Heteroaromatic macrocyclic ether chemotherapeutic agents

Abstract

The present application relates to a compound of general formula (I) [Formula 1] The present invention relates to a heterocyclic heteroaromatic macrocyclic ether compound of TIFF2025536922000336.tif53165, a pharmaceutically acceptable salt of the compound, and a pharmaceutical composition thereof. The compound acts as a selective inhibitor of ROS1 and / or ALK and is useful for the treatment or prevention of cancer.

Description

[Technical Field]

[0001] 1. CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of priority to U.S. Provisional Application No. 63 / 417,368, filed October 19, 2022, all of which are incorporated herein by reference in their entirety. [Background technology]

[0002] 2. Receptor tyrosine kinases (RTKs) are cell surface enzymes that receive external signals, such as whether to grow and divide, and transmit these signals to cells through their kinase activity. Many RTKs are proto-oncogenes, and aberrant RTK activity can promote 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, gene rearrangements resulting in fusion proteins containing an intact kinase domain, amplification, and other means. RTK proto-oncogenes include ROS1, anaplastic lymphoma kinase (ALK), NTRK1 (encoding TRKA), NTRK2 (encoding TRKB), and NTRK3 (encoding TRKC).

[0003] ROS1 is a RTK proto-oncogene, and ROS1 rearrangements have been detected in non-small cell lung cancer (NSCLC), glioblastoma, inflammatory myofibroblastic tumor (IMT), cholangiocarcinoma, ovarian cancer, gastric cancer, colorectal cancer, angiosarcoma, and Spitz nevoid melanoma. Oncogenic ROS1 gene fusions involve the kinase domain (3' region) of ROS1 fused to the 5' region of various 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.

[0004] ALK is a RTK proto-oncogene, and ALK rearrangements have been detected in many cancers, 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 cancer, papillary thyroid carcinoma, and Spitz nevus-like tumors, as well as ALK-activating mutations detected in neuroblastoma. Oncogenic ALK gene fusions contain the kinase domain (3' region) of ALK fused to the 5' region of more than 20 different partner genes, the most common of which are EML4 in NSCLC and NPM in ALCL. Other partner genes include TMP1, WDCP, GTF2IRD1, TPM3, TPM4, CLTC, LMNA, PRKAR1A, RANBP2, TFG, FN1, KLC1, VCL, STRN, HIP1, DCTN1, SQSTM1, TPR, CRIM1, PTPN3, FBXO36, ATIC, and KIF5B.

[0005] NTRK1, NTRK2, and NTRK3 are RTK proto-oncogenes encoding TRK family kinases, and chromosomal rearrangements of NTRK1, NTRK2, and NTRK3 are detected at low frequencies in many cancers. However, in the treatment of ROS1- or ALK-positive patients, inhibition of TRK, particularly in the central nervous system (CNS), is associated with adverse reactions including dizziness / ataxia / gait disturbance, paresthesia, weight gain, and cognitive changes.

[0006] Existing drugs used to treat oncogenic ROS1 and ALK have substantial deficiencies. These deficiencies may include one or more of the following: associated TRK inhibition, limited CNS activity, and insufficient activity against resistance mutations. Treatment of ROS1- or ALK-positive patients with TRK inhibition has been associated with adverse reactions, particularly in the CNS, including dizziness / ataxia / gait disturbances, paresthesia, weight gain, and cognitive changes. Additionally, there is a need for CNS-penetrating and TRK-sparing inhibitors of ROS1 with wild-type ROS1 kinase domain and acquired resistance mutations, including G2032R, D2033N, S1986F, S1986Y, L2026M, L1951R, E1935G, L1947R, G1971E, E1974K, L1982F, F2004C, F2004V, E2020K, C2060G, F2075V, V2089M, V2098I, G2101A, D2113N, D2113G, L2155S, L2032K, and L2086F, occurring individually or in combination. Similarly, there is a need for CNS-penetrating and TRK-sparing inhibitors of ALK with acquired resistance mutations. A variety of ALK drug resistance mutations occurring individually or in combination have been reported and include G1202R, L1196M, G1269A, C1156Y, I1171T, I1171N, I1171S, F1174L, V1180L, S1206Y, E1210K, I151Tins, F1174C, G1202del, D1203N, S1206Y, S1206C, L1152R, L1196Q, L1198P, L1198F, R1275Q, L1152P, C1156T, and F1245V. Summary of the Invention

[0007] 3. In one embodiment, provided herein is a compound of formula (I): [ka] or a stereoisomer, mixture of stereoisomers, or pharmaceutically acceptable salt thereof, wherein Q, Z, L, X, Y, R1, and R4 are as defined herein or elsewhere.

[0008] In one embodiment, provided herein is a pharmaceutical composition suitable for use in treating or preventing cancer in a subject, the pharmaceutical composition comprising an effective amount of any of the compounds described herein (e.g., a compound provided herein, e.g., a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients. In certain embodiments, the medicament can be for use in treating or preventing a condition or disease described herein.

[0009] In one embodiment, provided herein is a method for treating cancer characterized by one or more mutations in the ROS1 or ALK gene, comprising administering to a subject in need thereof an effective amount of a compound provided herein (e.g., a compound of Formula (I) provided herein, or any of its embodiments). In certain embodiments, the compound is an inhibitor of ROS1, in other embodiments, the compound is an inhibitor of ALK, and in further embodiments, the compound is an inhibitor of ROS1 and ALK. In certain aspects, a human subject is in need of such treatment. In one embodiment, without being bound by theory, one or more compounds provided herein selectively inhibit mutations in ALK over TRK (e.g., TRKA, TRKB, and / or TRBC), wherein the ALK mutation is I1171X. 1 (X 1 is N, S, or T) and / or D1203N.

[0010] These cancers include, but are not limited to, non-small cell lung cancer, inflammatory myofibroblastic tumor, ovarian cancer, Spitz nevoid melanoma, glioblastoma, cholangiocarcinoma, gastric cancer, colorectal cancer, angiosarcoma, anaplastic large cell lymphoma, diffuse large B-cell lymphoma, esophageal squamous cell carcinoma, renal medullary carcinoma, renal cell carcinoma, breast cancer, papillary thyroid carcinoma, and neuroblastoma.

[0011] In some embodiments, the method of treating or preventing cancer may involve administering a compound of formula (I) in combination with one or more other chemotherapeutic agent(s). DETAILED DESCRIPTION OF THE INVENTION

[0012] 4. 4.1 Definition Unless otherwise defined, all technical and scientific terms used herein have the meanings commonly understood by those skilled in the art of this disclosure. The following references provide those skilled in the art with general definitions of many of the terms used in this disclosure: Singleton et al., Dictionary of Microbiology and Molecular Biology (2nd ed. 1994), The Cambridge Dictionary of Science and Technology (Walker ed., 1988), The Glossary of Genetics, 5th Ed., R. Rieger et al. (eds.), Springer Verlag (1991), and Hale & Marham, The Harper Collins Dictionary of Biology (1991). As used herein, the following terms have the meanings ascribed to them unless otherwise specified.

[0013] In some embodiments, chemical structures are disclosed along with the corresponding chemical name. In case of conflict, the chemical structure, not the chemical name, controls the meaning.

[0014] As used herein, unless otherwise specified, "comprises," "comprising," "containing," "having," and the like can have the meaning ascribed to them in U.S. patent law and can mean "includes," "including," etc. "Consisting essentially of" or "consists essentially" similarly have the meaning ascribed to them in U.S. patent law, and the term is open-ended, permitting the presence of things other than those recited, but excluding prior art embodiments, so long as the presence of things other than those recited does not materially alter the basic or novel characteristics of the recited things.

[0015] As used herein, the term "or" is understood to be inclusive unless specifically stated otherwise or clear from context. As used herein, the terms "a," "an," and "the" are understood to be singular or plural unless specifically stated otherwise or clear from context.

[0016] As used herein, stereoisomer refers to various stereoisomeric forms of a compound containing one or more asymmetric centers or steric hindrance in its structure. In some embodiments, a stereoisomer is its enantiomer, a mixture of enantiomers, an atropisomer, a mixture of atropisomers, a tautomer, or a mixture of tautomers. For example, the compounds described herein may be in the form of individual enantiomers, diastereomers, or geometric isomers (e.g., atropisomers), or in the form of a mixture of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomers. In some embodiments, the compounds provided herein may be atropisomers. In certain embodiments, atropisomers are stereoisomers resulting from hindrance of rotation about a single bond, where the energy difference due to steric strain or other contributors creates a sufficiently high rotational barrier to allow for the isolation of individual conformers. Stereoisomers can be isolated from mixtures by methods known to those skilled in the art, including chiral high-pressure liquid chromatography (HPLC) and the formation and crystallization of chiral salts, or in one embodiment, isomers can be prepared by asymmetric synthesis. See, for example, Jacques et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Wilen et al., Tetrahedron 33:2725 (1977); Eliel, ELS Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); and Wilen, SH Tables of Resolving Agents and Optical Resolutions p. 268 (E.L. Eliel, Ed., University of Notre Dame Press, Notre Dame, IN 1972). Further provided herein are compounds as individual isomers substantially free of other isomers, and alternatively, as mixtures of various isomers.

[0017] The term "acyl" is art-recognized and refers to a group represented by the general formula hydrocarbylC(O)-, in one embodiment alkylC(O)-.

[0018] The term "acylamino" is art-recognized and refers to an amino group substituted with an acyl group and may be represented, for example, by the formula hydrocarbylC(O)NH-.

[0019] The term "acyloxy" is art-recognized and refers to a group represented by the general formula hydrocarbylC(O)O-, in one embodiment alkylC(O)O-.

[0020] The term "alkoxy" refers to an alkyl group, in one embodiment a lower alkyl group, having an oxygen attached thereto. Representative alkoxy groups include methoxy, ethoxy, propoxy, tert-butoxy, and the like.

[0021] The term "alkoxyalkyl" refers to an alkyl group substituted with an alkoxy group and may be represented by the general formula alkyl-O-alkyl.

[0022] As used herein, the term "alkenyl" refers to an aliphatic group containing at least one double bond and is intended to include both "unsubstituted alkenyl" and "substituted alkenyl," the latter of which refers to an alkenyl moiety having a substituent replacing a hydrogen on one or more carbons of the alkenyl group. Such substituents may be located on one or more carbons included or not included in one or more double bonds. Furthermore, such substituents include all of those contemplated for alkyl groups, as described below, except where stability would be inhibited. For example, substitution of alkenyl groups with one or more alkyl, carbocyclyl, aryl, heterocyclyl, or heteroaryl groups is contemplated.

[0023] An "alkyl" group or "alkane" is a fully saturated, straight-chain or branched non-aromatic hydrocarbon. Typically, a straight-chain or branched alkyl group, unless otherwise defined, has from 1 to about 20 carbon atoms, and in one embodiment, from 1 to about 10. Examples of straight-chain and branched alkyl groups include methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, tert-butyl, pentyl, hexyl, pentyl, and octyl. C1-C6 straight-chain or branched alkyl groups are also referred to as "lower alkyl" groups.

[0024] Furthermore, as used throughout the specification, examples, and claims, the term "alkyl" (or "lower alkyl") is intended to include both "unsubstituted alkyl" and "substituted alkyl," the latter of which refers to an alkyl moiety having substituents replacing a hydrogen on one or more carbons of the hydrocarbon backbone. Such substituents, unless otherwise specified, can include, for example, halogen, hydroxyl, carbonyl (such as carboxyl, alkoxycarbonyl, formyl, or acyl), thiocarbonyl (such as thioester, thioacetate, or thioformate), alkoxy, phosphoryl, phosphate, phosphonate, phosphinate, amino, amido, amidine, imine, cyano, nitro, azido, sulfhydryl, alkylthio, sulfate, sulfonate, sulfamoyl, sulfonamido, sulfonyl, heterocyclyl, aralkyl, or aromatic or heteroaromatic moieties. Those of skill in the art will understand that moieties substituted on the hydrocarbon chain can themselves be substituted, if appropriate. For example, substituents of substituted alkyls can include substituted and unsubstituted forms of amino, azido, imino, amido, phosphoryl (including phosphonates and phosphinates), sulfonyl (including sulfates, sulfonamides, sulfamoyl, and sulfonates), and silyl groups, as well as ethers, alkylthio, carbonyl (including ketones, aldehydes, carboxylates, and esters), -CF, -CN, and the like. Exemplary substituted alkyls are described below. Cycloalkyls can be further substituted with alkyls, alkenyls, alkoxys, alkylthios, aminoalkyls, carbonyl-substituted alkyls, -CF, -CN, and the like.

[0025] "C x-y The term "C" when used in conjunction with a chemical moiety such as acyl, acyloxy, alkyl, alkenyl, alkynyl, or alkoxy is meant to include groups containing x to y carbons in the chain. For example, "C x-y The term "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, and includes haloalkyl groups such as trifluoromethyl and 2,2,2-trifluoroethyl. CO alkyl refers to a hydrogen when the group is in a terminal position and a bond when it is internal. 2-y alkenyl" and "C 2-y The term "alkynyl" refers to substituted or unsubstituted unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but that contain at least one double or triple bond respectively.

[0026] As used herein, the term "alkylamino" refers to an amino group substituted with at least one alkyl group.

[0027] As used herein, the term "alkylthio" refers to a thiol group substituted with an alkyl group and may be represented by the general formula alkylS-.

[0028] As used herein, the term "alkynyl" refers to an aliphatic group containing at least one triple bond and is intended to include both "unsubstituted alkynyl" and "substituted alkynyl," the latter of which refers to an alkynyl moiety having substituents replacing hydrogen on one or more carbons of the alkynyl group. Such substituents may be present on one or more carbons included or not included in one or more triple bonds. Furthermore, such substituents include all of those contemplated for alkyl groups described above, except where stability would be inhibited. For example, substitution of alkynyl groups with one or more alkyl, carbocyclyl, aryl, heterocyclyl, or heteroaryl groups is contemplated.

[0029] As used herein, the term "amide" refers to the group [ka] where each R 30 independently represent hydrogen or a hydrocarbyl group, or two R 30 However, together with the N atom to which they are attached, they complete a heterocycle with 4 to 8 atoms in the ring structure.

[0030] The terms "amine" and "amino" are art-recognized and refer to both unsubstituted and substituted amines, as well as salts thereof, e.g., [ka] where each R 31 independently represent hydrogen or a hydrocarbyl group, or two R 31 together with the N atom to which they are attached complete a heterocycle having 4 to 8 atoms in the ring structure. As used herein, the term "aminoalkyl" refers to an alkyl group substituted with an amino group.

[0031] As used herein, the term "aralkyl" refers to an alkyl group substituted with an aryl group.

[0032] As used herein, the term "aryl" includes substituted or unsubstituted monocyclic aromatic groups, in which each atom of the ring is carbon. In one embodiment, the ring is 5- to 7-membered, and in one embodiment, 6-membered. 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, at least one of which is aromatic, e.g., the other cyclic rings may be cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, and / or heterocyclyl. Aryl groups include benzene, naphthalene, phenanthrene, phenol, aniline, and the like.

[0033] The term "carbamate" is art-recognized and refers to a group [ka] where each R 32 and R 33 independently represent hydrogen or a hydrocarbyl group, e.g., an alkyl group, or R 32 and R 33 together with the intervening atom(s) complete a heterocycle having 4 to 8 atoms in the ring structure.

[0034] As used herein, the terms "carbocycle" and "carbocyclic" refer to a saturated or unsaturated ring in which each atom of the ring is carbon. The term carbocycle includes both aromatic and non-aromatic carbocycles. Non-aromatic carbocycles include both cycloalkane rings in which all carbon atoms are saturated and cycloalkene rings that contain at least one double bond.

[0035] The term "carbocycle" includes 5- to 7-membered monocyclic rings and 8- to 12-membered bicyclic rings. Each ring in a bicyclic carbocycle can be selected from saturated, unsaturated, and aromatic rings. Carbocycles include bicyclic molecules in which one, two, three, or more atoms are shared between two rings. The term "fused carbocycle" refers to a bicyclic carbocycle in which each ring shares two adjacent atoms with the other ring. Each ring in a fused carbocycle can be selected from saturated, unsaturated, and aromatic rings. In an exemplary embodiment, an aromatic ring, e.g., phenyl, can be fused to a saturated or unsaturated ring, e.g., cyclohexane, cyclopentane, or cyclohexene. Any combination of saturated, unsaturated, and aromatic bicyclic rings, valence permitting, is included in the definition of carbocycle. Exemplary "carbocycles" include cyclopentane, cyclohexane, bicyclo[2.2.1]heptane, 1,5-cyclooctadiene, 1,2,3,4-tetrahydronaphthalene, bicyclo[4.2.0]oct-3-ene, naphthalene, and adamantane. Exemplary fused carbocycles include decalin, naphthalene, 1,2,3,4-tetrahydronaphthalene, bicyclo[4.2.0]octane, 4,5,6,7-tetrahydro-1H-indene, and bicyclo[4.1.0]hept-3-ene. A "carbocycle" can be substituted at any one or more positions that can have a hydrogen atom.

[0036] A "cycloalkyl" group is a fully saturated cyclic hydrocarbon. "Cycloalkyl" includes monocyclic and bicyclic rings. Typically, monocyclic cycloalkyl groups have 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, three, or more atoms are shared between the two rings. The term "fused cycloalkyl" refers to a bicyclic cycloalkyl in which each ring 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.

[0037] As used herein, the term "carbocyclylalkyl" refers to an alkyl group substituted with a carbocyclic group.

[0038] As used herein, "C 3-4 The term "cycloalkylmethyl" refers to a methyl group substituted with a carbocyclic group containing 3 to 4 carbon atoms.

[0039] The term "carbonate" is art-recognized and refers to the group -OCO-R 34 where R 34 represents a hydrocarbyl group.

[0040] As used herein, the term "carboxy" refers to a group represented by the formula -CO2H.

[0041] As used herein, the term "ester" refers to an ester of the group -C(O)OR 35 where R 35 represents a hydrocarbyl group.

[0042] As used herein, the term "ether" refers to a hydrocarbyl group bonded to another hydrocarbyl group via an oxygen atom. Thus, the ether substituent of a hydrocarbyl group can be hydrocarbyl-O-. Ethers can be symmetrical or asymmetrical. Examples of ethers include, but are not limited to, heterocycle-O-heterocycle and aryl-O-heterocycle. Ethers include "alkoxyalkyl" groups, which can be represented by the general formula alkyl-O-alkyl.

[0043] As used herein, the terms "halo" and "halogen" mean halogen and include chloro, fluoro, bromo, and iodo.

[0044] As used herein, the terms "hetaralkyl" and "heteroaralkyl" refer to an alkyl group substituted with a hetaryl group.

[0045] As used herein, the term "heteroalkyl" refers to a saturated or unsaturated chain of carbon atoms and at least one heteroatom, wherein no two heteroatoms are adjacent.

[0046] The terms "heteroaryl" and "hetaryl" include substituted or unsubstituted aromatic monocyclic ring structures, in one embodiment, 5- to 7-membered rings, and in one embodiment, 5- to 6-membered rings, which ring structures contain at least one heteroatom, in one embodiment, 1 to 4 heteroatoms, and in one embodiment, 1 or 2 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, and at least one of the rings is heteroaromatic; for example, the other cyclic rings may be cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, and / or heterocyclyl. Heteroaryl groups include, for example, pyrrole, furan, thiophene, imidazole, oxazole, thiazole, pyrazole, pyridine, pyrazine, pyridazine, pyrimidine, and the like.

[0047] The asterisk ( * ) designation identifies the ring atom of the moiety attached to the L group between X and Y, as exemplified below: [ka]

[0048] For example, "1" for Y * ,5-substituted imidazolylene" is substituted: [ka] means.

[0049] As mentioned above, the IUPAC numbering rules for heteroarylene rings are used throughout this specification to designate the positions of ring atoms. In this example, the 1-position of the imidazolylene is bonded to the L group, so it is indicated with an asterisk. This asterisk notation is used in both the name and structure of the heteroarylene of X and Y. Here, the 5-position ring atom relative to Y is not marked because it is bonded to the ring containing the variable R4.

[0050] Exemplary rings for X include the "1,5" ring shown below. * -substituted imidazolylene". [ka]

[0051] The ring atom attached to the L group (position 5 in this example) is indicated with an asterisk in both the name and structure of the heteroarylene of ring X. The ring atom attached to the aromatic ring bearing Q is not marked.

[0052] As used herein, the term "heteroatom" means an atom of any element other than carbon or hydrogen. In one embodiment, heteroatoms are nitrogen, oxygen, and sulfur.

[0053] The terms "heterocyclyl," "heterocycle," and "heterocyclic" refer to substituted or unsubstituted non-aromatic ring structures, in one embodiment, 3- to 10-membered rings, and in one embodiment, 3- to 7-membered rings, which ring structures contain at least one heteroatom, in one embodiment, 1 to 4 heteroatoms, and in one embodiment, 1 or 2 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, and at least one of the rings is heterocyclic, e.g., the other cyclic rings can be cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, and / or heterocyclyl. Heterocyclyl groups include, for example, piperidine, piperazine, pyrrolidine, morpholine, lactones, lactams, and the like.

[0054] As used herein, the term "heterocyclylalkyl" refers to an alkyl group substituted with a heterocycle group.

[0055] As used herein, the term "hydrocarbyl" refers to a group bonded through a carbon atom that has no =0 or =S substituents, typically having at least one carbon-hydrogen bond and a primarily carbon backbone, but optionally containing heteroatoms. Thus, groups such as methyl, ethoxyethyl, 2-pyridyl, and trifluoromethyl are considered hydrocarbyl for purposes of this application, while substituents such as acetyl (having an =0 substituent on the linking carbon atom) and ethoxy (linked through an oxygen rather than a carbon) are not considered hydrocarbyl. Hydrocarbyl groups include, but are not limited to, aryl, heteroaryl, carbocycle, heterocyclyl, alkyl, alkenyl, alkynyl, and combinations thereof.

[0056] As used herein, the term "hydroxyalkyl" refers to an alkyl group substituted with a hydroxy group.

[0057] When used in conjunction with a chemical moiety, e.g., acyl, acyloxy, alkyl, alkenyl, alkynyl, or alkoxy, the term "lower" is meant to include groups in which there are 10 or fewer, and in one embodiment, 6 or fewer, non-hydrogen atoms in the substituent. "Lower alkyl," for example, refers to an alkyl group containing 10 or fewer, and in one embodiment, 6 or fewer, carbon atoms. In certain embodiments, acyl, acyloxy, alkyl, alkenyl, alkynyl, or alkoxy substituents defined herein are lower acyl, lower acyloxy, lower alkyl, lower alkenyl, lower alkynyl, or lower alkoxy, respectively, whether they appear alone or in combination with other substituents, e.g., in recitations of hydroxyalkyl and aralkyl (where, e.g., atoms in an aryl group are not counted when counting the carbon atoms in an alkyl substituent).

[0058] The terms "polycyclyl," "polycycle," and "polycyclic" refer to two or more rings (e.g., cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, and / or heterocyclyl) in which two or more atoms are common to two adjacent rings, e.g., the rings are "fused rings." Each ring of the polycycle can be substituted or unsubstituted. In certain embodiments, each ring of the polycycle contains 3 to 10 atoms in the ring, and in one embodiment, 5 to 7 atoms.

[0059] The term "silyl" refers to a silicon moiety having three hydrocarbyl moieties attached thereto.

[0060] The term "substituted" refers to moieties having substituents replacing a hydrogen on one or more backbone carbons. It is understood that "substituted" or "substituted with" includes the implicit proviso that such substitution is consistent with the permissible valences of the substituted atom and the substituent, and that the substitution results in a stable compound, e.g., a stable compound that does not spontaneously undergo transformation by rearrangement, cyclization, elimination, and the like. As used herein, the term "substituted" is intended to include all permissible substituents of organic compounds. In a broad aspect, the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and nonaromatic substituents of organic compounds. The permissible substituents can be one or more and the same or different for appropriate organic compounds. As used herein, unless otherwise specified, heteroatoms such as nitrogen can have hydrogen substituents that satisfy the valence of the heteroatom and / or any permissible substituents of organic compounds described herein. Substituents can include any substituent described herein, for example, halogen, hydroxyl, carbonyl (such as carboxyl, alkoxycarbonyl, formyl, or acyl), thiocarbonyl (such as thioester, thioacetate, or thioformate), alkoxy, phosphoryl, phosphate, phosphonate, phosphinate, amino, amido, amidine, imine, cyano, nitro, azido, sulfhydryl, alkylthio, sulfate, sulfonate, sulfamoyl, sulfonamido, sulfonyl, heterocyclyl, aralkyl, or aromatic or heteroaromatic moieties. Those skilled in the art will understand that substituents can themselves be substituted, where appropriate. Unless specifically stated as "unsubstituted," reference to a chemical moiety herein is understood to include substituted variants. For example, reference to an "aryl" group or moiety implicitly includes both substituted and unsubstituted variants.

[0061] The term "sulfate" is art-recognized and refers to the group -OSO3H, or a pharmaceutically acceptable salt thereof.

[0062] The term "sulfonamide" is art-recognized and can be represented by the general formula [ka] wherein each R 36 and R 37 independently represent hydrogen or hydrocarbyl, e.g., alkyl, or R 36 and R 37 together with the intervening atom(s) complete a heterocycle having 4 to 8 atoms in the ring structure.

[0063] The term "sulfoxide" is art-recognized and refers to the group -S(O)-R 38 refers to R 38 represents a hydrocarbyl.

[0064] The term "sulfonate" is art-recognized and refers to the group SO3H, or a pharmaceutically acceptable salt thereof.

[0065] The term “sulfone” is art-recognized and refers to the group —S(O)—R 39 refers to R 39 represents a hydrocarbyl.

[0066] As used herein, the term "thioalkyl" refers to an alkyl group substituted with a thiol group.

[0067] As used herein, the term "thioester" refers to the group -C(O)SR 40 or -SC(O)R 40 refers to R 10 represents a hydrocarbyl.

[0068] As used herein, the term "thioether" corresponds to an ether where the oxygen has been replaced by a sulfur.

[0069] The term "urea" is art-recognized and has the general formula [ka] where each R 41 and R 42 independently represent hydrogen or hydrocarbyl, e.g., alkyl, or R 41 Either of these is R 42 and together with the intervening atom(s) complete a heterocycle having from 4 to 8 atoms in the ring structure.

[0070] The term "protecting group" refers to a group of atoms that, when attached to a reactive functional group in a molecule, masks, reduces, or prevents the reactivity of the functional group. Typically, a protecting group can be selectively removed as desired during synthesis. Examples of protecting groups are found in Greene and Wuts, Protective Groups in Organic Chemistry, 3 rd Ed., 1999, John Wiley & Sons, NY and Harrison et al., Compendium of Synthetic Organic Methods, Vols. 1-8, 1971-1996, John Wiley & Sons, NY Representative nitrogen protecting groups include, but are not limited to, formyl, acetyl, trifluoroacetyl, benzyl, benzyloxycarbonyl ("CBZ"), tert-butoxycarbonyl ("Boc"), trimethylsilyl ("TMS"), 2-trimethylsilyl-ethanesulfonyl ("TES"), trityl and substituted trityl groups, allyloxycarbonyl, 9-fluorenylmethyloxycarbonyl ("FMOC"), nitro-veratryloxycarbonyl ("NVOC"), and the like. Representative hydroxyl protecting groups include, but are not limited to, those in which the hydroxyl group is acylated (esterified) or alkylated, such as benzyl and trityl ethers, as well as alkyl ethers, tetrahydropyranyl ethers, trialkylsilyl ethers (e.g., TMS or TIPS groups), glycol ethers, such as ethylene glycol and propylene glycol derivatives, and allyl ethers.

[0071] In certain embodiments, the compounds provided herein may be racemic. In certain embodiments, the compounds provided herein may be enriched in one enantiomer. For example, the compounds provided herein may have an ee of more than about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, or even about 95% or more. In certain embodiments, the compounds provided herein may have multiple stereocenters. In certain such embodiments, the compounds provided herein may be enriched in one or more diastereomers. For example, the compounds provided herein may have an ee of more than about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, or even about 95% or more.

[0072] In certain embodiments, the pharmaceutical product can be enriched to provide primarily one enantiomer of a compound (e.g., of Formula (I)). An enantiomerically enriched mixture can contain, for example, at least about 60 mole percent of one enantiomer, or in one embodiment, at least about 75, about 90, about 95, or even about 99 mole percent. In certain embodiments, a compound enriched in one enantiomer is substantially free of other enantiomers. Here, substantially free means that the substance in question accounts for, for example, less than about 10%, or less than about 5%, or less than about 4%, or less than about 3%, or less than about 2%, or less than about 1% of the amount of the other enantiomer 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 is said to contain about 98 mole percent of the first enantiomer and only about 2% of the second enantiomer.

[0073] In certain embodiments, the pharmaceutical product can be enriched to provide predominantly one diastereomer of a compound (e.g., of Formula (I)). A diastereomerically enriched mixture can contain, for example, at least about 60 mole percent of one diastereomer, or in one embodiment, at least about 75, about 90, about 95, or even about 99 mole percent.

[0074] In some embodiments, a moiety of a compound exists as a mixture of tautomers. A "tautomer" is a structural isomer of a moiety or compound that readily interconverts with another structural isomer. For example, a pyrazole ring has two tautomers: [ka] They differ in the location of the π bonds and hydrogen atoms. Unless otherwise stated, a representation of one tautomer of a moiety or compound includes all possible tautomers.

[0075] The term "subject" to which administration is contemplated includes, but is not limited to, humans (i.e., male or female of any age, e.g., a pediatric subject (e.g., infant, child, adolescent) or an adult subject (e.g., young adult, middle-aged adult, or elderly adult)) and / or other primates (e.g., cynomolgus monkeys, rhesus monkeys), mammals, including commercially important mammals, e.g., cows, pigs, horses, sheep, goats, cats, and / or dogs, and / or birds, including commercially important birds, e.g., chickens, ducks, geese, quail, and / or turkeys. In one embodiment, the subject is a human.

[0076] As used herein, a pharmaceutical 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 a treated sample compared to an untreated control sample, or delays the onset or reduces the severity of one or more symptoms of the disorder or condition compared to an untreated control sample. These effects are also referred to as "prophylactic" effects. Thus, as used herein, unless otherwise specified, the terms "prevention" and "preventing" refer to an approach to obtaining beneficial or desired results, including, but not limited to, a preventative effect. For a preventative effect, a pharmaceutical agent may be administered to a patient at risk of developing a particular disease or to a patient reporting one or more physiological symptoms of a disease, even if the disease may not have been diagnosed. In one embodiment, for a preventative effect, a pharmaceutical agent is administered prior to clinical manifestations of an undesirable condition (e.g., a disease or other condition undesirable to the subject) (e.g., it protects the subject from developing the undesirable condition).

[0077] As used herein, unless otherwise specified, the term "treatment" or "treating" refers to curative or palliative measures. Beneficial or desired clinical results include, but are not limited to, the total or partial alleviation of symptoms associated with a disease or disorder or condition, whether detectable or undetectable, a reduction in the extent of the disease, a stable (i.e., not worsening) disease state, a delay or slowing of disease progression, an improvement or alleviation of a disease state (e.g., one or more symptoms of the disease), and remission (whether partial or complete). "Treatment" can also mean prolonging survival compared to expected survival if not treated. In one embodiment, "treatment" includes administering a medication after the onset of an undesirable condition (i.e., intended to reduce, ameliorate, or stabilize an existing undesirable condition or its side effects).

[0078] As used herein, unless otherwise specified, "cancer" refers to any malignant and / or invasive growth or tumor caused by abnormal cell proliferation, including solid tumors, which are named for the type of cells that form them, and cancers of the blood, bone marrow, or lymphatic system. Examples of solid tumors include, but are not limited to, sarcomas and carcinomas. Examples of blood cancers include, but are not limited to, leukemia, lymphoma, and myeloma. Cancer includes, but is not limited to, primary cancers that begin in a particular part of the body, metastatic cancers that have spread from where they began to other parts of the body, recurrence of the original primary cancer after remission, and second primary cancers, which are new primary cancers in people with a history of a different type of cancer than the later cancer.

[0079] As used herein, unless otherwise specified, "abnormal cell growth" refers to cell growth that is independent of normal regulatory mechanisms (e.g., loss of contact inhibition). Abnormal cell growth can be benign (non-cancerous) or malignant (cancerous). In some embodiments of the methods provided herein, the abnormal cell growth is cancer.

[0080] In some embodiments, the abnormal cell growth is cancer mediated by anaplastic lymphoma kinase (ALK). In some such embodiments, the ALK is genetically modified ALK. In other embodiments, the abnormal cell growth is cancer mediated by ROS1 kinase. In some such embodiments, the ROS1 kinase is genetically modified ROS1 kinase. In some embodiments, the abnormal cell growth is cancer, particularly NSCLC. In some such embodiments, the NSCLC is mediated by ALK or ROS1. In certain embodiments, the cancer is NSCLC mediated by genetically modified ALK or genetically modified ROS1.

[0081] As used herein, unless otherwise indicated, the term "managing" includes preventing the recurrence of a particular disease or disorder in a patient who has had it, extending the time that a patient who has had the disease or disorder remains in remission, reducing patient mortality, and / or maintaining a reduction in the severity of or avoidance of symptoms associated with the disease or condition being managed.

[0082] The term "prodrug" is intended to encompass compounds that are converted under physiological conditions into therapeutically active agents (e.g., compounds of Formula (I)) provided herein. A common method for making prodrugs is to include one or more selected moieties that are hydrolyzed under physiological conditions to reveal the desired molecule. In other embodiments, prodrugs are converted by the enzymatic activity of the subject. For example, esters or carbonates (e.g., esters or carbonates of alcohols or carboxylic acids) are prodrugs provided herein. In certain embodiments, in the formulations depicted above, some or all of the compounds of Formula (I) can be replaced with the corresponding suitable prodrugs, for example, a hydroxyl of the parent compound is presented as an ester, carbonate, or carboxylic acid.

[0083] As used herein, "effective amount" refers to an amount sufficient to achieve a desired biological effect.As used herein, "therapeutically effective amount" refers to an amount sufficient to achieve a desired biological effect.For example, a therapeutically effective amount can refer to an amount sufficient to improve at least one sign or symptom of cancer.

[0084] A "response" to a treatment method can include, among other things, a decrease or amelioration of negative symptoms, a decrease in the progression of the disease or its symptoms, an increase in beneficial symptoms or an improvement in clinical outcome, a reduction in side effects, stabilization of the disease, or partial or complete cure of the disease.

[0085] As used herein, unless otherwise indicated, the term "relapse" refers to a disorder, disease, or condition that has progressed after responding to (e.g., achieving complete remission from) a previous treatment. The previous treatment may include more than one treatment.

[0086] As used herein, unless otherwise indicated, the term "refractory" refers to a disorder, disease, or condition that has not responded to previous treatments, which may include one or more lines of treatment.

[0087] As used herein, unless otherwise specified, the terms "about" and "approximately" when used in connection with a dose, amount, or weight percent of a component of a composition or dosage form means a dose, amount, or weight percent that would be recognized by one of ordinary skill in the art to provide an equivalent pharmacological effect to that obtained from the specified dose, amount, or weight percent. In certain embodiments, the terms "about" and "approximately" when used in this context contemplate a dose, amount, or weight percent that is within 30%, within 20%, within 15%, within 10%, or within 5% of the specified dose, amount, or weight percent.

[0088] The term "between" includes the endpoints of the range. For example, a range described by "between 3 and 5" includes the numbers "3" and "5."

[0089] As used herein, unless otherwise specified, the term "pharmaceutically acceptable salt" refers to a salt that is, within the scope of sound medical judgment, suitable for use in contact with the tissues of a subject without undue toxicity, irritation, allergic reaction, etc., and that is commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, Berge et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences (1977) 66:1-19. In certain embodiments, pharmaceutically acceptable salts include, but are not limited to, alkyl, dialkyl, trialkyl, or tetraalkylammonium salts. In certain embodiments, pharmaceutically acceptable salts include, but are not limited to, L-arginine, benenthamine, benzathine, betaine, calcium hydroxide, choline, deanol, diethanolamine, diethylamine, 2-(diethylamino)ethanol, ethanolamine, ethylenediamine, N-methylglucamine, hydrabamine, 1H-imidazole, lithium, L-lysine, magnesium, 4-(2-hydroxyethyl)morpholine, piperazine, potassium, 1-(2-hydroxyethyl)pyrrolidine, sodium, triethanolamine, tromethamine, and zinc salts. In certain embodiments, pharmaceutically acceptable salts include, but are not limited to, Na, Ca, K, Mg, Zn, or other metal salts.

[0090] Pharmaceutically acceptable acid addition salts may also exist as various solvates, for example, with water, methanol, ethanol, dimethylformamide, etc. Mixtures of such solvates may also be prepared. The source of such solvates may be from the solvent of crystallization, may be inherent in the solvent of preparation or crystallization, or may be adventitious to such solvent.

[0091] Pharmaceutically acceptable anionic salts include, but are not limited to, acetate, aspartate, benzenesulfonate, benzoate, besylate, bicarbonate, bitartrate, bromide, camsylate, carbonate, chloride, citrate, decanoate, edetate, esylate, fumarate, gluceptate, gluconate, glutamate, glycolate, hexanoate, hydroxynaphthoate, iodide, isethionate, lactate, lactobionate, malate, maleate, mandelate, mesylate, methylsulfate, mucate, napsylate, nitrate, octanoate, oleate, pamoate, pantothenate, phosphate, polygalacturonate, propionate, salicylate, stearate, acetate, succinate, sulfate, tartrate, teoclate, and tosylate.

[0092] 4.2 Compounds In one embodiment, provided herein is a compound of formula (I): [ka] or a stereoisomer, mixture of stereoisomers, or a pharmaceutically acceptable salt thereof, wherein: Q is CH or N; Z is CR5 or N; L is -CH2-, C=O, or -O-; X is a 5-membered heteroarylene containing 1 to 3 heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, and the 5-membered heteroarylene is substituted with 1, 2, or 3 R2; Y is a 5- or 6-membered heteroarylene containing 1 to 3 heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, and the 5- or 6-membered heteroarylene is substituted with 0, 1, or 2 R3; R1 is selected from the group consisting of H, methyl, and hydroxymethyl; Each instance of R2 is independently H, CN, halo, [ka] -CO-C1-4 Alkyl, 5-membered heteroaryl, C 1-4 Alkyl-SO-, C 1-4 Alkyl-SO2-, C 1-4 Alkoxy, C 1-4 Alkyl, Halo-C 1-4 Alkyl, C 1-4 Alkoxy-C 1-4 Alkyl, C 3-4 Cycloalkylmethyl, C 3-6 Cycloalkyl, and C 3-6 heterocyclyl, provided that when L is -CH2-, at least one R2 is selected from the group consisting of: [ka] -CO-C 1-4 Alkyl, 5-membered heteroaryl, C 1-4 Alkyl-SO-, or C 1-4 alkyl-SO2-, wherein the heteroaryl, cycloalkyl, heterocyclyl, or alkyl further comprises, as valence permits, 0, 1, 2, or 3 C 1-4 substituted with alkyl or halogen; R n Each instance of is independently H, C 1-4 Alkyl, Halo-C 1-4 Alkyl or C 3-6 cycloalkyl or two R n groups together with their intervening nitrogens, optionally one or more C 1-4 C substituted with alkyl or halogen 3-6 forming a heterocycloalkyl, R o Each instance of is independently H or C 1-4 is alkyl, Each instance of R3 is independently H, halo, CN, C 1-4 Alkoxy, Halo-C 1-4 Alkyl, and C 1-4 is selected from the group consisting of alkyl, Each of R4 and R5 is independently H or F.

