Heteroaromatic macrocyclic ether chemotherapeutic agents

Abstract

The present invention provides heterocyclic heteroaromatic macrocyclic ether compounds, pharmaceutically acceptable salts of the compounds, pharmaceutical compositions thereof, and methods for treating or preventing cancer. [Solution] The compound is represented by the following formula (I). TIFF2026082971000411.tif45170 (In the formula, Q is CH or N, and Z is CR) 5 Alternatively, X is N, where X is a 5-membered heteroarylene selected from the group consisting of pyrazolylene, isoxazolylene, imidazoylene, isothiazolylene, triazolylene, and pyrrolylene, and Y is a 5 or 6-membered heteroarylene containing 1 to 3 heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur.

Description

[Technical Field]

[0001] Related applications This application is a PCT patent application, PCT / CN2020 / filed on May 5, 2020. U.S. Provisional Patent Application No. 088590 and U.S. Provisional Patent Application No. 63 / 12 filed on December 15, 2020. Claiming priority to No. 5,733. Both applications are referred to by reference in whole. This is incorporated herein. [Background technology]

[0002] Receptor tyrosine kinases (RTKs) are cell surface enzymes that determine whether a cell grows or divides. It receives external signals such as these and transmits those signals to the cell via kinase activity. Many RTKs are oncogenes, and abnormal RTK activity is associated with cancer and related disorders. It can promote the survival, growth, and proliferation of cells. This abnormal kinase activity is due to mutation. For example, activating mutations of the kinase domain, fusions containing the intact kinase domain. Possible results from gene rearrangement, amplification, and other means that produce proteins. It is possible. RTK proto-genes include ROS1 and anaplastic lymphoma kinase (ALK). ), NTRK1 (codes TRKA), NTRK2 (codes TRKB), and NTRK3 (which codes for TRKC) is one example.

[0003] ROS1 is an RTK proto-oncogene, and ROS1 rearrangement is associated with non-small cell lung cancer (NSCL). C) Glioblastoma, inflammatory myofibroblastic tumor (IMT), cholangiocarcinoma, ovarian cancer, gastric cancer, rectal cancer It is detected in intestinal cancer, angiosarcoma, and melanoma with Spitz nevus. Oncogenic ROS1 gene fusion This is the kinase domain (3' region) of ROS1 fused to the 5' region of various partner genes. This includes the region. An example of a ROS1 fusion partner gene observed in NSCLC is SL C34A2, CD74, TPM3, SDC4, EZR, LRIG3, KDELR2, CE P72, CLTL, CTNND2, GOPC, GPRC6A, LIMA1, LRIG3, MSN, MYO5C, OPRM1, SLC6A17 (estimated), SLMAP, SRSF6, Examples include TFG, TMEM106B, TPD52L1, ZCCHC8, and CCDC6. Other fusion partners include CAPRIN1, CEP85L, CHCHD3, and CLI. P1 (estimated), EEF1G, KIF21A (estimated), KLC1, SART3, ST13( (Estimated), TRIM24 (Estimated), ERC1, FIP1L1, HLAA, KIAA1598 , MYO5A, PPFIBP1, PWWP2A, FN1, YWHAE, CCDC30, N Examples include COR2, NFKB2, APOB, PLG, RBP4, and GOLGB1.

[0004] ALK is an RTK proto-oncogene, and ALK rearrangement is associated with NSCLC and anaplastic large cells. Lymphoma (ALCL), IMT, diffuse large B-cell lymphoma (DLBCL), esophagus Squamous cell carcinoma (ESCC), renal medullary carcinoma, renal cell carcinoma, breast cancer, colon cancer, serous ovarian cancer, thyroid breast cancer ALK-activating sudden mutations are detected in brain cancer, Spitz nevus-like tumors, and neuroblastoma. It is detected in many cancers, including heterozygous cancers. Oncogenic ALK gene fusions are found in more than 20 different types. It contains the kinase domain (3' region) of ALK fused to the 5' region of the partner gene, The most common are EML4 in NSCLC and NPM in ALCL. Other partner genes include TMP1, WDCP, GTF2IRD1, TPM3, and T PM4, CLTC, LMNA, PRKAR1A, RANBP2, TFG, FN1, KLC 1, VCL, STRN, HIP1, DCTN1, SQSTM1, TPR, CRIM1, P Examples include TPN3, FBXO36, ATIC, and KIF5B.

[0005] NTRK1, NTRK2, and NTRK3 are R-type kinases that encode TRK family kinases. TK proto-oncogenes, and chromosomal rearrangements of NTRK1, NTRK2, and NTRK3 are multifaceted. It is detected infrequently in this type of cancer. However, in patients who are ROS1-positive or ALK-positive... In treatment, inhibition of TRK, particularly in the central nervous system (CNS), can lead to dizziness / ataxia / gait disorders. It is associated with adverse reactions including dysphagia, paresthesia, weight gain, and cognitive changes.

[0006] Conventional drugs used to treat oncogenic ROS1 and ALK are essentially It has certain defects. These defects include associated TRK inhibition, limited CNS activity, and resistance. This can mean one or more insufficient activity against sex mutations. R with TRK inhibition. Treatment of OS1-positive or ALK-positive patients is particularly important in the CNS, especially for dizziness / ataxia / gait. It is associated with adverse reactions including dysphagia, paresthesia, weight gain, and cognitive changes. Furthermore, in the wild ROS1 kinase domain and G2032R, D2033N, S1986F, S198 6Y, L2026M, L1951R, E1935G, L1947R, G1971E, E1 974K, L1982F, F2004C, F2004V, E2020K, C2060G, F2075V, V2089M, V2098I, G2101A, D2113N, D2113 Individually or in combination, including G, L2155S, L2032K, and L2086F CNS permeabilizing agent and TRK sparing inhibitor for ROS1 with acquired resistance mutations. Similarly, CNS penetrants and TRK speciosum of ALK with acquired resistance mutations are necessary. ALK inhibitors are needed. Various ALK drug resistances arise individually or in combination. Natural mutations have been reported, including G1202R, L1196M, G1269A, C1156Y, I1171T, I1171N, I1171S, F1174L, V1180L, S1206 Y, E1210K, 1151Tins, F1174C, G1202del, D1203N , S1206Y, S1206C, L1152R, L1196Q, L1198P, L119 This includes 8F, R1275Q, L1152P, C1156T, and F1245V. [Overview of the project]

[0007] Embodiments disclosed herein are compounds of formula (I) or pharmaceutically acceptable salts thereof. : [ka] During the ceremony, Q is either CH or N, Z is either CR5 or N. X is a 5-membered molecule containing 1 to 3 heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. It is a heteroarylene, and the 5-membered heteroarylene is arranged with 0, 1, or 2 R2s. It was replaced, Y is 1, 2 * - Substitute imidazoline, 4 * ,5-substituted imidazoylene, 4 * ,5-substitution 1,2,3-Oxadiazoylene, 3 * ,4-substituted 1,2,5-oxadiazoylene, 3 * , 4-substituted 1,2-oxazolylene, 4 * , 5-substituted 1,3-oxazolylene, 2 * , 3-substituted pyrazinylene, 1 * , 5-substituted pyrazolylene, 3 * , 4-substituted pyrazolylene, 3 * , 4-substituted pyridazinylene, 2 * , 3-substituted pyridinylene, 4 * , 5-substituted pyrimidinyl ene, 2 * , 3-substituted pyrrolylene, 5 * , 6-substituted 1,2,3,4-tetrazinylene, 1 * , 5-substituted 1,2,3,4-tetrazolylene, 1,5 * -substituted 1,2,3,4-tetra zolylene, 4 * , 5-substituted 1,2,3-thiadiazolylene, 3 * , 4-substituted 1,2,5- thiadiazolylene, 3 * , 4-substituted 1,2-thiazolylene, 4 * , 5-substituted 1,3-thia zolylene, 4 * , 5-substituted 1,2,3-triazinylene, 5 * , 6-substituted 1,2,4-tri azinylene, 5,6 * -substituted 1,2,4-triazinylene, 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-triazolylene, and 3 * , 4-sub stituted 1,2,4-triazolylene selected from the group consisting of, and the he teroarylene is substituted with 0, 1, or 2 R3s, *This indicates the bonding point of X or Y to the methylene group bonded to X and Y, In Y, the bond to the methylene group is alpha, and the bond to the aromatic ring containing Z is alpha. The ring atom of the heteroarylene, which is beta relative to the point, is nitrogen. R1 is selected from the group consisting of H, methyl, and hydroxymethyl. Each R2 independently controls H, Halo, CN, and C. 1-4 Alkoxy, C 1-4 Alkyl, halo C 1-4 Alkyl, C 3-4 Cycloalkylmethyl, C 3-6 Cycloalkyl and C3 -6 Selected from the group consisting of heterocycloalkyls, R3 stands for H, Halo, CN, C 1-4 Alkoxy, Halo-C 1-4 Alkyl and C 1-4 Selected from the group consisting of alkyl groups, Each of R4 and R5 is independently either H or F.

[0008] In certain embodiments, this disclosure is suitable for use in the treatment or prevention of cancer in a subject. The present invention provides a pharmaceutical composition comprising an effective amount of any of the compounds described herein. (For example, the compounds of the present disclosure, for example, the compounds of formula (I), or their pharmaceutically acceptable The salt comprises one or more pharmaceutically acceptable excipients. In certain embodiments, the pharmaceutically acceptable excipients are used. The product may be used for the treatment or prevention of the conditions or diseases described herein. ru.

[0009] Aspects of this disclosure are characterized by one or more mutations in the ROS1 or ALK gene. This is a method for treating cancer, and for a person in need of it, an effective amount disclosed herein Compounds (for example, any of the compounds of formula (I) disclosed herein or any of its embodiments) This includes administering a compound, in a particular embodiment, which is an inhibitor of ROS1. In other embodiments, the compound is an inhibitor of ALK, and in further embodiments, the compound The compound is an inhibitor of ROS1 and ALK. In certain embodiments, it is used to treat human subjects. They need medical treatment.

[0010] These cancers include non-small cell lung cancer, inflammatory myofibroblastic tumor, ovarian cancer, and Spitz cancer. Melanoma malformation, 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, thyroid cancer This includes, but is not limited to, adenopapillary carcinoma and neuroblastoma.

[0011] In some embodiments, the method for treating or preventing cancer comprises one or more compounds of formula (I). This may include administration in combination with other chemotherapeutic agents(s) listed above. [Modes for carrying out the invention]

[0012] definition Unless otherwise defined, all technical and scientific terms used herein are defined in this publication. The terms used in this disclosure have meanings that are generally understood by those skilled in the art. The following references are used in this disclosure. A general definition of many terms used by those skilled in the art is provided: Singleton et al. ,Dictionary of Microbiology and Molecule r Biology(2nd ed.1994), The Cambridge Dick tionary of Science and Technology(Walker ed., 1988), The Glossary of Genetics, 5th Ed.,R.Rieger et al.(eds.),Springer Verla g (1991), and Hale & Marham, The Harper Colli. ns Dictionary of Biology (1991). Used in this specification. Unless otherwise specified, the following terms have the meanings of the following:

[0013] In some embodiments, the chemical structure is disclosed along with the corresponding chemical name. In such cases, the chemical structure, not the chemical name, governs the meaning.

[0014] In this disclosure, "comprises" and "comprising" "Containing," "possessing," etc., are used in U.S. patent law. It can have the meaning of being attributed to, and includes, and includes (in It can mean "cluding" or "essentially consisting of "essentially of" or "essentially of" Similarly, "tially)" has the same meaning under U.S. Patent Law, and the term is open-ended. And the basic or novel characteristics of the enumerated items are revealed by entities other than those enumerated. Unless substantially altered, the existence of entities other than those enumerated is permitted, but prior art embodiments Exclude it.

[0015] Unless otherwise stated or made clear from the context, the term "ma" as used herein refers to the term "ma" as used herein. "Taha" is understood to be comprehensive. It is not something that is specifically stated or is not clear from the context. To the extent that it is used herein, the terms "a," "an," and "the" are singular or It is understood that this is plural.

[0016] The term "acyl" is recognized in the relevant art, and its general formula is hydrocarbyl C( This refers to a group represented by (O)-, preferably alkyl C(O)-.

[0017] The term "acylamino" is recognized in the art and refers to a group substituted with an acyl group. This refers to an amino group, which can be represented, for example, by the formula hydrocarbyl C(O)NH-.

[0018] The term "acyloxy" is recognized in the art, and its general formula is hydrocarby This refers to a group represented by C(O)O-, preferably alkyl C(O)O-.

[0019] The term "alkoxy" refers to an alkyl group to which oxygen is bonded, preferably a lower alkyl group. This refers to the hydroxyl group. Typical alkoxy groups include methoxy, ethoxy, propoxy, and te. Examples include rt-butoxy.

[0020] The term "alkoxyalkyl" refers to an alkyl group substituted with an alkoxy group. It can be represented by the general formula alkyl-O-alkyl.

[0021] As used herein, the term “alkenyl” contains at least one double bond. This refers to an aliphatic group and includes both "unsubstituted alkenyls" and "substituted alkenyls." As shown in the figure, the latter is an alkenyl group having substituents on one or more carbon atoms instead of hydrogen. This refers to the Kenyl moiety. Such substituents may be contained within or not contained within one or more double bonds. It can be present on one or more carbon atoms. Furthermore, such substituents are not present unless stability is suppressed. This includes all those intended for alkyl groups, as shown below. For example, one or more By alkyl, carbocyrill, aryl, heterocyclyl, or heteroaryl groups Substitution of the alkenyl group is intended.

[0022] The "alkyl" group or "alkane" is a completely saturated linear or branched non-aromatic carbonized water. It is a basic element. Typically, linear or branched alkyl groups consist of 1 to approximately 20 elements unless otherwise defined. It has carbon atoms, preferably 1 to about 10. Examples of linear and branched alkyl groups are: Methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, ter Examples include t-butyl, pentyl, hexyl, pentyl, and octyl. C1-C6 linear chains. Alternatively, branched alkyl groups are also called "lower alkyl" groups.

[0023] Furthermore, the term "alkyl" used throughout this specification, examples, and claims is also used. The term "lower alkyl" (or "unsubstituted alkyl") refers to both "unsubstituted alkyl" and "substituted alkyl". The latter is intended to include substitutions where hydrogen is replaced on one or more carbon atoms in the hydrocarbon skeleton. This refers to the alkyl moiety having a group. Unless otherwise specified, such substituents are, for example, halo Gen, hydroxyl, carbonyl (carboxyl, alkoxycarbonyl, formyl, ma (or acyl, etc.), thiocarbonyl (thioester, thioacetate, or thioform) (e.g., alkoxy, phosphoryl, phosphate, phosphonate, phosphine, etc.) Mino, amide, amidine, imine, cyano, nitro, azide, sulfhydryl, alkyl Thio, sulfate, sulfonate, sulfamoyl, sulfonamide, sulfonyl, he It may contain telocyclyl, aralkyl, or aromatic or heteroaromatic moieties. It is understood that a substituted portion on a hydrocarbon chain can, if appropriate, be substituted itself. For example, substituents on substituted alkyls include substituted and unsubstituted amino, azide, and i Mino, amide, phosphoryl (including phosphonate and phosphinate), sulfonyl (s (including rufete, sulfonamide, sulfamoyl, and sulfonate), and silyl Groups, as well as ethers, alkylthios, carbonyl (ketones, aldehydes, carboxylates) Examples of substituted alkyl groups include (including esters), -CF3, -CN, etc. The following applies: Cycloalkyls include alkyl, alkenyl, alkoxy, and alkylthio compounds. They can be further substituted with aminoalkyl, carbonyl-substituted alkyl, -CF3, -CN, etc. .

[0024] "C x-y The term "acyl" refers to acyloxy, alkyl, alkenyl, and alkini. When used in combination with chemical parts such as alkoxy, the chain contains x to y carbon atoms. It means that it contains a group. For example, "C x-y The term "alkyl" refers to a chain containing x~y Substituted or unsubstituted saturated carbonated water containing linear and branched alkyl groups with 1 carbon atom This refers to an elementary group, such as trifluoromethyl and 2,2,2-trifluoroethyl haloalkyl groups. Contains a group. C0 alkyl indicates hydrogen when the group is at the terminal position, and when it is in the interior. It shows a bond. 2-y "Alkenil" and "C 2-y The term "alkynyl" is as described above. Lukil and its length and possible substitutions are similar, but each has at least one double knot. This refers to substituted or unsubstituted unsaturated aliphatic groups that contain a compound or triple bond.

[0025] As used herein, the term “alkylamino” means at least one alkyl group This refers to an amino group that has been substituted with another amino group.

[0026] As used herein, the term "alkylthio" refers to thio substituted with an alkyl group. It refers to an alkyl group and can be represented by the general formula alkyl S-.

[0027] As used herein, the term "alkynyl" contains at least one triple bond. This refers to an aliphatic group and includes both "unsubstituted alkynyls" and "substituted alkynyls." As shown in the diagram, the latter is an alkyl group having substituents on one or more carbon atoms of the alkynyl group instead of hydrogen. This refers to the yl portion. Such substituents may or may not be included in one or more triple bonds. It can be present on one or more carbon atoms. Furthermore, such substituents are present unless their stability is suppressed. This includes all those intended for the alkyl groups mentioned above. For example, one or more alkyl groups Alkyl, carbocykryl, aryl, heterocyclyl, or heteroaryl group Substitution of the quinyl group is intended.

[0028] As used herein, the term "amide" is based [ka] This refers to each R 30 This independently represents a hydrogen atom or a hydrocarbyl group, or is two R 30 However, together with the N atoms to which they are bonded, they form a ring structure with 4 to 8 atoms. Complete a heterocycle with offspring.

[0029] The terms "amine" and "amino" are recognized in the art, and are unsubstituted and Both substituted amines, as well as their salts, for example, [ka] This refers to the part that can be represented by, where each R 31 These are independently hydrogen or hydrocarbons. Represents a Rubyl group, or two R's 31 However, together with the N atom to which they are bonded , completing a heterocycle having 4 to 8 atoms in the ring structure. The term used herein, "A The term "minoalkyl" refers to an alkyl group substituted with an amino group.

[0030] As used herein, the term "aralkyl" refers to an alkyl group substituted with an aryl group. This refers to the lu group.

[0031] As used herein, the term "aryl" refers to a substituted or unsubstituted monocyclic aromatic group. It contains, and each atom of the ring is carbon. Preferably, the ring is a 5- to 7-membered ring, more preferably It is a six-membered ring. The term "aryl" means that two or more carbon atoms are common to two adjacent rings. This also includes polycyclic ring systems having two or more cyclic rings, and at least one of those rings One is aromatic, for example, other cyclic rings are cycloalkyl, cycloalkenyl, They may be cycloalkynyl, aryl, heteroaryl, and / or heterocyclyl compounds. The aryl group includes benzene, naphthalene, phenanthrene, phenol, aniline, etc. nothing.

[0032] The term "carbamate" is recognized in the relevant technical field, and is based on [Chemical formula] refers to, where each R 32 and R 33 are independently hydrogen or a hydrocarbyl group, e.g., represents an alkyl group, or R 32 and R 33 together with an intervening atom(s) complete a heterocycle having 4 to 8 atoms in the ring structure.

[0033] As used herein, the terms "carbocyclic" and "carbocyclic ring" refer to a saturated or unsaturated ring in which each atom of the ring is carbon. The term carbocyclic ring includes both aromatic carbocyclic rings and non-aromatic carbocyclic rings. Non-aromatic carbocyclic rings include both cycloalkane rings in which all carbon atoms are saturated and cycloalkene rings containing at least one double bond.

[0034] The term "carbocyclic ring" includes monocyclic rings of 5 to 7 members and bicyclic rings of 8 to 12 members. Each ring of a bicyclic carbocyclic ring can be selected from a saturated ring, an unsaturated ring, and an aromatic ring. Carbocyclic rings include bicyclic molecules in which one, two, or three or more atoms are shared between the two rings. The term "fused carbocyclic ring" refers to a bicyclic carbocyclic ring in which each ring shares two adjacent atoms with the other ring. Each ring of a fused carbocyclic ring can be selected from a saturated ring, an unsaturated ring, and an aromatic ring. 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 is included in the definition of carbocyclic, to the extent permitted by valence. Exemplary "carbocyclic rings" include cyclopentane, cyclohexane, bi Cyclo[2.2.1]heptane, 1,5-cyclooctadiene, 1,2,3,4-tetra Hydronaphthalene, bicyclo[4.2.0]octa-3-ene, naphthalene and adamant Examples include tan. Exemplary condensed carbocyclic compounds include decalin, naphthalene, 1,2,3, 4-tetrahydronaphthalene, bicyclo[4.2.0]octane, 4,5,6,7-tetra Examples include lahydro-1H-indene and bicyclo[4.1.0]hepta-3ene. The "carbon ring" can be substituted at any one or more positions where a hydrogen atom may be present.

[0035] The "cycloalkyl" group is a completely saturated cyclic hydrocarbon. This includes monocyclic and bicyclic rings. Typically, monocyclic cycloalkyl groups are defined separately. Unless otherwise specified, it has 3 to about 10 carbon atoms, more typically 3 to 8 carbon atoms. Biring The second ring of the cycloalkyl formula can be selected from saturated, unsaturated, and aromatic rings. Alkyl groups have one, two, three, or more atoms shared between two rings. This includes bicyclic molecules. The term "condensed cycloalkyl" refers to a molecule in which each ring is fused with the other ring. This refers to a bicyclic cycloalkyl group that shares two adjacent atoms. The second ring can be selected from saturated, unsaturated, and aromatic rings. ("cycloalkenyl" group) It is a cyclic hydrocarbon containing one or more double bonds.

[0036] As used herein, the term "carbocykrylalkyl" refers to a group substituted with a carbon ring group. It refers to a defined alkyl group.

[0037] The term "C" used herein 3-4 The term "cycloalkylmethyl" refers to 3-4 Refers to a methyl group substituted with a carbocyclic group containing carbon atoms.

[0038] The term "carbonate" is recognized in the art and refers to the group -OCO2-R 3 4 where R 34 represents a hydrocarbyl group.

[0039] As used herein, the term "carboxy" refers to the group represented by the formula -CO2H

[0040] As used herein, the term "ester" refers to the group -C(O)OR 35 where R 35 represents a hydrocarbyl group.

[0041] As used herein, the term "ether" refers to a hydrocarbyl group bonded to another hydrocarbyl group through oxygen. Thus, an ether substituent of a hydrocarbyl group can be hydrocarbyl-O-. The ether may be symmetric or asymmetric. Examples of ethers include, but are not limited to, heterocycle-O-heterocycle and aryl-O-heterocycle. Ethers include the "alkoxyalkyl" group, which can be represented by the general formula alkyl -O-alkyl.

[0042] As used herein, the terms "halo" and "halogen" mean halogen and include chloro, fluoro, bromo, and iodo.

[0043] As used herein, the terms "heteroalkyl" and "heteroarylalkyl" refer to an alkyl group substituted with a heteroaryl group.

[0044] ​As used herein, the term "heteroalkyl" refers to a carbon atom and at least one This refers to a saturated or unsaturated chain of two heteroatoms, where no two heteroatoms are adjacent. stomach.

[0045] The terms "heteroaryl" and "hetaryl" refer to substituted or unsubstituted aromatic monocyclic rings. The structure preferably includes 5-7 membered rings, more preferably 5-6 membered rings, and the ring structure is at least one heteroatom, preferably 1 to 4 heteroatoms, more preferably , containing one or two heteroatoms. The terms "heteroaryl" and "hetalil" are used. The word refers to a polymorphism having two or more cyclic rings, where two or more carbon atoms are common to two adjacent rings. This includes cyclic ring systems, where at least one of the rings is heteroaromatic, for example, Other cyclic rings include cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, and he. It may be a teloaryl and / or heterocyclyl. The heteroaryl group is, for example, Pyrrole, furan, thiophene, imidazole, oxazole, thiazole, pyrazole This includes pyridine, pyrazine, pyridazine, and pyrimidine, among others.

[0046] The asterisks in the heteroarylene ring moiety corresponding to X or Y in the compound of formula (I) * The notation, as exemplified below, refers to the ring atom of the part bonded to the methylene group between X and Y. Identify: [ka] For example, regarding Y, "1 * ,5-substituted imidazolylen" was substituted: [ka] It means...

[0047] As described above, the IUPAC numbering rules for heteroarylene rings specify the positions of the ring atoms. Used throughout this specification for the purpose of [unclear]. In this example, the 1-position of imidazoylene is methylene Because it is bonded to the base, it is indicated by an asterisk. This asterisk notation is X And it is used for both the name and structure of the heteroarylene of Y. Here, 5 for Y The ring atom at position R4 is bonded to a phenyl group that has a variable element R4, therefore it is marked. It hasn't been done.

[0048] An example ring with respect to X is shown below: "1,5 * - This is a substitution imidazoline. [ka] The ring atom bonded to the methylene group (position 5 in this example) is the name of the heteroarylene of ring X. Both the structure and the ring atom bonded to the aromatic ring containing Q are marked with an asterisk. It wasn't kicked.

[0049] As used herein, the term “heteroatom” refers to any element other than carbon or hydrogen. It refers to the basic atom. Preferred heteroatoms are nitrogen, oxygen, and sulfur.

[0050] The terms "heterocyclyl," "heterocycle," and "heterocyclic formula" are substituted or non-substituted. Substituting non-aromatic ring structure, preferably a 3- to 10-membered ring, more preferably a 3- to 7-membered ring, and so These ring structures consist of at least one heteroatom, preferably 1 to 4 heteroatoms. Preferably, it contains one or two heteroatoms. "Heterocyclyl" and "heterocyclic" The term "formula" refers to a ring formula in which two or more carbon atoms are common to two adjacent rings. This includes polycyclic ring systems that have rings, and at least one of those rings is heterocyclic. For example, other cyclic rings include cycloalkyl, cycloalkenyl, cycloalkynyl, and It may be a reel, heteroaryl, and / or heterocyclyl. The heterocyclyl group and For example, piperidine, piperazine, pyrrolidine, morpholine, lactone, lacta Examples include M, etc.

[0051] As used herein, the term "heterocyclylalkyl" means a group substituted with a heterocyclic group. This refers to the alkyl group that has been modified.

[0052] As used herein, the term "hydrocarbyl" refers to both =O substituents and =S substituents. Bonded via carbon atoms that do not have carbon atoms, usually at least one carbon-hydrogen bond and mainly carbon This refers to a group that has a basic skeleton but may optionally have heteroatoms. Therefore, methyl, ethoxy Groups such as thiol, 2-pyridyl, and trifluoromethyl are used for the purposes of this application. It is considered to be calvil, but acetyl (having an =O substituent on the linked carbon atom) and Substituents such as ethoxy (linked via oxygen rather than carbon) are hydrocarbyl. These are not considered. Hydrocarbyl groups include aryl, heteroaryl, carbocyclic, and hetero. Examples include rosicyl, alkyl, alkenyl, alkynyl, and combinations thereof. However, these are not the only ones.

[0053] As used herein, the term "hydroxyalkyl" refers to a group substituted with a hydroxyl group. It refers to a defined alkyl group.

[0054] Chemical parts, for example, acyl, acyloxy, alkyl, alkenyl, alkynyl, and When used in conjunction with alkoxys, the term "lower" refers to the case where the substituent contains 10 or fewer atoms. This preferably means including a group containing six or fewer non-hydrogen atoms. " refers to an alkyl group containing, for example, 10 or fewer carbon atoms, preferably 6 or fewer. In certain embodiments, acyl, acyloxy, alkyl, alke as defined herein Nyl, alkynyl, or alkoxy substituents may appear alone or in combination with other substituents. In combination with conversion groups, for example, in the enumeration of hydroxyalkyl and aralkyl groups (this In some cases, for example, atoms within an aryl group are counted when counting carbon atoms in an alkyl substituent. (Not activated) Regardless of whether they appear or not, they are respectively lower acyl, lower acyloxy, and lower alkyl It is a chlor, lower alkenyl, lower alkynyl, or lower alkoxy.

[0055] The terms "polycyclyl," "polycyclic," and "polycyclic formula" refer to a combination of two or more atoms. A common feature of adjacent rings, for example, two or more rings in which the ring is a "fused ring" (e.g., cycloa Lukyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, and / or (referring to a heterocyclyl). Each ring of the polycyclic ring may be substituted or unsubstituted. In certain embodiments, each ring of the polycyclic ring contains 3 to 10 atoms, preferably It may contain 5 to 7 pieces.

[0056] The term "silyl" refers to the silicon portion formed by the bonding of three hydrocarbyl moieties.

[0057] The term "substituted" means having substituents that replace hydrogens on one or more carbon atoms in the skeleton. It refers to a part. "Substitution" or "to be substituted with ~" means that such a substitution is performed on the substituted atom and And according to the permissible valency of the substituent, the substitution is stable, for example, spontaneously. This implicitly includes the condition that the resulting compound is stable and does not undergo transformations such as rearrangement, cyclization, or elimination. This will be understood. As used herein, the term “substituted” refers to an organic compound. It is intended to include all permissible substituents. In a broader embodiment, such permissible substitutions The basis includes acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic organic compounds. Aromatic and non-aromatic substituents are examples. The permissible substituents are suitable for the organic compound. There may be one or more, and they may be the same or different. For the purposes of this disclosure, nitrogen and other hete The atom is a hydrogen substituent that satisfies the valence of the heteroatom and / or a hydrogen substituent as described herein. The compound may have any acceptable substituents. The substituents are any substitutions as described herein. Groups, for example, halogens, hydroxyls, carbonyls (carboxyls, alkoxycarbonyls) (L, formyl, or acyl, etc.), thiocarbonyl (thioester, thioacetate, etc.) (or thioformates, etc.), alkoxy, phosphoryl, phosphate, phosphonate, phosphat Sphenate, amino, amide, amidine, imine, cyano, nitro, azide, sulfur Drill, alkylthio, sulfate, sulfonate, sulfamoyl, sulfonamide , sulfonyl, heterocyclyl, aralkyl, or aromatic or heteroaromatic portion It may include. Those skilled in the art will understand that substituents can be substituted themselves where appropriate. Unless otherwise specified, "non-substituted" refers to any chemical part in this specification. It is understood that this includes variants that have been modified. For example, for the "aryl" group or part. The reference implicitly includes both substituted and non-substituted variants.

[0058] The term "sulfate" is recognized in the relevant technical field, and the base -OSO3H, This refers to a medicinally acceptable salt.

[0059] The term "sulfonamide" is recognized in the art and has a general formula [ka] This refers to the group represented by, and in the formula, each R 36 and R 37 These are, independently, hydrogen or hydr Locarbil, for example, represents an alkyl group or R 36 and R 37 However, intervening atoms (multiple atoms possible) Together with these atoms, they complete a heterocycle having 4 to 8 atoms in the ring structure.

[0060] The term "sulfoxide" is recognized in the relevant technical field and includes the group -S(O)-R 3 8 It refers to R 38 This represents hydrocarbyl.

[0061] The term "sulfonate" is recognized in the art and refers to the base SO3H, or This refers to a medicinally acceptable salt.

[0062] The term "sulfone" is recognized in the art and includes the group -S(O)2-R 39 It refers to R 39 This represents hydrocarbyl.

[0063] As used herein, the term "thioalkyl" refers to an alkyl group substituted with a thiol group. It refers to the kill group.

[0064] As used herein, the term "thioester" refers to the group -C(O)SR 40 or -SC(O)R 40 It refers to R 10 This represents hydrocarbyl.

[0065] As used herein, the term "thioether" refers to a type in which oxygen is replaced by sulfur. It corresponds to ether.

[0066] The term "urea" is recognized in the relevant technical field, and the general formula [ka] It may be expressed as follows, in the formula, each R 41 and R 42 These are, independently, hydrogen or hi Drocarbil, for example, represents an alkyl group or R 41 One of the following is R 42 and intervention It combines with atoms (or multiple atoms) to form a heterocycle with 4 to 8 atoms in the ring structure. .

[0067] The term "protecting group" refers to a group that, when attached to a reactive functional group in a molecule, enhances the reactivity of that functional group. It refers to a group of atoms that is masked, reduced, or blocked. Typically, protecting groups are used in the synthesis process as desired. It can be selectively removed. An example of a protecting group is Greene and Wuts, Prote ctive 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 & It can be found at Sons, NY. Typical nitrogen protecting groups include formyl and acetyl. Lu, trifluoroacetyl, benzyl, benzyloxycarbonyl ("CBZ"), te rt-butoxycarbonyl ("Boc"), trimethylsilyl ("TMS"), 2-tri Methylsilyl-ethanesulfonyl ("TES"), trityl and substituted trityl groups, allyl Oxycarbonyl, 9-Fluorenylmethyloxycarbonyl ("FMOC"), Nitro Examples include, but are not limited to, veratryloxycarbonyl ("NVOC"), etc. Typical hydroxyl protecting groups include those that cause hydroxyl group acylation (esterification). These are alkylated substances, such as benzyl and trityl ethers, as well as alkylates. ethers, tetrahydropyranyl ethers, trialkylsilyl ethers (e.g., TMS) (or TIPS group), glycol ethers, for example, ethylene glycol and propylene Examples include, but are not limited to, glycol derivatives and allyl ethers.

[0068] In certain embodiments, the compounds of the present disclosure may be racemic compounds. In application, the compounds of the present disclosure can be concentrated into a single enantiomer. For example, the present disclosure The compounds contain approximately 30% or more ee, approximately 40% ee, approximately 50% ee, approximately 60% ee, and approximately 70% ee, approximately 80% ee, approximately 90% ee, or even approximately 95% ee It may have an ee that exceeds that. In certain embodiments, the compounds of the present disclosure have multiple standing It may have a body center. In certain such embodiments, the compounds of the present disclosure are one or more dia. It can be concentrated into stereomeric compounds. For example, the compounds of this disclosure are concentrated into about 30% or more of de, and about 40% about 50% of de, about 60% of de, about 70% of de, about 80% of de, about 90% It may have a de of, or even approximately 95% or more de.

[0069] In a particular embodiment, the pharmaceutical is mainly one of the compounds (e.g., of formula (I)) It can be concentrated to provide a nantiomer. A mixture in which the enantiomer is concentrated is, for example, For example, at least about 60 mole percent of one enantiomer, more preferably less It may contain at least 75, 90, 95, or even 99 mole percent. In certain embodiments, a compound concentrated into one enantiomer is concentrated into the other enantiomer It substantially does not contain the substance in question. Here, substantially does not contain means that the substance in question is, for example, not included in the composition. In a mixture of substances or compounds, less than 10% compared to the amount of other enantiomers. , or less than approximately 5%, or less than approximately 4%, or less than approximately 3%, or less than approximately 2%, or This means that it accounts for less than approximately 1%. For example, if a composition or mixture of compounds accounts for approximately 98% If the rum contains the primary enantiomer and about 2 grams of the secondary enantiomer, then about 98 It contains a mole percent of the first enantiomer and only about 2% of the second enantiomer. It is said that...

[0070] In a particular embodiment, the pharmaceutical is mainly one of the compounds (e.g., of formula (I)) The mixture of diastereomers can be concentrated to provide astereomers. For example, at least about 60 mole percent of one diastereomer, more preferably , may contain at least about 75, about 90, about 95, or even about 99 mole percent .

[0071] In some embodiments, the compound portion exists as a mixture of tautomers. A "mutant" is a part of a compound or a structural isomer that readily interconverts with another structural isomer. For example, the pyrazole ring has two tautomers: [ka] These differ in the position of the π bond and the hydrogen atom. Unless otherwise specified, they are partials or compounds. The diagram of one tautomer encompasses all possible tautomers.

[0072] The term "target" in which the administration is intended includes humans (i.e., males of any age group or This includes women, for example, children (e.g., infants, children, adolescents) or adults (e.g., young adults) Adults, middle-aged adults, or elderly adults) and / or other primates (e.g., crab-eating macaques) Mammals including rhesus macaques, commercially important mammals such as cattle, pigs, horses, and sheep. Goats, cats, and / or dogs, and / or birds, including commercially important birds, for example. Examples include chickens, ducks, geese, quail, and / or turkeys. However, it is not limited to these. A preferred subject is humans.

[0073] As used herein, a medicine that "prevents" a disorder or condition is defined in a statistical sample. Compared to the untreated control sample, the treated sample showed the impairment or condition. To reduce the occurrence of the condition, or compared to an untreated control sample, the occurrence of the disorder or condition. This refers to a compound that delays the onset of one or more symptoms or reduces their severity. These effects are also called "preventive" effects. Therefore, when used herein, unless otherwise specified. Unless otherwise specified, the terms “prevention” and “prevention” include, but are not limited to, preventive effects. This refers to an approach to obtain beneficial or desirable results that are not achieved otherwise. Specifically, for preventative effects. For patients at risk of developing a specific disease, or who report one or more physiological symptoms of the disease... Even in cases where a diagnosis of this disease may not have been made for a patient, In some cases, this may be done to prevent an undesirable condition (for example) If the medication is administered prior to the clinical symptoms of the disease or other undesirable condition for the subject, (For example, it protects the subject from developing an undesirable condition.)

[0074] As used herein, unless otherwise specified, “treatment” or “to treat” means The term refers to therapeutic or palliative measures. Beneficial or desirable clinical outcomes include Whether detectable or undetectable, associated with a disease, disorder, or condition Overall or partial relief of symptoms, reduction of disease severity, and stabilization (i.e., no worsening) (i) Delay or slowing of the disease, or improvement of the disease (e.g., one or more symptoms of the disease) This includes, but is not limited to, mitigation and remission (whether partial or complete). No. "Treatment" also means that survival is longer compared to the expected survival time if no treatment is received. It may also mean extending the period. In one embodiment, “treatment” is an undesirable condition This includes administering medication after the onset of (i.e., an existing undesirable condition or its side effect) (Intended to reduce, improve, or stabilize).

