (50 mL) was added DIBAL-H ( 22.6 mL, 22.6 mmol, 1 M in toluene) dropwise at 0 °C for 10 min. After addition, the resulting solution was stirred at room temperature for another 3 h. After cooling to 0 °C, the reaction mixture was treated with EtOAc (100 mL) and 11 N HC (100 mL), the organic layer was separated, and the aqueous solution layer was extracted with EtOAc (150 mL). The combined organics were concentrated in vacuo and the residue was purified by flash chromatography (silica gel, 0—>50% EtOAc in PE) to give [5-bromo-1-(2-fluoroethyl)-1 H-pyrazole- 4-yl]methanol (2.1 g, 83% yield) as a white solid. LC-MS(ESI) found: 223 [M+H]+. The following intermediates were synthesized using a similar experimental protocol: (3-(2,2-difluoroethyl)-1 -methyl-1 H-pyrazol-5-yl)methanol m / z (ESI): 177 [M+H] Synthesis of 3-bromo-4-[(4-ethylimidazole-1-yl)methyl]-1-methylpyrazole To a stirred mixture of 4-ethyl-1H-imidazole (0.73 g, 7.6 mmol) in DMF (5.00 ml) was added NaH (0.22 g, 9.1 mmol) in portions at 0 °C. The resulting mixture was stirred for 30 min at 0 °C. To the 161 3-bromo-4-(chloromethyl)-1-methylpyrazole (1.91 g, 9.11 mmol) in DMF (5 ml) was added dropwise to the above mixture at 0 °C. The resulting mixture was stirred for an additional 1 h at room temperature and then quenched with H2O. The resulting mixture was directly purified by flash reverse phase chromatography (C18, 0^40% MeCN in water + 1% NH3 aqueous solution) to produce 3bromo-4-[(4-ethylimidazole-1 -yl)methyl]- 1-methylpyrazole (1.9 g, 93%) as a light brown oil. LC-MS (ESI) m / z: 269 [M+H]+. Synthesis of (5-bromo-1-(difluoromethyl)-1H-pyrazol-4-¡l)methanol Br MA / IZ / ¿U¿O / UUO4U1 To a solution of ethyl 5-bromo-1-(difluoromethyl)-1 H-pyrazole-4-carboxylate (2.00 g, 7.43 mmol) in THF (30 ml) was added DIBAL-H (18, 6 ml, 18.6 mmol, 1 M in toluene) at -78 °C for 30 min. During the addition, the internal temperature was controlled to remain below −60 °C. The reaction was stirred for 1 h at −78 °C, then quenched by slowly adding into aqueous HCl solution (1 M) at 0 °C. The mixture was extracted with EtOAc twice. The combined extract was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (30% EtOAc in PE) to give (5-bromo-1(difluoromethyl)-1 H-pyrazol-4-yl)methanol (1.5 g, 89% performance) as a colorless oil. LC / MS ESI (m / z): 227 [M+H]+. Synthesis of (4-bromooxazol-5-yl)(1 -ethyl-1 H-pyrazol-4-yl)methanol To a solution of (4-bromooxazol-5-yl)methanol (2.90 g, 16.3 mmol) in DCM (5 ml) was added Dess-Martin periodinane (10.4 g, 24.4 mmol). The reaction was stirred at room temperature for 2 h, filtered, and the filtrate was concentrated in vacuo. The residue was purified by flash chromatography (0^30% EtOAc in PE) to give 4-bromooxazole-5-carbaldehyde (2.49 g, 87% yield) as a light yellow solid. To a solution of 1-ethyl-4-iodo-1 / 7-pyrazole (3.14 g, 14.2 mmol) in THF (30 mL) was added dropwise an isopropylmagnesium chloride-lithium chloride complex. (13.1 mL, 17.0 mmol, 1.3 M in THF) at -10 °C. The mixture was stirred at room temperature for 1 h, then cooled to −10 °C. A solution of 4-bromooxazole-5-carbaldehyde (2.49 g, 14.2 mmol) in 10 ml of THF was added dropwise. The ice bath was removed and stirring continued at room temperature for 1 h. The reaction was quenched with saturated aqueous NH4Cl solution (20 mL), and then extracted with EA (3 x 20 mL). The combined organic phases were washed with water (20 ml) and brine (20 ml), 162 were dried in anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography (0->10% MeOH in DCM) to give (4-bromooxazol-5-yl)(1-ethyl-1 / - / -pyrazol-4yl)methanol (1.21 g, 31 % yield) as a light yellow solid. LC / MS ESI (m / z): 272 [M+H]+. Synthesis of (E)-1-(5-bromo-1-ethyl-1H-pyrazol-4-yl)-3-(dimethylamino)prop-2-en-1-one MA / IZ / ZU¿O / UUO4U1 A mixture of 1-(5-bromo-1-ethyl-1 H-pyrazol-4-yl)ethane-1-one (4.00 g, 18.4 mmol) and DMF-DMA (80 ml) was stirred at 110 °C for 12 h. After cooling to room temperature, the mixture was concentrated in vacuo with an oil pump to obtain (E)-1 -(5-bromo-1 -ethyl-1 H-pyrazol-4-¡l)-3(dimethylam¡ Crude no)prop-2-en-1 -one as a light yellow solid (2.6 g, yield: 51%). LC / MS ESI (m / z): 272 [M+H]+. The following intermediates were synthesized using a similar experimental protocol: (E)-N'-(4-fluoro-2-iodobenzoyl)-N,N-dimet¡lformoh¡drazonamide ° v ' o l * Y —- ANi. H zO Z h m / z (ESI): 336 [M+H] Synthesis of 5-((4-bromothiazol-5-yl)methyl)-1-methyl-1 H-pyrazole-3-carbonitrile Br A mixture of 5-[(dibromo-1,3-thiazol-5-yl)methyl]-1-methyl-1 H-pyrazole-3-carbonitrile (0.700 g, 1.93 mmol), Pd / C ( 0.07 g, 10 wt %) in MeOH (20 mL) was stirred at 50 °C for 2 h under 1 atm H2. The reaction mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by flash chromatography (0^25% ​​EA in PE) to give 5-((4-bromothiazol-5-yl)methyl)-1-methyl-1 H-pyrazole3-carbonitol (0.45 g , 78% yield) as a colorless oil. LC / MS (ESI) (m / z): 283 [M+H]+ Synthesis of (5-bromoisothiazol-4-yl)(1 -ethyl-1 H-1,2,3-triazol-4-yl)methanol To a solution of 1 -(5-bromoisothiazol-4-yl)prop-2-in-1 -ol (100 mg, 0.46 mmol) in t-BuOH (1 mL) and H2O (1 mL) was added sodium (R)-2-((S)-1,2-dih¡droxy¡ethyl)-4-h¡drox¡-5-oxo-2,5-d¡hydrofuran-3-olate (4, 5 mg, 0.02 mmol), azidoethane (1.2 M in THF, 2.0 mL, 2.3 mmol) and CuSO4 (3.6 mg, 0.02 mmol) in 163 N2a 25 °C. After stirring at 50 °C for 16 h, the reaction was diluted with EtOAc. The resulting mixture was washed with H2O, brine and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated. The residue was purified by flash chromatography (silica gel, 0^100% EA in PE) to give (5-bromoisothiazol-4-yl)(1-ethyl-1 H-1,2,3-triazol-4-yl )methanol (60 mg, 45% yield) as a yellow oil. LC / MS (ESI) m / z: 289 [M+H]+ The following intermediates were synthesized using a similar experimental protocol: (1 -ethyl-1 H-1,2,3-triazol-4-yl) (3-iodo-1 -methyl-1 H-pyrazol-4-yl)methanol OH OH m / z (ESI): N— 1 -Ntk| ' / N. 1 N— ,Λ N N=N 334 [M+H] 4-ethyl-1 -((3-iodo-1 -methyl-1 H-pyrazol-4-yl)methyl)-1 H-1 ,2,3-triazole VNN_ \ \ λν Vn· m / z (ESI): N 318 [M+H] (1 -(cyclopropy Imeti I)-1 H-1,2,3-thazol-4-yl) (3-iodo-1 -methyl-1 H-pyrazol-4-yl)methanol OH OH m / z (ESI): k N- 1 ' <7 N=N k N- 360 [M+H] (2- chloro-5-f luoropyridin-3-yl) (1 -ethyl-1 H-1,2,3-thazol-4-yl)methanol OH OH m / z (ESI): N CIn 257 [M+H] (2,4-dibromothiazol-5-yl)(1 -ethyl-1 H-1,2,3-triazol-4-yl)-methanol OH OH ^xk^s ,r z^ -k^s. m / z (ESI): Bi 1 ·ΧΝ · / -N 1 h y-B, NN Br Br 369 [M+H] 164 (2-chloro-5-f luoropyridin-3-yl) [1 -(cyclopropyl methyl)-1 H-1,2,3-triazol-4-yl]methanol °H .