[0093] In one embodiment, provided herein is a compound of formula (I): [ka] or a stereoisomer, mixture of stereoisomers, or a pharmaceutically acceptable salt thereof, wherein: Q is CH or N; Z is CR5 or N; L is -CH2-, C=O, or -O-; X is a 5-membered heteroarylene containing 1 to 3 heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, and the 5-membered heteroarylene is substituted with 1, 2, or 3 R2; Y is 2 * ,3-substituted furanylene, 2,3 * -substituted furanylene, 3 * ,4-substituted furanylene, 1 * ,2-substituted imidazolylene, 1 * ,5-substituted imidazolylene, 1,5 * -substituted imidazolylene, 4,5 * -substituted 1,2,3-oxadiazolylene, 3,4 * -substituted 1,2-oxazolylene, 4 * ,5-substituted 1,2-oxazolylene, 4,5 * -substituted 1,2-oxazolylene, 4,5 * -substituted 1,3-oxazolylene, 1 * ,2-substituted phenylene, 1,5 * -substituted pyrazolylene, 4 * ,5-substituted pyrazolylene, 3,4 * -substituted 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* -substituted 1,2,3-thiadiazolylene, 3,4 * -substituted 1,2-thiazolylene, 4 * ,5-substituted 1,2-thiazolylene, 4,5 * -substituted 1,2-thiazolylene, 4 * ,5-substituted 1,3-thiazolylene, 4,5 * -substituted 1,3-thiazolylene, 2 * ,3-substituted thiophenylene, 2,3 * -substituted thiophenylene, 3 * ,4-substituted thiophenylene, 4,5 * -substituted 1,2,3-triazinylene, 4 * ,5-substituted triazolylenes, 1,5 * -substituted 1,2,3-triazolylene, 4 * ,5-substituted 1,2,3-triazolylene, 1 * ,5-substituted 1,2,4-triazolylene, 1,5 * -substituted 1,2,4-triazolylenes and 3,4 * -substituted 1,2,4-triazolylene; the heteroarylene is substituted with 0, 1, or 2 R3; * indicates the point of attachment of X or Y to the L group attached to X and Y, R1 is selected from the group consisting of H, methyl, and hydroxymethyl; Each instance of R2 is independently H, CN, halo, [ka] -CO-C 1-4 Alkyl, 5-membered heteroaryl, C 1-4 Alkyl-SO-, C 1-4 Alkyl-SO2-, C 1-4 Alkoxy, C 1-4 Alkyl, Halo-C 1-4 Alkyl, C 1-4 Alkoxy-C 1-4 Alkyl, C 3-4 Cycloalkylmethyl, C 3-6 Cycloalkyl, and C 3-6heterocyclyl, provided that when L is -CH2-, at least one R2 is [ka] -CO-C 1-4 Alkyl, 5-membered heteroaryl, C 1-4 Alkyl-SO-, or C 1-4 alkyl-SO2-, wherein the heteroaryl, cycloalkyl, heterocyclyl, or alkyl further comprises, as valence permits, 0, 1, 2, or 3 C 1-4 substituted with alkyl or halogen; R n Each instance of is independently H, C 1-4 Alkyl, Halo-C 1-4 Alkyl or C 3-6 cycloalkyl or two R n groups together with their intervening nitrogens, optionally one or more C 1-4 C substituted with alkyl or halogen 3-6 forming a heterocycloalkyl, R o Each instance of is independently H or C 1-4 is alkyl, Each instance of R3 is independently H, halo, CN, C 1-4 Alkoxy, Halo-C 1-4 Alkyl, and C 1-4 is selected from the group consisting of alkyl, Each of R4 and R5 is independently H or F.

[0094] In one embodiment, provided herein is a compound of formula (I): [ka] or a stereoisomer, mixture of stereoisomers, or a pharmaceutically acceptable salt thereof, wherein: Q is CH or N; Z is CR5 or N; L is -CH2-, C=O, -CH(OH)-, or -O-; X is a 5-membered heteroarylene containing 1 to 3 heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, and the 5-membered heteroarylene is substituted with 1, 2, or 3 R2; Y is a 5- or 6-membered heteroarylene containing 1 to 3 heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, and the 5- or 6-membered heteroarylene is substituted with 0, 1, or 2 R3; R1 is selected from the group consisting of H, methyl, and hydroxymethyl; Each instance of R2 is independently H, CN, halo, [ka] -SC 1-4 Alkyl, -CO-C 1-4 Alkyl, 5-membered heteroaryl, C 1-4 Alkyl-SO-, C 1-4 Alkyl-SO2-, C 1-4 Alkoxy, C 1-4 Alkyl, Halo-C 1-4 Alkyl, C 1-4 Alkoxy-C 1-4 Alkyl, C 3-4 Cycloalkylmethyl, C 3-6 Cycloalkyl, and C 3-6 heterocyclyl, provided that when L is -CH2-, at least one R2 is selected from the group consisting of: [ka] -CO-C 1-4 Alkyl, 5-membered heteroaryl, -SC 1-4 Alkyl, C 1-4 Alkyl-SO-, or C 1-4 alkyl-SO2-, wherein the heteroaryl, cycloalkyl, heterocyclyl, alkoxy, or alkyl further comprises, as valence permits, 0, 1, 2, or 3 C 1-4 Alkyl, Si(C 1-4 alkyl)3, or halogen-substituted, R n Each instance of is independently H, C 1-4Alkyl, Halo-C 1-4 Alkyl or C 3-6 cycloalkyl or two R n groups together with their intervening nitrogens, optionally one or more C 1-4 C substituted with alkyl or halogen 3-6 forming a heterocycloalkyl, R o Each instance of is independently H or C 1-4 is alkyl, Each instance of R3 is independently H, halo, CN, C 1-4 Alkoxy, Halo-C 1-4 Alkyl, and C 1-4 is selected from the group consisting of alkyl, Each of R4 and R5 is independently H or F.

[0095] In one embodiment, Si(C 1-4 alkyl)3 is Si(Me)3.

[0096] In some embodiments, L is -CH2-. In some embodiments, L is C=O. In some embodiments, L is -O-. In some embodiments, L is -CH(OH)-. In some embodiments, L is -CH(OH)-, and the carbon is of chirality S. In some embodiments, L is -CH(OH)-, and the carbon is of chirality R.

[0097] In one embodiment, the compound is a compound of formula (IA): [ka] or a stereoisomer, a mixture of stereoisomers, or a pharmaceutically acceptable salt thereof.

[0098] In one embodiment, the compound is a compound of formula (IA-1): [ka] or a pharmaceutically acceptable salt thereof.

[0099] In one embodiment, the compound is a compound of formula (IA-2): [ka] or a pharmaceutically acceptable salt thereof.

[0100] In one embodiment, the compound is a compound of formula (IB): [ka] or a stereoisomer, a mixture of stereoisomers, or a pharmaceutically acceptable salt thereof.

[0101] In one embodiment, the compound is a compound of formula (IB-1): [ka] or a pharmaceutically acceptable salt thereof.

[0102] In one embodiment, the compound is a compound of formula (IB-2): [ka] or a pharmaceutically acceptable salt thereof.

[0103] In one embodiment, the compound is a compound of formula (IC): [ka] or a stereoisomer, a mixture of stereoisomers, or a pharmaceutically acceptable salt thereof.

[0104] In one embodiment, the compound is a compound of formula (IC-1): [ka] or a pharmaceutically acceptable salt thereof.

[0105] In one embodiment, the compound is a compound of formula (IC-2): [ka] or a pharmaceutically acceptable salt thereof.

[0106] In one embodiment, the compound is a compound of formula (ID): [ka] or a stereoisomer, a mixture of stereoisomers, or a pharmaceutically acceptable salt thereof.

[0107] In one embodiment, the compound is a compound of formula (ID-1): [ka] or a pharmaceutically acceptable salt thereof.

[0108] In one embodiment, the compound is a compound of formula (ID-1-1): [ka] or a pharmaceutically acceptable salt thereof.

[0109] In one embodiment, the compound is a compound of formula (ID-1-2): [ka] or a pharmaceutically acceptable salt thereof.

[0110] In one embodiment, in Y, the points of attachment to the L groups bonded to X and Y and to the aromatic ring containing Z are on adjacent atoms, and the ring atom of the 5-6 membered heteroarylene that is alpha to the point of attachment to the L group and beta to the point of attachment to the aromatic ring containing Z is nitrogen.

[0111] In one embodiment, in Y, the points of attachment to the L groups bonded to X and Y and to the aromatic ring containing Z are on adjacent atoms, and the ring atoms of the 5-6 membered heteroarylene that are alpha to the point of attachment to the L group and beta to the point of attachment to the aromatic ring containing Z are carbon, oxygen, or sulfur.

[0112] In some embodiments, X is a 5-membered heteroaryl selected from the group consisting of pyrazolylene, isoxazolylene, isothiazolylene, imidazolylene, and triazolylene. In some embodiments, X is selected from the group consisting of pyrazolylene and triazolylene. In certain embodiments, X is 4 * ,5-substituted pyrazolylene, 4,5 * -substituted pyrazolylene, 1 * ,5-substituted pyrazolylene, 4 * ,5-substituted isoxazolylene, 3 * ,4-substituted isoxazolylene, 3 * ,4-substituted isothiazolylene, 4 * ,5-substituted isothiazolylene, 4 * ,5-substituted imidazolylene, 1 * ,5-substituted imidazolylene, 1 * ,5-substituted triazolylenes, and 4 * , 5-substituted triazolylenes.

[0113] In some embodiments, X is a 5-membered heteroaryl selected from the group consisting of pyrazolylene, isoxazolylene, isothiazolylene, imidazolylene, and triazolylene. In some embodiments, X is selected from the group consisting of pyrazolylene and triazolylene. In certain embodiments, X is 4 * ,5-substituted pyrazolylene, 4,5 * -substituted pyrazolylene, 1 * ,5-substituted pyrazolylene, 4 * ,5-substituted isoxazolylene, 4,5 * -substituted isoxazolylene, 3 * ,4-substituted isoxazolylene, 3 *,4-substituted isothiazolylene, 4 * ,5-substituted isothiazolylene, 4,5 * -substituted isothiazolylene, 4 * ,5-substituted imidazolylene, 1 * ,5-substituted imidazolylene, 1 * ,5-substituted triazolylenes, and 4 * , 5-substituted triazolylenes.

[0114] In one embodiment, X is 3 * ,4-substituted pyrazolylene, 4 * ,5-substituted pyrazolylene, 4,5 * -substituted pyrazolylene, 1 * ,5-substituted pyrazolylene, 4 * ,5-substituted imidazolylene, 1 * ,5-substituted imidazolylene, or 4 * , 5-substituted triazolylenes; * indicates the point of attachment of X or Y to the L group attached to X and Y.

[0115] In certain embodiments, X is selected from the group consisting of: [ka] * indicates the point of attachment of X to the L group attached to X and Y.

[0116] In certain embodiments, X is selected from the group consisting of: [ka] * indicates the point of attachment of X to the L group attached to X and Y.

[0117] In one embodiment, X is pyrazolylene. In one embodiment, X is 3 * In one embodiment, X is not 4-substituted pyrazolylene. [ka] In one embodiment, X is not [ka] In one embodiment, X is not [ka] In one embodiment, X is [ka] In another embodiment, X is 3 * In another embodiment, X is 4-substituted pyrazolylene. * In another embodiment, X is a 4,5-substituted pyrazolylene. * In another embodiment, X is 1 * ,5-substituted pyrazolylene. In one embodiment, X is [ka] In one embodiment, X is [ka] In one embodiment, X is [ka] In one embodiment, X is [ka] is.

[0118] In one embodiment, X is [ka] and ** The R2 in the top 10 is [ka] -SC 1-4 Alkyl, CN, -CO-C 1-4 Alkyl, 5-membered heteroaryl, C 1-4 Alkyl-SO-, or C 1-4 It is alkyl-SO2-.

[0119] In one embodiment, X is isoxazolylene. In one embodiment, X is 4 * In one embodiment, X is a 4,5-substituted isoxazolylene. * In one embodiment, X is 3-substituted isoxazolylene. * ,4-substituted isoxazolylene. In one embodiment, X is [ka] In one embodiment, X is [ka] is.

[0120] In one embodiment, X is isothiazolylene. In one embodiment, X is 3 * In one embodiment, X is 4,4-substituted isothiazolylene. * In one embodiment, X is a 4,5-substituted isothiazolylene. * -substituted isothiazolylene. In one embodiment, X is [ka] is. In one embodiment, X is [ka] is.

[0121] In one embodiment, X is imidazolylene. In one embodiment, X is 4 * In one embodiment, X is 1,5-substituted imidazolylene.* ,5-substituted imidazolylene. In one embodiment, X is [ka] is.

[0122] In one embodiment, X is triazolylene. In one embodiment, X is 1 * In one embodiment, X is 4,5-substituted triazolylene. * In one embodiment, X is [ka] In one embodiment, X is [ka] is.

[0123] In some embodiments, X is substituted with 0 R2 (i.e., all vacant positions on X are H). In one embodiment, X is substituted with 1 R2 that is not H. In one embodiment, X is substituted with 2 R2 that are not H.

[0124] In some embodiments, at least one R2 (e.g., only one R2) is independently selected from H, CN, halo, C 1-4 Alkoxy, C 1-4 Alkyl, -SC 1-4 Alkyl, Halo-C 1-4 Alkyl, C 1-4 Alkoxy-C 1-4 Alkyl, C 3-4 Cycloalkylmethyl, C 3-6 Cycloalkyl, and C 3-6In some embodiments, at least one R2 (e.g., only one R2) is independently selected from the group consisting of H, fluoro, chloro, CN, methyl, and ethyl. In some embodiments, at least one R2 (e.g., only one R2) is independently selected from the group consisting of CN and methyl. In some embodiments, two R2 are present, and one R2 is CN and the other R2 is methyl.

[0125] In some embodiments, at least one R2 (e.g., only one R2) is [ka] In some embodiments, at least one R2 (e.g., only one R2) is [ka] In some embodiments, at least one R2 (e.g., only one R2) is [ka] In some embodiments, at least one R2 (e.g., only one R2) is -CO-C 1-4 In some embodiments, at least one R2 (e.g., the only R2) is a 5-membered heteroaryl (e.g., -C(=O)-CH3). In some embodiments, at least one R2 (e.g., the only R2) is a 5-membered heteroaryl (e.g., -C(=O)-CH3). 1-4 In some embodiments, at least one R2 (e.g., only one R2) is C 1-4 Alkyl-SO2- (e.g., -SO2-CH3).

[0126] In some embodiments, one R2 is selected from 1, 2, or 3 C 1-4 In some embodiments, one R is a 5-membered heteroaryl substituted with alkyl (e.g., methyl). In some embodiments, one R is a C 1-4It is a 5-membered heteroaryl substituted with alkyl (eg, methyl).

[0127] In some embodiments, R n is H. In some embodiments, R n is methyl. In some embodiments, R n is ethyl. In some embodiments, R n is isopropyl. In some embodiments, R n is cyclopropyl. In some embodiments, R n is —CH 2 CF 3 . In some embodiments, two R n The groups, together with their intervening nitrogens, may optionally contain one or more C 1-4 C substituted with alkyl or halogen 3-6 Forms a heterocycloalkyl.

[0128] In some embodiments, R o is H. In some embodiments, R o is methyl.

[0129] In some embodiments, each R is independently selected from the group consisting of CN, -CH-cyclopropyl, -CHCHOCH, -COEt, methyl, ethyl, -C(=O)-N(CH), -C(=O)-N(CH) i Pr, -C(=O)-N(CH3)Et, -C(=O)-NH2, -C(=O)-N(CH3)(CH2CF3), -C(=O)-N(CH3)(cyclopropyl), -C(=O)-CH3, -C(=O)-N(CH3)-OCH3, CH2-O(CH2)2-Si(CH3)3, -CH2-cyclobutyl, CH2-cyclopropyl, -(CH2)2-OCH3; [ka] -SO-CH3, and -SO2-CH3.

[0130] In some embodiments, Y is a 5-membered heteroarylene containing 1-3 heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, and the 5-membered heteroarylene is substituted with 0, 1, or 2 R3. In some embodiments, Y is a 6-membered heteroarylene containing 1-3 heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, and the 6-membered heteroarylene is substituted with 0, 1, or 2 R3. In some embodiments, Y is a 2 * ,3-substituted furanylene, 2,3 * -substituted furanylene, 3 * ,4-substituted furanylene, 1 * ,2-substituted imidazolylene, 1 * ,5-substituted imidazolylene, 1,5 * -substituted imidazolylene, 4,5 * -substituted 1,2,3-oxadiazolylene, 3,4 * -substituted 1,2-oxazolylene, 4 * ,5-substituted 1,2-oxazolylene, 4,5 * -substituted 1,2-oxazolylene, 4,5 * -substituted 1,3-oxazolylene, 1 * ,2-substituted phenylene, 1,5 * -substituted pyrazolylene, 4 * ,5-substituted pyrazolylene, 3,4 * -substituted 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 * -substituted 1,2,3-thiadiazolylene, 4 * ,5-substituted 1,2-thiazolylene, 4,5 * -substituted 1,2-thiazolylene, 4 * ,5-substituted-1,3-thiazolylene, 4,5 *-substituted 1,3-thiazolylene, 2 * ,3-substituted thiophenylene, 2,3 * -substituted thiophenylene, 3 * ,4-substituted thiophenylene, 4,5 * -substituted 1,2,3-triazinylene, 1,5 * -substituted 1,2,3-triazolylene, 4 * ,5-substituted triazolylenes, and 3,4 * -substituted 1,2,4-triazolylene, wherein the heteroarylene is substituted with 0, 1, or 2 R. In some embodiments, Y is 1 * ,5-substituted pyrazolylene, 3 * ,4-substituted pyrazolylene, 2,3 * -substituted pyridinylene, 3 * ,4-substituted pyridinylene, 3,4 * -substituted pyridinylene, 4,5 * -substituted 1,3-thiazolylene, 4 * ,5-substituted 1,2,3-triazolylene, 1 * ,5-substituted 1,2,4-triazolylene, 1,5 * -substituted 1,2,4-triazolylenes, and 4 * , 5-substituted 1,3-thiazolylenes; * indicates the point of attachment to L bonded to X.

[0131] In certain embodiments, Y is selected from the group consisting of: [ka] * indicates the point of attachment of Y to the L group attached to X and Y.

[0132] In certain embodiments, Y is [ka] and * indicates the point of attachment of Y to the L group attached to X and Y.

[0133] In certain embodiments, Y is a 5-membered heteroarylene. In certain embodiments, Y is a pyrazolylene. In certain embodiments, Y is a 1,5 * In certain embodiments, Y is 4-substituted pyrazolylene. * In certain embodiments, Y is a 3,4-substituted pyrazolylene. * -substituted pyrazolylene. In certain embodiments, Y is [ka] In certain embodiments, Y is [ka] In certain embodiments, Y is [ka] In certain embodiments, Y is [ka] is.

[0134] In certain embodiments, Y is imidazolylene. In certain embodiments, Y is 1 * In certain embodiments, Y is 5, 2-substituted imidazolylene. * , 1-substituted imidazolylene. In certain embodiments, Y is [ka] In certain embodiments, Y is [ka] In certain embodiments, Y is [ka] is.

[0135] In certain embodiments, Y is 1,2-thiazolylene. In certain embodiments, Y is 3,4 * -substituted 1,2-thiazolylene. In certain embodiments, Y is 4 * In certain embodiments, Y is [ka] In certain embodiments, Y is [ka] is.

[0136] In certain embodiments, Y is 1,3-thiazolylene. In certain embodiments, Y is 4,5 * -substituted 1,3-thiazolylene. In certain embodiments, Y is [ka] In certain embodiments, Y is 4 * In certain embodiments, Y is [ka] is.

[0137] In certain embodiments, Y is 1,2-oxazolylene. In certain embodiments, Y is 3,4 * -substituted 1,2-oxazolylene. In certain embodiments, Y is 4 * In certain embodiments, Y is [ka] In certain embodiments, Y is [ka] is.

[0138] In certain embodiments, Y is triazolylene. In certain embodiments, Y is 1,5 * -substituted 1,2,3-triazolylene. In certain embodiments, Y is 3,4 * -substituted 1,2,4-triazolylene. In certain embodiments, Y is [ka] In certain embodiments, Y is [ka] is.

[0139] In certain embodiments, Y is a 6-membered heteroarylene. In certain embodiments, Y is pyridinylene. In certain embodiments, Y is a 2,3 * -substituted pyridinylene. In certain embodiments, Y is 3 * In certain embodiments, Y is 4-substituted pyridinylene. * ,3-substituted pyridinylene. In certain embodiments, Y is [ka] In certain embodiments, Y is [ka] In certain embodiments, Y is [ka] In certain embodiments, Y is [ka] In certain embodiments, Y is [ka] In certain embodiments, Y is [ka] In certain embodiments, Y is [ka] In certain embodiments, Y is [ka] is.

[0140] In certain embodiments, Y is pyrimidinylene. In certain embodiments, Y is 4,5 * -substituted pyrimidinylene. In certain embodiments, Y is [ka] is.

[0141] In certain embodiments, Y is substituted with zero R3 (i.e., all vacant positions on Y are H). In certain embodiments, Y is substituted with one R3 that is not H. In certain embodiments, Y is substituted with two R3 that are not H.

[0142] In certain embodiments, R3 is H, halo, CN, C 1-4 Alkoxy, Halo-C 1-4 Alkyl, and C 1-4 In certain embodiments, R is selected from the group consisting of alkyl, C ... 1-4 In certain embodiments, R3 is alkyl. In certain embodiments, R3 is methyl. In certain embodiments, R3 is ethyl. In certain embodiments, R3 is halo. In certain embodiments, R3 is fluoro. In certain embodiments, R3 is chloro. In certain embodiments, R3 is CN.

[0143] In some embodiments, Q is CH. In other embodiments, Q is N.

[0144] In some embodiments, Z is CR. In certain embodiments, R is H. In certain embodiments, R is F. In other embodiments, Z is N.

[0145] In some embodiments, R1 is methyl. In some embodiments, R1 is hydrogen. In some embodiments, R1 is hydroxymethyl.

[0146] In some embodiments, R4 is H. In other embodiments, R4 is F.

[0147] In one embodiment of formula (IB), (IB-1), or (IB-2), X is [ka] and Y is [ka] In another embodiment, X is [ka] and Y is [ka] In another embodiment, X is [ka] and Y is [ka] In another embodiment, X is [ka] and Y is [ka] In another embodiment, X is [ka] and Y is [ka] In another embodiment, X is [ka] and Y is [ka] In another embodiment, X is [ka] and Y is [ka] In another embodiment, X is [ka] and Y is [ka] In another embodiment, X is [ka] and Y is [ka] In another embodiment, X is [ka] and Y is [ka] In one embodiment, R2 is selected from the group consisting of H, methyl, ethyl, CN, -C(=O)-N(CH3)2, methoxyethyl, isopropyl, and cyclopropylmethyl. In one embodiment, R3 is selected from the group consisting of H and methyl. In one embodiment, R1 is selected from the group consisting of H and methyl.

[0148] In one embodiment, the compound is a compound of any one of the following formulas: [ka] TIFF2025536922000104.tif59165 or a stereoisomer, a mixture of stereoisomers, or a pharmaceutically acceptable salt thereof.

[0149] In certain embodiments, provided herein are compounds of Table 1: [Table 1] TIFF2025536922000106.tif230165TIFF2025536922000107.tif198165TIFF2025536922000108.tif233165TIFF2025536922000109.tif225165TIFF2025536922000110.tif184165 or a pharmaceutically acceptable salt thereof.

[0150] In certain embodiments, provided herein are compounds of Table 1A: [Table 2] TIFF2025536922000112.tif232165TIFF2025536922000113.tif202165TIFF2025536922000114.tif232165TIFF2025536922000115.tif217165 or a pharmaceutically acceptable salt thereof.

[0151] In certain embodiments, provided herein are compounds of Table 1B: [Table 3] TIFF2025536922000117.tif232165TIFF2025536922000118.tif198165TIFF2025536922000119.tif232165TIFF2025536922000120.tif179165TIFF2025536922000121.tif135165 or a pharmaceutically acceptable salt thereof.

[0152] With respect to any compound in Table 1, Table 1A, or Table 1B that has a chiral center due to the presence of a non-hydrogen R1, the R-enantiomer, S-enantiomer, and racemate of such compound are all specifically provided herein, even if not explicitly shown in Table 1, Table 1A, or Table 1B.

[0153] In certain embodiments, provided herein are pharmaceutically acceptable salts of compounds of Formula (I). In certain embodiments, provided herein are pharmaceutically acceptable salts of any compound of Table 1, Table 1A, or Table 1B.

[0154] 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, benenthamine salts, benzathine salts, betaine salts, calcium hydroxide salts, choline salts, deanol salts, diethanolamine salts, diethylamine salts, 2-(diethylamino)ethanol salts, ethanolamine salts, ethylenediamine salts, N-methylglucamine salts, hydrabamine salts, 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 Zn salts.

[0155] In certain embodiments, the pharmaceutically acceptable salt is a solvate selected from the group consisting of water, methanol, ethanol, and dimethylformamide.

[0156] In certain embodiments, the compound is a pharmaceutical composition comprising a pharmaceutically acceptable carrier or excipient.

[0157] In certain 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.

[0158] 4.3 How to use Provided herein are methods for treating cancer, comprising administering a compound provided herein, e.g., a compound of Formula (I), or a stereoisomer, mixture of stereoisomers, or pharmaceutically acceptable salt thereof.

[0159] Cancer is a disease of uncontrolled cell proliferation caused by alterations in certain genes. Some of these alterations occur in genes encoding receptor tyrosine kinases (RTKs), a family of membrane-bound proteins that transmit signals from outside the cell to promote cell survival, growth, and proliferation. Abnormal RTK activation can lead to excessive cell proliferation and ultimately cancer. RTKs generally contain an N-terminal domain that binds to extracellular ligands, a transmembrane domain, and a C-terminal kinase domain that catalyzes intracellular signal transduction.

[0160] In some embodiments, the compound of Formula (I) is an inhibitor of human ROS1. ROS1 is a RTK encoded by the ROS1 gene. While the ligand and biological function of human ROS1 are unknown, its homologs in several other species have been shown to bind extracellular ligands and stimulate cell differentiation. For example, mouse ROS1 is essential for male gamete maturation and reproduction. In humans, chromosomal rearrangements of ROS1 are a well-documented cause of cancer, accounting for 1-2% of non-small cell lung cancer (NSCLC) cases and a subset of many other cancers. These rearrangements result in fusions of the C-terminus of ROS1 with the N-terminus of various partner proteins, the most common of which is CD74. ROS1 fusions have constitutive kinase activity that promotes tumor growth through MAPK, PI3K, and JAK / STAT signaling pathways. Small molecule tyrosine kinase inhibitors (TKIs), including crizotinib and entrectinib, have been used to target ROS1 fusions in cancer. Crizotinib, the first FDA-approved TKI for the treatment of ROS1-positive NSCLC, has an overall response rate of 60–80% and a median progression-free interval of 9–19 months. Despite initial responses, most patients develop resistance to crizotinib and relapse. The primary mechanism of resistance is the G2032R mutation in the solvent front, which dramatically reduces the affinity of crizotinib. No inhibitors with activity against the ROS1-G2032R fusion have been approved by the FDA, demonstrating a need in the art.

[0161] In some embodiments, the compound of Formula (I) is an inhibitor of human anaplastic lymphoma kinase (ALK). ALK, also known as cluster of differentiation 246 (CD246), is a RTK encoded by the ALK gene. ALK and ROS1 are evolutionarily related. Both belong to the insulin receptor superfamily, and their kinase domains share approximately 80% sequence similarity. While the role of ALK in humans remains uncertain, mounting evidence from mouse studies suggests that ALK is important for nervous system development. Similar to ROS1, chromosomal rearrangements of ALK also lead to constitutively active fusion proteins that promote oncogenic transformation via MAPK, JAK / STAT, or other signaling pathways. ALK rearrangements are present in 3-5% of NSCLCs, approximately half of anaplastic large cell lymphomas (ALCLs), and subsets of many other cancers; the predominant fusions are EML4-ALK in NSCLC and NPM1-ALK in ALCL. Oncogenic point mutations and amplifications of ALK have also been observed, although at much lower frequencies than translocations. Crizotinib, ceritinib, alectinib, brigatinib, and lorlatinib are FDA-approved TKIs for first-line or prior treatment of ALK-positive NSCLC and other cancers. For example, crizotinib has demonstrated an overall response rate of 60–80% and a median progression-free interval of 8–11 months, comparable to its activity in ROS1-positive NSCLC. Despite initial responses, many resistance mutations have emerged against the aforementioned FDA-approved TKIs. Some of these mutations, such as the combination of the L1196M gatekeeper and G1202R solvent-front mutations, confer resistance to all approved drugs. There is a significant need in the art for new therapies for ALK-positive cancers with resistance mutations.

[0162] In a further embodiment, the compound of Formula (I) is an inhibitor of human tropomyosin receptor kinase (TRK). The TRK family includes receptor tyrosine kinases TRKA, TRKB, and TRKC, which are encoded by the NTRK1, NTRK2, and NTRK3 genes, respectively. Each TRK is activated by a distinct but overlapping set of neurotrophin ligands, such as NGF, BDNF, and NT-3. All TRKs regulate similar downstream signaling pathways (90% similarity), consistent with sequence divergence in the ligand-binding domain rather than convergence in the kinase domain. TRKs play important roles in the developing and adult mammalian nervous system by regulating processes such as memory, movement, pain, and proprioception. Similar to ROS1 and ALK, NTRK rearrangements result in constitutively active TRK fusions, which promote oncogenic transformation via MAPK, PI3K, and other pathways. TRK fusions are found in many cancers, accounting for over 80% of cases of secretory breast cancer, mammary analogue secretory carcinoma, infantile fibrosarcoma, and congenital mesoblastic nephroma. Therefore, inhibition of TRK is advantageous for treating cancers that express TRK fusions.

[0163] Many existing ROS1 and ALK inhibitors also exhibit potent inhibition of native, non-oncogenic TRKs. This is a substantial drawback because native TRKs perform important functions 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. There is a need in the art for new therapies that selectively target non-mutated and / or mutant ROS1 and / or ALK while sparing TRKs.

[0164] In certain embodiments, provided herein are methods for reducing the level of ROS1 or ALK in a cell, the method comprising contacting the cell with a compound or pharmaceutical composition or pharmaceutical combination provided herein. In embodiments, such contacting occurs in a mammalian, e.g., human, cell. In embodiments, such contacting occurs in a human patient with a cancer as described herein.

[0165] In certain embodiments, the compound selectively inhibits ROS1 over TRK (e.g., TRKA, TRKB, and / or TRBC). By way of non-limiting example, the selectivity ratio can be determined by, among other measures, the IC 50 The selectivity of ROS1 for TRK can be measured by the ratio of IC values, which can be greater than about 5-fold, greater than about 10-fold, greater than about 50-fold, greater than about 100-fold, greater than about 200-fold, greater than about 400-fold, greater than about 600-fold, greater than about 800-fold, greater than about 1000-fold, greater than about 1500-fold, greater than about 2000-fold, greater than about 5000-fold, greater than about 10,000-fold, or greater than about 20,000-fold. In certain embodiments, the selectivity of ROS1 for TRK can be measured by the ratio of IC values, which can be measured by the ratio of IC values, which can be greater than about 5-fold, greater than about 10-fold, greater than about 50-fold, greater than about 1000-fold, greater than about 2000-fold, greater than about 5000-fold, greater than about 10,000-fold, or greater than about 20,000-fold. 50 values ​​and IC against ROS1 50 It is measured by the ratio of

[0166] In certain embodiments, the compounds provided herein selectively inhibit ALK. In certain embodiments, the compounds selectively inhibit ALK over ROS1. By way of non-limiting example, the selectivity ratio can be determined by, among other measures, the IC 50 As can be measured by a ratio of IC values, it can be greater than about 1.5-fold, greater than about 2-fold, greater than about 3-fold, greater than about 4-fold, greater than about 5-fold, or greater than about 10-fold. In certain embodiments, the selectivity of ALK for ROS1 is measured by the IC ratio for ROS1. 50 value and IC for ALK 50 It is measured by the ratio of

[0167] In certain embodiments, the compound selectively inhibits ALK over TRK (e.g., TRKA, TRKB, and / or TRBC). By way of non-limiting example, the selectivity ratio can be determined by, among other measures, the IC 50 The selectivity of ALK over TRK can be measured by the ratio of IC values, which can be greater than about 5-fold, greater than about 10-fold, greater than about 50-fold, greater than about 100-fold, greater than about 200-fold, greater than about 400-fold, greater than about 600-fold, greater than about 800-fold, greater than about 1000-fold, greater than about 1500-fold, greater than about 2000-fold, greater than about 5000-fold, or greater than about 10,000-fold. In certain embodiments, the selectivity of ALK over TRK can be measured by the ratio of IC values, which can be measured by the ratio of IC values, which can be greater than about 5-fold, greater than about 10-fold, greater than about 50-fold, greater than about 1000-fold, greater than about 2000-fold, greater than about 5000-fold, or greater than about 10,000-fold. 50 value and IC for ALK 50It is measured by the ratio of

[0168] In one embodiment, without being bound by any particular theory, one or more compounds provided herein selectively inhibit a mutation in ALK over a TRK (e.g., TRKA, TRKB, and / or TRBC), wherein the ALK mutation is I1171X 1 (X 1 is N, S, or T) and / or D1203N. In one embodiment, the compound is I1171X rather than TRKA. 1 (X 1 is N, S, or T). In one embodiment, the compound selectively inhibits I1171X over TRKB. 1 (X 1 is N, S, or T). In one embodiment, the compound selectively inhibits I1171N over TRKB. In one embodiment, the compound selectively inhibits D1203N over TRKB. In one embodiment, the compound selectively inhibits I1171X over TRKB. 1 (X 1 is N, S, or T) and D1203N. In one embodiment, the compound selectively inhibits I1171N and D1203N over TRKB. In one embodiment, the selectivity ratio is at least about 5-fold. In one embodiment, the selectivity ratio is at least about 10-fold. In one embodiment, the selectivity ratio is at least about 30-fold. In one embodiment, the selectivity ratio is at least about 50-fold. In one embodiment, the selectivity of the ALK mutation over TRK is measured by the IC 50 Value and IC for ALK mutations 50 It is measured by the ratio of

[0169] In certain embodiments, the compounds selectively inhibit ROS1 and ALK over TRK (e.g., TRKA, TRKB, and / or TRBC). By way of non-limiting example, the selectivity ratio can be determined by, among other measures, the IC 50The selectivity of ROS1 and ALK for TRK can be measured by the ratio of IC values, which can be greater than about 5-fold, greater than about 10-fold, greater than about 50-fold, greater than about 100-fold, greater than about 200-fold, greater than about 400-fold, greater than about 600-fold, greater than about 800-fold, greater than about 1000-fold, greater than about 1500-fold, greater than about 2000-fold, greater than about 5000-fold, greater than about 10,000-fold, or greater than about 20,000-fold. In certain embodiments, the selectivity of ROS1 and ALK for TRK can be measured by the ratio of IC values, which can be measured by the ratio of IC values, which can be greater than about 5-fold, greater than about 10-fold, greater than about 50-fold, greater than about 1000-fold, greater than about 2000-fold, greater than about 5000-fold, greater than about 10,000-fold, or greater than about 20,000-fold. 50 values ​​and IC for ROS1 and ALK 50 It is measured by the ratio of

[0170] In some embodiments, selectivity or selectivity ratio, as used herein, is measured by a biochemical assay or a cell proliferation assay. In some embodiments, the cell proliferation assay is a Ba / F3 proliferation assay.

[0171] In certain embodiments, provided herein are methods for selectively inhibiting ROS1 over TRK (e.g., TRKA, TRKB, and / or TRBC), wherein the inhibition occurs intracellularly. In certain embodiments, the method comprises contacting ROS1 with an effective amount of a compound provided herein. In embodiments, such contacting occurs intracellularly. In embodiments, such contacting occurs in a mammalian, e.g., human, cell. In embodiments, such contacting occurs in a human patient with a cancer as described herein.

[0172] In certain embodiments, provided herein are methods for selectively inhibiting ROS1 over TRK (e.g., TRKA, TRKB, and / or TRBC), the inhibition being carried out in a subject suffering from cancer, the method comprising administering to the subject an effective amount of a compound or pharmaceutical composition provided herein. In certain embodiments, provided herein are methods for treating a subject suffering from a cancer associated with ROS1, the method comprising selectively inhibiting ROS1 over TRK (e.g., TRKA, TRKB, and / or TRBC) by administering to the subject an amount of a compound or pharmaceutical composition provided herein, the amount being sufficient to selectively inhibit ROS1 over TRK (e.g., TRKA, TRKB, and / or TRBC).

[0173] In certain embodiments, provided herein are methods for selectively inhibiting ALK over ROS1, wherein the inhibition occurs intracellularly. In certain embodiments, provided herein are methods for selectively inhibiting ALK over TRK (e.g., TRKA, TRKB, and / or TRBC), wherein the inhibition occurs intracellularly. In certain embodiments, the method comprises contacting ALK with an effective amount of a compound provided herein. In embodiments, such contacting occurs intracellularly. In embodiments, such contacting occurs in a mammalian, e.g., human, cell. In embodiments, such contacting occurs in a human patient with a cancer as described herein.

[0174] In certain embodiments, provided herein are methods for selectively inhibiting ALK over ROS1 in a subject suffering from cancer, the method comprising administering to the subject an effective amount of a compound or pharmaceutical composition provided herein. In certain embodiments, provided herein are methods for treating a subject suffering from an ALK-associated cancer, the method comprising selectively inhibiting ALK over ROS1 by administering to the subject an amount of a compound or pharmaceutical composition provided herein, the amount being sufficient to selectively inhibit ALK over ROS1.

[0175] In certain embodiments, provided herein are methods for selectively inhibiting ALK over TRK (e.g., TRKA, TRKB, and / or TRBC), the inhibition being carried out in a subject suffering from cancer, the method comprising administering to the subject an effective amount of a compound or pharmaceutical composition provided herein. In certain embodiments, provided herein are methods for treating a subject suffering from an ALK-associated cancer, the method comprising selectively inhibiting ALK over TRK (e.g., TRKA, TRKB, and / or TRBC) by administering to the subject an amount of a compound or pharmaceutical composition provided herein, the amount sufficient to selectively inhibit ALK over TRK (e.g., TRKA, TRKB, and / or TRBC).

[0176] As used herein, unless otherwise specified, inhibition of ROS1 includes inhibition of wild-type ROS1 or mutants thereof, inhibition of ALK includes inhibition of wild-type ALK or mutants thereof, and inhibition of TRK includes inhibition of wild-type TRK or mutants thereof.

[0177] Cancers that may be treated by the methods provided herein include, but are not limited to, lung cancer, e.g., non-small cell lung cancer, inflammatory myofibroblastic tumor, ovarian cancer, e.g., serous ovarian cancer, melanoma, e.g., Spitz nevus melanoma, glioblastoma, bile duct cancer, e.g., cholangiocarcinoma, gastric cancer, colorectal cancer, angiosarcoma, anaplastic large cell lymphoma, diffuse large B-cell lymphoma, large B-cell lymphoma, esophageal cancer, e.g., esophageal squamous cell carcinoma, kidney cancer, e.g., renal medullary carcinoma or renal cell carcinoma, breast cancer, e.g., triple-negative breast cancer, thyroid cancer, e.g., papillary thyroid carcinoma, neuroblastoma, epithelioid hemangioendothelioma, colon cancer, and Spitz nevus tumor.

[0178] Cancers treated by the methods provided herein include cancers driven by one or more oncogenic proteins selected from ROS1, ALK, TRKA, TRKB, and TRKC. In certain embodiments, cancers treated by the methods provided herein include cancers that are drug resistant to treatments directed against one or more oncogenic proteins selected from ROS1, ALK, TRKA, TRKB, and TRKC.