[0075] The term "prodrug" refers to a drug that has a therapeutic effect under physiological conditions (e.g., For example, it is intended to include compounds that are converted to the compound of formula (I). A common method for preparing a molecule involves hydrolysis under physiological conditions to reveal the desired molecule. The inclusion of one or more selected portions. In other embodiments, the prodrug is It is converted by the enzyme activity of the target substance. For example, esters or carbonates (e.g., Alcohols or carboxylic acid esters or carbonates are preferred products of this disclosure. It is a drug. In a particular embodiment, in the formulation shown above, the compound of formula (I) Some or all of the substance can be replaced with the corresponding appropriate prodrug, for example. The hydroxyl group of the parent compound is presented as an ester, carbonate, or carboxylic acid. It will be done.

[0076] As used herein, "effective dose" refers to an amount sufficient to achieve the desired biological effect. Refers to. As used herein, “therapeutic effective dose” means a dose sufficient to achieve the desired biological effect. This refers to a certain amount. For example, a therapeutically effective dose is the amount required to improve at least one sign or symptom of cancer. It can refer to a sufficient amount.

[0077] In terms of "responses" to treatment methods, in particular, there is a reduction or improvement in negative symptoms, and the disease itself This may result in a reduction in the progression of the symptoms, an increase in beneficial symptoms or improved clinical outcomes, a reduction in side effects, and a decrease in the disease. This can include stabilization of the condition and partial or complete treatment of the disease.

[0078] As used herein, unless otherwise indicated, the term “recurrence” refers to a previous treatment. This refers to a disorder, disease, or condition that progresses after responding to treatment (e.g., achieving complete remission). The preceding treatment may include primary or secondary treatment.

[0079] As used herein, unless otherwise indicated, the term “refractory” means a primary or secondary treatment. This refers to a disorder, disease, or condition that has not responded to previous treatments, including the treatments listed above.

[0080] compound In one embodiment, the foregoing provides a compound of formula (I), or its enantio Mer, enantiomer mixtures, or tautomers thereof, or pharmaceutically acceptable salts thereof. is: [ka] During the ceremony, Q is either CH or N, Z is either CR5 or N. X is a 5-membered molecule containing 1 to 3 heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. It is a heteroarylene, and the 5-membered heteroarylene is arranged with 0, 1, or 2 R2s. It was replaced, Y contains 5 heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. is a 6-membered heteroarylene, and the 5 or 6-membered heteroarylene is 0, 1, and It is replaced by two R3s, In Y, the bonding sites to the methylene groups bonded to X and Y, and the bonding to the aromatic ring containing Z. The dot is located on an adjacent atom, is alpha relative to the bond site to the methylene group, and contains Z. The ring atoms of the 5-6 member heteroarylene, which are beta relative to the bonding site to the aromatic ring, are nitrogen It is simple, R1 is selected from the group consisting of H, methyl, and hydroxymethyl. Each R2 independently controls H, Halo, CN, and C. 1-4 Alkoxy, C 1-4 Alkyl, halo C 1-4 Alkyl, C 3-4 Cycloalkylmethyl, C 3-6Cycloalkyl, and C3 -6 selected from the group consisting of heterocycloalkyl, each R3 is independently H, halo, CN, C 1-4 alkoxy, halo-C 1-4 alkyl, and C 1-4 alkyl, selected from the group consisting of each of R4 and R5 is independently H or F, but X is not 3 * ,4-substituted pyrazolylene, * is the bond point of X or Y to the methylene group bonded to X and Y. indicates the bond point of X or Y.

[0081] In one aspect, disclosed is a compound of formula (I) or a pharmaceutically acceptable salt thereof as follows:

Chemical formula

[0082] In one embodiment, the disclosure is a compound of formula (I) or a pharmaceutically acceptable salt thereof. be: [ka] During the ceremony, Q is either CH or N, Z is either CR5 or N. X is a 5-membered molecule containing 1 to 3 heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. It is a heteroarylene, and the 5-membered heteroarylene is arranged with 0, 1, or 2 R2s. It was replaced, Y is 1, 2 * - Substitute imidazoline, 4 * ,5-substituted imidazoylene, 4,5 * -replacement Imidazolilen, 4 * ,5-substituted 1,2,3-oxadiazoylene, 3 * ,4-substitution 1, 2,5-Oxadiazoylene, 3 * ,4-substituted 1,2-oxazolylene, 4 * ,5-substitution 1,3-Oxazolylene, 2 * ,3-substituted pyrazinylene, 1 *,5-substituted pyrazolylene, 3 * ,4-substituted pyrazolylene, 3 * ,4-substituted pyridadinylene, 2 * ,3-substituted pyridini Ren, 4 * ,5-substituted pyrimidinylene, 2 * ,3-substituted pyrrolylene, 5 * ,6-substitution 1, 2,3,4-tetrazinylene, 1 * ,5-substituted 1,2,3,4-tetrazoylene, 1,5 * - Substitution of 1,2,3,4-tetrazoylene, 4 * ,5-Substitution 1,2,3-Chiadiazolire Hmm, 3 * ,4-Substitution 1,2,5-Thiasiazoylene, 3 * ,4-Substitution 1,2-thiazolyle Hmm, 4 * ,5-substituted 1,3-thiazoylene, 4 * ,5-substituted 1,2,3-triazinylene , 5 * ,6-Substitution 1,2,4-triazinylene, 5,6 * -Substitution 1,2,4-triazine Ren, 1 * ,5-substituted 1,2,3-triazolylene, 4 * ,5-Substitution 1,2,3-Tria Zolilen, 1 * ,5-substituted 1,2,4-triazolylene, 1,5 * -Substitution 1, 2, 4- Riazoliene, and 3 * Selected from the group consisting of ,4-substituted 1,2,4-triazolylenes This is a heteroarylene, and the heteroarylene is substituted with 0, 1, or 2 R3 atoms. , * This indicates the bonding point of X or Y to the methylene group bonded to X and Y, In Y, the bond to the methylene group is alpha, and the bond to the aromatic ring containing Z is alpha. The ring atom of the heteroarylene, which is beta relative to the point, is nitrogen. R1 is selected from the group consisting of H, methyl, and hydroxymethyl. Each R2 independently controls H, Halo, CN, and C. 1-4 Alkoxy, C 1-4 Alkyl, halo C 1-4 Alkyl, C 3-4 Cycloalkylmethyl, C 3-6 Cycloalkyl and C3 -6 Selected from the group consisting of heterocycloalkyls, Each R3 independently controls H, Halo, CN, and C. 1-4 Alkoxy, Halo-C 1-4 Alkyl, and C 1-4 Selected from the group consisting of alkyl groups, Each of R4 and R5 is independently either H or F.

[0083] In some embodiments, X is pyrazolylene, isoxazolylene, isothiazolylene A 5-member heterozygous selected from the group consisting of , imidazolylen, and triazolilen. It is a len. In some embodiments, X consists of pyrazolylene and triazolylene. A five-membered heteroarylene selected from the group. In a particular embodiment, X is 4 * ,5-substituted pyrazolylene, 4,5 * - Substituted pyrazolylene, 1 * ,5-substituted pyrazolylene, 4 * ,5-substituted isoxazolylene, 3 * ,4-substituted isoxazolylene, 3 * ,4-position Deconstituted isothiazolylene, 4 * ,5-substituted isothiazolylene, 4 * ,5-substituted imidazoline , 1 * ,5-substituted imidazoylene, 1 * ,5-substituted triazolylene, and 4* ,5-substitution It is a five-membered heteroarylene selected from the group consisting of triazolylenes.

[0084] In some embodiments, X is pyrazolylene, isoxazolylene, isothiazolylene A 5-member heterozygous selected from the group consisting of , imidazolylen, and triazolilen. It is a len. In some embodiments, X consists of pyrazolylene and triazolylene. A five-membered heteroarylene selected from the group. In a particular embodiment, X is 4 * ,5-substituted pyrazolylene, 4,5 * - Substituted pyrazolylene, 1 * ,5-substituted pyrazolylene, 4 * ,5-substituted isoxazolylene, 4,5 * -substituted isoxazolylene, 3 * ,4-position Substituted isoxazolylene, 3 * ,4-substituted isothiazolylene, 4 * ,5-substituted isothiazoli Ren, 4, 5 * - Substituted isothiazolylene, 4 * ,5-substituted imidazoylene, 1 * ,5-position Exchange imidazoriren, 1 * ,5-substituted triazolylene, and 4 * ,5-substituted triazolylene It is a 5-member heteroarylene selected from the group consisting of the following.

[0085] In a particular embodiment, X is a five-member heteroalile selected from the group consisting of the following: It is: [ka] In one embodiment, X is pyrazolylene. In one embodiment, X is 3 * , It is not a 4-substituted pyrazolylene. In one embodiment, X is [ka] No. In one embodiment, X is [ka] No. In another embodiment, X is 3 * It is a ,4-substituted pyrazolylene. Another embodiment So, X is 4 * It is a ,5-substituted pyrazolylene. In another embodiment, X is 4,5 * - It is a substituted pyrazolylene. In another embodiment, X is 1 * It is a ,5-substituted pyrazolylene. In one embodiment, X is [ka] In one embodiment, X is [ka] In one embodiment, X is [ka] That is the case.

[0086] In one embodiment, X is isoxazolylene. In one embodiment, X is 4 * It is a ,5-substituted isoxazolylene. In one embodiment, X is 4,5 * -replacement It is isoxazolylene. In one embodiment, X is 3 * ,4-substituted isoxazoli It is Ren. In one embodiment, X is [ka] In one embodiment, X is [ka] That is the case.

[0087] In one embodiment, X is isothiazolylene. In one embodiment, X is 3 * It is a ,4-substituted isothiazolylene. In one embodiment, X is 4 * ,5-substituted iso It is thiazoylene. In one embodiment, X is 4,5 * - Substituting isothiazolylene In one embodiment, X is [ka] In one embodiment, X is [ka] That is the case.

[0088] In one embodiment, X is imidazoylene. In one embodiment, X is 4 * It is a ,5-substituted imidazoylene. In one embodiment, X is 1 * ,5-Substitution Imidaz It is rilen. In one embodiment, X is [ka] That is the case.

[0089] In one embodiment, X is triazolylene. In one embodiment, X is 1 * It is a ,5-substituted triazolylene. In one embodiment, X is 4 * ,5-substituted triazo It is rilen. In one embodiment, X is [ka] In one embodiment, X is [ka] That is the case.

[0090] In one embodiment, X is replaced by 0 R2s (i.e., all vacancies on X). (The position is H). In one embodiment, X is replaced by one R2 that is not H. In this embodiment, X is replaced by two R2s that are not H.

[0091] R2 is independently H, Halo, CN, C 1-4 Alkoxy, C 1-4 Alkyl, halo C 1-4 Alkyl, C 3-4 Cycloalkylmethyl, C 3-6 Cycloalkyl and C3 -6 Selected from the group consisting of heterocycloalkyls. In one embodiment, R2 is H No. In one embodiment, R2 is C 1-4 It is alkyl. In one embodiment, R2 is methyl. In one embodiment, R2 is ethyl. One embodiment Then, R2 is isopropyl. In one embodiment, R2 is cyclopropyl. In one embodiment, R2 is cyclobutyl. In one embodiment, R2 is It is cyclopropylmethyl. In one embodiment, R2 is -CHF2. In one embodiment, R2 is -CH2CHF2. In one embodiment, R2 is a halo Yes. In one embodiment, R2 is fluoro. In one embodiment, R2 is ku It is Rolo. In one embodiment, R2 is CN. In one embodiment, R2 is It is methoxy.

[0092] In a particular embodiment, X is a five-member heteroalile selected from the group consisting of the following: It is: [ka] In some embodiments, Y is 1 * ,5-substituted pyrazolylene, 3 * ,4-substituted pyrazo Lilen, 1, 2 * - Substitute imidazoline, 4 * ,5-substituted imidazoylene, 1 * ,5-position 1,2,3-Triazoylene, 4 * ,5-substituted 1,2,3-triazolylene, 1 * ,5 -Substitution of 1,2,4-triazolylene, 1,5 * -Substitution of 1,2,4-triazolylene, 4 * ,5-substituted 1,3-thiazoylene, 2 * ,3-substituted pyridinylene, 4 * ,5-substituted pyrim Dinylene, and 2 * Heteroarylenes selected from the group consisting of ,3-substituted pyrazinylenes That is the case.

[0093] In some embodiments, Y is 1 * ,5-substituted pyrazolylene, 3 * ,4-substituted pyrazo Lilen, 1, 2 * - Substitute imidazoline, 4 * ,5-substituted imidazoylene, 4,5 * -Place Exchange imidazoriren, 1 * ,5-substituted 1,2,3-triazolylene, 4 * ,5-substitution 1,2 ,3-Triazoylene, 1 * ,5-substituted 1,2,4-triazolylene, 1,5 * -replacement 1 ,2,4-Triazoylene, 4 * ,5-substituted 1,3-thiazoylene, 2* ,3-substituted pyramidal Jiniren, 4 * ,5-substituted pyrimidinylene, and 2 * group consisting of ,3-substituted pyrazinylenes It is a heteroarylene selected from the following.

[0094] In a particular embodiment, Y is a heteroarylene selected from the group consisting of the following: the law of nature: [ka] * This indicates the bonding point of Y to the methylene group bonded to X and Y. R3 stands for H, Halo, CN, C 1-4 Alkoxy, Halo-C 1-4 Alkyl and C 1-4 Selected from the group consisting of alkyl groups.

[0095] In one embodiment, Y is a 5-membered heteroarylene. is pyrazolylene. In one embodiment, Y is 1,5 * - Substituting pyrazolylene In one embodiment, Y is 3 * It is a ,4-substituted pyrazolylene. In one embodiment Y is, [ka] In one embodiment, Y is [ka] In one embodiment, Y is [ka] That is the case.

[0096] In one embodiment, Y is imidazoylene. In one embodiment, Y is 1, 2* - Substituted imidazoylene. In one embodiment, Y is 4 * ,5-Substitution Imidaz It is rilen. In one embodiment, Y is 4,5 * - This is a substituted imidazoline. In this embodiment, Y is [ka] In one embodiment, Y is [ka] In one embodiment, Y is [ka] In one embodiment, Y is [ka] That is the case.

[0097] In one embodiment, Y is triazolylene. In one embodiment, Y is 1 * ,5-substituted 1,2,3-triazolylene. In one embodiment, Y is 4 * ,5- Substituting 1,2,3-triazolylene. In one embodiment, Y is 1 * ,5-substitution 1 ,2,4-triazolylene. In one embodiment, Y is 1,5 * -replacement 1,2, It is 4-triazolylene. In one embodiment, Y is [ka] In one embodiment, Y is [ka] In one embodiment, Y is [ka] In one embodiment, Y is [ka] That is the case.

[0098] In one embodiment, Y is thiazoylene. In one embodiment, Y is 4 * , It is a 5-substituted 1,3-thiazoylene. In one embodiment, Y is [ka] That is the case.

[0099] In one embodiment, Y is a 6-membered heteroarylene. is pyridinylene. In one embodiment, Y is 2 * ,3-substituted pyridinylene In one embodiment, Y is [ka] In one embodiment, Y is [ka] That is the case.

[0100] In one embodiment, Y is pyrimidinylene. In one embodiment, Y is 4 * It is a ,5-substituted pyrimidinylene. In one embodiment, Y is [ka] That is the case.

[0101] In one embodiment, Y is pyrazinylene. In one embodiment, Y is 2 * , It is a 3-substituted pyrazinylene. In one embodiment, Y is [ka] That is the case.

[0102] In one embodiment, Y is replaced by 0 R3s (i.e., all vacancies on Y) (The position is H). In one embodiment, Y is replaced by one R3 that is not H. In this embodiment, Y is replaced by two R3s that are not H.

[0103] In one embodiment, R3 is H, halo, CN, C 1-4 Alkoxy, Halo-C 1-4 Alkyl and C 1-4 Selected from the group consisting of alkyl groups. In one embodiment, R3 is not H. In one embodiment, R3 is C 1-4 It is alkyl. One implementation form In this state, R3 is methyl. In one embodiment, R3 is ethyl. In the application, R3 is a halo. In one embodiment, R3 is a fluoropolymer. In one embodiment, R3 is chloroform. In another embodiment, R3 is CN.

[0104] In one embodiment, X is pyrazolylene provided herein (for example, provided herein) 4 to provide * Y is a pyrazolylene provided herein, where Y is a pyrazolylene provided herein. Yes. In another embodiment, Y is imidazoylene provided herein. Another embodiment In this embodiment, Y is triazolylene provided herein. In another embodiment, Y is This is thiazolyene provided in the specification. In another embodiment, Y is the pi provided in this specification. It is lysinylene. In another embodiment, Y is pyrimidinylene provided herein. In another embodiment, Y is a pyrazinylene provided herein.

[0105] In one embodiment, X is isoxazolylene provided herein, and Y is the same as provided herein. The pyrazolylene provided in the specification. In another embodiment, Y is provided in this specification. It is midazolylene. In another embodiment, Y is triazolylene provided herein. In another embodiment, Y is thiazolyene provided herein. In another embodiment, Y is a pyridinylene provided herein. The pyrimidinylene provided herein. In another embodiment, Y is the pyrazi It is Niren.

[0106] In one embodiment, X is isothiazolylene provided herein, and Y is a given. The pyrazolylene provided in the details. In another embodiment, Y is the IMI provided herein. It is dazolylene. In another embodiment, Y is triazolylene provided herein. In another embodiment, Y is thiazolyene provided herein. In another embodiment, , Y is pyridinylene provided herein. In another embodiment, Y is provided herein The pyrimidinylene provided herein. In another embodiment, Y is the pyrazinylene provided herein. It's Ren.

[0107] In one embodiment, X is imidazolinene provided herein, and Y is the same as provided herein. The pyrazolylene provided in the book. In another embodiment, Y is the imida provided herein. This is zolylene. In another embodiment, Y is triazolylene provided herein. In another embodiment, Y is thiazolyene provided herein. In another embodiment, Y is a pyridinylene provided herein. In another embodiment, Y is a pyridinylene provided herein. The pyrimidinylene provided herein. In another embodiment, Y is the pyrazindylene provided herein. It is.

[0108] In one embodiment, X is a triazolylene provided herein, and Y is a triazolylene provided herein. The pyrazolylene provided in the book. In another embodiment, Y is the imida provided herein. This is zolylene. In another embodiment, Y is triazolylene provided herein. In another embodiment, Y is thiazolyene provided herein. In another embodiment, Y is a pyridinylene provided herein. In another embodiment, Y is a pyridinylene provided herein. The pyrimidinylene provided herein. In another embodiment, Y is the pyrazindylene provided herein. It is.

[0109] In some embodiments, Q is CH. In other embodiments, Q is N.

[0110] In some embodiments, Z is CR5. In certain embodiments, R5 is H. In certain embodiments, R5 is F. In other embodiments, Z is N.

[0111] In some embodiments, R4 is H. In other embodiments, R4 is F.

[0112] In some embodiments, the compound of formula (I) has structure (IA): [ka] In other embodiments, the compound of formula (I) has structure (IB): [ka] In one embodiment, the compound is any one of the following compounds, or its enamel mixtures of enantiomers, enantiomers, or tautomers thereof, or their pharmaceutically acceptable forms It is a salt: [ka] TIFF2026082971000048.tif56165 In some embodiments, R2 is independently H, CN, methyl, ethyl, isopropyl Tyl, Methoxy, Chloro, Trifluoromethyl, Cyclopropyl, Cyclopropylmethyl , 2-fluoroethyl, difluoromethyl, 2,2-difluoroethyl, cyclobutyl, Selected from the group consisting of and oxetanil.

[0113] In some embodiments, R3 is H, fluoro, chloro, CN, methyl, and ethyl. It is selected from the group consisting of the following.

[0114] In a particular embodiment, the compound comprises the following group: [ka] Selected from, or its enantiomer, mixture of enantiomers, or intermodulations. It is an isomer, or a pharmaceutically acceptable salt thereof.

[0115] In a particular embodiment, the compound comprises the following group: [ka] Selected from, or its enantiomer, mixture of enantiomers, or intermodulations. It is an isomer, or a pharmaceutically acceptable salt thereof.

[0116] In a particular embodiment, the compound comprises the following group: [ka] Selected from, or its enantiomer, mixture of enantiomers, or intermodulations. It is an isomer, or a pharmaceutically acceptable salt thereof.

[0117] In a particular embodiment, the compound comprises the following group: [ka] Selected from, or its enantiomer, mixture of enantiomers, or intermodulations. It is an isomer, or a pharmaceutically acceptable salt thereof.

[0118] In a particular embodiment, the compound comprises the following group: [ka] Selected from, or its enantiomer, mixture of enantiomers, or intermodulations. It is an isomer, or a pharmaceutically acceptable salt thereof.

[0119] In a particular embodiment, the compound comprises the following group: [ka] Selected from, or its enantiomer, mixture of enantiomers, or intermodulations. It is an isomer, or a pharmaceutically acceptable salt thereof.

[0120] In a particular embodiment, the compound comprises the following group: [ka] Selected from, or its enantiomer, mixture of enantiomers, or intermodulations. It is an isomer, or a pharmaceutically acceptable salt thereof.

[0121] In a particular embodiment, the compound comprises the following group: [ka] Selected from, or its enantiomer, mixture of enantiomers, or intermodulations. It is an isomer, or a pharmaceutically acceptable salt thereof.

[0122] In a particular embodiment, the compound comprises the following group: [ka] Selected from, or its enantiomer, mixture of enantiomers, or intermodulations. It is an isomer, or a pharmaceutically acceptable salt thereof.

[0123] In a particular embodiment, the compound is selected from the group consisting of: [ka] In a particular embodiment, the compound is selected from the group consisting of: [ka] In a particular embodiment, the compound: [ka] That is the case.

[0124] In a particular embodiment, the compound: [ka] That is the case.

[0125] In a particular embodiment, the compound is selected from the group consisting of: [ka] In a particular embodiment, the compound is selected from the group consisting of: [ka] In a particular embodiment, the compound is selected from the group consisting of: [ka] In a particular embodiment, the compound is selected from the group consisting of: [ka] In a particular embodiment, the compound is selected from the group consisting of: [ka] In a particular embodiment, the compound is selected from the group consisting of: [ka] In a particular embodiment, the compound is selected from the group consisting of: [ka] In a particular embodiment, the compound comprises the following group: [ka] Selected from, or its enantiomer, mixture of enantiomers, or intermodulations. It is an isomer, or a pharmaceutically acceptable salt thereof.

[0126] In a particular embodiment, the compound comprises the following group: [ka] Selected from, or its enantiomer, mixture of enantiomers, or intermodulations. It is an isomer, or a pharmaceutically acceptable salt thereof.

[0127] In a particular embodiment, the compound comprises the following group: [ka] It is selected from or a pharmaceutically acceptable salt thereof.

[0128] In one embodiment, the compounds provided herein are those listed in Table 1: [Table 1] TIFF2026082971000073.tif226165TIFF2026082971000074.tif221165TIFF2026082971000075.tif231165TIFF2026082971000076.tif231165TIFF2026082971000077.tif236165TIFF2026082971000078.tif208165 or a pharmaceutically acceptable salt thereof.

[0129] For any compound in Table 1 that has a chiral center due to the presence of a non-hydrogen R1, such chemical The R-enantiomers, S-enantiomers, and racemic compounds of the compound are all shown in Table 1. Even if not explicitly stated, these are specifically provided herein.

[0130] In one embodiment, provided herein are pharmaceutically acceptable compounds of formula (I). It is a salt. In one embodiment, the pharmaceuticals of any compound in Table 1 are provided herein. It is a generally acceptable salt.

[0131] In certain embodiments, the pharmaceutically acceptable salt of the compound is alkylammonium Salts, dialkylammonium salts, trialkylammonium salts, tetraalkylammonium L-arginine salt, benentamine salt, benzathine salt, Betaine salt, calcium hydroxide salt, choline salt, deanol salt, diethanolamine salt, di Ethylamine salt, 2-(diethylamino)ethanol salt, ethanolamine salt, ethylene Diamine salts, N-methylglucamine salts, hydravamin salts, 1H-imidazole salts, lithium L-lysine salt, magnesium salt, 4-(2-hydroxyethyl)morpholine salt, Perazine salt, potassium salt, 1-(2-hydroxyethyl)pyrrolidine salt, sodium salt, Triethanolamine salt, tromethamine salt, Na salt, Ca salt, K salt, Mg salt, and Zn salt It is selected from the group consisting of the following.

[0132] In certain embodiments, the pharmaceutically acceptable salt is water, methanol, ethanol, and It is a solvate selected from the group consisting of dimethylformamide.

[0133] In certain embodiments, the compound comprises a pharmaceutically acceptable carrier or excipient. It is a pharmaceutical composition.

[0134] In certain embodiments, the composition may be in the form of tablets, capsules, granules, freeze-dried products for reconstitution, or powders. From powder, solution, syrup, suppositories, injections, transdermal delivery systems, and solutions suitable for topical administration. It is a form selected from a group.

[0135] How to use Provided herein are compounds of the present disclosure, for example, compounds of formula (I), or their equivalents. Nantiomers, mixtures of enantiomers, or tautomers thereof, or their pharmaceutically acceptable forms. This is a cancer treatment method that involves administering salts.

[0136] Cancer is a disease of uncontrolled cell proliferation caused by changes in certain genes. Some of these changes are signals from outside the cell to promote cell survival, growth, and proliferation. Receptor tyrosine kinases (RTKs), a family of membrane-bound proteins that transmit signals, It arises from the gene that codes for it. Abnormal RTK activation can lead to excessive cell proliferation and, ultimately, cancer. There is a possibility of connection. Generally, RTKs have an N-terminal domain that binds to extracellular ligands. It contains a transmembrane domain and a C-terminal kinase domain that catalyzes intracellular signal transduction.

[0137] In some embodiments, the compound of formula (I) is an inhibitor of human ROS1. 1 is an RTK encoded by the ROS1 gene. The ligand for human ROS1 and Although its biological function is unknown, its homologs in several other species are extracellular ligans. It is known to bind to and stimulate cell differentiation. For example, mouse ROS1 It is essential for the maturation and reproduction of male gametes. In humans, ROS1 chromosomal rearrangement is crucial. It is a cause of cancer that has been substantiated by several factors, and accounts for 1-2% and many cases of non-small cell lung cancer (NSCLC). These correspond to a subset of other cancers. These rearrangements involve the C-terminus of ROS1 and various parts. This results in fusion with the N-terminus of a na protein. The most common of these proteins is CD7. The answer is 4. ROS1 fusion is involved in the MAPK, PI3K, and JAK / STAT signaling pathways. It possesses constitutive kinase activity that promotes tumor growth via pathways. Small molecule tyrosine kinase inhibitor. Toxic agents (TKIs), including crizotinib and entrectinib, are used in cancer treatment of ROS1 It is used to target fusion. Crizotinib is used to treat ROS1-positive NSCLC. It was the first TKI approved by the FDA for treatment, with an overall response rate of 60-80% and no progression. The median duration of the adverse period is 9–19 months. Despite the initial response, most patients do not respond to crizo Patients develop resistance to tinib and experience relapses. The main mechanism of resistance is solvent f This is a G2032R mutation in ront, which dramatically reduces the affinity for crizotinib. It causes a decrease. Inhibitors that have activity against ROS1-G2032R fusion have been approved by the FDA. This is not the case, and it demonstrates the need for this technology in this field.

[0138] In some embodiments, the compound of formula (I) is used as human anaplastic lymphoma kinase (ALK). It is an inhibitor of AL. ALK, also known as surface antigen classification 246 (CD246), is an inhibitor of AL It is an RTK encoded by the K gene. ALK and ROS1 are evolutionarily related. Both belong to the insulin receptor superfamily, and their kinase domains are They share approximately 80% sequence similarity. Pleiotrophin and midkine growth factor Several ALK ligands have been identified in humans, including [specific ligand name]. Although its role remains uncertain, much evidence from mouse studies suggests that ALK plays a role in the nervous system. This suggests that it is important for development. Similar to ROS1, ALK chromosomal rearrangement is carcinogenic traits via MAPK, JAK / STAT, or other signaling pathways This also leads to constitutively active fusion proteins that promote conversion. ALK reconstitution is NSC It accounts for 3-5% of LC, about half of anaplastic large cell lymphoma (ALCL), and many other cancers. In terms of busets, the main fusions are EML4-ALK from NSCLC and NPM1 from ALCL. -ALK. Although much less frequent than translocations, ALK is a carcinogenic point mutation. And amplification has also been observed. Crizotinib, ceritinib, alectinib, brigatinib, And lorlatinib is the first-line or early-stage treatment for ALK-positive NSCLC and other cancers. It is a TKI approved by the FDA for post-treatment. For example, crizotinib is used in patients aged 60- It showed an overall response rate of 80% and a median progression-free survival of 8-11 months, and was ROS1-positive NS. Its activity is comparable to that in CLC. Despite the initial reaction, the aforementioned FDA-approved TKI Many resistance mutations have emerged against it. Some of these mutations, for example, L11 Combination of 96M gatekeeper and G1202R solvent front mutation This disease exhibits resistance to all approved drugs. It is a new type of ALK-positive cancer with resistance mutations. Such treatment methods are needed in this field of technology.

[0139] In further embodiments, the compound of formula (I) is a human tropomyosin receptor kinase (T It is an inhibitor of RK. The TRK family includes receptor tyrosine kinases TRKA, TRK B and TRKC are included, and these are NTRK1, NTRK2, and NTRK3 respectively. Encoded by genes. Each TRK is a set of different but overlapping neurotrophins. It is activated by ligands, such as NGF, BDNF, and NT-3. All T RK is not convergence in the kinase domain, but rather sequence convergence in the ligand-binding domain. It is consistent with the variance and modulates similar downstream signaling pathways (90% similarity). TRK is By regulating processes such as memory, movement, pain, and proprioception, the development of the infant during development and in adulthood. It plays an important role in the nervous system of mammals. Like ROS1 and ALK, NTRK rearrangement is structural. This results in a chemically active TRK fusion, which then leads to the release of MAPK, PI3K, and other pathways. It promotes cancer transformation. TRK fusion is found in many cancers, including secretory breast cancer and similarly secretory mammary gland cancer. This accounts for over 80% of cases of cancer, infantile fibrosarcoma, and congenital mesodermal nephroma. Therefore, TRK Inhibition of TRK fusion is advantageous in treating cancers that express TRK fusion.

[0140] Many ROS1 and ALK inhibitors in prior art also strengthen the natural, non-carcinogenic TRK. It exhibits strong inhibition. Natural TRK plays an important role in the nervous system, and unforeseen effects of natural TRK Inhibition can lead to adverse reactions including dizziness, ataxia, gait disturbance, paresthesia, weight gain, and cognitive changes. This is a substantial drawback because it relates to non-mutant and / or mutant R A new therapeutic approach that selectively targets OS1 and / or ALK while sparing TRK , which is required in this technological field.

[0141] In one embodiment, the specification provides for the level of ROS1 or ALK within cells. A method for reducing the amount, and the method is a compound or pharmaceutical composition provided herein. This involves bringing a combination of pharmaceuticals into contact with cells. In embodiments, such contact is performed on infants. For example, it occurs within human cells. In embodiments, such contact is used to cause cancer as described herein. It occurs in the cells of human patients who have the condition.

[0142] In one embodiment, the compounds provided herein selectively inhibit ROS1. In one embodiment, the compound selectively inhibits ROS1 from ALK. Non-limiting examples Therefore, the ratio of selectivity is particularly important among several means, especially IC. 50 Measured by the ratio of values If possible, approximately 1.5 times, approximately 2 times, approximately 3 times, approximately 4 times, approximately 5 times, approximately 10 times, It may be more than approximately 20 times, more than approximately 30 times, more than approximately 50 times, or more than approximately 100 times. One embodiment So, the selectivity of ROS1 for ALK is, 50 Values ​​and ROS1 IC 50 It is measured by its ratio to a given value.

[0143] In one embodiment, the compound is TRK (e.g., TRKA, TRKB, and / or It selectively inhibits ROS1 more than TRBC. As a non-limiting example, the selectivity ratio is selected Selectivity is particularly important among several means, especially IC 50 If it can be measured by the ratio of values, then more than approximately 5 times, More than about 10 times, more than about 50 times, more than about 100 times, more than about 200 times, more than about 400 times, more than about 600 times, More than 800 times, More than 1000 times, More than 1500 times, More than 2000 times, More than 5000 times, Approx. This can be more than 10,000 times, or even more than approximately 20,000 times. In one embodiment, TRK The selectivity of ROS1 for TRK is the same as IC for TRK. 50 IC for values ​​and ROS1 50 value It is measured by the ratio of [the two values].

[0144] In one embodiment, the compounds provided herein selectively inhibit ALK. In this embodiment, the compound selectively inhibits ALK from ROS1. Non-limiting examples and Therefore, the ratio of selectivity is such that selectivity is particularly high among several means. 50 Measured by the ratio of values If possible, approximately 1.5 times, approximately 2 times, approximately 3 times, approximately 4 times, approximately 5 times, or approximately 10 times It is possible that... In one embodiment, the selectivity of ALK for ROS1 is... IC 50 IC for value and ALK 50 It is measured by its ratio to a given value.

[0145] In one embodiment, the compound is TRK (e.g., TRKA, TRKB, and / or It selectively inhibits ALK more than TRBC. As a non-restrictive example, the selectivity ratio is Sex is particularly important among several means. 50 If it can be measured by the ratio of values, then more than 5 times, approximately More than 10 times, more than about 50 times, more than about 100 times, more than about 200 times, more than about 400 times, more than about 600 times, about Over 800 times, over approximately 1000 times, over approximately 1500 times, over approximately 2000 times, over approximately 5000 times, and This can be more than 10,000 times. In one embodiment, the selectivity of ALK over TRK This is the IC for TRK 50 IC for value and ALK 50 It is measured by its ratio to a given value.

[0146] In one embodiment, the compound is TRK (e.g., TRKA, TRKB, and / or It selectively inhibits ROS1 and ALK (TRBC). As a non-limiting example, selectivity The ratio of selectivity is particularly important among several means, especially IC 50 When it can be measured by the ratio of values, More than about 5 times, more than about 10 times, more than about 50 times, more than about 100 times, more than about 200 times, more than about 400 times, about 6 More than 00 times, more than about 800 times, more than about 1000 times, more than about 1500 times, more than about 2000 times, about 500 It may be greater than 0, greater than approximately 10,000, or greater than approximately 20,000 in one embodiment. The selectivity of ROS1 and ALK for TRK is that of IC for TRK. 50 Values ​​and ROS IC for 1 and ALK 50 It is measured by its ratio to a given value.

[0147] In one embodiment, the following is provided herein: selectively inhibiting ROS1 from ALK This method involves inhibition occurring intracellularly. In one embodiment, the method provided herein is provided. This involves selecting ROS1 from TRK (e.g., TRKA, TRKB, and / or TRBC). This is a method of selective inhibition, and the inhibition occurs intracellularly. In one embodiment, the method This includes contacting ROS1 with an effective amount of the compound provided herein. Embodiments In this embodiment, such contact occurs within a cell. It occurs within human cells. In embodiments, such contact occurs in a human having the cancer described herein. It occurs within the patient's cells.

[0148] In one embodiment, the following is provided herein: selectively inhibiting ROS1 from ALK This method involves performing the inhibition on a subject suffering from cancer, and the method is performed on the subject. In contrast, this includes administering an effective amount of the compound or pharmaceutical composition provided herein. In certain embodiments, the foregoing provides for patients suffering from ROS1-related cancers. A method for treating a target, wherein a certain amount of the compound provided herein is applied to the target. Selective inhibition of ROS1 over ALK by administering a substance or pharmaceutical composition. It contains, and the amount is sufficient to selectively inhibit ROS1 more than ALK.

[0149] In one embodiment, the following are provided herein: TRK (e.g., TRKA, TRKB) A method for selectively inhibiting ROS1 (from , and / or TRBC), wherein this inhibition is cancer The method is performed on subjects suffering from the disease, and the method involves providing to the subject an effective amount of the specified material This includes administering the compound or pharmaceutical composition to be provided. In certain embodiments, this specification The book provides a treatment method for patients suffering from ROS1-related cancers, and the method The law administers to the subject a certain amount of the compound or pharmaceutical composition provided herein. By doing so, ROS is better than TRK (e.g., TRKA, TRKB, and / or TRBC). This includes selectively inhibiting 1, wherein the amount is TRK (e.g., TRKA, TRKB, and This is sufficient to selectively inhibit ROS1 (or TRBC).

[0150] In one embodiment, the herein provides a method for selectively inhibiting ALK from ROS1. This method involves inhibition occurring intracellularly. In one embodiment, the method provided herein is provided. This involves selecting ALK from TRK (e.g., TRKA, TRKB, and / or TRBC). This is a method of targeted inhibition, and the inhibition occurs intracellularly. In one embodiment, the method This includes contacting ALK with an effective amount of the compound provided herein. In embodiments, this includes contacting ALK with an effective amount of the compound provided herein. Such contact occurs within a cell. In embodiments, such contact occurs in mammals, for example, humans. It occurs within the cells. In embodiments, such contact occurs in human patients with cancer as described herein. It occurs within the cells.

[0151] In one embodiment, the herein provides a method for selectively inhibiting ALK from ROS1. This method involves performing the inhibition on a subject suffering from cancer, and the method is performed on the subject. In contrast, this includes administering an effective amount of the compound or pharmaceutical composition provided herein. In certain embodiments, the foregoing provides for patients suffering from ALK-related cancers. A treatment method for a target, wherein a certain amount of the compound provided herein is applied to the target. Alternatively, selectively inhibiting ALK over ROS1 by administering a pharmaceutical composition. The amount contained is sufficient to selectively inhibit ALK from ROS1.

[0152] In one embodiment, the following are provided herein: TRK (e.g., TRKA, TRKB) A method for selectively inhibiting ALK (and / or TRBC), and this inhibition is effective against cancer. The method is performed on an affected subject, and the method provides to the subject an effective amount as specified herein. This includes administering a compound or pharmaceutical composition. In certain embodiments, this specification The method provided is a treatment method for individuals suffering from ALK-related cancers, and this method , administering a certain amount of the compound or pharmaceutical composition provided herein to the subject ALK is selected from TRK (e.g., TRKA, TRKB, and / or TRBC) This includes selective inhibition, the amount of which is TRK (e.g., TRKA, TRKB, and / or This is sufficient to selectively inhibit ALK (TRBC).