Ν' F 'X OH m / z (ESI): Λ y ' N Cl v N=N L / / 283 [M+H] (3-chloro-1 -(4-fluoro-2-((R)-1 -((4-methoxybenzyl)ox¡ )ethyl)phenyl)-1 H-pyrazol-5-yl)(1 -(cyclopropylmethyl)-1H- 1,2,3-tñazole-4-yl)methanol Cl Cl m / z Λ / N ll A ___, o-A~Vy°A / \A~N Λ (ESI): <0 HO^ NN' 0 512 F F ​​[M+H] [1 -(cyclopropylmethyl)-1 H-1,2,3- triazol-4-yl](dibromo-1,3-thiazol-5-yl)methanol °H OH m / z (ESI): ll Z>-Br ' X N Br N 'v 7 / N=N 11 / / ~Br Br N 393 [M+H] (1 -ethyl-1 H-1,2,3-triazol-4-yl)[3-(4-fluoro-2-iodophenyl)-1,2-thiazol -4-yl]methanol N'\ l V 1 / ΜΛΑ'ν Xy HO m / z 1 ' r^N X / ΗΟ (ESI): 431 F F [M+H] Synthesis of 1 -((3-iodopyridin-4-yl)methyl)-1 H-imidazole-4-carbonitrile Yo Yo To a solution of PPh3 (1.43 g, 5.45 mmol) in THF (16 mL) at 0 °C was added a solution of DIAD (1.1 g, 5.45 mmol) in THF (16 mL) in N2 atmosphere. After addition, the mixture was stirred at 0 °C until a white solid precipitated. To this mixture was added 1 H-imidazole-4-carbonitrile (304 mg, 3.27 mmol) in THF (8 ml), followed by (3-iodopyridin-4-yl)methanol (640 mg, 2.72 mmol) in THF (8 mi). The resulting mixture was stirred at room temperature for 3 h. The mixture was concentrated under reduced pressure. The residue was diluted with DCM (60 mL), then washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by 165 column chromatography on silica gel (50% EtOAc in PE) to 1 -((3-iodopyridin-4-yl)methyl)-1 Himidazole-4-carbonitrile (890 mg, yield: 53%) as a yellow oil pale. LC-MS (ESI): m / z 311 [M+H]+. The following intermediates were synthesized using a similar experimental protocol: 1 -((3-iodo-1 -methyl-1 H-pyrazol-4-yl)methyl)-1 H-imidazole-4-carbonitrile / z z' \ íj z A 0 A z m / z (ESI): 314 [M+H] 1 -((2-chloro-5-fluoropyridin-3-yl)methyl)-1 H-imidazole-4-carbonitrile i T + I 0 y A m / z (ESI): 237 [M+ H] 1 -[(dibromo-1,3-thiazol-5-yl)methyl]-1 H-imidazole-4-carbonitrile _ V Bry-N N= + ΗΟ JA T~Br * N=—N Jl Άβγ m / z (ESI): 347 [M+H] Synthesis of 1-(4-fluoro-2-iodophenyl)-1H-pyrazole-3-carbonitrile F To a stirred flask of concentrated H2SO4 (25 ml) NaNO2 (2.93 g, 42.5 mmol) was added at 0 °C in several portions. The mixture was heated to 50 °C and stirred at this temperature for 1 h. This nitrite mixture was cooled to 0 °C and set aside. Separately, concentrated H2SO4 (3.97 g, 40.5 mmol) was added to a solution of 4-fluoro-2-iodoaniline (9.60 g, 40.5 mmol) in AcOH (40 mL) at temperature atmosphere. This solution was added dropwise to the original nitrite mixture at 0 °C. After the addition was complete, the mixture was heated at 50 °C for 1 h. The reaction mixture was added to a suspension of ethyl 2,3-dicanopropanoate (9.24 g, 60.8 mmol) and anhydrous NaOAc (49.82 g, 607.6 mmol) in H2O (100 mL) at 5 °C. After stirring for 15 h at 15 °C, the reaction mixture was diluted with water and extracted with DCM (250 mL). The organic layer was stirred vigorously with 30% aqueous NH40H solution (150 mL) for 2 h. The organic phase was separated, dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography (0->70% EtOAc in PE) to give 5-amino-1-(4-fluoro-2-iodophenyl)-1 H-pyrazole3-carbonitol (11 g, 83%) as a solid brown. LC / MS ESI (m / z): 329 [M+H]+ A solution of 5-amino-1-(4-fluoro-2-iodophenyl)-1 H-pyrazole-3-carbonitrile (12.0 g, 36.6 mmol) and isopentyl nitrite (12.8 g, 110 mmol ) in THF (150 ml) at 25 °C was heated to 70 °C and stirred for 166 h. The reaction was diluted with EtOAc. The resulting mixture was washed with H2O and then with brine. The organic layer was dried over anhydrous Na2SÜ4. After filtration, the filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography, eluted with PE / EA (0^20%) to give 1-(4-fluoro-2-iodophenyl)-1 H-pyrazole-3-carbonithlo (6, 0 g, 52% yield) as a clear oil. LC / MS ESI (m / z): 314 [M+H]+ Synthesis of 1 -(4-fluoro-2-iodophenyl)-1 H-pyrazole-5-carbaldehyde [(1 E)-4,4-dimethoxy-3- oxobut-1-en-1-¡l]dimethylamin (2.82 g, 16.3 mmol). The resulting mixture was heated at reflux for 48 h and then concentrated. To a solution of the crude residue in acetone (50 ml) was added 6 N HCl (10 ml). The resulting solution was stirred at room temperature for 30 min and then partitioned between ethyl acetate and water. The organic extract was washed with water, saturated sodium bicarbonate solution and brine, and then dried over anhydrous sodium sulfate. The residue was concentrated to dryness to give crude 1-(4-fluoro-2-iodophenyl)-1H-pyrazole-5-carbaldehyde (4.50 g, yield: 88%) as a black oil. LC / MS (ESI) m / z: 317 [M+H]+. The following intermediates were synthesized using a similar experimental protocol: Ethyl 1-(4-fluoro-2-iodophenyl)-3-methyl-1 H-pyrazole-5-carboxylate m / z (ESI): 375 [M+H] 5-((5-bromo-1 -ethyl-1 H-pyrazole-4-yl)methyl)-1 -(4-fluoro-2-iodophenyl)-1 H-pyrazole-4-carbonitrile Synthesis of 3,5-difluoro-2-iodo-N-methoxy-N-methylbenzamide A mixture of 3,5-difluoro-2-iodobenzoic acid (11.3 g, 39.8 mmol), EDCI (9.92 g, 51.7 mmol), 167 HOBt (6.99 g, 51.7 mmol), methoxy(methyl)amine (2.92 g, 47.9 mmol) and DIPEA (15.40 g, 119.4 mmol) in DMF (40 mL) were stirred. at room temperature for 2 h. The mixture was concentrated, diluted with EA (80 ml) and washed with saturated NaHCOs solution (40 ml x 3). The combined organic layers were separated, washed with brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by flash column chromatography on silica gel to give 3,5-difluoro-2-iodo-N-methoxy-N-methylbenzamide (12 g, 92%) as a light yellow solid. LCMS (ESI): m / z 328 [M+H]+. Synthesis of (5-cyclobutyl-1-methy 1-1 H-pyrazol-3-yl)methanol To a solution of ethyl 5-cyclobutyl-1-methyl-1 / 7-pyrazole-3-carboxylate (4.20 g, 20.2 mmol) in THF (40 ml) was added hydride of diisobutylaluminum (33.6 ml, 50.4 mmol, 1.5 M in THF) dropwise at -78 °C. The mixture was stirred at -78 °C for 1 h. After 1 h, the reaction mixture was diluted with EA (20 mL), then water (2 mL), NaOH aqueous solution (15%, 2 mL), and water (5 mL) were added in sequence at 0 °C. . After warming to room temperature, anhydrous MgSO4 was added and stirring was continued for 15 min. The mixture was filtered and the filtrate was concentrated in vacuo to give crude (5cyclobutyl-1-methyl-1 / - / -pyrazol-3-yl)methanol (2.86 g, 85%) as a yellow oil. LC / MS ESI (m / z): 167 [M+H]+. The following intermediates were synthesized using a similar experimental protocol: (5-bromo-1 -(2,2-dif luoroeti I)-1 H-pyrazol-4-yl)methanol Br Br m / z (ESI): xs-X ----► N xy— F N= / °^\ f N= / 0H 241 [M+H] Synthesis of (3-ethylisoxazol-5-yl)methanol To a solution of 3-ethyl-5-[(oxan-2-¡lox¡)methyl]-1,2-oxazole (17.4 g, 82.4 mmol) in MeOH (10 ml) was added added Amberlyst 15 (26 mg, 83 mmol). The mixture was stirred vigorously at 45 °C for 6 h. Filtration and removal of the solvent in vacuo gave a red residue, which was purified by silica gel column chromatography (15^30% EtOAc in PE) to give (3-ethyl-1,2-oxazol-5¡l) 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: 168 (3-(cyclopropylmethyl)¡soxazol-5-¡l)methanol oz T 0 m / z (ESI): 154 [M+H] (3-(2,2-difluoroethyl)isoxazol-5-yl )methanol or I 0 ξ· m / z (ESI): 164 [M+H] IVIA / t / ZUZÓ / UUÓ+U I Synthesis of 3-(bromomethyl)-5-(cyclopropylmethyl)-1 -methyl-1 H-pyrazole To a stirred solution of (5-(cyclopropylmethyl)-1-methyl-1 H-pyrazol-3-yl)methanol (410 mg, 2.47 mmol) in DCM (10 mL) was added dropwise a solution of phosphorus tribromide (2.00 g, 7.40 mmol) in DCM (5 mL) at 0 °C in N2. The reaction was stirred at 0 °C for 2 h, washed with saturated NaHCO3 solution (30 ml), dried over anhydrous Na2SO4 and evaporated to dryness. The residue was purified by column chromatography on silica gel eluted with ΡΕ / EtOAc (9:1^4:1) to give 3(bromomethyl)-5-(cyclopropylmethyl)-1-methyl-1 H-pyrazole ( 285 mg, 50% yield) as a yellow oil. LC / MS (ESI) (m / z): 229 [M+H]+. Synthesis of 5-((2-chloropyridin-3-yl)methyl)-1-methyl-1 H-pyrazole-3-carbonitrile ci + HO. OH To a solution of 3-(bromomethyl)-2-chlorophdine (2.07 g, 10.1 mmol), (3-cyano-1-methyl-1Hpyrazol-5-yl)boronic acid ( 1.52 g, 10.0 mmol), Pd(PPh3)4 (0.81 g, 0.70 mmol) in toluene (20 mL) and EtOH (4 mL), Na2CO3 (2.13 g, 20.1 mmol). The reaction was degassed three times with N2 and then stirred at 100 °C overnight. The mixture was cooled to room temperature, filtered and concentrated in vacuo. The residue was purified by flash chromatography (0^50% EtOAc in PE) to give 5-((2-chloropihdin-3-yl)methyl)-1-methyl-1 / - / -pyrazole-3-carbonitrile (675 mg , 29%) as a yellow solid. LC / MS ESI (m / z): 233 [M+H]+. The following intermediates were synthesized using a similar experimental protocol: 5-((2-chloro-5-fluoropyridin-3-yl)methyl)-1 -methyl-1 H-pyrazole-3-carbonitrile 169 F λν J / N Cl B; HO I Cl | m / z (ESI): 251 [M+H] 4-bromo-3-((2-chlorop¡ñdin-3-yl)methyl)-1-methyl-1 H-pyrazole-5-carbonitrile i| Ί N-n ΗΟ.βΑ^Ν + Cl Br Br C| m / z (ESI): 311 [M+H] 5-(2-bromobenzyl)-1 -methyl-1 H-pyrazole-3-carbonitrile z / / / z^\ 4 / \ I O Ó I + ώ m / z (ESI): 276 [M+H] 5-((3-(2-bromo-4-fluorophenyl)isothiazol-4-¡l)methyl)-1-methyl-1 H-pyrazole-3 -carbonitrile ,sv HO· _Λν ”'n n yy x m / z (ESI): 377 [M+H] Synthesis of (5-bromo-1-cyclobutyl-1 H-pyrazol-4-yl)methanol Br At -60 °C, to a solution of ethyl 5-bromo-1-cyclobutyl-1H-pyrazole-4-carboxylate (1.9 g, 7.0 mmol) in THF (20 ml), added DIBAL-H (1 M in toluene, 20.9 mL, 20.9 mmol) dropwise at −60 °C. Then, the mixture was stirred at 0 °C for 3 h. The reaction mixture was diluted with EA (20 ml) and water (1 ml) and then 15% sodium hydroxide solution (1 ml) and water (2.5 ml) were added sequentially. After warming to room temperature, anhydrous magnesium sulfate was added and stirring was continued for 15 min. The resulting mixture was filtered, the filtrate was washed with saturated aqueous NH4Cl solution and brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (0^10% EtOAc in PE) to give (5-bromo-1-cyclobutyl-1H-pyrazol-4-l)methanol (1.6g , 15%) as a light yellow oil. LC / MS ESI (m / z): 231 [M+H]+. Synthesis of 3-(benzyloxy)-5-bromo-1-ethyl-1 H-pyrazole 170 To a stirred solution of 3-(benzyloxy)-1-ethyl-1 H-pyrazole (11.5 g, 56.9 mmol) in THF (200 mL) was added n-BuLI (27.3 mL, 68 .3 mmol, 2.5 M in THF) at - 78 °C in N2. After stirring at -78 °C for 1 h, a solution of CBr4 (22.6 g, 68.2 mmol) in THF (50 ml) was added. The reaction was stirred at −78 °C for an additional 1.5 h, then quenched with saturated NH4Cl solution (50 mL) and concentrated in vacuo. The residue was purified by flash chromatography (0^25% ​​EtOAc in PE) to give 3-(benzyloxy)-5-bromo-1-ethyl-1H-pyrazole (8.3 g, 52% yield) as a yellow oil. LC / MS ESI (m / z): 281.0 [M+H]+. The following intermediates were synthesized using a similar experimental protocol: (R)-3-chloro-1-(4-fluoro-2-(1-((4-methoxybenzyl)ox¡)ethyl)phen¡l)-1 H-pyrazole-5-carbaldehyde o n o vx o + I m / z (ESI): 389 [M+H] (R)-1 -(2-(1 - (benzi loxi) eti l)-4-f I u orof en i l)-3-(dif I uorometi I) -1 H-pyrazole-5-carbaldehyde I + / ° or QA or m / z (ESI): 375 [M+H] F Synthesis of (3-bromo-1-methyl-1H-pyrazol-4-yl)(5-ethylisoxazol-3-yl)methanone To a stirred solution of 3-bromo-4-iodo-1-methyl-1 H-pyrazole (500 mg, 1.74 mmol) in THF (10 mL) was added ¡-PrMgBr (2.1 mL, 2. 