[0179] In one embodiment, the cancer in the methods provided herein is anaplastic lymphoma kinase positive (ALK+). As used herein, unless otherwise specified, "ALK-positive" (ALK+) cancer, disease, or disorder refers to a cancer, disease, or disorder characterized by inappropriately high expression of the ALK gene and / or the presence of a mutation in the ALK gene and / or the presence of a partially deleted ALK protein. In one embodiment, "ALK-positive" (ALK+) cancer, disease, or disorder refers to a cancer, disease, or disorder characterized by inappropriately high expression of the ALK gene and / or the presence of a mutation in the ALK gene. In one embodiment, "ALK-positive" (ALK+) cancer, disease, or disorder refers to a cancer, disease, or disorder characterized by the presence of a partially deleted ALK protein (e.g., NB1, AskaSS). In one embodiment, the mutation alters the biological activity of an ALK nucleic acid molecule or polypeptide. As used herein, unless otherwise specified, an ALK "mutation" or "mutant" includes one or more deletions, substitutions, insertions, inversions, duplications, translocations, or amplifications in the amino acid or nucleotide sequence of ALK, or a fragment thereof. As used herein, unless otherwise specified, an ALK "rearrangement" refers to a genetic translocation involving the ALK gene that can result in an ALK fusion gene and / or ALK fusion protein. The ALK fusion can also include one or more deletions, substitutions, insertions, inversions, duplications, translocations, or amplifications, or fragments thereof, so long as the mutant retains kinase phosphorylation activity.

[0180] In certain embodiments, the ALK mutation comprises one or more ALK point mutations. In some embodiments, the cancer treated by the methods provided herein comprises one or more mutations in ALK kinase. In certain embodiments, the one or more ALK point mutations are selected from point mutations at T1151, L1152, C1156, I1171, F1174, V1180, L1196, L1198, G1202, D1203, S1206, E1210, F1245, G1269, and R1275. In certain embodiments, the one or more ALK point mutations are selected from G1202R, G1202K, L1196M, G1269A, G1269S, C1156Y, I1171T, I1171N, I1171S, F1174L, V1180L, S1206Y, E1210K, I151Tins, F1174C, F1174L, G1202del, D1203N, S1206R, S1206C, L1152R, L1196Q, L1198P, L1198F, R1275Q, L1152P, C1156T, F1245V, and T1151_L1152insT. In certain embodiments, the ALK mutation is selected from the group consisting of G1202R, L1196M, G1269A, D1203N, I1171N, I1171S, I1171T, C1156Y, F1174L, S1206R, G1269S, and T1151_L1152insT. In certain embodiments, the ALK mutation is G1202R. In certain embodiments, the ALK mutation is L1196M. In certain embodiments, the ALK mutation is G1269A. In certain embodiments, the ALK mutation is L1198F. In certain embodiments, the ALK mutation is a co-mutation of G1202R with one or more mutations selected from L1196M, G1269A, and L1198F. In certain embodiments, the ALK mutation is a G1202R / L1196M double mutation. In certain embodiments, the ALK mutation is a G1202R / G1269A double mutation. In certain embodiments, the ALK mutation is a G1202R / L1198F double mutation.In certain embodiments, the ALK mutation is I1171N. In certain embodiments, the ALK mutation is I1171S. In certain embodiments, the ALK mutation is I1171T. In certain embodiments, the ALK mutation is D1203N. In certain embodiments, the ALK mutation is F1174L. In certain embodiments, the ALK mutation is an I1171N / D1203N double mutation. In certain embodiments, the ALK mutation is an I1171N / L1198F double mutation. In certain embodiments, the ALK mutation is an I1171N / L1198Y double mutation. In certain embodiments, the ALK mutation is an I1171N / L1198I double mutation. In certain embodiments, the ALK mutation is an I1171T / D1203N double mutation. In certain embodiments, the ALK mutation is an I1171S / D1203N double mutation. In certain embodiments, the ALK mutation is an I1171T / L1198Y double mutation. In certain embodiments, the ALK mutation is an I1171T / L1198F double mutation. In certain embodiments, the ALK mutation is an I1171T / L1198I double mutation. In certain embodiments, the ALK mutation is an I1171S / L1198Y double mutation. In certain embodiments, the ALK mutation is an I1171S / L1198F double mutation. In certain embodiments, the ALK mutation is an I1171S / L1198I double mutation.

[0181] In one embodiment, the ALK mutation comprises one or more ALK point mutations. In some embodiments, the cancer treated by the methods of the present disclosure comprises one or more mutations in ALK kinase. In one embodiment, the one or more ALK point mutations are selected from point mutations at T1151, L1152, C1156, I1171, F1174, V1180, L1196, L1198, G1202, D1203, S1206, E1129, E1210, F1245, G1269, and R1275. In one embodiment, the one or more ALK point mutations are selected from R1060H, F1174C / I / L / S / V, F1245C / I / L / V, R1275L / Q, T1151M, M1166R, I1171N, I1171S, I1171N, I1183T, L1196M, A1200V, L1204F, L1240V, D1270G, Y1278S, R1192P, G1128A, G1286R, and T1343I. In one embodiment, the one or more ALK point mutations are G1202R, G1202K, L1196M, G1269A, G1269V, C1156Y, I1171T, I1171N, I1171S, F1174I, F1174L, F1174S, V1180L, S1206Y, E1129K, E1210K, T1151M, T1151_L1152ins In one embodiment, the ALK mutation is selected from the group consisting of T, F1174C, G1202del, D1203N, S1206Y, S1206C, S1206F, L1152R, L1196Q, L1198P, L1198F, L1198H, R1275Q, L1152P, C1156T, F1245C, T1151K, I1268V, F1174V, L1198Q, S1206A, and F1245V. In one embodiment, the ALK mutation is G1202R. In one embodiment, the ALK mutation is L1196M. In one embodiment, the ALK mutation is G1269A. In one embodiment, the ALK mutation is G1269V. In one embodiment, the ALK mutation is L1198F. In one embodiment, the ALK mutation is L1198H. In one embodiment, the ALK mutation is T1151M. In one embodiment, the ALK mutation is F1174L.In one embodiment, the ALK mutation is F1174I. In one embodiment, the ALK mutation is F1174S. In one embodiment, the ALK mutation is I1171N. In one embodiment, the ALK mutation is I1171S. In one embodiment, the ALK mutation is I1171T. In one embodiment, the ALK mutation is I1171N. In one embodiment, the ALK mutation is E1129K. In one embodiment, the ALK mutation is S1206F. In one embodiment, the ALK mutation is E1210K. In one embodiment, the ALK mutation is D1203N. In one embodiment, the ALK mutation is R1275G. In one embodiment, the ALK mutation is F1245C. In one embodiment, the ALK mutation is T1151K. In one embodiment, the ALK mutation is I1268V. In one embodiment, the ALK mutation is F1174V. In one embodiment, the ALK mutation is L1198Q. In one embodiment, the ALK mutation is S1206A.

[0182] As used herein, unless otherwise specified, "co-mutation" refers to mutations that occur simultaneously, i.e., when two or more mutations are present at the same time, for example, in the same cell and on the same allele, in the same cell but on different alleles, or in different cells.

[0183] As used herein, unless otherwise specified, "compound mutation" refers to two or more mutations located on the same allele. Compound mutation is a subset of co-mutation. Compound mutation may also be called double mutation when two mutations exist on the same allele.

[0184] In certain embodiments, the ALK mutation is I1171X 1 (X 1is N, S, or T) in combination with one or more of the following mutations: D1203N, L1198X 2 (X 2 are Y, F, I), L1196X 3 (X 3 is M or Q), C1156X 4 (X 4 is Y or F), G1269A, F1174X 5 (X 5 are L, C, V, I, S), and G1202X 6 (X 6 is R, L, K). In certain embodiments, the ALK mutation is I1171X 1 (X 1 is N, S, or T) in combination with one of the following mutations: D1203N, L1198X 2 (X 2 are Y, F, I), L1196X 3 (X 3 is M or Q), C1156X 4 (X 4 is Y or F), G1269A, F1174X 5 (X 5 are L, C, V, I, S), and G1202X 6 (X 6 is R, L, K). In certain embodiments, the ALK mutation is I1171X 1 (X 1 is N, S, or T) in combination with one of the following mutations: D1203N, L1198X 2 (X 2 are Y, F, and I).

[0185] In some embodiments, the ALK mutation is a co-mutation of G1202R with one or more mutations selected from L1196M, G1269A, T1151M, F1174S, and L1198F. In one embodiment, the ALK mutation is a G1202R / L1196M compound mutation. In one embodiment, the ALK mutation is a G1202R / G1269A compound mutation. In one embodiment, the ALK mutation is a G1202R / L1198F compound mutation. In one embodiment, the ALK mutation is a G1202R / T1151M compound mutation. In one embodiment, the ALK mutation is a G1202R / F1174S compound mutation. In one embodiment, the ALK mutation is a G1202R / F1174L compound mutation. In one embodiment, the ALK mutation is a co-mutation of C1156Y with one or more mutations selected from L1256F, S1206F, F1174V, and F1174I. In one embodiment, the ALK mutation is a C1156Y / L1256F compound mutation. In one embodiment, the ALK mutation is a C1156Y / S1206F compound mutation. In one embodiment, the ALK mutation is a C1156Y / F1174V compound mutation. In one embodiment, the ALK mutation is a C1156Y / F1174I compound mutation. In one embodiment, the ALK mutation is a L1196M co-mutation with one or more mutations selected from L1198H, I1179V, and L1256F. In one embodiment, the ALK mutation is a compound mutation of L1196M / L1198H. In one embodiment, the ALK mutation is a compound mutation of L1196M / I1179V. In one embodiment, the ALK mutation is a compound mutation of L1196M / L1256F.

[0186] In one embodiment, the ALK mutation is a G1202R / L1196M double mutation. In one embodiment, the ALK mutation is a G1202R / G1269A double mutation. In one embodiment, the ALK mutation is a G1202R / L1198F double mutation. In one embodiment, the ALK mutation is a G1202R / T1151M double mutation. In one embodiment, the ALK mutation is a G1202R / F1174S double mutation. In one embodiment, the ALK mutation is a G1202R / F1174L double mutation. In one embodiment, the ALK mutation is a C1156Y / L1256F double mutation. In one embodiment, the ALK mutation is a C1156Y / S1206F double mutation. In one embodiment, the ALK mutation is a C1156Y / F1174V double mutation. In one embodiment, the ALK mutation is a C1156Y / F1174I double mutation. In one embodiment, the ALK mutation is a L1196M / L1198H double mutation. In one embodiment, the ALK mutation is a L1196M / I1179V double mutation. In one embodiment, the ALK mutation is a L1196M / L1256F double mutation.

[0187] In certain embodiments, the ALK mutation comprises one or more ALK rearrangements (in certain embodiments, one rearrangement). In certain embodiments, the ALK mutation comprises one or more ALK fusions (in certain embodiments, one fusion). In some embodiments, the cancer treated by the methods provided herein comprises an ALK fusion. In certain embodiments, the ALK fusion 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 some embodiments, the ALK fusion is with NPM1, STRN, or EML4. In certain embodiments, the ALK mutation is EML4-ALK, i.e., a fusion between the echinoderm microtubule-associated protein-like 4 (EML4) gene and the tyrosine kinase domain of ALK. There are many variants of EML4-ALK with different breakpoint junctions, with variant 1 (v1) and variant 3 (v3) being the most common clinically. In one embodiment, the ALK mutation is NPM1-ALK. In one embodiment, the ALK mutation is STRN-ALK.

[0188] In one embodiment, the ALK mutation comprises one or more ALK rearrangements (in one embodiment, one rearrangement). In one embodiment, the ALK mutation comprises one or more ALK fusions (in one embodiment, one fusion). In some embodiments, the cancer treated by the methods of the present disclosure comprises an ALK fusion. In one embodiment, the ALK fusion is with one of the fusion partners described in Ou et al., JTO Clinical and Research Reports, 1(1):1-10, which is incorporated herein by reference in its entirety. In one embodiment, the ALK fusion is selected from the group consisting of EML4, TFG, KIF5B, KLC1, STRN, HIP1, TPR, BIRC6, DCTN1, SQSTM1, SOCS5, SEC31A, CLTC, PRKAR1A, PPM1B, EIF2AK3, CRIM1, CEBPZ, PICALM, CLIP1, BCL11A, GCC2, LMO7, PHACTR1, CMTR1, VIT, DYSF, ITGAV, PLEKHA7, CUX1, VKORC1L1, FBXO36, SPTBN1, EML6, FBXO11, CLIP4, CAMKMT, NCOA1, MYT1L, SRBD1, SRD5A2, NYAP2, MPRIP, ADAM17, ALK, LPIN1, WDPCP, CEP55, ERC1, SLC The fusion partner is one selected from the group consisting of 16A7, TNIP2, ATAD2B, SLMAP, FBN1, SWAP70, TCF12, TRIM66, WNK3, AKAP8L, SPECC1L, PRKCB, CDK15, LCLAT1, YAP1, PLEKHM2, DCHS1, PPFIBP1, ATP13A4, C12orf75, EPAS1, FAM179A, FUT8, LIMD1, LINC00327, LOC349160, LYPD1, RBM20, TACR1, TANC1, TTC27, TUBBB, SMPD4, SORCS1, LINC00211, SOS1, C9orf3, CYBRD1, MTA3, THADA, TSPYL6, WDR37, and PLEKHH2.In one embodiment, the ALK fusion is with one of the fusion partners selected from the group consisting of EML4, TMP1, WDCP, GTF2IRD1, TPM3, TPM4, CLTC, LMNA, PRKAR1A, RANBP2, TFG, FN1, KLC1, VCL, STRN, HIP1, NPM1, DCTN1, SQSTM1, TPR, CRIM1, PTPN3, FBXO36, ATIC, MSN, ALO17, MYH9, LRRFIP1-ALK, TDRD15-ALK, and KIF5B. In one embodiment, the ALK mutation is EML4-ALK, i.e., a fusion between the echinoderm microtubule-associated protein-like 4 (EML4) gene and the tyrosine kinase domain of ALK. There are many variants of EML4-ALK with different breakpoint junctions, with variant 1 (v1) and variant 3 (v3) being the most common clinically. In one embodiment, the ALK mutation is NPM1-ALK. In one embodiment, the ALK mutation is STRN-ALK.

[0189] In one embodiment, the ALK mutation comprises an ALK rearrangement and one or more ALK point mutations. In one embodiment, the ALK mutation is EML4-ALK wild-type ("wt") (variant 1). In one embodiment, the ALK mutation is EML4-ALK (variant 2). In one embodiment, the ALK mutation is EML4-ALK (variant 3). In one embodiment, the ALK mutation is EML4-ALK wt (variant 4, 5, 6, or 7). In one embodiment, the ALK mutation is EML4-ALK wt (variant 8, 9, 10, 11, 12, 13, 14, or 15). As used herein, each variant also includes subvariants within the variant. In one embodiment, the ALK mutation is EML4-ALK G1202R. In one embodiment, the ALK mutation is EML4-ALK I1171N. In one embodiment, the ALK mutation is EML4-ALK I1171S. In one embodiment, the ALK mutation is EML4-ALK I1171T. In one embodiment, the ALK mutation is EML4-ALK L1196M. In one embodiment, the ALK mutation is EML4-ALK D1203N. In one embodiment, the ALK mutation is EML4-ALK L1196M / G1202R. In one embodiment, the ALK mutation is EML4-ALK G1202R / G1269A. In one embodiment, the ALK mutation is EML4-ALK G1202R / L1196M. In one embodiment, the ALK mutation is EML4-ALK G1202R / L1198F. In one embodiment, the ALK mutation is EML4-ALK G1202R / T1151M. In one embodiment, the ALK mutation is EML4-ALK G1202R / F1174S. In one embodiment, the ALK mutation is EML4-ALK G1202R / F1174L. In one embodiment, the ALK mutation is EML4-ALK I1171N / D1203N.In one embodiment, the ALK mutation is EML4-ALK I1171S / D1203N. In one embodiment, the ALK mutation is EML4-ALK I1171T / D1203N.

[0190] In some embodiments, the ALK mutation comprises one or more ALK point mutations. In some embodiments, the cancer treated by the methods provided herein comprises one or more mutations in ALK kinase. In certain embodiments, the one or more ALK point mutations are selected from point mutations at T1151, L1152, C1156, I1171, F1174, V1180, L1196, L1198, G1202, D1203, S1206, E1210, F1245, G1269, and R1275. In certain embodiments, the one or more ALK point mutations are selected from T1151_L1152insT, L1152R, T1151M, L1152P, C1156Y, C1156T, I1171T, I1171N, I1171S, F1174C, F1174S, F1174L, V1180L, L1196M, L1196Q, L1198P, L1198F, G1202R, G1202K, G1202del, D1203N, S1206Y, S1206C, E1210K, F1245V, G1269A, and R1275Q. In certain embodiments, the ALK mutation is selected from the group consisting of G1202R, L1196M, G1269A, D1203N, I1171N, I1171S, I1171T, C1156Y, F1174L, and T1151_L1152insT. In certain embodiments, the ALK mutation is G1202R. In certain embodiments, the ALK mutation is L1196M. In certain embodiments, the ALK mutation comprises F1174S or F1174L. In certain embodiments, the ALK mutation comprises R1275Q. In certain embodiments, the ALK mutation comprises T1151M. In certain embodiments, the ALK mutation comprises I1171T, I1171S, or I1171N. In one embodiment, the ALK mutation comprises one or more compound mutations.In one embodiment, the compound mutation is selected from G1202R / T1151M, G1202R / L1196M, G1202R / G1269A, G1202R / L1198F, G1202R / F1174S, I1171T / D1203N, I1171T / L1198Y, I1171T / 1198F, I1171T / 1198I, I1171S / D1203N, I1171S / L1198Y, I1171S / 1198F, I1171S / 1198I, I1171N / D1203N, I1171N / L1198Y, I1171N / 1198F, and I1171N / 1198I. In one embodiment, the compound mutation is G1202R / L1196M, G1202R / G1269A, G1202R / L1198F, or G1202R / F1174S. In one embodiment, the compound mutation is G1202R / L1196M. In one embodiment, the compound mutation is G1202R / G1269A. In one embodiment, the compound mutation is G1202R / L1198F. In one embodiment, the compound mutation is G1202R / F1174S. In one embodiment, the ALK-positive solid tumor is characterized by the presence of a partially deleted ALK protein. In one embodiment, the ALK mutation is Ex2-3del. In one embodiment, the ALK mutation is Ex2-17del.

[0191] In one embodiment, the ALK-positive solid tumor is characterized by the presence of a mutation in the ALK gene. In one embodiment, the ALK mutation comprises one or more ALK rearrangements, one or more ALK point mutations, or a combination thereof. In one embodiment, the ALK mutation comprises G1202R, F1174C, F1174L, I1171N, I1171S, I1171T, L1196M, V1180L, C1156Y, G1202del, G1202K, G1269A, F1174S, S1206Y, E1210K, T1151M, T1151_L1152insT, D1203N, S1206C, L1152R, L1196Q, L1198P, L1198F, R1275Q, L1152P, C1156T, or F1245V, or a combination thereof. In one embodiment, the ALK mutation comprises G1202R. In one embodiment, the ALK mutation comprises F1174S or F1174L. In one embodiment, the ALK mutation comprises I1171S. In one embodiment, the ALK mutation comprises I1171T. In one embodiment, the ALK mutation comprises I1171N. In one embodiment, the ALK mutation comprises F1171M. In one embodiment, the ALK mutation comprises D1203N and one selected from I1171S, I1171T, I1171N, and I1171M. In one embodiment, the ALK mutation comprises C1156Y and one selected from I1171S, I1171T, I1171N, and I1171M. In one embodiment, the ALK mutation comprises R1275Q. In one embodiment, the ALK mutation comprises T1151M. In one embodiment, the ALK mutation comprises one or more compound mutations. In one embodiment, the compound mutation is G1202R / L1196M, G1202R / G1269A, G1202R / L1198F, or G1202R / F1174S. In one embodiment, the compound mutation is G1202R / L1196M. In one embodiment, the compound mutation is G1202R / G1269A. In one embodiment, the compound mutation is G1202R / L1198F.In one embodiment, the compound mutation is G1202R / F1174S. In one embodiment, the compound mutation is I1171N / D1203N. In one embodiment, the compound mutation is I1171S / D1203N. In one embodiment, the compound mutation is I1171T / D1203N. In one embodiment, the compound mutation is I1171M / D1203N. In one embodiment, the ALK-positive solid tumor is characterized by the presence of a partially deleted ALK protein. In one embodiment, the ALK mutation is Ex2-3del. In one embodiment, the ALK mutation is Ex2-17del.

[0192] In one embodiment, the partially deleted ALK protein affects the growth and metastatic properties of cancer cells. ALK protein can become partially deleted through various mechanisms. The first mechanism is shedding, in which the 80-kDa extracellular domain of the ALK protein is posttranslationally cleaved near residue Asn654, leaving only the 140-kDa C-terminal transmembrane domain and the intracellular domain. Shedding has been observed in many ALK-expressing cell lines, most notably cell lines derived from neuroblastoma disease backgrounds. Shedding increases cancer cell migration and proliferation both in vitro and in vivo in preclinical cancer models (Moog-Lutz, JBC (2005), Huang, Cell Reports (2021)). The second mechanism is alternative transcription initiation (ATI), in which transcription of the ALK gene is initiated at an alternative initiation site downstream of the original site, resulting in the deletion of exons 1-18 and part of exon 19. ALK ATI has been identified in 11% of melanomas and in some lung and anaplastic thyroid carcinomas. ALK ATI expression transforms Ba / F3 and NIH3T3 cells, conferring their oncogenic potential. One patient with ALK ATI showed a clinical response to ALK inhibitor treatment, suggesting that ALK ATI may be a targetable driver mutation (Wiesner, Nature (2015)). A third mechanism is partial deletion of the ALK gene, for example, via chromosomal rearrangement events. Multiple deletion variants have been identified, including deletions of exons 2-3, 1-5, 4-11, and 2-17. Some of these variants have been shown to activate ALK signaling and transform Ba / F3 or NIH3T3 cells. ALK partial deletions have been detected in neuroblastoma, sarcoma, and lymphoma. (Okubo, Oncogene (2012), Cazes, Can Res (2013), Fransson, Genes Chromosomes & Cancer (2014), Fleuren, Can Res (2017), Fukuhara, Hematol Oncol (2017)).

[0193] In certain embodiments, the ALK mutation comprises an ALK rearrangement and one or more ALK point mutations. In certain embodiments, the ALK mutation is EML4-ALK wt (variant 1). In one embodiment, the ALK mutation is EML4-ALK (variant 2). In one embodiment, the ALK mutation is EML4-ALK (variant 3). In one embodiment, the ALK mutation is EML4-ALK wt (variants 4, 5, 6, or 7). In one embodiment, the ALK mutation is EML4-ALK G1202R. In one embodiment, the ALK mutation is EML4-ALK I1171N. In one embodiment, the ALK mutation is EML4-ALK I1171S. In one embodiment, the ALK mutation is EML4-ALK I1171T. In one embodiment, the ALK mutation is EML4-ALK L1196M. In one embodiment, the ALK mutation is EML4-ALK D1203N. In one embodiment, the ALK mutation is EML4-ALK L1196M / G1202R. In one embodiment, the ALK mutation is EML4-ALK G1202R / G1269A. In one embodiment, the ALK mutation is EML4-ALK G1202R / L1196M. In one embodiment, the ALK mutation is EML4-ALK G1202R / L1198F. In one embodiment, the ALK mutation is EML4-ALK G1202R / T1151M. In one embodiment, the ALK mutation is EML4-ALK G1202R / F1174S. In one embodiment, the ALK mutation is EML4-ALK G1202R / F1174L. In a specific embodiment, the ALK mutation is EML4-ALK I1171N / D1203N. In a specific embodiment, the ALK mutation is EML4-ALK I1171N / L1198F. In a specific embodiment, the ALK mutation is EML4-ALK (variant 1) G1202R. In a specific embodiment, the ALK mutation is EML4-ALK (variant 2) G1202R.In certain embodiments, the ALK mutation is EML4-ALK (variant 3) G1202R. In certain embodiments, the ALK mutation is EML4-ALK (variant 1) L1196M / G1202R. In certain embodiments, the ALK mutation is EML4-ALK (variant 2) L1196M / G1202R. In certain embodiments, the ALK mutation is EML4-ALK (variant 3) L1196M / G1202R. In certain embodiments, the ALK mutation is EML4-ALK (variant 1) G1202R / G1269A. In certain embodiments, the ALK mutation is EML4-ALK (variant 2) G1202R / G1269A. In certain embodiments, the ALK mutation is EML4-ALK (variant 3) G1202R / G1269A. In certain embodiments, the ALK mutation is EML4-ALK (variant 1) G1202R / L1198F. In certain embodiments, the ALK mutation is EML4-ALK (variant 2) G1202R / L1198F. In certain embodiments, the ALK mutation is EML4-ALK (variant 3) G1202R / L1198F. In certain embodiments, the ALK mutation is EML4-ALK (variant 1) I1171N. In certain embodiments, the ALK mutation is EML4-ALK (variant 1) I1171S. In certain embodiments, the ALK mutation is EML4-ALK (variant 1) I1171T. In certain embodiments, the ALK mutation is EML4-ALK (variant 1) L1196M. In certain embodiments, the ALK mutation is EML4-ALK (variant 1) D1203N. In certain embodiments, the ALK mutation is EML4-ALK (variant 1) I1171N / D1203N. In certain embodiments, the ALK mutation is EML4-ALK (variant 1) I1171N / L1198F. In certain embodiments, the ALK mutation is EML4-ALK (variant 2) I1171N.In certain embodiments, the ALK mutation is EML4-ALK(variant 2) I1171S. In certain embodiments, the ALK mutation is EML4-ALK(variant 2) I1171T. In certain embodiments, the ALK mutation is EML4-ALK(variant 2) L1196M. In certain embodiments, the ALK mutation is EML4-ALK(variant 2) D1203N. In certain embodiments, the ALK mutation is EML4-ALK(variant 2) I1171N / D1203N. In certain embodiments, the ALK mutation is EML4-ALK(variant 2) I1171N / L1198F. In certain embodiments, the ALK mutation is EML4-ALK(variant 3) I1171N. In certain embodiments, the ALK mutation is EML4-ALK (variant 3) I1171S. In certain embodiments, the ALK mutation is EML4-ALK (variant 3) I1171T. In certain embodiments, the ALK mutation is EML4-ALK (variant 3) L1196M. In certain embodiments, the ALK mutation is EML4-ALK (variant 3) D1203N. In certain embodiments, the ALK mutation is EML4-ALK (variant 3) I1171N / D1203N. In certain embodiments, the ALK mutation is EML4-ALK (variant 3) I1171N / L1198F.

[0194] In certain embodiments, one or more of the mutations disclosed herein result in a partially deleted ALK protein. In certain embodiments, the ALK+ cancer is characterized by a partially deleted ALK protein (e.g., a partially deleted ALK protein identified in NB-1 (e.g., ex2-3del) and Aska-SS (e.g., ex2-17del) cell lines). In some embodiments, the ALK+ cancer is characterized by an ALK F1174L mutation (e.g., a mutation identified in Kelly and SH-SY5Y cell lines).

[0195] In certain embodiments, the ALK+ cancer is identified by an FDA-approved test or other test known in the art. Tests that may be used include, for example, FoundationOne CDx™ (F1CDx) (a sequencing-based in vitro diagnostic device for the detection of substitutions, insertions, and deletions (indels), and copy number alterations (CNAs) in 324 genes, as well as rearrangements in selected genes, and genomic signatures including microsatellite instability (MSI) and tumor mutation burden (TMB) using DNA isolated from formalin-fixed, paraffin-embedded (FFPE) tumor tissue specimens), the VENTANA ALK (D5F3) CDx Assay (qualitative detection of anaplastic lymphoma kinase (ALK) protein in formalin-fixed, paraffin-embedded (FFPE) non-small cell lung cancer (NSCLC) tissue stained with a BenchMark XT or BenchMark ULTRA automated staining instrument), and the Vysis ALK Break Apart FISH Probe. Examples of such tests include the Vysis ALK Break Apart FISH Probe Kit test, which is a qualitative test that detects rearrangements involving the ALK gene through fluorescence in situ hybridization (FISH) in formalin-fixed, paraffin-embedded (FFPE) non-small cell lung cancer (NSCLC) tissue specimens. In certain embodiments, the test is a fluorescence in situ hybridization (FISH) test, such as the Vysis ALK Break Apart FISH Probe Kit test. Further information about FDA-approved tests can be found, for example, at https: / / www.fda.gov / MedicalDevices / ProductsandMedicalProcedures / InVitroDiagnostics, and further information about the Vysis ALK Break Apart FISH Probe Kit can be found, for example, at https: / / www.molecular.abbott / us / en / products / oncology / vysis-alk-break-apart-fish-probe-kit. The entire contents of these tests are incorporated herein by reference.

[0196] Also provided is a method for treating a subject with cancer (e.g., an ALK-positive cancer), the method comprising: identifying whether cancer cells in a sample obtained from a subject with cancer and previously administered a first ALK inhibitor have one or more ALK inhibitor-resistant mutations; and, if the subject has cancer cells with one or more ALK inhibitor-resistant mutations, administering to the subject a compound of Formula (I) or a pharmaceutically acceptable salt or solvate thereof, as monotherapy or in combination with another anticancer agent. In some embodiments, the one or more ALK inhibitor-resistant mutations increase the resistance of cancer cells or tumors to treatment with the first ALK inhibitor. In some embodiments, the one or more ALK inhibitor-resistant mutations comprise one or more ALK inhibitor-resistant mutations. For example, the one or more ALK inhibitor resistance mutations are at amino acid positions 1202, 1196, 1269, 1156, 1171, 1174, 1180, 1206, 1210, 1151, 1174, 1203, 1206, 1152, 1196, 1198, 1275, 1152, 1156, and 1245, e.g., G1202R, L1196M, G1269A, C1156Y, I11 The anti-cancer agent may include one or more substitutions of 71T, I1171N, I1171S, F1174L, V1180L, S1206Y, E1210K, 1151Tins, F1174C, G1202del, D1203N, S1206Y, S1206C, L1152R, L1196Q, L1198P, L1198F, R1275Q, L1152P, C1156T, and F1245V. In some embodiments, the anti-cancer agent is any anti-cancer agent known in the art. For example, the anti-cancer agent may be another ALK inhibitor (e.g., a second ALK inhibitor).

[0197] In certain embodiments, the cancer in the methods provided herein is ROS1-positive (ROS1+). As used herein, unless otherwise specified, a "ROS1-positive" (ROS1+) cancer, disease, or disorder refers to a cancer, disease, or disorder characterized by inappropriately high expression of the ROS1 gene and / or the presence of a mutation in the ROS1 gene. In certain embodiments, the mutation alters the biological activity of a ROS1 nucleic acid molecule or polypeptide. As used herein, unless otherwise specified, a "mutation" or "mutant" of ROS1 includes one or more deletions, substitutions, insertions, inversions, duplications, translocations, or amplifications in the amino acid or nucleotide sequence of ROS1, or a fragment thereof. As used herein, unless otherwise specified, a "rearrangement" of ROS1 refers to a genetic translocation involving the ROS1 gene that can result in a ROS1 fusion gene and / or a ROS1 fusion protein. The ROS1 fusion may also contain one or more deletions, substitutions, insertions, inversions, duplications, translocations, or amplifications, or fragments thereof, so long as the mutant retains kinase phosphorylation activity.

[0198] In certain embodiments, the ROS1 mutation comprises one or more ROS1 point mutations. In some embodiments, the cancer treated by the methods provided herein comprises one or more mutations in ROS1 kinase. In certain embodiments, the one or more ROS1 point mutations are selected from point mutations at E1935, L1947, L1951, G1971, E1974, L1982, S1986, F2004, E2020, L2026, G2032, D2033, C2060, F2075, L2086, V2089, V2098, G2101, D2113, and L2155. In certain embodiments, 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 certain embodiments, the ROS1 mutation is G2032R. In certain embodiments, the ROS1 mutation is S1986F. In certain embodiments, the ROS1 mutation is S1986Y. In certain embodiments, the ROS1 mutation is L2026M. In certain embodiments, the ROS1 mutation is D2033N. In certain embodiments, the ROS1 mutation is L2086F. In certain embodiments, the ROS1 mutation is F2004C. In certain embodiments, the ROS1 mutation is F2004V. In certain embodiments, the ROS1 mutation is G2101A. In certain embodiments, the ROS1 mutation is L1982F. In certain embodiments, the ROS1 mutation is G2032R co-mutation with one or more of S1986F, S1986Y, F2004C, F2004V, L2026M, or D2033N.

[0199] In certain embodiments, the ROS1 mutation comprises one or more ROS1 rearrangements (in certain embodiments, one rearrangement). In certain embodiments, the ROS1 mutation comprises one or more ROS1 fusions (in certain embodiments, one fusion). In some embodiments, the cancer treated by the methods provided herein comprises a ROS1 fusion. In certain embodiments, the ROS1 fusion is mediated by 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, CCD The ROS1 fusion is fused with one of the fusion partners selected from C6, 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 certain embodiments, the ROS1 fusion is a CD74-ROS1 fusion. In certain embodiments, the ROS1 fusion is a SDC4-ROS1 fusion. In certain embodiments, the ROS1 fusion is an EZR-ROS1 fusion. In certain embodiments, the ROS1 fusion is a SLC34A2-ROS1 fusion. In certain embodiments, the ROS1 fusion is a GOPC-ROS1 fusion (e.g., GOPC-ROS1-S, GOPC-ROS1-L). In certain embodiments, the ROS1 fusion is a CEP85L-ROS1 fusion.

[0200] In certain embodiments, the ROS1 mutations comprise one ROS1 rearrangement and one or more ROS1 point mutations. In certain embodiments, the ROS1 mutations comprise one or more ROS1 rearrangements from CD74-ROS1, EZR-ROS1, SLC34A2-ROS1, GOPC-ROS1 (e.g., GOPC-ROS1-S, GOPC-ROS1-L), and CEP85L-ROS1, and one or more ROS1 point mutations selected from F2004C, F2004V, and G2032R. In certain embodiments, the ROS1 mutations comprise one or more ROS1 rearrangements from CD74-ROS1, EZR-ROS1, and SLC34A2-ROS1, and a G2101A ROS1 point mutation.

[0201] In certain embodiments, the ROS1 mutation is CD74-ROS1 F2004C. In certain embodiments, the ROS1 mutation is CD74-ROS1 F2004V. In certain embodiments, the ROS1 mutation is CD74-ROS1 G2101A. In certain embodiments, the ROS1 mutation is CD74-ROS1 G2032R. In certain embodiments, the ROS1 mutation is CD74-ROS1 S1986F. In certain embodiments, the ROS1 mutation is CD74-ROS1 L2026M. In certain embodiments, the ROS1 mutation is CD74-ROS1 D2033N. In certain embodiments, the ROS1 mutation is EZR-ROS1 F2004C. In certain embodiments, the ROS1 mutation is EZR-ROS1 F2004V. In certain embodiments, the ROS1 mutation is EZR-ROS1 G2101A. In certain embodiments, the ROS1 mutation is EZR-ROS1 G2032R. In certain embodiments, the ROS1 mutation is SLC34A2-ROS1 F2004C. In certain embodiments, the ROS1 mutation is SLC34A2-ROS1 F2004V. In certain embodiments, the ROS1 mutation is SLC34A2-ROS1 G2101A. In certain embodiments, the ROS1 mutation is SLC34A2-ROS1 G2032R. In certain embodiments, the ROS1 mutation is GOPC-ROS1 F2004C (e.g., GOPC-ROS1-S F2004C, GOPC-ROS1-L F2004C). In certain embodiments, the ROS1 mutation is GOPC-ROS1 F2004V (e.g., GOPC-ROS1-S F2004V, GOPC-ROS1-L F2004V). In certain embodiments, the ROS1 mutation is GOPC-ROS1 G2032R (e.g., GOPC-ROS1-S G2032R, GOPC-ROS1-L G2032R). In certain embodiments, the ROS1 mutation is CEP85L-ROS1 F2004C.In certain embodiments, the ROS1 mutation is CEP85L-ROS1 F2004V. In certain embodiments, the ROS1 mutation is CEP85L-ROS1 G2032R. In certain embodiments, the ROS1 mutation is GOPC-ROS1 L1982F (e.g., GOPC-ROS1-S L1982F, GOPC-ROS1-L L1982F). In certain embodiments, the ROS1 mutation is CD74-ROS1 L1982F.

[0202] In certain embodiments, the ROS1+ cancer is identified by an FDA-approved test or other test known in the art. Tests that can be used include, for example, Thermo Fisher Scientific's Oncomine™ Dx Target Test (a qualitative in vitro diagnostic test that uses targeted high-throughput parallel sequencing technology to detect sequence mutations in 23 genes in DNA and RNA isolated from formalin-fixed, paraffin-embedded tumor (FFPE) tissue samples from patients with non-small cell lung cancer (NSCLC) using the Ion PGM Dx system), Vysis ROS1 Break Apart FISH Probe Kit (a qualitative test that detects rearrangements involving the ROS1 gene rearrangement at 6q22 in formalin-fixed, paraffin-embedded (FFPE) non-small cell lung cancer (NSCLC) tissue specimens through fluorescence in situ hybridization (FISH)), or local diagnostic testing via RT real-time polymerase chain reaction (RT-PCR) or NGS next-generation sequencing.

[0203] Also provided is a method for treating a subject with cancer (e.g., a ROS1-positive cancer), the method comprising: identifying whether cancer cells in a sample obtained from a subject with cancer and previously administered a first ROS1 inhibitor have one or more ROS1 inhibitor-resistant mutations; and, if the subject has cancer cells with one or more ROS1 inhibitor-resistant mutations, administering to the subject a compound of Formula (I) or a pharmaceutically acceptable salt or solvate thereof as monotherapy or in combination with another anticancer agent. In some embodiments, the one or more ROS1 inhibitor-resistant mutations increase the resistance of cancer cells or tumors to treatment with the first ROS1 inhibitor. In some embodiments, the one or more ROS1 inhibitor-resistant mutations comprise one or more ROS1 inhibitor-resistant mutations. For example, one or more ROS1 inhibitor resistance mutations may be present at 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, S1986R, S1986N ... The anti-cancer agent may include one or more substitutions of 986Y, L2026M, L1951R, E1935G, L1947R, G1971E, E1974K, L1982F, F2004C, F2004V, E2020K, C2060G, F2075V, V2089M, V2098I, G2101A, D2113N, D2113G, L2155S, L2032K, and L2086F. In some embodiments, the anti-cancer agent is any anti-cancer agent known in the art. For example, the anti-cancer agent may be another ROS1 inhibitor (e.g., a second ROS1 inhibitor).

[0204] In certain embodiments, the compounds provided herein are CNS-penetrating compounds. In certain embodiments, after an effective amount of a compound provided herein is administered (e.g., orally or intravenously), the compound can penetrate the CNS (e.g., the blood-brain barrier) and still achieve a sufficient concentration in the CNS (e.g., the brain) to inhibit (e.g., selectively inhibit) ROS1 or ALK, or both.

[0205] In certain embodiments, provided herein is a method for treating CNS metastasis of cancer, the method comprising administering to a subject in need thereof an effective amount of a compound provided herein, for example, a compound of formula (I), or its stereoisomer, a mixture of stereoisomers, or a pharmaceutically acceptable salt.In certain embodiments, the CNS metastasis is brain metastasis.In certain embodiments, the cancer is ROS1+ cancer.In certain embodiments, the cancer is ALK+ cancer.