[0153] As used herein, unless otherwise specified, inhibition of ROS1 refers to wild-type ROS1. This includes inhibition of S1 or its mutants, and ALK inhibition includes wild-type ALK or its mutants. This includes inhibition of the mutant, and inhibition of TRK includes inhibition of wild-type TRK or its mutant. Inhibition is involved.

[0154] Cancers treated by the method disclosed herein include lung cancer, e.g., non-small cell lung cancer, inflammatory lung cancer. Myofibroblast tumors, ovarian cancers such as serous ovarian carcinoma, melanomas such as nevus spitz, melanoma Chromoma, glioblastoma, bile duct cancer, for example, bile duct cancer (c Holangiocarcinoma, gastric cancer, colorectal cancer, angiosarcoma, anaplastic large cell carcinoma Lymphoma, diffuse large B-cell lymphoma, large B-cell lymphoma, esophageal cancer, for example, Esophageal squamous cell carcinoma, kidney cancer, e.g., renal medullary carcinoma or renal cell carcinoma, breast cancer, e.g., triple nephrosis Gati breast cancer, thyroid cancer, for example, papillary thyroid carcinoma, neuroblastoma, epithelioid hemangioendothelioma, Examples include, but are not limited to, colon cancer and Spitz nevus-like tumors.

[0155] Cancers treated by the methods disclosed herein include ROS1, ALK, TRKA, TRKB, This includes cancers derived from one or more oncogenic proteins selected from TRKC. In certain embodiments, the cancers treated by the methods disclosed herein include ROS1, ALK Targeting one or more oncogenic proteins selected from TRKA, TRKB, and TRKC. This includes cancers that have developed drug resistance to targeted treatments.

[0156] In one embodiment, the cancer in the method provided herein is anaplastic lymphoma. It is ALK-positive. When used herein, unless otherwise specified, "ALK" refers to ALK-positive. "ALK-positive" (ALK+) cancer, disease, or disorder is caused by inappropriate high expression of the ALK gene and / Alternatively, it refers to a cancer, disease, or disorder characterized by the presence of a mutation in the ALK gene. In one embodiment, the mutation affects the biological activity of the ALK nucleic acid molecule or polypeptide. To change. When used herein, unless otherwise specified, the “mutation” of ALK Alternatively, a "mutant" is a mutation of the amino acid sequence or nucleotide sequence of ALK, or a fragment thereof. This specification includes one or more deletions, substitutions, insertions, inversions, duplications, translocations, or amplifications in a fragment. When used in writing, unless otherwise specified, "reconfiguration" of ALK refers to the ALK fusion gene. and / or gene translocations involving the ALK gene that may result in an ALK fusion protein The ALK fusion also refers to one mutant, as long as the mutant retains kinase phosphorylation activity. This may include deletions, substitutions, insertions, inversions, duplications, translocations, or amplifications or fragments thereof.

[0157] In one embodiment, the ALK mutation comprises one or more ALK point mutations. In some embodiments, cancers treated by the methods of the present disclosure are associated with ALK kinase It includes one or more mutations. In one embodiment, the one or more point mutations of ALK L1152, C1156, I1171, F1174, V1180, L1196, L1 198, G1202, D1203, S1206, E1210, F1245, G1269, and selected from point mutations in R1275. In one embodiment, one or more AL K point mutations include G1202R, G1202K, L1196M, G1269A, and C11. 56Y, I1171T, I1171N, I1171S, F1174L, V1180L, S 1206Y, E1210K, 1151Tins, F1174C, G1202del, D1 203N, S1206Y, S1206C, L1152R, L1196Q, L1198P, Choose from L1198F, R1275Q, L1152P, C1156T, and F1245V. In one embodiment, the mutation in ALK is G1202R. Morphologically, the mutation in ALK is L1196M. In one embodiment, the ALK The mutation is G1269A. In one embodiment, the mutation in ALK is L1 It is 198F. In one embodiment, the mutation of ALK is G1202R and L11 Co-mutation with one or more mutations selected from 96M, G1269A, and L1198F. This is a mutation. In one embodiment, the mutation in ALK is G1202R / L1196M This is a double mutation. In one embodiment, the ALK mutation is G1202R / G This is a double mutation of 1269A. In one embodiment, the ALK mutation is G12 This is a double mutation of 02R / L1198F.

[0158] In one embodiment, the ALK mutation results in one or more ALK rearrangements (one embodiment) In one embodiment, the ALK mutations include one or more. This includes ALK fusion (one fusion in one embodiment). In some embodiments, this The cancers treated by the disclosed method include ALK fusion. In one embodiment, the AL K-fusion involves EML4, TMP1, WDCP, GTF2IRD1, TPM3, TPM4, and C LTC, LMNA, PRKAR1A, RANBP2, TFG, FN1, KLC1, VCL , STRN, HIP1, NPM1, DCTN1, SQSTM1, TPR, CRIM1, P One of the fusion partners selected from TPN3, FBXO36, ATIC, and KIF5B. The target is EML4-ALK, that is, The echinoderm microtubule-associated protein-like 4 (EML4) gene and the tyrosine kinase ALK. This is a fusion of domains. EML4-ALK has different breakpoint junctions. There are many variants, and variant 1 (v1) and variant 3 (v3) are clinically the most... This is also common.

[0159] In one embodiment, the ALK mutation results in one ALK rearrangement and one or more AL Includes a point mutation in K. In one embodiment, the mutation in ALK is EML4-ALK wt(variant 1). In one embodiment, the mutation in ALK is EML4 -ALK G1202R (Variant 1). In one embodiment, the suddenness of the ALK The mutation is EML4-ALK L1196M / G1202R (variant 1). There is one. In this embodiment, the ALK mutation is EML4-ALK G1202R / G1269 A (Variant 1). In one embodiment, the mutation in ALK is EML4-A This is LK G1202R / L1198F (Variant 1).

[0160] In one embodiment, the ALK+ cancer is tested in FDA-approved trials or is already known in the art. It is identified by other tests of knowledge. Examples of tests that may be used include, for example, Foundat ionOne CDx(trademark)(F1CDx)(324 gene substitutions, insertions and Deletion changes (indels), copy number changes (CNAs), and selected genes. Child rearrangement, as well as microsatellite instability (MSI) and tumor gene mutational load (T Genomic signs including MB) are used in formalin-fixed paraffin-embedded (FFPE) tumor tissue labels. In vitro diagnostic imaging based on sequencing for detection using DNA isolated from books. (Disconnection device), VENTANA ALK (D5F3) CDx assay (BenchMark Formalin-fixed particles stained with XT or BenchMark ULTRA automated staining equipment Anaplastic lymphoma in roughin-embedded (FFPE) non-small cell lung cancer (NSCLC) tissue Qualitative detection of the ALK enzyme (ALK) protein, as well as Vysis ALK Break Apart FISH Probe Kit Test (Formalin-fixed paraffin-embedded (FF) Fluorescent in situ hybridise in non-small cell lung cancer (NSCLC) tissue specimens (PE) One example is a qualitative test that detects rearrangements involving the ALK gene via FISH (Functional Inhibitory Spectroscopy). In one embodiment, the test is performed using fluorescence in situ hybridization (F ISH) test, for example, Vysis ALK Break Apart FISH Pr This is the OBE Kit test. Further information regarding FDA-approved tests can be found, for example, at h ttps: / / www.fda.gov / MedicalDevices / Produc tsandMedicalProcedures / InVitroDiagnostic It can be found at s / ucm303030.htm, and further Vysis ALK B The reak Apart FISH Probe Kit is, for example, https: / / w ww.molecular.abbott / us / en / products / oncol ogy / vysis-alk-break-apart-fish-probe-kit These can be found there. The whole of these is incorporated herein by reference.

[0161] Similarly, we offer a treatment method for individuals with cancer (e.g., ALK-positive cancer). The method involves obtaining a sample from a subject who has cancer and has previously been administered a primary ALK inhibitor. Identify whether cancer cells in the pull process have one or more ALK inhibitor resistance mutations. This refers to the situation in which the subject has cancer cells with one or more ALK inhibitor resistance mutations. In addition, the compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof may be used as monotherapy. This includes administering the drug to the subject as a drug or in combination with another anticancer drug. In that embodiment, the one or more ALK inhibitor resistance mutations are associated with the first ALK inhibitor. To increase resistance to cancer cells or tumors against treatment. Several embodiments Therefore, one or more ALK inhibitor resistance mutations are one or more ALK inhibitor resistance mutations This includes, for example, the one or more ALK inhibitor resistance mutations are at amino acid positions 1202, 1 196, 1269, 1156, 1171, 1174, 1180, 1206, 1210, 1 151, 1174, 1203, 1206, 1152, 1196, 1198, 1275, 1 152, 1156, and 1245, for example, G1202R, L1196M, G1269A , C1156Y, I1171T, I1171N, I1171S, F1174L, V118 0L, S1206Y, E1210K, 1151Tins, F1174C, G1202de l, D1203N, S1206Y, S1206C, L1152R, L1196Q, L11 98P, L1198F, R1275Q, L1152P, C1156T, and F1245V This may include substitution of one or more of the following. In some embodiments, another anticancer agent is used in this technology. Any anticancer drug known in the field of medicine. For example, another anticancer drug is another ALK inhibitor (e.g., For example, it could be a second ALK inhibitor.

[0162] In one embodiment, the cancer in the method provided herein is ROS1-positive (ROS 1+) is used herein, unless otherwise specified, "ROS1 positive" ROS1+ cancer, disease, or disorder is caused by inappropriate high expression of the ROS1 gene and / or This refers to a cancer, disease, or disorder characterized by the presence of a mutation in the ROS1 gene. In one embodiment, the mutation alters the biological activity of the ROS1 nucleic acid molecule or polypeptide. To update. When used herein, unless otherwise specified, the “mutation” of ROS1 Alternatively, "mutant" refers to the amino acid sequence or nucleotide sequence of ROS1, or its This includes one or more deletions, substitutions, insertions, inversions, duplications, translocations, or amplifications in the fragment. When used in the documentation, unless otherwise specified, "reconfiguration" of ROS1 refers to ROS1 fusion. Genes involving the ROS1 gene that may result in genes and / or ROS1 fusion proteins This refers to a genetic translocation. The ROS1 fusion also means that the mutant retains kinase phosphorylation activity. As long as one or more deletions, substitutions, insertions, inversions, duplications, translocations, or amplifications or fragments thereof are present. It may include.

[0163] In one embodiment, the mutation in ROS1 includes one or more point mutations in ROS1. In some embodiments, the cancer treated by the methods of this disclosure is ROS1 kinase Includes one or more mutations in the gene. In one embodiment, the one or more ROS1 point mutations Natural mutations include E1935, L1947, L1951, G1971, E1974, and L1982. , S1986, F2004, E2020, L2026, G2032, D2033, C20 60, F2075, L2086, V2089, V2098, G2101, D2113, and Selected from point mutations in L2155. In one embodiment, one or more ROS The single-point mutations are G2032R, G2032K, D2033N, S1986F, and S198 6Y, L2026M, L1951R, E1935G, L1947R, G1971E, E1 974K, L1982F, F2004C, F2004V, E2020K, C2060G, F2075V, V2089M, V2098I, G2101A, D2113N, D2113 Selected from G, L2155S, and L2086F. In one embodiment, the ROS1 The mutation is G2032R. In one embodiment, the mutation of ROS1 is S It is 1986F. In one embodiment, the mutation of ROS1 is S1986Y. In one embodiment, the mutation in ROS1 is L2026M. In this case, the mutation in ROS1 is D2033N. In one embodiment, the mutation in ROS1 The mutation is L2086F. In one embodiment, the mutation in ROS1 is F It is 2004C. In one embodiment, the mutation of ROS1 is F2004V. In one embodiment, the mutation in ROS1 is G2101A. In this case, the mutation in ROS1 is L1982F. In one embodiment, the mutation in ROS1 The mutations are G2032R, S1986F, S1986Y, F2004C, and F200 It is a comutation with one or more of the following: 4V, L2026M, or D2033N.

[0164] In one embodiment, the mutation in ROS1 results in one or more ROS1 rearrangements (one actual The application form includes one reconfiguration. In one embodiment, the mutation of ROS1 is 1 Includes one or more ROS1 fusions (one fusion in one embodiment). Several embodiments Therefore, the cancer treated by the method of this disclosure includes ROS1 fusion. In one embodiment The ROS1 fusion includes SLC34A2, CD74, TPM3, SDC4, EZR, LR IG3, KDELR2, CEP72, CLTL, CTNND2, GOPC (for example, GO PC-S, GOPC-L), GPRC6A, LIMA1, LRIG3, MSN, MYO5 C, OPRM1, SLC6A17, SLMAP, SRSF6, TFG, TMEM106B , TPD52L1, ZCCHC8, CCDC6, CAPRIN1, CEP85L, CHC HD3, CLIP1, EEF1G, KIF21A, KLC1, SART3, ST13, T RIM24, ERC1, FIP1L1, HLAA, KIAA1598, MYO5A, PP FIBP1, PWWP2A, FN1, YWHAE, CCDC30, NCOR2, NFKB 2. One of the fusion partners selected from APOB, PLG, RBP4, and GOLGB1 It is paired with one of the following. In one embodiment, the ROS1 fusion is a CD74-ROS1 fusion. In one embodiment, the ROS1 fusion is an SDC4-ROS1 fusion. In the application, the ROS1 fusion is an EZR-ROS1 fusion. In one embodiment, ROS1 fusion is SLC34A2-ROS1 fusion. In one embodiment, the ROS 1. Fusion is GOPC-ROS1 fusion (for example, GOPC-ROS1-S, GOPC-RO In one embodiment, the ROS1 fusion is CEP85L-ROS1 fusion. It is correct.

[0165] In one embodiment, the mutation in ROS1 results in one ROS1 rearrangement and one or more R Includes an OS1 point mutation. In one embodiment, the ROS1 mutation is CD74-R OS1, EZR-ROS1, SLC34A2-ROS1, GOPC-ROS1 (for example, From GOPC-ROS1-S, GOPC-ROS1-L, and CEP85L-ROS1 One or more ROS1 reconstructions, as well as F2004C, F2004V, and G2032R It includes one or more ROS1 point mutations selected from. In one embodiment, the ROS1 The mutations are CD74-ROS1, EZR-ROS1, and SLC34A2-ROS1 Includes one or more ROS1 rearrangements and a ROS1 point mutation in G2101A.

[0166] In one embodiment, the mutation in ROS1 is CD74-ROS1 F2004C Yes. In one embodiment, the mutation of ROS1 is CD74-ROS1 F2004 V. In one embodiment, the mutation of ROS1 is CD74-ROS1 G21 This is 01A. In one embodiment, the mutation of ROS1 is CD74-ROS1 G It is 2032R. In one embodiment, the mutation of ROS1 is CD74-ROS1 This is S1986F. In one embodiment, the mutation in ROS1 is CD74-RO S1 L2026M. In one embodiment, the mutation in ROS1 is CD74- The mutation is ROS1 D2033N. In one embodiment, the mutation in ROS1 is EZR -ROS1 F2004C. In one embodiment, the mutation of ROS1 is EZ It is R-ROS1 F2004V. In one embodiment, the mutation of ROS1 is E This is ZR-ROS1 G2101A. In one embodiment, the mutation in ROS1 is The mutation is EZR-ROS1 G2032R. In one embodiment, the mutation in ROS1 is , SLC34A2-ROS1 F2004C. In one embodiment, the ROS1 The mutation is SLC34A2-ROS1 F2004V. In one embodiment, The ROS1 mutation is SLC34A2-ROS1 G2101A. One implementation In this state, the mutation in ROS1 is SLC34A2-ROS1 G2032R. In one embodiment, the mutation of ROS1 is GOPC-ROS1 F2004C (for example) For example, GOPC-ROS1-S F2004C, GOPC-ROS1-L F2004C) In one embodiment, the mutation of ROS1 is GOPC-ROS1 F200 4V (for example, GOPC-ROS1-S F2004V, GOPC-ROS1-L F2 004V) In one embodiment, the mutation of ROS1 is GOPC-ROS1 G2032R (for example, GOPC-ROS1-S G2032R, GOPC-ROS1 -L G2032R). In one embodiment, the mutation in ROS1 is CEP8 This is 5L-ROS1 F2004C. In one embodiment, the mutation in ROS1 is This is CEP85L-ROS1 F2004V. In one embodiment, the sudden The mutation is CEP85L-ROS1 G2032R. In one embodiment, the ROS The mutation in 1 is GOPC-ROS1 L1982F (for example, GOPC-ROS1-S This is L1982F (GOPC-ROS1-L L1982F). In one embodiment, The ROS1 mutation in question is CD74-ROS1 L1982F.

[0167] In one embodiment, the ROS1+ cancer is tested in an FDA-approved study or in the art. It is identified by other known tests. Examples of tests that may be used include Thermo Oncomine® Dx Targ by Fisher Scientific et Test (Qualitative in vitro diagnostic test, targeted high-throughput parallel sequencing) Using this technology, formalin-fixed paraffin from patients with non-small cell lung cancer (NSCLC) In 23 genes of DNA and RNA isolated from embedded tumor (FFPE) tissue samples, (Detects sequence mutations using the Ion PGM Dx system), Vysis R OS1 Break Apart Fish Probe Kit (Formalin Fixed Para) Fluorescent in situ in fin-embedded (FFPE) non-small cell lung cancer (NSCLC) tissue specimens ROS1 gene rearrangement at 6q22 is involved via hybridization (FISH). RT real-time polymerase (RT) via qualitative tests to detect reconfiguration (or local diagnostic tests). Examples include RT-PCR (Reverse-Test-Modulation PCR) or NGS (Next-Generation Sequencing).

[0168] Similarly, we offer treatment methods for individuals with cancer (e.g., ROS1-positive cancer). The method obtained from subjects having cancer and who had previously been administered a primary ROS1 inhibitor. The study specifically determines whether cancer cells in the sample have one or more ROS1 inhibitor resistance mutations. To determine that the target is a cancer cell that has one or more ROS1 inhibitor resistance mutations. If present, the compound of formula (I) or its pharmaceutically acceptable salt or solvate, This includes administering the drug to the target patient as monotherapy or in combination with another anticancer drug. In several embodiments, the one or more ROS1 inhibitor resistance mutations are the first ROS1 inhibitor To increase resistance to cancer cells or tumors against treatment with harmful agents. In the application form, the one or more ROS1 inhibitor resistance mutations are one or more ROS1 inhibitor resistance mutations. This includes sex mutations. For example, one or more ROS1 inhibitor resistance mutations occur at amino acid position 2. 032, 2033, 1986, 2026, 1951, 1935, 1947, 1971, 1 974, 1982, 2004, 2020, 2060, 2075, 2089, 2098, 2 101, 2113, 2155, 2032, and 2086, for example, G2032R, D20 33N, S1986F, S1986Y, L2026M, L1951R, E1935G, L 1947R, G1971E, E1974K, L1982F, F2004C, F2004V , E2020K, C2060G, F2075V, V2089M, V2098I, G210 1A, D2113N, D2113G, L2155S, L2032K, and L2086F This may include substitution of one or more of them. In some embodiments, another anticancer agent is used in this technology. Any anticancer drug known in the field. For example, another anticancer drug is another ROS1 inhibitor (e.g., For example, it could be a second ROS1 inhibitor.

[0169] In one embodiment, the compounds provided herein are CNS-penetrating compounds. In the embodiments, an effective amount of the compound provided herein is administered (e.g., orally or intravenously). ) After that, the compound penetrates the CNS (e.g., blood-brain barrier) and the CNS (e.g., Inhibit ROS1, ALK, or both (e.g., selectively inhibit them) in the brain. Therefore, a sufficient concentration can still be achieved.

[0170] In one embodiment, the herein provides a method for treating CNS metastases of cancer, The method provides an effective amount of the compound described herein to an object that requires it, for example, Compounds of formula (I), their enantiomers, mixtures of enantiomers, or alternates thereof. This includes administering an isomer or a pharmaceutically acceptable salt thereof. In one embodiment, The CNS metastasis is a brain metastasis. In one embodiment, the cancer is a ROS1+ cancer. In one embodiment, the cancer is ALK+ cancer.

[0171] In some embodiments, the compound is a human tropomyosin receptor kinase A, B, and or C inhibitors. In certain embodiments, mutant or non-mutant ROS IC of the compound against inhibition of 1 or ALK 50 This is the wild-type tropomyosin receptor quina IC of the compound for inhibition of enzymes A, B, or C 50 It is less than one-fifth of that. TRK Inhibition, particularly in the central nervous system (CNS), can cause dizziness / ataxia / gait disturbance, paresthesia, and weight gain. It is associated with adverse reactions, including changes in taste and cognitive function.

[0172] In some embodiments, the invention provides cancer (e.g., ROS1-positive cancer or AL). This is a method to minimize adverse events in patients requiring treatment for K-positive cancer, The method involves providing a therapeutically effective amount of the compound provided herein, for example, the compound of formula (I), its energy mixtures of enantiomers, enantiomers, or tautomers thereof, or their pharmaceutically acceptable forms The method includes administering a salt to the subject, and the method involves reducing adverse events associated with TRK inhibitors. To minimize. In some embodiments, the cancer is ROS1-related cancer or ALK-related cancer. It is a linked (or ALK+) cancer. In some embodiments, the adverse event is related to TRK. This is a related adverse event in the CNS.

[0173] As used herein, "minimizing" adverse events means that TRK inhibitors (for example) If so, entrectinib, repotrectinib, or Lor The series incidence of adverse events was compared with the incidence of adverse events in subjects or patient populations treated with latinib. This refers to a reduction in the incidence of adverse events in the target or patient population. In some embodiments, The incidence of adverse events refers to the frequency or pattern of a particular adverse event in a target or patient population. - Refers to a centen. In some embodiments, the incidence rate of adverse events is defined as the rate at which individual subjects experience This refers to the total number of adverse events to be tested. In some embodiments, the goal is to minimize adverse events. This refers to minimizing TRK-related CNS adverse events. Several embodiments So, minimizing TRK-related CNS adverse events means less than 40% of the patient population. This means that it has TRK-related CNS adverse events. In some embodiments, T Minimizing RK-related CNS adverse events means reducing the patient population to less than 35% or 30%. Less than, less than 25%, less than 20%, less than 15%, less than 10%, or less than 5% are related to TRK. This means that there are adverse events related to CNS. Minimizing adverse events in S means that less than 12% of the patient population has multiple TRK-related C This means that NS has adverse events. In some embodiments, TRK-related CNS Minimizing adverse events means reducing the percentage of patients to 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% are related to multiple TRKs. This means that it has CNS adverse events.

[0174] In some embodiments, TRK-related CNS adverse events include one or more of the following: Refers to: dizziness, ataxia, gait disturbance, paresthesia, weight gain, bulimia, paresthesia, abnormal movements, Cognitive changes, speech effects (e.g., dysarthria, speech delay, or speech disorder), mood disorders (e.g.) For example, irritability, anxiety, depression, emotional instability, personality changes, mood swings, emotional disorders, aggression Symptoms include agitation, mood swings, depressed mood, euphoria, or mania, and cognitive impairment (e.g., memory). Disorder, cognitive impairment, memory loss, confusion, attention deficit, delirium, mental disorder, attention deficit / hyperactivity disorder (dementia, or reading impairment).

[0175] In one embodiment, the herein provides a TRK-related CN in cancer treatment. A method for preventing or limiting side effects or adverse events of S, wherein the method does not necessarily For the target object, an effective amount of the compound provided herein, for example, the compound of formula (I), is used. or its enantiomer, mixture of enantiomers, or tautomers, or so The method includes administering a pharmaceutically acceptable salt of TRK. In one embodiment, the method involves TRK To prevent the occurrence of related CNS adverse events. In one embodiment, the method is related to TRK To limit the frequency of adverse events in the CNS. In one embodiment, the method involves TRK-related Limit the severity of side effects. In one embodiment, provided herein is TRK A method for treating CNS metastases of cancer with reduced associated side effects, the method requires For the target, an effective amount of the compound provided herein, for example, the compound of formula (I), or its enantiomer, mixture of enantiomers, or tautomers, or its medicine This includes administering a pharmaceutically acceptable salt. In one embodiment, the side effects of the CNS or The reduction / limitation / prevention of adverse events is statistically significant in the sample, with ROS1+ and / or A Standard treatment for LK+ cancer, e.g., approved ROS1 and / or ALK inhibitors ( For example, crizotinib, entrectinib, lorlatinib, or repotrectinib) It is determined by comparison. In one embodiment, the TRK-related side effect is the TRKB-related C This is a side effect of NS. In one embodiment, the side effect or adverse event of the TRK-related CNS Elephants may experience dizziness, ataxia, gait disturbance, paresthesia, weight gain, cognitive impairment, mood disorders, or sleep disturbances. I have a sleep disorder.

[0176] In one embodiment, the herein provides a method for treating cancer, the method being For targets requiring this, a therapeutically effective amount of the compound provided herein, for example, formula (I ) compounds, or their enantiomers, mixtures of enantiomers, or tautomers or administering a pharmaceutically acceptable salt thereof. In one embodiment, the cancer This is a ROS1-related cancer. In one embodiment, the cancer is a ROS1+ cancer. In one embodiment, the cancer is ALK-related cancer. In one embodiment, the cancer is , it is ALK+ cancer. In one embodiment, the cancer is identified as ROS1+. In one embodiment, the cancer is identified as ALK+.

[0177] In one embodiment, the herein provides a method for treating ROS1+ cancer, The method involves providing a therapeutically effective amount of the compound provided herein to a target that requires it, for example... For example, a compound of formula (I), its enantiomer, a mixture of enantiomers, or This includes administering a tautomer or a pharmaceutically acceptable salt thereof.

[0178] In one embodiment, the present invention provides a method for treating ALK+ cancer, and the method The law provides a therapeutically effective amount of the compound provided herein to the subject requiring it, for example , a compound of formula (I), or its enantiomer, a mixture of enantiomers, or This includes administering a mutant or a pharmaceutically acceptable salt thereof.

[0179] In one embodiment, the foregoing provides a method for treating cancer in a subject, The method involves (i) identifying that the cancer in the subject is ROS1+, and (i i) A therapeutically effective amount of the compound provided herein, for example, the compound of formula (I), or its equivalent. Nantiomers, mixtures of enantiomers, or tautomers thereof, or their pharmaceutically acceptable forms. This includes administering the salt to the subject.

[0180] In one embodiment, the foregoing provides a method for treating cancer in a subject, The method includes (i) identifying that the cancer in the subject is ALK+, and (ii) ) A therapeutically effective amount of the compound provided herein, for example, the compound of formula (I), or its enamel mixtures of enantiomers, enantiomers, or tautomers thereof, or their pharmaceutically acceptable forms This includes administering the salt to the subject.

[0181] In one embodiment, the cancer (or ROS1+ cancer, or ALK+ cancer) is fixed It is a type of tumor. In one embodiment, the cancer (or ROS1+ cancer, or ALK+ Cancers include lung cancer, such as non-small cell lung cancer (NSCLC), glioblastoma, and inflammatory myofibroblastic cancer. cystic tumor (IMT), bile duct cancer (bile duct cancer), e.g. Holangiocarcinoma, ovarian cancer, for example, serous ovarian cancer, gastric cancer, rectal cancer Intestinal cancer, angiosarcoma, melanoma, e.g., Spitz nevus melanoma, epithelioid hemangioendothelioma, esophageal cancer For example, esophageal squamous cell carcinoma (ESCC), kidney cancer, for example, renal medullary carcinoma or renal cell carcinoma, Breast cancer, for example, triple-negative breast cancer, colon cancer, thyroid cancer, for example, papillary thyroid cancer, It is a Pitts nevus-like tumor, or neuroblastoma.

[0182] In one embodiment, the cancer is lung cancer. In one embodiment, the cancer is non-minor It is alveolar lung cancer. In one embodiment, the cancer is ROS1+ non-small cell lung cancer. In one embodiment, the cancer is ALK+ non-small cell lung cancer. In one embodiment, the cancer is , recurrent or refractory non-small cell lung cancer. In one embodiment, the cancer is recurrent and This is refractory ROS1+ non-small cell lung cancer. In one embodiment, the cancer is recurrent or It is refractory ALK+ non-small cell lung cancer. In one embodiment, the cancer is newly diagnosed This is non-small cell lung cancer. In one embodiment, the cancer is a newly diagnosed ROS1+ non-small cell lung cancer. It is a type of lung cancer. In one embodiment, the cancer is a newly diagnosed ALK+ non-small cell lung cancer. It is cancer.

[0183] In one embodiment, the cancer is glioblastoma. In one embodiment, the cancer is It is a ROS1+ glioblastoma. In one embodiment, the cancer is an ALK+ glioblastoma. In one embodiment, the cancer is recurrent or refractory glioblastoma. Morphologically, the cancer is recurrent or refractory ROS1+ glioblastoma. One embodiment In this case, the cancer is recurrent or refractory ALK+ glioblastoma. In one embodiment, The cancer is a newly diagnosed glioblastoma. In one embodiment, the cancer is newly The diagnosed ROS1+ glioblastoma. In one embodiment, the cancer is newly diagnosed This is a diagnosed ALK-positive glioblastoma.

[0184] In one embodiment, the cancer is IMT. In one embodiment, the cancer is RO It is S1+IMT. In one embodiment, the cancer is ALK+IMT. In the application form, the cancer is recurrent or refractory IMT. In one embodiment, the cancer This is recurrent or refractory ROS1+IMT. In one embodiment, the cancer is recurrent It is sexual or refractory ALK+IMT. In one embodiment, the cancer is newly diagnosed This is IMT. In one embodiment, the cancer is newly diagnosed as ROS1+IMT. Yes, in one embodiment, the cancer is a newly diagnosed ALK+IMT.

[0185] In one embodiment, the cancer is bile duct cancer. In one embodiment, the cancer is cholangiocarcinoma. Yes. In one embodiment, the cancer is ROS1+ cholangiocarcinoma. In one embodiment, the cancer is ALK+ cholangiocarcinoma (cholangiocarcinoma). (iocarcinoma). In one embodiment, the cancer is recurrent or refractory. It is cholangiocarcinoma. In one embodiment, the cancer This is in recurrent or refractory ROS1+ cholangiocarcinoma. Yes. In one embodiment, the cancer is recurrent or refractory ALK+ cholangiocarcinoma (cholangiocarcinoma). ngiocarcinoma). In one embodiment, the cancer is newly diagnosed It is cholangiocarcinoma. In one embodiment, This is a newly diagnosed ROS1+ cholangiocarcinoma. Yes. In one embodiment, the cancer is a newly diagnosed ALK+ cholangiocarcinoma (cholan It is giocarcinoma.

[0186] In one embodiment, the cancer is ovarian cancer. In one embodiment, the cancer is RO It is S1+ ovarian cancer. In one embodiment, the cancer is ALK+ ovarian cancer. In the embodiment, the cancer is recurrent or refractory ovarian cancer. In one embodiment, the cancer This is recurrent or refractory ROS1+ ovarian cancer. In one embodiment, the cancer is recurrent It is sexual or refractory ALK+ ovarian cancer. In one embodiment, the cancer is newly diagnosed It is ovarian cancer. In one embodiment, the cancer is a newly diagnosed ROS1+ ovarian cancer. Yes. In one embodiment, the cancer is a newly diagnosed ALK+ ovarian cancer. In one embodiment, the ovarian cancer is serous ovarian cancer. In one embodiment, the ovarian cancer is high It is a malignant serous ovarian cancer.

[0187] In one embodiment, the cancer is gastric cancer. In one embodiment, the cancer is ROS 1+ gastric cancer. In one embodiment, the cancer is ALK+ gastric cancer. One embodiment In this case, the cancer is recurrent or refractory gastric cancer. In one embodiment, the cancer is recurrent It is a recurrent or refractory ROS1+ gastric cancer. In one embodiment, the cancer is recurrent or refractory. This is a treatable ALK-positive gastric cancer. In one embodiment, the cancer is a newly diagnosed gastric cancer. In one embodiment, the cancer is a newly diagnosed ROS1+ gastric cancer. Morphologically, the cancer is a newly diagnosed ALK-positive gastric cancer.

[0188] In one embodiment, the cancer is colorectal cancer. In one embodiment, the cancer is It is ROS1+ colorectal cancer. In one embodiment, the cancer is ALK+ colorectal cancer. In one embodiment, the cancer is recurrent or refractory colorectal cancer. Morphologically, the cancer is recurrent or refractory ROS1+ colorectal cancer. One embodiment In this case, the cancer is recurrent or refractory ALK+ colorectal cancer. In one embodiment, The cancer is a newly diagnosed colorectal cancer. In one embodiment, the cancer is newly The diagnosed ROS1+ colorectal cancer. In one embodiment, the cancer is newly diagnosed This is a case of ALK-positive colorectal cancer.

[0189] In one embodiment, the cancer is angiosarcoma. In one embodiment, the cancer is R It is an OS1+ angiosarcoma. In one embodiment, the cancer is an ALK+ angiosarcoma. In one embodiment, the cancer is a recurrent or refractory angiosarcoma. In one embodiment, The cancer is a recurrent or refractory ROS1+ angiosarcoma. In one embodiment, the cancer is The cancer is a recurrent or refractory ALK+ angiosarcoma. In one embodiment, the cancer is a new It is a newly diagnosed angiosarcoma. In one embodiment, the cancer is a newly diagnosed RO It is an S1+ angiosarcoma. In one embodiment, the cancer is a newly diagnosed ALK+ angiosarcoma. It is a sarcoma.

[0190] In one embodiment, the cancer is melanoma. In one embodiment, the cancer is spi It is a Spitz nevus-like tumor. In one embodiment, the cancer is a Spitz nevus-like melanoma. In one embodiment, the cancer is ROS1+ Spitz nevus-like melanoma. In this state, the cancer is ALK+ Spitz nevus-like melanoma. In one embodiment, the cancer This is a recurrent or refractory Spitz nevus-like melanoma. In one embodiment, the cancer is It is a recurrent or refractory ROS1+ Spitz nevus-like melanoma. In one embodiment, the is This is a recurrent or refractory ALK+ Spitz nevus-like melanoma. In one embodiment, The cancer is a newly diagnosed melanoma resembling a Spitz nevus. In one embodiment, the cancer This is a newly diagnosed ROS1+ Spitz nevus-like melanoma. In one embodiment, The cancer is a newly diagnosed ALK-positive melanoma with Spitz nevus.

[0191] In one embodiment, the cancer is an epithelioid hemangioendothelioma. The cancer is ROS1+ epithelioid hemangioendothelioma. In one embodiment, the cancer is ALK + Epithelioid hemangioendothelioma. In one embodiment, the cancer is recurrent or refractory epithelioid hemangioendothelioma. This is a cutaneous hemangioendothelioma. In one embodiment, the cancer is recurrent or refractory ROS1+ It is an epithelioid hemangioendothelioma. In one embodiment, the cancer is recurrent or refractory ALK + Epithelioid hemangioendothelioma. In one embodiment, the cancer is a newly diagnosed epithelioid hemangioendothelioma. It is a type of hemangioendothelioma. In one embodiment, the cancer is a newly diagnosed ROS1+ type. It is a cutaneous hemangioendothelioma. In one embodiment, the cancer is a newly diagnosed ALK+ type. It is a cutaneous hemangioendothelioma.

[0192] In one embodiment, the cancer is esophageal cancer. It is CC. In one embodiment, the cancer is ROS1+ESCC. One embodiment In this state, the cancer is ALK+ESCC. In one embodiment, the cancer is recurrent. or refractory ESCC. In one embodiment, the cancer is recurrent or refractory ROS It is 1+ESCC. In one embodiment, the cancer is recurrent or refractory ALK+ES It is CC. In one embodiment, the cancer is newly diagnosed ESCC. In one embodiment, the cancer is a newly diagnosed ROS1+ESCC. Therefore, the cancer in question is a newly diagnosed ALK+ESCC.

[0193] In one embodiment, the cancer is kidney cancer. In one embodiment, the cancer is renal marrow It is a renal medullary carcinoma. In one embodiment, the carcinoma is ROS1+ renal medullary carcinoma. In this state, the cancer is ALK+ renal medullary carcinoma. In one embodiment, the cancer is recurrent. or refractory renal medullary carcinoma. In one embodiment, the cancer is recurrent or refractory ROS 1+ Renal medullary carcinoma. In one embodiment, the cancer is recurrent or refractory ALK+ renal medullary carcinoma. It is a renal medullary carcinoma. In one embodiment, the carcinoma is a newly diagnosed renal medullary carcinoma. In one embodiment, the cancer is a newly diagnosed ROS1+ renal medullary carcinoma. In this case, the cancer is a newly diagnosed ALK+ renal medullary carcinoma. In one embodiment, the The cancer is renal cell carcinoma. In one embodiment, the cancer is ROS1+ renal cell carcinoma. In one embodiment, the cancer is ALK+ renal cell carcinoma. In one embodiment, the cancer is , recurrent or refractory renal cell carcinoma. In one embodiment, the cancer is recurrent or refractory. It is a curable ROS1+ renal cell carcinoma. In one embodiment, the cancer is recurrent or refractory A It is LK+ renal cell carcinoma. In one embodiment, the cancer is a newly diagnosed renal cell carcinoma. In one embodiment, the cancer is a newly diagnosed ROS1+ renal cell carcinoma. In this embodiment, the cancer is a newly diagnosed ALK+ renal cell carcinoma.

[0194] In one embodiment, the cancer is breast cancer. In one embodiment, the cancer is ROS 1+ breast cancer. In one embodiment, the cancer is ALK+ breast cancer. One embodiment In this case, the cancer is recurrent or refractory breast cancer. In one embodiment, the cancer is recurrent It is recurrent or refractory ROS1+ breast cancer. In one embodiment, the cancer is recurrent or refractory. This is a treatable ALK+ breast cancer. In one embodiment, the cancer is a newly diagnosed breast cancer. In one embodiment, the cancer is a newly diagnosed ROS1+ breast cancer. Morphologically, the cancer is a newly diagnosed ALK+ breast cancer. In one embodiment, the breast The cancer is triple-negative breast cancer.