1 mmol, 1 M in THF) at 0 °C in N2. After stirring at 0 °C for 1 h, a solution of 5-ethyl-N-methoxy¡-N-methyl-1,2-oxazole-3-carboxamide (360 mg, 1.95 mmol) in THF (2 mL). The reaction was stirred at 0 °C for an additional 1 h, then quenched with saturated NH4CI solution (10 mL) and extracted with EtOAc (30 mL x 2). The combined organic phases were washed with brine (20 mL), dried over anhydrous Na2SO4, and concentrated. He 171 residue was purified by silica gel column chromatography (25% EtOAc in PE) to give 3(3-bromo-1-methyl-1 H-pyrazole-4-carbon¡l)-5-ethyl-1 ,2-oxazole (400 mg, 77% yield) as a yellow oil. LC / MS (ESI) (m / z): 284.3 [M+H]+. Synthesis of 2-bromo-3-((4-ethyl-1 H-1,2,3-triazol-1-¡l)methyl)-5-fluorop¡ridina MA / t / ZUZÓ / UUÓ+U Ί To a solution of 1-butyne (ca. 0.2 M, 12 ml) was added 3-(azidomethyl)-2-bromo-5-fluoroprídina (350 mg, 1.52 mmol) and Cul (57 mg, 0.30 mmol). The mixture was stirred at room temperature for 1 h and then filtered through celite. The filtrate was concentrated in vacuo to obtain a residue, which was purified by silica gel column chromatography (PE:EA = 10:1 to 3:1) to give 2bromo-3-[(4-ethyl-1 H- 1,2,3-triazol-1 -iI)methyl]-5-fluoropyridine (130.0 mg, 30% yield) as a white solid. LC / MS (ESI): m / z = 285 [M+H]+. Synthesis of (3-bromo-1 -methyl-1 H-pyrazol-4-yl)(3-ethyl!soxazol-5-!l)methanol OH To the mixture of 3-bromo-4-iodo-1-methyl-1 H-pyrazole (1.43 g, 4.98 mmol) in THF (10 mL) was added isopropylmagnesium bromide (1 M in THF, 5. 48 mL, 5.48 mmol) slowly in N2 at 0 °C. The mixture was stirred at 0 °C for 1 h. To this mixture, a solution of 3-ethylisoxazole-5-carbaldehyde (0.62 g, 5.0 mmol) in dry THF (3 ml) was added dropwise at 0 °C for 10 min and the resulting mixture was stirred at 0 °C for 1 more h. The reaction mixture was quenched with ice water and then extracted twice with EtOAc. The combined extracts were concentrated and the residue was purified by silica gel column chromatography (PE:EA = 3:1) to give (3-bromo-1 -methyl-1 Hpyrazol-4-yl)(3-et! lisoxazol-5-yl)methanol (900 mg, yield: 63%) as a yellow oil. LC / MS ESI (m / z): 286 [M+H]+. The following intermediates were synthesized using a similar experimental protocol: (5-bromo-1 -ethyl-1 H-pyrazol-4-yl)(5-iodo-1 -methyl-1 H-pyrazol-4-yl)methanol 1 ’z 1 0 \\ rC ’z 1 + m / z (ESI): 411 [M+H] 172 Br Br Br OH Br z—N+ θ^Ιί^ι ' / -N.Y^N m / z (ESI): 360 [M+H] (3-bromo-1 -methyl-1 H-pyrazol-4-yl) (3-ethyl-1 -methyl-1 H-pyrazol-5-yl)methanol W X i Λ · XjN -- nM MN ,N V- V- ' / m / z (ESI): 299 [M+H] 5 -[(dibromo-1,3-thiazol-5-yl)(h idroxy)methyl]-1 -methyl-1 H-pyrazole-3-carbonitrile I D or HO I , N Br ') Br L Nvs Vs 'xx X T r x> N Br Br N m / z (ESI): 377 [M+H] (3-chloro-1 -ethyl-1 H-pyrazol-4-yl)(3-iodo-1 -methyl-1 H-pyrazole -4-yl)methanol C! 0 HO ? v > k XA V-N N Jj N Y ΰ-Ν -yl)(5-iodo-1 -methyl-1 H-pyrazol-4-yl)methanol Br I I OH Br Z\ / ^z^-p, ____ X^zYY\ Z\ [ .N XZ + ~N J ° ' —N J \ N—% / m / z (ESI): 437 [M+H] 5-((3-bromo-1-methyl-1 H-pyrazol-4-íl)(hydroxy)methyl)ísoxazole -3-carboxylate ethyl A? — + o 4 οΛ° I z 2—0 / T A ° m / z (ESI): 330 [M+H] (3-(benzyloxy)-5-bromo-1 -ethyl-1 H-pyrazol-4-yl )(3-iodo-1 -methyl-1 H-pyrazol-4-yl)methanol 173 + / z-\ Λ# or u? ' r¿L m / z (ESI): 517 [M+H] [5-bromo-1 -(cyclopropylmethyl)-3-methyl-1 H-pyrazol-4-yl](5-chloro- 3-iodo-1 -methyl-1 H-pyrazol-4-yl)methanol Br a ,CI jf PH Cl A Y=\ + t yyX je,-N < / n=< iz n~ N I^N \ / N \ ,Λν m / z (ESI): 485 [M+H] (3-ethyl-1 -methyl-1 H-pyrazol-5-yl)(1 -(4-fluoro-2-iodophenyl)-3-methyl- 1 H-pyrazol-5-yl)methanol F F I H° , kj / / =0 ____. >—< ΐ π + yr / yr / n,n N-N I Λ I / m / z (ESI): 441 [M+H] (5-bromo-1 -ethyl-1 H-pyrazole-4-¡l) (3-iodopirid¡n-4-¡l)methanol Br I Br OH | / ^Ν. J + yfp m / z (ESI): 408 [M+H] (5-bromo-1 -ethyl-1 H-pyrazol-4-yl)( 1 -(4-fluoro-2-iodophenyl)-1 H- imidazole-5-¡l)methanol TV z -z + Or” jl z íl o Or” i L z CyA / ti z z m / z (ESI): 491 [M+H] (3-bromo-1 -methyl-1 H-pyrazol-4-yl) (1 -ethyl-3-methyl-1 H-pyrazol-4-yl)methanol Br 1 O( 1 Br HO. v * — yrXr_ / / N m / z ( ESI): 299 [M+H] (1 -ethyl-1 H-pyrazol-4-yl)(3-iodo-1,5-d ¡methyl-1 H-pyrazol-4-yl)methanol 174 I z x z\ oV x- X z z I z Ay \\ o + (5-ethyl-1,2-thiazol-3-yl)methanol l z / 'z T / “X O— / oo / xz / i A m / z (ESI): 302 [M+H] (2- chloropyridin-3-yl)(1 -(cyclopropylmethyl)-1 H-1,2,3-triazol-4-l)methanol yz 2 >\ ó A z^ z o + A z-^ m / z ( ESI): 265 [M+H] (3-bromo-1-methyl-1 H-pyrazol-4-yl)(3-ethylisothiazol-5-yl)methanol °H \ n— + / — bAn n's n-s An' Br m / z (ESI): 302 [M+H] (2-chloropyridín-3-¡l)(1 -(cyclopropylmethyl)-3-methyl-1 H-pyrazol-4-yl) methanol o\ o A -Z.-1 o / / ολΟ z-7 + ^z m / z (ESI): 278 [M+H] (1 -(2-((R)-1 -(benzyloxy)ethyl) -4-f luorophenyl)-3-(dif luorometi I)-1 H-pyrazol-5-yl)(1 -ethyl-3-methoxy-1 H-pyrazol4-¡l)methanol φ o x i 'ύ—( ° \ \ / / x z-z ? o íl o + T / \ ¡i Z.-Z m / z (ESI): 501 [M+H] 175 (3-bromo-1 -eti I-1 H-pyrazol-4-yl)(3-iodo-1 -methyl-1 H-pyrazol-4-yl)methanol Br or HO Br '—N ν Π N J '— n X--- N N 1 H-pyrazol-4-yl)methanol BI, ΐ Br OH A N· J / + ,N ----- NJlVN ; / m / z (ESI): 313 [M+H] (3-bromo-1 -(difluoromethyl)-l H-pyrazol-4-yl) (1 -(cyclopropylmethyl)-1 H-pyrazol-4-yl) methanol Γ N —( + _ / ° _____► / F Br 'N F A Ν' b m / z (ESI): 347 [M+H] (3-bromo-1 -methyl-1 H-pyrazol-4-yl)( 1 -isobutyl-1 H-pyrazole-4-¡l)methanol z^ / z yj Ί- Ο / / CD n z I z I m / z (ESI): 313 [M+H] (3-bromo-1 - (4-fluoro-2-iodophenyl)-1 H-pyrazol-5-yl)( 1 -ethyl-1 H-pyrazol-4-yl)methanol F F HO 1 .0 1 Br Br m / z (ESI): 491 [M+H] (dibromo-1,3-thiazol-5-yl)(1 -ethyl-1 H-pyrazol-4-yl)methanol T / “N O—¿ CD \ z Z' ω o + h z^ m / z (ESI): 368 [M+H] 176 5-((1 -(4-fluoro-2-iodophenyl)-3-methyl-1 H-pyrazol-5-yl)(hydroxy)methyl)-1 -methyl-1 H-pyrazol-3-carbonitrile F F m / z n / / > 140 YA / =° ___► YA (ESI): V t / W / n'n 438 [M+H] 3-((5-bromo-1 -methyl-1 H-pyrazol-4-yl ) (hydroxy)methyl)-1 -((2-(trimethylsilyl)ethoxy¡) methyl I)-1 H-pyrazole-5- carbaldehyde