[0206] In one embodiment, the solid tumor (or cancer) is leukocyte receptor tyrosine kinase (LTK)-positive. In one embodiment, the solid tumor is LTK-positive NSCLC. In one embodiment, the solid tumor is LTK-positive invasive ductal carcinoma, prostate adenocarcinoma, pancreatic adenocarcinoma, adenocarcinoma of unknown primary site, or bladder urothelial carcinoma. In one embodiment, the solid tumor is LTK-positive lung cancer. In one embodiment, the solid tumor is LTK-positive NSCLC. In one embodiment, the solid tumor (or cancer) has an LTK mutation. In one embodiment, the LTK mutation is G269A, F218I, N257T, A13fs, or A214fs. In one embodiment, the solid tumor (or cancer) has an LTK fusion. In one embodiment, the LTK fusion is CLIP1-LTK. See Cooper AJ, Sequist LV, Johnson TW, Lin JJ. LTK fusions: A new target emerges in non-small cell lung cancer. Cancer Cell. 2022 Jan 10;40(1):23-25, and Izumi, H., Matsumoto, S., Liu, J. et al. The CLIP1-LTK fusion is an oncogenic driver in non-small cell lung cancer. Nature 600, 319-323 (2021), each of which is incorporated herein by reference in its entirety.

[0207] 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 inhibiting mutant or non-mutant ROS1 or ALK is at least 5-fold lower than the IC50 of the compound for inhibiting 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, paresthesias, weight gain, and cognitive changes.

[0208] In some embodiments, provided is a method of minimizing adverse events in a subject in need of treatment for cancer (e.g., a ROS1-positive cancer or an ALK-positive cancer), the method comprising administering to the subject a therapeutically effective amount of a compound provided herein, e.g., a compound of Formula (I), a stereoisomer, a mixture of stereoisomers, or a pharmaceutically acceptable salt thereof, wherein the method minimizes adverse events associated with a TRK inhibitor. In some embodiments, the cancer is a ROS1-associated cancer or an ALK-associated (or ALK+) cancer. In some embodiments, the adverse event is a TRK-associated CNS adverse event.

[0209] As used herein, "minimizing" an adverse event refers to a reduction in the incidence of an adverse event in a subject or patient population compared to the series incidence of the adverse event in subjects or patient populations administered a TRK inhibitor (e.g., entrectinib, repotrectinib, or lorlatinib). In some embodiments, the incidence of an adverse event refers to the frequency or percentage of a particular adverse event for a subject or patient population. In some embodiments, the incidence of an adverse event refers to the total number of adverse events experienced by an individual subject. In some embodiments, minimizing an adverse event 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 the 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 more than one TRK-related CNS adverse event. In some embodiments, minimizing TRK-related CNS adverse events means that 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 has more than one TRK-related CNS adverse event.

[0210] In some embodiments, a TRK-related CNS adverse event refers to one or more of the following: dizziness, ataxia, gait disturbance, paresthesias, weight gain, hyperphagia, paresthesias, abnormal movements, cognitive changes, speech effects (e.g., dysarthria, speech delay, or speech disorder), mood disorders (e.g., irritability, anxiety, depression, emotional lability, personality changes, mood swings, affective disorders, aggression, agitation, mood changes, depressed mood, euphoria, or mania), and cognitive disorders (e.g., memory impairment, cognitive impairment, memory loss, confusion, attention disorder, delirium, psychosis, attention-deficit / hyperactivity disorder, dementia, or reading disorder).

[0211] In certain embodiments, provided herein is a method for preventing or limiting TRK-related CNS side effects or adverse events in the treatment of cancer, the method comprising administering to a subject in need thereof an effective amount of a compound provided herein, e.g., a compound of Formula (I), or a stereoisomer, mixture of stereoisomers, or pharmaceutically acceptable salt thereof. In certain embodiments, the method prevents the occurrence of TRK-related CNS adverse events. In certain embodiments, the method limits the frequency of occurrence of TRK-related CNS adverse events. In certain embodiments, the method limits the severity of TRK-related side effects. In certain embodiments, provided herein is a method for treating CNS metastasis of cancer with reduced TRK-related side effects, the method comprising administering to a subject in need thereof an effective amount of a compound provided herein, e.g., a compound of Formula (I), or a stereoisomer, mixture of stereoisomers, or pharmaceutically acceptable salt thereof. In certain embodiments, the reduction / limitation / prevention of the CNS side effect or adverse event is measured in a statistical sample relative to a standard of care for ROS1+ and / or ALK+ cancer, e.g., an approved ROS1 and / or ALK inhibitor (e.g., crizotinib, entrectinib, lorlatinib, or repotrectinib). In certain embodiments, the TRK-related side effect is a TRKB-related CNS side effect. In certain embodiments, the TRK-related CNS side effect or adverse event is dizziness, ataxia, gait disturbance, paresthesia, weight gain, cognitive impairment, mood disorder, or sleep disorder.

[0212] In certain embodiments, provided herein is a method for treating cancer, the method 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 a stereoisomer, mixture of stereoisomers, or pharmaceutically acceptable salt thereof. In certain embodiments, the cancer is a ROS1-associated cancer. In certain embodiments, the cancer is a ROS1+ cancer. In certain embodiments, the cancer is an ALK-associated cancer. In certain embodiments, the cancer is an ALK+ cancer. In certain embodiments, the cancer is identified as ROS1+. In certain embodiments, the cancer is identified as ALK+.

[0213] In certain embodiments, provided herein are methods for treating ROS1+ cancer, the methods comprising administering to a subject in need thereof a therapeutically effective amount of a compound provided herein, e.g., a compound of Formula (I), or a stereoisomer, mixture of stereoisomers, or pharmaceutically acceptable salt thereof.

[0214] In certain embodiments, provided herein are methods for treating ALK+ cancer, the methods comprising administering to a subject in need thereof a therapeutically effective amount of a compound provided herein, e.g., a compound of Formula (I), or a stereoisomer, mixture of stereoisomers, or pharmaceutically acceptable salt thereof.

[0215] In certain embodiments, provided herein are methods of treating cancer in a subject, the methods comprising: (i) identifying the cancer in the subject as ROS1+; and (ii) administering to the subject a therapeutically effective amount of a compound provided herein, e.g., a compound of Formula (I), or a stereoisomer, mixture of stereoisomers, or pharmaceutically acceptable salt thereof.

[0216] In certain embodiments, provided herein are methods of treating cancer in a subject, the methods comprising: (i) identifying the cancer in the subject as ALK+; and (ii) administering to the subject a therapeutically effective amount of a compound provided herein, e.g., a compound of Formula (I), or a stereoisomer, mixture of stereoisomers, or pharmaceutically acceptable salt thereof.

[0217] In certain embodiments, the cancer (or ROS1+ cancer or ALK+ cancer) is a solid tumor. In certain embodiments, the cancer (or ROS1+ cancer or ALK+ cancer) is lung cancer, such as non-small cell lung cancer (NSCLC), glioblastoma, inflammatory myofibroblastic tumor (IMT), bile duct cancer, such as cholangiocarcinoma, ovarian cancer, such as serous ovarian cancer, gastric cancer, colorectal cancer, angiosarcoma, melanoma, such as Spitz nevus melanoma, epithelioid hemangioendothelioma, esophageal cancer, such as esophageal squamous cell carcinoma (ESCC), kidney cancer, such as renal medullary carcinoma or renal cell carcinoma, breast cancer, such as triple-negative breast cancer, colon cancer, thyroid cancer, such as papillary thyroid carcinoma, Spitz nevus tumor, or neuroblastoma.

[0218] In certain embodiments, the cancer is lung cancer. In certain embodiments, the cancer is non-small cell lung cancer. In certain embodiments, the cancer is ROS1+ non-small cell lung cancer. In certain embodiments, the cancer is ALK+ non-small cell lung cancer. In certain embodiments, the cancer is recurrent or refractory non-small cell lung cancer. In certain embodiments, the cancer is recurrent or refractory ROS1+ non-small cell lung cancer. In certain embodiments, the cancer is recurrent or refractory ALK+ non-small cell lung cancer. In certain embodiments, the cancer is newly diagnosed non-small cell lung cancer. In certain embodiments, the cancer is newly diagnosed ROS1+ non-small cell lung cancer. In certain embodiments, the cancer is newly diagnosed ALK+ non-small cell lung cancer.

[0219] In certain embodiments, the cancer is glioblastoma. In certain embodiments, the cancer is ROS1+ glioblastoma. In certain embodiments, the cancer is ALK+ glioblastoma. In certain embodiments, the cancer is recurrent or refractory glioblastoma. In certain embodiments, the cancer is recurrent or refractory ROS1+ glioblastoma. In certain embodiments, the cancer is recurrent or refractory ALK+ glioblastoma. In certain embodiments, the cancer is newly diagnosed glioblastoma. In certain embodiments, the cancer is newly diagnosed ROS1+ glioblastoma. In certain embodiments, the cancer is newly diagnosed ALK+ glioblastoma.

[0220] In certain embodiments, the cancer is IMT. In certain embodiments, the cancer is ROS1+ IMT. In certain embodiments, the cancer is ALK+ IMT. In certain embodiments, the cancer is relapsed or refractory IMT. In certain embodiments, the cancer is relapsed or refractory ROS1+ IMT. In certain embodiments, the cancer is relapsed or refractory ALK+ IMT. In certain embodiments, the cancer is newly diagnosed IMT. In certain embodiments, the cancer is newly diagnosed ROS1+ IMT. In certain embodiments, the cancer is newly diagnosed ALK+ IMT.

[0221] In certain embodiments, the cancer is bile duct cancer. In certain embodiments, the cancer is cholangiocarcinoma. In certain embodiments, the cancer is ROS1+ cholangiocarcinoma. In certain embodiments, the cancer is ALK+ cholangiocarcinoma. In certain embodiments, the cancer is recurrent or refractory cholangiocarcinoma. In certain embodiments, the cancer is recurrent or refractory ROS1+ cholangiocarcinoma. In certain embodiments, the cancer is recurrent or refractory ALK+ cholangiocarcinoma. In certain embodiments, the cancer is newly diagnosed cholangiocarcinoma. In certain embodiments, the cancer is newly diagnosed ROS1+ cholangiocarcinoma. In certain embodiments, the cancer is newly diagnosed ALK+ cholangiocarcinoma.

[0222] In certain embodiments, the cancer is ovarian cancer. In certain embodiments, the cancer is ROS1+ ovarian cancer. In certain embodiments, the cancer is ALK+ ovarian cancer. In certain embodiments, the cancer is recurrent or refractory ovarian cancer. In certain embodiments, the cancer is recurrent or refractory ROS1+ ovarian cancer. In certain embodiments, the cancer is recurrent or refractory ALK+ ovarian cancer. In certain embodiments, the cancer is newly diagnosed ovarian cancer. In certain embodiments, the cancer is newly diagnosed ROS1+ ovarian cancer. In certain embodiments, the cancer is newly diagnosed ALK+ ovarian cancer. In certain embodiments, the ovarian cancer is serous ovarian cancer. In certain embodiments, the ovarian cancer is high-grade serous ovarian cancer.

[0223] In certain embodiments, the cancer is gastric cancer. In certain embodiments, the cancer is ROS1+ gastric cancer. In certain embodiments, the cancer is ALK+ gastric cancer. In certain embodiments, the cancer is recurrent or refractory gastric cancer. In certain embodiments, the cancer is recurrent or refractory ROS1+ gastric cancer. In certain embodiments, the cancer is recurrent or refractory ALK+ gastric cancer. In certain embodiments, the cancer is newly diagnosed gastric cancer. In certain embodiments, the cancer is newly diagnosed ROS1+ gastric cancer. In certain embodiments, the cancer is newly diagnosed ALK+ gastric cancer.

[0224] In certain embodiments, the cancer is colorectal cancer. In certain embodiments, the cancer is ROS1+ colorectal cancer. In certain embodiments, the cancer is ALK+ colorectal cancer. In certain embodiments, the cancer is recurrent or refractory colorectal cancer. In certain embodiments, the cancer is recurrent or refractory ROS1+ colorectal cancer. In certain embodiments, the cancer is recurrent or refractory ALK+ colorectal cancer. In certain embodiments, the cancer is newly diagnosed colorectal cancer. In certain embodiments, the cancer is newly diagnosed ROS1+ colorectal cancer. In certain embodiments, the cancer is newly diagnosed ALK+ colorectal cancer.

[0225] In certain embodiments, the cancer is angiosarcoma. In certain embodiments, the cancer is ROS1+ angiosarcoma. In certain embodiments, the cancer is ALK+ angiosarcoma. In certain embodiments, the cancer is relapsed or refractory angiosarcoma. In certain embodiments, the cancer is relapsed or refractory ROS1+ angiosarcoma. In certain embodiments, the cancer is relapsed or refractory ALK+ angiosarcoma. In certain embodiments, the cancer is newly diagnosed angiosarcoma. In certain embodiments, the cancer is newly diagnosed ROS1+ angiosarcoma. In certain embodiments, the cancer is newly diagnosed ALK+ angiosarcoma.

[0226] In certain embodiments, the cancer is melanoma. In certain embodiments, the cancer is a Spitz nevus-like tumor. In certain embodiments, the cancer is a Spitz nevus-like melanoma. In certain embodiments, the cancer is a ROS1+ Spitz nevus-like melanoma. In certain embodiments, the cancer is an ALK+ Spitz nevus-like melanoma. In certain embodiments, the cancer is a recurrent or refractory Spitz nevus-like melanoma. In certain embodiments, the cancer is a recurrent or refractory ROS1+ Spitz nevus-like melanoma. In certain embodiments, the cancer is a recurrent or refractory ALK+ Spitz nevus-like melanoma. In certain embodiments, the cancer is a newly diagnosed Spitz nevus-like melanoma. In certain embodiments, the cancer is a newly diagnosed ROS1+ Spitz nevus-like melanoma. In certain embodiments, the cancer is a newly diagnosed ALK+ Spitz nevus-like melanoma.

[0227] In certain embodiments, the cancer is epithelioid hemangioendothelioma. In certain embodiments, the cancer is ROS1+ epithelioid hemangioendothelioma. In certain embodiments, the cancer is ALK+ epithelioid hemangioendothelioma. In certain embodiments, the cancer is recurrent or refractory epithelioid hemangioendothelioma. In certain embodiments, the cancer is recurrent or refractory ROS1+ epithelioid hemangioendothelioma. In certain embodiments, the cancer is recurrent or refractory ALK+ epithelioid hemangioendothelioma. In certain embodiments, the cancer is newly diagnosed epithelioid hemangioendothelioma. In certain embodiments, the cancer is newly diagnosed ROS1+ epithelioid hemangioendothelioma. In certain embodiments, the cancer is newly diagnosed ALK+ epithelioid hemangioendothelioma.

[0228] In certain embodiments, the cancer is esophageal cancer. In certain embodiments, the cancer is ESCC. In certain embodiments, the cancer is ROS1+ ESCC. In certain embodiments, the cancer is ALK+ ESCC. In certain embodiments, the cancer is recurrent or refractory ESCC. In certain embodiments, the cancer is recurrent or refractory ROS1+ ESCC. In certain embodiments, the cancer is recurrent or refractory ALK+ ESCC. In certain embodiments, the cancer is newly diagnosed ESCC. In certain embodiments, the cancer is newly diagnosed ROS1+ ESCC. In certain embodiments, the cancer is newly diagnosed ALK+ ESCC.

[0229] In certain embodiments, the cancer is kidney cancer. In certain embodiments, the cancer is renal medullary cancer. In certain embodiments, the cancer is ROS1+ renal medullary cancer. In certain embodiments, the cancer is ALK+ renal medullary cancer. In certain embodiments, the cancer is relapsed or refractory renal medullary cancer. In certain embodiments, the cancer is relapsed or refractory ROS1+ renal medullary cancer. In certain embodiments, the cancer is relapsed or refractory ALK+ renal medullary cancer. In certain embodiments, the cancer is newly diagnosed renal medullary cancer. In certain embodiments, the cancer is newly diagnosed ROS1+ renal medullary cancer. In certain embodiments, the cancer is newly diagnosed ALK+ renal medullary cancer. In certain embodiments, the cancer is renal cell carcinoma. In certain embodiments, the cancer is ROS1+ renal cell carcinoma. In certain embodiments, the cancer is ALK+ renal cell carcinoma. In certain embodiments, the cancer is recurrent or refractory renal cell carcinoma.In certain embodiments, the cancer is recurrent or refractory ROS1+ renal cell carcinoma.In certain embodiments, the cancer is recurrent or refractory ALK+ renal cell carcinoma.In certain embodiments, the cancer is newly diagnosed renal cell carcinoma.In certain embodiments, the cancer is newly diagnosed ROS1+ renal cell carcinoma.In certain embodiments, the cancer is newly diagnosed ALK+ renal cell carcinoma.

[0230] In certain embodiments, the cancer is breast cancer. In certain embodiments, the cancer is ROS1+ breast cancer. In certain embodiments, the cancer is ALK+ breast cancer. In certain embodiments, the cancer is recurrent or refractory breast cancer. In certain embodiments, the cancer is recurrent or refractory ROS1+ breast cancer. In certain embodiments, the cancer is recurrent or refractory ALK+ breast cancer. In certain embodiments, the cancer is newly diagnosed breast cancer. In certain embodiments, the cancer is newly diagnosed ROS1+ breast cancer. In certain embodiments, the cancer is newly diagnosed ALK+ breast cancer. In certain embodiments, the breast cancer is triple-negative breast cancer.

[0231] In certain embodiments, the cancer is colon cancer. In certain embodiments, the cancer is ROS1+ colon cancer. In certain embodiments, the cancer is ALK+ colon cancer. In certain embodiments, the cancer is recurrent or refractory colon cancer. In certain embodiments, the cancer is recurrent or refractory ROS1+ colon cancer. In certain embodiments, the cancer is recurrent or refractory ALK+ colon cancer. In certain embodiments, the cancer is newly diagnosed colon cancer. In certain embodiments, the cancer is newly diagnosed ROS1+ colon cancer. In certain embodiments, the cancer is newly diagnosed ALK+ colon cancer.

[0232] In certain embodiments, the cancer is thyroid cancer. In certain embodiments, the cancer is papillary thyroid cancer. In certain embodiments, the cancer is ROS1+ papillary thyroid cancer. In certain embodiments, the cancer is ALK+ papillary thyroid cancer. In certain embodiments, the cancer is recurrent or refractory papillary thyroid cancer. In certain embodiments, the cancer is recurrent or refractory ROS1+ papillary thyroid cancer. In certain embodiments, the cancer is recurrent or refractory ALK+ papillary thyroid cancer. In certain embodiments, the cancer is newly diagnosed papillary thyroid cancer. In certain embodiments, the cancer is newly diagnosed ROS1+ papillary thyroid cancer. In certain embodiments, the cancer is newly diagnosed ALK+ papillary thyroid cancer.

[0233] In certain embodiments, the cancer is neuroblastoma. In certain embodiments, the cancer is ROS1+ neuroblastoma. In certain embodiments, the cancer is ALK+ neuroblastoma. In certain embodiments, the cancer is relapsed or refractory neuroblastoma. In certain embodiments, the cancer is relapsed or refractory ROS1+ neuroblastoma. In certain embodiments, the cancer is relapsed or refractory ALK+ neuroblastoma. In certain embodiments, the cancer is newly diagnosed neuroblastoma. In certain embodiments, the cancer is newly diagnosed ROS1+ neuroblastoma. In certain embodiments, the cancer is newly diagnosed ALK+ neuroblastoma.

[0234] In certain embodiments, the cancer (or ROS1+ cancer or ALK+ cancer) is a hematological cancer. In certain embodiments, the cancer (or ROS1+ cancer or ALK+ cancer) is a lymphoma. In certain embodiments, the lymphoma is non-Hodgkin's lymphoma. In certain embodiments, the lymphoma is anaplastic large cell lymphoma (ALCL), diffuse large B-cell lymphoma (DLBCL), or large B-cell lymphoma. In addition to hematological cancers, methods for treating other hematological disorders or hematological malignancies that are ROS1+ or ALK+ are also provided herein.

[0235] In certain embodiments, the cancer is ALCL. In certain embodiments, the cancer is ROS1+ ALCL. In certain embodiments, the cancer is ALK+ ALCL. In certain embodiments, the cancer is relapsed or refractory ALCL. In certain embodiments, the cancer is relapsed or refractory ROS1+ ALCL. In certain embodiments, the cancer is relapsed or refractory ALK+ ALCL. In certain embodiments, the cancer is newly diagnosed ALCL. In certain embodiments, the cancer is newly diagnosed ROS1+ ALCL. In certain embodiments, the cancer is newly diagnosed ALK+ ALCL.

[0236] In certain embodiments, the cancer is DLBCL. In certain embodiments, the cancer is ROS1+ DLBCL. In certain embodiments, the cancer is ALK+ DLBCL. In certain embodiments, the cancer is relapsed or refractory DLBCL. In certain embodiments, the cancer is relapsed or refractory ROS1+ DLBCL. In certain embodiments, the cancer is relapsed or refractory ALK+ DLBCL. In certain embodiments, the cancer is newly diagnosed DLBCL. In certain embodiments, the cancer is newly diagnosed ROS1+ DLBCL. In certain embodiments, the cancer is newly diagnosed ALK+ DLBCL.

[0237] In certain embodiments, the cancer is large B-cell lymphoma. In certain embodiments, the cancer is ROS1+ large B-cell lymphoma. In certain embodiments, the cancer is ALK+ large B-cell lymphoma. In certain embodiments, the cancer is relapsed or refractory large B-cell lymphoma. In certain embodiments, the cancer is relapsed or refractory ROS1+ large B-cell lymphoma. In certain embodiments, the cancer is relapsed or refractory ALK+ large B-cell lymphoma. In certain embodiments, the cancer is newly diagnosed large B-cell lymphoma. In certain embodiments, the cancer is newly diagnosed ROS1+ large B-cell lymphoma. In certain embodiments, the cancer is newly diagnosed ALK+ large B-cell lymphoma.

[0238] In certain embodiments, the cancer (or ROS1+ cancer or ALK+ cancer) is newly diagnosed. In certain embodiments, the cancer (or ROS1+ cancer or ALK+ cancer) has not previously been treated.

[0239] In certain embodiments, the cancer (or ROS1+ cancer or ALK+ cancer) is relapsed or refractory. In certain embodiments, the cancer is relapsed. In certain embodiments, the cancer (or ROS1+ cancer or ALK+ cancer) is refractory.

[0240] In certain embodiments, the subject has not been previously treated. In certain embodiments, the subject is treatment-naive with tyrosine kinase inhibitor (TKI) therapy. In certain embodiments, the subject has received first-line or higher-level treatment. In certain embodiments, the subject has received second-line or higher-level treatment. In certain embodiments, the subject has acquired resistance to first-line or higher-level treatment. In certain embodiments, the previous treatment comprises a tyrosine kinase inhibitor (TKI). In certain embodiments, the previous treatment comprises one or more of crizotinib, ceritinib, alectinib, brigatinib, lorlatinib, entrectinib, repotrectinib, cabozantinib, foretinib, taretrectinib, merestinib, masitinib, and ensartinib. In certain embodiments, the previous treatment comprises one or more chemotherapy regimens. In certain embodiments, the one or more chemotherapy regimens are added to the TKI therapy.

[0241] In certain embodiments, the cancer (or ROS1+ cancer, or ALK+ cancer) is resistant to a tyrosine kinase inhibitor (TKI).

[0242] In certain embodiments, the cancer is resistant lung cancer.In certain embodiments, the cancer is resistant non-small cell lung cancer.In certain embodiments, the cancer is TKI-resistant non-small cell lung cancer.In certain embodiments, the cancer is TKI-resistant ROS1+ non-small cell lung cancer.In certain embodiments, the cancer is TKI-resistant ALK+ non-small cell lung cancer.

[0243] In certain embodiments, the cancer is lung cancer (e.g., NSCLC), and the cancer has relapsed after or is refractory to prior treatment with a TKI.

[0244] In certain embodiments, the compounds provided herein are administered as first-line therapy. In certain embodiments, the compounds provided herein are administered as second-line therapy. In certain embodiments, the compounds provided herein are administered as third-line or fourth-line therapy.

[0245] In certain embodiments, the cancer (or ROS1+ cancer or ALK+ cancer) is metastatic. In certain embodiments, the cancer has CNS metastasis. In certain embodiments, the cancer has brain metastasis. In certain embodiments, the cancer is metastatic non-small cell lung cancer (NSCLC). In certain embodiments, the cancer is metastatic ROS1+ NSCLC. In certain embodiments, the cancer is metastatic ALK+ NSCLC.

[0246] In certain embodiments, provided herein is a method of treating a patient with metastatic ALK+ non-small cell lung cancer (NSCLC), the method comprising administering to the patient a therapeutically effective amount of a compound provided herein, e.g., a compound of Formula (I), or a stereoisomer, mixture of stereoisomers, or a pharmaceutically acceptable salt thereof.

[0247] In certain embodiments, provided herein is a method of treating a patient with metastatic ROS1+ non-small cell lung cancer (NSCLC), the method comprising administering to the patient a therapeutically effective amount of a compound provided herein, e.g., a compound of Formula (I), or a stereoisomer, mixture of stereoisomers, or a pharmaceutically acceptable salt thereof.

[0248] In certain embodiments, the patient is an adult patient. In certain embodiments, the patient is a pediatric patient.

[0249] In certain embodiments, provided herein is a method for treating an adult patient with metastatic ROS1+ NSCLC, the method comprising administering to the patient a therapeutically effective amount of a compound provided herein, e.g., a compound of Formula (I), or a stereoisomer, mixture of stereoisomers, or a pharmaceutically acceptable salt thereof.

[0250] In certain embodiments, provided herein is a method of treating an adult patient with metastatic ROS1+ NSCLC, the method comprising administering to the patient a therapeutically effective amount of a compound provided herein, e.g., a compound of Formula (I), or a stereoisomer, mixture of stereoisomers, or pharmaceutically acceptable salt thereof, wherein the patient has progressed to or is intolerant to at least one prior TKI therapy.

[0251] In certain embodiments, provided herein is a method for treating an adult patient with ROS1+ metastatic NSCLC harboring the solvent front mutation G2032R, the method comprising administering to the patient a therapeutically effective amount of a compound provided herein, e.g., a compound of Formula (I), or a stereoisomer, mixture of stereoisomers, or pharmaceutically acceptable salt thereof, wherein the patient has progressed to or is intolerant to at least one prior TKI therapy.

[0252] In certain embodiments, provided herein is a method for treating a ROS1-associated (or ROS1+) cancer in a subject in need thereof, wherein the cancer has acquired resistance to a tyrosine kinase inhibitor (TKI), the method comprising administering to the subject a therapeutically effective amount of a compound provided herein, e.g., a compound of Formula (I), or a stereoisomer, mixture of stereoisomers, or pharmaceutically acceptable salt thereof.

[0253] In certain embodiments, provided herein are methods for treating a ROS1-associated (or ROS1+) cancer in a subject in need thereof, wherein the cancer has acquired resistance to a tyrosine kinase inhibitor (TKI), and the cancer has been identified as having one or more ROS1 inhibitor-resistant mutations, the method comprising administering to the subject a therapeutically effective amount of a compound provided herein, e.g., a compound of Formula (I), or a stereoisomer, mixture of stereoisomers, or pharmaceutically acceptable salt thereof. In certain embodiments, the one or more ROS1 inhibitor-resistant mutations comprise one or more amino acid substitutions at amino acid positions selected from 1986, 2004, 2026, 2032, and 2033. In certain embodiments, the one or more ROS1 inhibitor-resistant mutations comprise one or more amino acid substitutions selected from S1986F, S1986Y, F2004C, F2004V, L2026M, G2032R, D2033N, L2086F, and G2101A. In certain embodiments, the one or more ROS1 inhibitor-resistant mutations are G2032R. In certain embodiments, the one or more ROS1 inhibitor-resistant mutations include G2032R and one or more of S1986F, S1986Y, F2004C, F2004V, L2026M, D2033N, or G2101A. In certain embodiments, the ROS1 inhibitor-resistant mutation is L2086F.

[0254] In certain embodiments, provided herein is a method for treating ALK-associated (or ALK+) cancer in a subject in need thereof, wherein the cancer has acquired resistance to a tyrosine kinase inhibitor (TKI), the method comprising administering to the subject a therapeutically effective amount of a compound provided herein, e.g., a compound of Formula (I), or a stereoisomer, mixture of stereoisomers, or pharmaceutically acceptable salt thereof.

[0255] In certain embodiments, provided herein is a method for treating ALK-associated (or ALK+) cancer in a subject in need thereof, wherein the cancer has acquired resistance to a tyrosine kinase inhibitor (TKI), and the cancer has been identified as having one or more ALK inhibitor-resistant mutations, the method comprising administering to the subject a therapeutically effective amount of a compound provided herein, e.g., a compound of Formula (I), or a stereoisomer, mixture of stereoisomers, or pharmaceutically acceptable salt thereof. In certain embodiments, the one or more ALK inhibitor-resistant mutations comprise one or more amino acid substitutions at amino acid positions selected from 1196, 1198, 1202, and 1269. In certain embodiments, the one or more ALK inhibitor-resistant mutations comprise one or more amino acid substitutions selected from L1196M, L1198F, G1202R, and G1269A. In certain embodiments, the one or more ALK inhibitor-resistant mutations is G1202R. In certain embodiments, the one or more ALK inhibitor resistance mutations include G1202R and one or more of L1196M, L1198F, and G1269A.

[0256] In certain embodiments, provided herein is a method of treating an adult patient with ALK+ metastatic NSCLC with mutation G1202R, the method comprising administering to the patient a therapeutically effective amount of a compound provided herein, e.g., a compound of Formula (I), or a stereoisomer, mixture of stereoisomers, or pharmaceutically acceptable salt thereof, wherein the patient has progressed to or is intolerant to at least one prior TKI therapy.

[0257] In certain embodiments, provided herein is a method for treating ALK-associated (or ALK+) cancer in a subject in need thereof, wherein the cancer has acquired resistance to a tyrosine kinase inhibitor (TKI), the method comprising administering to the subject a therapeutically effective amount of a compound provided herein, e.g., a compound of Formula (I), or a stereoisomer, mixture of stereoisomers, or pharmaceutically acceptable salt thereof.

[0258] In certain embodiments, the TKI is a ROS1 inhibitor.In certain embodiments, the TKI is an ALK inhibitor.In certain embodiments, the TKI is crizotinib, ceritinib, alectinib, brigatinib, lorlatinib, entrectinib, repotrectinib, cabozantinib, foretinib, merestinib, taretrectinib, masitinib or ensartinib.In certain embodiments, the TKI is crizotinib.In certain embodiments, the TKI is entrectinib.In certain embodiments, the TKI is alectinib.In certain embodiments, the TKI is lorlatinib.

[0259] In certain embodiments, the cancer or disease is present in a pediatric patient (including an infant patient). In certain embodiments, the cancer is ALK+ systemic anaplastic large cell lymphoma (ALCL) in pediatric patients aged 1 year or older and young adults. In another embodiment, the cancer is ALK+ relapsed or refractory systemic anaplastic large cell lymphoma (ALCL) in pediatric patients aged 1 year or older and young adults. In certain embodiments, the cancer is ROS1+ systemic anaplastic large cell lymphoma (ALCL) in pediatric patients aged 1 year or older and young adults. In another embodiment, the cancer is ROS1+ relapsed or refractory systemic anaplastic large cell lymphoma (ALCL) in pediatric patients aged 1 year or older and young adults.

[0260] In certain embodiments, the method of treating or preventing cancer may be demonstrated by one or more responses, such as increased apoptosis, inhibition of tumor growth, reduction in tumor metastasis, inhibition of tumor metastasis, reduction in microvascular density, reduction in angiogenesis, inhibition of tumor metastasis, tumor regression, and prolongation of survival of the subject.

[0261] 4.4 Combination therapy In some embodiments, the method of treating or preventing cancer may involve administering a compound of formula (I) in combination with one or more other chemotherapeutic agent(s).

[0262] As used herein, unless otherwise specified, "conjointly" or "in combination with" does not imply that the other agent and the compound of Formula (I) must be administered at the same time and / or formulated together for delivery, although these delivery methods are also provided herein. A compound provided herein may be administered simultaneously with, prior to (e.g., 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 ​​hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, 12 weeks, or 16 weeks before), or subsequent to (e.g., 5 minutes, 15 minutes, 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 after) one or more other agents (e.g., one or more other additional agents). Generally, each therapeutic agent is administered at a dose and / or on a time schedule determined for that particular agent. The other therapeutic agents may be administered with the compounds provided herein in a single composition or separately in different compositions. Triple drug combinations are also contemplated herein.

[0263] Chemotherapeutic agents that may be conjointly administered with the compounds provided herein include 1-amino-4-phenylamino-9,10-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-aminophenylamino]-9,10-dioxo-9,10-dihydroanthracene-2-sulfonate, 1-amino-4-[1-naphthyl ... Hydroanthracene-2-sulfonate, 1-amino-4-[4-fluoro-2-carboxyphenylamino]-9,10-dioxo-9,10-dihydroanthracene-2-sulfonate, 1-amino-4-[2-anthracenylamino]-9,10-dioxo-9,10-dihydroanthracene-2-sulfonate, ABT-263, afatinib dimaleate, axitinib, aminoglutethimide, amsacrine, anastrozole, APCP, asparaginase, AZD5363, Bacillus Calmette-Guerin vaccine (bcg), bicalutamide, bleomycin Mycobacterium typhimurium, 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, dichloroacetic acid, dienestrol, diethylstilbestrol rol, docetaxel, doxorubicin, epirubicin, eribulin, erlotinib, estradiol, estramustine, etoposide, everolimus, exemestane, filgrastim, fludarabine, fludrocortisone, fluorouracil, fluoxymesterone, flutamide, gefitinib, gemcitabine, genistein, goserelin, GSK1120212, hydroxyurea, idarubicin, ifosfamide, imatinib, interferon, irinotecan, ixabepilone, lenalidomide, letrozole, leucovorin, leuprolide,Levamisole, lomustine, lonidamine, mechlorethamine, medroxyprogesterone, megestrol, melphalan, mercaptopurine, mesna, metformin, methotrexate, miltefosine, mitomycin, mitotane, mitoxantrone, MK-2206, mutamycin, N-(4-sulfamoylphenylcarbamothioyl)pivalamide, NF279, NF449, nilutamide, nocodazole, octreotide, olaparib, oxaliplatin, paclitaxel, pamidronate, pazopanib, pemexetred, pentostatin, perifosine, PF-04691502, plicamycin, pomalidomide, porfimer, These include PPADS, procarbazine, quercetin, raltitrexed, ramucirumab, reactive blue 2, rituximab, rolofylline, romidepsin, rucaparib, selumetinib, sirolimus, sodium 2,4-dinitrobenzenesulfonate, sorafenib, streptozocin, sunitinib, suramin, talazoparib, tamoxifen, temozolomide, temsirolimus, teniposide, testosterone, thalidomide, thioguanine, thiotepa, titanocene dichloride, tonapofylline, topotecan, trametinib, trastuzumab, tretinoin, veliparib, vinblastine, vincristine, vindesine, vinorelbine, and vorinostat (SAHA). In other embodiments, chemotherapeutic agents that may be conjointly administered with the compounds provided herein include ABT-263, dexamethasone, 5-fluorouracil, PF-04691502, romidepsin, and vorinostat (SAHA). In other embodiments, chemotherapeutic agents that may be conjointly administered with the compounds provided herein include 1-amino-4-phenylamino-9,10-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-aminophenylamino]-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-carboxyphenylamino]-9,10-dioxo-9,10-dihydroanthracene-2-sulfonate, 1-amino-4-[2-anthracenylamino]-9,10-dioxo-9,10-dihydroanthracene-2-sulfonate, APCP, β-methylene-ADP (AOPCP), capecitabine, cladribine, cytarabine, fludarabine, doxorubicin, gemcitabine, N-(4-sulfamoylphenylcarbamothioyl)pivalamide, NF279, NF449, PPADS, quercetin, Reactive Blue 2, rolofylline, sodium 2,4-dinitrobenzenesulfonate, sumarin, and tonapophilin.

[0264] Many combination therapies have been developed for the treatment of cancer.In certain embodiments, provided herein is a compound (for example, compound of formula (I)) can be administered in combination with one or more combination therapies.The examples of combination therapies that can be administered in combination with provided herein is listed in Table 2. [Table 4] TIFF2025536922000123.tif222165TIFF2025536922000124.tif227165TIFF20255369220 00125.tif233165TIFF2025536922000126.tif232165TIFF2025536922000127.tif123165

[0265] In certain embodiments, the co-therapy provided herein includes co-administration with other types of chemotherapeutic agents, such as cancer immunotherapeutic agents. Cancer cells often have specific cell surface antigens that can be recognized by the immune system. Therefore, cancer immunotherapeutic agents, such as monoclonal antibodies, can selectively bind to cancer cell antigens and cause cell death. Other cancer immunotherapeutic agents can suppress tumor-mediated inhibition of natural immune responses or activate the immune response, thereby promoting tumor recognition by the immune system. Exemplary antibody cancer immunotherapeutics include, but are not limited to, abagovomab, adecatumumab, afutuzumab, alemtuzumab, anatumomab mafenatox, apolizumab, blinatumomab, BMS-936559, catumaxomab, durvalumab, epacadostat, epratuzumab, indoximod, inotuzumab ozogamicin, intelmumab, ipilimumab, isatuximab, lambrolizumab, MED14736, MPDL3280A, nivolumab, obinutuzumab, ocaratuzumab, ofatumumab, olatuzumab, pembrolizumab, pidilizumab, rituximab, ticilimumab, samalizumab, and tremelimumab. In some embodiments, the antibody cancer immunotherapeutic is selected from an anti-CD73 monoclonal antibody (mAb), an anti-CD39 mAb, an anti-PD-1 mAb, and an anti-CTLA4 mAb. Thus, in some embodiments, the methods provided herein involve co-administration of one or more cancer immunotherapeutic agents, e.g., agents described above.

[0266] In some embodiments, the combination therapy includes co-administration of a compound provided herein, e.g., a compound of Formula (I), and an SH2 inhibitor, e.g., CGP78850, CPG85793, C90, C126, G7-18NATE, G7-B1, and NSC642056.

[0267] In some embodiments, the combination therapy includes co-administration of a compound provided herein, e.g., a compound of Formula (I), and a MEK inhibitor, e.g., trametinib, cobimetinib, binimetinib, selumetinib, PD-325901, CI-1040, and TAK-733.

[0268] In some embodiments, the combination therapy comprises co-administration of a compound provided herein, e.g., a compound of Formula (I), and a MET inhibitor selected from JNJ-38877605, PF-04217903, foretinib, AMG 458, tivantinib, cabozantinib, crizotinib, capmatinib hydrochloride, tepotinib hydrochloride, and savolitinib.

[0269] In some embodiments, the combination therapy comprises co-administration of a compound provided herein, e.g., Formula (I), and an SHP2 inhibitor selected from TNO-155, RMC-4630, JAB-3068, or RLY-1971.

[0270] In some embodiments, the combination therapy comprises co-administration of a compound provided herein, e.g., a compound of Formula (I), and a RAS inhibitor selected from aliskiren, captopril, losartan, irbesartan, olmesartan, candesartan, valsartan, fimasartan, azilsartan, telmisartan, eprosartan, benazepril, enalapril, lisinopril, perindopril, quinapril, ramipril, and trandolapril.

[0271] In some embodiments, the combination therapy comprises administering a compound provided herein, for example, a compound of Formula (I), in combination with a TKI. In certain embodiments, the TKI is a ROS1 inhibitor. In certain embodiments, the TKI is an ALK inhibitor. In certain embodiments, the TKI is crizotinib, ceritinib, alectinib, brigatinib, lorlatinib, entrectinib, repotrectinib, cabozantinib, foretinib, taretrectinib, merestinib, masitinib, or ensartinib. In certain embodiments, the TKI is crizotinib. In certain embodiments, the TKI is entrectinib. In certain embodiments, the TKI is alectinib. In certain embodiments, the TKI is brigatinib.