[0195] In one embodiment, the cancer is colon cancer. In one embodiment, the cancer is RO It is S1+ colon cancer. In one embodiment, the cancer is ALK+ colon cancer. In the application form, the cancer is recurrent or refractory colon cancer. In one embodiment, the cancer This is recurrent or refractory ROS1+ colon cancer. In one embodiment, the cancer is recurrent It is a sexual or refractory ALK+ colon cancer. In one embodiment, the cancer is newly diagnosed It is a colon cancer. In one embodiment, the cancer is a newly diagnosed ROS1+ colon cancer. Yes. In one embodiment, the cancer is a newly diagnosed ALK+ colon cancer.

[0196] In one embodiment, the cancer is thyroid cancer. In one embodiment, the cancer is A It is a papillary thyroid carcinoma. In one embodiment, the carcinoma is a ROS1+ papillary thyroid carcinoma. In one embodiment, the cancer is ALK+ papillary thyroid carcinoma. In one embodiment, The cancer is recurrent or refractory papillary thyroid carcinoma. In one embodiment, the cancer is recurrent Or it is refractory ROS1+ papillary thyroid carcinoma. In one embodiment, the cancer is recurrent or refractory ALK+ papillary thyroid carcinoma. In one embodiment, the cancer is newly diagnosed This is a newly diagnosed papillary thyroid carcinoma. In one embodiment, the cancer is a newly diagnosed ROS1+ This is papillary thyroid carcinoma. In one embodiment, the cancer is a newly diagnosed ALK+ thyroid cancer. It is papillary carcinoma.

[0197] In one embodiment, the cancer is neuroblastoma. In one embodiment, the cancer is , ROS1+ neuroblastoma. In one embodiment, the cancer is ALK+ neuroblastoma. It is a tumor. In one embodiment, the cancer is a recurrent or refractory neuroblastoma. In one embodiment, the cancer is a recurrent or refractory ROS1+ neuroblastoma. In one embodiment, the cancer is a recurrent or refractory ALK+ neuroblastoma. In this embodiment, the cancer is a newly diagnosed neuroblastoma. The cancer is a newly diagnosed ROS1+ neuroblastoma. In one embodiment, the cancer This is a newly diagnosed ALK-positive neuroblastoma.

[0198] In one embodiment, the cancer (or ROS1+ cancer, or ALK+ cancer) is caused by blood It is a liquid cancer. In one embodiment, the cancer (or ROS1+ cancer, or ALK+) n) is a lymphoma. In one embodiment, the lymphoma is a non-Hodgkin lymphoma. In one embodiment, the lymphoma is anaplastic large cell lymphoma (ALCL), diffuse Large B-cell lymphoma (DLBCL), or large B-cell lymphoma. Hematological cancer. In addition, treatment methods for other blood disorders or hematological malignancies that are ROS1+ or ALK+ This is also provided herein.

[0199] In one embodiment, the cancer is ALCL. In one embodiment, the cancer is R It is OS1+ALCL. In one embodiment, the cancer is ALK+ALCL. In one embodiment, the cancer is recurrent or refractory ALCL. In one embodiment, The cancer is recurrent or refractory ROS1+ALCL. In one embodiment, the cancer is The cancer is recurrent or refractory ALK+ALCL. In one embodiment, the cancer is novel. It is ALCL that has been diagnosed. In one embodiment, the cancer is newly diagnosed RO It is S1+ALCL. In one embodiment, the cancer is a newly diagnosed ALK+ALCL. It is CL.

[0200] In one embodiment, the cancer is DLBCL. In one embodiment, the cancer is It is ROS1+DLBCL. In one embodiment, the cancer is ALK+DLBCL. In one embodiment, the cancer is recurrent or refractory DLBCL. Morphologically, the cancer is recurrent or refractory ROS1+ DLBCL. One embodiment In this case, the cancer is recurrent or refractory ALK+DLBCL. In one embodiment, The cancer is a newly diagnosed DLBCL. In one embodiment, the cancer is newly The diagnosed ROS1+DLBCL. In one embodiment, the cancer is newly diagnosed This is ALK+DLBCL.

[0201] In one embodiment, the cancer is a large B-cell lymphoma. The cancer is ROS1+ large B-cell lymphoma. In one embodiment, the cancer is , ALK+ large B-cell lymphoma. In one embodiment, the cancer is recurrent and This is a refractory large B-cell lymphoma. In one embodiment, the cancer is recurrent or It is a refractory ROS1+ large B-cell lymphoma. In one embodiment, the cancer is relapsed. It is a sexual or refractory ALK+ large B-cell lymphoma. In one embodiment, the cancer is , a newly diagnosed large B-cell lymphoma. In one embodiment, the cancer is newly It is a ROS1+ large B-cell lymphoma that has been diagnosed. In one embodiment, the cancer This is a newly diagnosed case of ALK-positive large B-cell lymphoma.

[0202] In one embodiment, the cancer (or ROS1+ cancer, or ALK+ cancer) is a new It is diagnosed as the cancer (or ROS1+ cancer, or ALK) in one embodiment. (Cancer) has not been treated to date.

[0203] In one embodiment, the cancer (or ROS1+ cancer, or ALK+ cancer) is recurrent It is either chronic or refractory. In one embodiment, the cancer is recurrent. In this condition, the cancer (or ROS1+ cancer, or ALK+ cancer) is refractory to treatment.

[0204] In one embodiment, the subject has not received any treatment before. The subject is treatment-naïve to tyrosine kinase inhibitor (TKI) therapy. In one embodiment, the subject has received primary or secondary treatment. The subject has received secondary or higher treatment. In one embodiment, the subject has received primary or higher treatment. It has acquired resistance to the treatment. In one embodiment, the prior treatment is tyrosine It includes a transdermal inhibitor (TKI). In one embodiment, the prior treatment is crizotinib, ceritinib B, alectinib, brigatinib, lorlatinib, entrectinib, repotrectinib Cabozantinib, foretinib, taretrectinib, merestinib, masitinib, and It comprises one or more ensartinibs. In one embodiment, the prior treatment is one or more This includes chemotherapy. In one embodiment, one or more chemotherapy agents are added to the TKI therapy. It can be done.

[0205] In one embodiment, the cancer (or ROS1+ cancer, or ALK+ cancer) is It is resistant to rosin kinase inhibitors (TKIs).

[0206] In one embodiment, the cancer is resistant lung cancer. In one embodiment, the cancer is resistant It is a non-small cell lung cancer. In one embodiment, the cancer is a TKI-resistant non-small cell lung cancer. In one embodiment, the cancer is TKI-resistant ROS1+ non-small cell lung cancer. In terms of treatment morphology, the cancer is TKI-resistant ALK+ non-small cell lung cancer.

[0207] In one embodiment, the cancer is lung cancer (e.g., NSCLC), and the cancer is TK The condition has relapsed after prior treatment with I, or is refractory to treatment.

[0208] In one embodiment, the compounds provided herein are administered as a first-line treatment. In one embodiment, the compounds provided herein are administered as a second-line treatment. In terms of form, the compounds provided herein are administered as third-line or fourth-line treatment.

[0209] In one embodiment, the cancer (or ROS1+ cancer, or ALK+ cancer) is metastatic. It is metastatic. In one embodiment, the cancer has CNS metastases. In one embodiment, The cancer has brain metastases. In one embodiment, the cancer is metastatic non-small cell lung cancer (N SCLC) In one embodiment, the cancer is metastatic ROS1+NSCLC. In one embodiment, the cancer is metastatic ALK+NSCLC.

[0210] In one embodiment, the herein provides a metastatic ALK+ non-small cell lung cancer (NSC) A method for treating a patient with LC, wherein the method provides the patient with a therapeutically effective amount as specified herein. The compound to be provided, for example, the compound of formula (I), or its enantiomer, enantiomer This includes administering a mixture of or tautomers thereof, or a pharmaceutically acceptable salt thereof. .

[0211] In one embodiment, the herein provides a metastatic ROS1+ non-small cell lung cancer (NS) A method for treating patients with CLC, wherein the method involves providing the patient with a therapeutically effective amount of the present specification. Compounds to be provided in this book, for example, the compound of formula (I), or its enantiomers, enantiomers, etc. Administering a mixture of Omer, a tautomer, or a pharmaceutically acceptable salt thereof. Includes.

[0212] In one embodiment, the patient is an adult patient. In one embodiment, the patient is a small The patient is a child.

[0213] In one embodiment, the foregoing provides information on adult patients with metastatic ROS1+ NSCLC. A method for treating a person, the method for providing the patient with a therapeutically effective amount as specified herein. Compounds, for example, the compound of formula (I), or its enantiomers, or mixtures of enantiomers. This includes administering the substance, its tautomer, or a pharmaceutically acceptable salt thereof.

[0214] In one embodiment, the foregoing provides information on adult patients with metastatic ROS1+ NSCLC. A method for treating a person, the method for providing the patient with a therapeutically effective amount as specified herein. Compounds, for example, the compound of formula (I), or its enantiomers, or mixtures of enantiomers. The treatment involves administering the substance, its tautomer, or a pharmaceutically acceptable salt thereof to the patient. The individual has progressed to at least one previous TKI therapy, or has had a negative experience with it. They are intolerant.

[0215] In one embodiment, the solvent front mutation is provided herein. A method for treating adult patients with metastatic NSCLC that is ROS1+ and has G2032R, The method involves administering to the patient a therapeutically effective amount of the compound provided herein, for example, formula (I) Compounds thereof, or their enantiomers, mixtures of enantiomers, or tautomers, or administering a pharmaceutically acceptable salt thereof, wherein the patient has at least one You have previously progressed to or are intolerant to TKI therapy.

[0216] In one embodiment, the herein provides a ROS1-related (or ROS1+) This is a treatment method for a patient requiring treatment for a cancer, and the cancer is treated by inhibiting tyrosine kinase The target has acquired resistance to the toxic agent (TKI), and the method involves delivering a therapeutically effective dose to the target. The compounds provided herein include, for example, the compound of formula (I), or its enantiomer, etc. Administer a mixture of nantiomers, tautomers, or pharmaceutically acceptable salts thereof. This includes doing so.

[0217] In one embodiment, the herein provides a ROS1-related (or ROS1+) This is a treatment method for a patient requiring treatment for a cancer, and the cancer is treated by inhibiting tyrosine kinase The cancer has acquired resistance to toxin-producing agents (TKIs), and the cancer is resistant to one or more ROS1 inhibitors. The subject has been identified as having a mutation, and the method provides the subject with a therapeutically effective amount as specified herein. Compounds to be provided, for example, the compound of formula (I), or its enantiomer, enantio The administration of a mixture of Mar, or a tautomer, or a pharmaceutically acceptable salt thereof. Includes. In one embodiment, the one or more ROS1 inhibitor resistance mutations are included in 1986, 2 One or more amino acids selected from 004, 2026, 2032, and 2033 Includes mino acid substitution. In one embodiment, the one or more ROS1 inhibitor resistance mutations are S1986F, S1986Y, F2004C, F2004V, L2026M, G2032 One or more amino acids selected from R, D2033N, L2086F, and G2101A Includes substitution. In one embodiment, the one or more ROS1 inhibitor resistance mutations are G20 It is 32R. In one embodiment, the one or more ROS1 inhibitor resistance mutations are G2 032R, S1986F, S1986Y, F2004C, F2004V, L2026M This includes one or more of D2033N or G2101A. In one embodiment, The ROS1 inhibitor resistance mutation is L2086F.

[0218] In one embodiment, the foregoing describes the treatment of ALK-related (or ALK+) cancer. A treatment method for a target requiring treatment, and the cancer is treated with tyrosine kinase inhibitors. The subject has acquired resistance to (TKI), and the method involves delivering a therapeutically effective dose to the subject. The compounds provided in the details include, for example, the compound of formula (I), or its enantiomers and enanes. Administering a mixture of thiomers, tautomers, or pharmaceutically acceptable salts thereof This includes.

[0219] In one embodiment, the foregoing describes the treatment of ALK-related (or ALK+) cancer. A treatment method for a target requiring treatment, and the cancer is treated with tyrosine kinase inhibitors. The cancer has acquired resistance to (TKIs), and the cancer has undergone sudden mutations resistant to one or more ALK inhibitors. It has been identified that it has differences, and the method provides to the subject a therapeutically effective amount. Compounds that do this, for example, the compound of formula (I), or its enantiomer, the enantiomer This includes administering a mixture, a tautomer, or a pharmaceutically acceptable salt thereof. In one embodiment, the one or more ALK inhibitor resistance mutations are 1196, 1198, It contains one or more amino acid substitutions at amino acid positions selected from 1202 and 1269. In one embodiment, the one or more ALK inhibitor resistance mutations are L1196M, L11 Includes one or more amino acid substitutions selected from 98F, G1202R, and G1269A In one embodiment, the one or more ALK inhibitor resistance mutations are G1202R. In one embodiment, the one or more ALK inhibitor resistance mutations are G1202R and L Includes one or more of 1196M, L1198F, and G1269A.

[0220] In one embodiment, the present invention provides an ALK having the mutation G1202R. A method for treating adult patients with metastatic NSCLC, the method for treating the patient A therapeutically effective amount of the compound provided herein, for example, the compound of formula (I), or its enantiolytic Omers, enantiomers, mixtures or tautomers thereof, or their pharmaceutically acceptable forms The treatment involves administering salt, and the patient has progressed to at least one prior TKI therapy. They either have it or are intolerant of it.

[0221] In one embodiment, the foregoing describes the treatment of ALK-related (or ALK+) cancer. A treatment method for a target requiring treatment, and the cancer is treated with tyrosine kinase inhibitors. The subject has acquired resistance to (TKI), and the method involves delivering a therapeutically effective dose to the subject. The compounds provided in the details include, for example, the compound of formula (I), or its enantiomers and enanes. Administering a mixture of thiomers, tautomers, or pharmaceutically acceptable salts thereof This includes.

[0222] In one embodiment, the TKI is a ROS1 inhibitor. KI is an ALK inhibitor. In one embodiment, the TKI is crizotinib, cetyl sylvestre. Nib, Alectinib, Brigatinib, Lorlatinib, Entrectinib, Repotrectinib Cabozantinib, Foretinib, Melestinib, Taretrectinib, Macitinib, or ensartinib. In one embodiment, the TKI is crizotinib. In one embodiment, the TKI is entrectinib.

[0223] In a particular embodiment, the subject has experienced a recurrence of the cancer after primary treatment. Other embodiments In this case, the patient experienced a recurrence of the cancer after secondary treatment.

[0224] In one embodiment, the cancer or disease is present in a pediatric patient (including an infant patient). In one embodiment, the cancer is present in pediatric patients aged 1 year or older, and in young adults with ALK+ It is systemic anaplastic large cell lymphoma (ALCL). In another embodiment, the cancer is present in children under 1 year of age. The above describes relapsed or refractory systemic anaplastic large cell carcinoma with ALK+ in pediatric patients and young adults. It is follicular lymphoma (ALCL). In one embodiment, the cancer is present in pediatric patients aged 1 year or older. And ROS1+ systemic anaplastic large cell lymphoma (ALCL) in young adults. In this embodiment, the cancer is characterized by recurrent ROS1+ in pediatric patients aged 1 year or older, and in young adults. It is a first-acting or refractory systemic anaplastic large cell lymphoma (ALCL).

[0225] In a particular embodiment, the method for treating or preventing cancer involves one or more responses, for example. Increased apoptosis, inhibition of tumor growth, reduced tumor metastasis, inhibition of tumor metastasis, microvascular density This is demonstrated by a reduction in tumor size, decreased angiogenesis, inhibition of tumor metastasis, tumor regression, and prolongation of the patient's life. It is possible.

[0226] Combination therapy In some embodiments, the method for treating or preventing cancer comprises one or more compounds of formula (I). This may include administration in combination with other chemotherapeutic agents(s) listed above.

[0227] As used herein, unless otherwise specified, "jointly" or "in combination with ~" "In conjunction with" means that the compound of formula (I) must be administered at the same time as other drugs, and / or does not mean that they must be formulated together for delivery, but The methods of delivery are within the scope of this disclosure. The compounds provided herein include one or more other It may be administered simultaneously with other medications (for example, one or more other medications), or before. (For example, 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours) 24 hours, 48 ​​hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 It may be administered weekly, 12 weeks, or 16 weeks prior, or afterward (for example, 5 minutes, 15 minutes). 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 1 It may also be administered after 6 weeks. Generally, each treatment is determined for that specific drug. It is administered in the prescribed dose and / or time schedule. Other therapeutic agents are provided herein. The compounds involved may be administered as a single composition or separately as different compositions. In some cases, this may be the case. Triple therapy is also intended herein.

[0228] Examples of chemotherapeutic agents that may be administered in combination with the compounds of this disclosure include 1-amino-4-pheni Luamino-9,10-dioxo-9,10-dihydroanthracene-2-sulfonate ( Acid Blue 25), 1-amino-4-[4-hydroxyphenyl-amino]-9,1 0-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-dihydroanthra Sen-2-sulfonate, 1-amino-4-[2-anthracenylamino]-9,10- Dioxo-9,10-dihydroanthracene-2-sulfonate, ABT-263, Af Atinib dimaleate, axitinib, aminoglutethimide, amsacrine, anastro Zoll, APCP, asparaginase, AZD5363, Calmette-Guérin vaccine (bcg), bicalutamide, bleomycin, bortezomib, β-methylene-ADP(A OPCP), buserelin, busulfan, cabazitaxel, cabozantinib, campotesi N, capecitabine, carboplatin, carfilzomib, carmustine, ceritinib, Lorambucil, chloroquine, cisplatin, cladribine, clodronate, cobimethinine B, colchicine, crizotinib, cyclophosphamide, cyproterone, cytarabine, daca Luvasine, dactinomycin, daunorubicin, demethoxypyridine, dexamethasone, Dichloroacetic acid, dienestrol, diethylstilbestrol, docetaxel, doxo Rubicin, Epirubicin, Eribulin, Erlotinib, Estradiol, Estramus Chin, etoposide, everolimus, exemestane, filgrastim, fludarabine, Fludrocortisone, fluorouracil, fluoxymesterone, flutamide, gefiti Nib, gemcitabine, genistein, goserelin, GSK1120212, hydroxy Rare, idarubicin, ifosfamide, imatinib, interferon, irinotecan, Ixabepirone, lenalidomide, letrozole, leucovorin, leuprolide, rebamizole Lomustine, lonidamine, mechloretamine, medroxyprogesterone, megest Roll, melphalan, mercaptopurine, mesna, metformin, methotrexate, Miltefosine, Mitomycin, Mitotan, Mitoxantrone, MK-2206, Mutama Icin, N-(4-sulfamoylphenylcarbamateoyl)pivalamide, NF2 79, NF449, Niltamide, Nocodazole, Octreotide, Olaparib, Oxali Platin, paclitaxel, pamidronate, pazopanib, pemexetred (pemex (etred), pentostatin, perifosin, PF-04691502, Plicamais Pomalidomide, Porfimer, PPADS, Procarbazine, Quercetin, Larthio Trexed, Ramucirumab, Reactive Blue 2, Rituximab, Rolophilin, Romi Depsin, rucaparib, selumetinib, sirolimus, 2,4-dinitrobenzenesulfone Sodium acid, sorafenib, streptozocin, sunitinib, suramin, thalazoparib Tamoxifen, temozolomide, temsirolimus, teniposide, testosterone, saline Domide, thioguanine, thiotepa, titanocene dichloride, tonapophylline, topotecan, Trametinib, trastuzumab, tretinoin, veliparib, vinblastine, vincri Examples include stine, vindesine, vinorelbine, and vorinostat (SAHA). In the embodiments, the chemotherapeutic agent that may be administered in combination with the compounds of the present disclosure is ABT- 263, Dexamethasone, 5-Fluorouracil, PF-04691502, Romidepsy Examples include , and vorinostat (SAHA). In other embodiments, compounds of the present disclosure As a chemotherapeutic agent that can be administered in combination with, 1-amino-4-phenylamino-9,1 0-Dioxo-9,10-dihydroanthracene-2-sulfonate (Acid Blue 2) 5) 1-amino-4-[4-hydroxyphenyl-amino]-9,10-dioxo-9 ,10-dihydroanthracene-2-sulfonate, 1-amino-4-[4-aminophen [Nylamino]-9,10-Dioxo-9,10-Dihydroanthracene-2-sulfonate T, 1-amino-4-[1-naphthylamino]-9,10-dioxo-9,10-dihydr Roanthracene-2-sulfonate, 1-amino-4-[4-fluoro-2-carboxy] Phenylamino]-9,10-dioxo-9,10-dihydroanthracene-2-sulfo Nate, 1-amino-4-[2-anthracenylamino]-9,10-dioxo-9,1 0-Dihydroanthracene-2-sulfonate, APCP, β-methylene-ADP(AO PCP), capecitabine, cladribine, cytarabine, fludarabine, doxorubicin, Gemcitabine, N-(4-sulfamoylphenylcarbamateoyl)pivalamide, NF279, NF449, PPADS, Quercetin, Reactive Blue 2, Rolophili N, 2,4-dinitrobenzenesulfonate sodium, smarin, and tonapophyllin It can be listed.

[0229] Many combination therapies have been developed for the treatment of cancer. In certain embodiments, The indicated compound (for example, the compound of formula (I)) may be administered in conjunction with one or more combination therapies. Table 2 lists examples of combination therapies that may be administered in conjunction with the compounds of this disclosure. [Table 2] TIFF2026082971000080.tif235165TIFF2026082971000081.tif242165TIFF2026082971000082.tif22916 5TIFF2026082971000083.tif211165TIFF2026082971000084.tif241165TIFF2026082971000085.tif96165

[0230] In certain embodiments, the collaborative therapy of this disclosure may involve other types of chemotherapeutic agents, for example, This includes co-administration with immunotherapy agents. Cancer cells can often be recognized by the immune system. It has a specific cell surface antigen. Therefore, cancer immunotherapy agents, such as monoclonal antibodies, It can selectively bind to cancer cell antigens and induce cell death. Other cancers Immunotherapy agents suppress the inhibition of the tumor-mediated innate immune response or the immune response This can activate and, consequently, promote the immune system's recognition of tumors. Exemplary antibody cancer Immunotherapy drugs include avagobomab, adecatumumab, aftuzumab, alemtuzumab, Anatumomab mafenatox, apolizumab, blinatumomab, BMS-936559 Katsumakisomab, durvalumab, epacadostat, epratuzumab, indoximo Inotuzumab ozogamicin, intermumab, ipilimumab, isatuximab, ra Ambrolizumab, MED14736, MPDL3280A, Nivolumab, Obinutuzumab okalatuzumab, ofatumumab, oratazumab, pembrolizumab, pidilizumab These include rituximab, tisilimunab, samarizumab, and tremelimumab, but The following are not limited to these. In some embodiments, the antibody cancer immunotherapy agent is an anti-CD73 mono Clonal antibodies (mAbs), anti-CD39 mAb, anti-PD-1 mAb, and anti-CTLA4 m Selected from A. Therefore, in some embodiments, the method of the present disclosure is one or more This includes immunotherapy agents, such as co-administration of the above-mentioned drugs.

[0231] In some embodiments, the combination therapy involves the compounds of the Disclosure, for example, the compound of formula (I). And SH2 inhibitors, for example, CGP78850, CPG85793, C90, C126, This includes co-administration of G7-18NATE, G7-B1, and NSC642056.

[0232] In some embodiments, the combination therapy involves the compounds of the Disclosure, for example, the compound of formula (I). And MEK inhibitors, such as trametinib, cobimetinib, binimetinib, and selumetinib This includes co-administration of PD-325901, CI-1040, and TAK-733.

[0233] In some embodiments, the combination therapy involves the compounds of the Disclosure, for example, the compound of formula (I). JNJ-38877605, PF-04217903, Foretinib, AMG458 Tivantinib, cabozantinib, crizotinib, capmatinib hydrochloride, tepotinib hydrochloride This includes co-administration of salt and a MET inhibitor selected from savolitinib.

[0234] In some embodiments, the combination therapy involves the compounds of the Disclosure, for example, formula (I) and TN Select from O-155, RMC-4630, JAB-3068, or RLY-1971 This includes co-administration of SHP2 inhibitors.

[0235] In some embodiments, the combination therapy involves the compounds of the Disclosure, for example, the compound of formula (I). And, aliskiren, captopril, losartan, irbesartan, olmesartan, can Desartan, Valsartan, Fimasartan, Azilsartan, Telmisartan, Epro Sartan, Benazepril, Enalapril, Lisinopril, Perindopril, Quinapril This includes co-administration of a RAS inhibitor selected from ramipril and trandolapril.

[0236] In some embodiments, the combination therapy uses compounds provided herein, for example, compounds of formula (I The administration includes a combination of the compound ) and a TKI. In one embodiment, the TKI is R It is an OS1 inhibitor. In one embodiment, the TKI is an ALK inhibitor. In terms of administration, the TKI is crizotinib, ceritinib, alectinib, brigatinib, ro Luratinib, Entrectinib, Repotrectinib, Cabozantinib, Foretinib, Me These are restinib, tarretrectinib, masitinib, or ensartinib. One implementation In terms of form, the TKI is crizotinib. In one embodiment, the TKI is ecto It is lectinib. In one embodiment, the TKI is alectinib. One embodiment Morphologically, the TKI in question is brigatinib.

[0237] In some embodiments, the combination therapy involves the compounds of the Disclosure, for example, the compound of formula (I). This includes co-administration of anti-PD-1 therapy. In certain embodiments, the combination therapy is disclosed in this disclosure. This includes co-administration of a compound, for example, the compound of formula (I), with oxaliplatin. Other implementations In form, the combination therapy comprises the compounds of the present disclosure, for example, the compound of formula (I), and doxorubicin. This includes co-administration of [the drug].

[0238] In certain embodiments, the compounds of the present disclosure are used in conjunction with non-chemical cancer treatment methods. It may be administered. In certain embodiments, the compounds of the present disclosure are administered in conjunction with radiotherapy. In certain embodiments, the compounds of the present disclosure may be used in surgical procedures, thermal ablation, and focused ultrasound therapy. It may be administered in conjunction with therapies, cryotherapy, or any combination thereof.

[0239] In certain embodiments, the compounds of the Disclosure cooperate with one or more other compounds of the Disclosure. It can be administered in combination with other therapeutic drugs, such as cancer and immune diseases. or administered in combination with other drugs suitable for the treatment of neurological disorders, such as the drugs specified above. In certain embodiments, the compounds of this disclosure are used in combination with one or more further chemotherapeutic agents. By administering them in this way, a synergistic effect is achieved. In certain embodiments, one or more The combined administration of these additional chemotherapy agents results in an additive effect.

[0240] Pharmaceutical composition In certain embodiments, the present disclosure provides a pharmaceutical product suitable for use in human patients, and the medical The chemical is any of the above compounds (for example, the compounds of this disclosure, for example, the compound of formula (I)). and comprising one or more pharmaceutically acceptable excipients. In certain embodiments, the pharmacopoeia is It may be used for the treatment or prevention of conditions or diseases described herein. Any of the compounds disclosed herein are agents for the treatment of any disease or condition disclosed herein. It can be used in the manufacture of [something].

[0241] The compositions and methods of this disclosure may be used to treat subjects in need of treatment. In certain embodiments, the subject is a mammal, for example, a human or a non-human mammal. When administered to a target, for example, a human, the composition or compound is preferably, for example, The compounds of this disclosure and a pharmaceutically acceptable carrier are administered as a pharmaceutical composition. Acceptable carriers are well known in the art, for example, aqueous solutions, for example, water or physiological Buffered saline or other solvent or medium, for example, glycol, glycerol, oil, for example For example, it may contain olive oil or an organic ester for injection. In a preferred embodiment, such a pharmaceutical The composition is for administration to humans, particularly via invasive routes of administration (i.e., transmissible through the epithelial barrier). For routes that avoid transmission or diffusion (e.g., injection or implantation), the aqueous solution is pyro It is gen-free or substantially pyrogen-free. The excipients are, for example, pharmaceuticals. This results in delayed release of or selectively targets one or more cells, tissues, or organs. The pharmaceutical composition may be selected to be in the form of a dosage unit, for example, a tablet, a capsule ( (Including prinkle capsules and gelatin capsules), granules, freeze-dried materials for reconstitution, powder The composition may be contained in solutions, syrups, suppositories, injections, etc. The composition can be delivered transdermally, for example, through skin It may also be included in skin patches. The composition may also be included in solutions suitable for topical administration, such as eye drops. It is possible.

[0242] A pharmaceutically acceptable carrier is, for example, one that stabilizes a compound such as the compound of this disclosure. , physiologically acting to increase its solubility or increase its absorption It may contain physiologically acceptable drugs. Such physiologically acceptable drugs include, for example, carbohydrates. Compounds, such as glucose, sucrose, or dextran; antioxidants, such as as Corbic acid or glutathione, chelating agents, low molecular weight proteins or other stabilizers Examples include excipients. A pharmaceutically acceptable carrier containing a physiologically acceptable drug. The choice depends, for example, on the route of administration of the composition. The formulation or pharmaceutical composition is self-emulsifying. This can be either a conventional drug delivery system or a self-microemulsifying drug delivery system. The pharmaceutical composition (formulation) may, for example, incorporate the compound of the present disclosure therein. It may also be a posome or other polymer matrix. For example, phospholipids or other lipids The liposomes contained are non-toxic, physiologically acceptable, and metabolizable carriers, and are relatively It is simply prepared and administered.

[0243] The expression "medically acceptable" in this specification means, within the bounds of sound medical judgment. Without excessive toxicity, irritation, allergic reactions, or other problems or complications, the treatment will be effective on the target tissue. Compounds, materials, and compositions suitable for use in contact with, with a reasonable benefit / risk ratio. Used to refer to and / or dosage forms.

[0244] As used herein, the expression “medically acceptable carrier” means “medically acceptable.” Materials, compositions, or media, such as liquid or solid fillers, diluents, excipients, solvents or This refers to the encapsulation material. Each carrier is compatible with the other components of the formulation and is not harmful to the subject. It needs to be "acceptable" in the sense that it is not. It can function as a medically acceptable carrier. Some examples of materials include (1) sugars, such as lactose, glucose, and sugar. (2) Starch, e.g., cornstarch and potato starch, (3) Cell Roses and their derivatives, for example, sodium carboxymethylcellulose, ethylcellulose (4) Tragacanth powder, (5) Malt, (6) Gelatin, (7 ) Talc, (8) Excipients, e.g., cocoa butter and suppository wax, (9) Oils, e.g., Peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil, ( 10) Glycols, e.g., propylene glycol, (11) Polyols, e.g., glycol Serine, sorbitol, mannitol, and polyethylene glycol, (12) ester, For example, ethyl oleate and ethyl laurate, (13) agar, (14) buffering agent, for example (15) Magnesium hydroxide and aluminum hydroxide, (16) Alginic acid, (16) Pyro Genfree water, (17) isotonic saline, (18) Ringer's solution, (19) ethyl alcohol (20) Phosphate buffer, and (21) Other non-toxic, suitable substances used in pharmaceutical formulations It can be listed.

[0245] Pharmaceutical compositions (formulations) are administered to the target, for example, orally (for example, in aqueous or non-aqueous solutions). Drains, tablets, and capsules in liquid or suspension form (sprinkle capsules and gelatin capsules) (including cells), bolus, powder, granules, paste for application to the tongue, via the oral mucosa Absorption (e.g., sublingual), anal, rectal, or vaginal (e.g., pessary, cream, or fluid) (as a foam), parenteral (intramuscular, intravenous, subcutaneous or intrathecal, e.g., sterile solution or (As a suspension), intranasal, intraperitoneal, subcutaneous, transdermal (e.g., a patch applied to the skin), And topical applications (for example, creams, ointments or sprays applied to the skin, or eye drops) The compound may be administered by any of several routes of administration, including by inhalation. It can also be formulated. In certain embodiments, the compound is simply dissolved or suspended in sterile water. It is possible. Details of appropriate routes of administration and suitable compositions can be found, for example, in U.S. Patent No. 6, 11. No. 0,973, No. 5,763,493, No. 5,731,000, No. 5,541,23 No. 1, No. 5,427,798, No. 5,358,970 and No. 4,172,896, This can also be found in the patents cited therein.

[0246] This preparation may be included in the unit dosage form for convenience, and is also a well-known optional formulation in the field of pharmacy. It can be prepared by the following method. It can be combined with a carrier material to produce a single dosage form. The amount of active ingredient that can be produced varies depending on the patient receiving treatment and the specific administration method. The amount of active ingredient that can be combined with a carrier material to produce the therapeutic effect is, generally speaking, This is the amount of compound that produces it. Generally, out of 100 percent, this amount is about 1 percent. To about 99 percent of the active ingredients, preferably about 5 percent to about 70 percent. Preferably, it ranges from about 10 percent to about 30 percent.

[0247] Methods for preparing these formulations or compositions involve using an active compound, such as the compound of this disclosure, as a carrier. and optionally includes the step of associating with one or more auxiliary components. Generally, the formulations are as disclosed herein. The compound is uniformly and closely mixed with a liquid carrier, a finely ground solid carrier, or both. It is prepared by assembling the components and then, if necessary, shaping the product.

[0248] Each of the formulations of the present disclosure suitable for oral administration contains a predetermined amount of the compound of the present disclosure as an active ingredient. Capsules (including sprinkle capsules and gelatin capsules), cachet, pills, Tablets, lozenges (flavored base, usually sucrose and acacia or tragacan) (Using a t-shape), in the form of lyophilized material, powder, granules, or aqueous or non-aqueous liquid solutions. Alternatively, a suspension, or an oil-in-water or water-in-oil liquid emulsion, or an elixir Preparation or syrup, or pastille (gelatin and glycerin, or sucrose) (and may use inert bases such as acacia), and / or may be included in mouthwash, etc. The composition or compound may also be administered as a bolus, lick, or paste.

[0249] Solid dosage forms for oral administration (including capsules (sprinkle capsules and gelatin capsules)) To prepare tablets, pills, sugar-coated tablets, powders, granules, etc., the active compound is used in one or more of the following ways: pharmaceutically acceptable carriers, such as sodium citrate or dicalcium phosphate, and It is mixed with / or any of the following: (1) a filler or bulking agent, e.g., starch , lactose, sucrose, glucose, mannitol, and / or silicic acid, (2) Combinations, for example, carboxymethylcellulose, alginate, gelatin, polyvinyl pyropropyl alcohol (3) Moisturizers, e.g., glycerol, lidon, sucrose, and / or acacia, etc. (4) Disintegrants, such as agar, calcium carbonate, potato starch, or tapiocaden Pun, alginic acid, certain silicates, and sodium carbonate, (5) dissolution retarders, e.g. For example, paraffin, (6) absorption enhancers, for example, quaternary ammonium compounds, (7) wetting (8) Absorbent materials, e.g., cetyl alcohol and glycerol monostearate, etc. For example, kaolin and bentonite clay, (9) lubricants, such as talc, stearic acid Calcium, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate Thorium, and mixtures thereof, (10) complexing agents, for example, modified cyclodextrin and Unmodified cyclodextrin, and (11) coloring agent. Capsule (sprinkle capsule) In the case of tablets and pills (including gelatin capsules), the pharmaceutical composition contains a buffering agent. This is also fine. Similar types of solid compositions also include lactose or milk sugar and high molecular weight polyethylene. Used as a filler for soft and hard gelatin capsules with excipients such as ethylene glycol. It is possible.

[0250] Tablets can be prepared by compression or molding, along with one or more auxiliary components as desired. The compressed tablets contain a binder (e.g., gelatin or hydroxypropyl methylcellulose) and a smoothing agent. Agents, inert diluents, preservatives, disintegrants (e.g., sodium starch glycolate or sphagnum) Prepared using bridged carboxymethylcellulose sodium, a surfactant, or a dispersant. It is possible. Molded tablets are formed by forming a mixture of powdered compounds moistened with an inert liquid diluent using appropriate machinery. It can be created by shaping it.

[0251] Tablets and other solid dosage forms of the pharmaceutical composition, such as sugar-coated tablets and capsules (sprinkle capsules). Pills and gelatin capsules, pills and granules may optionally have incisions, Coatings and shells, for example, enteric coatings and other coatings well known in the field of pharmaceutical formulations. They may also be prepared by coating. They also provide, for example, a desired emission profile. Various proportions of hydroxypropyl methylcellulose and other polymer matrices for use in , liposomes and / or microspheres are used to sustained release of the active ingredients contained therein. Alternatively, they can be formulated to produce controlled release. These can be used, for example, in bacterial retention filters. By filtering through a filter, or by dissolving in sterile water or other sterile injection medium immediately before use. It can be sterilized by incorporating a sterilizing agent in the form of a sterile solid composition that can be dissolved. These compositions may optionally contain an opaque agent, and may also be effective only in certain parts of the gastrointestinal tract. Alternatively, the composition may preferentially release the active ingredient(s) in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes. The active ingredient is also microencapsulated, where appropriate, containing one or more of the above excipients. It can be in any form.

[0252] Liquid dosage forms useful for oral administration include pharmaceutically acceptable emulsions and reconstituted frozen liquids. Examples include dried products, microemulsions, solutions, suspensions, syrups, and elixirs. In addition to the active ingredient, the liquid dosage form may contain, for example, water or other solvents, cyclodextrin. Alcohol and its derivatives, solubilizers and emulsifiers, such as ethyl alcohol, isopropyl alcohol, etc. Alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol Recall, 1,3-butylene glycol, oil (specifically, cottonseed oil, peanut oil, corn oil) (Kochia oil, germ oil, olive oil, castor oil and sesame oil), glycerol, tetrahydrofluoric acid Furyl alcohol, polyethylene glycol and sorbitan fatty acid esters, and These mixtures may also contain inert diluents commonly used in the art.

[0253] In addition to the inert diluent, the oral composition contains adjuvants, such as wetting agents, emulsifiers and It may also contain suspending agents, sweeteners, flavoring agents, coloring agents, fragrances, and preservatives.

[0254] The suspension, in addition to the active compound, contains a suspending agent, such as ethoxylated isostearyl alcohol. cellulose, polyoxyethylene sorbitol and sorbitan ester, microcrystalline cellulose, Aluminum metahydroxide, It may also contain celandite, agar, and tragacanth, as well as mixtures thereof.