I ς 21 b l) o ° ω m / z (ESI): ν=Α + V n ,θΑΛ / W' 1 ' 7 -ethyl-5-iodo-1 H-pyrazol-4-yl)methanol m / z r^N — N .1 + q N—« / ______► \ (ESI): / 1^ / g Br । Br OH 1 411 [M+H] (3-bromo-1 -methyl-1 H-pyrazol-4-yl) (5-(cyclopropylmethyl)-1 -methyl-1 H-pyrazol-3-yl)methanol ! HO -n7} + oAity ____ \ m / z (ESI): N^Br N~N\ —N· A N-N V? N Br 325 [M+H] Synthesis of 5-bromo-4-((1-ethyl-1H-1,2,3-triazol-4-yl)methyl)isothiazole To a solution of (5-bromoisothiazol-4-yl)(1-ethyl-1H-1,2,3-triazol-4-yl)methanol (60 mg, 0.20 mmol) in TFA (3 ml) added TES (193 mg, 1.60 mmol). The mixture was heated to 70 °C and stirred for 2 h. The reaction mixture was concentrated, diluted with saturated NaHCOs solution and extracted with EtOAc. The combined organic phases were washed with brine, dried over anhydrous Na2SÜ4, filtered and concentrated. The residue was purified by flash chromatography (silica gel, 0^40% EA in PE) to give 5-bromo-4-((1-ethyl-1 H-1,2,3-triazol-4-yl)methyl Sotazol (50 mg, 88% yield) as a yellow oil. LC / MS (ESI) m / z: 273 [M+H]+ 177 The following intermediates were synthesized using a similar experimental protocol: 4-((1 -(cyclopropylmethyl)-1 H-pyrazol-4-yl)methyl)-3-iodo-1 -methyl-1 H-pyrazole N___A A I —- -cr r OH m / z ( ESI): 343 [M+H] 3-bromo-4-((3-ethyl-1 -methyl-1 H-pyrazol-5-yl)methyl)-1 -methyl-1 H-pyrazole U =' - NJpN —* VTYn __ / N __ / N \ \ m / z (ESI): 283 [M+H] 5-[(dibromo-1,3-thiazol-5-yl)methyl]-1 -methyl-1 H-pyrazole-3-carbonitrile Br N Br N L. ' / / L ' / / X _ ,ν ,n Br ' N Br N HO I I m / z (ESI): 361 [M+H] 3-chloro- 1-ethyl-4-((3-iodo-1 -methyl-1 H-pyrazole-4-¡l)methyl)-1 H-pyrazole α OH , ? I N N— Ü n—' [I ,N __ / N __ / N \ \ m / z (ESI): 351 [M+H] 2,4-dibromo-5-((3-ethyl-1 -methyl-1 H-pi razol-5-yl)methyl)thiazole 1 °H Br ' Br ,Ν. 1, ,N. , N ¡F -yl)methyl)-1 H-pyrazole Br OH Br Λ'Ν7] (.Ν' ---- ·Ν~ ' |A=N ' m / z (ESI): 395 [M+H] ΜΛ / t / ZUZJ / UUJ+U Ί 178 1 -ethyl-4-((3-iodo-1 -methyl-1 H-pyrazol-4-yl)methyl)-1 H-1,2,3-triazole / z O~< T- z y z 1 fi z 1 m / z (ESI): 318 [M+H] 5-((3-iodo-1 -methyl-1 H-pyrazol-4-yl)methyl)-1 -methyl-1 H-pyrazol-3-carbonitrile N. Λ / / . Xj) <, ν, n 1 / n 1 n Ho 1 1 m / z (ESI): 328 [m+h] 3-iodo-1 -Methyl-4-((1-(2,2,2-trifluoroethyl )-1 H-pyrazole-4-yl)methyl)-1 H-pyrazole I z 0 0 - / \T \ / zn X .z z m / z (ESI): 371 [M+H] 1-(cyclopropylmethyl) )-4-((3-iodo-1 -methyl-1 H-pyrazol-4-yl)methyl)-1 H-1,2,3-triazole i I ZZ\ \ I X / 0 0 'z I m / z (ESI): 344 [M+H] 5-bromo-1 -(cyclopropylmethyl)-4-[(3-iodo-1 -methyl-1 H-pyrazol-4-yl)methyl]-3-methyl -1 H-pyrazole I OH I Pn ' Pn Br Br I 1 m / z (ESI): 435 [M+H] 5-bromo-4-((5-chloro-3-iodo-1-methyl-1 H -pyrazol-4-yl)methyl)-1 -(cyclopropylmethyl)-3-methyl-1 H-pyrazol Br OH Br Á Ϊ Cl X Cl V n=< Λ -N- v n=\ L -N- \ ι^Ν v -2-iodophenyl)-1 H-1,2,3-triazole 179 -,Ν -K é'A- - Ay- m / z (ESI): 476 [M+H] 5-((5-bromo-1 -ethyl-1 H-pyrazol-4-yl)methyl)-1 -(4-fluoro-2-iodophenyl)-1 H-pyrazole-3-carbonitrile F F A «O I A 1 nA nA III lll Ν N m / z (ESI): 500 [M+H] 4-bromo-3-ethyl- 5-((1 -(4-fluoro-2-iodophenyl)-3-methyl-1 H-pyrazol-5-yl)methyl)-1 -methyl-1 H-pyrazole \__ Br F\__ Br Q Q । rN । R Na / ' N^ / ' m / z (ESI): 503 [M+H] 4-((5-bromo-1 -ethyl-1 H-pyrazole-4-¡l)methyl)-3- iodopyridine Br OH | Br I |ίη ' m / z (ESI): 392 [M+H] 4-bromo-3-((5-bromo-1 -ethyl-1 H-pyrazol-4-yl)methyl)pyridine Br OH Br Br Br / Iij * / —N ιι^Ί m / z (ESI): 344 [M+H] 5-((5-bromo-1 -ethyl-1 H-pyrazole-4-¡l)methyl)pyrimidin-4 -ol Br OH Cl Br OH 7~~ Ai N * Ν. / |Γ ϊί Η N~ N m / z (ESI): 283 [M+H] 180 5-bromo-3-(1-(2-(5-((5-bromo-1-ethyl-1 H-pyrazol-4-¡l)methyl)-1 H-pyrazol-1 -yl)- 5-fluorophenyl)ethoxy¡ )-2nitropyridine F F JO JO Ο'.Λ.Ο |> ?H Br Ο'.,ί.Ο Τ' Br N 1 n A J ______► N 1 N ^x / Br Br m / z (ESI): 593 [M+H ] 5-bromo-3-((2-(5-((5-bromo-1 -ethyl-1 H-pyrazol-4-yl)methyl)-1 H-pyrazol-1 -yl)-5- f luorobenzyl)ox¡)- 2- nitropyridine °·-ν*° or ?H and ___. °+° A y Άκ0 ν' N\ Ai N\ NO O V Br Br m / z (ESI): 579 [M+H] 5-bromo-3-(1-(2-(5-((5-bromo -1-ethyl-1 H-pyrazol-4-yl)methyl)-4-fluoro-1 H-pyrazol-1-yl)-5 fluorophenyl)ethoxy)-2-nitropyrdina F F JO JO θ-ί° Τ' ?H ?r O-Br Az Nx / / Ον-λ Vv Na T r N-a N π 'L-U. · \ N Π V—-< lír · \ . Π KF . U 'F X Br Br m / z (ESI): 611 [M+H] 5-bromo-3-((2-(5-((5-bromo-1 -ethyl-1 H-pyrazol-4-yl)methyl)-4-f luoro-1 H-pyrazol-1 -yl)- 5fluorobenzyloxy)-2-nítropírídina 181 2-chloro-3-((1 -ethyl-1 H-1,2,3-triazol-4-¡ I) methyl)-5-f luoropyridine Ya ó / n A z z * z o o y° π Λ z. z ^z m / z (ESI): 241 [M+H] 3-chloro-1-ethyl-4-((1-(4-fluoro-2-iodophenyl)-3-methyl-1 H-pyrazole-5- ¡l)methyl)-1 H-pyrazole i c' i N Y c' λ~- / \ Ά N ----► λ—( \ N \ A \ A k^Z n<J \^z ​​Xx**^ F F m / z (ESI): 445 [M+H] 4-[(dibromo-1,3-thiazol-5-yl)methyl]-1 -ethyl-1 H-1,2,3-triazole Br .. . x N=N y” A A / “Br OH m / z (ESI): 351 [M+H] 3-bromo-4-((3-chloro-1 -(2,2-difluoroethyl)-1 H- pyrazol-4-yl) met I)-1 -methyl-1 H-pyrazole ' F ' F N / ) \ N / 7 \ JT^· F y-A / T^ F BrVVN n° Cl Cl m / z (ESI): 339 [M+H] 4-[(3-bromo-1 -methyl-1 H-pyrazol-4-yl)methyl]-1 -(2,2-difluoroethyl)-3-methyl-1 H-pyrazole ' F ' F N. A N. A N / ) \ N / 7 \ y-A JT N F ----► y-A F bFVV βΓ^^ ΗΟ ¡ I m / z (ESI): 319 [M+H] 3-bromo -1 -(difluoromethyl)-4-[(1 -ethyl-1 H-pi razol-4-yl)methyl]-1 H-pyrazole i z m / O Ó •Z. m / z (ESI): 305 [M+H] 182 3-[(3-bromo-1-methyl-1 H-pyrazol-4-yl)methyl]-5-ethyl-1,2-thiazole. S-N Br\^N Br η Γ N— _____„ \ S-N >N· OH m / z (ESI): 286 [M+H] (R)-1 -(2-(1 - (benzyloxy) ethyl) -4-f I orof en i I )-5-( (1 - (cyclopropi I metí I) -1 H-pyrazole I-4-i I) metí I )-3(trifluoromethyl)-1 H-pyrazole F F ' Νϊ / Vn Vo^~V / \í-n \^N F-?k F-?k F F F F m / z (ESI): 499 [M+H] 1 -ethyl-4-((3-iodo- 1 -methyl-1 H-pyrazole-4-yl)methyl)-3-(trifluoromethyl)-1 H-pyrazole FVF HO । FVF 1 F \ k A F \ f / X -N ---- ηΎ -N N. jj V-N N j] \Ln ^N \ m / z (ESI): 385 [M+H] 2-chloro-3- {[1 -(cyclopropylmethyl)-1 H-1,2,3-triazol-4-yl]methyl}-5-f luoropyridine J O o \ Γ T / z'z ( — m / z (ESI) : 267 [M+H] 1 -(cyclopropylmethyl)-4-[(dibromo-1,3-thiazol-5-yl)methyl] -1 H-1,2,3-triazole N^Br K Rr Rr- / Π N=N / > N^Br kl K OH m / z (ESI): 377 [M+H] 2-chloro-3-((1 -(cyclopropylmethyl)-1 H-1,2, 3-triazol-4-yl)methyl l)pyridine 183 m / z (ESI): 249 [M+H] MA / IZ / ¿U¿O / UUO4m (R)-4-((1 -(2-(1 -(benzyloxy)ethyl)-4-f luorophenyl)-3-(dif luoromethyl)-1 H- pyrazol-5-yl)methyl)-1 (cyclopropylmethyl)-1 H-1,2,3-triazole m / z (ESI): 482 [M+H] (R)-1 -(2-(1 -(benzyloxy)ethyl)-4-fluorophenyl)-5-((1 -(cyclopropylmethyl)-3-methyl-1 H-pyrazol-4-yl )methyl)-3(dif luorometi I)-1 H-pyrazole 2,4-dibromo-5-{[1 -(cyclopropylmethyl)-3-methyl-1 H-pyrazol-4-i l]methyl}-1,3-thiazole (R)-1 -(2-(1 - (benzyloxy) ethyl)-4-f I u orof en i I )-5-( (1 - (cyclopropi I metí I) -1 H-pyrazo I- 4-i I) methi I )-3(dif luoromethyl)-1 H-pyrazole 3-bromo-4-{[3-chloro-1-(cyclopropylmethyl)-1 H-pyrazol-4-yl]methyl}-1 -methyl-1 H-pyrazole 184 HO? Cl B; Χζχ n By~y—N n3 * νΠ N N / 1 m / z (ESI): 329 [M+H] 2-chloro-3-((1 -(cyclopropylmethyl)-3-methyl-1 H-pyrazole-4 -yl)methyl)pyridine Cl Cl Ό / =ñ v7 XJ / n m / z (ESI): 262 [M+H] (R)-1 -(2-(1 -(benzyloxy)ethyl)- 4-fluorophenyl)-3-(difluoromethyl)-5-((1 -ethyl-3-methoxy-1 H-pyrazol-4-yl)methyl )1 H-pyrazole F F ^X OH n^< >o^o n^ < y>o^o O -pyrazol-4-yl)methyl)pyridine Cl H° Cl 0 \=„ > O V m / z (ESI): 248 [M+H] 3-bromo-4-{[1 -ethyl-3-(propan- 2-yl)-1 H-pi razol-4-yl]met¡ I}-1 -methyl-1 H-pyrazole Br OH Br N. JlpN ' N· jXXt'.N N '-n N '-n 7 X 7 m / z (ESI): 311 [M+H] 3-((3-bromo-1 -methyl-1 H-pyrazol-4-yl)methyl)-5-ethylísoxazole. O-N ΒΓγχΝ Br .. Vx η Γ N- ____„ \ O-N >^N. \ΛγΑ / * \ ó Jí k^N — OH m / z (ESI): 270 [M+H] 185 4-((3-bromo-1 -methyl-1 H-pyrazol-4-yl)methyl)-1 -ethyl-1 H-pyrazol-3-carbonitrile \ r~ \ r~ N—. ,Ν-η Νχ II / í ZN --------► Νχ II / / z N Br OH \\\ Br \\\ Ν N m / z (ESI): 294 [M+H] 5- bromo-3-((2-(5-((1 -ethyl-1 H-pyrazol-4-yl)methyl)-3-methyl-1 H-pyrazol-1 -yl)-5-fluorobenzyl)ox ¡)- 2- nitropyridine F F Ó n- ΖΊ ?H n- -° ΖΛ T ¿ ,ΝγΑ ---► f 0 Z^z Νκ II | N—\ Yz N ll 1 N—\ N jj A A -ethyl-1 H-pyrazol-4-yl)methyl)-3-f luoro-1 H-pyrazol-1 -yl)-5-f luorophenyl)ethoxy)-2nitropyridine F F Οι Oí OH Γγ o. H.O 0- ^0“ A / N ' 'No N 1 -N+'U and aunt and Br Br m / z (ESI): 533 [M+H] 5-bromo-3-((2-(3- chloro-5-((1 -ethyl-1 H-pyrazol-4-yl)methyl)-1 H-pyrazol-1 -yl)-5-fluorobenzyl)ox¡)-2nitropyridine Λ A o I · O Ví / T / ° \ o o “ Η i ' o m / z (ESI): 535 [M+H] 3-bromo-5-((1 -ethyl-1 H-pyrazol-4-yl)methyl)-1 -(4- fluoro-2-iodophenyl)-1 H-pyrazole 186 F F <x j] X—{N <X / / N Λ\. / -1,3-thiazole N^, BV\ Br VnX X'^Br ---. \ S '— NK 1· z Br T \ZXWs OH m / z (ESI): 352 [M+H] 5-((1-(4-fluoro-2-iodophenyl)-3-methyl-1H-p¡ razol-5-¡l)methyl)-1-methyl-1 H-pyrazole-3-carbonitrile F F / X HO / X v# >—c __► M / —v Τ' N—( N'N r' N ~( N'N 1 3 ' 1 3 > m / z (ESI): 422 [M+H] 3-((5-bromo-1 -methyl-1 H-pyrazol-4-yl)methyl)-1 H -pyrazole-5-carbonitrile h \ r n~n . r=\ \=j _____► ___ / . u L N— / \ N ' Br ' ' OH Br m / z (ESI): 266 [M+H] 3- bromo-4-((3-(2,2-difluoroethyl)-1 -methyl-1 H-pyrazol-5-yl)methyl)-1 -methyl-1 H-pyrazole ' F ' F N. __ / N. ___ / N Η / \ N / ) / \ y—( f * y—\ f Br N'N Br n'N HO | | m / z (ESI): 319 [M+H] 3-bromo-4- ((3-(cyclopropylmethyl)-1-methyl-1 H-pyrazol-5-yl)methyl)-1 -methyl-1 H-pyrazole HO ' i V ΛΖ'Ν BL z-Z'N N N / / m / z (ESI): 309 [M+H] Synthesis of 4-bromo-5-((4-(difluoromethyl)-1 H-pyrazol-1-yl)methyl)-2-methylthazole 187 A solution of 1 -((4-bromo-2-methylthiazol-5-yl)methyl)-1 H-pyrazole-4-carbaldehyde (580 mg, 2.03 mmol) in DAST (5 ml) was stirred at 30 °C for 12 h in N2. The reaction was quenched with saturated aqueous NaHCOs solution (50 ml) at 0 °C and then extracted with EtOAc (15 ml). The organic phase was dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (10^25% ​​EtOAc in PE) to give 4-bromo-5-((4-(difluoromethyl)-1 H-pyrazol1-¡l)methyl)-2- methylthiazole (426 mg, 68% yield) as a yellow oil. LC / MS (ESI) (m / z): 308 [M+H]+. Synthesis of 3,5-difluoro-2-iodobenzaldehyde F To a solution of 3,5-difluoro-2-iodo-N-methoxy-N-methylbenzamide (8.00 g, 24.5 mmol) in THF (60 mL) at -78 °C was added dropwise DIBAL-H (36.7 mL, 39.7 mmol, 1.0 M) in N2 atmosphere. After addition, the mixture was stirred at 0 °C for 2 h. The mixture was quenched with ice water and then 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 flash column chromatography on silica gel (5% DCM in MeOH) to give 3,5-difluoro-2iodobenzaldehyde (6.0 g, 92%) as a yellow oil. LC-MS (ESI): m / z 269 [M+H]+. The following intermediates were synthesized using a similar experimental protocol: 1-(2-(3-bromo-5-((1 -ethyl-1 H-pyrazol-4-yl)methyl)-1 H-pyrazol-1 -yl)-5-fluorophenyl)ethane-1 - ol F F Vn Vo ' Vn Λ oh Br Br m / z (ESI): 393 [M+H] Synthesis of [2-(1,3-dioxolan-2-yl)-4-fluorophen¡l]trimethylestannane A mixture of 2-(2-bromo-5-fluorophenyl)-1,3-dioxolane (1.0 g, 4.0 mmol) in THF (20 ml) was 188 added n-BuLI (1.78 ml, 4.45 mmol, 2.5 M) dropwise at -78 °C. The mixture was stirred at -78 °C for 1 h. Then, trimethyltin 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 with saturated NH4CI solution (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 Na2SO4, filtered and concentrated. The residue was purified by flash chromatography on silica gel (10% EtOAc in PE) to give [2(1,3-dioxolan-2-¡l)-4-fluorophen¡l]tñmethylestannane (600 mg, yield: 44%) as a colorless oil. LC / MS ESI (m / z): 333 [M+H]+. Synthesis of (5-bromo-1 -methyl-1 H-pyrazol-4-yl)(5-iodo-1 -methyl-1 H-pyrazol-4-yl)methanol Yo OH Br Isopropylmagnesium bromide (1, 0M in THF, 13.9 mL, 13.9 mmol) dropwise in N2 atmosphere. After addition, the mixture was stirred at -70 °C for 30 min, then a solution of 5-iodo-1-methyl-1 H-pyrazole-4-carbaldehyde (2.14 g, 9.09 mmol ) in THF (15 mL) dropwise at -70 °C for 10 min. The resulting mixture was stirred at −70 °C for another 2 h before quenching with saturated NH4Cl solution (60 mL). The mixture was extracted