[0272] In some embodiments, the combination therapy comprises co-administration of a compound provided herein, e.g., a compound of Formula (I), and an anti-PD-1 therapy. In certain embodiments, the combination therapy comprises co-administration of a compound provided herein, e.g., a compound of Formula (I), and oxaliplatin. In other embodiments, the combination therapy comprises co-administration of a compound provided herein, e.g., a compound of Formula (I), and doxorubicin.

[0273] In certain embodiments, the compounds provided herein can be administered in conjunction with non-chemical cancer treatment methods.In certain embodiments, the compounds provided herein can be administered in conjunction with radiation therapy.In certain embodiments, the compounds provided herein can be administered in conjunction with surgery, thermal ablation, focused ultrasound therapy, cryotherapy, or any combination thereof.

[0274] In certain embodiments, the compounds provided herein can be administered in combination with an agent that inhibits CD47 / SIRPα interaction. In certain embodiments, the agent that inhibits CD47 / SIRPα interaction is a CD47 inhibitor. In certain embodiments, the CD47 inhibitor is an anti-CD47 antibody. In certain embodiments, the anti-CD47 antibody is AO-176, CC-90002, GenSci-059, IMC-002, lemzoparlimab, letaplimab, ligufalimab, magrolimab, MIL-95, SHR-1603, ZL-1201, STI-6643, SRF231, TQB2928, or SGN-CD47M. In certain embodiments, the CD47 inhibitor is magrolimab. In certain embodiments, the CD47 inhibitor is a small molecule. In certain embodiments, the CD47 inhibitor is RRx-001. In certain embodiments, the agent that inhibits the CD47 / SIRPα interaction is an anti-CD47 bispecific antibody. In certain embodiments, the CD47 bispecific antibody is selected from the group consisting of BAT-7104, HX-009, IBI-322, IMM-0306, JMT-601, SG-12473, SIRPα-Fc-CD40L, TG-1801, HX009, PF-07257876, DVD-Ig SL / LL, SIRPa-gamma-CD20 HC, CD20-2GL-SIRPa HC, CD20-4GL-SIRPa HC, bi-scFv The drug that inhibits CD47 / SIRPα interaction is RTX-CD47, LQ007, HMBD004A, HMBD004B, NI-1801, NI-2401, NI-2601, PT-886, PT-796, PT-217, IMM-26011, IMM-2902, SG3847, BH-29XX, PMC-122, ABP-160, IMM-2505, TJ-L1C4, IAB, SL-172154, DSP107, TJ C4GM or IMM-0207.In certain embodiments, the drug that inhibits CD47 / SIRPα interaction is a SIRPα inhibitor.In certain embodiments, the SIRPα inhibitor is an anti-SIRPα antibody.In certain embodiments, the anti-SIRPα antibody is BI-765063, CC-95251, GS-0189, HSIRPB, H21, ES004, AL008, ADU-1805, or Abx701. In certain embodiments, the SIRPα inhibitor is a small molecule. In certain embodiments, the agent that inhibits CD47 / SIRPα interaction is a SIRPα / Fc fusion protein antibody. In certain embodiments, the SIRPα / Fc fusion protein antibody is DSP-107, evoluptent, IMM-01, TTI-621, or TTI-622.

[0275] In certain embodiments, the compounds provided herein can be administered in combination with one or more other compounds provided herein.In addition, such combinations can be administered in combination with other therapeutic agents, such as other drugs suitable for the treatment of cancer, immune diseases or neurological diseases, such as the drugs specified above.In certain embodiments, the combination of one or more additional chemotherapeutic agents and the compounds provided herein can produce synergistic effects.In certain embodiments, the combination of one or more additional chemotherapeutic agents can produce additive effects.

[0276] 4.5 Pharmaceutical Compositions In certain embodiments, provided herein is a pharmaceutical agent suitable for use in a human patient, the pharmaceutical agent comprising any of the compounds described above (e.g., a compound provided herein, e.g., a compound of Formula (I)), and one or more pharmaceutically acceptable excipients. In certain embodiments, the pharmaceutical agent can be for use in the treatment or prevention of a condition or disease described herein. Any of the compounds provided herein can be used in the manufacture of a medicament for the treatment of any disease or condition provided herein.

[0277] The compositions and methods provided herein can be used to treat a subject in need of treatment. In certain embodiments, the subject is a mammal, e.g., a human, or a non-human mammal. In one embodiment, when administered to a subject, e.g., a human, the composition or compound is administered as, for example, a pharmaceutical composition comprising a compound provided herein and a pharmaceutically acceptable carrier. Pharmaceutically acceptable carriers are well known in the art and include, for example, aqueous solutions, e.g., water or physiologically buffered saline, or other solvents or vehicles, e.g., glycols, glycerol, oils, e.g., olive oil, or injectable organic esters. In one embodiment, such pharmaceutical compositions are intended for administration to humans, particularly for invasive administration routes (i.e., routes that avoid transport or diffusion through epithelial barriers, e.g., injection or implantation), and the aqueous solutions are pyrogen-free or substantially pyrogen-free. The excipients can be selected, for example, to provide delayed release of the drug or to selectively target one or more cells, tissues, or organs. The pharmaceutical compositions may be included in dosage unit forms, such as tablets, capsules (including sprinkle capsules and gelatin capsules), granules, lyophilizates for reconstitution, powders, solutions, syrups, suppositories, injections, etc. The compositions may also be included in transdermal delivery systems, such as skin patches. The compositions may also be included in solutions suitable for topical administration, such as eye drops.

[0278] Pharmaceutically acceptable carriers may include, for example, physiologically acceptable agents that act to stabilize, increase the solubility, or increase the absorption of a compound, such as a compound provided herein. Such physiologically acceptable agents include, for example, carbohydrates such as glucose, sucrose, or dextran; 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 containing a physiologically acceptable agent depends, for example, on the route of administration of the composition. The formulation or pharmaceutical composition may be a self-emulsifying or self-microemulsifying drug delivery system. The pharmaceutical composition (formulation) may be, for example, a liposome or other polymer matrix into which the compound provided herein can be incorporated. For example, liposomes containing phospholipids or other lipids are non-toxic, physiologically acceptable, and metabolizable carriers that are relatively simple to prepare and administer.

[0279] The phrase "pharmaceutically acceptable" is used herein to refer to compounds, materials, compositions, and / or dosage forms that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of a subject without undue toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0280] As used herein, the phrase "pharmaceutically acceptable carrier" refers to a pharmaceutically acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, excipient, solvent, or encapsulating material. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not harmful to the subject. Some examples of materials that can function 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) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository wax; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and the like. 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) buffers, such as magnesium hydroxide and aluminum hydroxide, (15) alginic acid, (16) pyrogen-free water, (17) isotonic saline, (18) Ringer's solution, (19) ethyl alcohol, (20) phosphate buffer, and (21) other non-toxic compatible substances used in pharmaceutical formulations.

[0281] The pharmaceutical composition (formulation) can be administered to a subject by any of a number of routes of administration, including, for example, oral (e.g., drench in an aqueous or non-aqueous solution or suspension, tablet, capsule (including sprinkle capsule and gelatin capsule), bolus, powder, granule, paste for application to the tongue), absorption through the oral mucosa (e.g., sublingual), anal, rectal, or vaginal (e.g., as a pessary, cream, or foam), parenteral (intramuscular, intravenous, subcutaneous, or intrathecal, e.g., as a sterile solution or suspension), nasal, intraperitoneal, subcutaneous, transdermal (e.g., a patch applied to the skin), and topical (e.g., as a cream, ointment, or spray applied to the skin, or as eye drops). The compound can also be formulated for inhalation. In certain embodiments, the compound can simply be dissolved or suspended in sterile water. Details of suitable routes of administration and compositions suitable therefor can be found, for example, in U.S. Pat. Nos. 6,110,973, 5,763,493, 5,731,000, 5,541,231, 5,427,798, 5,358,970, and 4,172,896, and the patents cited therein.

[0282] The formulations can be conveniently contained in unit dosage forms and prepared by any method known in the art of pharmacy. The amount of active ingredient that can be combined with a carrier material to produce a single dosage form will vary depending on the subject being treated and the particular mode of administration. The amount of active ingredient that can be combined with a carrier material to produce a single dosage form will generally be the amount of compound that produces a therapeutic effect. Generally, out of 100 percent, this amount will range from about 1 percent to about 99 percent of the active ingredient, from about 5 percent to about 70 percent, or from about 10 percent to about 30 percent.

[0283] Methods of preparing these formulations or compositions include the step of bringing into association an active compound, such as a compound provided herein, with the carrier and, optionally, one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing into association a compound provided herein with liquid carriers, or finely divided solid carriers, or both, and then, if necessary, shaping the product.

[0284] Formulations provided herein suitable for oral administration may be included in the form of capsules (including sprinkle capsules and gelatin capsules), cachets, pills, tablets, lozenges (using a flavored base, usually sucrose and acacia or tragacanth), lyophilisates, powders, granules, or as a solution or suspension in an aqueous or non-aqueous liquid, or an oil-in-water or water-in-oil liquid emulsion, or an elixir or syrup, or a pastille (using an inert base such as gelatin and glycerin, or sucrose and acacia), and / or mouthwash, etc. The composition or compound may also be administered as a bolus, electuary, or paste.

[0285] To prepare solid dosage forms for oral administration (capsules (including sprinkle capsules and gelatin capsules), tablets, pills, dragees, powders, granules, etc.), the active compound 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 starch, lactose, sucrose, glucose, mannitol, and / or silicic acid; (2) binders, such as carboxymethylcellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose, and / or acacia; (3) humectants, such as glycerol; and (4) disintegrants, such as agar. , calcium carbonate, potato starch or tapioca starch, alginic acid, certain silicates, and sodium carbonate, (5) solution retarders such as paraffin, (6) absorption accelerators such as quaternary ammonium compounds, (7) wetting agents such as cetyl alcohol and glycerol monostearate, (8) absorbents such as kaolin and bentonite clay, (9) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, and mixtures thereof, (10) complexing agents such as modified and unmodified cyclodextrins, and (11) coloring agents. In the case of capsules (including sprinkle capsules and gelatin capsules), tablets, and pills, the pharmaceutical compositions may also contain buffering agents. Solid compositions of a similar type may also be used as fillers for soft and hard gelatin capsules using excipients such as lactose or milk sugar and high molecular weight polyethylene glycols.

[0286] Tablets can be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets can be prepared using binders (e.g., gelatin or hydroxypropylmethylcellulose), lubricants, inert diluents, preservatives, disintegrants (e.g., sodium starch glycolate or cross-linked sodium carboxymethylcellulose), surfactants, or dispersants. Molded tablets can be made by molding a mixture of powdered compounds moistened with an inert liquid diluent in a suitable machine.

[0287] Tablets and other solid dosage forms of the pharmaceutical compositions, such as dragees, capsules (including sprinkle capsules and gelatin capsules), pills, and granules, may optionally be scored or prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical formulation art. They may also be formulated to provide sustained or controlled release of the active ingredient contained therein, for example, using various proportions of hydroxypropylmethylcellulose, other polymer matrices, liposomes, and / or microspheres to provide the desired release profile. They may be sterilized, for example, by filtration through a bacteria-retaining filter or by incorporating a sterilizing agent in the form of a sterile solid composition that can be dissolved in sterile water or other sterile injectable medium immediately before use. These compositions may optionally contain opacifying agents or may be composed to release the active ingredient(s) only in a certain part of the gastrointestinal tract, optionally in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes. The active ingredient may also be in microencapsulated form, if appropriate, with one or more of the above-mentioned excipients.

[0288] The liquid dosage form useful for oral administration includes pharmaceutically acceptable emulsion, lyophilized product for reconstitution, microemulsion, solution, suspension, syrup and elixir.In addition to the active ingredient, the liquid dosage form can also contain the inert diluent commonly used in the art, such as water or other solvent, cyclodextrin and its derivatives, solubilizer and emulsifier, for example, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oil (specifically cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil and sesame oil), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycol and fatty acid ester of sorbitan and their mixtures.

[0289] Besides inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, coloring, perfuming and preservative agents.

[0290] Suspensions may contain, in addition to the active compounds, suspending agents such as ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar, and tragacanth, and mixtures thereof.

[0291] Formulations of pharmaceutical compositions for rectal, vaginal, or urethral administration may be included as suppositories, which may be prepared by mixing one or more active compounds with one or more suitable non-irritating excipients or carriers including, for example, cocoa butter, polyethylene glycol, a suppository wax, or a salicylate, and which are solid at room temperature but liquid at body temperature and will melt in the rectum or vaginal cavity to release the active compound.

[0292] Formulations of the pharmaceutical composition for oral administration may be presented as a mouthwash, or a mouth spray, or a mouth ointment.

[0293] Alternatively, or in addition, the compositions may be formulated for delivery via a catheter, stent, wire, or other intraluminal device, which may be particularly useful for delivery to the bladder, urethra, ureter, rectum, or intestine.

[0294] Formulations which are suitable for vaginal administration also include pessaries, tampons, creams, gels, pastes, foams or spray formulations containing such carriers as are known in the art to be appropriate.

[0295] 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 required.

[0296] The ointments, pastes, creams and gels may contain, in addition to the active compound, excipients such as animal and vegetable fats, oils, waxes, paraffin, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonite, silicic acid, talc and zinc oxide, or mixtures thereof.

[0297] Powders and sprays can contain, in addition to the active compound, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances. Sprays can additionally contain customary propellants, such as chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons, such as butane and propane.

[0298] Transdermal patches also have the advantage of providing controlled delivery of the compounds provided herein to the body.Such dosage forms can be prepared by dissolving or dispersing the active compound in a suitable medium.Absorption enhancers can also be used to increase the flux of the compound through the skin.The rate of such flux can be controlled by providing a rate-limiting membrane or dispersing the compound in a polymer matrix or gel.

[0299] Ophthalmic formulations, eye ointments, powders, solutions, and the like are also provided herein. Exemplary ophthalmic formulations are described in U.S. Publication Nos. 2005 / 0080056, 2005 / 0059744, 2005 / 0031697, and 2005 / 004074, and U.S. Patent No. 6,583,124, the contents of which are incorporated herein by reference. Optionally, the liquid ophthalmic formulation has properties similar to those of tears, aqueous humor, or vitreous humor, or is compatible with such fluids. The route of administration is topical (e.g., topical administration such as eye drops, or administration via an implant).

[0300] As used herein, the phrases "parenteral administration" and "administering parenterally" refer to modes of administration other than enteral and topical administration, usually by injection, and include, but are not limited to, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intrathecal, and intrasternal injection and infusion.

[0301] Pharmaceutical compositions suitable for parenteral administration comprise one or more active compounds in combination with one or more pharmaceutically acceptable sterile isotonic aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, or sterile powders that can be reconstituted into sterile solutions or dispersions for injection just prior to use, which may contain antioxidants, buffers, bacteriostats, solutes or suspending or thickening agents that render the formulation isotonic with the blood of the intended recipient.

[0302] Examples of suitable aqueous and non-aqueous carriers that can be used in the pharmaceutical compositions provided herein include water, ethanol, polyols (glycerol, propylene glycol, polyethylene glycol, etc.) and suitable mixtures thereof, vegetable oils such as olive oil, and injectable organic esters such as ethyl oleate. Proper fluidity can be maintained, for example, by the use of coating materials such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.

[0303] These compositions may also contain adjuvants, such as preservatives, wetting agents, emulsifying agents, and dispersing agents. Prevention of the action of microorganisms may be ensured by the inclusion of various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol sorbic acid, and the like. It may also be desirable to include isotonic agents, for example, sugars, sodium chloride, and the like, in the compositions. In addition, prolonged absorption of the injectable pharmaceutical form may be brought about by the inclusion of agents that delay absorption, for example, aluminum monostearate and gelatin.

[0304] In some cases, in order to prolong the effect of drug, it is desirable to delay the absorption of drug from subcutaneous or intramuscular injection.This can be achieved by using a liquid suspension of crystalline or amorphous material with poor water solubility.The absorption rate of drug is in turn dependent on its dissolution rate, which can depend on crystal size and crystalline form.Alternatively, delayed absorption of parenterally administered drug form can be achieved by dissolving or suspending the drug in oil medium.

[0305] Injectable depot forms are made by forming microencapsulated matrices of the subject compound in biodegradable polymers, such as polylactide-polyglycolide. The rate of drug release can be controlled depending on the ratio of drug to polymer and the properties of the particular polymer used. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations can also be prepared by entrapping the drug in liposomes or microemulsions that are compatible with body tissues.

[0306] For use in the methods provided herein, the active compound may be administered per se or as a pharmaceutical composition comprising, for example, 0.1 to 99.5% (e.g., 0.5 to 90%) of the active ingredient in combination with a pharmaceutically acceptable carrier.

[0307] Methods of introduction can also be provided by rechargeable or biodegradable devices. Recently, a variety of slow-release polymeric devices have been developed and tested in vivo for the controlled delivery of drugs, including proteinaceous biopharmaceuticals. A variety of biocompatible polymers (including hydrogels), including both biodegradable and non-degradable polymers, can be used to form implants for the sustained release of compounds at specific target sites.

[0308] The actual dosage level of the active ingredient contained in the pharmaceutical composition may be varied to provide an amount of the active ingredient effective to achieve the therapeutic response required for a particular patient, composition, and method of administration without being toxic to the patient.

[0309] The selected dosage level will depend on a variety of factors, including the activity of the particular compound or combination of compounds, or esters, salts, or amides thereof, used, the route of administration, the time of administration, the rate of excretion of the particular compound(s) used, the duration of treatment, other drugs, compounds, and / or materials used in combination with the particular compound(s) used, the age, sex, weight, condition, general condition, and previous medical history of the subject being treated, and similar factors well known in the medical arts.

[0310] A physician or veterinarian of ordinary skill in the art can easily determine and prescribe the required therapeutically effective amount of the pharmaceutical composition. For example, a physician or veterinarian may start by administering a pharmaceutical composition or compound at a level lower than that required to achieve the desired therapeutic effect, and gradually increase the dosage until the desired effect is achieved. A "therapeutically effective amount" refers to the concentration of a compound sufficient to elicit 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 that affect 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 necessary, other types of therapeutic agents administered together with the compounds provided herein. A larger total dose can be delivered by multiple administrations of the drug. 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).

[0311] Generally, a suitable daily dose of an active compound used in the compositions and methods provided herein will be that amount of the compound that is the lowest dose effective to produce a therapeutic effect. Such an effective dose will generally depend upon the factors described above.

[0312] If necessary, the effective daily dose of the active compound can be administered as 1, 2, 3, 4, 5, 6 or more subdoses, which are optionally administered separately in unit dosage form at appropriate intervals throughout the day.In certain embodiments, the active compound can be administered twice or three times a day.In certain embodiments, the active compound is administered once a day.

[0313] In certain embodiments, the compounds provided herein may be used alone or may be administered in combination with another type of therapeutic agent. As used herein, the term "co-administration" refers to any administration form of two or more different therapeutic compounds, where the second compound is administered while the previously administered therapeutic compound is still effective in the body (e.g., the two compounds are simultaneously effective in the subject, which may include the synergistic effect of the two compounds). For example, the different therapeutic compounds may be administered in the same formulation or in separate formulations, simultaneously or sequentially. In certain embodiments, the different therapeutic compounds may be administered within 1 hour, 12 hours, 24 hours, 36 hours, 48 ​​hours, 72 hours, or 1 week of each other. Thus, subjects receiving such treatment can benefit from the combined effects of different therapeutic compounds.

[0314] In certain embodiments, co-administration of a compound provided herein with one or more additional therapeutic agent(s) (e.g., one or more additional chemotherapeutic agent(s)) results in improved efficacy compared to separate administration of a compound provided herein (e.g., a compound of Formula I or Ia) or the one or more additional therapeutic agent(s). In certain such embodiments, the co-administration results in an additive effect, where additive effect refers to the sum of the effects of each of the separate administration of a compound provided herein and the one or more additional therapeutic agent(s).

[0315] Also provided herein is the use of pharmaceutically acceptable salts of the compounds provided herein in the compositions and methods provided herein. In certain embodiments, contemplated salts provided herein include, but are not limited to, alkyl, dialkyl, trialkyl, or tetraalkylammonium salts. In certain embodiments, contemplated salts provided herein include, but are not limited to, L-arginine, benenthamine, benzathine, betaine, calcium hydroxide, choline, deanol, diethanolamine, diethylamine, 2-(diethylamino)ethanol, ethanolamine, ethylenediamine, N-methylglucamine, hydrabamine, 1H-imidazole, 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 provided herein include, but are not limited to, Na, Ca, K, Mg, Zn, or other metal salts.

[0316] Pharmaceutically acceptable acid addition salts may also exist as various solvates, for example, with water, methanol, ethanol, dimethylformamide, etc. Mixtures of such solvates may also be prepared. The source of such solvates may be from the solvent of crystallization, may be inherent in the solvent of preparation or crystallization, or may be adventitious to such solvent.

[0317] Pharmaceutically acceptable anionic salts include acetate, aspartate, benzenesulfonate, benzoate, besylate, bicarbonate, bitartrate, bromide, camsylate, carbonate, chloride, citrate, decanoate, edetate, esylate, fumarate, gluceptate, gluconate, glutamate, glycolate, hexanoate, hydroxynaphthoate, iodide, isethionate, lactate, lactobionate, malate, maleate, mandelate, mesylate, methylsulfate, mucate, napsylate, nitrate, octanoate, oleate, pamoate, pantothenate, phosphate, polygalacturonate, propionate, salicylate, stearate, acetate, succinate, sulfate, tartrate, teoclate, and tosylate.

[0318] Wetting agents, emulsifying agents, and lubricating agents, such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, release agents, coating agents, sweetening, flavoring, and perfuming agents, preservatives, and antioxidants can also be included in the composition.

[0319] Examples of pharmaceutically acceptable antioxidants include: (1) water-soluble antioxidants, such as ascorbic acid, cysteine ​​hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite, etc.; (2) oil-soluble antioxidants, such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, alpha-tocopherol, etc.; and (3) metal chelating agents, such as citric acid, ethylenediaminetetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, etc.

[0320] Having now generally described the present disclosure, it will be more readily understood by reference to the following examples, which are included solely for purposes of illustration of certain aspects and embodiments provided herein and are not intended to limit the disclosure. [Example]

[0321] 5. Working Example General synthesis method The compounds provided herein can be prepared by a variety of synthetic methods, as further described and exemplified herein. Those skilled in the art will appreciate that the following general synthetic methods are representative and not intended to be limiting. Racemic compounds can be enantiomerically enriched by chiral, preparative, SFC, or HPLC separation. Stereotypes depicted without an upward or downward wedge annotation are shown in Figure 1. 3 The center represents an unquantified mixture of configurations at that position. The solid sp drawn with an up or down wedge annotation 3 The center represents the steric enrichment for the depicted configuration. The solid sp is drawn with an upward or downward wedge and is further marked "or 1". 3 The centers represent the stereoenrichment for a single unknown configuration. [Table 5] TIFF2025536922000129.tif209165TIFF2025536922000130.tif119165

[0322] Method A [ka] Nitropyridine I can be reduced using Fe metal conditions to give aminopyridines of type II. This transformation can also be achieved using Raney nickel and hydrazine; if the substrate contains an isoxazole moiety, SnCl2 conditions can be used instead to improve yields. Intramolecular ring closure of II can be achieved using C-H insertion cross-coupling conditions to give compounds of type III. Potassium acetate or potassium pivalate are effective bases for this macrocyclization step.

[0323] Method B [ka] Nitriles of type IV may be converted to primary amides of type V using sodium hydroxide in tetrahydrofuran. Alternative hydroxide sources include, but are not limited to, lithium hydroxide, potassium hydroxide, cesium hydroxide, or tetraalkylammonium hydroxides such as Triton B.

[0324] Method C [ka] Nitriles IV can be reacted with sodium hydroxide in methanol to give carboxylic acids of type VI. Lithium hydroxide, potassium hydroxide, cesium hydroxide, or tetraalkylammonium hydroxides, such as Triton B, can be used in place of sodium hydroxide for this transformation. Carboxylic acids of type VI can be reacted with amines of type VII in the presence of an amide coupling reagent to give carboxamides of type VIII. Suitable amide coupling reagents include, but are not limited to, HATU, EDCI, TBTU, CDI, and T3P.

[0325] Method D [ka] Halide IX can be coupled with stannane X using Stille coupling conditions to give compounds of type II. Various additives, including but not limited to LiCl or CuI, can optionally be used to facilitate this reaction. Intramolecular ring closure of halide II can be achieved using C-H insertion cross-coupling conditions to give compounds III. Potassium acetate or potassium pivalate are effective bases for this macrocyclization step.

[0326] Method E [ka] Nitropyridine XI can be reduced using Fe metal conditions to give aminopyridines of type XII. This transformation can also be achieved using Raney nickel and hydrazine; if the substrate contains an isoxazole moiety, SnCl conditions can be used instead to improve yields. Intramolecular ring closure of compound XII can be achieved using two-step, one-pot boronation / Suzuki cross-coupling conditions to give compound III.

[0327] Method F [ka] Thioether XIII may be converted using meta-chloroperbenzoic acid to a mixture of sulfoxide XIV and sulfone XV. These products may be separated and isolated using chromatographic methods.

[0328] Method G [ka] Nitropyridine I may be reduced using iron metal conditions to give the aminopyridine intermediate, which can be converted to bromide XII by NBS. This initial iron reduction step can also be achieved using Raney nickel and hydrazine; if the substrate contains an isoxazole moiety, SnCl conditions can be used instead to improve yield. Intramolecular ring closure of compound XII may be achieved using two-step, one-pot boronation / Suzuki cross-coupling conditions to give compound III.

[0329] Method H [ka] Ester XVI can be reacted with aqueous lithium hydroxide in an organic solvent to give carboxylic acids of type VI. Sodium hydroxide, potassium hydroxide, cesium hydroxide, or tetraalkylammonium hydroxides, such as Triton B, can be used in place of lithium hydroxide for this transformation. Carboxylic acids of type VI can be reacted with amines of type VII in the presence of an amide coupling reagent to give carboxamides of type VIII. Suitable amide coupling reagents include, but are not limited to, HATU, EDCI, TBTU, CDI, and T3P.

[0330] Method I [ka] The SEM ether XVII can be deprotected with an acid to give the pyrazole XVIII. Suitable acids include, but are not limited to, TFA and HCl.

[0331] Method J [ka] Ketone XIX may be reduced to alcohol XX using a reducing agent such as sodium borohydride in an alcohol solvent such as methanol.

[0332] Method K [ka] The halide IX can be coupled with the boronate XXI using Suzuki coupling conditions to give the aminopyridine XXII after base-promoted Boc deprotection. Bromination of the aminopyridine ring with NBS followed by intramolecular ring closure using C-H insertion cross-coupling conditions can give the macrocycle III. Potassium acetate or potassium pivalate are effective bases for this macrocyclization step.

[0333] Method L [ka] The MOM ether XXIII can be deprotected under acidic conditions, and the exposed alcohol can be oxidized using Dess-Martin periodinane to give the ketone XXIV. Suitable acids include, but are not limited to, TFA and HCl. Intramolecular ring closure of XXIV can be achieved using C-H insertion cross-coupling conditions to give the macrocycle XXV. Potassium acetate or potassium pivalate are effective bases for this macrocyclization step.

[0334] Method M [ka] The Weinreb amide XXVII may be converted to the ketone XXVIII via reaction with a Grignard reagent XXVII.

[0335] When used in General Methods A, B, C, D, E, F, G, H, I, J, K, L, and M, each instance of A may independently be O, N, S, NR, as valence permits. g8 , C.R. g9 , or C(R g9 )2 and R g8 and R g9 Each instance of is independently H or C 1-6 R is alkyl. g1 Each instance of R is independently H, methyl, or hydroxymethyl. g2 Each instance of is independently H, halo, CN, C 1-4 Alkoxy, Halo-C 1-4 Alkyl, and C 1-4 R is alkyl. g3 Each instance of is independently H, CN, halo, [ka] -CO-C 1-4 Alkyl, 5-membered heteroaryl, C 1-4 Alkyl-SO-, C 1-4 Alkyl-SO2-, C 1-4 Alkoxy, C 1-4 Alkyl, Halo-C 1-4Alkyl, C 1-4 Alkoxy-C 1-4 Alkyl, C 3-4 Cycloalkylmethyl, C 3-6 Cycloalkyl, and C 3-6 and heterocyclyl, wherein the heteroaryl, cycloalkyl, heterocyclyl, or alkyl further comprises, as valence permits, 0, 1, 2, or 3 C 1-4 Substituted with alkyl or halogen. R n Each instance of is independently H, C 1-4 Alkyl, Halo-C 1-4 Alkyl or C 3-6 cycloalkyl or two R n groups together with their intervening nitrogens, optionally one or more C 1-4 C substituted with alkyl or halogen 3-6 Form a heterocycloalkyl. R g4 and R g5 Each instance of is independently a substituted or unsubstituted C 1-4 alkyl or R g4 and R g5 together with their intervening nitrogens, optionally one or more C 1-4 C substituted with alkyl or halogen 3-6 Form a heterocycloalkyl. R g6 and R g7 Each instance of is independently a substituted or unsubstituted C 1-4 Z is CR5 or N, and R5 is H or F. T is -CH2-, -O-, -CH(OH)-, or -C(=O)-.

[0336] Analysis method LCMS data was collected using one of the following methods: [Table 6] TIFF2025536922000146.tif217165TIFF2025536922000147.tif52165

[0337] Synthesis Example Intermediates Synthesis of 5-ethyl-1-methyl-1H-pyrazole-3-carbaldehyde [ka] To a mixture of methyl 5-bromo-1-methyl-1H-pyrazole-3-carboxylate (4.50 g, 20.5 mmol) in i-PrOH (50 mL) was added potassium ethenyltrifluoroboranide (6.05 g, 45.19 mmol), Pd(dppf)Cl (1.5 g, 2.05 mmol), and TEA (4.16 g, 41.1 mmol). The mixture was degassed and purged with N three times. The mixture was stirred at 80 °C for 12 h. The mixture was concentrated. The residue was purified by flash column chromatography on silica gel (0 → 3% MeOH in DCM) to give methyl 1-methyl-5-vinyl-1H-pyrazole-3-carboxylate (3.40 g, 99.6% yield) as a pale yellow solid. LC / MS ESI (m / z): 167.1 [M+H] + .

[0338] To a solution of methyl 1-methyl-5-vinyl-1H-pyrazole-3-carboxylate (3.40 g, 7.58 mmol) in MeOH (30 mL) was added Pd / C (220 mg, 0.1 mmol, 10 wt%). The mixture was degassed and purged with H2 three times. The mixture was stirred at 20 °C for 2 h. The mixture was filtered, and the filtrate was concentrated to give methyl 5-ethyl-1-methyl-1H-pyrazole-3-carboxylate (3.2 g, 95% yield) as a yellow solid. LC / MS (ESI) (m / z): 169.1 [M+H] + .

[0339] To a stirred solution of methyl 5-ethyl-1-methyl-1H-pyrazole-3-carboxylate (3.20 g, 19.0 mmol) in THF (40 mL) was added DIBAL-H (1.5 M in THF, 19 mL, 29 mmol) at −60° C. The reaction was stirred at −60° C. for 2 h. The mixture was quenched with saturated aqueous Rochelle's salt (100 mL) and extracted with EtOAc (90 mL×3). The combined organic layers were washed with brine, dried over Na2SO4, and concentrated. The residue was purified by column chromatography on silica gel (10→100% EtOAc in PE) to give 5-ethyl-1-methyl-1H-pyrazole-3-carbaldehyde (2.5 g, 95.1% yield) as a pale yellow oil. LC / MS (ESI) (m / z): 139.1 [M+H] + .

[0340] Synthesis of 1-ethyl-4-iodo-1H-pyrazole-3-carbonitrile [ka] To a stirred solution of 1-ethyl-1H-pyrazole-3-carbonitrile (3.30 g, 27.3 mmol) in MeCN (20 mL) was added TFA (3.11 g, 27.3 mmol) at 0 °C. Then, a solution of NIS (7.98 g, 35.3 mmol) in MeCN (20 mL) was added dropwise at 0 °C. The reaction was stirred at 25 °C for 16 h. The mixture was quenched with saturated aqueous NaHCO (30 mL) and partially concentrated to remove MeCN. The mixture was extracted with EtOAc (100 × 3 mL). The combined organic phases were washed with brine (50 mL × 2), dried over anhydrous NaSO, and concentrated. The residue was purified by flash column chromatography on silica gel (15 → ​​20% EtOAc in PE) to give 1-ethyl-4-iodo-1H-pyrazole-3-carbonitrile (3.70 g, yield: 55.0%) as a clear oil. LC / MS (ESI) m / z: 248 [M+H] + . The following intermediates were synthesized using a similar protocol (including m / z (ESI) values): [Table 7]

[0341] Synthesis of 1-cyclobutyl-1H-pyrazole-3-carbonitrile [ka] A mixture of 1H-pyrazole-3-carbonitrile (5.00 g, 53.7 mmol) and NaH (1.93 g, 80.6 mmol, 60% solution in mineral oil) in DMF (50 mL) was stirred under N at 0 °C for 0.5 h. A solution of bromocyclobutane (10.9 g, 80.6 mmol) in DMF (100 mL) was added, and the reaction was stirred at room temperature for 16 h. The mixture was quenched with saturated aqueous NH Cl (50 mL) and extracted with EtOAc (100 mL x 3). The combined organic phase was washed with HO (40 mL x 3), brine (40 mL x 2), dried over anhydrous Na SO , and concentrated. The residue was purified by flash column chromatography on silica gel (50 → 100% EtOAc in PE) to give 1-cyclobutyl-1H-pyrazole-3-carbonitrile (3.50 g, 44.3% yield) as a clear oil. LC / MS (ESI) (m / z): 148 [M+H] + . The following intermediates were synthesized using a similar protocol (including m / z (ESI) values): [Table 8]

[0342] Synthesis of (2-chloro-6-methylpyridin-3-yl)boronic acid [ka] To a solution of 3-bromo-2-chloro-6-methylpyridine (5 g, 24.22 mmol) in THF (50 mL) was added n-BuLi (1.6 M in hexane, 18 mL, 29.06 mmol) at −70° C. The mixture was stirred at −70° C. for 1 hour. Triisopropyl borate (5.47 g, 29.06 mmol) was then added dropwise, and the mixture was stirred at 20° C. for 3 hours. The reaction was quenched with aqueous NaOH (5%, 30 mL). The aqueous layer was separated and acidified with aqueous HCl (1 M) to pH 3, then extracted with EtOAc (50 mL×3). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated to give (2-chloro-6-methylpyridin-3-yl)boronic acid (1.6 g, 38% yield). LC / MS (ESI) (m / z): 172 [M+H] + .

[0343] Synthesis of (3-bromo-1-methyl-1H-pyrazol-5-yl)(cyclopropyl)methanol [ka] To a solution of 3,5-dibromo-1-methyl-1H-pyrazole (1.00 g, 4.17 mmol) in THF (10 mL) was added n-BuLi (1.6 M in hexane, 3.13 mL, 5.00 mmol) at −78° C. The mixture was stirred at −78° C. for 15 minutes. A solution of cyclopropanecarbaldehyde (0.311 mL, 4.168 mmol) in THF (10 mL) was added, and the reaction was stirred at −78° C. for 2 hours. The solution was quenched with saturated aqueous NH4Cl at 0° C. and then extracted with EtOAc (30 mL×3). The combined organic phase was washed with brine (30 mL), dried over anhydrous Na2SO4, and concentrated. The residue was purified by flash column chromatography on silica gel (0→30% EtOAc in PE) to give (3-bromo-1-methyl-1H-pyrazol-5-yl)(cyclopropyl)methanol (330 mg, 34% yield) as a yellow oil. LC / MS (ESI) (m / z): 231 [M+H] + .

[0344] Synthesis of ethyl 5-cyano-1-methylpyrazole-3-carboxylate [ka] A solution of ethyl (E)-2-(2-methylhydrazinylidene)acetate (50.0 g, 384 mmol), prop-2-enenitrile (38.2 mL, 576 mmol), benzoyl peroxide (232 g, 960 mmol), and iodine (19.4 g, 76.8 mmol) in MeCN (750 mL) was stirred at 80 °C for 16 h. The residue was diluted with EtOAc (300 mL) and washed with saturated aqueous NaHCO (200 mL) and saturated aqueous NaSO (200 mL). The organic phase was washed with brine, dried over anhydrous NaSO, and concentrated. The residue was purified by flash column chromatography on silica gel (30 → 60% EtOAc in PE) to give ethyl 5-cyano-1-methylpyrazole-3-carboxylate (20.0 g, 29.1% yield) as a yellow solid. LC / MS (ESI) (m / z): 180 [M+H] + .

[0345] Synthesis of 3-bromo-5-(cyclopropylmethyl)-1-methyl-1H-pyrazole [ka] To a mixture of (3-bromo-1-methyl-1H-pyrazol-5-yl)(cyclopropyl)methanol (330 mg, 1.428 mmol) and TFA (4 mL) was added TES (2.306 mL, 14.280 mmol) at 25 °C. The mixture was degassed and purged with N 3 times and then stirred at 50 °C for 16 h. The mixture was concentrated, diluted with saturated aqueous NaHCO 3 , and extracted with EtOAc (30 mL × 3). The combined organic phase was washed with brine (30 mL), dried over anhydrous Na 2 SO 4 , and concentrated. The residue was purified by flash column chromatography on silica gel (0 → 50% EtOAc in PE) to give 3-bromo-5-(cyclopropylmethyl)-1-methyl-1H-pyrazole (205 mg, yield: 66.7%) as a yellow oil. LC / MS (ESI) (m / z): 215 [M+H] + . The following intermediates were synthesized using a similar protocol (including m / z (ESI) values): [Table 9] TIFF2025536922000158.tif205165TIFF2025536922000159.tif163165

[0346] Synthesis of 5-(hydroxymethyl)-2-methylpyrazole-3-carbonitrile [ka] To a stirred solution of ethyl 5-cyano-1-methylpyrazole-3-carboxylate (10.0 g, 55.8 mmol) and MeOH (3.5 g, 112 mmol) in THF (100 mL) was added LiBH (55.8 mL, 112 mmol, 2 M THF solution) at 0 °C. The reaction was stirred at 25 °C for 16 h. The mixture was quenched with saturated aqueous NH Cl (100 mL) at 0 °C and extracted with EtOAc (100 mL). The organic phase was dried over anhydrous Na SO and concentrated. The residue was purified by flash column chromatography on silica gel (0 → 50% EtOAc in PE) to give 5-(hydroxymethyl)-2-methylpyrazole-3-carbonitrile (3.60 g, yield: 47.0%) as a white solid. LC / MS (ESI) (m / z): 138 [M+H] + . The following intermediates were synthesized using a similar protocol (including m / z (ESI) values): [Table 10]

[0347] Synthesis of ethyl 5-cyclobutyl-1H-pyrazole-3-carboxylate [ka] To a solution of ethyl 4-cyclobutyl-2,4-dioxobutanoate (8.3 g, 41.69 mmol) in EtOH (40 mL) was added hydrazine (2.4 g, 62.54 mmol, 85% aqueous solution), and the reaction was stirred at 80 °C for 2 h. The mixture was concentrated and diluted with AcOH (7 mL), and the solution was stirred at 25 °C for 8 h. The mixture was concentrated, diluted with saturated aqueous NaHCO3, and extracted with EtOAc (20 mL x 3). The combined organic phases were washed with brine, dried over anhydrous Na2SO4, and concentrated. The residue was purified by flash column chromatography on silica gel (0 → 30% EtOAc in PE) to give ethyl 5-cyclobutyl-1H-pyrazole-3-carboxylate (6.9 g, yield: 85.1%) as a yellow oil. LC / MS ESI (m / z): 195 [M+H]+ The following intermediates were synthesized using a similar protocol (including m / z (ESI) values): [Table 11]

[0348] Synthesis of ethyl 5-cyclopropyl-2,4-dioxopentanoate [ka] To a solution of 1-cyclopropylpropan-2-one (1.50 g, 15.3 mmol) and diethyl oxalate (1.70 g, 15.3 mmol) in THF (20 mL) was added t-BuOK (15.3 mL, 15.3 mmol, 1 M THF solution) at 0 °C, and the mixture was stirred at 25 °C for 3 h. The reaction was quenched with saturated aqueous NH4Cl (30 mL) and extracted with EtOAc (50 mL x 3). The combined organic phase was washed with brine (50 mL x 2), dried over anhydrous Na2SO4, and concentrated to give ethyl 5-cyclopropyl-2,4-dioxopentanoate (1.80 g, crude) as a brown oil. LC / MS (ESI) (m / z): 199 [M+H] + .