[0255] Pharmaceutical compositions for rectal, vaginal, or urethral administration may be provided as suppositories. This involves one or more active compounds, for example, cocoa butter, polyethylene glycol, sorb Mix with one or more suitable non-irritating excipients or carriers, including agent waxes or salicylates. It can be prepared by combining, and is a solid at room temperature but a liquid at body temperature. Therefore, it dissolves in the rectum or vaginal cavity, releasing the active compound.

[0256] Formulations of pharmaceutical compositions for oral administration include mouthwashes or oral sprays, It may also be provided as an oral ointment.

[0257] Alternatively or further, the composition may be used for catheters, stents, wires, or other lumen interiors. It can be formulated for delivery via a device. Delivery via such device is via the bladder, urethra, ureter, and stratum. It may be particularly useful for delivery to or from the intestines.

[0258] Formulations suitable for vaginal administration include pessaries, tampons, creams, gels, and pastes. Examples include spray formulations containing a foam or a carrier known to be suitable in the art. ru.

[0259] Dosage forms for topical or transdermal administration include powder, spray, ointment, paste, and cream. Examples include powders, lotions, gels, solutions, patches, and inhalants. The active compound is pharmaceutically effective. A carrier that is acceptable, and any necessary preservatives, buffers, or propellants, and sterile conditions. It can be mixed below.

[0260] The ointment, paste, cream, and gel contain animal and vegetable fats in addition to the active compound. Oil, wax, paraffin, starch, tragacanth, cellulose derivatives, polyethylene Glycols, silicones, bentonite, silica, talc and zinc oxide, or those It may contain excipients such as mixtures of the above.

[0261] The powder and spray contain lactose, talc, silicic acid, and aluminum hydroxide, in addition to the active compound. Excipients such as aluminum, calcium silicate, and polyamide powder, or mixtures thereof. The spray may also contain a conventional propellant, such as chlorofluorocarbon. It may contain hydrogen and volatile unsubstituted hydrocarbons, such as butane and propane.

[0262] Transdermal patches further offer the advantage of providing controlled delivery of the compounds of this disclosure to the body. The dosage form can be prepared by dissolving or dispersing the active compound in a suitable medium. Absorption enhancers may also be used to increase the flow of the compound through the skin. The flow velocity is determined by the presence of a rate-limiting membrane or by the compound being contained in a polymer matrix or gel. It can be controlled by distributing it across different systems.

[0263] Ophthalmic preparations, eye ointments, powders, solutions, etc., are also intended to fall within the scope of this disclosure. An example of an ophthalmic formulation is described in U.S. Publication No. 2005 / 0080056, No. 2005 / 005 Issues 9744, 2005 / 0031697 and 2005 / 004074 and the United States This is described in National Patent No. 6,583,124, the contents of which are referred to herein by reference. It is incorporated. If necessary, the liquid ophthalmic formulation has similar characteristics to tears, aqueous humor, or vitreous humor. Having or being compatible with such fluids. Preferred route of administration is local administration (e.g., This involves local administration such as eye drops, or administration via implants.

[0264] As used herein, the expressions “parenteral administration” and “administer parenterally” are used in relation to the This refers to administration methods other than intestinal and local administration, usually by injection, including intravenous, intramuscular, and intra-arterial administration. Intrathecal cavity, intracapsular cavity, intraorbital cavity, intracardiac cavity, intratracheal, subcutaneous, subepidermal, intraarticular, subcapsular This includes, but is not limited to, subarachnoid, intrathecal, and intrasternal injections and infusions.

[0265] A pharmaceutical composition suitable for parenteral administration contains one or more active compounds and one or more pharmaceutically acceptable compounds. A sterile isotonic aqueous solution or non-aqueous solution, dispersion, suspension or emulsion, or a sterile isotonic aqueous solution or non-aqueous solution, dispersion, suspension or emulsion, or Contains sterile powder in combination with a sterile powder that can be reconstituted into a sterile solution or dispersion for injection immediately before use. This involves antioxidants, buffers, bacteriostatic agents, and making the preparation isotonic with the recipient's blood. It may contain a solute, suspension agent, or thickener.

[0266] Examples of suitable aqueous and non-aqueous carriers that may be used in the pharmaceutical compositions of this disclosure include water, ethanol, and Polyols (glycerol, propylene glycol, polyethylene glycol, etc.) ), and suitable mixtures thereof, vegetable oils, for example, olive oil, and organic esters for injection Examples of ethyl oleate include ethyl oleate. Appropriate fluidity is, for example, in coatings. Materials, for example, by using lecithin, and in the case of dispersions, by maintaining the required particle size, and by the use of the substrate. This can be maintained by the use of surfactants.

[0267] These compositions also contain adjuvants, such as preservatives, humectants, emulsifiers, and dispersants. This may also include: Inhibition of microbial activity is achieved by various antibacterial and antifungal agents, such as parabens, c This may be ensured by including lolobutanol, phenolsorbic acid, etc., as an isotonic agent. For example, it may also be desirable to include sugar, sodium chloride, etc., in the composition. Furthermore, sustained absorption of the injectable drug form is affected by drugs that slow down absorption, such as aluminum. This can also be achieved by including monostearate and gelatin.

[0268] In some cases, to prolong the effects of the drug, it may be administered via subcutaneous or intramuscular injection. It is desirable to delay the harvest. This applies to liquids of crystalline or amorphous materials that have poor water solubility. This can be achieved by using a suspension. The rate of drug absorption, and consequently its rate of dissolution, depends on the rate of drug absorption. This may depend on the crystal size and morphology. Alternatively, parenterally administered drug forms. Delayed absorption of the drug is achieved by dissolving or suspending it in an oily medium.

[0269] The injection depot form is in a biodegradable polymer, such as polylactide-polyglycolide. It is produced by forming a matrix of microencapsulated target compounds. Depending on the ratio of drug to polymer and the properties of the specific polymer used, the drug release rate can be controlled. It can be controlled. Other examples of biodegradable polymers include poly(orthoester) and Examples include poly(anhydrous) and depot injection formulations. Alternatively, it can be prepared by encapsulating the drug in a microemulsion.

[0270] In use in the methods disclosed herein, the active compound may be applied by itself or For example, 0.1 to 99.5% (more preferably 0.5 to 90%) of the active ingredient is pharmaceutically effective. It may also be administered as a pharmaceutical composition containing an acceptable carrier.

[0271] The method of introduction can also be achieved through reloadable or biodegradable devices. In recent years Various sustained-release polymer devices for controlled delivery of drugs, including protein-based biopharmaceuticals. A solution has been developed and is being tested in vivo. It includes both biodegradable and non-biodegradable polymers. Using various biocompatible polymers (including hydrogels), compounds can be slowly removed from specific target sites. An implant can be formed for release.

[0272] The actual dosage level of the active ingredient contained in a pharmaceutical composition depends on the specific patient, composition, and administration. Effective activity to achieve the required therapeutic response for the administration method without causing toxicity to the patient. It can change to obtain the desired amount of the component.

[0273] The selected dosage level depends on the specific compound or combination of compounds used, The activity of the ester, salt, or amide, the route of administration, the time of administration, and the specific use of the ester, salt, or amide. The rate of excretion of the compound(s), the duration of treatment, and the combination of the specific compound(s) used. Other drugs, compounds, and / or materials used in conjunction with the treatment, the age and sex of the person receiving treatment, This includes weight, physical condition, overall health, and previous medical history, as well as similar factors well known in the medical field. It depends on various factors.

[0274] A physician or veterinarian with ordinary skills in the field may administer the required pharmaceutical composition. The effective therapeutic dose can be easily determined and prescribed. For example, a doctor or veterinarian can determine the desired therapeutic dose. Administration of a pharmaceutical composition or compound at a level lower than necessary to achieve the therapeutic effect. Treatment may begin with gradually increasing the dosage until the desired effect is achieved. "Effective dose" refers to a concentration of the compound sufficient to produce the desired therapeutic effect. It is generally understood that the effective dose varies depending on the subject's weight, sex, age, and medical history. Other factors that may affect the effective dose include the severity of the subject's condition and the disability being treated. , the stability of the compound, and, if necessary, another drug administered together with the compound of this disclosure. Examples of therapeutic drugs include, but are not limited to, those for which the drug is used. It can be delivered by multiple doses. Methods for determining efficacy and dosage are available to those skilled in the art. It is known to (Isselbacher et al. (1996) Harrison's s Principles of Internal Medicine 13 ed. (1814–1882, incorporated herein by reference).

[0275] Generally, a suitable daily dose of the active compound used in the compositions and methods of this disclosure is sufficient to achieve therapeutic efficacy. This is the minimum effective dose of a compound required to produce a fruit. Such an effective dose is generally above It depends on the factors listed above.

[0276] If necessary, the effective daily dose of the active compound may be administered at appropriate intervals throughout the day. One, two, three, four, five, six, or more subdoses administered separately in unit dosage forms It may be administered as follows. In certain embodiments of this disclosure, the active compound is administered twice daily or It may be administered three times. In a preferred embodiment, the active compound is administered once daily.

[0277] In certain embodiments, the compounds disclosed herein may be used alone or in combination with other compounds. It may also be administered in combination with other medications for ibuprofen. The term "combined administration" as used herein refers to... The expression refers to any form of administration of two or more different therapeutic compounds, and the second compound This is administered while a previously administered therapeutic compound is still effective in the body (for example, 2 Two compounds are simultaneously effective within the target area, and this may include a synergistic effect between the two compounds. For example, these different therapeutic compounds may be administered in the same formulation or in separate formulations. They may be administered simultaneously or consecutively. In certain embodiments, the different treatments The therapeutic compounds are used in conjunction with each other for 1 hour, 12 hours, 24 hours, 36 hours, 48 ​​hours, and 72 hours. It may be administered within one week. Therefore, the subjects receiving such treatment may be those with different therapeutic compounds. You can profit from the combined effects of these factors.

[0278] In certain embodiments, the compound disclosed herein may be used in combination with one or more further therapeutic agents (e.g.) For example, co-administration of one or more additional chemotherapeutic agents (or more) of the compounds of this disclosure ( For example, a compound of formula I or Ia) or one or more additional therapeutic agents The efficacy is improved compared to the administration of . In certain such embodiments, the co-administration is This results in an additive effect. Here, the additive effect refers to the compound of this disclosure and one or more further This refers to the sum of the individual effects of administering one or more therapeutic drugs.

[0279] This disclosure relates to pharmaceutically acceptable salts of the compounds of this disclosure in the compositions and methods of this disclosure. Includes use. In certain embodiments, the salts of the present disclosure intended are alkyl, dia Examples include, but are not limited to, lukyl, trialkyl, or tetraalkylammonium salts. Not done. In certain embodiments, the salt of the present disclosure intended is L-arginine, Benentamine, benzathine, betaine, calcium hydroxide, corn Phosphorus, Deanol, Diethanolamine, Diethylamine, 2-(Diethylamino)Ethamine Nol, ethanolamine, ethylenediamine, N-methylglucamine, hydravamin, 1H-imidazole, lithium, L-lysine, magnesium, 4-(2-hydroxyethyl Morpholine, piperazine, potassium, 1-(2-hydroxyethyl)pyrrolidine, na Examples include, but are not limited to, thorium, triethanolamine, tromethamine, and zinc salts. Not specified. In certain embodiments, the salts of the present disclosure intended are Na, Ca, K Examples include, but are not limited to, Mg, Zn, or other metal salts.

[0280] Medicinally acceptable acid addition salts include various solvates, such as water, methanol, and ethanol. They can also exist as dimethylformamide, etc. A mixture of such solvates. It can also be prepared. The source of such solvates may be derived from the crystallization solvent. This may be specific to the preparation or crystallization solvent, or it may be incidental to such solvents.

[0281] Pharmaceutically acceptable anionic salts include acetate, aspartate, and benzenesulfone. Salts, benzoates, besilates, bicarbonates, tartrates, bromides, cansylates, carbonates Salt, chloride, citrate, decanoate, edetate, esylate, fumarate, glyceptide Salts, gluconates, glutamates, glycolates, hexanoates, hydroxyna Phthoate, iodide, isethionate, lactate, lactobionate, malate, malate Ionic acid salts, mandelates, mesylates, methylsulfates, mucoates, napsylates, nitrates Octanoate, oleate, pamoate, pantothenate, phosphate, polygalacturonate Salic acid salts, propionates, salicylates, stearates, acetates, succinates, sulfates Examples include tartrates, theoclates, and tosylates.

[0282] Wetting agents, emulsifiers, and lubricants, such as sodium lauryl sulfate and magnesium stearate. Cium, as well as colorants, release agents, coating agents, sweeteners, flavoring agents and fragrances, preservatives and Antioxidants may also be included in the composition.

[0283] Examples of pharmaceutically acceptable antioxidants include (1) water-soluble antioxidants, such as ascorbyl. Vitic acid, cysteine ​​hydrochloride, sodium bicarbonate, sodium metabisulfite, sodium sulfite (2) Oil-soluble antioxidants, such as ascorbyl palmitate, butylated hydrochloride, etc. Cyanisol (BHA), butylated hydroxytoluene (BHT), lecithin, gallic acid Propyl, alpha-tocopherol, etc., and (3) metal chelating agents, such as citric acid Examples include ethylenediaminetetraacetic acid (EDTA), sorbitol, tartaric acid, and phosphoric acid. .

[0284] While this disclosure is generally described herein, a description of certain aspects and embodiments of this disclosure is also provided herein. By referring to the following examples, which are included solely for this purpose and are not intended to limit this disclosure, This will make it even easier to understand.

[0285] General synthesis procedure The starting materials and reagents used in preparing these compounds are supplied by commercial suppliers, for example. Is it available from Aldrich Chemical Co., Bachem, etc.? These can be manufactured by methods well known in the art. These are merely examples of some methods by which the compounds disclosed herein can be synthesized. Various modifications can be made to these schemes, and to those skilled in the art who refer to this disclosure... It is suggested that the starting materials, intermediates, and final products of the reaction be filtered, steamed, etc., as necessary. Using conventional techniques including but not limited to distillation, crystallization, and chromatography It can be isolated and purified, and can be obtained using conventional methods, including physical constants and spectral data. Characterization is possible. In some cases, multiple positional isomer products may be produced by the reaction. In these cases, chromatography may be used to separate the isomers, and NOE or NOESY NMR spectroscopy may be used to assist in structure assignment.

[0286] Unless otherwise specified, the reactions described herein are performed in a temperature range of approximately -78°C to approximately 150°C. It takes place under atmospheric pressure.

[0287] [Table 3] TIFF2026082971000087.tif243165TIFF2026082971000088.tif30165

[0288] The compounds of the present invention can be synthesized by various methods, as will be further described and illustrated herein. It can be prepared by the following methods. Those skilled in the art will know that the following general synthesis methods are typical and not limiting. It should be understood that this is not a diagram. Racemic compounds are chiral, preparative, SFC, and It can be enantiomerically concentrated by HPLC separation. Variable element A is carbon, nitrogen and or represents a sulfur atom, which may be the same as or different from another example of variable element A. Variable element X is a salt This represents an element, bromine, or iodine atom, which may be the same as or different from another example of variable element X. Element Z represents a nitrogen atom, or a CH or CF group, and is the same as another example of variable element Z. But it's okay to be different.

[0289] Method A [ka] Polyhalide I was coupled with stanane II using Still coupling conditions. A type III compound may be obtained. To accelerate this reaction, LiCl or Cu Various additives, including (but not limited to) I, may be used as desired. Polyhalides Intramolecular ring closure of III is achieved using a two-step one-pot borylation / Suzuki cross-coupling condition. This can be achieved by using the method described above, and a type IV compound may be obtained.

[0290] Method B [ka] Halide V was coupled with Stanan II using Still coupling conditions, A compound of Ip VI may be obtained. To facilitate this reaction, LiCl or CuI may be added. Various additives (not limited to these) may be used as desired. The molecule of Halide VI Internal ring closure was achieved using CH insertion cross-coupling conditions, and type IV compounds were obtained. Potassium acetate or potassium pivalate may be obtained. It is a base.

[0291] Method C [ka] Nitropyridine VII was reduced using Fe metal conditions to form type VIII aminopyridine. Lysine may be obtained. If the substrate contains an isoxazole moiety, use SnCl2 conditions instead. The yield can be improved by using the intramolecular ring closure of VIII in two steps. This was achieved using the pod-boration / Suzuki cross-coupling conditions, resulting in a type IX compound. You may obtain it.

[0292] Method D [ka] Nitropyridine X was reduced using Fe metal conditions to produce type XI aminopyridine. It may be obtained. If the substrate contains an isoxazole moiety, use SnCl2 conditions instead. This can improve the yield. Intramolecular ring closure of XI is performed by CH insertion cross-cup. This may be achieved using ring conditions to obtain a type IX compound. Potassium acetate or pi Potassium varate is an effective base for this macrocyclicization step.

[0293] Method E [ka] Alcohol XII is coupled with chloropyrazine XIII using SNAr coupling conditions. The reaction may be carried out to form ether XIV. Intramolecular ring closure of XIV is performed in two steps. This was achieved using the botboration / Suzuki cross-coupling conditions to obtain a type XV compound. That's fine.

[0294] Method F [ka] Alcohol XVI was coupled with chloropyrazine XIII using SNAr coupling conditions. The reaction may be carried out to form ether XVII. Intramolecular ring closure of XVII is performed by CH insertion. This may be achieved using cross-coupling conditions to obtain type XV compounds. Potassium acetate Potassium um or potassium pivalate is a suitable base for this macrocyclicization step.

[0295] Method G [ka] Aminopyridine XVIII may be brominated with a suitable bromination reagent to obtain bromide XIX. Following the desilylation reaction of XIX using a suitable fluoride ion source, a two-step one-pot reaction is performed. Type XX is synthesized by intramolecular ring closure using the Toboration / Suzuki cross-coupling conditions. You may obtain a mixed product.

[0296] Method H [ka] Nitropyridine XXI was reduced using Fe metal conditions to form type XXII aminopyridine. Lysine may be obtained. If the substrate contains an isoxazole moiety, use SnCl2 conditions instead. The yield can be improved by using the CH insertion cross-coupling conditions. Following the intramolecular cyclization of XXII used, the TBAF desilylation reaction yields type XX. The compound is obtained. Potassium acetate or potassium pivalate is effective in this macrocyclization step. It is a base.

[0297] Method I [ka] Nitropyridine XXIII was subjected to reduction using Fe metal conditions, followed by appropriate bromination testing. Compound XI may be converted to compound XI by bromination with a drug. Intramolecular ring closure of XI is performed by CH insertion. This may be achieved using cross-coupling conditions to obtain a type IX compound. Potassium um or potassium pivalate is a suitable base for this macrocyclicization step.

[0298] Method J [ka] Type XXIV compounds are treated in solution with a suitable acid (e.g., TFA or HCl). Deprotection may be performed by this method to obtain a type IV compound. A protecting group suitable for this method and For example, methoxymethyl, 2-(trimethylsilyl)ethoxymethyl, tetrahydropyra Examples include, but are not limited to, nyl and p-methoxybenzyl groups.

[0299] Method K [ka] Nitropyridine XXV was reduced using Fe metal conditions to form type XI aminopyridin You may obtain n. If the substrate contains an isoxazole moiety, use SnCl2 conditions instead. By using this method, the yield can be improved. Intramolecular ring closure of XI is performed by CH insertion cross-cabling. This may be achieved using plucking conditions to obtain a type IX compound. Potassium acetate or Potassium pivalate is an effective base for this macrocyclicization step.

[0300] Method L [ka] Nitropyridine X is reduced using iron metal, and then brominated with NBS to produce type XX. You may obtain aminopyridine VI. If the substrate contains an isoxazole moiety, you can substitute iron. Furthermore, the yield can be improved by using reduction conditions for SnCl2. Intramolecular ring closure is achieved using a two-step one-pot boration / Suzuki cross-coupling condition. This may result in obtaining a compound of type IX.

[0301] Method M [ka] The first hydrogenation of the type XXVII compound using palladium-carbon under a hydrogen atmosphere. Deprotection is achieved by decomposition, and the resulting hydroxyl group is then converted to an alkyl halide (e.g., yo The compound may also be obtained by alkylation with methyl methyl phosphate. Examples of protecting groups include benzyl and p-methoxybenzyl groups, but are not limited to these. It will not be done.

[0302] Method N [ka] Nitropyridine XXIX was reduced using Fe metal conditions to form type XXX aminopyridine. Lysine may be obtained. If the substrate contains an isoxazole moiety, use SnCl2 conditions instead. The yield can be improved by using the intramolecular ring closure of XXX, CH insertion. This may be achieved using Loss coupling conditions to obtain type XXXI ketones. Potassium lium or potassium pivalate is a suitable base for this macrocyclic ketone step. The reduction of XXXI type XXXII to alcohol is performed using sodium borohydride. This can be achieved. Finally, deoxygenation is performed using triethylsilane and trifluoroacetic acid. Alternatively, a compound of type IX may be obtained.

[0303] Those skilled in the art will be able to generate the compounds encompassed in this disclosure, as demonstrated by the following examples. To achieve this, the starting materials and reaction conditions may be different, and the order of the reactions may be changed. It will be recognized that further steps may be used. In some cases, certain The protection of the reactive functional groups may be necessary to achieve some of the above transformations. Generally, the necessity of such protecting groups, and the conditions required to attach and remove such groups, This will be obvious to experienced organic chemists. All articles mentioned in this application, including patents. The disclosure of references and other information is incorporated herein by reference.

[0304] The preparation of the compounds of this disclosure will be further described by the following examples, which are the basis for this disclosure. The scope or intent of the indication is interpreted as being limited to the specific procedures and compounds described therein. It shouldn't be done.

[0305] Analysis method LCMS data was collected using one of the following methods: [Table 4] TIFF2026082971000104.tif220165TIFF2026082971000105.tif178165

[0306] Synthesis example Synthesis of 3-chloro-5-iodo-1H-pyrazole intermediate [ka] Under a nitrogen atmosphere, 3-chloro-N,N-dimethyl-1H-pyrazole-1-sulfoneamine In a 40 mL solution of THF (1.90 g, 9.06 mmol) of d, add n-butyllithium (4.35 mL, 10.9 mmol) was added dropwise at -78°C. A highly viscous precipitate formed, The solution was added and stirred for 30 minutes. To this stirred suspension, 1-iodopyrrolidine-2,5 - Add a dropwise solution of dione (2.24 g, 9.97 mmol) in THF (10 mL) at -78°C. After 1 hour, the resulting clear solution was heated to room temperature. The reactants were then converted to saturated NH4Cl. Therefore, it was quenched at 0°C and extracted with DCM (3 × 50 mL). The organic layer was separated and broth was used. The residue was washed in the line, dried over anhydrous Na2SO4, and concentrated. The residue was then stored in a silica gel column. Purified by chromatography (PE containing 30% alkylammonium sulfate), 3-chloro-5-yol N,N-dimethyl-1H-pyrazole-1-sulfonamide (3.0g, yield: 8 9% was obtained as a white solid. LC / MS (ESI): m / z = 336 [M+ H] + . In a round-bottom flask equipped with a magnetic stirrer, 3-chloro-5-iodo-N,N- Dimethyl-1H-pyrazole-1-sulfonamide (3.00g, 8.94 mmol) The DCM (8 mL) containing the solution was cooled to 0°C and reacted with TFA (8.0 mL, 108 mmol). The mixture was stirred for 1.5 hours. This reaction was then quenched with saturated NaHCO3. Extracted with EA (2 x 50 mL). The extract was dried with anhydrous Na2SO4 and concentrated under reduced pressure. Shrink the mixture and turn 3-chloro-5-iodo-1H-pyrazole (2.1g, yield: 100%) yellow. It was obtained as a solid. LC / MS (ESI): m / z = 229 [M+H] + .

[0307] Synthesis of (nitromethyl)cyclobutane [ka] (Nitromethylidene)cyclobutane (9.8g, 86.63mmol) MeOH(5 Add NaBH4 (4.94 g, 130 mmol) to the 0 mL solution at 0°C, and incubate at 0°C for 6 The mixture was stirred for 0 minutes. The reaction mixture was quenched by adding cold water and filtered. Dissolve the liquid in HCl, wash once with water and once with brine, and dry with anhydrous Na2SO4. The filtrate was filtered. The filtrate was concentrated to obtain the residue, which was then subjected to flash chromatography (0→ Purified by DCM containing 5% MeOH, (nitromethyl)cyclobutane (4.4g, A yield of 44% was obtained as colorless oil. LC / MS ESI (m / z): 116 [M+ H]+ .

[0308] Synthesis of (5-bromo-1,3-thiazole-4-yl)methanol [ka] Methyl 5-bromo-1,3-thiazole-4-carboxylate (5.00g, 22. In a 5 mmol) solution of 0°C THF (100 mL), add LiBH4 (2.94 g, 135 ml) (ol) was added. Then, MeOH (10 mL) was added dropwise to the above solution. The mixture The mixture was stirred at room temperature for 16 hours. The reaction product was quenched with water and extracted with EA (50 mL x 3). ). The organic phase is washed with brine, dried with Na2SO4, and concentrated under vacuum to obtain the crude (5 (1.0)bromo-1,3-thiazole-4-yl)methanol was obtained as a pale yellow solid. 0g, yield 23%). LC / MS ESI (m / z): 194 [M+H] + .

[0309] Synthesis of 5-chloro-3-iodo-1-methyl-1H-pyrazole [ka] 5-Chloro-3-iodo-1H-pyrazole (100 mg, 0.440 mmol) and In DMF (8 mL) containing a mixture of K2CO3 (121 mg, 0.880 mmol), Methyl methyl oxide (0.03 mL, 0.5 mmol) was added at 25°C. This mixture was then... The mixture was stirred at room temperature for 30 minutes. The reaction mixture was quenched with ice water and extracted twice into EA, then bran. Wash with water, dry with anhydrous sodium 2SO4, filter, concentrate to obtain crude 5-chloro-3-yo 100 mg of methyl-1H-pyrazole (94% yield) was obtained as a yellow liquid. This material can be used as is, or further processes such as flash chromatography and high-pressure chromatography may be performed. Purify by chromatography or supercritical fluid chromatography, and remove any potential positional abnormalities. The substances may be separated. LC / MS (ESI) m / z: 243 [M+H] + .

[0310] The following intermediates were synthesized using a similar experimental protocol: [Table 5] TIFF2026082971000111.tif67165

[0311] Synthesis of 1-ethyl-1H-pyrrole-3-carbaldehyde [ka] DMF of 1H-pyrrole-3H-carbaldehyde (5.00g, 52.6mmol) Add K2CO3 (12.4g, 89.4 mmol) and iodoethane (5 mL) to the 30 mL solution. 0.0 mL (63 mmol) was added at 0°C. The mixture was stirred at room temperature for 16 hours and then filtered. The filtrate was then diluted with ethyl acetate (30 mL). The solution was then diluted with brine (50 mL). The residue was washed, dried with anhydrous sodium 2SO4, and concentrated. The residue was then subjected to flash chromatography. - Purified by (PE containing 0% → 35% EA), 1-ethyl-1H-pyrrole-3-ca Rubaldehyde (4.0 g, 62% yield) was obtained as a yellow oil. LC / MS (ESI) m / z: 124.1 [M+H] + .

[0312] The following intermediates were synthesized using a similar experimental protocol: [Table 6]

[0313] Synthesis of 3-ethylisoxazole-5-carbaldehyde [ka] (3-ethylisoxazol-5-yl)methanol (4.00g, 31.5mO) l) Add DMP (16.01 g, 37.75 mmol) to DCM (100 mL) solution. The mixture was added at °C and stirred at room temperature for 1 hour (complete removal of the substrate containing multiple alcohol groups). To ensure proper oxidation, an additional equivalent amount of oxidizing agent may be added. Wash with Na2S2O3 (100 mL) and saturated NaHCO3 (100 mL), then anhydrous Na The residue was dried with 2SO4 and concentrated to dryness. The residue was then subjected to flash chromatography on silica gel. - Purified with (PE containing 20% ​​Â), 3-ethylisoxazole-5-carb Ludehyde (3.37g, yield: 86%) was obtained as yellow oil. LC / MS (ESI): m / z = 126 [M+H] + .

[0314] Synthesis of (1-ethyl-1H-pyrazole-4-yl)methanol [ka] 1-Ethyl-1H-pyrazole-4-carbaldehyde (2.10g, 16.9mmol) ) in a THF (10 mL) solution, add diisobutylaluminum hydride (13.5 mL, 20 (0.3 mmol) was added at -78°C (this protocol completely sterilizes the ester with alcohol.) Modify the product by increasing the equivalent amount of the reducing agent so that it can be reduced to [a certain state]. (This can be done). Stir this mixture at -78°C for 0.5 hours, then heat to 25°C for 1 hour. The reaction mixture was then quenched with saturated NH4Cl aqueous solution (5 mL) and then treated with toluene. Extracted (15 mL x 3). The combined organic layers were washed with brine (15 mL) and anhydrous sodium. The residue was dried with 2SO4 and then concentrated. Flash chromatography was performed on the residue (50°F → Purified by PE containing 100% ethyl(1-ethyl-1H-pyrazole-4-) Iol(methanol) (480 mg, yield 23%) was obtained as a pale yellow oil. LCMS (ES I) m / z: 127 [M+H] + .

[0315] Synthesis of 4-(chloromethyl)-1-ethyl-1H-pyrazole [ka] (1-ethyl-1H-pyrazole-4-yl)methanol (1.40g, 11.1mm) Add SOCl2 (3.96 g, 33.3 mmol) to a 15 mL solution of DCM at 0°C. The mixture was added dropwise under an N2 atmosphere. After addition, the mixture was stirred at 0°C for 2 hours. The mixture was concentrated to dryness, and crude 4-(chloromethyl)-1-ethyl-1H-pyrazole (1.60g) was prepared. , yielded as yellow oil with a yield of 100%. LC / MS (ESI) m / z: 145 [ M+H] + .

[0316] The following intermediates were synthesized using a similar experimental protocol: [Table 7]

[0317] Synthesis of 5-(chloromethyl)-3-ethylisoxazole [ka] (3-ethyl-1,2-oxazol-5-yl)methanol (4.10g, 32.3 In a 10 mL stirred and dried DCM solution of mmol of triethylamine (5.8 mL, 42 Add mmol) followed by thionyl chloride (2.8 mL, 39 mmol) and incubate at 0°C for 10 minutes. It was added by pouring. After the addition, the reaction mixture was stirred under N2 at room temperature for 5.0 hours. The solution was cooled to 0°C and quenched with a 10% NaCl aqueous solution. Then, this mixture was... Extraction was performed twice using DCM, and the combined extract was washed with saturated NaHCO3 aqueous solution and anhydrous Na2S The residue was dried with O4 and concentrated in a vacuum. The residue was then subjected to silica gel column chromatography. Purified by PE containing 10-30% EA, 5-(chloromethyl)-3-ethyl-1, 2-Oxazole (4.20 g, yield: 90%) was obtained as a yellow oil. LC / MS ES I (m / z): 146 [M+H] + .

[0318] The following intermediates were synthesized using a similar experimental protocol: [Table 8]

[0319] Synthesis of 5-(bromomethyl)isoxazole-3-carbonitrile [ka] 5-Methylisoxazole-3-carbonitride (3.0 g, 28 mmol) and N A 3.2g, 56 mmol solution of BS in 120 mL of DCE is mixed with 230 mg of AIBN. (1.40 mmol) was added under N2 conditions at 25°C. Next, the resulting solution was heated to 80°C. The mixture was heated and stirred for 16 hours. After cooling to room temperature, the reaction mixture was diluted with DCM and saturated. Washed with NaHCO3 solution and brine, dried over anhydrous Na2SO4, filtered, and concentrated. The residue was subjected to silica gel column chromatography (PE containing 10% SiO). Further purification yields 5-(bromomethyl)isoxazole-3-carbonitride as a yellow oil. (2.2 g, yield: 42%). LC / MS ESI (m / z): 187 [M +H] + .

[0320] Synthesis of 5-bromo-2-methylthiazole-4-carbaldehyde [ka] Ethyl 5-bromo-2-methylthiazole-4-carboxylate (4.13g, 16 Diisobutylaluminum hydride (16) is added to a 0.5 mmol THF (120 mL) solution. A 0.5 mL, 24.8 mmol, 1.5 M THF solution was added dropwise at -78°C. The mixture was then mixed. The mixture was stirred at -78°C for 3 hours. After 3 hours, the reaction mixture was continuously mixed with EA (50 mL). , water (1.0 mL), NaOH aqueous solution (15%, 1.0 mL), and then water (10 mL) Diluted at 0°C with ). After warming to room temperature, the mixture was stirred for 15 minutes. Anhydrous Mg SO4 was added, and the mixture was stirred for 15 minutes, after which the solid was removed by filtration. The filtrate was concentrated under vacuum to obtain crude 5-bromo-2-methylthiazole-4-carbaldehyde. (2.59 g, 76%) was obtained as a yellow solid. LC / MS ESI (m / z): 2 06 [M+H] + .

[0321] Synthesis of 5-bromo-3-chloro-1-ethyl-1H-pyrazole [ka] 3-Chloro-1-ethyl-1H-pyrazole (3.00 g, 23.0 mmol) TH To a 20 mL solution of F, add 10.1 mL of n-BuLi (2.5 M hexane solution), and 25. 3 mmol) was added at -78°C. The mixture was stirred at -78°C for 1 hour. Next, C A solution of Br4 (7.6 g, 23 mmol) in THF (15 mL) was added dropwise to the mixture. The mixture was stirred at -78°C for 1 hour, then quenched with water (10 mL). This mixture was then EA(2 Extraction was performed three times with 0 mL. The resulting organic layers were combined, dried over Na2SO4, and concentrated under reduced pressure. The residue was then dissolved in PE (0-10%) containing EA by flash chromatography. Remove and purify, then 5-bromo-3-chloro-1-ethyl-1H-pyrazole (3.5g, 7 3% was obtained as a pale yellow oil. LC / MS (ESI): m / z = 209 [M+ H] + .

[0322] The following intermediates were synthesized using a similar experimental protocol: [Table 9]

[0323] 5-iodo-2-methyl-2H-1,2,3-triazole-4-carbaldehyde compound Growth [ka] 4,5-Diiodo-2-methyl-2H-1,2,3-triazole (2.5g, 7.4 In a 30 mL THF solution of mmol of n-butyllithium (in a 2.5 M hexane solution), Add 3.2 mL and 8.2 mmol of the solution and stir at -78°C for 1 hour. Next, add DMF ( 0.57 mL (7.4 mmol) was added to the mixture and stirred at -78°C for 1 hour. The mixture was quenched with saturated NH4Cl aqueous solution (30 mL) at 0°C and extracted with EA. (100 mL x 3). Combine the organic layers, dry with anhydrous Na2SO4, filter, and vacuum. The residue was concentrated inside. The residue was then subjected to silica gel column chromatography (PE:EA=3:1 Purified by (V / V), 5-iodo-2-methyl-2H-1,2,3-triazole- 4-carbaldehyde (1.15 g, 65%) was obtained as a pale yellow solid. LC / MS (E SI) m / z: 238 [M+H] + .

[0324] Synthesis of (5-iodo-1-methyl-1H-pyrazole-4-yl)methanol [ka] 5-iodo-1-methyl-1H-pyrazole-4-carbaldehyde (2.00g, 8. In a mixture of 47 mmol) MeOH (30 mL), NaBH4 (84 mg, 2) was added at -10°C. (0.5 mmol) was added. This mixture was stirred at 20°C for 1 hour. The mixture was then saturated with N2. Quenched with H4Cl (10 mL) and extracted with EA (60 mL x 3). Combined organic layers. The residue was dried with anhydrous Na2SO4, filtered, and concentrated. The residue was then subjected to column chromatography on silica gel. Purified by tography (DCM containing 5% MeOH), (5-iodo-1-methyl-1H (-pyrazole-4-yl)methanol was obtained as a pale yellow solid (840 mg, yield: 41%). %). LC / MS ESI (m / z): 239 [M+H] + .

[0325] The following intermediates were synthesized using a similar experimental protocol: [Table 10]

[0326] Synthesis of (3-iodo-1-methyl-1H-pyrazole-4-yl)methanol [ka] 3-iodo-1-methyl-1H-pyrazole-4-carbaldehyde (2.00g, 8. In a 20 mL solution of 47 mmol) dry THF, add DIBAL-H (1.0 M toluene). The solution (12 mL, 12 mmol) was added dropwise at -70°C (if multiple hydrogen transfers are required, (An additional equivalent amount of reducing agent may be used.) Stir the mixture at -70°C for 2 hours, then allow it to saturated. Quenched with an aqueous NH4Cl solution. The resulting mixture was filtered, and the filtered cake was treated with THF. Washed. The combined filtrate was concentrated under reduced pressure, the residue was diluted with DCM, and then washed with water and brine. The residue was washed, dried over anhydrous Na2SO4, and concentrated. The residue was then subjected to silica gel column chromatography. Purified by Graph (PE containing 0-20% EA), (3-iodo-1-methyl-1 H-pyrazole-4-yl)methanol (1.6g, yield 79%) was obtained as a yellow oil. LC / MS ESI (m / z): 239 [M+H] + .

[0327] The following intermediates were synthesized using a similar experimental protocol: [Table 11]

[0328] (5-iodo-2-methyl-2H-1,2,3-triazol-4-yl)methanol synthesis [ka] 5-iodo-2-methyl-2H-1,2,3-triazole-4-carbaldehyde(1 Mixing a 0.05g, 4.40 mmol MeOH (5 mL) with NaBH4 (0.15 g (4.4 mmol) was added and the mixture was stirred at 0°C for 1 hour. The mixture was dissolved in saturated NH4Cl aqueous solution. The solution (30 mL) was quenched at 0°C and extracted with EA (50 mL x 3). Combined organic The layers were dried with anhydrous Na2SO4, filtered, and concentrated in a vacuum. The residue was flash-cultivated. Purified by matrix (PE:EA=1:1, V / V), (5-iodo-2-methicone) (Lu-2H-1,2,3-triazol-4-yl)methanol (960 mg, 91%) It was obtained as a pale yellow solid. LC / MS (ESI) m / z: 240 [M+H] + .