with DCM (2 x 100 mL). The combined extracts were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by silica gel column chromatography (30% EtOAc in PE) to give (5-bromo-1-methyl-1 H-pyrazol-4-yl)(5-iodo-1-methyl-1 H -pyrazol-4-yl)methanol as a yellow oil (785 mg, yield: 29%). LC / MS ESI (m / z): 397 [M+H]+. The following intermediates were synthesized using a similar experimental protocol: (5-bromo-1 -eti I-1 H-pyrazol-4-yl)(3-iodo-1 -methyl-1 H-pyrazol-4-yl)methanol N__Z / NX1 , + Br OH Br m / z ( ESI): 411 [M+H] 3-((4-chloropyridín-3-yl)(hydroxy)methyl)-1 -methyl-1 H-pyrazole-5-carbonitrile Cl Cl OH + Br0XN __„ L JJ N-n L and N-n N \ N \ m / z (ESI): 249 [M+H] Synthesis of 1-(2-(1,3-dioxolan-2-yl)-4-fluorophenyl)-1 H-pyrazole IVIA / t / ZUZÓ / UUÓ+U I To a solution of 2-(2-bromo-5-fluorophenyl)-1,3-dioxolane (3.0 g, 12.1 mmol) in 1-methylpyrrolidine (50 ml), copper oxide (348 mg , 2.43 mmol) at room temperature, then followed by the addition of 1 H-pyrazole (868 mg, 12.8 mmol). After stirring at 120 °C overnight, the reaction mixture was diluted with EtOAc and water. The organic layer was separated, washed with saturated aqueous NH4Cl solution three times, brine once, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (PE:EA =10:1 to 1:1, V / V) to give 1 -(2-(1,3dioxolan-2-yl)-4-fluorophenyl )-1 H-pyrazole (2.0 g, 70% yield) as a yellow oil. TLC: Rf = 0.3 (PE / EA = 5:1), LC / MS ESI (m / z): 235 [M+H]+. The following intermediates were synthesized using a similar experimental protocol: 1 -(2-(1,3-dioxolan-2-yl)-4-f luorofen i I) -3-methyl-1 H-pyrazole Br u ► V= / Ό m / z (ESI): —( + h-n Y < v ' θΥο OQO 249 [M+H] Synthesis of 5-fluoro-2-(4-(hydroxymethyl)-1-methyl-1H-pyrazol-5-yl)benzaldehyde +H.O. H.O. To a solution of (5-iodo-1-methyl-1H-pyrazol-4-¡l)methanol (1.6 g, 6.7 mmol) in dioxane (15 mL) and H2O (5 mL) was added acid (4-fluoro-2-formylphen¡l)boronic (1.69g, 10.1 mmol), disodium carbonate (2.14 g, 20.2 mmol) and Pd(dppf)CI2 (492 mg, 0.670 mmol ). After stirring at 80 °C for 2 h, the reaction was diluted with water and extracted twice with EtOAc. The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by flash chromatography (silica gel, EtOAc / PE = 1 / 1) to yield 5-fluoro-2-[4-(hydroxymethyl)-1-methyl1 H-pyrazol-5-yl]benzaldehyde (1, 2 g, 76% yield) as a white solid. LC / MS ESI (m / z): 235 [M+H]+. Synthesis of 3-formyl-1 -((2-(tr i met i Isi Ii I )ethoxy) metí I )-1 H-pyrazole-5-carbonitrile 190 To a solution of 1 -((2-(tnmethylsilyl)ethoxy¡)methyl)-1 H-pyrazole-5-carbonitrile (5.40 g, 24.2 mmol) in THF (50 ml) was added LiTMP MgCk (1.0 M in THF, 36.3 mL, 36.3 mmol) dropwise at -16 °C in nitrogen. The resulting solution was stirred at -16°C for 1 h. N,Ndimethylformamide (3.7 ml, 48.4 mmol) was then added and the mixture was stirred for 1 h. The reaction was quenched by the addition of brine, extracted with EtOAc (2 x 30 ml), dried and concentrated. The residue was purified by flash chromatography (silica gel, 0^5% ethyl acetate in petroleum ether) to yield 3-formyl-1 -((2-(trimethyls¡l¡l)ethoxy¡ )methyl)-1H-pyrazole-5-carbonitrile (3.4 g, 60%) as a brown liquid. LC / MS (ESI) m / z: 252 [M+H]+. The following intermediates were synthesized using a similar experimental protocol: 3-(hydroxy(3-iodo-1 -methyl-1 H-pyrazol-4-yl)methyl)-1 -((2-(trimethylsilyl)ethoxy)methyl)-1 H-pyrazol-5carbonitrile Synthesis of (2-chloropyridin-3-yl)(3-ethyl-1 -methyl-1 H-pyrazol-5-yl)methanol Cl Cl OH To a solution of 2-chloro-3-iodopyridine (1.04 g, 4.34 mmol) in THF (17 ml) was added isopropylmagnesium bromide (5.21 ml, 3.43 mmol) at -5 °C . After stirring at room temperature for 0.5 h, 3-ethyl-1-methyl-1 H-pyrazole-5-carbaldehyde (600 mg, 4.34 mmol) was added. Stirring was continued at room temperature for 0.5 h, then the mixture was poured into water (80 mL) and extracted with EA (80 mL x 3). The organic layer was washed with saturated aqueous NaCl solution (60 mL x 2), dried over NasSO4, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (30% EtOAc in PE) to provide (2-chloropyridin-3yl)(3-ethyl-1-methyl-1 H-pyrazol-5-yl)methanol ( 850 mg, 78%) as a light yellow solid. LC / MS (ESI): m / z = 252 [M+H]+. The following intermediates were synthesized using a similar experimental protocol: (1 -(cyclopropy Imeti I)-1 H-pyrazol-4-yl)(3-iodo-1 -methyl-1 H-pyrazol-4-¡l)methanol < / ¡1 A or m / z (ESI): 359 [M+H] 191 (1-(cyclopropylmethyl)-1 H-pyrazol-4-yl)(1 -(4-fluoro-2-iodophenyl)-3-methyl-1 H-pyrazol-5-yl)methanol F F P / =° · ,-^->7 —- p I '~Vn V {Ν0 N<0 m / z (ESI): 453 [M+H] (5-bromo-1 -(cyclopropylmethyl)-3-methyl-1 H- pyrazol-4-yl)(3-iodo-1 -methyl-1 H-pyrazol-4-yl)methanol i i ^N, X / Br -____ Br X · Mr — ih v 1 N—X I ' 1 0 \ 1 OH m / z (ESI): 451 [M+H] (5-bromo-1 -eti I-1 H-pyrazol-4-yl)( 1 -(4-fluoro-2-iodophenyl)-3-(trifluoromethyl )-1 H-pyrazol-5-yl)methanol + VN i -----* ΓΝ i N^O <Ln F^f F^f F r F r m / z (ESI): 559 [M+H] (3-chloro-1 -eti 1-1 H-pi razol-4-yl) (1 -(4-fluoro-2-iodophenyl)-3-methyl-1 H-pyrazol-5-yl)methanol F F ι- / '· ♦ MM n^n / N-K / N-K r Cl Νγ Νγ Cl m / z (ESI): 461 [M+H] (3-bromo-1 -methyl-1 H-pyrazol-4-yl) (3 -chloro-1 -(2,2-dif luoroeti I)-1 H-pyrazol-4-yl)methanol ' ^ / F N F N0 * ,-€1 F --- Aa^f * 1 βΟΎ m / z (ESI ): 355 [M+H] (1 -ethyl-3-(trifluoromethyl)-1 H-pyrazol-4-yl)(3-iodo-1 -methyl-1 H-pyrazol-4-yl)methanol 192 I 0 FyF I OH F\ / F A ' 4 — Ay m / z (ESI): 401 [M+H] (1-(cyclopropylmethyl)-3-methyl-1 H-pyrazole-4-¡l)( 2,4-dibromothazol-5-yl)methanol Γ + . >= / __. W~vn 1 A v v Br Br m / z (ESI): 408 [M+H] (3-bromo-1 -methyl-1 H-pyrazol-4-yl) [3-chloro-1 -(cyclopropylmethyl)- 1 H-pyrazol-4-yl]methanol Br „ Cl “ Ϊ V / >-An V * N N m / z (ESI): 345 [M+H] (2-chloropyridin-3-yl)(1 -(cyclopropylmet ¡l)-1 H-pyrazole-4-yl)methanol or + ^z & ά 5 m / z (ESI): 264 [M+H] (3-bromo-1 -methyl-1 H-pyrazole-4- il)[1 -ethyl-3-(propan-2-yl)-1 H-pyrazol-4-yl]methanol / k । ° Br 0H k— ϊΑ V ...