[0349] Synthesis of 5-(cyclopropylmethyl)-3-iodo-1-methyl-1H-pyrazole [ka] To a solution of 3-bromo-5-(cyclopropylmethyl)-1-methyl-1H-pyrazole (185 mg, 0.860 mmol) in dioxane (8 mL) was added DMEDA (0.009 mL, 0.086 mmol), NaI (1.29 g, 8.601 mmol), and CuI (8.19 mg, 0.043 mmol). The mixture was degassed and purged with N three times and then stirred in a sealed tube at 110 °C for 16 h. The mixture was filtered, and the filtrate was concentrated. The residue was purified by flash column chromatography on silica gel (0 → 50% EtOAc in PE) to give 5-(cyclopropylmethyl)-3-iodo-1-methyl-1H-pyrazole (187 mg, 83% yield) as a yellow oil. LC / MS (ESI) (m / z): 263 [M+H] + .

[0350] Synthesis of 5-formyl-2-methylpyrazole-3-carbonitrile [ka] To a stirred solution of 5-(hydroxymethyl)-2-methylpyrazole-3-carbonitrile (1.00 g, 7.29 mmol) in DCM (10 mL) was added DMP (4.64 g, 10.9 mmol) at 0 °C. The reaction was stirred at 25 °C for 16 h. The mixture was quenched with saturated aqueous NaHCO (50 mL) and extracted with DCM (50 mL × 3). The organic phase was dried over anhydrous NaSO and concentrated. The residue was purified by flash column chromatography on silica gel (0 → 25% EtOAc in PE) to give 5-formyl-2-methylpyrazole-3-carbonitrile (860 mg, 87.3% yield) as a yellow oil. LC / MS (ESI) (m / z): 136 [M+H] + . The following intermediates were synthesized using a similar protocol (including m / z (ESI) values): [Table 12]

[0351] Synthesis of ethyl 1-(cyclopropylmethyl)-4-hydroxy-1H-pyrazole-3-carboxylate [ka] A solution of ethyl 4-formyl-1H-pyrazole-3-carboxylate (1.00 g, 5.95 mmol) and CsCO (2.91 g, 8.93 mmol) in DMF (5 mL) was cooled to −10 °C. (Bromomethyl)cyclopropane (1.19 g, 8.93 mmol) was added, and the reaction was stirred at −10 °C for 2 h. The mixture was quenched with saturated aqueous NHCl (20 mL) and extracted with EtOAc (30 mL × 3). The combined organic phase was washed with HO (30 mL × 3), brine (50 mL × 2), dried over anhydrous NaSO, and concentrated. The residue was purified by flash column chromatography on silica gel (0 → 30% EtOAc in PE) to give ethyl 1-(cyclopropylmethyl)-4-formyl-1H-pyrazole-3-carboxylate (800 mg, 61.0% yield) as a yellow solid. LC / MS (ESI): m / z 223 [M+H] + .

[0352] To a solution of ethyl 1-(cyclopropylmethyl)-4-formyl-1H-pyrazole-3-carboxylate (1.40 g, 6.30 mmol) in CHCl (28 mL) was added m-CPBA (1.63 g, 9.45 mmol). The reaction mixture was stirred at 60 °C for 2 h. The mixture was quenched with saturated aqueous NaSO (30 mL) and extracted with DCM (30 mL × 3). The combined organic phase was washed with saturated aqueous NaHCO (30 mL), dried over anhydrous NaSO, and concentrated. The residue was dissolved in ethanol (30 mL) and aqueous HCl (5 M, 30 mL). The mixture was stirred at room temperature for 10 min and then extracted with EtOAc (30 mL × 3). The combined organic phase was washed with brine, dried over anhydrous NaSO, and concentrated. The residue was purified by silica gel flash column chromatography (0→100% EtOAc in PE) to give ethyl 1-(cyclopropylmethyl)-4-hydroxy-1H-pyrazole-3-carboxylate (1.10 g, 83.0% yield) as a white solid. LC / MS ESI (m / z): 211 [M+H] + .

[0353] Synthesis of 2-chloro-3-((1-ethyl-1H-pyrazol-4-yl)oxy)pyridine [ka] To a mixture of 1-ethyl-1H-pyrazol-4-ol (500 mg, 4.46 mmol), (2-chloropyridin-3-yl)boronic acid (1.40 g, 8.92 mmol), and 4 Å molecular sieves in DCM (20 mL) was added Cu(OAc) (810 mg, 4.46 mmol) and TEA (1.2 mL, 8.91 mmol). The reaction mixture was stirred at 25 °C for 18 h. The mixture was filtered, and the filtrate was concentrated. The residue was purified by flash column chromatography on silica gel (0 → 50% EtOAc in PE) to give 2-chloro-3-((1-ethyl-1H-pyrazol-4-yl)oxy)pyridine (45.0 mg, 4.50% yield) as a yellow oil. LCMS (ESI): m / z: 224 [M+H] + .

[0354] Synthesis of ethyl 1-(cyclopropylmethyl)-3-(methylthio)-1H-pyrazole-4-carboxylate [ka] To a solution of ethyl 2-cyano-3,3-bis(methylthio)acrylate (1.35 g, 6.21 mmol) and (cyclopropylmethyl)hydrazine (535 mg, 6.21 mmol) in i-PrOH (40 mL) was added DIEA (3.08 mL, 18.6 mmol). The reaction mixture was stirred overnight at 85 °C in a sealed tube. The mixture was concentrated. The residue was purified by flash column chromatography on silica gel (0 → 100% EtOAc in PE) to give ethyl 5-amino-1-(cyclopropylmethyl)-3-(methylsulfanyl)-1H-pyrazole-4-carboxylate (850 mg, 54.0% yield) as a yellow solid. LC / MS (ESI) (m / z): 256 [M+H] + .

[0355] To a solution of ethyl 5-amino-1-(cyclopropylmethyl)-3-(methylsulfanyl)-1H-pyrazole-4-carboxylate (600 mg, 2.35 mmol) in THF (24 mL) was added 3-methylbutyl nitrite (1.27 mL, 9.40 mmol). The reaction mixture was refluxed for 2 h. The residue was purified by flash column chromatography on silica gel (0→100% EtOAc in PE) to give ethyl 1-(cyclopropylmethyl)-3-(methylthio)-1H-pyrazole-4-carboxylate (500 mg, 89.0% yield) as a yellow solid. LC / MS (ESI) (m / z): 241 [M+H] + .

[0356] Synthesis of 4-(cyclopropyl(hydroxy)methyl)-N,N-dimethyl-1H-imidazole-1-sulfonamide [ka] To a solution of 4-iodo-N,N-dimethyl-1H-imidazole-1-sulfonamide (5.50 g, 0.0200 mol) in THF (50 mL) was added i-PrMgCl.LiCl (1.3 M in THF, 15.5 mL, 0.0200 mol) at 0 °C. The mixture was stirred at 0 °C for 1 h. A solution of cyclopropanecarbaldehyde (1.65 mL, 0.0200 mol) in THF (10 mL) was added, and stirring was continued at 0 °C for 1 h. The reaction mixture was quenched with ice-water (50 mL) and extracted with EtOAc (50 mL × 3). The combined organic phase was washed with brine (30 mL × 2), dried over anhydrous Na SO , filtered, and concentrated. The residue was purified by flash column chromatography on silica gel (0→50% EtOAc in PE) to give 4-(cyclopropyl(hydroxy)methyl)-N,N-dimethyl-1H-imidazole-1-sulfonamide (2.35 g, 52.4%) as a yellow oil. LC / MS ESI (m / z): 246 [M+H] + . The following intermediates were synthesized using a similar protocol (including m / z (ESI) values): [Table 13]

[0357] Synthesis of (2-bromopyridin-3-yl)(1-ethyl-1H-pyrazol-4-yl)methanol [ka] To a solution of 2-bromo-3-iodopyridine (3.57 g, 12.6 mmol) in THF (10 mL) was added i-PrMgCl (9.67 mL, 12.6 mmol, 1.3 M THF solution) at 0 °C, and the mixture was stirred at 0 °C for 0.5 h. Then, a solution of 1-ethylpyrazole-4-carbaldehyde (1.3 g, 10.472 mmol) in THF (10 mL) was added, and the reaction was stirred at 0 °C for 1 h and then at 50 °C for 12 h. The reaction was quenched with saturated aqueous NH Cl (30 mL) and extracted with EtOAc (20 mL × 3). The combined organic layers were dried over anhydrous Na SO , filtered, and concentrated. The residue was purified by silica gel column chromatography (10→100% EtOAc in PE) to give (2-bromopyridin-3-yl)(1-ethyl-1H-pyrazol-4-yl)methanol (1.97 g, yield: 66.7%) as a yellow solid. LC / MS (ESI) (m / z): 282 [M+H] + . The following intermediates were synthesized using a similar protocol (including m / z (ESI) values): [Table 14]

[0358] Synthesis of (1-ethyl-1H-pyrazol-4-yl)(3-iodo-1-methyl-1H-pyrazol-4-yl)methanone [ka] To a solution of (1-ethyl-1H-pyrazol-4-yl)(3-iodo-1-methyl-1H-pyrazol-4-yl)methanol (200 mg, 0.602 mmol) in DCM (30 mL) was added MnO (523 mg, 6.02 mmol). The reaction was stirred at 20 °C for 16 h. The mixture was filtered, and the filtrate was concentrated. The residue was purified by flash column chromatography on silica gel (PE with 30 → 50 EtOAc) to give (1-ethyl-1H-pyrazol-4-yl)(3-iodo-1-methyl-1H-pyrazol-4-yl)methanone (142 mg, yield: 71.4%) as a white solid. LC / MS (ESI) (m / z): 331 [M+H] + . The following intermediates were synthesized using a similar protocol (including m / z (ESI) values): [Table 15] TIFF2025536922000177.tif186165

[0359] Synthesis of 4-(cyclopropylmethyl)-N,N-dimethyl-1H-imidazole-1-sulfonamide [ka] To a mixture of 4-(cyclopropyl(hydroxy)methyl)-N,N-dimethyl-1H-imidazole-1-sulfonamide (2.35 g, 9.58 mmol) and TFA (7 mL) was added TES (11.2 g, 95.9 mmol). The reaction was stirred at room temperature for 1 h. The mixture was concentrated, and the residue was diluted with saturated aqueous NaHCO3 (25 mL) and extracted with EtOAc (35 mL x 3). The combined organic phase was dried over anhydrous Na2SO4 and concentrated. The residue was purified by flash column chromatography on silica gel (0 → 50% EtOAc in PE) to give 4-(cyclopropylmethyl)-N,N-dimethyl-1H-imidazole-1-sulfonamide (2.00 g, 91.3% yield) as a yellow solid. LC / MS (ESI) (m / z): 230 [M+H] + . The following intermediates were synthesized using a similar protocol (including m / z (ESI) values): [Table 16]

[0360] Synthesis of 3-formyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-5-carbonitrile [ka] To a solution of 1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-5-carbonitrile (5.30 g, 23.7 mmol) in THF (25 mL) was added dropwise 2,2,6,6-tetramethylpiperidinylmagnesium chloride-lithium chloride complex solution (35.6 mL, 35.6 mmol, 1 M hexane solution) at -15 °C under a N atmosphere. After stirring under the same conditions for 1 h, DMF (3.671 mL, 47.5 mmol) was added dropwise at -15 °C, and the mixture was stirred at the same temperature for 1 h. The mixture was quenched with saturated aqueous NH4Cl (50 mL) and extracted with EtOAc (80 mL x 3). The combined organic phase was washed with brine (50 mL x 2), dried over anhydrous Na2SO4, and concentrated. The residue was purified by flash column chromatography on silica gel (0→10% EtOAc in PE) to give 3-formyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-5-carbonitrile (3.00 g, yield: 50.3%) as a yellow oil. LC / MS (ESI) (m / z): 252 [M+H] + The following intermediates were synthesized using a similar protocol (including m / z (ESI) values): [Table 17]

[0361] Synthesis of 3-((2-bromopyridin-3-yl)oxy)-1-methyl-1H-pyrazole-5-carboxylic acid [ka] To a solution of methyl 2-methyl-5-oxo-2,5-dihydro-1H-pyrazole-3-carboxylate (500 mg, 3.20 mmol) and 2-bromo-3-fluoropyridine (1.13 g, 6.41 mmol) in DMF (10 mL) was added CsCO (5.22 g, 16.0 mmol). The mixture was stirred at 60 °C for 48 h. The mixture was concentrated, diluted with HO (10 mL), and acidified with aqueous HCl (4 M) at 0 °C. The mixture was filtered, and the filter cake was washed with HO (10 mL) to give a white solid. The white solid was dried in vacuo to give 3-((2-bromopyridin-3-yl)oxy)-1-methyl-1H-pyrazole-5-carboxylic acid (680 mg, yield: 71.3%) as a white solid. LC / MS (ESI) (m / z): 298 [M+H] + . The following intermediates were synthesized using a similar protocol (including m / z (ESI) values): [Table 18]

[0362] Synthesis of 3-(4-bromo-2-methylthiazole-5-carbonyl)-1-methyl-1H-pyrazole-5-carbonitrile and 5-(4-bromo-2-methylthiazole-5-carbonyl)-1-methyl-1H-pyrazole-3-carbonitrile [ka] To a solution of 5-(4-bromo-2-methylthiazole-5-carbonyl)-1H-pyrazole-3-carbonitrile (90 mg, 0.25 mmol) and K2CO3 (69 mg, 0.49 mmol) in DMF (1 mL) was added iodomethane (39 mg, 0.27 mmol) dropwise at 0° C. The reaction was stirred at 25° C. for 16 h. The mixture was concentrated, diluted with EtOAc (15 mL), washed with brine (10 mL), dried over Na2SO4, and concentrated. The residue was purified by silica gel column chromatography (0→25% EtOAc in PE) to give 3-(4-bromo-2-methylthiazole-5-carbonyl)-1-methyl-1H-pyrazole-5-carbonitrile and 5-(4-bromo-2-methylthiazole-5-carbonyl)-1-methyl-1H-pyrazole-3-carbonitrile (60 mg, yield: 64.5%) as a yellow oil mixture. LC / MS (ESI) (m / z): 311 [M+H] + . The following intermediates were synthesized using a similar protocol (including m / z (ESI) values): [Table 19] TIFF2025536922000186.tif116165

[0363] Synthesis of (1-(cyclopropylmethyl)-3-(methylthio)-1H-pyrazol-4-yl)methanol [ka] To a solution of ethyl 1-(cyclopropylmethyl)-3-(methylthio)-1H-pyrazole-4-carboxylate (1.00 g, 4.16 mmol) in THF (19 mL) was added DIBAL-H (1 M in THF, 12.48 mL, 12.48 mmol) at −70° C. The reaction was stirred at 0° C. for 1 h. The mixture was quenched with saturated aqueous NH4Cl (30 mL) and extracted with EtOAc (30 mL×3). The combined organic phase was washed with brine (25 mL×2), dried over anhydrous Na2SO4, and concentrated. The residue was purified by flash column chromatography on silica gel (0→100% EtOAc in PE) to give (1-(cyclopropylmethyl)-3-(methylthio)-1H-pyrazol-4-yl)methanol (800 mg, 97.0% yield) as a white solid. LC / MS (ESI) (m / z): 199 [M+H] + . The following intermediates were synthesized using a similar protocol (including m / z (ESI) values): [Table 20]

[0364] Synthesis of 4-((2-chloropyridin-3-yl)(hydroxy)methyl)-1-ethyl-1H-pyrazole-3-carbonitrile [ka] To a stirred solution of 1-ethyl-4-iodo-1H-pyrazole-3-carbonitrile (2.00 g, 8.10 mmol) in THF (20 mL) was added i-PrMgCl (1 M in THF, 6.20 mL, 8.10 mmol) at 0 °C. After stirring at 0 °C for 0.5 h, a solution of 2-chloronicotinaldehyde (2.23 g, 16.2 mmol) in THF (20 mL) was added dropwise at 0 °C. The reaction was stirred at 25 °C for 0.5 h. The mixture was quenched with saturated aqueous NH4Cl (20 mL) and extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine (20 mL x 3), dried over anhydrous Na2SO4, and concentrated. The residue was purified by silica gel flash column chromatography (40→50% EtOAc in PE) to give 4-((2-chloropyridin-3-yl)(hydroxy)methyl)-1-ethyl-1H-pyrazole-3-carbonitrile (930 mg, yield: 44.0%) as a white solid. LC / MS (ESI) m / z: 263 [M+H] + . The following intermediates were synthesized using a similar protocol (including m / z (ESI) values): [Table 21] TIFF2025536922000191.tif135165

[0365] Synthesis of (2-bromopyridin-3-yl)(5-ethyl-1-methyl-1H-pyrazol-3-yl)methanone [ka] To a solution of (2-bromopyridin-3-yl)(5-ethyl-1-methyl-1H-pyrazol-3-yl)methanol (1.8 g, 6.08 mmol) in DCM (10 mL) and MeOH (1 mL) was added MnO (2.64 g, 30.4 mmol). The reaction was stirred at 45 °C for 12 h. The mixture was filtered, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (0 → 5% MeOH in DCM) to give (2-bromopyridin-3-yl)(5-ethyl-1-methyl-1H-pyrazol-3-yl)methanone (1.1 g, 61.1% yield) as a yellow solid. LC / MS (ESI) (m / z): 294.1 [M+H] + . The following intermediates were synthesized using a similar protocol (including m / z (ESI) values): [Table 22]

[0366] Synthesis of 3-((2-bromopyridin-3-yl)oxy)-1-methyl-1H-pyrazole-5-carbonitrile [ka] To a mixture of 3-((2-bromopyridin-3-yl)oxy)-1-methyl-1H-pyrazole-5-carboxylic acid (730 mg, 2.45 mmol) in THF (20 mL), oxalyl chloride (1.84 mL, 3.67 mmol) and DMF (0.020 mL, 0.245 mmol) were added at 0 °C under N2, and the mixture was stirred at 60 °C for 2.5 h. Then NH4OH (4 mL, 8.57 mmol) was added at 0 °C, and the mixture was stirred at room temperature under N2 for 12 h. The reaction was quenched with saturated aqueous NH4Cl (20 mL) and extracted with EtOAc (20 mL x 3). The combined organic phase was washed with brine (30 mL x 2), dried over anhydrous NaSO and concentrated to give 3-((2-bromopyridin-3-yl)oxy)-1-methyl-1H-pyrazole-5-carboxamide (710 mg, crude) as a yellow oil. LC / MS (ESI) (m / z): 297 [M+H] + .

[0367] To a mixture of 3-((2-bromopyridin-3-yl)oxy)-1-methyl-1H-pyrazole-5-carboxamide (710 mg, 2.39 mmol) in THF (20 mL) was added TEA (0.830 mL, 5.97 mmol) and TFAA (1.16 mL, 8.36 mmol). The reaction was stirred at 25 °C for 1 h. The mixture was quenched with saturated aqueous NH4Cl (20 mL) and extracted with EtOAc (30 mL x 2). The combined organic phases were washed with brine (20 mL x 2), dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by flash column chromatography on silica gel (0 → 30% EtOAc in PE) to give 3-((2-bromopyridin-3-yl)oxy)-1-methyl-1H-pyrazole-5-carbonitrile (365 mg, yield: 54.7%) as a colorless oil. LC / MS (ESI) (m / z): 279 [M+H] +

[0368] Synthesis of 4-((2-bromopyridin-3-yl)(hydroxy)methyl)-1-ethyl-1H-pyrazole-3-carboxylic acid [ka] A mixture of 4-((2-bromopyridin-3-yl)(hydroxy)methyl)-1-ethyl-1H-pyrazole-3-carbonitrile (1.00 g, 3.27 mmol) and concentrated HCl (10 mL) was stirred at 80 °C for 4 hours. The mixture was diluted with HO (20 mL) and extracted with EtOAc (30 mL x 3). The combined organic layers were dried over anhydrous NaSO, filtered, and concentrated to give 4-((2-bromopyridin-3-yl)(hydroxy)methyl)-1-ethyl-1H-pyrazole-3-carboxylic acid (900 mg, crude) as a yellow oil. LC / MS (ESI) m / z: 326 [M+H] + . The following intermediates were synthesized using a similar protocol (including m / z (ESI) values): [Table 23]

[0369] Synthesis of 4-((2-chloropyridin-3-yl)(hydroxy)methyl)-1-cyclobutyl-1H-pyrazole-3-carbonitrile [ka] To a solution of 1-cyclobutyl-4-iodo-1H-pyrazole-3-carbonitrile (1.70 g, 6.23 mmol) in THF (50 mL) was added i-PrMgCl.LiCl (1.3 M in THF, 4.80 mL, 6.23 mmol) at 0 °C. After stirring at 0 °C for 1 hour, a solution of 2-chloronicotinaldehyde (1.77 g, 12.45 mmol) in THF (50 mL) was added at 20 °C. The reaction was stirred at 20 °C for 1 hour. The mixture was quenched with saturated aqueous NH4Cl (25 mL) and extracted with EtOAc (45 mL x 3). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by flash column chromatography on silica gel (50% EtOAc in PE) to give 4-((2-chloropyridin-3-yl)(hydroxy)methyl)-1-cyclobutyl-1H-pyrazole-3-carbonitrile (1.10 g, 49.0% yield) as a white oil. LC / MS (ESI) (m / z): 289 [M+H] + . The following intermediates were synthesized using a similar protocol (including m / z (ESI) values): [Table 24]

[0370] Synthesis of 3-((2-bromopyridin-3-yl)(methoxymethoxy)methyl)-1-methyl-1H-pyrazole-5-carbonitrile [ka] To a stirred solution of 3-((2-bromopyridin-3-yl)(hydroxy)methyl)-1-methyl-1H-pyrazole-5-carbonitrile (1.00 g, 3.42 mmol) in THF (10 mL) was added NaH (120 mg, 5.13 mmol, 60% solution in mineral oil) at 0 °C, and the mixture was stirred at 0 °C for 30 min. Then, MOMCl (410 mg, 5.13 mmol) was added dropwise at 0 °C, and the mixture was stirred at 25 °C for 16 h. The reaction was quenched with saturated aqueous NH4Cl (100 mL) and extracted with DCM (30 mL). The organic phase was dried over anhydrous Na2SO4 and concentrated. The residue was purified by flash column chromatography on silica gel (0→25% EtOAc in PE) to give 3-((2-bromopyridin-3-yl)(methoxymethoxy)methyl)-1-methyl-1H-pyrazole-5-carbonitrile (761 mg, yield: 65.9%) as a yellow oil. LC / MS (ESI) (m / z): 337 [M+H] + .

[0371] Synthesis of ethyl 1-(2-acetyl-4-fluorophenyl)-3-methyl-1H-pyrazole-5-carboxylate [ka] To a solution of ethyl 1-(4-fluoro-2-iodophenyl)-3-methyl-1H-pyrazole-5-carboxylate (5.30 g, 14.16 mmol) and tributyl(1-ethoxyvinyl)stannane (7.67 g, 21.3 mmol) in toluene (30 mL) was added Pd(PPh3)4 (820 mg, 0.710 mmol). The reaction was degassed with N2 three times and stirred at 100 °C for 16 h. The mixture was diluted with saturated aqueous KF solution (20 mL) and ethyl acetate (20 mL), and stirring was continued at room temperature for 1 h. The mixture was filtered, and the filtrate was extracted with ethyl acetate (20 mL × 3). The combined organic phase was washed with brine (20 mL × 2), dried over anhydrous Na2SO4, filtered, and concentrated. The residue was diluted with THF (20 mL) and aqueous HCl (1 M, 20 mL), and the mixture was stirred at room temperature for 1 h (this acid hydrolysis step can be skipped to isolate the enol ether intermediate). The mixture was extracted with EtOAc (30 mL x 3). The combined organic phases were washed with brine (20 mL x 2), dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by flash column chromatography on silica gel (0 → 8% MeOH in DCM) to give ethyl 1-(2-acetyl-4-fluorophenyl)-3-methyl-1H-pyrazole-5-carboxylate (1.60 g, yield: 39%) as a yellow oil. LC / MS ESI (m / z): 291 [M+H] + . The following intermediates were synthesized using a similar protocol (including m / z (ESI) values): [Table 25]

[0372] Synthesis of (3-ethyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)methanol [ka] To a solution of ethyl 3-ethyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-5-carboxylate (5.30 g, 17.8 mmol) in THF (70 mL) was added diisobutylaluminum hydride (1 M in hexane, 19.5 mL, 19.5 mmol) slowly at −78° C. under N. The reaction was stirred at 25° C. for 16 h. The mixture was quenched with saturated aqueous NH.sub.4Cl (30 mL) and aqueous potassium sodium tartrate (30 mL), and then extracted with EtOAc (80 mL×3). The combined organic layer was washed with brine (50 mL×2), dried over anhydrous Na.sub.2SO.sub.4, and concentrated. The residue was purified by flash column chromatography on silica gel (0→100% EtOAc in PE) to give (3-ethyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)methanol (4.50 g, yield: 90.3%) as a colorless oil. LC / MS ESI (m / z): 257 [M+H] + . The following intermediates were synthesized using a similar protocol (including m / z (ESI) values): [Table 26]

[0373] Synthesis of 4-((3-bromo-1-methyl-1H-pyrazol-4-yl)methyl)-1-cyclobutyl-1H-pyrazole-3-carbonitrile [ka] To a solution of 4-((3-bromo-1-methyl-1H-pyrazol-4-yl)(hydroxy)methyl)-1-cyclobutyl-1H-pyrazole-3-carbonitrile (872 mg, 2.59 mmol) in DCM (10 mL) was added EtSiH (1.21 g, 10.4 mmol) and TFA (887 mg, 7.78 mmol) at 0 °C. The mixture was stirred at 0 °C for 1 h and then concentrated. The residue was dissolved in DCM (20 mL) and washed with saturated aqueous NaHCO (15 mL × 2). The combined organic layer was dried over anhydrous NaSO, filtered, and concentrated. The residue was purified by flash column chromatography on silica gel (50→100% EtOAc in PE) to give 4-((3-bromo-1-methyl-1H-pyrazol-4-yl)methyl)-1-cyclobutyl-1H-pyrazole-3-carbonitrile (562 mg, 67.7% yield) as a yellow oil. LC / MS (ESI) (m / z): 320 [M+H] + . The following intermediates were synthesized using a similar protocol (including m / z (ESI) values): [Table 27]

[0374] Synthesis of 4-((2-bromopyridin-3-yl)methyl)-1-ethyl-N,N-dimethyl-1H-pyrazole-3-carboxamide [ka] To a solution of 4-((2-bromopyridin-3-yl)methyl)-1-ethyl-1H-pyrazole-3-carboxylic acid (447 mg, 1.44 mmol) in DMF (10 mL) was added dimethylamine hydrochloride (353 mg, 4.32 mmol), HATU (877 mg, 2.31 mmol), and DIEA (0.310 mL, 1.87 mmol). The mixture was stirred at 20 °C for 16 h. The reaction was diluted with EtOAc (30 mL) and washed with water (25 mL × 3). The organic layer was washed with brine (25 mL × 2), dried over anhydrous Na2SO4, and concentrated. The residue was purified by silica gel flash column chromatography (80→100% EtOAc in PE) to give 4-((2-bromopyridin-3-yl)methyl)-1-ethyl-N,N-dimethyl-1H-pyrazole-3-carboxamide (250 mg, yield: 51.4%) as a colorless oil. LC / MS (ESI) (m / z): 337 [M+H] + . The following intermediates were synthesized using a similar protocol (including m / z (ESI) values): [Table 28] TIFF2025536922000208.tif58165

[0375] Synthesis of sodium 4-(cyclopropylmethyl)-1-((3-iodo-1-methyl-1H-pyrazol-4-yl)methyl)-1H-imidazole-2-carboxylate [ka] To a solution of 4-(cyclopropylmethyl)-N,N-dimethyl-1H-imidazole-1-sulfonamide (1.14 g, 4.97 mol) in THF (30 mL) was added LDA (2.0 M in THF, 4.97 mL, 9.94 mol) at −78° C. After stirring at −78° C. for 0.5 h, a solution of dimethyl carbonate (670 mg, 7.46 mol) in THF (10 mL) was added dropwise at −78° C., and the reaction was stirred at room temperature for 4 h. The mixture was quenched with saturated aqueous NH4Cl (50 mL) and extracted with EtOAc (30 mL×3). The combined organic phase was washed with brine (30 mL×3), dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by silica gel flash column chromatography (0→5% MeOH in DCM) to give methyl 4-(cyclopropylmethyl)-1-(N,N-dimethylsulfamoyl)-1H-imidazole-2-carboxylate (410 mg, yield: 28.7%) as a yellow gum. LC / MS ESI (m / z): 288 [M+H] + .

[0376] To a solution of methyl 4-(cyclopropylmethyl)-1-(N,N-dimethylsulfamoyl)-1H-imidazole-2-carboxylate (400 mg, 1.39 mmol) in DCM (5 mL) was added HCl (4 M in dioxane, 5 mL, 20 mmol). The reaction was stirred at 50° C. for 2 h. The mixture was concentrated to give methyl 4-(cyclopropylmethyl)-1H-imidazole-2-carboxylate (250 mg, crude) directly as a yellow gum. LC / MS ESI (m / z): 181 [M+H] + .

[0377] To a solution of methyl 4-(cyclopropylmethyl)-1H-imidazole-2-carboxylate (250 mg, 1.39 mmol) and 4-(chloromethyl)-3-iodo-1-methyl-1H-pyrazole (580 mg, 2.78 mmol) in DMF (5 mL) was added CsCO (1.81 g, 5.57 mmol). The mixture was stirred at 80 °C for 2 h. The reaction mixture was quenched with water (30 mL) and extracted with EtOAc (30 mL × 3). The combined organic phase was washed with HO (25 mL × 3), brine (30 mL × 2), dried over anhydrous NaSO, filtered, and concentrated. The residue was purified by flash column chromatography on silica gel (0→50% EtOAc in PE) to give methyl 4-(cyclopropylmethyl)-1-((3-iodo-1-methyl-1H-pyrazol-4-yl)methyl)-1H-imidazole-2-carboxylate (540 mg, 97.2% over two steps) as a yellow solid. LC / MS (ESI) (m / z): 401 [M+H] + .

[0378] To a solution of methyl 4-(cyclopropylmethyl)-1-((3-iodo-1-methyl-1H-pyrazol-4-yl)methyl)-1H-imidazole-2-carboxylate (360 mg, 0.900 mmol) in MeOH (5 mL) was added aqueous NaOH (2 M aqueous solution, 1.80 mL, 3.60 mmol) at room temperature. The mixture was stirred at 60° C. for 1 hour. The reaction mixture was concentrated to give sodium 4-(cyclopropylmethyl)-1-((3-iodo-1-methyl-1H-pyrazol-4-yl)methyl)-1H-imidazole-2-carboxylate (340 mg, crude) as a white solid. LC / MS (ESI) (m / z): 387 [M+H] + .

[0379] Synthesis of ethyl 3-(cyclopropylmethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-5-carboxylate [ka] To a stirred solution of ethyl 5-(cyclopropylmethyl)-1H-pyrazole-3-carboxylate (1.30 g, 6.63 mmol) in THF (15 mL) was added NaH (401 mg, 10.0 mmol, 60% solution in mineral oil) at 0 °C under N. After stirring at 0 °C for 1 h, a solution of SEMCl (1.34 g, 8.03 mmol) in THF (5 mL) was added dropwise. The reaction was stirred at 0 °C for 2 h. The mixture was quenched with saturated aqueous NH Cl (15 mL) and extracted with EtOAc (25 mL × 3). The combined organic layers were washed with brine (20 mL × 2), dried over anhydrous Na SO and concentrated. The residue was purified by silica gel flash column chromatography (10→25% EtOAc in PE) to give ethyl 3-(cyclopropylmethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-5-carboxylate (1.77 g, 81.0% yield) as a white solid. LC / MS (ESI) (m / z): 325 [M+H] + .

[0380] Synthesis of (R)-5-bromo-3-(1-(5-fluoro-2-(trimethylstannyl)phenyl)ethoxy)pyrazin-2-amine [ka] To a solution of (R)-1-(5-fluoro-2-iodophenyl)ethan-1-ol (500 mg, 1.88 mmol) and 3,5-dibromopyrazin-2-amine (470 mg, 2.26 mmol) in THF (5 mL) was added NaHMDS (1.4 mL, 2.82 mmol, 2.0 M in THF) at 0 °C under N2, and the mixture was stirred at 70 °C overnight. The reaction was quenched with saturated aqueous NH4Cl (10 mL) and extracted with EtOAc (15 mL x 3). The combined organic phase was dried over anhydrous Na2SO4 and concentrated. The residue was purified by flash column chromatography on silica gel (0 → 50% EtOAc in PE) to give (R)-5-bromo-3-(1-(5-fluoro-2-iodophenyl)ethoxy)pyrazin-2-amine (570 mg, 69.2% yield) as a yellow oil. LC / MS (ESI) m / z: 438 [M+H]+ .

[0381] To a solution of (R)-5-bromo-3-(1-(5-fluoro-2-iodophenyl)ethoxy)pyrazin-2-amine (550 mg, 1.26 mmol) in toluene (5 mL), hexamethyldistannane (494 mg, 1.51 mmol) and Pd(PPh3)4 (72.5 mg, 0.0630 mmol) were added and stirred at 25 °C. The mixture was degassed and purged with N2 three times, and the mixture was stirred at 100 °C for 16 h. The mixture was diluted with water (10 mL) and extracted with EtOAc (20 mL × 3). The combined organic phase was washed with brine (20 mL × 2), dried over anhydrous Na2SO4, and concentrated. The residue was purified by flash column chromatography on silica gel (0→20% EtOAc in PE) to give (R)-5-bromo-3-(1-(5-fluoro-2-(trimethylstannyl)phenyl)ethoxy)pyrazin-2-amine (570 mg, yield: 95.6%) as a yellow solid. LC / MS (ESI) m / z: 476 [M+H] + .

[0382] Synthesis of (R)-1-(2-(3-((1-ethyl-1H-pyrazol-4-yl)oxy)pyridin-2-yl)-5-fluorophenyl)ethan-1-ol [ka] To a solution of 2-chloro-3-((1-ethyl-1H-pyrazol-4-yl)oxy)pyridine (35.0 mg, 0.160 mmol), (3R)-5-fluoro-3-methyl-1,3-dihydro-2,1-benzoxaborol-1-ol (31.0 mg, 0.180 mmol), and NaCO (33.0 mg, 0.310 mmol) in 1,4-dioxane (8 mL) and water (2 mL) was added Pd(dppf)Cl (11.5 mg, 0.0160 mmol). The mixture was degassed and purged with N three times and then stirred at 80 °C for 16 h. The mixture was filtered, and the filtrate was concentrated. The residue was purified by silica gel flash column chromatography (0→50% EtOAc in PE) to give (R)-1-(2-(3-((1-ethyl-1H-pyrazol-4-yl)oxy)pyridin-2-yl)-5-fluorophenyl)ethan-1-ol (20.0 mg, 39.0% yield) as a yellow oil. LCMS (ESI): m / z: 328 [M+H] + . The following intermediates were synthesized using a similar protocol (including m / z (ESI) values): [Table 29] TIFF2025536922000214.tif226165TIFF2025536922000215.tif233165TIFF2025536922000216.tif189165

[0383] Synthesis of 5-((2-chloro-6-methylpyridin-3-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-3-carbonitrile [ka] To a solution of N'-((5-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3-yl)methylene)-4-methylbenzenesulfonohydrazide (400 mg, 0.95 mmol) in dioxane (5 mL) was added (2-chloro-6-methylpyridin-3-yl)boronic acid (250 mg, 1.43 mmol) and K2CO3 (72.5 mg, 0.0630 mmol), followed by degassing and purging with N2 three times. The mixture was stirred at 100 °C for 16 h. The mixture was diluted with water (10 mL) and extracted with EtOAc (20 mL x 3). The combined organic phase was washed with brine (20 mL x 3), dried over anhydrous Na2SO4, and concentrated. The residue was purified by silica gel flash column chromatography (0→20% EtOAc in PE) to give 5-((2-chloro-6-methylpyridin-3-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-3-carbonitrile (120 mg, yield: 34.8%) as a yellow oil. LC / MS (ESI) m / z: 363 [M+H] + . The following intermediates were synthesized using a similar protocol (including m / z (ESI) values): [Table 30]

[0384] Synthesis of 3-((2-bromopyridin-3-yl)(hydroxy)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-5-carbonitrile [ka] To a mixture of 1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-5-carbonitrile (3.00 g, 15.1 mmol) in THF (30 mL) was added TMPMgCl LiCl (1 M in heptane, 21.5 mL, 21.5 mmol) at −20 °C under N, and the mixture was stirred at −20 °C for 1 h. Then, a solution of 2-bromopyridine-3-carbaldehyde (3.30 g, 17.9 mmol) in THF (10 mL) was added at −20 °C. The mixture was stirred at −20 °C for 1 h. The mixture was quenched with saturated aqueous NH Cl (50 mL) and extracted with EtOAc (100 mL × 3). The combined organic phase was washed with brine (40 mL × 2), dried over anhydrous Na SO , and concentrated. The residue was purified by flash column chromatography on silica gel (0→50% EtOAc in PE) to give 3-((2-bromopyridin-3-yl)(hydroxy)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-5-carbonitrile (4.00 g, 54.0% yield) as a colorless oil. LCMS (ESI): m / z: 409 [M+H] + . The following intermediates were synthesized using a similar protocol (including m / z (ESI) values): [Table 31]

[0385] Synthesis of (R)-3-((2-(4-fluoro-2-(1-hydroxyethyl)phenyl)pyridin-3-yl)oxy)-1-methyl-1H-pyrazole-5-carbonitrile [ka] To a solution of 3-((2-bromopyridin-3-yl)oxy)-1-methyl-1H-pyrazole-5-carbonitrile (165 mg, 0.591 mmol), (R)-5-fluoro-3-methylbenzo[c][1,2]oxaborol-1(3H)-ol (147 mg, 0.887 mmol), KPO (376 mg, 1.77 mmol), and BI-DIME (39.1 mg, 0.118 mmol) in toluene (10 mL) and HO (2 mL) was added Pd(dba) (54.1 mg, 0.0590 mmol). The mixture was degassed three times with N and stirred at 100 °C for 3.5 h. The mixture was filtered, and the filtrate was concentrated. The residue was purified by silica gel flash column chromatography (0→8% MeOH in DCM) to give (R)-3-((2-(4-fluoro-2-(1-hydroxyethyl)phenyl)pyridin-3-yl)oxy)-1-methyl-1H-pyrazole-5-carbonitrile (155 mg, yield: 77.5%) as a yellow solid. LC / MS ESI (m / z): 339 [M+H] + . The following intermediates were synthesized using a similar protocol (including m / z (ESI) values): [Table 32] TIFF2025536922000223.tif71165

[0386] Synthesis of 3-(3-iodo-1-methyl-1H-pyrazole-4-carbonyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-5-carbonitrile [ka] To a solution of 3-(hydroxy(3-iodo-1-methyl-1H-pyrazol-4-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-5-carbonitrile (1.29 g, 2.80 mmol) in DCM (10 mL) was added Dess-Martin periodinane (2.38 g, 5.61 mmol) at 0 °C and stirred at 0 °C for 1 h. The reaction was quenched with saturated aqueous NaHCO (5 mL) and saturated aqueous NaSO (5 mL). The combined organic phase was washed with brine (20 mL × 2), dried over anhydrous NaSO, and concentrated. The residue was purified by silica gel flash column chromatography (30→50% EtOAc in PE) to give 3-(3-iodo-1-methyl-1H-pyrazole-4-carbonyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-5-carbonitrile (878 mg, yield: 68.6%) as a yellow oil. LC / MS (ESI) (m / z): 458 [M+H] + .