[0329] The following intermediates were synthesized using a similar experimental protocol: [Table 12]

[0330] Synthesis of 4-(chloromethyl)-3-iodo-1-methyl-1H-pyrazole [ka] (3-iodo-1-methyl-1H-pyrazole-4-yl)methanol (1.00g, 4.20 mmol) of DCM (20 mL) solution, thionyl chloride (0.90 mL, 13 mL) (mol) was added at 0°C. After addition, the mixture was stirred at room temperature for 3 hours, and then concentrated. Crude 4-(chloromethyl)-3-iodo-1-methyl-1H-pyrazole (1.0g, 9 3% was obtained as yellow oil. LCMS (ESI): m / z = 257 [M+H] + .

[0331] The following intermediates were synthesized using a similar experimental protocol: [Table 13]

[0332] Synthesis of 5-bromo-1-ethyl-4-iodo-1H-pyrazole [ka] 1-Ethyl-4-iodo-1H-pyrazole (105.0 g, 425.6 mmol) Add LDA (2.0M heptane / THF / ethyl) to a THF (900mL) solution at -78℃. Add benzene solution (212.8 mL, 425.6 mmol) dropwise over 1 hour under an N2 atmosphere. It was added. After the addition, the mixture was stirred at -78°C for 0.5 hours, and then tetrabromomethane A 148.0g, 445.0 mmol THF (50 mL) solution is administered dropwise over 0.5 hours. The mixture was then stirred at -78°C for another hour. The reaction flask was then placed in an ice bath. Transferred the mixture and quenched it with a saturated NH4Cl aqueous solution (200 mL). The aqueous phase was then converted to D Extraction was performed twice using CM (250 mL x 2). The combined organic layers were washed with brine and anhydrous sodium. The residue was dried with 2SO4, filtered, and concentrated. The residue was then subjected to silica gel column chromatography. - Purified with (PE containing 2% siRNA), the desired product was obtained as a brown solid (9 0g, yield: 70%). LC / MS ESI (m / z): 301 [M+H] + .

[0333] The following intermediates were synthesized using a similar experimental protocol: [Table 14]

[0334] Synthesis of 2-ethyl-4,5-diiodo-2H-1,2,3-triazole [ka] 4,5-Diiodo-2H-1,2,3-Triazole (50 mg, 0.18 mmol) In a 5 mL THF solution, add NaH (14 mg, 0.36 mmol, 60% mineral oil solution). It was added at 0°C. Then iodoethane (2.94g, 0.890 mmol) was added. The mixture was stirred at 25°C for 16 hours. The reaction was then dissolved in H2O (5 mL) at 0°C. The mixture was then extracted with ethyl acetate (15 mL x 3). The combined organic layer was brined (1 Washed with 5 mL of water, dried with anhydrous sodium 2 SO4, and then concentrated. The residue was flushed. Purified by chromatography (silica gel, PE containing 0-25% ethyl acetate), 2 -Ethyl-4,5-diiodo-2H-1,2,3-triazole (1.47g, yield: 6 8% was obtained as a white solid. LC / MS (ESI) m / z: 350 [M+H] + .

[0335] Synthesis of 1-(cyclopropylmethyl)-3-methyl-1H-pyrazole [ka] 3-Methyl-1H-pyrazole (5.90 mL, 73.1 mmol), (bromomethyl ) Cyclopropane (7.90 mL, 80.4 mmol) and K2CO3 (20.20 g, A mixture of 146.2 mmol) in DMF (100 mL) was stirred at 80°C for 16 hours. The reaction mixture was added to water and extracted with carboxylate. The organic layer was washed with brine. The residue was dried with anhydrous Na2SO4 and concentrated in a vacuum. The residue was then subjected to flash column chromatography. Purified by tography, 1-(cyclopropylmethyl)-3-methyl-1H-pyrazo A solution (6.00 g, 60%) was obtained as a yellow solid. LC / MS (ESI) m / z: 137 [M+H] + .

[0336] The following intermediates were synthesized using a similar experimental protocol: [Table 15]

[0337] Synthesis of 5-bromo-1-ethyl-1H-pyrazole-4-carbaldehyde [ka] 5-bromo-1-ethyl-1H-pyrazole (100g, 571 mmol) at 0°C Add 1,3,5,7-tetraazaadamantane (120g, 85) to FA (700mL) solution. 7 mmol) was added. The resulting mixture was stirred at 90°C for 16 hours. It was then cooled to room temperature. Afterward, the mixture was concentrated under reduced pressure to remove most of the TFA. The residue was then processed using DCM. Dilute with 600 mL, wash with saturated NaHCO3 and brine, and dry with anhydrous Na2SO4. The residue was dried, filtered, and concentrated. The residue was subjected to silica gel column chromatography (10%E Purified with PE containing tOAc, and 5-bromo-1-ethyl-1H-pyrazole-4-cal Valdehyde was obtained as a white solid (60 g, yield: 52%). LC / MS ESI (m / z): 203 [M+H] + .

[0338] The following intermediates were synthesized using a similar experimental protocol: [Table 16]

[0339] 1-(5-bromo-1,3-thiazole-4-yl)propane-2-in-1-ol synthesis [ka] 5-Bromo-1,3-thiazole-4-carbaldehyde (1.80g, 9.37mO) l) Add ethynyl magnesium bromide (28.1 mL, 14.1 mL) to the THF (20 mL) solution. mmol was added. The mixture was stirred overnight at room temperature, and then quenched with water. The mixture was extracted twice with EA (100 mL). The combined organic layer was concentrated under reduced pressure. The remainder The residue was analyzed by flash column chromatography on silica gel to obtain PE(0→3) containing EA. Elute with 0% solution and purify, then 1-(5-bromo-1,3-thiazole-4-yl)propane 2-in-1-ol (1.50 g, 73%) was obtained as a colorless oil. LC / MS (ES I): m / z = 218 [M+H] + .

[0340] The following intermediates were synthesized using a similar experimental protocol: [Table 17]

[0341] Synthesis of (4-bromo-3-ethylisothiazol-5-yl)methanol [ka] 5-((tetrahydro-2H-pyran-2-yl)oxy)penta-3-in-2-ol (5.00g, 25.5mmol) and (aminooxy)sulfonic acid (3.20g, 2 Add the mixture (5.1 mmol) to 100 mL of H2O at 0°C and stir. The mixture was stirred at ambient temperature for 4 hours. Afterwards, NaHCO3 (2.40 g, 28.1 mmol) and Sodium hydroxide (2.20 g, 38.3 mmol) was added. The resulting mixture was 8 The mixture was stirred at 0°C for 16 hours. The filtrate was extracted with ethyl acetate, washed with brine, and then Na2S The residue was dried with O4 and concentrated under vacuum. The residue was then flash-machined using silica gel. (Petroleum ether containing 0-20% ethyl acetate) is purified, and (3-ethylisothiazo Lu-5-yl)methanol (1.46 g, 40% yield) was obtained as yellow oil.

[0342] (3-ethylisothiazol-5-yl)methanol (1.80g, 12.6mmol) ), dibromin (7.00g, 44.1mmol) and potassium acetate (1.96g, 20 AcOH (40 mL) containing a mixture of 0.0 mmol) was stirred at ambient temperature for 16 hours. The resulting mixture was quenched with Na2S2O3. The solution was then basicized with NaHCO3. The residue was extracted using DCM, dried with Na2SO4, and concentrated under vacuum. Purification by Rush phase chromatography (0 → 15% ethyl acetate petroleum ether). (4-bromo-3-ethylisothiazole-5-yl)methanol (2.04g, ) 73% was obtained as yellow oil. LC-MS (ESI) m / z: 222 [M+H ] + .

[0343] Synthesis of 4-fluoro-2-iodobenzonitrile [ka] Thio chloride of 4-fluoro-2-iodobenzamide (4.00 g, 15.1 mmol) The mixture of 30 mL of nitrile was stirred at 90°C for 16 hours. The mixture was concentrated and 4-fur was added. Luoro-2-iodobenzonitrile (2.40 g, yield 64%) was obtained as yellow oil. C / MS (ESI) m / z: 248 [M+H] + .

[0344] The following intermediates were synthesized using a similar experimental protocol: [Table 18]

[0345] Synthesis of (4-fluoro-2-iodophenyl)hydrazine [ka] A of mechanically stirred 4-fluoro-2-iodoaniline (5.0 g, 21 mmol) Concentrated HCl (40 mL) was slowly added to a cOH (10 mL) solution. This solution is It quickly became a concentrated suspension. Next, this reaction mixture was cooled to 0°C in an ice bath, and sodium nitrite was added. The reaction was carried out by slowly adding a solution of (1.63 g, 23.6 mmol) in water (8 mL) dropwise. The reaction mixture was stirred for 1 hour, and then concentrated with SnCl2 (8.46 g, 44.5 mmol). HCl (8 mL) solution was slowly added. The reaction mixture was allowed to rise to room temperature for 2 hours. The suspension was heated. This suspension was filtered, washed with water, dried under vacuum, and the crude (4-fluoro-2-yo) was obtained. (Hydrazine hydrochloride (4.1g, yield: 77%) was obtained as a gray solid.) C / MS (ESI) m / z: 253 [M+H] + .

[0346] Synthesis of 5-bromo-4-(bromomethyl)-1-ethyl-1H-pyrazole [ka] (5-bromo-1-ethyl-1H-pyrazole-4-yl)methanol (4.00g, Stirring of 19.5 mmol) and triphenylphosphine (6.14 g, 23.4 mmol) Add tetrabromomethane (7.76 g, 23.4 mmol) to a 50 mL solution of dried DCM. A DCM solution of ) was added dropwise at 0°C. After addition, the reaction mixture was stirred at room temperature for 24 hours. The reaction mixture is concentrated in a vacuum, and the residue is subjected to silica gel column chromatography. Eluent: Purified with PE / siRNA50 / 1~10 / 1), 5-bromo-4-(br Romomethyl)-1-ethyl-1H-pyrazole (3.0 g, yield 57%) is prepared as a white solid. The result obtained was: LC / MS ESI (m / z): 267 [M+H] + .

[0347] Synthesis of (3-cyano-1-methyl-1H-pyrazole-5-yl)boronic acid [ka] 1-Methyl-1H-pyrazole-3-carbonitride (1.0 g, 9.3 mmol) In a 15 mL THF solution, add LDA (2M THF solution, 4.0 mL) under an N2 atmosphere at -78°C. 7 mL (9.3 mmol) was added dropwise. After stirring at -78°C for 0.5 hours, trimmer borate was added. THF (2 mL) containing Chill (1.9 g, 19 mmol) was added dropwise. The mixture was incubated at -78°C for 1 hour. After stirring, the reaction mixture was quenched with a saturated ammonium chloride aqueous solution. This reaction mixture was then E The organic layer was diluted with tOAc and washed first with H2O and then with brine. Anhydrous sodium The residue was dried with 2SO4, filtered, and concentrated under vacuum. The residue was then subjected to silica gel column chromatography. Purified by PE (containing 0-80% phenyl), (3-cyano-1-methyl- 1H-pyrazole-5-yl)boronic acid (800 mg, yield 57%) was obtained as a yellow oil. LC / MS ESI (m / z): 152 [M+H] + .

[0348] Synthesis of 3-cyclobutyl-1,2-oxazole-5-carbaldehyde [ka] (3-Cyclobutyl-1,2-Oxazol-5-yl)methanol (500 mg, 3 In a 100 mL solution of DCM (0.26 mmol), add MnO2 (2.80 g, 32.64 ml). (mol) was added. The mixture was stirred overnight at room temperature and then filtered. The filtrate was then reduced under reduced pressure. Concentrate the mixture and perform flash column chromatography (eluting with PE containing 0-15% EA). Purified using silica gel, 3-cyclobutyl-1,2-oxazole-5-carbade Hydrate (260 mg, 53%) was obtained as a colorless oil. LC / MS (ESI): m / z = 152 [M+H] + .

[0349] The following intermediates were synthesized using a similar experimental protocol: [Table 19]

[0350] Synthesis of 3-(cyclopropylmethyl)isoxazole-5-carbaldehyde [ka] [3-(cyclopropylmethyl)-1,2-oxazol-5-yl]methanol (1 In a 10 mL solution of DCM (0.10 g, 7.18 mmol), add Dess-Martin-Periodine. Dinane (3.65 g, 8.62 mmol) was added at 0°C. After stirring at 0°C for 2 hours, The reaction mixture is diluted with saturated Na2CO3 aqueous solution (20 mL) and DCM (10 mL). The organic layer was separated, washed with brine (10 mL), and dried over anhydrous Na2SO4. The residue was filtered, concentrated in a vacuum, and then subjected to silica gel column chromatography (0 →Purified by PE (V / V) containing 25% EA, and 3-(cyclopropylmethyl)-1 2-Oxazole-5-carbaldehyde (0.90 g, 83%) was obtained as a yellow oil. LC / MS ESI (m / z): 152 [M+H] + .

[0351] Synthesis of 2-(5-bromo-1-ethyl-1H-pyrazole-4-yl)acetonitrile [ka] 5-Bromo-4-(chloromethyl)-1-ethyl-1H-pyrazole (5.00g, 2 In a 50 mL solution of 2.4 mmol DMSO, add NaCN (2.20 g, 44) at 25°C. 0.7 mmol) was added. After stirring at 25°C for 2 hours, the mixture was mixed with siRNA and H It was treated with 2O. The organic layer was separated, washed with brine, and dried over anhydrous Na2SO4. The residue was filtered and concentrated. The residue was subjected to silica gel column chromatography (20% EtOA). Purified with PE containing c), 2-(5-bromo-1-ethyl-1H-pyrazole-4-yl Acetonitrile (4.5g, yield: 94%) was obtained as a pale yellow oil. LC / MS ES I (m / z): 214 [M+H] + .

[0352] The following intermediates were synthesized using a similar experimental protocol: [Table 20]

[0353] Synthesis of 1-(3-bromo-5-fluoropyridine-2-yl)ethane-1-one [ka] 3-Bromo-5-fluoropicolinic acid (4.80 g, 21.8 mmol) DMF(2 Add N,O-dimethylhydroxylamine hydrochloride (3.19 g, 32.7 ml) to the 0 mL solution. mol), HOBT (5.90g, 43.6mmol), EDCI (8.45g, 43. 6 mmol) and DIPEA (14.1 g, 109 mmol) were added at 0°C. The mixture The mixture was stirred at room temperature for 12 hours. This mixture was filtered through Celite to remove the solids. The filtrate is concentrated under reduced pressure, and the residue is subjected to flash chromatography of silica gel (0 →Purified by PE containing 10% ethyl acetate, and 3-bromo-5-fluoro-N-methyl phosphate C-N-methylpicolinamide (4.5 g, 78% yield) was obtained as a pale yellow solid. LC / MS ESI (m / z): 263 [M+H] + .

[0354] 3-bromo-5-fluoro-N-methoxy-N-methylpicolinia cooled to -20°C In a solution of mid (3.50 g, 13.3 mmol) in THF (5 mL), methyl magnesium bromide was added. Um (4.43 mL, 13.3 mmol, 3M THF solution) was added to this mixture. The mixture was stirred at -20°C for 2 hours, then quenched in ice water. The resulting mixture was then mixed with ammonium nitrate. Extract multiple times, wash the combined extracts with brine, dry with anhydrous sodium 2SO4, filter, and concentrate. It shrunk. The residue was subjected to flash chromatography of silica gel (0 → 30% alkyl Purified by PE containing , and 1-(3-bromo-5-fluoropyridine-2-yl) ethanol N-1-one (2.6 g, 90% yield) was obtained as a white solid. LC / MS ESI ( m / z): 218 [M+H] + .

[0355] Synthesis of 5-(cyclopropylmethyl)-3-iodo-1-methyl-1H-pyrazole [ka] 3-Iodo-1-methyl-1H-pyrazole-5-carbaldehyde (2.3g, 9.7 Mix cyclopropylmagnesium bromide (0.5 mmol) in a stirred THF (40 mL) solution. A hexane solution of M (20.5 mL, 10.3 mmol) was added under N2 conditions at 0°C. The reaction mixture was stirred at 0°C for 1.5 hours, then quenched with saturated NH4Cl (5 mL) and concentrated. The residue was dried. Flash chromatography was performed on the residue (PE containing 0-50% Â). Purified by ) and cyclopropyl(3-iodo-1-methyl-1H-pyrazole-5-I Methanol (1.6 g, yield 19%) was obtained as a yellow solid. LC / MS (ESI ) (m / z): 279 [M+H] + .

[0356] Cyclopropyl(3-iodo-1-methyl-1H-pyrazole-5-yl)methanol To a stirred DCM (18 mL) solution of (1.0 g, 3.6 mmol), add TES (4.20 g, 36.0 mmol) and TFA (2.7 mL, 36 mmol) were added at 0°C. The reaction mixture was stirred overnight at room temperature. The reaction product was concentrated to dryness. The residue was then flash-chromatped. Purified by Graph (PE containing 0-10% siRNA), 5-(cyclopropylmethyl (Cyl)-3-iodo-1-methyl-1H-pyrazole (0.60g, yield 51%) was yellow Obtained as a solid. LC / MS (ESI) (m / z): 263 [M+H] + .

[0357] Synthesis of 4-fluoro-2-iodobenzamide [ka] DCM of 4-fluoro-2-iodobenzoic acid (5.00 g, 18.8 mmol) (10 To the 0 mL solution, add oxalyl chloride (5.00 g, 39.4 mmol), then D MF (0.07 mL, 0.9 mmol) was added at 0°C. After addition, the resulting mixture was divided into 2 The mixture was stirred at 5°C for 2 hours. This mixture was concentrated to dryness under vacuum, and crude 4-fluoro-2- chloride was obtained. Iodobenzoyl was obtained as a yellow oil.

[0358] 4-fluoro-2-iodobenzoyl chloride dissolved in 50 mL of dried DCM cooled to 0°C. Add pre-cooled NH3 water (14 mL, 370 mmol, 28% H2O solution) to the liquid. The mixture was added dropwise over 0 minutes. The internal temperature was maintained below 5°C during the addition. The resulting mixture was stored in a room. The mixture was stirred at temperature for 4 hours, then concentrated to dryness. This white solid residue was pulverized with water and PE, and then... Then it is dried in a vacuum oven to obtain the desired product, 4-fluoro-2-iodobenzamide. (11g, 92% yield obtained in two steps) was obtained as a white solid. LC / MS (ESI): m / z = ​​266 [M+H] + .

[0359] Synthesis of 5-bromo-1-cyclopropyl-1H-pyrazole-4-carbaldehyde [ka] 5-Bromo-1-cyclopropyl-4-iodo-1H-pyrazole (2.5g, 7.9 In a 30 mL solution of 8 mmol) of THF at -78°C, add i-PrMgCl(1.3 M T). HF solution (7.37 mL, 9.58 mmol) was added dropwise under an N2 atmosphere. After addition, Stir the mixture at 0°C for 60 minutes, then cool to -78°C, and then add anhydrous DMF (0.80 mL). (10 mmol) was added. The resulting mixture was stirred at -78°C for a further 2 hours. The mixture was quenched with saturated NH4Cl solution and then extracted with DCM (200 mL x 2). The organic layer is separated, washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated. The residue was subjected to silica gel column chromatography (PE:EA = 2:1 to 1:1). The product was purified using a V / V method, and the desired product was obtained as yellow oil (932 mg, yield: 54%). LC / MS ESI (m / z): 215 [M+H] + .

[0360] Synthesis of ethyl 5-ethylisothiazole-3-carboxylate [ka] Butan-2-one (10.0g, 139mmol) and diethyl oxalate (20.3g) A mixture of 139 mmol of sodium ethoxide (3.0 M EtOH solution, 57 0.6 mL (166 mmol) was added at 0°C, and the resulting mixture was stirred overnight at room temperature. Then, by adding a saturated NH4Cl aqueous solution (50 mL) to the reaction mixture, citric acid is produced. The solution was then acidified to pH 3 with 1.0 M HCl, concentrated in a vacuum, and EtOH was removed. The residue was extracted with ethyl acetate (3 × 20 mL). The combined organic layers were then saturated with nitrogen. Wash with H4Cl aqueous solution (20 mL) and brine, dry with anhydrous Na2SO4, and filter. The residue was concentrated in a vacuum. Flash chromatography of the residue revealed that it contained alkyl. Purified with PE (0 → 75%, V / V), ethyl 2,4-dioxohexanoate (19 0.0g, 80% was obtained as an orange oil. LC / MS (ESI) (m / z): 173 [M+H] + . Toluene of ethyl 2,4-dioxohexanoate (3.00 g, 17.4 mmol) (30 mL) and acetic acid (3 mL) solution, ammonium acetate (3.36 g, 43.6 mm (ol) was added at 0°C. Next, the resulting mixture was stirred overnight at 80°C. Then, the reaction The mixture was concentrated to dryness under vacuum. The residue was then treated by adding a saturated NaHCO3 aqueous solution. The solution was further basicized to pH 7 and extracted with ethyl acetate (3 × 20 mL). The mixture was then combined. Wash the phase with saturated NaHCO3 aqueous solution (20 mL) and brine (20 mL), then add anhydrous N The residue was dried with a2SO4, filtered, and concentrated in vacuum. The residue was then flashed with silica gel. Purified by Lamb chromatography using ethyl acetate-containing PE (0-30%, V / V). Ethyl 4-amino-2-oxohexa-3-enoate (19.0g, 80%) is yellow It was obtained as a solid. The product was a mixture of (Z)- and (E)-olefins. C / MS (ESI) (m / z): 172 [M+H] + .

[0361] Ethyl 4-amino-2-oxohexa-3-enoate (1.30g, 7.59mO) l) Add phosphorus pentasulfide (0.84 g, 7.6 mmol) to THF (15 mL) solution at room temperature. The mixture was added and stirred overnight at room temperature. The reaction mixture was then concentrated under vacuum. It dried. The residue was dissolved in acetyl (50 mL), and then in a 30% H2O2 aqueous solution ( 6 mL was added at 0°C and stirred at 0°C for 10 minutes. After 10 minutes, the reaction mixture was EtO Extraction was performed with Ac (3 × 20 mL). Next, the combined organic phase was treated with a saturated NH4Cl aqueous solution (20 Wash with (mL) and brine (20mL), dry with anhydrous Na2SO4, filter, and vacuum. The residue was concentrated using silica flash column chromatography. Purified with PE (0→30%, V / V) containing c, ethyl 5-ethylisothiazole-3- Carboxylate (0.72g, 51%) was obtained as a yellow oil. LC / MS (ESI) (m / z): 186 [M+H] + .

[0362] Synthesis of 5-bromo-1-cyclobutyl-1H-pyrazole-4-carbaldehyde [ka] 5-Bromo-1-cyclobutyl-4-iodo-1H-pyrazole (11.0g, 33. In a 6 mL THF solution (6 mmol), add i-PrMgCl·LiCl(1.3 M T). HF solution (31.0 mL, 40.4 mmol) was added at -5°C to -10°C. After stirring for 15 minutes, anhydrous DMF (3.38 mL, 43.7 mmol) was added. The solution was stirred at -10°C for 30 minutes, then slowly poured into ice water. The mixture was then vinegared. Extract with ethyl acid (100 mL x 2), then wash with brine (50 mL x 2), anhydrous The residue was dried with Na2SO4 and concentrated. Flash chromatography was performed on the siliceous gland. Purified with petroleum ether containing 0-10% ethyl acetate, 5-bromo-1-cyclo Butyl-1H-pyrazole-4-carbaldehyde (6.0g, 78%) as a yellow solid Got it. LC / MS ESI (m / z): 229 [M+H] + .

[0363] Synthesis of 4-(azidomethyl)-5-bromo-1-ethyl-1H-pyrazole [ka] 5-Bromo-4-(bromomethyl)-1-ethyl-1H-pyrazole (1.0g, 3. In a 7 mmol (7 mL) DMF (50 mL) solution, add NaN3 (728 mg, 89.5 mmol) It was added at 0°C. The mixture was stirred at 0°C for 0.5 hours. The reaction mixture was EtOA Diluted with c and washed twice with brine. The final organic layer was dried with anhydrous Na2SO4 and filtered. The residue was then concentrated. The residue was subjected to silica gel column chromatography (20% Depositphotos Inc. Purified by (including PE), 4-(azidomethyl)-5-bromo-1-ethyl-1H-pyra The zole was obtained as a yellow oil (750 mg, yield: 87%). LC / MS (ESI) m / z: 230 [M+H] +

[0364] Synthesis of 2-(5-bromo-1-ethyl-1H-pyrazole-4-yl)acetamide [ka] 2-(5-bromo-1-ethyl-1H-pyrazole-4-yl)acetonitrile (4. 00g (18.7 mmol) was added to concentrated H2SO4 (12 mL) at 0°C. After addition, The mixture was heated to room temperature and stirred for 14 hours. Next, the reaction mixture was heated in ice water (150°C). The solution was added dropwise to (mL) and basicized to pH 8 with 1N cold NaOH aqueous solution. The residue was concentrated to dryness in a vacuum using an oil pump. The residue was then collected in DCM (188 mL) and MeO2. The mixture was suspended in H(12 mL) and the solid was removed by filtration. The filtrate was concentrated under vacuum. , 2-(5-bromo-1-ethyl-1H-pyrazole-4-yl)acetamide (4.1 g, 95%) was obtained as a white solid. LC / MS (ESI): m / z = 232 [M+H] +

[0365] The following intermediates were synthesized using a similar experimental protocol: [Table 21]

[0366] Synthesis of methyl 3-bromo-5-fluoropicolinate [ka] 3-Bromo-5-fluoropyridine-2-carboxylic acid (1.0 g, 4.5 mmol) and To a solution of MeOH (30 mL) at 0°C, add SOCl2 (1.7 mL, 23 mmol) and N 2. It was added dropwise under atmospheric conditions. After addition, the mixture was stirred at 0°C for 2 hours. This mixture was then placed in ice water. After quenching, the mixture was extracted with DCM (40 mL x 2). The combined organic layers were washed with brine. The residue was purified, dried over anhydrous Na2SO4, filtered, and concentrated. The residue was then placed in a silica gel column. Purified by chromatography (PE:EA=5:1), methyl 3-bromo-5-fluorine Ropicolinate was obtained as a pale yellow solid (1.0 g, yield: 94%). LC / MS ES I (m / z): 234 [M+H] + .

[0367] Synthesis of 3-bromo-5-fluoro-2-(trimethylstanyl)pyridine [ka] 2,3-Dibromo-5-Fluoropyridine (1.0g, 3.9mmol), Hexameth Luzistanan (1.35g, 4.12 mmol) and Pd(PPh3)4 (0.23g, Toluene (50 mL) containing a mixture of 0.20 mmol) was incubated under N2 at 110°C for 16 hours. The mixture was heated. The mixture was concentrated and diluted with alkyl (50 mL) and brine (30 mL). The residue was washed with L), dried over anhydrous Na2SO4, and concentrated. The residue was then subjected to neutral Al2O3 chromatography. Purified by tography (100% petroleum ether), 3-bromo-5-fluoro-2- (Trimethylstanyl)pyridine (1.2g, 90% yield) was obtained as a colorless oil. LC / MS (ESI) m / z: 340 [M+H] + .

[0368] Synthesis of (3-ethyl-1-methyl-1H-pyrazole-5-yl)methanol [ka] Methyl 3-ethyl-1-methyl-1H-pyrazole-5-carboxylate (3.10 In a 60 mL solution of THF (18.4 mmol), add DIBAL-H (46.1 mL, 46.1 mmol of 1.0 M toluene solution was added over 30 minutes at -78°C. During this time, the internal temperature was monitored to be kept below -60°C. This reactant was mixed with dry ice / The mixture was stirred in a ceton bath for 1 hour, then in an ice bath for 1 hour. The mixture was then cooled to -78°C. The excess carboxymethylcellulose was slowly added. Another three-port nozzle attached to the mechanical stirrer. A saturated HCl solution (1M) was placed in a glass container. The organic solution was then stirred into this HCl solution. The mixture was slowly poured in and stirred at room temperature for 1 hour. The layers of this two-phase mixture were separated. The mixture was separated, and the aqueous layer was washed with phenylethylamine. The combined organic matter was washed with brine and then with MgSO4. The material was dried in step 4, filtered, and concentrated in a vacuum. The obtained material was then subjected to silica gel column chromatography. Purified by Raffy (PE containing 50% phenyl), (3-ethyl-1-methyl-1 H-pyrazole-5-yl)methanol (2.2g, 85%) was obtained as a colorless oil. LC / MS ESI (m / z): 141 [M+H] + .

[0369] Synthesis of (1-(2-fluoroethyl)-1H-pyrazole-4-yl)methanol [ka] Methyl 1-(2-fluoroethyl)-1H-pyrazole-4-carboxylate (53 In a 10 mL solution of THF (0 mg, 3.08 mmol), add DIBAL-H (2.5 M) MePh solution (5.13 mL, 12.8 mmol) was added at -78°C. Next, the mixture was... Stir the mixture at room temperature for 16 hours, then add water (0.3 mL) and NaOH aqueous solution (1 M, 0.3 mL) (mL) and a further 0.8mL of water were added in succession while stirring. The mixture was then added. The solution was then partitioned between EA and water, and the aqueous phase was further extracted with EA (3 × 10 mL). Wash the organic solution with saturated NH4Cl aqueous solution (10 mL) and brine (10 mL), then anhydrous The residue was dried with Na2SO4 and concentrated in a vacuum to obtain the residue. This residue was then flash-chromatographed. Purified by Raffy (PE containing 0-50% EA), [1-(2-fluoroethyl)- [1H-pyrazole-4-yl]methanol (380 mg, yield: 86%) is prepared as a colorless liquid. The result obtained was: LC / MS ESI (m / z): 145 [M+H] + .

[0370] The following intermediates were synthesized using a similar experimental protocol: [Table 22]

[0371] Synthesis of (5-bromo-1-cyclobutyl-1H-pyrazole-4-yl)methanol [ka] 5-Bromo-1-cyclobutyl-1H-pyrazole-4-carbaldehyde (6.00g) Diisobutylaluminum hydride (26.2 mmol) is added to a 50 mL THF solution. A 1.0 M toluene solution (39.28 mL, 39.28 mmol) is incubated at -78°C for 30 minutes. (This protocol allows for the complete reduction of the ester to an alcohol.) (For example, it can be modified by increasing the equivalent amount of the reducing agent.) During addition, The temperature was monitored to maintain it below -60°C. The reaction mixture was stirred at -78°C for 1 hour. Then, pour the mixture into an aqueous HCl solution (1M) and extract with ethyl acetate (100mL × 2) Then wash with brine (50 mL x 2), dry with anhydrous sodium 2SO4, and concentrate. The residue was subjected to silica gel chromatography (petroleum ether containing 30% ethyl acetate). Purified by (5-bromo-1-cyclobutyl-1H-pyrazole-4-yl)methano A colorless oil (4.4g, 73%) was obtained. LC / MS ESI (m / z): 2 31 [M+H] + .

[0372] The following intermediates were synthesized using a similar experimental protocol: [Table 23]

[0373] Synthesis of (3-bromo-5-fluoropyridine-2-yl)methanol [ka] Methyl 3-bromo-5-fluoropyridine-2-carboxylate (1.00g, 4. Add DIBAL-H (1.21 mL) to a 27 mmol THF (15 mL) solution at -78°C. (8.54 mmol) was added dropwise under an N2 atmosphere. The mixture was stirred at 0°C for 2 hours. The mixture was then quenched in ice water and extracted with DCM (40 mL x 2). The combined organic layer was brined. The residue was washed, dried with anhydrous Na2SO4, filtered, and concentrated. The residue was then placed in a silica gel container. Purified by microchromatography (DCM:MeOH=20:1), (3-bromo-5 (Fluoropyridine-2-yl)methanol was obtained as a pale yellow solid (600 mg, yield) :68%). LC / MS ESI (m / z): 206 [M+H] + .

[0374] The following intermediates were synthesized using a similar experimental protocol: [Table 24]

[0375] Synthesis of 5-(4-fluoro-2-iodophenyl)-1H-tetrazole [ka] 4-Fluoro-2-iodobenzonitrile (2.5g, 10mmol), trimethyl nitrile Lylazide (2.92g, 25.3mmol) and dibutylstananonone (0.50g, 2 Toluene (20 mL) containing a mixture of 0.0 mmol) was stirred at 120°C for 18 hours. After cooling to warm temperature, the mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was DCM. Dilute with (50 mL), then wash with water and brine, dry with anhydrous Na2SO4, and filter. The residue was filtered and concentrated. The residue was then flash-chromatographed (silica gel, 0→50%E). Purified by PE containing A, 5-(4-fluoro-2-iodophenyl)-1H-teto Razole (2.4g, yield 82%) was obtained as a yellow oil. LC / MS (ESI) m / z: 291 [M+H] + .

[0376] Synthesis of 4-(azidomethyl)-5-bromo-1-cyclobutyl-1H-pyrazole [ka] 5-Bromo-4-(chloromethyl)-1-cyclobutyl-1H-pyrazole (3.00 In a 60 mL solution of DMF (1.17 g, 18.0 mmol) of NaN3 (1.17 g, 18.0 mmol) mmol was added gradually at 0°C. After addition, the resulting mixture was incubated at 60°C for 2.5 hours. The mixture was stirred. After cooling to 0°C, the reaction product was diluted with water (200 mL) and extracted with EA. (2 x 100 mL). The combined extracts were washed with brine, concentrated in a vacuum, and flushed. Purified by chromatography (PE containing 10% SiO₂), 4-(azidomethine (Lu)-5-bromo-1-cyclobutyl-1H-pyrazole (2.91g, yield: 95%) It was obtained as a colorless oil. LC / MS ESI (m / z): 256 [M+H] + .

[0377] 5-((5-bromo-1H-1,2,4-triazol-1-yl)methyl)-3-e Synthesis of thyl isoxazole [ka] 5-(chloromethyl)-3-ethyl-1,2-oxazole (2.00g, 13.7mg) (mol), 3-bromo-1H-1,2,4-triazole (2.03g, 13.7mmol) l) Ethylbis(propan-2-yl)amine (4.54 mL, 27.47 mmol) , anhydrous MeCN (20 The mixture (mL) was stirred at 80°C for 2 hours. The reaction mixture was filtered to remove the solid, and the filtrate was obtained. The EA was distributed between the water and the aqueous layer, and the layers were separated. The aqueous layer was further extracted with EA and combined with the organic The layers were dried with anhydrous Na2SO4 and concentrated. The residue was then flash-chromatographed. Purified by 0-3% MeOH-containing DCM, a 5:1 mixture of positional isomers (3.0 g, Yield: 85.7% was obtained as a colorless oil. These isomers were separated into SFC (ChiralP ak IG, 250×21.2mm ID, 5μm, 40%MeOH+0.1%NH Separation was performed using 3 water, CO2, 50 mL / min, and 5-((5-bromo-1H-1,2,4 -triazole-1-yl)methyl)-3-ethylisoxazole (peak 1, small amount) The isomer (650 mg, NOESY analysis) was obtained as a colorless oil. LC / MS ESI (m / z): 257 [M+H] + .

[0378] Ethyl 5-bromo-1-(difluoromethyl)-1H-pyrazole-4-carboxylate Synthesis of te [ka] Ethyl 5-bromo-1H-pyrazole-4-carboxylate (14.0g, 63.9g) In a MeCN (60 mL) solution of mmol) and KF (7.96 g, 63.9 mmol), Diethyl (bromodifluoromethyl)phosphonate (27.43g, 102.7mmol) The mixture was added at 0°C. The resulting mixture was stirred overnight at room temperature. The mixture was then slowly placed in ice water. Pour in and extract twice with EA. Wash the combined extract with brine and anhydrous Na2SO4 The residue was dried and concentrated. The residue was then flash-chromatographed (silica gel, 0-5%). Purified with ethyl 5-bromo-1-(difluoromethyl ether containing ethyl ether), (Tyl)-1H-pyrazole-4-carboxylate (4.0g, yield 23%) is a white solid. The result obtained was: LC / MS ESI (m / z): 269 [M+H] + .

[0379] The following intermediates were synthesized using a similar experimental protocol: [Table 25]

[0380] 1-[(5-bromo-1,3-thiazole-4-yl)methyl]pyrazole-4-cal Synthesis of bonitrile [ka] (5-bromo-1,3-thiazole-4-yl)methanol (400 mg, 2.06 mg) mol), 4-cyanopyrazole (288 mg, 3.09 mmol) and PPh3 (64 DIAD (500 mg, 2.47 mmol) in a 6 mL THF solution 7 mmol of the solvent was added dropwise at 0°C. The mixture was then stirred at room temperature for 16 hours. The residue is removed under vacuum, and the remaining residue is purified with silica gel (PE / EA=1:1), and 1-[( 5-Bromo-1,3-thiazole-4-yl)methyl]pyrazole-4-carbonilicate (460 mg, 83%) was obtained as a white solid. LC / MS ESI (m / z): 2 69 [M+H] + .

[0381] The following intermediates were synthesized using a similar experimental protocol: [Table 26]

[0382] 5-((5-iodo-1H-pyrazole-1-yl)methyl)isoxazole-3- Synthesis of carbon nitriles [ka] 5-(bromomethyl)isoxazole-3-carbonitride (2.20g, 11.7 5-iodo-1H-pyrazole (2.50g) in a 100mL solution of mmol) in DMF. Add (12.9 mmol) and K2CO3 (4.90 g, 35.3 mmol) at 25°C. After stirring at 25°C for 2 hours, the reaction mixture was diluted with siRNA, and then with H2O. The mixture was then washed with brine. The organic layer was dried with anhydrous sodium 2SO4. After filtration, the filtrate was obtained. The substance was concentrated under vacuum. The residue was SFC(ChiralPak AD, 40% MeOH+0). The solution is purified by treatment with 0.1%NH3·H2O, and the positional isomers are separated to obtain 5-((5-Yo (Isooxazole-3-carbonitride) Obtained as a pale yellow oil (350 mg, yield: 10%, small amounts of positional isomers). LC / MS E SI (m / z): 301 [M+H] + .