Claims

1. A compound of Formula (I), or an enantiomer, a mixture of enantiomers, or a tautomer thereof, or a pharmaceutically acceptable salt thereof: wherein Q 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 attached to X and Y and the point of attachment to the aromatic ring comprising Z are on adjacent atoms, and the alpha atom of the 5- to 6-membered heteroarylene ring to the point of attachment to the methylene group and beta to the point of attachment to the aromatic ring comprising Z is carbon, oxygen, or sulfur;R1 is selected from the group consisting of H, methyl, and hydroxymethyl; each instance of R2 is independently selected from the group consisting of H, CN, halo, C1-4 alkoxy, C1-4 alkyl, C1-4 halo-alkyl, C3-4 cycloalkylmethyl, C3-6 cycloalkyl, and C3-e heterocyclyl; each instance of R3 is independently selected from the group consisting of H, halo, CN, C1-4 alkoxy, C1-4 halo-alkyl, and C3-e alkyl; and each of R4 and Rs is independently H or F; provided that X is not a substituted 3*,4-pyrazolylene, wherein * indicates the attachment point of X or Y to the methylene group attached 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: 420 wherein Q is CH or N; Z is CRs or N; X is a 5-membered heteroaryne, comprising 1 to 3 heteroatoms selected from the group consisting of nitrogen, sulfur, and oxygen; wherein the 5-membered heteroaryne is substituted with 0, 1, or 2 occurrences of R2; And it is a heteroaryne selected from the group consisting of substituted 2*,3-furanylene, substituted 2,3*furanylene, substituted 3*,4-furanylene, substituted 1*,2-imidazolylene, substituted 1*,5-imidazolylene, substituted 1,5*-imidazolylene, substituted 4,5*-1,2,3-oxadiazolylene, substituted 3,4*-1,2-oxazolylene, substituted 4*,5-1,2-oxazolylene, substituted 4,5*-1,2-oxazolylene, substituted 4,5*-1,2-oxazolylene, substituted 4,5*-1,3-oxazolylene, substituted 1*,2-phenylene, substituted 1,5*-pyrazolylene, substituted 4*,5-pyrazolylene, substituted 3,4*pyridazinylene, 4*,5-substituted pyridazinylene, 2,3*-substituted pyridinylene, 3*,4-substituted pyridinylene, 3,4*-substituted pyridinylene, 4,5*-substituted pyrimidinylene, 1*,2-substituted pyrrolylene, 1,2*-substituted pyrrolylene, 2,3*-substituted pyrrolylene, 3*,4-substituted pyrrolylene, 4,5*-1,2,3-substituted thiazolylene, 3,4*-1,2-substituted thiazolylene, 4*,5-1,2-substituted thiazolylene, 4,5*-1,2-substituted thiazolylene, 4,5*-1,3-substituted thiazolylene, 2*,3-substituted thiophenylene, 2,3*-substituted thiophenylene, 3*,4-substituted thiophenylene, 4,5*-1,2,3-triazinylene substituted, substituted 1,5*-1,2,3-triazolylene and substituted 3,4*-1,2,4-triazolylene; wherein the heteroaryne is substituted with 0, 1 or 2 occurrences of R3; * indicates the attachment point of X or Y to the methylene group attached to X and Y; in Y, the atom of the heteroaryne ring alpha to the attachment point to the methylene group and beta to the attachment point to the aromatic ring comprising Z is carbon, oxygen or sulfur; R1 is selected from the group consisting of H,methyl and hydroxymethyl; each instance of R2 is independently selected from the group consisting of H, CN, halo, C1-4 alkoxy, C1-4 alkyl, C1-4 halo-alkyl, C3-4 cycloalkylmethyl, C3-6 cycloalkyl, and C3-e heterocyclyl; each instance of R3 is independently selected from the group consisting of H, halo, CN, C1-4 alkoxy, C1-4 halo-alkyl, and C1-4 alkyl; and each of R4 and Rs is independently H or F; provided that the compound is not: 421, 3. The compound of claim 1 or 2, wherein X is a 5-membered heteroaryne selected from the group consisting of pyrazolylene, isoxazolylene, isothiazolylene, imidazolylene, and triazolylene.

4. The compound of claim 1 or 2, wherein X is a 5-membered heteroaryne selected from the group consisting of substituted 4*,5-pyrazolylene, substituted 4,5*-pyrazolylene, substituted 1*,5-pyrazolylene, substituted 4*,5-isoxazolylene, substituted 4,5*-isoxazolylene, substituted 3*,4-isoxazolylene, substituted 3*,4-isothiazolylene, substituted 4*,5-isothiazolylene, substituted 4,5*-isothiazolylene, substituted 4*,5-imidazolylene, substituted 1*,5-imidazolylene, substituted 1*,5-triazolylene, and substituted 4*,5-triazolylene.

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 attached to X and Y; and R2 is independently selected from the group consisting of H, CN, halo, C1-4 alkoxy, C1-4 alkyl, C3-4 haloalkyl, C3-4 cycloalkylmethyl, C3-6 cycloalkyl, and C3-6 heterocyclyl.

6. The compound of any one of claims 1-5, wherein Y is a heteroaryne selected from the group consisting of substituted 4*,5-pyrazolylene, substituted 1,5*-pyrazolylene, substituted 3,4*pyrazolylene, substituted 1*,2-imidazolylene, substituted 5*,1-imidazolylene, substituted 4,5*-1,3-thiazolylene, substituted 3,4*-1,2-oxazolylene, substituted 4*,5-1,2-oxazolylene, substituted 3,4*-1,2-thiazolylene, substituted 4*,5-1,2-thiazolylene, substituted 2,3*-pyridinylene, substituted 3*,4-pyridinylene, substituted 4*,3-pyridinylene, substituted 4,5*-pyrimidinylene, substituted 1,5*-1,2,3-thazolylene and substituted 3,4*1,2,4-triazolylene.

7. The compound of any one of claims 1-5, wherein Y is a heteroarylene 422 selected from the group consisting of: indicates the point of attachment of Y to the methylene group attached to X and Y; and R3 is selected from the group consisting of H, halo, CN, C1-4 alkoxy, C1-4 halo-alkyl and C1.4 alkyl.

8. The compound of any one of 9. The compound of any one of 10. The compound of any one of 11. The compound of any one of 12. The compound of any one of 13. The compound of any one of 14. The compound of any one of 15. The compound of any one of claims 1-7, wherein Q is CH. claims 1-7, wherein Q is N. claims 1-9, wherein Z is CR5. claims 1-10, wherein R5 is H. claims 1-10, wherein R5 is F. claims 1-12, wherein Z is N. claims 1-13, wherein R4 is H. claims 1-13, wherein R4 is F.

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

17. The compound of any one of claims 1-15, wherein the compound of Formula (I) has structure (lB): 423 18. The compound of any one of claims 1-17, wherein each R2 is independently selected from the group consisting of H, chlorine, fluoro, CN, methyl, ethyl, isopropyl, chlorine, methoxy, trifluoromethyl, 2-fluoroethyl, difluoromethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, cyclopropylmethyl, cyclopropyl, cyclobutyl, and oxethanyl.

19. The compound of any one of claims 1-18, wherein R3 is selected from the group consisting of H, fluoro, chloro, bromo, CN, methoxy, difluoromethyl, trifluoromethyl, methyl, and ethyl.

20. The compound of claim 1 or 2, which is a compound of any one of the following pharmaceutically acceptable formulas: 424 thereof.

21. A compound from 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 alkylammonium salts, dialkylammonium salts, trialkylammonium salts, tetraalkylammonium salts, L-arginine salts, benentamine salts, benzathine salts, betaine salts, calcium hydroxide salts, choline salts, deanol salts, diethanolamine salts, diethylamine salts, 2,425(diethylamino)ethanol salts, ethanolamine salts, ethylenediamine salts, N-methylglucamine salts, hydrabamine salts, 1H-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 salts of Zn.

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 pharmaceutically acceptable compound or salt of any one of claims 1-23; and a pharmaceutically acceptable vehicle or excipient.

25. The pharmaceutical composition of claim 24, wherein the composition is a tablet, a capsule, a granule, a lyophil 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 for treating cancer, comprising administering to a subject in need a therapeutically effective amount of the pharmaceutically acceptable compound or salt of any one of claims 1-23.

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

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

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), biliary tract cancer, ovarian cancer, gastric cancer, colorectal cancer, angiosarcoma, melanoma, epithelioid hemangioendothelioma, esophageal cancer, kidney cancer, breast cancer, colon cancer, thyroid cancer, spitzoid tumor, and neuroblastoma.

30. 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 ROS1-positive cancer.

32. The method of claim 26 or 27, wherein the compound or a salt thereof is an inhibitor of ROS1 and ALK.

33. The method of any one of claims 26-27 and 32, wherein the cancer is non-small cell lung carcinoma. 426 34. The method of any one of claims 26-27 and 32, wherein the cancer is an 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 or a salt thereof is a ROS1 inhibitor.

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 is cholangiocarcinoma.

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 ALK inhibitor.

44. The method of any one of the anaplastic large cell lymphoma.

45. The method of any one of the diffuse large B-cell lymphoma.

46. ​​The method of any one of the squamous carcinomas of the esophagus.

47. The method of any one of the renal medullary carcinoma. claims 26-27 and 43, wherein the cancer is claims 26-27 and 43, wherein the cancer is claims 26-27 and 43, wherein the cancer is 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. 427 52. The method of any one of claims 26-27 and 32-42, wherein the cancer comprises the expression of an oncogenic ROS gene or the fusion of the oncogenic FIOS1 gene.

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

54. The method of claim 53, wherein mutations in the oncogenic ROS1 gene or fusion of the oncogenic ROS1 gene result in the 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 the expression of an AL gene / <oncogén¡co o la fusión del gen ALKoncogénico.

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 mutations in the oncogenic ALK gene or fusion of the oncogenic ALK gene result in the expression of an ALK protein with one or more mutations selected from the group consisting of G1202R, L1196M, G1269A, D1203N and 11171N.

58. The method of any one of claims 26-57, wherein the subject has received 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 of claim 60, wherein the IC50 of the compound for inhibition of mutant or non-mutant ROS1 or ALK is not more than one-fifth of the IC50 of the compound for inhibition of wild-type tropomyosin kinase receptor A, B, or C.

62. A method for selectively inhibiting ROS1 on TRK, wherein the inhibition takes place in a subject suffering from cancer, wherein said method comprises 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 on TRK, wherein the inhibition takes place in a subject suffering from cancer, wherein said method comprises 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 one or more additional therapeutic agents.

65. The method of claim 64, wherein the additional therapeutic agent is a TKI. 428 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 for decreasing a level of ROS1 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 24.

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.