[0387] Synthesis of 3-(4-bromo-1,3-thiazole-5-carbonyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazole-5-carbonitrile and 3-(4-bromo-2-methylthiazole-5-carbonyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-5-carbonitrile [ka] To a stirred solution of 3-(2,4-dibromothiazole-5-carbonyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-5-carbonitrile (500 mg, 1.01 mmol) and methylboronic acid (92 mg, 1.52 mmol) in dioxane (20 mL) was added K2CO3 (420 mg, 3.04 mmol) and Pd(PPh3)4 (117 mg, 0.10 mmol). The mixture was degassed and purged with N2 three times and then stirred at 100 °C for 12 h. The reaction was filtered and the filter cake was washed with EtOAc (30 mL). The filtrate was washed with water (15 mL) and brine (15 mL). The combined organic phase was dried over anhydrous Na2SO4 and concentrated. The residue was purified by silica gel flash column chromatography (0→30% EtOAc in PE) to give 3-(4-bromo-2-methylthiazole-5-carbonyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-5-carbonitrile and 3-(4-bromo-1,3-thiazole-5-carbonyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazole-5-carbonitrile (100 mg, yield: 23%) as a white solid mixture. LC / MS (ESI) (m / z): 427 [M+H] + . The following intermediates were synthesized using a similar protocol (including m / z (ESI) values): [Table 33]

[0388] Synthesis of 3-(2-chloronicotinoyl)-1H-pyrazole-5-carbonitrile [ka] To a solution of 3-(2-chloronicotinoyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-5-carbonitrile (960 mg, 2.65 mmol) in DCM (6 mL) was added TFA (3 mL, 40.4 mmol). The mixture was stirred at room temperature for 2 hours and then concentrated. The residue was diluted with EtOAc (10 mL) and saturated aqueous NaHCO (20 mL). The mixture was extracted with EtOAc (30 mL × 3). The combined organic phase was washed with brine (20 mL × 2), dried over anhydrous NaSO, filtered, and concentrated. The residue was purified by flash column chromatography on silica gel (0 → 10% MeOH in DCM) to give 3-(2-chloronicotinoyl)-1H-pyrazole-5-carbonitrile (583 mg, yield: 94.7%) as a yellow solid. LC / MS ESI (m / z): 233 [M+H] + . The following intermediates were synthesized using a similar protocol (including m / z (ESI) values): [Table 34]

[0389] Synthesis of 5-((2-chloropyridin-3-yl)methyl)-3-ethyl-N,N-dimethyl-1H-pyrazole-1-carboxamide [ka] To a solution of 2-chloro-3-((3-ethyl-1H-pyrazol-5-yl)methyl)pyridine (165 mg, 0.744 mmol) and TEA (0.0600 mL, 0.433 mmol) in toluene (10 mL) was added dimethylazane carbonyl chloride (0.0690 mL, 0.744 mmol). The reaction mixture was stirred at 100° C. for 16 h. The reaction mixture was added to water (10 mL) and extracted with EtOAc (30 mL×3). The combined organic layers were washed with brine (20 mL×2), dried over anhydrous NaSO, and concentrated. The residue was purified by flash column chromatography on silica gel (0→100% EtOAc in PE, then 0→10% MeOH in DCM) to give a mixture of regioisomers. These regioisomers were separated by SFC (ChiralPak IB, 100 × 4.6 mm ID, 5 μm, 40% MeOH + CO containing 0.05% DEA) to give 5-[(2-chloropyridin-3-yl)methyl]-3-ethyl-N,N-dimethylpyrazole-1-carboxamide (100 mg, yield: 45.9%) as a white solid. LC / MS ESI (m / z): 293 [M+H] + . The following intermediates were synthesized using a similar protocol (including m / z (ESI) values): [Table 35]

[0390] Synthesis of 3-(4-bromo-1,3-thiazole-5-carbonyl)-1-methyl-1H-pyrazole-5-carbonitrile and 3-(4-bromo-2-methylthiazole-5-carbonyl)-1-methyl-1H-pyrazole-5-carbonitrile [ka] A mixture of 3-(4-bromo-2-methylthiazole-5-carbonyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-5-carbonitrile and 3-(4-bromo-1,3-thiazole-5-carbonyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazole-5-carbonitrile (100 mg, 0.20 mmol) and TFA (5 mL) was stirred at 25° C. for 3 h. The reaction mixture was concentrated. The residue was dissolved in MeCN (3 mL) and aqueous NH (1 mL). The solution was stirred at 25° C. for 0.5 h. The mixture was diluted with HO (20 mL) and extracted with EtOAc (15 mL×3). The combined organic phase was washed with brine (30 mL×3), dried over anhydrous NaSO, and concentrated. The residue was purified by silica gel column chromatography (0→30% EtOAc in PE) to give 5-(4-bromo-2-methylthiazole-5-carbonyl)-1H-pyrazole-3-carbonitrile and 3-(4-bromo-1,3-thiazole-5-carbonyl)-1H-pyrazole-5-carbonitrile (30 mg, crude) as a yellow oil mixture. LC / MS (ESI) (m / z): 297 [M+H] + .

[0391] To a mixture of 5-(4-bromo-2-methylthiazole-5-carbonyl)-1H-pyrazole-3-carbonitrile and 3-(4-bromo-1,3-thiazole-5-carbonyl)-1H-pyrazole-5-carbonitrile (90 mg, 0.25 mmol) and KCO (69 mg, 0.49 mmol) in DMF (1 mL) was added iodomethane (39 mg, 0.27 mmol) dropwise at 0° C. The reaction was stirred at 25° C. for 16 h and then concentrated. The residue was diluted with EtOAc (15 mL), washed with brine (10 mL), dried over NaSO, and concentrated. The residue was purified by silica gel column chromatography (0→25% EtOAc in PE) to give 3-(4-bromo-2-methylthiazole-5-carbonyl)-1-methyl-1H-pyrazole-5-carbonitrile and 3-(4-bromo-1,3-thiazole-5-carbonyl)-1-methyl-1H-pyrazole-5-carbonitrile (60 mg, yield: 64.5%) as a yellow oil mixture. LC / MS (ESI) (m / z): 311 [M+H] + .

[0392] Synthesis of 3-cyano-5-((2,4-dibromothiazol-5-yl)methyl)-N,N-dimethyl-1H-pyrazole-1-carboxamide [ka] To a solution of 5-((2,4-dibromothiazol-5-yl)methyl)-1H-pyrazole-3-carbonitrile (550 mg, 1.58 mmol) in THF (10 mL) was added dimethylcarbamic chloride (340 mg, 3.16 mmol), TEA (0.659 mL, 4.74 mmol), and DMAP (96.5 mg, 0.790 mmol). The mixture was degassed and purged with N three times and then stirred at 70 °C for 3 h. The mixture was quenched with HO (10 mL) and extracted with EtOAc (30 mL × 3). The combined organic layer was dried over anhydrous NaSO and concentrated. The residue was purified by flash column chromatography on silica gel (10→50% EtOAc in PE) to give 3-cyano-5-((2,4-dibromothiazol-5-yl)methyl)-N,N-dimethyl-1H-pyrazole-1-carboxamide (600 mg, yield: 90.6%) as a yellow oil. LC / MS (ESI) m / z: 418 [M+H] + . The following intermediates were synthesized using a similar protocol (including m / z (ESI) values): [Table 36]

[0393] Synthesis of 3-(2-(2,4-difluoro-6-((R)-1-hydroxyethyl)phenyl)nicotinoyl)-1-methyl-1H-pyrazole-5-carbonitrile and 5-(2-{2,4-difluoro-6-[(1R)-1-hydroxyethyl]phenyl}pyridine-3-carbonyl)-1-methyl-1H-pyrazole-3-carbonitrile [ka] To a mixture of 3-(2-chloronicotinoyl)-1-methyl-1H-pyrazole-5-carbonitrile and 5-(2-chloronicotinoyl)-1-methyl-1H-pyrazole-3-carbonitrile (300 mg, 0.810 mmol), (R)-5,7-difluoro-3-methylbenzo[c][1,2]oxaborol-1(3H)-ol (270 mg, 1.22 mmol), and NaCO (387 mg, 3.65 mmol) in 1,4-dioxane (9 mL) and water (3 mL) was added Pd(dppf)Cl (89.0 mg, 0.120 mmol). The reaction was degassed three times with N and stirred at 100 °C for 16 h. The mixture was filtered, and the filtrate was concentrated. The residue was purified by silica gel flash column chromatography (0→8% MeOH in DCM) to give 3-(2-(2,4-difluoro-6-((R)-1-hydroxyethyl)phenyl)nicotinoyl)-1-methyl-1H-pyrazole-5-carbonitrile and 5-(2-{2,4-difluoro-6-[(1R)-1-hydroxyethyl]phenyl}pyridine-3-carbonyl)-1-methyl-1H-pyrazole-3-carbonitrile (70.0 mg, yield: 15.1%) as a white solid mixture. LC / MS ESI (m / z): 369 [M+H] + . The following intermediates were synthesized using a similar protocol (including m / z (ESI) values): [Table 37]

[0394] Synthesis of ethyl 1-(2-(1-((tert-butyldimethylsilyl)oxy)ethyl)-4-fluorophenyl)-3-methyl-1H-pyrazole-5-carboxylate [ka] To a solution of ethyl 1-(4-fluoro-2-(1-hydroxyethyl)phenyl)-3-methyl-1H-pyrazole-5-carboxylate (2.60 g, 8.90 mmol) in DMF (15 mL) was added imidazole (2.72 g, 39.9 mmol) and tert-butylchlorodimethylsilane (4.02 g, 26.7 mmol) at 0° C. The reaction was stirred at room temperature for 1 hour. The mixture was poured into water (50 mL) and extracted with EtOAc (30 mL). The organic phase was washed with brine (30 mL×2), dried over anhydrous NaSO, filtered, and concentrated. The residue was purified by flash column chromatography on silica gel (0→20% EtOAc in PE) to give ethyl 1-(2-(1-((tert-butyldimethylsilyl)oxy)ethyl)-4-fluorophenyl)-3-methyl-1H-pyrazole-5-carboxylate (3.30 g, yield: 91.3%) as a clear oil. LC / MS ESI (m / z): 407 [M+H] + .

[0395] Synthesis of (Z)-N'-((5-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3-yl)methylene)-4-methylbenzenesulfonohydrazide [ka] To a solution of 3-formyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-5-carbonitrile (1.50 g, 5.97 mmol) in dioxane (50 mL) was added 4-methylbenzene-1-sulfonohydrazide (1.10 g, 5.91 mmol), and the reaction was stirred at 80° C. for 3 h. The reaction was concentrated. The residue was purified by flash column chromatography on silica gel (20→40% EtOAc in PE) to give (Z)-N′-((5-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3-yl)methylene)-4-methylbenzenesulfonohydrazide (500 mg, 99.8% yield) as a yellow oil. LC / MS (ESI) (m / z): 420 [M+H] + . The following intermediates were synthesized using a similar protocol (including m / z (ESI) values): [Table 38]

[0396] Synthesis of 1-(cyclopropylmethyl)-4-((3-(2,4-difluoro-6-(1-hydroxyethyl)phenyl)-1-methyl-1H-pyrazol-4-yl)methyl)-1H-pyrazole-3-carbonitrile [ka] To a solution of 4-((3-bromo-1-methyl-1H-pyrazol-4-yl)methyl)-1-(cyclopropylmethyl)-1H-pyrazole-3-carbonitrile (850 mg, 2.66 mmol) in 1,4-dioxane (9 mL) and water (3 mL) was added 5,7-difluoro-3-methylbenzo[c][1,2]oxaborol-1(3H)-ol (732 mg, 3.98 mmol), NaCO (844 mg, 7.96 mmol), and X-phos G Pd (112 mg, 0.130 mmol). The reaction was degassed with N three times and stirred at 100 °C for 2 h. The reaction was diluted with HO (30 mL) and extracted with EtOAc (40 mL × 3). The combined organic phase was washed with brine (30 mL × 2), dried over anhydrous NaSO, and concentrated. The residue was purified by silica gel flash column chromatography (30→100% EtOAc in PE) to give 1-(cyclopropylmethyl)-4-((3-(2,4-difluoro-6-(1-hydroxyethyl)phenyl)-1-methyl-1H-pyrazol-4-yl)methyl)-1H-pyrazole-3-carbonitrile (950 mg, 90.0% yield) as a black oil. LC / MS (ESI) (m / z): 398 [M+H] + .

[0397] Synthesis of 4-((1-(2-bromo-4-fluorophenyl)-3-methyl-1H-pyrazol-5-yl)methyl)-1-cyclobutyl-N,N-dimethyl-1H-pyrazole-3-carboxamide [ka] To a solution of 4-((1-(2-bromo-4-fluorophenyl)-3-methyl-1H-pyrazol-5-yl)methyl)-1-cyclobutyl-1H-pyrazole-3-carboxylic acid (330 mg, 0.762 mmol), dimethylamine (93.42 mg, 1.142 mmol), and DIEA (344.54 mg, 2.666 mmol) in DMF (4 mL) was added HATU (347.52 mg, 0.914 mmol) at 0 °C, and the reaction was stirred at 25 °C under N atmosphere for 2 h. The reaction was diluted with HO (15 mL) and extracted with EtOAc (20 mL × 3). The combined organic layer was dried over anhydrous NaSO, filtered, and concentrated to give a residue. The residue was purified by silica gel column chromatography (0→3% MeOH in DCM) to give 4-((1-(2-bromo-4-fluorophenyl)-3-methyl-1H-pyrazol-5-yl)methyl)-1-cyclobutyl-N,N-dimethyl-1H-pyrazole-3-carboxamide (312 mg, yield: 89%) as a yellow oil. LC / MS (ESI) (m / z): 460 [M+H] + .

[0398] Synthesis of (R)-4-bromo-3-ethyl-5-((2-(4-fluoro-2-(1-hydroxyethyl)phenyl)pyridin-3-yl)methyl)-N,N-dimethyl-1H-pyrazole-1-carboxamide [ka] To a solution of (R)-3-ethyl-5-((2-(4-fluoro-2-(1-hydroxyethyl)phenyl)pyridin-3-yl)methyl)-N,N-dimethyl-1H-pyrazole-1-carboxamide (88.0 mg, 0.222 mmol) in THF (4 mL) was added dropwise a solution of NBS (39.5 mg, 0.222 mmol) in THF (1 mL) at 0° C., and the mixture was stirred at 0° C. for 30 minutes. The reaction mixture was quenched with HO (10 mL) and extracted with EtOAc (20 mL×2). The combined organic layer was washed with brine (10 mL), dried over anhydrous NaSO, and concentrated. The residue was purified by preparative TLC (100% EtOAc) to give (R)-4-bromo-3-ethyl-5-((2-(4-fluoro-2-(1-hydroxyethyl)phenyl)pyridin-3-yl)methyl)-N,N-dimethyl-1H-pyrazole-1-carboxamide (100 mg, yield: 95.0%) as a yellow solid. LC / MS ESI (m / z): 475 [M+H] + . The following intermediates were synthesized using a similar protocol (including m / z (ESI) values): [Table 39]

[0399] Synthesis of 4-((1-(2-acetyl-4-fluorophenyl)-3-methyl-1H-pyrazol-5-yl)methyl)-1-(cyclopropylmethyl)-1H-pyrazole-3-carbonitrile [ka] To a solution of 1-(cyclopropylmethyl)-4-((1-(2-(1-ethoxyvinyl)-4-fluorophenyl)-3-methyl-1H-pyrazol-5-yl)methyl)-1H-pyrazole-3-carbonitrile (264 mg, 0.650 mmol) in THF (9 mL) was added HCl (3 mL). The reaction was stirred at 20 °C for 1 h. The mixture was diluted with saturated aqueous NaHCO and extracted with EtOAc (30 mL × 2). The combined organic layers were washed with brine (15 mL × 2), dried over anhydrous NaSO and concentrated. The residue was purified by silica gel flash column chromatography (0→100% EtOAc in PE) to give 4-((1-(2-acetyl-4-fluorophenyl)-3-methyl-1H-pyrazol-5-yl)methyl)-1-(cyclopropylmethyl)-1H-pyrazole-3-carbonitrile (160 mg, yield: 65.0%) as a yellow solid. LC / MS (ESI): m / z = 378 [M+H] + . The following intermediates were synthesized using a similar protocol (including m / z (ESI) values): [Table 40]

[0400] Synthesis of 1-cyclobutyl-4-((1-(4-fluoro-2-(1-hydroxyethyl)phenyl)-3-methyl-1H-pyrazol-5-yl)methyl)-N,N-dimethyl-1H-pyrazole-3-carboxamide [ka] To a solution of 4-((1-(2-acetyl-4-fluorophenyl)-3-methyl-1H-pyrazol-5-yl)methyl)-1-cyclobutyl-N,N-dimethyl-1H-pyrazole-3-carboxamide (240 mg, 0.567 mmol) in MeOH (5 mL) was added NaBH (23.58 mg, 0.623 mmol) at 0 °C and the reaction was stirred at 0 °C under N for 0.5 h. The reaction was quenched with aqueous HCl (1 M, 5 mL) and extracted with EtOAc (15 mL × 3). The combined organic layers were dried over anhydrous NaSO, filtered, and concentrated in vacuo to give a residue. The residue was purified by silica gel column chromatography (0→2% MeOH in DCM) to give 1-cyclobutyl-4-((1-(4-fluoro-2-(1-hydroxyethyl)phenyl)-3-methyl-1H-pyrazol-5-yl)methyl)-N,N-dimethyl-1H-pyrazole-3-carboxamide (181 mg, yield: 75.1%) as a yellow oil. LC / MS (ESI) (m / z): 426 [M+H] + . The following intermediates were synthesized using a similar protocol (including m / z (ESI) values): [Table 41]

[0401] Synthesis of (R)-5-bromo-3-(1-(2-(3-((1-ethyl-1H-pyrazol-4-yl)oxy)pyridin-2-yl)-5-fluorophenyl)ethoxy)-2-nitropyridine [ka] To a solution of (R)-1-(2-(3-((1-ethyl-1H-pyrazol-4-yl)oxy)pyridin-2-yl)-5-fluorophenyl)ethan-1-ol (25.0 mg, 0.0760 mmol) in THF (15 mL) was added NaH (4.60 mg, 0.120 mmol, 60% mineral oil), and the mixture was stirred for 0.5 h. Then, 5-bromo-3-fluoro-2-nitropyridine (20.0 mg, 0.0900 mmol) was added. The reaction was stirred at 25 °C for 18 h. The mixture was quenched with water (5 mL) and extracted with EtOAc (15 mL x 3). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by silica gel flash column chromatography (0→50% EtOAc in PE) to afford (R)-5-bromo-3-(1-(2-(3-((1-ethyl-1H-pyrazol-4-yl)oxy)pyridin-2-yl)-5-fluorophenyl)ethoxy)-2-nitropyridine (26.0 mg, 64.0% yield) as a yellow solid. LCMS (ESI): m / z: 528 [M+H] + . The following intermediates were synthesized using a similar protocol (including m / z (ESI) values): [Table 42] TIFF2025536922000249.tif218165TIFF2025536922000250.tif218165

[0402] Synthesis of (R)-4-((2-(2-(1-((5-bromo-2-nitropyridin-3-yl)oxy)ethyl)-4-fluorophenyl)pyridin-3-yl)methyl)-1-ethyl-1H-pyrazole-3-carbonitrile [ka] To a solution of (R)-1-ethyl-4-((2-(4-fluoro-2-(1-hydroxyethyl)phenyl)pyridin-3-yl)methyl)-1H-pyrazole-3-carbonitrile (320 mg, 0.910 mmol) and 5-bromo-3-fluoro-2-nitropyridine (303 mg, 1.37 mmol) in THF (10 mL) was added t-BuOK (1 M THF solution, 1.37 mL, 1.37 mmol) at −70° C. The reaction was stirred at −70° C. for 10 min. The mixture was quenched with saturated aqueous NH4Cl (15 mL) and extracted with EtOAc (30 mL×3). The combined organic layers were washed with brine (20 mL×2), dried over anhydrous Na2SO4, and concentrated to give (R)-4-((2-(2-(1-((5-bromo-2-nitropyridin-3-yl)oxy)ethyl)-4-fluorophenyl)pyridin-3-yl)methyl)-1-ethyl-1H-pyrazole-3-carbonitrile (500 mg, crude) as a white solid. LC / MS (ESI) (m / z): 551 [M+H] + . The following intermediates were synthesized using a similar protocol (including m / z (ESI) values): [Table 43] TIFF2025536922000253.tif234165TIFF2025536922000254.tif74165

[0403] Synthesis of (R)-4-((3-(2-(1-((5-bromo-2-nitropyridin-3-yl)oxy)ethyl)-4-fluorophenyl)-1-methyl-1H-pyrazol-4-yl)methyl)-1-ethyl-1H-pyrazole-3-carbonitrile [ka] To a stirred solution of (R)-1-ethyl-4-((3-(4-fluoro-2-(1-hydroxyethyl)phenyl)-1-methyl-1H-pyrazol-4-yl)methyl)-1H-pyrazole-3-carbonitrile (584 mg, 1.65 mmol) in THF (10 mL) was added NaH (198 mg, 4.96 mmol, 60% solution in mineral oil) at 0° C. under N. After stirring at 0° C. for 1 h, a solution of 5-bromo-3-fluoro-2-nitropyridine (365 mg, 1.65 mmol) in THF (1 mL) was added dropwise. The reaction was stirred at 0° C. for 1 h, quenched with saturated aqueous NH4Cl (10 mL), and extracted with EtOAc (10 mL). The organic layer was dried over anhydrous Na2SO4 and the filtrate was concentrated to give crude (R)-4-((3-(2-(1-((5-bromo-2-nitropyridin-3-yl)oxy)ethyl)-4-fluorophenyl)-1-methyl-1H-pyrazol-4-yl)methyl)-1-ethyl-1H-pyrazole-3-carbonitrile (916 mg) as a yellow oil. LC / MS (ESI) (m / z): 554.1 [M+H] + . The following intermediates were synthesized using a similar protocol (including m / z (ESI) values): [Table 44]

[0404] Synthesis of 3-(2-(2-((R)-1-((5-bromo-2-nitropyridin-3-yl)oxy)ethyl)-4,6-difluorophenyl)nicotinoyl)-1-methyl-1H-pyrazole-5-carbonitrile and 5-(2-{2-[(1R)-1-[(5-bromo-2-nitropyridin-3-yl)oxy]ethyl]-4,6-difluorophenyl}pyridine-3-carbonyl)-1-methyl-1H-pyrazole-3-carbonitrile [ka] To a solution of 3-(2-(2,4-difluoro-6-((R)-1-hydroxyethyl)phenyl)nicotinoyl)-1-methyl-1H-pyrazole-5-carbonitrile and 5-(2-{2,4-difluoro-6-[(1R)-1-hydroxyethyl]phenyl}pyridine-3-carbonyl)-1-methyl-1H-pyrazole-3-carbonitrile (70 mg, 0.190 mmol) in THF (5 mL) was added NaH (15.2 mg, 0.380 mmol, 60% solution in mineral oil) under N at 0° C. and the mixture was stirred at 0° C. for 0.5 h. Next, 5-bromo-3-fluoro-2-nitropyridine (83.9 mg, 0.380 mmol) was added and the reaction was stirred at room temperature under N for 12 h. The mixture was quenched with saturated aqueous NH4Cl (10 mL) and extracted with EtOAc (15 mL x 3). The combined organic phase was washed with brine (20 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by flash column chromatography on silica gel (0 → 10% MeOH in DCM) to give 3-(2-(2-((R)-1-((5-bromo-2-nitropyridin-3-yl)oxy)ethyl)-4,6-difluorophenyl)nicotinoyl)-1-methyl-1H-pyrazole-5-carbonitrile and 5-(2-{2-[(1R)-1-[(5-bromo-2-nitropyridin-3-yl)oxy]ethyl]-4,6-difluorophenyl}pyridine-3-carbonyl)-1-methyl-1H-pyrazole-3-carbonitrile (60.0 mg, yield: 55.5%) as a yellow solid mixture. LC / MS ESI (m / z): 569 [M+H] + .

[0405] Synthesis of 3-((2-(2-((R)-1-((3-amino-6-bromopyrazin-2-yl)oxy)ethyl)-4,6-difluorophenyl)pyridin-3-yl)(methoxymethoxy)methyl)-1-methyl-1H-pyrazole-5-carbonitrile [ka] To a stirred solution of 3-((2-(2,4-difluoro-6-((R)-1-hydroxyethyl)phenyl)pyridin-3-yl)(methoxymethoxy)methyl)-1-methyl-1H-pyrazole-5-carbonitrile (1.67 g, 4.03 mmol) in THF (30 mL) was added NaH (242 mg, 6.04 mmol, 60% solution in mineral oil) at 0° C. under N. After stirring at 0° C. for 1 h, a solution of 3,5-dibromopyrazin-2-amine (1.20 g, 4.84 mmol) in THF (10 mL) was added dropwise. The reaction was stirred at 70° C. for 1 h. The reaction was quenched with saturated aqueous NH4Cl (100 mL) and extracted with EtOAc (100 mL). The organic phase was dried over Na2SO4 and concentrated to dryness to give 3-((2-(2-((R)-1-((3-amino-6-bromopyrazin-2-yl)oxy)ethyl)-4,6-difluorophenyl)pyridin-3-yl)(methoxymethoxy)methyl)-1-methyl-1H-pyrazole-5-carbonitrile (800 mg, 34% yield) as a yellow oil. LC / MS (ESI) (m / z): 586 [M+H] + .

[0406] Synthesis of 3-((2-(2-((R)-1-((5-bromo-2-nitropyridin-3-yl)oxy)ethyl)-4,6-difluorophenyl)pyridin-3-yl)methyl)-5-cyano-N,N-dimethyl-1H-pyrazole-1-carboxamide and 5-((2-(2-((R)-1-((5-bromo-2-nitropyridin-3-yl)oxy)ethyl)-4,6-difluorophenyl)pyridin-3-yl)methyl)-3-cyano-N,N-dimethyl-1H-pyrazole-1-carboxamide [ka] To a mixture of 3-cyano-5-((2-(2,4-difluoro-6-((R)-1-hydroxyethyl)phenyl)pyridin-3-yl)methyl)-N,N-dimethyl-1H-pyrazole-1-carboxamide and 5-cyano-3-((2-(2,4-difluoro-6-((R)-1-hydroxyethyl)phenyl)pyridin-3-yl)methyl)-N,N-dimethyl-1H-pyrazole-1-carboxamide (110 mg, 0.267 mmol) and 5-bromo-3-fluoro-2-nitropyridine (70.9 mg, 0.321 mmol) in THF under N was added potassium tert-butoxide (1 M in THF, 0.401 mL, 0.401 mmol) at −78° C. The reaction was stirred at −78° C. for 1 hour. The reaction mixture was quenched with saturated aqueous NH4Cl (7 mL) and extracted with EtOAc (10 mLx3). The combined organic layers were washed with brine (10 mLx2), dried over anhydrous Na2SO4 and concentrated. The residue was purified by silica gel flash column chromatography (0→100% EtOAc with PE) to give 5-((2-(2-((R)-1-((5-bromo-2-nitropyridin-3-yl)oxy)ethyl)-4,6-difluorophenyl)pyridin-3-yl)methyl)-3-cyano-N,N-dimethyl-1H-pyrazole-1-carboxamide and 3-((2-(2-((R)-1-((5-bromo-2-nitropyridin-3-yl)oxy)ethyl)-4,6-difluorophenyl)pyridin-3-yl)methyl)-5-cyano-N,N-dimethyl-1H-pyrazole-1-carboxamide (110 mg, yield: 67.2%) as a yellow oil mixture. LC / MS (ESI) (m / z): 612 [M+H] + .

[0407] Synthesis of ethyl (R)-4-((2-(2-(1-((5-bromo-2-nitropyridin-3-yl)oxy)ethyl)-4-fluorophenyl)pyridin-3-yl)oxy)-1-(cyclopropylmethyl)-1H-pyrazole-3-carboxylate [ka] To a solution of ethyl (R)-1-(cyclopropylmethyl)-4-((2-(4-fluoro-2-(1-hydroxyethyl)phenyl)pyridin-3-yl)oxy)-1H-pyrazole-3-carboxylate (550 mg, 1.29 mmol) and 5-bromo-3-fluoro-2-nitropyridine (314 mg, 1.42 mmol) in THF (22 mL) was added t-BuOK (1 M THF solution, 2.59 mL) at −70° C. under N. After stirring for 15 min, the mixture was quenched with saturated aqueous NH.sub.4Cl (20 mL) and extracted with EtOAc (20 mL×3). The combined organic phase was washed with brine (25 mL×2), dried over anhydrous Na.sub.2SO.sub.4, and concentrated. The residue was purified by silica gel flash column chromatography (0→100% EtOAc in PE, V / V) to give ethyl (R)-4-((2-(2-(1-((5-bromo-2-nitropyridin-3-yl)oxy)ethyl)-4-fluorophenyl)pyridin-3-yl)oxy)-1-(cyclopropylmethyl)-1H-pyrazole-3-carboxylate (400 mg, 49.0% yield) as a white solid. LC / MS (ESI) (m / z): 626 [M+H] + . The following intermediates were synthesized using a similar protocol (including m / z (ESI) values): [Table 45]

[0408] Synthesis of 3-{1-[4-fluoro-2-(1-hydroxyethyl)phenyl]-3-methyl-1H-pyrazole-5-carbonyl}-1H-pyrazole-5-carbonitrile [ka] To a solution of 3-(1-(2-(1-((tert-butyldimethylsilyl)oxy)ethyl)-4-fluorophenyl)-3-methyl-1H-pyrazole-5-carbonyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-5-carbonitrile (584 mg, 1.00 mmol) in THF (8 mL) was added TBAF (2.00 mL, 4.00 mmol) at room temperature. The reaction was stirred at 40° C. for 2 hours. The mixture was diluted with water (15 mL) and extracted with EtOAc (20 mL×2). The combined organic phase was washed with brine (20 mL×3), dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by silica gel flash column chromatography (0→8% MeOH in DCM) to give 3-{1-[4-fluoro-2-(1-hydroxyethyl)phenyl]-3-methyl-1H-pyrazole-5-carbonyl}-1H-pyrazole-5-carbonitrile (223 mg, yield: 65.7%) as a white solid. LC / MS ESI (m / z): 340 [M+H] + .

[0409] Synthesis of 3-(1-(2-(1-((5-bromo-2-nitropyridin-3-yl)oxy)ethyl)-4-fluorophenyl)-3-methyl-1H-pyrazole-5-carbonyl)-1-methyl-1H-pyrazole-5-carbonitrile and 5-[1-(2-{1-[(5-bromo-2-nitropyridin-3-yl)oxy]ethyl}-4-fluorophenyl)-3-methyl-1H-pyrazole-5-carbonyl]-1-methyl-1H-pyrazole-3-carbonitrile [ka] To a stirred solution of 5-(1-(4-fluoro-2-(1-hydroxyethyl)phenyl)-3-methyl-1H-pyrazole-5-carbonyl)-1-methyl-1H-pyrazole-3-carbonitrile and 3-(1-(4-fluoro-2-(1-hydroxyethyl)phenyl)-3-methyl-1H-pyrazole-5-carbonyl)-1-methyl-1H-pyrazole-5-carbonitrile (76.0 mg, mixture, 0.220 mmol) in THF (5 mL) was added NaH (10.3 mg, 0.260 mmol, 60% solution in mineral oil) at 0° C. and the mixture was stirred under N at 0° C. for 0.5 h. A solution of 5-bromo-3-fluoro-2-nitropyridine (61.8 mg, 0.280 mmol) in THF (5 mL) was then added and the reaction was stirred at 50° C. for 12 h. The mixture was quenched with saturated aqueous NH4Cl (10 mL) and extracted with EtOAc (15 mL x 3). The combined organic phases were washed with brine (10 mL x 2), dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by flash column chromatography on silica gel (0 → 10% MeOH in DCM) to give 3-(1-(2-(1-((5-bromo-2-nitropyridin-3-yl)oxy)ethyl)-4-fluorophenyl)-3-methyl-1H-pyrazole-5-carbonyl)-1-methyl-1H-pyrazole-5-carbonitrile (45.0 mg, yield: 37.7%) as a yellow solid. 5-[1-(2-{1-[(5-bromo-2-nitropyridin-3-yl)oxy]ethyl}-4-fluorophenyl)-3-methyl-1H-pyrazole-5-carbonyl]-1-methyl-1H-pyrazole-3-carbonitrile was not isolated. LC / MS ESI (m / z): 554 [M+H] + .

[0410] compound [Table 46] To a solution of (R)-4-((3-(2-(1-((5-bromo-2-nitropyridin-3-yl)oxy)ethyl)-4-fluorophenyl)-1-methyl-1H-pyrazol-4-yl)methyl)-1-(cyclopropylmethyl)-1H-pyrazole-3-carbonitrile (100 mg, 0.17 mmol) in EtOH (5 mL) and HO (1.5 mL) was added iron powder (96.2 mg, 1.72 mmol) and NHCl (184 mg, 3.44 mmol). The reaction was stirred at 70 °C for 1 h. The mixture was diluted with water (5 mL) and extracted with EtOAc (20 mL × 2). The combined organic layers were dried over anhydrous NaSO, filtered, and concentrated. The residue was purified by column chromatography (SiO2, 50% EtOAc with PE) to give (R)-4-((3-(2-(1-((2-amino-5-bromopyridin-3-yl)oxy)ethyl)-4-fluorophenyl)-1-methyl-1H-pyrazol-4-yl)methyl)-1-(cyclopropylmethyl)-1H-pyrazole-3-carbonitrile (60 mg, 63% yield) as a yellow solid. LC / MS (ESI) (m / z): 550 [M+H] + .

[0411] To a solution of (R)-4-((3-(2-(1-((2-amino-5-bromopyridin-3-yl)oxy)ethyl)-4-fluorophenyl)-1-methyl-1H-pyrazol-4-yl)methyl)-1-(cyclopropylmethyl)-1H-pyrazole-3-carbonitrile (60 mg, 0.11 mmol) in 2-methyl-2-butanol (2 mL) was added KOAc (27 mg, 0.27 mmol), Pd(OAc) (6.0 mg, 0.026 mmol) and cataCXium A (19 mg, 0.052 mmol) and the reaction was stirred at 120 °C under N for 12 hours. The reaction was diluted with water (5 mL) and extracted with EtOAc (20 mL x 2). The combined organic layers were dried over anhydrous NaSO, filtered and concentrated. The residue was purified by preparative HPLC (column: Gemini 5um C18 250 x 21.2 mm, 20->95% MeCN in HO + 0.1% FA) to give the desired compound (22 mg, 43% yield). LC / MS (ESI) (m / z): 470 [M+H] + .

[0412] The following compounds were prepared in a similar manner: [Table 47] TIFF2025536922000266.tif196165TIFF2025536922000267.tif212165TIFF202 5536922000268.tif223165TIFF2025536922000269.tif224165TIFF20255369220 00270.tif223165TIFF2025536922000271.tif220165TIFF2025536922000272.t if198165TIFF2025536922000273.tif215165TIFF2025536922000274.tif218165

[0413] [Table 48] (19R)-22-amino-3-ethyl-16-fluoro-10,19-dimethyl-20-oxa-3,4,10,11,23-pentaazapentacyclo[19.3.1.0 2 , 6 .0 8 , 12 .0 13 , 18 To a solution of pentacosa-1(24),2(6),4,8,11,13,15,17,21(25),22-decene-5-carbonitrile (20 mg, 0.045 mmol) in THF (1.0 mL) was added a solution of NaOH (5.0 mg, 0.14 mmol) in water (2.0 mL) at room temperature. The reaction was stirred in a sealed tube at 100 °C for 12 h. The mixture was extracted with EtOAc (2 mL). The combined organic layers were dried over anhydrous NaSO and concentrated in vacuo. The residue was purified by preparative HPLC (column: Gemini 5 um C18 250 × 21.2 mm, 5 → 95% MeCN in HO + 0.1% FA) to give the desired product (10 mg, 48% yield). LC / MS (ESI) (m / z): 462 [M+H] + .

[0414] The following compounds were prepared in a similar manner: [Table 49] [Table 50]

[0415] (19R)-22-amino-3-ethyl-16-fluoro-10,19-dimethyl-20-oxa-3,4,10,11,23-pentaazapentacyclo[19.3.1.0 2,6 .0 8,12 .0 13,18To a solution of pentacosa-1(24),2(6),4,8,11,13,15,17,21(25),22-decene-5-carbonitrile (10 mg, 0.023 mmol) in MeOH (2 mL) was added NaOH (2 M aqueous solution, 0.015 mL, 0.09 mmol) and the reaction was stirred for 12 h at 80° C. The mixture was directly concentrated to give crude (19R)-22-amino-3-ethyl-16-fluoro-10,19-dimethyl-20-oxa-3,4,10,11,23-pentaazapentacyclo[19.3.1.0]. 2,6 .0 8,12 .0 13,18 ] to give pentacosa-1(24),2(6),4,8,11,13,15,17,21(25),22-decene-5-carboxylic acid (8 mg, 76% yield) as a yellow oil. LC / MS (ESI) (m / z): 463 [M+H] + .

[0416] Crude (19R)-22-amino-3-ethyl-16-fluoro-10,19-dimethyl-20-oxa-3,4,10,11,23-pentaazapentacyclo[19.3.1.0 2,6 .0 8,12 .0 13,18 To a solution of pentacosa-1(24),2(6),4,8,11,13,15,17,21(25),22-decene-5-carboxylic acid (8.0 mg, 0.017 mmol) in DMF (1.0 mL) was added dimethylamine hydrochloride (0.003 mL, 0.04 mmol), DIEA (0.009 mL, 0.05 mmol), and HATU (11 mg, 0.028 mmol). The reaction was stirred at room temperature for 2 hours. The reaction mixture was diluted with water (10 mL) and extracted with EtOAc (20 mL x 2). The combined organic layers were dried over NaSO, filtered, and concentrated in vacuo. The residue was purified by preparative HPLC (column: Gemini 5 um C18 250 x 21.2 mm, 5 → 95% MeCN in HO + 0.1% FA) to give the desired product (1.6 mg, 19% yield). LC / MS (ESI) (m / z): 490 [M+H] + .

[0417] The following compounds were prepared in a similar manner: [Table 51] TIFF2025536922000279.tif177165TIFF2025536922000280.tif172165TIFF2025536922000281.tif177165TIFF2025536922 000282.tif227165TIFF2025536922000283.tif182165TIFF2025536922000284.tif225165TIFF2025536922000285.tif83165

[0418] [Table 52] To a mixture of 3-(2-bromonicotinoyl)-1-methyl-1H-pyrazole-5-carbonitrile (300 mg, 1.0 mmol), (R)-5-bromo-3-(1-(5-fluoro-2-(trimethylstannyl)phenyl)ethoxy)pyridin-2-amine (635 mg, 1.30 mmol) in DMF (10 mL) was added AsPh (157 mg, 0.510 mmol), CuI (19.6 mg, 0.100 mmol), and Pd(dba) (94.0 mg, 0.100 mmol). The mixture was degassed and purged with N three times, and the reaction was stirred at 100 °C for 16 h. The mixture was cooled and filtered. The filtrate was diluted with HO (15 mL) and extracted with EtOAc (40 mL x 3). The combined organic solution was washed with water (15 mL x 3), brine (20 mL x 2), dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by flash column chromatography on silica gel (0->50% EtOAc in PE) to give (R)-3-(2-(2-(1-((2-amino-5-bromopyridin-3-yl)oxy)ethyl)-4-fluorophenyl)nicotinoyl)-1-methyl-1H-pyrazole-5-carbonitrile (100 mg, 18.6% yield). LCMS (ESI): m / z: 521 [M+H] + .