[0383] The following intermediates were synthesized using a similar experimental protocol: [Table 27] TIFF2026082971000180.tif48165

[0384] 3-Ethyl-5-(((tetrahydro-2H-pyran-2-yl)oxymethyl) Synthesis of soxazole [ka] 2-(propane-2-in-1-yloxy)tetrahydro-2H-pyran (5.00g) Stirring of 36.7 mmol of nitropropane and 1-nitropropane (7.00 g, 78.6 mmol). Toluene (40 mL) solution, add phenyl isocyanate (17.0 mL, 119 mmol) ) was added, followed by the addition of triethylamine (2.94 mL, 21.2 mmol). The reaction mixture was heated to 120°C and stirred for 24 hours. After cooling to room temperature, the reaction was... The mixture was quenched with 1 mL of water and stirred at room temperature for 1 hour. The precipitate was filtered. The residue was removed and the filtrate was concentrated. The residue was then subjected to silica gel column chromatography (0 →Purified by PE containing 20% ​​ethyl, 3-ethyl-5-(((tetrahydro -2H-pyran-2-yl)oxy)methyl)isoxazole (10.0g, yield 61 %) was obtained as yellow syrup. LC / MS ESI (m / z): 212 [M+H ] + .

[0385] The following intermediates were synthesized using a similar experimental protocol: [Table 28]

[0386] (2-(3-chloro-1H-pyrazole-1-yl)-5-fluorophenyl)methano Synthesis of [ka] (5-Fluoro-2-iodophenyl)methanol (25.0g, 99.2 mmol) To a toluene (250 mL) solution, add 3-chloro-1H-pyrazole (11.2 g, 10⁹) mmol), K2CO3 (27.4 g, 198.4 mmol) and CuI (1.9 g, 9 0.9 mmol) was added. This reaction mixture was stirred under N2 at 120°C for 12 hours. The reaction mixture was filtered and concentrated. The residue was subjected to flash chromatography (5 → 25% Et). Purified by (PE containing OAc), (2-(3-chloro-1H-pyrazole-1-yl) )-5-fluorophenyl)methanol (21.1 g, yield 85%) was obtained as a white solid. Ta. LC / MS (ESI) (m / z): 227 [M+H] + .

[0387] 3-Methoxy-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazo Synthesis of [ka] Stirring 3-methoxy-1H-pyrazole (1.00 g, 10.2 mmol) with THF (1 Add NaH (0.46g, 12 mmol, 60% mineral oil solution) to 5 mL of solution under N2, 0 It was added at °C. After stirring at 0°C for 1 hour, [2-(chloromethoxy)ethyl]trimethyl A solution of silane (2.5 mL, 14 mmol) in THF (3 mL) was added dropwise. The reaction product Stir at 0°C for 1 hour, quench with saturated NH4Cl (10 mL), and add HCl (100 mL). Extracted with L). The organic phase was separated, dried with anhydrous Na2SO4, concentrated to dryness, and 3- Methoxy-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole( 2.20 g, yielding 91%, was obtained as yellow oil. LC / MS (ESI) (m / z): 229.1 [M+H] + .

[0388] The following intermediates were synthesized using a similar experimental protocol: [Table 29]

[0389] (E)-1-(3-bromo-5-fluoropyridine-2-yl)-3-(dimethylamyl) Synthesis of propane-2-en-1-one [ka] 1-(3-bromo-5-fluoropyridine-2-yl)ethane-1-one (2.60g) A 10 mL solution of (dimethoxymethyl)dimethylamine (11.9 mmol) is added to 12 The mixture was stirred at 0°C for 12 hours. After cooling to room temperature, the mixture was concentrated using an oil pump. The residue was then subjected to flash chromatography of silica gel (0-40% HCl). Purified by PE, (E)-1-(3-bromo-5-fluoropyridine-2-yl)- 3-(dimethylamino)propa-2-en-1-one (3.0g, yield 92%) was solidified into a yellow solid. Obtained as a physical sample. LC / MS ESI (m / z): 273 [M+H] + .

[0390] The following intermediates were synthesized using a similar experimental protocol: [Table 30]

[0391] (5-bromo-1,3-thiazole-4-yl)(1-ethyl-1H-1,2,3 Synthesis of riazole-4-yl)methanol [ka] In a sealed tube, bromoethane (1.68 g, 15.1 mmol), sodium azide (0. Prepare a solution of 98g, 15.1 mmol THF (5 mL) and H2O (5 mL) at 80°C. The mixture was stirred for 4 hours. After the resulting mixture cooled to room temperature, 1-(5-bromo-1,3-thiosulfate was added. Azole-4-yl)propa-2-in-1-ol (1.10g, 5.04mmol) Sodium ascorbate (0.20g, 1.01mmol), CuSO4 (0.16g, 1 0.01 mmol) and t-BuOH (10 mL) were added consecutively. The mixture was heated at 50°C. After stirring for 18 hours, the mixture was filtered. The filtrate was concentrated under reduced pressure. The residue was then placed in silica gel. Purified by flash column chromatography (DCM containing 0-10% MeOH). (5-bromothiazol-4-yl)(1-ethyl-1H-1,2,3-triazole) -4-yl)methanol (0.7g, 48%) was obtained as a colorless oil. MS (ESI): m / z = 289 [M+H] + .

[0392] 1-[(3-iodopyridine-2-yl)methyl]-1H-imidazole-4-carb Nitrile synthesis [ka] A solution of triphenylphosphan (712 mg, 2.72 mmol) in THF (7 mL) Next, it was cooled to 0°C under N2. Then, it contained DIAD (549 mg, 2.71 mmol). THF (7 mL) was added. The mixture was then stirred at 0°C until a white solid precipitate formed. Next, to the mixture, 1H-imidazole-4-carbonitride (152 mg, 1 THF (4 mL) containing 0.63 mmol) was added at 0°C. Then, to this mixture, ( T HF (6 mL) was added. The mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated. Then, it was diluted with DCM. The solution was washed with saturated NaCl aqueous solution and dried with anhydrous Na2SO4. The residue was dried, filtered, and concentrated. Flash chromatography was performed on the residue (silica gel, 0 → Purified by PE containing 100% EA, 1-[(3-iodopyridine-2-yl)methyl [L]-1H-imidazole-4-carbonitride (309 mg, yield: 73%) in yellow oil The result obtained was: LC / MS (ESI) m / z: 311 [M+H] + .

[0393] The following intermediates were synthesized using a similar experimental protocol: [Table 31]

[0394] 4-[(3-chloro-5-iodo-1H-pyrazole-1-yl)-methyl]-1-e Synthesis of til-1H-1,2,3-triazole [ka] 3-Chloro-5-iodo-1-(propa-2-in-1-yl)-1H-pyrazole( In a 15 mL solution of tert-butyl alcohol (0.550 g, 2.06 mmol), Water (15 mL), CuSO4 (20 mg, 0.14 mmol), and sodium ascorbate Add 20 mg of ammonium (0.10 mmol), followed by ethyl azide (10 mL, 5.0 mmol (in a 0.5N THF solution) was added at 25°C. After addition, the resulting mixture was sealed. The mixture was stirred in a tube at 50°C for 16 hours. Then, the mixture was concentrated in a vacuum and tert-butyric acid was used. Most of the alcohol was removed. The residue was then treated with DCM (20 mL) and H2O (10 mL). The organic layer was treated with (L). The organic layer was separated, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was then subjected to flash chromatography (PE containing 0-50% dimethyl acetate) and and SFC (ChiralPak AD, 250×4.6mm 5um, 30%EtOH+ Purified by 0.1% NH3 water (in CO2), 4-[(3-chloro-5-iodo-1H- Pyrazole-1-yl)-methyl]-1-ethyl-1H-1,2,3-triazole(2 10 mg was obtained as a white solid (30% yield). LC / MS (ESI): m / z = 338 [M+H] + .

[0395] The following intermediates were synthesized using a similar experimental protocol: [Table 32]

[0396] 3-Chloro-1-((1-(ethyl-d5)-1H-pyrazole-4-yl)methyl) Synthesis of -5-iodo-1H-pyrazole [ka] (1-(ethyl-d5)-1H-pyrazole-4-yl)methanol (1.07g, 8 To a stirred DCM (20 mL) solution of 0.16 mmol, add SOCl2 (1.80 mL, 24. 5 mmol) was added at 0°C. The reaction mixture was stirred at 25°C for 16 hours. The substance is concentrated to obtain crude 4-(chloromethyl)-1-(ethyl-d5)-1H-pyrazole (1 0.22 g, with a yield of 99%, was obtained as yellow oil.

[0397] 3-Chloro-5-iodo-1H-pyrazole (1.83g, 8.02 mmol) and C In a 30 mL DMF containing a mixture of s2CO3 (7.84 g, 24.06 mmol), 4-(chloromethyl)-1-(ethyl-d5)-1H-pyrazole (1.20g, 8.0 A 2 mmol (3 mL) solution of DMF was added under N2 conditions at 0°C. The reaction mixture was then heated at 80°C. The mixture was stirred for 1 hour. The reaction mixture was poured into water (60 mL) and extracted with ethyl acetate (3 (0 mL x 2). Wash the combined organic layer with brine (30 mL) and dry with anhydrous sodium 2 SO4. The residue was dried and concentrated to dryness. The residue was subjected to silica gel column chromatography (PE:EA= It is purified by 3:1, and then recrystallized from DCM and PE to obtain 3-chloro-1-((1 -(ethyl-d5)-1H-pyrazole-4-yl)methyl)-5-iodo-1H-pyra Zol (700 mg, yield 26%) was obtained as a white solid. LC / MS (ESI) ( m / z): 342 [M+H] + .

[0398] 4-Bromo-3-ethyl-5-((5-iodo-1H-1,2,4-triazole-1 Synthesis of -yl(methyl)isothiazole [ka] 5-((1H-1,2,4-triazol-1-yl)methyl)-4-bromo-3-e Stirring of thylisothiazole (1.90 g, 6.99 mmol) at ambient temperature. AcOH (60 NIS (3.60 g, 21.0 mmol) was added to the (mL) solution. The resulting mixture The mixture was stirred at 80°C for 16 hours. The filtrate was extracted with ethyl acetate. The combined organic layers were then prepared. The residue was washed, dried with Na2SO4, and concentrated under vacuum. The residue was then flushed with silica gel. Purified by 4-phase chromatography (0 → 30% HCl-containing petroleum ether), -bromo-3-ethyl-5-((5-iodo-1H-1,2,4-triazole-1-I Methylisothiazole (2.0 g) was obtained as an off-white solid. LC-MS (ESI) m / z: 399 [M+H] + .

[0399] Synthesis of (3-ethylisoxazol-5-yl)methanol [ka] 3-Ethyl-5-[(oxan-2-yloxy)methyl]-1,2-oxazole ( In a 10 mL solution of 17.4 g (82.4 mmol) of MeOH, add Amberlyst 15 (26 mg, 83 mmol) was added. The mixture was vigorously stirred at 45°C for 6 hours. The mixture was filtered, the solvent was removed under vacuum to obtain a red residue, which was then subjected to silica gel column chromatography. Purified by tography (PE containing 15-30% ammonium), (3-ethyl-1 ,2-oxazol-5-yl)methanol (8.05g, yield: 77%) mixed with pale yellow oil The result obtained was: LC / MS ESI (m / z): 128 [M+H] + .

[0400] The following intermediates were synthesized using a similar experimental protocol: [Table 33]

[0401] Synthesis of 5-bromo-3-methoxy-1H-pyrazole [ka] 3-Methoxy-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazo In a stirred THF (30 mL) solution of 2.20 g, 9.63 mmol of n-BuLi, (4.0 mL, 10 mmol, 2.5 M THF solution) was added under N2 conditions at -78°C. After stirring at -78°C for 1 hour, add CBr4 (2.20 g, 6.63 mmol) to THF (1 A 0 mL solution was added dropwise. The reaction mixture was stirred at 0°C for 1 hour, and saturated NH4Cl (10 mL) was added. The mixture was quenched with ) and extracted with ethyl acetate (150 mL). The organic phase was separated and anhydrous sodium The residue was dried with 2SO4 and concentrated. The residue was then subjected to silica gel column chromatography (PE). Purified by : siRNA=4:1, V / V), 5-bromo-3-methoxy-1-((2 -(trimethylsilyl)ethoxymethyl)-1H-pyrazole (1.8g, yield 58%) ) was obtained as yellow oil. LC / MS (ESI) (m / z): 307.0 [M+H ] + .

[0402] 5-Bromo-3-methoxy-1-((2-(trimethylsilyl)ethoxy)methyl)- 1H-pyrazole (1.80 g, 5.86 mmol) and TFA (3.00 mL, 40 ml). A 4 mmol (15 mL) solution of DCM was stirred at 25°C for 4 hours. The reaction mixture was then prepared. The residue was concentrated under reduced pressure. The residue was then mixed with acetonitrile (15 mL) and an aqueous solution of NH4OH (3.0 The mixture was diluted (mL, 22 mmol). The mixture was stirred at 25°C for 3 hours. The reaction product Concentrate under reduced pressure to obtain 5-bromo-3-methoxy-1H-pyrazole (1.5 g, yield 87%). It was obtained as yellow oil. LC / MS ESI (m / z): 177.0 [M+H] + .

[0403] 5-Bromo-1-((1-(cyclopropylmethyl)-1H-pyrazole-4-yl) Synthesis of methyl)-1H-1,2,4-triazole [ka] 4-(chloromethyl)-1-(cyclopropylmethyl)-1H-pyrazole (950ml) It contains a mixture of (g, 5.56 mmol) and K2CO3 (1.50 g, 11.1 mmol). To 15 mL of DMF, add 906 mg of 3-bromo-4H-1,2,4-triazole. 6.10 mmol) was added. The mixture was then stirred at 50°C for 2 hours. The solution was concentrated using an oil pump and diluted with ethyl acetate. The solution was then washed with brine. The solution was purified, dried over anhydrous Na2SO4, filtered, and concentrated. The residue was then separated by preparative HPLC (column chromatography). YMC TA C18 250*20mm 5um, H2O+0.1% containing MeCN Purified by FA, ​​5-bromo-1-((1-(cyclopropylmethyl)-1H-pyra Zole-4-yl(methyl)-1H-1,2,4-triazole (100mg, in two stages) A yield of 6% was obtained as a white solid. LC / MS ESI (m / z): 282 [M+ H] + .

[0404] The following intermediates were synthesized using a similar experimental protocol: [Table 34] TIFF2026082971000200.tif115165

[0405] 4-[(5-bromo-1,3-thiazole-4-yl)methyl]-1-ethyl-1H- Synthesis of 1,2,3-triazole [ka] (5-bromo-1,3-thiazole-4-yl)(1-ethyl-1H-1,2,3 Riazole-4-yl)methanol (700 mg, 2.42 mmol) TFA (20 ml) To the solution (L), triethylsilane (7.8 mL, 48 mmol) was added. The container was sealed tightly. The mixture was then closed and stirred at 50°C for 16 hours. The reaction mixture was then concentrated under reduced pressure. The residue was analyzed by silica gel flash column chromatography to determine the presence of PE (EA). Elute and purify using 0→100% elution, then 4-[(5-bromo-1,3-thiazole-4-yl] )Methyl-1-ethyl-1H-1,2,3-triazole (0.6g, 91%) pale yellow It was obtained as a color solid. LC / MS (ESI): m / z = 273 [M+H] + .

[0406] The following intermediates were synthesized using a similar experimental protocol: [Table 35] TIFF2026082971000203.tif245165TIFF2026082971000204.tif209165TIFF2026082971000205.tif228165

[0407] 5-((5-bromothiazol-4-yl)(hydroxy)methyl)-1-methyl-1 Synthesis of H-pyrazole-3-carbonitrine [ka] 5-Iodo-1-methyl-1H-pyrazole-3-carbonitrile (650 mg, 2. Mix 79 mmol) of stirred THF (20 mL) solution with isopropylmagnesium bromide (3. 1 mL of 1 M THF solution (3.1 mmol) was added at 0°C. The mixture was stirred at 0°C for 30 minutes. Afterwards, 5-bromo-1,3-thiazole-4-carbaldehyde (643 mg, 3.35 mg) A 2 mL solution of (mol) THF was added dropwise. The reaction mixture was then stirred at 0°C for a further 30 minutes. The solution was quenched with saturated NH4Cl (10 mL) and extracted with toluene (20 mL x 2). The combined organic phases were washed with brine (20 mL), dried with Na2SO4, and concentrated. The residue was obtained by silica gel column chromatography (PE containing 50% HCl). Purified, 5-((5-bromothiazol-4-yl)(hydroxy)methyl)-1-methyl Lu-1H-pyrazole-3-carbonitride (450 mg, yield 54%) as yellow oil Got it. LC / MS (ESI) (m / z): 299 [M+H] + .

[0408] The following intermediates were synthesized using a similar experimental protocol: [Table 36] TIFF2026082971000208.tif232165TIFF2026082971000209.tif197165

[0409] [2-(1,3-dioxolan-2-yl)-4-fluorophenyl]trimethyl staglandin Naan synthesis [ka] 2-(2-bromo-5-fluorophenyl)-1,3-dioxolane (1.0g, 4. A mixture of 0 mmol) THF (20 mL) is mixed with n-BuLi (1.78 mL, 4.45 mL). (mol, 2.5M) was added dropwise at -78°C. The mixture was stirred at -78°C for 1 hour. Next Next, trimethyltin chloride (4.45 mL, 4.45 mmol, 1.0 M THF solution) The mixture was added dropwise. The resulting mixture was stirred at -78°C for 15 minutes. Quenched with saturated NH4Cl (50 mL) at 0°C, and extracted with toluene (50 mL) (x3). Wash the combined extracts with brine (20 mL x 2) and dry with anhydrous sodium 2SO4. The residue was filtered and concentrated. The residue was then subjected to flash chromatography on silica gel (10 Purified with % ELISA (PE), [2-(1,3-dioxolan-2-yl)-4 -Fluorophenyl]trimethylstanane (600 mg, yield: 44%) as a colorless oil Got it. LC / MS ESI (m / z): 333 [M+H] + .

[0410] 4-(5-ethyl-1,2-oxazol-3-carbonyl)-5-iodo-2-meth Synthesis of 2H-1,2,3-triazole [ka] 5-Ethyl-1,2-oxazole-3-carboxylic acid (1.6g, 11.3 mmol) , EDCI (3.36g, 17.5mmol), HOBt (2.37g, 17.5mmol) l) N,O-dimethylhydroxylamine hydrochloride (1.25 g, 12.9 mmol) and DMF (10 mL) containing a mixture of TEA (2.29 g, 22.7 mmol) is heated at 0°C. The mixture was stirred. The mixture was stirred at room temperature for 2 hours. The mixture was concentrated in a vacuum and then heated with EA. Extracted (80 mL x 3). The organic layer was separated and saturated NaHCO3 aqueous solution (40 mL x 3). 3) Wash with brine (10 mL), dry with anhydrous Na2SO4, filter, and concentrate. The residue was subjected to silica gel column chromatography (DCM:MeOH=20:1, V Purified by / V), 5-ethyl-N-methoxy-N-methyl-1,2-oxazole- 3-Carboxamide (1.5 g, 70%) was obtained as a pale yellow solid. LC / MS ESI (m / z): 185 [M+H] + .

[0411] 4,5-Diiodo-2-methyl-2H-1,2,3-triazole (1.65g, 4. A mixture of 93 mmol THF (20 mL) was degassed three times with N2, and then treated with isopropyl bromide. Pyrmagnesium (3.79 mL, 4.93 mmol, 1.3 M 2-methyltetrahydride) Lofuran solution was added at 0°C for 2 hours. 5-ethyl-N-methoxy-N-methyl-1, 2-Oxazole-3-carboxamide (0.91 g, 4.93 mmol) in this mixture The mixture was added and stirred at 0°C for 2 hours. The mixture was then treated with a saturated NH4Cl aqueous solution (100 mL). Quenched and extracted with EA (80 mL x 3). The organic layer was separated and anhydrous Na2SO4 was used. The mixture was dried, filtered, and concentrated in a vacuum to obtain the residue, which was then subjected to silica gel column chromatography. Purified by Phi (PE:EA=2:1, V / V), 4-(5-ethyl-1,2-oxygen) Sazole-3-carbonyl)-5-iodo-2-methyl-2H-1,2,3-triazole Lu (310 mg, 19%) was obtained as a pale yellow oil. LC / MS ESI (m / z): 333 [M+H] + .

[0412] 5-Bromo-1-((3-(cyclopropylmethyl)-1-methyl-1H-pyrazole Synthesis of -5-yl)methyl)-1H-1,2,4-triazole [ka] (3-(cyclopropylmethyl)-1-methyl-1H-pyrazole-5-yl)methano Mix 1.05 g of 1.05 mmol of 1.05 mmol with 20 mL of stirred DCM solution, then add SOCl2 ( 1.40 mL (19 mmol) was added at 0°C. After stirring at room temperature for 2 hours, the reaction mixture was... The compound was concentrated to obtain crude 5-(chloromethyl)-3-(cyclopropylmethyl)-1-methyl Lu-1H-pyrazole (1.16 g, 99% yield) was obtained as a yellow oil.

[0413] 5-bromo-1H-1,2,4-triazole (0.88g, 5.96mmol) and In a 30 mL DMF containing a mixture of Cs2CO3 (1.94 g, 5.96 mmol), 5-(chloromethyl)-3-(cyclopropylmethyl)-1-methyl-1H-pyrazole A 1.10g, 5.96 mmol solution of DMF (3 mL) was added dropwise. The reaction product was divided into 8 The mixture was stirred at 0°C for 5 hours. The reaction mixture was poured into water and extracted twice with ethyl acetate. The organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated in vacuum. The remaining The residue was subjected to silica gel flash column chromatography (PE:EA=2:1) ​​and SF C(ChiralPak IA, 250×21.2mm ID, 5μm, 30%Me Purified by OH + 0.1% NH3 (in water, CO2), 5-bromo-1-((3-(cyclo Propylmethyl)-1-methyl-1H-pyrazole-5-yl)methyl)-1H-1,2 ,4-triazole (300 mg, yield 18%) was obtained as a colorless oil. LC / MS (E SI) (m / z): 296 [M+H] + .

[0414] 5-Bromo-1-((1-isobutyl-3-methyl-1H-pyrazole-4-yl)methyl Synthesis of (Tyl)-1H-1,2,4-triazole [ka] (1-Isobutyl-3-methyl-1H-pyrazole-4-yl)methanol (800ml) In a 30 mL solution of anhydrous dichloromethane (g, 4.76 mmol), thionyl chloride (3. 45 mL (47.6 mmol) was added. The resulting mixture was stirred at room temperature for 2 hours. The reaction solution was directly concentrated to obtain crude 4-(chloromethyl)-1-isobutyl-3-methyl 1H-pyrazole (950 mg) was obtained as a white solid.

[0415] Crude 4-(chloromethyl)-1-isobutyl-3-methyl-1H-pyrazole (500 3-bromo-4H-1,2,4 (mg, 2.68 mmol) in DMF (20 mL) solution - Triazole (594 mg, 4.01 mmol) and K2CO3 (925 mg, 6.7 0 mmol) was added under an N2 atmosphere. The resulting mixture was stirred at room temperature for 18 hours. The solution was diluted with ¼. This solution was then mixed with water (30 mL x 3) and brine (30 mL The residue was washed, dried with Na2SO4, and concentrated to dryness. The residue was then chromatographed using silica gel. Raffy (PE containing 50% τ) followed by SFC (ChiralCel OD, Purified using a 250×21.2mm filter (30% MeOH + 0.1% NH3 water, CO2), 5-Bromo-1-((1-isobutyl-3-methyl-1H-pyrazole-4-yl)methyl (Lu)-1H-1,2,4-triazole (92 mg, yield 12%) was obtained as a colorless liquid. LC / MS (ESI): m / z=298 [M+H] + .

[0416] 5-((5-bromo-2-methylthiazole-4-yl)(hydroxy)methyl)-1 Synthesis of methyl-1H-pyrazole-3-carbonitrile [ka] 5-Iodo-1-methyl-1H-pyrazole-3-carbonitrile (900 mg, 3. In a 9 mL solution of 86 mmol THF, isopropylmagnesium chloride - lithium chloride Add the complex (3.27 mL, 4.25 mmol, 1.3 M THF solution) dropwise at 0°C, and The mixture was stirred at room temperature for 2 hours. After 2 hours, 5-bromo-2-methylthiazole-4- Carbaldehyde (796 mg, 3.86 mmol) was added, and the resulting mixture was sterilized at room temperature. The mixture was stirred overnight. Then, 10 mL of saturated NH4Cl aqueous solution was added to the reaction mixture. Quenched by [method], extracted with EA (3 x 10 mL), mixed all organic phases, saturated with NH4C Wash with 10 mL of aqueous solution and 10 mL of brine, then dry with anhydrous Na2SO4. The residue was filtered and concentrated in a vacuum. Flash chromatography was performed on the residue (0→5% MeO2). Purified by DCM containing H, and 5-((5-bromo-2-methylthiazole-4-yl (Hydroxy)methyl-1-methyl-1H-pyrazole-3-carbonitrile(55 3 mg, 46% was obtained as a yellow viscous substance. LC / MS ESI (m / z): 31 3 [M+H] + .

[0417] The following intermediates were synthesized using a similar experimental protocol: [Table 37]

[0418] (5-bromo-1-ethyl-1H-pyrazole-4-yl)(3-chloropyrazine-2) -Il) Methanol Synthesis [ka] 2-Chloropyrazine (1.00 g, 8.73 mmol) at -78°C THF (35 mL) Add LiTMP (1.0M THF solution, 11.4mL, 11.4 mmol) to the solution. 2. It was added dropwise under atmospheric conditions. After addition, the mixture was stirred at -70°C for 0.5 hours, and then 5- Bromo-1-ethyl-1H-pyrazole-4-carbaldehyde (2.13g, 10.5mg) A solution of 5 mL of THF (mol) was added. The resulting mixture was further incubated at -70°C for 1.5°C. The mixture was stirred for a certain amount of time. The mixture was quenched with a saturated NH4Cl solution and then extracted twice with DCM. (40 mL x 2). The combined organic layers were washed with brine and dried with anhydrous sodium 2SO4. The residue was filtered and concentrated. The residue was subjected to silica gel column chromatography (30% EtO Purified by PE containing Ac, (5-bromo-1-ethyl-1H-pyrazole-4-I (3-chloropyrazine-2-yl)methanol was obtained as yellow oil (1.29g, saturates rate 47%). LC / MS ESI (m / z): 317 [M+H] + .

[0419] (1-ethyl-1H-pyrrole-3-yl)(5-iodo-2-methyl-2H-1,2) Synthesis of 3-triazole-4-yl)methanone [ka] (1-ethyl-1H-pyrrole-3-yl)(5-iodo-2-methyl-2H-1,2) DCM of 3-triazol-4-yl)methanol (400 mg, 1.20 mmol) Add manganese(IV) oxide (1.57 g, 18.1 mmol) to (10 mL) of the solution. Next, the mixture was stirred at room temperature for 2 hours. The reaction product was filtered, and the residue was collected in DCM. It was washed with [method]. The filtrate was concentrated, and the residue was subjected to silica gel chromatography (0%~5%). Purified by EA containing 0% PE, (1-ethyl-1H-pyrrole-3-yl)(5- Iodo-2-methyl-2H-1,2,3-triazol-4-yl)methanone (188ml) g, yield 47%, was obtained as a yellow solid. LC / MS (ESI) m / z: 331. 3 [M+H] + .

[0420] 4-[(4-cyclobutyl-1H-1,2,3-triazole-1-yl)methyl]- Synthesis of 5-iodo-2-methyl-2H-1,2,3-triazole [ka] (5-iodo-2-methyl-2H-1,2,3-triazol-4-yl)methanol SOCl2 (5.8 mL, 80 mmol) mixture (900 mg, 4.00 mmol) The mixture was stirred at room temperature for 1 hour. The mixture was then mixed with saturated NaHCO3 aqueous solution (20 mL) at 0°C. Enchyma was used, and the mixture was extracted with EA (50 mL x 3). The resulting organic layers were combined and then treated with anhydrous Na2SO4. The residue was dried, filtered, concentrated in a vacuum, and then flash-chromatographed (5 Purified by PE containing 0% ethyl acetate, 4-(chloromethyl)-5-iodo-2- Methyl-2H-1,2,3-triazole (900 mg, 87%) was obtained as a pale yellow oil. LC / MS (ESI) m / z: 258 [M+H] + .

[0421] 4-(chloromethyl)-5-iodo-2-methyl-2H-1,2,3-triazole( A mixture of 900 mg (3.40 mmol) and NaN3 (454 mg, 6.90 mmol). DMF (10 mL) containing the substance was stirred at 0°C. The mixture was stirred at room temperature for 2 hours. The mixture was extracted with EA (50 mL x 3). The resulting organic layers were combined and treated with anhydrous Na2SO4. The residue was dried, filtered, concentrated in a vacuum, and then flash-chromatographed (5 Purified by PE containing 0% ethyl acetate, 4-(azidomethyl)-5-iodo-2-methyl Chil-2H-1,2,3-triazole (880 mg, 95%) was obtained as a pale yellow oil.

[0422] 4-(azidomethyl)-5-iodo-2-methyl-2H-1,2,3-triazole( (200 mg, 0.75 mmol), ethinylcyclobutane (182 mg, 2.27 mmol) l) CuSO4 (20 mg, 0.12 mmol), and sodium ascorbate (2 A mixture of t-BuOH (10 mL) and H2O (10 mg, 0.10 mmol) is contained within. The mixture (mL) was stirred at room temperature for 2 hours. The mixture was extracted with EA (40 mL x 3). Combine the layers, wash with brine (10 mL), dry with anhydrous Na2SO4, filter, and purify. The residue is concentrated in the air and then flash-chromatographed (containing 5% MeOH). Purified by CM, 4-cyclobutyl-1-[(5-iodo-2-methyl-2H-1, 2,3-Triazol-4-yl)methyl]-1H-1,2,3-triazol(100 mg, 38% was obtained as a pale yellow oil. LC / MS ESI (m / z): 345 [ M+H] + .

[0423] (5-bromo-1-ethyl-1H-pyrazole-4-yl)(5-iodo-1-methyl) Synthesis of -1H-imidazole-4-yl)methanol [ka] 4,5-Diiodo-1H-imidazole (8.0g, 25.01 mmol) and LiC A suspension of 1 (0.13 g, 3.13 mmol) in THF (50 mL) at -10°C is mixed with bromide. Magnesium chloride (3M, 6.59 mL, 6.59 mmol) was added dropwise under an N2 atmosphere. The mixture was stirred at -10°C for 30 minutes. Next, isopropyl bromide was added to this mixture. Gnesium (1.3 M, 2.65 mL, 3.44 mmol) was added dropwise, and the resulting mixture was prepared. The mixture was stirred at room temperature for 1.5 hours. Then, 5-bromo-1-ethyl-1H-p Razole-4-carbaldehyde (6.09 g, 30.0 mmol) was added at -10°C. The resulting mixture was stirred at room temperature for a further 2 hours. This reaction mixture was then treated with a saturated aqueous solution of NH4Cl. Quench with (50 mL), extract with Å (3 × 50 mL), brine (30 mL The residue was washed, dried with anhydrous Na2SO4, filtered, and concentrated. The residue was then flash-cloned. Purified by matrixing (silica gel, DCM containing 0-30% MeOH), (5- Bromo-1-ethyl-1H-pyrazole-4-yl)(5-iodo-1H-imidazole) -4-yl)methanol was obtained as a white solid (3.5 g, yield: 35%). LC / MS (ESI) m / z: 397 [M+H] + .

[0424] (5-bromo-1-ethyl-1H-pyrazole-4-yl)(5-iodo-1H-imi) Dazole-4-yl)methanol (3.50 g, 8.82 mmol) at -10°C DMF Cesium carbonate (4.31 g, 13.2 mmol) was added to the (60 mL) solution. The mixture was stirred at -10°C for 15 minutes. Then, iodomethane (0.60) was added to the suspension. Add mL (9.7 mmol) dropwise and stir the resulting mixture at -10°C for 1.5 hours. Next, the reaction mixture is filtered, the filtrate is diluted with water (50 mL), and extracted with ethyl acetate. (3 x 50 mL). The combined organic layer was concentrated and saturated with NH4Cl aqueous solution (3 x 30 mL). The solution was then washed with brine (30 mL), dried over anhydrous sodium 2 SO4, filtered, and concentrated. Flash chromatography of the residue (silica gel, DCM containing 0-10% MeOH) Purified by (5-bromo-1-ethyl-1H-pyrazole-4-yl)(5-iodine). (9)(1-1-methyl-1H-imidazole-4-yl)methanol was obtained as a white solid. 03 mg, yield 25%). LC / MS (ESI) m / z: 411 [M+H] + .

[0425] (5-bromo-1-ethyl-1H-pyrazole-4-yl)(4-iodo-1-methyl) Synthesis of -1H-imidazole-5-yl)methanol [ka] 4,5-Diiodo-1-methyl-1H-imidazole (2.00g, 5.99 mmol) ) in a -70°C DCM (100 mL) solution, ethylmagnesium bromide (1 M, 6.5g) (mL, 6.59 mmol) was added dropwise under an N2 atmosphere. The mixture was incubated at -70°C for 30 minutes. The mixture was stirred. Next, 5-bromo-1-ethyl-1H-pyrazole-4-cal was added to the mixture. Add a solution of valdehyde (1.34 g, 6.59 mmol) in DCM (10 mL), -7 The reaction mixture was stirred at 0°C for 2 hours. The reaction mixture was then quenched with saturated NH4Cl aqueous solution (50 mL). Then, extract with DCM (3 x 50 mL), wash with brine, and dry with anhydrous Na2SO4. The residue was filtered and concentrated. The residue was subjected to silica gel column chromatography (30% EtOA). Purified by (PE containing c), (5-bromo-1-ethyl-1H-pyrazole-4-yl (4-iodo-1-methyl-1H-imidazole-5-yl)methanol is used as a yellow oil. (1.80g, yield: 73%). LC / MS (ESI) m / z: 411 [ M+H] + .

[0426] (4-bromo-1-methyl-1H-pyrazole-3-yl)(1-(cyclopropylmethyl Synthesis of tyl-1H-pyrazole-4-yl)methanol [ka] 1-(cyclopropylmethyl)-4-iodo-1H-pyrazole (415 mg, 1.6 Add i-PrMgCl·LiCl(1.3mL) to a 7 mmol (5 mL) stirred THF solution. A 1.3 M THF solution (1.7 mmol) was added dropwise under N2 at 0°C. The mixture was stirred at 0°C for 1 hour. After mixing, 4-bromo-1-methyl-1H-pyrazole-3-carbaldehyde (316m A 1 mL solution of THF (g, 1.67 mmol) was added at 0°C. The reaction mixture was then prepared at room temperature. Stir for 2 hours, quench with saturated NH4Cl (10 mL), and extract with toluene (10 mL). The residue was extracted, dried with Na2SO4, and concentrated to dryness. The residue was then subjected to silica gel column chromatography. Purified by Raffy (PE:SiO=1:1), (4-bromo-1-methyl-1H -Pyrazole-3-yl)(1-(cyclopropylmethyl)-1H-pyrazole-4-yl) Methanol (258 mg, 50% yield) was obtained as yellow oil. LC / MS (ESI ) (m / z): 311 [M+H] + .

[0427] The following intermediates were synthesized using a similar experimental protocol: [Table 38]

[0428] tert-butyl(E)-2-((5-bromo-1-ethyl-1H-pyrazole-4- Synthesis of yl(methylene)hydrazine-1-carboxylate [ka] 5-Bromo-1-ethyl-1H-pyrazole-4-carbaldehyde (3g, 14.8mg) (mol) and (tert-butoxycarbonyl)hydrazine (1.9g, 14.8mO The MeOH (30 mL) solution was stirred at 25°C for 12 hours. The mixture was concentrated under reduced pressure. Shrinkage to crude tert-butyl(E)-2-((5-bromo-1-ethyl-1H-pyrazole (4-yl)methylene)hydrazine-1-carboxylate (4.71g, yield 10 0% was obtained as a yellow solid, which was used in the next step without further purification. C / MS (ESI): m / z = 317 [M+H] + .

[0429] The following intermediates were synthesized using a similar experimental protocol: [Table 39]

[0430] (5-ethyl-1,2-oxazol-3-yl)(5-iodo-2-methyl-2H- Synthesis of 1,2,3-triazole-4-yl)methanol [ka] 4-(5-ethyl-1,2-oxazol-3-carbonyl)-5-iodo-2-meth Lu-2H-1,2,3-triazole (310 mg, 0.93 mmol) MeOH (2 Add NaBH4 (35 mg, 0.93 mmol) to the mixture and stir at room temperature for 1 hour. The mixture was then quenched with saturated NH4Cl aqueous solution (10 mL) at 0°C and extracted with EA. Dispense (20 mL x 3). Separate the organic layer, dry it with anhydrous Na2SO4, filter it, and concentrate it. Shrink to obtain the residue, which is then subjected to silica gel column chromatography (PE:EA=1:1, Purified by V / V, (5-ethyl-1,2-oxazol-3-yl)(5-iodine -2-methyl-2H-1,2,3-triazol-4-yl)methanol (150mg, 48.1% was obtained as a pale yellow oil. LC / MS ESI (m / z): 335 [M +H] + .

[0431] The following intermediates were synthesized using a similar experimental protocol: [Table 40] TIFF2026082971000227.tif244165TIFF2026082971000228.tif151165

[0432] 2-Ethyl-4-[(1-ethyl-1H-pyrazole-4-yl)methyl]-5-io Synthesis of do-2H-1,2,3-triazole [ka] (1-ethyl-1H-pyrazole-4-yl)(2-ethyl-5-iodo-2H-1, D Add Et3SiH (191 mg, 1.64 mmol) and TFA (2 mL) to CM (1 mL) solution. Add 50 mg (2.19 mmol) at 0°C, then stir the mixture at 25°C for 2 hours. The mixture was concentrated and basicized to pH 7 with saturated NaHCO3 aqueous solution, and then D Extraction was performed using CM (15 mL x 3). The combined organic layers were washed with brine (15 mL) and N The residue was dried with a2SO4 and then concentrated. Flash chromatography was performed on the residue (silicone). Purified by Kagel (PE containing 10-50% ethyl), 2-ethyl-4-[(1- Ethyl-1H-pyrazole-4-yl)methyl]-5-iodo-2H-1,2,3-tri Azole (184 mg, yield: 98%) was obtained as a pale yellow oil. LC / MS (ESI) m / z: 332.0 [M+H] + .