[0419] To a mixture of (R)-3-(2-(2-(1-((2-amino-5-bromopyridin-3-yl)oxy)ethyl)-4-fluorophenyl)nicotinoyl)-1-methyl-1H-pyrazole-5-carbonitrile (100 mg, 0.200 mmol) in 2-methyl-2-butanol (5 mL) was added KOAc (56.5 mg, 0.580 mmol), butyl-di-1-adamantylphosphine (27.5 mg, 0.0800 mmol), and palladium acetate (8.60 mg, 0.0400 mmol). The mixture was degassed and purged with N three times, and the reaction tube was sealed. The reaction was stirred at 120 °C for 16 h. The residue was directly purified by flash column chromatography on silica gel (0-60% EtOAc in PE) and further purified by preparative HPLC (column: YMC-Actus Triart C18 150 × 20 mm × 5 μm, 10-95% MeCN in HO + 0.1% TFA) to give the desired product as the trifluoroacetate salt (26.0 mg, 23% yield). The free base form was isolated via solid- or liquid-phase acid-base extraction with a basic medium such as aqueous NaHCO3. 1H NMR (400 MHz, free base, MeOD) δ 8.79 (dd, J = 4.9, 1.7 Hz, 1H), 8.28 (dd, J = 8.0, 1.7 Hz, 1H), 7.74 (d, J = 2.0 Hz, 1H), 7.69 (dd, J = 8.6, 5.7 Hz, 1H), 7.57 (dd, J = 8.0, 4.9 Hz, 1H), 7.42 (dd, J = 10.1, 2.7 Hz, 1H), 7.12 (td, J = 8.5, 2.7 Hz, 1H), 6.35 (d, J = 1.9 Hz, 1H), 4.71 (q, J = 6.3 Hz, 1H), 4.13 (s, 3H), 1.75 (d, J = 6.3 Hz, 3H). LCMS (ESI): m / z: 441 [M+H] + .

[0420] The following compounds were prepared in a similar manner: [Table 53] TIFF2025536922000288.tif213165TIFF2025536922000289.tif218165TIFF2025536922000290.tif202165TIFF2025536922000291.tif77165

[0421] [Table 54] To a mixture of (R)-4-bromo-5-((2-(2-(1-((5-bromo-2-nitropyridin-3-yl)oxy)ethyl)-4-fluorophenyl)pyridin-3-yl)methyl)-3-(cyclopropylmethyl)-N,N-dimethyl-1H-pyrazole-1-carboxamide (65.0 mg, crude) and iron powder (50.0 mg, 0.890 mmol) in EtOH (5 mL) and HO (1 mL) was added NHCl (48.0 mg, 0.890 mmol). The reaction was stirred at 80 °C for 2 h. The mixture was filtered, and the filtrate was concentrated. The residue was purified by silica gel flash column chromatography (0→55% EtOAc in PE) to afford (R)-5-((3-(2-(1-((2-amino-5-bromopyridin-3-yl)oxy)ethyl)-4,6-difluorophenyl)-1-methyl-1H-pyrazol-4-yl)methyl)-4-bromo-3-(cyclopropylmethyl)-N,N-dimethyl-1H-pyrazole-1-carboxamide (45.0 mg, 56.0% yield over two steps) as a pale yellow oil. LC / MS (ESI) (m / z): 692 [M+H] + .

[0422] (R)-5-((3-(2-(1-((2-amino-5-bromopyridin-3-yl)oxy)ethyl)-4,6-difluorophenyl)-1-methyl-1H-pyrazol-4-yl)methyl)-4-bromo-3-(cyclopropylmethyl)-N,N-dimethyl-1H-pyrazole-1-carboxamide (45.0 mg, 0.0650 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (33.0 mg, 0.130 mmol), CsF (2 M in HO, 0.100 mL, 0.195 mmol), and cataCXium To a mixture of A (9.00 mg, 0.0260 mmol) in MeOH (10 mL) was added Pd(OAc) (3.00 mg, 0.0130 mmol). The suspension was degassed and purged with N several times. The reaction was stirred in a sealed tube at 70 °C for 2 h. The mixture was concentrated, and the residue was purified by preparative HPLC (column: YMC-TA C18 250 × 21.2 mm × 5 μm, 5 → 95% MeCN in HO + 0.1% FA) to give the desired product (1.00 mg, 3.00% yield). LC / MS ESI (m / z): 534 [M+H] + .

[0423] The following compounds were prepared in a similar manner: [Table 55]

[0424] [Table 56] (R)-3-(cyclopropylmethyl)-16-fluoro-10-methyl-19-methyl-5-(methylthio)-20-oxa-3,4,10,11,23-pentaazapentacyclo[19.3.1.0 2 , 6 .0 8 , 12 .0 13 , 18To a solution of pentacosa-1(25),2(6),4,8,11,13,15,17,21,23-decaen-22-ylamine (50.0 mg, 0.100 mmol) in DCM (2 mL) was added m-CBPA (21 mg, 0.100 mmol) at 0 °C. The reaction was stirred at 0 °C for 30 min. The mixture was quenched with saturated aqueous NaSO (15 mL) and extracted with DCM (15 mL × 3). The combined organic layers were dried over anhydrous NaSO, filtered, and concentrated. The residue was purified by preparative HPLC (column: YMC-Actus Triart C18 250 × 20 mm × 5 μm, 5 → 95% MeCN in HO + 0.1% FA) to give the sulfone product (1.00 mg, 2.0% yield, white solid, LC / MS ESI (m / z): 523 [M+H] + ) and the sulfoxide product (6.7 mg, 13% yield, LC / MS ESI (m / z): 507 [M+H] + ) was obtained.

[0425] The following compounds were prepared in a similar manner: [Table 57]

[0426] [Table 58] To a solution of (R)-1-((3-(2-(1-((5-bromo-2-nitropyridin-3-yl)oxy)ethyl)-4-fluorophenyl)-1-methyl-1H-pyrazol-4-yl)methyl)-4-(cyclopropylmethyl)-N,N-dimethyl-1H-imidazole-2-carboxamide (80.0 mg, 0.140 mmol) in EtOH (5 mL) and water (1 mL) was added iron powder (40.0 mg, 0.700 mmol) and NH4Cl (70.0 mg, 1.40 mmol) at room temperature. The reaction was stirred at 80° C. for 1 h. The mixture was filtered, and the filtrate was concentrated. The residue was purified by silica gel flash column chromatography (0→50% EtOAc in PE) to give (R)-1-((3-(2-(1-((2-amino-5-bromopyridin-3-yl)oxy)ethyl)-4-fluorophenyl)-1-methyl-1H-pyrazol-4-yl)methyl)-4-(cyclopropylmethyl)-N,N-dimethyl-1H-imidazole-2-carboxamide (70.0 mg, yield: 92.1%) as a brown solid. LC / MS (ESI) (m / z): 596 [M+H] + .

[0427] To a stirred solution of (R)-1-((3-(2-(1-((2-amino-5-bromopyridin-3-yl)oxy)ethyl)-4-fluorophenyl)-1-methyl-1H-pyrazol-4-yl)methyl)-4-(cyclopropylmethyl)-N,N-dimethyl-1H-imidazole-2-carboxamide (40 mg, 0.060 mmol) in MeCN (4 mL) was added a solution of N-bromosuccinimide (10 mg, 0.060 mmol) in MeCN (1 mL) at 0° C. The reaction was stirred at 0° C. for 1 h. The mixture was poured into saturated aqueous NaHCO (10 mL) and extracted with EtOAc (10 mL×3). The combined organic phase was washed with brine (10 mL×2), dried over anhydrous NaSO, filtered, and concentrated. The residue was purified by silica gel flash column chromatography (0→50% EtOAc in PE) to give (R)-1-((3-(2-(1-((2-amino-5-bromopyridin-3-yl)oxy)ethyl)-4-fluorophenyl)-1-methyl-1H-pyrazol-4-yl)methyl)-5-bromo-4-(cyclopropylmethyl)-N,N-dimethyl-1H-imidazole-2-carboxamide (40.0 mg, yield: 88.9%) as a brown solid. LC / MS (ESI) (m / z): 674 [M+H] + .

[0428] To a solution of (R)-1-((3-(2-(1-((2-amino-5-bromopyridin-3-yl)oxy)ethyl)-4-fluorophenyl)-1-methyl-1H-pyrazol-4-yl)methyl)-5-bromo-4-(cyclopropylmethyl)-N,N-dimethyl-1H-imidazole-2-carboxamide (50 mg, 0.070 mmol) in MeOH (8 mL) was added B2Pin2 (60 mg, 0.22 mmol), cataCXium A (10 mg, 0.040 mmol), CsF (2 M in HO, 0.07 mL, 0.150 mmol), and Pd(OAc)2 (10 mg, 0.020 mmol) at room temperature. The reaction was degassed three times with N2 and stirred at 80 °C overnight. The mixture was filtered, and the filtrate was concentrated. The residue was purified by preparative TLC (5% MeOH in DCM) and further purified by preparative HPLC (column: YMC TA C18 250 × 21.2 mm 5 μm, 5 → 95% MeCN in HO, 0.1% FA) to give the desired product (1.5 mg, yield: 0.40%). LC / MS (ESI) (m / z): 516 [M+H] + .

[0429] [Table 59] Ethyl (R)-23-amino-3-(cyclopropylmethyl)-17-fluoro-20-methyl-7,21-dioxa-3,4,12,24-tetraazapentacyclo[20.3.1.0 2 , 6 .0 8 , 13 .0 14 , 19To a solution of hexacosa-1(25),2(6),4,8(13),9,11,14,16,18,22(26),23-undecene-5-carboxylate (65.0 mg, 0.126 mmol) in THF (2 mL), EtOH (2 mL), and HO (2 mL) was added lithium hydroxide hydrate (26.0 mg, 0.630 mmol). The reaction was stirred overnight at room temperature. The mixture was adjusted to pH 5 with aqueous HCl (1 M) and extracted with EtOAc (10 mL x 3). The combined organic phases were dried over NaSO and concentrated to give (20R)-23-amino-3-(cyclopropylmethyl)-17-fluoro-20-methyl-7,21-dioxa-3,4,12,24-tetraazapentacyclo[20.3.1.0 2,6 .0 8,13 .0 14,19 ]Hexacosa-1(25),2(6),4,8(13),9,11,14,16,18,22(26),23-undecene-5-carboxylic acid (45.0 mg, crude) was obtained. LC / MS (ESI) (m / z): 488 [M+H] + .

[0430] (20R)-23-amino-3-(cyclopropylmethyl)-17-fluoro-20-methyl-7,21-dioxa-3,4,12,24-tetraazapentacyclo[20.3.1.0 2,6 .0 8,13 .0 14,19To a solution of hexacosa-1(25),2(6),4,8(13),9,11,14,16,18,22(26),23-undecene-5-carboxylic acid (25.0 mg, 0.0500 mmol), dimethylamine hydrochloride (4.60 mg, 0.100 mmol), and DIEA (0.03 mL, 0.200 mmol) in DMF (1 mL) was added HATU (23.3 mg, 0.0600 mmol) at 0 °C. The reaction was stirred at room temperature for 1 h. The mixture was quenched with water (10 mL) and extracted with EtOAc (10 mL x 3). The combined organic phase was washed with brine (10 mL), dried over anhydrous Na2SO4, and concentrated. The residue was purified by preparative HPLC (column: Azzota C18 30 × 250 mm × 10 μm, 15 → 95% MeCN in HO, 0.1% FA) to give the desired product (8.00 mg, 30.0% yield over two steps). LC / MS (ESI) (m / z): 515 [M+H] + .

[0431] [Table 60] (R)-23-amino-15,17-difluoro-20-methyl-7-oxo-4-{[2-(trimethylsilyl)ethoxy]methyl}-21-oxa-4,5,12,24-tetraazapentacyclo[20.3.1.0 2 , 6 .0 8 , 13 .0 14 , 19To a solution of hexacosa-1(25),2,5,8,10,12,14,16,18,22(26),23-undecene-3-carbonitrile (55 mg, 0.096 mmol) in DCM (3 mL) was added TFA (1.0 mL, 13 mmol), and the reaction was stirred at 25 °C for 4 h. The mixture was quenched with saturated aqueous NaHCO and extracted with DCM (20 mL x 2). The combined organic layers were dried over anhydrous NaSO, filtered, and concentrated. The residue was purified by silica gel column chromatography (0 → 5% MeOH in DCM) and further purified by preparative HPLC (column: YMC Triart C18 250 × 20 mm ID, 5 μm, 5 → 95% MeCN in HO, 0.1% FA) to give the desired product (9.9 mg, yield: 23.3%). LC / MS ESI (m / z): 445 [M+H] + .

[0432] [Table 61] (R)-23-amino-17-fluoro-4-methyl-20-methyl-7-oxo-21-oxa-4,5,12,24-tetraazapentacyclo[20.3.1.0 2 , 6 .0 8 , 13 .0 14 , 19 To a solution of hexacosa-1(25),2,5,8(13),9,11,14,16,18,22(26),23-undecene-3-carbonitrile (100 mg, 0.227 mmol) in MeOH (5 mL) was added NaBH (17.0 mg, 0.454 mmol) at 25 °C. After stirring at 25 °C for 1 h, the reaction was quenched with saturated aqueous NH Cl (10 mL) and extracted with EtOAc (10 mL x 3). The combined organic layers were washed with brine, dried over anhydrous Na SO and concentrated. The residue was purified by preparative HPLC (column: Gemini 5 um C 250 × 21.2 mm, 5 → 95% CH CN in HO + 0.1% FA) to give the desired product (50 mg, 50% yield). LC / MS (ESI) (m / z): 443 [M+H] +.

[0433] The following compounds were prepared in a similar manner: [Table 62]

[0434] [Table 63] To a mixture of 3-(4-bromo-2-methylthiazole-5-carbonyl)-1-methyl-1H-pyrazole-5-carbonitrile and 3-(4-bromo-1,3-thiazole-5-carbonyl)-1-methyl-1H-pyrazole-5-carbonitrile (50 mg, 0.16 mmol) in toluene (0.6 mL), t-BuOH (0.3 mL), and HO (0.2 mL) was added tert-butyl (R)-(3-(1-(3,5-difluoro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethoxy)pyridin-2-yl)carbamate (115 mg, 0.24 mmol), Pd(dppf)Cl (12 mg, 0.02 mmol), and NaCO (51 mg, 0.48 mmol). The reaction was degassed and purged with N2 three times and stirred for 8 h at 80° C. The mixture was cooled to 25° C. and filtered using EtOAc (50 mL) to rinse the filter cake. The filtrate was washed with water (15 mL), washed with brine (15 mL), dried over Na2SO4, and concentrated to give tert-butyl (R)-(3-(1-(2-(5-(5-cyano-1-methyl-1H-pyrazole-3-carbonyl)-2-methylthiazol-4-yl)-3,5-difluorophenyl)ethoxy)pyridin-2-yl)carbamate and tert-butyl N-{3-[(1R)-1-{2-[5-(5-cyano-1-methyl-1H-pyrazole-3-carbonyl)-1,3-thiazol-4-yl]-3,5-difluorophenyl}ethoxy]pyridin-2-yl}carbamate (80 mg, crude) as a white solid mixture. LC / MS (ESI) (m / z): 581 [M+H] + .

[0435] To a mixture of tert-butyl (R)-(3-(1-(2-(5-(5-cyano-1-methyl-1H-pyrazole-3-carbonyl)-2-methylthiazol-4-yl)-3,5-difluorophenyl)ethoxy)pyridin-2-yl)carbamate and tert-butyl N-{3-[(1R)-1-{2-[5-(5-cyano-1-methyl-1H-pyrazole-3-carbonyl)-1,3-thiazol-4-yl]-3,5-difluorophenyl}ethoxy]pyridin-2-yl}carbamate (80 mg, crude) in toluene (1 mL) and HO (0.2 mL) was added KCO (57 mg, 0.41 mmol). The reaction was degassed three times with N and then stirred at 85 °C for 8 h. The mixture was filtered, and the filter cake was rinsed with EtOAc (10 mL). The filtrate was washed with water (5 mL) followed by brine (5 mL). The combined organic phase was dried over anhydrous Na2SO4 and concentrated. The residue was purified by flash column chromatography on silica gel (0→80% EtOAc in PE) to give (R)-3-(4-(2-(1-((2-aminopyridin-3-yl)oxy)ethyl)-4,6-difluorophenyl)-2-methylthiazole-5-carbonyl)-1-methyl-1H-pyrazole-5-carbonitrile and 3-(4-{2-[(1R)-1-[(2-aminopyridin-3-yl)oxy]ethyl]-4,6-difluorophenyl}-1,3-thiazole-5-carbonyl)-1-methyl-1H-pyrazole-5-carbonitrile (70 mg, 90.6% yield over two steps) as a white solid mixture. LC / MS (ESI) (m / z): 481 [M+H] + .

[0436] To a mixture of (R)-3-(4-(2-(1-((2-aminopyridin-3-yl)oxy)ethyl)-4,6-difluorophenyl)-2-methylthiazole-5-carbonyl)-1-methyl-1H-pyrazole-5-carbonitrile and 3-(4-{2-[(1R)-1-[(2-aminopyridin-3-yl)oxy]ethyl]-4,6-difluorophenyl}-1,3-thiazole-5-carbonyl)-1-methyl-1H-pyrazole-5-carbonitrile (80 mg, 0.17 mmol) in MeCN (2 mL) was added NBS (34 mg, 0.52 mmol) slowly at 0° C. The reaction was stirred at 25° C. for 1 hour. The mixture was poured into water (10 mL) and extracted with EtOAc (10 mL×3). The combined organic phase was washed with brine (10 mL), dried over anhydrous NaSO, and concentrated. The residue was purified by silica gel flash column chromatography (0→50% EtOAc in PE) to give (R)-3-(4-(2-(1-((2-amino-5-bromopyridin-3-yl)oxy)ethyl)-4,6-difluorophenyl)-2-methylthiazole-5-carbonyl)-1-methyl-1H-pyrazole-5-carbonitrile and 3-(4-{2-[(1R)-1-[(2-amino-5-bromopyridin-3-yl)oxy]ethyl]-4,6-difluorophenyl}-1,3-thiazole-5-carbonyl)-1-methyl-1H-pyrazole-5-carbonitrile (55.0 mg, yield: 59.1%) as a white solid mixture. LC / MS (ESI) (m / z): 559 [M+H] + .

[0437] To a mixture of (R)-3-(4-(2-(1-((2-amino-5-bromopyridin-3-yl)oxy)ethyl)-4,6-difluorophenyl)-2-methylthiazole-5-carbonyl)-1-methyl-1H-pyrazole-5-carbonitrile and 3-(4-{2-[(1R)-1-[(2-amino-5-bromopyridin-3-yl)oxy]ethyl]-4,6-difluorophenyl}-1,3-thiazole-5-carbonyl)-1-methyl-1H-pyrazole-5-carbonitrile (40 mg, 0.07 mmol) in 2-methyl-2-butanol (5 mL) was added cataCXium A (11 mg, 0.03 mmol), Pd(OAc) (3 mg, 0.02 mmol), and PivOK (40 mg, 0.28 mmol). The mixture was degassed and purged with N2 three times and stirred at 100 °C for 16 h. The mixture was concentrated, and the residue was purified by preparative TLC (100% EtOAc) followed by preparative HPLC (column: YMC-Actus Triart C18 150 × 20 mm, 25 → 95% MeCN in HO + 0.1% FA) to give the desired product (5.6 mg) and the desmethyl product (4.4 mg). LC / MS ESI (m / z): 479 [M+H] + .

[0438] The following compounds were prepared in a similar manner: [Table 64]

[0439] [Table 65] A solution of 3-((2-(2-((R)-1-((3-amino-6-bromopyrazin-2-yl)oxy)ethyl)-4,6-difluorophenyl)pyridin-3-yl)(methoxymethoxy)methyl)-1-methyl-1H-pyrazole-5-carbonitrile (400 mg, 0.68 mmol) in MeOH (5 mL) and aqueous HCl (1 M, 5 mL) was stirred at 60° C. for 16 h. The mixture was neutralized with saturated aqueous NaHCO, diluted with EtOAc (50 mL), and washed with brine (50 mL). The organic layer was dried over anhydrous NaSO and concentrated. The residue was purified by silica gel column chromatography (0→30% EtOAc in PE) to give 3-((2-(2-((R)-1-((3-amino-6-bromopyrazin-2-yl)oxy)ethyl)-4,6-difluorophenyl)pyridin-3-yl)(hydroxy)methyl)-1-methyl-1H-pyrazole-5-carbonitrile (320 mg, 86% yield) as a yellow oil. LC / MS (ESI) (m / z): 542 [M+H] + .

[0440] To a solution of 3-((2-(2-((R)-1-((3-amino-6-bromopyrazin-2-yl)oxy)ethyl)-4,6-difluorophenyl)pyridin-3-yl)(hydroxy)methyl)-1-methyl-1H-pyrazole-5-carbonitrile (50.0 mg, 0.0920 mmol) in DCM (4 mL) was added Dess-Martin periodinane (39.0 mg, 0.138 mmol) slowly at 0 °C. The reaction was stirred at 25 °C for 1 h. The mixture was filtered, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (0→40% EtOAc in PE) to give 3-(2-(2-((R)-1-((3-amino-6-bromopyrazin-2-yl)oxy)ethyl)-4,6-difluorophenyl)nicotinoyl)-1-methyl-1H-pyrazole-5-carbonitrile (20 mg, 40% yield) as a yellow solid. LC / MS (ESI) (m / z): 540 [M+H] + .

[0441] To a solution of 3-(2-(2-((R)-1-((3-amino-6-bromopyrazin-2-yl)oxy)ethyl)-4,6-difluorophenyl)nicotinoyl)-1-methyl-1H-pyrazole-5-carbonitrile (20.0 mg, 0.0370 mmol) in 2-methyl-2-butanol (5 mL) was added KOAc (10.9 mg, 0.11 mmol), cataCXium A (5.3 mg, 0.015 mmol), and Pd(OAc) (1.7 mg, 0.007 mmol). The mixture was degassed three times under N and stirred at 120 °C for 16 h. The mixture was partitioned between EtOAc (10 mL) and water (10 mL). The organic phase was dried over N...

Claims

1. Compounds of formula (I): 【Chemistry 1】 or a stereoisomer, mixture of stereoisomers, or a pharmaceutically acceptable salt thereof, wherein: Q is CH or N; Z is CR ５ or N, L is -CH ２ -, C=O, or -O-; X is a 5-membered heteroarylene containing 1 to 3 heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, and the 5-membered heteroarylene is selected from 1, 2, or 3 R ２ is replaced by Y is a 5- or 6-membered heteroarylene containing 1 to 3 heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, and the 5- or 6-membered heteroarylene is selected from the group consisting of 0, 1, or 2 R ３ is replaced by R １ is selected from the group consisting of H, methyl, and hydroxymethyl; R ２ Each instance of is independently H, CN, halo, 【Chemistry 2】 -CO-C １－４ Alkyl, 5-membered heteroaryl, C １－４ Alkyl-SO-, C １－４ Alkyl-SO ２ -, C １－４ Alkoxy, C １－４ Alkyl, halo-C １－４ Alkyl, C １－４ Alkoxy-C １－４ Alkyl, C ３－４ Cycloalkylmethyl, C ３－６ Cycloalkyl, and C ３－６ heterocyclyl, wherein L is —CH ２ -, at least one R ２ teeth 【Transformation 3】 -CO-C １－４ alkyl, 5-membered heteroaryl, C １－４ Alkyl-SO-, or C １－４ Alkyl-SO ２ -, wherein said heteroaryl, cycloalkyl, heterocyclyl, or alkyl further comprises, as valences permit, 0, 1, 2, or 3 C １－４ substituted with alkyl or halogen; R ｎ Each instance of is independently H, C １－４ Alkyl, halo-C １－４ Alkyl or C ３－６ cycloalkyl or two R ｎ groups together with their intervening nitrogens, optionally one or more C １－４ C substituted with alkyl or halogen ３－６ forming a heterocycloalkyl, R ｏ Each instance of is independently H or C １－４ is alkyl, R ３ Each instance of is independently H, halo, CN, C １－４ Alkoxy, halo-C １－４ Alkyl, and C １－４ is selected from the group consisting of alkyl, R ４ and R ５ is independently H or F, or a stereoisomer, mixture of stereoisomers, or pharmaceutically acceptable salt thereof.

2. Compounds of formula (I): 【Chemistry 4】 or a stereoisomer, mixture of stereoisomers, or a pharmaceutically acceptable salt thereof, wherein: Q is CH or N; Z is CR ５ or N, L is -CH ２ -, C=O, -CH(OH)-, or -O-; X is a 5-membered heteroarylene containing 1 to 3 heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, and the 5-membered heteroarylene is selected from 1, 2, or 3 R ２ is replaced by Y is a 5- or 6-membered heteroarylene containing 1 to 3 heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, and the 5- or 6-membered heteroarylene is selected from the group consisting of 0, 1, or 2 R ３ is replaced by R １ is selected from the group consisting of H, methyl, and hydroxymethyl; R ２ Each instance of is independently H, CN, halo, 【Transformation 5】 -S-C １－４ Alkyl, —CO—C １－４ Alkyl, 5-membered heteroaryl, C １－４ Alkyl-SO-, C １－４ Alkyl-SO ２ -, C １－４ Alkoxy, C １－４ Alkyl, halo-C １－４ Alkyl, C １－４ Alkoxy-C １－４ Alkyl, C ３－４ Cycloalkylmethyl, C ３－６ Cycloalkyl, and C ３－６ heterocyclyl, wherein L is —CH ２ -, at least one R ２ teeth, 【Transformation 6】 -CO-C １－４ Alkyl, 5-membered heteroaryl, —S—C １－４ Alkyl, C １－４ Alkyl-SO-, or C １－４ Alkyl-SO ２ -, wherein said heteroaryl, cycloalkyl, heterocyclyl, alkoxy, or alkyl further comprises, as valence permits, 0, 1, 2, or 3 C １－４ Alkyl, Si(C １－４ alkyl) ３ or substituted with halogen, R ｎ Each instance of is independently H, C １－４ Alkyl, halo-C １－４ Alkyl or C ３－６ cycloalkyl or two R ｎ groups together with their intervening nitrogens, optionally one or more C １－４ C substituted with alkyl or halogen ３－６ forming a heterocycloalkyl, R ｏ Each instance of is independently H or C １－４ is alkyl, R ３ Each instance of is independently H, halo, CN, C １－４ Alkoxy, halo-C １－４ Alkyl, and C １－４ is selected from the group consisting of alkyl, R ４ and R ５ is independently H or F, or a stereoisomer, mixture of stereoisomers, or pharmaceutically acceptable salt thereof.

3. Compound of formula (IA): 【Transformation 7】 3. The compound of claim 1 or 2, wherein:

4. Compound of formula (IA-1): 【Transformation 8】 3. The compound of claim 1 or 2, wherein:

5. Compound of formula (IB): 【Chemistry 9】 3. The compound of claim 1 or 2, wherein:

6. Compound of formula (IB-1): 【Chemistry 10】 3. The compound of claim 1 or 2, wherein:

7. Compound of formula (IC): 【Chemistry 11】 3. The compound of claim 1 or 2, wherein:

8. Compound of formula (IC-1): 【Chemistry 12】 3. The compound of claim 1 or 2, wherein:

9. Compound of formula (ID): 【Chemistry 13】 3. The compound of claim 1 or 2, wherein:

10. Compound of formula (ID-1): 【Chemistry 14】 3. The compound of claim 1 or 2, wherein:

11. Compound of formula (ID-1-1): 【Chemistry 15】 3. The compound of claim 1 or 2, wherein:

12. X is 3 ＊ , 4-substituted pyrazolylene, 4 ＊ ,5-substituted pyrazolylene, 4,5 ＊ -substituted pyrazolylene, 1 ＊ , 5-substituted pyrazolylene, 4 ＊ , 5-substituted imidazolylene, 1 ＊ , 5-substituted imidazolylene, or 4 ＊ , 5-substituted triazolylenes; ＊ 12. The compound of any one of claims 1 to 11, wherein indicates the point of attachment of X or Y to the L group attached to X and Y.

13. X is a 5-membered heteroarylene selected from the group consisting of: 【Chemistry 16】 ＊ 13. The compound of claim 12, wherein indicates the point of attachment of X to the L group attached to X and Y.

14. X is, 【Chemistry 17】 and ＊＊ Rank R ２ but, [Chemistry 18] -CO-C １－４ Alkyl, —S—C １－４ Alkyl, CN, 5-membered heteroaryl, C １－４ Alkyl-SO-, or C １－４ Alkyl-SO ２ The compound according to claim 13, wherein

15. X is, 【Chemistry 19】 14. The compound of claim 13, wherein:

16. Y is 1 ＊ , 5-substituted pyrazolylene, 3 ＊ ,4-substituted pyrazolylene, 2,3 ＊ -substituted pyridinylene, 3 ＊ ,4-substituted pyridinylene, 3,4 ＊ -substituted pyridinylene, 4,5 ＊ -substituted 1,3-thiazolylene, 4 ＊ ,5-substituted 1,2,3-triazolylene, 1 ＊ ,5-substituted 1,2,4-triazolylene, 1,5 ＊ -substituted 1,2,4-triazolylenes, and 4 ＊ , 5-substituted 1,3-thiazolylene; ＊ The compound of any one of claims 1 to 15, wherein indicates the point of attachment to the L group attached to X and Y.

17. Y is, 【Chemistry 20】 and ＊ 17. The compound of claim 16, wherein indicates the point of attachment of Y to the L group attached to X and Y.

18. The compound of any one of claims 1 to 17, wherein Q is CH.

19. The compound of any one of claims 1 to 17, wherein Q is N.

20. Z is CR ５ The compound according to any one of claims 1 to 19,

21. CR ５ The compound of any one of claims 1 to 20, wherein is H.

22. R １ The compound of any one of claims 1 to 21, wherein is methyl.

23. R ４ The compound according to any one of claims 1 to 22, wherein is F.

24. One R ２ But one, two, or three C １－４ The compound of any one of claims 1 to 23, which is a 5-membered heteroaryl substituted with alkyl.

25. Each R ２ are independently CN, —CH ２ -cyclopropyl, -CH ２ CH ２ OCH ３ , -CO ２ Et, methyl, ethyl, —C(═O)—N(CH ３ ) ２ , -C(=O)-N(CH ３ ) ｉ Pr, -C(=O)-N(CH ３ )Et, -C(=O)-NH ２、 -C(=O)-N(CH ３ ) (CH ２ CF ３ ), -C(=O)-N(CH ３ ) (cyclopropyl), —C(═O)—CH ３ , -C(=O)-N(CH ３ )-OCH ３ , -CH ２ -O(CH ２ ) ２ -Si(CH ３ ) ３ , -CH ２ -cyclobutyl, CH ２ -cyclopropyl, (CH ２ ) ２ -OCH ３ , 【Chemistry 21】 —SO—CH ３ , and -SO ２ -CH ３ The compound according to any one of claims 1 to 23, selected from the group consisting of:

26. Each R ２ The compound of any one of claims 1 to 23, wherein is independently selected from the group consisting of H, fluoro, chloro, CN, methyl, and ethyl.

27. Each R ３ The compound of any one of claims 1 to 26, wherein is independently selected from the group consisting of H, fluoro, chloro, CN, methyl, and ethyl.

28. R ３ 28. The compound of claim 27, wherein is methyl.

29. A compound set forth in Table 1, Table 1A, Table 1B, or a pharmaceutically acceptable salt thereof.

30. A pharmaceutical composition comprising a compound according to any one of claims 1 to 29 and a pharmaceutically acceptable carrier or excipient.

31. A method for treating cancer, comprising administering to a subject in need thereof a therapeutically effective amount of a compound according to any one of claims 1 to 29 or a pharmaceutical composition according to claim 30.

32. 32. The method of claim 31 , wherein the subject is a human.

33. 33. The method of claim 31 or 32, wherein the cancer is an ALK-positive or ROS1-positive cancer.

34. 34. The method of any one of claims 31 to 33, wherein the compound is an inhibitor of ROS1 and ALK.

35. The method of any one of claims 31 to 33, wherein the compound or salt is an inhibitor of ROS1.

36. The method of any one of claims 31 to 33, wherein the compound is an inhibitor of ALK.

37. 37. The method of any one of claims 31 to 36, wherein the cancer is a solid tumor or a hematological malignancy.

38. 38. The method of claim 37, wherein the cancer is a solid tumor, and the solid tumor is selected from lung cancer, glioblastoma, inflammatory myofibroblastic tumor (IMT), cholangiocarcinoma, ovarian cancer, gastric cancer, colorectal cancer, angiosarcoma, melanoma, epithelioid hemangioendothelioma, esophageal cancer, renal cancer, breast cancer, colon cancer, thyroid cancer, Spitz nevus-like tumor, or neuroblastoma.

39. 38. The method of claim 37, wherein the cancer is a hematological malignancy, and the hematological malignancy is anaplastic large cell lymphoma (ALCL), diffuse large B-cell lymphoma (DLBCL), or large B-cell lymphoma.

40. 38. The method of claim 37, wherein the cancer is non-small cell lung cancer.

41. 38. The method of claim 37, wherein the cancer is inflammatory myofibroblastic tumor.

42. 38. The method of claim 37, wherein the cancer is ovarian cancer.

43. 38. The method of claim 37, wherein the cancer is Spitzoid melanoma.

44. 38. The method of claim 37, wherein the cancer is glioblastoma.

45. 38. The method of claim 37, wherein the cancer is cholangiocarcinoma.

46. 38. The method of claim 37, wherein the cancer is gastric cancer.

47. 38. The method of claim 37, wherein the cancer is colorectal cancer.

48. 38. The method of claim 37, wherein the cancer is angiosarcoma.

49. 38. The method of claim 37, wherein the cancer is anaplastic large cell lymphoma.

50. 38. The method of claim 37, wherein the cancer is diffuse large B-cell lymphoma.

51. 38. The method of claim 37, wherein the cancer is esophageal squamous cell carcinoma.

52. 38. The method of claim 37, wherein the cancer is renal medullary carcinoma.

53. 38. The method of claim 37, wherein the cancer is renal cell carcinoma.

54. 38. The method of claim 37, wherein the cancer is breast cancer.

55. 38. The method of claim 37, wherein the cancer is papillary thyroid carcinoma.

56. 38. The method of claim 37, wherein the cancer is neuroblastoma.

57. The method of any one of claims 31 to 56, wherein the cancer is ROS1 positive.

58. 58. The method of claim 57, wherein the cancer comprises expression of an oncogenic ROS1 gene or an oncogenic ROS1 gene fusion.

59. 59. The method of claim 58, wherein the oncogenic ROS1 gene or oncogenic ROS1 gene fusion comprises one or more mutations of the human ROS1 gene.

60. 60. The method of claim 59, wherein the mutation in the oncogenic ROS1 gene or oncogenic ROS1 gene fusion results in the expression of a ROS1 protein having a G2032R mutation.

61. The method of any one of claims 31 to 56, wherein the cancer is ALK positive.

62. 62. The method of claim 61, wherein the cancer comprises expression of an oncogenic ALK gene or an oncogenic ALK gene fusion.

63. 63. The method of claim 62, wherein the oncogenic ALK gene or the oncogenic ALK gene fusion comprises one or more mutations in the human ALK gene.

64. 64. The method of claim 63, wherein the ALK mutation comprises one or more ALK fusions.

65. 65. The method of claim 64, wherein the ALK fusion 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.

66. 66. The method of claim 65, wherein the ALK fusion is with NPM1, STRN, or EML4.

67. 67. The method of any one of claims 63-66, wherein the ALK mutation comprises G1202R, F1174C, F1174L, I1171N, I1171S, I1171T, L1196M, V1180L, C1156Y, G1202del, G1202K, G1269A, F1174S, S1206Y, E1210K, T1151M, T1151_L1152insT, D1203N, S1206C, L1152R, L1196Q, L1198P, L1198F, R1275Q, L1152P, C1156T, or F1245V, or a combination thereof.

68. 68. The method of claim 67, wherein the ALK mutation comprises G1202R.

69. 68. The method of claim 67, wherein the ALK mutation comprises F1174S or F1174L.

70. 68. The method of claim 67, wherein the ALK mutation comprises R1275Q.

71. 68. The method of claim 67, wherein the ALK mutation comprises T1151M.

72. 68. The method of claim 67, wherein the ALK mutation comprises I1171T, I1171S, or I1171N.

73. 73. The method of any one of claims 63 to 72, wherein the ALK mutation comprises one or more compound mutations.

74. 74. The method of claim 73, wherein the compound mutation is selected from G1202R / T1151M, G1202R / L1196M, G1202R / G1269A, G1202R / L1198F, G1202R / F1174S, I1171T / D1203N, I1171T / L1198Y, I1171T / 1198F, I1171T / 1198I, I1171S / D1203N, I1171S / L1198Y, I1171S / 1198F, I1171S / 1198I, I1171N / D1203N, I1171N / L1198Y, I1171N / 1198F, and I1171N / 1198I.

75. 62. The method of claim 61, wherein the cancer is characterized by the presence of a partially deleted ALK protein.

76. 76. The method of any one of claims 31-75, wherein the subject has previously undergone one cancer treatment.

77. 76. The method of any one of claims 31-75, wherein the subject has undergone at least two previous cancer treatments.

78. 78. The method of any one of claims 31 to 77, wherein the compound is an inhibitor of human tropomyosin receptor kinase A, B, or C.

79. IC of said compounds for inhibition of mutant or non-mutant ROS1 or ALK ５０ the IC value of said compound for the inhibition of wild-type tropomyosin receptor kinase A, B, or C ５０ 79. The method of claim 78, wherein the .lambda.

80. 31. A method for selectively inhibiting ROS1 over TRK, wherein the inhibition is carried out in a subject suffering from cancer, the method comprising administering to the subject an effective amount of a compound according to any one of claims 1 to 29 or a pharmaceutical composition according to claim 30.

81. 31. A method for selectively inhibiting ALK over TRK, wherein the inhibition is carried out in a subject suffering from cancer, the method comprising administering to the subject an effective amount of a compound according to any one of claims 1 to 29 or a pharmaceutical composition according to claim 30.

82. 82. The method of any one of claims 31 to 81, further comprising administering to the subject one or more additional therapeutic agents.

83. 83. The method of claim 82, wherein the additional therapeutic agent is a TKI.

84. 84. The method of claim 83, wherein the TKI is crizotinib, ceritinib, alectinib, brigatinib, lorlatinib, entrectinib, repotrectinib, cabozantinib, foretinib, taretrectinib, merestinib, masitinib, or ensartinib.

85. 31. A method of reducing the level of ROS1 or ALK in a cell, comprising contacting the cell with a compound of any one of claims 1 to 29 or a pharmaceutical composition of claim 30.

86. 86. The method of claim 85, further comprising contacting the cells with one or more additional therapeutic agents.

87. 87. The method of claim 86, wherein the additional therapeutic agent is a TKI.

88. 88. The method of claim 87, wherein the TKI is crizotinib, ceritinib, alectinib, brigatinib, lorlatinib, entrectinib, repotrectinib, cabozantinib, foretinib, taretrectinib, merestinib, masitinib, or ensartinib.

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