[0433] The following intermediates were synthesized using a similar experimental protocol: [Table 41]

[0434] (3-Cyclobutylisoxazol-5-yl)(5-iodo-2-methyl-2H- Synthesis of 1,2,3-triazole-4-yl)methanol [ka] 4,5-Diiodo-2-methyl-2H-1,2,3-triazole (1.1g, 3.1 Add isopropylmagnesium bromide (3.2 mL) to a 20 mL solution of 8 mmol THF. ) was added at -15°C. After stirring the mixture for 1 hour, 3-cyclobutyl-1,2- Oxazole-5-carbaldehyde (400 mg, 2.65 mmol) THF (10 m Solution L was added. The resulting mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with water. Enchyma was used, and the mixture was extracted with ethyl acetate (100 mL). The combined ethyl acetate layer was purified with brine. The mixture was prepared, dried over Na2SO4, and concentrated under reduced pressure. The residue was then flash-colored with silica gel. By microchromatography, the solution is eluted with DCM containing MeOH (0-5%) and purified. 3-Cyclobutylisoxazol-5-yl)(5-iodo-2-methyl-2H-1, 2,3-Triazole-4-yl)methanol (420 mg, 44%) is obtained as a pale yellow oil. Ta. LC / MS (ESI): m / z = 361 [M+H] + .

[0435] The following intermediates were synthesized using a similar experimental protocol: [Table 42] TIFF2026082971000233.tif53165

[0436] 5-Bromo-1-ethyl-4-((4-iodo-1-methyl-1H-pyrazole-3- Synthesis of yl(methyl)-1H-pyrazole [ka] (5-bromo-1-ethyl-1H-pyrazole-4-yl)(4-iodo-1-methyl) DCM of -1H-pyrazole-3-yl)methanol (800 mg, 1.90 mmol) (5 mL) solution contains triethylsilane (1.80 g, 15.6 mmol) and TFA (1 0.45 mL (19.5 mmol) was added at 0°C. After stirring at 0°C for 2 hours, the mixture was mixed. The substance was neutralized with saturated NaHCO3 to pH 8. The resulting mixture was diluted with alkyl hydroxide and broccoli. The residue was washed in the line, dried with anhydrous Na2SO4, filtered, and concentrated. The residue was then silica gel. Purified by column chromatography (0-60% EA-containing PE), 5-bromo- 1-Ethyl-4-((4-iodo-1-methyl-1H-pyrazole-3-yl)methyl) -1H-pyrazole was obtained as a yellow oil (700 mg, yield: 91%). LC / MS E SI (m / z): 395 [M+H] + .

[0437] 4-[(5-bromo-1-ethyl-1H-pyrazole-4-yl)methyl]-5-io Synthesis of do-2-methyl-2H-1,2,3-triazole [ka] (5-bromo-1-ethyl-1H-pyrazole-4-yl)(5-iodo-2-methyl) -2H-1,2,3-triazol-4-yl)methanol (800mg, 1.94mm 30 The mixture was stirred at °C for 0.5 hours. The pH of the mixture was adjusted to 8 with NaHCO3 at 0°C, and then Extracted with EA (50 mL x 2). The combined organic phase was dried with anhydrous Na2SO4 and filtered. , concentrated. The residue was then subjected to flash chromatography of silica gel (30% Purified by PE containing 4-[(5-bromo-1-ethyl-1H-pyrazole-4- [Iylmethyl]-5-iodo-2-methyl-2H-1,2,3-triazole (750ml) g, yield: 97%) was obtained as a pale yellow solid. LC / MS ESI (m / z): 39 6 [M+H] + .

[0438] The following intermediates were synthesized using a similar experimental protocol: [Table 43]

[0439] 5-Bromo-1-(cyclopropylmethyl)-4-((5-iodo-1H-pyrazole Synthesis of -1-yl)methyl)-3-methyl-1H-pyrazole [ka] 5-Bromo-1-(cyclopropylmethyl)-3-methyl-1H-pyrazole-4-ca DIBA is added to a THF (20 mL) solution of rubaldehyde (1.00 g, 4.11 mmol). LH (5.50 mL, 8.23 ​​mmol) was added dropwise under N2 at -78°C. This reaction mixture The mixture was stirred under N2 at -78°C for 2 hours. The reaction mixture was then heated to room temperature. A saturated potassium sodium tartrate tetrahydrate solution was added to the mixture and stirred at room temperature for 2 hours. The mixture was extracted twice with thio, and the combined organic layer was washed with brine and anhydrous sodium 2 The residue was dried with SO4 and concentrated in vacuum. The residue was then subjected to flash column chromatography. (5-bromo-1-(cyclopropylmethyl)-3-methyl-1H-pyrazole Lu-4-yl)methanol (800 mg, 79%) was obtained as a white solid. LC / MS (ESI) m / z: 245 [M+H] + .

[0440] (5-bromo-1-(cyclopropylmethyl)-3-methyl-1H-pyrazole-4- In a 20 mL solution of methanol (1.50 g, 6.12 mmol), add SO2. Cl2 (1.4 mL, 18 mmol) was added. The mixture was stirred at room temperature for 2 hours. The reaction mixture is concentrated to obtain the crude 5-bromo-4-(chloromethyl)-1-(cyclopropyl (Methyl)-3-methyl-1H-pyrazole (1.6g, 99%) was obtained as a colorless oil.

[0441] 5-iodo-1H-pyrazole (662 mg, 3.42 mmol) and K2CO3 (1 In DMF (30 mL) containing a mixture of 0.41 g and 10.2 mmol, 5-bromo-4- (chloromethyl)-1-(cyclopropylmethyl)-3-methyl-1H-pyrazole(9 A 00 mg (3.45 mmol) DMF (1 mL) solution was added dropwise at 0°C. The mixture was then prepared. The mixture was stirred at 80°C for 8 hours under N2. The mixture was cooled to room temperature and diluted with phenylalanine. The mixture was washed with brine, dried over anhydrous Na2SO4, and concentrated. The residue was then f Purified by Rush column chromatography, and further purified by SFC, 5-B Romo-1-(cyclopropylmethyl)-4-((5-iodo-1H-pyrazole-1-I (L)methyl-3-methyl-1H-pyrazole (170 mg, 12%) is obtained as a colorless oil. Ta. LC / MS (ESI) m / z: 421 [M+H] + .

[0442] tert-butyl2-((5-bromo-1-ethyl-1H-pyrazole-4-yl)methyl Synthesis of (Chill)hydrazine-1-carboxylate [ka] tert-butyl(E)-2-((5-bromo-1-ethyl-1H-pyrazole-4- Il(methylene)hydrazine-1-carboxylate (4.71g, 14.8mmol) Add NaBH3CN (1.20g) to the AcOH (15mL) and MeOH (10mL) solution. (18.9 mmol) was added at room temperature. The resulting mixture was stirred at 25°C for 12 hours. After concentration under reduced pressure, the residue is dissolved in RINKAN and then treated with an aqueous solution of Na2CO3 and brine. The residue was washed, dried with anhydrous Na2SO4, and concentrated under reduced pressure. The residue was then flushed with silica gel. Purified by chromatography (0 → 30% ethyl acetate-containing PE), then tert-butyl 2-((5-bromo-1-ethyl-1H-pyrazole-4-yl)methyl)hydrazine- 1-carboxylate (3.5 g, yield 69%) was obtained as a white solid. LC / MS ( ESI): m / z = 319 [M+H] + .

[0443] The following intermediates were synthesized using a similar experimental protocol: [Table 44]

[0444] Synthesis of (R)-1-(5-fluoro-2-iodophenyl)ethylbenzoate [ka] (1S)-1-(5-fluoro-2-iodophenyl)ethane-1-ol (1.00 (g, 3.76 mmol), benzoic acid (0.550 g, 4.51 mmol) and triphenic acid In THF (30 mL) containing a mixture of ruphosphine (1.18 g, 4.51 mmol), DIAD (0.89 mL, 4.5 mmol) was added dropwise under N2 at 0°C. The resulting mixture was obtained. The mixture was stirred overnight at room temperature, poured into water, and then extracted with ELISA (50 mL x 2). The organic layer was washed with brine, dried over anhydrous sodium 2SO4, and concentrated. The residue was then collected in a column. Purified by chromatography (silica gel, 1 → 5% ethyl acetate petroleum ether) (1R)-1-(5-fluoro-2-iodophenyl)ethylbenzoate (1.2g 86% was obtained as a yellow solid. LC / MS (ESI): m / z = 371 [ M+H] + .

[0445] The following intermediates were synthesized using a similar experimental protocol: [Table 45]

[0446] 1-[(5-bromo-1-ethyl-1H-pyrazole-4-yl)methyl]-5-io Synthesis of do-4-(trimethylsilyl)-1H-1,2,3-triazole [ka] 4-(azidomethyl)-5-bromo-1-ethyl-1H-pyrazole (1.20g, 5 In a 15 mL solution of 0.21 mmol MeCN, add CuI (1.12 g, 5.89 mmol) l), DIPEA (760mg, 5.89mmol), NBS (1.05g, 5.89m (mol) and ethinyltrimethylsilane (0.83 mL, 5.9 mmol) were added. Next, this mixture was degassed three times with N2 and stirred at 25°C for 16 hours. The reaction mixture was concentrated. The mixture was shrunk, and the residue was treated with ice water and ¼. The organic layer was separated and washed with brine. The residue was then dried with anhydrous Na2SO4, filtered, and concentrated to dryness. The residue was then flash-chromatographed. Purified by Graph (silica gel, DCM containing 0-20% MeOH), 1-[(5 -bromo-1-ethyl-1H-pyrazole-4-yl)methyl]-5-iodo-4-( (320 mg, yield: 14%) methylsilyl-1H-1,2,3-triazole (yeast) Obtained as a colored oil. LC / MS (ESI) m / z: 454[M+H] + .

[0447] The following intermediates were synthesized using a similar experimental protocol: [Table 46]

[0448] 3-(((tert-butyldimethylsilyl)oxy)methyl)-5-fluorobenzo [c][1,2] Synthesis of oxabolol-1(3H)-ol [ka] (5-Fluoro-2-iodophenyl)methanol (10.0g, 39.7mmol) Add manganese dioxide (3.4g, 39.7 mmol) to a CHCl3 (150mL) solution. It was added. The resulting mixture was stirred overnight at 66°C. After cooling to room temperature, the reaction mixture was mixed. The substance was filtered, and the filtrate was concentrated. The residue was subjected to silica gel column chromatography. Purified by 0-30% EA (PE), 5-fluoro-2-iodobenzaldehyde (9.1g, yield: 92%) was obtained as a pale yellow solid. LC-MS ESI (m / z) : 251 [M+H] +

[0449] Under an N2 atmosphere, methyltriphenylphosphonium bromide (14.7 g, 41.1 mmol) A 100 mL solution of dried THF () is cooled to -10°C, and potassium tert-butoxy is added. Sid (4.60 g, 41.1 mmol) was added. After 15 minutes, 5-fluoro-2-iodine was added. Dobenzaldehyde (8.60 g, 34.2 mmol) was added, and the reaction mixture was placed around the surrounding area. The mixture was stirred at room temperature for 2 hours. Ice water (150 mL) was added, and the mixture was extracted with EA (3 ×50mL). The combined organic layers were dried with Na2SO4, filtered, and steamed in a vacuum at 25°C. The residue was subjected to flash chromatography (0 → 20% EA-containing PE). Further purification yields 2-ethenyl-4-fluoro-1-iodobenzene (10g, yield: 118%). %) was obtained as a colorless oil containing a solvent. LC / MS (ESI) m / z: 249 [M +H] + . 2-Ethenyl-4-fluoro-1-iodobenzene (8.50 g, 34.3 mmol) In a solution of t-BuOH (75 mL) and H2O (25 mL), N-methylmorpholine N- Oxide (12.0g, 51.4 mmol, 50% aqueous solution) and K2OsO4·2H2O (0.10g, cat.) was added. This reaction mixture was stirred at room temperature for 48 hours. The substance was quenched by adding a saturated Na2S2O3 aqueous solution. The mixture was then left at room temperature. The mixture was stirred for another 4 hours. This mixture was extracted with EA (50 mL x 3) and anhydrous Na2SO4. The residue was dried, filtered, and concentrated. The residue was then subjected to flash chromatography (0→100%). Purified by PE containing EA, 1-(5-fluoro-2-iodophenyl)ethane-1 ,2-diol (6.1 g, yield: 63%) was obtained as a white solid. LC-MS ESI (m / z): 283 [M+H] +

[0450] 1-(5-fluoro-2-iodophenyl)ethane-1,2-diol (5.30g, In a 50 mL solution of 18.8 mmol DMF, add imidazole (2.60 g, 37.6 mmol) and tert-butyldimethylsilyl chloride (3.00 g, 19.7 mmol) l) was added. The mixture was stirred overnight at room temperature, diluted with water, and then extracted with EA. (30 mL x 3). Wash the combined organic layer with brine (50 mL) and then with anhydrous Na2SO4. The residue was dried, filtered, and concentrated. Flash chromatography was performed on the residue (0-50% EA). Purified by PE containing 2-[(tert-butyldimethylsilyl)oxy]-1- (5-fluoro-2-iodophenyl)ethane-1-ol was obtained (6.4g, yield: 8 6%). LC-MS ESI (m / z): 397 [M+H] +

[0451] 2-[(tert-butyldimethylsilyl)oxy]-1-(5-fluoro-2-iodine) Dophenylethane-1-ol (3.0g, 7.6mmol) in THF (40.0mL) Add i-PrMgCl (14.6 mL, 18.9 mmol, 1.3 M) dropwise to the solution at 0°C. It was dissolved. The mixture was stirred at room temperature for 1 hour. Trimethyl borate (2.00 g, 18.9 mmol) was added dropwise to this mixture at 0°C, and stirring was continued at room temperature for 2 hours. The reaction mixture was then saturated. Quenched with NH4Cl aqueous solution and extracted with EA (3 × 30 mL). The combined organic layer was then bled. The residue was washed in the line, dried with anhydrous Na2SO4, filtered, and concentrated. The residue was then silica gel. Purified by column chromatography (PE containing 0 to 100% EA), 3-{[( tert-butyldimethylsilyl)oxy]methyl}-5-fluoro-1,3-dihydro -2,1-benzoxabolol-1-ol (1.3g, yield: 58%) is used as a colorless oil. The result obtained was: LC-MS ESI (m / z): 297 [M+H] + .

[0452] 5-bromo-1-ethyl-4-(hydrazinylmethyl)-1H-pyrazole hydrochloride Growth [ka] tert-butyl2-((5-bromo-1-ethyl-1H-pyrazole-4-yl)methyl (Chill) Hydrazine-1-carboxylate (3.5g, 11 mmol) MeOH (15 A 10 mL, 4N HCl solution of dioxane was added to the (mL) solution. The reaction mixture The mixture was stirred at 25°C for 12 hours. The mixture was concentrated under reduced pressure, and the residue was ground with PE. The obtained solid is recovered by filtration, washed with PE, and dried in a vacuum to obtain 5-bromo-1- Ethyl-4-(hydrazinylmethyl)-1H-pyrazole hydrochloride (2.5g, yield 89%) The substance was obtained as a white solid. LC / MS (ESI): m / z = 219 [M+H] + .

[0453] The following intermediates were synthesized using a similar experimental protocol: [Table 47]

[0454] 1-(2-bromo-4-fluorophenyl)-3-(3-chloro-1-ethyl-1H- Synthesis of pyrazole-4-yl)propa-2-in-1-ol [ka] 1-(2-bromo-4-fluorophenyl)propa-2-in-1-ol (4.00 g, 17.5 mmol) and 3-chloro-1-ethyl-4-iodo-1H-pyrazole ( Triethylamine (40 mL) containing a mixture of 4.90 g and 19.2 mmol) is mixed with Pd (PPh3)2Cl2 (1.2g, 1.7mmol) and CuI (0.67g, 3.5m) (mol) was added. The reaction solution was stirred under N2 at room temperature for 18 hours. The reaction product was then mixed with The residue is concentrated in air and flash-chromatographed (0-50% Â). Purified by PE, 1-(2-bromo-4-fluorophenyl)-3-(3-chloro- 1-Ethyl-1H-pyrazole-4-yl)propa-2-in-1-ol (3.3g, A yield of 53% was obtained as yellow oil. LC / MS ESI (m / z): 357 [M+ H] + .

[0455] The following intermediates were synthesized using a similar experimental protocol: [Table 48]

[0456] (R)-5-fluoro-3-methylbenzo[c][1,2]oxabolol-1(3H )-Synthesis of ol [ka] (1R)-1-(5-fluoro-2-iodophenyl)ethylbenzoate (300ml) In a methanol (8 mL) solution of (g, 0.81 mmol) NaOH (32 mg, 0.81 mmol) A solution of mmol) in water (8 mL) was added. The mixture was stirred overnight at room temperature. The mixture was poured into water and then extracted with ethyl acetate (50 mL x 2). The combined organic layer was then brewed. The residue was washed in the line, dried over anhydrous sodium 2SO4, and concentrated. The residue was then subjected to column chromatography. Purified with FE (silica gel, 1-5% ethyl acetate petroleum ether), (1R)- 1-(5-fluoro-2-iodophenyl)ethane-1-ol (150 mg, 70%) It was obtained as a white solid. LC / MS (ESI): m / z = 267 [M+H] + .

[0457] A 1.3M THF solution of isopropylmagnesium chloride-lithium chloride complex (72.3 (1R)-1-(5-fluoro-2-iodophenyl) ester (94.0 mmol) Tan-1-ol (10.00 g, 37.59 mmol) mixture with THF (120 mL) It was added dropwise under N2 at -40°C. The mixture was stirred under N2 at -40°C for 1 hour, and then After further heating to -10℃ for 0.5 hours, add trimethyl borate (10.67 mL, 93. 97 mmol) was added dropwise over 10 minutes at -10°C. After stirring overnight at room temperature under N2, The reaction mixture was poured into a saturated NH4Cl solution (100 mL) and then extracted with ethyl acetate. (50 mL x 2). Wash the combined organic layer with brine, dry with anhydrous sodium 2SO4, and concentrate. It shrunk. The residue was subjected to column chromatography (silica gel, 1 → 10% ELISA). Purified by (PE), (R)-5-fluoro-3-methylbenzo[c][1,2]o Xabolol-1(3H)-ol (4.0g, 64%) was obtained as a colorless oil. LC / M S (ESI): m / z = 167 [M+H] + .

[0458] 3-(1-(5-fluoro-2-iodophenyl)ethoxy)-2-nitropyridine synthesis [ka] 1-(5-fluoro-2-iodophenyl)ethane-1-ol (9.20g, 34. In a 180 mL THF (6 mmol) solution at 0°C, add NaH (1.38 g, 34.6 mm) A 60% mineral oil solution (ol) was added gradually over 10 minutes. After the addition, the mixture was heated to 0°C. Stir for 15 minutes, then add 3-fluoro-2-nitropyridine (4.91g, 34.6mm A 20 mL solution of ol) THF was added dropwise. The ice bath was removed, and the mixture was left at room temperature for 3 hours. The mixture was stirred. The reaction mixture was then partitioned between DCM (200 mL) and water (200 mL). The organic layer was separated, washed with brine, and concentrated under vacuum. The residue was flushed. Purified by chromatography (PE containing 0-30% siRNA), 3-(1-(5 -Fluoro-2-iodophenyl)ethoxy)-2-nitropyridine (5.3g, yield: 39% was obtained as a white solid. LC / MS ESI (m / z): 389 [M+H ] +

[0459] The following intermediates were synthesized using a similar experimental protocol: [Table 49] TIFF2026082971000252.tif239165TIFF2026082971000253.tif239165TIFF2026082971000254.t if239165TIFF2026082971000255.tif218165TIFF2026082971000256.tif239165TIFF2026082971 000257.tif239165TIFF2026082971000258.tif239165TIFF2026082971000259.tif228165TIFF20 26082971000260.tif239165TIFF2026082971000261.tif229165TIFF2026082971000262.tif69165

[0460] 1-[(5-bromo-1-ethyl-1H-pyrazole-4-yl)methyl]-5-io Synthesis of D-1H-1,2,3-triazole [ka] 1-[(5-bromo-1-ethyl-1H-pyrazole-4-yl)methyl]-5-io D-4-(trimethylsilyl)-1H-1,2,3-triazole (400mg, 0.8 In a 10 mL solution of 8 mmol MeOH, add K2CO3 (365 mg, 2.64 mmol) l) was added. The mixture was stirred at 25°C for 16 hours, and then concentrated to dryness. The residue This was obtained by flash chromatography (silica gel, DCM containing 0-10% MeOH) The product is purified and obtained as 1-[(5-bromo-1-ethyl-1H-pyrazole-4-yl )Methyl]-5-iodo-1H-1,2,3-triazole (280 mg, yield: 83%) The result was obtained as a yellow solid. LC / MS (ESI) m / z: 382 [M+H] + .

[0461] The following intermediates were synthesized using a similar experimental protocol: [Table 50]

[0462] Ethyl 3-ethyl-1-(4-methoxybenzyl)-1H-pyrazole-5-carboc Silate synthesis [ka] Stirring of ethyl 2,4-dioxohexanoate (4.10 g, 23.8 mmol) In OH (33 mL) solution, add KOAc (5.83 g, 59.5 mmol) and [(4-meth Add 1 / 2 xyphenyl methyl hydrazine hydrochloride (4.49 g, 23.8 mmol) at 0°C. The reaction mixture was stirred at 0°C for 1 hour, and then stirred at room temperature for 12 hours. This reaction mixture is concentrated under reduced pressure and diluted with the residue .'' (50 mL) and saturated with N Washed with aHCO3 (50 mL), dried with anhydrous Na2SO4, and evaporated to dryness. The residue... By silica gel column chromatography (PE containing 10-25% HCl) Purified, ethyl 3-ethyl-1-[(4-methoxyphenyl)methyl]-1H-pyrazole 5-carboxylate (3.8g, 55%) was obtained as a yellow oil. LC / MS (E SI) (m / z): 289 [M+H] + .

[0463] tert-butyl2-((5-bromo-1-cyclobutyl-1H-pyrazole-4-I Synthesis of methylhydrazine carboxylate [ka] (E)-tert-butyl2-((5-bromo-1-cyclobutyl-1H-pyrazole -4-yl)methylene)hydrazine carboxylate (3.14g, 9.15mmol) To the MeOH (20 mL) solution, add acetic acid (20.0 mL, 349 mmol), and then... Then NaBH3CN (1.15 g, 18.3 mmol) was added at room temperature. The mixture was then heated at room temperature. The mixture was stirred overnight at warm temperature. After concentration, the residue was diluted with DCM and saturated NaHCO3 and brine. The residue was washed, dried over anhydrous Na2SO4, filtered, and concentrated. The residue was then flash-chromized. Purified by tography (silica gel, PE containing 0-100% EA), tert-br Tyl 2-((5-bromo-1-cyclobutyl-1H-pyrazole-4-yl)methyl) Drazine carboxylate (2.65 g, 84%) was obtained as a colorless oil. LC / MS E SI (m / z): 345 [M+H] + .

[0464] 1-(2-bromo-4-fluorophenyl)-3-(3-chloro-1-ethyl-1H- Synthesis of pyrazole-4-yl)propan-1-ol [ka] 1-(2-bromo-4-fluorophenyl)-3-(3-chloro-1-ethyl-1H- Pyrazole-4-yl)propa-2-in-1-ol (3.3g, 9.2 mmol) PtO2 (0.6 g, 0.4 mmol) was added to a stirred siRNA (30 mL) solution. The reaction solution was stirred under H2 at room temperature for 48 hours. The reaction product was filtered and concentrated. 1-(2-bromo-4-fluorophenyl)-3-(3-chloro-1-ethyl-1H-p Razole-4-yl)propan-1-ol (3.2g, yield 97%) was obtained as yellow oil. Ta. LC / MS ESI (m / z): 361 [M+H] + .

[0465] The following intermediates were synthesized using a similar experimental protocol: [Table 51]

[0466] 5-((5-iodo-2-methyl-2H-1,2,3-triazol-4-yl)methyl Synthesis of isoxazole-3-carboxamide [ka] Ethyl 5-[(5-iodo-2-methyl-2H-1,2,3-triazol-4-yl )Methyl]-1,2-oxazole-3-carboxylate (380 mg, 1.05 mm In a 0.5 mL solution of MeOH (0.5 mL), add NH3 (5 mL, 25 mmol, 5 N methanol). The solution was added at 25°C. The resulting mixture was stirred at 60°C for 3 hours. The mixture was quenched with ice water and then diluted with HCl. The organic layer was separated and sa...

Claims

1. Compound of formula (I) 【Chemistry 1】 (In the formula, Q is either CH or N, Z is CR ５ or N, X is pyrazolylene, isoxazolylene, imidazoylene, isothiazolylene, tria A five-membered heteroarylene selected from the group consisting of zolylene and pyrrolylene, A five-membered heteroarylene has 0, 1, or 2 R ２ Replaced by, Y is a 5-component compound containing 1 to 3 heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. is a 6-membered heteroarylene, and the 5 or 6-membered heteroarylene is 0, 1, and is two R ３ Replaced by, In Y, the bonding sites to the methylene groups bonded to X and Y, and the bonding to the aromatic ring containing Z. The dot is located on an adjacent atom, is alpha relative to the bond site to the methylene group, and The ring atoms of the 5-6 member heteroarylene that are beta relative to the bonding site to the aromatic ring containing Z It is nitrogen, R １ It is selected from the group consisting of H, methyl, and hydroxymethyl, R ２ Each example is independently H, Halo, CN, C １－４ Alkoxy, C １－４ Alkyl, Ha Ro-C １－４ Alkyl, C ３－４ Cycloalkylmethyl, C ３－６ Cycloalkyl, and Selected from the group consisting of 3- to 6-membered heterocycloalkyl groups, R ３ Each example is independently H, Halo, CN, C １－４ Alkoxy, Halo-C １－４ Alki Lu and C １－４ Selected from the group consisting of alkyl groups, R ４ and R ５ Each of them is independently either H or F), X is, 【Chemistry 2】 (In the formula, R ２ (is not H) ＊ This is the process of the methylene group bonded to X and Y. It shows the connection point, and The compound is 【Transformation 3】 Or the compound, or its enantiomer, that is not a pharmaceutically acceptable salt thereof. Enantiomers, tautomers, or pharmaceutically acceptable salts thereof.

2. Compound of formula (I) 【Chemistry 4】 (In the formula, Q is either CH or N, Z is CR ５ or N, X is pyrazolylene, isoxazolylene, imidazoylene, isothiazolylene, tria A five-membered heteroarylene selected from the group consisting of zolylene and pyrrolylene, A five-membered heteroarylene has 0, 1, or 2 R ２ Replaced by, Y is 1, 2 ＊ - Substituting imidazoline, 4 ＊ ,5-substituted imidazoylene, 4,5 ＊ -Replacement Imidazolilen, 4 ＊ ,5-substituted 1,2,3-oxadiazoylene,3 ＊ ,4-substitution 1, 2,5-Oxadiazoylene, 3 ＊ ,4-substituted 1,2-oxazolylene,4 ＊ ,5-substitution 1,3-Oxazolylene, 2 ＊ ,3-substituted pyrazinylene, 1 ＊ , 5-substituted pyrazolylene, 3 ＊ ,4-substituted pyrazolylene, 3 ＊ , 4-substituted pyridadinylene, 2 ＊ , 3-substituted pyridini Ren, 4 ＊ , 5-substituted pyrimidinylene, 2 ＊ ,3-substituted pyrrolylene, 5 ＊ ,6-substitution 1, 2,3,4-tetrazinylene, 1 ＊ ,5-substituted 1,2,3,4-tetrazoylene, 1,5 ＊ - Substitution 1,2,3,4-tetrazoylene, 4 ＊ ,5-Substitution 1,2,3-Chiasiazolire Hmm, 3 ＊ ,4-substituted 1,2,5-thiadiazoylene,3 ＊ ,4-substitution 1,2-thiazolyle Hmm, 4 ＊ ,5-substituted 1,3-thiazoylene, 4 ＊ ,5-substituted 1,2,3-triazinylene 5 ＊ ,6-substituted 1,2,4-triazinylene, 5,6 ＊ - Substitution 1,2,4-triazine Ren, 1 ＊ ,5-substituted 1,2,3-triazolylene,4 ＊ , 5-substitution 1, 2, 3-tria Zoliene, 1 ＊ ,5-substituted 1,2,4-triazolylene, 1,5 ＊ -Substitution 1, 2, 4- Riazoliene, and 3 ＊ Selected from the group consisting of 4-substituted 1,2,4-triazolylenes This is a heteroarylene, and the heteroarylene has 0, 1, or 2 R ３ Replaced by Re, ＊ This indicates the bonding point of Y to the methylene group bonded to X and Y. In Y, the bond site to the methylene group is alpha, and the aromatic ring containing Z is The ring atom of the heteroarylene that is beta relative to the bond point is nitrogen. R １ It is selected from the group consisting of H, methyl, and hydroxymethyl, R ２ Each example is independently H, Halo, CN, C １－４ Alkoxy, C １－４ Alkyl, Ha Low C １－４ Alkyl, C ３－４ Cycloalkylmethyl, C ３－６ Cycloalkyl, and Selected from the group consisting of 3- to 6-membered heterocycloalkyl groups, R ３ Each example is independently H, Halo, CN, C １－４ Alkoxy, Halo-C １－４ Alki Lu and C １－４ Selected from the group consisting of alkyl groups, R ４ and R ５ Each of them is independently either H or F), X is, 【Transformation 5】 (In the formula, R ２ (is not H) ＊ This is the process of the methylene group bonded to X and Y. It shows the connection point, and The compound is 【Transformation 6】 Or the compound, or its enantiomer, that is not a pharmaceutically acceptable salt thereof. Enantiomers, tautomers, or pharmaceutically acceptable salts thereof.

3. X is a five-member heteroarylene selected from the following group. 【Transformation 7】 (In the formula, ＊ This indicates the bonding point of X to the methylene group bonded to X and Y, and R ２ Each example is independently H, Halo, CN, C １－４ Alkoxy, C １－４ Alkyl, Ha Low C １－４ Alkyl, C ３－４ Cycloalkylmethyl, C ３－６ Cycloalkyl, and Selected from the group consisting of 3 to 6-membered heterocycloalkyl groups), as described in claim 1 or 2. A compound of [unclear].

4. Y is a heteroarylene selected from the group consisting of the following. 【Transformation 8】 (In the formula, ＊ This indicates the bonding point of Y to the methylene group bonded to X and Y, and R ３ H, Halo, CN, C １－４ Alkoxy, Halo-C １－４ Alkyl and C １－４ A compound according to any one of claims 1 to 3, selected from the group consisting of alkyl groups.

5. Q is CH and Z is CR ５ The compound according to any one of claims 1 to 4. 。

6. R ５ The compound according to any one of claims 1 to 5, wherein is H.

7. R ５ A compound according to any one of claims 1 to 5, wherein F is present.

8. The aforementioned compound is a compound of formula (I-B). 【Chemistry 9】 or a tautomer thereof, or a pharmaceutically acceptable salt thereof, any of claims 1 to 7 Any compound listed in item 1.

9. (i)R ２ Each example independently contains H, chloro, CN, methyl, ethyl, isobutyl, and metho Xy, trifluoromethyl, cyclopropylmethyl, 2-fluoroethyl, difluoromethyl Tyl, 2,2-difluoroethyl, cyclopropyl, cyclobutyl, and oxetanyl Selected from the following groups, and / or (ii) R ３ Each example independently consists of H, fluoro, chloro, CN, methyl, and ethyl Selected from the following group, The compound according to any one of claims 1 to 8.

10. It is a compound that is one of the following formulas. Table 1 The compound according to claim 1 or 2, or its enantiomer, or a mixture of enantiomers. , or tautomers thereof, or pharmaceutically acceptable salts thereof.

11. The following compounds: Table 2 or a pharmaceutically acceptable salt thereof.

12. A compound according to any one of claims 1 to 11, and a pharmaceutically acceptable carrier or excipient. A pharmaceutical composition containing a modifier.

13. The compound according to any one of claims 1 to 11 or 【Chemistry 10】 A pharmaceutical composition for the treatment of cancer comprising a compound or a pharmaceutically acceptable salt thereof.

14. The pharmaceutical composition according to claim 13, wherein the cancer is a solid tumor or a hematological malignancy.

15. The aforementioned solid tumors include lung cancer, glioblastoma, inflammatory myofibroblastic tumor (IMT), and cholangiocarcinoma. (bileg cancer), ovarian cancer, stomach cancer, colorectal cancer, angiosarcoma, melanoma Epithelioid hemangioendothelioma, esophageal cancer, kidney cancer, breast cancer, colon cancer, thyroid cancer, Spitz nevus-like tumor Selected from cholangiocarcinoma and neuroblastoma. or, The aforementioned hematological malignancies include anaplastic large cell lymphoma (ALCL) and diffuse large B cell lymphoma. The medical device according to claim 14, which is lymphoma (DLBCL) or large B-cell lymphoma. A pharmaceutical composition.

16. The pharmaceutical composition according to claim 13, wherein the cancer is lung cancer.

17. The pharmaceutical composition according to claim 13, wherein the cancer is non-small cell lung cancer.

18. The aforementioned cancers include melanoma nevus of Spitz, squamous cell carcinoma of the esophagus, medullary carcinoma, renal cell carcinoma, and papilloma of the thyroid gland. The pharmaceutical composition according to claim 13, wherein the cancer is or serous ovarian cancer.

19. The aforementioned cancer is ROS1 (ROS oncogene 1, receptor tyrosine kinase) positive cancer. A pharmaceutical composition according to any one of claims 13 to 18.

20. The cancer is an ALK (anaplastic lymphoma kinase) positive cancer, according to claims 13 to 18. Any of the pharmaceutical compositions described in item 1.

21. The aforementioned cancer includes the expression of an oncogenic ROS1 gene or an oncogenic ROS1 gene fusion. or the pharmaceutical composition according to any one of claims 13 to 19.

22. The oncogenic ROS1 gene or oncogenic ROS1 gene fusion is a human ROS1 gene The pharmaceutical composition according to claim 21, comprising one or more mutations in the offspring.

23. One or more of the oncogenic ROS1 gene or oncogenic ROS1 gene fusions Due to a mutation, (i)L1951, L1982, S1986, F2004, L2026, G2032, D Mutations in the form of 2033, F2075, or G2101, or combinations thereof The ROS1 protein that it possesses is expressed. (ii) L1951R, L1982F, S1986F, F2004C, F2004V, L2 026M, G2032R, D2033N, F2075V, or G2101A mutations ROS1 proteins expressing either a combination of these, (iii) ROS1 protein with the G2032R mutation is expressed, (iv)(a)CD74-ROS1, EZR-ROS1, SLC34A2-ROS1, GOP ROS1 fusion tannins selected from the group consisting of C-ROS1 and CEP85L-ROS1 Proteins, and / or (b) L1982F, S1986F, F2004C, F2004V, L2026M, G2032R, D2033N, or G2101A mutation, or The pharmaceutical composition according to claim 22, wherein the ROS1 protein having these combinations is expressed. thing.

24. If the aforementioned cancer involves the expression of an oncogenic ALK gene or an oncogenic ALK gene fusion, A pharmaceutical composition according to any one of the requests 13 to 18 and 20.

25. The oncogenic ALK gene or the oncogenic ALK gene fusion is a human ALK gene The pharmaceutical composition according to claim 24, comprising one or more mutations.

26. One or more protrusions in the oncogenic ALK gene or oncogenic ALK gene fusion. Due to natural mutation, (i)(a) ALK fusion type selected from the group consisting of EML4-ALK and NPM1-ALK Proteins and / or (b) G1202R, L1196M, L1198F, G1269A A has the D1203N or I1171N mutation, or a combination thereof. LK protein is expressed, (ii) I1171, L1196, L1198, G1202, D1203, or G12 69. ALK protein having one or more mutations in combination thereof To reveal, or (iii) G1202R, L1196M, L1198F, G1269A, D1203N, and ALK proteins having one or more mutations selected from the group consisting of I1171N The pharmaceutical composition according to claim 25, which exhibits the following characteristics.

27. A pharmaceutical composition for selectively inhibiting ROS1 or ALK rather than TRK, The inhibition is performed on a subject suffering from cancer, and the pharmaceutical composition is as described in claims 1 to 11. A compound described in any one of the items or 【Chemistry 11】 The pharmaceutical composition comprising a compound, or a pharmaceutically acceptable salt thereof.

28. A pharmaceutical composition used in a method to reduce the level of ROS1 or ALK in cells. There exists a compound according to any one of claims 1 to 11 or 【Chemistry 12】 The pharmaceutical composition comprising a compound, or a pharmaceutically acceptable salt thereof.

29. Any one of claims 13 to 28, to be used in combination with one or more further therapeutic agents. The pharmaceutical compositions described in the section.

30. (i) The further therapeutic agent is a TKI, which optionally includes crizotinib, ceritinib B, alectinib, brigatinib, lorlatinib, entrectinib, repotrectinib Cabozantinib, Foretinib, Taretrectinib, Merestinib, Macitinib, if It is ensartinib, or (ii) The further therapeutic agent is a chemotherapeutic agent, an immunotherapy agent for cancer, an SH2 inhibitor, or a MEK inhibitor. Claims that the agent is a MET inhibitor, an SHP2 inhibitor, an anti-PD-1 agent, or a RAS inhibitor. The pharmaceutical composition described in 29.

31. (i) The cancer is metastatic, recurrent, or refractory to prior treatment, and / or teeth (ii) The cancer is metastatic, recurrent, or refractory to prior TKI treatment, and / or (iii) The cancer has brain metastases, A pharmaceutical composition according to any one of claims 13 to 27, 29, and 30.

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